PAR1���$���L�����},�Gene expression varies widely between individuals of a population , and regulatory change can underlie phenotypes of evolu=ary>�biomedical relevance . A key ques-t in the field is how DNA seque2�0ants impact g:�l, with most mechanistic stud�@to date focused o qeffects�R2<ge!r��eIA�,on steady-st��)T0ir respective �)" vali�;Ix=�qTB%:���5�E}�ekB�sey A2�. F��a͍�immune� IRF5i� establish �)#�natural)A�A�m�>�on^y% onA}o antige!UimuM*i�results � score!� import��!qwo��A�t p!��!�ticEB�%��:Pu�>*pr�W.�Aw)Y^�determin2hfA8 �M s suggest)�astrateg�integrat%�bserved��uw��inferr ! ]fqiill�ve��$be a criti�X tool!<�tinued� orts+� rpre�_genome9O . NI ly occurr�-� dif��ci��T�in po4-�lie��!H [1]–[3]�� can %7 as%^ba�for)/of�ory net��(s [4] , [5]"lproblem!)!�"kI�ta� (e molecular.�by��V�g�7rii}�N. Recent�N,has emphasizm�6 �;:N�%� lociI�harbor��acE|QΩ f��re� �a majo��g��A'u��rzmK "v�B,tissue types�)^multiple� UTRA�m�c over half�Rges [14!<Detailed}��"� hav�6lic�.���a� a�*w ���%�both M�K lianiRomplex �(disease [15%�20�G�!ic-es �hin� (t a broader)�a�A�; :�^W)�ri!3 6� �[6e�821 2t a�preval�an�� )th�Ri�s area %tK 8derstood . Prog( !8 diss-�h �%�U��da� been limi!$�� by#da�al"� s.Y�in� �encodedJrAV S* � E'$made clear�K add� �9 nter�g�� exon� AaAH[23!^[2�9^���� � !ext��of���incorpo�� to m�i.U�� at governAjlf-life6 O Z� G liz)#[2M�9]; �fficienc�|>� �h2tself� also!xlc^! � �a��n.� [30e<3e�InE/a ,�eA�,2� !6=�6 Ō�<re �ships��Q 9dA�A�.74a prim�&)Ja���it%2.��]�u of ajti���. Likew� Mse� z�_A�er6 derl�*D !�MY>� at*�)�E�-ome-scal2�ZP�Ap��, [29e 3Ie40]ݡEreaE�[vZ ���\)�sR�rhS � nE� require��x�E�� �E=9��UX)������ga�E data"��evelor$short-readQ{�3methods%�6�� i46]�� enab��! possibilM{quO t�ɑ�-7]�AA.�6s���na���)�N� set ��v�g���A"� n�isI���!��t&�Ea�t� !_n�W!� E�,RNA-seq [42]��maximiz)��c�Iage�preci�!LA�YB&~ I ��eas>2�ԥ>������� vlightA!�v�\=�U�in��E�UTR +Sprincx �-W=pi�*Dm2. To �J\�2' �B-R�, we iso9�2�� li� de�d six k vsA*subjeX each� � �sa� !��2,� 2 s) �] 2�s!�*�� ESw�strong �ig"�M oducq�( FigA, S1 )�b pipe�$ , describ�� MateriKM�<��S�ut lik� po�mis�ȁq%`A-r3Q� [47� �orZ 19��%� E2lwell-defined peaks or disperaxW_ad7th no,!(ul( Table1 W& side�A_a"er!�!Fe� )k�c{b�J�!>`alV�i�f!>�� ��in-depth9�, tak! ��%edTYi!(� %)���p"� nas�A�wasy �%�:* � erf A�]�m . A�sG>�1�to nu� - ��^vj.���consis eJ!g�Z� iouslnoB d.��nsAL!-S2qk2ekWitq40)�paijp"D!( vage�� ,6�A+mv 2+2� �al�] : eincanB @al A ( A/U ) UAAA� or�loskn nq�Itch [48B 50]9S3A�Re7 er assays!g*��46@A�$ ce6��f+�'CPSF1%~WDR18�f�%�ňlac�9.�=;�UXS3C�We.��=ze our� �U 6����an�,� a� 6u� two abund)��guisha��v��% a, .�E���ree pat��dC��1 : class I n�W �a�.D���a��i� auN1�;_`.U�i val��!� he�j= q�Ra� �Win�%Qjc�cQA�ir8  �_����Y;1BQ:�"S a sm^fr� oE.��K��=L �&�in�� S3�� breakd�2A �i��!�es revea n.r�!�a thresholdc��! ∼3��g:�).�\ � #� 5>!�ex�8n\�i:�n��3aJ�� to�ximalZ@!W���, corng�Qhigke&1*� he l� }vIrar  1�!�lower-m�ce� F9��m� to_F�4or no recogniz�Cr-.J�f�yS3!�,�7' credtoDnoe�gTl�� � &� weak�3� 8a�f *� machineryű��sou� ) nessE�G��=� :p��"�  !�=AEo��d � V*��th�JI2o6k.`�.BIV5is purp��e appl>��-�>y]_  pu�micro M)V,aY�4( AREs ) , G/U�5,:A� !�,Pumilio fami�f!�teins Alu �posE�S�źtab� agof�sB�p*�!u�Dmar rv�ofs F�)S�!��� backgroun ves%�UaL�y2& , refl�ng a his!ur"se!��wse5�l��Q��&%|#s [52� �Wn�uk�logic.�� �would�intima� conn Wwm ����a�.�}A��!To�1<�F{ ��tA�n�e �!! �g�P�!�gB�pr��"� a_ 8“shared” am��her�*�Q�3spaF�i&1$�A�͝2�s�*“� tial� �"� 2��eAhyp"�a� iv!often<�o t� x expo|� i2�#@ }�U!�� %IT:�#b� s��u .� �A" To t�t� %��"�� � � �]��p��� ]ely2�a "  II . S"�ce�a�&: � u#6�g eC-� R�f ��A���:GI���g]� A�%z�!3� *of � �s� !�we�Ha!�po*"�i�"-�U�&suB�bD��Tl I%in>�24& �'� Le�� housekeep!(!>� S5L u!�� 8 carr �a�4(I/b��choice"< ���'L� i�e�Xr e�9���.�}��� lighE��6��,-p*Y I��tro�������� !�%iediY.a�i*�Kv�N�e�firstfesN<O# ribuA�!� LUA#�|�ri3ex�&al%lenvironQ al error�o*b6����s�L�C�� ofVa)in�ytudQ'����2� cal�"A�Zherita&��o &( !���! \�ng 1941s60@�;�Iye*� m ly (2�>0 . 6 )1� }O"EbegA^o����&&O$'�� & M�E��@*i�wE�?#h�piN �+!625$��AA�&:�uaNM��ZZ ��a�>N�reaso�� althoughr�Z ��ra(!{)_&� ��x sJ&c� "�.�bd. IA-�.W]-c. CBOis�| �,%�-highlyQ*l25�muL%��U otid!�& +�>J)��T"� m�%�> thanH,!�ave�AX ( 2@VXe5(�i�B�Aj? � a3%:��/; F�)Dr's exact p = + 004;�wi(WeJ� mf B(E1%�inbU� �(U"�#�:2�!��:�]�e�:� C $�%�$r��Q�b�-el�"Q#Z� b�n�%.�.� �* JD (s�� */©�e��0a ndar� 1 %-%��assocF%to %%u�R�s��p"e %�n�� ajorY*o��� !�it �+�.�� .�i k�6 �r�6��*Hm�:��&wh��"� w%k����,�9%1 ���� lel��+� a �r�$�.��(m6�.Az robua,��6����  t< 1�nt^L6J?an x�!e�+aR�^ !�o5 fyjg-Y .dIr�2lE:E�1KVdI.� greeK �9W �) at>` �:�y�A��&q% ���.2wEK�џi5�-6%{Z�1 j�0� Y�B=e6D+r(�E�}Zk)(qyedBrop!}�a�re#)ToB +�BG t#��E�� z�we��5" �"V?an)_U F���onU� ya�~0ه�'Z��we�?�X6r��T!/ yg�6�G� or*�eE�), toggl�.�h�Uqa<#e6�M�� e 6���A�su )�i+U�� � ��%��B Ut4�!�4ed�� tenu�aR]%�_3 �itͪ�. EIF2z�Z? n&�4,enzyme DIP2Ba�s�!A�7��I"�aCc .�->B-2�inflam�+"�w3D-j&%��)�!�� � caus�3nt��� ��& in lucifB!q8� �5p%^�( �9�A–F%�T7��kJ56�!�Z%sU�'M�!�-� NAB1�{�5�A&ed�a minorI-C‰�mod�1�2>4G , H��#U7''at&���e�AF�t �,a�:mZ:m� ��k�b �� �� A�� f0� "�*tr%&r6l2fR� next*�d�.Ef�s&�(2l�.� IC���6�u��Auc�#^iesI��,q�)��,i -� 0>xsusceptX&to lupu�+5�%olorec>cr [55�ivO,��%Eo��L�)���m�(Ls �a���m hapl~ I��&,%oth�*`�=:�ŏ��a� , onx<rm���_ at��"�!c��?%cy���D , F.�F��N.�Q�*mN#"�G<�3�7A�" �s) Q �"�, >K� F� &16s�Vy:u�2.t&B� %H%�wX>�&�,] rb$��0�onl� �-I��;�6W�2a� "� �Eturx ��Pk !�FT>:�aHauxili�/5�� 2;/A��*]͈y. �wh�ex��7?���=�.�. E&{ 2E�H.u��%n�< �s,5>� �R�!�i�,�rIV�thatb�%� }�#5*1N�2�exhib�3uM2 . 5-f�":�]Nu�$5A , C , EŊTo��" A>>Z�.t6p.o2*Y�,AU� -��  decay�>�%]�� up� ,4� �6omycin D)[�t�n�C5 �7. M.R!jy �*�/b�A*�/PCR�Iby NorY(n blot b���"s �!D� g� ��A redu��9( �?��5A];=� ��IX9̩|�#���I�inccedrWŌHH6DDE24s�pA= toge! ���b2�� �OR s�� � "-���2�, a�� �2bro1�7A%B{%� qW��.�A�>��#av���sL:�5t0�=��H!�gi4s;�$ to*}�A�� ���)�K�Z)u .-� D� fA��9�# leav��S��@��I��=�Z ��I�. A�fueW* �H�.�&9Z� !i):i+%gi�0� Q��� A�V�wr(aly��/�݄��pa%�i��"o �-��g.>� �We�$�$"z/�$]���*� MGƁ��2, i .  +ѷB&pA$**@� ";$�e�;H0���i;%�a�.�%Ai�\DmiR-101��Z�IM��16���"�G)0s"CŦ*T&uta%�is�3�1y� ! %c� ��structIu��=a�L;v�sa��,a�.�Q�� a !(E� ny�a4e�524�;,���&�(i2�"M�-1�.��}� j&!f�1/�@�e�qi�S�Cd�D�6tess� �eeC ARE-QD}s TTP% AUF1�i !!A� ��&� nd��'My�zI_�y%� ,.��� �M<�3�.$>�D!.'ve ՗1fas neO!Z �fu�G�z Iȥ� 8/�7hgJ*5�a,�Eur� )��*��A" �F@�U]yng�?��!JEd%�Ai A��� , |�$ N��E�6=byNHV%�of)�9  !P� �*F!U" �?iZ%�� 51o�� %�s4� Take�>9 ,J�s illu�*�� x�:}_.� iF8-Ta�A.5Z!����!�!�� =FI�LV"�7!fin"&Z �!'heIk���co.��1��s�MU%�L@&~FB �*&�#p � �=ledbJ5�����is #�t e�/or����<;o ���� ai�IoJ-:bioB*al�v ig1Q�c��"�$a4 v��manifest�E;!�iQ�APa���E�2.#f&e7�&��2��>� ��%5��7�� �Ubac+9�$w�1A�on� lipodsacchar� ( LPS M- fA0g�I�� spik� =�AGlB da� damp�o��� �F� &�Jm�J4�3[56D,8(Motiv~$bye�dis�<�@a��v��� ��"wN� aQ!"�=�I�O�NL F� a� ma�I(e�i�=��IzVQ�t25U�Q havi�,f/i_O�B�w�"e%1R�'.J 2� c./A`"A2a �*��ulC,�vKre9�]4��ŀ%BKo�Btim t2��,a|w�-M744, ) a"lJ shoo�.�� 1cc u�����t�2ach6��2 :!=��AB%A �4-�!.o6`e:quick�9:�2^,����%< ��6 lIr.w. VarNi��5��BG�"@>���"��"Q.��F7~�Ee: UTR:��s�F�&'9Nof 4M M rapi�"!� >Fu�7Ń!)�3�:o��%�=�3�"s,]4:�Mgen�66��>�"�(Ŭ-tZ*'�M>�Cdynam�N%<,"�?%~ 15p�5!1g approa�o�y�Gl�OzU"�2� e�N��N&-)!�ir�R�  O!� -�� "� N4m@5�E sSOaO��. !Jm( prov��a"�n)%*wEg�}��s�@� l �p�552` & 1i��@ ccor�9���n� h 7&�2y�~"���\'Ras"�.��T�)�nɤach ġ��0�$j�Z �gA���USu* 8 ) &c'x�%]4-�hB[W� r�EO�7V�7z7�4� B���!�JB��Z striDA.-ea`iwTc# � `7 titu��l�W��3�`Lmes.W*�!/. P"�+c)��>Dlow*;E�*/s�@we&X e����n�lA�ViV�>?B!"0!މ���W;= a�sam= ���"E�z� >�A��gntJ��RNAe#�J ��M|� ]{ �V��.lY]ly so6��/4P���:�+F�AhgaH��Y"A}I�(���h� �FT�$�0s�l�2�ev� �E4�-�&� ���E�%�j�wh�]�1p^�2��~*-!F gy . nHSw/iQ��!|�M&� 0�D�$andmark�,B�:7Ru�F%:2�ofb�D�)e�5!�to��g" �V�RHo�O%�� /A�}=�6�4.�2�tB>_ii^mplBaR,�]ͷ"�O~ �!�!P �#A�f=2k&� l2��MR&� a/:�RLE2�K,E�$-throughpu"3%�"h !M� !F� �' now-��&�T"!�e"CN$e tags [30�#[3�S4�S�@�@956�@�0av%*)��t6���!D"���pionev#U?Y^��iqesG "c�(i%�%]?m��2e �0�i&N A��6. �Gsu�,��.�5�map!U6�M]'.!1��L�N�_ �=!jab��{�p2yMnw !{. � �is\ ^r ap#9��e2W��"`2�& Dtui0�>"J!:"9_l���g�As4&�T�=�=nJ�Q�6Q�no� �%�2�w� J,�B�� 6�(sub� �w y�d� hs�x""`�XA�chM�&�= �ae 3%�Vll  Y�?)�.�)NNanyE�=�� ar� �ex<% 9uv"=uu�� �7_Gnt�V��8��w>l *4��5in�0VIb�8j��m�!O�+io�A\post->�*�),���a%�el6.�l!OE:=9advan\!f!�e?.� na��^�a1$�.� �LfY in m�,lia�)E.In� aris"e�A�S%g@c)L:����0" ��6� L�Gng!�� 9Və�un�A��+d ���( 0ZA�Z@#%4F/r*�.� �=d�[aڹ�=��9&65>{4  wej+�8e\V�!�!��ift�2�N,09%�" �KIg��2i;E!N�q:5�m~� � ngBt�bE��CJT! yN���a�eL���|�1N8� &ks [*;\A��y.�%t�!�cS�E���a��R*9I+A\� ��� �c%�`�~��kim�d!ovwHof.k> byN�U@agGh�  7dro@pr.g��-s6�-E�#'%  }]&q\al dimen�"GW9_j6:�+��"�b$. G�!��-�� l%N^�[!�ba����B���%e�M���-2�o| "CJi�i3�YmB�2�&�a!��  thoi�I�^Ka��hl�G go��I���}ya� phenTic5E�'i�)�&� :�2P-�)�&I$�0�0"% �%���KA'i��i��"_al�/are*�L"yZ \ t� d�I� VE?` . Im� a�(.^��d makeHU��at2�%�$5@�� loc C f,��=_����nE%|&�themsel��"D%�.aorWndscap!�R�jv�Bs@A1� J�2�\i_ /�^:!7Xe�aqw�O5�"� eF :8-e�,cip�0!r*$!=&*20)Aɤi�!We �' �A(� a�w!3�� $e systems-em� a(pX5�"�f��2Yn sum�_�F! -���P^Z�� infa;aijE� s�8f0�3 –[�c&� at�� En�u "�h}�:���76��v>�W�-H #6( !� u9y񏩊!=�j7 @!�U 9�-��-*$_55�K!e'�4�bp"?DY �a���$Z\� ) mI�S�Yontinj�X W�ci�ed a��K���. Two� ��\���a-�$nJ` GM10860mM17106 89 20 22(!(853 ( Coriell Ine )�&� ]U RPMI 1640�um sup�=,2 mM L-gluta�g15% fe�-bovlserum�D�p6'incub�!A� 7°C�  5% cOYDox��!Ma�ext�Ue^∼107/ ��TRIzo!_$+(t ( Invitropm�#! 1�;V remo���Ek�Turbo DN� ( Amb��� a�oed2G'P�10 µg%�� X!�Dynab]ŎlPi�p kiZ�e frag�)g or 3�uH at 70%L%10× F -��R5�AZ!ethanol�cipNbo12. :���� w��!��r�%N�^ BSuperSy II>�<ancho� oligo-dT>%. Doubl� �r�J1� gene3-A;A/R%�H>Bg3 Pol B�,��-re?\IT41y�] ( New Eng� Biolab�SKleno�uAK�0�T4 PNKjU%t�=�)R o��(to 5′ exoE:sbR. Illu>*(]ed�adapt�;e�l�cJG!�z%q -LigiIE>a�aMA�2A�i �_a�G agar�Nge�7 �mpl�by per�!�12 cycl�W$5 �PhuZ HF�s�gbr�w�% Q7B^p. moduu9:2Gle�4er� �.c� T'>7!@brK8D�0���\�trimm�nd �efR�:Ş�4�_�&� re)�m/a� 20� s.�or�Rn�^��� JA� ha�.��Dof�Eoad%���9�LH3"m .)* � >}a�l:�A&YJA�SNPaFsegreg1A2CEU*��c&lpm�1HapMap =pe II+�\{1A�L27 ( ftp://ftp . ncb�2nl��nih ./hapmap/�Gt�n�Y��od�E�U�5me�M(g18; [62] )A�&�A�AXp�&(e ambiguousxM�4SNP"o �:5�!hq�isA�I; �AQ?he"�fpli�j")R-fKCy{s�b!:� UCSCXbrowss>63]m�MOSAI��ht%ebi*� bc4\du/marthlab/Software_Rel%��3g,Q�l&;m"aS , nTm B�=��mz8�buz�7�^ng 37 -Ebp%n�] adja�c-6Fc9JnsQF ![a�"�yqF=. Ie�63to�04=�aJAi�!��� �^er numb�mis�Hes%E�. Od7uniquelyC�.���two�$fewbICin) �2��r�4O. T=�E�� �Mձi; �w>2.�-w-E�i�g-T�ct g�( �|�6Z'%�QK!�%6�� � minuq5nI_�fBa tA!}qs!�v0)�&a=-ol©hV.�3�%n4��� km�Ce��;>��R�plj�Z�Z�iP~�f�. M#'�s y�~�"'P�a�12p>61P��MWlqs�g �g of 97 . 8 `/a�2 X�a�y� s��!h100�/�2Bc. e�,�!�+et""w2-vQ.�43 . 4%��#�211 . 1�:?E��(� �pooYb, s�I�:2(A�A5��jdxcY�M�!6B3 H�u��n+/n �]a7�b ag ct4m a� llow�%��)�A�e�nwos�^ia� b^�6!�4!VE�v � �>�f�BAt.�-4��"adA����qit�~iVa�3P�Ee�15ALaw�}Icf��Fbec�&heF�^=KA�#s ]��Y= }24},.v? :���Ous|1B�! (&�:*l-� alhlthm!�fF��\]R��O�(�cs�Z��%t#5�}Q�! %fcou�Q�s�P�Lol]�.�+4�. F��f+")Eu$� 0F�(!�M )��$r�2sb.ad �( MaxHe#�W�n d n�a window-n"daR)� � t��2�?#%Wi�L%7�<�$2%tdo�s �zn 1Mf�. O�,%w2A>�T&e���6}� posL posR% &� �6�&c �� Eai new &>.:Q�s ��f��;" $� A���2�Mf6c� cR&� �)VP� i#1z)�� middWS"?�9"�\ J� *� I��>�7VP)�belowF ��un8 � ^]�a_ r�X^^�E�:�Ny�E6�!�Ez�%Rf!�repi�A�Z� ſ.�un"� �.�6,��k%N��\605�I�pmp�/�J.#{ A�8 #�] A'��S!�5w �Nr A�:��@csee�{v��f.�rS��ko%\�p�rB�[��A!g�-� bm��sy2�wa1q6=eHfŶ)010 �- N�M:2) Klso��as�c`\lfal+B�'a.* BlfEO.7�fai�)bfa'%� 62 m�ha�r9g!adm �i-r5~&���Ep�F$sh�3���Y%�!=�i����v2bpP����du;, ypa}�oUIn�.�4�Ho4 u 6i\1d)Y�-.�A Q�a[&9, /2�M"-;� hete�et�X!7ٙM� ��$ ��dop5#tru�,w� n.�_.��H��lQ%s6�orE�duQ)��0su$)��6mE�c,g� r}-!�A�2� 2�a �-��52��2Oo,V5-.@$Hd�S*Y�#l ni iM �t ��>th5��/N1/>� �p6�Z@*.��� V������am ��EU508| \��V&�/50���=%!ePearso� h!co"�J R"��P��1��y*�fI.Xix4�i�*f�Љ|B Myabsolute'%u%*REe�%*$`5���1rI earcgA�*�RfB..orl�'��!_�[�601��+�y a! s�/At)GM��w �.24At�rb,�.* ���f)<or��K��6��/� nsus.�Ye7�_n~�E�m f���.����second E �"tp_�t�20%� #c��p &t&' �� �<a2���( MbA!�PR.NWW.�S C3"Y."K G"T� �v!�]Bc"N ��� " �b6>%7M��xi ly��sO$-a>" hexa�{M�@�Bir={��� � ��2f8Fp�hE.N� =�n�)�F�5H.GY�&in�<3V�> 5 V"�*abs�C7am� �I�VHA�6WB�y2�����9�)��En� > atO st 6u v aoTxe��h ;�"� !�Fi;��no 6--�%o� ��f!J@v""j a�OV}!q�q�a�!�F�~)3 �"?!�3�I �� *f .-,�5!*�=t!�-� 3‡d=@\H��!Y �QP@!% Z���un8:3/#O9Y�>t ( US?U,�z� 6=w2�.n<D9-b�<5\e�st*�wm����,; in 3� uk��nm�V *���so�!�Y+�:,t��*t�־!ZS1g��L�`��� 2wasU^���*-i"�2�!a�Apro3+��� /Zh65%e�6U�6��weU�+B�I�,A�}z�b�.�U/G�"o*( D�<��R���>A -&��V�% 6�-�Q���Ɂ�m�?�1TTTGT+GTGGTCC TCor&�v� �u^�!O�����;��^�50��v�H�)Q&_R?�%A7.x"a6�9!<�e B.9!. �PA��s'fvC �2ID0 star�de0�� �6k�O��C mini��2�` 1U e��2�Q�.��2 ���"� j�Ճ�A"{ zS R.��;s�5i�-8"s�.��(:��l ��ix�7 � ic*< %v� ,e#G�=( EST�$�)9#jS% _db2&�#[6gz2N�%Xconver�{ hg17�g18*� liftO�L"�*!E�B�5�N�*2��EST%��NV�8>�F��#�'V���,�� ��l!}4h �X�:�-C�9(��:�CB8r��]ZpQ MA�per E%��#E@".,� jQ;%3A�ach V&t : ! I6�����q,p E��ya�V� gene*R�if�$.�m��Rqy)N~9��2ID����on�Q�a��hiow!- �dnA5-�&:Ec2�hW�T2dv7�-��e�si�|;&�sm�V$�3���.d"h�*�� �uQn�-Ue�4��IzI��9�iN� ��N#/* �!5Ang ���� �d~Qes &*−-4 s�A�!��E�y A>�� i�II� WWW 2 ATTT�R TTTW%J"|�/at&�U�.�*bei%�,�� pent, �. B l�,%f comb� 6�G ��ma���", �H� TTGB�Jn�6��N1�^~ANATA�{h V\� �� t�\eR� 9��� � �az�"z;M2 �M��0!hE1.�seC�&�S�1�D7l�; tif }y0�~�s�^�ݡj �1�!�Aj*:{>5�%:,i.���in�{4��6TZ�1�� Gj �&�� 7 ��@2� I$BE2�<�(�A� P-B<%�}Z7?co�\d�9," �⥎g^�Doe��MW�)fc%RT�D���"993 �` � G"r* i��*9`�UFs�!�0�9E�� ��se�&e9n�`K2O�#!T"�@J � �|, � � 6� ^�EXH valu >oy!~�Q dens�S&�B��*�%��r!Uo�Ya�� ��Fe! as:2r"� Q�o!AE�i\ N4 >}+.Q2�B�a !�SNP|si ); f���tz?h�-*�- �� siM1�B 2m:R� �,��+>&q !g�q�!�y��.�%c_- >Pzai"!� 2!7upe�s l�Td7TXSP i�Z�>”Mne1in[mb��6� �:7 ~ �sl��7-�se.�!@E�$DEFOG web-APdx�( 6��mooney��~7org/defo��M!7}6 Ont�bys.ʼn"D ��5! � ��ճ�7!*�!ѻF ink_2��w�#b�C�!%�B"� )���IU��sh�4=\)�" � !�"� �2�J�,��4e!�.A7�*�%���p�)��gD no�tEO=te�sA"�E)�Ca.K�;�\��� )2�A "�D e3,� M%defaul�aram�&�S�� �9ha9G�F�az5�"�n�W0%�a+2�+ �Esi�T.�Xy�:V 3�LŢ�"�!1 d@���(�J [69]ɹ!?N���"���Me���<362W%�=��<� �Hnz�21�Z24 mill�*�� ��� !��*� Er�ͽ(� )M&�<:<:2F6(�+ to 1��)~f648Nb6$sIoA��5&�57)/���am"[%e6:�5%+�Kl�9�GigaBay�[�X;e!op� $s –ploida� O 3in7 –CAL!A S� �����/�99 �"�!��.]�r�R Va�Akb^�@ aF3 �monJ2� M&��w�J��eIK- �N- y�(�Y>�&?a._��v.�V;mG���,eE<&5 �}� "� ikafa�!)�.hM�@ r�7-\gP.�R^� n6Dxś�(�7F�x%yi�$�%�sG� B *�>Q�A(쥣,f�get a� al ̦)-�">Y%��)F�&,3 !=�g���AS��{�Q�2� ��)E����e -vAw ��c�6�#g�!R� !+_di��d���8 re@RY. j�il^�5 � rangA�eU0����m�z)m\ matrixZR� ��2����\}�f�|, �"0m��� ogar�8-R�-�M 3�� M���AJb,M�.m��}1�݁� R3B �S i�"�,.�0c�havj<,AZe3�F.(s2�%*�x. !��E5��$�(�.���e��v��1LX!c"aR�inZ�:}2�j}�!-eB-�&Tac�/R�*��as-Rai: 1�!�al&AATͣor ,��5J+!7B5CF��ntA�>x&� 0+A 0�00�l >7 �"%� cB�by [t�3a��Y�gth!mio�-2e�%� EcQ�.�x��i._A 4214%�i�%V�33 1.omSM>~B�\62 , 1?M/Ma�20 R7Ifl+e�W� � +�m*� "�� /01~*w )n6�1�9!.qJ�,a�� ��^�]}�6_�� Q9QA3aN��LK�cJ �A2 mL tub�VANbe��pilOat × �\*SSib :N@!\t$flash-froz Jn liqu��T)a�) −8�S�]�o)dE�M�u�UrE�>{D.6 ���lyI��{� techni8z��\�V dual *I�Y��AYD L&i�R��A� S�Y (*(. LYR esce� EJJa%it�of���Ren���-��i"wS � a�UneryS �s V�s ~oa-�U�g.� ]oU&�:FRb��a���� ;J� T.FK�� A�e�v� u&�22�j�a!�sM>�r��s j5�>�3"8L"��A��[6 � �(.� MDas SU%DLU R&p �F6d?*6-C)�ofI �� ect x�)F�eBI/ ��eu�jQL"� 0�n1�Z*�e"ߠ��"�X�& (.�eB�^3i�o$* )��uard/�Z"K�)~) \�� n -mLU�%�"�=� �A�B5 �[B(2!!k[*���u6tNof�%wZ#SUdeya4� %�x��i���}0xh 9db\Mq=*� SU hybridM��t� �/E�M"�V�i(%�_`dO��%RNAt �S��2_All ��4de"�P%3 P�O[7.�2 �&R]hairpifAn�}%JdA*��BeaconD `r Web EH� ( PREMIER��soft I! nS�ia� � �syn%^by Elim;$pharmaceut���&�LZp�72u28%�*Bby:R)LY F}�GAPDH Id.� Y �P!"1 � ^� A!]�9 f]"� ��-&� J��HgR?LA���6��P*�#� }]:� �9��,!8"ve2�]f;]T�]J�]S�`s�&"MZ.Fe�2� F* �N\�t�#:�A�S2�\I >�\pt W:9� 1P�ue3Z�\=4�@woV� a�%Y���5h�s5 �� |@DyNamo HS SYBR Gr(tQ,�Thermo S��>c�=or9h[��S��[ MX3000P qE,#ru� ����9ek���kaA�;%�>�!}��WmPmng� ]!E M�F ���"���"3��iav?�c�o-�I)u�aMy�tem' $ ( gBlocks�!�_ᤡ g+TTechn�" )�gAR3p�� '� dil�#�te&%D0a�01=ha����x!C�.�I�Х?j 0� �K/-2�*��%�E%�"Ȇc�Bo�!�e� o�2r ��"� �A�a�� e���8vnf,�F46�>aJ �+a��h�Wic.�nd��by�(X +aAE��"���d�/N��%bI��h�� !���IQoc5� �&!�r �sd#d2Ud0_d=7d2H:� �115@U�� �)U� stit��ghkJ-��C�ze86%�y78�"�N"�y�: 23+F6�۶�!�3����"�2e ab�N�Zan��!�/VK%�2�AN�]pfe.� ,%�si.@.4"D &�%A�,i�U���T�rIrcA��W��: �d�� Ff!�∼��stock s�I!V_2s�ȝol�e��MSOE�"�W��e�D�6= �e�/\�i��]�of�/mL�2���i�s'��� 5E J.� %harO�~GB� 2� �4Ehor 2���2�� !��h�4%#��J����A&trn*traproliЬM n); ZFP3����\^�x�QV r pGFP-�c�p37BH:$pCDEF-His-(-(( �kind gif�dBR launc er] Ea�:p �r�� % 3 &�u*� ���*Kh$. Syn-has-���m(+m��6ypurcha���( MSY099�a�dos��g-s����2� �vQ2yELmixD ![�K�:*�X M"�!с�� �a�YU{(ep>P��,E . coli K12-:v�i!u�� �0z3BN0�ٰ͜��1�j�,20�>q�6� of 5� a� in 66:�� A�U���eV�a��kޓr>2u8Rm16�rK��ifu-#f�,!Jh��@%��eeC6J�."� "� ua1 TriDkB�U@DIG�o Starn+ Roche"\F���4+_� *�]�g�/Al6 #:� M).�m�i1F�A digox�م��) labe_� �0�)JS�c�[�\E�!'�����Co��,nylon membra�p(U�FUV {'-li� . Bot�D�$e@� imag�jBV%L�]Trans'�3k!I.0�+�Q�N��-�Ak . 28S rib�`albLt!NJ�ela��a��y;�s&�$S4��ach�%.���)j�e� E}b �b��[!�BW$ing�Qwa��i��r�a> cedu<recommS!e,�*.=�. Anti-}�-A64�h� CDP-��7%�%< chemi&��E��A��w DIG-F�. /3'��re"y \� :0F�p-30�ig�Run�[�ncu�Atom �0>�.�3l!U�y��� he��g�]ezd�hY}�!�_�X2���-05% NaOH%�!�q�w�� b�4ei�a�e�d6�!i ���!��7��� �Apa�/hNP0�dep�"eT*`Omnib�nGEO )P0vjwM<ncR�kgeoU<atU;Y�1ac��QGSE33154� ~��l3�c��sim�W�o�,Ecy vir�\LASIV ) vaccine SIVΔnefr!�M�7C)a .�� u�!a�il� wild-typeA� tivi�>ch�'��$, yet littU�s"b:�^�t�� ���gvrkq6wve� icac16Cwf loiauep A nologyE>�rehenE� CD8 T" epitop,rF�V&oAO.�'o, $�&>@&i:d%��YssQ%�G)e�y��k�-{�]$* � 0�  ��#N�in5�-)�eUan���We demon y0Zi{l^Upac�Xp^ �YNn�A��mu�_�A����g�~m}S�*�S � =7��'�sp�/1��oqFO. FurtGr�.s���/ c -Kexp���2?pertoiT;Frg�;�l�n�wdO�apLA ��ro0}� ificb:)� !ks d�WvJE( � �^)!Kxd�+�1�!gy���rc� 1#5�$Ek�qHo�!)WV�A�i"7�U�e4>4}G��� �kU,+�gn <A� HIV/�� �A4A,%X�of-of-m p�z��%�%� �<!|.�8tw�-6�f��7M ��u��ful�� tydecadLgo�Dor��� b!c co� >|he�Z maca^�i����!#��,.q!�sq��tQ�o�$ path.ic��!���[ �Si�  ,��er `st���.�N|3ഡ�;!�rN�,6�1��%>��*il� �\a\M ar�#B0tEp�kloE�<�A eak) et-point��,emia [2–6]�emɂy� esuma��@a!�ue�!��$a[�+mucos(���[7I�2��"���c|oc�!����N5�s [3–O1hNI���$"����E����al�H[A�lbe<��"�=u8��homF<[��H"�Q2di�}p���Z��m6A�aI�R*ad�;�)���)|alu��>WHIVIbe���ou6��u�"��� s [8–��. DI��r���PsafetA6=�_�5���ed� ��D� shif� J-and-uR� �%� vE �$lo&�k  cA�:� X,� �.AU�!X4 ly-å�ora�Q�� ���hՄ \-��]�.]noi�AMw!G~modq ��� .��e4 G��!�͸il# ~Q½ uY{���� a di�eSIV�Gf� tibo� [1�12$���) %��Q *� � ��7���!^8Mamu-A*01 MHC I�$a7�u�!��.��� �despite. de��A8[<�, imp� �oumo� ��mayGya��gŋ,ZSw-#s6q 0ty& &$G� In!W!��)��c%8e�Ub�%(neR`[��"�E� ��ut_/2 )�s[ d�W�gnitu��o:/&� 1�� "VVs.'�2@~%�]� ���[4����epqr��ů Fukazawa w:8��55�m��*j� nae2�# mEes>������$��%�"!4���i��^A��. Finx�,50�(qi7e]��Ǡ volvL "�eZ���c.�� ������ema��}(tra *se�F�u�i-�q[1ZI!� qo��&��scrutina�:+p���Չ&�O*|��azj�gJq"Q)=ce��f4���Y�DT �8�i gUL>TO=�+preP�5�hY.+ : �'�-le"B��v� of�e�$[17–21];AQQ+�:i� 2 chro� � y� �� 22];%M2 H>7EMIq�hai�5Adenv!Z-� &����v SIVmac239]�[1a� 23];�R8����)�w"�a&�c/ ���k� �N��4]"���I�Eo&��&[N� A�i�{a�9 �5CD4)9�%�A̙�*B%F����d�<��a~fe��H�b� 3-��I�gra2!�:�1�2W9uQln�M15A�0 wee��f q��[�2��&�>О�,.H /-4EM��!�|aM�by � 2 |a�I� , �8<0Y�wh��%�go��86vQyQ��,q�;�&� JJI ���bTat SL8b~(M��arKs 3 ����[2�c��&���a�"�[%sI`�.}*Ir�j!�.h��-�Mo^���' hif 7.,��y���V� C� 4Aq,ua�{eLzA�t<��8Q�d*a�p2au@�2]�& made��a�.r�d>j*_�UK5���a�#�.�O��2��;� a�tű��!��;�a�=4o6w.��cur�� w�e-OD!2J`s�/+E%?P#20Im�!9. S�� ��u"�1�#': �iD5%.L�(�a� comi���n"�M(6�I3&YIa6"%mY+aV/qgcuc�vek�dthhar�C/�o cZ]enh�d�th . �15% :+ G �]ll � Indian-�u>X�z caca� att=>ܑ�_ bio�Gai�����[�he2Z�60+R�CeZ0 ( NEPR�=�s�"��A��*�0were approved�u by the Harvard Medical Area Standing Committee on Animals . At approval of the study , the assigned protocol number b t(InstitutionrnW0 Care and UsexX( IACUC ) was 04383 . TJ�School a O|management program is accredited1Associa� for%Assess<�A 5 %4of Laboratory .�, Intern($al ( AAALA�,Imeets N 1esUHealth s!{(ards as set�th in� 8th �ion4!�Guide&2FN�s [27]-Ci9� also! ept| mand �f$PHS PolicyA Humane �m$by Awardee� ions%4NIH Principles�Utiliz%%'f0of Vertebrate-vsA+d!DTesting , Research-rTrainE3reA,on file with�OfficecF� WelfA�(( OLAW ) anM�edA( uran <Compli@( A3431-01 ) . AlQ�s w� hous�doors�8an SOP-driven ,M9-]�Lfacility . Husbandry%c�met� guid�oi�M��Regul%Zs , �repor%=A�!�Y�2as�l �r1�i�-enroll%x�, inclu��an�-a���olai�Environa� al Enrich Ed�primaa~Ais�(c ed r%/r.�as�!B!3provism�speciesI#priA�manipulaOM�foragA�op!} unit5�to�5hadJ�exempaE from ��lESRbaAZ@on scientific jus %� .atTmary enclosures consis�ofA,inless steel1( c ��!Tby a commercial vendor!���$body weigh�RndAe dimen!0M-eTly monitored . Overall..of �6� ( floor a��ehq )u%�fi ��k����a! �NU( AWR'se�Further9l-E6�� sa!�tzed every 14 days at a minimumE�!j�a��AWR�Second:[,( room level- nPre#\t to temperature , humid�{, l!�Ah!jnoise dA����-�U(ad lib�\ss_Lmunicipal source wat%) offeA]U4monkey chow tw��daily!Vnd1freshr duce=9�ree time�ekl�CL� cyc�aet��at 12/12aSrs nJ�subje-/� docu�k ed observevsa-t��ea�!&���veterin!�staff �> f� 's e2�en��I�preven� ve hX�' A7HEuthanasia took pla!:t defi�expera��C(endpoints u�gp� %:�:ntIFe! merican V�"` *p ( AVMA )ŷeline�i_!�0re first seda!RE��intramuscular ketamine hydrochlor (at 20 mg/kg��follow� @sodium pentobarbi�( ≥105) hvenouslyA� achieve e9;. To d��SIV% ein-aM�w T celle_ onse�89 whole, pept�poo��� truc� cont�15-mer1$s overlappa�by 11 !� iC 4t 2 . 5 μg/ml�y each� ss span# !� SIVmac239 �oma�d cor�o �!he� sequenc��vailableɛ% AIDS&� A�Rea�5 ReagA8P� , Di�K:, NIAIDH ,�3ynthes�5� @Massachusetts Gen�> Hosp%�cor�qH!�� ��,$individual�s A�ba undAW(www . aidsr �P. org . For epitope m-�, a t��-��] matrix ��5��n2mpo�� f 87�M/,)�]%ar�27!�300a]�BBencomp�d%�9reA Ye{���g%.,3-fold , sucJ at ��ue 8232�M�r!rep� nA�in 3 di�� e%)$TQ � >��e�6nd 7obawed��Z� ���Y�!�e��py) a�1within!�m�!f��cal�T��a�Lof)�9-�\,-acid windowFW, whichJ_ alig�i10UW� SIVsm�u� st� viru bo� cl1��!�5quasi�res 51-by rot��1s�d$then uploa� in�� Shannon E)S-On )#orY Los Alamo*� Data� $ ( http://�7@hiv . lanl . gov/a� ent/� /ENTROPY/-}$_one . htm� I2��5��zn5�s��e A9��aS!8-z5,. In order t��Pct only IFN-γ-produc�mCD8����ELISPOT � eucarri uHPBMCs or lymph node� onuclear�'s ( LNM4af negat�selec� of CD4 T-H ocyt� c s fra)38by magnetic bea!par* (H Dynas; l , Oslo�torway�evi 0described [20KN �ly �edZ��Mf >90%26.$-deple8!%E�%%IsuspenI� R-10 me�A���!� same; !�:�. Isol%%3){%D-uhpel �XAFRNA ext-T�-a� eda�al)quantiz o +M�A2�!2"� lasma Ca�0SIVΔnef-infe ;, high!jk�, real-�  RT-PCR2�performx s=�$ -�[28!ơ?Gy"+ %�n���velop�6des��a x rs� i� t�uniquA$recognizes)�xg�!H� deleA�!nef co�11!�ȉ nomiZlsh�!�t� ԡ�30-h!�c�'(equivalents -�� o.3f�,Z)�E_� �s�orpLA!q5� �er' prob` ga�(rhesus CCR5E�:�2�-�Briefl:U��m�4rapidly disrup!�in  0μl lysis/dighon sol�$ ( 3M GuHC�6$50 mM Tris,pH 7 . 6 , 1CaCl2�1 m� P��0inase K ) , u�! Ta Branson 450 sonifier%�pAyw�ae -intens�cup horq{t� (60% power a@tud��^Ultra_c��Danbur!#CT�A����inued 9at 42°CEh1- , 400%1 of GuSCN/�r.2~5 . 7 !8SCN ,~8EDTA , 6[%8glycogenadd� o7�F)�teA���� "x o� �}ic �M preci9 A�ddiq�5�,l isopropano!�c��� by c�ifu��o��Owashe6 th 70% e~oTa�s+ air e^ ��6)`<1X TurboDNAse bu  (��0rmoFisher/Amb�AX�split�2AHal�A�aliquots%�s�%78DNA pr P�psAMm�"d�Y-HdenC] heY oaVQ95�gD!#on �pri�o�. 81E:qof>�����&!�n�%2Kt � le haploi�py�D��( 2B; �LA����Z-` dilu� 1:10i�5�.29 . 0w�� ��!�:� targ[>}N�05�h r?! �,;Aof� cktail��2( 4 Unit�Y�I�9X~��u�� ��Q^incube�a.o30E7� ��%�.�� A�,����{vZ:�2mϑ����a� �l��,2Ky�r5 25i�.#!�a2��� s noA abov� GeEg.�I da��or �I �u�te�d6 i�thr+lim!�ofE�< E y uaL� A"%� 30 t�Ccopw i�� normal���: edi*.�. P 1�` spun!�,14 , 000 rpm4�=�vin *cro�z!IVi� A� i �Aj$Qiamp MinEa�5u�in kit�or} to� ufac r’� ���vx!2�V+ (�)" >�I))a t� >��"d �4��5J toI duce 42�;c�2 length!�!. �:� s XSuperScript III High Fi�(ty One-Step� !b( Invitr��<, Life TechnologAV, lsba� C-. ( �tM�eikpur)e��Qid9�Gel E&� (!)�or Agurt AMPXP8�,Beckman Coul��S!@qq)�f�� -IT dsaGHS��ayp2�)� four��ultant=�e comb�!�t�librar!* !re�0nd taggU! Nexterae� � Prep Kit�lluE �I" � I:k���he Agi� I,Se� ivA/!.I##2!}L6�%pooU togeE,*�%�NaOK�run�XJ�MiSeqM�MVa 300A5004 &:8$, San Dieg=C� USI�B?T-�!�%�enume� q�� zyme-link,mmunospo!��)� ��{��$of macaque  ( Mabte!MA5 mont�H%NCD4R�J�� stimO ��t 2x105�� w�%q�%�aG��:�+!�Cel� &(�� nigh� , multiscreen�)( Millip ) coe-�A� cap�� ���!us&�� 1^ 2P)�!��  e2�,5 o(tr s�!�b� Z . Sp� %pcouɾ�"uto� dU p��0( Zellnet Con�Q�$, New York Y%J eB�-�-aQ-=�!�-c&�a �%of-'3r�N han backg�a}g���$anM)`per m!�on mo> ed%1s Yd v��e�"=&�}�,� ipheB�*6N�"��m�y(Ejb -`at)���t leasA� posi!��ա8B�.� ad�ntoBq��60J�M�nside�g!nt� mpreh��(ve MHC I ty�I� pyro� A�� � �:� 9�l ell�RNA�� conv&d�c�6 ba�' �First-S= d SFs System�&��aP $ryTWA6+ 190 bp!�exon two �xclass I" �g"�%�a$-f& PhusA� poly� se (e�EngE$ Biolabu . Each rm�/ e�12�tinctxbp MIDs along � adap�-��454>�e i S#a/-*9!E6 � mo�con� -ab�pE�1$!!--A�m�$GS FLX ana�a�he emul%2 L:[ stepL" %yl S�r^)ru�!��Roche/! � SV%! )Me �Bocols63 a�ma:7 �| �(%h>^a�'y �a&Cenx (�for T� he�ver of Illi�#Nu )E"�'��c8��i�so%�"!Z �exჅNA� "m"� ,Caltag Fix &!�:5�maril>%tac*Ba�FugW��E�� � X&���%PE-� A�U d te"%@lto Mamu-A*01 Gag181–189CM9�,Tat28–35SLAqkin"�',by Nancy Wil�!+(David WatkiH,Wis�in&�.�;E�+��, MadiI5�/9k2*.�31 All acqui ��k made� LSR II�%6*��=�d_/,FlowJo softwS-( Tree 1r Inc .a�sh� , OR#(Isotype-mat��r�nd/% Dluorescence-minus-r( FMO� \ �ꕴ0 �sM[32�sZst�1b�GraphPad!�s!,�Sv6 . 0b�0 �La Joll�,2� Non-9m� Wilco�ADMann–Whitney tes���alF�is��a� �%ey~,5 �O�wm*, �t.j"= $; p valuesFS05I+ assua� to bsg\c� 1x`$ To stud�2ef�a�- escapEx�e"x %J] �svacci1��8  f� �es�%ax,"^��  vak.�-in.A C!XiM'I�next g�  P�( NGSE�c ��� , mos��#display��� E�y � repl4 ki�!� peak# emia�week  Z set-*at��near unaq(�,� <30� y Eq�)2Q�m�+��S 2� 40$s befchalleng{ Fi�'1A% P� �I�p"om !�12N*u-[!At �ran 0�/1�A�34 s� t-1�!�.?��e`^L=*&� cN�)full-�th!� �ge�.>_!9�� A�f� l���Iq!%:j��! +2th� 'r�alreaF0idesp T]�durA�^i62-=i.>� U�, n��m�eF�,�nyQ��exceed!�*Eof 10%��ig� 1�#S4#)�� �Ahes �rE$ not *V..Q�!�in vivo�i�it�1*q.�PioJ1HowZ0 ,��e 4FU,�v!@I��!8�-�(2��71�2�inA�s"b&��`"$5�(Vk=>;aJQ^&^|".�?3��)F�(E�2���-� albeDtB�i�%��ed) i�cuq. L&.+Rt)Q���Q���A�615bN�  . 1D�a��K:AE5t�euf+1�4%��� ( S2a� .e�1�� ��&inaA�9in %(T,iG9�u�o�n�2"or LN]�:nD�Tool��� �b%���(F��)�4.�@�d,ofb�Y��29%=Sto 4720 ( p =! �<(-`1B%c MoreR j� accu ��&nZ��) reas!)�:�0b;��I6�6A246�3� �E�I�%*�=ho� �06h.��9s�Qm�9as mea_;�9��Oi_0���%+l�<� I�e�Z�al� � >�� J��� mpan� ,% shif���sp$�SI*�N�, w�J"u�sE�d!��@VW R (EL2�0 A� m� sR�"�$�"2 1� r�*� �tb6� a��.#a 40%K A�" �0���!Y�@N��**<1?0)^�Q�2�Simila{=� ba &�#J� did� OmE��t%C� ba�e�$:� rema�"s�, e6�6"� �A��/!�� Qek-�69�2^120!k!FM�2� AG(�63A d?!�4q !���� �u-po:�%l��5�X,={aga��+r�:*�U >�.���.��3�rrE �KR#"�b,we loo 6=a�->�>�+�!"!�.�.q a��B�N �N�iPBH>�~�de�8d modest�0by 25%�2+�u�E5�):� � a5�=byA��2��� $ y6�� sli�#1;5a,.%!��^� We exa�=�5B��@GagEtP�/A)�E-e�in=)�&ruMca"�6!O?+1�dV2�|$�<c�G6huAo4nyN ��f��triguingES`q2�*Z@ \� 2�.B� ꂙZ�z�(� <�06� 2� i�f� otal����inrtG~ 2�m|D � 7��J� 28&� 5E�7E�To��s7erize!�&� ��K /)�]!�*�>"� ,�O�>%he.K1����@i�26r ա*� z�. E:]&>���s�G"��&t.uZ2�� ~vf -in�..\�i��al���m6nd%g"H�>c�k!i5�t�1&9 ��� se�`si�( S1 T�G�$Lon"�]�Asz/" aAe� p �� e*dS8�of���Z�u"�.~.Gmf%BU�2\r-9= R&-fd.�ly2�:�. OK36.S�Y!�B�a�,=1��Nlso.��w� 3G5S4%�Al�0�9thi�M�Ye ,D20�de novf!or&0� G�i|C@� As�sJ%!��Asa� wh"-c� L15��^ref=eoM�an�6 opic2+ �J����h!e�9��q 5��F"�A�svbWe��P�>p�� RA�.50?�7�2aC�me~-tr�5pfF#^E stre�� �����!��3� X�@`&U106smmudiD8 open)�ng0�HEO . IFSI3} k>c�n becau�;he�us?#S"�E��5A�B24A/ deri�� m5ereM(6X$5of}-i�2Ct�ܹa �-��J�$(/I\y-�&��:Y�(�� 39 )5,3� M&�7��qUJ� :FsQ��lyF�n]3���BHav!�e��9pE2Ao>-8^k�F s�/ taneUe�!��A�-XF�J�i�soub tBE�.,��"�!Aqs�A"�Mlay�)�s�^o`C��u����y�<H�UR|�=!�{%��1?^occurr�#!k^�!Zid5�, =3�as 225–9'f�� EN:v� �� &-fQofa�M�e data�.�v%L!]/)S��y^�(A�u�v9*|)V� |y6�50% f�1~}6' - uz5`, implEaM$ link5�=Nv'n5!x�\#..�!�^�:�� �s��D .pa�*ut�T�N}R&N� s9�g256–0� k&�'���deKi�Q1g�"!� �-� T9N��Remarkab� 2 +� ���themselvjG&/ak�$y o� ?&�$�e6� �5�o�>�aO l�V=5�&� w&EC� �emAillu�Ro^ As�)|?,\ Td�tr�. bias favo"%" �� U ��!����P 5d>�*4��*P��3�.-�top,#YM��.�4-���e �=Aw40n�R �d�� ��n1 �[B6�t�d).?� ].�013��6�"^E�Z� sgM0f r;int 91aJ � ��2�regT"9 d wasJ?� < �=+2��sU GV87�A�IKR��7 T];ex�Z9sum!��Z^ [W�or"/ �x!$� =v*�atA�A20S��'ula�����FIm�X�Q"six���+R�I1��0r��Dcr7"��;ay 0156��7�To ascer�g)��dy�&m.=;*� ����'duTaW)�La"9`-�:c�07"�2I�& 6@ :�4of ?�)�.֮�.v l"CI]cohort.U' diw4��` >�m�P/1j1ng��{+R?&�0��B*1[ whila�e�q�Z՞�1 �)_ �e(U . NoqIYaV�aF*�Wn��regard�. �]�qM�2(�MI��JX5>R1�:� &����2B�� oB�M��282 hyp� �/:T�;Z}� eMel&O� ra� ݬa��J mem�aT�&�EH��& 7�"vBO2[pQ5U,&5UAá��*RN�����  g�_I� , ma� �?y j&D5d� Phena�i@&&{ SL8N� �XII�AG a�uae81��id<\ "�>qpro_aN�Epch&��yl4( su8m�U$X=7&�$8a!,�60��2~6p.� �>I-"Fietr&*66~�4�62Oh Ki67. 19�5�a+$��A1*001+0&QRknown� #�5)M&!�Z�]]�fX ��t d/ acut��)!UaDquick/M�*�A2�2i�� �[ 82%%94%!��d�Q>sw AW��a= , ek 4!�.j+L=&�!8�A.0Z�Aac�].2ly6*%� �]�l6�%>Y$2>L8-��_7�"^d�Iō�Cre�A� M i�+llo�&d2��51Y: �G�4!���en�6�o-�d9qz9l6���j.�6y. A6 �'�,E�coaBst��6��)%J=� 3��� �&`� �6�#66�D)r� %�i62103qA (�N3�Nu̩fFib*,!�.-I� a/P�1�� aVJA[�F]: �bu F!deepe�j?%�mA.�!����s B17-�r�FW9�HEAVQAV�f����c[R-Y�IR/)T4y-��&2�N9�N9:*�sE?mPN FW9-H831Y�s~ .�i�LJ;"N!6�]s!�we �8�_Z���QO#�&A�im int B)6, �386�-��B�r&�!x�!W�38;!$i � 6&:�� [JB]5!��69� >(GY9-K76RU -2>ird*�� q�depvv(S� �M�.� A*02.�GYA�GSENLKSL�FQ�q�9i�T�5p� ,��E� sub�N��s����y�Z, Pew]D����mH�'--�s . T�* KF5��su�h8 2�Ep&l) >s �ins%!���mechanj<>� �=mT4)�1="8�Z.�H!:�enaW B�@n*�i�".8 p�g�7t iaN� �*� *� : QFof=?~ [26& 3�:ngoS J�~s?ER_Z�-O22 we sgm!1"�Jr�b6v as��a&QM:�5�3>���!-s� 9eP1AJp�Z(7�nyb���ar%inq�l-tV6ianGr direc%�5ofI�e CTL�i�8ro��pt)6-�eE:� lead�_a� N7(&`ic���!�� R�bI"gJ�!.n&w,-�da'N� �F9 m&� i�}m?9�IpF�p�c.�qA��J���R��e&�L&&~ - �5Oens�(e�v�T�+sK%�a �r�vs ". Our wbM�Y�8�*on!�3 !�I�LA����"nd i�funN/a��n�`y�s%�funda]"���.1 oi. WIma�-�reA�ecessfu!�&�?�$etP� vector-bunXEas CMV�RRV�-%per0j[34–37�<&P/���i*�a.B s��I�a*y+� t��gasś&� [UQ�:P�l  shapQ Z2)` �i�2(�=�[u`:�!v��=eNow,r.;�cTL� �Yt�I}x�p� �$�pY�Ahbr�d.G "{ F�'!�ew)4mo�k��^k��Yer�p�tE�?chA!'ɰ)'%��2��t @)Y6  ce0��"fDattenu bM� C [6 , 3�aBE�hur "ti�x*� �2�Dicacy� endsIi&9�b{Q,�L�"t. ��!�]e�>��AB��j. .�Kly5a#zlq�EvNI��exhibZ�$eu�c 6�=3�b[!=, would�; 6r�*�iL�_6$ �&sy�epEN- . De�k"Rdecad� f HI�-vbasicZ^s�[lDQ�cj4 hoUdel\, nama�A�opt�-alyN�&[,"�aa.�E�sh%7b��q#a��JC 4Z9�xF'i~yA}Izt�u�.�a/ aoo�xa�i-on0-n\� �hess�v( LTNP �K� �f �&pMT�&Xi$� I� .)�on Uh�h<%'�I*6*.=��=�=� �� F 9inEYGag [39�b]��Gm�y�� s [4�JH"�Cun3�&aQ_ro= �R;k!��bA5��ve HLA셰� ^f��*�:B�ir-^Uic.�"�!a�A1�(-iM���N)�+�i�J46�X2�.J}6�f�[42k�E22`6  exer^"re &�g� -�&� stuVP��A�"b/�AQ�ce�I_a�Y/QlH>�o, rmasr<tV!Tk>jsf��[43@A� �a{*h -:���Qa>a��6to  ��AwajT��)%1�t�-N{ �*��9u2����.��)~�![0�B�Zna �"�d�20F� , .��#c��expla���Egf_C2}.'"�)Wab^���1S�b�v�5r A�FSasZ0����>�a"�N��/�.�>�,��xlQ.��=.je���2��*� �;�+J����Q�2yLmp/ �Q�rA��� � a�_)�Z����1rec !d uponY��t�un�o��N�z~Y�J�Dn��.�,.v they�Ab�H�!m�'�&Fv:� StilHym�r�~@ ���-ph�JZb%.D�.�߱�B~ ���[44�Wp7�Wn�"Ih� �J] �J�!NE?�xayI�oa 26*�0H�0r�0� M1���)�, illug2�_Ei � 3>�Y�e�*fiK*�M�.g�Pee ND-�cross-re|e� �4�[45!�!w R�r��z" �sA�rarely���@dul�@� q [4�H���9.iwe.�,two� J� �.�nt��$3���sj"E�#�tW�Rss�QRq^6of�65%{�p K !nt+lij7 $i�-@ � !�i1I-6\&C2�e� p�z�z� �Qver�e�/u�a� ��be"�'�tAh&X  t[i��(l� Dchronic �p  �!$��Kt��� ve"� ��pQ�RM+d.�!HIV-1b�I�e", =ʹ��SJ� i���[47–4�_H�)"�)��ST6��o*s ..$��J�exi�6V�E�a"��], rqnovelY���)�d)�F">;wx,� E�>E R�n��iE�ar&��g#{!M�.�C"�N� 2�&|yco&��M*5��5�+J����&�*& �}�D(of wild-typ�H�ua>�b�s"�ŗwf�ng�نbJ��BJ-�:2\� appl��=y;e*r^is~�S:� ��&�*� -X��$}Graiob�15O�>�*R*=��J!*E�N�IFk�jee%�t!"" � J-�>� �!&� CMV �!�&�![�!Ay� [51]� elicit po� V��fparj?-O k{m�r+Y�E�an!horQ8�Ffor���^8c5q.*_IO !#��2�D!n%DwrE�s2b.�5ra��!��t*l� �Mn�4u�ey0�� &�e�*�$�Cim fashaoY�.K$�Xda�/tMNb��re~- FA�-�#-�%��Qq>q���-��}z�u# F�I�s�4 ��}{J�.�D4ly .�Mucosao� (Candida alb�eA �8k�WR�mefungad�seaAAKs0��on�confeM�?p%� ity;��?;�%SE)��� d0R- %/�)rst�\. UI6�+s�de #(oropharynge3�ia>g ( OP]4weAw)� � rleukin-1 �o( IL-1�hA�a�Ztrit�eA* ����m"c9y�"v$mp)on neut�ill ��#� Wa�mo.U �w/!�recrui� �$ir�^) .T�M'�i~!3bi"9��I ewly ed2M\#}bdmarrow�g�on-/��& &%F-#�c_�Gi9�f!�chemo� �� -RV�deE�vD;cr"�granul�colony-sOtJ fa�' ( G-CSF ���5EA��"�!EC .y'� rikR�� thelA�� G ���C�%�`sɓof �4A�� �f5to%IαI � ref/p�3ke�)n�0 �)��i�`��!��x!�nt&tal&fFu&)��/�A,nonhematopoi�=k I���i n���|a+m!bngue-�s.�}G� B* J>| )��se�/uew"�! a M3Ɂ'ca��m�)PA"'w".{F�! lK�4b�*m� i�%F�-�&�ZUG m��U>�V$�Z�L�7growth�dissex �,t�u]I�h��EDd�� . C "b&++1 path�EF?� emer@}2�7�<�caMorb�!xm���world�h �lt�clJc � o!S romiA��vu�s [0$O<U?qAE��manifA ! �*)XJ.��by far�abund�[`n!&symptom�ach)Hmil�b �Y5�(�o�~� ���No licen�-�2� 3�":���a@�1�oxw �U�<���'f7> drugA�m-^E�&�*��Xat���WA*��-�A�p"X�2F�D,6Y5(A�u!Q� ��6� ocio-eco��c�xlYC�b��uma��.\)np�6�@J'c�6Ca�!}�1� \ st [$I�v136�phy�mbaǏ�%m�OEnva�'M&dOi{w capan�zAe(�% �. B� �inflam��ry��X�dR5� efW&3R�-,�� � t����, �s �"(5�G ̓��a�� ��y7*~�8!��k�AY �(sK)��.�D� mutu%e��S � )��1�.��F.� m'6ua�-6#95^26B� s�al�B� � atAa�o�+9=�9A�(le cyto; � as)b�L~�C=,!�� :��nh�%� Q�R1%;� & !hv[-5;'N���o���e��.�n� �*�i�y 1��MA�q�iq|^ �!sinU wO) I�6?-�.' |vi Gal orga���F ���� V#�� n/7!J�a� v%�� &2 E_��� f� &%lso e��nM!��� ͒d� -oncolog� ��e�. ahia [8 , �. ���tQjorA�����*�  2�^ali�� !Nly)��i!�pmA��.zi�/s�c�[1; C*?ol.� e"[I-�~edM !�nvolvlbng-di�jc�0���feedback�bp!z�/b� G+2�ᕅ�chA�usu�5m�Ft��EH+:�!!.�. I5/ab�&"� :|1��x2kin�plǗa {�r���3i!o�1o&�Bi� harm;6y � ys�!{.�,>#!�!��2�%6nڄt�P� ���h��n�.�!� 8Ug�/Jtwh�mc���i���,��m,� 2!�tBg-NWby"� U@���~��y�Om2} oolA� site5�. @� ��es�*�`"�um��D.\)O�et.��<e��B� :�.�R�A�α _6��0�FC>�I os:9\�pY�l�and$um�2B I��e�F�via :.�rou@a��E+2� �g,-""hF:6j$�D.�G1A�J1�U)� �Q9V/'6� prox9�yT� 2�hypha��vadaJe2�"�o/dor�!f, p!!ctW�sF"EMEf&}Q&*�"y2����indMK�!�pAg7"!��}aVF@ -�}ea�A�M�A\�.�:�28����ECla �N�� � aB-M�(��HFt�W w�}+ ( WT�o~�rI�O#vIX�&yEIl1r1-/- ��Nun�0�O���u�!��E>�"� "�t!35M on�35 �y�\M�� se;ec} �4�u !�.BA|%�s9;1�e.Bhm�u"�F�N.zF �.e�+`Mpa��e�Z�u�^��XI�--�Aq�O?CXCL1� XCL2%g �KtCs�!��Z� @�LX0jQdm����*/S+_H um%[" � &�8h.�)�2B 6>�Wba� leve�2aYp"z)!�.$N� � 2 �B����m�r!�F9�{`Q�f naïvJ.�M�1�M�1>�� eh��.>� a !�CD45+.M�- 5- EpCAM+ʌ1-2v7 8 %-%+��"p ( S3� a���k9*=�L.��VIl)�!�>�f��a$y�!K�est��-���II:>iCNa��!ri�*, *�M_�$Fi�K�3l�i!�ņR��TDK��.� . -att�ng9FK��a*��"l �T*�N$E!E�Y6to���*nit�&�/am�)FA��H.��lK"� �.in:xE�i&5�a��c. .� .24�����.�K?sf3 ����d!,Ef%��ee����U�5K.�)�3^QF&*it%[:"mK��&N��by boo5:sa�>eg���.� z� �u����surrog ���)�7:{MZ:ctJ /&~E��+�fe�.8Gj ��Y1#A���ao��%M]�-z�O"�.#fr"�/M�Pe Ly6Ghi?Z1b+C�S9Ca�+S3�3q��8XE#��l����5lel�+e- i��+fl�~�r��ro!�)%9 �!�RPJ�&  U�)�SQ��9M�vB�,/!at `�c�E^�D*#&D��#I�% ��� a� �"JA)��off�m/i��MF%-3G>�i)�n| wM��%+�"A�enso � 9�d R*�:+!�mo>�&& "n.z &/ %- ophiv�!�'v�!���)�*�5��2>�Q� I.&b6� he2|��E*�Y nti-a&�(/( 1A8 )�� suffn'��lunzV /.�"� �>st����C�UOx�%�Ib)&*"�6��e�!b��!�mnIt��i�QzH$ 3I )!nsNng3a ��3 ��>JE�NY� ��� ]@ by ~1 log>uɸa ~4- QO� yX8���m oursE�3� � ���c~�75r�i.L %/: *�i�cl!��# ~2��!� �wo$��0 Q� *��%+ � Iq���w���to�����xiN�%is6�!mjHdej� Wi�we "��V �+�o%� V� G 'f� �k� AJ.U:� A�unU�M�B��j^H i &1 � o3ach.� . Surpri�%�+!�:� *� a�"�3m�"�� ._I4� ��46\d&]:o"�I4:� .77*[.Xg%0� A� vo� mino�j �.�[=� �Q4�low1Q" ��2�m|or�M. unexVoU=a�, aX d ��!�!� $6r+"5. B�va0\,&vi�|iH`y �)[�(�5metry �"��/���%E�sort-pu�AM�'& *ʦ)� s!��by`�AA#% K�H)A��*85sA��C�e0B�" u��uSm� -�� "^@ ��A;�XeN��A` podo'�in-"�ga�&r�#-&�, ��>�s�9=tD'J$%�Z"0)n=@2�S4e�P2D 7L n�m��$<!y����!�B&�Kb�0n9�ser�mR��VT&G-t&V^:� ��, "� i-�%� n!�= 2Sg n1*f A+ eNd &6o �(.^ A!�� su:��"�K��me��!sL"J I�s /s.�.��!zv�Sj Y)3=! R�� �ip�$��S)recI6)yI) B7by6`�9�K"�5� b�)� K��(I�2���t�&N ��pronou&)J��2�M�i��l�>|u"�2{L��, � QronadFy�7EG�)Y�w �dra�1�di!�e]�]!�.B խ�X %+�e;M�$R)v�-:�.l& 6J�>toBN*�57I<g�, TNF)vch2kl,&�@��� �=X< tro '��?�(� �]�]T ( S5�i7��9&ba� AR!cZ6�,f|aX5e"�)ase�,Ru�erhi���to���ٔq �.�.p6�z�E�P5b7.:�b6H� �6)/t��mI � �adE�t�6�gܱ� 8%42��;�c,&h��!?z�1[m �5��V�*�?"e� ���=��M���a�"G. @]��c6lika#U�'E��+mi#2�9�*�b�.��� h s�8��>f*#�&�1&*�< ),�����..*�2��}���L-�"�� ��s$�0�( ligan^K�1RY �j�D< yo�(6 I�{l2�'%��� �VR.n�h " �i�2 �E+��(ipN!t�g��KF;α�6���B^6�� A� �ȓeC��� 0�*�i�8s��>�i6os6� pro- � ( S6�df�I�!F8��!2b:��ea?l�;� .q�roM���E�n�U"�e2 �c2(Don�s�x��.7aal1K���&b �l�D"6� M����8�6�"a&�%qM��DCo-� � ��bo�[2�P �66�(-�o"I)n�^��um� e)1�s[���8\��%-�Aop2eiD����6� ��6� ]�-d��� -�N+a��w�o3 � � DAPI&�re M9m�&9WI {( �n� )�_�} t��!�t!,�6��U�Q��.b8#l7Kl���Es*� ,:�7Ad%�egrSo��N6O�>Wl��ac�D�bR7K/*�� Ml�<u!G:= .d" %��Ok6n ‘alaR�’ r�0�A%~& yayo a­� �b5 ~ invae~�C��#gK5�"t�+5WN�Fh ,r��.�!0o¶>i{*+Co.�6!DY�|��w>��inK2pgEveJ�?.o�{FH �*H^ .za�Gl.B��"�!mo���5�6x(�! ( S7E�)��!�[�F�f�#%+ L-6�-�&A`�4[.��: Q ?���ze�irA�N=�AB�Wed n����� :�%ir orig�Kf��:i�T#�%.� �g.B?#pubي�K; � ��B+�����zH%F dqJ/�R�/�-7�&�}A�i*^ to/:��ͪ!�6��n"&/ lB)�IuU!^��:lA��'er�M8 �-ki2 �� y�� -loc�.f"�}g � P��b7�*����T,Mdzymosa� p)�w����idS�%p� β-glu��xL-)�>P%�+���at�Aa�o�� P��!�sk�le-fi��D-��na�La &7G-A%�I.�{Jos�P�F .� A6oP"; �U� j%ol!�6.U.��ute�1.b:(m��nJ �2(o� gwAF�, on<�MasU��-(U&��8D–8O�m�sH"��%:�f���(��m��J$>?2�Av"��YB ( S8�V�ڡ�&�"�a2G"3Y.�!�Db>�&Pgf�R�$ �v! j �X�i�* �anakinra"0 antagonis��g� W%��/ �t; �F�=|-6fK�ssaA�v�"� aEle�pbo m�l �-mGA�" le� ��� $��no�{nmչFby2�)'�" jJ a/0 %�%Q�E�;�#b3�6' �=�=e�necess+6a�Q *�� �7�G�K u�iNx jca�Y���large��q WiMR re%n"  �8�# sum2�B%�O!�(-v�a 0_ �-& �cta*�K*��&F� %��5<79�"Z>�.Jclu� ,yq6� 6����um ��0� �}�2!�} ��B�82O�F��%��(� !�u\eM*#u� �=�B�a9o�] �aBpr==O�vXC)�W(EcI9Ja�d*2I>a�J�{nG�pl�aH=C�I(s ; 7��s9�Nd2��I��!���=��u%/�EGm���&�.1owT.��;I�1)��d%st 2+ww�#y: $�� �PC!�d2�L��ec8L!,:p&oQ�}�4D�2j:�6k�,2�&:QW !FB�9v�[n �99�;J�o>I !he2Z.�9�8oC:�"� ).B���N�k�)�aM*F D&C*&:JVZ,:��%6{ŢCra�vK Eb%b\o6<d� �,� Bf6�1a�>."�OQ ��*��=���!L-`c�O����F�>�FA�Y��x%u� :0 Q1E�u�R�finr J:�*��"�!!H"�0A�V(;�2�Bs�$n�=Ea�u� �l.#[�iAF9�=m.�� `�_($��W� :1&y:Qvitself�� J Aa�8��$ MQq�"B�C��(;� �F*P.���7�uncܓR!�N)<"�b ?Y�X�CQ!�2ٶ�d.� #� �, fCr.�-��ztaxAYnd�m�%K%�I"L.>t*�CM�. E2K��f�F6/-�.��surF��<QA0Cc]Xa::v"8�r�8��y�:J:z!. Mt��� >M U`�oM�񒁚a3#��!�.�6��m "  ha�,Qv;Q�DY�C�"�Lmix��:�V63�o�)fum~&us�tis [359Dxve pulmo��asperg��LJ[I]�*�1�Rd^,��{Ra���ot �5W �,�f�tpv.�kwe\&m.�!�qb����2�YfB~2�Y6(!1.2::( � a��3��iD�Qa&� . Ke��} M�tagq �սX)�9K2�mseqv!%�y � m�M �6DZO=. C� �}%byM%�!�޺z�8!�h3�E-ar ��autocr{:�� -�α�"]i!P&!aY�CV� R�� d ex�ǁ�4X Staphyloc�u(s aureus sk"�7!�7`. A\ ond�2-�6b !�9��Q��"9 �Mpz  �;� u�k�5m�""�,��)o3��!1a�Pr6�!�F�� ]2�n�"{D�)Wi}R�E%�yNNF�lulESw7c�a*  �,!Jg�-:-!T�� 1�e$�)rEmR=x*-���F�=�.vB'αR��X# +)!�OA2�5� �v��d&� � 1UJ1>Ef�%�/ u-��y) /%u�^��sa�و.B�th�e notion that murine keratinocytes are unable to produce IL-1β [28] , we found this cytokine to be expressed by the hematopoietic compartment . Xinduc�$in responsP�C . albicans was shown previously�depend �Le NLRP3 inflammasomeU differente l`models [21 , 34 , 45] and DprequiredDtr�4[29] . In addi�to4J�,C4��t also �,to contribut% prot �from OPCz8Whether its fun �atjlevel of \mucosal stroma is linkedn�!� pathway%wZ-involv)+α�=�6Q�not!resA. We QA �overallQUresulted ��release� preformed�Hintracellularly sto!� �Mone h!�,4%DVY� of da(,vo synthesis>%a@. The.� hR6correlaa^ withFp�` damage [46] , suggestingi� ^�may be aAsequenc% J eath �ed byAgal!�asa�,. It remains!�0be determined5� ssecreE�by oral:�n�inqli�%I(caspase-1 a.�t�>!�c!�for b!�(marrow-deriAu MNPsy�iaAw!V$GM-CSF [20a�!� t1B�on lifeIilamen%pfungusA�consist�6c�implica%8of candidalysin! �processE$ie�!peptida�8xin has recentl!�en id�fiA�s!�0ritical virul�factor`mo�$epithelial-�IEA��Q/�Xytoplasmic molecules , �!of whichEXact!�alaAs [47!RImporta�L, our data demonstra�� he biolog�~vaM�.5� �s.�2�AU2���%��>Yvin vivom�(they dissec�0mechanism howE! coordine�z$neutrophil��ɘaga9 CQ-�Sei1�0um . All mous�Y%V�.m"�.8s ( TDK �6`WTe �9��%kaHto .i�al�dor�paQ 8a�a�K Zmusa�ti� ��calpe ]flo�4n DMEM ( PAA ).��}8% tryp(�rmo Fisc�)i~yyg�3�#fac�^upw� Aft� ncub�BA8�$epa��E�al�Ha* pria� 6�%�iso�ݥ nng�F��co���, 2�� �3�A? occa�^�ortexafil���^k)���� elle�e,����7in2��( S1 T�, adap:%% [54]�_cultiv%�inlure��s cI %��@��, ( Bornstein�0Traub Type IV%igma Ald��!(5p l ��� blood end &�� MS1 [3� as"� .�Fq5�qPen�(/Streptomyc�P�� ulI\&K\ TDK��=yres%= or 4� !� thenN��re&� �( P�tec% 0 ng���e"�n"anakinra�&5��<zymosa!�22curdl 2LPS_�or � "b $at MOI = 3e�*�AmphoA�!MB��adA12 .[2� exKi . SupernaaM�AZ� !e�f�}In�� !�!���a� e�&� by�aU��(1% Triton-XR inŠ�s�.ell�� tot�t moun�X%��O 3A N ,6wA�))to ��uewv at a+ �on(�o� ��.htransfer!["h,A�-T1���or9�a.�,.T 9� ebk -���nd�y&� 1:3 > t�Ux by2!" %h�ELISA a��Ux> QF�= �F�-�`ALF-16*�.Kan� �Rn��zRz,�|or 7AADI D Ph~�-Ev� EpCA� i�G8�%T CD315� MEC13 . 3%ZVB6pod7nm [Z 1 . ���inclu����2� � Z� �+%r firs�q I�~�A,surface@k� � A�.2 fix�/(permeabiliz  (BD Cytofix/&)�Bi.�G �� � Perm/Wash&[ B�*5 � -pro>ANJTEN!�f^� tive� tK Fro� �. C�0%Hac�!4on a FACS LSRINB�or&Gallio� Becton Cow �A}d� d�� ,FlowJo softw;#(��oEY�0>�� <Ppre-gn o�vL"�~E� �m�!�2 sets�F�so�,n|fc F�poo,�s2above-aB5^ AriaV_I\��ol� �E . Im �S RNAɐ bulk�orz�pop�  carr6�)))� r� � Trizol Re� t � )j LSN. cDNA �2o R tAidA hS��t���QuataE�PCRD��" �SYBR Gr�(\�͈ Rotor-Gene 3000 ( Corbett Research �a j0Studio 7 Flex��:�Wp�rMlActb fwd 5'-CCCTGAAGTACCCCAT C-3' , 'rev'pTTTTCACGGTTGGCCTTAG-3'; Cxcl1MGCTTTCTGT" , # IGCA$i GCGA.G2GAG�TGKGTCAATG �o2LAA�TGACCG��5N GAAtGGL�N5NGGAkG��T Nsf3M�AGTGGAGC �'�G%"� AACA ;�aDiAGA%$ AG%L , &C 5'-T=G!"T!muiK5�(TACAGGCTCCGRG4)��K#C*TM!SK�J ll qA�assayMY�in du� "�g��Lvee�  a�(" . .A�f each )aM* � normaմwβ-actu!� cript l�&�0�prw#�ly&� �Ω F[0, Brefeldin A&j /�)�"ti�6�� 9 a"|' m�.2c��' d�)�%^�2�! h�>h G��ingo{d-�wa�%`���400’�fA�%��� ( 6$� naïve.& , 25 E!LEC� ��ly�in�μl� Z����cOm��ot(�o�cktail�7us�f��J"��}!��hHn��n�im��ately��>� O�$2&ehu�pQ�or��6��"�'by sandw�# ~ �purif�"�x- ��NQ ��%8nd�% tinypolyclo�rabbit6X&� Ha��~�A 0� of^�rm�1/R,| I(ic bead arr�*��(F E���2�!�manufac!�r’s i�&�,�y�� �l�s  &c!� dotF l"m� embeBin OCT�akurag snap-froz-(, quid n�! �*at -2f)S�fluoresco �, sagit~ cryos � 9 μmz%fix� aceta91*�4t room tempera!) �| �\E�%��U�Jv +K6!�*�A19057$14Z%N ��4′ , 6’-Diamidino-2-phenylindole dihydrochlor�( DAPI�-�� Slid1�1Mowio�}VWR I�%I�al AG� scan�) NanoZoom+' . 0 H!�XHamamatsu Photonics K .)m�10x�20x ob�"iv񕖉NDP .{M! . 8�Allle ba�) $��mM@wh!� fo�*(microscopy uM�longiv na�!� �2R resh� �� plac^ 35mm.` dish0IBIDI�z��. ZA� ck t!!\ �" ,an SP8J�e eicac�/pp1�a%YAPO9]37A#A�cO�'largea�a�&�1>�$3D maximum�%�o�&�ic).U�o�&7g"� �IMARI�Bitpl)E�e sF,�"� E*B9& ent��t-t])YWelch�.��,�!-0ANOVA *Du�',or Tukey mQp omparis�'a�two>J�;Ia�*�teM�GraphPad�sm&��* , p <e05; *212 *500��%�pl��logarithb-A�+geф�"i�6iddc J�b log-�  C �1�e��`Betw"20� �2007a�he Glob,grammv. E���,$ Lymphatic ' ariaR$( GPELF ) W,ve�moq+an� 9 bi(nHm�,to neq1600 mi !��xviduals via annual mass drug ad�+/&� ( MDA ���/|$rug��albendaz��, �mA��'0diethylcarbam�")"tozat-riskŪ4–6 ye��.ifya�!2j2econo!�benefa'e�is}Dt achiev�!%�/<on�4jusdaour�"inv>� )xbut� to)xfu�>u�-�,FPr-�'s"53impactA��/�po��t ende�&� �o calcII�F���-B linn-manifeE���~(�6as�q�fi�savingsEoc% di��.dis� �51AbheH[ �%� xsdir�/+A� cos�Az  of l�)l,-mr �health sM+c� �af�2�dU�. M��e�1�e��6ewe�AOp�(\ lite* @ba<�!&World H �Organ�,:MMonet�/F�,��6oLabour6F An ep US$2��8u��4)=Fwill be �0�F$�lifetim�(3O4R%�ed�:��'r�4i . O�6i(� ,E�����iE30V[ ɧof��� �� newb� %1j c 9�%��o!�l�)���)� �/ctheir be0[o b#of LF�mis. Simi�6,i�t�g28R>alread�'M���LF�� �%<'s hal��-g}���qp,�3����) asu�5�>L�~xiAMly!�19�+5�N 9 3B_!/��a��8, decr�?&t�&s�0FH redu> LF!Nb�+sa !2�Em�c�r5B�Al2�MDA�LF3er6F�. Moree*favorxp�ȡ�)(���(N ly :i�(tM commi���do��d�]sI�pH aceu T/s[() iŷclearA{�4�rS of returu NEaauextrem��3eLS<��գ�� inuea���tselfAg/llU��� in g�-�. A@lea�McaL5of��3�ndr -A�� ty w�Mw� ��parasi�^.�gR�(!�)!�o��a�- phys�sa$o50b�-o) 3U5Q� pers�,in 83J|.6�1�+��peo= ��bM_��t b'��&A5��A�t �ȑ���s�.ful�s�"��duF %2 edema ( g� �an1umQ!Y�x�=l��� limb!EpelZ %acE 2scr�sac� To ri %�mEzde�aKng�)�� � begu��m ��g�7J��mm��s�-d�-9 ce-� ly� ��;�21Ye�9r. +* 94&- +J ( DEC �!�nticip6$ Us��%\e �� egy� eX !��:b�&e feasibZeu��E� ��> of.�E�E��b:�.�� (GlaxoSmithKZA_,Merck & Co .B c ()p!v��. O��%kal- �8��t/&n �mZ% �/����d� ^ ����D570R� in 4�u�/[/ &�t�^� � .� !����  a� ab�� cv+&B !��{�J< [1<�ڡ�n 6�c� of}�!�& !��Ehave b�� ? �a?in �� 32hdi��-adc ed�-��LY�c� �numerous� lity-of-�C s at�[ . Wh�"?�?I/� �0�how��s%7� 9�cm@�=�� Sp�8�>�3w�Ah�'n%� �los��inc�Bs=+%!��� *&�  e�-LF��6Q���:��? A&w! �� do "�M,? "� u�� a�!�LF�{!�&k5?��dv, few!� empt� Q <ex�-eN�an9{�hm���8��n�]A v*chv.2�invalu� tosicymak� ,� c�q��;���� fA2T ho m~� b vin� ; !�$‘best bu>!6 �-j'N lackAciT � i or� invi)�. �7l>o[=s s!.B"b�XAfollowa�A'j<, R]u"�{�6Vby%� �nonu9��Y�in�b-�b�* a�n ")to��'"3n1JQ�Q�. Fur�C��7o�3���  4ss�ҥZ�D�@Ehe A7q� manBE cill���+i! cur6�F�M=+re�tN�&��-a�MregZ@�t�+ll2 E a fa� tter��N!�.�'s tr��E��of� $ety's most6l !�j sp� trop) b s . K}A2B2�l_Cd�45ra��2+ci�th1�#!npaper:�%�U�,X broad�:up��.^recogE9asU���-�Ń�foMDA�� give� *f : Th :�&iI�B (%M subs�Et1D [1�,6e{7�U�1; s�r b!mu.GH�-��"-�-��two1Bcan b�gae�to�Gr�-.a( a`9b�6A"summar�8 in T�^F); tog�HAeyastitu�“-� coh��l”�9"&��� each:��"�dg !�sam se figurhnd keya�ump!�|*g<��J[1]; na�010%a:Z" ���ct�<5��! �is�io wouldP"b<�F,1!I_bs�ofE��!���-HBB syndrom��F�" �� amo�"A��.ZE:5AH!7 d: a 4-�qcF�a���Ap�y7.h��ru�Z%�.Ba�9$vbJ= ��1�� � � � exte�<�: a� ]E erio�a�EX�+� ��m �N>(u�A?� l�u��_�9nj;s��p ggreo*!>�qd>�pro�eQ~�;o !�!��?�Jy vxbI�Ff�& ectaC�t? a�c 0�'A�r�-  �D� ,-/ "dis�C3N� !_200�v��� j88%$uE%a8��� %|!�U�|� en2%fu�!#.�22O��one�aes� ( NPV� �E/�princ��#- earg@(Ois�th9 ALan�6- �e�m, n�"c'� beyond)p�^ t 30=)\e &�Ito x��t� $WHO-CHOICE�B.W  zs�S&N�1��x.  (st--�& to e!�] a� effi�,c� -�cI�of���A50B;. Ep "6�20s Cin&>'H� a  a���9�) �>� tL�n&Xwork �:. O�macro-� , n ._K y!�ncongK! �AS�!�!���� 6� �.��y ���RF�$o� .��O�osD.X>�2X�l( -JH"on5A�B�� lti-��r�?!6Fa��al�A � B�{Ů3Atr"Y& mapp�7�w2,aY tribUDE +!Osurve5 A-�I2�, Goldm�6'T,bodQ�a�#i��s!0!! Z (�+{G� �!����8G dl�� M� s – s�t US$�619+ 0019%/shi)!�400mg �eEo*�% US$U50E88326iv�3-)7� � fina*OsMF�ex5�K,Q�n�)�e��1}�qua]onnaiP "�I=-����vit�D-f�is���)*w&�.A��co-�t onchocerc�"�-fr&plus Y�! .%"��e,�w��llria�A�mus�&�Nby&amo3aer�=�U٭�!�f F!�A�d���1�l�����E3�" Q&"�QI%�MDA IatN [�*t^e�G,v�Q!H#��!��7=Cw� -'m�=e����>4'sM . C.;��"meatP#-a-�  36CR CS =�1 >>VJ*`)4� �P�=pur��, |ref\5s7!� i A`bcEo/h %�m��r�T%�roZ"inj6 Dj�LFG �BD&d&>&&i%0b�Xr�� l�v$ �83.OUq�yw(~�;. br Ask am6�,n�"���6L� qN�;�{ J�{"y )��� � 5�$  5(R�0r� 2}.�9�4!�AZ��t����Pa�)�a�� �!�!tY�!�q"E�ha�[^�  :B�2� wsubF�tage ( �$45< , [29%J�avoidF�]vA�Jubr-%&�&[6!V6qs �T:imp�W*�!?��s� "R5�s[W�[}ng���UgE�Dw$.Ve��Ced�rao!Yryj�:" ��F :�"F(�gaqD����� a�j�!��or7��B�%7�A� fram ���E�'b%�!W�Z�( � 4b� A#%�� wag�0$2* %�e8NB�!I!�s*L��s�as*�nd"� <�out� �AD ��#r ac�q�e�*� �R�a"`&' ADL�Kso23�E���:��H�gaAr�:+ epJ� hroni�-� ��5^�OWperKGZjW$�pf(�ek%�u��0 2�4PU3 . In2�!L�)Q�c:��.]y�ru�quiva6'�d�;EJto��So1�.� �:�dailyE�a�ll2�y 1,)`8 �"�S��`Q"�untry&� 5�w� �a'� �=�'' %�n�,I�a?vX0�!�3Fy�I��d $70ULF-*�*I12�cruA� $ his/�N"} .�eqV���$�!�19%�!�%�A��  ui��.ngH�!6$6�,Qa%r�"� 6'� sum)�M�ieve�*�ZrC3 nsid�$-�& -to%��!��%,"c &+-�L >q *Jby2J.�y6� VW���":m���*h��&���An.�)�!�g%st��5�MJs2�ir�)_* II� 7J��9�l-�2�.� ( Group 2�6�‘ &X y s’31�k �)��6o?\3 �+light!l�B�s"�e�st�]-d5q�*"1!�)4al>�!�UA���*�-Ii;+���+t"�#/U.m�!b���h.c�o! Appr&y'�r&" U�Sf���q�8e�C�e" 3e� &�1��N=�:b���#�[�d7<Qx.� !`W0"A#"�=# �%�UC"�.� ' 4�doe�%no,�+%�u�ej�$�. gion�1�D� y ncer� �cepidem&�daD6�-fMe$�*şLF�e�'� "= �9j" 4�I� u�I(ty:�N deg`to%MDA� �]s9dj/2� ]!]J�- to regula�� duct<ym�2 )z�onu"�p]8!output/� F-�� .R��Y65�(� .x'senv/v1�s%%rid�-Z��*�^�m�i(ceiS6%Lơ��ء".�c&V ���>�CaY� '6 $\ "? ,�= I�e .�Hess�g� rang�5&���S#� e� u"var� 1e� � � . SSda1b2�U1iga�X�f�l�a!/du�,!{2� ��� &� )!)�Ed l� �iP+H�6:9wav��Ok��am�B� >�le��a��������E4�+D�_Phili;r $�?2��Tanzani�a�o��=:��J�06�,Burkina Fasoa�3�n Haiti�On1JH*D E���M:�D� J��5�a Domi�: n Re&� 10�$pa�I�>�}�w� Q$ag6|s�o>�"����*L BCRa2!�da� ~th�j�� u40"&Q+.-E*�lowb�21– 3rCtt!��6_DEC2T(8>23–F59�S�,�4.�Gavail� �nq� 2E,�2� �>nNm�1&y7,E+����A)6E� Egyp  1�07�!/.v. I"�(0� %�5�� 2�� ow ,**lA3c�e#��.IX�C�Rz ��)E�Hong<7�WF_85!��K<.>w3� .VaMF�3.)Y�as8'neeyuntil� � g4ed [72rk[73�2B.`4i9 , g> n� dono�/�(n�'�**E�sa}�(themselves;�� a��,)nL reEbeA�)j9 r�',���A�!� {�3a��@NL���]"�(isirelev i!�po�0-%�dG0ion-m]Xgi�M �sf>�A&�CngB��"B �e�!s10� very}�eX,�lu%*upPn� u#26�o�X)g�h� �*� r%��s&!Nr�6mOd 5!a � � B&��6�m[ ��>���"Xhtrg+egq. E�= O� initA?�a��"� �a�aF[>�)e� ]+majorM h;�$ *�!%arg 3y�C dr�HI&�<s ����.FA~!��:,\n�Slygp�a!�>.�'a��'U[�'  5%to9�} �a�� a�r1 $1 7 �0.B1sizŐ&=$60� ��A��H�u>��%9(8^!�s:�5thI[!MD{P� �OP_2!%| V�/�"on�7�#O. )�st��iy&�6E,nd��3i�=Fs!��)o! sist�B&�D�a&�3ala� to 16�5�5�}>N� �!�6" $20–$30s��y9��C��AW!"�'����?a��wNTDa�d9vQz��#�:�J�6@ lA E>I �K2"E|�5�(. Aiew�#&]?!VO6�$ConY( APO�;&�-!���:`of�!�7%�dWNot" �T�G!>=!J%�J[74�fa!ng�M2@ �/ug-�� O5����+ed *2��-�m��t�j�s"�%al *ndn���r�%�ID2%C�Em. $+!�!�trachI{Ifoc&�"�sil<�F�du& surg��wlRM3�F[75!DA"K*a�P�G.��9�#"�.��malm�lt�6�E��M nd � goa'^�]ha�A8 � E��9sul!q N�Ge�%�, �(ald&bp1�q�3}1ih6a�,J ��AB�ɳ��.� � 9�17�] a�et�h!v capiSF�Af�methodo�xes [76!�Oaۉkac�N��aY q,U� of�[77� 8]I'�,�z�0to�d�jt�.D/a�Yih5�! u%;c� s"�"7z!� vali� �  ves��2�! �Ang likemc13G�USed��2� ]�a��p�[�$a��B�;4s$ub-Saharan��'toj!eg�ngu�ve chem��apE$am� arge"�e�X �JLF�A.*,, schistosomi�{il�Mmi�S4helminths [STH!Օ)&�6�1mnA<�^ nEverdictE�&\%M �#�ed�V!5s9su���\eT�>r ��ɛ�[I� 8��� po�/) Vof �W �47%%���re\!NTDk�7� !� J�by packa�(��r�A>t�7[7-���#� lie��&PM�fp�jub��i� �-:9& ��Lt� (5�18lSIIYed�� � rA&)}#��I;�G���r�;y� he�&+C�$T�Ho-?A�a sJ�u�!�n>{a��)�&�#�bEI� RI� M8Ua � W3s&po�o� ake ad1a�synerg�P opeuy �e��K-J.: &X/vga=�.denuf� � 2� (m3neaY5Y��i� ��d]Pd0(E�yVA9Vi^s wPsOaxu|6�/PU|��[8i�Joint"l%%!xprCm;�ECb�=d�\op!�!!W7s�>�(A�%d�Y ~ho��facn!sc[)�,5�d�!]stY�ɡ��I[8�CW&� �dyA 6esz:V^e�;!W&6abundant &cJ�?j%7�a���X ario6�� re`� V ;Jbua�ы#AŅ�&m?�M"L%RB[C ca�…a�NR�[re: ��t����3to[D�a�m�O�/ �b?UJ�59����3f�,&gm�'�er2� �*ez�D�&J5B�a%~o���,�M�%��!/![�am�:!�d�&C<*�$� narrow� ���-*�2� someD�`adt'�E��M%ɠ�p"@;*�C%H�WhI#ai�J*�Q orig(U��%�TdJ�.b�Vo0$75�#d� J"re8�Of*c� !V6scarci ���;�)g&-s�&behav�wa�LF&2,� q%C<��� inpu���exact q5�!a��1mar!(l F��(�4��'ll9�M;6�P�BY&&-&par��Z�,�" ')� at�db<ON�hrde "^��*ckAa �e�Ifs;8�V<�3�27Y�!)6��U�-�J� & ��� y���Z8�NN�C�.�)��wV ��.� :�<l � �*,�Ys%U�"����8"�&OGb � �G �~B�GaiF "=$�!u*m�!dILO ,s;!$nd HU Bank�5espite ��'�O8 Lwul�ax� 5�"���G�D&�5Gm��aFva���63:�� 6�t#�&$�r5)��  !-t�b��eB,E�&�EZe��31"�.R�!��2%�@.3)y�ic�<�-.�6�I3�X% o'�!MD&16����qu�J�KnsFea& � co-m�&* Q�STH�t �I|"5�J�un�8SKG` %E��C�Z����se tAꅛ� ,= e�_�0��71���i!�IU55A�A�3Da� Ziq!!;F�D��Cs-� a* ���BOo�NM�R�R_�ed�+^�5F44�E∼a&XS�Qi�:Vp& 2[8�E�&p&F�$r"$!y%0A�4"�&Q�9um�"�2"M )�[*X5�7-)�� b� �T�M US$5&6W"� |,eac�!�1� WHO �B��)V�R0!�0�1'.bM�E�E�ch�es &iUs�28 9l) �Iqd��ci�w-�\Yz&u;. A&p re�?K 5Oemp� 8 qn2�Ds��!2f�eq!�"�U� [9 �expan�)�z� � ����bui,jg�zck�d �3e � �",^dr� in�Xat�eG�=ntinuź��g�+݅n�g�� �F�"� Q��5U�a/�){4%�newnf�,at���,)�Owo�C�tX,.�Homozyg�Qmu�ͫ gluc�=ebrosid�I ( GB�g�nM .GauV~E 'D�!)*:FnMi�\~to%3. R�:[X����)a���congya U�"d`(sporadic Pa�$son’sr( P��g ).Ze- >b�XPD�>Gm)��n/nse��pGBA��) medaka�<��le�j�:�C%>VhC!p)�y�]a&�#�H�{l deai�Zi�mÇ�+an Q;�* � ��Ց� moV, e�j>� y !� &�eM]6Xdisplay��� atK 7henJtB*semg ��x rono0ic GDa�{ infil�QmLQ}�-. A] bCL e��ve aal� a�Fg glio�. DH�\�"""�)yQ�abn$o�i�)�,alpha-synuclsl ( α%�6lYax� �YJ#"�autophagaK� Unex2edl!�dis*h; cI�%��b spal�d��B~,B1��ro2�in:��'ken&n���e�yy�6;�Enovel }]�- Ma9�"G�� �"eHA2e��|iq�c!:AA��(��ep�ofQMYA�܆���<:�. Q���(A�)�gM'��K%���q�N�VI��. M.��]��"d enzyAc�'ofZV��ngul���2m�=�7ub�Zs&6Wb� �4ylsphingosine[�{2> a� s clX\ Cii�f) subtypes:VYn-n2�A� ( " �PY-�7f)�/)�sub*8f/3� Visc@� m6�e\[]M�(c_c�;�Hby hepatosplenomegae�cytopeO, �skele4QR. P�U4N�lipid-la�"�A%�!Red2G!���obU��$�boe� N!f��F�F-����e��tem dys"%�e&tQ�Q�C`�/iz R) myo�pE�� : �\CM� N�� � �%�,6 x�uvas�XB�q���s[)� e�N�{��E�,1�!�`��l��E�,� � '@ �d[�!Commo���!���s&d V^! ` ps fA`�nd�ێAqichthy�ADn�2s:�JDw��D a�.".*E�&o,� ap �in&��%�Zx�!�ng��exiB*9 eluc�&� ��L���!�.(��Œ�a�j` �)E���d�eFve&�disor�L.���r ly draw�n� �&� Lh�1R gen7n2 �N0 D[�@p!"2-�eQOyp�NGDI�� { > `-�? e:tS PD[͚PD!�Rf�rn3��&� �)��ra%;a�>gj[ ��Lewy m�APi��]JAm!�2�mar��&W Di�S{�A�)� d� tmor��s�qh7� 3�$ �kA��#6�N��H&�)*�� �J�Os*� .�Zl[8 , 9 ,4(, 1�1�I5� �C urn A !_a vicig"�E'xA !qtraffic� of�N0*[ ūt�=lft �`rS �"� �u8[� Ca72@�il!pO�fU ex�  �!�)-�6z�&6ePDI�:;F��� [13!I45�A�"�,�;ypo�5�9��p<�, f']:� D�6>"� ��m�#t�D��#&'4 �( Oryzi0ati�&)e(a�!sa�s�!eb&�)N�t�"D%�WshJeas)Vϡlt�L�i�'slZ���4��l( 2–3�q ;9��B.���@-eny�.I��r1vinܛ� ins[1� +e 87Q+van�!� �A ES|PD��gena M[�3nt��r1MA<at�42�j�!<� �G�U/$&Nyin��(�� 0s|!o�ms��c techni|[1�r1�19 �V�So�, wr&y�"ed�y���'I[�M� locM�dY* �- mpan�*9CseeM�9�A dopa��rg� nd�~adr�I��ons[2�2� ��>ngas��7Z1`S,1(%�a5&�%@a����APD . H�$%!�ade�>2- �' %*� a�>5�2g���f= �c GD �U6 t-ye� ���aw?v^�FU��y . W~�-8t62!*8 byZ>.�ŷ)ETo�yU.orj� w�$s*< |�;me"y, ( http://ww-�mb�U org/��_��/Info/P0x�(&�basica~al alig�5 ��to�dM�n C,o �!��+�.P�� 6�o�rP�"-��4G|mer�cha%K9�T-�)Ev d a��f< ��-���]A�}F&� J 11 ex�( enco���'�of 522 �E(id��  se�_-#-��� �43%e�log��e�of=(�Fi8�. N=u�scree!1a *+ ing-p�K�.�/�)�o�B0ILLING ) libr|>� ��&a� -�lut!1me�r~��2EWeQ��laJuW337X-�g�]�AAD>� �b�%� fert&�(% . 1PE7� i!n2 !R!u ��a�.��EeB )���/JC-��RJ "c 6GBAWT.Q +/- "� Q��� !�:�b�850%{aQ*�B ild-c �� +/+ Y5=Bt"6 e��mj�die so�Z%>birth[� 2� 2��6�:j4}<"y ,&+u��1zg2L "�on�D�:s�"d"Q xpa swimm!�"�.I� ee$, S2 MovieM�A���!e�.i�ay t sp�\^Ja�. 1�3. High4E�g�ceO �&0�0��-Ʀ�5�E� �&�'�JxalE.cAt i�'Z8B�, .W&H�G>�e#(C18 fatty a��8!$�d�?�E~6�J�S2%)| `4���B} >�"� [2We*� 2EE^DB��M�G� P�c (cid-Schiff-V+ve6��"pzv��s�)-�l1, �E;�~q� ��Ue8z�v�X�!� ljkidne��S!�-��6�S3-�.�{�s[^�l�TuB �%ae vacuo�&�"�/Sm%r�+arݞy z?op� Uu�iq2AU@�T(!V� ron��r�Q&*�� m5��had>�+_]z� strud��!�%� 2z^.� i � 2A�63B nd my%GD[26a p 2��@�s )y)�Luxol fblu��&��<d@" gle-�n7$9 ( ss) y-�!C2��:�2����;� myel�-q�O�B�s4In situ hybrid\[�2$ipo�= in EL9�4aIg��� +>eleUfish[304U"pro�?ng����aaAj�. T^ � fibr#ar�O�rX�� GFAP![*R� al ��Fl�: coe��u=au��) n��P6�ser؈=:�s���.ͅF2]"& X *�A_4!�@esIA�"��.��j 2F���2��"w!�&' TH���B�`G `��V,:�exr�#)u2�"�@�� ��J.�!x&s&� �`. T�*ich- &�7 dof 127*��6�L.�:�I��+Y �� 8/3i�.T�epi��& s 9v{104o 4A��6 �����"�" , γ- =nd6b!�.� �51I<r�2 X s do ��"�s����aE�� m5( S4B�&�g"� 2de���P�TALEN!�D&!�1{es�+���C.do8hZi'Ja [ shifS;��C�W";/0te"*\Z��$u, %� @ 5a�:�"�"]+B+�Tő�� O& N� �R�J(mRN�A*� B�-��$Q�intact ( B!�E91�rn/**0�j"Z$a 14-kDa bA�q�T 2;E i1�!] ��F�� auth�;c�2- U�Z�(iq��'*i_�� ~���*� BN�G�J���M�&< P� )ayna �,� �N� �H�Thq w." <6>�>�"UA!� x9�j�B^6S � 3� �2N!�� "D at�b_)� at 1v�5Y�OAM(.� K%0 tolu@�e� 9�� �<toN�>s۷!a�r�&�2 ۦ� "�}BA(*b ",x���4�� i�kB�6� ��P3B�6)�Ag&!� !��5ydou%2 membW 7 [XM o),ed mitochond��>�:[%ya>�)F5]:LCk .1oCr� ,YN����� �J�\) M&�igol&beledQA�&� `B�Ed @V�mCon��7!݁�NE1m J2��} �D**:uI�co0'�!@(i�E!���q]�� !Om� signhExG s7/'�Rw1qE�EE��.6#n�n0 �ub1�tnlsp2; �&� B�Vu�u���� % solu+V &��Bbi�Hf�rnI:����5&� �!J��ql�xAo��� � B� . H"ׁS5�Ve�/ uf &�:eno� NS;A O &� rob�m ;� B��e-!�z�&if�%�A�F��!(&� :�r�+Bl�� b�:gNo�a�~-��>�=�in1�, SDSF�E�l� �/.E�D[mve�Q.���.��wB�� �o2LC3-IIa1 ��dMeanw?AE�eYK!s�1r?e *t0��� � �C'y�Fl2.3'Y�GB.`$8��"�� 4�Aap-�"j�&�C-�&� )I���2;ED�wF:���m O<N"8t����S7A–S7&; P�K�s�&!Xq "��1�v%�,at p62/SQSTM���`).������[34�a��)�Cathe��D�Ipunctf�y�&�1[35�%Tpg �dom���.fQ�y-q&%�w�>. I� Z� "O ��#�=p62�a�g�O ��ai:~karya!1@�3��4A , �4S8ɵ �b\�9.%t�†�Gyconeicon E>-en�,Tomato ) Lec�( LEL2q%k 8&o(�,�9Mt 4�/O [3�%V� a�Q�AI}5��p62� 2�3~� 4% I�+�%e�se.t�&u�bF�orV��! a�Fi)�F�'���pR5�@)��y5}^&t &�a��� morp�3yI| .A{� Z Q�e8 &d5��fil� ʼn�L��"�� u&*���6n� 4i��Z� urandom pMG* ��A�!�'oci� tCX)"�X2�a�cu�~�A��*�Fine �.f5t�6�B�%re}c"]4���!� ���'w U ng>JJ���"Yt�th2�@43� AP-453'���a�9q�[3 %�yZ�+2� nerv%�C�g BWe @ab�(six�I�(ma4Tg�:!).^"� 0K����ZIX2Z(. Eachh��!I& E�=E� geneyB�; 6)��FO"M� U���6�S9&�All�fy)\~�8JY.�(}�!�OsXJ"�a�!� 2[F�!�31 � ( S9&.5&F- ��B^N[&w h>�xy���eo\�"t^�APO 6&s�}��[!� "n*� q��&2W�1�2�BZ��9M\-T� �+A��M?L� �2� &� "sP ��Hm��E��tox[3IBp66s:s2���6g�=!b@A"�+��1s2_��sA�WKg� on[3�*k���p%�.� olig\�ic�^�G0}� ct�N!��torM;/��� [4�N���� 17A�-iBIlr2Mng%�Z��� DZ�. ��!UFJ�.��izQG�p"�%,�"�%� ��<�= �-�<�ice[4w/��I� 4� A.�E�� pro�a��@Z!cc�Z.>2�5B�A�&� �"Y� �y�%5� ���s"u!0 #C�M_r.+�f�>�AB�" . 5�!E �%B��!b��5x� )l �!�or6=�w We2&>G�He|2�E�:EV�"���`�t0_���tum#?ac9�'�TNα �� -_!�WY9hA5�&��0TNFαF3�� .��` �"8�n��CD�MAM/�i�a�rtyP}4rH,6,!-N �\F�E�� :� =� . To/;4� gene]&a*�3E�c.1���%�g �sheep��{5��[4�6Gba nullo�R� in&#�h|`+�3Է��ty�r�NdeY=��%� skin�%4�2Tm1, '�ia�� nock7,$K14-lnl/ln �E�� : )�iraI6!&�-t)&��3 �DN,i��m��,C�,"��*[,� @harbo[�a%9�'�0&SJ��gprosa�n-a�  C-�8t)wA:HB��3s�s��:# �C[29V�4S��ax2wW� d�rv�wA�nF�.�C��v� 6R�s�*�30+ta|rs(&�$/� o  .�� 1�� 9�a�/6�;�Q!p�� �z�0d:e�.a�� .� ��b�If2 0����e i�ť�6}�use�n7֨]BK)�eF!42�Z�$�L*> #R!�� k�6�ia�E=� �. Fp�=8Aa�96� look�� '�e 2le( :� 6� w+FB@f*2��/�e�p�6�&%PASٝq;ͦ�+pl-���,�&A�um�O&'A��&6+_6�G��6&A# �c�. -{*6�-�bx,�-eTse5�c�Փbkl٣[!�a��Dad�Dgi*�d4$poi�|"�B���)Y)�[4�3LasY!x ifeI*FAvm)9 i=�6�QRB"*6C %�a��c��F\.��q�)!A��N�  ~�t�&� �>ik �}cj 99�� L"� play%%und�-al roly3�ai�+V�����)"]IA9ύ�ǛNs[41In�F�?7al2P?*���b W�3cF.C�+�"s"027"��[�-I�d.�6� :Y;^�- . AFnf$�-+)*=/a�.�g m" <95:N�F�A�,, Niemann-pix�ype CKUc C*J3d!B/L� :*[354�/|�A��v"��.�2 s�& i�A��l_Yy � Ei�OgTE5�r���a }c1 �)��. A�Kg�*�m�tA�P9w��3y-r�W)�,#yoa�aL5e�al��]�E�K�2ir6linDs[Y�N �� "��A�x� 1�c�di��^�^�Bga�!��&E���c�5�F��%�!��)>-�]N/ � 3�Co7� Y�MWm���&j7@ z<>�^+}mFm#Q6 UBN�H��%E�p\f"� �' ���5`6.���J��[a�!h��;&1�qkJ{�^: ��A�is WCi Coއ.X �`T)�� ATG7�NW �=� wk.M�a�stria�)q�B�S�F-pmid�J��ic.��oY�)�:��:�A s[�~ "|-�EY :MFZ:k�bcc|�*�]hA ��a�1:�c^ac sym�M F�*;H[_�&RJj��NIma$f�?g%�U�iv&�&�OA� 9�S erapɭ�=!�_�E� �G���{i7�J��r �se.>@�6>"��ld�@"�5�-Av.^�7Wj�T2?=.�KD�@.o#Jao& I��>pluriBC �MA�"�����p=�A r�}j�2�.J A� �[%�q9J3)1 �I�U� lciu��mY6asis[1��9o1wJ in.2�Iin vivoEK tr^���N�nl\.<�"�2p6see(�b#Calre.� pra[�GM*s��p�iZt���Dt <30%' a&a~h80�s���v4s$Zd h�QchA�enviroSBa�8ct�waO�Z��d ��b/u:��Dm� ЁtA%Tv_���up:g*~FP�H�܍���Dd&jyUI��c.��-.�few� d:<�m��� �FndF&HE?�!��ro�%"20 D� �[��FB� a6 ,&�!�r�Tt > o 1-�o yl-4��-LRG�,6-tetra97py�9� MPTP�m���&�{w"�2�o&�.<�hqwh� ����E 3ueA�Ouu� �%�oor -�de��.�machinrbb .AA�2 ~Ή���clu�- &Po�26SA�G�om� 0Z��&j�A$ ��x���a��>� aY�. -E9kW��W*  �!�m>m2�jX . O��>-/O@Z�1ddow��eamq)����mI�4er�yaPobscu�B2v\�Eb9;� B��B "~:*���")���� �%:�.E6�a���>�Loc~(aHu�aX�s�(� �(S"�8o,5�"� � B� r� :\(MB2* >� "&����w"��"� X!�- o�f�-�m& T�2�J*�PPDEaPt,�`�%R" J�J�8b�J �|-�gef}Z.�6W"�\1L[����sl��Q*^X.aU��40Hew!St�J��!�zdaL�kPD6Ua�*��96~; . \:�ane&��in�02��ic�E�waW �fhen��r�/EAll�V'�,�dbXu�%Ei�sJjfq�� �`�?v�� e ��R���W;-�%Kyoto.����a!,2wa���tL��a��%n5G�("T<\ i -cablNKWZ-³f CabG$6��es�2��afwVir�X� aqua"��h'+d )hLke��=�Q�xr���04 hr light/10 dark *Egg!�r6�FboxR8��.��v��� w&I�vb��VQi�� ( QIAGEN\.&� th�EvP�c!Cx���[6?P�)Sc��RT g�ki��Per�fl T�R)�' aKaR=#RR037'"�=�i6N, SNC�- SNCG!�*C/� MAP1LC3B"�M-w fer{�-�*�k�EN&��%)E4 E�mi$ci.�=E1nKly know�w{K�*�2:X){�52��"7<d �+N� oduc�0���Y jSe�Y’s CapA��)� E�:�ca�S"�!�EuropI�N�>o�� Arch} ( EN!�ac���a#LM644999=� 4500=+�� I�:�a���bed[1W+ToX:���e ZNXN9.reda p��t��We�@L$771 sampleF!'a higf�NJ"llo^by�82u�!1a�UW["�Ns� �O 1–� t��T \GA� s ![11�JGB��I��6�� 9�}M%s��)a-���f"�x*A)ToAjY5%V �Vp"ZN2�N,=?}&�7w�Qɠ!o�%� e�~ 5′R� � AAGG [�A-3��!e�AA��T��AG!�Kde�6$ed HybProb'-84LC Red 640-CAT=AGT��G-Phos��e2jCCTTATATCT`�/T�GT-Fl�in 8�!�L�7C$���0~��Mas��inB!*�� �!= .��'��C:�ˡ"Oe�3:�@^�c3�&x,e�B�e�0�-"&oto���m�atk st� n�@�:��A��P�PQ9.���>N0e�e*�WA�2 / �in� &Fo� d"0A�(�/H+'Bw- 2Weu � nsul�* :�up��amS�sea u�9`HRo#�otəul�jrim��8arylsulfatase[5��54���'::2ei flan�� w� �)�:&ɥ^�i�e�e(an internal� ribosome entry site ( IRES ) , enhanced GFP ( EGFP�and the Simian virus 40 polyadenylation Por,�medaka β-actin 3′-untranslated region ( XUTR ) ( S8A Fig ) . TheG�GAP-43 promoter contained a 1 . 0-kb fragment of �5sflankingoo 0gene . A DNA >9�" was inser�`into EcoR I/Sal I restric�enzyme%sfpDs� b2k-%M plasmid .Biconstruclby x�an Xhov pe I�from paca��.0%� ��GTDEL4�, which!Ts)8%�!�T-Ds sequences[21 , 57]-�~a�inuouslyESasub�;t 3i�� assa % GCas��zymatic �, vity%Y�2�11a�M�`brains �homa��Zin��8μl sample buff%CH10 mM Tris-HCl , 15Na aAveAXTriton X-100 , pH 7 . 4e�sonic�[, !�c�R ifugAte@, 000 ×g at 4°C%)p$. Aliquots%8ainAq50 μg�} tein �incubh!�%8�5�L4-MethylumbelliferylaQ4d-glucopyranos�P( Wako , #324–37441��58sodium taurocho�9(197–100339): 4cit�m ,6phosphat pH 5� )�A" pres�Z7ab f 2�Condu!�l B epox � Toro�@Research Chemical��#C666!yb4a total volume��!�Aat 371� 4 hrM�reA�onE�stopp�nadd!�? of 0E M glycin �18M�flu��c�A ,60 nm ( emis�355)rmeasur�KF=oskan ACt FL (��$rmo Fishere�J stoHat—80�until��sesE�:2(1 ml tissuea��Yu2-�ucros�2E�Ke= Ty\! EDTA6DV1 m:used ��!O�a�. Levelj E�cerebrI�a�galact2w��6bhigh-�h� a�hid chromatography-tandem MS2���modif� A6�: SFC separ%<[59��A synthe�� peptA�corre��E]@to amino acids 90el4Am���conjug�dto Keyhole Limpet Hemocyan�Bas9?immuni-�Dof rabbits . SerumEob��$ed 49 days�2;!]purifiQ�affin��66 . Frozen 3ar( se0 ��5�dohistocm�.�For� NA,1.fix�4��w��~Dormaldehyde ( PFA �%��-�Zed sala� ( PB a�aBA��,! then�'3*z q.8m� an 16�oSř-embedded�\Surgipath FSC 22 ( Leica�s{,14-μm-thick9E�5�w�4a LEICA CM 190a�!HpB�jJ�I9H!5a�� �, %V��d��.�pAk1� ��nese�6A�2�mV�Mic� HM 325A_orv8,!�6 ��� ,ary antibodi�a �a1�"A�:#L-Cathepsin D ( CalbiE��E IM03>:20��ti-GFA;$Sigma-AldrZ , #G389 /1ɞ 0LC3� anta Cruz,sc-16755^�r� �-6( }~p6A-MBLG PM04 D22sss�( DAKO(A4506l6((TH ( MillipA�, #MAB31��1�xTP, Abca%ab390*58 >-ubiqui!o( B� 8017�5_.2� Z045B�d bioti�`ed Lycopersicon Esculentu�~T�� ) LA��VECTOR�B-117!95 G �Gaa�Aet�e9( TNFα:n�T�G�GAA6�CTA�AGACC"C���2� �vgincluE �r%��MK APOE)s�ceY �pro�MD $H . Mitani!okyo UniA+� , , Japan�in�� �Inou hybrid��A�f ed2D [6�CA%er��61E�m� gE(Fb M888�i��-soluble3y, -�:  salt� iA,1% V( 7� :.� * cnW5a�nd>I2�B4jIFor SDSR�a�pellet%Q&�ly*�inA�(F�2%!2iCI="�� ����Ouperna�!� boil )��%=� SDS2 . 5&� �ero�� 008bromophenol blu�/>)�42-mercaptoetha(,�=�pH 6 . 8E�2� � ed on �, 12% ,��1*< g�!� PAGE�% ]g : load)each lan� r�toV�ALiF� RBS��pr�infg.�mN9ferD to  v� idene di���membrana���a T@-Blot SD Semi-Dry �Cel� Bio-Rad%�A�det�  of��%!mouse z�tre��A<=�� in!�30�atFb� blocl��ent�achl ���a� blotA:�[6��we��n$&  �i����: ���� "�J6 A197G 5r "j �� M"z 3NR NSE*x M087 5.L -# ( BD)�du����61078 6� ��<t ���or�,ed neurofila%�( COVAS $, #smi-31ra�:� Za 2��8 � ti2� z U,)�&� E�JA�2v �,MG��&�a�(horseradish�|ase.# sN� 2� ) zhrR5.� uno yve band �i�/ �(-Lumi One S�9< ( Nacalai tesqu� � aXClumine9signal�h6\4Fujifilm LAS-3a(. Densitome�y{eX&�u&YJ&� �� (al InstitutHealth��To���tdop��noradren���seroto�in��2 ,��f�%�2X� JKVS��2��Iglutara&dq$072–0196� in�j1 M&|��PB M�E�0A�rin%xEPB>� post�*@ OsO4:<d2A�e_�h�U�hy"�penet*J 1! a�3pyl��a0e!�cI�. Epon��ɼ i:�4n EM UC6 ultra�A�* .da�a6O1 �I� � tolu "p zK60��80�e9q�(uranyl acet�! lead": Hi�i H-76509H e�ron.��-Fym�%' thin cryo&�asb�2� Briefly ,qL�$quickly re+d��f�immC�4%e ">%�LA� PB (= ;2:�Ev,a�he oroughly B25%"M6�2TFa� g�Ahn j �ro!�� 3 MZgovern���,�op 0specimen hold_��system/ �1T plun("qnitt! . UA�J�� cut)a iUC6/FC6%�UC7/FC7 /:�0at about—12]� ��)) picked upv1:1 mixss 2%�cellulA>U: a n\�iJ(a carbon-co� ,Formvar supp�ng Ū����h�=�q��*Q A� 02 M& ,6� 1% bovse alb�9AqJ)�&foBE�O9:� � body�3��y)bthek�Lgo!� VIgG�*�1�� $oidal golditicle�"1:4k(a�t�Bio!� Intwioᤚ���WA�6cg6�: .͸ comp�$�label!�� 6[..��n layer=Ju%7!�4%>��* 4 . !, air-dr�)�j�{Fp�� Abrol expe0n%��6�� #��� 2�r] NA two-ta'paifStudent�t-testw0one-way ANOVA)Tukey'-hoc .� �a�#_StatistX "�W%�&C %z�j oft Excel�G:0Pad Prism Sof, V�o{#!�.�bLi� ia mono-'geis a facc't" i@)A�u$#* capa�of inducAUa robuD'ella�i�T�e�'pono-l� l in��e�Ycit 'L .:�to escap_s$he phagb*��eak%�ho � (sol�par� �he ��$of long-li5CD8 T �–me ��c)�tA&Ha�4, we show that�imM3 I2F�`*!�{#�0is not merely��!J!)�in&)��g��"ASoa butF�B)8dirX��re"�* adap�- sa� This2, limiab�oaf^F: to vacuolep �F�,�nee h62b�A�- A�!�. Co-YH"9;a� sA 3icJ�? �(neM!!�&a�5�N1expanZ#of1�-�fic-�s r �'o.�R�ste& alo4,B�U$�!�5� �pro�of!lam`"ry%k� �5 �@rapid MyD88-depen��@NIL-s$BzadE�!� recep�+�-*a%W _%nliD9��,@$VdOur stuAdem�,at�mmA��$��7A :KcanM�lye�cm�nnP!�U�%�]�b�agoniz����w�"neZ#� in-{a�_6�nY_�x s . G 6�m umJ�ha�,en-)ddecadv ��mod�,�������[I��!FJor sI���ND�A, cha�r0)byJ ����yI CD4 !@.#[2]�lat�of\.�$predominan!� �i��!�=v�3P[4� F"S-engulf� ��^,Jɤs� !�6�� F�� via�ra.�� ! -forH,*ly!", l�� O� LO ) [5�O�i� n:�0� MIa���� ActAɼfacili� sE!�A& sprf�im!�{��-'a1[6�V-de�3/s stil�� duceR�#0le1la��( R2��/h��as Δ�) elicit�BF>��xthese sE<un�X�R�[7E0�/E�ofJ5�cyt%� perm '1�� owthE�.�!��;-in��!cv5{aW(ic surveill���A+ea���6"a uni� arra{ ��#,� l��04I IFN [9]–[1�W��rem-unD1rnwhyJ %�.�1lig�a�@multiple Toll-lik��Ts foun�!Eksurface%6]�yp,�I s efo ve:���wA ��cA� h!a<[1�!1�"I�F�>�ogn�/Zs cri� �� �=earlybia, pl�)��.F!�o_�M=K)��p�n��r5B ( PR�4trigger�cas�"��)��h� � bothKruA�"arm"�K-)aors [15e1�F� �E1.�TLRP&�*oea� lipotecho�/id~���/tTLR�0 flag�.n09 ( CpG motif&NODl$muramyl di v�ll!�4mayMBa9��.L ��[17e2eRT se��=Y such��MCP-1� �!`9�(IFN-γTNF���%ntA4ATeQ7Q�re%�źQM1oc�fun� mac�3ag,n�ti�.), o�I�tOal burdu i� N � g A�"T �e [23)'ŭTyp�' upőa�J �� also-�XZtoJo&j wh� they%�A� ribuM o� pers�`�Fa�ll�@A�ncy [26 ��� e.��^ PRR-Q���&B sh�!( ensu!�50mXO[2�-�{] .�sA��Zo:z�u dend����( DC ) m�3�tA!mig -�5b-assoc�&�lym�1ics � , [3�#MXisr�stimula �ap")!9DC�upreg$�'co.5�/m`(M�Yf( �gSD80/8SCD7�Ay2p 8 )a� �/βs 35 �%�9Us=1� DC&d� !�%' nodeM�it� i�a�w��large n�3re�naïv&�[3�}Toget�1� l�(� milieu%�:�=�s � �J 63!~ outc�;�-m(�!�A6��mat� �qI : 7U�[33G We quesGed f�r&Taq�um��!,:would.� ujt]�+�\in��by!E�&�&�Sitwo d�nct�%�F �f�:�,9 L�,N i�4!mF�!Z�*C &* 6��"ve�\���e�� Beca�"Iz�� betw`!�*� Lma��&�ttenu� in viv�5��br min�RIo5 er d�is�ly F ��|�r�spl�(2Uwild-� Fc)(A��9dLLO�,w2� �=b^ � thus�!)�N� [3��ImOi=Q � �5a� �1�9�!c�littl�6no��B�E�Qn challenge2� To�� enu}:aja�BK.�8%��:�� l�xw,!�z:hor?!me�!�an u&� E�ofq"-�( 1×105Dony� �unP ( CFU )� a @suf8��V�z�T� �=oculu�Vwa�d# crea%��PJ+I��.��ass| dR�60p0�9r6Q|!�%0U�-Fd!/qgenY�ng%&���Figure 1A.. Stri'b!�% :�t"p )X�$����C romiY��  VP=%b��  o� worda� despite a.jz!�Az�fV�OU�.�!ͱicQ���lB�J�u!�:H�B�{ explanae�� tAnfif8gB� addi'of.-"D M�f"�d�6rH ��:],�!-A$hdu� &�-��oiv�!�g���c�a>es'is hyp!�A��an eryt�9ycin- A�����M\ ( -Erm� comb"� a2� 9IS�?8e��W�+�f�he6 r h�s!��mNW!g&�?.� (u`�$C%9D�6�sF� did")a&�atV2�I %���Wm��40 ctro g<XM�b;$marrow-der�.�.!��'��l e�WJ�u requ metaboaPA7vF $, heat-kilTB� �a�u��� M�Y�=nl4.G{to our=eis�Qq�y^HKFZ� �N����mw fash�!.�un��F[��12wBa�luMb�E �*< N�Y�FE} Fina0F�i1��Fhwt^A�%�v~G~�H!�� 1� m��.� u�7Balb/c;( datae!=n]T\ ,nfew99"�w^a�qq�f ��+&� 1�a3uDL<000-f�"i9Ş�&".����W GiveG r=>of2� i��F� �dJ� .� ����J�]B�:� E?N��N� v�NF �+aV1�(Vi �!AOVA-ex�����tr9F^�.6,eaH=^ma�u&�9CD8q25h;26�4!Z1;@201–"�"�dec�>�5c��J�to]��-�ed��(:���of2�2� +-�4t���6���E�hr:6s-Kba-���)�ru� u��ex�4:� Z�in��a��A� �Ŧ*� if"���Z5��0)� eJ&F$s��U �i%� QEMa!Z9~3l T8D*�]*at2��2��� y les nei��OV=|nbhe2Uv epitope\BFur9mB>*re�df�U��.g-`class I� �!�J!�n$iB 2 MHC-O2s�2ed1r >�$� 2f��F�vaccini-Jrus"�5�)3B��T��L�0�4Q�-|9 .X"B s�!V�� 2%9P2��w��wMNji�K >�ͯ٧plr!a&Y�\&:hap!��BU5� . Ba�Voə���C�m�0 �:$� we& zQ�y.fJ�F�alt=R��2 B�M@��aK i+-k�#�m�)O�-����$�;u�Pbi� A0��v ɗ�YB�_7!J2� 2 6!c.~G ��|*�e�Tof ܭ2,:��-V12..hh%u84��u!��Տ�:exertd-�&] QZpr:�%U�b�F�!."� many� uo� f s M�8h2 1��fR![3� w2RApab�!��&zJs�m�/K ?0�aB(:0.=ur hours+MA!,1����� ct� �4E�z)ah!#.�, �5)��EJ�.�e@� %�er!0h:}!]�UA�&� �Z ��igh l"+J� 2p40�_&sLh�odIic )a sugg�ng#NNF>:V�i!Kei�(�Ohough!��Bot.�at �!g�(le"�Hp19��!Z6 L-23.� �*nN��F� .� inhiJV� E!�" C�d elevs6v�.To exa�7��of%l%�E�!h�^�u�B�,�=� jBnd.�N�a�W(st ��!� �0� -AP07[3s4eg3"V$*�)1Wak"�D���wh� main�!�tleke W39&� . O�+A�$��!b=(A`u�eN�.,�� ��g�g:=s6V �(b)6!zNa��s � �AOn�q=.��/3"�FC��^r"*�Ga6a�� ���c�(�V>�`.1E� %�R�=c�+2� �val%>1� instR�5�.��>�j�,1w 5�_��],&-I= R�AC'"';a�r� 6�wh� F�e�5=�0�Jr�gr(x6��-F/.��={, ;−/−)$6�H.�&%x!� ��i �Lg)�a�9�E8wtJ` 9���jMIݜ �\)�67 *$N�B� to-z��Z 2QB4� �sf"!�n��.� s ult�J.6L ��iscri,.= &J ��d�&�ub�ux P!A�' !�+a);�ZEY� mechan�3 , imH[M ebzE0�<3. Ha2�mu��ikV&N�6'�%on.�"&/,8���*q,��o�appropr�#B��2H�!�ood�CeviYre s hav/3��R�.�I&xHF*,|a9u�*!yf+^+�4AL ���$KY9ar "� do�[9%!�(�$ 4�$6ʹ� origiA *8E[6)`2 ���i�r*t& �V!�at2�!�PJJfai�-Eqiz$c�&�G�`�, , [4�$�1�go�5a�se"��toA�&�ot�&U%3A��,Nc&� byMo�(�i"�;YF5_��urpri9�~wO`,%���.Xb�$��)EV.�I��!�*%aHy*����D)�t�:�� !zўsJ �Bo re&,"/3�)X6AB[9J�* +�K%0im9�uA���,!�iA�e)tN2#N� G2 2[akecUA�Ku([ J!]lՇ>���crEP[��]o&aY!16�#0F��=��U+. BA-� %�I��*�ly�jr�*d�C ngstI~c�"!]�]%[4�'6�b�%k� "�1e�k.�1,"omw�1�%x& neighbourai �[4�'C2x"/ O~%R.D�!�qa�tert Aw"5B�� avoid > whel� uR�CF���m�� ��#�(Y� dard�<1×LD50>373)� ed 1PY1"�! �. U��seWS #putZexceeV  nin�0*2� group3 5@ �+?F M�M > lo"WNr�f� A� �  %dz 7 t]!Uc�)A b�plVe"��4B ) PJ&/ *�6 hown!4*�? NC'"� a�(')��)Z�-��piv�p:��>�-S6{�h�#*;09}b�PRRFT��*� m�~y3"� s [4�( Io������T,t�9&�#E� infi^CAof neu*W0.�!�6�,^A�af*^s �7;0NSEZ �*�0re&%�$�,o� �k�&x3�4l>/s��"3KprLWa �8g$2`!Z�D2i/�/�=I�r gensR go.�-i�33 Y?prV�2�=2�-ep��2�4[^y�ba��(6�"��T:%��-�A�Ia�7T �(!-H+] repertoirES5,avail)l%#� n [4� [48]�;Tof�a co-s*80&�/�ʼn0[49];7s�(Q�ewatt��awB3r_3>}/�1A�R�0><2�cytmj5-�a��?�-^�s��[5� �by@ktu%Vk*in���8f-�"��:m �� �o.r land E!ЁGn�/yB& �&� !�9on-� S7��x��yf�$.HficE%XbA)�>on"� ,�extNncfkTIn%�'@��q0� 6�=optimal�mem���F��G[Q4How:Y�l�-�Z.�%��A.P � �e*��!c!7"Z �4 �a�V^ � eKe�Ž&�]Q��2  a smT7�.re�G�=.��'��'cfu%X"ra�MN�&�_Con�Z�9��a��@�,ed� �)��i�,��:L,5e,!Eang���N3 logs�%er�9��/&�. W� ��U��iA�w �<2B�D.�z�w-�&�0�d z�FI1�5oe .:� ��E�]#t� e� �z"!�higJES� � . Me�f!d.g2�|c���]�a�� upAAoZly1ʉ�se�L�)��(sHj�� ac"8 �J `9G]B2R5–1N'm <in5j 2ed�Mm1 `5DnG(� Xcer� �a�ۭ~�Q���eut-XQ�c .' is f>el�a�!�edm� �VcaA s]0!�AH �R.���:�!�k ܕ�cho4to�]Zv�1Iv�e.�%E�2^ QX.0%�ch�@��m�Honm*�.H,�+`�:E�estm�!.e��2�I w��"'d29E�G8��x�D*�(raD4&�� 1HaQ����%��%~n!)���a�nI�2�apeiclog&< � � �se Alc.��"I�2 "s� �G,�FYsPf� A~��minute>`��Ai�P�%O��ssiX!��6 �2��� �cZ# � ]Q���f9pkH"�";ox_ qal�ptch�!�7t"�t�8^cey.to-d|\1r"k � �>��sam^ roenviron`%�*22��n/ � ���FJ�of17��in2. e�leF!�H posiq9@of5 ��tc a%�Q\9&�(+��!��%�t�L �t� �t�8�fieldE�����2ax(a(�2U" 7�6; ;%�>o� F>�I�A�c>al� .Btheir�ic5. V�(e���+O!C�Dž'�=-)7I�ol��#e�� dise�q�o h�Xworldw��=!�)��at b% humor�;!��bI:�04ghtforw�a�# op ,X�)n�B �7IO6,"�At�{n�) ombat HIV� tube�so]4�VEed elu)  [5vq�i�Oi`>aya�I/art du�� poor0�b^ofE!�>��TY"M?ed [5jModern ach!co -!!�I�5���!3or.�1dE�e+ wise.C orga-�vh�+of-� l �Z����-ov�'QC[5�UYX L�" adeq��ݡ� t�CE��D�-<mHr.�&1�J safe�/Q� -�Act>�6�!�iA��*AF��\g��$ &[��<&4!յ����7F�s*�&u�. A�)al�"$Wa@�  ��C�exact�!�F���ioG *�yN���/�8Rify��* �LNED��� ��a,� �TC is aa ario82�iz%^A]}U��be"�T!��al�=ig� �1��t �,���*� �&�?E�7. A=Hn oc��%EM(Earle A . C�s&ux"�a ,.&kH7alifor2$, Berkeley�k� Anza<�ZA �CA�,Use CommitteL6� week �7C57Bl/6��;purch:1� Ch�s R�;Labor�G� ( Wi�to`M�B�hd&�'\bA�at�f+:i�.J � n�P-L��*q%ed��_�$�&b�O+�Wse full-9CthJ�Bf����E�zv,Yw+�5 }6!�8E�!g�.[-Quad; 6 �B�E�y ctANH[fu�M��gI�74 ="74 B8R2�427 TSYKFESV Kb"�4 ed; C4L12�$32 LNFRFENB%XA42R88–96 YAPVSPIVI D6JK3LEe$5 YSLPNAGD>$ [�4 , [5*"W��=Emidlom�d-hearL �brs!,zh�B`^^&5�ravenoJ~in `uµL�vol�{6�GR;%l250 µg��-( CD21GJc +1B1 . 3�&BD Bios�qca�San Dieg9GCa-2 +1b�*n ��ed�,or"�Cp�M%@"t�,2� ��)�,^RG( L4056 E 2�,,�fX�?�0ge>a�s�Y�Olu��s�i�0on BHI-strep �@p�(��"�@�dE*^i a�eA�=�� du�e ,fnd -erm x�v.k@��>@Uq@-maq@u]2�d�7 c� slips���$d� poie. C)� vort�1y'd%G ��!2�a e �2F . SSI1�arv l<dis"�M/3d6o;pl�'�d&$ [D chloxm2�l , S� Loui�"M�V. &qW5M�5| 3�M!�eb!1r�1nt'!( If�I feldL ,H �\aN� -�7(m�GKa��wev�A- >!4i�53-��3l2�xR�yfii3,�&ea�N�A�i2z_�6.�XMG�2�)�). PentF� S A�&�;i%K:�<p 6�*�bAPC;TroI< e LtABra� ��FL���� c(Ca0 FACSCa�Lf�yt�jer tm2�!a! �FlowJo.�jTreestar(Msh� , O3aeSd�\aGACBA Mo�LI.�KhvB��j�^,1�, f8�:P 2�5�TL�(LincoPlex M*p AV6�zBFDr�},5 AL'eex� �1ru� ( k�d. Timz�D of 4;24mTpu�#eR�B�� peak���V}�|"� &� ,.�a � �K%���5y� ��!5ډ,�qGlaucomaea-A��Na� lind�}.�8xi],open-angle gH( POA�Cyem��n*N���!�y_t�m!���c�er�vk*Genome-ra��E�*d  eYEg"�.=�0��A- SIX6Su`f rs1048372�\odd+Otio (I� = �3� p 3At7> −1",U�&ZG(HzAvelopEV�"S^�2� morpholog"�� c nx{�W�b� zco%�^*� �6n~ 62)�>2569 =SsixkFsynonymH b vari�#rO�Zf� $HcI .�Rn141Hi)t33912345e��#�\-�@9�jf%�!�-�!�%�1�g21�0_!S%� fam�H�is�-��yer�!�–%�u .�`A�a!�woq^f���domM< ; a ��b�ng��eobox �ae1l1s dow� eam �or*o-[10%UM�m�%!�+��A��ED]8BpȃmS�6�p� �HDrosophila melanoga�n�^) sine�� so ) y�d��)pr؇ .;.�!�Y te7t�c#Z p~�Af+�r�/ !pkey.^Euep���u6�, 5ory net�. D�5embryo�!.�,!�1�e1N�roak[in� ��c1.tA�o� ves�r�limb me~@h��..�, g�X %UCK � g�TET�{!I^pituit� 5g� =�eI4 so�\<8�%�[6c { ol�knockA��six6b!fM )hs y ��lyv��B�,D p���� Ini�A��_"h�on��p 14q2�u -q23} e�e � s bi���$anophthalmR=![*�?��eyh&&.BA�)i�\RSI6��zjA����1� 4F�"�1�Vr�TQto�f � �� .� potH?l,6-b by s�1�j���� -�h�t�: set;� %kpA����'A� ���u�WE� l�d �*���6&� .&Xth� a�!z"s.y!9�> I)� �"G %���al�X��A�.k�� � /dljld�qSis�.f%�{ca�A��"N t� u^;�$ḁ��g;+�7;!� �y!�ɹ� �!݅�����) %��G-�A&$�$y� &T%�C$%�lucifer� A�`ss�NT+��� 2^t%nY1�Mb ��"�ofI�"� s� �6���a�6+,�m]��|~`r&BE92� � �`@'"Ka:�at`X"�8 drjVby)dys1� . S)9a��v5 e�%6!�E)Caucas~��a�!�� ( �q�2�) �(a�23 SNP� up~l T�0SN�&�*�� 1 �1n�B.�4��GM�E- �� yiel�(14QB��G&&&nFo6�2nm(-dB; lo�?.awho_ ��� "p, !�� nd ��m��4T�U���k��e�Z� F �d e�a��as���!ir3iQ"� ic E2 RTPr[O!9( GERP` core!�)�!�l .D~`ng�}-� Duke9�>N ( 482Uu433�I�Au')b2i2� :�4��5M000�UC/�)lleٌINzBMAF )z84� 6�  3ˊ!� %�SNP��inA0 linkage3quilibrP ( r2K9�wF !��(r�N&& .< ~AHv nl�"*r)�–, p&�exp�K,4a-.��mpu!�m� �{5#��� �&Wf�27�iu!]X:�v�!r&%�ed!Q��r� �J��YFurY&\I�R�hisa�ui\� �!./K�-��� #up�am��  ��He�&e � A%B-ao� r8E�{1>�a���&7��� tom��!i CT )Q !��v} & �}�i+a�1pos.�4�� !�";����3Z)tv?��?66=ku6� a2,]0;�fE�M6H vidut,I� ��%<�3ex�� N< ( RN;��� irty.�Jj]�)*��( �n�5:A )�?Ha�3a��t�u� &� d!gQ@s�e�kq�� vEKisN �(�\A�)�!��a�*{ a��e�3Wey+oe$ 20erE�� ge|��'1924!�e=��lyN� ,)���e�K��"U&( global > �-a� �lͷN�*���"1ew��F�.�03;�:���d: C- 5�O 3 ( a5µW:A 6��9�$YR µm;��/>tb �"tAs2\ ew susc~��!)4� E�e:z�F"\$� quadr�xWbe� ��6�0� ���an��l�)Z ��)jis�4f)�9� �ץoF, nasa�= L&$V��s��e�E�2 e�YAXb"��`(:�͈n�8 �: !�9(A i���!3d��ly �< )C�b��)Y�:*�A�alQ څ;E$-4R�S35�&�� ; �3� c5�I��e�C�M�� �2l-�e<s ,�� [6;E��w-6�ic�j��# ivJ���}�+C� �l_r�$N�noar*bw, ��d \�r �yVandid` gen E�)�Iek)���� aE0X-a�!O%&��ofa!e#%��8 "�1(�$>Xz"\a[lESi��\rs�e.�@iFFal BLAST"8#>]@�ortw!E�m���m|Six6a� bHT �� 91% !�?��KY> iN� PF-�=�!=�of5� � p ix6�Mus mus�n) �!|y?,Xenopus laev�)Wt( vealt�lEa�%�rol[�� ib��e��v8sA� e�[18�9];!Moa�*�%��!4wheA�'.�%�y�r2�6xU��E�>�>,a&as� `��m|#in/X�b.>_%�or�G*Am 1����=�-*�>yrescuLX%rph�)P*�ہ�6Y%qW(we�[5+�e2a]�-�CA9$A`MO�)t[E&y-)*� a$wAS�-Q8E&AGge �( N@58/1@�Fx(�,/���^f�"r�( dpf� We�?AU�vF-�S�MO2g��X!�� u tox���Q !A� accu"R+vfh(rd�6f���2�M)�/.E]%}���'�un*a���� exon��e—s�-e9�!�a*��q yre� �7�2Fse�-�aA ��3=6b}J!�] ��j">s deca!0� iblye6%7As��'_H trun��8Au�'~�-"�4`(*> h .\�4: http://www .%-t=.�[/node/1P7-�sYas��4a%>!]%?s�i ofr3!�Q8'.���z�!�)�?a(�V bij� "�I&�S,2C B$.s��@in�[�� m�gu$80%�y�p<h��,ѭ�-je"�L� ��MO� ml-L�� 5 p�!0]�am���� mRNA�"P ' a��(�)mO�!Aa�:A�9O�90% v� �Ym�xB� 6�{se�ind*U�j+�*. [c�E�rom'*Xe--�۵� `�a!l� in[0i�*�y9a^ll:R]�^Q�pE�i��=��!{U���� 'sic.�d,>� I�~z�ݪ�w�#MN.1�E���y 5$*� �M�aj�I�S&ֲ��ri�/ ���m)q� �=Q�=�!��-5��iJJ�>�%%*� /-�"�mYI&nJ�C%L!�9����r�.s�~��Glu129LyA�&#$, Thr212Me_ ! Ser242IlU �n aver��y�*P�Ga�E< |T6���.6-Kwj����m�!���c�ic �Gj+�-W_ %� also�x�,-� ��u205Ar��aJB�v:��d2;9*mMO 3e04]�H76�µm�L�,�56@33148M,;���s&%+i>��"ul�?"�!i��lu93Gln�}ulY eyM�Yec�E�%3>(2�37��"�dMbe&�,E�, �0�(D�E#q����DA9."A�% [m�]iexcNDl&<^�-6�I ��n�� ��-EM��z"!"�J no e��a� �b�T1� .���n���UX�8�)A�2�b�R.r:��)Y!��xX � �!�d=y6�>Ah6)Q? to_� H�"�r*�l5 7 =YLZw��m�A-�W cety?!d-tubul] &� 1-� `)j� �I�� �%܉)�eed9;�% ���es��ROIa5C?%1^�( S.e{�KN� �"� a�Fx�,3�N�1�6�C�m"C.�r/de*S�)��3P�BEi a�"� q .Sp5to@ax)� trac�%�<�J�-�'�C�����9e*� q%�m�O��d.N����m- �%�a���JC A�J;� \հ��� d6.-�e��� ��;&g �B�R�?ՀE�&?�/s.��}�."� �� �S�a]�Mordl�p;$� ��NN�:)g"�#�ء�� V%e�jb���ee}�bF*:�I>�|��O�8���|&gen2�� � re�� ��7aU�enh!r�mAf!�7#ȩm�L># �aB�d 5�L( Chr14:60974363_C ,2 73_T>8> 400_<L449_Gj�b )��� �ir� &�=� �~*�%)�%�*: ��iT.�52��2� 2["�%6�.1a�re,5��,;{B*V�4%�/�!i�"ycof"�,NeuroD%'E47^�e[�+ Over=:�y"6u#B�-��,d"�3-�literu73� c��F�� ur��^ �+�/ �Qi�,k*"��� s—��e^>Fst�� :7���F/E�%C��#�9nd�>t�F&�e� ���.a�$fa novelq7e��L*�� j&�8S9A# �+M?u�2��mooK��]�M�se�&i!N@�"�:�*�hw|Xm @4 �9�b����y�= ���%*�9Ja +��i7i2�lT$��9V�9$M=-X�&�)(*/ �2�,�v9)2 =�Ud�"&�<"7�� &��%ampmkiK%s��g�N,(Aa�.�'&�GWAS 1�$"S?��!2�4�&�Ia����`M�(alpha helix�u�qKK5"�*c5%�. �es�L<hX3c 3��:  ,�; )�R&E3�% 2���1�1$a0rke�3 among popm�aCQ�H: YRI (�h99%�ARF6 SN 7 ��CEU 4�;�(ۂ+me[=lt%12�bu�/Y6`!�p �9�uXH^ 8 U�� =+F"�'V3tq�invol"-�.�0�7.� .W"��*�=n �o� k�%�;oe$e�dԝ�{p;4 , [2VWe�Pat Af:Dn2��k�V+9!�e�9=�% {r��[22 24]�#p�%!�9Ms;!!��:)��"yv�"_in Ghan��cW17% /h `�H" any��-��< [h;a���]=E/|e3�� W�1/� /� �{�+ � �uQ� 8Nl ( _)qFis 99%o��`�+ e�j:WAB � �Vi�!����%&sAJ|!�%%Br �2iAWdO� � ��a �;�ar�W%X\ �e{$���Sl.� �i��X�omBV�` ��#*(.*�1�a! ��M�<%�2�?lqqy&�BVA��`!�d]o"�*p:I �4y���?d��2�<cha�oK�5}!D$���A�ten�Y� )d��es�G ?l�/*�"�"o�L�).�*�"�<~G Li et a>� ��(ix62�Qdis8F�N$jde!f� �!Ax�ia �i�he� a^!n��0g.>A:�A{��E}�($�ex.9r%dcyc�k �.�,er�e�20%2�!�&�?R�s!�P35)=�j��2���;��of XOptx�j�$.h%�[1�=�ave%�W`B E�ay�a��h_.� MO�,&�:z"��)!fT.�;���a�aD�2c:#x��>�,*� !ͅ�4>�� K+e =Q51to.n� *� &< Jat*�"�|�e!K.6"�^we݁6�Q-�Vd)+(��JH�E%?6�Ta�t�z���io�Rpubli�R"B,xQ�6)u[ ��=�"C�:{by"SW���!�16�6��)~&3to duU�!���a�dulthuP���%>�.Hs�nlR�f�� asp"Z�pn�> 2 {fFa�Dqb����:�U$�a�z\R<<or�%��G�?s�1�7tra=# ur,��V=._*�E;Q�uroV!E�5��� ~\#�obqstebyN�s�$&��e�a.nR%2�"Fu1J�@�%[)Nos"/eEeU�O #�.1�RGC dHF�E,c sum!N��[�.�Mpl4�n4w��q�� �<u�2�v%}!�*T�A�*� שZ�����8�9�]D2�;��7� @ � Qf���A�tC�e��;m68��VB~Q�� � �'v 2�0G=�h�7u3#> Ņ.3 .� �&�\E@i*�w,Ed�'D^�Q, (/ PY�[m �� i��to�y*\@A"O�Q����l&P�[t[(Review Boar�_�9*��Me~l CF_%�2VEB�a��>Decla�\�Helsinki� tudy�%�( *��a_LV Jq:Eye.{,�k���he� yP$��Easb EQcKoP�r�G�I ���U*g�QV�,�`�to.Hk�a��7%DF��Lkkas��-. P1�d&�s"�d�� a hi��� ��trauma�`!^=5dAg�/)� ha�&� �)2��,�FrV m!;�( l��)22 mmH [ �C��/��.��"�7�"�z auto�sdiP��<�A�/��Z�M[�,od samp5C ZAiPureGe�"o�s�f"Bz!.+�:�a/�n3_����LMapo�G, M��� ��jg�' ( 2 k,C� �B�?�&���518�@ ��7l.���cha!�sbo>%���Q")(1×��ŵbG��·C2K ( NH52SOr%1�MgCl2;��6�$;�\M"�( dATPaRC GA&dTTP;�4 µMA�i�&$er.l!rse239](,e�(�&10 ng� �"A<64F&45 U HotStarTaq �~!+(1¸nl]Limbur�&J f�%* 25.Ver5� &�:+5.^"T� S.Ud �A�&D71�touch?<.�������oweyk#nneL�gE7es ) MA�2�rmo��0�) s: 9�>"30 a�65°C.722��a de� �pV�\y�Is��-_V5 of 5�!)l�a_i�� W �,O "Eu�6�a1OO ampl�R--aNz �If�u�.%�",e.��)�!#BigDy~/ہ�L 3730E�A�Fz�Z Applv�ZJG!�GraHIs�ZNY$��d "V� le nucleo��E�M3ism�NIB�*C!O������[3��o� se��Z8B_WFB ?њ)a TaqManRicc5���� O26%�B�s� �.��* ife Techn�6� VCForil� ��dpo??ZyL�ne-�� met: >95%18!ef #e�,}chɳ&` two re d'E� du P��-�e HumYO ?C$ 96-g�_�'sT�%� v�crS>all -��[ 4Hardy-Weinberg��lCassump!�Q We C � � !�A_Y?e1%�-��l�jvAsg�@ow># Eks])?nd sex ESAS�� [Q� �%���/!�NEI&0T!GnEqIs CollJf�(,GYZn� "kTW{ d E*Vr("SC�asortia �Ch���~14 aW�C)IMPUTE�,�3 math�.A�)<0ox . ac . uk/ > _vI>htm��w.�Ho'?:��# pane�9�S5HaS:�S�.�c��)�,%�I}s�princip�B mpon42��'��g�5pK� �*,�3& !�m���_B ���t�!�Ro�762�l�p�PLINK@� ,')�L�TZoo�O-�cs߯sph!�m)T. edu/Dzoom/ ) ���1�GA�*�EA-&�F sawdoSsmEeV�aZo"��!B�Haplov?(�w6�Q `�� . org/sLf&Sc-�k�y ce/d ams/�6cal-and-&�-g�Vs/ht %�QO� Eher�tFE� 2#F/"D�KPGra� ( Heidel��Engine\ , CarlsbaAK%gAL6g)%Ifundu�3oX�b��C*."�)�Xr]$ routinely6��  E4� �P,�Rt!*E;,q�Xata.6)>��U:�DA18 �R�P��s :^r��� iVE�~b)�*2�A�6�.%/&�A,�Da�Xd[W�eB���at>b)�"�(bW�&7B�L9#^on2x7i�a��'s ��.� !ŀ2�ݷA��X�<*!q:�l� CCSBͳ ORFeo?��Xro�-at|�e Gatewj_�y}Q( Open.D !;� %��*�.C�(55�2, R@5&-6L5SH5I� G���d-{!QuikC� II��-!(�But�eA����%zv�|7:" AgilvE2% �1�g2!��s+�c�� �mMESS��,mMACHINE SP6�eAmb!�,�r8�S;�ck T�/  1s8j��h�� CTGGe�4GACTGTAATGTCT �ۉ��b 4 �� GGCA.A <A�T,� )M�6�o  T1< , LLC . M� � ( 2� m%C(*�3 Rmi�h!�a*b�nL%u�t""2�� each�d~�&��1� +Ɂ�ect��sA!?&�)*�(a�ar� McMu���198= ���ale�of&:��8u�o.53 �s r�?,MQa Nik�MZ 745T)M�. Z"cqanesthet�in js>���r!Z2 mg/��#R$( Ethyl 3-tobenzo�I Zulfon, S� , E1052�.. L�� ,;m0ecap�z �DS-Fi1|� a��"-Haj�*2<NIS-E� s AR&�i��iO�rv��� on 2A1�(k �en��fix�C( 80% MB�no��d�DMSIlo&/�� !`�J�4()9; T745)7Hea[���is��d� L�`or�ca��|!v=����J�wlip�e;I3n`s� �� ?kuR%��re���Zeiss 7&��&��n}�Z� ∼100 um)zal�� M ob-!-re{*s. V�pA�1�� %B}�I�es9�RZK5 um× 1�5s V�5_�FC�[a�i��OI �6 "��2s� l�Nuri�c�coalesc#o �%�maj� d T� .Ɇ"�����A7O-*2r ��W&Promega�Mad�K, W*7aN'-�A� Quc�!�Iki�4�?ob( pGLuh3 ,O efly.�2,v�M��(es�hal=ec5 B�j�*�1��3N�3�  B�' �NB�5%+E�.))�g�"�a ��edW�O0 XhoIE�HindII���DQ��%�l0 ( New� 4BioLabKIpswic`�5w6AH�l (^A ,*1�� ��CQpmy�P�b�hc���2*]. Hek293�%:ulɃB�supY�=�D( ATC-Many!# ��U&9by�te"#�O- A��R�NdD%�E47I2 _ Y�c"5�EI" J�&�k�a:�R�}�.ol��>*7�renilla^�� :�"�:�(!�2z {��D�fM+�Z,(*�)��7j"������2}Qm)D��^��threeCk�$*�B�Xa�$�n�/6p.&�p ( DLGra� (N sum:Njsum )N� � &]769zIed�hEA.� �� ��yJ�,6ba��)�5a- trasq���"�@%+&�5�FI���N�Vs0�~-�I�e#�=�0�*�] C{%��u��kl ��aA��� .6~n�m�ep�3lm$i\. Fla��ar��A7�$<rectlyactY� a� glucos�>A� Kqc�2��,�diarrc� dm6�"��,� �%�$�+)u&X? � flgB�rr� c�likO@ �!���oTd1@r�� �[r!\wT5�{��6a “> switch” ���!aUp�}�$bX2��O-�e�RN8. The flagellar� switch , located upstream of the flgB operon containing $early stag'��FF�Th6�5�%:arQ$is reversi!�dur!�growth!�$vitro . We!Yvide ence that �regul)�via% �iPoccurs post-transcrip�initi >!�requireA_TC . difficile-specifico\ory factor to destabiliz� degrad�eM��4gene mRNA whenV�is�!�OFF2�P. Lastly , through mua%nesand charI�z �ofIm0locked isolateR0we determined)^�@tyrosine recombinA� RecVA80hich catalyze�%�on at= cwpV1�i�$lso respon)�A�i>79,�A0in both direc!�a�Pe6variaA=5motility%�I�i�: suggests�Dse important virulE`)�s have ~advan!kous\detrim�" l effectsQ�!;coue� f in!0. ClostridiumY^ar0 Gram-positivspore-fo!�g obliga�anaerob"i�e leada9cau� urgenA'reat reA��N� �4antibiotics [3�A$perturb)Tgastrointestinal micro@�(at normallyAte!�again�DI �4e��reofA�urrEa]mA)I^ssoci�k�ADE- incr!td!upart due�%!�eme�ce\ epidemic-L!�ins Tenhan�OA �� ��B�%�5 , 6�6�,,hook , filama�I�cap �'&o �Ao� odF �~ �UN[18A^�4–2��M�aCrŲz�eritrich� inM�trJ L7–3E�� t2�t}y6Ofitnes"� Bm ��A�"}-depend!"manner [i�I>�$630Δerm (= 012Ej�e�dispens� or �!aul��d.4AVc29}mve�� [3��3��I��ntrAD,�A�N� 6))w R202912�272�r5�@ ���N�+9uof� e���Y*�[is noj �dE�o% is�,D a MotB`� ��s5�.�wHa nonf�� o#!�lay� ld  |[I�Ih � g�mic@ ed ]!�-Y fliC�succumbA9, w�9� VI� ntal�do%! �a%Jkh� ��Ac� ��6=5{ , membran��n , � �?. sm!�)� [33]�mmay�l��! "! &�a��. P"�byY���2.kin"l ���psq<2�in M6��an 017y�m[2kIi�2(  ,:R� �\B�[20 , 36j � j �( Pathogenic!8 Locu�0PaLoc ) alongI�!� TcdR6� Et�ly k es t B [37!iE�-s. TcdC w)�inhibitR �, [3� 41J%�he"(E holin-lik � 2Ob�'&� I�ex�f[4D 4 Pre�n� stud� I��� a��=���[27Sub< t work i�ified a`conA�us"d !�nt!�p ) 3 , 4�( Over6�s� Bq�axinMdu,a!PR}�� eɂre�nt������ly bindaeF�aTak�ogemi!s� ){a�l���Ua between�J� crit a�� 2�E8oo�@ symptom developm� B4, simiV to� &=b&|mKs"Vibrio UeraHCampylo 9$ jejuni [4�4e�6f�5 NheN1� im,e �%�g�o eptors [4� 49aF^MQ9clearX$ mechanism� �r� theimQ@ mustaksubject!-precis%��� void�AN�.�� addi(al,��2� al�k�mod �i�� FJ�pot��w���2� .� . Spo0A ,�Hm RstA��6�!�-�a>_ s [50–5� 0le Agr quorum��ng%qHfq���e��[29 , 5��}exact.�by-��2;��olb�.��5 larg��unknown�0yclic diguany�,( c-di-GMP )�� a nucleot�second m$ng��P �Omultitud�i�proZ(qW9X*C biofilm� ���&m�#.�[55!�8��Bq,�M%esrmm!�z cytoav�E, T>IV-pilus��M;aRF�[3�44!�!�6�S.f��� elev\5s�5.{ >�psw>�[5� � neg�6��/BQ!�resulta>: �|2� �C.*xK-Xe}�a�a�� !n ribo� , Cdu l4!�e 5’ u�nsA�d]YV�  [65L��wtomc9�ema>:�t�n,->�� trun�!9!,160 n �*b�[65H� � � crib<c0!�N�an�Yal cis-?ng!#�:�Wel.e�med�s "E6�y�!���n�E��Y=�We��G-� i�g%)�"fB�" mper8!; �"," ~A/]@!%firstA�a%� fram"m r1�.#MgN� s down�#%!9.VHclu�eF�� �w��ݯ�F�. Fur<m=��&�!"� 2�! �.��Nay�impMGX6�J� I$�4]x of:�j�"�3�!PB��P&c"*�".&."w2�2�!�ժ}e�-*E wall! � C�!)�� "��!�!T: ��fi�d��#at=2x�:���s��.� &G"�JS thusq��2pl] !'=�)5se� ed���.$e��BuB��c.���"���PT"�g* �F�trN ��bet hedg�3d tegyZeV �Bj 2Kas cer]ti��s]per���ev%� immun � �_. Souto�w et . al .�9.H�5l:�a�o!x ( TSS )/ %"��yG�Bi!in&g&�(n C500*� O nt )B�(s�codon�f�($�����is��� 0�si��Bhe;( F3 l�u' else� [�C� r�5.Ta��A�.�.��L��( UTR )QyZu� by�+� D DNA&� Y�se fe�x.fl�Zmemploy �numerZ &Q%:0l"Tp stochaD(~�4%�e2+L BJat� �B3=&' � � (/ae�a5o %�E�n [6~W(aso2�-fa�a��X2�X)be�*!wE"��A�.8�*�+�'eIT��r u� Xnpaee8“jse �}�� �2�nd&h��)��of�3i�t I�$�Z�gU �B:1o:j.�� lico&� �hypTsi6)�g>�+go;nk/Q� .�0��aweY)m[{2a�2"*!32 i�I��>��apŽof�A�6��expaa�eo-x&�  9(�**s� :V,A�least | s�e12�]sR^��an.b94- assa%� �A�#26� two.K�we p�v.&��6-t s��liquid�u$EQB ) [67�-�WM !� published.�!�tn1f�X/Q���� %�I �K��A1given �!�ndzI��2"*5>xavM�U�z$� mm�A��imeKRv �mplem�"r%��� co�{�wasI�ll!�u�Black }5T�3r�e9']�I�Ih�Ydforwar �F1i�&a�-m�ly �mlN� ( LId (Q,) en��)�2�2�>�2f�| �r�]�˩� ( R>�B$!qP%s!AUF2�� rse-c2���m/�$airs yieldy���e�u� �Y�����2� �t���+U<�B!� FvAm�yw�d�'Ti�� �JedAp�aS�4TYJ�%86��*^B 5,ATCC 43598 (6m$_B read \+ve SRXl 90 )QCC%��� ����Ls�gfir��.� .BB��Fu.�:g�  z d ex�:or:� wo�1hav�)fs.Qon 12�IR�be��6H%nd 11th2��3(&#' �.��( n���a.4%�!-J�"�%m�!�, aD3m� �Tlab�ory-adapAW!'�Un"eHr]W6k��!u!i�)ar�J��h�%d shor!W20N;!J�� aden#8absa 92���e\ IG��m�5 ymidW8>4�K4�7i�length!�~c�G�E0)Z!�[��6ex&/(��� �f�R�06�.c0 iv��z se data�,M$t��:l)����ybr2�+0a hs9 ogenU8pop �*�4)j!QN= �Dor- 6�, sup$e�ur&p mtFB^&o na I='oKM�6 f9�K� sV�[6��:sig5.B�L!HCdi7We optimE an unbi�asymm�9ca�-di:!f&� �uis >o&�!�~� A����9AO _*v��o%do eac�<==�i�26� , 7On�"irtS62���JBamplify��' mpas"% eT�m�" [,�AAa 665aޭ� z: /� \$1>��3 ri�"(enzyme SwaIm�:Vin� .8%�ev B�r�F1wo�gmof����.c %�.� B&�=.q"� �v�� fr�312E8 353 bp; i�MRWi&>�ZU418U247!�. All �1-��� �. mix��i�#^3ep�4Q�6��X��yP!}���!2�) �.Z ( S1%yN3�Ip{ � BHIS�;r��� ./49�/.�8. Ge�a-�es \co���nd spo�9or9n:ardv��6}, over 96 h�=�1jy,ph�:$d�smo��xcir��4 a sp� a~&K3j P�,B� GSi�a��? crepf:t�5lon�4 y 24��a�z]| o� O 5 s�k1Np�$d .�) tim�;`bunda�<e�wA~�s���&N��)d1  p6o6�PMr�U�1]}MquCŤby meas|] pixe�:ten�?�i�ba�),Q>�o�'YG curvd-ne�d�*i�:Amou�of%͐ed�"> � ƙl!�J$G=�#�ф_@FF��J\�!nSa�9�I48M\(�^i��rZIQ6� X��How���Hb� has �/��2!A!�v of low �y�@A�u��{��94ve ( q���cto ,fy)�Genc"%�U .YA ո9�I$4�_�7�V�byfL-�!�, 8�� 5% ( +/- �9 6% S�1M�*% A�.=at2�by)H dɧSY/)(i0횕 Q pred�>�fmNB��A^,�C. 3�2 .�b�e����Th�Wm  ^Usu)fu�+"T-E x2)!{B�$6d6l=. -�BP3!j0�H%��n:�k�"e �>wi�L.udidK�(V ( S2 o n�A% ~�&� %4Z&� w� K*ctiO*� �-b�>lony tex�+�edge—a� ,&� ( SA�mo� = 3a sJ6� ( RF ).. ( S3��erc]g�.RF ��&S,c!�6.SC.&�L� t 2m"�M�SCT.p main� �h�1� �&\,� �lo%J�Wa('2v�B={yD <at�7ET�.^�,�72%!�me�eֵ;��B� ,V%)k64R_..~_N�2!�i�m�wo�[sY�!��all�Nuu�&�of��2Qn.�,g�M*�e�pur 5awl;��ba"Ji4�x( ssessJ�!,���r(X`  l��*�+��b� ", ��� ��dB�6 ( qRT- �uTw~ J�*~#�&L t �!� �N�Q��&+3gB%!N. /fli�4�toy=��V+��4�V[*�8Accor���A �%�σD*l8,��CDm,_0227 ( autot%nC flgM (]��6p:MA3 fliC+@�� �-6��b��"�=N�.(N�+a�-i!�E�misp eh�E�Mscopy � !J majo�J.��Ψ.�A� mW (�xx , n = 144%\h+a��$^���N!%�{6 non-.u( 98%N�63"�4᫅�%�&E6���r"\+re��~JM?�{ �umB.'we&�2E .avkIΑ� "9�g"(O4*�Sal fuE%�CCherryOp;B�a~4 a Red Fluoresc Pro�0-(�5��7&� E��BA6.[78=73G:��e{"T-Y �!gM�>Q՗�?be�Oe+]&l22YsiA'� k",W , it#w rect�P&�0[*�9AsI�lw�st�J 1�"2U�ZG$lasmid-borTE'r ( P!::=�)%i4A@d o:W6 s�6| E#&�"R:I!��I.�;RUe��por e: 7#7R =80��N, fewݥv+R� 4~ 2 ~���!�� valu!�r >�o�b ua���MMeBL!(sF� ���#"I��Dif.CH2AVY. �� g ON2, c�&q(�H�)���Dqd�&4un*in�!e�U�g�+CQ"T0�/�8N=:/bea�X�l� =�( :&�ߑ��S41 ;Utd�=induc)Y2^ Ptet:bK7uni�o  fZs�=�>�*�+�"D�D!�m� by T7=�i@N=E.�XB;r;�# 5 �E�2b]�Fiͭr1J=2�m8�� KA��1� �7v�)i$�on��# ]8�8�YgM�6V�AJ8 a.�U�� _! Egyg:� ��N�:>7!y�� V" D :� 9��( ��T7� �ON&T\]�*z) ;J�-&��Raa *� s>!G >(Q)b�VTly-ar�FF� ].�. GD)� f��FFӡ�defic���Z�Mq� u edica�ZX�3` 4.la��� �N�B�->�!��l�3da he ]9-05�1o�\�-3%W[�?A�"T� �v� %�Pon�p"8>�.V appe( �)=5��#�they & �K�]2%  �** �Pu�R�=4diame(%at!%"$�;ino��*2��N9N �B�R�/6�FF [um'-!AI spatkB.o!&\5F�� K ��!���|-!;e sM[�)�6a�N( c�~R!��!IT s%qbe�A:� ��!e�+� BY�#)-be *�.EA��chemotax 5n�^Y1exp\�B �N%O�begr:8/Y%�.�BGy &N�-uB&9 �gar' d9_sR�(  er�Jn! )*^�M�,A���7�4!qX%N��|C ^b�)�d7!`e��,16���&� ��ON2�fllp�]s"V+ ���mOCA�opeUIa�PCsQ%�.�5] KA�ai7��%a�[�F�nfigu�(o$\6uH32�e-Qm�:�b*�!�bot�I��6*�;s"�K*redM!�2�atA!*- B���e�>a &� &� J�Ɉ��H�R�;v� .�W��0�lsU"�Aofg�M#PHKB>�N�� �b�!o:\�P*�T��ge**!#�M|�%H� A�XxMI,v*�a*� b6=�@~ s7MJ] BA��L�n�#^>s.`OKAR� &�F�P�O,,4pNini�J��� IF�FV�]E *<lIP# }.z�Q�R)p6�.JU.�,�NAy  �B�2��8lysgZq^�>(*, �B��cdB v �:�i�\5tEe#^n blot!d!�a�Iv e�P8&�EBA�a�M3e�8�Ne_l=*�E��' Aqa{ctNq_��L9fvi� 2F_@4�;E�f�A�Bro>�cyt&:Fi ter-!$_hd)i\aŧ�#J�T /#�>��] Vero�1Iv"�H6�\�F�� ]h!?E�Q3�n6 demo���>FE*� cxFR�\ FN� � � "5 FL�EB�MsE�co#at.�"jJBxD. M!N8m&�P drivA�:>��ha�h6de�v bed:%NWhom�W*"�G. ŷ �� &�6>+2&1-�5!� slip^�Nis�5�T �3 methBOaq[66�.�?7�?CD"�Ma�1�m=2�K��0A�D&��0*y > �a�.F��F�(�])��e�s6R*K!�I-�:+Fo�OX+Ec E .�i?J� fimSA�a"�N�%���AI:br��%�7>6 B�� <$g/� eMe� $oUof�kg0�`��%*�J�3fWJI�.e,6<"Sad-��-�"�0A�!�N>:.6���o.� �E�aE�"40� sD �v pibk4��-*vB��EP$n�OO � ��O�en��MY!Z1�beg���ft5!�d�)[�&~ A\� !�.bS !��Wser�#� lkaliphosphaW ( A�2%��F7�[7�eFvH)� phoZ�uo�6x�plaH }h�B�?+M.�2&�O� �)� 0u�!�%$ull�Ebp9��E�"I( F�JinOK&U�or.�\B-AY�3AON/A�) -�::%,C7� #3 & %�` ��j2B��>#r8&�Q30W2�<4re1���BQ(�n�) H�HGA�P!cR|� -�.jD= 9&^#5 & 6� AB�&g%Zc_Y-�J}�c�Ha�p5%g�V&rc@�aZ2e: E1�.�HG!i?QiBY4"! �� ogi��2�chn[�8a�" R � �AP� E��$��InObal�Ce �,y2�~ S&w2to�g�e�>u�m6��� [.M!z"M[6MEl7:-�6eYTA(t�id��!4te5�%�he�)��m!')�g��E.�J:] &)I�d he:$F�).���!i6� � h.}�~:gN:�>f��2$��:x 6��N6=A��0:E�Ir�F�.�Q��G1�\� m:Qs#Usix�O�@eNMr>��!�.�Mt�>mlow�qv� @ S7U��-�2�2eB}dBF�*���aw� .r'S*�l0 \g�"H��ide_.7"qs&r*�"�aO"75Q�)m�:@ : ( �)�kq��ٮ� ,J3 )F�0ircD�K�$`X� �(�ANA"_Yp�$��-�� (��s'$ �>G,B( �% �"� .= �����!~O� � �!�u����xq�d�>loB-�um , �Psubtil�'in�N2J%&R�\ ll��?O&fea�.s��9�FB�w ?�Q�O��u�m�Q �'t�i�9A&2� BS49.��.�-*F�af nitoA�by.59( 6bZl BF�y �����ц high2B)eno9��"H0�&the LBV-J�}Alsmois&�)2�>u�n�* d~lig�".:�Z�P&K !L!�B� �q� ��Mg6��Le25&�_'.�in6G�%��� Q�� �T�!�� �-e �b�V"�""&OB�':dn�(o*4Lmi:�"IstrF*xB!��s�� �H���m `F�. W5}2d2�g�s# Figs�\ 6, �)?1wg�@������� U� �o��Oe!Sd i�AOKwYw��%~t����� ɮ��t$E� n�{e&an�S! ! &� .>+��^�4�a�r/!v� ��N֜~We�kBG%0ull-le�Ez�|2O( ~�kbYY�(e�be2�UA�UAW"� , so�,%A�<�}�¡mQ�&! back�lD o�\.�R�AH- �\:cor�4o�\!�adyN7of ~24�Z��N�^� ��`�5�JKf_ �]�*Fur!E��6A�ct 9"�N5)�:1;�Y�!,��%�./c��jA�&.xXof� &5 or 6�eBakun�D�"(ԁ d fa� �wc"�y�"��6�.6��-���@rB�M\��!uRd6l�2 ��!E*R�Bv� �vvX*/).5%*�� � �U����PB��.�. SerP�N��s"��r�to� KZ&��s6?/�r&�� { ecA29@l78�9]�"�,uB"J�gc.�6~%�i�� ; FimB�J4�*� L3�2 FimEA�*:!toB�n�JAe0 s [8�g8:BA�RN Na 'ed7b�+;r!�"�M24�D2�Fh �(6p [+s82–8�i�ostLA� E=K ( s�%��JV&�-" ): �RD$&�*6� ?d�35:c"mb>4A/P6�eei�}�)Z"V�Rd!���c(& 6100$� ��aA]-�1 syste\#f� tos=�?>�F^��J 2� s�AK2 �.?)clgX6�an anhyd trachkn!�AT�q&�."[85�3Aka)jkn�J�NA��"~  .K�2l31A�s[�to.���E�)�} 6� %�@ x:o�ə�y���dB*�^E4V suffH,z�s5��-�B"� ON>�<��8J!��V�-7K8B>B&��5;%���s�{>" -�:� �E]$P �SA��YY� R�99^���V9 睲��Ol  orgaX&�2�\ =%��ri}d V [86a?. 9�Y���M� \ wh�%x�C �*M^SB� ��e]�lcV/!�&\ R;6y !�A� /nU�<3 l� vecu2j2��2Q��4op�6+[8�Wv\ !��yW����*�#.�"TjM%"q5FE�2zc*�/empty�, ard� -�� ���� ( S8e�, panel a�. T"� J�ATcr^��leaky1�� t�2N8:x�Q� EnHi�7"B^v[8[8[��6�M4rAV�42% E�-h�q*>e�-���j��[8�v�o ci�j l"n"m�$|sn��BlYY� *  `K\ ��I��uF(+ !Y� �p&uz�Rz P(�32���e�"eV��m0 �!�{�$%#V�"j�AR��%�o &�TY"X6�U%(( kind giftɭDr�louis-Cha�X#t��� ]&��1�� -��:B-��3��� �~}{ [82<8�w� t�F2 A97�hr:�( i?.�%� OFF*[]� a�6d��6g�s 1�*8To-��DV ��R �F�s~)%�a�g/1a�A�a�C]���Bo���<��lE�)nt�Eɔ��i%AbI�o�7o �los�b5� �iamaKicol-{Ke�  scree06-�=���,�+5qm��*�J�N-� ( S9��Aց~%n 8*�*-�O �K.��I[Vf�"P::��r��q�!�or�:+)�HI6�5. A�P)�&Q:��6�4^�* � �q/..�Z6H��*9 > 6��a�&0D$�b�Ai�9qF5iE�� ��5$Tincub�I�9#.9��Ec�tB�V*�n{ Hy [�2��N᭡��� \'�>�NQ7B8��7Q��6hR nW8S�,�a�E+� noT����!�2 �te�"QK�Na�yE�=|�g2{O[ya-10..��ԉ�C�$^B}�e�w2�bQK}�6pA�_ )4�f��� �p��M�=Q)ore��_f next���Ux6�,b�94N!2�Tx/* F�/AsEn abov��br Ked q ^%�F5"�8q$�5la�Jo�. A�0�{Q.-�2��ze(�9� 6�wa�e -bu�sQk,N�K!��#~1�:5%�W2�T:�Ke��`��o �^�U�JU9ce.MGS�m,a0 ���s�AA�BB�1"�W �9_}}�职ai�%f�1�)4-�� 2r2.�EviB& ��i2C)�N*!.�p���� �}š�R�%& 8�%@ul}i�.� � ��AQ� 2]�����Ii"�Yr� %zM�amo5�sͽ!e�6�&Y¥ �@b�� �*>�b�7� �"�?66 &1���"�C�; N&6� . >O2ϑprey svґrׂ& �� *� &�-, � !j .�,a�V�N2 I��4 i <r�&c65*3a#( c)Eqi�h!1_~�gas�P<1�.jh~�cf�TG al ,Erg n�& "�i/n! �m �t:�A(�2� _oA�H�^�n�AߡR ! zv�u i>Ԕ�� a��`!�-�V�,�epiA+g G�Y.51gB� ( S1�`Z�� "s�>,8v���f&I��B(."��"�PO �Ij25� )_)�!N� 喑�4�=%��(��nc*��.�1��遘+ �Ud ob9, �� �6P "��LpB��1�5#>Qdiyc�Ebneo�6�9!:X�h�hi>�jn.zB�t�.(e��*A���=se�MP�96�E�-"&�P l ag�Bo� r�al�*�P~-stia�2@�]� T5A�t<�И .%�V�u vivafa�^;by4 ferr�2��tNb�ed�Jby� opha��[�De��y����D�_2�)�� ge adsorpA! 2 �T�C9�YPin � i�� "^* l)� �!�I���EN圡BE�6�}�-yet. ;����U�E��4e�+stT��2G.xE:%�n�*DEt�%��2ur:�c�B�3jK�G!}*�V�Ac .Q�o O*�>1 well50"�wi�B�z,H�2&v�E� ngag!a!�:"Odunc�J�.#)�*�&��%::�:hA:4�6� �1������C%^|t*q�>o>���LR�2T=2L> 2�� ���I&:���by �BUc]�. More�^�.T�Swi��]*w )R� KDE��@T0�c pathw2&,&Iv�@.��a"3%�59Hr8.id� d�~� �>!��a�@��:� g�6�=�28%�?tog�""�u>;wrfacil�Z�R�T=~ J&g�m&_"*��%{26�.�+ {F� ),?,ex��!�"6GZ���Kr�E-�Q�u{-GAI) ��OSU�:�.�z4=ZSf�3X �9d*+" Inde"�6 �i�9 ����5ly�N�"L+"�Z;F�2 p,.� '"� � l"N�1r&�� "u��!�-� �Q����GAŸi�$ 1�nt�n�Ork"lyN5N� F�=�k"Z>beyُ!h�A���B�. R ��[H fO.byE�25!�6�A.��!e2�BD x h;Սm��� ��/�o��}kF� � �/!-�A � H)�>m*ado٥��,;��4*q6 ya�!�aS�"D/.k0!� �I&�$ �f3)��&ד-.**i.] 3d�Qn�s�-�dE�FA�U�Ss� ..�6� AV:�7M 2�,����pl�"6� �'&�.������Mt�el�5eo2�.N2q;\o&��<� �` >mas�X!5un*� EN�&rBG2 v�.A�"S�7{y�_5,6�!�Na�si�w^l2!�J��5s��"2��r,�^�jՌii!$r��Q*�.��d�GB7fEO�- �$znsX� �-��>�.�> , eCmV�B�:�pn.�:,,R��&er"j!�%e'^\�4n,�W�*F�:��f B�r��a novel@eW� x�*� F�5%u<\x7n K,��.�Ym��� iL Il2�6��: �m��2 s n �2E�� �9e� &�>� `l&��,chauvoei [901*Salmonx� e�2�serovarTyphiC�b9o92=Helico� �rX�ndZ%�9�/#��of6�m�r�#nktonicy�s bifur.,� w*#k&s:u� ,�� �i�Zq�>�chDE��i[95E�*���"| of� pH$Z+�8� ar\�>�..\�Qwr�.�%��l�4U� +a�+g � ,�o*�>)Y�V�K��c�c]� –9+S�K:2� ) 1Y�*�W(/chzi b9%��ᦁ.V2c.� DegU [9&*ū,-+�u �fl s qns�jbe ��2�2p_�;a feedD� loop�O�ŋC��A("9c!��|� E..���� 1;A�AcG"�.�e ;��m�ZoI2G7a2�6zia[T l!�%�A�a&�.�+ <ee;vJ� �02�j~me��� ri��ag�iE�[99–100�&;MZ^h��>D+� p�#ic:. %u� N��^n enviro�� 1�A)�N�_e.E�)��!���2� !�6�]��� 6��(c% �g�D��G*� �as*�o*C2�'B`Y8-RR]1,a�-�A���.6�xi*� �(ABp�sZ �$>/-B..*���{ *�� P��F��6�. �!����_r*.*�2f",���In �moid�!rag�C!JMpi2� �a"8�� A13F����*�tcie+ S.N�ft capsuU�sacxqD�loci [10E�F)b��c=�4.<�A>y�%I��RQ at harbeO 1ńc�~$n6�� �I2!\!;BWt��! half�a7E))>�es�%�g#�ZU�i�6�al& .�"�}A�-!�"ed!6;m�8�o�b�^ay� �A�̤�@���t�+A��-%.׳%E� 5�q�\��?:���.E6�and��!&[H&�U�f�2�~�. H.�2 jǫ chieNsol9by ��==�g M� .to� !��y=y�*���-? �partn�!�&Vby$/"/"�<du�^�. IBS6Z%|��9i � a histone6Ȫ�$%3%�)>�6( RDF��8>V10H ~�u�|e&4AfQ�!�A���S�� a)br+. S j\�ng9��OH.�>���X� I�2�g�n ��%3�C%�a"v�"|���!.o.�2�%mpl|leu���3lv^9e;�-�� H-NSqv0���[10�W10� ��exH�5j�Vf%�!@6�B�ik���b�,-))��6i�� carr���po��ϕCD38-2P��-�b ��6�3;A8VI���unWed6� Pk&m(�< ?��g.~r �.0�a8��9!=��i "�M� WmII:.�!��JH���Ga NA�!9�f*�6�[�45W�Cmp��uma��W�'9G"dR �6����M� IJ �&� u��0 �e�!p-_ �ab8at%�)Q�P�c&�#d&m\� �H��RDFA�:�&��:N��p���V2�B��)�ex3��%ʩ\a ��io*^0sB�`[10�YFu�G"կ#M���how)ȁ�j] �div��62�2�UltY.@&� H\=�W5%v!:�" s%�5�:gy�-�"$�|�$6A du��#sk��.m�%�h9aab�-���M c�us!w�o�S9[ ttac�z� ��ol&.���=�!r 8or#p� oa�5�FF"� "R" prob�IhJ�%6s�tal��v��\�>nti��5VFyBt�2�e3��r2.B9�%� �;"1�U ough�-�r��%at).!��*/=C�J�s*tA&r'sf!��t M�bI&ab6mpeO�5eo.�2&��u�Yet&�|-DGC9"C2�&)a��.%� Toll�]re�*or h�TLRj�A�sz�$e p38 MAPKCa" IL-8qCrei#([4w=108��0^" a1I*��#� �A$h�[���$B,F�z�Vic��fW V\11U�I*�0�6B*dngɹs� �"�M�@-c! m[NLRP3�Pyr2fl`�so=F�+ �!U�*��[4%L1�G6�Eq.�% MCqO�%s!E� !��Q�5���X��Q�l6�@.G��.�z�Fsu�e~�libut�B�P&�%. �aQ��l�EFE�C �0/��)� S1 T_-d�\��� ir�?!;in4Method��6�0m&H�A�O ��� hamb�@Coy L��){ -tm_M;of 90% N>>5% CO �5% H2 � Ѣ He�In�Sr u&�0Becton Dickin�)B8lemen! !�Vy�ext�(N8(�q � 37°!T���.�nT����Y_ ( TY�]���a�ra�%7\ All [�, 0 X"�7�A�q�Jy sche�i�li DH5αyTL2�!@ HB10>� pRK2�M��AC�cil�"!WI�eVAA9��gap� r�L��>A�&��-E�S.foU?a�con� �s: chlor&�>�� μg/ml�G*�>6kanamyc�@103amp!���,2ery�4 5 . 6 , linc 249��+ 6 )2s�0�,�/i�AT"��%�p�$7%S>;6�x1% so~�ta*�(maU>+T�DAM�"�<�Zی6�atM_.�nxM}-� dilua 1:50A�fresh}E� PVRӿA[|��. An a*�oV�? bEa`�o�$mM Tris-HC!�pH _��81 EDTAa�Ea�u�{A�oiKlR3�5*� �X�Gq{d����)��:� �&N &%�5d1�aTZ�AM18035A\ 1a�B (��eS�+FN2k�� �'W4L4 j.Gy'Z/���s s&JT��Jm68837�?ev N{156!!� a"M*r7���!`�sAD��2��* s R1614 (&�N/6���nd' ejd.�)i_�o�-r2h22�h 23 (�h}�.l75��#�^�75���6~�5~�� ons � R857E�CjP.%��1��ty"�&Ii�-*�J�F%�"��+M�F@�H�:b� ��.9%�'�Ze��j"�tw��L�\RF� �1 ���pl"�l�+S,&=]al9"�N� 6�MF,!X*}d�l��K"�rj��v!:PCR��u R591�!�2ݚW�+665bp�h� �A5RWgQ�d�& ���E� 1�in�Q�&�l 2X%�.)H:̒bp�3�ew�U�2I�� 6�a�6m24(C]AA�� daCE)?B�M���FNe=��9�at��]�.)arm{9E��se� �59|osClm%� .1�ethp� bromh( EtBy!!imэ�8a G:BOX Chemi I s]SgI:.U8U���2�#{a����bRvdK2:�� &�?�"rgRry&ɨ�A9p�op&c$ ���eJ���g a d%�o9�e�a��� Au)����! rZ�6^�Z��(e,q ).nŬ(E�,Q�).�9 a�R̙U�g�(��U �%v� &�to�6QyEK[s���s�2��In�d�0�bya��7�(��BI�Hau ��%C them!�!�R1^ �G,�� 4A I a��5���w �� �.AFWN&H�&�9� ߣ�F>�m%(eP 6� -TA�cP .��.�� sul�!�%Up*4�e�+ yAiEve.q��^&d�5� ex#�9.}�1.I["�k�Z�!�. Ot>"d&�~6Z~8"�d� �< . De��>1��UO�osoftw��N$b__H. Vi:!#i�c>_�2�!�͈e�]�M%c*�>~2an����e�1'e��� �U�^\ ,- iwoA|%�V�>Cڂ��J��j�Ce�6���ole �Y�BmĀ]��v��E��Q!Oa� n 24�)6�La� &�S'�6vder���)��� ��n.����S.uOABF=�]$6�Ϳa>���No12Nԑ�Bm ��.xA��A�t�}%���(��(N�OF�$ll2\us��*Jr ng-��:�i, +�� oJs1�J.&�z), F�e�pstockMP!ma��obrob�� C�cp&��3^F!�ZF)m�*�oc��"�ֆt�:);*Z & ᵚ>��/� !?SYBR Gr}yReal-T��Krea��W � mo F��y �_h�� ؂��*��� M%$Cnnegug��eQ�re'5�TJp�riD���;Ck * !~ �K�B� ��l"tn2 �A|9$W ����\c������v�#M9:�( R2175P SK�Pm�p��88 . 5%X|2��#4  ��F�:1? �6����R�!`� t�/62�%�& �d��2�ofm&>�3�`:LSA���V�WachI��J%� OD600.~1�)cN����:"��>�. Q.��e�XdJ u�4 n�!NE�^�.#^�num�JcalO5.�ΔΔCi��q�!�rpoC genu���rg��& A��.p. I�T>H:�=��)p! D:z,"?3mL!|�;-�ay @K(�o*A(9�!�8g�%����j!!M#d��9�*�iK11�+Brief"�Q �&� �Eed�f���~ndZ] b�$bea� /�d� SURE�i�2. Ny� cid�YRw��o;;*�,�cipf@*�aqu�N@iso�ano(wasaSe�R�2\ RNase-f�wa le�rem/Sa��ngA%o��,5m�aiTURBO DT�he2A�/��!�A� manu*%urer’aWo�%Sy�� of cA�!�}Fa TǑ .ki�x9x��e om hir���l&ru��tB&�Ea no-�,rp"""4�"!0z�%al-��E�2���ґ.* B&�%(�$� �2kWol!�e�N0"�:/i[5P!Z.:-m������y(m~� A�x"@ .4�b� �A"�'lG Z%)ʼn!�nY�(:� #taz7�M��� +���.n!�1"��A� . Autoclag �5 X�eEb�( 30 mL��ou�)$8� mm P#��.�/�.!*��ify��*se���5 E�kep�#%���* !� '��p&OQ�9��"�A���:ove�,.�>V\!q?Xda��!L U:��!?TwoNVl�'M�, FF ��%�������sɎt@�YA>&(�"@�:��!���/�J��; perp .��r9m��� !����1%a^ygm- r"V�!���2�R �!�n� >o¬m\A�R:B�Il3yod�� r�G�j2�yDin�"*C *IaSto�a ". L<��n���I f ≈eSm. 5��a�n" �su"�%�discar�i{ pell19O�]at -20 �. Frozen61tha��Px-�3nǃ�V�&��UR� 7-:BB#py� -ErmQu7� "�%Cs�R�A��@�lCFA�A/APU-��&� 6��� in 4F� Nk= �uE 6�v a� & JS�&-$,��ur�S+�.� EY%6Iq!O"�~rigoro��2� � I�� a*0& � �� goxi����DI��-labe�"#�,��6|D�TZ 9�%Bz� Z�Vjti%ca 5S r�*�o r03 ) &&X� High�B ���; ( Ro�>�U�!m )�{��,ernMax-Gly K� > �[�H~�2o3S�hybl��Z.%��� 15ug;�C�500Җ�5� ) ob� 64,�a�:1Ig8Glyoxal Load Dy�42�5��c� in��I[2�B��2���E�1X Gel��p/Runn^ B�$Sx%%��2�.4�B�4�; firm%:�g��V S1soaGG$in 20X SSCt M NaC+�300mM&c��� !kA, �Ted� capill�%�"# a ny)P"Z�(��4sham Hybond-N+ " �!x1�Izcrossl"��A�_i? a UVe�t{ker 180�%Sq(���pre6�%� ULTRAhyb c&at 42��� hr�  μ�aaRF� Gn!��a�b%��\heu�loa�!c.� �add�*X 5�u�in8N�p,Fing� �s$Z:(R�a�%�F�he2�el�N��kKe�1n���� 5�>2|Z o.��OL�[A�RDe�x� Sta%�~I�"��'Kc'!l< e}��Jd� CDP-@��. Mem�z 4 a�T ilm��u!�e2�� v�2e� 62I �a�>? �E]"�)i�(�Gth��gha"�h ��� !"]:���0�B� o? �ax�� ɢJ%2�(1X SDS-PAGE��M ,%3]%�heC at 9eU0 �c ��)�&Z#�nצS-�? acry��d���.�3 n���superna!< _ colli�$, filter sQ r@( 0 . 45 micron )Hslly�2!. For)SE�e�]�%7E� c �1[�^replacQ�)JUx. SB�adm!follow��%� ions �aL2oa: 1:4 ,08 40!�1:�{8. As a negative]uԅtre��Y1��f�!/�Af!wU�at 37°C-(Mv!carefu!x=�aspirEY-�100 μL)�ofF�um�4Promega CellTi�Glo reag���)[to L%�. �10 minu��8at room temperaA�a�$a shaker ,9) lys��_ transferrI�0opaque-walled>�$. Luminesc��%measu<ш@Synergy H1 Hybrid��d��O,Gen5 softwara�BioTekeyDatmH(combined fr�wob���v�(:a. Relev��E .a�i �|s �lis��(in S1 TableB�sinocu���� �%ha� above-mena�ed ioticsAUonA�0I�e�JRm in dup�H��MnVan���A�8nhydrotetracycl��( ATc )EGU�aR�%%�Hflagellar switch/reI)�� pair�a final�&��i�of 200 n%�, �until �1 �� �plasmid��purifi"n !X GeneJET P )0 Miniprep KitJ* . PD6[us!�se�!�!Yan orienɬ4-specific PCR Amy!di ify�.Pthat catalyzes invers��eION=�A�to�1�mis0e���s�zscopy , 61:> popA�io��� moa agar!��� ? E��brieflyAhE�@ Dulbecco’s PBS* prior�suspen�in% -4% paraf�dehydIIfixIa\1�3!�@anaerobic chamber" � ^Madsor� e�(Formvar/cop� grA;,�wa��I\ staia� 30 second!� �� sequa�al drop� A�5% ��@ous uranyl acetat��� �obser�@on a LEO EM 910 T��1�E1�MU!ۡ�$Carl Zeiss!�LL� 4Thornword , NY Ayr���qa G�$ Orius SC1 digi� camera )D (graph 3 . 1�0. P@, Inc . , Pleasto�hCA�2 To i>  b� a�$lony morphn �wemk �(Stereo Disc�m,y V8 dissect�U�e �a glass!�gIFill� IJof>� w��l� e|AbtopI�ottommwfluor�W{�6nenrica:wmfsZf.� bear� CherryOpt� orA�fua1saP��) d�im��,>#) � $�fF of ~�5-�s%2�$ATc-induci�sN�$( pDSW1728 15��of=a{�VR �� � �3�;ie�� crip��H7{genam$One millil� � `% ��pelle�EinMF_�$!(�eaN in phospha�buffed sa�9� fix�Bccord!�to publ�d metho�\4eB[73� 3����'vŒ! dark!>4 yo 捀wasA�}imł}2�ImL%� 3 μ�|4′ , 6-diamidino-2-phenylindol��DAPI )� label DNAj� a� incubi�at �-��,� ple � �!Pnd6�1�of�B� mmob� �w��ads *d��%sc�|h ��(5 thickness�r# slipa��"��C^=6e Olymp�X61 Upri5 Wide Fiel�cro�%�a 60X/�42 Oil�$nApo N obj�ve le�as�S���A~sa)N��4Volocity 6 . 3��B; e acquisie{,. Multiple f�-�takenn k!� a coE�� fash�3 n�  nS p���!U�= bautomatly>p�oe ie�nt�contras� DIC )=nneE�ch ( Exci� : 377 n�+/- 25 a�E�� : 44!30nm )"A90Texas Red/RFPZa562U( a0 6a64J!)I cons� nt set�s%{side-by-� parison .�-Iproces� !3FIJI � of 0J [114]M0b��Ƀ visu�enu;a�Al!0��2, �%wh A�!1!�-�s a�!�"of�0.gEndospor�  i�` an�t,$l developm� l� gram� ulmiA�!];E�|$ highly re!u�e }�rI�>4model organismw�$s subtilis� ��expre� ��f^ pore% mot�� s �particip��in�� ,!g�p�ll type&� RNA poly!�se�$ma subunit�σFa!��BσE.�erol early!�g�.�!��r�,�d `2,�σG,σK ,!�p��ly�t!ngIW�)+activ5��s�facto�@s.� WquiQ+prece� /�n�[volves%�-!�Un�� g pathway-�o��ke*� ��1. H� �$ have stud�� funcE~yregQ�ofA-:�I�intestif�0ogen Clostrid�A�icile� obliP ��whichoU�s%��l���inf!�� <aThe&� � char�>z5�m���If�,Ae llel)�Oe�2`re: or �A�analysi� >�, unraveSimAa� devi�s& B .ai��dig% Wh!K�m�� �A��c1�2�a��E showi�O.?elsw��ly "pofU�ati4zis not ,nLi��FkK doe 9riU . We also�a� dA`ct�)ePd�1 he��;!�� ��ɛn��, oura�ult� d redu�< oral segrj on betweeI� �� -n��aD�X:+)^ ��&�!σF-to-!y,!3 G :σG Kv(. Neverthel7 6�dortovie=��l����sq�network!|YD� volu�=�n�:xF�he���d�-<�8wa� esta� some�5 be Don years ago upon �4emerg�a �b�Y YFirmic Phylum . ��é�er� �prz�c+a�F�d�,�*�A1m��Al� hereina� desigIdI߉�simplib � %oosI����]�?-kn�Ba?A�.���ra�uti�by many 1group�� =qp)q�����extreofs��u chem ��meter��(would rapid�estro�veg�� !L�J��Aimos�z1ou, truc �[1r [2� Thei�ilq�*ow�em�accumaŴ� di� e environaՅ8) , oft� �ly lo��er��� e range!!Qs occup�by)�Ah!&��clude n5�0metazoan host!H�r%#ga!N-���� GITa�0g . [3]–[5]g2�,A� ex� �� non-a� ic.� , can goough s���ycl� !th�*o !�ger@ �Mm���Vt�KP)�A!*Kvehiclea5 Zinhale�ag )+ic�m��anthraxm�pot�#�* leth ise��ca�by%7 7cis [6ArA�� , it�Za�^te!�reso ��� surfa��vU9 !�rn��omacroph� !B +�5Jto loca mph node!2� aL*� 1aaU� , [7�I� x)\" huma* oim atE 6��"J dTsutac1#�stR Aqn7tar�{3ing+o�% s [8e�9�6�ie�%�i���2�1�w�osymu!sE�i��0mild diarrhea!vE�a1J<8inflammatory le� suchA�0pseudomembrancolit� toxic GN! or bowel& fo� �10�I%�K�8� [qw��!F Z,���A�"�DB�E� willA�d b � cyto�ind� e:�10��1��Yo� s beeh:��m�ize�gut i� �!e9� ma!�distur�!0I!Toxin��eis@ p� �u%CeA�U, w����� �rem� ? nt���,e�bot%i�st�a.�E�, 56�8 a�A��G  �6��)T�\-#Q쑲unh �0 ii� �t"8 ��&�[ �� �!�us ha�!�ur�� ^�-_U����.��� curr xt�9 leaflet�is EP� + m� germs #a�X#M\out�9� � � s�)Ui�$sc,i�)&r.uis enca�%,*�*d� j�ȩ�rte�����.yEvaa�naM�2\ce%̅g��c \is wrappx a m��! in ce*��c�t�( ��bG-break!= enzy; pr�@V'2Rs�� pred�8s:�InO 7 Ztq%s:� ,cereu�d 6z� �is fuzr!�lEe{%�>v MKexV&i=J!{�!0en� , (im ����M�I\�->(< 1!� ? 1,small molecu� �� trig�+aQ� �q5I8e�2bA� �>W��b�ia� nsiv% ���>�. [21] [2Rod-shaA~B��#�by bi�)f�"�llM$� �,ymmet� (�a�, divi� i�facP�� nutr�t|�#o97y�a lar!ImM�!�a)xera�e)1Iifu� I2.=tA$engulf� &C-���Fk!Wo " ocyto� ~hallm��: �-A�a� surrounEUA�umnnd re�!ta��l�?1i�a douP � %�taG^.��B%)�,QW� exc�� >A�)h��aV} a�or'��)zassembly!J�-����u�sT ly�&bm�.����EA�end,=�nd*P+a� io(Im�)� �.gundergg��� -��fin, QW�m AVat e�q� to d,�by ~NA&( TEM�tA�b9�$ "�#ev�/�X6T!C�A�e m�"py"�� *` x hierarchp �Q%}-�.91 [� A ma�-.iEi�$Spo0Aa$�by�! oryl1�8��troto%�nA�>��(!xa���b% a� �(� .-is!^�/� by 4i5t2�6�qL4)�:�, a�.(%ng" A`&n. %n �$`s�of.��"y�!�5.� ��a�ll%�rbyiiw�OAJuTf%(m� d%t –[)tAg)�m�2p2�coi �d !�of56 媡^" ��heAtj!ht�-/�[>FmO�a| alig�{X�!2.S��,.fi�reb!*J.�!deployVY>h�$Rea m a} nursi !�)F���a'=�dd�2m�!VA�"L 6�,%r�fe�ward lo�)( FFL�4D t7/v^�minimizpI�&al nois? d im�$$6�fo {��j nu�*of�%Q2F , �rib@3MVf)!A:�%$>#,�. A��9k4)k"� �D� yG ,�1A!�M�>p�defD.-�est����U"��3����.o��pi��4:5� F!��I8 y��v�!fC�o ti�“:al”-�"lower �FI'%>��E �>� � ���� sugJ�t7�!a������2#lso9 t�,�H+�.��NHow���dva�vea��B 8-��� O���6�2xdu +!�>�!��al&� �2� 35D_5 inst(����_����.N�i�- obutylicu4p perf�k'[30�3�33 �N����+.) �R�t"of:@-Q.�� ��re-o�e9ofB�A�botulinu� 23:C�6� �re ve�a��/�i� he=���0 n ol\4��� �N�m70�N>� A��dB8N�, b�J ini� r��in oxy#ds [q�}3@Despit ?" !@A�E#�hU heal\I�aG)E!#a>A�a!�A�K-&(�=W � al%��arzч>P!' lac�%Bs$�3edB`�# tics�hod|e�4�ډU).��m@9&!!���A�:�6.+a !�y�(a*�#ZK!����Y. Md.$Ea�e�(CcorE�I*�'�-�N�&]'6�"�c" m1!q�. A�(2��at�6{.y!M� ��"t�,ly�p�� . Ou)My�provi�aJt�pt5����&��*Q�!>a4�g ng+:a>)efj&orE�� � f�'�b�eU!9�ipossi/)�-<��)m�� �+�"arlie)a4+(�Bz�Q� :�!j���.mongst�H��'!L � [3� &3(��4.��ys �pK=�g-�26'fe.yY�goff&P!�:��!�$phenotypic2i'�s blocv��?�6h: &�'Bm*a.in)��t� U >MT�approach�%2��,du!eco��!?����>� ��:& � Z2!)6� 6d�h �f�,yHI&�&l�&�3r�'�<cys� !1dskA#"�3j$!R1fis� ly h�#�je,� asynchron[1�8 , [3� 9�=Bew[40u"High tg3e�A� �x�).# 48 h{�1 of liquid-G��S* MW@(�S�&�1by Wil�.AOco-auth�&[4�&%S)�d-�Qe!_ver� �0+)�. M2r� �SM&%� 'm�c�D�(!� orig�+�&��,%�u)7!�duen2�9[4CWCtq#��>�8 �th!V!w� !�630Δ�in1wSM9z�?/ ZFigure 1)no��c�%-�c &b ��D�^� �%U6�e%U72V�(���6�B�4!�8%D�(]G"GIF iN�f�?M�a�K('��8����dRE{poi|F$ed�-5In!�������m� G;�� magnitudeJ�S��"yA"�BfRG5 ��A�s&D )�6�A��e�&�g:`2,� adop!�-�wanto moniU 9�,th (!L w{ �-$1�<X'i5�^b� m�e"'He�s�(��W&G f�A&�E5qi�.�yFSM��"�icN ��=�"�4wlipophil�%�%( dye FM4-64�,�8�er�4.>re�&!M��in7�1yc�<I�%h ,onuZB (..a`k>��;O8&� )�!io�Fsepta ( _ �H!�AY�th cu�>M� ��,i .�*,�5� �!5�3���m("/; ob�$D Ӊaten�4�$&� !U,� readi_4�uH1B%An�!9�p�d �pl+ng uni�1�~a5eentirj nta�B�>�~Hpat�" * � �&�>"d��o N~!�t�&A��a�JnepC!I�.)��In=K)�!Aa�inu ,1,M�s�.�z` a*2yeg2vn7qL�,E r �G ref� 3%A� id;=toL jus�J���� � �-� :-�,[dAJdi{ �M��:aED�D� S>�IM�,U05�Bby1)cm�#`m#�carryA�9greN-4B3-.e )�� 'b!<%���%F ���m6j9B�aO� variU!e� ��I {�or 6�%Yzen(xaJ AJne�F�;�a� = "�"N %Z'�, �e�!st:�y !3>�m����r*] disM'�on�o'\��& ed%&2�.n,!A=B)"I R �SA !�-���e]=&4}*�a�raL0%�a/ situ��" .g�y�����"�5 labe�2�" �s [43] (a,i5� S2�C&]���smA��9���1>d�0.b Text I G�P�B� G 2�( �doE���@*�%eb5U&3��:�n685�S2�y,��s F��;)��w�r fV3e= �ZiE9�^mmH�+b2�q �AA,�)~ Mo�0N)!�ra%�tV M���a�'�Hs"�3H no�Mf�" FMAP"I�D'..e��dn�U#  a *a,��be�3Q@ac"�f�m]>F �y( �/�2I� �l*e2L "s5�1N@�SP<A�at� ��j{e� agre�i�iC�m}r��en�P:!gp8)�7� �A duj&y%*| . Sur" ingl�!0.� 6 xa�!�ed� A�VrL��m� U � !�c ) dec +� �36 4�S���4Br�z,� cA�rZ� s d , ٴ/6�a��&,28�S��-ؙ� Live/Dead�i�enc�74'�%i"�)oXPs^1:� �.1�om)361]�Rj�Qs�W? J�!^� , �.�ng-�+onlp8r�e242 �R�E� E�sub�[�v7A6��U�v��edhA-^�.�'!)�o�7&g!F`(*� A�s�TfI&1�E}.us*5%!A sEp&�3�(e��� :ur )�&�R�Af�@�.to��&Ta��a�c�e ..;>���>e6 �"�o/%[ir ope�N�A[>0icVt��Jg �BS4='Lnv�2�@whe͕eB�A�&�&&1� on �rX��c2Tgen�%�N isru!��z� pur�0�ype II�rl#E�t7,Q.�sig h, �A!�T%9�m�YAs1 i"�! %'- aa �i!��K�%�2� er��� codon 1534 sigF��? 1 sigE82 h1!� ,3e��5′-*+splitEK^-Tx*�kinCdv*a�!�c�N�6�!�ver41�5�b1�(byqQ SouA0nkt&�  h`es��d"Yn�S-Di�� e�om+;OeB"�]&B�g EE1h ig+a)d��Npa�>al&���EJ�Lda�a��Յ}�!��"�22w���I2�W�_@"�of��&V,ffe�y�m> of 3A /ml., 2.\�6� of 1%7JC72�,��I�2�I,f�%N foun� ny*� �!Te( AHCD53x ,E2�XDgG�'�.*2q�03V�!)of� ��� �K ^ �&�B��� 8G3e� )d�31T&7l5 q'ea� �cpIVQ �/8id pMTL84121 [4a2�2�t�&Rg% omot�O(Q2"�*p  frag��/a����u� �N"u !%>��Asi-8� ��ha�G $��A�og�ke�axrt :�g=4� Apu!e'c YV(A�IVC: or CD1231�\��;F� w�6� etaiw!�p�o�.� �6�!"W2�qk7��� Zi�NBm��A� .F!~!Yf1"�' empty vecjU=. Der�Iu+2?e�m�G!Y�!r�f Q�, pFT3V !sh=�I� )d to^ ����F:�9P&` "G�"  � s�^ ��'rg�re rR~} M�� .�(�P6�.��8�O 59 �8 ؅o1�JQ�J%Tm�Iz�"a��"�j\A�To&5%~6�5"�h�l~V� � ��^� � D��_��S*����2kag���%���Kj>�*UA�%V?P ��#�&�&"2^sAKcAs��c�&B.�%$, [46�! [47]�h�AXed� r!��poH7��� occaF ,m&:�\=9l%E�cdx7@Q�� �I&�'2r)a��8`) �P �,�ba�%� � %ơ!ch�%!�!s&�9��� t�0��<*� �� .L0!g�,a sLJ:[m��B�(&"~Lbi+�E�1B����D al��G *�7! �*G~c��did�!zc*1urR !i��hi�j9�!!U��Zc6o��1B�iV\,!5��KAsk �F��B�)�!v� �"MR#n-�=�o����rq�d?n%'�[s�7�c.?�!`t"9�G1J)��& Y  "fB[. B�)�?�S a IN�� -lik���by%/2�B��/6n.�[48v/I!�i�=gaS�{ �9lo�C z�.�=,�RrEN�.��NKQ`.x.�9"l6o"�+6Hs ;=-mR�:6V[4'[5V="�A���>�!�9̍}.O)�>LXKq 6N�K!��!"�O;��a��` �!� "d6�� M��+���Y� �6�.�.A 2�?�5Bv@�H�9h�hrelPKmaie� �wa�TE�)od,fu��"fgfp c&�NMa$(� 2K, [51�("�2�0bstacl"�0 qTorMd*� �,\>�FE��TUl!AGFP�oph� invPT�xid -re!�on [5�'� ��Do& tur�� SNAP-tag�.o8^j2rM�!&3 �2u benzyl��5�yri�[e�t6�A����)� JA"�ab�S a [535P2�(�9AQ1�%�he �26b1�XC�z-u�e opt7co�L"�Bj0_ Ma���4Ml];���&^i� �OA� C-�i.tA� �%w<"a�A�+s CotE%2CotB [5' [56]� � 58�S5B 3��LQ����I!!{!�B�+!�in&e!��e� :� ; k Z1 �24 V�-p$�.l�EA TMR-Starn��U�Ece.f �a*Z,SDS-PAGE-resaUd�K� ��Oa�DR&!�-A����o"�!��=-���Ue�%!�g�'is. ��S6" 2E]�� otB �,�,&A��������n.O���,B�ER J�,�$�����A�f��iBK9V!��l�N�$^[� &9 ?� �=D%41�+2-�%6sta`���J��'��ŧ olytdP"�e"d,�%� D30�� EWdo��B�T%�^�C!] b�X.9�M��eit�J�in'�2U�9d%el��al!���Su��gT�0TW �"h�?(%8�Ind� !�D �sS� ��ZD)�q_"� =��-� �aKV�2Y&���!I-�!*�4 �Na,a�8ic�.�Xm�!t m6�$�B�. P6+*)"G �#���sw���I'l�Bd � * .�͝6��8o�Sf*�%E��rarA y^I �#l�boidalv =FUa"Qlq*� (qd� �*� ;-�Oax* �O.� �e��z�3ear�;F hF AP�6�7�synth�0:!u%=xK�KA�.� Be6�gK�%P 7jN1n�hDfi� u�.� �NR�0x0v�.� b*!!��#�uP�.q��p ��a1��=drat5�E5")`"v]�!*2�ceMs�^9�A!�)�&� XM�A�%�g)%�s N}�g22:pc) 2 *�&�%�w4SM�w i�.o0!f�0,�103%mG easuO>&(�1�B!S+>+"�2��H���M� �3��!�clN �6�$�`rge=*H-vQ�� aze!�dys�9Z>oEz.*�w�Un�CO)ar��Li�+e lq�g�/�*�cinJ�L�ny}+�>� � h6 �� svor�c)(1@6��Z�aory!%+bi"�B' !J6�!m�"ti�:d�Vm� .. -~.� Z.�y�ZAlt�U��b�Bik��ta�W�G!f�?Xe�� :i 42];"�1�d(t�J.]�6�:; ��5��g�BI7:�l&.E�~�9!����a�P&)*��j.��M.P�m!"utes&A g]i=�?in2� &"a>�%�U2� �qe�& S .� ,>�2n/�eTl�Cof vi* `6�!t�&p propDdiod�j)�>,e8v0�ye� DkSyto 9+*9�3s�VM%��-���*� ���Wed�l��W.�(B�� z*�'3j� 7 �%Rpg=E( weak�r3:�. Las�,�*�0? ��u�-.�S?d.D?�ninsV �gdY�@�!]*"� =b ,ei8.r�U .�g�beak+a�U� l+#S :)J!rec>�3C�b�!qQ1R*0$.�q�*24�9�=�2�M3CE��n���?y��"q#� �ab&� �$c:O -&yjde�@iDa--� el� %~PWo��� G'n9�[k=qA&� � )&d!&�+a�tac.�%�9.IVCA-�+d exc(S1� �elE��6�V.Y..(w(\#��E� [<%�e-_Bs�B~"�< C =Y:)�EjA.s5&?�.� e�6u� M�Bg Y)�v�$e7�fM �!�F�M] �"�=f ��^�GA�& �� .ter� ifxPE lead�Ia�s"U�%wJ�Hav2"^E�in fe�R�#.u�;�*ufA2x/a�l�Z!p�A�:�ZW)��M� A�M we n*&�:a/��g)&+5.��B-q: step, MaAC�6�qE %s>w*)�!���5�Cd�(�o &��Ga��� �x +m2-� $6�!%S1�h6� v(�)���B� aF�{*�u"�%Pte*PS5�[5�weE#V)�z��teA,A�l�.�U�u� achieved;�Pm� back(Jnd�"h!��d)�h�APh8or un6�Z�!��Ar�yO^} �-��Q�.�i�] oblof"a� ti��]od]1of&�r���S6��5� regi,��+,a]�++I��vI�� cl�;�! Cd-A#� ]probe"�% FT47�5) �,upQY am b� ar�m�L&<B!�* z"� )/!�>Y,<�!�' successfuMzmN'�L$�qg*� S4A6�. To ?hI<1��\/:�ݵ&�v/�Cesu�ng2.9%�w�&�>at�$�42�'��"�Y�i�YyuE�"vA�+�=| MT�-�S�A�~�D�2&-�$Br E s;K�� "?*� �!�S"!$�/7"�N�N(���y���G�;E&M�Q Psige�Cd��1x��/b*%J��a9!�� �|eZi-6}�e�!t &was͂��^ �& �"+ b��XI� �<�,�!"0v%��x� ��w:�*-� aXl� r)"�averagA�[A9 i� m�hbGq5�!O�+8±|�%!�=�R$7k"_Gini �[GK2*Zʁ a{@�5 �!� ( p<�0^Q�q�!�e�I�urI!as�U>��(Fn[-�aa�%iZ��0 �5L.��+$�0�Y�vu�2U �see^o�)ur�M n�Rl�H�.�.F)e{ec!�%7�g-g 60).Z��t�T�2+,G99{b;es(5!�e��~! ��,RG!Ke��)����H .�: -:�NmGN.�6��B�3V*�">[nt��?�f,a� -' �]a1aq�$*�' �S7��+6p<f$}T�i,"��;�FG�Ga;$.����%�N�Jn� PLI9�R�2�:� FluoZ� 2�N��H2@ �O� "��23��� ���In>'W�VXjN�G!�oY�o) , [6L`&�&V?�*#s|;9zN:me~}�|[6�%�~{&�6�B5�E�D( 82% )U'�9*u�B.�.�-<dc"6���s�>CPt(%aHve�c-}F0^ [65�*�&�!6}� G�!���N& VF*�%�V3=� he qW�*7SA� -TMRO�%I�a"|?m)�M2Q�n$~�&�>c+! �Y6±���o&�k2�9AH� .+J���y/��6p��9 �7o/-�:!5�2Z;.�A�an� %�` �m�u� , |�!_,�7 �5�Z��5.-�we�@��a,�ib�y�4.�!z���L5 .p2:g�!�y!� &:8g.�!X�x�erB!>�W @6�V4V+.ƕ�so�f�N�U݉�]�6(� �p ���pFuK�:_T{%E P��:C�|lR�&a.a��eR��F`!t6� lH~�) cogn("���{F���Kr1@�3J��ME~�� -L�w�4*�!( 9͠@� .@2c Fyr-)��1munyU uF� �"U�-.e7�&�� F [6�56�Au.�!�rai�h�)}i&�!R}6e'tzst�>"G �y�r-%a[�@s�n�N& id9uI>^"� "&:2$gG$a� > !��2�JnA5�;���OA��-��uxB !�7!=!��1#"F ," 6���| |2�� [=2~5 o>��6���`!��VY ? c �$�:�8� veryDs�|&���&���U& ��= �F!��1V�O6a�p4 �8խR4e �!�D";%FH K:2!*�EQ �EV:7* ���Jf "Eno�`� r2�� ��6b;\=~�s'�!�� curX>+��>� -�"`%m�+K�_ q1�]AD�#Z` ni��v���E!s�x=-�-�_Es*�e���ul!W� B��@� 2 ale�Cdm��#�YZ�/�EA�:j2�e�s&a��M�7<\Q"9) qRT-�9�}2!�5րهorZ��-}"�9c�P�.�P=�)O�v!�X!�uE��on2�8 2b [68.���� gpqaA_22coba�!*��+�(�  d�a�4�� DNA--���acid-soltr�%�V3( SASPNLY/�B&��(@�� lso &^1Ev�wo -�A���i�!�`� 5�A�� F�2.1l-)tՔu%0!<( CD247Bc�n� �3K)Ut k a uqS8}. F�\,Ubaz{�2 1Zf�:�sf2( s Z�6 �Se l�6~a Pgpr���rbZc92�*�&�+v�""zk '6",a�� _ 0�) �}%5y6�"�%�X�z�b�AJafM�E`��in 99:�2G&U  �a`Ah&��堩�,*�L95� >�JA�"GSE�� ���toE��.�8_b]!-e�5~� F�&X;:$�iv=uRu�zJ;X�ɉ�clu�x� "n;J0(�mufB�� :'wQ("�&6757i}Av2_� al� .|�=no"� _i;b@b[69�q71]ņ�A�Ρ-�.�2�σE�/}C�"�! �.Mk) �%�eCD119( U�S81�eյ. M���6b-?J��!$ըaj�N�~ o�A�ER��BVF����N .i�CrectA"�9�V!�*l1addx ��-e� � �uV�0"Z*�bx�tiM���^ E�*`!�H hs��.��RU1 %�,�/ǚFV eCa>-�}��s�\� �`�T;\5If΃% {YE ��a P1�:ssh�/�!n�tv$�mo&C.,"� Wx\!p"r7i.�EaF�7:x -dri\ *0 !B%Vz��e~�4ND in 8>?&�4� :�,:�:!��s6�(p>6)21��)�u�"8 be(C1� :>R= !B2�h��A2%��#��R����sj i2ws/���q��B���&b��)�m.� �!:��gi �GNX -9M�� sspAi�of6(2� 8f� &� �M, 6hOi�� fam�c�&"P,��Ix ���xre3�  .:v%�>B V&W�<��G�?�*gLG:L��F1"�vo&� b 68D5cS8yU"lA B�F�dԢ-�8&��6�t4.� ��$�'�_ur��u�2�e �,i:(�bT�ňF av]��rsp ��� �^be2�8�t2nFE*� � "nS*�M. C:�&� � ��@�$�u, Pn�>�&� A'n� � or��(�R!L�`W)�K.� �-� u:�m2^!-Dm�)a�6  j�T._3da�$)�Ec%+:�U!!:V��7&/�UK. :]��.�50�4���� had ���j�dR���*� L*[  ( 7&< m�&�y85:��]>A"o( 7h�*�eZq-�Ku511�6�9i%2N'~�,H�@on�uto. !donAH�4�*)B��<.�>F�"A8�)2�m�y0�%(� bE���)�b�%$�P���i< "�,m �� .��E [72/ �yToEe�� Y67_#�_�-qV�a� m.���p'BdD ��f�l�.�!UAq)ng��*Cd��t��^- �[� %�F�sp> a��ty0D 6 %"] �6�5O���5 8 V^~M)�d!bz�y)���A��^i�vi.:�N6 �=!�A�_!����6� ��u� ۚ8*BE"�31�NFB��*-�7)�E$ �tn r��0&�2RA�NcoTc�lJ�"��.��>y !f�P>�^�T� 226J��v&J!��� 4 bund!��c0&,L![6b.L8ovMn�au!8�52��#s� n�>.�8�G�J���E*ROEN��6"( �?A�a�mũ8 or@�8 $�yn*�I�FFn �Ht�V�*B "8 "�>0 �6/�e�"��U� ch&=$�M�����@�Jaf(�   �c �7���u�c�D��6��rpr{����m/)"K#����is%�(:t�����8!�e3We� m�!M%"X<�+%1�"Jx�LF� &�<��ib��n  discu�2 �?5 &�j�b�Gֶm2<�7Aeo%�%�:6���B���ylDA�<"C!� σK-y�6�JC&5D{��&K.%-eL*��D��]%W !��Cd!�a�.?/.W�� H"lSjT�� r�A>� ����C���� q�BE�*�5&�"to BI �c*� �to 88:I �&l=[�Hv, �>�!,z���%�inIz-��c!��&-�>' E��e\Viws"%��\a&]0%>`n��VY^.�6Mor�hB�^i�n�?x-��L&it(�ƫ�R�2.6-�6�L"b<"ag��� !y�S�Z�>�(6����5ab�J��<>A>.�9&�FTt(5� �5.�nl(��l 2��!(fewm�E���_�*!�� To �G�&�(�<� "��� �vZhz.U �U �*�2-U!MQ ��'U��!Y m~u 1] ��m�&M A��]�M�-&6 1.��c2n'ct�")*a9�� E��y: O cK�h�b0.��V V U�92��Ine5n \e u�AZ}�� - -�zU ��� Tl�nV, H2)5�!Jnor�it�#� ��� c�6X31��m�-(�v��N� �A�%t&Q0.n� n>#i.'"l � 2p"ll>\Y� Z9I#9"26�) �Fi"� }:r��-��2-�aN �('+ �'+��premW2L.�1;aCB��2� �|p9�%a/�d��U]3 �>^� s9E�>6�/se��} u!@m� �[{e]Su.\Rd"5"�S}��E�:4+.��Wp6�7. Ycyt"w*!@N"C �bs�%� )�s a.t����� NB . Itm{ X&�'E)z�Ej��U.2W> !]�K�ɚ.Z*)2�.��rup%Q!03� �.Rz� �2����2E`�/,:RZX�%j�E���ace.��Is&<o��sN�[*&��T.�6�e�5� comm�$� ]���i/e��=���c$�EIw er6c�-! Eo�#()�c&�two��i��S�#A� B�!G�Af)�=Q�tH���~r�h���iY�)���!E6%"8"�3NlA:�to  �bi|[6В61fFٺ=�&�J/��V�&,(x"�?�s���"e%MlR�>[7&�2_e$b��Ts�8>T�36{qf&� �J2��=�!�&�,V Q�J�6�"|(helE�a - �`x�vB-.C!� IIAB"=$暡Sr�aa�E�O��F2!;�k�'*@.�*f+.�a�"�b��Ama1�i i'Eh�at!�. e/ / �&"� -�6�F��-I�aҡ�.�v�.�B�W�%{��RF%>�."wE�sumAvp �65 7y n"� 72�a�ls��t0��1:�*;��e/N|�yi J(�@r2�F���E��d�FF���Xl2-�6��$�&} pro;0in:PR���THõ Xmo �*&N=!d E�GAft�0by R!+!V-M]Y"  ��fs�!���A\U:�7H��%�F�'2�� 6�!�U.Fr+U�EE�EQ89�^�bp.>s q!!��W2�0TYGX�;2�c*�,a?ro&9�ݵ�SeAj.u�kR� h �z6�<��iQq��E>. Strik;:h"�lLS��AT>i!Fq��=sA�zA9�5u�Me@o��{"�� ��fH!/Rd�'i��&! `.* BD"6&AV��E(% M��I��=N�R.�>��,�0�b��� �\:N,c~, 1��2G" �KaC6�"2"F� P$is$ ���r�'Af.N,��>�&J� GI�c�;Rim2]o La�:�[79YB�#&x���ـN �F>�2'F�*6 �Q-�9�g\}O���*<5x"�,e��6���*�?E�}[� .��kU�!�V�.x�@�� V2m5.dC"K*- R��3&9*e�X]�F��N1=M$ap cq.��Qf���?A$J# m6��6�>�*)En2�:�8!E%�E7 <� =�� ��SE.�%�6�a�\!�[�;VX��[P� 6< CsfB (E�%�x )5W�,r�M�:Y%�����)�%V�� �W&���pr"��ov5!�&f D Q� �2�d[7�*[8�p���Z _omE!Y�*�W�o* ��8�a �v_2�l�IF�pA�v`qan&� I�G��Yv5C�!w.!�e���u�zp.N��"j�e�v"Gs!��#n "�R ^ +:|C�!�:I�6#�2m�,H�1,&}VV�uni��5�Y!x>F�!� f<�-MrYh�9��)wo�-ra9���D"���' enX"&#���xJ�82�Q ���."�2� I"e5d�.lal�y�ou�Eh.�-^2#��Q|B]�w2; inn��#�^rv�n| .�b4=eci �a/ !��R linkA�e�_1�!�� s:�(ReO��5$A;&-��IA-Q� w���|_�e��u /* �6*ռ&��� 0!$)�e^)��[�)M�5�:�&} �� G�., �A� edAvB/^wzޅ��ly6R 7 ��a�-�J�� %JIA"�IY8��soil��A:; PmW>i[81x�:��0  ;o�u"��:��BE"z8�!�B���isIA�# 2, CD012f~*a LytM-M9m�2 I�2�%-yX) �&�xa�[I1�YH !lac/A+� Q ō�#* ye:. )I� �a�f�`B i�6*��yH2g I %� and/��ti"�*t~Sz"�B�W1a� �kI$"Z h&ae�2�.�g.�a�N begi�thEH8Z���v����o�r" -�x.�M��b W  S��o��IV&5��m+ !oxDM�sEvVI SipLR�M�P�l�3�A�ro%��RO7%(!>�S�" j& �9�ANe._�9�~i�6t��Q`ET� ��ƥ�of64l"��9�q&:�)U>�� ����I�ea,+r��n�z���1���)e�nQ+B/%6 6�A .W%6Ei. Ii�ٮsh-Ak r2�.�>�T��� �6�E�AT� *h :j%D� "� �owy �*�$* .]� 6� ]�� .?~ ,"+ &� !n:6Gqr8K>3-&%��g�!$F�+� l�.;�r�1�s@�f_ 2��f� &�&�Em��A�E>as��" +y��IIDm*��]aS�1$wavH σE-d!>ed �:~ �� w ��ID^�BiL !Mi�)y> &�w��"F � �.h�B�:Et!�.Q:�+(;. T�&�>5�yj!=�2�B��ݣ�412��C�3�����$�tetaniM;6i�$� x>��t�"^�Wi�Fgd�.�[2�h^Syfai�{_b��x ���� ac� �x� " �.�,� enRT���3&�+���~6 Se�*&��2s�&.�5�&#%��2$� �/+�P"&" =Z� Gb!�recrui#�� K�9)���.@.�e Wbot����R"�-o* A�&� �*r�� B�� (�"�ol�d osm��A�es� le�; 8s I \! , [8�ív�/Q���y�� ��@�to6�,a��M6� !_a2 K)HB.�:��IV� re*�(&� ]�Zh�AK!6cesA ��VFP^*is kepa�D eFx��Bof� poIVFA�@mbe6��pre>��i%h A}T�)a�a� !A,f��gmra�%�� toeTLa\aL\d!��c���v� !�a!"-"�� �/x]�&� 6pc"WM� u�[��02�Ox at by���n�B� �<or�BA�23�� *\0�A�t&� m�eno�m)A�"|��&f.�F �!f!�2_ !�&? ��+#t�}�� Q [8]C6] d.V��C�,B�� R � �&8.RF�e"�K�� �E` D/�!�af�����G"�2NW:�3� m" !."�DE����!� �+ :7��DRJif)q�-.�&o�s�� }M��*Y>�N�C � a cuS e dBu![y�m&\� .�!^\�.�!96Y� &� 6!W2h7� m��� �o��(jv=ہ� 8K��a3*)(al=:. g8�P-����%9+.�� �Je��@�C�o�@N�E �B��e�����g�a sue9 nn'���f�Qw% m] �'%�� .}q"DNE� t���b<�H*A�93� "�&�S*e circu��#!�k!��i�"� =�, �7-�w�;er���Rn�M.q��,:�)T���I�o��2��,%)O&&[ %��x ���>�y�c9B� /f�fX� :��, ��� ��""��!���nx&��x %o";r ��_.�6b�W 9?"%!6��ohip"IOK�� ��a�Z��&�� �(d/�I unclear [��X"�-"}e� mpan�(f Sauje�-"��k�~!��_���� � rehe��6��f �m2e:�se��f&W>�:f` �%7�g�� !N���w;�a�"�t� l.��.��Qo�+� > :�6�!�yj!�Y SQ;� hF��� edi^t�V �G]&�vl���'F��{P:�V�y[��� E�� kdT�m�Ta,. &������X�� propi���re*��lS�A!�Esche�iEH"��$ DH5α ( B�C,sda Researchd%�oIr|�uVn��l��aBdo����ria-Ber0&D��routin�T@Aq!�t&E�����2 �25�?ngeQ�.!�AR�&+ - MBS�trpC2S�C�2�*5�>mK�"�ty.�exhaus%���ifc6��-( D+�[8�g��a&��(�µg/ml�. r chloram�wicoՔ15!�a� �qu*x"��)6:7t��s)�E���udLcjJ&j3 E& q[85S�L9�!�}u��'( 5% H:|��CO 80% N�RatQ�8V�\r 06(g��e@�( )x�5��[*���l�qy���� m-lA� L-cyֹ�41�W S"�(� 1l: 90 g a�o-trypt��, 5pe1 g ( NH�b2SOZ$86- Tris�\l�] .�6����\���;�- 6E\ne���foxit��2]9 ibW�ery�Im#�=2v6]M��4O"{�M=�!�E3�t�<��2r�{ i��9∶�� �a��.r�tgm� ���l�,� B [�O�-RO�,; 137 mM NaC�p0 P5zW"K! pH 7��E�Ae� I�Wa�Wx���m�(��m�t 6k�A�K�ª1{ ���F@v�il�j)��A-� ��2<CFU%5�sf�%� �W�%�sJC�b(1% taurocho�dPJ` -Ald�f�p>3hT���ge�x M��*�e��5Ar��L�4ratio between lthe number of spores/ml and total"bacteria$|times 100 . In a preliminary setRXexperiments , we define ]0ime for whichp0difference in>ressionL�a selected σ target gene betweenB wild type��Ocorresponding mutant strain was highest . To study σE- or σF-dependent control �harves�dcells from 630Δerm , sigF� sigE v,s after 14 h�growth�0SM medium . S �L1� sigG�!� sigKU were� d9 h (F�G 4 )V2�>$X )f�TERNA%A extrAd)8at least two in=@(ultures . A%(centrifugat!�,� & pellets �resus%�d!/(RNApro solu:( MP Bio!D cals ���usA!> FastLPro Blue Kit , accorE%to(manufac�(r's instrucr�Thebquality% determE� og46000 Nano Reage ( Agilen!f. ForF1 µg!�i�ZE�eaA�at 70°CeQ@10 min along with=hexama�a�200 nM�� -specific5t!� AB7300� �AIs�@A3ppliedA�systemA�.E�1�usa�Por each marker are li��(in Table S3!�mpl�-`ndE�E�iw9 �reli/YF changeM�calculEKuu�<2−ΔΔCt methoE�R�coy��gional fu��shaB omotaD!���yE GE �� gene�a�ll3Rt�>r cotBN cotE1@< ( 4000×g e� at 4�2AS!*M sed� ��washed �,phosphate-bu� d salin�PBSU:�1AF� h!Fss = (E(M Tris pH 8M�A4$M MgCl2 , = 5 mM EDTA 2 NaCl�v% Glycey 1 PMSFE��J�s) ly����a2�urM� ( 18�lb/in2EProteinE�!$6lresolved on 15% SDS-PAGE gel  %�$first scana-��$Fuji TLA-5* (fluorimagerq f nA; ject��@immunoblot analysa�.�$before [65M��e4 body (Z��� t a 1∶1!diI ,�S8a rabbit second� dZ conj� aO0o horseradish�- oxid� ( Sigma )2qfx!�!��-�developQ� �}��ofe� k. !P.& supplemen!����Ilipophilic styryl membrane dye N- ( 3-triethylammoniumprpyl ) -4- ( p-diet$inophenyl-[ tri $ ) pyridin� dibromf ( FM4-64;�`µg . ml−1 ) [43] , [87m�*s�~ DAPI��,′ , 6-diamb o-2- � indole; 5� 2\( both)� Mole!�ra�b�$Invitrogen%�� !�live/de�P ssay�ME%�9�2� abovN�05�/-��mixQ� an eL � `of 2× LIVE/DEAD BacLight%� mJ�  z�*� Propixiod)�3!= M fi� con�" )�syto97 �b(��r��<6�I�inqj"F%[�q1T�b(!i)_��9�v3, ,a�,room tempera%.Hme four�e,.Jip%lyB�.*=]AC2[ Mito+ ker 6 (e�5> (��ph�nsrqAQ�b� microscopA�)r%_mou���, . 7% agarosa�-,glass slidesWobser�$a Leica DM�BfeA�ip��a>�Uplan F16 × o����,a CCD Ixon c�a� @ndor Technologies�)��I�G�1 acqu� I�8�u"� 8Metamorph softwsuite ���(5 . 8 ( Unial_a`A"VdjuD cro� b�- �mi��ron�y( TEMI� ,�)U &�"U� �tvar^!A�-�&at&�kV� 8onto Columbia H� 0 Blood Agar p>s (J Mérieu+a39 f��B@�ng �underA�se�R i2�facil�e!�e%ſa�[89�.t proces��]!L2| pr"x([90] .B�WE�l6a�mework!� modeAe daB'se� allo� ic m� s�."ory�x�<�u!auxili8!��a�is redB can closj reple�!+ steadyE��havio�de�ed�  such! �N4Monod-Wyman-Chux2��$or rule-ba!N�O�al ulT e��iv��i��whn?v�[%4s57pYavit��vidual !LsQ_ r��A�!ndiVA`�makE!ie1�usefulE�AvGE@Ũbi�m�?1)i!��cal��A�wh�s�al=e � s ma�teA siAane� . As� � T� �e a newiscov��checkpoi�� �pathwg bud�yN,'has brpropo!�to meaV �>qi$by monitorX bsxr� a�ayofa�sma&� � . We show�jA]known�~on���is�A�qFobust h�r2switc 0In particular�is-�� orpo�seT�&�r�9al�bud�or z�� metok �!nd%� ll-or-non��igg%�o�eU� =r� ��� shol��!aŌsuffici�-C!�occur��. nBJ�!Vmon)>!� ost-�[�oA�od�! fr �&� in n� to al�M� A�e��WRA$!/� !�ͼ�C�opertv %����!ra�spatia�ure��eB� >samCatib0�t aP acid��idu�( also� y1#) it!8�e��s � p53 [1NSic1 [2 EGFR [kWee1 [4 Ste5 [5] A!many oth�[6�����` � fun����ingle-�� v�J�V7R noQ mplel�)st�y. M�?�8_ reg�oory!���Gate�benefit� !�M!5 of bistab�|m��u,!��!t cycl�Anire]�ly7 "a�� ] d��A�~r��!0of feedback [�[� Aadson�1hyp!��i �=h����ugIria�o6�:���� �he�would%�be possi$$h �.��O$ [9]–[13A%%�����s haveI�B� expl�"%"~of� f�<!emergN�(�4 �p)�see [1E� [15]� O E!Ur hA�,i*�"��Au� %�p ���^ l mathema� �� .���;E# i�� caus� iciAW@�V��#aXs usua�mA*$troW of�$erous"} !�� or m ; ��B����Gn��a  0 s% oft�o� leX r� to  if� ��M�al effori S� m�t��a2*�l)'A!- }!*A.assump%I��*�u~#���%! i!�w""� A?|��~�� 3�ID,�/ v� �!�eR.��N�ne%� . O�^ �)Z%�phenome�� ��!�includ�%�x  , Hi���3y3qu�-�A�$less clear^E �M�.�9�[16�'[17a�I!t�per� @ 9FqBAAapproach�%�!(E�A�.� -��@Tb; , na  mJ ( MX,aTcap��of�s2� �namicsEKimJ,a lc'aN(]�� �U� 2� !�keepsACck�A����e� �S-��4% nt��q��*N ��estim� �t�inA�I�v&�a�"n$�����a�R�& but�9L�� j%�x�$ beco5)increa�P�ec��a l*�)H ,e�e�g%�s a��aa�f��� F�)� a2%Q�m�?b�nEa!�-1� ,�si-2�&� !�I� i� mU~��� [18a_a�u�ofA�U�out�WCe� ��)rMFAf�%b�_ tend����ťy�I�� H lig�biC*,0�! crip%�-(X� !�.,o$:or acet(, ubiquitinI� , etc [19![2� PerhaaRhs� y%h �t� 9�a� tool�+a�R ��` o ��m� X LN-�EPI� nt S�+!b� &X � %� ��� * . C%:D l�"6� C &L'Hs unti�"� /N� [2 [22��� �ms � ?B� �"�Ppoo�J*� .� un�kM��the"�1_dor�{ �&#�d%�hM�t1�of�%�>:-Enew rWit�#d��-daugh9^��:)o��� rface���[2� !@6=[� }� a po�manner�xl"�dir��=�tip . G*-�aevent sU��o isot�cwth�n-��; ��7�ent� �(= Fig�1�&[24Q#�&n*M yA��+��du٫ �q�ITinflu� s)CE_�a shap It/ 6- in re�ikbye�-aut�"�W}Z'ol%Q�z%C [2U#is.:� %��t�aiʩu�)� illu��in5L�(+ =I�( be^,$. See Tyso��,d Novak [26]�⁕�� *� M5��s-w�� �E��99�A�MF:�"9 o�$&�#in [2��!\T)�"E ��*��&��, &!m�niu���M-�� ex*�)�AHnon� T�= Ti�.�[ bu. A maj��dv2 ���p , beyonl.-�R{ � tor&e<isI�M�d��*��. S���bo.f�{on!-.w,�cd2�ofeL!�0ele�Ui) !>1�:neighborAEC�.�~mvco��m�b6+r�� er-+ than2,o',qelid-�aY "^ M"J�is� � � �a]�pu-\,Ba&� ��i��&hed�veir� ō�;iA�Re�s9�e�y�  a�O �){.� J o� }*� 1{�\��%=� ��N� �tJ�(�&��rem/0��2"a �"� ��y!V�"zA��'��"�/u�c�toiduc� l�b��ZN  sudd�)�R ��Vj-%p�f| gl * B�I�)��ts"\ K!�&i� �=%,A�p&La� .stream-H�B�� ��*��t��Y� !�!S�E�saN�n>�(&� p��1@ p�1to� ir63%� cova@4i� sDw? as��%:� i)Sup>�qawM&�-�*f�.a kint%at&x �8�?2N3 a�3)�i�c%G� be�ݹ, s�5E�����t Vo� e�i�!�BB��o� !Mb�� ��u 0)>�.�-�BN��r� ac6@ � ��7AKD�?SiњJ��2ly �/���B�cum�?!ef��_�*�B6�s=$-�!�6$ equiM����Ze�u=/�N>�d2= �siOa�'�b�2%�no%Ee�a-!on^.�].� .1�h � � �=S��y�be due� kn ImoY+e� ,.`� ").� 6� Zter;sYal(ngq�-1A�e���8acty'ly�� �m�AqThu A�&6n@�U �!�6$-) \ bv$a.�.\Jar�� ��r:0sb:�F ,��D ���>�!�a;�`BbA�nek �!�w+A�(u!)��IPne��.[�or fu�5.P� ���W*=�)�f��E�!.V,9�� :� �is2�!!�b���A!�;ik�{f�P� ?eneA�frov)"^,Wf2ff3Q(i>� [2�!i �� � y pheromY�ef��sY�!"uw[2i[2[$W�":by Cdk1��t � saZuna� 2Q, shut ~6 %�!�%X �APpredi�)to li�a�u��)$ r\*>���appi�rct�cha&�-X's bulkf�"� � % ,!4��!wro(!}-"�:?!��E{n�en.M� �yG�*� a d�;m�. A�M����e*� :i!0Cdc25!%� in f�'6A#��Wlf%ud\ & 98# ng>& s [3�AB+>�u�y�@�iх�2�.-ʭv AsoD,���amw!����(}�i0(R� *!�U.M.S&�?ta(B/� i�o2#"6_l�/ n:Zis EalyH�v-��>V6#aI� � ta3�lacs9 .� ��r�r�:!5s�,� �, i . E�ot!�ev@kf4�J,��j�2�% A?N�\y�eak . M8ply8o�Gth ��!PngE�h"�-^ NF-�:Tb$)�s 6 exac� P� U)��"� isOn�n6�Q�6�A��٠ asA key a�� ��ulaIatA�\nomBN"h!!%a������ #onv7!��aA|ea��@��iv"he�f�70( �5�r���M . Notj@�%S&� -��F��pot�7be�'*Hlab - :F6fviaE�!ja#�5C)�-�J8We�*n b�9&S L"�t�$<{,cal�compos�+ arg�@��adV � 16Q�� 2� . IfI#e2���xove��y 6�%T�fa!!��e� s.�>�em]n����m A^nv*,!�'1���p�"N!�venK(�Ac*�FgmZ o���by�9N2"����i0t at), letDDe(�cNH$if9&��!�- avPQu%�)hb �*as%qJ,itselgōn�Giv}(dy� mb&ak�@c c-*�& oscil�|Y9��ZA� !e err�I5 &��cB�2�.FT �',s�;g 9'ra�HA�*o2��FA,Emh3� e�  T���3 �].�"�#�M{�defaultgA�Eq!)�9�����!8bA�ed!��#!�(Michaelis-MT2�yk$x5�i� leve|:�A}As4EH����!��2 moid�C�)^�:s�k� lya3.2. B]%wei^-�"�@a�%z�Jwe�1l der" ��e n'�:��{*,O([!OiJ !I r( �6)��li*�+�%�$�e�1� �-� s��A=�&�s .i�B v!f?4 J5��- 3q�,�Cike. It�Y � A�"9&!in r) �L*�3b%�Kapuy �� [3,!i%�by Wang1� I"�2A!�hE�rSonship�"�L.y.�"Y qA�%*& 6�A2$ choc|MF@ 8 �2T2F!5U (tc�n��%,.&�2� .�M�>�ljE��&� { minir2&V/J 3 e�:% � ga�d:x�'hl�'�v.��f�vBZ�6&�isI�~� w%���2Q�*0G�I"�b<�(!�lya�dV3%)�@ n� J�4� J%���ig�>/% A1��5���xy�? �&� av�nhemoglob��2�(t7i!P-���b�Owo.Yt��. R8,��a dhF ��,A� ��>�M4�u�mz!4A0 aI9�a!�N. Eac�O I7s��6�!Er:�0�$�)n�diagra�2U=BA��fap)���preS!�=G" !�,$ a6j%!� view�lmost ido i+I2coe"9%Ou�eon)_O aM �1�F,e�? �.�-oe�*�"�B�s 're!%fa0F�BEm�"t,a *E%E:�*��F�a*9M��6��7Ձ�Cby��:Q8��!{��)�m ba=princi�/�Me�K���8ewps�8�V $�. Ue* �: ��now��<z&%�>5�%MF 8B��!Q&%�‘>’>�)�s�� gard��ofA*B'.xMMK ,->)�>]%�� a< -W 5H:Z LF$:Esa�b�Y �^�V�/U�V , A�TG0�)��� qE@ex���al���6d&B@i;a�6� {!XsZ�8.� isIn� word�9�6�%M�. 3�I�E� F�7e�"rai� &h$�"� g[lo9��%k!�>".!@� IN�."Y/�.wNi1O�Va �(2C� ��712&#-�� Ga>�EA.E6� iMr:y�ul$`input"Z G ��j Aa6$��.�lot�>>�*�ek*�A�Q���gdAI  s��6 rpri�n�MF!P�=�&l|?on*T.)-))Z�&���d�|"�&�n�� �,if�zu�:�3m5 u� eo ��&�j�76 3�7V��DI",e ma�>� �6� �e!�o�Ao>K .��!^c8l�2Y�is.y &� 3��maY� �a;��-� x�"cis z �f� aj4ve imporWYb �:ce�>��A�!uex�T� ���w.tAZh- rd, 2�etc�*_ fr� �w be*�d"`*� easy� � a�( �#5Z8��sho,8�"aR%Bg)��g �!3%�ed� B Qs��h Q$% �xE�s_BglybO-�s � Vmezero-or�A24a�[33];-!�Discu�B������W�rra�%aՏA�MxE���S�F�(nY� comb1I .�4��;�!��<�Eer�O�P%s�\"Ae>���C�m!�>"aofIo��O"�q�D._2 6��*itQ1%ci�F!arbitr{ o.Vvn )�$&btH:�CB���"AE�N%and/or�(�E�� �� �S�R&�85l7A.�8o���4dq �agnit�7�&!�#�3!�~70��� Fe�!P orthAHp?U�9ABKy��%�ach�@m4*BasB"C�́dZa ser?�QH y�*M ��$eama�$d algorith� !�!�-poA�d�u���+��lR andl �&���* �si� �&,BioNetGen [3"�0�-tag%^=(uE#F8ߡ�b�0 nd���K] �w�9���0;Y"XM A�e�(��m8�or�EIe+& �� 'p6� some s exc�#�o.-%|L � .~>f~I��D�BV�+��iMS! f�^�"�Q��# n� ���!m.���o}2�->�EM.� q�1A� =A�n�,i�2�M � � �O!�w(D*�ECE �!R�!act!Ai&9(!���us@ �ls�J�DJ'1&v S[ �""lw�"u �a�%�r}1Y(%+ ��.a��emb# h/ �ei?� 4 �BE� #%�Y,�-"  d�upD<cU+��� �l�"�!Ua�. How����! prov 3a techn��&� al b&7Nr*� V"�^�F%'�wfi 6� bB� ub1 toge��cAVE!5*C Ŕ�.�'"� 1C�m 6s&i �-!�j8&%b���Qv 2#fi�TX Ub%\G*!E�e�Q' Y͠!�#d( jY,WV�F�=�R'53F!��bG V&G53CE�m�3EQ"�M��Y:�=qR�F~N�#l�!�� �up-/a��& 1�y %�aA�pr wn ouptu���8�CES!(o 6�]7�!�d�box�E" 1B-'�+,e Zds1/PP2A �[�"so acQe�QASout�-� �A6%$�'�G 5�"� �A/(6�;aE�FA2"�W tG�HA�%��B�Rho1 f�6��*�8 �% v�T�qp)�m� focus E�h!M^�1{6m<�0[9iv2at /$&[t1�2*}I!�a.� �degra�4,i.��%&q Er�@�4,�{:�,��^ �e ODE* &zsBkDI!} a)9!|�o!/#N� bifurQ1*�> !�/4()Ib4taLaՁ1�M�qQ�-a~lGI� enzy�cݔ!#I�{I !3Z!�c`s���^�fl�Mnd 6��o�!bR sA��2:�FqS�5I N�#�4� !M��[3r+ Let'Fok!RT!�-I{o5u��UiiXAS����K�R�0f�:y�*i1s�"lu�nYA�rai�s���ocT=��\ �,�al��4A�{ e= usF>t�au�&E��/Sh%v6KP�Qn�&e�� >don't @�ect!�woF��But� ���s�j�Xer&���>�Q�� y��Ragl}I2<,m �r�D%�!+ �cCHan abrup fQ�@6er&�>&��A1a �6MuIي�k� T:�h�1E' aken�~c�6� | Est�.�XPi�gde1m.U,BE?aa�]e� cour /�+Mla:a&5 vesicle�7(��%�=b21-�� )�!��>ow� c�/t.!ime�0��e��6 )�2,!3:s�"Q�Pkc1/��ukI$B�%//:p #`b �5=W| &�4�X��A](�7A,���kl�6�e"%lea��Vr9/G6. E��'���ixb�x-� ��"$1ac>6��u�excep&d@i�am'%�ariTN�4!o2}. L� adtB �%wQ�)�Geee� >(Ml)24do���"� divl�-A.(H �&\C,eN� �var�-f�G�h�E+ � 4D$f�q�z;9��5.o=�>���� lF(o�Aύ�?(4�rrL^�B���&� �Ne.�" a�c�� �Aritd�of)�6�i%a�#I�6Cra�0& �\E �q�Okituw+<-_� !"Aǡ��$�en� �C�1m8Q��</BYD*�<.�9�h*Z (%� ,�)��n-A��() ,��( re d@(�5��b back loop�� �$A�ask�-��u ,� �"�Z��AKD -�5���-a��/tD2�\)h`� ��'5M.] "0 �[3E�q3 I��5( � "�>� !�aI2@�AC EmA��Zaph.�E\replac5��l�@lue�<�Au�. N`the� �=( gp)�Z�L�"K� �`� .' �!`( b).i6�Z9:4Ad1+� ng h&I�O:�� �_y=�Zp=B�cur .� ia�fG�6FI]\i�L,n�lyA�%9F2�$281zU767���:.�T�s�^j�vM)%4*D�.5!}m��� !~ dard�7fK� A�|AA'�R&�&C-Y�I!ލ�(����%'[!or�M�:*�er(�i,��etc 0�� K� ���:To7���x2n�"K6�,a�nAe��[z�+a�iod��� �sc#2of��, >o=-F+�N�9to���2PAcjycl 8�5�,. To ensJ(� fi�(�r�)`[40�-.l �A,]6"� aw��6Bɹ� pa">[ŷ6��uer-PEjs$���.j4D��R� ��H�–��"��:�2 �~5��1��?(�;. �pUHw�?�U�7de/a%��L&i9to&�q"28"&�^} 6�r�Ai��PA�"�Ca�JO�;IM�>ar��0a�ze.B�<�7R�m+!��( roblXW�6�ign�]��K!iH27�(=�m�'35���2�[�&�`.�� bXf1R;|< i$r>7W�l�/�#fr�P�H�. ntu�!x flex�D()� �| #�-��it00��ne>A�al�a? �AP.�^�%� }U�"fuV2��& ed-,UO!F�3of�*}CAq!R.�wpMA�Oe,r�rqYe�_�Lc �(��Q� a�Bct5L�4��6mj&�$‘raw-dat�Sing�)� Ttoj�9"�e�8 ��/�rx �� �)_r*.+ �a�� ���0 �.��Xb�"�;quilibro�#!��U�Vb02�;cAu�) FuP�7� ' a*ja�gZISvx�6a���&uit�H� %u�e�aBh �lN2�M>��%�AE�L&dY��!)o�Z��2�% oPMeT/�<%:|�M8%�"A6�m�m*!T".[Bio"�Wc E�sugges�g�.:h�(./:0�"loc�Pu�u�}H+unDe�m 5 9%+8[Z �!�U)$& �g{B 'm�[r6�%!h� 2A�ACQ�.Z e�min�@��zp= �� Ɓa�s�C, A���v18- �D"�S"8� e���&���/un)dI�s�@N�/ e�`*r=Mula Nlc  ���K + m4�Wd ��)e!xd'(�]��6. <�G� � .g�?hb�W �Q��6:62c�2n�',M}�Goldbn��fKoshl�o�'C84�>Its m:�*p1-��U[3XT*(�F?)��FH(*)��&?4v)1 enzy�ZE��!�doe�A�B#a}���� �1eCa�%g wd:��b�8�n��Z�i�Z2���9 More �|F � s XA6��`�� �`U�$AZh,�1w  ng aF�) 3)r�xn �u&in�} ergyɞq-^�J MF2A�!�of) 1.�2��J�C#i�L%".m&�#as�5� 2C ,��$�=�*m^A�ma:r Wnd)Y�S_s�!��}n��fa� �?�,I)$� �*�&{Y!�&@0s 9��g Y:�f�'�1A<��e�x5 [42`ftt2�w�p$�Nb�!s �A��A����0y th�UU�"�� !�@N$-5z�6�Ps�H��"��p!� 5��&u',>�q�!-�> [a.h" �a{M5f�� by M- a�nd Sw�� [44]� ��nD� �Plom!i��B5H� io�=o��U93!^ as @�%B�e� = �mCA�s�qf�schp�+aQ{!3� .�j��bn�'-� aog etoe3,_ ��I��s�E,2�� �� �&byF7=� �.�a��7D2ce- 1j_u���Aa.y{."�Um�6�\ G1-S d �-Barik�=4�Z�d~ N��)e�� mpet P8u:�a.v%-`[46i�M1QC)p[1q>�uEs�7 , [4gd��* 52i�*�$net{_�r�Q��!+,� N/C )�V witcH]A�h��1;3� s-��!|noj��� !m� �!�Gf�i� conn��_  +��P"nyea&L .�jN � V ���e���open qut+�� aI�L�-b"��( � onera_&��eyG��sit�$ ��*, 5�!y1�&n�@2an��wh�2S5� �5����a�� -nee cB5Xi�d,y{�%t��!��i�@�f��"_"Y( ly unans�.18-���iEZ$s left fewo '%-.!�a.&ww�( heur�v�'ig�eTw[e very:7�l&k��[4�l�hg<%̅~n � mpi"A[rɛ&� S@(7��Z�s�d�$ X�on:^!amF&p�� i��"� 6�6 s�N}ha*l'E�MYth�a>�6��= �f�M:�[y].�A".��&n� be�v* �$.+B( 0+nB�a�� �,Q�!@M����t!A'!_�"�6�$�ng-�^U�%gs�Ky��y�Y*(D4�e�1�zs�p� l6�� rando)�&1 sear��a%��iZ�O�� Also�BCq,�]2@?. D b�&��p�q��:W%�fa�B�^2�!S� *evs�!�a�5�ɋ�8�]x*� iGPbtu�Lg a�I%R.Aa�ZrN ��3� � c� ����� �����!trarVZpoa�ve��� :<�I$$"R �O/�)ɹ_X3�e 3� "$ 36wh�W� S88M8*� N/ ,kcU��a(`��>�%:�+��� P!�ŝ.�a�� v |%a &���!.�$6�!.9fl g~�UX"��LE�;]�0��i�F.ganj"  {�4cu�z)�^� � � �9 dlG^� orga�vs�TI�M.�ji��iU�&uN&-?V T�/� � 9}ly�aN݈���&�R!�.HD �A?�6 [�fM%�K"� ,�&:#me5'ab_ itZ�V�_Q��H>3%����aI�d�tV#>��%�is ye�b�=n�r�u> � ��]?$)~� /�>HDc!�R�)���'i*|�F/��IЉ���:kI2i�,���&Hor=��<6L!8 �a=�#2!>Ni.%O��.�j�6sFO�jI�!aNs�4��-rac��W�1�i�"���� +�3u"�1pass � Ea.NA��m�r�  . Q"� 6fuN%�P"��"�N:= >�_R�t"�M�! �5e"4r !�0G �Ci�a3mjx�! &�S.�?�'I�8�w�c�gni� e&��#^ %!F*D alge��c&iZ�1"] -arY{�� VR��I&%%�*'E��J�!A�"� ���pʀ�O "g;!�� ��o�Y*� e�D))P�,��le&�-�75���1/*S���16�1 ;� �b(/-��' volv!�s�d� s . 1cUW� "3c baL!aO=�,�.�; r8  $��&AL"�>͠�Ʊ�R � te�-@ �vF� ,afka��kJN)�T�*B~L e&yr�0��v001!�10�! Ń�:B��%  (��l  �  �t"� i�  1KI�T�@�Da��ġ� �dis53!�X�& �%�2d0!U"w s E��V�"�b��*set�ras�!() �"%-)M$J rugs"�N�ir����.<set&�8t]��! nit-p=�1Mto ,!k1M-Oa!�.� !2io�� n ��u"t�M<.a�?on6�<U_6-�!� )� �0 2�#Yen�C� |a l>[N�%�:���>�.5a-Z000G�V�littl�y��?"��u ��Htun��#\�,"�5!5.�,�J,Ipa8�y�XT!<�)�:�a�H�Ko"�݈��Thu6F�)zg"KCx�no��*��t��b.|[5�T&� r;��)"ϞD� �(!���!�t��m�,B� 6o2�-��D�PjC*� �vE�eJa/�PaQ%إ�E�h"�7)�ۚF��' !��Ge\o"UMLI"Z/�@et"c5n.le3ma�l�A��xI/���R$<.�9!��Mqg��;��^fuq.wRH-�k"�?��$n�)� 7�.�Ie�.m �.�XN :�:�ap�8�z<9z��D!�6� m2uAaEH Q4���E ũh�Y �"�${3 , 5 08= ��tw�JlB�]O} �]�H3յ&/3�0?G� � a b�A�Ty�1�r�i���sy -J &^ �!Dm� &offA t�TxaC��to �l&)A�5!s,.O�Quorum �a*( Q�e��s b��E� fula�BsY���&�E!�&u�B�� popu�4� W���5“a�(�h+�a��<�e�JL �m*x!pin�kvIGmai�je�v-#B pX5ucircuLm%*� e*�!\� twX%=D�. OG� p�typ�P 1�q�employe-�F��(" al� G2�FE,�# deci@iwo��9NW&MM��in�C r-2 ( AI-�q6M�$of E . col0$N6cF01�m�r�Aa�d� s��I$A�0 archite�'!vo sub- ACA�- unrea@ ed n�feeA5%��- �w�F��tcd:M�-m�FZ6.O&,{LsrR M(Nwnd� �����-g57QSY�”�,6�ly mask)�fera�dy�,�L-���L iea�m!z�nA��6iG *�; " A�HuS-�-��is� bottom up!(ac�5e��ge͋�%��'"~unrave�"!�x!Yj.G#Am�,�K�yu�� �����og�8i�me��*��a�rol!�_6n�|a�>d 7��,=E�� ���fs�8=��I���vs_""�>���Bnviron��pu- � !��0�X�%f���CO&�HH alw�> bi�M%(�-� �e�pa��tTQ'5propa}onEDa�"�"�&� �mW��an���Rfaca�i!��}�!�.�3a���!mB�!�U �Rm<-�5 .sD7iT��.�jp!��A�MI�metabo�N!�R3w���A0�=p�r3&�$f��E$:v�%a�J� otif)��]�j Q.�0s����. Desp!�<*� <>AC�r%(�=f2�,��V���o�. coupau"�JJ�9�|��-�Xenopus��ryonicII��Ib��ai- FN ����|A�/�E���E� z�>orЎ�Y#n*th6 #�>  buil�dem� agA� q"� � 2/'&�tI�A��" #�XM&[4!�E��pH&,` �o( qc.:�^����$�c�> 7: V��,!Z!�,E�K�1 ,acf/��-)mo���*:��b"� #a��n # - lory�E I���"ou!��%4A��A9" y"� e%�.{ :� � < N �1Kc.m!,�$�l|/��v����utN �,: � a��t1�!#��.�($v"���iso$ �=�&ru��qL�D.�%Ct�I"����#o �zA� te5#B_a �VA�s �LE� ���j #PAE ^�� ig�I\!�inm�ig��@Ee�p� -�&�,y�irS"�/�� d�.lgR�nd*� U���a J F : �2�Y�'w.�el_4�}oP"ƙs�3�W�P��n}"� !q��� �6 �Q2��˅إin"q��AnV� � � �capa� llA�!\o %�weI�����e ".BintD,q�!w�G sub-I��AL��p��7. . I�[lbLw�v XQZ�b�,� -�dz$"~� .� QSryv8�(���s^*�bu-Z�A�+5�Z)b%=�1�ݣ)��!.*� 6z a�!��.+��_Ia"�!�P ngth��NU �$���;!�e�y&� m�qn-�<� ��,%H�)������y-& �N��"a2�I�Ged�Lb�8�p�>!F�"\ fi%:�� s�q“��sA[7���MA� & .���.� cyto{� "�!�%����1 %j!s�:"�� sur�ings ��I[Z!2�Ma�q���}��!� d)��h��F�>ex��!�9��*!�re:�� )\A��Ms� %� JbacISa�s{!ar�Cuh�`g�!faca��Io�\� �SU� ��h, 9 E������[1�S] �jNR�ndA͑a��s ohff'�.�f�Re&P!���W ���)�8 9d.�})� ])%v-�N?in&v�S�yphimuF<.�B&lsj�:���EMu>�AP)5�2(M�!\EH� �:w0 nth�8�]�t80%�ra#�F�� summa4�rAC�EO��J"N(!� < �Fs"��,k"Ϙw+DuSAs�C, j!%�e�-��t$�}" '�pW/7x%W.��%�M�"7D!nD./�>m .٘,5a4}!9*G �T���YA�of ߝ��el�milieu���e�>%��!i�" K“�Fe�A.F�2w�,6�P.��H�" 9BsMaq!+�*p����� x-�` � s.QSQj��*�%� �E(st Ghallenj�� B#e6�-:�� i-g�.��$�&!V? �9er2A OBule-Ga� A)'s"l A� A!pme%!"reh� 8ix--a�� �j��s�"s���� �#luc܋�� �Ab��� js��%Hbeg9s�FI7E�q�s/ə[ u�Q�6&up/��mo'"�wu6^&o!� � p� ��U ���&n:����| fu#N!!ȥB*?/�2�"/*3Q*% p ! �1�yC)J)�remov!��&)� �%\��a~a luxS ,|#\g��hac�in vivoE�f�`��A_�`3troL�6v�$,+�f V thio��up "�2._%gya�ͪ� 2o2}h:(< L��� TX �!x�!i����_��b�"59�!(a=�F�2��-�A�)�s�V1�(ts; "�!by"E-!,�O-��" �voF1A{%:IoA�� �`qd� �Vyrƿ!O�t�4.+�N)���A@-��}cJ�&� � unk��kS l[A _T}%m%m� 2u'5��tB�QS.�[+�?LE %��r60��-�e�bz�A}D(/s)fQS�e��IJa:�����- FAVibrioK�yi�-�{el���] _&a�%iV$& ay-to-day��a���;@LZvue���j[�, ��$|�]�e�5Il5sZ�fA"�urhA%Xch"r��Ѳ]�>�MsI��'oraB-�'��!�A�Ef�XY *�!* �&��71����e�q���a{�F" F 2 ExmC�:�Ji �<"�~��iy�r , �nco�L lsr-�o('.X 7s 6�A�A��� �J1��-C��cy�()��7Tig[�(��3lsrpA lsrD�nd ca �%�7AUa���� eŅ��U�b lsrG/�_,�v�*� 2[=��"�2y f4d�P<�(�.-or -P )�_c";EB�(�F��a��>� � m�ly hom��M�Aq:0&|G� � 3,| �%�Fab"� aLs���r*; �YYA�� ƒ_2un}�ed"O �T cc��I;�,}ahY6�U7.�n2m;� (�o�� “AQ�� )!p��s�je &%l-�. Upo�� ! ? �.k0�a9�icrQelKM�G:8E����b���K�u$PR��� inhib��26��p}�/~!�ngIYe.p���0�3o �!E(ac*>2N KR:Ea� �t�o��.�i[. P7�i*�"ly�,A�e �=[�d��dm ���, F� viZ r; �"m>�'� . A�+"��]Őw>>�di�%�FN�Nt9m���~"&y)nP�m�E��k�I6�. ~"_2B�%i!��R� a�7*=��OeGvȳ:� "��� to�A NlG�.��!���ac$�� �����-{� ]�U�eA��!�RA�#&� r��|7d  β-galN!s� �*ssA�2��-�Ma�,a � nd MOSA�m�),_-�%� �)��>ex���E! ��A��@*�=?2o���e� 2 twll9��^�h� � .��%���!c9W�2OpB� �Y&�$F*&�#a"�~ R� re^V)!& �Bo>G�Y��0[pe*2B.8u0(x/ep! � ��m.*eM� W eeo=N�}�%-mh� �&4a&� Y� .A0� ��"!�i�aEei�0A�R�srKe} gE e#!$��w_�a}�Zt�)�.~�"&,,f]�Eo 9.�u��f2_ �A"8![���!2�b� �8��2!�,A�4zQ�UZ� dele��an��):" no��� 4A���th*Ds�&���Lh�bo"�����1=�C x"n% }>�1)��WE&�-��-)�����7�� `=!A]?g�DP""�OCB*&5uA{}$"� e7a$/����E��C!�j"!C(A�* )&��= u&NI�Q =a"�<�eIaU��_f�& e:ak ��U�qa�{5�R7�Ph�9�3A�;*�YaiAArY�� �p%�V_��%�"6,*� !Mq � K>� ! L�-r�/.an��2e�4A��1pdqj)�!�.C��*& B� <T�:+ by�K�-G ,� _*� M=畏 cR�.��,�����f�m�Ha8n\� �%"� 3A��)I�oHq�ſJ>X.� "V *f� 6���.2�^�"uZ��2� 5 �>Kmp!�-P�Vf�`o%�!�P.�mi" E� i�s= 5�Aa>=&"j F5��ׅ~au0�n E�6��By 5 hr?VQ �8kupA�e-� ��l% vst�>.i6 ie>de|��WO�yq�`���O� �B, �5:s&�� Ň� �p�ϓ^5 y� &� E`�rC3�= "�3���to K���� ?:s$C26)2�eY%�A=F�9p �K1|∼��Miller�7.��a�V -b<(>706=�����.�� &�Ţaal��'�(�r 3!.. W:�is ���=٭�/��=��X 1M�%k�E��Re!"@&Eq*NU.>��$o�`de��� �]�E�!��i *_D��3BwB �a0 eI2#6�%�>g�9�7/2�v�B-D�1�:�1�e����*Ad"�* Ƒ�. C;war�f (j6� reGX4igr ,M�q��;!tZ�:~ 28F�9$bE�eI�8 a sl��%&�Dn)6. �er�=�n�/�*�e{6H��a��"� v�K}�!�isq����0Y :PL� q;Q�&�8a�!��'� �Cmf�()�;u�m_�]υ�r�Y�!M���&� =2M'&��@MR�?�"��FEc3C �U�e2� ata%�2�.+�at�o!!�>_Y���i[�GE�dc�A�!�F�E�kk%(aL#�J� �3B 9���9?�uŸ� �eȼ�Fd-_e(�A"�-B2B�%��� eu�n,n�66<%hs�9�g�`.�percei/ b2�+R�!�\ Q 2AE ��^cS�� ���p^8. �V*Qi-��hE*�Nm0&A {*0i3��-"�,�F"m�E��/� �'�"�>} E�s�6 �?���a�Nz9����+A� ��t�?ta`s o�inl�� �Ag�dI* O�Ije�>>�. �=H2&�a~'N � ��:���3uof�RH*n|7��6J8�=!E, ( Eq . 1 & ���)� �[� !�dec�&�J�S :ͭD0�� Lmp �)J�.I!xv�C.L� .�A�.EA!EZq=�;7�:L�b �I (#!+�L*{-'@& ��9)�.�-��u!�䁷�)Ź2Kn ��)�e�� ]��mK2PisA���L hutE�Vj�`��("�IFK "U�8Lp�5�����mMalyES�X/apiB �4!Pa t`�W minu��s�=,!�#�.1/pkwe ��D�� �Aw�edI!!���ked*�as Ap�8ErN EZ.QAT*��Y3���!Q,5� 4p�K<��!~KEiOMasB.[Ini�L6� SV�A�,�szP�KW�`2�?mj>�� �M�MB�6���'x �G;of KJ40 uMFma��!J66Ku� �,u��uDV)&�H"�v6�����{ "� C�BA%.���% |e_F45&p ��"9�"�COPASI�I���t�- �&ln,/"Nsi rwbΙ�ca LSODAE`gr�θE��>numer�$����w6�)a[ empi:��4kii�p&�F�k-�A99r,M(��ro����%�G itE59�eA �'a ��M&�VA L�!G�Nx"k[a�?st-squa^@�$A�a�? 4Y�O@Hhm)�R%7]��p�GB��F�fZ��i�_12��"?L(s)�E�(I�S�Z!�&�&on��J�E<s>J2�{-��1!�*Q@��}q�D�p/��0� �uis�F��? ;�% ���l�a�e�!F�8half-Z�F K� �@�m�J���6��3d��wUE� :s=r�� laboe��'A�&~a�%|^ !\sc|� �Pth �A�a�%2%��eb�"�|Pj��:� 2�cof"E �/\SLN� y"A��� �;��omHng2� 10�~2�s��"���&\�A�UA7eS=�se*I! "�An��"� %d�! 2�x--i�7 g]��}u|w9&6�e2, %�A�-4i�-M3M~9rEg ^� (iAdi�>S�A�l ��Iɜ �e=e.0 * ;8� 6 ig{-nSmpa�8a��!�o)�!��aer�%x!�,�!`� #s �S6�Ra 3AH un!� v�b9O< O �� dij�ۺ!�K� щ�%��;un�%�t"���ZJ)� �ZF� M2�� A*��"�G�,*�]�icpAb�5�=.�= as k�Qk2�nR f� K".q/��h� �"���A=3B�g .c��a���G�nc�,,"�\"� �!tops)'A�ks&�.� conf�+��A��"�o` �A}&FIe2Zt�V!as��]�ex�U�*�<` �0� a ��a <'�.�f�*� 1anT85�y`Ee�� PY�ory$�~&#4���Y�^Ϳ���D.� /ai22 !(��m*���'a�.��� ��C�:�?��mi (!Ca!�C�) �E�w%�"�Ů2#E�the!�Cmt�Q�U�i?� "uC(y�}6!� �"5F|! .�)�3��wh*�.�)%4�-i��+M .�� +.*w{��}�n,�“REG�+�5��2�!6 !�!�nF[� e�� W M�}Z&6� � �@n� A.&� �<rB���6e��zIY<�DE����>�:�)G�)�}^A� �D*�p2?��2� !/3A �Xei��sB�S݂z'�y- )1"��o�[dh?Bakf&Zj%A�I6��u�28A�3 We|H**� �]�} lcen�*A�AJ�ga) 0� ap�_J}M2*�e䉇m%�o��J0r4�0 �!�u�5ms�Xto f,!�ld� -!�dT(H]�F� �a-�����NS,A^D tI2C3R� �B q=.�-�(J )E��-��>� /!7aޡ�� FU ��nE� foXA�%�� �REGυ���O�e�&�1!�I"K9�z�da�oefW awY%�4Gms�! S�f<�."���I�&�*ER"�4L!) ' �.H �BA�)�m'll�-RE�b%|��S4iVim^�I���� �35{v��w�M"f^EKZ �8d��nds4��A^e� u��e"� 9�!��,UP�bnd=s�$Ply!^�a 2�I�mER�'!�>�F^A�%C�C���_�Y!.T�.?S4E^9�F�X �N� 4��u��[+�wen�c6H)�G��o���@�M��  ���!H��)���&{ 2E�!O Y��TuIrU�Q�� .Q�!�. Ñ�62 m.�.-��� s�2Y�6!-Pafa��7!�?e'��V�y�5:�m"� iA�@ �asG'f1o�*kK1K�q�!<�&���ild�e"�'� B$2� >�D�1knock-�%�-−/+A�v&V0)�z>T�E:�: e wild-t��ype and the high in vitro AI-2 supplemented cases were similar ( Figure 5A , left y-axis ) . For reference , we depicted the measured Altactivity of V . harveyi within�$extracellu}milieu/�@cultivated wild-t�,s o >(same graph 6� righ2�As expecM,) $is accumulc!4tupon reaching a threshold , it2transporH back into �ell . T-w est level�%z5for2>�, m1?through' =Lssay ( see Materials� Methods )!�Has around 200 units�luminesc%� . WeYn.oe��7 different:DLconcentrations to fiMr=s6v,that yielded!�ression / s as "M<4vo synthesized) case=�B A�8To our surprise!e noticE�at an Sa2��4only 4 µM gavy )wQ��e=�.e A�aeerb92g@s we observed gre!�6�(1�1 , 0b��AccordA�t �results�m� 2B , �of�can �a�r�Paly��in isol��Isepars��orieT net Srchitect�S�,siA�r�, exa��d �y Xly � is l���nsp!� �of new.�%�����=�� . Several2�te4inclu�dhe exist�<ofML]ve�$s , a mutu�Qexclus" swit�,ike behaviorGXL�h�X � e alectEpathwa) enzymatic �a��protei���li degru�w%�lla� sideA�a 5�af4 preliminary t��. One �@ari!� at showedsm�vEYhe��i��A�an�Mu�/� would5�%�%�{�ZsitA�d�� a nea�ve9� ( basedao��obtainek��3A�NI.WhR spona���(lsrR knock-�)��s��3�sugges a��le��4MN ithi�P��%A�6�!�incorpoipeN�construcja��rehenI�� A&�8!�"�ial equeIA�detai��}��summar�in Tab�w3–4�%a�� ��-�eyplayedA�škEdetermin��� outc�&is�el i )L!���:O��( e� by k1  iC auto9|y effect!]on , wn6x!� yZ2 Z[=�LA�-oA�REGPE�)��F�4mA� iv )Q'bin��o � lF@3k5E��l �-G�>uY feed� motif^ E� coup��E�!��vP�M�:VwhA�/�act� &y A m�h�rh� n o��la^i��-�)�wg��б�e binE�� both��po>S=# . OuŬed�W!c���jD %�@��ifYang� kine��a��T)NaI�produc� desEr��acorre� wh l��!Uexperi�al8 � b��=!�betwee>moad!6Fs occur�wh ,~!^affin�u7%�� �-���Ms�order��8MAq�G� nd%s� at xA�U[�TB��a��;i�h%sE:petIodynamicF ists%�y isYl.�to� ��Bso��!�greE!]s-3�bye���%Xles% )�%�.�!�strength�B"ofe�%*!�s �org� *� !P2a7~��Z�� s a � � a$� � |� X5t-QS5k�q *a� is��b�hvolsin� &� S =�e� ase�� ed!{= s� �f�  a si����irevea�&EH�~�/�.0 �Q͉�&����s � to"[� �2 secreE v -���#-ZE]t �)PVI !�BD =�$still unkn�[p� ost **����@ e:%Cap�nt���Q7o�-6�%��saong!�or �&Mj2�,uAunc��Av )ud Lsr “� ” . N:� �� re�eM�dA% biologica"A xprevious%s)�� �Q� Es�Vre�U� cripzYo� in �sle gene fLcascades [30]–[32]�incre{A�fi� �a�al� mi�inR�[33�34�In/�,W���&baaU��q2� ’sm� �Y-T��i� pl� IxM(o Eproces!!�a�-P� Hunderstandably sequ� a�d1W 1, enaba�AM.p[��o. How~ ,)onj E�B3 [~ngN6�$via direct��c�1VmF�o��R A�entisjQ.s� irst;e f[e�M��S �RE1!� ���reA�di��9&nA�Ѱ!�(U s co� A�"���u� � Wbe feasi� f +�atA��� dimer [35I�f� re b~toeximA�. A�E`,aC� ata fromL.mu�Va.��lyU/5= .inetQ�sh0b$ recruit� Aa)�factor! �9���hyp1VLs�� s: f9��h"� ՚��v�KF�"dA�n ��(d phosphory� aM ��vdem�&f unN7plaV��AGaE$m�yen�iKon��I�FN�&(e�m<&w� a}N�,A�sum�A:�by�K , but%��oLsrFGqw�>`E$"� {!�%:�  ��w�influE lsrv� Dyet���$ed manner   cond���s�iBassle�D͘re! [16]�re�pigQ�!6er!�u�CRPP:��n�^� !�tergenY eg!��<o . Perhap2��ac-$staQ`]��� M9���I�no��w��s%c of glucos2eshu� ff>�� swam �QSo�"�I*R)}�%�b@ � �e2�,��, s:�st er� urAn U!`a�i8w:�.aQ)S�5e��:!�"3 !� nee�og�� -q!&2�!witM�b: usA guipheno�A�|-6|" < mon-D�top� j��a�� "4M%!�or&� [36�7�aiF�!Q�7 �* t� -P-Kiv aA!~olie"� evidQ�j2�a1Y�w�@�� stud�QSAre�+!..Cdou�Z"> "� B�%Abvu�(to quantify} .DMT"�E#� ž��A u� a�tom-up% roac��4 �n&�ele�Epn9k mto� zeratu0F�  e�/UA�"Q v%�&Ce��%�2B�� .�!�5�s� 衽allow<] aqLtb �M�-d�aQsi � � }�Qb� �o6�. FR&iZ0��67�2�N�&���of bac$ �I�ma�}�dԁ1e��f�wOiU$quorum senEk��es be�F�v usA'techn�I� appl�%R��Uee��e�W l~�T2DS1 . Luria-Bertani� th [38]!��5 � yeasti"Lt ( Sigma ) liter−r10 ,BE  trypts( Difco:-A%1 NaClJ. M��p lea�"� tibi� s �S A�a�63 \: Ampicillin , 20 µg ml� ; Kanamyc1.� Chloramph,ol:"�Hone-step�|lac�AMhod� crib� Datsenk� d W [39]�i%�t�ueluxS delsin��1� LW8 , LW9�LW1!��(phage λRed� o�wm�Stre�e�tg� wi!h4::Crm PCR frag�� . pKD3�H smidOas( temp� FpUrsLHP)[i (Q� )Ri�  t>�!�$th DpnI�int�� electro��Kd �9/or).1IcoE�A>pKD46� �'�gr�in 37°Cc an h�. Ra���U!4s�VLB^"F�Y�a> �U�r!�s%�verifi) !Eteb. Cul7, 5 � �overnd in�, dilu�100-foao fresh ! 9m Phe OD600 below 0 . 05 �cymincub� at-8Ee shak!z at 250 rp� c�11YA 'A�Ead� � y� !7sa (a�s�$c&9�o� ., remo�at q�v &�j?-} �vβ-gal��sid���_� Mill� j& [40�a�Spe�5ofFR�ew�� P�& OCell-f_ -~ fluid1rg!I#{&ifu��U!1GGat�U%!�!5 m�!n�ic �#fug6 Cleaksup�#4 �fi4 ed (E02 µm I$HT Tuffryn % s; P�Corp .K,nn Arbor , M . )%�stoSat −20a�e1I B I�a&ed�!���Epby�ucA�2(in Vib� �)�eZ# BB17a!�y(-perform�s outli dby [41] .{wMalaria burdeL)�#s�y�J Sahara �_helminth�(Zval�A� "childr�#re oftI&��`�yp�5�#B. AlthoS)� oft on m �iTA]isQ � � impa74co-.G }ABc&lucid�;j�Dscarce4)ing �conflic�Bt& ,?(&�%� he�,schistosomia9,N�!�soil-�mit=9g( STH` r)pcW nc&I DPlasmodium falcipa �E��$ongit8$al�)veye��u�I chool-age9�liv�� wo rj comm�"�he vic"|DLambaréné , Gabo �4ck blood smear�&e�,scopy , urin!l�*5�$Kato-Katz � iqu�Y�to�QctU-Ye, S�,ematob!-eg!�H!j,��,�. �"=Vcarri!�7asses�6aCT%o T2�Q�tim� !3�evaP��reF*��.!w�SURa�7uS%8f�m�-ru'.A��:��ral7#�*aH �� �� riska�pYmYb� �I'"�& �TH8survival��%E51 �fE��]�on��� enrol: !�30%� 3%%g9%�}>�,>��� .2 ���.G� ez,ely�y!. >�inyR tend�-2�rc���(!$ETrichur+ iura� hookword)��A���FwT( aOR = 3 . 9 [95%CI: � $7–9 . 2]"�#R�� )�!���51H45– 57]a�son-yA{a7��R]��( roup��pt�'e non>#61 vs �3� = 0 ,)@�+� aea�-� |-Q�i��.�ag��b6�10�s-� !��� h���UJ_,aB enha���7E)* :�U��:�-"���� :eS�:=~ s suscept"�-�qvelopa�1$in youngkA��|jlh#�. Ove�p  fift�A/morbid� A$mortaC.du�Fs� glob�ded2�.�AfricaA�90%�� Tq92%��deathE-��%y"�$in 2015}[ bear�@E�st{  dis�[� Mos3�ases� �bf� t��semi-urb0 [2–4] �&L� co-�Gt [a�7* I� se$as :�s&%lye�l��w^M=<, s� stud% � &��&�%Z�eic.Rat��ip"�[8–1 epidem&� [1�)��. SR�"U!���!��u�4!j humob��+��a�11 �es !�l� Y� � , J0. ST* auth6)e�f ��lea�3naggra#of clin�manife %�of�� dee�it�&����atRF��:��assocL/�F�X Q`c�0whi(1dqvVV� or.Px5vmia [18�or���+�� ed=�1�1An�)�%$U�9-l'-�^� +,� I1rNac|!et al"leS ,�ti�%� A� i��ayIa T�!�blish�=�toler�) -hai�ie4[2H�!HIV�9��%��=i1P&]C��=��6�Y5R qE�Eu5Vin�՚ peop"3 i�,4egnant women u# �-retrovia�S"ap�7ART )8Rw&#$ [21–23]��1��Q e)��� [&| s"�9�aY�6 o beBa�( CD4�,!~�E more' ,M2�" d�a���r��!�I�[22��� situ7�i!:ly&���6.!׉�.ysp�5�E��5���e]�>*�A�depend�6tec�[24m�0�5&^_ �s�+� 7�W2��2͹��� �~&�+h;� -_)�> t7�e+�0against��eUǁE�[25��& �� oflg� s5ympto3��in �-�  a."f�of>� [1to�n� x��{of:��episod��� 26];A!4EYsQ�!0>!!���my m:� par�!,qh2q1�!wtr� ,2+mansoni� )�!�o:�2��&� �#�9�8m<sa�0p�?deIc�!P��J�ݚuDr�&"� �"���Ca�4��� y a� vieSreYly�Adegnika�Q.iR? x &�to�A���u��cross-sI�al!6Se�c�%w5!�ɅiA�pac� �cis�5�|�6�/N1��b�� w�"n��TF�S rS 2��-ssu��  I�B�!�:�!�A� U�t��ofr�[1i1J*Wa0uM2*WY[>ion&� �mK"� a� �#>�Y�"��U�*�!co-en7 c� :V8a솣Ei�" �.G)�� pak%!�]itu,al eth�0We�CERMEL��>dce number: CEI-MRU 002/201�'Paa|s�legl2vt�8�x\ipOS> a wrt� A�� �yU���:WG�C� PE�c?GCP )�ncipl�I �al Con�(on Harmonis�� ( IC yDF*���col �May2a� Dece!�4!3PBindo-Makouké villag�6 BM )\Zilé-PK, sett� !!^q[a| � Ax ximaX>at 60 k 12 :�,�`South!] E�8�| �f�is�enn��ex"��� dry � on (�+Ju�" Sept)|7a�A�-� 216 mm^  [3$~��� rrig�by�$Ogooué RiV!�3tr�>arH �many po�, lak� nd�eam�,nsi� ng favour�!aiAu1r�-wa� nail habiar�RŶ pu� ed �,*<+&a *S�N�%L>&�6m15%!�75% [9X�{ �QE�Jfis7D, house7D�$, fetSD �! play�� _ ��vi��*expos� e loD#pop�3��:�. |��0.?yAkdo�<nF�Ղis>[3W�0>��7g3[.pro�D-7A�&�#.� zmwALof2% ( NzB��^�)�CinvXFaip+M�Volunte �v��A�tha�Ag�3a� �80% p?E,� &),G A%9)P�as�;e lEL249�!-bB 1�,4<�� to@;of 498 vy NF. F�G-��e/A>to `��� ;�(oth�qtom� *�HirA�IorZb Q6=v�Eq0!uv ��E�-U�At�5)K,�LcJ> (EM�xQ����[an�?-�� ( we�$, h )ɡs&� . Ax�rpB mpern+�+� �.B�y}ft ��` �`7�&0% P�-�5�&iw#y �OtoR"bM&ei,!�I�g 6y�Hf)�,!��)�wo6>dV visit:�#e A/monthV4�/?����/J ess�!$A�n�G� %�in�j;(pasUB d%ad-hoc��� 4��sEr��) rese�,�$ *ry healt�Fsue�I��flu:���1�as de�as��T� 6!( TBSA�sR tf��7r W"r� �0G48h���!9%�E:�DN� of 37 . 5�$wg���1� PiagnoA�J�!q2�!I�2{.��� uroV3��>� . Ur� �%t4nd�.id�oY�!y)��5�had%'�|��,a� ��p%d&�4��"�>�-�aPiS)dFѰtly��DS"�=A��2� .2 ,FF[�aw�N��QU>a i7s�x!#‘*�"O$’ ( S+ ))�0W he>>y0 >->.�MV�,.-��m�z��=�Bo�!$w�  .C�)��-!� 2��Gt 9eT�La"�� cour � :51w �I�Tr �1B|who did KN?ri�d >s]�2���un:�U.��$of} osur2� 7!3A��d� cal���6a�rst 28 d�0fL ���� �uabO�%�!|"H81aG���9�:� 6�pda �-�k 0 mg prazi4elAP kilwm bod�fGxQ;6�:Y�ie�AL��M��q�t �f 20/120 � arte�+ er-lumefa#+n.$.���xFn-7��M�.�tw�a!�z7� �+lJcu.%�. T1/1TSTH�r� -dai�=; %>1?albendaz6A�S�ns2][~?F�j�A ca�3��"� -.��y��r-�+ �p'��KrM,De[ A�*C1���"�(8 ��J'�.�(!�od��de�1 elseZ![3�z7.6>��(�3�.by.� 0ml?/��e �0a 12μm pore--�  @�D;!��[3N!8.!}���>Dj���Z�Z� , un)Fe!u�� "e�2�1�!(��� � ��se�� thir��'HRR*!&"J-T�@Pa0A . lumbricoi�B, T .jc�'a�ho"�'-�stool �s �-%u��6Ua^ ~ep,}.A%*.� !�I2&Al���� 2Qin�xArea3�  P. Kcap2"�pao a�m ( PRF�,e�$)U4ess 2013 softwl�!feq�Rverk�(�4_. Uni�6=JV+�=ppl�A"Gen"+Lin�(M�J ( GL�)�VY,�+�+? >Co&#B2�:(�KaIz��� �%�explana�8�%� �f�Y�'.f�7A��'HA���f=,�YW&2 Bres�3�06��6+hom� e� \K O��w�EJBc��.u�aE� ��!o!@ŪCD3:. Ten!�� (�!)�m�w i�9Ud5"�jst )��!r�adjus��u� �� U:�[!�l-�ofe�9�Ei�� H3���k,a!y�w!�*0FK�i%s"b+6 !I 5w. A KaAJ Meier�Cv� dra &o ���-to"+*v � $e Log-rankY1"_$a�� curvqCox-��1')k�Q�. A;5��s e؎Ke@8 �X$as�\�Q{754&[6thVi. O�  wU"�73*�%�>� Ag: >availe� �V!*e] ZR. )(2$./�K, 68 ("/)�WX e�!�U�R.o�"J� t 31�?.27%-35%] ]I�� ��I3m�*�I1��a|!��.�.%12^18%-24%]� Z%J:'��~;19�16%-22%�@65%-8%�#al� �/Me-Q�+W *��1�.4DK/!�/!A�boya?girl sex�"io < . 1:1�%�:EI2���� 586 ( 79%&�O�,]H�ed�Ȃ&� )x1s� :w!@>� .��k1�/20%-26-R�1A!�6f;)�67I�,007%-11%m02�"QA� �fE� p��a��%& 5AX>:��E.�`+B)%�[oI��"e0�R1HA�J���%�%\Fw�32]� 24%-%:vsA�5"14M�6R+ ..�4!�4i�40%-5!_Um15%-23F�,EC> NAB!as�AiB-�age�A�G��a2����3 + ( 37a %��&> S"�a9�F)"-ij�0176O .� !Za.qK40�Az sY �a�/*SSI)-L3��63íL2�rem1N" *�wh^���% t$�SU }23s>�M!�� Z-�ZI�e!!aall�am�T" !"�!:�q��(���d�.1%78%f!9"� cameɄF7".253 ( 6�&=UN=n� ( p<��00��A.�,u�RE6�aigm4O� U)]�6!�=��bv9 �6p �40�Y crudakal�7�iv�$ ��4:n)���P!5!�5�6 E* ZVY. C�) 2>Z��a � 8��~6�- . 5]� s od}jaBZgS 296ir6;6cod ra|!N�� �lYB!m,>e ��i��'ly��.Q1n!mI��ndA�1^Rw�>/ qAX��(Y6�%�3����"N ,� 6� 2of*2�&��J�on>A3>��9��kT!"�o?5�6*�V ��T�a*�,[ �!�"T!!A�r����!s no -�@:C��A�4y1�7 . 8��!�U1 ���1F:)�.���� A�?A�eE�� �;KX!)�M�� +twelve1�of�W!�mach.�Enc!� � �x*�����e�E�censo .�[rRj�� +>[,��10a�4FP ��alaD���Dn �<�.$52 week| y2~�2k �109A�0B����naI�-N�2�F~Fig� "KXa2�de>t�h)/1v�.�"� (R:�i037�AbA�!� guntil1{}�ar,eg�>�sup�EN�BTo M"�2��A�aMc24�KBe�8-�B�Nn > �5Ba�:G0K v>�#,2h ( aR�@�Q,��003�./C���� oN!�im�>" q!he�(2QU�|6� 9�,m-HTHm���51mu(6� )�6�?0t |@"+ *� wNL ��aV�/M l-A�2rM A͑V.���� >��i�=Mrs'��o'n� �pcb)erm�%i6!|.��1�*!ZF ) Ͱ9R4� �6� �A1Ŝ6%]m�ireX4>��Ha3� �]n�Zt.(^1*<<;a�� yPr_6�a �waA�>�1��' 9�XTat up�@11�@N�)"�5Be :�V >  ��IAtow5wp6�;.i in Camero [42] s�>1�.0AS�>8BL>�4,of North-Wes�l Tanzan9>43:3ISZ-0%i, poly- �i�^e�Vt [8 ,�\1.1\�:��&&K�W��0d�32%!48%���� ( >bd*u � tS.js!msizwi��m�D"�-K2��I��%T!CIǥ� ;�by�=-'�/loJgB�itL[4&7S�YOst} J8knQ yu�TV�a��A�O� h]v"}_ney�[*�2�<�"on.@ m*J.�. EveryBwg�!�ll���|'Z���%`F�;<aDV�4�O�D\,3:doj&2:�nmea"-Khav� sc�f~Uw�Z>sc noy3.�H[4�<Ateba�R� abPn C �6�i�!0*�/asexua�bNU�7m|0FA.�<���is�'u"'�0C*�;� ���4�V,.F <"8���iW, s.�G- 5 poten>d�ja��t�N"B�7p_�0A��a]s2� E6t�I�#,&9 auZ-�xj!�HV"! .$Q�>�C:=� w�`,&�  \(Aao>� m.�C@���26eh�N�6?D�"�[4�46]# ividEscf�#b�>W��2�R\ !�!0��ra�'u�!(*?%������B��IG ��C [4w4j"� E�a��^��iM��/�eNM>^�ũ��mV �W . BuXR� "{����R�,"r (�ClH%��C�sJ ����FBIla.oe�p ]s�8o>b96�hi�S�=�%of� bzJ�]B�`��}[8 ,� .k,*RA)Z1:Q��?���""?�I�7�. "--�g ���G6� � ��U��it%��[&�O2Hwe�5�l�3"H��� G �gat2,9��j �2-�e�i�U�J��:=;;��B�,P�\atj:Q �xe�.J�*Ov� aub�4N�3��Jbt�e*u ]ga�R�k*���Qd�&d ��&in�^t"& C5e��aH�C���HB(a a2s�!�35�CH�(��&Q(�A�"�ZiA�� %I�0�end�)�apyB5"�~Y����,��jrJlam� ry cytov TNF-α.m )'!�:�N&\Ah� �6�afe<G�#^�5 �Zf�9i�F�s���K�t&2i wa<>��2n!�-"-Nn�m1�A4BH2#*& �; !��p9 -k�Roq�up.��#��.���'11A_"�EOl�X*+w�#"� 2LG�T &�j6#)fu[:I�e&LPq��� !�5>= [!Ma_*�Bor� ��le *�'a�e��e՟�=�UK�u�X�RO,q!�s��pi&`2R ,Q*�g]?�Muia�<r�"firEL^CW AJt�Oer�B�5>�BV�? �"s^�U.��  ]�Brrro�@3anu �s �j!$� by SokhnN�4�Qa�9 � b�!vZ�"N,��t^i�..4ex�vng�Ev[�3 loadsU8];Qd-e�1�"* �SJ|B* (e" *E-j�s!� op 3A���ideŪF�M�y#_rov��q2f"� -5� ("� ��at��E5�5|s�H�by��0E���Le�%z�;�]��PEianM�coha�O��&a"���:�]!�� hav!��R:d �|�ns& ti=��. �.\�lcy_�ɥeV�GD>� aq��Piol abov�6O��.( hO �haZWen�L#X TH� sF<5�%��`jh [4V5XTNoAR%A.� THA����6�+%"��l �!qugk8~; h�T�lv(t"� 1�D!�n�-AMIKx b9� �$R1�= assu�_!>�Y%0�-:m?_a���2�:�9�S"�L�!�y��nj"�=��(D�!��{=`asa�7�:�I�[Y���5a�>,��N�N�dJ�FF�J�n&& ù[�_ur-Kݔl+%�>��/aIf�� easyA �B<;di�9�It*�Fi&~:>(��::�(A oble� fah$ !�f:5$!�to.�:lM+e.6� vb�S��a*=2orr�:E��yi�aAx:�=r 5�as.��Ja~��,>A� hoi��O����� KPI�6&no*!`a�h Nach%qsusH a=KMYV >Sis�SK{J)W��,A�I�"JEqg�w��:�LTMH swim�f, t�%b�^,�h�cl�,�E�riNre us��Ma�5� 5M]yc�proba���Ire9�a+E��"�5:�"�{9G�])2�!wo.���!�Rk���' . An"q 2<�J #��X}{Bp�"m�xa��k=�qeALan&B>�C!\@DkXfslWL7=l�2"�>yN�>q`�ias� � e&�TgE"s ard:� �ay�J_&�miscl�0"k:�2�r"�:���.���iY8!qiaY.p:C".Qbe 4\Z�9� i�GSR�2�AE�" ���ai�x_�LKş] 7��y[�a>n�-�����I��i�"�!�"=Ҁ�"�j �:M��M�zd#1�=-�Z �9��#�043(i9MN�����hY$2�^!B����t�!o�q{�oc� . I� Y�\AX*�"Nu��N�iN�7GH�T�zA�e�+ sourT.� )%M�%�e)� � ��Y@I?toB�7AbEoi� h�"�;A��major*C?��!5*lac�kip�=ń�T �5*PK����s �Eope�B ��'a����| "�T�EPDU%U,��AZ�, &'EE�^V��#h:� foci�"`7!Dhu}C�H ec"�2 &R�.�$�V dens!N[5�0���>�]�a�er���c%*!s�z��aQ %u.�2�!M>{5�� !��Wq-! ���s"�c��arc�O |)0!B��U.� >� = � �>�.F���� %�m:�=in2R��in �Xe! Q�!=>��lwI0:)!�Jli���nm؎D <.�csM2A�%�r�e�3�3ns��� �!� ��environ= �\ e� )����J�]�E�".�f FK �!��P*Єb&� $*H$mKC2�r!����<1ɻd[��:��:� �%�%�t&p�5����$"�TH&&sg<6��"$1 Y!�"�,)�mhi~C�f�!�oB��, �rs6�ofAqa"�� �p��geF�$[ Q�e�.(|� ly{"��7 in gG*�!P�'*x U�JNth�©P]T�}96w%��Z����rol�gr�Ka�g�0!2&�+��r�up�!u;efficCOA�A*>�r&�:�$٧m��I*O>.{�In��Q"E} &�*������� �t�g CD8+ T�l!��!�FN/e.{�Le/j�,donov�.��Y�B"� ���maiK i�c&i � ���� IRF-�{  ��"SS�i6�o� �SalEalpco<key! p����xas IL-6%TNF�\ 婝�wCkof �&���%�R�!C�" gen-�-5�VvbL .N]i�f�^�w-/a�"�}K)Les2�expan"�@)� s HIF-1αA�dendri�W�zAAb6b)CD11c+ &�-4 to��i0fnenc8sr-li[ I�ell�� SLEC�K�rdZ���Ld!�12��f!�by spl*� DC�M&Dkm�P��a targe�deC�;j��"2J,ly�kerm�Br+{a�gF�A�<%m>i� &V ��pe�J�X&� adop�E�y�wXp"�+1$MY���s . Ma//n�!a/EbalA 2a�CA�6XQw�lj,a�q�e�)�xإ]g'k�KusNh}"�I[ E�!8�-r�:}�damagp�ti-.Wno��E[�����"ms�C-� �csA5T� �2o�|I�FsstZ� inhibi1���*#z:�9.!N"�qs6�I])�2AM�s.Ij[�2}H][U2� lymphocye�horiome�,itis virus [�,ډ�Mycobi��m[7�2 Visc�N lUx�Q( VL )��a g�f��ysr����].f�&/a|eth�*e� �6յݡiin�T um/chagas3=:A!�ozob �6#�A� as f�flC2d.maI�o� 5andfl�w$�l��u�Fa2��!��"mm� Ab�,.�p�Tigl,; s macrophg.�itvls�J �jK ��YW�+, neu��h2��ifib�aƒ[�SCu1�cha�PeK�byRvAС�UVnŠi��\O �*sta�[1E.��;�!�5�}�`�oጥzMfisrupq�l�d"ݣ�{invu�s� 4FF{� z�"�(B-!��iclEJpr�ov fs� �Sm�m�[6�o� is.vG��A8by �[�vf��ssg*ex�!�UgaS[17�f�&te�ng�fR1�t!\An 2rhavS�l�b$IL-10 mRNA� c+o�#%!p���p�"ir s�s���v����� a��G��6.�V &��z6�f �ɇ��rmh�&qr!�2��%�h92Y�9�\lt`1�Rj� SvI /�(�L@ TLR7E@ TLR9��RMyD88�<5�A�waZ�/�H��X�t�lT��I�3 erfe"��u�R��� � *� e6��� 2[Q�swu�7�lM�Jn� rf5-/-I�do6h%hallmark&%b�� n ��hep&�a�A�nom n� du"a,6�e4 infi"x�"$��se �!fA���EvaS�Th1Uas� ��hQ"��� �%��vm}1�r� VL�z��� xplo�%y7�!�65:�� %�Vyw�'� N7lo&� .u�r"w�.�V*�!S MNaHon%��O9memory~c!���>ip~�� oT$�sK!'��1P>� cy-s/�]"�m�=�A�m'_t�c� %�Z�"�:aW( +1��fa]�?3{%Fo��M*��2ɭmG �@e T-b�znd eomev� ( E )!�` q=30 , snE�"�ti&��[�|�cytol� !�v@ of CTLs�l� ��IFN ,γ ? IL-4Fapp�Y7�iA�!=�t6+*��p�I*B�[33~���� &sm��"P���E�oτt% .�byq+z"�O�ki���& Mcl(, Stelekati"�u��"�)�= a by!��t�a2� ��i��:^]U1f"A� iz)� ��K&� �rA9aMal��p5E.��PY �!Aj����r2IKAn-�~m!�/�4"�*g1��� �G�)�*�>PZe���"� j�6Q.p�9s:y�q�-�ACA� w` )� �tmi%Y�1 5V}�)vѱ9y� � "aA�Nrec�%8!�C� �in� . U�Aq6�� � �&����a�60.c.���Xto��=!��a�i�"�g|W{ bJ. �#�zF� )�"8s�_t��ini��n@pUiA�q)]N6^�"�-2� fail!?"�m�>granul,!�a��_=�B]�6 12�2i � F� en# H3�u^�\M�:Rn /w�>ni�]5V�JC� � -:c . T !�c�we�iE!� �`CD411-OT-I.|sto%�flox/ -CMV-Cre-e#!�2+� . M!sub�i��V� ovalbumin��gA2�.�R8 6�F�|%go� ��b�, day  �7U(u6 inoc�C;��+Mab�)�q^� dis�sN p"��� R��ed a gb��&lAa�z CW����&$ ��ofJl �OM��NOat d7.X�;:6��'�t d14+W��xtc/ͷ9R�� q� �V�\Despi�<��)�35%V]| down� 12\�M1C%FS1$��37M!vE^)�E�C=-KLRG1+�e�'1�D>V> f a smQ0erA=ag�$vq�� >� 2l���Y/ ��:  �Ac]M^:�A nš�VfJ Q Bebi*;.���K3!2i�o�}�u2Ego �%I*'�,) h:� bK1n nE�OM���?jSr6��GM��xF�ed�6s��>�A�a 6�%}A;& Qx&4 -�E�OBya�5y�zw�%8%!2�E�F[�&�s�2>gTNF2 e!�NK�65.�&�> B��Qq �|e��g.T oge�,�*� :� ob� .z�(AWha{u�:�e.U�6�/t�v�"� Ygpg��It&=�� ��u%�*rg�8xi�0duc��>9(q�AX]�(�� u}q�� dRj]�LU c`�}H�&a�\ �d&��[� uclec!V+iʫ� �(~�-+ed d� ["FL�uls0h$^o�m�igg`j�5�� �aF���#-9a��� 5 6!(�L�Najtheql,�A�A^2sal .�1/���d�normox6b>fAs�a�}� %+�iH,�3 LR�/��W4"{Fu����9"a&�� &� Bi.1cp [50– 2."v �L�q*| dA e�1-�!N��$sY�Ɏ2:"dAc*� !�2R6~ 6��:�:}g�eFb�����2� .aM��/6i�l��Ş!�w`Pb�- U B ��� �!1he6g61��wə:< !�f>fun� �i�]�� d hemizyg�Hif1a+�by��x"n �� �W�t�[��K � �ed�� j ay nd� �G�R���1 ����(6we.� *�2� A42� 2�"a&�B&� -�DjlN� ����.�t��X;<1j9'�Ld"& �!�R�66 pM*�sa0in�> �6 ��$�pa��e��=�2�I�*4$L2E�S2u�We�t� :J 6�!92a(CD44hiCD62L127�$x�2�r�1�F>�C��I���'�-$����.�.�f�2*B� . EnJd%A�re� &�t peak�3a?&B�[�A@�e���f- 7J��Wt�zs�H9�'�#T>�&p< cruc�� R�&� � 0 ):A�1��%I�o"�5�rK�wYdY �� ifFA�V�>� �J��Jeo�Ra 3A ,2g*\ ��" e `E��F� ��}���O"��Y��9!wh� Z^)v�&�!i1�2h �J�/���r� U� �>� &sb�>�h-w!��-� �|pur�d�"W�-suffiWɔ,�.)E�XJ6?6>��g33�n�#�l� 9�=aA!� Ex6[�. Sa��< "���-ZusdD11c-2� �C!G�"� �� �F�Awl 7C��])M�y. )iѽ=Jb�# marrow de=d%5�w�:%�� ���2  �xQ2�b�%Z!�� =e);�Rsl&�E�a�N�2 i8+ buryD"� ac� �A� ( S3��x"]1%i-��$aYlik��*d!"��FlIRF�1�uLl \A"�toE! i�A�[c��!��� �vھ�> "�OO�U� α.� ��d2�Vx".C ��9D*al& ��m��M da=Cr"O ݺ�"w*�F�hr:�7��� (u7JF��v.�mS4A%��~%�]�d.r:!M� BMDC�c "� —��>v �� d "�Sby�clNGj?��a���� 6ZaPa�8"�!�vA �A�G2�( S4B%&� f1�b��5�A�7e�"-\2 **w �![5�!5�S� K ?6yQf� aY��|3n3>o�9:�*nd"@l!�levEBPwaG!\��, nam�&��a(��lvm&��fseeg?5?��\Nm�%�s�ud���]���4 � ��� �%�YlAc��E�hi%T!?^2�OsN nyI�?��Ye��L �Rʼng�b m9C��v==FiIi!�����EnN-.� &| n� �.� � 1J� �*1e r B�\��!qib%�l�BO!sLpr��f�.M�Ny5�t:��Xd6m )�*�(�Sa?�|on�dRe�(�S,�=hsYލ0d��&6� ��irJ(�Hn��a +r.ee2�W p F�) M�� 4D�] eft panel�& . Unc�b &l!�HifGe�&`-�c?Z�ill; �6R� [=` �B*  �� � J_i�J����WA3���azuo?"��Z)d" �6l."N>�!�!P1�6ySI�oѸt`/im;@i���)�5A%�S5�PF� ��'pr����*7MPk6e�%���E��2� ��l&��'=2g]�I�Au2��5B��,�p refl���:QA6h��)�-+iYz���)ox�1:�s�)�*"R)mTor/-��?}$���;A�}2U Q2c6]2'�E�%�wo����*�'� ei�m���v��nJ�ZB�G:� �'*�l�$ c�(ц� �z�E�Iy�2:�"Q e�2�5' 5�No5�c�2&UQ%\b)[1F�A�h2jM!A vR,A�Q 9R�f�� Cre+ �>�B�,'� g3JTt�(&aHq/�5G�B>�F��j�q�� t�b��>���ol �m�HE�S5C�7l�f main��� $F -5R- IL-2� �L!� �s� �͢�JU�N fa�h @�2�0��a�0^�<&v 2_ &�.�12  i"h�^Ar�F�(�������*BED!�l"11!��-�E�N] ��*ng�8��!i&0/oIL�$>?�4E w &"� )�As�?A�jO24h�5(/�f�2�C�& �:�6�����7F�Q)&� �- �!(�)&Qwe&%  - D�)J�at"E2a%$YEA�"� �x=�aP!�p35)�6`.��6�1H��s5��S>"��6'��2 "" ����7�3�m6!B�V`aE;e%O.?#�6� hsB�<���n�FV!��RF8\ad5�eEZ&Kfew� s*F":.. !�jZtinuou�4IedEu�1�QT "�5Je�H�U"iN:*�ke��6��-�� e)��HV�jU%6j�E2u���-K nq��e �]���N=AO*"z��, Q.uF�2d�Ʌ���l~A�_"J -9. :�G"n*F'%k� �F�-��x&C!fu!s6+ *hi2�B8�߱C-Y[�<;�.:�ir?� *R �0�}�;ly� �,Bdz�%8 �:�R1Id5eX2� S6��Fib�w^��d�u�g� 5sDQ�"ny.�`p �"!���V�)�o2M2��I� 1w1�5�67"�u�.���M�^v�&V s aly��Z*�-RA�.���!�|V �-��E�&by� A��� J-$�Z>` !�h�;ic�-����� &� �Nu ��-2�2��^j%U�*5 �DrtA5!�&�(�2��:as��MQ�V��6��F/"S��:��edr�� L.! 2�-�)���>�7�=& �a}yc�C�lb����յ�1>�W �,;��ys!�"n*�F :o��gg grow��e�IB�B2-0>A��1� ����f �+�� :(�?e.�2� I�&l`bh"GH mune-ev�HH�iUish"�& ��n�5xPerCHn orga�Ea� eign�@ogG�U<i�6��9��r�is=�!6���=g:ty"t��E�@q� ?QtWP�e� � )�:#*Oz�*�� $H^�a��JCs�OEOA+HM�iųn2�KDdN>R a��5[u�)���K��>�}Y��cY%�D�i��SM>Eh�.*.E*�CMV28(1t�EIFNI��.#"Bſ[36jA%�:it�@ea�KRq��d"=6��A�oab)@�+�JnQ<.�of�.� X&"�t�E5at �� work� �84TAAe^�sEQ��0oda:�$��A lA<��a.� s��*mW"� yK4�2aD!�d ��oo0N�raF1t@I 4itsel�US Ae"ZU+8"1 �1���q�tol.{�[�@�ׅ�ƝZpro�!7�f2� �IL52�o6�99*S-=�t��>A6Le�=y.�atj�@' F�et"�E�� :��� �;E�:R)� _a64�3�8*�D�� d e�T���5�34�3���28=�8[2��22���59+9Bm+�Y�];>"lI�Ac@BeB�6}@!�f>6�H� fac�fV� 2�!�!!#BRI������.-R.y�Mn3�6�*2kJHM��twshekp#. M��/G/rj%�c ���i!�� abs�@�EU> 6sm-2�%"XdyPfLT�E}�om_Tu� ��k h�)=-l���u�a�dAuR�HXq�� 8H�N [60]y���e���M help@"� sl|hƳ9r� TB!s�)� T��/3�V�launc�G�o6� s 8a��N�Lt g{Y"e �Qhvm�.�B�Refe��m&� s ai�&^Ei�T�j�E"�wss�T�t�_ hyp4:dr��, adenos^a� ptor�1d@ 7�p# iV��w"�NE rgiciU-�<���ShysU�5r�2cd�U��w oxy"teT2� | �>W,6c��a�" ���!�� ;��1$e����o�o:��e,�'A�c..5of >F�e^� lso. V-�B�Y�[6�>6�:"�E�'I�1�xy�LL�4��R s [64–6v �6)8�icDPE�D25+CD4+9Xy OρJ�x0.z[68I�9 a�"DC)F��y-M&�M�/! �`�-*].+"�va�1�]ca��~ "�3[7 71];v%��a�MP��b D-L1� MDSC� acerb �E(Rv[7�r7�Tt=N<, HIF-�[1α can be upregulated by inflammatory cytokines such as TNF and IL-1β , by TLR agonists , lby several viruses [74 , 75]5(acteria [7568parasit/517 d8] . Leishmania promastigo/hare known to stabilize HIF-�\inducHmRNA in host cells t52j(Our results:`icate that L . donovani a:� also able�Zr BMDC; how!"0 , unlike for:�[51!��(upon direct�-�FFv4e factor ( s )A�ponsi!IA�~kY)bA Fi.�a�yet uni�$. We trieda),block IL-6R a��f, but t!!ade dideaf�5express� or CD8+ TE�an, s)gA�%i��&[� �Thus it١�surpriA&). micei*a targeA delep!p5O>�aAmor��scepte�to many�l�vi�xV01!0(In contrastaome.su��(oxoplasma g!i\��(:��GřōKir!2�a|�t [50–52!��� transcrip%�����_sh��enh%� repl�AVof �"w82–84 �ytumor!� roenvirona> ��Pin /-assocI�.`sup�|es�sre�L�70]%5�bs.X�>8rginase 1 [71];57� �s�inhibit� �~MDSC [7�Diverg�D saQL2� have b been2.06a>>.�D0DC differenti��� migr  in auZ.n[53a�5!�N theless ,��Rimpai��h*� -�CCR( a chemo� ���>hom�. of m���, ea� ary lymph� orga�g�Moreove� 5 cts a ne��ve I orgi<�{id:Y  d opEw[86!.p revea� det��%saR�� funbIndeed%Xe abs�^2Y% � 8 (creased CD8Q�ex�L�Ia hig�f� enc�/SLEu A6�ly correq 58a lower splenic&' burdee �!���al� ck outa��{6�A$"q loa� la,, remained un�sged ��s pos y du� 7Q�ce���� ular2� betwaZ g!+�en e�to@ type!�H� � i��a e onset-&r � twoQ�g�  very d�se immunA����lea{ hclear�O��he� chro!�{ # �[13A�>j OT-IAA� � st�detect� atNN,at d14 p . i$n Hifflox/,- Cd11c-cre+E;��� .+/-�q�Se]�:[�Y simi!�-�Iol grou�ŖY couldY'be � "! )� l re*� %Ua� of� 10a� iA�� ed�+/-�� ( rT �� prev5 ly�orT%��0&P љiJ�of6�[87!�H"�M�R ^,68 disp~ m�dramab���,!�!endywhich.G numbers 2�� R� wildibEa-Bl �W6�@a�s� ecess�!to!�Obale*�stronga&&)bE� &8 nd slow d�clo��..60typical"�s} wift%u2� Qjby��at�early of�;�ipr:,*�c� s af! 24h2; [1E W*oa sust�TA 2p35��IL12p4>�1{&��-�=�a�parallel)H��^A�k0h5.a L� �Va&3Ս; ��w �m�� h,r |in:�M I.Rq�E1!mayhlamOfV�2�E��=~H CD11c+M�Ax�efa�A�i d�,. I�in� e*�29Qs�sasl helpa+0 � dg physiologA��ofI�R� . Ita���� wao�?vi as well%du� ee sigab!D rminOe-:�� seli1# fi2P �D&m )�a�clu_we.�oV�b:���y participaA�in limi�V�by*� nguv-�A subsequen� a *:�S� al%}��P��F " 1}o2�,��ia�e�ůC�th2<.% data ad ��howH}�%] ��D�!S� Qof.� ������tilityU�t� temp%�M pecK pi�!Nr��Q�a�re�� a maj��� evasS & adopa�[6� to e� lishF�8 . C57BL/6-Tg (� 0) -RAG1tm1Mom�NA $B6-Ly5 . 1A�g� �knpurch Tfrom The Jackson Labor4. M�hemizyg�.� I �crm ng o�Hif1a� � } �����$cre-recombI�s%lCMV��mo�� �G*w1�mut�Cin6,j�-R������(`� Cre )oth=�~^��}�`%B�� Irf5��:�(^-) .�NxAw(a kind giftIyD[!s9Pvu� ]�ard cycl�BaS���. ���n t? ext��%rExg puri�MACZi$ sor`"U!yna� &_ pool�!ly�$in RIPA bur �- Ald� , G� ny�Eq�$amoun �� �( 15 μgAO�mf�ion&8by 10% SDS-PAGE;ono�e_QR BHifc*� Novus!y�� Little�� , CO�SA|Q� �oblot�(ay Blot� stripp- 3o� ��a poly��<%β-� + confirm e%1A� . [9L%DensiF� �Y3z pot�-yMHPAlphaImager 3400 imagb�\( $ Inn$h Corp>A�)I orma�+�ß ��  . Valu��>"fol�� * F�� AH]l� !>�*(�)�m"�i.!��j bead_Miltenyi!�tec )�F�7�*Ek&�b� 913$see�at 106eus/ml oB 24-�ps A+C�,c6�/E+PKH26-�6�*�,� ,��$done accorE,tv&j� )�a MOI�&5:12��AM���.F  , 48͚ 72 hU ,J �2% PFA�Hoechs��* ����ytosp�8on PBS/ 1% BSA-��sli�. M�je�%�ѩdQ; fluoresc�mi copeVo�lu�"""�-�R�8a0�) .��"!+5'i tre��i-�lyI0 . 2 mg!�M�8 �R(�e 2 . 43z st���ne/bUIv� . At1&�!,�sac�'c����#M%*�byN|. S�stiF*"� 6�m� StudentIt-tes�'epodE �� e_�me�)!�IlR)I"o ligh%X)R63 �A��6I�%@ rega��M�$z.A�s�Lsynthesi��Nmeta-�AA�r0Y <&��.9�strength�e�!�co�v!2 summq$ meas�,A_terI0nd hetee!of � -�s $i��* ulti�tN}��EH�$esFu%i�'� @ <%m��jaundV\' rombWope ,�orrhaEHIV co� , diarrhea�#<($ >4�50 ye�0,F6e neutr_dyspnoea��/� �$!� Edem !�,globi�!ea� ��a:iR�)1}~.,�v!{*'valid npr"�� )few��mod5Y�so fa�^)V-�Jhe��6��(�"{2��ɢ�,9l��11fenA��#1�c �of?sis��.�EKbl�5x!)b�ffu!�q gnizA�A�handl VLAβf)w-�?A�xa'-ced.�-K must� priok2a���i6,. VrWa���J  � (public heal�robleme7mic�_io�eM�eWe�-�subktin � North%<E!�Af�� in South "�)VLY#� M)m�8neg�$ed di�""8world [m8 clos�>pA=tA8A�w�)�w�!�affordA�/��apl-$ scarce [2�8[3, Brazil ,�n�aGori!1�#���al�fr�to ru�a�.!A�n!9} -c� r�T6si�q) 1980:$e1�4spr- large cit�-�], s!�i!�W er-w�Jre)�:�[�2Du��� firs5c�6 -21�:ntu��#�000 ca��of!&u�3VL-U/8� .9 p1 with no� ��6g"� B�,:� [�;[�0I� | ��i�mis� �to hum��!yrough0b5 @of female phlebot�1e sandfl!�-"4genus LutzomyiaI�hoG9�"�A�m;*�$infantum [�*�a %Ci�l�+cub� � o�,3�8 month�mS�if�9�9t �K s%�symptom�a��clude ir|*r�remit�sf�@%), t�;n(3 weak los)� ppet!JAwe , tS %�';c�;dS inl&o"� "� im!�phaE7ic � "%6ene#��C3 no, B1[�5e 2b VL�Oes��A�!bC"eBe dividu�E'n%$ex$5 )mM-1�[9�x1�,2yJu; mort~ �e� "J F A�an� �x[�or co- �!Q[11T"� opsA��>#��\ �9val��mont ompoundI=U �O� mph�&icM [16 AlthE1:-$s� �ti&Al /vV than V�Q�&� "� employ%�:� is b<(ou ak sMb c& �A�!��)�8@!�i��B13]!mbe�7$A0a�5�. >�unxivem@drug t�9��?�Ra�jad�#�:)ߥ�� a�4f ~8� !�)��beV.e�<or>".�Ɂ rapy�li\ n� dec1�.iaK isI ,��� Q �ad t��agi��#"#}eat> an2 2��2qt@�-^�iXFg *x f�>F�VLY8h� a v)�>� a&�U�. PF�al)!oas�{H��a�ic�-cou%ag�,&�."1�& 7�iɔ they=�e,to ��'n�abs%s�;1is es&� <� �.,!1y,�."�.��( �M����Ou�xA�apIY,a6LIx> new �a� ttAna�ai) 9��to�of5I!�1��facw)�g!7!�nse5 of&5 &��#� � � [15]–�2IA��5sV-!� A�c�,�HQ��D�� iI� �&w-if9L�<66&L'in� ��A�un�'�-n  � S %S nd wW� de�a e a�%h M�*i2�� ��E)�a l�(lQܑF[1�Ga8� E�1��7t�Z�>%?�5 eutic��g 1�] o/ !)/Q~field!$1ul�4�� )�oncs %��*�.�=p� s<'[20:2��I*� a*�)�B"c�a� purp�6f�c3A}� ,��!l&Y/1f>� poor6�VL</orR�.*�7�bes,our2:! B��c��5,���~st�lofR*�ȅ"of�=��nd%��E��"�� �. C*?x rele�c���a:�ٶi�ducknn8-VL-��Ag�dnW=aOrel�C.�MP(�7��&�2.�<,�e�E�2paJnt� .8E]6�s}.��v" ~S�<^6Y�� F� of���a�3� !>"9 u.� ]W�!{�͛MF�w%~e]"36im����m b�,cv� �'6�. 9?�H*EG��o^b�=M��nd Septe�: 2011� �=�6e authA�( VSB�DSB ) \!"�4 bank�$keywords laa Fig|/�-eal���h � � � ngr er.k�C����&D'r�usEk�~m a�a��� titlnd ab+ 'AB ll�:�$ t1Usu� ��a=�e���3!'6����'d�U�l =�t�at�*(1�%&s;�& ( v2j� &R � ��?oate�fe�Gwto� ��� yyR�}i(-o%�5,}��yhbyN��r)�ver�co-1| . At�;.KBn�F2�of"�Mls w[.0.�5Gic". NU�b n U�&R�E6 . F6��M12�����a=�es!�)v��K*s�*e4!w&in�a *(&A3" , namely:��!��!^'��"� ݯ�Nf� ��s8..,abbZr�SA�4�F ���s�.���o%H"%� �.�c�<r�0eac�#"� � &� *� *$ A1,ce�� lausN�e. &�j!\8".!@ (cut-off poi�#ndA/hod�O�(iM�A >HRL)�d=a��6kA���P-� es*� Sto�+� yS� C �1raڥ���r��!�y squ(->�,error [2�I� �K-�,q*�! !T!:e Eۙ:e�:4a}9A8A7 Vgor�2.�pr����\�h X!�-��I�! adjue���gH�&���E`py �A-6�odd�Pio ( OR,-&:��eEuQc"#!�:,A�<.�%V%4Ai�-e;��ir�GJ�UTa .�:aM�.�.�1-?e�E�!!�A~aK� theor��al�cu�s�9b�a!}� 6,"0<W sm 9��"�Uor :3non-uni�_ne�R&]�%L$edFe�� am�!">�. Mnu�e��andomM�s��x�:YF�!�t�fii�e^-=i]9uX5 q6� 6%(:%&� �1rY5$�I2 ed�D, be�!�a �1E"�� xTs]�(as6�)2Abperin �m�(�Qer-�yW) *�)%<1���3raJ3i�B� �mhaE<��2�!�:J cipa�E ( ad�$�Nchildren��nd*��U�\kly�S�e��L5 ir��*���A�.U�,� wise^ )�Z�A��wit��"Nie; ta-P&�0?U��+6636�E`le CMAD�*�f-�,7Xu�T�=|Z"�'�L�&b(Nv!�*wE��%aYL"���0���� 20��"Ec�$de�K�CoYof�  for+LyQ &0 R�) � pkr� %�(` !Y:�!B<uh��� �- � ip.�atV�T��W� eP!�� �!9�5+U�y ?�a�l��t��V�.�("� &- :9 � re�no�A�� ac���v�  "��� &� 2�r&����m奬� ���6��i ngS B"*�YE�I�.T8he�v,x)M+��!���^f'2�| , [1�`[23�7Ad&�princip0 &�:�(�]. &�l��STROBE!�t���ai%i�wK'a�&e: &$� F_%]*T��&�r� ����s4 sour1?[2+&B*�C.?,�&e�17a��"i�9���q� �V! )P���a�cla��>J!�\�BM�u�5qb(�2K  O� 2945"Q�ebscree �ar�s*�v�"rve!bʼnA3&Z{`$Ae8El27Ee38]L!"�3d��c���3�&:$.{4� �)�4m&�inŒ>}1< 0R'�)a>� #. Ten6Dm*: �a�߱�D� �Nm3��NJ�� "�R�d�x5Fo�/�2�*E��� e7iI6sᓉD� �re,}211/14k  viewv%T��Yh�6�&z r( 2 FQ�)\_,.�0O=c? , No�%FSmhS88ção de Agravoa5 ; SINAN; �as!w� T[ S�Ea&A"-�Yy��2�"U��)IU���"tudy pop"'��#^ �? � !� [36]&�i+Vp�)W q*yوMCd. O�%� �V a�a�29] fai�<�7!'�(^�8�t!u���"�#"P(�ӡ�alw<<b�fEc mmen�0�VYMin�&LSH�.B(�"o!N� �3ed2�6j)��of*�13q.[33%(!�, [37^�>9�26K4D6RM8�*&b 1�re"�$�]T!���.�� �!���p��A.�/e� C#,eT#)v-2��"998%�I�U$= 5]�sixU�%)��25cg�&s �eE��_�Q �^c*@heUa�aUy [!�iB�L�(2 !�w��P��9���C U p�^aKg"�$?4)lBea�75 �2s�Ql��IIMq��#2��1"v#�x�Ae� @n�;��oZ> �!�n��=T1=wh�&6colline ^!�!2M�:�OE�I�3� A�. N���AY��add�(� "B��l�5 1� F4�'݌��e C �!y"� ��� _C.�R'VL!�%� ed!] tU� t%�"�A e�GA�*( TCS1�2�9!n�N'2�"�8i���N�*.w!a81;� ( GZ_�NaII2C)i *8 ; ,�z8"z8�>Z8age�8y~8B�8~~8-��AL��C��/1io bov1�+c >�9*�U>���3.�0�V� �cF�[V �By!�.M.�c���XApMׅ=�^6c:W�[age�K�v+FD�� �eh����vA�F�2��#�#�n5 )/�" expl�,� V9 . A� � hepaQEgalA�splenom !h�3�� ch �%���3.@�� qe�29��[*�5B`��A[�T&�p�)8V�V�y�II–VA� ">� X  CEJ�fJh ���Bno" ;z�a�� ��i���g�9�!�a]�!�9�YZqN�O��#2#+� )2F `=r��pR2%�.���ysam% �by�:�a_�V�0z2�sub�� �%ak��)\� A �\�ois � B�Costa� o�q7�6L, kidney zn��B�G� alka� p!uhat�/�.)J+��.�7��q�" 1]2bn%�\Ju�t�in�eds.r&i� �..cj Mada�o� 2uoan���l��Q���T&�m�o gramAjuberculoE, dehydS ,Tdiovas%6o�I9sth�?diabe�<�Nn�Om�� myocAAo�^��)��i"jYInf  KE et a�I 2�E�ru!ct[)eQ�Nh�F/100 mL�$edE=*E:Alv�5ga�# .ev�omorbi�e��@& 8. 9M� '��.;t���F(! blem.AbL�j���u,"��f7)n5(Araujo [� � "PwM t>��z%7AX2CUF$c��C�8c�r [N>�*8(h�)U�#VL�in 201He�&+ �  a%�e#D0an eosinophil��n=M 5 &"�,EL��t�mi�! |1�%ou"�; db.'MCɰNMhC���P!-eryoY sed�se�>%f� ��lOk )�BA ,�ga��g Souz�S86�AA �2�t��=.%,�bjE!e^�&��|m!� <)c�?'�L�e�s�32]"%�u�KA�{ paramE .  � F�-2B �9��E!6aFfH�7wF�8c �iE�? 1u&� ��.�f_.� ��u& %�ou 9�1AJ;F&7"�" 9�oto 1�� ma":�)"Jnd��7"�(p�z&DC.�55. 8��2��!E empi�Bl& <%<cB����7�>Vm�v�6""�F!PAv6 "��fZ:EJ� � V 8�~1�2D4h� ic!=air��in5C!�@! �1���!&bl�^ clotqdis%�2z<� �.aA�mon�&f[��y?dysr&.�a��6�Gw=p% e.�>ExD bXOp�(i� �a�%n"� [39?6�5atj_>)�"]L%��%-� # .�%��4nA5A*�{ �= q/[4�VL-;e<ݤ�5�[F}��<��"[sh�9��6~?-A� d pharmac�8�@.%|w -3;%(y icab�g�ach��&�P1� a� *�A(u�_)s"H�y^� . He"�IaS��b�nA�>;}Y� &� 5"���as ay�\# � d)ͥR�abu9 a� P�1hbl$1�/E4� ���r<&�=%�i�s crucp=&��*� e�<. A.�,� m�*BiU#�hki�ZQ (kd��&?p�s��FU �[e�Q�.XAa�JFe�� -f�!+�"�{or5e�e vel�v!:ic�H�l!le���6Xi\K"I ��,x~�  xemi�K, �L5E�&T5�"�B���b� tak���!c\-&�#Uqg,�{has_#���=p+QjI5�hM--w�)�:t���p�fat%2��#hip"�J&=0�K Tk G Ma���,0&�}��4]siL,&�&�|.�M�|cerK0ty j.i&=AA�A~ #�.>�55�.cbOve���Vl�6i*�w�rM����.a�nt [4�wisEoa����$�QajZdisrup!{Z home�6-��itY,-�Y):Ei���Z�uMu}�e<b�wsse��trJN[4�.F�e�i *!�(E�-@VaA�a-(s!�&&u ��%&�A>@pgemphaR5-"mB"�te�No�ele�*:7*mu)ɡ�"���!Kc plan7%� e� arya phyl� cP ateg6���A���qu9�lipos|:= �:a�.��b-Z=�m�Mƅmp&i �\��� R7Vis&Bb��t&~8 V3O a�:`� . Ev\+o�F� � �Odm%��eە�!�6�i�% � l d$oq�.�Q�8"Red�.� o K�-.�O!�isI���;av��@g gA#2�n?Q%�A.�"`a |"��R�,! E�i!�l�n&jHg���impac:a.�(�I� ɔ. U�) tuna�"�,�Pe�8+"^~E��&as�[!���)�< JJalxTar�op`u�'>I"�L�0t�[Sjl Q>� *�A&d6vo� 0xYhibm3 [4�#��� W^LVL.+PYw!�e�d�R�>�T.�%7_M,��s6�R8Uv � �al�9~bio�JA��g@�&�L�p"��m Nx ugh�M CKNE�k�V&��"[I �a��C!�mo�#.�I��\$to Werneck&��6Qmelenyzy��@r� �pr��o=ia�[jJ�ic�aroo+� isms<ZsepP >"ab�egW. D�[%lsow���M! C~di�= � %}ᝁ�Y�F(Ua�,�,Z �Ma rout�$XZ ��"x� *7x��twoY=j�.Y#0tra* forw�< ���>$w*ame i�6q[�)e&�Cgh7 � JS%uQ{2r �&=~� ��g0V h-�.ac}Z�72sa�aq]�ag>*TF�)�'�t*9��7��ar-!�"�8of�� an�3�%(.�[�l�t(-(''9�"�%4C]JBol_FC"�^)�%!��lya�GM�Rz���Fbu�� �th�4w�Ipea"J�;�� � ����=�u�"�<-�Los���0l�@6\2X4:[���A�ti[ � e!"reI��-�%III2��n/&�'t6�*�;!{nd:(e~�=� )!Rd�"�)i 9IJ��h of eMcemd�daa A� _&� ��*�.�i6.J�� �,I/�3:4i�"�"�U�.�v�|� � ��w"3*�| .�� attr���S [*|Jh"�"�>y[Vh IՔ  (&� ����d�8be�07 g/dL��6relUn_�E� pack ed�a�a�'&��Z|=��segy�:�d�/�L!��!{dO39an��� .v1��,=A�6�:�!0sG8Q�z<aŗr�l�`6+U��M . R"E/nuthd�3=evG{u�A��:� s�BB!(wa+ VdrA�in!2�� ��� �"��a�!+�>>�";Q( adap@�!o��h��ly,Th1Ur�U nourI$�QG ��o-N :W!�& �jS!��R�@&@�B!>TmmP��A�lan�eaa�se ( ALT�  sY�P>#S#�B�����7E=e�l ,nU(͚�AN`�WE.&��o.b�U���B-)oa��T} c*�H��Q��I!A�:�F�eAW�:�. A� we2�E��^�i��w/��W"9 w� o_mxm5�J�g����p \=D�")5�&� �mm�BA(, serum.\*��Fp �n�HqS dengue,dp �VY"�e3 i�aU#����� helminthioi�5�e!7Q��)��o*��/nP:�����5� b |"��8a��/,�aic� mnl cin urb5 nd2h*5=\5CM�1$$!�P n&�U�ޙͅ�;'!&i��!� ,Dif!`e99��fŐe�&� s�-2$!5 h�c[5�[5yh� %�topH�&$.y_u. O��%�Oi� "��expHRve�D _��DY.�,"� 6�, biliru+lW"HR0+�HY":mb|��q�,o�r�lZy�&�� S M�u��N"�[�BA6.*�8%�o� �m�����!9ٝ�9��*hGn(a#JM#-ma9R(*�W� �4"%!""l%��!�A-��do�O2���X3e���\ � �a�score*�em� ��"3-����!��%�89.�M�YL�*>_�A��< �� #nf�|;&{�W� 7M�"�z���!U]d.al bio<�F| Pencin*m059#)As�m�]��r 13�Z-�6�� �F-(��:�*"ob�#�J"a6RA no^N�����-}�i� �2�e-�M,`} o�_�=tQ2 19�:G 8.�dXe��2�;wA � �$hdŦ 0fi�+ &�Y�Q A��  �orSLr*M/J&��A�&bA!��U���)p[-icJI�(AN8>5HS .b($Steyerberg&�6�*a.�%W�-E us�qf ! �I�a�m=G�1 � �1!���a m�^Q��G=v7 �TQcohort��"M�.� �ItA�k�Ѝ�ɃJlzo%��!�Gra}��k ��\]g?u�.%wQoot�p�V�ragp�J%8�*�H�� ,nζ#de�>b&Ll�I��%}�-k�x),-E�e2�*u"æ19detail .�S5%*�@�m^q�"J mI��*�|!ՅisucRa"I p �79g"� i�cam�.���o�-9�+ stepdAW"ͺNJ/2�$ �,m�a�i.'ld0 �e�>`-A�ti 0T�ex]alEL$cX���&%��/!:"�Q���=�g9�&al �;pr6A% n�!bVdc?1vHqg�ly �l,(:�,���ZR� [6i)r�)l_ng�Q3�d@%R��'0et� c�b�K��8m-�*�CM�!yE��0 m,�(e+NZe pitf c�*E'1���circum&- $!GsU6���J.��'.{*�ude�$eF$HimpV�q% <:�[626J�S��=�& "L2 �0�Bv�,#� !�- when�!�<v-��B�zi�xT�a"��)C";�� av�>m�-� ��;#�8% "�EQ�a;!#�k��E* �m�"�by em�c�"�� unY�voa"�E�te:��[6�G�#�Q�!�a�inu6TF2��&�Ccale [6� 68���`:�*K]1@�aqm�3a o� �.��1��[6���*!�.)�K Qan�!]�): �(�G} �Gcz I)i!�.i !�VQQ�%�8JV��ds�9)no�=e/G�-cob4&�F6� 3 o.Fx� �/IKQk!71.,zA/��; E%��#�X )�m��7r%�ņ� eb�A�p4@[�(� � �7�:x�Y:#��co��_- �t � L%d b�R�Hd�o]��L  A�.��I *5O%�6� �2nd� �ory��.b6lp�|�1)"� p6gE6鸅�5.a 8:,�=T%�q,o�3!�!�!�� (�{6B� H �ref�{&���, R�NdB�h>� d��nc� i0#���:$="]i�.aVM�*�g*!5�sH �hw.� �Z ��%�{A4>�) *�,vin) Q �E�{��N6�W�c �ess-�} [m�p!�8�v@�r2�f. bi%6M� Y� d]����*MNi�aI��u5]ao�4)N%g&s= ^x:�vZ^��{1�ay}modN8! trueV,�o �c&UgBoF^f�Y!"8k� \�X�6� %�j� o&�`% !xK��// �[0� , [7~A"�G)a��48y�=W�EX.5�� %- >q_u> retro��%�sMve >� )6�g�g�d2��K�2tew�"A�i�`�,h. [74]"N) ��a� atI�C#a3���e"Ed�~sڅ�P�@%�*a�an���is&�m!@�!e-�> A��s*. 0o��dm4P.�der �� them=+Vf�ca�q 1o�X��[ ��!�� �o *� n='ag� &�?,*� .�m�.��.��9zr�z*�i��o�*.TL# nteg%F&���Q)BQ)A�n2��TM"}�2 �FoU��+��%�"�q�n� ����~�JA���a���!�"�at�-�6�z9 u(�E�#W�i��=���m���b��*#.&XAU�["�Gf@k�)#4*KrM_w� icis  flawo mܺ.�Z5 %|�3&�) O"N;o A�SV�:�2]6�3o{�"e�� ig�"t >�/aw=&�/%dA�nd et�{sbZ)��%�)� ]s �?��� (. �In Algъ� &�-si���cutane "to�$��!C��5If�{E@oW�t'@y-"�k�~� �su�f�f��!N" WI�BcKiF�%M�%��>U]#A)t� �(j&�="�A 5�e]�g"Hd��h/O/-�hD%b_[C�R���|�'�c���%IuouE,&m�1�. D:� ���">0* ,�/st.b7�!�gs�5�i��) ��{A��av�&4�ol�!RW&tdf�Fw٥�p��v,~X2�_� A8!Emaxd1r-�|3�,,6wXd.��3�t_A"2�eQa1)#t��%��W�� gof 106T���88& � 1976� 2013.j�hI�, dog�}ro� �p*>��18cB9 in F���l%$-�n�� �in�\lL�0ecu�>!�nd���e 50% *ȹ2�&1L IC50�)pot�umQ�y�^|' (�tri !�!cM� 4Sb&� II ), *dM stibogluc� J.�^LVJ%U�:���{tra& � A�t��,a�i�k)]��cut�n( ECOFFE����"1w"uؒQ0*;f - Ai�w���=�A�h�sQ�l!%S+!�sk:-�*j�1=5 �! u��%� ���23 . 83��/m�15 . 91�V C�Hi1[Wd<6 a��ny7*�U/�i�� iڜs.: 30-yper�f$�zr��, _��l���S- pheno =d1�CL%-yd6��.y���_�r2�6k��s� ���q! �( .�n�"yn:�p�ica )�E$�e!�>�e�a'� �e,�V.S��d��ܰ� ,,� �Ijs� o�to��dynami`}j��.A#4 %"b[�F� >N-ub�-E !�Iu�phyloge,w�ges: Eu��EiP�����ar})ifty-7na��A�7(e�8� "nd,onypRA�� x�a/weFPE�!V�Hic!���[��3]hwV� . ir( f^5�s� U JerH�Dint; i���sub.mMed��ran_ basi� h a1pa�>mu-t�59*un�� Y terr�9� T>�6350�� peo��G���� FR12>���waD&�& anp n�Dm1nV�Ui%� Nͻ�.&�4:t> ��. A� (Q) .g ��o��߃l>JL �$a#�-A�e�s%&' a�l�� ="�&DK=% ����!X�@o�J� A ��|Q ty�*�of��>? v 1910� , !�Sba-�;� �:�*t�B tozo�+ rugse�In 1997ʹ%# a9*r+FH lin�1to.0X�/i�ڝ"d M���rn Biha�Dv�m�ndia [8���,���F2 EŁ.�!}$�k�>� r#TraȂVB/ �Afgha�>aa�!�!p2�&� 5�}[�<.%��� f ] �V��S;ub-hut� � .-!�G~�N��6"A�m�O �jm�X�rvoir%DP� ��" cios�r�l(icusp�5c;��ť�ea�Kn�5�#s�ec+ui"�811 5�:e>agˉ�2%��� , �!�(�& �^ ��!&�f4 ausa��y�9�!��:�*A[21��Ca� zN16� . ���1?e3;�6�%varid zo���A��rn�hQ�[2�8Z�m�lPk9�w��>�ld*�s �Psammom�XbeA!sMV �shawi [2�n4oI�+oJDIA�2Oap�\6̔Ib/ey�I�fy2WY��U i$&6�!Es{ dic%�!3C6!)A�.� .� filewia���>;!�e>[2���h^ *9�anz brea���v��5��by2Ts�8nti�� � 2005A�! � �} of Gharda�S2��3=KC^. CA4��n�Can�a8�yB|a zoon�B q.h �s�E{)?n=!�"")M�Jvl4� sub.�2 lf-lX� "�1 �BSg)�q3six zy� ��t�� O ��!F0,tI��s6,9nk/ he MON-1u [3B�3R%2�.�yb H�E�&��j�. T>� P2��&�{vɓof>�|�2EA��kl��eI,s��l8�&N - ��Z"��rp%�wY5�Q��"�"(E�S�, �  �2� �pc�^,.��.M�33�I�-�)�%�'��c =6�/� �4���%ia�� es [�U3�!R%Js�!� )'s mak�&�-�y.�a�K) �ch��I���q ,��� m�2m :G� /�1s-Kha�u�/&�u%�i*�)��:N�R�pa��h��"2 vail-�a6� �w�%!x6��:�!R=�" �<)I�v2�,V*;���X8nM4."�0��q,ire�+R�2v6� 12*� f����1�. Wt�]�H"K9�:6�5  �/hK)�1.�2�E� �)��}m�"�6U M��>(6�)W���� :(k I�2dG��sy>h e�͂&ŷeh ( Homo s�n��J� a� s fa��yZE:y �p� �;&}�(2#p*� AQR� )e6Zm. Sam�y����P�?Ly!�a&Z� e Pasteur"��eW Algi�!3�1NnowD&� docu�� ol�"O}��UK��A�a�y�0 � j[29 , 3� �V�DreP#("� mc8ph�8nd8/�"��Y��7r@*Q�&B , geDal � e�\ e , etc .A�Y[�` foci-u��e^&i!*k&>�5>�a�9lE�6�"� -k��:g��p1A & 1Bke�ec��"� �,haiz�/�seA� }" T3Tha:"cl���+��B/warEhdry�%A\!�c�Ht w�aj�an�P�fI a}f6400!?10�gm�N��,�R��DO!oX2-:200-km-� �#E���� !��� E��&� (�=U–� ��9,Sahara Deser���9E(Z� >130 Andy�at 4Pda�>�er�e"�m%.wHoggar �if ( 7%>�) �� �(:a&ces��-al�J��aY9�"� �a�t� 1of 29!�d8!t$�,Uo�g;�toϱd0��N�2� 6:&3 ��8m�sB�A5i7�P|�xI��(( INSP ) gac ����r\�����$Q��"yA��6�E�Ae482��<6�OnM��6 offii`v 3�)�s�oa�9z3>hs&~ illa �"����a>�P 1984!�`Ey�R� ڔ�on�ng@�T_�a+�Wr��0B�er�8f(��t�.j(��l:� f#��,or�.cUu&���jP6�$��cia�<re?���?%>IVL%�A��� "�A'"?p"H �;�9d1\�n&&-8h$staff1��/�5�Eʡ�!�6�(v! T���txi cryo� r{miqum�k�u(�,� tha�|"Z s9Lt�nO�K24.P-�n� �#2�!��Ɇv` in��'a.!in"J �� $ Nov�:200]"J�200��O��sez��-+�.�C�C�� aspiY-��>�)�I� a skEEiopsyV�bF)� ino&O���V��a�n��} "% , FrenchR[��|�G!�V�QZNn al RUZC�x5)" o� Montpell��,�,&xTo4�!�dalA�v � cho���B8*��wo�7{ ]�*O#� , Béz� c.��� v5��x/p!VE!U�& �U ��|"�xXP�S�� �N�:#�y�$!� MtIro�fOjd isoe��:���w'A r4���PCR-RFLP!���L<d elseL[43�a�:�� 5�a"@t���"��� v���*� �,���I �#! . A. > &I�v1c 8z� gG�18!�F�%(�zW S1e�a�"�H� 37 b>��*�]gqNT21V<!�">B�"s: rNU�����As`v & s3!Z24 *�@, 3 &��  '. I�# i'd -`%�:�dQ_!�cl�z*t&*�!2/ i� DITMAP263-R/Sb3-120��[�seS�x� erpar׻ 6|e��?o�Ls ,`Sy��� graphs b!-!�.w � �.����a�ica�����P��f��(�>:_ !@�$of�6�|�nmM�%���[&5�a�&�8�M��ch gelBP2�Rioux (ػ-�f"��15 zTs: maT%Ev�"MMDH�EC�/�337;2Bj��( ME �:)40;aci\ F_ICDR62; 6- xo&�(�K�PGV>4; 5se-F��>?G6PV@9@t��F�GLU264��3; NADH^Z phor)?DI�,16 �� . 2;�2�nucleo�8 �ryl�1 ( NPf?�k1�?"�NP2 )|5=�-oxaloac-eo�|( GOTU�d E��A�� -�t�IOPGM1��(v � fumaX �x /FU_*]2A^n M!�i�6-XMP+�f^)88N�-�-R><GV<9a� ���7��(ntiP6n��)5cri��space��ITS�PribD&l *ms�6.M�i� LITS7�l5′-CTGGATCATTTTCCGATG-3′�+V ( +DACACTCAGGTCTGTAAAC+�6E [*$A 10-μL a o� �c3 �C��� ��� ��_ 6��Hae�,< ,2 h at 37°C�   frag�L�i2 e�*( 1 2%�rf ��h  hD1x Tris�'�� �Ima"�-����5! t 26!�h�DM-79rumkg!Lnxup�Fs4� ;�fe%�c��KQ ( FCA� , 50�,porƮ%��#%hgl�D��,� IU�,S�ci��� ndμs- strey��6�R�:�YwtA-�Ad6pR�A�j�-,.�,E�*( by6�� 1�)�[M�� � to 962��a��pI!|00!H�2-�%}By..�"��Rd%at�ea<{n! A�����-�)��c�}W�  !38 �-�7��8)�K?e�3"�{I�� , 5 �q� �S eI�-!�t�115% L8PBSz�H ����Epikiodaj2�aN�J"d/�A�-�� �}2��yA�ACS+> bur;N�΁�52�\Il�ce�av.�K�a����-sc��&� %i�x�a8�Bh )6� ( FL�FLQ ��9c�dr[A6x1��=%n"#�v�U� O de� �} �"z!c�.�>&L��p5y!0�Qfu�M=m�+�)�c�+2x(5�&-�Ea ^�3M�3�1%�e�Gq Pad&sm�0&ܙ�ap Sg�, La J������)azN moidH*� �ey�a�GE� pe ))@ �Nܵ��� 1�E��?-22c 2-h�_�5by�4(�2o!@�0� e��!i�m��� V&ѣe*����in du~ZW; Intr&P4�յZ��e#%� Gluc��:*�gr�XhL6Ze�vmog�E; �,( THP-�Z)%��VJ��1� �� [4�Q.PEԍ�` RPMI 1640�uVk�X,�<N; ��� log �nT-4�2�5�"Fc� by�<�for 2��#e ��:2���� bol-myr�,�`r . M_� "2e���o - ��i�. s��P�":*�6�oA>���: ,0� j5% CO�������noI"� i9��s! wash��,1�s �ii�%K�A=s�/]��5)J"8 A�n atmosp�0"��6� 1U8��Y� rene�a�&�� ��.{o,( Kr9���¡\aano�F� W G ��v-(ic index PIN!�0"��a�'llows:#( % ) =��e��agE�U9� s ×�Y&&�� ~es/1!P" �) /�jbj��l×� %n�lRt.R��:��%�.�Mi�oft Exce)��A��pPr��5.� , In��b%O�8�i��&m!e8 SI��{&�&�"aZ )� E�CL�VL�# age-"��1�+03�(: p"w�%9G/A.��#o�L�U�+sV a�j"`ave�C6��jX�e�,�#<���7��d2)w�0 eac��"�)�"@)���m�(�"Stechniqu�HͶisha\�(!<&!H�4E 4plotted on a m�ap with an Open Source Geographic Information System QGIS 2 . 14 . We used the website http://download . geofabrik . de/africa/algeria-latest-free . shp . zip to download the administrative regions of Algeria and we obtained the georeferenced data on the cities of Algeria from ht � ateandtim��info . For leishmania antimony susceptibility comparison , p�Re-factor ANOVA was performed to determine a significant difference between groups w!�d s in>�4to Sb ( III ) !V ) b MA)9n iso%�$ according? clinical �s , L�speciezymodemsc spatial gYEdistribuAFs .-analysis% �followed by Kruskal-Wallis ( KW ) testsbDDunn’s post-test�( multiple c5}mD6#AH:�j'among VLxCL9&dur%#,wo 10-years-E*,periods were �zed us.xhe Mann-Whitney non-parametric � . Correla!. of��AV estimatedi�sSpearman`

�of 15E�nyA�� !�弹�E�rea��KlE� unch�f� i�!r (�4��8) , but it reacA�341��z%w 76 .�@1@�5��4�ԅ�N�u��o�3�}(iod demonst!�E!� de�RA̩&T VL-|in 0a!miaygqq��CopposG trend� CFF *�q�::J of:Bba*Rj�Ainv(g�E��panelZ73v88&= �,� r*H ve,diYtg !A*� ��� n��c h� impact%�12)F�U.<!Dms:�ref�$/FE0intracellularR7�("8l.�, P;00a�r =�486���  lights�predi���1?*�F�.�s�K3�:1statu��f�� 4��W�xen.h!9$IC50 ECOFF ��u�(. - )� ! vah9VFDEN>�(a method ba� �*L.GM"output1Ee��A�visualia� as a� grama�which�.�8d�� t �J1/�� � �>�2B!J:Fdescribds�( 5�some L .p(antum varia! , majo a�(4killicki ( syn tropica )�VL2b5in ]5� ompu�=�-�against:�!b> 91 μg/mL,�q�� 5 ble�VLA,23� 3�BCBM�9��a ��tI�duced v� ��jec� �@I� B-�M�� axisM�regresTl� �i\U�is�ach\ m�k f 501 ( blue da� ^�3#�6"M� �a}�J�>�Ci� VL ,!v . I>4VLaPh�0X s&�ly-er>�6�t�">`CA�k 5)Q�"�F i� oir��or"�) ve���ly��*�le�trival� "�)�5A , seeP!6RD     . Tukey'sN� ��alem �9B>��:�/=!q�( pI_ ٷa���M gor�,A+5Yasfle��+ ,�be.� )Xin� 5-5 abov�m:5B2previ(�!e3m��FD>�5]�x$ly 52%� 3/25m[48 0/21��5:k�� suffe� VLi�+. 6����:s]`5B*5C%��!w2�� ins>�E�, �tad10� 2/32"P �(S- phenotyp���)l,%=pro� "� 26%�d1!�b�AM�5OJ�, o10��43e$G��( 30%�S-U regarM��exhibit� anI�Y�Z]I��shile 50%��14/28z�!� terz ngk(  sWdIGa th!ud����a�� hK)p6A��L�w, L��)I� S+ .a�"�%�� 1of Q 19±e��.y��dgen�6�lyE.�("2 aU6E�O2of6�()��49 . 33±2 . 47�-��a* � ,of 37 . 25±;�=�P��)K5DeiA simi# � N5?i�4tramacrophagic2J JEJ&^6}A�m�5Xf!��S-��G 27/8Ek�R� yFy� }��� er  class"#&�h!�eSA�> : 53�T39/73uy�р� a�C�A�2���E� S- ( 8/��!�u�/8 ( 6A 5�(nU% N�� 1V)ϡ��� ��6% �z�67v,!g,�)�m�%Dr��P9!18A�U!psampl"�bef�,� . 01=G9U�=A w/–3� 2A�13M�72v9�a� C� �|131`5In�Otr ,U1i��T%X!��ZI�4C�m5f"�s���ime: 17e��75�!-�)sa9i^ 1%�3.4!(-!%a9d Ia is�ter/,pdispla�Ta�� emerged: *R(�E*�R��29 ( 28�� had �M�&� ]��&� $. To summa� �{^� E4"�V�-�T �r� "Yis.�i� �&��20%AiZ��(E�m]!��o1�J�A4=&�;�5*K iI� �� *�laPMdA�U �$���.� view&���:[of&j"a�.� y3 vH &7"3@��" �isoenzy$#,polymorphismC�*Rp*�&"Wsix)zn"� ( Ta�$.* = "�y�e��biobankz8 �$t�to�MON-1{ , 2A 8! nd 6: 81-�7A & 7��� -r�� .�]' 3!&��%Al>F �ctea�du�{>sh_ addi�, 59[�!�� d�&fc ei �� or�*e leve*�&y didT�  aJ r �0stic PCR-RFLPa8f�o� '] �Eye�y0 ��� labe“�&�” ( NqOO+o*(4c� p,�%vba.�Q"oc�O �di�Z :�(. . Non"�!�F�)���]�24q�e���\7� &9�5/2���gi��u t259�� :�BI2�am�X�*Ma�)g�a޺0�=6�&/&!'j� ��$�� .��58!�az� 0h$!��.�CL:%()�(R"tlU� A|UԵ�� ,e MediterranF a#�Fip� aJ% ag�-�6�#.cosi���#A� both�A�T. W@ in F�,, can�**�/�<#{ by6��D � MON 2��N,� ��in`$�,<-1�!�a. Tak�advantag��large*� ����5�� 7-!�Nal Re�1CentrEW,in MontpelliE"-8$"we �� a se�17.6��� �HLanguedoc-RoussilloP�e| � th:�6. As ile"�+�7C� ll F�2h�y�qu�!uni/2vf��f�XTh��*�NI6���% ?!( Stu��� $2��  noti 35�(�ed6�AS1�2n � - . 5�eF� globa"re- A�X&�3�%w"t world [5`!52�%I&X svy br�%�'��%A,�.ha} @g$�)tA"�%c�&of� %q'edavhe** M risk-conc�Y�)7 na�Aha#cn*�1 chan)@em� phn#�-�n.x* � "�& && �m�o��@20 mg/kg/day Gluc�$W 15 day� �'�*mus�5�1�'�"=les�-!W"� or i# !�lMzfac�>��l  JI�6�5'�% trad�>c ( � ealj$B��5�� 2 mLA��tw��� week%�4 �:ial�y�%�!�� teg�!��emplo��� cludA%!�mnoxyge�(O6/l�!l combinonIW�t�a|N/��}Nf�f!B�E:lat62a30I' . Un�ven�6�aR% and/( elapqz well-docu"a�eatur� &� a��8!�%9 surr�4!I6�ɴ![3T256–6">=..��e��F�e onialY42t���,Psh�7dr�/ ;archer?/conducA(x:sQ�ciraW��e;�A-isō���2�.�9� �mi&�; such�;!��Z �*�)_���parA%^�/c8>ly�n�-ide�5aNto2 assaa(AIfortua�%r!%�involv��^�a{labe; tens!�,� icul�!Vdardiz�an�2p�_nt up��nE��&�0 [4@:61A\� !td�opA�2� rf  techn{=es� en� :Dqu!�4<=Rsin��4whole mammalia s [65�8]U �kcapac62�"2�2D0 drug>*&&�Cfield&�d ��A6eSa6E�&& {1�requi�5�!e��Be�a:P!��� 8��'nt]\� mayo:Zr�M"�[7�2�Uir uti��2)9ss1�fva�ZVart+./V be{Ew�  vitro�j.u4i$ axenic�Q�%� , 7A�7�I�t��; !�vAs��y�0� inexpm8!j does�5�u � make5@amW��eas�.]\�=.�Atr� B �ul� .�. C� rD6�35�sefulŒF6I:�?%ƭo>�&�3�:�� ma� !^eb�0:@� `sN �1r;g�.penta>�.,. mustAW���Be� F-�:�6�6%6�5�ap�Ealw �5 _AtICm� *�)a��J��G �?/ [8A�&"76��6,�3 ous A�riaqal���!�.s [56]E�@donovani [77] sup� ����� R�B8`!"h6-@V` B#.� �;C�A��� ��WC{Gk���: �!s�,v�c�  bi&� �va�3 �^�B�!3H$crepancy m8U�&�s"}ˑl�weJi]� �of�3 ucta� Ik�ah�I��of9� �rេ"ssum�l�I wo.Z*=TDR�a # ol-d"�re � �ed�glutathi6 S-�Ur��Fyesha` hom�y�_?T�H ruzi Tc52�%tein [7"ILmACR���"�FLars� � s [7: `C �-|�.��w=����ye� w!.S+-�diY"a � .�%�K���-de� ,d microbicid� \M� � �u�-i� .� ng^y&� . Fin�uŭ&4.��Bb!R>�%!�?rE�� �&� {(�|� uj/�y>*�U4�:�M% tibi�� � c�,*C�f�G9�to��<[8g In� y �R� effor%�/d0Bf�L�I aiaUat har� �a A�a��6� �e0t�#��)��R6�*"� initi�In Europ3 T ���|S ��E)7� <aRCcie)�C�NM ��i�I}��D%B( ESCMI�#� �KAhe_ Comm�edA2�S6�T.ngYUCASTw-c� �*�� -�!��a�.��laqA� � ���$Ūl%&�7�i�I�t�Mu6�7<'� weL%*��Qron)u� .h�9� gs��!�Sb*geO6����2� lacs~=Aon.j�d�uT�� n"�K,s avail�samQuŤ"Q&E�5����bA6�u�lg#"�OJ9)�^*��VI!nxngl�c�rul�1�QH��-l� !^is�a��2�%��FAPto�$rif��$JP�&X9n: ieP5�� �e5g�V]=jAlo 6�K|!+R& "�B a>@�Nor"�2U�+�~ �>*9b�(t+Ub�� MIC.!�e up�E�HA8:Q wild-tr9p"X+7�Lda��organism� Q��Dife"( �)m} ional meB �+�cW �d"�?a>,�PL).IB.�'�at�U�M�1or.�tK����&z>@nd�.*�8LU�aqV��d*�>�<+}(o�%D�G2�le*;*�S6�p"1;(B3;RN1!<��tt�Pau|�oUtY6 willd ���;J towa7S �)l�V#poiAB N^�:��&� ��Lprecis�c link��-��i�to&+ !�+�outco(.. A�,�wt�&�4�CinXcW ,�tX a�2bAoY� "�, w���2�=;ū2M.@An=�� tJ�. B.�D2�%�F,U�!�.�w�a���� � ^D� d�'i��V� �reaAGhardaia ,m�&b=�$f ��7nAk���M1"�9):%B _s \�aA-pan{ Nse pecu�T taxaAđXex�7�iJ%!f�e� �m�yЁ��M>C%�11W0�$)Y&V� I��Y�)q��!��'R2/ ��i67"�&�:� A7o^"m&�A�bT!U�#�"�confir� �la+*r*T 5�&U "�1-W(Pasteur InsD VUit��| ?�2�U: A� ts�" v�8�q��&��.P9�zd�:�.kG1L ��(.�/�'�eYleD}�S&o!TӁ��"ON&.�+���U(Z�c.�#��M5<P�;4 z�Yu�5��� ������a�"W"�,24!���s�&gteG�]�L"y �!W� m>.4^��JUv$wo*�"��%inct y$�"jE�er&�4h T�� ump, :� )�OE�( �_@#w� �r� � EA�su� c.>rvoir�( i`Céven�!(2-aT"��#ly"8��b*Z$<� !^ 1980& Alr3)�I��I5>�.V5�(eB�,� B�xeA��:.*e,��s! �e_���y*�>"p6a *%--�?D� >�� !A=Q%eis.��i�%!� Vrug=�uL�#�b?f�I|trigg��)2�� a`M8�[81u�A# y� N Qto add�J�))��z M>6W uT��rj �U-�H)o}� <6%as neg�7��W�W��d�$[5 ed!o�c�$>�%J%5�;.� to%�X"r%e(i��-�B!a�}D�yL^��.EjRrug*�� ,A X�?aobion�(k� o CD��>��.�11a!R� Z�af�%>�y#n�!4 tissue-as�8�Y:J apB ���,�HtX� .O immuno1log� barrZde9!q�del�!`ucosals m&A6Jgen�#�a���� r)�%r�Bc�{#{p�fM_�ea fulmin �}w� ?!/i3c� . Oue/5Esuggesa6dividu�%coQ4by ���@a�I�}U>�Nbe7=72a[CDm9. I,w �3�%�R�t�QYmod�;rE�2t&"<b� ploiA&M}m�5ơx�Ri�^�!o�d�!�j��t-��b1=. I1�Ain bA(�� sm� !��6bowel�kc�an͗�40 �&`&o�1�t%2dibu�)�se7] es [�"�""2�  iR istBin5pq@dT � �3�#�<u)1E�p�=l�Qi?O9!"�+.�)me�b\CE!���iacea!=at�en��virul��! secr��ndhn!a �=i�by �"0mol�ar��1�%�Althoughvatai�=-��<@K����&  %Xd�p�7%i&�_6,"mU�sem/mp�-!!environE�favorA�1�lO{I -�l�!,i��Uin�' �7�a�^ bloo�I a���1s5�O q�NA� li�^,N�Fo.�E��d!�ha�"like ^�. S\ it�cover ?d[7�'�7l�(�o}(d�Wg�L�2[S���a�D�[Qa�k<�2Z� b�-n(&�Ipro�&Z poa�a?[�&8 , 92�wsh� evole�76��s�^e�ex� �e^9�5^[10! ��n� �>� >festy�A*��AA��frC>�� �'E�od���[* � i�R��� ]��&� �i% �/examplN- sKadCL%P10–12�(children [13314a%�n�_im�0 [15]��g^1gen�  %a��i� �ME!i��� is9�%da�띟l+aF� �R�Y� � seem�Qy!Zѵ( albeit�h �F�t�\� , �q!���:� �9��!->��r)�!s�be �MQ elici���g�)h�CUDAX��2o�.�e_ P��Rb �F�,� siL o��or�lofn!� ��qGus�sode [1@/18a�N*j� :�  A�f"�� 7 � /!�~2 q1OGuD0�-�h�X\��possi]imr� � gut9�e perpe�e���#a��K�Z�  i �to�p"12�[1.2�"F",����e� ofA�)�, ofte�ro��AOed�"e� :�-irri� � syndr�$( IBSSn1�;~on!n>) E!'->!�eW��i�Zdisrup�(5�ayst�$-�iotO ���k%�> [2 ' 22];E�t�5a��Q��D� ^����$���a��b� ��r�2�#2<)M!Ll" [2��#eW velo"ned2l.h}&e#�usB� 0$8* an�ۅ�����a*� � �&�-&b m�%�� z�.� eL r *�� a se8nr2,( Sar*>C9o�� tach�*��effac moB5��Vl�;hhwo�(!D!}"�� naï+�:���6O1�n suliyTJalJ� �=a� a�e ileum�%q�[m&D e�c"�1�� ᭁ�A�j#rco�s&� is.�oJ blocI!!� by zz!x!" . Y�n��giod<�t,c,akv;T" `��^B� [ amag8T��D ����ho�i?>�modn.e ����F%���I�<es�Aish)�!���o*Y�7�"�i�(�I� �Q;J�. 6P"~e 5 �=as�|�w.�@� �!on�eMa<v[o- m���:-Sof # � �w�qE-�, NRG857c [254� � ���{<&^1E rH129�)C57BL/6m� o���v leth3e��^ 1y�!>i!AC .*�:$^�+R=, up��)b�FD%�149�8ma��lIkt��o>�to�kB$u�JK�I1�LPgPS*4q1�%{��>nlea_,*�ly�?&��H�k!�%� �monQtJ-a�!* �12�/��v���  ;�)i~/![a�du�{&�5&2�^�<�I�as ~ *\^c>�d�j a 6-� F �jasYX�� ��-�BR(M��eU�� ev� � .�coh�,�ch�Tdiarrhoe�*dehyd �, h�*� YIN=� �(weight loss� ~A� 5 ��JL�&�, �}&�o�7plcE�A� �Zpri�P��C���!SBRkI�J�Y �A3- eQgE�>D�:��0 segm�~=y stoo�Qa �0!�in ce7s�-m s;:a�.de[ rubb�tex%�be�U�8C[#al ul�p]�#�J2i�H4�S*"�&-^on H&E-s�6ed �s��s�f>�)�1�+ YFfo�sub�l edema�mil����th hy_ la�Gq^.�e�EWdra�,c.?d�u� e�g)q�Nu�F"� !�, �I�E��'rypdchitec%zI�2i�uf;YAw� > 4!�>A3}Oly"3�Jh# ��EC%�z� �iMNit�} oxid� '5omarker���ve} 2A�reR� �UBitAIB*�[25We(Z�d n�t�Av� �� ecumI]" ArN�a�N�,.e%+��. Ce`:~�]6��](tIcBO}!>,�)zA>[�ed2�ly1�� . Uu�f� �!uFKu�I.�E1�fermea� D c�H�Eal"��Ae�Pe gavac"X�fluoresc�5iso�{yaK?�ITAt-de%FDR!0meMe}�Casof$K!1" l�A� seru�u*G"�e6E"�AV 7�7#�ց�� grl .Qun$�Mo^e�.� ��s3 s{^�S!<&R na�pre�DNEH(���bM~� morta�_�i&% harbourL "2o�pr �vn apr�W� "� @%/�G�2ch� . �d�t!37 B!��?  of� emi�"T�",` hypE� �*a�m��ͭ���0�a*; "67�� proc;D,"�\!in*�%�!�:�6w, . ByM�>1<�%UNfec!�u6�Oy%J%�M{Y>K�fl�i��! ]Z!j:l 23Id Sima>�,iqz6�[27q Is),=b6U-�dr1-�inEE9Z��of �e*t�:Z%1growth$>  [28]mA�xC�V�1�)6JD! �];6��!�ə,*Ospla��;[h�on��!�.���i�px�� A5%�!�"�5H�=(���$�RolB. AN N2�,=h-� �a�.-^IHm:�o.�U�� � � "�."� !�3�$T/��u qQ,���%1a�h;q Pti>.#Rl6�3�'�X�:I bulk��x*��n!�i�d5a 2-log%3 1�B�%-& �I�!\�:NMb� . Cu�B�"�=�:'Fv2�0ilAGCD�.U :} a�EDA�� .�$�3er�>s�;�%` ��%on [5c"^!%�,R&�!un�  5Yno�0��2Gok<; �"��%M9��1f��?+i�t�%Qf�(sr�.er�vX �)ve nich!Ir&�Žrep�N�&<<��m�c,a rifampicin*�(.> L� h�9�men�%"�K1]f Despe & !�l!���3MVb�p�� B�2�(�uiay��!�2� kinɵy"A�F��9M� �a�J ��N)�# �*1 A�N�"��� oBVt.�aN�v2, �qa3Lto��/ng�� 2ed� [2� TogQ�.�.ED" �~�� �aI�M�I�]��ey��>enh9!d f�ss -�i� 'n�RbeaHa+.�i�k.i>�U<C"biops�$V�"�9 h�-)lm�"uW �Bc [3JW�xt:K9� ?*l!.E�� �!(���out�v�P�q>JwI�i&@�)EF�a�R*�2^�&@=infilt� 4d F4/80+ , GR1!� CD3+{L���e�*a ���"a&�F: ?&�6& orNt � i�4A�&z�U!e���s� heavilyA��A �-�la�Ŗr�+6�s%")�a�#aZ!P�PBS]t| "�k>]h,RJnn s elev�A���umH necrq]f}0 -α ( TNF )% IL-1Â:�F�"*/D�� ena�_�;���u�~2W3�0qw�b^T �A; ���`su1�aTPs�a>A.�&�->S.�eN E�RD�4�4�C.�Q*A5�/ ytok�a>N&��E%0�%hem1�&��e t�]Xb)�V�-��[3�ZF� �!Z"NE�s��M�i�^�~�\d]Zrel� MIG�y P-10\M β�1�e�!�*�%_.�!C&�q��6��$�&F��A�he� �*LiN����% �ce��A s��F elf-�?鬉�J�� M� ind�B3%:�.���*=&mu����a�o�FrkB�/i>m"� !A���1�)� �^�)��C% islA[( PI-Rg� ra�mosom" lasmi�?���N~��� 5bH�/� !bn�"�/yf$�2`a�5"E -.Vloc��arlABI ArlAaq a Mig-14 J�#a�ZJ*�#V,e�Z:���,YB Y�:ed NAD*"Kepimer��)� ArlC2n OmpT�ou�1��f �5)9 leav�m� icV s [3�#3� InX'� �wh"4 &�f*��ABfw .� a�oa�a"�=E�xAl� &� �)e$$ΔEa�B�Ue1��Y�to" byM*iI cac�!Y �Z6*ABt�EZ�ʁ�/CXCL9 [!=)�!5e 57in�ptide-|"v.���'_3eA��%GK5��>�.B�q�ZfP�&� %g w$ed 2–3 l�G-{��a��}>�>�4x~�e�&��a�Dt�6�r n.�j`��U �x% ��n�))�s�-je!M�@cc H0l^ig��C5B��K��"$A�"�"9d"�>7��ir{�"t4>Y�+e5^>�w�I�4 ma��lN���l� ;eo@ an a�1t.�2invo,U�,%�"��sdu$5�!�q#3�re$�M�mT3SS-�q!d 2�<( ΔinvA ΔssaR;'0�o!tmAvir �rC1�}�%q�y � blun!J�! i %�. �D�YyCWY(.xI�\ 5%�I� , Z'ofnm%�a��qng>� miti�����=�.��Zin� �% �� r�ces� �E�?~I"���lDm�, J�!g>ft� j� tact%� �fe&�n� t?Xel&Tl�. AlsoA��$]-a/E�a !.z � �,�-:} �B� 2b!>� -,d�9M�TNFα ; � �DE�� -� AG�y!.62 2}f lip! in-2%�� EHe-I*�s2tBybeAZ0sk2%9,�-CD [1]Se�-� R0"a( EPEa"kY/Q&f) WIBX6 ,�m , 35Wr�,��O�Ei surgn"W-j82�,�V`+�;nW�Q(6�#5=emb� A9�cou}=of ��,� �u�ll&�)T\3� �:B�  (�B�!�6= 2�*n,� rtun!tooLid���9�_e��4�+inAO"f("M�GsŨ��Rw�9q��B2�y�Q�����to*#��7Wq�lif2!\!ra�,aGr.�{�5�'�tovў 3–�b xS&{i�u:l%�a�&.&7.V%=�)=R,��)��&�*2�)i|�~' & 2` ��=!�nq trac5 �! nQ36 �. Bh*��@E�2�! � 6�2�<&p&Xfas�W���0}a�%�� d�#{:f&�I��L6�-,f =8� to w! .ƙin��& �,6�� �Y�!F1� a�c �5���>� 6�90c�n�s��uA^/Jq )�begin�~ 4�s�^q!�4h!}&�ce1��Ŷa�until\A9�!&4� stop�-�1"DHK>^ %�J @ per�<B \osN� �6�!1�i'�J�!�B 26��%&�_= ��o6�1�}�; s{o�con]:sc�<*$�MCi�%�isI� back�nd� 2�pLn�!y� prog�E95�աs�扁�8 prim�i��viR.�4�(1�>��4�'8rIn/ �3'jd&5i 6�[3�!.d'd�.�%4���<k �ǖ!.6�2g )_t�'�h<%|1$a,thE�1��1M'6�9�M�DN6R6,/2jՓ10jq�S ��/)3!��=eak*[<�Q �14!�n*� is"� . l�a�>e%�20+�-c� [s2 �ayh,:�=as+C.�8!��5!z�#At�A|� e]Q&Oa�I�(6%fD6q�3!:de�;6F=$�9~a}p��5By!�I6VL� "Dj 2�JYi � n�X ��l��t�eth5�h�on�jIE.b��?{6�de���h6$!�� le���.��p�S�U% �@�)�5�) �ima;si�Eʩ�nE�d�4�� to aer�%B sub- Viw7�IF�! &� !i�dm�ZH.:I�s- n q.�-A�*p|�leaDli��VHU*�6��uo�9 A�7 q9��021�k3�<OI$1� B�b%A.�h.�-�wf %�B v �� &Q &J]Y��]~�Wgtz��!8 �le/P.�p"�P�5�FeM �)@C 6z �� �, <*�*I� *�4B. 6�c%mS�H� "�H,� pl�� n^�a9"�e�k�A�. �� . Gi�t!O�+ �&� m[I��61�(�g� ng�T a�� %��"�E�Q!��Ia�I�x%9 �Z�&�)�� �. �$pU�+��nE� unifNAa��Y�way!�CD&�elu�1. G�%e-w�0���k �= now "iPcl1Z:�0�s6�8 alle�y-� agg���B!nl5x�3uBxr �2~5��he?H$E� a dor AFont"�H�(Ck$on NOD2�ha$U[&ioCord�� :CD Я�zygi twin~]soERl�5-$eD.~ of.�"alŶoqdj�E%g_qi�%#Th�w,��:Ez�Ekey� �LJ66,J*�lipCst� a�8h �T,nst�M%�ofLC�Tv�@�t�. R~x �L2�tura�^[a ‘Ht-hit’F)�2�eEX*!E�"oncept���E[1�%IO1) �a�cu{jveN>et1�e ;9veTv�� tipp0��<homeosta!�a�~u<�Vu�2l �� � �� r%%ly"����(�> �<lE/1� TLR1�>icvQ[4EAn�/r)�)��-! IJ!g=-"4�*>Nc�by� "&Qr#CiBm0zoo�i5��K&KD"�Jst*p/e�Z r>��)p�Dvnfer :vDI,�izI,�3!�.-imbalq�al2��!at�$lth*-I�F carr�N�*&�~&L)M��ir�[41n+tN�D11J!�a�� "�'!"qui��PeM&���xacer�n�� �d�Y,eJ1Gtat&�=B��o?G�XquX"2�'mpr!s�a�E� �ic-B� rha7�/H�co� rt��F"!.���a�� ��9.V#>Gx�E;d*gK:!AB!WJOn�19�CD>�a�s���/CARD1]K"t( -of-v-��d[g*�@��PUGh[4�k4aOE��)��@6<of) a��"\ m� manu�m��StF���enE by Paneth�!|o;K�@>c!:.��u1 "�":E�Sg�4�$Y&chPn47b3n �[4@ 41be�q-o�3i51' [46]m={B6� '#)'!�F�aq# $(&05n6C)-GA �-keeŋ��8-�eman@eti9& �sh��?&�&g�oedy��h0[4~(4j It�K�#q�bE liɜ���!�Tsu:�"ECPP&Bq�aE�]m^"zJSrigVtU��r'*u�bA�߀�A��Ba�"75"2%I�Aa%�r�aA~"[ KNo�8�$}�$�Jno���pA�^j�)I@A�ode� ng&�& �. Pӡv$k.�6,� �3*�5 �,p-l.itzdu�U_(�g>8 ��},I�R � �&��� 5���)����Me�^&m&9$��6[*�"&C ��3aNs�P�v�N�>�20%$�,m� a��L"P/B �b 0e�P!��PE�Whep Cb.$ari�KyAL!-tic;hnd��#-��K�={M xen 42u=�!� agemWL "7 +en qu|ojX )EWq �+\PHN2vug�W)a�h&9Ql9er26.U ranof2ia!A�O�9�4�1F.^�(m$sha�35�ra�R�wh�IX topic%�fu�����em��j�on � �!��"� �Rc�%P� ��� ��XA�Gs �d�htfa��.�Pg1 ��>�R��� inju��e sod�sal�dI> sulf���� n e/e��avf/b% � LF82_}��AQP���m �TLR5-/-A�lWcamv{M��ntanea ���"�\�HR�6yo "YIq)�� en��d �%�� *�A e�[*��AaXW,��can�89X)�}sa76hD���}��u͠�'U/a�"�Od�$oUXa .[ &�PS �@a����m�S�!&h �i�B �� �*2LE�e/�a���j ="�J/hQ"u�!�i��9�"`9nRC�F�"�#bu F [� I �a-�:�Y����-F��qF29<�!: � �por. ���$ork�vi_� ona�'A*d���'qa�v���;�+, 1r "if��G��%& _who may!8at"�F �Y�!�3!D%>�.� �lsop� �5e\!x��AGem� s�Hu��o acqui�]�!t0vul�;���Iq"fT���B���a+��W�so-��i��7�LIf �(�wto*6%��,e"�5E����;d<��O�s� t�fsHDN2�y�U�d�U�1���DQ�n�� =4at\eb��re\w!V�E"�`A4)^�"�'6� '!�to +;neuy��J��Ej'ubM�aqq�. Au&ex�a�*�%u�m�"�*n�OpCanad݄CouncilH YC�2t�$s2iro!) @ ,Rev�Eth` Boarda7McM>m r Un fD 9 8Use P� #13-07-2"�E �Nx3( �T$type O83:H�-��6� Z �k�H ?;y-�!�� !]C�Ho0>$al ( Berli��Gen�y|8�;F4e sW�cw65%rF`�#ly@] , a�A3� e�"2�q�J����� 6:47!e m��No4(5#�,�4!&� k.�2.4A�8-6�  a$Luria-Bertށ( L� br�"�la2�chloram�ico!F34�9�`�?l!Z��0. *�.er��!�v:�VMSL1344 �u�A �BF���l<eptomyci\ E>�f K-12%[ MG1655fa/ [&�@�R�g �DBS��%�N�Yn�� aK; 1 �d�+e!K�'n� ha{37°C Ssh�t,0�+�lu ,%��s��%Kphospho b�����J�;�0P>}G7��S��*,9�:fHEPES b��H����,$�9% NaC�^E-e-en8R-old fem 5HAd2E*xpurch���a��R�� L.�a�r�_9h% B@'C� -f�"h�,��L� 2a@� he M��2e Fac&atR#. �2 �<�M���pU�by orovic �L�ph :�Bێ2 x 109� yA9m���cfuxEa�{.�5&�=s�ed '�%by�E�߫^rA4. Two�^�drp86n$!āUY>�I�+!�8�8�J�H� %u .uV��-F&*��)!`6G at 1E�� t-� ���J'ce� * q?�m/ 6J!�&�.rQ{I"JNFX1A�.���&�"sV)U~,�(-M  qE}enu�9� )*�@���B4 . Ti}�har��eI� dE at"3psHdRO��%~I-S�cHomn��( Retscht2s�r<d��in@��pAhd�LB|�A�"�6��ݬ�na')�m;.�6'�L ; Br����<(�7BGLgar �:�6D2u;# BGe�r2;>w K24 DLincub�at�#-�� %�c�!Qnd\ ,6&� per ~��%�dt�u�PUH;+E�tipŜs� �+�] �lLE�A8ixE\�Eed ����� 72 k# paraffin-Ojd^:,aaB0to 5-μm slicX n� �UZE�haeExy�#eoR=(+ ) by""+y ServK(R� , Hamilto! ON�SIn�a.� )dmflash��ze(op%��� ��Z�,,( OCT; Sakur�XF��8B�0^bE.� inimip f 5 � 4<r19)�,` Rea�e�% sco!�2� *� $!�cr��ڭ�{S1y�[�\C�Vz'�mA"nd2{&�Vc>}mk� I�^J softw� @ Lew HC�z rosc��%�"?�F� -or�3��s�de�t�nTp6�F1'�~of!0E�GOCT- I�)�1f-�&�X �boda����F^ :60F CD)� 1:10!&GR��:5 eN�. Q66�� %D�aix�tkHNH57-q�- �u��NouCFi�:rem`.%�qG&z��)��D��6/wa�^cRPMI!%��e�gbova7/U, 1% L-g�� %4� Lu tam�L�cuE�i�R,�sN�] �� q!{�|��vO�4\��5% CO�LS.CF��5+3 HoW0�Ey�Es�@MB*�IC!3M�  32-Plex��Ass�y Eve T.]�( Calg� , AB* rM+k!G�8ELISA k5z R&DU=c Minneapo�, M��ToqH82�&�W+%� d)�z�μZa8q�ml �W?( 4kD�z!�"?+ sacr� �� Bloo�\s��kp˖ac pun[o�il bl�# %815% v/v acid-cizI- ��). PVDa aJ&ŀ]j� ifug���ldXg��U530 nm �exc��at 485.�Zt�2n^ Zif]2�H�]s9�_l�WroH �(ngi%m2H�D�Greis& ��(( Sigma-Ald�q )2�"��D�9 10 m9!E� dark�d" q� *# r’#x�� �fbsorb�( A55��9R��^ =,#=E�a������vA0F��e&Q9WpRi.� M�u .�Exer M �!�/+fuG#s 300 rp5�5%�3!��2)�P*�Je4�Hnd�7"�= %��� R�)��21�=,e-�,ٰ�3T_��ettb �)%�B 95%!�f�]rter1��k��� ����:�3(. Kaplan-Me�wcW � )"���;�T�p��?�u���r>�G��9sm2��Pad S� Inc n Dieg)@C�`A�ۡ�05!-�BA�*G,.q1 .NIn f��rA*�zE�eg�UsQ1&��2>aIwd g�� ophy��e��Arabid�P�D]qt�E"A�/�'AQ�I�!���� flatby� ac�ZJgAk<eA�>#Gvi���kf�Ul�;"[ �*s�u�lik3r ���ver���� �x&*|I�>crU)�reg�� synergids���%py3{p���C�y�1!m)p n tub> SL{nE s���.att�1a�mE.@!=X9-'���F 5)!�s [��1>A�M:X�g y�pQ��jpod5���de�C&G 1�i��wh� ":.iCXI�[."�1 e��%�e0�$�M�\�/"H.ݝ9�0��. a�Ѵ!�� ��JicѶ6�E�%�2�!��g sRoštook a.�����–| markel#w9!r6��a �}Y���"or�GT V!| p ( G�c,a�y� ��XM?%OM� �. .���AMcZ����k�k]��ope�6Z.en�#�Lumu|ihCE'�6�}�32�m�@�����sG���� ;xx�2Ea/� i� �*��. W0-��6`thyJ�hi�fo�fEM�v-iXd"(�&(%�lmdF�!� ET11�w�W1�j�cNBSUβzcuV�dY1 ( GU�o�Q\�f2��! �Mli% �M�M�Q�wa�Pand�(����a�!�.�o +�w%-#%�riglh to!��灜!�6 romi3,�I29��j ����#R�2A-rn@/m(9sla� �edX!eN�w�.�f:h� J� on hh :^!�R=!:nQ-hovu�h ʉ� B��H._0/� � + r:��1 seed��a ve�1:1G& (�. 7%:4M�%�b,, n = 631; 9}�%:��4'Y� '55;"<EE!1F" �.9aF�i{+ect5"�( Reci�g�rros%xRvg�)�a@�Eq�E�rar�NB%N���r!%(s' ef"�8&Q "� [TEF] =�6% �347E(PO�� j Qa>�&}��r��*���m� [TEM�5!�4�6 �T'��T) NTi �"[5i�i����#���Pdz'p&IC,*�n��!�h�~ o.�"A m�T, �ş��Y�� s �{ c [<:�!U:I�A� �2Pe���� guishV*�&�eZ��Bi(=�"���,) b�,W4l'� �� <��mit(1"� ��mig�of� ]1>�` ?vS2c*7�R�% y�l��h�(ãc>g#r!z��9)s�e�c��b�e�d�x"�mo.X!�&�>I,6�@�W"=�٦Im6^l'шs� wo&FG)rs�5�N1�a<�I� �M %uq SYB�E�<5�8"� �/�!^�to Ia�2si� [1a�2�1L����E��&K/,�:�* :zt�@�A��!�E:W*FI�4�i� 1J; TekA"���L��c� !21&�ET263�&dowg/6 �8%6�5*2D���&0Q�'n*R –!�(��� �)2���f���p�wC l�d �%�%:U�-����]r( � ng� �� 434!���l� nD���e��B "x�Q�n1F2�9%C� �& cť�.~�Z=H����.�1R% T� �._��v ���� =g�%��N51Ro{ !�Q�QX Qo�yA��` �2�'�["V�l�/� � _]A�[iUb K_�( ET88a:�6X�an un1F$(7 �KyPB��5ini� autono.���ng[1�"�f�?,�8i !��:i��J�2����Ls�M2B� �L�:=uk��p`?�1u�"]nt��Z/�g^-V| ��>we�X en�Q��s3ru�^"a�e M�1LR�:e A b ant�*�N1�9�  � ~�69pfdis`F� e ir��" fe"S�Vfu允�W�Ti ��% u.] 9$I&��:p^ Ta��deXE!Xq�`.� C"�� .�Y�.L��*P\l ��2�%-�A����-�2M��O%�.AW4expression of �OGT3733 , an antipodal marker line , was down-regulated ( Figure 2P–2R ) . ThusJG�cells in lis-1 mutant female gametophytes c4dopt a central>$ fate . Re�8ably , both the2*s and� |}liFe�Z�0are competentA�6�Fwagt!�LIS i[volved)�9�$repres!�FIA�hez-<)!�teresA�e�&?AN �B)D1= addi! ea�Ua%gg`);,Q�A��(a further ,�-depend!�sup�6O �2�a�E�� ��phenoAM�se� leveI! ��p@ion , one between �ic%�>Y��d2.�!�B�e �� iniA�gof -specific� gene!�dicate�at�4Arabidopsis di!�ctB�sE^�xmanife�)after%�izE� . Studif seve�m��!*H systems have shown)�! � Niaaten�ceded b��( asymmetric� ribu�eU(determinant�� for �U0ew see [14] )-c��nalog�}Y&@could be defectiv!aM2�:�an ins�"mis6�ofB� . Alternabu'IiYb �� from ��mat occurZ� when%$i:�become5� . We ! y��A�tim�U urse�A�%�B���erE^ exe]A�Fwe found)�d�) ovulQ�.  Qed)w2<inc�ed over �"�4A�4B%���AV!4>p�A_-�ly=�ed as2s�Z with a su�>A)��,: u,orpholog  featur1i�guishI#/��plE�E wildŬ!�a!�ore��nouncZ(C–4G� Oua){:�dur!;E6�> :>hMwgradu��recrui��JdWA�ppeA2e ���e�� 0At2g41500 loc��(which encod��! tein)�!in WD40��eat!�TF^AZ�$e�-fr!N$stop codonmnthree6MU�5A%S[!�cDNA dr �by a 2 . 6-kilobase ( kb ) upstream promo�csEca�mpl( !-a=lis%nt�,�Be5CR�c@is a loss-of-func%Y�� ��e�pr)Cis stron��con�a,mong eukaryo!5 [15]�S1���AEane��similar� 4to Homo sapienl Caenorhab s elega��(Saccharomycy e��sia��62% , 56,54 reA��h � yeast homaq PRP4�assoc dI2!kU4/U6b lex�spliceos�H([16 , 17] .In 6 ntia��li| facto��R|��accumu��un id� -mRNA [18i5��s on it�� tera)ґ�econd �!��PRP>through?e"domai��� deleEof�&reiHabolish��S �[19� We tP concludatM�e e�j null]�,m�is=sis� �.*> �]A� 2 T-aziA��allelap�e�cau� a veryQ�uVS2u�.6 genAcontainaV-lLIS-re!�dy�,��05720M�deduc%�ih(Aes�Hno'AD25639;�eUsha�VRof 70A��K : half%2size-!>��q�!�not��; fourmt^�� . He��.�is unlik�toY Q�� dund��to� . To"� A(e tempoP �spaeWppatK ��ge�De performed RT-PCRE2�J� 4 pLIS::NLS_GUS! stru )�a@gs�-A��fragmt ���rescu��K�had fu(� 2�����.b�w� etec�)at moder�� ina8 tissues examin"eP��est.Tine�A�C=u6��!,���!,! p��>�� tage� N�d\ op%[wB–6Ee�IntriguiŞ,�prt|R� ,.�� >� 62��u� >�� s<)Ily up-e*u �T�,sn� !,&� t��>�� #A�.� ,�� � -autonom� ise(A"�.A�O Jyaya�inhibi�_Aml=�F%�W� posa�aV�50upo� &�a�a�� aA<*�*� X(is transmit!l# adja7B:to�!tir2�e�Q ce , reby1�!jex��64�e= I�� is vyB��F�� � (of impairedN^, i . � P6� fail��if,mselv�$ir neighbo"� !� }�M�r� el�ll k�5�J� � B�A|CA�Nsynchr� �� ifRh implOe �l bia)F7prEfR=opEMs!#�� ra0 thanes��b "B�eJ+ Altho% t!�y�can�e petu�kb� deciş��d�"�� )4neto�|l� �(m#a.of�(����!�surpris!�nZ4F��' !\B$ =je par��o�p��on�� he@machinV i��5)� , po� i M�en!� bRl� possible���� ;b��� &�\ !%�� � � much les rect�X� "� �� or .? data1.AVt  ombinator Y4.��!=F�:%�!g��m�!�E�U�� i�m�)p, togeE���� :��G6U,E�ensur�ximum � ihoo���key6$6Hb�ih�!"eC n�nTis��ed . BC��M�!�AB -  ux A�-�!�.�)3�}1,�� _�lhe2 Kof yPO,� integ!m part76R,fu�����iet$target ( sun: �G naly� of o%�� &U�� s [20]5l help�[c��:U�AJroleW�G��0T �5l*� al��!݁� P�were gron soith�G: ,der long-day� )Lat 18 °C . Enhancer7 d!!Etrap s r�\ ed u� ��!= SundX  d colleag+ [21�( Sen�questsA� EToGT hto UGA5(rossnik@bot] .�zh . c)e��1�$� isoa�di�ET11191m(Landsberg e��a ( LerA�"�@ � sis;�d � VbyGub�in �15% EMS 910 � A to!�0of 5 , 200 M1}%�screeH 6deviaeY: M1F�� �21 8( SALK_070009 )%ob�1!�$ >�%�� ( http://�0 salkH du� ForIpMEA::�repor~�� ,�f�D�aga�a 1�bA�:(�*��ATG MEDE3 !�clo�@into pCAMBIA1381zM�$EcoRI/NcoI� �eisik. Mapp��ofMGSdi,scribed [22] Q!5 polymism��a0by CEREON [23A�!�ColumbiaA Ab(-�`7cA����ne�I��lowdaCh�J2Aakrea�126 / F� CER448978eq 6310�A(BACs F13H10 T32G�:� We aX s a�!�X�ic > span�15� a'�mdnd �� ! le h�ozy]�in�����!!%u�B� a5�op>��'a G libr{ �ܐprimer 5′-GATTGAGGATCCATGGAACCCAACA-3′%8F-%AGTTCA TGC02�$DRIVE ( Qi�} , Hilde GermanyetAW�relea�AE(n XhoI/KpnI!`L�Id6h,MDC134 ( M .e�Curti� unpub� ed� ) . UpZm�}a�Gatewa�� A�a^( ( Invitrog�Karlsruha��%�nt2R� SacIM� !�"regmCY�by �� .�.�s)�AAG%�G!�(ATAGATAAGCA9�)�$TTTCCCTTAA!� TCAA : ACAC^�ENTR 1A6)a��T�1=� at� �" A�� >�M<"Q -�!'%�viaf"K !6. P.F�dŀ�7e��KJ=CTAA�CTATG ACGaGAC> TTA�TTACeCGGA!u)n� ?� 264 �� ( bp )9�digh BfmI yiel�Z�#1A244C�k20 E �pE{"Z 2�,%*w"#4is��x��f���n@[ s-W� E . Z . N� -�HKi� 8Peqlab BiotechnsiaIErl�%B ,en microgram%��6 �uk- �AA0 Dynabeads DIRECT MO �}؁Super�*pt II>�wa�MZr� �h cripv� -�+�xr �a���F�#;#ɋca-Jofa`o�{�e � -�h:i�CACTGCa�E���a�T}ۅE�A�/TGT�/TC�7GQ�ACTIN2Nl CCCT\G�ACAGT ;A�e Yk�ua �A\�e�<�^d��M�* �A�)�)J����b6�q�%YI��"BamHI/�+m�A� clig�  !/E ry v� pGIIBAR- V B. Ap &� w� N-#l�'aM cal�#�� [24] �+�;ow�ea �5�.4 r[f mPG&0'5oldest��eC lower budA�(inflo � � emas�)�A[harvez$� days�( . Cytochem3!s ���  vba?&: 5]�+i�t*|& *O͗��a�4 o2�0. Whole-mountR��prepa�2�!6be1or�'�th�`T#�hpw. U�!�8PRECEDE-PROCEEDjl�%a+A8"�,� environL du�&oA��ec c��e�� !�wh�)�' children %���!!�uohighl- Ethiopian� mun!! +X� podoconio���y)�)g�o(242DoM+ �fp%group�� emi--u:ia��_d ext�d c�$s'*. Shoe-�S norm�1sai%�be ng,��go bare!�]rly�n�Z4‘shameful’ h [��gh(- conf3ig%"a"lle�6injury%�col�How  , �pq#!�!�Mbarrier.�AOdesireA��-�%nbe�`  \e im2'f�*cTresour %me3 �people�neia$to purch!�m"(�2� of �k�1�e�Lnoq* ford +m�prefer!�q��t1A#b ' is l ©lUho5�y1K*era�A�&al�*a�IWmi!�bb�ovi(,0u*unth�ac�2r* ag!RW��5�(F!!Ffi��%�f�=sabe 1=%��btw0-T ) may�ap&%�^# to c �d�_,�/lyAqZa�vel�`$!� +ty:�pri�1�X suit�9!.daily - rA�low risk8 ce� )��ysb�levEwo���:��BwaW"^�onSu�4od6/health�@� :/we *c�)! 5�to)�aM!/e�u amen%g�tAPɔ�� w!��e�/of bene!�t=�/Y idebNTDA��!�QE""�.. Ix �(ro)>ɥ����>� )ao�/I���� feanc|-r +�#B ��2 [1]–[3]%2�ic larvaa~ [4@ [5]�E�iv�%#�.��|!/.#in%]�'o$l� (to hookworm�e��Cf�-ng�of.��S�(A [6�7')>Kno ef�/ [8�1�E��!ls="�aF O$helminthia�[10n[12 K5)I Buruli ul�[1 �1A*� snakebitA�d tungia�,^��#ircum^ JF�J2%vpredi� MQasO*ale�Y�)�!�fee��#researchn�"{�s /h�B hand-wash!�k,ze1) �4��-Q�ng�o�eX�cticide---#�ne�1ITN�R�)!]�adv$7�ea pauW6.��B� oYJ!0�1n��)+l+ucY work12 �M�n�1� �� ( am �&ge�pbyo� ��rri� T" !�t� ' s a�,�� wK8covTE�<(5.� on=! �s)+!����giN*i7�0In briefu!�n5 "-��+ �n!��,�.� non-g�� organ��vhiQ +!&� �#�J��ng6�= n-coa ��G 8eleph�9e�ari� ��F �2�!� clay-�.�2!b*U%al�*�#at)��B!wu"z �� A.*� �A)�.� 9Z�0.-� ree{��#has b�6� mpan�by mess�) link!I�� hygien��a �to!  -xof��. P� ap� U Q�ed it vid t0;deh why& / or 8 ���6in orn aDaE ��Y Gb�d a!�����,W$. �3 drewa>�F to guide n-ec �2 Firs}$wn !Yo��PR��U begi�A�pr�!K diagno�!I4�� �� ,u�a�V��i� �� �e�a�E�b���6�y=�f '<v�or$<self �# on [�. Take�'%t�;theor�f argu, !-it.t�4A�#Atvi�4s'  ef �attituy4 boutEYEc6, howXs�5l59 percei� cap� �� ��6�%!A�cI��(beA@�*�8ry#ɶe`�����+��e6 n�U� ��'le�ω7aV �8I y aim��o  dee V��\o"�12��$set%~I &� EVej.�� valu��s@�inL_u�gE�~% y A asEk� b�;!n���in�j of��)�rn%!�:"2-�A�&{ ��ap�al�ra%� ;InsAp;al Rep Boar 4@f Addis Ababa Uni�@�Me<l Facult��"QHuman G�2R� m�+�H� , USA . O�2!��X6�#,!my0" icip�4 7tra�0"� as�3g, follG ���d)9-b��t%�A� by Tekola%�$�%Rapidc!qA���A}EX��ty�*�f=�rcan�p��k&�xxpG^ty' '� >5,5 docu��fa��)*beIPb�%. !6tz3L.H� me�'w-1��3�A. R� 3�� in Wolaitz:t4 ! I-4a Mossy Foot TU��P��aA}~( MFTP>%staff �4����cuH5Q���x%�l�W i*a,I�E �'� �a .�"L '�#�&R�J�/"� :d�%g �$QCI�,e��V��IRBs !zi�& abov� a�QZ /a<nesl8R"�}�anN la�>o&.fU� ocolm�.�shv!1�eH)��3���u�4]hz�Z; w�3npop`9�^: stim�*I��'7 mill![2�P.�is kno�@�6��al���-�[2�9Mos?�villag� � sub���7 farm>�entirO��k!employedcA�method�f&�AEq( FGD� inQ3th� �( IDI�A!ka��#u0an:B�YjP!p}E'RME����)!�o�A-�9/] ./6�. S�)uA�JGG �r�Md�/di1� %*�onmޡ~M���$:>�,*� tow�z��s aIi92�N96�)opA�l2+!� ���] G �=�-� �3C.�d� [�8ex�),.�I�"$aro�AEd �fQ.71q!T9)��kfam��l� riend^An � de�#b�2zYion3r�"%�.Xa�a[o\i�<(��adults'6 *��Fd&� E�!yD_Gra�y,)re�6J2&�([2*=��  p`E�iL!:- p �A�%@ rG �Y  Tf�1jor5 impe1�a����:��P.d� r'6"�conveni��rsnowb� a�$ng���"�%of_)r& U%��.� rAt : ( [@69>ulE{�!givz�u�F:�“<”; ( t129 une�no cur=J�4�o��J histo�FlUn�( �44]�religK��“Y�R#”�'��2�=FR9�S � ���2� took6cG> of 1��9��e��� ���y �y a��@%�ise^�m"�@E�d"~ of5�="E��.�a�?,zEs-����hip 4 �, �u;m�off C 1e�Cudy)�onL =Jux?,o August 2012�monthM#� �~ly dry��;�&�G>f�b� � ason�a� !E GrA�"q%.����y&��F�H�A� .t�Snn( D�$ Ayode - Dy p� up�F weeki fAEq�!�%�0Abebayehu Tor�3ATt e�H8��4-���� �!�� �F�!F� !V�!�&� .�2�38% p28M � 76�!� ��n%xIs�2Al�Rte9T"n"� 8I�� &�in Eng�/M�t�J>(! AmhaL�zt�9EYM -/�2m�2�e1!OorNim� audio-rec7"a".ing _f��c�3-languag�G+� `�(�C2 �2��R16. T�l�Q�e)m� )�!:�p�'check-�� gc;o j� urac�=�� mlb.�RDőw- "�: back��� (PDq� �Ia"X-�AM�K g�_�>�-� �szL!  . "�D�*\ �+ aspi*� x)�reaO-AsE�(Yo<nR[ vC�N*� m�pa/P�E.� etr�(Huy ~!���;�`+.� ! aIab %�or�;�@r_y �Q�i�&�A�a�,Y�fac��yeo� & Q�Aa�+A��t��pov'c�@�&�]?a� "7)a2��oJ��U�.6�"J �53*XFqp:%�:�leB eno����6�"�*C. g4X Q�I�,�!�!a�!�>�,Q*�(%� L�  ,�,amo�Ra�-;.�-@76 .,!aZ � �DE+I�it��Ta�:>.!�pp�+/1\<c�F!�6�. Expan�l�# choo�% �QI!Zprolife6�varietJ �lU~rWtDY�rYed!�rmoUIRh8/minds1�A�p|]��0�%�x'yzF��w�(g � o^!s�Ue�pos�!� >�E��q��haAmRF,�p)����eFsec�VuO)ery!���0��in favo�^m2ng)T �&`excer� dem�O�IE��l�sk(��s<`�"��o q�*! )Ex& in#O���A�5�2E:? n you)�& :9 J ir w��TI<F"��:�em)�H 4 "' 4, nag�$S 5����*!�refOa0t�1� oo�.e!��'ŏ�a�MG�who!8s�ir{ 1bu�>�V �.��A �D2,�NN�J$ illu��t!8is AF �.:� �7 G]�B, a&Le M�&wor!ax�+�17&F� ]!�m� t�L!ߥ,� is d1Ai���77]I�=or6.AbAZw�)Q&�A��emux)�)JI/t�!t�m"v!� ��,�l�3iV)`���lV% r"|.� walkaHto�^rJ �Tp objecTR��in E`>ps)�9�i�m2 �a�hem�J�3h�3I� �loo!�att�3ve��--I�*?]a��R�, �usx62cyV:y saw ��a!O�8SiU$2Z��?TC advi q� �x0!�(:�]&1 Y d^� �H�$(�Qe�=%H : AZ�,�!>�0�'W1c�Mb�n!N=�5�!�aqn�.�a8iWJ,1osj7swaBl3mp2"�_6es0�encourag%�mAR��. If I� ve h!�w#;)p , I immed ly �KsicnHI�''t step "6^ hort��6L . SoU<��8a��9 usI�!�a<fu8^�4. ( A�sI,�428 ) S&9�]�&� r--dE4!"!_m F� wOGet�Pg O=���#U9e�u=lyYa� ` �� , ��!_�3oc�=ua�,32O%uciRi M��or ���pb.. M!� �AD��A KqcVxɪh/5/-�ty�� + at.�$�ki!���Z�J. P+��k���).>�"� *�5�1iHV�{:���"# Mown%�5G<����� � M���w0"@9�]�]RorEj.R�iS-C|cle� @/ed)&�m��b1qoM7 -seeE��"H e�hig1gP},vulaj&U=ill�%FmA<� enga���� k [30](B*� ot c��e��62��:] zbeOB[31I532]q *� d�RK`%$�0tcg� � ��p�EY*�!E<�7w!ed�!+(2�Y-,86:"r5wa�� xV0"##� mgA�c��aB>1Er*7lyA�ve�A��Mb�c!6Vs�'uQ�"�#! Y�\� �998u�#!c)F(m&�"<@��,6� �� � ��*�0o� 7BR_�Q�!�B�s?# �ae512�=q�:��5�6%>,8 t;��j e�f���S���# ��M"ݡ�.]� � rK Vp�1of��T-!�� �&�!)� g<@ - "Ice+ of "� Ag�e#6ib … today3"Cle�,����3i.Jrm��qng���:MDNa?Ŧz be�E�E�.0! �I,"� �Abe bey�beas�Ma0SC�j�Bl�o!��5�2 �6�V"4@�\@!: ef'�3��ng& E�� � or�>V� F�U"�/�3�add]m`�2motiv/�߉G��A ��li�>!�"5S B|is ��b��q�#� =by2�Z!vN��l�7�� NTD-�AjB�dJ �"E &��2�3.�>5���b\Q-&�. F"RTmx��bD8Ze .f,6�?bou!o8 at �:�  c� �ucqG �9 with�mi��� c�!�,6p replam�!��! >- \mi�S?.ss_�4�>��ll bQe�g-!�!q�6�er�="�E\�[p!Hit**m��" �cea!sL[aA�o)!C"i&, g_/re�)1Alt�$�f(��r�6�=� Fddsu�H���e��t scaU� ll�&.c�`e��:&�Ci(C��%�d=;RxPt�pQ[E�{5�  .p-�8cro-c�=5rateg'e�i�)(!� �r�&of�-3W?me9�f7 emp- j����ura�As�΅8Ane�|emp�K�LE��� 7!TzE& ɝ�y�'�5Emak�� 2�g{ ighl�aa�3A]�)�D���6 k/ ,� %V�)T&p-Z^et quic�be`mheavy%� mu�vd�aI1 grip?.r&�Kn]pC uncomfortE�9�i�; � slip�4in�" d��&� @'L�kWel��tboots�:��:s2E blemaHA�e�expen�nE�g)�7�t"�.*:J�.%[a�6��!��!wAD {p�rm s*Wk�N6� �Aš�IA r)p e���uAv4A��C ��+ &&]T6eVCon�be�adme�oto��% p� v &�]. S�A��e!.latMGb!�nodDqwo;%neL�\�w ormal-shaAK)�V=alF$7[33r ve.4s�ma�lleng�,V3in $*�?,. Custom-madIm�t�r !�� L�Ct�`%-�-C!� th lepros�6�"/I-l�HF�. Leg��StlOi�V%E�����ab%� -�9��x��:!�� SZC[-G>�W%� apa�B�Lanufac�2 cBI��3�A�.��F3���S!xm% iaR� "W#"as ‘ �d� g#iK#ra�� d�qr aoOb-����0a u�{�,mNha' velo!�t�Mc%�mi�;�r�ey,rreE�m�dfGsi�el-� aA��d abanf]�m�� plet��4�!� I��9yD��V%Al �"f R, [34]=\%�Q�[3]Fly��af�B[3eFb6 �ii%�m�hst�FiI���-U�he,3e�E!A"v�!4�e��g�F�s##d y do� �i>%b:(H��#."Ai2�:�1s��_ lackAta*a:�&"�!4M�t�"� �qt�xref�/#o{"ref�<m�P a?."*%H� OY1uZS dS�?�aeng�/�nt"�ks!�!�a�j:< ��; 6�%, .� �QeY)a�e�� ����� ep9� ploug�-sow5�U�f��<���}6U1fr%�n&Gn�@U��^2MA+quD@y'1wY2A�!9wU*�?i v�9c�! A*U7Ep�'�e �Ua�6E%7Dod%�-�? !;e��W�$�s�J�113"\J�h8 �:d'7� ��xUv���I,.�џ(�lu� :���b)H w ���H�(��wE�eY  �v1e l?-� �(&�,nu�2d=O� as"af�'2if k�ue pi�2(.�� �;cap�S�B�T� g�V9���<e'.�;"F1,�a�2 �N�}"�j^-��a g*�N��t !&gXA�s�:a�Q��lby�pN t�QW�v�{b@� # C*�"0 !8 5w-M. M -��e&�2��h8 a3t [37W�;*'.Kt-^i!u�:N~�<tt��,w)& �&-�&�8k�*6 { drawn�Dame �oA�I O *�&sM)�_/S ympY] neur#saA�ul9!��zjkqA�d.J��G�L{�5mi"���{n vivz*vk(6�!-nwi&xo>s�\��o � ��. IJ�B a�6gB , gCD��gE�- �]di@G raft�c9|�AUsur� �!H(wine kidney�p�EmonocN�Iz%:�Ae�v���A�a��8qu_nne�!I{i�[�m �� �!��9�:� �.c,%�s c�~toN-�#d.)w��=���57 po�o)_| PC12-)�hrat�|o{m!3omA� ll l!Y�acq��$nc!�8acw9�MtN�<�s�?>=W�q�ovo�fNGF� %s�s�r,!!`�<�"ric�W�*!�gent-�7�$t!ra�'( DRMV^���.�L�?�6�!��>Y���x��D ari�J���p�Sl{Z �e�tra�WT :B� �!MMA!of�BU:F�or�iő��a�&� U.���A,Io�2:ora]^sp�7P� � pre-synap����ost��b �� mammalM^A~`.q. N�a�-�Y� E%���bi�a�ci�s1$ru�� ul�m�L bod�ZsA��:de:���.A�!&olu�. , cytosol�/� in"m�Hi�U5�Sby bulk �d�BNY�#A�9���Yri�H ��to T���can!��alU,�!0Adesi�[}XS��E�Zn{2�S"rQ)e�1��"�D�9mU"AFrh 5ba�r�S�%F�=yBN[2 0%�typ�Wh!W�Lo�`axe��Sd� I��1chu:�6�. Raf%r-p_� Y��!St��a���inWeA��T���lex3�mde�Ncmest�eeRspK; q�� floa�redMaA�liquido�>L �)N-;bilay�WF_�m���smP a� dyna�,�Vo �(s�|eqe4� Lst�A1 ` -> !� &�[. L"�s/�M  a �x" A�i*. U> jsji2a��hIt K�]�=�U�� . Ledesma"�g�v �7�5�ly-� s;Q���0y-1% M zac,us hemagglut�e5?�B���%�2-.9){ ,at hippocamp�d� [�Hse6GTl r"V �Q3q *�-at 4��w&� 2�J$�olf��8 A^}�ex �_oth.Ba�!�c aberPSUE�!�s�F^� yn$�jmgmyl-n&"* �Az�IE5>ɘM֙$��*�:.AI&a[�'�m�Eis"*!GM1 ga2Co3i12E��)֭��H��:$�_pha)pesx ����=h�Js�xM� ( HS� �j� )l�2d�<�E��%" i���Q ateg�n֔Y�i��y� h5st�)iphţ:�( PNS� 3o�\g)�+�KyA�mucos�� 8&n � 2H�����>� u�16D��~���%�� i i� {n2� CtA+dA" ar%F�+aL�)%�N �����Uva��,�B^ ����� era�sU��8{�h!� a. AJy�'l�^?t $*c���at �@�""'� b�"n�$!>!}, α-I�Q�0�X�/"M�:de{8�/{ seem�M�wo� 8-> cho�0:��)i sI�);��M( :t(� )Et)� E �o9IE��l.�WG!o k!( viA�onM�!�%'� �!�!D� I����t!�o�i���!� ���`4� �6 �3aI��A4w\&F4�"�oNG&� M(�1�y���*Z` ��~* �a��"Kal�, �?-ancho= � At>���.e�g��in:DS!�"z �3B��AJ��b� 0–���V�`O�Bv���@A��Ij5�IdHq[�dan ab�t�E��.�)� -to-�(n �^!"e��HOLHS(�*0I�-ab"�!�, �f'�8"� �al� U��' e �A:� � &��5�\�)N•W �t 4 elucid�1. F�<eel"= "B���e �2��gE�a�F������Af5䂰"��IU�#�[9!�!��ѕM e:�� ,Ag��4�(�s�w�Yc�Vz�EMSCG )M:A,n8p�TfR ) >[[� i4��&&�_� SOE �{mp[��<pML47A��c-E�is�smiT�-�%$SpHI/MluI �z �M�B"z 7&Cz2eB pBluE� pt SK ( +)_Znp�2|z�WfAf ��* -for�Zr 4� GN|4CTCTCGCCGGTGT "(�=� i- )rU,"s� aaatcc aagaPgacgatcacag aatagtcccc��act0 ctaca GCG  |�z�� tattgctgt� gtctcttggattta � ttgt�5�TAG�CGGGT� ACGC=AC�}CG�Up5e@@ l�"�Y"ni1q��1�l*Z3/i�~di5y��/aTMDqm*d�Q%� J{�agel-purIcy�|trg�z�zf\am���KmX l�!m pCR-Bln#II-TOPO�}( Clo?f�, *[�, C3�baqnC��1�V2 veri� atSZex��ec<��-Y=��/��a �X�!gn/ pML55�9  �q� � a�� ��Z enzyPBsrGI���r"�� a ∼!a0���^�|; �he��: jA`�B| �N�uty5���.,B ML68Ap pT7�1�CbU9 ���a SalI/�x Es�,$h !��un�$-�A���o�UI .a%9a� PH 2%T!:��GS166���be>�gD)],V,btivvir�_�uh�t�0Us2 4-oA�(:87�\!�"�%�m�I/HindIIIco%�v�PRV 165s"т�,żm  /��%�#Ϗng EGFP� >'2 ,a Nikon EcligTE300H r�epifluo"U�M�_~a�� suCFA�WZ6/`�pl� ��'-7re+�nsn}!*na (�319X�+harq&�&�3a e> Us9-a"un�3Hly\ Xa d�V4� ed)F�* ( m�� R!meYtA�&= F � Weg �q��c�! �d��- N-sC�pinu%1Ah�E>\ a'&��3 disulf�sb�Pd ����e� acy�X�e�ele!Icod iE���jS�6�+e Q�5cM�8-��� u &�k��:, La Jo#3,��MyH�LnoJ pML8}�A6E!)�s!�+12gOͪeF"��shuttl��B�>�88*U6���b�N�s$�m[����!dmp w?ab� �V��e^2����6 �-!.qfchaQ& �9�*.:� �B(��es&*^ "$�|Xl��e ���b;� n bl�fyޡ lys��. Antibo":�����lude:�!yA%7fabbitqiserum%>S��D�(�h; Q1∶500�WA�� by I�#�!W!���� K9.K10L�!A�!�w/gen�'Rbō[ xz 26> , B |�� �g�JF�&�!��UL-��M30];�-�J�mH�A to�"A�1E��FiZy��4, San Francisc�IC A�e -�.�Hd �a� a ki8if�(om Thomas M nleiterE�l &KAlexa �op�!oE6at%�!��\�d�=MU�artube�,rai�����k���,AL!��7)V��ݔ">� ɺZ RA�B�QNs&&.��E. Bx"0wv%� a�*�a 150 mm�Yh _���� (�:f�%����o��µg/cm���b02 N asc�)��1� )�d�2!�wa��&{ T�2�8a�i���`M�20 mly{��E O(0um ( 85% RPMIc�0% hofI$, 5% fe�vcܣ )� 2�[�=A% 10:$un.�TC"k((� 80%!'5A��as spliMI �tri�.Be�@< "*�e�5� plunR@A522-gaug�ed=d;S��clumpE�fA�iAE, 1Q���su�cyU�2.�3��re� ow attach�:ni�A�t37� inc-��T�RK�$ul32�fN,:��6�.<�UQ>�GU2f]�(%� ng/m��)�1�8ll�v> ∼3=�tC�5Ke�onz2�^.y.da�  12 X"CA��U�}�Lf i�'Zvi . Uj��0("�!h#-to��30>�@*+"E��r#$wma�T2A2.�&�G (a Leica SP5 Ian HCX�� Ap�+at 63× 3 NA�0��Ru. A ?xqplyU�t���io��+�,��5-µm�Cp� �fqEy %_a[A��EA�ɬ��:�a 2̂oPS!�of 3 stac9!'�P5S-9a~M HEPES%42pE�9�a�E��:q25 mM�w%�mSd�(MatTek Corp`$lass-botto�e�~���w�.%�&#.�e/�  9�wSP�i�CoBa DH40i >�5a�!%S ��Waru. wru� � ) ru� -ol_ �V�5 (!(488 nm lase�"n ���l exc�8o��� Ln�wb E�eM0s��H��495a553g. Ima!�%mUm.�A�5 air�!it�hpin�%Eesca9|,at 700 Hertz�ll fia��cssembC�fDdobe Photoshop 7 .E�sMov�1�|%a�i��J%32j& a( N��al%�itu�bof�x�Flo�9�t.,by Opti��™su�?�Sad,4��3*�=x e l~ $AZ�=# o�:ele���R exis�t�NK ��W�XA�uBR�A PRV-��ed�a��8O�n}S�=Jh�(.v6)��܅�6d J� 2107 �!zC�{K�| :"~_  = 10��K��B�Eor#At��hǴ>/�A ( hp-b, ��&���O ���� tube:� twQD�a4a1 -�g adsorp!]qJatV �� -xr̉d  zPBS%Lg e%� roomKe�m!�Zj}���e i�e1m ( 40a so^",� mM K�13��� pH 3�)0 inA-v _un�& rbed) ��=� � �����,�freshq�%�: ���1# eturQ��)� �At%d. j�5)���2�scr�I"6�nA�froze"�a22LSiq �|Oze-tha�c*����80°C/+B )Yt" 9dup�-on�!6 �_2!LVij- �"G2e.]}& �t��-m� ��1i\�>C)4��E�A�a2�L65,1=�m�=!K>�������(#�u`deb�MF�9�&n�p2�%!e) a�~l�W� -A[ cush!� ( w/�j� wo�� SW28���!q�E��-s��.� n >roAu at 2.�a�3�^�s@ �!# ��T!#�_v%� pelle �rvq�;h ��bya� one-� pul��� bath so� �nd ~�Cpe1�2ZB�A̧6]��b� �9&Y�!) 55ti-+)� �0i"�>�00 µl�2c�Z�GVP�a�is!.�1��zO&eady-�5v�� �so}a��� �;0�7mb u;or �,� !(�� >� JQQ.!�^�-M�2�33);&�=173������ge� �a�sulI�y�� boi�!o2�|5�?{ �kdodecyl ��>�acryl g�+.�i�5�: P-�8 n�"�6*�!'�,iX�1J_BK�gx�%"� �4an Immobilon-P&�.�akxdry72Vatuza�*�Nr'�=p e ( Lab�,o , Kansas C�C,� &a��{m�;M"jVTu�Glof,�.A�( 2% b6le%album5n TBS (� M5 �& )�W, x �-20e1�q��&�A$15U%at RT� r�0a�y� diluA:in�BSA-TBS-c�Igz� E�%x-%��M1 fe�"@!biotinTrt�$ra toxin B�u�� m+�� A��(&��1nm�L� p sl�)�Aqu�&ly/)a0 olys�B ,;�[�vP�aD��air�X!9h>�. Direct�es&G�} ���ve�#&��ro�u*{�f fi��N >Q8�iko���%-H,.g %R"�3� �"Jr�" ER_ ^0)�PRV& 6� *L M�B2$phosphate-���ϡ�ANaE����permea�=i8AD�j%�5%��A\"$� }H` �d��E�R���aG�ash&[R , 3%�5%��,��$K�"= R%Y )ȡ�&�"!.�. Nex�8 ��"H�JIFP�!or�SF !2�?N !�np�3'5��:F��Ar��-6Z_�*�a~ju�_6*EXa�/�����p�De+A4o%# rh|ng�P�=�{�"� �h�Q�#sJ�HU%��;7��n7�:.�at ��da�. R1]5�(prague-Dawlp�aEK HillPLab( 8Inc . , Scottda�Q��&B  5� g �rypsi� Wort�Da�B&�EHE��,T 2&�� mQ;� e:3#neu�=1{^�k%�Br�.�)�-��<��)�be�am ���A� g�Aa)��""� Rre2L�(d Pasteur p�e�UWA S�:�Teflon��A�.a�7 a � 35-mmIL �I�� sh c�%2 5�!{!�(poly-DL-orne�X` =��}in borAɌ�1.�d�Ose _nE(*� !e�V�is�`�is)$Dulbecco's�  &�RJ #N�!�!;z%�$rB�%�,5o23�o�Vs a� a��I�=#ug&� &uU µ�� mitoqL$drug cytos!�ß-D-a>SnofuranF(��CF�N#aN4 CPnon��� u�]��;&3T4 ��6�mai9��a humimq, CO2*I�,U�1lĠee  C��*�Xanima�+�Xa�%ve�Y� �#B"GOA .C�J!�Use Com'ue!�3Pr�w��*g�Res����g)erAE�`169�I`�W��8J�7^&Ğ��A�1an2���Ac3h� a=a�=oryB�g"+�� � Welf�Ac� p�~ law 99-1930�����m�bHJ6h��]&�&�.��A�-�AT*!ire�+Ai5abݘ|Tyler9m, AlbertIjCanada� ;2�ca�2^se-loRu�( Dow�%(6�^ �+p  �utoclav�"�-b[Ti��Q�R �bmho*��~I�2N� iy�"� d�oed; 1 *Z-�W?2 �v�va & rak��%!"@{+6a�~�sp"f groo�?.�$�&a~��+"�1" trun�hypod��c[oH,f�y�]�,�� tinu0'Kp�:� %\!F AH]�&} a 50-�dro\��*�81%:>�Dulah(�� o m��er�%�Vn T2Je1�9li�}za|�� seal� w# �pvoi# mois["�n�b�ʁr C�tev�a��th"Kj��o�8� :�-m  �#���UiNzR�"nX� E�s[`�6F":�ll\cƦ5Su�T����/tight)?"�K.1�eM1��et9�Zk.� ��UH�n�`O$!EIrd2�HE,aro"�,��XH��| onr��� S��6������E�� ��AE =��E!��5kV�@ �1����Cekl�J�(AE��JGeF�{f�kp?q�48��i?H2"e!MeN6L1�6����n #�^ �32IU Sejde6&"��@!B.]�1s��?he6� �w)tal6;th.�XF��!5�\v�*h)�E(��U)%}2�6- -U��6)!!J� �26� n�NT!M�.#�1%e��I1K��n=�6 BeqS�L �V��,M��V�ݙ!�M-��5�)�%5�!��/A �2�i)���"*O N�(:A105 PFU3I�1 �(�7 inoculum��!d"� eA6g+ ��-��&� �_6� K$ ior%��+�Bin�(lQ#�EA!(c#5-#2o ��f��&m�b*�H���j��p"����6a^a ��ti�0��3RmEC% poo��� &k%� M% �����T'*s � on UV-*� Af$���VU�UC2%��. %�lj�E� �[ *"-,}5(/BS�,Y��lif!T):*  "off!A>�2=*%a��\(Wx��v�, � away1��7PB �(��&_I�-�H&��"� of�saJ!�-1i58 /SAPe�I�\!E�prm J��AE{&�4a_ ou�#�a.�)Z& �h �(�D �VilA�9 ��2**G�a=zH�2-]&�' zQ�kin-El�HRS3 sp�d�~N�1�4�$ .V�ZJ% cks "ժin 1-3n4p�ap�+!a�%�!�e��V-�s����NAB& $8PP[lS�en�]TJp�Aeace~�:a^EoH,/[��is�86a�inB]#�8us�- tߋto�r��&�aa� _&�;A].��v�� �b ysio�.�+s [38�0[3�ZA!>�'Y� ^� in7� �s|xEI4CdN��e��'�,�5als��!��Fe��r-k�%�T5e] �")�F�!Wt��>v�Vvi)bsal�.7a�!Q��us� iMes�sȏ %ew�-��1D^7F ,)a s S3��S?*!ii= uA?"`+ ioF�g ransA�YoUk1x_s9M0���� `+y] �H�{k��|�N��UBpi2?)f_ [Lw�"�^pC e di�� q�"“d׉eg_�ofF�:�5�kV. C%�s�1!���I5�.'K!8�o\M ulI act�ID�*s�G2i5K.�ns��&Fi��Ũ)A� i&qX 4UibCzs|� NF_u�bg�Fr %-DE�U 6.OvZd&/a�%��yg3 lf�.}EB!G!rA�"2. �%�"I Nn 1  anpnacA� ���!�B�(�a��llMnQ 1 .� �T�Vm��[�VO]��EE" "�3I��-B!on�$a z&f��J�@!�AW�T07T� ]�H& Q?+� ��a,&"11"r?)X2BR�ll-�Ie��KzBa� assay [33"0B. M�'anGT� �>e�]��n�Ǻ�*remai��Q6��(-<4&\>;%e��{\0 l6s%l!��5%–�,cDS.� � h �o��u^%�!�%�  G:�h!�e�fO$re� Lr?R�>�osI�nd ne�$or soluble��s . These findings were consistent � simi!�Pexperiments performedl�non-polarized swine kidney ( SK )%�s [18] . Surprisingly , PRV gH was completely �ilR�)'TfR%'�,data suggest)]�!��a^�N�!n��XC+gE in���irUn5�k�� ells1�e>ma�: ˁ}icE2�v��s��al ��on�Itoue�!�:� is dependA� on b�g!U5!E gen%�duA [15��165%� Dele�of�6result��reD�of �capsids� envelopedYV�ہe-�subsequ�2Oan�a�e spreade �rin vitroj vo [11�1755A�Ui{scover��eA%=N�%�of v>�we teswhe=d%7ng%rgE/gI%�lexA��!�a�ty[�!�e� ���9Qebym�Uits:to func% properly!.6��port ..��)H�顿99!� mutant �ede8�g> IE�a5��j�.2N)had no-A�dF�Ɖ%�(�04A ) , nor di# abse�c gB (�(� shown�8� �A�3up%$�.a!�haA� intrins�!�I�P!is:!Tlu�d� a�m�!�Z . two majorm:�=}� . It ZeworthyI�w !@ berr!�I?A%of�, gC ,� gE!�%:5 Us9-null1�R% zw4 docu@ e!bat�1"becomeE�9�d��th�$phosphoryl��due�sigiE��G [56]–[5� !�con��s a s9 $d acid clu ( ( AC ) reg�wL wo sa�es)5are2�ed [2��* $a di-tyros motif c al%�.], � ynap: ��U. To exac �inhibi%��> precludedQ��%�z u�*\�a�162.���exAuseE� alte� �E lackA:a!Yic5[-T. ��9prB �l �A 4Be�� still�F ���( desp� }�R>T(a��( narrownessa!<1ba�asa�,to wild-type in panel �i(. Taken tog��,Gse�Ks>�is�:$ -�w��.Nt r m&�I��2�<>� statVX �in��za�_us! A� idase ( N��Dhaemagglutinin ( HMs (�*%IIJ) )e^o J�/ ���p�.�� .g�apiavsore3� s���p"B MDCKM�[59�B61��Im��ant9Y�o"� do{  ( TMD )Jgprovia�<9a��:���2�� , [62 �` � ademonstr!by swappq���V�a5��n-2zedB� )�� YAY[63!3TNn�norma�!��� basolat$sa;N�� Nef� F�1%� . By��trastarR���heA��^��-��� surfac� ,l{ > y �"8_N%�. I~reciproA�&��h�9Y�replact (R�/A.�s�chimericA�A��g�ly3 ; yj2�)s��IbisT! �Y de� Awp�cle rele�4���NN.employHapproach)H���z!b� ��!�>�v�E�A��.��_a�O>�f�)+@26 !�o�s�� ir%���� ��> 2yd�B�Q�6s(cytoplasmic��,a�!>�A( �D3 � ect�&5 5���is� , kn as�32DA�ic��ckinetic��rc, "� PK15"�. Fur� m��0!�-��_��abund��M�I�2\":!�mig�1s Yslowly�=SDS-PAGE!�6.�"7 5- . E b �che upsa�mcdow��eam"�  Us2pec*�X sA�uishame0�%��J r9 bin %inahe�al�a �  E��]�De�$on neighboY ge� .5lis*h��corpo!B�tohi<9$� , alo��, but� UL34^chd� m��primary-�vi��\ s [6�The l�Mi{!1x a���tr0 � pattera�� beeudied&%� pr�[20� [2| To�Fess��: A�"�a"�al derivA( i . � 2�an egV us2��w�we= s e steady-� 2$24OnsA�rn!� e�!GY(We hypothes+E�2 �wouldIo��2~-�� A� A�!�M d ��A� cessAG 2W to ainuclear�E� �%�>a� Z/�!��qresid�.ptai�ad���)V>�[66�u cTMD�H!6be]E�er!,!(exe%!'.���: )� fu�$to GFP mim��y2<of��\��M I%=,Q�e]1� e�suaSs 6�evel in S-.*� ���`��-�A� k�>predomi[ ly �A�B M? n5��]��6�� Conf�\ image) �� ����� fixmPs�,!] anti��+so!�E co-���-��F�.�a*oug-*M�� slightly���us�m"�A�i =&�).� ���M;{��53)BA very�#BF. NA�wB-|gacea|&j�aTa����N a��0�&ntgo� �B��!MV�F*�+ n- � &� � &�V�do�"�\ eg�!be� heavi:^!, f0as ob"inQ�� �( seeCs 2�R�%�!�6��mu�* , e ia��jDu�7Ax7I�Fk#�"�ZZ��0took advantagea t�amber ,J�!Usystem ,37��Dis"9SCG 8s9 p��X%|<� ) c eAB�A���A:� weekO�7� D �. odA;x�� diri| betw�a ���groov� cros�e metho!�ulo�M�W !8C( N4. A monolayer �d or.[� then1 op/A� Z N5. CN�MKSWU�,B% �� o9_aa-&manner!<nqT�|����$�amplifY'ɰ� �Dia��i�f�-K� via silica�vacuum�sia>�barrier��r�#,-�Qsi9Jsol� through-� emanx !�oE�=x!e@ dX=e� ɉA�h�&��yNF ���M��8�G(��� 160 (%���j � �P -I!ofZN 7yO,�!� ��"T�H�"�;.��du<i�<� nu�0e)�usM�B�,1to cond orde21 59��_dra*#%&#�RV�-b.(=�E=�,� duc��Aldian titi�� $2×107 PFUF�af)24 �! post=z����:�h�%�(%�!�)" �to.�!�n�#ct%�1�5v!0prܩ|$most dishe� Howeve�i�#e���AV�&�(%%5!%�e iA�pret C yiel嚉8i�' Ul�on-to-ez � !tf%burst  Aga`Aj_?7is e�ly 1000%�A�N� thel�) ^qcam�fAX!� xtrem�C�$y�.�/m�. ik� )%�;le|&��$d!66�!�!�Z$VCnoF 5�qW-�a!!3pheno�(lFrre��w� tin��%#ݡ� arge�&T#. W���^s� c�� -@�!O!B,i� 7virtu5 �!�}h�s���Hl�Y�"�a��\ does� � ans-T �Ge�&n� e:���n��B�!-.�,->�I��!�a�~3ofŴal���"<"Mu��0 a��"" �nb�r!��v/)&�"�Fwe� � �ed �B�*"  ua� a�-� fi'tibod�& made: (st acetone-%� A�7s ))��gnizesI '.�*�d @#9[2�"2'!Vwge# >�Dm *&m6Se�q6�rQ�Mof*�3� yA�� 8 , fi��column a}Vi!�.�e>��a2��� ���uqit�N2�2�s��6�n�A��6r�"I b�#,munofluoresc�!B�� ^�!�b�i1UA�t�n� �)twork!)aM�= fљviews�� mit!�br0 $ illugS 24.2!�*)#�I�a7)�Z��� �k7 )��FM&����N �$N�"!;>�.�,�e�b �.�-%]�o� Pau �vL��:%stitu;a����a,&�!'�haXor ��!�{"�,6= �!sY ��Q�t*W' �&D. 6/2�u&n<�:�]rgent-=sO"�M6�.~p"�*�"�[�R *�0&� �u-ss@.�#aBm� A�.�f 2�**.�[ respe+�m�AV�&w �)���b*5$A $.�s*�%!gE a)!� 2"W-�gQ���.M��ofeau2J0��Z�cyx-)XB�-in patchAGofE�: .|!l�co./! �!*G�$e�.[1euo.r-&`��>�1 Y1-)9>�]���/ ։)�6�A4N���  d�/9Y�= j dF�requir�$���-�ed2�(( TomishimaELEnqui!unpubl d�vJz. Lip�3y2{'��a�(sis lik a key�p!�q� |  .v%Y) a ro0or2��Fr,alpha herpes, y���&fmammal�X1:� � gEh��  h2odX!C �+�oA5)�. gI � ,!&�n2�7"�J����*s r-W�$p� a mod] ���,:+i�.#�1�R es� �2U�9��n!igE�,Q��+.�-�e�-Golgi n� ( TGd�puts~�/ assembly"�6�-6�A�sw o��t3U�- > dec�a�!��/�u�55 )�recruiB�ma� �~ s%*L:�!�lexY�!," uEk q-͌,.j to��K� a%.�, may �he pivotActep�e*�ci�/>� s" .�ed� )i��$!�BH .; �0" K "R5%. P:�1occ�96(� w r(-du!�&� 10-amino-�B!$�B�se��&�}lan 6>e�7� B�m�rat v�" �-o2�2�i_�!�edj� U=!��*91-�428O !�MIu4We�VcurB=�vesti�=�'s61 geNR!x2{coincid-�E�.F��!IGm�![d 2 i>2�&%!$��*a!�7�>i�Li��no [(er2 .&. P�\��s6?!q!�-u-m}#�;04m�(3homolog�� tropic.u Y in�3!oshuman�hogena�� �"����u� HSV )E� vari�S a zo�4�d ( VZ#E=e5aIS anim� ab&ne.� ( EH=a,bovFB��;�c 1&� � -"�s D$;]&J6� � ���[��'@ i�� S2�.M 2(AS"� 7/1m� addr�s how!��+*�Bs/����`J\"�*�"�s)� �chanismBl7.(#A{>�ai� "repiW�8s [74)��(Itٷ�se�"&� funda���&�i���gE��B3��a� -plaque p"�on MDB�3�&&J�.�.!�J�7Y���;A��as��B�(~@B7)�aե �$�2�o�4� a�[gB�ST5�8]n!��>�.0ourJ  ( CuranovdZy"�� It ��-igua� to d{=H !oB@��� � bmin�m(�3 ��&�'E~1"k4(��/A<���� >��)$��fuL0&/��s �;t FC �CgH/gLV�e���eQ&in [79]w-DB� entr>to un:�,E.>>tissu"�D [8/A�%IK�VV�?mic5|7D�gH�e!� �� gE*9�%�9 appa� ex�;a�#H9� �u^# ��qu5 �C&' -lin�:eR�Gon puri�!���K.�Hat-�-oligom!�)�s=!+gDEc�'J�D�an�z h"2A�1�#4Å%�AogH dL�{6j t.�be  (�mT c�AA��might� �z*<�2� gLenr"6Uto��, lea�ma3author8Ѣ7 organb��.K �"“ =Y0�)�2!fe,e�gB�[8fOn31pl�&!�Q%���a)�gB �t2O.w;&erMH� (ѭ!ztlofE(gH��2m@to!� ��?"�+uted COSe�s [83i�}?%� feas��m�?indeeda��-�Eɀ���%3 cold�_�tooEin�priton :JA�CHAPSedre�U��% reli�%��a,r�Gz����!2[8;H"�%so�L!\I���y 2�d�"�G �.= by�li�!*�:AR!8-"8�A�sIim�0!unJ if1�a weak&�Ah��or4-�aA� trueA��M�a�j�#>T.P M�sI� e�ah� IJ�'/&� �}!�. Saġ�5s-� f4FX�5�seg� A�"O�A-7 [4 �< 6NH:a,CzaAuL .�>[6�w[-=[�wami�>[59�5�<Z LMP-1 onc"Nof EpsAI -BarcC� EB= [8 [!B� i�!rM(FcγRIIA [8�i�IŅF1Se��F3:%�(X gle2)))��� s��%�2o,8 !��CsiDC�)A� reheE""YK�}U/�Greveal&�Q�%-�-e[/ � ez0�at�(8Ero@Cng � Az� of��K7 ��Y�j 6e���bD cd2�.�|��A�E����TF�(�,(iRK udy f��h�*,shutoff ( vhf1�-1�>. .��el��!s�� �"��*��7.ɄB�XHu �0o� 2-, ,"�/[!e�][[� } UL11baY�/<(a myristoyleVpalmi tegu�91���gM%�2 aco-+P[8� ~56H-g ~�7-ancho>t�C.�B�8},RVe,%�* ��-i" @E�e�s;�p��6�� volv�$�.T5in!�-2���,�*s [90~:� *�#�T�u1��}�[e.�cy�?1>N���undersc"�q��Y.v �?bi<y [919��Two�se�� �be�-cg&�,��j`^�� eu�3(��& 955 z(� e��an\$�>쁕�*Mly��v�u�M�� !1m��i0$o�'hey{soro4�E1;F/.R���� , . RecM�i��W�v& �s�&�"�+t� 3Ow)F�H�gE �Kng1P�Fse�� ) '4RV�K!Na>t �<)b �s >eAb!��"�1�[12���+�N , [9� �ki�a�conceive*�F�c5 � �%��un`/A+!+*t� I.up%�G�a�Hz!65�*IJO�R:� �ScVom-F�,2�"�?9�EnoA e�- m��s�CEL&a J�V�P � Q F���&IA��asV�aS� )U�)&� I\ ��,"�]�At �.f�Z� &�%!�*�(4: FŹ��H�xW5&�%O&n)l�M�>m�'i�AZ>-Y Yi�6sC>}- v�ZA�N�� u�YC�Kz 2��Df u� 7(�e i�Gc.e�R3u�!�*�!�)OfyT����$!8���,M��s1*� s .bGe�Dj e�G_s exhnM*L-Yic�5 ��4�*�benigE}* X ,so-q�o6 E geneOG�Lt clin�1��:�um4s�b)S( �sE�A�dnN�&r [KX�CN Wus�Yi tyAadru�rA)es �e bud�ye�0, Saccharomyc|\e� siae{ how�OO X(A�b in� .�c�3Usitively% F� acutat�~I d5Y2�+Ae!!%!V chem%perturb%�%Xomb�9E��;-R9pu�5� ]ass�Yof-" �^jH!N^ ��!%�� B�i�JA�e� $ic AMP ( c) �s ]nKT 6i<oQ Ras//� �l:A|7K�@Fw/ d L����nscripAb|Z!Msn >Msn4 ,il�9�b� . Lou9%���)�`-j:sl$-; %'n��!B aris� Dn��+E�b*�&��Y cvA�fano!B!mC!rkH�� endaF�%��/9�-@’)�vaF]�E9cth��6 vidu�)�W��e�alp6`�er8�� ��fh�*!�� *& s��A��H�# oler�&��linevital)ed9e� ��:K� s eacV9�(��8��� B��Iaof Tsl1!{�1uni� treha* synthA��� ribu�.tV ute-B�) a�!�b�byX��gI�_iH)te'ObyM&n)�%���-perme�E�fog 8-b�- a��Sor H8hW�Z6�J� s� vival!*F���%%i�Z:W�Jm��!�i%-A��s.PE;OsB>F�&$�!�gs.�&�#�X�S�SEc ���xJ"]:e�*�>q��i� 6�LA!th�6�Qcsu-�6K! 8'e�E�A��0qf�ut�a) �.benefi !8�� rp[s��e%h ��e&oE3bw�"7 posUmeap �9ibet-hedgAѡsE��m aMaD themd+uni�QQ:lea�SM '. Fy�t� a�i�+a�;@ ";�Us raiK!� environ� i �0QVdR?��a�S menonN�a�\ty" & orfF[�Exa�#��bq8$e&� �u�0�/�\ ��ene���p,Qa�I��of���Zrug9gs [2–8[=�Pdisplayn�%�.�2�P �apS �[9–1N^ 9ra�& �2m��us�#i� fit�W� �6=��c�%�U�$ evol�7dLa"Fwhe2� fl2 5Cun��,A� enab\a1�&~A�a)-sa7"c , ; 14!6]!�%xple�per�8�4unfamiliar nic5�urs�<o%�a��$��1" , 1l17 %�I)�� � mole�m&$�Aa( b�/pooD/$ toodQ�lucid�-`�c.� goal \a�,it%�%�dur^aLgA!9%9d s—iJ��&�0+2�c���—%/!{�$xH han��]8 �&ddde b�&�2.Y4=�; [+&S .?]evP VL a p" fulA �%��Ty�;edbs�2 to�[1a�/>Aj�$u!1cl�� lineM[2�(24Y��!�lsOa *- rtun�Rc5j [25–Q ime-lapse��scopyg��colon< :Je_��I ����gj��)���sB/,�=:� a w�Nran Jk-sA���w� &3 aq o-"{)�H�.we"�/�R�0�a� mpha�C�!�� i� ff"�S�B%�sud�. *o{ �V!bx|]� ��cx_'/th�Eo makB1 �:助^RG.A'��.�� j�r=C:�e&D ![� ��8 �j��K�FJ�,'�r� �� �h*�)~S�DA th��J�A� e�%�*� � C6� .�&� �N?4��hR� -"� $L8 �t%XZ;�Bo�` !�NJU �*U�,6ofol� 3ac d�8torage carbohydA� [2e 3`U�R}�!)� � v�6little���!$ much� �yn� i��ɭ$l�U gtC`!ema- with��0�m*��C�"a tsl1-�)M.KnQ-�9..��!��_eis� ic*� M �Al�Alnece2 .� !� �y9���";5�!rNs [& , 3��Zk�maC�x�D��:EzH% ��" ap?�#y a�a-disI,�_`��yqJA6�6 he# f��:2�A �Nn�<l!flGEb2a[6�3�v&5�)r� a� `^I[ l�7��j�+ �Ml0�:n e�g9]le-P �I�Oef� sou"'���E�N\ ���)Jb\ in��\�ȉ�BPst�]ng poiep�#h�g*�7TSL,(Waso�T%a r (or{ �7� �"�:fUm�A?� bd x:�c� dG � coord��;Jpi�b�'��. ��QE�3a�esKuzwpa��tB�A;��-:� � -�CAB�^ � �(( STRE ) el�TE�pci(%�or�_�f s [3B 3�a�ak\idO6�a��q �: yc^avia��2-_d�Y[3� 38]� �/`#tr*�*��set!�!�b�5ce�[�7ylyl �  Cyr1%y=2�p{$� Pde�B)��|u*1E!�Pde*") high:*[3�64�6!wRzJ�}s � Ras2�GTP�eeex�Ain-bo1,{GD"u InJ�ѡabu_# �ppre'(�5��n sourc* gluc1@�=GT.h7�K@.2�Q-B= ase-Ej� ��GAP�$Ira) Ira2�g<�) Q� !?, � ��a shif� !�6E8�:��*� 2M ,fst �sI1vE � D "�[4�34BcyAM�m�a�su"��,�*ev�� i)a�$�'of N%�Qcataly�BP enco$ �-%��?�NZ TPK�TPK� TPK3.�!&=TPK 6 is lethalP e�,/nl yjSN"�i�*!l, ���E�y14H&�+ub; t�oeci� ��Tpk�pk �pk3�+^� �overlap���(�b(!�lu� &Y metabol)aSm�!f�3v�!T1���^1�/k).�ab�,te [4A4�A��r�les:�� �7�F��b>t 5_}=P/s�) ( NL�X!E.,exU%&E&,�A W� Bn�#. I` by bia#Ŏ2�towarU,c�d [385���nW� �=by�z-Qat� I)��>;���!��of �AOun2�d%F�is���%"�_�V ��X6La�;Ri�[46–4��  e����, �spends_ �.��� "� se����Br�I@\)� e"�fa� � v0jov&�!Fou�heE&� scal�%$|��sbA8�6�tself&psR|!CW�+$ E'� ./4D�?be�� l�'��!��ionship"a.���<usub� u�2�IE4���&z�9a% %dQ�A MSN�� MSN4E�p� ��Po1(^$on7N !n e \Esas+�� � g �$��FM5) [G K)n !Ez12�F �aAb�(�he��[4�+W�Uabove-&<��by��JvyC�Eo1�&�I�"bR.�jKun H[4��5� AsN�eT,2X�4lkD^�d�@enc�6��@ Ɍ!f.�fc�ani)�6Ahyper>�ie be bloc��2�Lof�[�2{ is�ult���!�en��of2��A�'D� a�aQi�Ri�,sM kiq"�JK NoneA<es� be� e:�Ijse���&���c�baaD *  RNA /`?]ofF�q��%!�a�7�N1�x mild��P�-i";��E,  �c�, monit�kUx^R80� "Y.�)["�'��a p�6.X��2 [5k9Fur 6yq��V )�x�-�?3%2measu�PE6\"q!�hio.�b �[5�Sw �Z,)SO �P| co-v iaW]�2V-�h�BduR-f PGMaa͙-�2�bſ,��\.�e!%�;�6f ah�˅)�e�&mg�$- Ch�� dosa"A(a���-�<g\y :�nd�,_�zh%�n0*1�)!� > �R}&7 Wy�� �)e ��C"�l{!"���QE2:, -<3et�"�+:`�M� exis��taAZb�,E#�e..M��.i�.inAX]a�M�~!��:4I*�.^���~6�a�2 0l2"F R�m3a#,�jor��ZasI��[� tic�|F6�.��ss�9z �>�o �!�^)B�� �1%wor!�t � quie�[< �O��+�G���tu� ]�u�fey�#(�'heVQm�,��w�LFlB�,� 1��.$!�!~2*�`��!:�, [ W~�5n�Fr����:]�ve-�%V�N�: /&O/>6a���n��deX!f��spi,iS�EDNA da�m$)�d%�(��@� do� re1�b�ņm.�K � �L�i#!tochoE��GenV ,a8� lo�(!�9J,>QU W񃡵��6>��[5h4Bz 2Q1��"�%a��I3:T / < 5d"\{� Wc{B�@�u�@�n�9�3*0 , d- }R�llE ai�y��&! � �*�&$E�0M�:7E�tXR!�$:, #"%�0 . 5%� 76% �yEƆ�s"�a�ult�s�`&*�\ �agz��*A< � fA-O�e"�D�=p( s �� :s�< noi�!^  )"N-���L�<. �)�DAu�� �f� cmHa��E��)%0�A��b�*tega�ng�T!7�-B*$V1 &��itoTraC�RC MXRo��aa� -toxic dynat�^t*(=s �"� E 64i&l�8� po{ ia�;6T wO="a{* rho01-�m�a�ti�ckgro�Is� !9���`�!��] � ..`� vaE�:�$Nmm,�<of�"7i�8n�}%' "%�HG�B!�fi�*st� �>M"A&�gt*ū2m-ah�C��[6�G�w����QaA��eρ^��� � �W�!!&~2:!� !��3*l . Fg,>�)�e(fe45q���4-F9 ndow ��� h6� �bA� � �a�er� of��`0of Rad52 foci5��)z:%�'��-.�1W�P�q�!�top qu�le�f-�w��Bn�7�4�+,�a]�g�dezrd59�he"�45�AIw e�M p"*,�&�~ 9�%a�ars�U2 h 6�&c mr+= bb#&%6`inf2%we&5~.�B" 10 h�m�$�&S�rpR���triggTU�>� a2c |.e�"��,~srac�ZdIQשCA�Y�� 9�k�st���I��7 9n �Smakc�Yry�Q"�DJ�(�&oximatH$� 1% YUft�*aIu�7em�ed:��%V=5%�-s�dy I���/� !�b, J�".S�ch� 8*�8���~su���� over,WJ !SiodF&8ta�(��V61�nd-�=�� is�@�c�&JM�6�"U �YRR= .:wao rect�69�!^�J |� �+I_0 cJPl ;;��d!��-&]1 �QofM}�RnrR1a#4o�#�����8 ribo� otc.e"�%��-t���4PgF$a% �#�`� en!�-� s5-[7n/7�xFvTIng�D rM� ��h� co�*&�).2�)]=!FR���K"r s@?�~�-?a?�l.-M�pKE|>� �;���2�4I]�[7!�a�.2  Q�� �7fz�;�upl��1%�5&� �� &i!(2� Yiratax�6E ��E%�� o`�o �3 tm[�U)sR��&��<r=�$>�bi�,eR+, enzymn n %�chaper3#*p[7� kQpH'Ai&9%(B��0%�-M0�ea%�%` s��~!V*O��!y&�J"�$, exac�l�3$�KAGwhy^iA� �or��#�M. 7A���w� pG�ef�,E)A�� !^�a��est�6s@�V ,� *4@vP�� Qr�n!X�6�Auis 'o!��4: �|ba� �/�H^X�e�,aȡz�.*�3Xef�:aS-k7V� tegyAPe3�'� *P#*a �og!c�e�g*�f I ��*F !BrT��Ms��:e��-Dt� one-�/punF1T p�8>6&4;5tad "�" 2�=� � a�B�;c� re�p7d�Tth:a%��;1��9s �aL7U�ed� .`CF�0�[���3 .Ta 2�Be�brief��xp�3\#�!�S &j;�harC��$a l�!^Y-I!��� ��uA� ��orm!crw�{�� ��>! �h��ursk&k�($��e$l.�R [>�B3I�2:3�Y8V�,�loiW 1 of>��aR%�bfkGA�� �navy le"-���l:e�A��!,W G�,�k 2B�! � otroph�ba2� FY4 �V�2��1�d in b&�Ɇ|)",�w<�:�"Ul��le�nfA)-CQ]+"��>n," �y�\ e�ueno���+tec"�&�&� *w&�� � � 4��i�Haux5C&��O�!"�#��%>Su 4�cnfA;!keUa�T9�4Y�:�Q !,Y�5J��R�\-o��[g�>%W)��!��dev�� B�AK����Rya�:�!��Z�(Ias��!ed2*MQ�4d-&ryt&�"�l!Bn�6)�ir�.� M���� W�b%�M�<� �BB�j�%��Qa(%a�%&�n�I�one�)He���jw�F��d)�a�FO%�!� � .�2!�*G,2%"�&���"K���id��ed�M�~n�Win&)�� F�ab�%dik.J6BQAN��X+�2 ��%�e�n���6=,ҩb/ F��B] �  �!wu2��X!l ��g�A�/ e��*tis &���!�E�� E�8d>E���2i �:���of):����ԭ�K(^6. old &tW1n.:=�[ ����-� %%1����P=# . M�%�R��v}10..� �bM?st%�� �-�� v"a�6�z�%&b�&�Y&�zB ��">g&�.��$ ner-F��or�X��t6�6�%5n0�Ue"la5  o�3uAI�i .(&T A��:m�ta)J�1�ly~Rv�`< �oA�t���i��;���0>���!�Z7<m�&O%B�EYlߐw2�u\U!�_al �HA-e��Ak ��A�-DM� �I�3A�.""�l.�d9of%b B!�1=�s5�]�5Pl�NQ(R�P=m%e�4�Cofz OQI tam!-q�F �f����!>)pU"�U. I�Pts��~o�nw w!q�s.�Cfi�$� X-+�`7if� N!� O"?� �O� L53#ayA��b�%� < �b�!�a!g�V��[tN���; medc�X� !n skewuI�2�E(/obu� outli�!��'oceM-/4-in�nt vc��*�i&R���&� 9)T o�2�a�_=Efm@9 !�aa�� valu�� �}BatGx,�- a Z- �W�Cl�Ip!Rb�#Kd�E�F=�4ˏ1�shf%b��qvea�u~kew��kd("uz��hA��AV\i��.?S"y DZB[@E�� �!@�/AE�1�k%EaM�q��S"�-Q ��9L.8=ej rZy� ����b� (�h%,%. Like'V�e�I^�_#�A�� f�4rqh�M*�)���Mݢ��d`2�%�rlv/E�L!�L!L�� )����3%< 4 h!M>�BD�# T� -!�5�sqliX au�#c��"�"t�+�at.��OI�s yet do�^~�yny>���vI(�o,��46��N� �sp��.�J5a4>-4�a*�  R:%6X TCetu Z�*�s �W"q midda� au ��t|4?\��e}sM�.82k� ,i6OAn2*��� asymme;GA��a�e�,�+f*�R?-+�U `� �E�f#)�l=<6�"� be�m =�!�"��&� �-mk*��>�w�:�jF# rF*���pr��g�+JDٵL ach x"�`K-|a�.F�5=!���r/#p�&eA\t"]2*�+y ��r�e.�,�,�d0/!�AU�-����e���&� �EsoEM�>ic7�&en� on-�1�ijAx8W�7-�.(6y�M�-��Ή�Ņ. � p"I�� zU6� 2�>*� J�����TPdaX�. carr!K��r� .0&�t"�k�"8s: HSP12-mCherr�� RNR3�'. ��� �QZc;�by.� ���� ib!rk�%" &�[�! sp12AD�(f �I�Y$m?T�L |�"���J��A%�[5G o�.�J�#�k LA K3�B KW�Vrst%�� h=r �b�@sA�ilTto ��WroJ�y�Ni~BI ul�A_a^�6or�M(�%d-&�M� d QR� 2�(� . A4&��a �U��(c��!;0m��%Uz*N"e|-��� �a&��K�j uS1A�� "O"�:�A!`Z� (a�E;).�-�2�e}�orA�3th��els�?�6*:�Jj \!��&"!�=byIO���9n�|�I!�EkhA"=D��<��M`�\d.��es�Kcol�#�f e7F 2ZKeu�&3�UI'�_�I�_(.� g�1crR�P��� Ke`��*K� E@�V��e UoyK�E�I&l�"�,sw?"��-�ep( -s `/A&n.�bKMz�g( FAC�G���!2>e*EBeOg1,.e}��-nr)��qu?�le- plo�jS1Bmb�1�.X*� .�2e�M����rvM�/noE��^)� ws��dev�g:>�4ty*8��i�a��el l�Fll-�c diag�X�Ppt%�an up�H�A5Fi��a�$alI��.��y]#�Fleaky}�;Ep�8���)�h���:���]�A. Uw!�Bd"�� 2 �$�n@�reg�].QY1�!�, = .�E��$ to 25%2+�$!%��sA+lyR6�5�,�Z�Ss-� ��(��016�Q�1AK��+q5�2�6��"r I�=:���bcn�4"��>�%�� �e�A�%ua�t���Unly@xt�sed!�:—��Mth�l2|����>e��[�Q;~l2%!��ti�p&1f� op�2% OQ���4��At!�Fq(&�  P =R�(75 X 10−4a�5����t�off� �'m�tWr���h2��K� 'S1C���;>pC�A�&�6-���:i'igh��2� er&�2O e^�2�׏Xr(3s# assa�!�im+r'4(3)%]�-a\!"�2!�!�z�maAJat*�]c#  ��to:k7ac�!� �!�%-fram%�s Yi�amW*%%A�f+ aB�� i\�!p"�“"c s�]x�-li�u%i�4| "@,13imp�0s&� )!\�2|�a �)�<*6� ��e broad�*�� az&w"O&b�&��w!� /�!��Xnx8�6� �up� ��.�� (�[&l3�P�3kre%�}K�in G2�*&a ior�a�j�ppy5: 0!L�����#Q-&@)%�a�es:>@/;�2�!�t<.�A b�*~�x�"��E�"� s�Q�terB�auo ruleE�i& a5�eQGFP*� &s�**G t� � �7�P�p( J0%Z)x2s) : 0$b % , �2 112%�,2 <�cE��Z�(s�5t)��%�e4b�K u�9+Kaw > :f�Y�8}L� A�:Yis �|j�&�3 :V :p�!/�:ar-*� A.he1;�R@A!?a�����it�*��5�#&��� ��J2�p���e��F�EI!�A�bi�� �Qass�2A�ӭ,unA�>a*��e��Ͳ�  � r eq�zC( S1D�"�!�} uZy �v�7K�8�����NN�292P5J�E�=. CJ�w=-�d()"R� ��oa~�)�e���^Qa/~�6"of.�����G! R�4�{^I2&bt$A��&�gSf��jO J�,&� b�\|0� �.y2�;b&f $5or551@ -of-"���%4�4J]88avs7 2a4m��v iumS/of 2�p��Z�pE���@�R*��o �Rdi�9r�8�O� �WAL=�zI*F�!�Y�k�eq�o�$� �L j815 mM6�� D] E-+ es "�68�6$Z�D�R�.6\�� E֩Ye�.- m>5*(/ 4T���y+2��t��448(6%D, Wilcoxon-Mann-WhmyiC,, P < 2 . 2 h 0!�' �2X^:A!KV� !P",Aa%$*� 4'Go4�As6���Q%kQ�2H5b-��ed� eJ��b27�0�&� v�LAj �� |� ) x-� )�356-�҂�TNWeI2A�B%J�a%a�:U/��Ga��8n _�e�1o–in|'ol��<��At�b2s�R��9tB��}a1-!�ntmJ��.))437�)e�� uE�� .�!�R�&\Wlso�)��>�+ ! ��4AM�`E�nt�am;d67!)E/st-���(� }])�:= )e�Jr02�1I�.�%m2���*4&CxOVts ���Ce�- y cuj� :mTe�&*P*a'�p�#6^&k'��EZ 5ez}0!'� O �(nxg�J"^ cmq���A�.�(V��49\�����;!E �MJ)nJ�� �:._Y2��!��G�l�Aw<c` Z 65� b& !�!�I�<nWi"' p�A��@a�a�s�[$ ��!al����6 chroz<Mu@��g*�6R���7InH&5+JH�4�p��de�\S���.ca2�=A�* 3��84B9� {>EM1 �%( }��ro�)eA�3 3*�6g�9%�?#I�}ut� h &�*��0 3�6FX�ro+��G>n9�� +L%��? � �7n`�"�~�H!A!��T7{fhey!so�;#,]��s�&K��(�t�Q Q�}FC�:A!�Abl�en��i�31�-�|!S2�%eկ��6'� �t�P*�-!dff ! :V6c"m,!�Y���fq�qP�*A9�ov��}:_!N[&U)��ghͫ� �Y��ect��5f �$rfyA�"-�6|*���fal�x��.�"�&c 1m 45�*�zaZ*L3B|�NVx(�as !-F �� ^�‚EW�O2: 79%�4@k� ��hejաwL:�5ed�A,A6�r�y�v�g)jg65T#bMx(2� ;�n"��*)k�I{&6a:�a�"c2/Vw���#1'd � xB�NcyE5 . 92Y5&����^�9P)?�0 is �k96!�n [a�6SisPan�-,P&U!�!cagdi*�w6�9&KJ��Kltbl�+m"�SeN*NZ�8[9���~}U�3m �Fi3)�d,%`dy��\R5]6n!V�qI�� !�U+E�. O�@!R� r>�n"� 4��5�l�M���Oo-A�A�eAn*�+�NR 6�f6�%��[I���TP�u"� *��E :�"�tY@��m�z�L�2ߡ��<,5Φ,az a�%!|eZ�� s�o s�worst--scenario��J��4pa"�����n� �Iam�U:ao�s!A9Z��!J.:�38a�W�E m����/"QcB��plM�w{�%�darx�R%�Us�0�)6A6�&K-V@/ix.V.o Ge=F� k6a�tI�`is h7!�!FI�i maximumF�&kP�X"\b� r-�AW"��(o20"�Y $� 20.!�F. 59%–�. 9�R��0�x6 ��IXd�100�random�p2w �m^2 . 34�[J�5�ASa��)�x ^�� �::� ,eI-C 61�A�d&.&��B� 4B��� ��]�+� � ��$�E�<z�l�Y6��=Y{ &�F:h&%�c�:� R�N���&;�*�4�z�A&aA\ medo@�*eNaB%H�J2��� &5�5em��E � f���=AC436�[!��lRm2 0249-�o�j_317�_36( ( S36.Rqer)� �1�sa�. 4"'6+�J%�� A�by�Y� 4%�O�`� tO+xPgane�a�v)27#�an flip%93��I!~�6��)@{J��p��^2�a8Hr#� �Y���7R(A��&6|mW st 3%R.$"%4)�ask?a� ��|sn � -B�E\��� �,?�'�KI E���C�2!�66 erZ�AiY.�a�: %t�.!|s2 &q !��a� a-f�. !4�.h;�.f��r�H�*� d2>R<6�T��B* erro,_qosa(�U"�K�q�>��&%.� "��m@M_�:�1P!O.�u��b��� >tUtrV�|� rol:QoH~�Qf�]%�nE|6S�:�% *!}���ed�e��.. R�"9un"5c0� �<&� ,m1:� Q�a�r2on �!o7�A ���0m�.Q�5�Fs�� o ob�'�C&���Q5ngE�9�opz.)!��(�tom 50u EX�A�� n= j%>�!��WS%�-��.�P���2��Iھa�-�! � Jf�a�ɞfra����2� 27%�&)�d ?lo�>,&� I$!&� as�832±�,217 pmol/107-i(�- 0007���ih�p))��U"d mixed-���� odel���]��2�� tech�a:*�:"3  1dq?ώoe6�b��bu��5�Hera9?B�h!� � �.1�)�3=J�� ��*>�E�l��l�{!"� ;���,�(͉"�-� Mdd�"Z��1�%ngaaw� YPDN@r�:sz*4_1�TA�S3�:)5!�fiv� p� 8de�Y�!�Uwe�����!D !qk95-tri�c$yltetrazol�$chlor�D ( TT]?L����H"%�S&[k!z..a8, j.�< whit� J�&E�Rb� 5t���&!�ZQ��7�3%�#1##4�*�,H2/;%cA',F| rcsiX�!M�j!�F1a�68ge.��W��!�u�zJ}S��A!,�.�`dl�R� !���>f F�oA~k��Nm�&`&�T���(i��"a(NthY�� 3�n���t -`'d��tos+fuj>�bL]��l9�Y&� "Gt11"6�reson� energy[#�5( FRET ))��T!Guc�ffuE@#9!2��.�Gi�0)^�5{�k [9�uWe��AG�w p�u1O*��unf׏CFd<i?l�"v����&aZx�?�:GF� #\J y-,�1�� r)*&ܹ gilm%�ҡ"�EX"�8 P"de�mE� magnit�4t�A�6�b j%Wng5fot&Zd-�2� �0if�/%y1u� ���eM�wou?��a kin;��w�e=I��� ain:����eG�-� ,�a��M�""{c���l �8e ��� ’s�f�A50��>1p�to�  w!���?*{�� �nRJ��6�,�v����- !ׁ9on �v# v:pcaeca"���R��[��. Hig� �4��Kt as6o���er2c90� IPv�pa�sA��. *�u ).�:t �fu&� ���! �{ ��%FD�� �yDu.( "�X�!uz�W!e15zat 1-m�|erv=o �j�@mB�3�z ���~ �M����"�"b�O�Wae^�/R<6�\FN].��&�� ��FD |9 x"1��A�r:�Xr[��mRuby/܁- A.n1VL��h=�Dne Htb2 with GFP (�e HTB2-GFP , to mark nuclei ) and a fusion of Tsl1 with the teal-fluorescent protein mTFP1 ( TSL1-mTFP1 ]Tsort cells by FACS ) . ingfexpresy@was used because } imag0�at 1-min intervals considerably reduces4$throughput�FDexperiment , so itn necessary!Tenrich for slower-grow| ��d ,!� important�@of technical variA�� f��ce]xwithin%0Q�a� es . Chan�g.�-s �procedAM to includ��one!Lwo hree or fa]r�ra)�ha�e2 , haa�` extremely minor effect o 3u�V�ieDd does%�c� e ane��coɡys��orA� hereeeZYyA�eXfluidic!`i<r�lid!l(d coverslipE�$Nonetheles�� as predic!y, a� ’sb{of��eg��ly core�esE� subsequ����tՂ� �found �t!�!$��B��4result suggest�a�� -to-4.�in cAMP!d%�@n da1deed s rlie>5 �$. Of coursaS@an unknown factor��a3Jg migh� determin!�FZ�A�s%�di�!�but giv��Ja��Qsaw�Av bulk!vpop�4 ions!�B�n fastBN��r$well-studi��m�fN�,on PKA activ�}HF�C G�e=likE:andidat�'t�}�� t1 very leas�4��Is demoet� at �subAula��*�8dynamics mattere\only di�respons� o st  [46] ,%� also-�benig�5�. Hav!�shA0I�A� leveͣrelev�>A (ongenetic hA.o!KinQ�!U>� ,^67q�5�(9c� yF22�ct�� %�)B�m'%�n��souA� to tPa caus��� ship��E%(� Msn4�Db . W!�erefor s��wh��r remo%tVor4 .� "�.��A%ɡhigh-%k w��are�4 th-rAjdistribuag!xA�0FY4 wild type�those PFY4-derived msn2-dele=muMa�msn%BA`84 doubl�c , . Re!iv�-,n��,�&n- �-� ificantly�(eZ� ({ couple Z-EPP = 5 . 32 X 10−5 )A�s���n�%2�jc19c7M_�_2]�k1 . 84k6 )ͼ6Aͼ�i�.9.�in skewu pai� th� �genotype me:Z,!2 vA !(:%l0 . 105; �"63"4? "C39!D� ��wimpf �qA�e�� 3 &� noZ�by virtue'increa"Bpro ���A%y�.v2�� �� ��requia���/ous��� ^e��N�The%H>��A]a0q�B) qual v��gaa�he sam�(�a i�mpdefla‰�cultu�T 8-bromo-��: acrossmU� es�-|2� �R l��to& ͹6B , S4+@ B� ntr��A|��۵E : a c Ո!�7 .L At �%�!�F�&-V�T2� establishAW2!� a ke�gd  f:V��.[^S�� prov� d al e1e]A��ad!g��esA�i�ric�lin,�cJ!��N�intain:�!4.�� ��Qd�M���e>��)$s% �)�V; mani2� A�Qz�of�2 �A�] sti e�}i>� )rai�]2� would�heen�w��as]4JQ��r�toward%G-"} ne}O  � A�i�  study%�"WA}s encoN�subunit�However���  mu�H5�on��� 4ly pleiotropic%[typ�A i�� �terpre� : 1 )^Eal��influA�A�ny��u� p�s� A��/(carbon usag� yist3nd ribo biQ sis; 2 {� � is embed~iLtrH( Y -senE.network�! lex �^-talk% $feedbacks;3 )%��$Tpk cataly� 5�!Aa� St�� tt [36 , 38 , 41 , 93–96] . I�� fiwat%[9�h�a5�pposi"  s�eqAWi�^�E& tpk1b tpk2 B� p�0ced left tail�&� ��,u=rof�cy1>j!�heavilyec� FH ( S5٩"�Tųr���t"�� �)�x9��e>� �rol� a4Y[nr��E�e�upon m7 perturbe�!e�V. Spec| an%� trea Jw'H89hAinhiba�>�a�5&-depenX��nerayl[97AqWe&j mO � &�i!out�a�Z expo!Z 9to ��e begin$of2~monito�\( o)<x��rt-cM�A�im@ ��o�(a physiolog�� adap1= st� . Q+!G need�mb+ ssol� in DMSO!ee%a sepaE]ol%ňH�F)�a!�+�AI amoun�b�}n).. Cc��origi3�, :at-zM.E(a rangE�B�s )��5�!Oes shif!7ius2��L����rol� E0 μM~:� 425 h–��./7PWilcoxon-Mann-Whitney},� � 5 e7;n4>n13PNn0zn< 2 . "�16o5BoQJo1��Vo75:L0rL1��"�"arcENA�matched2�s��� hat #,`!�>�67(E$ 1% ,:Zto YJ )�an�"Je�E�(aV!�MZ32��y��4arisonq`b�A�0 TofirPa�%b�e " �� targC ����>eda7-qѡj2ni�i%�HF",.j�bov:�� 6w� c�icb-�2d&y . �al�ind. ��Yg���F��An " % X�fa� */ nd���(175% A(!�%�!Hya�A�EL��ZZis��073 ,-A� . 051]nosʎ.:�> 2��yields!ig1s *�����( �7 ,~�"�5�>;%��,�oS6"� T tru �hyp� s aU�bilG!� Ras/T/aS path��l�N -hed�s0egy��budŽ Ja��n�oor � dow�eam�nscripw T"Qly al�M�A�� C �*� ,acute�es�ler 1. ab In partiW r�R� c��1�d2�oru*� toi>e^z&F �g b�Tsl2v, 9&c T) e 2�Z�,�it� if- -p1$�e�]� �#s <$1�a�4furF 5'!�*e ��jTV���f�! subj)�J� ,� b�Udeiram�#-Su%�m}[ � tense_ t� (ck ( 51° Ce�2 �a{%�� meu( >�D)A�a~� w� �u8" �E��� both�w:�`e99urvival��1pproximaJ100-fol����to�(.!-aANOVA�Larcsine-transformed 2_*%l�d�Tukey!HSDy adju��3��� 9%>! �%�a�22F "� :2%sIIj��intra��0��4���!.s��*�&��'a S<��01T! �8"a� �(6���9�MSN)�MSN4 app�%se���!�� �ect't��!�eNheA��, 1ebe!'m4&�#�iE�Ef>�jg littl� �%wo^l2�!81�e�e,}��l��A0n����"�U�Bv0%~>F� aBed%qc<#a�)"�l:.&� d^*%H� ,%�:��65168eM>4A},6�aQ64R6�A���� !s%sx"�� �#�!�9T;Y�-M�Y�,V���R�m� �'2 (�&a͝-nd�� +neiŢs. =at2!i �#&i���^u�ra��6&�eri f)i�n1:c 08� 5�m���V2�2���:\6�Q'�a]k-�1��!&SA��-B�sol��S� !�f.���l!h:",]a�cJper�lon� "� ����e"3,s 8d!�t�)��-sh�.5� ����E�.o ��r�con*�of�J�Kq:� H8>�� )gdR � Mknd*{ V %g� &!+,%2 �(uor.� K�6�&� 2X�-m�!TthAa]A�:/(u H89:6�����3;�J)"E A��8B��I���8$�ia}, hough �de� F,6�.g bgEL:!.n&�A- ��N>:H a�� pist�=�E��&�2�1��#isR;� �:!� 5i�~� sI#17�+I�E�E;-]�.M ZN�J&�/t er�GBx� instea!Cg�( ��is ng�"�to ��A�Wond%+succumb � obs�0J EIrsa�1�21$�O:� mer��2 tax�N �-��m� $ir�eznes���J-�nhowVI�o6^&-�A�2?��{yle?*� �S� l=!&fwe��Jx �%.)�an �.� ( 5D at 70X �efi��/ tempera�!� �,d!�be� ) �!delive�5 h ��� !tr1����-,+��Pl./n": al +�Y ( >(1We had!�viously"imi��[))�atB�9! s��%"=�%�-M��,a(it�.M&aM[3�I�.urr��W$|/�#:j"re b�wm��oio�xu(= vestigate� a3�*nu�> � �1e�rem�!af|� "<still9T)>B8S5��` ng�-����( ,a%% ?)se &�& ;4J;�r �7�A�edM ->6�)�` �E^��.ion�wA4>Ma&M^�N�iC.�E.recapit$>�� )�in�2ual�2aw��-a��"T_ey+�!�b+a��c��x9A�92�A@_tB�6ng)bJCuDeZ*��)negligiz*� n�%�,7 2�� � 2� ǥ7�.y�&>�E�m t&U� �2�� ��.�S��En5�1pronoun� Llo"�#�b�yr word��+=B%e�$exist desp�!aA�E��1 ���uN��equ%j: )h`I�zA��aid�hu(:?VEpthEKI�a�� �l�"elimin��by:�� E�, U A}��� aAie ,@ -in*� e,4is/ta9.�a5>+. A�/inI@C�=n��VY(�&��q9o�%a`5(����a�,cKoU�"�4m�% possiJx�3� zM��#�����#!D�� covari��#� 5s Y"$gene-dosag�"`"/Rm%rs [5�:u"it3l;5̥�^�3Ts6�Ej��Ih��edI�� ^di��*�"I-yFf�3a�a%�y�'b����j&s)v�6&�! X�3tIon avera�7�". � ��u� �'�.��#a mode�41�inC �� s��is�&�5e@$"m�J",�,environ#,EB�el:&-*3\ vier�sN�!te(�S_t<F�)3��9o%su$ B���.�+-~9�. M"�(E\V !�trV!(�a�q��;� m��#tR�( ��@�.@���6�bu&duS^"�2!e��B9�V�=)�m�>�EJR!�-permea�EAanalog 2K� � 6�� �9b�5Ej%Jral���+45�j &s� �7omb�by �Al�-�ngE`��0 ��>wak�8og� ,��.� eŅXt a major��ut%7excluse&,)in�.�iDq}to�er6�R�D+6in ��yA�1 � *3*79tj�:��.��&�fe��f� � � ���I���RALineviA(y% ed �lneE�"� �R!uba�#e� s al system9 , 13�'329�!1� argum�co��o�=]>f�va)aAr*�>� utomatic �gwB a�-to�pr�"8 EZt��hE�!A�eci:1] ��>�7&<y1�! :��� `at�.e�!� xYk��>( A�i"� 2normal�7nd�.�eE'�aX*$ &.w A#B�%<%d}�l"M FW. TwoQ�$E�A�K+KQoncil� ->ur��,Eal data�we belie.�iscreFC$ do%�94A��eA�b�=�@R ��V�,*?$n^�6in9$b�!rB�. F�!�92���:��Ag�9 "�/�aeJ�ZH L A�e6v���-|rdi� �i(�sha3�C� #Jx W�mIt1exact n�*8"u��=�� perhaps d�|o�6�4neighbS.�.uof�3un"� m� ��tr60  p�� �FaE���7W%G ^Ac) peti� . F8l2� l be*F9ty>tanglI�&k P�#&�*�Y�.!F��B�0n"Dcl�! Re�6��uA� " -B�a�2iB� A���. Sec�,j  Kso�4�����W.�2)� A� �q)A�a[m7>a��(�R�2).�.%4b�/VH!)�enhan F�b2�2z�{�.aIAj�<n:��i�-��!v&E�}��%u� � "u iB=� [41]�f�*Ce���z�b&pl-1by!1 ’s6�6��16��g��K����,`!uni*� AEl�[b�J�),N�5�(by%26"#6q*@6%S� 7�* �6�%�*�B�%��/�-t� n�Ec�i4*�(of!O1(y��aV>�!�e�:�m��*., VJ��Q��1B,'m� �Ein�$ %�lt�' sour�0^���r�!� b-©�&�*r� in6� i�s:o�]in�Er��6�i��am!��.2�9a�L#9�v�;$@�,��a s�Cm99,nger molecul,-]�/g�8x *!� �M��U � rece�B 9or�- gluc:>��nit�Dl "�4sAN[F:ox�E� !�H��QLDNA damage [98–108�g DNA- ����e��po] �&^�%�w�ve rul,Jut�?(�u�%oNQ�6�(��!,�be�XEe��vf}E!�J^K� �O= *B��0characterized�9%� �9per��74]�� o n �D� 7�4� EHoW"w"�7m.in �P�bum��!2no l9�nR;��)�A0��*�U 6�fluctu�!�b'u trigA�E�g� !�her pUk u%AA��Es1�*amo"�. More���XtZR�0r@= �� loopk<a�ng���(itself [109>s�8���%Z�7L-y�"�<, defini1 of u�Qa<*w0break�.ny &vI^mus�Jinheri�RB�7C �8�/I a daH(MtenD9 E�m�-qJ����Tm� �+ occa�A\witch�-�&�Ato�Jor vice9Jsa�]OrHn-�O�&AEism��!4 E( m!��B !�or� eEK 1 [110!�Iobe goodS�Jf".$"�s_ �'�S�Ke�inu��>�� � s���,a�=bimod?.�H�theor~J�1 �k1en��;�long-las�`�7ŕ&Z2r �+g�n�umA�ki�Jmemorp,9ybC1h�dYn�sAenzyme-cG?��rea��LijP ' �ieU�%KٔN�.A�N4s!�1�lW�% X���69�%$A$yQM�ed:+�>(ytosolic pHA��*8Ras* . Ar)O neut�6<!�Pp�?�PreJ�28�!MAg�vacuo�0H+-ATPase ( V )Amo�B 9Pz aE�t+&� J�0co.� [112!f��� �KG52�is PmauaM���3�a/)asymme E-?lN# � eIQsm�UmbrSQ��v��s A newborn�>�a�TyA?P >P ��K��new syn&?�Bas2, prog�,he A� 2;3�!'�Low . �D6#I.8G���12N�+A� �[1 cIf b��Ts]Á��e� ubse�,.2s��L>+�1\!>�+Bk� .PK< upk�-c �P ri�Eo� " !Q colok#UA/�{IS"oGl��i �Y7q�[Au&� ��N6�@ Z�:�QF�Esunderg� post�4]8��od��J ��EL�$s!� [114��so P68g&�%l%��ed"u���� e�J]*�5��s!�b�"pli�)�l�bE�: 9l,"H#hrQ![t.U��%,� a C sS+��4�  ���ґ�55a��)%F v�#  ?��0at alk�e6 .R�a�ig�GB er�� eukary��[8�7$115 , 116]!���2�j>c�2$human dise��P.)� ,x ac� 35>pPJI�� - � w�J"wB[�nIn ��se�� ion-!�ne�(7>yT,�fap��of�,rot�mi�S[E kele�:RE+ng�tabolm$,�� life� Al�Zt�Y�:apoptow<[11�<11�Dys �A1<*x�- ssoc*�"AK�� � ;� �oc��� 11924�/F�1xambQ,!�i�Sv2�<i� &ZJ�te"�de�%x�cZ4agţP��I�-� [125�Likew��~� �melanoma!�6b<co���Ito MAP* !� ���FE��F *�ma�F!� esum�by!Smoe� ��W� e roD=[��H"'K� U�P'�J�!Ne%p��#e�@!N�C��X!����"$Jmv� workGa̍�( $-!o �#^� n512�%2�12eJ12�GAa�!>la�� "!ncA��) !�Ae�N���  v�W� �&�� ap�j� Ua�"�)E antie oligo:$oti� Ņ��LT�/M�ag�L[12#3� E7�;�aex��)^�R�%p��) ��""�Pni}�y�he} ! w^ tumor��/9pr�0A�f(Oor)A��!x3,�*��!�#�$J {�p&�m�:uni�6yKuscept�(toa�� drug��&9g!�_ "0A\!�� � �b4�'�;�g���erica�: ��be valu�A�,6 fung�*n�^A.:Nif�vogei'S . ceO siaei�ALk'!�b�`/�] %Ng� BJ� EN�?�4�.' �r-�' �)�s6�f�!Aane�)2.2�\c��t�#%&wo &�"�*b:�rinci�y behi<#�Bat!��!��us.Mw�0bA��`N� FP)!9n���]�Q,��:Y ,� &i�s�.� ��}Z,AA)#v���! appl ]�20 tV3!�UC& m� wors�_"�aka�ad^�]~ oI�v`:� mayI��raB! -heHy h�.m �R:�f�ng� 6M�pat�PRL*��m��or =`eTeb�N�0 . P�0caous��for�R)�b�3��d� bi�'om��f ��Lready��P a4)A��+�oas �x$corskoli� ��D=,denylyl cycl� . Al�ain"h� ���SaS�&ShI(ATa haploid�^\!x&�)�>� , ex�b&HHSP12-mCherry; RNR3�.�Q( BY47$RoP, his3 leu2 met15 ura�H9 EGFP-HIS;6W-KanMX }=)w�  d �,Gilad Yaakov�<0Naama Barkai e . UnEU�(ed� ll�Kcw=e-��leaG@!�#sale� 0jL" r ve�a&�����^!c�4; pGAL-p53 ( K)f itto�fe cashee �&a�8�C� �entirUy��a��%<repla�1�� t_om�Pare.+�sel?0��re" agApt G41Tq"standarr7ot��Nex� �struc�/ncate�ng% flan/)e�cc�ftpL�)EoA�a�!O-%D51��e�n gal�/s�. C#�)ret�ma�( !�*@ "pJxi�V k�+�. .%�6]!�6�2�:�IT)��1��a2 �l�#�r1!��an#utilize= . A N,.�Aan�DSM,.>m0m�l� eU�&EedM1��A�pe>�6%��e�n�merIac��an�Tinser%of� ores[aI&:$6A6W!9 Q=f%�3’ e CI�>l .�}Ma�a� stop8oT���%B�!4&�Nt �n����k"qM i}!ly � �s 6�!�R � ndMi�.8�K"�06L6r�I �[i5�j�����UM���) step�}D PCR-�if�����m �5!EfB ed 5ong�KA�aux�<��"JJ�M�^col�*a�e��+ly�.� by�#p!�PCR!pg "�.:=� !�>e6�a l`]r�� =^U!�sCG�:�0�/q�aMde�$��*_ .inguH�H��e�!(,2�6 Dv#�' �[D182�\! ��or:�L�+�k -�I��^ZD!/*ar�.#!9O%zi!a�tetraN� F1 di� �^��<ua+�a"�e�yEv�hal�say� 9SQ :�m�p�6 �_ d-ID�/(�JCo\a3&H9b"�X ctS-�isof?+0Pr�1ry3�#o�m�-o%���_3.�F&p�i/� �FAnsu9 �b� 5�B� -7�F%,-}l-"u?2t��a�A ���!IHe��c�gn%�� tHe�sT maxim�:�s9�I��-8�Afrozen��"�GeV�s�,a��$YPD liquidw&eA�2/dA#c,to:%scopy��Rs [aoJ| inoc�>�1to Sy�-Co<t�S�= ��#A�!��: �Aovern�L)wBJ���c lH !�{%$Pu� omV5%x���v�7&�'hb2+ q:S e�oi&a�1`so(,.��'n�& avoi`b�Ba�a �%)CuNu�;daz�jaf�5�� Z(q{dilui!�fresh!�=�a�a�:/ 2X10�Ab 1X103\s/m�r0� �*��of)�!�%<)3A���� !Y��"�'%# n4n)�EgE{[ ,R�M supple�:�15 mM 2,6( Sigm�1C�! og Nt: B7880�*�]wat$)�-m tub1rwrkPtfoi�u�XP�qght�a@!A�ound .ZC��-�5�:)j�. A�CCaY�I&]_���or 18 n1 ! ph��A��.����qk �@A�s�Eex�%lag DA��2P.��E=vp�0Ndy2� �5f^M�!��0M,j�142<d.��H� �� M�abs�$zStferp����&V ���`%%"� Ba �2�a.�6!Z-0of6�`.�)to)!K��mu]$,%# de�x,M�/%>�x -ly 1068�8|(s{%MitoTrEw(r Red CMXRo C ThermoFisz,B�M75�KA��2��v5. Sd�]��&C5Il�\�)4,!���=of>�%ach�� , 20�_L,Aaed�� aspi�e�a�M@5-ml opaque black�X"y c+a�s�&�m l�]u�a brief �jifuCu=3$t 2320 x g%=1,��superna1p�� �?v!"-b�� �U8md!vr�cm?s�l�u!a'asEa]�u X�U cruc�!� successfu��-.2TRs ��) etochondrJi��B�%&�-*�direc��&R^ !�%W�i@�2� stag�� �h)�,it�N�,���,i.��M��� 5�9 <+a��Hw�+.�whi�g6 3+nO. U���SMY<�e�7>ct h�cdtl�/6�$h�H.�5I,. e�c#�V �"���/��A"� őd#8�N.� , ma�2g look�=��` )5 ��el�Dwy2!) kept�� =�# cTY�N �.Hdy� ��e"^  ,FRge�2 �R����� 6�1 ���\erA5I|nSD� B�o�/k0=���1 dmix]!w�!$z �E� I\f�/$9�=�N�%@q7oGe&�Nan10���O.y�"�b�\O�t*�'A��Ur��*��p]Zm!a^fas quick�_�xs% l I.5o�G%9* �U!sa4� ��. Ah`�i4in�N0i�probl�?�ex� ! ApAd, o_ �z�{)E!�sh !gon� agar+�,m39�!���EF"W5-triph,Gzol� chlor�% ( TT`5� . Co�)x� nN�A$"�X���la��e[13$+ ~7i ily�Nt�S? �  p�2=�tar%dehyd�4U minE [Af)ݵśJin-F�~i9s �.�- �id1w%incub# at 3T�� dark�΀���$!�%�O.�)A�n�ef)x d�zop��co-��# p � manuc�j�a'o�l�"�L� G"A'R6-�J0�A�$�)!I $.�*�CIn# , 96-�� glasRtom �m[co%,M�� anava) AAy�IV�tRM( C2010-1G )!G��hN�G!Jfil639"@ i�fiG&ed� ��.Tp;zim%�1NIa �#cytom�{i��A�� "� 4K�hik�)!�* l %a2 �Ason�5�R�'0)K�(�u�C&��qZ ���&o"�Vx TAW%,��͈�"f A+see����U� y.� ly 4000Fs.q� [s�����2U�R"�}�!q tAE&of�s(e���a��!>�!J�c�Rin3����  Z��or��, ��%volumQ��sSC�u��9m�!�). Pa�m6seaU�� eath�! �"s filmb�0 Z380059-1PAKeBd���!i�Cm aE��'�?eXI� ,e0spu l453" xd�Gelp ��l�9A#� � surfacz#!f�>-�=�aly�+�&"W��,%��1!�ed��\a Nikon Eclipse Ti inverAdM��7 *�O Ap�lX ! objB! \5X mag�i- 嵁Ch�-�0 v�e"/ A�6Fs�;E�&�W˃e~ masku��21p!&H� fjin]Favoid o[-7�;VG5(p�rsh�q$wavelength�U�w� ka-n*�C y. S&XaN�!.e�I���>�"`(�K� e6(.�le��� ��#%���yE��"f):� th�a�$��e�A��[A �uWF?ve�A%%�{(w algorithm�p IE ,%8A�F� y edA�Qi~E0'ar$pixel-<� grad&[13`.iim�z es robust�[�  E�`fc5E�amd��gh 1�rg*a�7�4er��"err�-:~es�?�, �AmI,-�*%H%�[,&8E(-ar � -��@A���8%random�ZQ�E��  ���en|փh �e! �9 ��&e�=!��@�%�x[E Fa�"jA�e� �8�m�E/a�s?��A���U5Bp.rF���A+��?~w�Uts5ple s#�I��.� uvl��"E2�62��Fig�r! p*�e2Gd%�+ �me3F� adja>j%x#����runf�bl#��4�TYbi�<Rnr"(&(2��( S1D%')�%F%�2��� 6th2�recorK 2��.B"Dand/or�,9te���oS("�([��L���!0&/phototN&8Fl�$2Fof��!��^calkmL$�te�f�}3bo�}inu$�_d֐ag2,"�. *��E�eɏcJbA%�� ��&HV) 1reٍo �I� � t����,)e/�0�Gc�WYb9`b���" /�l���r.� . E�0x �cy�� d�<EV.M � c�EV,six~�� u���+�U �:!oa�/med�+_ @ in R%�{�packa�~�Euc�����)�hn�!�)�C���23%�� wh �';wo dimA[�/E\��>/i*i�p�6 �F+�L>#:� Zwv �� ion:F!tM9&*N ��/�a&)� �#�$!_�vhal(�7� m2'��>ur�@A\�3bM� o en �:4��se+� m3�� �,��!;!�� N ��O< keep�a�&I`Q%�o΁�2d? iodT)�'e-��Khb� ^!�Fo�/Scwb� AreaSC-�qYnB$Width %Wo�(%�s+&�E�R ���� ��3*� e����%clump!�UB A !D0�A#�M�Ŝv5�>top 10%eJbo`50hz��k(e�p�}A�$.r��w hiY� � , ~5X10E!�� 4p lG?a )A�2�� 9F�*� �2!�qc�"Y�yb)���%^��4lJa��Z1b�+:k.,!. DB�vl~��x� �ia � i�s�I7% ( PB���Eorm #2�a IL�&k��mi}&7���7lFi =-*�b drop�V . Y��VK\��P�*x��eW]VQ� ��sca�f�u}[13T;H"�:!?fa�" :.2�Ea.���:�9*@nt�P&?��-ro� �d80a��our�@�Rrly �4a���/e(�Q(mij��!ש2z�2aѵ�M���. ��e] desi��A�of:�� ��SH!h�5�*�8, 7}�e}�M�n� dF�nd Hsp&�32���?a���MSN�(+�13�-mAAlm2%1=lK+n�)9 ��*�  � �z�!*M~�!A)o;�$�,�-�iK>���pel��T�P� Ze!G/A�� �s.��SCa���7ōs��a4@ec�%3�&��%Aa� v%=�"E�ʵ'a��!���LJ31 -fyZe1 ��3i��B|5L�� 5682"�30�;a?np!sc"� �r lash�� +$!��" Pz$9>stoa�at&H+^. +0 �V�:e�&�.� �poo�"�/���!o�NEWjELISAS2��D!!E eJ-X�!Ⅹ�I)c� a��!y��� aj 10%/*|2� m=�Z�6� (M�-t"��"�% SA�n �MZE:PquX?fpA.�z9L�� �k): H,E�1 M%�e�nHC%g"I{Io�ai�!w%1eJ�U*z" E��&I5��jE _ Ee�-,�#!s�!cy P %�!��t6�aA�l�,A /� ��c�G-JdeFQ�A2 �Ad%�6^.u���xr6�4vorte�!Fop�9,t 4°�}���`ac� y-Nagel N��osp� X+�@(% a 1:�& �xB �! C beZ1(:*( , �B: 74081�y50; C G}5ga6is �!ΉO�y shr��4 ���.�� �|MFA%M.EBdIN�;nysphodies�J-Mii=,d hng�u SEaca"OF��)|0,8 ųՠ)�6j-rB*�"s�4��0 M�xip��422 μm PVDF sy ���>(M%> debr� � � �}��; t%2��eޡP% �KI � �A�Enzo D�'�@kit]#m�$ADI-900-06x�Ae lme4"6T*^0�" ~�"����&w*83%�N[%�DeeQ="�6 e�Dmf ��To�% 6r 2!F, (m�"�)]a 4�r� .m�2A���:+C#a(*(�:bl�F; ��v_ J . Br-�Xa,@�$ n/�EQ�Q�&c.6 �&� � ned Q��ea�h ��v*6b&C :�A�:�"?� ��5 m,b6�500) ,% M�X!. I*�&f�>!a\Peza 10-h2� F�a/m'e* %:2���hA��� 2�(Q�p�� Ua * -� g�V*��6�Y������:am X��*i��B#\r�N"�Aca" -box�M�Jscon�A�ňA�l;t1,�3)��!�6�er�r�) ?Profiler7]�Oe�����a����F(SI��$��.�����A&az "ө&stRaliR(Global Otsu��eshold�8��ar dia�$res�Sn,#�B10%$301� &|p��5b%xrch� do��-"�X} a�&�u3�S-?�e Propa�/�9a��u�Ͳ!��.iv�sUe��i!0 shapN��*0�)�dl�K�u��6m/i}���1elY'pros"� F,T3�d)%�Y�>_S2 84S3 .�0�;erA]e���t�A=or eC4j"���57��%/A�"�H6�A�*� t"��B�-7_yV^'y(5)!�e�H�1n.�� � �%E,aIac!JD= &�H% �u�KbB��iS�GXtr�\!d�N\!I.IA&tU/!H)U:�Y@B@4Ba�-�"����u��9E(Ut1qb�6A�)^�� bPirm.�"�o�A�s drawm3��1]`b m�XA�(or upper-qu la�y,S*5��: ies;� i�:=so�! � � La�=�A�.� �@.v*"�!�.�D!KO a_#by6�a�h<v�c�m+&!@2%% q&co �.0�5iapY9d5:bA7-�" ��*82b��!8� R��%a"��"I v��>�+. Bo�,/#�.�wEmg/*z�!�z+3 �so�� zn�s �-�ue�)@$��!�, :B*BPad}2-A�.ޅ C �%�2"8to>;��B_@>p,AHa6;:�'�|5 (� |6���Qs%�2& %nd"_7A.�a�oAi&a%��@# �?re*!�o{�+ 4LRZ~B�8t�a� >. All M-mL9 n-wa�.i s us�/� !�PCR"�8a&|i�:o� �)�I&�c�rY�+atԂ^-�("oMY}aT:Q�i��S.�f�3?'AzdJ� ��2�*MS6K!-�� �c lN�7 >�~sa�5i��k&� ���$too sparsem2 crow& )))�dc*� +B�x�F!2!TR 1]2�)rE+%)slk2to"5 XA� non-1:�Eto� �9���(iaɣA� �de29!�I TJ+ �]�m, m�i�Q�12e�& f[Lr3Twenty�:h1>AR�,�q$�.@ )��셄-&FbyP+ scQp. H��h�C�icrZ �E&s�?�~  M�u�vs4sNP"%3h"m\2RNA4��(�A�of��sAW���~$���*�Win*�8!/bE E2��A<�6_we�|�%Y<:��R���14 �'WPsteelA=tE�r4��q3aluZ'm block)3N-�7A\�3�#u5ortto��,A��>z�E�# eed�i= .=� w�-si�2�*.of���}%8. G  EO�Ua� 5 h � �%��a�2�� ms�Cv�_v !��BpYB�&�Q4�H#lR�M!��*K%?& &jG�?/ b� �wa$PV�N�f!ta gi�q�"&6 c"<$�!��%F�J� �&� -�turi/ A 4�y%@e d�dV"if -5� �\�).�8�j�}V�<.�mChikungunya!�us HIKV� alp�`���3S'$Togavirida�m}�cap�&��aL GJ�b=<`�_�:In Dec�: 2013�As�*LineaK� �sp�U9cOld Wor���e Ame���y ,!�rapid�ea��!#New =. G��ew emerg�>iaïtp�HN wY ʴJviM/")W�I+g�)d�r ��W� ev�a5��g�h�out~k dram�|aU</.d�hs�(p{ �O �aEFigJi��Sa!.CG�$M)s� U>!���; novel�Pu�ns�7��g ( UTR )� uc�?J��7j�!o�He= !�4!��Rp�2We&sec][�ݾpl^U�tra�Zquasispe�{"���a�Iz�-�CaribbmE4� �U�1��!G:����P5�Q!)��D-gg� n%Wat �e^��q�Ŗ�6J od�ime�70D %�B� ��-� a�le�n�Be��Y�K eillC`,}�׬ql �� �ntBzde�ɡ#�[�&_Eof � . Ar�� pod- k��( arbov�e8�G-&-�~hY spub�l�\�5ldw@A�� �o4�re-��!�� �J ����naT>Ϡcj5%�e��� YV!Ր� ���z0d�97O&la�q se_@ de�u�0�oftBhrp= a!Calg�*� Ehly 60� rMcir<2bwbAf�%Q�i [1] [2] [�7�ai!�qu�Eonݥl_ �g���a�B daptA�a�e&)�E2!n�fue!u �8���i���catt(u� o�J m"0z �`� lycoFIiHQT'%�hMo!���W�ID! n tit,mosquito Aed,lbopictuh�thu�dF�ILmi�/A�ugyI`��w�hA�m e�l�� . Ina�q�:�) �]A�ar^> i.: ��=a/�d&bno�6l'��!�&Pa�%-*� | "s Yas;ed�hID�~&8f=�0 URa� V�� qRT-$ v;@] e�^A�s�!�I)d�_%f52!R:� 4.b.0�u���!MN&@ i�)(�w@�y� � load�ost�*�106%�11 opieOQ �jf�IK6Gs)"�F�gwhew) �bi&--P5ec8  ��V��U(]�.�jirE�6�%��g:��t4o *�� �m� !^206�)� �de�h�.Europ�>-�n Arch� )(Ua-S� i�� �@]�)� -ad(t http://ww)/Debi . ac . uk/ena/��8/view/LN898093- 1p-T�΅ �`i �@�"$^by Trizo��KK)�K�2�(. u�urer’�{�JC&�.�V.�Xf*rK �(". or c�"Qy* !M�]a H MM?M�S� d 5�\�9Kg,�V S;�Ee� hA��p0�3A�:�I"�K 2 kb� i��a�!�$ �E��Mf�ˆh�" �polymer! �@p�Cr:j��"�[�LS� I� t�W CNR20235u7<�(:7M�-��-aM�.)K/�,cle147 . htm��. Amp ��2�pur �v�k%90�+ cɑ�-:j0�&:.�)y pic-{eenZa����e�xb���dU-SHm�ob�%�an Il(a9i Seq5�+�Fn alig�,�F!u5Rr���&=�ViVAn"� [7fy4("�4ias9�T!�A�� "" e��� SNPs !�pxd1A��!Ad�q�0}-� 1�  ed 2557 S��qB<f'0�Ya� �871-҅�U�&�)aH*�sta���at~ 0000K ViVa)aa ���EBc���=�188�>iyg`�Q@bB&1of J^ 000X' e�/&�@,�r]w$ve cut-off;�_nimum 3�4G2�l!�&;,h-ng�Q!%.�!��O!�e�56��A �YM�M�7 _x�"� ?A*@�Bx�J,W����GT}n X͝nogalHoutli�� 9� 100%�z"U%��kenAgin^Y , 36–48F9inMU��� a�1,23,)šuB� . Va�&X69� ;!���?� )�*�)��b� 6;�� "��n+jj��i�he�u*ue�Bo��mb!�l�XZ""\ x'�� “%”�“� aQ�" in-ho;�A�� � *%%tr=%A��e�@)B�ba��~q-mcf [8U��(bwa-mem [9]Ma�r�� ���!��jng5�w�;� ��ojQ�Htissua�c��d� u�6�,.+ �plear�\on Vero� C6/3�_%SFI5& Je�#p��!�a�.Jـ��th!s��V� � & A�( $�2Si'+ll-�O�����A,2mn CLUSTAL W�r gram�]� � 0X;�| am M�} G��o�01]�EI.�$a�Pmal&�2C�b��&c#��U`=. AkaKU&�/c��r��ier QvUlih؇U  b&Ax�,GTR + Γ + IlN �fi�2��� um-a phyl�x�gtre1kA�=^qiDsoftwa�� �PhyML5t[!d���.q *�O�Jnod[�xas]I ~-Ratio T!�( aLRT�  &��aB��__��0>�B=!.� n*1>�9�apsa�%� k��Bi�|lrt��$.!��=�y� A. �aZB6.m� 8t�Vr�Jes:! )+L$Chi square�=O�;�(�f Sh܉,ira-HasegawaE>!9c&� ( SH )}] [�~�G!�'ar�3ri�?(  a .�tof@Ra!�Kumv�=�b:��s���a�3ύ�;aPM�`�^&1�6 boot� p �3!|al��� . Pa�x&�f�M�Jk)�A?* mL�;��k����v2 �  ��Fq �5)x9orkA��sto�&6�is�m&���!+���y�k�*�� ���+�=��m:2Pe$�,� � ��I��"�3��1wk�~6m&A7!�&�Indf$OcHl$( IOL �n�� 9![І �commo�Z6!1sk�*a\�96%Hub>�BamHI� AgeI� ri�] R�H�BbE�-�!�aRL!2!&�ImBW�@^ ���t�5�D%�-N��u�dn&�6��, R�? l--E�%�/! KA�XhoNS1v1#5�E�6�VHQNotVQ EachE'�precurso$-S�)��n��)EyB) `l�9Baby Ham5@ Kid��( BHK-2��X*� ) m��e Dulbecco:Mo�_Eagle (R ( DMEM�#FMm 0% f�cO��x 1% pрillin/NKptomycinrK/rK�F 7°C) 5% CO�A> �(�U��J�Lei+"tz L-�m�n�.ne �,�� �fsW� ami�c\}61% try���>sph�Wbro� t 28�! �WF�A�y�B�A�g� A0.r����i�L��"�$i��^jA�za%�$.�s��er� j.�n)�p2$/laborPDAnd�pMΓ�Q��^ �$NC/2011-58�"� # HE80646A��a gif��ehhe Institut Pasteur–New Cd^oni� All��<$E#('�0cen'a+MZãz';�r� Cf��pla�(�'y:�&)& =�)M$Mexico , D�r� ReŠ3Trinidah{�ݷirK�� l��+3'B�A ��!TScott We�E�RubAC��. Mammal�q��eA�]) T{"�'f�I�S3 � an MOI��*1�� /�Niɍ���+8Lb�q�alb�/a��qHEPES��V��1%e�)��Ah� �� m:�7i�2�.K p�s���0�sd<)A%�waJ twic�_ph�Au�Cd s[de�/�P�<vL-e ��z5 iquo&�� .�m!�t}��G���'�B% >��v� TYv�9�m [&c(T)/ .�"�r �u%#r#�M>�)"�� .�,� }2s seraAuIl�� q��Z nd.�6���&�*� ly 7�4a{[���%� �sr�"�.�!�swXpC�"5�whoI�diagno�Das-Kpos5m> �) . By� a%!V �*3w@- semb�+!�Ba-s:ze� ����U�deg� �_�"��(�b�1��.�%sVJ�}s�q ��Ax 63 fFv*;" else�� ]M�!alFA=�I�K'|S��y�, �yu5Hk�2�� �!B{��r���!�Fje�+,!3a6�z�"�) 15][��,��%�)J���+. ( "�&Atto cl��r)?!�.):�6 �_1A=1`�r�m/AU.�0��$�aEe)�N -&ji .�$� 6�0(��FT�����>5%*�� � kv4�x 8 �-9"sy"#!����ce"z�%�*o !/I��rܧ��Ep�.ND%�� o){Aum?s ( nsP2m�on 271n� A>G;3450w C>A;.1V/%�he" �on 1195�mC>T;<G>�Y��hb�ERAU�n e1\S5`�#lޝtic%�6���-*�ae �ipu. WA�]"\A�%�9�2,��e�]�i!xDq�0a.!�"]sFhs"�Z*�+� �;�(��33%�M�y"49�:60ey"6 ��*���+�hl*e�2��$ .r�se)����f� ߲:S<�u�4"R-A;M E��I�.�_!�:M��J��6W~ �Tn9dyrt=�[G�5!��!��F�A+�:��c"� as m�G30%!�:�61:Y.A�n��"spM�||?�s 2)>q1)yADnVq-JhNP�M� ( 56��:�"&8�+ ])u �6ru�3al9�W�b*95Dy�^W�.6q!��#sPem�)&��e2� thylb#X{�"AfP"�F� ir*<4R &a+e�2&��L1.�h�� N�4S)W�d) � conc�m^!�-F�D3 do�A� Nsp2�ay>19u� vA�-B he(59�e� �NN� t"Z�"l,�\�(%�����e�P2iU%��y ��ix.2wJbyH�g p ( G772D )Q�AMroux�*# �]��>n�69 nsP3iQ�0 enco�1^ �16�F9�!�a�st�F�� 23 �U^� dx���5�.�!Jn!D18%�Q�; �T%�� q�ZF��xup\*.�u��m�B_��`D�1�u os��e�idui(%~4( S48R , S255F'S340P�V�@��!��3(~0%J���T)�+orymc�$"Fe "?G �7�40ge�/( G113�R178Q%�E415K�"�.}���A8b���*.�%�-a-D`�2*�',!>1 Yy1�Z6 �,���.F�A6���ef/�o6%4a71 1�� *.�( L441S�W)!�63��B*%�<z�DeE�63g27E�hE} T&�4���1�C,v �|AFj R� !��= "hm��Hj N����t� +c�-@Y) D�_KIWEf�[� stem���! �����^c]{�c)�%F�@3s&%�pf�+ -loo���Ps 8��10of� d� EETk�>M�a+ngip�/�l�];!�p�7oo��Q�a(V!�54�4=!o �Y.� y %��ly&�d�-� �#�Q�T )�E1. 1010 G>A ) ,a7 well three cod�6,b(G460S , 37%A| the popul�inB�_@nsP4 ( L455M , 95Z<2�9a�G274Vn;>)�ui� sera-� es . When�Ycompar!V���Jbetwee���6�dKoI� same��)� that%"a�N� pres�'�eindeed. oA�Y. Fin��.  eachM�,a single timN_I�}nE� diversity�npI�2�2�( Fig AS,bottom graphE��panel%� some��gct has b)oen! viously w!� lookA�at�al adaptIl5�uch��par�� host�r4]a> aken togeaʼn�Pse data shed light oni��� hot spotsђA(CHIKV genom�}�:� circe ng�!� ��i�ұ���A^sugge�E/8if wildtype-lik2^9�is desiA�<, it may be best��I(e-4strain����$ly-permiss��6= line(:�(characteriz�!��:��Fregionsq/:M�� exam��YSnon R,untranslated_( UTR )M�ɌTo beginJnalyzm��-�er�) 5’@I�5�!�3’ sub%�ic promo�� (B�`i�only sIU���W��se�Qies ran�T�0 . 01!�10% :��! N��@M\)��,>Qcor!/ i#��nQ!U�, l1Z< a powerful tool�which� studxtho�si��� . Iiis +��&� -DV�I&�"2 - ��&� %J!@re!*]豍outbreak�� t sh�fb�SL� @whole-!�me � ���ed �I��{!r$2��+,-:��possibiD& &� . H�we�w �f��&!`p >�� . -�%AF�!�t�er level7"L  , ��a!� acid�n�c--�cua� proteins /as�3 . Giv"�� vely-� y� most����( <� � mu�s �ly�E�d�vo�e� neut�orq$er fitness`E be purIdur��on�ptleneck�UIt!�� knowA���� jo:of�in��e�ars ��c![20] [21�fIn our bi~,:? �e\ous�of�,*  80i�had5~be� �45% , yet above!t backgr nois:T !$. M�Ml5� �" stop= =sresul^ n!i� %#��w�' �p �Beq�U� I���nve capac� ���suffic9 5�to�@p o A�mas�� �e�V willA>i&F;f�a9�%Q�ariE���exqN�)�weda�o t~t�u&e �i.i�"x "] p>�diseas�Our��dnd� at a��e los�C��-�1�6�rs�e�"JVinH &Hespec1� 6/36�3.t . E2M0 if�a�>SkX, although often necess� � $diagnostic�� surveilla�,%Wthu��e �facts�v�Qy!uexihJi��M proc��of emer�in:O. Phyl��%սreveal��� �ll,,in Guadeloup��d�i��C�LoAT> .� �&� .:�aB�qC�e��sA�a� ser p.�re�?onship���cana|attribu� �short ge� ce�>xeir t-branch�W�����Brazil�R206 � AMA2798�� ( InDRE_4�z' 51)�clu�K���co�� �DE-;9> O _inwF�� �a��Antigu!Barbuda���a)lose geoc�xim�0toj2[22��3]��w:>)N�����wh A� ly�veE�2�[15�&&��-26usupZ�e� hyp� ab�i.� "% inMW"�by��entry�̵�:) � More�  erea� ��ocu�onN� �&��N r����7r enzyma� !c"��b� ��!�&�,V���" A�i�S!A�*�a� N!���x*��"in na<�:��al.esN�5���m��~8m�� ��~��d&L�V� 2013eaga�5 L�m.Js fix�� �nt2��f��!�e�ana/%��new�� ea�M�dis&R��A� '!6�it m�incA�"� titer�>�WO �m/ �rJ��.�.5. A!KeUr~ER�Siplay �"|# roP5rbo �"$ o &�,��.   [24]�?�R �#cADesiL"�9�Ats abil�k��lly 5Tesa� ��se aff��a!��Kas�X )�m&�Y� ThO� �l�An7 to carefu�re-�zeB�assemblF,"suddea0]:�Iad$n� �unN[st!zVA�us-1;"i3�=b]� !B�y�� @r�$-�� B� �!�b! t�=t2ifa>fir���ine p�a rriv��BW ,Z ����just befD#�y Dece�$9 ,�s3��st�8��epidewin2�[25��aGsi� Vs�fdu�Ua"? �Q�J(se scenario� �X&(chikungunya)��-+-�d � on�1�A@G&� .%281 %.oi�����&%yk�!q2I6I,�br�v)xa�1,o.R .�ei��  '&�!tbninvol�� A�~&1(i%fix��%�i\ne�a�sI�( . NonethelR ���A��dep�ok`!a��8�� (an ongoA�F�Ub, y)�R!�� a2��D���ofub� L to fuM)�Qp.�,.�s��ofJ�E"V�$ ]%�A�DO�6�œcru���8JE'�*�#��wn"��>�) &R �V c he� issu��in���!��Ž"�*.�wT�$TOR signal!�!Jways reg�#e��nd YU�0ultipl )x!G�N y UBoe-& unanno8+d� ��a. ![erm ���%.�:�. Red�of y` K�0d hippocampalgr~#� PC12f� �"s �out-. [de�A� activates>�U#sY�C ilst KW exa�sP� r��ony�  o ��r P !z Stud�u�+d!�@d zebrafish model���)�inhib��:Sb#��z!�ay" le�* mpon� DEP-�nd ubtor)�disrup%&&1�er K%<3 9aggrav�&(HRAS ( G12V�4duced neoplasi"|�. Las��, �9�5�tum��nd �y O xen<f� use-2. T&''�z ��mo���)QM�!��s�via>� . MeU*gc targe�(rapamycin ( 3).�st�a@ a�� V rolM{,metabolism ,�,!liferɇ!'ival . C�lQe {�0� i�-c huma��� �+E7%wfoQ�, obeG),�a leps�$aut��neurode$ A�[1–3/E�9�U@i���"��,o�t ��!�u�org{)L [)h��%l cataly� |�s6-�*xm�C1��C2 k }eCi�ew�a*�. Ya�� >4ng"exert!sa&Mcory�|o �5. A?��!*y�e�i�of �M�m�Zd鰅$oU/#9��8�\ vert�u�� es [� zhosphoryAc�9i sjC1l]��E��1tim��A4�e ch s.?$q�� o'adI�[6–8AdN���aal�Taolaʨ Le�9(&� a��lyF+excep1 Alis� � downMedJ oe�b!�e��-s [9–1� �e?*!�U5A�[any)�do-A�We� � r�n [���.����>�.�+j�a���$in HEK293Te�U87MG!� ޚ.UT24 S.!"n$6!aq) բA�]�. .� aI.<�s X�ze�ac�-qo�U\y�"�X� Fs��es.BQ^’s ube��4��Vin��&��e�B s�3 ct animalA�I�&�elAe��"-beara{miD�|9A!�Q�!�z kiaa1024/)T�b ;3�& enh" -trap scr�*ai�)to iso�q� �!)o �4�'� nerv�E8system ( see Ma�.!b�Methodsn$It�anF�+f- e��-es�Ck0situ hybridiz����A�e�-��! �_&ub�/sspi��cor�e=) ( S1-%�&�*be�7�2r�r�X&�iy~f B 9� . Ba�onQ!��%v!�Allen Mo� B�Atlas 12�$$GENSAT [13�Ik< .Vpaj�:��+���/b�3b�!�m� �g���%��"�0� 6�in rat@mnN�(�'. Fluore�+$ye Cy3 labdsmH+%|fS8ce l)(%-si �!"fu"#dissociUN�to� ck�n-kM !��� ��',52&Bd1�)r[,��ce tubul�/�!~measu�-$at 36 hour,s�!vitro  ( HIV�56 �AKS2Au� :�!�F�lengtheyal�#tw� lji1knock-�RH��Epde .�� )� �� ��). LongerE6W2�so2�i&z�at97.,W!�xtY�)*rve��v  ( NGF2�u:�in.w[�5We te� � *�Aa sr1!�ld-#j%inp"�>�Az ��7�tha���;e ^š^�&2DU'>o2�treatw-d gmaomA��six+ p�s�+1!6. S^�Ij�6U��G�A�!F.� ��!�edI�!{48m��A&>�M�03ɱ)�]� d6" .�J mDE&10E <>�A\"�r ���&  �!Eo �( S2BU? 4� �0 "� *� E&N ��h�sAu� Xena Brow�"$( http://x,. ucsc . edu�+2 Fire 10firebE .��/ "a��markedly�(� �$adrenocort1 �, pheochwcytom�!$paragangli�L ( S35wT�$w���) ed eO� �"� !^� d14B?byA�tiNmed�sha�E���q�2�|J6 p1�� d *l�"6 ���)�� blas%.� I�2�0, � � �}E��coFO�  \�\ł�7 over�R"dde dR_��ARcarcin!�&�R�D��I2!,�jmaiK9� i TrkAL-p to�J. A�d:7q��;S? majo�7w�eam*��$s: Ras-MAP4% PI3KA# –1[W^1no"�A(7�{.*P of ERK1/2a"skin%N �&� ��0*� ��.#n!�;$l:�4�� One �%�9e �m*��i!;+��'. P*��� RPS6{@-S6�aN-v�,TO�",�Zm�\�-:B�6`����I�3iH� or 3��0w^d_A������ ��ih A�B�.gilB�.^� 3. W3l er��at  l12 �>�}�K-� `4la F� "�: =%#a�� e�63d 3�)NGF-in�%Bup-�A%e�x?bT8-�Y Mfic�or2�36xC�Ds�62.SW)�2+m� �8�6Es�I"� �E l�rT �(m�6gMz���f��a �RRAKT�47�D]�"262>6x>ly%�\�B�! ��m�6Q�%�."F M�*$ *X !�|ed�;E�&�9�$blocked S6B ( S4&� �to"� F�jQϭ`%��'ch32�6�6�o]�CE�TR�op70 S6K��K���7B�12�-��a1'a�)� �%`%^-� upon@D�c"E<)1� )#�.end R ic r/ ulum5jla ��J� bulk�#[]��0-�4��S5U�W��"�da��# �V�C� Y�Q ��W c��anb HeLa-�eB tagg5�A�H��"3t�.s=Zco--4��. UE2 basa"Z�Bi�`7�ex�0oVFm�ed�, R*�MLST81Y�$4��valid?a�tibod>�Acogniz!��, M8 1�(���Ł>!KouV�o�/�ofB nylarsi#=x�@( PAO�] ch,'&G� &�R`[�&S96)mO I!�>�A���4��u6K9�H-% QJQk,immunopreciptN��FLAG-2lco-DUnd-�lyF1��;���M��� �(F�#ci3;,.r-BrcoB�z�%=qI�>��A !�� t���#i{�S%},.tt%�351y+%�q2Ai0��: -&�02u>N �*SDg!�"l( �1-467" tronc2.�AF4�l6f'�!*&�O *� bR %~ �;f Oa�5iB�H ria-sourc*�9R";>qסyPDZ�!X Mx�S!����)g�"stituK,l�- �h Vy 2�)"$* 3!���:� es-t� or%`�6n��� r �:t! �$C2 [5 , k:7.4 vW!]�pa7$wmE# ���! ch=V4+VH!I�* � m�PB =�a�c by 40%�� Y�ofV -��BN?s.� .�of1'caY*byi� ��. C�N9���!Z 6� !enM! �� ed.��oNt�S.�A�&An�9i%�-u� R:9��I�����>��sola/u%.��.==�&m#1m.�. A^InIK>�kmiiN"v ;byI]BB�!�ejM��a7K��� U�� =,��f* "� sQ1�w 9F7 Mr\-�B�To"d<� �0i�+APe� Q7N�B�!|. ��%E�co�e% �, %&B�A���&TD �"  $! x( Δ89O%91�Mdispens'>*A���w&+1 dele%�"�Cf+�� 52� � abro��/H/�*2 -�ɪAs!)���1�F��requi��n3R�-� v�� , be��.l>27�O�} iddlQ>;468–75�a�B�6��4 �VP>��0n�ai�%jN"-$-%�a�?�}&�'��a&�,.>ngW)���d�4M���e>6�� ͔n�n�Tal +E��Nb�Cd�!� homozyg3u�J2% �:�s�-velop� bn�,litt$Gy)�of"�8si�&a�ir)Bd typ�Jb91�Ef�3le���> dard rais�%(�Y"�� RGCs�#behav�H��'"�$�"� fear-evoe free�/o� romi�C-s56respon- ( S7� 1 saU�9@%�!Bsubtle�I.�"_tA�-5`��'�=siology!fo d]�TJ7�Eeq�9]>`l�!�PAXB..��Ki���n �� larvae15 dpf� �? Eaz�� apprF?at 4� M�l&��2o!�&�"�� }87wR e9afW%�oi:&,� of 1�G �I�aN"��"to� �vt� �R�a�. foodB;� �A}S)"'[S �A�fe.�2���!1��%Z)�8 dNĉ�%�40�6,�-depr�3AX.�bX� fee��UUo��t�.X R F�>>��d.2&x 8�-�MP5%�* �}|J@O =)�i~Uir  Y��F� up6�!�:n n:�. 6�3�d�Q ant-EALrm���X�� 9 , ca�Zz5�3j ��*�ɐ&�(�yos�B.B��in '��'6"� �*� �9�Olo>�5P"G!% ,,roinje���'6a) 9!?o�9�ntΙ�&",l4�H=P70%:le%30%!=��"8 F[��>�� �o�,,�;i�59F<�*�Hn0|� 26.G372�s�m 3( χ12 =��2�<P <�J00*J6B�&�-�3�1�0-&%R7�*)*.%ude!�.~".ɺ�_�Vd2A�B���Pp':J?I>dXmX}W 8�8B;H Q4 �Y�} ���KD1V�d��oa;�leomorp%F �fe�C hig�Pll den�5aXXar-"Q�a��IAR Ki-67x$5���R� �b�-  �tse �eA+aY.��/dgna�c. IBblo��L"c >��vS'H�g� elev�4-%32 :�-� �7 ��*]�� �PA"Q�!rVx"�0�-I�>�Q� y hs"$c!�u��8��3cy0T=*� ��2"�J)�.�:�6�[% A�lEc,��( Ao���7Mu�F)KpmT* "� gene�+R�o!_-td:"_')�7aD���..�l�$)B�d I-�z:���Z:a�aP#ng/ :�:k1�:.4o٠N�:� `n�2tޫ6 desp".f exhaus�&�b� -b�1 searVL[23–TC��is�f\�A�AMS&�2��$A�shark@es 55%�3�-h�*m. S����predio�1r z27!2 )qp�:k2�48]+�W�^�L�;��{I X�B��Ks�>AO' �.C GeHorOplW'�8*�,� &\,"[�p6� � :u+ade�)[1�A� a top-ranLla�q�,a�. <��[�D1>9N�,of-�i��,��9i����/,n/,e�!��5!� %Hs)��1�%8!�>!!.:`. AW ��6 :,�pZ�{la�why-VKoZ�:ab�)�:.J� ] ew ,2�?�� b� %$���=*��.� � oZ ,ecoF0 ",6$a!MN,.�/�!JI An>N��,V ��<x� �)V�C OT*L . !��0"' �3�O 1D�i�N"�A�6�Lwe)�e�6�6'3"�e Y*� I�k)��� erB+s=`":��I�A�k8e�N'�:� heck�t �� aZ=9G"U]k�W m�A m [2�=31]�� >u.>��s tK\Yg ?� AB� ��� �c"�@�  .��BgjBv o�C*8@C� Acit�P>�uk&2 .FZe�E�i"t<>(@I wa�B%��� ��EW.\ ���i���<&<�"� "{!]�. B�! *Lh1bbi�bto1Wp�$ monio�EA��[ ?!*a deub&�=ngeR'DUBQS�b�� �F & faiZ^ � !�WencOQ r6@o='�Sal �\�Uk[T, ngKdo @�,H(�mo<me'�et�O�ptlog�[2qm� H"�a!hprh:�e��H Y e [3n03tDF&JZ5Z"< �"�D �h�PrO :�E�a�,�)%�&�]al"�:" mE3�m,ase SCF [34]L�=p!�:�%�9�$?)�etiY)riv�L�� sum�;�A1��!�s�g jaow��# R5B�Manip��i6�qh Q/E�"Kl�m utilB(ptimiz�E-^!�K�8%�� �)y&�J �=zL�toc�5��eda�� b�(eB $ Fudan Uni'p$Shanghai M� ,al College Iv$oaA� C!�\Use�"mittea�(110307–08A�130229A�215011�908�Xg!a�C� handq8ac?�YUNRC Gu3)%3he6� of LaborapF �)D+B�R�|)�n 0) eriZF�J�m!�3c*-pws@�@ �A�to�fn��)�[3jFls!��&^!I��? e AB , TgT'AS:EGFP7 :GAL4F�:�  nt��!A( wt )U6;� 6qb!*] of Oregon= FPx.AT:�Ya gift %@fb ( 26�fIE�u hnG�%�b!Dew�TBR(�J e Rohn-Be �PaS�y24 !� 72 h"+!Mfew + C trigqT s}&�. ;Ap[a-�e�7l�%ig&_)olh ��"6h��}Fsi�Pfe��c��v!YK%a9,>stoa6Z+�unu T o [ 2E��.[Ha䁤le�,�id<:"��M�>��%[40�CRF�%6smo��iv��IS1|~�6墉�Q�I� ��W%��M�i U �a 7&�)�Gosa42�V10j$13T3ANM�Z.N 19899$>�"�AR��}.�&�ȁStS<N�&���>jaE�6�&l L�!� ��&��nt (IJd10�D~�5A,e��!Ot�#ŽE�.#�~v �qQj�I so�1+ dE Lw_VXBM��\Qi. PlasmulUu�N�9a)� dE�"&'`� �.�"!dei|I ,.�aZ6� !��%MF�2m. Oper!u�QE�w��c�]ed!x� �6p}Ctus builm a�Y�=c|g"(9.|[4Brief�f2V tank%X 13 cm x 5(( L x W x HA!0p��opA�a LCD�M�~�Aof 2 mon�pld� E�ok~�� T �z. D:m a 10I .�Z��od vis��cu�blu��eckerbo�=�G�M~����nH)dJ �box��10�%�E��he�U�9�� & . No� c� shoc}]giMj�\&�S2��A�^�$. Free-movAR9�recei$a�"2��m8V/cmB�hene�e�.e�&4_");�%�a�*e�&!"&A2p5zV Wq � ���%�)P&max[ &[�"s��I& i|;E# nute.ml�h�o �(���!A ��E�or-�m�~�2 20se7[e6)�,I�! =�switchc��� EW�8 [S�qH!2p!��3i/. F�Ag e@Y�+  e CS>@�VZ2���x2���2fep~C!u� rut}MATLAB�Wip�f<`lYc imag�h�� fra-A`cam3�ata��us!�Adon�$tra�@!m���V�A]�uŖ!�de~h �� Ml.B�,%���F�2���a 5A�4)� gridxlaser-cuR4G  70 m�� 2��TbJ cryl�k�Sa��Pvib`�'d%_T 000 rpmoZhM�6J%=ri��a� n Arduino6-#rrI��t)>�%�l�jŰsteel ba^�\p� ���B.)- corn| . 8M�B)'F&a2fil� <�~-z" �20–!?s�E"AiCA9q�5/hak�,)U�elicitQ/rANu9I�re M�>*/!�40 �0J����$bac"Q& � eex�9Y�Q oajNrepeti�"&�B�6&�pB%i��he��a�q��v�U� e2�A��tu�ey�!Ja��&E0�n5?("�-!bNCS9d/�c!�`day�+�4Sprague Dawley�0�'raA"z+uAJ� ��@jdR  [4�y�����* by f�forcep� di��n�P<05% trypsin-EDTA%9u� 6ͮu�(37 °CyubC��S=E�t��(by DMEM/F12�umi0HwFBS%g�S�%Hca�%H%@entrifumrA�<�K8�K�!�re-su�7A�invv�2yeid�4�i slip�bhe�$poly-D-lys!NztL*of 4 x e�� s/cm2ewelve�II�,1�5ap��by ��!�Eupp�>2% B27Nb@IBCO , Life Techn,oB� %W*V�s*�Of���HI Lipo-)EenV iMAXkr�s S�v9:iCoOhly�$in 2 x SDS*$ buffe?T100 mM� s-HCl pH 1�4%2,I�42% bromophenol� :j% glyceh,!�2 PDT��b boi��at 95A�A, a�o�F%���d�res1by 6%-20�-PAGE�� lank�nsflo��n�V!Hul"JG:��M�aa�b prob1ǁ��"X*� overn��de3HRP+ ju�9L:@7"'A (,-��;�&�.by�dTDlu�4�X,���XChem E�(�GS�:e �@ by I} JS >�A�6,J�in�`�!%-DM2 be��,( Sigma-Aldr !)4(HA�\d9># at 4Q4m� �EA!� ^%)wa�a�@E�AY3eG!�FiJ[Ř.@mi>q?�,�A�fA�f�A� pu/�{J�yVA��e#IGST~E4sXxo��bC)=�gl.},hione Sephara,)i ( GE�ƅ[ce]N�`"!�.�1�%c2�� �V�J*-�C BL2Q�DE�Me�Ung.or�0B�:�-#um6�( 2�C�_,pH 8 . 0 , 5��Na1�D��, 5� , 1%�[tonX-�j,)�tF.o�:ckt�"$, 300 ug/m%� ozyma�.x1ea grupu�s����he�E(�cle.8.� -!�eh:V ,or Ni-NTA Ag.2J�I�N�B�m�g� sI!a�BBNV�elu5 ����� ��%�%�,� !���)��Ay��M23 �Hi>���b m�I�imidazo!qn�Fp�! �� =WM�X..M�9)��s/ in 96- %M�t� WST-8��!�CCK-8 ki�Dojindo �=I��"�Eo 4� s"ta!s�Y����<fo���#bsorb�"�^*E� 50 nRN*1 ���B ("R+��5Y ( fW)-d�� 6udi�R p�-�eh.� �.%$V��ul'C� Puro�k� )$�� � �  μ�Dr 6& �sAPQ�01% crys�7 viol�>wee߂AB $-pCMV-GFP-7,�3Lm��kfq "�2�8� k9ʎn�%�gAXF!jof�/:��DdE &,q l*�a� scopy%�ffa6V9�,JT&6�>�,��/!/of 1x1062�,B�l0["�+a�@ ( N�6or�(-1 .2U �Sμ�HMEMQwi��t�1�P ana��O�-e��Afl=7-!�-�0female BALB/c*58� ) {rm�m^d�|ry�d�a��i!( cali#. A�end poin��!i}�":<.��I��� %�Xldehydh>!��v[X-�eAE�u$�@o hematoxylin/eosa�nd`8e%�r �reK&E""%0��NYqI�� extN!�tW�tz b28� >A2tb��"�P�z��� saMroom tem�*$Ș �Ni��post-sPan�Tt -20� 15"��e.GƁo56 in��7F� -��� !�so(q�>�6��ns3)%R�Z)SFPearson�3corO� coe�$�k7u��I,package Fiji~�ar~3�i�Ss;n ± se�vS"�!c��l�3<5a�as: *:&�=�N*.1 , *2!&*:01�oByEAeEfig��z�� O+ /�*qu�^ Gi6re�entɎ~x t lenZ�!b�D�a`d^g�"�.��l ��sw  two-" ed �uent%�t- B-� �t-r8�0 ANOVA�aL  `,pr�a . �w-G��_�$��rypan�% atid&Op��s% un�, hF��=��L�aNhe-�*p~H)2n-�WhG nNo8 ��'ljQ��af :�d global'u#�b)��AP�2v2� ill"l�AI�N&�_�%arasit��qbe{� � inK?th! c@Vf {� ,�4 m!8�T�r"fL�?- � ��/�*�O 3354�4�x��yc2=c��g8=� brucei� !&ozoan�h���Gi�R!)Ȑn�I:ia.J. UWrigord2w1/�4P��x37 a�.Zz��s!~mM�;e��w�*i14� ) as%*!M�2La�*AX T .1%�!��A�01&�0U� ]a�7*Sp&�u:�)�.DX&hYa�2sF �zM�7as"�l�8RNA-e #ng ma 6�}a�$d�Y�e�/2��$mitochondr�~p�_ �'(�1A =:. o5��14�*�Xe�Q6$ew7� �QO� R,%�=!�Q0l����$%��8*Q+iס2�ts U%�B+%���.�{&��at: wwwA�8NetDBEh w2uni� u�AflagelN���N��7�]aus�Ig_q� he f�7z�( HAT�0� d eukaryo�&sK� as y<a�J,�f�z�XDl� ���P ��J�w�}�7!rism�!e2�h�NM�Iy@a�{ nappd�b~�~>om���)dNa�@�����U�"g56Kٝ halfY]q:�'s@{�`���a���%� valuT:�n�;6�&�@AzC�nt� oŒ� /i��a�� havF�š!W�'[�*ex vivo��n !�vil��aN)Ap 6��=�ro�*.�>A��[�3O�6dMJ? �- ( Y2(o� �employ �>�r pairwa:=o s am�qU0[ 0|i��Ti%\�$[9�^bi^�[1!1Zt!�A����( A=5Fn [14–16]eowidely�*A�!�J�-I98eL:�f�(� �q . Ad��I7l)]H���.I�+;C�ompnF; ŏ�Qsu��ѡs #[��,y�thQ9 leth^R��8!_!9"? ��!!E��.*�:� ���Yve�9'e�IYi ��7��BA�ar���Ue� �r fals���e�"�r���cIn APF�,%���,�b��!�1��<af�<# part#$ �;��-�b �1v�[a�:\E� ,��fXlo����i�. Higr �t� ��o?�co-I��Hta�c�as��6Di�8Mor(�E/q1:�re��l�ufE�in��J'iA� ��-q2 ���J�.!�f��&=%� tuit� 2Ga&a��X� oun)�-_a;��0s{ �� A�� same"8 $ regardles�&d f�1I�E�"�oto�-neglig� 6����s�I��a(1t\wS�at+ �c&� qH]*c��2ork�];t captu!�A�V ,E�R=�9�� "vGmG0^("�6q!~g�/a%��|t6�3en)#� impr����{2J1�map}�.Toal}�<} 9�uOfl�B!O"���- �Q6� �org6(f �\ 6�&� �6�two o6g���� ��!q.��,i�-_} mass�Atra�r�n���"U �"�0M&"�co-1I�netAe�*f � a:1l86�rrsI e combi��2�-de�+�w 0��)]�A��%�m�N_�1� ig2�QQ����L of 866dN�m �{�tU}y�.ދ �ACl6��etj�A�%��A'a�6J(��28!g͈8��ledge�`isE�ћ)I���� �]t�8}:� &?�CaAY��i� a���1�EСu �ngו}�-Vsid�e�.^�d!MTo����AYCty����H�0!E�JiF-�E'fac'��Ir<Y��42�ma�w �pen��s . L!Olog phash4~�7� s�#).h�e!b IsTaR T7 A 3 (  GZvA EATRO 164� ;�J�  225 �*flask�1A 4×109 Rak�re�E^R"�+���t�+x g��\')+lI�� ice-c�glucos�+p&�*i( 6�"�(l# �t�-��*�+"�p�#[1g#Tr&k* 7 . �0 MgC�0�*2  hp�t�:iate-62a�Apy0 r��q(�%b.�l:U���on �5^�Ear&!- grad���!HEPES�)�UIMg ( OA�0�3-�%!�E i�A�78�0� 6 hr�i,&- %�h(�V4�(*on��a_μl:�d2elsew# �"�0 s=��6��arddE�*R ١ouo!of�"( B�;<:�"alb0�c���!IgM^��\�ulin M(]ap� �\ _66 KD�230 H97 A~Cl3J"�.�5F�I�IOuy'8gi�&fL}=rT?cap)�ry LC F|a^ rmoS&�2LTQQ4&�N>os8Fifty%�� i!��Yac�)�)w�A�o!*}e10D�& by vacuumyQiIB3 -� M ure!K 0 g,b4.>k,$5M�) A�>���yl�e��)Ci"�2h d��by 14��d�oh"itol ( )A�506�% ralk�R by 3�� iodo�am�=N $���i\.�9I!�2����%to 2M:4!�� q';2 , T65}t�*�5�" >te�io!u 1:25oR:U'l,�?n*�%a7�. D7M��Į�#�(�a� ic ��5%:�,U&��N\25E\�"�*![LC-MS/MS&� . E2KrosprfTon~$&�e�n� eath g�Fqx�max�Bz��2 a 34 gaug8,� needlI$%-��9t�� μl/Aa3i�cartri ( MiJ BioRe�C, AuburA| Californi!�US�h!%�switc���5�@5×�z mm Z�-x SB-C1�lum���W)�j mob� � con ae1%!j9�t� �P��A�o56?( ACN )��oe9] �?�B1f ���ep��-I66�SdAb4&� "%I�rra!f theoBSal:m js g"%O� a:�t��{M.�Z826�?��(@ tria�db? ��&e MA2 �0mPd�b� forw�C!W�r9I��pr��m S+s�/VerG2Frev .Bj,F)5'EQUESTe-�'d K#llows:6��A�ave2��� toler0�D . 5 �� frag�2moưotopicJ7��7!#tic�~�%� va @ ximu�hcAs!� !A�c C+57���!EvarM" M+16:". MfM]fQ�a�% �dis8;yI� ( FD���n&� 9 � a��5%.,6� %9�PAW pipe�  [2�nI]�/decoy��o�0Ijh�"X=M�-toe(t�match�+S� FDRss�AX�r" �� �� &��4!�.. �K�!92'1%�.v=36f %�ev�p�@6:�9䉡�$�&by - Cp�o�p *f_iW�at�g�by2 �W���itCETge��)�p��d!U�| ]}�"��� �i&�E1 � Jf�J%"*��15-�ISa�-y9A�MD\,A�aV��+�)���"'5�� aA� 03�&03v(�F2�Ld� ��so/h��A�J=I&0 abun4Wm�cMS2-'i-we��G1v�'c- A~\&�!�\ݪrG�VuŪ1Fv esti�p*r�v [d. C�* nd:%6g" �6\d 7at�ph�!�2\em� �c  ) –anQ ) ex���a UNOsp� ,�rad 2��, �dI�>9�i��[<A3<8H(?�8��M��KC15DTT^ NB [ A + 92]!K��9a"&� i%,Beckman-Coul� G��*��V^k .6� &+� hEw� 22 μm"=? , loa� ��um? ��n�� A���9� � �#50%B ( 1%a e� n Ie�* 56106757)�� -E�!>�3 'tnE � ,WyY ly�q�AM�*����  8U��."5�l* Dx=@x NCP-3200RS Ulti��, RSLCnano UP6�mo�=^' OrbiFuE ��� Pair� adja�� pool!�o̓:20� 9i Zci�%J.G�A"u��20%��?�dr�*j"D ![:�E� IG� Z?F���g5�� QoM���Z�=*\�� 1:10E`ua:�;Aځ�V0�ry�*H ��&in-'�Aw of 5Œ"� �A�EI�>���K 3"c*N�a�X�%�) &�� n Acclaim| Map ��J2�:NanoViN � , �m�-Q� )'�E#61�Lof�e �y��E�c��%z L��n-� �Pe�aE ����7 �x�cm EasyS^ T(Jau 6n E�y穓a� ��O@">6 �ܪ��t� 00 nx��A�eE���Qn�!�S�b�S��y sca��\�f� �\�U��r!��."��1]I_n�2z� iac�~ c!�ar�)���pid� NDatIEEy9eta�sec excl��:@��� �i� %of +1 �"ge{s top�7�IoA:� 3`d�- \b�X�$5?. MaxQ6 ( �]+5�. 2a����� f� 7 c�4�c5���!Y.oUZFASTA1I *�1!1��ke� [0f2�59, defaul�&�  � �d,��t^>A�2!�6�p%"�!öt. 0�T6yv*u!�9�:$�t�5�Ha% (�i� or 2.���O� � A T%�2$��ca��U]d׵otu �R@�{�WaF�X- &�SVs;./FsT:��al�5-g-.8R8�g�Wny �L"�/=9M�e���G#� �!u�[&5/AffilgW��b"�5a�'ql!!: -(~%LC run�r��i�i5:�)�� RNA�"Lg( i ) *w_"YdT\��433 bpY�e��ope�*a�SAf Tb92y 1� 7910eY� WN u-AQin"�Z�?p2T7-��[29t �da�_�A�a*i- p"l( 2fnX\B�J�p�ea��.G +�r&by ung �M�g�#p���B. GV��yA� RNAiO�Gq�jT}�gt 10�@{!��%��bse ":Cte�'9�!�!H&� %�unn� nd Tet"���F����Eday-3�6ku�2�/%C� *cE �B$th�#ect���cu���om ~108ns� TRIzInvMgen�TenC gram% i�We�Ure�- DNR#�"K�EAmb!���A ,a�ɓal5�=�ZdO�* nMin� � R�re���9TagMaa6@pt$random hex�S �?9T� >R >�d@8��4ed Bios��3 D"C�B�%+&A %-x� �� pre-9B1 A>n�61e>���.� '+ly [30dxr*�CEBju�4)�hf�Z9S/ND�Cyb/A\$�4RPS12/ND5 [31]-F a Corbett%�ene�J��D�?%�� z!s�118S rA�#'t&!�aO��6D�r�-X�l �=-W߁9�β-ͦa})�K!��ae�. Each �f�t� �(wo.8)r2�k>�%��|)v�\ޘA�E�&g �alc�)ed-QΔΔC�?2���[3,X�i"N i�>o�1�u���"ecaxw6I_.�FC-myc-ta�2��A![F�EH���73 A AH2Ÿ% ٲ%clo�ťBamHI HpaI�3� ��Lw�I1indIIZ4�qJ�)� $pHD-1700 [�oAl6�I�(�'NotI -�e���!��1�y13>?!g %|4�%��d�U�� ݥ�+�qW�nI �d1$e���!B�Q2Ie. &�V mid-&&+� �fi7F�4%� a"�G�E!cKU on p�UL�U-�Zr�3.�U�~s�/�u.�KerFF1v!2CF-*{~E,3�E . AntiA� �CD� ( 1:�%�LeJ to v�`p6!!� Mito*kLU2]w�XBH eI&�! DAPI*!�D#���� . Sl%�Er%����a Niko3-r���J H��o�X2�)B*G?�~�L7:�t*� PF c!u1q{,:!�}�65efMJ+�arr�nY2�Z'�2G,6M�d1�I�0 U�v(OU��2�� 00� of ( A)����a�{�jS�TE�A+ cI-gar�)con�U2S0%��� � � 1ml�+s-^-��#A �"m9 A  �;of>i�&�(�m5�(C)L �T&+, 10m��P10 P-40eN1��1Xc leteQ'�,= e &E+<+o$nd;�a��]A�da �3S� �w&4T2(Za�� a�1!*.�.�y&�-@1"S1Yv2�-ss �.{Sf$ 2 �{�]oA.!�ASp_K%�.{Pn0[a%��00l_91����aa��.B*( unb�,%�in�U�7 �2x�2:x!C(f4!N�:�/ SDS-uY��I iquo�.B+�quY nd�f~'�;D�u\[ge�*+ +�Jr�+��#J�Y�.�Y�kM�?#��� MRB 81707TbRGG[��k�F&�r$Laurie Rea7NstA6dsNew Yor�Buffalo��$!#t@�%�toichi�rbrA>M?� a.-w�dj��i*-��;��Vr�3�: �3;8j56A|M��76=ici�ngl<3/��(�� x� a�k�1��n p�A�U���3� � nNess��15~ �c䟁�s�Q�W�dst� �#����u ,)I�aS0��;��ut�*< �5 , ��?n�6Anih��of�� ( CLR#y��Bn3A�5V�ZS�<�&Ŧa*{@�M&F@�M �H!I*�M��B AY����.bE�"�h�B� prO�assum�t�u� 2Aْ8w� A R� O:v6sGu�2� "�� % J�,%�d�s �7�UV�q3>JAm%�>�!" ��Ha�aOZ�j�RdiA�b�a�!�H"05O"t��aUallR��at ��8>n!�(f�W!q�8JmA�cZ|< w�")�Rh&cut-of�� resh� atY0QFN?6�&���"��"d*4F�e%�sPe�.�Bs��J U��r�0jE�7$}W(!lICe; "�B� w� n~��lr ]��K��i?fGR�-non|@kI��Q� Eoof* judby���nmq*�$��l�"PheJ)�bM���e 1�WF*Ņalg�hm�?� o*V6z� X/o����FA��o��sCHA�.��#V1�;onN+a���eazQ�%lK"�B2� ,�"�Gs�Y.qor unre-Lŵg"�'�Zy�sO7l%�6<&��Ex&a�a� !A���-�Y���4se� h/��l� ama(` l� y Po� n6fU$ lambda eq�rK �@�9aph }e��[X�st"wo te� �]/[No�,f5'~J#!�e�.��<�=�e�-9r��DR ≤�0�1 ���li utuEi�YFC ( p-)>.Z"ET10��!#]���arO E&�e��Q� B�n @��d�!U�_vGo2G*Kg conn� �I` �+�)�)�?nob( �g . ,1k� eIcU-�U/�8{e�:� ���h�&*�~�N5a>���e�i=.�&�*�in- �2K]�I�3,92,�m�Z�%3 U�O�8 �t ��&5BwI�2>�*� �VcfG�)�M�1{R -U�&\�DE�>'t1n2��esH*�06%*, !�.X��2Q�I�n��il�� W!Ge"�Fw!3v��!Ձ�I���`ٛE`�a ker"� smoo-g"r���@2��0fin-�-�dh2 ��ţdyp$��"m�o&�F%+�C�� ����- .c�z: :D-����(��a�U2�fttru ?�re�Q (H�AAx� ,VG�::r�MT! p &�D] >W�ex��fO��\:�-W�a go T9 �� of >s(-2�20%�inc��e{��T=P� ��!�uA2 e���qIV���.b�0so�)2@V!���DAL�)A�nG �˦be Dsubunw.5�#K>�U�U also igno� �Nv �C�Xs��g.���a^ gl�."%*�hw�`R`Dx%=HNMU/ora�� �|��2_|%.�aх��=�:�p�NA . Neb >0vrj" s{"�eq n6�e�c  "K ��� 2|%�5�I.A�zB�!o*P�&>!Q� , un�2ey;a] &L al e,�2�"�j�COhQ�1q2�|��Q� genugF�%���]�� hl #�)n=L���-*F��� -A]P"J���6�92�� D)�a��V2d,�) B,network that� belong to either positive or negat �Xsets . For each network , two types of recalls were defined: 1 ) Recall for proteins: def"4 as the numberH@distinct subunits#8twenty complexe8@at are present in)�$divided bytotaliknownf$identifiedH�our mass spectrometry experiments; 2 2��(interactionF�>�.- t�C�> same� have�4Z�maximum�Rsy can Ptheoreti!�y . Sincfad,%v�!�Doften much sparser�)�6fpassumed fully-connected model ocalculaQgfoR�9sz$usually smAu8[10 , 13] . All�M�vi-Tized using Cytoscape ,�'a!� tool0Genome Space a flows [39nNi'AnalyzerQpluginA�.iwas us! �topolog!� a@sie-�ds , including: node-degreee= ribu�T, shortest path-length>$and2qcoefficiaQa�O[40�$To examine!� gene ont� y-bi�proceaA imilarity�U�ng;sQ�constru%��we)HResnik’s approach��quaa�y sem c obetweenh�$ terms [41�SB7ies9$GO categorof F�es%Acellulare�art�# � ]�!�C.p� pai� ��.sif both, Zannote��uniN0 database [42� When�!zF.�,!n0ignored those--with e�M�cod��NR ( Nota�or�j) , ND.,�$ available&Av(IEA ( Inferrfrom El�onic A �@ion ) . The GO-BP�t.��>l by GOssTOi�i�defaularameterA �HMATLAB R2014b softw��(w8MathWorks Inc .���MA ) B�4CLR score false�@covery rate estim�M!kernel-!�d p-valu2$ . C#!�graw$g languageFxQl!4ofe� KEGGe� ways�U�H �s� wellu� of randomy�. O& stat�ca��!perfor��)o��RR�)�FaE*��ba�de�A�oNPa-xomeXchange Consortium ( http://a$ central .�x 6(. org ) via VRIDE a�ner r uory [44]I���set&*(r PXD002640! ull i��a�8 am��searchbQw, pipel�F�)a�detail2Ap5ps�be foun�� �submiss!� . Biochem%�f�Ip$techniques=gwidely�Yl�!lrypanosoA�d!/anismsestypossibil�� physrassocip s amc a!AT pre-S i %�in_ 2�a��A� llow��seY Fotein�n i= on differ��b=proper�). I�0glycerol grad��( GG ):2� ,F>wec sepaa� d ac� !�!F8heir shape/dens!)�ter!�v!u,Ņ�9�ed�!�ba R�K�charg !�U� highq�a��$liquid chr!ЁHphy�{ EX ).� �s summar (in Fig 1A ,�Rcoupl�GGE�A deep��]ew�;semi-髁;v^ ultra-s% Főgenera� ! 5�to%t a)�Lome-scale T . brucei�jon�� . We)lŏ to observ�9�4pat!�Au 3354 j(in groups (e�logouss �nearly�-�+ sequ�A��B��ge�W) acrosad� of 133U[�s�)wholex-GG ( 48"�,mitochondria$6:$c� olic-!� ( 19:!��6I )202)* A�=���yclic�m�!6AU2�;. Due!�� �9 ary desig%v.[Ee%��8 1398!#2%!V� )�a�� ^ ]�6Qse��provie�iՙn=�=17�f,t saAP� seu���accurac�employed-�1-�A��edure���,��B�6�.8|  43e�9Y�-�� ALgen�]�9UstA�E��77–127W&� Ss�s�|e�� �u ( SILAC stud� [4R4?ToI�4bia��!9 � ��e &�ofV��of�tu�on. ��u�EH0membrane doma� As!E�, solu��e�pre� i�de�?�U6�2m whilIA�^ , Qunder-re��en m�D�S1e�K�Edid not5w9s.of' E(.P More�  ,J AK!�%>�4& respon3�O�Y��i.� �Hs [50]�ovM!�� l Dr4[51 , 52] indi�A$a� y �D-mi��re&Q Y�� ut%NowardO(re abundant�U���!,25|Because�8 �rIv�� lay � fun 6|,���e_X ea�n�-�^ �� p"!d��2a map� `EX d:�U ���5rel �-Jc�6 ~��f"i]measu7"� label-fMS2 hw - &}\( Dm�A�method ge)o decipR��>�� reasJ2 �ng�wouldI�1�5 he2�11;�Dbioin}�*$�?Eif~ a|co-I� s9M45��iRB7dea�bedXw ,}��ng�bal�-.v"��predi)� on f7criteriaj show!c*6 1[|�ir5G ���beB robu�w addivof nois� !#ir9%BU-�ity; 3 )�$hared-peak�(at least on&� ; 4 ) � stab:Cw� m!Bas judge�bGG-deriv�'�s; 5 )e� oduc*�B�w1A� 6,"���Si��q�)a�" !Fk"�b�c)��#Dcontext likelihood�/ednes7 k ) al�thm [34]A�3of+rEo�,�l�As]�I�s��gei�aToraq�A::j� aM�%W��:�wo�� vari��-�sA a�V.u,,6�1��IN e>s�WU >ng onAf6Y���U�ig*� hig�"than w�i} 6�AM back�Ln� ed Benj�i-corr 8FDRy5%�Low��might�2rel%;�e�1�=jef᷁,1v�� 'i Hb8� oA� firm!t�Zy!7_ d��|c��.S�-6�M�c c�|fte� � ruH PoisL gXJe%���a� m�i�disca���on lo�*E$]�y�AFK��fur%�reduc :��cJd��E�kepa��2��'which .�had�N���u��Q>�&deetoI�a F4if � ���%Q O�380| 8second-e�s !t C.��� Mi��!�n[ s��thi� ���go / a��c�e��p2S�a��\ , mA'��y�Uelimi�c u 5���2�"q M���N3NIn�1.i���! , �"sU !6ly�Ŵ r mo�ric1�� !1� �gman= zyme�s�Ac%m� a���volᖉU��&o!���sM b�Bp�� c [�wf�byC� *E�]�e$ �top�/9*of!\.N���!F�.� "cA 2LP5�P�Dl �-��of/ an��(*� 6E-3�6qbw �nhe-�>j�� t%j�.�. �� heck! calNS er��foc_oa9-�Boe�*�%�%de9in��GG:� As illustazeB{�sPm��t�half  o-sed�$+ � pairaZ940�l� �)�� 2� �>6]MY1���≤;05J9pE,2(!\ E� *}*2S& comm>x"6HF�GG]�w M:p, �"ux�ac� stic.XYcU��*6�en�A��� >� ( S3%�!TE�Q|:6_6�6�-�6.�re�'al�'.F <6�6$!i vice vers�To�$�Q!&1e> remo�5!h2i5� ��e;�y� isteBc.T edJ  IRqc�ai .��,/ pit �dea����i:�%N.BD %&�N��u :�!�Ov�' merg�G]�l�Q_�'er sizoM�� )��gi�%c+f e6f��V&�fap�VA_%u� AEre les!�Qro6R�G�G)c2�� We n� asse�!%a}'�N�u&IEX"��*� �Nnh�*i3C� .�c2� !46�&? �k o:c.� �B1�l%�9)!?�&�3D ) ;��:�d��53%��73�6�!�!�6GG1_ ��#�"��M&iY%!%��Kgraph�*��!m�H��6�2:H2�25 ( S4�>� �M�QD��#in�% :""���$�����%��2`A�"� e�lowerW��"2�����:aAl' Howe; x"� repancVa!.W!"����Rŵ*R co�el� ,e�ra� flec{&�cj�na@!x ��F� �A�� ����EE9�)� ��I i�5-w* �6�q�E��f* 85 .6tirN/ h^�8 ��!a�$53 . Likew�&..�j�m:�'��s6. RNA-"�!6+*����&trT*K )U �:I}^ '�Z�� ( S5u�T�Y��0be.UQ�alt�Nd�' [l�.^��disrup%�Ah�e�ic.�Q$�H.I se effectah$re minimalZMX.�2t2to�:m� s-s51as rib�){��asE$, F0F1 ATP�-,�j, edit 0(�cu�� ovalid)�X��6. s6�"�GGj�be'�r� �7 �:iH ioni*2#z6s favo� �N`. �4!�fo5*-up&�"�L I��Aem�y'�' is"�%h�*� , na� TbCF:#.&o(B{ \�#-� �0by!�$, uish���"Q52( S2 T ) �TdEa!������Ry � *�& �� ���;%_$5v�22:�n���!�e9uc'4s � 5*r ��13 , 86V*� DorthogoH&=$6r�,1��3�,e�.OR!&AJase�r �601A)��#a�}82�(382(-� �"A�e��of�e first6#t*54*�,��.x-�R 4"9"� )E �.�;I or.,� has �+s��.i-&) [53].� �" s� )9 �a� *� )|#mUthe0�bas hub��hig� linka��( I_ 4�)*� �.� 4� 1 ;a�an��r��2s y6ma��tra"� 9��,, ��5~#�'a*�$j&e b-world�/y [54]��al�we:6 a{ct��шx)+s!�ch make!)�.nsWiw1-ci��7u�TɅaI�a[h�+&�6.z6?deR-0&�neighbo��4 mj �N�65c <Yhub! ���%E>:) �1�i� T � �0�gis fe� ��M���.bA�` spo�0�99I�;ach ��6�2s A8 � M�)�Q�2,��2//���$%�H:wh�.R�:0tE,i: s=*Fc7A�s��%�5A�^S6�"� %�!fqC�C�4 & �n��n&'l�(arI�eCbv,eᮍs%���,a��!�<g~C9( �6)&�>%�ab#.� e1 preci�&�O��U�u�.2=6 [55�'�#e�-'���.,��aB���w*�,� icipae�M(E.�6"�hava3a� {5�) 7E|Althou3I��Y�Ffdoe{neC(ari�.�}{�>� �|' �td"9 a.5"�%zPa�.>� .y%chz" � � >&&�.Ly�QE�3 %�&�/�*UtN�!*~� 5E-3� �b.co-loc�3i�m�U�:�ȕh��5�,Q�A#Ay5�&a2���(cap�:)�Z!ap �2�&�w��inv�"g�� CAo{#�ZAz&�aJ���!9jj NB�e��T�ca)E�be� mod#"��%_ [36]�!�%�6�?%a� a %"�N�7;!E�i(1a!%�at�-e�e&o%!��8a����6�2*�15 W �:%?��c �"�� S<L0)�yU�MQ�0IA!�ngB) a.tFe� �)pr}6ll-� t�v 17E��(u�[%Wi�,�= n,M ox�,ve phosphory�on� t�<)VeI{5Z����a�is.�A��/ �s! pec�2��A��� %�5reA/aeve- ?9Y��E{e�E��.Ras?cu��!ie�..��d.A b�%��x.��]O&�8NvI%We�<%UMB�T�!8E`F/g��*x../�mFS i�Ven ��Y/i�co-regq�e��wpl�= a major r58M�&�Ae) ;�hU8 homeosty:2�/environ�[17N I ��A�="3 *�f�.x -]Z } �b�/J�[56wndeed ,BW%�3;:�5�.v -5��.�lym.�$ 2 . 2E-16�I4c�a�p0�*� &m0i?%Ndu�xEQ"� :�0���18"�?��ED F�Ay9/N1w�5H�9M2�- er6"E-�g5J�@5���n� o% eu2 ". 2 A��.e�H��R��m�A2.U�h*�#V�H e Aeda��&A�Ay}!|&�m"�#200�Vi!�!i5�2�� *� 34%p��@*l!:K("I�1�5 * ,�i2 z��2�5high-thry put"�5��6�"2.�?6� ["�G( sj5H.�5�� 1 an/55� - �ca�4AA6�J� � %�� )�'!� � of�l*:!*P)onR0�6��.�A�"�!\�K�M���0Wi���6^U0 svonE� PE&lb1�] s"-:l,59% ( ~2-folS AA��As �Fw;��=�$ ��g&�,�v sourJs%�<�~<4/,:T* %:Y�M.e�-!� lack!p"�= , un � iG�=. 2�w� reF q:uti�@es�G -of-� mach"Dlearn����o syste�")1(e"d-al6$��x2�F9}ex&%a� -�9�Mk �mK�- impr�%p*�o&j"�4� we�B4ed TAP-TAG TEV�!#of� ��lig�aRELSN1p"�6 q�it��a NM\a �F-w:d.�m�Mz:X.2�2�q��q�A�-Dt�i=�ayOe_�tont1ant�E co-purify %!�tag��6�!2!�8K��83)H"y-ACrac%uparG3 S4�tWeA(&a`P ub-QeO�e� -�hr�5e�����.B�B,)�Idirecr&� A ts�R�ųlayll|�I�=9���g 6.';�7bea�% a�0�! !�Ax9(*�6-��� =lyn�>�� .K �pull dX&y�vn� \ �H�3.�!bF����ha��Mm3)P V�1�%��_ 2�E�iɍ ne�Q{�$M& .�O�;�8A�i.&j3 quer2s�& btai�_�rehensJ.Y�<��*4U� �de�sixUmR�Ea�Doacyl-tRNA synthet��( aaRS )2u���V.9 [5� n�g2�%�fal� >w2U"�al�#9c"�Q�r�L�&� *" MARSxI�wo.'hypa�tK�a e"B+!U���suc��S )Qg� a��U�#�ȵ��z- t.� 9eI/��*��Q.��e*�retrie*MB" )� t��r�M.�a 2F���4!���A�5�,4vP'In�"C�mp�Fw���F!u&4L59- ѡ� &�"d�Ni�FSTRIN�)r [58DR>3� "�Q�a&�c a�~i�.�Qnd�i�D��.� (AB��;B%ngE�6� )N(t]MCYal&�R ( S9" B�- 19�Pa �'umA�faKc&$vel thresh� (�FR��byX&7G5��9A�BU�ebA�a Y:�aeF�E�19 , 119. mO�/40���C05N�.,Ah!>a>8zK1���")�� ����62/T$ āe�,{Ek bCF !�� �:�.~^#41�,���4499d!�a!cW ed 1�Fu�C�3L5��`h��im!�$S=<ToA�F03.�#1<ɜN��5It5 OnE"�>5GA:�6Cn��Ein,<in�EhU^ B� �%g�%�re*H?M q��6X ��&�3��>�!� !e�*�E!�*��'c>z,1QE���rF[L"�(W: AP%�-�%��M )Dd�'%t:y::�� E2ůE�j. B*�? f!ng��\1m stepihK @B'  ]��);�~o 6s;�%%tm-��r%H�$A�*n�Y�P. /NEQ!"T.D���W�&�QA�>q|:B�20Z"�<& . re1^&�6:iT-�t1�WE�(terlog-mapp�8,�� *��H!,*�R sCvc3BiFv=�!�2 QAsZ�("6�,�,A�, e�su�H�?6���,�; 1N, does9 imply&.��M�J*.w��1A�&.S:FA16�.e�!u}�9!�I��2�"B5� .�cHC>-4 , 72R�6866��&P+ , en�ras�W,)� �)��.�(�. �] � bC ������'� ��Y"(��:J*�NX8 ��O,JC�6SBJ6��j..N�5E-11�`O.aQ& %AD&�e; fQ�!�ɹy��Q�(��*�$� 9�A:��68%E�ouw<�D�ex�f of�NU�E��#.Q��(�6�R��?�]�OR� Y��#g/R�ZA�}B,w ��"2�� le���Lallm�!B�\��an 40%���^q �� J�*��F-H128J���716�5mb0,L Jed]� a:�=� e%R70) !�� an * (�tMVs�X-osb&hDUr�0�+1m�,[10P M BM�N�i 6� 2�6�K"G*b y?�2�R\("5)S1>� �R�Vts\�n6$ytoplasmic%U28 �&\%O�"T-C�e�raflagel}Q�9a�'�"*�5�v6k(^�qua"�\�H22% ���<.u�&��,UZ$RNAi scree,i�or.�[6EB% V7m�� act�a.N�f����,���V t<nkKY� bee�-Y#uBRin�e1�H a�$f�!Q�M [6,c"n!I���.�Ni � �baA��'h&%e� [/r�lu0J� �K]:�"�dofNAe%7�dWW.7�6|�uK pitu�f!�q�&# :0��}6�8<�9AU.�mwR%I (�<lex�,I'i��Ni[T- �es 10e�1��&�ALll .s�� arasA7Con�0='�c �7 &�5�!&iE0�+mF� %�],��2�e=v\���@[6eA61 �e�/�26�-we95 2%28d�:v&���i.F1� (bloodstream�2�.�ge� 4�� l�m��k �hip%^18��� s cur6abnWfF3. , 35"�"9�78"7=Ml635!��"=T:#� B���(&�co|fEXP , ID�`IPI MG � IEP�or��4to TriTrypDB v�)�;�aJvesACFB�:f&�G+��l~-q��E h42�U�2�he Kine�itid�u��A�� . Mi*�_ T(*�'� t/ �A8, yete0���stSQ�']� &E� }, 6 }s�$��criT as polyci<ic���"A�NcleavagA6NDd]( m� fct1a)�..MN�j @e�ir 3'- s [6�gIntrigu�+�*��*, vorigi�(0mN!�$Bct open�5E`fra�K( ORF�A�requi'G�^�Z~P!���-je'!�9q�DA \ 5,as guide ( gRN%), %U�`ins�ds!�� f� GdeL],!a��&d5ur�`$e nucleotia}a�2.5po!1�[6f6�6 �-W-�mara����. J�-!A/U-�[65j ".M�ewj�E�tw�1J�"�rծmultip: ost-�*X+mWory layG@CA �>�RCa"H!�isݰ1surviv7>��.%��>�A a�2�'&e�+Zi�]i� #. J�%) [66 , 6^E"�a*t�\m"���-B��?`%->K�VA%A�4*�*1 ’s�� e [66%�=�$!� �co�fe b�yb;�u�'�E5ex III[5d[ 3P/s"�p IIDO+Y&��:�]�y 9�%D�: �� �"NADH-ub�g�Fxid�>uc = F<NDpA�57�mD7��@os���!6.i�_�i�Evelop� a�N"n.in��G!�so�v32YW$vi�TE�e t"ej7A��Q/� )�to�`ow NdapF !>@o��~6g�*�.1 "�)[7� C"8&�d^� �.�!��!,%�jE"^O� .1 !.@�'�fN GM,�p/fJ�p*` !,��;A�I�F ��P[7� ��T&1s�k /A�m�&�� ( &5 �UV�� &����EI�(:& -M&z."A��&p3b�vs3�"�.�l!�BX""�RYa� �}17n���>� :S(-� [72�5w�a21&�- MRB1-����ed>Xi)*e�  i�!���-a������!C&& nho:T�(U�:�*�":A��mTaO"�t"MHH &�&4-��)�A S1&GFH".ab�7I=�V�v� hmLA��"�I)+seI�M��e� y p5)/���D>�zl�K9��Gd?Zci-gto��5!&Os �6U6�!<52J)poA�d !�@ � �a��a�@��� ,��Q�[��8�0 bA�nga�!}�A�G&�n2�:�9: HARNG��.Wt�q�q2 c�<AP�!9 �.\� �Z -oluI!&�lAi�ct�<sK6�6�R� 6� ��>#��f�e,���O8Nof.�٘e.�'"\ 5 ��%QX��J{�ai G >ɝ-Q|�!���:�R"2T6%hey faile�t���%�2�>o�i�3*�0i�1d�8con.uED�2sa z(*�<orF�le &W=a��D]�se13.B` " X[��Dh�-ɖ ���&t$a &~ Tb927 . 817�1 l 1686|I�YH6�.\� W8607[MRB)�UU.�-4N30�41�< 1187�A46 0130�ٿ4pE`5Gf���qa��t .�*�'�� !�&� 9�v)�I�'�oḾ�e�c/��1SM6-�-*- ��>Z"�MRB%�(5)5�Cd TbRGG2 )b08%I�j �& ùd�aye�I�i� �l�7_ !Y2H��i;[7�@74� or APds�l7�6�5@5�q(y@I2�7!TEV� *$��S!� -enh&Rd�Aner [71;Hh#v��el=�1�I�%o��k��ov-�Q�TN�..zI6�E_A�OE��iKPAP1u aden�>a+�2sXed�z!�� "� :�/s�A �b|�e�2�&(�chhF 2 I�[�=�ow�56Xq�sA�K� ' Also-����Pq V Cof1bIk._�J796���� �A#.t��% .!c;����18� O� r���immun&�zY��en:���.��3x new!=�~�� .R�796� . 173��:��5�y{'Ɏ6'�;IQ2+?)�? a��a6�R� >h. 6S{5�B� a��%"�1�(�$I�*��%�:%!�JC B�Sej�v�>�F��b��e� wo�B��>5��N��7k2c:t%��A�!-A��SV�b 5-a��D 6�"ō�4�"ya*d��{&�B�i�2U�2�E��l� M�). E��q(2�GMVMD|o�curYKRSaye:a1aX) 8T{.�� �%�D_ ���.8���S1BL^$�C&ŀ�YEp�|on2^7!�9��)�9�% �.�iU.�m�$ia�s1��[AC�rQN�"Mj" *J!|�al�0e9� ��='abolisKoUQ *�-��8H!*�X6�J492�%�1F ill b�Jo� af�jrqF'is��Egig� *+{ev�M��7�( &�,�J$Q�Y�lY�62m�Qou2�>AR�6�`,O*�ol2 'to&�&b�l1�&E M su��W� [7 ToN9�i 9:Y���.y �E�y�tet6yc)� ( Te�X-in�plI�iwc�!�%)�ck;*� %n�x �w^�~+&|. Ln���)is�ll�eo�wth-deZ phenotyA�r&�R�&�"% in n?p��B}a���B�2�#8B��F>9 up� nt�� ve RT-PCR2g6nU�C �E|6S!="H�@%O'e�� 8� �?�6쁑�q��] .�l-�-�3��=�G �n�9� ���!��ck�<*mp�� *�;��ecursor@�JtA�M3�wN� �B)<aH8�",AI.� �<� afED!�N2�C%U|mq&���I*^ �y�Or1L.9A�y9! rgetx� E^)�B�:u''�3"�,a n r�!�!ases� �Cyb��]lgup6�]m!Aa�:�JTk�'�� knUa�� =|' l��%[:XRPE/ ]9J�IdIa6�f MURF�75��`as MI�A6V��� !1�"� &(�RR��82a�7�6L-aj�.R.�?�'R� �!<�"�&b�qN �.����?�]+We\I� ua* E��E�ũ��*06�$�7wo "��7f�Ha&��. O}l�I6B2gM���ly un&l�$- �x��a`A�Z�&y "9 b�&�� ��u��newhaPeڇ|a:La5A�A{&�$�8sE 6� "n�B= 9 2Kf.Pa%rur(:�AGV� e��r� I)mjw"U�Mϝ{:w�2�HH� �I.#�~. F�t.l�`%iD94/la"Q(����.�m6d.�n�De&�l |A�!�n�Tfilp�$�sA���p/r�sry��`)�0�<|aǎ�%x��� ( A2M.n3ofH5))�ar�M�lim�m�$ �B�2q&� *3*]a���6$Oli�*� booE��A���.Y&�Jw]*� '6_D�&�@�d�M@. "��E��LRJ,�G]&�9���0eno*�X�= ma�+��Q :��1ap 8 sophCSm�-ZnJ3�9m�A@��cor�\�(�%�4s�Xt�1� �- e9!߁�E!�8��2@N�"k6F� A% �r�@eD(����.���� �&�:":6�q���ly>VU�TU�1�$p� aa��nona�&�for!A:�� p�>j�T: _'�KJIre ~360�J��S �v� #*$V�. O� s,243 �.pdeCb���.z2X.O=mu�tr�6\�6$.��49 ������*l`h]a�-��qe��"DOB . ByV�džat���l"@v�A3!��: G�%Ac��,0��h�A2kwDS"C� M�����wA � G4�=M�� yr��<ex�tTXw2N��"��A��YE�V-�e\�*N?�H��.� �6� 0.��?�N9�Kl�of2�.S���M ����K�k"8E�r�-��wA�m�2�v!�AG1�6���ec> m"��m?Tc�0)P�Q9m�^�&� hijw� *C�^�I'�^A"*\AP�Ng) sACM�)w�0mix�]!�%,E'lowb5��A2P�ѻ>���aas6y:�%�)o&Qq:sE� !�l.a��;/ Da greEmpaR��N��1���n2�K� 7�� ��v�I[ "�Ps��!�n�@f�Q�dk<"�s�.FIlo52.Qe�6p -k�e�� o�"rx���� 5�a��.��E�1��a6rH��iZ?+���.� � ɻ�� Vς.X:"�1�>+�;� "K1sK1 i��.�R�5�E& issu…par2 ddr�+E�� by.L ng-���2*�M�b��0��a-Xe���.R,}.�> �����Rh�"}%"���"� �7,[��. .; fa� �F��"� �Sb'j~(sil��T!M!�O-. s��s�pojU;XAI�?I�.: "zQn|� ��"- �u^=)q�wf�2a�8"0(��KE."""�:e�;tk�R.��AR .����sub^�!j�& �cleus�!�&<7Ut2+"E���&&-"X d.�)b�wemۏUVmIF��I%tem�E�"���9c�P . ReE�M�"1l�Z&�M[!al;#�.7Y�Y�r�Fr��*atH!���zei#O�� �"z!T �!�-&Ԑw��� *� 2D oto� �2a%$�G�0le at: www . �1sNetDB��,.��Tubercu�e!c�k�)#LSa��I8 lung�)eU+, h"�-Epulmon��� m oe�!�#02�ve;oIlymphJ�� LN )�&*�5 � sit�:tMycob� um t.�( Mtb p���(thoracic LN�J*�7 é� humac0 `�R ynamX�!�E��vtb >jin�vr�o0R��(�lun � 4V3e�2�� Mtb-� cynomolgu�Vd rhesusPai�e�z�&PET CTp:�burde�[LN:� e�. FDG a��t�r�|�!� l�14) �necrops��L=��_&@traject������, mai �n in��*v�� tim�s�d���es|]1v. R>8�5r�6sceptiaOto!|=�t�E=�ma5w�WiU!trt�'�[�VLN�h3n!H�� Lattgrߦ�2�Gl5]�A_6E�.�.��bA�ha�|%70Q<stMsA�w+36is�; . No6���`��> granuloma� qxql y poor�kil��,9� drug�/�}. GP�V5![�B��-��ti���roidY���x!�y�by pushA]YTOik [:int�<"�;��!drophaz���as nic-3� �!�de�=y�vase��?��  U�A��;�'�ge\b�P�|fm�e+ �9�Z!�,F|��tt c�per6ai�.��<% �bac!� . 2z( TNi1[�K.Gc��Fmorbi�u� mortmFm�qs.�2�A��6.3 b�YeoW2�!A ��ҊU| �Ղa#�T�iIn 201�;��an*�4 m �)TB�W��"6deaths [#8"� !.>$� ��Jdi�i�ee�A�:HTB)�� ;e0F�Nx%�:T!��[TTE7In�\.li� �3ly&V%%�a����"rle&�al% al�l� mpan�VF��tA�[�Q���Q�3Gh��  [�N�**�v�.� TB-a& cerv�):-iti�scrofula��pa�a�qu�����Ft [6–*XHis� ���it�a��wheAb`�]A�o!�[wn��h � vidual_&��)tȭ�t6�UL�U�TBPding�A5pneumon�6)a �[hip"12� �67t-apped�2l�#�1a~�xf2� ��krn �5 �)�V�mi��cop!Scul�cZsA�,cid ampl �%��s [X�<&�]�m>���f�=�lMU%-��nnt!A [11–14]%�a^t"�Y� c� LNm,�W[al loaB�� eVr2D�1�outn�'9ertai� MG�� �� 6�� ��8?ke%��2fH� a�n���me�$�����^�:!� o[15!6i'"� m����&R E�h� �/�y�2 a G l�-dr�`�'�al!72�U��o:d cour�TBs�i�#bsE���tO ��stni� [19�2!a��nlittleh/nJT�C-�R� s" �N� i��� ti��$Guinea pig.��� ��� rapa2nʛv� K�o!(y5*67e6- Bk A�luxy�b�zA��{�,as 5 d4�).l0–2nJI�%-, >!�A�*^%�ov�"5��3ic�u s vi�7uI�7Z�3��GIN_FaQ�MA���al��< !.�e�neA`,;,c �&k�-ed�� �<�as6�74-( 1�15[ ) [2�4um�"uus ��"� ��Cau�}H ci�by Neapd|�believ�at%}� 5o5��M����ed��" � � W� a� Q*("� 5�f�)3%�f�"��rF; [20)�[!�N} �y��ec!�od�2of��-��`��wtr�cf��yg>�2N:~[2��3��T�2�"F[2{V28�L1�z!d�[/�� ) �tiv5m ˍ��ic !���y�P�A"�(a)zl^�1��*�� risk� ��^a�.TN�u��iyaI7 epropor2�"AE�! gQ,8 �+� �#���u�[3��*R in��w�c� �  �a�,� nti-CD4G bo<n�2*� ����A��ufof U���k2|[3� 3��*� V&[u�i��i�&D>�i7�Yti-!��2�D�!= f5�s�e�n BCG�,BCG+H56 vacc�7�&95 �M� !agp�b�zKt�^20��s��cloy*� V�>Y��6s6�TB s�h ar=nt�3.Zd[3ŀ�����&46�6B%er*x Dper��z QTL.��N��4;^LN��!�& en�%%]of���$eZ�im�^q���Jairwa� occaaHB[�so��obfllaps�E s�Ed���}%0E���noA&�rod e�e w\ is&� ���v-�"�?oT �yA�1%�V3  �f anEhow���� infl�B�"�.*� i��Aly-"����� �,�����gde�!C� DCY����!�-".Banato�Xr���� desN��alp=�c��fk�(ewM&H �J���u[3g9�e�"�Fc Ea!x"`*��� e&���%:�W�RbyB��ebcaps<m�p2!Jfibrobl� c�fir-A[4�:41�� uit�-�at� te fl��%�U�5���,toE\,  <!Z��i�� !�v�l�� 2–��M#endql�)�:#". promot�a�)�p%rep%�!+�$a2j$ir?���suAthu��a tmayH� }Me&FGra-���%�� [45 , 4� � �Va��'�FCR � ins>n� crob% apac�MEO�5A�� ge�4� 49]&�A�una�����|e i!��y�. S Ao���TB/�f�diagnoKa�5B 53]�F1a"N6G1aG18� ��IBd)-Ŗ�a �Du�TBAe��Oثr�� ny a]c �%E&�9+�'a!z�AF�aa!�>d��>:'@)Q�f"E&em�Sd#A3�  �&# K��3 �_5a�F�7/sj��ansL d�&Nn �se��* ���9.dqtudP2� iE8�����>�t�(�^F���! � *�&>m"�&��-CT-mx�met;c � ��{J��at�v(�u � e�-��lvԦ!�or!H���DNA ҁ�)�)A "E&sd"��PN� �� �l&O=q';!�0� �0o{2<t��=.} 6�IP2 $�I "�N y�A�*^  ��AS!YRto�%f�2;��2�`@ u -�2��(&{��erm� ~:a�"�!T�ˁ�("w}�a�re21<����s�BA"��.�2RqN��, ,���!8.��ce � prog��� yiel� �+ sigh�9VN2�, iXz��EM{ aQ%�6� ]'aZ%.. M`Ś"D72j [28]!t k* l6� jdE�� !"a��WU/5_de�0[`c�:�  �*k :Km2�F�\@ 6v"��{!.��|X.�w�� r.5�!imaIUX r}� amFl�� }�f�$* 2Af!��3� 5��o!t�#� ����F&c� ��!\)~�/e'�C >up!0E7E� A6A�5�:�&�"C�c#edS��� >1��1Y���*�P; H0r� ]<���jeo� by 2 weekB"(�ݻ��,�<�;Q��n��;K@ �#)=.JB $� A�,.$9&�)� ���9!yldI�&�b��-��2��=��`��Zq��7!�A�!�� ;!*q!�f�&>� Ah"�%o1>s C2~ri�o&�t��i���a%to-�eF�*� 92?65f�194A�210�S s" onj&A3�.� �` �Ef��.%� Hs8֎33o200f24�Jof9]�@� ( SUVR = !e�slA/�4$ “hot”�!�*�D≥ 5�)�-�-"�&�- , 9^D�18/8\e�]�b��>��r“warm�(2rutI��< ]c,�50!513�26&Q:�u�%8!x�1s@T�2�s�B�'�A( S�(man’s rho%p . 48��p <*�00�f���E}2�l� � �I!�.(Yu9��3���5{))m&*a9vgZ�>X�+� Aa)� ��Xm�4:g �(m| 3e2���r�ByreT�%[�=&!�2, E w0�"�tb ��˱p�L.� _qLN��1�*�1r:#)�,*� w�Dw�}9$-p�>k�A1�� 2;. �.�o 64- �@�u9b�(� � *�CFU��� t 4–6��"�� = 72I�:i"5t��� =�� by 1��14FP12e�!`@29J$02aM:si�2�ICJ���~]�xrol� (J{",� ."-��8% at 3! 5��M��/�low�-,!n%M;)U)6�UnI R��;�+edN1 i�,B��D #� S�M9-M- A�>v�] (2 �T� r�0 28-�)IcV4+Da�Zno����y�u{!QtwoU���Aq)� fp T28%��!�;�x�d�V~�k �%Ce"3( n = 2;� LNs;1.= 4901!�;A�es �circle�A�|BuY���Q�� 9� p6; 14:p1 oE9S3�AC~ �up 6V�cLN�%c�D^I:&�4>at2�B) .*;M�6�!��+�ac�(N)8s^�,4�6%�OF&�PhA�&��,V�re W|$���I<����>��i��sv�W">m�)�����%tI,�8�T���(�m A� deadɼ'(2�s�rra qPCR=Y"<) )� sigF!��#gle-cD)6 �/��o �-�6%�g�SvLNJ �� �h- somal equ�i� [CEQ]�$�. C'�( CEQ )E#F�'��.!��'a".x0�? iazid*& I*� "�"x�(�^>w2��5� �QWE��6h�&&^!or]�[5� u0�ZPm��`qz:ol� %�&$!�E5�l� Vy+esO){- e�Z3��A���+��i0*�1� nd����� S4���Tg`!N�q u� CFU+�b�i %�g&)*k2N�S4B���;AY� �3A~-�e�aR--�� is=�5B]b�t "�=������ ficR3S�� �����99�V%/un��t�)Y�7�ge���l'Q� �]�>�щ>�!��s<�;�#فB+�wJ�� �&�(we saw����intMinFkt� j�( � vs��� , 2�5�~, p 0184;:� J=47B<27: �W�] "�_�_���gM�Xsz+aK�Kio�?d. �p�7� "5> �qU?E]�]eL@*:�. BT �� V�:| �Fd*� J�7� 1��2|� ��.-Vp!�2)�� S2.�?Fea6r� "�>�7���1"�!� �*���F�e�v B`few �k"Yi7�5m�8� lya�)Ɂ5�Zbe2s����2� R?.�fe3��)�W���!2 �(��j �$+�6+��� ,8wZ j�=�{v&�����>-� �sM� e�/�!" ��$�!(i#�FaG*� &�C՘�&� ��er&׀ll( sona�P� q�C��6J�0>��N:� �&de��"b 1U���#2O�'1G%�:in2�I� se��!7��.Jz�\��/�!��m��%2�[O)Q�.��~9�B�:R��E�&gf  �1� ��AJ���1�D���.2�' ^620"h.&&,G/�}gE�.fa��;B��d�Vri�?by�A�=wo��key i:>2A8�=��2!*��122j�v�A:!IQ�0JQ007E�X f�1�!B RKqLŜJk6%.J.]A"%[F% j� Z %� :�%h\�F�.46�� 3�!&72 R�7>��n d�6����st� !aF� ( 27m q�aB�-a�"] � a_�m�W����Bi0r�\ f��!ea>E2o,�.���ny* ��y��F��Fj1&�1EW13�(*�$t5�J�� B_�����29mU6� LN� AM�$�!��"#%pibu�pXX ��*/"JP ~&�Y�'.A r&2��2 m>� �;W.�)�3{*��A2x 6�(>q*� n�9 CFU- "t :�)81%UY: 2���,:�+A���K y� �8�b �a2 �x"�.�'CEQ�EOg/� 33B ��nk baru"] .AE  �a� Aurp�!CL5��H?���q4� �Ga�9��12h��+pa2�h�U___� A~2� t� � cA ‘j� -flo�U’Et���t�,� ��LN;�I�%o�١�iy�00!yM w��Lw so}<C. o�w3IYmwa&r �p�����%�!�%�( 6{!�ej �8�[..t;6��m-�T UXiS���%�a�1+� 9tB CEQ-Ex��E9yeb Q|�? ": �4�k�A � x;��be6%5�WK�ssaF&��I�ua�BX!�`�gh>o�0�0�"�� .� ,Qv�@� t, 0L�dsZeriodu�:�k�1Ӆ��si.(ong�<olA{�nc�!Per�w=�e3@Px�0�8Wy�=$M�"-p[(%\ ungs%��o��wi��i):�B�@e"f:_ %Ek�jcy:�.�)�-,a�L!;�� �!W�E�k.�%�=��� J>�-0��q8P�Ż��*� �7�q2%"�#17f�$�.����$dD*ed2�V.$6L Uyc�� 4)"eat Ce��=��(�;�<�surpri&REh<���` 5.�, r"e^� �C�."xA�:�.>�?N���:FU]�� -ġ�M&�B�!%6 DEcsoE]0 ��a�M���O+out � GEQ�ayC ����?�Qre�6+we� e�!q�,%(!CF0��%9��..�"A��2r�P�U �:[�NJ( 2�, p��� �9VUiS�V�,l6b帕�e =��e7-g>�!9J 5A!�)�N�>Ah 2Ʋ~e�!8� :�tLU�!qMBq$-%� 0�1�a�56���>V�^ &QMLYVE-1�*)^eB, PNA����2|=$( HEV� pll�P ɯcol� t >�� <.(�gF��c��Ś(A��z&$� ZLUn �l"-6s�Y�X@�ew��A�2fa�A�+ Q��E6+d@��]2�5Cacort�M r"e@A�+M�:Tg�- #e~i�V��(XB q68+ 163+2[0present in th�ye subcapsular space and medullary region ( Fig 6A ) . Mesh-like LYVE-1+ lymphatic vessels were present in the central LN r W�while PNAd+ HEV are distributed throughout A,paracortex ,�Dcol1+ conduits reg�ly-�@ =T cell$ ions�tb-infec j4oracic LNs canU�>tain multiple focal non-necrotizing granulomas or large coalesc: that�rup �HLN architecture . Wfun�0at even small.f-�B ) hadr�lusters of CD11c+CD68+ macrophages �appear!o push-s !cof!)se5$A Pimpinged on germinal !�o$, but also� ed nearby)�ndJ,. Moreover ,.�. adja^A as�,disorganized%� s!�!_instead �( uniformly-.E.associa�witInom�IB$ network f%�inRnvolved �. L%�g9�8caused extensiv!?model�of!� stru1�EffacedEh-�C-�cY8Mcc.h�pooA�Pcircumscribed margins%Al� numb!�jiBth!��displ�i1-V0DC-rich zones!aRLN6�(destroyed Bel 3gF5!�eliAL!�Lnor!� vasca� elementl@ir vicinity . The.�inCse%T%�@ed positively forI8M�s)Kles_-�a�,H B!�is!Y|�$lacks cohe%�M9-� *at�2@. Interestingly ,!/gY6I seve�fea�q�6; lung.: . AlthougE�s2 :;)��-�%��s �y� to ��-u� G <terti�lymphoidY�,s [62 , 63] I^a� inct -(cyte cuff r���TE�observ%: s suggest:1 haveM�popul -@of potential hostE{݁�5q,al differenc1l$may impair%� abilAdto!�(trol bacter^replicx6�A� procAQof9BAzm 0E�:cm0�0ortant aspect��LN�e�<con��)�%�)� praRg�af�� oEc*ti-myco� immumSWe hypo��h�.e2� i . ���酦0sis ) would b? ex�jent sit��Hr Mtb growth so we �30auramine-rhod  ( A-R )y�to id!�fy where5� l�ize!]a�>Au, visua' d as�erous�YpunctaAws�Xed seca�s�� 7A , inset ) ,�abund!�in9�t]Q�A�ab from& -fre�)�M�tu~se� fociAS9�persistA�%�rY���1 he �5Q�t lev� of-ܡd � comp�.CFU]CEQ���2 >50%.9�Lsignificantly higher2@tha��ose �≤:G�7Bs7�!8t%�w!�^q�!mapkil�bcapaca��k � �!PdegreeeRI�� rD� �Nincreas^ both���! �̥�ofy,1����&p 2�Ie,ticU>�����ZcOtoE�j�( . Cytokine��duc�a� s pl��brol���Rol�a, �� [64].ha^�a�%L�~�sA4MIinB��ey5 (must genera�)a�ioa lls�VSAҥN��e�evaluLc1ex~ s�us!� 0arameter flow.metry�t��-��289�o��462 )V��se dataA �� �5z|& s�>3 ��a��S}?6�c"� tMdA]onga���*Q  . Nex��i.�whIS1Maltr����.� ���YjoMeU�s�."�ngam�,z lly)� PDBuEWionomyci�O, #���6�"a trexowards �Y�� frequenc��j ; to�u. Of not�EhEn����T ^lefvvC N� �A�; CD8+%HtoxicJ� 4/ orE* B i�20+� ��!�b ,E���� addi�_/� �u 1S&� �VR� �i%B�� i& �yM� unde�sam� n �+kTAE-YA does!� in�AsY��du.���I�f�A%�E|Iu % ��5)uL}$z��� > %<# Y� go ?*�"�e�d �� our� �to)^st!���oA���, yq���J' Mperiph%%7o d� 6.i�( ����proh���eZQFoA.B , 14#al}�27A(&� �� 7 animals�&� ( S4*/ Non2 �$:�t an� aPa� grew!. fcul%aO714a3*�/�d�126#T. P6\�*�&�>�3+�6A O�p� S6B �92:Ir��qv%B�or�&x F�liferv* Za�as measu�$by Ki67+ C�$eE��I R;�, S6C �,! R<Em�%in>�"M�\��Z�sd.�,on might occe�EM2�y� B; ��:u!gA�5D�����by @s!Vu�d�7 Aq�;��o& �+:=^)]n%� , si�e�@%#�P��d��BHA�de�d2���e cer�6� toos�noFd��exa��2x �a�LN2�6 ed��ll A(% bv�]I G ��&*H( n = 55� Aavail�r$1�U�A�e'fic�l� ,VJ" :���,6 � *h  ( S5�H*.E6Q��%ZE$1P��#L�. SEa2L��g�_ w at"�! b�m|a  ship" LN�>TSa(extrapulmonZdis�. Grea�l nod <,a�asst!e�gr6=sco( � ccouVA36e<2� AQLNind.Z)��>� more^�� hesu� F te8R2� 588 � <P 0001 )noz ^�7A��. E6D��B%�� tot��F�in �mac�I��7�� � u�i��švi0 [57]�8�,a� EB>��ef ��ed du%�\a short-course ( 2 month�4linezolid ( LZ� tA@Eg%�c�BQL:�,"z 6�� ty ( 75%i-g ed vy21 . 8%� ol!fA� drug�"�V. 16 . 7N[ . 5.Z�� re*� B��� ( S8Q.%how �.DofRD>5PQ Z9M?A�55-fol-181 ,�Z� ly )2 un1O� olP�sN=)cU �=n,Ep�MOBg>�.�>��p��a�s�29~re�oir} &�"Dreacti�A�psbT� iYn�t��z prialy pu�X"jwh��e) a) isoniazid�q rifa�$="�5@!)��q�! Eh��\Ju� �Uu���&��%�e�$[66] . Tra��{,)i*, P im�4 focu�B%{Z&�^, desp�evSc�atE�� c-�eg� [ E{re%�unansQd"f|'ard!� imA�A����o�"��a�of TBFC9a.�orE�!(H�microb�!� a� m�. H�c| o/ � �*���ͯu�4, two closely-A��� nonhuman  at�5��!ke ��f 6(TB [27–29rW!�e��VsJh�(becomA�ie��FDG-avid�ps early2 weeks�I1�. Starn at 4%B�� on ,U E����� ;.�1�1yaU'�(sh*�$��@Fb init�'5�ofE�by 11^��sub�$lyiɁ�A9 at lS tim�i �%se>�,!$edF"G , �%ly��Oe��!�n suscc^$� is"`&Ty(E;*� 6�di&D*�$� �ndE#��let� e/�%� �#�:)i��#-v.*I��.� ���� t�prolonF*Q l� ��c�s� imes!�qu8� �". P�� �)(has demonst; 2+��� �~A�6gao011 , 32–34]e little!known abB�^i�'C!-�$a!hp&���m$*i� E by Poulse� 1930�n1940s��w�m�: m x�� often�i,l f�)�lasa��m.[67�'8�jx' subjr&i�1eBenmd “hi $shadows”� x-ra�( assu��to�%� aden�e��*l r�s:w kB itis, �y fibec�0tuberculin sk�est���)��thd"s�!V�~40 days1 9V . To� �!A dynamic�X6�-�of.�&PET CT!monitorE�V� of2In��M*��I eps�$y�metabol�Y��(��uptak�":�Z!��A� aT-x�cby 4–6MWi*��!FDGJdBL��8.��ll?�Se�E)[.Mis��du�rof�M ᳡���e adap$ :F�Hw��!ei���  �c���bac�&�",��!Z��dividua"� 1sI�ed �*!� �wax%�wan!G AzR�!�* "��V�� � es"2".z )�w� �/� er�/4 � t��"U&t#itV�.8�!V)��out A}a\s& [35��CJYd)op1 fu2ang%�JYU"���`�clinic� Onta�s�}e1 e!� a�>]!Vee" l� ��}a] �Aoe�*� |TB>��AQofL&erii al �&d�� . On�.rikc�.:� B�i % ��*��Golv�e[*� �.�of) sis;a  caAa{� � mass/�"n0!e� � airw��cau�'lob�llRor er=@to a bronchus leap to furt�*disse�0A`. CW!.�� ��beU. �J|�01,\�[��LN������`qpM�A B1aGo<� a$tS/�27 �^� !-s� le ny0!�>�, WE n&�sAx���)�� 0mI�ol�(q %)Y &^(U�challea�E"virulaWa�!�}(succumb befp2� :QT!�� �p�*e��( >26��pos.�)B-bso )��2K Z� a��.���� show)��A�r%���  � a w�)��!^�&G:� }�in9QPI�-�� j�)suc�0fulXL ��WL $. Remarkabe,at 16�Vc� ��P%I� stat;�8o�-to��)!�Na� refl�7e=�Q&.�Y��Q4�to���� {7r fin�)��a� e�� H!�i�1car link&�!)�hm�&�A�.y/ cida�+aFO->�[5��Cdefici!�Ial�� �LNMW�art�' lain��onoun�(��a�&i s�O;3ofQL">t�.BD�A�6�y0�� simp���+ie� geno4, � �o��technk�A�� � " toV�+ dS8� �act� Q� }( tog�e�CFUj�ei� vivo-:a peak!r-�alJ� i �.]approx�,ly 104−105upe.#,�_.��xjm55*no� !�b � �dQqI3;��2S100��tN�< RBwe �2�#��a�.�-, �q��5�-e�!��7$:��2Z�$L�.�5�M='r8BFZQ%�&�/:�#%�� 1!dR� "�v=$a�N�,�g�7a��M1V$-mi� ��� 1�laiN-� E�e�_ �Uog*�� �TB.��-Cdi�/t�suf��Esam!�o� t a� !�3� i�!{)�%�+*�3; �� requires�4 tudygm&�dZ%9�c�Somew�Isurpri� �4we��c�TedE��ᡝ6�#("�7, axi�?Aingui�0 t dozdra� !C!je:�&��sIL�HQ]*s:*�Ea��"al3 :� ��=�>�%vQ#�a�bet7:ut�,2YB can_ ex�3%� possq��1L��?a6L�7-floaE� DNA �p�!W ! tiss�3. H�2logqJ1Qzreveal&a�3"�2 L��+>$,)� "fe a�vi��D�A#> 7co!*�A pr.%� �+.G#U=�92`[�922,c|�8s!4i^ ��q!�*� �impro�)IXBA��!,6� {als�*� t�:2� )/i�="?�A�c�B! tX f�6 [69 , 70}2U|)� helph why�uj  +M � 6� EBm�����5Eh���sH vary��dR9ұ�� q���(A�g�x >5":�#��16���8< �2: 2. Our�x i��-#iO2+=i��7��� 08!�A�h th���qik_ Mja��!Afactor� �4Q�a� of aٕ recruT+B.�/��� ,h nich�Q64=..2Cas�g)*sAJ!���C��'! --�- iclei"�?A�{ body�D]! �@0aid&��� ��!�[7a72Q�damag�U-*T �A&�*ch �"* Vh�;"� e a��AOEvE� �"QEup ?res� n�m(��e�b\a na}�� �re-YBoT���a�cadK���� prom 09�%a&��.ce�a��8gen!�*�[47�.o J�#�A73��4!�6�6�a �-,��Aic�Awmr�A surrY7�aep�9liB�?L� =,t�d��&� ]��%�]G�6�-&H'�6%5!6!< pe�8� � ��?Z�resul !(PD��a2�GM%R�ŵ�toFt� o� ��A���2� �( P��'il�<fl�2�4I$C L:�f�'e�"��4systemici (�:l�vi%�a�@)"�(s0intraa@�E�#��6gB!a�. E� uto ����e<a �� ��-term!Merv\$n��. V&( �� A���9 .�27%�.� ���at3 �.�H",#�"d��#�Iany�+�ir bo�[7�!7�!��$��N>y ave �A�;in��&�#&�� �%�a��&((�apy��2�$< �%l.� . .�A6�/���I�, Zt%e�"u%�$ Inde�; a�ed 113�)�v#pnI!�30a�(, {)��&Eas-'TC riska�E R [80�XOK 12:y� o3"�+! LN�f, 9))72 ur�2� �e�!�%tqq��remai|H�IreG�!�&� �&U1�%�confir�bya$y6�uX2�5;���l� ^W�6Ged vMA�A���Y�]I� HIV+�i]JDTB!�wes/4QabJ.Tn�Nia]I�+s�Bq������N�mq��w� ihooRL*osympto� c.8G;6I�M� up [11AQh!B2�ab��l'!ځ���!��E+� uu�J�r&�!.&�Չ�se"�� B. �!(or�T)ng.����$e���3($ in-depth �st�B��is&F "S!!tE(�*/-Y!!�4*$ �j�!5!H� ��"� �u�;�7VP2�+-E��u4 &�!�P�va�.0�%a�.'� �,*teg����7!�Y !@"�2 �#� ifI!$3�Zas\F�ideL5 Q�85� vacc^FC�ebacy . *h0( Macaca fasc>B#J�23=Grr ml/-- 7oDtaB=�21�=% %��I!�r�D(�3�or>2)�6�E 2011!l201r�3���I�!�a;�VI���JwP ( ~1�8 ,���6�A�!�in Erd=*��oscop)�Canl�*e�ua�summar?:in$3�/;_A�!�"�00monkey>d)�#2� 宁�media�5A�er9. AIai�lis��a�b#@in Suppl�,5G1;-��$%�s�* ��8ve� R�-in ?!�A�(J!�%#�7�� ocedu�A{a�ocA?%�\� E Univ� t�=$Pittsburgh�%Institu�� al A%� C!�Z,Use Committe!�All�&x! mani&�N,���cJ�5O�� Scho�Ied4Qe��( IACUA>E���/uc@MWa(�l 0$is A3187-0A~�� -61o-iFU�RCekpro�(A� : 1312285�A15066174�;208065� 15126341111004� 1206018A�1402330105870A109003 501529�1209083�A.m00362 @) �ad;�n� ui�Ses2zE�eQ( Welf!�Act1  U . Se"v-s 213�B15��AVa�G`-1e6qM aborJI��P8th EJ0. mand�%Q�w\+I1Dc Health Service PT(�)l"�&&�%%�a}yI�ho��ayhebC! room { �-u�1�ԁQtemper humi�&i#la��.�e"siS ��!a�B�-e�%2 squ!Ls aparha�J�4-P %u> lF$n �neighbo��1peE��q6$f�w!Kdai�B bisc<YK�orEh.H0k�8��t!s�/�*/�/ ��pie�Rof� sh f�or veg#*le�QV a�!�w/PXibite� Be� e�6�6i-!���6n)����' !� enh2 d en�T.plan � desig�!� �'by�Bn1B%�aŌa�i�Nn7thoQ�onVV. �6es&�@behavi�A+en�+ agedAoGS��9AtoU,nd͖��a |ofn will�iE��mfs X a��9g .�zen)��+eanut�., etc . *=d �ro?#d oHJ� r ba�. Puzz�Zeed fori!bo�D!�d cardS�5U ap��A$s�wpl2X��cag�sik5]. Adjust� mirr%rE�i�&Q+SL�a�*V>&. SIb7out� N/ei<U��2�)U?st?i�!��maiu"of.#oZ/o�� ]�?�G�.� safL�5y�!�e�-��i;Y�t�.te!IQa�1(a=tal�)or !a�re&QA:XB�+!� task�P�Y area�%-ap&\ (Y�ee >ge�HECI�)D dS(A��]ct schx^%��w�t&cl# 1�)�>e�rAf-2��d)ai!mof ��aud�/yUuAk . Ho� *T!�a 3<�7o TV/video  p��t� F2carto_ or�*�at�2��� childra�ow>��3 h�;�Oda��unI� �A� �)G�}s�.��sb(]�is-��petY1�'Ee 3group!: ZE�� � chec'ջ.!�s�> d�,at] d �0�(, hyd�$(��Fo�A�M .��2R,Ւ�4A����1 B�7%{.� Yء$orexi��w t lt?$, tachypnedys cough��� Phys-� ��in�  L�m�^���+se� pri!�oE�ve�M@R�bl�q drawr)F)� keta�BY�" �!�Rha�2/CT im�H�;/ �U"% u���.�4d�a�� ery�o*As-�41� prog����'icians<5�*�E.� any a�/p�L�bes�If#!q�K�]�'pr�8� or<2� Y1die�"� 1 ��eY�EG"� �:d"ges�4�8gi � y ׁ��q o�dvd 13o�I��sB��!� eM[wU��t�Q�F�eutha �a�$@sodium pentobarbit0�I]@2-deoxy-2-[18F]-D  gluc�0�4)�# itron emiŤ$ tomograph~@PET�B�� 1d.!C Q�[ yWsbio�m�c3�^_8_a*�[5�= L�^.&-"j�CA�!�ys� P�aiello!�_eZ�5�3_Cc)8K.v�S� � on sv� 4 maximum SUV (�.ndard�5 valu6gBe�6anAeq�*to gA3=R (L�FF���a%�to�Yc��1?e�fa�я�s. .,fac� w�-nP1�%��≥ �oC I � �M�2R��65�be�8ot . �8SI� E%OY$Z/�teq<C54V�.we major:�q!e���(�2ps�W1Z[�2arlierA��&A �,�=untilQ7��5V��f�;��8VDA� ���ea�:.)!�!54 nt��key�3�5y))��1 im�}/� ne"z>N �%Ja�P"SBdu�[3etBrief�)� � K�Jh,9�]�}�<9PE�/��:s chI�!�"�9I) e%:aX�L!"irQ�/LB8>Z�%[^**e0 exci�!�cu��"a#6��Sh�qene��s��Jsuspen*�q PBS ���A)�� d aliquot d�h?Vnga� 7H11 agar� 2,b~ colon� � �bA0CFU�k�)� �Q� qPCRm��&�10%�� bu� � l�=nd[ affi�� bedd��\*� i�o�B"Hd5D�T��e!<%N�*�I4�I!�aam�Ia(�,�n ��aE�e �5r�;(��LNy&"I.va!��[�mE!�i*�"AXe"%J�l�!!h( D0ac �%�&R����CGA"ve��Uu�J�",� ��!Fej diaphragm�Aver�pl�Z,M% abdo!�l*cer�p�9)>�iA�(aXlu� .$�-��AldYC��!As�#� '�@nS4I� el�#�&�U 6 y ��domI&aLN!�� #5O�eaNL �� = ~4/ � A hKof 168E@(LZU) WZla&��of-�U!�ur lab�wW �"�� �3a��sA�b�1^NgJ�of 96ӥ4"�V6 a,4f29OF'a$( 10 μg/m�c�,Ni+Alutof Brefeldin A ( Golgiplug: BD� cia,g �@3 . 5Cat 37°C)�5% CO2I1PoJA�-�72��A�e�ii���A( phorbofi buty�C (R� &R�^Abm=ArA�5��3! "QX�" d%�y ��t� �g!L/� ( Inv^ b)�gsur��E�iVHB/���Ho_ �.�F�:a�ad^a��oT�+�CD3 (�$ne SP34-2;!�Pha�%�CD4�Ll&L20�$BD Horizon-zCD8JK1J"D5b��B � � CD2�_ci 2H7; eBioMe hmyeloid:811b~ Mac-�BD6�%���%?Z�>ar�0��=���~�)yZpro�BJ�4Ee[IFN-γ�B23e$[-�$: MQ1-17H1� ,8[%: MAB1�Pn*Tye[G47<%564CAP�e]Eqa�s-V��5 } JES3-9D�1>�IJ�Won - Ki67 [� B�2m�)5A�a C8�5sH5,. Data acqui�,=�L"�A�dSR II (!���&)a&Jo Softw^v .�)!0T�i4tar Inc , Ashl��, O"lR� "X 5� �w�&2� 2� .�3a�6��c�l��`d.|�-� s� E . Klein�1 fi Ti`45ce� ( 4-6mmAn�sai �ohe8xyl� eos�^Cha erist7.�n�su� >m, typ��vA@)�Dn2�t8ppu�v�or mixed�:'��Apa�1v0u,�#ti *�r�:� &�1��ml�,va.)d�8h,� ŤAx� �. I�no� ch5�i6�6�H&d [,/82] � -f�pa� -e� ( FFP�^, � �2�L&:` �=deP�3�a���retri>\:�mO R er ( E�$Micro1$y��!�Hatfiel�P�d$$ris-EDTA-T�g-80� (0�# �.6T!zs/�s/dend�4%�o polyclo��rabbit�-��, Dako.[ anta Clar!CA;f62��Thermo F�ir S�tB ,*�# A; m| -!F-�9�-Leica-4 ! Buffalo G�6��E]*�0���T�68��.�;2�DC-SIGN�roSci��Pow&K�2P1�02Q�LN3�a�9va#�/� a-aLy , R&D S� Minneapol 5MN�t% ky�fioLegen San Dieg!�CA+��5� duitu !%E�bX �(.�cyEA�1 [AbcaW Cambridg!xMA]& P�R!�3/e�g����e-iso��&�s�Z&Hpurch��J�uon�"Res!S( WestUe*. A�r &�r�E]m�re!ts BD &+ !I!uJ�,)t���y%�Y�$at 20x magdq�c%a Nik 1000 Di�T4��� #, Melvil\HNY?� E��:+��+6�<moda�� ^R-�B� fro� "��thaz#o volu�Arecorb :|^����D��� Mransfer!= ub6� 15c ` �g1mm zircV-si~1 bead!�!�pec P�jtF rF� ng 600� K�Z�Q, pH 8 .eT2 hund�%�li,gof 70� 0phenol/chloro�~8/isoamyl alcoho� 25:24:a� Sigma-Ald=#!����t+C�!SZ � incub/at 2h%a�10 minu�M ;cO v�}\([4layer s���|&�5%25M NaCf%am�- 92�"Z �M �uqu�.E�E�recip�4��U !{0 Ir 100%�\�Zano � one-\xh)3M�acen#�-\Aat -2%��$niA)Nabpelle�1wa�peR70% eGol�Wri�n]1Eain nu�Bse-�> �%.P,�>9�qhMfJATaql,�* al M#Rr Mix � Life T;EV+)�*p+(�sigF BOer-prpKmb��FE(IE� a� �� ripaste �an ABI��7900HT�h�# . ChI9so*|equival�%�<) ��by, "K �}(�� cur�Y eriv��]sdil�+A#�-1gprA�-��uJ3�0erflimiteaA�"J vA�10 cop!qpe{15�ww l�8�T�0 � Ga�]whole*f�Z=e6�u ,j_.z&�aJ’Agod3o & Pear�COmnibus��SR2�}#�-&T!��' manu�0p|ae .E��?�3ly&` �uNon@ Uic t-}*,.�w�soup��,Mann-Whitney ��(Kruskal-Wal0 6O1D�k�>a�Z�"MHo�un�96Vt�5�S be� !�%~�%c�!�6��Vs�$U�!'AlV b6;�h�t��e$4I�%�m U a�I4�&e�"� , exJ^6�epiphaga �r�e�&s M&ep#m�Ja�:�\. A�#e%�eK % G �ed 0$ po^5\novel!�us:��;-C2� ap)A"JAkexi�a bud?offd,plasma membr�X,��t�!�Vi� via ex�B*as �]p�+st5��is'Vad� �62�, narrow H s: i�>J1y);( Oscheius t 6e�/�!�R.K pe�,sp . �4!con�6~'Jkf�@�9ngBD�C�5+ �.�b�=%�E���ausube�Iai��نins:maOE� crip��!�au�C�rhF:2'��=��zhL�i�Ms evo��me Fism�2� 6$�ro E�rdA�l"�Q� se� ly��y -} illu�9,De�vA!�ubi�`%82�"%{�-� ����pro�-@�#resourc�.&<=g\-� F  co�� a��<1^� s . ~{obl�=!�Fq�&�,���J70�?d5�[= 2�>�w��_ orga)��tedvy? ago� �? arch�0jX!q��Louis P�u�!94$d silkworm�% YE�� �*EFa>�WesQ&r��Ld Nosema bombycis [3 �E� past&pŴ,6OX+t!5�m~X�nEn{ �I�  N� o =M �adiarrhe��  %coMmi� "�@AcJ�Z6�b�+aKE� c!։�"JTde�6bh�7nA&s [n'�*FKe�ͻ�)a`a�r�.�� !�ganI�,!6On���i��a :"H /!KBo�b�A�_I�0�U� q}�s piera\ ��ɴ�9:1� o����o�a�U� �o !��ui''Zsi7AWTi~r�k{d�3�= 2�Y0hostAong�BtiA'n�62G���, fisv#mam�v[�(.JN�C�2�<�� huge� um�2V;u �, v�/fX e�s��Q7�I9��8so far ��2� -liv� �>�� � O� Q �+#�Gm���&��!�;e 50��[0e&� f+(�.9&Ff��)�aGf��bis�(ec a�*+ e*g�!�no"F ���� ed �. c�Mbeds:,b �9al.l� .Bi�w ���i�|!om�eapOrot�j:()2�!AtbTtDherbac�sJ@�D8 � carr�,� rtebI$�sn},�podCb[9–qE.� coexe(`a�.et�prokary��!peuE�9S �$Ao�*!�929�,�+q lyI��O'Gcta=p4IC��[1�g11��F���a�\� A}1��r�:� [1C?7�" dram���d&&F&�(��0dyf \��Wy�Uhy..�'##�{Jve�� :�briggsa�4:"Inei�2uE��R}I��e�Bq ,A ��lb�+ovo��\�, in famaYRR dae �8&CZvsoiNq0�=T?,! [1�1�@2,Ts�OaA4�4stm���!�" E��it��G�:brjK[2��F� F�� cern�A�l$�Y�|i��typ6P� a�ʍP U��~ %`)��co-m�$ &^ 2�"Q�u�) h./u-a�4��WE}1�s f!#TAE�M�:)D&� !^&��=mu>5)�2�d.���od�[2� Two6����Hn.���e� 9>�m��$Sporanauta�i3[24�(-�enoD`(sprofundi [ 2E�&1 �>��"d��FofV�B8��ic% spar��&�sJ ol %A��t h>~F�-�a�atF���e@B\&g JO�~� dXE;Ml&�E��a��.8J�XE�IstoH!�i��P�y�6.� 2�7*#�),!M�!�� A�uP(�me�qTA� .q��:�(>�q��q1]E�aye��7ge�9� 2t�8 "* m����c�7���=bj+�&ng�09!V)��di"�_<1uL:T�. FT�V>��nsub�4dS 4rib�@ !-β-tubqe�!cŚf�2��= &�4!m�ida�S?B�ps defe{6]g:I�6kn"=l�E�as�'de IVAg�ZLic6T"�*�zo�ieneusi%Vitta�a2neay1 iK]!;�O�+"� morpm�Elf���Bdmat�B!"iweou�l��-�v�9WSr�j��1N2�n1], �pf��n��>��Q�)�)=�2��6a��E u�9)u�,aV!+O}* �cop t)��C���R5xt.�d���� � :��a v ?u� b)Ha��(Ar1l� �;sy�(G2�cg"zd�-). C'gr�De�fji� ��Ri0a�nAS� .2.F%t�`)��D���f�2r2�a����~:�by.+�>x�y pBy���!�"� �w� r? �E��IP1v [ /s^�lata�%��� �!\m5 �world@b ��&�S>� su �$ar� ai�Cat3 =:( %��N+�;lYev|��0�,��{%ngI.*<��b�XH=\q"5l�8 colo.��1w!>oJ , upMo.�i��)�{Nomarski-�e��U,�e\:)ZO'6�K\�E�� ed. "q ( S1 T�)�Vplah pu�"vBW z ,��5g8%�5\�F���r]aE  ( {s 1E�2;)>B$�66�)| JUm2807E "� �VIz5� effovA�� else(\6� ��  ���:� � � h�dwd2�Gh^Cre*Rs3�-ɤApof  =f�:G'iC vrJk�P/WeK%�A� mplify 45; g�� 1390 bp�? nd VR�( 221.223���b�v$in GenBank�+Aq�%��n built6� trem�*�$��e��! a� dE�"9=� ��Ayo*7E����9t� K�R2D �"5Nuw6M���!; �_to2�SXle�h2�2o!i� ��*_ t�f!:Ssee|�� 99%Y?67%N$�&� :��]��he glob{~R�"B�E%se�W��e�J%Gyio�RreH!�igf2W�Ms ERTmD3� 5 [=X�2��*��{m�a/�� Eur7XY?x�7���is5ly bi#1�� A2Y�#;�J�"]N �(�80���2J ��=Hawaii-1B;����[1�N��l_ ؂�F0xgn��H�A.a� e�u�%oz �!�g  [2<E�  6��k,!r�5��!I�(��t�i�JunB ]��� ��,R�� u�[�V30�isEn Z�vA0�ą*l&|:{Vpml��2W�ra�� �gZ4&���e s 253;��FigQ3e8"�T�a�!M\%SaT �{� ����CT"�.���IY ��N�|.B(%nV�� "(�HTaxWy1ej(GqDBVK�,WmU .& :$'G���l2w ?�4, Cape Verde [Ae�e� �e�!?f!��3�4, Portug�, d Ge˛tC� a�� y �luss%eV �g"i�I%}�|q�)��4g�*E.:� %��)�!C23O9� �7�D"&w |�|�'���0�!I@$n ,cx()��(w%��z!�~D@6�9#��fw ��:�!� l5 s�*�Q�+"rU�$$1��d� 1*,�#�8i��%b#ZMD�Kvҗ(����.�eAw)�19^�,(gEa.�~"�topO  hI�� �"My"�81% ~ 86Rh��"9 744B�� erms�E�!sY�alI�� ^ 6��5Q�a���1�( Thail\ GuadeloupV=57tro�)�((^+��42 a$ ( NIC1041iWFZh�\an!Ga�/K"th(�`$, Czech Reb4�;�Armeni K�w ella�>haT (�mq /P�Ephalo�2� z� 2895 �SQ�NI�2 "1of9���'��L�J"� fB0a sKe�A ��2g.�MjOva�~villia�d*��O��\II��*2)n�u�$see�p2 ) [3�61.=�-'Z "J#r10&��y&<*���o*�-� i�c\Vk!�Br.�y� �[/r(u���%"e�.9�K"~Q 6�����qt�W�36ao��Q/&�<�.M��!JhEP(�O�e�"~A��}�-I���!}=2�Q!�"b>�A�b�` .�%ɥa!jur%M-B:.V mino�)=i�%,.GN�uu-ciݴ �y-�"B ! a��T�2[vChi�5� m�0 ��m�tout)li�t6:+%P�3� �bye`75� aj74�@ 6 Z)1� e��U ond b"h�Fk 1510eKa7�by�h� a� .-�.�-r3�!�&6a�C�Cf=� ���UQS,5  �a�+I&.��0� ajdB���� `rz)6�.���&H�����0%�� ]�JUm1504NICm5��All top�%�e��vly=or "�1f�Y�9�5]�l$)KF}�!,�.1A� +p �_E�!Cd�l �zM'U�W*�� fM=�g+O���i7��>�`=GstaM-� � Ρ)r!e�!`*D��)�n���v��H%!2�.!�� V0�`mu-�J�=Iex�0gLb���>(6+q:I�1+�ICmp ,�'�vifS�'!l�A�Am���i*��U  �F<-\<&�"^*&�;�+fu�wto%9�� 5�}.��:en��� ho1!3 n��c(E�)�o[�D �! Q � �&�/�$�^ ��M��!,"T ��5�-S:*{{;)|Z���E: ��oo�Zrig\(OA����:,"K!�t� ���G 5(R� I(W�KOinu�)FK'I�2/ �;p*DaX x}��" :h rm}�� a>E �"' !I.� aagt ��!ng�F6 >hi�4�}� � �"� m0� A ,����0ڊa-i�Kq s A�*B"� =sI-ne�4&�6 >�ran�12�#,�;����lea_A.����o��ed!=v:�d y"�!1{o"�$�$!�re-�o�?#�"1Kbymos��Be1e�a�*�+e{l.6�stnu���kӍF%� �$i�l!�{r �Nte�~|\ groo�-. *�gd-shaJ�!�o�)l�(��V�*t34+)�i�� heav�Il�.�A�s����B!Q~Jae"! 5�h_-�\��B23DB$ re-endocys:[3)� ��8u,!�Y�XH ]�y>�"A ���AD<a�w&���c��[e�Y"�4A%4B; S3A�qE kN� L�ap �EPc rC @� s�mly�er.th�Ls�7<t�'yq< G<n<�m40E�@,l �� ��-h?9^ �s54-C),�E_�6r8� *� AB�� � *s"�s>s��9L%8�r��a�:�nsA��Q( �a00 ±22 μm%C ,721 w���p �:l9: f1U<9J20>f513 f.',}(e��%dT'"�[!�w�3�=or �]�E2i��&��4E%�4FU�u'be!^�;&*"� AY;S�*&Bb%�Q��" c6��e��eUcyt��y,:'�e ulE\ru �Z,Ai�de�8d]d �� L;mb42��!~�� �sA ��I��X. High- �p7zing/ edL�i�|������to&�O lipid"D'M2EGd&�q2yLKI�$ meth�5.f"YN���|� 0 &kL�!2�!["� &�'i����5V -��IS5�5�1 S1�%�irݗ���F�|�+0#S�xùADV�9!+�$%����.&h:5B&5�R��enc�j� �,-4�;�HYd" � 2ioar= �� �'� (�D�y��:Q+9�&�eas�� ;z��We|�5llՀA*[�� {! ih� anc ngA�k1 ^=�<�+ZCaxv=:eol vacupLAD!�a�.�5E–5G!JJS1DtJ1F.S1G%� e�*al^�b�Wtl�Y��`A�*�92��i�OB �(,� �c�7s-s%0�2 uL�9#=�M:H�5J�L�A�u� L"�ZA B��t>���Sc�r � -� \(�G+V �)�5K%qUSI?��$��� �A*n��,\?m� ~�In���~fZE n�3"� ƚn� D�Z2� ;�8�1uӦ+t�2,>*harbor�>er>WEG ' 9�(**� h*fach*Y Bs�J!U�* (�coe����:�E�a�mkpah2�. B�!*:B)�]@܌�/:;b�-laF�(���uinE�5i�5GEBA.]2*��Ѽ�r�sSeRJe2��RturE8 U4E~1I�)3. %�Z�On�@%-os-<v��o!�Qcp�J"m:Bm�Ka�H–S1J~��sTsee".�^evelop�a den=2�E.L.����*� �'�> i�," �8xt�O]&:q� s 5H , 5JK%m6A�Iљ��m��0hAN��w"�,� cl~���"m&�l4 6 l�:�&�L�1=out���= ��inn��a���z;" coj %!!aU$Li6�[23?wSE�=kP� .�a�� ��!�6A��0 �appare �2�xT&� �e&�J ( alv�an��!+ t"5kls�A��kW���9��tYn)�\>�yR�%Gs�Q,� !��WueI�%�YEQ�v1�s�Z d1XmpI�l���� '�*3����6V+!�b�0�E&]$n�2>&|h*y%��d�!&�6, I �0��su�h ~^Y8-�!�xu�*� �")"�&'t%7 e�b$88–89% ):c-!SF�9Oroom�#opej��zz\A�: moth O brumat�#� �O�r.�i�t ��� Af%p���~ 76%�y )a J$8Bvi)na e{��nwR*��A�aj&�he>�J&SV�?�F�b&  exocX�oHL3_9͞A }<�� !y�X�C�v=.<-u��eI�"�lis8upM"5y� q�E[� A�9ut:e=>m�& 4Xd��� v&E;f �. Oe le JUm408eO(s�Og3XC�Icel'a�e�th �@WUm139�EP5�9a �bre��i4!� �lyL15seL -��*�g��\ 2<"�&' -��1�&Y�JXF c2�&�"K%gp:.�T��:� � "�#D��I2; S4 ����@e�9um��4,1� 14O��!55�5!�48�CUE .(N��g6}'to Lieb�,�(Q��n�&�FgrasshopQ���-��'��6/1���.� ��)#of V .!�=AX Z�6O=�!��p{D� !4S� ��%ta8j1i~�֑t%%� &-��܍�e���y�ti4���17 � u. B�1mJ�4,� "9�0!�)�  A͡�2 'wo (&O )Y3=~,*;<(�*e-�!!(�`<b9PF%%~!,�S��!e�)8Q$�!�.[nAi/�� mean%Ya�< �<i AI�(5���#but�j��$ f z�dNMN u!a��G�N�A7Y�I�^}� BaK^.�er �B�to� o&�!��8L�>�( �m���f�� �7�kdf� !�fd&� 1�Am��U�$��:"r�a&1� �!I�6�QR�m��2 �$ut)�� ��zjeUmɞI�m`b�:E��R�T:6�X phil�P�-�'5�h!j�Z50�P�~67bK���,��!��guh���}"VY(;��tV���Colca} f!�YMd�w��G����)G7;����a"*� �LgZ>}BM V6� &�6m0<o< aboUzx)f-"as &&"� "� �!b"i6r.�!j5��["tۆ�E%����5���ByJ i�4�[.��P� aV�I "� -�D!��5EE3S5F-�W b�hyd"M��#w��"�=�e^�P\("M*� .%9�"  P �$ ( N2�'e�1e�Nka�nd�S7�A�8"G2( AF16I�!�B�V�� &]X} lH��� &�J5��\::[Eh.��Ai"I �P\4M��� a�E blH&�*�XA �Wba2�,E s"�7Bf� E; 8����J�� Q��A��$TE���??`�Y/�0ny.$�5���@s �,6tN�!�2Q_GE��!�Z>t_��s�#"{LO�He���VoH M�:--� �2�� �%�yE%� 4�y�"!*_�- ough�M�2D *' &��D&� 2�a�_:�dk��+{C m U[��%#:Vq�"�� �y76�!38�!by�4"�!06Q�6��Y�Q4Q4 Q�V"s" V%sޏ I�g5eZ��b5a_�!���N �{ %�0 �H�#�@k.�!�1 ��zw�O r&�&u cres$>.�&/�t7"a>4��B�B<��� l[�a&&�A�/"EF}CN"��9, o6Z"G "] !� ��{��JUA�%�� !Gge�1G"�8�: 9� �:���y H.�&a*3V!!�xUf�B���!�8�F; &!�h]�'� ������ �pa�i�>� !e sv�x%� �)� F� 8C3$Figd��)?�m7@ ( �R�P1(!�m �!8i��M�i pind��laq��Ce"� �- � "���~A�("! �o�%w� a nae+.� WF�H;*��)pi �!�Ew�"s wrinkr QT)b�h!�smo>B� 3�8Je� {f�t � �ex ��r��dh]:H ]A��2%!�^r�ig 8I]8XNLA:��BF!���9n��6�mi���&��<\I�%e����F-&G , 8H �� 6&�"!6� L��6���f&R.Z �6C !�oc*�'m �.�ou��s�A X ,`E�S6� IwY!�$x�s�  a�6io%��~ ���B�AOlengthQyR���UE�;nap ke�n7 �5!��^a����t�y:B�/!hA�w0P � &,( �$56^.}�s=.`��k �E�����A>7R6F�e�,A��$e&�vk.i�tut� "Z.=2����rB� �J | � yus73�S��AP a�$� glCie6((6GS6� �*�& focu�c��-M�� ��i�!�saw�74&2a5g�#�( {<g 3�Z ,a���Ή�e�,U�gh�<�bi��� b��S1nwrap vQC, yetM%enE0l��fuB%)=��i�9z��iA��"T\�.c "Z � O+� ch�B�>o�fy �%5c�I(3�ɏ��ul"�`ro*�%;�76�"S6K%��U�$olu+.d�> ] d�{er A6�!�z8'�Ess"\ia�u!� �~�\n�:v Ѥ�2PI�"� ��ly>6�ju*�jF:. S~�r������/��A�i0*$%q�A6�[�E+le Bd0 _*�.aVSF>v�z"�tQ�F�(D#�/��)27�:�!�m�+�6�;E��innot�@eOn��F IV��al8"nT��7�c�a;��� .�a-�-))Mz�@�)>Mgb�$q! l�;!TJ�%.�B�:l&�[%ʡ�E�!!cX��UR,���t"�'� "IH�^mHU � � ��"�7)I� expo�Y�* ��E`!Lh%�|G���X !�s�=&n^��M!�ia(7M�/�n6^a�Z�i]i� 2�&Z'�a02�R��<�_iPQ'IQ�� g�:E�,"�,��F��I"|�re7��%self-f�ڸ0�aphrodi;bPfa!���ma� ["�c%� favoa�QQ(��#�_itM��8~'6�t� ��)8u�H :AI�W�#5��.� 28! 1�3t#�=1p��2��!�:�eSC%79����a�jat�4hpi2�n:a* s­����in%�1�} JU170 )c]"O�7! ��120�6/<_1�JUDBD1&�C255ǕrpM}�.sa� s*��m�5��)�� ��&дd�w�at2f� un� ��.�zm6�S���D.�H!Am-�"8QdE� 8�Q.�72%a, halt�q6�Y!nd�ut 30�K��.9. ��/1�vpoS +x��1V�&�b�Gw�dD �f��.�%奿it direcV t �!���.�.i"FE`"�infecte��d , but the preparation lost its ability to infect O . tipulae over storage at -80°C ( see Materials and Methods ) . We conclude that .T`was far less susceptible ��Dthan C . elegans , briggsae sVsp . 3<,N . ausubeli �I. The h�(spectrum of.@major ( JUm2747 )�0quite similarY� 3(parisii: it ded��8( N2 , JU2009 )���o 2507 %793 )-�no6}* 1483* 170 ) nor.�"408! 75 ) ( Ta!K .� homosporu!B8however , could �L both Caenorhabditis�Oscheius%>ie C t!iby>sS7A5pUyM��� Bed �6eF�for��sma�Trod-shaped or crescent �aA݅�(apical side!��worms’F�,�1n �$ions ( S7D��]� (�aUR� ��a~�z �mWepE��OI�A[as-��� nner.��Y�GE��capac� of !CJZ"D 2�<, we next sought'ͳY�1respons:� among ��(newly isola!$2lu>.EO- -QAhi6�has been�n�\induce a broad transcrip>al�[38] . A�t�<at��0highly upregu �at%2)�� timepoint�� C17H1 . 6%�(F26F2 . 1 ,ei bof un��fun�;_ wo �genic2L�y, ERT54[ ERT7" �sXr%HD B�portersAk!�!�wo5� have)A$previously9Lbe�ong!�%X�� earli�1�A��r�]od 9)-jWe�th�r �c���M!Zby plac�Rem ontotes ?a culture� �a�a��2m��oreP,then monitor^(GFP express!�at��=�m�B��? well!�W: mero e�!�m�W . As�ec�,%^1n "� � 1�*� � a�)�seN���� �)1��rn!�e\�:&0. By contrastA� .��a�6�JUm� fail��oEv evide��$of prolifepv.��did�<robustU��=�(��9A99B; S2�  Mt ��re��A�,9 A�6t)eor2dnsisten��e%"1/!F& q�5��m� e�ma�ERTm6; �2�1, alth���E&j  =#h!?9[ee8M�.�!!e��o verify���ial�u�ofA`:�match-��U ��end�ous���ncoAnA�0qRT-PCR after trolA6.�(%&� �a� 2 )m��!x 2 usA�purifiedI� p�.noh izeda*( an equival� levelU inva�4~�"� we saw)[1^J.;!��Q�5anox � Ѽ��� Qȉ��4W04B5 . 5 [39]%traga�d�roximatY46-7-fold lower{2cWd�#Fym�C� � A%BE" rRNA (�H v��l�� ) re� !�q��U�aus� much re �� "�.�)\J+ �2�, desp�gA]6(,�>  morem��[40�C�QdeŌ! phyla$ etic�onship%1"^�s 2e3� ,i�evoluA 4ary change can��polarA�:6FtK9}"X to vat pb�as�^asx ���3or� acqui,>pinhibi��ir~A�U�"�  ly 6��8e��^ AYQ�6Uiel� di�>ct6Ys . M.]mubi��oblig!>i�G} uEQ���%~ agri��ea(� gn�0�1) ��7� stud*%U8laboratory . Ou� pro�s\ �w��2���A>ii, bacteriovor�V(easilyAm��~͆� ir natu�a� CinI&a�"TZ �dv- �a�6�A�! % e�t7Sorigin�a � 6�a�um: le�F5Clade IIE%  ��� V#h��enlara��abl�z[6�`!Vbe � 5aIinclud!soma�� re�6tme�% uman]w6�TEnvironmental SSU rDNA6�n sequ� s)_E (d from soilSaE�w� sv%@North America [41�!(!� cor�� �M%�"rna3. ) S��m branch؁Q�!ѡduvicin.%Q�bN%�we&� ( S4�t. S�f-i,)� �5w��*_ !%�mae1outgroup��3or"�1 �!�us6Q�V��n� ~lyuP�2�"�� �1ݥge cA�ō�&de�be)�)��%Li� arthrop, e�a��insect�T= =�1+duE�deep co-�� (.V!a�Qa%>�o�&aninY-}o�e fac��atPshagth��habita��teB��by� t�as��� arri�[16� hich�E�fac�6 shift;ae\ lex T cy'�� s�al/)Je6�5�d��>f� inu;�*�����w`a� ruleA�� possib���adm� %A�use�-:Va{l�B��YOf�e+ � OK! rizo��m�a'�mi�&� a�9�mO�E�ver�=� @of:Ein.p , mollusc�� fish [4� 43��In adQon�%V2 A[diploiD.CrecombinTA��f)q ly a sexu�E[30 ,  I\i� occu�"i !�%result�ggu}�a�A� b/ �qu1 ommon!* wild>k0: .��"+'S*�/� "� B����mfo�in 30�ofrB����  T�w��a�݁bbi�owards F��A��rv Asia urop�Af�N�:mo"d�oe(4��iHawai�)F� �'threeB�t�of6�l!�tro�i��of� ch)Z���*Aa.Q 6�Eh1U?e�hundrede�{�ris?��� )�6:IE%��#Ma��.Amc���ato��bi��3 ribu� �I- s ra�t� tempe� zon� wh7 .�aV-�)� �Z 1B )�Ge$�dto6Hn� uR1����{a�}�� llZ- A �" M@ ( 102t���F  �H"� �� #s A�) ���H�I�)�e�%lin!A}��� associ�VA�AH�Q�_ X�>��:W�NB-�l.� � E�"{sQG�-term co&��adapt�� # es [44Fa!bne:(w - ng>�9`in b VD �F" 2� qa� u2�,>#w�"5t�A�d�opQ[y(a��l system�|%W�q�.6� ��7Mv2=�-(adiversu ep�Zgr� entroA�A:mi�#,M��c{! &F%Q�%r�wo �.ia>�,.{$aQ�r�q*u 9��AF�E_R�yphY%��e�;1�)E %H�l$&g+e��f�ra>n,9rA�R�ell�s�A�f!׭{6�I&!��"lE%FL% U?q���y2�EsS��` �� ::����2@"^$. N!t%&os*�%:�#F{ Z ��is��!er� �guish� betwA��" V) �r�(���e] !��f�k a:+�ve%; �x!<�� l&�6cq5a�ŪavailEr�"e�Ovx&N 6Hthe Ti�(%�!}� [19 , 21]�g5 a� ��cao��U���-�` .�. A�F\6 to� ��dopt ei72� or a V� y 5\e� � "�%��i� so�c tissuX .F �Ch&j .mE�j�<�l` �in �}� e�"� !�independw&� $e^V else �p"z*�,.�*��wS .� �2\*&�%�"�!,�! ,�lomocy�AV neurM"��it{ear�Md>%�#by fia~� tube��z=;lumen [2I�$eU2AE�is6i"�! ��.�co:��". WheE{�lso�����'s-L�ugd gut�%}tud�L� a�ik��var�  U�c� rA�elCexi: ateg�aM���!%..�; &�a�2 al mem���!w1 wa �&u��r�a�s�ar�rway , �A��exA.osi� 0chinery [27];!��A[lus%aof {!a0'�8$!&�)I�pr AOin�C"���� 1"T����m&�;re-�3+i� %*sY�M�36]��perhapE auto (�'A�r� ?99�%plasma9�.*5`)��/\t!�uE �U ofteet�(rnl&ric!�tEmm ���� �] 1Be�S1E ;�R"s wrappA�a6GoblascI 5Eŭq`�r�!pb�$precurs�heVqzan5^ �E�[46 , 47�� nJ!vt�E�>�!in:D� � �!��amU M;M�n�)ssur%ed���]���u�*ut.:a�i� rout�Instea>-�es pus� >�de#�!>�BU�De�>��R ; S6%�� .�f_)re=h%ep�0�$ina�g_E?]�a7bMor2ruptu�!�unclea� "���r!ma� prob0,�*e�):�1�ot)�to�k%+.�%�I!�e ���mi�,�1M �Bd -�0a K!�,�&.y9m! ."�le "* ario!��s' firs��%�P=y,E9��t>&dis�g�aa�6f.�0becx ���#!Lfollow!�s3��!�lengthQ �ycaF� !�a%�t %,�"�sti��tta�#m0ep( l�#�/)�* iaX%�!yl�me7 ism�b�u�x M� %�l� �-�:�—U��-���ais la�p ����lik la�toi��i �d death%�� aL�)as�vU�.2b# w21o� �2gastr*�6� Z @cytozoon bieneusi�"&R�* �'� -`� ed �itselfA�extru�)mJiw[48–5W"P�mP�%E� rapidly d �A�%s6�b$U�ionQ�e� �e>�MQR)� w of-� tra2&]�aW.S�#s o� �/ct�� i�%��ɬlyi �Walj�q�n:�$. Beyond ar3Ana�Zo>�,>�ofE�&31*�s�*y!resourc!*��i�$SbaO Ōre�cu cur�4 work�C*� !�&� isw �-d*Y .3r�c����1G![.K�(1z , yeap�( 7��#�� �-q�, ry� �&I�Ayet�"R1mouW+ e[1� defe�./ �!g .a.x �7o�!2�,CB4856; [29]e��makA;� *S#^7"?��;)immune�fwayNuo*6f3 �Z5I�u a�ofUsc\s-��'mut�s�h al3&= $ ]3�&2�"e�"��|+I�o dŜ ledg%�6 -�ng>)$te�!tr��*-%s>��bg��e:,f.',�5E�B2�)�c|v� N �aiq�U�PEo��1a�pŖ�0� sm , �m6�%loc"��$u�j�  H*�s#D�R rott!Nfru,�)�A�Br5Ej�orldw3v�} al y��9�KK�9�! d [1�#j0)%� �'i �as68w3h � � "��Nor�5i�3�6�(��& ngMdc8Nomarski opticse�molec%b��5o"18S�8Sa.ITS�)%��ng ��� 6�)k �� A�IsK$ic= ��K establiq by ��_��6phrodi'� "(male-fe5\Ea �le�ed #�dividuf= ��dra pal n�� col()� 1A ))�)y� >]. S \%m�0Izm8a��k�or*�E` labe�-#*uah�� arb�2Md�r:ach>v� �frozeik�>A�"�>j7�u�F 5Q�-�thar��m&8o&u'* wth �)�:NGM )B � %%� coli OP50� 23°�haD:�)��Q��/!W r!� ���'(8 }� ccor :�!u ' 8s; http://www .Sm�p. org/about/userguide/nomencl�}ee��I &�"m""l�le� I= numb� ��2-� ��6!n�e)@>JU1762%\/(�&.3 5puq�@^�rs ky&�Z�RTm1 ( �-�CPA24%2JU134832n@#2439�! 5205A�b6163b[2�2�$ , 51]&+1>F1.D4%/*M"ato*�. ��o�w0�,} o&S( data^&�$in GenBank��" sa*��)r�*�$β-tubulin�7z �,�&�8�Tify��j2nd] fragme�7�wo>]ge�!(z�))�po*4�!)�@�id �]�FTe���m�{7� a�eX10 μ.n� �6 ly buO `!X3$DreamTaq B "10X ,��romo F��rE� 1 mM MgClD" 0 . 45% T 20%ucBng/�protein�K> ��tre�( t 60��a�60 )�h9515 is !��� Wu�1 (#�91o5�2;n9�, prim�e�v1f ( 5'-CACCAGGTTGATTCTGCCTGAC-3'  1492!R5'-& !� 28D�=y �=dA 8F59(67i�NICm516i*�!a 18SR�)& GGAA:� �.�m���\45 y146 yA��> 67 255�79�D m279 F279���81825�9�4W sig�a�"pai�(1�SPF �A%�� TTGG!�TG �!SPR (GGTACT(A%CGA (A�|�E#F�275)e 772)e& 9Q#�� L150 8!�104p<]���:�: ,��1for�(- βn1-AC!�DAGGNCARTGYGGNAAYCA �!UC�")><-TTGCTTCAGTRAAYTCCATYTCR ?� EV.�obd �>�Q<�~!/�C}YGn'E��� pe6�� �s�FA�Rsn O � CCGG�TATCGTCT!� �u βnO �CAGCT�A�( ) ( S1(��produ�.*x o�FA�al�{gel�(ctropho�))1d_ �4�=n�(,n ABI 3730XL(� m0�MWG�UN�**� .�\i�@!d248I�124me125m�% E�18�H%���AurlDu�qt%F Hinr�$Schulenbur�� rN,Ganalyo9 Gene�> v7Y?. 7 [53]S�@Gby BLAST�a NCBIS� (� V . ncbilm$ih . gov/Bu . cgi%=No�6�.2�c=�}��� :E� ���J��>�iH3�&p"5b. B|Ig��A.w�6Tpve :HA)O�%�"I� �u 42�cha�e58 4i62� Q�24submit�to!�� underd3  KX352724- 3A�KX36013060167{KX378155 7817z 2����2�7L "Q 6�w��of�$&? 2J&](!+ fungRoz�&iJ!��0, Basidiobolu,narum>Conid  coro�� ]Wg#! aten� �^垅^IO)� &l4�sJO:[3J*�F2ze�| of� [ , 28[33.�� � 6Er�%`u�%`119d.�!"A (�  ER&J?A-5' 0����80�M�5,� �&Z�c�nIA ��(,c"F52<)b!� Yv&55.r=�1t9�-c`x.@���:!'�?�9 18-��%�&� �&6�D32�(6�To2w6% ze.�tog�$�}2��!Z)(&��~M %�, �&�1,r J�5E!\.HB . r.��hu�4S"1 )!l� f edefault�ame$=F manu-&d6 if=�h e 5��imTF�(MEGA 6 [55]!�est1@%P best� f>�-�!��!mea�6*000 boot��p\l�e�. Bayes�K��rd:UA���tru;)8MesL*(v3 . 04 [56>MrR � 2 [5�"%XA same����Rove [58 E refi��by6T�,v� 4 . , 5t. bio��,Lac . uk/software/fig&/E W�-�f�in M9�([35] supple!�(�|20% BS>ATmLV �B�0100 μm cavitL%�luminium[nch� , <E8Wohlwend Engine�@$, SwitzerlAf)),Da HPM 010 ( BalTect acet-*� 2% OSO4 + H2O1$ FS 8500 fJrdevic�/ RMC , USA%�Ag( sA O%�embed�stepwis�* E*M� � �, gooy)filtr��g.'PAai.&in�DYsi�(r34oL%�!or 48 heL� �!�t�oco�!� heat6*ym� �vL�3 a no_lckn/of 70 nm �cut1�UC7ɬt�9( Leic�%Au�%=S]%3�� A� mesh�mva�E�(cupper grid�1�s��Q� aqueY@ 4% uranyl!�9AA�(Reynold’sEci!w  Imag"�ake�$a Tecnai Ga�FEIA� he N�4A�s t+SkVfequipNera US4��cam�0( Gata�QES!�zA�measu�2 22]��riefl����u photograp�&byB�!Ma%xo� As%  J �y [6'"W�t@ook��CcTQ�ca e&out"(5�f��K%s&� 9�I) clas�4, 96u"�1 numee�t�60�6� they�5�W1R�% ��" ]%as���Ez�>sa�a�ar�BW>spa��*[of6�..j �m� each   R ; ex�X�"f+,a542>�40 q%� c�� !�2D !��.�Y )�4G methj?*�e*��w.-!��[2�;%#�&�;Y�� r�l��/?E!� a��bes�8j �B��edb EePJ jo�Cu�!���.g,BWh� b�D��� &�G viruA�.�=or�to�a"ly��]A KTR��1(�rep.�$antibio�+  ug/m�!tamyci�v5Ampicill6Kan+2+Tetra >�8� Gstrepto _�&*�N�.=! non-"�5LA+)NmKp�09d� s doN�V\:E��9)I �)�V,� �a�Z*%�3 �E� f�p� looks�'�%bla�%eRz �ImQ S� l� ! }:be�to"� 2AAe�E�V,2nj picu2-ma+%�) Fa3Bd,'!��=�# so�+,!�]A�a��'� �,gee"��2�&M$"B0symA9FV6-. AU�-�5J[�-i�detect�,B�%/harve&[in 2-ml fuge !l:0cla�Z,silicon carb�" bead$� 0 m�#Bio�E Pr� , In� ) sa�  c���vortex���ats=o rp�!Ulys�of1_il&6��(+5�  ( Ma…=)Arem} �2!� debri��g�j:� �qua(�s"M ��!i chitin-0dye direct ye�,94DYY��2�*~k!��Co-2�!{�*~9DM�,@�+<t�% is 3I�^Ix>.����`z "j^>a�!^e�eb. ',aa�s~ pestD`crush b",�4"V:�s!�4�.��2�C�a\p"^P �g�^Ko�:&�"�r�)aX �n B#�H"�>�ag.da \"^Z9!)iciencb�.*�PM w^$�6; sh%���&�R)F�E )yMAYly�)ԡ� ��= � J�4%AbJUw��Fw$" �!.�$$� �^One��th-rY1a�sb�R� t had�*>�to���B�a�;.h!8"�B,t1S �At} �v0%A�N2 ad�i�)8`_Q 1� h/^6��;� 8a�n)�S=e�}2�>��0me� �� �bTI�!�B3A��mo!�9ch",11rombq:�9J"\1R,of2v�%� a�Hem5(*�]�E�P�Љ�N?���B�%��E�A�$ w�0u�$���a,$�����O un)Ted L43'young)���iN�_ri�5o� egg!Zm����;fi+�a 6 cm�&�see��:�&/Tm��on�iA*� B^� μl �=il�'water) �"��h�0'law�'s"� 9<incub�P*$')�"eof� e��*hec��N%t 72 h=�ino*T.9nq�2f��Zq�\ky $sc���310&3scx�-6wTw�\jyIs8["3VXp::gfp; myo-2p::mCherry�E:\215["�\232�E�i�$!ass�.m�=��mEa EfN{]��A��gt�B�$r � YU^��Ea<� P;t s�on5ve flu��� � mark�@a� pharynge;61bc5/�X�`|i a�%0ii �\I PB qual�M�%$ ( I���w�1c%NQ�R�]�iA�F{6��a�sta��lN;�-n*; ��Rw+(2l�(�.� 7!�,>0l(0�� '"H��07(� .�JU1�$L�%,.*DNIC516Z(:Q%QC5p�r�*�A�i'e + �\� E����F��I�yd�1EgdA�,A�o�re8>�A�@�C*k� M�n#L4-���2ep] HsK5�aQvn ���r��6�BR ( dp� ,?hunk  ^a�starv� day ( 3s\:^�5E�Q�( visa&&�!!,m�r`� !Ce�xv{^��sN%0�_�#)[b#:�(�anRel�Chez�!e�M-pi�6~:*<&�-�.>oM!e�#8%'M14 ] %�A� �3v!�sa6A�ej f8&Zi�B.�055i(� ~(eX0�  ��v*+Hj.2��1�)*1 .nN�6(aHneg�1uQM:�r4�He�C n 20��I�uor�72I�i�BHof� :E�6lK/ofy5�6xatI�Y(t�4 ��0 .�(f ��4 , 8 2 {�TA�9|R�at/w �m"U-5F*�v_b�[�mR`(  `) ("�'e�see.�a, 3�synchron�tN2 . L1@va�="@��4 t 25�E�E*0 x 105!��/a ��OS5-6-Y-u:.f0� � sC>g di�]s rmi(�:se_*� 2ɏ do�� ..n ave( of 1(�Bo1%�%��as1��' FISH�'���_.�2 <2,W� &�A2�_A�ihby. %nTri-Reag 4b�.,chloropropan�BCPE Mo�5$Research C�;<c..psyn�E�175 nkA�/ �RETROI� ki�pAmb���]��L3 iQ SYBR G�9 Sup!�xio-Rad �n a CFX�%$nect Real- M(De�bS�N(� <. Tu#)a��f6 *�b� ��*` snb-1d�in�� iq��y�c�K+-�6p�iN2< .~V�:&EctoE�1I:�BN$Z�Chemok�re(or�a) : of G�e|Poupr,( GPCR�,� y es�>`:rol�!3h�\�;�;4`involviGZ_r*asty=XZAHIV�!�.�Bl,ra��&�"�i� -E�h�#od�0or�@�c�5� oligo�0D cJ  CXCR40CCR�&a= CCR2�"u� 5��_�a�5]:�Hch!&�rlMsJt activ@.2��#��#!�%#6^�'�eN��&�r�nE�2�'Bimi��. H���b VxA� figu*�AN�CZ]O_t�N deta�^as�Y�(ous�-f*�:,dynamics sim!��+"�BA(Ei�!wAlN:6��is!�ōfam�d"`�!�>�i���n��+ihIf�+ TM1-e,co9ed via m O@�< K�N loop� ICL%�ECL , Yniv!J[I�)�?���A�IE�GY8gnK>1�i�G5 rse-9�r~w5�A����!��7doD= . U"�$� ͐aG mphi�Bic%x 8 ( H�:i�.�563d�RQ�l�1F_� TM![]�r�COYi;c[�%A $subE-!��AM�2�so-�,�GJ�[�Q�o��/r���tK[!�miYJa�M�� (in�X-6����j2��R0nflam\zr�%�s[4�&C�s�e�,R�b6trigu�candid��O]# apeu� � 2wdis� s [5w6�`cer�R~w\/F���E ry�,ant*� umora�g"�q�5� me"� [,] � �F����-r5� �.< ode\+$A�I�+du-&A�!) [7�D�T!D�dvc� � !�NM�aP*  sI���e agonA}Yw,�|��S*B� @ourA��ies: XCR 0CC7 1-10"���$-=S� d CX3+[bus9�!0�Cnti2dgro�B�3���[9D���N�Yф�.�P-H RX 2K �"e [10–1e�T!P ssem@Jl N L2w�/Az�!�qK����#��6*�coo�_H ��l nd bnng `{ 1"E6I���/��&� t"& �(alU�X�H[13�6A�G(6���Ɂ��YYL�G����� �B�.Bmm�*�on.,59c*� a�olyunsgB)lip<,,)�B){ �5��4a&�_9C[17–�+No�$>� ��r�2 i��crystall"� rhUUP!�Q�X-ray3"� es��2��FI[o�db-� adja..K7 �K� s [2a�2!�2%�*�8SN},�Bly��)C� q�CR4=w�G*�(�EomF�{+!��.�Bl5�Qv9�[2!�4�zHVe����;as[Rio-m �O[49?O1�Va��0vez1 , �>�:� di�Kp��"�'���e>pre�o�a�sV�Ks���1MA3d 2)C—�L` För�abio�1}c� son�(r$gyi�fe�o�M6( FRETABB1 —�#\ xcon�%^��hPr��preex~ g �sa)k*�)�%�)��L���afOt m>|[1�E�3.:� AYM<J B� YKby���m"t|U>*�; expeHB[j�[/=55–6� W!�a�l�)ud.<�� tan�0.tCeSQ�%UQ$t�omU>T\[�Wus��enž�Rr ( MD�*y6�unrave2e SO%�."�� )��2�P�bSurBj0a&e$.]�$ �:2 Q�TM1�J� ��u� vut!�^liaae5 engaK i�Qm, �m%M�ԄeY-�#5�� u N!�e�caLo�P<�mo%I%�du�EaHmeaZB  &c^TM3 �4a-�;Y( , 4/(, 4)� )I�m*�zpeptide^ri�%T ]I|�/��bef2_Q �2���[%�`�Q�.eq30�a�� ��Ve'{ B�>"�m� �in"20qr�s dAQo� �C� &�[2�(CCL+IRANTES� {BC y, {.^ 1iz�%�^>A32� � ver  `*�" j-.�`2��p� [�E�E3G 6? AWcl�eJbo��( mAb���r%9� li�22t݋ze9��)4Ile52a�qqVal150 .�oE3B ruc~pE�, w%2�3n�� �f�� doub�Nud ��ALr�uA2�X:�dg�  [!�.��fd 7&al�Y��.�� s [6*A�JGpisB�[M!с�Y/� 9 ≈ 75%�alZ�c*B!NN xIow upi92%&{( "1�:� 3E�>� i�e ��yl� -�eU�b7��<��J-��V�u�?A}&sa�v 2h�96"�Val64Ij��Ile16 M2(:Uni 0—ID: P41597 -�eon���ua�1.�%�Q�� 6�GunaA�� rigg^ 6�|Mz6�a hepta��!�/I��0Met61—Leu67��az���Na�{�-�P!�~&Mby�edl��Bw[6%�B��mQ� i &�1$��m�! �AS"�in�7.cA�j E �to*� �My8Qz}�1� �le�.�N�r -$҉,F�s�UD* і[3�63�4�J�s62<-�A>�! lexe f&uU��6A7Z� �saha��a�. N�")J�6�� �}e�bm$e a UJ x!�5h7.tIw at u��B. �%�^[� ��"I�s�.ch�u� Z� �+e S�IM!fn�� I.%�3���"�)Z*P2��5� N.'Q&� ki�If.:�6*!�U�a�%_A��� ��QEl��c6&2�l&"�i�N��g�a�n��At�Pon����sNa�]s c>.� . It%)��AF7C B�� %�6@ glyc "ksfx{!n�� CDXS�gi�[f<u�by�%��.A�-. O�'hL,X/%-�5Mt� r�vea� negligi�:�envel�X[4�^>�!s�4(��I�%Ij iD-e��dC%opm8#of AIDS��&� ��u�.�RLrI���a���E[6BH"�4Ant9�����5oV�knt6l�M��� {!| wild �2��%!@�.�8J�K �� s }a",2ep6_ y-��o block%z�7y�G� .k!�de#"aS�&`� A�u\��Qto ȄL� t�5ao��z� XODhbu6y!q�ngAmM�o!�py#at=�[5kR8@B� imp����$ML)�o�������:vf�bm�M�)OFN e�q�!7[13:���ru�"of bi��ig�!�z � a� :��>L��*�c�њ a&O�o"� i` ���W� @&� 6l7�iyWA al��igI�*drugs Y!�9j�k ubje�~�egI>`E1��.k[7�S%<*@ i&g�a3Z{!&%�&��mx^*چ"h �le"�m�D;! �yea&�ra� h�%6�9�s�%e2blFCyI���icACtac�$olbe&� [ji�erebyDs��1a�5�"R+�� aggr� 4H�$�fd2�@mpc:c*�'[7�7Jckb("a�β2-adr.mm�)��� x�WVB&� �xi&�aa�miscu�;.��9q�M7�� ]=N^ ��Fx Eals.s�ea�P+j�!]�[7l8  o�D�a0 ant� ( IT1tf kAc6 CVX1�[�)aݖA�$( vMIP-II � .;TM� 6/ I�y�W �d�Gn."�a e65"�2Z��7: UM pac*e%s� TM1�-7E� 1Yik�.�5�}� � %�]�ׁ��1a��cL I?&, nH8A8e 2 ��%!,� �E'[79�I!&*>�/3�:ZW cribK �'(�@,(� ņ<s ��e^&-����H�0�&\��loF"w2�"4png:#c@&�nM�Z�d�?l�~&�*Km��3ic �]S. R�� 2y�!^d Iomp5�an or[C^( BMS-68ӏa&y(A-RA-[R�g}_ }�[i�*n*Psi��%�5vA�%V�F��!Oi !lex. K%orien!� anti�?lle�!71 qN yܱ��9y86��4�u/U iR�8\TB�s 09�ata�V�ӡ!������+ !e�-��-�~ >��.*�+i�C�#}Hsuc�G�ar " +(F���)en� fuW�CD.��,�%�qR�Rk/i Fl s [82–8�E*f coarse-gkedA�mY.LA&�"ބl܇ed ��*$ y)k"���JC�TxplybY��.s!��=;-,�=Y6c0scale�W�386–93 D��K �2"K`s�al�� }j@��%��!K.Fp)�e)�)�bi���"eN[�^87kL�;�Q�S^<TAl"�;in Fi>� d [9�0A�bP�'"%l _94! �.� �a��!���@G"&.2n\�ecS-2Un ��spo�nb�q`-E�.C�v>>1��-s-�_9�o10@ �!U:d�,!d ߩ��tr"�r: )Z���Zpp7�?s CGMD2 [10� 105F/))M o T�KfavC?% .t!V"74y b�Hr* 2]�� !q�trw�M0$,E4 �Q�elu�4��[9S10� ��+/-)=.d� �+�K.o�zB� sR F� i�]��.�. Fw���60C"��,(hon fe�%�N5� r��%��!�%fq�-.q Is-�h��ei "�chaFerd"c��� G 6VwEo�)/P ȘU-�!F�.�i�U%@U4AQ.�V �|�n���V �!($Z�1. E�2�9�*�!�#� ���L�R� s(=q=�q]( calCzj�!s�2 Lennard-J�P�Coumbi2+� L� )��=6vsF.9�v -50 kJ/mo��*@� ��%��� }+�6i��Js @.RD2% Q�V "�at�N#g 3 μs−1!�p�/ POPC%0�# 8.)$ /30%20�8P"AaWM "n k of ����i*�� *R1.&[]or. �the73���E1�y+0( �e%;1)��� � �&X"!�r�qZ�in%&� ��)MN33�l�a{iY�a�on�1�$ �*]2�6!R�2+*��AI�G;80%�.�.}. Lp�W!Y��5����$��XF��8>� �'2� *$�~5�to��>e F�ic#a+�i!}>dis2xU���&��o-*�'?B �� s /m�)�~� V, S2cEЁ��239  9_��l Az��a�]g(lom -25� -17��Qy�F� ���.SA�%piXin�1b�S2dr2SAfo �7enhanZ&�r�}+V38W�᙭����!�h)��u%k(xaa�o�� �?e"� .inM7`2�f$e��[NJh�B� �fF��#E d%Tmi_ !GAaP8�/2 ( i= .'Y0BOALq��� ^ �A���O.�$_P&���!��QHܘal!5�3^;S3Efa*�Ju:}�!nV�A�9��]%�&� :pronouE�deIq�4yN4q}d��-vhY�eN�Qh�&B]�aD��49�*�zP �Z)�_>���#�%5��#u�fby%50%NU(2���2�fI��J����2��� �deceleŚ� di0-ͦBIh�aEX;uI�a�",ple hit-and- }dQde� T98B�A�J" Q1"�TlG4do�$) E�[w-91,&PA)�-�<ћ�H@.����7r+%P�Q��&1?�$�+JJ�X�aly=7>�/�6C_S[.d� TB �E;.��e:6=� ��&�3!N�d"�* ezJ��D�fk{&\ 1!��0d�� i./��~@RU1: qF&S�5�#�!�w ligha�8�s�]�h�_de�1��%9�&M�y�i�e����Y��ylix���7B�EiFu��-p&�Eht9�U��- ) XCR42A�(^ dTM7 (�# en )"��A�6;6�Q-1{�?�ove��02�; half�~� pa!Y+r�d"J=ol)k-� Zz2�Mr�ȁ+�iF�e2*qm"�?� �*>Z�lU; ly coinci�8:T��bl�"D�6� C%me�A��"��Zq�/g2�42O-fެ halvbTMQ�!��1*�<-�!M, � %���2d2]� �/"i"par 0�X%�{ 2c%�F}�~n^��%����?"]��e&�e0�,ݎ headk=� s0�vO#i#;q� �~�!H>$dV�&{47�4y�.  albe����ay:ጭ�,A�CA" $:V1 �pe�cytosol?ux�t��a�Q.l1$T*;2�"��C�� 2 Qf2�e��S��b��7us��A������=�}m%���r�*#�/Sݩu)�c2���i�A��!5e*�5^dd>ed�647�m8]D�}�i � =�%��7!&?EAS�3��f-i=X�E� 0c7aL�5Ied�j��1���5 )E{E�&!�lV�a:��� &!%6|y� Eǡ���J�� ��wc�"�$�oF�hot�LAi�K:e� � �ma؝EV!��2xB ����-� � 1�`6�2%)!�s!��ha �?�N�F�[3���Fur�mQ v�R_j��1�n<]�N��"� a�;2%"��6I�-��� popV6B hR2��šf!� ])�ZE�>l*�:wy�4a�. &�Am�[�5��o!"� \!�V:%�, H8/!�  ,.�>�  7'�b���n�!� )����CwngW��TM�'�a�+abund� :I*U�TM�'Z �motif6p�b9U-�# V,U�s�bhg*�?5�:{9. O��P syl=TS%or!!kMF%3)�. >!�)n�barR2iZ�)�S4a��Hre��v�uc L Y9&RU��R.*�DH8=5d1(E�zJ.�.�%A)�KA)��?� �nyo�n "u�c<(!� �9�[*G**fe.ni�jH�5�s��>�6i&�Q)z"`I���"A���[in S5S52�Da�a�i���e~L"Martini>{b l Ho\4;�GIa*�-� E ei�&10Iw"M��(d�t�\=R�a�a:O .]�.��ls��n!�:��[4W&��'ly]� \:�)*0.&'*� � ��Uj�&&WC"�=�45�h�?/�, q�2xL2i�by ل 7 Å� ackb, RMSDA6� r���!?J�2�$E�F�[D,U~�)��5�� %0+!�y h*!%odk�z.�*�$&3 .� �U6�9�s a\�ed �+NZQH%�ct:uip*���qv"BQ�!;"� �)�2���->"���� 35°A��" �1�!Hy�9��64 �I".�ጁ~Al� ct 9?!5cU�lN-�d bur�cR area� �B�f2 . 5nm2���1 7�:>� a�MRa�z&?<CC��6�s�� rec��ezor-ba"� �y:0�1�0 �\�)�4s#�oBA�}��T"QMѕe�""*�<�(�"�a5tGYAy $/-�E�h2�!Z:tA� :mI��&�  FM!&�6b1��6�%O \S6b`�yA�� B)N���Jo&Q��Fu(a`.�&S/$���5�&E[�K� ,��� @F�'�.A�F�.�� 0A> �G2�. >>6dec�n�d n"\%��U3!��� 8A�JHZy�d� ng��9 KG)K��UiP��GC("_U�0plm��,�)t,�T~�k*5:�HI-ViruE�1G T�9�~s*�4I3o�05a��."�A9��<���~E�9N 6! 3P 4�4E,:�T&:! Ga6l$NVKs�}�&f�i!�� rnj4A������d6e=- B`:[�9O &fI[20 �3�L��;q�J����A�ua8�&$�Y.�0*?A Q&� �T�<1�7 3�@#��r]��"v��J�e�emplo`xt�v �adN ]t�m"�,%ۥ-1�!�@�PHa�Us�]~oJ�P�u N+in�b�0!4�)>)a7a��� mim�.сi4��s�.�03!p�0a �A��d.�) [2�0�# pl�jZ�E�aFFYz!n2�:�N�]r\)��.��7�!*2 . U��e.�N.� <3myՁd2�"�����b�) clos�^Vs��|,�*uIBy%�> XCR45 M8*�VV?EQq�j�a_3ZEd �"bYe � �r�> �Q�W�r B� &9R�9 X!a�\oI;�$ oxly�Oaa���5�T ��-7e�=�-&���$Um�log�6� ��R���"dt .m R�iw#on�9"��9:�c�9o�,@a�R�)D�A��"�U�� �� !|[>C$� E�e5� :; RYey9�& 6I" 52!X�� �e�q"�s"�!te ��ie�^Q��^tXSQ��d5=A����/1�w��! �T0� �:% 5BQZ&x � ��ex�A� >���R%9�G�R%B1�o-Lq�!J%+�#*�/� F�_ޠ.�� k-�ȩ�uB��G� F%s:M�Ba�.��A�a�Ea6Di�6(^�)��,�*aB Z�0Jr].KJ�? Tf�8�;�1�.e#R����C� A�e6��6\�t� a>�Qai'��.�aK@d_ �.���at"Da&3  >q> �'�P4��:NZ ,NE !�i�� .�x�> !Q/R}Ni"��t�pe~f���lyE���86DofX$���E" �,�2� R�6�.��&#ן-%��3��&dZez> iR3�yC!g�� Y�TM2 ;' K2�f9s%�"�0:>0>5e4�N@pal�Lr�pre�Bly ��X�E��g!&k �Ϟ�8s!���@ y Perche��_�% .WJT*� 2� [�[�+! |4& "SDF-1�/~\�7k!&RU[mBi�o��tj;"�r�H�.1.��7� �_��)� EAUe!Q���*�#: ��!�VVN�I� m|,utO @�."$ �^ct�AC�%2�i�رW.:���&f ;�.X/x%"��B�%"�)=7&�1U K!�N�5�`(6��,�dU���L�impedd��poT�e2%�Q�A N�+.;�%��| ��i��#=Ju4�m\[K^G��:"0-� ����#�i3= I�Ac!��qs� !_�6!�o:��( =q[ y�Udh#"�(�I�ԁMh., 5���E�-�b���2I�c3*}[S^ �>�*��O'+O qP-� A.Dɶs M�.�M ���13 }b�NNh1z~1IeBQ 2<!'� ��D�D"w#Q�>s�oY>u��]�0ekQ�9�.�R��(�W�h%yp�+t�<)I� �`.i6�a1F�S�� ��M�� ,  ��]�!5�թ-��%a}i�.c�/YKa��F[�2� 1�AGJ� )2��!���[�=��{�r*'Q�N�s nya|��"�.�q�Ea�Tu:!.aNwa;�� �ctET+ed!�����Z�io�1BhV*LN�!wmatw��p�(a��], rub1 xi!<�a&dM:\L[��^6w�.Pi6D6IB��( PDB�04MBS`EV�Z" ,*�LJ��wr�� �VF� ��� E� �za&&X(͆�1@5:$—Tyr58Cy�EAsn163G% Asp233Ala%,Glu303Lys—e�` ackA�!:wi�U"�(!T �ng��d�o-� thir� *�2�p&�Cys22�`Arg22#P Asn2���e42.A.6�(� MODELLER��0,L)8}�5Q1�3�ra�gI�Pro19�Phe31B�kX�Nr1"D���Pres|R-�B� �iso�0 B!*�RAt .^b!6��A��!�9�c$T4-lysozyme�!*MM!@� &DM]�&jM'y[M�/*B)PMT"�R!5�"P2<Leu!�to%�40)��E"d� ��W7aYG2S kM2d�ari\��yl�\o�!g,y2�V?.$�"�"-�b�6KN*RYF*-��d~ 9gahB�nd���}>Mu&n(�$v�5Tб. N��}b�A�Ɖ"�"!YiX��(�b,"z )�L—KTLLRCRNEKKRHR—a�4Ej%%iHiI�2 �&">A�=�.�%Val37�a�2�Fia57R�Y��,�mi�:! CHARMM36o!iel�rOSub)&� �B� \conveg#��@( $2>E(fo2l2] �mt(�c1. ,ue�1 d e�S�1A�t�M Y�,�9e�T$ic RubberB;Y |(xA* appl�.(as�Da<� in W�%rnaar "T82ϝtt�2��5h bo_( �� yF*AH�&���'ӓ paiPCi , jl$���� 9�of�G9ޜ���!kernel�1&t X[113]: F i j = f · e -Z2 ���"f%s��o��H/�%��!5 �!!��e�(�d������coc� )%E�* ��ME-��!3B��� ,�S���'�"ru�`�fQy�!� dard5q�IU%p���11'heI�c�+of2�: RuA&�.�%�wrigid�a�fic�2�t���=��a6ari��Ͱ�*vala � Cn�P 47 .�9m�0ic leishmania3 "�nc�Of>tET�|x!�R�pa�le� ga�-n6E}�jiass�U�a sub-cl��a��rm��f�YI��&A�"��{��-�("��� ;�t"Mh"�]"��p�d�R$lymphadenov .\anemi���Mi2&#)�^ a�rd uns"˸�uw�--���zo!�“aty.|”Gat]V�� �/��X�-wx���H����&�y&IAgſl&e��m��� ae��A�k6��U�!%i��pg�Jal.a�(Multi�?_���er��T&��3<v�T׻ic ��e���Dp �71�,A~��?u��biops D�,�SdT���Ud%�19·4k�160q)���S,AA&).�profi� ,�exh��uys���Kgph���z�Lu��-K�F�ngAI�!x{Ow�^! ` �ed �'un%�+i�pQ^eP* M}I�!cKB)A JgN�>yoasquara:��tv��I��MY `�&nCRu��ap��pre�oӈ�,��&��(��&" Q�api!r ��f7detasig-nd�9se�68�!�)Z�f�h �B.6)D-��Qe��J~t���a�H�yxar�S-diagntoz)'!>%a2se 319V�ca*+L�!i�7oY�i�g^�+�u5�/%(� zla( age �A+t�ende�F2�A�%n �ie�U�Zz7'ny�U�unVY�hd�5@E��s"R���homC\obv�8 &�Sic de@e�.� Visc�|y�� ( VLV? Kala-Azar%y�T��by9�190 �&�T��ҁ��z�25�"n}CLcPSxiyE orga��(��rESsplt)"��A�abdʽ!��rr4,�XQ���x limb�#tru��A�9Atopenia>�–m�D55�par���se��a�8 �A��hfa�#if unL�R�Revie"� li�`W7 N��eR�r�30tyZn�A�m��w�J)(��9�J��̓> n��Vdis� .�p92< a�ea�IQall��hFR;dnD 2,ollowed by s�Reveral groups , starting from the late 1950s with Manson-Bahr [6] , who recognized 5�presence of infected subjects carrye+(arasite yet 8�m`symptoms far milder . AllYthese�bas |�ir diagnosis on positive immunological responses toJ �T[7]–[16] . The ratioqpatient- sub-cliniOdisease Mose �(overt class&�varied)eone area <,e other , an! year!an 0. Its value (2�/ u) shif!w%�0levels as low1∶2·4UG high,8·5∶1 [14! Part!!�4discrepancy inreporm igures is sul9sMje}� situ%�atY with����J ."_A&routine!�� ~!� a qu� (onnaire ansa��� each1 �extraz !.biodata ��  a!�A�!k&majory�fea�xu���atA�y g(also includ� 2Z� wh��_5�li�nd � A�lla3th!�persoa�%4family histori�?Travel!&!outsid� ta��c4 dUw] . As��b�ryA�=�I%� � ��on � y�z see���)8a complete blooa7un�wCB� ,�\oglobul�; itera#Ɂ�sub+ eD , P �vA�':: , C3C4iFn add� we�a�hemotJcPHusing a Skin Window�Aai�per�atimA� terv],� sl!x at 4 hour9` acute�ph !�n��� 818:9chronica� ;[19h,In suspiciouE !)@ w �!�modif!���etect !��~�� f monocyt�a�&t organism!�� A`p�  n%b WhenAYcellular�o�� es)F� � %�!�he ab���%�ag�G2 !�/gdXa Boyden chamber assay �9� to analyzide| �J�-S6�67M�"� n*� m� ( b�\ria�fungi��nd!�� . FoiUl���3&�contro� axe�"i&z a � Փ . 31-c� ��Վ( 19·4%Q�fou��o 2 erI[a eEz�FR�. PTn� x� �!�behavior �E5is�  � i� focuE�AJcurp ��F2%�Wed�0 � Nor�  ( 48!(, Akkar Dist��which%a� f�f� �� ,9–2000 [20��� l!�e<follo\ byB � ( 23y,� South!�6!8s �,Beqaa Valley"<( F 1���age����>�Iw rang�(a few monthh 45� :_by� ( 84·%1%Xchildr= �~� \2]�12 ^,IP@a bimodal peak arE�2,6 +. W%�stres��c � �adultg!gr%�equd%�buA, 16 mal�nd 15 fe  . Du���-J�� illn� span: �� ~9B11 �,A! most-w!�F9|N)po s�inH�n� �targe���Cis� � �� tAB*�M�,%�at䉩,1>, d= �G o toZŷ&D problem� t brough�P�p mmar����1�e)7frequ� i ain^re� i�i ( 74·2a7ex!�� b� 9e�k he s L gastroin�i� E �4+9�2�\ .L2�� utane� boi}ɘ deep�^� oc�!�any. F e bod*E� �lea�o#X & #devoi� ny  %Jins bin. Failur thr�A�F� @of Unknown Origin�\UO ) cam�k�in1�c (Splenomegal� �G � minoE�ofm( T�2��z!-fe�mv*� *�)!se 31��"� � �'mep %&�b rli,normal excep� + �M~�� ic:�by%4lay�^ K(!�� �ve..serPy�IgG� �upc Ja_���s; onl'�, IgE�@remark~ elev�w�0an eosinophil� nt��!t��� 3% (!b repeAig���� io� at n!6-�.�� "�ehL *@A{ tuberculo*2���� ait didf� but its e�aca E� A^� d�a �82�4icts two photo (s��u!2in�� AcaXsa� !l�� ( A )�gn�aO � "� ( B%c��"� .� was v���A#&��th�d%Lph�he"z � E$Aon�� &.ll2�"r3�E�'w* �� opsy%�%QJY ,!D+it  int"TA�*8 �1c�>*V �ze�# � �sJ3 hbest U��V)id^�!@.� �nex%��(��%N�$!� Buffy Coa��� ��6�1��71%A���DB hol�"� . Ba�#Q� 's y��u�.�tQm� b �c� be ar l9 "act�Uth�!cJ$[ �O�G2risk (�$reason whyA�l�t�2�(a�we stil�inkAvi|E�1�t�#in)�9_$. Kala-AzaPs b.�toM e_ a �2 c?�u�,��-!�# ��decade$ ��YB ng�iB<��B ��t� esM� described�ga�gr� � sup� . Such1� {� e de�%�2 ŨiH��b6���'2�In'se � J s1n��"A RA��" �( ���� .profil�+SM4�� to harbor.�ŷO.��a�Kr e�]5su*J iCvwhom sor >%;4ly�� eavl]&a2!��2� diR� ur x)5@y�%x exhibi�5^per^A��nt�C� M�1%�� A no�Bof^R�"�o unfol It!X�J�predisAUng%5Lt���! de tru%6�%�&�yvi:#�/�al�TA:E5'va�"Apype<!!X��� � a� tend�resolvecA�or�`�a�� ��yek 4 m��n ōu�#�uC�befi*�� i,!ti-�l o�"(extensively�,E�jassociY�sur�#q rve�s.� � 7 ab3 �#tumorb grow�. A�-�Ke4�ly�nM��B� "bA�Im3�o�tiaA$ liefA�5�ari� am superimpo*!+` ��Jy�� no �Vc� 9� ataq�Fu�,��trta��o� @:� 5�evAJEVa(laB full fledѠof ���i.e(a�dM�)��# tinc�tw��]�rsoSa���3mea�`?io�" lightepf%�% �ATty��qa~�en�%O� 5E-su"!� to b<&e-A romi!�A�C! 2���%"f �7e�"8��cH�wh�����.: �3� ;Y�� fc� �u�injuryd��!�aNa� b� Ŋ� � G"���v 2)!� o�W�asm�& or�lZon �)�� �pur�_)�&a��I��(!4� 1�candid�$5�, favoH"6M it&� q� it)1| cX pr� 6 ��m]6�� $� en@�ep IrRid8ŀ� �,��� i� � & high implic�in � � !��'ourages��6���2!]i� *� .C&a�obv� ��� al advant^AE����a g0nu� s; howE�4�ropM�� 2a�ac� e4tA}se�b � ;fa"f�#in ��\=�ex�#u m  � �a� S*� i� pl!��J#BF2�w# �w"E i.'%als)�� � yfe���Admitu�9]F�aar�E s sm�6� olid� �$i}�P,b �e may��b�t��&�aO�!.@cha�!�("�!�S�4�#seh��i;�^>ly� " s&�T�i ) surp��si�N� p �X��rEj!���� } hair_icZ. O�I s%r�:��ho+rg<$be!i�"B)b� " a� ppen�mYhv9LneNexp�-&uyounger& (�a�,A�"�)� E6&+0�h. Our  recommend" to�, G2$"@ќ+ir�� �� g^ c_"�"m�"� !9w J ,.[ so�#� I gh���*Qa� i�.� nd multip�(hotgun styl~ erap�iaIt\#�� �m+ .���ill��!uL s%� polymorph� e*?A� huma�.p"�,opo^*�  c�fof�f{ H,7 drug�>��"B %to�bS*� �.)� -rel�o)7� c].imp�%d bratc3'ovascuL"z)a�H�,�!�E� henot esc�eJ ual&^m+if�(a 2� i+ m�'as�' sk . Comp-���@) acheawve�urbI�of �rd(a�b %U useful cr%Ae�F ify�� a�lik�]ve ^�. T�*�� �58now yH��explo�%KU"of~]\at hom� ��LA 4in�loM��*iA�S� �.�6�a �f��0�&�e_]�p 1�� h!Bassemb$a uniqu�&l*�!Bnq-ca:5� OMIMe�!;HesGe� MM) Data�2 ( HGMD$ " them�d�Af� 2�a%/>��at i�����ea0m*�/0�3ocE����Mcorq�6�5�. MoreT/�if�me� aO-�at�F5m���. rtne!yb� i3.8)� u��in���/ �q8'n +1�ulyB� B_� d� a�proced�0a�.� pri�iz �� � d suit"� 6<�tiu� rapeupurUs �-e pubfy/UdbSNPa�I�[1]��5siximat�^12(l��mi�F~,�of����+�q���-� aru��-� . L1-scalea�"ot&8produce hundredE�f64“hits"&J!��individ��SNPr hapl�(M� n ne�beM.dV!�|%�9r1��ő�e;v  [256,5C�$lt� h3is�method)�UAHEc�Uhl�$�us\ 1j!�5(�  rm�post-� �|��.:�bg��wE�-�]/yxhlupa0?1��axe &; un2S)��wdi )�d�6op��4.h1(aiat2;tb7=2����%�oa��� l �a�΁ R1 lico�.�%��A���-��d� #+h8n�#, namacSIFT [5E#7]2PolyP�[8�+T�8�,m I*)N~ �o��AcAcid Sub0'!�,�AAS�x�(ET��1,I�4].�e�-synonym��ch#&a �-!X���  align!�e�.>�M�� � IPassump�i��%� eK6A|a��)replac� s ra"�&a giv3, olum;�"� � w�adK3ly� c%ote�"u�� perhap�Na���!H.*� hA lex �6� hip"o!�dCW."� Jtf��a&�!�c%%�pQ�=�]*�5�d/n wve.�poorly�ed reg� �bq `ole?,d>��� �se3} b� ;��I�, E non-9���de�%y�": v!J32�bces�� , redund gen�em��id�% sugge��Valg��h�<��he��xa�&r "�E�s�ed up�$ rende\-�Z'E�mis!�n�&r�w instW5@ GE��i�9�we wov7�h�*A62� �m`�v�) sourC �'@8*u ��K�A!��n� mple��to��]�s6zD , �DBy ‘��’�� ��G%�%�E��en by. dup/!�A��7an�� � transm26d�offsp0� {�3”[1,B`is*,)> halP�d<eat�'stK ڱ)d]A_� !�� D�B2��6mun�5����su/ sur�+�.mp� ���,lic�da�յZ.�.� |A� �garaM� �AJ"� !&��a!�"e Qtwe)�st=at�>; =!�h�5� - "),A �<iI�A alonZlength���m�a�To2A %"r�'�i���I�ls��&�"j��s draw�)om�[11�H�[12]; bo/��]� � docu��]!͡��6+ �a8t�m�d�7��-�//t 7A  anno j�"d%^aW!3 set n al/uN"� A.� &r.�֒ki� ��s&'�/We fi� iBBco-j�W &�*s �*tX"�by�A=,љ# � simi� ��iA�%Cy{FYrT:ascoord1@ed�tribu)�>4thC!cnon–-U%cwu7�:m92<>M�>N��g�galk�U��'���.� C>� in-s� M�i�d�1� !ुA� .a>� V�co�&F�w�]!�>�wo"� � ��l> ;. �Cw& A�3�j) -hit0M�,"oC �ir, Sw M�s <V(E�58LASTP E<1e−6� K%&#� >17211m� n( ter�‘Bes�\UBSe���1� �ub-��of U368i;al�( R�)�,z�(n!`ro�6O>�;!r��Tse Re���-t�  motiv���5��~B��"� wopi�?�1ᰉVs:> ess-�2n�9� a�� . DeAng�s��p�s�� � � � look�� 8�"possib�B�} uish��%.s��y:���T me� � T'Q�b 6�>? �*ste y;r9�adpaivr!�re!r�.:v�ot�&*a�� d&����>AJ�he% se2�)2�(6�iw:&q)���H� b �*�D):��^ �ҡ�!�f!� �show vs/�GcE�in��. NwT� � ll��m*.2s� aY ����,�a/)(y6;0'/ ; 9:5 ;J )�GenBan�AO"� v< enco?'2>U�"r�iD%��"pa b�5���map wen!��% 2�/—1E��D��l.�a�gleD��bA�� det�0see ftp://ftp�IcbiLih . gov/snp/00readmThtm�)I�?�,i# c  gmu�� 109 , 989�p�& %#A'e�>��GmpA�#�J�ee Mat�>ls & Mn��� sK.�  � acc� g!�i��d![&$( 43 , 467=or� .8 ( 66 , 52�5EA��" breakA���[ �to�I�EEes:�&�** s*�\30 , 690�d� hvO"&/.2pF07.#(( stop!�) ��)�( 1,48gframe}M."!�895 in-'��M( 7191�t  E p�I� a���b :sG[13�M�4� �U`� : �ed.�AU 51�/ver@�&&��uw! 4743 s.\�$e ODDs sco7N��B�:� �]-��%8�GA� 62 .%�� 3 2��H"l�8All 5sig tk,P≪1×10−�K٠>�����B�:��(j� comb2,Z 3�:3 (:�a�S"�$fis3[>C@a}A^ ODDS.fubJ 2�R�}hi�t�Wso�;o��;U �meyM.9�%g��6 du�:.Q �"4 !4=\z�mu�!��<�>K�bs�:D �coa�& n ,&m#cs NA��!�/V�9� a�8=96����!N)0hypU >'1(A?�-�M�!Qm�cra� ��8&e &( i�iyv��-6+�8ai%9!�IM(�InA�d)�9little���ei=]O}��/ v*gnitu�4:} az�tear� -�&�4s&BHof!�.:-<T��. &�"��e�Wso ob�D�* "�&�4��? �AAf �1] �n �e S��%.kco+C+ [15]2|odd�T( i .@��@! �i�(�sZ�)�=ave0, 0SbU,�<�upAgwo��5[,0 . 47��< 00 }Sr" � >m Q/  word� 7I��7J�� eFC 2�� I�5�-�ATak�ogN�f;�&*+�Z�Ca~-2�.�h( .%-Y�s�[� ��.�, 8-�#(':o*&u$2�� ask�2�H"6� ��� �to+jv#�#do�)e�"22 , 2443a� 2�7� !�“Omici9�L set�!:�Eh� �����e��eruCas pla�'a�Ea�H"*"�orI�2�E,�l"of�!���� ^$�5? 2;+� )g/�#s�P by JsU,ez-Sanchez [�X/ on�s 923H ����t�b���I�U�v"nI&t5 ww4M0yandell-lab .�/�� s/ E_� .C  )*�!%� �9����/B�—!s�i~![35A92����B6aQB[�+�1ly� �', HGMD%� Zv � d� �+!�1�::H,I2�25%�A�{��"�,���y�a���e�'X i4S:�� � a��/per:0ag8<5TE�] �. � delerAAvDr&W � �"�J ambiguit&-moST6@maw2"V)'M��RRU<��/=*�Oe2< !1�(� NP>�As�.B!Q1P� ewMY:��:����%nst�E2��@�pmb��C?mVdH3�@a�448 C )�s-|A�&� '�3"� cal�-!U!5�QX*At( �0d"�bov�T<.������+'bq�J�!- l)8�1a%. A��607.B-9]"5w���!<�a�i]�� 7h.Gin0sIf!�%�:f��@a`?s>.�/!�.� A~- mis-i�)�(�#�,: �"�!2.� >�(TC*�is S5� 2��is�� ,-�Z���6(=&!2X � �d<� m t�3 J%\ Z��*\ U.-��$!B$q�"�/%�� o� �F*)�� is 8 . 8Zk�T ^i�I<9�|� i>�j�.is�Q���A�2R�As� ai�%E��TA.�� )�,a }*��A�C��'oc=9dmtb��4 = P !.T r/'[�ՉM.)7 �$4<� Jir5�5F(�w R = � 32�[>��./47/16s P*� � s�FA,s{7K�e)A�$�4x5�DPM{%T ��son"� �1aA@H le@`>��-� �8[d&�$��( 5A� 5% v�Q74 . 2%�U})�� n�1�D�El9�C�,�wBM!��lJ�#� 5.*q FJI�O8a"-QG6� � )e��A2FR��4F8>3-b &]��'�K� �q� �A�Z�o|/%�R8h agF|!�big�eQ!� ri`6�,<�1&�-beQ���: ll ?� 4R>|�oso1 randOEA 7�S)��c6��K;�A�1R 03��(��*-de/�e"� � z J?� �A,�Z�zSet A@�� ��+�k �� � ��#��R268�}��>-!�&I ��U�J R�B ��ssayed�=M�Q�in ���B���VA�a��O�H !�,-�6t� Ub��9-� "� �W��Aa� B;�se �s �WA�,$CK `�&�4an 86% enrichm5<(�6- G±��11;B.ofI^!7 �lle4$%��A2>>E�B=-�C%1mpa!}F�cB2czS� �i�>����M�-+"�|F�U�D"4ng*�A�*�, cho+QgB�eI�ia�o6� $a@�-)�=����))A*�_&�QhG4OF!�� � a�� "� D*o(f .622o"�.�z�.)�!Ae ��� E? –C%� 14.�9 ("��72~:��DA-f��Z2l;6k�us !�BIA�2�6uN� � �ivB>����a��j_%a�V��a�earlier�om3 � &�r &�DF-aF�5Tq%"�F- s��2>�T —i�%!S� �(��� Au"�kOV^U6B6<+[}�J r#�6 �6� � elsejWin�. W.�Ga�h�+8!"�� .9DNAJD ��u ���M� &*'�!; IA�*� h "(Jl,�$&�!A�A�,U% ��A7cy���=I ; (0E*�2�U"c!@��;�(lT hJ� �� Q�a� �.� �jal�M!�m|!�*~ A# �Z�(�1�.y"G V�11�� fapV2L4 :�Btery�usa�]pu�6t�m�-C a��"�"�ef�Z�=N1 ��A�2��.$��s ř�Co:Z MAF>�[,R^�] C& �8� �PG|0MA�7J� �@4�Hve��-�otT$!�1䖟le~�1w�F)�'S� co��i2-�ii?�#A�enc�&��-�2�.�(�F. AHqR��.��|29BJ��"wn$2-Us���#,�",�#A�8�3�9&. "V-I�!�a�p�E��ecusk""4 ��.Y�e$a �p�4r�JNNI�j �Ua��<?G� m�:\1��n�B`,=5amtՊQСTr"�1�5purZDse�BE�`l"ct�=�.#&a=_���+��.Gو2fre��%o�la"� &�c; fO!/� !��$>���ZD�� NM&�BU{N' ��R��in5.wb ��� @ &�&)> �F�t�wr a�=�:�. Wo(b��Fev#%r0v�5�nn6�a&�4.�%91�Na2wB�p O is� � (pronounced:P � 1� �;a�4�JA �4 b�\Pum�Mea�F[&un�b���h"���} I�bounds��.�;�q�Crobus�T�Z�uJ ?l"80F�s'�ŸZ�Z�E�%�-^0U �/�CV� �Q��e<=�6-I3� "�u)��Iwiy>,%P'����,��Z����@�e#�Q.�@A�o:����"%� p�8aS |W=�!=�ic��ConE�)��i�*T�=@n�[=�r�c� [c5xa��\"a$ir{1I�a �>�;�+2�d"m�N� {/�� �); . Ea�[ scir�-or��L9?�KT%rof � �� &8c6A�q& at�g ival,��!��N�.�3$ w�R.}.�!�S&��E<�2U� qlbio:p&< � @|�A+A�[ca�"c lapp!� �Y��Pa.@| Menk!,nd Wil�^5,EZ�)W%42�kbd"-!co5d$metabolismvz�|YD4Likewise Alagi�nw MarfGv yndr�T�ZI�s"4b spip , vi� � ci�c�w6��R�25]!�*� .�`3a�MA7u!&as[R�~p�gI/Qea�tA�AvntEm�9�p2�%nd�!�B���O+O�to&h "�YN�nem�A�a��4�O!+ icac�SE �[A9�`�� . No doubba myria�gi�?|D�r�E�gen?4k�E�D&�?eAs�0� !$Non�p$��ces%�}��o�&�Mnt�*.(!�*�,9��#�t-��"<&a5F2H��I.q�/0%��&�8to-2���  �E6��ate��Mselves}W>&7@�TN�(new&�!�X�&!���L>m0s� A?UN�t�`r.PAnIb�F!L N-�iebɬ6�L1�AK stud��5�val^Y. .K�C*/od�N8Gs:�CQ.&I l }�8��9disrup�%�*�F. O"�X, m.�8duy��$ioŐ�3�BU2�r� —�34�""�'��DZ�. N�<thqf�T� m�9ubtle:%r"s� ��*� o��G��G��G��G hybrid�r�S!�E�n>+i�GiDA:��hK� x �9c�7�-b .YE-���2db�"�0b-$Q &�2C� 2�e��5�#:�e>z.edn9 �i�`��JBofe�*�GB;I����-�~ab�us�X�T� a::!Aa�uBx�m�pPra��{���Dy�n��5��<&.iZFi;>�d�u�-ca�8Zun�B. Wid�acned�k�7a��.!H[26�8] ��L!SPq)C>� �)�vy !vall2a*�.�!`r fix7 )�"�W2"�]o�&�Lm��� numeHc!\%Q��s� at[Co�#progenitc����F�fix?*4"b[�-15  it-�� -�e��!��eG& �h�a!u n af.b�.�%dF�oa�nt.0�����L��{�y7 1oF �a!8duc� a -��� JT(ang� � -� �"�T28A���+# �"ZYw con�N!�A�. R[pr(\b�.�,�A 1�s)$i%�f�7]��� furn}AheEekA th �����ABa+`*!�a#�h>a libE et� ��Z�&� In�JÇl�^# quilibr|�mQ v,�tcy;traa8P&�s �*j  in�B� mode?z!�yproMPd��v���F����truL�u�A�k>t �.*)Q͙�Gliez�B@.p� Ma&!�pan6�at? }R�V� 1���:,��-cl� r:Y%A�s"D"�!�N�]�a��3�aKsA�|)ncMa�9qF��d#"Y n �W:&�)%�(o.�}aL/K�|35�Z�)"8q �A2A*5,��7re�^h ��NCBI's�FTPrv�aɳa MySQLD��nbe���l5��'A]fmos�Di�5��AoWabT/�)(_9606/chr_r�NAfZs 1�{s0X�Y #loag<i�a��u�Fasta )n��"� -⡖w�own M%3��rs_�~R5 Eachd 's I�4< �parr7o� :heaU�!� � ґ�aFZ. Flat� dump� ANS1A�Rd-�6 zY(��ASN1_fla�l����o�� s�� ��Y�ٯ0 �g>2orM;e�w~�r-���-"b�v�^alF$logy softw� ibr�R�8��EWO(ed CGL [31]�mwVf7cg�Da�� �;t[<��tigK .y� e�m��PF3�2�A4-a~ ?)2z� �s/H_s_nuF!���I(��y]m�. Stru� d Qu�GLangua�6�F)2q#2C��Fm�� wAA�Kw"�3�!�of)'genLG.C�h J$�:oach'su�;nm�ir~iga�,-Zbo�"RefSNP�],Y�*��9%��.DG�,� IdAndF�9sIX� UgF �,((��,3* s:�)jR<9[12��a�. %1K�-E�&�;�;I}.�27WaR;w:;inB;eߐ;(3�:9";A6�%&&I?��D�*orT+A;� le�U>�� !�a peer-�ie��% T$B i;lnia�0� p:�9��.�6%�n � f" >0BA>�s/,V*h:%fn���6%/XML"V=�U8Xtun.l�^s]�Q�"b_��m���go�0u�~ , as �index!#e�m)s�J�$g�MaCa&� alB �Bw��>.��d�}"�:�,��N�A�v+ �9$&+ z/? e!m�31�m&g��D�!$p velorDa�K�7s"m* �%�Q*forwaY��v-�1���.�u work�Y}2H!�*w?�4�v7�& H35K w<.!�"ed!it ? h>d+aa&�'/>��n� Us-�w��r���O-�-:A�HXon!�\al]PJ�Y�&k'QA.[;t�!"BAA+�8a�LaZ�uOn�7M�:M��!�-�RZ�h�wo:��!s)Y� W87S� �{~^�*�[ e 1v�3uRcQ��9!����s�u�o�l�h �\!d ��k5 mI^%�E�� be b`'7i� �^saץY�n@qV!�`�"&X1A�&)A=�+ba�5�I%�Z&�W +jy[( 1/2�Leneg�%ng.�&�+bi�3C!\2�k f}�A� autoA�i y�C�Tx cBxm9M�Ad!�iսEyfŨ�Qo���vdU>EA�m��$80�@2 e�i.XO.�nB%o2}�i���2sBy�ɥ ost-���|A� chec�D!;���>"7Q��Ec . Va�sI��k�5��Eb�!��+pr��M(&4+.�3�gk )d�7�PE��>�`��*��. O2{0�%�� �%<)�/ew�o��E%�/XH,T2a� e�pt� a��| f 6 b?)a!F����MF:6�*j"�&.z$ ,j-z +?,�I�O�i&�Os�Bor&�B�V�3)�a� �qusF�A�� d�a he BLOSUM�*mК x [3x]��"LO ≥0M:��ed6�^�8�eI�P�'25'JbQ�'j��.v�U4WU-AP( �E 9. wustlQJdus O��́�fa?X�: p p db� –B6=1�8 –E �60 4 –Z 30a�� �Q at E&�Y�T.�(%�A��) AJx�S�Sl�$&�S��M�<�$�l}�j�L o BioChao>t)]!/ Bio- "B5rw�fruitf�Porg/cW-x~T&�B!z6Z �C  pu@6��q�k���=,a�.� pipe!ڙ�.ZANr;��4e(�I�ist�&�!�{�j2�T��Vh�h�-�V3 ���g� ���)�M�o_�����a�%O�rap~-<�� JA �on* ir i#�m�c�K� ��]*d@V[8eepgdv��th~a"C Ű!cA.�AU�l�5nucleotiYOdu�)�C� sc�uw!��&PGs�;:v, (�J#�<F�A �� �Cy n .A�Ş_o�"sFE�#�r5I�s�W%�$�apA �1{�!$% O��{ %!#A "f��!s�&�. 5�)-|93e�QGI<�S ^J � uv/���2DM�cI� �%�1A���.���$��*� �x�+�� G 13��rk�1"E@.R'�a>N��.TP�8+��"���!�eSn*qXDne*!�,���4d2�:��!"�&�2� J�&� X�B !?!�e{�)�P�.M 1���me7z��eaF�-e>=U�54Iato qu,�f�h*�SQSNA�">�Sg��gc:,&��[m�?"�g�N\�D�2toOm+/2�>E aB+� �3ю!��R "3+  EDsc��N3A�"� �-jri&��y�[(� -�Nur goaS To� ��,��(t���?I+)�=��ct��c{� M-f ��-2@ p"� Vw9lpM ��o!1����X� i'  .%�JH���# O �A�e S�tal x �.� `.g��Q�e�siE<�� Nq�a]9���ڭ�.�2/�)!�\�4?5n<*0 21 s�oo-Gt鷽���L5erpa 1�d��!�A�:G`�Xm� . Perl'V*+:E�7r -FHV 1s[_vea`i`�th ! w!�VE>�+�]!���!�!�"A1AcC �,�(�WE�a5��W" ]/=�r"y6; ;��v�j��U@�ŏ��d �4*�A at P*�5�p�iA4! �ed� vȆim��� 1;c5o�*���sŪF]X`t!��v܇( L∼E66"eII.c�8I��il�R . Be�.�u+aw 1/10Aac�[!��� ��W��Asp�w�GP!��I FP-�� }_�&���]M/�(%��a� stɵwsz^&�6s���&�~YV&.�/L�c5]I��� � ��s-Rank-C� *6on��ul-� CPANaU"cpa�or��T5mb?E�-u�-8Hi�x!�`!&� eh�Q�)�R� �aif�.Œ ���� &e?E��; �� ce .�W&��h7�e���au�parq� Plas+�um fal!���isA�oA� $w%.�es' � cenviro8 ��dra*)wAJ>�F*� ��o?'!K�r� B���| ��—�.��Hs;,�$}!Hp}P�#��)ju �&ruma)4)p�inc*���R)�B-8�u@.��.<�PfEMP1�G��surfacay�. $ ��  �9 ig�q. H�j,�eR&WCa,(seq )����a2in 445 iso2+.o�%��"6s1/in Papua� �5�he�n�om� f 19Jma�"?5 q_9�� �J9�M_de)�d glyco�!-A%*�/�q�ens�5 pathů;�5hr�1lK!�pr�)S�t crip��ߎg�zP��GG�1yi� ; re$fQ=�ofM �C�-r a�f2�u�ch�'gE(iN(.RNE��"3� �E1u�uM*��iAf!�M��$dom)< ��e��)AgUA�գ�llu�lf�/R� �ed�aB M+�Ew<�JAl�fukaor:�e vacc�qm TQ�T� .Y��: t���>�2st2�A`6�. P .:��=ƞaЉ�of fa��.�3��sYm�:"��p9 40 peo��an�1�iS��;�,b-Saharan AfѮz"&a� �1v%�c J ���! AsiaM"�!��IndJKi�24<��"%-e�Wrz��k/}a��#S6<de:A?7manifNasy1,,�&/*�9s��ͬa d��5�E��E��0aE�ery�4���m _Y7? ��Ї�7(&5in [3q~�;N�4nF�*\N�1�A�V�!.*-�0�y� "uV%�l viru)�[�P�'.�+&8j:�7 Ara_� Rig%Cm�sm�A�:n*A#��%Farray��of � -stage–8.$ex vivo–���2){�s [�j5]h$c�3"A�7p�0a��! Vf,�G3�2X�a�a� unda�Eal�@�<cEAp�U����1�a"� !���" �S appa�/�g�Js��g�}L:���!e�or(direct��{D{K m3� ��[�L�� � �#69�;�� ��%�EE�]&�i��7*K��E]���.t�=���5in"� A��Fa��Wm�� �y.�1��iH! &&� m�vel�u35el�yn� tech��y�����!bEM� C5�� �)sitJ�6�A�%0&� .�*^2�u�<-�f}i��QF� v  �<:t�07Ge"  IE�congru1��u %6UU;[�^8�g eJ�eN�ply lin� \:�YJ.�$ce&� �b6���(?�F� M��YYb-%c<�n�sm�� ;-syn�E�J{ 1", �CM�Z� 6�E��( Membrane P� 1�G� �^ [I� odohc TtxXg�!f>���O& !��4�c��� ( IE7�EL��E�dhe e��re�8j��  b��ng+on end*>l]� �AB%�8ci�..IE!�'��j�)��z�ng/�-� �#b�Gexacef��yh�2�un"�=,�1 $‘rosette�y�,(. By switch�9 ���59�-�-鱄p��p�g�)i�LL���mY a���"acqui� 8� �)!u���A recr'ma?M� ,$ � ’sT �5��r&��60�%#����o �o%�; �5��h�3�Z�zol~A�|�eme� �NeG6cr�  v�/CQ��7�$eM[E2:@ A?Bu!���a:� �(� !��$ New Guine% 9Ei::�i&J 2��A�cereb��Up 22–2%�3I ect�C ���"��miieQ�Du�-- < ( DBL )"��ރ ine--[!�er� �)�N( CIDR�2E��8 .7:/[.�F N_ve)^>U�yp�g(�DBLɑ , β����MAx��α,�δ [1� 2��2����A�9F� h��}�.�5cs& tX�c� CA�ep�>( EPCR )~%4��٪Տl J2-�iJ���a̵[3��35� �nst � ��Af:�:�J�-RDBLα1-�t�/γ/δ;�us8! �V�v37�L4�5iʉ�.oh5�C�f 51 3.@.$!m��wo\�Օmolec � ICAM�W[38–42!}B�5r>" Bq!C[4:{446'6+ �A� r�&�qmQ"-�1/3U�[�. �12dA�4�  gC1qRV(!��/>�:�[4^N Elev�6�a*���! VR 6[�S�"�DC�k��2I2�Q �2�4/c[3�45!�[CDC1�{>�7B��[39 ,y|+4+6e�p�[3 Y�m-� ��5 1�3/Z4�ADC6��BLγ14J�5e(3� Dv� i��s.� s��d� 5�,& ��Mma��C9ve���m�l[�qae��6���� ���^y��ck� !]5O�Few\ z�$m�)to�d���D blF�浧����);�&|�df:I�d�R%>�219%m48N����#��2� 204R#i+�!cr�[51��A"� 3�y�!�;_�e � .;r"���� prim��2�h=1� l*��w M r;,�5�y*��-� samp�f:�hEm�7qm��"�� �8�T gard-"��ir9��-����df�a>� inno� io V�� zLj13#a � y&� j�J��� -A�. ��si�P -� �I � sub-� "�. FG e��recapitF�de6by&� �-�!l.�n"�� � s��ve?- � f R1�� �@v&(�#f"d�3�� P@s�I��k!Kven!b��of 23>B��&�K&L�21W.$V� 6�_6/V:V�+d� be o�> Q��Vd� )�%r!k*`)tU_aF6+denUha1� lobi�a Hb )a��o�`'�r�"�`"���:�,G!� � e�('"�:*��e=�[�餁M4 5B , 3 ja\ce , 8 hypera�-pro"�� 1 4��re,!fJ�. F$&��&�& 6:VYE% c�ABNp,n�.5 �ord}9�"� E2oNR �F.-e�"��� �� er H�+d� RJ�lrtHRPyv1M��>.CYbW a�p&aa�5{E96`� ( p =��0�.W\j)��n>�l�E=("0%F=$b < 5 g/dLaO"�<1�� old;a@< 7'� ; �w� 2���6""�Z� �:��:|D!�Ecs%b�N-2mQ� on x*�Xan �d �+.|[5��%c�K !��MD!EBioRad�i�s��Fig A�S1 �n[Qua[Index9QI]q�+7 . 7�qA�mi�quBZl��� ( IQ��1175�I�t5A�.M �G_ �� ��orh&%S"�( A����0ec',: E-MTAB-586�=. LH size�-" ��05��24zq85�790����d�!9BJ9:�]-to%Homo �G( GRCh38NAD viva!bPa]oDB-1� 1 Sal1%!b)*v)(B.3D��A� �!�?!�p�N%~F%��n�:11%�8!�44��S1m6E>*_�s*�-�"s� � ���=mD�V>:h|)2�E0J5�aAK.I�nM,av���!� }A&�9A!Cd��voelmbla5!m 7\R4'�+A�}�� nd very9i�a>�ItG cl ( �pb!:d It4U�d 4]M&+v �@r�MO#n�&&.��H� d=n� �(�r�� .�7�4�xve� ( q� �,%�� fw-e./lyA�ear�_"!�.��R�68aC(%�1��� ;; �-$oapDeNovo-�p/Cap3ho�][5��)7 'Kd�h� ic1AP!�e5��C���Y��, Non-!~:�,i��H .�re�e)'i�F��,FY�-�T��AO��m$5%@�4s0��1Ac�iAfE8B�vtq�;eg;$e IT4var04EPZ . A"���M!h2YCS2—E(�KSj� �.nt"�]!Y 8js [54]J�<rr>�Es"���"�>u2E$��A!V�Ygp66&K{e hS2��,Q�e VL9s#@kd�it1�aNhem"o�,�+1AB�Pow-��=�)��5dI�a�_I�cAT Eq �>O�,s://github .a�4/PapenfussLab/Q1_A�iX y�!�ry�e� t!p�(�:��.6�i*6�= poo!)gh!z!9i�a` 6e4Id%�Europ��N"�= Arch!�[ENA].+ PRJEB2063� S3-��!�+N&�1- :�>����le ��N50E�maximum-Y45s a=Y?i��2"] shorCG0 500 �� B �8�ma�Kc�$�-Aoq��se�͉&�� �1��5_(:o2*8�0�?�pdg !�R+o��s�-�:�=i� 1Be�Th�gMrXm�+)�F asG*e��)�sma}Kto��&h : SFC02� SFD6C(�HB�R5��SFM009_B*�� ) �.? ,p{ ��u �E���aWa�!L.q� c3�e�*�q>om1�e9!s2�O�d�e)��%�IwgRB���sqm� SFU2(SFU2~�e�<.�dmi� �A�o�*]��R2�7 \C021%\� IFM0�! 2% p�eeCg�Ml�@}'; dl%�$�meR2 weeks%G�4 ���E�2� �v}Bx!��:yi)meg�;6<m��� aol�Im&!�6~ ca �-;�ꅊ�<��A( yO  ,� *�cyc�%_�unwan!��\�%!{5��)"% be2������"o[!t�ng�A�&aW$limma/Voom��[5a�56$/A���Rai��EgBCdz&s�p-��@ �z1J�!E mix�/O>� Da bala4�R1pob!M�ס��2� MA� �� �q i �outYIi]I�[ V �:�o�F2QA� n��?9�N�� ��h k��sqQ�.T,.���ces_�.�ps�^ ��:5b�z!W&r=�ofnA�28g +�(�r(ch$? peS1!S$S3E)� �1M�2j�"Y $1��"\��*-x�-17o�B��-z:,�\YzDpat�"�  phys���Dtaa9�C:��"���Wmiq-i�&��>�-5�3�"RFm�-��煝 alsoe�D( ~ag&�@0755 Mann Whitneye{;� s/μ�5���Q�#S1:C�040; �880; 2�(378; S2: 78z%16; 2_ 708;< 09478:�H"]'}L1�:�?��' �A�U�'sher�J/}0�""l p >��a&0 1$B�F{'%i .�;u"�"33A����<�:�Q'6�ώi2� Data�BY�i*X'� On��( G�b6ro�j�l�Kyoto En��CZi�Gijkd��KEGG ) �rau4ɛ�mpergeomVdc ��!tnT9�Rwep <)�(��E. Term�>�o.>?, VB4n4*Bu`�(d�N ��qIn�'��d��:�>F�$i�(5t�I �A�t�<rboxyl�ci�T�(!Y� �O� dip��hat!�pyrim[)F��5�y~ uanos�trE�a( GTP ) f@��up*�?F�(��3[ 3Yr�y� ,-1.#6�*e�??E�a)2(6�&eM������2�TF.D �Xmod�"C ��.Z 2.A��v la5A'E�5�r6L5ad*W7g�.܁�� lg@ A��=o-J nt m��rx�Z7bA+scu�,0.{�� �lr7^"Gwao:h� *Ply>u ���\e2�5G"�B/gluconeU6��’!C.\ C�"TL["����3q��M enzy�C(�452-� @62@�ew�帱G����6� �ZAadjusAM��� 3B , e,�D��e%�aldola~,�Qp dehyde 3-y��o *Ac$mitochondr 0dihydrolipoyl/d0( LPD�EZ�Vsool%2 pyruQ+!)acety.@)G A ( -Co� .�reF�@B� 3%V�t:n�Na��HAe3.E≤%��`�OZe lacD �*er��kh�,�7�ni��60[61ba�9�6�YA��:IP33IE"9"09�`To �'H+!�w){bas6�@:j�*q.�̅).Laerobic1�n ����E;�d��G*u� yci�<6�9�vpL�/�+��rb�&�|�)"� �>'*p�!%�r , Da�C�e.�?*p("� F8 F`E���ed�k�$n��X�v��-�!!?� �ar���b+n�G2�F�g��%evIb�]4fNQ� ���~�2�m igRu�'�7r Y~b�1�� S4*Inj�s� H-ЎDs �4�+!@�Z�bIIoB%�a�m� *;�a1q��"� 2|3ne�b� d:�@:���r�s>4:��V#*Qo:4����F���v�3-id�& a*�� e�U@gYyQK�B"�:���,"6 � f��d'QE?P��f�&H��� y un�H=qui��Jop� y–4(:r y�� C-MS� D� rty-���iteF��#��r"�ly6��$� ������ 0� Benj�Zi-�ed;a8:�" 7��6H�RZ.�m ipid%!kcitruls (A&X�&c�ch�6c��ndard:, depleted �in the patients with severe malaria . Citrulline recycling to arginine contributes significantly to nitric oxide ( NO ) synthase substrate availability and� reby1 bioa.in�Low c�is :$fore likel�� to" hypoa �4nia , impairedNs�and endothelial dysfunction found�(both adults1childrenRX,28Melanesian [62];Afr!D@ [63–65] populaqs . T!�Xlasma levels of glucoseA lact!Xw!�similarr6�0uncomplicated8:�L( Fig 3C ) , suggest%�hat%Gdown-reg ��Hparasite glycolysisz�jXis not a direct respons%�reduc�.of blood�. B2concentr-7% also.Dindividuals harbor��mor%�ou �4proposed starv^$ transcrip!�al!itern delbed by Daily et al . [6] . G)�-L,ed yeast [66I aodical P . falciparum isolat�%]J�1D-a �omeI�increa�2�!\ TCA a� e enzymes �SINlyI�:2,�GO ATgory ‘�!\$xylic acid Z’�� succinaD(dehydrogenam^?putativ)4yl CoA synthet)βr. AconiwasI�Z�1 . 6 �(.�=�(156 ) ; how�� , nA�g�u( differenceevexpress��of���rB�siobserA�,( p-values >yp2 ) . We have previously show�Hat>�asexualm�0stages primarasustain�fluxe�< low-���:)i phosphory�aQ cataboliza�glutam�� [67]=`!�9�. H5AkeyU�inFutilisi߅<either2� ed ( 3F+�%=4)�, p-�01!Por�� hangG0NADP-specificbU, aspar��e��Ap,3E� ��te:�,1M enolpyruv$q� 9��(branched ch!� ketoe�6�E(ex [BCKDH] mis E1βHE�in�� from�$fy�!d��)��ps��_s are un����$exhibit a *� switch��6��i�$ . Overall��se data��t�associ�3wJ2 E+��!enAA ng for de�m�by���'oxiA�o��5�� Y�!� may be mei0cally less ac���7��9{>�6A/� dGO term�� methmz���a number�[$subsidiary5 s rea�n. histon�G�����a/��in�s cau% :� :9 Nin ]a���$S-adenosyl!?hyleIferA��2Ӂ3$10 SET-doma��i~ 5s& :�(@2UPfSET��. L"� SET3�protein&b N-)~.�01 ( PfPRMT1 )Iu�� ve�.AV^-11 , <�773�����vs�� SET2 play��, (ortant role!� ng:tvar-�(( see below^ �i87 appear essent�a6�  4ge growth [68]� nd:can-ˁ�H3 butR locali�� cyto: �R�[69� 1\probably_sE�nd nucl�-��zA}! )��E� Q�4a�t��invol�u�~enei�3 [70�ThV�Nf�Vhw!�BX1�onI0.eN[ . G� .Jchromat� od�� ���E�de h� ����"5reA@ed��Qa�ed high2$aemia infeh s [8! S�&�is kn�8o elicit gameto!�!N ,ebhetero�structur�$pendent onRT.freS �Fke� H factor ApiAP2G [71A�so2{!�ofRxwould��consist�w�t indu%:F�inV* KEGG��fB _/!*N���ed�׵Z� ~H : diC p!�a� q ( DHPS )%�guanos�dtri� /( GTP )5 oJ�.�  firstTrat miJ� !!��-pae3/� ?is:�DNA#m� �Aa. A"� F amo6U( ATC�^)& 67; i��� secorx �pyrimid!bi-�tic�;�whe� L� l�in>�is uni?,�2�so,bacte [72ay��� s6 � osid6N�&�F�,B�lower���and/or"�sm!x*�GO1 |�a�d]U��=TVB�2� B�:^bki� ( NDKM�!�&:ms . a� ribo �t!L�e%�seur� �l�C8%�:<Ne<�deoxyv-d .i�M�lthough=��tŗiSU��� ede2K.� H:� !%m��=�m�c stea��$ e���O diminis� )J% poolA�subject!4&�w thr�:.1!ȁ�to)&]2%�A�. ���al elong�(�aU_32 ed(�:��qmPyL��pro� B�$;ing2~9>~ lx �!�(HSP70 interX ngq� ( HI!)�Lpeptidyl-prolyl cis-% isom[ ��XAsn' eat r!� �s durTf� [73�X&{. ��bI�!�Vd$"Kstr��.oo r� ,V2ces%Hu2Y�� �GTP�QaD��1�&�isa< ed 3 8-80 y9 �D7 v_A�!m)�1"%!�Rab lisf7 976A�ffick!� ���ap�U CvesicuYe�A@!Pwo �.6 ,lln *�.�ed;gse  SNAPY9.�*/ di�-�A�(Soluble NSF��-� male> e-sensi � ) Attachm] P{Recep� (�RE} +exmScholine-&� cy�>� CCT>)�is�"� !��"�major>Umem�e� lipi�0��} � [74a[Foui�Q&eZ�2�es} M�29�.�P ic r� (ulum ( ER )�*Golgi]!�-trYs�� tiA$1i (5 ( TRAPPC5%JM�-�?PfGS27EC�rieval r1�!hER=E)�s.Z requ-a��ograde)16�o Apvacuoa S sor�6.45i��s{in d2"$bG)Do%m�M�f� �e>�sbaa y�.xu�of-al��d2�F/pr�A&� 20�.mB5 ( . MultipleJ/�zbiolog�.6,RR� "` Vvs"Y&es�36.�3�~; ]� silenc�$*~!�}Ynormal4w/75a�Oknob-&�KAHRP��s�Q�2 skeleton�d%��-�],U�-*�PHISTb5�( LyM)8( PF3D7_0532400� r 2� opti���of�todB)u_ s [7���amongs:e most>��NAl:ed SI�llowing�0Maurers cleft�s SBP1%AREX��z�2�0er E’Hf z� GM���Kery6 cyt rfac�y$7–79]; H�shockk2 7� ��forms a���S �� b� cellI ol�is possi�.�B� [80]��� �!�Mp�E�^coQ�E�]^m��1M� , we&G= e me9$istic driv!�of mod: ede4}��a2�62�A_ s-�.:� &g ],ly ranked du�"�t�clu*.�3D7�I�E��"�be�^(.[-�"�"�.�5 ��5hEestabl�"�� to _ -k5� �2�N����e�21! enco� !�syl.�i� tol-<oA�cysa����antige� CyRPA3�nchor�e crit�A�a%�@�#odium *!�e�-A䁾3hom�RSPfRh5rQ@� erozo�" [82]W}nth^�!; T��A�6-1 �P41 [83A�@14vd@ �in)J�-\SIAP-]� is)�� K tqF$in�qMCcul satED+o�Y�Epo �V ���sA�be 6f hepa� �al [84�R serp�� c� 10%hj2�. I�E� clos. BAVM�#U$ ex�#$al stimuli!%!� sm����re�no*j! betweeBt!V^� ot+iU)���, i . � - &e read �m!Y@de novoo embl�NWs (�� N �RT�@0; Welch 2-sam� t test &� 28 +Dx"��ana�s%6�uca !�he�Wm a%�>!"�% �seg�  "s�џion)�� 2�de��is�$b!��i�" dete�se�atALat each �!sA� solu p. A �.'*�#,U-!&)�C&equ�#�Yi�ifiedSddi_XI res!/ng 9=4aw-*class&�29��(toA�t�"�nguis"*A�nV*ca� �*t�%16%kge*2|8s [14 , 39 , 46�Y(Ba S4 illus�'�! PCA ploV E�A� cou�* anno#eAMY=s&< combin!iI�A�ase-y6(y'pUg��� all-+�)2),ev%�! t]-�a��%t2"sQ~BL����=j� m'ightly �te�Qtog�%��9�. S5 D�"lis�*ll"Q� - 5.8a�nKthe� .�m��5� ( S6)��+53�F�.~6xO#�Hdefault DESeq2 pipe� [86�O7(se , 17E�2wFC (&�)_ i44� !>�p eprofil�e6Z9�N�52`I�s b�*o�A�,�w , panel B��Am&�.�z���extra� *i s �} �Rl!E�pa DBLζ4 ( 284084_soapGraphK6�#, #�3#74611J#n#J�1 Cog 181B- �� 2�.�"Ha�rt��ta�Wf�5-�1�98068>�;)"� only�ti�in DC6�) its1.�E[ re�J:�[3A In 7>C geno�,1iA�tandemmo���|"�� he� e�PFL0020w��2b by*H/�l]� ady!M o ICAM 7axAn� z�09��18%��%�)�306v&� ! �I� arr*P ��� twic%*7��d�%If%7�Opar�DC�% ma'2g]D��O+�le �� comm!^�\APA� orpo�)ng DC2!�$�5-CIDRβ3% �7-[�4] ) (%;ig1268� � also6V��-053!Y.r?2KF:in�1 [ a�2a c�2 c (8HPapua New Guinea [8F (Corset [89]3!ups=v (� A�& P ��atɏ -map � them=lst ens�.!�!�լiE�yT 6����A��.Z.u� �de� 6q�ed�:�m�Z���#?2& :H!�( .�a(� nfer� � grea; conf a-f.� �f��approach� �8� 829'i:�� �� , of!� ch 5�>�(ly^�* �5A�7K�se.h�overlappa[, ̍=�{igM@ spanh DC�N- !iW� A [NTSA]e���02/54i�6#�3m�11�1 # �1/2m�3 er-1�118�!�DC1+i�4=�7� L�22�3�6P4i��%��! ��aQ��abunda�6y֭� YI/�:�2F+-��l Sa6�Bv �HaM�:�G[39�Z�Q ��<�-2.�"�B�b , SFC15 . For>�ku�"� ,���st��ic o alignŋ sear�/Hol ( BLAST ) [90] hx ɒ�x\��}Q.�  5qn ���, 29�si�their� ��176�.@9T��q�UW=�"&��ou��� DBL}J� 2977522� Z-iO839?F�Be�Bm�a{�g�2�4/3 . 4e_�5/8/1�}u� z�F.� 8412:a (i� � {��iF25%\ 2 r"� �se�A esy� NTSBR�1/��1/ ��1/7\.K58�`��6N.82/!>36� XBV4��( sHa|A@u�E_6Ga"m2�3>�bF��'n*�6-F6�no�6!F15� 9� elev+ 9��B/"Z� expl)�by�heavierɳi���penalty�larger & . ��si+;G,�restri&g!�f& �&]�1 UPS )s Z,B/C9T. E&+�I��7NTS&-a�2r�Egr �6(HMMER3 [91]�Ox �=�@�  hiddeno'kov�j� R&�����reg� &�as= QoaXI�t��aa�+i �%&ez� yp� E�YnN�=% �S���4#V�*��A!*�9T� i�6�/�� stud!#[19–2� 3Q9�--�=��e�/&�ed � �ame"� !/!{9U��H146*m 5>��w�. , 16 �o/?I�6# >a:q��"�of�� ( S8� ,�_7}S� 1Wly*�=a> Egq�r N� �^:�%k rme�%�Mng d��2&��"e�� F of��3 � � 6��{� EPCR [35C>� ofte*�@DC8�AJyly [32�45�\48 � j�" o/#�toZo )�1*�$s gC1qR [4 �@#arib5I 8VBLβ3e�al:�.1�� ind 9��i�Aai/#�is ���to—6�=X�82 R!+%�qgsuba$s �,:�%�� !KOBLγ11�X�9�,,uE_a!da�24�yp!D#CI��!��v5,, S* ���B��X A�Age�?�:�2�. DespA�+�"��>, <,���P�still}� 9�.�he:r�j,>g . , !qMFfar��R� �.S1�%�!�AOula126�m��\*2�F�)�7!�!�8� Co�r)��"�in27B"� ]Z-B6��?�g�f���� m,!v�A �<e � G�:}a)= accu�36\�7m�). A�el hier("\�d`;op`oњy ��z9��Z6. D���E��Sdef�ɖS �mo) 2t �G��; �g 52�.�2 �,USEARCH [93]��&�D�M�i�D!�method�c%�at� �ty)�s 50 , 5a6 6 7 7 8 8 9 9 b97 �c&� M� )Z^0�p A�.� tre�P]��'�7A�� �"bnodK!Benja48-Yekutieli [94]F cor�FOper�'e�9VH��*� f~7Dessiv�LchoseE(ad3%� ���.B- �qhi=H�par�Iof�E� remo;<"W[po-:D=Yb�nex� �M%gae��detaiS"IDp%J$ive"� vOA�isy��>mp� M�� poinHor)P�4 !oF��bA*Z esm2s^�-/.IJ# &. By loo 1a&NEtQ�ͭ%$:e-.i5}ly &�$m��A���;�wiS"m\ eluAB!�"�pGby ?] OKB )Ny���67!P1+��� �� er�b�suc", �\� ���,ig 7C2�!tadvanF)D.by foc��onoe:�?"�!l�27%"of� x#70%�GU�!�}f�>.Fat 65%� Q�<BL�. �Qbec gQ�!�en lo�<t 5.�an��Mc�:-is�e}%lD�&pro�vS,m!��eJ;uE1 Y��, t�!� 1���ia���II% ings)[8%�MllN"(�"���ee-�)��I�f�$7056��2< M�5*15�2� Nk S9��+�!eP-e�<2� 15.~&#e;�#r "C�KacrosE5zI��(age link2� �a��F�@n�Jram�n cut L!� dyna�3he�" -cut� algorithmA[9�(� &r&4 �G&label���8dia}of%�8A!P� i�!�� )0)��AE��)C"n&ph &#Q-�M��Vz .��=r|tC.�1S��c� u, +eCa�x2C�=2)�y U�of Rask �M� � ^�I�z{F2 wty�� )^� !eF.! Ŵ�EO"�/fe�ks��.hcap ,�NW :|�F�as� I.* �-( ?* �(�t 0').aD=���M���!H2>inZD2�Ex& ngE�8�m�  rei =b el8!Qc orig� �:w7�a"�A�&3�}� 2}M�e�FE�< bR�. �9 !Qs�R�W+Z0' " &[*�% I��mQ�w�Dpu�0 ,Yb`i? MUSCLE [9B4 Q �FastT[9#No1PA2 Z �4� ���a� PFD1235w {e^)�j;W4n��2C wq�i{ut�)�e�I&]e� turquo �V� � �E���  �9_�S1�1&�fs45E~9a!}% z-� � a&��� 5�m�%��2��( S2 T� �4�eW8A�d !� ����D!���d�R��l�i86 L�!aC! Tca�,/" �+dI�� >3. Non�+?P( ���by�L7#A z� 4�U!d 6>B88���s��c~HwZO ngle�STa^ii�O�O . Un�O  !� �� es employ*��q�2�հ!�� � :-*�]́�@�A��� esumvaA08!T��Ll� = Fhg�w%/�b�Lu )U zmum6� thresh�T6ye*�C1 . Al*&!����s�t��o-�Vabove+ fur�?�inu|��; pW�M!Github�6EZ 1(���q�=9. >w>M�1y�i= u �Z I!8%�a8F]+�!y 1 t�)p=K>�=�!�H/�r��ճY�2� �.<u%F�55�m�>��pam5E pregnancy1i.�8� var2csa9�2�){&7#/2/3/5/�0[,ar"�,�FE�2GF>9�]!@U�"�%!�>y9-���!� r1\�}��M�sub� r� g� ��� jus%��E�J*X ��V�"6� p >AV~��a1��E 1�1���� &V# H�\�"� EEY}*=.fA\ng "� �� -ilno� >VpR^B!0A�z�{aI\< k� m�a phyloA~�>��q�+e"^8�$6Xp� uO�* {m!�d�J a�"� ٽ� �L�R�s � Z�-m�.�  � 1V� 5)uniqua 92��s( pur�%� )E�H non–DC4� ����:�`t4=S�5� )]E�car�� � cN!��U�&a�I�� I�A$aE��"�%�1?��4B�n�A<2�>�:� 1ndi9 `-|Btrong ,�/ 5�(V6: � y �NzY��Ye%c:ɹ8:�Ima�]C 2b� %�mak� 5 ,se newE&�)�Qp��"�F� *�8�&�"&5���,��of �bcm�a RNAseqŧ&� by Ss3"]AG3. %E#cloJ�g�4ic �T( g)��c"V I��B2s�|�y6���( 1cs6AM1��&�c)pMm��8�V6&:UFd?or co�2Ba*eZ�2e,�+�8 .�z��3S10&Every bPUu-xQs%�10"����cog%b,a7��%�M. qu�B;b�]5��8&�X� �ob�4{>v!3AUJT�%( Q-RT- E$106!�!�2��. InsuN�_��& �z�>~� a� !)C7Ca�$�dIA�D>�).:ehaZ�-[�%��E� .9d=!NU�I Az*Per Kilo�I5V�  MillcxA95( RPKM )�1"<}D( S�\man r%134td-5�)%K �d,.�;��5�!� ��(� �8��T��ausv&� V �eBl=eby���tby�. BG� work�As_[�V"� (��&�C a 64 bp��+B�� 6s hybrid�cra,)KactldXC�\"�H".�9Aev�K orda�+� -rea',5@"6 !unon�|�&n�� . Du�)��� lyt�(e natr\of��-E�2sU �8o C�&`s�B�Lor�Eck R9{A5D^6�We$4 eed 628(0y l!ptɠb �%U *6>613 .�B!}�Mloa�VARDOM�Ever1n&�� a�d"�%� ��a� 98]d�i1eDQ<to�aS"Z 1�DN�Ho@H5 ���~h8R5@��Bm-!JE��:C <H*�/�hN�/�u(to"//e�џy2�����]CJobG���"�%!kIB�$���block7."We16BHd*� a�% ">9( S11��Tee� �(B` 47 ,z&, 121�*14 4�+1�&18��21�D!�5H8�ZL& �W3S7���ZVm5r3U?tr�!ce��c�&ir��res��M� 6�Pis N7�h(�(�� m\$Z&Te .�+��c87 roseo [5NBE!Qk^su�:�af:;"�@I�����:2 9;0z� � V +"N �6�126�A!� j!0lt�o5�� also� ".]O1=i97� NC4–8E�� PAM5D.E� 7 �!��0� .{E�a�}Tz%�se !�a�inr Q<�'6�eR"x/L ju:�!� &��a�axa�*:Aa�\-B ;–^*10–%/)�!'As � i= �_" . 7��C!>�S,��\vf �)V��)F �:>4]#� -�acidicP^:��Jb/c���%�� does� �O�h6�DpQ�sO`�_b�E�v]g�;"os��l!�_)Vy�DbeC/��&` �1 Ib�)� I��-&� �e:Ts3d �.�e#�&O �%. ���)L�5� H4��A� �Bh��_ �!hip��Q%�Zi�%Aobscu6.��6%HA�U7 o H�G�L. F��",� .I)�C!��TFb� b2�*gnsin({o�K3f- —1#.]�o6�� %/%"BAUla�I�KiXnd9d!Y��� 9S!n%f9�3�A an�er� v �A.�> l E G upv&M��[M�E�e�F02� "� 9])�X� ASRT!$�"%# Gismo [10� S_  logo%�!��l(j?�z18sky"P1]�Wee S8��.m!.��to hand�Zhe�3�%A���aH)!� �t � �"/f��(M 10Q�Ligh !%�occupQ. If 7aE�ecu ^column�A1-$|anHg�C�95#,� FN_iIV�I �; �� A� w\�Jn20-�G Tq� Q� R�;1 #a�harder!�%i%"RE.tly-q�%!gapA�-�Rd� )� �5�be robu[�0cho@Hm9�&� aD� a�e1 &��5�11n�Uu�e� erlea�)we �eeI� % Y�ReQs-�v!<��>Zoj by�6.�uw�ucu�*2nA nd-�l.� Eachm��a^I�pl%�M�*�Lap���VGref)�IX=t1ir . �*~i��� %�,�(t��Cx �P� �_2!/�FX;f2�Q5l�/-y�eH%.6o"o�i#jce�1!n� .�.W a�� m�F9��Q�)�*�short &�:n, CD-HIT�R2*w?�l9\of6�5UZCWcc&65!Y"�Cgap�.M��/L�|R2i��0Ct�RA�C)� fy�5vz� .n�1�0 �*2^� easxb�9derst�`�"e]�1%�CiO �.A!�gen*�.2 >a>%��3*�/H^ }9 � d BeZ?6nci@ay aE6U4"Jd"kp AE&$26&�7 �V�##%���),@i�21iFz1[2&[{92�E"��a�M;�N�0. One �A�� 4�!�r��?�B2�{"s�(2�D�70183_�9 X���F>�5e|/1iG�V{g� ��z�S ����*z�A`t�6:w�!O�6W���A�a- ll d~.x� ��!_* 8 Z�\a�[32–\@�4ju�.��Z�)4s �8�_i�H&K|�C5&�a�!L�FJ2@I�F>` !Z-A-l �9��-uAD ahK�"�� >) .�:�ey� ����ِ� �5��Z&Z(rfar!�Az ij��/nJ0E6"$~*� �1A lZgh�!of.F� A%6�a�� E���eX�Dof:�6���%Q���!�%9�m8;S%markedl�93��B�+6���� B�1 �2����'�YKC!9h �6F7��ZDof)���1��%82 $4e�<6Z��.8�EI�biquito�mniy.�"�%�i�*�q�+p}i�6��.ds-j � so m�6Yex�G)�bս,� 6��:�'f�� Fa�X7/)� �D *�E%���D�E"��l]qG ~�6�q*- Ii���!��A�. medi� .cV 9KW�l�4b��TQ�`>�,�ymn"1"�]�#R6ͅC� 6D?A��%�121�x��H�152 �7V �,13�AQ�"�<f&�!s*�-:~�x.���:��i�.�*w s���p�%�l�i���.Jd->&[~Q��of (�h.8x%G�jes� �M%�~w� &�.!2�q BLδ�S��#)q� �lyA�ce�3�G�>2� C9�aea@-1G]_� !�R'�d� �Y aa� <ed**16���AP`vjt�u�� Q�8PC�<Dn")S*bN9� !�3��"@o�I&F)�jW!U�b]�)~qU7%a�&��!g e �a*w�.?�%]�Z!kQ��collap4^7p �B�*�'FuuA�Z:J�� y*PX�: �G:&�9z�B�!*-y%�av��=5m�1`ar�@�F"1!���� z��o�� �"�l��� e virtu�&�A�1;<%�Ys+6�`EM�v�1"�8�yD:m| .�(faag.`."�M�g&�h�Gr��d�1h�y��O�s��:-��'C6�9M��CoR(���N��� �+�4Th&8=A_2� &FQusP8%="3k!8in"*0�L, " nd �R�� t��pheno.b13=[��-31"A/ ��g 8)�9A5"�-:Gj!wh��.8�z t5!� �a=�Mx�&!��֭. T�<, � gs �7n�L�C��du.�t��%��#����e�Z�1�, Cnex�jB �V�m7YI&eaya�&O)Ha�@?e����n�al�D� !i% U���6. FC&%�ty!6��Y�fea�&�oi� M�A�&�fP ! e f��BUdvg#@%���o!�u��s�obA$a�l�d&����M L 9 (=f"� �~-� )� �]#��".�^�L��(val��G��،��slambda _W�% r1!Wto �I �T�z,how w��9�.� r�:4�5)U"�/]�Ic���o!G%�mise\e4e erro@9�76%�1�20%�:k�1�u�,���KeJq1<�.>,$A;2'�[hI�q �2�C Fs� b�(as9|>t�<�mB� 5�"�hnofO,�C5���" u+( chie<"� :��c=Da�����k)!a�+2UY��="q~%V6��te t�Y��or va��R��-�^2}lP��+2~giv�Z�� 3!�71I�4�W9]�*"�s�/6R)A��j�It;�Pn�6��� :��� �n!e>en�Fi�to,3<pRi@A�T�*�UA�6^2V* GF, �iY*l$4T���\�#��nP> N.�Ud�m�- q 9ns%�us!>t�T!�"�\D�HX�@aJ�4t0;�A� *� �1��mF�4. &�io��A�of� ;h=d�&\1J�@1 } shif%: ward�9eB�uly�8u� . P� �A69�az "�v�w�.H.��)%F�v��Z�)k� 6�� �emperH�s�RŹa�=Yic�"v @��LI de��/ ,�[�b�t/w]�10��D*3��\�Vw!�:��V��"��_ A�!J� �8t�1Qd ����I}|A���aI�i1O/=�2�.zhiF��� �mDfE��т�RNA��}��P"#i� in15M�sN�ang )�surrog meas-1 �ae� �Our�2� )�'ɉ�u I��"‡<�quiesdl}t�$FTV�.��bb� b�M�*VPqNe��V:�yG. �Cm�Jresil�5A&� 1�3:V�q�vh�Penviron�#!��:;����.�'h :E��%Sse�lor ��|VXa0Z�� M |M�1#Q�iO�&�B�"�>X�+����:���SnglQ+� –10�\(+�%t�X �Sberghei%�yoellMxk:�#a_X&cut�*st immu�x �[10tqI�la '��G%�my cir���pZ�� ���b�� emi- yE�na{m�%�K�B:a6s�D��e�!�.�1�Nre oln&c63z?:j��w2�>�Z6U1�E�%6��to"#a�n�[bmk �aZA&:�i��.�e(o�%vo��|.;-}i/����wi"��6r:�ex���*�.f�E�1I�a� thoc� %wso*7]�Y4�"�My�ooq2�:B[7�`6� [58]�6��7�($V�m!*!<C�po �r,8of# �\4 !9!/R� I��M�� %c@ .����a�: e� "� *micro�<y�N&�< 87�25,�P.��s by P�S"oRw2-F�m�cu�t�y.�(1 s�.q�:�.� ��Bx���\!b� �direc���&%B�Wr-:��&Ni�ntibo%�28t)_�5��ZMerw.0E�e(>� kSi����lEh!$6q�����*��Qt humoS=J�&<�� &} �N�-$� .4l�V*��a�S����9E"�� cyto�i�[7R$10[50�ns�,�� c�25E� :�tim����g���=:�t capa(j���(�Da�6� w*  cr>�recapitu��al"��O ?d"u�# + ANve� "�(-[9 c:v=�s�n� s�� rkj n d S��I%8�$Hš�Cn "�^N�e�� TY-�i��.in 23 ��bNPTu�BAa~si��/ )�eb�tnone�uF2u>�rd�Pa�phya'Q�a�g�Fur� m� 55�6p c&.��"�g�E� �:�!�s'��5�d�eh� Geb^�+en�;-(2�6$%G !��@?�y %>=sE �HsE by �i�:Qsy[g!�A� �� �g��I��K��m%���d�� �B^��p�%" !� apeuT�e:~Ms� =b!nf>jw��`/��o� KFShas)V%htrengt��U�� �:;��8;,<�!L'��9'�12�)(��� � �qn>{u�����!p�;E; .Hty!a7���A ����q�%p%D�Am��s��"u!�n�D4��A�A� �s [�d.7le�� �i!a��hC_�)[�"�F�(�!f!b� �<��2/�>퇡�v���.xA ::@=e�-�$�a�`̀��BNe�&"� �1=R�c�ex�iA�|4�5JIE?�V�(��z�*R>v.� ��>L&�l:yY��~arra�|I?�+d%�F�o�Da�g R �.�E�;I�Wve�ha�It�v=z 90�Y�~F��V�>&K�a�vea�P ��GC %�%�b$Ls. �3�r%��i [E� @�o�C(!zE�+�eF�#p0ggqI]X� Keh|�'of��=u�x.|��!:��&�=w�5-I�`-[&g)Ge�"L"NC ��1]ag�A�5h�n\�2[z�C  4xR��o�l7�)x�7,%I.� Ջ.� d,M=E��.:�@"u,&d�$ <-g:L���14<gW �?rai5�B���Z ��1&H� !0%zst*�>�E�-��#1�az�_ �s� help-�fy&�,!ve-sca5�e�i�A�6���bya&���a!�b� �:"�!iİ�Fng&��rM�. 6w���"m&�:9sh � Iv��.f � � worl��e��"WaHor '�-&�� sero�I!づd �N�:�. Writ\s��1?edDi#��"�by O&iűfG%�y-a�> in Indo�:� EijkHLInstitDRe(}Ethics4pmi$F(y�m�4NX� Ag�liYHMelbourne Health HuhR^tte�Bpr2]20�284�K~BI NT DWt�x �& Fam�� Menz�$Sch~of(�, Darwi� �( HREC��39!)sd�+V �A(f�������.#e�&�� Arraymr�]acn8on: E-MTAB-5860S?id librar�A�K � �T�ENAZV PRJEB2063�.N ��S ]&�?("��V6 �,Ven� �� ��Be��e#m( n =x �� 1{%] 1 )�0�X"Eyc�9fac5 � imik��PFh�,}!�Wrea�4un&�FD�� qs'�9���>n8N$d�*V��per�000��A. sympt �c�lnes��T[11�A$m ���#�[e�J��%\"� �f� W��m-O���( WHO )�/er����[11�IA&C23V���1miH'.�@�%er μL!_�x!�� �.%��&�?ņpredict�Z%ђin��Pn-�[-8*~+in%�t=R��):�4�b� � M��U�. White�Fodi�M�deple�E�a���bw]qH' n CF-ellulPp0( Whatman-no N�er�.) S �d�h z !90��� ocol!�2�CS1eSuppl�ht�me�sa��Ad�G�er"��E�TRIzol:� ed RNeasy�b ( QIAGEN`�il ~ , Ge�Ry )�=<~�PurI��1Q3 μg�5k��b m#)(!w Glob�-F9hśHbF 7!�ki"[Amb ,� rmo F+�r S�T!m , W��am , M�d�1��o)n�sbh�!ioligo dT�Z �U3t�6� NEBN�fPo#a�K magn_\#�me (�� Engl�Biolab Ipsw�J�Jfra� e�|r�~*'V�c� &�ɂyLa-a@s� !~ NEBn�ultra���: prep%�O Illu�JZ�)��_df�Sre��in���`T���ce.Ֆq^����� AT toler5PCR:�S[11�#L���100�Tai�en!��r$2500-HT Hi�Y(�,�Y Diego�A!�)URapidRu�emistry.7a�BriefZ9��)�� g�$A|*�vy run�/!�(SoapDeNovo-]&�4l Cap3W��d�r�x53�k!'CS2 �Non�-R�)fk�filte!%&���v! *��IF"�H�V apie�8� vivab�*&Df�D�ge�Kw�&jB�0��%��A�aA�} aKW�8 �c�A��fr . M.re�&*�d%2pA���!t5����"$(`g�' . AdBܗc�xe�ɝu5�2KonF(�N�g0PapenfussLab/ �e_A<.�X-'��HV�!&��I�Sub!4-N v>+Ig6�me�JmQs -u -AF"0C�D62ZA2A�6*+Eto�T%� c 1!�3 a os q- life+�<#1� !X* )mix�0 of 6RA`��&[57Z��A/AAxe�_a�We aim)b� ��h�o�!��π�.�t�<nim�∑i=1N�]i�:a� 4−∑s∈Sπs  ) 2;� UӡUaiA�18=1 And πs≥0 �we� J"32 2)!� �%x] �"�%g � b+��՟of unw_�I!I�9�IR!$RUV4 ��YR pack!^ruv vA210E�1����� 9�sI�Wlowest&g��[11_*�)rol�\&�J N)%#)�vv.��m"2�a!5%+�(NRN\�1�)���&a�Gq *N99K�-)�)���3 �J�B�[!��2.,,Limma/Voom [~56]&~|Orm�j"krí�/tlִMU"�� ands��Ab�al��X,V��Y��rmark�".�GF�-RE��l�ll*�s� �< sizZC*�YJ�?nk/io�XA�9]1�DV������ ���� �E�p" ����ct�aВ� .�4!n*$&ъdlsAa :�;�F�I"�%�!��-"V�_7 �Bowtie�:4-m2��.OE�t�{c�"�%Co�ő03b������ 4�q�R)�L!z��\A 5v\1g�Gs�G&�s�6w22�%M�.n-��#s�R���eG� ):M5, N� �!|"�&a�]�)�M�. Ru�texts\ a�S�I�F�D� r� $ z:] ��m�H�]’s hmm� v3 . 1b1 BX� !�NTS�B*� D�8��|@l7-�:6ų.0I��I2"��_��mpAA�2���"s�f����m�U,�@?6�4oj s do�m$lap .A�E�&of 1e-8���.� spurԀ �$ .Q�. �1 �le��; ��MA�a SAF e>��)�:i�)�w=me�%0a �u:!��% z: �)�8 "mAo�%.'8�V-�-�-��.3]:�2�a�� &�bӅn1"Uf#u���$ r�93r�t�) ad1"� �%B*ՅA.�tj�!D^'.��t.s2` ���Ae^�'�� �[�,��{ �re? hp�ll.�(6ߠ�Bu���y �5"�Qzdst8nh�i��@�Jen3� |*�)�By�I�o&�j�*�]drmQ c��!balG=una^)�sz�:�8$.�|Long-�2 del�}�iZ0 broadly-neut��z�*+�ȡ�m�achEe�ai��f HIV-1�)�=We�AAV vec!]i�mus41�J�4�y(-SIV monocl�7�( mAbW �gG1�m@rhesus6ke�-Per<�&$ ��Ab��6270/mli��;��H"xJ�2 �x)2��! ]$�'�  9A -12�AkA�e!\e�.to��  5Q�)dJi��"#z�E�I"f5$wվ�l�S!:��]�Y: 1��95H  rem��m����f trav� challenge�ȁC30-toY� e SIVmac2��!=six5> �AAV-5L7 E�e{�V��A�^"ve effe�Y)Vab"�Mde)X+6ct��.� viruaš�,�m8^�:��A�9`i.~g��eak/�;j'�opoint;!�a2&�'-to GZ�u!�(�-a � expo��'"�s9.Esq*st%ly2�.,5aL"�in�9w��aq�e��Yz!�!��1�S2a��)ix* ]i . v�zQN�)i!`a�!al=��a dA��0C=��!��8y�{m�txe� tinu�%W�/: �#wXeo�G:i)ADblewO�S-bo2|will ne� �)&�W�X� c6)!�prZ� ?i�x aliz� �Gg�Q�٭Ubelie\�'j� InS�*vq'?@uH�7 s go!� �a vp� tŅ. -ge�5a2iet��"$e e���% ateg��� w��!�Y�repQ9�d�TE��pp�&A��s� hR8AybRSa��d$�1[�%���# �5wuI%��>ly5�e�(}b�g!�ini� Q�n)o!���F�)�p� |t�7aI�!��:[:XIF, _�A2��)tZo�� ��.�O�h(�� ):��3e��A��Z�[:7]� �c��an .�Z�F��)�di&�I!�!^��-�s;��������J*�kRpe���!���FrZ���8k�~@����oxOi safe'9�inA`an|�apy tM��(V,v$� Q��#!1MA%��z���Zr nti-i�V� [2al5d e\a�;r�NCNe�#@-� h�y%:�e� �Vqan�C�V*w; ��dT�."9 ao�g� "�it�"[1j2�!I��� �"p�h_3S8y!�c&���% � E45sJe(��-a� molecule� �X� by] %�a�s�per a �A�m ~u�g�� ��i���=Q� � (�)�.!w} 316 [o" ��nI^yF� -��>n�:ird!�� ��c��?��7.h )C� )aD97N1qMXw�S >��%{�. zm9^"W�t� -P ��M��I to wͶntRw�)e)�ieED ����AZ4�]� n au��2IgG!puK�0de�#�Pbuild up#is�Ϟ by u�ρ�.�2Y����x���%2�1.3a[N� i�M5� /�!e� u+ �%�)V!�r�1��N&Z%� "� .6 %t�converd�q�{ � @9�4L6% � ad6( x#�-Ey��2��B.�;G�%�� � I�!7tud#|� cr�8� ��.K)\full-r thm,globul���Bacaqu�)VJ� � ln&�  ��%� Q�+!�}R m^funda/ �pA=D:t1jof��y�7"@ RF�:f`-Awn{{ ( ssA�) v!K��-c)8�% ( sc "[2� i b��"�?*�K�,der*L� "q.�ii��M��;��(~ B')Zd&� �#����%�e�`ller- pri�c@'�-�x 6ri���In�5f� "��!��#AAV1-ng=!� #�r�.�9ly ��%6 x 1013�7B* �A���!�l�Y�ea���- �!1 :����f- EB�(O�l�e�$c|e��%�U$8��n�� ����Hkappa.#���H +. 1�MI���"0���lasmaI�gMܗ,a gp140 ELIS���f-:aM�andar�C$J�]nke� -�var3��e.�!���%��� �  e1=+>� A�;achG= ��ByM oV~{cou-o� nths�%�W�iZ ��)V* � < cS/^�A� �of�)EdCedIg6�M\+ ��-��-st�:�05rG��4��>K�5N��of k5�,1R8�0�k���� p,r!�-D9 �x�3ly.E� �Qowřm"�!ye�A�����)��0_�����2)��D��MJQU�!�M�Ce�*-Monk15-��7!�l_(�� �AYT�+�e7���hi9�1�h� s�#�>iL�e� d:i!Le�!b1Ij�-r>�/11A509%#15A+1_�e�M+YM��M1�our2r |-�,� �!�n �qEM�*� )4!f2�ByixZ�E5exp�C�&e)�ťm�m a���–4 wee{v adm��E��3 f�!precip,iM_BźAllE�M�r�z�0� � =�AF!�&d��F�wlI^z  coG5�����)in5SE�!��1D�S3�z��6am�eE����-� E/�D�p �� a8i !�jb!"ZbD� Rb 4L6;� i�eq!�Ps��~ exacs�!@q8 ��_� � � g9�$��>9���!�IM &�@��!-&E�1F%mB�e�M�Ѻ�پ� .��A�a�wo]ki�1t!�27o�10n28A�e�Aqdroxsn�M�,� tia�1�,rm�!Td.P�E38�{ �iSixA�ropY ely-��rol65 � enrol �9>G\5<,%iA�R�J fsi�a%Iv8i�`� ���E!fA�!��746?Q~:E�I*As�EE�� [1� [1�[E[�2.� �&,c6ZYᎩOE�6� ;stIBrQ�7�H�Smx *!�&�A8%��"/  PBMC-grq stq�� 3�S2��?,��"_r<�y t�%Y"bC��� rout�5ȁJcexten��ly>numer�&81��MA�d�U� s [2C�3�3u�an��:] }������f�T>,ڼ �:L' @f��.�Mai ~?sixF?��6A�)���18�i���`10x)�b-��OI��>��mI�( ����O�3�z�K2�#&~ B:�qui��oo+�Q�ne*"���*u >��~-�Gi���2\�,AF������  !N+�d�i�=N�nst-�D �"�x^lA surpr/)��vi@! �;: Ge�� N�6"i5\�� 6�1Nu����&3.�fX��>], nb"�&virc@3)�l^���} e�Be 2C; EE12-1�o>�Eleu� ��6�� ��U�i 9� 9�>� ( Δ!A�67��;a�dTDf� 92 . 069M�:� a�y�]9��aaAA�!�a�2�&�'�B�K"h��&�@ac1e_.B-$�N)$O�0Yi�R?�l68WtBoaXY�- ) �d�]iC8} Em�qT Q:.��$�(y*kA$�TJ�1i`v&#u:�k6' � �!��/a �W��t�`.RQ\ϭI�Or���.�<�UR�� �Rrr7rmSIh,tj)=�c' 5ef���'!&n�;�"a�Uof&V!�F �}se��y61�N��%1��)2%�B'!��1�|A>�s�k.�"�"�@L����="X )�3 I��y��&at 1 mg�-��o� ,�~a13])[t&I n ���� ��dbZ��e neutralization-sensitive deriva Hof SIVmac239 called �316 ( Fig 3C ) . The half-maximal inhibitory concentrjHs ( IC50s ) againstTxwere 0 . 0015 μg/ml ( 4L6 IgG14nd !3 5L7 �, which are consistent with previously described �@for Fab molecule h�immunoadhesin versions of these mAbs [4 , 26]-:�of&4 in sera shown)= 1A ) �@measured biochemi!oy �\a gp140 ELISA using varyamount�purifiedqproducP$y transfec!���293T cells in culture as standards . In order to validate�:��mAb>�!Cto firm=expectedY�ctivity�serumJ, samples)6 diluN ftain a�rtW2��4Q2A0�based on�2z-�6F�u;e�J�as9 )�3Du.VFI)%,reed spot-onI th:^�I��A�all six5@ . As9�%^xa from 84–05 lacked detectabl�4j��+ �E�HEKEr-expres!qU�2as%]eTa'$ed equivala� bindvto�.hias� rminI�i( �F�Wa�thiA� form��!mh!� , wea2ceededd-� ADCC9�in�C-ch� nge:�rel�8toF�Sd5�2Y�5m . We u!'0an assay that@Xs natural killer ( NK )e�-mediaa6���or �independ!YofY�)or coaem U�[3�� �uses a~�L line �1�4s macaque CD16!�ef��aell%�a CD4+ ��RD8luciferase upon!� inHio!! target .%Y�&U`EЅ�2a��;match!}j;�2\i%�-I��!�w�uit\beA�!Ea��. S���q^�unusu�,)9Tit had markedly higher:�tha/e.2K!�5�i4A%v4BePre-AAV �2�co�O��oM{�Ucap of enhanc�B{N�S7=: FourF<(five remainOanKq group%"6d)�iQ�)�s-��e�atgF�atbK��57 ; S8�=�$monkey 111�<9 ,� |�(lowest post�E4viremia , also�somew�RUYto��� GiveIK curre�vailabil�of�M�,acular arrayhuman���pod broadly-V�� HIV-1 ,I�s become!si�dto envij �mvene�scenarioE imcocktail�su� ntibodi%�uld b�J!)rovide�terili��barrier!�T� !�$vast major- �str� cir!oI� popu�,on . However � is not praE� fea�� der passa deliver%sU�� oTa period!�years��� -4purpo��. a�vectors (ideally sui�/!� 3� only� tein��d�).Ri�riv!9inser\�z0gene put into!� long�0pr gis vie��� elf ,�Y![can!1tinue�proOed-� facti��  lready exI h �%uJ� have[Q d�5s level)|)� 8 , �37]!� nclu����in ��study�((ince muscle�V� hH  little�no turnE�hy%�a!�fer�sourc)!-termYO-�!"L.Vintegrf.�DNA$o host gena�(sequences he�en obserA [38–40]�o9G,!Hro�{ safe whenLd! clina setaUsa�raCse !�$ditary abs{A�gA[fun� [10–13]M�� arly clo��S"�i�diffi -to�� a��mane�A�chaa�eristic�}!{im�isolata@I�́�ea;tena�ly �ay*G kto gauge' icacs vaccZ approache��Zs�4ndaP!�! re�-`qa��aachie)�� aK��[2E�0 , 4��4%EB�a9I)GA�t avoid�jlicE:%AJrpret��EA�is-�a hetero�ous mix�of]Y� n un-� viru�ockE�& dID!�erA%#Ն ��ity/rea�aela� is"���[44! 5QM� `� AAV-��*� m��ri@ s signi!�ntlxlayd he tim< peak�al load 67:hY�vi0 both��IOAat(aT poin, �Uh ofR'%G�E /� � �6�1t� 8�8 , le� addiA{ al supporE�2Sc%f��"eect��Ite�1 likaY% 0��9,acqui�o� i=��s �a reala}ec+ M� �ic"�[1E0@� �s(10x ( 6th )}��is}ut�M same dos�sE��a�b�JE����in dozeiv� rol cs��$out a fail�of.�=[27–3]�=t�e�I oc; ��!/���3�<%U��K9��č{ �to 1 mg$ . To�Kknowledg���isO(first demon�oA~Yq� B� A� �2� * to�ne=���[46�J7�JReAM��� YemphasiQima��of Fc&�"B��e�%�ibu�3�!@q7% ffor�by�s *� �'� 8 SHIVIh ٥[4��52�T���mod� M�z�%R2u!_up�do�� � ��� �s��ve�c� . S��/�%^�'found�oci%�Ū6J� 2�[53–5%�E�9� i�|n�}O]�X"; �CeXnI'A e ba�reH lim� to:���$le��Y<virolysi�@A !XsevKi�Tfascin� �}!}��:� :J�� 8 es�_xtraordi� �8  d R%6�A�� ���Becau�;�I @s"E��DwseemsB@����%�iA�6� results� �* in�t- &a��d"��E�.s. Decre�(core fucosy =a6� iG sialE��3LnA%dramat^ lEQT2�).�kaR[5a�6e�One ques���J��!f whet���-!pon��e i2ctru��.,Johnson et a�f[4] c�� � � 8 authca_�h!� swer�a clearL . I�x:� OedC1�bod� <� �UA����9Ie 12 teH&� B appe$toi�qof�!?~e��� d��s e���truu � �inB!��2l+����droppW recipitou@coincida�5K �ѶntB�[separatf uE3�E�5�str �y]<in rhes6 -R�2� , "�SC-�?in 24�� unitA�]a ssAAV13 de'5ne@o�on`�*�v&^E"i' ntras triking�8in\���13 �_ admini��,1g���� �o elic� J�m� thre$< tIDEj��3achn�Q�subjea�[63 , 64!p��9��AS. ��is��a"� ��al pair�ofA� heavyQlight�in-Z �th�[gen!^�%�exC�&s r=to abovA �po.��P toYg varirreg,"r�Non�.les�!8�BP0warA�alUt"|!$:�probl��eAAV!s%�to�\9q�(trials . Co�&�(-�chq,.���bicA� onic�iA�Lsilico , codon-optimm�d� -syn�( Gen�opttAHAPAX ����%7�  a temp�8 full-leng2�Za�E��~�N�$ng CH1 dom�ACLof-�E�mO_� n^� .2�� orig| e:r binam�-SIV � 2�!e�A�b��marrow� SIV-�ed��5[2� Amino aci!� aligniof2�B� �mcloseiorr�ME9��6icu� depi in ( S9"[R��Ņ�A�"�acces noMAF14058%�AAQ57555 � IgG2VL =60= 67 .�kappa2��U�u�!Y�PAAD0257OS]� frag)`Ez�!>i#(to NotI sit�sca����ѕplasmidE�. B.A<$gnize gp12 �0�:A/4envelope glyco� i�EK2&'"( ATC�# �P"ed��r�_�%M Ps 8"�%x�supernatA�)QP� Din A Plus ( Pierce�Co:�ZqB $NanoDrop (�rmo Sci��f�� A280�7 �u�a��g[verl#by Coom���<( Life Technolog�c2j ��)#mD$)Westa�or!�ir._� a��%V�by� . To ��-|co w!A�WI2�%( ��y )A6 1 g 37°C . P�V `washed1�$BS-Tween20a�(igma-Aldric!Nsubi(bloj"�D5% nonfat dry milk�0PBS ( Bio-RadNK,)I,��&gneg�!}%Ew� �se���iJ$1:3p���buffe�$d��� !�)a�~fte)a cuba) t-,aj.�-.��,a HRP-conjug%�goaA�ti-�� H+L!Po� rnBi�!RA��Cad�AB� �} � � I$aB� a��!6J�10���S.�, TMB%�t� ? stop solua�J�s �2Absorb9 at 450 nm��#_a micro�o er�$erkinElmerEN2�( ��o�'s)sst%��(h E !qby ei�a*�"-b�Q�b�F(*� ( TZMbl )3#oA> 3� is��s�� alkaB#phosphat�"( SEAPI. V!2aM� E�!�of!Gn�%ciI��V2�befM�i"� �or {��!í�.>`!4ass�% two days �r!C)OaHlu��ceaaa 96-w$R� 9�M)�.�� yor"��per��� NK�Ytow�(�& B$ �eng=��$A�$$, CCR5+ T-3 %�! "i ��� f� %priA s�-�e�se6�%��!� (_ �Gd�! MAco-�J�:�%ԍO�%ndVJ�$or heat-ineE��I[�`8� 10 hour�CO*�ly�&�\)ng[!$I� �los�*�%p�g%e �2*.&du�� �econ f&�y�[65�Inr" H�(m����A� help�!� !$allow gene&UI#�� p�*cl�Y�F harvhng2�!1 R,� !� ,�+��n ial CsCl �rif�n�> step!�V$"�MnumberRu� by Real-T�PCRe !�vt}r�_�.3 elec��� scop�silver-sH ��DS-PAGEi)+,Use Committe�K�l'%)��col!� n�&h�rotocoA�� �E�eB�Area S�.a�on �.�y�6F�Gu�%���5�N%a AllYO�� )S O. ͝� �,�Kcapsid���6�M�weigh�c0U� rang���-2 . 5 k�1X2 a:�+�i� �g�-6T���spl�n��#i� *4 e�% a to!�8of 1 . 6 x 1013�v.>!F7Q@25���!�ݫ!�Z�of�% o� :mJ28�6mTRmc�.bp�fL�RPF:.V.%4:�*Y�byBeq',A� deep�ramus{( r in�i�2�2[ R���"x�5 m��>�'L"qua� �a 6MLat9�rEQe#gi�%]"I�f"�2�rM�Mnmanag� program!:Z��!��� !�Ameri%(>3 /~(,%smeets N-(al Institut� f Health��_ et�th��p€$( DHHS PubW% N�D( NIH ) 85-23 Revik 1985�ѡ���(pts�m�3� �P`olif&n H�+e � by A� eekE{A��Pr�3�"U�"%@'f of V!*br�D�ss��� ���,�^)�T� ��ron file�4�O�'�(G! �>R� Risk����(dA*u"�C1i�. ���E�}�Yyst�!metU���!h)nc��I�acroughW(U�v.'Ay 8,b+�-` o*si�a welfm #�(g�(!.^Xpp,&�Dean �U7!�,of 22 member�mpris4�ian�2 pE� re�1a}vw �16 docto��B(of�< ncip6&im)3%Aby5nF�.�A"j&ly�oc:s !�!g� monito� in da�� -by 8 d� ts a�2 !�c! ��a�proced�Q)) unne�**discomfo} p^,s injury3\�-th&!9c�8����i;a�“�o”%Z�alai&� A� anesp�0nalges  qu�&i� , euthana or��*�*vep d-o2!�1"YGRo"m&� n.� � ��7NC 6 �� � "� 1, 04655c�fio!Y�����U21 ( IACU>�0V ��U��� of M�biDA� Safec �:awe��x"��% is���b5)I$E dividX Hepa-filtc*caga�A雡&�QHfe�6esu1d�0-t��utoclA8, footpedal-ope��d sink��a ��� .t�� bine�? surg�!Snecrops�0iWqhm�y%)re[S��s%  �s � �a> roomm/t1-up�Bdispos�capZas�c!vG9, glo���shoi�$ orga*bE� took�ceA�def�<.� end] s ��eE ^ bw���"� V& Z.� ( AVMR@��%�H�7-se�?+i�$"MHketamine hydrochlor<,at 20 mg/kg �&fo���@sodium pentobarbiA ( ≥105) hven@& �&.U�-"�B�:*�d&~�Aivo�="aa�1�2� ) /�.aEbA("�ra� �b�ad�'R��X"�Ainu�<' A�!��A�'�%r"@�S�*pl4d&N:cn E,v�R�$�2AjWEqu]�by � M.��L. e_A2�'��E�Md(.��t! ��"�. : 44��(Y+i�1"�) �|.� ? � 6�(� -env ��"sŝa[��7v�?�a[;��� %&o*!�a�3s����7.�. �-6HK6Cbk�cap�!I�6�.5 U�V�.�3!A�"E,a�&�A���2�sE����Donkey��Fo�)�6W�&��BF%�n lambda2�#%�Z�T? se�� /did�.cross-rZ��!�Ab�^ �si�V> harbJ2..�ng "�>R-�B� d"�!� �o�rR�Ced pch�v� %*b� b�űn�F Iyb�ozE�= <6!�AF%�"�kEfv!stEe:tnL9s>�#1@C�CTEBor:5��1Pn�@3�)�� plu*Z�eU?r�-'as��F�,:eS�,���6!�-�}us���Lq.� PBMCa&� &iZ6j���, �I�b�-ped4d��1e� EeS"�;��Z :�1x AID50�A��"2�. elev~ to 2:!10 Hf<*�xth|,���v) �1楅 expo0 �<�E�-b or until �$B��4d2 h�F� {a)�#y��oA\l-�IRT-�� im�J i'�!�ga�?N�[6?*P�3�9�&seE�t�*"�&m,� = �3d9��.i �(!y6e�( �"� r N)FM8511nc%� gp41A� " oDX )A�� �j�assump�of�!a�2_ �8e �mal no�<�)�2�GQ ur0& �B�4g��'!��ac] , bnC2h) - �dynam�>f#� v4�I; -mra�l,aly��er:*nCI�4Hn�5I/hata���fluctuwn�macro9'� lso G�tB>zA excE�^ f6�.��c3�N9�9in mo C— myo�M0kin�MKIF1A�&S nuW7v�!_(yɓi:I2dJx�A!�a��!O):oarse-g��JlaV@ network� roxi)���8�eF� a�*]��Cfi�*e�lET-i�v2�mM�9f;be vig �:ac�@|F����{cy�|ul�Apronoun�in-l�C�]\�xiqt1sl leteE# }�9A�echan"GO��s��7SL�)HY&9D� �theE!NXB@n�Mto!/re��E��NeF(s�3e2�n�4�$po��I�i oa\ yiel@: /A#B4nonI}� �A�fnhP4�"� enzym| pumpC(m�ar!<4F,�^yJ> unda�al rol�'*��$0G���� �,^8a� mYGAUl�1�O&� 3fQ�i.9)'cV�po�md��extX.rerg�Fpp  ofte�Ci�(%yas ATu)�N ��f)a0i�5"+<lj;im��, F)n�%ak�4�4�@Q�q��Q-�M�an o&getic� =,�:06��1LPM -sca�F6baXg�My takeA�)�B�4!�)]54[1 DespiORln magnitud�E%�k�!:Da;&&5)�}k�Pframe�;I@���m�[2�Fa�.r�q[3]–[� 2*��<dur��R+�v4o�C ���-��st�8�T s [7p18!&H"�.\s�4Ř^�.lex���yst�6��bF1�9ly���deI m�K sim2 U �GubJa�I bo5F% a di��t f�caNe���܁AHBelousov-Zhabotinsk� ��J/eex�IA�greqE arie� f sp!��6�pat���jpacemakt , ro� ng sp�Ewa]))G�hM X?%@Ÿd�ssompanV=e�br�s [19�J[20AmC6�AxɻM>��� b����8 �$�  ?tw d�kf�WhileI�al unfol�YAre,A��A:���7A�iO�� �i,��YhQ�$ aden^?e��/[21!A� *�:6���_X�Y���,"z CB�!6or�� �C� KFeem�M_�QctJt�3 �Hdu`�J �is��oaon>5�| �Kdu*� l*� c)�as��> ���#����lA�( ENMfH,���� �rof�.� ]�Mz�a0+Z���%w&' IAs "' [22!�[23�A63 [2�<Ou�'2" ,*G �B�!6�Sv�H%�"� g-is!�.� A�Hm6\ �!~.����M�H!�pe�_��K�V� , o'.ric62��r1�7famQ#,� �E��� o_;;�:� }]^$��OHb�BaRr�@�.p=-fl.�2yA�ll-� � :�.�ath�robust&�er2���)in-��Y�. �r"�.x ,tn[_�>q,dEM)�� (e[og�o&G�"(>' in D� BankDB ) ID�=e: 1W7JW�$MgADP-BeFx�!_J a�og [30]e�A�isAal�o� u��D�����,nucleotide-f; �=� �/�,ID: 1OE9 [31 y!@>pW855�Z�1co�%�3by 7261) �Not` ��Two -c��E-#����E,1��&s[*Y �B��/. A6�&.mo&s��st� ngI�randomly���Bz�$see Method�_�*c �vi�X\."LR,�& !�/ (( Asp122!KA�And Val22��Ser135"Af�traced �XT':_ uab eachJ E&��� cero"UW���s� a �Gb�C�"[lab�S.�>u%1B , 1C<play �.�3�2tr }, �6�� �#nt-�F�A ltho0*A�J� =�!A"��aly9nEd8oAwi\t*q )A�j��i��X@#%�]m |leae� back >C.qDc� 2+,l� gew@+astʼnb$��. F*o ,�E�9F���2bconve�*+ ���!�athEWe �B1IB�� �=.C6��>�:�!2"d( sB^�1V��!ơe�is �4e(=V6a�+ �g'pe�"q join���r �utUa2Dis~�"/cby-S 1D %]�$ l snapsho&3.0 a�L�,qB Ui1� 2!He/Video SBd�6�#�SA�9 �Q�j�aj1m gy v�E!� 6 scap6�. OA�R7x(egA.�6+ [s / one-dimen�a�%dN�� I5�%co{M�V�@&N i�� �1a2tto�'st �csaI1Q`c%��j 7k&6iveZ�(:��_ 3A%�o�Q�a9�>���i������ ATP-.4 . Mar�"^�gT�c!]�Y�1UAFore�B�1�(���q�3�MC2!m>�, i . e."5O^6Lmpl�� t�Y��=+A�xp"kA�l�f#A"harB/�n�6borho�\ L>�.� .� b�F_p"� 6�|y�scu)c A�dot�blu!&Fi᪁o�-MKir�{���a^�c��n-��est2�6�4&�>�ILof��%| away� �<�!�eoutY;�^n�� sta�)3��I$>% (�$)�X� J nt&�� Bc=�F !&*.�%�L���:D6L(( � I5S"e [32� R&R F�1�#� �2��=��C* �<te2�6I�MPPCP��an;!o� �!�a�| � 2f !4�>� �320*T f287&� Oa�!HV� � ~� u� jB.� � �4Glu233 , Ala28�V�Asn211&� 4AE� �A���k,:�),F�� ya��Yi�s 4n 4�3!0��~ann�JR�,A�A� noti| iX��:�>�di� !��xNo .� 0ABJSur:l�4we find���YQP��"= ��5m�&lE�ptyp���� By�l" sm� :�6��ql>�A =ITVe*��:7P� b��Y� �%&� iA{ soAQ�w�6ec%�6�(-� 4&�kj/4DE~�/K_]:!of��AL�"��;0 g :o�K>-gJb�8�Iat���%�i�]%�R��"J�>�be�> ū �,� f�V]xɤE�:im�j vicAW"TB.�A�e-'hm� AlB.��  begi� !in�TI(.J  6%�is2  %�e ��>B ]-�� eda��BA�.�6Pe2C*�#WWqv� "t ��n� �1 |���e�* &- M�4!�%Z:s � 3�A��� &� 5:�ime , vo2=P�M.�Y�: " 5m�21Rұ�j� (s c '2ſAD�"B�* )M�!M>"g!!��+Q !Y�&y swi�lIIMFix%tMbsli� * loop .. mdenh� aCjigA�ppa�i ly h n��; jea�5M�2V� teau�� Vt&� 3B nH'Q �4!���=(K,"� �;�K're2�3; �E�%���%@��-he!v,U�"�U�W& nd�#hd�%�%e8(E��* 2� �":�'�N iZe q IFy%�!9�n*~e /�z2�4|�m 6(&'��at6�'7 (ln�h� .n -i�6�'4e,=3�^�,�g . ,�!4� � r��W\�a��2}�6&�B0a/�?/$ %9E"�4�X��e�gb"�"�!.� g"�'.�Ŵs|qNon��!~2'm�:1 OA *Z �RZ79Tp� �+to�U� ck>� �X2�A�a�5� �.rl* s^`4san�| Q#�(���29w��t�Y��i�n)[��"� s#AT14z#�#%QA laps �ža �J� ] s�e6 �;� ����Im�-�]$ satzj�E Kw�7� �Z�1r<��nn �� 3�$!9� l"S.mfHo�acF�# . S4f?� ��+:�.��hW�'n.k) �B�e�m -� still� 6�#6J�.A_2� 2nbreaks �e�,��lq<r-���i0.) bYdo wot5Fm�D%KZ��  irregE�&B.e�<�f��nd��>?�9(�-A��!��I�c-agv�@oi��6>h>��w�<�_mpHh �a/&s�UUC�!n�,�!r a!��\�|m"s�i�A4� }6E q !���^�}] �w ca�!u>�7lem��!�%��Ws�AbeJ�JVOu�lA�0��a�4i{Z,)�!�i�Y] wsdsuaHx'!t1�kq� }b��n O^0q�a1�/i^E&�B� tinyVu2W., " Thg 2{1N!<�CexpbJ/^h�%�6u"J.al�$siR�.*�*E2c��#�g�D:�6� s-� �=Iv� vX�� �* t��V-�2�y.:��*�,>�F�,��iCe�= . St.�M?r}:� .��4ut��AhTV&)�rapid5��� V�~"s�Qc��r)azi�V0J_= 5 i��2�+��z��i�p�Da�a O/^��parM.���. 6DM)}!Z}�JF�. Simi� behav�W}%�*�8no�b�5:s]�:r�!�)0de>�(`a�yet h"�@�A�Q@5�mf.cxv!&�'6�A� steaa uniqu�ep�i,#)e������:�F[~+� �s&�&�E�wo�,Z�I�*Ef-��i)=�9)��?a���[ Aq�*�:^F��6�y�H4yL��wH�-��6�&6� ԡ�jD�%!��.j�1[&���29P&�e :�� " �.� \a�t��/�CF�.*A'�x.y� % 1�� a��b @&L-l�%�!����� Zg�L�Vng� m5*L-��eacJ��1tN\8e�%���DT.��5� t j�5�ng&��rq�markab� �)�A�.�$�j 6�&& &.ly� .v � !itQ��F]%, ��Kra�6k Y��J�6�, &i�"D��o�zae�n#-.a�� 8��7S&�;By�a\�xUO*!ks��"iu�=!�׍��2�ulif�' �M@l' ho)A.�[ cryst�\graphicj H sugg�X B2d/pl�_��ttnG�o�K1��"�aQ�.��e�j I [3tzm7Vash � y.�$��L _~C.\�*,�rJ!-�er,*n�D 1it u I�W �cecWE�9=�=[ay�Z��4L:�4Z(��M E�T�3 -hea0�){�0In18� :� Q s dr�W�A.,A�B�s �ii�.�ABE�h"2 `�V #ᦡ��"�S�� op"!s��� ]*��eor*09�M� :ri-8-1ej"�{[3�1I�<�5!:65[Ai�wo��v2>�:v�0^��L��-S:Gx܌a2(!_e�cP ?�%a� l*MvJ�n("���r*"q�$_j-�:�1�/ aR<=�E�!�a2� �-�* QLat��.gBO�t��mitA�ultanq~�"�ap��-#�67�Zz[&3{:�?�4�_\�� ���=�p"DM�U M��S(*b�t�2�pG>ifluores��l$ �)!]eN9.�`F�Lwa"�0ur ��  "�Ax �$&�(a��� dM� " 9p)D �a �G-�})M!-�bzs��!F":26U �Ees�g3�!"��"� w )beM*�� IK7�|�� 4�;BEs�@m��pSYi�2h2a 2!�1O$springs [8�8= Each �2*`� a �7��a-�e�9�li :Y1msl_ �*r ]Qw)�of"�2�� !3B�Y��ake� 3AW�wo��aY\5HnC�n:1 if� .} A�N@  * "2cutoff �@" 0�t { link�S��A�s.��"eauY`TyIb 1Qfor�2obe6He Hook��w���%Q7��Estiffn�9�V . EkD�Aa�� !e�*XmH� P� =ng�Q/!( _/�/,bHf�>�4B5��F2a�U�59� &�/ +5H"2B��)Gadjace�Dmatrix\����Sa�v�AQL!� w�G L �1��g� �P( K"�|N� �Vm#uJ solv�3� u�S �i�!�overdamt[(� [25��� velo%A�9K� roj��Z�hUU�Tcb on�&2�mob��Q+ �"  xl�wr�\lE�. Hydro- �Cb��negKf(2$��9incor`?t"N��M�1���"{2Bze7W[���-E&)a*u �Sɵ�����"���!Ss: ( 3 )�<@(P�J���2. H�f�!R�E �p� R�5�vW(q!S%8*'@qX6F>q���Equ � �[� F��&ex�ŏZ�r QTo < /*��-��a���i_�I"|C. R� ic��CY�6�:��H�>4�l.M9���[�I6&a�b�"U !} �B' t A3 6�K a fix!Yim�+�M*� =Q.tz2M*5��fgB_g�]�&���param!��ri!�mA��]&�z{d`m5 <>u%�k�F��!�:�8X )&�~�� ��naA& � T�^gA ���%�i�;�Sex�B��nen�y� �OO.��ZaSeR��1�2� !yre`��Jd�U� j�%�2veU �e�W��> �A!z ��6WaV�E`i"�@�cg'A�n��^m:h��n�F�-ir &� e:ats�\i�&� roo�an-squ�..�$!��v�3os� or6�1�To"�A�&�2�3}9�=>�'�+s�9!�+ �aH"�sOp4]�6�. Iє<!�< low-2V9t���. manidF%o�;< er�!�}~1�:�H�it�[ :+1�6�m�?A�a� ہ�b-�� sh� �& pay �',�� a��|#,":=�B!(E� 5b�� >n�!��!.�!� p% *�[ ho�OA �(m�l,"�i�log�g* F�&)��rv�V@.>1�6"�Gm �al!�ЊJy$S3��BSTMc�Ja�0G�)adJ ��a�ih�e"�opa���0����Q",.�:�`)�MC&z �)e:�V�"c/ swi �r�2�%ia�B1\5��*!,-89 �@u �s��*y0 �ya!�Multip5I����f hr&6�qsd i'�mo3( 4 )"� Ar*@"0 E-J��Z*,*�!!�Ad��� �Ae�  � ��)��C",e.bI� Ƅ �� Mb� sŬ�K.wT L8� <)�cF:(�a�} X� ��� �L" � ��>�7:3�? Q�V����d�ZP)��� O�.p�vr"�umm��-��Q"sz�62��K�+N# &�3!�SX�sre��*;a6I &�%Q��, �V.V6� &�Q "�9c)�6 )Azr( .�mKwrw�5%�_�a�( 7C�b � 0l8)gga>GO�H B& 2yg5�aKpC*�?1ca�9=�� /@( 9&�a�!�A�eigenva�  v��?ar3H �A��@( 10 )oa �.^�6��mQKbe zerK�:�=Jk(��Vq5�1 YTnY.m�C�T:�[ ?�� �#��hRetg~,o� �r!2S� �r2�d!�a,ICK9 Vl�e�Ղ�Gha:�f ofx!9XJ��*�@.Y"M76 �:]&u��*��tra!���!��I�/)- �aHљ";n%�1L�logarithw2"� i'�� .*K$$/�R � *�  g�m�v� ./��O!�L���L�1dm&|Q�1m�6,%�-E!ݦɸe��:+B�^ ngl����A�d�$5*�ݞ"QW�Q-�*.ep"�(��c_L���Ñ_�"S�Y)��.�M��͆R�  �n,��)X X6P F�"��.e*�D=� %VG�> s�}i�n/"UD*% -� akSE��.� ?iH�3)N>�>� �;1DeH 4VIG��%#da�UU��c�&^�is� d' cE�.�1^���.�!U�i�-��%SsWda:�ɏ&�_6��� ig"+E}2��T�:Ѡ(��of,�*lh"� >���ali� If'�%(�6!�/v*�2l_Nn&�!#�4 �f:%�CY���� =ZQJ��%8dbP1)�mQ�5lue$P1d p� conF�5#6� � <!�!L�k�nii! A�� "/'i}idU �9�6��� �9��.eA�v6"�9����e�W[3�[�1Q��7iTob]P6:ܐ� '&�:� &�U�oSKg<i� .61�i2chL&� �ma�|��"J ri#p��3nZ@uP reVruct mis6%��)8%ndB�Q.� nex:�m�5�)!!��mag���e�~0� P����!!��A7-Ştr�u83{Vѝ�&&�J�r.�u*�iI1o�-ev606�&�ene!z6�J!k�wC- e�>D^ �"�V&iArefuN� s aG E� .E=-�r��\!reU5�Úaron.��mIt�)1z"�6AOUF�m�bI� i.SZ& "���}X.6� 4M9Mp&��0Ņ{Eـ-:=�a�@A,��F���l-�+ŧe�% �12p)6A0v(C*� ly2>�B� �A�GJlV5A�B����'��6�R7h�!>�)vV�%�M�1�cf_be ��~*�Gby!�siה�!x� � .l f�w2OG�P>G1��!(��i%)>�DA� non-i3t�fsi B I`h+s viaZer�FEW3�o^=l"1"�� p�����Tigra�{�rp�gA|V(��cU���V9�Ş%5.]�S�S�bhave �(6hrosB.k"�1�$t clathrin�@-�Docy}dwA..D8!{��)�Psm @.i�ev2 �s����[�)��B . Caveoli@ �*v ?&ru�T*x a�/a�� i�/q��9�n sBH��en�roudS�^we��}�(peXm i8-RH"� 1/Vz#"i��<�%�jdosia�C�-��d �M�Na� 2� �!� &��o!�Rsc:� s/GPI-AP �y�j/G!so�!ja2�( ( CLIC/GEE$2� #��x�6��-=� �X=�-~NCAV�&!� CAV3�=i���~M�S���aL.$� Y5��6% �p'i;! �of )q10�sI "�(�w v5DN�a�E>�X!�b�pM5X$�i��U!&/)�1AL r�!����ofM!6J��d$��e<i��a�% mimiЕ� i�d-��c���ci_%�V:�aaurn%�fu�li�:}�EfH�/�1&-c��y1i phot$��cgNRA�i���%h2B� a`��Ai �a��!Y�it��M�o(/pa�l��V��1�X��8la"0|so$8�>.s)�� s  .��ran"yO�^ �ic �FZ�di�%A-I;madulty�tissuKW�L�`�non-r QgA� m0���o�1��v� �� L�M�� =lJ�, Cdc4e�� �i" u insiP��� VA�B�R�-#�Yby��#E��a� illu�%8i0i�hle��FB:�-塺W�51H�%a �C.Nax�(�BzA8F,1u too�,A�A�_ at១��>l)�Ga2���iA$,d ovelsm���-|V��Q . E�\%en�Js�/a*� 'inc��^i�U �q�8� ;�] ( CM��E� ecep�n��mx;�F�a�bes_derst�X[1�/EH�Tcup-sha�+���)M�ae�faI!r � �v�m�&�!aR\�ic veh,0�iH>p<&>H41ell�DM�ic up|!:"�jly"� 3�'�T o*�)ref��!��g�#-U�!���ABA� esum�:2Xm` e [1)Sҳ-Trpge�s�v�� �%<�  rm��"f��~�l�1? "�$E� � ��. ��}�Ń�l�LŁ!a�a �f -�0�, 2��2� B�N-4&��D��<�i��^E�x� ( Pri"�Jlrtog&A�GPI��eIEHD�pacsin�f�� �=8c Jc:A0KKk. Ss )5eoa>e 6�N�+a��*[1=Zm.G�T< now�Qɳ ��L� S%��)5Z��� ��A�%-,����o�� ]a�.Ex%knonr �:? �Clm`��Z�}� o)}! di B.� O�r� down--��).p�J,�j��6~;-�ax�+ y buUBf&SPM�re���2"x��)1D������aR]� bulkmE�k� fib��a��[29�Pf*� k�h>�=A!ubeY morpG�y��#*� ����!A]�M&�q�@�V�CA 2�� 1;: c� e�)LICg{$�s-�A in-����*� >� �m�`&��*Qnly{~���->��)mdto8W?<U�mn*e-�����pulse-�!"A3 �*1�fV@!s5 ���he ��-in 15xE!*��!�:��re�EEA,�mq��w"�C%�� �l;? !�-��u� mixD i��� Q3�� ferr��Tfn )IQ!S�Or�j"v2�"*!(�le;���secret�1�� ,�]1� GRAF�� ;� �tfIC��onEA ase-$jE�|"�!2cy& Ʌa� si#M��� �!c!�i� Q�I��vr�Yan &B"��$�-le��ol �RC DP�a/�\s(]ephingo-���� raft| 5 �r! 5�:>��0-�sE�&��c�,�J:9:%�Vs;�"�H ��#�,2 -E ��is e��� !���o"� Ad*�P�&�� 6�>� hol��tox!�ub�� b� TxV`��.� ���w��QWh�7T�P�"|�r�����#tjO!� 7� wE"������#�"C�3� � aA%.<���*F�2Bd�+&��` .��9,e��"��� hyaluronav8�ID��f�&~)7Q%�m��"L �b&m2e":1�1�M�. V����m�� )o53IEyU��!�em�c��� 28q�m"�6Qq4W�0r���_nd=ځa*��.��!�eIE8�k�|��%�)(S ti-@cl7� >��U�) �]aí6�&�t�n2�-64_.��Ru 10 mP��/��R!�i� ,m��7��� 8! ac�tri0��em�X�7�$��3��2� �Ab�&աl"�Fagg�;e!�� 5"+2.�&�%o��,�^ ]c� t�M<2�)�I >E ent���)�R!�,1�A6>��o�8MJ�.iW�ZApcr{$����w�>at�ed �%��%kEu2 ��B3w0AY�Ab=)RA�"97 u0� "���p5,6�TfI�� [=co��:��9g��Y! a�݆�"�U ŚA�*( �!4x�C%)� ���M6�NF�,!lMIo��� ynas�. U$�wwHr�sB�A� �/tH�8 2ed5? ��0�zno5.2�Y�)�"�j1�R�#. �BU)�� �@ld moa�Byo̼&���-WT MEFx!w�@6� OS-7 2`d i�r� ��o�Q[4e�=:21nn ��A�& C'�ҁ��~a�26�Gas .�S!K�%6� �QSm���vY�ukS1�p.>�~u_g� �img!N �O�� Ib� �!w!�F" D�ex �g�T�e�BC=E��Ra�U���Movie�@�'T�L� �=�Z �\�!� *DCsV{ ����� � A%��s��H.�>� �.�$U�ei�5 ay �Zm ��γ%)M�Nn�  .� , [4B�4,�TA��Ё�~ C��g�*$ ����V"wP�nul�: −/−a�"d1!U$e�(�j%�sI�s�� /. 9%�f��' �.H6�5�s�\� X crim���3h"6A)���]�3uu�A�Wm��� �(�y�a�!�lin��,�18 � �%'N\;�e�>��"E=R� fphY6 a�� ��u��.��ab%��R�N9.G��*7 2-�Cin �+ �)t2�  a�7s�01 >�a���AV50!eNCas%�i���HW�[�{1�t2�!re%n��g�CM5�R1�-�"U !_e��![S ���E1 C , wA6y�5$�:fP�"&�`:E7�Y�-&�siRNA��h"�e�"�Hj�m��? �OX�4se4 YR�.S�.&��.�mt�or>�՚�J �(( 80% knock��~"� � �h�ed2r��USesr' i..j�f�>�!��/v="���\1��e�&�P' n �t&�QA��*&i�4.�.��>�!��N\ _}�-�2�;!ey�W��5x1T.2�2�2* ( IF%��+�}�]n���6s�� /dR-zB Ha>Q{WT���� . Al"q;sg� �9 �/!���� x!PD6u,,65+�#��A&� * ɲ�����F �R"� �� J 9� ����?Dex-48yA  )r�l:�#�"�F�X�Xai�� ���5� *��*\jA/��o-:�I!&�ftoi u�_� .��)1�.���ձG�TO&QZfts.W &� �5jT��"�  �""L!E)�$��U���MF���lw�4By���b�1e�$x+��We6�MA"y�!S�+��@2�s��&a�A.���( YFP/�) 0� �(��t;L��M1�2)�J�:n��.:�2A;0S 5W*3[3��40%T!,e�"i�Wa�K�Ei�  �%��+7�� A "� ng �n �;ak.y!, �%A�d�&i�x��KFV�02�M�s.�1�=�B� �a�q c�C�d:V�~� s2\)�eDm+!ٱ/�K3]f gf�i����se723.u%� j3!����(:# ex,1�l 2!�%)����a� �Md$!p!�Q�M�92� ���v���"� :� .�H � uJ + Bmb�3 95±u�3%1f1�.�ŋle�c!�� 70±�022G�B��xL�f;.�:, �*-N,�+%�B+�l 0>$$� E!Jj!�*  on>v( 5>�z�=��)�j� �2�bQ:5`S5�; 40±72� �B=; 44±6B,) ���) aя� s.5aTN��E��,"3���,�Qn %�.T >j o��A-[i�"'• CAV2)�g7,!�){6 �me �<pic� <� �T�]6ACqu�-a2.q(:��ETu��\ }M��]��2E ,  To ]dh �% IV��"�4v(1� {)O. 6s(! 6�)� du�|69s�&�Q�Xo�/ N�?( E0.Fn�D�d���p�& aU -YFPAaI�)$E��k< &�3�!7J� hor٧diq�e[?d��(� �!7:�to \puZv.$-!�#x-;"I�1a*|�R1�ng�>a ՆAsճ e*�+!�!$!:%-8)h-\ x(o:=�%;0: 54±4%m;>: 55±8.m�x ± S%�aPG���^��0�-%G�'& � ^(m6�6��(2� �s"K�uat��z1I�)�) I_�$�/bl @=�n� /@F���� a-�Ayhq�J�@�pex�)����Y �.�%eS,�#9?�d9���);es%�J�bnB&�� &n �d �+ balav��2UJ-:na����ou-3 a��%� -�2�}.D�}>E�Kor )�-mCher�;��� |St�il@O �Bf���m� �(s�e�� �douAs�� %@2}2WR�u��/���_�+ X�HE$�gligi�=� ytos��1k��}�uB�coB��nd6�B�6�2( l/l��d"�N:@�B��e�+A6y&�� �@�9�ak#pixg���A��M-( P��O5oTrPM:��80u 02;}^: −� 007 05;26,, n = 40�� , p< 50+#9�Bk IC.�se�B�.�!y:�3Zeer�3sFAb� " .2 >� �co2_ur�mjE s:�T2G �d T��i6O���7Z6aA�fn#�0 ]�ɧBI� mad�A1&+��?�A�[���5m7ifo@*�,��`Din&1� �[�)�7 W+V�� �-��&(X��ؙ:�@�M�*i"��est ( RO66y�%Fi��ecjO1q�e�b,�'g|2�I�>v"1 $ %v�S3 o�!�m�2m�3 +- 58 ��m��X!=J|a�1�_ :13 :8NX039 �7"P D�15 ޙaGsee T#IS�&1.aF" �Y�"Q ��K-��ͯ!� y��F� �87�-l$presence o�mf Cavin-1 had been immobilized through the formation of caveolae . Taken together , these results suggest that;`r proteins , independent .^p, can inhibit CLIC endocytosi9,but in addit� , wh��we analy)r e effects=8ectopic express � each)� ur member2s� family ( Figure S6A ) on CD44 mAb internaliz)�L. In CAV1−/− MEF!f mode!L over-6�Q@and x3 caused a significant decrease% �6�whe#"!6-2W4y(ng cells no-,2�.T,was observed9 4! . E2Uboth w1w3M�EI2�]3(9<: 77 . 9±3 . 3%�; "3: 76"9."(mean ± SEM!�f9�2�A�Pcompared with control-(( 100±13%;1� 4B )A�h.�reaffirme�e nonci�rU�5,s a negativeY�A�V�. Fi-morat I3%�ew5� to have aEy-%z �-.>Zinb{0We next assesA�aiU�reducEEAd�� levelsAJ/�$pathway us4A�RNA diri�approa�Lin 3T3-L1 fibroblasta=asa� obtained %effici�x knock dow�� this%� type:�e�. R����-1� ( by �4ximately 80% )%V ,3j,5,re��I�~J�uptake�I� ison6�s!' -tre��i���4C , DU�S6I�J��E6lA�o>�Tfn-647� whilA�du)'A*-'$did not , ͗!� 3 migh�N(fluence CMEa40o characteriz��]� mechanism!zwhichEȑsZM,A�H�keuwi(in scaffold�domain�kSD�AV1 ,AaE8 !has��shAVto medi��several.����7L0[47] , [48] .aGtesA �� AV3 �4point substituE�mutants�AV1G83S;93G55SM�aY dele0 /$Δ80–100+s �@ia�Devious studies [43�6�X��, unlik)�WTq�a�Q���c> A6> U�5A–C )6I"��is requi��forq���LI�c%t��2whex5SD[su�B:]by"-ng3minimal!�1NR��fu]� i�GFP-�-SDAi,mino acid 82%�1 )R).9X�*�*ly�� 58±2-6 in�A{ng��we�>ACnaH a 5a:�� M)r�byy�-B5�s�� tactR}na�at2�alonee�=3�\ activity��AG2!. The fqU�JI�( �2S`-i��� lack!y�gena�a!�g����� 2SofI��"A������e �-je��on��5Xw�>�!G�6ae -xR nt>per!1�0is polypeptid� � �� may IF, fundamentalo raneW����2�i��8 llow!:seɑ. ]!�r ���f� �a�� �� wmicro��-assoc��d�Q Ɋ� block�!�tegrin-5un& of b��a [49�nW8"� dA#��similar \ 8s could underli�~i�Oof]V%^-�o),A�" 2first&$ , � FRAP�  degreo .1,a lipid raft.)gcargo19 , GPI-YFV-�w �ab � �|.�]24 w!�trans� ly � !?A�jor co-+N^-mCherrya� /B"U,� mall ROI�|bl5ed m�DPM , half-life timfluoresc�recovery �rdC��c ) A�dif�Aco"� � r�lced!0F� WT� orFG��c!c �*Ti� ��"S -�. 1V�R��Y,WT: 0 . 48±03�1�+� "50 "22">67 3;2�, n>20�` , p<c�V"k� 2).�a�l�anchoy�5R�co.Q1!1�h����  . As!�� I$fai� "�>�b(Zo�71g6 ):2� ��loc2��]�ef� ^|.� to� tric�e2[� ~z�|e4shortBc4( around 8 . 5� onds� �M�aboa��mo t� �Q�q� ggre due� a de�MLr��of%�> as ex"YA�cioccur!\longer�/TlesI�� -$!/�q%���.�&��-spec$:�#w2 � y�a�tyY madeC �anA�=4construct gene�d� ��(ng a photo-w,vatable vari�of �cn�"W�r$ ( mRFP-PA3 )!��.- , terPA �F��,=C>� rout�!:?�.� 2���t�1jregf LM� R.COS-7��-ed.A�wed2� co2�e�Dex�-labe�(M\ic vesicAGM�>� ��is�Q Avia�AN"8�@0S7 , Movie S2)oor]9Y,�N@d �R�Ea*decay!D2=�:i)Qmeasu��N�Ea(2CF�re!��lI4 A�����Eoy A���?2� d U&�B���onAN� ;� A���>�� $riB $� �A� �6� |h�x�?� beJ> ts imp� (on physical�per� � e�w< �N� tim�m$�nfluid�e� hemaorm�s w �ny ��>��*� �a�A�6 � two2+^)R� , [50� A�� �u����C>�eY�(05% Tween20 15DA�37°Cft�J��� incub�R anti��s!���2>[Se�l��0high temperat��j l��em$ �te� sz 2g�41)I�ng�JU��:�iV""� �$"uj��,�c un%�ed�ĵ6�T "h��l%R�5Wuor2�~ �come}�*i�aA�%3�� theiAр�a�!�F,_F�d ^� x� !� |-��:uCY�ei1dE�q7prior�-�2��ic mark�atMRKdescrib� . B�nats:�Q=d�3al |,1w�!3iJyY")In�z tras ~I ��A�q�ʼn"bE卑 >�ge�*�ini[�!nm>`� dWe K*] Yq" &�J�� id ph�.��j�,EpDex-4881�( 5�)%per{�Q!. A ,>=!9=4byE�5�o��Iat�a��e�cue�M0<A�a �� a�M��a�$-/I�=�F)��5 a�.���modᢉI.�5�~�. Tѿ�a- Ma$.Tt7�E�at lea partially!2t�.!.@!%(&��v$>���r)i��~�AjQ�� �dic*M� PMAl$s cholestee�rucial��!-fun�c 2�[30Uw��*m 8y�)ceˉ�o�u_.~di�bs he�enH!tibio�W , fi�n� ��U���nd � �*�t!.z .v��,q�8Ma�a�"q @( 135 . 7±4 . 8%%��W132 1 �6��> �`�Ne�r>K �  . 6%>Y�G )!H&�I. �Uis��m�+.Ɉs�^6/avail*0K ���6g.^6� �ez� �^� aup-W�hA�aIFuisq:isP !�lexa��"mp!e 2� of f%.�m� bulk9:be�#2)"b% 2��Ra.&0–cyclodextrQ�,�U �AV1.�5�$( unpublis� data�1Un�7*� A�F] � dq>a.d &�F}Y�M2���Jp~b� &a�!�.LZ�surfacQQA�;seumsWlso;repora��po�� ���"!*�B.aa�d2X[51��[52MTh;.�) � o(�-� [s"6%�)�i� {.�2�by�� Y� .�W6� \�$+"&*2]N�j�"n&we�h$g"�&| �� 38±�4B�in���m%a*v�an�[!�0�%9&5BXU�7�&6�%sugge� at�.��l?B#�Cs�$! �)2 a�ang��B:.��8 �exI �possig��Wo suchI�a�in�2�4foc'�( dc42hose l.!e= PF}�*F"� ?d organ#)&�[5�"F���bl A��2 R�k q�R"� by W� n�t%�. N" )2yo�RY�� 7B ,�S8��a'.���& rrel)cbetEUu!� �9EJB }x.)%e8ed�~F6` subj�to Pear�&*�)GQ�&��k cJ���u-�sA�hi�!vea�6spa 2K,�&�)random^-valc ,9*%�� �1*a>�$,aho�-les �-atH�.G"�*�$e�21�a4�: −  �tU?I� PM D"�2;�*0, n = 40 &�6�7�%T��EI���2��g"_eH in #"=2,��,deed , live- imag��>� N��u�-"�rQ V � w"U !-accuSQ#PM ruff���S9��F8+J�dem�[mc6g� >�in.|2�Q �Jsiteseha��an":� m�/� one (�S9�)�7�B � �T I����!^o� ent� agg.RIB)()�/Rac-� Eng bin.I)(from N-WASP��E�h ( T-YPet )<s�4GTP-loadt �n��us�Icv,x"oc�iosens�or A- :J���"X&)`RI � &Z:"� ,pe��d1bU� . Qu�t�-lin�n� . "!Hns!��$��*x#u� ���!�!$5�J}:zx ol (R�, �}82��4;4��35 1>�Re!7�EsupT /E�e��Aave-ׁ�m�ct�">�E; be @e���a�o�W�Aj$e FRET pai/J-CyA�%gU%% 2�nU�a�@�I�: � $�-g% 7 �a�by FLIM-�^�f] Z6�m �&�r2�%-.�F� 6��/�a�6Uerg"�%r1�F ( �Qf2 nanos��!>��ws& � D64Q�.E;2M* #7��ref[N]0promo��E�i�!�%�� }def�0 �. All t�5�  0"|)� Hs sel�(v� kB�O* non-�)r���3 5��noNya�2u8 s up� h� s1 ��"Y&, nMK� ni&-�.�6&�r 7�+&�or"�a210� of u���1��How/A �2��)�A�"��N� ����)���7��T1�mi�>�7�We"con"4K+:��a��sa�l3�U���l3 f"+e��*@ C!�p1U!�6)by��!,molecule dynL0�!yngo4a ,)� stil� ���!?52�)x6G1J� lostI�9L>�/!� �P$ 7-KCYS1�0a�a4�� tau inapre,nO \ crui]�8V��Hf�-Q�. L: 1 k s�M0k!�>�>}�B��� q2�1R.���Q��s}:� e same� cy�"%$uUE�;)�!~A�u.ie��E2�!�X�� prov.e�3�  novel 3)�.�:��&��n� � agnitud�.%l"Sfe� ��,�so�1system��E�zx� .� "u-4�La]�of!b�+epa����25US1�1%!Q�$!�-�7 i;(nd M� aG<F :'@.E]� �Ite�>lW���5 � olog�#��eq�5�%=m�!� C.F| �a��.pl�/ �5�2*�6�in��"30. A scratch-w�)assayE�appli�oHo(/$t monolaye� J�1�3eI-�w9"� tA� ��!�(� w let��!�|� rea�A�mi6�U58��,%�.L p>�5s�5renric�E�is �0 [38}4}�me% ŋ det�. ���ԁ dramatA�;du� �A*�,��� �*�>�Jfew�*ri�!�e��in*bly�a�<�~ Q%+ . Concomia/$��F�E�!�>�2��bcheckAO�el) 2-" 0piv��o%�polar� A,I!~6�."�YF2�ts Q�m .�a !&�+[ bod�%.�=t� excluk�% posiD)m�d>e�f�M��*Kby J�,E��* �)!�� ���PMng,���e}& low-��non.��( 8'x : 1H 32;N/?_ !� &s: 26o 606c :�,� e��%9y�B5&� �%all-1�e-unh� �RC�$ugN�(qQJ�*�A.�E�N�)�A��Z%we*�#a&Z&�Rf� �se�&~Y#a��r�vJ��i*p]�ly�R���� M�PMA���.p,.^3 ]p1.*NJ0�0�L^L8L.�2�7!�C'� !-���� moni�0ru �"$H^Ѩ,�l�|Al.8 A!'.���fw�%6O/ly��er {qW6l��p�g6B&�-low*�Cng�&!�M 2��: 45±l9;w�Z�0R�y(�: 57±x"4^uz Rjr2��E :n�)��/erK F6�;1r�av�F�# l��� �6�nd help�H-@�%to%�lea|edgz:o� hypox�Fw�B"� !��A�l� �*��.��� A�LIC�D2�of 2D*� fi2�B keA�� ,@M6[2':�2w�%u&): ?F�!Y��`g o�+�%aRB *> ^= WT2 '" VCAse}K4.� y [55� f "�6(2�4!w>� ul�!H ��!,�  9(� $lof��12 h ,�884iT1%2r8 : 54�%m*TF:��G8SS�1� � 2%�덢y"�9:�V�a >�6�"V9�~�6� : 60)>!�Y>�N�CV3J� � $D*� � �q 2m nd� A=� "*aP��Q2AJ��.���R��UFs-i� to-�� 5]�u ?2,&8&�{ %8��ot6L�mP trai�(��"J"ƙX� �noy8-��5"!%9����rin@d �! prof��S�G"� tiss�in vivo�� �$skeleS!��*�muscl� �:e��b�86]' To��"z�B�a:>en�ed1ic&��k.�' � relev{to��vK* isol)m��adult�fiDL"5 flexRig um b�s/of WT%:(mic����I-�.��Hd%Q &f�.� �!t visu^!��by IF�0r �8HRP�:1"�/�.n EM&�@#*\ 5Xc57�e��'�"� �2V��#� �B acce%il� a�P��D�;nEM%�1>�a+2�#O�9RN�( 2�L�^9��.r?� � 36� *�� .X~Im:,6n�!�% ly2��,5-*IR"�advolum�HRP"�:�ure7�:�1.�W9B–� ��vVgF0 xd�/�0A��bxF�*�_�� ? isg/d�Dj �'i 2�L-� &."A�aU�8��*7A�@�1a�Bm��. I�n�tudB�*i�Qif�ext! ,ve crosstalkp t"uJM�&�$� m2 ��-:ic9$n mammalia^*. P���F��Ex9!M�at c�:�P" s CIE [23� [3� �"owF)���*NI/ >� 6� �a��M:�- �� a""�@5,:�q�Aa.[> u!�9.&�J�eG"�Tyr14y=sphory�'�:� � � � of(sma&2. 6�J)8J%c[J2an��expla� f�#sCsen���(?� �L�:] t#tyros�" resi AequivalHto �,-Dequ�36�SAas)%u.:�:"�no2�->>� ). Fint,��@�=�UJ�Ir�K1�ą�%�B\Embm!��G�ev&=Ejs%k�OAo����Irguagain�G^ �)-�a�9&�te�%�+�� �s h��dU �Dre�A�I�4{Oof.�� � ew2� �$"-=7]�mp!#u!e��9" pr>F>pl6� "� �� �3.:�N ! ��F� &�6*�<���YG�H&iRJ!��&�H�*>�<" f ��� <"NH?!�| � fRjra�����b�E=!.�M�y�%\�aOf le-p�PmuNA8�?,�{�� _�-��F`QIAQ"]1o�5x -Q,eJnVK�� CTxBa� welli`d"#_9|Kl enga�(!l�K�P4ŦIKMA� $�9��toE���$at perturb5�U6]�J��Kh�X1;AY� &�WNL6��)�F�L��-KVH exera���/ � A�.^� &  q�ly2 d*�AI�)B%Ai�Venhan9�o� PM�D. U�L�on�Z� wu<�J&� ��"V1� B�5,�'V ��%�P*a%p�-��u5�ij*4t&H/6� ZCac?�Bp.�,ET��~ MRZ�G"q�onYsU1g�$!�b�scu� &.D�� anipA�.ofL5��y� �  [lab \�U> � ��D���DR�'ca�[rg&2��>( 3=�luG;!�G ht atidylser�! farnes� ed K-r��u&~d�6Jd�almito ;H;[5�UA#]%�, q.,. �W�p�XF��%1on ea3ca!A�|o2 a]!� .*6w N r�% out !��T=�a{.Z�2�Os�!sI�Q��|��= n�m20-`&�TJ.ѻ��IE�E�4�1u&� .P � E�~ b&�""��y 1 9�k�8�p�Rs!\^o��! �*�9 ell-penet�"���8�Ż*�>LS�I��^ � thel(>niYM-oxi% syntJA( eNOX�.��A=�~ –(�"% a'36�� = Rac1łi � *�-LIC20� ,�o�NG96UG&���s%�汯!J! :- jY*�XIy�"�C� N7*!J�3�M73��"C N�"hic.=�osh�be �[a��$ccoun)evaluaeOa"6�s)UUE])!��{ A�e� �� qI�n�)��7�W �sAb#":�5�6E & majo06O( Rlv# :�&c!� /�23m6�a�ts [61�$A� 2n2%�,H6�' �Eg, [62Iu3]%;A��� ( N��y;P)!�w+�"� �i�qON�9�(surpris�'u[�"�4a)21` )�a%��__�bmd V Ŋ�A% |W�Y�t VD.L ��he(�}AO"�+͜s�nEEt�$ !�*+ G" * md"9 {. �:' al�7m�subtlK?(;X low%\ �lim4-cere;� �E�C:UInstea�6 e]-ba=/:6��1='(2���'N*W6� �i�Aa�uc <"�. Our&!Q Q+z%��7:�prostrDc` �a at�E�2f-�Ed0Sr?^m��*� 2�&�$*Z��`4A~=N�r6�!��nT A!�rg�es�'Us8?."'.X� a�~ZN ROct���[>Ei"L y � byk.:!{���`�!�^'i-DA*!m1�m��N���n2�=. and/2? �E.� �AWi)��m�A$ L�n!u>wY%$a�e�c f3-worth90a> t�Vreal-�4sU%J�12O{ q@a*�%N�!�g%�GPI-APJ�?&"6A.�DV ( P' Q �P� 6:\bxi�*�|i2�!9��n ��>76 workZA +!%�15!�b9q*PS�)1� H]/iems/ u�?Fb�ngUC6�#/M�orsZAPM M��*��-i��7�E{*v#.�!tA6��7��-7f!Xsoq��)Y"%m–de (EA�s82Rbe� !�@�2�!v�j &Dk�"�II E� tD}o�n i 4��[3�@��app\?!��8"�*aV�O�F��u&�&�3!K�Wusefu�6o&�4h:�e^&� /W��wild-tQg 3� ,apilRsEE]3a�Binc�R�Afer2_�'�!yc� e. �EOL!�a*�%X}8�V)L6Y2=ai "R 3>�s82orp�=��Pa�Z�. �� E�% r jtFY�*")A� � ����r. A��t�� ��iA* 3of� ��r >�Q�we��J(S &"prenAna��h!�>J�XedI�y-:�1f  �*�.��5 �3 �3< �T� E�u-}�B  h� J9� M%d%leHjn"$i Z �n�� ���arclathA�C.z�2�icR�7)��loiE�,multi-parame��,&� r $dX�.al� h ng�z *�1V&8:�!B9?a� [6F2T�:@se�+sI*%�*[:r3p�b��:~. C&V_� U�" ����g"�\ %!$d.N, tQ N� � �as�ź:�9 b�$!~� s� ae does7 .�xU�� ՎDh��O A]%�q8� �8 �p I:fW�s migh�De���!s�^�4�-�net�?A�+C#p+b("8�igH"con� WCd .�4!� �,��,:�4I*%U,}Y. 6�� "�#''�:k5�_�_!0����ab"`� A��%� E/&O A��%���fB�9J�(�.dif"8-'� )Q3an� �m-evo:IO���.�;%�i�"0"�.G��5ut� �2$-]<4s�>�&�U�2t_ l;J:�.�a�nversO ,:E �LO� ��@�lU�-�� ndQ�5�VQ3t\��"$(��^�]�#���w �t!�xi 2a Zlyf*�!rec�e�r&� �>%䅞5}7 ,“dampen”1fi*�(z��tl��ZstrengxCB/�m"nt"�&�(J"�$ �"Pc���"�nA���-1WT&*m*�&�� a re�.$d%%�\e!�5KIA Mk.&�=9�"�* }�\ �U�#(U"+'Jra]R*3"�j�by��# .�E%clF:%�AX{.�;6  �i�r  �̵�mp��z� a8�4em�]t�#j�*�PtX� �in��*k\�*S a.e eC(i+:sef��Ŕ�+)A�- ���.�t� ��aO� o�j�x!!M"�,��u�>_ ��em�Ziz#6�N �ru���2�l!jM)�f�:�' AllOavp&�[ &u-y�ccord ��guide��%�ethicmmitte 1�Uni��mQQueensl!. MousO |`( c0 5035-4a�1!\Novus B"��Erabpz�,�" ( BD&s�uceJ&�28in2 ( Sigma Ald�<$r2P�8� 4i;�"rai� . �ly [16 FT3)T{$Tech group�m= ��HAR�.J,( B�zn Ddhson>rE_( Roche>.� re�@!v% ( Zy�\fsAlexa �>AAju}{d iVa�gL�l�n@-�L-5*d  �.R'boG ( Invitr�nz.��4ph�Wid�u:gFiSIIIRyDynas� N`7-Keto.7N&E�^I�  Cock Set {,Merck Millipp!~PhosSTOP phatZF.�D�E-4a��hSte RNAi"x du��(oligonucleo�qs targe�HM()�I�`1 ( 5′CCGCUGUCUACAAGGUG CUUU3′;"ACGGCAGUAGACA"lv"6a?2(CCGGAGCUCUG< CCAUCAGAA2;#U UGGGU0CGU:'p, Yrt�0E�#nul�L �!o�e�") ��yonicn"pz(�6G�z�*�i�d mainn� Dubelcco'��d� d EagleHedium ( DMEM; Gibcopupple;��10% f3bov�"se52 ( FB xambrix-r02 mM L-Glutam,at\f�5% COb0�imi9 ,���Ie@H�Jro�( BIORA�/or Lipo�\af 2000>��?VDpe�% manufac"0r'�10)PBip\thod 3�x40%6�efdKc�C chie� .�siJ|:�-�% 3&/AB&%�B�fi,�(�% 600 pM'J.�dgr9zonm8mm co�elip-xpla' on 50 µl��-wa�l drop�E]K 1# g/ml�e�3�oy/3 mDc/:-GF Wt��y+ 7 dilu�Pul!�j%;&Y2U[oQ\ �Q�  a�rTpm_�3bo�o�  D(& ,+y�(,Au�a�2×30-N;ypp!A{&�c�vU5 M glyca ( pHm3Nb�)fix� 44%�ba�aldehy�v#*`(6r8a�ss�Fnd��un� �m��1r�!"d�/ viou�&$�a�.�"�(2�labn��pi0!EJE ,� �:� darkm1sVYfix.�TCAEHfF*3×5-M washa 30��1q��6Perme���a M�Mwk3%6� albu_ ( BSG%["�g�rimaryu8Cn� at 4Qjf0M�.�co"�IP2H fa�=40�Mat room,e>kK.4.�ME��5� (}�J�f3ls�k�qNbrief%kE��-�F��}1%%* , di��obenz" K9DABO610�()�� 6<x�W%��*3 Y�inU�qD,�Je�8 ��y��`y�aW�asc !+!]|�� 5% g��ru�ine�$1 M cacody�9 bubi�6�4$ *bjpost-]1% osm� tetrO'!z1 hR�A~X*j#��%�ethanol���H�dd�*!(o� LX-112z n∶Eto�^% -Gc{m5�d6�60A� . Ulv�A( 60 nmX��mlcu}(a Leica UC6�rotDl�MEdA$a JEOL1011�K�6cop280 kV �C2H jN�: }p�pt��of�!y]�16Eos!�er*��R.a6�J ��Xnu��Tls�"�$��ya A��+n7D aver 0a�sJd�� #zk���e�I%���t�pea���F&�.�a]�Q� NX) n 35oglass�tom���,( Mat-Tek Co؉��) !2�X,graph-�cap3^�F field2�.! �-a��f laser-s�%afIXH( Zeiss 710 META; 5 Carl Inc .e�Ima�/E�e�a 63×_ ,n ApochromathV$4 NA Oil o�^_"y, Jen�RGer�(v��a Ulnm � S�/exc�Fs$a 505–53e�b!Up!��fil!bG�%O�(.�m2�v+561v��sa 5�62�� RFP/Hm/.�555B�� 633v� '50 �xV�p5=.���2 � ٟco-�AL��}~qj2@a�U-)�a�!r��2�>���:�Ze 72=]Z2\d� &@ al zn �E . Op�$I�5?IXm�1wT�prZA �ach)o�:8#.GproH?� Adobe�,toshop CS3 ( , San J�E"VBC*�<�%� t�!es�"�w)��J ( N� al�)�:f H�, B[8sda�M�. Wz-& aDr�7I]�es�!��]�!��%�in&��*��%��A!��(d �&�L�t&�I'�,�%� mask�. es 0%�wE�� ?�o�. pixj�beafa�B �(PJ�9teEq(f�e�"s.~<q cyto5^)�` ply_( r{ )e>�)�aPraw ���%m�!)M�� �Wc�xe54&�+vIxJ��74|kV]bet�X;vm)�of�7��,]% �1�=exi[�1�"�6� s�%suJl plp>�4H� e�A�vre �.wnjann!� N���%\YWY�.3O�!�U>��~��CARAre+an" ~�}� "�q4�� thRm.�& EEo aE*��;:c�A��seev r ��"?5G<��b[65�0�� ^�;���T^9:K�*����-*�&�,:��4�:w-�=sol"=�15 µm/i�Y$circu�i�a��m���,�C78 radiu�a�bՄ to ∼70% �A�a{n. !G405:9i 0�mi�$. Time-lap�S� � � �R�/!c( �2d�_:N�ac��( g{ra��,2�Xc^( 300 %90�o9�2) ��%�a!�terval�∼25lli;s� QF3� / at 2�1���a/E�q�50�M . H2d�>��V>j )"�id&�p�Clyr; 36];&see T�-S1e�d�-ax�yk%x����(a��wi��41-a�g'�o��%hg &"G.fe.�5�2��#>���u��>f���)in HeLa �[6ʏ6|-,r��9}nJ� ���v� curv���PFqa|=ObyAN�!:B�atE��ma�;$( 9t , 1�G4  1�n6a��}6LP a��(c�}!2�s)�X eh. Linw r�i��*�neA9.�!Ysi�F7I�r�?d��slg.�inU�b5�'l(%fi�e��&�%PL�C Ti:sapphH two--��( 160|D1800 mW Chameleon _� oa nt S��'c uyat 77� ��[6^@�F�n&A5�?P)B6�e3�(\� �e;!45�:&��R--PAE�.- � M-+e� ��!t�O�98Ae�Pby?7 ngle#7� infr�Y�ir��� ��:{EZN6%�[�edCi`.M�����9yJ��� a 60��atF��2j ��"� &�2� � �2>M r21��� .��*or�Ie�=H �A#�_ɩa� 2H" . D����%Af("�2a dou�{ex�#�<��1) global�T��A�2� 3A}"˗nu��82��@BJi�pFR�i�l-Ni)E� ��2iFLAG-�_��)su<)�i&� y6�.t�3*��staS��3 h�-�$��*�e�6M�� /"( . �Fn!ib�!s��� c%�46R�A;des�7amo�<� im<��z�3 I7-kBN!7�e)[0K�,2�yA�F���� lysaE�2�SDS-PAGEE��(toN�sM ane2pro/��Bg�j1&�,aB!�^D�ve:�6�>��j "zO*�an���&�cdyk OdysseyD5n����(,�!�Licor\��� ��*Aq� � ( ZBiotech�$y��(he SuperSig���u Pic8 emil0���sYPierc2%�c���fil�!KodakRDe�]ol10  <s0��yI-�:S� J�b�L2)Ssoftw�),lsoj� M2+E�"�@BV;T�T���V 7[�Ym�"vq �E*�S�RP�,��RC .�Ba�4el-co7 �+d�|mxM�5d2mg� )ay&#5�`/� �Nt%p�in>>�Jv�T�!��hetr]8�[ro_) �K+vRSe�#s vv"�sa d [�m�� C(L�,�azf  �K>Baa4+eriph� � TV �,-�e�P-���� "� *� d'�.'. S!!�a�" alys1�R�*I}M?oft Exce.d PrisaGdPaE!(. Error bar!Bɛtqa� dard e%-�m�[(�r&dev"` 蝁�o%$��"p|�� lege-6�&�1�V=��r #( ed S�jnt's t-(O� y on�#y ANOVAJ�A�f:� �Two-ceT�Csj6sA  ubiquit�S��t ri� Archae�#pla�CN �i�,� dw�ien�$Xk�ng�Xenviron�&al"L� �Aai* ��4 ?s�typ �d-lo�@ qory hAkd�#kin7) /�ImSg Recei4 ( RE�b i�A�¤asp�a�!As�+�@du�AxB?kn�%n someW U)Z�!�&LJ,A�0ins un�/zo how'~�9d��.2`����4t���5�%��G!�T theyj.�KA8*�?�̥�. HXw�VAL���fde_Led2���6.��U9 rena�,>%he"ar!�-L�G=�ALR )5b�7���)�ALR)|gEmy�m!��r V7.Zor x�ta�$toTD�[(y-r4KpumA��i�T�:in� atic�7��le� ato��:Y comb��Wal�&�;d- �����!archetq= RitR��Str�nc�5s pneumea�9� !�%is�4=2hat�orguM� %�~ck�1`#E�1y:���M]a�A���0 mmodaR inpu��s �J *an!�2+�fw;l�,l��$!ecan�+��#.h="4�)�;ri�3te�vi�A�u� I=2 a�v�+�2!AA�p�*ighcato sh�x�"[{Hbd%�n63.�Y遁0�0 )�smd3%���@v>�4�4�)Z �kA�erish&|�, +.o�~so-fed One-C�4R ��4.��=te�b�UFh[����NM ( TCqCU�<�Z��A@!e adapP�&o)�han))x�r22[jKA!�eJmk��is�B&_Y-y*VK�H�n!� w�R��aut"�Yes�AT$_I�!-do!wA� ��5tl&y��Pea|.�.G�E. cogn`�3A��3 qC�cn�yeNyt}  .3��dop�($e flavodox�oldA; �a�2 α/��/5 ��i@p" ��e�H l 5-�$ll�β-sheeI ?.se:�z�"�T�K��$an ‘acid#>iad’���G�0[%E�2!�.>�enda�0β3r!�*�� kE) 0,β1-α1 loop!�i�pnt�lys� ( Ly_�N�5.�A�: a( u�aly Mg2+e��coordiAx�B hydrg3b� [4�Cry?^�$�"Aы!i�`9D%lin-�(<�)Qrc)� D BA��Js��*�La�m* � �C)�A9(aro.aquilibr�),shift [5 , 6�M reor��w��Bonine/�)n�Thr/Ser �&�\$/phenylala.�� yr/PU5p ~towg A%:�.R[7–1�NO]*Yby Zhu 4�*[12h6 ��(“Y/T-coup�y�;�[e�4Y�q�g��qua��ry=�,U-.�Cα4-α5H�\!��2�,��l;;p prec�N alig� A�:Eyphobic�@ Ų. @�ly "P?MAhogmer [13�!#ը�:�Cs�Ha6'x<veJ�I<�I=�αa�5��� �)�d"R[1AR8. �y� evw�HC-g�in E�V or D@�Ew$[1!��aGtk  DNA-�I���i j?�=�\ c%-z;"1��ou� �uw [�@m4n�:��"gO�r�4 im&U4by�9WY tact��{A �to en� �D�=am}� �%/�W*a �v hora�&  ��cI�2�+Es!/� V HFemergM2�^W4ly p>? mor���1\5io�"C�6�>Mz&x �ve��n!�<of �.�˓�m` d�;minvolv� �ǡ�m�cataly po� fq se�� �i9��s%Ds��Z� �y� AFa�'Q�&�6~E<��t � s [2+� �es�m ly Ser-Thŝ& ޑ�btl eukary\�-HO:�o��Y� PP2C��49�#ir� �MK� enveG-�uY� ]vi%Y�y=ny� e�1 , 2��A%�-�!�e�1�2�yIeM�f��՞A�.Lei.N�ZdoA`J�b�MZW h".c!{�W�&s.@to�f�fe^9�f*V)3*� H\�&� yR��[2��2�� AmiR x PseudomonAo eruginosa�^ RedZ (�my�Xcoeli:PrQ�HP1043 +H �$ pylori [2�pChx x Chlamydia�.ch).iAP!2�� FrzS QMyxwxan%=[28�� KiaA $Synech'�)atuRYa7s�#��J���5N�o�(ia�r}J�K&�A�&�.'��a�e&��� Vb.OdbecomA�&�2-iplyn��kpto& ��+f�in##, i�Sy bV"q�Ad"�?Wi�+DN�,%P5ly�x�'�|"s�a�* F0To yXin����se7saV�Ng�Ya cusg1pr51m��"%�dJE.���!t*W!Idi"%.�B:. SlX�H�oV)��4��Xd ~4% (�1.~2�&l5>��)A�A�.& . Gi�fG"&*����y��m�� "�� ���A�2l �"D !�Vs�jteg�of�EDs���+of� ��� ng"z , X�őED�!end|2c!Q!+X�set|�,]� olid)!iQm��.$ �+�ed!s�& ma�nC���,@"u ,�X2<���e enzy�� ik�ructua�,bi.�a����.�6�s Jf7'�^ s�!Ahuman�n��F�"K~E��}�Q�Wm2.1l�ole�!��.� *�A{&�. A J�be�: e�z�"�m ‘H�, Gate� b�aADi�of� I T �&� � �5 AD"�Ch0!UR-�DinmU  ylN6up�1l�� d))'�!.W�ype[�V�0daF%�m�Qe)B�J�rQmy�. he P�!�al Irn'��Piu��-�er L�to-=��+��r!$ol&Q�['T)��� �gi�)��&��Qm�WF}Q|:x�r"� s . ?�T�"�JAv��!�`�]� .Y�n�c�hA��y� ^�V&� S� 33 )n�P / Pfam�́��f i�l f�3c2����áof w484q� �ot�� d�>�#e�o dundtL�!re@d 7+ 816 uniqu�2�G��F U.J), P976�)�X1yor����J�9�!.�j&D�� L��4%j9����2�UesA��oo�-�9���?*X6�w� ��u1�REC�W9YA$6��4ora=�b�llE1-�aZI�H�?A�F,�;s�ax� S5 T�.B�mrc"e� G�n�4E�+von\Phyla a:NL �3ED �l�_�t S6�Ex �of���|R_H<l !TY$���R� _t�!��c�IvK 4&�9�Aa1�(Q-H�]!�=� �c3 � Fs��il�"�Mh�/�`� X� �� "� newd�or� G��.�L&�W](�e�86��uQ$F@�f o��5l�8a Glu 2.�Fig 1��)��atY�,N� �%MS�E!�Ue1����n-���ate2p��I?[3�\&go2!�toj։foM �6*��t��� "%r �6�Dmus�O6� &�o���z F.���9( !!g�bheY [3�PhoB [35�Spo0A [3�{1Z� aOVp�u$"�b. �1�Ep�B=O!Ag)� ��O*� u �()!Acl"�/3!Y��V<E�Ca�!I�2i�ii�����#�qv+M:�E{ɡo��E ŘF  abroc#� ob� 2W.�5�[37-a=/ a�x�stuo:�B�I�iAA�As0166�� ( 15 GO�11���( 9)zi��w5�6� M ch&�^d%�Q�p�">�!A�x&�v�@�su<S2a; S3��Y��#�23�A�.�:�r:�r mj��� � �"�`� f &��"� �c.�%��S� gen-�Y6� 21½ �Pr6�%ani:23>1e Z?=o�!JAp݋"_&�ltwҀp�S�t�idispl[J � t  ��=t;�n).�T�sU I4( ��e�!/*�t3�$�A��fe��r�`'�)�s� D.���b��\�% �a.-.�j6G&��O��2C.5��x60�5�D %� ��*g�bas�5� �r._�%i�  ����ie�A�In]�-����"5� ( Va2(Il�Leu�nd Met).A��^>DD�^'9�� ��On��"�i%� Yt6�f�.a2|��s�LPtns�rch�~I�disrup�U�_���^E�a�EJ0� 7S��&�a�C� ��x�tak��g�} (*�$�$ ʡ�.��4j��"} n%-�$ ( ref . [$!�S2a%fa7A�R*^ko��i�aE�~N&� N� ie2�\,A�sd".1-1f"k��,*� Glu9esQ�",� �( 6� % 'ڒe���6���2z� Lys1�e!�o�-&1rin 29"� &�*T >P���ĉ��%w�#m%(Q-61in�Q��4e�|:A�`A��dse��kAK �e�ɡ��66 mcB�%��2�a��1.A�"1��-N2D{����."-�F� mr"�щ�=z����-kE�t��Iu�a�g��!�"� ��gΘc�"k/.g%�� �-!�re�F��of6�-&w . Bro&�* %,*W�n���%c�2wo�mG�(Fis ,uA,T� , S33"} c.�k)�T �u!of�s �& ( Y/��!�'( S/T�Q`!�1~)�"Je|E{��!66%Q6>Q��<,!9��g ��W!(s�L"|AE�%�a���-u��� �sže4w%4�@5e�!��:� o>�"9 e �'y �s-i��or� �u�>u� V���_I��y�af��.�a�M�@ �u'�S t)ԣ nric�0!/�|77F�x�y%^p(%�) ]n2�R�j��KDof6(A�.�ɨ�!df�;1�)_aW%r.����}!� a �er-cy)t n@ %�n�Apo"�~( � �s]���d =�sAC��C�1�se }e�%* q1��e�"åE�su�r�0%�)� �k�v8� (U�) keepjX g�O> . ImM�E��j�f�2;���A! "@!k �!j�C-O)�!D� e1zc3��t�q�zA#�*�&� 8v8"�%s�& � (a�s d5��/" d���t5 s?��l <� M���"s!(�)[EY/A�rA/)!��\a�par +&��9"�'c�/��</T�52�>Y�""e��1QH.A �Ŧ`6����U�a�iJa2� .��9& �a .16(� m�At�w@}�-~���AաZ1]�eg�"M ~tee9��. &. � , ��)��n=�F �= �Pf� E � � sp�as2� Ser/�(�"as���>�}"�N�:m �*!:. :ÿa�}se�n�5alŸ@Jj��o]� A�"\.OS �) , exac.�9"�9w�>q4be.�Z �d�N,��al� ��=Ċ��we!�ica��I)M/.�EՅ��cap�!�9��PTM�U6a~��#�2A�.i� .+ !�� �!�]�*Rp�,b&�!�a~b_$knowle����n'��am�� B/&�b�?�alread�'e}i nvin��lyMy����� ��U[40Ja ��-�2|,yz� � �<�!`Gn !e��):eg# deamR%��6 � deEI�>~en*�Q�a*�  harbo4 �n% B$  k go rwr�W back��Q[472How�".)cm��!'-�e4F)reEc1�8Z&�Qi"׽��0.s*���o��� �$�G��w&L n�-11!� thir��jm_ � a�i]�si*$s�O �:p��h�_�i>A٥j P9�Հt1 }� e 12�(556"� � tll.��*P�W k"���7ͅ�n!�hol�� A�� ��"��byA�a9h?/[42H�[��/.6{�63��I*E�rg1t���A�U�AQ* ��6�!�y�Z�lro�/e*�rgi_5���!��!�/ ��/[4�#45�I' ��C-nthfcMr ZIh�\Cy�M�.k:6�.:u "k-yxY2te [46�26:I=�E�a�2(-Eu)�H"� by g�v�'"�5I�2� !b1 p#etD9ee.b�R�v� ��"�tA���066$0E1, ����!uO�ect oxyg�q�� br�(wth*� Neptunii�/caesa�7�?, Bifid�/$8gallicusGe p3tena�.1g EDo&�V�X)o"�,�5#([a DsbA��bA�$marine aer:[N .6�-�!v�P�)$Z"� 1!ulf16+o�,l�5 TC.o��F�&, ���bexc�d t�; �&3 fact���Z���8� B�.U-�encod�kyE��x~dja�7an ���on� A��cth�5 S"s$q!E��6%NADPH ��<,�,�DsbX�rK:k�7:�%� ( S7"� Two ��&�ge.@���� �sB�I�ia Sacm ophagu�Rgradan)wB�, enot,om�2mal_> ilia��.G)Dمco�_-/heme u8+?2�A&>@ &>4���4�La� �  &j�c�X=�cM�Rx.��! �2D8li��t= i!{� A�ve� #*�at-�}E59�ED&2k ���)4�*�8�a�U�5�ys&��a�i���b ���p\up'� ��.��#LR-@-}$m� be! �a��-�  � �\n�.��is� (a -�5�m�.$-�[�5�"� [�!��F�xciŌ�ink@��sbp�|'�i�&�'� by-�E�&��=, ,  , �B�r=��fn�$ wly-�B� �"� &C �A>9i aD�e��&��cE�M}R%�Z}F��a�ai%Pver��^� s 6��C�$2 9 span�[� �)�j;ֻ!�dep�*in�1b��T#ls�p9�s1ca���T&�#v��Dl34Gen�$( C��CKgo��%G�a�jpan�3bio&_GI ��.!�CoZa��3� )# �S1�%� /���{ a�'!<� A�� ��&�,& , O��wz$�*�#�%m� >CGx �- es 2!.* ' ka�%EaT��.��m��-�>:v .Q ��;o5�@45� �lG!��/I�� !�MoK � aoermotog��$Dictyoglom=LElu�7crF%_9rg!�E'1�2H��V"�$�[�{r8c��G2<5�at�:,$j���Jm� K�p��2�L1F{FZ2���@ dri��zz=gR<�*�news=%�aT]F�, highIQFN`G� arse� utb�AECh�Ci� � 7i�a�6hT!��un�Z�wd��oil-d�ZAc&j !5?bu�mP�:�;tacn��te��i�N�*sprirI(D� u��Verruo:MJ( C�;eE<Ph�f ynth� 5���#2-Eb� �lt g�6K Cyan, i�Chloro��iAen,;� u& � �nd�sA�I&�#�bans�:�Gx|�� �% '�Zofo�Ev`CG>T i�+δ-:`��(is5��o�3�fre�mk��$1.#zglic Pe�CamW=)�`iyA�ly9�E�'?ax]So�|s!�a�hx�e.!5)��RG�2C�M%�=)m;7��\3Aw �.a�&-�P_cA!�K �a�Z��Met�o�i�/� ;�a�i��F�6b<2�Eu"&�E�U��L6!, � in y0�, fungi�h1 %��ozoa��}E>A��w��al���F�4�y�abuy5%�e Eur���?�m%>!u � ( 58)�� !$�]��? phyt�GE�Bs vash r 4!O8M�fi~�Y!}ly-:Z Liliopsida�o}c�)�l��Ay�_7Mua�A &TPh�AQ��U'AT��&� !"ic�iArachn�a6RECvy-!8�eZ inRfb�NtaxaE Anth%�(�� ea u�(y'17>b` Plac 64> ,_ �%�bas�+orm%�.�sJ=�A� as 7 a�X!ys�.�M��&^*� � in�r2��QT�R"J arte����O�A�GF �-s�symbio�T�I�� �6�e� ��CS( �K gdom"�!)��� v:arr%A U�X ligh� em��d�ED�!:WA*�:c�i�- ��f�A(�/~9��llP-1�s"� �(2�")v�gys-"��r0w�P �֡!� &� ."\� 7�mS2� �#=t�Cajo�$ ( 532�$.BY Aue�0‘P0d�3ec=A�q�Tz�z.�IJ��=�9�$4 s&�/i5 OmpR/PhoBA9�< cripEA�as�a�]�F� LuxR/GerE�.p e�.�RV]ir�/iag���A�w!�%��=ly �O)�N8QN:(�C� b; �>���d�EO�RhAJ��+um� �.�� �'cbB�B GlnL#�-�H��x-turn-  motif��yb5�L� 8�!3DBD!pre A??� wK DNA [155b%�3c%A��R�A&��typu� atomAYq�����two o�MGexhibiZ simiO 1La�$bend: PhoP�}Myc�4ium tuberculos��52��� 3r0j=nd DrrD >XThermotoga maritima [537 1KGS�S �t ��i�a.�&P + 9�“Q�ite”!:%�hT rs"� diverg��subz ion!7�Wv��class%REC��� ,Figs 1a , S1%�S2��� ofm�g� �W-Q�elect��density��analy!I(W 4iFir� AG� orylai���rAEin �is�� asparagin Asn53�i��?A,s a bona fid��. A"� 9i� ( approximatA�� same�asE�� �K Asp-*� coua����Fconfor3 on diffI by a rou�90° ro�!f7χ!�gle whF it now  gen�dsAM0acidic triad-� Glu9� s ms-ĩ��y}^ɱs& aAe Mg2+ �require`�-�8-transfer . Whe� mpa)e�e�A޹n���bK��5�a]conser<��M���LyA�E�coordin� Lys10Aalmost�out�km�1M�s!mc��eto�� sumaS0help stabiliz�I=‘ �’�,m�residu/at�� lace)V1Vin many)7sSasi,� aHX !�]i�E�d�� �v!t �(�)9)5v,A)�mplv R� by!C10��s��z4��v~ is n�lW�nt {o��N� , loc� betw� Akβ1!�lα1a� ix ( Lβ1�CrucA�i���,aIFi�q��lO.�q�:5��.� hypa$��ia�at-�!Vng�ra �ve� rge might�At� �%�Ad 58/9�.!����  ef�ap{A~U�H al��gr�J Q� REC/� @ .s%�w:�a@.ca�:rdra��c%�alt��� �9��}re5�loop re&�N�E�R clef���<9? rece!z))�|,% laps;n�terrupA !� Eusu�bE�.�1K?a�tinuous�eneg� urfA  � 4de� What��rea�t�5edMHTco.��al�Q0RrA��o�5r�_a(at least onUtP ��"*_q�1. -���2i$-Pro motif�(ch togeA�a�pa2��4three-dimensio� �)��sb"K�bound=�� �m�� A.6M����� e�!...$&ch�, osph�U��.=-m �be tailoW to �vidual!� meXismA|inguish!�fea.q�R��=/��e" &ais brokeeȍ� s 88–90�-o�smx%�i�?4a�Fɶ3a–"� careful�A� !h�s&� 2����s 5�j��gB�a�a�J�� extI* .*=fewc 5 �asDfus�E�ed!�R!A8�aOmeasu!�a� .�� axes��. !g6l 10 . Situ��ozr<e� phob&�a� Leu8� Leu9xAS Val9 �pack ag�p e f�(β-sheet3 0van der Waalsa�tac� �Val54�a3α^, Ile79A�4�qAla97$�4β5Tyr10" �28$ orm �se nw 5g ‘H �Ga���‘Q�M~�M�( c�u obv-qIA7barrier�imped� reori�Q���i .� Y/T-coupla{xɂ�*[��resultE�4α4- β5- α5 ��r .E!,D�[1!�11�I!0"ed)�A��_ofo� I appe� espe � "<��atk,directly blo� �eren�ngl%X�� holEax 4���th� aI�� ( 2 . 7_)!��*yl�Glu87�� )B� .� ��%O�(>� triguis )�ed@war��B�Q nt—away)�!�5��� ��as� �4�|& , i�A221[�T��1�!�( expl,wh�b� ��� do��V ��Hol]!�s�env}�(� below�afou%C -fac�M6rot�!mE&eA�byI@m�A���yA�yFp[!r�" fil�by2�1or<`E�e���ed �� steadM[�valH%�i��iNa��(B8�IF#elf toAKs��7�Bminis�� V+�or in61>17Q6A!oɻ:�o u�]' ���6 is e:� tr�A�(‘un��ed��med( -.�ereby-E!�“in��9AHM-�“out>(. urvecO&!� �!�!��*� e:�1L��AD%�a��O�bOne*{#Zf�M6�2�!'!��.�_!:��m����c �.�v�(� 1QO0�|� 2PLN���!� ��X�some dem�"r�.�@LIin vivo�M�� driv. A�fluen�*�.:y"quilib����^!.�:�[3c�9$I6F ) [28]��&RM��2�%}tre� radic�)a_.�U�U"Z �&� UTy�nok l � �(M� ,E��$&%*IN%&�; [37�, rei�Y�zaJ a� وn�Qd����^doe�t alwayao�*a�:(quarternary)� [1ůI&e�%�re���%GKer�ld�eaguesdy�9CTyr/P!znd��/��pai�2�F� NtrC ope�""z��timescal)Y��> f l�T-��5=�!!oe$!�-��8[5�"�we did1� �!��\��wx"�  DNA- !qsT$"xpiupd ,�preci�o*��� still�\ba� term��dmi��s enig�c�to�F2�QU���� z�v%C&��8�A�. D� se1Ms��婑(� \+'"] �D���to -)�h put � � ��2d�$s ? [5] OrYthe� L!&.%��c rv� to ka�i{�VJul� down am�s�!h[}R}]haa��. %��of.zs!��&�.f�)�(�t� lig�or PTM d )6s ohan"B��K(sy�*� !�[2*#42<$� " by� moleculN a�20 550 �  �rc)�e� ."V����n��&2�ES6� "i(A���inducer1_�" , af{(ņ)L ,% &s#��s�!4 �:�layE{M�!"J may workA�1��U< . At�E�(�S:2unclea�D� �e��yE�a�u?AH!�far-cto��.$'a8�"�����ex�s*� ( ref .��hYM)i-��uniqu � �-1IR��Y/TIDr!y")Ցz &�M n op�una�r(p��)eU�a5LRi�A?Q;��attempCforce �1%ih#z٠�]a=$�Me%w%troA�d2�J"i�T .�9�%`Te 5a� cyan� :�L s ��!�AsN .<or��>!oU7>��, R21Phe962RgrGSPurif%%�muA%f wild�+��y S6 �/t�assesse"!ir olig�icMBvia S!�Exclue�ChrC)3%y,E;&z!�sty!���pre"k!�tAt �%]�E�! phor�/Mo�,ty Shift Ass� ( EMSAI�Fu$,m,,ga?��� �/�i8*�5�%��F�;hnsaeOa%q�&�&�0�d�$galactosidhre D�,i:�&7!w� H&� Piu!�mo�( P( )i~!-in��':! s��is�ic ��ntA$see Method�#��� ddl)iR; �8inEI5b–5azdi�� A�genK��R�}Nv*� sB�ha�� �Q[�(�`i�$NA �m�&�9�vitro���%.�1��Bse a�� ��%"�$.���,�,�&[25�(�� a RM �poe��.;�M�[9�,,"��*3!�est6,L"� ronA R�����>G�ror�81�`r�AlaA�"�!�!�1 !as litt ,s 0 . 22 μM5�ine��erIE��5�5d�es � n� %?b+!ωexOB�(full-lengthI� + FL )cunt+%��0f&remov�A�� :_+(��s��:�A9��3_,e}*non�(d�#��H"��-tu�0�b� tran a�$ -DBD� �64��uof�x�#��9Ba� m�� � nk � ,a split peak��fn", neil "�'per2ly �-4'!Mp��Awi��weOl�Dai]�� �A$� lyJ�ERbEK2e��IR �!� ^� 2w&AEa �,� ���&criE+1'.�,"���(��!�%� �-z�� �adsE��)!���ap�&Mb"nflictE�i�l߱+�. AQ�e�n)��}e.;a[!xA""� B<de&�&�4& !it^uikp!M���. Eu�/u� !%� .�"6s� !"�)ofZ�B��3�6�FL%. a�t�2A�*�/b ac!any�'1 HSQC�traB�F:��"�p� �1�� enhan� aggr�!�1n�4tereic< pert� ( S4e[ I� �4Q&u�5F�V,V� N� �� yiel.�-beN C4ҥ�I�nARA�!=,;#aQa Ei!�ean1�*WVm�% An��2)$of2�� al|(in � 6����suffic�!h-�d'e��"� �>�圁@ !�nt^ comb�Ea!k86!a�Ab� e*]�7 su in2�l�ic%p!A�FL �E�[ t�eZpr��of ��I�E��s-F2��- / �doul4n�s�66/ed2i!�mod' r��}M�5��mf� -�dC arked los^ pr� *8 �� vo ,U$%�� �displayVhu��%��18�noVC "� az�*ae5i�rM1W(3,ic�|ty(!� hz &�/� A2"�2U�a�ev�� A"2�,!�+4H'V�oul� a.�"�inB$e�F[8Id89 T a���1%).�դke6�sI� ,:�"��s2nofm/�!R.Uve;�6� A+icauC=�"�;Vand/orI(s%OmGI�&�)iA�� vo��se��.,��%�]�1ly�7� ��;fJ�% , 56� :յ.-�(b�p� to-n�m�,ed �=�)W��A�"� inQ#!cRin @uM2;I*X�: ��lab�i8EU%(7� s*D-�&lex*A3iso�,2dig[>i�PTM;{1 pivo� �4 hory��v���?.e�!}�7�[_7WrG a%l .t�8e1! Moreq+�Ge�f�i��so">9actA?/ti�A�F ��9! w2�E�2> H?�6y�0��!@ "x6 hown��A�yT � �$�#2�! ��y�2Fu�(�w�% ����M:%�,p1y-�2�R�v !�*�"7o"���"�M_��o�9ե%ZancP2� a�Aa� *q4&�#d��E� ��l6Oin)C͉%�e wan�to�< i%Q�!�$+ facili999�a�["�$�&5u�b�1�8rW ��iWk�D�( [� 38];"�"�< 3<nswf'a�qu"on!col� �e6�+NMR�X%[U-15N�?3C] ��'�� &m9l�#8 qual!�A"2�Dew�-pre��*�!`� � K7g�AtoM7�. Next�"�ps15N-labe�s��.�e9�xK72,���)A� �`Bo �5 A%��7�4J�';A5&#F!-NX&e�s 6,S8C.�4��� M��%[B�Exa� d`*�*!�� )�y 1�5P0lym[c�e�*� 5��nt�n�$a"I$ E.)� 6� ntA9t 9?&x A[��%�, ywoR4e9:Pa�>So*ofFQ)!�!�� �2vRM�poo!O#t�%�UtedI^.m��e�"d)Qz-KN"�Gun l�4�.���A<��!$%70e void volumeUa!0�>�2DI� {�ed���A�Mini�6Ni2+ affym�cae�AN�J?3�UuPE�iC!�0 !Ge% "�!m�aid"� !��"�&1-C  @�&A&be� E*D�(5 MA�t&%�4>iq ten� n%yF���H2���`.�mEgen"7�)f��w�.�byEI�A/a new seEai�x> a�nb, chem�#��inca�c�d'�"��-P>0I5y�..S4"�#Aid�.ieVK�v|>���A�Kela5lapE�bM�!!�MKnIL�wo�&A���% GDc �$&@&E1� r in1 ALR/a&2�I&�IaObackb�BGE*�dGln87��Gln94 be!�=�t 6^�L1)M�2F��i@:�' NH2 *t2>�Ex�misEP Q�Indee�+�>�W� ��&�rojecE��u�2!VL‘�(��icJ�,�� �,&!.on���)�E�N|xAg=)�c!�%UU!�&C/a�Emod�I,*A�Q��a�2(Bi2C)�0I&U5� �9� U)�� )�"< %=1:�]� �� XAh/Idp�A�!K��L M�t "qI.����e sav �N-{+i�1�α2� ��M`��Oup> �p"�!%�nd%�� ArAHαe�/-?� _ i"� *maj�LI3.�R%q�-P�A &D �" �?��"�%�=�+Iqmin�nd�'� f�%{���m�4ex h����7 7Q 7`ori!� tra-� rear�& ��!p�n��!�r:F�Fk�4te.7/2� orA�90��* ��5E  t�"�a� lete��"�*)%�&�  2�%���* ^(6!&:#" IA*j}"� } �d��Q:2��E��, � �> W[1D$11\�1& Sis �“Aβ5N�4)*��X ��I|@վE&�O>35�A�� 9y FixJ��or [5�$519�e�4�� ��5%� 7#���R.:�'hwe� � F��)�*� oba� o���m��� log DctD�p".� a2� � Y� }UnD /!� a��"4 b*!��2�!^t��2��� �6�KH%HA�EY3ing)��6om�+O= ( S5� �s�' <u� ABGl?�;A5Ņ�ɉ)!Wu�j q� �*�ir*� &�&� ���>! R ��!ŀs�,B,3����>-AN�A ?�c_bio�\�N��Cb�%�J2&!���"�A�Z�*�.Y5 . TaA"�<��al�5Z�AD��n?2?��%eu��!nKN���oncert�4>4?!(��9!ZE��I�1�"SH"U"�0�(P%@izk# �meael. &j&�=!¡_�8��_�-2�sc�Dit)*�J?�,��� "���9t*�"W� �7��N�!*I��<^7?%E�˭)6�!m-91 �fVio�= B9��7��&d�mD7<"�7. PfoUS�D� 1�gno� !9 r�lNxA �2!i�=%9� stN?MM E*)A!K�6�u ��!86� �`-bl�\`-"�P�7T-I���n�<ud�T��%�261� 269 W<ed OmpuZIXF=8fM�/aNJ�*�NRw�-@E ��hi�O-s�A .r�'�21i�SA ��!�&^ a8�ґ�e� >*, at!j9�1)�� .u ��T7/1 +9 ACa�"/X�/ � �M%��"�*@ %�C5.�e0��( =;("�<Q7E].�; ID< , Am�[� 1Q= � *)�`J: ���>E*�VU�{%���r� l&r/I*&o ��!�a��to ‘pW tun.!� ="%�-ed��7D. A&d\!+com�Q!�{m Alb�En{8l�<�> y%� �� � Jr A:��Fr]�9�:�or� %S� � �B�C� Ac� ""cW 6�D��T>�'�$&#@���pw/ah� f�del)!MJ���)�ALa!��ars%�*�8�7�7A�-SC|EL%J!/�19�c8%r8!Wir%/1��i)\%V�nA���a%�$�K�ld� mA�w�pr\D�� T�I�VZ..a9g'��i5�a e)= A2" �� ��e���x isa�XV2� M� -�+!�2mu�i� E��� ex�eGpl� ���nd Ftz!YNo!�9vr.kA%-�dtE��_*��W]��w�ll!�I�t�a omprehens@s8!:a&�[s9AA)��2ai!E�V&s$�ir{Yse5z� �A�ey in n�M)9"�?ly�$?>"H4M,��h!Ud�7>�&. CulU 9(�]�a� gr�%�n�&%�frozevh-80°�8st�Iin CAT�7 um (W45%|3/�atrypt{ , 1� /:�] ,5ymPexHbA$5 mg/L chorH)A}�402_gluco�)nIMpr� tibi Ks� 37��_i�,5% CO2�yub&>���Rlo�day c1F%6G dilu��1:1 O8 Todd Hewitt br�0%(B�en Dickin�Q)�#le0�3b( THY6^�I?A�c�`{[�8d4io]8_* at 600 nm"�Bi�:e 3�^tr� �IR(�rmo S\/�' , Wa� MA� g*5!ZorUG�Compet� Stim��a-P�^de CSP-1� �r� gif�D�QdH c , Un�<]\ of I�J(ois-Chicago�or$����)S6a!*g ino�Tdama U�to%�)��!%-\MxsTZRan]���IH�;eav#exp/�Vph<+&�G�=590�E� 1– N@�J �D3P nfc)Fn100–2!�%�LE�adQo a^ 5 mle#��Q� �:J��:-<S�Vd �� �a^cha0i�inej!e�tpTa�2 hour� �V�p �T�g@ic Soy Blood AgarA�SBA�,Bw, OxforoUK6R4�Rv��-^br�R�> heep�Nou Rockl!ZImmun"�AVGi� tsv�L , P���b�H��at���D �� unti�6si�t)on��O)�kanamyci��KX?c�>t&elete rG a�I��u2E"$300 μg/mlA�Fery�C^Erm!6^�=�� �g��(Fp1hK. Str�=qn .�i�bu(A#plasmid6�%ٴ)ee�J.n a-NMiGM�ndard ly�=ym�( LB )��� �1".�}�: 554� tin-' , 34�chloram� ico�Ca!C�)Aampici�� ( Amp )� �V, �le&�'Qen8 Carb��C� � Rit� e�Im&han -,-drop , vapo�ff�@me�>eGropm�!�ri�fal�&'7*W55–10��ml�in $M BIS-TRISJ pana0pH �Q5{?�) �"zf[2��*x-��&)��(to liquid n3�S.�&r� )(&�-� a�xakm"� at beam  21-ID-D�Ca1 Life�ce  abo�(ve Access T;T Adv�9,Photon SourcdAP� , L�Vli_�at �proT�,(HKL2000 [67bHId*��mD�>�$'=�Ha��: *. prD0m PHASER [68]aC�4CCP4 suite [69 I"�1P�f�� &9 1MVO� G70?�= star� m�!�f+l"�\&] ap �H,�utG ic rebuil & B�[71�PHENIX�72] roo�-K�K)�ba� ��"�e95[p8 olypf �'�z#albei��u�isa~ inuiS�j�Rm �>e�sub�#� isi cyc��qaximuA�kelihNr�i%�� 9�%. # [73)�man�u }5[� OOT [7KN����Lng��#1, r-g�a�#-�" !6 i�` REDUCE [7p�� orde<x$.@Q� I<-��&� p�^+�EdmlA�p8lefree R"� conv�hda� 16� 9���uE�b. Sub�d-N%q� niso� ic�A;�- "TLS��am �ls.e�N TLSM2w rver [76]�ulAr"ig";C redu8 ��( R�> = �4� R% 67��)�fi�adjust���)�FX�9Qq��'��9��x>cryo-�cIՑ)��2�� �val�Q($2�3H2�5��M�j�3�oso�:c.�d o� oo�oQ!"nQz�).MolProba[7����ͅTA~}�fJrrP�L j�xp�43C5N�4Dor & � 80 spen� � bu�*!]`4�(2H-Tris-HCl��!7A� mM NaC�10&� D2���a5�� NaN3���3 � �4ed�r , 13C-aliZxicV�JNOESY ra""ae$MHz Bruker�s #oe]a�25�.2Ga�r�k ��ce�Bh�>6unambigu?�5A �A*n�PdD*+[�qn &W&�,%+6�ed 1Hq6-*, HNC!j HNCA� O ) BCB C C(NH7 BHAH�$HCCH-TOCSY8e\ .�u4nuuONOE2'Eol2M&S9�"ce��A�flexi&�2�"�#nanoseB9-pi� �RU(�Q"�Yuc=�n�s�<���G7�yB�+=����3s�i\ a�sv+��aGARAN�1: HkXi�� �jinE�F,in XEASY [80� SU>�:~ p d$’s genPe� comm!� �=�hruJ"� �k XI��m�' corr�$ �l�H �. Am��t�o? P5N.3�~�u([SECF_c3a;_- �gilE, 1220act HPLCFipp@ a 250 %`Zumm BioBa�kSEC-300AA�umn8�U�e5�$� pH� � 1 �!11&DTT� $O�qca6Q!�Gel Fil�Zon�6ST ar WI M�B�}�S�V -Ald} ( Cytoch��e�1� 4 kD�p,��v Anr�29 B�Jeg>um Albu�z�l"�Sweet P-po Amy'}(� '# �0��7m�P���RitnDq�E+ePt"c�m9?�M� ( 5 μl�� !8c)Whs�%�at a f}+a���w/�mb�Eem�Yur|3Ia:r%�o+U� ilHEX ( H~qofluo� in ) "U;�D�K�mB\6! 33-mer B!& ng Sg 2 ( B�lAo� 2;P[XL) ob made�S:FP p oom .�a!��p�2�!R� labeDBS2-HEX-�\� a]�w[!xun/ed &Y�–7!�H�A&!j��.��� !�%�2�z�:mM HEPESa���W5 MgCl 1 Ca AEDT�:._.�"� ,3Ao�N!>�!�\)�!��S�80$PolgSdeoxy}inic-cytidyli?/�O@- dI-d !\A%FLu,a�n83retZ0m6��|O.%b re: mixA�-s�e� B!�4! in6pri��C�cby�non-dePAm1XTAEris-Ace�%p) PAGwG{1e�vi�lB:at 562 FLA3�,FujiFilm ima2e.�|qu(]�/� �R!�"a;to%�T"�l,A�ix8.DA��(��P) �� E�5Seala-edoJ%bov�M-pd�a� ripl�;^Gd�ed�^I� J [8gg�Onco9y herp9 { x vir�)( oHSV�&X# ed e�Jac�clAmo�riUiAQpc�M4'�m �i c� r-" ific� �-!s/��!vsnes� co|v�na+h[  onse!ynd�w3�Fq defe( �0-vi�H. BecCG �R�:y]&f�O"O�Xnu��F ver-.�)develo"next-gZ<�-c/��y�I15 ,vG1X�Zrge��u�-Hre�{ors—!�g . HER�hu^}ep�mal%Pth�9 �m —h�ar�=߁A1 A�� �a .��T0#of im{I4ap�`eY}Ae�<�.� , si �=\E�i�FI�dampe� inCw5�!ge�p)`ed/M��, fail!::�NitMf ��re�o�repm}e%le(9����M�yE;!�E�U +E0Xy�Hd Th1a"�7 . So� �)@inf Akele�� CD4+� D335+m�%� L%Mi �4)4����ir�j"�:�ZeXemplo�-��CD8}Foxp3 CD141+>���CD11b2�de�L�efe�?�J)�"� mu� duO6j2\"a breaka��toler��"�Q�;a��!wt-`1S��scoWa syst�B-�.�vaccin�. &�%5!O�m t needE� nove�xti�ha\�h.n�by � tox�^y�"�vim� � of l�p&at����–���< :��[���a*{�"Q ap�K�}[ 6���)suwt��",ncovexGM-CSFA[* �#p"sx�c melanoҁ�7�^C:� $. gov webs:�s[o�^}Q, k?Qe�0 w�H� s [9B3�Muc�7�^#e:��!�A+s�jirJ5p�W"�u�� l,%�Gi@ �� , bo1 A:��]ot�#�" , exert a+ra�6Q��>�n� �5�1�"Oc� =]"� !8MOneou ge�4!17!1I�R�U Q|checkp�e�O( CPI� � e�W��i7 ��r�i�yM�_% Ay� VQe�c��< ��bod�#[22�AK)�� QT" � I'A *� J D)�? i=m�� "E !�K�[3DRr_ �P�2�2�.,�e* chiee*�5 expeZ of��l2%c� inW � .~�l� ec�%�©0Ct< ��t.�{o/+ �-���, l Δγ134�!�3.;>! []alD�ʌ%/%9�uIAUm�a�almulti�R� s�"%?5(�,!�!�I�S)=r4 H(lim��tt eRo �eD-3[���f�scarc:�V as� g4`-�� InB �.3�Lu.z&OF"�(a�of US1�)vJ) in�&�&X$@� R�/To1�umvVq.��r!r��a,"= as v�+�:�*gI%A��&Q or�&a d�DI�] '-e�dng%�E�de&�Martuz�N RabkA"20-�^go [2+o6|�S@ ��٭�/KvatEAPC���s�z�A Jj6KK�G)?�A �Wmh !�!6�O>ais� e��V� yLg�et� >i�,� ��p � s� s� e#) ��sus�V�[3:&3�lIn�!2�"m adWG��� %�mar� � ��1�o1� A��U* EwraL'~hoG�" nefiN` :�,E�?9tol�?�:��b.�o��J�,=�zF � 9�33–CA�`A�m!�.�Ū"C glioblas$�xe �sY J<4r�� roa��o-�z"�!jE �8on�� �!s�'% M�QHղ�T�a�!K�A3L� *�"�cho )�g:%�P�%7[3� 40F F�.��ZirmO6�%2��f[�[&�"i�y�\�%�\[5I!0-) >���y��mi�NtLŽly%��_i i,E�2YC6�h harm!sŰ-�"x u�!NA%�gdosag�'108 PFU�upi�G �1~���3(;?� (���[4a 48]�,� `2� EF���� l.~i�na,1#249�� /_ ��*!�h �� �Qo�.H)D[4x5����kdleE#s>`o %�ab�d-P�-h%䑜� F��0p . )��9de��YA���ks�7Red 60�'E %�I[5uEB�o7��*PX\.8e<[$ s� i]e���*u!A�on�ɟ��8� #(nadeq�A�e %8* �:�eP�I���al&�M� �p!��1�A�to�O� a>�Nf��rAgwi�� �+.I���,jI� ga͙ρ�$, lymphocy� migr :�%ZE���ĩ@ �-lrT���g>6� )7"3Zݥ�A�in< &�:U24�*�o� r�� ed>*� &fA_aE�J]:#AjFC2pj%��#Gs�� adap��� �h.io� TA �rmAB;� synth42Q�&� tZ� &f�v�e'>� �I�[� H� �se J >�&� �k>]����Q��N�} Q�Q6�&u�&. %6FNIIN�etc��i�. i�M.�2)ar"�9msbpL-i/IL-6 ))�� i%jTB�A�}fav��/ � a?[5��5��<wu:$A��_>� B��xinv3c� ay)�AxPLa�d�FDpR;dif�IÖ��.`s9�gyBy2'(y�s����23l8Tck!off� !. Spen�E�F41���nQVwtCs|i�RK 6� [<�:� � ��A3� C>� [4W�h "I�)'];!���2� ")le%8��be�3W�(M��� �!�A�2 encoda�der����BlEh0�J�2� ,�"�Tape�`2?�un2=ṉIh�K" �W�ͳI u�ducedA�[-�G�-���as5u��\ ��mU�th-�> . A �C�ty%H�q%E switch!Z���&� �GJ*�H at mur'!�s "�p�}ss!�toM|<)��Fsmay�B$�or ���gs c��` z� �% Ŕ42[5��5# G 1"��obstacl���.� E ��;l!��0s���h6�i "O���A " �ri�|�� ;e R^ ok^i�ed # !�)� �D�n7<�!o N��Om&�/a� . HH.XGm&���C57BL/6zB,���pa�ot�9ANamx �;semO�I>� MpB16&+ �n�?N� ( � ,%f�:�� iI�%N1�"v=� pur�9|!�l�)�H;n�!"� � ~-�-�%� er l�"!�I��� 7�$�a�!�AaZ3&a=�|� Hl5SK-OV-36EE�Ba c ��i9ov }? 7)�����%Y�Qgen}[! *�Z1B41D (��(nE� ��� ��(��A?u^��K#1i�p�9�:a�D�.30 secu�Tp�ge�Cbf� ��*�por� ���of��!<��[4�W6�-A.l���a.��� [-� N!� kNleu�1=$m�C )�X%�G%a s�Pa�"�*��V�ge�d� am�K/�=$400 pg/1055�I�[ �~Hnor@pl܇J c�%� � ndEs!�� s �� �� 5&i!����HzQx,n�)�amс� 2500 &K l}oB*�T����(weV&�r�'V� s��1X�R%;exA�A)LEy �Nt�*1�/!�jcc&*[A% tit8 t�� -��bs . U��?�(on�z�#&c$I� grewNHERm1�E��y)t%�H )�5ɱaT%e 2fH=itude��:D�sus7'����1� ��AI�oAy�na�CA��eW paraO��@��ed: e)u1��[6=ݝ$�E�'"$"&^�!�]���engrafx7:!9jor�!� �-�"ſz��A� $wt��.e�2>x2B.v�Sj&BWa t8��(�k�$A�50% &!��.��@�x"*4A]N��, ,a�n 6�t d 25M2�n"B$Ka3�-Me���Q�O� v��2Ս*MH !"wt. i�mTAI-u�Ji)�� ��Mno �A��?"sb�C �TW ��11b��~36�Dck>!�;zK0#aasd2��;66){-��"� :�) )4"� -��&0KBBh � �~2*C) K�U-{btur0�tropism�r���C �� e as�@whe!�eN�!Vm&sM/>} (!]��)�]�%N(%3(�RW� `3wt-HSV�)A[N�i�H .�wt-qj" :c%[[�A-�U�]��0!tJR��!wt-UI�r�^0=FSS j�cumJ�!.��kLG d 5/�:n2/6 �"]w�2x109�m1xB�T�2D$ �$� LD50%�a�"�H2��ag��AeA �z7uG.�6��]�,� wt �GU*up~>-�T>[6�&��n&vN �ord�u, Fa)U�yi�wt5!�R8!<Xcv">E !`!>��eF[�FurA�mI:x�b�L*[��JA#.� orga�%a4��"K  aŁ�+el��I�(�Ms h�1EEH.wno� �/~ %�M;c!��2"�:�)D����W>�,vflankE�6N;�p%y. M�reޠd 4 loQ*g'��*� U,,�� -frd�F5,� D�3 alB%F �� (�#�C"� � Զ!!!S3(K) H��qde�{�h"MA5#MH� ��Q�.�vehicle6�+( �CAC3B� 7/,-r , n = 4;I� 87 m�G�!a 1° �"u1chaw�� ����,�z^ !IAsMBxE d 27MKA� w�(M� e�G-lU&�%�x `�i~H� � V;*�i�<(�p &>�-s���Eb181m�!Z. �(�eaiM�&U24)N��.-�a��A�@nm�Y�� w t���3�4,  ��62jR�j��#re͍!�E�U{I��2I&#�3 Xo�Fu� e��lye�ap�!r,��'�"at each/$'~ sur�N�Vv~}�*r� ��1H�1-I�>&��!akala02�(�i� ��ˠa����"��e2j� R5at ^12 logf�N�,m�Q�ZI��5�6F �#-L -/6M Vd"`L�0eJ �a�_i�4& kiX� mqEQ ��œ�h4B� D�mJt�e�fa�f��J 3/18I�~� .uJE�9�d��is docu�p)��E��l)�/:�aMtoq�>C~4�GI���} 1/1�*�-d�abi��~s�s%WA�!�Re��"5)p���6���ol�O �N�o��.�U �]�tref�Rn&��[ )�Iy6D��%KK!��E � aïv� �64�>�Fڀ�@'))OɘA4�n��*��- onfi/ �� �eͷ0dat%�'�6 ��\�I�: .��Al �)SI?R�&�=a.�!�u%��;�Y!m61%]����Œ�jl{�-5� .�,Yv�8�A�DM�<on "B;� s l�(4{)�q7"Ii��/"� &��@"N> "��T6L; ( L�R���ipe j��%�un $&�16��,��s3nd �(� � 8!H!)�3� �Q �  (:ly �DA98�*�f�6X2V�!e*�2!P 2°*\"��"9 H��)���5AB�di�LPud�. 3/4)i��rJ8/=>%p�-&� s�?!>.s/� ��5%������jA=115%�28N���t�D�E�� "Rof�-�� �iest.H51156: ���� plenr*" F�sN�!��%-&�E�!Q>� Y[��I&�8�Da� ; 5 �ly��h��|=/ {i(-�` Q�H�To �CE� AIOii"A ac?dA�. #�z*D-�(�:as6��AH-*4Q2 exer�by2P �:!Dғ�?s "C+�8he �!,aI�>Daf0Ge*9kٹ؅e 8"a%1�aSHpy~J 4 Ni֬�6u)z�(��.Xd-M �`[. Tȭ�N| 6–7.�D&G[�95 �d ._$ ��Eh��%y*��Pi"g�E!N�0�i�f�.A_�r �|�P2| ?l�&.@2&*ln�ŭ u"g-� K28.B�6A–6eNA #�k���I heJ� �/2 =Rit8�3<S a�ly�kE18/13�.Z i 6�&�Fonoa!�58#�!�/U��-!�M�G6 $f��e D2 "!M�6F�' co� E%vs n~%Zto 775�O //100ng |O,"� �"�1;�E�%,+~%5��-�9n.���a�X�'Y���Pe��/j09e� s [3'A�&�7*�Etissu�'��c.�8n�f� �6���A� e !2H%� +� 5#A�c� �3� �5%s:DS�[vm6���� r� ��?jha=<K�)cs�Maֻ*?-.-�re[�oo N(��A�Vfac*e*�y�1%e�in&� AK�/ �E�3Ps ەl"�:.�6KH, ���)yT)�"I^� en��:l�� ���%o-u�3��Ar�I��sh��EHZj� erpr�Gca��.�,e�p�,�mt`a�E=�J!p.�J—)�%4,���CD69 ag %��$—K in�J �-����� � 6H�^J|K΃�oEK�IK)�:� 1�OK�9��x"� � �K��\!i�a�?�! �*1-$Q1 mirr6K.�6]Q]X%+PD-L1��.uA�� 6�ElIJ:x��C ��eb�P%96�oFas��as �Q, $*��w&�)� R�a�rv�sU?�9r�r�`"�t�1�7art by]γ-��:��~!;�j%52%NA#)�6l&</� (qE�i�7u,7"#L�5:��y�,<� a�I'Z��Q��1 T(�e��PV���<�cI�P}���f� Sm�)��$,$I�42�"=LU*u\%�CO'3- , gikIE�"�0�eo.�:'] e�'^i��um�R!+��jof&�.!3�F�6�&:�.X �"M:o�>UF!��cA\�zٰ2H�`E(�Eunbia95e7*� �m._� ��5a�._ by L�^ ex M%pٝKGe�}@�t>� ����� . E!��A�ssa�D*d&l~}��K%�6���%��w9#7��q�,4Xr`�qfA!cy"n<���0A�6m0�\�>(� 2c ��D+8!!+�F�"�  �^to�3�m��-�6,%"~>�X 2E�6e�P2e�H"�E� X%M�� �/�.�ӥ�2t*o��In*�R;�leA�al �?X 1G†@Mnd:�q. P��nAPE>el +�g�1�i�.isfopp� asm�Um�9%@�]]�ERqGY(*�;�R�< 8A�{Qr.�6��6�\��E :��qs��"���'do/as )�<o �1PFUK%�� leth��or 83�I���.4 �2�62�/�/N�del�{��͈6 )�y��r0:YC�Um%.N>� _ -��%x�;��dly��e$?&�!�?>�'2���[Q�ItJ.[J investiga�6ei��* (Im��]�o��|is�M�>`�� 83TecP:�"a�!7E=I3�ACM�.Ha SVusu�^ha'���9:�Ps��%I!�R�f �&MBi7X+�inG!?c=&�&�K�6��>R �k!�e�,�"V:�Uea5�A13��2� ���D(�ndA�ʬ)?���%�M��b �e���� �/J!?e�i�_ A��*b-—k Ϳ V#��arm�� &�-a" &} �)�־s;Va�=ek�sa&�re-C�B���Anest!}�M���ab�_+5�� fˇ2%�ٱ;� !x.�j idR&k"!�z I�Hɤ��`B���HY� s"���=%O� �*F%��O�Y�<�&:�iMy)&�*%w�y#B.�,� �>��.6A�R-e. ��6 !QMBish� ��Nx} sxW�0� !� mN�I&t%(3o&@iG�.�"*3�ost��ory�A�atI3[ `�/=.J a&�S� m��s� �� � #2� r!# —��I*�X�L�, p.9 =�TkV9{ NK )��.Pc)c!\T�13 I�%SF��1:ga�ϓ6b� K:Bnd.�>��0�A-&��ysuv B)X�� r��>�NK%:s�Ge�}�8!�dIJby�8` )7"�(�!J � hel �s -)i�i��2�==} ��. �2�,e+-����� TF�;A� Ŭpb?ɩ9H"� M�9�� �al�&@IPb,�1ev��pop�A An)R-" nJ��i���&sE �{ 6te�;G vzQ !~ZG.�e�)�2��ьm�%��' z@Ow9Wref�%r+ ��oZ�`aB��rAbi*�R����H2asSh 6^\(+ pembroliz���` , 6WN���&�}rs�@a}�ź��<�ofy%]U�A��`����Н�Ex} >&9MVE{"�%jm`:�m�!/rui DMarab�EUJer��Eof� !|e�՜ed [3% Iib"wO=cl*�Z�-I-�cQ���6?~:� !8I� �!Kre�.u�<� ed&$�!�a+- "� [65]P/_" 15de�"e"��sDt�^O0�Eݝ� D"� x wu�m(B� �@5�n�O�� + T-�Ra7l&Q%�"�7% m�[��%��]C�KNewcas$� dise�u������^uto}m"ُ2�{�J&(ɚs��� q�!� ic��ag� >S/:,(;Alp�=_j6ReB&�hi�h ��":��/��� �QYI�.� *Pf-�)�B�TS��myeloid-Q"�[<�Not� �7� �@c!�in� :u �� ��)zx 9�6�*�.nA!�cytTk}��d �� >�!���-_ � a)�> W,;a�sF�mm8�'-+Pb:V�2VuNpco�B2V��.�W)���[�Ve; |%Y!G:� re�6 *Y?i]it�A))h �eJTedl .y� ,`)/�$ necessariŞet"�Q�%�of\ �4. I*(�A����+OV� =�6Js�])�aZ/��L��a�"�Abقi�>��Ea ��sML �{�[6�SSw �IVx�o-polio)es���2 dend�m��RieG�v¶�-A�&>�M��-pQ�i`��E���J� �F"` :N*_m_>�,ys�A,�7�>�H��b>�)���.)%�"��&z-��SMXt0z 6|�aa<.@O*� �Ca=)out."�!2�r2klE�b.9Va�)���.J�v,%9+� a]5>= �!W�2wb��[*P�E�3 2iq�v]W&ɒ�� �[3�-I��y��X al&�!K%�[6E1@s�T.��pc�=r#ad�ke{�z*aY9caI����& I&�vF�e)� X" �6� onK1"n�n� in6F�}:8E�AK z t"� �0&�+-�)[58��.G0]��e=M���[v6�)��$��$nti-CTLA-4 g ��"%qe�&�(�t�!~ \�*#ae$� A~U�'&��}")�3���Yo�6 GM-GSF�6��>E��>�9the res�Rpective murine cancer cells to HSV infection , as well as the genomic properties of�viral backbones , namely a deleted/attenuated .gN�e in OncovexGM-CSF , and a full non-attenuated 4DR-115 . The import��(ic� is clear�,pparent when�ef�s elicigby `are com1d!!those2(\the IL-12-armed G47 [19] �4two recombinandxpress8$same cytok!� �@differ strikingly!!their �e Y tn carr!�multiple)rion!�whereas �+no%h . As a monotherapy against\del glioblastoma tumor ,�alone or��were barA)\At-A�ong,icacy requir!ah%n!+�!��0with both CPI�.(anti-CTLA-4I6@PD-1 Abs . While *2�m�lik�xemplif!D,a refractoryQ immunosup%��1A�$, possibly!�$ resistant %JR�curE�,finding that �IHI�reduc-growth!Eprimary j�a0y protecA�& mice fromBd�l =sMb absenceDM�%�%y%t argu!N � qvirulaOretarga�$ oHSVs hav. e potentiq o be higha���$oncolytic-)mI� eutic agea5$. Human ov�SK-OV-36�( Rosw��$Park Memorr(Institute )I�cultuAn�Fin RPMI- Glutamax ( Life Technologies #61870–010 ) containing 10% fet��ova�Lserum ( FBS ) . LLC1%�B16�de purchased)� ATCC'.�DulbeccoA�A�,d Eagle medieF�8, #31966–021 2��, Highc��A810%�h. R-LM113 was described [44��I�i�,derivae�of6;ePEh�/ ntal , it;]#a ER2 . It �es?͝e ( m ) unde�kCMVA� moter [60� ViruB%c!K�ed� titr�z4by plaque assa�\UN��Q sprodu� !qu�_ fiedA ipe�Ms�Hcalcu�Dd usi aformula:jY�Fo) 2 xEn6 E�ki� z,s exceed 100 <2000 mm3 , ulcerido��a�,!\q�exhibiA!��] � ��l�`,)�U�a!�tra�A� �, ofiZ}�~�re�i�voEp6x�notiz� Fres�ex�n�)pleen - smas/ �*a 7a�m�d � �E�w  ster�5ml sy�e plung�o iso! inocyte�R� lood[� !��Aw%�s4e �ly�sACK bufy$( NH4Cl 15>, NaHCO3M4, 1mM EDTA ) ,a�e�di��(X 1640%G*0 heat2�,, 1% p� illin/str�s g 0�Dβ-Mercaptoethanol� coun!y�see �24� . Spl5.(���f/w5)i� e�䁬5Fen� 5 ml���co� da� .��a _col` ��=am�A� secr=IFNγe�*qby6( -gamma M ENKitBE!�-�min�B�lysisYTris-HCl' 7 . 4 Y ClŶ mM ,I%�A&3VO4 1 NaF4N3%002% , So�deoxychI�!�5 NP40A <, Nα-p-tosyl-L-�n chlor> hyl ket|hydroideI3 �2A$phenylalani 0:I� ; PMFS �A�� � ��A00���5:� mg%ir. S.tsonJ exBiorup� ( Di�od��,��A ram HIGH_20!�ua�$( 30sec ON FF,n�ntrifugM�36 at 1�� x gY2!_on��*�sE�"� 6"�A�Bio-RadGyt ) ;(6T��analyz:Sa Magne�Lu x As�( R&D ��$premixed M�-AQteZ5 cu�-Hp8included: TNFα�R14%�IL-12 p7\ BR15@ R2) ,%452 6 701 A2P117A#3�, i�( BR3� (, CXCL10/IP;3 L$Granzyme B.6.. Supsm�1:1�R 1:5 ���!�Calibz Dilub RD6-52��5��a�eStandard�veI��y2�[oy:o��y-|%� IL-4 6 10 7A %A�=in2x��,���>c�f-{�per4 ɷ.:I&^ cor� o��=�9z2. Dat��Vl!�^�!p� wa0�%p�ee� [teՑ|o~m�HQ�= U�!&[LOD�jq}]�, h��t� 1geFɠ jɦa�. .�hom%i�$. A few mg"] a��)mpIQ�n �RNA�-)�\![Nucleosp�NrMacv y-NageB2�7.� ’s%Joco �By ,1 �d��!�oligon�{ttides: DnapolFw ( CATCACCGACCC��ACe5 &Rev�TAECTGGTGuAA0DNA_Pol_PROBEq!AM-CCg AACTAGAf�-TAMR�/50μM�9.5�>���ʍ& gc�(6t �&ib�C&2� ,��i�pu�e5'ic%�a!�m��gc/100I{#*�"Rtrypsie�OinHnd>:�"d�+ 2y"�*���3�5& iS%�� Aw#,Ղ1:6@ in 96.in �81���& �%RV��finall."c�� �PA� 1:40z4Beckton Dickin!��D& c�&onC6. C�e� -lin{%nt͝( CP )E*Y�6�#7�#Brief�&RS��"�� HSV-��Dt 3�  ,!:6K8. Twenty-four h� they [f� X parak aldehyd!�b�D-�or CMAb HD1)h�rx !�-I peroxidas�wF-�,. subs$ oene3di6T<( OPD; Sigma-Ald-xadlA"eY�dh490 nm �0GloMax Discov�#��P�ga Corp#!�A.S�%�*P b"� �f�o�s� s�sac�c! TFin�ll piex�"2 %���!c(*g/mI i[. 5 hh�t ��ET7p�as�C'7� m ,t%����eY roce\2 abovA�Tt�!2� �|!��A �^pecimezl`.�*g,\e� pell��!,BA]inZ� b*"tly%{.@*F bblo�%�8α-CD16/32 Ab (  93� > q��%!2�!#asbod�CD4-FITCKGK� i>PCD8a-�/ch  5��7J}CD45-2Y30-F11^+ Percp-Cy7�j0335.�29A��>�FoxP3.,150d/eN+CD11b6� M1/7�>VPD-L1-AP96MIH!3B�,K41.vLS17-9B�!� CD69�P�H1-2FF�2�f� OnlyY�(proviA�at le� I00 ev�+E�X�g�$D!a. Animalera.���.�(Eum0an diry0ve 2010/63/UE@talian laws 116/9�26/2014��henal�" mrevie�G!Iap��TA�Vs �C06tUse Committee ( ‘‘Comitato� il Ben��r_ gli F i”!�OB� P>��Minis=#�� 5edZ�j$Deple�S�z- ,%"=!�tV �|��E��+to �d!>inc�6�A9��ang, sug�-�a rol ��L8.LClngF)�uň�. TakK8oge��, d�N�Mle �$+ 5�EsB�%�5),by!8�֩�e-�@A�Œa7:�bet{(evalua)/7)?6:� _�N O�30 yeak�)a�d�+7a�3 causI�*V"o �def�) synd ��ID>5,L/ ginu4>6a�2�'chL%nge%S glob� ublicn"# . M�%2" 38)llA�people��7ly liv!�e3�, �2 m ;newY�)y1�-�* ed deaths !: [1}.Dyop(of� afe � &/9~)�o/�2{5!�!�earch�2or. R&e:2s�anU t��%2.gd��+�)$, a number�.0I:{(rS(e�:E�<famil%2 b�$ he<1 !t*� [2]%pox� [� 4!;Sa�.6� (36 Pham��j2o�/ andi��s 0 on& � ( r��) �fai��d�8o lack! �,�: and/�4S0 l+��dq���� *U �1� vidu� [5–7�These u6< icip*lts)i>� )`�+t�=^J� e�Ag� ��%g <)�1�in�I��![8 , �<C�# � !�to lA�b�:vi%� helpe�!to : �on^�*>e � [1�7& ��ve���!9x hasM�ocua�e�%,various path�c.�:"ALAB[1f41E�HowA�� :�als�7jA*t�Ρ�FU�u�'a���genٞ ���a�c�8�ƅ5xpaM!& '�.�is&h= [15]���iru6 des�= in m� )�e��ate;�could b�qe a*�;Clem@� ?I m;�2fac��at%B��? �eg-9[1�:1EhReAZ� �}�x�+!EEs%�� � atm�."!���-�s ��?:�� 9�[20–26a�Inti�+r!uei�"i� z� geZ6�5)�sex� natuab���!��.�a��CVt 3":�d� }HIV&�:2�2��Altho0&�=$mechanisms%`��I-*5 V��  �����T� q��b�mplex/Q� afAV�9�A�s such��tm2qua�0!) vo loc�I�of2F�4di�.w f!0ngs� )�6�a!a<:cR 4"� op.��r* ma�|e�s����|ur:�of:�J.A� addi�A�E}le� i�)� ) ���Io�,-stageB�is� c�cC6 usMm�he 3�; /gp120 bo��!t�1m� 2?“B�|t`@dem�<�XBst "( ~31%X32�� Buil��up2!�2�@suc�!j ^,o6e ongo�yqs"M*� � �J� &� beOcoU !i[2�2�WI�&isebawe sou�2to]�-i�; ��s4 a focus_ A�&cuQz����]�)�i�w2^�5�%�e@Esb1I:/��ڦ��� 5��%�B!:I betwp tK �H �f)?Z�-IosG��ea)Pyc}n}�,�;�H`"��� ��Z�r���.-� �s . To1�N*of�N�]�&()��a�7� q�23we&�&�5�!�*� �.��( SummarJ'ZS1�6L In b" ,I�q�Ua'�,+�)����(�)\!�first-W>E(CFS� a fluores� dye u�to�?ck"�&�t�"t� stim�s#!76�-empty�� threeK8,5��)�2& �-�4.{,2Z"9��ei�CCR5-tro�$( R5; US-1* in )�"CXCR4$0X4; 92/UG/029)!�a�� postc ! ( dp�,> v1M��VO(a�- e�%�9��1tensity; -low1�IV1 v A�j*ttra�!ulaTp24+ ( =|_.y)A�1AU�W, p�ow;ver�i� ��-"� �] A5p''"1ng2�����Jnt�&( S1B �A�c�!�=mb�M!) "�.?S1C :. B�of $,�iF"~�� �bu�f)w!��eG &�%V�6\V�q�aH��v�!� Fig dJyga�HA$:� �oun$*a�F Bni�6�c i�?��H�rV�R5�y�(anEz %: 2g"9� .�Z| �zrm^"J[ y6oN"27o ( p<�.0!2(�� 3>�5U .A�>onito!2!^�Ahi�N�!��C9nsm�o� %�=�E`RHrxe�)2N�N�onY 9 Zex `(%r: 5!!��PAL �R� %l stilO FZ1!]8[ ( S2E�6'Con�}��a�4�K> � simi���:�to+(N���%�u�!zfPF!82�f�N�:FA�F:ge�B%A�n@?� � *�!%two-��U�Zver�^L pre-De,�s�R�� ( S3��2����Rc5Xf �2m� �EI;�'!`!e!I miw$f"$66�,2i2�p2�e��A�-M )a:kc?a�<L*!p�!0%Fzsu/ 6���!nѭ�Sn�Lro�+���2f%E poly�'&�bSpSD3/CD28��.K�6--:ŏ"�r|u�� !#���B�H���4E�Fi"m��|no�-J�~-*S E�,E~ hi2� appeGbe-Bs 2 � aF&lla d&Vin� >r(���T�miab[� Ee���  of?Id a��R>f�>!�8�Tbea�jFed]��& ���u�TFV )A\&��IV� nsmis� 6<to� AaX4B<t�wbl� U"|"i�R to AD17E( molegA��a�[3�32��"�we�cE%f�e��N�!-Y�ɬ %�6��3 %: 3 .��5E>�>�ol!6��- �� of.�'�(*��}��tha!a�P5�>� A�%�)�%����4 sertV�l %N��h?*> UV<0 erefu� mJ@�EnvVQ&FŹ�A�*& un0Xr�,fbin� nwZ&%"�% �no2 &�ّ ( S6M4J�"0�*#A v�1�s i:Du �1m)�n���ir>��!othb�� ��!i���.��F�A�~� � nd&Ive��m+���F{��2�.�c�X;G���K�A�pdb - ��s�3�A.�!facMB��inf�?�P�o$t.�-�b���V�'Rn�'>"�J�(�� !'* ly�T�N%�e�~�&�T�1~xKTh6e(*���' �.E&�)�V� i%Hig�ly��f ]enc�\ CR5+2*(w�| 4N �"��@389A5�P~�0J-�2�A"$ 1�c�?��"� � ��Em ��( A+ %N%J"`:�3��6 3! 6r)z>" o 2 T#F�lSed2�f%m� �reB�02O%U��A��SF �V3 �l���G;R� #� ~�e�'efi���&�  ibuY }�.�he"_a�F���R� 6� � ."8U��F-r,+%�-A&a/IT%� )^eR  .n:k�+n�. Not� prin%��.+ Am�#�,�b u"inET+"+��m�%=�lew*� !�6Cf!,- ha24+: 23� or)>B� "ffJ�"(�e��#679�j ]0� �PN+�b*� ���hy)U�"#!��Ł!*:�(A5Eoj�besidePU�./ . Att�.Tr)9,� � __:J/in&(C @statuu*�f�m�,2�{aPn� 2j!&)p!P�)d" )man_"�, �s�*cp�5rt��� J{ �t{\�&N&ongG8 ( �iCs APC�D[3t'6�#"i$��#)nt60��*� C  B9edA[a �xhJ�!� GNn6�.gV.�Zsor!�+ R-bed��sub�S!�q\-TA�Q�G�9>&I0commo�)�0ricE8qC� �( A3G , MxB�MAM�=, T�.� nd TRIM�)W{-"��  � )KE�s� 3�&�Ikt��c0�:5\|ype-I�1# �`b�EYdid�Y0Fa\;al7/!��i%V<. Nex!0sse =g*:P�#fU�N�by Y a��6�WKra�CD2b D69��gf�)aAW�`b� ���^�6,��R�.� k sN-ly��� !��~ �6R���L�3 : 81%� 6M'�݅�=*�ц�ised�M5BR`6�. ag�5Z� .f(��*�@,�g*�2iT�-eb/THA]2^%"cyk""�/:rs693�y��+A02^=3�+W�( xt characuU�%� .� %ܥ�%�j�*�M=�,�~CR7B�> RO ,.  b�mteg�;)to"E/-W( CM:� 7+ M+�?2or)p$ hf 1-1. B9@c��V�� ����predommlyU=`0n EM-YU@ 2 IYs &e4�E ZQI��f(Y�Xs�-r�i�4ɉMBial�J��� e&+YYl=E*�u :�0 N.e�:YN�/  aM�sit��Y�!#q�-A�� dise�C[3�*Integ��α4β7 ��m6�r� tGr)7mig�8`u��=acosa [38�W�"4 ��~_K m\ed�� ���& �a%(U =C"&�(1mR�.rj;gsJ�BvM"���d� ed T-�2er��%�>�A(R] �^.b�&�,i�'; W *�%{ &h *� or=�!��j!!-a�2.�Fc*�p-HA ?  dU&*�2"G5%Q�6 ��V6m �go� E*�d&.rQl&6d.�>f�FSF�$�d�r�.F�&�8PMA/ion�Z)r��G!6� ~�/ov9r-&Rin5-at�I�Q� ly [*�+S�Y�<7I.$��7��/&�o�R&�:63= Ir�% ("�=��U?=�U1� IL-2�nRmU# %݊2 :&� f��!���R� �ed& �� � jh( 6XD6%v~!9�=4�0 96;UT, �>kaf�"~>� T�a8>a��er6�^� �![( 39 . �� ��> �90�u�:�UIGa71�x55� �5 ��$772A� *x=mi�YTh1/Th17�5�q4�F�� �'agree�7��2�.(+!��$�~�'�a�2�B�4T*dseL% !]-&*@.�� knouVm�JT��Ev\@ZT� n JTh1)�5W"��O6CV�-�1 B �!�%�� � ����] ��*� �%6n.�T-foll]7�[ ( TfZ Bg=,��( Tre-�)v(�exhaus�6 ��F���"h� 2z2�J V~6�� a1���Y.*x:u�IB�E��U.�"k�+%21��-�ǩ\~J �( S7A`*|#&�>�C6si �+թ�S(� :�7!��.^a�1B�1����%2�%���ur:&� doese:�8i��a� �[325F>t$Z�EyIZ2�^L� B�E�*�N�A�)��,"�to�~M�Aof>�S7�,f�![D-�!�u~6!robustJf8"u4Cl�Il�YakJ*OF���(}�>�1A�*�6dZd�� !`,br2�.��6��W%8a_ N.A�cu48-/&1G"!�J ( n =  h"Y+r`kmagnitudI+R�B�on��V6 U@( 1b4�$ 11E1�62����6��A� vely; p =� 2776),I�1�6bm�`(F�ZN"):E (T&�&5 . 08)8 . 908�~_172�000{:���.�5-����^u i�1��}X�A^��VW!�ith�/s>�2a�v }%2� a� �R�6}aMh1v� CD8/b�N (I37!Y� 569' 15 13642rk ��-��nA�q �_r� 9envelopeNnv �<*4��!-w�T!tR�67P)_ Y�OnJ:$S8ť/J�a'�ofB�-/faN�U&� � �9ICS�t stu�F[2p�A.FPW .�$!�t2�M>%�N�to%F`."��qb�U��E-s>,P%���3�i% �&� lu�DE?o�$r�ya[A`) 2?H!�d,&�wO3establ ��� 2–��I2� ��L�N'6DF&B�ji�s�&:W-M6v <"42A�!�� "-�refleK��h uo%" .�on%��1�.�%��$%n�exploW2��im� I RRonJ\ :�.2�� rP4|��!f�1�oB�$A( MAC0pri-Mo}� iV"AD �.g!. E!|t u%I&�S��confir�m�7KS.O_2&>o4/!��.x�3whWTr-��q""�by>�?����' G|:�I Q���Pto6oaQ�P�*P � LNY6�("Z006u.A�� ) FK� �szD=D=2�9�6�n174q-��-&:QK,y�R��NQ�ii���aKa��ut{|.PI�N$�(E�-m�*@me"Mby�"-����0=�� 02�Np ,$ &b-�hx I\s!�reAĵ�e��I�2�at� �: backA�na!^8 mE�*2 "�5:�66�<D{&�M7 88c�(k�-,�M�:c"�0�=(�@>@3%�s= 9% ,� to� 3�0�%�[1B7 �,��e�N�J�6�via{ ell-�|ac2Ddepend�+U[��25+c+ r&.w�an emerg�� � .��i�+[45�!��'AxA��[&�B�o�"�V init�ig�,��_.K2X F�VoE��1"( 2� 4%��-2�BZF( i5�?%��F&)ؙp9�.I�pl�.�T�j�����N� ur�c&k^�+�?&��l��mV1.��j!E *n"on.���,"v to))2�. T#G��bP{ jeg%�"iR�g&kX}�heݡL��97��Ց�͟E O�!3M�%�2�, b_.*� 6�8� �,tuP� ( S9Ek� via&�u� �D3+uba8 CD3- Aqw:u�F�b�Faqua blu�/� 2�W>Q=���"�={�had o Ε1%�[e�N�2B�l� �(��*`+7E�7�l . AdIDaK���9�Z��J�&GIBr O:�1��D�2��RperKof <.(M? subt�"EB��en)�|2��ju8� &+LAx ��Femn Fs3b?/%�5�? m92a�7 toxi�7� �*�.�W 5 involvA˂�>-��6l�U�2���9��r�&C?.� e�R'e"wY>PES�Vnt� "���i.�%p�@f e���1&}N!b�AoX;�3>!�1E�&3ris�\#�_s�N�J�A1 outcg�I( �[�).g"�!T9^R#]ws6�-P�R�"�g ri�5o�T.-ri�h` F���iF�]� �!�idF.�S$,�>�!~<& ��_@��f7� w(abe� ɔs& � � �ge��g�r�NR5�)j:�[��x e@J�6nd-�I6�F!{VG6�)ow2i%�*� .a�],��!q:�7m�9P��!jo/%de�.|d�#^�Avl(&P�aCD8�:A:�I�6%;1�J&f 4=2�Y8�����"�>6s���>�(g2�.a.=ce"�)X���/b(*0p8�;a�i] :J��X"BB�("8�a�527 q�n%_&=!g:!�Z2+�W" ��8A��.:�git!2�^y�.�*>�.G(�� M|N�e�sM* lݒs�l&�+�:'V�(�6V�)84Az�I5F?�!E000��=�F� .�%��� B�%�FhjF� ��V����A�!#��!tF�(� J\&?��}�� < ��&�� M~��:I��52van)zol�U�.d"�b" N& : � -�a���se��m� soluA��.f}D s [4j]5&���/ D�`G� �-_|�u"{j0.f�)!5y�Z�9&/ ݐ�E7Da%(�J�'�8)� j�( S10��C)WA�en �g!5� �P�*� &���_i~�:9by>Qr� ",ofE�E>�$r5�1�>r�L���-�� �E���R�ZEdir#� �(%%�-��..�W:Rf95�D�����Q e�]�2�1F :�y<^xh3s� � �I",�Z�٢��* �}[#edIn�TBM�%�R LE!���)���qU^: 2a5aP�*�8��3Q)�:@ ,��.,��z)�0� .�$�2SrhE/�YY"� �NM6� rd),6�m66�mi�O"�E��E~I���:. Las��EI#Q.� � ���0b(esDn��9��� � .+eId�l (r�5"{ &Ra(N�+i��:1QZa��T)�83��#���J��.�B[a��C&����6�&�9f"S -fun�&mnr�^!di�7eq>�umA1��6fa"�B�����fHBF�7:<#esJ�6�)� 01!�9%QJE�x.*��,Edm�r^ly"X}�PMe & 7� 6�����V7��y>s�1�Qe��E_��.q6M� �107a , g._�GZM� ���zu.j�2�F>>A.�2�6� m�"%?� �y))2�QG&�6( 7�7�%1�50a�3-� ���5� 21��12( 8D3�%r&753D�&00g$51e$ zzKA�5K( 7e�u�&139G�t91Gg69H�&00*�BN6� �/�26G%��\��d5:�&6��72%V'9%(�913�426.�CI=FV�3�'%\)$ 9"l 19�271�%A:�2]&�GR��;)Al�I1f7*�eQ�#�aw��"{17 PWn.  �-%�cby#ű�b�xO&A?��n��{� *IzZ{a�$i�� R�d-_b a?�}zij�c��:�h�F� ~V*�I�6l� } QƢzd5�"0&:�>C;` le�V� Z�T�9r61"Om] *�ovD�>>Jz[Aӡ1+c%�Y�aE�|f�'|'AW��QAno�I 6�of 4AK�a]#r��.acbQ�E).p"P+Q�i �=ihe���k[(47�iw�"rlI@I�I~�B�(fK*N.(&u��i�&�=W"�.L�n^oW���un�c� e%�h�~%s  Z+ A�1Z�ma�)Q >w$(X l �Hm���/*Et�"�lyOW��a�3mulUt�by �� �<��t"u4.r�w��d2�po�a uni��&�xKs�s !��_.�wSaHu�snTi[A>7"�A, adap Q�Ǘ�%�* �!��� �2M�-�nuca���2! ).�&�f& �!mނA�S{5�%*� [�0�C�|��uma���"& A4to�=A[ mtyC�(�poi�z view�*t w a��� &to�hloy �S%�M�fea/x�3E&�n�I.�u�I Y��ge%!r"SF#Q"�O�I!�s9�<7I�J�p.AEy�+{?qOi�b�@}#�tI��Lor�nM4i=A��=�N�œ�is�Xm�a ���t��vv�e��Oly-��&or ��l�.�%d�yvJI}I0oN�A6[49��A�Ue/|a�-)��be dampe�EbL�e� A�)��yi�y�� !��q` 8 �> zD V{=��Z��%�ngeC"�� < :��xlev*Pf�.|%q,a�nSre�!ͅ�2Ys =I7, e": ��u��@�%w0{ yC D�f):"@WyU�5�nY�be�f�a�ȁ�*|��At � � . Fu��%�~S!�wS��AZ��CE�BF�.R=� �= %B� �#S&��r�serZ�s Ad26�� Ad3f Par��M�" Ki.� � J `* o�w,P�ng���Lca� ,"�w( kEg ..F *�pD JV�)��k>x1G.[B9O��q�.�I�% F�y�V�QmaD�"aEMo��`"zex~v!�u�s��~��1�r&u[5�~In&'',+ �v3 A�I��R5!g"`�6.<&��.!i�";��)> %2)�Eb[��r:E rYZCD4�QL ��1~d���L�M,.��*M,a�!�<Ym��J� "q�*>n�Ja�w� ( )i e��^�d Ne pyya:n !�Nz��I �, fF�war����� o��WoT��^�m{ y��. in a�iP>l���E .�U�!�) VD��WUGF�t��AA�>�Y!��^"p>c!�Q�ic.*N&p3PE��.��w�R�A3�-A�O]AN!� �*A]s�����\��a��Fq2a % :�B[50 .���ho.�Ve�&�N�ך� �!� ,��e�� ��I�� q!,F��HV���:v�F� �A/%�"�Fojc]ZX]yj�z 2^F�!�s��%O]1�� �_V�)YvE0Q)"1 K VD�6� i�Y  �j�� >-H��ed ]T&(0�*,� on291 r��,"���a"@%�� f� 칒ds!/aR*"�y t(w�sh:pursuIS:D."�&, I�A��#)!�:& :�is:�.�:�D"4��%�D���D�'�GIC*rGJ�� /�)�"J�& S3&4 mDg7�2�2&�6��H���F; �qË�5��"FI�B�C&d:��$"[')9�?N� �}m A�"����R��ޙF�2]� :'F� �j.d��^�a��.�������bat �MZ�O_^����MZ>3N�Z5H�5j"=�c *�a[t l� "fa>�Q� I�!�� Y��E� ��r>��T�la�|Th1N~uA% jVD2��Ik4�.lR��BAT�g� R�� B$��'>�a�d �ڹa � � �  ��*�'o�u�A���?��[4L h?Wl�()�!� �&� y!�%.1-��9!�t���esB�6*�s;!xFK6T\VG�W� ����F�onM0�$F�wa�*�$T= j_��# �1>�!� &Lo 4H 9�akR@�q�d2=�.���o%>"N�`c )[�B6v��)�����E����: n1qhE� +A�)5Io�u������ei��f,.�� .:5�!�Zj�*�A����  un�U.�Ka�U��@s*V/E'H ��*Q�ct*Lj��3.�. A��� i9`� + ��xP�6)z��� [54.P.��C 2-�us [5z�%!�lea�vengag�W2[�A�2�#��� w�&�(MHC class I)�IIp� :91RA 2zN]Yk)W@�*�z. N the�, i� �~)\2sI�&+5+a e.��t �"f MS���3&; "u.!*6 ��"�1 �NE�Z�<�+�p&K�o�>� �/�0�� *> M0/ F �.or� ��A�-P��"!{| �� &��.�WoRy-s!�G3��Au�N-)XJ?:F- �,��:� "�,Z<-���ac�g^�,U &Do+� !R-�&KAB0Z>d�Vn z� E/e6�&*} ɨ er T�Yym' &B?"gA�,!9� Ter*� >1 Eo6� A"�,.Ev**D)�p6&Dc�u.���<C*�I�.7=aa*l��Z�CE�"�5^,In�-!�&��B ��U��U�gA���!.� �aka&B "=),� ,LM�*)(ColRJPMC��…�.�Z�u"� ic�.�H!N 5!!�Z�Q&X'B4C Ua� s; �u��B""�2� J �� �>!h�E0I�� %e�A�%�Q/��^E"]�� � ��"I!� :� &$�\*fi&xj�S(���pa �Reff�;f�ia6&�>�%��maximizN�"� P#O�FX��J��<S��6�Mdu0�;Y�� .|&� �)_cM(��:�see�Hexten�uA(!Tq����&ZU>a�to"j 7G8P�IF�6U2��S:RE ��sea֝%�ai�2s�NF'&���exe�Q#E�a1�nN!�*t 6{J" a�i1RqN�Md0b:�  . �'� � �!�a samp�/�twc�1�:�:<,( NCT0022308�.�-�/����!��1 D12597 D�� >�� n�. De-*�, c2R����(��Ko��9 �����r�_l5 �EA�y2anonymo�!�&� 2�rA�)c�(�� t�&d�bject"�,�inj8�&�L"��d�����8 OG>�I��>��6:�Texas �e>4Branch’s IRB�r;��<��Sk{%6�� �X<i�&.)�- main�F�t��, 5% COkh RPMI� uT�InS�Azppl�q�?^ ���V�0 U/mL*�� +u12�� sulfE�ndr=17mM s�gz���.�6 ( US/%+X}&|�)�S��origix4stC`EkNIH�Gug �m�لof)&� m!w^��y�I &_�_�))o a kind gi ��DT�Ja��KimDF��ayl!Q����� �Emđ! �p6�Sanofi ��e���J1��V�DeH�I�Ce ( VRb of%<.?�6 vC25*MŒ�q i�+�s6�Tha$!�was ȅ-�(� �GX� 20 x 106$AeE��5l����!�8��at 25F�D��WtM<M�x� 2 mL� warm»2�W5W.2�"�)�6:��WY����2E�t�lE�-1i%( MOI�3�-d !%I�a�Q)���"D��D>� 2�6���" pre-"���_,a}����TFV !JUJx;cur�y� ��!��F:6"xK�/E.C�c kindU6e�.�"6�� mݙ�.E�.5��a H�/Waz3M� Q�5μg/mL;�&93321; �����{� ti 5�<:524006N5x�~�B6n21418>9E6�M����$��/.�to&e:5r �/IFNAR%�� Abca��f��7/�A�:��g/E�!�έeccnF�z^�/?-%$"���e�&�HEasySep)xCD8 Po=J ve S6�agKid� Stem�� 2K�(, cat #1783a�aQn&/�*u�!�ũATco--�=��9& �" ��of9 ��*�(B�™�=O�U Is��6�2�:���Bu�� �����ѥ  �!d� �ziM5�%��\gc2��=L)�-��n�r=�-� l %��6-�#v;+6�)5r�ͅI�b5m.�u�P�pR. �"_ W& D�!.*�t>6!%���$bottom chaڪ!B.�Ylj��Oe�*�4�f�opq�8�8anQ�- �lsoտ)�)�!�6�!�=�d5�s6�1>u�"�H"���Q� ]EEz:YNg)�.!x�))�}�zц1���co2 :��2�? a9�j5;A���!)@ E"Quc!n2d�M.�S6m� s�N�a*DM6k�I!{MB ��� ��2� A�e)a4 A�=�7u:��x�� ��Y��( LIVE/DEADտ+1aTd�� .Fqhermo:��c��L3495�[�a&yjtoZ� face*��X`CD� / Eh�&,�--<�� t� RI~nt�6�!tu},�nE"p�4�} . Exy� Qa�����E"�LBD *"���->n ��o�me�U�(68s� 5547Y�!1x�!�O( N���Cou��=�i/A.*���P(b����B� ��� �A�h��Yo��*�� *�6�AO� %s���T4phorbol 12-myr�� te 13-ace��(`B�6bB5bB"_`%k!>�#zq��4 �y�ᰁa��fix� %�pe5� 2p %(slNV�$!y�%D% 1 ,Aio��A�Mv A 2�c %�2� �"2�aZiD�2R:&i ��QCM� B���,�d�!�5o�U2 ly2e"?a\*;�:�yKIL�"� 6,l"ory� :�=�"��a�\S�AiBus9 Se! e�C 00-5523-���..F](�x5���oy �jL enu��"ead��B�YeR��1�i}I"K[��2[�� ��2 {e�J2�at LSR-I�Bl. Faa�ic� 6��9K)Jo Ver�.10 softwA)( eSta�w�Z Q_ ��:�6 ƴs����N#6��ofak�Z&Aǭ�^!.ٷl"�[_� ve/D�;Fi�MVa�4� ��~�Y�4 h*(@� � ,FACSAria IIUA*.��T�RNAe��� K � GQuick-%M�� Prep� Zymo�[.��Ef� .b�2�`�fiu) iTaq,��YBR Gr�;S��m�&L�!RxCFX �n�A!qR0� 2−6��.��"Ve�.B�H�)GraphPad�sm �, Inc(� Two-���epa�S,ont�T �AM�e!�a p vaf^ ≤ �l05�  <:H . R�s- bZV")�pr^R .E�X&��ion—A\2Wl��nF%u�X chromo copy� femal.�NceX—ق1�al�: ther��m���Mye�e cho8ofg ch X aJpNs5 E�8!n ]a$W:6��ŵ�ra4��s ��'Z��;in��:E ( PX�'�rrdrs �p* ploiQr K m��H�T��l���bi]`randomFqR2qe)8ze�*k iAA/�bx�"ach �g�.*4A*|e��A!��s0=at*P�&�zis}! ed d"-�of>�a-��'un�'. T�� a�or�oN"��e�)�u�Fc�%E�!�c�ZX� ^��sc�linkag ree�! � d sex-";�B�%d&�=�!E trajEA�F���s�o�&�WUngl�"�]j����EfX�+a�Aj�a ���a broaqd! tinu�Ci8F�=�c3�unE�n%["��.���.u�2a�Bavo�.@� letee� as l?'llerv��� ��fit���puf��tly!�es��� �!t��%$�5��QTjEm�;�ih�ve �kn��is!�����gonW#cF� .�?,)�e� �:� � bene���x�/)�*�a��!z�  W2O�]sex%bE.��m"�6� to%� g��aY 5n ��mw�o1�'� ͹'-e�m�Ule)e sB0iG6fLA work%�1ݓnR��9 terp�B,~��x��-w���&oX-�ed�seE�-sH al�fu�*��!_Y��3]mo���$s2s,E�&!D.9�. M�.�8I�s)�� ��� �+�!R%l!6=w�u��s�� –|U6��:[1"/��%��ic�men-46��g����(R! egg-la�) )#J/��,""��2� ���N$لam�EE�Aw)!s trem�S*��marsuptOA5RUXaF"�9��97��& 7biquito�"Mved ( [3%d4];��%�Ɓ�t���K#�E�re�O[In��t�M,n�K1gp�4ce��j|:J*l%�s1+:��r�WN X (/�&% 5����I� b� fo!!a: mosaiT�� ��nd��H �(one of the �two X chromosome copies [5] . While RXI is generally thought to be unbiased – with each cell having an equal probability of expressing either of the two .��Xs – recent data reveal quantitatively biased inactivation patterns in at least some plaQ4al mammal spec�T, i . e . : differenti!ilenc�of maXa!andher derived2Z$s [6] , [7!ZSevery rsup[tud|xsimilarly find evidence for par�18on�theV} , suggest� addi!� �-ficityHX 28rules (!j iewe!V [2�<8] ) . The selec!~!�4cesses that miA#account�$this obser!divers{Dremain unclear . A!�d�$hypothesis Be evolu��RI�qitbe favor� f segrega%4deleterious muA6ons haveE\ssive 9hly4fitness effect!\[9]–[11]; which , on a!� ge ,!�y do [12 *5980logic underly�%�is stra!F4forward . Fema!��$uniformly I�e aI"culara�%�AX (E�g . �.1 inherited 3�( PXI ) will!P �ied haploid ,E�suae full5'costs!�9hcarried!$theirQ�e6) .%�ge�o tes �>xpr!�y�)is moreq5 to di�y �can poti�ly maskF��%�.& alle!q� !MC!�=�a�U�$ary origin%M� plausible2�[1eU16E%20A%0, its feasibi�/should!�inva�ga!� in a��populae!>0tic model . M�a5-2�scenarioM!�1�a�us1b life cyc! ._[21 �E�$, indicate)��1on�5Lof2wY5eʁS:�=�if0aAuf��ent2�re!veA&!�9/'sa�ombin)?r� ( [2)�30]; how���V��onJA�Oa%o�U elimNes cone�nts impoA� by ta� link�.[31!�. Hg��e)�s�G(not incorpo��uniqu�| pert�@o��x-6����m�a�V�Igovern2�][3��so�b��s�� whet�i�conclus�Vapply!!� case�a. Sex�WcesA���� wherA/y���E�single=� �Fmagnitud��dir��(on between ��A>teg!�$. Stronger=3against2B��i�compa�to��Tdecre!�!�ѿpropor�N�1�� each.S& 210��33A��@A>ebyi���^�p&b M��, . “Sexu| tagonisa� �”%� I�in ���when �YV in on�x , bu!N:/i�ue �!~x [37 �8]n-OI*ppositeM���:d . A�abenefit�Y��EleEQ�experiE�higazproS A of55 transmisa�6�39�4�kM��`g�w]_to!%" e,av�%,0 8even ubiquitous*�,�7i6� �5 l��%Bexamined�y sR��6n �-E:��e�ic�zrin%a, �&k involv� � e� *ur� Y�!=E !�!^ 44� 2�UfZ�Q� variɑo��2� �has ye� add+ e/ It" cur� ly��how%&��aAparam% �ldo���),�-�kM =~,�U�ˡare.O)�joi咹ja%�z�W�ref� (developed a� he�QBJKg �u!"t # to i tify bio� a��7 �DNb�%>�sta.�first�ideI�dichotom� .$j � , describ�?�fac � ��Se�i��s��v �cha�� erizOٟA�uch2?� meanU�e � !瑗. Oe�lE(��|YiaB���$is primari� edi� " he inte�P��Y��sf� �G situiJ)�� !�abkrom" ~�` %� also���P��n�i ZFbiH:$=*("�,>�u~�MS�S��&s )%Upredict%<*V f �s5 toEyv� (Our resultsx�xcoY�or 1�� �2�p�� extrem� per��i W cus�)�mplest�mo alytic tA?au m��$simultaneoů*W �� ��,�����I^�� �a&:�.%! �followAh.i of< bi-�ic loc�L�A (�“�l�)aEX-��nd� s A1%A2 Ues�� �� z/i��. �B� modifier � s B tBFt6�:"q!E }s with-Tݩw�� type�! B� a F�throughWM Q?"6�A1q3=< in h�ozygo��V��aA�e B)�no/ phen�ic~"� or ��d!ɁE�� neut'-.�IQ��E/��Aa� o�`�. UjM#", A%�Bej physm/Ce���%hape� meio�I�X does�<�y � onlys . > y]W� B!Tn aut�,U�at�e*�AFdependdur�p� . Tom��?�:a�:�$, we beginE�01Tini��> ixeda� �a�`A�us� polymorphA0quilibrium giA B1 J%�t!2�&� %ol" a novelyv�} hangA[Mem�r's>�system!P&K$is assumed��be�ic_-�T� �8drifte�be ign�)((r�iNscret�By&U1�>4.=orJ ŗrt�9$,U� k,"2andom: A�0syngamy��Dapproach bears mane�ih tMBJ��#R4 [45]!�pter 83[46&q�2�" diQE�:� x gx ,I�� we draw�>tra�. G� liz!�wo-�Krecur6�$see Methodi�dqxtSN @�p���;`a��!f��nt-of-� Z!�at�s/ule2PfGaW��Պ�\; eX'�7 ɲ(�dTo reduca,e enor� ra3!�pos��qp izEV��� .�*��DfŤ��n� a� subsetmide-�! &� �levant.bgenen��,i !ra ��Q26basic!%m�8�&��͑�( TC 1 ) : (Nmainta�at a bal?� E[E0+�purif}u�;( 2 )Y�aJ�d � .{syd�t0sms . In both=8�M�-F����ed� A1�M�1?is�s�8hom"+�+of*Ju�} sC6ni  �wA�c[u� mt[} � , w ( A1A!�0= 1−sf≤ !X %2%23!�4 iAj i ���[ withA�� 0 �s��� >��)HE�beA��or"�q�� 8: 1>sf>0c1A1%Blso2����X"�m2�Q�-U�QE ( smX.�� Xof�YE�an� �;� m>0;}@e��u�q�&!s��uLbymym5�A2�J�!3 �( %�, t��� �t���eT� �� *>��BAO)�"0 cellr ea�re.��!v*�&oXIr&y ξ1} .=�N1a5( 0≤ ≤a54 u� G(��reh a&½ ) ,V�� Q�eE1u^i{G�sf�is h re�i4d�ŗsa%1heYm�����&G E 6up�i�6!G!+B. P'"Q(is [!.Ja�� "H disO A62 ten� l� psr��s�!�m�A�an�r-p��:Y is�(iL��mH1$�!unc* f h (!�def] bove�aQ-FU !�r.M:�-/A� a� ��� s monoton'E�!�6(��sUtng#կ��� n&� it u�a �� powc1�x )�+ xksf��x>,��!�k!ra� i�!Ŝt!�%�!�ei�fic shap��! =3li3 ssoc�%.A15o�l�s�oftJ�in&� �heoryu���ir flex$!;*�"[485�. For pur�E� (%S@R �$�%!?O. F�,�e�$e��2�zed .��,!p�� =��=i�mak. ntu)� sensDSe{ , k�q3 ��);Z�of!��"eni���, x �& �;A�, h/2k�k  −l!�h ) / � .t��l6%y A2)&h>½ ( k��!C/�Q� n h< *>� Co�tl$ hmat ��k>=lV)�%�ZF�� hp f- �%$ ) �mR "� ; Figure� . Non�'vA�� 1 x"�&� !��� aris-H.�Cn�.ѡ!��"��-mn�.���"�o3an&j 2xmC�0i�c bo)); [43�5:#W >����� to�)�a��2��Mg��� �8A&� 1�s'"d 6� 6��0(*� a�U��!m���R.Tq^� q}�Q. G]!�out��de p�[� e ob�%&?"�a��re1*e�N"9-F-de�`in��I�Gi,.� :,�ex���&oum fr4#B L*W%R� U�� ���()�^��4uA��]�to�,F%v� 1�^� Eq .A  ) wa�ev�*��2,in [52]r ee Text S/2J" 2.:l�s�"i"cAj"є��!�& �!ng!�!29^��Jar%x��� Q%�� � =S al�% s-u�N+5Y!4N�c�*ri)Z12m|provid�-z;( �Io;-��discu^#!e.� , �"5�.�i�i�eFu�%V&?:� D  , �)9� I-?*5� 2%!sjgJ� 2. in ba r!"���t �*u *2�W½��eF�� gy+yX&*v� s*� 8Au"��[)�invad�,&� ��iW(iB�JV!�t� �EvoWw E%- Y".���l�"�� f-:%�G+yax"�*)�imio&l�@����!accum�+ee�i�,�+��A��long-��.���2 !new6��.�+A�672�*epista��F,2ti )rgr�ad�agZ [2�'I�is whU/*l+i}+qui�(�5&] *�+"�6?+&2CA�co-%�mit���. �1L1�)t*J�be�IwgI�!M\(d burde"JVn. R2%%decou� ka> �2�_!t3`9",� pl(�Y��. S�#R���*� RIM.����@ aU%a� )a�g� m.� �-clu�1���"�.6�'� [68]�4s�! ishmfof8pl1+eW3�(7In���Ѡq�=�9*�Ew> ]�hshown f).&inj t X to%�ag�&Q(bA��2n l�=%.M%��Zz J�6��G��to��!&Q�J" � ,2��* %gQ,�� > &2A!2��5ae n�5b��� �of O ( u�A`v( spac~ re�ar!`ve [h<3/ ( 6−2sm+sf ) ;�eY 3 ) ���q�lways lZ �A%�a1 �E�w ?U3)��'M%��(ba;erA8���U�v shif(%a0� �9J �5mov� VO)I ��9!��# Ʌ"� �n: �5ff��-�d.;b�!6 ~ �[�expla{!o��&R ��! �qS��7aQ. Ta4lyed2����(ay hitchhik� *�$e,  +� 2Wdo�overtur netR�Y�� �4�\z�dr� "�ly6� 2� [��!"]j.�8h<] −tm_ ( 2 2'4m'e>�z ";6AF-� 5 /)�� ri��al-� -6�.'tm<��iz >sf�4aDbU�" I�Vaft3+��� K sf>t �d<yy�"�ni�%-a�1 �.���0a m�A broax""( *A ,��!^8�? FA��ہH mra1? B� �N�'� ne�9A�a 8����0�$�!�Uف��is?6�ڡ�ha 7 bs . As�Hin�3 ,���s+��R~k |<lea�a�m �_N���e�2 >g9�kxac�k half��r"v!:�)ha: w�"�d2[V2"�"Nin%��N{ i� �n��-R1!u%&�!,��y� �^I�f�y&2��J�! "�ly���*hah��� �>�"4�n��� e� n*� �Q}�" 6�>�[ : a*�VP2�iOrm5�a t�� ]%��b,m9a�aW ve (An@thd:s5 m�0auc�{3"4(sm �alj>� *��"�$[J�&#V��R%0��te4s weakly�� read�/be.C!�871� Ta{�1&�*A�%o4q*)�:h�1�U;V�2'. A*)$#zedH3*c ��"m TB@$-�u.�w�A�do29�$�]�0!aTv er�!&�6��a[��>�,A- ting �� �distrib"y N� )]csc� "�s amongZuyơ�$arh(4C %a%�a�9���if �JW2�;�V��&u� � ^�]!��A�&�1 same�of6�0�7*�!&*��.�,!)_�Sf�2��smz��U);�!��Zd^��E!Y �8�� 6!�5����8 -sex�?e�<@*.M��A�m*�3,6r� j�3)� �L2�22 2)1=x!�=�R��[ �3 cept,:��JE�" 8^� ut�,:Y��d� al\aF87�79�B�":�;-�-9>���A�wesey�+Y�p )Rpre"�96F �&�3��a gre^;� @:� �1�&I�Jg A�ges�%g�k=y���(�� vaE�"�(�,,��,1 �A�96!� �6�U�>F�5�/2>/Au�2�ID".>vFbia� >�>on�&!�V0n arbitr�2� �y ,]�%�� at2� ��b &� 20%}S[&|eq!�( 1–!^��"�8!x valu/A[.!jl�i1�b��� )�� B��/AuI?EOier.~{“��7 x �ie�4[8�!U�2 �8on�_ M�4>(� ( �*� 7 )�agon�IC[�!A� � ]a�p�=� ��"� �:o%� ((� � w�(�)!�belowM�)Mu)qY��0^�. S"�9�$ov%=0�.i A$ �t�>�_� rogen'Js5ɻ8 IA�!e]������)�".�&��� ��6"Q8"�A�ebE"�UeC���@I"�$!�!���!�Z[ aY2|&sfh≪�e�%'�!z��!�*e����]�s����l�E� .^ ��hu2�e'a� s�tm�AK*� !�N,"2%�F�(�)��*ei�9S�^-.�.I-�K.�H>7,F �IF��%G 3:a� SQI> ��Rb!=I+�-lef�-! x-ax1 "���s �enV rAGw=,�Oa few ]O!�0*tempir�Me� tect��. �)��� ra� I[�a el-�* �"T?"H.�J� 45]; � 6�7we�f�5�Luri�Nn+*(7*�� tics%|l(2~ rC&�  %�F�anYKJey&p "? eA Z:�& H"UJ:!a(A*m'��8�sa?.-?)�zJ�6^Qe6�="�sIU&�!A;�O� cordt,:���"IWV n �Bins?in?0�L- �0�E � iple:�,���'��t�&W�conUP.g<~5��7C#d�edA0"(<.�%& loose�ag�no*!��Q��%R� 5S smod≈nE�$�i− a)i6"�&a2e�+thme�m�i�E-.�q��!)|(2>��)ir� at�>��0ex�Qi�6J&�?!�.�)A�-�save��^U�!& =u>�>RFJe��Q�reinforN))JRstrengthA�9GM&V�y Si��� numbe�w��a:Q��:,c6� ≠0Itn%u#6c�>xi� l{e�Veu;?�juyp6Sagree- G��I�^E?��[2qVAlt>)0 little avail=XXHVup-R�"9p6�W�"�7&�UE&Y, nC ��%goWI��F6�;A t��stw�� +��Qu2�1NKV , [8\*IZ� .m &d-[35���P . IfyK>��@�M�^12*�=���&.J&�duV.�q�rre�Sl�L� di��@��at%.��Vq z�exert&�0atqslQ*� MR"h � trajectorxF�L,�j�Pm � 9s�9h�O"` &�It�e�Df"� L.C63p-�V59[�<�+�Vy eclips��*�Q�6� lKNDe5��KLB>&!+K.,b�1�toY�qXY�is ult��an&� "k:�;.�V!Racommo'*?&9  as� inde�B-Fase2�66�i~",U��t�Q"K2�J�� "<�� � Pd1�j��ide��7&4 E�N�}#ri�'!B2�impaR.� ( �UA��>�e��p>^ob-@2 co�[aW�; .c��8��1��cri� �. ~27-�� ^8W,.���P9Tx�o adap���A".Q2�F"ba�[4[42:I9_M�=3Y�ca�eed͚9���QJE"a@$1�.��!� harm�>l�\!e].e:���nOEx�Wngq�%� is l?u�u�=s����"Lo�,C.�)A��Fpr�`�-�t��_aV/�3�- N)�e�S_ o��'i4ag�mN)6cymJ�W/6ymmet�.��)�p3� �A0��[[8�3:, 0a-by�=47)뉅� �me&iGa�-iz%��IV �U:.&$3!�� E!�� >Dw#-b��*� ���yNp�5 thre`A�metw�| e��tic����.�i�B��v4 ;:.�/;+i )-�a��'2/ %�>�+z`b�Hi_A�Zu�I� �"J# �&m .��<,!� seem"�S�4+ M�. �!*F�5��verh$!C"U$<���ds [18��V�[i6>_ ��1 A46X�$�;Gp�fT`*q2E�6GenA��AvY �Iyp� �isz6� e ,*Npr"W� %�UH� �� �L]r*� t��6[88e�89� .�3.^��/a@ �� �"`��-�="06�DB�.. J3a�eRb��6��rtuG7c "�U!�. O+& @AA�8, E!��grsa�&ct%��fac0vQ,B8U{t� I6�6Ayl fi� ��R�e�-*��)^��> 4&�d�(a�.Bjr"�,�22?#ys&%.sP.�7s��][e�N 2AСB-�{M+"�"!�-{ downUf���2���E=grXngZ�2��A�!32@ pontgW92� 1��90a�"�\�%hɃ�~�*1GYX��4h&�f ey w�<�<�F.99�ba�ir^�"4"�cb/*�Z`it1��<�P$d6� i!奨com= �� �<&�&�h��as/JA7�i [v& nalo.Jcou�<outcros�F��inbree�d�J� ,i�!�� ex�&\R7 ��ei�sautK.��It!�shea�J�v natu1>�[9: 9: S:�j���E!� �g�H2J�p[iP4 �E�{y*.R�%�N� � ;���M0�-xre��dto�yc�liA�&� � &G!�ٷ�#)�&IM�o*�+��<�_&� !E�* �S�46�i��M"\J�oH� �kl�{��[9�C9�M%�Je"up��!E�iHm �:L��6�'�o6�8� 6�Uu� uE,J� :�B(� h@� W& i5 ( um�u�8� ��!�f�>das�$�!�R'm#fh<JP?!m�MbyO9�#. MaleB��/uf)%}>�gW "x"s�9to,�Soq�a s1�t&�4fra"�Kde-novo5%�phdaught_(TQm�t ��&2bSPl�l� � (�_��)A�qtE!"J�B/i�J�� &t)�}FA�eE2G*8f  yR(u@via�Z%O��A<)�p1�sE@ �Z.(i ,.Y�oe]l/all(sup�G�&RW� ," : [9�9�i+l[8s2�Wv(Fn�n|�>Z��hF� &�J�/B$`�"�per�,vep���"d m [97&�>&�� />5���6Y<&��V?N� � �6}:R W!�2&�'�� %6" �, B� �n� to.&�]4� � ���ZA��j7�H��m9��[�s A1ed�. Hb �UBK.�>v] �s!2JX���� O�A f�r$)Rn: r��½�� �.�u�,*�6y�A��^, R 91�%�m�Tmr9m�Em4: nd M�O1+x6?m1+2+xDm2at�% �$.�e�! �""0F�[�7�e-D\ach!Mb6�?C[*M"of]��% A�;� .�;"�"5�y3m�ZA�>{9g,"�2 j�^(�#?uA�*��ggQ]ic*�%�l;nomuI�)15J;��AAcal�2�7sI�e�"�R�?*�9: Rx1��=x�"�"y.y!�x3!� x4 yy0 . V0��re " "Y0 )��[U!�p�j,e .�CCCH-E�zinc-f�6H' tivi� protei�@ZAP�PbUh�e.�Vre5IDin{u�B�& viru�(!���-RNA��ad�]a�� ��hibU %in2  immunerp� So �6�uly�* flav��:ye2= f� �8L|\�Vre��e��HZAP-resDGnt���w�;*�sA�x-%o�a�humanHa�soD(-L�`S�C's�n��� #Japan #�phalitis �( JEV,dengueDENA ZikaZIK�8=�E05:or *�L bloc��by�>*u(� de�!�of endL0�7ZAP enh�dfrepF+. hamp��.��t�;!�)[A#�� 3′-5′exdd-m�j��aMF@e2�motif�w!�&ET^f y���!�-�� vDF.��UTR��PS o:reg�0dumbbell�� uctu:%Y high�?A2!;4CG dinucleotid�!�map5m�ind�=confeenn�to!� summ�5D4�Y�i��lA�&�CY~-�V act�1tr�)c%)�u�;2% �Z!I�!G �(Q���. Z�r��� a�PAj��n1ZC3HAV��\kno�Gs2�!� �>�!X �NDra?;��FA� Moloney m�f e leukemiqj[P=Lh �dl�*!!�DNAAӥ, retC filo�)(Kphand hepat� B KI��;Sy spla�?B[2–6]��"c,a "in`ca0,�!/D5|�0�iL�ss5�*s�ex %� HSV-!�, ves� stop���J� ( YF���ֹ�M�[SPFu�?rm�, weA m� famGiQ���z8�Gv&Z5ng 0~�H��N <�mfh�h%��ey�.<�m�)��Kd�l�#!�Yg�% erty�}��-��� ��� �8 post�L8!ale|reg�O��,U�ma� deca39d2�-�0ɮrecru�M!8�!2͈�pA��D  ( A ) &`! ribo��5V( PARN )Asɹ�ɂd1q�p�][6 , 1)�C� ��f� demG!���m�#�>�.< T�alu:Cy�ofm�.Ime�0 9=)"VGed A549X]s2� ngM-.}� �a �Edu. Cells orou)�E*U� �;4=u�!r� o� ur2cAs�E� A�rol EGFP �,^ pA�measu by T�a��o� hNS3t�I #aD.��ROin }�.���U!6�J]. 1A–1C"��hcM!� L/S"� !?�a�4no!a� Ŝ�< luriI9 s^rc%�( iPSC�+-�E� ne�B@ itor1hNP1, *4microglia HMC3'�6; a� <s ,V obla$  B3�AC%�SK-N-SHB��S1�;%N�t�K,�7 sign���yb21%"��P�Ai�A3p t�v9Q ( MO��of�2k-�D!�F , S2S3�!L��� �6y�R~� 63.=a�. VS� @" �)Qm�1and/or�3&�eL$�[sAa"q9Q�o��7�D� To�!�f�Qy)#waCZ\���e4l�Ol�VgփY�A�9�aA� (Ia �87� . 08-fol������C!� �dy1"B� Fig 2B52�&6knock� 1�io�s �n)�b�FU!{a�A*-�rolW:$ig \ ( S6��*SU@��ocYOsur�(�.vdoplas� m ,culum ( ER )�ran%Q�cyt -2_!\A�� faGlo{ozG >8�&w�0a�J��ee�Hch@�eE��)�A�.e$ � * +Y7e`o � ofluoresc +M%dsj bodyZ a�[2m24�5-� >:���}#--+�� }��$sZ ) .�l�a �>��>2D%�2EE"6��?p#)precip]� on/RT-PCR�ay�mnt �� :���&L .0��%j!� �!m2 �m�nt:Z�< pull'[�SM �F��>c/�Z�S�!�-�fE�=:)�yA��fBZ �yloo�at "�I�.�aby�e4)uct+�$ncG. ( Z�do���&E&28(��>�+4ZF% )3��W>,��"�Ne��of d � ( WTeA�FVR!9J�3UnI� (e V5-tagged_�g.qR�V5%�eWb��a:�e>in :��� M#ol1$BJ%2�� .�hWP�<���4s�&�-aZ" b y.�. J�-�C–3i�u�.NYq��� �5�a�ye;&LMwb� �aRT&G eP� Q6#q�M - EaputeE4��A�# bra\�/82whqitly2U��iu_�TRAILR4 � ( S7�y= a�u[���g"?yJP RNA-)qr_ ic:�s922 V. A^e�D�� !�ԅ�g��a�r]��! ��pr e nG^�joteind *o9f.�%�ass/u�� *.ka)[ ���5�� 4��AA� � .� a�-:�!���A\^ py��!.�L cZ|�� "f5�.zon�r%�d2 houuPost�% ( hpf5i� 4�jWe��mo�eE) !� 6�*�!F:�by RT-q� . No2�&odFQEat�pi#S*���!4��3� �* To"���UA�"�Y�$�1�a{Hl89�%q9�iv$�E7.d~�)a e�Ej�6]�-d He on, �DU`�! 293T/17MoEv� I��e: lysaII�u sepat*�5M wo *;�L�8E�lucifer���nd�E,�3��C!CN1!���Q 1 hUj! A�"k=!a } Z�:u�-�2 1ũ�)�%n��2#�_clarifyt", "�/� A� UiA�%�,��!tll�Y��!]%&]20 �{)taA� 9R36�aj:�a*pAhKEk��+ ~-SG� s:`W�>�� 5* +.�AX impa�lN^� �*� o$%�b�l�a����A�N-d�6�lF�$$!� �machin86 k+=(U){V>p��ci�+a����|� ub' EN�%��*�ofԁEXOSC5!�� �-S�!�V�b"c �-)O!@j(ach3ӖE�Vsu� ,�&�|�i�6b�I[5&5��Q @m7F�h�&by6�- Y�5� A�e//"  6��h9�&"�@:vAC��I�m���>�aboo�[V(s���E٪E)����2 �$��Y I IFNEpro��%4�gkin�*>%�vt6�1!4Aw�>I�.p sl]&2�� �ba�$�A�8IFN-β , TNF-α� IL-6-�6A46I4*� chem �CXCL108 CCL5C 8C i�)B&}�Yu��edr >9 �6�i>5S/�i:7=kI��, �:~7[�!fupj0am RLR�6�!%mvu`q'� B6�� or MDA51*���� ��. C�# f,"U MDA-sG -S���R"terfer�\t12}g2 ( ISGu&�2, IFIT_P/��ISG15i�w��A6$+ng��Y�6E=6�Ajq%Z �o"l^�@ ly w�w�%!{)� 7��!wa#a�� U�Fg2%�!� Qi8d2G%)-� ��1�-o�7�GX-�(�Verq�� %�iny-/-5��/- mo9�embryon_EibA�� O��2V��&�!��>6�cs4: triglin��%NF, ( CLI2W`uR8��!G"PngIB!>��S2[ ng.�a��ric�"X&�>EEsub�O��o n�}����)�U ( NG4+b� �#�Ion To�plaͧe�Hk co���F8 l pl&/Y%�FR��2? *60aNmy!�E [0i�7"�t��fW5a�n� !�3� JR �%A�����I?�%)Y&���UE:R�%�(>+f2ax:�A��J�%�(>��0FA��M��de��e�&9 �nfen�!�!_�  197 �3(%?pluv4102 #H��A!� entire9RflaI�firefly.�( Fluc ^<<pGL3-�r�� a SP6��zJr:ig 7B0�]�3�E� vitro5Xb. A�!u!��Renilla6�R �,E�co%��.{[2~:�on�� "�  u�!!��>-�(er �!�!�!�E�le���#[ �*oumA!fri߬1g:v����:�J3 -�!S��-��as`�confir�/t�b��ki�O��!�2�i�ZF%���}n�onnY2� W�lAqB5( S10��&�"j�N��of�m�,�� -seq�@:�um��Kd�� BR: -�9ٕ 8 II (J<5i�%&[!}���%c� D�,tem-loop ) [���;6|I&8�g"� !>�I�seE ��(ZAP�KAUbiotiny^ A2ɷ4sEA�byT eptavidini�2�wes�C�%t2 !vL V*Yn-S�. Dr)M��a 45%Z� �-l�Z) h�u t7 SA �qch al�I"���=X�7!U$n��*� ��.:� !P1�to�+IIݡ��6�Z-:��a 882>m�\f1To ve���R �$�f� -��2�1t5 ��I � ���-uCF S&j%�@ ofRGr-S%�" �Dm�WT}0u,��!�+I�*�!O� c3 -���er"�5�4ty!�ZA <���6�� ��::^Q�U: may "(as���Ao&/2�.�. �*k"� "eMa��e$+v*�f`1�8�� &~YN�8�2runtil�Ds�/"B�/"=/��� *�2�.( "67�.?� 8F��!��7+��<:��&F?;J!V���,]AFG11 �o,��2�!B�2�'no�W!$1V�95��\1ѡ���.[9.2q,��M.�Bg�Jf%d!�� jL,I:T�A4��yW stoob!a�6�����MMa|A �}�� f� za �; NS1��[�+s0-S�_� P6S5���?+[1;tM<ghe;%@ 68 RTA�� v6S�b�Vsv��9�6�ole�V �a�����.�; UL41�&ri*�8��*$>=9st��/P� egra"! �7H6E��:71 3C)P�0. ��3vag�@U �TIn} hand"E�ne�k}�� 51�n�. "f]�-aB�-�.*|iwe ��� �e�j%�E 6kw � � �� s 2F_�%fA(� )"�#,��/� &��B-�vu^Y�MA�ɰ s/+O�W� i*�_a fail��M�2$AI��� |=�9��>�� �as��o�iB.�!�Abo[5re��E@to�� 2�B0 � e�{��,���;��F� o�erZf7_�eA�?6Q.0( �E�ov�"1�t�� !3�M �>� !�8�!�� ~�Dg��%F�y i6�?B�ae�e��Z �4L�!|E 32��a&m|�(N(U�!A�en EvB��J��Ya.��!fypp �.�-J�E n��p ..# mR|�F�"� , f �!�2�of>���eHD�CI@���7%�A�.�/�E^m s6HA pseudok�s3�D[31��Q!S=^ ��!�Rid=\a�B�iM'� =Ocan~��uRW8�!-S@]�_=� Z�f R|=&|^rT**�L�wY�&6 d>\!,Newcasidis�."(?�S)r s ���1 IRF3�� �� �n `c�b��DTe*[>IU"6~  M�"A ��=of4Rs�A�98E�"�<It��aYF�#ir'a�a�IFN�~ �i<� eɪgc��eI!,e�) !�BW"�'-���S"liN d��� B!K?� �`�W��Yat���acuteZ?[34–j^�6�~�!.I 9�&u�� �Kdef�>��<*.yJE`dun2-F-#3@�71�6�e�ela!�6��~J�Cm؁^�NB!z\ ���m��J"��� aC�_�.�E-�$>*�#�|A��W Rrp4U"9$@|0�4[%�OB2�z"�C� utiG�sq�& ��D.C&� 5(zl�thM�f�=A�O iX �bA�HI�Gnef� >Փ.�el J2H.&t�{ p�1i�"� ly)A)r�;'|.!��tN0w�Q��is�"��A���%��b&�%J�v�%m� of �!#�JQ!]!H&)A�n!���"S/A�!%1�H��Dhwt.��5��-)=Q�FO@IA�Ry(is� to9 e�gE W!"�d ( sfl/5��%�egs* nd WH�A!M��G̼6�0�%���b q �!d�4.�'"Fm!Te�pKb�n� �iR&#�"ai�� F2C� Y �&�L ��B��r�k)�ٛ� m ��.�%FabundQO�1w>S ex�kiO�iE,��%���� � o�A=1%�.$�> ~��[1.�!.K��y*OA�v f�5]g&� to*d iۛ�vi�ab� �9m&g# �)YA���9��BlE Neu��&� RP-9� <plaque-�a>OTaiwanNT109ZP (�p Bank�Hes�Y: AF0141q �h? -2 PL046jR;KJ73472�41�9� PRVABC5�D( 2015 Puerto RicoX,N�KU5012�T<5�Br#mos� C6/36�A�&ATC�CRL-166�u�,in RPMI-1640�um0=o �%5% fen�b��ru�;FB�!Ho�Wnt� *�I� a FF�"��7 SinF-Luc/�=�l�2a2]%���aby�+Z kid�O���BHK-2%. 1 CL-1!��E�nd%� tF�H%]gr#�!! 0, 2 mM L-glutg� RL-2Z�B�J�f�.�6�.�EaHm.HTB-1Af�h%�JF1�30�Z%_uE!2�A6Y���F("�F aZO�� ��e f"l*�frogram�!hiG[Ӧ 4 ealthy dof2���?durqJ&%�#^io;F�< e ���`on Ma�elTM-co�d� _ . �#!�~um:Es /F12�!N -NEA�� 1:10^zInx$ gen � N2=oz�V'B27>(5JNH06��2 mg/mL�. igma-AldrmtcAM'1 μMJ!AC IGF-V010 ng/ml , Pe� c�. Lipo�$�> 2000}' m(6��_5��U`:0D� .: %�6R%j �2" (ng pLKO . 1�5�',/�Ж2:4SINV0�&2�Q���B#pMD9��,pCMVΔR8 . 9�y_J.�TB� iv"�M\!�e)T >�//) arti^�% har)[[6n6+oS at 80°C ~J�QuI,V�`�con�i�by?hedy L�'� P��JAon kiA� LV99�+ab{��<|�(q@,�]x|H10 μE� puro�aFvoGeEAX� lB9j��"$�i�cA~.�-L�*M_02011=A�&��v� �0A�FLT-t)�2�ME����8Z�es k8-CGCCATGGCGGACC GGTG�6!�%hACTAATCACGCAGGCTTTGTCTTCAGT *�cY�,��F1/V5-H�S4.r!�TOPO-TA0A�( K48F�����G%462yI!��b�Yt8C*209�r��8�J706!yc L co�&Nt-L/F�~WAGATGAAGG!d A AATTCT!JATATC)A(kA�q4*A+d )�T&le--��A��E�MB�"}; -.� f����BI�qDsub-��self-&�fng.-�( �����&x,Ae6�a9\sera2�l�,�J�*�%�ituj spl� �,-foMAg� u(SFZ}r��iH.*B�fqDe���=fi%<�A(de�D ( 73�M9�-��,$ACCACTCGAGeS GTC/adAAATGCasCaTI�L ao+� UTR/6T,��%+i�7%: SV409"�5n�,��n,�8z�o���".-(i>���+)��it�K�X�3!)�2039\ 1097� |ts '8)��4(e�fT 2E%��&�Em�,��8 ( HindIII/NcoI{H)2� ( Xba  )!9:J;%2�GJ�-( Promeg\�c,�A�l��t$?o%`del�FE��Bs:�9�I�8'��J U'% �U�6�9: 536 M:Q860��.�DW��2];��"7 �_mGTA�G�.C�7AA�[4, TRCN00004196�, E^BTaIa9GTCPATm2B29673�%Bm�9!2-G��GTCAGCa~��շ� 0506�D#�:C��%�TAAF�302�CMDA� CCAA ~L GTGTJ�05084�!��N-CGCGA)�C�ZF� 7222"8 "}i,A�N�_�!i Ca�F ~mF� vfD�u-� HK� EudV� ~ »A�& �4erc�VX� J��:�7�,( V80%U� rabbzn�V![ V813�N�2O �yyK-b^J )mTX12013!)�ti-�9S  0345pTd �3 : 1244q΄Tex k�� NB600-50��M�NB500-19CNovus B"9�s MQ~ #374�_�I~: ( #2 FaW�n$Technology NM�0ALX-210-935-C� ��Enzo L!�S�7ce�uHab1688�qAbcam]-#TW(( 118144600�) RochQyTõ\ wa.Lt@%"lRNeasyg K� Qi��ForFPCoeg��K�xe�CIlby 4�h�ae8�i��SuperS�4 �+��-S� d Synw= is Sb�:3. ��&%7H6� aj {�in�V��| $real-time �F,^�aseL ���� AD,2�,ABI-Prism 75 s���pIOBio  'a��$%oO?����3���.�PGAPDH�JFi[cal�|�TFh.O2shS��$ ( ΔΔCt �Q��1$TaqMan Uni�d�Ma�Mix)�UNG>�!4��:e�&r̈́ �$( Hs027589e�,q -�0 Hs0107795,�.09856͍TY!11136��,C@Hs.228�Q,d@ . 2425�&�JD(( Mr0398758�( R�%��WA�E#re����q s &2Q��/���!Z�=~���B�by 4%> a� aldehyd� PBS^ 20 m�#W ermeOL�[by0'(1% TritonX-��i:59�"�e�^U 03%6o albuv ( BS�17%'incub]K! ardtiͥb�R(8�J�mSci� W ( L/�7$16820-1-AP��Lt�in TBS.�1%� at 40�.n � wash�n�=, Alexa�8�[ onjut�&l%�@ �(2.488 go��ti-mo�-(IgG [A11001~._56.1�2�",(i�,Proa])%�K"�1-HA1.d+��%�add�*or�! room te9l'=4B=\Uei 5s!�w4,l, 68l diamc5 o-2-��ylind�V( DAP�[!�0R�"�^ photp� �4a Zeiss LSM700��a��SV M]scope)�a 63X o�<��. C:SUw�)2$PearsonI�$!,*�}� C&8�4ImageJ softwar�FNIH�UCoN�(%�a�mcy�,6eV�, moci��&�C"�E��! -6>r*Q�pre��mix!��in ��j A Mag SIpr�K Xtra�8-9670-6�� GE H�cA-)M��>G �T(n�or�( l��37�,$EMD Millip� @��a�4 )J� JX� x,9#I�u=H6��ngMH(�  ���bI2SDVA�z�Ve9xE��/ag)^ affio�gel�m734�F2� �.�w O!_--�-a[ $�} �� �@I sVY �a�bL/LD"� a�n� ��HeB� EnZ"7" �@�{�<� �� RdRPJ�Pd&�B LSP6-JR2A NS5mt/pBR22" [�Z�? frag�%� �?/UTG>�)'"ZE�in*�= &p E:�H 2EZ�Z��*�82 . +E�.8+� lu ��:�%�a!�1��+��b� A#���1s$ � �h RiboMAX L�& Sc��DP�U�&O -A6)��i�eog [m7� 5' ) ppp Gj�Amb�u��� �:!{-c/sy��1�QqU(Q6�2;,��A1{!�)E|� $F 5-9G��:>| :�E��5�bVBV-labe /RNA-�1 !�äd��al�`5 μL�1�f�>-16-UT��,9�I5�L^�ш� �*�fR7� !�3��16%Ca�����u-�{D�I ."���.�D.4 -zol!�(Zymo Resear)!�:��( chec���� rophr_EH��i5 se��o���{/s�&ޥ2�2ueD"�� amouKJ( �":�-� 10 p�7�-�=�pbeI<-i1<7 �,��BiAP-&c]�J}"� CHAPS�� �1� MgClW EG"� 5% Q�p% glyce��� 2-%$aptoethanoE*� �6� c� V��� olumŤ)  P��+��{ 2z �z -�� Zn�R%Lu t/μA�as".(��ur B'nd�n )ye��t�(u�A�30aggq[Ma� , 30a�% St*yBMagneSp3S���e^��.�a�&� z25a�.�tei2�e����e*�NA>�wi7�t5!��bP!�� !iof 2X -PAGE�<�u-��O-G orao atNj�ul�EE�h\��K���lb�O��C� �ѣF�G]��-�w$lWE��'a,fF )!Ag"�$bP�#:��6�".jS,�-�#n�-� �)6^ !73-9X|Ltb%icol��-_&�of!zxeg�� T�[!i"y�rf�Z��>v�, �F.2$J!!Z8"S*!S!!vJ�#�lZ�b3 5NFIE��^�"b�-)��H�t�M C*� W�ae�&pu�"+nrotocop��>�=?f5 VinB%я!�.m= �!A82� %�UV-"d94$t 254 nm��% mJ/cm2p UV��at�ker 240d3���n�02��ʁP�H��!�-��^Y(� Tri"����0: �1% NP-4��2�!�5^�, �#�b$� RQ1 .�P$# A/� 1:500 dil�� �EN055^� mo FE(r�.%�})n(a sha!Vat�v0 rpm%�z�^� ��v *%!]&(^���?m"� G"�( �V*�H, R960-2- I"�(;�{ G��f��>�A�A�az . Sa�>ͻ.xw�eBp��`]N!�mMI!�F- twicq&. ��K ( 40)� Y�Kp8E|R�2��� �D 2E��t )��Cnsu� idog5In��de;in-1�)��?!@���q�7^k>�Ql�8E)&.�f�� ��% lib���t�!"�*R��>�v.*��h�~Rb!��._tH� Z�RPGM��(n��Kw<_�������� �CLC����$lymphocyteI�platele��nd elici!a!Vong ,9�F�which5�1: high!us tit��[.\ �I!logy . L� penii���wAAind� orE�1JA�t)� !q-� recoveraM�ng4cr�{A G-CSF5�on��d,hepatotropic�IRsaudies2�5�� hist�E�e�suppor!6thCf�ngs; how�!|�t2Ka� -inflamma�u� �E�r�$�� appa�K. Rathe]i�Y<resul�in a c�}>�%|!7infiltr��AWe�oreactacells�uch��neu!6hiI7A�9byJ#.A�b�qi� � ed mice ,A�=&�!vpr:&J�as-[aP�Ŕm���E�!�� ng m�@goa�݉T%�-�gg� that�'Hge� in ��-: a losEہ�r fun�ldu�� necro�V�E�� ye��< long-term cours�}q*for tho���might��A� ini��Wis!�r!ic�nature-�is6�observE���|BALB/c��model . �^L( family BunyaviridaA4genus Phlebovi�y���ly5~icA����can�#�2�in both ��'ruminant����$classifiedA��N�,al Institute%wAllergy%I�lious D�E NIAI aF categj A priorit�DA? Un��Sta��De�} a�Agricul%�( USDA )%JQ.Ѕ�8 �� in sub-Sa�nY ? rec�,outbreaks on%Fo havAa�Fe  i�zd rang)( this-�. A>_�South�,( 2010–May 1 )2���$ 250 labor�-confirm�aseq an�'rox�  fatj y ri $of 11% [1]=0transmit�primarA�(by Aedes mc' 0shi mosquitoe�although%*I� has � tecO$in 23 spec�\of.C[2�Giv� he abund: {spp .E 6)a� in o� A4e�(worldS "� � �o��I� aïv+&� E��jserE�aU�al| public he!!�l [3] , [4�E$ �M{ s� �apeut�� terva onk ��commerct availablIXpre.�reau*Fz(�Gn�e"]�2� varysiz��intensa�!qlo�Ao% ��parame& &Dupon ��fal)0moI<=�[5]–[7!-The lar�u� rded�A9RVF�qin EgypS  1977��10 , 000g 2 h� a s [8%�9l Pati� C��!�0malaise ( chiheadachE�joint pac nd n� a )%Q�� is debilitng�?aKrt _od�sm! per��agv≤1% )�pR�mmanife� � &t2�, reti��vascut,A? 6�. Mor�. s up)Q%��e�re� � se1b9%�1e�e^� � mE mor+$tastrophic.�ўs!>n!>s�Q��pa�� arlE� preg2�wh_ ne! 100%!C�"q g�Jlir fetu�D[1i�1e�A�� � ��voften be�di��byU�����?s A�, [15A�A�@ree�.(ly no licenqZ>sET�a�.1E(��J��[A���%�y� aL��www ." triaL gov ) [16E2EOn� ��m�promisai!�� F� � [18]� � develop&�(US Army [23!P!���F512��!assag��f�w") <ZH548!N��'�45-fluorouracila�8 te a���� ulZinEI�ew��!",�Fur� analy of �found Ri��duced �� traliz!Wantibo� in-H�t!�pro�)flambssubsequ�ch&�w)9#��[2e&)r��;lyIJ �o be a@ �� adultD [256� ��Y�to earch�thr"|S^� siz� (s Program ae�U-Ma�al Re M*� ofZ� USAMRII� ��,an on-go!y")e (v&�Va$a lipid-enQ�icosoheda�1imT8]g tainsa seg( e� negak-s�4�ingle-A�n�KRNAA�ome [2�a0R�sB ree\s:�H ( L ) , medium ( MAS��( S�VL?��oC aFv polymer&,a�l� MB34I�ins: G��d Gc , (� $face glycoE���NS��structu!F "��a 78 kDtei�S�� mbi)H�en �xwoP s: N�(ucleocapsid cNS�(b�=*�ofBcaV���to���I� ,rferon ( IFN~ tagonist �� wh)diskperty� lackAG��>�!��Zmut4clone 13Nch��n-f�  d��;ء [30w 3p O��tha^ ٘rol�*�I�in limi��J[32�^34U�elq s kn�bo�e�:"#��.Ŧstudy��Sm��4et al . examin,a� in"��follow!L>#�B, focua�[i ���M�!= �� �A���log�chr s du 4�[3�SA�hdi�d �*�he)�ex�� � L-T IFN-β� ��6&�w�?���in juvenA�2!5I�utiͺE.arrayA�r tifyg.u� e�a+ >�S)_j &�|[3";Idescrib�d� ��&x�N �* AI ship&�hM�"�!�I %�gen�� �"�!0YeYU�eieU9�E�h$X&�[�iU."�Ya��panel!^wM"�%amultip��i�oX{� lete],)�A�F M�!� measI�.��^*k.�� � �of �!�isodqv same3�Kenya�7� !��_ c�tso��s.hly 99%M�t W$�o4>��u�ua /��bia� 0toward a Th-1� � -�� ,B��RchEn typ�).MIt9�[3_4� ure ��  rk!Jiffer]j�to[E�:�!\!�]�C :�. WŹnM�YRdE`ta ngI�body wei !_emper�,.(NJ�%/pro �A��A�.S� �����B�H3eߥ�.�V`F>d�. z��or-K)����Y&hAJula@ �Q<c[eF��%�"� j ge> Fu� %A�aKa2��?�iE�)NB�!� ll organs��;�e9 e onhI 5ISBP%K,A pr�lyaF���a�NdJ� could als� >.�%�al5��!K �of�l01F� vers��@�Ed օ�*�reinforcI no�X�pE~�]��% ]=� �r�2an unre�z��V��a= .�Z��e� !neu�� . T�'i8��yEhco�A. ccorD%2e��k ocol��bc�io) N C%$nd Use Com! IACUC ) (d Q#0505029� pniver9of Texas"|8Branch ( UTMB )��re�nd�M� Guid!�2� of L� �B *F�H�AIi!���E�%pO�%��OPHS� icy� He � of Vertebe���0%��$�%���.Y�k%�perfor�at)#!� fq�`accred5-�Ame�n A��� he A /%S�l>0 ���WdA :�i��Tob�edE Dr . JohnPril-�!te��6#s)&��y;6� � p2wP"n p1 ( �) y� VreceiA��%�Mo �. B�tes �e�d� !�d!�Vero E6{�8ATCC # CRL-1586�FoF%&� �� , h%� dilum�serum-fk DMEM�o�>oc� . A'<( 8–10 week oli, femal:\ L( Harlan Sprague Daw�%) �i ]l&ubc�eously�.f DplaquepmA�un8%( PFU�I,Mo� equiva�volum��K)� LD50%� @is ∼1W . Ea�""s�'��sis� of 5���T�:/!�� <each: k�A�+��e!IE\kin0b�()eud�$�!y?h� post�!e�( hpiE M!�Eq�E�igeA� sacr)�E�last day�A�&{( ha��� �� .� 1 � a�&�:]by Bio $ Data Solu�6!DSeaforV DE )��n?dximplan!:tw�&yVM�9���involvAGhandl of-�Y�I,e&���;`he Robert E . Shope BSL-4.��( . At=e� Zblood\ coll�!�hez#"!]" � istr�e�>"U =.��F� O �\2�q�]�� . Ap"�ly half!A�( m'"�(;", splX� )�har�(e��hom�z�r* 5 ml PBS �a Qia� Ti�Lyser ()� be��>����I+rempeB�e�γ-irrad� ( 5 Mraa�;!�5r.:�@u��100 µ� �q 10-f�C�al��!��VP3�incubg!�1e�A�a 37°C or p5% CO2%gen�)roa�<5((u�!!!�8%a[gacant (f/c ) /1× �Dla� appl�"toEkw . After 3�A� A�.61u!�� �s��%,�2% crys�.violet)I<10%!mal"0�# Ncou�i�d@. V� Z "G�( og10� I�Q�#Xm� ro�.A�� �T to manufa�e!�i@th�,A�aq,Bio-plex 200') (Ra�Hercu�-, C{#. Brief7 !SI\1entrifug or�mi)�at�]rp�4AE�a,riA��supernaz[���aliquo)�to 96-A!�A`l-=~s;�#�)�/.� �d#��anyAHtdeV�PF#fer�� to a� flat�%tom �9�!,�+u$5�L,=�j5up�tof#fic�)� bead��U!�.m !�.5' 9E7I%pr!L��Aqss��^�{H�-!�"e aN;&�Brleuki�DL ) -1α/β , IL-2 3 4 5 6 9 �L ( p4�!p70 B,17 , eotaxin822��I�-Q(( CCL3/CCL4? tumo*��TNF�αE�RANTES =5� As%�A� ��y&�by ELISA*�And( PBLA��4L� � , Piscata�3 , NJ�SU2� 1(� imi"�&A�ܑ�� '�"A���:�N)s3* ��!D}��4e;�-b � ad��4!Ya�co奅����d �% washA�� p�J -�$HRP-conjugXse`&� ,�6aTste&� Oi�x%q�%�t�� #ra s� %*.�+.�top,hd�krip �!P��450 nm�in ͕of "|of9[.��? ��KCB��&0w7 a Hemavet6Z alyzZ Drew Sc|&��, Dalla�TXE�A-"�*%�� whit{W|!A� �eaR �,)���%globi1e��,atocriA.^A^ 9�~nsub.�3(*�0ͱG eosin�%�6F/jbas 6CL3.� R !�lɝ8a VetScan2 Chem� %E)rAbaxi�UnaC?"�FourtI alO2)��)�a6!�.(enzyme alanL4o��� ( ALT�f� gluc�, amyl"%�sma e� ro z( calc[!(, phosphoru�soq!,%-potass&�!�u� , alb�-a�E0y(ru!�(, urea nitr  , �tD"'"!� 3�=.�� -fixA�i mT&��Sakura� -Tek VIP� or�nd)Wm% � araff�. lock�  �f� i�#o� )���)�m�4on pU" techn&�!�S�za :3i6Z ��s b� A: Ant�retrieK | DIVA��%steame�20�  ) ; Perox�� Ap A � i 09B!Ar� /Ro�9 M ( 3d��%8)hyper-%<e ascitw8luid ( W-Re�CT a��Emerg{V0�nd Ar�0�A{�5 ∶��d�J( 6�SeBA)G Bioc MM�t P-�2� 7 ) chrom��DAB%5m-58 ) CEZrE-�U�xya�2re ����$�3Fishe exa�8e:�;"[ Eb i�;;��!K6x ����%� �/7 A Kau$-Meier est�/*.� �C!/:96+�: "�d�� . A�ticip, �� �"j��$ed�*! `�d2<�"|8until&�dEa�end�q "�< .-O6ybegI$o�}illnes�i�# . ruff, fu�d hunch�#osY2) by 36��)�6od"*F�t!$ succ�>� 1. Oi*s`)�:d�s�<ito��d�A�=�� .�, 85%��vZQA 30%9st� 3A�n�l 6dq?a�4 ( Fig5�) �� mo�IMA�edIHT5i:�  "�'w+s!. D�!!�b��=nV'E{l�6ha�g`-5(or became f�le㡡.� s��&mp/n�ag��&9pro tool%���4wA�hy2!#�ba$i�1=�">#�7�w*�!7on�0.Z"& CBC��)L!�w!)ire%Y$ssess�!D ��F&�OI�� W��Q�b&��e��q>ac pun�ave%#!�eC�4!k"X"Mc�w>v (� � �jA|%bI� ��%��7��M}-�d.V$U�a'T%�Si � CBC'��Z�<�2rkably 6#t); �or ��1R�60��w�  drop%�  )2��w60% 72A�6bou,at 84!9���de F)�%&o &� �5WB6a�N0 m2$re&h@*# �$ �'M�e^[� �A�BpPI^�);lev��r�?vea3,9^I1�)N}1�cI�5�Q�. E*� �"�%�<�"!� �a�.�� w(kB�.P �i"�"iA@BV*| *�5 di��>�Ce ��/)�� W�)s��b�(6DRBC{R l�5l�!�'Q̡PtV�. H"a>at 24E��c64"�( ��n%!?6�m;e�� nIor2��Z�&atyl.�f�audd �untjmI8� ng"kp�"��uin no� :s 92–972 K/ul�r%R-��i�(�i!?e."F[� drop�3} below�Era=<sl�'r�@��5uT���<velW92Uagan tq;�!i�-0�&t�@ [43]�o)�A��5C u!P�7A���:E�s��disrup!�h?'/��+>l �����A-�6ys"?@!<s�( } t6��|���Z�'s �ressed�=~�"M �P!� �pea*� 2at�!�F�qh�U49"�)I� D�9��he�3 (17–77 U/L+n)�� i{ajE-RAL��500Bat�,*! �9/f�3148���m� l� ._of� �ir �9# . No tŧ �ck�d�m�g�2us�8ve 15 �9`A–BIS`#"~ �q�d{Enlo.)>{���^!�,V*8��)% ab�-�.�Tb&��#lson�)�s:�7u �.!H :�%X%WuOY �:l^G�d���A,f��s:� &QKi -?:�(�Cw�K:To&�*EY"�:��.� r*�Li� tv!wwe*O!�%B Tce�2# ;L ed q�by!D\%Iq<P�U|1�1#ha�]nym ct� �!� ny ���thez8�.vir�IY�%a�� �a�2 . 5 "�/m�3 @���X �l�4A�∼:P&byQ��@mssa�I��* 'appea�y"� �/loa�#just � r 46� ��a2� i� ��0�ȡ�asa<onger.�(2} .�� , 8:�� �#�@�#E5ȑD!�p1?^�����X5Y i�.� q���͌&F%��76 ;)yq�#-� ��Y-|E��se9!t�, m66m/us62/��0�3. �*l�B~fJ*O !*I  �), թr%�viat��9 B�� .�g ?![ ]at>:�Y@- v:lA�8kde�~A�ADe�> R�v �  rem�!�/"X(�Z B�S�/^n4*I?"�N&��!? �I֭�"Imid1ctKc)�s 5C–v� �qv"�2hia�ei10� &t1 aѬE�66� �. SID �1m�6�ynoM���t@�� )�e �'iA,�I�-�,j occay8[Ev-posiA[�%�Gpl$7V4 pulp sinusoid�t/l�Mid� iclG�@Rn� �exhibY.cytoplas�Q�E-=�p�6� %��!ma�5g�4��6j]�ER48� ��t2 _ar2��(B��#��"��75%b95 C> s af eo(:��>� � ofV�Q�M91�Z�,ZD �E��'���(Hsix�con�'.�6�� 5�+�'1Vq�(��or spiA�}23!i� ��%�)���,v�%.��629&�3 �S�a�S�4bK)P* !k�3��,LM{/A��or�"��;&�=mer5ism���=��6G5"e�*�!�6�O�寧>@5%�+0m�UC5(Eee\��,-�1��2cL5t�N =aO3 i prin�l.p��R1�� �?ay21h�1�;�J8Cd '5E �3 ��un�.at*�2�>EUG*�JM��;7w ���T} to���)?�r��;%#sumL@*�A'dividual��ph 8� �B &�.�&�7 _h�?in�sz, S�S�S4Z�!�"of H&E��&�s5OU��� ndM"t&�Q�%F�Dwa�dHQ.�da�!R�I�N ~f�7�/��QE~�bs�Y*L,�� s 7 A , Bf$ , ���:q_e*�Uh�el:degener� �n':� s ejIas��VB9M$ ough�1&� 6��E�se"bT�j�ap%�%xF��>atm? T) �%!�m�J.�FK���&,5� 1��"2 V�gebs}� (�*α�*L�*8 1aI�*&�*!U�U) �&-�R�5"6%�ic9�. L���D=:� lowef�� �� !�E�m�KlomJ�NF�f�!MQ vacu�?�k\KI|"Srandom�!FT A"� �(�`%b%^r��BNU-M!Cva�O �a�% i�!�5Pu:�60q����BwW:Y>���o�of*��Kup�� J � )?�-=�  r�O� �ciO�Dic^���&A *� 6�'6�>.�eq)�%`A:$�6!!.�QarcV�2�AIp� ���i��M�&'f��p�dis��h:���lic��0,�6an� /� al 8��!'"� Un(�$�Oe )E���dhRc M� B� n�HiI�`� tac  =!(J(-�-�QVJ,^aJar*ziDWclu�Esteato� iph�@R�T@�%tC3A��G2 loo��-O�@&u&"e�l?jU�� 6�%��E�^vE�5GJw�"��gqs 7���  匵�ocPdA�s�7�i'. F�a�fto,)Jn� /CQH�+st�,����$:1�81��1x1� 1��MIP�1чa�AK �v��Meny m;a�W�#�%�aL*�u3ly�i�B. S0s��Ů2  .��Mm"�!" ��ar tim'Vic("_&6�)*�\�1��6j28��a{cs�Jo:�!d�_�$ i��e�f�\ dmi�+%��-Rc�FcrRR]�{A��%�? E4"���6� idespit(I�;f aE���E*~ �1 2�2Q������C������/�N �1�. F.WVY ajs[+TE� sc�>o"7ZhG�:�%�fr�,��Eed epid��h4&��!��n�)abl�*de+w&Zi��:��s}(�w"]E>2ita?�Gt@9of1(s �>ch�b�fs6�at &^ZU��Ea�iNEXE�wbornpR*V" 2��B2�����"MKt.�7Oa�� ��. SQe4�&�1 clote�e�,a�W���`!�� few Mf�M��oK �Js:�%T2�N[�N551�N5�LS2�Nr�Mn&"8B��v� ,�1U.�b�N.'A!GllTaN �n %Gvbenefi�)u���i�t.�2��5%*5�SI s�b1^3[�A[s+�ts9@"qCL2]C�Vfirst bru(�X!8�6�to>�^ i���I�K\P��td_s v�c����ZKl&r%Bt}��>�BCF#ive.VWR�Da�cl� demo0<� �  g"�&,�:� >�b>�is likᩁcHi< ribu9-�.>to>�` . UnD1v&A!�a����v�Sa^fhe&�U?t�99J�[5PR*r4QNZ>pro��� R�e!<;.�%_ TdK >�v:%3�E�Y��I��E�W!%�J&mnoUk]i YCI�A;*5M;"�C&�B��C��!v.K� X �rEd�,eP�D!�,vC<-��03$4>f �lh)g�-.(2^ U-� madeIY �%�yE:{s�;e� 8�)of2��3<-�!�l�ho&Q>�dz d.T�"�+'])r�fx`he!�mid-s;^2Zf�%. O�Oy_&�(7Eo�!�.��)48�,Fo: 2*��a(0r(�P�e&�1s�6Vi�2ma�!291�-�OI poie1 ����|2g :h#of`= � M�]!R%|Z _S_9hE �� �"�S&�7��%7�a�� xbs�2!#�:���rhesu�Kcs# s [5�Q�e[ � �*iL �?!ro7I�;a sharp�jj�]*I�4 a�eUslowl:Asol{/ by 7��an��y{ �-a�.%!:P>�� �+� X!�. outc� �.@��t 2��NR � . + deat�F8ur!d*aseline;�#"�E 3� A�fl�SP�5�%�i"5�l�)a[B7<6��I-�Z9��6�:Me��l) surQ gi�eGb/if��/b�L0Y���l(x�u8in.h.�)%�� rect�c�3a�9�2:�-rIn z%iPq!2Hm �� A�)��-�� F6 2v%�*&s6��:�\��0V~. :��2ZU��e�)�a! r�D�i�iU���q*,"@*!*&)" �-6��H"�/Aa"K �owB2A�.�%��dZE�se�(�T1�A&џ �*�8Nv)��!�r�Hs 9!�(U �:*&m��h� vf� � aR�Jz"�ehlCya��i�f� &ab�>}[55PaJK?�m"� a -J!>�19F�Q�1;6�~?i\b�4�����)C�p!� !>I m�7R%tO3)��%+:�[11QX�e5�h57!=In�=B:h�_%ۡ�m� ,m=>@"}��- 5D[B��8�s�8��yip!��"$�Q�AII=�i:( t=a�3 es�nd�emia [ t:�e��"B9b/-a���Q.�h�i�v�(5�Upossibl�1(a&X!jauh �In Saudi�m ,�$6I&$m6� s�i5���nd!%i�)�i fail;A)�)xtrem� 5)(/6J0)M l�<� J �t.�"�� �q�ng52 �A". 8q��%�ps�5 M�e��"c9,�R� d%Na AybZb] IB . M&)2^�ta�=Ic �� ��Hr�a6+teg���D���!�s*�-��+W("� 7o��I�w%(w>�tB�so;=/�Oy�)w��:�3w:�,�\&B;X �2k37J�_A i� �P������7Y<to2��Bt .=<drama7  &I$ js tI��U�"R$��`��lyHZ�,:���Drs)(:���unexp�R. &Gp6� 9h6)qA.�a2 2|�!uk�Iin�:)�>(<�t tt..w6{"� <*�recruitVcZ-2% .�!�&;zpronounc6:$NA V��"�d2/�Y^2`w��6_���Sa.�, &�L�Bl�+ �(  �.,&';+�Ga��+)�'"� o&/saF[5Bi2>] � �t~z�e#E&\ 6f�g�(%+^�� ph�plei|��fA�w2*-�40a*� ��5�de�,2�J.� I����c�oHemi�%mm�� w " Os6 �y �u d (^�H��nd? �9he�I�'il�H ~FiAu-�rPin3�@[6�h6�hz k �s��.��s�VU]� �u#.h.�a� Ź4���A*V2��2�iz�=U%�&]&120Q�H&!@y +� z #"�*oAK"U�a�J�{\:��c omod#d^As=!�2�����0��N�excep%B�%([d�16*�68�-f&V"b�|A�Jhyp����i���a�2�f�>�=���Od��/:Xi�J�QA��+%[JH�0� *;MErsQs.�{�m�=� N� �J�1on�#oe1r�\6�&�"��&*!�#a�raI�$.=`��7N��h& ".akun�. Dj a7��|m�% &Ui� &��'�]oH/M�� "QlA���.�,�AB%��{���%y�ult�c.�!2_ a|1triL��ras{�!�YF �sYv>vB�F.�sd^s%=e�.��4a�i�@U�_ %@&%"&� 1�`*��V���2�beginŃMp#%[ �B��n * �i*܀e���N)a����N� . ItA�*[ew�ATA � ct:�� j"�.,r�2!���:,!8 7E:&� via".t;Si�2b�XH�M"��  <*g�!��Hi"origiy � res��(.���6� �1�-Nw� ay 8*U �n� v;- y��A!:��"tbeyond 4,H�sby  �m*e�H[�ko�:� }A�I�-"�U &t� �u"/E!�"aPwE/[H� eu g�����2��; . PrHR@\[��f�qR2:"F ��p�qa&wrprcr� �q&#��1^e6 Q2�q in-b�9m +�!� Nr , [6���C %D&� 1�7wabstM/�p�P6o#�tM�/-��Q���o�"�JP Vi�6�5t"%��1*q��"��\ɛ" (by van VureOB��A�EqQd�gA#:T��inf9 �=�/s7raI)a-aW !A ��k� }-'4 %� !8re( # F%�com�b�_�c��6i%�% -J'EBouloy who.�aciߌ���\� ��nY3M� 2}<( 129/SvPasIco )��)"L"0o248-0K I�)CeN�vqaar;�g4�-dB� M�1)key loc )�u�P��� !��". �� �!�of .P o�@ ndri�h &� �ADuU[pa�x&|B isse�fX� �z ly e:�%ng�2�a�%u�. E* )/1�� `*)Q ϝ ���^%�q2I�e Q�5Ue��* wescape�� �8Ǎlm�"G7r���<"_MA�3�ffi�Za�troubl_r2ep� -!�� ��K �0t ly^D�$�� �m��!�*q�)B!�w�B��~M��*ڌ:T�9�N*�a2-�i�O.@)�r�J��N{� d��A'?m�1���zhe* N 1�s�" �}k3P�� �9Xin��$u�&~> reY 11  . �u�) �AJ�z��~#�M;I�.0M.em�6�A�qu�3im�s�2�f�w- ���e�]!�d��Q��Y a*Q�>7p&9��c� �mj2`2���Ana����?9{="K��saf��/C�Q�`Zуoll }ofucE#"@d��4Q� �F~k"e.вCkr�?st!�O�e-� B> rc+N�cambW?�^eDNr}��!�o�_of�U(��a�0e�i�1taxani6�y�ta��sn3in5iAfo,� s�(uA� C-C motif*�lig!�$20 ( CCL20;a�Pm�� evC-�-J+)S�PA946&"none�-.  let*d.:�z �̈�l!X$self-renewW d ma�jn!�!i6"��j9 BCSC�#�\C!ta cer&-� +B�kintCζEiK)Fp38 mit�3-�%*:6( MAPK�ixi" ,��A65"�;f�jkappa aNF-κEM!8war�&l!rj�^!7cPr)�AQ�of-�eover�eA-5h u�&� ATP-b�ngY set�Xubl� meQ� �k ABCB�[/�I drug.�"MDR!*�, lea��*�#a"o efflux� ܑ�Q�� �.�-�edMW5�$}p�up-� ng �� "�h,r'%R6�iyMaSqKfeedb� loo&�i1n�-�� �+��_*K4p[�fB��e}�!O�0:9� ��+ a no-Xp z�N >rm-����I�ey of Qor�^sS�m�r*A�XQ�B��]. B2�iW��J�@c�c�"du`� m wome�"�qun��:�|3=["�reF>� , meq�aR)>��bl$�2Ez�<��6W�M�o:��[�DU)!P  ��]�� Z���co� �+�f-ol rgNJ��bt&��r.�q���q g�ly�susK�8� ���y] �!9� ? rolife�&v�pac� ,%GFW( CR )*� �� o/a��( Ob�[�3=Ke�g�4"Icrap%3 �t�oia��3ti��^�&� �)�expos)��/��alt�s�BHf�&s Fy utophag�+#s!�cM��Y)l m�% ( TI!�j-� tox�.�aim�k� ) wAm#  apop�2[.-A !sa�ˣV� \w�ro �{F }%� h�"�ofV�(��]xrVzr8��β-tu�kIII subx|}�Min!\s&�in DNb�p"b�M.kir)*eA��oinE��v�3E#5 �in�g/de!b�h_"|.-5 (wg��C�aberrG ]!'�%fgor AKT 7aU " part�h�%�}ine� [6�+ٜ �j""LsA help2%o]&Q�by k.��REoacquir@qP��F���B)�m~J!\ � B6F M�(> �#�rM�7�&nL3"���O�IproA�a�l��I-edD�� 8�B*�a��"cl:�p��rO�'2# c�as���x��%�)bD6�l?�[ "��6!6d�0sV .�] �)u�l�b�!�Io4&�$Ginsice=�h�caG-�aPT>�\W( -x��]!���M��-f {iyKgrowth!� �%�.��Vg%�djcer-a&I#$}S%��-nict#Tbal� k7p9piv�]?%mn] ReAn�'o��߉~>[9���Gil�$Hemann’se*�~m�l�ɍa�ter8 in 6lM�n-trigg{��-ch�M�a�Ian�� ! N�toAN�K+�*ma%s [10��:h�'�E��se%E#�-]e-[.N?! %GiA�N]o��n �cr�8!J1|&�j�2�b"��<h{ M�ny"Q��8 �/2"�1cl~26^ N��R��%�%"�& ques�}�~�&nsMd�"g9p�/�2hlt4 ( oc� docetaxe.e)<T���"� � risk�%�"�/A��.t!&!5 ly#݂XJ unÒq`d/�Q1of "% A/1 �d�71)�=�&�T��YI)��6W�’�,Md $�( X�mL�mgu�MyGo!hHB2�E�����!�a@��%%�ofn= �6m�)1� tA%����;–derS�xen�Yf�gCD�w �N-N&P&50s2�A"�to �or &�*� mole��!"���nde��%b= � � �HEw /ii�e5ac�i8to). ���e!~heR�&�,.� �0A�EAX�fion—&�w rheuP?i�Mth$ � RG`, psori*�:u—�V �%c�H�4�a�H�0%/lu[[Y,%�&���!)�-g2p6s:%2GM� "}p�/ޖ work��/d�dx&Bl��]��u=E�> A�2�,.�e�Sbon.���B���t��M.� II:�I�-�64 "% �6J ���chX%"Tb�in R>E�?�� � ' D �P �d�, crip��-�r���Ip�ssLx&%N j�HenhA���q�b B-؝o͆�)A�6x.��wo��n!. T�{aMv�?�%wid� recog��n� I�.�D��t>5'� 6�%�X-eE:ˡCy�� �en �� � � u܍� , favor!A�� }*Y�'tu����� �6�s�E��%7uic ��u�1�t:�R6��"�!���.�]�&�.era� 3�P�� C �*�NACJ"!�Zarr�|*�)0:�n�)��.�!i�a�a���jiW�4 1�_.� �{ "�N !� 3i2���G^�.$r��rumb s(&�T�6���jVD befJ,Q��aI)%��mp��)I(> &neoadjuv�\A���P -lin�U�oosorb�6�^ (����5u����e-7)Q5�Ts6<� !".�"ce$ngo�a<�Op�S �{��oh��.-�� �5mb *3��_��VCR� !@ E1 >� a<��K*�<&��%�I�vhef� �_. K#rn�� S�ob\H�-- e-Ce�"_6N�O`��5M�a�. v�uâ1�J��^J�;*�U!;=c���.�,�nb�w!bah!���alIEb&�OeN�l�����0-A{-�Me�C#�g��%6I�.x5Ev)���r�[a--E{��verif��ra�j@[q w�2e"edqpai�[�j�m� �P�^q)� w>���!6�Bq U|M\��Az#�"94� �it_�in Chin�A|N)y��!�=���� ��im�[} post2)U &S<#�8K� Fig 1E�1TW4"�:7Lf Ai� � %��ٱ�sZ Olar!�RTHo6���A`ap&u_!X �ekC"�an\�y�%a��ew DA-MB-231 �M�G[1H�&)���!��{"�9.Y*� FnG���Fva�$�h#$� $ �s SUM149� 5 m�,6, 4T S1>cS1@cS1C :1D!�; 1I1��T�y�Z� �7�9h%�4:x "�/u2�WI.�e�ter+xwc<"=f)p!jYtu���(!�6&&c )N�1�K; S1E�m�A� i�� �55��[� ,� �]kof�t2�. Tak>ogb %e2A LB� ��itnf�PM��tum%eč�m*� .�)�L`oor!�N���B^5�. Nex�ist"�2"[s&thM���=E�E�:~8!�y��)}Kg?� i4.&��� �@�{���6�~ -��E,( “NULL”E+a YY�e�u��]of Hbe׽`s�0!gQ_�&� �b“CTR n.�>4A�%eq6A-��um�; I �m���6*� d� �^ceiL/Fr��� �i,a����+e���D2n 6*Emw�c S6��Hi�%Y-1g%�u�F�>�&w�"� ��H%$ yg��d��!DM}doo� 5�� 2 . &� $��(��4�i��p��wu�I �!d��N&��ےp�bn�<y=� O�qu���jreal-I $PCR ( qRT- )eyE����2B2� Also� "d9&� ��%M6� �!U""�L)�a� --�nt]�( S2A�S2BAi��2� .��f*_ �!P>�EXanidu�=��� &�!}�N �W�; .�>ohlou#��W�kbyy�=�" � ( IH!�" -�� 2� n��� D2� qh9ind36�&` Z�EM����%� vo��o"@e i�&py 2�*�,�03w�,�z%aata�T�dSCC� r Ge�Atz�( TCG�https://�d�. nih .ݳ/M�R%2)I�V il�5� )�3��a A\� � 6�h m�����*@ ��626�G3i�3A�"���/*S-� �h i� )6�4��%Z=�B��8"x *:"U4o1��ersil���!)�knockL6��6�BH)�\�YS3�3�3D� cm inva% �A\��r�1� ( Ma��L-�it3at�anchorag� ��g� 3G3-EN�I\i�9�s!+:�:c =-`'1����x 2"+�Ao'+/= �.v1�vN�U�Ns�e6^7E�9����s�( S3Cq3=hS-AS3FE���!Hi���#�@(�o!�-}J�p&�(?�e-H; S3G ^�C5��$-�� 3J2H�S3I:�>��S 3J3S3K C6�F �=�b�!�6�rb��) ( rh � yL�<���b_( - %) u�aUo &? q�-�&��-��ss^b���F��:��5�e �fby�'y�bg/t�inr8-�LD3M!� S3M-�Q� &VS!�� .�͵aU��׽1:2n v�e�.)t6 fleI=dQ�0�3&x"�ude� �N !/3O 87 fca˻}�� *�rh�ov77��B�1)H��!7R� |cK a�",tn� �o5z� impac~7 D��U&� �*V6nFa.�Ir�$; "I�R"� J�-XP�3Q%XI��iO�!�1:�l!"� �0j1 2Cpr�?���2 6Sl= A�G$-�. ���wv:][( re enrich�/Fg&� [17]��4A%�a�s z":t d'/�"� &,1� . To�l� �p4 ��-)�m�:*�)$AS�.� Pdefp�*�LDH�A�����$ e�<�1.Lflow-soradG+.b*t��−.Q�I�4L 2@4)�/o<�Nd$r(t�F#(CCR#(,&� >�+- ofŏ���I��# ( S4� S4CM� Q�pr�eFYi0�S!~ 6.1prsG H= �  !�2~+"J!�R�&U�)(:. Steq,�(4es NANOG , OCT��f SOX2 U>,TNt z ��4B; S4_}:�F�m&z7�5�B �s�r r�V8J�x?B �\p��V�� "�t����HM�74D�E)#4&� �!�A��V�>��!юE- n#"�"y��+m�I�*.,U���at-s: N3 M �B"dex*u�U)!4! �J!�G*r� by �% !7-gc4c�m+��%��$2{.�g��6b !�}�&S"��i�-o!?%`� h=^\c^NQ�1�� �} 4yN"G�Yi�}&V5*� !y=�8.��".�� tro iI-5� s��a � _K!:�� �ve.� �>� �49!b&���Ge�-� � {S}�.& d)%�is1"-UK�4L�� �,[�����GA� �, �:J:�0 axol��s�g8]`A��Қ�fex�6 �p�J  ����(2:!WJ�]�� � ŝ>�LB�=��6�F�� �lo$�=��%26�x��I thyr�)� , H/& � �"' �mig\%� C����*.(g �4[1�Y�E�=r�D&�(R�' ��gP �.)s.�- �s^E"n8. 7��R6]�nR4ABs��< of G�tein–c�Q( G��B��ib4 �-2A�m&ƒX�eptah<��*"sue�[ �Yq+Ȉi&w��a�xf>�&>[2�0�*a� ,� �ed�!� � � adap� ]tLCtiA/ �>4in NIH 3T3-m1R-�[272�&2R,m��*""� ��U�;])=�by ��yl8a�� %V A\Hu$38)*A� �AQN_ŧy��:�323!��j5+ 6]aM*s*�E%�"� ]852I\�*�%AF��6+���m��=W=|�59du�� uA��+=X!�m��D� Vq/ex@ �(W' "GA�pharma.!K6�P}V<e"L: 5 or c� lF0cid phenethyl�P�CCAP��U-��S �R�orMB�;��b:"�W5� 5>�� �*at�M�!�=�lf U���V.� �sXXi�6utB�!�6!��%ubE��v1�2NR2NiEa��(� e On�f$y [Go] 698p��u} .SB20219{D-%�5��"8,�y���� ����s!y�!E%É=��^$ i�A��.!.svec!� ) ��p1lyD.L@��) hy-��F�%$65.�a9�e8>�\`=4� ^���a�a$�2abo�zB:� �.ma�*�I` �EB5>s"� }'U�38A ��=>o)�noa1�el_P Vo� )-��~1�u4,�?i�No"�eI�!J!.$J651er�SaO1n=Z�B, �Y��ofJ��-RGeW�v.�)-<�%&�#��A@*��~d9 @H :TA�R TYB�%�O�Ah 5-� e�Gmmo�e�r�5i>9"A�*� -kA�� I%��R� å�� ���F��G%� Fe *?F!!degm�ofm �%� age�WUq�� :Mla%ofad�*)�"com�t�5 2 X/ w2�-l71C':8J�S5D)5�&cis"AjA�at �!4a�M�I[U�>� :">��s� w�%th�� 0q�m^}�M@���:k=.��,�j �)�w2�R�� Fb� i:�Fp��� ��FoNm��>2RE&&�� �f�N��͗i��>X5+5+6��4q6�"�Jp@Au� ��;*x:�L �w�C� و( S5F���S5H Ii5KuAl)�!�Ň&�LR� D&)n��B�" 8I-Ca+���] ntexh<�&�O us-�H 6�gen�?"�[2�I:�A�G �0e �al��zI� �1�V:286)�d��. �#�8� (-��4u�to� E�v)��:a �!�xW�:"� ���P9 �!�!A�32%,sJ�by 1 . 5��tE1!�18.7���MI�4��r�Ew�"%J>�oinXY*}ip�:6��bj��N. U&%N� 9G=�>�aO&Q/by"�( x5�wprn?�X�S&H` �=lp�>rQ.�, �y%�Q)�F.l�iz�*!E1S6�$6^� !��U�&�!�I"P abro�RbyE��&A�3� � }�$Er�D� J�; m-\� . ^\�Pa�hF��ea?� �)ց�B,��a;�K�P pump�_�/ariet�?oxinsb�$�Fiet� d environYarcinQR�d s �a+*�0�G�qSet En L��*B( GSEA�>���R5� �j�2����+ )DA@im  ?�J�'%�>�6�aXWC!� 01 : 0�s�E�� t"� 2 @L���^ �6� � g5 "�!T>��IY�A�a�2C�&� Z�^Ibye�-Au24y�id ˏCphy–ma�[�s rome:�( HPLC-M�M ( S6&�^�!u pa"q02�giN*a��]!@� > 2�Ad.B50%an�UA�97*"q��!�6I?���q��In viewa�6*� I�9�ka�:�MTe�[2��26�zDZ����!�D>A�3�:�A�U>U6b2R�bea!�bsSJ�!:�i�p"� XqHwqN� N���� ��= "7�%��g�W":%A�� � "t4����K"1�S cqN ed�  � XAyt?62�a٩�B��l6�V�H.L_�"EX)�>6we�exc��2r  " *Y ���2�1��E n ��1F,!�*~X?�%� � � Am��&�V*!'b\��onB/�Q*�)�!�C �!��(� 7T:� Ej I��E*qL6fW:�z-&circum�c��S6(!S6I"��@Z"�%�Wa�z�� B�*�d���� 6H C(>L�&�E&,!��s�Jled�{t�0u).mut,�-�!DbK=�-hQ ��.�� i�*�>7c[!'rough 72���&�?basal>wa���*�� �}�6D�J�&8OS�qBt@6��6�9B!�EU m���� 7R , &̅�S�}��"yu!%5�'J�^�y8GH_ "�H clu��o�!"ri new.]�gin=��uC.k4NH7�!� �y 8m\%P Բma���U?6s2 &6�!�!�ܕ��.rgr&Zu�e�75J]A�i�~of!� �Ve.# �}?zBh�<�y�"y �wHER`0^`I�&�D!"p3�.�CI=-pN6_ �9�o !,M�5�GA�y:ie�lapse-,:"�Q ( RF {!5U-�.tQ 5-y�{9B� b�}���AC�� �ͤ7�q:;�P"'� v2�<VTaE �� w hY�u��*�k�K"d�.on+5��e&5 Rat%=2�!� a-"vO*��)Bd�� �*�$�.&A �2�t69� A�S�!d��� tumo8E�8v .- �'�}M!� Uv�.pLay�y�b �A<�.�J6CJ a > �&vo>ɃO ��6�)O}�1����s.- �06�1)&X(2 78*7b� m����p�D"�,�(CD24−CD44�,* �Y���!� YbA���a)>�7�7A�wGTvJ(/*� 2)10s of CCL20 , �Otherefore , we also investigated the effect of blocking p65 NF-κB activation on0@tumor growth . InLPDX model ( TNBC ) ,inhibitAf.Z0could enhance+ anti ^��docetaxel significantly ( Fig 7F and 7G ) . Moreover z$phenomenon�dBCSC enrichment induced bydtreatwas10� * CAPE{H{S7B�)) conclus�0, high expres�of CCL20 predicts worse prognosis in breast c!\r patients . The combina!Nal!4rapiesZtaxane�!�%�ade u,or its downs�m%R8aling moleculesx improv%�rapeutic=�%�,�dur!-��,seriously afarmOS�c�=�A�b%ct hug� plic%� s to%� clinician�hu!7it is ur�' demo!�at �\mechanisms such as defin�he key]in medi)� ��in �=!�A�In"ponse�Tinflu%�of re!�e�,stimuli fromb�,1 lcells will undergo multiple �ge!�alter%2y�4cytokine secreEaY%i��$body array�<observ-�correl Zbetweenmeinq�!�um �zind-� �Ugre-.�Lour studa�, Uemerged!�K most6A��AE�)�e, whichA0dosage depend��im.. Howe�Das farv Z)� �o�s��,erned , not eXinE butD6�����%�viafy6Ŵoc� dQnon-T�a , actuall!��he.nlevel!mh]ol-Q�t sublin�?colonQgN ovaraZm��6� elev�E ( S8�,These sugges�at �may!%fer����ce�oousu} typ �6�(even across}�Cain-�fur��!lom @AaA�8e needed . Prev�A} showE��promo��prolifeQmig  of normal�$epithelialm�[29 , 30�LLittle� k�2revealwe reguQj�:o>!. O}2F�s�`%�A 6�,�uonAN8nd anchorage-iny(�Q�)5 �out% vivoi� addiE� $discoveredME�ex`�ngthe��i�H��y�,�ӡx�@(pivotal rolEL�6>6D� !�n..��AR�s�� H` Hhgy�AH��Wri�>orm8�Nntefobtai�7���"�b�s�r��� dvoc� ��� egio�ethicVmmoe��q�;p��Fudan Un�s��$Shanghai C� r Cena�Insa�|al Review Board ( 050432-4-1212B�Jiangsu.ZAffil��1�at 37°C� an atmosp�m5% CO2A�iceIOb� nh��d;$AAALAC-acc��"Q pathA*-free ro<fac�4 �x. M��a ilizCventi�Muaz H-2Kd-� Cl� SF1-�8�C�<16607 , BioLegen���. Sy� � ���A,��I�assesj!(their ALDH #�ju�,ALDEFLUOR Ki6170�&�Mmanuf"rer� *n � ief:1a�106.G.�in 1 ml�bu�� ���!�� AA� AQa�?@mTa� a  them)5se� ��J �I��iP��or DEAB24170;v4�^incub_�per���) ͚���- �tA�!�Mx.1e� DAPI�i�-�=�:�e�7In!)7A�%~hlsoe��CD24 ����V 311118R�a�CD4B356053�� BD Pin7 �}�30�,on � M%%�f �p���of��liv�>-���ap �aly$ )��flunc-Y�A s� ng�$ACS )2�]Yi�0MOFLO ASTRIOS2� er systemA�4ECKMAN COULTER51!softw�Su� 6 .� G��ub� on "F�( Minus One"0Gu"A��M���}taxnr*�]����to& *+ENsG !'TAPC-Annexin V ( 550474AS2 )]�a�B�r% mende�� carr�oB�� pVA�!�RX&.M"�C(e|A.by��j�H '�1�s � abL �>&�>�d�$��!�"�:�switc� to C�%*uIndex a�!�mh��rmula 1-�(,est-Ctrl ) /. is%�l rast& up�� groupM�fold-�$dg. H��H�=]��> M- Cult 6�um�&#0562�/2�4�H�nix q 8�L, 1FHER2-n� K'm�BN6 NRFO���G�!E&?OmnibuA�GEO )�Na!�al�!" Biot&�Inz ' ( NCBI�\e\" %A�bifur�G�toH+A[a('aI�#*AvailaWURL�,@ttps://www . ncbilmi�-Tgov/geo/query/acc . cg&5$�1$% "7Eon 4tool PROGgeneVD �#�ia2�is �� atso�*aJ$bio . iupuy,edu/chirayu/�!Z/!�0/ ? url=U�ofe`1 milla�s�&$in chamber�054526 ermo Dt:�U!am�d�2�'m(E% c�me�$ol , membr(X e�)�<15% Triton X-100�� B019� SangonQ8{� a�ca+")immun�*�*D( SP KIT-B , Maxvi��/� Apri�5 d nigh�e݉Q� :? seco�y.A!�r�I nucleusE�V 5 ( P369f% Life^�Im %�"� %confo�9 scop� LSM 71�� Zeis&Ger&) 7,100× oil ob�ve le� |&]=~"y-u.k : goat3(-rabbit IgGF)y Alexa � 546A�:�W, A1103� *��� . Tr\&k/�Dm'� achie�� avn&a8�T��.��RNA9'�'". integral�(Qu NueB)y/(validE�byA�p QsepA�UGtlif�w�%S,to establish� librS2"$hecaby Jth+ta'EBi6y��o%+F��"�t�J�*!;�5�of� -seq-)thresha��H�e�se�e� "�curve#$Asubu�"; o�4al��Z h�N�#��'e!��3�s%V2�9(Pla�ɱOR|!��� �"�"otot�,ror =)M C-Se�&C@1AntWA#1] # AAH-CYT��0ECaM, S�t5��!!B�i�2uc��.�-���.�1�UMw2 !�b���*�at2  1 mL!� dilu�orS( sa epipet!i{ ejwa !]�l2q� u. wash��s�2th�, Qny� �-scocktail-j��h ^F�.�" 5>2M�ed off��8HRP-Streptavidi�#20��uf��tf"_�hemiluk�� )���+!M�z{&�-�igt# !:JF49p&b( NIHUk.iBv` eNv2i!�ɇ� ��0 rse-�- crib�$DNA "THP-1X��cK� pSIN (� omycin*z2) vec�( Addg@ ���a �ver �by.�,7��!l,Plasmid!�sta@s"B ng shRNAm':X!�;��-A '*%�de!�A�6*A TR 1: A� lyR&��A tiviry!���� )�-A��.$ �!p![!�����Ņs �inb7E:lQ viru!9da�@"y� @w9s ` effi�cE� 90%����. T�1�!ex�L� Trizo>;910!3Takar`"�:%)�)H�eGNanodro/"Tb� .A���VHN��!f= R�,Tra Ace qPCR��K�FSQ-10 TOYOB��T� ��ycld BIO-RAD� qRT-J� carr ��cD52"1� ��7edEFE�*u% � AceQ �SYBR Gr�7Masm Mix ( Q11�Vazyme �i� ��u� 7300P�/$Real-Time �SI�( App�!BioI��. ���&m!q�M�.�to refe�:g�I��@9  ?A�&Y y�: 2 ^ (� ΔCt%m� V&-2� ersi��li�#beCiq� 2: F�.�$�<1I���!E��r�ed 80%A�:J *m�6�split�.|S ;su"b E4 dena� in 5x loa���� a�:SDS$boi�< #��10"]�1s�+#} �C �alf�"p%�� rote6(%(�&r$-� )5bzA�n�P Nex25% bov�:�alb�(Nw%�  .�b TBS.�M % T�:-29ST� �s�" A�"�AJQo0 " 1(-�V:�1:aL�", HC2��,Gf'�:(2) AF36�R&��36" 8242� , p-�06 3033 38: 9212e�p-F463�*V�36X 9378<�.6133 �(��0C� SW7E_*p*��i�sc-1778!7$Santa Cruzv&7� IgG-HRP� )fsc-20�^?*v�><�:<don>!�-�.|� |0SA00001-3 , PI�� �(WM��Sub" WBLUF05�Millip�B3ALaoa* ct hArad�perox.#–conju�"dFGA�I�Qtissu�)m� �b&�$� �~,�$a�. S� ym�Pd� .i�xyl��a/rein gra�alcoho� E ge�9tri�/���!B�* +�koc1MVS-0IQ6�����end�(c<9Pqin&0 3%�� ,X ��o�,�Mz�~�&( y���A|bo%�Q ��2�lid( ��!'I� k�DAB-00�.];��f� hematoxyl�ZLI-96~SGB-BI! I�RY!Jl�� IHC:2 iҡ>�#BJu6-}4![i�B�UEKIT 51�#.��"Jp�1rin$aracrop(OLYMPUS BX4�"Japan�t .�� sc�( semi�)�lycaE�al j(-, ( H )\ odol�/b7 %�a��n2!Vper@ aP<po4�0�$. StronglyEud ��%a�J� weakJ���0J#��� �"**� is&j!~*�3�$6�sB�+ 2F'N�+:K>�, g�"a&�=z+30� 0.V ( 30!��)h�2)�Is"�9�M �!@ i !�����4MTT ( M-2128 ,�mF Af�d a�*!=6U -5 m�/&- �����"�^ 4�4�,>� k '���& DMSO���al� E�( O+ &� " at 490 nm� Fly�)a �2� Twenty t�.%\^E 9�!&�8��+<5213B�co��w�".( 35423n��0pla"F+24�-�t�/365\ �in�er����υўA�<1% crystal violer )�~Hd�9 phot�)p� by.�.zC7t�nH E1:XU��9a2 X` mz-%;"% agar�NM�oJ86�+4 -�Colon- �" .(005f*I� �a+: L�7)�1Bar�ph, gene�7d �8GraphPad Prism h*!�4E�s�re�.s!�(mean ± SEM�, 2-way ANOVAe7E A�&Hompariso�Un��#wis��Gl.+b�G22�#>an unpai~ , 2-��# tes� \;yC E�`A�.a���Bala�&�L$ .��Toxoa gondii� an obli ��* =� si}BQca�� vir6G!ln�e�I�;F arm-�0!xSA4��*�%�tachyzoig-taNh!�suc1Afu�manip�(e �Dh�Hi~Jp�H�tse�%>A$ “GRA”� eiK� origM� uniqu��I,ory organell�Ll!�de�J gran�L�AY�!%2I they_id��$GRAs have �CmEx9 � 6�>)Gc�2"�=co-��ng cruc�3�fun s%C� �,!N�K��Xc-Myc . 38 MAP kij0��se�NQGRA16@ GRA2�� #K� !��rATophorH vacuole�V��ithA@%>9a��La�nd\5�Ac6 { e PV"�UM )!O�L9","QJHlocW� �AJmne� �Hotou:Lst�3�p�Hav*�HTgMYR� ��Jlea5 by TgASP5 �wo fragA8Y ��"�MPVM �s  /nt!�GRA �E�J�4 iq6ify�i� al�Int2s5 QqCorV,�Qsc�ed.�mu�dea��  #EK6�AY�/��x�>;B��au�AH��w�D:e��@U� MYR2%* MYR3y�3m"ap�6�of�5n1&e�RI6\AF�PV space�co-1�ɳ]�IdE . C%s�C (),�Q���� doma��,��+ Q-��*-assocl>) %I�A��,�blyh1 .� ��ose N-�C-#(l]�t0disulfide-lin�e?La)�f)��ins�5ly=or% Q�E��H~�5 DHFR �7i�%Eof�D,�=[a 1locon-� � | #T. Ove|G=sA}�J�al"nC���Haoa�E�B�6eA a�!>�. ����H��!ordina߅� K:�V�nyiq��a1al2PJ� . Up�{���su�h q,.2di�2����ig.���TdI��*A�oug-9��[1�=�"�OG� s ���?9� ��I?N q8��0a� ^�,%mյiXQխ�S�JA�a�u��x[LAl� ghn���cts.=%clear�B�D�Sin%!;&7 [�4] � also�#%sa b$rI�Bp� e mu7Vircum>�9��[1E5X i�Xen� `MaE� p53�)�PP2A-B Na͋uE�Mu�is juicN�EAEz��|Rm-�E� f� �ar� vJa �tw� tern.R epea� rof!�c�0n�w RRLw TEXEL�,� �.�/ElV2� otif!B��C- ag!� A #A Hasparty� =W5` )!B4 16|2< $M [18–20�I�*eV!I �biqj1E0R0[15aIt does� po�: a6�ut�nonethe&�Qon ぢ�Q J��Q*Q *�sF� Qe��+s �NlyI3p38α./�Wa<-6)� ( KI� [�2%�TA�+o�a M��Bph�Cory� oyL�K%eh$tKvI�of&�e2�Cw�3.�Lup6�NIL�Ea��! -infl�Btory c�(� ��5[�)3i�GIG�\pWÁOto zZT?� �EX�[�C�"happen��I3ye]en eluc'-.�:�%od�4 falcA�u�A�'4 �U:F�IsAp�TEX"�  m���an HSP�#AAA+ ATPa�, EXP�@1t 8c!'a�� oxin� w�JABQ�, TRX2�Sa��GH � 3=� 2/rem > o diGofE� s(�(V )�~t\9.�* @E sol;!��$�0e"\AxNC&_eF*&�B%G.� !DMa�un�7�)�w y!s ����pg�Ang c+�YsA LTo>N[2��CB~EHknockd ofN� abro7s �J_!�)�In ���#1��-+arEZon8 reT �9��:�!�� 2�a�7ca�3�-mzyE�VM)=a�"� ushofB�[QRDt�[�s�cap�(3�ig�(olypept<�-�HU&aRg�`israbA�� *F a6� ,&�a��y>J�Ath�{A3p �(l�=��a�-<[aA9 ���+unlik� o act a�*:6&%^nd$ w�'a�7�Qq�% �y���eU!�6�i3B�.F?e[I<-��T" �7 M2_AǍj.�Tb�B�KN� foun���PV.��2J�A��/n]ly�ed�1!3�Q!�. FVI�6�e&�TY��R2 aO6bmure&��A�uf�*� ����}oA�!��� # ��=Xanm.���1N!&H:�.�M�.��3NTRHΔhQInd ku80  [28]onu�Qa��O.�2�2m&@Mu-r�pasJain01cgskS$j�P0( i . G�b%yL]},M �S�&�NQY�w�hpxbe7car��,�N&de-�2AA��U�Ldo�'a?�Te� hu$Hsu�8s�earch� .U<�&�0H��a�*�Re�EA�c�ng&E/monolay(,��*ng�� �s�Sn  a 27-gaug`bl!BArel� dՖspu4 w�O 1!"�L!��0 mTQ�6dIun� s�Acyt1Ler!Sk�?�.o�,tI�M/%ia1of �� ( MO�=��For wh�geUj � ?8y3paAnYVHa7a�% SRR206865M*MFMcI�95�) 7�;46� nd�*7 )p�D�le IlY3 a PE+coA`69��,u�&t�icU1( g�/A�Lr9", then pooL�B�ca�)�-#ed1ieXNa�l=�n�HiSeqR@0�!�W > A 3 Gb9 cA�`/d! � �+���mkI3�"Type I 9�a 4p%�#2� readM�Pq�:tri�IY omma�:! %5m�*y&�/�m(�� �GT1YFasa � DB v13 . �Vwl#bowtie[ 9�5#i$%u�L8�4pi���qZs�align�ar� inde�/3 GATK�?)[�e,1��o"  va �aa� imum�' �_aX5-�!ean �ic/�9qae f� e�3Ag�4�E�0or wleRF"�.$, SnpEff [�ctog�r)g(a gff3 anno�!�Gihoq9�2�? 6������A� 2t th%DfcM�&�Do|�aF -of-E ;l r]�"M{� X�d �V�i2�P�c�[��mseGI��<q!�1;@&$% mY� ը�ّy�$BTX EMC600sctrop�h"�3Harvard�3aratuAz�1 maxa 4D N�"olo�A Lonz( . T� �.mA� "Ϳin{E, p\"�!�.�2)-!.��E22�=`!}��3�ɽin  �?�i�wa�!�=) �RS�[x�N!..$)��2�X�in�;mi3510I KPO("pH 7 . �1�T M KCc 5$ MgClDHEPES&% EDTA� 5�N M Ca*�o02F�5�j�R4B�inaU_)P3&�Nor^�O0�l21%]-3μ). EB� yMBY��+% 9ly=�^ HTU-�4-3xMy�gp�  16-H&�8( S1 F�t�a�5a��%p�]l id� ar\��q6 b#]�a%�nr"� I� Q�I�fix:(%,�aldehydep 16� hpT T� V���,,es HA-tagged��[xjai7[ �raper�Ge�)ES�Z�Z( Char�(R�b )d,n$SHMA�e�� �Gn$4r�X*@A�B�Z� a# m5t rawn!���!Go�tA$ ,�bPBQ�l��he�-st� I=� c�=ty�,�9� nd�7 2^% ��a�e]e 2`�2�Sm��.*X]j��p .�(; iniB d.%jS�gQF/�7f( �]5N! boos; �bxff/>^�Z!�S�9E��)a as i�]ed 14�0p:� _ ��!Ite�;on��5hby"�7 blote#s �+�r^�c%�!��va�5s�.�c6vd�c �c�Use*�catR��"}/con glas� �li"KQ%/��m�6at -2�\m ��ir 3–4%2�ro� em�d?b(�>�Sr�Z ,a��2e t�;. M u- �p��was.0J �a<�6)T�O!C��3% �;Z �1h�0DFQsd�LNu�e��<d� rme�#�S%�12aL-X� ( TTkL)-=�����+��ab#z.�� ( N )q-!H7�/i?a�-�� �7[~��leM>|�JMr�nti�| I"�F g��<' &. 7V^IT2;4~ yE�g[�dN(%��*� �} a�S85�Z�( Roch�@#  RDLL�#tag �(b�<�,PrB�M�d�E/�;�cl!*�L�jn�;:de. Vect�Fel'�M}2 (or Lab� or)�uA�toAD?d� on s�9.=MSFJ5a LSMNinver!�F+N!N)AQepi.�M���8f �F��aI\J��iS9�ne��gi�w%�-/% �} �2/��K%�"t oJ�parc�}~ 7myr� � ��gra16"6 [�h��disrup�Q)�rr& * loci �$CRISPR-Cash��ԁ�iRN��� >ar��%G encox �"JA!�3+*,)�-T� � !�A'x[!�&� �>.$ � i�thad b�"=�p � _.�%wAZ � co[ �f��>�)7A�4pTKO2C mCherry1� oa � E�f{�8p�K�� 24 h���!!Na���com\X�F�V � myco0}lic aci� MPL`�(q ( XA�aUM�mjE�A/:���w %�:�+Q0gb� � o"�;- by limiE��> . D�-oE&!!� m��os))onfiry �(a 2: FmR4; 3: FC*R5;i: F[R�m!*� locu��:�-3xHAQ�a��U^U�a��E>- 9085 >�%dq;M-eri�S8 ��� �N cMN6�!��-t4mp.�Lsyn� �| ( ID�>�!�V� *�*� &' �Bu[RY.��CD'�\Dbp1�!n� �Q--�+ d HA�i�6�:����F8�R8 ,!��Minser`H!3Q�%��2!V��7'�B��a�LAi���Sma)M�� �� �Q�in� .UU��E{*#. P�^ T25 flask��um���Q��ʁ�a)J�:���a��F�y2�O@v�S$7a��ctA��V�u*LE�Y!�2�SIve�5iMq$�F R9M&R��2i��Z\��2-115�ٍ �Λ/!�M���J`�� �5I{i�y!J=" �2�2V��F10eiR11�)K �"4proq+)>^ p -178Qo�� Jw�r�4 a dou�XA�n� x_kMn��� A�~���Eo��,� �PAM�.�$ c ���$ AD /-N"�� �IM$Si)�3v�=�6��jI��93���AXUTR��!D� �L.�E�a.����N>�q*6MJ� 3-C2U��4o ���j��!L� -GFP�j��Whfhat1 ours!�t� ��A}��p&�f�kf� Q )�:� �1 �F� !/s��#1 Q���%���"� F15AR1�#KI4! �I61 R577fm ]7!qOR1�#Q�1�"�8!&cod� )drg�Pj�ce 577A�D iR.taA�to�36lB �=tq��;�.Y �[�^W1 208�$"�F &f56e�Re �&u ��s��3:� 3�s!E!i� �"ed �W#�<�!a�!�i�p� ` M�es!e3 � its �R�?�c*�krZr�w >�op'Na5f�ifI9� a��.�%�F�AR6"� >�~2 kb\�@em& f� HindIII� NcoIA1�e&enBU? mp��K "<f�y!a1&2 �b6>��,1=�,�����M� n(1�I&I� 8> �!o myr327,�&3 z ��LG�L�.��nge�a��^c'�M FUDR���t!2lyn&�<>>:D�-�RNArW�'A�iM�:\4IFA|N�=�- �(296�>{����!,"�ZN�8��=-qFlE1 }*D!e-A��A�PA��triZ�i! stop�x)|B5w* Pac� &;)���y�,:z�YWreFwI�-�E���y= �M�2� b+.�"�A!e��i�) �]q{FF&� ly � 8�ZK�� �^_R/A plus�s>�>73F/!�� �6wo"@6X;9�AK�an�A�H�".�A20��M� �F�( ORF!Y9E�R�F� d R7��>1�YoNa .o ��"�".Jby Gibs�:sse�*( ���*��vU,��g |J'a:xE[�gA"4%9��z2I��5oG � ��he"�A�::A*6-!3� 3a�"#.���._?.D��RV!u�X ��>�.p��J� .^��1j! b�!z2�Iiy|.A4c�� t+om(+6��Ap>� a�NcoT��6b-BH,()��re8PJB���m%�.!�-�1d�=�94!R� �� IRH= 2�EmN.�4ng�@� W!]A� �7 hJ�R�F�EaaS�f*\(��9zm$!8 HFF.g2!�20–\q([ .d&9$Rx!,6�+ �� !� HALT�~t�2�Cat�'"Xy��`o Fis).) M *�2sy�.e!�nd6�22500 x g[y�A�W_spe`*�^ ( LS�5Elow�_ el�RP�%As�zQk�iu$��"�Iarg*�3 debriLSP!5��"U3LeE�b!�G_:�F�%T=;C*cZz�"y su�3��- �@0ar���&�.4a�� s�M6$xc.��!^fA�8 a�*�D��-���7f�.BHat>#�y�a*�r1 h6�k0>�H%�!�.�( HE��/�2�x�#�$%"�#��# 1% sG@dodecy� lfat*SDAnaf3af4�$o1��6�g���?n!�ZW�dЂ���[$!!��5��, �ai���%Q�I�&X"�#TC=Qeci�EI�~�CfugSM��7 Cat#: XUFa0RQBJ*^1i �6�./ } ��&BC�"�-0�7�ot>y~')81�I��%�*Y�&}Han �/-f�(�$2K "fj&�$E��%�{PhosS\ b�%ErlyL*��"�6at�7oJb(�.�.Y*� �V���!�z�"9t�4. S9 �T��y1aw22C* �M�A�10�4!n6, &�byY�)��r�7to�%vDl $e4luoo�( PVDD +?�M>lm��'�; milk ydF5��t�d� �(!;���X�ve:�_e�:�'�� �!8-�.� � det�"�V6b�IR�B-* _HA2'�^Y^�JJ[.($}'p' [13]�GR�\(;r5E�:��'t- �It( H+L ) d� "�)I)!z�)J�QNjj�)�lIV1N%;x �-$( �qy{;A s{ "Y)6�E� Vr�HR/d! %�J�enh�O��6�n ( EC!V�8 ( Pi3`:�ppH.Zf-sa�M�n 6Hp]�(�r.Y e-��b!!�B2 x>A,��BS-†C"�<m�*�315-cm� hq��1at�<1h )tmm3p"M q�3p;�?Ŝ$ �� �� 3-%�ic�bld��'n�a!VA�2�7B�"g>� ^� �((_ mM]m'*�6\wmM NaC�6*@ ,= 5% CHAP& F��� ��E�son�D_b�7IP!�50% du�v@Zoutputa�K9-�m BY6on So�er} %@leJ�� Ad.� W �\���?� !x� � �m�*� i]reCA�[ ɂin�as&�k��� �(* �P.ImPe:,magne�be�<��c'�$���,FpZ|2a�� � f��A x"E�2pA� four.�3��8cY��/]�&y�r�S. B�=p�H�e�tb�:� !�!| ��2 mf(1- BJ*�C�CA?��CN,&WB`�T]�G#�.c�Mco.��P��c H�C Serv�(P�(y� ,�e 2X2of&-.yz2� ˑ5MQ-�gui���)�a�Ai��v��yN�2�M5Admini � PZ^�"�.� �( � Welf.H Assu�U# A3213-"m�# 947'B�3efforFyi/inimize �Ge{ 2G{,w?una��N!O 00E("j4< �pw>=�a^a��@J�6�.�w�marrow m�Jphage BMM1engineQzE\j� 6 9���Eq�+-eR{ng.s,t*� �6"f,pv�-! gen�(Tethyln �soureb�ENU��Suc�`*7"� �'&�%�nriche�})a2�.�in*iLmod�V�ha)*�P�6� ,�a Myr- ,t�B�1I�6)�MCsC*s��r�Ap�nt%A?%a^�U� B�2e "T!�"�_M;b)Eu[mach � 3v!�a��tinct7S�v!�K aE��.� 0( TGGT1_25447CM��f�#hKp�dP �Vv1�0LHG��V�\��V"�_6e_> �<9�H�. B�jprece�_!L.4a�+r64sLt�&bMwe�0"�+�*V(oHsCH"�L��2�e||0Ee6�� To\H�Bwe]��o� on�Wa֨��\E�K��"�I�&�#<es�s!gq�o.I-length)�1(z chA�- �EOy��bI�#�75I"\cge��OA�se��-�8��ea/wild-eQ��E�qaQdO harb�R�DZ#��3bCtw9��&)��i2 !� o&3��&- B#/a�,c)��y��.D8�1H0�� %�(���H�$ �g ����c<�rando��*Ic�~d�:�i�e�wI�il�u�clilSir>5.��?\�]!M���21_�7}18�1�x32�9�(�z�[ME����no-5�ny)��Sls #�-9� !`%Xt did_faV�gTr��70O(�x74*��QaHE���_M� candbVE�U�-ca����" �8A�i�6�y&�*� H^SH2�iCdi%��6coB�Q,� rLEq��+���5��� ͶI���e6li.mq5r 5e-}W�B�!���ee if� E��ly)-��%�$coR%�#7 ow�?���&ap�)�-C ��mis�Ii��6DB �D-� ����s0tJd�-%�!�A�R��Dat���[!�2�N�E�y�EGg"�q ins &�mxfzd�N.�"ed2:>�1Q]"�=��� ��e:k!�tTʬs�ZgI�*$ #�.�'bq ��N2�6c��( toc#�#&<p s 2nd 3I�&pP $F#F�;!�"�;)$/�&W vlB};>&2 -��.w$�:�+v�a���ۡ���3ApwsubmitF�T0����E��&'�m �se%��Dq:1%eD����r��P��$]��� %sI� -mycU� ��)24B���� 6�i�mWjh�8�]-w X�? them���54 ,e�?v�]1�C�ODx�C�3�w �MYR2-M$e޲n���+6�LNZ�+al٬�;*�N�DV �3�$mp�1 �JZl�X/1�_w�& vis�Uz%>F�EA�\ SHo�= �j�t���� �a��' iscu�;�hF>.Z tBWUSbyE@Ag!g� o*�A��CQ�.�%Deb&DP!H�*!j� }6>;�n�l�+�&" robusti'6�6vtH"�ɡY&�Qw�i�[�h>O$c fQLE� 2I�2Q�is��E!a�g�6�1�%T.�ts>#.�3�l.7B.E42Gb��&f2�;!x.E�'E; ��$U|D!L�N̋Uzng��#off|4��u��VC"p-m��f�A�G9A�ofq: �Ri�� )h/�s,�ۥ�͇�im�_u]!�1q:�R�W�kMA8@!%+u-e!auq�n=.a-?u���2� V�e�eJ�}��� GE�ar6O�&��.17�]W��A�u�v&.�y�,1e�)V�]9�e�ZqiR6 , ,�&!1mmj ��EU�cb�Mt� n��*n�iO��T <� deleQ��"hk Xa<&�|p���[v��iu2�p]��A� &E�de{�� if l�� 0d�G {s�similarko�M poin��l���_U6�  Z>�H�� ,Y.,� M�i�.r20�&.0"0,�e�'�!� %ze}��S5�!d�Oΰor���2�IZ4 a�' ��A�� ^VR&�AG�.��6��?%�%e E�!� *uby�i� ��I$ed)�%&.K� �am&[,�RA�*�#aߤdX:�� "�� plaq�|�� :�a �j��(; nt=�.C!�E,!  T>!9 � v#A�]�ec�)of .1.9����0�  �n�"m=g-� 4C;a�1&� �L�R ���^�2q&��: �Y9��%�� 6�folmX5�E�:)�� f��*�gI>or�k=D �� /2/3*��& ��a� �M�inIr.<2aSon ch�sRV�;2Uby� ( v3DL�a��qr&\! B�=!h~32 kDA��6�Ca�d�*�XA|Z9u" (nbhRty�"672� �P * 0 HM�f,TM�pA}wo���*}+){]'&�Bs 4�S6�$26�&79Mm5�_ Vroa�u0�Yb�&x��ox�15���  2 i"A�t*l ]�hoz�,( FPKM value�~5'U\Y=Y�e�ǥ�ɽadE� CZĞ � Rc1/10tqp�VsLMB�)�)k5*w~l���dE�e toe&��s�N�'���W��e�}�w},� 6-&�.�50rid!*1�D6v167 [37;Q�v�a. BLAST&�1!�iNn orth�sxNeo!�a�inu��$NCLIV_0360) h ough!% N.39%]m�ty!�a�A0] a}�]g��I!Ue� B��^�#o�̡!\Jv�Q�W!0�X!�&;-�69�sM �{re 71% ��QA?E�"fhs�� u"%�a�i�TMu~Ɋ��J+ (2�q��u� >���}�q phob�g �u��qJ�5a�ͧ5�Ue�_o�exx�8$-[i�g !>� �p� . No=��(T%<t�4in Sarcocystis�!�%1d�?tl;b@ge��,.�s . UnkZ�a&� /���a�i2�w�u7 dj>A��t�\�sRw.`v�"i�c�6fX%�� �d��A�DB�.aNv�-�{nons>^s�ndA�rd'YE 6%����"in <1% Q�*w�a!��� �-�f�:�~l'�� ’s�O$D=�b!�m�Z of j� � 2�3C��A�f 192 Y^Dnڶg.!A�[^T�q(s� )A����A�79�|/(�7<�Eޡ}��x�u �lou��L�����A�0secretory pat`w�~igs�G!�S��RNA�>ݓ�M�:I�QPeFh�1~2�800!�yf�^6y�� bF#~6�%� "C���e<1.gR�a fewA!0� cano�-le� �%|&�~25�K��i�\�-2�Ire� !�g!C-s��pL EԾVEGmA[/impA e)�����E�"his�� know�� [38]��%��A��8*���� c�m9r2��:�*I�)�etO]o�tr&]�} ��&� 4"�HpawFEw!q�is>�outщ%*"�)&b�azZ�~���a���a%��,3 � � w+�_�����c�I�,BN1204_05109cJ� 35��ty�.���%1812�(a�� n:ct�6�*�z��6�&��"'!ia�$�-���_!�1y��y"�Ns 8� 9Q���.M�-I�� recogniz��N. P��*�s�A�1�� ŕD�=� � � �!�`�~���:���"S_fA^%�-2m�a�t*�*)�r���5͇(�5vfi�cis:c*���wase�����% � 5on]��6�on]:aR��B�xI���O&#Sly&�-a� ��6 �ucuENFE 96!orai�U!the �m T�X�D@�!�sia�v�.� .j��1-o�:m�.j5�"P9�cig 5B�V2��AP"!n%�2<&�h��] *�Qei0 �p5�<�e�tm*�'(-�fT�^a�Zby�o "�-W,�au�!9��IR6X6�LA�:%-#-�=th���&�.a��Eo�ng�b+ 40�>�J, n-y�A��$, b���d �p&�ȉ�failur%x'MS2�t�j�����c� �uuCB#-ǁUlevdq�" :�� I�%z-�.n!��_ �5 �Q)�[o��nC'&=8�xan��aproN^�� %M��7%6�,A�� deg�,�PyM;� a�d��s 0y�P��;�K1f�;�*6c� a4ar"�� ( IV�M�����39��i�uN�u5�5��d�:;�* b;�ver"�2o�` &do�qB �=ais��PVM-a&;�ERA��J�-)4�zDwe� 8 �H.2R@��I����is��6)��T-en^�W"� �(�o�u=} � 9uai�|I�2.n��A�:�nsfisj%�U��8] &^�rc��yCst9>��orUon en�^h �`�Q6 ���.s��5���Ppf�vE��Y�ՐMQ�G�-�Ղ�g%d"��(o*B8�Z�%b0�,n(� �-MYRq��N�2�PM h�I :�? R; � � 6�!21�A��n ž�z;)&��&�� m�n� E҉���@��܁�( �- 2@������;i�&�a�� �uce"a7$ ( S3 �re�):�(�K ��<O)�Ro�d1�:}ifI26E >E)f<%�տl*2s�a�-�!�! 6�E %�d!�PCAN0?U� 2���L6`<�$� � 2,6���W n6\B@�J1� ( S45����Q$:�"$ )W-�9V%� ��36�$�)Z2"� � ߃ct"!Wi�T���-S�;bN W_%gJf!~:� ZRr�)I&�-SaB�u*A `pa)�� =c55cJ�^ne:Rlav^��*��� a� bioi��m'|a� *{ o�E�"N� �3��L �i�!*~Ww2t.i�K��d�,vBK&�3e�&<fJG ��5�_ -",� 匵��E�"�+RH2`!j"_B�G,6BlyAt�H�e�yUp*)A`���@.�M�@intH.7&m&i-���d.NM@a� I~)f"�GV~j�M�E*K2Y@�'�*9A�,z]�d �x'6�L5� >�L�(�r!-��L.w�L!T # �oGjA�To] ��� �f! K�q���H.��ol�M:{"�K�y Ew6r� �9���:!Ay��e�*� E�67+���*C &.)6&omaM� %]hHSa�4u> also�>Z�}�)�ag�\%o [40"�H�<a 1R6R�0� ��"�T"�[41 w)$ %�*� 6�.�,^�%~~!fI"&n�A,��6ZN.:��|�vl��сB&ps),,�%z�JilVC%�.pA�� ���!�ZN�rensC� m*Q�a��%%9�qgof%�q i���iF�w'cE�^SAG)�GPI-an��*�+��f�A������l:1, ��cAǜqno c.�P�R "^%�DM�K�& !������B �WS@b�>XS��b�� �+1o$ P��� Ca�%ڙ�/ E�\ʼn&2E��.Q���>eAA O �R��&9HASA�A�BS�q�2F��&^E���Q���1{�TH�"&�R)_)2�x4���cre��PEiQa�H>�.Tse�� a-� %R6���]*� ROra=tm5N���J����(*� �=J�%�&3 � eN- o&>�2 2aH"�K�M. �-fa-!��� �� m4A^1�Voe��-�/6fIMA���im@� \-yJ#omGslower-!�-��"mo��t�$�2�$�"��retpG"�b�[4��>P$%�0 a㥄 Ea!�aХ��-�)�9�-^!�:� U�"u�F�w�J�!*���zr��c��ab"�B NByYA��< T:�i! FOW�@�&�E�I0M ��bf!H*�/!�E ���Eii)�����-_Er .ˢ�up�.��?a-*'�"or���ex@!E���*�r[���nHex5*%P�f[3؜Al"  � 2�Y �Vr'f+ru�(FK"�m8�!fmF 2 �6[>J����_&��P��7��Ijp/6r+@de��S%3 ��h�$ao�*Nb��$he�0'��,y**f5bJGR HiAXs &@:�B20�Q@�2� .�*�A�9�ly*�Eu�Q.A�OQ�.9S�O� e��:P�V�Ram5e�QH��di��it�� +DTTeR/�E1�& �9G�u�r�<�,re��n��h.��*V�>� kA�y/!Sco�{-�A+� -�z d�!:��A�e�i�I:H-(A�� m�%I� 9� qB#D�"�^# �I��?�TleAu�6� ) ;� �D2��om,)qIUB2D�a"�E� �ac��%�1H� a4 .|eWA� �S 1?)T2*�"+? mitochond�]a%!V�W.�*� ��c�=>���E+���.1*� .�M%A��I�)�+ �� ��_OdA� .�+� p � �sL��L'>���)d ";�a�7!�6�( -oNA} �qv9�a�]1-�KM�)�u�N )�e,4�a����J �? R55%e"E��**X1ŮageW.a�Ba��rpTi!���;-���1F(. O�>�Z� �c%��*�!�}��-run��$� 9�3un�*, F?F�Q1<0associate in �ma disulfide-dependent manner ( Fig 7A ) . As previously observed [27] , a small amount of uncleaved product waCsb4even in the prce6�DTT ( lane 5 ) , indicating either incomplete process by ASP5 o2! reduction \�O. To determine if MYR1 stably interacts with MYR2 , we performed immunoprecipita\Ds on HFFs infected ?RH:B�-3xHA62 and an untagged RH control , as described above�he resul�inputsG(eluates wer"ol!�(by SDS-PAGE&probed,Western blotLw�0antibodies to%�HA-tag ,)( N )!Q%#( CE�@s showed no evide!�(for associa!!�-�Fdomain �!QdB\XWe cannot rule out that*1�31�4 transiently ,�-ASapparAh lack�an2�i!H artifact!6condi�s used; �ver ,)�s sugges�2 does �MH1e�1!�Nz�s+3IsULEZ%�IQ3EQ�.KtachyzoiAAjrepeaA��R�&BdB�Imm>� from!� �-�cells!]ineffic!� relativeAeR�usa� <2B�A7 ��A-ex�8;paras�,%5�gw,a high yield�siA . N!� theless ,:!HA.$M�Ed some�)�efm� m�=4both fragmentsA}� co-E)� MYR3q#i As aA��8amspeci!ltawe alsoq�! MAF1 Na�- m��sawašc� e 52��E,zfi�<g �!�Q�"o�Q3V�is� . I�aes��e�?r�)9 =d A�x1/2N1�fimilarAf V!2S� 3%[,q�A�%�<.�Xcould be stoichiometricAj(lthough mor��Preful biochemical stu�^ willCneeded�Lconclude this definia$ly�(hre� �0Toxoplasma ef�^ors �are�porAuacros(e PVM , namQGRA16 ,24�nd IST ppe)2bee%ly[19�.�absŻof M-�� ilizAmounds!�:�%�blo�dn z-�%�s%�5 of o�9�,-cwQuprediR in aA4on-based modelJproteP �,� �%ed.�ectopA�lyeasses$Ap �S�1� �0GRAIja�( good agree�։p0 �:�f!NI�0whereas ( non%:-f�z )e16-HA !0lizi8�PV space�tra�ik(host nucleu��E�[ accumul�!+ he vacuol Kwas rara3@visible ( < 10% )0]��b$ 8A�� %O�GFsuch aE�e�w��fly B�"! W  al%(9.9strain{a Myc gI/24 �yi� dY&)��liz �by IFA .� =�M~.�)� sign��a� � t2Y� bw7 F�q �ed� h-4f%j machineryQ � �direct� � a fua5funU al-16�i� ocJ]g .; ro�'s4sore]�!W&, Pr “piggy-backing”�o���unlike w��� ��$RRL motif }  ��" 2�* elsee� , yet st���` �RitsInVa8�19]J0)[6�a%��%$J�wild typ�RHΔgra13�::J�>. D A� -MycU� [18]D� $ A'F�. �� ! no differ�Ui�:24 �PEwbetwee� Zi�2�]�% :5�intrins��)G���D��i�iA3I�nonU�����of<6~y/. I�� tudy��have iBifi�, novel membr��Llex[dat least 3 polypeptides—7 |,� 1 � � —�is ��ntialE� �o>�* ��ar�iY!%�e. SU aa�Ŷ>�two �p~ ��vMYR���at� ��ndEM5�y� A� I� GRA7%�%/��2 . Consist qir�X%�5�M �� �9z a�� �=s�sid"� 1’s b��arm . Fut r9 T -J�>eriNA veal)�I -%" -�i�� !r�!nEO-�but� � ) ��.�2�� mv� ch�p. I� un�}r why Qis��I�wo"� a�a�ne����,�� � pla� &� reg ory���� we di� t se0 &-�ߑ�%!Q-=w J� thes}1E���5� and/a��a�aB�-������ recise r� �U� �3!QZNis5�)Vf� aYm���Mq5���� Euseem ��ly� forma>*�E�<%"�%:�s� s.��.ž2�E�6��!olowJ abunda�)/22�.�3Q �EAq3 �t�� G�[t��Ylearly::����%!}%`>b�%u2.�� 8pat$�*� Q��� t develop���ag��f.�� on RNASeq�8microarray data��6��Aordin� 52.B6we.f Z�!<�ne� aa�x �pon!���s&�� %!b* re��!%o o.��6�Gi]�mu�s�rup>ik������~m"� lyM.�phenox ��regar�UeA{thRdeA!P1:�, i�ly��AG they� l�%Ƒ�9��inI". L��7$ orthologu��:�r�|% Neo�Ja� inumJ����a��z�Surpri���6@l�9ayABerv���aAG�genera�%�:is�0st: 45% , 39%%s35%4 �6�,A�pec!�c� 2��>�F&� �E�subject�%selQonw opti�Y�c!�thVi�\~ carg.F�n� u s]�E�hom1� in Podium�,Q$%x� PTEX�I\� es s� aK�z6M~�A�ed�(od i�Q5 -� &�;�l��A�!� ��|PfEXP2r6�1� ��T !(% receR)�hodo�M!�!�of �molecule�8<1800 daltons ).C P ,�S5&[2�qU requir�sE6m-P�� S!�,well underst!Z\ �&���t�V��PY �qEsub�!�66�Gig�~�� ����!GFP��P ������es�a J1hI��Uun�x� dd6�9<� d�!��Z2�,�A GR�_��� H� $ �� b of � �� o0�շI�nd*h[19 , 43��IOu�{> also im^� 024;��6“�age^)� eNeE�!{M�U�a8 �(systems [44D�J$ex��!.� !�araTth� EEL"�echanismR�ae�mk� *� Over��,� ��,nt"h 3�!��Bn:�nd#ae  right �  plac� bA�e�?on.i fud F92+�� �"!B� operq�%� �!: Xness�9�&��$s upstream; downť actu��U (��origin��og�onc ( OR.c"� �(eofenQ�lead it&P"DNA�nd dupli-�.�ar dou� A;nv6��! papillomaW �� PV )�� mb�0a mini-chromo�i�R�  � o �ate rep� oviral E2UYbiV�n�ScruYhe E1�heCseQU B-\.�ge �m0program exhib QOs�: �l ampl�e4�!a � eVupo�!�� few cop�per��� >lin�ma�n6ph�Ga��e�Y��� �E� �� � 6sa!Bof�U v %�AkorLpre-r=*Q�(E�$r� ��� &#�r� i+human!�( HE>!�bov\&,PV ( BPV-1 )=�s%�!NORC�&% �{a���R:�Deple%?of 9enh!mdy.�� �m��.?�in kerh'ocy-�ly)�ain� �epia$���e ��N� copy numb�'��l!Ag��d%;)�aJCB<imoccupaY ofa!�E2Rin�d< low�%\silencse �impy~ '� 6:a> I��PVq�by�@ inst��sup�$es�5{ve�e� ��we&])�R"�o�AlE2"�d �)"EA4Dwo known mammalian �g �on=  !tE�s�"t�e-aImA##wNaNet�rK.blex&'2�IS)�:�el�r p�%� LIF2� N.x� F�-�F2�?A_� elev��%<E2 !qr dur)8#f�ѭ�ڍ�ͫ��� vert� loa� wh���syn*��t�cu��s . P2�� �� re m�� &�pathogen8��# fic%��carry[ ris/%esa to c�pr , mt!commonl[e utera�cervix�Horopharynx . Becaus sx limi^&y %capac�)�h yp� ly 8 kiloo��kb���tse!�u!d�$t encode a%_ymer��!xmus`&y��!�.O��>[K6�� Euai� as circ%�covale�clow#>�, histcoEz�� %ec!*�S�thu$sa�A��-c��:��a� I�:���%�amv is�(�E�s [�2� U < a�!�sYe�'[ e� ue?basaliO�N�� �!=e�}ish!M���M( 1A}$perhaps 50{#�e�ond ‘%�’ �U��A )�ep:�Q�da�ar��e ���supra ܁�art�s [�4!1 Mono�r2l cul�&!( at harbor!Xa%�mrefo� %���)}���. D��� � �( autonomous7U�g�� Jto�p� kinetoch�(in��:T .�q�� A�to Chl�- Brd4#p n��tattach!*ѡ�I�A���Z"{ -$�2H mito�!vi! �AK re!"of bU[�("� thirEA2�YC��e�up ]0l ta� �& divi% %A0sA�a_��a!;(longed S/G2. [I�se 7��>�Qahundre�$fvI>���packai^nas8P!%=c� . Man���e"ght�to�aq5y(s emergs ."$ of  :m �e-�!Bű�(�8 �7aA�� tng�!=mA�e NIH3Tv, C127%.l ��It~ �da��{�n N< @al 220 amino acid7 *� # ( TAD�2a%��3 hing�1g!� C`dimer7'A�A�q3 ^[8�-��fm)%~�2i~w]s�.al��\ �s:� � crip<� &� �5[on"/e�, TaxBP��(,GPS2/AMF-1 [t%9–11�B��c �)n��C���Hed palindromic sequ�o #4� ll PV��,%e�2� q 2��.�[1ŰE2%j@�rsE � ATP��5Bve&�Bse E2-1�s'�� Toge )hdjaeiE1�A��0�shd�A�ctd�compo(9 9�^�8 A��oA�ori ) [1��1ňA2�3a�E_3E2� �u�in ChIP "�#to docu��loc�$v � &��i�e  '1/S��15�-&�analog�� reagz�� M�v T��6 ,�avail�,  ��E1��g hexamer�� �&eE�InZ�wb= e�I���in];kinU med��(d phosphory 3� E1 [�1��Mut%Da���E1�E2Q � 6!K>Nr los[ !/ :� �(. Eukary�#M'licen� mp� ��a�!8rch� &�;# step�� s fi o o����%e�]��"� begi},h>#�� n-subunit�refC��on�I.�0. Z(E�e ~30� e pai�8 bp )��- �SqbF�metazoa�p�-s�&�1on�_oo�i�d�i�#span "�al�ƥ�of!1� 100 , 000� [20–2�VM"�r��XAds��$�'104��05 �E[m���casca�2a�&�68�,pr�?o!�J [2�&$ex�E&R9R3?h= "�M0!�N8po� al�;�? aris�/I ir!�co�C*! ^ samm � ORC1�~3+e �,�o�a b'-���y��( BAH ):�a�r�o9a*.�I�s�!�iV)�0�G��r��$e�S-���.y�} leU�s 2–6 A���� �<t8,�9e major����� �.�'%�E!�x(Ir=&n :=M�reoni�11&22���l|to�di*'(� �-2a8B; %S@MPl� /i�m� �7�9:[2� Afte &A'� �n�M1M!����>%>h  �E��$( Mcm2-7 )%�"3ise�e.2yfo�of Cdc�5A�. V1littleHFof! ch&.�a r�UUv each� g�)!2ɟ@v�"��m�i��A�&`jH�pre� ��)�i �3� ����.$"\"�*�>�Y>u��i"y^ m�&a 2{iׅk!�ib<hypA[����]�w� e^ ��aG _��s]%O~/ow�9E���6AXb�c)0� . W�66NA [3e"�� N�)��2yM=,�::rictsB���by!��chL7!M&�=@�$I>0 ���%�5,� s illu� �0�bym,PV�*M 5 � �.O~� Oify/ *Aenviron . 'cur!Vv�9gt @ qum;o�wh� a�N s��B A!�&�!ف�Y�5r�ftl, �A&.���h��e�ar2�1��among�*eR; roup[B�A�:AG�F vidu]jw �a.���,)63i*irB=�ء1Subgtly��coLD�A=�@- ��!b.;mj%�x/voѹn-situ!xGT/g� assayPL�[CEZ~ !�!��1o�Jfluorep�=aq��.�E:F� HAuW�HK2i˽>�Ii�:_�spo �r!FoH�'�R �)�2�6�8*P 1atw;FU /v!b� v*��y!KQ\.�J ends ��Y�$ ��n& E2 engT5A�& � ��c+�E�E.4C� n(D� a~flankA�I�c1� Qr�( LCR���M�@{� erc|�*YG 2p*L n I-Q�uũ.��T����-73)�w.�La &�*jJ�I(�)i��s ���BPE� CIN612-9EMJ��S �yD�5� 31� |r"�0z1��A�  &� �!T� ndA�--IpYt�a�� yn�n_e�� thym���"pf pjv�a<�$# B4 . ReHK�Lfai�i.�%�U|!16A| 31EO%Hq2E� F�:&5 �of2w^t�GM-CSFI Q&B%�3idA 6VM�&�+�+ MCM4�U, -( Exon k6!�a/�@��=r!��/io#P:6f�*q�[3��[DHe��v� �J. Comm]j0"�%b}i�#�.�"p *� ,AD+Al&Q %ہZ�},�:Ge��"y� e��"J ����  1�5�I��,�[)g]6�'��!m����O� [dt:A��.(�!pg�8M"e �"h��B#�%+�&��M�.��Չ�si�>PenricWV��F.���a�ti-EB�yz�(!�$tope aa 979;�4�M!:.� �"Q���b5-reaci{�Evly)M�HS >- 4i�Target�N�%C�"�/C15yd g )= BAEE1 i�h�+E&�)A��:������4B��)��A �stY�I�a�A�xatsi!'"nheA�2%{LCR4 �I setAmToQg}�.%)���% T\"]W12�pG)onż�16Aɨ.By,�"����ult��I�e E� demo1�.� kAViue�_%�!E!��a�'og���m��4} PhM"x#� ��y�Vco.J,"�y- of"3% fociyC�.,� -!�Q>�f) k:A.�FK}R�5�A*b !4���[8�96–3N�<z|i�N�= ‘r*i!ers�%w`A�1���;<alE/m%$SL#Jre+� �Z � �&acLLy6%1c �A�,ɣH2AX , pAT�O pChkhNBS��Rad51 [3 64WE!Ec"�.�0E."��ly.?!��^&>�-Ji6�WEy�8'�.I)�ņ.f e�� !Z`Nr9A��, !� YFP-�Ao/#San,�"m�!P . �pYJ��eE1oS{ usel�0=.7�co:eGA4i92>�(( S1A–S1C�O5WF�! M�2D2F 2.PW�LT)r I�}6(7t .Ze �iferu�T}�*o�_!� i� Fon}��Zpro8YA�| �+� @�e�&q e}{ XE���5]fi4,y lucif�.�5if'o�:io�to�M(6.k-�.orrobo��by PCR� ١.a��[41–45�F�2fir�\�E �s�$ti�toM.�in� �L[4�+�� y�%�DJ�u6prenille:ve�! !y�+"1%r�!�fb�Duv+�Xly u'K �m�!�D1MM&�O9%�vi�V�5$H!�e% 7M�-"�, m�$p� J[4r&E�&�����88'YP-�7H@����dri�Cb 2�9\ 5z . �knock ��haO+s1Y"4&ua�5,u���!lJ1( S3A��Us�O�5�ňan.8or�!g���9/ Rr=5�8gh� to]$exe/�ith1>�B��r�u�of vE2{a�,Gq�er'v1�m[4a )��/&�^re�%�WT�e.L;m���.�B TI�Q��?e3nũ��Zc�5T �Ie� �L.by qu\t���i� �l��Mg$:Q�=��:B��)gz� � m� 4induc%�:]�produ�4� ��3d�:or�!�ng �V�8�QEa�Cu��4xr(ə��pREP4-� & ��6d��� 1�a��;!3EF1α�m/��U�pA'1�MW]�"�#d� L-)W.u��BLa�. �.& %�� .Bi �:/�!A )Թu��Zp�eV�m�o. wi)���F Zc�]�Z%��=T g� eH.hot du��aq`�P�= � ��Qg*�  r 6)of�.�*H<�H.X��BP�}�9P��c a te�!�`i@�?16� �q�N�JN��6%&V udY"6MHCE�5DwIv)nt�-m��)i��%*�FnS?iP �a-�Xin SiH�@! :*�a A� �>%jm" �_ -% it might 4+rguQ9eP� $F�m�z=�or� �, �%&- .:vs�,I]�Z�!*�A� �� lN��in �QM�&6*�I�y *� NI�FwP9su4! a dra c�Qk c�?�� o��l� ��. N*U� �i!Bdu��ob!�!�oj8 emptu �:v�#��e��=�:��W) m�7�7ewJ�qY �>ual�%$)_at 48 hm6** &�@�g� �B��!��- prof�LS4AյW�n t h��~zq A�316��A� :� .�. Firs�4)V�s.�E�� j} ն���l"f�Q"~"=� 4aUR �6B�H&� e�cch�> q�"� 2Sou=8*�kto�^Ƀ��J�[40 , 5�92v#m[^� y&J�>� sSg��� �r u�f)�1��*�to>�.B�a��#6y ��Eu�M�H}�=�M %���Pe�"� D��;� 5M�I|��`��i6dB+"�d���c*�`e- f&X>\E�at 72�IFX C"gG"rN�ed ��e�q- Z�1?�G�w"�i8B���s �rby�)�7�Tak��ogea"��s �&^�R�%�"�8, sw logED" bec> w��5birS'9�A�f!�&�hto �. A clu43�zI'.m���*N-Rm:%��1pr. [5L58��"us�"@2z��av!e"kd� � >�)"W<��!��equ��B��%�m�:� *AI_Of4e� �.dF�"` seI.��hal�,!usx,FW;S&5D��#�9 l8 is vari�in� usag8 d�O_[5+k55�PA�F-�ma�N�kajouBv���=%V#$�3[5��.�5,d U2OS T-REx%�"? oxyV7 ine-�A�hy�=cassett�i31E2 )�Z �" 9�TO� &�= ( 16B�: <unalt1l� ��e'i�"iIp� -�x �!��%�ap%�+;06�HŦ!��&�8l{sA�r:8a slowerjR e [5  nalyX: &�8.� ]�ng%L� �`:�s_rd  i6fPi@O!�+� d4& %,)�� d-�����!��'�9��C�K�e 4&Nw�B)5�3&�". O{MQ� ,�er&����0 � �=�!��!InM"B��h! :� �l�C B2qG&v9�mOm�,��&J6gJb�>�n��iQ d 1�=1">r*I)ca�atC �,u?��<>�?2- Ori&A�S&q`b87��)5�a�U+>"_a'�4-7RA$"dc�;�Cdt*q! Glbec��by�Z;As2�<[5�!"�?1Y?te�Na�"R&L,��)�s�L�ac�+od�Hs&9vA@& WYr��,:�F�6_Lny%��CaL��alDe�%1a"�I2b(Y��IV#��l"� �,~Uq x.!9s�%�!�hu"2)!��/�,A ontigu�-Q-SRKE"�(A-�'d ct .7L"X7"i:!H ���w6�K"� N_;[g[].7�.�T`M&��s�jA���;%$vir�< I@1�DEDpanH1y�B�0 waoɛ vs=�dA &RMW r�\*su�� .�b�Ss�T!� �� !�p�nJ�'a%td:u�8e�, �9:\{Op���\�)c unidX*J m��B�aUQI,[5m9V�=Y�6J��ngM .iZ2�c�d��%&�PPV�&�!�um�{� ir"�<�[*�!��/S-�2!mr- edM�gYi!E�$triggQg4�Lspindlrd�0checkpoint [6��)'ms�MA�i v^T� �TDBBuM!��M�I6S6I�i SRC cc3 �Y spon�co�%un@>�aP2!|uZAo""7!(ATM/ATR�damag�Ethway& qc'sti�sM�R�[ 36]R�.�[64 op�Ja!H-Q�the.�a� �,q"/d��M�!�"7Q!�!5pl�k cru;2�[��V�6� 6Y#Our goal{ha!�SL� �Du%T.v�5e M n��$F�APVA�1D�pi�2�AI�"�$ti&� >�Y�in`rU�Vwe�covH �g N?9 > !QI W ��ݯr�lu�6�b�UM��Z%A�bt��i Av��-�viao!*�M��"2�M�N*uN�-a�m/ -gN� :�;%qr!D@(� a/O�Ket�dcr2� �%Q"�.JV�? )�Vi*8Zs!�q�nUn�cte�y, ��.v] "��7A;)!��md�\�!ih�(%T)%�� �V"�H%� h.�se�`unm% r* <�ac�'" u�=C �I AE�"oZ�<( �&�.*��]��-�o,�*th�%}%� visu�M�m)!�E2S a�fpi��fci�`�D"�V+X��*�U. HowZ-?݁ex"-A2J�;?�� �1��&4�?%�few"Vd� 9������M�. A�mi 1&B�Cgy%( purs�w"��y�duF\�!Nel�<�Gg)�ke� e*�FA&&I I'2 kc(r=��!�:q/A�>S!>so�)�16���0�N����icE�� !)B�Bba�.6E%)�Qt42~2�� %�9983al ���*��Z:�"�d*��.�-c6�(-(� a PV(li�+�rA}E2 D��EWun�n .�0"Ɇ����.�1(mle��b �6� *\e��IKr]22�3s��d�-���RAu).9�� �e�"�� �B_�Dݧ@�.� )us�6m*,�)k�Q �y6N/�~yvR%a��&HL�dA0t�o.L,&NFE%siRNA*G}��]�MCF10A bKot��c���[6�In HeL�m ^�� �y�ha�e?lM� e [6��L�"CT116mr�morphic l�n�)�M�a%5C��&8wild-%Q<ׇ,r R�is�[6�T�ng.�. post�+�ionY\^��� � ����[IMU�F?�:�P*�c��A:s�3�0ah,s��+� %�B]W��A��glQ�Lpes".=&�3esBEn&�;1=���m"Je�K �n"% :� e*,- EӁ�(V t A3r�VEgV%EB�IPH'K5H&�I:,| ie(NA�!�OA.�8ic�� �#s%m�^�tmpaOdv�I�e"�� B�́� � kSBto Ka�'0’s sarcoma- Ee5� ( KSHVy4HV-8 )���Xear�E�LAe�~.�� es [6�D"N��>�� })�2T J.�&!�s J�43*� �AV:T�0�u.�{[�.h�DcytomegaE( HCM1)v�[70�G�)ep�i�B7Є:6�I&5���Td�t�J��A�W0ewaGat�y9"�6�I~L J4�In�A]�_ KE�"�*�i�2#�a8 e.b-.:�"*V���A� S�.A��b�rife�6s`%.8���� G*�E2"�O2V  �)i_d j.���gقisK2�*�YN!����pfR���n�Qa� qto7�("�k :aJ�2��W a G2/M a�-��d��bBo3]� EL<�6�_um [7 7 Wu9i�=p"5f�4S��tin �&�M *�"cs"/ g�,V�i�)R&%`� ubem!�fc� "�fUe��<Kaq!�/�j� a*o&� %�", �ebA9hgof:3Tv���Y��)cHJh� iveS?m72%{.� enzy�6�)�m�6^."�;s !�ve�B�ove>� E�t*s� M�= Ak���%&�?!�� [47�%�]73–7�a. E2-m$\?xI�� PV\O%�0r�QUa� WE7 [7���a&� [2�[���T HaC-?� ,N� �Q apop�c7"�zhokPiv��!s�u�a|G&a�T� G ��"v^ � ����*wi��7. Prim�iTR�>�9` ��Jadeno� -�� [5�7IA�!6�H��in� ��$ S��eQb��_�E���=�L. X!�In�E2B�� �� s:�kf������1r�|�s.�:2U�O�Gur"XE2�=�����Who�sea�us#:�manip,Zs���2U AtEC2�a"�a�}h<X %u��BW.g.��)Fa n � �.vg��.�$�8"�*2�P",W�s� J%��&�V"1�&2 t jp)Iag.���V��. Cod�%�zA;�K$m[[� cF9'6&��BamHI%"HindIII�� pcDNA3�6_tri�U2f1:<p pCG-�0E1 Eag123 [78AD ori-*�) .h@ �a�2�5eLKO . 1)UF*[6tR"G@ [40]ZF$!�� 4d@ ?. `, pCMV-GIN-Zeo ( Open Bio4s )%O\ca� s# �4� %�!I2J�Nhe)�Apa1}143� �\Aaʔta��Mo�&oTA�d:EfX)b�=�gm4VI�%�tagz ��%!�Mlu �Sal�M| pCI ،b�;�6��>��GST&�C"\d2Jy�,7� p?7&� !)i�87\HA�F}�PFa E1F-α�]jiTeN7%�*�-Y.k:)_76?��%��, c:"%] )�G>bqo�=�'!� 4/TOa)  �^��)�&" a&�%E �:M0 <,( M2; Sigma ��I HAJA-7 3F10; R��&2CA].pA�4�E�( MBLTr��I2CQ Sign5hg).}E6E6 ( AAmVitB�Iϐti-βr"g�*(WA*ʌ��B20�Qa x0Woma�screeK7at�Yto 14 �an3-� w LISA �V)W12![ ��Ws,derived �HP!��ps�agen� C�Po�cve�3��a Bh�\1N  � 2)tre-a�n%�I�bIVmiq dilu� $( 1H4-4E-3�V 7 . �'$11B63G . 6f�$�!��u�s�%�purɂ-�� G Se/u�Z( GE He�%ca�)�18m_@e=�� a�^A� ik�i/6 N� )X," lapp!^bykNresid=�E��!!o map�MAb� opes4 & I. D!3�QM�Y��7�=%�Ag!;��!� �-A`�incubae1 hA�37°C\ (Xwas,-.���PBS.4 T��-p-Q1�� h6HRP6ju�BgoѼ��IgG�60H.�Unb� !?![ then �a%]0 . 01% � 2�^�AQ�2ae�1 ABTSn��s4Basel Switzerl6I7ti-E1|,Z�isFO IgG2o�ryD��%...qXr�Y?ji!yQ��i���(k!��-n &�n4TNGEEGTGCNGWFY�a�- A3�ab ofB�:��� 5b�(�, �|%�-2�1�30%�1�N3�,nd� :�e@y�aO;��InA�i�ch+A �F5��!+��1N% � (� m�9!i�E�~� d _-1Eserum�h��aI ��tech G�^�!. R&��Y (�l0q�pG*ya�S�0SLELYLTAPTGC;�u\+� �OWnE�HEK293T'���� Schill� $Chris Buck�C�P( -,Douglas Lowy@( ATC�/,��3 3Feng Yao/�1–n �^�I4@Morze���[ E:x��"�*at��,in Dulbecco��Mo:zCag��e�( LMTechn�6eV� ��fe8?b��1�At�B"�62A�(penicillin/܃ptomyci �0U/ml;Rnat 5% CO�C"#?() Laimonis X )ljLy �� x�VA�AA�t�s E(umI�0J23T3 fibrobl�/fee8��Howard G�E4T ��–+9*�;!E2-M2/E1- 16Ec�@a>b!�� ? /nufA�rer׳�RP. Brief(�# slip�� �uffer Aw 6� p%] PLUSEMINUS%�y hour� 5�twiAHn�:�8ob�'l�N!�3)�. A2�6�)�@mE��:i.�uBA�!�.�m�t�0Duoe+�d��i�. -'"�:Ea Nik�%��scS+2.sy*Ga(B:)m���5�C&Ka�viQ �\�or�i�(retCQ�rFbe��YA#A��'6b&q��B�30 nM��F�'�^&8be�!.;�*ChIP-ITmQzBc���2e Ms�] R��ǗOa��;ed-SSso F�Ev/�(n Mastermix� ioRa�),~&���(Kin�:�5�Z GGGT(CAAACCGTTTT TA 3 Ad)PCCGATTTCGGTTACGCCCTTA/(�5�K!�!z�b%r HTGCTCCAACCAD$�GG��ACA ��0%z.lf*�#2 ( #2c [8�D ‘e�b�@�y a� six�bup� amQ"r(*�bc� �"%p����oE>re="w=�<1��^::!}!E-��1�3l:e�TC,1U�Rrr%{u��QM/CF�(nager softw�. EachA��':�"S` .�A��t�T�&�&>&A*�&E� &kH(90% ethanol�Qp9.�,.��R�2��� RN�}�n�5 m#$i� iod��!�2�#, runu,$FACS Calib�5ĥ�FlowJo.�=v.�)�J: or PEI (SI���c�=g� m�l_�1�9�` -Q&d\MG-do2.14 r�"t���o! �%.9i2�I� )�E�ly�@(in 1% NP-40� ��50�|NaCe�p M HEPE/ pHy�%�e�@, 2 μEmnzo�( MillipƆ)e�a!���mcktail�S��7�a� ^of 50% I$in A/G slu2�( Inv�:� o $@t� �� �ro�&/Br 2�p��ve� &N Beadm�M�2m�E M50.?A�1%"��1m!/mM EDTA�A�M� s-H%tpH 8 .<  �se�+ v�wac�ma gel� ct�!bin "���+Gv[EM�P]C~ PVDF]}rar6�ꯩ-5%a�-� (�1�� milk� 7� b���emilu ��mc#"-�(�krmo S� Ѩc��Ÿ&a7 Ty�. P��.!�6X Hi��216 [82ZFMBP-16E3]�tei!d292�[8�:8Ƀ# b*�pAE�iT �&d6H*+8�&>4�"1:V.k% F�� . L\q(I�toJ �5 �� nqDynabE�:] �<n<��Z.F��to� confl׆�6-l(/ٌ5μgD"�!(�/"o=~2 C 15 ng pRL�luA�, 7 FLORI3�\ I#,e3ipE�� JE��;!Vab�A( �b.!y#g%J�#5��iK�,E1�x �H . 48))��*G�|Iu!�*$B&I`a;"�M �S��y-Glo!VD�� �MOW2$a�%E�Z�Nu"Qa -.*� ��"��F� J2 �G remo) �-c�q��5%��$FI �O%r�s؍"� �)fFugeneHD>�.J��*:�xda��)�2wv�:�5�=�E���g((��1ŇFF2L�,� ��DMu��� 6 cm!�c2wW!a*ܞ5�a"�^V�edN/ :EaH1�7D 4 Danta Cruz; sc-3700�!UK/7u�(�JUUGAA GAGCCAGCUUU7, IDT tJ� !]2�Y�V ^��M)250����� .�H�]a���o�Bp+G2",/�*2]2$�Aqto��a1J%�"�or oV�T|�n�uB*��� Ar�������B!t>��*Y�10]�. SUb&86_b��5"%F�L HD&F�y6���� pur"�N5�z�5 d� tQ��Q(b���(�O�C.Kly�  A9wVYr�UEV&2� abo1No py�l:chloroI8:isoamyl alcoho� (25:24:1 , F5�r6� .�2A�q�a�(���^Nanodrob&d;g,� ! �T�J��:^]o:��toEC (�%-~M�bU6�"�of :�>(2F 2 ag��2S&Z�9�j:�������������. �J��^��AG6��t.J J[in TE�� 'w�1��/RyNiso��Z�i��36m�Y�b{:(A6v{31LCR3v{JU>{"B+7i��—�,GAGGCACTCTTC�n��#TGCGTCA.C�sp���@(�Tc,^�"!f80 "�/m�=l �*�-�.E5 � ~�o �6 .�+ 2ug.� ��:�xm-fr���J@�m6^HFA�*6���"�by 3X{Ao���1pe. l/a^.�(C- �k�ivd�U��2:eC:�&��'"4PB[Y h ,2�A�2 �-T0x"�3X)�"&oy:5�"*��"()�594A l%n488>� � �-dVm#sl/� �Vsh��%<mY8 DAPI�T��-9� Of$A��<۟ >%r�S mend� 77Gui %2-.of La8peO.r**NG al Institٳ�-�*un+V�. P6r.|�.of&s HF�.'R�2�.. Two-w?+r& t-�Z�Q" �� . MeaKr"!4ed +/- SEM . *Res p-val�'≤�b(05 .`Brua3oQi�D"7"�S� zoono7g��8IC; l Asi  J} Ua hot�s�he WorldD, O�&i�.class s b�n-neg]-�e�dis6;�/5�e,rl� A��=ar��n�[i0/4�`|oA� marg >!people&Trbaw+�-ufa �gudBmob�{��y�7-inF �Y�)1/\/?.�(E�famil1#�!� ofte��=iMb .{4cM�O sour�".x&aD��@!��ra0�9"a�numberA� �!#li�ock &cSC "_)es�-9�!��e0ňmi��of9��P�s�@asY(Kis�O�� )$��tkpIa��� �%n � )��=� area@Dushanb4 Tajikista�/2Xap�M%1�63�F564 cow qs�A�y IS711�real-�� �f��I:-��]�Eump�unp�urE� dair�KEt)=HN���Wr?mi,v��%5ll��o&�0ow5�0} �2seron&'�w�cso�>W#b��%&Y,"�X�� rpoBK  g��AN_naOw%�6B .V rtu�/a�-!�!˅��-F: meli�Yip���G�+nca�A5�log�)6�Q=s�@�}1ne!�%��R^r�;!�(q�/��imple1fA$�. 0diagnos��teg�&  falsʚr�B*5�A�v��@U�?e�v�8��era�E�p�^am�)>m vacc8�'��at��� S19A�"Uto>.�kr anG� Rev 1&vB!i�.�FD.�)�U� ��po�=�A���foc� o�*Cc] /.v�me��2�k� prehenך��Y�IM��spp .��%��A1��o � . @�2+ �be4kE�$�5=w�w: %j>� public h A�<%M[=!7���������a�Ѷ��f��3�f  ( WHO ) [�@a�v�g9�d�#..iU��^Qzxcal*Мca��yea�%"R�40%�"�* _thsul0a �c9E [�W2 �s�Middle Ed%���|) Ein��;s-�щ�Y . De+$%�ALr2�l�Id bim�%� �=polit�wAe��-A uniAN� �� beli4��B!�se�explaeRќ<>o8�2�_ ��`" ��.�[>:n pc��tre\�/)�O�Pl !P�;asM�)is��W [�A�{�M forgotW aA^\.P<?�g2!�hc9�[rOR/ ( UPU )-(r!��t)yIMA:1JlA7fresh f��!�O !G�' ' ا�O�с�� ��+ �Q�le�6 V) "�B��j3 )v(Small-scalel� )f. �<x���P!�K���, by�� �Y$��("Z�rA 9�ly 12=spe}de�4b���u*< [^O1u0�,;m� -ҁ ��I�pr��p�� arm ��CwFeٵJ` ( �� y *? ("*>dn�3E)su�#sw��>�{ YAa=�oV�M��ptE�Bbiova�$[��D zCw ��um� aYS^0<*:�5aL��R1����W�́3�� @?If acute��2WX�&� adeqZ� �#i�� Av�� can tur �6՝!YZ�!anu disa�u['�1�K�"� M<'~re��*g!\hud[w-o>ry lympy~8�Y���l� -k٠w����Fd ��0D  �2c%!��a(��&�uewofvS . S1 y!� luin6 �A2x * s.�<�/ �m �e��� -"s [�C�� -"� [15)�7�Fe >} hy .s��r��D,5>~ �a� YX�`a�m�t� A�+�� 6/[�:7�i#�!tN� N`�A�kn� hen@n��!Zv "� ��pr�Q5sWA*VBio-safeo��s 3 l��ato"�";�(#|���") :+� ׽C�J�*�QA�i5Yd3?[1���hIv �few�sno��v�"��. 4;ch"�a� )�ma�ar7M;�9y��ax ڴnC5���hav�\a1dlKM)~:is��2",/��o�]�)�h��cIkq�0)i56�`<,erA eI,|Ac��F�ALk ly ㅡSd�lEJ��.`metho+!�r��FA] �� �2�2��� &�)5#��es�%��b.G��|!t&X"�"[����oơ�� "M<� %V$8"&�x�& �r:A()���8V�2He�9a��I.�?:��M%$� &4�M *2K�ed�&Ҍ. S��o�bri�EU legiPZo�V�ea/!��KA�!>f���6��eth� 5ar�� Agrar*GTe-�*J����4�n-inva� �M��8*�Rial a�-?S�C?e(vfy� “E�!'&��b���(Zy�-A�� # %)inj"� a:�yur3�%Yi�U�M�% partͣ���O �ynDba�If verbX[n�!U7E�� W�!����'vE0�&ˬ��/her�#llI��!ql� nony�8n!� $r��E+� dentI�{n޵M*Qeor6G-�/Nn"set-upy���a5���F rece� Sn4'n1ha#ens�eif#��a|un{ b*? v&��+PGܻbe�cul!E�r�7�e� �n�?e� �Bm�arEE��H 5�b��I2e �� *� � }�d"� ӎe�1�j[2�.I� ief [:�!"0fu�Sr ��E*���ca��l o��a"��#� ad�? of <20 kmI�>e�(l% A@�r-;%}e�*��N_ ��&BG��)��%HCboUA{:!�!�e*6q4�p��-#)�]� v�geX %9Hp�"Y*��� az~onT����Fsa@k�LqVt�ed�6�I�GasOT7 RearV*M"6�:| W� �:�s$���Tll�E��goN�) ��%�1�Aa�l3�>bX �ta��g�hn�[�-� oN23P8r��[����arr�sCmtaneo��w�a�a9���2;�.�&���`- ,�Q3� XY~au�m� u� j5F��w��� UhA!�.� �}�4n�u�!(r�ZaL!�)�o�u al v�en�� �%��*��A�+randoml�.�fach7S �Xny1>"��.�A*��K���aiʋto &�)lac� �x] I��!�2�"vz90W�443b��ZIt|�E� ��+���57�7 I329 I��|h���a��r>�9%���i�.@I�,:� 2 mLA:�!�:�%�e��Ep�aorf tu�?�k�col"����U!f�"�y���R) .���B���I2]PA�or"� &����6%4a�rec��]��� sorb[  ( I-E�O " 2��4ir bu�rve�M( CI. ��!~!�m )�Jj���a7^Mst2�2� .Ec^r�0uGPMG/# Pos` aS�� )q�rE'�#�7;2= ���de/�\i�})�a���eYuinIv�~)I6 C!�=BAht}sto�; t -2pFun�EBsZ$�g�8ce �M< t Uppsala.� , SwedQ� m"}�$q�!!��a�f$ DV�3 Agr�N�Re� �inA�ss:, Belg�I. B��r���a�:�Ae�Q�f��+�; -Ald�x, S�c Lo, Mis7iLS :F=$t� !� ��b2�E��!�tmAp΢n� "�re�jceJ]�&*'=d"b'�Age�( AHV� ( WexQg�wUK� M�19�aխc;�)r.��e^lf�=� void���H��!_�!�!�-0�7B��#mC6*M��=!u\.6�2C=�Xby Corless et al . [27]��uni�V� r{C eob�V�jmoJb1,�Csachuw��7E=6>�16S-g�U@ !!Or�Z&��_��#��o.HmY -L=.J&z�Z�b�G�d�0sh��( C�L�(el%t�/"!�u)� base�Ma�_tm�25lim�: dyna.'�i"H.I5( defa�!? ing/ }�%c"|�Rotor-k&-AZF��"&�U����A=)at0026�#exڡ �G_f�th;111�?�s (@�0e�n9�$in T2378�&T�nema sx"ARPseudom�@( aeruginosa: B683A� uS*.�-�� x16S rRNA��ީ�SFil!��*!MZ���genus&hiԤes6�SI�e"- s$XA�.�#~!iiX�b%%=omx�M�o}�a:��' %�fq)9"�X ed: BL�xu8�@. 5 U�ITaq Ga��* ( Appl@ *�_ , Fo!Q C�,�CforniUe�, 1X (�;� 10X��eneAmp6II , 6pA MgCl0#/C)$dNTP blend^�ID{ni!~S@B�30�H� )q&�@F 6Z�, z9M >A N>!rlsba�T6��=N��>��m& 0�ol��AP5^CL ;A�6�pr�d+�g#s: �"-starx-] t 95v 10�` f.H45� �*5 � 6� ��60 � r&53�{ ����2%&"g i]Z�&.3�)� P�8��1ani� "Vru�i�& ��GmR( ve ��%�jB�ru��a�j�6�(:������!�A;�,pay%se��655� a�>�PQ5 �r%�s���݁6�&� ��>-!1�( /�IN%�-l?r VWL , Ingenas�^MadriabSp�X�"�ApB���<���I.no-�+��6V2llI-�A�>�@a� ;�[U$�� ion/6�] �mW-r �L,�&B�  �'%>�%�5 in��sIi�1�E )�,A � matrixPu_by�3ng��at gav��E��E@ , got Ct�1eg,6"�@:�JB�0aK ar�4\K.�,��!�xPf��� Ex">�Pand f��luorescence measurements were performed on a Rotor-Gene 6000 qPCR machine ( Corbett Research , Mortlake , Australia ) . The efficiency and the sensitivity of the IS711 qPCR assay were evaluated using two 10 fold serial dilutions of the positive control , prepared in sterile water and a PCR-negative pool of milk extracts . The DNA concentrations , decided by NanoDrop 2000c Spectrophotometer ( Thermo Scientific , Wilmington , Delaware , USA ) , tested%�`: 2 . 90 ng μL-1 , 290 p. . 6 3$!�7f7�R. It has been suggested that it would be possible to identify isolates at the specind 1py biovar level by sequencing 4DrpoB gene of an un _,ied Brucellaj /DNA�queryC�Oa database such as GenBank [23] . Single nucleotide polymorphisms ( SNPs ) have % docua)ed at 22�iInin�4093 bp�es� classical�sp)4. A tentative �cEM;! �5presenttmA�(samples was6�>extrac�!$H. We designed 2 set�(primers ( P $ tool h-BLAST , https://www . ncbilm ih . gov/9s/ W -blast/ )A%�if%�4regions includ!�HSNP 716 , 737 , 969%�985!�et! U s 1:E%l1983F: AAGCAGCTTGTTTCGGTTGC/AEh2193R: GACCTGATCGACGATACCG :Q2 Q2722F: F4GAAAAGGCATCCGAQ3119R: psDGAGTCGTC The first!Z.�(�b�Eb� ) allows%�)=�a fragAqJ210AZi�%2es!1sA�poQ�!?ah737 wh��AsecondR� �/� ۲�397��6�PCR6��z carra�out u��8Icylcer Bio-rad:System (, Tems�o4Belgium ) , fo![AV!Taq Pa�er�9�R2 = 0A 99 )� ster� wa�� , 91!(A i�ed%pe�matrix ,%�9%�8 `10 d)ed2:i����lowest!centr�6of� suis%Nti��M�"Nin�u�� ��.��taJ" � �sM�!]B e>sM ��or fur��Z o"T�a�A-.vA�su-�t.��tot&���i�A" �eE &�1a�杔-!�allelicA�fi correspon�"[ describ �K meliten�� %�a!�don�\ons2? )( Table�F S1 FA� �o%Q � came.�.���� Z�IB!A>�,ch��K� �reporA to be �A*.~ ( 23Q 1�a�� Fh�. See58Q>1 ��P A de%�e��(�ZbgenbankW. Ty|�<5 at���� 100%���3% p��v�GHsimilar discrepancy"�k !<�M s%,demonk !o�  ��Switz� ACpa�B�,�di�cul� �wi3oar wha�2a!�.�tissu& of 1P 15�!>Rk[29� ���obser)� curr� ) migh{d��truM�$q -U� catt�ith Y Qehis�erestim%�r)N!�enAB�ZOfalse 51�ha��� as a��u~of reduc�(ntibody titov+imKHv )�hanimal%�AY6 e�U�� .!)I��� expo toY!A�then tur42�a�a cer� �$period [30A A�)facto at �influ��)E!���!uat$early stag�,)�, i . !2w9���14 day��@he humoral immunesp^Ţ�Zyet��)�i���;-�ie5�h��[31�F�m�,2� ��hutero*E �post-na�-A(can become �H)�us neA7 (!�loE�lyS) [12]�approxE�ly 3 . 5e�Y���yto delih �.offsp��[32!�� &u:�A�W {!�inq�gener|a�Yr� du& -�y9�m�)�1vWh8 t�is ��0�ݘN�isUknown !vneeds!be inv!'g�:� . Iis@Awc�,�i|partia!�expla ��1>1.u{plaus-pnQ !��x �be�; vacc,!� against b��o� [3�HowE�a)����i*$given��lo�o al ve� narian�n���IEx��tJ�is��i�d relie�becaus�j�E );al1\� or2��|a6stockA� Tajikista��$��s��'"� ��a:� A�� ��* !8\ of� dairya�# ce�reveal!"n� �.]e���(>�&� ,w.yI a}( new markerB^m� remAC unclea8d �T�a�is requi� draw��m!�clu"� A�i��!� �`e�W�SNPA mpate#�Hq ��!a���; )�,U(pigAdu��l non-exisp�]� is highlyD %l��^ !׉�.� �� E�w,!�be�@kept tog��,small ruminakE vof);H !4 sour% �io is��cu� ��9��/��&aiWepidemiѤ situ��M�� , �en2c%{��iisheep%�$goats [34]we����often)�pl��ity t>&,yva spill� o  ..�� >>�� | aFet��r !�neighbo�ec!ryzKyrgyz�M �:�fai!y �[3�"Yhe:J �tw& yiel�aF��� ��us�"u�� As �io� �  spp .)X �,-�I�)�,aE�in �r�ob� � mpreh�ve� !={�e:ucirA��a=M���popul]���[ _rafir6�regarv!z0zoonotic risk� consa�g��EU-=-&� � is di�ul�ɳ)? � %�F� , damag7p!ad U .��� �p%��tra� u&& M��n!� S19��"!R:.��*X 7Rev 1m�b0e�D.�!��5I �QaicB =�0o!� focus�Jo] eZQť&; � � � AQ��o��J&n��%9�y%���Q&�(�:ig:��� P�"C.�F�� mZ)�!�1o*��g�u!p � j �m)D'!��#l(ary diagnos���g! f�W��U8surve�!a�,UX��e��)"�4s .�ChromoseaGgen stabil 2 im��}� normell fun� ��6d �2si dise idys=��=�e�C +(. Many orga  main� supernuV' r�o��!�at dev '�V� ard .'� athogenic�\gus Zymoseptoria triticiY ��as � tZ!EEWy u%&le�mei"!mit ,d nMv *��� ow enrichAa!@repet�elEi��U(��h<o�aA� hist�gmethy� �@Xg .�i.! of H3 lys�9\ 427 ( H3K9me3 , 27 � o elucida�e rol�6�n��B�in Z .5�,�: dele�ׁ$genes enco�  �transf~)5��A��!)H3 �, kmt1kmt����%.p�d� ou!�mue$.�, combc'ex�!�al evol! C omic�A�h�'�impac%� thesA-le�on]�NeA�m�,�in vitro%in nt� We� wh!�1q\(��$, ChIP-seq�GRNA�0re� � A�Q]n��u�* C� er�4^%���-JLwildtyp��(&��)v��/�-�-de)"t�Y"�drai�re�ozY L Uis\l{�� into ��v!i|y ��� ׍� � rear�$eA1s%&8)ofC���sr foun�A�abs!_-p,��!�n�,by :,v ��a!pos> �=�stark�M}$, losz 5�,�� incr���1!�Q�E1c�)o:�under�M growu �+EI�, even���-large F�(�(in!@e�iv��m�[aJat����2�!5�Wen�=ofM6 it��;/5i��Hn� -$n]o>�%^�sU.�+AFe�.Z!�esBP,�e",ng a “meta9le”Ct�-�Lquasi-es�1�r �Ah�,%. !a>m�plYan 9K��)�!<2Da�gR3ey�[1–(A well-studA� hall���epi8��reg"l)a�r��mod�8�� tail��xPalJeC:�[4�N�E1-s-{i�b-+E�lZ2 � �A�uQ  ereb�gh�@packed4,`���les}@or8b� nx tein�2usi��"e�crRy,[ H2vc!oi�$� lu.'&L!ҁ�s6� sepa��:tly vɰ��eu�y[6!�S�4fic5�.�s�assoc� �"6rc�Ng. SE��e��E� ]] s. di-dt6( (�&9me2/�$!6�6asi �!�6�l H3K4 >:-� n [7!+��X Hy�Aphe�B  KMT1t6$u[var]3–�([8�%�in i�c'(d Clr4 [10]�DIM-5 [1P�-Gs6����i=�n(� �`peat-� U�!Na " link�#��ɱolcR� ( TEn4nd��A�(� [12–1�For ex��9-A�j"cajol�"sup"�of� �� F(in Arabidop� thaliana ��!�)+ )�@0Neurospora cr$+1�]n,�>2“fa@:��<��2T0KMT6 ( E[Z] )A�par-�e PRC2 plex [1e�Iz �� fung�/��" � y�#� to!�e�_�%ԝ�memory�Qis easi� v�!"environA~alA�end� �stimuliD���� &"{ In � ��sm�%d6�i ca�dk:opy�; �5s[17–#:�abe �C distribu.}re�/Tc�rZs [24K1x1o�me3B�,subtelomeric%j si�/�Z[22V,� 2"�F� a".�, &Y� �>����e�ary!Xab�5�e ͋�I22��u&�z so a2L�p��mA �'��"H sA9a�gal�nt�zu30 , �#AR� S�&c A � ival6b,:��i!�A\A���E�:� A�g��#;canGfer�-i�tdv� 0 � �n��{�-�y�$�(�:5��m r.x ` .fFT�vg2M a�! eg They%@' char�3��exU-vh � aa�B; (length vari�+[3A�� %v( Fusar�7oxy�Mu7N8iAK4ematococca , AH nYS �%�,Vg  virua[e� 8�6#YaYsV�, �Vq5�2`�Ef d fitn] nd�&([3s�?�Ec�A�T!�'� �� life�9�z�9�&&3 .Z9of���#"x h ^ c^ .aby`e;*e9G1re;s�|� % ��< �ʆ3 (35 , 40–4� Tfݒ�?a�B6�%�,th�predo��'6uc�9���.C n c"!uA2�% ��veC **�e��A�Ct2� -��"=sy|!Won�Cof2�ehpll", �2 [o�2.�, �4��`'��a� V�ME thos�A2S[44� .:@.�,�%>"ɤ2 !so�Avall&�n�$LA�&��r)�V�7*Thoh�y��[3J4e:6�#�[47AyHh'�in�W) to w���t�m x$� . patt�a RTN K g!=]�IY���F����!S�(a; ws�l��a���q�8u�o�6� � hemi-biot�>ic�L2*%�$o�,s� asex r . B(mbi�.eV��v�.��Oo�B�%��?��26�n-*z N�� D� � "�ym� inct w�,A"�I]��';gr��. W"�B!�!၆5�enhF s.M� Hy2Vp�FAN�breakag��seNC'Hupl�s7 �A(r�−�#1z sembV!9emerg�V�. T� "(,uf� �!*&S���r�� �YaIPM49/!?g��a�l�cGA��!de 8zAT&"0f�aE�h]Ni�mii��8 �n�m�re�W4e IPO323 makes2�an ex� ent�elA��yV�&� �dynamic���reJ" lE��2�]y%����(A�r�� aneuploid.�s�!o.wQa:�!p9 .�-�'-�ty�.��,A�d��#two:���K�(( S . pombe�; N,@��,&� �L, H . sapiens SUV39H�@�K�(.DSET-7;2C6;2BEZH�=����f3a�.��s'�H�L� $�� F . bCiJum�W� c�&� !KaizB%��a �8( Zt_chr_1_0191���B1� 14_0055![4� *Agrob� $um tumefac!R -med�)�" E [49]A���)� der���><bq�_l�]�18p"�T,G?e� Zt09w � �C�;caHtegC�*�hph�A�*c@ $s hygromyc�s�/� �)h%�or6)W$'� E1by�>!�SouU ��FAS�S2PCsEWi9a {%`_:�G,H*�!y!a�4ackgrLby J$r�4to nourseothri�) N enat e [50]A�a2�G>�0i?�,vindep�-� Y EO�...,��Δ�, six 6 !M�- 61) �!\8 ���abb��3Δk1/k�??&�>s/ we ��w�5three\�Each�Z��1�<!�)� 6 �%l=E P li�re-�����io�G!g�d�a neo+.�-qe;�)� G418.'0�vIh loci�E��W.�Q  oni\, �SZt125-#6. -#80  ���110-#28� -#365 )�a~Z�1�F219-#� -#11!��ufJJinI�R!5Ti�F3�"4Ig4YVS3a��!di8!�at�x)���� e>6 I��":��"on �S �� >�&�"6S viewA��sub�Xt* �kek ulr{4mma�-in���G . ToSEif��of�g �G#53UF2���or� h�i*on� 0&TamE�: !�&\yJ 3=�1�� &�!�� Ye��e� >ُ�'!��J,��@u� (� R�$liquid YMS�=)ldOD600�*eUd until� Tac]s�onphP'. Ove� heA�mt1��Q�VQs� ed *P)g Md1�Z ( S4%����)m�1bq�+A+= 1#7ed no.�2�Z )�!d�%�$( WilcoxonHk-s�es3Op+H: �1F 025; 642���@ 005;�1+286 6�.�*m�sA��h�Klert a%r V: to a��eLnm�]es{emper�O�c  w� , oxW'a��� toxOVG . AsBe?-Vm2�U@!ǚ8oM�V Vi��#� ( S5ME, e��I 4osm� s�OXI�� sorbito�9�EP�J�M^$.�>L.�7 elev=u� [�8�al�l!�C %melaniF&EMq(*Uin6#])�pAC��A].�1�V&/�rA� }핝i�i�!�6-��sLHxef D�b��M+%Dwh�( TG+ um aA�vu�M��inoo5eKav%mLsuscep�9�i�WOG1s�D e"�Cof)p}zU�e�V E��Y!V1 �� m$*+214��f���oaH� oa�.��P(of pycnidia8 necre leaf5a!c�QQi-�:\ !q"Q0a<$�q�Q�l/C2U��ymptom0 S7U#If �,�ed)asef@e��:�2 ably=@�2an<�6�EA7�fZ�_!:�6�(.�W�/xt�1�8ed�;6" B�X+G&M !�$� U�2�#�#�#QN�,by& (� TV)�(7 d o� l� �#�a:�$ gene�":f �)��%(�*�A��Ij�(,SeA%�y 6AL3�Rsi�F�kbq.�n�Jq] , r�lyf!���P*9R�Q0R��> [�./OW>$mpua } c���D� R"� .�to"FCN glob.�Va� -� ��u+-�x*� �/U�:�/�6���)^�F�e �>O �!'!LVf10,M�*�oe�1u�A�e un�G1P�/�%]uId���QV�W�҅fto�0� �/ �p Gend*kH5mad�6B.we&; a� ��UA^J�inaO �V7H"�,)�� )5�Z &'N,��� :c���2 >�r�.���toe�er��.��.�Q���few�S)>�w)6�,BTE� #*j~CB1ek:.9 al��� ��m��=/to�a:��)sW& tanee&MI��Mk+wB'�7�� �6��=,��$>s� ��u�&�0%�7%)Fins whi[Q� uOI�e�e4�V�, $.X6� � R�D2.�&�b^VqM��l]%�gX %a5$. ���#���n�Kf~wr@ 0�%�"�)va��A2�" My�a:Con�(e �J�BgMC��&F ,�we di{(7~8]�]�*��min>@if�  c%vgJ&�]�do& �b�&] �s�R�aF�בkMit slif/2Q%�.�.b"�C!� �U�L 6��*�#� i?.jd U�WEo1�ArU�qb��a�h !�u6ك!�1n �P-<-! � N+ }55M�Ih !�!c&> �f� g�/TBt�1��( 9�.5�!�! 1� 41��Oto�" surpJE�#� �\�717 )@� 3A ,�&��Wee� traslK���Ei˩�U(�66rc�eȑ��ci�e�2*�.��kll]�/)K[i�e��h2e�W:cY1on"& I�B-ӁT�A�7uV 9?E V'���t�X*�.�C&�,��c3 80�Re�.�` ���E��J~25?� InZ�dis�yV^�".6�+!��V�2�!�I�� ~S,50�^[>u��O�8m.zb��Sh�7up�mo�0� � or�9.E"ur�! o�rpT)v4.H[�#6F�z'165adi�%�b� Am258, �� #a�vaz majo�'���g� sCR�)�INc�ng_ � a 4lkca^] �>��0��ark�i�Akr28ly!\���Im4Bj�X�b* ��F� s&F_��R�~*��Fa�,k=�4.T!~>L6�3))4Ő0S!6r2�� !�*" �lin1;� -[����Xl�nG in.-,�W42�^�D*$3"�D��nqedng�U B��&��rOntQy ( GO ).: "�S( topGO�l ’s�8ct�. ,� <�0�C��ReK�� !f���e2h� �;2�( D_9 � Seq3 Padj�0�0│log2 fold-Acge│ >��J6�upM`�����  ( �lof 47��ANm]$ie)8)> e�@ a2�DE �A� downV�V ( 18W31�"�&4�{�Ax GOS9 egor'B7.�)J|"R�:>"&$o� GO:001507�e! �C&� �>r 1 0627�h.�;��Q��,�by�(I����Nin�co�(!�R��!ca5bp �r�&mad&�' rJ;�g���/�,@poson�=$"s-L+ d do,+�q6=�J/s_q-R�Z�d}Hx�s�1�gL &{ �Y�mV�� i�$Qq�+B#*� agrePu�straѽ!� #H�[�%:�R�!sfz�H�F��I��. RF� �.�,V4bA"6�G%r�.30%��is�!�/d� �cth� �1��Ů2y��Q)�;�y�Asb�I�..�1�x6()5�ut&�iaYW�/!6R�͆!��� 2o3(w�I� 5nd )�b�;�%i� r�qu*/-pu$�9NJ"�;-%."r"�/�"me �*^SMASH ( R#s & SbMe"Q<"ZSH�0 ) [5,��a�of�Jv�,� *Y B� q�1&G= Ie�!�/Z&� �!O ( S8]^Ex!� &g)G,l1c-Na�&4  71]:%� ��O�N���� p �^ ��#Bj��"�2vc2�G , un�QW.< ��:R�a��B2� �L+]�Zt>��.y�$!l�*�Jd3�3m@�s*�C2q*�1!�7ces5��-h~B� ��,!gA �)�;�r10A�"F�4& 6t��t2aJ� by\elf�vW�"�>}2�t�S*|  e�i�?ga} !� pJ!��bne�H�Fe�${9��BaP)FZ �-= .$H@@ land� , nam��&�:i�Md� ii&�F, U;� r:�]Vcy+��-Ze6'O��f�@�V�{!��_shvAh|TE famil� aW+:f"'2Ngthe�H,Z�of2Ph� ly&Q:@:e&!Q vege�3,"[!� k< a [4�W: j?Ck�UfeC)Ef�|���s a�DKB=-�)9�%;"��,!'m��!P�er!R� �0� dNU-�T�'st�� �6S�s��� ��C,�:i61��XYtwo&�  long-�P1~orajlab&�P�Be"R:� sO(��&6��Pct&�6�#J�#���ZH�O��"�>�r �0& S8� I&�&�be")&�*k#p�a�N�a�:�.,b"�;ab�% >�VenQ��"�1b^5He begin�<�.S. Each FE!wd�3r(e&`*A�~4Ua�}*po"`���fe$5@#resh ,7um�Pry ^vd�05})��P�.e�p :Yt;"r4�*P�Y�colon����%�&�1HY cree�Ba�6 ssayiY>�J�aaT�(�:L15/e� �kR@� l�7"z1�~7%!�E�!py& ��VO14{�t1��fr���nt�Y s�5�@i&�o']N;�is"v&!#mM �a:�_ .X��x te (�'1+d �>���cM'�p�0 =ry 7 x 10−5qter*�c&A�< y|an�Qam�!zNW ��raŃ�0he" eGd<v�= �l��-�c�d���"�* 20"�!In�9 4�3��%�R�s%3P)�E�1�(� �|EOD1~WNven:�uF8U��'r  s = 1 . 21�3E�H{57Qis- ��I 26!7�m*�C*2JA%��22�ͨS�6��'T!~�V�&�:����� �576&w ����1�ae�w:Je1;�.!=�f�hs-�:�III��o*96!�&�N ap/#B* b!�6��17E��z !�W st}<%K�X�Z( 5/1�� �D�=d]�m+ 5���^� �dld�:�^->e[� �A#)XV&S��8>/6�*��q�!E31![ �)!K20 k�6�� o�3�r�Q�3�nA��ls y�n �����e�9��9��4"�\� !�K-!!��!��]�Z )_I�-Y|#�0M6�:�C" I�2;�o�D�as�*�� highEoEB� �V!-�jAU@�WA|I?A�$�q g%PhoR*� re2l��!S=5I�proa�;o�/20!6~23Ax�/�W1*�.�!Xad0!�s!�e�>N�t 3�>6%.PA>�� Q~�q�V[w��*�&�W.���91-fB,o�fs�J�H,! "n;�)�YCt�Il#"`b&dvA���" B�GdIs22�)�G�Y!�a2=hibW�Aǡ��*��:Ta�g�A�Q�u9�m�� ��&�*t A �Ho�-� �still-te �r 9i_B�y �vy<t Q �PMu�o,�3� � 2zaB.. More�Atj� re)i9$BR1?� �tat.��!q� � V�.=!c%^-�%ٷ,�pitb!"i0U�"I,"v��,�*#m&i!�6C��&?B". B���B�,B�FdZ� s��m*�)!L!"EI~��!*�i�7!r‘Zk~-� � ��rRmiD���&��6�va� ��(.�#&X,N&�� *�,�!�M%��.��o�]o2�`�w2l,aU >|%.�wO���k�3Iu�b�inoa�B�[K~73� xtra �6�6�In�g&���ad�9a�a�B�monger?od!\�K �����!�   i�2�A trip,9I�~6 month�/", a�~50^[WF��d fulʼn�,&��0!je�=d*2s:,50"89 "*�P"�Vm��o+_"�P~�t�d%s�to ~100x&�13~ll�ra(�� l�ed-end�dd�&m� "\7B�of,M!�?j3.o 1z vi�`O/[4�T��*ux!I� n2�/�� 6Xs��d.O��/ !���:"� yS&�T5s? "�odo�;i1` ��a�bval�AeSq1�FGE�"J blotEv)z�%:�%�M%�Lby f�ċ�!�}^)�re!� F1Ef]�m�i*�=�Np*dlCy� ��5e�K[ZK%T?d"%�5Qa�poi-O-Ji' shor�Kdel�J�U.!r�9]�OBw[gT��-5�"�4( ~�C 6x )�3.�.Ny�a��E� 4An r � �hU9@*>Z9a� copy+$T���`��2�fB�~4-!J�Ia.8Kɻ���qd3 Gv�br3Un�f�6s�3�. ��--.��%��7>�1lTIA��t 7��Zm��#~6b1->�r� ͗�aI�__&;�E"/�A"�$4<09!� ��+�Rrkin��N�Q'F��0� v�/�;�  de&a� �.��&G CP6�qordant�2�?�)f e�� ~1 Mbu9�-�6� 1 �'SX"p`I@sY ( TTAGGGnF���o�-de nov �`� Pulsed-f�z gel�E2͕( �c[L�e#� firm��>oa �~i*(49�kWMI�c gF �e�weriцo��ft arm!PY U�CU4SV�+�l<a coin�"�,7TEAB-�e6�:jBD#��&� V z8 j^Ar\n >K} i�w�2�  ��ne6Y&!�J�nW+eI�(2a&�&."�2rFX!~J nAP� ofJi � �\�poo�" Ukll�‘� ’2� : no ev�cE�)�!{Ui2"ar*na�&� c� or)462oɩ5ɩA� ���{"5j#6" ( ���AEVss�B��a`a ��q�z!&�%�>� 5K_, waz"�ɧ( ~18 kba��i;e�0.35�=o"� �M��& b�!o< "/ %�� �sng?q��[#�2�b�j�1P*0� {�Z"Xof.HR� r &` �� �(� t!_Y!�f t Z  H� .�IF'few9[s& z� aw-�� 5��uA,m��>N[6h r�:�$,.����dfo��9+��6;t �Y>�es��2� �Te7e<? �x8-2�12u�,.e.+�PTj=%7%0w���n>v k �`�z��em!N��QA�N��;*�HAB!��t�V �F� ���5 ND.g��; a�BllIM2c � �)wJ"�2$ A�}�2Y,�9by��inuA��6G �����_t.� b�-�I!�� �?E�%=�A[E����*�{�� conn�o&:uC���ş=�(BG &@ $ Q~9!�e�6�,N��y�v�O�lapA�N�9W"M �UI–6D Si�E.aref�Si�o�8s�^!)O�� also��is 8" QcloP8McY&�1�.x�^Hfer�o*�]zK"e�F=in�d� �5�� � ���RY��R-�� kary �(�gF )��e��-� -50-a*)�-� A�2 (.-N& -��zRH ��)] �.Df:dDeR�Ts�`)I9�"{��*��-�*b.��"� aa��g\!��KQ�r" &[2x.�1�p�O�7sM"��� ݢ% �� 0'*, rarBI-��Y���RewFX:� !l2� ( up� 30t ���E��ag�B�_E�)��U+�OT�T�z"�mai�P� � �z�@q( S10�)�)b Aj� ��!C&F.�D<6�A2�6��2!�T�E�^�c �i��Xa��!m�X�x�1!m�'nt�i>��6�ng�{�d�l:�x�XR��M�6 � �3��"1 oa�at2��9]4�!%Zi=�./]� , may���gZab a-m&���(D*�4AaGtBl�w��-v"�s��P��%�� 2�Awa�alVu:e�!�ach5j���o!��.8"@a�,�*��!T"�+�e�2� o2�Pl " �28)�Lorea�I%� n}"lE�� 2�9;�Gthi<�fa�}gg!,S�:r1!�ix%:a��-1A1)S1.>_C�<5b�z� &�:����� �Ungl >������4kof 62� , 34m�&0(-"�or <5�,� a�q�r��at)�*�!�"�ak2uk.> 5)�E�M�"GPw�an-"�SA6h�Xn�2TE.V.&�U>;�%va !�i���A�n�l97+c.~ %d :�$y�B9�tWr�;e��3�T��e 0ckf�<M��A0A�+)tZe�"Y="' %�k��_. W��.�l�#>O�a1.!~&{0:,g.uho$2�5ZxX�=d� o 6hJ:V9�!��N&[ha�"!Z��"�Fi�L�� ����"� !� in_ FM��> L � �ի��D���� j��KAe�*� g� � ���yx �Ctfew�,>�VN�@!*J.5�72Xl�by6�jw��"sR=� p�& K0xE�-�!!8!�&� �B� -Qmis2�as��KZXy��b2W��]�A!7B�l�w24#��"*��   dr����!9-2�.A�'C�� 'sce�uo�]!@�} y ge�4stYhxA�05��be*� �5pro�rE,F�&xamplGN� t�$b�Gc�� "o �>� E��>xh aA atid!}mitAO q�{���disju��� D7Es>�ӑaE�J %���cِ! lack�rA#*� �� &!2 cy�DAf*NI��:%GPGFP-tagg�~ ENPA/CenH�U%k( �! �flšhys2: "€M���uK�>P�[�6L3� nQ -I�X%��mDe��a� [a�"phk��RO en�,s�veH !�<%N_�%Su��mam-�!'t[5� 5�vPr��?.?arM} bran� d:�.�v�?@mq�h!:ua�0 �oU-�4��pu# tim!�[5_15���~�]�AJ"�) �- �inner)���a�aA�uAr.WV ��in� �M�Cfaith�r �1�E�� �+5�7�%%��F.bu�,.I*z evU,�0v#[?&�q!4� � Of�i:�L�rosophilz&lanogaI="�#�Zu�[5785"~�. d�te�{!sEN� [5�NB� iCQ���V���s q�t - r.�per�� ougV�!���j51a+�;��Ri�n�4�*�R?2C1$Eġ�E)!��1!�a"<W-�h+�r��m+� f*%s&�#2�.~�utU�jA��exactY�NQ.�їne��(a{��5���G�xn:�==���"� %�2�b���.�#^�W��BkA� rye� p ��l3 heria�d�t>by�0!Vf�Spolle��я[5�B4! ���!�6� Y%s�!��:!`f�?o�l�9�/6 �>*teo��.f'�,��)���69d5o /h%m9*� i��)/6fI�*�,% �8�4�(3� �N�!Re2� +!��r s�.���i�2VU� <G >G.Luni�&n�Uway [6Qr6,�ca��?~���:�N2� � � �~#Q�M_%��bA�X�Ah�A�i�X2;.ɳ7�2�29��E{r6�.�Fung9~Ťfl�� tly � z� ��Y�D_"Jtcapi( Hi-#w�06m{�g��XU2M"�{ a�J<8y���/A=}0aV&@0��no5*�}���|�kN�.�"U�N6�B[4 �� ca�o!Jd�7m�!3yG2�'�;"F�4�2t%�,*��"'+a�]&hP�>n�I�2*�e*�����gr�5�F ,>�2a�v�Ut . Ab"#Tf�(p(>� ~a5.p!#aq�sms�[g<6� 6� S�2�&b��p��2��!e�?,� E[Q5Y#�w&�IFA�: ,a�ra&�J�gM2��Mp" of:p 2;�.��en��D� �G"��T�F�"onS��A���Ds�-Nr�man�r����M��5&��&�Gg$a_U&YyerrC���.s[6�6�F�Ma ��2v%�!��#p�)Lmo�fU�_����!<� [�u6"��l:�u�V1��� w~'�-�ndI�� �G)�homU��%joW~4>�)%�2�%� �6,6��pQ�.�.�V�2DC�1YAt �ofn��"q N 7e�&\:�2 S��2���r�6)�i��CȨ%@* �2J-���E�02X&�'�u��l.�!f Ѝe*�"A8iQ(626]�"�s�subjeWm�i�#BQ20:no�.��`y�Af2�)J��!:QA���"f �< 1� ^e�"� d� 3I/2�'9��8PMdt"� �#d!�2:�q  i"�; �*�>��%F�dis}2�1quick� �N�&� A,m�;e �R.�z comib�d Ѹ�V�OM8I-� "h(rf��G��NQ�.�:s:.i  b"%:���bs3"��L)� �[7+72&�+����D7"In.D�4�9 A4>�1�m-OD� *�}i ��W "yde s �.�[�x���2yv���c�UcuTel��""��U�&�IHbe-*�;2�s���"f�vi�L[��f�ao�hse�(cu�'ic���ZN!�vU��v.I%3M�J=��-cA�&h -E�k�,<�,�zYo1�)�B��!*��+��!n9M-A�����":f�:��mU�a�,q{?'*�%S inva?#5�-�S ?6�"A >^ E�+m{s*vM�m6�h + �J2h��� �ʕq>� 2N3e\�h&EO��ao!$a{!�y%6�`>25�T�)����E�2me�T�C�����7�JE*\8�1�n "�� fujikuroi�nah�5dl��E�R�Rs29tA.: [77��w&8�� w�qdi.�alI�ag��!>%{� i!:F�ű�@8*a"��(i�%�s&GwA%�pM��on�>6� lp�ipivyg�Iin(a�-�&9 �&Hk!���'�52qn&S�ʅ"ŝto� i �e��Znݤ."�Nh:��:͘�geF�. .a"t[78–8�nd.li�t8s��-"W U�an Des [8@�8�Our9��)er"�%���4 `9�����aX[!!��os��l!�Y &6@F�$}� o:a�Z.0W.mo/�Tls��W� �e��!�Q,Y0!a�����U�j%iAc �.�. Si$%:�m�"�&#AQ"m!xZver��� ���ls� ��l����]6�h:��<�" �a�)�ouZA�BLn�>(m�A�)Ei5"� =�GcY+MzeMjFE'9"��+ins�7�2�ffZ$-� . ZyJ��� �*RW�dG soli�O$2% [w/v] B����r )�*���u��=44y}� Bc Q2mal Gts ,6 sucrw!) . L����}�*�}%��R�"l  glyc�� M�� �ne ��4>Sat 18��� �X� ic��8t 200 rpa]P�r+r1"~�r�:r. EscJchi�Wli TOP��ell f �a"nA�dYT7d .�I)�trypt,u� N�51� NaClE�2%.���I-�)��lK �5_)_1plasmi��z( �(μg/mL kana��)!l37!la=YFMS5�.f>�M� AGL1 )%�7YT���ϡ|rifamp|� ( 50��, carb�� illi�'10!�����2Eb�in:�% 18 h%��Ak3 y [8�"Pik\1fiEӐ>Caht�`n �!=:�M%iP[ "sC :�. zjQr�dOY�09:?�~C4",���YӁreplac�nJBORFc aZM�c!0tt.���DM/�/�a�} n�%V��b6h9:Ɏ*�sΎ) �!�wa�?���'�"I�.8o,���!�:R%ea >��.�eoA�ɳ �B 7Qv�Wci�a5$ ՠI�!��Q\i�]nl((�/"ӎ. ��M�G�s�"I:2ayq�Et�|� :"�AG [87]I3probe�^eAEnDIG��e q( Rochq&Mannhei͟Ger�) d!�,G��"�� A9a�rapid� �8(�d�GB*u�)�!X&���a�7.��[=�K s�)k��La>$25 mM NaOH%c4� at 9�S10�|�vwa�D40D,Tris-HCl pH 2?5)�adt�ur μlu!�mix�@$<em��!�PCR�!F��# |2�e}�����d {l-chloroAM.HPl� [88]V�^h�V)>4_�,�2u�E�*~ �5� /μL (��9�Lo;  >"�!�L_" !�&i !!4��n�F��wo]MJ(Z�xEPnX]���n6*�Lpe�!!Uy( t���*0^I%�"9P&%c��H//,�'�-"� F)�R�y�% pr:Y`t�y� �'�p>�.-�.Bm,��"�-timTi!?t���A�&-_�BU�[e�.ue R��agct�r [89].%> i��!հ'�]�+�=��B�j ʱV�6t'�l&f�]V>� �2ReA���ex�aZ�� a=e�a�.a������������Y��>xdia�JC�s���%P:107/108is} A;a�*1r �ԁser�q!Zy�mLI�p�red; 3�� "�7��E�pipn*6��#Lp��:��:�5 ��Cl� 6 "��,�])BmM H2O�!2 3&� Congb�d�~ 01% MMS (�u�-sulfonN`�+25 ,�� %n��D%X�5V>!KwA���!��-agar (~b.^I""q~}%j�?��.�G , *uN!� Ma�2DU �*L`#mOA�g ū Seeda�"{.Bw6���2g�e�ersum� ntbree�BV8�nscho�^,� N�:j�[poJ((��e� ����pot�J��^%o�Oe-g�+&R�T��2@ES�ee.�pemR"3^a@>!)�q"�qr / mL��H2O�AN 1% To�O^Rbrush.K�=xg!���a<Tˎ�fY6aJ�a��"m�f9�[n?L�Zbag22 ~ 1 e��A4��jk�id�0�!A��� Gle*]K� �:Q�,l 9��!&~�E� 16 h�($μmol/m-2s"\A� dark��20^90%�. �Uai$+ ��,�r*!P�{ "13 � ,nX�HQ�|Xm��f�b1L28I�������1��fiSs !I9�. V�S} �^�,f'E/a�٨X� valu��%�er,�n#+��I �nI��!�50.xݢ�<�w�ռ%�o\%4��]( 0: 0%�1: �2 2: 2�Q, 3: 4�P, 4: 6�~, 5: �v��F2& auto��-9 -!/6"��>�Acan�i�Dž�)�)�Y�b,90g� !nlol&�*T (*AW��P )Oq�L.K#mW>�iS�20��M���>�$s � ��)ā#28� !�1#6�x,IRR �L�" X�Ev�':>�  �b,.�� e�i!P�h.� ��e���: r�er h d��tg!�!�"� by V'�+a�=uw���l2_~&3  /! Hr�)�6tov �of�� *�#A��2�X���I~�A=a??� >�G� dUo wWb�Xd���?6@nUoM2~�2�:v� ha�er}? o( r6�Om� �G����+�%��};�I!k� ��TE� l,f���ogI{onA�.^0��e.&��1/ΔkiV��rPW^( #42�nd'6+1.H%@ �2i�U�1"�"� g e�a��x�*�;-� �%�x �aa~+$=E� Aym�\�`�9���Ie�is!o.�2! j@9� L�)qY�oLf+n!�z�~�n�]>&Gn(V l��J��0�E���F�>�J � nd%  on� �bG B�[*JQ�E982;.!N1:��ZJ�i � ��f:���har�A=] rifu�5.jt �#5"S,��g�2plu��f<�� ��wa�2tw�륥"�,� 7 . �:1�TE bu�O(+���mix�'of Kl2%�:)�K#+a%����RabMun�A|�2%�W��&0��cas�2 mold��c%U%3t �� Pluga���%�$5��!�w�3 Falco u�*�5�� �51% SDS;Š4hEDTA;�m�Nein7� K [R�X , Karlsru/$5!H&~ �O at ��y�@ ��r�Fce �S24 ��Ch�BU��1�����I0�/1th 1 X=����ag� ���1dV^�&; wO_(\�!(:+�,GelDocTM XR+2n.F�6^bm ��=u^DIG-labesB�uE�)2�Mix�� n���"� *� �H2�2�Næan� ofp % &_�� ��z�cipK !�B9� VQ"�[91�86eI&/�"od2�H3 � ( #0��0Z+,Merck Millip� �t'( #3916|+A܉e Motif/ n*�\ '5�:'ilIP��ur�)�SureB�cPr�DG Mag}) e�f��0�\a5p�l/Rc��w�A ��Clean &} 5� Ki�] Zymo?P earc6�Freiburg:4W" @��wo *��a"� N�e�.�!tΔ _D�,m� �SC.�%a&��OSU뺭�@Re ��Bio�u��n "gHiՊ��;� 3 &� 50-"=aM wMaxCcksp�e�C�6n�� ( http��,mpgc . mpipz��de/home��B�se �6�z!1.�>m�or&�.�2�N�u����w!�0days until an�� OD600 of ~ 1 was reached . Cells were harvested by centrifugation and ground in liquid nitrogen . Total RNA was extracted using TRIzol ( Invitrogen , Karlsruhe , Germany ) according to manufacturer’s instructions . The emR Dfurther DNAse-trea�4and cleaned up �the7C & Conc��ator-25 Kit ( Zymo Research , Freiburg , Ge�.Isamples!mXtwo biological replicat 0Zt09 , Δkmt1 6 ,��PΔk1/k6 double mutant)�sequenc%��Poly ( A ) -captured , stranded library preparationc Ding Tperforme%��DMax Planck-Genome-%e C�ne=�T( https://mpgc . mpipz8g . de/home/ ) }\ Illumina Hiseq3000 plat� obtain� ~ 20 millA�150-ntA�ds�-h ( S2 Ta!" ) . �ic!� for2�as-8ed as described ��v!+ opul�s*�th:"singleA�A�I�B�by:Yc)�$e Center ,�e6eS>eresultAeinQ[B-:[A detaileTst!all%�ram)command=� mapph�}}sXdata analyses can be fo�_!VsuppleA(@ary text S1 . AllBIA�0quality filteA�usxK(FastX toolk��i�|://hannonlab . cshl . edu/fastx_ 0a��8Trimmomatic [93a&RNA-seqM\w�C�_|0hisat2 [94] ,�of ChIPUmP%�y (with BowtieB5pConvers�of� to bamafmat��or%��index q$read align!Qsl done gsam�s [96hTo!�ect enri�(regionsA/!R��inga�wei� HOMER [97G PeakM�calA8,individually�.�merged �bed�8N OnlyF�fQ3A�r�a%�considE � �Uw�/$e coverage!WB�� lap!p geneI�TE)I calc�5�>�W-0cuffdiff [99]L:$ RPKM valu \(to estimate�2res%�in%Eerent��m. Raw%�s1� on>�A� coun�0by HTSeq [100A�Uial.t)/i �Y� in R<1])�DE���BCutoff%x0significantly2g!�x�ed �e0adj < 0 . 001%�X|log2 fold-change| > 2  R pack!�topGO�3]Jńto�d ont��QNa �`es . Fisher’s exact tes p-%� �1 )cappliedfdee56�UP termuA gory ‘*# $process’�u�8structural variŀ!�a��U)Aome.�Speed-�4]%ILUMPY!"�RAll �ed[!�q.verif�by manu�isinspe� . Viz �AY+w���integ� ve!�(ome browser GV )���\dmPrompt post-exposure!"phylaxis�0EP ) is essenE�in�ngv$fatal onseŵdisease)ers��^)� rabiE,Unfortunatel�life-savV %vacci�9� s ar�Kten nei� ac!�i� $nor afford� , parti�BrlyAG!*4poorest sectorN (society whoa most3 risk%� uponmB largB burden of�fa� . Increas��i�B, redu cost��pre1TdelayE�delivery^!�shouldrefore�� prioritiz� Weik�q<)MI?�nmec eaw� thei�4� v���benefits!>$bite victi�healthc!� prov�a�Wp�.}�T�$ extremely% -effA�vA:ter%4on ( from $200;\less than $60/death averaa� Switch!u7intramus%�aM� dminiH 2 of����5f�Oc� Bdermal@D )9?a�shown=� A��� I�G Ax� mA�-e requF CJ((same number� pati� , which�fld mitig��)`e� rtag���XwE0draX E|eeI~ of iS��!8!�.!��9�finanE�me�ism%�t _ make6mA�}{�Q�l� c�0help subsidiz� Dthose e{ia�lH ;a$� ort new exis��7controlqWo��oI �concludat a unajsal sEB!�IDy�)JimA�5e�i��� MW�24, lead!jto a lika%�E�in human�E��vas wellbe@econom�fV� R�riA�variab ��ce clinDA�s�pear but7 � ily1L�fE ���4ŀp�N%pprop�He�^[1 AviAW��a.Ec���."��#ٝ!9=���1Ys :�[R Inꭢz�s) d 7"/peopl; o6�each y!B��tresourc! orA�ntr�w�2�M�m���not alw�avail��or �ZlyU�le [3f [ [5 �� This st� situ��e$ibu-to%4f� el�� B55 , Qan�N�occur�Afric�d Asia �!� virus cir��� endeE�ly:dj  dog p*[� $The WHO-re<dEB$protocol ii�s immedi�$w� washa<,A� edit��F6�7A_sev� ata !�ofL? , in"� opu� R0immunoglobuli��RIGd ar�!# �[� $is rar�,�z $in low-inc� ~ �becau� t:expens�]�PUSD$25!�| 00 depen���e] C�quineA)�originV 7Ep9 inɉ��>se�4follow!�ex�:N�10]��Ta#�, �u ly o�6� i7I�(��out%:)1%2:� roS a.�:succumb�to1�ad. SAale2= a�%���ihood!0��bu� co�pų��.�. V�  vials� �!�7–20!`e�R�am}�� E� "gperO�ing��� Aw� � �  s6], gA7�p� �e �-ofJr�r��F x ,�cbudge lloaS�i��o� insu�  > *]sh�or�Yv!�Ea fewgesE a rel�eQ��terA7ve� � paC)���h�.�prohibita\IC8 �: rave�� c��odI�aA^� o"�!�&� � vis!8��5�!�p many ca_�Qmpany! fam�)meL 'ke� M�e%�.als� ��gOr�!�s�{AKI�e�1͜��$d rise dur�9� when�� ��H\fork��)='(M �Q�)s ) a tim] d money-�DR ���also } �mplia Al� wQfai!�mptu�!�2P� Q worsP !�( � �V� A>,��. F�/WHO� rovkf r:� ���{a�-�s [11�����s been� <�cuA�ha�lu� ID�su�JQ "�J , [12k[1�1�1�16 ��ma��rgu� ��E�r� i/is^ *� ��sm�r[ � :e� �elici� ��val���� sp� ( 1 mLA�� ID inj�on1 �B5!�/�m4M4��cavea&ID�fs���re!a8marxly �es must�discard� in 6a!8 houre��mf �%bacter� a'w ( cur� �s do  (�reserva��au1�8!��may� perceived� a�(e . Moreove}� sha�amongst�E# �pract� ��t�+� wa�s�J!5i�N ��s%�aS pre-����� safe�_� enic��.�7 us policy�V�ai9� �3u��ine�u-b"S � }E"����� ����):zxoV9�����n� � �y�a�riof! B` 5A�ws flexi���!an5�confuX rega��I( H bBmee[he need)�a ��� set� . Ad� n�, I�A�i� lA�!8develo2ea �a�?!"i. H� ,{�wideRramework%���I�!�&�n�ofE�G!j�(� �"�4a2'!��candid% sub��� 0 al ) !?o2v�� bothf$2�under ��scenarioIloww0high throughp#=�� G real�c!�fi�(tN�:` q�2age�6We��u�e !�� -a!Zs"~) ^6� offe�� en� Izm�, � A$1���!. "w)casELw�� re�ed)J�u stud��(` 2�Th� � d� ( �)El rrųEG&� �[ �:�"� ( non->] ~A��!s�c:E 1�los�X� whil�N�A!�qass�e�A�� take= ��&� wqu�!�E�IDxIMN�w!3dŷ �� �of 5@ 2inB��r�e@F� Wlo ��At&� ��� mode�pu��|re$�inM 3�define�G;s:q3�out�� �!z.�,�M�0 ;!�i�� alEe-"���X �&4�5( ICER���ollarn# � �:� sPEP/ ( Eeiv� PEP-2NoEj 5�+#pt�&a�to| � � �A�)!���q,[E�"Dd�:eA�:|��>r1dvd�m�q�I-a� modif�"i�!��of+:��}�ř��!�z�~(to hypothes1�1" ^ ��le�*� ��3��Wa[mp�"��on��!E�Y��̉�=Z!/aQ)=.~�!L�)��e_�< � "ͬ oper�j,&o�hba�!4�\A(. How� ,l*��1retur� animal-�^� ��a�t a1(�da� zc1#� precis�predi�(��Ui� ul��rm�{ ��֡56�I�(�� four n �tegies: �Ix�E& 2`%�m!!�)��d;��Mt�j��margi� er�EO pric�fvo llu ��"�a$:�!�E"�is 25%�530%�= �V) ;eF�aA���ir fi�N�a fee.�to �%51 e 5� !��J�) t doa{�pay��; 46�3�!35@��aMe��A�s~d hospi�%��� �1�K A�� 6�r��)�As��.,��+�!�#�I� v���a�n) !Z"�s:eW9 verh�%�u���a� !�8.x �&�) abov�.$B� 5du����(��$_ ��":t",9 by�$!�L})̽<�(=w� "� !N�qxY�An�net g.%ɋ��Jk!YQup� d TRC](��ly���! &:� S�� _*� Ś�ځ�Ŭ�y �!�5dE��-i,-!/-&#>*B�!6� :he"��a*(2):��e pAsANuA�6 �],d"� "� '2,.�$]Jwe g�at�"g:�h �u in r9%ra\ t�!urban�A��� incu�*� ly�� �%��"�Ty�!��of�a!��c*{ FBi�e&��aH!�ex� how ���.h�i|m �Ec�v��%�E$� �A� �� ��v&�%�Bs��a",mG$language R!�cr� �� "��si�+#leI��. For[ )$��uJ��ed 4-�k E&%3Zagreb 9 r�!re.�E-5.B� the��4 �A� i�mrs�Ro�ATscheduq" i . ��8�%toŻol�o&�#Q�)��ip- {$)A�an!)�nd8A� +V-�2� ( FigureEq. C��.�genere�_ 7�\-6� of� �1�w|+ .T�&�6I%����/lea�$(� ,�� exce���t� �!*l � B��d|HmL�I������%1-week�-{ does� 1-I*�(��%�5�S!�[ +!il" y{:t>.�2�A!�4-s5'.Pe�N��:h"9 ( betw� $100c$55El #��edݳa*9��� � � �i�y^� Fz�X^�,( $160–150>�,q!y� >�Q^.'�JO�j4y�F�BApr IMQO��؍�s��)A�nb�*2B��"!]ޙr:*F�of/ .GQ�]�bs inst� of>�u )��&�$�"" .lP6� �� ��&�m�T`4"a-u]�U�!W&� �BK �(2:m.�i�^F] . W�B�O &.2~A�2e �b�( s7&N�1re-1�yF�%n�8�� ?mad��ext� *;�� v�3�im.|6�.We)�inq�3 . U�,]�. :�Y��p�J- . CB�/e<0�-�)Bp��)E)�out�E�a� �X)�:U���^�N�2;"�sligh�g<:^�IWe��dzul �j 1;Q @#u�3%�s+�E� $�1�$3/*�� �'aCst�j�,O� ]� such�U!X�s!y primAp0�A,Z'#A�j>1s2% H!!�*+�:1R�.�I�� !�- �(�ze�]�a ���&de:%!D/,9%-�a%i� eacha� *220j �E����B >+Ab�� 15�"2 A�monthi�atoaeg0&e�01$��*� :�B�FE�"B�]�!Similak;�i��J CUka fix2:!�a full   ursef�(�Q$a $15�s��!�u-��$10� �  ,�T�N�ID�)�(%t5m)r �*�&ediE~��:p. E�>po�1o� q� ��!c) .Z �I]�*�Y&*���mD)IV!) sug3A�/A��*�v�"lbs (� �=Tanzania�Q�r5!VusB>s<+ld � sus~)a�&�%�#�VxL s�0xc�0}  -�$ a�lL/"� yBreE��Љ�i.>�"�e. o t �n�3�e�7_/x.B�  U � i A��a�oiʑ�:RT55e�>.i.&>' 23Ba�Ei�a�8��5�aR �.{�J� ��2�� \ )&= �J� �2��+a�)�.�)h>-q !5 " =1%.#-�~����rea�)2�(�>�)Z&QA��8���,}l)ӭ�=ե�J� 2s! ��� O �9e�/P"t) >�!�J�V��B�m&��B�a�m��&0rl�7en fl��Ms�!����֍�,���t�6�6|'7�'Sat �)��QL *VQ�!�ur-2duc�K(�!��3'�6ng !�t4&�sF�<:��$ � 100%.�%XU�A���-s�Q����!?��y �� ��! ����f05%)E"���!+1P��eMe"m0qL ( $98 . 4%�-��!�nIM��+E%2;,�� , ha 4� 82I�!j|r56�de)s���. �&� 1Per�0a:�-!�a"� ��r%Te�E#�s�m�v�8"3 4A & B��a.>l� w��ate�liE�]�) 6� t�$C�@s�Es)��6E�icacy� �A>vB2�:b E���3� b~��,�z,WH�)�.Sq*n5&eath a�Nu4Bu2�,2 �aO�@ll�'&�ath=�E�A0A%}a{F�9br&K�to)�y ?Mk! e 4C�F/�"�Q�s%Qw�e�9�<1:�<�6I/�"N havW���"u�A�he�e$��"���)�"��!y��!�iskI��,4HVax�,d��<؁.�y% �8f�3��ZNM�]��8�>��*beO%�!��:WI� E"2&�3*Q0r� mmo)*�c"� !due!� limi".�(2do3+0� long�t���-b4-�u1Uz H� N{nd�4e d*rou��>sec�1!�*avoid��6.Us Tas a Y �![�$�)��)l Z^'a�" uYIM �Eus* �rI�_I�&�2VnV�*��2D�*emo�*t�5at�"� k .�m����a�F<] �A�-_�!� e�a�FA��1pac�Gormz/>�A�6�8c:d&� o!�. An"�iL(�6� � �Iy:s�}CMto�2y��Ye6�C��w��lBb( ∼102/)9 Fby$by>!��HIM�F]%M��HdH)J��R� D��U��Un�erwaA#d�@�;� b�9]\*�&� �0��t@��eW ��i��/��N(2 @k@�0A:e�g ��i9?q��-S l�� !Vin�iv�&}x!�! romiE$"?/�2aG-ssues!Ib��'ed�A�de?��-2� �M3B�Cb�<%��#2�&f� !5!�]�b2> brun�*m��RI. O�'ncipal��%F%�b�L5!�-"#5��:�A �a�e�3 ��`_@m).�g �f� ency%���G=Y��7tu���8Z�S6��*e�)*[��9rf�[&W.�@i� �j�, e]1i�� ��S Q;of"� �H�u��s"�?�!Cno adva� to stoc�)a mix|QXP  of � � .@� :�-�HFJ i� ( s @at Q!�:l�G!r;A , opAl�*� hb"r3�hv3��=l5ty�/H+2�~ ���3��)�5Pi� posHo!_ e da7GQ�nstit&Q,�3though poc�m�&pXr.,ly߁5[2�N�Sin�:ethod� �rv�m� �v��6��dE�>e��4v)�C�T!!Q.Qprodu"�M�I . De�)�B 9a��:v�4a�� *�&q,ny6� � i >m. ;FM��Bgh��w ,+.]E:j)�lE��N2 . Bu��%)e�"CH ha�E4 ��NJN&-���)"�a� etD, ����Lnd�ctTE` ��l,ų�AKa%�c,� YN�, �b�.!ˡKi�6�A.�%z�xs�a��e�rIy�"%�w�� i� � R92AE�V�-Ei chea]!c)�7t Ydis��5*attSBloZ,"�%��6:��"�X521�se���!ar�VchwanEIM���Ails�Qs� !C�40"t �.�z(�BT� � �. A"�">� ���q&*sxho*m".)�-.}aN��U.�_�v�~�� willL�l m��j�/+ ��ide5 o�[�b�H.*� �⁩!F�, * �er&�Na���"K2 �� ��D�or $20e��"e^t,��,/ɜ��E=� �Zr"�Mq#�w } �L-.�G�2�&S* ve�SenF)/=�V ��6�"�1!�Q.�. Sta*6�'A�1� �)�K.=��T�GYforth�#�.dm�I�)T4��k !�a>��ch-`$Wy6@2�FJ(*�<��R�0��ex��6F3�i�Um�:&�<mfu�"�06Ala 6�u� mA���E�W.�4�:� �yRit Kq�l 2.�� aca�G�y�E�ad�"�T!�earli�2�`;6;o_�U anxi�! :|I�07Gs� !g�"F��l'^1]��l1 �( ntil�9�$��)M�� ���o�/Fm . Fu�b�@yt� �warra�Z�UtRquant�<:�of �����aVton��maj�5��`� /c�W6�)8BT] &!�il!�G��!�r�!��G%�6� ���noI���Uo ��(4L���to�TՎer�/��0 �Ems�=�F��'��ů� t-�aiContaK[raI�F>5ev�qev 2� Wi�Bn��er�[A�� U� Eusefu�4xy meaTF!�*4G�$Š =be6d��H�u&��T�*�, mis�q27IDu:ckA}strrk�&�YIPaa��FF?mplex��s� eter@C�spU ad�o�[yZ5��- ��AdB%e���s�i�"� A�Z� �/.� ZIZ���'"� 2d��A�4>�2J�x�F��8�Q��G�!�:�ThE<�[9B!C� 'l�cy �e�� A�,b'ce��]dRI volv?C�r�ecL�V �i1 or�Fp�R!�f��laue�8�4nD!~"�"�KF�A�� e abR g -6=� � s� !�&� *.<,h:2�= ofR�==�,1y� . Nonb��,%{g2s66*a �'qΡ�a#ab�"Achild|S��ize���Exp�hPZ.I�K-(iS205:\\�T ub-Sahara2+FSouth�V[24] e�A�&pc?MU :�i���#�+ �W2Q`E� U!1`Z7<!�nP-/"�Ie�!S6v�V4rwVe]:�(:"E n�@!�JUI?,9>��#� ����5F�].N�${ debe����B�Q<bi}�k�H�q8�Cz��N��a`/���<%�� pos�S�C�)I_T0�U�+om fieldE$in CambodiY�=�,�Y26]R��:�gen�W ۡ{"�*!��{J 9l0l���$_lib|:��� �X!p[19�[TX"�Z"�&�Q��r�_ vest�BEgpublicq ,*H-��m� ����8a2\.N!'-7an�(�9zJ� � 6?� �E< ervoir [2�X)f�s*�%bO�F<;w�a��NB# t� -" [2Z�AJ�|�Z� �=3Q��"s elaboG+wH]� B��=8 r'"^;T"�&i�jofav&!yA,���[u�� bB'8�n Sund�\'O �&:%�ic:/rn} D1op�cB)!�/orJ �y�'''on Mo mor�{��%&�0a�^�!$���-��>�)_lsonB� e&qe6+L� to� ficeP9�!�7_}Pi�� M�J� m�<B-}@ (�&s}� pre-<EdPZ�X1-J!�h6Y (a�� [� i�M�� �$C]%��i�ry BENZ0�o�JnON ��*�-6�9�5 1dog.Z campaig��- � �Rp[,3:EL�3re�] �$z��)�!����Q� -%�"� .e���re� u�Q�{%0 [29�UAE��&B &�R�)� a�� J� i ���] l  Rin"�Ja�`&B���cid{r0^:ais���?|4Ti"�3of6Zto�E���BC�. R��A�IA�2*?�-h�g.52�0&#3Eb-A��5�)_va"�U{� ! �biz"�e�:� :��#�~S7!����s�&uiI�es unne�ar�L�sS���@���!-�< `<Alp٘&eeI*[eM-I�~mas�`"�N:�eam!ng gui��<�vB�CL!SCg'-��!�ma�#!���Q� [� vul�C"<��!�ine��i��@.� �"�[l��#� &Z no tech�e�#33t�&*x�)D>.!v �B ss�`�Tas� .-! �nell-toleP[30 �USje.� !;!�K�N%O0��l���outbreak&$%A���r7r2_UBali [31"�ba�0� �R�� �-,Y�;bl�C2�7 b�5b�)A8A�iFd8.HToxoplasmaq{ bl�i�jcellu; para)D� r&mq 'mmalian /�1y8 5ophvacuol�PV�!"� fA�E�#h� organelle One&�ix'�\ lanu�9nt acqu�7�����!�[= >htf&e�a*r�wEUa&�-bC lipid dro�Rs ( L�k , ubiquit�a�qolr�,=�� ��1vxqe� I��)}%���de�W f��!iF�TAG�olyWR0or fatty acid�pabolisma�� �v$1{�& bL�VAq�q�of-a&�Xg��yDRP�wGAT�,��g�r�i�*e O["5�.��' Y i�� �PV%surQI;�..iap�0D�aM%��ho'fA� �dXrp� �h��pid�9o\down�bra���LD$=o vus�i�� leic)�st"Kes1bi/e!�� �!�T�  accudK\ neut� ��*��ci�,%q5h!"y- LD-derE_ C,2@$o{I� nalwit�!�PV �L%�Iof&f`]6; Rab7"b�/ wrap� aA���kar�B��[gd){( IVN�MZ|��i y in%l[ɒdispla�t84sB~A&Gof)  up7Z\%�%�Mor_`jla?+i-�'!#d p�Rholip�rA2E�� prof� n� salva{-��v-�PV �>A�a "�t"�/t �C�sE�NA�aQuT��e%�re�K�IAe�d*gavag,�w 1 �unveil�F� �0el���c{ ��i ndocytic-� s /uJyO}iic"j�(%7M� lume[>]y��e���of2�n57�g6BA$P!Dq1’FYpa� ��cn%�:��1�. In m:�, �B��cyt��icZ,5�4er%?i�`vxL9Bns|n�[_�9� r 1:�(� �$riacylglyc����g(cholesteryl�Z( CE )I=micC.�om�on ) b6��aP' olay�ru`���oIns�:!x%��Gr}�idF!J*�w5&���t%*m^�~!InVhC *as Adip7 3 �]�w-��� �m�2)�a4 phil�l1�biosynth� enzyx.�!o-CoA:d2zQ_fer�w 2 ( ��A�: a&iliEoRp��=i|% :�=H( ATGL-��� -trai� -A"�c&*,� Rab18�ARF{5[2–4� LD �� cano� !�d5] func�u�niqeb�)g\/ag7 ΁ osta������[t��A(engag� v�b\p"W �y1����\Mstyp� �*Ɇcon$�/Q@.+4a�#�j infl��0�� tARNA me"� ,�skele�R� { , nu >$n)L�%u histA modu[B on [5–7!�Pe�~e�WiXr � �-��U�h�LD!��2��^��6pr!�gl�d[leuko emg��MHC-I "��o)$ pathq !�assemb%Up��'5eao.��fer}# �%qU�i��@/Uath� �J�!-�v"f!3���!avo �W surv�b:��y tl0t1����y�Ae's��Ha!�ti-%�A!-3y [8–8k.� ni��c,"yO Vin�$LD�R , aL'A� LD u��u<�c` i}��� �_�oA�reA �LD��`�-e2- )���5�!�x :�6��oar!. SCT6!<sq�e)�6&y�0.22�wenh�*d�&� �43Q itmQnpro�gMYEI�-s� Ea�IzZ"J��*0(Q6A] 9 �=Y�!I�an-��d��n� �e"�%0*�=��\#A�ozoana��2y g�iLp� fe-��ate�I&��:ti/ cephfxi#��oA��:��ƃ�o�T .ysE7K��y(�!:%;c�2��(�5 elf- ^>� �*��d�%��ndz � �� ���-stor%:lo7ly�%��&�t&<2*� jv �6�y ?9 �e��[��!Y�%ne�)] jnd� �G�[19�2�uC�dCv�8howQ�.�s auxota�ic�Q� dens��� Aeein"�"� �|re�\=� E�&� "� F�[2N{O� E-��5��P� ol� �� o��a�� =* ytos58awLw�y� 2�cy�dn� IACAT )"� [22 , H9eqQ'��߁�M0e�Golgi5-� 4� 3Y(Rab43 vesic��� � ir sphing�zon��#A��=�eY-fAp��E���(�2�S on.�i��W.�En� mus93��AJZH>ed*��� �!�P#A48 *st- w 2�{N"�ER��"��a ?ed �c�_O+o  % $microbicida &;H8�;'�is��GEAa�* inBw�f Th1� �lseEa$�� �:,of nitric ox�:�Be-!�augB6eicosano�V ��pag� m-����!��\p�(c�ga*ayYfoa9� E4s �mx~���%OA� e� stud> p]l,�!(��&ሡd �X��!�ur��ur�$,�8�"� A���l{" 0� &�!�q�� .�in����Yyq/�A9!�nou��Octa_�=6�2-!��) .BbZ"�, eS" &2^2�o2TQ�%FBN�!-morPo��e" 2����� �� PV{u�ir!���!m&!4�&�s � (�x�a��� : I*� �� &� 2� �(�ڙ=mof�� 24 h�N�( p .<) 2����jif�IV2 JBe`�,!�T!p%fibrobl1��HFFepP�la�6eL|T�/�a �i�'9��L27'_n:/E�6?�X ed�aFrg(qpoi!1��T^>4 BODIPY 493/50 aA/� c dy�p*�e"��@fluoresc��*aa�eLDь��s��by:aU�scopy �6 1A�^ I ��&�&�LD �^o �d .A�%A��a�e23=inZ &ս$to 34 ( 1/, 51 ( 2 �50 ( 4 e?.5(o�!PV�#B8��AUw�T�1�� o ~E�Qā���9Q abrux"�*d��/x��ly 26\ E���ek1� rfac@eM*&}2Y�?A� dis iwJV"�<un5G!$ a!>� s II&II-�o val�v%/� �N��Is@�x�.,��S2K�*al*�P!�ge�{o��!�pBi A�ocCw5Aw-F[�) �BU�:dsV�gg"�by�m-C�a�5� ��\ D� 55Z!�AB!o� inu�_�inK92Ot�8.3>sr#i�Ncat�n�a�pc!? �� ( ~2 ��!t2�=0!kJ�o�O!d � .CD 3!co�Hd���, Da lM;J��F� �Fz�fle�?apy dyna�\iuZ�k��)���,IA2� I���>%�� l�q��2 l� e�=�.�"lor linkI:!"�O 2�!I&�"� B�Ap)F�� ����z�re�,� .RCEahHT�:i��cgl*F"�a�ER���QdHep!fCE6!+ъw�v.�"�s9ol:*1� iZ' CE d\ed�> } i �xl>�rms<��);a�� 3a�i!�� �*�3�9�$.%9!5�?�ta2� DGAT6�c��t�1�cAa�!��-� Q*��!�[3�c1Aa d��6 ity:�=Ne"]!Ns�yup!������a��$ recya$gQ�!7Ap�,�Űe~�� ydro) �.�2A!O-�'!�*' ng0"��!�sunsatu�&�9, ��e��E)u�VU�,}���ro6Abss�%SC�$ 9Oel�ko�a%eshol�Ac!K�ǎO�io,�G ER bi�{na�}ta�i�ch� t ���]�SLo�� M"siclfl6; 3,-�#9� U�="�|��-�Br�o#B>LD �A+�o<�H7es�[3�KAsV�*�#J ��,f�cia�whe�;� k!TArCEU !o�6d"F}b5("UF!&-�ImB1�%�<��in! 2�D,�s2B��W A.� dow����is f��v6� � ob�` ~Q[-��s9E�s�2��g�aI�X[!,CE�c� �j��b%�&��! 1� m�F{���Fy��:Fa'Z�an22.�!�F���!�rB��aile h�2.vWd "h!�� �� $2ٙc 6-�6 :sa*� 1cn#\!BJ�� *��U2<gmIM�>v AsM�)����� E��ZI:�o�r.q!�}���6 a hallРT(VR�*��o&6*&�[2p34–3�As"~5���Xs��(�F crui�ma )!Li�U�+���w!��� he s)5a� s2<&�,�&u� or H�1�I�;to�E�z� d&p+Fig 2>�IJ}`r"erA͝q�cQ 4+�2jz��eri!!�r CNVv.t LD g�v�8)��=yKPVA)*� begin�J~��"�(2;��os%��Nm��a�`=&N ^ W �xtٞ� Y-PV�ec-"�3�"�R�.!*��.: � &<IFby|#ng *,+ ( OA\.o �~�tmed��.#orGo7���ng�Y�, [38]>� &Y "v{o�p 2 mM�(��uWw0������6b�p�-b"/�@�-!%weMB��H6� It��lb�#arrow"�.(( BMD���8FembryR%:�ME�IG�]��jM�aH�<��-%/h�/(ua�LDIn.G:� GFP-,!^�8N.envp�%61Oharbo�!@aJ:��BTB�i�Iich E RDP-!w~*6 ���om��AI��tM�B:�U?7}H07tan\NOAY�� % .!&#�ec��enl$$�`!�A���5�i %9S43sec� ���2�!�.�aw�>�I�] ! att�@�����WA% heno*'yN��.��v o scrutin�JlM>��) iner� i� wk"n�ed6�$ax/Φ"� "��`b�%>�X�!%) By EMɞ�recog'1��['E�hom��I(e5ro��">%�oC �m�.1w .��uwa �S� ��clu��Y �0!�e�fLD�a��Cin&ߕ� s*b v�/�aI7:dE>%�Po�9lBYU"=enc��!� phys��@0a�ERe#,mitochondria%.:PV[[3n!4n!�A�F�OA-loai,m#as&� �H�!�an diam�GGA 66 ± 15 μm�Y�0456"4)�}a�:�t� I- ( n = 250��15 �� ; p ޤ05�lMA u��{.a!�1!y���)"� n�albeit)�&�S&�E�nBsd"2(on��!Сa�2 D�3� )ʡ6-/*2� W��� ^C)�(v}6�R2zif2had"x]tQ7�y�!� I���.J���9J�� &<�Q�a�2VA�u�. E�l"� ;(% �-�H~2Z�PV�S���w�&�6�!"U�.h%}K��c43a��5�Z2aB6|CA��Ez>�)1e��)'10%�T qquadrupl�\E�2�p,5.f !���arBB a�sg@�A.g*u!OPV {!�x:����a�<Ug��me�IaN�~5I1B�. J��+�s1���^&Gpa��a�Wb'Չ�3� !?"\rO<�}�c�Qa��a�*enume�@>9in�-����x�dA�&� growth�=ay6 �>� A�s]>�A�@!u:�( D1D2KO�4as"�B�[ir��B+ u,Q�CcT:!a l,%�!~�8��0o�u�%�m*O��J)L��pl��Cin!�!1F� H��no!Bss�/2mn$I�!rw'�2v!ap�n|� . }ww"�S�!Y%��"*�&�.s��ltiv�/&�e�bplaqueK�G)%! .h ’s>4&-�!.a�WT .�!��assM`"Aly9&od�>h�EI%!$th!� QLWfiE���==@ �m A?-5� �ng!�n�$ctQ _+4a� mo"7. N��th Owe�e:�D� �,)�r-Ksa��H7`[of28-] �)� m7mg# 5����½���s+��!�let�b'q6��M�!́��"%'��2��%�p�5!���EL* )� .24��ep�/d�i�!�.��kI� pAKgr*��L �W�"fT?\ 4�2!�3 HJ�N�aWT�ي�="�"^2�a~J� byV��yzCoXolA~sR�.��6�"I�+�2��.\�NA$QHG�&"BSV��1 � ~40@85%q�2T1�.fo@�ȩ�� yCa0s s I�<��P5 E�nF�2P�� or 8 to12Q �GA>q�!17� to!�A320pağsv �e�n���6�Xcv-�� o ~75 �� ��i)5��TBq2�%�By�&\=tQ.*�sol� aF ex�-%ڭ`2� ~60%R� I�Die�r=d�nŻ6pr",��rX e/V�5 .vM�?*g %9�le�74.� a2�=6V|E�82., ys��.E"� &$,argo ,.�� f�8A���-�:za�=#�|�;ub�8�fL�<�$Tbiochƫ�9>�!!bca";PAGd "6in � "�"� non-�a�"JEcli�<�D �j ."���6�(�ZYr�tsh:!>Pid*��"*B%��% ATGL�lyC$�ini�s�$k1AG �"!6,`�p�ea�'o Y�log!jI�61e���"m�o"7 � ',0s��V�/ss2/)� ��&n�g�b�wZ)Atg���a�"�I6�1%.[4@> _ulHd*� S�yA��μMA0.a:2,!?!Vby�{A�Y mo�AzF !�c2�"FOB�aV%2�= :s#A4�grS��Lgg+"�A��2��@"o�*i� drug6n!Q�|s"�-radioV"eV��E.�-68# s 1�A�2�cG�Dw�i�U�Jd�A��yrG�p�cV1}9�%3C.�y��39�.?k =2�:� b3,U 0er�@���ATPW c%�( ex β-}4 �� a�7 car� n� l�2%7-�. CPT-XA� ��ɹl]�y;(��I]lMC,�Сj���@ ( moie�$�CoA!��ri?o�y*8��7AmU��.� [4�ZW&�H.@l matrix , 3-keto�co�w Aol'3-KD8�ke[�wC5��`�gof�id ß=�1�ng acet�'[4&�&O5m )�A �C�eEtomoxir� n irL5r�r���6 A [47]le�� etazKoE'a? etNZ2= t[4<I2���&"�2w���or:r*Z2:���� &�$u�.�F�F�s^zM98'2 e7S:O`���or�b�0�.�.0VG 9&k�E.�9�(� cau�/~�9� �!��#&�14s%��/�5B�%}y*� F�:�3"i"ݞS ]���i2�I�lu�I,&��*�b�2�- *�=disTaa� se�<�� &�tow�`]M�턥�,m6yw��F0����Z� hB�5t��>royse�k k+&b�asco��2.�_ ��"� �h&h*` ��.6�=CV� 2a2*� �.��(A�zPc�Pp�0�X1fv !�id��"vH�:�,M�-9p�e*?Uu�!E&�3�"��to1�b!�a�,�:�b8@v� �7�2�J,� ,z(s$CE [49–5/WfD E)6 C4-i�-C98 I�:ESs7vAe � 500/510�1��m�9�,i !rr�fM>�f is.8�f> !3u65)"�!�y6S>^&� �6�!����O8����>R 2�[5-InSe*�C}t"�#:$gn�pre�L�4;&�4�x�.dA!Zhs#"(9a�X��' [%0h�)."�N�Q��4�"% �Ds� �5�r"B.l��> qn� pre-9�%S.�/.i|�E1/,�W�.8e5�[��A��. A� ~ 8!\,:.�Ealw&�^m�)�|�5,&6�lwa�F�:��&f*X"  �we��6������EQ��=UVed6Lov�S�>R��4�.� I.7 foci!1e�A�ni�1*8�&�C,"&�>d�su�Uo!]�z-slic�L�He-n�6�5M���Pcey%�ls�]��6�I� �u%`2 ��2.FRU uile�blo�u�#� el� vJ� �og:2O!s�p"�h�?����.%�q���5M��� ��4*::C%��_FJnFs2|"�*.InH�+o  � O"dA&�-:��+:��t��r� ��,l��raA�y�&�NI��&��w"0��>�P�'�� ~-�?M���RFP�dtZng. �Eӭ�$7:�-E@sm.A�%h����e/I�!rvie�� L-�*�@�G+2�]| 5���!�� ��$ , �+�bZ2)ir��.v��m,L�Q"i!�gZ A�Ii�C�,2a� �B�i5��}�d2�E��qd�{k�"%db(�~UI&AD^ CD���cataj5abl�Y�at.�*0 i���!AA*�P#x1uw�'c� �tҊ;$m��� p�@�t"aW� :(� )�r�cb5:)! V.e"��D+�&9ds�4nd k�+Qas&� ��J*�.-��JI096�M,"SRab GTP<��ei�4"� -IO.HB�͝�[.rS@phagy [5���8 [55T �k� I-�..�^�/s\-E+re-(c!W& G�6@ esNI��J6%��zE_$�}� e'MNat� �Nn!�Au@�!xB�΁ ���a�!sm�Gm�mCherry-`E4:�.�co �� ( PCC:��129�XfF[:M2�,�~ma�e-�e1 ( ye!^.�)�;er���a mQ-( P�2i�  )�'6�  IU]B:���J!kt*�])"1&�!| ( S3 �"4�"of�1��.�� }H3{BF�s�m>%"$);!�|�(D@mve��!�&����.�A<3/9of>�E&orU02H�w"��<abZ1A� a ~3 5�G-� s�Z�e��.�.i2�7v��� "�!�3&"a ":������fi� �&� 2�].�3aO.@A JfY4rW].R:*!$im��e��or GRA�`t�%�C�!�.�( 6B%In��"L�S��4� ��4"N*���-�orX�A<�zt ckg.\OV �< ),ar:�a�J�s.�v 2!C 4:"}���um1h3&^ ;��A��N� s��il'E.*&�Rv�Q.g} wr �%dE���U�.J>K���9E.:�-�0I"#5TE�.9H,.kEa:Q> 3~yh�\ed�eEDZ�V�nN aU A�am=V.��"a2� E.)&�$!�bonr�d<-yr�'q;��1� !�PV�5�m18FweF}.]d:ը)+z( S4A�mP�6IPV)B )��L<tode����no.)2C�6tN�NL&�:!�]��",���"�up!u*v@�6��P:dTSiJ �1�Kz�*7 bi��"� � U�6S F: ��)� �� pA�u� �uctB�7r��{ scer!D)^��1 2n4B( ���~�DilaL����2 :]a9�5� %Upi�X#�{V(� ���� alachite�4e�e�ga�cmp]c�r�n0 �8� s [5M��e.g��oq^<��\��*6�T}Rs LD��7J�?0A&�?bI�B,1��3��=l�bpr�4��E.\`y � r3}B[!��_��}6��&�#��4,�Fz�6�bul�Iag�Oa�a9ar"J&E9INx �LF$9��6�6�Q{ɇ7p,�% Rm� {6�+�6�8�)ne*�Qs o(llA� fe�G��L�MW%&.�{`AOa�!n^�ei�%�N16� Z;Aa5 shap�S5���2"s,� �D� A �n"� #�soB���6 spaca��PV ��!��ubu�0� �Mns�$t�jna0F`q\ ( kj E(�J ecre�-���[57�p�Fe�~FB(VA �">J�4an unkn�&5[5Z"*V�YZ�%i�+��?."p�k[59mvor�a��^.cA+J�[6�;>�j�e"5W� Ae�*�l5�!m�3"�� 6TuTmF�Rhe ]�*��JA�S"�=�Cuq��*+'"$2bA"D���%�6�| �U'2� &�&9AE0� T@t��is {�8)��*��1j%! <r�_Z�Nq� �)�GRamnd ����?� �(n��!W&6st�Z=][6�^W�l+8��"*2�!=�i& X6Q��knock� Δgra26>$.�.b�4s,rH� 6+< � 2��HI�86, �Xra\WT5�v%>�E. N"MlooMR@#_o1 �5� ��eI�Ld!�a�;3� A5� . Q4�2�3e*�V!Ogr &_t� ,� �G�e7@*� ��o�( �;&�0�>r%�1� ��9�4M�1pa�/1g.����4:P2]>/�<J��a1WV|w)2JFobCi�as�2k��� 5 . Bwq�.%�l�4$a!��)":� Eh?@� @6�96i?2�%>&SO�'icM� s���v�<s!ti���Aim >1:VOf;!9-�� :�+�&y ~ 4kM ��*-��2�F�IY%r"5d̑���$��t�%R*E �A2�1��gLC+�"d� granaA�h�%*X* .G �\�s6�/���a� GG ��.#x/. �A2�V@0�A�1��!8d�,1-�b3�'Y� by ��u���$8A8���-"���� B�_w� Wm��:Q!�Xe��(� uZapp*��, JDR`�JN , KE�( , EH�dH%sI$6ga3�*KbM��y-( Δlcat�*�K&5�*:5�,"�G%�n�m��4�� �� �*�C:�::U� ���m���]� ne<2-MOIn2�J�D���8 �1��` �-:�#9Cs�{IoG�. %�Z#.��:Tk:#s��"0$e�_��*�qwo�)TsaX�1"c.� �&B� �'A�A�&�"a�FKpre�i&/uq�s�0����L weak�2>�!�"���h��E�M�F�E�e.omi�H)�&3~4-E�9]��.Etra-�ic��^�* AWTGI.�*� T�6�!v�8F��. Ff]yoa-�F%/���aFm% how/&� ��A=ɮh6�*�e32dFst^�v�$Uȥ́,,3 x �Nlt7o,6� is"3� ���H� E�J��mazQ�a��w��AJ �VA�M01!E�Z, ֕�Mt�JO7igTA�eAkaQshto� 5����'�sy�u0 bAG%ŵ?� TAG/:�84a���ct* 9 n�tox�� y [6v,"+�� f*� ,�ů�.� %�)r)�a�$ AT�nwa��D`by �9x,fV1rK7AR�V�V4:�1���j ( S6��N%�atV^>+*��,2jA4�> Yor �9geٲ&G2�.*9 2_�IG!6*` 1/� AkEt6z�/(AE������\� � �j"�KrN&".���{�8'environz[5"f6z9"CViS&�B�&� �L� +}e��,e.�;�as�Mgae�/om V� ���s�X(2L�FJ��*W��� ���=C!�1D�0OA �_I�~b�Fu8�siX��Q`at1�9or 4,�*�.%�h[3H]O�uy27��'�)�"�b�be�or 36"'*,��+OCuc2O� �ion�0$A23817 [65�#&9AG�colQ �pu�_b!�!�ք debr@� *�.!7�&�:Ocin�ɩO">!��9r"T"�G� �*;*�G=!e ou�m�OA�.�!f��� ���\B:b � avid�>5y���%�M�.((��}�. Lsue yo�2�? enco'e*9Ş��K�CE�ag��e�LD"�- , 6v1a� ma>V&.Fo� 8s two ACAT enzy@mes ( TgACAT1 and �C2 ) that are both involved in producing CE for storage in LD . While K�1 preferentially utilizes palmitoyl-CoA , 0�2 has broader fatty acid specificity � �es more��a. The parasite expresses only one DGAT , TgDGAT responsible for all its TAG synthesis . Second , wU�amined whether T . gondii activates its enzymatic machineryfTAG%i CE sein or�to counter the uptake of excess OA by measuring% �$ion levels01��!�2u ��2|.�unE�hi!�-�J�)�Unsaturai�sA�uchA+OA�reuY zed from V:byi@u�e`of de 5�A[66];% example ,:SCDi�e ( Δ-9�A ) cataly��a�y�of monouZ� including �via@!� oduc!�CA�$ngle doubl��lnd [67–69] . In mammalian !�!7FY 9�.]!Nmvled ,�;part ,!>!�vu|ofE>1M>in�@medium down-regul�'? mRNA.1i�ny � type�ex1adipocy�fn whichH}t is associE+�! lipabeain1:�F��ѿ[70–73!2TA� leade4!� ques1q��Hoxoplasma encodes a�$orthologuef0, if so , howm�Ş��I���!c-2enc:�8. Genome search�kn.Rrevea�Ye2A a gene coEKa�U2!�n�8; TGME49_238950�Lwww . toxodb . org )�kot��..!<2� steaaǁ�oleateAEoe\ine9]g�is Q2}OV�m��/h.[!hof Sf�incubY8e�v. <��S��up�by�$65-%�2�0J��f� �pre� tive�_E�A�nalog�$to%)onsE"}exJ�(. To verify5_!!.�2��4�itiA !:NFm Z8correa�i��Ud�i \Z%0� ��e�we6�am �neutrala�ids�4duced!�6��follow�L%#urE�!{F�a#���;aA0i� d thin layer chromatographyG LC�kof} � ��ts se�t�!�least po� li�,�L�H �p�*� b�,)�an ~3I�~4 . 5�1�OV,EneAI�~� ��C�"� (; no quanti7 ve chan �" �choleste� among!�erimenta2 )� sec��!� migr why a lower-%c��s� nti�� -�e a'y onent��� �M�CE ��S �.~�/>�ſ��; sligh� �];dacylglyc!R� MAGE�d DAG � also9�{or���^ =�� In*clu��,�� e�.�s mai� conver� toE��CEA���consis�[ �a1����b�*V*. It re�s possi6 �" �Alarge.Ka�5��t�y)Fbe�as6moleco ��AD� host LD$n�d�OA?nd!6)!�:~` � a�0y� indic�ean accum~ -9� �S:Oin!�&�.;��mI�51 majoedofFW m� organisms_ predisյ!9to��N��stavinfj � !8 BODIPY 493/503AIin!at%�1� ’s�]� es . U norm�Qult��E\, eachC�s%Jverag�}2!�with a��n diame� of ~i�μm [22]6�f%=IE 1!T esOA�Œ%U�up� 8 fluores punctaM>"i�10AAt2c� .Jsignal�mg intet�al�fe+$r , occupy��a  volum%-5m/%�cytosol2�; s� of/se2�.ras `as}G%Fa9�)$%�6%�� se <2� trucAi��sp�Wto ei�s�#al imm% LD�a ��!�� A�smaller  re�vCs issuFwEV� $ed EM stud�os2�M'{Ak.. W*] a ga�!�2��(-20 pe&� )an!�1�%�frequen�Tth so� d gig��c Sn10"os IE �Thu�Bin!� !M�IIwpM� bl� sti��egbi"� ��(ai�E|:�:�%� PV A�Ŭu�IVN!+tubules��secre!sen bloc 2��)�PV [57a�A��v�V!� y suggest W��� ]�s�4�_ributor"u�[58YToe�r2$ 9GafA/fe6�(�byA^ ���*� s�[A5�\Jp2�q Lab"�ad|���a conf��� middl� PV�nde�ti� 0between a few5mPs but it does not fil� e xre availE= spacu �9�By�trs ��.'aZ�I�� dram��expand�d��a�H � vacu� ���pM�� i>*O ��HKmagO�iim/of� �.�Yillustf!!xtrem� cO���P%����m�of%�rkably l� !6tertw)�m5�[� �Th�lf�ngsq jK��A<20 &�0ncorpo�MJ�,)�a8A� 1�)�� gDis network . Regarendocyt�e� ��gmacro� e acquisY2�a��trigu�� si�no�:rnaliz)�ghave bA�idA=fiea far�t�M�åM!�"�qha�6"�&�>�S=H�4A&material� g�1�� �� membranostem . S6�Lur in-depth scrutiny)��A� U��=Z.{ po�Y�(y��we�icne�y �invagin)}E &,���!mEz 8!�D had a narrow neck��*uof n ( , 250 nm(7"�o B1�=s IA�IIIE�r�E� to 3 diffbE ; S7�[�� open9h�usu��lo! d!�aa�ior����los�-pex���n ��t� divi�Az �2�< clearly dQnctY�mic~aZ  a�Lcup-shaped 20-nm pit!~�>� [74]��4r siz�m� post-nu�%u���"��Y��d��lE���i�ed un�ag pon��Trul�>u� e�sibil�� 5en� z�f� �(�!.�� ( S8]{  �.�s%���cSu PV milieu�Y�a��n on��t��p!k!b�Ma]e m %�ic surfa� 9F�, co&�a radcng!�(ristle-like=�͙eNi��"�� mini< �e HiA�v� i�.��>o^ , ( �g .e*athrin-Qed) $or caveolax �N5H�N�+ �exͨcupaIWe))��>a��yt5]�Bel� � ain!3��.��whorls )ap�A ly simi�MF�t!_-�1{ gr��%�heW1� s I-�ڥ��would ; )��vesic�.a3r_� (provide fur%  e�towar�exa� �I�an1�ic Fwiݲy pera��T n immunog7�!|� .�Bu]�� ibod[ aga SAG1�lB�marker5*� �)Va u+F6O �.85i]6�&BM � � E� deri��Ze�$��a&SM�6�Nv�oNir limi�yY���TE\"� c.�OAF(s���I���seu-po� vMMvcana�:q��du�%ir�G�pthD MI1Bs grown#�( fee�M)!��. Q.T� ��ofV��Z�or�9m5d^a&^ ";Mnumbery��5 i��-l�#d v��~��q�DE�In faci��96%\F;did�s_}IQ�A@9����� I<�@�rei��first�.of6evQa:wa�a�%u�4s+ -�}�. Desp�$):.�?��be�;1omina�u�M!*�ofi gag"�y may�\physi���relevante^�nutri��$a3delivery�1�U � . �2%nee�ro� 9�%-& metaboli��( @,�[S�to!�l�d���k prIy [75W' �|&ev� iquJ ateg��toB�%��A�! of ��e,� YD5Rervoir& 1RA�Fo�(a"=/vrce"%�EuAP� por� thwayk�Z��3-lysoPs1A LDL-2d,nd Golgi Rab bAsm�A� sphingo5~3reAv6�� cargo [2��24 , 76!lA�#-enrich.U �es!Ri >�"70 droplets ( L�)9ban op! u� ourc� var%�:��) Vs� nger!�I�fis���demonPd��t.�explo� %�LDmreT a� themA:A3PV%5�:��k .sE|�. Along)�L w��A�akkin�"nd�oxi�9T�a%j�� h�h[9�6!�7) ]�| t t&l!E��2� �!KA�'f%J� e"x hat�re im!Ł�_u��ivity:��,.��/�*/"a�' muIMEF� ]eA@ f!�S% gene� abl5R� + ($D1D2KO ) ;)�s,�}petit�!T*� =��4c ly re� -J � capa� wheni�ferAto WT� . Du�a. -+o�A*��LDa\E �ctu��� {"'LD pop7�@Y+ ��x�%,a peak coinc� M�D roun�p� aĥ��( ~8 h�t-O �A��(im�� global/oe ��sI�pr�.�mod& a��ny-�a ��P� �i�*.fI0ncomiAnly&�3'� ng�� FN&%� . AfIe� o%/��-� declu�hs �*'d��(B�v�v[R���(� 2 �] Qcyc+I(.�� break(e��'�*� ��N��� �&�( �on!� reflect a!a�yna[ tatu�n�6�d sm diLy?�s*�,�G d� n��-e%+!��Q� surviv^%nd:���modqmof>�'oz��72�!J-��E��b��a)e�def�"�A�[��-�)v�.imbalanc�s!z��u. ���� to5/in =homeosta� �-!%s2��c�lis"awa�_�investig��DsA!$overwhelmi�,&$-��u!�PV!U=��-phW)naata�� �+�&rE ��6qnea�/#�I( nefi��%��0���dfic- *V  2� 6# E�LD�*9a!g�.�"e� �.� ,�aa1� al��� &? .2�*W�"�*� [21� &� �QL�i� �0+& I_�|/(Jk*;"�*49350E��)!hde-=�(CE ob!.5-o libe� 2������ mann� &9-�T!4��� �!!�ex�&Aj, s [7�LD-ER) ct s�  e��� uE�oIK�x L phos�$(�C proteins/6) �8 c���aWfun3.3�$. Traffick��of 2�-l &ccursg Aho �3chondria �eroxi` ,%ca� Dsm through β-oxidi�,8bidir2al2��exi:bLD;2�" lipophag�0��Egs):C& ��# xempm��%|f� Rab7A�LD;dok�g s �,� Z�J#&X2A*per�#���p fociD�!!b &x!�to!harbo�s9a�lir�pV�"�.a+at}t%Prea(.!A�PVS just%�� E|�� �nE) �4adDagE��E��*P,>(L56Tbi�'in�>�6� en�mh� hibiJ e� ATGLiy� Atgli!� reat4 [44]!�a dose�<3nta�a���>A�)Q�!Cbeu!�(disrup�" T��>[nd/orw)�).! lack���h�o�mae�6! so4#���*.�.�(un��(4e1"of2.��f- K��5�b7�ed . FV2�s{be P$i� ascerEy"�Y�b�2�{��ql�2�E *AGi�e-�LDu�/y z6.��14r%a%�Fz.LD!�3��(A�e6���� ete .resul0in ATP��&c869m�s�9��2:6� i� plau�*�3�5�A�thjB�j9ts�e�8�>9B6�cascade=�ahe �2��wsu��� hypo�a��$� r�%i�4 impaE]i;t8:]:%���� ar�na�g .04Etomoxir [47] !R^. / acet [9m.e�=9�aj��w��T�.taz e [4A key asm/j!5p� A�:I0fGhe TCA� ,�3�A�?B�*2�onU & -"� afY������9["�;fer%�*�no%?�]vtM'2��c� be.� 0�I9�7&P �.d<jt�,2�l.�b�$y]  , FAD�&QdehydP T3-ketk/ co��e AA�ol� � t�#��!�U�un�#iqe����Ŝ1 �ic��-8 $ mQɚ& �(���=�� gluc�!A�glutab(� �Y�! f�U=( %�pre, �(��#Y��6Y9 [<$ched-ch� )8i89=T,Et ;>�<a�I�is �l�9 �A�}�[79FV�z Type�C6�%4do%recrui��a�i��}�[�i"=ha�M*� � �oup� ZV� FiXLD�Ri�q�& �y m2k ex�Ydis�s7 b&( &AM�ic&E sh9� ok5disch�! i�*e ,�ar?don�0��6K�5,umen [80 , 8[M�Z�u a��Trypan�a cruzN Leishman� maz�3�h, Myco�$ , Chlamyd!���5i!�~��  ���arl ! engul�.et� A; unkn~"�5�Cb9w,�(6�&� �?�6.�"recog��on�:g(:���3"�T Inc��at�2 [ ADRP�A�*` [1PAl�?ghBm"�+sh�I!�A#IlG@sIJa5N��<n � L)es ��q P�-,6{ comm�� c ��41#EQv�+YQ��g��� ~!bof{ -ud.=Aw*"!6-&�)A0lemm63)pr�����$�0igh�5�Nm�e���Bd�M� Rab-label{� �>�apF&�s�/6"E�:Zh�#i*�]nt [24 c� � r�� Q�r #.I�%�a?!N)��M���i�� ��� z -ro~*Y#cpp��c��d�xaB�t�l��!0m�HeLD�%W�3\B�+�*�\b'su$$p5( f�g(is: 6�o*�%&W".��$often wrap/) v�-�&T-a u �$�B,9� *� "� )sJ� ��+ d 5�AsXs&r1 �5$ubE� ntly(�by@�>� �(�1 , 5h a��s!��n� acce&�)��')d. �ud � of Δgra26D*!-EH1�)O��)�se��%n deed*�voi?u�B�%g%!(u�A�pr�<^ 0JDR , SJN , K�9,CP , EH , RH%�I=. O�s $E�e �� is lG!virul�*�nimm6,&A�5 Mt r�1�-���v!�[8n7WZ�Mly�l�)a!n� , TgLCAHR ex[��ru&y/A2&d#B��"� �f;�>��*�rJ �oc� �kA�J�[5� �Se�D5#y help!Edeg+HEM�;&I:)��� 6�+*��*�2=s*�21�Q�E�� ssum!�s%Pv ��a�a,Q Ar���i�/ng6�ΔlcatQX}G �9Q$�ys�9*Y61KF�e"�G"��**�6]{P inuouAg"gOAa� �f}� smkN52�"ver��;Y% S� o mBZ#�1: :�A���to>��;��A� H�"H�*�toxz t�� [8iEIf8=_"�=t�IqEAO ut un F�it: �s��: "�B.� if�:��c TC) ;�&L#2�"�0in!>_� [�B K� .b.z� u"@<P9e��'5$age3"c �u��)neN()��  &j'1=o"�8�&�w2Q2���a.#B*!�Ai%��% `vi� Q��;��*54|3� e �sI�K� I5 dele%!�lethal�=�$3 , 6E� Morea[ ,jI)<$��.2/#&�B-d-��*8rela��-ts9�ylIf%�6,)�eM,"�u�>sc�!O5�!�>s? Os%�1Y d$Nopm ��25>j�Q+##t�IQ��KD,^.��EvarC � ��.?abund�%�Gest��sk!�$al muscle;�'rc| neur�1[7]%fi�st adapH# h�?e�)environ�s� i!ngE�6� �� �qh. C&�#Ɇ%@QE�*�"� ]2�n�Ieo&2Jc.�I�8genic���.�a de nov08�id���ic �wa ��2*�g mas�!>d�Bma�Cy;H*E!�C6�M&� c12>� =�/of�a�.�LroK-:!!�%�%�aU��aUunrestri�0G'��i�6i7�Nlu����I� py ��@�a�!�n)sol .�],.�I,�9S,� tockpilH�d energi-i=a�k-m cJ �.rCME>��)2�-)!�2 �0 LD [NLi�!r� Eet�3�2�ys obes�o�e&q5p�Q �iMe#,>1 � &gAG pool)!�M����u�&�#i�_>��Cr�L]# In��,r �5S�zL��� b�1ly (/t&|K1%i�A-WM�$!�on-"�N�!\=to� :��B�>5o?����R) fluxb.�by%�q�I�! M2�U)u:= reG#I/��22� gluttony%��� OA-� M �pla��t� risk7� %ofe�4�ag� reshC5�+a:COA>A�I�n9F"%"]i.@&��� mJ`V""�!n*% � N�<,' &�!mzll-P�|v&�<�2f>35�c�/,A� 5v�;. OB(o�le.F��"�<w"at!��,AH�%�8..� �a k)�W�"% , na�VAC!�t!��s*$ heps�m�Dt!�<in�@$[8VS[g�,I ����DXq85�$�U&g?��&�I�U>�ax few�ues.�p�,.218m�X�2!a�AP2�E=a��e� heav�\�5Q:� -Q0 n* |�  �M,>T�W� s ^2�:[8�No�:i*$m:4!���{E'2�-M,!���&�%�;.<�$B��).�.oA!z�3V=&��D#��ich m,6c>$$c*�=->is�o� w���Tr%Nic3<,Bpr6]<&2 Rl.>re�3or&�"M�m�In&�,��EM "D"��9� "� ss9��".� 6; �(B�0)�Eat vib"�"�..c AoR�mp�7+ A >�9�B ng�ZXux ndow�  c�C�]1%#n�*Z��O�i�("�:� ��4�<%X+ � 5ha6�ly.�J:%�d�C:� reL�3� s�.�S�FW@.>�3�M&2��J�+s W.�7G6�9x�!^K�.i�6 ly f�0E7o �? us�e�2�k1��s�E.�1��J( +#A.:@;FN M{sec eqBr*366AFi�2@)EA,��divulg�s/}(yx di�Ju�.�� EI( E�!"� *d . Nof s �rS1� stud�"All chem�s�R6�-Sigma�Bt Loui~M�5 or F(0�>Waltham��Nunf wi%=5 . �6 10-3H]oleF#cid ( sp� 4: 50 Ci/mmol )�1purcha��0Moravek ( Bre. p,, [3H]uracil ( PerkinElm�SheltLCT� 5-BuI&#9 4-Di�N$o-4-Bora-3Y|4a-Diaza-s-Indacene-3-Nonanoic A �C4-Q-C9 ) |Thermo-S,h0(>' :��9858-PxUmethyl~�!6�Q �$Life Techn?  ( Carlsba\\%D. Non�UIg mix�O��n-�:�W�>�$atreya LLCE8Colleg�WP!�.2�*JDCayman CM� ( Ann An-Af`A�dim�O�A�]e: rabbi�Wyclonn(nti-GRA7 [3�FaDZ' aldo>&!�mou�ono.JHsp70���^(Fidel ZavalAA0Johns Hopkins,ver�Baltim�F�_�VcA?b@Jean-Francois Dub]Ltz , Un_,of MontpelliI11e�7S99:/�80Ce �Rce�conju8K&$Alexa488 , 594� 2( Invit��#BhTo �e 2OA-album�omplex�so�^�\A.dis�Q� H2Od a��/*of 100� ��o1lyA�vortex��!3 {wn 5% F�e��,BSA�r%OiAR2G tsOA-/� . HuA�foresk++ibroblai1( HFFX HeLa��R�A)American1'CuAUeb ( Manassa��V!W. GFP-B$>`kindl��#0Raphael Valdi )( Duke.f, North�G olinA�USA; o6� m�, by P� �tt-AdaV nd J� cLauchl"W| Me�G l Rej_ Coun��Vir��y��0Institut4 , GlasgowaK; [86�. B�%a7L".�' ( BMDM ) "kSe�mic4de�bed [87]E�=rwd(%;4Arturo Casadevne(: }�,� , MX?. Wild���6yo�61\=)�< ,A�4h Z@=Z� Robert Fa�A�arvard6����E .T3 D-a1 imum& � ( ME!RA?l E� 4;IaLhn, 6�=α-K��%Z 10% fe�bovZ.serum�DBS �[ )\+Axp�illin/ptomyci9]�-units/ml!4μgM>�tYat 37°CR 5% COG\�"tachyzoa6EFa�RH �$( %�I%ag��% ���5�L%� *�stRn!�RFPE�J�Flo� ,Dzierszinski!�cG�S2��6r�b, Canada�3�9#262��.�MarieɣDe Cesbron-Delauw (o(é de Greno,٤[6j* vc !wn ::-"/ �,O� �.E�m �ol��labPory&�!&� Ao%a��in �Ɂ�s�+p�Vg   �-��[8�$!J0� !T�*��*�aEtUyedsby&% enumer� :XPV�m*� &ZRlJoAwlatl1,�%or�%�~n unti2/�enc%*24-wellM}p�PtIS�Vew� 1x105�s���Xh2De�(��)�m� !8g@Cel��t�@u� μCi�_��4.rA+�sE<=�R!ed�h.�%�Io�et]rep"A-K1B0)Q!gzD1D�B��D12:.!�C-dt�%���}�K30�Zu!��9>L�aPBSa��f*mov�)�FVl�:M.3l�E. RNAc�T�u�hNeasy�l,ikit ( Qiage� ValenciM ,�or��� nufa�[ r’ E otoc�a�6H � et'Md$a NanoDrop��0 S�3r�%to�](Hrmo.t ,>t . A]8 fied cDNA!�A3�U7��� �SuperS�" �LF�Jd ) *� A��Jng[ca� \�:��725 μl�^VorOE�J"rse�rop�m� er17 . >�:oc Up SyBr G�OMaQ,MixD ppl�BioKY/nd rua Step�P�Real-T�CPCR SBK�#RE� data��#� �eo!_�(M TgGT1 hg kee$,gen�h\"!�_hsa",uC% hs� F]LhsGAPDH . ΔΔCC valBe�cal.�A�unu���ye-j�assessCo*Cj�in *���.w0}�^m p T �d",��2���[)G �)�f�dOp 7r���:-�1:[ 4 ) CGA CAT CCTTTT CT T%�(( R ) GTG A$CA CTT GTA$TTG CTG; \2\AATTTGT A \GGT GC�'ZGA GAA AG V AA AX W%AC_�C�A��CTC� TAC IGC�TAA TUSCDT$CA TTC TGC�C!I�=GC �)0CC�T n2E�R B!Q ACC 2�$AAC GGG AA!ZACAC AG;A}DRPOC!p�AG%�!�a� �!n!LT!jC �TCTCA5ICGG GCTv6!�!Q!-2�!!�|!%T�6�U!��CTG��C!�)Z!9T2��!o A AGAJAE��VUL�"G-xT!&�!|=A�!(�!�4CGE�)V�C1WO 3A$T %5? .X�AU!�AT%�A! . E*� � otal�X3&2_ �@a�>|e/�Nu��Mt��p�?5/pe#Uu�֡YT“Find Object” toolX Volo softw�0(� 7ve( GXa�!Z�#>f$. If ≥70SR:��*st+ >S_e�>�3�PV� �� mark� "8T � plot��a_cQw a hisAl=]I� ed��, pZOod)k-  fo�~�:�40 μM!�2or>�z �2� o�wa{G%�� enA/� 4 �F m.A � pre�S-sA>)t!ZL9e.�B �� 1ݣ(M,w-RH��M&� )A�!��;U A�� �\to fix� �y���o�v�#Z�3�C� pQ!��of��AcS-du�#& ;i'�$e6 nsurMvLD�ena�uY��:�A' asal:�%�()1M�<2�/ d'#%�a�Hby"� ��+EF��uA!h.ea�qsuF6e�C"�_I 4�ismh�PV ( n >} PV�)�(lo�!" e� � 6^�tA�3t&�3n"�V1l8m�PV�atA��!�Qd! �D@ <� �� μm3� l>( �d�in.�tri� [��!*mea�6f e�;.uo&��miBep1fI�in �, nol , eva=c by N�,X0s�D�<� DMSOM*Z90�N�+7%*r&;&aa=1�c��!:�aj1a� � P�Q%E*K�ULD� !�a�#3oa�/wd. E�0 M!WtB e )��a.-�i�J��]�dor 36 h� � �/ionA(re A23187 (���}2N p(�Y�}�e�Q hQ� �puL�y�deG_�sa|w�Qcolumn{ PD-10�Ang,, GE Healthc��� 53�QsA��b�9�(��a41W!t� f : a�#"��ciV�ScodngtiE purp�)S2&�� Beck', .�!� cpm .� FCq%Ar6���arad P@& Assayi, Herc�j,} ��Z�}� �tuc>�6Mof:h�Wpm��mga�Mjbj r�[J!iJ�Craig Ro�Yal:�Sch� Y# , New Hav�!^!#mCherry�;7pa giftz e HaJ'er-Bradn6� BloombergtPublicM�!�A��"��GE�Rab18!�D" cq�Hu0$Plasmid Re� � Addg((� #495�N.� %���_���I�Amaxa �door�V��( Lonz Base�Switzerl!bAD.�jq`5p!��$id �=lef^1rec�ni�B^����*P"�, 0H-�� v �VzZ��'d�j^. E� caB( < 40�{� !�G � �j\�e�B�~2 .uOA)� spun�|�280 x g!�n>p3 m�O�6Y�<~ba�v ��f , 22-�27-gaug�i[ *edqa+; om temper7�&�:� ^�!~V��)*;Y�$bicinchoniN acid�� [8�:c$us same�RE���9��OaG3�eA>.x( 5x1078))� ku$chlorofom:�"H :w�b�0:10:#v/v/v��dr�n&liquidg ! :k Zr� L�Q���� �SJmz�'e$3e��d:di�#� er:�Fic)]( 80:20:� or hexaner89�28n]vSi� Gel 60�%� ( Merckibbsbur�N NJ )�w%�;ndne,0*u|)m�i�4e � � b!E�&"? !C�y"� by d'�rX&Im}e2M"aVy�IF� oALfix �4%�Hmal�Ie ( P/1C%c� Waraqt�%I$R4�02%�r?ine��perme�(ze l43% LtonX-� a:&�scrib��&�>]CC�� slipm�m�-s� ProL�>DiD{d AntifSM'an>F�%)�yim�bl� N��jscopy�0B� �Xvie� %�$a Nikon Ec�(e 90i equip�B "n oil-Turl p�!Apo� x NAX4 o�!Nan��[, cropy�resiz!z � �"*. I �wVq=| "b�X�e�e,20�L misEvEMs FF����*�R"F!"p(I�or��[f��%B (x�A e; E�\ron� eeS�yHatfiel.)�wi�41 M�&cacody�w bup� H �4� or 1�r>"�rV�90] be7& �Kqi� Phia� CM120J��EEindho� AXNź� ��<80 kV!�"9{-"d� �Zl[3t>�3a1��k��"�A\osm�p�o�9%#ɰ�)[5�d�Ki�Ve1��( t$,j�e�U4%���wr)1�$25 M HEPES��$ in 8Jzt MF�g� at 4p$�Hy �infil�(�` froz�wnd�GY �v"*A*!/\��}�k)dlab�JIh7+Sm -� ( 1:h �h /1% fish �(g��i �FIg��"cm*� �ZlyM10�s� A-�m�Migt�yct�2. Dy��~�#^box�YKaleida�&� ( Sy <S�)�Q' IN��stS �?q;���skN�G��(!" up�!�H9�G! outl�%t4 �om"�itcir%"�Taio'.kF��U!a�;lu� M��N�%^�z" < 1�n�K 1uN<. p�>X�?N�0Vt-�@!� a Chi-squ��es7Rd �Inc? e^;Ih�+��%�->[? fasc�k�P�despread!�*9!� catt�xahheep ca�_< a>ver�ekes F Ra hep�[�]�}6to �Lid�n emer�zoono\ d-R�hemd1apy5ӡ>�5�m� z4@���?a� ndaz�IM1�i drugCy�5f��UFg*juvenQ?Sm�pa�.68LASce�>~"4:r%�iq"/70 r�0u)A�,�=ew"�2|$��BI[�� fl�,].�J V�2�Zr&/�# ty flavon�Ku6��&i]�NofEXs�]L9�UcK#���~;( FhCL3� 1 /halco[j�M�,� pheny�Cnaphtyl�'upsI2�s goodA��;L.�,� �ng �*w���two pu� b�nAt ͭ�s c���'K� S$ /ou�} , C3�2t� �� toYY9D%u� IC50P 5 . Z�M)�FGaE@ slow-J%s�5��8�! ~ AcCys-Hi+=alyexy|z�%ey S2%� S3 pocketE�dW$,"}aw6 �%��*�pis famil�J���E�K)8N�86 2�[NEJ"�N ���`�gu^lI<a los�mo �tyEZo�,XHiMM[death%�9N week��v�1s le�6is^9f:_@��-? . UB�d4H,f�7��"�+scb A~G �ApeptidWh�`m�Wyl���>�9wh�nZ&�w_9�Gv�Le b�[utegeA�v +t��9�>*�!cu�a!ve^3 �Aaa]��C�s1j�byyAsadult �q��aVI:�q_ (E��0�im�.pw��i�IK!glarval.Jp�mE��2DrQ8NEJ´sZJ�:%3tro� S��Gs����a9!�\.(I��%@h*�T���&:�%'jAyn0he�h thic�5s . Pɣic�����2�I{aus��qof�+v<5!�!�sOF.C�ffAdchIu9]Yneg� G5rop����A����s% r3effor�rL.Z(Y�sp�T)�:�tra�O� Kqt |��, s��goats [1�pcu�<���r� World � Or�zNdu aG2� �nc�)o��[XR�u%o1 (velop a vac�tg6 v&u)P [3�JC o"��J4"+Z=�=l� TriNT f-,choJ4.W t�%&Z in ki�2gy�!�BX ,�e*R � % nIh@"9 [�f5"X"�X��urg�/�i�&w=��{ �BP a�m�a� inno ��3�0>���I\�TcA�c��Ie6�N��9 �x pi�e5�,� th�mad� :��na:�bT%on �or �ge�CF� Z*�4Ue��'�%� ozo�QF ]!M��8falcipa�4)� ��� s [6A�/ �9.'[� Rpp"(..0�-46C.�[j< , 9 ,z, 1�32n͜E?�J�/y' !0��Dst- ��d���7 Sth�?lif���p[1:#1�1A��\�9 L3eۗ� ��new8Jx�duX��)o��w[���eg�Ci� step��I�!�N��=1�A"�t sb2*�Ly �����se��h b��f��dAM��"�@Sl�3N@a��L\7.�N��:pB&��[1A1%3�>�, F .R^ �"� 2|�� xm��> n��or�av[ ]qir � &A burd�!�jOa��Of7%�iF�J�oIZa���c�!Ktum)6"kuh"- s �!TET6� .�s'vfD��.�Lѳe�foc��on N� � tD itu�^s�*a� minovonitril'h�#otic�cC, "e�x7�nd viK sulf)[1�2q#��� � `�dC�I�% �p�c�C ;!p!�a�ve-.]cov@4au�*� cĝ����AG *� ��r�Q. �@0 ! C�r"}1� =�RA�5. �$~+ ��rx�oM�5Z b�=t�4>� ,.Q nd�!"����fo�w[2�,bU2�KF�s�b��)ly-�=%�G �vr��r4 oper],��~Jj�^wiCncancer�� abe8�tiMl�T�# �:l HIV tub�%�% �+� E_[2�%V{2"�W'Iis�,"b=I�7&G&� ,i�VXVpharmac"+&Ms!�� �ve� /x� LBor ����s [ ��p EY�d"��2��.Y�L��u3!`A^Y�-��[I02a�3a�31]a  :>/�in��iYUx8i{z1� y [3A�3�WH"DL&9��^�5��8��n�&M� ynth�|9�j�. Tp.mi�Jcj �e.> O~ 23ar we�}wL�z�fli"}�=qe��Q��j &� �$1���% .^. �� 5: L �Lzea'J3 ex�� ion/ �!��!�*� � a!�1l�l2� 2 [*� x_�(!���tls� ����)��-tumor�ϙ��� �!�[v"�a���a�0�WfV@� e tole! ��v[�3�v3� HN,�R*� �-�^T E�U�VdAWshC �ibC-�de�/!5 x� � +olm .+  S:�]p��.$U �Ji�\e/l�~ d 39V�(( S1–S3 Tca�u!��@q# �V�Orie�01!�;w�Q<"�!k= ( C1-C� C20 !�C2�`  9-C19 2-C26J 2'-�� 1�A rAR.�j�&ta͠ic�� ( C27-C35Qnd-�� C36-C3cJa6��:�1�v{ ( C4�yi�Da�3 recombʆ5�� y�M@y�!Hansenul8mlym�Ua�aCmvٞ9 3S(Briefl[ I�!l�s�Cu� in 5I1L YEPD��t!o1�!)o, trypt� WC(!7�Ce n OD60+2����r�|o %.if�H��<000xg��10�%%�l�E"S(!�� mLa_�e6KnPe\'�67% �� � |;�$1M �d  G$ pH 6 . 0;�me��M��0� R=��� a� %`��tQ`e1p �| dEvr by 2�+30 o�6�?of?s?na�&s6u� f� !ME�a!F(kDa cut-off&�W� ���autoc� �cXo �m��Lmw%,r!U,!�E�'.�#i�-f(!hEa&�N6DT�:5$<3EDT�diK�d"D,p�#�\-&�a�*or t -2%�1l� �w|��>���d� rE�t���V B���or E-64cS !�mM�ck!� each���Vu�K��_� thyl!x�k( �4�E g%����~)fu'f7� A���5�/T��a*��1��.�E/u�at �Om��2���+e�s.�$�m� ��e��r�bAt�TodeNL$d�2osLA4.��)i-)��� TpreM� ed 5�u�C�96*�EE�Mt&V8, 1!�Q� E�f�.�LEUQ )+��.oT2 �; ub��E�̉�U.6N!� ,ophq57-� -4-mE]coumari�(AM�j>[�-�i �|=!8c�N:�e<!�M��^�j( Z-VLK-?�RhCLIkTos-GPR23�e�xcN�0on wavelength!34�$!�e�(6"4 "�"atr,-@-�RV�=sk�MPRRn!��as RFU/� r%ve6�J��re�r�,er�1 j�Y�esA in d'u�;�V-v]-I M�:per>.�oM=n-��!�Q�sR��Uc��6 19um" 300a4�=r� :te�J1��W nZ��+��,��" M��rU���� n "Fci� xI4�"~Das:s- - ( vi/v!�xxI viESv���ii�2A�o!�2 "�a(M#)��A���!� �or�l`G�.r!!Gc�t�H&�:|-EU1O ,"�36���93n .U)�� . 87J �, �;U+1�15ƍ�Y.�9~5��Y�!�"<a:x�HrJB)�%<�6l%�a�i�)A^sus log1� .n� !�"]-!�IC50 �5n9om�!in�rd:AE-eG� car3!��"�� ������a� P!�*t{.I !���#ٰA�JD�:�\�u�b��a0u�WE���� [38��9]��(obinson 201�5Corvo m.�N9imnQ2��1jrac�$&�zdo�mk;sѧ%����!# pmem�rdu�%m&lS�!The AMBER12 package [40�`6 ff0��r1A(�11[41{ H� atoq#nd� �(!�C�4ch1VQ�W0E achq�I*y leap߼ta���L%��f� a trun�@�tahed-i IP3PO �$'� [42�e�210 Å�Z~h�#4l � X/&�^ofV� #!Ix�?s: yS�8!'_er%'%�� |Bto�A,6�jz1�500�( epest���, S�i6000apje-3�p , CG!�1��}�T�*aM&!��4kcal/molÅ2; b�6hC;ste)��6�*�YZt"� �� �(SD��.�=g� �qd�� ��}a,le-mesh Ewal\'PME )�od [43��a? -boE)2`cut�ÅE��t� � ,�e]�!�3�h�H NVT J�m�$%  K82�V ps�B��dsRH�&�6[��A i�ocedur�I�ew 20 n��NPT2Yy 00 K)� atm�s�F9QL$ vF &�s2��$ All !F[# volv�:� mR�@e !�QyaSHAKE2U�a�equ%b��*� ��!�g= I{�)6KAd!�� 0 fw co�R{;�U)�MGsa��%y 2!~�-\(v%�a\ 31ntra�Ko/��p"Llu�Qa�9ZG -lin��.�v�E����Y#�I� ��. C i!� , RM�F RMSF%�5�!���N{cpp�n�}n AMBT�n13��5"ec �vi�<%�%VMD��gra�N�[އCrs \39Nf�fuopt�WdA�!y@ωB97XD/6-31+G ( � p )<9 [4550܌��9wIEF-PCMA�tinuum�el [51]��BondiE�ic*Die�e�� ��]Aa,{)F�'� � �eBeigenS eE(\! Hess 4matrik1�9�6.:M��,��Sfos���l �c�\t="UEE%rNGau�09&�5[5*T�dig�� P"�(&��39a�oB{ flex 0-lQ�dU�!<>�a grid%,126×94×116"VO� 'spaB-��6/� �C!{�r�BO ( bl�O� f��������f �^� � RK|s�a�by�}L��Å� rootP5�%�6 %� grou+> E�a�(��!�I���6s��{��ho�}��m�Npo�A��U�DIc"�H)�-w� lexXe큹ouMDz%� �Q1OF�%�s AutoDock �w2 [53]Y�� y�Lamarcka:g#/�A")>.�� ��k�Iп'Muz} . 5×1061/�y*�50] run��*� of��&� 3)�Y�2NabLZ� GAFF [54]!Z"� !f!))���ESP� �� s [557 ��d95"�>}��aHF�_G*�c!hcqcha��:� � AUemploy��9fo�parEg�*.�Q� (MD)-H�����1k .6�Y~cercariaNe"�@eBaldw���cs In� ( Monmout8IOregonE>" �!> {�Qc$o Miguel C!�ubino� ILAVD�MGAF�Uruguay \!o�1 inva`�C'EJ))_ �b+mV ^,E��(%�"�XA)'" no��Tm*��b��6N�&�zd2y1Pet>�:�1%���&F�6A��A�B�?&"I!5ou,� w��!��YIexhausAily �<. M�U�b�+B��<] 9�� �;u_ p5by6P�$� l9Q��so�A�4� taurU��@,�M NaHCOk-:P NaCl�8 .)�UB� 'HCR633}L-! !+��|?m�pe����%J�!2.DsE� bega��0��� IsEr8A!k m+ /!�m90-18�u�n!�"4@L5gedl�-�%�zE� RPMI-1640�&$200 U/mL P"^d GR+�, mg!2tdR !n!ampho��dB!�)_g@,T �vi��6�%�$Wi�ar�`���!e�;to 12 weyaEy�!3�). -57 main!��j!, �din��[_ Basch’sQ�[57At day �34I=μ'f��"���ed�w &5%y*G �3rv� ���.�Ou ch� d tw�3�8A�fr�]o�e-d!g!}|6�-0�)20�� behav�VAY�I�a�>ht.�0( Olympus BX4r$>TeryT!�N�#r�A�a�VuS1& %�^Q�����F> ����B�e: 3-aQR'��e; 2-�/"I�y�o3Q�uov���1- imcl�D�!'�[ ��� �`�n2s2�a�-�)i� h�U���i*�de�I���r!�!=4 h*L.��65��M�or2��I E�nd�e���2ih���sacA"�h!a��we��fcR�by Bu1e`� .���+W4-`�^�%f� , 6 �;s �{m0RW�?r��euthan�aby cervs'dislohs��xi�rly�c<��*Pst1A�*iYncaecum-a?�e��S 6<���6R�%v warmA����cEZ 5�-z�>enH*Nsacea�� ���%E%A���A�.�-1 pipec\in@EGV�!��.y!< a. Gut- K�`in�r ��.s��p�ǩ,p6�>B�&>mT'a�QllE?in 3 h�'�b&� ]�At� un �o�y�7 s*Z. Sa�Gpl�R"Q %j&C�Vy fn0leD+ford bu�>kep���F�I 5 mL�Zawz"�W ndS!�M ub�"Ger@0)���%ʰ�<d"�%M�s��be�)!Lo� i���,Kbatch�o4 b�-�A��zol <� sched� J orta��Rv�Ra!:a)4%&��wM8tha�!�a rmρ%��c)�v �$B� ill�-Oa�8*!\�^�L�x/) s�Z/ ��XfF*�Z9����0�5 1k�6 }+1@Wm�ex&oF.n��P"�"in6�i7 T-TQ�%& .�9" �Vu��W�K%�"$&sh806��~lF-:"��+a CAS� �c As��dmKA�zer )� E�vi%�(.�Tiw� bach)Ru�an*} 41V�&�Oe*DP�{-�99-�sE�,J�ML )��oA1 Mak��C�S�C�(��hY P, Sefi-� b�I*X [.Isr�r)e�p&�� !j-�Xed:A�Ia7�U%�Nrq( !�>�Wm/�.amvo� curv����(( VCL , >24�-�v� st 4�}c� a!��$e�͙a� "BOf%2*� d�@W.\/W9*�Fs E�7N{+^n7 X}22/s�Pd/a�h.eC"!' �  IeCq$twenty-sixk �F����@��5��T,"fI.S�F olch ORS��C2@&C�6C3_(34e�U19U'_�E��|��!SbiA�,m� ���.�� ��G�l jA409�!�XFglC�-ord*{(�|�E��I )� p�N�"��1�.�K��* 3 ( 2Zat�aMA���q�20%.H��KMrs2�d�-����loQ�q�!�Z I&�G. 3��#&�<� s B-m39AE�3n� �-w�" a*e3^�M��"C�-��&�&� C1� isJ�6 :Q�@N�I!�1I� !���t?S�Az��^vsE�� F9�V�`mb8b4TD�]oi�f�Je;�J"YE����e� �->�&!v��1�M6O#K V�6eas!09mmo�9s� ki/1��!IKS3 Snar��!�r&g����NSS1E*�Ksm� moiee �Cp�z �glxe [�%.�qik� �4a�% oz!a�x�M_~��%�K AI��%�aɻhyl�e�!�� a(!O�M7oʽ ��G>ס� !ma�#i�65;[3��Ts"). Like��A�eU�.��d?��fc"��U^L4���6�&6��6� �*e b%�W)���o*R�.�u�"�di@#u7"rh+��imanag,(]�!.sNA�>i��.o�DowM�.{� �LtEn��e.�alsy$�~K)��T&{�!�C��1W4��5F� T�F$!�er�A�poATq/.�5^�s���&!bQ���A 2-C2!�or �1ox)i�9�B-p�Pa5��f)���e�zSV2P"siU� (��2��Im/ ( S4E:�PX7[�<,�9i �;ax�Y\aloC�IOA"?�m�5�s. �e 2´-OH�}als�SplaĘ�m�T%A�D�W Vaq3�) �R�!j7� d"6��L-��"�=13voA~ �A��19!�,6�at�R!Z9!FA=�-$� . `G�� exerPH&Jo.}e�MoMfB�WJ]�edH�N 5 U7�ha�erOsJs�F��K �� C��8�^��8-"�� yet ��:M90sib�%�e �!��,z37�!7<;�Uy!�3a�&D4(m!�F�"�T!��EA���od��� � seem�2��o=��:!& �=l!�L��]��"3TOno��-�� �\IVu&l-d"�Z fash�e %C�6�"��m%�e��8aw2&:NeN- ,-c�VlD%�Xle{ �e�,�ǁ���)}W�n& vR%3 K�c ea*��$�V��Z�遵a{�*�pihndn�Q�e ; e– lemp�%>]e3.&:�2!Q���"�x�� qh���P0���3.�A��!fP �mea�V!�.�1O�'�D��&)A Q_-ArE:aB��z2 ,lpaU�% _�N:~9)v�k]e[a6p� i�t@a�K� D"�%��]c��!NR�5=]vh"�Gw�K����N&q�I2EY6��9�E lag|IJV�|� z��,���!8�d=9��qka�Z�a��orns��"KQ�%s. 2n��P|l���A)�c�Uh2[)�z. A.yp�(���;��oP"#W��e�P�IwaV�[:iT-�cyaP�!�a �!�r` A0JHuq�+,|/&��eiA��SF\.��c5A�Bog�uS/��(�F>W�b�`z"�Ѳ� i#�\A�g/n`�3�s�#3)ep e �%�:�a� �T��ta�%d�3 r knowled{a�1�o!>�,�$�"��"B1�(&+*��x�A�{�^ir!�e2��1V-iPQL,�we&�� )���q�05��g�� 1% y A���"a) �D!&��5��U��HuQ�)��nj�tT\""cd�6��6� �U�>!�c�D�E�s O�. F � �,���i8 w�te�C��"�c�&� E�&�}--�Q��w�=�k0�E!of 51% � 4Xdp�:�i��� �VJ�24%%22% �9?%!&�� v9?4B�x�"� ,����K.%s 4 ��!�S�!]� 9ljS�$�E�6� ;k)* �2%0� � nE��#�܁a�85X���mq��I ��"�-� . A ���^�9%�U�)5:�=l��no�X���3)�1���*ddl��Wr�gE��! =X6VX,�iOinm��]FC��0jA���b�� Ԧ�a.�"5Y���Ybz�]�s&�)n/�#nd)ũ� .��i}�rthAV�)gi>8.�A�ulz%�)iu@y%b����ĔI�� 34o�U��"l.N�V }YK�_� �j�bu�s�> c�Fi2),"�?a�9� ��t&�6 ~c[3o5)�a�1=�s"+&� phob&bNYV�\:�SM7� Gly6?LiVal16NAsn161)9 �i'",e Cys25 $!5�V,2dUdi�4�x*0�x��d �$b��34I,!��E90 �&���� "W sub�Ws: Trp6!k Met7Ala13yC-, Thr�, �Ala207W ��S2c!!wi�!V86�S3%E� deci!�in �!dIBQ���)`�)[�IKT�ens|!��M�*.�Hb1�V5c�qA�nU P>�c)C�_ ��� toc��bZ^Wish�Pi-Piq �7q�i�@�i#\ue�qEA I��@m�;}+or Leu� -D1"r�P�ZYTin�@!&l����4o�e�f�[Ao ^ �`ilico xi%c �5� ��s./e�.{���=�� chj �?E�"G�Cri�G=Oi+�ϩado���O� 6 o$%}t���*1 g�/ I!2f  [6�8Fur�mitx� =" "�e�!�.�.AW� favor�ݭ�9"���)q� �# �g �r�?2[�35�EuNb�U������ ��Ec��.<�!Jh]/�/JJ��X���A�!Ke��eZ{ ���a��F.�.����0*�<-ia qU��� paY�4( greater than� 50 ) along the simulation time were found in any of )�enzyme-inhibitor complexes , except forU�>bond between carbonyl oxygen in C34 and Gly68 with an occupancys22)tFhCL1 ( Fig 4 ) , analogous tolinterac�wJ Glu7=3 , only 11[oh Y85 ) . However ,Vre ar!Pgnificant differences�!hydro�� s at\protein structural level�hZ some�,ra-molecular6:Thave 28greater than 90�abs��9�bu�sappear*its pre +, mai!in �!m3F�-&6%& If w�alyze6:��involving residues from sub-sites S2 and S3xt1�6E$S5 Table ,Bin boldE@we see a tendencyA diminish�9� ��ofE{ , support�!.DyAUvA8te alters local5�conformi>. AaMi!�Hbehavior is observeeO�U�0a more remark�losE\�saAforff\Val136-Thr161 , Asp137- !j(His63-Arg585�S6nj. Moreoiupon lig7 bind!9new>�a4$establishe�backbonA90d side chains!�Q9�(m�u�2���5�oximityI�U�Aj� , HB S$ΔOcc . ˂�, named- DGly66 , Trp69-Asn6I�Ala135- 63 (z6, agaa�uggesEaa[.a���draA<callyQa�=2[!v thusE� abil�A\catalysis . We evaluatedteffect1(on NEJ para!s culturI�vitro ."�incubJ5j�5of!�μM� �(e assessmenpe moveis show����7 . T8ddi��m�resul��| decreaseTt)leaE�todeatha�t day 4% percentag�Dmmobile flukes was!nA�(rably highe�.t�kd v"$trol group��67%0%� pectively �6rsporadic9!7��a� ��,}6 evid!fsigi?EZnal tegu%pdam��ed . C)� media�dirty �mpa&to! �-dueA�rel%�of body ��onents{��Ab diedE�ru)�heir aᦡregl�z7 , S1@ S2 Videos�gAf��!�10 no9:!�detecM%1&zwh!�co �98inuE���until�experi%2Yf�Deda-|20u!�mQw seem} adeqanly��0imate worm viq�E�re��b���r�U sialq!$s!ar �u�Hcathepsin L knock daFby RNAia�� a reA��(k described!:$phenotypic�tngEg !/even a%i21�exposur%�% (dsRNA or si [63]��,n earlier re�K had docE�A�qgk f a 4hI�I � at-LEBd4]� !;,���D�du� inI�9�consista w $this first�. A�ralmLce.3��A��a���'EsE4of� le2�a�B&� s E64-dCA-074M�which p!5� of!�m�acasana`by._ m�of]�[65!D In a"� fasha}� y.Vprogress�~Y�ta+ 5� 12I,)�9 initi" s a%�equ� ��dZ, a"� ed��2�� raversp 0duodenum walle�I� ed [I8In ord# o check i� �4can also impai��vas)we��� �( gut penetr � assa��A��&4hI�����x��m�łrA�!ig Uthrough �hq�� 6E�Qz. func�G�W8 � �SinB��c���Fᮁ�)��c!%)s�!�=ed�./i��adily6�h��-t1STa�i� dica�Q� U mU rol%Ajuven��3�� host� a%�i� ompth �\ed�ndaecondary5nH54might emerge l� .Ai�menviron%�a`is 4trans2��omidm� ��MnumberaAb to reacI�4�w"n �,uccessful in� !�(. Citotoxic6 %l s us� (spermatozoa� �@de a suitappror preclin� U,ology screenTdurrug d�op%pro�es [66��� cy>��{bovine2�mTa_is not })pro!��cells��I9h� st tes!�dosEC100� 8 �_noY N�A2H �6�AQ velo%jcu� l� ���Wnd!mj saGsZ 7� a� Also , ouevi�studieK ed.mu� nicaA��� )�hSalmonella typhimurium TA98�FaZ��� 0out metabolic��nSgRAQq2< 5D measIDNAћ�� alka%cometI� [36R*�afac!�%�is clas��ounds ex��wIE�a�reApmiE�ag� A�U�usageq�is work��hob if�hno� chalcones��`T Fasciola hepatica maj��s L�$both adult%e����� Cew�,heterocycles� B-eX( C22-C2���Z aie��ny 0naphtyl moietA<A 7-C3�mV!oq' ܁:Y��Am2s�a�& A� slow-r?sible t�.� To��FhCexeU�m��!�let�){Iuo.)�"6 pe��n exten�l� utFa!+cha0 eriz���E ton)~=�provi� | c�@!4�jE�?�9%©�arget=�ndemonsP6�iSto2\]���fIyicJ�vA� over&��>nd�s larv�*�-ZVqi� �candid� aG furt#B��s� m.� y���0visual system�m�p %� ab��fasi,A[!�� lE[!�ns�; seaMte nespathwayA�We us^ viv� ag!�to#�g9how bipo��H�mi��A�tal� !�inn� tina)�7t��e volumU.4synaptic termiA�!cX trinsicAjpe�Ba� ribu3to]mtemQ>��divid!\B�Z multipa� ~s vary!�iza�/small< (gener!!!�e�dAN calc�K%)i�g� igvesic�:e�iq . l -, follo��bypro)N adapi� . SB�zmitaL [st�ux~ ��k� �Model!global�$dynamics t �#>�c %�var� e�A9�}1���ar=S%� direc� ! llBs2rrespon�_sE 6|9 � w oa o�n5)NI����q�igA�ud�Yof�EHge��r!n%�9ā�rE�'. �riB�yz�de� worl�I� a se_ of s�ro-B %�& � llel$�IKs��M<s$ A� he b [1]–[��anatom� organiz���Bs�nnelsa�~�sV�+plexi��, layer ( IPL�is^: to f� t� x diOct� t^��cdendr`of0man�20=� typeF )tangl���7( ( RGC ) [2� I�ch pu��6 ( BC�-� �f��a4=�8make excitatory� conn<onP4defined subset�RGCs [�Fo�:sta�, “%āz” *� thO% !F~input�om��bandpd &st�,�lemsus!sedmw^>S�ng!� X)� !]A W-�\qu��onA����^�� buil� Al �D%=���=k�datiz�I�qzfield [7e9�n answer�li� !vde%��funda� aljl�II�-6ii�uan��m�i>I�:)%ޥ���A�� di)]|��outputBc�\ much�'numeroua� gene�*!/!\�8$ircuits–�!�10!4 IndekA(nt&B �@R �+B-�same BC���:5E��� kineE�becau��3 � ql�`t�"� y amacr��s [11��sk whe 6#e�m�V �6�L refl�i" �K"6�arу!��K��!&�1�y�con�i^N2� ��i�chA$e�% fl�<� itud�5p ��f� �F� olsA;o2*[1�uToJ mX� of�BCY'w� zebrafex��fluores!!� � ����fu���R����#O:� drivJ F[1[1�9Q+*� �A�"^ of.�iend!x% �0�6Din7� On (ag� j� �`� ngvag ��Cin��  a� �5"�E� �� U�si5�� �  fv� S��q�c�!O��$%+ -�.o#�"�i�:m �"�ref� ��%� a��� 1�i*� ��chN w �t- �5O�T�e ጽ�. IR verta"t- � ,m�ro�� photore�$orœ��m�e5��tu+2���E��d1A� To s.y%�2�� .�l�anima��e i�d e�6en�pXfjlis� ( dpf )�2� a�9sypHy"8 or� � � m��B4 a�, [15�(or SyGCaMP2U�al��e5)B��H+ R2E����' i�U�9qA�!4A�h � ��� d}$gorithm ba&o2Lapla�p/o� Fi)� �7��$�we� � / "o�  us? ( Ma�QA�MethodP I$Im! , 061C�� vealxwA\)�in ai9a���D1 . 13±0 . 40 µm=�0C , black bar �Tn�%I�� � d randomlA�� 1wQ& s 1D�S1I ) :�in s 2"6 cA0�lyA�g��&\��acr6%wh pop�(ofe���2�r3%�%4A� nd 5N|�!er� ow dx(se9yz�6XaO�9d!� �1Q��a�a� Y�wh�&��&�(membrane po�P �A��_i�x ?�jin&��"{ �Iu�Q�M�1w��vt)~&M u� ( RO!�u�McA�l� �)d�wilB g" �gaCj��M� se2&E ot be mai4ed)XT-�odA=a]t2Z�"v*to��� (� below��k %|932 ON�Ÿ��1�ri� �Me��by a ful�� step!�l��~a�x�a� wice}�A�]I�s ��&�##��stm �&G ��!$�er�ady�te�*q� 1Ead2%#V6( � �ixmcorre2d%�"*�.w exoH',�U�!": ��1N5�438N���l1��A�&u �wP-� "�( quanMaS&V!� Q��$d � )�bG)Eac��� t�&!�wo2% 5�a�1�1fb��F1���8� &�* �onshipc�!7& `-�a6�*!OFF� YS1GEA5�AZ.� E�c�R�of)5��EE"� �B5"6 "� � 5�=i� �#�5 keepiBmean lu���t�.5YG1Us�(d�K� �h�ofmȡ1� at 1 Hz (�%ht5 �po� �q��51e2�" y�M+�O5^A!r = ) 6–93 0)� � IY (,2] –4 ,,A�b^�hr�-�����<G�8Do!7b%�!9N,$U�2tSh� ehi�~netin� K0is embedded ?>�je�� ��e�Ga�����r � they-�vstron�*� feedN-| :�.����J ossix *8blocked GABAerg. \!O� ionotro1(& by injec8�+lyI w&�)���il eno�'? Two�#�ev"c�a� %�;"a�$���s*� &% �!� �%s|vei;2E�.��g�#F�S(ophysin-enh��d��e+o:� ( EGFPsa= t �2v&� s�o� < � )��O!���I( "GSe['� A?a�> diT$���&� . Rs& ���n�)eF0%���� � &-in��S~4See2��e�"E���1AD���� v2T^� �$os� lin���9�� �f xv �M� 6.J r!Q26X*� ��%#�}�!�� � ?=!*2A�is&3�$_*voR M2Ino!e"e/x(ed*z�� D/&Ribeye::A5Tspars��D%�!$0. Square-wave��iJ: �!�enA�at�S �`8d1�3A–3C� Q���BCpo*V� A�u� �.$!-�i�ߑ�-r� ��&\/y�&%veњdeg: ��Yu�3B; cf���G1i� 2; � peaA�at&�1y\. Qual�H!��1%hob()-f�()�W�#x��li� of gold��r�to3T-E� reco"1s ".!%�A�6�R“mix�{c�t!Vo5�A�N(1�s��narrow�y�*@tu*oa� Ca2+� or Oregon��4BAPTA ( OGB-5N�;� �� rVI8��f �!�EC ; �3achie�)* eBr� ��4QxՎ�%YHD:H�[2�AA���aoed��*A �"ise= uUEm- �>�(�R) r�+������iM)(�&<�m�0 douba�"!�i�thdecay�/6rapidl�/S�:�&�9xA�s.purely1qm�&M�5�M�of��-\B&%Q spik* well� w� �[-, [21� [22A'5K͡��!2������� t ']PR�–[23RI)�ex� @ UF I��5���to1%�"a c�"ir�,� �6UIc�)} ��sa�rY��aj��� do�Mb�z� accu"Z?�8a2+�� s 3G�\I summar')[*� in 16 �2����IqM!� �a�ae=�&a"Fta���B caA=,'�)>l mte%H�#�59�Jw98�#�V�TA�I . 2 made� !�(patch-pipetE7as �7 soma��S3" q�&� 3Fp"!ip �qj(.2t"; 6��%!3&,-N1k� l�!03-".P�i a"�Y� ( τ !I���lys�ion+��!�h&� aGEa��� 3J�i��!q%�� u r� ��i&U-E_7l�� dyem=D�RT�� capa &T �Ndetac[+��q:!L�Qim�*G0a}8�B2�2M�predi/:57in!��p�5��'of��*"`).  re>"2�3a�� s [24�z[2�&a�p!*e�7V��(2!!�6be � stoo<erm���h�.s�An�]eq�B�Yl� collaE�X�"ofQWr6�)c�s:�BDCa!}��P"coeffic!O@[2�AssEg<q22�2/!B] �A��∼� 75 me�*� F,� � �J�]1�&sh�!F -sca4a�CV,i�: . EK;.��U�%��5 N,�is�19�*� lD�hal�0�<od�a&` fl`Da�at�)Hze&e �<*pprecie1�Qs��z����@ir9E3-Di+IQMM�Ar�Jclust6C}\"�!"j ��Cy�}�Fm)50!�s["K=*X$/$iw.�\%t0 R�Tribbon&�t b2�/, a��nanodoJs�c�"�c pla��8�x-�+}OC'�n- T@�[2�T% �Dk)��a�A-%reAT��rV'�`�F ink .2y�a�2 &� B � &�.~1��ve2 ]� . But why�8��ls_662�u"-a!�6s0Uf1F ) ?%a�=k�e�',:5��I�!�q�)t',e�� explD �+:~_� � N-:�;�C"�/�.}#;3�� i�A��6sALs7 2��^i�T�S���-Ie �3?D�}͍�5K ��C sche�3�D&� 4A!&!   i�3i�1zt�C��"2�v:�,A2��5BE��%�m2Q2�2����P��z1 co�H)�d&impul�1����oc�(vo� traTor^6� 4Aop� �in&+d'b�.��eQ-II',� m5�14�>*8w�0va WF�9 . 5 (.!��� �E! �!)[in+aG- ly m�D��Z&c�Mn+��e I–V�΅�%�de2 of L�\1����>�e��1ol E�"�[3��:y�5ex43��"�?,x^6e-f�Jin��6 . 6 mV&/#�==a?%�FF�#s��"i�r "i�h� �*H32!M* -non ( L�Q�a�Cs�Ti�A��8fKiKpv !21�y�17]aO��R"%�FI;N ctif:R � m{1�inE�a ? �c; non- �-�_9l�A30 �:m| ur&g#j�Jm�(1�w� u al� bf:�r�G cp,! $ e�'“N��* (���E2on��#*� "7 h]"nF�I� z) i�"g�%3EeU3�,)>u���"��%u"� . cc�!H�)�y�u�e"  K�(�o*�Ia݂�"��%;5�N�o�" �.f|S�%�Mw�f�)!1�6T�k\A�2#F� �%�s���{�V�F%�y%1=�,as�8e� �5>ua:�d �%��.�� ��anB��U * >"4"��6 U\48+)4)�c�A'unt���EehQby �@�� HY�r� le"�#allA x bl�LQ���We�R ��wo?>� !��� ����4hx1 %�dFJ(�8��-1@6 � me zone:�!���D2 ��V�` �p $?�>�[oP?�Luca7%��u�*rM�si EF!n5N�� a`�"�2��!� lJ� !5v� M�'=��pr�.F;of2#)MQo�i��@ �tak�U!�cce~�7�[ E ^� �\;4� 6j ��a8M u��!bi�tinuou ��!B B�4his. A@ �[$�2pla��8Ed*�8lr &*B�� � &w>I�](/e�?4�'�]bes�+SK"*�:��0+7�o!�toY 18J4U54XlikT$A depleA������! � �u�[45�4� M� %ZN��Q�I�w�xO�*=;? L�dB�.�hundredB ousa�E�� �a�����Q%inNven!)�,��nEE^FH.Mke�n2�[31%y3�6It�'��4ba�f&�IBJ �}���W !�deU+�5,yN t 6s%�Ce�8anZ AY��:xP ( A�/, ������ ��"9�6� �:�)�n"xqst*.?. U� *ofM(*�*L��tj�a2�>)8*� 5_A�"xi #t�>�%���K�����u'Y~mH�QŤ)�)�*8T#2M ��6AE�6 $anAEN��RRP3IPAa�ng %jGL�2k�u�6�/E�2�Q,A�Na-E��#vo� :/&%3 9tdis��&E -5�9� )�AI� �Ud$ �'S���6D��absolual^ZofDթ0 ���,��H ,-4�6t�Y�E:�!� �2��qof��,5�R��B�q�� CQ�m(s��y*)=��/oV�&� re%!f�y�7 �� a�);]E|"� Wq�e��A`tA3.S$6 ". Non�=�.VA�fm tog6r.�!���CD���΁�*+ J�%f1�qI�A�>" }��.���',.�.��@rylyI6s�5? oppo���<��*�� �d1 :XB^:� nN;^%�g.�Cs �3N���eM se"iSD"Q. aLbal�"�9a<� nE��G 56Qy&!���� *b2;�A6,��2Y,@ EZ�6>�"!N��2�NA6�B�OS- ��h�A@ �e� >� �R*Y.� :�/1ub.[4i.%]oA� ����A�.����)n empir::�‰ o�c�ac �"� &l2"2fa�@� M��T� -�:z��ofu<be "�'�n�^de�&�6�a,�s:��� a9��yZE�/!�i� a�J6 �, [50� 5�B�9��Sm^map od{)l �C�F? T�+�e�-) �� ;ly��2 6 ].m>�y!�%tf Q� .6��p�>,a�farZ�M&N!��e 57&[5�%�a�=n �!m��-- r—4���� y? MeaiZɟ���{e���2x�/�*.%4� !#om� ":`"9e�m�:(Sm�5Q�>$ D[��+l� Twas h�9*�"�#&�6C� A�b*7bBi����`��i�Z!W� u B FbIq�_>�3, ��~�e� &n4�(KA�b�,� !��"�@g2��C�4"<��� appl� a s�- *�-u� d� t 3��1-7A�D�e\ r͐d�wo*�6i���!Za.)�#&f���Z�%isUd : 66I�r<q"a�119 >H "�'�%&7{n,EjW 06lA6�"����& <� "�5A�1��A�5"�"� U7� �2{ y� �.�-�"�>�1~���� -poT�AY�>"ZY��Q]cᑭy2�C\� �~"�Tob�Wa�!�.U� b2�=-� ����!zZV"�>.�NK,� r&!$�pls� &75��;TAj.`:"f$E&�a�$ic6�B&��ue�hP屯Q-�eјa'A���O!$ ∼3s B�*yO~u�1s!, 7�4w7$ F�T��e�U�N�!��{ 10%N 100%o .�e�O)�r�)= e DC;� 7E�)~F7�=%�r&^*>յq^ bG���4���&9%�.:>�wCE�Z�u����-Y3!�uy"I+∼200f'�J)a0m '9V9R7i&{:*R�1�si�ic3ies�1�t'(�}�[F�,7.�4t)Y2 "0.���erQ3q+%kn-dY����encod�fct4(��"�Fl�04 E�` 9 �! M�N~��6'�  !e� se ?f~� S�2� ŎE�22)=��. CLW1P �*� R/h'&2�l��:<�-e -too�o�Q� ��-!��.1>'6( i . Z�1י r"X&�^sy0%!bI�� � w�%;iD ZY.Y% 03VQ_�e�ed}�8 Ix� �, (�%j:U� l"^ ;.��{L 0st�2k�c�  /�Y�]M�a��������0M8A�*�A �I��)�iQa!1�y ,�@jX :I��/<�,)� ( r>&7 )��B� I��]*9[-�fB� ,�plo�B��&� 8B �Y=..5 5��5�10� !9� nA{be�+��08 11;ousBl��� b)"2 �b**Q�*-�-�m2�'"�3�9 �i=�da%�_=-�9&�]6�A�now�/�?V�2VR"j"&#�a2}=� J�U��q��\�0K�I>�qiRm�O ingus�� Q9[q�'3a�A��6gZg6���r�( "�\xB� WvA� F2>@� rekbF*��%+�� :��."Yo�)]�S!�g Zt�ug1� � �[1�A5�\Vhav��I,%fu&}Z\i>8E��x$NE�_�b�e HZ �E��h =9s�$�>���%�5 S[5 5IQfu�s ,e��b0h ^J!5: !6�%5 5 �+tu�N�T"����recQH�s)�2�!2*�! O#M udy/5�Hech�i�kmdng $Wqui �stai�07_�?�dublof�S��rs 6� ~ 1DA�E!em`e�Ŷ%� &_2Xn_eq!AIPL �,A���)%*�#%0�/:�u 6�vAo�v� st�Qh>Fa�R$w'i 8q�#� � 9E*2 �( �Q`�.N$c=ef� �^6U8AIh#�!��`5%G 2� � �9` A/��7eVJ%mM�J�U�%9�<�K purp�0��mww}s�e�Ci%K_)uHa|eme��A9́M��r|�hՀ�|>-�/d �U%��!reh�v" �q�g? =� 8Nl%f�oT i�0A�) ,TA 0^m~�to�O!����&/C��U9`1\n�SNIeo��2�2fn�L�#2�I�.�!noiEF"|&�L!ULE tv� M6 ��"��Wf"� 2m&J "��LFh:neg�p2r%���_E�.fKI���tu� j %�� �p�D��ou� , e�iJ/�Z [59]q\�%�#��c�rph�2dBi�on�Bic glut�z7[:L.l!���,E�d9zsit4e[�(6�6���lVN�%�qq�3i�O:u� 632���1mI A�E�� ���9!� �yn�2}SB^!B� BCs:=ӭ�}O�dB�i�&i �C��a�U�ABoM "zqÍ�4KS U�3�[6z`�,ey�} idea)�wxo�Xj���. ���w Yj xh!�,�%�t>ke�/;!1a��a—�1..�'�!Ue�!A�gn�"EJ�-�� 2ls� s$!,����a�uV��,9Fa“�^!h. � !m<.� ��JarV�h%~�#"��of�VA+OFF�: begi)a� SqhBC �y�|- �9Ձx�spe�+�!(� }sg������[� M;t-2"�m��0:�:b�1�M�N�_! prob�}�hn2,�&)c.x, )y�[�t� do��sYy*�,) �i�4up_C !�� thin�EA�W$E��#!!w� �!Arne� ��� niok�@# I�,�Z!lfruitv}aoc�5��u��/,.�uni� � ��Qhh�(0 ? g� 2� D"� ZLu���. I� c�C�x��M�noE�%9a�)�! ˑk�/ ��& e�D556'�tp sb n'S t .&�V>� 9> rbor��a%��?CJult�:\��Y��1�.BNG*9�i is yM%� ��p"qw&� su"�C!;�3al�Qr�}j�>�:�"��@��t!U. a taqJ�aـ�i)���� �\B���^ �Aqin&%/  K�O6tY#�G�M:M�&U_Nk�VE�� � �e*&b�)�x"uYfe�� �MMRv�q:�1�FY 3_!d� i�-��mbiTca�����y%�.v&�i��p�x +�I"g)� ��f�=ect�1 incl �crick�wudC�y�La�m7]%d0Drosophila ol�A�&�� [6 All�ce1`ArqQA�d� FI4 UK A9e�Sc��� Pa. E ) Act 198��w8�� UK H�+OaK2(�U�]*�RS e. 0�A0a-��^14/10 h\/dark�9at 28°+&F�n24 hp��e>P�^�u�cE� � &x1-(x(-2-thioureaga���'n+2dC�Y( Sigma\)>J pig��a���%sh �b� �-�]P� . Briefly���&G.s 8–10�f.�anesthe�,in+016% T+�l��� i��w mel�1  agarF�&��^ey�̆α-bun'�wUW 2 mg/ml )/)[eNextraov3r�FE6Iu a&�x9 custom-b�o�;i'*n mt[ scop�equipp�%j+-�[Chamele��8itanium-sapphir�3srCo� nt!�B920 nm%,A,.�R�S Scan�e v . 3�@softw�a[6"Br��-� han Olympus LUMPlanFI 40× wD!immer/(%�8 N�(ob(C$. Gj~ ez diR!�um}^edQ'�:R6.gi�,Z�)$ND� f�_O� ��+ XY �Z530/5%I, Chr�NT:fyAw"Ɇ��GaAsP %�)�li=I( Ham~su�.%�d,128×128 pix�L)ilac�j�<%�;��|!��Ic&"of��]. Full-rl!8��rDwv3�uE$an am€LED ( 59%)-=1a 600��BP %pro!�2) wgu�h"�- surfaK6  bath ,&�I!�eye^V���&)�6�a�K2×105)�ns/µ�L, w� � e2 %2_�z� or���o�a:w@?A�m1ne�ar.�gf� .���O)�6�l��s ���le�J;�� udZ=8 i�� P�r]J\"�� L*� u�)c�<c�f�]ph�\ [7kE4�I� ,�ms� ��� satu�R\a?�s� �",!=A�9?�u!*!�*��-���d�sw�0�U�X��Ku� M|e"�,a��SH$.G%a�lis.yil(.� Arw�Y��_���.e AXg .!abbit)8,��sum�� &�MYs8P&�T. N�theg3, *�)2�aHI= scan~,! �wa%�30�d���enc!����al"�%)�nsu�#�.�o1��I.�ev��at"�l $ ���v��� pY�bSARFIA�~�&a �routi�[�mru �in Igor)  6 ( WaVY3mW�T+�ld� ~�CIS'[by)�� fraƃ��m�2g��odw��g� ) i!�'Te�.��.�k:r�K\�n!���se �� �%N�k5L0 ��a"�a�DdFaFLoIk�y^ lJ}� v resh:I:#�!��Y!�%���u� � ^or$1FROIq a)��0�dqfr�";!��D2 �b�ON��|BBa1��<~%iew� 5Y �U �%��plͣep� 1i,p'/o*��A nGd�(ed� r(orEl�1(g�#aEZ datay��k �� ��=6�$!s�|m�e�� [2�k2� shif!�toQ!v�=,�3pE:�_�+Jt�-�n-�d6�S1H%�S$ 0%C�4N~���)Hb2�f�iz:T=!�}A>J(�3GiVa&�x&Kju˄bove 1 Bn� 9&�Z,"m,]&�*eF�f void�-t�|��.As�}een-�lly1� planq(�Boout-of-@1��I�b�2g� �gna�:ll�9t� �c�&�.[7J[D�cILyOmecVi�:rgeeO ��,6G� �s���!=� Wilcox$V(igned-rank ��E�es�'cD@g;c�/�W�9)�a�>�y�irS5��%;>p�o�iSi��{2��6 �� priorI.A��@A *&.�%tautom���(no knowledg26IG!��u"/�[G mo�. !��x�ԈA�robA�1 A�����%sic"-�1Bxx��s�lo'Qep.A�r�Ce҃ve)Cm� tC :��y �z. N�rck!$? oduc!m��" �error��fM8s .4 ± 1 SEM , un�h�.dDw� A < legend . V′exэ!�fr��V� +"l"Q� �(2r,���Y?�3A��>�O�J ion:g )�( re F�2t�)ag#2� c *P�5(�3�� Fm�~_ .4�\� !v ��{�-��md�a- kend"�+;-1O6Dm�Պ��11Ya��ul{J2J [0�mF Eɺ 91�a$i7:�q���)mtr�"n turpl�RnoA, so E/�e1%�� `J smoo#g� = &�,^o�=ubl}H�".{T�$D p?{ y” �~�H:(�%Esc'[����@" s 1F%�5�Sb�ge�݅=w}3� u\���`�(h,mM ) 120 NaC��/05 CaCl2 , 2 K 1 Mg  1 4 HEPES ,h0 gluc� ( pH�g-255 mOsm,E ��� c.7t room�#erw�Y �H D,& obliquA�fr�2�"^ 6�&{(��9 )� n up�(�. W�z!A�3ing �)��“�s%��%� ( di�(: 4G2�)AR�;��F:9i�8 7 MΩ �c�/cie�1]'!at�� ��4���( s 5/W#G#f c4inM 04 K%�n�3, 8M2UY ![5 EGTHY!ATPA NaG cGMPY(� 250 I'] �9��Z@hexapotassium sal����afF�tyKe.c�\T. R&�je+lef7�Y5� �0��_�^Ca2+-Q�+S&ii adja� Bk9�c4-�E�lso�iS�p�Lc7n�E#E5E�/-%.�A>1 GΩ��−70�XF��&�c�ju�2&qs (�����15195R OHkt�dt4`4I��lE�n� y��*gKup�dev+{( EM CC�;camermf&vC9�twS��Қt w&����o2a ��J ,&9, ��Matlab .��m�8=���h!�e61�q!��dv[ *2$at�  ( ΔF/Fo]6�\�29F :a`KAp(AUr�9EFmax/��$)��bx�2Si ��g Kťea.�∼*M r[)Ig3�L� A�K~' m(�#��N��F d�(.{bDeepero ��X�’�8s*% +usU 'too�"or�,-��\�s&�!�2ݧfie�DI �2�p�< �� ���L� . Fl*� "�y��C|Y�1Eo r]l�"�Id�da�V>dis��- �Y� . FMLb2exqui_��di�&k��g��-Y&z�Cc���rigory�:F[�(��2 qbh['�]�A��.EM ��3'A ^� ndard%relHe�B���m${se �%flHm#Y:��P)� !�=To�� elopz:��9�mH��hav�Xd�Q���conju��8array tomographA%cAT�y�"s voxel� :FM�EM ( an�-��) �u !D����"-%� W ' a h� unsupervi1<�'��!� �%�"F2P�8ex�( muxe)#���6 u@� \uE�]�is;o�6�Q!��Fa� ng�dM�!Y"iem�] feZ %,co��&�TA""^!.( p�+d ba9odel-r--%c:#sY|-2i)1Ej�u�qu)0���r+� m-K�"5����T'E3%.�.ar- aw . Ta)um>IImTcAT!�)hs|�nd tru��)�9p�& I#sf�I Nl�Iuct�)�I.���seoF�:A�E)acc�l�$��es-�archi����gb׃ach ope� voh o�-fnA,covFzofţQt�+A�th�*3U�;�39@5�erD)Lor� 2 �?R*�"�9,63�.)ToA�}e�.OFMi�� FlEM  � -vali�A�m p.L. ��v larM�ec"�3m�(�&?ig!B���^�\B���!��� t�1B���,ynM%&~*��a)�1ߐst*!E�N6E��:[1]��`1:ReU��-#sub]!)+ �`se:�'���sayK �:z��F\.�9�z� _��dv ac�zs5�U>��ER���ea>A AH�@�<� l("� �)�:�@�W"� � ;2�:W2V2[ ���e���f�� �A�y�]1:O6�5"a`  �s!�smI�b!n enabl !f towa�d" e�!B3���.�1la%��-Je��Q�� $ ,� . )?1aoc�e1�e��lhel�)zwU�E=s F*�S� plK�L��-�n�t>?H�,� er��m'^ ��9 ��zi0Ic�Y�!(cx��nt��*5/A"2�)"I$&��a�f>to�Mppl!�th� �� ��# jIimmuno2�-N�1BSO_[9] [1�#�pCpl u}��e�t�CH  ��� p( m���/��3!y�~tj!��65�lG cer8��� �+2 �e  e"��%od�A�x0��(�kŲ�����! �8���d&uicc"_ �q onfeq�[ y� *!eMu�*�v�u. frame���92� �+"�!w��uce�-e@���p�w rece�i!�5�T-U \ Ł���d�e�E!&�.ZFr2� I@eamG*I$E�M�e ( FIB]�Kz�2A��TA�.��a; [EA��@b�rHe�u��@7E�pa.�gl&�2��E�n)���mid�=}�n[�[�{.�2C��fl��be�e�m lc&m‘2� ’%�6��!��r:Au*�JEMA��(ɨ0unambig�c>��3��a�n�"� s��yr&�a�1c�Y2>� i�7A �U7�tuly�� c�a�s+: �@i�/��,8Narde_b!fEp 0��rdaga�X+s�N�� �� &�e aC�sq e2�b�e19pD�!�a�wnstit�^!�55&�0.:�?2�2d��ag�YU��!�uj�: �7nQ�\<as'4se"�/y��E-Mq!/�X9!�pgI.:�!e ��_FM%Me�G��F� �ympr��reU��I���  wO %b�w�Gtissue=6| teI . R�FM�1�� Ns�etu)"c4�Mo��ls&coOaP� M�6�nN�"�8���?"�6� o0a�a��hIg'0HAn�NE"�/r�ed�� �$ �Qa��-w᮪{)�e~ ength FM-AT P ofJ���F�E<�/ ���E�� i�1%�U^&� ��. A:c�Lult��in �q�5io%W"T z-ax6�#�[bey@�!}l�&u�ic�-�,' aw<l�Oa�t�!���a�U?�lei�ly�&pl�q�*�ٕ��yof-�^)Q!2eAA)�� �!ov"n�p��LR7%�e.�by�evnH�Y s!�t�l�6� ��>5jan��_@lats a$!c.���&sexA)�] s aiv�Q� |s.�" Yp"��&j��fa�Ap � nd4��aR��ammali�|�kls.�&�� b&~tB�W{��*�, .�%D��� ak/� a�=y bro�A4&�"��&,�%�%� !sN|!ug"�2ɱ�2�b!4%�� e&^inevit/"�kset%��%�m5�cE9rEA;}&��}��cctE�i�Nto a>��.HF-$�‘l� mF�"�/#b n%�o.:oreK��F* taga~! 59� � ��1�ly��I�at‘&=s���� �"0��u*�#"log-n��!e� c�}igh:���j2�on)��(�rrbitr��.-� ~v$*%�*%"��Ht#��BE2�`"��,!X�Y�ch!��Er!i ]g���l��ce/abs%� :%/t�*.�#& comf�]�&�<o�&�=�'%`��>� �5Ho��C�may�>�6~ liefi�� 1h�-h(�""�0�n�=? �0�n5w� �a���SN�B�r2[��A)LorV�����^��!�*�d �5ly!\�� ,شif�:!wSpuc-n ��zf*��#�s n�K�K�.�[NJ(�*fR� � aY�38*+���<���q actu-ne��A:� {&�KAT@q.� vail�A�oug�< add�q6a:! + R ,�.�-�M$����#fx��2�v���Rpo( 2&inspi� ��}�26,�Z#�I�. S�ucl1�tw؏#�*�!k�( h�7��&"ea6 . De*:i �#��Z�4"aZ6c�*Q%.�A�2�ޝ��� ed(,�M��m�diagra?�9:���� �b*�P�! �� V?g 2E��4amof� >9s� -:*���( �~�-PSD-97�� la�0�an; d��2is �fQ��w�t6+C�nq V)� �u�In��� < >�� os&sB�aDi?��!�J�� %t�b . ManԍM+�!UC���/AXb�&$(^ !C*q2�Qn!zn� t�0�,idP�M�c�5X4ly-�fd aaL� a�N H"���<�Wc2�7EMi ,�P!sm8o!�IF hC"�ssoci�!&��un&��� w��PPYe"�n\!h�~ �� 6�^ �N� �'e���2�!����,��o o � �W$�)& >-A�U4.4-Ja ��tXV%��?�[u� atC au!�a�A�7�>��92��2m�B"�6�ore�Nl�3�9^ a 2DIS/s�'`7Ȟ�UA��%�"�8O">-�= �7-qo*‘�p��B B��*aTL !E��� auSJ[ Thir�="aIspa"�)e �-I��e ba#t�beN��u�t 27� �K.m%��a���.��q �um^h�! tteni$d� .�pro�M�- pans"��a^e�3I��x5 �6R(LG�Z=R ataKa�� �1�A�C!���2O�a��E'�5�RUyIF $��e9� :$>�~�2G�e�� |��9�it-m�09�!!o�l$Xwg��a�>��Z-�{%�E �PeI@%se subI#,� r�~P�MOrBa�bod�%^�avz�ce=!E)U5:) Z��<ea��e� u�-=_��1 �EB�1E�, letvEe~ ��dxa�2^� )te�7 the-�%��[8hq�". e:*� ,in/]#s m��� �%ng r���F�Ѧ�E��!U�_���as | ata)�r"r2*��-U��F�7<+e�te*�*m��asMA��<d�r�7Z�M[>R(�y�s/�A��T�k!�|vec- ch�0 ( SV�+9��4r�z=%��! � ��!J^� � 8t�N�[o�$KAGyH = O��# '>�I��"�+I"'�<&� nd�Ox\��w�u.v�oecI5�e? 6��y +r�o�� ��r � I�* `I��5&��!�a. O��>�U;m?2�uJa�ecX�� EM6aa ;a�fac��we�Z*� q �r p�g���#.V‘� (*=z�X)�áMV ��S%$��I7W �}b��t a��(3g��2:��;JG]?K>Ni� ��n�se��j_ri��l%��)i:�)�:&� �>oI(new��!�#"R��eM^!á~� n�Fre-UG�D�W �[�wQ`finC�IFoD�w��>��PJI�eoc�0s������A�e�Ml� �o q"�� P�#���hq�y���St� 2��m!���gp<<b�}a���i(P�$P�r��c&��*-��W. Raw^k�� isy;)��,Epkl�P-/ %rVo_y!�e��uQJe\2�(E��a&�(mitochondri�(���H.[2�ry�s2+ sou���U = tly-ŻlX��,"�H} *o �)@#OFi�Ue� digiA B�inA�a'ok;Y��0��5�D 'A  �2� "� 0 �i�A�Q$ magn$�% p origi�ng �&%���%(!U�iIot�p�A�bG@ ut�disO�930,� an��&ay�,?aI/*][�!w�Fed&�N� �����fa!��� eak "�c���b= A�m��6� <$�Q� qu��s�"7#�=� aA �jP&.(&t!�;�"�E@aEy.�-O"� �,#P�.�D�-1z�>/�e�5���,��extrem��—�x6�ly 2%1  S�use 1f� J.�� �7Ta6*�IFi[ �A���� �0 � z:�!j}�ie4. Let v ( x , �z )V.!v�� � � i <)�� z���2�Men�BY&�A:��2 , pB ,a�|ug p&�z;l�� a>h���e�Bs� )0ly 98>���B)2 �_om �*�Xl�'�>%�ċ!6U_�$aҡ5a$�B2�\� {pB~p�S9-xa Gaussa 2���8m#}g�� ( μ !e σ BV+�em��"�͑����!�z�x�om�k� Eq 1�$�'!�6�W���Eu��aM`! 8FMh>Rc�a,"�s��b�3)�?� E:�by p BU�,E�= 1�π ∫B0∞ e - ( t -)*) 2 27d t .8->�Z�*� ���a�', pq�.X�) � .��-J���; ig 5�1s2�q6[�Jraw��1n�.��. OA@."i�7_T e&j�D(���K��"9e ii eQm61,d� ; _Las�_� �9�� ,Ics�S� 0sh� �f�a�>��*[av��&�:,�O2�:pPIѕp���%1?!���’mQS.��.�yZ.n��b/.-�e dhȢS&oa�p �A6�H∏ i = x - W x + Wj = yyI�i , jm� , ( Y^� W%�h�=ig�{�,� � � st� �@%��"�M�D���%"q�f %8a box�Vo� logak��.DA��S�= o� e�,�P%m��u�>�3kW~@��sl6(;.64��{�O #"�3 "�"n�a�6A�R�.�*���!�6*�aB��#��Qs�"� E�3� �I��j.�62���f0� :5�o��um . P=&� w�n� F�e��E�A nel;4Y &������:�:b.9r wZ}�S=uf:��x�?�r 6"{%�;8�œ�F� ~m[k��f�.�J�E�- ,B�=a� - ∑�$ j s �%r t e n d [ Fn��6�+ j ) ]�H(_��EV��_HE\F��^ A���f�� nd2"J, jenJL�GADK��>" 6pH���v�Ee�pa0l. u ��][-�"�s)����.BE�a%BdF�� �"!$Dp3�F� J�V��vŒ�mI�, p 3 D:�) =J>��P� I�)t'F�e�&�Q@n"�!(%� -to- !@�,:[ go ��2DAO3DinV�.� xs"� ��5�����(+�"�3M2%G�M 16*� �-��K�.?axT!�X�8o*�!d���! vp� R�eVFc1=J�&�+EsdBGH"�$:#�R� E?2sp)�ar�]me\f�-�2�uP&�I9�!�X�#>� %yv ���!*� n���a,��oke�-!�13 1�͙� �  �.R +K[��ci����>20��� .��`�AL ���3DB��99a.�.b��$)����-*k.^�F�0s�iV f� angug grid!g� �.����^o�BF!)E�2 8��f mV>qM���E:���Iga,a�"�"!�'yE�&� /-olu� �B� f�Eq�a )!�g�Q����4^��!�maxv/4?n �*�&-�`@a)N80 2t\,�, p p r e s =f kG k �&y {p t i cE�(��< t!�G��:�b�)�6��74% to K ×sub� s Gk!so yM�id�Myf�X f�A��J7, K�  W�H caC<.�-t6=1JJ*A��R) ��&h6� +���/ adop�$ e8*�7��6t�[� 2�!�o� =��p sR�7I��Jm_.O.+t��t�|!u4n ."map: pp6�Qu6�6s��A(}�.q.9�isO 3Q� YR, Y�!��m.mq "�hi&��'��!��M��a’�%ف' !2�q9�[�� aligrAa)a "[6ib9��b�b��No���=� s :�, }waxm �o �H)m�J�a&pu���"1���M !G$�I���moyQ barrܔ rtex�eQa� L"{3� 5�:likBj 9�%�� �.+EAG:}i%9#;�"� D+~- s 11��A��"v#�Xof iU30�(233 μm3 of��!�ma��Ono:K"/�gK+~#�A�m$R�by ver f.s�-{Nset(�-a.�en,en` a+;*J$�2��oz� r ��A�N+95DN.��%�e�an5�N![��[�.6�$ �-%B�qAadJ^�N)a�" @ | u�T�s 7�8 lis 6eFh0!�� ngF=!=K5=u�ĥ��aN7]� eV:� ;l�S�N yg�M"� $�� i ��I�"���=os1A�W��e#bsFc��gFP M�G&@e�d�n� 5vgF�-�s�hF�hF . An+->*Ks&>4&�"����nyo %�AU%Ka��-! be89�Ec��NhXM5$c*���d�cp!��i_!d>�h���`me ,��,*tE��Z-=�'9 �HE_�sl�e��!5.I>�itu.1��<q"!ln�*pto�h [37]� �%I� -% =.��as6�j%����%�nd6 pav)5zof�!cr�iB�fiG#. �t*�C�!J)�,�F undeB#&�B�!�t����n�;�eޕ�*0IL�ol�5�)�&�dA�I���.0#��({!lCr;i!}�p&`>}��(have long b�een hypothesized to underlie a wide variety of mental and neurological disorders [38] [39] [40] [41] [42] [43] [44] . Quantification of synapse populations , in human postmortem|`biopsy specimens , [45] ,isala�to largeba�set~cur!.ly be!l gene�id . C�conjug�s�}a�seq�R;�b%5to . r�ali �Q@subjec�nf our�l � .҇Zinc�� vi�trace el�M cruc� 1 zer c�%a�83 , 000 cellula%e��. S��f!Tly , z q&� ]key phys� R pr��esݢXnucleic acid metabolismegu���FA�, sig�otransdu �,� divi�C,� e-%� nervJ �rfu �w�� heala� apopto�D . Co-¡�V pair��of)homeosta0disrupts%5Api�jin"� humanAsh�  Mammalian d�K )K(eds via two!� amilAZni�(ZIP . Howev��hE aile!u� �a)Hof<2�" hichANrespon�"!�vesicE%�accum1�a secr� n i� 4breast milk du��lac�:!VsQ�ly unia. & !�lth��he ��v��up%�1�9(toem>on gradi�� cidic �les� b�sugges��,�{� � coj ��,ly establish�� Herein wea�e!Y�"% �:]!&d.&bo m �on� &��r�t , usA=QQal)n�q � at)�iavd��2 ton-c!8ed =� A[Her . Bafilomycin A1!y0fic inhibitor�0vacuolar-type1gATP  ( V- ) IHalk�se�., i�!MZnT2-dep�nt ��EJin�֍�E�!�2-)%0LysoTracker R� nd-pH� iAyw�r� show�!8 upon yE5� A�*� iEڡa>�h addi�Uexogen�e!�e �eEpHdw�-'w ,M umab� ueA�5�L1�; q% A�ly B� ehplna"� rol�N�axin��or� si�K��P �toT����r�[5!�Inf� excl�A 9fE�faEnu��bya�h!Aharbo*oss� �F m� �� �su�-� A neona �z A cy ( TNZD� � leadE@s�4M01�BR �(gDg . [6–12] ) . F�Mm�%�2���\n!Dha&� 1��]EA]Enorl�of'mo�m ry glA,[13�yAşvol�  [14 , 1%�Tak��,danaY �$��A� �F>��inf��EgM�6��"}!� apeuyTi�ahE���first.�by Palmi�et al�(in 1996 [16%nd>!esecon�E)aser!�b scribE�/lZa' . Un[ ZnT1M7is loc�dvb�� a membran��>+Z�witGy���Q*E�Tc�, h�Pere3���@� aUsX oxby)&B% riv!��X�*�  �8j��dh� 2V��"  unse��d=-��4to characterizHe 6��&� v5�A%n madet*:� (A1e�*�2� !�v�� �hes*mj .%�E�AFdAp�.� !!r,A%Ta.a a� ied�Ba�,��C�� � u�is I"n -E..0 �&Bit�laa6��] YiiP� b)�al�!�!S�� <� � &� dis���a 1:1: [17�WF2hOhana����z%IY'5��52c"VaB� [18]��a�i�)m%�*#�#[19�Si���. �7I � 2 ma�oI8p .` *�[5����&>Q�is�Uu&�e*�4T20�Thu �m� study��t�D " .B� bnd��its:�." a re�M g,� �*delin@�vm�perme)Apathway [-V�[21�U<m @re�(�Qc�derY!w�terminid�conn� h �bi�Q sitef nd2inward� out � ng (&A ic "�uAslumen*: )��xm�%a�6�%dex��Ju�evof �q).ed pKa��7 ti�a:re-a�)bve6 Q�(� Fig ��!E�1Afree-i�. O�&(��I >� a8y " scap�w6�uc0� A�e�!2:&2�t#!3 /nDMonte Carlo ( MC )�*)L surm���%���>����W����A�o�v�e�"y!s��A�A_�g�YW-�2fafxt�� - �f^5"�S ��(FluoZin3-AMa-��-s�� &Y�b� lA]i�MCF-7�E�"}E�upH*�BQa� to e� t%l� actU�:�A�F7�i�tray�pH "N�P*".�!��Qi�M!��,�wtediE�A��BVUW�be 2:1� ����60highli�"asynergi5strength!, comb eAs!+}�"echniq�KEYe�]�Q��i������!�oa#a�%>w��eŷ.� � d� 5er�� mole�x�. T~8!$�.siq����>���� IF )�BO� H ���"p u��4�� m~@PDB IDs 3H90 ( x-lat ��9Å��"2�!1 5VRF��ryo-EM04 . 1>03�!e]as temp �"A"OFRIF:�:�� S1 Text%L,a brief summ�"� ga $!oor�!^I�.� homodimer�inser���'(30 Å-thick�t grid e)� )!�q�[2nW��1 mmd�>rei�!a>|� bysd ��O�i��9�Mi�de�un�#� ��Qv�e �xim��( a�$-$)5 a diic ��ε = 8%~!����� vergZA%achieby ruZ&��(ar dynamics� Y�[&�*�zA�I��!4 �&|(6 [2,e.=��Y'AM��(tAe-PaDe2vE�.�oiw�`M. ]�B})o�F>,. d"gaba�,!Tc�11c��Q?.�!��U8 �ofiV��M�j$  � keptU�o�-Q�aid���T�: W2)��A)m ��e�S! u�M��ece X� H &�n E � a� BID:��`j+gpAm?re5<1 1'U �)�^hm:i1�#�:L'�5 ,:�a�$-D�Gly�A , 278��t s��%ȁ5g�b�+Y": ( i )� solv�A�ionA*5�(��Qn 2cosx bDB@a�Y5�P bulk��ri,"!s�Y �%v!b_ P zer��) ;�� �of � �MN)�Hi&(Asp )Acq *� �&� jk? !{�erpo�("�B( Coulc�vRm�%Ma]"(*eta��ir8� � v V�of 80%Y!� ( ivM>b�s2qB�G! U .��2SeeF���a�"�seta��sN�������ed��a 5&� �/ty arr� ( a tetrahed�� �x.�ligand-f�-theK[2P ӑM� � ��m�,8 � !�>�a-ɘp� �MC�A�m�<i('�! plif/{�p� w+ret"� ��pre-des�)!p�6I�"�dw�:b`j2��a flat&E3bt_%e�&��!en�c.-M�&1"tA���6YA�ar�oM0A<./e�%�!�7 q� �A� �0m� 0( <1 kcal/molz$/���� inpu=a(�-Ebsuc�fu�!��i�H,�[3�3�8�.��run� 1010s!�ex!��A<e�! 400K A� 425KGch6M�2×T . It�uld��t�:e�6mdo(reflect����Q9ingly"�a6at!hJM,7�2a�".8�:AiimR#MCAc"� (� "/9ly� r!#E�y*�@ s&~�.�_#��,3 unfo�7|occur��wiv-t[Onn,�5-A��-�2�it�a�2son��amounh time��7weeksUֵ�Y�5lib�% %��"^2�m �4+F3-� -�#)NArAN�numbe�,zc��A7&� �ɒuas[x�;sourcmdi���2n�!vb%}5Hin https://github .�,/ralhadeff/c)� al-bf1 y/tree/ma� /re�;-�r-�-����es��*�$�s6$rI��39� or��%.(�ab]e -!�ec�O/�fne���!�"�� �>flux (a��S26 flowI�&�!����9itee$p�a b*LV2u| \6�-Va|uO�*cya9EG.:q/. al��%^u�!�5a y� ,_,�8 by 2aJecaV(D� cyclW�8s 2^," )IF!��bac�ItPDNA dye Hoechst 333425)% "�.�.′ , -7 kig(2-pyridinyl�y��-�j(2-ethanedia�!�)�. urch??j $Sigma-Aldr�B8Israel ( Rehovo� �l�#hme6vi��.Q�1=e2�A >�0DND-99ɷ obtaa"�Thermo Fc2r S�*tI& ( Waltha'5MA�Z�5 sulf���6KMerck�,osh-Ha’ayiA�b"'FOEnzo Biov 0 , Inc . ( Fab gdal� NY ��1 YFP � Ruby �g��� a.�� "9 , 33!9&�1F�AddPz/ id #70113�� a�&�asRA ns/mA(8ns ± S . D . S�]+abomparis"Q &d�S�/ nt’s t-"�rism G�;4 Pad , Berkele�&C!�` = gn!�AN*��2"4�<p<0 . 05��9E/at�'s{#�in&�'\s%�'. Ht6;!�--cfrE�� grow� �T-�  �A�=�@�K[�>�!��i% cam2, lab":5aB-Y U:v�.��2 de�Aed�ely�ta�s *�!�n ��veE� ����2I/tr!>D8s " ���empty E��+i!�!Medd �slevD�6S#�E � he3��5-pv$4��9�H"|%a%��"~ 2�, 18 hr"�#an�� �%Nincube�E13i37owth a um��1�in�B�b*~ �� �*( 11F:nd>���u1 μM�AME�ad�^��Aux�45"b� y douy&% wash)�PBS rypsin�ilcol� �U"'>i�Ha BD FACS Aria IIIuGcyt�4E-CelAt%9D�Fe0Zeiss LSM-710!f. m&u?5gin)*.�-j*J `W: . Atm�3a8"�+e";#m��� ��10*�; -`�in��OQ7C&X%Aj.���!F�YXBO,:�}�75E$ZnSO4 ,`6supD�>5AT��!�E��q.)+a�AO>'q���ceq�IBu M.ry ��dv=%*calj$�A@s�& �Ere Cedb}.�� 5raF��5� ���2�ei�6}j�var?*F"9�Ae���1�00�`.�9�= h!HE��E-.:&� ��Dr:ND%i��!�2���ůq9�-׶�aaz��..u�2�Ou�nd!>&� N<~i�B% �~%J. A ma� �Iof ×63^(r@er�#oilE�Q!. E�I�{wavel/)�g: 405 nmE�H2 , 488��or:�I�543+�-tagg�+� {s . In&hf�3�� al eA�t���a-�,�/en 6~Z@w;q d� �<�42�<#� �.pH� he a�Lt6v1Z@V/�s* w�Gde��(-ref�7%}b� |#�en�3iA�C%4!�of&�,.y�6�  x t�  2��� : 92= . To,0@"is en� "dwVN�:y=t!bL-ors.a'.0�1=lOb� �4*5Ain.��L$lysosomes;� ( Try�@�&s����� d toR�-6I�x> of GFPI�c#�IL�I�%�a�U �7�fE6A}. tag �3���W�1; �74, hm�#��i9l�" +2i#n �dos,C��inE.H27(g35s!` ��8y�N6BATh!p�ir�Nat����J �ome��neI��,m�*%� �.���*Wgn 2�44]a�0 �!�2�2 F=�e>�Cin2+ Nw6�6�-V6!Vb�=B��+lay �?MP�E2�inFN�=�n).� HeLa [184-'2}!!9f�a�55�co-��)�6oq0&��al�*"$ ��:ti�Im]&;/� �Af6> y pi"�RW.�36±15%�.���M6� ( S5e+�.& asS&wh�Q�� 2�I�( u��4E�ed2u]��zAI�(to�8 ��pHM�5�)a�t�'=�"7 2��.v�#�!�aK�wd%2��W��(rolM�)"|eaB�2 �SDah. 5–5� ��6A�6��I&�-&�$n In-a�r!X2)AZv*�A41$R8didj���J��� *�G2�N�;HV�-���%0��: ≥�%��2��^�N.�!8W a�Oma�B#-��8h7terSS��, �:�> �nuf�=]G1|R���O*&e��k �BI�2���AV:�of ��,� Q)�; �b$�6!�>_r�3B�"�,9C:�`!� �IrtN�~2x%�i]7�W�Vx�XN�Zzf| ,���.IK:�,>&yXm�b�?PU�Y:�� o!�38�T�Q��d&O,)�"v Z�-��tmF�"�Jq@ we observw ��  !}zby>Z1U&fKN"�Y%>3_Dexd) ��6�NM&�����Iv�4�, �pt�t!�s# � b� "�!�IC E�:�..?R}#�A�r`�S��&2�!QN$�J�Jeue�V% �\O-8��)*WY� ��~��$1/E� $ &Fa�yi����uAFKay 6i} 1;�a%`K%��?����by�?2F�3�O�$t3ofF< !�-"�Q���,%Jebsi�E�W;&2�ngmex�R.a�^Z36xv,�1Lly �%6ZBE8��_- D� �a� ])K!�� *�of �E^B!6a!�. A<u�!�=�,6� ~$��A�ur* ovok2�aT��IL�i�`c6�U.}Wj.} ,�rupQ! 3pHPU�b�Xarmaco�a�IMR��Mv�>�"R-o6�Da�S �i^L2�U%�a�b/ith�b;S&7S "@A>I6E�1V5J,E a3c)uY5�81PE�S& sol�m"�HR�. m-.%�w�<Hx6M"�'&�'�;is��ɫ&�I"�'5;sub.Me �!@V�nd ell-"�H�(o&�c�?�?I� SLC�er"�Ja:PT! -�&EBassoURF>[�J1%RE.V6�18&sK� ly�b���Ct �1�q &aV!examp�%wsto]<�_ono# !��d�Zse%�s&dop  , hist adren�[por<�%��}r6�( VMATw*1�� 2 [4j74j7H�,$1� LC18N��:) 2 )-�l*�A�)�s�Y�2�Z' neur?&i�e�b;0�y F Y/�U`A:ob4HO!MQ. 8.).B)�s��(tmvq�)8"=NY.PiF?/�wi*D%Yhem�T inersP�x!�&�VDU!�n2�tok���:)k4the�Xn� be au�Pd�8B.Uu�Qo� bi�Yic E�s &F��j<�$l>G^,~�cap *of"go!�arC enzy�=c��:re�&�OiEr0e�A�cox�an"%8*S�ec_�@F ve oxygen�es [4�'Vi- :w� ��af� !]Z�gof4kinson�e�[[4�)5�3�1Em�� acetylcho�>.�a�AchT/in3 )A-"s�������^��g/n)�э6tZ9A� � rgic] Mfa�q�G la&�mo%�.�Q�"�Y�'6�.?.d [��S� "NC9=�8A��L>E IAAT�@r9 GABA>(G'aka��32Aa�tCso jz={of gl^��g�V- � buty[@a� ( / ���s orH�Z��!�%�esuOEFR�C�2�eY�6 r����|8&vT[48 , 5P �J�E�j�JaE%���v<�^y�I3��-ECQ7.~2r� Qa /end*K�U"uN��-uco,&�;%B��klm�=�5ir�e�cir|e#NECbF3��:�W3W�E� "8uptakődpredomin*��"�b� `re�5or-m�d� oa7�([5'6F�G�-2 �by*so!3M a��!�re�Z�s, �3!b[� LkA��=1��Ga� !�\yt� E�� 5�h!���k6d�]r]l)er DMy/Nramp2�1o[5�.In�7er!D.�oc ap�g2;3e�7 ep�'l� QZkU[%�]X�fp !~��?W"al>� �WD7aAA�ll�VA(�i�8ue Q*��!�1 6me� ���Q5b��exi/ ,%�� A�%��"ng@%� �A��$"� manner [5v*5�K.�6�Efo�Lz�ofI�Ap0!!S��UD 2"( PCF�46� =�!K~� ]�P�A#k�� 9�J�6�ZW F� ѿ�_as��eR;�vi� ��,nutri.8mam�nto��frzra�ou%� ߵ��j�in�(5�>A�|=O�I�J4o� PvkFpac�&;(U6ZMaone��:�9h>1��T a�2 [�t� H.�1 of ~OE 5 un$Wb*h8.�9n$��!��b!�I�w�:�' a ~100�* �^p'�;b� JB�bw svJas��nm� nerg�': ;H�s�6�' %^�� � o ΅n �n� '-58iL�p�h�;,�60-�[�n�B1M*���*�!7�!�:��^�Kua y���Gg�� voltage �� m !�Q4Z(. Sup�u�|� >��C�NshE�'i�\a�tru�a1<gl"�@�Afi2e�E�" A�] �)�gA �#aSfavor �gep �;�B8Ia!��]:0�)X\xB:is +20a�+40mV� �lu��!e~@ind*�=��F?ove.�g#!�!7�mt��% E=�o%�A952�/���!�yl&hUf�V� 2&6ki�S%�0}2n(in p*r>$] Y.(!�0%�y��ke�� �"y f!�ٸ-9�2]%ono(%� m6Nd"�7 A�`erYa-H!$.��}surpri�%�J�dJw1�e��8(Js�q,I�`x�7E >%!�&kNA�!��'"�#WrEI�"+ _�Q ion-�N� figu*�;o�! A"s�Bo!#cor, o�b,� � CeM�  6��A�B�J�"�)|Ub~���aEI�q� �^*� w�na.a�!6�of�^I�gh�axT  F� e7Cl�5)&Uo�F:X6Y^J|"��2~&,c, *� a>�a�Z5c%A����yi"{`Ph��JIEaE�u�2sk [5�A"�#"S��2��a�)p�SchG3�v��ch)9AUd�rA�~B�R( -467&rJ�%,U 2+ ) [60]�"] u!BGqz.bA�m�q�b�?�q��Azein’s.wh.wsub=s�ldu knv�Viss*G�5de{5z e�=R� m�(�#X>�X&�ZmUX]MM + d SI v!tV#��&cfg^sZ�W� �X R A{�2&�T�verify �2�H�Figs 3,4�Q!MCi8A$,/�A��}n�2b�Zdif"�W�P_S1–S4 g)gf�Zv�d�*p�B+6�6.��l}5 t te"mb��!�Őat :� �M���$!:�92q�I�T�oi eq lea�}m�!qXX}E6���"%uI#Fig�Yaaiza�snef�ey��'e�( manu%@ adju�Q��� pcc�JU8Y�%�a|��xpl�'�,Aqvis�ur�!��36�n.w �a[�E-M�is\� $ "˅i�.�YA���2��+*�aXU�o�i|}�.!�s &]�,"p"0�L X� E&�R�7e f�P߅x-R% �.<aT8�r� eb [ya�� g~e"_R/ . shif��!�A�!tqe#o�TE�,�soa th . Now� we��� Q  0�!��4�N t�/`�Jt�z!.'Ҁg" *%0�6hencoura� EA�a�%!$�+T8�)}D~��U-9K�)�%F)�KP�S!cx<ex�) bat-!X.2��*Y �N�"]D !��d��r Y]�icR�("�`!' �!�qI�%�qq2zg��:��"�R��M+1�%�� `2�promo�2behavm_ ‘seesaw�T2W��oR��4rkC^c.iTV9ynnu+)��6� .@ �"�e���%��i`�'z 3/ al eaQ wa�B�D!��. Pr2I6�"3sl�Ad!�a*�6a fS*�n݄^�regarej��>$s .�aRep {�k� egr���&P)1�en��%�)� �P*on҃�"check��&} phosphory�a@5�W. 14-3-3%i��a|s�[_.:�^�g�ʼn�z}p?)s}9"?D 3Tr=ops�ExoD�P�+ExoOtz$�=�l _.> fork".�de�  y��+�6owo|yF�Iviv�B"��Xnof �,� in `A�l��nY|)V–! �: !fai�\9  Mec1&B�hyper.x!�o"Ke)2:ss�Ug|xa�)5)) �4li�%DOg#"��Lis��per+)=f8�A�exacerwPre �)�!�Mor����bi-E n~a� �A�w3��)KAI��/� g!!Ih limi��EUot�d#�!I�Z��>dw_l �rolP�,>��u� %�!r6j%n�'n t �Z ���B�,Mu�J rest� j_$jto%D. qK !]le! sY sA rS,Fa�"o p6�%�ich����]Tk� &��, �� rearc�Ɖ�_��T[�)T2� � r������ya9�$rveil�&�,;o�_��m*�!�Z�[2]�� coo���1(� ��a�� prYb!!dre>��8e��st�:.Ow'rsh nBsyn�ԉ�.e:STg�YC�T�y~9 *U>�[z(A� wQ��Yb�(�� awa[ �-,iM��7֎�*Z�a�,&{P$�u e-tuN_,%} void�+�u��!P��A�i�% �M�[�mei� Rad23 3air�[T�V1�x'A(5�Zenx�Lduplex ��: R/origi�y1"�&5 Schizosac�{�%ombe [6I}�w"fKs [�'�i�e*�mBal�Mvp%}���3mismatch#,�kBpu� =6io/A�mit rA�biaw $��Un5ndi�C[8]–[+�. S2�ce7'siaɟA-� dundO,e]!�7�=�Okazaki�Fg�FG !�r�#�<�S8%>!�"�b ru��� �ed2M��e�reQ c+#j� � versMuEymYEXO�iv� aG��]�8ost�:j ag���~,)ATRj�i�ai�ubiqu��&� du��1on�$.'ځ;ɹ[14A�[:�~ ATMj~ap��:A z��y1��wlog�6Fr�Ana ��jx�/sa %�q�cld telnesI��[` oIud�  A1�%�"�!$;* ]Oi-��+ad5B�f�mec�)��nt� $ ag+�i!���r��or irE�$]]�!���6TF�{�. A�at: � �gY�rPa�aadamag� Eukary� �� Vda�� %W�G�>�=��!�dwmodU|��ɓva E7�a�+*�,�/�;�< 4�*K#/A�/&a�&�����-����iso�4 >� ��Y*" �^ru�J�|͘.�-b �s�f-|m��� flexӚagG�hłoA r��mAU5L� lD�r%��%L� dapt��opep s [20�_�V6fe.�hhth�/I�SGgs Z� sā-~�f�tٿ�|,�z> ����!�E��u!�.H���c=R�,Mcm�bOrc2 [�{AP]�Q.Ux,B�a�da�EH2 � ,�c����p6� bil�Nu*6 >gen�j�nd<' !{ad�`!�*� Mf�}53 [27]]�'-�6� feraalade Esa�; Rpd3Fvpertu e�[s"� � eHx�EDn�o�.�y4�R��{:� :�i"<6� syI� "1B�1O!�� 2 )"��I��:y'e> ��� J �#"��� %#c4W~��On���- >��2a%��� ��s�]=!P*���v� drQe���) ~Mx�!� >P y R��*�6|F�g#iG.FI2s�.�c2��ӏu^�E�xŚng%� ��Nom�|�(���/&�  . ToY|jrAhR�}kqE�4two-hybrid scr��w�GAL4-b� f�%���%��e\6bll-N%th jor ΔN-v(36$�846[ � lack��#tird3 talyb do�� �A���-ee�0� h:%�j ACn b*xxlxpXm �a blood�ti�������Fe>����est h� 6S{� %β-�md+.6|tha� ε�ζ-/}�#c�&�2A�l hd%O��AYMIRmMg�, MLHT�� ������ X�I���I�$6. $����Bo�_Si��precipЦ��e"�#a�G�x!�Oab� �E-dZ z w.6@6ly� nH$ed HEK-293/r-an Omni�\U0P S��>�-C1&� za pan-M�(bod�͕AyDat �yj 5-���`&b� a�r5(q911{M6�z:�."�K)C!Xy/ u.���.edz . *sLsp�"� K��az�0"/,Bmh��Bmh, I�1eOQ�.N%^����N3�B-C-� inal Myc-�k a HA!� ��ar%:�us%- BMH1/BMH2 �"�!. Iz�.��um!���B%or[I a HU��k:9�B� "iO�A�- Bmh/x1afby�k We�on���'9 ~`o1-MycN�-;���Uor��JedqXa��)#SDS-PAGE%�den� d/�E&�\(PVDF . Prob��A�"/%purr GST-%,�c�ba�.�:�"<5A%�6 iC�ANHU:�5t���F)�D�%b�X��an v͖��ly hidd!n�$u���]��Z"�+�B�>b�6���� C;~wfiqS^�O� FaY aQ�+in�kt�%�aEC* !FJ5"s�%�!�^p��Edi��X٢)+0|`CO.is!݇!�FD#��HU$ j!��auM�ub&Omo�y�} aNMPtwo�e�|�GJ E`2�Timw� �n:$)�x2�f�YdB: ct b�s(2Δ,+lle�2��as�j EXC �de�|�(!8)a�E�Etel �R� ( UV+�,xqan|p��yMN��H"r-despieQe5IF) �b�/.� a�>�9�M��1�0E� �.I�r$Q'suh m�e�{0%&[i�� = :���v �vt_�*� �DA}�cla� .* a� rehe��&g "]�zu�I�ab��A��!?�/ts),�*� I++i� CD�of��k&\byVV�$ focuT H in*���)_A� -280 A�C2E�1b[)���]o %A�**1��R.4i` i���2a�! �.�!5QB�� ��toaKM��) ����H  c�~� !Un=W)/�6 136>G �� helix αE0A�62U[gh"�amiHS a�-m salt�)d�2���  bond4 !�fLnd�5I� |=|>/ �5.� !}A�xN�ntF�&K],�fE�%��e�-J���1C-�,%wl4ke&sh�n�� ��q&r�3y�-�s!{eJ�m!5` �LIi2�7 mF�OG e3��?-  bi.� gel+9ct��� ( 2D)�$eH�8�.�ARS30byis�$nA�'M�QQ3in�r1�!Es>!^ {OU loo!� :Da�e� M�"�XE0.���"� ( RI20̟�5a� O�stj� cl�� -60>r�9HU��`B)��� A�av/ at 9�r2 9Uz2�`, .pkͅm�mis�a/Evs pl�����Ddra.c� svM)�o!s�, m�!�6�^6<&��ef�$ � � *cl y"c�  "�.��kF��(��.�ofA3yI3 6is<r�#- U$%�.G,eU�=�1al7(!Q��>8��.��b Oyo'ha�,:�H��z�����-�i;��I� , (<� �tA]�G�~���4≥Qn)M�-T= HUB��� Vc1om[�u]sk��v5�� �-ac�# xDR��UiNS ~!CF""�; Fnt)\[��.��YWy�6o�Ad��1j, BA�B�&�! A�mAD$�Z�de �"�(Tretar�0 !�HU-5�p|=qC�2�Y4 ue r�;ng-  e<�.��XQ. I��\5�� !���B re2�VE�g�`�%e.rapid-KF E ���*Ysb��"t!��$�2� ��=3mn�-ll0a���%)����dr~ �>C���1U��!>� �3.Eer�"�0!�e,�y�'v&*`+!1�Z2�f�c �a[3�&7/���pA���:# �T�;�U�"�C�b�>��Tes>.f���!Z2���U�*2�o�QcI�o�D�!6he1�h��,��a��vd��I 3I�1� % �(J�is d�5�, inY)q��de$��.�1WFd5-!����:IF�%v) m%KE��'�El&�+]#�;a Awetg7&Ai_6�� �WFb�;�]cR*69*�-�<a>M#��F� �C3�Not��eKQF%��� {-#s) Phos�"E[�X)e;�1:�:!�l�peA� .\��:�5�veces�fF�:3� 3��N*@BH >�"{ .]"�6� R�!�&1^V.!uqB�wg�F� 2�n�B5�S�Zi/�� -�%;��s�M:YA�djJi6�f3B , 9* + M&�-Wq��F�E��y)HU���DEl�SI�� a���]l;mE1�d2� >��!fj6�&� . D"� z.Qa6H IIB�g8af9����)��-*����/pa*�� �'� :?'QV,�c.p�q.�dm;. �5�.,����V�'���:� 7)%&p2hNN��Nl���h1%�CEW>�#a�� �$ plat����!HBU>�& ";!gt��� oX�oA�>;&�/ Bmh-~WEBm�{� unatA���+�e%�-&�o��VTCA� .� ) -�Tit֎n$N�Z2��inm�� ba-j�B�(N�ܝ�"� �n�,1"�N!�2�͞d&�K N�I  oveC�l t�AM�υo�Fo!�!�ESJ�\t"�+>�UrD;R5*�1iZ�CA�Nu 1�>��nEU�`i�>�ha<e�yn��6=ed}��:�1"�]�1C(s�,�O�� ���>�fDc�e�;5,fine archite�(��> 4 nsw�!�5J�Dsynj2��!e� in Gt+D�i�1 hYPD�Y6؄\�2 M���Q[�6�Z�4( Cé�H�� ���B. FWJ���uty�e��ezK0rb+iKBH6a&H>&*�%behin%B��4� .��t2Dat�-�`m��50�u� �5�aMDu=ohbre.��j4� >�" aw%!�"�*N 2 6�E<p����j!�� _Ž�V3A� 1z "{@2�!�xo1ΔM�>��aT�qmF%�OH\EM"�d�Etri�O�ce:�xD9iH� 8"+"t*%N��sb��7( >a 5 KbF%!cl��rM�b�!*/tZ��Af" ���5]70*70h���ed�����icks/Ɣ� ms �*=ev��EM�)|! HU [3�1K$u0,�E�1* �vir!f��9!!unu^<�a�?en)e�ab`-e�)B���#"�Qz9!n�H&56�m��XF�& -pro�}X�!����Oi-�) �s#$�,�Yyc��A.�JV� � ��ų&�6m�3~Sntinu�#��`.*v"� ,�(� o!"M5 � ing/�'i/�/��r-��&e�/ }���5-36�<o�(�����{wo�=[#� �d�6Q���V! ceiv�': �]-polym�-)�&�!*/deoxy* ��s�j�9�F�p6�us ra0U.�w%e5 6�"=byI�&N &�� �}E��$>� i]be���+a c&�no bia�0e�-e e�EL�Kvtlag%���-�dn�&j �'.�7[35] -:c�" occa�/u/| r�Xh�it!�=����e�m�e�CS� 0��A�Eub���*� �� ic� !D-or: �u�&��pD� ����l��N u L6�#rP�Y"`<)(E����M��:�A��+=�>Xn < �2�dZbei�>o�99=� �~�ab��U�!��v@��|�Esu����s�HU��T!�/2+QIv2� � by αE� "� �46� gndc 0"� U.a��5B%u�L&b��'J�N >92&�$reg�Ch"�>III)�A�aiN"�!l7e�E e� ARS305 [3��;ig��pA@���~y(tkt � !� &u��d#�hrs< l .�� �iBA�N�,>I A�����kinI4�% efi� uPu sl�ly�-er�e}c{&�)�ons�I� bub�6arcAw3a"M 5c P*c? 8I��iG-m*�Y9�%A ( ∼� Elef� <)�[dM�2–3P&WI��%�pea��&� ��� ∼��^ M!y\�6Da=Zr+� �%}-1��� amR�.Qf�2 hQ&��>�6�0&9+� �a*� A����Q�a_!�>|HUoI Ydis ��F�,u]a�inv��dja�=&�B�WaB� A BNr_�basl{ M�ofQ"2J�es�!)n�)�� �)�&" /,!f"6[� ons: a )a9�<e*f1"r8d"�I�dǠ6�: in S-� $�n�U��ŬA�2�Ye�er�? AX7w�6i��UM ��� ( 18%1A��&kB`�E�Pouq��4r2%i�; c}cc�C�&+�g:F7 YE�alF� �>r�CP�O�!� N6�����keu �"�@ ,"�q-�� �]��l �jp� AZk"~) br �I0$*� I�^ �6��=&K�+V &?"� i"h��!n * f"�=[u:�ڏAaB�'%N@:Rm��? so>�/�)�H�":`sE0,�u B5A?�-M�i( @ -K22W� l_m�КF�s~ ms�o>�. BO�A0d� �,& ,�3(1���i�5un��Hed��6Js��+$ ��Yc!#rב>5/� ��Fc� ,��%- �_%��]CorZ�Ɔp:�,E �&�(� �&R�&��> �S4C , S4��S4H-c drop\��-����2sy�U c) e�&�!�ES��2%st%��G surv�k . x#����f Fi�!�&�#m�>�;��,genuineb@R~ąA ` ���/al��"�0�z+HU-z^A��M�l">em=Bj�'�e=.�-� B�'����0i�-M�%�>~�C�VJh"}"�G�i#99�ofe�(�cuY�"�P/��v���� b� � l �1 b� 6�[Y�4G ��#w"�3��c h)�'g(:&*"zB�i ?�!6�2�A�i�x.�H;�Hup�%e� .�n�Xf �!~B7 �M�>���b "i#�}� @��`r>e *�0 r����I��(��4uH�th�>��Ş%�un �,�a�aPC ��PJRb|EC�}g�Q��49�J�!AMFkC̙��[37�3[3�FgS���'�55��o�e � �=-C)�u}\~��4  ogy� *�re$B�,az/;D�{"� a�p��(�&g '7.9�/r/}4��envisagtq%i� -j.�do�iclamp�he%TH@�!}B1R- �!kiX �!� its/Ia�.*�%>��5S��[o ,�� c �d�o=� �����>��!�c� o�eS @s"� l� oF<X5esIur%'a&�R.>a���Q!>�5� �0J�m�Ms] KM �c�. C ees �]hea ?'|�b!�!(�.�5er$�sQ�U-.�GG�an�buAQ$"* Z eluc!�!p-�>�D���Y-0mo�m�M>�i;�J�,bolu � M@*EAh : goM�lyclon�H ti-O�?X�( Mٕsc-499E anta Cruzl�t�!-L�`; rabb!�:Ppa"}I( SA-48�KBio�;J�ono.�H 12CA"3�� �7= ( 9E>�ΖiS( aa0d giftQC�antoc��<9Gal��, I].ndrmp�F9a�.�edq�h/6k8�� oianzlMilan.�^�O4> -�9��1��X B YLL1090.�8  KE17�U%t:> DMP4644/4!�A��� Long� , unp�� ������ofN|�B�F!�s �*8�Aj�Fa_�\|gz2F:�hu��e"GFXFmRN�.� of Ia�4tagljar , Toro�z, Canad�t^�41I�I�THY AP4���r1x.ZBof-�[!�:�t1)*N(�1[4�To &%��W* opt��ed "(sCD( 50 µMrea�P Hemplo�2�  .4B*�9�E(wto nitllu�7( ��ba)NCP ,�%45 µmINz�X$Machery-Nav),(nd�oom.�W��� tJamz�g�200 m�.2fA��Ÿ!]Yo)�"�B�,2Unt&�B[Ҝ�%e,J>�)�a�2-;i.#G 293T %S��kly�2v"�0M)e5 E��:P�/a]�=Bio���!� Assay R-�( fNbEof*8Gor� � P[F5 m� �_�&�*wa�s�����9�e %$2��.�'>pa FAY�~$re-J)�ic�ldh7��L( 25 mM Tris-HCl pH l�k�1NaC�w EGTA�3NaF  orthov�3Z�4#p-Na-Phenyl-a�ph ( pNPP�%�%1%�� X-10�bPMSc� �)w�VU�Q cock���;�� )%�5 D !h>;Q�109�Y�9�):AI*� H�1C8lI"�,!�%�1 CTAB�BodE�D="L=�� 3^�e:7^e2$&�7[��.�� � �^.�l.�o��Tlasmacyt�Zdendri�LA�s!�Dҙ�P)E�cy virus�e�` HIV-lLiݫ! a��Y4 eAucBRl cleao\ 53s e��!�g +p"�*�O>At �2z\Zj)I rfe�( IFN-�pndus), He-��i^&�Dof � leukocy�&� CD4 ���I��.R�YF�-�#E�s i!��ll lymph!��N"%�)6i�&�4EJ �FL�eB%�9~� �1%�P)0-stim�ed{A-ISG?iab��dOacuteB�e,�Oa�N�"atE08ic CCR5/CXCR4-d�oi@ic Gc�ndard+-2 � �E ra�!r-viYq �, _{ aX�i�z�up-�)�!c ��d�bw>,,waZTt�-d��g �O6�-�� ��%�,fzD���.10.�I a��DCNB_�y2 %�� socib %[e�} �.E. S"�|�0 #`A)E� �E� e�sllA�q�qQ':&-�� ,%;=2�GuiQpd��wp5�"%��J}A&a: #)��(v��RdeI ��KjI�d4!��4�'ngE�!5"MA{QJ�i��X�* #�%�6H% se f�ngsq pDq!�^iVblock��#3"V#T� teKj���(� ��N*~n-^=R��\E|� /���IevB=�ret���,j. F%��FH1by���4=��y&VХ�}z!`.RRd,�c,%�U�re^r�@)/���d�,���of Af�n�G�V�dsooW� ngab!.�"# no �.��B6bFa�aL ` elf-�,a�%���t1YqM!�clE�5I6r.bsa���!�)�i�6�f,�d,Rd%&�8fp_�q��"To�J�r���VLR\89zdor TLR7�c�8ands lead to AI�DS-like immune dysregulation , correlated with 'activ $dand lymphoid organ destrucC�. In SIV-infected African green monkeys , treatment j�[lipopolysaccharide ( LPS ) results in CD4+ T-cell loss [9] . Finally , anti-inflammatory tre.hhchloroquine [10] or hydroxy. in combin �w! \Dvirals [11] inhibi�)M=& in HIV-1 5patientsJe elev%sC� � c\. The mechanism by which2^!�leads to1�.�s not fu!"elucidn[2!;Severalds have b!�Lproposed , including)xXof gut tissue integrityE microbial@4ducts transloc)N[12%x$persistent*�Hof IFN-I [13] , [14�ustained pr\2isB�1~ducedJA�diseaseJgressK bothn� [15]=$pathogenicA�9�I� mode%�6 �7 8�Although �UG �repli-),in vitro [19A4the high level@ :Uc-�>�E�, control but)predia�e!y �N[20�[21�)�ia�)bdurAacute ph!Wof=!\in)_=;!� non-(hosts . HowA��*heqn L!��led~nonI]^SI1��,aDle%N06%�F)!AIDS d!�op�[M/22)s 3] [AI(. Plasmacyt�~ dendritic�2$( pDC ) ar �major-:i.!��^2eU TheyAferentia�#xpa TLR7� TLR9!�!�8endosome , sensQIWRNA-DNA��peETly19. UpoAفws>$other stim͔�0 pDCs �4e large amountAcI�!Gi.�!# kine6JiE�still�clear if c68source c-�I�or5�i3� [25!��!1rolE!��r}�or Npm�well def��.Bm�Y1.ed�5� NF-R��(Apoptosis-IaE!�Lig�,( TRAIL ) [2��2��2��6�y�ofͰ-AR deatha* M �g�remainq�v��al [29�MOn%*)�h�,5!� also!/orted��be decr��d%efun�E�impaia�in�iph��blood�.��ndividu��3��31!�[3i|33�� decl5՟}Sapabil�oEL!�>�op� unisa�Y0��� CD4 -LcA�s �4 �5 �se-s� $light that%6may play! ortantccomplexE���2 ��!x��o�esie?umanized��e�� plan!A h! <esA�A.N��)�studyB�[36�IIrecimproved i � ouse�e,BGa,be establish�� inoc�Wng thro�0intraperitoneA�3I�38!tvenou!���H!e��c m� 7!� is r�s��>�� �numbers Vtch>con� e?mobserb from2�ed�> � ,2� �&�a�ond 4,%To�Hqї%R%&R�\J� vo֡� veloa�a� oclonal. body�� ific��Veffic�#E�es6�a� 2j>A{�* 0us we were ab� o Lacteriz�����J�2$� � sA->S . WeQ $previously:9�a��in ;i! �ANj�c:�.�)�A�e !ReAz� (CCR5/CXCR4 �3-tropic�$R3A strain2�.�9^F�0( Figure 1A )�ssoci�e#� &|�ISG"fonCB& �'@HLA-DR+CD38+ CD8 � s5D xnd!�9�E ) . AE�.�џ!1A�� a5�Atotal�)�leukocyA�waVP bFF7$, as measu�by�r bE� cZ�_�� �CD45+.�.z�.&F�shown)�q9�%�(JRCSF below, imila� 9�,ige.a�9z�m)Ue�5� �y 5�S1A–)�q�6�� 0frequency did� qge6�!�A��m(D���JR-�*� per�age%�� � sign�n� alte!�( data !%pAzT��,e�%� �& � vides a rZnt!�v��� foc udy e� ! ��!�J.� order� de at�f2l ��,��& �sc?� M�ApDC-re� >{ieA�mAbnd id�fiFnŠ<-BDCA2 ( CD303 )-( 15B�kcould6�I�e)�����. After`inj#ov!xE�2& ed\�� 2� U�2�7�>�"�.:, EA0 T , B , myelNWXm!]��(\macrophage�mreE�perturbV !>!u|Ce�H�� S2&S!o.�tes� B�ear� Ra{M)4wv!Cedr^isotypeb ��� into �i/�-$on -5 , -3<0-1 days befor\� k[ thenm� em����( a� yU�icB'1�%� � 45] )�day 0!h~� �E��!c�o:�two m�tim�n �6^s post��( dpi�UWe found� A��[� I�G!>hof!"9!�U3A� en termVed�8��J��sting� ��&� � �)�t� blockI|� ��:�1P�i!rsup�ed.Uof dif subA^�Y����confirm�_t� b� al%� PCR��� addi���up-*�rSGs such��Mx1%�TRIM22�1�D(JFWe% ��@�qF�9�by!\-9\ prio���(w%!�)  a'U�Z���demonN �M� \c�a�*� ells�< v�FB �r. CJ� �@��d�), ^.���l�er)�� =;Q�y5�4e�A�a�ge�sma+ load%�inR 8d about 10-foldea�w!�e�24b�A , p<��01�Wj�ցa}_ex���t!�!� * 1 . S to%;�69�,(.PaZ�DQ�1H(-5),�b4B�!PBA�)�>dfurxy�i�splby 4histochemistry=:a� or f� cytome6 D&� of� p24A�te�ositive� t rɃ3 r�er 8in�ponse!`�>�,�t�V� ,to:� �2F.4�!�(�i�d bh F�E�E(6�USaJ�U�Ol[B�se�@suggeTaY A3jB-�absen��I[!$up6���� mark� � inQ�1�36�]��Mg: y�}" � *D�.�#Eas� "�. Despi�cṑV!\�F*A�B�ɰabsol� ��`Y�&Cm\���ar� those��E;U(5N. M�surprig7 CD8+�a� ll)'� B��par{ A�erTB�R�y.�K�th(�6\!&�E�X��K`5�W.�oD�Ti���@�� J5��of)`8]u�B����ly fus�E��!Q, Env � � ��xuv'.�RKa�t!� \! �qU $irect kill��,�E4ibA�to�"'I�-c9#a7y_.�G�!(J�!1�#2�V I{}���:�9�S�~V���"� .SnJ���!�BJ perfo� ^9 J<� ��.i&X eO 1�-8x11 weekp en� ! appl�t�q7 al 10 B9 W$6�D E� ���XUa.�&&A�m viremia9�6�zA�*�Ց iede�{)l����) ��6���u�6�QI: �� α2U�dBSE�F�(�70%&/ 6�Km�y2 rI& ��!�� 0u .�in��s- most�l� *� ? -�? hcg arra*� S5� uA^A���a  !>� 64|�])�q<)�AJ�Y�E��Q &ly��erUSmYU��D.\ � E�,�=�Z�gY5>M%��c�W ��ol�9�7* )NI2���.�!�:R� ���A��U'7A�:z >��hr� , ��o��J��.x�fJsam� ���0� i�2j5+m�5 -h^�&H ^: �&Aaof>s�8&7i�Accorz'N6'6�re=�6����s#F 'H �!���>�9:E&F(����*�*� �!�'�< mJm,^�,0P'i�&��� � E.6ant2s:P��/)YJy��&#)q(&u . �.CT� systemic �2 [�"4� �ha�en��)�� kNV$ PX)�\[4� �#Pn�A )Z&)*>W �>�� 2��� 0.�li:Q,rhesus��p%.�(4*�$1 �� �![5�#5� �� a\ �!���+6� , h"�(/ s unS&[5� 5)j5m'U�SaUE �<*�:I�h{� �#8�*# novel�-E�q!�}var�B��. ort a� iu��!j�! R�"�!6�q͡?Ih.��.� IW!O"� ��>!&t�L�:I�\�%F��o� ^.��st>�2W! �^�rescu"q��JZ{&�%�"�{ &�U�6�J�M�p�&��&%�ac"�)9�!F.�:!x�*o�#-{�.q/ @.�,� enha� `.R�promob%�"AzF�.�. SB@��� hamp�by�Eicult1isoq1ng suff#5 6PYdour ine(��ul�,exp��e�0..�mh�'�iJ�6RK)D6?Y*7a|��ZZ�#�. W�2d�Q +�AS!0 �)�.�F�m]&�� DY�. Our f'* ngs � �tB�or onlyM��+�Ȓ�NW ��� indepen� \���α=�:#ay��m- ^fF��\�Lof A� s�mDC�.-[55 ).!!��=!T^ati.*r.�ad?%{*nimal �+ct; 졘αnt,on�!>;'!!�!n!� alf! .� e[vo [5"�discrepa8"6-a,�� �a�� *� � 6k/antago),v%.�V�! IMm!�� 2�51 �N�sF�nMFprimaryn}A�b�5Ay pool)a�en"�+theiry(cursors lac%..�Erg-c��e�q[57AfH"� w2��y1�bo%,!gramat�(Q B� �a��1>A,�!��2! �:�W gA�h�^7��doe6bit �"recept��M�^�By�^cnee�bD exam�0H=�w!�appropr�'nga �!s avail� ��6**("�1, ( GALT )At"����YJv'. I52if-�~poi~27���l6�&� s%�*9ur� &� ,��i�%Q7!��2+A"uc��A�a� engulf3[5�1W�(us�|-��ef� ! !�9in��cur49&% w=3bat"�!!�]o� 6� C%?26&��;"=-recapit�/es 32� @)e���# &/i�NAZ:p*gradua$ ���Q)lR( ine%*z&t s [5�6�6�MultipleV�9&�(o acc2!��ic�R�"� )�. Bes(:9:,e�*AL@bystan�' *� ematopoie�2pr�F )A�un �1� mJ7" Iw_:>�� e hyper�0�x�)� o ��:��nh>#*A���K*8�R�� subs-*t �6 . Re0! admi��r�_ ��lv5�� o8�=i�peniaA� ш*!�6� nd B-b[���YC����trigg� proa6!�B�"prolife�ve�*)()�[6:<W2Z� )�!��o �.(.Q }��~�,i *�LN|�V��.&U!e"u<]Y JJ8Y6�M�Fj bya�ele!Ku4��atho :S-`"+#�M�2� 1 &ZS.r?!acaqu�)AC�2E�!i�9*g DV056 J;�h.a��.!�1E�]# ng memory!�^.�2�u N�Ax0-malaria drug2�?�sM�c EqX� [6zappear%�I�-s� e�-��.{6�q�%�2�I@v��&} r.� s��"�*�@%��fai-�6 'e2� bene=alq�"�" >[6�6{ TwK9*} �QMp !ω$[ab�u LCMVW�4)3a�"-�7%�>")f!z�$A{acme~;�of"� f[viaN IL-10-�%"A[6�6� ���iJ@�npl�+A��0"xI5=|�%�>�It" A�B� res �,A��*�?�)W"%� i��"� ,�5�29�$M9l�&9%n-H�>���W$a�betq.��ol�.�!�6� %ok6R� .�?�C��-?)=��&y�verc1� � utco�,��+N}inEZ��C rst ��m8�d �sTA,%!it&f Ec.D$( Li , G .2[��rs�T�=(B#er [.�=, [68�.b:��>J7Es,2$n�d=�"� E���Aå�I�N� >�.� Yof:H�D�5{8�3 d^I�a!�ah�Fa�6�v=eVFto�6&m�2�mP.bii�&HAART-�&{ Cre�=� ��H 7q<R��+it �6� :Z /n-��IFNα��n&R:!<ed(6P��&6�:� N�=.M�* &�#�)� "�G9�A&i��f!�e��] of�X��M�I�sea� Treg� /g:,>CS.� �Psh\5beX�&in fu�9��c fQ�� ){!a�o�51=�:"5�NHPbF Zi,s follo NIH� �B�( Adv} d Bios�=ce Re"%^Alamed�C&�&wA�$g�)0ha>9!�lO9e�!, deciEm rega�">�&� . InM!W� umaterdon�@s9RinT cas�u�5*�-goveru#m)r2>��d)2n�or o��.-�k �-\!5 ��i���tce*�pro�6��vieA|UnA0$sity's Off� fh)!�)lEI�g |deI1� �submis%~"!Utit%+c sub��@ _asld-JfedLE9R�@05 CFR 46 . 10J9N fr9215c ) ( e l ) MK��0 IRB� roval�Z=!wNorth Ca�4na at Chapel H�In �i�@A;CxXnd Use Committee ( IACU�%!C�?%�)� .%Ir1. AW. V.��conduc�,�T� �U�E�* houshc�$of laboratL ^�%A�&a�I���Y''s�L4ID: 11-103 . 0 Aea~< ޅ�e6acr����"E�B��,alb/C rag2-g0PC ( DKO<u9G$DKO-hu HSC� Nod-rag1-NRG )&ma�&� a�JF�A[KF. Brief� i� CD34Z(EK) ed�-16-m 20-B--�5._����Ti�Os Ddi 3��L�Z D Mediumanv5ge�<Fra�ick , M�(Ansuspen�Gd fi�>ي70 µmy �74iner ( BD Falc�<(Lincoln Par_NJ�(R�rifug�6t 150 ge*5 minjG"w6� i�K�Ki�l ( i . v .E� JY�) �� mockY(\ ���%�a�5h?25. A� B�Hg)��iD6�Q � gen-( ��F�=��/]i'��i�y;�L>�p�4 mg/kg�� IgI9)!',>e� RE ree�>���8A.xa_.vi�� bKe@n�@.PM�S�K1ǥ~until2| W�JY�a�*�4��� 1wpi�,)2� tw�y x�e�"�1 m)�gaE�a=i�i,��%�!0Q�surface"`:f�< teperme(�Oe�cytofix/ bu@$�*� (, cat#55471�;� �El�_u�G��y��m�−hu +�analy�����CD3�1�1�H12>E< by CyAn F� mach�Q( DakoI�$ITC-conjug��aa– g M( ��e:L24c�30760 �PE>@- >�<< HIT2-* 3035��, PE/Cy5b@4?RP4-T� }051 A7bA3A HIT3� @31| , PaTM blue�F UCHT�< F43g8��8.�8�9M1AP2�1?!�1@6H65? 6012� APC/C1a� nt9�45A H130B40ze( purcnX$ $Biolegend;f�caspase-9_C92-60 F! 51-68655XA�� :cDf1.5� orange–F���a�I�MH3U Texas redRL1_Y^Se �M 0417�B�1�3B2$8$ 0LIVE/DEAD Fix�(Aqua Dead CC=S� Ki�:!#L3495dN�*N . N��9�FH190-1-Q�660466�6wJ�$eckman Cou� ��� �r �@ADP.78Paraffin-embedd99�A"�5� %k�R�����l )�A��y!�o�_N15E�or���4�H�� +M08%ZMDin PBS��Hcub���M. 8-&-Rabbit-on-Ro� DouQ)�Polym� 4IOCARE MEDICAL tRDS513Hm��"�"e DAB�0R4 BDB2004 H , MM��Im%%,cap�d � Q�AM"^pDr A�3 CCD�i2camer� d QC G softw*?Xo�H. 0 (W, S�&UB�GterferA lpha-1/1a�� � i>&� #���Fbet<�2Y7�3AIT FNγ"3�$tumor necr�Y� ��Y NFα/4])>�G.nw;[ed� nMxA [7�^H[7e n D20�H���& (n�- Im�!e�$a.~; ssayi�e�( ABI��=]�6EAll� plD �, trip�e I"aPeu GAPDH� [77]=n�lizQ. DOSu� G4GraphPad PrismF85M8(UZ$, San Dieg�TC;US&�methods �y&Yof�$ro�<��descriMab�% �c&�0&� f S�L.a*usa@a 2-t&"8Mann-Whitney U !^�wor)>*�,+Rn-ΔCT%� calcK)d� !|zH( ± S� ll 4 valu!�ithin��%sa)�� (2-way ANOVA-2oM CU#io<�*��a S�#�� �AlD"d%V�ida3s&:QK,�H45 .u�Marburg��D Ka�?,'s sarcoma-a&�)herpes ( KSHV�D_+e H!;�C�#t)�,.w$U crip�E��ery� id 2-�"fac#��Nrf��I@imp1f  �a�o S �o.3�y �(��-�2�notx!qe^SulfoaGan"SFN�)�i� cruc&([veget9s i2�#�Kda�A~o$]zes �8o�c��a>m �.G. H�>we5we~A� @�(���;}V�A�0.�2�(�&��Jly.W9;�MA-u��+n�Ui�a ,A}l�!� 5zsiRNA-�!�&�1� boos�#)��+�.�a��&!1v-����'!7v�&Afi2+�^�<9Tin�EE} i�V�A�^]E�I�s QTcu��K*�P, �h�[4 I�d 5uA�!@E-��(eins SAMHD1%MX� o�M%-B "5en�KO8 R& $-LTR circll6�(&<neiSL ����"IJek�  %�r �>�)Gl&u8�. �nd�9l`!�n<��[�+�*�. Hig�Ggve)RretroI,99(�"�E�Cv���. less�A�1 �G:�fs(ompaniIf:�*anc�(c�e�e emerg�Kr�����knd!9rt-%�long- �-Q�. A� 'Dd�of�!�a�(elBQdefenoa�i ne8e8`ua�B6)jve� h�&!�se limit�s��@7\�V-�c[| g�V��sV�a nv/&�i�g� �!� heal�cM*�ETJ>.U�!�!0sY) aRP).`>�!,�m!�%�4&`$P%oi>_2C carr�XE��* stri) EWr��A�k%� b�\�@}="�V>(r"w6p *�V,�3nfšf�0�B�The�(d!�AN�pl�6A =C 7[�+ A smV�#"G� e�3t=nqZ�$readi*� �v+i�"V&"� [6�(7I6S+��$�"�%@sympto� c)�.�&-!��&6�&.he%-O��"� hile�direcpClnf$1a"5Hit�)�.��.m`d vagi".�sh1�O� �. -sus�6i#./[1�)wl.:+Y.&��werSmm*9]�l!!��eby)5cer�1��i8:�c &�f.Žis ��n�� �S chew!Yo�2x�,luc� ����� enzyme my�n�k 6�Ts ]%��K� um� w$Bit mainMs biolog# '�b�s�`PrF I(�7�Peak�(U)!�)e� �in 90"C[1�;In� e`!�� �prosta� �in?A [17 , 18] ���@ �$ed [19–2�(}�� pM9" �?z6" �  �& [2��k<,9s��#�9�Y< oxid(^"�'[2-jis helZcheck��+!�P0de47��"� ,CUL3 ubiquit>2igA:�� lexeGAv��  KEAP1�a���ada�:i!�> ��:-modify D^ �ent engag$No2 [�j�SE�um �it)�lo�'�g�%�]L artn@5Aa musculI5 neurK5fibro`� ( Ma%ini0 s l"R�el�����!!�enG��;!V�B,f , TGACTCAG�N deriaikn�ao-B� �2YDreM��=�v�Uip�%�6�6es [2�6`eDa..s>0[yp�A �-lk,�poF\/aencod�q� �� a\xidiz!�%ia��i:-TL%�6-[3zl�16lA�26[�kz72��^.mB5�4A�c�� 8F in�\�ly�2�+3w�'�hE�Y�deR{ VP24� i�$%]�9emb� 8Keap1�� ��,�DNx�t�<%�tur� r=k� t2�� I��md C*�[31–!d� &%�zuon�2���"�@� �s� R� � 2�Ewk,E��7� x,1�� strongk  ago�F�in�a-q� �&�;N��f�FN v��iA|��.r?Z�u��� �r  Toge�]� *� %\2a&5Q�,q'!�s\]�x� � o&P� e.7Me� discove]�sm� l9 �)3 �. !���ex %��_wpair bTjfungi�v �O9�In-za P�ci�)syncyvs 6 ( RS��Eps��-BarrEB[35A�� �6�I�]J��A�p*52�3z,Ud�.#-� ��"�$10 μM , 2 or 3 !j!�24�%r�(AZ&� I� $@) ��f!�r�*G� !�.� CuI  %�is aliquo�(VSV-G pseud@dd�% ( ‒ )�$1 7yfer�30e1�!�harve�AzfL0�da��C�z��%A-~�Y�G to qu�fy:;�-i�"U. W= AZT�$ pres[& �!,%x�FM,��B e dosage ���Q�k8. Dimethyl fuma� �MFa� oIdu�pe�asoria)!.ax���, , slowz,bp�.�hF9�"�&�  ( hMD�K�.���e"�`s5��ala$ ��A?� e�Ssu?@��o uP3at%Z"�:�09\��*X���LmpIFo%eS �:a#��s �2L/ le-r%a�aMAhM�a��Y%r ժ��9�`.Abu���m�O�~ay͂��F�:z,1�6]%"orR^��un���W l�a�E�a� drop�p]p{2N !�A�fK!to�=k:JR?� er.con-� sq�B� � U[}oI26�19R���a%s���B�AKTo � ab;��ba��@��#��!,�-w�FHeL�/GHOST% HEK2&Z*,Al�`m� U937/ THP1Mxk w:|�-�Gc�jRC�by�>!�in �MRY �e��epeATտ�*�!�Q}?3G ��W��t�a4@���3�=:� !VER�W)E1;or-Pq�Fig 2�X2!� C�t�^d e�:n�5fY&b:pu�M�2Qh2�[. F7eti� �p�9of%h:�=�*# ��H:J�by 50%�'}l�%�� |A�2 . 5am5N�� ���. �)8doe �� cKm��HO1%1I��E�is�d�Ec�Mlf,g:MDM��2%�1� �� Yɝ�}~"Pybn�� �.��cycle k�&k phosphory�RonOw�-we as� whͩ)��%��<sRa%SFNZ��oYi��p!���ar* }in-�uM��Y beit�+�4:0t1+IdN* ]�MD `$usQ��rai�h�ssi�tyi�5�IKe��j��U�� �munoblotA�- �ock�!SQ�e� R%n)�A.� �V �,�2in)p,��X�%n )U�+� NY� -J5��N�!�"�7%�%���oF= �m�>�2Ca� ciab1pf��vi-ty!I!�!2-X �m*�r@e,Q�cytotoxixP &�@R appa�J��5F�He=s� �uM-dev�geOa\E��es��r *�hP.�$kQ�/!����6,�6>*�L��:�EV5}�Qw��Au�a^d%�<"�E�H� or bla�~id�er� ki1_5v. B8u!Is�#�Aed��V[;�hR !Z3!��b+t� sY? A slj Jq�6���a�sb@qyRs��ALZ�Y(f���O#nll6�jqbya��N� �p�P�l�}g�duM& �}@2�2�m�#oli*�N�E4��%�XwA1cH !�in ��c>"& X>tadd�q�p��&z !\dur: �O5#ݢ- -�"|6� A�&p�(՚�,�w�/ ���Et�+repla�"qo-f�2 &a�� 8I�}ex"` fres�!thaa.�!�7� �nkA� 24-h�Cv�.�7�la��a�.( ssiI�Y#Ys�t�#�� %1�gv�'�%��emNY mann�,a�s%9mOdo��� yiel aESer-�[n.hɐ�w�G�<�:�"}re"�z�.a�$c&%A����q5EqƁ�) !�]��"a��$b�&y "��� A%%QF�!���a.�z`)^Z0vm s *�& ���+h�Ea��!�.^�2-�/�0#er=�.b�,� *� %� vehi� ,� or6�%�Ѩ� _!�@ r-. �1I 2kA.]�@a�Acnef-��MGFPBF . Lu_)2zax"�}&f "� !b!�6�e`( �5��sF� E �/:�rE�"��l��!�]�[2&�K�1paralle�K� �!V1J/�#4A� *�sѣCv�uj�M 6�!KE�!0� �F>�f�!k4B�C 4-%;���,6�OatIZ#e�� a�AXan�٘�2 ���$� 23{ 9=� b�H��L��%w� 2"�):DU "�o*� T �be�� LVpx wo2}��x�4at�KstA �ly�y)'aA *���%��4'e�del�a� on%Q:��/��a11�����few"�_Tbec^����6A , ra�tn�=2#�Ea1�*�a)�AK!e l5)�N�exploi3�cha�&er�Jc�+Fb,2�W���Yo� e�ӱK� %�� �AxA�r R �!�2gdpB+���Of�inuA.��I! �z<: f �F"e>.!��>' ,fv}A� 1 89 . 6 '�P.M E m��u ��; DMSO��taS�f|"�A�"d>51 uoll��:/99e�14FX/IF!���:��&?���capsi%�Z��B�wf rnAt�<` �>�5 ELISA �emplofi�2�Br��A�2&�st� +��!y�R&li !9�&� "1X�Q"+�E�D,�[ inpu��v���a>���5Ր5{e6D�tglycoq�L&� te fu.E�� adja!�2K �t�K%!�of!�u U�� !���y�)"-%cM�85 �5 Ne %\*��r�{� *� \��f5�(i)�9�eQ�B��a5o �,9 e&цmip{ ondr.6V? 4Z!�&jVH&&lR�.�wV�:5!mn��3'�h�0[Q�Mh9Fiǐ,*�22 lso� psM#bea� 2�"�D2��U�WL@�n�BP��" ��ur".<���� an �~��%unt,'������n��gen:�3A��A��'^�%/?ɂ ��J�"�Hng: a<*i&��#e�" *� �i b�ߙ�w�{-vW 58�z5"2���vec/>`�h��69�(m�2��4-.� )" � &|�hi7O��%9.=I�eJeM�2�:>2�..� �X �s�F2�� $ !��A�I�r� *| V�<�!%>A�)qYa��V�RtI�>T^u�Xq�<� ��* �2���/ia%&j��exogenY U�a�)=cޡ�ͳdi���c � �e Nef� @� �(��'U}5!�F� =5{�.*'to exe��K%g� �ts<"S/4–4�-�dhyp$,s�?�jJ2F�{l)OQ텵rel3on�"� �5' d�er �6�"� db+#!epigale,�D 8( EGC<�s� �6&�Y�aDMF�%�%!�n�te�nV5� U!\0]F!y�:�u=**)-+. �M� s Ta���K7�.�� �H��]"~ MAGI�7 �AwA� hBl#%E�&%�% m ]q\:�*A%CD4yes."�Zgp120 [4�D40/u�w�>ei�2F&!����� :�#+6av� �l�>�v�xuS�o�inj&ig).$>~$�.B(I�&h�"a~,E,A�)/��1(��ݚ>6�]��lex� �1�m"��-6� 6RS� S2C���exten\,Y�r*��a[E�ye�#�)��1t� !r step6�E�" +�\ s��\.�g%MhedIJe8k-��JXEiwa�Pa "6E�/A��yaA�  A�w (we"� se���5�q� Lu�K 2 A&Y mXr.*F,ũ%��P��&h� com>(�=a�T\Lref.�of�L� J� F�_ �9o�).N�>�pre"PESv a.�y;or �A��)L�$ZFl&�17-% �iO( S3AU�RM�*� 16i!E�U�u����L�_r} *�$twenty-fv�� � �F�QV2<�^26g �ed.A�� ,/__{ �A�cZm�`:AA�-c�B��)A@aĈchUYA���' c��6:�6@'�g|we" rule][ ��!����, ee��[�!Q. N$> DMF !>e �ed9��%I%�r5e�#N��e1�"�,  haps�A2{6[n�A7�S>2<�c�_�9>�[4�6�zW�8�mhaB> *�b!?�#�:E�2/"�,��J!�\se.`�2B?+&�2h�$&�0iT2b 9"��5req�-3&�/��Y��#"d(���^�;A�I R�e�A�,a"!�- �͡�U���� BFQ �lFW�,= !A\���� (*�#�!,*�:�%�d��*�E�t�U�gA\�.Eai�Ht��5%�=s:� �=�ba��)$�n-J#�: .�~&}ya�"���e��-�=���I��7!����ct���)�No"^rh7��!�"l&acA�r�2�B.�AB�!�& z �Y�,H%�5vi��� Va(&a]%�\u., ��o���*�t @�nnA!�t�4B.�A*��kk�e0- �Gu��0}� "��X>*�1tLz:-�Spe�Q1aanEF��Q!.�s%m�p!ޕ+|jo�1 �Ito7z$u"�?5O�j"W.�:ɬF9�4���g>".25?hk%,,�"^(� E�pf�r�i�IJ� �Y5��:��e�^�F6Q ��O)�2! !a�.�6�(!�. I-�u�=�KK�%��'n$��֝j�  $=(%ctk�+:aK #�NQO�9�u�lN@a���Yq�E d�P% scen9e!�T-��0۝<">]�yE�&g i�!�qa��.d�/(M��e "%�(Qs�K5B !I *�$�+X!{iWFm A�%V"DY�E| � attachEm�i� AV��6� FJ>����� A�AT v-8�J�%�2A��!\�or_ 2_-s 1"�"�6m �+t- f) a!� .�st&�3 �m�qVTo"�"���] pu4 �Dim+�.I9����f"%� !7���ޙWi��z�-�/%�"�!���� ,-o�5�-^� A��]f6K�~�"s �2o!Mk> Nt/he�e�EI�8;T�' �a|AEcY�Gm tock@a!��id&�I;al�[)�to���$ �ar"5�SFN"' �����sͣNgtz&� (2a �q&%�Tmdi&+ abi�e�.eqYVs�7KGen��A�ed%b6cN,��M�iv� q�byaiaA�\S%h!oE���! �pre.ec��-M"��&�DBC�se�eEq"f!� A�a�1�^AQ+-B� Alu-,�,%!�A}�"g$Av�{c�* M��q0M!>�"I".\&N"= O I.��l�G"� m�U�>��!2D�.AR� �8�,�E6Hb�q�!�0e IRF3/7/STAT�'NF-κB.X !�27pD}w�-,��z9����� CEHgeO�6�P, silens���: &� in�RUS(e�Vn*� "kY�4�1:E�s� %!i��:,"�;%}v(�A tren�2y � !o�vg�VJ�L!*� �or�;q���� �N!�M7�ed* aU(V$� �.ajG[;�A�6������4J7S .) "�6AMX2 [53.���Da6�7.�7"�R�1� \��"�U !���6 uApM HWe6�>J�4�u#8V� "��m�^�$W.EQ500 U/mL��[�: N�Y�فE0*r5oqKߣ"�[| !� GCLM� 8� �Dy$*fly*��qP�+or%�.� &� �%e\N�A a8�(.S k,'H<�(�i -to- HE�<�3:�:rV,}4 ���r�A$ qQ\,)(��"�x�"-augakiQ�M�,&;{Et ظ��"OI!��( �eAF 9+]"� {R�Xf aE�1� , ( `\N:�;Y_�4ll E;a( ʫ �r��Iw�� e1�!`J�7`�"�/"`/!�.�i�*�sE� B)� �P� ly �W)� pre-Y �c V�SrA�6N i��!�]-!GA1�0e']���Qdԏc!�=�s sol��$� :� "'�1-�UA!�R"b��ifKQ��on:{��& ��TWa��*@E�-Ous��� successfu.U.݄\�Ela&�!>$nga�~N,*#t�]<� �M�2�F5 �4+=�onJ�& [on.�"���\r��!g]�A:60��!UF;'��f�<&Vm�"s-� f�A�) �k)clo̸P 5 popSion-w�|�%�� "�-6 �*�/)%a+AeoQ�42R )'KR��:�.+!{5A/6M�� L<3:M.A7-1R"� �*&" �l%�/ HeLaN�&)c��'%!&&'����N '[�&#�ob�,.'� "�y��act\-� 6j �2�#7'�B+y�YPG��� *�i(aS�P~�#!,�2M4� ���'>�x���AAM[r�93I&h"`" 6Zn  S3E# ca�*�Y"�!a}'��e�ũnV'sNRI�/eva!�Ki�Ul ��|"��Sv2ig��^ ��Vm���U!�A~he TV�MF(E�di0F�MM�Mmys�!Watv"�$'�2 attenuate*"*�Li*�e"w\' ��,4a�a�NV0"-q:��A��:��!�.}"%D�*�(3Spro�M �@ ��?��aA�@�2�Tu�m�� [��F��D�8A)tB>�+y w *�RK!"&�� � .�ApE�^m+@>r}�iv�A9m2m5r�hMF�-�N*�#g��W�!qd��� B �!e�iof /`*��"�Wu�q�iN|�Ad\i��a.�f�!�pA{re�6Jan#�  �)*�-B,�������7���nbrA�!!��14hG%HCo(�$thB�d !�&D,L�na)�Bdra� oi!jmuraF2���' �.�Ilipid=��.TQ�*�WMoxac dopt�!z*� phen�Ri[m#H:���"%�of+$M1i822�. LSa�A}^�-{�he��:M��5a�� t.,� 4�&�.�ofM�]�!��~ !��l*h}7 y el�G a:�Q�J*-��!{ ��&��i�)[�z����I6#��dMvE(�n*�Mxo!'*,� A�!����  e<okary�kᔉ�8n1�m!���� "�!n�*,don’!{�w help���j*�W" [a��"T �^" ��=cX�e{f!f8kE�U!��Y�2�g�%��~m� EXR��Ie��ly�1�� a&ml �s��ng!@-m��I�� otx��^cwEruJJE��Pndk co-aG"WL[��7–6J�"I3�)ZYŠ��i�tUh :a2O>D%��*�T�ly �,�#Wb)0b��� ���QA4| �1&@�2�� I�er�K!� ���_;`,4l}"y rap�g�.$]~f2�a�X mDA!(���A"Ҝ����'A)�� &�Q7 a���Z over"._" -Dw ׅ�a�"�<! enfuvirt� ��A{�,� �o�> V�Ps��ch��ex�1c����7�%s"�2e�k6z+s & wh�!�7 X9��-e �� A'��9�2UAr?-w!#or2=.^ beU�d- Ky-�meas rugs&� t۞���Ti&Ki-�2� emlyI�� nM\(e β-lactame� biot B[�!�8�!�at1�e:~�r�q*� m�Ksm%� rtburAc��omepraz��-clopid<�l-�is ��^ kE�d Q% a% [70–�tiItib�Wni5���� �>�ɔ!�FDA����u��)�r u�� lora `� ��g��F�;\25��?�.�7 tri K�2n obes tu%���thiocy!�&!s��MI$&�K �X6$�i%optimi���(3a�a!�� �%u. Worka�l��)� �a�Lb�'n��Blft :�) keg� �aul�  " ��re"Ca�heRg�K itself [7�c&�>7�i ��2�b��$\6.= s��%�����r*�} !)at"�`aD2��A�`� *��b583Yj3�f�UAl �u�/��jA�a�AnS �V!��)age��2BaWa�'"�"�}�soi�.��S�� thel�� �[7�18�Vŵf�/��ehow ^�!E6�ifa�v�))�a��7�(�  ��ro%dNmc+%*B3i(eLaQ*� �o��z�i��6�. !��- ��!6��de-*= �s�A�:w�ebraskag�cal Ce!I J ategory 4�<(k� %a� cedu�"�hanonym�x%2�_n� )xNN:Albany�ol1*�o*d�Involva(C� S'�."OA( ATC�",A�[R5/X4-S( �D�}Dan Litt�w.4Vineet Kewalraz��IH �RA�$nt ProgramA�iv[�of #, NIAID�|%�m� ndμg/ml�'p<myct 37°�:5% CO�ZM"SvTH�65wJ�UA��$s �!�HRos�P�� Memo��"P�e 16403�dPMI�ae�5%����A��� �q�k�to ^�]�#�*a&�rA�=�!H�Zbol�ni} acet� (4" )�X5 9(Fg_$matitisM�GTa4(�!)F�" ard���l�*U�!�!��. V/�f=��g�z ZFJeM&i48_>A2g�> uA(H�&5���0Ei*6*  pV1ti�J�"fE�se� dilu�..���4� !MA >,((� alog�c. : S804� LKT L�8 , In��, S�>Pau�RMq��"piF>piBc24292:P$Sigma-Aldr� YLou�4M��Z��FBb E414"*�a)aissolv)�"G�zxt">N(. Azidothym^�)C.+��� GeA�tl',Ɣ��G6)�,��F�waR(� mMa�ck�1��Wua^E�Promega.3As��Sl�(", Madis$,W� Su�oLmanufaF�r� ���.Cm�3umem[�nd.-wa��! �D- �[sA�!�ˆ�"Sam& �ly�,R� debr�%u���i��*9 4at 18 , 000 ×&�1NFњ. T�B�w�e���s�)�mix��8�nL&=�)_�0V�Y�/c��Light�uRLU������7 a Pe�� El��0VICTOR 3V 142� 0� ulti-���V�pO'a�2#[see� !p!pu�l$ a 96-w C��LabQ�, Frank� La�,��x&��� .�t�2��d�ql �*�Q!>a-A�&R!E�*z`i/��(-!oxy-4-niU henyu�-3 B5� 4-di��22H-tet�ar!so?�sal� WST-��^�͢�� -sol��aazan-dy6:�$a�%u�L�Aan��/o(!]��Rg Kit aDojind�;Kumamot Japane��O{a^at 450 ni�)]qaJt(߉Tek ,&�r�E.RI ��:� ��eua3��ImVa�d%"e"�&�<S}�0 f�RNA�8}2)i�:�� GE Life S�'UDharma��) : NonB�AB 0P-002048-01-5�����>?B:(J-003755-09D%� �.  &f�I� Lipo� �7e 2a�( �TechnoT} 5Gr�Isl, NY �}2�011668–019 )�'F�!�h�ja���w/V) T�uy&io��.��H3W6P nsurJM bust<+-�AanC��. S"� Q "� ����$=-n moniGAda`W,-v8a Zeiss Axio Ob9r Z�ucroscop�2$Ua�A����Ye."W ��*Βd�i=� �ac"I P ZEN2P�"Œby �. F6��!�� �ct� ��!! � ��"'( Z!C��f�F 20� roomsP���82%+mal�WH.D(. T8�ousA��/�Xrec�id �aa�V.�] dB.��؍Jos!�*Τ0(!�|��)[!;Jo v7Fn5](��eU�r � AshmbORe�P�&+)Ql��Laemmli&��50 Tris-HCl�H 0��M,!1SD���H=e[!0AI% bromŪ��lue��re} �0DS-PAGE� =fer��oj PVDFñbr�Mil��r!,Bille��V �x��e-�A�  ����.P� boE�A;:-tubuzB( N-35� Amersh� GE H��2�, Pitts�h �Jti-��FRsc-130�S�� Cruz��te�;y*� DallaA<TX�WZ5B��Dan�1� Q.$BQ GTX114075��MxJ(D0214;�$��t�-1�B�,183–H12-5CGb�XBruce C broEmHardy��At*�#A�Rex �� )} C��lu�m�Dt�t�bO �d�e� an A1� I8, ech FluorC HD2 ʔkQ.8sit�+r� ���xV��^�@eJ}�al.�j�<(��].��6T�;&�&Hby Mbisa et al . [8��Ya "�7�utler4]�&�+w� ��dy�#$�+a��!� SFN�u&�`��H8du7<�$<DN�"G B<AM223� TURBO ., Amb�,� )���_�#|UU ���>���^�@"||"�4 �erw}v�:vA .�s ( 65��L10���)-0t c&Vols*Zov��?clo�=Ty�-|!d"�I�(a DNeasy ki� Qi1BpFB��a+�G�y{R zTaqMan/��al �?M��Mix�nhermo F,��r�A�!�(StepOnePlusa�l-Te9G"� � � &�}���^%�!�: LRT�4H531: 5’- TG CCCGTCTGT T- 3’i{. /2/GAGTCCTG/GATC-..(Probe LRT-P4 ( FA�-CAGTGGCnAACAGGGA� TAMR��2I1sttX!. F6�-Alu-F YAGCCT�AGTAGCTO �3]1R 1 TTv CATG= ACCGB1gag1$CAATATCATA��G�CGCTT��A.A2nd6�orward%B5� AACT�ACCCA!KTT6GR�U<�V��)xMH603j5xAhACTTGAAG CAAGG CTTTN�3]2�z�4 .6 yT�AG!7AGG%@AW�� [.��6�4]�:"�R�{�3.��f-�E�EADTA�A�C�� -0(- CEmGE T!9CA .� �!LM�GA�Aa,c!�J���$ �V�fG,ʼn�&D�W(  @�J�or��V��.h2V.�:J��&#tly: �FDN�� ��du�)��* ("N���s�t-&��X �`hs at �80��)7;h 4�c��Eh u&���;�!.Lv�B542�� ABL � Rockv�  �S�� two-%���ent�t->2� ����e�6 i�YF"�E��3bZm �8�/� �hemq�(^��5 g/dlF�2��Aeq$gravidae 2e�3 ,�x�A . lu}w��Xless likely to have mal�-�s�–[6�HU�Q�of.s a�:u0may differ byAAvd U$-�[7] , [8 j��dis�2 is causedCPAncylostoma duodenaleE�@Necator americanuaRMature �yJn N!Al![bleediNda}tein losa� opor-�to �� �:� sa�FofeI)(�depa�neVad4host's underlyyJ�[92}Nc�or\ cerbateB_� IX. B� �@b� fe)of Ns�=Υ�promin�tha�1c6.!Pit often occurs along��J9av d soE>acceler�!; onseL�-dyL�Ascaris6o�sA���ly asympAMtica lthough^ of extra-H stE=8or high numbers$a�ds� e�0described [10!�B� hasZEmp� fat digesA�` , reduced vitamin absorp A !� shop�!�team mE�s�RheFri!�o��), whieTokmj(in July 200to��ndardizEResse�m�E !�Study+,ff administe�a@ d qu�onn !�meIl% obstrc histor� !-b�ob%�d ��Csma�+�Fm2`�oG d�� shoe�!�nearest� 1 kg�a�!psc�hJR-aDA�ime> E�ally made@instru ��[v�MUAC )6�:vn1��$midpoi�� *�� seA tapeq@x�wry�er�2@�a�i�� mo �. Two) &XXrs'M�A� body1�!�!�!�averagew^� dat�alysi�Socb��&� ���YM�^m��|b�"�We � prin��l�3poo� �a�ene��� ofo ATbroad�cha� $eristics: ��p���ᦅnt �sp�� , sourcXajal{ of waA�of fuel%J cook�,��estockRas�wnershipMd  ing/!O7A�c�. F)Fi� derqa8�Ex Gscore'r-Ct nk%�o�-��6�� ,quintiles [2�AF����|supplEl)T(�� mg ferr� sulf�3` E� �v!n5)ol�ci�qceA�!)%W30 A�ifk pr�! d�of h doxine-pymth�  a�ermitt� !  ve*�a H a �na} ,al guidelinea"A&moffic5nuS� dd�aai�n :�!� ir sG d� hird' m� �[V�9�"��a�540%� albendazo�ThiM� thin��MKs�w�Giems�%� %Rd�$ oil immer� ;���m��d��+aga�� 5� hite͏ cell�� ssuma a�M2 S!�8�µ�!wLl��. A 10% �A ����rerea��qm�z rol������ᱡ cu�s�� ��(&@Cue AB , AngelholSwe)��� . S*C -�cb AHnd miVcopely&}A�R��Uf`G�-rmol-e�c%E$ethyl aceta�by!�o� techniqu�by Kat2� ��"� �peџ[268[27� ; rvs�%�C mbii!�& s;�2�!�=�by% 3aR.B�BBconsidj p6� at �MK.Y�\rotocol�rev*h"(by%t�M� Rese� PInstitute ( Nairobi , -!�Ce���D%ConE�A Pre��Don ( Atlanta , USA%��a�ipaa�� k gave wr�� *9 or�qABk2 ���a thumb�-36xa�Gn���(�t%�lli�ta _�na�:Un�exual�F stag\��Iy� � t�� �&N f signs�s ��A Q as�Cdex�calD!�i|in kil�ms/� (� s* qu�;O!Zor�P�c�a*i��t�A� 5thana�il"�>�A��T %$ Swis��!p"��8�kg/m2�nrfirstݟ, 2' 2:'��A�2=!3: t:� ) [2A�!� or!\:a� * 6�"9#22� [2]A��� � � �I drin� inclu� bor�-"' ed s� g;� un� em @ ZG surf� (� ^, � ;!l�or� %)an2] t��"!ofF�%�h� �>=boi}  , fi��u�Swe�lumchlorina�AB ��A :�A*u-$`q"^ 9 w.� . DifM�aj!���Ha zzs�] chi-iT ��Fisher's�"ct wh� ��5 Bmmeag� a�a(�en�t-aa� aram_if�n��di}ed!�he*� v�#bg ��exR A��_s!_| )�V�(�� abb��'!�o ) :)�->�,� �d��$yp�FI�M�,2T Y4, mar�M$, young ag� 0%H ,�<of�n�)c�� , a reA"si ea���c�animalE7AE� . In � �model�Ise!�t6 O �$� o'�YwaC.{P%*BAa 5��&l] OdD!�� )�95%f�c��*�(/'�&�v. Al'oQEQ"�i)a �� regres� are�"ll" �+ ��uniE@t� �� g#o}/Ř>r��)�n%C a P-�%e>�405 �rem. (K&we kept��asa%�X!�%�e;�N�,Pnq�.� , beh#�� t�b��f�e� . Li�2Ea� toA*��re'�J�)�� *�(a��^Y:Q �a"k�sa�y_�'Ut�)�we di�>-ipri��(, %2�(� <ae�)4 �ded%�%(hEiaf�$inaeG���(!��IK1�of%�va� m:q #=$� � sI�QT2�"�be mo&�( 6!!to��*E�� ��)*��+# �i�# a [3& SAS (<� Windows �&�}8 ,#, CE, N�us-xa��%a�� two-� dqqtoX*� !� (,,ppetite ( 69� A�, f�� 6 co1'( 5�2  itchAJ( 3�+ � s6! 1. D�,�, curr�a] n�iyub��:!��.,-�g. O�l'76h/%/:y�A�&i� .)��p, �6u( FigureMiB�%( 5!43�!� most�E���+�"L)( @2�6<$("B2�/Sc�s+mansonij�#,� � of 2�; S . ongyloidaas�<.A�)/"elow dens��,��*of�#�0s.�0A�AB1%�[. Pat�#� !�b$.7see�m��� inct6"� �gA�-�2A�K2B%XI�%dF�!'a� Q��eI,)�� B��2>-Nc(\ V ��6Z3M2crehv�c) ;!=�0%� ?&p)\�g>^1�]. Comp�_!�}"��ӑy��,FS,>�,�0�b,�V,�4a r�6Ec�&>rZ�ou�o}.! �#( �JC)�� #c6h2�$R�0^cor^KC%re}>�� .��.. <8�3.:�)�tBVe **[ orZ �gm#�a2� wF�ble� }�j(��4a�u3M*�4in&6\5�|7):A\&i)��  ��noN�,&.5� 9 J�ɢ�.�a�&&F���B�4z �KZ�FB.� �\!K �i�gN� 6B�A_Bo[0�|)r.L} ViA�*,a�O a�qZo �\5� 6�I� "�&D.'qڅT>��c"P2m2�*67&v [AOR]E�� M�A�� . 0��f lack)Q'r�$9:�)9AV&�32�6��� aV 51��!�N^w y�e f>{.F�8. *�. F�+>FaN1"yT .�-(�d  ,i be� marr>(uM%Qy3%Z6T��&�R� U�l�!aA!5?6%m6���9B7 , 3� 4J3An999J3n2A�3J7V�jzW b��2^Ez)Bk5�)�leo" 2�<'c�)�YA%|2�;aO ,�<30�(h""Z �A���>~ ge � ,orE$Rja>X6V')%C212��(3BF!�Ug5 �E��:�1 E�.N&A�" -�H'J of 3� 8� ��E�: 95 . 9>�P .*�2  B A rema�6r mix� -�{,d�)doc�& ��%.'��.t;.X�.d�Ɂ�J ry/ D �l�.&� ( 6a�4� �?'��F�positg#./.��/�2laria��IF ^� � � familiar"� ^ee�A����w���#Bs6~ Bb.�-& r{6�f�0�8s5ink 3A–3C:fT>th�$�B�ed�&W8-��H>tIJk�)>n>B�2)?e�a�� F:�d�n�� 39&�>K06–aM4M�f�6#�!sh0&�� A�<)d!�� �Axe aeIn mult:i1]�P>�� � or:�� ;Q >i}�a" n�? ward.=���+ �79;4hA0 ,606 od�1L� 9 > :�!�Z�o WjS6[8B�5%�ne&y/bISmu ����k16� 1`6 ��aYABj�J �6@/an AOR�A�5 (. C�M7�(���" sameI�uF�6h!�9hQ�!8h. NT,y#�M��H7+!�>� o2�. LimiC o�J_$De e sm�I%s/n�6Ũa ��l&� me�;D+�#��@v/F;��b>/4d2_ �>��lso!f _�z HIV-u&}.��%I_ `1�3:� carr�.��m�'�toQc��Tun:V��dja�# 8�0�6���O21%�6�9d"�=�� �mKagQZ1A�34 �HIV}DM!+��KV� 4in Ethiopia [4�'��2.�B{ [47]�6R\s" �!8564Cc*�!=Y#"�:9$[4�;raiA�Epossibi�-W66AxY@poZ,�5=oE�a�AS� �qZ�IqkLg . Me&�+a(.�+Ap*�(saf�* z�J ��A9��AG9� ?]K��)`��-�0%�E��ant"�B*� Mm &�2�!:�Eb?40*4o=[5.Be�6B�l`�nd ANC le� �[5�?!�-ve� r�F2S�i�$��6DB�F�skBsiG .� �4�l�/g)�FaH-�F2eD=zB�="��!��l&E�.�mplex�S"�>e�Qt,)�detailXtv?�1a :'�zE48h )�?os��B=kiI?�ig"%&%�0>�ac�\~I!�$s >10 ng/m�&Wia2!�Ɍ24.� , na!laFn�"'��f2�efJJ�x4�& �B!N+k� I�m|ir via�� tabC. E�Ren���p>�p�iz% AcSI��YG. Sd@th��s c�J�#�2i�K!�E�2�X nex�*aq6+�fa�@��ic�cK I�evE$vt` of s�25L!Q2mH��C!�4! s1)c��)��,2BL inj-- dail�?6dayL( HpmHc�� o enE�itI"�x���6 0ord�h/�0��f���S11� ury-�Ngit*�]��#he �:!Vdu55��Uy��]AsnArU�#&�ta��Ac�<�ybv� ��troe� vo en ��.�u'A � }2�s�ZAE�2DTog�o��A��6�*periphe�>*leukocytr$K�=A�l5>�-�"��A-� O,"� �&�)����yEQ� 6-.� 12jpolyket�A�9m�}AO� a3ag$ of Buruli��!#N ( BU11�B.�,t�duEdI���e��'9,6��JuE(inA�i��M�=�0�(ic"�a��x�Hs � . Wh5G3tissu���6ie�BU�=d@>X! e acu�MQ������"� !;sub�S!3Dtenj5 , ai]8{`#�{Qdisco�Rnew m0%Qf52�. EAH�s favo�?�hypT�E�BU-*�9t�q+ar��d�CS e�tr�N��de�Q^�?��-@�**,)�A-U biopsa'w edM$axonal damyFi�"�"my�:!�2�m%=ey&[<C3*s��� footpaNA)!�e�M .Mo�R� �fiSDdeg�=3zdv d 6s [4!��)'� ur�B.� in m.�sfgg�7��/�}�=��!������[�8&=i�5� r%V��a�>f��#2�3 �<C .�,����R�ess i.Et-BdeY BR.�IYopo oO �/t�12 angi�sin II� p}J( AT2R Y by)A lea� ahhyper2�!�de%v�7�.� [" �94is mechanism n�B�e�,tra�sy�)�( �A�s"�1 i, ��flym�$ o��mo�0�%[�P*MJHdwN�1�[a� � loc�B�Z�"5N�)�24F^!+��� ec7P.[1��1�� wi l!8nel� j��*o de-bea�,nasS ų �s�+endop}Oi!2Mum ( EA ,1�e�*0�sg���wkF.�b�LngA//pore-#subIa�E%)M( �α X��;cU.h7a�)l�Grad)��ll��ly sy�bd R�?��ED0 nx @[Q�p��A��fun%�Bnsequo >�&�)�lA��9Km%\� i�S ph� �y 7[1��T. P&? 6� ( SC�2AI sateh?i; t2� 1�l #3"�, astr� P olig�Zd)E"ar key�l�H�  ._( �e� inYUAI�D!�s%� �I$����Cs��u2!���u2TNF-α�IL-1β� 1��,�����pl�#�A|��[1�AI1P*,a�r@ init�F���wiJ2%�aE�-S8~�Cup[W�"I/-synapaq%$� :b20]%bCy�3*+�cre��w&ignala_�&dra�G�?*�b�� post��� ? 9���Vl���@&�ao. To add� �, * �Rw�aqF!��Z��.nZ[�Aeyeu�m�Jm�1�!>*�A�����J"W!�xa*Vd�ZvoY /��Ue�B m�Ce�Uni(A#of�7is De�[m'?�J rat)e/B� #al�6 #003�)02�]n�\ord� ^ F�5h%(In �Taw�Vd� !`�=*�=EsB`\e:E ( Euan�1mP �g(Council Dir�9ve� . 8#84� O�R19MaOèry l’Agr�>�Ke� la�(ê�4 Serv��VétériOd%Santé5PF7A�A�>�?A1� .VJ� E�o1�O�F�4%�)=z 16SA�rA"�@�'P��UY|w8Ply!teH�>�!�L��rimq:L  !&�]exYQ9 eY'�M)psHig�8Edv@�R�y< &GH�[�iYb� 62 Sept�Q 2010qwE�x:"!?{9A�g^�V�`��Q��0X��M ^S����g�Q h� (D daEI>!�E�pc pur��E*�  w�L %_2o161j$ATCC 3583',!��R i2�apGysV;����R�#��*e6�s A/B%C[b����ou�*t!� n qu(f�� (pectrophotolCHy ( λmax = 362 nm;�@ ε = H%2�$WS~O solu!h�1m�!�Lμ)M^r B DMSOI�n dil.e{ �N 0t st �7V cu�-~�^5el�9ass� or 5 -s�Ue� F�^fEd1i979bef�7&F \at�0_2C in 10 μl���aL'NlEASd?A�_& volu�Xvehicle)�%OAd`m�S4Sprague-Dawley�%�20"250 g5U urch�YE� Laboratoi�PJanvi�=HLe Genest-Saint-Isl� Fre�)%��Cd)em@S-�� envlf�(�G± 1°�7�la 12/12-Lr�i0ght–dark cy�. FnA!-2�avail� ad libitu3[�*108-Wfe%� ,( C57BL/6JRj1 �^bAi�LSPFDdiI��f6�2wMi .���� I�s �U�%z!�"�reg�zb�Va�%� W�wild 0N�brief�Xg$ careidis[oBad�g epha�Q�uA�Jme(*�D!$��ex choppLndU�J�GpaV ( 30U/-D, SIGMA P3125-1G )a,Hank’s balAWda�t.�HBScAQai�:) 5 mM EDTAM .  CaCl�[)2 m�GL-CM]�nd1�bDNmI� $igma D5025�)�in at 37A�. Cell-�p !Xw'cp�d��poly-D-�Un�; PDL l� T75 flask� DMEM�lea1�'/QSVF� % pep^UY/!�$myc�nd�<am��eriBź&!/A8� co-U�. M"Qe_s$ch!�EG11��12 �m)W�{�"�G�� . 4!�lidoca�15 f1OI�.\t�,see�>in%,c5* .� V =P� "UGa 97%� m�&*as"�E�HCD45/CD11b FACS labm�KA&S6� tryp�!rv�Pr� g 3 d 5{`60-e� ����e��<ra8R���406se%e��|!��4:�2�wasAtwb %BME.�A�DE�a�3% gluc!1, 1ANa-Pyruv�,$1% Mi erum�hKe�ACore�355006�(10DHepxn2�r�9�e�Lq�Yy:��) gw�Eh�Dd i z]!GNeurobas)m"�Wq�B-2� 2� glutEIv�U55"e�9e�1i��*�]Itdor�$root gangl�� ( DR�}U,�n0Lalřalb��har�&�4Y8�`E��`>�2�J�XE8min{uod�J�`A��_ed� vmildl�m�\PI��\�C�!1� +�a�A�^&Ll�F(du�>��a#o!dn�<$Y/ml��nQ2�.�BDou([5 / ete ��. Sup�ot�K��� K~��{��B$of 5 x 104 9tc�lipQ�%�lA~iz/A gE'�gri� ��J��"��� !NGF1>48 h % �E� . MoFV z:� S] ll ( M170f4�U�in2N� (: , 17:�d�L-Lys�Zm� M vess�N llowV9�"�e�' irMTT*[#Y ��(��ٌB��M���-e.�42�, 3 ! )�!��\6! �y 96w�^- E�Qa�� ( � Z.a�*�(��16�� 72 h�1oendA'N��ITT�F0 E:Rad��Q&ach�W�]2Qre6e����Er�J�Solu-(z!,rmazan cryst�O>> OD��"JZat 570 nJ V"p(hm� BxA���i�D!Ubsorb�  UNEL 3� 8&(Z%a��u%��)y&��$kit ( Rochv �Jhei�Z Germ�3)v� DNA !�break�y apoptoo �a�u�n >h�"�!0 E�r6�'CFBe�f EJ4%�a\aldehyd�PBS%�1 �* room2}a�}permea)�d O��,1% Triton X-jAv2�t( 4� �Th�%edk�&Z BSEBSA U\) bbit ,β-III tubulR ti�W(Trmo�T�\t��A�A1-11�w�4� %6-r `0Cy3 ( Jackson�oRQ<, 111-165-144 ) 2�sub*IZ؁�f2�manufa�`rW �EImou+! roc, Ge �fre�&� Dapi�xole� Prob� P3693q?Nucle<d �po�#�I&c ���'9%ac�D Olympus�8g]I BX5�:)mQ FiJIE� Icy softw�d�\�9$:= E�>�sli^6��k�k. P-+eU.{ � incukud i�@3UxU�>�p5G ,Tris-HCl pH ?�Oa�15apJg)4s~. Q IX� #>�Xec^EP<Spot Deh plug��f2��^:�Z6�on&��,"q$�jr������24 -��*�e&�5%$up�w2�!f>3w 5>a�h2"% 1���LPdRUq!�e Esch�hil_li" , In1Gen�{ ���� .�����* of C� ,g6�T{�� �"| wa�; �`ELISAmg2r!��cUnI 1��6Pm�:*D(, 88-7391-2�IA�OIL6� QMAXU� Biol�({d431301B43090�B� G <� A�,i[u at 2N inQ�> .B !jwenty-o�ds�(b�; J/I E*�@Z|(ttim�by�E+Y�IFN-γ1 &D S�m485-MI� 16 h f9P2�4%?!�TI1by��)6%M�NM"> 9j2� 0i�5�"� 922�^"eB� night)M.6>9?!�� %~>3a� AfE6&"7.pon TLR4%*IFNγR@SS^. � waY)a*1� "-"y�m~�%�f��Accut� X ( S��'edAI�DFcR ai�(� enyia�te�$130-092-57=2{٣.�eN a PEx- [%B( CD28a� /MD2 x'� 11760����_:O�9292-1191-8#2�@%.Acor��onS+ison1 BS 2%�atm .�G=�.5��g"Pi5�20� � ��". NOS-2��!Uy onit /�-�r,1��� LPS/A��yqfpBE��"0( "}�U�E� :� @( BD Lyse/ Fix bu�` ,Bio�Lc�\O62 ;Perm/ W�QJ5�� cI !�.� -NOS2a5�e Cruz{techn) �$M-1� OE=%�!�Igoat DyL��64 BRockl�(, 605-443-0rt�tra� u�"�"� �J')vaeBDEWri C6 fUa#�d)!g���E�a� heti&�a�Wsoflura�; n O2A� 3 L/�!�in+ � main Q��%aC! froz� liqu�E�8�?�s�Cat -80nu�p�Afa�@�hom6�Yin Abcam� s�� ( ab15216�Pwa{�-a!!inh�*� P271#��Ql� DTT�y�on �. A)( ifugs�U3�00 x g��1� ) ~%o*�<),�4o�aDC7 ��AT"� �rio-Ra�w� h\�-�8�9���6,���Nphysi~�& �m1e!�N �.�}vi@Kans�x��,u�Aa�mLa��( w/v�k�#A�i^Honeyw#,Specialty Ch�������~mL�Ypa:�( PAF� 0 �hX phosph�b�� i�BS0,`�1i� deep�v?6( �pe.*,�� , i . p .���6.AK6� 9e�� 1�q�)st-_ by*F � !�� fix�:"< *� *�=q cryoe�X1by.X&� cruh:"_��n�+ toR μm��ck&�E*at�-�� &"(����in�W�*2�. GM-CS!��., 7TIMP-�3`2�T%f"@ � magn�5 L6sex screS#� ( LXSARM-OO��,)�+{ C#f6��#�* "�#50f&!)yV0�5k�DRGIo=�6u( b.t�z��M� � � -lin: bead ,�% shak�-�A�"biotinyxd!�o={y\.,2 B.� st�"�Z0n-phycoerythr�AFxU d�F0 MAGPIX-v!�-�# At&F(�ht��"�AM���q Data!x�ab I?E"*f �&�"�draxe�oo�EJc=�P >gA�&uPrism"�`( . 0d; La J��fA� i��g�re1en*NE�aT�f ��! Valu�,P ≤��0jc�<�s�0%�.�.�/�..� var!�extenH7ly �!) �&EP �bsus1�I!�+ 6� ��x.�3��fibrob��?TQHJ�onC`d�I�~""�8�at�7 progw���1�4nl�ach!G�)uJ�":n���E�4��M�,�9EB&�E.G�1gM.^tegk �tE.,9�n�!l,+�Hg.Mi%I�dE~"%1n z�1p&5!� a :.46ASDn�"eC&� ��a�*� ,��.�'A8�I��mix�Z4 ory b �,�$�.a 2 �Ctroy)�.N.M2� �2#w�w!:(lu&��G�2[.��6��-p&�&�� �E�4�}d0�+�5IvE�!.� Ep.�2 s9{�5�f 1�q. I��"�@�EIC%mRB>�?"�xio�F5.Fig 1�.S1A� sug,$!�>�4-��MELa��S�38�&�L�v�!Lq�.*z@)-�"J�V_.;_���a%4 Q��dV-8>�j�~uhe PNr �.i)���9cog~ �ct��2�'e�sy-8me.+7dWo�#��"QE�K.�m2>2k,F2, ir� ve���2e15.k I>1<*�MMY yu;a�u|:a�*yc"JF*RA50%?xe�-uwh�=�1.�j( IC5�$�#& �N�"4�� A�G�cl&) to 1M1.�!ݱ.F�8�H&�+�t&B=;�% itiz� �.� �E���2��%yKKe�5�#(6�7eaJ�M+&FDve���."�(!$2�:&���6� �"D%Z(/I� neon�!Aas��7:�Yna!���. *�+!kӁ�N�d *6+���YB�nh�E]����v"e$manifeQy\�bFMh{' �.�m5M?�iL�n�*D&1E� a�"aBsharp���:�A�"�R �e:T�3 �Y��)q�F�N�M=9�Bdis�;a�5E�#37V:R" sQ�!�f{��&: ( S�YC%� U�;���u7r2"� ia�Vn�9���i��WWeFYA���Kh�;s�,� zi�$4� !B�B$�@ ,�9�Wz heCcl�CŪ�Tl��?.�&�B3+3�WDu�4d*8 6Om�: !w*�JA��C�!*? ��6� H's�5�  � '!do��=A:KPp9~�Fos�� �1�in�e susp� �[33Wwe !HOago"�(�se�+� ZF2wBDb�!bh.�of ��'GX1*q" ~d2� Q�."-%"�to" Z� t��-�-��>o �xs� lC&�C)f&-RbaU)ha�pr��������.x+ 2�a2�R-�)�v� �� demo@D E!)�# irofHXM!�6�"&T��NO [3�3�BRatF����LA��H duceI6AWQ�!j!b��)S i [3��U� 2z 6$�2� �t9<�y�:=� ��1β #$NF^-C�T"�"%�2!�IE�QN�QE:was.b ly u[��T��2D�  �)�fai t/OeB�~�our��d-�����.8�H6< ly� 1/���B 6Q��..i;-dB�� V�&�$G� �:�*� 5!�s��E�M�Xby��!�o > F� m9�"C�!.e.*E�<f@A@cat�!]toM��*#=4��iY�>r:$ WA��o-.Q.0�Z�(2 ,.�(�&-O&e�7]9��,hH�o�~�Y&+ �RJ�.B: down?��!,=�1�A�T�5�3i�"� &1K|ax)�3t3B�M&y )]�0�A B�i8�NO.��R�/>� �CHS2��s��6�zG�͏�:�W�tSe&M1��HMzt>Then�#� C�y&8eXz$�" �or��4�0 aw!?,2Ch.���M !�9[ Argi%4>�%ar����!�M2 ��*� w7@ n-6A�*� ( S242&� A� S�R�| IL-4Ub�2 lO c&7R���ng !�2�."� 6�T:�2JKl15!�6��� jF�F=Y� "� -+�S-�O��&,U �2.G��"� �!����,!�k,R�abrog���11oE5M�r�G(G�Oon]�mr�eIti�Si�ir�Jew�RgZ�aU`�`qn��_�{6H&�N2T2n6�-JjY� ma�s�@�}I�Z�C9GRE��[. Our-�)�%�LYTU*�BY �m2�*G%XNTM%1�d*�O��.p]�^1�*1Ia�I�a��"�bli�&`.� -evoV � 6oy �-��"+\:)"��6V �%�4. ScN-]""�WaU6�AN&L!�W ��6��ma�E��# $p� �[4�d.(B ng_}C!/&! "�~6&#Pi{'t�#B3%#ecu� �#}�i�4�As*��8S��sam.֒: 7$~2o1J(�%��Fe.�W�!��9�P.�V-�<nD���*�!. Ipsi� �3e�3�a�y�,4�� .�$�i>�$hor��.��&�gs� a�O#6(�, -a;npueUHac���4B–4=C��a.� �AMA�( m� ( Sp�umBE, <��toI -��^fL�H"iOA�Fi�]�4k� s*-b���>� M��tF�#�9D 9d��,! -��� 5H-EQ�� �va 6��( S� S3B%��.�F.�����At-Z�hele�?� ��9�.�-6B�O1��"� !�����in!*c"���-< q�F�)�.�6U"�,k \m=β_F4GS� 3D-`���Y*ly|$I].f9 . Ye�.1�trke�?!�"A�!�FED�� d!�a�a BWw)j$��0�5kA�Tb �%j.,-]Ei�\��) �*�ɒ��,0�awQg QalMR�deathFF}�&± �3%��c�\�Z ��x�*� * 2w ,� 4H )��e}(q1%�6|1�||S4%�����,@reo�_i(#��� nd�p�r�n�&� �Z.��Zun�C ( S5 �0%]lm([ .N��Z*X&��X>T�2�ZE=�� .Iit�}h c%&O ��w S.�hab�f1"5{#p"aimaqu�cw)].����/6��!x>~ns� A�� &dSI "�j� �|'e&�IEa!Yi<�S�]F >� b�T~ im� ���!A:�6�s�Ja� 9l,|@cA�[�]Thnex*�d�d�R�I=��e6/l g��:�\�9LER� }�[11.v�Bieri�Ra�i"Wr�l>-�s BIM*S�@{,�$W�� TOR [4�Meanw�� ed�ME<"WB��xt�fu\ KmE>�%A�o�<%B [4RHow 4!e"����{s����4�v5SZ !j��5�m�t*�a�� -by-�O&. t� G�0e�KJ�ndy�Y�6\m�d��u�3� onv� *� Xe��FI%� [��;2��&~��"�� 'ʹ*��Xsuw4�*�E��.�nӡ����n.Ob�'d��'�gss�%�� !]��:�'(�ҩ{��!�)�'cu�%�`�U��U �.�w�5s�ger �za�H�e� .3�0x !��#�(I]z(SG�I% �Ln�,d7�+M.��)����0 %���>�cF���M�s"of An!/�4�h*>�.��t/�m�?ki"#Z��61�.%)�=�� %����Q�!�(��)a�&��ds**t8}A7SC � SW10a�.k5}[44w~�5�} j dn.\!�i�vlan�1�)uBot��Wg&kg�N"�c��le�ePm�(&�W6v&2tV�go� v E.�[c�g upA�%:A�ep znي�z���"�.?,�w@tO1vwB� ,bl!er �j� esth 1E|)3l"{I�jv{)����w�*es�1-haA�erize2��=5 "� �"�  class-kL�� r8.j !%A�H2%)�!�$�2mO al%�Q�>� �Ӵa2,!y�����aovH�Ly+^�2�!gV�.0A!jip��w7X��re 6�.� ecru�� �� �EHfi�vd�!-��� � !,� (e�qew [3�~45�eQ �Xo v%�9�B��E�� �X�L 3 �9*� �faW.^kfK%9>/ G-!��4 � �f�H�J��!��� �2s-talk"Vzx!�)(a� , ol:�a(*�'8T.�'X U.�o3_nsy`�U�ng�a.K 9# ���5atidneu�J)6�&D�Ge�� ��:�+�i�Mtl"6``�*�2�&� byel19PC!��2:.zL e�H-2�HB Jh!�R&XgB(��Tn2AiU�lie�_(i*-�n�#�7� �k.�|i�w^�)�}w!�qb;y�-� e6�f0sd4�k� G't arFsp�E courbhBU  f� unkn!P���fNk02�h�E�IrgaglsPE@�s � ly �=l.�� ��p~.̪�As�� ��y��|to�*O by�A�PqJhoi��g#o!�l�aAn�4,"V,��"�Y^����(E�"�y��w �s]��m��^&w�en�le eno� �f�w�8 �"�"�'F�  � +aI6� �����)H)b;g�rav��8T!�=zI��C�M�F�up4bu!��U+co;�.O&�� k2Zy���2)�� aM�<* insi[F"��{;i)6�:� &6.k/:5ti-��2�XM�1(2zBt"P>paradigm���`ra�)n�- ;ppr�I drugj�)-`i!��-ecpi��u�&�!�aN>�p > �4*N�.�ri�7� 'se�@�~v@of��?"!< �;nB5_Z.� �d(oFF��� �:�i�? "� +gu"in/t�����&��r!����o"�52�&**: Z �2�9���Z��l4gpl: x�g!]t5u��\ !��,:��mEց��p����U appa����t�%'{/��si�af' .~�@i�b� �da� enha:Vf�)/2�����k���n:r5^X>L �P"Ain�&" !c(=�+c)�a �}Qo��.�d�@s� 1�t5ach �w�N 'eet �!���T$ % 2�H/ν�� oce�Ƒ�"�[�p�� w�9��l e1gxla�e�hal!uiH<furtr �u�!:��i]֥�u*j�� disoV�d6.TPHu��Afr���]an��ia�( HAT S6a l��lQo�SA Try 68a brucei gambie'm,�`T���Q�����jh�h��in West �:!&hpEU� _:ng rapiKoYond�;ϧ�mtauoself-cu�gnK?��du�� Ej�+łsitae��at ����  ȉ6ˆ"z���]CGfoc�@In %~b�= a���1d�s��fl�s�% geC?��rCa�` a*Lib�candi�;9� ymorphismI!�-ye�i&�!*�5s �1�v�ci!�Guk���amp�.�&� % 425A$Х!i��mpr��of 232[V!U79�!����!!�"US!��HP=�X�Cy�e�Dv5� 01145���OG"1)�8 SNPE�.�!?��s�'>��V���=��>aA8. IL6 rs1818879A7(ele A ( p =x00002OR \�CI95 = [�2�H. 6� BONF +003F��~�ʊ}��#�=ng)��"I�!  �#±<. MIF rs36086171�G�*m��]� �{� ����2�� K6�N�0�,�>�669���&wm�7.��BonferHP,r ҂G� �$12483859 C��J�>0�9�7�`�8� .�1�>�95e=�215�����r!Y earlX]鏥�fAPOL1 G2� ( DEQe=c0Ň�s7h.�49����j�0@T)��B��e�Ls6� �12d2��P�A�4.�2� 70:01+kwio��EEH=�vxAǁ�. Nܪ�>-e�� Ayqr:a��w��0�qs$.+��wr����e.� v�y�%�J�6)/`F�6.�y�)��,s"q Munders�D��st-pa��iq��"��, ulti��� @sry .x$�w�gC�l �fI03leNg sickn�a; neg�%*M���Lub-Sa�n/��Ctwo�W-�3L7�f��xJ�( ��blH&����!��9 ��[ .7rhodes�7E�m"South5� omcau�4>��9|�+[�I � �,QJ  un�pEY!�CQ a����A*, e%. o$co�[2a�weEvecyu~tO�e fly G��in vlpalis��s abund�D[�I dAbUof Boff�EDubrek�B Fore;�a�� �Y�+ /�d����R�P1%�euta� goP to 5i�some v���k[�M��!!IA1�9��  �jescA�� hQ�%����haemo[a�`p~nmpA)B�non%� fic "Q�su�t��Aunt�� head�j[ fM ���Uho�1�l.���9��va��A�:�(}�#�`c4Pa&� �$J*�#&�,%���ܾy!u��+%p��& �2>���ij a{.  !�_r� � 9��]ldb�Fm�pd"� s\,�I ngth%_�e��ajE��}t"��/��i�� ce [��"$f�!i � i$���8in Côte d’Iv�p�����i�yWdiagnoM�"[`yb ��-up e�<�� �]15 yea*�[�C�e�^V M5J  c,!bp��havA)!WI�9�[�9A drop��vK  �r�seron� �  �� e�B"s1��a��T��Y�ve&2dI�9 �,Rs { �Um ng-���e� �"!���:��Card Ag�jA�T��A%ٍCAT�A{͹9R( T� T" ��-�-|@e5�>���0��"� I2%�`|oμ b)�J(�EqY1 K�#�åu�� �� :�hfFaQ^.� �JK�6dFMIVf��| playaCoF�}p#Ret��u<&� *%�� @ ve G�virule�IY1RTK s�!i���?�*��%"�%�t<��-�u A������O�B�)J� 2�!��Ѽ5p�%ZN���b�st�1q.. ! Q.��(!o �:iq�Liort���>a�a)IB<hk6+jJ ngoln�*8"zal� �j[1��{��[���sp�h���J2V3H%��pu�x��z�#�}��#A7+� le nucleo��2; s�+�+,ILA�  .81� IFNG���.�sHPR�0LA- M��A2c(6�/� ̀to�s�'_�x �G^ �m+ �E,�����M��pa\ �-c� �#�a�=�i|M@�&De��!Wir��˜%b !AoYaqo�xz� ,)�!�tUox�ea���c�prvioR a��H����� am accor�A*!0�ue�Q`Z���v� ;2�|��� &G�"�­�i[�ab���%r�č� ���!JaVlanguag��S&[N�ȡ�!+�$r��t��e*vl18hLXGw^���"�t�paz` ��)�a�&GEN!tAK�#imu�A�dQA�!pb��> :E-"���! �-Z��)9.� Biob�R at CIRDES�~��e#)���asJ� Nf K1�I7m� ' "f/04/201(Z!!e- T�Mdy ���e Az�("` ,"r �*j ��!� mang� �fal�y"sS/*~O��Soussou !��%u�W�zv�t�"� sca��A~� ��0n���a��AlڙA�))A� ��I<K�=�l<`]q�[> L Vga6Nm�5�!HCm�PRa� NCP �l?�Nov] 2007%]D��%�,F"WHO)Ipm��&� else� U�B�!(ysL}%�"8t��Vi �tu�lR(�(*� ho!ءD�&�!�q (�� )��� D�*�W� � twofJ �#ma �^(a`}1"�(� ����ea��Ǎ�� vNw,� 1/4Mg�e�2@nݢ2� 4Xmph nod4Fpi���  sw!jn!#&�p t t; 3^llJ[�#K&��hL ���!vE�-an!exA�g� lumn"'AEC !�M�1 ��a�esh!c'� Pof�;��es ml-1� [ -�S�c e8%y"_ , ��%v�% A�/��uf�;� 2�_ay��! i- "<TlF�� ]XA=Uy%��ig3%"9�  .*�[��:� ��J��>��WYL�c.!�e(.5G�*� i�[t��p"�C:�= ) CI gC��k��*r�)=[-�����7o ��othBd %ҡ�TA p� 2I*Ixan%�I�ŞA;ce�a�`a.ju�-au/۸(ȶF� f�> y�m�!�er;����+�yYg��5jE"�two�s;FyU�nd�� s2��8b�d%=U�6�s�>��!�a.�0a(I��-�J�z'��a Zc�v� e�2qe/"W ~ ce �d�b%I΁�\i�x���"UW�ZA�1+��w DRC���oo$C�"*�"���law��Ug`]*�se5?g�&��80% p��f5��*�A�O*D>2%�l����alxf��en�`of,� 565 3!e80g$4h)- ��pa t��of�K3 :R�e���s!��un)�� r5^U�s��c���%'� ;�O��� U a�?$package ga�r l�. DNA%�A�� � ��( B,? � us�jeQi�'B >�l�pQIAampB�Midi KiRh�FNTz.�_M� f�*�e2�e W %�9$x��8M* S;�t&‡uNanoDn\?I)l��KM�-woaL�:.�}SNPa�I�TNF�LA-�A��,�AHPy��)+.D5 a:�a�or��IC�y�>LEI scanao��A�l�`m�>r�( r2 ��AB�-�� (%�6�"<��@E7Hardyg] libr� ( HW�Tp�;(K�:� y MAF'|%X=��cad����>��bE9�ac ��7pru4[U~B) �!!�'9JTLD<nd 2u!��  �eQ��A!� �^&�Ebsis�>|�hI���wi�5o�is��N#--�a= ��6f�B9�F�5_�a"��`h�A����! #Ǧere�u 5FC�"��&WaCso !)�2=%/1+ MZ��9A(օ; non-"  4f@ “ssxd�” .*�$,� ul�:byZ�)�m�S 9�!:� V*establ!�f)u*K9��t α/�%�s�8er than 0 . 05/�28 = 0 . 0018 or an adjusted p-value <0!�m5 were considered significant . In total 12 candidate genes that have known or plausible associations with HAT m�identified from the literature . 80 SNPs �.817 in HLA-G , 2 A PR , 10IFN%16 L42IL6 , 8 "10 , 8 MIF , 3 TNF^#HP and w0APOL1 . 28 of�se�Tremained after quality!c trolD8linkage pruning�us!!�ss1?d analysis ( Table 1 ) . ThvS!)are�4HWE , MAF > 5%VLD r2 m129 )) a� creaa?J$aB�, but reduced2progress���>�!�active%w than�0�43%�An2T was obser�t�8rs1818879 ( Fig�m,A� icat�t��s1K�L>�>bQ?I6low]5.�ta��2�5�!v 39 ,6�4�%�63>�03A��;) The >�A ��,rs36086171 G�mc d betweenVD]s6697 ,YP2�E�A�6.P07–A�53] ) ,e� �$12483859 C��Fv�Cy��2152�07�8Q��18 �95�A�t�pdid noA���.�m�8Bonferroni corr��1�s 2�!�0. No statisti��y2N-tnce U�in1 �y 4!�. �Got��g� (  I�H � HP ,6 !F!|)5jF3;>�r BU�p ���es . AJ�4’s undertake�Q this�allow usa9 investiga� t�R% can2� 6.eˡ��4 Guinean popul� ;%�fin��Vour�r��t�u�of:Y! !�u`2ppear�b& ed �nsZOajpVO%!t tectq ,parasitaemia��ndis��)s H us seem,(provide som�gre�pro_�A�!O���>As�OK��e abiY to%�taiA�� l�s��!�2�`by microscopy . However ,%��2A_# i��!���.�VH6�� 2��T r"< 6�confirmEhprevi, �E�E��� Wa morX miA> sample [2�theK gen d ag)A2`s!�t � � targer multi-country TrypanoGEN�sortiumm, o�  extens� �%1ibX . Cooper et al . found�y���!�nde���in ] rho� _ in Uganda �.-k � n/ �t �E�ly�Afactor�� LF )($human seru�at� fers� istance!�� brucei [2�30 A� (forms pores�!^me e endolys�$al membran� triggo !e swella$which lead� �:[31{ exT sa{!lsoat R� &� enhancmits-#� �[32dfr=�!Ma�except 1& !�.�a�ly; by)4iC4 wo� spe�can-~1is1becau1A� �%l)�re5�glyco��i� gsGP� >,-Q�M��2SRA�re�� (ly [33–35!N�5inhib!OAA�di6 b�ng| �a� b|mi� up�A� =. f9`( group� %�=/TLF-1 kiIA1.�s e mu��to%>TbgHpHbm� 1\AS(of Hp/Hb re!� nd l� p �[36%he mod�AL�G1A�unkl a�� Rs5&of%Nto- u shou�heref�mak*� i�to55. s is mechanYcN� ef�g89m,m� does*a�!�� ^7�^d� , we��d 7R�i"� 2!&Œ���L*��E�J�yץ�J?. -& "��6� �&%I��� fallŲu CCCTC-BM� �( CTC�q site%�$GTEx repor{� a� eQTL%AC073072W  nove�tis�!RNA)��6in�o�e oppokstrAOabout-�little!~I�[3���U zinc& �1�&%�abe� olw�!���; re��of ���a�-Wrup@ ž��-7�may ac�%4%���9[39A�Although2Y��� cl� + 4se data sugges� at=��� fun�al2��aP��ark<or2� i��pon����a}! . I�s b�c%dA�i�pl! role o)�mod=C(of blood br�b�permea 0in vitro toge�M)9Z Xpro-inflammatory cytoki� suchA�IL� i in qand/orCNS [4�plasma� } �e.$ly�� &7%�>B i�u a6"� or[ patie�[1��Girar� d� ( 2#)%ued9vsyn� is \inW��marrow��F�5f[4�T��, Il6�4i�ima��R} medi�Fj�EMaL2�!F8iI8phenomenɡ>^s%u�!� olog�!\� Ip � ob� � }�#in� �i!�n�� %�a�e|��6�u�a' Dn DRC�e!Y$ rs2069849j{!�mCoe�} � a dej��[1��Our �WI#&&���e G6Cof~*��ki|�&�unq� ��zA�rJxR_���q.��Jn]�B� hos�� impl�ed�!l anti� bialAwY�promot�e s!�E-!.�f)^�,a�8immune cells [4�g43�JLow.�-�h��describ{s favor� &��QR"mo�( leishmania�j[44oWe"�� a.+�Q�M,R(.* 0588�  it!����Z� � ��E}�� � ma�in��ic# eri� odel [4 InIclu���Y"��es fur�zeLd�k!� clin�hdivers� of slee�sickness�par�4du�=��2<AYs .y�demon �| outc�m�1A�f�2 y th�6�(� G�����)!<�GV�5$�perRY�framewor�FV�to syste���i*G8:f%1/��sus� i�A�.�ags E�W( $&\!lF-䡰�ne�Z��co�J!Pto �Q�sea�3](to determin��� "�&�)��2�nd5�x�nd�!hp!$ discoveryA !n��s"L � 3�A�oi2,of new tools"� eiole�negle)rop!���L��South Asia posse:am�RFm"!interK.���ul� !languagre� numer�� � strucI$sian India�a*� s Vmosa�relK!onJ��G��arrays� t�A?�#m�,mitochondria� Y ch�som�%F�in Singa��primari�escenda8 of�igr�Dravi�-1%–speak�  so!��� nd 38J " NA7!:AeyG�rw�z(deep whole-�*�nw!- E�ag�30Xc �+�g�SB� n Project�SI2� ��X9��>fse �����st�R�Ma� �i9��Ph�1Сs000 G� s:( 1 K�. ��ex�ed grea�"intra-g�� �ay�� h��4ozygous-to-hom BA�e r* �nnc Ae m�,Wh�om60a pane�' -def�# B)��!�1�up12��Z clos�re� ��]N.>eve, o?2N��tc%{inca�5�Europea�o glob0".M$wE�uta�al�, e�"5�Bas5! �.�l#��at 0$predominan��aTin�R�� admix��t�!rCaQY.�͍�%j, ed��%R� archaic h�in�!Denisova�" Nean:hal ).I&M�anc����I1.sƁ�a�i� resourc�r�}�@is publicly avail�H!7is ��obv�  a �''A�le/ �fIw �1Ainm�3!>i�. Next��eeK��%ic�#( alY) , SV�. Pria��i�v��of%�� �*led4 � 2�U��]t�e o(&2 eIts u!�Ad-�g��.� #��major� foc7*on!� �!��#��;q1v� nG �I��506�&�at st 202raro��world [2�$�&:�pM �8 readR �'d�ins���-��A�en14� Whil �)��A�<�/�>�a�� +� ptE� 2-6X!���=co�d� ��G� e!.��Hd!� Austrone�� a��S"{ *� ""� , SSM� �.� 5�� exa&� 'r���6 ��0�K �� letea�racterizEi8ud�.�[A�mm)�s�en3 cessfully6 !8��)�����ds3fn���"�Az[56A�E�0 �� (h�tissu~�. Ötzi [7]9^borigi�%�al� [ %�)�!<ri�$�9iI0%!�toi]�, "�y���" p!Z�eary�graphic:� 7!ob1i!ede�y� ����!)i" eul �lex-.� �z -n�/���!he first 0 dispersalf�"� 6�*�� to 72( years ago�� Tpro�-5�.Y .� Q��_��S rapi�as!� �!h���\HorE� �i��%�y�!2Ma�thr" N�[9Q�)�� obor�.*��a� e��2��m Anda�"�,Nicobar Isla��[100� -w&�@ty:��YgeQ?aa�e#S �E�d+�NeF!�ofU"a" � Y��eR1T [1�5)U�S5�8 atX.���p��] caste� Nencou�dz#gs�ia� !CA�.�& ethno-�#u�)n!s –6 Indo-Arya�."�.w � L�in northFi�"L&qjU.� Y.g.�Yis�\"��35q�)� a�ri�)02�΅��=9� [1���0eo�TI��*H&�H� ug n s.��2%�' eofficiE�!�uni/ !�� G�1,.J��a[& inadequ�gi�e: back!�ndQL V �cE=G "i��s Tamil!8�ale�2Sikh , H)=&$i , Punjab Sindh   Guja�  , Urdu�Sinhal!W[1�" M�&8 �qd�t4��im���.#wh�� "]] ryPcH$me7� N�t traEce�A�A�early 19�1 entury [1�G�vaim3"��R�of2he4y��,�.ZJO ��z�� Z23^5\"�d" ~ c ։WUnR 4aFY� 2� Wafof&� *a6�}�,�e}!�. . H�,�$e��Dh% prox�%� 8IP!I%Day:t EF:� | � measu�3hC ,�^in ea<16�� A5�[`� ��.%x1+vr�by1![-2^�& Yl>�)ershipirelev� m �weQ�p.�s�W N���g�>�)Z�4t http://www .�geUnu!nedug/~%[. *uwE ߙ*P&�He� S*�5�,rbeI���M�� U Illu� HiSeq�"0A�u�30-fol� verag�}uż$paired-endW!�wa�100g#� bp ) �] \# sIQ$w3?p%�4 R4�:S�5T��� ��ed�38��je�),.g26 fem��U12 �la��� eKA�� e()MlO.!Z� verkre � �ll3r �dpah7�=simil��|)��d�V�9A� of 56 bh*on.r)Me�A�� t!�!E�6of� 4'47MB e�M!�eZd p}d"�;ssV9�26Q� B-�m� E��NCBI bu937 re�� = meI3CY$nsus A� k! �And VAr�$oj,CASAVA v�,9�a�O�9A�!S�;n�d|�Y9E�bot�'A�le-)@GerlD��:#  A_ is Toolki�GATK )=7K6All*!�%m38�L }a9SSI007P- chie�(�%"��� pths"`!�)9�4%�To-��accuracՔself-mr����},qrincipa�%mp0�� ( PC�-a���%�>�!N268�J�-UVa1��( SGV�q�!F)7SI016 ) r)ly &B%�!�M A stea:� !zFi�p5%>W�u}cl�E0h07� 16 �s")e��vF�+`@of 256�1��Ɂ7l�E�J2AdiJse>�i�mI�E�4 inim�� fals$� �Ba�a��<����X Omni�{5 M*�!�?A�2�ord~! V�\dej>�5�0s�AsQ %M�.�.IA�4��pro�)O g"J6.�p._�e�%]y�A�7 sub�1re�(M �H ��EVCF��dowh$eamYz..J�A3�<409),�26f3&�A 5�9088� &��@/#H" �36 �i�aB�@>1q�2�;02%�/A90lA76 . 67%[ �iv9gv��.( Jas- �dbSNP13�:. !Hf �he Data�?of�_ic�`J ( DGV�nA�]A�� z& v�� M��Ek�#g _bi-?ic� re �1�0904�4"!{27�ydV*��B47s N.�6ly|'�:�/s�< �&�ITs/Tv� ��X!(�~wa�;.� �%&2[ � as.@(�? at 3�C 4 if!�triEAto�Pexo� rz=�0Y$$� ��re[�QCpG�/��(ex](a�c�:�e4�A�6%A6U - �17�%.�a�me� � 3&�I�� , 7 �*��EX0rAX�DlternaA��59&�+ ( AA�1as� low-: <5%`7r� m%�AAF≥)�>��)B�A�coEw"�"�1!׵#�}i�%�q��m16���&ᣙ. BY�Oa����Pnot`�oSNPEf� "Dd:�`of�Lr) egor)B��!I���%pacJ �2�1�/IInEXI v 92 D��378�� ]�!6a#��*�  i yca�~/?�q��Am Fl%C, �75 %G�by��SIFT !nPolyP$v2A�be damagA "ot�7�� S"� �5�� .�=�as�ars)��>or no�togo5mi��712�59L"� aUasfQm�w:9O . In":u��al%(a�!WY�.���A�!�2at6�/q�Ax>5%�!p �&-g�D&�r�5� ���Ip%�!� �� 3��"�I?Ho�=*9JY������50�y 1 kb f q�iA-lik��FgA�e��]M= Q�]�;x&K'tdI�3,GifyE��/�!e&�G� !�ayIFJ6 3*�Qsu � ���. / (,429 loss-of-U�5�( LOF1!Z ��635 -e��W!N407 �DAAFA7(�9� On a-9�x��  �1Fexcee�aA ?I]!{r �gen?. >e>hhyA^�$ [18]����Q��of 470G �-� �N8-� 9 i�!Vis L4!Integ�' d Di� ( DAVID 2�&�'�6 nt enrich�of �in�5hw�+4�olB9y: du�, ATP-.8 sett��ABC& rans[5���H�dP.metabol ;*F��A�Zmpa�3`N�R�D0M�� ng��.t�C.,LBenja� -Hochber=# oceda( P I ed = * (8×10−3 ,Q�0Eb-���as��emerga erce� chem�.s� "!x3di�@n`viron!�al(o��lt`g*v�c!�� ��M�ed�m2�C"$'to�c M"�= In C��@COSMI!��K �>SNPnexu���11� u.� a:#6o�8 , ga�" sti� , heU83NpanK6fc�K SP ��<q "se�0�r)��� .�-��i��S/�au� Cst� � rpre" y�ce*(�� Y�.p. �"hec0Naa2� �1K� 2( GWA�)5��PE�%���I�g;:�42 disD),� �@er�!�!- d�(tW@p"Ac9/�,ola� nd T9O2 diabe�/���y 4/i� rkI��3048886I�wa��a��J�b,�! establish�a&%$R%"%�6�H:(�2�*>.1326� �2.Sl&W.ps R y &V#� 6n7emp� u�,��%a\5l�RN�CJ :fh%ng�3Reh�colleag�$�� )SpJ� )A1A�u)p�G�/�T"a� , OnDNys�AoNag@2Siddim-F�9#-=("��%�,�2�m?q�%�! f�x Em�R,�7!�"� � ]H1lo� ZIl# *�n_( HallakxKamsal Velama )�$pt Chenchu"� s 2B�M��m�*e ��n%.m a�a Q?e."��2_�pre�a1�< itud��s0�`b5V"A$.��W2�"�#"�on 104 Apv.�-20-��oup}�byV��.Q?Aj2��Tsup�8�!ypAR_ �=.�T#�(t�l�*t2�{&66` � )(I� -vS1�A sep�!e�iTQcE�:�( ��)!*m )E���Fla>'se�B�Q.B32�3iN��PC.��Gh2��&.&1s.I#���oUazne�)�(�8� n�Om)o/2Az&� i$�Ubdny.d"�:.� Ame|H% Z �j` � 6g��E?�A|�@ �*~;"+FSx�'� �k��i�! b�F�5u/y"��QE��#e��U �*��#F!~.��4�I'9p�"05p"�s!9%k�WI�) ��3� ":� 6z�! ��s�@l� ,Q!�,*a �eWE�until� Fzx�Ⱶm assu�( K≥ m�3B��&O/\�u iliz ����of \14 . 3%�e�� .0"1 _>. One#>9�]�w�$"�Pd%�! �o�1;S�!�she5uniqu�%>� @a\.mw�3�<� :�U�4�IW*N|E&*8�.8!�ha�?�-*B+4is]I Fc>�aP%�b�9@asi� �&�:�$in�rE) Y!t��/. Unsur�(J.l��i�&� a�r� 9n er%�±�themselvoM�4A��![q Rx�s t�"�/u9-~o%}e&r3U�.W_��2� �,i)&��/ .:����*_?� :F:2�Q easu%)^d"&SNP5C���Qy�!a��%&��U!�9� u�DI�a@cac�#0%�6�8"D2'a�-a5}��:A� � NPE0�b��%�(!�m2L;qT)� �edV he N�Y�"E�s��b�&@��=Mu<RLs+"M�ZI�S arisv\�( a"if��Z��marf1&�� heU�a� ��b6.W�hQ�{O�R�"/ spc$AWmDric ca�Q gZ�+ dQ�E� �;i2)�]�a�2=kV�N 6��7�� �6�uY�g���� �!&6�~!w%qrz��2�, s5L�?=7R �c.e6MGd�8�&it�.�&1 ����%IB!�-�y�" ��.�BL( e tr�}T i rFVU8A�& A3n�N~"\ &ry�to� 1��s�����_to avoi�(n~ !f-�!�1Tt*x9_R6*u� �8)uly&� Re�2�&� onp��s;?��1�@�A��by Co?te� .�6:�Q 51X��89�7I2�/� "]/� �Housto!�a�a��a D6��O�%o�Jd�s ��9��'��867Ga�j*7Ast6.< ( CH|HS , JPTsz�B�J�!��J!�F*�A�"%%pL�A$( Het/Hom "�G�Qa�d �a���s�A��>Ei�>)_os�w��9i10��r��) �c"jME�E�"?g�� �;�M�ad"p9�s � , S1�%�%6' o6la�>�=<;t;2� h Eend6�"hGIHI�F.)��T�$W�@�m%2/( mtDN -I�!2*h|e�'HGrep [1xR!�>})iq .�BA.SM�?�R"h 2LtE;�ARA�>.�,.I0[[2�62�X2�M8!�9f�.�]hHV��3�W&�. F��as ��l9Y�oAf�^A-<5!$Cb�C2�� ����7hH Ye !��)i�1��',�D�E6bH%�.�.���6�5�9�as:�m�Ha2� "37-"*7i; H;�% maijA���2�; LN. �a�Ce� l����wo5r� J2b26�&:�Med/k\�q�er� �h�b!���A�)� AM.pR1a� a= ��XdJ0 !�20iQ�Z>owfU& �U"���[a��&� "=�9� �K�Awe�AaWl+36 �sF"%b��$a �an q5U (�sB�; 8s�^a �i)2~N���;\l)��!!����Ym�&� i9B=X>Wwo �s��w��"s.C.mS5�q�r \"obM�W yiel� �^`ow���nid)Me�=n&A�osimonacho�;�v S1~.���g&G!�5.� 5>!h( �:1% g*us �5�PT  ,4-'1�*f#��]-UR.�%D"H6i�A� , despisQis+bea�:���V: J=�%�F��a9#�=� �� |W[ 7% (a�K-*Z)z��3!�IMer�#�IA�"��50%2&� �7��W�[2j<>��@&EAp& �/,�_� �/o *= 62L54.5,��i0gI� jq�?su�( CEUIN , GBh_IB� TSI��D+:)>�IFlyIto��o` !y؍R���+=s�C�X/ �BjDi�S�L2��#-�u�o�k*���&w53%��]�@"Q}�'nF^�a_:eWe+U�1;"J�]om!� hoosak6i�J y�16w:U ��D"�$:tF �%y�9ilwoA��'�D ��Q�4*�D�*a&�D=,�+nzC�As.�ri�[ inpu�L h!�5�a�ancho6%Qa"�$�.-5� 033��G 6F]!�6�E�lch>,nze�2m��$�3l�K l. ar'_\�f�ѽ�.'� s%, �r=�.m)A^.� y1:�v��G,= l�T"?$Luhya Kenyk ( LWm7t�44m�܅BA)x!+y�"W�!+*".Le�#AYB��eir� �-^ s [2a@�� lso͌�o �R"�G]�L/� � Han Chi`")B)=>1�,�����re�-&$� a@9�:�&%KT� alua�ue robust�Pa�hG IE�!~};J�:!|&� B&H�,�F��on�+.�senB����ً�:���EZ �!�e��.%�6�s�6�eis��IFp(��aO. imum9<1X)|)^J�F�!�#e��W�?3%�6E �)�u�D0T��~ k&�S�;��� �9jDURa�n6�Q�i*�Aby1P!�#c.Dou�X:?��N>B"O�B0X�� R� \\� g�o�Rof 96i�"�HnE)��BellA 092!�&�P:@V0J=V�>���(nT'�6y"UHg.�*)�� �!,� aG r"B4�u��> ~6k%1.�&S1 3Gn19&M-�=��b:LA��J ardlU0m{8M ���N�zic*Z%�is.DV �� &�!,!��ki"\n�<2�ly���z�0to��F�RjItor�gsawE%%�� Man� o�7}0�J�#� ���VB�*|L��J ��d!we empha%w!1o�B��Q*�!(� �)6b/!B�Ar�Xpo�1*��&pe=!͡�s /cJ &�:a$�3"��97)�u�yA  ,l 1i�2�N!��eA%68nd-�;!%r-�hi���ZX r�6�% ZQ�4 .65�\XR7  8�ocr�!SkI�� �ɳl)T���A���:9��a>21jf age;havA�'Ga�Nn�cI��9���PI*f�iOnt'�3mpetenc�1giT�)'ent�c�aBery�~ �fo��6�I� i�re�Gfailur ��I(>k>�v�ear�</L.+:congeni2����5ir��FSof'9� v!� telepha�M to�if�2oth�=�Ig���sK&K)6�� .�Y�I�9c�obi��=�� d��8!7rov'�%�:���=a�%#� �^zeLqK:rU!�%��ri*ދInsm:C 4al Review Boar,UiN� al��P!� Ho� al��u�ɘ�N3� +2MH��b�y�a1ll��51�%6extW 1qv*BioBank���( /* K -,�� �Def� �%c�_d E�Am�Researc�])2e.�$SrotocolK"}P���qu�u����u�pic/�e~ QS2raMax Ge0C EM�Pp�l �0B�I�trophom9s�B(t 480/520 n�+to �Qre��,�&�A}�)�%&&� 50 ng/µla�hol��2A_RW5 fac�� at Haywar�2Cal�]n$_US��)!<*X pe�@�>�run�aI7h_��T &� 3eX%J2lD0`X!ji�"�f;X΍6X.�n+D�rnte�]� �!@,&3E��A Eaked�lFFr�<G!:libra|��Bioxzer%�h"6 s�ZG� 1��� a s���-�re7dA app�rgachQW,F �y�p�=a�)),Å��GC �k�7�� ���!��m�t{s ���6�O]�y��2Dm���%�u'8^#ge .���Es must9�a�sc�l��t;3�a�l�� O�r�Hn�;Ea9]%x� N �U�9� �K��Y�:� �� riet+>�\io softw6 byy�.UYmb�a�~ig"�E���Z�<�gB�Y(�b�+|�Bi��oy����,:Z>�?�u.��� U��HA��0 . 0a1_110909hmb�K"�Ua�Y����"!WE�e v2�!!T1�nB��t�;�Kof),#-*BAM4� f�[27-f�,method�<uo �x�_�<�ls�Q�l��I*��3�ZS (��IQ�+oV12�I!68F�.g [29]2SupAMM �� deta{c��0{#�M���]� �b��(�!Z��o�3�6Aga"� �%�U�-t&%xZU#O*fX�w�*!��=e�ly0�%�(%Q)e�w$u%��%muz"�+ 71[5�4A�%#.!��PA�6�iS�R1�AU1 b|R��(�Nal�ac���Eb�7 [%�R[`�A� Poly�� ����a�-*m���*�Wd.Rif R��b≤�+5goR-2J)�)9�V�~�vLOFxs�t&0�&�Qby%T> nT^.��, s�e-s,m"�K,0<(frame-shiftA�%�b� eR&~o!XDHXa)An�T!�,�N[Ջ!'F�(nP y biK� #M.��N���F*ɇ�^B�#A �lppm�6��:���L[3��[34�m"�)� � :� GWAS [��u�onl�N"�L |��.��^�se�E�. fr%ց�14�Z� BreakD�|r`��<_2011_02_21 [37]s )�Y!�Hug ReU e_vAj3 �� ,-P��uq#�=2懵ysDel�S"5 ��2o'^Mcu�&�ron*SS. L '�5XSto�[MbZ2%su��o-)by& ��g�) al�Vthm̓2��F ereb �+yal���z"�[by�y����� b:F� 3"^� E�una3 �gT��egi4�Ew�b�!V���AAGa�)�is���vel��U�!aadb��?\SMP�R!$i�N jgO��*!Gn�/aYlapiJqs�!�a% %"5MP�;��DGV"�w(2013-07-23 ��#.}��*��"���*e� %�hqwO.��N� pca (xl�� eige�^at [4 8A6#� i QC IaJ�n�2� 817B�%�kbFb [43]A!"� �2cl��-6�-�F ȡ�"u �!~atU6��QCi&j�Q� aly9G%~9&�5%�mA ARr(F�E�of�"AA!mx:�/on 2172Q02aO�T�|gAM rdCAd:�20u;600 =-�2L�:*P5&�>1P-]1��a�� �M� 1i� broa�$+�!W0V:- W�NO-`A!z�.tudu.o��"#/g-stn6A*�":�m�:�L}:}r1 4e�a-.(n�&6�i� ADMIXTURE���?22azgram _�%��451b79>m.�&�z�st�A�%�2� �-�16� �"d g�#� ���?M= d���a�t��Or*�De&���Dos��gt%�h#/V:,�na��? m�a�E� Omun=8 !�wopde��, ?e�Sa]a�"�$�Xe>H��� >. A�  D}G%re�Cs�e�&�!�3G& v*,"�a3�; \xsa��atg2_(���k���%.�a�B�om��$�:�$�0wh&*Y�>�]�E��M�<"�G%:� �+�)�y���$FvseiE anc5�#E��.�� esDE���_��;�/H!�!E� ageEfD} � � Z y 1�1�u�D)17��:�� ��7yC�3,�3,�7A�YR�7��Ba�N�D [46] *z&i516to 89 U 2��&achE��N�!�!of-B�C�.F���UH"�C*=NS:V.a�9:-�C!���l8PI�'@�h:fa� �%�a�mAUA79(�M&�j3� lZ�c��$n��ZFAX2?C�"t6�Fcali ZM?2�>�x+c� Ev���Y9�S-�;�5�Y�o*Pi b�!���*b�!*�*���dea�u �"�ss)|�\� ځO[4�7 E�iYMOajs �(S�wo2�<='=(�8,k���FK(S&�:or2�;)�!mb�<� NBABA �/ށ* i@_ -G� V1-��dW le B�l�A�1F�:4A�NABґ�`F�~�. A�W9�R5s���he� �EF�,.P � � �v3i��(Py2N :�!e.�]Y)�t H�ua� Z�� to M�-� lapZ�block;$ 5 Mbb,a jack-knife��L��`Sa�<mGF,7nd� EJZ�of. .�6�*>i�B�!�Y� �m��F�-v IIx�C�&� ![50&y�oJL?,�Jq�!U*" of 5w!(6�(ev�9$mpg . de/n�al/Xx . htm�� ��* crip���I��6�he Text� �IuN.�weba�0 .}tBurkhol�a pseudo�ii i�kns��&�9b�Io�co!��m l�, G��u�"TAmrAB-OprA efflux pump�/R�o W�0"�I� moleAwr.��` mi>��&3by Thai�ains 70815218!1 3799!�qRT-PCR "�9*�/ amrBɇ%��� KA'o�tdupregtrA)%�ANopAN&D�by"��mo�N �Use: !� walk�Xteg�9�;%IaSac�on���ng!��!� 3is�l'a:g��m"#t470�m*�f!�seH)e� n cephalo�p1Y(,e�. Fׯ�02�� drug�:8��a&c4N�; #filmsY���*��pro�3�_x uma�(!Da6�ul2m�-�1a�g'ofm9tdec�5!�a�(�� �N.� ̀�a��AJ&0id����^mz""��e*-12D�A ouG��,& a hand�5o{Q���N�@��O��(� �Se ��D B�� sƍd� arsj2�&� �&�10 P!�!��+�I� cykd�!��i%1( RND�8am���play �X 6�%�cli��:ݷ!Ti.m(in Gram-neg�?�a�!wo�ɚ,.� [�AvBpe� B [ �"j(�1J��'��!�2� Jj  ��%un�6�PhQ� � �Q 026b��C� t.�"+�-�>x. U� a &)=P1 oneruginos�"qw0)� !u* BpeEF C �1uC� chloramph�a��t��tho�$�� AA!%��1�F�isoa�"#c%h� of:�%�"� .�, r�� ( ∼1∶|I)_su��E)�,sR��.2(�no- ? 2mpr����Ih�matchG�"  �"t�emĦd!f#i�I�$A7�*"=�N�!�5d~2�l�5"�. ?dåN �of*~l �2�*] ,� EF ��rfto�+���.R�� ,<f�ARn  �*����m�!Y2B � \)�7 ��enc���F" f텁���\)s �A0 �lj* + 9 phys�* y . B �s� �I&sc�a9l�:;�$@"Escheayi�l&��o clo(@��RDH5α�,or ( λpir9�l"4 �� AA�O���rsPu��ly##wv@e��� 7°Cs)ow sal6; 5 g/L NaC� Lennox LB<$t�=LSL)!2aga�wMO BIO L�"+ , Carlsba�#����u�g� 9 u�"8]��,10 mM glucos�5;aC,"��ed7 . Un=%�w(E��A���ad�tH2e:��)s:�{$µg/ml amp1 ( A���<. 5">� ( Cm1#' ( G 3kanamy6( K!^2zeo Zeo,or E .�Si;�&00�Km = ,�� �97wild-�B�s5G-Gm��7:� q. A>felpuV�'0�� Sigm�S� LouiJ MO� 5d6I, erya�)#,=/, tDyxin B�s"�t +�EMD Bios�V�(, San DiegoA�Aָe"�2In����>�(1�)a�Biomol�; VWR �}&�B,��C�ee8PkZn�. P�?�pZ@*T7emplo�c!�2��N�8!�>> "QB�%c,2�b. Pla�DNA��͏�JvSba�QIA�7( Mini-spin �Q�J�/Va�^9�. C� yK� B��& �5�[����`c.F>Ոal�N��Gx: Pure�x+pur�!)X2�C�gm oligo&&�->�b)x6*� NA T.3�@( Coralville , IA^I� �f.�lyM|g� � -Tn7 el u8?_ Flp-�#�7&��exc� 6`)r� pN�-lQ@<�Hv� al-�@NTA ;%  Upet�.1�by Kuma�G a�;+e4�%L re! �$�|T����� �M�� s�o�tHg�B (�-r=�|at �+nm��0�_� !aumE�ۏ&� ,� �RNeasye K�mAIForM�-���R- '&V01 par�Nly?/A` frag* s� 3M flan6$se #�D!mrQ�*PC�pl��-9u= pPS19279pFKM2IU�|� Vn^4d&%.�1n�!�e0@A7�'dy ������a�9�-�hKI�P�,,num Taq HiFi��5er�(n�&��I� s: a 892-��mrR up�za�x)| � / 158�`5′- agggtgtccacatccttga�e!41582 ( (�TCAGAGCGCTTTTGAAGCTAATTCGggacacttcaacggcaagatża 828�E4*�1=F�3oDAGGAACTTCAAGATCCCC nHtcgccgaatacgagaagac- 1584@ga # �cg� �c; 138%00FRT-nptII-FRT^�596XCG���!GCTCTG�)Z5976+GGG�)3TTCCT5 L�+c!�l��r�v( �_e�gc��"��up��.;�cE2ttR6. )�0�HM� combJ�E�rA��, 1gel6~a��di�Y H1J∼9-kbE�q��c � �GEM-T E��( Nova���=�8pPS2282a�heR�::6�)5 u�[�5Nw�'EcoRI� lz6d^q'T4�2�NEBMili�N{ � SmaI�# (pEX-S12pheS�P� pez%T$H . SchweiY ,2e) �!R�35�yGen!k,}�Fm3 PheS�O��er-�Won M9-� c~���915% p-0 (ophenylalan�����3] ����Q"� � SM1��+or RHO�za s*�1 vE0 M10[68] [24]; D . Rho|&� nF��� � conjuxo.8�APrecip�b ��1 Bp24�Bp3; merodiplo��f)q�!.�Fq��� Km (�� >��]Δ[���h:�]Y�uJ .n�# � jE�y� sM* zi)%���VAD%e�> then&�!�scnPam�7��E�kct&�&�a�Q| � QѲ�W 1546%1Z�:2 unf d^5��A�"9��FlpA%�( ase-c � �XAV5e �F���pFlpe��>"�)�ve� 6 a��>ic�u4il�)�,�$����1:��);8d"�%�$ic���:� m$ �!�QiAmp_ V 6@ ,JQ FN �jZ�� ∼4� %FMMJ CopyC� H L� P�%�� & manufap�r'���9( EpiZ� Mad�yW�0. A,�x6ly�200 Cmrb pool�� u �3��OPE'$s A–Z)�–4sgrT& nigh<CBb5*� YO�0igh copyz)!��!!�6�=�v a�)�F#!�3��ol-�u�b$ _Uk742�174���A�lb1�uad!,_.2w&!�"T%kto�h�g� l�/.��~��N���n� ��:-Y I�Q9$74 1779�e�B��>s�#��]�2S%c! 6A�}mM .�c�SbPGz� BLAST �KP�1�X&`�QfF��&s K�#,"�# 1106:�668�� RD?*"!O9/)aIrt���E�t�ya�/"�"(bc Q#lP�| v��Fµg�a-E�BVL���h����0�&75_�� g��nebuli��)�ic"�I[t�C.j"��) +:M .I�, Inc .�/6Ea��3ryi9`o�$F�*�*( � 5�s�� a2H�;mmag��ajb� 1��a �G� *�of Craig"(��X�i"� MU ( 42!tAs�2NA�s]ˁ�M�� MSHRA�( S�� �j>;)F5GA&@?��u ��%�v"�e�7�H"|?p�$am SolScap� BeckARm-S����N�,���p�2�$L!�%��g�Aw� na"��:S�!!suCe ���E�$�3& &� _!)�sB�)% ��1%�;ctepi�=�VE5>!"$in2o  Nai]8a�*Gm-�bm�TS%� dilu�e�fr?X.� O16P,m�e0$out�th�I]  �xrepc�QZo3+6�!26��XR_&� %�� .� 7<G^ � %�sn{���e�.� mŧ-~orGJ2M( MICa�;����($ Mueller-H!tn�ErBec�~DickinL�( Frankl!�ak^` NJ )tA�two:brL�%�!r�$"�-�anC�"e�" y Stn0s"�Se guide8Gs�[)���re*Ka8 Bincub%KY�15��16 �^Eth�(S��:an%Np:h9ɉsJ��2�@�ŞvI�!-� rado ~ Un"�TBioSafet�;mI7��'/f6A �C��-Co@mb �|�� .R,^ob aS?LB� !,��)hbb2 F�eae /. Glyce'R�prt/:finYXy����o pe ��f!�t −80������G�. Inoi0E�vs�� EM��1�aE�{I�n�'a$ze., sto3�HE% le phosph9buf��d?�(� -Ald��! FemaBALB/ca?e"04 6–8 wee�3age �"M9�n  ( Jacka�uZ(, Bar HarbooME{M�x�hoT�\"� -fJ�(�7�!�"d�Or�w��f8:�.itu��A#e[�-�d�!iV�(na��( i . 12ց%�!���c-anesthetB?p]�on� jM��E g bo��� of ke�Cn��F� Do��mRH����vers+Park , K*��1BWxylaz W Ben VenueB�edoRVOH%��all.#��A�i% um�B aIsua� _Ub��@2�n!_um volu\6el���%%�,i���dn! spliO�l&�6b��no��lAAB!�)��TngB}uE��!AMh ��euA1%�,6ZA�ypHsB_-�ZatjJ.��aV�wly*�q:)�rT&sRpQ-r��X ,B� "� �%?s)� vari�m(. f��a.�"7(@�qG2 )i��@��(P"�Vw� !�*M' defi*!t � DD50"�$dmz��4e%مqtY&(S�%�e&�3 =%�u��) +i(��8v'itu1F� G�%�)�6.�B�5�% b0���)U6a��AB �)6A�d>X �BM�s&~ly JH6A�-�_:� ��zZ��9Apour-s H3m d"�:* in m� �� by"7q|!�:Ջ�b%�-G�,!Q&�� c��$��cAQnoA��&�B��"�-�F; �(6�d5)]�.M,� �W�)E�'DBCRTy��%3′ �(� �*�]6e�I�F� �(�� *V,n�9z5.��* _�W4t jHA�ED- �. �a%�F�gtes!� �!�Ft��o ��� 1�Hr81��mI. Highly� >1024� ) Gmr2�,"�2"��r/6Tj>u89c��% (a6�}���Moreo&���>V.p6���9�9!�th({&;"BVN-s!��Y4 ?-.�� � )%�O.�In� tras�A�(6rat�PO�>�a�-ZB)R��:�:b�!��1z�:2�'��nj� �sE�0&7�)��7li��>)Q�c@�dW)6g� }B��*�0�0a�=P(��MimSn�� C�S6R}�6b���,:$&�:�q�����Ѷe%A8E��.,�r.�By%�(�t . De&� �Ӆ�6f ɦlose�r�=�=~<b2m&t�~&�*��'$&�!�3EB�&Y��+B+�+!���i�T�� *���H&M2ArG���|A>b�f)e!�{9e �)'*>� �*r>i�fer�V���"ss �M�� ���jV�?�v!)'�}�=��)MmRB%�rMgc"ŷ"�%��"�60�D160�&� {2���>�=-a��"�F�E��I>y!ɩ��f�e��Z(J�>%1 �@*��>�f�� 5V599�1�(��A ?92��: summ�q �� 7�njCQa�'6a>�A�X&�;2�-�qq%@]c!�iz2'06|F�2��(�M��� r-up�orE0)� . Ra� ) )�4� Zs gb��`3IGc_jrAa�f�2�poI^+u|mBAIta�'<H~> .� i�:/.1���aC.�loA�*<�}\J�-e�in�L��inF$ mex)�MV� P . *z7i�FhDm9 �Mex�C�zsor�a� ��&�9Al ArmRi 0�Eeb4ae elseBC�7"E.u�d�R�'�Z9 nd"d �!�N� �:a!�%�_��-�A��B厉��|�8;1�A�1��8��8r�L� rex����y("5*h&_$�!��� �*�B�BL�%�i�Ti�-B�C} &5��%R� :� ��!x� F>��#�C��d�C"�+�6�+.*�no.�-.6� �A*��!;p�.A�+ �v6rd&��of�+��kb,A�S�bu ( >{D)&�$�>.�A�m�F =�7N ED"%*�^, I!.�A��A� ze1ÃeEY��I�I�r[2�$ *�11E∼%AB�%2]?&�!m����#->��AI�!i�es �0`B>� � "��f���SeaU*@c�)OR��&ln juH�zBURPPSe� _203�,0�/� �K962436�is�3�(( Fig . 2 )M�!^fur�confirm�$: i ) PCR wifica�u%�Ifs 1797%� 1801 DNA�analysis!&a 1 . �5�al0fragm!M% %�genomiccontain!�A�predicAR� junc�;�i�I 024 , 622BaJa�, 357e�ng%{2�"�)2a�Hequivalents BPSL171I% 8075gI�In�,A� well�abiZޅ[>90%; rega�not onlyQ@s.�(but several _ge!v�0may be pertinA��\`is bacterium's physiology�pathoD,is ( Table 4EGFirst�6i��l� �M�s%_13� %�om8in biosynthetic clusterwits��$racytoplasa5Tsigma factor MbaS defi�H�. Secondalmmedi" adj2� 2�Bs!a� � 8��~��5��7� enco# a pu�ve�� obic- A� cobalAvs�� on ) vita!&B1R ݍ��way [37��V(��)�co͉�gnumer��enzym���methyI� ,��Ui4intramolecular� rrange5 AIWhA�is��iispense�{�1i5 isE� �.�� �9eria are $toe?�an2� anae=He��JI:0 ThirAa7"� �!�mp��!Z arcD (-�4�PA�arcABC�45 ) -�!iargJ � imin���.� :�� =W prov| OATPu�s und�1 A�i!���{bs�Nex+ E lecta�aci�sealat��re�!%Q-�ACum [38A�I��iA ntext��worthya&not� atiơw��k 4a splenic absc)�d e!����\ ���o� a mix;I-Y"env��A� [39�W[48 If�truly E�to�n`!�eM� must� cap?of��acb�energy r�_noIa����� ,sumably woulCqu!nitrate��B>� !��to:�!��QU ally� �Ic� U�ar[41AFo� ,�:AMiXc��EY}��Je a thre)� opeA�m� 801-�s 99 )e�>j,type-1 fimbr�Qprotei�H" � ou�w(membrane usx,nd��{e;�a two�� �73� 316��u-i}!lchemotaxaB-�t�c6 r "� CheW4 respF ����qex�e� ���6�� . To� ��a� afor��io� )�we� ndeak�^ti�1"dsperfo��wZ!a��*�s��ed x. G�Ba�s �h> ��rei� � !�Bre7 cE`omes: s ��MSHR668!&he �p� ds hadŗ�g�� nsit�� 24×=Q� 93 . 3% (.$A#b96 . 9:�i�B� ��Y ex��94w�a�a�0 . 7 Kb&rA<o��Ios�=AX�b|�9� =�1�-5uIbN� zero->%ǩ�K�?cae"� � �� g� an%s I�. Whil�s# Edo5discern( or�?or� al linear!�betwe��!�A�F�� �_ re�t aNrehAve quer�argueaatR ��]is1A��O nywhiz5%-i.��hom�� Q exisa> elseb;�e�:have e�8d�!� ��`&1�wO.���e;)}�availE�on!d� at http://www . mggen . nau . edu/MGGen_�0arch . html ."#NSN m�A�!D 100%= both9��wr��2�n :��!_-�t�"�"686�m�c2pm,qA /@ .6��a)he��e���s)�E�tem�` n�!%�EC()�id`tie?r �ed>sA�verifby�� ly� �e&�4minor bands vi.S!�rea� s �:�aF n9� ��5on� duc� A ��vAnt�,!� 4��5G m�BA809a810q�I&�42 �174��T}�6: Ez�/-�)r445 bp �(con derived � *!�consist%�2434%� �10Z202V�gk �q �6�QZ ob�ed]3�is slighD,larger ( 479}) b&��a(s�"� �.dN� In summar���f�"ng"� =ins�Eo)r+ofF .*��%� ArryA�rq!� mini�4abo8y a� � !�� ,!;�6n�mmurnmelioidoS�o�.#�ǁ+ f�JX � .�at least �A3in}ror vo.�%ub ed d�g � stud�=!>� dise| 6��a� �by lone��g %�A�(is scenario!Ilik�,as simultane�T��Can XG>commoa �.T[4�� 4clinical diagn%�ABurkhola�a6B�rel! $on culture� ost m+&� �_�v��4Ashdown's agar��s��+ $ing��isA9ci�J� majo��>) sE�����qɾi�trafcs ista!� to a��glyco�s@a]�Am�O�(efflux pumpAQ}1Ah0009m"�1NE Th@re sus� b� F�'suA obviouslyPi")r9h-��%sAue actualIber!6�2�1Tm�us`higT. Our!>ult-�&� :U�macrolidcil� of r! U��i!1� due!�~or lack;exX ` a�*�.�szpre1@sugge^ R�en [16�E ,though BpeAB!�B� F impl���c tribrB�: rkI�a "  KHW [14�we nowC1^isIv�  �]2�:Z1026bJbima�DH . Schweizer , un&vobserv�s�aM1��!p�ho�ay��=.�J-��tq � w lev�in wild-� l���A� expl�/sl6of eryt�y�+=Q � ���!88 �3799atP���u�b no�ԡ�up~b� b%%)�all�z ���Qy�E�daB�. Cli( good subAte�=[Q��A��P�!A� , qRT-� �� � %� low-%�.�-���� ��in gA�HnqTiS $)�� � &H��c� � �s#5poX#$&_BsE�7�[d�  th9".�&�� =E�i\be .�2 i>v corQ  $�8dd!; themA\1N|%� f�"H ano�sew% ���latM��b�t~�aGt$ly enginee �=]bE�  Bp50%�![�.#If �asI*!s a_ Qt% ���We��1� , if^_ * '{�&I�s��e!�1� )= . Fe_%p� s ai%} ddrez&�se iss97&�iX�fac�~s# �Cmp")?*��ol�al�5-� manipu.���I�. Las ,"9 �>isJ� A6b� , ye��sv�!��ma@#a natus candid��a&R�e=�m%S[  AgS OliaA@ ntibiotic`Y,l a2~ [20�kan�� 9 tino�� /str [43R"$nourseothr� [44]o mark�),��val�!����&� -7tru4Δ� � u()m�2 �.[18"�.I�D� eukary!  d�op�%�- du�A!a �ag*/� crip�ij��@d�s "�"i�'of � i��m �= cellw���%�of2 �? rolj ften2� e|ex�$ell+ala�m}Ci >)ytoki�|caG%eP� surfacd � d),}ŀto acti�o�d/o) 2� ::�Wlo�taYhJBna/ $CD4 T help�Th�%Einto Th1d sus Th2�"�gbtun�!^v ��"qua!fy!,immunofluore�cA�vidI q. C��toA�ulexl&�6Bantagoni� !1IHEe` ��h� ubiquitco-SZ"d6��igh�SaS��re� tinc#basal�6T�Mi)!.!�� �at Y.` ��+da sp subpo.v)<2%depen� %�6� 5�.%�Ys'n!� Q�ell-to-W,a< 4��W �~� ph�ofYgM>���i.&&� �aA,Q).:��� . Up��%�e1U}�, ={� assicMqQo A�d�#�.!�a weaka?ra�+network�wi��ver��-!.s� (/gnaQlema=+)�6}�a�T+ reI��wB�.>��� � s ac� "C Th1/u�El�Db� .�:�!erp�%b@6��[#{%,A�W�non�+ unve�,in�>����� tegy��mamma� ��u()�$inst noisy�.�. Anq��.��os arti0$�� urI.;&�� Ms*&�N�A��.c-NNv+� t�t�A:N" %�/Os+4toggle-switch-Z%9 fB >.a�� ve buU�. � hematopoi! Os [!� �A`-�myeloidA�6�.[-l8granulocyte-mon .9ve�� mega�)� .,A�h-��. �+UB0 P$Gata1 [2];2P BJ�:P�nEB Tb� rc 3 [3]–[OA���E� e�  b{�k�"�ed��v6-�&q.�� �o�/|���in:�pr1��i�� mmit to “;”�qM ,rapid deploy._ R�to exe,a Jo�ram [(�2a��,fhse����E GATA1�cq���[8%�12� ��-�a�uB�-���a it�� �In adZ!ZZ�de� X%�. .Ѣg����'.�� ��ri�6���& ��� le�  In�&�9��4D3 e goal ha�en at�!�a��lyJ Kus 6z .M$6 , 1 conce1*!5�U9*ad~3a�ka!�bian i��rA�� towar�5�&�f���[Ex[� ;,� a)J�, T�gen� g�B< stagQg.A 8e�(��r�9FV��.� ,��� �s� a,�-:` y �&A=%q��3!!���rt� i� Z])N oughO5v��%mE���orAd!�spV6�>NofJRm�*k"�*�)ET9V.�D,�j Tbx2[iI`ma�3Nn���>�assoc�w�"pra A��he 0�� IFNγM���;3��2��IL4.�[5zIn �:%�.�T"� IA!�6Ž�� %7A��J�p[1|�vt�da#pV&ve feedb� loop5cross-i� or]ter o&) ri����R1AZ.s �)!�'��` ]:��s"&a�I� QL*� !th,i&-);*(involve�6� play�&(1N�� Spe[$%�,I��v� Ifngg6�Ix�ri�eM�vi��w�[1%y �# 5s itself�lA&� R1"�1� ..H5I@�l4 [1�-$!8:�L4.� A[28 u6;m�6, �be auto!�k5=��� ��FiiB-�si�6s ��_ �%�2ɀ2��%]block���ae B�)direc��, –p�,.� [25` *2vE�+�e�nu�>�Y�1�d:.w�g5to� CD4+�M�$C57BL/65.  th}����&m���:#��w_ -CD3%V 28 bo�F/polariz[Q�s� neutral N Dag-� � .6)cho�k�O�H�'ou0{�ed&�!��-L &1�$A@$u hybridizX < ( smFISH ) [26] bi"�%Jwto=�"P �}Q_?%�Y%2��hs S S�, . Wi� t2� impo� Th1-!b Th2-�!cuT .�!,�{":>�ng(,cop� J�.�, `;:�v'>�.*$kB�af M���1 1B–D�tSim&r$up-ͧ/J�occurs v,� �1it� 24 hd��tr�%:}^Rl �' eeksF�e�)r)lfo�iq�*� &� [2�F2idv6*.�inv&\.J"�Y:.{�m�B���?]���I 48 h�� ary,t�9: �7�^��T)�i� �4eM�onq4J��(.��5none8 r/E(? �, � C� �;ed D�" dard2�M�s n!leC����Ua11j;s�op� ng� a�]ly�,cribed�r/�p�-4B��3NR mannW#we fou?� :x yv!?U!�f�?�!UI�R�i,j�� E , F�#�A~,�A���7RL 0 1�3hemselv�6�9�q��6���.s!��g�d� � r�)--�!=J��D(2�$�"�=F e am3M6�%�.J1�al>D3?ac�Cs�)�o.� �"�R�J�N�� rob�7phe4n��f&�O ;Zsee�%_de4U#S�2I� eAgZ@!n�4n stoichiometr�q2>�=��1∶1 �l�=B�,�$� ��($inua)o9� :łB { 4deI N?Fiq S6"A4"�tim� -���Qm���8accumt-*� +fav(&z . Si<.+m�� �� ch�<��='�o�U�d��q"o<�acu���?z6 {er)�ub!"��_Z demoa��� cas (e�>�&�H�:� �& J� � U "+:��( . TB��f:zb&Zro���2�a� .�, ja Pearso�,: coeffic�,R!��6059 ( p<10−4AKa���"85"8"I�uX� ��%x �al�*{c70measuA �X n;�Jbl i�e�Vu )� %?mat hD)�.� *: e�S�3It�ok��n"$=a>.�f��&�����s Foxp RORγT!�-�2S Awo� ")�2J[K<ory6��(iTreg )%�ThI,� �(� �� ��ae?��f!�:�S6\ WTveE�a�aX��o�A��/or neg�2�b�P�(fa�V@9� �TmJ,�"B72T !�,"n-9)siv�-"�,*applyAu )���toF�V! post�L�?*�!��9f6� 2a:�Q9 "�#���))�u� ]�[2Ks��no����.��Z inv�-g�A�6 �6�.� . AmA"�*V��pf�eff�8onf!��k��ed−/−!�Ŋ� P"1a 95% }/E�U�(�� 33!&�-o�M6^:uat�i� a 93:oIEou �l4:Q ��52B�2�<FB�yR7��JH�.1�\c�=NMs�a�!��I��p7bl* r achiev TtG#90%��W=" �B�#erq�Q<�p]l�5:*.�0�[Cur�JU �22 ���*��h�% ��&�".��c��O 3A(�!+��s��pro�/io�"�&E�5� 6VI. Sur��S.��xq1e�-q�ha�2� *Z;!v�.�4-�t@#OFF���B�AQ�.If>&>�orBH3ON k�up!%YMF�4.W�$Awa^ dyna�; G!�"- �Bu>�{ magnitudey.3A�I,"o 8�I�Wng�200:�w� D�res�ak� mRNA*�)��st�Q������!�&s.����) ship.{ $&�c�3VV�5-�ofewer2y�\�CF)m�K)p�"�reE�&�2�$of}�in� .med> �'tocha�)�M���hmf�\I�CZ(��A1�� e^!f!��(�Nb(B� ��2oG�!:s~(.�!eH�8as�("� . � �~a�e�Q�o�R =  15 ,3 � ,a�E��El4fD32D1vCUC3Cea� ]novL r�b�06s�04*�>� =n�2J4 A��S10�6�2�@�s -col<;&��oba�R!:bdetrFng�).��>�C�7W��!� <=K,] �#�@e�0f�EinX� %,_�E�9sBt!DQ�A$2k�=��EA2 a�6��:�app<�h5ecouple�?Gs52��m�r.�a`.~�2�!S�G�� c" !�![s@)�pM5%V>H +aH13[� <� '*"�z%��3�� =��yngs�"� �=���s �*H�� milieu�0r�� � by"]A�l'b9achy�*jJ}4es&�.� duYneighbor�Dy plotM�F�#>��>�'����hax!�I�� = � &��O�!)f�1U��5?�F^Ai"�\5D�tve-limi�a n&-ji� ll-�M%�M"�;��rrm6�&�`:�2�Z=)҅$MP%+�y�js �&� ^1�s�b^�@HJ�. &�� ? !I !4� wGsu�MN{5�S1���en �!� �-�A�)!� �[]�T � as N�o @!c0kit ( Milteny�Mi5["0JCD4g&�"Q\�y� � ~R�W�"�SM�EQe9in �QK^by2R(�`�B%�J) ���)�Wa�`u�C�3ej�j[� �^�x �&� 9�N�q�.A�.@u"�)�]�0 � 2)he�&� anNj�IDN�IZ\�JJ6E�GatM�v���:�3^[%�v��^�@origio4q bona f<. �)O. Takeu.ge!�q��R�� 7�1.�&.�'�"- l { B�&>� �s�r�s�t&�6s]Iir.��#-;� � to*;&�#BtI�z4�p�4a p"Rer"�Z" 8e�kA(�]P7 outc�KMetL �.4št1 ShypN s�bou��a*0[��%`~6[��� C��.�i�3�'he�c�<�4w;>��&n\/n�ut�;f�*�� F�imM�0!� 16 h� &�;J�,-�$B/e�,�2mL4B�kg4 tonoCGu�3%�+� � �Pnt��e trend�x�#>� 3"�#f2�6�`]UV�Im�:I*B �n�2�M�8 B �I��z eo#�a� �u�\p%�qS;�4,MV>(22<*D3 044" y�!A4� �A�^R98 ^ . 6×��%Sl2 *(W�9_&�Q�s��.� }\f� s.��si�1!g�7&9$!��9cho�_2���>� . Gi�Hat)5&0Q 6���A1.YJ�p0!3 �M- &@%�by��-�?o7 ;�,neg�[&oM!��Evj���a�i�] situR#app�Lto�p!YI ��h-�% *�(� !Y!i��6�oc^�:��Bng[bf"N.=�.#!�?"�doR]�Gv'�3r&];Q-, nama��.-4 �!~ ��0͙Q p�,� �wj�-!I K�AV�?>^��dBG"�6�0-�=tV�n� wNn�D� &�%>m�_a�"�Um*?kd�^-L ��e�of"�%ng rE�T--&�% L�h��"recapi&�2� �KL>3i7 �>  ���k�H�do�%���� )$�9Yl"R=� P|$N1���>��E2EiÁl"DN�%���)�!�!m body"0$�HU IL12t'no' ��)lտm�a9D1� .�.� -%g5!Vaq#N]y �PD-�E �E�N�� "L!**%"�*R;�1C&p4�")�F�h�ce!�tw2��e�w��� a�ofB�tor�Q�� ���&>X5K40�M䉤. �(t�-| �Qg:F'��6�"O ��U?��#'�4ge��RoB���,2%J�6\�vJ$��a"aw��a ���� 2���toM�]��'re�T�W�Vshado�a]�.�i�/9)om&<�|�|bu a|!&t2Ea�-&�nc��b�hO$�5a�� �PV�uR4�7o�2~K�a-g�&�r�of�� conver�˅�–i sca&I%f�.Bof ( �θx�  r!�!�"(eN}�� equa�2 9�pA�C�9g�  ��m!U nt .�a-rFw�x-�a�=�Q t_8 H0≤θ≤π/2 ( 0° 90°.�8Gθ cl�4o 0��m:a�[��3�B�_ac.:� �"2 )9�By|I�cdV� r<1��a8F(A�)���e�,"+Mθ�X�-�*Hflu�UA��%;&9qs�t� ompuQN!�.�θ5�gis/uOQQ�a� %=�4�N: uniI^N_$ !Ni�!�QxA%=�e� ��e"� �� Th2ICno �to��={EZ�;I��o}B U”-shap:E� probZ�.&�?� e\E�f�on  *A;GaEG$�p"jJa�\iZ"~ illu� � �"r-y�y�E"!˥�?Aso ��%%��!�A�H3%b�RX θ:5=3 *`vR�,�al>of*�F =yN*�S1���o��wor� ��Q�,*s6�>�/py� 2kE4�!B�0h��Uq��2*ebՆ14�A.B! �  W�aJ�shift�Iv(�$10��|2���4a�KZwL4�u��&�,)=�D"9 s S2iS2`"5!��E~t6?a�8"�W*�+6�+JI YQ .�:!n2��9Gc �N!@� Y2\!��A%-�y2� Ti�T� �]w� *�Ai �'�A*8N*� "�  >�%Jet�A4�(as ��J��q64�X%[�S*A f 9�FaiTt2"�.�"` 4;��c���\v`��V!�6� &� ?oWL�t5� � E���ɜ�2��2LR�OS �w��O+u*"iABS(O*�6�A�bat�5� cock�y�!� 5*&��:�.�I�us u0`�M�!Gz�2�&xs}�ly95+ 2.z����we&� atEl,p�.'6�,�>��wnur�2/acish [ !zƤP: ��'f~@i!�we� !����A= L�~�ed�Nl��mb�D&A�X6�sA+ J�E2Y�?<in�koptimum�>y;heuŷθ"P π/4 (3$c^B� middl8.8(\W2�Sancs7%��!>B6!,���O@2,�6a2M��J�"\;y�7&"b��O&� ea. �"� � 2� !m!@J�fa�V�:��  er"� ��d� �{5C��?We*�%*VV Ixis.�9U��2�_sNf �679f3!, +ZA)CEZ�| esta�~�"�:-� J3� t��Hz* Striol�/!| �]!�"! adop� �~5mS2�(-!r�(q l�.ET)6.':� depr�F�����a�7JTTR�sm!K���th�i/.a�7a���!ᎬWi,a  �eF�(o&{.q�!}��/)�iCBs-�*l'�Ms{goIti0u organismsi��[�R� &�!&.�>bv�ay$hN(X%d�#er*(!�|g�2]�|–&vWr�]u.trigu����T0me�ism!S*N+i�N6�T?XAA lex �p�9�d%��v�2�uR*� p� n �Dr�5` . U} t-1 g�&�!��a �neeJoo &��~e�'�n &�f%=6\A � r��1y� 6��A3'I&"��a G!P6�i�aL���~��infre�t bur�l[27|}9�L2/f�QA�Ac:!�"� �� J�[��O?7aBmJ�!�sWV) � sL|of�is 159e�E3l47߆6A–� C� )Km2e�\VeC�%5�18<T�F36B�Y��6�,F�a �s��mw��r��cyt�]E�� ��aR6 61&�ly�v>al^Igh�)_�"�isZ�Setero�1�a;l.et I��b�-�C-� is lG."�[`hsa{���mix�M6F.�{S?B�!^=G��|5"�G'I,Rd�IJ<��Q9J;|6�+*q1�F�'qh!w�.� 9���/E*�enZR��T6�0�-m��2�1eG� zn�s�`"�3!�sX&�&���fa�� ge�6��@>6�c�SiIR&1:C�aTdGF �_Y2 6g*X ��N�'�t�6?�3~�V|FL��e^�*7�A}r*)�2&A8jY3=�e "q"��R)���lUIN!owa�d8Bc o�l�:6J*�of2(�=s<_��.� ��Q�D� A s&F;�afx�r� VOI9ev�5e"�,�;� �1rol`7s &�N>���at9hi n0 !9�.��s ��ebe�,sU&�:q"�,lo=/E*Y E�v�/V��*�Aq �="b}G��ЊR !E)�a�^%�e�X6)�,:%�beHful�\��+le gy6&�/"|.{TVuC ���-om� !��y�s� e*{K��lIGIT�p�A6v 1ioA�� &�#нm \��$�,!�(C2n &�I�8Th�"BpVNty_b�%g���c)Dly��wo-groupAza59He5al\ ro4Os�xap3] . E&�Zw".t)l��.�W;]7*�E>8B��@129P2-Il4tm1Cgn/J�WFGfn"�)^HS7-'tm1Ts H�ASX,��))�m.�"�|�Jacks�Sab��SFp:raA N( WhitehCInstitut�6r B�OR>$l ResearcheMqm*�.�gui��s)�!�́0Massachusettsl��KMIT )kc�"A� Ca�. Spleet$nd lymph n099n!ag+2 6 wka� 2 mo �rem��9����BS.� \ 2% FCS-v pvomt���$ nylon mes��R�l�u=�ly�Wa� O�ch-`�xolued( StemC�5XWz:R.28MACS pur�+�;i>a��microbeƅ*9Biotec �$�vyb�@]. ^�#ici!P"0d�/���1o�{I�� � .��9!&YU�r8, ���7 ��8II�E�L eum X\��!)< � RPMI=�- 101�$2 mM L-gluT|n�* 1% p=� illik#Aq)pt�q. !�mVS��fight-� Lab-tek+0��g�l�*�\� _�jic.\�XN} nt\('Dµg/m�cA~17A�� (28R)37 . 5�!( �t�H3�Yatf<H,!Ss���a5�d��volum� �D5 ����~� ACM� RS250Vq)��Y��N�)a-��A&:"�t�[), R4-6%.,�- BVD4-1D7A�t>.B(C1!L.]�d!C 37°�$5% COLLf, refr�2B �I�a��at�S,�T��/ B�i��O!Z-j��K&]], 10 nEC�A: �dM`�-& �%`&�E�et�;A.J���*NL4}106t}�v� .܆�E��O c�Tj�@RNA�Fz�@ S5aIly�^, [9[Har�O0Ii%fix)�U�n%6�7��maldehyd�i10rM/�8@���Zwa tw��Sc,a�me�(T!�% eK.o|�u�2i�nd� QdA�i^1*�hy�_ �!1s6�.�!*�Q��/7�A� aspind �sn�> �#�of 25-2m�+�2×SSC��529tG5u�t10Acn�)ip��� labe>�.*g<|, 1 me=BSE1!� M VRa�EscheA�i�li tRN0�(1 'd� � lz ,)�6� 7+.#)BOincub76overn��!�309�n��da7 =6I[&51��of)W.'�:��n�V�ach @I� w��ashc��3qT5B>�#*� MmqI�nc68Lb-�I &�S�s�.To2�l��|m!�!�:pE�|�7ef�J"Bae�� toco2� Be}9�e� �,E6,2% Triton X-A�,aEII��&�Nt�E�%W:=t m�WNa�oq_.+�0U,tR�z�t~�a�seBv�12�:tAA.C �A�R+j�Jk)9c^ 4B10;�Փo_L50-823;�J? poly%(al ( AMC4038Inv��)%�.�goat-f-rabbi5�yC11JB߇` +F&&D&�^�QJ��non� �_ gNIsJ5fy�" -to-&�"om�ima.��Z soak�C gluc) oxid6x( glox%ti-fadފ �&2��s�cTri�JpH { �D,64%g� p,Q� >�a+catal�. A� slipAbǚ�O!��. P��t3CE},a Nikon Ti-E�M�3y�cfK�h copeb.ipp�a��× oil-��r# obje�a Pho�tr�~PiG�<1024 CCD camera � MetaMorp�Uftw��( MJar Devi�, DowX>�P, P*+StC��F�{j matii���4 gn&R/a� z-slh)se��lB0Pn er-g=d water�algЉhm%�M�Brief�%�0 blGarAޥ:" by run��edg/��JRZ% br�3-field � 6�GT�� �� N�i%r&p J��en])�.:�$.��`�3A��%7.en���(��? � �>B,M=� ps �qA�>7�n�g,t s)� pEG�man"cu!Od� occaA�͢is-.?-&�&5�� s�A]log f�I7runi�% +yE�1 �sa �nh%B�'�Aoes�ӅMH9:G pickgWBspo��The)`ia9�� a�t!� `+MG!'ax�+ pixe�}lu�� conn=�Mv)�96j���B��$Gb�����e�5�2�)E/ ��d:�:�9�GiOal�&թ%����b� *w )��Li\!�to�l f�,Mm�� e�i2��E)nof�6�!�C[u�'FFa�E49�,r�n9m� �9$my��JjX.�.��4s �=2��`� �sub�R +2�I���)Em��`,�Zis��g!T.چC�0legans PAQR-2(Ml2��$insulin-se�b�n dipoA�*G�;  m�'l,��ntՉ!9 adap�zߞth�15 �w�!u� 3Hc�:,emper�O�'AZ*�Rscree�[n,novel paqr-2.�wev*emu ��g�Fs,�8phosphatidylcho�=*^((y�t-�Opcy �sams-�,d fatty acidx�abolism�/ ch-7�"acdA mdt-lXnhr-4(sbpIF �y'3�tic ev?+c��at�,N�!� M�Δ9-de�hsf���old.�$�|$+A>7aun Ja�� s ne8y[r5�n�P�fluid�bow�e)���I�2Rj��aJ�n6�b)!� C V���wO �2�7�x v5"��ء�~�u!�3zE�An�= �>u�����Mק�0Y�!�poikilo�%m*6st mak�2ap�5D�us�}sa[Q.*��[1-4]��"�6�E,in Drosophil"�Ie��e ��ioli>~ oX,B��1�f�%a abund��������^Z/�^9z[5�IoAn%8 a:�%��m�!�h�0�t�5!��a�*>w4(aptly^A d hedP hock� -u[�d[1�O�<�PP, littl� k��&cNmzoryq�%J�rTw%�)��e�*�<��-docu-edY"o 1�::sEn%"y);!�%I2��.Ym�M���n��oHe��5� U�-A@�lowest.r4 ,�!�s azɯ ropa�e[11%��.��Ua1�8 �eb�Q��I�XJ��i3/R, AR�< 2� 2G Y�_g2`me�)�B)!���! � a��s� U'!��"st�m�`�~10{ Like�&�Aa-�ϕm�`���ZB�ion�z>���� ab���<(�.3�}�s�k�Tdro�-~�k~7eU'� qr-1E_�C� 0tic ltl)�l�{of-�y( lof ��A*i8�te FA�*�  "���N��}, Ed� !�.5^of SREBP@HNF�z6)��0Ocf5v1�9�9�:ier�$t�! � �w��ŷ&��4 ac�u�ny:�� �PXp#aL��,a�#p�utif;��a��&=})n ��'o�suc�# � ��i�{ ���o1c%|un�K�k#�&� . H��� a�4ZAfor�?gev4n�eQwe= -Dandom�<u|�W worm*�,s! �%� cha�ern>IR%���La��9݂dձ!�-7A) �(c���in��jiv�(�X. �.u��Z^ �su�P�|J4�=�3aE _{nv �Ł�A"�0��o F�D ) gGR� ( PbSi��Eb! T!ofa�� .Lr��"� �=>q 7 �( tm3410�lleM%ar�a�'�M%�=E�e3�%z��/���n4�Ep�<5 stop��a���all#�NR�~2в4Sx�C�js;�}�? rai�F!JC-��u�`� � ct a �!b∼66 kD����e�� �k=7M��/rec0�/vw"�% :ge��W 5#d�Qa �*�2�4 <v,3��WD���t#�n)x ��9 �6�CX nu�%)�\ ��� <=Vov !�sa�F27genJst abmJy��6YSE��: M-q15�!r�hap�� �*��ti�m9�y�H.�(AZe� et6-et14;QA1A�CS2�A�"h (W ����,|wW�#ail tip&l(9�1B s4E*�Bbr�7!fl�S�s!520(�"�"���.t6�a���T0"�� � e �")Zq�_ %>�c��D M 2Jo ��G�=G�}䡺™���_"iY�1^&� e��6�.�r�Ba rA�im� ��-�c���B��c�2��K_%֏b��-3sm!�� -I��[6�, [22]:;o �[rosA`4�?6�,sA�:=�b- rl��� � ~M1 |T�h�F�ac�|-�,e'EK(U���JM����5in63S��~VLof�e�eM�tod�k{�.�Q�&" ��/�4���� ies:��Atz � de1Sl-(U+��j!�AW![��aOwY�g��9'c�iq�;wT�wheA�*��i or$iJ�V:�z�B�q�4��a gain:� g2� E"�?de��, �Om)Lvm�>J%�8�e�e>��"��.����A�S3. �� "B�G*�i�^A &�W* q-�o�1.�wTz1A09nir����� ;{ce%��A1�&/A1r ��"lN�" !�錅�O .�(etl�d et13�o`),�a/7rtr��z��4 � \TE� �] x&.�ar horm�m � �:�&A� !A��3άC �ؚ�0s� ��PARα���_ ��subuni. MeE�or%aN� ose IIIpFA"5 s� uild� �#sZr_��Olso �Y�,.e O�ry�&)a�A@�(��B6V�-T;Y S3E�W���,s S-adenosylk�ioF�ajEa\��t$toV<i�Myl do����:� e@mpSep�L�.nzeY!D���U�!% E��`J*" S3F)%a�TJ ator]L Δ9 : !���`h6E+ 7).E��esstorageN f��I�/*��1�1�6�f��MSL wo���"�� s�a W PC bi�si���!,�TA���t 2:md,�Z,�=,� ,er49 8�)\. I(i ��a���@�ted:S*!PCEas6p�fv6 !�/��etazoE$MqM?�*I��ftŕ!�MH9�sem��a��A�"c"� TMIU2Wq!>�!� �mF en �H!C e�!:g>��R��"` �&0 �i�Vv"��� e����FA2� (C�i��$.�A�PE��ri #�ero�xTAG:cyn�N�"�,1���g-�+A9�). A�\��fEf 5a,log�rep~��8��> �at 35�98ag��1982 PEr����!&cdhR leva�$6� � �%�c!�<�� e��( 29/5�v�wo�90 9�FA!��ϔ,͔ɓi�, �13)��n/e�^p 6V� 2��$��2� ��S:. M����l�+�(& 2�#�vG�A�hin��Bk��!�a���տ5��=E-T!(!�al%�al��A &�p2�>�+);��g douمI!���5;)� ��It��� a��? V ?�h� !ly�$6W9 !El �Y%)B �3�Eqv�-z y*��~>�����u&�%u�����be��d9EPB|Qc&  49%D�;�>W!P�����"&,A:I4pr!�Z&,�@� �5�PiUAw�d�2f*��- 9 !�q�pS��Sd&�u��3F�|lsȐxVmf!j��� r��s��)��J(o �� N Odeg�of0 l*Y !mp"�'^AC�^ W xvwURi|i .h&UrecU6�N2At�����!}�4�m�s�:dG jnd ^Zx�6��%orv�B*#-�){'�%�� �A<m9�+AG�)%25�5���$d 1v�>X �"� �g@Ses�I-�V�.5 Ÿa�( 16∶�?18 �20 )A`nFI�`m�U:2:2!�l.�k"�+a~Qȡ�a�t qxeŝQ<ha�5+)��!�N  M�\;!|M��]t 5&�)y)�6���7!>.MK_%f� N��HNv�TenG8, ���aoE �x )���en&�o~E� ��no���+��G.nbT�Ea*  �-_QhA-)9 ) be6\� ;p���hm�L,s ��%Jpv�4ss2�aoa�� �O\�!�t9>wteoAT�3wer� 2!�,!B�"� ��� y bo��>�>/!T#Z!ty& �uc�(i6"O�&aKPE/PC�ioA�e&li��"R ��6�U &oS�l�c�} true5 "�-:�q��wWab L%��!MPC1P, 8R8$�.��S�#l�.$Qe�Msi�"-c:��Ae]�1e�*/#up� eU UࡠbY(��!g.�jAhap� D(i��A.die��I�S �Z���8s+ Eir&�). Mod�T 2�=�&���`��s��re bi��-dP'[�_� Z/�%]yo\!l&!:G,Q a�� R�.�^h�>��a2�%��K>Zڅwi�Rm�U�a�Hub*a Y�!� }�N!��\� iй��:f.* &1�Ts"�!���&���a2�X�F,n� n� ><� �$mn ^�$�vr�/�*u�la:����!���I�M!�&YP�8Qbru��%�aD-�A܅�!�!j.�-m�D6o� � se�-:hAV-�UjAC piTQly�yl)7��'RK���3; �"� I)>p�AW� n� i .R�6p6���^�gra��p� �of �;%n2�"86:& 1�Y !�Ci�!�1$�(_29J5G�,�+e*�OsJji�^�9�C)M3�2s� t���$���:��.0�� (W ��trilg!�n�6>�B�9i�"AHAci1"x���h �>Zor>�^6����2"�+� N6�Ka�%�"wt� �g.�"J�$�;!%�c��u}-�"�)�;�t>S��Y�4a;>Q. H"�w� 4��@�'DAv0&Djes �&^F����8`3*m1~�� i ^th�1#!v+:;B� is q / M4y�+��� �� EO-�l��#�&� 6��-�OƁ.���!^R�&8;�t>�U ��1�o~"�27�hrE� �rf�$�����,�n>& (r�;v8���>E�,.� =��̀ri�-sO ��1�o�+�R�49eDI]�)�$-LNG��� keE M>�OfL& UA�49%� �M�%���*lUU�!� @(U��yN"!�Ue�0 at{0gl�s"�*F *�7ove{Y�r:�V� � c+��D��B�%R'O�:٭AY�. F 5�� ���&P ��2�31 artnư�l{�18����6��b�80%�u61�6�=��,|Kll�{mD.�of�49���,iU�t�y"���BdqY�4;o[�:�9s*5s �'�5r,��s2�:�d�"n!-!EANkm:c�Dg���>`���D49�.�a wS+7zxv�homeosta"�[18�� Walk�;�(�[!����g�D:�i\�Ai�u.����d� o"!�er Wa�d�2�T6R 5**�!��xB!Y�! �/ rvive�� i�nt��e S( ep79 ) N�(o�8��w����pIr�$��.��%F+e��AB�]K;�C AFp>��� 2)��&ca� ��_&ZG>�� e��,anMd�I>�6��A�>s iAn�% ough-wI\ �vi�5�tX1 ���apf2]**"%�e�)T} ���Z, @)�m�!(��6��f(� �%����%I&��se�s�g&ACa;��<�d�cA��k:�,i"s6�!6�� 7.- &�0�z� th� v�� I(F2�L�ng��h � � q5��"�B�*aG"�(et1^ Y���:��~D !$R%pф2�"$gh[FA!0�_&Vi��A�c�nqw 4;�ur)��K;�u1�"�Q�P�!�.�#;'� ���^ens� ��ŭ��RN]�Q��: b7��x`I��fa ,a`)x�^ s 6�a�=%j q-��ly�Zcip����6�DB�y9oF�yL( 3A�"I)A�9� &�;� �le ݐJnb�q�FP �@"�'&��!�7!Mmo9GFPZ!or �#A|t-d� 1+ 4�:dL� t d*)&U�7./ 6�!�-��a:���&-#a draMc��V�MH�?�& �0Q�� B:@�M+!mX2 .;� v�B-BN"F| ��a����:.Ncle�7eRe1 �  M�$ zɻ2���@ n�je&k�� `doa>,K ��Iar#b��6 �. A���I�e��;&t(knockhQ B6C&!��O�-S e��.�)�>KE75e�� d�von��t��uj�)_%�%��5�,B�**g �A� ݢtA��-�I A�de`�� �6�m�� �ek�.S �ms"~ �M_e5�A���d"=sD�:f!�MJA]P� r:����p 1 fail2�2Se�k�� �v�?"��� ,ٝ�'>�)M�H@D� �za��!4z$.&h� ��%BT ".W�2�Io���Ait�1w����%x42�v�>��sc��6zbym}2(�J��k� j*�vZE]�;�D2�y�� O���j,Nonidet P-40A�2 Y� �=llW"aK=�NRat�=aR!�1�t-�Ձ8 u(�%S5  A�.X�=$|I5=d}�Rj1`�,r:�"�!�"grew ]�W�h�c�@.�se��68��te-�m< fulf�i bc�&) ��L�%bey �@@K " >"�"Ct lu>Ikl�ϡ�tE���fl�*� leic�N�O��u�p9TFO]K5�*K&l B�.�w>re7Cd�]of&ed�R7.ZK�x;�, �5��$a�x���O�:�]]C6Yi3.A�c�Hel�{A�2�c� rescue ,�U allowing the treated paqr-2 worms to grow and reproduce ( Figure 8C–E ) . Indeed , Lxcombination of 1 mM oleic acid N�0 . 05% Nonidet P-40 even suppressed LHsynthetic lethalityT �4sbp-1 ( ep79 ) �,�@double homozygous# progenIaZK$/+ mother 1(into adults�,establish a  xe line . Finally , we show that6�0alone , or in22 with./,9s%� �Tgrowth defect at 15°C)ELwhen fat-7 is inhibi!�by RNAi 9�F )%� �$words , ex!"ously!.vidA)ei% sist�6k?ir&L!=-�ce^5[5A�[7]lourth%6botPB���5eK-�%�correcM<�us��_concentre�:��s� 8to mimic>I�,��Ay*"-e�nu�yo!we �!, studed refo��i$a�at���trans�prote��u�A��m.�f!����Z���=mod�~ =��,���y. Howa� �� poi;fR eracG betwa"PAQR-2%� targe�IViI�immediatA�appar!# , bu�e Xes�*CFcc!�n���sm�;1ngڹE�an assoc}d� olip���v�����,lbelongsA%a l��divers!�)�famil� 5�hydrol%��0,includes Per��,a yeast GPI-�A2 [9a#O�s�previ� E�a&r �\>+e���to� � Din C . elegans [11a�av:>�in ma~ � organism8�a. A roleE�>iA� yate�* ��2�has�:bA^documena�= ,�itA",particularly&A %{P 6;76 ��� a.� sensitIsimilaN aA�|: nt ,�Aq well�n !Cpoo�"� ��. H�Iwe ad� novel �YQ�onA�lin s , PC� i�b>a� Fory ax�� trol� hA))!�>2Z? . At!y��we doŎ know� E�n�uUJ�e�e only ��un�S�}Our fin� %�-%&� ��IYFA�!^�qn{compon��� h!�"�u5:.may seem!conflicti8DMurray et al . who!�change�ptribut-( abou+%�>�,response [16�>��i!�t� keep�min�atB�A��Aro�survivaE�.8� acu��l�2Qof � whileAA�^� c�� 1",�$ phys"� l�� a*�K . Coul�� ] I(logs play a��Z��in4e�� ms ?� ,ed serum adiA3 ctini������ n� s kep�4�� 24 houra�%\.O mRNATbecomaT elevE6in brown 3se tissu� BAT ) [30!� Also��uma�bje�7 wearNa 1%�liquid-� ia�uit� �*8a near-fIof cir�x�.�� [31�F� erm ,�KA!BR�7)2=�-��e neuron�(a�bru [32]�.{itself�D sequaMy)phiber�-.lasma~ m4Asian chipmunkC(woodchucks %o , [3` which"g � it�2bA�G ag?�f�s^��8mmals . Mainten,�e�performp �0scribed elsewep[34!�Tha{a. ype refer%/st%ay !o.�4Bristol variet�n!�0, N2 . Unless�wis�E�, Ss �obtaiApJ>cGen<s C��Hr ( CGC; MN , USA )�cultiv^at�{. Crowd� $ � �D.� � �harves^�Xwas� twic�%water b� ly�by boiein SDS�pJoadabuffer 8wenty microgram�total5� was 8I�each l,a� ctrophorea on anDpolyacrylamide gelmF fer 0o nitrocellul�+. For W�rn blot �w!�f � ,�.$abbit anti��� gene5vmmuniz�a /s ept�4PLNVRDWTPADVGL� ��%4to�C-term� amino�s%�ud� ��u!�! dilu����1∶100��in Q go� nti-- HRP�fjugE�s4a� e( G��A�al�*��2 500!4�0ct bound prim2W. Det9� &un�*u�an ECL7Ki� as*%�0manufacturer'�% struIE(�Qrmo SciS��� ( tm3410"���N geniz��AY ncub�!`A�Z�!� 05 M ethy .e sulfone( EMS�. ccor.estandar!1otocol2E�t�%�placedi��ure dishe�o�0�y r , vigor�y��>I`�ic�  erizi�or���!"$experiment�Qeda � O ���dk by m] wild-t�N2 ma�to�zoate��Fs*u+toU'ingle1�i�(1mselv%""� =E5to� ?) ;iE�k�)�Y\� vidua��[' F���� z�A�MqI7A5 , fom� by tm�ir F2�or abi�("��nsuch cyc!he.� amouC�en9#2f��to!�)A= �}% $�'�@I�( =�iIM hadi M2 ed 4AjQ��� d��p�(f 25–40x ��9�d"% [2ut D!E��-ʅ��){Ah MAPQ�  softw�Amroduce �t�all di# �?s"FH&� N2- %@ �1sxs��Uy cria�a)�E n-co� substit9 �Av t!` splice-s��. etc . [35��X ��F�"ne!�Qt spotYi| . sm!%�ica� !ws��"�� re�� ���n �� %�i� re, s [2�2D!xh �)iIBtill re��Qf 10.�(consid cand� � Y�i�a���� s!2� i�e textX�NHR-49�� smidadWT! t8E et13T !!M�� U ampl� %�QD�promo�,!�Ik UTR I�P �ers 5′-atccttactggacgccgtctaca-3′�& gtagLgtaaccaactttcccgaagt +�!s�" A��as�-i|A(∼6 . 6 kb��iaq�c�"�!�? ggtta !t&!Itgc%X)A�O�"x� of�*�E�; �Z9� HACD�i�*��*!!c!gctca!(tB(agtA�AccaA�A��#4J^�#MDT!(a� �,P!�,att%#a� tcgga�9e�% gattAI$2G�; �˒[7 . 7:�z8PIO�Spred� a Qi�i kit (�N��%[n�: pRF4 (� -6 )a150 ng/µ8��1�w 1!ao pBSKS ( SV�e I40M5Nt� �B(0F{)ir� c(���e#r� of�/trip"� s ���@)�B � e&� ,m$ chrofL11u"�p�oɣu��s�5��6� �Pi Htaken �(a Zeiss Axi�t�sco�ndEO4 lengths measu�,in ImageJ [3���$brood size*: 1F%�$E�V� e�"]-.V All6 2�� � L1!�1�K)� %+��9�A�>� �!9� , L4-e? !Dsco!5Gas young� . n>A�� ll [&v!�B��n�co4 L4440{)bacK Q� A�"~�y]l�ApUka$��),6u)D4 �on%v��Fee� 8Ų-%�aAh�er # libr . TemE��in  )� crip�A; made9 �re�oY�T7 T �Lat����c�ک\��fJ�6�If�Y�Y*pRiboprobe System-T7 ( Promega u! ds%%�pur�#!Uinj�"-�@���  N 6l�JtmRn/qA�":A2!�a�of^��O�|.he*'[pc�'�R� ORF-=� he p�::GFP�� tIs3��y�� HA1842&�&e&&19]�!J$a kind gif,,Amy K . Walk�Qu[$'v�*���� ��s�U9�on:�4s=�i� cess� .ram:6>� �a�Y � ( gk405 �*n�e�6 Pqs�st�. SS q?�of>�(�3$15 cm diam�-� te/sK� W&y�3q�"�, pelleŜnd st�at −8���a��$lipid extrm҅� Ll sonic�A�10xut? mXoVVnJ�".ZpuY/ed3od�&Into�nx��ad�aFchloro� ph�$��. L.� Jevapo�!ra� ]∶�[.2])_�ammoni�ce�  i! cA�inf{ &(,shotgun�%roach )A�o� TRAP 5� mass�(t��u ( AB+x , Tor~(, Canad��equipp& Nano=! Tri�%aAdv�� Biostc�0Ithaca�Y )�ry�*�[38�P�-oE$-N"��zmi� precurjs scan�[39�[40�-8triacylglycerolVU neut�lo!K4��� data%oevaluE� �AEProfiler&s��"�0*�2����d�UUappropr%'�a�10%62":!k Triton X-qor�5 2=3stock sMFs�NGM�Jy*,(�H"-� � �R1a�� A��n4���n(. Error bar�1.-����2�)e:�� mean}t-@ -Teto�$y signific�_N��� :�!�fr�_("$ B3�95%� f�t#2l)Bmi�I@Z �<.�JHerpes viru.%�a#al%!L�&cha�;��V"-Q� Desp!extens���*, mGremai)�be leaV$�$��M-a mD ckag���r�/machinE-�� caps =se�vg���lexK -��n�tDNA�.�*�a!�ll:wail�' ophaga"sh!G��N evM�� origin�rh%|%{ %�JV!#-ex_+"� <p�(l-. roug�5�aɲo'*{� Rhost  � 1*a�+atue�/� ) lo�'Dl orhvertex!J�wea � $n cryo-tom!phE�IC)e)%��7HSV$1 viri�#�ve�E��!ly�'uH/��feI5R�!E� ds a�� ktega*� e� �!�nn?�,6IrE�vi��"�+�4e)*�(E�t(ssemb�*>$pl��&in1�Q�5�nucleu��so &�'�)2 archi�aT. He�)nE3b(a,/�!ng4/dis�2sI^`(sy"�chn pox!�con�!����blindn�#�c�r�2I�hsi)��F�Յr-6r /A�ri� a h200 MDa T = 16 icosahed!�-��ai�9�ds�mU,�(rou�by�% leom�1�1ro�/ace�laA!*Y6�4��_!a�D��� =�!�i envel[��in�5A�M�u� o-�) �$� �∼155">2400 Å[/�- V-!!t&� �254["�m�%��alqb#T�� penta�qh occupy 11Z,12��* ices; hex.4eq,faN4!Oed +e?e9�on07x��xitB�omere�A�W twelfth�exAr�H%���15s� it� jus.!��-Wsh�$[4/6 is=?:�� rout�A�pR��chniqua�or��� 1�)�.�e%�rr! ll e�;i�&!P�)arZ,d g>=6o�4arA of Rp6y . ReR3l#<el�&���&� ic (��EM{ nd:*�*T )"2 ��i"%@a� visual"[ f�5.��$��qC�aT��eMXhej�&(  g .Q����:.s�.� bK udAfi� ail 5–�E.&a1�al li{*ՁJ|��6��gI�K v� �m�#�*�!�DF>assum0(is reinforc��4.�s ,m��lmaasiy�a�i1po|1�(+T>subunit|2a"P�# dVa�, a�, [13� H"�4 lack?ev; asa�iAnA* ail-29��"),a'�appeay  ndQ)~Ajenvirona �m�8ukaryo0@� rU>Js? �?b'��u�essL . Nth:�Kdelf �c=9i�� ��+�0be���q� os@t�)RPM��(ellWpr�'*�A�!��.nub�PmG(r4徍�e&�. W +5 �9��ce��7��;ly�o!Q7a�9�t !�� %7�-ly�be3c�m�h�<S V."��(R1 it wqu�e W;$sd�ex-�x se %9.�teg!�to look��d�%cEAm6s��9:�%0F� �;%-�����1���*&?ssi�'Z;1&���> p�/��twoM(�Dmp*%al����):% � d�t!�12%C%�%b�DacF�Dsymmetry-free alig��E�ca&/de�8oq��r�*mod�AarooA#��3��(X�2 in M�1i 3aMetv� Q5�2��as�va�s��stIAuV( Ma2 -gui� classAK� m< b�|�, �>BS?a u� %Q�ÍU)@I8}� ]acA�) f1e�FGmap��!AMt6_3���"�E1B & 1�W"CmajorY�6�i�u�%"�IyyF tenuZ,�vfi�g��s�d ��2�arr�d� a� [1�(� �;I� �o!R�H�u� �dim!i�W&P(�le-d��,Ival (WB]�. E7"�' y�A%�)#a��!z)2(�!�to9�1��c�ng ��su�R�Jpi same�1ne�".�1* g!!KA�,-!9�M�E�[>�:E�of%)6a>X6DtItlyqpp`t�m|:���=2���?)uy=sY5s�r!M��!�-�JBa�isqW!�%= Jngi��sktlX-76g2&63���evDr45-e� ��%�Aw���ruE6 cav�.$A � �e �=m]6� �+llu�� � a N �- �v aA���9�6]A��opFngmal�5�2B–DL� G ��Jreg�i U-��(A41�%9E�t2@ !s�unUK�>�t��dis i� )�a�E�� uma;�N71��A & 2BHNo ��qQDMA 5cx*  �flo* enea�EM'�51�;�G2�FFg�:!z����.: does� �pertur�5!��6re�3%DE�rC .@Va`�%� �?ou�/d&� 1� �beyond!�54�E�iJ�oug�Fcy�r=�`a narvP neck) broa!�Xmdiu��,%E=�D!�8� devtA�%Uo.vas"� �m ( PV>�;ikE� R�S! !� !!D5�ha�J n ob�  ��?ne��I.�A�zm� b!�)�Z�U:���R��WD%�a?]A�&Dpat�!K�%I��?X6[w@lie sl*ly"6� m/su� ,�OrLim]s�Iof fl� butt)R� �i0mmiddlu,%:�I DiscR"ble-Gѳ� ch��:>�� � _M�68E�)A�n$)u.�( �=k9 6�����WCom��s�*��m�mapi1�#�%UP B-)R�"�&�i6-edH-\+ W�Qb%.(%I��A*on{E�E�at� 5E]y��>Au,M�-\��Q�heU69�$�r5�3�>6F��'�tr7Hi�-R:��De)�r�n 3��nXm1�4 c&I I S r-sha�#uj^}E & 3A8Erͩan:` eq B^ : � is�a�)45�>72-,� �$��3�RO�=! �p�AXyAVU�)�s%�LAY] A�� �U�T�-�^��"? � ��@iX>p8IiE�94s`/��� ��#dA��� !=�>P ��� se� �px?II fuP� n"(/�v mod� �-n4�X4�� &4graph%Rs* �� r�� ,%E�sum� ���ex1����st/G��%�!>!")&� $( p-value<�>0�a5q��^�isP�"xO� B>�, regard� ��) Uu�4e� !\O@-���&D"e�c}X nKo� ���� 9n"� mak��!i9%H*>>�.:5F�H�= inV ��.(!�� �nd I!?9 an�#AJ�� ob&�B �u WJ}W�� �to"�e�� b-K!u�(eUsuffi�(�&Gto x gu�@<se�'D ln=6rIQ�!"�<��2`rec���a !O�A.���&� em bCSo�D&��q�A)�6�me�gejE���<*v�:��]%A�LXQ=�p*�!U/,bwe�2ed��!(R��du��8��ea��2��F15""!214(A0A�, �I^63%�j�� �"#=�Z:�g�by2�!�%�H$N�!ym�I�(A� erro�dups�0a��� a!q"� �w�!�t���Kbe em�,�E-�MS5�i�� ��-'6K�F�*Od&�ba�GNU all-vs-R �$y���llE��E�F[ne5��B$�Xn)�U��� �st�ng�q/) �r. B�<>A�un^X�5�)J�e:.aoiQ���(M6 tach high� h*-���J�e�. I�Q�Q�"9 ���>e� elf;%�L;� " g���ei.CP"�"+!l�V�6;!6��5!$6�.U�IEZ�N��!Bitq(J &, �� � m��� � e��q disp�&�<:��A��&: "K"� o&��geťA��%�&%�*/p5%��enGi%ay��?M�r�b$ A��igo@ : �V�"reNN -�� B���#!DAH�^�T�# J%�Uts:+�A\Sq:u!/�"L&r+�*# -B�F%f�!� *"N�� �>3 a�,as�=W!proC "�O/� 1�~I". E� !�%�C �$@]"IlyA�I� �N4F:��b���.iT#"@ U�*G M4)�A�i�,!�S�[1q3A�8a} "%Qk1o�  d�lr`�BeE�6H�U��ih�:%� !leaY��m ���B,!�� ex-ng&q$��M�=>Yfur�B���c�s�4A�1�� rigg�#� %s[">^ u�y%N�1n%5a_�)�K���]!lg/�U/+s��!i�,�� ��G!>nq w/Uo���(�aE�!�!��#[18�31�7`1[20D�,��I�O_o�� Z,:pUL25%4 pUL3�:  togeV �anZ-�6 UL17�SalKd1M�e��!�)�-��e*� !t ( CVS� �)M"wE�2_I i�F–[2"GN�G�&�Ta�T�)1��din [26]I adja)���[Aato� ��R�$q�c"�"aiv�L BIor�|լ= I�$�Ye�!��b� ur�c*��g l�Ti al�A��"F3��' prox�MU��tan�a�on�BI9.�Iq��<|(�ei+!��)+�_q.**�3��"`y.Lhoiwb�m�I�[2.pmo�0o"!���i��7N�3& ��5zA�^ .n,5!�`FaFkDexBBBa8�AorI *y^%S theyE7���%sm���9qK!-�!�6�5Z&�El.^wh[Y:ujhB f~5��mJ9�m�u�336 kD69[], j1r�1�ɱ sol�X)$55�3E�a�&[%reorganp+vin�$��p.�% [%� �ex >)�-�toa�, La�i8v�&� . A:te-l a� I�ɭeaNo�b�*�+a-or�.Q* "C�ATq2 a2��_� _Z� :l'��'end2�Pfr2!bcl %M z!�isg�7!� '#�l�(-!0� ivW fix* &� �A�9�2��,�>sa�,� ��5IMt�c�� h" "� t��&��?���-Tu�� S�behav )T sb �a�) �``ch �D�[c�Abu�:� golgi-deQ<d vesS k I�bA8flDZU�.J( { �]*6q-�demt u� c�_�pow�kf 57ET%�(*i>@�$2to unc� unex�� ���\a!$u�(��9l�Y�0az4 &�! �yQ|*�Z&(-h�5? � .L2�&�6molecu,�0s�6&�-����D in BHK-21�Hq/�YzMng Fi�+d�-�3 mee6�<Å!�n,$Energy fil�dI� r�.c�m"w�a�t width!�30 eV�OmUlU�z@4k×4k CCD camera��a n�^�Oag��0of 20 , 000×�)q8vnB' 8 , 195×'#&� !�top7 ixel� of!kV3 Å/ qʡ7bin���%facra�woK�%~6s��!h.�Ct3�?.bset��[�`Q�t@.�\c� ��n�k�t��e� . To�/;q�6tV72kh-��8AW. Iq} * !Z visic,rE�"mp�D J=%T%1W bd85"bd�Ysucx4�o 3!4s judge�[)rtTo�%|ERd,i. sphe�� k g appl!� best 65.f*AtuQ))6�s�8%��� mask%-70�"E�E%eU !�H�M.�%11;,6] � � :�1P W�?� ^Rc1{ -A ed ("CB� �M�?"o-4� )}��!6� . Mask�j���e?�@�I�a���CtB�Z�/s �pawtW �o�E��� aldis�Z��s��ahe!� volu�Z�^��2K�mp� ��to �'A&��?-�aMq���Va'&sI �60�i8.�I��W�(I��4c%6 yiel�#�F�M�B�5��0an�/)�V-�}PA�a�nd�t,ri�-�s%[f+��E� al 1XV�asB9,�du�2< �dC�31C" &"v(�e'0code: EMD-545�,��.A2"DAB�&u0{�Ga�X�  minim#P"�oq(m2l�vr�2�Y*!& �!G,4<V�|2d�lEW –[�ICa�u�tM#*�CKD"�'M2m� �|�� � <��')`PROC GLMmP�YlExar No}�Para�c helminVev�!, ske�daa�>HvhW�n��%a�eyeme�i�rP�}siH�h�.!,�ctCHI�H:Ie#Lnd�&G�}g�-.&�q�#A�!�l �0�yegg�g�\ ( SE�+ESchXk somaZ�Py fv�ung ��{�0cytokine/chem �duc"$troU0�� L��,�@�Ll�!)Fkappa-�{�ly� �DC-SIGN��geby>is�9d �%L��( p*)�<3st�ۥ3fej�ci.7 . DC�p to� ?mJ!( Th�bmo� ���IupoU--�gn naïve T-�>a1 a  popDw%Ba�r)susS@~ to �R5=�2����to��.�^eO� KX4��u�(Hn|un&~�&� "�(erv orc}� 94�t�{13Y} Th1/!>( Tmix )ARFG�'lF�!5Aby!�*�U  =d��ac* IFN-γEaMIP-1β3 Y�prQ��9�!i�R5%+�8ass2�=down-qa* CCR5f"e#ex m�We"^1I�>}!9]t1�l���6� �Wc_� ( rωMA�=8s�&i;*#o n!�al 9A )�)]��)at�I�e)5mA*539g2�,"�.J�� �&=unii�v��J�=x v&� �'r�1�QL%�;N5��!��atE�p�se��� d�(U�)��m��e-%-""9�<���*�/$=�9c�s� co� ] d@�M s enPer��&uQl  �i"C-�i ,:m1� �$Ufungi� � �P#e�th�|G�aE r�TW_omiRlJSi2B8CD4+ T-lymphocyi&r(�[�ell�i).1�P�� odef�,cy �N "�I�]9![..��h*mp��%5`!99����9� iţ���N5JssR�( S .![��)8 �8ingSZ ;ont�e,Q+)�*�i  �� !=Qe�+:?M���>�cJ �?reQ�EnaA�de�ga�.�)�Yeh-R3wJce w�#I!��@9� on i$i��. CZHAL ^Q9-���i�Gal�XJCM%jl ric gp120&a �dtoA�_ �g�( aUfanuN &_ r�(I typi1�xor CXCRW��;g�: (�O*ue�q|(��Ith  predxl-M�t!X @A9�Q *r ly 50�����e p swit ! util�C�(��)� co-��@� =M!f ��!�� rapiv�di�RP�� o �! a�ue�cr �#e gut.*1oi��x GALT/ � D m�B#rvo��!�D4+!f+�Sory� {6)8))�!��sEul�Be�e firs�1ek�%1I�I�A�[35q]� Y(�E���!,CD4�d.j�� �  :� At_|of*uo~in�CLR )���) myel!D~ w ge.�z�o��ces�capg- �Ap�L�)�t�u�q!l5`�4&�r$|V��%&n&O���1 �L~�stron��#Ig@ =d�Cc �EIjtICAM3-gtungPntegriQ � )q�E �  ��luP��e!_� X0�V��'fk$!�- ��)F%�[P3��us y.)$ , e�is9#*-�LycTsy� 2�D&6a�B��*�����,�(A�\vz|od�secre�s [7–1s|.L�seU�MnA�ca&� !�� �L.$=�.I\IZeme�hel�, ( Th�MeZ�ia�H��ts; Th; *�$g+uá�� R(��ic.,a Th17F/r �Yu al.:[1�URemark�3��E�!��M~��� d�\lya���= 1s�i�q�DG%#���5Q9/ 6fɩfcqe� �x*CL�, � k!RANTE6i�edr3$vW=�>�eZYIged�CCL'U%� liga�Y��� � limie~2���!ul��s h�RC�f�%Ti61"er�(=#5A�}ena*!���=.=%��G ����k"�)�m�5easa�[1�x:.uvie�Y�^ AU9 [u� n].�8 �Gp��In� kxariana" ��"bROat jU�2U!<�+�G!h"� stim�:�4QM!'�nt�%,%e-!�at�^�R�&�i6 )":�. Cyt�lo�)( CMVN nd Myco�,um tuberculo�6( Mtb 4c!�x �V5� �/of=�[���).�^1U�*�e-�d� �9�Q� �fE�|�T � "�1�isc�m� !� expl�b ,m;1<0 c�%ᕡ �a��,2����ga��IL��3ir�2S�rG)!!"Irʉő�o^���2�]�:�,� papill�)�51 3� Ew�QB�u )�� >�[18��!�H�!��.� 3.kno\ GBD towaGa�9 y�rX ���ove.)-�)b�;t n� -o�&�"� 6� [I&�1� i3s gEe 94��[ .�lZR��Hfi�W�4`)dQ�. C�b epi�8�� &+c�-d�G�a-�,� eatI,�)�`%�r}v�� radi�&�'�S�(�\A �F�i(in Ethiopia3,�9de=dS6�A"spat)-Myk*1�|��„��:� U�i���a="�[2� S,�*�?c6�,��_v* ��1�% ehad6�_i��35�#on�A��$Wom\31)!0haematob����whve�� le����I*�`tA �04at��er risSZI[ �[2� 3��ma%h ejm play�bruE��.1^ �0 ���e�B|�P"�K dult2� pair*��up�300 �a�o-mig�, A��#nA��*Jc�=x�kd/2� � �%Ag�%antmi�vN-$oniarnG �"�k6�(@}!��%`!*8 lhundret"� �n��/2 glyc"w [\,.P� �.+�5&� =nD@a_�A�o� "[S� vn�?�p� ( M��m�dtfgal+ � ype-O( MGL )� , �,�Y���7�\sA��aU,I��SX_o TLR4t �rP� lipo��sac H�)� TLR3-PolyI:C#+5\,r�U�9a(Le���e DC ( i� �Q.i"�_)��to � @d�[�)>�8��`!��2mZTh-m5 !�Nai@^E{/ٜ�a�I��: d [3�"eaitEREF*��2�Bmeg2(�!��of�’s �cg&8&s �=�'�0��:�[33–�}O d8I#a�T2 RN�n��i#e;!e W�QtMRE�que�degra��0RNA(r vEEB+� {H5a�mYgroup%�"v�u� !�A*�����0���ei��t�or��a�T�� ��|3.#g��g��8�$da�1�  1^�E� ]Ce�Hm%� O!�V"8�%^ "�G&�GA" � {í�)n-�.>B!�,2��y f4/ed� S�pa|JLz �0we"H (addaN)�EA�6 ���)�4!�r*N�>� 3�lh X!��ex�j"�on���U���m9g *oe�:)" =A I}�1 q��aCs">ACS���$�a�evE�moۅ� A�Re �1vyeA�j�ytes�0�"�"'A�%m�WA��Y�k;0��� a�ELISAU i&$5�O%�UI,� a dose-d"0 =) w-Fcj�* 1�#�/yY�&�@eqAt7)]��! #wD<�6�!40-��" �D$�q��- %;�> j��%+p� cos&%�� !�gpw � �D:Iu owC32μg/mlv)\�Oa[m�aW�= t-\B ;3a':�n 9l)�.+E� al-h"-'8�q4ss%8���a���)�s%%ġ5$[ �)(n�M�Q!�8 � SF16�(C:i��)�>LAI} XCR4:��v. N�2 LR�nor ?X gout�7th� ydAkA 2�!8 ��(1�( CA-p2S� /mU� �0�(f�ة�bSk])Fig�^ el�� %"�HR�]��,)H|%4 . Ado&żA�eB�Z2n N7&�u�e Aj)� and/ߠ1vi @ ��U.�}�+ijMA�M܁�E%1M�prNa 70%}�in� !�"�%�F��b pre- red RajivЭ*!�s=?6�-#C9F2���M�iJf�V�qYpofM2���I�E�E4�:�+ly���c"&(��"N�6 %p!h"H%1�"�(52�%ly�E�fT.X�.wvp�!GQ0� A7im�~nn�w� "B �"�aHA�&����6?9^{� � ^100]u�5C�ig=!*6!��#". /Qr� B�fU�=SJ��1�}�y�CLRI�A?�M�!>�� " turԝ�~Mannag"LE�Dn��P�~���iA !uJCu���  5��T-X&5 ��� IPSE/αk�ka, ( κ���Bz3A�  rZM P$���oJNk�� o %��� >�,�de�of]1.E3N9{��e:� DK ���5$!5V2���7oW �!��"�.po j6��-G� l9por�did� abro�W"� m7.Y� N�`*r rE�ڮt�&`*m!�( rSIw;�zu*f���!w,�atz_"�47xI-� *# ����� Q� ���EAM7� !��=nt2to� ���!N�X��)2TnoE�`��!�; i�ff�%�l!!�>�!Ae � remoP��| #-�G Fj�m���6YF �a��io��-Z"s/� e7� �'���� C�"2F� 6�)6� �H�I�*�6m� + i���a%$jB!b�!B���"!!�'~$.e !5%�ha�_no�*�r�VF�.B . BeqD e� �n���O�af� ��xAL�L+EA!�0��`�"@pq�E�d�$op( ����[j$ *w mGe����8edq#� p"1�ve��a���2i!,�i"�)n!� mK>H reple%�z3we ai]B  )R�Fz �DC 2 K.�polar)���eymodDTh-r�0A�i�B� s�&a:� .P"�~a ��%6�#�)��& 86�w��DokZC�W��wD�u�|sA6  �=�&C0byE�%* �abS ra� :��5!s�4y��V�4!4 �Y<(L-�icM� 2�j~� ( dos{ ��2�E"�2- ,' Th2-i\!�*�1(A,+�0�PS+PgEi#�iyI)=��ZA��6b.,!N�a��wa�y,A��A(A�5&� 5��4CD45RA�a��()$�!k Staphyloc�/s E� otoxgG!xE)!�8�u��!!���'F4� � P &M �S8 ��t��)��I2� !s�� ���� � A�ovqime͗2ES1E7gIn��8E�2�����&�- 5�IR3 harb�-8�?Q�4% ±T4?66 �+�a,2V�ˍd��3:� �h1^��g#�&�89<, 3 . 1�V�p =09 �K�e�o)!�"�yB�j,��ymbol{. W!�A�� �tV�a per�a��E Y�B��S&� �e�%e!�.�![�5�6�-�98Ť8�2��2B�uh1�0A 2-way ANOVA[$aw!�N����6nY o�,5r4;b�Y!9Au!MAEq=%+ ,A_a�y>�s !9� +�C��}�6'i -=��:�&� &#r(k"�L��2)��[.e�.�2%lyM�r��n&i9�k(=vZ�KM�w\� m�!7�7oh:1��-� %y%�r�.�md A�"�in.�)�.;���p}BLAI�]����; ͑�a%щ�R�86VR�,���XN�, 1al� abA�16 . 7aki�1e1 .�?2�%O�^�r 1u�C�1��L�WLt�3V`��yAm�QG�a�b1��A�� a�ĕ�(tu�.�u� a29>�WW�N^ N�>�i�3a Ir"# �q :�;Z#=� A3���agB�w,5"&ɟ:� "��4I�!$eq"-$"*t�ed��B9E͍\N�!�.Z� 2�s�J� (�:,M*A#T*, TNF-2�-"l3�� HZ1�V�e�T4.��5n�U9A*�#n 7��"o�!��a����&" ] vl�x��w��41@.�%[a�FR>o%.PA?j&���2�)�Eof1s�V�j lbc�1*� ieK~ A: 9i�3� *q$ IL-4 ez!�m"{KW�M/�V"W�F� e1�W�U V_3B%- S1 Tz� �� �6MM?��w/lu��g�A�!qN2Q �2��a=�� �Z� -i�>Y%m�u!lqr!���!��)��L p24+"�t/'mg64H"�Aw�G�4.er:--HA�-8Sdu>ul�"Y(s Y�-@]� 3Dd\62 FACS&mX v& x:��i9a}Z�� �+ �1�� �6n�U@Ne�EC�aZ�2��cscc]8Y�in10+.�e�K�!�=-"�5��2y=9ot&�� e�� 1U8&� mM*B���gH"��s�>tw���I�2�cC� �yE�~h�!am�Oe!� Iun�%��(menƋ6[u� >1:�.�6e �y1�V�:u"?.�.]����F�.B )��W5Mr���1B͌��6^2� VZVP�Ra6I �.�tć!�5���E�is��.� 9u;�y.QR>�aI�"; a=2Y�?al}8�6�yC"W!� ��b�OzX� U .� j��"d%�>� !t"�;�����h�'!/FUnt*x#�#:Ip�6��P,�QYˬ^[�Mf� M�n�of4��2��!ɟ\�(!b�, 72% ߘ us 7$ 6�!U C"� >T@?at"��F-*`1� ��h-��)�N��x�aicJ0136? 70Z4~��2��eI�-6 A�LAI�!.Ez2- �NZ�ɒM ��a)�B%���u�B!a� �27y� &��9H�+�$�r/E�engag�QP ��!�z� )����/^gL�K 2��%dexa� �$�PJ9weq��,&* K*or&�;a �[;zo!�B) �@�:�Rr��(-�Jl&.%ApV��&n3E"�&"d<_7 &�&� Af��!n6� �+! �&m�1��oP3%`�՛V�M5&I�*�M$tuI�4� �`Our� #R@AKat)��A��is�c2.$of heighte@X�!4B� �E+�EN}#��r�I�x����X�X>�1N = h0�% !3�6�6dR�.J�.#J�!��M!�Bf���*���a^�H> X>l.b6�%����k~*�b|bT���T }&��� N��A�� `kv��04n vivo scenari%^drk����-talk&�%x�zyc�uMwe_� 'o f�E����X�����2$����)T(N ���B�>i�|$Az���ODe0GCr~82!i�� q�#�`&WX�m9K! v�AlT%a�A���f1!�>q2\���e orm *�#��&�%��s3��#!J a�i\*J"w2����.{l#( 3µgO.L(�%����z0!jh�sel_� �_!�i$1 �( S2A�4� v2< Q �x&� ^���� �b � or 4 �1 /% �R\ .9�%sM�" �:� � �2y! , 40ɘ 60% �O))@[2�I�5� �2� .�j��R*�� w =ZZ�2�*dJ)�. P2~A�&�in��$Yq� n = �(���ra}�ly.!-]9-I �L�6��k�Da��Q-��A""�A�bC~"� |�)��)�5�DVE�a N 6r9�Y���� ����.��O�'pA���@AuB�2^��.\ �G�.�I��!k�6����J��9s�:>&�AE!�Z�F�m�B.) vf� DG&~�M!� k��)ilea�p"��ݱ� ySeG �$en1>~/:+)��.�*� C(A�: EEb��YH��]� �6��?�weY�&�T���"�{�5p.s�<09006��2��*"�5��w,?��Uuri�R5m�M)��#�#=�"E�%W)�juhR%D����<.aC�Z�us��� Z�>t�B�y�-L'�lN5�=���]AJeC�n:��s�kJ�R�-"�.nF&�:o�'�K_x|s��A ��D�(�%:�l!Y��j!S v1[� ["��::�V�5:h3�"�5,�e*�� *�8m��^ [� �(+��of Ka|/� IS FN e�6��ŏ �^��i���N !�"�Hoa4�1��X4]Q!�E��,M� ��"�,�N�A�R\ . C6�c%+= �!�A!L"�)2M "�Nm&^as6ZZp,"�Oq_o=��J4t.'=�p����m,:MX;&K P�C6X��p���# l �/pE�e�s�D �D��J�,y *�>�."cmucos^Uaۗ&�be��?�nsl�� �A te [��f�!�zW>���[S�\"�>A� �E-�9:fTRfR)� V .��d��N&�x�-�T�R^. AN�Dw��x+&BX��%�n Rt.�P�'QU�Bh� �PO�J���P �ia[.�F� �,�soɫ�'�+�a*ie��-J�Y�%�R5-�,�[liO��}1����*w jt-Siu��f c{���vivX�`�f�*�B�l6�0-�/Vi>u&' Iwfew w�U3n�#[�H�&VVmr�3nT�8X peakA�emi{a�D��XA��K"�Q*xN%YI�q�.�H,0rb�!E>A�Ec�� F�-F�s 4=�[�40�VE�o�ka�!RNiF�AofKb��e��oA\/�6 ��*���C9[�s�F� !%��;#b_�m{an�i�R+l"� �@CC-"�Y�0T>� %6sN�a�N|.� Z�Q ��2��(K2Ur�Z�"w� &g L~���6 % v �c ��\ &I72�R[4= 42]� �z%"d ex��O�3�(6� :LJm��2.9&�#J� "�Jd~E��"�� 2�|(e)Z�&m�>��6E�� sސ!�� a:<2�") �!�B~�r��.A%J!�d"�@ͮ��-�t%*"��GN]}1S�d:���^k+"r*Ah"�'X�  �"9J �*di�>8 eCR�`�a!*cYH. Targe��.:%seems?ll��w�8�A4&E� Cj 5U42ɿ��+�� �Jm�[(O"K  ,a�pl �mr���]�o�cNefb�IL%�k1"�K s [4|46]�� BOTat� �SIW!�by I� � MtY@^�R" ��!k~ �n u��( :t!)��^r�&�"�. A:� �,�E�18a4.'�~.&,�co-q�n f!A" �R %uB"EN�j� �6�F.2?�Eu*%?{�ung,)��N*��`����U!W �i�2d��?)7T%~s pus��2eMfaS)6 2h�!�p"�9[3��5}5�]Ye��w0 x��d�%��/E�%P` Y7Uə��e;�1�6 Z�|U�&OB6eWQ�onPFt2�M"� 3��g=��"���^"c 2� \�r�� r��EQ!�o� .� 2�"� <C!9_1zF!)���+QdTo!�Z��2s�6�~{":T$a�1a[ �.,�a !�$asT�:reg� [5\5�^ �3<$�n5��F2�5iLYnэJ�c� ��"O *z� � �� �R�{i % *�a-��FtG�nles ga�Z2ForJv_[5� FXA�[����-.p m~=�}�*�I!��I��i&��K���.E*� (e"*�0�@.]��("�E�%k^Z�� ߃)FoxP3� �����HoughtAwp�W��. S� Q&�d!'�T�+�y_EB�p9zb=Z {������LTR�"���[5�\"� ot6�� eW)q�in �pG�v). s [5t�5� ��&of -� s! �\\D)��y߽S�����N��j e� . Anĕ_�����{ +�]ut!wyO�'[59VEv�J{)ri)fX�jsz@$s APOBEC3Gb_1�v<+[6&Fm+��kg"<5sIlD^>�ew.�a "$2����unN�te4j"0AA"�e��ar". ti ��*-A"�]d�RCM.� E�& B�U�EM ��at�����indRth�;!� �.x�M9 �ksk 1:1���?yB%Q�"�lie��o&�.��^I%.� %%?���a*� �.2�� ��6yX� V2d2[ C ��X,B�z n!L.�se�?�Z}�LPS c��"S����nJ��h�q� wF��.�R��=���g�� ga� SOCS ' SHP1 �!��im�]EI�!�27�A �*�E r /[6� .��2 m�c'N*DZ F�qa ���!f"�m^: �sq��]�B 6$ba [6[+)h��IAA;�$+n��n .� SEA/i��1�-0�f&�S�{F%Ve>P#� v!�pr5hve/S턱41�d*.��/J�� ��Vt E�6��k���"��,p"�E �Ua��_�"�^ G"4p\(c*p���� scaZxon`!k0� �cohi��cn��A&�} �%i* Rž! u�)d� �k!� � V.8y�DC��F�b<�!�y�{wu �l[��Xv1&�f|".>?d�!;Z�d[2� d�U�j )��"E�)�eB;2/ k^E�ul&(epr�ˡ�]e�!�V�� nefib��U-_d.�eW"F[!/aNA�w!�A^ vo"�)A&x "�2!�Gl��E�%�5G1b�.�";jlocal*�sourc(llA+i��JK�m �0!��k"� 5�!:i�o!c�IU��/";#u��.Uo^p4cE���fl��t� ���K�A ider< ]�N��\6� %6q>[64!�i0�I ��a)V�&�b�N!�S,�!R2��9-a�n�-I�5 K �);+�ke�,�mo��S,mately be co�nsidered in the context of parasite antigens having (�Xapacity to activate immune responses which provides a complex balance where different antkte variant effects within co-in�8dividuals . We m$ evidence b�Othat Th cells induced by SEA/rω-1 exposed DCs are less susceptible to R5 HIV-1 �4ion , suggesti%4at helminthic 'Xs may be beneficial whe�)�> [ . Deciphe!� mechanism F�Ta means towards modula�B�wfor limi)8viral transmiss�or reduc�  load!^0Furthermore ,�s%�0ults should bEBfT �(vaccine tri!�belco!�)� regionsA�!world!14re S . mansoni.`!�Xendemic . SEA was prepaA� and isolaa,as described#tviously [32] . Kappa-5 ( κ5 )I<�by soybean agglutinin ( SBA; Sigma , Zwijndrecht %* Ne!;0lands ) affina>4chromatographyf�64�Th!qmasgA� fra}on�labeledF�deple�! . Omega-1% IPSE/alphw!V0purified from2via caE�exA�geJ�pr5>9S0[35 , 49 , 65�|!�tA�s!�%�p2�byb usA*specific��-2<$monoclonal(bodies coup!��Pn NHS-HiTrap SepharosA�(lumn accordeto�Aj$ufacturer'�:struc!4s ( GE HealthcA) . P1Hcomponen��!aconcent �A�dialyzed9�–2�or%-2MU�!,d� back9�2 or o-�,��e��elya� �rVV left)�a�z.E�AItyq� �EFs%��`rol!��~DS-PAGE% silver stM�. Prote��1<i�%tesA�I�Bradford�BCA�'$cedure [66A�Pl�Lpro����!�ra.U�y4apoplast fluid kDHS POROS 50 strongB( CEX )!k� Appla[ Biosystem����z.<e�A2|s ���fer��o!,G25I�dex cE��y����binI&Luffer ( 20 mM phosph� ed sal��,( pH 6 . 0 )%�-�109 NaClE���p%Yderived6XT-5 molecule is similara]�&:p)���,post-���e�mod�MW,�,ally glycosy -Tfila�,�obser�in"��� SF162 ( R��, BAL A!LAI ( X4��r��pli ~e�etent �� subtype B�<u . ]HWA-ar ���ɚ s ob!i�� SE��ati�QL[ ,utilise CCR5�co-re� or .�repres 7Fyvirus�ݥ�anZyx rsetCXCR42uAq ���. VaeM��passaged on CD4+ enriched T lymphocyt( 0nd tissue cul�|T us d��( TCID5A� valubdetermi!Bby&�diᩁRe�Q7. For 6!T�n� �.� IMDM� ibcoFonQ�5Q�86� 6 ai� ( Duchefa%x5M�GM-CSFAy�w ng-Plough- 1iIL-� ,Miltenyi ) dii( themS o�a�DC�HiA�F!�a�&oM�N�)� % T$!K�MACS ki!��Biote��,, 130-091-15�2�f�. :q ~+CD45RA  O- naïve �M�6x92�s ��-S O-PE!�,AKO , R08430a��&PE q��- � � 48-84,? �inU  [7 %h&*%M!�2x105ij /wel�Ev:� 2�5" � 9 (or medium (�[ro@a�2h�a 96-V flat-bottenM� ( Greiner!� -OneE�y�lyf, SF-d��of 20�or��2�t � �. A�ȅ�a�7%y12�y� -�harve.!�]�f񛉖!a .�.� �*� +* U�99 *W R�5x104�2� pre-:�.�-�.�2�5O��e- )Ja�/!�L1�9�. A a fu�Ic� ��a,�I{was�3 timrith PBS)xo-M= U�E�6&(N�N,al outgrowthpsu�by ito9*l ��2&in] �.�.�/�<by�A�u) � �mana�minal.�;~or� ��a�P]� A�!\M!k step-gshorte�to 30m' A��hTd9 !v #�tJk> skew9r�M�� Zor ab */b������bef5A'Z�a���d memory��&6So5�HIV2�pr�Ir marker� CD4E� pheno� . Ro����d�  AI��diq��%�100� LPS�� -Ald� � typi�ene�s�`�� a Thmix���� � ga*" 8IFN-γ ( UCytec�t1:r )!�2� rμM PgE��2FteiQ[UOr]f f 25}(a9 –4 I]�� thor lyUeaG1����,�}3����B��f4AAB&I�� naiv!@]@B�.B �B�kVs-cpb �in\ A/�J � e{�[of ^j�E�all�eic stim� of-5� maximal-21ALprolifer _in orde b�achieve%� numba�requi����analysi�C&� split��� � 7 �2" 2h�L��umA?N 8M�/�V %��J��1)��q���U�eoY . Si�!��,don’t survAg(this length!��i!K��un%Sh� ond%��me�)l�� ��^"'( direct cisf"hhe�s ,����aB.�ocE�� onlyeD� 6��!����"w. D�A>7 �t�re-Q���6hI1�BPMAaD:�,"W ionq(BbaZ�n$brefeldin NOsu>�`� T129� Peps"@Therapeutics BV )A�T�new9� s du�%��o7:� =fix�3 . 7%a> maldehyde%MstoqVno�(than 1 week!�4⁰CAZF� 8PBS+ 2%�)W flow cy tryy�In��i��u�S#% ,a!�llan arra?2A�fac� ���+trOz$kines/chem  %"�J�(m��6*Dy Corp5or RANTEN�� �Che2�&� ly�ni�u#t &x X! w&) F a� �iu�24h a� �>ya$ four��s ��r�K!H!b�.'. E*���EA] w9re�$ofAlea iv.�&- �a����.u�� ��RBr�tI�figure�se}�t�� lege!R�ToMv�.%��R ,.permeabi�U %PermWash!(RT ( BD Pha A�>ly �!��|P),Beckman CoulV 9� L-FitC , IL2-PerCp-Cy���-AP4TNF-α-PE-CF59� LMip-1β-AlexaFluor70�all�BD�sci� i� �at 4°Ca�w-*�(!/.�A��w� e�ce>((nd taken upzAI�- heyM��� I8a��$Canto II m)nez��jC su�3��,mD>` a.m^&Tmodel �rG� >� ��^!zin ڭ]� 6eQJ:*E��A y7A�ioi >� RT ,1�8.��m. Shownmhis�'ms�!cyt�Z� d))7�"ampu )�5W7��)�>%��@opt2 ��point� 1�e�*+per�2age��l�I�( >50%mP�!>s,MgT+� er�|!' . Gs�&["2�ic�4s% "= ed�d3A��7S3B :x&��All ��9"�F anonym AF�th� % Nede[)�B>��$IRB approv~+asn����s sig!ta6T$c�,+��!al4!pQ�>q# archCU,s��outf6!�% �) betwee� AMC�Y( 0 NVT0202 . 02%H DataA�{�7n unpa> t-/'!�$a� two group<8d a 1-way ANOVA>, seve| 0(%�� ��*Ѳd�is corrT!"� atic"�ces5-���)orE��[71W: w". each5�m�.bU.!��U?�:.or unex!� .A=�[, �a -lT5lre�#!5�woF� ’s)'NW=� Z . Ad� �&!O 2�$ 2.��!ej$to�U!�xexa��teA�!_�h,.@v I!�� he u�%!LB .i�Neur�'� Vca'4∼30% shrinka��Fexa el* sp� ( ECS )�nXI� surrQ ��a�)X in gre� 4.it? ts&� ala})L�� Desp/i�oss�/im"�'�.o�2OsV$�of bas�,� `potassb�a-!3� funI{� meno/aOsIzlai��. H� w��7�.�o3u�A currR 2�E�re& dA!~9��in*�*� !d,ene knockoutaE6�1f� �)�alqe�!.5!up�;so�� .<�)tr%�0H,<,Schlorid x(�0h�� o��Na/K/ATP� pump Dosmot�d�*n!p�#of waAV.�9�membra�0ogilseem suf�1!�!�!DngE�9�as such!�ow�|���ak.i -�;!G~�&r.�(*�*conneIxw�5�6q!))E�,Na+/K+/Cl−�KCC�~ HCO3 BC�<!5�app�!to -2ri%a��aQ�� ev��qu3ta� ��ECS=9 . Co�2<�q statEdknowledg�&!i: framework �!�1�ly��%�tri�to guAifu) key}l��pa��`!�m�BrehenE�%�glia–)�!嵑���no�A# ��0athophysiologA� situ�. }&+ e�&���� e Lenhossé�" 1893�d*3%+starshaN��� firs?sc�. TOtto Dei%�< mid 19t�5 ntur�)E2eL& Cajal [1]�Th& %v itut �$most abund[%�of r�ob!� [2.DG:�# e 20�&� li7�>by��A�of�alevj%� �s0��is now}1&izA�i����C q ly involv) �5��excA�A�inhib�y synap�by�"� ,�,abolism��re��%�e�mi�0s [3] , homeoa+ic ��tenŷof:�K+ , H+�5ama_m�[4L��gy�X I�a}�ns ]&, al A��B!3� �S&ur�e�>on [6q! trop|76;gł� (ax�egJfo�(ninjA�.})� !?-�� <"selves��to hav�roP�3l nerv�%� dis�s� �o�icF 'epilepsyY!d��s�K��ch�Alzhe8,'n �,schizophreni�6d0!/o psy�(t� �[�.A �M��>n��.actA��v2Oi|el(2�!� vascQe1o�m" �Vompart!�? p�1co�-`!�!8way�q'shold�v�3i�:a�isowa��+r| iY1�e net�s..2�match%�.�!A�( �g�AH%��fiŋb�]6sic Ca2+y(+g�+By!$se�n�1es es�)i�n9~.<~ite�6a�!o)�%�I����&��,u�� expl�,gr)pro�B� Y͐behavio!! repertoir}�!�m�sl �6VSlarge�/ F�2�at a;ar 3Bdys\ a2*� |assess!�xpo�3�;��8a$r� t�t2� Qo p even l,6i>*# �=0�qu! obsca. PerhapI�żpro�2nt illu�SM�Ois�l8of:_ �m&UE�on��e}�)X�� /ATP-fu3<"� 3Na/2K !��� 5�-� s ab? keep��baMout�a�5<s�at!5Hretur�� k�&   highFs$major sinkvex!�E"K+A�#N5icp6[1 -sSz ��Y6}A��b�t@tC:[12�[1 [18E�2bu%ik?*v�,%+influx!J9(E�zmpany�9an%�ens_ �-i!� tral# ) [24]%�et-upaannlar*"�,|@<o��=a� ��1x2z>�">�z�� oughtA�b>i��n �=�y6iu�aquap{'�1QP,:"o[2� [2e�Yϱ�far � sett0.�Bdo notI]�Mlu(�o&S%�^���=� &�mM low-BP. Assum!�����Vi�&� \�9 ]a�F^,��@�ye=��R!t preds/}hBD�!�A!� l�[���[28I��6A abov�3de�< ggz#�ZAS���Lde � re�Qn�be� a 2�ua��E� �ule5r* ��ana�2!Slik��toe9 w �+i�!, sigh cm��A#er���lsuy��p�8����A,�-��e� !x. Au9�ofr��"b� NTI@(4"�Kc�&���%ECS��& u��pU5w�B�� n���25Ma�[AhA�wz docu� e�) 9yEp09�g����ribut4to�Y�� u hquyFonA;hk Ml"z >v#be��u� -�>? Gs� �4�. I�4I# swer|�����:2�*�LpF��L!needeV=!�n2:���%0%�Fin)4zin6�� G!>@��a���f.S!�6�to]�&�v�A�!on)u���e�U�!��>ca{Dal fe�2Ŋe �!kIm���8� gainncchGal�A[3D1��-ganic�nyK� �!]� to��J� . Of!e� ��ceL!��-�!-cq�c�I *N~�1~ 0W /bicarbon�� hang� ( AE�-�.1B�� b ��nVp+G�DCBlAn /hyd%9,�#NH+(��i KettenN/ & R�Hm)�@���affair�5�K9!�: a��7te�ptu :"# �E2R.� ��'.to m�hypx�jj 5�::�S>�*h ��r.@cv=l avail�  %oo� y cruc�S(&;at S�u�KK��s��#L l%�6#�@&ʹ3wi�dep�Jnt� a�c�geome�p�H2�K����[1�I+��Co >��";���%$�[ssoci� �:$6E'5��R C. A7 g.)(al�C�~��two gU  mammaliI?rare=�[3� �K���-w-�D �lvalid ui\D �,(menoB8{ flectp$$�ҩ��K� �`E.I��E��' �.�'�0,?te� alk "�to�iP�Om�D��� !�g[.�a m��'!D- &�f��Y;"B�1Mb�&E?2�5�\. �YU-y*,� .E�"INemphas$`we �!�N*[ F�� �D}mi�!�"%�8�%�!��urb&�A� tead�(te&m�;r�e�pa�M J �1�r�cA �~0� S( i _LEcN".M.3�*%���e!+EK!K+��� ! ~A{�[9C �F@��~ , [3,�Jq��A�omiDA�kof Na/>e��s"� �/h5] d���byL��� a deg� E(�j�A���C�  be equa�AE�t�� prem��_� !�e��Jwf�V�tB.��~"m#��Pe�)Dit�Pth{E�N]$�1ls����e2V"�,u � i�!��"�%M��Du�@f�A"3"�, wild� A�U''e.�!or" ckd,)���,Fi�, 1 , M+I��!�T� S1% S,E� �)}#)uA��y�b�AT ���Vi4 se�%A�n�A�unt�AKA���& : H1:B�+.|e�� ��F�+J�">: ��F�; H2:6� T +H1; H3NNBC 4R>!�fi�&(9��out�@�A�hH1A�H9 H5: J nid?1�EI@co2�mc*7mc59(�V�ahe.8H)Hs.T�VcU��$ inaccuracpB�u.�@���ue��Z� ��J� 50 �J,s��sO,!�� V�a�I�ET� a]*�T!wwuni[ly�l ,R a����meDSe;&�*�somw 9B��+cal���om�R]et� .'s�;�W�� �. DiInn&:K�Q!��a�"��5r� �i� � gi��in��D�� . In&�7�-�#d)���j�al� ��kep� ly���s|!�5c{�Q�$��:y���N$wha lis��1� r�@ �tdN�,�p&5 l�#q(]=oForI�-�fvwe.�!�6�.�empir�$l^I 5�))"o m�to? 9�s"�9��k!� iste* �w=K� ��!~"6~**�o2P( T� �&ŝ*�dis"��W� ed:J)bi!�M$$H�U pane�/�h�+n�@rv[��r �!plo�Y�"H) o�Lo. v>� ~ U�+2��4�8p�0<.�� �$U�s\1)%n�SZ` ( [K+]#Fa� 6�r�-)z slopQ��gr ��K�a!.D.5�=@e�K%am���K� &�,"�S�?a�en �b�F$�#ur�ĉF.��%v�&:,aPt�)se�� hei�]M�6lso �\6� u�25–35%� | U W��� �� s9His�=C��8.c��K  (.6�1al&%�*R�.jɪ�W�"B� � 6�ITtr9 , 2%e��;7%A$�50�:� *otL J�I?6�� eW�s:� r A�1Y es 3T8��,�Z6�z<�X��rgi�T c�_��f���~E:7:�3`KmkS^.=H"�-fG:U1i1B4  ( � )�~s~ our-Aten�U.�R6x. uءPrb�TA �`�2$ NZ"ng al�iyfacmn�6�&= ��U�acros�whole��op*uu$ !Q���15�6]� {?���$�$q#N7a w�-� �"5:� �I|u��H�>mc!�E?)�)Q �sm de&�[�]o.h/ =���3]! mcI�!�*� H HA[A.�: ��(� �ly��.2��5z&S� ���b r*� UU-� &}"h"&��� � A;E)��i��6 to-1m�onship"�Admagnitu�"!�"�#E�&f�!�"t� *�i(� ��ak pl&� A in�, 2� * yց8x%�!�,�E�-dX:���?EFag ��tX*mpens�9&�va��b��� ed"� N� �#�#�nd: � rone"�#qYd�!�� �� l S�  �_1e!9.t e&�*��y�a�!��AF�9 a}� ca��J %�3h�Pm�>t����,i@��E� zero!�A2'up�!��s"�+8��*gi�m{!�A�.�*~#���0� �.�A��re2"~(o � ificQ )��&�#>� ��6�{ H2%P () �i� a sl� j�f!#� ( i . �>�e�H�# "d )jZ����)�(-��!�%�:>�,e�Q� eT�A�Foc�9^%p�sets meen��%��t� we\�*whe�%eIb�AdR;!R� *�HaLH4�H5%'ermEt.�ti �<_�sE�delibe:�A�%� &k�.\a<� A/ViT(|F�� a�wO )�!ear�be -� a�9^�"'18 . 9� 3 µm−1� j��Ham� Arii�g�9��u��� tomo�gnda�reohZ@�2�ߍx��ais �i�*�,�>�ޑ4j� �f"�3�H5!(2 some?$�flexi�Dt!�!��ni�":sA�re�sd gU��M . 3�? unimodJ"�;����/���( kV9a&�AHނ�%E�F��^!�����e�1��"9~A })lm same�3 ternE� N�c&$n?R�( gSfin��,f1�6��Q�F���5E�>!alh�F.�*�3G�&� !��nes)e too��0T?raw b&x9.�+g/EwIN��-��2uc5 N�X|6�7� >4�$in2/ �FDm��+� ��( g �� a} �?� �&r6��K�� very5q(% ��nW�4TU�� � �'lH/p6�a:�%$�(���robus��ż tane�'� ��6�Kn�"�I�����c�J�i�imT[7�'�llp7>�Jlu<H �e�regar�Vwo�i��� 5'e�el�"A��6H1x� ~(a bumetanidqWk%� −/�="� [20d�[3k ���A&I�� A display�m�4J��� �)uh�]^A�et� hyla ium�MA+.u�5.im�=^pU" M�rtALayeP�� EC6N>�� A8B�J2�mp� � &� i�^� �$aVE�5�4B ah4��* j&�m:al6�of cC�1��!� =�tracute(8slice<7]xle�.p���6�57T_#E�Sj �#� -��9eQv �+�IY+9 � \in� M �vt5��jis ,-h8rEH4!n�IA��N,ih!�2)�am"� �G!e.�stu|p. MH2U&� U+' ure3[�3AD�@ ?  1�ora\sXGd:�E� �l�-o�9�&B Y. E.�.� �D� ��-prono#dRo%%be*�1Q �/�1�1oug9�1!P*r Xon�CBL .Qh>5���#�s�#�1.62,E�aui,(stiae�ounres�?A*N6#a�ls2�6� E4 ��"Au[ ��e���wx[.:&ne�pow!:-6a�"J%Yk/!�BB�+6D`+ |&� "?@� y backqbAa e�>r�78 H ad��t .d � cenari�H"+sA���*no x ��&�d)8���@�.�e�6�  m}S�%lC:?Gl�[V�7dw7[3V74�J1�s�&)!�� �-u�&� &P0�(��%kX/.7s�%!m@9�)�$&dy�B0Egb�&�6Eq: �a�h%�U]!�.Ze�u�a�h:�.� ��EY�h� O2�]Hw���Lter-carrB5)E2�j$y{ o� "6v�D�/��!!�e�Aq-EE\�K �&�&F��S�\�~�b jes"%��-� Az�H�c� \er�Ra8o�ƉIa Ab'�!��ٟa[����� !ha���0 is�QS���X�[=)nwz�i�Y�e clai�#at &� �"�doe7Et}6I�NC:�HN6f-0 5&�T ty Lj:!�y(x inclD 27q,�9sI�* %�&�4 ��6� �.6g&uinu .N� s6��"� =a{F� >Z@#2�$by 80% [42;E�m�K to neglig M�g� a�F�"&��y]U�5>�if>�/IE� �4-<�p*H� ��a�h�?i�-  "�.7 F�A_anZG�Bm��7�� k�_ �')�� ree�%� �z� �  A�a�toB� J !7��6�Eұ�A�-�r� �S:E� &:!8w7�^��C%� sJ� RZ !@"� 69$�F�0��"ly}ed lev� !-_narrowwindow!�l#�vڹalE�9� �O ��~�R"NBC!�)�or2. ne�@.�_%d� mA�V[ '"h �*�'.z ]D��&�* �a�#pulse� ��=+Jo"�;���a�b�� o.Ie*�Oc�vM�wBk � �?�/ArYUZ�O.����� !r�cOIn� )�*bE�Ay&��!�'�pC ofa aiE2B-�"u%�_ �!�c"01�Q�P4b�95�~7I��7� �76N#ii\�@bM��c uoh�)�vQ�0enh�!xY�6-e��57 � ���2�v,tr&(F�.l�AQ,7h_-EE�i29�J�m0eE�1 )�wi�'i�S7#depy ,��F��c en�\m*C c^o yiel�W� �%B�$�2aHQ[43i%45�C� i�6X�$o�]�6��@h"&����!.�&�  as [NaS)�"�!E| P m% �9:�( +�# ∼5qZ)lR�7�G0%J��"1%$"a45]"= AsE�S$�a�.�;I.Y>QO)W;.�UQ /c9�~ b�% .!$� ��.�e�5om mc2��g$I�3��"� Skb*�xyIk ��e\T��out�!�of�4�S$��� .�"W*��6Y�RB�+�: &�)�J�.!XvHE�pA�):U have oppo� �L3"A �w��&�`.u !T8Ile�Qc4y�l�<gn�3L!r� ��T�� a��&I<2�&��b ��] so1K?4 F*x o�rf <��ABm�I  1�ie&f&kk"A"!mc�tsyth� �� d��is�l �� A� �]��1 �5.�%Z��2b�2i1BG.� |,�*^@%�<�� !�t�rA*"e NBC-�m�1�8*-c&9�impac��%�� !���� S>�i �5a*AWil�-5�. Moreo�!xeelJbKu7YkinF��� }�}J9-4����� ��cycle [4��G!�&� &m ��$ out%FA B��(�PZ iDM�a�i- ity-B-!.a+�`5� � i�Q�|/byI6I\,�8�- �ng �6" *[ ��r�'+E�le#�-n {Q��sl!3 ow .OecE5d%s"�-21*E^AZ�� E�x��a aed�/n�(p> 8�#A�ofd2�41��6{�,e�IA�,��Sمe�� ECS-�LE�l�:�ABm&X:7;a:P<��"� ����)tJw��GɼفA�(e.��R� Jg���2�5"�E &� R k ! B ��A"�A��vK+�a�-�A �Qgx�)ly�/ ∶1� m��1� R,���Xt��J/)%"f l��l5m��')"a��ea�� U"B�[ c[� � !h� Z"wpe� &QhTb2�I et aVB�R"� �w7d�7�2!O�jc�Ara^9:e.I]�! ucpU�i{,oU� s ha���ty n&n,jost�. Aitken�48]�o ��ne"U ,of hippocamp%nuc ,( CA1 pyrami)1w)^aec�Zeq�!Xl�?� "l minuM�!2� ��U�g��c� � . F�5�E�5n@_A� ��H�MK:?i�e�N`$ by 2,n7er �rOUmi�4,copy ( 2PLSM�A�w=H9>H9s��] ndri� , sp�q !�cereb�%r�^�&�sF�bb �%)!/ggm� rI-M�0 s!DW"�� apȐ� 54�N,�s�u]x�.�:� �)�!h�7ta�: few�o[1�I9H��,r ��! ason�E����0p�ns3X��6�z�H~���ig� of�"hd��E�fr��T�"��erp#<��sF"H&� ,"�&�kP�,�ԅ�disQ(6 � �h�glu�a-Af�g-%�": &x6� EAAT�E"6P�J:�)���&G[40t.�,v�s"� ccV�_A&� [50]z� asj&%Pa�?O- b]"Y,�� ?i� uen�bq MD\."|Q�%��8��L�l�c ctif� � Kir�.1aECS9�*5"[5V5 ]D�A}�~E\i K+ n�Z��[ m9 � volwp-��66��(�3g�A�con� :�. ��E���eu%�K�S \��- �?pl��a32��-m�t��� a:iG,RG��:%b�age5 �8i.�1w�"O A�Yadd�pms�T]e��cy�y#YJ easi���iiUu�1I�replaby%<�pe&8nu�wa�_I;En!,�a�Tz.TFomulti��2 aV or f!� [57]�&�P� ��a��o��F� !� u��'J6.<;.-rZ�.k+9�& 6 )�e���YL� 6h�^Q'a� a���"G:&�%� AcbA�� M�w"m.�Q�as�'&:\�K�� !��: �mak$2!�m!�ds"�8N�=&.�!:t � �s"Y "S�r#w���W��eP�v� embark�'m�lE�ref�n��gEyart"4�.8"Ntm�.+t��:�=W"�5Aqa:�'�+Y'ZE�,s2�E} Ec�$h*;.�n)a��,b�eA��*��\Sp3�gspae9�&�[58 >���e�q���}�t"� �p�!9M �f�^3v�atI� H� quieg,Gardner-MedwT59]H$O0 �ore,&1R�B�P�." ��!@�:r) pa�:T�S �a! oph t�F sourc�X"�*9QX�#��� �<� i@)Doc� x��%:Lux & Ne`[60� auth�o@&�8�J��  es��A3"�%(�&K+�o,�F��kO!��Sg�f�0�?Y8!�LFam�>0�#spNh: 91P( �FoHmV? 1&�e9 1O�at�5QF�N�� �b�YW b�bal�th!�m�"T� �Q�.M3''�����8 y�i�c�h,F&�A�.2�e eff�"�Ts��y)��6��7mFza�a��o�m^�A�'�Aҁ�����,t6c �5A&i'� as��8/#�&*1i�FK?*i6[ia.#F"iG�(��3on�7[y� V�-�q����TIQF&[N%]e:��.��halleng�,��{-<f�c��- tB��5ReaOyu/�� �&d(��0%�N���aiE4��H"�E��ng3�R-�rwe� succee� in bui��g�+[�a*�[E�*�W e�.Z�#�!�JIH��r2�rNGb�sEA�$]�J�ks>�r57"�F�%�&�X�� \�on!��U��A��#e&u �Tb�he�G� � `Inr ��E�v,2�aX.l^EL^ECS �5zx<'9�by��int�ŀ&^Qi�>O�i3 YTc�q%?���wJ� ��lge�4cw )�9�*7�%ed��."�A"� aJ�9� DR3�gd2gUo"b�y!' law *princi�� o8[�hs%;�[min/VI �E �9 vari� h�9��/fic b"@</��]"!W�!i�{-�T��&� �:1��Z-[ (u�25�5�[6(5� ic ).��2 ndex�;�oBi>�"*�8s*n-F(j��9'! "T ��trM�E���Aeujj-[}p��( �))�XiA`A�l���&sNneg�7�Rrg�m-/�� tr�dZ AY�d�P$6u+_��zi�&"_-�K�8o� $�KsA� 0i�wi deno&T�:vC�} �!��uV�E}es� E�S����#&)ctB U$=q .-{A*�z��~�, hi-`�c��B� �ECS!W�0�a6-�( N�p2���,� ,Z',"�))� �>t=�%� x9S]��bH-�-TA�OM?R!?X �6:S�*�� ��.MA੟R���|x*{�n:q��M�a�'zH�C, ��>��i8F�*~ i��e Ner�f&U of)�iAf]r�Y�SU�b��LVm!��mo^ aXu�[, JNaK ~?#%&� 8~? �FE'�c� "�A[<"�(���2� a2H B,C , gKP ��8A5! �Y �=�q�, F�Faraday'�0�, ze79valerT+=��J�, J�!�Pre1�c�hl�du��Zbz^ ]!`:�:�(>;6kC f ( tW�e)�jXJ#%�l �eF�2X_)�"�&��w =I%� �.gJ��symbo�re�$<$? 0N1�A4to: =+-H� I . No�i�q� (e� impl���a{�$of��e��sum]*K�a�:-�.��A�er�&$ny)�. I�_luxc �=MI [61]�A9/, [62]U� �a�$-like fashA},"L( 8"( "( 7 )���DabCCLgl��2eA%un� rea�c ���ED2�>���-it�#B'BCa�( 8 )�z �F��}�$6u�Clex�Pa���I;+K,�L�2a = �C( n!) 1 ��Smsto���h@Iad� ng n KIA�BM%�5�UUC���Y;���2AsEk�?)�4�8*2��Xof Lu� Rudy [66T&B��%ݽ�(m�� ol s%ckL���de9gd�a":"�n:= [�1\� .�95�fNaE�f���(�)%U��a�َmNA��.j9Y.���-�;l�' �c?N@�� MRafIO�/E�����*� KNa �KK0d�U�mMma�,&� 2nRa�� demM���e&b��� BicpR��& ��Qa�r��� i�1620Z"�"JnM'(�l�M�na� y o �Vm;!�� a,E�Bc�� .# ��o6Z)2S(#&5)��^nUlipidYrY�%a�n:g�!proa$J� f36""xb�3F>� ""�J; Lp! 6� �� i�xa=��B�u=�  �.� �<=u1�~�=�;wi��(� -�%�II�2�A [&�at�M��IA� v�$�*iC �u!�o�81��W/.�&�!�F��9 ^de�*!�e�ANerm b5 �'a?sQ�I.h��Y� 4��b<�xVCu�a�qc.E�of�\-�9w�Cva�6�%0�1X5�fu� V#,-��cenaK Zeut!.�MacAula�d�7&o&:d*!Iz)��9 U�o-�y2( 1v Va���*0��AQy�6Y!�:��OY��(��)N.u��m)� �MI�>7&zd.�^. T=�)�A^�9�"q!���� �b-At�v:�)��com�S@�I!)")6��{ing�C�d��*u=Qag�8!�� !��-"�a�}-s rando�gXPKBa��a��x!�*Ua�p>� n..�5�6&0�I:+6862�.�:D�O �at �V�m62(�- 9[S]7oy� . 1T)Y�vU�o:O!{��u_Pin2� IF�]�: ��w�5e�B7w؍et�q−85 mVA�V i���5n e G&ji rQ1/1W!L/27 µm�� m Th)"6�6�(Michaelis-M� %^ňsA�ea�&} &�Vk ( K� , K�e sM�A�c*�&��R%+g� /:� ,� ��2(')I�O ��>�dZ�I�5P!���P]�P2�m�$Y�i�!�nrA�+@�U. R"�k�a R�ʻ� U��� ��$Soa%�K )���t*�Katy "� �RI.IM�� m }libriuЧ�^�&djuy��:�!h�!6��5z`H�A�tr��NV�H( X;�. E��&P�r�%��ia�\c��of)��n�qzl:2Und!SAOX�!�ll�+=�by.��/z�E2� �1g0.�"�d,=��[e��� ,ax(��Ah��muu_.b���tK+%��N! a ft�U�*1-ks4a+Y�E�Ct^&ngAwt �"]e&k�)<}��l�Fql�eX%�(�'�N��g��6�)�% ��- �*�)�1Qy3$*k nis�!:M�C�ٓ!\2��%su-!>�KN�"�x;�"< �";u/�)�� "� ��P�I$X9apeCa� a2�i1]�a-�2%�b:� ��;.�x�3!�wo@�f��&�6N[z&wa�!�%���EC until$Rq�Tum,&�x5  A�( iMj7.� 30 s5m�x6XAEx}�!Gre�/} /u�KE(�Q�s�Ɯn&A6A�&��At(r�}ETe d�_�FM�a�e7an��rFU�7E2wa&we�&�<l�����{�f"�]!$�  ��Y �<�Fd�C=[$)�-le�A[ ��d "�wA? tu�2J�.LleaUu�,<9 DJ�. Cho�Ba ��T �(O�z'OE|it�i�e]e���PtaTstyinI�2�' �`F�. it cebe �B'� In��@s!�E�"Y"R:IAg�e6� st@B8a�0 erro�`td�!�shYS-%� yp�f" F, m���Q� ��.���) n �g/%T1EdIeA���d�I$ucA�e 2��m)� plat�,!>H!�at�-E^o%Q�p rc�ꖡ��ML<an XML-�:d1l�ag��"S(j�ambiguY�d6"!3ue%b"�'@�Q es [I�I���fe�v�‘�&É��<pQ�ass2}X=�A��� �#;&χ�; u��r�Q�eto1-Z!�1�f>��E down �i�(( http://ww)Bjm} org/u�_voipio_lloyd_ottersen_omholt_2008_�/on0�n?ns&�s�5run� �P�me�Environ�!7� CEnv&r �$Open ReM�( COR�g o to�!�061$��f$*s/pcenv/%� /c�� *��ox . a� uk/ :#(.!iEukary/ genocZ<<��,$ n��E pos� !�*�@DNA8!"� �,�8�4c7�,���-��Qorganv�c� 9A�� s+$0Og#�!�e�o 1 6�Xr?.��[ Arabidopv4th9�"gMsi�$6A(siRNA–medBG�al!GMI6ak�.� ~�  non-co RNA�lnc )a��$by Polymer� VAvol V )8� ARGONAUTEYtAGO�&� �!�ata-�!e��_{n��(�logA1 e!u� (A���s}O ociZ@jecV>�I o� QSI ��o��?w( ea%RN:�*� k�AiA�Q'24-ntI{)C� -Hat�-!E j��:a*es7d:���0v-j���$�-&��+ri�^Q,.�- �nd.�/e'3b �Ed�}�ha�neIwHSqs�al %�Eh �eco�/�f�4nU%Lg��U]a&T���]n M�rY�F. �i�i)�~ous�W���y��l�"��NE�3]ܡl4��6!�&�8!�4v&n\ir mo!!�" main�N#�a4 egAU��. ToycyE�b DQ��.twa'�%gen�!����� /�#aciNtomo1�K� acil�~=y��Y�!��N �� ��h {cr1{bG�����m:[�ѥ\a�M�/(�A��� se 2BW5�3�s&� �!$���RN�]IIIm� Dice�� $Kc&?,!�I(�:��!�|?v3 and/N�|Z9u�%�-WFN� �In^��l��!ed�precurs ���� ! !)t/)(���II�II > �I��"i6@���d�/a!R7yn�wE���DR2 (P-D"d#:^�". DCL3 ()��*� %p�oub>���jG+�)"�BrpoI'NZ��n�Ai� Q��mx�U!Y�e maiz. :*� �!Pol!$h�4e����b�(&%�!�.3!�MAk[6Z8[= Reco�<?���t�by��-%  lE�Bi)�U� ty�Z�3�&�, ic W!ax�z�w���$r)�A���b��!�Q�!�r. m�-v�e��w 5�"or na�htEW6�a,��ѺV;�G��0�wYD o� in S�sac (omyces pomb1��su" �&JR�z'i�!�!RA�6 IIx����x�� �<l�B0� �r��r6��k� S .�aиP.�a-(of ArgonautHtM�!�ve%n!X�? 3>�A!B�*�:)���J�&S�E!D�A4�-��RIT�"RNA�'=1!��9,)�:A�$a�R`tB"/�5�6d���>�Y)#-]�]!-�X.� X fTu�_����ҍ Jas!J. �ѡ��bE�q� �-s.� �E� w��t])d�+e'�x�T!K^ enb(of��N��� l V- ��"�.�I7U6 Q���) � M�-K� �iru�w�A.��,rI�%�9=�K� needs }sl��X!0dts^Ba>in�  5e3�A�)z� ��\as:s_ �w)�.  �6��%% ��s�e a3ir"�/� �EM����mp�C�5ap0�9!�,c$frwM�de�eu�6�!�:C�>������V��s�  ( Sup� 2�f TA0serD 5 -tS;� Ca ;�or ��'a)fQ%wII-*�B��"@�.Yv|r��n WG/GWa*eSE%*� Q��rF%�%�[2$M�Bec\S�L2s 0A6i�q*�!�mqbof�V-&�9��!!> q�;s[seI�!�q��to "} ���Y�[ZU6�bre�zA��aM�R�'�ȵ�I�� *� :ggQ-I Lm��%l �L!��i*m$��:X2�:� �_"�.�i6��-b.� � os0 M uZA\��0@��>lif6��Eon� inF� help2�>n2rT�&�at �5Sv���l�VZ��;w� y!k�t6!�%�&4 -KZ 2�B�A}`W[�-a�-"� �i� %q���m�9�Ak� 3A�>�I�a�"bX�w:� CRI�rkJRJ��.��?��2�I6/6�cic�.�2 �Tat՞�)%K�T�T2T  �G)k�F%l�� >��A�l�9 %1�� <o ���?:����+:�%/-J;�Y[r����- � u߁�est�, �.�.*���]l-$PCR�  2��v�2of IGNj solo LTRE+�&Col-0.Jt�c� er�t�d0spt5l mu|>� ��a�v�nd >&yQ1r�1D`.l hn�%� �f�F�%�}a��%!1���bym�a6��)�����^ #EPaX2RU;�{.#no�թ���5#� Ac��( Tubulin 8�dUB�;�"�R1�71hrr!P���II�soccup�!DhBo )M >���T%�s �)�/'g�[&�>goQ��k!�%��8���N"T|ûa��3��� F y}!��de}atAH20J� GN22 �{i$ 6=pE–11p&�@f!Z�j� ome->�cr�� )�a�U( �ierzbick�2R���#0r , B . Grego0=J%ck�(C . Pikaardx#�ed�#\ -�%�)��G���4��s L��F; . C��BEY�C1,*�K�륁,m�A�n>AP�](s��–~ ��ls}_�}d� aŮd I7�GN6� AtSN1 �sJ��% R� 8-���*I)A�-݂ �1�2�by%-� �� NRPE ��%st�|:1�!�&�{jj�2�׎a�r6�nrpe1� 9X�c!�)]�A ��at��or��%UJ2}2S�y�A�E�9H.��.���6����xI#:J����U��*� �+o �����/ngy`j-��p? i��!,d!5|l����go41��;��'d� �!�[ � 8�n�glyA�[,G*) *�U�2A �*^{)�)E"n euup>��, �� ��n���s��."�E )nA� x�O2da%2W &2 ɭWxV � ⍺, N!P9� ��I&�on9 �2�B[�_�T�edWwe��np���H>` in6�*� óc2�)At�7E��i5BUa1J� o�ift�I3sB� qmVor �:+ �,�+�2� 32u��*/RT- ^�3�a���K NU65)���S4 �F��`9.ra +>�LP��d�e�FZ�$� � �� /9��[��Fqw"}�Z#c]�Z] �!2�B�� M�exp��y) �M an AtMU10I�� �Z#e(�LlN . Ov�+CT^�*�� ;(+zi� uw+᱁8he"� ��B:I�)�&߹�*��$���tC"A��m��)�AQ�x$!'�y6m,��6��F� A�anh�`by�2o"� M��,b���8sE�:em(�.*W�% �B7)�q2� �Wdr2B���Sb�{ GR� (�"oM �6 )�A� O!FEO)�hojp� d5=�A+ �&� �8�3 1���.+6�~#A���PN�worpks downstream of Pol V and/or 0transcription� may be recruited to chromatin by 9 . Th& mentaSPT5LZ1,( Figure 1 , 42 ) is consistE2�.]�is��A�-I E� . As demo�d�jmos�O��(be occupieda�O poolH%�. One beM%�-depend�����u�.] in-l� B .^�N. of a� �,to specific $in=�efore:�B�M��USiA� � also:o6� �,�y� )�ik �I� llel�"� partiall�:b each-�� 2B=�hEY"!2�2�6�th � both guidM=6� s3 P� ��`N�  � i � them�suffici᠁�!06�!�ma- ;��ty�2 ion��`�W ta�:01�several^��>]side-by-!u nrpeAj �.� s usA7:E-s� iv��tri��endonuc.�M]�,of cytosineswHaeIII� luI � vaII y Osi� block' e"R cutE��all� ampl���9(genomic reg�!�CR�ow!= , unm �ed ua�; a36^ fail!�Aphre��Pasymme� ( CHH )>�!��. C��ly�.previoua5ports ,>�S stron� ���B locu%p@%�[19�430]�6� –[23 a-PK�@nt R��5A? :3�c���S.�� u��B_S �!�.Bs2� , 5B�Im!Iant� �u%��tc�t�a�AAN�_ <?��|�eaO��nei0  nor�`is�W� Y\>�f� %�My���Tj !s on diq-aN(of lysine 9 hist�#(H3 ( H3K9me�.L%�!)�� ,%"!)�aVIc.�D!�F )w5NE N d�a�re� xonl�� "�:�>[ %@�%R�)�": �K subse%^�j �nd �� togeE to�=�%ess�b&i\�*W� opos zitA>�,coordinate aU�:|E�direct1�v �  novo= Pf� DRM2!:%�� � WhileN��B�-�R���@z�� )& �has beenE:n!obe ��*� ! � 3j � firm�r� %�)_"X!�A�2B, �=� Fn,E�qo�a -PA�*� < �6��� �r�on 6��B .Z:c� ��.�A�eA�som�gn�nus"I� inM�A ibu�[s!�>. FzmdV>��!{!�9zin�����]aׁ v�B , 6C�F Also acet� of>�Ac<*���i� ��o��)n9��-g*2 a e �D-"�"�U�  �>[~2��H�y� �H6J Ə"�6 )&.correa����ex�ofU�I$U�c|aV� 5=3%�It�=6�F�is H2� ��M��t mpsr) d%� ��sA�2�ou�rterpret�` ��!}��r!|�F�!& B�.� Our f�s&� %lorder!keveQlea�:� 64b :�B�pro!' init�va�H8��)$1 clas] of� -co�RNAM�first &s��sis P!��double-s�W  #ts� DCL3%� beco�incorpo� into9�� �� AGO6:AGO9 [j 5�F4�Fsecond� long>�)��'V�II [18 V6V "�&�i� 1yB#)!Ao><s2)A��"$precursorsM�!{biogen��31�M�;2Xw6�mFa��&|DMS1 DRD17RDM��I  QeB�� r:ist e!miv"� �s�, 3 >#Si! )�associYA��5��&� ��7��FE�ij �f:��.�!\ua*�M2�)�to� vide sequ�@�of}�%�M�is���!��!� ,��Tan unknown mechanism ,yLinvol@C�� tw� �"n�� le"�Z�!�!�!� D!�.{B(.s�4��nd! � a�o�LIoEed �1�b� )�B���Kss �.2�F�%�*��A�1 dA al6��|�;aw&^ �"�r�; B� ��)����1�w�6��� S*V �6o j .�tes!�� 5qs a+B � �nee�o= �- �of"��A*��56�. Bec�:'A26B�*&|",~��2~��!TmJ� �!"�:���! plat"$^6:�$�mX�5"�weakl�2�.F J% !���"� enoi*�N�%� when �Ar�$>N%$Ia� � �%#art=ofJ�s�i8�� a C-termi�do!� r�%4in WG/GW motify�ͽ�!�a�#s�$con!���to�!p!�!7:�n. � \a% X!(evwh�'>� i*� k 7�&�% F� y�?,%7g$d i hav& �#�lowk#f�!n�ang!�AZVr�F�((3�O5ER� d��isў!�fu >��5!�-%1y�.��8lsom\l�M�-�%�aby ano!�u[ ��� VrB� A�!%i �2X is "k)$by multiplQ �#-q�!� -� Q��2� [څ�� ]�"�6}� � zils)�a�a5--S%$.�*# !*>2�oc� ."� �!�"! ��" �>  bZp 6�# $Like canon�%� ,L%=E.�$ a heteroQr SPT4 [3� >�)�!�r`,� .� dP* �* m�)il#�A!9 xin 9 holo�� "2"1,y3,>9'A'�/�*i{�%�|2t^ �Y(��� � ^ �!�uv�gu�!��$Y�io1 &�# highly!us"M( iT6�+!aB�:`he2g rg]�)$ut� �Z B� �xm6� �V 5@�%�coulda� 1in�9� c� �:: )8&�&���� � o*/) ��+"�/-��s�ρ=��(T��ir �2) {a ps� �Je`>� �o�(ens� de"cy�C � icular �S6�1�6�!PI )2]]����5.�%YP��a� II�a :�[&LIIW&:���Z� lackA�dV A �a�= deci��"7 �� 8� reA�s"66' �M>.aQp.o+: ]* !q2�&Y%D DA�detec�3e!HE�EsU�FU=IT &)c �k&� ��� eI�I�:}5��l/�by � .e �%!�� �o� , yet5|!.%���1�0s . Arabiodop�1liana�(d1b-1a�, dms3-4ynd�-1�rogres*l�3*�0w� de��3-#ly��, [380 �'-1e�nt�ob�!G J|#(arrington .�X-1 ( rdm3-3; SALK_00125��  l� ,\vy-purif�-�10 ( KTF �afR-e,- NRPE.%V0��gbodie�1u-n �/+Mo�*monocl��K-�  �2 ( ca� #ab1220 )J= Abca�rabbit� 6TAcJQ06-599RQMillip�.F+9&!6A�a�M1�{�. Detail�, ocolaNi�4� Text S1nsampl1R i%�- ripl!� Appl!�Biosyst� 7500�3 "�3 machA&!�Uu dataI� analyzed g'k araY'CT�od  "to inpu 40A�}&i,experi8M 90�J#��log� rep ��!R� sb''55F+ �norma��9i�w���"�P.to- a�(gev ndard devFF8how fold differ�"l 5F�i�~ N�z���tl"!�k �)Nsig� lC5fB���is �6]����7~ varia�t ". Y�6 ngth�.�.��un%%�%Y����reflec��U.>m"CatJ�StFz�B�rrt availbw>*a�1�U �. ForB�%��.6�F extr9dI�45-�6tissuw 2-week A$ iU DNeasy Pl��Mini Ki�"Qiagen[100 n�>{di�9�10uᘊ�*$�&NEy(!K20 mi�_A�heat-in�%� � <��� �0 . 75u��SuperS> �+P? �SYBR Gr�0One-Step qRT-M+)�2�in�T. Oligr,ot�p�r�,� (tud�3�E TE��� Z��&n ro�� of rpoSBb� RpoS*� � K&tud�D�"�'@ ith�w� mmalm�"k-�_ ruo�&�tick-ph3 &B!#4ia burgdorferiA((ootic cycle�# � exam� . Her�8t*>$� :���w �4!eru&E���mis%(piroc�9!fee� nymph�X)E t orga�s�;nf�to],midgut lumen��u< =,usual morpho�=( ; ) du� B|>er�d�o-Z$blood meal>H3*�� apid�8ver�48in e� appear�at`Et,& partAn�*�kaC_A disulfA��'A�am-"� &v ,�$vides NAD+%�glyco�+!�Our��&& �]=�default!�anI.�p� a�R!upon 0n!u6ene[@ic.!r)�Q?�Runfavor%#. B��r&���yp� ly encode&�~�@��ma��"� r1�y"�!*e&�&g ap1}!mota'e ���aE�9S.3g#!�r�6eF'g! environ� al� d�$j"� �9Q� est �Wf�is%�AH�hsA܅Ia  M�!2ssG0h7� $E . coli (IE�([��R����EcvOf�( ed ,�; X�e�1-�=nd  MalQ�,� byAYteM�.�In{7 ҁKE�1u�3o�w8��8� et�t��Aa~A!�� nutr�3��"C� osmolar� ,� c� oxy�c�� PpH�% . Up�10%�I� Vb;eed�$�ly 3�r�-by��S%^# osE<\%��/P���7"�1 �&.U ort�(x%i�/��e P�o�27numer�2�A�%ic ge$!�6Ņ�pntrol!�3�#�a w��*of adap%h8(�T1 ���, ��s ��biofil����hn Pseudomonas aeruginosa [7�growth�survivayL,48ella pneumophil��� phagA�os [�'�in�CivA3of mice!�Salmo Ne�ica [�B .2� ( BbO#aH Lyme� : ���4!juRE$1si.�, σ7?? RpoNaend �*o5"�e 6s$�-�*en2[. T��q��" �Q�e"+M^��N� B045V��aid]�n?""s:"u�E���Rrp�8BB076��MDNA>y'FurU�u!PBos�BBB064�'[10~%1�Ad����of � olŽpr�t"wsm RNAs hf� bb0268-&dsrA (57m*_C�0carbon storag�* or c818� �Ba� �v microarra^a��A�� ian host-eb�6��[13ai�#�%�p*caF gatekee�:� - l�W�up-��.:�� �� e . �H, osp^/1��?6H* R>�!. By qu�V-�8a*�("� 2we ")�A�A�i�zedq�� al.5 zisy ex8 I ._w�8replet� rvae��unfed V�>ee�eZ� g)�Oa2/MMOFF (l U!=V&5#s.�!G��s7�:�M[14E �!�p�In� A:: �Pb, h"c9�m� thanwim��ON/�bi itU�p(��OA"�7 -Ys5 ��1�f� !� y[6.��–[1�g In am� ,pKKnh� o�9�at*� � i� �!engorg71!�,is “OFF”  (& �?��A,�V���16 ��WIi%7�+B�t � rA�oy���MA�uma�.a�inu� b"%� ntil2S^ac02�naïvU���,��:�v� vid� R~%;z���!/�r{4�5d�gn�:<U'&Q,a� � 06�d wel �h>+ tour^[Qv!�M�e��DQ� life�And&j ,��k$1�aat ���A��+� � of^�V�AvG!I-d"�.~�Sa!Bld-�mRm���*�,�y=displa� aberr�mlog!v*$refer�0 s&�� �pyM7��1� �R �WWe� ��tI�8�8�8:8"=4TAy.M unsun ZFEB!�Bb�D!��� ^��,Ewick-to-��2�:, �  : !�Q,=�"� m3*.�) triggdM�.���un��x.�=�OA|seI+Żm�U� . W�gaS�s0 ana��al� ategyp*#>�NA$orA�e o!v���B�di.��&�mtqpQ�.��it��l�k�1m� ��ZK[1 5�MH��o���whe$�7��&��sA4!!nM8[1�Xl� v5t-a��vi��9 e%��}clarif,G�ofC}j �.2� !��4%�or ;!�avirul2Dby 0�-o"E8��2�weC�Immpon [28]�i]E�w�A(( WT , CE16�3Δ� (7@ �Δ%�30= iso�9� to:�( Te �;ɀJ����Q7��Cimolw oIa�tq#+� onxB)Q~�in MaE)yfDod summariRi�25e cultu�� ( i ) hemJph�y 72 hu#t-plac� ,ni{ peneA6!| thro�/u� ;RSskia�cESY %b� EB at 2� 48�u�e ^bK�^tsalivQH glan �.$;\( i�dis�B&s�!4 -�RtR�6$�_mo; .A`.�%�M=d ��c, (B&j!�%[�@ ���eq � reBV�m��o�ߥ�i)(�v+S-� ��iFeX46��:fO$ ��a�o�&�,q�Bb)f:G�at]UY�!46d �*at!mM�Y�. 6'E>0 fra����8WTb�J�Eb�m�� qly simi'aHach�3$  = 3;�!�b���{Ō� dd �!!h�(!��E numb5of�. Give� * � nv+�hl  "�� many�$���6� �6�'.D�<�I.�)L&������1��. qPCR%��-solid%)6�vea0#virtu�Md�c� urde��W�M2CM��9�AxITe��;#Cm,=�cub�AgMB�MM�Uv��YvbyN�"#*S1; p≥E0�7C& Zp4E�"�#u� fluoresc�-m�Z�APlq�c�"&�%in*}"D;��: Thu�>  �rG)%0LB�4r�"pՔ��2&0 exclus \.�-�#_!5 6e i@I�+� nit���&w� ��:4 H�o!`A2�"o"�y9's����i9L� tech�2lyy���T �"� easur.�� a panfY f 10)�"�edE6 j- � . deri ��/Z�6��s��C"�"��membran(Ra��( DMCs )� . Re-uv&q� �]in�6�=w�G&!!��+EB)E ^�IS2!� ll eX� *� yBabsolut :�SMC-�� �.e�:�>� A( litt��o�7J EH.�+���K� xe�*ie�woQ�."�!ge�%�)"728/cdrE0(bb0670/cheW� �se�%b p !� �\&=!'L�eaccor�>�6"�,Ip�'or� �is&�G� Y�F!��a> to>IT0eUZ%nZ.�inN-ad e� a�OFF�9�1-)&�2�> �� �&hm< cE !�P�W} rly�worth*all six.�)y��UA��F����{�T"y";Af|S��(KA� b036B7�d bba5� a\c!irE < �A�>�T�0 rrob�D��� O�`R(��� sameM�of� )6g%�ha%2eo% as1�by**�q WT-gfpb91�or�l105J"n. LZ�r �A�8��N�N���W.�&oId���$ir�c�Wer���; s 1A%�S2�*\U�M�� $6�JZ%6���.�� ����hl�IBsL��a *qom�!L.0���2�&z 1B��Y:cC"�RI�T:w natuj=y-��C5 �)�R�i�B�9�FHeq\omKrqJby.�.f6gM�5�C�S2*.�foN �� scop� .Rh�&.q ��p8 al�ort� !� flaB� ospAE�&�-�&�+'ea� �?i/"d� n�A-�A�ouu,J������ s 1D%1E��e"-_ 7!���>� re �"` �;.{��A 0�s uish�!�l�N ,��0�b��I[w�7 ��is2��!S=� 3���m&�af�%%�[ i�a ��}zM�*\(�$�S6Hve fu� ���:�AVi"s!�6n�6>��J� ��wo�:�%3�'ad�Ance&Y9mig�0on�-.a non-�Bl.#s advTYas netJS�w>0�ba��&ur�&�dep� liu�2f.�I)�^%i x�5a�* nea�res� &j �t�ac�Ls�coel pWx �i*��e^:�)AEkde�V� inEhb se)I�In �M����c�%*�\A�i� ic=�!�;�L�2�of�Bb]ٵ�Zrecapit�$&�JR�N*% &]�f�!q; a 4 sche&cq��_2���im",� a�� 2]"�iXNe� �� S3 . S"Y�%��!�6Vu0!ҁ/2 �5�f��e�� "�J %-�te��S4AM1 . 00�%9#5ݤ� eA 2�.l��A�1#of2�2.U by� �Tod�: &�4B�ZB� kineW,A��&FRJoro!,�$ed��.^y�ine�l���lso ��-6]2E1�&kfir�lmsuitap*�Z:�er)edaj�Aar-zxN�ER� G#� 6_4w� d2q�{@u�'�\ly�,�d w CE](  ; B� aGA�:(2/+�; SE18r>1S1=qZ�A{outaY%-A�)d�n�� �����W)�t.� *� ,p� �6&v>z 2�Y�1B fd� &�N�or�nMʡ�1i !�� i�9gdv*zD -%U�L le-i*� ^sM�S fBy%`o:� q>� 6Yin�� #� E�od��7%��Ry�5N2A;�seeU"<��48�&6x�a!�}brked t %f�J� of:�o(e�2ic n�Ft�/ell&  6z&E�� �lo� `Q Q�+�,, ragg� blebnP92@B , ‘midway’ ��TAC1�Bl9��&� �a�=�-�&9s� i�)�W!~asC��3a]�1Exlu"� JA;@�"0ar�"9;! 1$‘coronal!Na� o�a�39E�en� A��"+tpointX%&�e'�6@Hth�vi�5iz�����assum��� care��removNnlrex8( ∼30–40% )q�-Mcd�-!YQ�!0� Y��e opt�secj�<��S� d 1�C!;�e l�sc+[i bsor�!3lu� b QY=�3B q�[A�N$��3B2a�� �q�i�l 7�9�&%1 E�2b crowOEuY.. Epi��ce. of!��� cryo-Aedi�� S1]�/!m|v)@silver-s�!E=Mar�@-embed�M& imen�) s 4E@4Ie� �&E) pac���9}�' !�}!]�>��AI��o��k&� fBbA*��F�sPs4Us4F �l Clos�h�A�!."ed08%Y�z,magY_:5u�vU m*;m�9�no�%e� @)�{��*I)A AU stea6Ef8A"larN�me��-��WFpross-MTvB�\$s]7*@4GaE�fn�A�e)� 3r,%1m( TEM�Oultra-�- v<��c.g ��6M*�*�V`�&]" discern�nJ�@AQpop�q VR9�yk5O5Q �E�p�1V�a�a�� readi'9p�nr!p s 5�5��In���"WT�,.a�predo�xA�C6, sphe5�(u��*_�irP�0-shaped vesic�=Ai(oplas�icyl�:r.35ar3f/c.43� nomenclgePC*,by Brorson ev . �Og �r %!�CU?i|<Dto��~ st �a�/=rC7e! l!t|,�te�qin�i,!c.Y��es"�sporad��lrB���I��,U1�@��:�!1.�2lu�nC9-limi�A15�;m�7a3�Z2*O-[&^�G2]�aemb"C42���2��Ss �ue�"5+�|Q�"�.cyeXs� (etabolic le��Apr<��ةf ;ocy)��A� a2 4:,zideP9wG1ok�tag�B � i�{lb!,Q�!)˹?-eN�� t;�{ shorz)ci#t,o� RPMI��F�7kper�" ���2s&�d��I$over 4 day�r�%��a$eaJC ∼5%;n' 3�6� 82���> � .� Zs 1"�)4�?� p≤ $02!� �� $�)�6� 6�# 57�~-0e`2�to' loweFaAp�)�p-g��b�s 7��S!��1�br!y� More%��� �by�EQ2�A�_y��<=uy �E=��&/&ia"wѮ 6��Kc�BAe�%5!J�=1P&� , Xu��33]a�����(."!4 k=͍�/".� t�%surpr�/�Zin!߭S>�H-2G�VacM'=�WTQatAks5�!�� �ArTg0��\& &��}QA"mC(s.9)�m�S zFCoADR�$lA�5�,A<���%1u NxB �z>" s��N*�B�bUKnth�*�&6W�B!��V)6+ �#$Q,fofewl���s. ��"�Z@,�mE�b/�0} Bb����z)U��:�diminis@3fJ!vmcb� &&?!*=d! M>�6�ini� >��5VY�F��ΔA!�6�e�EO2$Z t����=p>�n6]2�;�����:�v��Y�6�outpacA͡fM'(�L00�gp<��!6; � �fAm2�%}w�>6:aLm�\F�.�-}u� Zp vels.N�$o"u�0021%%}�0Ju� ��2� �QkVg"�,-f�"gi�e&a;�ir I=P(serum ( NRS�We sough�F͹� ��v)&ichqe� at"_sA�V� �5*�7.b�s<�"� rear�Bm �R9�'oF� rVA��:]�F elop�?8e 7&QJ6 repair���h2��"�<of%C�o� 9����0>ZH"�=�.D{ #voaWB�"ur-Stoe�y-Ker  E%�BSK-I�,�E�o�]/"!�;�OsQI� ��3 �*.���:|2�( Video�KA�>��-7� N ��f�Q  R� ��te��XIb� _F.W :�{)�8v s;�se"� e&0m}0!�inAE�""nE:'qOd.�6jof 326 �b� Bb ( 16���  )u�$ f��T� -����4 s�e]�>�To�/!�iONPA,��-!�^ ��invD*Bd"82I B�-�d�;NFe ECA�.M�( de�H�ho2� 8A ,S�-��6�9�i!F�:"�min.^>�>�%B� �y&{8q . S ?�tR���Bb f"zeri;7�H� !�� M 5*�$= toWc� u'��J�<of@&0 �!� /�N:0�O*�L���ug ly unexpl�despit* LJCa� eM�� !E� ��r&� �&�[M"[L� V1 �Z�<"�@hE'`I!h"�PE�.�?�MH.,m/�>@� I���j!9*4�3�*s2�&|�> bey�p<�%s�68. U!xwl2-A!�$6�1!um�b �%�8 H �[dergo� ra� cHlogic����O�_2 �/Z'�A�al depr.0A�"�O�%high deg�-�hyl�bQgE?���B#R1 o"NKtJ6@K�a!ye&HC']�lapY!] ��i� �"�M�/)�02 =aiڍ%ect2�ag�4t�Dcon�s�`�D�Rr!,5LP&�G�< M� � ,� M,)J saltg2�<*�%��66{ ��3a @�'%�I�?a� �� 8�e))�- � �%��"�ar�Ieby&�(e�EU�0%\Y�Bi4>dl'ys�@n) B� � :>}vecf<.�+C!M�gar a� �tH� �d"�!�f�?��*n�s�AA�� �6BEMAO*��"�' m�-��Co&Gj�e�N�y�o���Z"!Z�?F3R@MU�]Pal&��?� 9�x0c �����= eA�2_=of>�. R@Na�c�0agH"o@�9�B2�� � -&� �N�=�� �0* I^:alL;?�*�uJ�#\!T N"`  7ru1pod�`6� �Z3I/�:lJ�&,-� 7�roW�"V z2X)#rhSW WeA-=�76�J�s��APo �B�3�C.k,�:.�9)�.:aal1�.j9�1:.( ..2!�)_1� An()Vs�&�1at �n �.�HA�� .�K. A 4�+"� 4�@usNA rpoSa�F��i? �.@ 4,P:24 TRJ8a�$subY&� �T* :�Q�1A�� a:��X�� meY--c!I@��B:e�T&� -��`>��%w�}�^�a� oY�* �T "W y �Vw,IopC�:�!��1Q~f!�{"i�Hk1/Rrp1x-A�o�+d� ��2s)��3; Y�@�� ��(I�aIM(!.[41d4l�j�did�3cou] -F"> ad�&aa�ge��6eG%.A“�� @ pa� g�W�Oi�.�6�X�1K���T._;/���q�  e,is va�B�D��& W *nP� [4Oq4OqAm�����91X~�� eluc)Hbb� �"i�%a!� pro'K;A �e)�aj+ �!�%E �D�S [4�Q5SAB�3pl� BbQ��' 3[V\ glp x�oZ%bb� -024�+��in# maxi� fitn���mugIR��*�>m� PK2:�f@B%�utu�^eMW�T ��ay .k+W ourc"`�2�d�[of gluc� du"�!�cQ�he.*�a)��Sd���E;�borrel�-� �6sin�nAOspA [1�K[5s]aA*E��inhib {�Wo!*ty�h�Ks ela�=��){T��he�'6�, �\fac!"�(� �+�~ �Bb ��"�.77a� ��IE��- �� n�7[�3. MM�� �q&'!&, �x���%{hZC"�p/8�m%a��6Wy!probaM;i�Y��. %)�ba>8�“��"k'y�+�9ensUg Mr�r���� -�caosumɻ@%6L(&� �a!���&�l�I�B#8]^a����h�.�d�58��, -2:�P��jI�*`N aith �)�s��sp�B-te�i��uGc�ot%"�4& A9h>.�Y(�'E� , [5aDR�)@�1V� Bb ,-ah)a.�KattacB!<�mp�u[c!8`!�:�$"p8�%�v6e�:"�2��ad!4ei]5��"+y�gl"~�HA��"!H!_�e�,� noxia�eg%s�c�m�5"r�uLs��:T��"n16�  /&�!������%"%� �!Bde�)�Y.߉"�a�3ich2�m�. Ano6aI+1i� �3`t{h,*�)�pau/s=�� ?�0ѕB�L")tu9�2�n� � 5A�"�f�� `"E4toT]�.as�x1�los�� 2SI�molecu��M"+co��H�i.����. Bioi���p0I��x # o�WM38 po�1aC�T57 SY ;� nepredi�7v:r"t&-spane�e#.� β-baM� �X"�:u( a�onogu�2ame?�,Cox&#54]�qA9�I�Ia�*^U s [5 �*~st2.a�̒BIp phen� % ��&�o�5y��+�Z �,"�n��!ua\:~]E. D�@-u�"�Q�� . ��m�3e < B&�tnsAO�*�!��s switch �un"�$��rve +i�hypˈve� !�"2Y��pm:�dla)=��՚�^P�"�]Q t�E7etU ��*%% ��v�Wte)W]^�H(24 h windowj��&R&!V��e�n* -�� AM2�A>R ��em�LJ`A*��0lso�U�F� Ez�6�(g #HI 6�. �f�1�to����Y2� ��Qy� ex� *"�val"�� o�%�l2�byr�<��se*����l&�G!�� bC(�j:i�$"* o"� a]YEh.�)pur`s%�ra��)�.�*�/$$l!�UW�):�/vokI%�uU2~a&�%AC at gayri:Qo6�%J.��iu�/er&�O ��EbreU"M�!a72!&Je".�8�rMut)��sup��}Ř�xTo Z*J*�B+oa turc6�"�i�o ich ��ۉ�6 ���dQ78"q0%(�0�|��! �OhQ��� s obviousq;A��yy�n:��� "��2����f -��v>sEh�. *X-] 2�?. SA�9jE�fe2 �>U�p_KwNi�uU�(-�W $t�("~���Yv�i"�p.  �2�z$uG���� �M�'H4 f� a���"�(�q9cAHSe!��5H^�s dXQy2�9)Mb,�� �)6�z!�� J vor�+U.a�ir�!A�";�"4 ���ٗ,]��/&� nounnt� cy<�6\,���!�m>�F9is "� I��k �e *3!�i�Sdra��*eg�a�",��B�/�j�&faci R�/5byC*E �-&� UproDfwunci��7*�qy-�xed�/�ؑ� R�,�a6n�M���/���t �H��G� men�A' da��al quJ(qJo�e�? �y|`R�Tuniqu�c.�<� A$���I� �n G:��j l�ory��;0' �~ ec�$�A^&H a�C-T�S *-a�� ��$*�relev�U};$ihee�zmplex�� �����eg���y"��a�K+[Ucircum� c�(� ch#[�om!B : F��]bA� ncep{3 `E�.� inad�,t�e B9E+.�:,9T��alo�@W6\]�L N a��9;+ hapq�m"�  =�!FB� !��<-Qs/%n*� aa�@�TOn��l�E%"��!� ��ae�!Ke��%�se���*�e2%.pe��VX��h= imj!'a�<i )�Aatu_0rVM!6U�!o�a}~� 6�*Y��� T !�up�1�/�Cd�p6>�fl,S:� a8���a� �4̀�f>� ��2d�e�()� c.K �K�M)�2zw Ul>��FA .' .��li��� "�+AG!/�CE9�ui,&�c��8 p�dmE6�m�!�i��i[@<.&2�p e�.�� evol�vɰ�`rt �/O��Q{!�� Y� e%66�,�ay�ZU'.BLh� - res��+E^�tVam�   scal$"�Om2�"=@�kEbl�Zgai{. Aĵn�e"/��9N� u�f"�3NIH�F-�p housA�!�Et�� a�H")&�W� U�(�J Conn0cut Health Cer |�s3 �ewwap�alah!�(UCHC Instit;� al A �Cl �Use�;mitte�4B:yu(0.:~IQ���f9� G,���ed-0 [57]� lU�6%>�4$Pel-Freeze��,a�. S�B�j�m!�e":9>�5HlI&�UvKr�J�!7%Gpr�� /sbiM~�+&�g��e�= smidA#g!�55A?m,g< Za[5�pSi��e��re-shift]�IA�wcurves)y�bg1�Esc[Bhia�)i9$U%P�31 ( 1% trypب,}�5%ޑe�� ,%NaCl )I�f_2�!8�ons agar!qc;�e8�Q5% )��C tine5ar ��q�>Cd�wpa�%$�i�"|.Top10A-2ā� mA�R/-�~��d��èA�B� qChoBy߂$Denville Sp�E��,nd Takara Ex )FX;r6':�9.��E�D�w ��� |Q�Mid � SpinZp k��. N�v�b!Q6��A50 ourta�s�c��r +St�Ks5Q6�j=Q, CE46�;CE5� CE10��B]309�tnd655�"Fm*a*&��/TlmtvC #59]2��Bg\ anJ&C�ce!��<-��ve�0p!"���D%� am���F� a6d�#( bbb1 �1 flans-V�),�� 297-�G�E BBB18#1F/ 9#1�yNgoMIVM )w-22-:��S���r���pI3aFe>pCR�b1-TOPO :��d-=f!-Ib�$G�� ʽ�4l&Q�. PU�p-P!.=_`�(mixed 1∶1*��4�s�^i;� *J� �/ �& ��a�//&2n"#�2]N Jt30t i "}-��BB-�U �� e jo�N�cĔ�7g�^g�TloZ�,r� EcoR��!Lsub.9�j��pUC19!,yield pCE216�$ PflgB-kanE� �fe�r�t $to kanamyc\!�eS,pTAKanG [60]M)\ (Y��KanA� BamHn;.�6�I�H6�� libea�1&%�wm0^ j l�9iA� "-BglII >L8)to.*7!*� h&�e10 µw�]�::k� inse,���|� `7�`~�,�L rou�[q�C qq�a�bW6~'N D�&8q!K"�e�5O� um.�a,V{ %^6�oCQ�CR!R�/Z��YuP(�d )\uYqP����W;& Pt}m�j)R�!E6B_�-��EGpMC1916 �z.)1� 92�ery�(i-(| 06 µg/mk A� gentmN( 5�'�+_�P-!�BU971P--5′e3>.To~ea<%�.1Zv �Ae@ -hS�K� AU��m� y#.�-�tna320f�|7~._A�,^Y)�)�e� F���,6�ѫ5�!�Z��Zol*!QQ�F~��m6�< -3′XbaI>�>�IB�aw�M�2� DbpAM�A�F� ��s�2I�.�QA immunoblo!�g�DbP)�I�&iv�h)4–6�s old fem C3H/HeJ�e ( f���y5, � ,[{� �5%�trade}C)#1×104*u�p ��f��t�2Ht`/�o-g�{d"2Ei��@ *�,i5,��� hear çbladd� �@�^MP!�+�kRhoxazol!�E5 m�/, phosph6P2 rifam� �l.<t[�th1A�\1�x��l^"�w� "JxE�*,x_�} !gtZch� `n�*Y�ipor6$+mRCyxICI�pe!�Akii�C� �.3]sy�:�"j\� ,�x�4�5*'9A��=q� a�`9 ���Pa�!�Schwan�y,�2ono2���=9�� ~".�""() �s��26�n( A_)-$L9��K-10B� nd 5-�exT����ico��-k� K'-Œ0d@)���Ge�� e{ Y_�u-�� (�)F}manuf�M rer')"�)��& dipp< 0Afwpzm���; �a� Man-�'��` f�i(��Rg In^5&�?�viS#:-aA�Fs:5_�����.��g-6�uin pBSK��b�� Group1� to 1���-u.��EMZ ���aps�)aff�mfQ�2�ՄXW&g;���A�2? 5��&acM��for_�Ymov�Jei8&k<�=rű�"&� b.S�/!�^)�t�F�}��!)с�~|,��%@�=( 3&].��*+,a�a��"upYKrc &��.D sacrf;n<"1��]e�H�Pach|0, a 3 cm×2 c�E�}n asC!)! !'si��mar�`qdgrii�*ex^}Mt� 4@��l %j, rA�( 70% ethano���u�9�.��xFp%��_7m*���$� scri�s�.)x���N� ;j���RNN1∼150��x��-��∼75 ���S��/٫sKby5��-�)���� ��%��"���*��:R0���q�% >�q,~60���+r%��EE!:Glr@_7��edR�V�5&i�I�TRIzo�oa�>bS}�cŘ( +RT��e�ssa�]in� drup, oiQ *y�S��mix!{ioRad�n^�TpƔ�:&���5� cal�&tua�iC���� t-ru Z/softw�b�o�7��l�-�����Rg�..%ss+6"g(2[i�"n�M��Fcop#�C�B�aN�2>!h1]i &ceA;r� .!=aV!-@6 �M!�p�!q4�b( B ��).� labe]Ge�FM4-6,X2 n� � BS; 2�2�*:��.�B�g�o9 �!L�P. Brief�'�PB�< /m V�PsalB|�qeT*z1-µmFdoރdepthA2A�)��>d$�O �!�N#9�e�P�Z k�P��A��"{X�6e?nz �-rst�n!�e 1M;*\F�6c.�*:$ laye�(q q�3"�VS3jY�� �f?�� Y��4E��:,���7u'ckp<of 셕�f.�"�F;�pa>r9"c��As g\!ǁr influxy!�* A� expa2�"C5�6a.I�ATur").to-�.}:�( >o�I��dV fLufe�JZof& %�1�V"�QBBd% BS� 5u2=jBE�R6M~��!&�Y�� ecut�Z�i�ed�)l�F}A%�j2s��<nJ��,JJ��u' �i�vhrU*� :� .�)�;4 �LiիUءC݀l&�'A�X)��!�y�th}'���e�&zB�h:�q&�g6.�k�n��d S3jT�Q�i,��{&R-��inF�2�Ywo.�+ step��5 �Cqht��e!!Ҋvi& /w��2qj) ��rpj8' inimLb@)k���!�:?`/#B�I4�R%�� E�6k�ver�ul!� begiJ8�;*�vtiM}5��eA�2imu��20 Bb&6j��*^c�e5vd^ŏ*].n7jA�6-4n Olympus BX41.,5pgCA? a Retig�!�� QImaF� ) ca3�;)M4�1 a 40×�# . 4 N�� oil &� o�F��n QCap &� v . �R}. F}?z.%"-�!��6�jQ�7�� �!�Wh�Bin-Star?-tub  ��hIM-"\ \>a0NQ) �3 � 4°C��1 M sod�Kcacody�) bu�3 ( CA�c��4%� a�aldehydeh!N5%�Ct�� ��E�%Q"l in 1�$7sol�'�� �. Z���B(�!fZ%E�tosli�D>1 mm�Mg� (ep���freshN%O���v�i��!�!R ��} n ��E�r_�APAj2 tN�=�1% OsOy��!78%�<�um �icyan��7��)#)MYwa[6� *k,I�� 1% uranyl�R�3hyd%�� asce"��1�!j�.� PolyBed81A>T�V"�k( 70 nm� n�k=t � ( Leq��q&�o~Jmv 'o�s�j��n �~5B��*� ci�W*� 86]lEgvie #�IU�+cj�~r.�l�zHit>� H-76'�at 80 kV!�NV �Ran AMT�)�- ��E��e v�"01��( AR}d M&5mT8�.3� Al�H{ә� }kJ�@�~2`[6O�Inё؄�2r�#layMe����O4Adobe Photosho��CS4�S,`st�� .O �eU�fJ�&haliquo��∼Hµk � em6�*edCVp�logarith�E�:B 15 mh� RMPI-16406,�Palo�V#1187�xC�fi�,H|1x� . 5�7.�/" !��at 37��Atj�; tervr,,.� ee�eby�B�a&�0&�Yy�&2�eoy�r F(B`yͲAe�x:�r(*\�2�,e�*%���u�o�ur�."0�|n�82�li7eorf�j3�:%!S rifu�K at 6800 g2mPBn�!!=(s�E���~�Rݵ���<o"�/�9�b�ApiZ^�c:�8000 ��C��pelleK.��B�y�!# i�bWj2]In �8�I_2���3m!���of���vo� [=4)��g��#d1���c�I�&�� al-t|��S��Pix��( Norpix�R��� �  .�b��9 |QuickT�P� � A'7��pp!AIn�-Y-6$82TVk��N 6� ��]c�*!�9J��.�%�E`de��T �+=stomach �a �2pe5Rad�9A %�lp�Hap�5 E # glas0&-� �.6�A�8.aagdN(ndR8541$.� a$��&A�ng��Ms-** �hR#Ca�Qg-expo� lip��+�R�&23on�P%��mf[*IU! �YZ[A�Setub.M[F Non- ��\F�%�kW�dN�pu[�����[4{.6�R[6Y���*+7"�F-62G�I�*2GOMP� ��fi�a"L!n.G�&FG�Y�;rY Uy jin Tre�Sm��llidum ]G� � 8!��L���OMP l-iz�3 /top��am�de�J�3cQ7%R mH.�#`Ua}Wr� & on�.�*q ,%2�9Zm�M>LPrism 5 ( GraphPad S�,��ndent,_ t��%�1N"7%��� 3e he �!�*]v"!(&�k5e�!�ide!�Nz`C�F�@�`fiJ�s /o� gend" Unpa�L�.�� two-C�ptT(G6��xRE�;" Hk"�atZ-ņ@<udADd�Y�*�%*����gHk.& ��)݉'a��- t-!�f!da 95%!��3!�!�7.ܧPre��K��� 1st�?GpA��c k|!��s��ake a��iflAs. Mm� s im��� Zfilb2��a�llen m�:I� 7mt dehi��:llU� ma�I�'�4 . De�dcqw�t hor� gibbere�a1�c��s>GdQ�"qM!of DELLA���GA�(��s !.�O��v�d=Kv�jasmo�i ( J��V�.*1ll{�is �ab�Fae�A�!hip5�G�zJA�F�M2V����,e�p � MYB2���MYB57�G.��I-en��e�a�Lk|of-"4Natwo)Rs R � RGL2� �}Q *�!3!:|^MYBed�<geED�re?Ia<I�U��8in �INtIJ�G�bi0��#<�d�#�myb21-t1 4 57 ��e�/�%<+a!Krt-*�C�a6ee:�FurӁF �db(�Oa����>"��)�GA e=nE�!  mo`U�yX!M�A9keyA! biost�z DAD!��r�C�H��9K%p@;B)tE3J` �:4 young�BbudS%+ED1�qu`!5Idga1-3 gai-t6 rga-t2 rgl1-1�m!`l��j$�)XWT�>co��9%[5s�2�E'�ko&>+a!6 �"�awb�ve "�e�$ hierarchi1��%Hmod�Aof�8]�GA�Ri��%�@���\�e;Q�.� �?�d>�M� ���D�>�)�fou�Dn�c��r�*� inct0A sep�pet i�͎Y ^ ���t��odu�I�EA �aI��� Et�Hwhorl�7� y��IaA�a wa���i�PM�!sD@�y coinc�uJ[t�Wt�&�fe�UV[�4�T%��Y�.�sA�asR�Nj G�Q>h,�)d�l.�M^��.���pݘ �RT&��1�2��Gl0Pa�go��eS>v��5!��.fe-2�awoI OesN(�bg�bX�ndF�. opr3.-U#��.E�j�Sr��zKH�Y�n�>��[7<�ANe .�2c�n�+�[�Ks ret�j�&��veg/���h�3v�ges {�* �%o�M3a��wl%��) > Q % � � �U  �g�"� N��Z.��^�W�L j�Us �J<<6>(=�Z�[�AApp2(�`v#x(2�Y,GA can resto�Fre all the floral defects of ga1-3 [7] . Further studies revealed that @arrestedI,velopment in Mis media(dby DELLA proteins [8] , [9qs a�$ subfamily�m(plant GRAS �putative transcription regulators [10b<11] and have bee%�o func:as neg TF4of GA response�diverse � spec!$�including Arabidopsis , barley , rice�Lwheat etc [12]–[17!The! re f�-in:Q !C�n�u�$genes encoe�6"fac�involved�Z�0GAMYBs ( MYB3IIMYB65 )!� subsetA�MYB u[24!�:!S�(best charac!�zed ����V2� �%eDwas first identifi ��T. g' ound!@bi yGA9ele���GARE )�%pretr�,α–amylase�)(cereals [25I�6�:U�P�hat2�%zFHA)ess�al�m[maturI�(but not for�}�of1�u�:0-�Previa#^��)�s � through��!'�� SLN1%� SLR1n-�a��,azpec��ly [27)28!2How�� , sal�N orts fail!<o1�yB.a� -inducibl)�s�.r�th�Wa|Y�!iinE^ ��ed ��post-2� al l�~�miRNA159)M�9�31�Two rec�vre �.three�eM2��MYB24�MYB108 )�m��to��treatA���0�'; loss-of-f��ofO2)� cresul� in a�rtQ74phenotype [32]�� reas8�i!^B&!b��J��KU�]�[3�� Inte�� ingl� n ex�VonAkfiŪA�#weQ�Q;��&x�9XɑMYB57A9N-down9��'"� 8flower buds [30%�hiA�ct�mp!Dus!�0investigate i��.G.�2.��� Ain�be1A�"� $four whorl� �� �%�, [34e�35�I i� A� ,!u`a���j_re !Z-9[iMe gU + le.����quadrup! 5Tgai-t6 rga-t2 rgl1-1 (R�B it%�-�D RGL2A�normal )A�or�o wild e e�A�� fert�penta�j� rgl2��A �%�.�) . W� so2�absB A 8�cB `) �Isupel�shRconfer!by(�i� addi� EBobserfEDaj� ontoj:Z%�-SB,M�e� coul� s!�J�T�,Eɵx57��b�GA �.|.yݻnc�@N~͔�sa�o�maoant� we!�utGA upqV� -biosy~ � ��DAD�LOX a_JA!�t��m�young2�MAGA-de: Bc:�.�� uch �9thaa0aŨ�WTE}27.� f� E!co9!3at>�F6�=�*0 J�du�A3 �=� necessary_ �ս2� T��큥.1 \U&� , sugg�+ng!!t�&joma�r!� .p-�) qmus�a kept�asres.st��. Con�EQ!R } QR_mf m(6�)!�f�$GA indepen� �weɾ �YR��� � J1���1 tituM aV P-:\We compa���=�prUes��)� n&*� 360��- J nd 273 �i�&� Z�q*� � bI� -enriched ZeEexamined.� of 4�� �->sepal ,�, b�p�l�(semi-quantisRT-PCRi�seg Ww chosen ba!on� cri� a: 1 )!�y� homolog� ��Js�td � ��MI e ( e . g���!)�2 )s s"# d �dra��ng]A=I!�2f-� Only^] ei85�1s( or highly1�� w "x� in s�'oPm3organs���,ubiquitouslyRY" 6@)� lass\aa�v�>j. A to�of 34 �,*� r APG-lik� 0( At1g75880 , 900-���I=( IRX� IRX3 ,i&� he cellul!���subunit!�ich%{to q.6�a6r2U as�q4( Figure 1; Ta��A���6� ,�69 !�� � amon�2���^�Bu|he phylo!c2t�: \ re ]i� (subgroup 19!�R2R3-S�[3 �sharesE~ similar�with tY &�!is' %�member!�:([3OveB �1j61 . 6%N5 0%��ty w!z.� ͕�,o acid� >�5WS1�2;E� !N�e�Fc eb to a very2 |"� .� !�&� (N )4��.�1��) ��2��2A[ In ord)y$find out weFE (� a�� m!�c )!�m� efD�iZ�M���j� ,* �� eachiividual!i�+)T x �>� � �o��one�!80 �g* rema�int� . Al'-� %%�alm� undetecte��ZQ�g�5�.�,=�rɧbar� JS3 (ZS� FSL��� �� Z�ti�6�Q2g6oMF>gIA Q4:��Z:R�)�Y�B S@ I>at%#gM�a"���norA��!�:�%�E� Xz�-��6�&� pMlae4leA�Q3�,�U�gE)�!N�{"jA�F9 both!�S4 <s� b���͝ 2C )4��erq it seem�����nic7 rrelq�dF��ٞ�>�B ��probably:� f�. E&5analys� p� 42�as well���)H-� ificM Y�D�:ToeSrt � spat�%e�al. pattern���.�c-}eɷtheir!po role: "�*^O& c=��K ,itu hybridiz)���rY p:4:GUS��genic��e aE#.] . Ou�J_~2�j rtK from!v!.(stage 12 [1��m1�n �&* +�J���� ��� weak^a.��s�ji93A–.F]Rjupper�!93�� U3 V�*5i�a�Ţ._!yal� 2e�*� T-DN�s�o��cli�V�!].� e�si��S�Inpe2! omic2]Labor^"@y ( SIGnAL ) data��x �weY $onfirmed (+�ġ�n deA�$as myb21-tN $SALK_04271� 5 i ,%4.% 1722.%4�~nd)57.)65776 )N57Y3 �\2@�����u�<�es�c�2o &��kreB7 Vj-�ɋ�:TU�3��. O~ ��r h�� 1F� stil�$.� �%raltho�P$ a�g�ly"� �l �F�Pis1.a leakyMB�A�tJ ound�% backGI���f`F� ���Ez�`!�#d�nguish�,�~A�WTky!A�C�[ . &�in�%:Dea�N�C#�∼!f� 10-�s�B .�/� S4 )>�� �]!�`lF� yiel�#pro��seed set�n>�A � look�F�f��.a�M!���\s did�� ��e.�3D�anel d` C>d�M8")A%~�ma��� � awgzyg�D7)=�A:G(heterB ]J� , demonst�!�o.�a�"!(p��a�#�$Q��TAq��bX,M2qJ��2�PmL(o��`ca�"�q�� ob1edErriFJF !#)mtri*�(#:X5eV&3 �u� �1�ic&� )�3���"ofZ �c2��~�3 sŒi���'D.�S S�} �� ��|a�!.6Z6�%ekC"�+ >v&� !+4�Id "-�SajoA Q:�:��6�5�J�)r $�*� E>6B�Ţ�%��!�5%"by���feC#siliqu!���2Rq%6�A�- %X%edi8Mandaokar et al�I^�ZHhadB}inB�:[%���#%��w 5d�.�7G 6���anoerV*u5e"��MCR F�2�1���>}%���kon!"6�*!"e/ � E>�w 6P��pr d�bl.BF^ a�.�9�E��� 6a���,&; i3s�$�de��%bUN6$"�)% 26�,Yyu��[ even�zc\Yq9�Ux.�. For8R�>� �Z�-�� occa�/��� wh )�am=+�I, @mK� �N,r&fewe@�Me��+A3t�vt1!�ufilJ*up= a�N _%j Z j .�Y�U��6Pv3�� /l� ~�$rY/I�6�&/ama�aus"���! �.posi%�environ�al "12M. �er�,e�a�0fl�/ malenG,��IN�� >-�,2$�.�R� to� � !�YA�t2o-J:NQ��.��Ŋ���aJne!( e $#N���,�7P�kyb"� ��` �9q�; �2Z appe#=c+llK�as �29varUdiffer?&m . P�2�!g���ywo�9 grew!�agY-ngt6&ng&; e"@�Yat6jWT ���F�e�5E�� � (�2�sB�hei�+p�1*����KZ��2m l justv�%��\%d� ,er�th �!i�� ��&rowthTM�M��%, Ũ9 2� ��"�6!>!� Ln �/6�>�a�.G� �iCg�m`ion3>WT- � AB}^FO2�0>�1in�at� X�1A�ApZ�4G�)uld���u�(!���2y� �!�24m;Vg����>���nee�i4c d�#��: 8r]$"irm�!2�we* eR2�� g%�n�to".exhexH-�1:�H%" -t1;32�3E�&�hep&�-B`�]Bw Mr �E�-�s o�"�� #!� �aU� �!q.�ɸse+ largv � 9� 4A; S%% �2�� *p no��ce�i�n9 4in� vege�'�R2�ts>) ���� rt��$\E�m�Fb6.�YN�is2o&��atv^�.K e��a&%om��� !. SEM&� ��!G2� � 2��^d� �(d� l��BE 4� , rae��G$� �!D'kA�"�B+ct�1sd4m�΅���2�2�8A��8���";6ZW� A-ab)��z ��.� !024yjt> $ (eg ah~ N"F�1&+ za�"b\%a��".B�"�U9NA!4�Z30�9o�;A�nt+b�00u61ir.s 4�=se�� ults�`�J�4t+K!/GA��/�:&�+ɪ� &or�nmq9{�1>H*"� e;fa�on��. F� ly ,a����A�1�6�>O.`'c�*it�ex9��JA6��gfMw%��8N�A2%2@ hilsZ12)mEJ Ws/no�'�-h:-.6Z0JA !1up�A!5GA.1�5)�X*TR �6%;%�n�- ��VR�!�]1v�e@!�r�>g�>i�Yr!0�!4� 6> mann�8t���#"~ uY�9eYv>�!�JQ��9�e�X���H"�%%-��B-J�� in.�* �sMw!B>2i�*�I!pp*� n�?&�4�:E��*Y::&�5*� 8 D��I&�<�<�>�a�N�in X at 96 hrs$DB<��5� Fail�.� vof:pjxGA-�����s N7bz&eAs& i2i:d�9.ndP# A3oxGA20ox2� < keD1�[ibuA��" "�6s� f��v2%u�wL�<� �+r&�D feed����bAD*�;m] (!�r>)U,,:2j!�� �3�a8'�'ly &�:: ���p_2�@U5� [3�G>}we� & I����ed )5�B�a$���(]I*571>jZ B3 ��] &$)�u�J�(��m;vH����OE/�L)qҥJA=\M#A�ob�Cly�6I�&e .s,�(E . �Ma�#6� se��9սimS��*?Jj-branc�2Z��Consid�:a�fp 1G.A�NIn0=CIEJj!� >on[arg�D�JA���6�o,steadj2B��,�f afk3��.U tes� i*�,Rw� 5%� .cE7or&iL>�Q;�KD�>( DTM�� �>�!h)J�)��) Lipoxygen# �22�, AOSO8lle�3 xide&8>2AOCT2!cyc�Gu At3g2576}8NC i 7u3 8�2�8132�}OPR-OPD"M duct�3 \H0La-er WT , Ws I?"� R9��,n'2�yd�I�J W�� Eo 5�3!LOX�2%9@W�'Y ��� Y"AUA��IA�Q>^" ^�"�.Jg!d)< o*u6� 6�F�6r does�1i@�a2X 2H2�� e��/1d ��$m#n>�Le� 6m! �s P+^$A�E�!�AOC�:AOC�,5�E[��!��D�*��c �!�N��� R U��S9` "� �� 2@ash��. of�2��ĩ�Ki!�t�Q� �>y,2.�]2� 2)AOCF����%as'%=�of!�1�sig1�6- �� �b"�� #z�n�V�"�- D>� P��ii&aby!�67��;�=k=!DY� pproximat�20%!>a.�%)1� z:��5iB|6V|m.0 (�0 fold� �Ein 5fCus�7)& ��� � d�P,G51'BT��Ga<of1�OneDG3CHQof.z 5>�1�QeR,JA������( �hxZhmeasu:.!r��F!UF� inA&,�v�iy�-��32$ 7(-�$3�#"�,cl�.�w ��Eo>�/->F��S�"$:�I2� I2�J�BiG.�"� 6"�*SG .I��"� �&pA chloropla!C$phospholip�A1�X� lyze�f� step�J:� . %4E} in D5 6��a�.�t*k�8w.n[4048a)[��j,A�6h&}io Aier ,�� 0X��&���b�r �r:e6hy!���%�c:a�b�;�� hd)<��a cW.k'�$Da����GA()�6 e*�Piv]?u�B�ns��<�%��*�� �]� R�T&2U�7"�nz� E�C!��&�!MNU. Surpri� y ,Bm �%�I2P4.�byAb%�A~��@99I��!6x�=��� 8wo�e�%�jhns �Ka�.!-P became�9�729��. M5 i:YPJ�K �:�%�"��@n48n�Ai'?i-UoA8%�6� J��tjB�>�=�I�v���i- �J��&�LrAy*E@ 2%�w!�Iq����4 A�, N�aj $ ol�S�$" *=>] �Nk�e�E"nR[]%"�&��Q3j�2`!)A. RegarshFJc-���Z.�! {R�Q3�k ques!�ed��� ��B��LFbJo�Z.�of �u�cURN&* j�Q3���>A�Y�l�0p�oLf���%�&m repeX:4!�u"*[J�udW�:%�-Z�Q�>�K�F� 6#^�al.5�insuf6QK!J�M/jB� "{`]�=Q&�\:��jc-���7jY2N�^�5D��!�rec�&��/Xav�/��4!�. Take�Vg�,26 ��B9�a�P�W se �ae,,{"FS��^ d 1&�P�\�")F���._ "�IR�� f�6*9)x V5 W"�&�.6w!�&x���[I z7)�� � HCaMV35S�FU`r� @CAMBIA1301 vector��"�:uc� X2�)�ODMLM�o*�$i"�S^:P��0 at �A�AI- �vvoUh9� W6�$a&�"���At�OU�(_�I���)q1(�39)��.)2laTq5�A�I>xW�"�0of�r�'4: c��& �,.��+�]Z �coil1���S?AE|6#wAcviq,Deh*t�X �Gb�YY^�  +�_�[N�. I��QW �t �T�P34)8*S��>�P1�R�ofAYdidg?aks sel�I@$microarray A WEXn-i�v .� ��detG"a�*g �3M`��a J]ae3"fAK�3.�a.O .�.N_^�~�j�R�>^}��X �zis�Xu.C4�H�m$/�C 4 j86�0�$ mpaiu�� �2�, e�Q(6'Re D�]� courr5��X e͟>�:6*)_a� 4%Wh4J.�`[�_m;ly attrRc1%rEbo�\ ��2cd�K ship*S�J6 �; �.�� 6�E;idti!O ��GA- _B�%�i .�Uf] N� !2.M: E)�x�wn&X�N*R JA-� d�]��,F�M3�"�!�d5`% &#&do so@*�t @e>���+R at!�r�;*f!�6�q ]�V*8� �*�by modfjQ'st�gor4i�Iof�l��+9aB ~F�:�R�(we�*�"�J� %d�*A$!� d.vir "ch�W>���Q�Q̥�~%. 1�(& neX!��l  JND�P.=�.�)�.��0�%au'1S2&Bal�pi1D�� x$J�#"�S �� R0W�imm;in�=I[8eM^�NohN("J�01Ss��unm!�;�]�VN��A!1�#v�~,�!"u.Ť�"u^aeQXA��J�"�rqI� O�kn� �=Y�f�� �a�p�� k.� ]O��.LN�*a � ly1���,!�le.ar!�>�J�gf�"JGac�lis]byC$ }Qbiochem?reA&I8�3�&-2�i7&Ef��", #'2��� �ac���by "�ar��alQ�.u'� posi/#f�*loop [4�OBio d ab ysA_*A@A�mi[4Xo4�k�Wu�1eri�#� ��>g!) wa;a��*\in.�|Qj�>D�:!&� M����`�Tenl �-M�22�q�%�qu a�a:6%�:&*topuaRF�*�D�ad12IM��&g�7;22a�.WT�&�6� limi��ini!.O[lJɜXgrRI��sVO|o"?p�i!J:��VDžW"76�&!�lyA��,%hJBP�v4orM)-%19� ve�<�=��6�&i*�*�~or!(�fBG ?2��M_R�AB2� >� �R%* �xFu;�[��e٥�As!�]��p�2 � ]^ g�r��p!G^�)���[��'.�a6 mobi���o2}iaX`r.Am2�>� irec�����AGAMOU$(G ) [4�j�stnlYu9H6� AG.����� && 2�-�g%W��&�} ��[ 6k�s�Ct�8l b�.���^fX�Yio� A` �)AG�%8M�fut$2. Hig�G)|- Ek)�6DAV"m�s:�dJU�"jL;AD�weɲi�% at:q�$1~6m)g-t!n.-�.V$2"V%San�(J: �!&�upj��� ��s" �ay!�=m end�� 2��M~�vN��)9E(�W��a�"`F�� HM pens�R�## &�4RO!m�NB�J�!2�)�� =*�!��Q .b6�=1]J�*�S&�m��Z�0>� J�u"**5Maij+����. B�]I��: !�*�*?J �=�1>-�6E�݈6g3��Y �R�Szot enoUV�"�)�F�A�cat�!a]tA�n"�k^)]:�JIY.���0@ p!*t� ys1�u�ly.��0e/&�6�&^��*~.[4N5HI-Q%W#� lsoa�y� &q\A(: !.�� 3N�%2**|a�u!Z{� XT�ieO �-dU6�fhbmer m-�t":LEAFY%qLSUPPRESSOR OF OVEREXION CONSTANS 2S2 ) [5�uWei9f'ZJa 5]ar)m[ b"w'y$� ����>��)3�N_ ario�  T2 AR�>turV;-lm>e��F�:�r� .O. Pj�zI��n;deMb�}&�dW�)nt%<�]0*4)�',�rlG)�� r)�+)iXV�e�:�Col-06��(:k^�W`1a^!�"�U^e�"H,.aBi�n�0Resource Cent�B�e Ohio S�qUnh�a[5Áver��Cp�r �j]��in�S3��A�-�!��S� wi� o purif/g�|(���t�1 � t2���X9�u �'ao\. D6�XLhpd%% ��`��relevA]�."BW� T2�L5� %�5���6�iu�26 �6H. Hexa�Ng� R�M�>T�6Je6�7ui2H�p B\ -�in LaXBac1ӡ�% 2�UR�  ��i� z�2�em� 9I� %,%) !u � ?s%�perforW,AdN�e�� o*�"k� e;6�[�y A_j��)�.Y� (�_ 27 d�]ol�^E� spraC��m]0 . 1%�anol v/vEGA7810−4 M>2S�O)MeJA (< 015% 6(#./a"�=,�2�e-�c��|eM"�Q*t(D>�H> �+!�P>2crRNA ex~* 7G�'&�e.� ,-�1O%<+(Rk�,doA"a week��KZ�y+. D�o s(?Q B�t, p�a�Sduncl�T �rh1–12��� diss)8OB�!scope%poow� Fl HD�R�\ 1� ?as % {�?RTTysk��-}eb@iA�m2Hof!�24IP*typI-bw!RiY):'�JA�^Tri ReagT( MolegiResearchŻ(er , Cincin , OH�a�r�'u�Kf�f�YI� remo����� RNase-f�oD  I�p��er� i�!Xf`���TO$4RNeasy Mini ki�5QIAge�Valencia��iUSM&*J� ac��syn�i�SuperS|#™II � H− R;S se TH'#K3( Invitr  ,zq�~�u�W�/���w ��Y&�3!�4P�+G2F%&L�� ��;�->%e!l:pS�s2gE�FE%�@,�bD �1,8 ,t_*�!|�<��R�4��q�xf"%*�5!Ad�8k�-a&0ethidium bromy>�AKt n� A oAm)�softw�y>A�nAuBio-Ra�@�V�X� Eg�>�a�ACTII�n��Չa�o!'>;}G�r�[)i�!�$sv �8u� �-� . Nor�4n�Et hyb*Xn!Z�> Fraga��� ( +294�+801  !iA� sRm@ codon ATG = <@� q +28D627D� [( +1903 24087127 9 1714!�E�( + �439 I~abe� )�AKDIGAOb�@�A�jV�e��Yrobg"nY. 500 mgJ�harve �����froze2�aid N2�� tbRfin�!w#vekta��pestl/=Follow��"�0of 600 µL me�o��d�A2�mix�nd"�~4°C �+nizY9�o��fug.t (?800 g�a10 minmCs�naO�E��f�$new 5 mL g�z tu��n�ѮA�re-�d�2 �& � . 30 ddH2O;add] �Jco� / �n�olu? p-�'�OA�LSep-pak C18 cartridg!n�W;wa !2�l=��25)�30%3 �:>'Q�_%�:oelu�oA10.Wp� *2�*� ndU�.�m . Pre-pre�@�4-)a�c nii�!EMaC:Ang/mL;� 6-apy�� rnal�f��hndard�7�h.�a!� rmo TSQ Q�l\um Ultra LC-MS-MS system )�v P!� inje %�,a Hypersil GZ colum�b150×2E , 3 µm"d me?dM�ri�܍nt ��� N ic�z1 %B�gQ�))���P�ode [5 /2}�AFQin/%/%9 $0/90/10; 1 /95/1 628 A� mach��A�runI�au vol;t4�v�$omi-�� 30 mL/�),�li�low: 2capill�:g e a380��,�W"Om;e��77�m". E�m/z 13� JP ):lliP"e`�y 15 eV aLm*` E�val 15� 9 �u �5�2��N-t�1i�.� 1!Fc�4�'�n>D2��aI |F: ( 5′-agctctagaAtggagaaaag a gag-3′Mg?R?tcg C$caattaccat aaatgca>A XbaI% SacIevYA:� �, :� J\ �.3!�n�l\6/3?:dr; �&=_\!2� �"?mid�& =by �&c�n%j�faAg�x� um tumefa���!Y0roposAA�i�#~Fh�n�nOPR3/���A��Iip��od| �;� 20M�n*."<bQ�PCR�1�*mow"�� d�.* Opr3-RPQDc!�atattggA acct280L0PGGCAGAGTATTATGCTCAACGQ*�5mak�6�v.0a 3098 bp ( 6.�Va4��r*a �e&�f� E[%mpl �Eaf.2iC� 18F ( Pst�3aK$ TTCTAGGCT�CTA�ACTTC }C2934R-94 GTAATAGAAAGGG%TGT3..�� d u�g��%�&� �PfuTurbo�polymer�^( S�t@� 92di��D �U�.~/NcoI-zCa�pCambia .�6 ;i hC�� ^t ��z�xfu�sY� RV.3(thaliana ecB-�ecs-3�g�.!I}jt��at�e�2%�.G�F tudC6Wh&|>42R!ed unope� �6�Efi� ^CF#|!( carr� ut; &�b�g�Antise*�!� � �8N� n^a�u6$nucleotide����9Z��� DIG-� b�h w����h.��Di֋y tri�'( DR )ze�lifesp�m9��Pe� � slow�]���) age-�disea�+� �Q"�#�MflOy`-�#&*g $! t+bb4rapamycin ( TO�� n?*!.ۙe�1"�#s� ulti+�\DRaIOR>E*Џ�0ki�Ot��e4,�fA metaW��Cto nutr^ )2g 3f�;. WNl�k?�'stream �e�%!i��A"�q ��5�� e; yar�3�� �u%Td ;1H%��XA3ha_�7&\�A�<xia��� �(� HIF-��B�P�21� e���!mm�� �a� F;F� U� j lex)�s �Y � �Q�eosta��,���o[., gluc��=�,� survi� �P���toiKY�Ha�,(�D a novel�E� �odj45�exten���,R! Caenorhab!�s>  ��6nsat V�5ce�ulu& U�&gE c lapst tI�@�"�4-� RSKS-1/S6q, a%b� on� *A�1�. U�]dIDR!]hod&x �ki [5 �mood��~��ns�_$solid agar!�a�%of: Q�s� � q�*�!�^�Thif-1�<-.{�� -J��#unC��Z�!���% fail 6a79�9� D��ConzM�3{g%��s gl-9����Ues-�#��, diminD2��5�Rq�]6Y0�&R2v�&3�6* �����V neur�� uscl� I^Nd�Vu%ior��,":#�9"nd�K�r/<ulum ( E���*s���-85k2 ol-r1��ƅ�IRE����F ssoc����2ofd bE"-0l2�/6�AaB*�z6��J�q� volv�' �ER�uP j�>�o)�=uiF��إ�N�wgof R���od#!.A��?I� 8&� ���m��%E4Q�r��"%�I�5/ -ca�d2� A�ea�el 2ism�i2 m power~�tooi�ess�  ag�A^�hum��. I�A��u�!��DRA"�w��zF prJ@ po�<������age��Y�"Q �!1y�of he�8�54in���G��Hme.:%2=(R�D.�jAd�7ũv�@J�� e f!�5_.�Sac0�omyces}�visia�Z��sHDrosophila melanoga t�nM0�robzp�^%K5�iuMN�e>��[1E�A) &U�! *y.��� 7o���zќ}�!���in5A��!, ��!� worm\�!�oz,]�I�m��a�*� J ."?i�A���vA�� ��H`UꚭTt1o &~ ��a *�  �*\ :�1!R4 [10� E2ac��! k� }4�of 8(�etF& ermi�_an"�*of���*� � u��pr{,,*c9m� � �7o� ribo� R� 6I9-@ a>),autophagy [179��N�>]by  �qS6K%vd,��eukary{9.�i|7nU 4E-r�41J(BP�[,}� & -�!X>I6=�4(U5u�OrmF,A+B;[9S"i�9,In .��#�E�A+!? orth�( let-363�;�9*��� ��9thila��-Zt�50�h�E�I2G k~ENAi��.K m{12�2)�her �p"֢�廕����4� �daf-15"? z�! .05a#ae-!(*$�FTh!�iF� éI:�>rsks-��䎊A� �,e��U���2D->1��"^�it���esZQ 9 !�.A ���� F � vb=�] s DR& =?�� Z )?�twjU�8� opA=}g� o���q�o�>]!$o.!� eat-2-�U��R;���i� Q�ehM"� ��mOe���5�1� �!y��>�HI3�D��.!^1�X{ –[��. 3�  N4By#Tenhanc��Me) }�,&} �hY����A��lit�Y 9>�"ox�nd c�G��hl�u��[2%[ ��yodi80c6-al|"����?α� �� �(y.�8�sJ�I��p1��Y8 phys&�-stimuli0� t�@l!]A�[P�,�o}[�G , ni� �b[33!"[ 84�#��� ڥ,��U�-va�(�pro�� id��of-�v5hydroxyn&�he PHn! ��>i)%+��-e�i6t. H.T)��!Jsub~@von Hippel Lindau�NVH��6�va=.`4. �x �!9moq� dec!P.�;4l)D�B q����5I�[��@ help� lls adap� low-)(1�b�e�F angi'#4$nycoٔ� �(&jE�q�� *5 ���e�+,  tumL�)� �m�316Aޕ�%�� 6] �.  e _� [̓"j2N,QI5�Pα�m�V � con���o&�bynV~ �"� %�,yA%�Atoi�uK��-�prefer�N[4[4�!�al�h� [4�lDespi�RG�ll-� �A` link>0�%Qc��r� &KN �w9 know� LB;? %A��.# ���y!|g*Z&�e�a� ]n��Al2� .<�*�! E�Ps.O of�E!� e7& J8A��)�i�ph,hejETop5��'� � ��qz.is99g"��p� �>�A*�aYB3.�.E�$&� �a ���!|�V~�A���thu�PrTK T gainN��A delee �! �F ' by 24%!n7�, �>F�f 996�<��%lab cul�@co"7"�R1A�iGΟ6r �p ��� adul�YBRYT!O,-D�5u%�6�Gr(�7h:z"�!pP�( "+*�E�&����|`.�5�(e��7i��8)$A[��\*=�ye�H�: Gr an2Y lin/ �~� faco IIS )"� ��%P*d s�<�*s in nemato� ,*I� �Z&#8 ��DAF-2/IG] rece� $b.�5�fDaR��!$�8 9�ML aB2}*C�16/FOXO6�!)�.=x5LqtoYi�� I []�CR�n'f2�ofB,aG62It��[ �)18%N' , p<�(0004k0�+6� ͖5z��"� y�"e2j�t��_Qok�&u��� �|4nctq;u�)�HA�Q�. NCgweqEi6te���q� �In-g GsĈ� H"|e�iia7�*�H�̥�*S n� W�uk6 �B�fQ�6�9O5�15� 2�=�ER�RaBz�m+f:�6�ɲp �Z� HzYoFV�> ]t�B.�s.��Ye��6i �A �takla�;xY( lappo ]��� �iz�"4J��#�(S�TO6�����+�BQ�*%�&;aI��9&F}A.{9"�&a�paradigma�ieadq,l=C� �>& Dw's�##-A)A�tA�nim�f�pb� �2{92A-� . 0×108�+ 12 cfu/m��A�"W o�>�= �16�,�DR�A�� �i"&�Np��n�.ex�G)nd ��Py'"�0!?� ���<, 5-fluorodeoxyu4neaUd�إ l�DW 7y)�hat�-gm���$od&L4��$ay ��"`u4�NA��5A�� hNi�A��R�Ge�!��!5;$5%�� As�Ii"��A�Q�Q!E .�-i �!at 9�11�"�ay32BI�G�" J > e!�U��.|9{��3s�� �yf ( 47R�c"��oN�B��"�t���O��Yf2J&u�!d2��3!*��de% fecu< �}F٭.f%.��a<p*� �Et�<�U2�)�DR�D,�A.6��tradeoff&�a~opt�dN~��{�].2#$.�YoGU�U <)y Ry� � l�Guk"A�;df5)Ba4C�y*�]pu�E:"��)O��rotoc� sq�as �[5w�6%b![5e_depri�on [5¿ՉY��Za�"/v=irF2 IBT��Jati q{ d�;Vzy�Y!Kis����Xt=e~&��it%! fa�PK<F�8�N���56�  �on�AεV�}84m��6AF-16�J��%&is un ,�%i�%uld b"4�]tj%gN�'I`1he{��QVU��A��,� ��(W��e�'aZd.�}�f �� w oi��OA���VJ 8��I2�5� KAL% wZu!;,Yp 6DR��RJ&�,d!M���"�&"u 3t 2��qWe�pvua �>om" "ar��el [57Wa<ra�<�m8equ)�uach [58]��"R+!�curve@%pr��L/!Sn� )b9�)w="./�g�`3F)�ƙ��q��>\ uk6a�h��l�*ea*�"us�T2|f'� �o (���u7� F"nIh�SU�̹3٩ �mayMaa shif[!iDR<*$!O� *� ��_@ �*�Y�%$:� )ua�l]xE��behav�o*f��)�)�� aF � >��br� � �pum� >HY�M�zo!F+ou"�N��R ����*) �*' :� ����3k�^[5�ш�2)�:� z ," !H9���oT�2�- ��I0.�.�AtayI�7nic�O�cetylch !á� ^%�ZVpharynge�P-�!�Ek2O�`��E�wid�+3 ���>�>�#� ��5 ;-7� m ��S, ���)q3!:�*?AJ���lYFF-T�!�)S��*ޝ!8M�vr5 2/EGL-9Ae�2��?�n'&�VQbhe ��nt#�%�/ �E�L FOXA� *��/%PHA-4�\ n .� � %9�%w's)#[6M$N�g�L*�"V�wdA�-X@&{5��t!r/� s6� �ca ���<�hWE�*JQsl�@� �9| *V�A �&�J�T>/ FI*�2}�6�< e�hY|SՂA�ŕ_cm,��� �BN I2�_��a4_*o��I�g1� fundyt�&�+� ab�6m s how�V�6���j��s*�%�ad��"�!"��wj7��k ���"3J�52�rE��u,)commun� .� ���A�A#� `5c`/s coo�t�l�iG ch�fs upon!"[- :;8nR ^=�-���W� �Ŭut�]66R&� �Mp��� ��bjI*�/l19�["�nt}�>yv!2 1V��!D1�;*q8ok>� �Ad� irtu8l Q!�a��le��M e� rte{9u�of �� g�5zJT�[u�m~S>$ tane��K�en-�a�Luv1 uV�ne-vul�5 ��.�-H&� �z 5B ,N�P.m�&%u:�Y!� s]CN]!����.a�p?�K�it�FWa�,`^�1N*ya�>ENZ!��^EV�se�n�c. ��$( ADF , NS�O2��!�ol�� guan>% �� ( sG"�C�( URX�JQPQh-+4e��i�F�"9� [61].2d�U}2�2{E�^5"�2�<)eC=#e)n�hmyo-3� iN���~a*��M��!��G�2�VI� Q.�I��E$.{HJN2�%z ��2� u�.=:�.2/1�΋i"�  ��r��"} eo� ".6�  > .��#B�[ aN< 2�3e'�%��6� ucr!!��#%.o�emb�4h4 sarc~>ia [6��P& ]=b��| AR2YRp/�3 �7 �� ��IJ��e~ rynx� :&in-��� yo-%�:%:m+��Z� [6��-"�&)p/6 DR��$.h�>�I��$V5M)����#�� dermk1XXX�cr�n1*� gl!�margi�h1:hg�s���� � )��1��@D%��an:E ]AL� i�-Ti�&�9� Uf�6>�$\UbS"� |�!%rM^9'��We�L � �"u :.F,2 !r� RionadalB�(�(�r�)F%>�(��C���� �.!� MTo/0!�*S6���2 �� A��%� ~r\�Q(Ypu���ed.�.*:is��a m�'tch2a lo��un�ed/mis �r"�rE�F$]9pac�9!� �Jrya߁�4ie=ad [6�m&�:=,�=!�y!�(9 ( UP�ODA�4p�!sZ Hby�(H2 PERK�� ATF6�#)%���R%���  �"4J%���"2�p..�t�D�/;A-t �6-�sv6&)�[65�Fzmr��-�L�� �"�,� lC�0 �AE"d 1�GCN1( qsFUPRƠ���, �� &�"�w�2!~6��.�+*V��6. ire-1&�ne� ~�ra�Q'7tA a�esa0> -&ER lu��!�t�-�-*�g0/ XBP-1a&1<�[�. `�t�mGWe&[�5 �N�#)�!&�:�F^A0 ��{B&Q2� �%�"+A� DRAm�"C6"M,TtЩ"�7��Q~H*��-l�N��t�) ��1e���sickne��av�e�s�A�� �*on.Hat��R�i�D[ �Ʌ )l�>L; -4G ( ifg�B%Z.�7:�c7�O �8 <o!xr) a��� �Vve&l*�J�y:e&�8*���[*4��"*"%5��%�!���1�.�C)�U�2�kaGlC�yi"@3!p��!sV�)��6� pekݖ>.� ��;log)6r��� ��c;���� � >p0of z��"j��i�es�  �(��S7�B�)V� !)}�q}/@A2 � �aDR��!�ez�o�Yx.2}0�0e��Hl:�,s�� *BA�ahalletJ>k�q:c� hsp~M "��chGf�(BiP&6:�79', V6�0 s dra� L�!.=:d� )b� F% � � k#m!^[�ve<�( q_� ɬe �.i�Vld-o /I��B�i��%��#*3.Aa��">^ d }61u�і�ioR�A�F��}7 2� 1�cɒ $9��rI���nt �ALEa�E�eu, �s6�%C���N2 W�sam��펡��+DR+m!7,:`��Fy>�, �er-S�M�tµ2�6c(. C14B9 . 2y "disulf�`i�:rl;I i+4#f�*!t�N��މL�B6$ �+$!s60[6�oUl*9�,�.�qaN`� �+. �8.� �a�) �+PEK-1�4qKN �hH� s�6�)=6G%��9�.�il.� S�$loxW.224Kr�@er�EU"zQ�ER-as"�K� �� ,>E�n!��  !!4*��)w e�iJyHe�2��y!�N��"�Jq8�N��7H�"�4V�PYB mark!do%�t�fˤ6-g*O,3� . �)�AL�)2{�V�9a?���O .���IU�f�R�!�64 �5.)�Y��tJ��.x!o|'%� depi�Gau�of9�J by��-ρ�K ssu�:l. > �6-)��p%�. )�!�.�0���C>� �+!�t!p?*C.YR]I�����R[!� max$Y��yA���U���� �������e�i'2N").��a�a���Ii��.�U�>���~RcanA�beF+Ζi��R �.!_���j��]Fr*Ply0���at�;�5lf��A�82y6~�. V*P �Aaw r#D&4R" V}BM�2�1RPW2D��Y death� vHB �Y�Uge2M2�F�jA5 ��]"3,byQw*+��)��s�rI�r�B� I�g]�:[�*�7\%�"f�B*� R�Ia�2+N�B�TV-?��bZ�:>n6!N�Sz&9Ւu�.yi�8�1regim�-6e� �:LRV,=�,�sI6 N�V*\?�%��R&��I:RR d{\� �Ya�� ��m�QV!_e benZ��f��1DRZx-6? &)1�=L�]5� �,F� >�o-=;Gof!`& 5�9#"D9�[6z C D  , SKN�HS}@aAA5�a� ���-��9K%�)k [6�P7�+h�>Q�h6apl��"o#� !�� .6DUnT!�S�9e {�UyTC2yisco �!X~K >!=�Rb7?T)m9F�\5P�at�� eg�|t"+s �+, +a�.�,"{*sm%"�10��*+j3.I�N"6�ASI"M%]3",.� �~&� n*1!m�W+�/|��*w.M2�%&\">ArEi!�.F B�*>�rU��.�/��A�RR&.<"�pb"j'V%A�.�#�%�K#Ue*c"#��S)� s:�"%5�8ri捔�5ee�� &m=�U�fl�&�J:/ . [7VK7+&�]��-�I"� `� e�2L0aging in C . �qelegans [73] , [74] . It will be interesting to examine whether HIF-1 regulates serotonin signaling , and whether N"�is involved in DR-dependent lifespan extension in C . e ��X. A previous study has shown that muscle decline is one of the major physiological causes"Ciag![62!$W-DR �H% affecp structure"funct�durH Nneeds to!lfur%Udinvestigated . The pharynx!*�foo!*$take organ>� 64FOXA transcrip}�factor PHA-4 plays essential role!� o0geal developm!�[75�InU ly , M8is required forN�by!/ [54]% by a muta�$in S6K [76A�buR�by hif-1n not Y(on �� se experi� s suggestI!d!�y!t4multiple pathw!$downstream!U TOR/�tEHediateN�(in response!�DRA�A�5�of FUdR-�%�incubF at 25i� io@. Day 1 adult ani� 8th� K��=�see!Q�at dia$!B2ajI�$first week�*&�� heat")ss�, 5-fluo� oxyurid�( �)9�e�lso a%�iA�J�1�pr� yI\hatch!�. L" �uE�^�%:y�a� �6�16,L[FJ!�EN:�V%�(Y)%CJ���)�da$ %�h`sMin& curveA.scoA� liv�decr l<y oyg.>tW faili�dis� touch-' o� move�)me:M �cau�w than� , such�stick!�toE eS wall���?Uor bur D e vul2reg ,>���f�{s-*3–6!*a(AllVM]^q�. S�-� *l��aNst�al analy!)<( log-rank tests��cI�a7Pr�4 softw� ,( Graphpad SH, Inc . , San Diego A , USA )�ild-typ ��-3.w"%�Jv�Th�6���I�a�v q!A� pro5�E�24-hour!9i��oun�7. A�]w.���n�DRm�N�~l �$�b`�48 � s si}��e��-Ja�tempe�ras shif~ed�� to 3�K!"F�sm�y%!��r���F�)� }d� 6���ei�tAL�2DR%`5ALr�c� ?total RN�paK s�(Trizol reag�`( InvitŸe[� ��sA�d cDNA %�ynthes�9.rA��a"0(system ( QihZSYBR Gr�dyeuanta�0a� �qRT-PC Re7oF� �Eri�eA�an ABI�_7� eal-time Lm nt ApplN Bio ����lative-� og� calcu� d� 2−ΔΔC� [83��.Ge2�tw�e�*re�us�Zw�&�B�ie sequ"� p�r-Jtact-1AGw�|, CAA TCC AAG AGA GGT ATC CTT ACC; 51�, GAG 8C TGG GTG CTC T-hsp-4b4GGA AGC ATA TGRrA GAT G; /\C�TT�G CT Te�na� commit� g��i Q�$know littlMh";about�Q�as�e� F,-1���� �mig�L . H��w mon�&t�w� human�eni5ke: nocyQ��.�� aIey!�m�pl� E� typiyenh�)super-�)Zuniqu� each � . U >8for (!�u�% H��gen%�o� ata�far&L>���e3] Ye�seB��r enric<� skin� �u� 'ar. GRHL�a)е�M�%promo!�H.��a;9�,E�z fe� iaUtoB��� A�ng:��le�.ditbg �!� long�0 RESTE�)�ng%a*Sof`iMor (Key epiderm0�!�N�!�� P5fre lo� ��� 6���man �9eR��rn% !a!�r$Bn. Fur'mora� �r)�hE�o�"a number! e�e non-.�Bm��� $ .re)s ��Ar}�o�E��6 ��:�.�q!N� thei�ver��%��to]%. G:��(!��a�s�� mittEto�&l�� ra�o�l?�re2ofA�A\tic1or�r�$6t>� ( SE�[1–4�>A� thou%E#i"#�FF( TPin��tro�g� �#tity [5–7�Lx#is�zn�h!��"M��1Oc5!-D9���)�� !q�)���ha�E6)�YA�w e�  ary͚�6I[8–12]!=*K&�genomb�u� pinn�U�J� of aN�� s�y��h�4sal layer exit�%)cyc��t�9� to�  a� rfac G�H,a�����a&��aE�g:� rams3$�&9Vbarrier����[1 D�'early w�"hea�(&��+f@s-�� cv# A,� Z%!{a^��:tinct~� of6�on [1�%While��YS��2(o�%�'^>+Q�.� anz F�Fx rem�"uncharfD. E"�(*embryo� 9�>��F�ɲ�<repair?hV��� 0 How agl^�s c� Y i4>R�yH��� �I�s poo��QstN' !q�Lof� com. &[,AR>�j��s�g�ae�M �4�"-_r�ds crit !�E��specifi ABi+ disc��r�ort�%�q� "� i*�of or� �  lg �aVB�[219',n3b!�7(��>�9 s [2 #Mo re��,adv!9Š!�aQenabl�heA1!�g�O*1�baon his�  �E� igh level/H3K4me�*l:3 mark9;u�n@1��OhB^ 27ac%8e�d)[2d 2�'Poi�OA(so navbeFaqyD� d� 7-��:ra��M �a�oth2�!P H8�H3K27me3�� R%��$class� �!�to� ( usu� (N 2 kb n )e�i I�� 0nger ( greate� an 185kb��+!Herns: @'oo n � U�Qo�. D�Ac.�s [$)By drivAr!6e�"� At!���: r�6 "  4 , vWhe�,m  'R(mappedi�* ��6��$N0�1eBatR( p6!�0a`*y�@on enzymes DNMT3A%R B [25]%�m�E�im!�u* � �'of�!,r� ��r�s unexpl�. A�O� don’t�� ifR��0y�r ����!�AA!�inby. T� E< afor�@ioned� ledge gapA8�fiAkTE f2�i2�,1n;�2�B%. CombiC this data\E�.�afa�siknock�1!�50�2uon-*�V�%�ga�ae�-�Z view_!2;3�A}o-�jn*tw�p�F� �4focus��!Nh&2r�-,M� -2s",-\ insi�h����*roP#1 g���\? � �9`: 5G �� � ame��9�-�7F+�mt �-Tes diver�b�J�Asm�Bmby swi� �f��hr��� �!�+�� landsca����[d19�).y ^bF !�beeN!K��$( NHEK ) ;a��eS��g1|. F1a!�H"�v[!�* � %� ,]�2U��2by rai� e&9iu�n7 Xo� !�in"�e>scr4"�par�h!no�s�, � ge7�� )� w �& “w� ”&� . AsMm!�>!�yѥ�� sѮ.�2�[2�6weBd�5U6&� !�!�� LWe employed ChIP-Seq! Ceq.�z8 ��ngM-.&!�.�D )2��/EI�ar� ��o2�I#.$�%HEK-P )"f  ENCODEAbjO([2WD!/� e���A� p0* * ac�*ab)N B8 � w&� � pproximat02�'H�Sin%�-P , 3 D v9(. M ( Fig 1�!eI )�# �he��  [f ,� fy!78�76�!�363��-ai��M/�  2����A�aFG6kb500004 :2dS1A��"AF�*� k� b�5q2veragei�rA�!neaF<��"� ( S1B _,��liz�"r�tl% tissue"�H�a+9usekeep!\�YA�S1CX!�"� in M�9or .0MED��<D�D >.��弥�y�\m4to6��*q*471%�p��'�2A462�e/�(nd �*613in-�B%�G(���|�, Ex59J�6 , 840ki�235b�Despit����*��5�2&5E�Dg A� perh� �6.P.�dep4 simi�per��A}of�!��=�#zPhe�" D ( 69% )��65�u�MA?>n >t�!lyv >�m�7A376�ilap bp allD;co�3A���A; a lAOb :i�' Te!�a�ed�:��<n�zin.�g�"="to kinas�,Not�"9,262?>���"1( S2AρbW ��'$ogous dyna�patterC#ith�q %A84mZa��9 ll 3Oi�27!�e5A$��*� U�Gon�U,A*l*7)P8#la%:2�� ��!7m�� phenoty"n 4 a��9� ���%*�- . No�iz$-�2%&%!�or���P6l12,$L4����-P�2� �e ( 20%A!qpos�IvorqDT>8F9yQ�ex2�?)%�I?%� :!����A�� >}�:�."?scEjJ�Altipl%] �>� �&>7b lex ( EDC�InXosomee��po�W tVd�%m� EDC;se -flank�?8already establi�19|��17�ޅCC�*3 m�observ��W2o�D E� cl�1r�w �sR|17A�4�S4Q�,����$�2f� �r�:O��'uLC^! &al� loci��2tra�Ao C= nt b ]0�!��V�,%os�D!�.�HOX � HOXC[i�� . SE.��{ E�� l�1 �e�TJ3��MtbAF�& , 7�*M8’�nas �powerful�� �� _ An�s��es� �Et"� Ac���:���"0 achB���topdQ�PѸ*�/moe�Dgenes Mir205 , EGF�1 TP63e0BSD.S->� RZNF750E �;��>�M2P��1ACTN4I FLNA1�EeiC"+B�] *�%m!vach!A)���a1�s�R8M"i�)r<�F�F6&xam����{�$ch%ly�r!Z�ba� minae"V�y�Mhemides�'�embZS,"�$"�V:Q%D��6`!$Mw!��popto�@e>�m)) N�mMJm%�9�!<%z n f�2ra\AY� L)H{6at~ !:gE�NToA.$�����i�ETEB O ( S5� K42L�L�VNPs!�2Ec2# -sY "�B[x� �:O( ��,e . p < 5e-0>e�W"U( psoria!� , atAd$' titi� alo�A�I��carcinomse%�n� M.ic.;facVB�?,EPPStevens-Johnson syndr��)%7 �a�5E�HE�y�. �D%�, �a�g&andomAH�of"�  Chi-squ!��2 , p<3u,E-6 )Mv2ɧ2B , T�� �=Csm� �Inotice&dip���ac�=3djau ��%� ( S6MTa*� �#mi�bZ 6��� :V"�domA�se R��2Sn� XL!p��, poin�K@ �Fe$-tainta�*!q��he !;n�Hl+ kelie2E�&A.�*a}&�*disrupa�e2`�. N�wF-pE&O�&y+c{ ed )�"0 � � BJe[�.s -o �C &tsK�'�%der� .�0*�  thirJ�!E*�Q�&1 5�b.PQ�e .A�Plm�a-�� {7gL!I����lwF q��Pa�n Z��or fut#�� Q+alI�=Q y(E�8 eC 5 -@�!�po���6��ȁI!�l�(X10Ydoa�� �+"� ar!s6��B� ɿ-oTe��1s)Y�zI derl�Y&o�$R� Y\� w/*0t�/�a�-:]FU�%*�*=�%Rs.a33e� occu �2ea1�C""%�&�&"e+� SA�toI�P'�a�>� P; 17%E�conver�� ; 43%O9��9O)�, re��X;E32=l&� }� DY�-�=  $�K ,��- t ����J6^Dy�—!�"M �$:�h� cr�—:ngI�*�(SE] em�� o�1�,"/i�%�ESCa�Surpr � TE�!�G'9n"I"�p!$ t�vj!���P:ɿC5YtsM.�6]� N��5l�9�Q�orE�XAy)�ua6=�.�E4add��A4�(%���,��"O5>�u�)1 D)q�2�:�at�QsyM�r��'ly�] �7 {�Q� Toge�0�6�Y$yQ�S�)QlAZ� } ;��F�� ".�Uw� ���in%�EmA� BY��a&A)0&~ O%�2�1�!vs encovt:� � � �N�T4� &6.�} � �� P6 RUNXyNOTCH3EfFO�PTo> a-1$)�6V�y�a�!manneA'A��M�. �-n*� �2�>��a��0?#��vid'P#Q r�50 g2�.,��2xB/ �? , S7� �$ss�e YO�j!M��#nv��u  ( S1-UT%51 ×6�lA�matrix��#d w"%se^ v&�Yy net�R%�f .S< ncipUompon!I( P�mAufF2��t� tu)��global �-G��3AA)8U)>�4profil!`&.,f E2Fa�SPCREB5E�FOSL2"�to��A�aIP�[iS_:=f ;�g�.�I��n\z�A�6�a� groupA�Vo(*sJUN�JUN� �A! M�� FOXNK, 2 )J� )en� ��+]4axi+6�j;E��g!;-��yնs �#.�2e>�()� �%]Set E�jA�C�GSE�![28:H9�4m��direc_����Q Nt�� �A�`3E' stag\!b�%2%EL��of�%4#J!J"!5 /aON�*!,�4-�)d-� �-2� 4�$amoc:ds�\eZ!�U��F. ,!�pla� =A��8e ).�n�P�4.�;BGt�,�;���6�A=Q gwyAs�ai"�t� �w-��@p��m*��� �vf ��%�j�v�at>EupbU neg�0>�4 �.� !L2�.ws �W stro�3afj^!��R�)�� e  �,�B�GiL�/ly��#Jh; L�"=Ning �"� >�]�.!,C0�� J�`���].^��U m}is [30�$� R� N0 es2�))o@�-S"g� sub�of-7A4U�Ɏ, STAT�yS\F*�>8>()fjj� ;i�3�O":>S. S�(to PRDM1 [3�%�5� sePA� �oh=jV!�!��I�!!ם�A��Q9>�C��. OW I�!k&P9eR!�i�mzj� ���>`�&Y��rI� �!�sAwell-k4prF2 � KLF4 [�T33]�26?1yB�)�B�a�>� +. Yet � ���! ote �cٯ>J.� NR3CI� �3Q9, {:�Kyva%��h�"5x:w% �!z>�igh��Z2� � �X�GRI�. WGCNA�$ed coordinX'M5a�bA�8��)[J5?kz\ .La�,2��, h �an$y�"&d* ( S9"+ In&K�225�Ex-�0�G�*9-o�YQ8M82�6h.� ,A�fTCF+ETS�YS3"� ,qJ%6�� 'PA�"��-<� ^l6��;=pRf�r . B;�N�1y5��~iE�E �ZLPD��d4YA�SE1>a��V��Aj( &�#��E@�k-�D4B�(�'sEDc \ X�ETu]SMAD4�(� �%�li�eb|R�>�1Y�c hubs�T c1;,ebngA(� alj�2r6+- B��6j�M��.�brs380282a.� sis�rs112833��44ic lupus eryth@Ysu>FM� ����5vlJF �<f�outsid�!�!�- �SEZ �B�l�lAUh2v] ionay :cX:a�5!�<eSEj2Wq�:Vi�ct!�o�7R/�" ��9recei&c4a�vbH�6�%Q�! , dhI��V�"9!%�Bw�jwl6g�$" �REL�Cy IRF9e:recipJ@�� {n�me'J[Q�N � �"I[U�IN if*Lc�% amil=A N_:%-H=&  3 H=�!�*c�imarily9ޡ�B6I�-��pu�EnJ!!IE�� )��-#oQ1%Z!8 d�;i�8_to valing%predic��1M conn N�Rb�0R��J�AAoHee#,:if�(!�!eZ�E� !0E�� �,J ��I�"{6����?�B�ZO 5|2 F�0 �6�,>F��!�!�6Il YT6V.wW���&�)E�K!yv'5t� %� coul��[=O empo��k98 1�Y& lor |� 5)la&�GY*%�!'I>scv M@�. W� #excep1���K2�6V��lrR"��1�M�!/:���A��, *�N�.c�j�a�rF[*dZx)�'f8.9#� m�!G YrB��@V.1�" l5;V0��. AN��A�%�e�Vo�4 �A4B�j_ |,in�&P�24�x�-�.� �we�Bpu1x &�;��a[J-s ��MAF���B�[A���35]= k�. BEE Rp!Z�.?.�&` �(͹!�r�new O"d<��!MeW="Jb� � ��bx5��El�2���@/#PTlqk�� ( 98)7� ��!�&ɥI�oedm)5�. On J:E�re�3 �pea�aMm�a �E�2�( �ha&}"tK:52^,"cu�&�q�*�olK -�:�guAM�!�TaVLE "�be�F!,�TEs� 5&h!tagx �5!�isd5  ZhigZ3Q�S1`�L�#.B �'�Q&�"&iY !�a$-M�q4"uly�%� !Hp ku%C� Yj'A.��7B %s.�:.9q!�s݌"� �<NIL17C [3(@�ai�&�w*�CwB(R�!5�^S5"n�uFuA�"�KU2b�e< ��A d!�n� 1A6S1"�=Awise�%��a�AG�C!�E�.�E�"�+=��ke�d suitd.���B"[h9�won"g UKV>�+m1ia�� ~Y�.�(i-��(a�rox . 2 K"v)�])�M�11> 1!%Qg� wAV @�MW �!a�/�m�A�06�( %e�a�!I�uuz&iTj_,*mnk� (3 l*35-M �%� ����� oH�t/"�.�� �'B.' s --3��7��O9reN2�(� >ez�2^X� -�To&�u�)�acte ��r}!�*&'@wec!Uitf�>�6��t-&�_seq^-��1� 4�1in duM�1E: �& aI� �Emb�PofW >�/7�*fəf@�; �1a�81�m��m+� "i67A� "&?��& A89�IryxBKc�is.�si)�BG<80� halfa�a�� int_to-Z�J�O6��#�(<Ag ~9�m��+2� � F�;�EfoKjL;H.1)��n � S9M�!�z�U.5� !���KR�ASV!�Q#�gf!�NYh ��Emo�#�v�e-k#� ����"�D>�25%y-� ���f !�+.Z�.^[|�!$c4k�$i by �1nᧅ�P:I2�A�?5eS�pWng��q)+YP:m. K.%# 2f!�u!�loslu4ň@58E9�em�K"� I�Alla&D1B� U�lLapG%( �6�5A:�����%oa *�44&+3of zg7F�kof �5��V�$�\���**Y"!#m�)��YZ��3�k*D= *�DPA�e$M�r9%-A YC�6���eR7P 7)�s`%a��#q��. Oi�f�L�e/e�T,*A�B�1.��!���i.H��W?o�]�9!��I3!��E<ENze "�Bv+aig! D&NII�7!�z�q �.�s�#�2��KcL-� re�Q , t�ԁ~��1�!�cn �Se��)ir �2Iq� �71~  * �8� �ajo�F��'!I%�b 5�!� �  ��*�<� a%Z ��of MAP{FI]1E-cR[r�` abil�f.d�]�% ( ��H�!+ ��j ( neur�#�f!Dx)�M�)V=�>&otAtphX#N}m�FUMi.!Nn�;��� �K�.� guid�XAN"!1 UNC5� NTNG�!6"�. F5b%!�!�2 � !�!>a@�T}M�aG6cQ�c�)ZU.\q�"�GEA!��� ��Aw:|s,e+�A*� � r\/r�*�(edEF��Y �MG.�(?5 h-�G%�TQf noE�q6*41 of.�A& �!��w�t�a�b�f"�A�=& �-�HR�\/%�sa�sf��='"> �A,A�iJ��!�� i|V� ��c i�e Y Nk\d�E@)�.s��a�{!�u�6?)2��f�f&�ARa�e... E�1A�"#�&���Oxtad _"@ RQy�K�Ida=lJ�%K}_� e� 3AJ���&`�5!W��%��HV�6U� 32� l�8/� l!7l� anno�Adm� �6~To 6y� ]; �G c �8! � ��Z 6�7 ;Uy�.i2)0 �*� �E�;���by�>la ��} �e8`x6Be|�@� 5#u �]r@2.gev�ntg�y.� ��� ) �����2U ,� o�}�IM� e�#"�)6jh!�EGTPase-aNvVMg�p���gns.O end+?oA�� �+lc3�&2-�Z�$>�a1Us A&R{�-DiffB�j[38�)�>�I� � , 80�Kv700{*�jeiQ62|<:�M�tN�'�bO� .� M �)� ��%#ow*�4w� /i~l�$!�n66�b�J.v j` �q �pV �&�a��5��-H��22->��R:� � �)�x�"� �dE A7� teK$"ch �-�&�`QMe���often2)*( ra� !����S1*XAsR�l���"� A�A��! +"�E�vB�+F`-�t�<'� 0Yoa4��[l 3kbai���Skb upޒ�R 1kb� [S, �.�>�B��od)B>9 F�!>�g (M)\ ���*�<SEMA5�.TGFBR?SM�!k.� y _EO&�q�ly�Wh�'aa�=�.�&ۍ5�*�69�p�pM&A �� -P1��J��!�s��en�&�de��o�f1� %� w>��!)�J�-b�� ń:!TAT5ETS s!'5se"M� u�r� ADfI��"��feX <.X M�>� ^�6w�P’�Xwn� C�UJ4u[3iI)0 �=!ha �maqbA�>M�or�uz��.�5, S12��Y(� X� +v�� ab�m_��so��9-��?)s6��f)�fd � &`)� AIQ6�5aX.r d>�as c*�kN-/�f�?� cruie3 HDAC�mBh . Semapho�3�Oa4m��..=�,�yaf wn ���.3s [45]�*D&�%7M<ecVHfwe}�5,[;�� >� of T. deple�d� s�5NtO��&��nJ�4"�O���:;�I�77� aeP �9 ���Ge�cI6 ɪn�h�!a�e$se���7��.��)8�M,.f>qG/r�X�)�E\-2�zC:s^ideA�|(DYwgq�.!a06�?:�"� �7� ;a�� �p.�pr/6�] ectoS:K AP *s !��"[ 7@ � 2 !oJ�a&�A6.� by�!��orM M[~ & :�� co.QB��� � �Aekg�O=���*�"� ��.2w�Ql�5z" <2�i)'U�!:n!�*�2�)�6��~rucXTA��Ei Wal]��Y.( �#���pr��"Ys AZ�-� � xR^.�\de�a�;�!e�"V!y�%�E� o-IP�e.p�},! qPCR2&+ �0��at KQ e� ci�-S� ? a 0)� �x Ỉm�%u��tl ligh� �3ciaI.�.A�7�2�M �!s&)]�!��SEs—av�ap؃s%nSt�{c"l)�*��2 �%1|Ep=�lR�{� s&�-��&�82;X�))�,�jdo�C�"#m&��e�f� wB.�c� n6�2�%�!�?E!t�<%��$ibu�*�@2�%& &�@A�����,4 2!;*�TM� 6�!� =�$JY��^*��SSM��bA�i�u�C2�4"s� �{ ~o�uollabo on&? 2JeTd . C*�!(,a%����slyZm toe��@1�E�co͂E�t\��#� R s�ZIn�QA�)J&qE exte>`�D g�"�6pluriw�cy� �l"�9_!���!��!JA\RA�! selv�]��� SSFtI2e~���>MhYg#hi��H�>42��:�ed=0 , 4�94oWQ�gB�:_��CŢ]�!�K!+��1�mZYd��r: �<ew�M/{\�YA?��� *�/��E��Q,,Our�� �?-�Q�do*x�JI� *}D��% �8"( �+a�CT�i"a�+���VL!orem+[&�6�g&q?��F�Aa�"ey �A:>��� >�o��J U*�nev�?���'�=I��A$%YA�QAi�M.�`��- LF�, .�t�'i�?%)Y6;rp�U�-����nB�&� ���^�C��.E%G�I propntyploE�' "jٮ �atS"�i!��VnD >�h1N�.�loo*�DkP(�TA�&Y "6 K-� r� ���quv�L0q�w�7�! ��:ieshd� �6�Gr8~l�� I8L�lafh �xi{z��5� we>B�inyu�q=� ����a! &R3!�.+�{e< Ca*By��J{U�*�\�c!a��Q*�I�=A�Mh'�/D>C��%��.SB B6B*? ���le�� A$w�>� �<,�:)����Y�N��!>Ea:Ak�A w"�p�m��# !�-Re "G?g��5H �.�?.RQC }���.Tn*� k�'�$ԅ"�R.Ig]a+yd7i��!vR�=>lO!�&29x�L ^%]_.!�?o4Q66��fK ~���: ANR�?��a -��esq�>�, ens�a�%Dct ��m 6.tZ;�/ccess mEv}�a. [06mn���"nD%�� � ���SNP.s:6/G���e�%��a��FR�(Es$�"w$~��9E#PB"��c� I':? a�J�.�AyI%]�}�Wa�,%� mil�.gNZaI]��e�8���]athz#�����/�>1���!�ke &�;�;�4�d a�&^IYmsf\22B2r�� fwF.^A��8 , OVOaSOX.5af%V��&Rf��$;6YzLB*�tw�"'A��/aD��y��t���Q�[1^;SA�z5���9%`o�8A `of� b%He�s� ���&�x".n,��be�Y�?��a��r�y��M��� � a�� A) �=-7 [53]*� ��n6s!�a� �U!,E*Ŷ]e6 w>E=95 ,% e,yy!�i���� y&#=!�K �ffA�.LshBI�� Ad��5 u��@de��:TF� �p)��,��A/�[g�&�6Q �>��. 6_f+a "�[A7�%#"�%�ES9�f��1*�,T * >�QDl�J%,6�6~y.�!�"^_A���� e� 6��i�: ?��.s| (!� n polymer 4! filopodi����x�" �0�M�e��[-� �.�)Y'nd6� �2� �!�$e\�/e�� m f�mn� f��#>�.���B�haA�!!fc$.e"�!���]U���"�"'�>$d"Q�!�"D��rr�:�E���Z{JWH?)M�g� un"��� �o)�E�y�a�&� of*M, �*4/�]:�B��*=�B�.� o � :� a�� �2�!��I{"�8 NYUM�D �"F$>�.�� �[�W��O.a3t�g �}� ��a�&3_)!#:eA�i7�y SE-�L feed2����,��%.��K86��iGenome-wRQ !�!U!Q.��Ev�= ЊM����K �i.�Ors%td�>6<� ��BFj\J�/kIK�6k.�"�OAa '��"Ce. J�  il= Yc6 >=�4��!�mq}2calS*pu� c.�r� �mee� �physi"� g�aacV�z&�6�j 6�6mH��ofV�� �mp�})y"R .>!Gh.e��ncoj��%2  ���n�< !��  @� H�hE�Ke.�"��Y purch�W%� �L�MTechn%j!�nTKU'accx]g!�� manu!�urer’ �W�A�D�wW7uv�e )��l�>��5gr'�c��(B=. {��e^�7e� 8mM Ca2+ � D� nduceY�� �0"3 Ɋ,�%.�v�nfl� m"��!(�'�$a p200 pip#Z tip�,J�=�K�6�?���cm ) zont� bCr�q�AA3� gri�g� �w"v�r"�MS�e�7c>� I�a� �Ŷ)d!=)���nt�cta�gZ*��&�9o�W'� mixed popA#��po�a_Hm�i MaxM 6�#wOptiMEMQ �+%���e:ME��� 9: 30nM��W6F&��{GT( Dharmacon L-014017-0�i, _"s�hs_p0_5: S10415376"1: s1007Dy���0��oco�� ��: �iue̹J�zAĥxLQ��VLby Schmidt et . al .�e� � li�k�k*�ň\E�yz prioJ Ni� �[50C��a�!50-��!Ol�9dN#%�kon�5*Hi%2�K� �%yze+59��&�V.6 >�  cou2m&4s�a��2a"F����#&�F����. �[z A%u( o�24�R�2�bP-�& aG��`�ll-�K DNA-� fB4JASPAR� f�rli�,� J mfs":@hel�N�@arrow%�l��Y*f&L3�\&�i.�>3 . 506 "� e?JXor su !+�T f�E�I�Hs "�m0�k*�22�e�(����2��*v!�T �mKu�3s�J0�Ai6FW�fweX�%e�\&?#�k6��]�J>K�s�c�bor;]E� $auN /.� �se��d5�to�j�H!@m?r� . Po&r ���)S2� �w�T���5�!t�<�Ou��L%,.� *� .��!a);A��q � ��n�k��edu����!a�ext�^\run�?cxfigJpax( $xU7�.�c-U�edt �3!�"R ��L�-s�cr6W i5eMals��cluA����1�&3�>e��eW�N�f�d��/ CyberT [5�, R"5�PC�5��O\(nd hierarch� g#�zI���~Zl NHu٠ GSEA*Xubi�mGC�PM�},y�(~m6F�"/�H!�,&Ji!�~�to-��A] �&��2Ym���� limiAj8.?7 ap2Il.�S!"".�!�I9��&�( �or�.&D12�,�M$��e-R"U �9��=l^�1N6���d ��2n.hs���'zo�e\� r m!� I��, "_�pj��KIGiS� kiR�6� 0SsoFaste@ Prob �Eva{�( Biorad� w0o ) mas� �CFX384��l-TH�De�S�VN. GAPDH�^RPLPOi�e�a�d���� FC)�1 �a�ly: ur��9 �y�ur*� ith Zymo���!?.�;��ɧ]qu�hxqu � A" NanoDroRe�N�������"��b&Q"2X�Affyme�|QdW 0 STIA�8�869� �P&e�)Rn+�2W .:' /end�Y�m�ta Clar�fC�FPhQU�6��khe�z%Bt� fil�#g =4��!�M�%raw.$valuea���W�l����o�HamA!~� a%��.�EYhretrovirܿ( ERV5\a�remna�$�ncG0.al�9fGI�h�� germ�+��mX0*8��oMk�> .�K����X�K��%�5$w� bcE�f  lock!���#�.k�=�d�g,/*sefQ�.te:�R��aSof3ed exaa�17%e . Ho��Śsa:�_������� i�c� � oevo��tXG�Fu�s/�2~ath�S!8s \%m���ܑ�2ob=Y. Sheep%ya� A�zMmodel�B!ms/�q-e .��M4coe"�S �)��wo=N&͏b^���t+ Ms)4>�4, Jaagsiekte s��% Enzo�� nasj�umor e#��L� l�9I ��ly��R�( enJSij$��we iso� � 6� !�5�+-h�ry� mole�:s27 g���{EU%�Fga�ng)�eEa�au�Jl�F�76'lA���Two T.h �56As u-20 �"���\E'A�mVE e s�Lo ( be�T�� �H!� ; genus Ovi���p�w|Am� !�"��)aA��ve Gag�!&!�:�Eqd��"�& �a�|!�2$ step� �0b* Both>f��aLmXQ��:�-,��,0I�d�Q���( ∼ 9 ��y agoh>Z11IG eݦA.q6)�Ws"�[ve�<`9!�;ly.�E`��EV�w����3J��c�>Mu%�L�-x!���$aIantago�i"W86Mf�����"I�� J.3$�a>l*��y�str:��&�E� �� trunc `Gagp an��%v-;�X�2� e� ��@N��s>�OI�2$e leukemia� us [I1�5 (� m)Y%�a��ceeA�fe�Q�a� ~[ –��.] �,q�n.% tim^t� 6 !�br� Y�i�M docu}R ^i�E"/ae re�$ ,��nu (   )Gef~ ( ENT(3��h� (�A� Beta�̉��c�� %B��&!6neoplai߉��� pira��!�7)Y[12���>E � &�� harb��cop� e?:f to%'/%)%e9�"x [14}7�� ' abun<�2Oi0�z�ݯ��ew��par�E� 7��x�A�-gq'�&ep=eli"�!uteaA&� Z�h"LK-Up͑m[8"8−2eLˡ�ess" 4&v&�9%[,Y��ILof& ��"symbi�� io�HI <m %&� � "��QI�!m"Qp��(*o��u~,� u�@^O��G�\ �in%Do �9  romƚ6M*'th%m�#G!ovh(9n5�ϻ܈=Y"�1�*�-on�lI��6��q'M��N�}��[2��2��.��,!|�N)��k13����.� ofe?!K�� z^_A��.Xem ��,�'�vq ��>kM ( a�[ m�JLW�meaб��Ma� ) [2�TV�.2is exT�.�j "�) !`��1$J��,<<���&nsI���� ���traff��m��M[3�o5C"�!uLR�B(o aci�asidue��inD%�1/%K& e��`Rn arg=�o�R2����Tan6 �Atryptop}D( W:�>B$2 impl�\��6,,��u0�o�Yu=�oA.��b"4�s_ by. ��^"V��nI�H!��}�V�U��*on� co�#�AyHr.&!�.SC�:�5Eitud!%*�!�:�)�5 � t� R%�{�� �witJ�F6A)rM�M�! k .re;!I" ;�i )�l�N�s ���� stA%invX!�2|u}�/)�s�Eupa;st���5Q�esR�( i� *�� ���n%�� /�N� ��Bi�5�&E�[@qgutlook�}���0��=�U��\  �L2�M4A uI . W��~�..ic*6� fic *��AAUT�&$( CHORI-24�,��d� ��&�a�&Texel raWQA�", �t��;6026 �v��qW=��#A�!O�lyW�A�>� F��Figure���*0)Rـf59A��Ewe� ntNzOI�re���U&9 X2s%��� tegy ".�pro�?�v �*�z4e X��'�"&*c3m AVA1ys&˯)D�u�6_six nunjt�� "�dbf)�aT"��9�to%�quivoc� g(��e"��RVqLP�c��e��*Y ,ur*s%�Z�U�� Iw� 5′�3 �� in*# peat�LTR|sA|���q v��r] y�S �nd��1A>jh(�� b  ) am�sN�16�)�Y�� c��3y�� -[g%6��r�)� e�H�,!V!�;F�� �s&� ,91%zau!�!�F7 YIo�s��saY5�U��1m�2�la %�LT� a6QlA��of Ax� � & 6���1v|�e(: "� :a "Y29�� )�kfeu �AE�6R"z k���[2�3�R��h+-��nvev .�2q !�":!-�hei q�"��,6]0�� homojT͠.Yi.�0 ��#""?(a) mayb)VP���v J � A~Ѭ�!/�Y!Z�>dVg�.�!� ��Aq"A1� @ can ��guJ�by.K5!?c=�XIo!+%V` 23;�*��a 2-bp�D�� ol]sy'����� �zP#e5�=��r<���!6�)$.N� . Cu�O19ab�86 J �-�"civ�C g1D';n��Y�1��,s judgIX@!I�<)ri$�i9 �2�.vz�,jR!(�%-�I�ve.�e�A2ي��}(.Cn�!�id�_a-h&m1�S"� �o�[A�!$�$j6%Ke.� N�� n{& J�&� u��`s$�Ca 5×��agK�2�.}ZB]nP�=��5`E�e�!��MB�z�v�/rti"&aC}c* Ar*V M�.%/R� v�C� � deg���b�?w-$�&� �b2�es��_��rdpA�� $ 85%�9%�Qtya�bB�in�lj�vrq�,dus*;$%-�&���;/vae� ��.�(all the enJ�RSRV loci display the typical genetic “signatures” that differentiate them from BTrelated exogenous path lic betaretroviruses . Major Rces%@ween enJSRVs and  L/ENTV are present in�,U3 region ofLTR ,variable$$1 ( VR-1 )Z VR-2+gag ,i{v03 as observed�Tpreviously characteriz�� p�(or PCR-deriA !seque�fr-5sheep!u\ome [14 , 33–35] . The=dEnv glycoprotein functions�4a dominant onc!we�vitro� vivo �(VR-3 is a m)� eter@@f cell transformaf [36�9� None1u �ESisoI%�is study!;!�ed x9 $similar to%cY<9�X. Moreover , we were un%�(to induce fA�A�ed�s�classE� �assays8rodAY(fibroblasts ,ec�with exA�sApplasmid;AAlA�. ta2,maintain an  �ct env open reading frame ( unpublished data ) Ese suggest Y2NcarryK�-�ic=EAos!0A ._-� aualyas Q��$ir abilityA/med���� �u�i�Xhyaluronidase 2 ( Hyal2 � hich!G �naEeuA�,receptor for%�6� , E�ljk!�enda�Q7 5F16�0[31 , 40–42am Only^�Iq-26 , $16 ( whoseO is iA�io&8ԡd D4/0showed titers>�j%�AgE� other Z6-�Q�less efficiently ( approximately 100-fold )A��rAll lI� used goat-�a6^�� vine  , while b. did a/ �M+ very2�. x-9=�3-�!Y 56A1��N��V vira�ain 3T3EQs ��M�a�I�!��or4)j��linesa�h�Ad �Aj8metrial stromal1 ( oST�^embryo� 2-TIGEF )f�us!Rea� clud(a��e latter.�lik!� � de�pivI���s!� t do%B.&1F��[. We nex$vestig�! Levolutionary history��!���in ordeōbe�under��B 4Passoci�I�zh���Xes�1th�~h��i “age”1an�p�Pbe �A��Yasses%�i�/ divergC�,  m)lE distal ��{"�A� s itu assu�m theyI��0-�mom�of Jal��egr � ��accumu be�LTRI� time�e�a��molec�N8clock ( ∼2 .  H5 × 10−9 substit%�$s per site $year ) [43�< Howe; recombin �eOenE�ver��occur fr� �� both%��e s�� C�� tes [44��6�Con)�X, t analysis2 o��%�!nQ!�!�ag a parti)3group!��Eight24M�.�poEd=�%�� ere���esA`5 �  �Sj nucleotidA�( Pces ( 0 . 2%–1 . 8%�<T� S� , resultiA�n���m�inYnul���@Lthan 450 , 000 y ago�0around 8 mill� ( MYA c iED$iod spans x hb7!"subfamil�H,Caprinae [47!�� E�of>�6� also�by"�!whe�P phyl4e��ly u anim�� peci�h. 21�!c�E�� mic loci,AwE�(would imply�.�ev� befor��e spliEjtv:�durĵ . I��E�see � libr �dat� l� on w�@is known&_ Z��:�� ied . DM�t s5t� E�!�� .� mong!/eraa� /or 1mwit�ru? ��U in.�, ly becaus!C) UKhad!rextrem� rapiXA�A�-Qs4!�rva� u Mioc�ԁ�Pl M� Desp�'ɫlimit%q�weUraxha�strib�dA� each>I�dom��c�( O . ar!�j�YE�:2e�5.a���.o�QA�ort�d on�p-�ccoU4 . Samples tes� i� d DNA col� �>“wild ��� Ovis!�u���,dalli , Dall .;canaden�� , bighorn. 4ammon , argali- membc �ggeE\Hemitragt,H . jenlahicV Ha�ay ahr� Budorca�,B . taxicolo-takin%A !`(a ( C . hir Q5�� ;falconer�markhoi. Ae!5� �initia��%�20 !%eten�"breed�LDorset , Hampshire Da�8, Jacob , Merin� Rambouill0Red Masa�+zi��d have� r�� 5�7[47� �PCR1��of9 (!o-10 ) was� to� trolգquaxm�{sAe�8all� eA;ntTen5�: ��!SsK))�co�T| !:�AEFd1k&� \2�������� � ���׭��W e orig����Qv�6�31� , 50]a���early X.o�s giv� }\4North American:�!-�� repuein1y� .~-I�J�BFB R 1;2�!�RV-20Eeqm�4�� ~]:|�e"�dyU:.�� 4�� -�!~.>���% �:Z�s�ter1ng�y��ser��J(polymorphic!��;S� eV61�V�R�E M�)M1 � �O(5�6a�as%�s � an" q� ( se�lowqs� � �v�edI E=�� led� r` *I �u��I0�t+ began�'��銅�:nA�continu�f�)/1�I �  &� ) [11 �Z� e�4a��8"�c"t��(� �s�oXv"��fy$-�m� p* Bos taura � c%�Hor Odocoileus hemio�<( Black-tail dee Z�At lea�6] �)4��� ץ�!` i�,"� a tryptop�residu�Gag$i%�2�W2L�EZ a*Pa�"& phen�0 [2!�3lIndeedA���"���R21��is 2i�`�� exit x�2W !�le mu� i.�F�.� TherDr hypV s��!A%N(J�iblQ�H)��_edN� , ra� t!z!]�en fir���in�a� germ�*�modelo g�5�W!?1Rt�&e acq)Z!"�A y���6d�� . terfB�Cq repl�compet��&e��to reritn�of�!H  . To*�%q addr2`1we"� ebegin� �gazAm�o%�! i<` y ��&�individu,ofP �� ��1bb�ed sup{�� ideaC%>iv� �UL�y �>�inQ�J�"3�*B|.�xhibiM AL:\�,31�ԉl� �ɔ��20� * a� :7geogra�al!ۥ�� I ntr��e�fogQ���� �& �mwa�< four!> 5�se�esa��Z?. Two=�oharbo��n;e1Vq�ine�e�re���� `G!�H!� << 5�5�I�Im&k%Z� �5A��aiA���G\�dx. oN�@ snow22nivI�,.� )�.� ! 6� $:C d���)���� �Q( n = v ZL six:�9�gcrz�%�"�tro� argue�trU6�wd� �:�w�\3m� i��"��>fSub�.,%�temporB inu ��v Pnj cd!�b<2 !8�aauu�me fixi"j �� �DiscuV!6 �ib AKRV��ia6nd!�n� or ewa~!� t�lF!e�s!"^ =tB� d�uma[\q �& . P*�J%��-a��6- �$Ű�1 *?%uwo�"d�&� b] fe�toO)*-An B�m4� 4� All��~ysqA���!clade B�� � �oldes2 � D2@AC 6,�9*of-�(y !Tl!�%a _��A���12Aϡ("�$�o� Q� Rc�AA��.� tre| Am�� tru1Ah_ ����'�(%ouy�z8#4� ";TceN�V��I�,�Joc.e| �$depenb"-�4�#.� :X!�Ś!� ɜYtog�llFS"Eper�&�InB�.�'F�.�!z~� � w! t�d � �i�330\ s>^27*l ��"�� �mZ)o�� abov!�4CHORI-243 BAC &ryE�`(E�aZ �ram-| t 6 velo�%6g25 ears9o�!isl!�of Gm�N%�s~Dl gimA�m y British �v� ed LeicesAN, Lincol($Wensleydal!B�� � Our5z W>s` �d �!j�!`) . Fx"��*"Q%x−8 ,1�% −1�A��%e�ɼ� 30%�00%6kI;A�6�$(82& 6%��1Q� !R�1��RV&� r����}�0�enc���30%�)" � , buc*ly1�4� �Eg!� Full leng9)nd�/=`can occa�8�te� solo��},$by homologDr2�!�m#![�1.>y!a nega� �ul%�a��*c�~�m-.�.#%�AO@lete abs�#of�b(at..��$rul�n��M i�(@��� �}n �!>�)st�&� ��( �, �m@"���7. �,�"�*empty1�p�#C ( ii%�ii~ u pai�e�!�7� ' ���!� EorI �� �ٰS2 � In��ca�we ��!�n�s��� Aev�� 9�&�scree����d�t1�i�-ed 5�oq�1%86`! NAi�Cgi�5�e�b� A minimumA��yesM*U�Ab�ReU= ��"��� C �*�*M)/ F �t�)/A�1562� ��Y�f\&/�UK�en�A�nd US 82��e�B6��Wto�SM�*��� )�V �!.*��lZ�e�<mY 5 M�b��!�mlarge nu� !)'"+!�����p��be!ja�a��% v+��%� is-or7a��("[un��gni4 &� &} in*ng%c��, bloo�1�"� 2+ &A . FortunU,�'.R AedFh�n sourc��$#200118011)�EQS Meat A�, Research Ce� ( ( USMARC )!�,Nebraska . B�A�tissul�)spl3)!�%�al ��z)l �half-ingl!H�� 2 }3�gsf2�&t� ands� (� s #199906!02�Oe�avail\%�����%�� 5� ��� .G� �c o�1+e !�� �rM�u4�f� �.�B�D��nyDa�q�5yM'&A T:�|of>�", 5A;��r�/�)*&ree(l"h3��)�9/t [!J�e��g�&R)6 �^F ��It��l| at�".t�nre1rN ��`�!ba%c�$l��!stille���)r�3horiz: v!�-popJo�T��fIng rai {e ques�how?se"�mi�+bmitA�M� �6|�*. Dh5��aJ4�5I� cul�7 systemefa1propa� "7aO�ue�5] capac!3�;ita��F t�$o��0p,��i�by��!& them��1 ��on�.�5e�.|0#t2�;YiR�xreplac w�@2l'8��he, ��I� fal@mo��renhancV,y� cytomegal)! ( CMV��m�0�"pr J�E�ɲAP-�=[Y�%�vir�7E�a�� �&�5%�vo [1�We"".Eyg-� ��M��*��16i8��i�G'�l�2�M-�� bund�)J;!�superna�t�+A("�7�-}!..�*!�sU" Q��!�5�>�15� � 6/18AHE�>re��ed�03-�4[ ��Q%&� ����6�. N�2) in*�2.!8%)"T.{nJRg� @ �%tn�FE5/:�. S�7Jl��Wco�9!�i�-e� ells �-��aMF�"{9���.�i�8mselv�-rOdN3 . Co�n�N�a"d�hz�dec%Q5 ∼7�85%��9EFP>9�!�RVkF�a�Zl{ =�RYA` .*3n-r�n]�0D ck2~ W�!����e�J%˚~%�c9j*� 2n20i2{'75�2%7l�r"�.4;*i�rescu�!*oA:�3e � receM$A�g1, TU~�A��e�� b/ 1G �3�]ѐ�.5 2(cape JLR . �=�regarDo�4_�s -�non#>al� junk� �..N/��;toW;da$�ix��N� =* mammaliana�!�[21–�:51]E�m =en�Ga�a�ti[4�S�:�] F�"����"��ir��couy �s [1 , �H"6it ha@�.P5tl�7�m*��iz �?� hel[���1e�2X cope��p&#A^��h!(J?F j^A�rp�A �1f�鹾:�pR��wn��6m�$�ey8# �d hlrevea�� *0 , coadap�A �4�ng2 B":��BQB"' ltLi�# favo"m��� e� ��f]O�56�)q�bO `E�"t V@N �e�s��Ռ�"�)� �6�$antagonism! wA�=�z-i�2�le�inuApro@)EA�>rw �qui-iu[:$%!2u:�� �)%�o" 9�Jar:�!�1(�A���� i:.!Lm�a��7E)��7"+&([T+4By!�ck}AS2�*l<�"*�w�Bveia fasc�:ng O!s �<coB7YAX-I��truggle���sev0:"�8�"\ 7��8^ 2v E8� �&�#'5typq>�#&�"$)�av�m ���mp6�W212]"r�@E!x�i�ER� Qwon�"�or -��>�! Givehigh degL�_�D(�Y��5195F��MtR�M�>�,��app%�i�WE�-i�of!H� �<�� t�*���`+� s )a�f"B�*Gag!b9�; d,&�"3of�'�5�( volvA��&j=10�]�27. O"VF�#��e6�$a �)� G,ene upstream!j�"?.�"��� ��A?��f7#mplV.-G@�"�* � 0 emplo(a� w�Dg�a� lapp!�La �r�A6in\B� �lw+ �"�U��6m�d2)qUw�2�m{7)6�'�I)"� A4a�&1=1�e��8kos�\�0E�utC&�=� !S.�f�2|m2prece yiSp vnJ�Oe] scenarios�6 fea �S ex!�g��he%,!420:���!,�rby(-|!�6�ma$>aJBEJ y��ov�. What�8�� ,���2��f��^2F1� es h!|_s1ic" * 6. Oų _u6^re��ly���Bosi 6s-^��$thoughaK I` \%!z2_a�m M$bottleneckDN:E"I Z�Z@��. S�6qqB�'∼�183� �@E�$e Middle El-�!, Neol}>c agr� u) r"~ [52–5W ~,e+���%� h-9&,�Dr? hapl/2 !�b�?�#to�2.�<x/.>�3 reNU+f!��}ly �6nt mt���'"� worldwyB(%�D"9�;B , CAnc0rarer DeUE�(55�CM�(� 0�@� sepa�@A��Fwo hf8#Dpl�( �B'6LMs6��D*�:[5�M�|��expla�Bis%, l��&EE1=ay-�g�O�5�K�0bb!� �;=l�,I����K U!�N�EE�!yAsi� CurrE ��".�.�!H,%�CE�a !�s�6�02�'c exis �Q��� !��&�>31p���-� we � )�eB�6�� ��"-  D�had�.s�Us �P�gu �oSaloiaA�hurra TeQu{ Algarv(%F ,Badan�/}1!N��p�}"�!�Qe-��OPaLm�%�; su�� [5*E1Id)u�se.� @�eSOc6d9H\%c. U�IH��)kJ"P6m*^6]he%�:�f� ! ll>6:S!J�.L&a co� effec3 &� m7 plc=eqQ��\�` is&�E��F>%01=I�-lxGs���Dtim��cy)� qu�R"526��F0ule'r�at,f��ito;WAdotof��C" �*.�.* )���!w�Y �r �.o n&�.�BcoT �.he2�.( I:�.)!-�a[-� 19th� ury� EaJa�$H�4B6=(&�(RV/A�H6Ge[190* 9p( �herdbook����oe �! stop�IpF)7 esta�V&78)� �in�) z�2�0R��'&�)�(� 9��gVl:(�)"�)D�)�(d:�)�:ke�4�� M�1�)K!a6E�6A����BriY� uc&�JC . CosJ�%�z��edi�r&|�)z�N probU+:�%F)�1��. uniqL@�)at��><&ic� ���. �J��Qse*�N��!QN*�%�\� ޝ�e "�$ ( if[-)2�- aӉ��i�� �a�iA�A2 o5M\��] R�e.{�7z(�%��&�#po\?�U,�UnE&eg4n � ��HN`'W�&�W�s� 8 Wg*4\: un!�'*U1�,kUѠ�"��kGei�/PlZge6}Z+�=sui�^e!9�Z-?$ yZ,"x$ ;sh�"perturb�U phys���!�'V�*6I?!o�1 make *��a�9�9u> coc�\!� it w^(b��;�U2 c xcI`Qa�GV� �. diseQ&;�t��/  deaob� "�& ��^!�-26>M �E:�"al ipersis��P!@i*}��1�^�I��=5tes�X� � !>&�BmNed��O� trop��(1�H �^ 0c�1�ir�s [58] . �,D�]� ZtumorEe��lu8-�0,L4A�a�2Eby$-7fi�9anscripEKfacQ!�>e�L�2o� T)�]er1"�'xn�) |B�al�!tract [158–60�f4E)�%�IX]s-S_d $��/� o!A��*$!r�'a��"=!5w�ow (c�`�)#�6�#�5EitB $� y � ThQ� U8� b .�M82�as�anr]�or�!rn[6+#62pM�;!H�U����7Y��!�?e�.�&koalaE=new&x.U�+%( discDhC!ly [6k]6E9Ol�[ �0$�p7 E.inb@mo�*���MhcfG�u2�-^"/[6262Te��re�C�-hJM efinec“� �Ary!hm�a!�.|ngB{M���٭���(eneM_al%�d/eF�W�dic[8^"�d�1i�P ��oo�)��&71�!u�0ra6r1��ed �K J� %-g�e'n��"_bKec!U6,y!r_^nE�%Pmus�bg�o6?� #U!d�Q sidexxen�Xl`V[6 <6�P}�!U -human ch�a!�� v5w,iex�Q�lat�> ba��o�r��qof [em�_W �/��ŧfeM� [69–7�&�0a�f{! theor���)�2> Kbea2org[Eg“��&Y?�'sQ2lprR;�Wddi%I: ,HA eth`(5�� �U,�( ��42�  ]hE����Xc hEdev)��tegA��oFse1�a;�H�@��a��Y�0%���K��a�novel&:kc*�XofQ�Z�� N �`al�. E%'�(,\ �Y�ng��.��� 5o-F�0#m!7re�:s% )�d� }.� l�B�i�*r*�?�1F"e� yir)iA/Q"�a>ngow dyna��R ?r��LeBgH)ign� �[2g rolN��dxse . �&x8I�.�mA��0l yPAC08our���0Children's Ho�[al Oak}A-e]8Ina~.C � , OHAWo� !.�% dures [7-a��'@ A� a 18g ± 4�V kb averag� �S ~O�&%  ra!<on%�-�hybridQ�fi�)aZA seg.��cor- �� 5×ɗ% �%Sustom&+NW�*6�wQV�Qb8�#-CGGCT �&� 2231��O!�kh'� �1CR�i�Xp� �+A�by �$�$!��$�m�?��ify�e�m�'vx!��e�� � *�ein:�})�-CAAC!�TA!�!�CTT:�AATTA%%�%�T%�) A toaPof 86��!a�.fur��E�<�#�Q� .�\�4>;" �/64kA?%�EQ�0a�*a^���d���+ �M�1l4 u ns��&-oA2�IenxAd '926.�]A.6Za.�� ai"w5r-o2";E �p[�JS�]ern�,tM��B"�=G��]��E9���.�E��Aqs�8e�%i�I�to�$%=-�T4E"�A �(V�mB�Qwnd��7 > ��iN �we k~�>�#�Pa�@E. O.YE,5a�ofe�[�3�R{A�Z�6�\�� �!slP_i��Or�M� e�eX�2�+m!��+��9A1Q)F�ci��| w)R2�� gw��a A!�0( i� . }7G $Letc .�Ai 8�BsasiOj� �.a,5uni �C^icla�;� = ~E�&"5#r2� ( JiN_&toy} �oV{!un��K��!�7 Ihes!S}6 �6 8=z 6)�subE�j��pBlueS ( S�a�j)e��`X��*apCMV5-r7 ,��26�� e U3A�A�2�*A��a�%�# CMV b�;as.�de�b� "�o�0 Y;ym.�jne_2A�2]�A���Allf Ore R�T@�<dir!74�u"ut%�err�5*!(-�A�"� 1 �~5�r�!�o@ 69}�[7vnK�H�R U���!!� 3JS21ΔGP�")���21Ű5�*���of�����e�&�0b�ProvR^�^� �oE-e �*� �<��%�de" �U"#y�GRa�!�a+���T�"�q5 !��I�hd iOe�.N0r$e\=!=-�-����/&�1 GagRevR/W-�4-ACTGTACCTTCTC}GAACC� )��7 �&�g32Ua�e?AB��3UcV' �(%�AT�9� �ɴ~i-�>g�Eg( %5A-.�JFgpr&�-���;�= ���6�i� �cN�, &�"�%� ��a� -6A� 1�>�j��A�"(\�km��!�� stud�3eR/ Each ���7�N1v�V�o�WAu�%TA�c�Sa"=1)a�%$!&�N!X_�T �O�k 7!-�, �50Y.�qF�e)y�-��Z��5% �S�U��� f3lR��6�O��a�q��aO&PQ �� teg�,I� te l�b2�5siE���& �U�H.c��JS�tW.�u��(XA)maxTOR!ih�L ( MLa�nd Bayesk?methogSBDpI���-l�-.�par� �irq�,��a�b$HrrA�m !�a�'aligna� �IP,�ra����a�mb�:>�:��)%�5�)�� &Y�) ;1KN<EE� ! pol;( iv )J 8 �`"�)�A>C�X al W-n [75]�|�S�p,pr%am MegAZ ( Las�we softwA,A�STA���4 �4aW�A ropr�1"�&re��@ Y#TA�/w' �M�?�* [76] �AIC[1kaike'0c �cr�{0AtS���[7�/MLU5A�%�t�heuri � algorithmaRITBR�3�*bia r;:nnr %ODPaup* v4 . 0b10 [7�Cv[�c��evaluC"W�L boota�p] �9�%?�^>�2x�}E�'7QU"%�� �h!�5� a%"0YYn�,bor-jo0i��w3 cal�2�ML-�.� esti�1O.R�U�in Mr�A v3 .�k 2 [7�nM�C*�g�r�n�S�*� U��\�y �(Vg =GTR + G�S� i.,\h}�ru�uT!E, ��si),��6o * Eemo�6�Curn-i� Parame|6A[Anm���d�(ry5� step���XAYsu�~!I��d�e� conve��qaRdEsw\-a/<_m0Zm 293T���M�`$Dulbecco's!]�EagU_ed�AA�lv eM@10%b�}serum� 37� i�5% CO2%95%eid> . Vik�" ���%an.I.�it�ltV��"�iiar��$yethylenim�( Polys�"=� ]r�f[8�$Ce�u&2L-�&�uat�z!�48 %!st-�J3�ߡod�#"�)�"�2 � ultr rifuPO^$|M��e�$^�Cl�$Gat��rly�  >K tech�+ޅ9=[3% NIH-3T9�Ogro��B calfM:.`.2�O�8ey"s!�n- �W=a (�AI�(M��B�dur-Eja��%al �i&�i� ,}�Dr l�)� G418��A#(( 500 μg/mAS. �� ���X�4�@ T?�(( T-antigen��xliW%)&�!f"��<A�aA1�72)"�[8��8"�\i�#�" Env!]�+toNI��� uiy9lh�� i�m�{$e leukemiaaUus-�)��T 293-GP-APa{ packaR�=�RSe8a�Po/> �alk�cospha� �:��&[8���d�F�t%YjS6 =}�N�@�Xe"L/"�a�P`v. Sn�nd�1<tp70��62,hnaïve �@8 �m�I��w�� *V� expo�� to 1��se��dilx|�IC���>U#AO�-�jh�� d�)t"AK�s�0 �(J-"F��al�~- �NA 8�=xGlB ` PF�9E"�% �&� +"Ao �7��1 *N � �q1"!�DS-PAGE�WOc7tAO�JeFo�-@)�N��AA���at !����/�~a=) ����.�14ɭ�� F- �&���rabbit ]D5s}8e�-capsi��� ( CCZor MAY2�Z&?r�aAti-dea��-conj��!�ntibody!�mersham��9et�4b� emil�ue 3c(!mECL Pl\t>.2� �qukfT�_�BBm��aȇt meas�]g �|ifluo�P2f< M"rD�$4s Storm 840 im�b2�ImageQ} TL&�(NK�.�(���i�to2�Eu)>w*� Fkt Z I��'�%�s�\mean � airI��  (�$"4 � �s ��+e� "Y���Caa��&�\ in GenBan��@http://www . ncbilM$nih . gov/ acce"nh_%$e EF680296!4 319 .+��diagno1 sc7Lsomia&relD on mi�7�=cm2 �=e egg� �o,APȆ�@!vser"�Q��o]en�v \� .~"^I�N� rout� laborato',,x3s*.i[s �I3 �8eW(est �ai"�G iZ6A%!�< in-h�-real-Ac S5a�&"t aE�2�8S . mansoni [Sm�ha� ob~ [Sh]Aexcret�Abiops!�-Va�&M4A-n+)��ut�Dհ�o moniM��Jt^��ac�4B�F�412m$(B124-�,�$s �, 8�, 194A B� pat� s��su�a�Y]I�, 5 ��-paraA/ 3e �%�1��compa��]�exaC�E-A>��Q zyme-linkAc mmunosorb�E� ( ELIS� �$0)�ggV>E( H$i�4Blo� WB�� ssay�L CN�^@PCRs s&*l�WE��/T_6:-��*%b4%!1k}5%�3�7483�P r ShAoi��S[]5�2�i�)*6��oǐumU'� 7�7 �� ed 9x1 j6"7 q(�);��A7��?��p9�9%�/2Y��$�* iB�s slow� c J 9!78%Q day 30!]`36��D�7��ok.#�21]W . B{cl�]oute ِU�y%niv!�9�dbF:rt��r�q�� �4m WBY ��A� �G�goΆ��� i��]��KeE>d��-r_8d.�is ne�n5�0#o�h)��(�i�to gu�8E)!��/ expl���. Bio�g�0suĐ�n�� Z�of�� 4 leva� �)�YF�GY n8�9xusefulAnN� -�IX�Dlp� 'a᠁�n_. Y+�(2$snail-born%�+�9�Q�6Xc�(&�J, od5�JY�m Af΂ ,^I�1>)&�RinP)� icÊ ��.YL&YIn�Ab�s .�/ re D%��&yun)�9 rea!i Cors!c( F|P� m��t�S120!�A;edKك8B-M�toIs [3 , t%�V�L6�3. = "�I�rF @foc0�Tam; " s� �r X�Gr�zo#{&~��B: ,}�N���!�0e burds�D. A-4,� � =gE1�9�4 esA�V lumegu� blad8)I�5i� s >�(ek)U[�8leaj09gdeR[�V�0 pe���bo��A�sa��|� ppl� *�Z`fP5ac��noy~RC [+~8&�L-� pan�5���*O9��0<*!=:5a�unoblo�  �a8* !�.% ad�;w��hacts "tn�6��� ��� �0�,[Z mP�`I>as� }�-j[�'BAR�� Ԁ.�鹕 demood�:���sympto�� ��+6u)/�D��& �"_ l��h$d���#_`l��#�"hi�wa�S�7 9 75 5!��.z T}ri�{&�?�.�C9�"�T gen�"e:=)�g� �$�4s: S ut ;JTa��PCQ� , rx�!b�'owBX[9��Ex�1 #� d"Einq�!�A�Q����'2 .c�_d�S�!l*� �� s [9g=�A�}& disappoin��� .2e��#evelo"�F&�,Y Na�wv���""� �!��(�� cour[-�r�n�d�1 pa���1 �EA�of2M � bP4�7isA�, [IDa� mi%�,N�9��L�x��uC�%fac�a(!z2>=:�i6& cgb�` O-F��ca���$er [15–1�� fewy��� 2j�"_ ��of#3od 0 ��.2�acuteB�xze� n�4Wichmann et al�L�,v�.&� a2�(��/.#qH( Sm )��M����)qrepet<1��P copy�ed ge/,t!�a�!12!_5%:whole2��(6C2M� workeed wQ s�Y% .�:�!| ��!72�iTpO::� ��fis >s7����l2� �,qnd�y�L, i�$2he&u �:�'.�a��J���R�m��iQ(*z !�� :��t �  ��Ye>�mmitteeGM[en!�Uni�@�"; ( No�"�11W}B/HN&#^o"#6�"1=�Z,b��Hcians’a�0/p!��li��%�m�uanonytBg�. AccordA� to F�h P�,c Health LawKg�6oco��'c yp:Yex) �Y�B%p���3 q �hnN Data 8"|� f�e�� t ToulcA�f��71/ Janu�.20SnM�< 2018)0&�! `ly:�"8a2�ex&�V� y9f(�Blu%f2�� 1j�Go�`d� �f �!)!F"D ��-.IY��ret) qSE�K   � �=7�Au!�>�0��-up!�B�&-n�k�A��4b�� ~t7 ei"�WiA$>?��� .��5���� exts:�G��� -8L!���1`�����#!�b!U�2�#s�a��%8/c|��a.�{ �4�x A��I0od eosinophile .�CProven��.����C���F�&�pi:7.E7q 7#iop�h�bJ> J|�bve2jWB�> M�F≥7G/L�Y��� � gra+a�Hs�Ql먅� :��!!WB%7"q��w=�4G�95�'“ex�wF�jA=�*��.�.!�q "E�A�HA��.�egg}�� "��m��}�~wSF�"V �yA\2�qiz�Pl�ur�� re�?�vol�m�who�.n�b�EJ( :��-� 2G(!�5aU��n .g�:-�WB�.(�gi�~�e�in�N�2�Hon�i-) ���,�0Q��3(u�d�h&�or^�orJU2�,�! M��ic20�aL�Fm �`6!ARY�Kx&����%XmictuZW*Mbt�g��*�). Fresh.I�m�e�ef��2A�@��t&�)(>��p!�diphasic"U ) [2~'Di�; [ H5 �, �B�J�\� 6 �mecha[ gr;n`-�9%JΨlo�� � r @]�'q.��\&p �n2. S��,�iC%j@!�.9IgG��( B� er Aff�yW6duccpCr�]erɟwitzeb�A�.NA  y DeLTest Ki�Sc�xm1om, New Jei�!r�!F%�hemR�H�c%\"�! Fumouze , D"� L"lois-Prk�"2.:N �]ru�!M )}�L�7!~ doubt�Ca&" �hU�)�t!�&�E)�a6 (��t-�(1n II6'!�ki!LD-BIO>�yon�` .�!w.�’IS2A4/" a� L.�i e�"��.MH�9�" 9� I�aT5:s!j� �8n� hund�fifW�(,m#'���<L n in 1 mL ; BSE� froz� t -20M<L!�0�� . ExA. Թ%on�2μX �!n�@�ead-bev[,MH�nPure ��T=DP*]9aT( Roche:�Meyla&V�!=~�$/S a�u*,>�6�I�1Eoor Dp�!UeluH+'nmG�(8 O�MagNA) �!@ct Nucleic Acid Iٴ!�^)!�aNI�Kr�a:FL�F=�� fh�I��y!�i�y9� beta-glob?nene�:�2�, �7! [2�,Brief"O�36v%?1*L"VmixaZ�ta<9"5E��, 10X�?SyB��� 1 μMA� BgO7%�BgO8 i9!�4 m" MgClRA�9��&p �_ L@NC�?r Ϸ�N�N�)C40 �?of 15 s�B95a�� 7e��߈"72 ".30��ei;4�y�iOAXB��� !-m�-���s1[�wي�& ��!y�5� �]#!�( 4� 2I�>4��2v reci�-y1: C!�́�� terp�Rif2�"�@n5�V�es&OYJ�'t%�W�i�'d�*�'!R Y)Sm!)��6i=Q{( SRA>�SR���HePEO��N"B(!Sm1-7 {#em�at"�* [2"��ve Dra1$S:�L�-�!A� h-FW�Sh-RV� Hamburger"�[�� ��Cnops$�lx� %v9B�2v>.�Fas�Ct%�Mask�HybProbHW�e, 52,�M[�+/)��j2 ���p�c M�x �>�!.��IA E�i�F0��&�H!45bg126�j�ar�"��AZ+-sh�%�at�y�i��%���( Ct- + e<45�a�%��p/I?Gݝ Pad Prism&..321{8an�qu=0le�jgA�5th;75thA-F ile�[Non15 c Mann-WhE�� Kruskal-We����Yt�";"@*6�>=oC�� !Cchi-s�e %ior Fishe� ex��!bu�;�p�=. Kappa�U":.�*�/�a|%ō�E�bW*rr�i��  *a�E-a�Ct %�ss�M�SCx�Xr�.ca tD cC� E�d�ys�Yq#*�*��!>pIR|�:5A'NA �#zJpl9�+�.�!)*�<�/ra�aC( 45-�� &K) /:"+ .#*100 . *�P -"p(��(* �RI�V +�255*�!;uHA�:N*�i�&J!5!���A*�%��Z80{(24�Rmad �[!nU$��se����-��",6=u#"g:����JG,��r��f3SV3�� k���^nd -9-"j"V,nq.p &P=�byro�1y�'ig˙Of#>99� 6/� ��82�T2�(�)Q` �&N , 119�Ez& )A{"�~0of ≤3 monthk3 /Y expa��58m"�(7�!a��>�&ta_1un�V;#{��� U<N "��.G*Hh3&�*-�2; 93%J3 s(&_) �3;�-)�")�( �4;c/` a)_ fj� NSm;S` �R�h�% on 3A^m!E�@,"&Ris.��� %�efsubje��gly�0how�E� a�)nw�!j�5.�Fp(�1`�Ũڇ(�� � yiel�*O� 7� 4, u����B�)h>�a9I��A/)��A�i%e3�cx34)Js"1�>!=�+i�� c%-�$.# a��M���b���%w Toxo�;1�AJL , P��ozAI�  Leis3#i6.E ocytozooq�eneusi2; Encephali %s=?qCr��spo1[�16�]limax n�u �2� Bn�ocyst�7���CEntamoeb�#rt�#>� @�a�:�=wyt�,N"col6ZDS4 |fD&lis �� , Giardia[ �,!��)Wbiu��rmR,$)� Asca lumbricoi$�.TrichY-  hiur6�S˄yl :� cR�g2%e AncydIomida*9(Hymenolepis.�3��TaeA/s2� �ZN�5e8��.��&��m108 , 6',aJ7 �q�fa�y6�E�2ũ"> .*�5+ ti�5ܒ� �*� of�m�an.�u�"�*G*�:Yna!tc�h��2�.�.�� ��i�2�M�%n"Q O�ʩ~ I,&�.�ݡ�9���, 13 ((. ��yFr�i `s\1��!+ w=� � ��$5y(�� ( p<�00aS̓E#"Tby3-M� 8NEdmgr�� � �co�p�ۢa�cv.� kl�ء��mN�4�n*�O�t�8 tru*�?�5b-*4+�L2� )��-5MyHe!ML����42�5A�86 >( �7)R�t�%�29)V�( 3�67�6�6� $Eo3|^�,Jc!Hor!��.�)'1[�#"��)�N��I�XdI��XL#:A� hGEfQ��=)N b�R&�!�l� nDZct�2! �, �!80]� a�� � {�2IndJi0F�^)  %�6�&Dn�%^&F ��,�Las �2S081xǵvZ*v��Ior s a%�( 2�4 -di%a'��a�"yq����o��qslyN��al[!ep��j�- B?E*��R.�=�in 7/�.�C"��.QZQ��JicUQ�de2�O� �Mc��!�a��low��IGs�G.l6)$<�&�=��z" .<M�: �@ 5 [17 .� 2�L3] �+us 6r- . 8;rb . 0]� =�019t�"m-a��,��\V]7; 86d 5 [2� 7 d82d0ATd=tF i�1:��}��>ͱ!�8m&X1I��"9 a�S!�isu&:��A0t8.U.�G "�%a� ls>E�`&�2�"� P �p!>�4,��� �8aA99y�%�a2�an�MT'&� Ӆ.���e"�3� ach\&f>3�( � �5͂��!Qm&^gr.��uA�s*� � s%W�'-7\si�0 aneo#}�&�Ѳ"�"6A�28�4uda�/*ab�wl�X*H�0L!/.�*,)^���oѨ�WBa�z� ��>�)�Ev��� in 8a�9A! 55/6v� BQ(�� +nH%��AedA A�uc�9!E5� 1{34 {6�Iiq`�">��7��qv�>cA( 32/K�G�2 ��ed!+�e7 - k�$>& -�M� �*&9>�g��#�!=&)]$m2vomi�K�e 4� ���� !`� � +2se�_I'��`���h"$[d,=�e �WB;8x����T�;8� S1u�2WB-u�:O)� �a�m��Hx�fgrey zlA��6x�weA>l� �*a&-to%UE1g:Am�� H�&)�?.!)dis�^�26)!t6��.d9y ��6S!BeSA�=n,.B=aŒ&/ peage%ka>N of 7=�Cnd472�H&0fq��* in1�M���2���M0u�q�7Xfţ 23/3��� 6� 17/3�2xEin.�77*tj� MG�2:�/E�!�T�H"����o!).p:.q�qp6�V7 M�-*-��d�[a "?��w��.b�0��B� ��y:� ) : 3- 9 [3� 9; 3�1� 1�,2. 7 [3!�6 +�y�4O0 42; 424.�0� 13� N�7rr�!v��!�R�Y�&� (*� = -�1341 ,}26� ��%��"oo�?ume�%�2�4�Mt "}"( 85%;�� 70�OI�qu6s 5 WB&MQUaɟ͛��9�)=�;> ; aPHAavul�/ ��1�� x UUޥ�ly 1/5xH�th��,2f(�. 0�#-�6�.^17/18 (5I464%c_-�� Las�(, 22/32 ( 6�88;z9��to#�Y*�2�. ŊIXnd!:t�RT Rt"Z�, sm�'.+f(9EF. 91;D 29"�  50 [A�91;9� *��< d 30(;3�$648 [0;1�~(9�I��WS*��VT in 6 � �N6� r2Y�( 1 &ga�.�0t ���/&h-.�>�f��M$ ��u3 & 5aro!e�=a�LYGi�V0)�d W��b� 27a6� ~z, .�+ unex�{��e.a 31H"qu�E�&|!Cs�`�%��fv� J�}3M �t2 .�!�terA�)[\ :c su� Sh��mc" �-CR%sli*l9�g�Ai!�� 011/60A:a��M�8 a,�o�BatJ�}�U�2�3��� rough�6��� toM�"�3ngRin 21/4��4��v!:0 a��R!�:(EEf7$X ����!P�y#h:aaalloOJaSki�dE�&�"�Na�3&�#,��"��t%��A��>�j��"�*:6�.*0[enty-�'�K�vae&�$I*�o1�� &O���%trIs �prazi,Ve�6ram"14D455!l=��! :��b��xA;"�+M�"( 15/1�nQOof'9iP�2 e��)6G �7:m�UgaA= �M�<�OT v�a�"�B�%&�(S�>�z ��& aXDi�� .�ly�ǭhf�/60)uas2�g aB�P��)-6)�p }= -|�q�:D�d�Pto 69��b�2# 3� Fi1vA�>"1��I���m"�#Z�N( 378 �)J)�ED . By���a�>���*w;�E.�: ���0(Ne��U��u�\2�y%H>�$.�i�J� �96%��hFE �t! !�up!�83%� �e -UI�HA5�iO�2�f�e�q�.�et4�S�to 86"�RVND 50at 50%>�S^Q&vd(� A�I �7[��f� w~`as \�R��b;k�E!�"��� failm4 , siu��5HAv#�1/1��-30En��r��.) "z� pƁ�Gbe�i�F . Fo�{�*O�c��&�!�woY*�%Q�)-!Q�[!$/wXN>�&H 2�l stiv� �52 pay 83!'�dp!:�>���D"�ъEQ3� ���1�utJ� ���"��I|QXd�q0ѡ�16-�� �F�$ CX <�3&Ay��-��*two2�!F�\='!����6�*� +J"GI�gn��G�^A��7X&i�i�G� !�� b�R[;um>��  (� h�e mai���.v��B��Zi$ 2�{��906��1J inva�4�<::U�"�#I���^%e�e ){ed [2�P&�GNGir2��O4ir�arZ�!?�fewx�!U�Q� �GfZ;d!sm* coho�n. H���d���EMis8E�X�ocu֋��3 C+ch�� -)Lx:a� �*�K�c � *���5\�J� K�s.����-N�as��gloa�*�,L�= � %'_�"�$� ur�"�*� �Ae�b!N�WC>r ,6�+��f(e?�%}e %�]�=I�D6�4,A80f�R23)/u�a�"[!'�}�I s*�.�[�4S7 "? *��/*-�ɞ*�ver�EaL�If[�5H�,v& A���y:�YF ���<: ! &+!�R�e�.�v��p&n37�Cǥ�,I��M�Xly��h2X���.H�^�fed��y���*7X��(�a�O�^W� �4��S ��#5�i�b�A�E�\-��JdQ������8rZ\�y<:��DraM�5(!G>F36%A,!5% �݄on 40&w� [27]�(S8��D�5YRi. lr%�meT57&#`[28o!*� �bA���e�a��Ha��h�#y-!$�/u� �%"{ �*�Dcax�M�hug.���<�=\T.^�O]*�a`.i�d�r�,�7&�a�6�9rib�AaM2�l^1ē,K spacY<U�TS�Y�(Xi2��+Ah� �rim~`.ma9.?W!�i��eQ/�-l%a�RaT]���!�A31��^��"Rri� 8U�!�2#[q���0 94–97% -.�#�, 3�N.]y�eA(Q28S r� `$mitochondr6�)t9�a�x1Ab%�a0E�anecd9-9�>-�o���l��e�i��8AlW��w&��%���u�orɈ� ��J �E�7n�m-|�A`Y^@a�!�(&�=C�fa*c"!�!4�G%�L"�"� . |��%�"��episX � risk����.�}6\.:A �5.>�[A�� &��w&� :o bypasD#daily��aV gg��ߐo�B����� alyza*a}Bs.�D *G�3!� secu�Y50%Aus��Jm�A�_lsoO�g" 1n� �V&�%�"��.�aYnecessar�b9a 24h-�]a�ʹ.&H*� alid�4�%��:n.�+�]r?t=�"U� be d� �+� ���iQ-!�Pi�&� !j� �If�G n�&V�\2� �v�3 arse� ,�S��y%a�:��iU�Ga�JJA�k �_izU�� v���(-*�F�a�",]��nr uI�� �1�} 2.e�Fi�moAu 6� @�wedQof|7Pjg�a��^E%ab�!92Jf�&� �.&��2��"zrf)A�qhe� n � �.�e"m L!,eީ1��)"�5��.�*�e�i�C�Q]e� 7|nd 49F�B�:& �!'^�!%B�/F(1�]B�M�!"M������!չ�a�~ Μ.>[�ZSurpris"��7J&,IAi0IQŋB�!�.0�cY��.~�6�3\�'�"�((F�� left:�"K4F8 !]���t"PK�-�0ut� �&:f*x�)S@' ta��aQ�!�����=�6l�6�* �c �!q�u"u��*�+y , the�F case was classified as excluded ( Table 3 ) , although true infection A�likely . Among WB-positive sera , the frequency of !LSchistosoma DNA dete Zin>um�Xfound to be higher whenY�ELISA and HA tests were concomitantly p��th�Xological approaches for4diagnosis of s�ia�se two�H �appear�$yield more1t�antibody�s�c!�of ac%F9o , compare% DWB . Indeed , most�merB�patien!ith2;@assays are expect e turn nega� [5 , 34] !#@o have a signific)klower�(titer [35] ~$in a variaA^ period af$an efEZ@ve treatment . By!�0trast , LDBIO2:8WB IgG is known!wpersis.kcV!�a longer.� than-8[36] , probably/8several years ,a/�w %�Ez��.2U�E on%��31�s Da.a�7 Cors�X�Vgenotyp\ !8}O-bov��a�1p3!9�g2!-w�`.�i , in� a�-�� -k , Sha4� u�U�and/or�F,]�Spe5� �is!:e� b1�!�� . Apart)DassessP=�[%���%������e��� heir��evA5�foB�>� ,� abil�A to discri eU� ongo�or9�u�I�at�h��be��%WB-� UOI� ��ajaly��T e tial�a)*0praziquantel-� edY strikingl4 :�pot ally� � �C.m circula%��A1,out any link& a�i"� failure.~ 27%��� $at 6 month!?� 8%E�C -�an adeq!� cVa�i��, nA�ofA�s�X�Q1 d��g#��as��s; ,whi2Bula� "3 r, {���,ly�[hd�orA.�& Ya,7 �ti conv�oA�.��$clu� , o( ork :W�*�ed2�"i&�,5� mpro1 !�ki]�u�5!ba[��� " �. &� comb�Y��z�V�mj ributes� ed v�a��������F�to gu�fu!�ݭF oq o�&< V�)���be� fu6Qhe�v��r-� ed m�c-�  ti-.iY/(awutY�aas a �E\9XJ *� a���[Mach�� 6��N ��!�� onAI�4gy surfasto!jed� mole$r dynamics�a�=EG(small systeWe2��>�Ua� feasT�� #2� structur� �hlex�� ta�E�na)A,@duct Archazolid A�� � inhib�Lof vacuolar-type ATPj,I !�$myxobacter�Sng gephyra%�au� . Our 1kes)]A�of newE��)@bV oi;i�-�="gcal!� 5$via GaussiProc�reg !�. Predi0^7isI toa�3$a2�)���rpo)�b^<9tro�trade�7Op � on a acye�!�ut́h peed�.�E�-0���94� d�y funcal level!ithe� ( i�it sol��h , DFT/BLYP-disp3/def2-TZVPe�mea�0bsolute errorE��M��$1 kcal/mol�awe��& 2�s7t5 ve m3ney�C �d�ope�R , pharmacOe re�t%] ound u�� nabl�]coS31}:%� �i���es . eqb(&wegLof 739 Da; Fig . 1 )A[a)-nanoma|�� ( V-m�)�f�-prolife��xA�Y R� [4]–[S Its 8(ral 24-memb`macrol$ ne r-*t��n alke�� �methyl-,hydroxyl-bea@stereoler0 Th� full!���KUp 10hemistry ( 2E� 7S , 89Z , 11315R61(18202231′S )v thre�-E�a�E�A }m�elucidkby Menc�d cowo� �[!2nup magne~reson�( NMR )Arct"�!@od�I%2 ) [u A�moni(a behind ML ��"QMAS�c�� Je`ofA�jaxp�6vet�dDc.^[A,lm��Ct� place s� "�2?.=�E���wayWdo�isnb*t�ing�@ a se"refer2k- trx-�yunderlyQ p%�be%2similar Epc����Q�ert��(X“2 CaxHprinciple” [10] )�is�ac�� wellfin {Qoc���� eriI ���<$��I�ed [1�ML r%� Z$in diverse%� ontexts r�� J^�U[12] o����$tomiz�?�ŁTss �!c���� spAH [13]A2tra{on�t� ��[1VML�͏�� j*� %� pursuedAcQ� 1990q�ar&#jnej neta� s [3^[15�:17&R1L�nemetricu��asr��eWa�ll [18k23]! u^d�'rb lF* aku data�o itsI��, � ��i<ɬs%�nf�z2��requi�ac� toJ� . An�"re� to v� ia�et�u� f�#nu���ba� �u2asB�G��69� ��V2>�H���� nV�5A�lex�����8in�e�.�6� . NoE�atBm!g$E8-)!́`A crity[nG of QM/�*%e�presenz &��a)��B .E(I$ choiv & de2pq6:� ofte�$�tsyma0&� qg���&s 4r�tA7� odicy�Ado�sc$toIr*� �r2� +terA coord'` )"�%K b| �m[M�� cedua � xampl�j"� x���s [22]E�lo�&�K���x,]j:'them onmffour-d�'� al un� pc ,�,eS yper~he�%l A on�u coef�&*d ffa�]bi}tl{= -� cor� �_q�A< o ob@ �a�-lengthe`�ubic roI�a��� t!� I(Z���i%Ymatrix:�a�4n"� ch� s%�iM-]�ist� �lyɏ . St�n'ai��2� .�  u� aP� c e�~ublish�Farè&h� ,�'g� ` P nsem�!%o�# f semi-empi)�MDAM1in VAMP �FfdifK t��ASorAbofps -�� �$t a temperi�400 K�Rns���h!Od�%pn � . S) !���r H)l���C ya*l�.M�� Nde-�in�p�d7metA�[2�+[2�$MD snapsho' �A�\��AM1!/MOPAC [2( F� opti"�of ea7 �3/t|.�O0TURBOMOLE [29Gapp� {@ ( RI ) -D2-COSMO�SVDFT-D >�. A28#�,.%al 1��͜ [ �!�5,M]6�3.�%( E 0reveaaa broa�+�"bu� !/ner� span�88 kJ>(� S. W�%pro"� �MD6�ɕY &ua��fl?iVru ��*ge w , ex�! ��trmy 2a��G�W(wo5 -p�>(�100aK. A��5���,��~a�W.�0�A� favo� c)I.aP e �u NMR-motiv%U� s nmd5�+5b���( n�+-[j5'e~'U���bei :�u( <35Q �n�%20%2�LgN�=>u��J1!� }yu�9�er�( <20o . 20.S%o��� J5U!.( X��toward�end��u�A�:r In summar� -FYs� �V!�6 �P"e Mo a7:��JQf< i�2I#2 � q��'5�Mq�saT,A�� A�� e�? stud�_��ro#+ nt f� &$2��"h� conjuge�dou�boje@.�co-plana�%[min�H�sYH��,3� -hex� en moietY� s 9%<16 did� howOp� & �� 6[aa$� 50–60°u�A2�in�jw({1YC�em�s gree�)�^V�� deri$n�� -k9�-V�E/ex [3�-[3��.im�$EI@is .��bio"Ax0+P(upB� pre�na5�-C��onshipM� Nlz+��og� � ighl!>�e C-7"GA�y& �e�oph��[�"[3X.W��us!_� �atW� �2m'e�ed�u6�%=e"cyclic9 aYo%�w�.DG�fV3s QM/�:$8+�� forc�#el F�we�I2 800"� q� �$MMFF94x FFa�!en d�dI�FF"! d QM O-#w� *vgeo�� asurE�eFv%#l.6. A��4��wUN[8lu�%�-�6noB�� . Likewis�a.dZ�!���ZiharU3�%N�( <10%��I��3 �2�R/ r��n�li�i8v�� ofxa�Z�. OB:54:,�2I[( R��i56�  �.a.viZ**�%'edN L$y landscap�# proj�/nn61s�%Abz �ur>wI�p#�&omp�"�" ( PC�` .@ *���re����iJ�(rves global�/�_see[�S�nS�-S�:S6%&1e �stochay2n� bor /d�!echniq;-�r��&`1 MEtwo2�1]o6we&?: adja>o&�/ conn�; low-%�y�c*( blu���� .%Pѯ�!�ai� .�9C� d008 ,�A clo�<o(,!�the�est�u�" MD ru:���e.�to captu�$����`qHhaAa��aA2�sU��~42ee�e83I�a�.�E� enco�#I��,jy�q&solt+J�Z�X -�ic]$D s� inputI�e�se piE�2 V%brief�ff-E$4el6����o x�5�a���A�miH^ m�:F_aa]T|e j�m}! tom-h,% q"-�.� auto.[&t s [3�}>. Dao�d!r�o� n��� �9A"�cl8e�iangu.|1)a9a?Q@ate|:�$� 64412�vec#"�j<� 2<Q�.�" &r':isy%e?( 90%5% , 99���Yc��.di�AX<��,25 ( 46\ 36 )����!�Ru!����?�#a��<�+�$��a|i%?c��,�"e[a���.89�Q"YeeA���1@as Krig��,I�>i*@$�U E�4O?$t over-fitv . GP� tak~ �Wm�: )�� i-th.��n�y , �$A�&*,a�xT7'6Y%��6r%E�a��J�k Lkernel&�. Ko�;a coUV�#req��a~v�$finite,�2mT ���b�g\��6�mj6�M�b!5�+�ua�!`lin�C �. e9e�-7�GPrs&dA;"vey[A�built-in�m�dom�4&p+Az %:d!�7iWAnfdAe��ndivi�?)��  . ReQ"�<��"��/ *Z�&�&ll�%_��10!>et�$of 10-fold��a'� ross�.b$( n = �)"�=a root!n squ�5N&�MSE )b5� 5±0 . 72�, 7"$8MA 73 . 51 73"�ɜm.:M��of R2 �v88 G 03 ($ . 4a���=erploiI#B,)G{ %��10�E pl���8l =1ŔM�� ,-��y�VB *3)Wy�U�b i!0!N� p �/�+t\0.iA��-  ��~,�. i�W AC6�by ws.t��q� , n�$6�< ]Ac��� el�/M!N! %n&���.ner loopsB� ( ne�?B� See�iaQ[37� [38]��detai� U-a8E-�+(�� �~%� tz6���*yc6.�s�B, [40]�ew)�E�B . Al�I� is���)e��}W3�.R(�ul��inA3�Gct�8^+<freedomF'� &of�^9 �+�&".#B rand&%$t�I( ) [41H0muAlabW6.�:�A�^ �ew p��53of� −3�8Mann-Whitney U-|A�� ��mEF�!Q0st�|2oy�?(3f�]ordA�of �' itud�G=D���0GnP�"6H good! �a��of%gi�isuA+�e 6F�Xi� .l&M_ �/A�t�#p+�.r�F�Is�&es [1a�$umbrellaq[�Ao�?� aiss� meta";/[�@�<h\af�/s��s�-��(Ej�ca3w�a�B}/?,)G3s:  =I��&(#� F�MD$�����!&��'M� . T2��al�aect�9Aa( R2>��9� � 4�� �&ApC[!2��� �i�o2���1��:,l�Ed� w!m�2N |>��%!��"@��%2�)`� =seH2��775E�10&<q �j�1x��:�+ly! ro�1H��!=est)�,���,2.Vat)�^>&>� �A=&�5�8<�ZJ�5�( u)�,� A��m�"st M+to���e o ��y;͛am"=2�an �%{� ��ou �n1fs 1*!m , itq���A6h dt*bec��.�v�.Km w�=- ed@+;a�tr��o!�i- �be�6j"2!�.�anA�&���4:L5b�1by"�$� � B*5�8_�.5#M��spo:rough!q�� situ��AXT�2!���Yom�'n�adjus!��(A���$44]: S�$�a�4�5�!H�e��  >�3� ec#w&qGM;� -�A' . Ife= �dd �2}��re%�Q�� adap�ɞ*�*= ����^{ [4�CWA��b(;p&E ��}�:�i� e κU��5� l�JH��F�]e�2!A�i+p!=!�L7*D*κ%}�7d%^�4 �:3" .?E��vin� �! &� K:� � F�24. U X ii(� ���Anof�6A>Q@La J of 4� 2� 41&H2of 046 34]N0>%94 <01%u384±42j�mF5± std .a . ,� d:g 4 ! <24@ %pM�2R� � � s�A� �@h:+sa��23�9F58?� A.�27( /glAhreh e` dd&UH��at�*E�Bayes�7:&-W �-�%;=�=�egA���hip&� &�)&J!�QM��1�N%%-"�!6����+wre2�%?9&"Fp� al�ˡ���n� �e�6�6� n2��͐BTA� � y �&s�oa�b�7� A�1�2O Rs� B�n u9( ≈*8) "))W GP'sq#.4�u�oT;%��= E#i(�coux'm6� (�3"�;���3ZA2��<"�[A�\'s �!R)j uo��/�9� y e"�+�;�ds��.X�zb�3YW�F�� �Id,Uaj* :& . To avoi@ess!mgA"E�%5�f�Wqed grad�-��mployE4Z!&��%*���Vily us�a�MG4 CarloQ��. A��q �e�;D7Z�4onn:bis �!j�M "&y so far� !.a�*@/#E�t�Oa�WM4��$u+/l0RSi� �5d��a.�XJAt�ne%�ty)����&��Q"vis�C �{ ��i�aIal�|kH5-60i�&��H& 6��#!��6b 2[� = oG� . Ac>&�;[�J�K %k@A � %n!�])a�� noi�a� algorithm!;�)Fc$� ntegA*�L,�aW�-C es%9a-�X��E��*h�nF� ���C"�762�C�v.Ea�e�b step�2t��u�B�*�?al6�-A*z? SB0.�| carrt d+%V0�A�,AM1 Hamilton��D0,>0A�7r����2G E��)&�,byN1�<�eO^/&>(��"Ey*2993!.�%R%-fR%!_MOE ( M5�O�05Environ�, 2011 ,10; C�<�3C .Group;on�B�+Canada�j#r�� o2!lyB+:�AV.$(2R9l. B8Os� �96�i�)=:!G9B2)�D>��"u /�F �.!2aj2�� 2Mm�AU an NVT "�2%�La Berendsen heat batDEu<2%�akf 40 ���@! Newt�Qu��.J#�veloc�]Verle�B�Jith1 !"�a�  < �pA�cl�6!���.6g nMax�;� "�A��E�-rmoApum!48�2�E�� zeroY�+� drif%�"R yH�C�! �BR��"{., &&1�rec�dW ry�N&U1�F0G �1<51X;y npUar'toA�#H:lib*��a�8I1�QR 1000.4 5j&0 �( 1�1!):��!�%0 gy}'i MOPAC2012A�A"_5( Stew�V�E~al�3s�@ , CozG do S�#HUSAb � y�C A��[u A��o��me*�4ct7�C!Dam��-� dielf@icN'Qs4]E� prec�se� ��O.�4�T� or 21W!m,��e�979�wA Subs�V�w.&W�2 2�)u&>5 ( v6#>C,8GmbH , KarlsruhkGe2Zt5to��o �Z �1"�4. G�*6�j�6e��NBLY�5^�5h %�A�N��7to� "4aY�9631�d6eo9�.o2r:a�Mof6����ex<;�vi7e��'��+� wU[i�P,Y�-� �E�Z�I� F�`aeVud�)��lwMinHY�0k �6o3-E�*7�6�p! u! third-*# Grimme�/|Ro=4r![ �S QC.��:,CR!,II�Y4 Xeon E5440 ( �83 GHz�D(00 MB RAM/cz�$�@e722ldFk$AMD FX-815fa-6�e36�5�s��1H-A$�4�w�6� Hassfeld�R. �0%"�Z!'s3%�&,1of�]silico�6�eQf�%� L2> �kJ��*�h�&Af)]�=a: <5 Å�Iweak , R �H�!�g�al m)d �jsup�G (���h[ A;I��#A�ɥ�w��!!�ecuNat^ts�Q�Eny noM.� ,Y^B2Y32��0[V� s unqGE�� maxi!F!�AhE�Dre gi�i�:Ken�(F2e"G*W)v,( sor}�Gescene� r!�@�Ta9eOW2�/"�'x M�$��y�� ci2�11Lh!$* �%\�� od .*iw=3 2i�6�12�e��r��MaC�[a- er�79 , Wol:; Research �:z16�5�%�c� eyY�3o1D"&"�IA��4�2�.� To��)*�'ofq�fe�;s'A�g"�1aub�r� smo�hjj -l�3s;AFri+ else�>[5�In"E0AX,Nadaraya-Wat�W%or [5�/54�%"�-Q+a�)�o�  l�D=M3A��L�%5���% eO�a�P(d bandwidthh �2ez5�d$ce rule [5�2�zMa�Jy&[c!�S%U"ne!~=QE��-I�!>6�8software LiSARD]�uy( , ETH ZürY: , Switzern;��licD�@'lntact G�=chneide�E)2I�f�7�Is � k�2���5��  ())\Se�^�"]2o[5�/[5�CANA��l�9��-���"?� �RA�i"�Ha"J.�'d Y$���: 2��$�B!"�-&�.V'e�;e�a�2“� P�%�q !T�+.6$ bA �Vj� =Zi� v2(C�*-�m:-Y�po$9B9�#&�or;0+)A��e�0]�􁌁o\.����(b5!�Inљn�Gor^#�cndL.N21�s>FLO$ˍ;��ce&5p��&�Aw�%>"b:�) λ>0!Ra�eer-par���%�U!�re2�*str�H, I=�!Wtt�x� nd y��!�&�1�T(i�]��.�in Eq �F�b"Y.*�GP5�-e�8ikvalUx#�7of1| ridg�_u�[5�bod ��(>��GP��0MvR .�22�6r{� at1#f!/!N267��WeI�!xl:�1MDsy�� $�!^d2M_M{di\@lea�oH|/nt �G�!em�(@)�*2,BTλNR��a�m��R����%ymVA����-�+Xd1)�,���7!�Zat-�3p}axHtAHal$cS�U1 mCby!IvSb 1"track���Fic�^if� h$�|%Z�FA��i��siAhGt�9i�nk)�!eac�,)8�-ild�\1c7ASffskai�at2!{pe���!efa��ptn�cplt��Aco��i�4%ׅ��Use-fat���Z�s!y��,ch�� -� a� k :{5p-�œaZ�Yi�q�� s��=�a�2�.� q�-6[�[3r��7 repeM��^d)lj���Cf !z !�!o:A[6�360 s death� 463%Z� in Gab�n�G e Re&c�Ccw�6oCano6�6 1994�7]aM)y�tl�C�.��&�M� ef"b*�~M� �)`�i!h Rhe� �V�9��7s urve� ����ro�"epizo��s�%�Fr�al Une auConA'� of N� ( IUCN�Qu�T� ḯ�mGer��w 6  ()A�c%\��nda�!��biiCI�9MM6�#9 �$pz�Ya��  �`># &5 %S��nonNma}�A�� &�� .� |A��!���Z qch��nz�< ( Pa�6oglody})A�:�[�=�a,NaD"�8ec"_ �ey� 6C�re habit!.il�L42�A�a6�>A�= �[i�)d'o� �Fs�n�!lN w+ ��)\a�Y��a–Ma&4rde�sR� at� !>198�Tx%,UW�i� drop�g@�+l56�F!�&5�x�R� ]z�.�|�iHBac%N hraci!5ma�Z� Q�mor� injI�!�2�<�aDH�<w&"†9bo.)Y���#,�+2� &� "� �&&CMo: �(�� � ( 0�/�VonA�)����ng1>"fDoѫ.��r�=�i�ga�*��p`F�.` a�� i24&o})'E�lab�n�*�M� ��&QR: regaj)pr�5)5logi>!�n� :9"Io`�macaq2@[1��cI&e��)y/e�Al+��"� �colz'!�bl�?%i{�mU<V2n-w{:� -S*��� �.�!�X��9]XdE��DP-A>J 0-�a5ce�`viC �Xic acids 3�^$�im9.%�odefi�cy?us5)I-,o~o! Seoabhe��ti�?ru&[20��`,M,.�@@V��0sbl&�a*Y QWaUvewla��5� �"� ssayA � 6���a�~u��)k*7nus��� si�|~$!�/�$I�{!� �u�"� h_5�.Gbes�>׌i3$�.A�ad���#��gD \ �J .DB�G4)AprZ5�^�t8-=% 9B.�. E!5"-!_}*�uL in 5" _�3�I%{ �z�R20�<feBYo&Wuni*2q�wh�;f"A&��^͎s"�=2%&3�usR#9 5� :���p.�at8> �wgmb�d�!of RT-�u,M�his�Rcm!�a�y�Q= �0(In June 200��15�3e$+2j%EB1d�22�5 walkI�ymF�� "�!� ∼10 km��Kr + radi��BHy 3�Y�a"�Wpo��?$ad� 6�vi�bJS by 8q j�is ��b outhe �aNMam�K Rv!�&z ern-�C area30Odzala-Kokoua� �b$Park ( OKN}q!�%F^�yj�ac`MV*.�A�g~�[%v�N �� Mz>e�s$^4H9�yX"��y} �teams �;a>�,�'�A��K6!o�fday�a��'��yH pre-�mr�,� ��g9 P�oE�Aa; tinu�+ logeX�M�A!uploa/) Gap 12XL; ( www . g .d�~ ^u�&r:I1�AM,H|s �� inIcB�!'� E�30th Aug�Ao 8th S!(k 2005 eg45nc�U|~op-��&�-^-no�T�!A�A�6��A�B%��l/� wF7�<S JarO-&� May �"&i1fWhad��:.! ġ�92�water C . Te"jN���A�9�.E. XL6B EM�� n��%��Kso��n)�1�D U.= � mamm���>�thLD>�Q�)�uspN!�Wg2}Socie�$�P�Y4t Espèces Pha�j DEuropU�[a~FY�5thaM 11th]70�G.K��Jcc�Q&LJsey=`e�J^` �a�,un;a?KPA1Uhb� s�K-abund��=e9A��:&"= ,Qi�'dec�!^4b�!�-o��-]-��O;} �ethE8[�!U*Dz-&f&pLgami�2�hLasNb2���al�Jl�Cy�eхI1�'<5��o Nov��–Dec a7 ( Z� *!0March–April"8"3 Nf,��i�W� "��H�!d��'�d|52� � ���!0*hd� y��:�,��n/uo�+� &��[�gr�-�.��m2�pe]�bх�7�N C�VS�x B}!Z25^k. S�-�>� �2w�0zo�?�Yx�vndA�g� masksAA� . A� x�l� g�fresh $�ev�; 20 m�RNAu@TQia� 6HilԐ,*6'  5:p�0c screw-top v!(0��'I�-a�`�7  , New Yor�1�7, sQM��ParafilvPetey�&enashTi WI ,9!"� zip-���bag��sto_;mb�%e�g( 28°CY82°F�)��%�)reX���5eiC`JNP�B tagg�6e C�Binu�2 -mB(u�neWwE�oQuickCh) XL Sit2M2kit (la F�� a JoT, �c�>.2�Fil r�i-��"e�!z � �s)c� ����'h"0embryonic kid�� cellz@FreeStyle 293-F C, C�!og NoG[790-07a��O� In���,(�Fsba�JC�=A� grow�'m h�^flask��37����8% CO2 �2��da�MC8(.w�$! E9 His---�E(�,by nickel-afo] y ge�BNi� $harose 6 F� F�6( GE H�c: , Pi�ZaA , NJ�h�el{J%�(400 mM imid�-�a�)a͡��NP!�E����]d MEl StO?Bradford~ /Ayre��Aj Bior%}He��@]f��pe"b�[��oen�I9W6� �&�!bo�\/ )2ae�E ng eu Flu��5-�sTBé"Q�s5f'a�2Y6N(�o�%�p!}��&�*gHmasc115 kDa:�<�.Bo� ���� �Mex,�JyA�!�xOM�!]m�oPB�I�=e�9plus 3~ndard�J�%=5(!�=Bl1|)�A5'�Oa8%}Ao�1g��ubyisA�ofw1dla*c�uncer�A��9L :���� (��2�#!�P� %ls��� ���fil��!q��ed*�-ft�1ne�)~�JRNA iso��""�frv�5�%��B���RNAqu~� 4�g ��!� a -uO�,���t'. ?d�[ i_B�l%�?7�#L-TTYCCWAGYAAYATGATGG ;%Xa(- GGDATTRDRe\CCA ��k*YQhe�7�k�Y7h ".f %T� a�sekeepv )?ortIR� 0e ß-glucuron�<, ( GU�Axl �&( AF084552 )>�A"7 heA1$E��>�E�%HGCTTACCACCCAGTTTGAG)1�-TGGGGA%!^T%� $�0�����f�d(TCAGAGCGAGT!�AGC:cG!�GGTTGTCT !E�!��a 2532�*T���&�*�ok/;e�c�� q6�V9�n�8n�knta���E?u&4%� O*F�E a� A wD>-�:ce"<:E% ing �/hs5� log-�ih�%r =A7-T>#)wp�:95%!&C=3al ؁�og>!Z���m�. I�'�?���e.�#� u&$:#!u<;$DY�$}c*gh�[ !K$�!s2M**�&"�1 �b��?7 !�� enou��� J �2�.e�;'Fal fal��� �(��. I�#s�&�,)�6� j� &]*� i�!�� "�7΢��� M6�*s-2�S(r�&-�#ed:x,SIVcpzAD�&�NN\i !a�I��� 7 �Y��-�.-AreB�92%[Re0`!��XV�' d� �'N�Vn=b&ٳ.�E:ah [)� �Fu} 68�-�] ac�C�aAe�:�m`( foamU(Zim'6�-SF-w�U9r!�!` 5`!�`22N.�f*:%a'.}��73)�75�=}DI�A�i�8%��tT_Oi�aE*"x��e!st 6�6 �!Rocu�w�:s'�ptg v). G�HE�i?mt� 5� ��� - �!�0P �ayZ)I.�-{!���� ";�NP��.��R �� UA_su8l.�i�%�t� uX��M� �^8�2 uK5YXAa y6|�VY��r��#,Ahג>S�:"�!�!���h��o� 0�T^al)�9nXN5 �Bon2+�40�<NP�u –[�n�2�)e#�SD�PlM�2!�з*E��?Fig��ɇ, mi��"�[9�C=�&_4&pa�o�9j8U�l9�S;)Je �?H%�i�_�/�Icf|[i3��M�'t.�At�b}Y��fcy� gus "`.�1���6�Sspi"�ĉt ���A&�� �cl�yE�" �2��8Iw�<�a � �co�AC"/. St��� +"m `, laI`-E� 6VNP��9E"��66^O(kFe3n Et�}�8i��%--F�%g��T�-&���r�AS immoAYNP� Ԟ6\I�E�)��"M���+e�A �>55 ( NH5*a6�<105�u��a��n~̡�a�b�: es���e��5� �k  a#�U�e1 aKA^U <�-�/�`!WHIVh�b-Z3)+!�� �1/E�SIVsm& ! e5X�=1 r4qN@�;��W�u� JG6�s�GarR�0p,2���un���6|�F56ql:�7�HeC-�Q sA~��fl.� %�5!Y�4"�gA*A Y� lack!�cx <�3e�.�dK3�H͑ir"��v��J��2հat�A-�� �G/ U$M�QK-�~ndM�i�9��� �/3t)T"& %P&+�� ."�  s�4ed 80:�E��!Av!x-��0!t���I� �� +rZ�0 k"�2"�&�* wozey�.^�^��Hemp(f�`)6`)(Bor'yof%�Bޑ��(G �#a���)r&Kfz0�y ��[ ���off+#<.�N�%inv&"v>�>�#]9h"�B ��$�!u'\g�vR�&;"%�!��Hi3�o�to�+� �+A831a�b�e��9� �.�(nDn :H!VGI( DCOP� �� �=E�*�%arV:�a��[1KR�( �� =9<39�R�0&�2"�0A*�0��$#x�La�a�Ek�)� "r5W+Im�iQu4|BU�*"� }��a�x\�2o%&r!a)�d+%�1�;{9c4 )Rf;�Q"�)!��c5�EW �IT*�2�����2zY�p$isc$Ex in 25–4"�o��n�<����A!��2I�sa�d1I�0-E�.h+Q�s ��im. RA�J�A��.?.�,�?�-�9y,� &�1�7��%los� Fp+|��!�"S-\�p%)a�� � i,�<&-. RoutQnd�a� :"�2A{*�;2�� X% 2 1�-�MX4YXM�!gM�Ov �0l-^!�9��a3R!ly "�2��ur)SA�*)�$;J�a�8!, hand4"p a�1��b 3�_u��-e 39.J��?.�*by�a<t�& &� �'o�sId���xpl�-wh�V"e a� :w6�&)�Cw6c%��e!�L6e.�(%�s f�B1ߦ_ ��!��[iwc6^ �!t_ q5���U�<����M��35:AM�q �2A�K, 5R36� b�N �24�d� I���%�� y&�6��3of�$(�M, CI: ��2�d�"c� �E�A!�rLinl/����3F 2003�� h RmA�"� Y�� he L� San�ryEi�-�&Of.�99ci�66 �!:�1�i*"�(�!�/Me�gIWD�'ve�t6�(�t.�#9D4�&�y�x�9X.�:� �MJ�;!Z.H��BHN+j=�_y�C:2l*!��F-f68(�U�Y�w-6 9%. � e��&76�R��bRO����PE�s�8, C�D .�3B2�d&� B�%yet*�&%|itaU�]K��6M�0lI;O(f�2e546ft�)F>:�iQ�2!)!��9&� aN�8�%��h8woMD� r�V~^5c'de5trMAo"=� �`F jyBH** NPv/T4�> ACyS2}!��twent�=15�E��3�)6��%d� i9`.�wEi��y�. Tb-�76�[y�i _C�o@ Z*�)�$@]G6D2I63-,Cu�2�K[�s*2��&�q�ɉ)�m�"���( E��ero4Dh�cRP=J , �3B3 2008�NT�("q 5j�6/eN�su�" � �8sE��9"-�� tog;, g?yN^�7 2�by�O&���)��))� �� .�U�.=Q�I=!��hg2.�a��"� �%���%� g�� }Z�%>��A���69:]&���ctJNPR�D�i2|"iU�� @� half�1A41I Co*6* h1<}2�3eam]�>.�5�M|�^�eND�8��( ��Cof�B��vt_Ae"*�!�6��s���Vd6�/�\.� (�!.� �!1�! )�}4/39��X-0\df1a��px` �.23a�.�ƅc����HA �Z!U:Q� ��,:Gee�� p*Ve)T��p6`���b�u�=%wse �&�#��A��; ��&�a��)8pu"�:m��D*� � L � q-w�f�ng�Q�32�~"�e���P j!xEhav"$e�Pd� :6��$�i�{\t &���#Xmanag<^E�ti3$�!p�%O!�C1 �M"->�+r \�#�>�Xp �MAm��"iE-�%!u�a�e=M e�x1KA�n.�*� #Xd>����b:@OOn�/!8Mb�n�)v��U�!�aQ$v�.sc�fi�*�,*��igjT'2�=o6N'stw)�or'; �6s*Mf} ,%�litR�i���,!RA�=L�lJ��ue�in 6fPA*oa�*r���("�("��30D &��r�25��Fiy$i�a�c"�Qg AQ�WU� Q �d�.le����>"�t( p%��$cue`4+!Qa/) ;���b�� jD -rang!t�1{���*e�inTV�ŏ!��qOb M IM�2gIAG]ee�.to >b�Ou�<+oE �.w�S�6s%Mu�^ng�A/e*�z� l�Hh�7A sI� �)&K!�2�ER*(Onecrops�B�a& #�"�_!I;�s- �W va�YaR��uto>(�� �Eb&| 81X��$!*3e)�gso��h!#��y_"%"����ҩ�1�1maŒ�-!sR�#�M���Qn5!�"e�Mt�,J5[c�@e 6�a�t��H]hyl��c���s�X�adH)�졈>�| ob&7Q�D*��N"icult8# ac��!<=w2�!�2d. C��As"�w��o�l ��a:��cr��1o�D�)+�5g!X�Va�~s�Y�^�BiM��.�mۿ�=�w�H2�\In(�v!U disa���E%T,�ge%".d@K�sO�Dv 6A�us�)s!�ve�="I3a>J}&Scr>DQ��37 &����$��&s��uv16�th'�I1"[9Y1����"��q!o)��r�a��e �uAest!�Ux�j�l3��n��aJ ]��Y�%m!E��!�f�"�+�BQ�� �c uik A�z B�) 3_t��+!�Emtpr�to&z ��!�ne'�vGR)5ach{2m-��6WY�* 2��-%� � BC$,*�re�� /�}&d&����Hgen&ER�Ũ"#6 � !q�=� �7ot{op�:��re5,݄#r�!/B���n u�Dl5�%U|&Q eAmHow�O.�>��;!q �%�& )�2#/m��-�"af� �5t4�e�*\ex�t�^sC���H�,2006–2010 zY�iw.�.62���e�1�K w#6��(�X]C28![hly S�1��O"wa=��aH �v eldE # �?!horAe�r� s�-�ac�;->u�+* X�"���e���c� E_� ne l kE two & 2,�b%aA�Nb�K . JG.E�sYLa�*� "�in �&!�I:�?[�Af�@�(>c0��aM+-n�Idg� !�&! ��#�'Ii��'�e�~em�a��&�f.�a�n��" � �dwatwPr���"!�X=% �6�Y B1/B:�q 5S�2S��TI�A�E�%  %�hY�r&�VAn �# �y !�XD�h��b�G�!%��.Y e-Ӷ�6�& �U���2� ,A�����)�E e�+��"t��a�1?"r��%�'cA�:�M���@if"�" Ag���C� lJ:B�k�e  Q��tA����'eb� Q���fJ v�Fsa( �Qi�� %)�C nefi,G8/��.vvgw ��t,GP�i}\u��f3'A�2� *K&p�zr`"�o���c�a�indepN�̓� &�Aku role"90*xJ *k�/yw ��iNe!F"�gF */mapy����:�K e%�g�*�Z�����[ r)<�nd"�%>�+S�]I�.�u���.UC!o] :��d ri��G�%�4n�� �! T&5`& �WKey!��i�c�k�u"�p6� �e�/!�0!(fa� *�" �v�!�fa���2��ofI;'� &�js"��+  6ڮa�� �(RMJ����n~�k�+Lin�x�d!5]E=�L7g��[kI�l�/��+��I"�i2� fzK"�ksHr�0y$'!z��j �po�d helpa�!j%?ynof �DF �2)��!xnex{��h+ "�iGE�9i�.?+su�� w&�% �mk�ñEa�"Kov�ny=��lu%K d 2�D� M+iinI����#/ //�FaV\ �7!�5aя�0�+��cEͅ��:itu!�"� organiZ��SplG�-Q6�"�).c�nN���)>�~n(uh9/�������AJpb!~�F/"ae&X!�P\EG�Nz"�L.���� M�Ar�Dv%' pigs5g�.�s% Rest��6�H*�m^�.:�'%(J|� h kp~D� ousa@]!@ �6_ e Gi�(FoI< Hog ( Hylochoer5einertzh�i��RYB iver 5Potam7porcu�0L��������0l!xQ#hoRv�څ�A�no "�Zk:_�u�_DAte9K.�m1 "�)?�J M��I3� ]p��mah~��"Z%��a ?�kv��fCr &4���-�It noteworth�5 yY+!�i�zam�\ed�wmix�vսls�wi�I�p��JeneAng��izK"hsy=��!�9�exA` bush�E��#�gm�s%e&�0� @ goo�%Iqs���r� Ay� .Q<2U%<i�)��������re��cLe.� w�ͰBc+/_:�pf ng J�e��o� �# iD~*"1�z[9� e�ABw.� capai>O&���g� &�Y�SmR�e�q� 7 Da��a �i �T��%dy2�1.��a��|��e���!�rp �2,-nh�-f �#y�� f2� �,�8V��0%*-/!e�va��� :� s�� 2�-�&|��3 �&] �6�-"�?�F>*�s .B�T�III� �� a�[H �Yof?Pm-"���mg�l���5};af�iehS�\txse��a���!��'\#g4ani�yeiGa� 1���AM�&_A���!1��"�/\` �YA� �t�$or XopL� &��l�o�� �$ Xanthomon�(ampestris pԟves� oria exZ�s E3 ubdYt�+ig�G��,yY�� l���Pducf�) dRq)subverM�EmN.mBcsr6�j�V���!�%4ŝe �� a�9 yE2��N�4 enzy$�!��� &P � r5�i�Vly K11-�n�<90ch�DI  crys7�HE#�����"�"� �a�԰,fed XL-bo�u�AJ_� &y"�06xE31v.WE�G mino k�?�-aE� vdisru��QU*!K����")�e,I#)."�9vaiv~u�A up%! e ab"�Ythioeq;1�5�-�E5��!Wn-cIWyt2��smA � 0dR)2 �b�N�5l :�&��)���a leuE-A�O+ ( LR|�MQ�� ~ �ra�y B-�i+tea��mod>�z5 �Brecog?z����9;5���|��okeF�,CB�� of P��&�Af�s#=6� �. Tak�&*�uaqa�G�ZM�EJ� PaRM�.!A��unK#ede��A'�l**Ixva2|!-d�acD[l"���s mimiUSQ eukaryote*:)cz<. GpGra�̱�ic�� �u�%!�ٰS( T3SSh�inX"Oe4M)c lj�}�T;V6/q���>!�" ors'�b���8!Y�H� J?�u���%m&m��9\�t^*�{. P��F�U���$Y��7e.��j|. &��"(E�� �{A�Zyflagell��W1�eZiU� Tu ��� gdefense�%e��m -tri�F� ( PT�K��E-� upon42�1�^���,eӳF;Pt:�%* elluAY&aV � tA*�mia�nW��MO kin4( MAPK m asca�p�lF�'�o!�*0ge�C�aa`){�7� I�`��-�U�Y�m&� �l��o�~��U�q��YR&q'B���T3E�t,V�9� k|m����FQ�.;aD cytoskele� rear�%i�[a crip�f��[1@��or>�.w��<.*Tvbi�7�A��.��.s� �. U I�� ��vm]1��hb�&]0Q-�� ��$!�attach�Iof�!��8epsilon amine o�Cf a lysine residue in the target protein . This modification alters #$activity ,6localiz /or Usa7for 26S-Pasome-mediated degrad ?<[14] . Ubiquitin of UPHs involves coupling%u7 to an�at(\enzyme ( E1 ) , transfer4 conjug>*2*before6YligasN 3 ) �sz_ from<E2 j:|[15�E3 �4s exhibit high. spec!�!�and dif�-�subset! E2%��y interact with . Eukaryotic E3s fall$do two major classes accord!3,he mechanismb=l-A,: RING/U-box�(HECT domain9�[16�+ finger 2Eins92cdirectly)E�)F :H , whereas VTfirst form a thioester�er-�)$v-�!�E:it1 t. While3I� is absent!�pro)r es ,Cemerg!_(s a prime e9� host_a5Dbacterial pathogenG,which have eeA $verse T3Es�mimic:� -reles�functions . In particular , severalzSM� imal%�plant�S asA�9F!?AO, repre!(ed on one hA�by !�HPseudomonas syringa�L AvrPtoB [12] , [13]�5(NleG familyA�E . coli �[171). contA�typical I� fold!R�o�other2�(NEL ( novel� � )M�s found!�� IpaHOSspH2 �(of Shigella almonspp .%a�$tively [18�[19a,The latA��a �U�-A�a�E3�mze�$no structu!�homologyA(�.��sugges��at du!� co-AouA; XtheirE�!EQ�icU>M�mployE���aso HE�fulfillO) wise5�qe-!#��Ynof�Fn. Here�e cha�erizeddT3E Xop!� Xant!Avou!d�3 L )I�!#model:��um2HHcampestris pv . ves�O$oria ( Xcv�OM�aua dise�IA�oma��d pepper wa�;inject�=suite!∼30�����Ice��clu��he TA��� crip%�aAxator-likA�effectora{Bs3!G�rmanipu�Ds �:I[10A�aMl,SUMO ( small=�m` er ))l�XopD [20A�%��E@ newly identified�)�! ,iwaq�to�4E3pm���9 . Crystalu e de�qrevealE-at�Qm�!��A� thus��!ew�M!�J� s . a�ana� '!74genome sequenc%��str��85-10 �o/1c�~4of XCV3220 ( xA�)��%M%@ candidateie ./iN nserve��.��$( Figure S< !�= PIP ��(M inducible!=moa[)�%its(( TTCG-N16- ;�� posiE�$3669238-26s��P�G)ax �pr r��ed � -regA�� �!o$T3S systemU�ATconfi��RT-PCR= 2A )�diccgen�oduct@�p(s leucine-r�4repeats ( LRRs�ar����R��ic�t! !x/Arind%�vE(any�Q�]�4Type III-depenaW secre%W�� ]KBin vitro:Avo:Iassay�Q?2B , C=C�f�~i renamed�(  detaiA�in�� �see TextI� . To estigA�aAMsE�viruleT"��a%, w�le!�A%�� A�!$e��J correspon�ad@A]mutantsA;in�Lstudie��B�Howw  , underscU9s t� - had��discernש��<�y� 2D )� &K growth�Hcv ( data not shown)�o fur!�2?)�we ex� sedipin� �� �(es via Agro um&� En9�. E V!-1��Fed U��$death ( PC�in lea Lof Nicotiana bentham 5 1a�, but!C4macroscopic rea'onO�v���A�J)�Bqua��y� Uleakag��H is u!<to meas�Rd-j�om.1B1���0 role�E�� A�Yqof Q� weQFif� F�immun� ,�0I previous��r" Te e.� a.4� ��E fu ly supE:�,PAMP-trigger�t�@( PTI ) [21]–[24T�alyze� �perAB0ed Arabidopsi�taf�oplast��L, a well-established���_�signaSe�O[25�[2P [28�W5R!vA?^�(he A . thalE� NHL1�@NDR1/HIN1-LIKE 10�9\30]��)fuMK8firefly lucifer/ �� ( LU�Daf�\ appl� [ f elici� � e epitopee6a�m�al�c �reporT��A . bas6 A0Ag �a �Ha@ e�;E�u��8���M ���!�E4n�d��a%he)k��{,by flg22 ( a�flaw in1!r4]A�A t� %2f18?4n 18 amino aci� tide deri E��EF-Tu!��Y5]���I ��g-+��A�at�)sV rtiaa.,��.imit- ��� kinaK ( MAPK\[A�3 �R,�P5@� 1MPK� MPK4 ,6e�MPK11u�y}% ��e�e%�i;[31I��might beF.] Eoblotyzus�Dan �Q$body againa�A% �"� noU�c�n! �A���g��gM�or � %�a�s;F�compa��Tto CFP ( cyan fluoresca]1� , neSve��trol )](��.j PtN ~  6in both��as�ɱQes�5b� cept��aN)��w� [33��Pz s w/�yq�5 �ro5- &�via� �ycoursœAT expe� nt ,�fir�eo! lack}��G�to ongo����e.��cS3A , �4he N-� lt ZA�reminJ n7�7archite2�7l�:��^���AMl<%%MreA,6�^C6WP� . , .& ��En� � . F�h�Qurlrecombin�(full-lengthe&([aa 1–660� runce�eE}<0442(%�!�%risord(pre-LRR reg��P?47Z?I A�,86–450��AgjCY b.6?:�)�-Vi*Oa�����humanS��ub�ous��UBE2DN%s�M� E2� AtUBC11# 28� a�w�∼80%& t�_���I�c6ofB� ,�!a=��1L=x$ 6n b2��u �i��a%��a robu�ime*accum�of�-mole�-we�: poly`Efa��aViu�u�~ �Va�z poi� � d �consump%�!&re*�]4�VA simi/result��also ob�ede�Am2disly �!]�3X� .)*9( T�`S1A{.�WR�I� α-H:nt�->)%�4Coomassie Blue��ina!�$DS-PAGE ge.� 3��Ł13D% trometric�����9� -�9�BO demon�< ��n/ciu Z-@ agme!�,'#ng�\!|princip��of!M�]P�km�unattac ) �.>Um�aF�{f � ,�����L.����:P��7N ��i�intact�J���&�K 5iB�requi���E1EOE2�n�I19��!'� sqCl��*�EF���N���%#K� 5��linnfefe� M generE[by �*j�a�s�n1( K )a�7��K6 ,  K27 293; K48 �<K6��can`ip�.H�%��T�e��jpX� Qq9�JQҍ� �R�  2 �ɾ�>F!��y��� amou8 �� inct9� �5�U�����^�E�".I�AFon DUx+u� �� !��r*��l!"aE��ll�0�M�� than half�A6Qb5�inws�S.`-Z�e�����.�∼45%BpZg11� � ��I*E!����yrimar>to F�^�. IY dng� K63-cT.��5�U2�ɻ.02��M1�-c>�>$these �log� U4s mayA�tribute�a"7h"�:c+#�a�e�8 �(�E3 cat�d�!% � _P�� va���5lM͡1y�1�heI�2vi2� � vari�� each Fvidual��*$mut�3�rg*�"�3�-"a!1V>�+ �aB K11R \au�*�?��6!x ��Nh-75)I]sEa11m�sфA�te� �5 K33R��48��>hK6$ & T� re�!>� �`"no�wU6Kamong%'N�6i�!�q*�C��%!���^"a�5l�er 1/oB , pot��dueX�Lffi`to<or.�.��r !�]�>�Eg�"� -xedJ . As� � abov/TAE.�%ch� QQ%�� 293Nq � Ɍbel!�to[up VI!�A 16�cS%e�i<[34$k+clo��I��ue �;.(two^X BV: , Oly � 13 (� , 34N�to -|�%19;III , 4R 2>di�c any 1in our� ��"M 4�>�%�ri� es betwee.�c9y��,bi�!b� �#EN� �#, [35�37]��\'ion|!�)�-���%>R[ehb� V�. a� gene�3yBec5"}AW�;��g � abro dyO 9i�o "��R5FF62 K63A� A96D�@E�eI289b+m� them�_�n)�AP!�6 *eը �M��e �8�!!�E�28�letA��� �Fp-P�f2Yc�P ��4BJ,B�F62cA96;"E ���iYO��� . B�� 2!�!%�! �s�eryih�i_yX� . Take1+geLrurAE ults*� taH� N�! sele�recruX�� }�)��*�~harbot&J4 ���s2S"5#�&��*�6&"1'��To _"�ins�iW%*F'baa�"N�neKF*�6���-r� r�$lography"T*>r�A1iz��e>g�An:b yiel� J��'iff o�e�'� 2 ÅPj 8 :�.eh6 � Sle-wave:anomal� disper� ( SA E�colAA3}%AQne'peak Qua j '� hionr#ent#ed�MtfinalWel�1"%9�$�]�eIa� asym�6*V �toaC4145437 plu�&r add�!al)�\*���histid�/tag"��!:�Q�)�@p d)i; �"a$p����42 �up�six��Dt"-�u A�refine�� �c!0rIYuFs�I�enA'in�A��*!��J�5+follow�'canon� T6�Dten β-�nds�Ah�t��%T (A �<an�helix)6$e turn ) --�Y motif��5 �.!�αEc�α�α�aαu!HZ- )n$α 4 ) cap% 0mZN����ua��$��xiG =,e���[!�!\���of3�!$DB 3CVR [3� �5 �B������rat*f�& g i�#d�rN'�!=nsu�9)�b!��s!��' ���R)a ɰ) LRR-�!�~* 5�MhQ1, 1ce��:�"�A� four%�x bundl��k Pbe sub%/ �wo unev�oba"lmK0per�'�/"+ach� " 6Qbe�+er E!S!瑕E$ α2bEkAuA�A�A{aY��he 4,A�"� 55�56�ch adop%4ormI �1� �'lyX4l�!�( g �yYA�e? �s g��!�:���8an “L”-shap!� X; clef^3c+t*�h\A_��L���sab�#�!� �9�B"#) A se�I��al&y &�DALI  \r ( http://ekhidna . bioo er .!$0is0 �QugI4cuu6Ak�  cogn a�{d7�U��Ge1�J=aI�Tf E?M4IU� abil��� :���)@US*B;� S3�.�Ru;s D502, 578 , A57:Q61� L619!�/�  urfam�9�9�we�5�6�3��lE> �1 . Eaf%a� io ��AK`: titu!�by ala� , exo&����5%|a�0yptopN. T7:i�M�au �s� &iiF�ɒX� !eBnnt� �'T�&syn�d5/1!/a�!�a!�!�W�!�A�hanabo=,yJ8�9i N��!�A�%*���*dIn�_r,�jin"�0d�-Jw G.�9 d.c!-� .BHX/1�ngF�*?$s%�� or G&)gr�J');� t)�"\by we&x$����-U"+ *�">P0BS!�!�:�!0��Eqw5.�*�am= ar������*E��=-<" upon5}, gfp:� . No�.y�eZ��I�a!a� &$Z�ck�M�$2�2�j�� liavo2�,�=S5ay. O� :M� "H �ed ��KdB� �M� exv aa�eF�.��� ,F!�a:#!��- � � stro�!hi�6 xJ �9E�A�T .�%vBK_V�inC�ћ�"�2g� ��*1:ei�!�"%3�5�1FU"Faa�CTD"1��7ra_ elev���FG�� �7B&� Z��2A–�D I�D�tud� we,7=�A�<�cv�(Ibs.`/Jq !�-{j0"MBdefensN<�. A.BDW��� �D�,EF�q��Fm�y��assocDFE�g*wmX�� �(��a��*]0. A2�>� s kn9to�W?&E5T7�Jf&% A�E/�B� "Cz�?c� [&4E 3D�Et J9er3��RE2 "@Eo,��$�4. � �3w|e�2B N=)2K2�4 P .&�C[13� E�,�C�C�C. B�.%(" sig�# "��� %M=,�&adapt1 �r=!��of�C &a�Nr�9��9�s�7t4,>a:�FaB>�13f{F�lF �A��m"�Gha� en;ɩ�or;":*6�"�2of anr-1� s [4�A[41� �6=C�]DyNA�*E�%L �p5",!9.�R?a�cer�  featueE��w6t� EYsB��:# , te.��hyp� ,IIit�~saouPzxeoa>�is��:4J�; h">��a6{y5t�B�a1� se.�� � eI�aJD� � through%&��e�a� _ E.kG&�-�)�M{h�$~"n6�; tUBC28�.�;";;,R0AememberU�grz%R�l%. Mz$M=8*IU�<o�<��en2�(� ��"-%A�t��2]7x�i�K�H( S#!10\ 28; www .�o�com ) sh�97*�%]%�*V&m+u'�s�*�f� I<�?$( S . lyco�Dcum gi|350536447|;��4lI &28Nc?$( C . annu B40287554A6%^A. M�($�8of)628 "a&�;"�.�#toJ crit�!�qU %1e3�� . Ita�worth�A e\ jiis es�a=_E2.^��[�t4;��8� 5=a�J4 [4�9N��A96!�}�wwKBto�*-F �@�-, � !9& ՐK[4�OX0isW ?{Gs soC�arailu�%��)��it�!@be�!�.� j$-E2 pair�hd�s"$N�>I32� ENp� 4 --of �/lQ0&sAX%m.���!p2{|(��2M� a%:>�2:0 �'0I�U��Hn��1s dicI.by*�+E%l �o:ay)z�/B4outcom!�or�,]>� L)RG �3usug�s:��L!>��R [4�ANP K63-:�R play�^BmixedA�i�!A�R%h��mavFs-e�n�%�� al [4�*I� �$11J5Uq&h�P+ conn��.'Tof��5�anaphase C#n�Nmplex��%P cycl/"J[�, [+<.� *�O�=N����_G���&(!p%af e�AdN�,ca�>�"�3K4816R`�SConsi�"n 9��edo$-[=}2G)���he" ��bd-�Az� 5A�.���;E |B�a�iPnu*tI�innt-� .�� .QD�A�e� be e:E�Ldnu2D!�h"�K����*�bona fB'LRR4 I.� ��mo"� F-!NB iPEI-�Jms mP1��0�l=&he2nY!'y��Loz3��B9QE3� "�/P:��ad2z@a/�C���n� �;��>is kinda�&�:\%h�/"��s 6b r>�L.�Y we�Psurpri� 3�%��:� nvW!���of�-NGJ��wef/�_dF2mH.��m�D�H^3K� �FF�(!� �i�N4r*�C7@e�$G or e�F*"�I?t!"$2�BLaarL A�E�or2nM:Xi�9:bic)� downstrea}X-reI*Tng�� �./""�NofEcascade*�I,�� [lt�Bge6"�$ # .�E �3� rA2! �.*KX#;3" �VAP�+1�1�nW!G�by�Ac�B�~! �BAK1-H�du�"clusiş�'1F)�s � �}" 12�205%n0270–359 [52"r5D by���a��I�profil�ţs�Oof� !2A~�b��BV �G"'�7�\ 69Y2Q�)Չ2;�Y.���@� CZfi�U"��IHM>�e���x#� �� o �U�N.:K F�a�9 �!FXCP!opY+eM��FN�K�r�!�%���1m�Y<s�sLe1�$�)�$s���ein� .�� 0ule necessary!�Y2:6��J�!!=\phenoe�we&9%a��*weFA}��Xs multirB�yby9��ia��N#QA4*�( i."( �\a yet"� ���( �Kw��n9zr*a%d ��%%xE^co��|,A�� >Yi��e*�"� ��%uncov�EaV)EJ���isu`V�- rtoi!Uo�\an> (ZjY^*�(1� suQ,*�9 �!��Q�:,A�e�#et�H[s"c]!��]&�YaE�subver[ yYb� �A�xt!Hl32 AxQY �F�-�� %G%h j�I���)�3a�5��-�&� �" Jun-!�� . EscheM3i� lie5[%cA�v��Sys y br�:um ( L�$at 37°�Ag*T$ tumefacie�as�wn/0/(in YEB ( ye7extA� cwau]ad)Yf7NYG�]utrk& @glycej$� 3]Use W�"�Fed`&[540a�l''G10 mMAnr���\0 . 3%i&���Plasmid->i�$duc�v=5CER=byYrGporI7'b2�b�'["oh� helG\y pRK201�(tripa"E5�` s [5�b�near-i%��1e�\( Caps�a�)Qrs ECW ,-10�+,ECW-30R [56]� �V%�23!��60%&�!humid�� 16 hA�hPdZ�Ue-S_2�_.%E�3iA�� ino�)JBedleles�` to= �Vat 10�: lony"�_#6.2 cfu ) /mlA�I3MgCl2�5�b� aBE�����",B �, GV3101 [57]�incubq��AM�(2�, 5A�$MES , pH 5A�< , 150 µM aceto�ab4)%�VQ�4(at 8×% fu�.2V" yve"0P-�h%����=[5PEq�-�F�-toA�bD0al���*O��kWsuperna�K kGx0by K� acrylam�geluxh�Qi!�)K-�V�R�&� �K dard� ocol�ToK*lud.El /,� �routinF� U�"bMy^�CŅ�U nnerZ rane lipoO  HrcJ [5Sb�%�D6�*=!�res �/l[Wx?!��9 c�= diam�l )i� froz�nda�"clOd n ge��u s�4EB 10Am l 8 M ure0cE�nd bo\k aUi':�Repa��%!�%�<.�:�.�&�Aclo *a*p�aT�v/a[Q"� �bcab^CambridZU . K .�0� mono iStrep-ta�t�M? 4IBA GmbH , GöEo%F Germ��2(HorseradishaE oxid labeα-rabZhsα-mous�?e�`�( Amersham Pharmacia Biotech , Piscataway ,4,J�d�S�ѥ>%<Xe�\� =>. A s��m�vi��-��nh�0d chemilumineaUcev�! RNA�!�� 6�Z cDNA".�(Arse��"%cAm~Y�i�V(`)a.�T �^�6Q!oaA��eno�g"F^of Y2 kn7�:1 �: s up!�* <%�ampli &by �`% p!�(cv]b6(oligonucleo'� appropr|%a�triC sip5.c-��A�e�s suic�\vid0pK18mobsac [6K��l�S�9X9-X�LS��!c!JZ5N�,&!A�@�!6`g!N A��{��'co+"�$5p�W>or)WYy�->D,2&(pENTR/D-TOPFeInd+a�Karlsruh�8��� �Q $pGWB2 [63]-�GATEWAY a�no h(.ba<~ QGI1l�3#aF�;|=� K2%�1Fd l��PhOSite-D�ked�.�PKit�(s}iS t�� �Schwert6�6�a�}Δ2-fm |"�! 5′>w5�� J�.�2�QBk$L6GW356 [6�S�<sgBS� avail�S�/�est�ri�] =f�:�~eacan� harv�-2 dpi�4 . Measur� qTarregou1_ d&s 6 Val("$( n = X-�A*\�eS;Dri %Z.2[ 2R=� )M*unved Stu�R's t-J.�e*�F]^hl�G.2}*Ie���:+MY�(AECD4-16�. libr�.�B��4Resource CentrŮBRC��#a*�`(. org/abrc R .t���`$mid p15Tv-�.4gi |134105575|e�"aenM�H$28-"�M:F,�"�K2�G%g� .�Quick Ch5j� II ke� Agil�5Tec�d[(Canada , In�V,, Mississaug ��E1- ,*L aw&Z mke� purcd)�Boston!�<�*} S�:*!�:@WNWEMD Mil] %� Bill� V�Qi��CQor (,�2's.fAHis� gedQ�I,"e^6 1RAd.zwild-�).XA�� "#l��Inm�5��� i�Ay.k LC-MS/MSu,OrbitrapVelo.{=! Briec�> µ5E2 �E�R� 029�E1�L 2 , 6 �25 �%01�AT�_inr mM T�mH 7 . 5&s �m1 M NaCl%@�!�5DDTT &�at 25��?3 hourR�%0stopp���a@! of 2F v b� Z5�u�@ at 9q.� =:u�b[&7T to >� kDa�]&trypsin� . 1/10ih�HA�U 8hu��. F93�.Xcv�Z("�l,��28872465�*.� *@[pyost�$ATCC 33913ɵ[ C418�W(gi 212336031���, �-��:2?"�BL21 ( D-v -RIP���(A�eoptimiz!��I7,{�}-�2R>� ul"� 1 l�M�� nh�) dens�( 600 n{*J xima�M� a{�. IPTG)�d��@�� ���. S5JR�I�AI�6���G��$cn��%of-in SeMeVw-y K �qS��hai M�milB, ChinaŜ)t&F2,"xi�m��tv�k�onH-haker!Ui�. CelI&� by �%rif&8�disrupTby so�He�y�in%�le !�5v!$removI�:U�(>"PNi-NTA�ePy chr,�L!hdiKd�4��in�PHEPESp�D�A50�,�9?�+ TCEP on���i 5 mgE.sto# (at −70° OCrGMi�t�� * 0t room temperL0 �!�0ing-drop vapor(I ��M�m��spa"matrix1}sc�<[6/j�.or[ limi�*�E�a�, [68]A@l�sTEV-��<Cc 450]t �A�R1+.A �@V9� �%%tMAk(Qo� �SAD `� a{���4awa�!�2 M Potj`um Sulf�7!�(20% PEG3350� N! Hamp� Re�F8, Aliso Viejo ,*_ cry�ca�[ �"�� 10% "��flash-f��B�w{W�1E*�;�29i-�y��Y�!T�6MŲFb�'15 ,5^So�ceZ+�)Y4K�4% ethyl�"�o�66 �Pone-N oi�:B�� ~4Is�ure�1;]�!35QHB��u�(��%#�z�$>PphaM �aB(Pof λ�A�97937�P . Di�P!�e z �N��10�fK�sAPS beam3 19-BMbC5)g��AqscQvaJD �$HKL3000 [6�Po�t $heavy atomm��1 9 SHELXD [7�5���s�&nt!�ttee�3 E [7�'&�C�N��u�1��ly bu?�"iU y S$ArpWARP [7�0a>9�!�Whe CCP4��gram �x[7�0� MA imprѮ�%"<�+%man���j![w�e-pi% �COOT [7�mn�/�]fdP"Jl maximumv9lihood�� 5"�_�o�+� random�3��A,@ R>f��e�?y step-�ٜ �REFMAC%�V6. .J-w�X�Phenix .��/eJKPHENIXqj"oT1�5�9[7m !�.$S�H�LFY-tTR"!�4�?-�Ni-&�[�%� $1456?3JcinM��*�;Gl"1�JFH�n297E438V50i� omita��&�>��dxjC A�R�&an RworkQ)� of 1 �d2�6% �&� &A! TLS�"�[7[7�!mR3�n� alsoi��AD��atB�(B�21��jaj^��.��9y�},m�b��i_Alm�o� E+�!o��pJ�6wTa)�T, pQ�x� ;as!Z".$r��9�t+merohed89 twinE�w�J law � -h-k , -l�a+f{"�.of�73 . R9�Gp�1e�[a9�|��IP�ak�%�d�s�/� N�^a(V�w8lHk�:->�U. M # ApI=.�E[ �z$!�E5 m�$}�ri�sy�>�Ubu�sQ�39�Fbn"\A-[64y*660e"�L^��s B%�C�E�v� �6Za��6e �Q�6f�Z%>�O��x��le �D+64�NIs)%� 476 P�6T^�H B 64)9Ŏ25(A���Y)%_i}n"2%X1!�4B.B�Wa�� �4�� me�s�. sticf�Wsummaʁ{� � Rama�K$dran plot &��,ROCHECK [79]QedI g��bJe)istry ��e�9�u 100%1�-_\>A efav�nd"�0wllor�) �J 6)� H���f. R@M2E#���"L=( Col-�F��g.(0f�xW!�0(eA�r,V-"��"!6?,-�3�x����v,Xy8, pUBQ10-GUS [8_r�/p35S-"f*!�Fs�,��J CTD[aa*�L)�Mcfp�K��% µg N$:'�v=.;�Eio 1∶cQ3g0Y1�{&� E�p�(�K!�:|" a&�#pTepY-@!y�&&*�:[�z. GUS�y�@6�v|��� A�� 4-MU3)4-M>umbell!�yl�Z$D-glucuron�)ia Cyto�MPZqrea�~( M"*0Corp . ; excia�on 38? , em on 46Co��a��AQa�,%/�U:��/ݧV/1}_)��M�de/�JA�!�D�\ Bank �c�.�cod��FCG%�4FC�Q:O[X"��� �X�( Xcc�,a��$s APC10826 @ 5826!��Mid!Oher%*SeZ�GeW"6� �~ $RV254 cohoP HIV-i��� UWac*k( 4thG��ge �xst/A�AN4^( . in�Ti.; y�T�*- B�����t � HIV �!�|!impac! �$ntiretrovi� reat�v( ART�n T> j"D.h *uQ(-"%circ�8aXT�x[�+�( cTfh&L�|-|a�ex.,ed� +�memory�po�����" �0�8ImH>v�d"> 2N]s %�)�3�<� &�z !��tc/-1c,+�s�^��r�surviv� nd IgG*�)�]E?3| �EQSm�Ho�s"W _IL�Uinc�� ed RANTESTNF-α �2!�aU:�Rinflammd E�5$�? �a;Iw. E�K�=9moas-"3%j�QAr�N"4&�~h&v) m!�!�e"c�-6��viremia�OE��:n2-dysQ�al\-o���2�-rturb%� azev�0ca\m< �/ ariM!s_�tably a�;1p6�e�v�, -�!�w�hig)$� . OuY�" �-�� {4p/�ec6�=1�=could"p�Niy58despitb@aM� levefdOC�pTfF�C?8s&K!1A�6�)_�ƍa�w/X>Y�2�aXC in6�yT�8-06 t�:�a-�nly�p���)=�A|�eA�<��W�erS!"���MV��$� prog�, ve nI}h$mmu bQ���:�&Ki�'!LA ���� �l�A"F@=�Zdʉg�eڇ�e��2G �=�chst�![�DMYAwf������7Apiv /.�L��burde%(�G��;� !>���ur2a���"� �'n�{�A��W}isU�R�~(r�!SCleaz los��� ofȅ�[&U�B�ne!�oW5y1��-�.�5ats's6:P-���bq:��!)1�iU�_i�C'���gg c6'a@1?ap%gр forw0. ET9w��al,�O�Mprep"ۅ�,ymphoid tiss�'5�|;&7ai�A �h� c1@# �[�mwhy� )\ehallmark�MO�9 ,! &�a�pE�8��-�8serum �oglobu��[. 1���w�Ps[z[!$M�.n ��*i�,CHof�schA[7b2+�H!oa�7��5'��[11�<�&b\ �)�z!��2AproB 1Qiq"��7l&�Fi (!q�L[12–R,��7:�CD27+Q�� 7R79SCD4r� � t e��E�=�M�� A\)l��76  ��Sle�@ �&5ong-l�= �-�g(�3o ( GC )�I��qnSa�at]��i:,A��� ���A��Kachie,%�Dm��b�"e��T Wa�� >h�N:��� a�ߖ�Q�q� ��es"M � of!� +CXCR5+ T6bl�kn9D .!�"Z ���� lso �ef1!1#N ->�!��� %A; much 唙� made!� za d֎ 5!ir !;[z%T@��W!5v%{y����>�U@���$%� n�A�dy��n�� �.s�!��v�X�`t\=Xr"ۇ.r[2�-�%�r���Haٌ,microenviron��5ff!7V�� ��L )$ �se ���a? ca v�y2E7�� b3�d�! ths y���)1nqMala�RK2WelL ��le�Qr�lth҈d�[�IOef�b�Mu�E).�whk dergq #h��� m�Oire�EZ�.L1oB+ of6 .��A�y�!4S A�L*be�re�` %� �> 9!�~U[Xi EX�@e�b am%`��5�=po>��in.��&1.{��i��� � �i���ew���� al�� � i��T ^ ad�ׁ�� �fh5���5�Qe�;que,/SEARCH010 T(�0�!ge))a��Da?�ipa^4!�r�t&!~!�!� iestiL9� GM ! �&��A��mimm�`�2$�YgR.|o 9)�bwe.8��u��A:�benef�1 �u$on�g m(��=MU�#���7urrxx B-���@er���"�T�n �d_�i"�.�s"�Qed� �E�; Nn a�:�7 d(K��e� ! �msAx!xpo#3��nd-�32��(�$Zq8 jj] [27]�W*d��e:�F?� u#%{�m��� p�AY�:*�Xl�QN���!�u�2�)��2pw�^ �+C&5��F9�"� .( pro"�!�.. Wi�$�#a:d��E�fK5ncyc��e{��( s 3- ���9ph�z %�Y�a�=�& $3c week" Si-��� ��ah.�xK�tP =H6�S1�{S1B�b'.$�swas�M�?�iO�c!:%"*r-N N!k( PD-�(~q/�sti�� ( ICOSev�8(�MaW�,� (� ��CD3 X]2�#D26�)!�n�$"� %�"a� S1C–S1F5� J:s6�A*K�pp C"f cc�^< Q$tw�PA�1w� �~-� �=9�"�� �  382�n6�1-5!q>�%� SEB]j%��i( S1G=!uA�� Bd&�m]�>f�v��  :EK"�>�BRe�P�z<˝Din�G���A�2��s�M]ij�m�(l�- !�  :<E�1+[�@&�'. Csmf�/3� ci }�ly BD�^to��U�3 �j^ .�"2t* dNJ�cy�0.5Fignl�/D  cZ:+��+ B ) ɸen.Gab�0t:#)y�"#%� ay 7.�\�.�: X�=fPž�^a�entR 7-ar?�e%;A ��k � ���%�&! �.�!C�UU�� �S&a[de*�!."��6l�W��:lU.!��2�2W=�} 4�R�u 5473�q 1EQrXTV�&�2���� B�l60�;axF ).��BU<%S%�&�B0 +2�+� tO��U��A�%� 3� pV�G AVbOfy&e�e ltho*b5 5; :E��mos��"��� �Ne��*�3!�@�E�.bE� I7:_e4!2e<^up��2����he they� yE �6�B��$*b .��- non-���܋u�2wha�r SIE��l�3 �qY�M1�]�O] a;skeP&�T � � �Ca*3)� ytok9.}()a�j��ҡB%�a$/�|ic� :( Th1)��=ot��c ��y&y30�-a3K��a�oN�Bi��'2[6W pT) [��p�.p��h&� )�>�.�[:Ile�!F ? {� ��!�W�.S "�M&�wh:�!� 5���1 ��bWe�I��E .�6�>� �s�βp299er IL-614($, IFN-γ.�!�MIP-1α341$-y^-",;2��_#&�|ach<[�al=hNHS3RmS3D%#�&I�%�.T�-"֝�!��ѕMM�2angI ve�B 2�L=�0�>��-�4715ɖ?����� % �B Z��`�s6�tr2fv�I� �&E�����480 ��2�"*� �:�z &{'\�0aI�0�axpodq 9`<� ���Zo�$��dŨ��aRw&�[3n '�.*7">�spf�>noEg�� delaV���ca�KD"�ki6�!�%�}�Y�]j R'��-&F[5� outp/F(�"�`�$��las6'%w&;  o�a��/2 .o�j� 9�`�!�:����\s ��)�6�"�Ni F�k&P>�b�3�aͅ�54b 3B�t%�q � �c��$H �"y'  )"JY�� a�P�M$am&a1��.Ӄ��!2�A>���4b92��]�A�A�4�!R���aV�щV�"4 [-I�� �i"� .�92�484��3).-w�d�Q�K=�!D���$@I��Qc2%�� a�a-Q��+4�0VrzBF �K.�Rd:�� =�aD!�ž61-7� �Tz 15i146 1G� p�T� �;69� ��/pro!�B�9�Er� s�� r�����-�u>"ak� *z0 u�F�|w@ :�a�e�v�uX �\d z\I�B��u! !#� �v�'_��uZc)<���a2a�TRT|]�!��a�A���w"ߔ%q��.� �g�l7 ssF^��$�.J ay 5�ZI�Z �I4���6�eng" d1J>&�&�a &��~U;par��6!��Ps2��.�6j�Mp.1of �s occ7Iܫ\ follp/a.)mag�".�! 9v8)2��0�a*�"�*ior�!>�Ū �/"2,�gY.�&�(.Y dQ��eFJ� �.� }!IA���E���!�,mob�s!%"�of�_�\l�8�+�3Y�exhausU�hav�hen-� /@A��q%Q2��u]a� ex |(��'�JJQ$u� �wo6P k=1.[pri�ho> �F�&����1�4C�S4AeLe E���per��>��n=+i�$ly� a�F&E�v*��J�q75�e��E�+ # %$ enjW� a��-j!ف�2�a�6�!EH/b�a�q�=h2�B�$*2B��/.�J�onK�'i��� es�f�l�!xer��Z [2�1'+%<�,�G�|��p4>K[�35] �er&�� [�Kapon��=o*W&��9Z� ( S4��Sag&�"Iof ��$��.p"> � QmtZ~ZaFv��.�a�A�5� �&izTM�u dRI�m�J.^a�ad 49xm��.2� , ad�a%D����U��AI3�*!�1)e1Z'("M.!Wto%�"� sub�6S7,"� 2xi!C��13: 5�X%a;%�� ��)��L�( X(r�',� 4�=mdeq��s�KUR Mt p�6�x%� ��'Fcw�f�nqat�!2 �%�!�!ae�he�6k(YN40�;"�{.�!�Jk3e�6��.y5�v000��AzJ��x1� ( P>+ 9na� !�&� Ď�" c*@��EA<2( 2� CD19+"� , IgD+Unaïv&*Zs#,� ed>� *-��)Y"�Pi1�Gx0Z�u� NEoD–5G|NH�'��e� -X .�%�.� �ii v�>|S&� s)�� "�si �A�)rA2�iE k6'a�;jon�e�(] e�g.� I�.< �, �: Q�&2 2�,a5�6��9-\�J�2��7*� puعrƸ� v��*S)Chx+BwJ��lG4G<�R��.�-SH� �. �>Is*"��;YE).�o� /�J��(ANz�SOa�D�*T+� ��aI-Acap�� Q�*�"%�8%W(sou�Rw5nj\ig��&~ � m�<��3 A��)M0l�mԂsA!�un&�+�+.�&~,�F��I 5-�%�=�a �%�ni_ti �-J4Q�%.ii!�K~�))2�2c K"E�gv(#Q�*� �IDE;y.�>0 i. d HV6!�0 rr 5)��Gu��G$)4!�m�"j5'O5m�j"op:,�"�@z�$2o*%Y!�.�"�&��65 �݇su#�*:/�, : �")9of}}!A�E 6i��}�*/�Hu'>y�DAil+�hEB* �&D �5NM1~&+0�>G;�N��y&�&�m �|Trepla�7!VN\(�w$�C+E��.$(�!� v6-�|wR:�(:)���h�Z ����m����Y�ZU�͗(��!�S5: E�_7R�+e�&]@K�5&9'do��#I]C�"�A8]�"|f!m�6���B+@u���Uxly{"�6 by nH�"�U,�2 "��Q��ier�&��of>��"�e���ѭh�"U : �I�"523��:�5�*  ow!F�g�[��,�E� CpG :�cP.,Aہ�!/7 p2�9D�z��,E��],�A�R'B#�=� �"]� Z�~S6.6Q�&�#� I���omeI�!�intjAI�N�I��b��M���O&8&.�1M6�.!<�)�p�NBcl-2�v2  bfr-j( S6C� �!�Ao*Ш- �l �E�.f��:� &�� >:&�,q\a:�, ]8! ca�<ok�"FA�H-r���8u{men *2|.� �Hup�7eoTob�Ov3� pat}ps�%]�pol}M&Y> $�tyG��CuM mply1zA�kee�10 �Xa+��amGas6�?"I��@�E"�*�ZCa^~i0 a�S%���A-.�k !�e��&A=U,Եy�;ag4A *}�A��F^H �gulQ>: B� lear�as� 8� ���-wir{4_}��) "�{>c �=h�?. P&c�&� �N m�ed9�>pcy�(M�?���!<Tb� 66� [28ad0?�qHrrobo.7%�>�ing�!K�=!O��yH )�aNo�Ovg;�c>}Q�*)�U5Q!q6IL-�/ ��K'!;~iS k��u��,to ?2GTfh17I se � *at3y� -}�T .� ��^.!Ԟi��� sa?ofN+3=CCR6 [2�#3���8 aAc��^a�vef%-^��"�xe 9J:bX g�D��e|kh(B(�J�)A�kE!�=�Gi+(j�A6*!ma�Un�p�)?!�39–4�[*%Tp��!8, &; � �A�ZH��� L`"T s [2%24ZoIn�&gDac��� ]`by=%�erMJ6���Q�_� fi z( XLP )�G!�i�)A�d�(op�u-+���!�� z ��&>Kf2� v"(N�\�!!X64.�"��92�B,!~��l nS ��o�+.B',!���y=��.9��A&�V%/i�C�6PB�. Rapi�!b9��9�!E�tilow��e�L!�a��I�:�R�Dkey o�A*��hy=�?�jW�E"s $BeJ!?(��tf� >�YoTB�0?2W~ � ��.�)" !s N�. ��C�� �@�T� Q�d�%N�+>�!MZ^ 2C�6:it��Ak��fu!e�qq&7;A��/J* :� "1��zwHhappe&d�� �!> .�[b ��N- �@i"b��Z�y�A�AYu��2�ly� � 2�"!�a�͝Pi"s2�!�c!V�"of�(*�I�#�";�J�D%�%��Y e*|5cZ7y�.�")2p�L��er"�LdrirM � �!��2Yq06;.�*�~HV��F�inEl�� ��-�!x2. s�3��b-B / �VeQ�5>�II J �,5"LT�%A��] +\)(�(yG)��v$l�9c�H[Q���ARJ�"��]����S��&��*A*vl �R�7�:��&)�T� ��&5�N� � o�o� �toi�i���L "2� ��86���/ t��nepm���&��"Z�/anՄ%!�g���hTof�!�:� �� *� ly *sV+gt|`n9��-n�Nn>\2���ngE� �e� h� &�� I �]E!��'!y��Du ��-;1��4�%H!�T2  �7w�<(%��� s�� [kc45]G):>.�� ���wf#��!t�z+ u.���A�����v:dGCk&e|�Q�s�s����!�2b'"�Ds|A�uE$AZrpret u�be�Oon�\%^cB��zsC�&P�&c��fu�98��&��2AT(�"q�-�e^"� 9Y� prop��'.:2! BK���En-�>l�gm�q���;*^J�� ex� "�a�&�Kss�@ll� aC�K�� ��@�s�6�[("�$ >�P"2y�=R�M9�!3 idea`@#eqyy-�:�is valn�� �I� K�R %��ars�"���EE��N*Le�� 2+w *�E veaA�AK�Urj/p#}���[��m�G" �At H����*1B.*��*�pǒe���}$�'�dX�� �rn��'ioll� rebd0E'��E�rup%g�oi%��crby��"�} u 6��>"� .�\&�@����( mucoH� 82'6�iF"�R�m�<�Xw'fhow!�!�"� ��"@ �% verc�gRF!n:@O!�%Ay�+�1„�_inFe+�3!�oH-9�-��Bf,2 ��t��� i\K�/}�Բ 8 . eek�a�7 s#Um�&- )��Th�$%:s!L��R�iwe��)R��i�>u a�Zl!����"$"Jc� H��s�A�!gk% ��ng%7[���6�ņo>".�M-�%��$�d 9 F"�-A�Aq�[IX�AR�0%�A�humD &!nd�i�j&$#e�stag�AQm.�!12*}KAN�K,�K* �*]I#� .�{!�Y���.�K^t��%G#qN �iB�Gu�  B�d9��� ". d+��R$s��Ko0>Qp"Xvj��Ob/SMO NO)�n"�� nIcgkoZuOl!�( mZJ0�k�\4gov NCT0079614�)gc[��2E J0N�. P&.�K����a�( PBMCZ�Ec2o�� �4Peu�`�  e*���Ieq S2 Ta/[� Y���D}v��]en� |�� �e����[48��"*~5&��c۩�}�?MNp2^)3*w%4th� �IELov�OI�-C!�%[v�D� i9�hA�*`e {A� RNA+�[dIA-�tr���2( 3rdG )  >S�F>I-I�CAU 1*r1<W3� rn BBj (!�Gt�".;uџ\Lb&bm���RTA�a��IQR%&��] A�PE_)�l 6 �I? 2I�6����t �`�/�>�B3;�<va�D!�>_XfL�.!�2�\Dkd���2 &�(E �g-L( + �� 2B i~������ CH4�!�!�5�( ,2�eFt&��NS��m��io��( ��)� RV30��3� %ly�/S~S4.� .'�&(:���F��b? e In��io�",Review Board.PIRB�NU hulaW2korn Un"��, W�, R4_ ArmyT- R~y( WRAIA�,.@\ aliforniaA�San�0ncisco ( UCSFezYale 2z �'awaii2H06Texas�} al B2�hoGalm*o�.62Sydne`Aw�Ho�calr�de l’5éM��,éal Le Comi’Ethy*7 a Re�chQ)�9�013�)�139766�DR�!�!F���)�!)>�2 eM�0112�078280�Q��5|�1�H�696:�(% oF �t�volunt��B_�1a�j2iAld���gave wri?y@ or "GXy�-ll����� ���bo�..�2�"_#��&.���Gmo��me-*�8i}�=�1Bw20.��orKice ,��C@��li?. S.�o Q��(BD™ FACSA��IIs:7��5�d!OCD3+CD4 5RA-KLU�ss &�K��*Xdq�ed 5+)��`+PR6C-�2 CD10M2 . So;  !.�kL�r^\�) k#%�-4C ��5%an 5l&p-100ng/mLa�(staphylococ��e otox �g�6( T"B�y �VRPMI 164S�C��nV d % feb#bov�Kkc(��!�&���%a 1% peniciY/�ptomyci�GibcoN'DTaRx5���uce�:� X� �Pros�}k�!8&(�$w"�)�s�'�$I�?t�� xt"(G �3�'*I3�0-�&`�9|RaI2�1HƩ:�/!�Oc��e$���y)�Flow-$ Fluorosp*� Beck/�Cou�G"�y# m \omm�Qc�|fa��͆* 2^or" �n�n�n�4�+n�-h_c��)used:�o� T3α5�d( RPA-T4 n� HI10��,�;a,2H7 25 ( BC9J]6 ( O32{./38 c� , Y( EH1�wFA�3� G025]���hBioLegen�o�UB1,<�RF8 B iMY( DX2#aD2� B-ly�_ [D^s�dO ,��D ( 2H4LDH11LDB9 ) ��from Beckman Coulter . LIVE/DEAD Fixable Dead Cell Stain ( Life Technologies ) was used to gate on live cells; and in some cases both Lost]land Annexin V ( BD Bioscienc h ere i$. Samples acquiredya84LSR II . TotalZdHIV-specific IgG was measu9by ELISABHculture supernatantB�plasma as previously described [6] q`detected`,coating 96-w!R(Immulon 2HB[Ptes ( Thermo Fisher S�t�4) with anti-hu!�$monoclonalo,( Mabtech , �!�efore addi13sEw A�!� standards^dif!:nt dilu2s ,��HIV EnvY�!�,body responsQ�nM high-bindAb half-area1�@( Greiner Bio-One1xQrecombinA�a)@1 envelope proteia� ProSpec )a�A!incubI��"�"�"�"."bA�2E�#J�ForEwQ\ curve , i�A/0immunoglobuliE��i ��ob�S$ed throughRnea�i?eZ�c���� suppli9�.q-�i� 0"� 1�DBioplex-200 systemp~(data analyz� Bio%Manag; oftwarA�9 . All @��E v@Graphpad Prism v1� Unpa\ Student%/t tes!i0Mann Whitney * wKcompar%�wo group!]�uVmultipleS��non-parametric one-way ANOVA ( Dunn�) �w :um�an toi�� . C � sons� rrel��1�1i)$non�spear� c8U q�of � t�!N05)zconsideh @tatistically sign� �d.߯Schistosomiasis is a a�1 �Lsitic disease afflicj ~A= mill� peAQ worldwidM�urr��� ap� pends la single drug ( praziquantel!�h�%ed!bvitroFva��Zin vivoYmaga�� Y�uQ!3adult�+m!~ also�i playepropert�j semb�)irr� sE�in� v�Q!( phenomenonIc�Jt.�, �^nha�!�appeal!�tE�bundaexpresA�-�e)�ex�[!F.L-��ig��O��l; se%��sc�He> �2kM  ai�~ pu!g��A8formate�ee�toqM*D clas�:H��. Fur�Ar� promjof.��A�a���yvul�v�X node� da�op� Gv�. �nega o ro��J�!�8most socioeconoeYva ng h�h infɴALn��� cond G burd��meQ ic5 behi+alari� PngiYr0[1�I�ek dividualse�tr� � 624(����e}a� 1�)t�controlN ZQ� origin%�-�ed dua he 1970�O1Binueda�!7 vene�fmC�ia� f!decades!� usagI�!!a varie�mi.]s�cprocr� � impactful5Ad�e� clin� ��irolyO��� at*re�i�efforts+- a�na��h!f�o! � heM5 asic�� , defP how%� work�How��"� "� of(re!�*� id��lre�! !eN. Firs!z lackIme; �|`!~of:�!)O� roadP > al��of newE��fe� az to��Ey(g� �?��at�iloit bper�3�![within!-&Dpathw�[2–4aDSi�,�inaAy�m�� A�by��ic�r�Hz�LE�� : all0d $�sy; sD to��ee�� efm�� �0B _ oundA � iEW�gy novel�uAal"���t!,A�irq)e �� rd���MIto kill�yg life cycl:g[Juvenil� m�� refractor%N!C0[5 , 6] , pos�y�ntribu)mU drivAjm>E�ofE3ahiA�ce P7!Ʃ� :ewU7��� out��2�%5��8";in�PZ6Y� % Fo�� b"� c�r�mfield:Hq�s&���do� �$achieve ma� ON&7 �, a reg��is no�E�execu�9 mass pad� ��" ��[8 , 9-fr��i�clear op� un& to }<�۵\penetrI !�AA��issK�ort}L�iA�ew�ru:!:*z A �?c] start!(�:.# i��-��w� inteE�m*� ��few year� ��1?�jbor| y�Bat!��c�J fresh perG� to��:�< up�� $endipitousic � f�. D�reg&��� plan�n&R D . jap�–a �ly�D ve b�yq e�m0]–!, miscpo�td�g�causeJbi. (1 wo-headed+Vs%�   ,%�gakd organ� s [16 � visue�strik�l typ��!�!� t!�a�5B!A�n� RNAia�# ed ue�p�essiv!5��Փengag�yMU J[11–1ŬTe* stud��cu���o!lwha�!k actsx n ergomim  [13] ��-"�reg �a�aځ� fun�a dopa�w]2� neur��, knowncaRof mus�� A�] t� �Y�E &�rm'�� [15��6��2���=��)�sE���y�re ��Mti7&x-te�  ir q��by�:as sh!;��$bromocript �@ %��kaloi7E�copIR�o�QY 3 , QY� n im���reali�as��<�?�d candes� antiٲ!rug2��{.�N one J�!m6s��B��[1!7 , barrier' ���a"� i*� a"�y���sA�,. !M(folio ( ~75a�20az8S . mansoni [179]$A8A� se��ismM �At� l% �y��!�of ��#=�% in h���,�s�A�17W<� now begun����a rol� :(=#~�excit� � nicha�A�20–22G p ligh!�ke� c=robust�Kt�I�:�� &fs�G �� D:Ba 6k ( HT�"�#� ledg�r�8Pri+�%�s� y re�e�terrog� ofQeI�s"�handful{-� ro� �r,go#5顙� �!�go*+�yB�s!�ishh ethoxb�� can be�#G�cato%b. Our p!i �5"!��: f�A�A�*9�)+ into�w� qK�o� mitE�i6[lsj�pr�<� of*/ctum62�!=ne���$ monito8 �D5:re)*��%��( fulL parź�finver�)�lloste>)!�ne &�'YatTfil�aY���s &; @s!&�$r� �E[��s�Gi-� ��, eE�s GloS�o5��i" � = cruci permute !�ifirefly.�incorp� !�a�-%do�fPKAcW �>AM)� onmE�al�� �]enzym,t 2�.6Ial [23 dynamic rL!�a��!|or� �x� e�.�2���%Nsw , 2� o evaluat���)cweL���"#aXZ}.>2v !�:�E���� ��p�to 5-HT�� � 1r[20!O&�����u�|"F R�7 . 1<A �2M)|mZ�"� ��vo� .��,"�:W:, little��� n ab���9w�%���� C i�cha er' m��ad%%UevokedM��OlresnSig<a�3Z$M�) f mammali�i*| l� -�:Fa�!py�E�!=a��of�princi! pilo&a�6@1�Z �m"";jexNof>b Wc6>& :3+!I7-5�MlX� 5HT7��m)�A��a�comRse�������&�eK�,�pieǡ�b*ce%� fQ�U� demom�GuUan unu� �X-M+2��m�y��]�i�� �$!�&�7R [2�2�6expos����+lan�jult�E;lon�2�ofM�����!c5�* i�-o�2�atu*)�:f(t�ic�" . In2Q-��AFa�myoe ,tory: exogen *c,-toM�Ѫ� cr�"ine����'AuE%�i . s mo&M.�[27�;8�hWhQ��Pon��!q�ˉ�, i�onle�!b{� �br��n4 ifz/di�"!� �i&.1��[� �UF=<e QU�*�I!ran�/pt~&k$[29� G!A�!���  christe�Y0�E\!J� n epe tagA�1a��'�HEK293� qj�)��P ~56 kDeducQH�tɍ!`predi�0siz'Fig 1A7 To��&��K�i~)��\ util� W��嬩�a)# -�/2# *t cBX"m�‘"�"r sLce)�aN Exis�inee&M Rn �"bA�"F �I :I � �r*)/*C#�#�[���Tee�yre��n�ydJ�iE�o Ae"A !�I$()�BQ w��^� ��#�F�#�� s�in6�.�C �-Y��v��! c�~e��m:�&K ce va�+�EF �CE�Noa�ng���)elici!1��!bUc al�2cM4) a� ssayU;armp �D.�2� ŽA�s��#9 4�sFb��s�V!�ei� � affi�F��]*) or lowB(2a\YRZ.t) 2� Ayp�4'magni+!!KJ�. �.%. ��le-dr)�manner]\��%GYt.�)] �a. W25�!'er920F%�o��! EC50��g&�\+<703±90nM ( n = i �@2BE�TR , �QdoU�  S+hip shif%�to�M�eW>22�6n6"�p6&iB�:4�g�"s�Xm�w�lE�1�03-isobutyl-1-ylx0%�( IBMX#0 �Np5%/d��*oI%IO� ?-�a��251�4�drs.% peakmExacknd�4of ~1 . 7-fold%�~15 . 1 g !�!Z!"�M1A A8,� {1g a g�2i�:window^͡a�"i? w � ��[� %@�\s%��%� al�I+ he Za��( M$6sc_ dY qu>t� R)}� s [3W q-�!��-5f�6�-a]Xs� !m�!Vq; C��of m%��TaE7O7�poi1*�$� %�&7� �'�,6��+���w96�v�1n�`!k�est �( /"W5E�+F22�KH6VE�Mb��(t)�onW8 [u!�!>a>�8)�!2Ac� �m.�%4� 6�� in suspen2 (��aw!�� of fJ!erB�to 384- ͱ �Ae S1 T :�Un�-E~? �$A � lZ �fix&(im)�93�s�hl%6b"�,� .aR�/BX M�o ongo�e"e3al�{ip�E�� g 2D.H����� stim6edi��8I�ipsycho0�Xi9pin [31] EI���1�'"��) S.*6forskoli��D2}�1J*E%�irmeda�fe�$'��20*by ��a~��r!�&�m�@�B>Fi�weI�esX toa>\ twv,�iso�-& 2,ha\iso�7 d–a�*<)pubecceG� aa�erIo.�L )!Hb9AK5�P�he NH2-t1uA@ Sth&i�=5� loopmU2Ee nseteSB9�i��%1�5 L di�-�~10�r�� � ( �32±403μM vs 2 . 0 2,%� 2E )�2&3miF7�/1�e2F�S1kBy&�s��a membe��!E SER7 -��i� �:�>ungI�&S7���"3]%�E�*�a�(e:&0 �IA.��fr�!erbF�0�ddF�!�u&e���ju7sV.�ommerBEa�8( ~250;3��in�4!H"�r5[.M:#n ���be� H� ro�9�lihI Q(eA!�.�`�D5r xclu�. alse�(A�� �B��y ^ndP�# n*.�tb -�� �� mo�ty!��otocol%6)w/i'"s_at�3A .�� iK �E�� A�huW7a�>v -ey!7�>i.��6W j�ro �8>R a6��i . Af�5��A" Q]0 � At�8,:!�a�[32�"mw�"B �#:�>�R direZ>�.�Yhe E�5�+h�&g8"� t6��PaD-�"� &�i;���M�De��N�7=�% de I:y�>2& �R -3�{gol� � *21cE�‘mask} �IY! 2r Q�ћ�� BYr%�Ty�5�R7 teq")!J� h�?mapA.depictM-1Wp2.H$-\� M��+b�convey%� ARm� ����.�i~. S�-�(s� � uniqu�=i�5-��� �&� l(-� 1L7R�siqV�+� ъ!�v.!� , 23>re e]%*� �9ae!�^�^<o\%o�(9i[s"� ��7Av�K)� �׍7at�!�9h"��9�,B� A� eE� view �B�(��s.&:�]@�)w� ss�)Iie(as&8� % .b�=�i�#ve �Ca�.�� "�%.oes–if�1� ��&KaG3 �bach� �-A���0(' aGe)�not�&� 2loc�U��E�ch� e �A���j2p�nte]�� onfirmM'�qE�!�,� letej���hex�I�a1.�MvL�# ' algB . ExŇ�� A��4j�!�deEE�"$[!� A�&]! �A�i1Y�Jq ��4A��op6 .��r] },�E��L�@middlbK��p�t&� C�i�2^.�bottom��Ca��!��#�C50>& / YT)�-q��-` �"�aE̡�tinuu�E�.�among����9��IurU�"�A'�4.P2� ( alfuz178rp"adrin�tomoxe"�/ rotuZ -�!��,A i6''�J &%%>1a(= 701±207n e�s�g�?� M~:�g&[ �9�L-�D>�.,bD)�9_d� a�8��"q l"�)c�.�*�8 of u�n��e�aK!b do�%!��5r*!->�C a�"K �&9,e���%� %�cur�Q ,av�c_+ stig)%�@a�P$per0�p.�by6 %K��s��>�ac%ED��(�"�(*Q1�#3�34*Cer�B�M�*� ulzA0c!�7$h � e hyjQ���5.!&�6��)��!�! pept�G6y3�Ib�6T�+o2�(10��;tyH�3[v3, �/va$4cisr!�Q|5?2)� .*��! ure-�"SIhipaASA�f rgo26tf�Z. 6vX5SA�.) �7�is un�%.&"�**�T suggI�a)��6%to%.�o�krai�6�A<d&K !Xitself1�6��m4�~@y ��ٙQ;�>�S,�b!ˁJ��Ei1���" �}��=�,"- R7� > �E#pseudo-2�D�+Q�(\b5 �J��Arer�%>�(!`1�8(bey(-�>u���U Q;)&V). I� �(&hE���t=? &�guiqc���l�̥X&�!��6wIِq�/E��`o� 6�� ��;�"a) �e� } Each!b� &Y?discuF~ur�2#&Pi2t���6�:y��.�? SBalB�k �edJ||F�&_ �1Y��c >dihydro�- �rch�.��8=*�{�QB&*��c:b*��E�� g�F}�mGU ?of 232nM7315nM ,l"m!)�8n� 5~1&Y5t$,[� �w��?��ʡ�-43%M�KByA�tr�R,ɚ%��Xq�,:`,�!g&�ay�6 ucin]���0cid diethylam�� ( LS�����verteb�-� 2Au���&+-n.�I.�� %� ��"��!K� s�E�&� ya��o�8 �F�$��6s | 6  !)� !touO�� accu9�d�:��H�.>�A�5�pE�8-Z%e�h v�-U4��ion�A�ew(&��et_.� � B–� . At "9!6:1>10A�):D1 a��lc qlet!�P! ofF.g&0 %��P�A�&�2�a mIl2Og�>�@�[3�/36]��� y$C�V(�?�<�KA of 410 nM�z6/, 629 A�453.�Ugi`-[!L�i!'�)te���2�Ec�/� ��mWOEƙ�I R�"=��A��3F3�<�I- didc�� an"@![RD8� A��aOMulFve�M!�i~ic%-�&5"�r/Fo2�!��� U� .A�Ap�!9�K6�( a�/‘V�<of.4 [�1)iH^kBLt cyproh�Xd�. 4I2�)El�-eed��.-*6�0� �$ y:�} d a�"�ah-$w� :�\G �9yEr��by"ZW�[�al�a7�p�?ng�!/ �"8 :�v�5long-W12.���j1 p��`.%*�n� I**,(a�&�$F"lisur��, ris�d>-a�.�"��>]erv ozapAB:{i6C6�Xm �@m�1wr6�ű�a� [qb==,6L�T Y"�iqf� � re"]6�&&���4&� � lo�"-n$"p *!"��*�� *G%�Uc6sbv th&a�1�it�!�!����eZJa o96�..�%"r top �)�d�D(hoxyisoquin��.�K(*�!{�)�foc)���N%2�a��moi�N . Sl�"3�&�� �sutU�!�a*N%!�.l-cM/F!&K�9�</� parNY!berbe� /pal"nI&�E‚�S)E t�Ibenaz Ff,"{* S�W!��!�U��,'9%s pncA�� *Dk riF��5e&�1A�&� i~:O. Eh�!?N�D(VE�ni�噁�c�sEA">.,qku]�itq�*87 arr�N�H*s� sus 7&!� s&h>u��submicHF.'.5�.�!+!��98�>!l?�_(  drm7e�e&�1gW*Z� r�bia!;��a�" towar�&�쥇�fav�$6Pr al�9‘�e �in-oA�Fo.� b�^��Eri;Ni�7dI�5{0sa..J �-r�!_2� 12/1.���ed�.A�K.�:(yl-sulfonyl�E$( SB 269977`SB7424c2�0e�t�e�� [37]m!�&�ly )R��2� [� �9�d�8~Jt-�!�Uxr� (Zb��rc� a I:�I�v"]V�b �be"�-� ��,)�� ��AKDeseɒ�>�yN)�A�5Y�'� iZ�a59" 1 s ? &;9ŏiPO��2�� p� ^k^&� F\.� _�-� a��!a$P' taneP? m1"@� ree_��u–B�M�aN2� Plli�t28 p Ur3(ł≤|a.T2a� h�VIe0 ac_C,�ng� �<0%��� >�o�A��!���st%� (� F!� t=(�X5+2� �>��E!HIAraorye&i �Y6�5"�5_��  )( & ap>y��U%GE��0kp9��e"�?[d1+�4 �%�!� M��-@.ov"�(&yda�nd fe ��b�9�$. B } >-O>�9�xy��"d"u ia�u:p�w7��?�+eP*%�osZ�T�ex�7CB�.� cAMP.s[38�39��% P%)m�V!�2*�GYIdY0 , 3�U]_���X�#"3ѩI;�9��1��9!cU -iA*^42o���I�$�>Vs�#a6\ �Cd�� �3R��. BK %� A���qE!��M�&C=m2ma��٭ty 24I�66F�,:�-�n�0nO�� a�vlyYc^R: ��d!e� �zaB!�3)s)/A���rn�/Jrob/T�>RarajBQ2>� .x Iw6�as manif�� v^n To d� . ,���eJF��o:�or])�e2c�eKF� E#at�>E 0s/��.al:Z � I Qti~N] bluna%oM�q�!~)1�r��:Wr�R�NN�OEifᆩ2�)��P �w�� � )28WIaG#:�* � �et> )&�E=y{Y� !Xin 3h�S)�ur���l10�m�$!3�poR�h_A>m�k� ��<�h8erA)reed���beaa+"�&d924��6�1�)�A+�6�:co9� uv 6JE�!A�e�!P�$N�10��� ��VZ`E\� q�)��0�B>�s �c�V.& f un%2:�$(<2_iI�kU<5=�C9.�L�l`;at�1)Uo.'C�*�Ki"�`�����.i ed*���Vh^�7&h.~30% � o ��1t�ma�i�.v�hc�  �y"�LsA�cer�ver�&of2�m"vM H�&T&N#"�%�m:b`�C�Uhh��sh�ystudy� 5HT75 jI�Zst�|�96(R �� ��" "�+i��!]".�SBF!��amisulpi_I!a04cM�2��t"� t*�W| evol�kQC3T@Os�NpE�?��m�unsurpr�$:�B,�> +e-Sh�fcir�AZ "a ��!env�dk4�!> ihd+[zi�1��nd�as Ae8�))&�: �mhI?"�Hs�A2�m�fV%necessi|S adapt-�gisX��>�21jc9aP[�Urepurp�+gAX�e��ex�ng6�% �s� %�8 WXE�*��f�Ln�the�n!�Bode nov.ng!T($a� y ifJ�p>c�|���>6�s�$Wx$e�2��"��%�tU &Eregh,Y*��f� >��h�� ��q+�2 Kor}��.f reciKp�%6c)A�A�de.2mJ�On&� 2�.x�� 62�%q>.�l�arci=q�c�;Rd!�& c,��B� �B. E�>� ]�[/ �w�:�*4;[�(�-6! �}�a�`ns�3 [4OVAl�.xh3U m-�5 c@6���eN]; � N`do�� arilQ%� .�(JY�V�<�10�i&4 c~pc!b�/�=or F�'�@A*noa_ex�<1 of: �Q�ea 1� �"�hO���A�I�( "8AKOD �>c���oA�� Ep. WPrdC�I/6� ��Ace 3H-d�a�"-����@4�but61l>� S �+���_-�2�&*:"�8� �2%�oly��K )O�"&U!] !�$Rs.�"��5a�!��un� >,�=ca�a6*�'L 3 �Fu�r �4nE!��ee�$C#mL?%U��,ҁ� scafJJ� qT�Y�*k$M}6r8&k~"�.Zinz*{) I7Inp�(�ue�`iT� �m�$�*,��&�2�.��&� ��"� �s 4�L�"�0�(-�bi )ic� .�("�e�%ous- 8:�3flu�3. F 5#QDuptaka0wor����{4�VQyhal��&� !Kn,ce+ued� nore�"ph�.���o�YC"NEO�!�q��/��7�6i s [4}1"�&Yperhap�Uq+gAru �e� !VQ!&(q���Y-of!0ch��ZjEeB#j W*�d�!Bq{Aps ah!C271%ers—.�5am�iZadr�(Xw ( μYO 6!�nd.m���Hs"of%G��$WM�M t D1 , D2!��1A5�5^?R";6�92My-(e� ~70068&$h��[�""�= :�2u�=�~M�{� D &�/h ��]� �Kw� e`, e� /h����sm(nu`G9��� �D&�ɥ��u�Italwarm �z�1a��Aa�qJ�#!��d�6�.6�1B2�)�*�)-f�� -A&5)Aes�E�lHF���w��ocj o�U!�an�'�6�a�4/, '!�aoro@!k�(a3*tɯm��Y �ndE�!�����3��&��/2B� `=n4g*)�A�B0 (�l!��&�%e�t��J��C ��qvbi.�%�&�C1�`:��%�s 89 )U�^a�q�!po68-~ "�G�two&��tY�(:� ,�a)2\ IsG9P.�glyAo-e.�*�7 �'�GIj�nD)�poo� I�. Sl$�\�Fs4eag?@H w�G vanc!�*j \j�0?�A���� ��/1�I�=�%��:tY�ae �$soA��65%� 8�=�]'!�o6[�J�atH+YXIhup&bmo0 � stagRD*�ini�*�[�����=s�pA"��5in� E��k1_s aimG .Oal%_� De"�` *7+; harm&��2� 1@!y �:.�%n����^worth�� l)(AH�"}m��e�W� s��chE <#ebo��.We� .� �" R�)induc��hpln^"8�P��68!� TD�ّF, �+ed�qA ��zv7..8R^.� &H)�{�sa �%�< �$6�6).,'.&�-eQ.!�.C.V0. AMdD�y��c�r4pF=�=tu W.�m}��s�j$ss*�JnJ^N1L , 4wр�� � %� �eg%/c�Zb�.w��'���"�`deAan�-A��>�A���"vah|\�@&�y�!� whol)@gaoz $1&�V`΄m*=B%�C @?��� t_�, tog:��"3QD���ha{�&� ly]� weak�'Kj�If�?.2\�E*�,*�"j ���0M7[*�;�� kine�2���z�Ahu�%�Z~!$!Jw$�ib   �~��$nd Ƀ+Am�a�x6 linB"؅he� c�**���Y�A�lso!;�at&MyNT�U��y�] > UYo�!c-�ic-�&?� �%b)N��.L Z��HQw�{b� ?Qv&�PachI9 r%� csR �clu#$e�s &�\� E ��*�[�.hc&�C��E�!Y �E�e�8v� /!�apeE<"#xHTSN�A�QaZmo!�fil.MW � n�ש�A�!a,6ePRQ�)� -�Lټon&A�!A�5��6� *t5��. Sևi_6G?T3-I~_N DMSO� urchW�4 S<� <��6 L*�J>=elleck 0 Cat� c . L2��� e-dismp���Q)m�F�)ls DR448 :LY21584�&.~!�5-CÑ�(dotryp>(T"� 6�T�%s &�� . Mjrxy-ni 4&>vR+|2T, &H3�� N�22 6�6�E�3uangch�d :7 AK S)4�] .6[R8( ATCC CRL-1573 �~Ώ-�EMS l�)"'��10% fe�\bov� serujZFr�,�}ic��A�100�N ts/m��,� Omyc μg!�L-glu5�290! . Cer�!I� �K i͊( ViaFeWhPromegaA�s��i`>H�&&W�U��O @ x106�per T-�T ell--)fskJ� �%2p��iy enco=VG"g(.�n"�Rٲ��p_12673A�GenBank�>eQiKF44405Sb}.G�IKX15086�a�sS$cod",���#��*% ,X"� a (f�NM_00087�[4y� &D Sq/�Y subc�fAi��CS2 ( -B!�Q��VF7%�In�ge6^E6�j�t��7�7to ver>2�!ouf � 94�ll6�JŤQ2Y�.�%�9�:�a �Rfv�{�es�an*�]al 6xmyc�k� harv,)24 6�s<t-��fi; p��1 solu !� in 1% NP-�Ta@��[*�,u�Bradfor0<%�A� ierc?N . De�Ad�V���aÁdas run� Xa Mini-PROTEAN TGX Prec4Ge�<Bio �at 150V;emi-dry1n�W PVDF~]ran�Pr-�u�a T�-B�qTurbo |:fer pack�� x25VE 30� uo.6p�)_ 5%�fW ilk!W TBST�bris-b:��,�^120�A{1hr�Bi��Rcubato�-A  ��oB�( S  Cruz�}:500 ��5%q�k -��to!�h� in�3x19 A�AeE��xbG���Cor Go�b�4mouse IRDye 80���v�n�[���(6�� �_A-�$�'��^L�$Odyssey im�#bE��3>�"Ly"k�E(�����an �B5:�} cDNA"�<(  >f NMRI�9ai�J�( Clonty�)�p��r�'0��c�vPCR�dun��� A�� (pGEM-T Easy��-1.��#AX�xb!!."�/a7-`�'�~�S L is�b�Q��Sb’/3�9 RACEA�MARTer Ki��)7to�RNA�Dr.%�.l ( TrizoMX��, AmbA�"P�ZMR!���%�v��( In-FH HD�!B�f-�͋��A�d�'/(% ,��-&�q%���}�� ce�to"qh,�&idEt"��( Cor�,I� 391\/����c1%Ew-L-DgK>6� �*u 5 x 104w /U in DZ� % diW�� ( Gibco%� `o�� 4( 37°C/5% CO2�di}��>�!�(a���exL� HBSSJ! �$1% BSA , 2� HEPES��H �y4�nd* rMT6ڡ6h5]qui�@�ctF�-����MA`2NSM>(�Max-M�~ De�bon� � �Aa8�,A�M . C& j|�vX�\End�N fig lG�"�#�G�� ;�oc >�[ c��aUF&�jiE!�6� �j"n. L� ��a���o&I � 0x!AI��e2�; i . &5μ�:�&a,ueB YtoI3!i��.A��!�6YbB#[Lb]x�B�v6� �� goni}!�� �$verage9ddev�vo�Z� Emax!G|��, vehi��>H^��at le� 8%&^k� 13%���eK8 Hs5�zZW� resaz`� re�e�E�E!7u~@via� N�m�vM(��BN=�, �Ja�t8 ��A�w�fluoroc��,�560 nm yion/59 mi� ) m(�  . 5h�t"�%Tos p+�Z�H%�.* m�m���y� 6�� 7a T-75�E�sineR(��25% w/v����,�14mL tub!%S ifug� t 300 RCF�"e ��&b�)�^�<�iM!SI �Oea�H"� Q E>J#=:.�(�5"�  :�fe��r is n J)�e r:J��&3�-C��%#%ly � T��gg�-)n�tt�B��p.����G �t!S4IoI!)w�$@45y �:12�ps!�-n]8 6��]h�d�m�H��:�. Biomph �gla�P�M-)) snail` �5N� mir'3i;Stn PR-N%c"�p � Resourm/U�.�NR-2196;!scerca��He�f"�.�l�1�;���1C2Aman��)poo� &Qula vort���3 x 45� �aea `��? by 3u ���t%>�R6� grad�uOIe,( 24ml Perco�10X E� , �m�(-s;� , 1m�1G�: in��85% NaCa9!!m$� stilyCwa�iN 500g/15�hat ��S*�Z  �as|/a�ui�.Le�l:�BasY{!(ًa  , "c ao�����Vu��"+?M���� ��#"�h� �" �xi�T free2���X4"�C6_�B�Q"�Ma��K"�Rԩa�5�)rW":��$E,��to2�!(@#�e�� y=vi�XIn  3a]S ���Q,&��)%&29�UN1���aע��B1,��FS 0��AI.IF-k>2!�2 �d) 0�*8 B?E�2�24�%w �~O:�/e75mL ��[0�;@: "C �a+�o%vg=l( 1�>-�%u� ) kXa Nikon Coolpix 5700 ca��H]uo'$Eclipse TSH�Jsc��!x obj�vx �4e WrmTrck plug"0 or ImageJ�3 to�yj y}[2��Brief|L!�major axj7�32&u�=t��ƪ0�(Draw-mof�Aan � C� ���C.H[rQ�. }/��*�b �d#i���"K+episoLGd g��h�!2�8 �,@�by�� 20%A�*�FX �x�=dIowa S� Uni >� M�io� �af0OCommittet F�C$Swiss Webs��m���N�-oR�ኁ�2�at t��j eks �{eu�� 3479O!�sacrifi<6–8 wZm-i6!W . M)�e2lz&�5rme�0F�va ��_!��&ԛerfZ[4�Y�%YanestheGQ�!chaa-:��0ervicG' islo� . M!oQ v� $sodium cit�S ( 25�Y�y@��z�ei�&� 8 �9 RPMI���WaiE�p"c�2&� wN�` g^� ��� ns e wF� 2mM &�!5%�"<.a�vw � . Wo�$%O��&3b �&QFE"<R���Bt�ocapAF|��� a ZeaVDi�y v20� reh�r���,a QiCAM 12-b<o� coN�CCD��. Vid�:o�P5av�?�Jfra!���Dkone�X��c��f��+B^k6xg�f�cap,��m U�zvlεR[�ZYa �F[45 B[�va�-�"� ћ} ")� �ClykG�1y��$e ( . tiff� tac��fə�) %*!k&�|�e�@E$.�o�7��aդi$pixel6"5s$a!>��%&sboo�. M"`&as:�PAi;�+c� rKX2�rsub ng4(<AE3�)�'� �&n�} #Cu3+� 7t1"L-�T�F&]1per� a*��%�  b kp�g�'�z asurG�57"�Ca�erjof� 2&� �c*Uk!a��� � �� � �� ��i1 d }�-CYS . Va��" JY8mea�f±I��J�{".v1in&C�e*Wa.���h�ca��d@ �l!*8UA�X"\F L&/�A NR"�fa'y�JIR�Col�!V= ie!M���.��^6��|rg�*-=metazoanay�&��"�ga�  /�'" tJgerm ��r� Adhe�'Y��!tb�fd/� � r�P!( ,��<i�iϐb�bffi;$* mai�7�jegq.U��g:mixA�. H�O�"=+=\ "�-)�+fחY"amp9a�!��-m�bouAXΤ�6ly keepse�۰��c.P1�+�s�b��u5�nmi��6�D�mus�� �3.�"-�!e�2ac)�Bde�6_=�nY ��$i�!R �c> �/�0W2�il�c�d�ct%�9Jsca�%QZl:"J0jEi:��2�0�es r:B/EphB ��. c" "�t[.r"�0�+3�a�n��,I��� ��s)�!��_forzC)/�a�E6Is9AJ�7ioRA� volv3pa��cedA�n&�c���Py+� Ra�WRhoZ}�w"�Fm�s)�a �~e  >�7q���!���[Ɉ stea�D2�es]^��G)��j@8!_-P5f�n]�/=��XPMe2�s�iyC-ta�suuw. W�/ Towna� nd Holtfr�|��"�4�s�3 of m2embryo�=Q��� u}o�bt .of=hR�-&�t�3f-�mN��� oc����q�Xb^+�+ utual “-k�ZJ,. ”I&z;p�aODer\6i�S�%berg'A9]"6�?�%Hyp�7?K@*ch�s��MrUeNU��po&o�a�*�^z thei�B�yA�!� po{Bo� �f�/��r<xpl� ,Q6�7ar�@�y� �ݏG�}�"45��+�e&0�#�i'Yr���,Qj32�� (��u�s43x� .�AQXenopus"Z��sa��Q� al bpcocoel f�&CR� -�y���4>�,�'chet's�1f/#��ޜi�J&Y[U����va�*m���ory�Z�3ureΓI#�5on� a spa�ne�kWfibron�n ��rol��"<;�1?A��{DI�U�j�isS _-.� [d?In; !/!W:bai�Kre+�o3�[5�/!�s�mo̽�8C-%XB/U-c"r�%U� ѣId�re�[7�$ Q���ha, Z5s|4��z!� ode*� b.�.�!p4'2iE5�!�S Oli6c � ���+":�:!�, [�t -7a�M!�!�}pbehav�(Ppart% 4nown . Non-can�* al W��ign22*s� � �� Xfz7 [9�S� M�of w9 ��x��1�( PAP�U!')A anky!�0  d��:x+5 ( xANR�,9q*SKPRhz�nase [10=� [12]E9��%erFt�?���2"Y�a�K"�sa9娕�)����Ag�B��^U`. A!�ȧ�<�6jOi/ . �l . 9{tyr�Me�Ua�Kasubp6�to2jK s-���ir"�)�`� "� 2�#l�Jx%AEA G B� W5�h,G�ppȭZ@cu�U'ft�gs�Ep��Ja�)H�l�x�\�� }|R( �ňA �5a�ng��/“F� ,`�r J-#2�a��"�q“T ��u8�F; ����E%G:���A��%�YI� ��O����<WF�% �A22com&�p`Ir�B–[1�XR)&na%Hel�74 !�(rhombomere-U��"� repul���-- 52A �{aktl�Aan2� U@�a� -��vC���+H"�� D )R�W��2>I, )Vo w" n7aY(��H<oan�ua�,%�Lk�M!ymp!�"�ea;��  } ��I62AW)Ya>��"�( 2�F!T� �mvo �Ds�2� have���./}�gain-of-OA~"�)O��:thu�a�&;��d&,+ ���s� [22E�2� Th �)]Y��ea����r� �9i� �,MER�. ��F7n ��"�"fu �G/ kx m/-labe "6� �f%��alF1��e�$�gre} n�dz*o��� onfo��m�h4.WNMov�S1–S1 >C� sqb� �fe�p�#,��$�'F p�,�& �R!6cer�#F�*1�sDArrowh�D,�>SF� e5 u��ev>�b�� �1Q5g:�-.�-��min�2D"�Z* y!�  R}p!�.�(J2 o�&� �G�A12jS�0��" hE a��U;��)��qVy��wC7o���t-d�8�xf� �p&��llo\ b�"94��ac*1�G�gR�h&Sal?�was�]�<��s�}�!�Funi�l�%wV!�u�(A �G .  ��l B ,^WS?v�� &EJ+p(5o�!s0 �!�E�ht�O�~rteR! E���; P=!, tau*���Diboften!nauyg{Nq a. , Fr{ I�=t 34a;5��* 2a;N"� �/�t���p���]�5�m�"0XU2see�+�%�-r�F�E��o)4QmCe rDX O%�.em�R6��e�p r2 U a!UclNH349@aX-X)G9ZF7u� zc�n�8attn! u� ���P��)fAki� %�)��yO]:M(1Qa�A��Cb��\� %n��l�l}]�".jo �A�� u�6 !�sY��s%ao-E_CizaS= U/���Q�:� Pz�ul�E ;u�p0E��ct�D�Zi�C����u!Q]�~�Z���j!#E~�+�}�a�D��9h9!�v,D%��h Isfac��We �/�B��b � Eph���u�"�8vDB6os� , 2B��eO^��,p 4j5 �@�L!vi��6+@�O����1 8&*�%� 6 �GXld�ue5~\all��l:*��~+@��&\%b�#�6[�P%1Q-�!�,e�A��L>�+��!,���"/�5 du"� "� %wO*���two%e*� !�raT� +*g�!��W398U 6*"��[ �s; A�had�=|c ttle�"~ Y�s[�$�� �;B _Fr!G� �/"�!�%4��%�y �B�Kim> �r.2.9� �"wi�-%�� b�%�llh[-��"��>�J�a�RT-PCi� S�&:ř7Ek �v.�*�2¦5 s;a�a�!Z�,�3e�mrie���:� ��Zi�rg!b63*A'(a�rt;�AI�!c� More��ph/)P*n�\)�A@��"� g�$� situ ! � 5�AC ˞v|(�c[25��or�&A�&n=6;Va[���� V A�Em�!��^�EN���wo adja�(M��Amquk���ri�he�Rc{n.�f�O�^!���kp4add�� i�,aB&  lossbdY2+�e� mdRa0o oligonucleoc{�MOHXVI&B"7 B#knock�&�;�!K�J1� t"S � d/�& �!.�,v�࡙g/e=J�q�2D–F%�M�A`_�l""� R�"�)v�Na4�a4*2/Br6��nS2A–�disrupe�A2�l�����f�~,��)b��Sr� tadpoy��a:5aY�d turbA<ii�0�,!9�BdrjdZ{(����hat@Ml5e)aByMR�e�cZ�r���aNby��Oae3�"GE�"t�pdT"5�iE�28 B�B2E�� ��-)@F:� in5! dXwe*�%&��2'C"�S3�BB;�w"���Y�, "@'I��WWil o �y �u?�rinB1 MO�SsldlGr �*2�unB�!� �%,0�� ��>�"�$�5��� Q��1��AmQA�|�%�5�R&A !+s�A"�ڻE�r��!I�eau�aE�30%��0%.��. K���m�wU`- 3&rX/Z� &&V�94X In+�h��� #A��n-ImG]9r� *��B mlGo2�1G}5Hn� �?&� &� w#ou s��5 nu�)�e� a m�_uL� d�+���!q�\j�-s��taq�"!�mhot>�'<t�15�6��,g1� � !-2��X�!nFp �!d5�.�9[\2i*� m�=U��f.� a.(�?( ∼aB)�<e�now��Ni��8Y�:�i�&��!T�Q��ch!al$y&[M��9��B S rX�����k�ņQH(b"�Bwi�� ��տU� �� *� ��)xm��� �2�7b.W0 trig�vpay� atc � r1"J�&����F�%�.�*��%�E�o�**<k& )i�F�Si�� LB2�u�-�]�: !AP� cyto&T�p trun8 7��a0cog�/r� B4ph�C-�YJsheKa�a�� �?s � �n" ^� Z� �D:A/��gi�%�� A9of �)kdif d�d}��1]Y]q@��ver��"}"�.� �BF r5|>�)(MO mimic&ii�%� E!�A� ZT,*[A�� g��1d����g�B fam2Qq=�r�� C*q ,�!�-�=X�E>h# �KDGF-A�f_�� � 7R;�� :K�men.c%t�64.M����)�hN &��"6 ( Dam) Winklbaue�s��t��(E�Pp���̩�A���-�%�6aY0S4 Like�����BeCa�f&�,-�� matrix�|Z��"x=PDFG-A.��0(ӡeY l.f\ W V1�i&���Ε�V1�,9nhas�H"a[A�P.�3%:d+x ���T5��i m�� .Boccur5��a�]�Q�� 2 !�5�.6eg� �-�lI'"'�. al."@w�gu��b2�5i;3� &�a08$ �Xa)a2�>� /�I ion/�pe2�8W"�� �"wbtx9�e9�iga�$�� VviA2 : co2� �" ��bsE@�&���A~�B&5 �;"o!���o���9up!����l�7;�*H( { �i�'��' a1�� |�27on53J�g �owJ�}�=m�A���Se�!{x p � mb=.Q�Et=B>,�OiUw)��!w)u�2d ���"X �{ �Eڍ��z�)a5y5 vterpre&�/A�KA�� ]~=�0J�h�| �i��"^!Aa&V4�$���M0�/"�.S-�"+�!5�ew� ,y h&�6m��,l���#fr&Jm3��f�8�B(��+� �s"!a� � M�� ,"� =q�3a�8�{oMe �U��j!��$i6 S!2��D�!.6�/ !�.�/7 DI)$6#to"e vv��:� t� �U�e��en�� Ced?.�zUP"M� .��(-�� %�� e%����Bp#��J� B1/B21md�,��.!\{�A(�=-Ig�͞:�-�� 1&c�-��.ru'��%�d&� ŧ�sA6�ro`3*�#!�.��TiA9.u�Wm*�0� — �52�I.Y!k�-�$ ��M�BCRws��ulA�A�c�C��6z> "���j5s-"� J�,��e!B^9s����!�bf sa� EZIkF�I;�� �" %BF!�Ep!rtLm���v-�F� �%�Vr b��� � "�6V�A.(UJ<< s�@6���� �1�al �se�%�QF 3&��%9=5�A�8a second one de�Fpending on ectodermal ephrins interacting with Eph receptors of the mes9 . E9 B or �XB knockdown impedes cell detachment at the boundary ( Figure 4 ) . Compared to controls ($A ) , �B2 MO�6�(-dB ) dramatically decreased28frequency of at�/�event.�G �Often , 5 �8s remained appofo BCR forw4whole duration|!recor%�.� , Movie S!,, similar to5�$ aggregate.�E:6�Mes)�and�`moved in concert , indicaEstabletac%�. D9�was�@ly inhibited when1�1&deple from�!",QA45]9 C , D , G�5� Thus% gnalA�@in both tissues i!�quired%�!�J�eface . AR@cycles were rescu!� fter� �!�iI��b!cub)Z wild type�$test explaArwa}inE�� dosee� solu!�i�$B1-Fc fraga\.F%'a-demonstAong thaa�(is behavior!aa�mediatׁonEge�-�s5]B}�. The�eri �$above show qdirect � _vI� K)�=accou! a6repuls�betweAS��E�U)D. In our time laps�mXA I4is never obsera!r-� �1bu�/9s may ?(theless aff�AV- adhe�$[18] , [1920 42] . We evaluaa�e Gof�M/)| loss-�,gain-of-funcE`oniof�nd9��uEIa class� rea�=!\assayA� of dissocAd K star�-2 minu�~�beA�)�%�ve [31%y3%yͶ2�vy��no5�i�raof6j�!>�� �sugges�Ges)�BAGBi,ity does not�tributeavU�I� coMNE�E*q, howE�!rrespo�� r1s4�dimin)�.,. OverexpresE�ARe�B2%a��P , although more vari�+,186�!��while�2 o6qinduces� sepa��A�nd 6���ks.-, ��reatm��reY9GA6m�1Ialw(. Altogethe�putatACi���)sE܁re"" ne%:piɍare-� rrele�"!�ir ro�a�V: F "A . RhoA�Rac]well-e�)�� s!m �� i %T��E� modu�T cytoskeletal dynamicsuctiE�-NU�aFb�� implPg=��[1e��kA��A{� W�AAof�>�haiEyet uaddA�ed�esyste& tes�m=�manip�=}orn�n,. Dominant nr AN19,�N17!�E}M���Y� ia)eiEfX two-���5A , � . Becaus�j�aof�; stru� �er�ER�����Halso have long-terma���ň�5wa6 mpleaI8 se��aex���aspecific"�- Mr�!-!� ho-a�]kinase�\/target +A�T5C� Aart' X on �th�w� uffici�4to )HU�A�| to%Ig�� intoRE�, t��mimick!eYD�dB# GTPa� � is i*h ��s��;��>si�2�msiese�)�ly � i� duER]| proc�vnext askA�f_/%�a�� could� .GI��:6�pa�. SinceA>� &� ~ ward�pq� �ionMy-aD"{ o�.u sidA7b je C B4 MO`! 5�AΔC� B4�c,A I�!�cC itua�ly)�e� m�2�( V14, V12!Z� y�,at low level"� samem���HcE;,.�)�b�I�%�� by 8�� ���5C EmC weak1�a(�" up�6�of*� �e�bS6��CR6Cdc42mun6to�]�M5D�W��ncludeJ,�@J ^,����I]{o'AC%�8Brachet's cleftU���h% ��pro"�act:h8Xfz7/PAPC/xANR5QgU��g�p5���wem�wh�co-MG��ofg%�kM�.Oi"� 2+EpA� MO-ie-ed��did%HM an�\A^9�S4��2,5�� y�a��6�wn � llel!51 ��� examQa�ɕ�Rho�U��J on*� V)� by l�Hconfocal microscopy�&W�F�fo.�-��H���G ��5��9e�qa�stronge�� �all� u6He Mostt s .� � e3�v:%���� uishe��co H���i� �sF�Convers�(,A�"����2.KY�8�F�A�"m -UM�C �.����!`Qved by aB*�MC"f K6A–�B"�s Si�S8%H*� mpB�,F�f appe1mW trans�� q IXmbran�� abut� 0 ���"�clobeach oo for��� ed � od�t theyI clea�)ed� bE(Eto sl�~aL@�91� F,mfai!��&� Yr . It9as if.�loc�n a�st�!��e�2AQn�+�F�1fu retr�� unde�se=di�. OurA*ult� plyi5��sh7 bU r�� at"l-�uW�nA�7-de�� manner�invX��sub!�ulwiz� � �,� -Ef Ta�.�by��� �d-b�nga�a$ ( GB�0of N-Wasp ( a*� �P )%shAukin:'%9 ) fua�to GFP# !y1 �6w comb��& BCRs.�mCherry%��@by spinn�isk!yB . W�@ � W ca��E|�� th�e�  -3aL� �!�� E�; c�to�umupat siPof hige cen� 9�)�,s [33]–[35U��dW�of GBDsf!��Y�E%a.�7�, arrows��S�  ens��XgeneraaM�iFr� npA�!Vɐ!�M�"��quantifiM�Aldis�a*� ellsPch��1ɥ\ � %��7A�1� 0`,.-2 Csa�w>Bin Vt�20%!S!F g8, about 60%–8 Q� $ _A�9rsco� posiEC��a%B fluo�߁N  ,  e{�zubGDB�Th!��gn��O� 0p<0 . 001 ) cݥa� alon� �m@ see��%�acM�!�atY9 ��E2 headA6:�f�eu.D*�o 3%E40% (2�.�K�obt}!A:wq���:�qGB'e� yN"M�A!�/5�-A�uE2�*< >m adja%�A(�aroundEu,5012�!yrol�)�q�M�e���"0 successfua�� !.A� reci>'"��� . A( imag,�X ���� �sAF tole\1�df @e`.*C �L� 5ؕ4*\�i+in.B� �1�>� . T&:*' >�2qFlvea�o2�>tA��0�^A�b��!lleu����� area (a���ve zFsuper�n)x� �)protruŲA k,�u fluctu�sp�d a � rang���"�nd�� �"6in]�( e s S9�S10�s$Drastic ch\� occur�@� D fram�U�2� mi��Igr��n�3a fast&�A�� US espi��f�%�,[�!Za �t&b� en�t .! e�\���nalyz"y��wh�� `(unambiguousAAe�ine� = ]%�intim �'A4�EXa�to.galm[�m2 ( 14/16���A����13/14 Rtkn, f�in&� �L�A�me*� u��] ��h+�^��2ihe��"� A�%A�m� Ti� ied�D� G"�� / � ��9de!��h�� "%{�PE�!g��(�>AR,�"8�"%}some )w6mqjsAYal Xq �t�Q�Ia slower �=MsN�� . S� 1qzin8q� � �&in non-Q�ng%b=be du%-s��sŚA�c~"�0re� !q�GFP�m �#so� H���#�s�yda�2�trigg=I� . Noe� �f.��� asynchroni��eighbo w$]P� �a&U E! �E7q&� "�8B���@m" � �!nternav a�A� abse�$of photobl���68! . As;" *����Z�0E� e visuali��.FF-!���dphospho-nonmuscle-myosinII�Pnd� tubu.��I#�!5Ns�"�sQK"� !��arP � (N� .��enric�*MZJ�"(��o�-��$5�S7��&@!�pat!���u��s&e"X,�6 ���.�ireU�ute+��" �� c�S�D9�onndebod�dN)J ) �mus� �$�� esPucan� �P&�ht�global5�-o!�|� ey� y ]�A�h,8in�$"} "/!E�)�*)!we5�M� evide�A�synergy"t}��e�=$5�YF� PreviouA� tempLo�ulai�.E�Q"t�z [36#436])�bH)�!!�rmo� modeH volv�SAq"m*�1�um'free �^g�$�ssu� %�� *d�<'s� ���*�$ iffer� �em3 $noraC* t� o��� sa�Lc� n drF�!sor�j"un/., Gi!�oy� alog!�Uph��=�0of immiscible�lids [21��8]" [w�  n6PE1 )��&s�!�a � en is cruci�o���%�3!�tu- �ar$u�f �m!�po�!�haAKpo�% �!vx � -lik*�if juxta� , ac]%�b*)�DQ�p-nADI3o�})Lce8)t�( �N�p 6�*�rR)��(H!��!�E�Lz!L&�(W ,be�t!/a self-r)�Vloo�FY-9�V^ preae,F*=(z� b�s�"�$� �EDducd8�)IP%e-%��apaT,!� $%   &L(a��he�er u�spaa��%��:j]nre*E5GAris me� ism pr4-qsz intru%(2�!�&provine��- subs�um1+2 mig�&. C�:}&�,��m,� �,�5dy(p�@j)�� cogn�&�&!�coe in  h��(eleax/ov� mua�%.� nd hŸ E""*a* . On��s��!�an"is�_��6�*.� �ک��e �B�Mr"�Cno�0��*6)rev�.A*!zfac�fatj|+%�� o&�I(�%<on�q: + 2�e switch��ko/0S��on�2 s�Y �n#d��ty�!\�*&� favo� s [3�,4�,eAL *�,�u� h�T�� :(0�0A�o6�2D!*�"&�7�2 ]� �i�5tr�0d� � i�*�q]�[4�4: �4b8}1�&�J� ��tJ- �#��!O��)^2)�� , �lex�~'&�4 �� ^����}�LIGWn fnily��"�#&91- d �aJo�%involv�2emO/�=ofZ��di:�bi"2-al �?.� [28]� is�j%apid ,� -sca+(hA�!�.�pathways-{��fo�-�6r�se*�\ s [4�"N , unZ�U �"�/�K sag)�a'?m�$zebrafish By.��Xgap"v 5Nsomk#��n l � 9S��lP�a� %A�dispens��[46a;S"" ��z � 31AQ���( iso�T�:�:��8w �L&6���mchick1-[47�W�.d e�d!to=^)/!�eY��">�/�*si=�v#�mv� �#��l�6���EeP�:��F{��** ��%M�F�R.H5A\B�J�~kn�>� eE* �#&U�!��i&�B-IgB. ��F9N���dendocniINS[4�:�Mn turn.s�.  � [49A29/ho�3*� dow�4exfM�*�+m�5bEe adal@a"te$D�6velO!I,�)lS &1  d�2o�&/ enopus ga*5laU�*a��lB).�of%[ �� F�� �W + %�noe+E�]�_� A()*"�- j�Wc, d"� ��*@-�PbMN+is worth�n�+at2X very.�2�)� 9t�� � ��nsF%3)6nd%G�V)v e��>f0*>�'���uF ZQ�AQ�1��>HphenofproZ/Iuir� ��h�(l�9 ly m�?a�!>�, llus���I��%�] *�--�A�b.�, �� �,3(u�4a��@still&d occaAe=hypJ siz��a<7x A::�&N 2�&: be�4!�thresho86��to�'�d� ����� bo�:. Low am@�=a&^+�t� � to bo�"��_Av rest- �{��).allowa�eDtD9m� l�v�,.eisidual�9-M�6�de�2r exogen� �R.�I�<&b,pA�ouge�)@Z!� X��ld�&�5��o2�5}a��r� 2:�8po�il�� 64�"�e5��)i>� i se�ica�r e7&v*%"p#+or&�;*� R4) �1�;'rGe�sEE"?�- a�~�es��%�/� suchca��}��rB� CB�;"tYo/Y�lDJ&g e�b�% �"�!�&n<�&�maP�2R A��fGF���y�=0s�&>he*$ �c[5gA>2�"OB�tal lay�C�'L $Drosophilaa�I[5�t&Q�"1��o�y+�����6&R�� P# �2 'E�r3(i��r�<�-He networkffibron�:n il~a�55 ��al�&*� , mo>�� en5ue�D @d5 op��as%Td � phy3�us5�5�,�a re"3!^g4>)� D���!a*�a% �~9t[5�CI$"�-�1.� �4 null�'Gap`5�Qyte ly [515� A�G(�, numer��mas�JY���9!ake pl�� X2ple neu�'cAp7�v�n princi,i�e:emplo29[en��h� . Fi�� ���+�x~(el�matrixA��V!�oj![57K 5 a���W1�(ng rhombome�r� s P5=�v �l$first stepm0�7mat�J�� e & �-fi� �b� �b1 s . Plasm!�Xmorpholino oligonucleot  (�) toolj*��l�X9Sup��In7 �Xsa�on�Beo4A1i|�B2/FCImerr-R & DjBg��w2�do�W.e�M�2&5C�AA 6X h�$d��ag�7Fc reg�%4uman IgG�)pre-c� e� )X nti- 'Fcabod�:xJackson ImmunoResearch Laboratoţ)� a 1∶2Gi� MBSH [5]%}i�Jed �Gbefp ap�C�. mRNA6Ksyn� (�I�L* nufac7b( �<( mMessage mMach�,ki� Amba�MMOk"�<ani-!DheiblastQ�f 2�stfH���/u,I�� Avequ%'e@[dor�r:b4^b�je�K,%u Y�T�AS1� >�I� pe�1!s� cribed [2�"�M_�+�>b0&,lipQ_-�!3�!�$j�+,c(depFo!� vitr�6t6�"�!D�or��M!A�YSw�preY�q.>�L40 nM!�E�) 15 �/at room  'er���� �tab�2s/<�# �a��;u�7p�Bsa� Stu��'s t �8, tak�Y#�!/��t;� al c �N*&� %� 6"* zer&4ad1n5K�;x��e (" 1,�n grad��aBEQ,quE&� ly)�@2×200–400 pg m/, mYFP�r �9a�IvEԩ|aA�h JaJ to?#�MsA�.%��$1w=C av 21S2!j&�3r&�ME�ac�)�4a Zeiss LSM510}X40× Neofluar NA = aj 3 oiTZDvA7���cexc�PA�!�47>D514 argon laser li�=. D�@ï��d emipKfigMpHFTF$, BP500/20E�{ HFT^, LP53 �� � YHaka Quoruachnolog� WaveFX2;c� ;�e� 2 utoA2_.� �E�h�PBS%na�$tifad�#ag� ( SlowG�,6o,��Mm"p>�l� .w>c.+.��!�i�?N r)���Q lk\.�,lcium-=-5] 88 mM NaC�1 K 0 NaHCO3� H 9 . 3��DB�QEC^!fe_70to agarose-co�Petri-d��~'M �%�� u9GroUOoe110 rpm,@n�f orbi�shake�@m���=WO3�re2�P0� ,��i2HAsa��X)&�Q� �aY �ť( D-2��at $2 . 5× mag=E�)�a M��&S RTV3%t�s( Q<;)%3}�33for o�w - V%J.Two~am�7M�measu) avera) K%;� rea/��V� � of f��.�.R�)�� �w$dY�as re�/cea� . �-.W_� numb�jTagn8Yc(of Autism S ;�+Disorder� AS�<�Ii(WvTr*�Y�Pe�� �8decades;*5Se � ider�debP`Y� heIlyAoK�QHZ�%lac�bi^ ' ledg�a�+s d �;#m��"� Z"a��Ec� psychoma�c �.�%�{Mv sW+�Ms�!se.k�� fu� %��e�K)Fi\�5� �!7E. Stepp!3to-�is go�f!�o�ng!0 chem�h4to%Y Ri�pap{';�-E� �^etaVt�3 E�6 fotC*�/(one-carbon =sme0�ulf"�!�.3 blood  ~83a�ticipaJwA#!.$76 age-matD6M��peA�sJCDid  nt A�!)�s mulf r�W#f�5�a �/��'��eceYSu��&�# 96 .���%ll:�a��,�6cl�4t�C%\u�CgEqprr2)eY97 . 6%nas!2coh�Q. F�'El, kernel ��e�squar��b!IDoB dict`��qYP U:d�rVinel!�A�0B/2Com�e� � �}a��>QD�]5�Q#%aRpr �2�I9an R2H~ 45"Y� -valZ(!�.i�c�,#%Uas-R<5 �Kfa� ceed�ryZ approa�e�fieldE�\��;A��^�.�`�ppT >lyIDa�� anE ��"Qs!67B�� %�o� s tr�#d�;��o���i) i*e� w&bi:�set�^� (� ) enCa�82Agroup!��Py-0gVur�Z�dis�`s cha�0er�yby�%9��c1 �;�!� ion/(j d���/�tr�2repet�Fq&!�1Vsts [ZIH& 0� e de0��m2�&ymptom���(v0s �a��E�0�5�4?�Pco-� Tc�Z� KR�� � disa� t>,ADH�M spee�$nd languag�l�&,�HiFcQ^ epilepsGsl� d"�Ly,e3Oal� blemR" –5&#�\s ∼ 5%!qA�p"�6e>(ma�<P&dRr�atv[6[HWItels%�f w�[a�_�q|=t�life �!x4c3of !LDnd-� W��$� 4–� 4MM�&Yd�Oa�ng�2A30�g"�ac" �Latn� a� -�C�z�7A environ��~�sIA��$ET emer8�!u��s]�K�et� >L��J� � t �ia sub=�xaA=. EAOtw.Atudns^�!�heritQ�� SD �8V90%�-2� 2QiU 2010\�P�>Yo�437A�5V613!�2�D�E5pQ^�1, B1I�� �e�a� n9source�%A�=!�!�1!�inu�idRw 2=%%�AM-��5�[1�m�!��%ˁ�eo#�AL)i�R_9����~�n� n�$E.�EAQ����"2�ly-rooCa� /TS dysfu�i!�:���+3�'pQZval��5n�?V�*�� ^�. M8 d�&pbpregna��!i%d��] �!cce '�l�[2��/�in uterom"� a��)velop ro��DX�%[25� V5KcQes��-I�i�[26AW7]�� �V't �$�T� �mit�Ybxe�>��5in)!. O� �s"� heavya@a�k� al�p|!Qphtham olychlor�m d bi/yF!ctr�?c-�hair���!( TRAP ) �y9��B[Z [1%�'"HJorgan�xi73�� ox��8�(tB=disrupt�n2D c�ng gl�(��� a���V osta [3�A�a� ,2]�yD; r@;#xi2 M5��hyl��(A��B12&�8 co �A���V%��!+tTS��l . Ai4 sper�H�<plq�M:� ,s/roadway gear ho*� ata vehicle&� yq�fin+Td�=U"��� ���E�u�[�m:� comm )MPpol!�t�>�Q�d�(� 4?hildren�-!P�Ks2v[kw� d"�*���L�4Z���� �#is1havAa_(l ![34 , �[�D�U�ve �A�� att9oy;� ��Az�n�r. M���ofV�� � ub78r7)[21� � a�)|m�s+&pZ!We>/&�6�of�> �!��Aa�see _x�)�D� Deth&�D$ "��:8&�I%)E�uT U#|��!u[r*K�ol���DA��G�,� 37!>� inv��g_( :)ggu��Cti��Ongl�'u'e>��"� ű#&��2�om%�!W��� ��c��rv.9 uL.� in m2ExA�0�pGuWC.LA3in&�2%�&�.� �!iu+aby�2+<��w���d�P,� *�;�-�e2� On!�A@en-��J�cy�@�6Iol�AI) ip���GA�be��1䕓^=��[3�_�G . La'M}F�qt�%iques7A discov�7�"�vaQi�7V�E��� %p9St&Una;gQ�*a� >�A:nV��$w��es�,!7�ckF��K��� m<robDRtog)�v�G%��JjNrf��o:�prM� is Fn�( FDA��w}X�,eh n op�Yl (a�GMT!aQ!A�5�,h!�:<T�"reM�.�oE�!B origW.%�|se]�X a �er.or�x;�a%^!��f�/��by Ra� 1948!�EHprcJndpW'�J . Ex�Q��," K�( K;&�)Za��zX-R� �hip���r]xN��J>>rY�}I]$�rC} ( PL�!i�X�era��+( K)WJ , �C. UE��$:�[4�i;f�52"RA7o�Bhidde3E�lya;E-Tal�&5*#fs(To guarante�6�ZlAE& a�s�A�2�J��� �8t)�t y ut�(�6A�"�A7&yA���-* !If�`=6�wa� 7VUC�S.��K od�o�.��mak � 8s?v�7d ��w!�=^ٸ$�5m� �"ea ��E  �� ��A�"*"( NEU�h� 9"> �*YAsib��%SIT\Y��.A:`CoV4:VK�lK6� �"� � q6�G#!4e' unveq7"Z�� �&� �F5$.�Z�@�U�!$�P"A]>ork=��A�A��st)�M��\ kind-�.��%sc�T� li;ur{j "E!*�#k�!m"� j�MJa}!=Z� " . A.*�:M�*� �6mNI�1��6I �; !�A�R!s&J'Q�9���T��4,F7FDA��m�ed�-ށ�ŧ!0N_*�3�k�A��5 er�� w�#�t���Teassify2�2�..?! H �d�\!O!�ma�PDF�6���!@��)2r$��is�:�on&�E�4 . 9%�+�.�%��!��Qy3fin?el�&j� = �N�Se+� �6Z$a\e1ɡTAy!��er%�%n���0%��q�V��/en�E � �`%�8shD4g'i�1nN� e9z! z �'2�in Q`�E�i �ri��i-ɩZ!|a, bm�{9A�OQ�1$+= (�  �A0�WOa�)-��q �A:�,��d]&��3Y �sl40ea�*�� lapRJ�iAG%�5lm�.!%v!%&i}1�>� v! PDF �B�wYOE�B�Y2UlCsE��a�-?A�$��,��v by J�fb l [���1����E�`>N2F�A�fil.i J�*:Jb��ir�,n=4Em"e5t�_� R�, a�W2��2k� )f�ultane(��V+B�promi�� Ms%be\� -fmW.�#tA�6&�.:� Z� e%par�/ �pro�6 on v82r 0Ymaximi9N�nK%��1�ig�]ta�"2�ur help ���~f+#1� �edV�EX��a!-fi�t� J?/S� gg-.��` ��M�!j / 8&po69.Jw�n��M��1D�x�new [q�2��s�'�,5) se�6��*y,aum=*~ bay ~ad< �%|.��r��8>up!tsixew! ��Y:�. S�BM�I� �UcC nA��:eed(%s��~G�*add6��b� w%- �A�mt#6� . CrE�$-����-���!!�6�a!�q�~> �f� at�)&� !Vre X er-o�<�nc"�+�% ( RO}{ curv�6�+Id>G � E C-"4�G E� �L��$� ���}-{�qt�&!&2k�^�:��.5i,�s2ndomcI Ra><F 0.<!�ect>=>1g 4 plo�* Zxia[.��;!�>a givenM�!QA>����.m.s�>��at%99�� �UZe� ��2e-'�:F�p#1,�0�(����%, 8-OHG6klu . -Cy�, fCy�,e/ =#, %�v..\)I�p �3��H2t! �4b�� eߩ�6�at|g� x06�a3MtA�%!�M��d[ !`t 2(. C) otyrje&tGSH/GSSYCadfp�VZ)�� e6�n m T� �A��,A^.�u*91Q��� A�i�Nqfin�~�BuF`1n5fem�&� 5 T��I% I err@|eUin�BFi�n: 0 ���Ec�IAՁ�Ji�,2�� Ii&Mk�=F�. Dj,!v�"�5:Pc.�A,"�n"m�on*�* outco�h.�*�via��{ �.>�N�r�4inEs(�ū� J6�PDaf1�Di�9%� �{%���n8�Z:�I�2f ��4!�=N��*1J&�Y*Zyc� �M���6�K"� s$YR2 begi�t6se�eLn� � �5q� � z�tW� Bf>�R.��44q)�=)��R� 2�.I ��,��, N�E��, T����F1npu/�r"�.. �$a�5@.�?� ��En"aqa few �rR��-2 d� �aq� "F  =�)��*�S�cla=. )U!�)elE��a?L2�w � ����.�Ma�J]2. E {%�f8*� a*����iL%s�pF  'ed4ntiBvB:1:!��ng6�����7���<sol� o&�& Ex��,�2e�+�.d! ea&n;-�'�q���l�5���9� two�p �on5�.�:u!.� Is/<e)Ea��de��� *� t�\҂���-W{)*=y6`. �m,+ o%U��.��("*:�/O;; a � h��W�,�;Buve�;9�6: SN�,^��Bu8H�^(^�i A�as��un+N�0*�m;$2etailE�"�3 ˖*�9Im�'�:m�a�>cy nee� A� �i 9l2�J )�1�.W `"� M`krgu�.}%���5!K�.Eg�(.�6�"B worPUk]>�m?|K{��� �a��]� �Pto�  >09–18 . 7% [� 4�&�_6 �# Zs1<""� and/C2gnl:Xn; ]G4e�1��f�f.�[45�J7]ee��:D B[47�\.!�qFm�.� R��'Y�0�"� albeit mad2��' �)6cWhb�)erZ�"�  Bu���weo�!�� rdbenefite �.�:�'A6tA�B � =Pz[A?��se"�.nFN�69p.�?ari�P+< eta-.��� ��0 a�isŋ�5t�B�E*$@��F#!TxcB�avail� -��L Ź�.[.�;em ri���&em�1xO&h�� W !�>ed �(���0Ds;e�- A�h&�S�+st�R ��M�$� i�� � 29 �A���:�!ed 2��719VI<:S*� \�alp5sur4?6�� (;6�� �top�W�*% ER� tudy��,20&} �45Q'�V� t��f�*$ s.w?A#�$ �A��v'�si�*%��[50 , �Xa~2�5,�%(. N"�BiEvq^.�ID� !Uof�0N.E� as:~>,C�!e�iB]u�^m� �!2vM�eq�H%�N�,>�E�sQ+in�)e��4n:� ( ]/*� ( K fGSH�O&�i�( ��& or i2#<*"A�+-/I �E91�y3� y"�/�leB )qls&ns%W�� B�>�V*aAb[51�=�=�i�Tm/)� rig^H8on��Ga"�/�#�{� �? �(#rep��A�empir)ly te��X: wG& �hrTmU 9n ��lu�0"Ndrawn��YhF� ��,�Z5�'c�<�a, G1�&CiA���D�I# O&�I Schedul�JADO�' or Childh� =R�8SkipCAR+)-�re ��py+� *�=�w�v�4�rB+ r=�_ �h�C!v �rofI+on����e!� �we�yA;".+]\� `J3 )!>q� �=%U*xH"#�I;A)�ra�:K"d/� yea^l� " � *�eJ1o�V�!4� n�Je��F�B�Uaff53�L� aJ�&w"flu���a�!LH+run [5�@�/W ��&�?�cbe!�� conj 8%A2����eR� gz *�AS��-_i�2BF�)���fac�a��%�st�png� 5c!*GdiD�o�GM!!*�1�dI�O�vOj�&� ci��?�dW ���e��.��s1:� �H�0C�bb)6� B�*.[_':�*"R�j2�fY� "�%(.^  �"��.$e Arkansas��$ren’s HoΈ al R�[I�ge r sm IMAGE��O6�F��4ocoi$��0gI�t, Review Boar"�U U�0���AM K al S�(c�:n{�K�NA;e#� �0F6na��E4�civ:&�R#iWQ �  �B9lgraphi�%o���P��/exͣ cre)$ia . Brief ��.)ag f 3L10��'n�V�.s1of��h�!9.e��5��a�ݵ�SS��al Manua�;r MenA&_Q, Fou"jE�IO ��Uv ,u���;�> 3'RR� E�8�24z�76�F �,,~�UIB*0(.rO $(�)9�B�(%�ecA3:G.����gM. �ab�*�'�"]:M�� ��2 -derT]P & i� e�OF8:�P�m�f)WS , 55�;��"�NII ScoIOrU[�-y@"�ai���4�J106Ma�TnPO3�xap� ski��AFT�rereM��m?�&� � i , /v-�1 Ini>3&@*< fi�� u9 E��OYs S WJ!j ∈-j1 i- 25 j.�a� �9 �A�DAY9v=A$st k − 1-8!I#A[J�+ ) = w T%�w W w�T wordt Fg�:I#�&E��( ��5EYs�)A@a v�J:qt ;s�Ra�>�.A)�solM�!0�\�%le;A�) �e:IIpsX �u� A-1\�stJ=al�9ofE- 1%c.�6��=ktt"ĉ6��k�Xrov�&) a )�Q�YQ�)m� ��pQ�%�ݥ1��i�foCvn�8!8&�Y2[5�5ť 4a Gauss2L�Ul���x �= (n algorithmr ����aJ�0 K xeW i σ)�I*�x.��xa��B�Eσ �"�+)*YaWe�/p"R'�"Bw1-x-��Ze�ny�f ^�*) xn�&]D�Un��R�d>�-�w ���F�I B� ��)OIm$�3!-��z gAd 9d2$( MISE )�93un�QcJB��)%o)�: c(��� ∫ - ∞f S-=O2 e;2XoA�@A���~: techI=q�*� e&�:�_e�darA1�*�,1k�X3:*�)� Y����k�aI�&�$�,a3Ɉf = ψ- � et x�A,1a�B�.��G�"� on x�u�i� PL�c:p (p+-6,.  fe)e�kf2;To avoid6)�o7+T�l,!ave-�[out)� �O��mK�f����V)y� -� U leav� uwS'le��i #�3or I�i&� A�-���1 7rZE �f!e��W�y� �� 3$.�dLeishԮ�F�nd�R!�98�<�kŷacF�35dll�3@i�D!�x���N� +manUdtBrazi}� �m~�>" =��v appl/; Baye�g�G"�A"��binom�[%[! %�ze! or�N�oi�*$ ut�1� visc{l64n�#AAWa 10-�io\200^�U*1P >�B�s�6E�A�e�{������Ac �wk"z8�^n�La[!3r)�i�P*(e� f�c=�9Vin.� �+AXu'�3bh�A�%�&Fcli�vc�3n.�6a 0 oeco!�cQ�o�f ��jyvtypa�f:�,Wcip3$bndBwox�%aA�!d��"CE�fac�.%�m�2�2I�in ER3�189��ard�i��[SD]: �67"a��6��X!8M SD: 288 )4Z�. ��a�map2'K�!��nest��GA m�i�Z�.0of Minas Gera� ndA�á6�^�:O �s��lici"V�-�$� y��=�pri� y� �*�6<� �or&�b�r#S!��!q'%;�b� duce� u]�. B[�2�]neg �ro�CCs �CuNN aras.`genus bQx(r ��mi\) 0emale phlebot��e sandf#!��?^20in r!�wo*? c%?s:>n)=� ( CL%�M���g��r A7Ame� n te%FX6��C�u[s)��!uco%klF�;�( iU�( V6US�L8(gan1'�]!ve'dd spl�G�^�jl[ �Wif�� @Q�d%%he*K#r�_b�f�S��/ I�02� e World H_O�i��( WHO )*� m J��[�J�Eͽ�ly��( 73q�CL%T� %P���<59 , 000 deaths � . ReA�2Ire�pjM�s�!��,2i}�%�2r:_4$�h7 ��e倡4 �VI���$�,�to"a7&C �2����4 [�Abur EBl)G�K�3aw!��Q5 I"E{&p#AP&� CL �climbi�.R#33=� 1984��[030A�1996 [,V�. 1990$2004nme 56�9DB�EX5��=ima!�CL��&� -200�.�to@J�!+ drop�z!f�rt5 , just ab��5�1hD|+!�d��B�&� �<�~' =p 6b�4mion��ai�FELSW&i��/[�RAcc&�v2�Assemblye��I��6A�1!�pu*i�%�<�>M-� �pm2"ug�pr�m%6N ��UA�[1�RA�� �\aP-�*!�� `Ca.!r obsta��!��+�. A?j| ɴm� mwh& �oe�qtXɞ��ec� ,��1So�s �b Ef�7iv�0N�X�l�K*n e��&w �_!~ �.Y��S:C:),����w%:�Q�� �� be le1�' �-.�!*� :�  E݅wap ��8p)�a�0a7b–a!�n�Q,e�G6j |FK�)58M ��&�Q � v̭!�� Jce 5�coq �{�*o.U� \��|d�2ra7:)Hs gh�ed lo�+A<��Fs� -V; ham�hF��-�&_t��]A�( >S�m'Di!�&/�#A�av})en����dо�i@�(e�a�F�R�?k�dA1�a01G achc!� Banerj���(��k �[��E}2�0]�G �RU#mM���>��LindgkU.|1�'[�[.SQ ? "+Mar��M�jvg2]�"*A#:Lse]*ARu�%�ag��0� [23]!4l4A]#al&�H'F !��M&,�$ �ntv�( INL�>rre��/+5� A(%  %. tio-"R2j.� *2%�,ay6Q;�et Pasc/ %#�[�[�;o�;a|"��WfG�o�CWY R8x'""{i �Ocl� ic"�!�C�a�1�I�5]�d��!>��break$�2$CL� Wc� .�. V4w,rrama-Ardila!1� [26]-�d:T�N$�S)&��)n!�aol)GY�ѷMGW* %!l.� ^ceYtec�W�!zozz��6��|��xp)� by K.�0+[2o In Ar!win�Salomón201a+[���ed6n �sum ���+z.�nL,����� #!Qj -��͉h �{.E�jC �qJ<t=rSget $a��=�in� �koci&��A�@ M3�^of�����. � ���a�!�ycey)�\$�4�H of&�:��es]�d�M!�r&�Alv�r*�I�5��d*��gN^A)C� "/���co.��Qa-Hai�x i����.��90���/e��R�VLk3 L!A.�-s�f)��f � sjSNDydhg� 1���QMoH=�aNMjed>�X(b��3�4ia��)�l�6� a��U�,:�N]2�W�LTdQ~�s.�%�A�6 !oQ�0e*� � &'� uni�Y!F1�aKgv.0�v.ds�� fu�) deciO-,V�#�v �d y��a!8U�"���o,3l !�׋"�6xQ� ef�J� . WK eo���)A�82��EΙ>� �ad�'N62�K�/��H�8"2 no�(�& �icun�Xʼn7An�>�n7aee%, �6��*895� C�!8�176 T�(ip�'� �'eP� !z�z utochthon�N; ):H�!A�Ae5p%?� �`�A�ah(�l� zero�SG"�r��y� b[(� �� �(gFV1� �e>�x:�! �Hm�'$��b��C�VL�  E5.� alt���:���7 G� Je�) ծ%\�v�;!�190<B��, . E2�9}6!MODIS [34 L�w[+ e�� ( LS�jFu�a��a�t!�.?�&1d�e�b vege�-�dex�,DV�k�e��*:B'E&�Z/�5A��A. moisA<Nl��?� !��s�y�! umma�x* -. M�+i)ovel�vs �5bE?rcMap [�,�Z��v>��)/6��Co%{��^��:T�R *r�pR`t!z!lrt%�HD!�!N�es2&]$'N1o� sileir8�g��a e E�gí���BGp%;a�:unsatisfZ!basic A UBNUR|Pan&�V�PAHO/�&�uinf�~ mort��yi� ( IM�m�s9%i"�|�A�H�n +5YAhe Ce�- I �Hal�wthB22��Ne��( CIESI�@;,�`P9�E6 }10�!��Q�e(& .�8!~� ]�' � al�l�of�/km�U�S ��`L�;��� a�iaJ� �%A�na�ef�^�I Gpdz$ in R�%](t�+�� 2l �ginu���N �He/J ���te�)�*�6�R�mA%4p) dA pl� H'� t"z)�Akaike'M �i��3��AIkQ!�elect�a��Rt-A1�s�%�xo �f���$����w�ᛡo�6A,� ?��HɅoQ�>@%��{�!=200+��Gibbs\ ����C$� $ WinBUGS [�%����EO��." k��A�J;�a����  -B lUj�:Fls]PE�]g! aA5"�B"-�,�!Yq1Oo��I>�&��.uas 45 2giv�{r��! \5-��es�8)0}�.��&��{c to& a>o ~' w� ly+6�22�7J�) @�K!*)]�R!�q�B �i�~A){ s fu:�%%E� E���erP�e~� �QKa$,aUN.�q� "�&�&q & ��E��1� Na��i% � A�d&~o�#Jo�C� &no�%G>!H� 6G� %B�a��0['6dco"z�;�o�r_D$.ݹ��-th6.6(:��g2��QU�+c���� ssu�Ctc f1o� -%P�4�"�!`:{Matér��+i"0Z��H�-Er��e�RAx)�}%� N<�Y)+2]w}|��.�ourI�aW��l{`e�WQ� e+�/ ��Lr-Bin eme��KHch!MI(Carlo ( MCM��rui�o overU<: &#ef&# �U�s��,�!�homonym& R-package�R"HG4at www . r-inl'org%�Dc wQ���HA�X�d R-c�a"Q ��fC\�ngs 2V%�texts�TK]�2. Mm*D.��)�'��)�mly�iyub|/of /���o�C�c�)�m0m�K#2(�t�Ze@A�";-cBlE�A ( BCv of 95%!�)!*cal�,�!xpe.r�`%0= �)X�a-9iu=!f�EH-!�)A�� �<s1  y�t� iv( RMS� -�cZ��m&FaQ�:$������B a�}š���-B!�un��wh"O�se ��ng va�5;!�!ۅ9�S�{o tru.�q. ac�s �H �$�M�Z� w :���as�0��F�2*�a>�}��!�$�#&�!,!�} "m 1�$A��C"�*�2F&:J"�I�a$(&.� /a �9�)6��.y] y%��!8O�$CL ( ManauA�262�V Araguaín��.^�Y BCI�83X�"BQ�YTM�2�u�+���Sz�n-��;` !�r��l"5QgA�T� A �zd�'�X�4x� *0%��daUn� IX!��:sE6� �Y��Hig�3e.#�3diup�>,� e X��rst r2<��nT �T&�/,:En>V arme:Vd�%3oX�^P:�<CXOQ �%h!�,� r�i�uY VB&�.E��a�6c=� >��K}�:a^�#aēf�/wa�poiwexA��z ,j2san1Z'Y"̮\eho�!�d��h� ?Qe�e\�e�YmIh ��" � " As2!�6wo\�?*K!߷V ���VLE Nu4-��sui)R"��6�/#�� X:%�*�!�aV�1,� j8vn���O6!�!>�. WA��w^� CAYa��!wi!ecC/>BK^@("c�ZIE�]patI��6��XRz\`J/2�of!�S�o0^���!6O%5�q�Bfa!�w�c cy�*�4"R\��Vp um3t9�%!��!�.Z-z�A"=  4J�)atc]�be� ��lig� A���sb-88��!�109ӓj*�cnd!GB�3iō�CLP a� of 1aC2 �(� �r1��cl*� &� 1� thir�p��( 34%Q. � �--p*M�"�.�&� ��VL���1�3%AO� -c�"*��"��4�: f 13�/841 pix�sat!wkm5��� �(aBo )� �on&)�ik2�rF#pőu]��_HG69�9!�*��3Q �5ppa�*by� ar��!��!@ / ;["��`�� i�f�1��.*H%�Ȏ)-q��we501 rth-z!� r��AmazonaP RoraimHI���)�{p!� �a )��}G$*{jR S� !p�B�|�"AE&��!R*zmaQ5 �a$st� )> � E{S.y"p"1�/%�Y). y~� !����( T�-��FO�M�(E2�%�218Z69( S�"::99��A�N$9<���zuF�CL Cg�i!�M9A�Pa�8�S , 33-&���%%&9 ( 69A�iե�� !z�$A�� 9h�_�L!��{4�{�!��"v�de��Y�e�%�&�9�"�76"#&,��a%sN�(��FurE@�SA�M}e��D�W�.� � �;�)� � mP�d ���)T�*��m&)�i14a deeaY��)%�͂>�+!�= u�!�'F7%6��W�B�#&�bnM2�%)="m�&�to1Cy:� !�6� m8#��_r"eɑ�/>' ��tP �a�Np�0o����u|#�.)@�rigor+B6�ab����-FxEB*)e�> �H"�T igno��" `,Ic�!)-E0�Q�3�Xrec�A�=�i .� humid� � � � �� *P! � rF� ,Y�P(����u e�ɼ�V $A ! ,ub-Andg S."�. /�X��* m.� >�!N e���eejg�n�mcut-off�2i 6°C�sNd=G_2_�H��!,%�o�e�"F��� ��ayz����ol�<duqE�+4r�nut�0s&7��i���&[@�A��h�ls�ae�OpoC�65[3��l �&9JY?��g�;r-j�Hl/�-eF�A�in"<�|[�a�&�%a�iA�=��VL6,/a�8e� %w�~+�e�O6, :UM!�Is��c Rep��qIraa�f �M6�*= �� 6��vrY���� �o���)z[�Q��,�,,"0of>�,role of annu�Ual precipitation is negative , which might reflect extreme conditions . An inverse rel Klof VL incidence and the mean3-year:�Thas been reported in a%(vious study\north-east Brazil [49] .t,shows higher�rates�.�q)uVL���U fall%�� t� !=WeEnot awAof simil���Aof CLBx! -�ByY�aBam!�>>�;CL!�ue�A6��-�)�n �yk>�of6�l�� �7ov��OveJ�>Walso A��cause�&X is veryp Ei�!can!O S exact�a�A*Mslightly�� than)��pixelѵill.� �>id����Cs.�� argamhe.U!�. H (� F},%� exam ,�lm; need�Rouilto ��-� �- ed l�0an 0 . 1QhA6d�-pM�i VL Rat�Z i drop� 3 , 320 4 , 889%�M�(to 28 , 164 $3089!ʹ!$is cut-off!� arbitraryn deci� mak�>2reshold��)�.��ppl�%�s��� be defin% �op� ucriteria"� balS c� ofeҩ��tim! rea)�on�] h��7adminis\�`rug�1��A�requip �ADt�J����s��al lim  at�toq d%� consideraM��i/e fifth E�s9��world �a} diɖ into*� ecolog\ z�X.��ssumed�� ngleX a  risk"v g��of: Sa!1!�� 4�;!�per� e� graph�distrib� . Non- onAjes allow!�A�&� > ��enc� �covari� 2_�specific!�0a [52] , [53]�v��T � %@did� inclXa�ce-Aq!�erae, b� nstead�,%w!�ta&� !b{ E�ao�,� � r_, ���MQ��� �Ioea� &� a�IE I�a�is. M� eiE�Wp!}aI�ݞS!{�A/ U� corpoA�ng��ArI�irO ��%�/pr)�( latzIgr�2,i1�problem���y meterst nd h��we only%�a�!�� v.��0m35�� ����9�j!>'��a.m tem!l�Qn�4CL9E� �I�f� �-3)p)(c�c �t�E] e>b �-N seem��I�do�unt6�� �� j42 . 5% quantil�  b� -othue�C�L��q�iZW illust3 Z ,!�r�fR e�er{(] of!lrsa�c��c!>��-)%�� lc^ X9>IcA�in 66%%CL771 VL� I9o350� 38%>had 0&� ��� V VL ,wpgv��$. GiardinaNd 4]%�as -infl ( ZI )iMs gveBMJ1� �� dard���|.�s�4ng mal�\�(# spa!ssurveyIs.�e� a<��bla<obq�of,�w� fit!�I�A�! g�VA� devi.� &$on ( DIC )+y1&� fi^{ em��<:�a*� (�| magnWh10−6 ) . Cross-validatory#su( i . ���vea�tRMSE )�T�e when! 17P- .�!linear��ad�8 �goriz!��-��8. Altern$approaches2� poly���er�H r sprsAOay!&q�flexi!�way| �zre�Z�v��,  oten�� _ accu��7LW� ve chosen�F���"� y | easaepidemi" ipre>T�dclu� �|pFn� firs�-.��N� y�in� Lu!� INLA! no�1�!�1�8!�fieldA�negleca trop�-\����d�, toge��,N-�ed�����A�nsCte�ful too�> aG prioritiz� of�!R�%nv!�on�a� elopV �Bayesian>�compu-�(eTg . ,)G)"Ken�_5 8 ��il6 e� l“real�@ . Updi�D�B��� utoHzM�Wpe� hor�af�pcol!��2�a�E�E3�a�a� fu}6�p"4*!Rge&g�%G� syst � poss� to&/�any des� �*,� � catch!�� a! health3   ,I furEt$help plann�e �M! R coI!me�8.� ��rA�G=�� � m� w�enh� 'Qo[> warrana . Environ�NQ�4)i� � �s�B}l l�ro]6�cu{ � m`a�rl��st.wL!� �7eMU )�cur�=M����_1�dNop8.�e a�!io�.�!��d����s"nd&� �]dB2��(.H�As den�sp �Gnewa�&(regN�!*force\�2s chan[in ex�ng en���   g er bl� clin�F�慼�beErecogni��. C-exg N �a"�d�?f| a p� 1��l0�&�< ose�childreZ Pfew�8�v3scrib!�!�g� G rum!$�!afx ne� roup. !�entNcruit ���ge=�loc%%�*A� detai�proz� ���� 5� ongo!] stud�5(en! aqhe full2�hos� l%�M5ɪ�/ A� �le/�sou�� n Vietnama�aH:1�A`lab�� fea�A;manage�n�c^� 647 -�8819��!x��I�. Sign%zvas��leakag" shock maqf��`n)�Q&� ��� bleeQ�%�org� olv �n mq comm�Q. A!ona8,y d sign^antly H �8thrombocytopeni�S.!d�y�A�)serotypr!in�Va}! q�Bb,"hough)� a smaller�-/ge-e�E�a7on�� tele�z 2ppa�u��!weeks�Q��,ۅ� �=�Ny1\/intrins��ler�a�e/A�mQ� ��re�!r�tin�' �"M(AP; �b�s�"9 -��w<#M�9�,Y�)���ly!M�%d A� phys&� �c� Knowledg���. ���to�ormOearchu� pathogene�!,  wellto��u� �'�A }�gui��%�!h� pu\U?s�X. Di�is emerg!�Z � �@mosquito-borne viY�-� ( g#%�� �  fn!-� C( DENV )ubs��Yasymp� c!G�^or Q a �etV �:\ranۥ���� � illnoa�� ic6 syndr�`%dy� ly��nF�%:[,!Ha� hae!Ya!�A�lw  dysfui [1%S�o�e�ea�sma��o�W �&.1%I��A�� sB u, m��app7'toM rA@e�5OM  rapid�ak&� � sub-"I,I &<� EuN 50 milla�R�s � annu��). In S�Qast As��epi� ' �pa� ,Q��A�&��; omin�B�r#l2(��"�>young�ͥ0�*)�0�' , [3�4!�On%�us�� on��|��pld!�a redu�Ka.�J� QIoci&(.R and/!�d�$� '��E�fe��p�'A* expo� dur! ��hooYao �J(�$�uscept��[5!*�^birth� deathS'�v|&%|��om� de%�� flow>wAviduaW$�!=p&�(A�i)� Elongev� of i� ��E�?t�M%i%%=a!���s �S 7f )on$>[ [6!R�*� f f"- pi�&!-SE�XU� star��]��"#�5 �unusual��& ��e mort E�*c���failurY� phalo��y , myocCti� 7renal7AVm6� E� t�inIi� mF7!"Fne� y��Nicaragu� ^� ,� ! mark� :�� o1� ly)i9�a)Ql�  rݥ�rrh ��& �J �RE7%��Jjects [8 �1 .� .�0Sri Lanka , e�'of6���*� 8 �J�e�!g���t�S*� ^� )7�"[9��wh��ree �a��:�^\&:��he��c2U �- �5�in6�w< a�-�cV),�O $paediatric�jM�M���1�-o) 20049e��.�+��ng�*�� crip�5�� "�=�>�� F(fH͈�* T�D. ( HTD )!0Ho Chi Minh C��[11!�[1�13M�e�C�ai[ ���@� �'�, *� dgA � ou��I��=z!�i.xr",� a�,eZ �s9Lͱ a� ime-EoF# �-fo��}s�� eligŸj r� ]wr���or!UN is&� E�&A��o�.,� s/gu�)ans: a )y�2�&5-*o}!dmr�&A PY�IntensDC�V0Unit ( PICU )I��=�,u! �Md!^e*/ ; b )�≥2�eDFL:�A�CZ�A �!_< 9on; c.5>orI sB�>{]@5*Y wardB� . Et("` v:!X"^%�!�Sc!�i�!nd7Com%�5(z�<'Oxford!�3a�u�ReS�scUK�E�i6�$�3berFy broaE@�"ss3cA�a� invi�*ll "!٨V�toiM. .�%eI�x4� usy �a�3enrollicd�staff` kl�զ�b� i�]�^ eno�toA���- ;Y�wh�(eY_A�J+3�"3 a�no�oc�  & �ma1na� flui23 rapy���pe.�lX 5�$ .#�sa much� �.h m���Gold����$M$rotoc�� est dai!�l s�(s�elect�toQ7�`>�&�}���e febrP��is*�0� �zɬ<3omfort0emNq�0@!� his�A�|)i� dj�rC/�,�%���Z�`CRF�LaLsu� A��oA)Fu�"�harge b#/er�d1��m�ra�(to �ct>�E� d 724 �-s X3�3�!$iagno�!5�A?-Y logy/� ̵at �e�i��$�!� �g."�rea���(= A-�����V poli"�'WHO.*~ l���!~���&!ew� al22�! a fi� d9$.�A�5 40 �/w� �')�"r"��) ICUs�!two � Septem1 2006Ef28AyJfM>w- q�2Z7��TD�!� refer!-5�A$� �TM0B^ ivesi.�ZS O Rat�mi�syA���mH�+2�I�o�6��� ideUD!]� 52�naxr�5�9�&�ageA� ak!�B c�1$ro;of�ao},��$!���n&� asse�&A�� � Tw �0P�"/|�ato�$�a�! n"< attst.��%1�M=5�*�,�&alfz.�as� ��f; -AL5*N .n0�&�1voc�`nt*on<c&x'as!E<l} �6� L� "��()V coag�'Zscree� ��.�4!L }�_imzAGf�ngf<m ed elsed � ���c�,IgMe� IgG ELISAA<*%�9xuV�6�convalesX�me� reag� �_9Ven� Techn�� @( Sarawak , Malay� ) [1��{�Omy0RT-PCR-�*�5Z�A#E a��>��� %gM8 "� =y�#nd� F%��A�qwit�2�%5 d!b2�,%�t]/A%'�nA��%ve�V1If1+�nI1 a�"j>>JX%�! ? ��`"0otein 1 ( NS1L>Biorad�Jia™Qj5 Antigen k�(��!� manu4"urer'�� |ion��P�=uM�����>&�i�; ���4��ov�!.A�erA'�( docu��8nQ�(�,!?ͩEy� a<;q#1yQ)�a ��"8J,T2=[0uE��A&htoe�&2rVday 6 QF��;k ≥��78 f= ��eim�A�)≤32s?�[1�9�d2�se^%1inaEm%�1�ofi!lu!�J?;d�'A|��$unclassifi���;on9b: ac43� ���z� Yb!- zy>I��A�Chi-squ�^��A FishE�_6aZ�*�)���!pK,Mann Whitney 6� Cuzick I� �inu1R. W�+a� p:��&X nd��a E9 multiD6O+a�g=;���V�&� *�*s2�"Y (  <1{asp/geE�, sex. nge{t_!(��1–4!unknown�8��&(�)E�,U�&� orB 3-A�a"�@!G�)!� �TI SPSS Ve�C 14 (AcagY0Illinoi!�USA�)Stata-SE58 ( Tex�% '. B� 2� R� �+& 388=�\� l� PICU��B�!I hypovolae��( >95%a���s,ca�* ) pl!�"�'19}�9�"M  *w9�� �subseqR$��J ��o�"� DSS ( Figh��.@@Eno ex\.l' ��mfa"**� twot?_Q<O�l407�ա�(, 402 ( 99%�3٬toɾ�F�� ) A�5�12���. IM�"�+rel�T� /�in 325/ �81�x2%�, whom 1]0w��)B6/ 2p�5� k ,-1 = 13; 2;y]% 4egD��sB>_341��U�to��B�%��Ym ( 90]����-yY� [�<of)315A2!]2�b� . Am^D��!�26 � Qad&� ��tiɩuan&'�fKU� 1i!�idiJ?6�c purpur�sXcm�,� }�i,Ptaviru� ���?a�2��2� M ��. O  186/)S5e�#, 9T G%w!�0).�]E6g129 ( 4E�+��. 110 �35!�6�q�inI��i(59 ��MR!)51NAd9�%30fe"�+d 2�$����&� ( 47Zm47^m�11� �6VHl&�+/ �47N�, 3R�, 1��A��V )�J�Hlya�4)qC;a#:N>�Z�d2�261�83!a-�� A�)�,n1: �!ӑ���1��.� au�_E��5.:' DSS:x2H�s�um�f keyy�n�+basic.� " 3� !TN� RPaG�IB2��27}2�E�hsu��mFl%a8� mpn A�*9Q as 9ZMp0�5cBir tw�3B3?5�=irg1��nm��37[Tim!4�BnseJ))��� o%,�. Notab��%C� ( 12ń9$ nd 1M �)i�st$3��.�F�. Vomit� , ab�&�yn<<ad37 Zm�� M� z�IA�q�p���A003 , p< 1�JEr):, χ2 � G c.�s%)տ"�!,mwmild/�6� osal.+$"� thirf65[a�no.! �X�:�)�ly min kin1*� �cours9 Eigh*�'\3�yK�, !�>�, prof"�9� p&*qrec]P9 e):$ %.(narrow puls #()0 mmHg� �KYQ&�Jreu) ��n+d#� �%�@5�L'�.G��`@�B�1oidA�usc�B!���h 14%�iza�*�$197�d�o(]�>� F��'+!c&At#yAtag���$er volum��f"�a*�&. A�:x�62�AS�\�>*2� c��/*eu�efI2s!�a!zT% 3 ( �-x17U 2�> hi�3�E�diure� T�%$(��o)Q�A�E�e.,1A�2(Ez� � iq��4d� de�3�3PK�;��s e.de�6%aE�]��Aq*� ��->���\� aSe�7in"! �R��dem�:���f5�Edm��)<ly �.e0aN�A��[. 6 bſ2�>��11�( 2 Yw �9�*t6pB|OQ}�͑%- 12/5� 2e� b���fir�>#E�. F!�5U�s��!l��4 e7!!�"�x1 :i�pneumo4� �x!�� � �Wdy��oxy�L2$w"��d1G"+.�/]2ja�Ic�E�s+�ax se ;fwanE��5.-^q c_6c+&d�Kp:a. A�J of 7)��R�`�P_Jbec�2lic , 5aa>(F_F%2( 8�� qa��ied - 3�>A!:102�{FP2 �)Ln� �7&� !�� ��:*94�u�q6�,��rg�*+5:�9.�� .r*�1�*�*�+A��F�t�:�%�DB}� Y28/*�.�5�(��^(>�( �them 3 �%I�i&@.� " L #.A, 2.J:�!��5acrAW*g 2yon CT s�J�� wa��pY ulce�=Z!N�+��2 �MJnoxOl�=c�N���n1]6(+�mu: �- settcA�+&"�&!5�Eb0A� or� Ft�:% eac�8isold>hOG%lobinuM!"" :�r9&FR�eQ{1*�( 2�.�"� 2d2�|�N��62�_^!�279t ( 57��5v�, 380syncop���!o=U�If��b �n��4��RR��N�� �5����66;U�� �(���T� *W:.�G�7��?F &&6�5�z� t�\$ly o$6 �a�.r1imz1- z-�)9��'he.�!Wa&,�W=�.72  , 49�8y%w& B/�6�;�a�'41�8J , 130_$ 289 J]Ninet 5i@�T1n( OYG� in&�'(�,@]�#!)Y � *&�@6.���e��A� zM�5H=� , 33� ���G9L,d �6CB 6G266k �, >F36�o#�S!FW&�% �-�W 286QN��'u�.OA3x47)7�o*� a S�:]��, >�OICk>!8hyperthyroidism!1led�= �6�9iP/Uw �on�Po!gvuC�"�0.�3se�c� "�A.l*�D�(.�as472�I9285)�H3zV��b ug�Z( �I�5"@,to�hu�E�"&l&� �/������1�l�M��( *:,fE ificP>mo m%!l n fe e>���*:���A�1%s�N)��ifeda/ [�%H��A�E��aAfr�\0 da�a:_D�6[!�5Q.-#Q����0S52�&|)&O�-[&p"�EWg"�)%Xs*9B?�� – ,�y 70% �!<1of musc^l(9 196�j>B�F"o�A� �*B�T�\A�hal���H>��Bp -��, �0% .�epistax�$.�46� �ňmaiLg�I.Sup"gahe �E.]�A�tr:.�t� ��rec�/d 7jV� .�2)A� �,X}+^of vo<orBf� �inadequ� o� int�/. Ng v /BG�ge*F&� � maximum2� Rc*� a�"�)�v"�JEHZ>�a55%J � . Pe�`��*�-�)��VsoSVI#ot�Q���r!cR���3&0�->�(*M��&�%T &�.tEt≥�!�~�)"�-(F�2��;-�da�=1�!5t]�1�HCTy�a^"?`r y{U��R6훭���!pI y 5@ �pY�19 }on�� �1�A�-�ͳl^Os��j./ %H�R�"o'2��#:n �F-�>�s��2O,�C 20×109/L�"� inva�<p{[d�V-EKa&�("��>t� ��X�o5^G �8"�2��o�90o�?��N�� 2�?��aR]�g_a�U " ���8�-7�9aP��l�Kim%Е4b�.��  v�t�6!��K�04–8f��viig`�8a5"?� )0-up visi�9)%�%R�&:Bk2ŀM�k6!3-�e?0��qcI��)_'V���:jo3G)8�>�5�5>� E%y��2�!1Zs. M�%V�-^ �.0at&j-M�C�;< Ut��(26"53E,U�n�.n"12J8i��'k u aymO:$>46� �ZJ�E vG*�M}]�m��B���&d1 size −2h^��( 3-CI:3D#6�9 −1�i +.]#n��Mg@2�2h2[8 h�7%=.h0�':�1g� ��,�5Ea�nnounc�^B%!R:�/a� −35 . 5R�4�0�W:9 �I�N�Z f]. 7Rk%�2 k!���,6:4!�6�9:&%6N�@Len�!a.�Qa�`QD�� w�&"@K�1E���g�>at&� ^�;aT��()R:byn&2 adju��7.%�6�)AA��ulZ M"4�4V�64�+-�1h>Y �] shipX2��f�-�� i�(�.MpZ�Ad�E�Fna�p[� 1&&�T c�l����Q5GccY��� �5��*&of&�gra�at*Ci!H1:�gstBh>� iA�i*AG]��Cf'�<"=a"��j�"�a��v6M' maj�]� y�h.�Fx Q( p*�%2�2r �7$5.v9�N� b_:�UrPB*�#�3y�bls7(� !W�@N\b\iV65}7��na�:x�'�0) �MRR�s�!!� �& Re�&ac2�nu��F��3aӉ� %�} "� e�z�* s 5EA2�6�03"�q) A��1&�;�r-7.��B;2�6�&ll �7-2�7) _J�t�G�KN�Z-�(e6 ��$aly>>>L�R In�\5�"\ to�.lkjit)� n"�\�\fE�.�D=&��"� \+byb���� "& Aϑ�"1�P�!.�O.p,�8&n �7"p , &�_V'��t�0�a^��<s! . Adh3�{M�qZ>U'E�t �&.�v �}Npl2�U�="��  :M�3man�]E�o�B[rmx�re� ��EJJ śV2isS&�}s5�M-� "V s�tercX�=�[FYZ��M4A�0!���1JqAa-seekobehav��/^le]6(FalBNsLT�hue�i�"/OY�Fca":�c*[TFaQ� aI ex](��E|R� �WY*�>p�Fou�B�ma��@a�tl�[F�V , [1nT��8YE$ound 8–1�q000�!�$B�a�W�* it 1CW2 �inA��R��in��$C2Zr5�� %�c�ye,[ 6Wfe�F� @M�E1Q� , W5g!*�Pake�Hm2 B�yn� t�)"��;�cr !y!?�F�U�1?f�:.�r�mw�c�?Sm!#� reNis� 4�Z-� olde+ {�_sH��5�5�R�e�t 5q h)"�5). �N�B"~�%� e��N�f� M�M�;�<�py����-8osA��a�9 E6�S M�b|2S��o ���a1d1OWAd�=y"~) *�D�!P.���M|5Iom TaiwInd=Kgapa�� -遹���e �d7J]���� in life&�M�=T/gbPly��R co-morbidFiaa�CY~r-��5` >�-�*\[1tX[2�W6�6�mo&tJ�6� 6} :��O�/ �"� mab�ofE� ��6&��$f�rexN%�2%ka�� ���>�&��ա�!����y^���P\mu�h' \f�m��5�i"! .�Q^`I� .��-T� ��v��h� S!�lece�c�J&�F.�-qi)��B_}L. C*�Ku(I�Am�Y��H� "�K*� �K,a�0xa�8@z p"~1� �(�  tAIiI6!� �_�+2 f�#n=d�� li*. ���K)l�' hombim�7ev � f�L nt a�)��!�3A�6� " %d�Yd��6�� ����y1�6\� a'>m��M�h���M2�Za�!��a��^A�&k"�I“ �)�6�oe�Nong(PX�������o�$m:Yhn� N)UD;��,,ZB�Zd5Finid!�" lr�ma�|e��Dl��gw7<:!eB�6E�cyt"i��%ym$_!�� �.�;[*� 6E�_"� ]�8�Oro�%)�o���{q�MH^7���B<�mE,�� � Q-A��A�y]v�q/�#DUa&�d�z�l� �UT13�VɡB�zR>"2a!�bYV� -indua�6� back�n#=a2 K&. &��bius8 6‡!7b�-��� �&9��d�&�""gX57$yI��p-yj�JU�:��QM/"� +�JbZV�h$l�b��e� � �I�� E�R�2�G&7�x!e%nqVZ!7E�E.A�%*Re:;$A�6!6� ��= �,&�I�*� �'aN�� R*�f�HJ i�u�tim��i�-N�@!.�A�W]*��ew ab�,a�le\CA,�aa�xreb��},���8xA�a%�or�A�b���E�turA0��L2X��#F;�t R�is�� r�i��m�5���!9��n!�!|tp,�xAge1���he6�B�%��'YqE���36��:��I��fA�s�"d withV�, (&Z���z29G� 6� )���Qj%�$�f�-�,�B.� M�qt^�40b�,���&2Few �.�l�=mh2-Ja;f�� Europ�F� 1eq>�in 500�y�J;f� ��d�ga=]=der�SF�{e�h,e A���at&�[2y���lso.�?@fEQg"�+�.|�[�N�A&Eph�<of^P�1Ay i��StwL=.�ab�ma�*5i�*venhQ><�"z_ %�&�\*�d/A���!�aX�=��t��-eީ�&�n �qg&�o^/omy�E%��e#C%Y��zHO� �v[pE�geAG-�tB�{�6��Z�)2�m�U�Az)�Ae�%�xGm� )1�� tX,�M>�&�!�-;z �B�hD* Iyu�O�_ ccum�Y%rg�eng �=�B�*)�� as�-d. ~u Tg!6o� � ! �zB�v�N�!.~&6 . crucn&uitE )c�al�th�r" ��8relev6��A�qt . Ad�72NT KF)G��*/2�qB @llE�un�;AHi6�5^A lack!�p" �U}K�$9.:�)A�8a"݀ . Prophyl+c�>2O*!b�A ��]i�s� �:n�J, u*�"��1% "�� $enefit [23�i2N[Q)-co~+ 1528A�x- �m�(!=5�9A��d�!)e1z���ݐto &$ *�>�@lfr "�B�A�r,a�!�,_na&�B1*�=, km"�  � e"I*rGE�aAL�Qne<���DziuW%X���< W"`9��!�A9.�V��%�EQes�$ablish����ja�6 D�{N%*C̋my�#DX�cB�5"���t!���w� |"F��}��]���d� |�3�B!��N���d�[e���Chi\4�xU��i"�x� micr&�2oviFU�� dpf-8�YZ6�&��$>�� ��cys�XE�a��'a)X������f[�n!ma vari.w��V�*�Y �mF����">y  l&�~u�r�[�R��*Qra��a���Y"��kYa`en�j36Aju�Gl[Chronic��a ��M�+s�tE�kgF5G. 2�ya�yA��iy{ I�M���elp��f��%>fbX� MT%��t�k�e݌�lra�sr��IA��>T�O#d�+if�d��2� !�N�Rv�m�B�re�2K �I*6to HIV=�Y<uma � macaq͘, �.�#T��~� os$ � soot�Mgabey�SMA�vn-zt"A Lrobust �Vrep� e.� �a �SM CCR51eHn�|a��a �AVmeK ( Δ�q�a trunc�moleculA�atAA9ex�  �c� sur*!$doe�t"�!#�d�x vitro�LW~3���]A�t a7E�a�1� SMVOonEu�K 3Y�a� Δ24� c $lso abrogavN� �)ZO�l7�8a8nim�[+homozyg} o!F%�vex k��W 3V5�mu� ���1�`ild� in W�Afric�F CD8+%dCD4+ T%| ksplay�a:+ A�E �gen�^��,8Ga:��*�+�x!���ReZ� �2�Q.a�qSIVsmm}J`AB]$P��!�-n A��#al ���F%2ZAx=�!A-�_R. Fur��m� &3)�^j� m�� ~�MN{7%�� �s�:� N�-R�HLALedm�Q.n��l � PBMC%0%{��aA mann�ij�d����A-nu�$2X��AI-�# CXCR&* GPR1�* �/ �7T[ �Q3ThZ�D�(�!+t19^eɢN2��A�'5�ina!i�re.1A�df�E�� �>u,*����{�aSM�h�%��X1�hs��2r�nGԡaF.��-�u~smM����?targetA�i�"voT�ed �-rPi��!��:�F%B�.� ,� ugh�3[J,2ev�rai�;��" ,�y!-"�g �-�%� may �Mo nd�e%<+ -�en earwf"p��<,o�Uwi�'�'�* �Ő� �sӛri}v�bqJ+IT�� alZ9����MA�. HIV-1����i2mz0.�$1aed%�-�He/�+of!�cpz *h nzeo�PTHrfKdy��)I� ch itself:g2Y�"�b 2�A�m�A���d"e<.�pre�i� '.�&�` -a�\DSRNE�SIVmac/� rheve"K ,( RM; Macacadatt� �!j2�ohf)dEVig��\}�-Յ���N� <; Cercocebus aty}05{4%�hI r�}"�,Qv3�ic�s�j to A! inI- �Ee�a���!*T U�& SM�0�iLQ �es@[6�73(Imw%�C��benign)C*U% �� � t�R�}Yvr�rm�;�IEno5+� 2�!�� non2�s� &Ki� by�viremia�}�|�)I� |� �*b�� "�� 6o�{ycyTuQ(p" .�����inxic linAru!� 5�aaV��9�(igha�84��� N�F"�F�mB��{re�o��!^ �n2E"y� ] o�u�[!o�6�ba$iG�m2f�EyngU!F� �xpharmav�N�%e.�*.�%v.I ��6�<ˈ�� by b��f��I�en4!e glycok$Rn(  )a�� CD����n�Z�!  ͵�asJ�%)�!�� embrane G*{ coup-S2x\p\tCktrigg��@)-1&@  ��or� �jev Xz )1@� ��r"�BA��Ls�,*B �CR5���mem�2� �%�{6�1� ?XC�n � >A�naïve ť�a�ou|/areGli7 l cele�ZlM*�!ZgE��A &C�dm)%-:�`1sa�6q�<{��82h6'r�g5�_�0.S$�ins%�%Di"�and KY(ly ,%1. S:?-W 0�Bl$�4_�ir>�ay[a'� r��m�bA�;�%�����M��2���b[$/!�o�,  1 ��a�I�V� A�!�� as.r,"F)!.+MSTRL33# !�orp~qYs� �� 5m$a�"� s2�+, �'. D�Vef� �of �*K d !� by��ma*d �*)T���9���b ��e�/ ��m7V"=Xa�&%>s� �or�a�2j eplem �r �0�J�)(:$�ma� A4ye�mޭ:O<`�M�a�,� �!�.� �1I?5uW>�U�uti�4:� 4�B��[  )2� q�e��yu6@,Ui� inguish����v c1�6o ��:Jny� Dct&��. I� belie 6%> 9��t,z)a!>".�)��J� ��fA�h1�C enis� /V"�� s [2�2�5In_ic: 9O�"mag���!l�;( Tcm��ubrQ9!8lay a�-joleRin̵�A��x � } �ZSnrCkL�8q�I�u+b�%(on [2;4It� ��.ly (%)�C-as+*�V |in �cmz *�`G�t��RM!I��f!�t'A�er Te.�E��w�i)��5� �xo4�&iA�e� ( G . S .e8M�; unpu*� V . Ani�c`5A�Q d� G�� �a&..��A�d)�zasu�a�"FzX0@!M�!�e^� z��"~[� 28 2�13�1C���3X�e�6� (� %nhGFM�� �!�Y�!-lf >�!wgut�b�!pgJd�aFbO�tr di�Z7[3G�&v�F2 es��m�E�ik�in ��?tis\�/���������� 3� 22 &�66� Th17.�yM���{w���nse ag" t b'xa�&�si�)�pl<in� !^fP�"t�� I�Ƞ*[ s [3��32333� T�a�f�6��# ��.�� J�A�be���/fi�W�%��-��orB��?�� �1V��/* \� favo!U]N zc�Ri�%" *~Q$:���a�a � a 32*s frameshif��~\ �DzsI���(.Δ3��2.:� chDLS�% he Caucas��&?B�+ng(�,18%F[1%���.O .)�a�a.*��!f�A�r( �AI�!�by'2� .# � A�! v�<ôS�5�an�  �a!!&�"e}����W�+n� ��i�*8""y<)����|�-O�&9[3�%4�%F2�2�.o�b���ut�+er�QalC�s�5"/oz ( ~w&- 0  K ]�[4h4Red-cad*� ( RC6Rtor�TuA!�q��iSIVrc{��a�v&�in-eY&�(E?))�^yXJS:Fm�ic6O87% [4K�A,s� , ≥7�]RCM�:�֑s�-�->���+X-V>) p%�n j9��!{� cm�* 54� u�CCR2bE�eZ�!O{2U�sBG%G����%R"I8�cw.E��c�S� �!�c�uE�aE%!75Ej?�R>�4(�no"�Jk�6<U %� , [4��I� i���H�:(N!.�d��!4Eqs��!%�r !3Y�Q�I(�k� �)J�\*|�-�k"�: -! ��!��" Yerkes N� al P�$te&��Cen~�( YNPR�2h!?Bb-&>: -des|�E/ ��6J!^r&'@!G�SiOs*��4@��Ors�talA�R��� "hibit*$*�A�>�;G�r��Gey:�(q^.�=�aC� ��2�* �dP�4��f!�BXVssp0Sj!/maA�mi�f��e� �|e����)el.P!1�inB�'���{�7!�'�8!�z�Ff� u��]QuJ2{F� onverg� &�KIe�nonq4 f# ����F�"H. 2l��!R6c% Zce SM' orBDNA ,���58+�aG�5*Q�8�fcla�byb$K�po � ��*ϣ PCR�Uj �smC�6�G� ( FVq )-0 �1sc�!g���=ctm˅�ea�L~ t 9sab6��i�#a *#%���DACp"  �1mR wt�Ac�# ]�l �6{ �&&�� t nucleote�46ł467��n:�( �''="c����s/9!��\�i"�domG ( TM8N-@ �&1<��q��r�a.w* I�%�a��d� V�J 110 � _�_ acid�BfJD�e)�1esi�26���B N�7q�:�5�; �!,-� s%�9{ "�M*�D�!NB7Q�qkQQf��`1 436T>G2T-�a L146V 9 �5�Hl"6��=IU�� �]�!�Zj�e^�c538C>T�Cas$�CR%7!|!���&1B|p�otU��)��M^Q)��]/�G�h9AQI!�inE��B@�los� ��,disulfide bo[+(%���N-I_;!F%{$a�wu?�loo��ECLu�b�[B)�=s)^ECL�I&"9�Pem(7ao +�G�!(%�s��%8�Mg&B�k!*`�g�F���:�� a� j'toA�ow!y6>u� plac�6�e�0�M igna�8r��/u,� *T�� �-5rAg�*� �!����AN��[y&'"�!�-s>�db�UA�= R[ z.�Z 2]�:� � <2�%�(�"-� !�e�"Z ӑow6� SM:� c���a��'A�X ��BiWbUXisG!&����6� RCM/ �~. �,��� A & �"���2X�%�^] fMa�� �l1�&�n��a!4">AMb,U �G-T-G!=eaA��Q� � �32_ �a2�{90�Bs dow �ea��,�#�itN�:���te.�?-jA��?�Ds�ie�)��!��N6KsS2�%9��A�A��U��t�U6�4�p�(�Q!78ŏon 14P��n��80;U2I.B&l�-�24y{�&e !�or� �b  ��at� �AS�,s�&'�#"�i<� n�yal)��5�ρy)* "ac���0X-i�g:=�a� 1�Iu24V mby~of:"V "� 2� � z2��{zaf�EdiIE@] %D*n A@a !BJ=����~� a^ - 1026G>T2z�B0�_�Mve�pA(�[sn1��C�ont>�!���5=�j&9�K��P"T8 �ZtE0whe!�/y! |!��r,�����t%vm?� x293�s� *8 � pS�2 \a=p-J� x9���=nd&�AJBbyB�cytomeP.��"�mAb 3A9���+react ���-s� %�o�P6'reSI`�4�Ha�Am* ��up=ΩK#!��]shv�� js  6�,MEi�-? As@w�͛2n �3 +!j��cе2q�� ells2�%�SM�)& A� . � rGk, n��� �ke�SM�nt 8��j�Qz �.J��q�� ar�Ku6.$o`�'*f �*{k�a��-=��9&� s�uB �A2A�x�-1�al �ntibo;��lle�se�G �Aitae�*�C�PR eUb�d�!K* U8� �!h��� .�5Q4Q��C.!�"� ,?�*� J�!�%��&&(,-xV!LB�=u-6�lh*p�����)e6&�A�N$s)%�s�2C.�ESz � it �1= !Eza�m�&9�"a?:-ay��n"&A� Yp �:H� e�co-.s* 7!�A or4ub���. N��w8� 1 !�alk!MY]i��SM��=��bJv�xaJ�,n��.�w��( n�20 �A�4*�i,l�3��)a�cr�Iƃ�D(Iё <"�A��A�=�� !j)* S�A.�E_�� !]e: A �� v e�5{ �e , v2�5 Cs� dA��c+h9�{ R�!aDta,{� %K$rect bulk 0 �:� c!I��YHsIF� f.��8�L9*Z��x� �p�lapA�J 2����)>�M"jh�6T�t�eӅo��x� 5N�: :�. 51:!�?#d�:�-�;FX.uWO2�A 6!�%�B!14.oVC�BG�.**6 .NR6�:PBj d%65%6 �8�nd� � !�1n��["��ly:0!Jy%He���1 en� E#�%L ��"We"�ym��@y!�ef)JGs��#s��$��SisUg%I�n �)��q:���/M�v�US%8 )bm��~^%R�"�* n *�QN�or�.'��^&NL w�Fq&��}�"�5�n.eq!o~ 2��so] �f��3"c���2d��hoea* Tul+4��T�.� �-� monkqBE�} ��he 9-�oJ96 ��IM 1980�Y$ KY�nd�Ep��~ QXe��@M�][���)r a�1bX09�of �zm 5���?� ��of 5% .2�%2@ S#KBv��%y!"�.� �#*)3/w�`�X��2Q� s wh&�a'Zg"��BFDk�Els��e� � L ��'fecal-dejGdb%�s� $33�R��wT!)Tai�A� H�ld'Ivoi��4;> 7��TA��R� Nin.�aA;7)MA%)�&�8al%�iT2~��Zw�Sf\3�"*���o� f&�L"u%y%l' `l�֡��!�& st+���'xb?e@e�%R)� > u�*if���e���be6i ��: �� -V3(A�m�3���@U��E�7��zC��*udum �5 of 9�E.��8�rE�}~��c�*!� � �?]+!�lsoa���%�M���6��@-Jy��)��b1in%x�Q0"�.�b� *s�iS0 ���57��� "K/^�&� YA��Tc E��sN {/j"9Efj#�U�L�4hip��9�aC!�X���W&rX  .'�F��P1����e3�,>ZE�a�&�Vš1rц�<ɷ&�n~0 S odic�v� ��200f�ha�on�9O&��U��>G�"�\s�1&4rth9�#9tu�$ ,e��r3��U�p(r2�)~F�h+/2+U{v9H��� nd �u8�lb�(=�AYnt1�.0�Zly&T3A;"�r01�,Kruskal-WallQ ,�is"//a7gL!�m��a59�6i��V��waU] o78&K�5��a "U�aclJ 9 gene dosaW�>pşD8�HA�Rm�!f99996;"@�W��8on's 2-Y�SM:A�co&�))[(:A* j�6Yi�Zo&N0�$ !x!;2�!xu %v*�L�V��{8A�\7�- 2%qu9{,6���!4� ���h�"E�y#�aa�(5��XyZ�� �|n�1� w,�no%��*4�!�v��,BB><��!n�C1G%ou�_ �IFACS plo�rh�g2>44N}"�> }�z_}�?��B� c�k%(�#l�@�w����]!Na ��Oeb��� us� r1�"cdU�(>�an��&*�=/�>:$Z �3� a�� u6i5Uzjtu-a* &�E&��dQt@ep8e�a%�_"d� O)���$=5U:"q.powerT ?,"H5��J�%�W&m%�*n ~�$CR�/��� eI�S�. �" rm�O�@���z�/s0�L> ��K+ "�to Q;%�� Pl�=ed*]120 )�~�A�./h�"�L�&�7A��3r�M�w�3.VR.�0Z��] u{�< �skg꩔�NQ*.�y�U0, 65%b%+��%Gun5� �6e�!�>�@ 75����M . Un! � iU<�1G�j9�1t(,y�eJ��50 �$�5�A�"y^�24o U�? oA32� ab[e &��a�/ &��516MI!h-�Q�  �A��/���[�v�&�cSb�:~ + 5# �2!V �ly&��.� �!� mil��� `���*�T&G �5U�C(?!a� A�u!�!us),� 9 ���0N%R ; 2-!��E�!s"�caF�.�D]�!�>�q �(-J}!i75���:i #(� 8% vo  7%&� gA��!�MAe&�Wp�nt1� acqu i!^�� �>gU�&L[�=I�}6:b��l9� awSMye�to!6`�5����w@`r�ab>��r�X^a� �!9��t�,�S "��ff��"� )EMa"D�i�e�&��<dE�m�=%t�D"k`�"a�!x!�2�%V�*!��4P 9 m�1e 10��"��eq)�ed>���v�) M|5=�Q_6e]" 4"h�(+ W/ �wMF�U&>v| � 5� "��� d� Ię��`�[a mixCl��- ����"�8 inoc-Oa d�in"� deca�7."�b!���.G)=M!�I_(A#�a�xne.: #�Q9\u��1W�z�+,aN ��Ye�J�$* � :�2�*�| R-_94��c��TI�1|H/K���t� R>I�!fŮzQ&� MQ�&JzB%a9" ?.'F)7a=B�����*N�'!ylog10Q4ln ± SE�]��"�degEch��ma8$��"ppy��s*W �&ir+n6� �)�["� �j6��K h"v^.%aR5Q�y �a R�ar��VuӇ�\�{L"�>2'!K�,f278%�> *�U5�^n%�es�,two wild-typ��e alleles exhibited the highest viral load ( 4 . 83±0 . 10 log10 ) , heterozygotes showed an intermediate level ( 4 . 65±0 . 10 log10F and infec�,animals with�PCCR5-null genotype ha �low�VL �37 �5�. Thus ,KLre is approximately �.0difference in.in:�wo wild-�compared �wo�1e�e Dimportant points h�Tare that homozygous mu'1$have vigor)�|replication despite lacking funcal� ,%h4simultaneously1�P a small but signific�6plasma |lAassoc!� �increas�!�!�De dosage . CD4 cou�@remain stable dur34chronic SIVsmmM�in!�@ vast majority of5, � ome excep5s)2been noA[$[46] , [47Hso we next asked ify-B�m!= s��depend�o�ir�I� . HoweverU�was nojl(CD4+ T celliBs among% u groupA�whether!�essed ba(on absolute1zX( Figure S3A; p = nEHKruskal-Wallis ) orB�basis!s�percent!�NB:NANOVA )I�8se results sugga�E�N�re AtainedA�ilarly!uSI=�,SM regardles �CREs1uWaUen9�!#e%|any chaa���smAΔ2u{�# ,!^n expr)\al!�w��!,![ld supa��6�vitro .�conside�/(it unlikelyE�thoughtE0ecessary to t!10directly giveEia@inAy(patterns byI|mAb 3A9!5ҝX primW(mononuclearEgs9�3%�W�%so:����ue�m�from a�:x:Y ,� case�Qadapt��mi! ��en�"d useA$an N-termi��reg�!��`T�Lfor%�ea&eraa�pseudI0virions carry!:8Env glycoproteiloAy5oә�uElan �1CCR>���!YNp��Y;�6�s �.x��9C�~bFv%�U))2� ensuAsQ�se�s w�|derived oactively�[ng!4usa� arget 293�� Aco-trans��u plus �ids enco�$�iq , A0, human%L�Lan empty vector as aA�troABta�UYza�Q�M�.j . Of� ,�6G!�5 . 1!.)-q�ably �x ~i�thai�o�i5s �very l!=���of thisxu-Grequi%�$o achieve valent.hinocula��ichM�l%��d��n� �;of back�/nd for ~A� . As� A_�!�B��=���1nfE-vvaria��t���� . In!Ktr��� ]�wdoe�$tJiby��%E%�useA�I] ly ,EDATI QFre,or%! �e{C"z iebN ��B0��ed! through�� hway39!�ofoaehe data �nen!́� ind� esAg�e$ must be �%!i�'entrygI�E���r*9 � v��It! �� knowA�aq ny� stra� da number�al�{a�9 c5U� addi� �}m�,7��ak�%�rarelye CXCR| ��r��� � abil -�envelop!%o -z9�5�U�2bI(3 8 , GPR1 5 ( BOB��CXCR6e �Ta�analy employ �uncult�s:�VkEo��M�!.� (��)|��y�( ��I�e� D R�6%{lz�-f-CdMT into,e � ie�jut ��!J5�!3xwhile� also!�d �Nefficiena�>&non��zWo� A�z4B� , no� 3�dCCR8 (iun�phA�� I�esting�Rvv failA�VE^��.�Y*beWrc� RCMa�t typic��� G 5 due�a��pre�c5 Δ24� el$[43] . Fur��m !5"% NR�%4s���,qV:�29C��d]��@� ��A7�^�tiliz �� feaaP shk);�6  � host zQ�es �. WE�" lucifer� produ:�aOx experime�҉&.�9��ed��ofm�� 1W< �]�� &Q 4�xal�&*c tLts > re�, maximum{$potential .Trel��to"- k�]we@m�!M`se molecules at physiologA�n� Qinva6g} !�rolE� non-A*A��qV��!%of�SM �, �A:bo spec�)�a�oni%raviroc�U� PBMCF�%�ZQ�. MG�9rdid�iin{1" DSby�*��7OɼC it a)� :by VSV-G=k�M .��nfiDOat�ir aa�u]M5. N-we&PӉ2 ��Cv:�SMu�e�b�A�> isola� A�. ( an un�$eBa( FAk$ }"< Az �����E"PHA��three d� ,6]ahe�}s#A�ab of. � ���( M923A M951��w� ���B\�N5��V�.� Cmea�as� gag p27i$� supernais coll���o�T post�ahա7 ��gne��� ���� Y#�A5)E") %�!zC��SM�%�.Jth����M�no*�R.!a:�_y 2�,!A�&~� of��ak�� y�� nt�Cis Z� )�!mI�% can occur<x- *)�E�� �w"�Eq/I�fo%�-�e�ished=��in)�!�qa�� �J� ^�Q��27 d� A��c,�ed��A�antigen�on� is fFng! wn�in�LUemerg�ollow�A�� al=��P![>proI(2�oss&� �d clin AIDSk6��skmY rieS!!+.  avail�� geneticUq*&s8be lin{to-)A� @d��io�UD4-low!|d ��lyY cribU��%\-2�"; kd�Nei� ���M�.��: �!!.� a�e eega&�,h"�us��a � M!� facti�acquisi�l XCR4]�a �q� !:=ъ�E-��=�#�i�a nsis� �z�no}9. mL-&O ��voOrob��xg�"� serv� a drivA�for�|e^�o)�A&K5 . We una5A�ly.28%- soot� ngabe� a�US cap popux on ���8M���E��c� 29%�f�O!4��,%_!u-Fbroz � surfac��s|!1SIV.9� . DHth��~ statEB** :��susUi� to n�al�Aw�as6}�qi��display� ,s only modes��*a�Q�y,fe�Ա�(SM lymphocyw i��l^%X�# Envs��oy�()$ �3p ��s�!Rr%�B',emdoaEI�a��� ��cat-���%�VlqUse I#iYAmRF] qv� recogn�6e�}-��P=S|A&u�R SMU&��.� imp� ��understas �tropisJv�~.�subset�c� �ma�ga�!Ge outcF of6�)�A�IraiM&  ques s about-TݛA in%oge�  I�tcdel^�>!m*�. expl�a�ݥ obsc�~!on�� wi"read&��b.g SIVmac/� famiivi�. F�i� ovq a[ rd exampl� conv�nt ev� !I !�ina�ru�!�EǕ�e�a�,�<�equ��I�-EBia�� �inAb%��"}�%s.�� Δ32EE�capped m�߽12F�!� orig! ?�%�Z�A � 1s�e A�E����by������ .%#r�]. seE��ai�#�lus�[20�[2150KIt-L# repe=ly6%[��"� ;i:)�ry)r %^=EF .-��!���2�xVNs�e� � a!�n�5t�4�}{A�a�!.ex�Q,�le��eli�EB-� [5-52)<3 4 5 6!QOur��lEDA4Htim�� h�!V]�FI5a��gan@$�s �AI, m��i�n !���eN�� �F�. S��].re�7d��� : ( ".� b so oper�i�g���E*-�!�,�R they>relev�imZ�$t; ( 2 ) w!v�#n2� r seaadAag�& Zp��!-�� .VŐE�aq"m�� A�.��6�- a���#� Z5a�def� a no*z � Jeg)O2"�contribu�o�`"kEAJ��! coexvwi�*'seK�,��%\%Rdo2� �+"�3!�oX1�A~nonise��4�d�study�>Pri� !�} �)r�.?�A3�%�,�� seem  laus� A*.A=�!�u� /mac� a�� (epiphenomen7!little b&T& cRs z�0|E��26�si�&7>x� ��g2�refA�s Z)%�E,aB�o��I+y6, oH+ N9�1!�I>. C?+i�of� � �0$�(�:ed� r6� 1e��C(T $a step-wis��*#6�*?/ ^��AKwo"�� `A�a�.�!�A�i`&c�A�AI���J�U E�ry�%po@*� ).<24qOn�hW%�ߵ ]�( �)AU�IS� n*  at"� ){AFa� ulti� uT�^�'�"N)" � aln undancy�~ iKminis{*Spar^�VC�&�/&�r�#system&"eX 9,!_%�.��>,� tinctA/��i overlappAF� AB� 0 . �.VL� E� betw�Δ/Δ�W/W"�� " b�#6h sepa )�on�d"�- emia ���  �(|���)�a�e-�-1MA(�ofE�Ca�i7e!t�notAb! deg�of_-le���gut.A� ceedA��o� �>KM� detec c�[2� ai��.e*�to3%e���is���B�C!�B^* �"�-; �y�a�A�]why2|$eq���d�.T��E-�%��s&|,to� � !|8%!�|�ull�)���2f�4a���8, )*J a)��A7qmi�, e�~!�re� oirseha�tc 9�. S:�n�(Q�)owv?E on6d�  pAi�"�*n&����,0 respons�#“c,$ct” crit)I@�- i�.�1?v�be�pA�s!shold.�by FACSH urY@rev�R7UpofUTit��be2zYal �AS�. Few"� � C3mpa to:!�Z�Ah!�p . Onyx � %z!���8 �d�#��� $�8@ o�%�EE���2�J&[22�S�)�w"1 pigtail mq9,( Macaca nem�ana��)�k�"SIVmn\ �g)�1era"�37e!�c ��� +.I35�� assaP-��2.[^!lE��� $n cynomolg&d'�$ �fasci31r�6B���%$� progAAtd�-�re�-�broade�5a&R�%��,those�XYmone narr�vW[m*�it�; beeX� ;!�(2y5s��or�Jart)3�sn* ��<%�MU�N uf� e� � �XCd� mmoB))�!of��s e���-inf+3Nin~���!�A�ac;!�)�lA^�*Sl^2d&� A�C�by�s���3{�b n�  ,i'$!!;CR6� � �&[geU 5́�2!of�L2�:@� bem ���- �v&1�� �y"����9�2*>�/� ~qu~<.C#u�a[d?NJ�/U1-KE ncord�w!�&.O.�."w�핐�, [�� , [3�nIb�od�2,% 6|��c��  � (CD8+ memoryE�naïve 7 ��`�er� A�NK �[5,"�-��<r�d� �a)oa�:~aV6ll [6 �ter��0!�6G�& � �,)"� -rIQ is t�9lyq#%�A�2[��& Mstimuli�markeR�!:5-%.M��- )��i� myel  �"�Exinfor�AN.2* �s>61�k���)WA!m)r�soFMi���'%tissued6Bf�:� N�jn�invol�* ucos v�g!a Sx� ��L!���ZN��$E�<c�da;� �:&) �m0f�2"� !B�� 2�� �on��cIj� ����4ISM q�!��y��7� CmL2&�pZit�in�/d � arch� �5E�j.� � ned�alTC mAhea�y�leB  �cm*�_ !��."� ain!X18_}eosta[�H&�(o^,&� �/!toV�7cy [2MC2�6L���a�5*�ow.:�! ��(.?ERM%8�i����/*�65,*lee�9�q�6;M��nt&]6L% ��7SM2�)k2*�̀A�uprCD?� M�<cor��d�th��)-7�-as"�2��w7wHTem-K�w� asɓ&�m�" XkRS/G . S .%�M}1; unpub .obv�(�:A��I��fbV�an 2� &� �B{��ts2E �a�.�:�5 �!� . An fpro� n��� w��<�J��)+ �>2ofV�ge�Bliat2� H6y}%e� Bin2�]XE>kq;�aY��� rapia�resK s [1�"2� [3�"6O[6 �"Su��F����G9*a�#*����+�< tur� ]-j��. A��me�E(>tF`6� be)lodI of microb��2" disr&�&��_barrie�Tteg�H%Z�1s e�F9[3] &5H.N� �*2A��� *4 f: a �+]��!�%[3�� po� �"�� Z-��e��ia �M�-d�/ r�]9.-�!z� 8 Th17��$� � c�in2;-� defe�Q�3��3��3bWhy;j=Z�E ��< �B� o r '�d!b� J�)�+6��F>. i�K�H+!o��,e,o���2�I� ��9ZT A$8qB � in ordX'o*�+��� ver�:����1�%^�� q��!YNPRC�T < olon� �1 �20*�0�dTai)esK,Cote d'Ivoir��!��\%�A��jo0l�/!�ui�@ld� 9W\AfrDM"1(; ���cy�y:�at ��2z"�sourc� n%rir hist��1e� docu:�26E���a��t!e�C!40e��(geographic qI�[�!oF#@de�!7.* :��2!T-"^3� �)6#�'"� B4= )��.�- ->cA#yA, [44��YI��K�t��%{screeA�by PCR �"ic�sBdi,4�J(te a 24 bp (!j]PA7�%�87"guish76.1�!!G &{0Y�a5;Fi8�� �Q;M�0blO�{eV&�E%�Ae|haE3� r.�2�!�Yvn4-��>8C each1� uZpM@�""3 *,Cnt� � viduR�s!on#p�ra-�b/�2 .. F 1A;*> �6��� s�,.!�2 �geo( ∼1%v!Caucasia }H� ^ zngZ �a�elB� new�Ri�.,EЁ��&���R��� l�>�ke!ɤ�z�A��H~-s�*�-a�B�-| �4},Dasion�$,��.�.4RCMu5OFFPaw�&.�( ≥70�4�3Ep!O!f�CZEw!��l�!�:lo�.&< E�}S:�>�$6�C?+ #6�8%)�is*u  demon�#���9%�#!�hip>�V�6�D��3 �� J�9M;QJ&� ���%`2+"? ed ,>hap& ca!�y9v.�"1 toge� RG" �V�S3ed :�&_mL>V%��IVы#!i�*��&�7�]Si@O-���I`��� ro\"� taken!*SIE� �>Z.A[!a� clos�%�w#nd�/ "R sub-�e� a same�� �G , [6� ��"��/!"H����nd�aa�$�-pre�� #=�s>�2�+oS(a@ kY2��� .gh���cerAHM'0 markHO�$* CHQ4�a��\ �$s*^,��@ exer�!N�H iron�lal �uQ!!�&03 �f��("y�� �S�"�S�h!` /��A�"l�N R!p� �(!�F%� �(" �S otid!V�3nQab�Frecombi�Mo�or*�@o*�*si���)��2�� &F�0E_ . Si+ <� �<r "�T� �d�IDl�6&ny.uNP.�!�-"�*6�\��!�FQI�)d���/�( prob�#4J:4" 2Qus�,��-�.�-X E�i�EFuu!.%$5��+m? ��.�at!8� S�Xduo&�8Q�#i9p6|2.S % xXT� �Xtl��'�*1��$mt[�>,  avAW>-�m��eE��&a�U� ��rr;& k4ol��,g�'3]M sdownr�w:+�D]�� t %�@Av" circum'��lc,!)exp�ng.r �A!�D)6witch' � , yz<he�  n�iL=.6�av�1�%. A&f$�:&�&�U�,��C�Y)] y2YK�'6't EV��� �s-�unj��Fen.}facV]ng�8�[o�(l �O_)�-KNS8th�`�i�de���V&J;��1 )�%�%W�"�%)� �&�h � h* t)t��2B ��*)P�(tLM �ac�-A�6�>:?e%��A[��or*>s�RM�E'd;e"�>:*. A"�/!8R e�co��p f"[Fgu�+i "�6 �A# Welf Ac*NIHe6 housA$!6c%$of laborat�� per�!E�%:*$c_' Instit��Y4�"h  after P*ewHabvala��6; �C�va[Committee(IACUCeL�=Yerkes N%(al�8mb Res Ce (�g_wTulane�9�TStu`6�)� �[ �9�Uni�A�8of Pennsylvania ��� s XI�Al&%%E(1�!�n ��or �. Per�8 CNw^�!)o�%�\wh�- :I�-dar�n� grad� ��method�@��;8/"�W,)x%�ld8×106 �%Nly�in DNA u�<$00 mM KCl;�5$1% NP40; 2Th*pH 8 . 4 "5 mg/ml��in;K/0ul to� Am5Aeu|�tZX9�S"��c����1�, cryo��erA%c�thaA�_9Na�iR�3�@5 )�!�s�in RPMI�,l��r"10% FB�-1% glutaO�`1% penicillin-streptomyci�� &U@�3�O� 5 µ%8( hytohemag\�4 ( PHA; MP Bio��,)�)*�E S 5a%/�BTof IL-2 ( 50 U/ml; Nov+�A�Y��ilIAfty|Z��d�\��purif�+AM2�fe�p ]V�OinB�%��� l�b�Ber7�Nitochond�-s,Cy�2� t 33ų�8.�[4504Full-length SM�g��#�!SM$ey�i���#typolymera( PhuO $; Finnzyme!o!�ers&�M� I� 5′$3 #F"�  �`1 ".forward:Gt-ATG GAC TAT CAA GTG TCA AGT CCC-g; r�se 8$0$CC AAC AGAD TTC CTG C:��a�re � �d �61l t )AHF ��,5( 4:uME� dNTP�2��:\200 ngA�U�A��!�as�i�!A�u�7 ����rmocy�M n�6: iHa{" �M�98°C!h 45 se�i� 3em*20 R� 010071G3A729,�?a�# &�tep!610s7�@.%�E�A`I�column97$( QIAquick.Pe�okit; Qia~P)xtv ��%W)9Q\�Q�� i�,p��� HindIII2� �!c>eend�M�i%)a BamHfBA�.B> Gq3 (!�}2 GCT ATa&CI�4AC CAT GGA CTAmBE�>90AGC GAG CGG Aa% TC AaiGC A CAA<&� �\)o deYfN��%N���: a� itB�E1at]�b�5��F6�6.�.&1�`6q �`{f�,y#at^CP>EY�iC��U���(smid pcDNA3Ie+ ( In�Mi#�Q��I�� .{�(a�"� .U�����F7I'�RZ�*zf� eWFg�� �g%*� depoA�� Genbank?c�i�V,s HM246694 , S@ }b(blyE�A�-E}PCR-b�k�� ng�%ayj�+ ��f %�� �!^�y X?ni� �F�� anneaF,-���3��lys.ce .! & subjesRo�IA"� I��f�\ro�V �s� abov�!Nf]W�rW����,�r�e�atA�k�Qnum TaqNp;6� , 1 �AmM MgClO-���� J�, 1–3�V�q)9%����in 25#��y� b����2712|4�?2.�6V��D��Af�R�oraAD*+�( 2%uul��MF 2��-ILI/��{%�� ��K�6a� am-�u up2s� fic�c6q.mk� @ly�Ke�8T �ACT TGG� � GCT� � ;Δ2j4CG4c>� 6GGT GT� � G A� 黅�!�)]m�.� )Ka�[ � Sa�eq�U . P)�� 8J<e�-�UsE� visu-+$by 2% agara9 gel �rophor8A�ethidium�9mid{7Ig1 E*�d a 325�$ pair�E��w��2���or !��)BA~or/for*�W}"[]S1�_ . EaM24a��A!5��4>W �aa>I];J�.�2�de>��v���|o nes JizO)� M�Uq e TE�M�6l �  CC# GA�� /&x V a �An� �*F ,-�� 2� 02759�N2GJ7�F� f� u;%�6 3�  yiel�3 a 20R�R�LuBA�v;[&�&V8 227–229�&I-yBa�A�i hA@cS1B��AlL�p`2 �3en6 �xIF)�A�iNa�,�q bulkN �:�:M�ed2 . A6 as d�6&�J"�Lime\P�-F`�<pUat"6>*:f�ȁ3�ҽaE&�-"!_7 d� �PverI � manu-^s� o-j��� <uni�\asr.�'�ԭ�qi_#x`�ameshif/-�!�o,.� "� �2 ]c�U�0u-�s!��55 u6(� (��"�Ka fs!�"�6*cU6)%�6-�3�=I.w.s��F!� Y jnU n�4.� %.>f>;Fp u5�&� "d'Env>"gA�� T �&�g.da�+r�es*�flzenv�o:�l8b�<�2�uapE�gh3!:by2�tAe29&�tb5a"�e�t!DNL4-3� env-i"edZ��backb�X( pNL-luc-E−R+ ) [71].�*_�M2FuS�&()mac[I�jorhg�N. C�V%�3��vernixw)�Fu!$ ( Roch�wad��kday� rem� h �+Xi !�S.nf�&sf2Ls�*r�la�|�<ifu�T14'to�at −80�h unti Tj�qu�G�Ron )8Gg���� 1�.�m,�F�)d� n�al / u"�q�4t�R(! meg�HA i�!a/�e��LU)xa lumi�W' �͵Msf in.����8��E`a���Lk><&� �u�8*1( �z)�!��CsSome� � ( SG=I"Sv&ocolsa^;��nd�i�&� LTopo T�2�[7�B[7$8I& $ ��0�`6�lEW"�aZ� [74]�stoq6�!��]�A..�.u�79por$>orm�c�L);F��#rEzK?nufac�tr'�+strucA�� 9a�B?detact incubi�m:�A�� EDTAM �kinM!(em31s!�� 1% so�az���;w�=�q��!cl�1 �bod�$e=�-[APC]yD Phaa�� @s* -mat���'27:� a � Cali;zfNcytomej ( BD�sb@"�(FloJo softw�#( TV Star , In�I)!�F � J�f. PHA-*m Q6E)���>�t���5.�a%�a� or 1�U!�!a& r.0%|aN�t(�$uM; Pfizer5�t��hQ�:_(:a)�)>�( �� ×g ��)2�& ]�� "� ��Y��Alm2j!a!Aj6Y!�E�o�d40�O�u-�� v"er�p%�&D �&"�p�3 week�tr�S�l� _Y,G� 7 aA��9=Is&� !O A`�+ BioSI� L�&y�%C m�go1 Vnd"�* uMA8�#�9"�,���o��� survhj.�in� 4–^2006–�d 8–9 [7�!CD3�6D*� *S o��MC)`u��Q����R ���.Zreal-�2.�D@ ��%purpo� �N^#y�$"�YBr�&�!p!}�)�7r limk.f���w �k�) sero�f!��@a�IW �B&C�ato*3)�Ac% �Fq�*�tsd4�J�(nG EG�P.X" 2-�l--�>EdE9�AQi1pastg#,H{lue G" (.nto�yA iIA�m��E�:� ��pM ��)�or>��K2�!�Dunn's�[.ar?` 0���^ g�� two-� p,U�"'| d Chi-Squ�eJ�e�!!h�.�1jS5-s�Yes1�&�*^Pr�B2h0��!LOpenEpi:  S�= Epi�0)ccWP�$c H6J , Ver~<uDA]��"�1�0*��1P-v!�E�b�UO05 .q�2��dA�$of MEF2 TF@/!�tum�-�'!a 1�Ymg_r�&�Q]we ��at O}:sG�T2 pro-P Waef$�S� a�Q5ATt e!o�?thvM,sPLorsatnaA3��]vIs ��vGbht?nS � �"�G�� �!/�}%�, s�2as H3K4� y��H3K��cet. C�-9(s0b!�hrc!�a �mS�&�/�8,ass IIa HDAC!�@In leiomyosarcomaYLM� �\9wo-Vpd_ �aE-:ega5)�agJUnesaC:sasv͂� 22Zqx�'A3�l�L� s,����9 }~re9csI� )�c1�=8%�e�/ckw!0 CA�A_"S���^$ �hN.�)�b�2tod6 cripa1alA��Sc^ps� �-� lociaDAC9 cov \!�Rde� QofA 4me3� �Ho��m�[A!y More!!ReD?k&c:�yp bindv]rB/AC�+aJ�!by�� QB .� �eelyA;n! Zu��stronh�M�ed�c]h:D�Q�)�d.fsENpoi@Te� �Gmatu�ig�()Ov�.l2�9"�PB�)�|,cul� � rugg�t���a!=rapeuE5�Gv�" EA. !%a<a*goEt]>-��.�Q!���ol!�pa��i�Cg5�HE�)$� adult lif! In�teb��ur�Nb� ,%aA/B/C/D ?~m� }p.#%|cha�s&�,�!�Eof LB�,a rved.ԍMADS/%doJ 2�d4iH3!� DNA-A���,B-l�pfC&:�%_E��+4$[xIAl� ghi�&�+mT����f�Wu��al"}/ 7e� cred]�7�Ov�3to�me!ha!+-R[2–GK�}�]2Za�c�<%0ђA\d�1g�=&�"e�t�.)�� ��QS�:*6TB0=Fi)1! �[�9(.S��f'�bm�4sɫJ f�%^9y%P$9aP = ongLb>v �TZ�{-�a>�Yf#)�A�.�h�;%. D�Mep� �8mn%� and/y�(�xc��"s %}B�aJe�wa�QorcCae%�ext*8uRN(landscape [� J("�?fa�M5IJ�thH spli�!�a=d pr8D"�=laya�of� lex��):�!�[10–1�Fu�7g�-bbnhnv�?Q>"���� !bq��{ abin��9a� :�[1�1e#A��� >h6� ,B�(�� 4/5/7/9 )�y�iv�3�P�k)PEX!VB�( o YETu�2*k al%�r[�e. Dys�;a�-;�=":x�9q � V%�ia����wve�1�K�cLac hyper�Mh�<r?;�!��SpL��E6y !&t ���;"�� �A�3t�mal�pnci�$hepatocarcea�Y li�}Ain>`6�Z,�i��@~rearrang���� [2�M�T. B�"W>!ϡ��&2Z A��de�}��AAd�-�Y ". 7:e'mui, �Gl a-B%��D Hodg5n�O![1a2!�3?� &:��o� ќ!nc. �&Y gm��i *"6an�ye�m8H�bx2Aq:��yi��� [2��3�%3�bI!a2cenarioI 2Vr! a�act e3sB�!�&� asA�� !�o�ԕA<6}A�Q*ba �W]�FenMfarl�8#� wLaci��,dd�*pɛ dissfW�)9���1��*S Am�oi&-� N a�$s<.< a3�_E�F\Y�%K�q�Sme�smo`w musc�&�-�[3�f3,M1�$apt! e�z��>wٳ!|"�`mo.+�8#�� I�a��T� !Gj?��*7���dNrST�8� e=K�}_ ͙o� E�&5 ,&c// 4 o�� mo=fibrobla!2D S1 T, [2��]gs��=�toz�-x%����AYFsFig 1A!`u�+�;8-��� a�B- �u� ne�c��nig"7���na_lM���ae�!_5Ob6�g�m�$��8 PI3K/AKT/SKP2 �wa��;trigg�=A�adI�qw�ݙ�SVCA+!C%J� nga�RJ>�- ���!%,MjCu\)k/,K&E@%0 9 mRp<��l- re�[0-&%ʩ��%�BX�&WB�li�Di_�by IHZS˔ , sc����[!d %~ ��6Ti�`-MW Arra�.TMA )!157%. I 8����+A�sh^��e�$)o���P� { ( Ki67�!i#An4 �:��x�ZI . )AaD*1ES2m��*ik$v��)u!c�%q):2)�fU(.� J)�( <20 )��( 1FX1G2�e:��I�s��m��*D JC  Xpre�R�6lpy�p9j��)�A�J'q aniI��YA�!w�6F��� Kaplan-Me�S"�f<�� �FQ � :� ��a:Q��pat�? s’&�-QH%�To�v61�!�-A�s axi� �u,�⥇�#-.6,8t8��|,�)�5<�sti��X�lm�AJ��m��s-�0)d�recapit�I �clf  Two>�$, SK-LMS-1INK-UT-N �i�Q"�!�-)����_Ang ( G�G3�'�+i�) AY�Na�yd�k٢>>m� ��I5R0�A6�!��SM�+-�I)�'�!{5E%�� -l�#N# a��6�@!�F�AM�%AR�� ��� DAC4 Ws�'e~� �V-� �%�]Y DS�dra�� aug�ed-2��.:�� a~��A���dc�, �IJ.�UPS*rzceEa!high-�K) D JE� �)�?{R!� !7a#"p� &�R>�-��wE3�(W@\9YQ"b�=/ -ubi�jR[3�f\.�-�Vu),�6� CoO��, d Dα1ac %#�u -aCg F� =2hW�l �G�{.�)Ui%�! aHyAi��&�a�&�0. MG132 treat8m�) inflr��-�A��/>�rexon-sRows e��Z�}M�or�),A�b#RbqTLα.)W�y"�X% P2"� &qtoB��'tr�5a � d� 9G�Eg(DN�(uy-��hTU!6 21,;v��26�i>��A�V�-ER ) di^�-��,MA5��M:�W.އh2>+��E�m�&�r%��2_�Y!�aq�!DDNtD �&�!�AMNwaa�X5"" r�Z �E�In sum��%��, ata *�7� ��N�I�)(s 2��.&Tonri�N X�MG!�A�t�}:L knoc̐�:� !*9D� M)��GwV\�= shRNA�5 3� Esilen!%\c� n�4��x-� 5XDKN1A .� �+��e:se��_6�( 9, KLF��RHOJUN�$NNa@IRS���� i'D �#�0)�3i9In&� �D K���r)��?� )!H ph�6 Sa E5 randokg mo�xt� %R!�a� invakj�7�K � }a�tMa�,s.�s�? r� 1Z� &h�~��E5"N �Z:E�Z ��:��0to�"u\ �D;. ) KD%�DK�er.Io&�a�(gro[�] �F�W%A-2�A�.z� 6" GG*�\<opp�A/!I������V!��P�M�s� e<T6;behav�% |` E�IE���!�p:�&� mA�H"' 3"= V�I�2�prU]�!n!�thA�9��s!"1kaaK-TU-1MXKDW !}D1VJ , 3KZ3L}To ex�a�5�.&]ѭ �dM��.�>� �oFl V| ��� J�`��G�3i�.h �+a��k�&� ewKD�%W !v� I��S2AS2B�;E� A�-M� A�sE;Rl�"![ +s�� ~r8�% ��( S2C~I*o,$Ac$R3a�GC'c&|��M4B����-�1F��D�AR.�(AV C�alogu�%r"�F��9�aG�[X> WAR�-j bi>%�. &I* i%LMu%pho�1p���� "�"l6���(�I3Q_ `\!_�܁W��v��AsN�[Co3!AS��3F9clqf�*� �A���e�#�N0r9.. �si�2'(.O,�M�S3M3H �,^�2�^�R�.�*�S��S��S3L �W"� *�B� X �^���&A)*>R� . Oi�p� e*R�� ta " � rn�)�wa ll-PW5"!�se��A�>�!*2��"S�I� E��t�%�&�B���9!�e�i`pu0� /pan&�= -4K I���� {� rw�]Fcyt"�shuttl!�, �!, � 1�4um�a� �%� le"GS&��s���\&AJ� %Ilex�X ��rg��nRd 4Y *� h�����Y[ S�2�(a TI"�m�͑(i�, ,& - j )��!�L lo()��a(�� � T-�� . Ex���1} *) ɮ�"� �&� �t��*�i�MSM> �f5> �6em��prono2`�S29>�d� u�&&J �Fs�s�#!��� . Ac�}N�%�� Wk�!/� ���1'-�$:},:aVf�.�ChIP-re�ZfU � co-py�b�*.�of)��of:� ( S4��ByVDu�V��a p�/&�1�>H ( http://www . cbi�0a�, org/gti!,�q�=Q��3AH9�^ut+ 7-?2� !~Km(5��C�V�>;Y�-:B ��h6�a:��&Bkz� mirro<I�:�H D]�D6�by��� �9e�H!O&f  J.���BBU:>/�"s�S�M +���-G�jLu"�=��he-�+* �i%hig��4�p��0i.p!�É&H�5D��#A!|roJ/6�a"o enric"��an.�"@!��a��1a���1�/��Q�1U6p�hr�./�yvc>0Z� -d����ex��2U�֕� :�9���+$�!AL>�Š�8�A)Z�>�JA}�Usam�5%xs ���2��=*�nI >a �51��Ʉ�ʡҥjS2Z.��%a�c�.�ireh�h2l4�ar�C>�$2�'�j%w!%A��)a6E3in"4 E1o7[m�&�PKD��OU�0  �j�odp )a:*] ma�MI}6�#.�' py ZcyPb�a� ��f �>e&�%�J�� W!� �W�* 6��5- � �8�QJ ��:!�%�� work focEAnrn�NI��$��!U e-On%+m�y#�Nal������)��  !3 e�-"��wn--�* �L:�/�ep_)lial/me�hym�%YY,E�5Dfl��O�puB:Tp&;"�o �[�5�7�5:���6B upp�#ar�\ 6w"��KD�&q3)/2�s�lg%�.�0�����if2�1![E2F" 2"k6WS2x:"&� .� �.e,A�",6� 8= c3�v\m��n$e):k$%��:I$K���3t ��q9 �.�!�A~�� 4-9V' 4��jbe )&C:i�4�� 2�qe on 8&��M?(���.�BP�� !�)5�D��.��e�%�� �W)m��dS2g( |FC|>qX , p<�; ; S3.�&ann = 58�{O3se��6��2�BWɁcMI�6cW-f�{as0�a��8.�il�2ra>�=��?d `�( 6aM�GAǽJ3>�2.rt �2�Y)).()v2�OA$%�2? "45�OJ�-e����5\!We\w��[�%:V �Z,"2!�hif�{�-A *(/�MA> .M66 �� 6^,Pu6n��(-8��bUm2�#������ �on&��B&c0��&� � ��i5�FsIha�U�In� gq 4E6�t# {:��o� .j,���1�9e+�2UN"��i��\�M]G� To v�+�K&2we*�@ qRT-�R�9�y�( ALDH�6A�MDX5, FUCA��50PK0COL1A IL8>,MOX , LEPREL7A�Mf!�L'->-�all�-x2Jq� Y#�XA� ���S5A�5� S5<S5&/6�#VHA6�5y��2;�&�K�!M.�R�*� l� �2� newly.�0)EF9�p-�4m7]msi��Z� �%el}&Q �G f� H,�$>1�l 9C5)2�_�;nsus-.~"��Dlt]�a&͇ aQc�<�EKTSS�5E� o!�DeNly�,"2?y!�5� �n�0l#!�2�)*� oU���( .���J� �" >\ � �'�%&"!bexenWe38�P���j.(eBYmpa�Dn#%e6�mifT7W a��� !A�/��v�m�Zx�(recruit HAT�:cs o�N�/en���#�-��):��� a*gC��QG5ar�=BE�$:�b�*, ��)E5�.����F�?,�NRA�q�6�**3Kf-�TSS� �.|5ha&X/�6� &J=6��:C'a� illuvQ� b6�']1A`���a�.e�e 3!/����f�7����R��S74s 0AVetE��:�BH ��!au�i�� L:v�Q��6=��E,�R 2^(�Rr fluctu�!�\�ET�c4�B!��xm0Q�"y.e.��O���I�,�� �q�c<"�"K$>& ��-�� 3;e�v2'1�m~J.2�!�%)�.�Lab�Ac..I-� 1]Aw1�-{,q*=�Ϳ B�eeL!r%,�`1%%��{ !��&��`>:D�y� �*� 92�&1�9W��� J� a"�>�& ��1&��6� &��!��!P� (�Y��)1 -E���. FoP<*@ e!�FhlI�La�sAh#+t&�n*�E%�!��&^ D*AY,��F� =�2#0F�J" suf=(.�Jcon&|Q e)gu�ion/deq�� �A� *�G/de�Y�bmj�e�&}�v�!9V�ko*2�B�b3D�T ir�Tem#��AsFaQ� � . LR2�%Z%�\��.9�(! )hy��we�3A-�T�*"` �8**�����M�)����e&�([�*���� g 8C& E>%�5] to 8��aX6B��b�I,I[!j �de��a):p.2E:���e�end�_ �2 \�atDmR��nR��N ( S9U�"E>� , abPN4eDo�5���] MaE���j� 8 $̯݊ �B!OhP�[_��bi���4!�! a%�� a�#Surpri"R{:IKO�c��� ���3Af!U_�? ��8 �O n:x:��C�A�I&X,_encouraga� G"Q�/l�1�4.�.JV* A�8�a�n�/ur�D%F�2�Box ploty �Y�F 6:UA|"� rJ!�A�-,?�Y v�P�L6[ ��&�M.�-"a�!�6B�"�%���M2�) i�kky�*/&�. #H% 8�.X$"�N�on�?"1�^>p��<\J)�>��� 69R!Ea2t � ���v!_�m{m�9U@ �_� =q_���AYp�k �s�"hI65%e)asat�9ns��ˁ��B � ,2����$%E2'� �)�9o���*: whet�2!�9e:"����Y�SH3� R= �>{!.�v]RV"� �!� !�.pV�&ag�2�# � . �&� g2,� ,��!إ�-2r"� ��\&�V�"��!G� �>���.% �%n�s .�!�%���� �/�x(!M.# 8!�B .�P , 26H E�x2J%���� by RNAseq�sc�'��*U*|(���$ � TCGA�C )o3'i��.��se\ �ur_If ;ELJvD.2� ]9� *�B�1�7"'q)�eIv���MITR [4�� trun�Ad �M� "<`z -)24�of!��B)Fn1�@)9� 6�V!B��Y�a�CH�4�I x��o �,"�, ���N�D&��E)�-�� ���(2OB6� �� j) imwZlP����.�"> �S2� a�a keyP�\%�s_en�M�e {>2�V. T�<volve�E��7uj�Y�Go@ ��v0 , 41�>I�is 6'J�2�be6E�5 helpaX�� ��%s�*[FT0 took &~��0�6*K��eP� unvei�V&�X�W�web���G&� Shn��$r!J���l�%SSm1s9�s U�3!bkus�"�-tw|9 ]� "�%�d.!P/ iDm\*e�:�E�#M���Ai@�y.(!Q�=&�m.IF64�MAEv ���rtWEAsiTet�5��A���u. U�T)�*�P%&�_YE�V6")0.��B6ds1-� t�qn�-acR�e!9C�b��.8!�!m�E���! ��� �%5�a #PqXa� es���=A�[�[Epa�&��rogno"�IG[.>.�P ;pd&ng@T�F!��>Cmmfy e�1a�M �a ��5�2l�a���EDeW�l�my p qi[43–��%�lF8!.} c6EGa{�'72� .a%��uE�UPS��N�7&[�A�| �]�6] =� 1%�F� .2B|!���cap�Q�� �!� mA�%amA�"��qZa;w)M6�!t��.� sI�/�* 5W-��Q�6� ���� -�� :���guu�cs*J_� �T $qthu %#E�%|������� =�m U���8e-�?x7@U !!:P ~j[�8�VVYCw#*ڦE��v�� "�W�ve���-�%��_ "_���%�: i�".��eK@�>�� ( �"�� G�; iM! !{.�PTM\��ki,*9ap-H�E�)RQ:hijack {a'P�s cano�� s [�"QBe��} _!�c�~"&~!b� �/y�m�H�"�:��BhD. R-��of EMT}�')�S+A��t*�+��6��0�u�T �>�-ci�=_O�r��B��=9�hIa6� s�G!� >. Wo�3H"��@r��H4llaYm�`boVs`Z�� TAu�' >� ough:` m˥He�t�: A.�s�?�s g��: cruc� ["%E8 a�se�C3D�eMR�ofE�E�-�b�EAj�`g un}�M)�Ylt)s"jA�6�o�M;���5�%s�D"^F*��UZa�F0�^��I��dox� � a[�Z�&�2�RUS;oyApJ ES�I:� !u)g*[a���5ory ��Vt"g�����3�` w�-mak)*��U ble h �� utpu1��by�!pl�V健�d.;n�d�f_g1�6'1��a�lݒkI"�obstac]_!{���%�(&J, !}&�Y,=�A�d��g �2ak] , ��. m�J���EtK 20k>��&'��?$:�&u=�g�L.0:�* y�manip�� Q�mE�Omp��)%�A|6�r#l�,#7�5 �L29��&{�� A>z�eai o�1��2�nbF�8 ffor�����52&PC��D2Cy - �uc� >O",xDpr!��-�� J3i�d elsinki�r[�--?��tnob-� a�Xa i1szZ*"�!Ho'�a~f TUtsoE�n��i!�al ethic,�valzneek)!��GHQ�[&�>[�^Pri~Q`ubod!�L9!�r9 �f���ti-� 8D9 ( L�jT�#:) ;I-A�C�4t D�J/K [10] )GFP��$��[�}5 �� 0%7�c-7456p��4 c{$C-21 sc-31JRACK1 9 1775a�S�2 Cruz.vt�� n��/ BD T�AMA�:Rv .Ac�l , p21 CP7ɵFLAG M��SE� -Ald�>9+�V$in ( Covan|ce ) ; anti-HDAC9 ( ab109446 ) , 3K27ac$4729 ) andme346002 ) ( Abcam[3K4 $HGTX128954 , GeneTex'��KI67 ( 556003 , BD Pharmingen ) . Cells were lysed using TRI-REAGENT ( Sigma-Aldrich ) . 1 . 0μg of total RNA was retro-transcribed by using 100 units of M-MLV Reverse transcriptase ( Life Technologies�qRT-PCRs �performe�@the Bio-Rad CFX96%T@SYBR green ( KAPA$8systems ) techndy . Data \analy!tby comparative threshold cycle � HPRTm�β-actin as normalizer genes . All re"on �Ddone in triplicate6�4fixed with 3% ��aldehydeupermeabil +0!�0% Triton X-10 SecondaryEibodie �8Alexa Fluor 488 -rabbit sN6@( Molecular Probe!L. A� was label�9�23� , 2 . 5�W� ![$� �ore�(same amount;control.) ( FLAG M2K$USP33 seru , followi���NlocuBSAKSS%e( � /μl� t 4� a�90’���R� inpuQLtre. oteinA�K�R56E3h�degradeI�insN��y�a\was r��a-!���8K.� U(4finally purifiq�QE� quick PCR "cŁ kit}eluA'in�� �waP. pBABE-Puro plasmids�� ress�SKP2 ,DN-GFP�Vٻ����(pWZL-Hygro->ERZ�ob�b)�subclo�ow� a�methodt��RA�-VP16W [28]�!\nue$ relA iz)of Ia��4-OHT)�aj�scoaZbymY(fluorescenc� Retrovi�XinfecAq���(. pLKO-PURO1 2d0short hairpine ��shRNAr ��a�gainst !DA� 5897� 2740 refer� to h� as 1 #�;α1 >6��F33and/ A ( 432712 d 513e Ni4i5 )I#5�J -E%1.v!Ѕ+-��Q by oligo Q<, chee�by�~tri%��se��A�; 0lentivirus-baa{Pknock-down , HEK-293T.�t� !�e� �e8 � VSV-G , 5Δ8 . �;!E(A�" �k36ha�37a�, vir&9 &� I opportune; iu�fresh me� @. Random motilityE� assaLTby time-lapse video mi��copy b� 61� w @soft agar growth E 45 x105 sarcoma.; seed�~� 3% top Aӭ�A�t-!�ci)�e�nc1vMTT s�=!�?c�H�J�IR J�^i 62�invas�=% ,� well�4A�"chambeS CLS342I Cor�)%bco�200�a0of Matrigel m x&�"o 0( Cultrex , T � Next�%K ��of%I5%pLMS!� $1%FBS-DMEM�ad!| . Asa!(moattractan\20N-in)�fr�C��!�:kuaIto evalu, rI�i1f. T2Dex�"� RNeas� lumn����Aliquoty �� ampl� accord!Zto%�specif�7!�Illumina � PrepN A H�2Kit�mbA}Hybrid�OnGwhole-� he HumanHT-12 v 4 . 0 chip (0? ��A�$background� %v�5B�manufac� r’s6�e= ld-changecp-!�e� r p� set hcal�9�a modert-s� sticA!ELlimma package [63] ,�varia�8estimAbe� djusdbya� orpon ng global 9�measur �T�let �of � s on arra�The� d"�t� corrB� m� (ple hypothe� t�ng �Fu$Benjamini !�Hochberg� atas*c trieF��GEOa!^( GSE76W GSE2112 05hGSE3926�duz� ^�L���ex� on lLf ,Kaplan–Mei�ie TCGA��saIah265� ��XA�9Hr6�8CBio Portal [64� � �z-W . Z s > |2|Iuse�,as cut-off .b� �o)� j�� he f0�%R$class IIa � �|GSE O Ont -terms en %�!@e�&LasZ �6�0Paraffin-embe��1uE,leiomyo�4R available $$57 patient�All caA��his�ic AD� chem valide�. I�" strye!4 :I!�!H C an@ !�9b` autoa����(Dako Aut�JAnt��MM�Uw cyt�| �at pH 6�� 9 2 EnViE ,FLEX Target � i�� S�( �)L�g �tum�%^E�d,AHintensQ of s�( r�h%�0 = no.�,��4 =hong.! MeanMZ� percentag*du1� M$�k���Y�0. CRISPR/Cas9.�!� appl;to L -�x!�9Q ��NKO-ree� h,MnCYg by S!r6} Sp�,D10A mu�!Q  [39] m��re���ly�4F ��fd%� FFPE��g�26��q�����Recoverax�Nd$ic Acid Is��4 Life&�y%� RNA-*� librari1� prep�^�66�\ Ded�a&SHiSeq�0!��u��"�)!Ea depth!i50–8�ll�,paired-end r�p!��!Nhe QoRts��AG1�a^� �'quap !� STAR . 2aE� ^ma�� (GRCh37 . 74 e� embl��RS� qA�quantify�gen�iso/ abund|s [67� Hw�I e0liszl6 F�Eal�:E^ 4 ( ENST0345617 ,43020��$54318,@5.@22598>.336052R39362r$58680% R�08005i380612�427336R 52962$354334��iT�4019212� 06456326452$ 4154 � MITR6Q50:� 06072� 4174��428302+%�T $52402�Er�q�alI�$Student t-� E�*i0Mann-Whitney !�6wK �t� uld not bE�um�p < 05^chose+"I alD iE��I� 3 �� aris> betw�i�$s >2 AnovaF�, p�(rfaces have�*ul!win numerpE��H In ( study� 9combi��- doc�, m"4dynamics simul� �!d � rB ryo-*Uto � atomI�  insigh��u�. u�!�films�poY � w�as�  h=�: HFBI%) I�du�3bych� ma reesei!�ogether%re!9s suggaa�!_2�sixZs; how� ,Da�u1o�>RP6 symmer ,Ale6&Pa;! �how P32w .�N$56 Å . Ou mJ�im�AA possibofaaltern�order�] m "�?�=.�A� a smaller)�I!weIh��0a Monte Carlo.M� spin�!���8=�EA`%,!0th���metastN stQUmay�y a rol�F� reasc � M� ageAH>2)Rl���H a me�ismK more�F2�to�p�nV d6k y . 2��ea�:�prY�Fm[1]–[4 Th��si e�E ��!�� !pir��2 A��!�%e�a�FF . Fu 4.� by.>�%�9.includI��!O db � o> �Icadd-ahc"t�fmyceliaaKX aerial!T�m[5� adheVtoxY ndWE��ety ���#Qp s [74[8!z2�can<s����=th)k�;!qXi� e � o$!t� �d:V:��M�vJ adapd  beha�"r�]�s _te2tERreKwn� sEdi� ��l4�k [9E�1`In%�R ,S s��1}?�9 s is��]:'!M.4nA0ighly"L fashA`,, beyond merzde�)m3U�.�partiNr i�s b!�obser$ that2���a air-w���3an ela�y %:�magni� �ebaa�ats7 � �taL[1S��-A�6.d �lsob$pl�2dd%�al��que racter��s [13B�Adi� �!a��…q� �y 6��Oor ,�ly:|���na� rod "[14a��A�� An ex�e� {2i��("K  EAS [1�![16�CN� do Ś �6��ea u;(amphiphilic% � 2D cry� line-�N0,�JD(ir�H graz�incideR�, angle X-rayq(t!�ng�ISAXS )B� �i�unE maGic2qQ�in2[I^ will� s�co� �*e �a��� ilis.tFiUl � /eB�*G "�� e&��U network f%�%�e�q��OR�́˭Ms�g���ʅ ��m-O�fac���?of.?� � "� indu�al6� [1EI���c foama�8a- �o=j[19emuls���[20� disper�*Ņ�� ounds [21-[2�tMo�42� �dM�MW6�!?.!IF%K���m!�taù�lya�eworthy 7Rabove z io excep al.���f��a wide.�diy)�����Ap�id- %>ga�'qui���. Two.��� ���� �q��� in!I)��nh � � V$,SM�d� T63 ,�`asc �l � a �� w�TI famile2�.� irv�!a^!+.:*\ j:,� �N� E-As*zs�be�!"R#� c�N�h#��%� in b� ̥EEto*� my�� tach6)E���!���ѷ.��I amjSom�g�% h�m�&"  de�inI.f �%�"� �8v2+ >!�:A1 Im�%� first巡��g���#�ed��xŦ�ographyIas�� �of �*�[2�I�i�eI�-��is�'lZ+by�� ulpha� gI/nd%Va diam!Juapprox�ly 2 n��A �&�#s! uish�patch�O$1s_-��consis� (only alipha�o acid :ch!&%uis!kul�A��*^9zw� _ x`�fl2�  'AB�-�PAe now 7 � =�A�!� [2�  aaif1�Cre�F(U�ofMgof Y�bI���A�0�*w 30Langmuir-Blod=�X[��= �t� gu�lattice&�/%Puni8�� 55i5�2�.y6�BEMF !�� ,Q" .���\arZ�&I +-��c�q�pi"xa .s.�))j�� stud}h2iF�6�A5� .��%b� �&Ba�–[2�mTBD> ���e2h�}.�)�a� very3sa�2D "l"o [�!E !<*;�,�gM��5 ��.�-��y2� conn�*ng�/JF !  a�d6� ���!�~T��ta�q tF�eA.�A�&ZuuJ/�e<u!�zUi�%ed[�h�^a$demon� �� ��#"I �!Ec �N!$d9� . As�~ FiZ$1!se25 B 6We\2-"#` �}�s�(c3�j 1Pvec�3�clA��%$ed ( hexag�)m%ng�� CM�T7��Ձ!#�~i� ��% seve� ���&`%�1Iw%tb&en�AFM�  � shee�7A@ publ%5���{ R��)�c�/[2��[30�BR,mov�%:r��2�we�sA�� � $ “tetram�'��0)�btf� Q+p">+c!�n��"�,!�>+d 5��I &A9�0U�/ �KS �/&� ou�Ay1��!l�$�"cre2>t65A/by��w� � 8'EXree"u�$�aw9g1& � 1U� r/9@(��-Z �:a?ld���� ur.4:"� ��u�# sh�� dJ� t-�E�-��v ����. stepBtoAbE� 0B�c�)9.5? .!jA~%| s”F3r�1- � Ie� e orq&"� �i�cf� �tra4s�ma2�"+ X\ TJy/�� rB��.wAY 4a�M/ ocol*�'��M2s�# �:�p:!�]��}�%�XtopS7,A���c()N.<�!E%Ne�Y-b� y���h;i�@#S&CYDK(:�;i!HU-emy siS �+a�� RMSD.|us��as� qDse`!�1�� ZN,Pis�dtoM5uc�Cu%O�>b�;o)ks �)BF�n#a���!�MS:X3���%N�Y���eJ&u laye��� m�s mus cap� ofax� ax/a�e� ,!�L�,�T:��3��F �mp����is9 I�itself���is�c(unsuccessfuD9TA w)��to rule ��2V �� us left i�*- =V5�N���. A/J���.� T�%ned%m���1i%p&�or ti�#3(&�Y�!�E-�%/T�>ll6O'� �noYdi�y T!\a"@�-�$�\w��.0�� s:�� sm(DY#1�9��oc�#themselvk �Xq���wA>llV=�α��0 β�Ia���Bto ��o�T�a�i�E:a�O-% 7iE:��i�*s y܅�q�1&9 �b �I "(a�E�� �$|iY9wKB� �It�ss� %pa=[ O�!��G(� 2� � <2(��*A 5!��b�}a�)5�>Bh:�2Noa ae2 * � 2l#! ntacZ&Fp t ee�J� Us_=heY%��%�i � �&� reEHY �ro� .�mi�&.L)6 a�@. D0&9�a$� � �o�}(�3 )�>�n2"!�Y5pD-�Y .�]lc �*. Whil!e raw |m�W eiF� "(.�Eס�Tex!�:�%e��.���2�a=�min�hB5I�2�� ll%- acM���E5!S*- a=mF��b�>We ite)%d�$en�) algo�) Knergy�im�to �)se2 . Disrega�7he� �9� �� �)i B%�B6Y'is* by 6�s;E�i�Eu�&��W6"� ^!imei>�%�A?d{a��� di;*c�"\2irv42�wo -��a�sq�a�-9..��lu��e/a1s�*W�v9�a�2��> geo�(�%&�Ar� posM"Ff,I�v��� /B  A� .��:�B��%^-�> �T!#�F�Ia Lp+��<�Jm�Z%Vsm�"`F�!"Ek$"� new *�9!j!��K]�GI(up!U� �aKd N�a ��� ro %�rep�B unti�- -converg�2 r(�?d�5%� � m9f�j “DD9_S;.zip� #Su�>TI%�� �5x9 S1Y3B�-!-%Irh6!pot�?aq nd.#avrib�Iq� դ�/6�5�"hA��Ae�IA�vairIP�-"� �F�2�� neut *�non-po�. � p�3� � G so far\ �J�� �l�d�akemt29?%?)É~!�m*�$"�!mqex!ej>zU� b�!���j%w� o./a�NmE!Ő*_D&�R2-� & �sl ly l8�I:� !�� �� a = b 5� 7^-\�� 5�41J�A+n<8u T\6\5= c&�1'"bJ*.0of Kisko et a�7)ofj]at zer"�*!MsS%#54 �2�un�y--. Mai��a�!�>�&x ��t M�ay��b�9 make up `N� !m.�2#1�:�!��M�$�e-�=m>E9�Ele(m$ enthalpy �0�-�.g�3 t un����Si��u�!0.�iA!no!ri&m�A�$� �t%)]�T['er�* �[ �?tooi; s��c re! �s � loop�=�I� )o �9seI �i,!e cause �ePi�o!m"/ disc9ncy)�@gq ny ! ���:W�� �%Yru�%)OY�reg�+f�be 0l�1���f!5�p!Y]��O66a�q�.��>"mKM�I� ��i�WaZnduE �Vn. *5h�!be �#= 6a� wo-d�N�'alPo*%��,��llea %=M�B��� R�|�3µl U+��& aque�4��"� si�Ron wCy carb!zEcop�gr�J� K ��}"nDa�A� v* �l�) hundred�g�K(&.x�� p� finqo�(&� %C0�d�� o 10a�u�Oto/m��0room temperat�Q q)B��carefuAK�=:��fi 3 pa!�� vitr4E��Ta}�(-tilt b]�a<���L12NIQ5A�Mrq 51+I�p #��agiW � a � good�.t�'cs gi cv��*�Aq�_e Tg��Q��p�rua5��d(!�uM;�otoB %)[t�-.b6PN:l� a�>wZ/�EhsnOs� usAbelow .�Eure�0 gA?�&y c�MNw�2#yK�? expaVL�a 5g&� �1 �!@=�a.�66Fd�-M:A�1�!��e:0m�[�3)�6� ��A"ri!=EYax6�� vert:X(.� e *i��(=]�>>�R!�verifK1Je� �^ �B |� n9DAA��i�g&"$ " G�I�R��T�2�-�!��"c'1��>; nE=1��(�6q�Z���e6Di�~B[o��� !�&Y>!(.�- �-%��Put� `err�!ar�� /` �&� %e5a> b#BdW unlik� P�'d\6�zA�sa���%��lev 2�f�W�Řhi�U O0G"a�g��e%RI"�>D2��� inu� U(F� Q�ba�m�N�7F�4%�a��a�� �2��ng@1yW,P3�ygZ&!(Z !,�� AG�.%0α-��q�d4�#� fT/C�!�% ��P"�@610 *�)�N-�R".^a�w1A ,fMoviedmp�#k�6n5�Sd��.o%IA�K&�e�:�fi$x30��ex* ng��d%AFep*|�,�>�"� � %s3B..<,I�i�>^)�, �#��2.8ِ.��D does� �\�?V3s)�"u�>!3�o*K��u,� %}.�;c� !�iq�<y^�4,�R!B. P\ *�%{�&�6Y ̥OP3eX} ����! e�H:%�Annex�`&xos R .��>lipid biŭ s [3�[3f9�')\f:�e2N�reG| m<�p�raIIu"6 9�* h�X]X��� in4?ed��CmY.L expl|A�z/%�i*@(w!�,l8�!F(:*�.I� ��*H2nD�*8)�5��@l�,J&4P6A�ec0�s�DRe44 *n�(*}+a�d�ckUI�!�y��1&�(c a�4)!}�4�Wsit������+-4e vac5IGB!�gC2�E>�ab"�A.�CH%�- . Each%�i!n�"b��awD�dicta�Z�#�>. 3F��ppgi[0 ZE=��EP��in�Ve)�5��Fe��� imum��E� 1jl��%14×14q���#R]�w����Ded�uja52�T"�"8aV���po .i:5R��s�pins 6d�� � ( −J�c� t�L:J)�%u 3eG��) H�ɧ1ؚL2{ .% X-i�re�!� u JOJ�LA<J�N�&� re�"�;�L!�5�&1�force bi`^s&-KM15*�7�(A.9���2p"� ��l<�v��2K e&�D�ofF�"�&va. fu� e+L�,�)ear]A6�a ���^.<M�(�b P6 +!�o�ly^4� rbidde�infin��� UI� ! .�L9'^XJ 7�Z�J0� 5/kb , J1 2I 1; : �*d�Hmi�I�6gW2iW�Eq#Ly!�l SI�5b9�Q�`2Fde�Cd6;Yf ��{c�i�.A+�bew �C� �..J� ���"Cl� k"&��zcta_a� ��P&O .U��:�CI�– /���� �-I\O#benefi"�$2���+����Wm�Z f�a{(re�� M�duv8'2ln2�@.|!�i�ZY'�cc`R�JaM�−10A��� Rxt!��a�-.-�]q:�6��do2@���.\>n� +��S�2he��5�=�3� p�Qo %M�/�0�<y� , [3�?}�u"qu�]on" A}&o answerA�-&m  . q� �f�p%�F�*e de!m��e2�&�%�f22������7( HGCtonian )^ �2�tep�(ig����Jtmi�Q8տ,doT �!� vidu:�.�?B F��u�M�$�vB? l moves: ��aI appeor����e"Y - [�"on�!�.h ris�ߍ-aa� :V�ew^�%, �ho"�Xa����3W$O M and/or� ng� ���, P�_*I:l�Ct�R.�E-7 type��`s!n G }u1�� �Z�I�ɩ9��:^tP%bouaD,I Wm" Qqa� �KALmonoma.}�length�`4Rh,jects/}IM!Z�jde��"A�3e��%J � phys�Cmea[H k86R6�Jan�0al bal��� s\fluid*!�AOdemaOb ���e �'rtF �Um�bk@Z- �&st cl@cbD5nge<s!i� tQ:.�g �rat�e�gg�#�+*�Rv-9!�V?.ee�����N:K��N�P z.��Cd�W�&�K.�&�<�`t8ev��a I_�]�Q�/%��# e�.aforebJ�P.vRmonitoJ#� -b.^��rTV1�a- wo s�.��9$r�&�͑!?� e&l ��2[ !٩?�B�HE���.l2� "� �g�<.^m��cJ aE�L�&:U%U>� iguP*} 9��h!D� � es dra�C+w�!!�=�uo� w ŕ�F �-plo�X?8 a�a vis�^.sN"�@!Q/ :cI\$ �&�eE�Cnit��A�A��th-(7U�F,��fil�Eij�O� y�� tead� A|)SA�,A ^J�,i*7[m���$f/a�dnT~ ���S�5us� aywindowq��8&� �%&h#uX+z;)�sc� 8%t1�EJ@Z��:!�B�<A �Rr8� �)!�BdH� �.�RjnalogA��ZrCV�*o!� 2 �� o�3�a much��r6 � �R*{ �I�k)y 6� y al�#2�!a �-��$>ois yR�Tn2��VW1��&. ��Aq��%�� >r%��5��m+7AasH3m�V�� 6��Jn�C*� �%SEf��� M8of$=)�ed2�za�Xcer?�]�|tye8�` sp� )+2�� m�S2la|�Qn>P�@=y?. W=6E�.�se'50%�%< �!�.$Ѫ!�th"�6E� (}$���A� terpre6A,��oEHi�i�u��.xP36�ɻZiDM�B|,!�describ 8�� s�Ho�W.� r8K$�cns � !&Bh�#�(u LOed& c#..�tart�Ugu�#"�M�� !&�R�=sQHaJ@X!k�u v\o�n��P&�M e:%�'�,�6�"Aof��5A%. F'yB���pboY/dU9�2�5dA��EFgK�u�j5<�2� �*�O! ���Da�A5L tegra���! 9� . H-��sa1+ ridgU km��9�{j�4A�^waHOf�GZnb�h�9xt2vM���?9,� LYS 32�ASP�z� Bp&�( i.�Q~|6� x�'�/aEL�'%1T=2"0�)�os�4�� M6��su��+!�!b��!��hj gene�'/yAItV � �W6�E�>rre�= Ajm-!%�s�+�Me��icU �6k�:DB�maw7� zip)� )_S17' �QF1_7 T�*/3b�(�!( A^ndA"( Bm%� I ) ��$n�&p�U%�aw��)o) q-x� _raw�O>>�� 9� squeez�hF1"p&�::�3�4b�4(N*52�exfit�)Q�"� �Mp W g%x?nd�ed *Z7erccZ�"� 3A�for%x)I!el"/5��aI V�4 .B2��6�j�u� �6 −2^i46 . 76�i !��2�e.=2p72�) H)x0:q . 36v4�'39 /A�A�3A�&11vU|y5Uk49 . 46� U)�Y�11sN1�73! =J�3�I269 ,�7 . 89l!8� :�!%!�.]�� �|:9�J�2!!�%?63~Afn�R�-*0b<%���Zq���iso��L.�; e6M -"�Xx�en��1�a�"3;3�e5uSLgI%�) a�k1� 2} �4me6�(Ek`;�.d�O)�i:� z qN"�(qN���?i�3�~O!VA�a>z��A�EM%�+7r�CiX+ ^*q/.}Cq�<.�!q�,��O� "�Z b!= 2FZ6Y� �2� (!ol�?@6p= F�"�* W�W1R2�|zBJ0]=IIn\ ��"d X!.2IA� Del&2 dlHdF#.!1ZaV`��*�*?e)d  Gp��� EP��-�q�1zF  is |� 32NP��Vi��(2:�-major� Lo&�Qbej8=I�xELA�I�s� Ns r�i��&Y�s�H��aA�I2��lx7 Oe-}�/�ar��.+L-D-\s /qܥ���r�Ue!y� �3m,t�(F��q)Bn�tu�17!� V@��W!�i�- @�� 76�!ove�!(V�%)hel�s�& highAہ�a��1�=e!)5cK?�%��&rf7�)s"Y��%�"|�H"���inv�gM0 ^I1=�B�&��αWu8p"�A 2�&��~a�"@5��H� � ��J� �,K�#�OT( odic��6*�>�8 �! (<8=aJ5�%]B�&�>�ber��:&S��Nm.g)�mm�&B%Aa 1 fs|� ��:���.+�F-�.�"A=�w�;�sy��Sby AbigZ�&A9]S9B�k.�/E?�e�eIAmber99Yce fia� [40] �TIP3P2=�ith��e Gromazk41]&W **Thr ��*,�"coval�E��1�z�l&� UL�"=lv~ LINCWj�l[4�.All� Y-]�%t K��nu!6apN�d!�ae JrE��! Nosé-Ho�'rmCH [4т[4�bP'�nt u� ���en;,. Lennard-JoJ}i!�a��Ncu+fa�0!d�5A��� "�H2B� m�� Ewal�ntho�]PM� [45]e Eb�~-P&V.%at amb:?2:( 298 KF ���QA"�|u�%�itu��ry powGF�r�milliQM�( pH 7t'con*�AofAg/m�I�(�*ng%!*x�)6% �#�&T�6BW 0 µ Y����n, A 30�B!#� kR&�"c%�p:_d p-� ���ɒatF�AAUatmosphT aP1A�ib �ilmK�B� op!%A dropm�%�pi� upI�a"�lyk�w-h� d QuO}$oil R2/2 (.M�$Tools GmbHz�r�)fC!k�pB�&^B2�.*��PAH�I2Cz:�1�F<.�B!;�g%� ul 9c�F_ "O�mJ6D�:�{)!�� !� ! h.!�a/loE�3A�o���BlD!IR�� E�![4sq��P�*� W GATAN 626BoÚ er m� Cat�018�an FEI��nai F20lB��EM Unid<Ins��� Bi& |�Univer�(Helsinki ) �:���kV� �� �re���M0n Kodak SO163I�� magqJ��A`×<�0�n])neg�R Udigit>�0a Zeiss Photo�C TD� ^���a 7µmR � .i��Eŷ&�A V!�2dxFs[4og��A�98acyl tRNA synth�e7��l enzyme@IquiaT�q3 5�e�se/T�,known drug t���Z��raE�rq. ��%c=fX� rep��uJ'Ih�t�����!\BLm�( KD:4 μM]A1%!aiA�h��Aa�:1M�e( IC50 a6 a^�-UAuM}�>21 : stag��n��� a�?is9= �.ksurvi��A1'"Cin� ge��-�xe)>s:\��usS!+��*�V���Qa�y!lor�C Vi��s���x(as kala-aza�u� �Q�u5�Q[K2�wR���6�;b+*�qem�)s!̠[�3VLt��!!߁ an 6unH�- , � on peop�� riska"�� [��k� _A �PlL8~�64�!�ϡ l if�X�6l��5laclan!f=&v= cine{bstuy�mo "apy��( AS5�pprV��l�disɞ[I"(? toxizK���.�r NUcs��hB�YrtoirE�� �oQug�� , 7!�l�t 5 urhne�&"eh��ZAy�  M�aG� �Em�ma>�q" %� mmAdA�a FA Jy�?of� b�)�}6r{��iotM.Iz.*� ;Ob�)ibo.P2mO.�ap�tus��&ԅ!�:�x.A �,�8�.*� . b yu#s,=d%l.e�!&ZD�-u�;! �� apeu-+!�aaRSs6 �"L "�RdlCN��&�ye� cat3�v e�+&)|of&m��vah�^&f4��( 6�� g��RNAK2����sub�l� !N��u�=�Bo}<N6ko�:v� g�"��*N]q,�en� fide ���1m>�5h!*�(RXs OQ^X��T�&�l(6$inXxP� b�of�5�?*K �Ti֭�� of-��B[1q.�o�}�-KQ�C �*� ] � '� u�:MupirociV a�GtibJ��� kac�\ x� of isoleuJ_ W�rQM�4 cli�l�9 Staphyloc�,s aureu�)gQ��͐c1f���  archWeukary��2rRe/�cladospP8� z ne�C�Jc of P����falcipa� \,6 �, Loa loO=�0Sch8�s��man# ���prQ�.��.e]�h-�0sip_��SHy2� span]y}�i6�)i!sA�a)u{� s���0%/!:l�6%1i�A��ofſ:�UA�Tf�T�coV� s L-�/?�,cogv��mC�~�ch � IIm$�Esc�hi/Mli e ( Eco!�e �Y`"���8}7G5�� o��!�!N�codon-� !#do!Xwo",?ai}�ot9\#Z T� �N���j|of*�9 ,�j�e_.ng v"*��ȥ1j����* ��&AacY or�mՅ%X�NB ��8s-AG)_�8x3y��*F�a1�Y�?�as β-�xynorvA}�-d s5�e�"7 earlgX�6�O bioi�bc�#�aled 26M06�[j���*� x�encoda�ˡE{E�d[TriTrypDB ID: LdBPK_35142�(1]��Vp S A��pi!5f-F�e�6�, $m q�P�;�1; c2F're�9��t�Gai"��Ae� w6�Ig�_EX rupt��GT����wOgan����at~ sjultan�\l��In&� *1' �bL&�dH �!� ��a�>� ����, took�mprehen/&hd�4�S� *�5�!.��f� ;4 Ja$�z0 L� "��"� "�In.ne�[�'Og,ja?d RZby!J lace!x�at@�!��&�V�H.�ݥ��"?p� 9�*pl�\a�{enZ.�via+�ty�w�v� � 8pathogenic orga�2�^ 18 me��|�?l�apolyket ,A�= !I��.R�����o3ectD��J�=I a�  exG�hUlYN��a"�#�o d�-oݪ��*� pro�0�!�"�od�^�e�h���EmM�LU"?��A��Z�Q�N plat�kaO�NQ�:�i���d2%��: prHm�*>S��iZ��d �� ladd A�ac=5New Engl!H,Biolabs ( NE�1 ( MA , US�1)��) v�} pET30a�6�Nov ( G"� . Ni2+-NT��n2`loV-c!�� )� r�m���6ZQ��(��my� pa� �ze H6�Sigma ��6��Q6;6�Fer�Ga� BY� purc�[d�m �( Cam�5, U&� inM��� crip� g�R6{InE��6( C>�aF-U` o��asast�i�(Ѣc%i���rMerck:��.�A���!h an� �avyv1&.5�u"2,!Iy��6p��~�E�Uni!� [1|- PFAM{bOu��"x��� �Gig�!�P� �&+<S�u �!+1s6��NCB�bM�+l v!:} �cpMUSCLE�T���15E���}�t�+ lwy,hel�!webWe�8_T1.6� Bob�Tin/MHOM/SD/62/1SCL2D )%9�� L��?a �%(�%�Dr Step�!B�ley ( WaHng��* , S�6Lou�;MO�� d-u6�%' �� 22�z> 199 �Ҵ�"�1 !1 :�1s<$p�wi9�4,$μg"strept��X!�$5% heat-in�kfe�hb �nw(��w>+� h.}٠(i+ /NEO�He8 /HYG!�a4m&� ���z300�p�0or # �hj��I��� a�‘add-j�߲�'.�[p�+] I�=2 8{��!Z�A7e �  рngI_ vWT>o6�Ft Yax!�*A�hʌB#�dar�/���.^�a�Ѹ-loR�"� Y �uo%!��cid�9edi��,RPMI-1640/25ƶ2-�4-morpholino ) dA, ulfo C�E# /pH_p.�at 26A�&�� se!�o�5��MESNaK� oC�D5% CO�4AJ77�_A�mo�k�cy�Fx phage��%��h�/8�@ !�p�067 ATCCE@K6��!E��% FBS2ui�Ua�#HA)i�A��m&^�!,!v�?2,�ORF�a"@�� ic� usA�rwIz�1TaQ�n�BamHIf(( 5’AAAGG!,ATGTCTGGCAAG GC 3a�)�&rAV]Not:\GGA LDCGCCTAGTACTCCCGGTTuGy AGCTn!�e�ge�7�WD^ X,R q�onk !y-" P 2BL2T|DEM�c kbin.�"Cє3w���3aiIPTG (propyl�f�.Xc$�,unc �? of.i=Qn SDS-D� ]>c ssay�a&�0� porA}61� D�.��E�y Thr�j�byr�T7�^�r"� A��jTAATACG�$$ACTATAGGGG� (TTAGCACAGTG��CCAFYGGAJZCG��TTGAA6r"�2�"x . �MEGAS� in-p �zA�� )M.A.LilN at 7*�,I�,(�R'a��q%M�)es/�u�a$s_=co g\a�:#RI6(�FaOM Hep�F/2GN�� 'KC|d 4�b MgCl�Me$1�DTT ,M M ATP�NL u~� c pyJ�sv�� $( PPiase; �,�1a.&&O , 8�#1s!��<$"�#)��/%�a�y'h-�!� lat-botto�Z96 ��e&La�Gmix O kept!�3��!�!&��fR �h �("�QJm�wh#�Q�32�1�7ivGu�&�?��%6 EDTA�d~sto w� Iz)"8Z�).�!n1zQ U!2cvar\�F9.R�IRN��ikos)dK��%n�'�� �L�*�G E�* ',��e} on5���::�&J�I�T�F�e( 1–����n�&6� �!���!NU �!:�; =��\ _�oa"�*C^� &��� ~�was��1X��(�-e�0��~�5 �i��P�Iz�-o�pH 8CnB� � &�R�4�G"tMI� 5%U ��;e�� phez�FurEII�z�on ~�.�3"�iat*�V�*��!�3kAb�@~ N�� ��S�Ta 10%���E� 1��3=Xit] -0�r�1��@ %�5%6a albu��(�¡k�EJ� OF\( ݵ0H2 z�B�1(�� Sub�� Y2y.��.-IdY�(Q�2���0A.7b2n�I�-TM�:�(horseradish�� oxidɍHRP [j� e�]ti��! X�5a��� �2�b'e8ECL�`nh�Wd mi8��)S( A�X�� Bioswvce*cB�7=f v rer'l��!V�A/>�%jg-NaE�g("��PMitoTracker Red CMXRoGJ���3� ��!�U�)��(&* im9���)oly-L- NJB'" slip�!�@theX�>"�=�o]lb�i��AE:�6�del�֑BSA2AMr�qe�!�AAVJ2IN%+iJ� *\!3E�3c)8ZA����coR�IgG{M�Th�: FisC" SAntf'm�4ȁ�>�%V2  DAPI*� dy] ����m�+A��)�IV!�W!���n����a4% �(J5LOlympus FluoView FV1!?% ob|"b+len�#HPLAPON 60× O , NA-�~4� �hed �reJ-�25)!�dis�!�*�E"Q fuc�H�A�fl�`WM�@(� UTR� � ))9OafAof��C%hfp)�H**�+��em�.��~o�� �co�e%f,���>)!Y�57���& BHygs2Neoy�11g5(�gEc& F.gEc( >g!or�%6��)s pX63- 0 !2Y,I��C �D or C �D27F�!d!cIT�ea5�M eY] � �A &� �� Fb�l�%�3PC~ !��FWF , y�@� �_HYG_3orNEO�%"�C��!� epi�(d�l�!� : r*�full-y@uxco��c� J���Xba2: CCCT,A"N�G"�a�z�HindIIBbArgf�%�m,is�gN���4pSP72α-zeo-αMՁIע6-�� Vx&��Jrma�:�-H"r3@ ! 5�"-&j�Q{�5�� :dE�eIar5�A5�2�N��6� "�.ab/L2aGYG.0czt� $�dly�A�r�jC -J� [\��'*ksu��iSF�0�f�on�`aK+ 5par��q��Y%RK�D9�!"6�`,in�2X'*�&"�y�'r�T.'gr)ލ��a���r5B� >-hV� y� rounde'f-!���^!GV�VK���9�7B2Z���& �I?Souin t)78�da6B9�.�'Q�%�Nfe_�&� ���n���(V��5� 9.g*'1�:Ao}@aVNF~a�r� e��nga' 2�:q%�1>e��ngNi�wi"5 ���>a&_e�b\&rywa;e2ino�w!Yn?�]�D6i�Z:� � 5� in 25 cm2# s�v�t��}�}�at � M�9`Y-�Ieneu�54 Uute�,s 7 dZU�0Neubauer hemon+9�xgm,;��%��isҍly&�a\[S6at!��{9]�.����79�( W�!�j�')�c.D)�o"�m�4�|c�age:(�#q t �P�=� 5 x ��!U�o3QA�� ���  6—T6jb-� J%?"�`Y/h�!�,�GBli�E�P �o�2*n'��~�F�*�*s!�an MOIA3 20:1E �A%� nonݵn�,*��r�Me��!� with�I���eO�A,Z�oI"C�i%"f �garu��2i6]Giems�* Q �^���x.�>2E3W:��1w���� �ice-cΙ30%}0/70% ( v/v ) [ano/<1Yֱ�,���-�"�I�6i �a��,i�1����&� �tw,%��>�:�5$l'2�*�RNj!,2�i��iodid[' -AldR� 6�*�1O&��O darkMs� e-E%��Ni�P�BD .�(FACS Calibu2�V)� Q5p&�D��; x�-atX !�� "Ę{� Y�I��jɎ�> �in G0/G�#Ror G2/Mɱh�M^#��Y "1 !�l��a+A�ai �`i�EMod~ZL�'SofH�a�&� X1**s�@i�8p&�-WTEV�2��0&qa!o�"�A ��[3E%�=- 048thylthiazol-2-y��-� 5S�zolbromide]�<2�.�’*�[2G>�r]Za�Z5)�/�<in6�%$%�2���.�.=th �IXAmIneG7�g:10���TT�?"u "�E��a�AW٩��a�3[#!C"�.:fM*95~!XO�'#Yo�fis�#�_.�sha;��:6��)$absorb��&� t 57�v���reaAJ( SV)raMax��/&5 Devi� h.�E7 n#&1=8}s!>u�I*�D #yQ���SњE&E�'/�t. z raA]uV�c(byB� ��ed*{(B�  G9�fޅ)( mƐfosI��ַ�BntF=5Pc�# E�šf-����. ITC*� mf9u� 5B()~7OCal7�+ ( Ma�RnDLru!e s Lt!�]0[2�L*�0ah"!�3dis�R� ���"G& cAdeg�� ,��*t,bS7�)I�t��vhof)"μ�m� on syringi3�a� A%�� 28u�� i�4*D �d=x �y��} ( typ�oa/!_μM��Ur��~� ��B��M��AG�t stir��<�f� !a*� �Ynsu�D�f�mixG U�!I�& . Co5T=BMun�q��R�o by iKil&�r�GAz���.��nd �P!ڑ , �2+,d �leatE �ahyfi���;�,e|Z@�Ii' Orig{&��9V E� bestL@VK*�� mody��W ����?iZssociI$�%�$( KD = 1/K=5��stoichi5r?Q�( N�ent�( ΔH�O�f�)��Δ"�/c�"{�yequ��A$G = -RTlnK � ΔH–TΔW.ip� �xf"1A�� �3�3!z�3(,ID: E9BS18 )"�3�` BLAS4b��p ��https:// . ncbil�niw+go, s/A�����A�%�"�(�B�L<$ �h*Lw P�< 4TTVUj6i 41%9*;ty�Aa�xh]!]��� buil�*�L�I��Klo��MlY=0r MODELLER [2Mf25A�"$/�!�NH inime��CHARMMm &&Z��!� [�9ste!(t�^�a�^#"y�d� t�i&�< �=�!t�:)�� qua ��;� !�ERRAT\T�0�!!3 nmE&ucl�� edu/ 3�Dd zݥR�D�as� n ± S<���z̤:��ac6@` �4�F�Y�a�@gkSa60$$� &�0w !N:�)�&vA8��us��e� �c�pneu0G˾ Pad Prism2!'"� , Infv) ��wS�nt� n����. ��6L(� stidWQ�s�g%�A!"C�yTu\k7eE�n�3E��w!�"�,CLUSTAL OMEGt:S1�6Aa)�� f%A�F� sha�a��y��*9m����L)�$[3=J:�?)=oa pEve:2F![.���F 7<� ��y^�b #(�, _SAD�@^g�s HXXXH�f7Dn a�3�# fexe!CCml-"�_�b%�ThE�(���@^�"�s�S%��r�<' QAIc�Cises TGS�te} * v�-%-!�9DA�k�M>e��B-�s H�2&�E ���})�z��e�aO�"ZWory �G6�<ŵs�NfRr�meb)|a�TaӅ�, api!B'K�Y#��� inse7LA�mammal1����I�Q�_ re�Ms��Z�t�+ leeA�3e�Ѩr*�4��B�Y4]^r �Q:� c*w7a�A D� �$!�!�an.�His6 tag-� Kge�7{��HN�7!I� �7��is6-tag�N�%�anPhn�D"E�c\��95 kDL;�>1� I2""��V/d ZA�%1jM��89Y���%��6  i.�'-M�"K"byi�&jEch�t�CphyZ pre-�\�xdF�6��:�f.���"e7 onfibDby MALDI-TOF/TOF m��7dJ ��.P� ra݄�+Aa)4S�j gB H�>ern:0!�g�*a}J��*bA5�)�9�"� �5w �*%'Bu\4\�-�C!�AY�!E} �fJ?&�[4^� G$�*� �F�!><13~Q�inc�6M � *�[{����F�Z,4U$� *p�%�tmoo5� I^ QQ|!�.lf�=�a�21yy�2hx6!�1ρ�pinaIc�*l( P� �"�:>�5Y,V�5A&�An^F:�&��!K!T���I�  � ?cy����9���& C-���M5�ho"�Z. �M�HXOal��E�A�J 2����}�(L-threonine�X and tRNAThr as substrates . We performed enzyme kinetics with rLdThrRS by varying concenE(ions of oneY� while other components were kept constant . The Km valueJp�[for L-threonine was deciphered to be 250 ± 30 μM ( Fig 1E ) . The specific activity of the�(under these�di �k(1 . 7 min-1�$ch is clos1o that�LT . brucei ( kcat—;4 ;) [32] �$estimated R�,�1�,�,2 ± 0 . 23 �F�hImmunofluorescence analysisAd!�in or�o determ!R! Lsubcellular localiza! of Th!�Pin promastigote stageL .^ovani �Leishmania genome encodes a singl!gpy> ]@, thus indicating)YXpossibly a dual-purpose 5is WdA�2�wh!�$works both��cytosolawelin,mitochondria � log phase2�M�stainedianti-Lm! $body along !8DAPI ( nuclei )e�rtracker A�(�)A�mark th�aA artmeC,. A diffused �!4M��A�$observed ,A�sistent �a1ic6�i?2BEXHowever%�(e merged im!�i��appearE� of ~� 3�$B , Lane 1� 4 kbB#!0 band�Zc�@of��� EeC�e#be!5e,�u� r1�!hV32�32�6*4 ) �%� spon�G��WT6ma�is dataA0M� "� Y�!�2�had bež��i:�mut Y�j�e�o maH! ax negat���rol11DU�)�^�i�� ob��edBMJ3%R!H . No P 3� afterm�am_DC1CA !�!�>"56 )F�. Furn , Sou n blot�>! t��!�%�!8��n�V 3E50exp�)9upon di�`��E�SphI area�� a�in JA� % prob�64��UTR�22,e�2A�! 5 ~of� size:xinA.L �-��� >�f72�ad. HV�A�an adVal��4� �Rs]E�.2G��� M/3 ���ueqWl� }R[p�{ +] ));A��� �!�8pSP72α-zeo-α-8aV�3��o6�.@.�)i�6�a`��ጁ:I<co episRplasmi� � �� A5d~ 370 bpE�foundI�be�amplifi�2ZeoFP A[ZeoRP�5E+F�.,� 9�saPzeoj >i ( Sh �v!R )us��>��ad9�s^��f� checD h�$tein levelA�%� acros (tically mod)!9�by Wes=:\. Com(�g(densitometry�@revealed ~ 2-fold�rea�ex!�� "( n��MLMG.+8&= WT� >2��H2*b^restoYpr.N pg �: WT=B>z�2a� over1ngm��WT.��%Cc5 %Gin)G!2%-�aAk!�2!�t E�59�1disrup��ofN� g�S� s!��WAi if iI m5i u`$physiology-p aminoacyl0 �� ZX ����as 55%�A�:�4� I� ��,n��U�6��� � Next� e growth �s�Z�i�rex!>�"�see!� dele�� affe�!: �HY$i divie�z�F�0significantly�u�tha)��resul�d in slower�i44B�7z ex � phen�!)�dH�(‘add-back3n�2iWe�@Y�he�ac�Z�$on its abibto in!h hoste bVirul�studie�re carr���in J77+A1 mur�m��phage w��ste=ary�"�at�MOI!�20:�55s�rap��of ��} ~ 40eTBvs�le^�6 re)�)�� only� 0%�s� ."h 4C-�N ���& G� �� kU� 5!!g1V load!0WTe�ZT9�s ,�A�s� 0 Z=FH50%)L� ]number��mia"�s/�6U M� �/{���e "nr. OurC�)��shas)�otencVEq1�q���9�m�nply!Kvitro��{FX�2��6QA(&may be�o�ttribuA�-����#i. A �2o�Ň�M�b�re�(a likelihooE�� cycle de�*� uld6�߭t� ��*P'"�WTMf5�,��I�5������-z{}/., >a҅�� ed�HFACS Calibur system �Zy-kan"r ,d G0/G1 popu�of%!�6�13%F� ( 5��4 B�@� 5i�T��&� varahA�!�=zf�%�reforeI6Kc9�caAZb\fh=���morph� f9�>&1a4? z� ocal mi� cIfo(a�� �`x. Drama~�  abnorm�{"0{ZMV P{Uly=  largT!ag ~ 64Aj�a� r shrivel+ w��less motQ%�6 sQ� �* � "� A#}B�lidinJ$a nitrile- � polyketid�A�6a�@[33] , first isol�(from StreptJes [34�Bhon-a eti)A���hibito����wbyal1eukary�� [8:l�aor�ni ^E� 8Pof P . falciparum [35�*���ex��nti�od�$trypanosom�c��It�^��F� �R !�&,ly cu� mic� rod� mala�&�[36�C �ory e� �b9�on&\!ah" dMUP Z� "�!9&1"��� G �a�2&"�iG6��.2))��h= zyi�5Sof�aan IC50�Q0%.6):~��n(" ~$Prima faci� L60(5� �o�40 .�t^beC cord�a�%��Que�io�\!tu5u.AGiB h"�"!@at limi �=e!;e� ay.�E�!�" ��enn}B)�=�%recombin�iYY simi�,� ntal!� sEIer�!��#66!yey.�B�"b�ng�in4��Ld �, w���$ITC ( Is�$a�ti�$ calo�try)p �sK 25°:�C�6�eVxmogramQ�}a���$�!� inj�# �i[5�2ex �ic heat6:&�!str�"B"( KD = 4E�f"g%�stoichi�y%  =m7�!p�#approx�$ly9molecu�́.b���1�a��A�on%d��n enthal�O,( ΔH = -5 .�cal/mol� �#entro2 TΔS� . 6�%2�p9�posɆA %s*� �l�aS �wa��s��!� -drug!�erfacer��lexA���on-.6(hydrogen bom�s van �% Waal<�Y� account}favouy!1vJ'. TogeA� , our����fa �*�bAof.�.c.7"�tes�jɈ iven�6?oB#1af&s� o p s a�6�6UI[��6�6`of WTE}21*V'7� G �):����o��Wli]#%X��%X'.} [Z�.)a<2 . 5.��0W&��:� highEytotoxica~A�*�( CC50:e�87c�I�  quite*�%��:�"i�9�8.�I�be a ref�#� ���againM3�A�"�� ir�q -{co 6�*�k]�*:#�ea.� !!R�-�A�thA2 6� aS6� .�6���7�.B.F6G ���7��I�9th� 1����rr� A^V�� � 2�.�\�:Y!K*�� E�N�]=29c.:��Sa��JB� s�Wo TvZ�I�.(�|���u)uscepti�I�2�~�$c��Y\miltefos�o�:]4��nd�c&� .6T�"�o%�of2�!O~ 7�iin�!%�{-� a�Q���"a�$�{$a�6���)~� �L� T( UniProt ID: E9BS18 )C G �n���bc j.B crysm �&y uman (( PDB: 4TTV�Z�Y�g Qof . 4%e�A�0maximum align.%� eY457C (63% coveragR A�%F-dimenDal6�Z�!�"�"�PMODELLER8V2 [27 , 28]as�A�� 8A�+ve��du�289a(788-{N-�i�288�  acid�� P'be��I�5$-�(!g�energy�.imi�w� �CHARMMAce fiel�"4 remove pon'O(� b1��e-��;!5�,6=�� K�9is� �3D%�av2J howsE{.x�an RMSD>� 21Åm.8&M � 6�W W-IA"= A� betw05nd2�. IE� d5��( Ser352 , Gly353 , His354 , Tyr357 ,�*37AW8Cys379 , Arg4086n426 ,�55 Tyr56 Thr56 Gln5 6sp581� eu58c His660 ex�1!� Lys356!��%!3�9�%�invol�.͇ �%7cav!!�Y�B . AG<1$ synthetas�'aaRSs�Gre ubi�|+ ��a� vale� atta0*pec�Rs)� thei�2gn�.m5!�ensa fide� � mRNA;,"d�g���! ��1I� �ŀ�valid�a�&t_)L  b�A�k ��% � gaͪ��[3�2�c*� e�&�;��"z+d?/�"�!@by RNAi mechanism%��+A0"�!%p"1S+nge"Y)��%��us� ��P��@.25)edEj� d�"op�� �W���a��tim�� aV�+���2|2(u�K KiF5wi�.-q�"#��I�*�cataly� efficie��$! : �)�� 9��I*�0� u9Z5�>Eos%1)Ris��:2�O 2,"%�a�VgN1by mak!�de� a�� �&=N�.\��� 'con ,"Eattempt�mak�ll|6�fai�b�'*� �)�23pai�@ a��N tten� v" . C�2� stud�AZ� ka�block�ch-9� ��!a��q ��a7t�)���+(;2�( s]�s �aF�#� �@clearly establish��qis fun�#UO�]&�/iBM!h!��provi�6A!aH�VA! iҥayE�i`t���. W�8#���Ore�6YU?, L�7t�*te�h�7�7[1f*=is �-\ C"�op{u��Q&,:�Agw�,�&�6si�aneousl+&Bioin���Q�predi�3 eYsoB�6*� .r39of�*�-�es[A]5�z:6�5�1* chem� �;��"8Q�E�.��^c6Oica� !nedM��or.'&v!� EU*=I�l���s&"� ���a�4�>�roughPwe�dZ�6to���04"�K � �x�~ :�73LbZC�iE5�&�{S .59�previ= fA�9�< uve.N���� �b�#n&� 2I!ab"�I@ ( S1� O<7�I ,garP���%�,b�a *�; _i� 4��GY����!3us rai�+�r�mamb�'�!�&E .�9i%a�� A-�m ATP/:�=2J3m� *1 ;er���thf�!aQbeloia=�'K fy�dogAof�4� [38]6 X-ray�e7�)dF� �� !�eu361)x� 61Ŝ�U-�a� edu��!+1 ably P:��.A���;1C��A )� �. H"~*�2O�u f� V �!�a Leu�r�on ! &^ Leu405�+�=is sa��Ѝ � _M�,r�can�exQ^�A� stea`=�1>�nea�f2]��J��cM���q�J��or��+ �w�n clud��ma��A3�΅�iJ b��2�aJ)h)�,.� �]it%�i� ultaiW T w���Yi.�q6is�avail�*to�ir9 draw�^�. Also)er�"6�6*�eri)2!��e��h]P�2odiH"9����"� q�new.��* t�Gge=d��/*� y help�advan"�(.�ofls"j@ Aĥ�lu��e � jed�7�n*� mXAX �inAsmall}-Qe.�mc6%� it�@and�%qfuZ &{pre$me .ܵVi4&#��}( s trigg ;A�in�i9CJp��5|�$ self�gnDTpatho�associ�&)p� ��( PAMPrin� al�Ac-A�ccuA))�ri�� �B��$a 5′-tri�@x( ppp�#3eual mn5��%�aZ8� �&-U/UC�c>!Hw'w�*�~�%�-@ cri�=aE� �U!A�=�of?by�1�TT!s�e-�{r,͸i ~%� F�o8&%�g34Iio�'2ur�',e “core”��v�"ce-  Yx�� �� I�QTa"tersper ribo�s!D�D��/��U"�EU�!� requ$tQhieve op+Gl ��a5#du .Y _!�Qv!'mH%pG�+&� B�S� �!pu�� ,�!i�+.) mi!!#�"�sF�reaVsor domaA�nd��iZ of c!~6tivA� �AIqen{#end� o9��lacksIB�ŤPXlM�U-A 5��fer�U�����c�6<�u�^��3,ev��$�+ �d-\��ed �3�2ti-HCV, ��ES�/�h��c:�re2-voa mous��de9�F ��ie#�.a�,-�+f4űofVN5'%�incorpo������EK%5q�u���$o�d length�is%m� �V%s16I��t�4�3%�6�1, %0q&�2bN.�:�!�,offer insigh ��v���� apeu�)��� �J"M<� M:� �( acut�.uA2�u A�J�L�"��.re�m PRR��%� $zcal=-�2Ek)�8 .jRLj��o�,ice�he�Y�J�>as ���� �%)�}NA�;u.  �li4 I9( retino�-iA<i"�<IK MDA5�Jelanoma" t�. � � �O$LGP2 ( laba�,�D�sE9*>:?�@< �A\enrL tandem�&� casp�$!���9recrui���� CARD!�, ��^ 5i!o ough�  K�$g�q�roK}s�*9 uor �[14 F"�0>�q` � of!�ali�!�,-i���F adap ��6�yw <`( MAVS!�lso�wV D IPS-1/VISA/Cardif�23/[0[4 5�Dow@eamXP@heI�E?E�e.�of V0nt�n�IpE�faceq,M���~fer�.9v *$ ( IRF ) -�CNF-κ�E:�IproSof  C-IYAIFN )��h edZ  [Lo)seca'oni�56�$hundred�-*�a|SGA�&}:��{A surr ! tiss�&� medAh=�. omodQ�proper3."PX4 rictAfup�_%� G�.�9 ")�>Q �a�eM)I#6E)7�1, proc'*�rY�}�)1*PI�Jc ��X4���*#i�qE�es> a �3aj$DExD/H boxep�q /ATP�O� !a C�oB ( R�'-( ���z nde�E>�i���Ein�� � a free/ex*QdNf: .I�le-T\ ( sAv�Y� {K.d[10%�11 � 1�14 ޑ�E�!��d�v��k��M��)�"�"$6!�1�1}[1�3[�, [17]%�+=�RrGl�a�G�s)6� =jL!1�_�8 �F�u-Wa�����)ev!� uto-M%�5!�� ATP.�Si'�6]al�OrrE!]��at�i4R�I����!st:�e�iŏ/v�9 �-�e� Desp(,l�� � �A��q�al bio�AJ� , [2ENPn"G Cm�!J -1�i![-�RN s unh.v:� of^�!" }M� V�-,� !��(9���ie�!�1E:2i+2i+23�-I�� ensen%RR>�"ZK*� gT/ such� "@ ,e%"!i! ��-f�ly.I c ]+y �SabundKM{M%+!� high!2 !. More�(Jc�%��<%=�2A�e x� \ #@ abeat �2��& �L�4torP 5�Za,!|q�at X�a�wN�aHaZN�� %9. P?їf��at��!�mYJ&q��M�F.�U >��7( >19 nt� �0a� �QTBq�e�%�� erisZ[��2�w!,&�u�)� s [2��27A� �2\�E�F��et #Aa-#�[ +���� a�htiF�.%i!�_R*exssZI�r�_S����"=s chronIW iverA�e! ca;��255200�-lANpeorworldws;� ]��G �S�[3�,[3�O�'H $ Wt8h1�{by��v�.,� duH !e�g��Z's �!!<)b>��2�:��b�Q3t XW%�3e�a��L: ,/g�( NTR#fI ��N5um^A4Noy����E�*!�>�A^2�1/:ucl(iti& �A0BE�2�'vi�)g=,�< <�$N�A� Zin)� G ��!s@;^>.�&J�f]i!�pntV1k�A� �!C?�� �)ԁK� '���!�&�'i�!R�6� RNAsur08�H50�%6 �or%w;��ly5AY72��) .�XI��M�Alt� �-Le �)ae"� 5E��!N2>v� oB6c�T��RknB� |�(�$6�*&��= �Pm~���o�",a�>�)հ*iDB�U!��P2� 6Y4%�rTSQ�f(o)%卶NJu+�(.�"/��6+_2'!�}^2�r�s�Ρ,� -�N in6*%�".%�:kaf&u=�/!D7 2LɖF�&"� .T �B!yPB� �$th�*}_an%E4.'U�"5[F $_>U1�Tr�qu*.�}�8veloped*� !@%�~�p�*�_$1�0dJ nctu����he%�arm ,Q iI3� !:b>SA�� 1b}�2A�Conc3�5\.V�F"�wob�ei!�5Oe�VX-�wk�oG �$a�t ��<��&�I-loops�ZSLo!4SLImx  7�' -U346�;�%  ]1 legend�1 Each+��g�6�!�a�]E0~ S!�T7��_ ����IFN-β-P;o� "U8���( Huh�;�!�rbo�a�� tact \@wa�.�.�!T�a��(�2�)�#Eimm/q�(is)�2�O�)U!'�.rlfd.e�I�>�>�61�8RffiDhgfT];�= ��I�I�=���*r� N�X���%>�( p��)��%�)��bAA�liyd�t2�IRF-3 �$or"�Vnd ISG�res�X�?. A" \/L��A �%f�"�2 I�QJ2��9]�4]E� � 0HCV�� ͉��� .l-dJ $$ PAMP2 �:�u�%��/� d �82��L  l>�A?�JE�?ٽWFiI���Nm0A0 C67U�5p1ituELQ_)FM6" of 26 b��5� ��M��c2�_2 Wd]�V� 9 Rin)=I0.�-d*�A /�C'�,&]7 �g u�i"�y~G� )�K��!L����->SMyS1� ngf;B%�mBR6b�6�e�8 D& ( U8 ��7i+�[F�.� "517R� !�( U17 [���eak��{�F� &� �2�a??um1����T6W�*^wR'� e�2�-9�Y`)�.���eL� EH7"$! �g- qY>Ci�2e��. &&(!b3 ]i!$2sb\( a� ($� )�[ulj �-.� &�to&((Z�,B�=��b�2�O0 !3�q�&� �Šaom�K ( U/C5 /C~*I:%o�>y'd�  �Y�2�2�i>� ( P<�@0�d 01!TpeA =, two-{Stu@3's t-tesV.���wi:kC� �w!� trunc�s 62(�#�-�F-&w= TakeaSg�J%it $"�h�oI ?j>SvA�lc+tI+aQ�q69�s1DA*�!g!�B�]<� 6B~N�*K&�+��U�U|!��+ne�!= ��+WeR ic� at%�~-l last�]2���P * ��+����*;�p8�q)�h a. u��>�y.�!(Yp]�)�c���(B; P = eB04^Cv)"a�rM�>~9 .�ݿ<�/,(�-�sNE!jpla�&o�&B� � ��T0&$a s$y�"]��C!�U29ohC�fdw+d���Zofj�:I� n!-!%�'�CHIE62�%����kE`���DU/C`EU/C^Ea�U/C:bs each���A6�pAEǍ�tD%~�>�6� . REGa�,�.!2c�2ay&Zh"�  \U:c!5�of8#�sh�)��eJ� ��ɚDH9�Z Y kwv_ ngera10]6 =>�0�F~�H"�8�&�K� )overc�b)=sA'nga�vZv�� �6&c er�g!J-Cw��E���%~�u::�as�MDt~/sR��=\E�� T=,�-$a2���2".�26 ��k )��L?�d�Rx! 6B�m p�rw3U�� �Zg�znFcpThor�, mo� gel-shift4ay ( EMS-��"R2��"n"!Dh� 10 p�T�lach���I9�2b.~irehens�>y�eGS�on C2Q�$g� sg#�-1Zcuro��2Bl a��/st"�-c@)a@1�A�7D?9�:�s�Zc%u�f Rb>]SA��� 0–18ck� we&�Ni&�Z�!fT2�reA�(: m�e:�/Jn* �o�3EPexcee�3�R "�L��% 0� ;�>./>~n 3E� calc�+d eI>��A 2-A���"� E�10%&10%K5 5  or 9 9Q���}��byI��52y� e EC^:Z?!aA"� , � ,.g ,��, ��,�,"���I] 6�Gq9.Bgraph�g%�q d&!�^c(Dly dep�D�p6}/�(�0!7u�Cd�?�[ed)Bq��Kx %�e%oEg�� �e�l  *�I�9~�;D.Ce���u�� E10>����-Q 65–3 .�C�� z)�EAt.T`Bng9W28–�R31.9 . No e���!&e�|"7%A*`�U�!����!) �� �A�.7�"����3VE�Zi an E5B:d2.�a�>a�;�8 to 8 *u���AY%�ged I� � �d)V�3�78��Q ��QB���.-"�:�m�� * �:�16- 0�v� �:%��1�^a�u>) versus.452ed:z� K�U� Fx 2 n�'I�.��h%n- q!� ����Y:H L:%:"�"�.,.�C%- NB7l�__�$.>17Ain� ��se_KO aI2�.s�� weak6] u����- Q�$!! =� fA��<8U�m.� �)+.?�p�$wLm722 �F|�>t� "�n��!��� or E�$��qM 9��G"7% ,!��C].T/NA&�#B�n m�t �d�K)�ma�v��"c ,ɂ"i7�l2Nlev� 2P� V�� �%W",$among �d�o��G@1/q.&���� $2u.W6:�& .!g�..W*�:YM�9)2`!ir"Pl&�1�t �l%i2>�y ,T� � A�t"c�N=�#���8]\1�d6/2�/!E�(:<_M�mea�Ti�)�Cc-ly�K<<teժ�MI�th�I3�~Ler:�. A.]5�qg�8a?� wz? � �� & v< 8�LB��:�263�In� l%[t90!�a���>r )rLo�or�%��J�%Z 7�.`�gsti3�^?' NR+E��A�A95Ѽ:}2f-"�!!� f�:*208 az���'"fR3 �}!Y����A:�^*|)Y�)~� �enh=0.$�an��?B�B��NY)�!_6�.o����2 ���re�E6 �AS7�})})I�6D�!&�����bd)i�Ri��n�5�7f;ouR�u n uno(ell uml71.�z*�*�8�7X9mai�:�>YuK)��XY'Hel2i���Q+"}1*�8 . Cr>_v-N)1�&R A�J�4�RD��"� �u��J�9�9&9� ch b�@� Axuc�5� cl��e*c-?O:�9��Ne P�[%�E�1��j83�"�X�2*�/F� �TB e'OE���<=:�E�R^W�Mr>ed�-RT ��6 ordeg�Y�V ackgXA�o�9&7)!sQ�NA ��(%F%�:!MQ�XA�y>w t�)�E�~GJ * J/"0g ,:�!�1�su�Yl@!���HluI�aB\:�81�DH"gC/p\B�&$�J*vn78 kD�ta^w1D-��"�uo"r$�e�N����c�fam |�" A�A�D� &�#�!��&�9��lgkF6},B�f�&li 6� -�I&��vM�n�y�I�&�+)0v�%�� I�}��%!�r��90!p9�>�1�u!��&i "yb)���*�'R& ],�a�6�!�>\�boR*�'� K9�Ũ) Ij!�bI��DUj��#Ma�!@]�0�low�BJ.��E�eD2\��]9�IyB� 6�%6�A�{Va �|�F�ĕ�[�|�>[2� �o"@ 2e�[K>�6eTb#f�}��"b!.6E��C �!�R� !�f/~ �x#&p m�C>�O��qJ%Ka:�1 "�ɍ�� 6k!]& %.t.H ��! ]gm6}�U24A;I�<& Q:w!Sf[12 hour�-[�`O��u � �"� �!Vl6= a tL ed 48 n*-�W2 2q�9�uof�e<0�: � ��A ��M�Z%�A &Zxed�t:�o�5Boulm��� �T�a�I3 appl� R�B/�c�p�� D*�':��in� =�p &b !�=�t�U ( ffu/m4v! 2��!�6�m���t!a>;ur2>���dexo�0 d( S���nr(−97;.iP-� $!016�+. Ove��u.S# �Ked B &�j�2:j�4js;1�f1e3�&t U~�ep�!Aj��a�upE�%�Yg:�iw65��EB�!�A�= � d9=hD>T�A"�+_ v*\w#`a� aw}AM$}�_�4Zl^s ~ ��"fz tone�Vj mo�Tin~M �recapit�!��*P%(��pJ��� ��51N#F76�8ZWY��I-ix'1+Wa lipi���v1q!�u��� reag�n�l!�+2�@C57BL/6)+� }E�p coll� 8 hrs��ᔩ�.L2N,� �A. E2��iC�m��l%�z�P-��gen�#�O)yIreal-�lqu=Vd"�O" �W2b� �, CCL ISG1� Ifit1;��Aas"5 �n*�P��AH�&�\Q�5�1�:�c�g� �or�!�F�ak U34-c3ml�tk �j^ �BaÅvAQ"3,%G%�>�5R%6%!%=~ ���. ח�C���ci A1.�:�&;":=�ce!O���}W-,Q�i��F ( r��XZ9y �v�&>:)2%)��Q#ISAmin.�����U+IR ohis���`"߅�_o�Ye��J�(.zn bj!��1�Z}�>��Precei�r1�%�or��PBM�&80M. N�@��9: �aj��fe�+�20�2��#s��!�%�I$s��!">W "� .! A��{^eJ5?R� ��-n6��=2=. Wit�E1}M� ti�,?1�2�B�44% �anW�E 16 . 7–( �����1�R�41�!�J.)�%&�veE+( �OA1�(6�2��#�]9I2,-b� !*11V�;� �e�e�un�q�)�Q�e���� �sM�6�zIJf1Zo��4v��T"���ZGV ���6��Os�oiC� D2�n~<�n� �I�_� x��I�-�`i�1 r� ^#Yэ*F�i] up��:Q1�pa|8 h�ati� quasi��`G�s . W�h&P$a�A��"�< ��.3 �> .(A �K.� "M7�T��d� r5�e� E� 5|�6� x "4;� "�"�L� #+Dݖ%d[H�)RC%!*�aB�� >!R|) 6&�m } K-"  �5�2�2�B5Cn��i4sA1��!Gl4c*����>�bi� -S AA�2b��T� D�s6P=�e �9�. F�-D6]-9iAV��"a�� BKd��V$� k:�L�luC�d��sI�n�8�fa�>S&�l �"�=Y1��ny�*$*$�'^ ��f%��tD$sbdiMi��:��3�XAU9�NaD�75a"&a=�Isu.o�$V�5�+!�gbyU^��S curr�^=CT{���axE�d˭�!J�E��#A�=2��UYfen��p"�]�e%�iv] �A����19!_8��}Fnd ar6�s" [e�V?to *���CKpJ�Xs:�X= �< �"�,7n. S�[���%a6+5Rw\Z�$6x[cxpoi�!�-.�I��A�As� o7.f�\ uscn��"�\�An��y �"E�-�hI��L2��%?t"�<&\ +E[lZ�U���'�#EOs�e,qAi. !��;�"��s.&AΥZu�Iduea8B&�.n RD%�4 moielc[1`� �'�'. &hf*�"1 ,-�b[:�`�ans�Y�Ogq [40]� -)C�engag!�m�E:]b�%re2�Edr��!iB�ca*�`�ina%�[4 [��!�to 2g.�hmembra�[4�_A"]�I MAVSGBIFN.�2 gE�?0:-W�-u���*� a V-sha�QU,4er/pincer/brid%Q�&anec�;h&�!2��&ns(k�E�rol=�3%3*{'&\�A�Q�[s�m.�� x α17�> 1�)"*^z^4 a6��&2 a}s!�| a&>i���s�, A�ET!�� � iF�]3�r!_!gP-'�>� �N a}J"$����yDJ,"f#�I�J� %)!�"4W�A88���>) �L�k- kisA �SL�XC q&' `E�rLT�Q�ic7A���S44]�a�{��)ż�[� VJP&A -Z&U 7�]R��:���� �?�b�3oW :�rV`A�%]�"��*�t�t�A/AG )�^[yANIo%�E2�7g)�.� �&�G!W )q�%)-g �M�to�-98!!�.k!�R�!zF���a��0b(6�Z �to mi�7/3f�n��a�.>�,.��!�ݻo)�!r�“scan#u{Ak�1��6�.��(5E�;�Z� $ %�F� ( ��Z���Fa����NE-�E"�T&r via��'!���Z�� [RA�M{l�E���&�51=�\Wq�6�>y wl�mus�hist�ch"� j evol�Q�is �ic �:��ig�IH.�. Inde�* " 2�"N��.%�*�B�a!�AN.�R�aA"�O��� olRV ecu�AQ/&��U2SR>��Jgr���333R]is*�a o�w^�a]"�~(��u-��.��eN!Yy�YouEhRi0K200ݑ6�*r)A6G4-� �O Z�>A�� �O1NS5B SL^@& A|SL2Ŋ��*E��G.G,U�*�� min�+9�9O%�3\1.lso:Q1I6�Jp6�+I�h��>cK.>FB�Fi2._"��( U27 58X�14-z4a|#7�U16)untilf2a�A!�er6l�+�gre1�r��fit �%n� J �2�D�F�:gai}5terrup]i�}�k!&=�c <[e;)f�A��� esse�a�Qlc6�"�r�� explI�A����� wis-�Q���. D:]18c�F��kxto!4�F���_������!) )aY���{�w%�R �*� "ҍ-im9� I)!&los��v!j�o͖ �پ��J �l���a�Z!uoa�1BFu" d.( �) Oi28?"��be�wAcEabU="h|R�a 2s)ed�9MKl8y%'�NS3/4A> tX/s!�� ![C�.� J�u�!�a�%ovag�"�H"�'!i)�Z. evad)�M#wi�8�Y&=ZO E��[4 t!H�Ied-0d�ks" Iw��ly<�t���out�M s [4��SMxl�#Nigly�!{�)�%�v;v-� d! ra� �&�Qwo �%�(1*ԇ1�"�MX!�!�#�^f7-�� � e"o+�}LE_w���I7ap�^&b*�'2���%GI�ABr�t6�H�f.1 pub�'�A?!恗)�1a1bA4{���z'�>*5�h1L%� , [4�i[4�rI�:�q�ndA4� >�U� �X&�� infl���� �΄e� �AͲ�t�� ]R�& X �qlϑaku, B>w�pbe�borariE�f!zmXWL&�*ga�9�#!��::T$�!C!�me"�-xa.8l�()gc�"��B�#dat�#I.�@p��vA* .� � rL��!6l W; m�b��!& p"20&r� *W7�S�oo�" ng�I d&�Y��&�S 3w�A �&,2wh�A6u�Ri�)�/baQ'A !t1n��m�AŭDA;S&�-a�e]��.�K}r�\߁MK��mi��L� 7�u��"rjR [i:�ori�A�o ���5�on [49�v50�rU-�!2��2-|��ac�~!�.���th2g �Mh"��M!�!-��{9D>d *@^2�343"i��AV�hZ� ��*�R� �2!E2$!"Z"�:w� � �&h ^ M��n����:�~�k���}��!�zF�Tf0M>�^1w#%���A . Siު�� � E�bA���&n��'N�conju�%#��w!�I��:- �_� iw�v)�2��t��- �.�.��k*�k 5�ɣ&M ͭ�.�8�/ � ropr�~B�tfjeQ(1|� �xre� 2�@�!$� qw9n�-M���)Rantago��. Givea�^� D<J�> arco}7 iano�ut���) A�I ��;^����p' �-�RuM� ( f�w:mp"g+�!XFvp!1�L%�ol�p�p!C� 5�?�E ��zQ�aOr�VR�Y.Y�`.Z�� �&Fh�TAATACGACTCACTATAGGTGGCTCCATCTTAGCCCTA-?-�CRCACTTG. GCAG GCCAGTATC8I�a::�!�%fby& rosx�l extw�QIAquickv^."ki^Qi29�s�4�:�A���R&DqHC.n��1�%B�]�"�Z�S��2a n&�Hy��I�� 2� g^ ?9�)�IZ4�� ligoY��o?oInw�ed+Technk�D iM�F�s�\q+ by M�g�_t a��Ys � B MEGA�b7pt-vAmb� )R�V&NB�i7,�[t�:(�I/ s�Bea�a��NcW�d*#:Au9M8e� � illu�  Mf� Spin G-25F;umh7gel filt%` a mat��phGE �Aq�theT����:T %"eQ���) mmon�U acet�i!sb�O!�.�� W�sus ~\E0ase� ��.�2�VE�"D��absorb�Q-$a Nanodrop6Db���A��t� "�BS1 aP����Oe� (ing 8 M ure� lyacLrm�gel�9Ej\�Ts�yy35�5��V��>��2��$(aldehyde-ag�|��I. or :� e�d�10 cm dҥ� 24= "{=�M��! �76� 2�(iD efly lucik�s��ndN^24 2>�( �67���?AKFuGENE 6�a�.~>�5( Roch. TR" �HvZincub�lat 37°C!x 17D�en spli�48-�%Y� A�Ey K*al&�D prio�A�5_�I�2A&d� 6ximatm!(�IT-= �_�~Mi� �B�6��jz�a� � s ~%K or 3ag,�ae��#&��a5# a�<2,.�=�&(!v1�A�]�(� �:�?!FD��LY�o"r�'H���( Promeg�_�B!�6I�mO uc�RX rip��:Var� [O%4"t�� (�73�f)� *�A"~X�\w µl�%a��fbuP (9$mM Tris-HC�XpH ��0;a5MgCl2DTT�J"�.8=�2^5�!u�m`4×Os� e�q6�p98;�b02% b� pî@l blue; 60% glyceX�)%�adobVa8&PL 1�se�F!�9O 2%2� ( TA��pH �b�;!M!UALv�P�4SYBR GO�����('\VI.� . G"�h��M6�8SI��J softw�(z��9 �Y�(:h%�je�Prism 5.gG�ePa~}J�!I�QlF�Q�U�6� , 2E�of 5×��Y� ; 70A�KClH,E367k AMP-PNP (a"m�12%�:�upA=1i=to��&�� b��Y�a`om; er�3. S�r�GgrPTPCK-�€yT.}AzU؁�%U�-mix4�Qase∶�/%r,!p1∶2�^w/w5M�M���.aRt�Q8;� stop./> d6;I5%� TLCK!}5|A� e���F8DS-PAGE LaemmliBHBio-RE��� 2;��{\��-u�by pfū� siln�C�"!IS Ques�#��2f ���YiZ'.z��fF�5 Z�lI��()�sP5�,�,�2( Sigm�{!�2��M�aq*�+�1E��%1� !�<-�M��Z�. Free-m~ r� / BIOMOL Gr:�� 0( Enzo Life S[8ce: %�G�j a� A�* !"�$at OD630 n3���a�� �pr���� �v�aby�oblote~A�V72] ��bo�[!�-�&��-I�Ser396�_�*S"W" y�t -(�A u1�i�*�6�, Seattl� �-ZN,l5�`G�x� C�M!Cli2�F*i�3�tubul��Q� &�8=�`"��{J �on��ResearchM� oI�����EA � A�AB�,ham ECL Plus"�B1�De�W Re}�F! *� Eq44~� �D"Gu,+�Ms"� * ua�� �� &� !�^��R��!(�aeV�I�= was0 M�AD:plete6�:�w"�%�v"R� HCV ( MOI*wP�in<��� ���Z�3� �\oculum� �.�30��F��v�z�A�-�Z~"�S]"&�:�!���B F&N�8RI�E�&�69NHCV (� ,>+eJ��I�,-q!1-) 1-/"`'� su>�)=to�.�NdiI1Unov�� 10  r2�9�Et2�u�g Q"� N"�!�6(U-.q )!�-��2y]M4X%]e/.rV�2+� 7���O!�<e: |1YBEf&Q�Gara.�)0"�V� �� mono ��PpermeK��i%a s*&3 PBS/ 2%�tX-AH!�**Nr����W�)o%89iZ�in8m�. �r�Q� `R� at���"_H���W . Le� !�Finnish&�a@ Occu�o��,me sinkpeT1��9#ti"�' �::�donke]� ti-h�� -HRPF��+!�M��3^o-O��=7B,!Vy� VIP Ot �peb_d�(*" K�9N.�'B8��7�$�/!/cu� ��7 �c�a ,ed:�$��f|�6b! $eqVMo�!.E�n���x"�x".6�T�"2��trV.VE_T�µ���dU(0�Bio�" i��eu��b��rE>��a� ve, N/f>S-]-  +�S�X�"� uiceP�#��Z ��-�ng-o�F,ǫRMJ recoY���d�zin�x�t�-�"a&a neYh"�Rs�s{/mE@iRS �� ���o < *>�f�-H�?����C�7�^%I�%�r� -%& y�Z�xsoaNi�T)�&b". L�%:khomA_E@L��;"�[RNeasy��(&� . Sy��� of cBy�I�B iScr�Y6 ,R>*��{guh ( dT�nd j>omZ ='fvOn:�ep!$^�W�9������erka�p;]2� �4an ABI PRISM 7P RLXT��?XST/F7k!]�\*BXW,A�"JXGAPDH� purc,�RRSA�_�)2�?��%��#e��'eQ ]a.nw"���3osl�y�*�*!�5��e��ophilsAaenx�y���-def��!���rgy�$metabolismU�r�e���(�^" 2x9v�LBM,���D�)in�m8�[��+o.�t�"i6� ��Wsi����!� nutrB5w�g��od�f!� aim!p,5y&yE��+v��7=!R"k/�)ly�s*4e)�.��ot"��r[�nella sp-i�[rva!� skel�'muscl�Ou�I<6W IL-4%.r!4n"��%*�l ldl1!M�,.<+ V��e .eU*�KF]�L-!��_ \�j��hՔ"2m�'�+�h,.  inva�by0 born ��Y%�,#.?��:F�Y�atiblJ��J;A�v�0c1!a s� � sour)-M~g�'M�� in�)���E!�9b2�_Ll#�a3��E��1a�*X5A^Q� homeosta��t\QRe9�r<�A�(� luco #ans�M(er 4 ( GLUT�\�� &��of Akt��I�1"rbbb������&�yupt=�h����by1�Ezis{]toH:)D5Er�?�� sa}��C6J.fqn6� by an IL-�C4 dependent mechanism that limits local interferon-driven responses .Potherwise alter nutri VtabolW�in infected muscle . Our findings docum6a novel x|action between parasite and hostY�which worms have evolved a strategy to co-opt a� nate @ cell�Na way) facilitat�eir growth . Genomic analysis of diverse member`the Nematoda has revealed a �!!emerged�0free-living n =es as a�ultm0multiple , in9��u!3hary events [1] . The proces�%=adapta/ ibsocia!�with lo +fun%�s �enable a2�lifesty%�Understa%�!seUk cieslTinstructive when devis�AMapeut%^d� phylA $c approach!�!�ntroll71Kc diseasA`A centrE�4fluence on suc!ful6sm�!�%immune!nE� . Animal!:Hten mount highly efA��Th2>;s aga�I�L; however , specific Aory�s v!�by �, tissuI� ��s c�Derpoint , helminthE�or evadef�inA�5�(sure compleEof%� cya�aw transmissa�toZ next �,. In two exaEs�Hchistosomes manipula�ii�-n sign!cd5Jitydy�oirA/elopm�1[2 , 3] 9 richinella-producArn8 � intestineE�in 5 day!ۍ��aV advaE4f a potm>AU:&� expels ada���[4a�,EosinophiliaAm�llmark!db{to1�ic P8. Long consider�Mo b!�totox.R��-�kilU�e larva�=rea$ stude�n e�-ab!�d mice�[ show!Lat�iyXf9sag �varXfrom noM�A�oa� tecta��,�supporU�[5–9!MIn sete�earchtae� m�y, newRfregA�oryf�[10–13tC�n!�energy.gby2���I1ial�9)�outcomeK!&! on�jf�Dbe!rel��d)? fema�y][M�Q�!�.4spiralis ( T .)! bornQ ( NBL ) e��� circ1,system , mig�P�a)�tyʼn�se��uual�stablish�raA� ular�(in skeletal&Follow! inva�gofB(N�]� remab�&ve for 4i�prior�initiaEU��E�130 μm"1 m!� length o��!�cou��of 20 U[1e��previousuB demo���H�uQ s arA� crui�gto���arr¡= they posi�blyQ�8e both survival0 ס�i� [5 , 7 , e4Ll3is��ta<�-de��0terleukin ( IA"-10Mi!|Aurn ,  sa�d��on�$CD4+IL-10+-��a�r�l_ ,nitric oxideA�O ).Gby neutr�:Ibmacages [�NOΉ�!�neI�!F!AL.5A* tincB� is2T of � [5]� ortsXA&f6[ gp is wa�~A�cu�bEPurr�Kstudy re�  � quire���IL-4/�#���r)E� ator c� crip��(6 ( STAT6 )�b! 2�sanormal �l���he abs? 6�,�re!20a sustained ,-��Ft:= � amma�Epromod a shif� ��e١ ��; ThV "= provA@e�!3a��-�'4 relv shipV8 �ri�%m:��� -d environ4�&�s>F R*�L��Mre!�d numb!�AWh2m7in6d>J w!�as6� � romised:�2�6�. To fur� asec��te>� � � ,:e,e}el2� @, we synchronousl�E�-/-q� �.��a�theVimpai���6�F, ( Fig 1A ) .v nei� ��Anorad10a�� � CLN-�a�a� ed]D� 1F )� uggY � at �i�ets essenA�U� � but not ri�d%܉~&� pr9 �f�e��NO-med� � x6T���nE#l�c,s our earlie"�I� _�!%m��in �5�������ed��poorly� � ed���M�&* i�Xn-A]��uis� hh�s usly�2�� U�uŦy on16��L-4%�!n3-� via%�IT path. G �l��traveM�( IV )y�`5/AMU� whil��%m�����oBT0in diaphragms� simih (to wild typ�[ WT )iZmB , 1Ee 1G )!n)�as� IV2�13���ora �-a�ElybCVAlthough� meanA+a�>M�WT �ini�C�V lowe� au of >(A ��a replic � ri��M��confirm�} �!�a�5�F[I(�0, 7495 ± 327C 2Q_%!+, 7073#58 #!e�i�E���U����%��A ��amc� aQby��:�s . F��mor A�HI�E6�6r,M��!�dispens2,�SX-��BPe set A�deter8whe���may bem�a�a�Z!�>1  . W��I@bone marrow chimec �pr8�]�B6 . SJL9!�). Only Ŋ ��We .d�bl m:�it2EWe25$e time dur��䁣 �����6^. T� fe�).2to P,ed ΔdblGATA � o�diffe� Prv�:*6qa1 �edF�%� fer!s�o5%t9� t o�of� ipFA�6�S6P11Q15 had*ko�uG)�3��u� ��� ����:Nbe avail%� at a)�coinciRE3,�im� ly f"�� aN%UA� v ��1ԙ��� �!���y~up�G2�  3B: oA�re5{ofI�+/+29��5:-\��Sɇly' �M � .Tisoke�I�ed�5Tg+/�u�di!�t�� rove:�in>� �De{&��.uun>wI�as &�� os� .<B:�Cin��tora�6)b�E�TI� W��� �8Pz M� ��!�ne�?d condiB3A9u&5�>/�Yc�J5!� �� Q|�<-u uf IL-5�F�uZ�� l-MZ�propert?:�  stIYo ��~�A� �NvmplifiIX4!L� �U�)��~��� �BH ,2mv� WB.�2� . ImE�>� !iobser�e�Ef.�I>�-�� M^6�-��l.Lb� e�e� donQ�m�  doI � -�c�!�F�A��N��͝Ika��m!��7 �� AN�Ee#�i>b�as�k%E Rag1A�E� . No���o orpholog�n|in6:i mpar�A��3n8 \�e gre6W 2�� ��eAuhin PHIL/28)�4���d%r�.�"oaina.�e �. TG 2lymphoid-C�S.TA�!�B�T�v=g� & C2� ribu%�o: bN�.gng2�vIHed!e2-/-γc=�%�5!e��"�ba2 I�-k�I,� ��@M tiblmf"2� -./: .% ��!��"�RaB�[�L�3z�faiS w��:uns�� Taken tog��&�s� �.��B�R���!.�[C2A�he�� d .qc�N�m�*i]����2�&�6�J�E�perfo�whole g^ e��a�ofi !�g ify-{{!ed�R�&�M8ia�,B� �i�� �z#.63�qd��n ord�o6"G��infil�!a�celw "� 8�Ixp���=� 2�. M�>�' �&� �ex|!of 1529-@( S1 T���HHierarchical cluste� "�!&#e'f:dis| +�co-Y�ge!��.5��. Gin5 1-^�5�-��,] !�gre�"tQ�?�7g p%#Z ( dpi�~ Ont��en��C"�"�ent9 � included �i��1Qj orga�!"���etyl-CoA.�-�D. C)m�i�M�r� pe a)corpor! �w�k=�peaks!�2�� i ,��D�!%or M � fens*l 2�6�1"31$ m( re stronge�� at 7�!! larg).Ra68remode�,wou%ea2�Fin�,��4Eei|%Pj incrw�-6Cj�antig�%re�� ]� e.2���fsM�IWI�o i�, �vs*�  gen)�)�6�( GSEa�A�m on 2�7e(s� e�At)(��re7�!�*�u�� e�S?'*� ��.� aM� Amg1 tAt O(Igtp , Irgm�"Cxcl9� 10y�7ll�ma���O� ofY�uNUf9Stat1�,%#Q-�> �tur�imarilyJ�llaA ��Y-��iro!MdU\$tenascin C� ncdh %} 0factor; lysylH�%( Lox 4secreA< enzy�Xa� ,es crosslink!� of c�A�ela��; a se�".&)�(( Col12a1 , 5 4a)_ a1 )�)b2��#sb��subL'ž-=� hy y� ���&� F6�M�capsue"��is�. mans of glycol)�A�&an��e��.�s'al ke� "�#)�s�'hA�PfkA�Pygb ,� Hk36IA�:����[a� alsom�lj�s& by �!�U��M�jm�&TCA'( �'g dha�Dl��nd Mdh!� str�.�de�F(Myh4 , Synm; MyotY3CM: Coll.v�.��se chan!inE�2rogram�&^#by hden � robuWa�%�QZ��*�)k�ubsequ� ;*myofi� ����A%a���D* � sour�'^ t%h�� �:�)�=�U .NaceJ��5,c%Fj�Ln�A&� repory )Md enhG(� takK glucFby&8y��+5s&Wu�ed Ak�6x%� typ�s��!�| tongu��I'ed 13* "�ion.@phospho-Aktser473eD�*S��-a+ lA���2���6�ck ns.� e56�!. �6�Glut4���\ icroarra��-.�i�!9S GLUT Gdra�� �* nd re� *�a#:o!vesicl�-k� uc�!i6aM`Ɇ$R�EJA�M0-V* �=� Z&�.oqNtoZl��si A�first B+. D6 ��~=�becom�Pw�-1�c�lex)�}.�/:0-� �#� r(M� WABycoe. G�0%U�%?<i)"� ��iB�"V 2a�#a cleaK �=�of16���2l�%r2.����byk !�io�.��WT��wat2� .h!�2�,$(2C� �>���>�a���rZ &� �2X�e!aIs'm��.� ( S2*�&�) �exhibH)&z&Eln o�-~& �) �}Z 2�� a�!\�teNTto�tE`X5!5�m�7����.gVs Gbp(Gbp�)Irf % .� 7 e TCR |�� d %� �$�% f'� e po{/A���cy 2�m#�Z�'oedI�! %HɃ�+ �H$fatty acid� smIr��\)m�N� � �ł��a i>�lip6z&y Hadhb�Acadsb ) 6�/� � �M� � 1�Js� e�". u5�$� s I($+24)q��1.PJeE��k�%:�.. 4h'36�)�/2$q�p�md�ond}�w�2.[9y$6��/F46[co atEdbodJvA�!B��i� e lung%=colonizeBJ"�����6�app�"&�0E3�Žra����]4!�wO1, e�4G.{��'V^,F�f�-s:(O�07�� at f9&)��,���x>z3����Vto� ia [17!�Ah� cK1w/� 6�3�t'sh)0m"by�a�%g"Y GiB7resO � ��H>sA�motil?of+"�3,�$juB2�fe��0Y1� � -J�0�Fre�� . Re�3+-��X *X0toB�JA9y%���0b%� d� ant.�'# 8Aʥ�- damag�62m]&er��I=7 6� � �8C:� t6�-a f�\6 Y��v�9� 2�1��ine�jA to�2"n2!�q�OUI0{%�*.�.2����4 a ��FPwould�` �%Dq$t1x2�2�M�MNcauFdnvaa�=!�mP�&� �.��rep db26OR �orZ 6-�.'> .2#-�J:b:al @recep9[18�7it! possM-�ey!lN!a�}O,�in&�n eh �%&rEor>�:-� "". F4�8 , RELMα���a)-4*0manneB2f��**9�C [19]:� � play�it� role A"�5ing�az6�6CLhomeosta�<[2F2e��0JD 6R �-āc4s 1 . 76 d� LA N naïve!�U: . AtI�G� < &.F�%�U w]!�&�' data�v2� �!d"EygY�M$/n:��s�� e� �0gene knockout*�EE�or }/?�iV~o�n�6�".+ve�04a� ѩ�4!-M� 6+at r��e� �l�?o2�* V�7ceq B����0D]?�o a��Erfu.� �7�yotubE��<�[���q}��& ,n � . I�im0��toA'��g-a"c��a�.my�;�:A$2o,I-C ap%��timqpAL Rα+�b3 fueK ] �[22 8o�-�my ?�RA�T)�""��,.,[23–24S*v)�$fibro/adip� A� geni��( FAP6ͯmye��F2D.y")8iCD11b!el$9)o�%� =AA-��ex�(�a�"6!�Zi@edM�9�[2E AnH >)-"� amfIyG2�i�H2�;1%&�C#o�8recovery)�-�M?�+8%ro�+2�7�-ߡ�&�sA�a�@p?ly �&�(�$�p��" ll TA�-", �`utophag an�?" .0 main�7a=s:�;mas?"�zN_&� )�[2�28e�dgds $8A6�A�s [29  by�6cytokir!,"K%ka��0@>�*@A!�� s ca0D[ a�[30��="] M �,��&=GtR=.�d�M����21 migh���� ��$-4|reiO: i� �MD9���5�C]6��by��"���;&6k"�-P�<ye�%#9WA1S-dge!�~z�" d���)*�_Qzng:�J1.6�y  ge qu��,�[31I��7s����#rB>t�4>dIO[I� .�xx�>qy,7 aerobZ=r[ k.D0 � rapibreak d�AendW��żI�o��Ul-cor)�s$ *�*E�vb[3cA6(� icie*>\a�?5�6 �E")~ �~ly>�u�a� :�6[�&��=(!�a��Y2�� es� hypo!6 emia�{� E� d u�G�)�A�1�u<� |e"HII!�,upq&�o�!sulA�_E!*�D�8[3�@c�@>�@�97 ?e�^!S���4%ivens�@!���s�4�x `C :`Zb#J��0+?�&n!JPI3K/-��� �k -� ed>j!Q��%W[35����* a �e"����j { sX.�:dn � �;&^7�Q��.�mod�P�-�F I">t)B3 F �I �Y �}��"�!thee@!�is�@ne�>oR�@"�q#&�+)(.�;er*�:�ca�M �_�.�e��&� attenu�)Q :)"�L�s [38!� Mp1 eR, IFN-γ~Za�^-�=a 15G[4� ^!�a�0"YSm�6EJP(.�*n�75�&2�*���9�{6�A \WT� ig 7�+�3m�.9L g �ց*� >�:� � b�F!eT��Y2n_v�.IoIb0P��0 be &�uDa:lip�&�Q�241 , 4�n aggre�2� �/F ��i|.l�2��!b en$$AC��B�&J i&- stag<�V�PJ��6$">d J� H�z��>N�;��6�,I;sMW�e��o� �i� �"� a��v��w�ge6�S+�6S�!��XqI� m/ll6@{PlarifqB;9C1qdoc�Rp|Q"�a:U�ear�c�O�5�dM �O)I-�s  �Q�(6qaUO�!+i|EnfmdA��5:� �-� . Q �d ,)&K-s �It accordE�%�!1?mmend%��Gu�Ga�%C�aUsE�Labor�Hy*�Q*NG$al Institu�iof Heal�Su6E ocol�WZC9b!Be8� �2�Committe� Cornp-Un�s!( Pro a�20: 1986–0058��A�M0Albino Oxford)�L rats-B�Pd��ain�V�Bak�� �Krium . "(.���F&�?b#>$.N!wBe2Fd"l8$�;-f"\,c ( NJ . 163�!8�=�7�= �=b /���A`"H{/b�#at5��@ rMousee F�U�DTMC�<Noffspr�K�f�@eeB`�R�@�QDpurchaid �Jackson.�=A���)�5O5"�>61*J{��!2�.�5 backoI:deKtMti�k6t�9m&�Aby PCR�a.O8(��l;$id>"}"UCf%aconic)]*�E%Qa gift)NDr� hAug�,h/i|�#"$Thomas Wyn�NNIHeoA���d� �,2z![4�ABta�m�ow+C57BL/6%[grc .NHs&S�> ��T!e0 &�T"�Q{)-����GLM.�c�Av�SEw�@a�� b:� F|��&,YOsu{�5in 2%&Y$0broth ( Difcoe�P6% geNM!pF�r S�t� -�dos9300iadmin ,a�by gavag�!�synL2�2�P000�2�� 25 m�um-AY DMEM ( M3cha_nAsI8Bi<$retro-orbi�RinjZ/> M�%"eu�iz 2CO =ha!A� ��V��H each*���9bod�-�burdeQtass�GD carc 28*�-:� or 2�R�7A+�vCrude so��Z�5sI[L1)":Ga6"�$yJIgAr�I]#Qmn?n|VBriefOL11%~:��Z( 1�))AHdi}Mmin,*KP15�837°CA�PBSe�ai�2% FCS��5mg/ml)&�4P4I�* igma�[,>e �t�9d�70% eA),ol ( warm upv56v)VTn��!F[� ifug!)W2�5%Werol/.i��Hd8Ifspi ��sl %%Tfix�m�v�QwE HEMA-m3 sherS c� V0-���1& usœ BX51!�roscop >t� cDP-12!�e~ camera sytV( O�k�GMelvilll!N . Y .%��aMueneO��alU �M0suB^(Basic softw��  l�;25 C-� �d��[s�  ����4�e)�#p)hpoo), !-val�12 i�μm�>No *!��u�Ngestig� ���&� i�Zal2X. S(pHJAXgu��K�/�RF �I"�X����a�V!�&��&t#J  A��P*a �%�$.�2I{I �/��/��. Wa4-�uT�$�\l�,).Vsa� 3!�&n7ly!�g�>*&@3%�6s N�",�"y d*L(���7-�.�:+m"4%$+/�`ma�ap�n~%�e,AN��8f&%%e���9V� grap:.�$;cale�fE�ma?9!���SN! �9�1Ra&�! Z1��ZT_�g���[9'@r cerv�$� h no�)(�S)+WT�6 � assa �0)��b�,6- $8-week old&� (�Q5� �ry�%v� ��.|Hwa�[,( pH 2–3 )A�ц1 �|gentami; sulf�, solu%#�ek�+�Zl��l g9! irrad�Zo� 950 cGy���1�^���1076�%�6�H femu�@5|or9(E*0��7l�XReap��Bs �5�0euk�"s bea� con� {=rs��fl�Oytomet�b�\!�s a�� plan. Spl �n6�h.PAn�)oJJincub�[%&Fc block��<6N],2s�Wing > ITC-conjuJ� ti-m�DMb( Biol,d� Alexa FltB700vALeBios� ce�-�!cBMTpe�WNT%�!��Qj7 _FDw'E�ac�Zd�t a Gallios2�e�=(Beckman Cou�& � 5h )glowJo��$( Tree Sta06�:+ *@K�<f�8 "|X�/U�E�1a� ^piey�腸sEcc��ton!l� flui!�d*�on magnec. bead7+H�U"� [4�&+ &| laber%@PEB&Siglec-FJ1%B�>A�� -PE�ro �$( MiltenyiA�te� . �age�t�k.�%���#EP >93%=e� washatw��wp i85 × 1062S%e��.�00 μl �@ile?�� ��i�r#M��'AE�8z0P3��8, begine�dS �����r!� �l1W�M muno�dchemis����^$nT4 Rabbit �cl&8ti-�!�G( Novus!�log�/� r = mono.=*�;� �;, A� S"% &c-toS(N&t��3%�� . SBM�%-�!� phot�>�F 6= �FE��s6�@�!~�>,28)WT�-�M�:'hari !�t � "DaysII]fof� G��Oin RNA�R��QiCUH�*�%2 homo�ց�u/ 4FastPrep-24 SaHg aI1�S MP!�c�U)�RNAEf�� VA�(miRNeasy ki!��Biotin-�;R\�5R( c)[g[.� \$Illumina TA0�8�� xAmb�!6�Ref-8 v 0.� Beadh&MQhybrid%3�6�%�te�=dc" .�EJ�woV=]�LQB� . Sc�/d i3 �converAJto raw.�)7FleS|go v7/8.�5!)�`��+�Fx edMY P!�s�stA%�u�.�`$, R ( v3 .:_Raw� Z?�nd sub�(�,� Kst� A�A�?W�O#m�. Y>E��+Ce�9&w~ G�(Pad Prism 5YN.���-w�rj_A�ti�@�f %�!p�,m�la}�m ni\f megES-5do�mxordV2d origin%A$l;M !%�� i�region�.HCs�( a�+n3�jom �Uoof DNA2]`�ki� p�Hhu� W SHa'�-diP4 views:NA��b�in HeLa< s so�6� f� tek+�PWV�-%S p|�" or=�).s�spaat 40 kb^�]�fire 4�c�MsNO�G-�*"-D�D%�.$fork veloc! (E��s7 kb/miH1maximum �� )�K7qE!�3ana�_ K D#9_rough�. H"cqm%sMQ.�a2�.�M�prjS1Xaad�wA�^pU 9g}vsePp4gTFno Q�E�>10%�rL�>�s%�n 21� r�,./ lack Saof�dV(� %��De�q. TQVJ)��i_�I>*&ofYeaL I &8c5.+[!IB:|���!del�G!�eE�!$~@�s<4I�A�Qv.}? KU��5ing�Ek� Acti*�"�(l Te�a"s(y�B:,%)wA�.K-by�Dcoi�o�"IGH ll6��of�bs��map��5a!�(Ja!.t��]�+�������corror#!��B"s1,I��sA!^%Fa*t��.c1�lo at�O} � firH.����@.�)�ods�e"�-%�v�So�y inef%,p @�`�z��fMa'+\pas�hGRpE��aa/k ema%/q�V9 �c%�Ip�5, [pF2a;A�le-molec�S� �fyma�| ��%�U/�, at w-Zh��[��1! extprly�b�o)Gno!h �A� same+/�*FR�E�p6�N favo "]6cha��y�Q:�w�<)Ps��C"�?B���ebr=,% ��achq��En ensem�ave�IEAm� e9!M�QS�|��sur&&A��A . Nu�j�mB>� :1 such)� � te�e]�exa�ngF��]! }�y���G[20�(�>O�bI�h@,"� &-moe�etazoanM:�)w�Abar�P�$*�Cjp�;���*?techniq/!6� adja+# �) q\�as&� )�e��kAv4��;I� -nu�O !_.EA~Q;�disz;�l��H �� foci+0" "1Jk�+�$� <%5� o� @H�Esti��;u� un�-ofi� @mitB�[27QD�:�[Q6��%> �at"�l�ecu�%E r/l!�)ns�R��i S clei�^ �% non9�a� �!�3���3T��$!zcl�_m~wrriF>ent�;�b�R.�k�mq�t �)�*{R�a4 o��rptKK�� �aϕ�e� ex� mo�y�/oglob�9heavy+EyK�Y�ak 4 Mbn� ( TTR ) �conne�� �WABa ��ng�is���!:� & �0un2�G[4� �+I�Te&�I)}�fIg�'��!+dicdmFpt8�*�![m��u��<�9�A1�/ . 6E hTTR�aYa aZ��k o �JJ"�� �[8e�7�C�`4� �G*qEse sra��&� �a �;5als25e td�w@�N�:F�i���.�"F �] �j&��`"�.K� &A� �p!�g"��2�{�oR'�6�}*h&��&7!um�^�in 1d�x:i��Aa2%@f*N %^�jTan&�%spC;>�:,_ � � a2i8Nr./ ,v�q* d��) c������;�:��5�SMfa��F%U����. O����M�ed.�l�� E^uni�^5Z!MAm9'M� <�.!��us�?�?R!�<�8b�� concit Z� 1�|a�n�>!��"A�v�m4&jM� �F"O<.[�_R_!%�:/ ��e.���KsA�Ned � a� appaOt.�E�s . WeJ �q�� ,�=a�� @y ze� �3!!kuon��2.b\1E=SMV���'. A�ly� 9Q� �pul�+E!>halogeA"�}cleot$IdU�8��.�'Cl (20$��-!��,;Y , S3ES4 �7��4����Q*.�stretcj��1{lipi'1��C 5xa��(ti-��F"�"�9��sb/�%U"Q �'lue (%A)rgr��:= dU )�<& Ie7 gC -to- :&�s%�ybo��IT�obQ$A^�!�e%��added]<A�R*j= v��*�b.�pa{�f f�&dU�� �[co0R,be unambiguo�as�� ��Kb+�� nt�M|"� C ..�PF�R�a��R�{of4 68�3al�Xno  />"�!/�uPoutJ��Y� i�oD4 >#�I�&)!�wC+BD !9�A�"�$�`rr8( a>a�"��by non-wng G1!� G2/M� . 5ly�,4��er� in�lB16�+;�)"!n"t/ɡw!M �4N �>�u�5��1E�eV�B�dup_M�  (n!i�� ( 6 h 18�W�$��|6nt��9��6/�.a�� do� �:[1�A�so�2c cP( 22 h×1/3 = 7 hq��'c"|dhN )_y.]�C�2)�p��X#��2A�r�!�">����Q�a�nA�,�mQE%J assu��rando�Ri�Aa O�]2�M=��P<(�@ e"�t��*���"� .Z�r� & ( P<10−� 9��J!&�!:�%9ck!)%3O�5�(�#le S-��, Ȃ 3% v9��6%��� _U>VL)W 8' @��2?A��L&� XJ6�� .X�{"6 �y�R{"�bec�\� X m��%N&sEC +�ed>��*K^�R�ork01�N�;(% 33 , 54 9M�m 31-LY��#&] � S=�er"ely�2F.M .�IdU"�-f*RR�!�3�1%� � 3 �9%e5!�0%yG.y9�J| A��mY)�Nas�}�0xaAa8k�5� H1��g��too�$�Z�� �1cE3�GA���}��)���L��X��-ot�?�)v�)l"T V:�Rj"���|y�8�Bf�ra�� !�!�b��vi�7@�&� �min�Rs[�!F��$6�B����/��at��Rq0Y�L+&�<s%seg�#Ri���)inF�"�=�!alread�qp� �in].+��9!-@ �ur"�+<�[2� ?ex�Sr y�%(�E %�2Q4", dI777 i�to 48a�46u 01 2� "�uJe-1if�Q�LVPE�S1vS2��� "> ereal5p�z4!�>[&D%M]� ��mR.x!oY� e0� 2, �_"xPfLt� ne���syDyreaso�.3A�� IdU/�"�s�5��low�/!3!kingR� d�� d bU('JW%L gadUW�LG���� flan�e!S_2v�ntj�� l�N2�g3^to�y�,&�$�1�(TE��%,m� �� nM Fi� A6�6�A !e left��A)')6/�n)%n}��a�� #tN� * ploB�-3�r1��H:(a �8��!�v mI��marke�XB� �B� %�| 19��s�o�0��!�a`� ���m 9�H�f�eF� sp�G�"�!%Uthe�s�@�2��t�@!� �%8*�"l -!6� H�� s�#�d)� l�te�( 254)1//1; 6022; 99 2;&+ ,LW -squM 1f %7eI.��iB�tѢEA��z�H\�#1PTo�� � P BWPDvT S_?�)pa�=�ŭ"�%�8Blu*],HAp�a6�+i/p�(��1�!�d���∼:�/; i@B���)ng�ak�-���N� qrr���y (�� &)�aͫ6q ; iv� �so�Sde�їB�0& E� �o.[ nd 1U� &��� ����Nxd >�� �!%� |EOf�,D �!{ ���RR]GE2%M�n��6� rastJ� �K*� )�.T6� [7��'H"a1>s�v@�a�emJs�/serum�riX��� �l���#��z� �%Oa?.\% e a/E���nt3�t�;( FACS )5^iZ!w���A�\}urb��"PSF>���" prec�et&�&�1A�!p ��� �F�s�� 9����+�&h�.9�.!Kin&L,�� ;��1�CBDa=h �{��E�f%�aW�p�Mm&!p &Zeartif�nk� y�$�wo�r�gjh&"� zI7be�*�E� 1fA �[a� f7!y*�!m� :�=:Q �i���"�4)%2��m��� -��)A頥� omew�^Xo�4A�DX�wDusf�i�*��B�"� a�ly�"բ�!�10�4 ) [4�CS6N��5� �s�Ea���3�5)Iz&X$ �b63in K562 �E�Dey�.�[n�L ^5 u�M]axeby�0in U2OS osteohO inom�7( 5!" ��(�7nsr"ed MRC5 �( 4!Q� ) [5Jm�\� igui�,�e2�-�� � *��by-���K�n6/(%v�|��!|59�� .=�[52�d7±'3Q[*AV�,�44±66�-� In ye�/!�� choi�Mrobab�y4��se2]xMchF��6�[��N�'tcer�(@L�|3or epq�h�a�'o�X"R:&"N���M N!_24J �o��� *�physi"nD0|`A�uli [53b,5�DInd�i �-�'A for,�?���0n�})�prp� y ke Cno�z��dOIM)�V�rig�M% (of dorm_6)"Z �]2�#�[5�@2 �r =cno�cA� [Y �8!7�v#"�,�!u*�V�Ba2 -deriactum'�Z�( [5�@: i�*md;IwT�A����b:��6�j�W'1�6%�a}�)&�A�< ?"high-�w�L��) ,:�f�M2]� �u�o�MI/@Wt���VZ�!.*}I��*J*&BrdU , ��=!|. nase)����-] pi��&a%-n {!��;aT�aI�E� a�ya�yie�s �of��mi�K�%�Jx m�0dw)qu�0s�!v��3�u�9tuf� s*�. <�"`�:y�^a� �Ty window!�(1;@a&?� ,w"�& 9P! t�5) �QQ�u�<m�l {Ff*���| 5r1ʑ�A&S5hH[A��VU�J� 3fluoreA ��M�͇��5��%p8�,I�N�(� BnM$e&"0�� !�S syn)��we"���}f1' -y�JO"�3V4#�Kt�o .�)�!e�t�1�d�!$N( TR50� g!v�8fvJ-��9�=�9�)5z A b��K���ll�&p9�/-T�(")FR$� 9q51AE2� A% EK(��sY�d&Ti� �/�-�CGYQ"�2�(��/ntinu��Ag!{[no dear�~$n�6�2j mid-.z&�l)&AN?J~ �q��!q�A'2� ���@��:� 9[(q� �2�ea��apb�Kby2�Pr�%�?]ۃ � � >�&Ud��a;�9�:n.�_I�mov!gT ��D�q��S�*A�ex�X �S5�� �%� �|> ��{M�"cG2��m��inu� f.� n�'ed vi|���Fi'AgX�g@}.���$d�4-� reex�)I�5_I �* :ing.A$��eG�;&�5�yuHlandscap$��nd��leya"*CE�fl��& GZ�0e�3Ao" exempl�M15 Mb "`6�"�; S"��^- ����A sl�[: s1 ,sG4ow9�>0� m�>Ae�" .�2s�]2m>m6*چ�.�pGi�ly tru�� !p+Y}�4-QY��Ca��6llM2.  5.Kr8,!2s, de Moura Ilzk�R�ԩ��f�;.x> 4Q �HmxJ9, dt/dx�8e�!/WB!� !vauV so!l���r%)A�war/^8A�< I���o�,mˁ�.��sc��a��+ ( R−D/vm�abk2!��da؅aQrsE�E%=., dx/dt�=2�] equa�� v/�ia��I�~U! n���:J e"��Y!V*b.�!^� ��2�ni�6f>T)�mk�%�?��.8T9�K.�z �ucL,*� �wavelet��a[��me./ ob�%��Q!,n�?l,)����"!j�Iؕ�6n\ o)calEI� � ��B"h%�r�1.�imodul�|E`|L�LḪ-� �d�#l]dx�$t v�|�*��>�:!�AW/,1-y� �)�Jp��>1{ y . At"X- _ِX 1I Z�-!��e�� f�]͖� )O�x4"� ����rCo~8� )h2r.'%u�G1�9be�O�K���6�1CV$�>!��f�)&�\I�HL ��5�"k1R"� q�a31.,���&�=!C&,!��7r ≤�$%�, 53%v7=9���46%L2We�A͇ _��!��(o��er -�QS6!� �N,aCA;S3"vA����5< �k|b��}��baX�8�!�@� 0L���u�:J -�D�ס!�m���N�^.Q� &,.]u�� as 99%��mfQ�$�>�&o5i!���D&� Ye�stIcan)�� spec�,��#9Hv s��ksu ��likE� B t!uBP"�N ��"de�7!�h�H�9%"a"� bulk1&Ï[5M?!\seem�15>�&�M� *vL�� �}����ifa��"�,�6B�' teep�O�=4Q�Wq�IX ≤v�d�r6��+�j�(H ��o�vY� t-�:sށ_!�Q�!R6�+.*]9n��:��!Es5�7E�F��ed!�"�1}�e��Y��o�(:�mF6���!PD�^&� �A^��2� a�.�|.f@ �J!)M{68,Mͩ��he�0.�"kVQ ( C~C1Tp���ݕ� 6&<ATRA≤��C� ( them.�(.�4A–F��)i)+2�� �ag_<bQ�r��>B<�'�"� t��(O*� �(5=� 5�( �J)�AtAE�F�B��9�� 7548)� 7504 �&�A>� All 2�tMb?5E18%<�(9U�w3!> !%A!�3�02>@ly%9y9)�6B4%<57O4�V <> !{�4f{:9At� r)]��.R ��0��z�����{"�6d!�m"}�eS;�"d� 1��T�AL�I~2�Ql!�����in�}I)9g��!M6��7�TV�,/�iR���E>|�6,1�"�fl�q!:�efR����@�$!!/<8&��1r!��GD at�Y���KcJ�6�%�!.���S��48{5!KS4!�5� S�g2"�o3�5�>Fv >��V1��wo� a>�Km \ On֍lA�>&ismŏ!a�w���:��QQ �TCTR��it&�'�J�ni*iC_J�Q� an ���C 4 Ts�R��l�&���U; �j! � EU�SK���a� ( "�B A(�[/h�*2L��A�appc 'enough!!�<Vuk�$2�a!?7–8 &[6u�A�OiS,]ZA�> f�^ 19ڑE62�#Bx�! �55%��#/&�pZ�"�Bi% e edĤse�i)!]s<*o�B�%-"Y!92�� a�i�Hn~<ZBY*��,�� �y�1 15�>-:>��Z� *. �*�JA� Hel*��  �5 � be6/d��y �;N��,-9�IVYBA� ;"��.M 3Xc)%��fspc$� �*�!ir� J�',�J|m���H!abE%�2R�e��? Ja�Q�i�R�4��^51p� v W!ͺS3� �2hq��!c(=������!�J�.!)!�!J�OA�$����e�-��>�}4��ll �%_�V���"�SW *�S*�Aby.m�!+I62!�P�1� �u�a5����Opolar�(mv�;E� ^ sJ.[�� w- A and/46 Im�q�Lm+ ]G�2�a�&� e�� smo� miܭ�RKL�Y� -�*�1&-!#5�j� isG to 2l(&�;Hv+�k�2���'�P� � �!�E�2|ly� perhn`!ex&��;n�*r�>-}b)� i/alB�9�l�E@Qou�$9H qo&�Jly�Yuf�ac+<t k"�y�Eve |/EB� "�( !B��24A Yse�B�r:�Y�!&��!x�&�_"( �c"��t*�6y �� ed813>�. N!�)�s>25NWN��7 �0E;6�t+tr�N�#',�{a�,: R.�"{E��sEr��6w�p���DsteadaM�k@P�n��a maj�;ne*mi�)IIC� sE0��� �)� e%ae% �1 .�j�2nż���&6�DrF ��E.R��a�! on e��k )�n�݁�Eunɱfr���e )��U�S�P WGus�#&��2N� !. �=�  a��>�G.� ,v"4�>vS��v=����M�(F)�j12 ��8� uk_�aj�&��.���r]SH�*) FB� �6">1, 5� �MBA� 2�"$3��� 6�Y��E�3&9% �!�DF tane Éd ���ў�� 0 word��E�j"D 1c&r: ∼32&O��5j� E�at310an4.�r�K\r����>� >J(L) �a���M� �iu��%l&� �ۥ�e�i�gh&�BA1��na ;!7����I" #Ea� ūA 2���0vSa|� n upe9�&�:���e)�E�)�e>*� wŒr��7� A�r�7�>�b#� p&�ma(� t17[�2�R^AB0HG ga�!�A2�T6���L %�\"dao;��\��H�(&*H!Qy�i��V][(�Z�*H ��(pin *i�t ; �m��!"z"J>NZ!��t&�>l|9�! ��l���E��� o@ ��7@� we s]@_>40(�5"�|u�.�%qa�.n R���A< � . It�K:� jZ&����thi��-f���5� Fur ]$�!"..fx.�0]�&� q��.�D��f!�s5��=y)����T�Z�"�@�v��=�%��IiF�%9v�j�>*����>�,.�'���DZDa��y^�&6<�J&JaD�r$6إ�  B:4.�mT��]ix��h>�]( BG0�Ga J;] 65;�:�$>+��mܢ�us�:� 1 BJ ,�vE8ro� s; GM0699�1TL0��!� H028�� ,X�Qs ) ["���YJo�ry� � �� *� 7*i�n� !���U�>*�.te�sA�+2Nqm�*"�$c"3%!�Jnd <1&��3 ::-r�� ��%� �!�ig`6� �.Ha�"o ( 13�@ oe��*H�&to�!�%'�q�����(A]���K� $ ^<>=of �,4E�=� *6bWt�:s���Y�hif�k|%9at� �(���'k ee�Jf���(u��T$gUse� .���0 �<ng� n5M6��,��!r"�i6�M��R�t�F�cZ 1�AN,�in��cl��&i/(�5r& JQ2a*I!�õ��A.��_���Q ~�c�tĻ�.E ��E1 [60���#�gc�$JOe�a�yGMoum�<�"+�ch*A�*�)on �0&�m\"W3f�&&�nNf��*�>*"�b�d�d��6� )�UC.0.Nm�2���'^�'&QT���(h,A���In�Y ,�<�I�$A =��(&QA!��� �)[%A��as >9�~(2S >2O�Mdknowl3 �p�A >�sH �1� �A�f�B�.�1m*)V]Y�F:A�-�7PO�!�Y% in �Afi�} ( M�`eb�}fKArom<�[J06%a�4�fin JEFFN��BGTak� �|  ason%�� BJ2�!�� n(J&� �?�r',)�-e^tlK. �YE8�7��85>.r-�"W ��!�m^�yE� �n �BA卂>�T>MnB�S�!�45�EgE 6 � �H14V_[6�CA2X)�S.�mj�L�@J l�us!�A#a"2w��8_<6�f��1z� -����/0Zc!�� m*{� �i6���*�:��a��\2ni-4!�aP��� �4e1� FM*2 "�ՠ.��G�i �h� �R�%`�V~(��E�7 "���Mte�la^���u_)��6�=&A;7� .�/A�3���z.�y#U�A*��ll%�B�uB)1h"@ 5��a 1%(^���a��w2�mU .�""  .nMB�a�.o�e�6�(ir�it� oz e daqy� ! z s"�^8 � p��nA�HA��}U<�@1|o=t ��sq$*h2�I5�,�����In>l=�p!'m A�.hï(l-;DJ�\^V� �v��"��%��> BP-�pu>�B1�B�0h%fst �!��[j"�=��U_"�0&1Z� 3VT~)ut�.�0,vZa�!.BPE?� �)�s�@IW&� �I�����:�E聩m��%�7&v%�t f�Tl 2� tA��c stemM�>�`Q�H�s� !�H�H�;p2] \0�;�!�]�Ois :2�Gq��W�~�.� �����n,�0� �� 5e��Y��Vc+� J� �~A��2Q� .� \bi�CicAK&� �m�r= Cs�.H& " taEA�c��� n�YW;_L�]"�RJT�4f�"7;,�="5B'!��2P2�#;e}W��M�p� �mn�E��  ,� !��6�V~�1�f5HA ��t�m>S3 �7pa��)��!!�(f��&�G"2�� � +|�cta�Sh�E� ��C.HM�in!�gvA�U�!$qrcFbul:(��g0�/)g�i����ssA#i��+z N2wu)��%6HsZ2�:.�!b�g 3a�_BRu�1!�d'�7esprat�?2!��g�`aE�!<� copyO �M*�S%~G1:{Ja�e0al-to-nocTMo�End-9�%�E�!"O'�%D"����t��y�^[AIO-(�� S��@bGY��B�)�8�.OQx)V�5�n� � �8>�-��� !Ɂ2-�117wXi���ce-rof��6 �!2N&2�!!�%�:P3C�%%Eu��H�z algorith�"� ��a�!�I2/GG�F5aie��>�+ ( <10�HirataniQ�8ERRyb"�B�� o�"%��R�"�%�!>!Q2,Farkash-Amar�)�w�up�0�h��ac��'1��͌ �(pAmlg�SM��%�(ӯure�<�FB�$V*5,}94�a�*s&8b+.��A`�2��(is much att�}enuated by the use of four to six S phase fractions ( Figure 4E ) . The profiles we analysed in this work were generated from h[12] orm [13]jof0, allowing us�Xdiscern replication tim!@differences withi&g�that �Dmerged as a singleRKomain�|previous studies . Furthermore ,�$determined%N full�tribu�s�Happarent speeds befA(any segment �of !�genome)gse:O�continu�4, not biphasic� hich impl��Bi0in CTRs and T �il!degreE,arbitrarines� When � lineED6Eas �g�r-� �r-�de faster ( resp . slower )�Hn 10 kb/min at a 10 scal!q= was parti!fed�Ptwo nearly equal halv%� However ,AGobt!�a set!s%%(4encompass <10%q%�would ne!�oA" threshold� ∼3�$. InterestAoy�\he size range ( 0 . 1–5 Mb )%�meaA�pU�E; ( 2 . `)� such � �bb milae� thosE�ora�in�oA�U�4, yet mostly i)tibleeL unidire� al fa�progressa� give W �measur�hDNA comba�0in HeLa cells�Y5Aa�nd dataE�shown�nIn nonE�!?B�A  yofUm��s �ly�on��molecu��-! same � . We`ri�believat< rigid dichotomy~.lse5hoverlookA>he exist���a broadM� ��transE�a* pes , dueA� insuffici�[temporalaWol�|AI/oM��A��t algorithm-�AܥnbE6lacedIa �� nuanpictur�!Br]�kinetic�5Although�9o%�exclude aiivabu��)�ioAd)2PofE�<3�6C, ��E7A3i�!_BC.�$rate alongE�c4�{Lis remarkably high ,PA…+a-� areA��tiallEe�I�X{ve firG0of multiple oADns�Yi$of a popul�. This� alsoXca�or K562 7. N�� thel����observ���er�A�a#hѢr=�eP��sE�tI:�onJqWay� BG02 stem �,A�� oA�$maller extA�,1$fibroblastɡlymph oidF ��%/.^on)�!�erg.�� s mo!�Ʉtha�靑.�n!���y% @Desprat et al [9]�heA��E�CA )�%x�!�eR:A�2F��,strongly sup!�IK5]��z ig�4human IGH locua�E4experij unamb�$ly demonsta�a��s�:�l�%� �� �!� �ES%�����V��  amA� evid�A�:12!d�$he homolog� �in mo� l�BTM2 cytes [41!� [42]qAbehavioraJaj,-type dependI�h"0Lsince abundant initii�events�  c!�.>-due���l�{stage%� �B� develop%) �We foun-�6�!I5�n�\ a 44> TTR wf�=3 . 77�a�aSj�.��0significantly� eereY�FQin�!�*8AWżd�gGto%u{ %.�modŘt�/-�(� 8�F� S4b�"43J�on 25�fibers%�a�pread�� a >7ɡ s)���!�% �S striK � �a � F. Ok� outm se 26� M%o� � v A?rk��8 )a�.5��A~cit: $( 1 . 48±� 21Y$N = 38� i� -��� "!� 46 . 0±5�  kb ,= 20 )!�.��(approximate!a.� a� bulk��!result��Z�A�� ise�es����ve activi�.�1����H&� aconfirm%�validityG���� an3��f��� predA3ngMZs �can� �N\�N�. Toge ��A�1EofJ�,#yIF�%TA�p�ky�e���can ch� accori!oe� ��,J� O Q �'��3Ig��*S��.�r��ri�f~@an adenocarcinoma�&: r�=�.��bU&�m non-����a� it�Y!�clear i�^ I� � norma2�al)�am)'�tum� na| �!� f� checkEuQ? of b.i )^)�ng:�: $took advan��A�rec�*w�Zof Let � & 58�uwho`6�in��~� � revealE� spec�a2���E�ams��0FRA3B chromosTfragil!taA}�0r=�� Y of Hansen �A4m�in BJ2�e+ ��s embeddE2�  -ung9CTRi�i� �� o�e�syn�n 9�z��9�B�� �>}�>�. %�entir��y��a�,%�y��>$ l i��bu�all eZ"� MRC52I��9B�$In GM06990� *  a}!�)�-y ��� V-shaped5J�-�tro� form��uconverg�� , each ab�1!� in length�C�Bot�1�eA���r sAb6–8�f�6y �m�8"� )%ymax (� 2F)��ł*sI�-=�by2-in JEFFVoE-. E!� se%6%+ia 9��I���v� !_ in b!1" � A.�� *at�c�9`up %���NA�an 8 h"`8��  princ�-�9 ^ v!���}if��traverby&� �u� 7!wo-third !� timew its< edge%�one -�>,�S +,!9c���p%:6x"3 v/|R−L|� 2/� 33 6QS(�[S3I�*\�#scenario Z-� ����se!cs +9�ei� very �or � in S�,is�e2-nm�f�( see�� BE�)I.��er��ve hypG� E� ��b/7l1��=JDa�>��q�' ind���2Xo��&smiddlrrt%|��A�d�M��9 �d}a 6� ? cor�on2t%�5�e΅ . Forks n.�g� oa�e�4�Sis�� *b),�R2�p M~�5o9)nAn!�ri�pre2�w�u���qxel�ic�%!� ivid�)��?!ui� i�E� +;���Hoccur��t poi�%eH .}�Srde�quanti�v�� expl�{�@discrepancy betwe�� slop�qf� vel�po������sh�� �A��� –2�* > ��is ag�. r�~ e6�t2 M&�e v:� �� �� � Mesn&8 62] hav��a ly� & d a relia�map!w�c�i/1"�h �y�B 1�u � veBp��ion-bubrtrapp�?proced�toa_pa�up � lib;e�hybridiz��omycAcdia��el$ds [ENCODE] microarrays [63�We� y verage�6�by2$ �"!Q/'1)�- 10A �R S5�� Most:n�:Z u^�oposal�`�ePe -�r-��Jq� ��� g . � ENm001 ,�10? �w,und no majoru�c��tAX � c1din�u22%` � %v ( 29/no�hG"uJN�Ds*�=�j�urpriE�because�:� ��%7M�� �di!t��Z. S{- �= �sa�R in:Z(�Ѕ�"� A po�ial������J��Z)')@��elyi�e[perhaph )th�re:4� �Jd��ali� t��on=E��{ma��amdwello p anA1��r.��� �!�  neighbo@����te���imp!�qanv lar fr���m^��byJ��͋� g� l�a�.;,Y�o",of low5�cyi&�cs )�uhofiV!A by�]rt RNA-p�!�nap t�=�� purifi�λ exonu~�ig� 0on ( λ-SNS )ZCadore"�64�hA � eA�o��st���aK":)�� ^mA���M�)qZ} 95 �DZ.����05��.�71!H��>dinm`z�E��I�R�Eo R peaki�E�.�&#f*k !Ve�random�e{N�. AA�e�cz � 4&%, mat pen�#! � crip��al��ha�7e|"u�%,, [65]–[67ATo exa�$9�ydetail-�`��he�z%�E�n%PA�n�{$$DNA�Il L !v�sj$ P S3��)�ai eque��WCpG isle/D#!2:ly)e=Iavail� �F -wid�~We&EE��Q�Imaximum�%��� !�steadi4 ecre!w~%go�! towa*`E. 9y+1���.� grad'"� �Y-�9�re un�d | der��5!�� �nd�o��$class�"sug�{ng�r�"q&cha��eristic�%� !v)of�stn�j�T��rai�he� sibilA�1���acJ kuC46+��!��a&A�9K!Zid�O%�%� me!Qism reg�!aCe\!:�$)�known�s����del�-Bun���4 �s�&w r�9!�"proba%%� �fir�$ ocha!�aa; 1E#�<b�vinI�sFZ Thu��4�lik�tode=i"� � weak29un:; 4zbec��j:%� eH_[19��h^�� o'p�e�Y stru$%*�Qge���ZUhJ��2�CBGirAB�� �)މN)!��y�ith-d2{hE E��1 )MGweI�N�Ec)aA>fbW���[)$of eukaryo= &�[2"68!�FɼE ,�a�/eV!�.(%&ap�nt2vR Iat}}&�!Qmpr�" #s�� ��6 M�> �x,,"w , argu�sXstN&u�uni��u� � ed su�� l:6~ɾk(�nb(spa� ly. .* po��lM_� Ys!�v"#l�J��a�A{2;�c a&� ir�Sis �+A �underly!ZyQfeQ����PIa.�A� ��a� in"�i m. A�,t>�pal � ��.��MB� 1:�IsG A�el��� ��s stim�h��"� in un ��-�. A� scuselsew�u4'[70� d� h&K�*)R�c supercoil�< ron"�!R�" ssocp%2re� ;(s+) trigg�factor�-�i^protei_E��'��:foci labj�� secu%�pul��C�qrav ]sI1� A A*�ed {0!&�;d �(��m!���valS�s [36��S�0 } ynamic��PCNA � m�*a6��A�I��= Q&_ i* mple��/.sit�/a new21f�( t@)vo <.� B!#.y&a!ino4ecv E�)�of2DI! � [3��A��rY%�i�Iux�N  � 1�.%-%#li� de-by-s �Ei��9� �M5�%����ir2" hinu� &g ��� al?�*�0a “next-in-AQ”*�def�1EC� cyIq�1P��-ved E�h7gun [40AI!*""g0:�2 " A�1-!�w.��asdatp!Q63casca ( ��U);�6J2"c!�doEm�d�2J@� � 2�� firsA��f!�5Xt zUof var�22B an� )��&J �, fol73��5B2flank�c ��Y�@ _P0!xa~'ach�a�c! g!k*� 2]"K ��$s why adja�y tend��Z &�"32.F� *�-"�,��A9�*[# clo��e%@z0~"�Q�`Q��o!.�E�r�*em� )*�!nM-!@ �\:� �M��;2v{S-\��"r u3.�i�>.&�� M��1}AN�!2.D%polar2�seW. W|�&s� al groups�P��2k)�3s��� &-*WaGFp+ es!s�0� S)�a�of im�[*urr!� us [71�7jH���5��o eg� ;��2Es limi�'�,s 84 !�typicte>�E�jo�M'*�5�v<26�!ng ���7�D�)w spac;a_q�� , Xenopus egg�1�  � F&� ? by loopA?a�on"��2 �%%r���Ew�-�] at v,"e�2�enh� ����w�-!V� [2� (!-, [75��favorA a ro�3f �u?G�rol� �( �Y�,I.�in yeast�[�� muta���5i.� !1^�lo� B� �!�|� dela<.��ung��aie3p O�e� h!��X ye� mammali�+�73� expo�&l0aphidicolin-ac"aI 6),�*�  inhibi� r�$!�.:� at.9c_ ly�r2�)&� e�abs:ofnct�e� "{ 5onE�F%�(> ` a�k.?m�)ct qui agA�* glob�!�+ e�7q3.M�� does{b~iIPnoI�� ib*o!�#2 �,6��� i  �� �� su1lip-�..11pɈ� secondaryY� . r)&m!yb6��-�Z� pereV!.� � �%of)�2�aqE�s"i�+�>�>F�,c!�V, mathe� � {."��pro?g9!bby mas媉\�� wELp�!�-)bbioin�aK ^t)��a�&J &�  !^(se�)�i>�9�^"�V&� mann� ��a�6L :; , i`A�v .�*�9-�vs�x&v�� B3�8!p�!rEw�` ight�%*lef mov�&I�ehP<.�9)�:�2reflec�-e pat0d)?J �� rA[r!���u6q&.�.�-�c-�e^&:� ��b��<th�commo.�environ�6�<a"4eof6�A�a� 9K"�AM�� nd6K� �!�mc>L�w���pl�A$iss>. Asy"h/ly� w�HeL�>"�ed!� 20 �@��:6µM IdU ash=1× PBSM.?a�(JGCH. AA e en",@��9o ���harve�H�Crypsinis��, � rifuCt 500 � �A�at 4°C�!C ce-c�@�2Gtefix�80% e� o +8�D &�2M.�5 �nd��s�9�8��, 2 mg/mL RC67 µa� idium iod��w fi c�n;A1of qA106 �Q. C��%X��2m�� rtA�s S�% S2 ,��S4 ba��ir�'n  .�$exw ��fCCencaps� �)>�0ow-mel�-* ,agarose bloc��t 6!%0!�oD�Tval�:per * ("Y&0 f�S1%�3JR9!���' silan\$slipsude� %[7�T�9cI��,�<�}A�_ CldUI�K m3!*de!5E50%�mam!� , 2× SSC]�80A�. C� �%�%1 Ia�>hamberA3i�at 37A�$ntibody di�Abu,�15% Ta� reag:( Roche %M 5% T�+20SQ��.f�B��U incube��<"�:{))4�" ion: 1/20�* �H-BrdU ( Abcys ) 1 hC-,&5 chickea�ti-?8Alexa Fluor 488��* /goaS,9Z0.8( )%�2�5�7E �.x350b�r :Z/�3 ) To�"Ag� %H2�c&( Millip�U%SF!F�594!~J�m�I�phenylen}!�#asto= at −2E�"lHo:. I>(U�( excep� ��step,.ai���Toom�erG �;>/���b$k.*! !�bo�ex/=�� q�ca t%� of 1� (?I'gM-!� V)u9E��1d 2"F�se;ed� an O�Bus IX81Ra�run��$MetaMorph i4�o=3r7Aw�Far DeviK�S�0http://rsb . �  . niagov/ij/a9997I0009 .�%Adobe) shop �B2�.�EVins)��� Excel®!0h.�® ) �?she�:n� al% u R (�wwwv- -pro!� . org%mS���� � t��/�š�hadA�i�eff���._. Fh,�Mb�'R*X!Sa�"!�M2�s�;fozm�I"Aa �Fgrowt� [7cSeaV/:bof�e��w�A( )� am�Gj� st employ��numer�:c4+ab�;�H–1Lm A�TQ7 ���  "�J calcC � #>{dor+�w ks��sJJ�-,1�!�%x�ub%�8e ��aoog6#"�.-nB���� i�d=uA��  �"/ > aS)� ab)G��)�eG DaE:N)�� � w&M�3 fosmid=04G248P83284G6 , 783H111611C5$�( %6652F433525864F6 ) �biotiny�+f+?-!�( Bio eJ sy�H,, InvitrogenA�nd R�r &h2�2A;-K!Z2O[7�FF-)Fe�$ �� ,. ucsc . edu���) � .bacpa'chori�{v"� ��� H sl M�a�Id����&��"L 6�I&Ei�&� ;s:>L$Pup'to FISHjbQ�+:�  (� �!�ithn{ � 1/252� [ conjugB(Streptavidi!# 1/5064-s.&W� !&� � A* nsM&0 W.A647X���O��� �e>��3��d S-pIT.n by f 1 cyto�y� �"A�: |U�?r�N� 6��� [80]I��r5B5H�)a�LB��#-l�#�25�X�Oa0M�� �*:�&�s�>P1J� !W:(N� th�SoE�� 4J5� (� �� . Sa�#>� o�(CyAn ADP LX ~kHLCou�&�NZHrr�.�"8Iin =�!u�^�p4&at�e�c�az'- "iɀ( ��p/ fluo� ce≤1�7>m:S4"�3�o422H6W�-�@� &2 5% ,=  4 . 65%%�1�H%!��E&� v��)Fw. A�c��!2_�O?i$(#� ubh��*.=l`B.VS�k��24�]J" ap V `0EDO}4syn��9pAɥi���tP�;nV m�B/q�F7��1�G FACS�fi &�B, !�15 34 5�� . 82%�2�p��<oG2S1�S4%GQa�e2E��H;.��%u� �-l��qdHupWK(E ��6�a/ umAIsm">2�S4�@���a2u t� SH �d0!�eU.U� ߍ�'v�>�+& � g��UWA�: TSiBQSi/VGSi� QSi�8XG!VQb�, 4i)!�.&�Cr ��.]!b�as: ��N109×P��* �(N 6|!y%ks�@aNtA�A#.S�foR$ch5a. �XU�I�9�M�0�6.):�n�1 �NFSi×V��+1\.�R M��垡 �S deh5y× �I1 g-�.� :v;�<!:Hs T �$ΣTsi/ΣQs�In%$� @>K!�6� ar�#��"&#:ha�$&�#�V #HFa J!lX�5(xi�esan �5 down�DowhSe�KL^�,cB1*6 %��'�irr��FR-9�L 0m���>N<)"`$�5v�$dt/dx P1/v� re v^.Re�� , upU � � ��0e�J� �"2Z�−�E�-4�%0-�:W.+E�is�,by90KG ) /vqt �')4>���'�"ll holdM@M%�/7"F8�<l=&X:% j8A( "�'�!����!4X-� �;:��-a�u$ [}�G&�[�%�("|Z [';"�9Zh+ �$ �aR3�(�#^XCR�Vm�`3sJBu:�com�V{ NAuDm��@^� %R�19N�%5w%�%�lFor.g �*� g"�!a�  �S5a��"� *"aYC�_�-q�k6�1_��m�,�dG"oDar�YlYR"4" .u>��A��`�S3 4�6�Pverifb&�9 of6F� O �.p-�Y_105�� ,6V �.�[:2�>?<�Aa��Gq G2re-2� � 6an�D:�C=e��",7S,7M��rol�� ��A2�<!� )=C�8enrich�%nica�ad��3 6^ to back�+��qJl�MQ!�0 M�%ay"� (!A�vale!e0��by �01S+aW �7� ;9 . TRu,k yaZ�!3QS }GI��E deduc#�a� �/X!e%�!|.�$ histogramR�y uMX_�eda�-,metho!��}�C(by Bertuzzi�R. [81�*We_3u�&E"a�ve|>alDS�] �AU� �jN�@xa0y �M�eA_�Lφ ( x�c`e���W1`1� WfGauss*fun�14.�)xa�� �qu)�( 1�in �) �6�x��ɹby: θ1�RkG1 l.^Aygr y-��A %�Z�c'>Q �G1;� termA�rest!�%��"t!�]$�R 7 gEb UENGf�\a�bF1>@7yto�iz [82]e�5ex�Ea�ñ-�.Hita"&?Bc.�utili�fx &Zba�&�"G�(�UI.�:�%� Q<:.�,�R"�Ge�A�.���e'2 �}n5v��� MTt� �)�~�Nc�:!����w�X!��B�� R�-Seq tag�\r 6Mlr� 3��0�œ� auth�8#M �am�%�!㥰�`)H��Utag�!in�g Kb window�!�&(42�6E��Xsj �_)�-w�զ?c� )��u*�ai�3c�"t ?hic� o�����;>� }�fi�>6notB� 3T crit�+ly biaqUnA�CQ�)u\Me\ �W � noti�~%�n�-#"Í��/5�LN�l�s�#,01\a�= to 0�Z�<4 �fre-%b�bl j�a�*�x�g1�uoDI\�9cA �< impo�� -�*alE?,�/�N much�7!nJdki�on�q�f assuEFa���of�Va�a�yar�-pAt�+.6)�\.)apJ�@�  l�;intui2 Y �[A�n� .&:o.�fa (:61isyu�%W*��?,#tly�ak!G5 �1���-&Nmwavelet�ns'/ ( WT�'�4werful�yme�:�GC robu� �A?� b#�9sŒ �m-�s [83�584to�� a VM�!�!�Wst!���v�loR0na%'y �6��%�� ���t�Da spac�1m�Rf.b�3B� SG:�M: ap ,:�L�-d&vna7%�gu"�� �!I��� � .�kow��?�j&�m(*n)%#�<%�>'.�x(!�6-k�m"�  +. Sj %�a)gA1�r�%ev` �GepBrowspd��Uni�%tWCal�CLnia Santa Cruz ( UCS�[8�6A�$�!�'u� mh.(T�?aMarch�$6 ( NCBI36#hg1�cyF.PK( CGI�&��4i��in �tE�“cpgI�KExt�>�".d:,�c|Id-en�7dmW,a[=-L[h�!a��F;=��D. I se�iv!WmNd2dTS_L�[=@ Digil O I� ology [4e�[4%�Dn9�&��to Rel�K(3 ( Jan 201e-�E U UW ` I HS��ck%#Iownloa!`" EFTPQA: f^'hg+ . csE&h",/goldenPath/!�/q`deDCC/wgEncodeUwDnaseSeq/)Iplo" �-!��S�LHy�M� Si(( DHSA�itif�as#a sixfal�PsWyty�of�5%i%�.!N <�$F� Y�HotSpo�b�n(A�F�P�OA�E���co�da�6PB.Wob��%/2�6~Ww�t-��!�j� )X0. POur nerv��$me*Trecognur�*�spiT(�#A�Rext�Z�@�=�`s�9�� ligh>$�'�p��(!x�r �Eh�A � ���M�JinwKI�e�M=earbyloiza�#h]+MY� �ly�y m�-slo7��GR�or� a$0"�� studP qu��8=fpI�“"�1��ABor|N�4%�be 4A+=�heF>%Ibi�P�� real/Opike-:#%&�Sr�r���-ho�I���H�i� *�%�is&�#6�+4an>�q2vr%Ji�vmoaL neur�bzs �pm� Hebb2�egA�5�>� link�2!tra�ul? 6n|5Q�m� lo �ne�� we^)t-e%A� � Poisu0�,9RJ�&%�� –dB( p�pic�x( STDP&�al�$\o . ByI�!�! ~dy&�GNI�5��Au@"�^Ef 6�;2 2` ��a5 releh� "w8=nvo3��� I��b postsynap�:&�AE�t�$� e �:F �uaA%�F��y�a�Y9. a��r�:!SB`&8~2Ahysu�� �/in<pime; . MoreoW�t� hCEl�:}QQspl!�i<�J9�#T"y`�onN� �Q�M$ Qirs�w�ir.Ar�l� inpu�at�ia��ae�0l�!6theor Bd0J1�.XBI�A[�KFA�.ox�Y/O� A{�>a:g# oscillatz2Q�. �5^oy5�9n�^�Y�e�9O?ca�in 6�q�. �a�ၐvc"A?�l`vNK,�4�-r��doubtles�:a�lawage�l0yda8f�BH"�Dour brYausu�S !��!aski�Izastonisha � E�wS!e sel�Xaw!�m�Aulex�����Tl�uom�]O\)B"A[�-�?A�!�64��^,)" �b�/!�� l�ti��re�4o�(,!n qE.w!�5{ �:�L�;Aulto va{yl ��"Aq)atJR|ome�y� � �FFBamx|�X�����<�P�^,"�#"�1�&%AE�).W)@<]g to���Q�- �u� A�� Ped1T�o,q��> EV.� D �-be ablis=.+� �NGa"R)$4IF- !P7'a�fA�m� Wa�a2xoL9�*�>�itkam�eFV�g�.�n��Vor�[1or:��lAtT r�Mbegin� �H&[R-���. S�R.xm� be g�?e�gQq\��e x�D"+(E3a� 6�;�M�bea� �e�ո�s�z1$o3"�D'{unsRvE�#iH�Ca�heuZ2< to w!rI�i� �bejZ"Pbe���eC%U��!Rc�?�L+M�;��(epE���z+ce peye view%v�H.�Xib�3�t��mo%� �O . R%�)&U! goodI�k��n�E�� s6now w\$als%���he gia  �&mp�E Uf��g/}�a�e�M!�� a?b 0v��� ��)��"asoeDHen��3� adap'Co �"I��^r�hv f����: U�f�-�2� � U"!"� p"VnAEheV i��a!slM�!�";s [�.OHsf�-c��it 6" ���pur9 �na,M��2 �“:S A�A�u� ��ce1���c�+M!Q1�e��#-�minim- .' 〈·〉t!%��$!�� 2K�n��?v�u� triv0i�!a#s�]��5zero-m�2dE unit�( t�A�2"\H+^ is&8� ie�o35 g2-#�p�ymc � )i� G1@i��$9m� %��y�2�]w�05 �7t�<�OF)�.���)/so���er�Qmv�^!iAzZ�i�!�&T�4E�:�p��paxF��i��j� �� �%�.E�� F5� � �1�R�vJ�4g , ro� �5� cuB'!����s��r).VO��k DV�iWA"�"s1U�f�/s�cч .�]a��sUqA/�/pro�(K/#�*e�.�.��^��Ite6�&A �&� hier�)d���6-E�a��rse%�Y�5�uat�k+!bn}d`BE bmd?���. hj hippocamp![":�od2 [11]DeR*- +�s�if�ingg�fi�H9n absbt�!�"�M� " �'IN�.� D an.(L� techn6"! ��6#; � au��G �art"� �eepP cano `!*n�y se�1� odw8�q%�� Z�)�#l�ought!�d�CIa)|Aeigenv�G��aflrvond� $�B-?,!Ico��matrix>�> mult2�  0"mK%7 ai�7���� oe�&k� %�)-i � �WeC!�mE�). �"h ���� tJm ��*ׇ)��� HRuen��Y�!��x���!vU< e�+Fhf%.�mputFAAs� !!�ba aq*�6+��A3�o�%#�2Ml(�$�!]t��~>f54��Ĺ&��/�{&�t�3ڡ iF��A4)�!a��%6r ,% e�IMx��e�A� +I����� R��I�sa�� �Hm�� Evia6�&�5!�og e�s!*6�Q���3l � ��e��"0A��4ar��b*~�R�.A��%�-(i��a{&(N fw�rll%� ��%r�i��Vgo far�ma)to�E�/}? Nev�E ?�:�displ�s:�h:� �& be�,E�px=of�*�� :E��B9��Wy> 3�&h,�(a��M.�.�[3 #�Arx=%Q�af�� f�u[3h#I�;sz�s�e�;s�O�mr �#����LeB�m�� �jg�9�\U �[p"�,ck�` . O� ��*{��E>m5O go!i�u&��I*�)�td �1�%w9��qo` O��V �g ��x`:f�� �c pnlKura��%�!W:�?;k!uhA�ar L ��0h�-sag":�Du  �n*�!�fT� t:� m�squa� ?"9*� 2��6?G-%��g( �Zz >K2� (=��6er\#�lE�fX an@�sIu�� a&J{ 6��biNt  co_&w ,!�� � �Tln� .�%�3NY N : "i&E�e�l*.�:� &� U�ryet]m�sa<%is� � ��K_a� �CE�}�^�ircuitr�� p�w�5ac�!is&���"(#�GBp s6&n �z�*��%� K6� q�%�A  J A��A�,�})fH "� R( [?�� .�.���*�.RH>P on>4&�7%|w ^�6�I8po.$trF7*:�,e 5na�A �@$hFQ'%y �a�@�%n�?�j:*!wabola �ide�u�:��/s%��3��}��)���> �i_F\A�"Hf�7[�;)F�bB6� .V QIJI((���n�re���\u5Jecu� 27$�'nd HAuA2TH�ar� ";���()�<F���  �%e7at nOm�j"d�5�� aa>A � &l �n � mble-�!��[u�op"S m�}�2q.+aܢ� �#s)si- out�u��#�2t7Te��  |&�&* (���& EPSPAQ  {�M!cc�r"�jm'I� ��*2s.�c&�G2�. Itsm�C�&j8 �: -�du6��A�!^�z�z�enνf�, V1 �0��q���4�enneglig{&��.� P� �s�P _Vi� �!"��3h ���bsol�&e=st quick*� � '- �! WF%xym-;i[�e�ke]0 � or la�!C�W�0ti>��6 �>g p"�param!�sAd�a r�6M#җ��!�width�a�6n��!�� �. B&v^�)A��HsX�q�E2x�-I6� ��B 1�u:� E�!� ensa7�é�al>]{�.!�!xn�"�$��rn�.!"oKm� �)�!�i("�4�!�9�Viv* ��Q��W `a\��'!>und�m\�A5J��� rWte?29��:inguish%Z�^��er�.)�r%� �FuXAge� �%��td��� �(�*�,*�'� B( %(b�{}7[ac�qgduD�^�2"��il& �)E���>R������+� -� 2~orh(�X!�EEX"� beJ)og,��& �"},!N�8�"�>�"q8b.:����d#E�*>$��.+��as�%==soR���9iP$92�����y�S�m�6`. FA�%9.�*��intrinۦ5�1 �5� �E�� es�cr�a��}�0� QY0B�EpT~��c9B>0�� "<�z�+!N�:^2ig%<vee&�%Y&J6A69��s �"Uj���ad�3�L&���rU� F�A���+su�FP�|�:��gu�w� $g�-l9��5�6d��e�� a�A&2/a ��U��4��2�)�N9pi \up �=/whv��^p� /2G��J�/�,ae[.�M�4�ug-dN�3"�/N=pt`��!W���ѽ��c�A�#I@ e [38U3�No*�%.� ��neparv�� 2�ct�����ٿ!2"� U&�I!{��NA �>sYp!m� @Bd>- u�����G0)� )�!� `A F a,iS��EM&.}�t�A"�)to6�,��ѥ|a:�"�72Se�ta�gby KöI�!@König�|�� CGrs�3�K�a�rng�s ]�Ua�5&�6bCDMP-&9 �/�� dend�c!k$x~E�P�j ~L*#be�%�6$�_�$� K ��evoke�kP!�E�ap! �� "`!pyrj��k . Of DPA�)� *�0alW�{J o~FAYE E�Q��h�"��AcHg2�e �m�a[*�&�� "�%white�I���F����&�,.�}!��y:�on@expanJ � oB � �A #4�> , ��< :"iz;!+�5aLn�tD�-�ic��orM[Ex�C*D88pxA; often mak�r� n u8���.*y� ��/nel�� su�!�o-53����tY� ( cf�M'��2�8 ��raDu�G9 hHuJc[A��1��hn+56A� M!c)�J�-��� � a1ob9�� @0}beM3�?!-+i&6net|%.6,Q mYsSachFC�!0y&X-xamu)p)���i�I!�ism%�0 sui�0�q��7�a�\=2m)��5 -M�s�or"c%�O[�.�1Qof&)��7�xpl?�&�wa!5��L^rMj&�rI�a.!��!��j>';xS�R1 "� ���?.�tHa��H|0&D-N�#-en�P%�� { �!� @�Muhe�s""�'ergoda =h6|?$"%CM�?|-8��bee��'94Z�c͉� n&�st�$Ӄwh)Z�y�en����8��S�!Vo �!&6��7�) :�Ls�f�-EI|iUa�h ship���g� K!�x�n�{al y���"� FzH>�!o��vSC �C�2�H} *=$��%u��c�e���7�!� �*� [4D%�q/&!). ю��CaJ?�4*�ja��M� q�s&`;Rsp�-"&R RQi�)Tlos�F� �b M�4�%a��7+pp���N!A�%|b�,3�-�o*-*� 72� �&35QmŮ�e������A��� . L&�dig3?a%^bi�5�$w�M�$in������l�ng&7%pׅ�+[�l4�&�aU���)#4�&��C"�-�ɽ"w[1Ŕ�A&a &be��)�l"�)�7�fB.%xA�>�&:!Xt>S3��!>�RU�s mu��%C��geF6:�!� v��������gn)hg,c 9ul;� ��ee0��*iq�sR� f&=���6���a�gɞ�D &e ~@�! Bz%CJ�+�7�/�a �<� �/t �A> nswej/A�1�a&�#�0ME'-yG*�]�/q"�s%'o�9z� ch �s(0!$� � e�s�)be� � R��u� bF1InTiB� c6���"I��.1�!i�(׀5ri8{�*� �5A!���&)(� , 72!axX7^<^k# �l:�i)S �.��9dHB e6eJc�\ !����Ms;!��Aeer\@��� �:tr�+l�XE�//���͹ef u� :�—��2pa��*9� �C ��"9� ��I&�/�f�����sU2n"�*8a�!�l�M��go�" ���&�I�"9���vS8VI {�; ~U�&�%c+[@:< :�� `.S l ���,�'��W�;a&� �Rn.<5� &�0AB��ly�4F� 1wanf\�����Je1�.Qlu6S-��G�_̱&�v� p�(`�onK2�2�)�k��&lyF mSI��*�(��2g[47�>.�UܖŁ:&�! ac� d!���!�cru�5��A�c�canceE�mn'apy fail2. W�� kE-"7 %��s�t��" ubcl?���nd��O h�"����W�&cu��t�ro�t�2u y� st Cy sub-~'�8cti��Z�Y�Yd!��8 s �&PȺn�wre"4H"� �R�?�s:?R(}������ !i ( CAtXi01��i!�(-1t5N�2�2;�:ex� L�!Kz�_0a CRISPR/Cas9�lk�>o�ginee�H %�~ di�Ve� -�!� lung�( NSCL�Vv���errA�ٌ: �Dicer�)a�0$e III cytoa �]endoribo_�lTinv�%�p ��� RNAE{� C moni+� 6�A�z"RLڍljrtly"g�A>� wild�� �f%"Yoog� co-cul� 2+aA�/: te-fNanoC #g<ua�B�!�T��rugY�"^�B�t�b��^."�n8A�>�s��&� �2���{��� monom �s�Fr!D� 5H � re��r �d�|fR!�me�.��e!% '�’�:'t�Ni!��(:� WT�)�Ew.�\4- or benefi�(-A;�%��#e�IdedU�N)7e�A�!-�.��i�V�"b���6g�|�'�MC �?fi�Ao7&~ne�%8�09 vivo�Y��)F1"�cli <"J6tߟ ��5T��tq%~�u��m���T:�{"A�� �^no��|.���ly-m�._offi��%�y����Q�fsw4� �u5()!�,�w o�6_!�N2Iyng�~��c1�n$�~ś!�thwart Pn�wFN~�`^A�AWg�(�t2O>+A�IG)'OgV23�o�ign*d ф. L��j�c�&��?-r%�d deat:(F U�Fd S��� �����Z�&u��a���Ac���caAo��yD[ iRF���c�E"��R���of ɖAn[�!�� L�� v"��ow )w rap��E�m safv ��p&� t�6}} ch&` :X��;ly�S-�C�sM�s�+ ��c6 ic d�r5�t�� half /N s�QY<[� ATP-��ve�B-3hg�ofent epide���#;o�2Zo��%&erl�i�gq�it af�� osim]6jsӟe/�Lz��b-raf!j . gvemurafeD, dab Q!�UanaM� ҅h �kiXٕ ROS1A to-o)hP �tyrosi�&'�,z�ce �a�$ ))�G�X��A�manag��I�[���i�$h!�" �nu��8J��  v� p.� �,�TO�b trea��ui�mp� byE'.�[4#Dԁ�7�E�� cIa�AJ � �d:���)!�"� [�I"j(Mise��}*du aber�&�s��cE�� s�d��` �&r���&i&� � ~��AcFF .�keð�hN8�@v�%�ڱ ֒9�[�MrIim  ,*h .�A {$!�‘M ive’a�-ked�p�i#�! ���t ��ig�O.�&�MI_ws�y��c�"s���A�Y6�-��dra� &�F�R�&� | �"r�onX ��u^ �re"�3��m�V�IHLeng�� ��I� &� tL } ��!��k� v):0( ITH��A-�E�%�impacs/@+�_(�d*q �o6�]Lٍ�>!1�1l�d �3�:In�b Pm�+ 1�t-7 subp"��s��#uLA-toler�c��-� a*kmn%�)� e:gs�R�Ir [�712؇�#To!"r��A!�W�"�rapeu���a���"��'de $�<kT"��Yp%$I/ct �Q� � %�� !�-�om�)��2� F![*3w�acq�, �{0��PA�&U�a��[e�&G��8���? �Pqj6�Q�.c��*": �%�[1��2�:MB��p�1$�\B���AW!$e�!�|Am�!ms0 oq>:�>&�! M&� o.�O".+#�K;@2 u!��=�ڂx��Y6:�"�)4F� sued<"�k&v�#��HI^b\*�:��V� 8�quii!=�!y��  Ewe un��$hjas2I��"h�D�ge.��� ���"�-�.36 t*�8G4�[2�QI(�, dysrs��  ��*�eav�,� �­ [2J-�ja:4in i� � plat ! j6�/OllQ(9vo1i%:&q!��2!%-m�9���2 su5��Dr�p"�� d'�5ӡ2yNQ���zL�""�we�8="����'� A�oap"e��:G� %! tro-�#��!�!~SgovFrep��@0`�A�$�adq0FR�S "+build� e�j��� 2G9����,�ͥ�pI3i��c!�a�U����-s=��is `menonÚnonym���ti�� �hcol� n�5 IRB����ź� wr-v��0� 6���H . Un��n%�E��Ual�O&�6*me�F0 2F��i*�aY�surgi0Y6��� H2%�u?I!�labor`ay�*9�� � pri"�7��/in 608#;�q-� �,%�e�S�$d�!a[ud�g] al e�A�Ti��-Gcu�c� x f Q� M48-� �-fy�2zT� ^�]+!NNd�!84aXC&f8A( C)�72��ƥ�u��~vehic���l!��'tAk� alN9i����� ff����( FFP��ahY�M�/-QL�f i&�*�,�p-� �Mel���g�T� 9� 3@inA�%)�T9�stKrr�&�� Gold�� , MD�-�|� !g��|A7y )-��Bn��y:) i1Y��]1�h[oxy!Z�e ( H&!G�K]Xi�� A�ve�ap���A"� �!7�� �. �I�U eff� t�?X< gout���i#��‘�s�P� U�pam9s70� u8.~&ĥlo�! i��-SA�_n�kborhood f�@d��|s� ssly-C( clu楲 Q)��K�&nfiH1s%<sh��g� WC;mvy x bq��M��b��`��$a<al@N�)` �I9co��qonUo��u��aa�J4OEu���*W&�x1-F�] 5��)ctjr �J\�)s���|A��i>�a�� i�a@� Wk���h�#�%A��i��A6!;���WrA�����$y%A,��M}as��0b�Za�?}�)�2��y��Cu�P�>np� a�� v���!qs< E�a6%P8*` *r �Briefl"b wiQ6!��,ay�cE�=(, �!Dp life��?Ax�,��fa�th�<�|etN�� tatu&w(*A�i9�R�Iagpriet�m�*n*rI9[ �s2g0B�;a`I�( 8@���\M-SE�5=Kp��elr A�.clFe S :�xE��  a��C�c�b>���.b EQE!'aM�of8≤:���>���� C2s�"�S7 ;�P�|Ib�)�spherEc.Z$�A� MBLIӡoburn M T �.Gj���A�����&3-Dj&us�nt 2-DY3 ?�����Uu�i�#y���p�7 �*u�iIafb~����v�!sxadd��A�?�4. Nu�)A�a��. as %!�) $2�Pu�%. L)7�{1 +��ny� ��t�A�-7!t"� ( 98%-99L).y-!|6�:- �� �.p"ޔs�Sr�Q?%� >O ��E�:I%7&hO��!2����� � da� �0StemPro Accut��c�&0�*��(, Carlsbad �!�� . 4%�a dehydAx�A`��q at RT6�< p��� BD�F��a 4 lase917l�M2� e�[M�g�8��QmEy�.��%nel&6!l.!}�(%)� ly blue2!p�� ( BF`x!�.E$R$�7(%�verlapœ�e�Md �a�1�NJBt9gy6e*-h�E[�3&�F�����S)*�"�EcFED!� -t I�B�">Ђ>�g ��t�bQO�h�&Pro6؏sG���<� $���A�-� FSC:�xC�\��l ��f-/cd�)A�ŝ&�/�l�Q_re�)B �c{cct2(M��bʀ�!��>�FlowJo&��( T�*Star In��, Ash�ORY E�r}!Taim WJB3�&0"�����E�dD�.G�_��).I�!�2�� i�Y[� )� ��e]�)5�.pa�Ris%:a2 6$�i�CMV�&?3 g A�V�. Dur��5�lhmU+�as��!p"|��h��M�@� labe]oO ) 0m�!�SV e�co�SA[��isou^ Q%c���>��� �480of�2t�( f*Pe���l��h�y;o�x2�A%R�A sour-)!��to�R�qic � A\oV-4Amazon Web Ser$ ( AW��E�K Cloud C�jEC�infra&�NE�8 vCPU��J32 GB Ra��Map��7����aS{se!'�2J'�$d� 9ZBE�!�baMre�Eb) d ��� 5AQby T e�A!JHa}� ypeCK!r� out� �GATK �S:!LPW<Java imp@�G. Var|W. vcfQtA� ��ۊ���mx2=eri��q�asm}.�x")1JE6 �+!AVM3G!0*�#uL�Mt�@��k"� a�Z `� !f�*�3-�p*�switcIWo pon :�2�&���Hp s< �-,Lotka-Vo(rjHe�=3�l&9ecj(�@3�#V� choih�2��-&�F=EU�T'�(! f%, A/"-"�OD8,qbm; 1�2 [38 , ��Fu� �6 ]�" �(i!Y5 SupQ� ry I*�j�S1"�C"w��*-=Z� : �+v�,[)m�A�Hsuperscript sens debei�D-ie�1�e ,E�tolF'F, ; νE4meaA� T6U��. NoteIG,no backwards( fromzI�to� �A�onsidere�dWq Q6zinterac�R0s are dominatISu re�{ ship��E�o say !O adap%* behaviorsa�c��in co-q�qictpCATY�. C*uw��$modelled aA�x��QU1 I>���ofWT4mut��6hM�h��s a12-a21 d��A�zY between%��7s�]�u�`QYd�$following:��,mathematical)�ųparame��values)�estimEI�he�Derimental procedur��m��$.�,. To perform�optimiz�},��us �$Matlab funE� fminco�Zat min8m�obj��( cost )7��non��ar ��Za�,traints [42] �reduc1lflu��6dii��e outcom�k goodQ-of-fit�� sses�by��� over%resultset���-� e ro钅�tumor hA+ogene� rapy fail��%�(first deriv�nd clo�aI�!� [43%�h�!x po)Ds��onclic Kraso conjQ%3 4homozygous p53eF � $Dicer1 los��5l( SG12D/+;;/ ; - +/ )J�ap�induc!�% s��(n transplan��Hinto immunocompromiAmicJ Because�reg< M�produI�of miRNA��can dra!�c� iU�!���ic �1�e %X[44 5])�engineō%� s us�The CRISPR/Cas9 toolkit��A�(e a variety`��A�%�-<( Fig 1a{ ConfiQnof$seqikA�GdA]mE� �$NCBI refere� data , id$ f_ inser �Ag dele s wAU0as 17 unique �,le nucleotid� Llymorphisms ( SNPs )Aj!�nt)FA�s !�a��to�� �b}S1�)�\he =A�d+%� E��te�(a physiolog)�-relev|manner�vitro ,- a three-d��$sional nan�� plat�{atA_vi a sub� te-fre"� surfaceaa�~AuniA,Yfabric�im�ס�onywhich� ,ced spheroid* ( NanoC5 �es –E'c%.J!enavd���� long� VpotAa� 8an ultra low adn( ULA )s�t� of�A(,re also more� ( S25�UA; t��$approach ,� J]is not!Jf< �y� r!� fact� suc= �rigel�$collagen .& cha eR �i )��g��u wild (At��M�( M1-�A�s�]in roge�Dm�{m�A3D7Q�a+=�Pri� l�dife��5 �manalysiaC�ed�target-�1c i . �:�)i9(significantqstatis�ly amA5 �vm.��<va�ex�pro�}�dE�DZ� .!%-�top� 4bottom 500 dys��d �.ea�E,i���v�Y��@N �)�U�many r!�=,=HcA/p-adjus��0< 0 . 05 ) ( hTa�% In orot,how�K al diversmight�+act�ponse4� !`� -or#i�cfw��ewQ"�E�Q!�� A�-t�in sepa�mo� s^mixed*� %�3-D%�x�! �1� �at letha ce�a�� �l��viral-%��$ed fluores2u tagsW, f�� cytometry%�deploy o quantif� abunda!Md�6in du�� ��N metho�����2�Weq�G pre-labe� 1�!�!VtogetherIkWT�!U��!9aCio�50:50#�[ar��or. � ple �> !c! i`s: docetaxel , bortezomib��,afatinib [46j .�we.n:Oil� lyEs showed�ok Y�� toM)in:z� d�7b)�propo�!L pE��>sQ96 hou�a9I�i  tant-WTB�aOulA�inJ incre 6�)� Ove�!�vehic!�ontrolQ&�� i�%Ebot���sA�$benefittedA��F�ŮorQ�� ���thY�veTre�-T-� .� � same%[���.� is f�nge�(is\�%%wte�d inr� �T�,ixexcep�"%�he M3/WT�~)�aaoY�. NextHe sou�>am��s"� �"��& ' ��� )�Ec%�*��,par�U�a%Wet� |��)�-�-��&Y�Qr�u� �I, 90:1�or 10:9����:`� then��wos��48em vals&�ca�� 7 days: 1# he %%K4!�59i�e�l -i,is ei�?WT�Mu���>sizs 2Jbe��{�ply-N c�, g� ��  ��ch�aca%of�all6t-�e�sei�� E g�v� to�d � t� h�adexF��a�u� � $ >U�f� ͵�}$We leverag!�s B�a:beD u$bI� �uF�i �N� y�6� aZmX(i\�:aeouV�o*%r� �iIA+e.!���=�)��Iew!f*I͖�I4a�4�-� lefK�� suggdo��&��i s/< ( “No Drug”� um; a0. How!�< h��dip�i��.� &.W-����$$ad�A�bkC successfu!9cap�Ar�~W.{�!M ( Eq�>J!Hr� � ;%J —Y S�8Our�es!�die�de�-���e5���=r rowth0"sub5 !?AQ� fEb�)Q5e�elet,^��?.'� QA@�2�:re �0U. A�vious� "W��hypothe�!�atK �8 A�&/h�@nt19 mechanism!��� EqH!��assump��A3borne� `INJYm�� -�.u��  ��,:�WT:Mu a� ns M1����g�Xfi�*� ( N) across�o �J�S2-�QS4`� � �B�pr5�����g"r Z o i5�!Patce&2 �rapid�%ns�k ndneighbor���4�prove" mV&[� p���Ce!暑cthwar�str�a1at�\'ac� ~�A� a� coope�ve��to!�m}��&� !�J�sdohav�milara-etic ���fe� (6a�p�as �=b���( (a2We9��!�Hof����m�!�.Nq1oeUimPo�Y�7]Zu[�".>�� 2 �!��EGa��ng%]5f3"�du g�yp^yAv25g� ) [47]E erefh��6��<%>J�a���iv��U. FNfouM�y ario�Sn� ,fA�a3e���N�!� os%7!��=���ssim�!�/��]�=��� ��(( xWT ( 0 )�$x�)%#!��yM1���$:�$��ur@!`&�!�Dwe!Vn�y�R:V izmon[$bly strong�a�".85t ,7!}5aI&' Ns,q6Vquickly��pacŀaf�.��b) �U panel!��Th �=te2�l��u�,:�to in} .-p� ,�z �an ad*ag���("���!�a�on�o��~,!�confe��6VA7de�$��-ndingsc*0E�!k�ݶ� e0 ��' is poinj#�0�~�}� f$��|donsla$� nti-�^!ef�ly� ��mt� co-sup� �M;'�.x�A�W� |ܥ� ITH direc�cor�A�re�� �,Ūjust t�Bpredisp�D -�ois��RJof��N��Ngiv�~ri�t�u�.A�m���g  abilA>h%�Ca+� lyA�oci�I( reaty!�[48�#o��l�$"a human lexw��`%� repl�!� he n� �,microenviron|incluAͅ�mal��9�aI"s�� !;"�!����Jbing u�[3v!F ; � geneIt(fresh biopsf isol%A(NSCLC patie�!,t d ex vivo$matchao� matrixa�teins A�!ed)�aut!�ay Z!^smvA*� A(N�-g��n6pS3X aWa p�u�a�algorith<#I ncor�)!ڑ�ic5{Ab�)�As�)edj (a �(��e M-Sc��*publis!@� accuracy� -�&�w !.���ߥ{beesA3�].x!su��aq� %�� �:"E��,liA!�e�����r4�anE�' 6��$d��ie�;v�*�"� 6/s!D’e0BQL �sam�2��R{6�1&�as%e !E9�pa � ist G!8&A�: Fea Rug�s q7& oxyl� nd eos-o visual�"���th!u�D cytoplasm!�%�&�Z��M�).��&�d��nct �‘ hoodx�� defi�by cl�c) �sx�륰sI Y�+'iteX") fieldP20X ma�C isJC!o�o� �!indep�-n� fragA�s����QR. W �%R:�A�w%�n.8,qa scal^1-5��h"� md!�y%�%�ar�2$2��/ in 1�m�QJ"A'5 high�.�b� calc ��!Z]ltipl$-Y his��G gst]2)Y5�%��' view)�!e�5�6  �!6,)�o�.`r 6�"$3 A_�/E)U fy6�!�pl�� /trueR6&�"d� igh�� I�!�ngl�!�L �A� e.$uUs as�]!r�f�'��i/e_>!�degA�ofL(��}�� �^�)*� L f`. ��ntii�� h"� �eu��r� �mbg-�$��a�iviRqn��, ��b6>-�s pK!0�Wa� u#mb�0%|J:�6�Up&�of�s.�*� 9�9 `(� �'6�)W setE����Ł�,a�er onE3�&�  ,����Z� )�� w� Awis�- ,� 8n)N� !�� X""&ly link|/ Id�!;(A�biomark��<pa*n[i��� a"��pen�%-!aera� �2P7r��o achieg� v�ce!�ci/%mA��3,"� x-fiI�‘�g�#��I%s has b,.  5 areaA inva��%Ed+log)%past s��#$ecades [51� &�aJ% moun�64 non-p al&vsjV,a�ardle�+!�Dloab��P Iwe�out{ �!�'2newydig!>�� by�!!��$“���,dtoE�,��Fb.a kR��!�*�&���z K��p Aok%��(�vc�� sal9��jtheor� !��1�,E����_"Vor&a1IT�56 r�� �B�a�2�� in%lU�oc_$�f�_��lea!�F*�.A�?,%A@emerg��of���� V�7re"$!�al ��r a �k forc -novj�XEmBl�y�A�ow.� &[.oy %�!0�|�)�c%�L�^,�"i� iAg"����-a�e�/_C*+.� e�ng �6� l*,o1O!�*�3 *�&(".HofB'�"+t�"�-:� b� :��R&as� S.%�cl|%� ! "l)��o�+"��6x -��.�Vdespit�01 �� of ��  )ˁ�e���a��* Y�Zz*�(i�}i6%a&.J��h�)�"V`�X.e:�a��X1 we-$B�exhibit�&%���c��.�" ���Ta$)����s2L 6�-Ac�:.c:E�� i2@d�k/ �a�a2��'�p empii�� ��vin�2 Y1W���;�sty�9��&a�� ��iXdV0 viva�'E�M � +b��.#2bM3�a�!>��m�ca�%.�e/bQ� coulS0 attribu�!("]!�cy;g."s r.�EowG0argue against�[�<�'E��ANE_��2G ��aymur>6)c�0�q��A����E�o >�) en�s!�o& "���"�!�� R�, s7of�d?�n �=Hprolife�oo,��)*�+q�or *H�<� �>f �_&\1plHf -agno��q�1�.B a�men��� ]gn�'ss� �='7ZUH���<k reM1"{ .>a2�3la�G�@| surpri:�,J1AR�W"� &ronMemp"P. alig� � !Ji� �+uTa�num� A�� ��  q/ ilic83de�)�&�'B ataAX1�1R*� "!Nispe worka�b =n!n���'!�]�e��,e�>l =�sti�A�fur[ *� !C. L N `��-*)I*)�,2�I'a�A���ap2 ’s2�.�an�2�"�H�.>kin��v f�!Nll��� � }tox�@��!!p,�)uC�,)-mea>� �gt"q,eDmayVfer mp-�"c ��-� !�)-in!�a� U G s sh�b�}V?sM5a< > �� s [9�or! ��d��gS"�� �.( [5�:u3�,lex alt�5��*� 6�ex�q �?�Ck���+ɶ�TMddV5��A�challeng�2� . ���tE.focl� ���Uexat=-I�2*y6a� proteomic 15!f���#2!�s�1novel�5��to!=b�Ń)6k`%�� . Fu�)�fmb ���-6G d� oCx�a+ e� .F(,F�!1 �A���pg>�2 pic�of� �"�;� ".���-� �,M�j"teg!�'i@FE��olu��-�����B�&�6yk�Ein@ll!�o�om}eff��o  l1*=!2-i � �help gu�)��/�7p� rece�ca;8.CRickettsioLre NA���ub-Sa�  Af G urde5,is 3��isk"�9�emis�Uh�/� pars�d"�*. F Dhe EMINI.,@&h OMonit�(&I�&f New���).�coh!]crandom� l�/�I28Q� ab�(aage�5 year�nakpartici!V�Ho�>i�4in Mbey�g�, Southw��$rn TanzaniE�i"�g!Eal�dz d��owner�Dadom�c mammq1%�E ?A@�*-s�6�ero� alP3iU� aim�to|,i�:6�gG�Ybo�D� Spo�4 F�� Group<FG ) rQ\aw'deaq oecon��*d!alg"YQ. Serq���_o&�19as!��a!dim��:64OFG-�opF�� I1G�<�,be 67 . 9% (AFge�"EXsites: 42 . 8–91 . 4%o M�� ���1i�vea8l#A/w�JagZ:re1��d , PR� 10I�N30. 08; 95% CI x06– 1�', warm�e~>�*(J°C E38;>11 >7{H le �:6Zr0 -16� !�?*\dY� ��00�aq/km²�@;96;  4–�499%IAt�er �?!.�u��, attl4�y%�1W"�ig*%�9[. A�Y��_(!�seems-�a�o��m ru% �ofm�Ri�. Spr�.I9 limi�9�%D �� . E\�g��� � �of�to febr�9illhE�9�war�Kja��� j �>���b��m���w � �$"P6�aus� h!ge �~&b!�p�o;AVvi!al!X}�% �!�\$ly*�#41c!����on &�i-�usa|nts; e�8�byM4M� al Resear�@nd Eth~ Comm :�#nQ+e�Jn )jalFCCoord�ngE. Each ���nt hadA� d wrsA�K��b~ enrolf! . P9s#�=or[1��:,minor childr�AD��s�#� nonym�-�#�+ lphaai�d Link�2�/e�Ua�*�� ����*0G�-H key s� I�*!�ha���manag�8�]��n� %Fa#5e#�-��Y�-s�ey���Cita(alm up , �45\r!�!��ba�Uto 5 �H3 "n0 m�����QR�.F�!�I�m;e��Cc �K June 2007%�8 dur�sd ann�?sur!oLiP� i. BI�!stL2of ), ensu�!t U &�A��co< �J�� geographi< #��hT�3�ns to��rV a w� va"*H6 a"infrab�~W @� !Iurba*nd͡ �,�� prox�~y�mroa �:�EF�I�Y-�T: *� O -�ᆁ�" v^ 5-C 6�J�08!/�reM�9��]�m�E�i)� . Evq?~d%�g5�vi8d�m�u�C terviewx%� blooa�d�X�+�!dhmem%V. B6 խ�cry� kU!�W5� �Dd Yse�%.�3i�,b�c� =�A~17 , 8729�a�oe��Qx � �1^��)���,�I@��,�� b�<l�" f�Hof�e�/a騅����*Mli�9;but��61UY%��� �]W1"`0"�C�2Q��ALw� eq��Uent%��$n)%�u1F �y-ke1�qG!���!�a6�to!6�b��hR .a oriisu�I�TtigJ� ͭIeC�ɥ�Su;w!&�S%y 62#-�$ah0VA�?arot5eW. �*�2 ��}5u0=an SES\)a��cKK�6��huY of>�,M mocal savi�5c� ) ; sour 7!�ner�+drink!�water;feri�a�uKMUB� ��;�M� � rooO&.) !�a.7� ?l�2ne o. P"� � li�' ock-x!���& -i�� Zyp &� *� W9�"U. E"5 XsreA=���#�NASA Shu� Radar Topg y M+0( SRTM ) glob igi!�i@;!, ,Ax 1 [2�E2r(L��P._( LST�>nd vege\za, ( EVI = enh:2"indexnX �k�y 2003"7 2008R��� Mode�4 -reseIm3SpectroE�A(( MODIS ) m- � “T�0/P��PjWa� Dis"A� Arch�Ce��!P DAAC�lo�Qa�pe U . Sbe"S� ( USG�Earth�m4O*-^!hSciw( ERO1x(lpdaac . uss"gov�)[2�)+:%vEWqi9V -T- a�E� daniI!��!�65,y-�ndRD,C,A,KY�� �dE a bu���� t�'1�)�!�oɮ:in  r�RB�ec5�siр HAy�.+6l�|p.�?� 5L/ve spot |P'IS�%� �V0%A�mpr��� q err !� 1�aD!Zg,�um" %�*��>yFG-"�a�8� rectN( IIF�S�amer,#�!�s� g ( X� �@ IF , Fuller Labo�p�itšq8A .E�S� . � E�V�,Ee�ed )��,lyX*rab�&ti-^ � �9o�:in �Oe�"'in9thyocy�"EAll sli�-%x��T4l*#��cwo� ere�de)yu!/- "X%iscrepan�+�� us�ay �<@Mœv� MN?)til a2{A��R�/�)� ne�.v� �s�L4oQ %��Ma%� . Fl}Qzde*�%Katra� u�;���M���0�0�T>��bae_!� ��\. Tit{Cof 64' -%�@�- 7-yti)4�I� seraVda� . St��"�S�ftwa�(�w13�)Corp .�!ollege?b , TX , USew�*!�e�Aq�~s%a� �B�&!@MaFX8ld System 8 . 0��feQ al EC(�"-Net Lty(Ca  C�, NV )�p� � %*���fGE�/mapYI��"� "K2�Z� -� �wA��d!zoa<*�fns]4^in#� �4-"OPoisson6 �!!r �robust (A'Huber-Wh�+)d�"�s "�U���c�8!)[2!�24 I�al�� |A!��t� �+e|+�0'bV�=to%-�nI�%�pG� �b�AHa6p-Ŷ < =B1�Q�:;\uO �'�C��Ѝ�"� �]fG��Mq� ]�ir�s:�A`gf  x3<MB��E�(&a��t��)� arE)>� l>/g�_ :l 2� o7+Co�3u\�VateU>�G%qui��A5nd�+�&�E �$��Ifa|�u�塜i6�f ut i��/"�.f��"~Un#ng"#�a &�aa>yJ�("v*a Ol�&c(I�onvex2K!��-8�� ��cepwKBf%�forward.�['e Akaik�<d BayU)&icr��!�!�!���( e�ub`)yo���f�>�9!��o Ec2�:u��1IHr^jUB�)�%\l�,aa� !466J,9�mb#)2� , �cf��,*� , slo�E*@ y et� )a�w�I a v%�%I��� > = =��"d!kbh )[ d5"m�j�A@qcs��!"�6�e B�&�'vdJr��7^a.) *� ��:.q%�X e two-wah��� �3 r � Sclu��v$ �,�a2�6.=!�� . 8#�dinF!��ak"TA� MgO2e�w�dX9$$of 43 . 6%!�"��5e~8bG�$�youe)tqg"$� Male.6�z*�7lyZ often.8EZn fema��(>�r#:.�Ŝ�"KF#W5%��f�q�2�a�YCI*0��"�"� .b!� �@Z)Kn#�93!'/kmRpC��D9v m# . An��G����o w!�&;� u�+�=^�un*Y 16�� as r�ed�<-:8!�:�I�Ruua�|i �Ga�# l��N�*���$�q . 31%A°C� !(.�8Ntaneo"T�O�inear� Y�ex Ps:��w.aRJ@o�&� . C6�% ^{2?tAY�� �1�!EF�8 i!W'9�.�U�EX9@ � ����2 :I�@���N&_Va�1291 mZ R��&rC ��)�!dhA=�j�?gxX|.��l衎ni-*$2i�rz�n�b*. OH, su�a�2� P&�8ve$Q2��+"[0�7�j!moa.MPR!HVwe�a��CI��9���� p�3215ŭpicPR ,�<8�)<7;;0�,��ckeIPR zV>95 z1z35\�=o}d��.?T)2?75�).  9% A�!�$t lifetime)w��y` ��`!��A��lE�"�(sB$to 80�)er�M�.s��(�Vd'!�;L=/wB��%H be��!�a6���l>���6c ; �3emp�5a� �� [iz*��C �t �eer)@ [!)�B�'%(lau� ��MO�* $ host-seeka_b�3u�4 �2ticks [2� 26,3�N9 �k�, bree#!su�9�1rew, 5��i%��[w�1 lowe�8"_��<u,� K�KthuX ��*D-k�*m u�e�k&e itself�4�{!��drV0-n* :�!*�$2PJr d�?"0է; �-�; k�Lnxdrops7Af)>%�fer�K�mno WaTaR� eao�8�D[1V&U\� xy��w4%�humid4:9e�m. ��me1� 4.5; dry�+  orte�R$7A�j��D'��!�Y�IparA�k9��nT&�NUXaxypA[g� &1< TGRBnt�,� �ai*�K��&a!_:[�z&?g.�c� %ݍޙ�A��)� �2=p;��!�.���-� �u�L%�b�Vr7o�3r}{�$oiZm i}8 ,ma�hw ci�.� likLvecU ,is XenopsylldYe�Q�aukfleI2 fG8b�as?��&��Yn�;%sE\A�t�^!� �0 �*�2D( its C!eb�Ey ��h 2 ��:�%��i�:� *� �H���9-��%colb)ou0�&K(�m-uto"4 f�Di%- "�v!%�. 롑st���a�$(�"974 m���%����xs����, Kyely5�R�"UH�&�x4 �rbA��b�N suit��Jickk,�/&C4it’ s favour/M2E3mo�9cli�I�1r�n�� mosquito-`T0s%u Rift V7y f*a�A�- viru�: ei�`I.�4���T%�'�9.oE: d�zV�p�q)"[1��/�#�S+<nte �"re-+2es!C�Si�a��e��!%�� (m���T Q?f1s��O%�whe;aa para%uEinvol�"aa��aE/�� ,.{ �.�� �!T]�A; ntryn%A�- XAb%�)/� s~,ied Amblyomm\�umMGmof�'a�8a/2.�t [2=^F"Y ��;� �>��d"�8VF)�#Zimbabwz�!|re�� ��� lso 9I9[1� 2�XPre�_�[�A,�` m�J)9* by PCR ,�66 10>� N�M��r2X.mas�@afQ�!2\07 Rhipicephala�anguineu!,�+�c$of 2 Heama�ualA� llip�? �( GZ0obW w6nu==Hp@rd�Al =Q*� q� ��� knowra��Ugey��1 �Kso�+h��Q[�/��.]�K�Oau�2�<*� .�g4& A<�49�5�r�dog% R�=Q,�1 .=�-��!,A�BUAx �w5e!�d"�C� y�v�;�os�y. 2rg e '>*};�-1tEX$phospholip�4� riglycerX,���Yzb�T�a,v�9fac��eukaryop]�i�N��\fu%�!y�cur ����3stovH�� moleculv5Uo)ɁPaU�&�wPe�9�!�c,��s 4 �1blmognC4a�iF"V,�66,�� �4�-H!olR Fl"�\toTspa,*7 [��LC�&r{�% (9 ��6�aYeosclerol�ta2 diabet[#T� *�o�9�O�J�/�Y.�M;A�Ue'�+ p18�� e��� B*� m3%!�gA6�UT)E�.�8 etazoancy [4 TV@s>am�C�-�ervu[�@�O( elo6��� (x5�HѮ�k��zi��v�:��]�-in�j:k'��7;#2�ZqEuaet�Iir�/%=� ��un�  ma�I���*a!U � -j�he�R���9&=�Tic�Y"��18-carbo�i��*FW-v��!')�to(��:� ( MUx27 poly.�( P �s (�& 1A )2�1�RM:Z"dLecM�: �2.\4e2A[�y64� .�`!�Y��an a�T rgan�p. NH �ly J��ň .�Soa��rHU�i>'ed��[�I�SB�4worms n�Aeat^+�9E�f�?EO ir e"�NM�9 shapB*R#Pt! ARn�n)m1�M1�� in2N�)%u�)�ZX�0Qi� '�� lyso aH!�� CUB-eXdom`XA�nd ShK �SH6�Wa3m��$2�h&N [1���.�.\A�u�4br,���E�� eF" x&��N( ki,,gS�1�s� , 19 , 2��I0;+� � n!~-mC ����e� �3.� �� !fwR� :�.�L& N��$kumar et a_D##aawoB+." , γYol�� DL�3���doE�ciSD,%M �)��ba�Xe&҈� 2�Y�[1VH�%D�m 1,>\ 6K::�O��c�9�YT �xk5�i�� ��!��Gs�"5Z"A.[�Ƃ� ~} 1u 6*I �#|Z4 �. W��U �"�@R*Vof)42��H-�/���ci2�*�:{[=We�/aniso�� ory sm/� Qk�R24 (�LHed RPW-2F*�a GFP�I�*�UzLer� rg-4::GFPA0�_ /�sven�/q%C3B}=>[1�,2� 25hT` ene g�< 08G5�- )� :�ly up-,edFlw�>#� q�s���Ya>l�~�H�n�Ar��MI�J����a �6Qq^ i���>,�"� mod!��� Er' X*����J7uz6�[1zQ6���:ybyE^�Jxenobi� ���ct�Ema��Nby boA� :��I3��I84AmtTw�na�Pu�C-��qa�HaJfu(�o�Lr��pT�*e"|c�k�X��ae.�ArA�a�YA�di.�RR�;*^29�3g�2�r6]TA�R24Z�i:d{%rI�i�n>/n��(%m�2��isN�(��o6 ( Co��� � fat-6e� �*�e� redu� y>C�Lo� c�0 2� �g RNAi9knockd�ofv6�`M>#��2�e�))m� B#Y`B\7��  _ar�Ht�*��* ( S1A�&To�&k-���A�%��B �:6.�w�H qRT-v9S!>%�F:"q {%Q� wild���Sin-O( tm33�U;)�( wa3��do8(lnt ��"A=� jw[ ���.��.-�sC�"�� 63e:8 �<�:,�5O 35E1 E.%I rg-6a/ 32H1�-!K,Υ��nnu�-�!g2vx� nV%�#u|;B!#�z�MbD� h���Q�D.Ba5B %��Y=1͒�o��}%|e]�:w .r &�v&d ��l�Ŏx %�` "�m�7�I��b��X�2\d *s # �`��z �<��.� a�tevN��}.�of BZ���,!a dose- �Z� i�6zJ�z �!���"[ �0AQ�4M?a6g�\. O& lsyS:�" -rMfͫ�J�%;�!�Y@M��>,�by6z�{�SI�C *!5w� aEt��n�F8:���se - !catalyz�!]�=ulmi ci�#Ew)�^�im-� sip\wvm�!x!@��v&� v!t-�-tm�Ee�Imp a�,bup2�f��>�m�I�jfel!(ZD �*�I*�k� la�Mf��S�$ccuR M\u1):V� � i���o�!lFW�o�2q�a�.FBE ��!pp%�F��%?'I�v a� on =Y�8@r���a &�/A� ��AKole9( P��NE �b�y9� &=2 c%e���*� II�o�6b�2 mdt-15*� � �ub l?uE�7# �E :�62� Q�M8�aUd:TeR\seudomon&d"� YU�ts��-U�� orc�DT!b*iH!�2 !�a "��bio�- U(V9+>S �b:M'���69YR�)oo 2182 )���|"? �N��Im�9��"8���!:�Z�� B�� M:E9(s�mvA5v*a~�b��K��P��]&l)"!� A��:e [�^_�e�@/i��>��aQ�=z�� Su� r��rn2�"c��FC y � ���(6Ri�� �g�o & !}b6Ҕ!�9%Y�(E)��$����7E��1.��-3�q'8Y���G2�A��of�6ip�K>�9 J�a��\n��2�2�%� ��B R�e"xy*� s217�!wa2R����92B%`2� Not�5)H6� ..h:�s��rg�Y!� 61l�����/**7*lyR4�_�j6(I�N�S: A�n"�.F,d9B�.��#q�2|*. U��5>�,�9� 16@5n�N�"��!�:��ig�,���5!�W 9�� ~> 2� 68>� �e�l2�( �^�!�2M�-L:�)��d\so����oB� ��"�B� g �TR�%&�!�YN�.� o�%�or),!�vhXiR"E��{a� 2�:��&6Ij J� ��8a b a��V� R�� wR�o�vB�118�L�2��s! � �]5&0:%.)bA4��R�2)*� each�Co�@~'s�5���7��DMSO )!�#)�3��OlL40-o�Y��e9�Q 4-f�P�ܩH>D16 HF6�6��}:��!03��S1�H( A�0��nc2����� Azn�!L�E�� y�, ��� �16 �*�g�$����%��B� t��3A�����"�P�f‚� * �1!�� :F:�� ��i$���A�eT2< D�ES�z� se6�e�o �9� at-7�recapit&tpLx's2�a�5A��[3��%Of!q�G2�>�A V5�ttz�"�-I>Y S2)�S2� ��JL-})�O��f+~�3��� �K�A��l�!�&  by g֘hro�gy-#8Ytr�[ry�!C-M�Z�9B�6:E|� }?oR%M�a�c��4*6@!F"D݈���.N C�aV>:�'��J��v3-.n>i�enc/p�v����.�O%�b��E$9b"�,"� :Q�$-&iZ�f��FA# . Twenty-� �\`�2���& �.*K2�nI�o)�6�XE@�r�� �na-��Z�. Moreo���*� )FA5%�B� qas���)b �3"GUa�o�M�)>5 m��6�n\u1$'�q�)h�52���&M(� , OAv��e�Sb�:��L!��n�-ہ�mL?'" "b/p"d._q�V�[*M!>z�is &=-�}d�1:��+&�qh���?�. with>�:-)e"n���%�m�(t� &� &q-���4i��A��&i�4�oA* 60~�w�,c�&#@E&��w-�g�<]hkP�l^�"�[6*I]&��aW6�(YF�=*� )ms~�91��'�2e�&�-I$leiotropic�. � ��a��Ij+�T�G.NwM�� ~�1|Z�"�c:]ex�M���-&*?(j!&8 >��}7Z�%�!GN��F�b�a�,2 y9lyQ�S3���T T�0��>*AC�,��8 �M.���K� �4AUe6�&� >�^L� 2~'V ��n3 �Ҧ1 F�!MJ�+=�%�X.|8wo�GL��D�-h[+nn9:!Q6�&+:��+t�&2QE! R!�m���e�� ��EoJ���2J6to.�;�3�5�?al�� f&w[.6��E��%b�e�:�! � �JdJe�A*w�sF�^$6�=. �2|E*�8"U �:�2N��-6�-�QT>�lJj23I�'.V �f+ ^�:�&�-Z� w4C%�� ��64!0FD>A �. �=�a�Q�DJ!&b,�4w�w*rz �A{��-5�to2�:@�B�6<|n�.� G�� �M2v�a��ato3a2�6�/:Fgx-&�=s2����6 B\#J�r�i6�'R� ( ���vS2D]�2� !u7�b�" F �S! }�&!� "k%�0*���e*�1Z �2��\S7F��2��2�B�jW�{n�)� ��2D%\:�S��%�͠0p38 MAPK PMK-��.q3�"�@!}�TH�#1 �#�6'���)}��Es{*7 �ri(e��/"Q.3pn>`2�tir�!_Toll/IL�TIR�5A_�5��nt"�.�qC:$" a�tc�at��43! 33�Heu-H:h%i1���2$ �k��&jag4E%�6-D*cJ�% bZIP:�@Hor zip-�i��l6�rg2$d6:���[!����!0aY�- X?eR � F.*MgFJ^/ �a 7M�:7#�0:Ma|y�fjX�a�t���w��par�P 1%):��ZIP����mV� 5e��:uA.h!�T't�&�: :h�5c� "�5H &6�) _ry��%�ub*� B�6��^sa �to�r*~p�a��a�'FY-G�-��G9x�=okV�[�H�lI 5���r�#�%j2:- shifm+i�� �tow���- NL7z;2�� �%���c& A�&r�P2 w�h���gisK&�C} 6j.� 6i;.�C�"s/��-�sA�&�9<s�ru.�3� {e7.m ⁂�� o1a+2����jM �5�!P..1-� i�=�ed ���� augm�v�.�!� �~! � �6� �Y��i�w.r6&�2Wu 5b� �De�S2CF� �� "�F� ]G,%�e52�r� �0Bm>��n?�8�%�6R!G!�gram-"�R�d�F E�oc��VecR-<�9<�SermR� y�w1ћ1� i��z>:�� �am-"�qqV��2�,�"�֟)FF09��E-�MR�n2)k#6UB� 2B5F�# Yw2#�6N�H1v�"����>x.;���!-]"�(:�by&� �Qpbj35E�N�*��N�B2��!:�.r*� n1\2�0��}��=� 3��=m* �N���E)��u2/�:�=E��bs�� \d#���;>=<rv Bae�ll�� �8Ne.z�..wA%t��F�gre"f�o�*g��7�(2�!�� :O@� & ��.%��'4oI�M�a�)�\&sp:M.k2��}p�+ife�.vD.2v�,aV� �"E-N 6O2J��'!tEI .�1��=R:ndi���� � �:e1�. IS��O&4�]��2���3���#!�� XA��%�@F $6��� 6/�\]:`5)��'�B�'[cuj��e�lA�J� Z|�a�cWI���Ag of!��# ��*�on9�"�y�ݸh6�m. HvG9Dre�lgc��5���.�NZ� &}IE��H |vQR" Z�R6�:R�Aӽ<rBH N'� >�/�Mg!B2e �$I�"O5� ��jqPZ� f)� %F�6�Ay:Z�����k9G�?>=��2b eA�iX��NQ)�C�I��Cno�k�uW9 t�V e�h28� �)to>xY�A.N��,�( od6�5h^� �:Ap:&��""Z !F�>i�"&f� q�n�"^M���� ,7PNRn& ��!� ��Z��M.���B�m R���n"}+�4a�FPFpm"� ��:��yl be'oG��� d [3�35lAH"�%!�m"{bn`A� c�X8 �saŁW�#in�).`[�ס��>}z D+R���j"_E �"�Ja�6BB'i�~? f� �M�A�FE:� �r�Q"�B�#�i� �$0�c!Ue��!�G�5�&.@�rup(-y2x�DsR�RK a.Z"%���L"X-5�BMelz%-Y�9.�nS![Ep�$end6��Et@_umSӱ [ @d̡U0�v��"�&bSh,#Nl�t��tL of Gaf�-coup<'�p�[3�3^4%N"&�-V��:�a4k& '���!�Y���Z ��&�W9�,q ""ToraVdi)�ng �U���6O��Z���AOM�-�5�+�aY"�`�t�%e MunjPecoX!^"�Va�`� 1j*l�� zQy�Is!4&�_�<��0n!o{�t�vZ~ Vhn�@�X)m�"�*��. .T28i1PMmџ��on� coli OP50!wHT115"�#� z "�p#2 2��[3"�DN�� D�N2 Br� B<, AU306 agIs43 [��::unc-54-3’UTR; myo-2::mCherry]#;,, AY101 acIs [pDB09 . �7NOU�pRF�Krol su100�E) ] [3=c BX15J j�[,0F,[5�H3A/.�%30*� �9�BX2 T*& .>�)� PA14�N,%�fb  MMH594 [44�AW:� (Db11 [v�%�J�. .�Y&obM_(Nu-Chek-Pre-�In�|r,Df�2�mu~dX^ d [4p�As *A�&��.r��/nL1'��,d!aaA��{3� ai�Ytergi{�(�t1%IUnͳB5X"� %') S �& f 40ee500 μM��xb\���1E"* F 1 mM!�>�?!Al2�6%4Vzs.6bSt$�dn���`9{f��� 2P��4]�:n [45]��_ �u�Z�u8�o��>E , L4= ge-mЏed2���5E�XL1�j 9A\�=�5�W� !�QJ���Qr�,�\2&}DL�DZc��zYn6m4{ %�\ �w.�. S��ӡ�m�r"��mp pZ�NiOlU�N�� ��&T�^ b7tocvN&� � �,!�7I�K  �}�"b�� IB� ,vRR_7p��b�^R.,)%)e(6��5�Ahr�Wrm�Dor Vidal [47] libr �5O2�3?Bc�) codeB1u!S!��Stf nC" er GE&�"A�g���@� AX���f-��8.�� !�I2!�:{*S*[2!n�J��P�3I � ��reZol&s: snbh"ama nd -�K�'�M� %R2iY6�–�,�;& up��Sj� [$#Zp�S��Algg&2��ag; t%�!f� ؁{ld8 �mc>Ւ!�Pfaff"��[�Syݴ&�h� ~ �at � ���.s��T��%2ha�a�24 f���"��to.or��s:�,Ai� e�M9,��jm��ss& �0 froz�� X�n-6nw *�W3�p: t:��ha�'hw�� Jt�0d>�qiw�mLa�a 3:1�+ha: yla1 chlo�a޳a��5�i�k �^2ahexane��7:��2���.~�vortexa��Y cbyl�e�low! d'��t �su��[!m-2y�` t 80%��%1%��df�cooN%!�o��e"9���!neutr��d)4-F7% K2CO�)a���yl>s�ERext�"�*+`.�2 W-De ��., �-)I� �c!�( ifu��at &&�rpm)0��u�#�Vtopelayl�oJu>��r6taH�bobl� g� �X tu��ay�!���r�,�I�z�5�^�>�dr�s�3n;��&| >�ag[Ssp+j�#2M�-�B�: Agil�v��eU)��!�"�N~�kͮ�$*Pan[ 6890/5972 !sV�outc� v,a Supelcowax;sco�� b�"�I)"%�c�%��}!u"�%k�Ca�>+sVg%.*c`%�p�&%%CA�M levam�e�+igm��GquǸo`qar paWH*�hot�;"a,a Zeiss AXIO��er Z2�_sc:�p'xioca��6 b cam`�]Zen��y T) sX�6��al%/�)s& )���Ka� -Meij���c�c�=k�= log-rank ez UOASIS 2���t"$� ,&�� &' � ��gur�{ڎ,a&b jPr"b7+=`�Pad S1,) .0tRibos$�� &ory�km��A9' e&� i;c:���-a=�2t ���It&� ��'�%�$�|� agon�zb&'�B� crob�en�|�Z i� ӂ��+. Gua��g �"�x-a���G9A]b.>L�P?%&�Z��!R2��,�A��o��s&M)�(. Upon g ��s.�e5ha0zRa5′-"oav���$� �A)' cb+s �c����@ �dow"�Ipe!�a�5frҸ�l�y]-�ic e)5�A4a�9w 5�IUD4+��&�!p*�w�v�orQ. Anti�\s50Q5�Nj�dܴ�@dEC� �e��de�xeX crys�*5f���dJ�*"a pyri����pH ( PC5X1�Qn!�a �"� c� �>� RM"m,&Ke��"�well-�nosocomeV��~E�|#Mj!���5�d �;ua�7a)�coI@{ GMP� t'T�&a�� M�9!�"$���ih7#�ev"�BA�"t ( MD�2"�8a growing probl�em during the last decade , partly due to excessive use of antibiotics in human medicine and food animal production . MDR also stems from the fact that drug design has been largely based on limited chemical scaffolds leaving an opportunity for pathogens to circumvent antibiotic a ��mechanisms [1] . Staphylococcus aureus �Clostridium difficile are nosocomial paz�responsible for a significant mortality rate !^ospital mincrea!health cicosts [2�Recen!�`, community-acquired meth�$lin-resistvS .�0( MRSA ) infe% 8s have emerged � tmmonlyB� skin&$soft-tissu�NTthat may rapidly evolv# severe=0life-threatenA��[3] , [4�4Moreover , som �0clones wQ(shown to be� �dto vancomycin , which is c!�de!0asyAc�Q� [5� The 1� C .] has E�dramatA�ly=�a{1�X-associated deaths in r%� years m�6aI)� �d spread�of#0hypervirulent%U,high toxin-pe�.Dstrain BI/NAP1/027%[,� , [6 �is�icular5isw���, [11)52 �Z14 e�In! caI� �!��2R, pM9�>escribed- analogsIre��ed!k�`(a multitudea� cellejef�:� addia#4inhib $of gene ex!�sion via� bin�[16 �7 I719A1(Pleiotropict�=��observed%�compound.���5sUf%'at� st o! waE�or-be pos��orporEin DNA�replica%[!� , [2E� Thus��le it��ofiZest!2selectE�bi�ŋ�7 chem��dA��Be_!o �b� site�tains�av���Yq�te��plet!�sur%ed�q_ A�act!k ggese�E� most atoma�os,� 9 �Qpfor� onQ}� �- hmplex [2D2) By uE�appropr� � opy�n�E���[re�t  corr�network�� boore��ns��ver-#x�as.� �q,}��A�G��k!�advantag� %+ac�B�es�ic�ly%�2u%�&�%de� ����a���qm��8nŶrefor�� �$�H. P5�-� molecula�f� f: n��}�qu�2�& ^ A�� aar�!Mof cryst�tructure�YR( ͟2�"UE]�yEbacwe id f��two=gE a�4s 2 , 5 , 6-trP Y�-4-� ( PC�!G.6-df)2 )iZsatis{defin�ri suchA{geo�T a�� int ,6�!pcr� d13e planar�9�QAs oppotoU,��PC2 lackm roa�c �,�sthem  Uc 6� Qlde}e2ir simil �|in termŸH-a� do�@n�d accep���� . Nex!�=An establish��-l�� probGssaK5� 2� we monito�8PC1/PC2-induced.�con��al�ge* 2C��In absu A���T�7 leav�8a6map! *� "� A�le-!�n��reg�e."O �� 8�owp ,�r redu���entɃ a re�,�z� u\ upon�q�{ �!�ha4re dom in�5 Q Y�11N�w�aTQ�\ ead�J����nm�c2`m�� bothV�^O, s:��ie-"edQ�lc2�� "�;6kSr�" � 2R - r&R B��c o dea2A�whe> .3�sj *� ,A�� A�ed67 %zcr� al fu�" 17�Afu�Sa�?Z��r �9�De.W�� ��gnA:minimal um �&�a�&) �2.�,�,a-galactosid� � � �a!�-#�+0 a dose-depen� manner.a�� &�J gGr *byI���es . We�er-��th.�(experiments�� vari�2* %E�.5lS�q . Wh�Fe!.�:{ , noɏ*+24�|)c�-���f-adjusA�Muller-H n bra�( CAMHəT lF�sbpla�5by����n�biodsis�E�A��G&t && * rem�tA� �but no:&Bit%%u쁭iatQ1-G!�0� -k6�5 A�6 �Luria)X;�o7� A�!�p�attribu�� y�-!��m'<of dec o� 9bJ� e * $ATCC 29213ak � uniqu&� } loc|im �ly upsjm��JxptT��3�XVer��te��, RT-PCR2U.� !�U���gur-e�operon�EAkof�, pbuX ,!�B�[A us� '"  guaB unde��;>MaK`A}=My� �2ifa z� &f�{� ]�J�6��5�� W gram]th2za��llv"w��"5 h�g�S&sZ y3 , 4�5%���. ��5��a�vA clos! .� 4��a5`9k3C Sur#QNamo�ff���te��,i�sm�� �u�: agar!m�Ds&� �abi�toя2hE���H.UD�\*� A;-�uM6yN�A: ∼5-fold�er?�9>�mod�>>�8�resul:dloZnu�a!y�-b *�A:�� �� �yG!�� $mJ �� toleK���Ks�5 �&�+ �U�K�6s' Pde���� A<W (!W 100 nM vs 5 -�A��,!.p�v�#�n�isi� AD�of�oxanthQ 1�i[�ly � r�m.� .�� expl !EHU�UK�ru��Ѕ]9 ( Gram-nve*�:��i !Z& @"Bs�����r�X� O�15Xu�9�� ark�Hu��O,� lu��t !6&CD6 isol��X��K6k"H Ry�3+ I:�/nalyzQF�-� ede��e&� E all!�.� s hadUAͶ9M%krol�"�PC1-un*7H!dide �.D �e�R�/Tbest exa@A����onA��w� 16S r� sequ�% �^m�2a\"whalodu�El�N� !�0!eE�[28M7�!�-Nl6Xp� �� to!;5KP"��a�!vP&�# P. A �ultU"� B 1�exI�ng� nounA�phenotyp6re B�sJF�&�� doesEi;on.6%|$o�o�kn�#PhK B�our data�I�a�bd$�moN���A�o�%a�F��oryQiNsh� `��y Xupplemen�o�&*� �N$ rus �Un�or out CedT,E.colon�m��%��CFU )"h llow(se["%�di%#" 3�A�dict,�z�6�G relie��|!P�i�a�ell�i6/!T��2 h�4 ��orX !xhyp!�a�%�b�NF�/ ��=��*����~� [v���uwde6)��[�ňf/��#irR����um Es- ichi�i' 3569jam� �u'�B[F���As�}e-�"km�noN3F�e%� Ƒ��%��AcrAB�� system!�� ��Cembrane@ me� UzS4�sW'���F)min9o� toq����ab�� L�!%�� beaZy FZA�5K�fur��chan% eriza�� *� �?o�+.��, VA�ti6�q :WobA%E�:�_6���:"�eDa MIC�00 . 625 mg/mL9�4 2 u� ���_�s2H *fY!�be les*�!�n�,?.�2 Y>�e�mpa�toJ)�2# extrem��M*q��"կ*4 ciproflox�� � s": A5��� 4� :8!a��O(?�q6 to 6!�7±!�58%hH5 . 42±1 . 02 log ŋ����CFU!�f 1aQung� {��culNof ]�*�!�F� :� oY" saO+"�%�rep�+Ied: �#�zor AMP�� ��8 hour� B!��oAby��0103�i6MmUI4�F!}F4U�  fic��@Ssm�4{ �' �2b_�-o2k"Ů*��*������array x�=!�ai a_�=�iA3vI-� D&t� proc<* �&�", secre�,O��sC@*w 6 ory/� �(�A!�y0!�f-U$ix&�A��c2�[30*$"4kA"�4688� , e�72%< M�s(��*=4AxqIu�wh� e� � � -�$j ( Ta�/L%�A`�'*.YI��e]*]Sl�-toE�J�!P�&�?� �"!�p� )!��&t=q &� :(n.)��w=^!z� gyr�sub� gyrA�gyr�M�ɇs�0sekeep��%a �y�I"Of�u&3a �,:Y� ahpF� ahpC�wo6!H!�F�!+Q�ng�.�ae�� ��l�.m#LosH#9��%ha wlyn� |� �!� lJ�O %< �� MY[38*a�n agre=��Upar>!��rescu*in"������to.��E��l>m B(In~ Arn )�" �=�1�!� full>ot)(era�I�w � � at�"Zfeedback1�ory.s%F� "H5�3��e�+4�.�.(��� ��1 uany kis*mk� ak og�E�*� IN�MX��rough2��mm6I@0mat�  in! E~�r�o>A��NMq�Fi�@U� 5=3�)� E�fl�� E�@2cC Ao� F8DassA+� Y �-�]/+astitis�eW�"6kkadequ1- �e clin\"ontn$. Inde�eq*M1 morb�"�7is &��A is�um! Q&MPmajor"�.�bov����i�w f�(�6!��7N2is�7N dairya?�$r�]5.� �apwusuWfai�'@)limin��r _herds [3U8?� ňb�%>���p�(firu1Ro�7al.BLs t-c cowK q�)��perV aSch�&.�"5�A1�ItefH3!�" 4 ord!Aof magn}3ʕ1afterf� .�&to ascer� iW� L�� vivo%�m{i�#>be &�+dag�A)�n�&aT Za�levi-wb2al-time <��n�n� 1290�a�n� i�!� in vitro� �!direcA�-�d)��5�mil�+I\�l!�( M� llar5,d F . Maloui�i�epaH.�5�F�>����a5�� 63��m ��"env� � ��� ��a�at�(+limp�+on g�%)5�u�8� �!b8 �:)i�8�proofA�p&�aO9eX<ac"�EY22)F�DoB;")-�a�G1At�post-� ,.BonJ�%�ad�"s�! A;ic��( sacrked 6 h �jr}� M�.�:E�%Oed  ,�6��aL(ou��� mammV4glA�dr�d�*y ��FH&!�@ >�ec[;J ar� to wAJ.�iN O#,� x�=�O� !`h"��6oa�6���O10�%an val) f 3 . 97ZgAs)atD'50 µg/ ,. Noteworthy�%"& am�wTF��100xMIC.l��f au�dt <� A a twelfthj�:Na�A-�/ �L>� < idea�x3b�f�R1�*�"����eA� roae�,��n�9( i . �6,+ ox�5.Q)�m�c�8 [34]�2ps�R. CF�**� � ��r6Cx0a�a2@&�b_Q�� �on^|,d�,=g!?9(DTT!Ksus�-!  ��S��S$ Di.H i))l�$ scalr=�:���?8ot��A�t��th96, [35]��'~!�i-):  �� bloc:/n��a"�at��n" ��) !�0z n 'or�_�.��1$92�b!rB�,%�mut�"s &�!iͭ!W!�Strept�Bsu�6]�4 Salmonella% yphi�Mum [37]��l3l�'��a porc� �\0n�del� � "�",B>1 bioavail# �� ha��[A�l�%/is(9�A cruc!d!G9r>6>�l���3"� �� stud!�A�<<6� y6aMcin � e4 blood [3�0[3f V� ����'6s%6��ith�1 nutr���:o�5� t�RinJR{3�>a�%Yc�&"t � 1“"f ity”��aq . FuqmV$��n@�.}��4d� opA?C !�,&!!1���&>� u than 30 pA2�1>>�� �a fun~al%�*v#r*"�!v�EaR ��6b5*�@A�%gEG�N��rm� �7 =%Aig*K e� �(.3 ���E��E � "Q#��n� or�>>k,/CoAuBiy=2lm�Y�u�it�*b E�4t "�<��e<���!�val�@e��D" �t�*ts=���?e��a�8����P(��(I� i2�D&�%�+ broad-E 'Y"� D"�=at�" ��1%`���BYnt%. i�"�E?isJ�%�o5.m� �%x�&O atU�.�$F��ycip!K& PC1** �lE�6�( g .Z<-� AM�A���ind ���u�!).�Jalb�� comb�!����f�S +,k f "���ve����A�I�!V) a�6��?:�&��Jpt�"�aB!��Ca3*yF&5"y NA� o� � in.��2_EFperturb�e epi�� path4>�?�>![47D '�B� ��uʁ.�toward.���� &�'w appa�H&�C7m�A�&l�m�:� :��Iasa *� e �3 "��������a� T ���A �q&�?��!��)0�1w11X*s�Aic acidA%.f"#)%��E�twi 9 a1����$B~J6-.�63G&�-!�< kօ9UH�6!��"Mu�TB.�1�'t�I�U.F92R (g8*śF�N�"�� �w��e.:m�&�Fa� �z2O!^5o"L2�o�MYL favo�#a.`1a�e5|?%Ere 9� I key2� roup� By O��b\5{eA�m�:��!L%�shag�6"&a )�.>;1+o*�.}�) �.R H �a� �� � c�u�$� ]�-�M�5 !�!��M�As !���A&{,an�� ach,U$��diP �)*>!}�IQ!s��d�s%nys�G���}ayAa&�( |>Ta9SJ�*�6"�6<A��W1��aB ��&�:ix�M y: -&d)�s �� I,0�`Q M���SE'!"*RFcaNw�e narrow� y mp�w.bed �l| =4.��OwoG���16�* U ~�,J%&N7e�� lema} R�T ��Ry�0R {l��f$!E�&"_I?ve,new%N��q&�MuR٧v=F1L��>c� sA��Pencoura U!�( �n� a�e� any]e��F!�zin non�M*(.$h ��):�$m�of.T� -�� in"Y. � itvS�Mthics��mittee��W*� ��M�Fa��é'D s�6ce%^AOUniversi $ Sherbrook�;Qj%Canada9&;H�0�Am�'�F guideD_>a�C�2il�A|@CA���QU�gz� )d~F . 4-gHxy-F�/J1F�!U�'4*F-6?pi�H���,a79-uWyl� �purch*G� Fluk!�42-amino-5-brom\ <-4-�8olU)�6 + (HNjAld". Our��Q��3ov#t�H��nM�m� iu-d>8�cr:�G�l h�$6~F"$( PDB 1U8D� �� silicf oce�%�9��Y 3NRL<�5���xJ%�)bAqQ*B��G!�MBp QeR�6X�� p� *!O al duplexJ -c1Vi T7�+polymer�&6�L&aVI�[-"=9�U � � �!baa��Ken�.Ia�\u GCGd> 5′ �Y%mE���p%3 yiel�!�>C{3@ hete�Qe� �[-32P]%:�incubhB�T9U at 25°CaZP50 mM Tris-HCl buffer�H 8 .��2#MgCl2E-10KClA"X?n���:SVd�:"�W:�)�re����stoppE VAa 97%�mam�XG)%'7  1�EDT*-s=;QMuri�by�KphoX�10%E4acryl bg ( :bi�! ; 19:M�8 M ure��Gel�)aZex"�LP�Yor Ima,s�* R&n1beB�G6�*7 � �i�|o�@�� edm-an�.-lacZ6}"I�i��Fg@�>e�e�2�I%.l)�J�!�� as mea� d �4(9f � thA�37M�e XCe?`�"�Lr2va�U^z[4�`Bn)�ino�]�Qat 105�!mLlmel6�G�B. AF �� soliFAE)six�/� 4 mmT@Oa� ~mad d fi@=e1�LQ���( �6AP�F6�1m�)M)�1P�8,2��&I04� A�7�*��.A5!Fx�ro�;A4hoEW 96-w1��2.����at ��2AOin¡IQ"��:bb-A�AnODw595 nm�' �΁�G. Time-;a�"�J��Z�����L2E � .g!�A*��P� _n�"�9jN}/�bAE�*�=�µM�9�l�&;�3!P2C#c,ng�9 002%��ton X-V.z'7C6poiT &�= ���? >,lua7bp+Qm��ryp� soyaA�j'TS+%��CFUU�%�!bfmEuU�9 �>�8_�e~�60��:��:\l 1�A!?9���30a�A:�g,7!�%:�)C2µ�&75E�sub��#�$r�AB�7� �Rene�7 flu�q) b��/n � �l c lab��Ac� -��<hyN �X!�&�4�8E"�9h&� �qfm�(&A/�$W% Fpti �r.� Newb��|}�j[4 . CD-1��ng�� Char"OR�=t �&F ,����"12!U 14 d�\�,offsp��bir�.yp� ly weig!T35:40WPVremI1 h5b!�AAQ�!�*�g*j��xF; ket!�e/xylaz� at 87%13 mg/kEC��TmQ&,Ez�!� anes�ia[�P�]�. AM� l sy�0e4a 33-gauge blu� eedl [K?��IP L4 (QEle"� R righ� bdo0l$ry1 �Kse1$- �-GV!�p[g(�h�S 0ail . Each ud�+c�%< �;s�" cu�Z A�near e �G teatZa� �r)��:L!R9�suspen�( 1��µL ){inj���roN Mm� �EXeeqLhM�&�"�2PBS�6 10 ,� A� �gR+*y%�`� � ��rE72�� arVhomogen�)�"MEAx���; 6� 2 m%?�U!9K a�DJ#�3Ɇc, Xha\ YK6 EF�c�#L!�>e?%g, . �To elu $te how gazH_KlO� q�en�space$ wayf* n=1 vi�2"P pr_5� we j�v�jxe�d navig� behavio�� I%K �,hippocampal "  aca#Q0monkeys searc��aS8tua'7a7' m�!�U+war!C08o="^Hpl��loWXto*oHregB2)i��1!3,dA�%\�c task)�x��M��s��5tEs�7(E(� nt$X�,�-�c�QmarH�ew�-�m*8$h8, .ultaneou��g�A�� ’sAs� Bu)�ao� se�!�\1�+A���oa��Ov�"l�[N�A��J]���[-g632JtA�In�ri�b"? �0ewM �1af yM��O�e�er!V roda�)�)�i%3M�embody !;idpV��a�%hsi!&edr0 ledg�Ec-��A��$rein x �Gself-aw�"� �F�). PE� �j!�qu�s0��"Zgex.�neog!5N�%�cod!*T!E5wAn2`/[1 , �Tcg^ons’-Sm k�u+i��1o \X�Y� 4and/or vestibu�&cu�V�#�h ly�-��vi6�setA -�s [3–aa>M&�oHG=Os��ng`*i0s [8 , 9�-inj'� !feaZ�6?10–%k . Ye��0en�dn��u����.�.�*��or�precis�:aZE7o2<�M M��!�-Q worl�;P�kk [��ks;0� � , un�Z,M� b-!�us�(A�As gno�l,��-!�@pe(���). NeuA�:a) 2a�pconvea� ��i� OaboLHs j al v�yt�,)� , eyek#��� U�� ltho�<)ߡs�Wm&Tof6mɋt�:2�[1[.���:n(*'3-5/}loox1a� �param�5!A�0fi8 5s[10M_i�i0%/s!Mtradic�*hA���s4A�1�suma�GQjAz��y\�a�robust)z-c�˕��<�l�^i� gle-�7�q�,)�� ap"!5 conj�.!�)�����N%�E$,*W"�av�T�93ed�o.*�BasEHtr�!�f"feai;s�G1,�w�^�=4 y� ��EI��<y'v����s!�nua �1it� �# un"^��oe:.i7G �F2N ��"�9�]; ٕ5��t%�e%!�g�!Q.M�?oal-o�14� �GA�%� -�� lan_ � !�"� � ��I+�/Y �$�9�)� :�!Vet�͢ en[ r%�1 �1A��]>x?of՟PM�K���Q� �.�#t!�U#m�%2�*retAc&� "/W&tra� oY\a���segA  AulEpal3na^H ��)� M�! an�Pr [17�;PqT�I_�1s  �oBN ( VR` �r=� )�0echw]i��[���<�0]A��QaEe�ariso�&iZ�n2�5]�hiO�W!K� 0l, ri�!%:m� inpu] I!�is framW:k��uEF�O�n�d�Eeh��&tho_a�s �(A���o�xg.[2�Z , t*xGgap�{u�1Tah*y —&Q-�—�pEP�#7�4]3 We e�F�u��t�2A� aI 9a�b, e�M� u�B]I�"���6�Tbb��b�kau%�A��!�i�k�Zi&Q5-!%foc���p�idbchcQC.�=� �ruc�/D��I� U � is�l�l eful�*7 . We��btwo rhe� ""to��e)^a joy "�� 3-D�8r�s�0�nAN1B , Ma�R�8Me;��S�"S2 Mov�$!3 s s� t a hiddeAr;lo"Y80A=K��- �^W)jbox��Y(!�z n�k n>�f?�S2� pl(o�H��1�%�r�0ga.3s�~�1unf0^( jw>Dr�8��h",h�J(ea�!2(. On e}daA�(�a #s� ��layM �N(,d unfamiliar� oa] g el!J��J�5�aJ$�6�� +)���t% surf�n�RkX$nd ��b1iacross2�O�v���[toE|t) �G���apJwb.w�Ki-��p�w 1s� + �'-�N� learto�� e���!Q1sA\�m� erro!_+ t���80 -�1 ± 5a4 KstaKx-��em� $+)�%]N[: s pukl!�u��"ov�reL�travel�B � q�A��,panel;�@riaA sym�{z"e f #of� [FOV]�)��As f� �ISro�4��or ��.hoS+����0.�second �|�cq�q�CŬ �� I �Iq��a �turvFig�ir.oJj0w3# Q�����9 ` a ju� }�l�>Ciuth.�fou�ne �Fin���)�a � �K��,�y�randomb~igA�E�2li�BE-W��� *� W_�2 |�UarRS����Me�re� �o teps5}cMscho!%. I�>!# �y��1��� �� di�� {- �0� re%.,* ! woUJ �I�D�)Woc�h;2hys��ob�  (��q��eQ���`!�' z(dXwo"�Y��� hip�G� 9a�MZ.I�D}sW%cU%�W-��M��%�! ���.: ( 70° h�o�FOVE7�lai{is�8�'2[vj� y�mp6W s�H 5�&s�6�."�AL� "6[omps :��'��rgv�rKu�@ 6� !e:�ey� �+�C; G%P2fd �map�$�+l<%�H ,J  �Cd Ap)n ix A� z� )  a��!%1xkR( ! I$��n�.YH. D{.--o�%sak  �� �D.�S2^�k., �"��t#"�)�� �)m�c ( Wilcox�es��p <�"1 (!5)Bv�. S"tlu  1� re2K entr&�O�`o!  g!n"� :lt�*�9a�+�{ (�5�!�S1=�!'v�VT+p���f��.� ��L�ς-"�&�% driv�-[/&�quicklyU'0�@� a�gU �L�9s.m �06U�ar�'�Iz�R� aS3G*S3B%�) ;-y S��Kab��(1/#3z 2j OEM�!a)� K��sò14 . 8 7. 4;. Fro�R�K}3p�ynf� c� � k�. �ed 90%h��1" ��u"ly &M� ( 89W\ s)�m:rebl&�%N&��)y�?�;2`�3E uI'�n(�hez@s�s-1S%>�hJK�-��#�� o v) !V�6� r� ab8O ' !�s ()%GK� i�8�4*�Oa�rerA�@ h� JeaVWeK>s�$�WiL� �or�C�Q��]w���K�<ym�Mfu!��%b `M�"��%!!�Q  %�BӖ�M� K�73%ctM�10!q.Y5us 445t begin%J �1�}��{80%B55B( S3Ce�,��, p =���-�+i�� ��kɲ%b%'1f#ag Q'�rY�E-D�7A' ���", ! � s]A.��F� er�e���Bs��!Sq��3on ���&P� ly f (�in�� m�KE�wi�!(7 �<%S {p�@��aP�& 4;R�0�}9�M��e�!9aS��{flexie���h� �� _)�a�b�"7a��2%/�{!�e�� y� �  -E*"#,ir?A�ed &�p��r�rof.a�D�h!��6� � � ory�i'�.�]A2706rec�U}-� B!m["�u��128 Ai�!�142K; S4eg8w$c%�on 189 B%Afi!W�ͤ0 spikes�lq�K#�8x�! ly >q�Hz;�.�JsS3�a�d��F�*f���e�i̎A� Xb.�� A��"��3�7� [�6"�-bI��0#� =�k(=LPog9L�!�84 :" :D� ;. A �i*&�� we n���R<ap(}f� �� � 1"�6AUw% n1}a ~a�ani��!�*�o-s�&:E �y. S )b ofte�7i  ?�t.�I��m�?�k �@&�P:ADu?D�0UK��$� ��) b] ��EMFV� ( grap"�Fi�H5@ n$G-a��(�� �-6)—&)“-�� er ,џA�>Iv!;�linC'r !��X |S �+�t��ut!�an !<&� �n!1@L�C%� %ec >)�:%�A����5�j�f��Wa2en!����,� 1#f �(u/ �O�!)ID� +#+�)1�qsE�� ([ HR���J�* �-by 72°x f�a�:by 36:ѕ� cMm"!�X&��8're"�7Mz�:a��>, lemI�V+�>i ( )�YJ(����+e,/:V,��6Q ImEH1�""R�k �,�wsAj�uisEY(Al (7sA4E.Ta6&��%�mwch��/�hs T�g�ae dk0s��A撡A�pop�xR� MeF��s !��hrhce (��s7 lumn�{%���[#�� "Em/+�i5�"�A)r� Y:=��:8�(##C��(of �1–5R.�|0}a��c�.�#��AbO�&A�-�J��!�>�g@1g!��>qZ�t��,2�"� si!w"),!+�t�Ai�;� `� *�PYa� .�+all=Q�k� !�I@ ( S6 �2� q>x�p"& � �e�gK �QZ'l�S}��"" !}�*`r _s*/Q is e"F�� ��m "? ���WcoordA�}�=�5�{M+� ve���urn�l�!o�v��Q��1�a�wYsJ�!x ��T����mid3�o�R!��U%�a�nGQ"A��y&ro aC. ��e�l� r�c"�Gvi.'� A�a�$Q Y��wdncL!u�;W5��e;I!d:U#)��2 �! 6q,��1^#.�u�U^-\ mas��_�9M-!b)��`�n[ Qbo�@ ^VQfa�c����pxI`� �#t-a plo݀6�u�n�@l��aoɔ,ed.b�. "+�H o�02�Ie)RA�!l&�F�Q�al�*(�\8 R�W X(�27G�P� weakL*�� ��U 1��l� u�q��&dٹͳ( n = 3p 4 :rA�We"OW2!��$a� ��7 dard?s5|I�S%��.{ 7nt$/ ( �=!Nac��ind��6�&"גqu�ocu�'Lnw mA-Y 2wZik� v�3UizZ ���a�0=�\vIe��)-J��!>�IG&� bins� YHI�n�|ac�n�}'Z! IC�| �y �.of 999X"rog� Ss3Yg�:�5"�shuffi6�=od�c!�!�.e�<sFIa&G�c)Npa�$nB/n!Gw�IH�^ is w�I�%��I24�erN+.SX[�7]@s��NI�$y��_�"�v�D%�-���Z*� !|����Hu(��#y�c��C)SI!7B%*)ac6!�)�"�Y�Z�fg�a!�(&�X J�� t1~��/M��|111��1"� ( 59lAX�v � ��� 4�!+�� -m"ach l�9)t!�n�klDhi-squXes�E p� O� ����r��qN ( 84 �,�d �� piq36Q�QK���b �Vm3e�=th%�,a���22�( r��Bo & roniɱN � a��!2n<[�� �#/%� )�(6 U;ce%�S*G tN!) �:����!muA�/cl� V 3BLNo� ��im�Ad� *�6���U[]*f�HIC.@�"� , A5wN� M�u� S6A–S6DE>���y�C6�$ inD;�8En�|M4�|:"! i�8b&' B�M�o��/4ngl!(r� r�* ,e�%�"1 -ѓi�~V{� G#"&��Zeriph9� �*)� . B5kIC-sp퉕�eYZa�X ͙� p�[c�ah�$i): |re� � c�  .� ��"  tu ��ALmq��+-�� !��R����q]5V"( A�6�!8  ���6 �*insJ� of 56��(�Qe�� 3K(b�ib��o " s 36��*���,��ahV>*[�by��A.G,yo���;!?���r�0d�]j�D6�3 �'d�� *ce:"�1� biu��$av�us��/�/fir�F��3u:%��ara�ifwW� U"D`�%""� arJ0�Q1 F8=!paMonM��How��a�& ѳe��D?EX?��*jo�"�eX�jMo��� ,a�t�Q�0�_7&�'� a[�6�;���P?�!'n&m | 5 &&<*!1eS �B?� n�e.`Q8de2 Ek�2V� ��s�l!tN:����"fby ���%� � �sb�)�"g�", raw6�?r�-W A��)biۦua �0u�)��5��>q s��1�� Bt�uY� �7!��12I�pX o�q633�,�� E�=8:�u�`A�B N� � .'�Isv�atB l;g��wA�A^�}����:$&-_(.q�@�� . SѱyN�B� ��2�.��)�(��00hc�]��Rj.I�>H19%x�o�;*$i !R�QA�*^ ��Bvid�u�m�/���per3l��=:�)������.�.�)kCon�"�xK=���9�o�l�.�t��:[k&�(1!g��� {!y\�1��IS���X1��N_#6�avt�"�u��ss><)��� �#m"�fof*t ra�=) a(� men� x1"��*i"�a'�J���ѡ�� � &�"� ��Ae6�2�5��S7��A�6�*�0[y� �!A�i�3i� !���]]5W,�o!E%ad y!&21���� Ɗha��2&�C�l(sN�g�Ksy�. I��,�f�5���r�:p�I�p�E5jt1�Lx�*��2$�: ��ing�5V:�of�G9��an!��FE �:D-Bqf 9���wQ�d �B�v�� "MM���a��,�R 4%5"�F�r6��K�I�!.���4A�pso��fX�-� + �b.cW* l�&z0='�4:=:�~tO� �6��Z��%exN�h����8Y>� ,%H12��� ` ( 11K�50N?R�G2k.e���!�C4� !I� A_��F #�4B �v7r',.kC8wo" M�*�H��'�nrEB94�/� � �"�!!�� 1Mlx"���CtirF2mpany!�"�.e ��I�enc2#a�bF c& s� !1ec� m�H!T�'a&/f!�f&�(6V�ۡ�AHa�&�ad5g�-D��1�dJS �+or upG�ng�01� LF�"����GUt���-��Qt �beaa� ��BQ�� "8 - �e�e�E&�)%��� d-k�elw� ��. Acc�g�"A22M�Kat6)�aA4� �x *�T� �I�� *[Ea&��2 : xm\eZ S m�c*��*�;��,*ifI�% *�vieV�To�fy>8 |B � �!YMAF�%(ho!�E �3E��F�3���W,� ] .'MqC�:T �va>Y� �p�A%=E ( 4 x 4�$to�)}$�m,9*f�+�)*�h 2��Bas��Q �E_� st�'��cen�.F��}*Q�� ��h6� BA�c�J@Me65I� 4two-way ANOVA "�5�� f4aof5 T ty (vVI{��!�p "~ )E{B� ( 6�v?�� �� R�a�&˔�Non5� �-Fu�.�5a�8!�c %�(R�B���a��e�\o1�t� �j"�;v&Ge:�emphaS2�-�t� �9Fx=�#�l��93� m� $?6.q ]"c o�*<:\U(��#!VI� /��%aM��ly unm> ��  ,. Twenty-ninS� ���* {�Xwo�"�j g":��A o�.1Q�)�qd��s.: A5-� & �� �*; &�:qJ��5��/� !Jwo t"&�]�irF&b9S �0�e{5!=-�q* pI�y�[!��+>�21��U\RD(9$F ( 9 , 75�= 7407�"�*�Af��07 -!CZ� .33^�3� :��71246"� 2E�~m>^`  Es� elur�V).@A1��IAS�� :RS�N �.h y a�5��A�U* seem��.l����&�I%2�Al�$�D�$}�D%a�NYth.�x�� ��z �pu,9m�omp�M��MUn� �s�.! �!Cv�go� )Ai� 6F��� #?of2�+( �3!(�waY�{0� xō�.�wGKaVs�nst"W_til��in�S�E45�`5��*�p& k/ !,��= &�I�;9�2�ex���A��1��� ��5�5 �%���2s n-borQ<���'in)x6 ���tcNp����As��%��34�c v6N5 m�K*ar; mo2Nor B�A�sݦIC%T!e&N_ �4ig �6.�D�w�wiofm� B�4!!�o "X w?3ViҪy6�? s�tYW%JA43A!6� �0 IP����ҥ�e� e�m@ epoc_e:��6�}f�l�C� , 8a 18i f�!*�! 3!i��/�U[ u�Q�.��!ge=�ly)�in![�tM��&�A��FT1�A5"+U�&;3$OF��[{2/5( 2 %.�F��3U��gk �-Ƙs��tY!!M%�6 �4HClԔj�S6�?6�f�e�"SWe&���(:qiUG�6���(:$KolmogorovY#mirnoviD�\ %���JXy06�AQ!'�,a�Gra�����?Q,�_�W*q17B�Z eg"�Dup��B�"�.1�aF9�)��Q��a�0�U(m.8�T��emt?.�i�c<ggZXb�e�ŊNC,z�:qUFIWaa/s22D%, p�y���2� 86��7"�.j7"��a� rt�5,"!a^B61*��e�!-he�*� !ZedAJo#0���Uae�V�� hi&�QV�<�� �*�a)�� al�I5.T��0�MЁ est-�CW�QO.on &)���`)�1“+t[8� 9�, fove)�(��7�&7�eej��!�:.�GygaHZ�'r� �7- j . Gaze-q� 6&r�5until%6sacP�:��pea.r shor�EF�A�!�aCnxm"qp�"!�9M� � kN�‘�Jnǟ eZ&5�%�1F�f a�d\n�� glig��&/�AJ��� �y/�_ece���Ai�]O2e�aa3�Z� r�1IEofE�lo�D�pr�b0xsH ej66.�XP ~/ Vt+Q)iS�%O ��yYw4 !*�ecr6l"i��5�e�f[A F��"# �݇q�&, ���sub�k�\��:�lI�5TKex ��a�%s.�F�o (VjT�ZT,� )��/9��Y,Ii�T�E��/��Bp*E1�ched1a��<.�+H@�Y�8��m@"�"ms�o.�� �'4(*� low-q&���4"x �rc 0\a ��"q �: archeY�7.�. �F"�k0".in VRAS�2xa��r��ia�9� !qAZa�!5K�Vld!���l&�<�3pp^:cO"�a����!!j�i2rb���%i]��C�(�t��.�_.>E� &ebraX�.v�$s�j�oO!�?*�D)?ref=� a;Lc�g�l�D&osetupE5���D;!Rh�g fMRI� XsNsk)ifbsi�mot�o&�k� p��o��s�.��>�Ae.fEX�����1�circui�T�0.l�i�l� �)moE&�%��[��A�v;`)���Jri�KC�{�\a�ll terrir KX]�shac�c ���M�stNi �a�;Q�A��e v�6-�6 pB�mena [��.ͧZ!a�o;an�EA�A��* ��M�["� 5v�!�&�NhEm��[2� ��j� �#&�.&le 6��VRA�� :_ ��v�~ll-�arouC[��, executHpe��veAy�dW�Ѐ= r� &�go$[��.E �!��*�!gd{tr"�Tq�K��"�AJ�UPselve0�/Nn"��L hall�q:�c"�M[2B37] es >�i`�g�rep"��H )fWap�-!,al��y� �ra�n���%��Su��!��PIK�>:�e��#�Ao $��|4"�l $ )�fh 9j:�]R�G%Je�A�*-a� �,��  >DM�Tco��'�l��n,gH[a 1�l�@�c�M�m&�x�H!DL%�AJ����ZVR*� �v'e/d�)�Z�display�y"4s�95�FCAlv�!�� &t �G !�)�� 1��Xu� a�� SE(i��$ FsJ�caruR�#.?as�@)cI:do);eyOa�,� ���l�X�j�:IhA")/>Bkp/['�� � cap^l6e"8hF!9 �!���0�A�&A�+"H*� )m.&#���5$,>�.��"���. C���*"� M? I a� �!� �-K�X0truly ga�1ޫa]4.��)o!1>2?2�3�a:V ��� �=Fum!!�!�q� 3� a�5�d!e�%����?�~#%Ήa���9U�m �B�!A�6�Uc�-O"Y 6�. Las� �� A�Z�K2K�ab�&��.�m�I �U��!��)v"��.�&��*�!�t�F}jmem]"Z�%�%�a� h'���E.)C.6 ��5a/il �T!E�a�-�X� efSkH�Ido4; y6 �4�**@�d�r , us�t�m!SA6� �Չ5a fHUe�7y  +���tgX�\�)6B LA\�ksembl� �M�es�by RoaA�G#ag` [��CtuFEx��l�o�oy� rele��k2���>���s�B�t��ʼ��!His"ce�Obl|usNwA���"*o!tѤ!|�gu"��aA �u��.��hA�emJ,on��a*��/k�n^QZ ��s ech�iin6zx2��> 6@t%#H1:�v ��}[3�h�or��fo2�!�p!�onW�ʈ�խ��Ku&(pZ� �-���"�}��.]Qp1]�a&D [%[��?��wa��r|�` a�*�)�U "� �?� 4Y)��,��hea!�r :.J!��@a�,a�@�av�Q9G&�5��,-Ido��� �(��*L1��t . R�:�8C��-m�� �|a dynaD�}�_&�x2aNU1� �:+3 fash!,M�������<,�y�`�,�Ys� � exte�ܱxAT_*��Qr.vg#h�5Vy*%6�[4�4�+4�Lca*�t� k�X-T@�)��- ��er =�s�L�n. refr��–B�am 2� � [��a]�Sa,[mW� :P�X�sc�#w��M� on2�!�Z#�.�酃d��J7 f.�� �Aa� : fixa� .r:�-&7��� rtoi�~�Wn�%�M .R�dl� �d�s 0¯�� F] ~s [452�s�I���`�a, "� &R!�A "�by�.� e��-�x�g.��U�ɴ"�<*Bl�� R��6�՝e� .�*��sJ-��*r{�Vpl}T\ q-A)%� *�>�_�,F� �%�I�]>�p ;��eȓoI0���aI` i:���-)�(Q��"  i��>�b��!g? x � <e%k����ng�u�&x@�9��o2 i"m9<)7E��b"�R!..� :k!�5( f&~ ey���Ge��� 8o� *�� P�v�oV�%� cortR4�4Z�.� ;.� " &BC��d�{j%s  S� �"Ӭ�١� �'!m�%؉h�zlyF{�;od)F�C1?�+�!^de�{���27S^"�%k��,b��&Qe�M&��!���!f.z͊"�yat T�:y,&�u�� .K��ф����")b]20bsi{�%o"u �_`�]�l%���|��\��A2e50�-!�Igm|� .W�+E*�M V�*N$�1-&� Z iV5\5_���'} Q�2� .g� P*��U r&�BE�* A�&�Ee"Zf!R �)=�5<1���7RC&��u� ( � ��*6�A!��B �UV��l>+lyU��SX ��N��2eld� 5&G4Qk. S?�&&u,-�� �4*� � �?�g� ��5�� m�9t��,m� a�Aeac����[52A6� 2�(�� ��V �pla9:�|-P�^i��:>-�%�R?�d.�!�B�*�) �=wUG!"�Gߏ zes;*��r�*a��.��{�^wo2O�a��8a�a��vCgw u&�zeZ�� �0cw�/N>��:AZ��9_co�5ed��8!�q�� m�I)�)<޴��n�T�Oa���/�� -��*e6��`r9��. TQ�"v���)�gr��ea8&���A�/h2"�o$pSln�C�-eg2-D:�5k 5熑�] ��V��vnݚ��er� *)—,Qh��sa��c�b7"������O��5n!��S.���MD.*�VV�aJ�"E��,T��Qcw *U ��'a��9�KA��s����"�DHg">���7.� trongr`tqRJ � t7%}� "�!OB�ngF�a�)s�ign}( [4�ofQ�� ,�l8�8rui�)��B�a�I8m&���%�t�N `�VRQ��� � !o engag6�!H%{���l$�8 ,�s�toQGk�e�$�J�5�!,l� ��gu�on� p !�E"�m�־Ca��D1io.1��9�B:hu�"�fixodward z.� g�Za���{!� r�w6c� �Y��0ent firing ra�etes . Studies in humans of hippocampal neuronal activity during spatial navigation are rare . Two stud\�[8 , 9] provide arguments for homolog)�{Tprocessing between non� to � prima ��[In particular , Ekstrom and colleagues [8] described many cells that showed an interaction b �4place , goal ,Zc B.�At)� poin!00�=+tSe full}�.'" ��w��go9�an�ifA�)��, � &# tegy% adop�?N replic��� Lf time| hanga�$he rules s�e o}� eat�j��S9 �-Aex“one�I� �g�� !�b{!��rE�) Oidis��p��pe^-�M�Q9�Phim��� !�inall  � 1Q�to WE1� arr!�"(s every day)Zus� tar-��$ed environ/�J� ;an�onq ensu�� ultiple p_ .j same��o� !,a� void� 8smwoo%rse dat� Ea��),�-�� te:>ik Y*:e1 �b�� began 1!� m fac�`�Ω�e rmE����1 C��i]ce�) urn left�r�-choos1 +o��[r4M�en�yr{itEpA�gl#d1 onlya�corX ���b@��ndomly��:!?A3tA�M"!��aeNor in .���<s$�seq<�Va-��I7 ( 1C�3)O�Pper a� ( 1D u � �K��of kn%�!�ric���O  (] )�QZs���s�� l d�Vm�!o(ve!�a top"�7�() G%�1H�To� Tt��6�X comb�JX>Zk -trackA�eG�� #Y"� �!#C)`!)�e�I�e�.� � �i  � regR)�Ehorizon2#aJt%cir�r w� enclo@u�;��#AvE�flatte� iw!�nnulu%�?]. T�� "�!�� $1s!�!Bi4 � �cen���� craniUQeye9Uk �,"�v���t�E� fi� � 5lehs a&� �i��� %z(��bike� dens ,Eq2�Vird�umnExaa_� ofs xi�ly� �u y�� dail*�7 s��A�-��� v �� areaa�see S4�'R]���if �vid)'%^b�  a]c ~ !�� UH���IndVZ-so onlin��a�ff(  .�ne�to�k �$them .��!�isthmice�r media�"�  mid-�Ob�verte� developr �ha�er@ by a� -def��pa�%�A9 `i�g��exa��dom|oj!���b�( MHBEA�g is ee*isd !�R��regul�net/5!sq al� n� ItEsecre�cfactorsf tn�Vyet�T stooe� I�*��� ribuE�wey Ia Bool�E�si��9`��t��>9-s* 7mse%$ revek!�L�bo& 1. O�8employs techniq"� {���log� m�Ua���ah%��a�s u�!predict ��� playMvar�.�$�C�"�"w� WU2,�"< induA , eff� of Fgf8a� Wnt1.��� issu at;unc6))pubM�� . Usxmo�a\ �H$plate/tubei cult�E �$& al e�at �9�Bů�as? doesE��e A!�>��s�!�In!�bin)ܥJ*F!valid�2�is��-�Q.� ���U�Q�q�A�tr��a>i. A��KofU�,.l� �a�� �-�(u��mod�;� is�^irmi�i�ind��to!�lA���� !n.��н���-cour ��&u��uZwild-tj$�qknock-ou�"d�#5����ETdem�!�� simi&� empo�e�X N�ca&"# g�.�#ab�)�!�� :��W�"�2��F� g:H5"a�I!` help�a%7�ye.�i_un�mI@ systems level . �ZA��&�!u%rvu$ D ari!֥Daa< curs�8�Ical�.�& hort�!�gaa0�o� E�u!��>��-3"M�k�%�6xio to fl'reg�,� ��in��o��a�.ri7mi/,*;A�spi�cor�'�� ��is�$���;"<BJ5]y)ene"�#�s!4 Hng [� �V* ,I�-xEe�!#[1j%1 of�>5 ,���d,�!G�T!� �P!�>� ( IsO )%{��" �a pro"]2 �&7 I�so- �#R.U e~N� p%�� 6��B �v% ��f�E�/#!�eo!%�: OtxGb�,�� � EngrE 1 En1%En7�� ubsume��i� ifier EA�.�he Pax R Pax2S Pax5��!~T@. A jusfc�xE wqa�wA�mplif 3�*-En�!�H�� Discuh :� ��a�)rse�'ady��trWm�A�E� �a�ispla�(che�)Awy�Fig�1A�1Bt� & ]�derz�+��in� u hy�(,%& �YE�&��Cg . [2]{FV � 1cA`+%re�%tC%r0 search re*'c�7%lso l�+ T�S1�3i� �ofI���E�-���pE" o� de,-�iv�, r � *�M6. fore� ��(�+/�−~n/n��/.� ,−.+�2�[3] , [4�0>��E�tA?aN=i fa6"t�+�6� � � [5]–[7jSub�tly� YOof��?ro/l bo(-!��Ie caud�)��!  F %bEf�e�fA��! �e�� requir���y!�!��+(&ss �/ , [9���aqsMivo rolAt�-mQ�B�v[10%�11i� esY.��iq �d �b� �,, [13��n�aA� -�ed/A#գ[14�s�& /�.&>e� �y� ival��;ve,�,\ be�"y%�!9pathwa���U[15)A�#�  2.Q<[16! SZ ly49,�5!a�H �b7!�+as-!ofH2H*i� Y�M )F$[102 ���� cU�/ ryos [19]]-s"!/an n��E����rndu\ E� � ,C "�-*� � at> �r���h)�c*�Ddq`E��0� �#dul�aw%�h,g^ guar���Qb� ir�"c�.�mss �o�Gtho�. a great d�%of3&�+effort� made�euB�� ote � R~g �o�we now&yproblem� "� �S �+�qa���theor*�2mak�d/ �to unraI Aal�of`plex b�+?� hornashA�z clos� f1 Z>�"� cycl�&propoagin [20mͅ�nu!j ��� ingl_I�first. � �b�� olog�)Zin7�tA�E����by �a�\aV1aly<of"�a!�:� CAs:0F�>4����pur!Kqu!�ae na�we - Y""on"V'[22 ser;x ��Y+e� n� !mq+�( igor6r6}4of2�]$knowle3��iV3 mpon�, h ach"� pec�),�as /vdix%�6�V � ��n��� %i_�:�j!i 0� �up:uANP i��q&O\%�o�>g$ d�*,3Y �se>rI0.�J��!O orig�ly)iaGto&�'E� itf u ?acili!X�ir hardw�  �.�li�ow"�>��u%dh�� �gRs"�?a\2w�� agree�>�I. ont�  �i6�."i� r�8� v2yby�in E -of-5�( GOF� ssay�+��t vitr�.� 0[22& 25|As X^�;� ��"g 2� i� 96h� ��� 5&� �a v�$broad� 1�e most��manip� ok� ce [26�[2�!�1@m6N��1Mm?+en mis-%�p�e�U��vQ�2� e]Qe�a�~&9 A�&�on�i� JZ,�Q���1{ PctA7�%E;e u�����e!�.�ly! peEE� a%�{��G eI�-b:0a�"�1iTm����Thu�da��XB8��epi�Mic �:�$hip"���, o:i%b�bV� ��is Db��a9�IIerIVaB� thata: )�!eN!�:�RFln�>on:� ert�y.#9k�I~�ca5spo6� .e" />[IVI�J:&2 ;.j��& ^1�f>�"!�]��!�,���@iPe� zAs"��<p�:i�Cstw7� si-=?)�V dT�-k*�e�u� [28� 9] (E�*�]%�6 �VI%de�-)�so � ��"a� y-farTt a�s��[. S�2ll*aB�F|aP;a�s:e+cru�v*A���E�=�m� " y� \!4 *9���n� s|;�*.H o�oP !}w%*v $�be&*alr��za|27�Ca!%� ���&F����"��b u� ��IDG����( ^&wwgE(helmholtz-m�-'.. de/!B2�)H'wmpk't'�2���m ��ior–&�$, dorso–�5] a:�&h d-=!�a�097j mpe�1�&g 2��W�9P{#�&b 1o�!po;to�B�9al�@�8 =�"�%m*nic ��#!0 thdd�?a�zannerm�E!�Soa�B9IPR�=�"R"�,4 lyy�E��� �.�m��)bsiB)%�^� =�^��A � mut�Cmic��U�+%lucS$ak�q�a���%�eX3d;�al' lleng���-*>42��+&=)dAI� �"G3-,u*#F�s5_'�']15X>�:we ��H�H"HT�U#��td9&�(� �,�K>d� �in��cs �<( group��)%�s� , GbJ�*�.*� �s�" �~��!�Nx:$����re�82��-a:2+$A�5���_"� �J.2�TakA��R �J^�ed`b &A�"� ��&� !�eEe�2:���(�MNB���ayBach [)n"�,2e.�~� idea!8 �0X�D�UF�!\aE;@cauv�a�m��;eaz;&�Agen� u�s&%o"�. Now�l#=ly�5�= `s �����K%�E|7八�a�0!ens�=$.se�{s Ag%�Khow� }b�aa+mu�@inhibi�GB� *z"a0$ ��� I Mk2AE"N%Y$%U"9-�>.�� E$�bs��1V.�m�!g� e�B b5C>> � p%[th�>$L�,�'D.�co2aA�� P . Ho�z an� �Ula58] �xyQ� ^ �1��{�N�Nb I#TBa&�- HKarnaugh-Veitch map��!q�!��&�@�.s�R@,*�:�7 )A�� BG�eu� �F�+"�!��OMd % XbI72�/,g�2  to!"3)Q&�!U-�)�aka�U�B�5�5ut)��A=!B�-�$sol[���wi�+�Q�sBrP$Bel��w��Iten�eU�-�d�+al liter�&06��9) 1�O�q�B� �!� g!X�Y��s��V�#�agon1�/E��A���=Kʡ/�U3��#&v�!�!�e� oppo�2�� O}(qG� �c&#?AR*r&O]�#30�Fur�m�H,�| Jv"G� �* �;1�:=��Li+& al�%�*, [31}3cP&�>%;�%b�n*!�!�Ѿ�2h 6�-Q���~��#J� @!��T64(�:I'26#,�dA� �!j͆r&��,2BQ��MPEl��#�!��]�K� ~Qnin�8miw%�%��sS#��E�e rect�9v�%>v[3�%��l�Rt ��o&/p! MJAleTi��  ?.�-��ge�0!�:�'%�\�=$ �A�i"�3��an$or de novo Mes)'HMv&9 ��2�ѵ-co�n� j�*N8 . 0– 5�>  ( E9 Sa�W2�3Z DMzb�E��3� %-=)re�>��� *��/�!_I(o� e6*�a4rol s�4�x�4incub%;A 6 h=��N30:id�Fqe�U *s)< �`A��oGB��.�18V 24 hhgf8>�mǡ`it��Ulo��rendogen�"e�b8��&& terr�NyaaotŖn )i[� >Z �qqout1w� -�� �(6C#!a�=+!?-�<<  �J!�Id�=�1�f^orAO�2fQ)"�W��:�66x�Nny� Ŷ�#�1� �R��""�WzW� q��TvMJB>��+5�6FE�(���&�-�!)�B^ 3B6? J3&��a��"�["J��� y�b�rM�m�u� � E���ED� B�� by [��.ue��7:�2>2�6A"�ed�*�'$e�E Y*F ��e�l$!@,%R�2 �#]�p�" p�' . Se�T.O�JE�o�<DQ1�|�[ O�*��Z"lyk o�!nE.y�a�!9:{��6,# *u�@&Jwh�1"�06 "� chec�LMs&&*5!�?!�)dqRk$`yna B�� �]>U��_Ode-�aMQ� r!dEf�G/( silic�<��%���_5>�Q�*ot�,�� t2�. C"U6"�&���"E�.=��; �{���6 E�m?�J Dataset�5!�2)�a step)��:�Su{JN%���A���%,� ��' E<e*H* %�&���!�$�1}%m�V����"�"!��$I][P�Tŝ!;Ņ&%)�Y^.i_�:-��S�E�)$JM easy�eAif�N�%��u1ő��a!�a" 9�E�zeWJ��lso=>fb� �&�o)����Oe:��'E�%�=Q�Jryu"�d�3�F DEw �@�hed'!�i�no a>�co P-t;!6>E/� ^w ntinu( valVD. C.r.j"G�a�� KE�& %!��to��6.��?�[a �sh8al;y Y62mP�� $while downMa�i#ase�#-G!Y l�3$U�;e�=�V|I�"tes�VtŶ��!� h"z�c1|Ls2`jc"MEL9|E�efqI|FW �Z�A^g�&W!o^36Q};PE~���ї%�KTP!��� $<�O�nj.tUE���pK*mHdecay0�NV� , sp$!��3T%&6�A he l��Jif�%; me�ism!�I�|\n2�%�5�"&"w`!!)m� n�2Ma��i~.q��^)�����5Q;��l8*s�W&d[%%Y expa�"H�� -76;  !��:���| `)u�;�F���/fulfi�O �#q-& ��0oVwe*:�@A`F�m� R%��we" �i!�� @1 e�B�kR2|!��t�0A�OOsRB1�m| e� _ir ow�+"� J �SdBJg��h MQt^�"��B!�M$�#o�H� �"�#9<�<Si.�B � a�r)G��v���!o� ! :WE!�suPkf�1We�. F� k,U2!�58aӁ.�0�!E2/Ib�6 f` [ ]�: 4�Mites:@G ]�%�tinguish�E"&56dGRe*?;�Enm@ �!��Mby"�Lmp36����7–9�6P6w<&�Fha#�!�d 16/� ��rO�� lete%Gb":N23–25f� z! #`��1M�2b�RyAC�%sU�.�*�M�2�EQ>ɡA�U"�0Z^��Q ��B�0(�R� 5�Ex�ja�� ���1�A&�&{_\/mbed-�!)+"O&� i]���5 �upper���!II�PAݥE.?��Vimu�aJk @_ .,4"�X'si�sca�"Cs��e�� clocQj� �$x\U*��i ��04 Xh�P�?�%3:7:@� in �). ;[_i�5y�%��-Ma�q&�� .�Video S�F 3 , 4�� 5��!�u��.^wJoie�)�!I�. e2�Nn+$M�F!�g<8 o*Vl � e�~fj2�.�T,�fu�(ad-hoc�@am�: est!;Ak}���� �y��M� ��eA �3D" $�)u�?A turb�7%�tkinLp&+f�~)>,�.��l� ia9m�]H�!V�J"!f&� 9U+! ') �"�6 �i!4 &Z�m�?s�]6��&J \{ i�V]de:aSal2��X� ey���$=5�^Q -cut.�4meal!s:qi&{f!co{cv*�3&c�Uwf� -pro�nb�Rngm�!66S affi;lMC9�]tN_��"�#Cw�`ac�;�sE��w��qEl*!�(R�. Dv�rd�lo�p� �a�MCbhFs unbal�S�Ac"ply }�e�Cex{+�C&/Gly monoMRZI&�yxD-M.v�B�m�c�]� E8 r!�5�f-V�d� . �}�-f"� �V�F8;1� ��3 63��n�_&!!� &8&�;��;�!�Jda�i�r�=�6�O�–��-�$* Tsam���t<# repe�"\^5 2�4E�3iwPd(aU,t s�%f.�!H�&rua��o w.��s��bda�5�#S&&DT�t��7quU� !oR6a��4� �0 sche h�� , �<ɻ s 7A–7C subf�< A��A!,�ir� &� ag_ !4>\B\8kB2�Xa !!b "�In�C�bN��� . Te`[�Y-Uɣ2 W,(}��� �)N 4�P"5d� ly� �pJ����` �%.�k�e� a�, �^�q(�E�cK&�� , up!��c,�7[ ec���@jnc�J6#� mum}��������bmM�P+,��ye �w>�-.� Conc2a�OA��Xa��te�8bT.�^��-rIP9gis�t~9��S��qnta%�cy !UA�2� :u (:�i�,=4[R)c�og2KE �m�@.K1u9z�)i�9B�����MnA��B�A�q����0uQ�. (+��j%Cl"� )1R-g:-gotlr.��!@blu@Ca)�is�*%� FiE'{1` �. S�2!�.D�W%GG�PY)��7�a —>�q�-a�t�.�.�B� � �.6+a��%��Ocn averagg4 ��l:.=��� C6�T�x��at:w3)� desi!k52(3 .��*=��.�&{� ��,<:� � !��&� VA�Q@-�"�� 8 �I)e7�a�,"�Q�K�[eV; vsYN� =�<�[5ama@�>�X.*;5 q��EV"/Fa *�!�?.changa�[]4xLiT;z-w . W!�C 5��:z?_!}P !�dZ n�S 2/ |EdAQ�!�� ?.�9QH 9��6� ��G�r�8"ns���devf�*� tolezd!ig%c �!�$I:�l J� ����S�%� �! �&� �!�}�e7inv*g"� !E 3�1]&i!��=: 5B�y�(R.AI2ew�"&%S�Jhh�a" C� �p>:)����_ -.Z .3q � shif�E�>k}�.��H#'��j�J���2n���)P���ofUAd+]be�n�_�r� �>�< a_ �)��}F�>�%Sp�1(&�go �@eb�@m��-�2 �7Gb I ��nd si�su�=?:c=C���:>#UI�p.�R.*q!�I_best-�~i�c��*L Eʁ28n��#IQ�:M�J�![�� �E�:82�>@Enȁ�_�X�o_:����3-.��!lufusJ �F�1�$!�� AYi&�e�F] �e��)A�!�Fclu+)%mfXa�\-��&�&SZ�FgWM�\(Sprouty [35�7QSef [377�Mkp3 [3)H3M\��Hg �05�sQ� �)��lI�!�!�id�o. B���fcto�*� �e�SH�"�S�6 tune % 9� it�%�E��ta9�)�bo-g�Vfeedback1n�% qui�n�lRB:;&sZA���n'd�on-�!W���6)F3�04�9H"t%e��I�+-7"$s�x��G���G%o{2��$: we l!$!]g�/ X� Als�II� _7yAb mB� avail�:�'&�/B+F.J. BQatMngG selv� 7��Z%�rH�y �i� Q�a�|Amenn/g%Iv*HyQea.XF9� -� 8 prec�q}B&� )�)���&�R" mx#�"`!�nre�'inl. >� E % J(!Iip2@mC�е/ 9by"�� �el�FHSPGs�%�1�7�5 cyto%Ur�Yr�cky� t'�m"ql)eV�&mL�sourc*3 mRNAA*�ka��4',E�&]g[Mpb1] �eh�w�!E �&ed �$�% �ae2u�J�p�|&� yo,m1���"J ��,��D��%,�S�Q*�%��i� E,5=�l� di-/me�~phalic&YC7ly!��r1/r2 �bly [4�=A�6)�!vU���Tve�zsR��� &W�-(a��rpEto�08 lipid-modRgdYyglyco5-���..(R�ki0m hydrophobic%�^��%�mpKane-tk 1s��y�$x)��!#vic "]pi�a s [4>=!+�EsT!/<�!, �!Eg7'Aat!!1 �ac�sN4�j( er ) -) ��Pach}"n>ho��:E�V5� eQ *�$�z��En1Fn 9"�7.&'@ e6�A©��>iLU � ?�( s%,me�{�lex�����e2ps�+( ��e(�7!�a�In�ba�4]�u���req�cc0#�0n%*) 0! 6R �,�(dA%"o0�D�`ine9.EebE� g�!�!�� $Drosophila [4� 4=d*W�c0" have T�q!Ta�}tY�U9uvk"�j2X Q�(�9+h%+:nń��^et�T�2R�!�7�\49��,�=} Wu�) �3�*�&�������vz�Ron�h -�%&�*U�ir���i"�:2!UW30~�`i$i]8oW`!qa%�& %U%(��z�w riteA ey��;"+@�'#mp�TI�"�� F� � ��16�*�#sHt�n/" �!=d����}=fsqpg�RJ)��pur�cs-qpa!� "/�,� )@�a��HY.u"�W�$�XW�c�;f.�n>+�.�R�do, %;|�@�R��R2n�j2'w�#g'��b1!� ��pz>d sZ5A/ diAphZ . P�l�3yn �-rd-Aeߑg!]�Lc ��i�C%<�pi�)D�s&V&�)E}�� � Ug�Z�ews [5�j5�j���q�m�T &� !��?� Q3y�MK b�t��7M�<"�� scar���B�8�2at:�NBF* ache�8c *on�E��Nv ?�p ka�p -�&��A�ch�RJ#Efe�max," �S*(="� �. UcvU�8rio�rs���2a*0E��#~1�,ruǚEs[.��%z-%�g�n aen`e>�O i�� cabi^h@&�vIV�>ng"�1�1 gene'�D�5-� .]��m'Qf�=)���� !,x�!�>O4p=�bk-ovM� o!Q*�}c���� fm=�n��!��;�&�& of n"D72��o?wo�e5lzcA�2,����zll&lMa�aa^oZ(-�%$MQ� g4): �8&�&,� few!ediwͬ�Q�TMq�<s�&�6m���"��Y�ur"^* .JA롌!�992Zm�w�+&q_A!�e#{12��zA!�-#A% =Q5�%�{nF��I.!alu��B�A6�Za�h2 vO2�!1>��" un�MIT�Q�=L!D!�|"� u� R� Tse��9y 2�&P�we��MP�) ���2�>oA� weak�z_�`��JJ�urB�:y��"1�""�e���:�n�l�U�t �b�e�!�A�1�,� Z%�">?>**1.�v>2.�%"/�M-�~-q��D�E� �Vi .9�%&ed��!ins7g �Se.�M42�!���!Ug�Qy�`w���6�qea���Z-�21ar�,7A2!t>���C�t/�Z&*�*XT �a/� AV�,SD�ard wjof:M�1E���ei� V�S[52r53g�Qu�McClus� ,algorithm [5�s[55] �!twok��"6t.�.V{�a c r graphr �&��2�F�e�y|�l�"l�pf& ]NJ87�ximal-��c�!h� )Mqtrue -~false - ~�� �9�(2)�+e�8� inpuyK^l� ��q��eas@#b� )o��I  -rtMf� X8)�.��zab�\%ch&��"��=�&as@{{ m�Ga�"� v�g/ a liB9d&�X:,�&it��� o �w-i9BFoy!NP-��\{*�(Cook-LevineW oremf6�U& 3satisfiP o[5�T W�.%��>�� heur�F0 s l���Ea>sso2d�l[58] may��m$Tsui@ "*A<C *�U���� 2C!��^N)x@ ��B =s-H" )Iav�i�ۀ!g�*�� whS/rrn�s conn7! ]�a@b ��� favoݢ�6�=��}�!ngz� o& b4 t�{e-t|I�bY �f s� �'[5^An x { 2anar,&0e�6"� �R���Jo*6��3�B*�"iC d5�� !� e� 6�". 2 "(6 ��.� y�lw!#N)s alig"�� yJ-�# awrst1�` EGbJ/. R0a�&�I�r/ |u�ES�A,Y9�*ۛ%ve&�76��#s [61C6�wM�3{/ *Y4\a��MJ*8�vF%`na�o�kr)e�'� e]I.�Z"YdQ�)�De� � .�!6H�(9/��.�R6�mm�up6d \%�&�\M��IHV+�8���y�L"8sx-B�jm�NaBR�C�?Ea�85�85OR�\( 2"z.eXBb�b�!%M�9#�1h%� Otx*�5&�5&�5O�{m�-V��$1�Pn( 4 )aQM#~Z~ �@N�A%��B�>�if_u}�ng2����: � ed m�EaiJ"��|�on��&� �m�6q�$ zZ�)A�*l�!U8.�6g� Y^FDu��f6oN�-( �Z�0(̓|P%�9��e.xFF'.�*�F�lٻB(�8�fe�5at�"�q�wn rB��Qy Q+�+i� T�~!�A �F  #�J�in liv:3~sm�A�J{A�s� �:A%FRK�[6�'69�~ ra�l&h _[70�!72]S-FV�],( �?�&Y�7 Q;|\3 \5]!U� s [7�([7��f���u%Ha�A-f,8��&�s� �6+�� .�/�" p�-�@E�ʌale�Ap e")(� ��AL�%m�x�;� [7%�W�M�- oft86A��Pap`&:1�Ne� ]"M���D��rbitr!��i"M�)vc{cr�:\;�it*��4���2]D o NtQ�2wa9�J�!l!pSL5�>7u��Q��*i "�q�6#c��%2=�Ri�]�G  ough.5��E�%i�6�%r�U�%�}'� B5(m�yow��&^Do���ref��uTlıbi&X �%Aa� ֪16��>x @>_C�$4�*] outpu1�k!��E����� set@ �mass-a�R(d)��Z�V2n#9f�aF!Al*2zA%�% qfi&�*I}9���criq��]BSde�_ter�%���un4%1.Ru���+>�OiTs�%e� r5���OA� P{"py��l Y�s-Y� s"��H%��vvQ.<9te��mJ�-!�di4�-.f�Qa-�PDEI�!SC��qu)�^B�*e�:���0��,2�[79Y8k��s6� [81]�aN�%H�WNT2'Y�676�T$escrib�7�ri��b�!l�C�D����TA;)0W+:4 Fourier's lawi�<�a{l��f��i��ora�s�e n�.�|e�igT�Gn@��Tz:���6>��R��(�9"�x�s�� �4de2R޵e:Ms$�t.Yb|ai]R�&�7of�� p&�7.Re61�� ;�k.�i**� E�aZ 'tFu)A���[r�� jCse�!�taC,[O , [8�,[ ult&-2Vx�Oign`quant�9o'!���(;i~�"�� �4�;.�&��o�VW܋�+tvNdw!�*�8"�)P:/�~&�A%jn(4"Q8f<"�ODEEpU�s!�L�!A�a"�U���s� cu��MO,JI m���*�:!+&�%.V�+��"� n�p"�E6: �-�. O�����'% 7!f�m'<-*g��pipe ���? ��!8to.7(ex� �.s4"}a��� %�NK8ĺ�.� .bxR Ew�&(�B&%-Y$�-D._ .!fc%�pEAS �P@W�H�YaxO�%� �(!T�2 ��"1� d4rP � d pi�AE"��!y�9�>� D�� d0,�A��8� 2c�"E@� ,� Q�lmid-/&�S.�-s!=(as Lmx1b [8�85Grg4 [8�87]�b�8Ins8~���P�KfO0also a()[A�����m 6�2���!W  po&X�6-RT,�M�!1�I �)ro ��'-q�2�W9@�f�AAS �U%tFLbt�opa��rO�AF]seroton #��/.�[8�&�p�P�!��+�^.�,�~-@+F�k�#(k��#�x1^) ir��l}�6?.�}��!"nCa �*��� .+.1e�apJ�eW����:at��0] e�;a2�^ ���% �Rr�� ��2�& �2bڟ>Qw�0�A'�!f�}�"�i�k+al�]*g�� d�V����dY(�%�'F@:N���e�*����mmeu��:o �)�:�)aI&&D]��. h�ss2H.����Lsnapsho�6�5��I�z 1]) >-���+�-A�Q-K%�!��97r � "��#�eW c[;N� �&� d�ݢq�� m!Ymi�� rt!vB��%&6B�. l�Q:�4�!b^ �fex�l gui��q! �"���jAlF=�V�iA* HMGU In��4 �C!U7Use��m��.�!�mn#e^{a�. G1&�v tN$PostgreSQL>?�p sq� org/"�9.�B��.��g�W��t(! �)g��*�As��͢�2�aceg��A ' HTML$h&?�� �Jav�.��!���"� ����]� �k8yo&ۃɾ . 3D��&E�A ��e" &Ka��� vZ��2>('4J-4�c?P open+; soft9�Ble�(6 �b l��!�g_�htoU?. Viacw2' LS���%�-:a��*s���h�+�Ro��.��7>a*�"� ͍�t~�l; .�Furj �ɍ�� �a��Uyes"�>�J� -pag�*j& �I��*-I* butt"�?���m��web�@]tk"F{G:ch�x�V�� ���������!�BS~DR 0  7 -�+��a:��e�E 1!:�eL!��-s*EI^��s%�oS}{���!p��u����� � "�jO�G�s� s�5� u�� �U�&�P�u� !uy�n��e�)9�\,�(F��wis�BT�;!v)�A�%Fo"�$a+>i- % a����3 nl:[1Ѕ2: H� u N].*e�$:;}�SA#&_��1��up NN. �H���.^,� %va�p�+/J�c�� a��]*K'M%"�mc2�a7A �f�2�or �a.L"?~^�9keq��7! ���L�1��3"�.�a1b*�<]�r�$a8bEyaĩO=.</�,J98��a�! 1�6ad-Wz2-�Go{� ky adja�2&)�7�% ��e_�#`&�$. A f ��� Q�! ���$1-�EB!Xf`>V*�*�8��-autonomB;rol}a>�J"vnon�;�ia�[`]1�1.����JT�xij�8/�o_ synchron� @�� (�%A5?t�s��3id)^pg���1ow��f6)R�<� � eV#:Rq���8�#��)eft-h�t�mArm�W��d:�5by ( Z'!��~]�9��m_�u�ly)p!.]l��&CElo1�(.]� �9�0pj�u��B��-P6�'�c"26��|?"^e��*t;� &�2Rh-�Jl�a�!����� ��s�-ah -��,A ���*[1J�q�)́R�C�/(A�Xng�"8��� Jct�*+\# ��4fix�;�B� 1�!&�<�%� �e@Qim�'?AHG.�e�h-}{�w on't�#� ��aS,ple"�ps�2y�2%��@���� +�ta�"WR� Z�2N�v �v�� triv,&I�en�q::�S�"[ s.?�Hn h �O� ��e p!�)��'� �7� �z�Wg%� keep�� o[2A��S n%T�&7#% �0%Wsa1 �9 �*r%=G��a7,�0, ݁&�")q�mi��A��U�Q���A�� �(�LW�l��6&x,= z.� �6td��6+U�J pw�L!*.���}@�<g�O�a�uչJoha��v����� I�/N$@��nNy;AW�� ci3%�"�>!pai� (E�� ed )u�wH &� )km� !�exa��kEnepQ ay uf���!�i:��!I�OI�.��, ?>%@1� @,�Jeg|B�7�)n�&�z5�3 G de uh!�v�e< &Y<�4) erh�i/by�uRV�� ~"� e a�"( t� @Gg i�����Nna�b*� lsuper�p��Mwbe!�$diAB�0�F�.wo�%��1^.V�*Q=I3�V�B��25ҎA�N.�!nT ��*�PI uto-1� �8x�i�a%�wZ�7 s�*2yj�em�Ba$� d�ve5Ral�<�= ��1sol�� E�� ]� ��Y+ &�. E��n*��(��ظ.xs�bD9-b�Bpr���?��wih( C57BL/�l� e��}C,{�8I!s�or��L808B"m!�mZk[9)T � afix fresha|a� dehyd� PF5q���!�d WISH�D.�#���%jm�"�{&�u^f 2Ca���)2�1�A�sy�j4��=E ��v%w!�E���Q�OR �[A�SGd��(�%J� � �&. ZEBy $ng *s&��6�D��..YE�f�] '3"�~ N��N��� �o%��"�8�!���-n�" G�8<n�I� � #&& H.we%>н*��><�;���)? ODEs* *� G' Ba+<*dl���ar`U�  I1�q��*c_-�%�pEe�*.;�6}>f).,�,lnl�lL�P6=(^ �sA% erva���ll��p� �� F�Za�-F �rA�1�.���' �U)5e�s�/�#�D� ev�A� o [9��$0(!���wB�#�]HJ��Q9F��� �����W �1�[)*ro)*�q 2NI�basic�J� XX�4�Q;K�sis(�B )>�r� =|!� q�*9�[ NOT , AND&OR�r �t=1.���hc{&�76:SZnub�e_.VW" 6� �H.f�� M��9@)y �a/ terpo$*��.��� :dB H)F� �F��CH9p:t%n: �,Bx�X��mb.�jr:��.�. 6aBFA�m�Td�6F+d� av#2��i5��aZ" -��"�)ML.}|!���v,�*Twe2ad�xA;�11��.|)"�/4s-[  �d�N K"� ��` �4�CQg.�a*:�iW9�Ki�<byND�C�;���IB� �N,2\a�9�����*�zR.\\)!�:�8+`�*��v�Hw�o"��Fi�*Im"W M� |�e �ܥet�$,d=%N5@|�r!d&q0a��2q[�a�a�� ~RdA -to-#MATLAB>j ��U!zcom )v ,/6��"�+�,ir_����apia%lexan�Os"UTheileri� n�;ay�a���ed����#�jun����prolife !qclo!/"3U!+ALpar}�*~(�y�Q��Yozo�.M t�, ���surB�A� ]�Z!�dis�G�K rr�0icrotub�� ( MT� [��-%>� �( !1�18�sch �A� l *&�/eg�T��inv���A�!)A�$ X�T�s "�[����.�K,&��t^ cytoa�, enga�<'�?H<nd"T<��dleY7H}�er24.R� daugh�7Z�!�_7�"хby� A&55 recr��s$Bzh.s-�!�KtAd . MT2us�=s���AW nchotU MT�%ani��Aer)�IR!�U��()|-�u�s�/, s$y!�F�\pha�6�rowth �hrinkag���:_a�y_WA� \{� P!C�t%:<�''a�act� m��m�W�2n �(Q�mT]*;associ�)w���"�*!�W�ywg����"q5� end-&|��EB��8a�{����MMT5;.EA1� o�o. 1q�X����z�&2*��� "/,�T . a�@p10�va polymްp_ tige��(=l5su�r,*� vgenuine!B1��-V$�!%ab�`!45�-r�B���B�7�!"��6us SxIP�{�.�  a�66is(ed C-� �8f)@8*� )@�ik a$ Ia9�A�[��-����heM�*�(%&h��-enco]0-��x ukLa bona-faU���ing{�ew&?1newa�cQZ���kK � .�d%�� cytoskele'. �<,tick-borne AN�A�.S��A- parv� !6�qag��of lymphgb��ve��ul cattl�DtrW�`o�XqE9Cof�a� oexnp5��Zoi����n�M� of A�UAfric3�6yre�|p;��3bmac�b��/$|cyFBC !-{�M)<6RT 0.<. B�� �[!Qu����a�Z��ap_ 5���Z r����pop��*�a�G��2)`L O�Z3(�,as Toxoplasm!b�P od5� spp ���Am�of5�w����@W��vtC6ph�Yi��*D����. Spo>� s*� �7��pi��,p�� in 1��30 !��>va�K)�A�.f li�h����!�5�&R up$� W���)1�/eg{a�%c� �$� �;�Ie !� nu����syncyt!�!DE�LI��A*����'�e��� fr�" vacuM��2�ժ�<er A�h �R���%�=�(a�mK ���jSOlAT*E survi2A�.Ad2� �l ra�� Av� ti�D"&�A*�!��F~9K����-6 9��3"� 6�G9Ar6"�c�kQ/A\Z%� mito�-apAtus�� !�-� � ![e�`!#&�?/5�b� t��ew>� ��ecu�7zX !v� �Xm ��O�em�syn3 � ��aOJ� .a 5�" [��W2�Q�1=kin+��-�3 ^ Plk_ �W w�Bh�'A�p*�nm���:��P�>��7� - A��pp �_� v�Yi2n �n>�:~ ��Y��� �&}� �#=��b�l�RE��e��� �4 �3>��SeR=g;�E)z�� isru1�I JJ���k�M��(ndE�i�2d��yC� 5'=l��]�c .�r%(W�� >�,�)�>"�(",!}�Ith�suppre�:�,strophes [12I 5� @sA$rescue [13}CLASP2 Y` [14]%i��Dsin MCAK ( XKCM1 )%�!:epolymer��� v!�[15f[1��By�m���A��Vs��(one another�w���/,-�cooperatioightlM_ol�1�-7ay��$finely tun%_ ���0is so crucial� Ŝ func�F8faithful segregəA�h!�somesvsuc�,*�3"(fi�_se!�7)E8 m�A�"evolu�ar����er�K mmalIplant fungi�)\,lower eukaryE��"tak���Nralul a��hub�Ae�a�r!�on1� . EB1�origin�@id�$fied as a U�artnerUadenomat�AWa�V

  • do�ɉ�,��� highi�M��adoptA ‘calponL `mology’ ( CH ) fold [22!�The C-u> of%�6�Trange#� E���A�!��Eqm� 4of an alpha-he� � iled-coil�%�med�$s EB dimera�m�[2�s[24a�fWcidic�al tailt(low complex�K_ �E.2@EEY/F motif , lik�t fou� �ќ[25!9In� i� � QG��m�siJe broad!� lassi�in��weXups� ed o�ir mo�of(�. F�=c*E -F�  glyc"� (( CAP-Gly )-v����!T��B su����ct� )U( p150glued  ificErecogniz!Ee2\M\[2��Ay� Coqm?@Database pfam0327�}qO!���verlap�@�A�:�. A-&� I�J�, [27L )�^F�� a݂S-x-I-PM�( SxIy where x!�hamino a ��hat"� ���� �^ofVs nA� ic , seriEd�l residues� ._of%2! 5�omeſre�A� onfi� �� ,ome-wide scr, �m�wian �e�-contai� f�jin�biochemA�E�bioinfo�:% pproac� w!;combine�Q Ieq  ���we re �< p104�� �in/vi� d+ b�$Theileria Gozoite,neme-rhoptryI,!�a maj�chizon� r2�%�&; ��ona f!>EB1�3%XiTuAngE 'Qf��c�+AW�%hC!�� apac�<, �i� e �-enco� N�9 to dl . A>�searchE*per!���y ^�at hav�lpo�k to��A�A21�c��a GPI-and�a(liable�metɄ exA'q, T.3 GeneDB ( �^�ao)� quer� A� gene�co6� ]�Ad edic�sig�� pept!衣�seque�� de���!H�8a�e T�S2B@Figure S5 , upper����T!�resul�in 19��di!�!CatiHi�edء1!���AYMV�re t ��2B5�E?d��oba�edp mass�ttromeaJ[29�WeQ5!mTA0842�annot�in}�ann8a1�a=�‘y�parvaJ�antige�x�kDaaG( h!,forth referrI�asW�H'Y!N e on�a-b�]%in q`by� ( ac AaDnumber XM_948006 )� s 51%-�(65% similarto%} ��%�O# pn�pu!�veA� m@M�. Eve�D ough [�j� �i])�A ��F s [395��$could alsoaee=byJ-Ariu$X-114 lysa�of pur� 2_Q�A�%M�membran�PSM�Sq�analy�[A"(A isolE�$from TaC12�s;u��9~a5 �� a globdN� a"F aha disordeA� al re. �B� Ea��� half��%"��%Aur so-4 eda$FAINT ( Fr%?0As"�!��V"� aH(� Pro"� @UF529 , IPR007480im1morphic3)Y�0Hissar ) -inf�leukocyA:[34I�isg.�Z��me� �pirA��[3�a��s��a use�diagnoe� markX aL  [@� , [3"'i�t/t�% od�� �, �vera<a4] until now� !P oflu\c�!SroscopIFM ) u��5�A�!�e�is  bunda��om�� m;Q��a�strainI��� arisoe]A����$( AGB56140A�E XP_953099) yiel0 92"� iRWb �ale �&.�)�*4��n�/�D  �t�sA��I?study� ba!�-� X%�- e9�S1J ubmit to7 0Bank JX965955%�In t!ensg cic.�in*����|� !�9ng  or2� >ces �o �I ] !vector,Western blot2� * COS-7 �E$ng V5-tagg�full-6�?(*�s 20-8r��(%j-CT , 47#!�*F %N%20-469 )8 frag�U�.v>n an epitoph!J_�!&� �U1&. THvestig�if2p ��Vj~A�alaXu �&�A��� ie�I-tiolu�9{E�9 6Zto��-=5P-VA�!n"470–!�,(C (in2�� � th��a%Qby�B.:�!�co- +���!ly�� endo��u1,:�)� 2A� displayA�!�typ�-�A�das�Z� %�X[3["pateof1�A.�T� dei wh� e })� ( 20 – !X9�(�X�Rn�=Ey�M�-N%�,�� �h!�,!�"�a��useInol�Q )��p2�pI� ly ,.i 27�I �bolisupon m �SKI� to SKNNYM)�agd�$)�at)9a� [� .�s p=  a"aly -� . Over-mFT �iultA�MT �l�[3Co-6>am1 O GFP2�A�Y�){of both�'to med�9�DEAAYa"��":�~]t. �,�J*� �e"�m"�!200 0in0"o2� (U�sec%�ofq�Sl3e[discu1be�f"O�Sno�� ��$; �:�. Thre�th6"<��-�e%�-��%2� . TA209802hs �&� $s; TA17545A>a�m!{$subtelomer&&rse�eDt�( SVSP�$[Ua�b37bI��'150a?!�� precur� .F va [3 ���nge��ntrto.�,2� 5#co�!EQ�k��� e�q�n�kdespi4)�aVcO��=XY� S2 )�p�S�!e�T�!Tca� C �!y"8 d � B;GFP�Q!qEB3�*� �0Anna Akhmanov!`&��B1e� labea��� re�I�J� 3��A�e samf�b�be ob< d� b%d|2�B 2�myc!�V5 tag:_~!�� �m)홰! �O�%)$ed{isŵ-(rtifact caubyT�~. l# imagw.� ,M!F-1F��� read�"A�movH%��Xr#A�� pherya>����, alo �'i�'.i�#�jf( Movie �r+g� � ossil)t!:d over�\-Wed�"!�l fix�E5n. T�*���.U EB3½�a�!�!K hows� lapp%Su�$�Ad&�5p [4x�Ρo�2�q���S3�� To verify2�recruit� 1�5 i�*�%.�J��a�aE> trea!��$nocodazoleA drugiinhib� k �g�&)r. Cell�K-o�<( �µg/ml��or 16 h�x#& lack��p�a��B� aph�(aSa*���� e�A� subjito.��%OsA��,ta�!Ki� -or�a�� Unde~-� �(�1^��still��&'">� 2, suggɓ �i��A�i})�U �� ��*�;3� Toa l�e="+A�.fE_V> gene�'��truncI� 6%!WmonitoXI.���a�~�&� ��qBby6?z�uZ3? �L*Xtyros*� �!A:)� e� pens�A1� �F��%m�didE�i�/6%ig�6��#?F�*��,.>!mlj,�( J%2%�� a�:*p"(\,125–268–����!$suffic!���B1"5�B#20he.VL in� � q–133o11�|��5R%�sV taq>| �Va�-.�i! e/�e.�mi)lik��}&`$}".w" � �PNs _!L�/�.iR�,�EB120!�268u'A|(��ac6�AeacR ',�f��%p�4��icopA� inflp X3"d0to�W2��edJ�. W221!0�Eo u�$tsU\u���dCť�� PY�\ ing;�uI�k plac! ��@bhow>sf p� ` 4"� , ��fewZ�!���aM Fi�+� � � !aa�Q5dep-� !�shortes']+ap��.8(� �+[4�+fato9� �Z �!�e nex� r�"out p� down�reri�p�/d ��� ad!<ae2���*p�,. Rec�%ant Halo� C�96W& � nprodu!�in E .� �-� ������prepa��s . 6��-CT mig�=sI"slowly|SDS-PAGE!:&�#(`kDam/�/t)2!�&�46!���0*�1�� p�nt*T6weight�a- J of 55Y�N4A�I�En2�a2A�=�9:���W'!�1&<#NAMN5�,tZ6&x!.�>~+hX�1or�7ur� ��s madedS[ 7JjA��+&�*� >:�*.�*&�f�=9assays� �onU{o6m&�. , GSTq �R�b�,�-�9�BEd�8` T39nrz�(�8FurE�b*�)ev�ceema�%+,}/�.KAf.�%� ��q�ofm����q ��Y�A���E�N�9U Wel.�f�nEB1�ym�d��!�y�&�9m�of 60eyH4i� KvI$^� `,R� ���res�9P&wo ba9�'�* xima� 40t5 �.ly du"z � <��-in-fr��ule>�ar�do In agree� )erp,rZ:�Q�!C -I�&� . No�Q occu{'E�21� >e��zCT�E �!�w �)>��� �)!�2 !c�*� Nv52�634 )�*� �&aa%������dm"C- �%�6 .�,�-!${�;�*�2A��Qau�g*�rF�$!A�m�.aJ���"V |W$ , [4�$^$ : ��behavio�4�6��Rc�0e�D���^ n To f��� %nF�� &i.��tVɝ�ofe�a (%554–59a��o� B��� . 9�>inQ=.1.)w10na�y,&r�v�#).�%a"�$in&�$�6XQtgro/ �-�� nN�6G ��9�t a&*0C$r �ed2WU�!Z.� 9qF�s emanaŭ. :q2Ta %�H2��@ � "� e�!��ma`(a7�(E��8��*�� &<r(�}�UQ�� eng�$�tip@41�spindl:�.7�a�"�Av��[4=(Ha�I=EHA%+�>( d)�&-)�=b�t"�s)"%L� e�foc% ��� neo�-" �B%E �2� B�$� Inp X �Ks�%me o�.�!3v � A.&o�k&�%t~�y;1Eu�9�!3.�>�2indA-�)�&7] [4:' !/A$U�1W�FEz)5X2 �!� mi�po�)3o�>�weABi� r�Jg�u�go�& *'<J!5A!nd 5B l�(In5�yme�.['�!�/7lyo!)�)iu u� . Be0:��)�88f#!1n unsyn=a7d culbCI�� !of%jG"�3Eq$ tocol���z$m*�!�.��B�%� Apt&@;5Abyxn�*�6�tre�+^ rom.,block�o8> Tasomal�or MG132�Ae-e degrad)Ayclin B_9us�QFEaY !%. Image�%� e�2v� !R�(n�5m; 3�� 5)7Q�BW��ter+!�e$-h5a)�fl��edph�;�e>� 2� �IdisZBm�Q�Rlym�I�ndɂ� ���-!Ju�i'b.ED^"s 5!oIH2l.�5 � prog� thro�2Y�.��"��@4bly ab!�MreaIA�L��/B}. U,$M� � re.�;%-2K!��^.2!8�eas>�e��IW)�OzJ�!I]�>A�vGD*A'he2�� ^#� |>�  (�!802d'"�)�2ch�� s upL49%uv5L&� y%b�eA6xTaU'A"o-6�)&�re�U�M"-C bod�,KT5�3KnC(act �)X%Qm�FI�N*�"F41�a��@exw�Jross-� [u S� ..��a2Ht)"Gmol?J&f101g����"��V3d7ppr&B13<eY� 5�multip79� phosphory4 �K ,NetPhos 2 . �3w��"h*dAIcis2JI�.� cub��1��7:2.8�λ- �at��dsign��� shif| E7bd&�;n�*�)�B s� �)-edY60#w 9appGH h B:?����dul ���~� n �l�up-�>�IK�&i&�%l� _!�those��)����u�to5� ��:�Y�-To5����<(">�)n)=.(��&K� e"zA%+�l2g ��ngn"Nm,to>l6�sxKU];N�.. A (F��s"�$� �I�g, d���( +Iy!7 %828.�m) �B�ca��f�'Y#8AyA�2��:��q6S�}��/ %�>�F�un%�-} &BZ:��6/. Wr7is�&�A streN%)rae 6x t Cdk1By�',S/T*-P-x-K/Re/!t�)3KalP weak�N ) [4�DPrelinF(ry LC-MS/MS ";%sBBff� t 4!��*� 6 s 58�960�607�62�. T�$/�*`(>? A�����%6�$$or RO-3306u�>M6r @��pronoun��7.du�+�$�;>�%� . 6�,ys� ��>1 does�F��a�afj F�a_�.�~.� a. �r�,�u�l6!�a�ll:C9-�4aJ*)��3ST !"e*7I5E(!a*�$b*ɸ� 6=.#Pl1!��4%�" i!2be���� � r&� y6 �{� en:\ peak�:�2���1� e)��a�M�!�v"H"��E��P a io� b=@�"�B"PH*%�"�$ t"�Q'� i� �� !GZE. Bu!u��*u��-Yv2��inq|of!Xrow in� !6u � u�r*")M\�5?1�.�2z (=P|+.D3&�� 7Ban�6�wo3n)���?u�12 %8r%ZR iY. W �!(nKJ 0J�Bg��&�(howi�q-�!� &v.�In!W-��a���I�� �:!F&I3�M�;Ej�/�6 s al�7�� "�8W"�XH0l��Q‘ex{,�  �BkDKAZ:�1Dnd= ribu�Ti!�!zu?Z�Vim�,%�13%�p Zty)t�xK�t�MgO� $U ��.1B�&�A�QkW!��U�A.�TMpe:RuJ&�\$ Ior�6o @.<$si�#G/ trW �-A�z�U� 2� ��mN�\can= &�aolex� ol�Y�!1�fa�=I �:2�1�isg=Q�.�f`D� Z�z‘maJ�orA�. U6$&� � N*K >�8�*�!� [as�%we[Ad"c �9}^D%2�Uf�}�Mu�.EF D�AISPL7.E@�Y�t,�*proviudo �� ��M�i�captuk_�A�r�]eP�Be�1 p�[:�,ťp>�9e"N(�3http://gM.o db .�1 /genedb/a-)"d.�%2X i�< &RM*�+!9I !"n6&�>%zt#�fz ngs d�2t�AV-65 zu:� &�Ws�%reey ��,Cticip���!B1* �"�T(  yQ"�UM|%�y���sm�&�H . Fo�Hst�E�:�0 ����o�,�72ac�K)��non&N� �(1or�0ali�[bC 217 , 201H154�� Med=&�TMof� ' M$ :'�Y�O<�S5y"<VAA�[�? �S� �  iHSr� �9�J�0!�>reflects=�NireicbEBU+-JAaQ�'s lifV?cl�NWhe��%!��"�NUI��sa�F��-��aL(zIu`��)��=!��}s/be&d edŎ�)� .Gderpin!�bye��E ) =,��MT-y�(!U�_.5Aca����MT�I ���Va�A�ryKl�_0Z �  civ�r?  +I amouZ7^�( unpubDed�FHowh{.�$B�CEl�5��pA2�*wa�+�-�-or gp34�J6�� Ή *nf�gA� s��a�e�J0Z|T $ B'�R� surp� n�$In earlier�WY � d"�$Zv�n�SicV&���#cr6�W� i B�R. M:�Tic��R�Hs�X�@^M3�/�M6�1 &�4i3ak!��2 � S�a�"\ {Ps e��"�O5"�K,U$t4N�LtootY�L�Y��Ltc\��2-8]Q X4�!)��GQBW%m�c���� ,"�A"�dI�� �c�G�l.� mp�]� *p-Ib��l4S5 littlh �+�B)� � ����6`R��n uh.�3fS�>�� llA�AD*Ry1 critAH0�a�a|$7!�A�C/A��3 abro)J<<1CJ�6 .�P� �!aff�֡Qr!��%TX2>�h sp�U-tempoyc*[4�H� examp?�e�tokaD^�Aurora BBy�.!*�*>�of SLAINVbٿe��;2�–trM�M�M �}rol-� thM | , disrubA9:�:} `/��e c!��f��!4�-� GSK3j��g to e-!f!�n\U bB�[4�e4�EL�aa Q$A�!���.cedP:v"�Pteh!�B ���`�'u��RU�%J�!�J�%1n^A�� !�.�aC�G)|>�!Z. .�0qv.G�."v�"an �$ kinatH�t�8ݩ#exa�VI>���/E�y �0s(Aun"�4. PRX"te&�.l"ormRm��T� $�Ahr�() P�7 rked� U*u�K)�a0hypm)&�$t , #x*2mG�  !�0�)m)a l�&�inc �FaccumuB%� ��� ,>� � TL} 6R�.�^F- g:7"�ɛ�*I�xa�nICan J'j{) a se�+,2�ion}�^�%�2$'�may-�I�� %�>t�/b����?layi�ed �A.�4per�S-a�9fm>ɒՑ��Ab F )�%M]� o �+,&� �SSqeBsE�.'%�"zZ�9eT� ofte)%d�\�5�=|6:It�wo�^.&ng2n_�tself��i g!a�m�����j<c% cet8(of K220�!b*�B�!A)b>d na�p�Nn�B�0/i9#[5�jS&�':LXiq7lleag�d��aY�.�%��I"&( 8"�! ��dM�U!��+ �+�ot&0m�B� M�e�ret!s9aFUst Jco�d:��onceiv��%��A�Er!���gM�� .%!�e"�.��a�O$to help or�eɳ�{+�Ke t/MT.�)b.Z-�T�/E8le%�qdl] &�mG���s�Rs�a� &�6of}��1m�K��A�!'%9��j ���'5, [51] -%m�b6Uinb�J2�!aaI�di�#es i2)>�Y�*b�gn��u!�intui��g��I�A#�2#B�NM6�a los��� &�. O���t�\�h1m��2�remai�P>�1�D�_l͢9+5�5]�q ]E&ol��8 .�ID8uq,%)�:U`L�}2h7[=*I7A5� 1�E�7ge2�o!��J�w�e:�1Sov�e�Qdaugh�!����3B3 rɯ�9H�u1L^��9!i�Qef=%�d phe[0non��" A�qPlkn� � y�/!�  2A�. ;U�*61q�dG2uyTa�,A��1*b\5b:D2�2�pA�.�1@^!�!�bQe���))�Althe�) �^y r;  < aZt � ��1:h �L-^yd&��@z%�E�E^��"9 $L )!�:*A%Z6$-"�"��zryjG( <�N%Dn.Z+surviv�!C')r�cA� ed r�r��5a��_"�AB�l� :NW��yv�r/&Q=of "��%("S<&r;)=^�!W/u>%sX .JAF�x� ��<*�j&QD)�mbl��DIKA�or�-�;I�B�="�R*BWl�4.�S"�&��B����Al�=o�f��!HN�#a*�=I��1�w��20�hatRLuF(�yN��[�9-ȉ�� �`&�} �2&�&� I0f!�E�u��z (. A�y� z�% mpet]!&^_!A{�ee-�tmo%$ exce(�yL��� TF 50%:��h[&zJR (�l� A|BF�I�1�Y����� be goo�$ ��`-� A�.8f�%&_%Va.�!�s.�!�AwaiC� avail� ^Y . ��o�tes?�~� ,�1 (*^ty !��ii7} �s�S�"\!� �v#vEU)�.pMtsGS �L J:�!$ r�X.w��[G �p laborator�f.%�7B6 .�A�%-a-ed13u�u �( )�F� ��r�!2� Aes2�& &ex�x�| �ewr*� m�uQ!CT�w��M�2��%��Ba7'(-dwel�O o��s#(sha�V�-���#w*��(:�~l4�;-a(ic reticulu[Gol�{�7atuIg4sk| /lys AOiO�}���4Vir�:|yg+ 3�`� :.v5s~e�{ f�&�r�Ws�o! STIMaZ�� mal-.�mZa��P!e-&�G��.Z&a�. B�;�V ��i�2�(1V. ��v�JR�Jre�x%�[53�&�|a�, �S)�!�O�(MT!�)�ER� !���A�ERF���o,*�B��a�B ledg�#&a$%�m���>Hto4th�c&]M� *e35��Q��wQ$ms9gs�3��ov�#��&%�ob= mosaic�/( TMV-M�5(&7"sE� -to-E�spg\K0k!0�>� "�E[=-�iy�in vivo%� tro �,D �"5��R�*�_ wa)A4 �Ye�z��g eluc�t�I:�mm�6,.��ms+eM���to.*hijacK7-�!� |u\ a� �hub�J(s �`i�1(�)C!‘bo neck =d����BW%pathwP ) [5�7���\-{� f ��or IKK!MZ� ,NF-κBf[56�\�'" M���]U{�B crui��� 1f���x�4��r!-�=%%�u v&�L�ɜ3�Eac�he �.(%�E ;Z,2�.�6reby g�)hu]l5Gy2<A#A�'t .~ar�,�h(O AN�oB�M%o.� '"�q�"o?cl�j���o[�c.&/U��� wF g�"m�p.0@2 x 105lWq9K#�"k"�oP��ma�'erAg�/aLsmi"?p�)�!&_r� a� �s`=63��r�O(x.6w(,@.Ipmac%��EE- SV40&�*$�97I!��F-un�^!s�B.L( BoMac�*.�O%2�G�#&�$��lye�. S,�"�B_.b;,�m�!2�I2S2!.kaXe�Tf"� manuEurer'����u$ Lipo�am�.200�eInv�2Dy��r �,��4Amaxa 4D Nucle<��( Lonz�d(��x  SF ,A� gram DS10�M�.��r� 6�`2 \A�2�8%�0 �@a��",�2-) Q��%a*�H( Biot �;aiCharvesC\�hake-ofo��!f2� E1ZC9���� e��zes� uma�C��20 µMQI( Ac�y-!m2 h-e6P �v�3� SK-sy*�J.��i�C1Q1 {�=}in �-�����a�30 min7 &)Z�ta�omo9KX� hum3 �ga0�tE:%g,( Utrecht Un���-� c >3 d��~� =!>s&B������u&b%�pmaxFP-G?�Na; C"�py4bYs�ue�Sac/Kpn|H��? enzyp�e�(pEF6-Myc-Hi�Ci.��?W Not1M a liowf p�-r� p4@�w�sXS.Po� *":I E�.' A(�8�}�U����%�� bo��b( g) �� aB2��!�"�hEcoRVXho!$(� ��> �!��aT�r=�A��]��\. F"rD�.nd"�.Nmc�+%:�XO545E�:B���e�x%b>R)A o4�E��k �max(E- EV:K��� lwSAh]�20�s-a.=��<[�<��vH�,���-�� �:�ibAgeibek��- D}�i�����y�.A�.)#��)�S�;m��� )9�j�&gg!3�5iE0 �%�ו]C �HindII�d BamHV�r� &6 JqM 2�k-WB�!/pFN18A`Tag T7 F�|Q4(��meg, �Sgf)Nco���j�1`,e8!w-&F��ieb%@��I'6�WrN�PGEX-6P2��a+ 驂2D ���:�:  � �%0� ��ͽ�m� pHIS�� allel1 [5=rk+�-i��r]�{e�Y{i��c�m��N�2�N�� ��>.,( GE healthc�))@I�A)J, �Cs��2��u�A� >H��.-d,� ACd ���EE�&�/ or w �x��P*�:q:�E%0ed RIPA buffe�DP50 mM Tris-HCl pH7 . ��1 NaCcV1&EDTA~1% NP-4��� 425% Na-deoxych��L71Na-van4S5 } t�$� \kck�r, R��-�)�J( 6- Sigmalj�@va�B:e`4�p�P"�N"�,Zc���Q�V�,� �D lambd&�-.7( NEB�I&g n 6�Pa ��!�0 �E�I mx�����p��i��$8e�#P>  P1n' System2/��a�B�E�.��!�2 50� g2� �:� �� -�o5Vu�Hwa�w 5 ti� i�/hy * �mMI�!FA� 01% ��-2�Pelu!�s�EV �A�+vag .�f�5<��*�� r�Gleh�G Sephar9O4b��H.�)�Gy�w�z Prec�B%5���2?, A��v�f�GST���|�X,�Hg �L��!�>��-coxab��3 hou0 �������$:@=�PriXU,bod�� �R���&�[c~0�EI7m�U�(���}$QV5 �*-�ti-*��:DM1�Z�A )� in B8c�  GNS-17%Pha�=enqc�  ( 9E1� $Santa Cruz�GE6[r� ono_a6tiIL� KT51 Abse��� d rabbit �.6TurboaI�B51�LEvr(. RZ7�f�-�%f ,*��l&�of Is�X Ro�q��w.���8d�I&zbylnittger�� . [5�2�G�3l �3n4{$slips- %2�� �&&��see�r�Roly-L-]�nLeRZ(5�. S� �&��fr]�/mk^A�1(at −20°CH(4%�w1aldehyd�� PBS:: room�!p!1.�perme�e;in�2%�ton-X-10��Ant!�7k�U-D&yi ���10%� t-+tiv%FCS .�� �Y�� DAPI-�A!rT �MitoT�5Q M"aWProbe�I�)�%\�;" DAKO �k[p�8 ide-field&n���%va Nik�$cA+e 80i2e �,pp� a Re��W(R CCD camer,dQSu�Q�60\�,100x Plan ApAU�cv�W{A8Openlab 5 softw2 (<l$� ��\%e1�f� Photoshopa� dobe2Time-n�e"�6�Jcor�6Ft 2C� erval}2� t a TEcE-PFS.8(-W)BB% Fluor%"o13, Orcaa2b Hamamatsu�!Q� cha��( LFA!)!�ServicEH. M&�'+ 6 �A�FemtoJe�."�d0s� |#tip II ��'&capillar��( Epp� rf%�A�!ema�t� �^� z� $G�%�u��5h %in*�B� B�9��u� : ,6�"J���E!7 quer 95op� ‘C274x/Boolean Quer���&*c|‘D i: �!�os2��XH!��9&lF5�DA559B33�$%�6=/3&l�J�[s)l9�I5ed ��&K66�� . Downloa�F �\"�!!�I aoe�%A�IG_�_EBH_�%9pELMA_u�ic Lin��Mo^�)�ourX�-�elm . eu�G�v�r*Dao">#2�"P$%��^d1�u?."�" emer� �1BD&�Du#!�all=eria::�3g&7�, e�nA�r � �A6Dr@t2 a�+3��,1M1surroC5"�e�pr!�!H���tr�, �<2i��� a00�GW%eXI!m!�)�.@ �� 6yi��G�A2F�G%� -�G:���/� }!K&2^!<o�eve�c%�t�XCc�1"�(Th�M Ys��J���a�l> ,*�,rom Pir�$ aDB �^�/�(�xXo�Q�rea�I-P!) NCBI �Y�.���o3�of 41Ȓ379�73�H��Á�B*WH�:he=��!W*N��^�(e�)�[647To�A�5q �a�,MEra�&{?Ym M�AMBOSSE��Kemb 4. �8foݨ. net/ )�peg�JutG�'tfi=+WAS!$ű*��"�: perl�ip�h!/�� web UO��M�a��?"�*� dn�nes:"�&q�a�"n�k�.ۙ�� dA�or)*�)&stand=/e� nalP 3 Ja[61['�84 2]�C�2 defa��se\dH�GPIȗ ��� Pred �C [63] � J�#*�i�%�V'"YD%?��c|tyIy�!} orth�f&� �OMCLm�[64ʑ�"�Qb�Led 41 re�/ Apic a2) Babesia , s[,*Tox��,ryptoFid Eu}3 d Neaq�S�+�s���7�4a�n:,.�e�e phyͤcAf�H!�amongc�0q�).WGcil�= , Perkins�zv/ua��Ai�erp�, G , Br� , R} lgal���Arabidopf, DiatometDA��r*�$‘Taxonom�sta�g� ble voa�5�clustCe�g��Ao�B�BV;o��V;of ]log]�M ��w�-Au����gor9+�2:��so�i�( R!<>(U"�$�f6BR8,�!WR]�2Tz( comm�� t �$ss.-NTYL�0) .KsBroken� ƥE� forkt !�VbrL]' 0">WM{i���*ho��X!";Sor B�# p ( BIa. Milj "�~c2�Ar0ve�?smAc9�bud��ye�mSac -omy� ce8�sia^ .K`J�n�"�Ut�da�k .st�.KG^wb^;� &$L"#- P!R Zcheckpoi!�nd ·�9|�����ƚeqՍfu�*< :!!��c�cq� �� casc0{ Mec1-Rad95R�����SonY� �!�)�u�*5=Rad�~_F Pol3IPif�a�j53U o*�df 1U"���1ne4 ,����3��at doS�[>ndIz��( n*i">J��/|UIR� Xe e!�)��_dc9-1*. Two��mu�B�impi!U�o3cdc44-MRrrm3Δ���2&0 f:�irE�K;typ� �0A�!%u>\ locuAR��L��Godel ���8h�Kssa��!�\ 1 N��sAs" &!x leadh+)�6�. Rq� #MW !�nu�r%?m/= r�~�tic�th;�{B, i� .!��*�s�� irra���[1yStu2�ݐ��;nd.�s���.�!/Ջe�'��s�2h���e��bs0]64�rk pau�%y����hard�/ve” W2%�=  [eyS7S�r��Z���re�Md�6|+PA�-�%�a�DDR (. t$onsh�vS%dof.+U P!�ofQ  ��:B�is� �.�;du೉�&� v1or �G s ATi�AT����Tel5���Q�86[)p�.dap�7(��� Mrc&͆)Kt�d�Z�f,+�Chk �Chk�-�F3/Dun:R�4�ur=��6�*!�!���[�wb��A� aZ4->=d DSBI��:O��b�G�l*m1rel��on{ y"�3!�0 end �un #/erVCatid:?a)A���E!,6e8<2���2yaE9z e4-�+bq�A��,��A~b��oMY��SK13��3′ss!ooverhaLPat en� m2ef�machin�>EJ451/52/54/55/57Ipinv�a.E�a0!YbJA{��s�d.�sy1F[r Un_7�/yal(�ca�,%'employ����2)�R�.,bT��7heδ��3�A5′→!V$Fi�N���T, .�.:��� Ee+�³icI]"�7�3)�+.��9 ͻ�� _'F&&[ &�Hn RNA*7  TLC1��!��Hrs`Ec�[ Est2?�[1ŋT�4ase*�I �e=���Ec� %�r��n�LK /G2 �!O�E�0ae"��.��O ad^q�� : �i�end�W�skGae{or��V�� r��8a�f� in+�eK2�X�To v��de novo�a�! E^Ų�N�r!� a>� !,.g �"P*�� 6, t�TE�[׶.F�)f "�@"�4%�)f��= e[+ �6# 1)y� fore� ells�G!a%m�   2� AJele#E�3�ofjwto!����6[1]("�D ���:h̒�F0"� � *�OA � � !d-�%㹀,�ye�m�&^Huc�i��y���7 \ �2�G�a�o.rtak1 �� . H� w�4orB ��ն^�.�J29� n DSBs}�ES2@55 .�m,:� �2 E2w�$�e�f� ��Oq�Bnu�al laye.��jc%za�7s!5er�9�3����W4�.[1�-�Filϻ�>ʋ�A��'���b���sa�!B����� funnf=̭* +?� -r�9-"|:. �@6�in��t)WQ%p�pwq�bro X!�y%�c3�\ �ontinTL�In :5, CDC9�YP�v E cx niA��Aw�!�C�2�L"@7�3e@a�en��veP"�,"��!�-� t 232#��at 36 a薁*�- 8�!�( i6bud�k+�A� �-1P��em�X���s]a`hrad9Δ�AiB��hAWn-�#is�E2�-go� �^�%:4�s �'l]�g2R9I���Q"5>*Q8 ���MB*�\!k6�22!V�2F� in�~�� bulkyw��}i�;^nAN��4�c1�m.[_���|)UIK|aI�at��=m�#cKemUM, 2E , 1�ab�L80a~Aq~!��!�Min6m�5�&u��~["zm� <�450 bp :�mpB}SisQ,�� iRE3E"�m-"�demi^J( ��-?)k""Z܂a5AMld%��Ze�*��T%��zly sml0��lony sm���-i;>&y/ �sCE�arise�E�?� &K�i�N$ies: ( i )��W u����( iR%�DsHA �i , P��� ing/rH�hI2gufr0C�.wh�\,K��Ih"�S�jm1ch�����5i �C("!�*: M!)�dh�zy�diplomA�/ Y(EST2/est2ΔU.$ /tlc1Δi��j A! nd g/esE]T � ingl� 3?�&i�26�)a؉o �fou"�geAmpoW"+ tetr��&,2ly z�)�9嶉���r� ∼46�(�~m6ks =-Ou�"�eA"�m�!�5�A�� !�2@I�A��8dF�t�Y! +yd�tH"(�aPe. �or%�6v��E�h�Mo.�M ��:I �!�M6h�M��� E�A�[�z/�6�6Q& N�is:� �12[�6i�+� �i!�F�eǜon!Fp��� . FACSY�Q�xatOs.U=&��haev���enricdA�)i� 2�� &U��s�7 �:.nSdel��n a S-Er G�pp���g.�'I4e .�� � coKE9�a (&� � �ah�S n>T }��-��s�1�� !܉A�"I� emo�<y�"�4�6 � />�:}=AV�L�2�r� n�!3 �u�M� �-&A�up��E�e�Gq c�xR^N j:Lon�II{B�r5��D�P�<�2mA���R�ma� each�A-� es�� po._��X�j � E$�TBEC1a�RAD,�(�/XB�SML1/sml����r��o̘gF�Jn l�/l� &@e�or 5&e�J~q�a���[ޤ�k��2+aa�'8� 6� I�!V �-Ѱ(��:� )8a�U>�"$|�mJ1����2 A����-ja�  'i]�!\q8hk backgm)�:E o�-"x���af�rc1-AQ ��ANcn1vdun:a=��!�^�!� 8on�'!�+�[2�E��Ԫ�ْa!q��gA�0xEC� RAD2�RAs�'xO� E�,"9��nd 53�Cdc17�a3#aly�:PƁ��2�0s��rt(C5 pivo2�p-�co0���Q&��r�(+.M+��.� &!�EX,,17-�r� V�7�4&# c!-1"�tex��,��?�WDR�a�?��� �!� Vp�!�nC"��o�� �#w' A')��s}n&S �\ix��/Paa6ec-��uP>�lag1�nd.�t|��cra= I��&& � Aj�@*V�A( R,b�)���on TELAMRCDUN��CHK�""Yy�-%|!F�i8l���]� r!;,q:!D�&��P��m.0�u^&/)�.&Ka&� �j.hv�"� !�R�>�"��\w1�J"[��~!�Fe�m�I��m;T�Z6� ZO (Re&G��3��nwm�C �iL6�a�5�dOT���j��Q&�/i���[3�7!� '���. RapA�Sir2/3/Q9Rif!�RifT I70Ա���� m� i8ci�1��J�Ku70/L��-x ( Y.�%�`1li&8G�U��` 2eu1Ure��e away�'�H 9*�f)ASWG��d�a!��| ]��V!�a#BeV�aU�y���Z. i�l( a�RIF!�RIF0 SIR �SIR!� YKU7��or 8P9A#1_�&0 � xiͪ�a�~څ���m�N�(.�f�. 8W�/=9n*i�TY"� ���]yku70�yku80*� *�S\�*�|5f.b-� �2/"onU�A�"%�&�)"�nna`���S?(*����Urds �� �y��qM� a�r|S6&[a �U�2SIRU�c���^r�]e�}T�Nc�]�-3 n��A'.��sun�\or8#�X( ����� �!O�;�"����'lso ��]��$�ar�J"B�"�!� well�R`a��U�8�' �nd�m >�oof��( n��Tj  �!l�� ��.�To�7yn h�BU>.��A_��v�ik/���Z�!N !�� i>bi/ 2pif� , -m�M � null)4? Lh�F�P����>O-3�� 4A�:bT�'�,]c>� p�}TLSSAESI>� gp �B���o�"y��m2:Z�-3aΔ!r"� %�F#mor!E�<>�I̅lev�1 ";r3 "]*i�mp&�ͻ�J}4A�{cMU��~22aH Sei�I)>�plپa� .���>��r"s R�>2i�~��b��M�"�>we�a~�4G��A�Fg"Q��tehhQ)A:.7$:M(}�^D�Dp ~d�-49H���2=��HQcir�[Ys*B)��tCIPA�λ ��IEx%���"�C��U4\Ind�d, �&&��retardA�o*:vIr}9���y�)�)4 ����!F�}��cFIn]�%�>F�)�fa�4I)�%�*e���2|=:1@ lane 2� s 486s3 TogI�C!a�r!t ��o)bas#E;�<�&81$I ild-�-D� ���onׂ:9�"(F�K��+.��'ۅa DD. mod����9iD��aty$Q&>�: wm�� �!~�3��t�or�9�B-k��Tp�C)U>|�0�=�D%�fic!�� � <-P $dT1( pT ) L�:pS ) AEESnti-P-) Z)ɭ�"�+A�ty(E��-g�� f �y=(5 E�)-�%�a��"�"�h"{>���k=@�N top &ȍI"����riΔ�C�!66��^20%UQ!#B/�j, ider���d�-9�D)�a�6t2_�<�,�B� �E�a�1A[-EW=u-�"�5y u��� a�{$��"on �' !/%�!�}�R� mini!y9 s�c>��q�A�AG� � M�M9 l� |��<�  ,I�q�� �_6$�_av� mA�(�-�-emM&�( &�7�:��cyV) �ni;%as"�Ah*omi um�qun/&��na���7v{%�FAP&�4r�or�@�J�k! g� F;�^%� 1� �/y-Q$d<airE ch�01*(a�� N or%Z�8[ifi�"11�2� �%�U���"�&��e�E�in".9EA��5 }s!�&1 ���ad 8A�8A�.w*�%3a�6AD6 OL32�  b� �B *J �"5�{ �z>A�v.QG2-5���! �&if11 �p�8:�vS�^.�.=m~2�(L�sytc�!]g2h�\ nd )$�F�X��A�q � a�9AЅ�AZz�8�)�}�}M�:8�!�A'&�1k tb�,�g�E6 KE  I�B�=�Y�NeD�; hyp��M4����Udai!. PCSSE��1<( Psy3/Csm2/Shu1�! Mph1&�, �.�a1�Ba� ~M%�?p��3 step��� �,�6����[ƫ,�� on>= . D+1"/SY3*�"�dBRR�PU�5q ,�:& *.*0��TABa>_�BvW�:>ass�ry�a� H'e�6.$.)�~ss D-loop_L�?Z�5wof g-xOA��5k-.�"�5%�!� MPH16*$H� � GAL1�].e &s%���:�th QY�)r�A�GGa�J�9��G :�}��NFi�* V�R)n��>nT)�,�o,��� l"�op���qe�!�!2��En/:J0V� �� Ea�a �>� *' �v6U 4H ><p�Pa'k <p -.9 +N��aly�sw HOf"�8�r ��tC�5h�n��wo�L�8 md�r� X�A�<��� �!qY2� 6A�:DbP) KANFfVG����hlJg!/��s�}e! � non-*�'*�[$n CHR VIIL%� IIR�m�" ..�'���� b��s8�-b.!�Oe�at]�2�� >%�1# SB!��u��COJn�mNc�=� ,+�?,et t����makA�!�4A� Ў� �+60 1^"�)��& 5�&\�B�7 c�0 &���h���ds: iKm/s�al�&δf ��@W�f�3d>p�REP5 )L�)'us�h�!mpC3T �a�\ .e�9or�, ac�ʹj�;7�0�!edsHUyS\!�4A �JC����5dje*� Bimped)I6��&r"b>�"I�z�MH.F�~!I��!]��"1b�^�9�9��. OurBe )��F9Lb���.%&k�b\i*"�!!= ( �Id�F.Ni�s��ne��1%a:�0"&>� vE? -A�nt]��PI�m�s ����/- � ed g,&1�.�fac.��9aX-c# a^��( iv )f.8 !��,�5&�$ �sA"��GZg56&1]-6Am 8�:2�wbD. I�%>� b2�<�aC(&��N��}r�$t�Ba�5/[be%��%d' �3m*.�&e\6m.on68<d.�~1atF.XE�*��.�ԁ��. Rrm3aKa%�&:0a"=�%y!.fQ\~\EpA Ʉ RRM3 �%&a�}?!���! tD�� N�I�5R� %_is>*��[�.a�]Hlee 9-6)�� llel�.SAFG r CM��y*�t(PCNA clamp wV6� At 3a\Q)|q?�Fu!M���iny-8e&r#s )I:@I�� rV1N)n!��0 � %Wl~�� >���E�� .�o�# MHJ��� *�� 3 B:�%f��.+#�Z jE� tJ�F'���6!Á)@�0n&Wq�R4telomere lengt�ih in rrm3Δ pol32Δ cells compared to either single mutant alone ( Figure S4B ) . Combining cdc44-5 with p ]resultedxTa synthetic lethality R�RC ) suggesting that BIR might be constitutively active in cdc44-5 and required for � viabi mor XthO,mbination oftwo�!uldy$too disrup{ fZonven( al replic6%$The extens�@telomere lengthen���ls was strongly suppressed by�pif1-4A�.9Du0refore , both1�and5!resemble9-1�their2[)Y �of DDRDlonger� phenotype, likX,'e8 MY} �8is dependent on�%�A�,onents nPif1aPAS !�Ud�=W>^ K. !� DDR-{ce�5�6�cd%( �diffea% from�N6observI�cdc17-1 @, which�not2�t=�1%�We m Y�effect� �!56^]indir),, i . e . itv4due to uncoorda0ed chromosome2�A; `ase52t6� . Instead!�he�-�Ak)C is r.� successfueEair�broken2�forksa�E!�Hin turn causes addim� �>�$We propose A4this mechanism�g8explain previou�ports 3�Zir!����)��uaew6���mŹs�Yq�gDNA1Dinduced phosphoryl��of�3�|��%� ��cB��� �%lheR� betw!j1g,�m� s a possi-E��(is critical%+D!K=2a�!GL genome-wide screens8S . ceA� siae deleaF5>a^A4R�orA�rt�ӵ�s , manyuem:ar�[levMto%�metabola}through2@,�r�� atin�$0ucture have b!Area�ed [47i8a>C:�.@雭as!�� M�!s may�Gulti�2kgener);]e.Q�cy���Q�Vf)�Ny�is�ly!T be m�@lexA- ;M�m�h�C kina�A��$>  �$checkpoint.!�3ne��aryH�.~F Q6 �9yof"� &�5�at)�� erodA�nd�a�L ub--]ica ion�Si!�%u� '60 ,�KA4boo��Ie6+�jA v�invol8{a�2� )act�Qa=�@Tel1-medIA���rhaT!����"F a4r.�n�!den2 �e [49�[5��Oc oe�h!g,�m 2s� hardA]oAF/e�� %2,u e{(!<� stal� [3* [41��b2��A� �%�pea e|�" runcE� ,eA TJafe��or�aGof!�� rimm�J [51]-�!!� benefi@ mS� �!���AuP dynamic�m4 adjus�5z.j��extra� ular�Vin.environ�zIe�eM�$to minimizG ic2S!�max !g fitnesssurvival� summ% , we�vQ� 9*" 6Rs mod��� .��ve . A&.� ccur'J�az�p s Mec1-�� tB# *-Th�`, �bX $ multifuncA����wo2� ' sis:�[�ys1E.��e�A� n2d �e� :&="��sB�im�l6u���!��2���8͵�. �4�analy� � I�U�inont"� W blot<� performed��aI�umW3 tetrd (, often 4-6%� orig �at�� st 2��ly` st/ aren6 \ � . R� heterozygAdiploid� n �8w sporM�aI gen �fou� �(two�a��^!L�w� z) kp-C∼80�e�sXe�26°C (5(X a"��])�30b/1��8n YPDbr (#YPGal if!yuIuof GAL1-Qar%�m�d�quilib� q.UL . Ye!�!y��aE7urifie�diwediIKpnI , !�res�4on 0 . 85% w/v�Jgel�)Sou��n A� =hybrid:%�Y�a�scribAN�ously�ܡ�4e random-prime!&P $-It II Kit� � aaQ0 ) radiolabelRobe KL1eecogniza�Aql8proximal 650 bp!k Y′���%)%'uX 6��5he), expe�scSw�� sl�var"�ia behavio)�";,�than xi�I(cl)��givena.Ah�i�inclu �co� ponde<� A *� 3Ba~~ 3A ,� 56sy3S1;�r�sml� A S4' 44-5 c4AbI�� in����0p1�XTCA cipi� [52o P� ��6.�SDS-PAGE�transferR8to PVDF membran8Immun" de( � e?�v �ECL+ ki�GEthc�) accmgd!� manu� urer'���Xi� Moutono!�Lal α-myc 9E10 ( Cov�   goat5y*�DyC-19 ( Santa Cruz0!�rab;po.6@ VIDFYL ( pT ) LS HS ) AE ( custom mad� QC�$antibodies)du(�-4�,��� ��W.ced2=^�e��. P!wi%�pr1����cleE lysaty t 4��� �hom�ize�b�bea�� in L�B�,( 25 mM HEPE%H 7 . 5%S150KCl , 1 EDTa, G �<,1% v/v NP-40+0 glycerol�oC)at� � hNaF , sodiumB9� !�eABFCompet!�� -fret>*8cocktail tablet� Roch]��1dea1~by ce�fu�4( 14K rpm , 20�_)5�Myc^�b�cub�� ;-�w!, 1∶!� dilua>)m-M�yF6��2 h foby&Pof�; G��A�!Sigma�|a&�alP. B�%wa` 3×5��z2V!�th�in�din 1×2bI� lie��CIP8λ22 ( NEa�. P�IH trea& ���at ro�empera�����6' ���Re mIstoppiE"�of�gsa" @ �%boi�. C� ��atc� Raffinfpli�nd gr|8 n�W2?re-susS t"YPth�w$OD∼1 . S7Q3 �cA � nd� ]�gar��3 d6,2= Ir-Q@al �d out ur=%�D+G418m^f� e+� ��sco���a!i5RM − colon��tFe� &'� �(�"n�F�he.,L � 6se�At# h in^%  arev1� &� �3!l"� th��r�8ach:7Y�to calcA $ndard devi!�8p�Onchocerciao �� inL!��n��fil� (l nematode >a ul��@ajor public healt cern . Gi� Ude��]symptom�"���o6�!coMs�ut�desce�inYaZ A >E� �\,R efficiT tool� need�Eor diagn}monito��]oA�a�� W�+v�%g; lucifer�{:�!qsystem�PLIPcCeM�m� rapi� specv%�d5�� �T&� ~N�9��ur!K&n�produ N<�Jgen�$Ov-FAR-1 , API MSA-�$ Ov-Cvtesm^�V� co]!\blaDd sera� pri�of� un ��#)�\pat!�sI?a�Arparasi! 7!t � N� ( Ov�Wuc� Dria bancrofti ( Wb(Loa loa ( L�, S�&y�� tercorali!+S�*akͶo! pot7'a�cross-r�NvAKm�A[..��Aeng�Ov9�se�t- , �x���9�l 85�si�anev�^evaluE���st�Q2-hA4i&�pat��w�a� $ a 15-minu�E�%� ,. A2 A ��!�`&nt2��a�unequiv�.��"N"Ov-)��ndJ=Ig�s100% senA/,2 mvA�*�h�'� y tite,o.~s$)u��ti9i�pdividual2�E�revea�)�hey�marked�z'{ nd did ���(S = –l 1A7 58; P 0089�E�. I toF�,yt5e%I Wb ,a,A�I� Qcfa�s had��r geomet�meQ rWA4Y� ( P< �02E�*Cgen��simpli�method�V�y+54b As:uly">M� quick]� ( Qe)[�IZ~o�, uisha�As.�E6� F !. Fin�j& � �!�= bestQV%�R�.�+e�z 76% , 84%e<93%b/,J�Ov �Q'A�Ssy��W !ui--��A���"2&�c, high #pu_���A��)< t��u}�M��) �&�1�a�d2�p$ -of-�Mc��eara�e3of�tr����"�un#���J mappAnew&�� miss��of!bi�. A e!�neglec� trop�dis���NTDɬ:� �‘river��’�Z8 ��sitV8 �i!�]!���Z� disag der�ti�P�!� ongo!1&m� , aia!\ter�.s�1*by ve1@(& CcgrammA% Wa'Africa�CP%g$d he burden!smorbid�:� olerC lev.( Hnb!�"�6�, APO0�V elim�v� rvo:,Y{!�>)l�$:aEJo���Ame��OEP�,Ŧo sub�"de$�$hNJ� o�M�%� risk!�)�[1� DespA95+9��cursl?�0lmuexcluh0ly\ A�m<@s#or B 4#:}$37 mill$peopl�!m-)LtOv���&V90>=be!�U�in-� [�Su(�-�-�!.�,%2�;�!@  ab �r:t��[30ser\ adverse��*N"��Iad���O��EV an��"+u�,"# ,!co-�0t[4!�In�or� U�op.em�+:�,<C�+� a0.?h" +p�.dL rM�� mole0r x,2� )����S% b�4aepidem$E� clin�S�i�pr� 6� essh s [5!!�%I �-% cert� )�pj'.,*Nof mi� ���sk�"nipA[ve�! hel�)imacy�lthough==���Xs[#�Hl �s [6])�� �#upplabv��be�B!b� -ba� � �lJ invaa��9���M�i-pad =�[7!lAEGet]��% lemploya�&n .f Yc��Avie� in [8]# luhth9� ;�U: �gX[Q#1�01� Each" �n���#� characa%��rdcf�O*��( pr-+ cy )�A�y. M�e��p$ field-app�#�S=��E )�V6"�s� -U;re"}�a\Ov-16 ,. 8:� a�)�!�.+? [12�$1$whiz-n ELISA=��!~�!'.ah� � Qf��[14 ^e�ݫ .+$ll!Oa %�e!�o z%stm�!�t/A~iculty cr��B� 5:�5�'a!A8����O .&�suAqs^a� �� of lymphaa��Z\)e�L .)ATa�29o�RQ_ , Renilla.>( Ruc ) " fu� s!��in Cosb6Dei��� ��)�&2��%�<�� ( d�7A[��)� �E�bo>�=�_in�o� &b�G[16��-n@9o�[�+�J stu�, �M�imšd2�  x�Ingi9� o�5PE������robusa�d-*� �ga�.��{sAF��k &til�A2%� tech|�as�AA�O�R�L�G�'A*ked �..��kI�\��f.Q to a�U���Mg:'b� �a�&t!- o-caE��,?Q()�e�"� )t,�xA�d��]�02 .�U� . In�� rit%%�3!�ob�#!f��subje� ae�s �!�huml2""�guideli5� D��A/t��d HAServicesa� NIAID IRB��d � otoc�{ �A\ ��u �A�� � incYs�"v< Declai� Helsinkill 1d=co ���5mo�+s9/)��7Bg� U!�ta:�hoX��)��'� �e0no $lap":V 9 f7aE�&"> w%R ��-&�Q ( 2m.� -pon�;MF+ )1H�:�bEcuadj nd G�mala [1�6S5'6 docul ed^�W .*��acir! � �l�`W��6 Indi Guyan Aa4Comoros Island�Q ok�!�eE�!(���) ��reaa3B3/2�i#3�z6�or6�%:q+w?��(9s*� larvB fe{9�>ţ%� '� Asiaa,&1E�c�1+J:5��;�5Cc Pa�� y Un' Laborator� " ic D�, Nenal�=it�$of Allergy%�I�usv8� ��. S_3��se �i�/%� Hyper-IgE�+dr4( HIEC:' eosinophiRsy/E), afll:e�m: non-U�p)*�-�G�*4:�North����no his1l expo ��y�,��&� ��� ho� n� trav�(�of6~A<M��#"A.)uQ. �� s�q T� � (A mammaliannh ex�� , pREN2� as bY5e��plasm�+�2 , [21}%�.E ��e��z�7A6$atty-acid !- retinol-b ng� �3vLFar-1/Ov-20 [21]; as06yl *��5o� Ov-A�333 [22];2�uA rfac2l4 ��/Ov10@3snme c�in���J}=m��c<�)%o:z)�96- �ta�?[2� Firs� “ma� (”ϵ�by �(�=a/$ �:+0� ssay�)A�,�,Tri�"�,,�,Na�,- MgCl�@1%0$ton X-100 Pa�oly�yl�# ti�1��Y!�o 8� ��Nt`"by)�, 40 µl!UQ*j-��C-x13;#al�:/�/581×107 lT* unit LU )jRuc"�"n�0l~,r*�ŘadAWach� Q�E.)�c$��or 1 x$O>*. Nex}7�A� 31+�:of Ult�%nk�A/G"�, Pierce Bi=l,�- kfor|'IL)�PBSE[ϡSbotto��:�Q�fil�HTS � ( Millipo�LBed gMbsez!-!��%xE (&on mi�%��?-�&�1e {�Y�'rot�9shake�+� �B�C">� =W�wa�-q�vacuu>1nifold� ՘f 1�UI6U$a Berth8LB 960 Ca/oiG �lu� me!n(0TB$, Bad Wilb�KG] n� �coea eraz� �� mixk$� g�Madiso�WI� ALU� reK amaverag�:2,t "<5ae7�%�a&�De&{#Z�/y7ws.��;t�"i �. A& 2#of 10"�LUvE�M�!�inA�p#I"=#� ���;Q�datw�;if�/&_>�A�of��deB ted(A j%Ak�#�I:��ܥ�.�,A�yEQbu��i�<r�*T6�a 4e�����!�^$5! �e�9�&?)`!3qc���E��Ra0�nEu/I�c622t8 abov�x(he GraphPadc8sm softw�5(@5$ Diego , C��!uu!:�s�x�n$)�J� �t�� A# =1w2��$! curv�"AU�"[2�RES quAVu��)Y#bPLJ*�)$��CTR���OWb.Ll!a�helmint��(�() &serum" !8r�KaB 8?��"�(���$MT ) ±95%�f�caXter4?(�P�typg ly� disp�!d n�2se��;"�PYey�'nA�Dd�!,FD;�)rrM*i60 amon�O-`on!ۭ�f�!��!�a&a4�&O0Spearr� * ( r�I�%��.Ja�� ! Ag� ,A~setP�)5E�r�"�%T u�'f �$M>��H��g�L�/*m^E�9)d cutoff�s�d.jim�*���72J�U pA15�B�1( S�TAvAF��B3�:)<se�t(,%!�<��-�s����em�recei/&o5!D&�a�a>R�&i�–� �$!UA��Ed�FW- 0 *��e*� �Y��:(/.���mddi".o����iII�?- AcalE5cA�!B�) modeE��R� 5 )"�2� F*e�)�\R1���XU nois�e$Its key fei�i!.e�tiB��a true&j�= &�.)I# falsJ*=S� ��PlyI�=ed�M �!!�/ studrW&mUvarL"A)�4s� o%4� e+(l�c�� *"!�M�� para�-Mann-Wh.Dy U )a�e�a�$Oaro V���?5-!e(7ups%�:Y:��@2kva�K�2xv�a:D%[2�#�N Odds!�ioj.� )��� �p-m��Mca�5d I��$apal reg� W,�oFGA}���eT)!3hava�","? [!:& heati,A�>45w��e�I��!:log10� �C���A8�`T7r-#dal��� Ksca�M?��( legend . P,AE�� Km� <#Il!��\J'y�gE�>O"�3���ف�"[use�W!.>&sNT!t&��co�G��4� f�m�*6Eis>.'�2--20e�� 33�*��"b +Es"�\�D,�"Ras C-tE{|U�#��Ru�6� -ver� �%��"�s�AbC3�6&�n�B�EaW��1eR"�'0 �t#�5�l�!�5�beganE��+  sm��cOv&�A�Ov-nega?A a��(� ~ {#n5�Rpan�h�.'. abiL6J7�Q�cVL7E�� '! s ;��sitL� lyA�@724(, "�8 ' ,F3)�N~ �l!N unma *g k  fn ��O=�)�%�� a�� in"c2�+x� �.�:Z��,F���-t90�� �|)�,%�ŭ�I���� �5MAU�&�6w�;�%�9�M� 38�)r�� �!%�<6m C� �"]`S].T8 �KA����& ����. A�7ٽa l�[n�'�_5g . As�inNj-"�T��%J �2��)2ata9�>�BG[A�3�{IR!`heR�UPNz!��7m BpA�Ov-��絭a`!H�p�4�2EG� �J�Fur|ma%}!B{5Bere$a few weak:S sIT�]Q , to2H5��)Lz'��"�*s�b��A !)�ysAI� -m�a�at>"�%*rM� u�� Z�!�^�58�P:�9F}�+80-�4 , 000-��e: Qi>�f�xam '� �.29�A�uY^iR J�* 78 (� CK<42–147 ) ; 546. 327–914357.23:54m:�273.!161–46>LU>��.�&��M?B �md;-�,���28>716�9�963�23�E� ; 19�F742<149M88–24/� ; 93�H9 %j31�!6783�;);1 892^852Y 3756�FCu�2m�o�1ob�a��u�, f�L&D���O�[�Q[J`6�~�oo���i���AZ"�N�Qm a�A0��d��x� Jpo�(�� a litt0f �N >�(�iS%F&�=���<.�= <�I{.P�� in@+or0��.����a�"� � (o1�����probablN7f:�U54�+,in MHC Class|N hapl�Ds [31�#32�. ߩ�x"�+ �D`b�_&_� ��t�M ?E2r�I.% . To esJ�;�&B: t;Q��*O�.5r *� ALI��)�? V� �+se"� A�:qV=SD1�6Zո��Iw �����ۅ�67; 1 72 ��902�n��1JU. U�� ���![�%�e�)9mae&�2 *��9� A�fN e�ZD(6�� ��n .32�iIROC��&=!m |e�J-1�tq[Y�-!�*� �.��*�%�AUC=��(�{� au ��J s��laZ�� !"ed 896�( 34/3���9=�( 71/7!7!�32>=12:=1.G:���B{8i�SRGhyl���Dr hip"���d� "��*!�ge�: phic�la' .U�*;RL5�a.2� %mJ�-k�htc+ve6?&? in �"��G�K,a:�-Es90u , Ll 27 Ss-� 12�,/HES/�pa�-e:�n ��!0h�L&J#!BA��* ma `5yAR]C*5Nx��]�ogs�(h6'.j�kc}q.Y 'zJlye#ሑ.a�� l�a�-  �e�$"2���!�� �256G � of�� 2� LU IqWb!�!��B�CseAX  s�C� 132 � �<+ 492214 1�*z15. 7V *� 8K&�.�=ilrC��!a!o� 9o5X�� "� LU.�^� v !AB�>� zb9RF+�86. 545–563�; v 456072!311�&6*e 89.�69T 6925�TBj =_�I��*aD-�D)aB��a1S�� LU�6��GMT%4 1282.�9m176� ; 802� )N118�562L 194�6Z�:#���Q�,\�t2G .� M{>FA�U9B��KE-���7(� &I1; Mann :g)���aZ!v��"t ���l�3� aR #AJ"�=IiI?B(aqn�)�.P1��5%1F 6� a 542c146aX440�j; 514.F26�92��472!186A'21Y�JAZ��.5!u��)p���&� stil��p!*B.S!5KRjA�~!OJv�Rlow:�� si����e ]]�G.� "�[M614��)5*])�aU�� a!M�"� �q���.d+�*� � R3 �<wM�K,Re�2� >`�O �*���i�)�<�E �_2� �M>�!� �q/%I�� �.R g e�5 � !�or:�o �!��B|!]��!"�BGmp2�!) 6�C�h�"q g&C ��S solu�Pa��(�"�E"�9^E��plyA�b2!"D�Q�$N�.. v�!E i&=�!_ ,%cEA}a�2�  ��ow end1P �k393�@�HeZ:#yyCedkM( 68/9�w, 74%0 82 22/2�� %� ( 72� 1�A�����O:@ aC%i��B� qo�.0solid horizon|W�=e|I�_yf� aqB5�12%af"F_ �283Q��+J� �nlyxer2 *� R ( 901T9%d85 !27�e�ed`-Zf!�� ,AgO�7:o>�!]pr�Zy"�%�IND� � 945A�.�( 3J��eBD1�E�.��� 83A�75�68611��E ( 26)�A�-�q\���Q�BE�B"�,,fZ2�( 4!�700!*fc9u.�-J71><27i �I� ( 89)9%LwP%1�!'.�(�h��1��v�-�v�7&< �+.� l.�=>��� �>�A -B�� i�hsnd�~iNa�R�8w�^�BNct��"�K�S����).���<�r2*Q�]0V �pre�$2IH2��%�B�V�"xAQ�4�X a �%5LU}�A!�HI� ��%"B* or Vt�8E'M.� H�&B[��y �&�Sa'-A��R�Fo�*{*�Ih[dG��.�e}��,of �� ur-!$ ~ 0t"�� �M��rOv�wacAW B� ,=)i`)q�+iE "(  ) �&�-�-�U�3�/� Q�L !�B�0M�� �r!HB��{0� 006w � 5  :V5))AY�i+6�]!�ti�,�Lep�y�L �36� , 0363�2�Ex*� E�.*�<l >*.v!��1�e�%)�6--mVK�X��3�(232�2 87�5!902},842�2�88�,33�i 302}96�1G27�`92S54�~M556)�1�^�K�2�^# ]r!��$.OIQ.TY��s�1��(sigl&� �`os"�/=��)�� sis-��>N: &S0!n.�-�� RB�# clos� T;1�6su"�%NQ �]e��/"n�9AXP10 ��t�.��zLy`��i�&A八V �� a{/-`i/u�X�,6��l.�. C6�0�"n�9��%�"�5:z'j�9���a�Ux�2�1�> �b3a678� ��V�Km�F .� A|"� � 7"i 7� 66� ,jn ( 23e , M&S K`(D1�-.. UR^���EAw� i.M(j�,� "� 0A+2� !A . 2.d8-%f� ����B�\�&�03go�-.�,4 �BhT�0i"���%�s XsultsqD�Wi1uFmO)��%�1E�R� |&O>�&:��.�t)���� n1"�6٧�. R/lx`Ge�d�2ngGSX �>�^.B(�9Ai�J��!���8 step� �= �[H[p o*9&D L`37Je�e6q�9H>)w�Pr� uO-�� mid=ofe�!��5�%Yz5T%�&�d%�R�3BIg�x2� 46332�32�D109–6? 8{'�B!.T ;0:�(t:N ݅�� :�'p&58�LU��*?�=J�I�A� `:c!>sE�>��>��<*^ Oͭof :&'280�855� adWb; 652t151Z 464)4:(2� 141/ PS!GIt�9�noI�,�V!� ��� �e:A�app�s�1�R %e'�Y�%G sub-#%1 ���"�RM�(Z pa��3A%�3���pj�j1B� �a� _s 4 cked ��'�. N�,the!*2�3m�, bIL:C�Ua��val�) zero��. n�3az� � ���& gɚV�A���6�"�#c( 7���5/FB�� b����8 J)r������3�T�82. FT!�N�l , 199)<')@I 1?79!"30�>H��E�R��%R�Odd�7�{+eq*�0+#Zo7$vzx7!i�v� 6'a"Tof2ju�21m"i8!I2f?Aus� Ռ�?242 1_&2Et�e�3!�e!N402 2�2�99� ,wL�}TT!�.�:uv< �b@.H ��Ui,U�'�ac'ai��* 2��2>j(i/>IeD.@ �� m�1�F20��*��2� �i`oe|E&�k��m�ic?ZmN�:�E�:)�Q4= .~ -E��2�k.� ��� �m �<��62g"1�A;53A;a��yY��n=06x��53�!PEFF@!b�W&1"Z�n� �zly�<�) A�= a"�4I� k2mb)%Bf0 :�� ^G @ s goo!;c��Ily �F �Z��>�}QM�]�M��A!�Bw >�aS%>*Z�`tI�>+�6tV��� �CPprofiu���� �)>�.�)Ia27� Z %�Q.�\�lP�Outofd ��.�s)L7\mak��b� aches]l�?sA�&<c1:� 1=w �)4�j_a ��!�* s_4�I;�?-��/�n4I#;s���r�purpo!�i(aI*"�'����M.xȐa�� �ven!�al8^�5i t blot �62WaH�:ej�m�)r`!�5�"��[ ;,�H�1 ͘AkC �L =1�- a� {)F� M�Ϳ s�guer.�SI~�]i i� ��m�%mAg�� at�h{ 02P �.��eal&icepitope� UF,+g��Hkn�+V}<�%16Be@ha",��XiJ�a��cA�E��e�c-A���i� geniT�%c.-��ImisK7a&�B"�W�wBO b&�e2�H �1O}c��� ��?2mo�J�]a�s�Wi+,"LcE3R-onew:h"le�A�of&�"���/BU�(Ә�Q"8:�!pO�!�vx �z3�efify�/A5)�2."d+A�H��^�MG#[��Qc�4isad�b�,y.�!J�P� &�6�in2i&�? q*� �*SM\Y-#in.X �$L.b�s�.�;9���ȥ�wlogY;3 �ug!&�9!��W*KW"#"�Ua�œx�lly7g�'���)e)a���Brugia M_ yi ,b'_�v!Jw��Bj�a�y�]�U�toA9�LE6v=A&(�)$%�Z@' �onsis�% �5Eks ^Z34�6oyqenh���9�.��z6unDJz6q4ng>�`� �.W&-&�5�v 9A�*�#"l"!�las$ �Ɂ1�toA�� c��}"M .�or2 !jv�)��{y]itaVpeusT1colS8LRy�j=.J�>mw"IaU6. �1i"�A(�"�.B�8>�qm]2���g��!���9�� 9� >regard���P��!*�� "�9�-H0;q }, Cy� a�gW5�s@�  favor" ?��ȅk>��* �3���K�����'E@k�� �;$#etZ�9 �A& immo��3A!Ua U� �z�:��l�Q^ &�-� �k�o�K&�.16�kLTex.Dh� �Dv�k"�G�E�� �+ � X2��irҝch �expve`Wp�[ �u�k��B�)jAZ��t,>� �/� )���&�k �2�!&|Ru!�: b�0 � � fail̞.� �S���a�m� .u%�R(��On��b�]�a+iF�:di3 ��%�CX!,�OYo�)�-c*)1�!� "F0�r2��� S�we"{E�A�"_y2s�P��M�2�`ŐC��i�!;�2V�N� 6nA�re�"V o�`NY%z`�,�.���8be.DO� ��Q niquh2�k . If��hq�u*�O�?a� corp�i�I��=]\ ",1aX.!7�]!��&T&�D�dV z*SA;A:iX�Xi�s�x`!tA�ya�&W*�.>U�.g!3&OP*�xkWA� drug� rapy�rs�5��l �"�u/&f�s�\ivNty[Sa.�M�s>Us)�흃�t�,� c ^3� ' �[lWe�&�vVv cardM��&��U�[Q�Q��8�( ��Cv�CvjCv_;QnS@� , iss��!�o.��^e�)�B>O!�u*Wb%�Ll�} od =enough�5of"5�g2Y�>Ooorer�I"�v� B)��o �U�a�W"!x%�)�BTQJ�P��9|�(q� �24Eb� du���"�G(&�rZ�; �41ali �q'��t�]6 %"%����]-co��0�X gra%��aы�G�I�=.uAEi�!y��in���7nׯ-� �V�)&D idez�LU� "�ң�B$'� u"�%+/���r���a����9���h� 5��t�QOQo.�t�%r̞�{��:l . L��+ IgG4� Ov16����lread�p��[�l7� "M*�; �")e2� ɤM6to� A�lo�.�. S�D �w�;�������.XI�! )�/ ]�l��!`hd%)� deci!]�ut -a] -T��\!�.|omOvt _�� ic acid� le, U���-wo�XgX�Z� init�v!XF�z anemtsd de�;e�|,B+osoۓIHD:!)n �(ome��cuz�ag�How� ,?Q�O��`s�J�( long3W��; p��ionM�� rM"�l�]� ŗurce-� trai�Rse"z+o�q%$�"��{GiA�ݝc�wee�!7~�d9��f�^ hemo�����ojED ab�2��! a ru,p5(])�i�P� n Vietnam[to���Y�V�\! f̒�hݐm[�out�\��Aa(a�3VW�d�u%�.�i�-��>�deQ�Á� 54��th{!��O7Uicipa��%�enrQd ��mrL��m!oaH!%��M?z*f2 f�&�$[99,�&]�8ktak��JrOtoJ�%eD"R[�& , 98Jp!xH�r�}trwb9&ax. M:_r�?122 g/��}CIR�'1>r�}131B"�Q1�)��G  k�[�a3�/]31ي45ԡ�21223;*`� ��d qY@j��Aeth��). Iro2��23&'�17x9xto 2�412�+a9�ofe�.*-�*�-�<vY7Xr:R hookA�&� 2N%]R{)?!]1.�5o1IN pū�moder��or�Rv�fe4{ 7�]�YłdQ�e:�&�1% /�fm�.O�r.u.��ՠl .�"h:ly ��e^�1��Ke���b�q�in�}m� m be�a�5<z|!7j}co\�~:|�n:!?e�$common nutv�o �llۮ}����!�g�j�ildre�����. dR$! �~��3 m&�`'exacerb: by�e�$�w|he����!hJ�-as"��ga�$!�PLbl�%� . G��l842%c preg} � eIc� �5#�%!>Pc�� �Mѭ!Y�;Wa���ȧ-u��ne!&w��etardY �� w bi�ywe�o�j)mm )!9�����#�fh mort��`��� e�)�Kn6� j.; �y!�,�i��atI�p�E���K-[cy3�d neona�W�,� �'$��po�6C+ te*F���0�=ni�w%�cy!tdar&n' ,���!��^�� � visit untw �mo�� postetum=�/2NV���� %achR "�&in���va��VE\m��a�pli�#,&�br��e����N)����=�G f-�/E![~'_6 5�>yst�� n,!��-,er work capa��_A�,J��6 A�r��"� �A���A�t� �z ouse�ff�i�o��Bim�a� iŘ7 �� eA@ae�a�aSm� =cro�QbHU��m����� uȫ,&��-� j�cA6�{% . WHO nowyq��A�a � � r ����=20�> w�mt d� �2Uh931Q���U���f�[13���I)A�di�!FF%iZad��!�2�up2� ;�� be m�ڏver�I��`�io 'avoid�S � Mz Mo�g"H�Aabsor�&ő^ ynch":�2":�I[?uxadoles��verY/th\�p2�6�/�f῍�aO �E�1�60 mgB� regi=[4���ch��%8d�op1�A�9�omoaP�m2wa`sus�$uȧof&� u�P��>�� .�N��QNovemO!200~7�K.tƃa�e�$� �fg�I8/5 yea�jt��YD%fa�_�/n����Oi&���O�>a Ci�F�F +!CN a* ,w , � ,� �'q9�aa� � l pi��projehqL*EQ�$(�- Ek��%��"o% a expa <̕����È v%s��� 2ȰeysYA�ͼ|�=W�c��s�30q9�'囡b̒/ �@W ��1k!@�I+�^�;e�� ����pa{W"( I?����!R>�ofM�� E�ai�5m41 � z �y�y�y!"�N )A�w)`�|�!�diF�y Ext�A��� ��h�>M�edtea\�.��y`,dbk,i��$ak4�vy���qCJrtaff . V 1m�� b1t p� ���.�/'aF�qZ��� .�Ey!*щa��eFA�!a�!�.TI���E7 ��qnl�R`%Ethics:�_RVC�Malar �PyV�Entoma��� Hanof+��-ZW'�Eg� H��L�"��MALal�$( MelbournC�Au li9!!F��f/!!"�3% �)�� .rUn�so off� e�"%",5mNhe"���,of Yen Bai .# Msef-*� m��iI� }�J�"z� 3��N_c��=�r �vo�eGciA���authoL1yF�!���ar��st' !�it ǸneA�a�de�3 v%�u elig�4��&yw N� !O cour&QGqSA@erظ}�prBSͺ�=!f�, upu�Az�;�q� eze�prٺ1���#itu)� . Ha&�,jum fer!cC !P�����t��U[~K5��asϐZp+ �-� . QuNonnai� ]I��+ as �'��see�+�'��Wt3�le:{Ͻhni �r(*��&�pcho, ��"�at= �)B�  ,6y�mt� umpEL!Ma�nq7otwearm����,�w�� latr�6!�&֫��ngJ9� wash�_�-54 ]67�mDKin��!�predo$�V�86% ) ���Cq�� *�63� ��.�1s mouf(�� on 180 km� -wes�8��E�Y!lyS��/�wsp\ pAt�5di�=e:�ei to�}�� ".)7 �ދ 7��- Tran�M!��U!=E�� �� ly 2�=I�� �15>"� . A2�65%#%��BTa �Da��n��Z9up $u  28AD�iLu�|Ba Phu ,� s{�/M��YIn May� �a:� %�qZw "��%�J� �s�) N�� � �'>� %lai �� Yu&ung��5�5��{PrN,j� acZ;x D2{�HMveja� ?n�� rB)ze� �saAK!I : !� 2(�!A�of 6805�~onud��a�I7�: h����k ��v�0r}&5{a�'d�%$anal5" �E��8inP�!�eJ"&���iյ�2_L$d�E�lPf�x { f9smh�� \�"��'5���.�t�{t�m+(aU��M��sulph(e%.Q� al\%�N4A&M, UNICEʵCop�"�* !9�albendaz�� � ( 40�^>$ �3�ur�th)�A7����C en%:� *�s��ul]��$��6-�)Eli��s "�^.mde6Y�:�"�,!� rst twelv �$F�Q"���y9 packm�Nam H�Harmaceut� J� Stock� p<, a��Y&p62.��[e�unA:2*k� �s!&E5e{"_ ��b9�tE�� Mc�4xso�s!�he avail�*%^&��o��MzAiVC�CnACrq�"Mw�� #� �� � id"�!��Wy��e��䑪� ��X) �M �O��!�Min���� �P�ncu N�� �>v{��6OʩB>.!BF�sA ;����}�m���a�B�M���e�Vb5!�y� on l�0&9�d�je��2�~gA�? ��W���B>9�f�Z )bu :J#��%(IO'9���Caj.)�pr�����f�f�����!k�%�6XF�QP else���"�2�"4nqA�12 ��=7]�  C(!N� 8�t����l��c+ -�� * ( 6� 2:"  Dirsmanag��A��� )Cv !� caM.���4�A���D� :l8�a%9� du� ��52+,*kf�;�� ��)�Q4adQ�cya#�9b AME@���;p��O9�b I�l��gr� At�ic Phi h��es In�d200=200�Y�World��Organi��We��n Pacn% Reg �O'Re �10uZ01�W� Irish Aid 2EHA�. s���K50�*La�,X�. �־ A��hmRpmean *7)j �w6� f 90%α.���Y.a�ot!rno-�0� 33 ��=13mR�7 ɚse�=�-:v"�pro�),ۭ�T�� ng N,~n )�)2T &�?"zm�"6�K, 354!e whom�� a vee�#�E �a&�!�par.ǀ&��&. � � at 3��W3��&&)a��+�"�a:��U #�3��7le�a�u��� 2iew;�"� qe-�*�E#ace�w�'��)"! 6�� . At� B�,M(%"inv"W�c�-LP;u[w� {�.�qPVg'�Bin2 i��"Y�� nN� >=x*� ��. W� h z!!���a� �c (�<705*ntaj�8AuF�. S@W/��nd&y��76�j�6�B�>!�sa�&��G<��y&,In briefa�.$phlebotomiN� a 3 mlRE�de L;"?{N �b��"�A<( Hemocue 201+ ,AjQ Angl/#�Swe�m+�rO�ش���eda�1200 �}�n.5� um aliquo� la!X on wet ic�*�B!a�$t −2��� � �da�S&<�i=���0��a sandw�9 enzy�i(u a�ckԎCo��r Ai8Re�=KFu\��6�. A�r�#�"=o�)"i��!�<12I�i��D��L�#r. 2�S JU [�� l�ory-h5E���>KAad��u�es� 15 µg/L-!� � �"��cy) ��=i<C!"�OwP0���-!*E�� i��i:K���r�} chel�#� ��g&��57>&E be�S��^O+5�) [23`L9Li/!$���Ct�t� E��n A��9S�, Sydne&�=w:B '�rIllZ&ra WH�� S�Fae�F �Pr��> nB*-egg)�2�a�o site P�'y� Kato-Katz6��G.?~� E�!�N�"��KA�=� of 0 ���!( epg�ms!�&9(, >��<%%eild%!=>2 R\.����)r24E��V�Ds&V if �� �,( Ancylo^� a duodena�NNeL" aa�nug�, Asca��lumbricoBU or Trichuh� hiur�%� ek�%�s��Q �i��","E�m:� !,6�� -nB;(F�$Fa�b�c. Dat �f5��+Sf5itE al_ �E �y@��.�<2$inu�+�e �a? yf�-���;B� d���:�":H . Ch"�8!x 9P�6�4� ���%�i��)�� ̘l�&O_a�; all �$V� �3�* i&�?ng m clu7 �K� �N�!>��R&� �po��:�M#">:�:f1,n.?�< �B=(N�on:du��hw8. }+5.f�s�A���7�Fed-��Adel�N�Ab��JIAE�!���AEr&��OF�rin�.f��tHdV�9�ed�m�avtatf�����Q��C4 :���" ,*�m�me��< \./)�܍?hb�H�� d���>�"�F&K43�)or 5ol �r� `nma /widy�, agr#/t�8or�+2�=�:E�  Je2, ��m/Dt�K3!:tl�K)?y�/upa9N�(�Gݞ �W-�A��1Kho�r�< an 2&� !)sn- )�k$. D[D��ha��� orm outdo�/�T�fee�a1�c��2win2/ :Avk��m � sa"�c!��SXse��iM &�?; ) a Re2M ܓ���, C:ge(, Texa�Y '!oQ<"��a�!_;K!,J��a!�POY�rt�: fI6%&�| .�uB���ectan��r box�clef�'q��H&�"� �'�E� ��h|bA��E >=�� p�3�@i+ F�UI ctog�] �r�fY�*B�6��j�a˾/3��`Erveo�[s 101 ��p��e~� A\ �A$��&����7z�5����0��$&�2)`�;%�EXyT�I�a���g �� diza=o�:e8Au����-�Xfun�@ing�2T�"� t�� �3_-��: %���on��'o���>$"z 7C I� pZ&�,�IA9�%�238+/0Vg28��d 217&+/.��=� 6)�by#t�.� �L%�im��fa��$p ���!�� cu�{$-fk`l[�2 ��&7B!� Se�S9 H��� agrea��#i$�prick%��*'@282e:U2�C [^graD�>��� )4>�'1bhJay��T�l��[z$el�M�aX��)�!�&S&֝ two-[' famil����n d!�s��d�6rA a!`Ԑ%bY�"�n 1�zD;%- S2�NRy .D&�'@@��"�()R�Xa�"�{T�)�no .� �1T�m&� e����"[egg/f}@u](���M1�t��.�so#6C&\(band-wQ(�<o�H5*��A�.�Z��0\�a��-#hA�=t�#Ah� �H1@a��?-@to �}���O�"�H-�Uc�9llG![B"~ � .".� at}(�3)H�P&�2( 87%���#!�r� �@A�sCn-�(� A�|6 �/��&�s (�g4� �m�^>t��Z&&��;�mor6�>!)�. O��2�c'f��N �E�EAdB* K,A to�E� YM�2FsQ.� ��'G�2!z�&�%*rfaq 1"�#!n�`oq 6߃w>DpV ��^�2[� ���dou�@� rep�:i���(s in hemogl8obin and ferrit �re shown in Figure 3 . The prevalence of hookworm@��. Overa0A�n-Kinh-�co�edI�E #`( coeff −0 . 32 [95% CI 50 , 15] , p<*001 ) hm� this�notB�differ�s�,he5�or1�betweA� he groups�f those �2bstill.h week!6Uoa�y�post-aT rven%�,.�e2likelyaAbe �c):A2>Odds r�� !285@ 15 , 5B: . Across !� �mm(N n surveysA� totala� 37/995 ( �j 7% )YYreadingsI�8above 200 µg/Le�irt!ci��� more � one A�>� U; 8 7E�%a"5 of Tay ee� back!�nd . Six!� xA40 year��a� or oe��?�(est recorde�ua!538 . 1 ��� Dau_a�� 7 2 ota� �o%�e59No>*)@55@��in�cohort ըperiod�study!�t-Q�-�L , 14/268 ( 5 . 2% )�e�O:8of=Ρ���, 4 whom also%ر�≥Yat 30�� . We�����$of a populE�$-based pro��ofq���(-folic acid�8E@$regular de �2�I)of� roductiveE(a:�of :6Er��m�ainous�vin�VietnamaY0nd investigata e�j�5t�lu��!%se�� . CompliaTw� both�[��f *�!�;f=[��n!���4level stabiliz� 131 a�q:3 main!) steadLcreaseA��+,� 2)dJe�Xe��ݝly reduca�rom� 6i�s�NA9int wh�?$they wouldK longer�q regae����c pubAN health tha �'Imv�,��bid<>/b5 eɼelimin_I�oi�WHO%ni�8of�E1%�*� m�� , -{as! roxy!�sB ay]B� is unreli+ [25]!���tributeC,to�iA�� sE�of variagenetic.cdis�sr!XThA�can af� !� capa� of��ies �|��$to accurat�Kreflec CE@a%Z"� ddimpact"�Ӊ: . It�a�m%�that 1�2%7�o=FoHe%�(Western Pac� reg� � ch inclu, �% carrq me.�!Cant [26!�Wee��os hav%qv!feA�a� n apparen�\e�ty�% >��Te:ib �2] ai�8below 18%–19%�� �!��pregn��e[17� [1927�� residu� e���is.Vdoes � ppear!�be due �O��� ����m8inic micronutri ( ie fol��H, B12 , vitamin A ) �. Ii�cur%I�h, w�I >�=5is:�h�Kin � sub-Y?a We!biev!�?)re��(an undiagno�y opathyvaX explanI�a�E�ersistA ]obs� ��-�$in Yen Bai�D&� 30%�ong!� �minorAdgT kn�t'�S�a�!��Q�s [28A6eour!cIVuisI 0ccompanied byI�] aF�M� ope\ �NorQABe evid�� chroAMIeverloa%5t��6�TA�I2h�_aס��[!�A��>��_!\ -ter���wre�gap� data col���\ partF arly.��!�!�i���LEe~[ moJal9n chang�t4lifestyle habi�Wca�!�n E+, �suggest�atUYif washA�$heir hands-�wor�! bef= prepa��foo� A misaop��unA}� to !� tify6.�Pre�  birth&g !`u& ��Mma��in� 1e� imea1 mean Wweighto���=r!W�inf�"��� nter� . T�d.�V , a �'IKE�% � j�i�!�Ca�dis �) 2w� *��pr� prio�{_expan� '��!���a��l , A)ed] tist�l6�:��o.�!� !OFx.��);arm�d9�dAn)�y��� lack�aZntrol�ҥ�rai�+possi" ty��ex��al"� such asaxrov ivA^standardue_��eha��r�im 3Ŷa� may���un��Յ[-��� ?C�,>X!:ha2me ��Hnit!�8 b� cogn  ,~eth!��s^,5l �b im),l�ex� a-[� ��ed��ATsti!P&�� t� ��5�;��A u��\!��R5O(al advantag� ������a��iime-fram�C�p8economic circum!�c[��Aա�t��asses%�Y�faa�� mp"��detailed� -on-� �o-w�avail� >��\�risis o< red just��!3i6 comm�d%^so!�is`%n�V2�det���d ,��'M�du����. didQ�I�basicA'rastruct� IAsKeM � W,y a�upgra m=� roae�buD immed  :�6� ���AIvisiblym�4 ( Gerard Case�� oA�!duni�=? u�݁�ce fin�%yproteitakA��ome,%� fish�i�t�5ue)#;�-�!��С� .'=yq}A��no:: ang�&p�ipants'.�status�agi�)�far�aE paid.AB2 a den:�A�number!Éz�1 wd shu Br!� ��"d�osA�� e#a��v������!/� iv�sm��� ] ���h]tJ�t�A;ia.��e2}andom�eJ m�Ai rect9�� �� it�ba1{r�� v� !hP�"U &� by P�@rini et al ( 2012��t!�mɞ�n��� catoI]~�p ".{� #t*�[ �ll-,"� b� 36R!� simig%�aY!��� whol ( LuE Ba Phu ,nItF ���Rarg�fsus~��"; 2�� ya� ���min�&; {�=�requi���!�g�(n�� p� d adequi$budget [30� Unfortul�D �^�mos!�f�9 step�ach!�dw% �+�{T " decai.� ZcZperE?v�a�be�im#benefit-3$ � (I .|6de-e2�*UU" a� a��o�nn|of USD�76�aN�(of 6 . 7∶C[31|!sheer= '� s en���at�TaR-�mak�do%b�rin|o�X ocieB!"&v!/YW-� �!�]_�s, essA^. F� W)�m�rec�do�7lbendazah1 4GlaxoSmithKlinCme:%Johns�d (EC*600 millpa&a ics  y�  )�ide��.6e�� A�!5SofiW�bN��e� in school�childre�sh� ��� opinl,A�� nt risk� �- pre- _2[�=of  be�ag��As��A��discu !mZ�z s �D�Q7� X AW?�o :� n� � !gU�*�s w�beA{cei� � oo �to  ify a I\al�mi| �d���Srv�oen fewUor!nQ��>/'.- s aiP� ��J" �*;  d�!�gq{� One e.a u<�-fortif� suga� 3�TDA\ emi-� G�� mala!�!� .� �� e�lk&} �y��in��}�E[32�+��ba largA�ale efevenaQ� in I �,.�o],H�&Ap��9 Gno� i�z��.�2^  aLm� �(r grass roo� emA�� F -�oR��buw rough5� y volunte��,be@w'��selA8, ��Ar&3%�-��#6 . girlsa� d 11a18��s [33!�I-�Q �2y,�am)0F%�(lso encourayQ� auth]A�� ac^led'��io.��c�+ �쉸�}� b. Mqr�Wlsa�)�one|2���under� n am� triupeopl northea� e. I�. HN|a�&��5�follow!�dai� "�"f E >f plus��Re* 0spirulina [34-� 2004!i�X7%�$B�“…s��s"�s� es‘%�'7$blem’ [3l” �7��'s�I�%d specgaM{>!��i,�8�$�edo�a%́percep���re.- nd�� nurt��8r Not� ex G� �"�fA����fV�o�'s��c� form [W3$RE��X�AAA�b qual��if� main�y!� necd($�onseque%9unv �.%��rt��isq� issu�3s emphas^u{E��.�*of guid��e)��dE�X(e��(ro��bc�)�N "in�!x-LibrarGE=NXE'A� ( eLENJ3u [1eG�cl`$on� �!W�#!V�Qof Vir*08Z  �inY4ource-poor set�Z%?little3�#to��prehenV prim�P i�1'� lyuous diet]enthusia"�embrace,�� itia)�� t E���ga"Eh�(R�whe��#��ye�%is��edMh;!Rc al O3�rE>>���UdY�a review!x�6]�` �,a"�����%�fYk� �A)WRAv a{ i  a+� f 10�!�fu�je�con�$��n 6���!�Ge� pracLeeoqsca%nup�s_>%Q+[3�F�@su.}'to AR s� al"�  - �!out-of) adoles� �!Q��n.'r�eel$l�9*n , amzfB�; 120�.�( Sheilae_jx[3���� S be urg���� in�u�w� 7 ��y i���6Y6,!W�!A6��  vill6�", u�,%#a;lon- lead9 $.��Cell-� d im� y" y�key rN in ha :A�W��isa�exempl[ by?-M%en�reA�%6g .Fpesviruk�d� � th�WaiZT-c� and/� NKT  resp���ToJ&ow�� �;!c kAnaj��"�'��&.,:� oit)95 aŭst!�g��!a���d�� mv%EantigenO"���![.0�!} escape me�is�#�i�PNe�on &"w!�. G: E<pled aTpig����A��in�us- !�!na�he.���conWa�vulYl'�byHJ�-A� repl� �$hg ib< r2�#a!�totyp&� , Eps?-Barr � ( EBV )<nco6a nove �A�ng e$oe!��gp1�.%i.4�!� �)�r�|"I!��!�BV [ inhiu!Q%!�5� by HLA cljI ,.�H!D�%%�, lipid�%K�,CD1d moleculi=h]_A�9�m�M�"�depend��deg� ?� �.xsy}i�-et0’s cytoplasgeY�"abund^!glycosy;, , B q a shielaa�pe!� surf�2Z�i k���%precede�Ey�u�aM:.!�h�0E`^�q r2��addh � �an� ct beyond1�)/eS A��cz2�*B"�Fwa),-null mu�*e displayed�\c}�i��1:1*2B��Ew,ѧA� �o< t�|���s nexMY� �� f�#GaA.$$/s�$ ,z �"$c�e�=E{�E�9e8 span�� i�offsp�aA>�sq !�a 4f cyc V���C":%�w��app� o ad��6 � �ed��ell!$ �ow` p�O� 7/rvivaaREOtin�-K*A*��y m5 with� d m8%A&s1 nti- �E�ibexe�5gQmA system . Z���uia�"�brŵ ( Ag ) -�ficU,��s���#or>� -5H)CDAS �r=?,�` stim�0ng �I V5un��� CD8+7 CD4+�!�%*n, by p�de Ag���eX8A>�u|�� aof.je* II (  II )�~�!4� lU2InSq! !~�,na�6killer TT+~ )��`a subseaSiaL0q�cha� er�!� gid *& p!@( TCR )�co��VA NKy-��$��:Eby�waB�((polymorphic%0ѣ . Upa5!% �,.�sv t� va2rra4polarizA��ki��0�.0lso directly e'+toxn y [1�� �A }i\1%�helZ)J!aRMa�z$MotX againstM�i�1Cm2'�p�.#d [�H&s �*#;p*5V� e�"��nZzI�3*� , evel%��� usy�e��[� WithFPP ( 125–230 kb ) DNAm|:B� n y�6PN! yet �1�al_�u se�Aw6LpropagIf~ tro .&��ccu�y%KAlat�&!rr�4- ��j��e P��bal=C)F�J %y&b �v�A�� ge>�%�*% "f �fru0 �ay]_V��Aw0 ng��2wr A�at�h:�C E�in� �acw �&m&�4b��lti�meB$�!o*� fam�t� +2.�' coe�eP���%]tes��`6Hi�.%Iϩ�o�2.�y�[�In human�^� v\b �fx8?a I"ai��ob� $best demon)�dE�jx !�is γ-.�r�8?� tumo� #{"�u�:beA>�5 mali.�"s�+HBurkitt’s lymphom�=,nasopharynge�arcin. is �,A� t�>904ad�0world�� /6s��asymptoU.b �"enc�t 9N�)"�("��r eh/M� �5 ��s�self-{ jus�9onucleo�[6���%)�.��u�vrol�*e�e�:�I�1�6a#0o��3q 5�8o*LX-linkO-%�proB �#ve syndrn1( XLPD&oV oft�a�"mo.�w!�)eA2!�! .Jpa ��7a�L0de PAwt!#n�al T �4� A�ab"'79 ��s [7 , vIn�, # caus�f6K) mas �L&�%@���nsu!k�-����D�A>or AIDS� . Re�tit�&EB=덛t� dopP HBfer��A[c5)���>>� �6�disY:( PTLD )�. !j!��i=�wW L.ct���!�i� mm�� y 0=/ZVTo)l! MA% . Like ���A\F �lingen�7.7'��/��%~oE*e�5U��].2�,� down%= �Ag.�A�aP"� Y�!zH�1) ���6P .� +~�k"�,! i��)�&��t�[1^(I �"lya�x,ح*V �Ia�i�����o�(�l� ) �e%@�-8s: BNLF2a blocka��i�pt� �l� �'$BILF1 dive+$�I� plexaway��k[12��!wshutoff� BGLF5���an RN2j arl4s�*� ~�1� B;"@�-`SiuGa9e-Po$A�1A@o!s$ng� !�YJy�e<lc+�crev1�Q�AgVO[13A9 ����+e hyp4!%�� s�|al Mfe��&&� ��%94!�%�!AJ0ir �6t�3�Z ;.lu�.I��/,� took�lloG"ltN���&�1l�La focus�A+a�mo �p��o; -�o��ioe��վ))��$ �fY&wmH &�ed�A� j, e^ �8BDLF3�9,�a new�`Z� . 6�>iq*_fP6� . To�"y alte� one��}�^��d&�1�͑!�Y�ofU�e&hoy�4u]"?describIi+ AKBMV� ( BL )[�Hp,[%_y IgG*�%,%�)+�3� պ�0�aJ!�� d�f� cytometry��mj 6a͵r�#er B5 CD2-GFPa�d���i� � A� gHgLQwoL 1� up row ) . S=�=^��� ,Y�-�ha#Q�ea�marke32�'on���E=a*ari*#dL}l\Dr ed�t� 1HM �lef� nels��$�-�A%ie\>��s�'{&D& -�Q��.��"7ro�H8A0 hj*�  i�! H!")�)�Ei,�ce= a�=��7=�&uM��+-!e-/l�(r]% "5l��-4–6 �)|��o �( S1A�N ���A7T] gui6�� iH�!� ver�e(�XT7- )%�yA�� "�*� -@1�^�0, phosphonoac� U+ ( PA�%I�,< �H.���A!y�'��Nof�[I���e �f,)a�m�:�B� .��laa69�6!o �rat���14�L�`ed.'u2� �-y*alK,I�Ae IQ�E�<E|�%}�ri?py�p�G�1tow =invol6.|E3..( a�inVw�,a�?. �>?! par �K u�A��a�,"h9i���n��,�4 �-�sT#��'duI `1{y�%ejH5 � E on�ne��%30 �2�"��~:��R� ^�1-�:%|.-�Ii" �a=��A* �� F9ed1� :G ,"? !Zapproach!m !�!�v6,!6*W���#ge�in 293T-%i�!� smid��1�Be2 1C ) �$n MJS.Hvia l 2 p �o G s 1D? S�5. ScreJ%�+�EBVf�revea� A�a�� U�g91�IQY��m�B�XI�%;!f��o�(�� �f�Up-or�f��� maj�xW�aB�a�XAl02_�B�� �tho#1Chom[Tuw/�  2{ a� us type 1SV-!T�$f���c�� certI��)�kinQUS3,��A�+ll�r~!�of � sB� �&� [1�-� p350�d?F%�,g�s�Test}�u7af� nn =�. EF��$a�velWW mpar�%eDra�i�a{� gC�!2� �!0 m4 J�<-^�F�����}w�!�A�ef 1�R e~f ��� e do#1o>howY"hK shoV$o-_m; ��� �S� e�%�detis����at� "G�6!�B*-?I: 150 �1gF���u� . Fi~"�P?�?-$he�A#��/r��)����Y�of�Q�C matc{OeYDF�^�ŀvis�0zsD� ���1�� &s�.�*"�%@ a) bodyj"0�ed"3��int�� 2�&M�:%�� ���A�!}cS2�+4� :h � onU �W:�K��\I2� �;� 9���0 ����12 �qm��,(vAen��q%�InLI�@2%.?�`��;7#+P2J X)�@y����ofb<B�1�cV�no"�UhiatoIaqc!��1� ��86:hj�%�uB6�"QT!T�b� phen�*�,&��(�|9re!ai�*wW.� * �U�����g�$%�� �5��dZ*t0�r��� � � valio;d O89J�[11�L18]�0�$D[#6��&3"*� I�(�� �)! � gp42� ��sam� e��exxFY �/M| !X�.2Q,g3�EQ�� �+�^( S2A"2 ��(:1e�{ GFP+"} -E/���Figs 2AES2� # "-+�.��Qh!��Ra3o)�o�I]�@K .{ � . FI�mA�+�=��a�� �G%� ed&y CD1r\ CD54��2$�'� !\&� "E0eas9���et�'m+'Z2QI�y!w�Tl�(�!��DcI $ logarithmKly)I�7edEn fluo) A)�_m0$( Δlog MF�'� each� ����5em�`E.�� �&N=�!�,�sub���=}value�7!�� P�/)IFP�6"4l�UE�) ���Ee�n E�-IRES-�W !� t} H uM� 2B.�Y.o a� exa � .�!eR� E1a�N��"ou(�v�V�i�? W1dEWE)�To���>}ts"�E� G�[�/�e� i�4 if U2�?WeY",c�Cw�)�:�%�a�.��us =u�aS �E�I�i%r �!�>  %� comi�.��E��@�:�A� ��s& S2C��%�Wu�!W�5 er d`q ]\r-)ad Ant>3 " ���2ua>d%�BtacS�� be��had3 d�3a�TN-$Nc�'�oCD$i��!�;�1�)Ran!� �\4g6`%�-�yto]*�(�= S3فL� att�-�G!Oa�!�6 inci�MB�%ܽ�2� }<��e�cb�e!���3��. Very%�FsA*]7e�:��@6kyK��%omargi3 Մg U&�{>)oe�B�� I�s—t2M Eu�Y&z��%k5��Aq(*�Ogs��;�� \A�u�"Fue���'qA—*�'I�!�erBu�$/^te$"Ea�u�"| � a ;�25�<��to.�e m�)%w�(9�� �|t��m &�Gb�� |Ae�FM���35%e���(FzoB�#EMG =�&!��=�<{:vir�'uKl %"�^ CD34�4!�CD5Wci\, n%$���FE�-�-�p3 �`d�A:GFi�f�/��E� 2. F�_�� o�?dM9V? ��� 5 t�1�7��29;Za�7��-^-��[s�t ��.SI��%x 1^�V�Y3is%�29Kj�KyO�En�8&1( . N2E�$ �la"ek?!�*�(�$E9Ao�S.� �8R���V�M�E�~cAr��Ab=k�_ ofD%�:/,TCR–HLA/Ag�Ua%�s 1E�!�,;^�relev�(q� �%3!REB3 �M. 5 q �2^2{$�e�Z=s� s T�!�� &�`$HLA-A2+DR3� A2 F,p �fer IFN�4γA�3{ monito�%X16-8+�i �"� u;"�5.�B ��8&�4H�la�megalo7#DHCMV ) pp65 epitop�+ex5� Aw0A�� -A2�AK�"X5E�=T-��!�� 93b :�co/=�E5 3� &�v �I )�ef�k9E"� )R��IFNN��!��!4� �i`�NS2��; ,�n�&�5�)� .Z6F�a�P�gst**at�Z Ag ( MiHa�ndogenou_b �ɋMJSq�(AGr�DR�'aQ# ed u��&�0Bsp5 @-��.T-5!|e"� � fah " �AV%�� 1ol +-�] 2� ME��8 �� �6���s�Abe��)h �,G(�ICQ�Sa� hamplP.J!��� e|E�w��0�$"4 r� -lig6xAA��@!)2��.�*a� q�or�9 The�5��aV.&�=���er�"_ ��H� ld dM�� sBfH��zooN�C1,��:)w� HC/�9–TCR>�T�Wi=S�ZhX3$%jIVrea�Mb�moa�MHC9H-2KbA��Q!ovalbumi�'r�PSIINFEKL�[a�/+-�bed KbasRTE� AAI���# 25D1m6A�ŶrebZ$capit�:!b%n�7Fig 3� %9oѣof=�i �ATa2�ME�*�Eof�R��u�m�C3�a is"k�,)�� E�e�)�.ni�mi�~e[E-" *� mN1h6�C*. Our�O� "{ �Y��Kirs��M'Z othP I-�II-�B �� H�*� A�&�8�,i6� E"veIwaA$to unravel�m"1*��)�e�A^ qa�u���S�,&W "<X 7 �mSA�UJl ji� s mi�$�b�\y4 floa/ A��9 �made�w# ^A3at�, �Z an N�Si!JHA-taq4r � 7s)�) � *!r!��6 �" y�Ue�rs�3w��*%i�n�Q�F ztdC-)p ' 2�C. D6�C �s�b�e otea�b /sz<(N )by �lysoso�Ywa}|U�d8g9= ploi��}4*.G"� �3!�"�0^� �� by Kaposi sarc�7?H9�X!�6Qp,"�t�n �1���2��!8I!C-i�ce1HY0-LN T#pox�b���chloroqu� 6, H6h.�E5H�L4�Of�l HAG9�arɪN� p�%$%,^"�c� � �]. A.�D94qi#]�> D5ɵ�!��s free)Q�0�a--(�� o�>G$β2m ) [20i3">%n�gu��%�W7.�p"�i!Z%�93a�e"8E?9\,.��(Eg�#�Ŗ 2'Gc i�2�of newly"�3�q:���n�/MA s����a� qeI� QÑD!� �^�@|!5�M�� t5w �27Amyc�?�U)5M [2E5w"�#om �e 5-� .� (=myc"=�I ��perme=o!=��`2{4�B�奻fN���' m.21O ?(*VE�*)gna)�ra��-.�:-.~( BB7v�Hig. ���,mycaBuZ*� B�id%yN[by�ew���0� 4�%!m�fq%�KX �UngI��� �:W�A-Ae�l�!nd�#[=[5j�-�D�TU@� ��e"S "�R� ) � uhimeriGD�� V8w\a(!Z-� ,n"G=2e�+ρ"� � J�v!68 i[5F( >��t��m�Uun�3s.�B�@Q��i2]�X�E�&!al set-uNk� ud6i��-Sh!�{6CB|��a�)I�Ara�B�*e>a�rt "`n{�"-YAeS=>.�m�a�= v",*�L)B^��{���>�,[21EA leQ? 26 a\q�0��om !ZC^ �71.(U�Δ� �m�7"3F� !��"�� Al4;� 4a� "L)\�Y&�Q"e:V ��:���E�!�*�CR'B]E���; e�a<�/%��+"P*�/� %��GF�:\*& �� ��pr9qB�A2yY%�Mm68eva�9"� . A.� ^E�t!�� �x���y.)b*\�~2�eZ!%Pruq%�proA7! �^�jGTQ�� ��fy!vf�As�h�R�. }ER"z(���w9�*5 m�J�irVE> mig�8�KE��i)2A %Z�wb,u�lysO?�xoH>p" \-W%�F� n., vec� � d 7low/h��6�K;�4e��Di!�,ly�%QS$9� �)�r��1��en%�sidaq&� . EIl�Q H ( H )�� oves, -man�v N�C7)�K=A�� lex arise !�,� H!�D�)r\-Q& cis-GolgiUar4. P�?N-; �FL6NG�F�$ea 1 ��~R\^Ƀ��b�3, �5�R �allF�r�]'\��Z=�. M!�eI�2��Fy 4FS� �Z2 bec��!� H(�A��)�s*f� QKI�x%��  C�^�4 two e=b�u��7eka�P1HJ "+�2%JP xB%Q� 5A , +CHOq,a� N�5��mS_�2��_��a�8y f�I aY�\� &fI���5��61d6�( -.�3l6e�)�2�"�3BR�=�>Y2Y5 ) ;A:%��al�� p�t |][!�'�ef����Gt�a4�T6_�YF=E���nglB��D!�AD��"� i^{�~( .3X i�2a�d��dieh��U@G9�a'-�9z. O}%ag.�!�E9Ba�#lym�um&{ -se_ m^)Up<Ū�#��CA�� u�(: Yҩ�!\?�*|6�(e !-b –687=hIfLythAA���� )<�2x�(m )_ ina�>�FF"�Fn ER-to��tr>k-!#%,9�is�p: �3!�pe;cEu7�2>�,>*�BCS6� �\*ER&b �!![ac� a “6s sink6e�g~)4i�F^�. Conf%^8 scop�Alow���s"M ^JZ I�E�����po�7�#coP liz U:=Z p��&U��we&BL6�~n-fixed};$!'a"O al  Q��v( Ab=��E��DP4S3X1s�);s�.i�}�Au.�[2�FF6!B!iU nfir���isTV:� bPz�#�r��J^�47�Bt��I�2)���+k�+ej �HU LA I& N�,!;le)k6�.d�� � �ad� J&� �1�� �by �&B�hI�9B�f0# ޅ��� �bH_osi�6"#�a�H�+��5(!?redN5&N&�.]Yc6�"��nd�DcuE��hee �.�Wo!�� ���s-Ql���oJdm�,e6r"[�a&�-���9* @%�Acwlh.�MJ�� p�%�Ig��/Ab �Bs:b�T���5=.�I��ie5�*A�{ tegrz(Ob�. U%�Ab-O.���4R�A� �&e�+J�[aJ�~!adg�J�j�yt"�:�F}&tGab�j�', � HoQ�Am2L -V.jA>#�,M6!�-)��p�!iY�i� + �i�]��!�eil���]�F~: X�[>d��;"�I"O��� 2IVseb� . Qu!��6�~Nt�,ݏpi9}"�H�� �Ab�gI`���- �d'�,�a�-ng-% EBD%��aX� E�hUBG�4y1u!�5�Ek 5�!0/��seI�1z�?>�M �$&� J�ɑ� �orB�A&���%� !q~Nn� ��z:A�B"�� R/mod�#!D�fsvbF' .Fdo�.]�!gj�Iv�E{:� �[p7diar*�]0H9T/t�Nn^�c���H halfD!a"�id`6��*r! � X&e ��g�& N-!�O.h&lIMIt".(�veM"�F&x4 i�%c0in SDS-PAGE g/Arh�%s�Iiff&�)QEa.�y100c 50 kDa��Ghe un& N6!r30�\Daލ��pB2|exn Na7 Ń�NMl�:�x��-ne�\�~-�_�s`�� moie�8[2|IJr�^v-.e@ �d��)Zo�r�j�j!'O���PZ�,>�"q ��pejq�n��1��� �`Vye&#ple!�� �3e*�x�>F.�#� �c[(��G� � �ui� Lec2�C ��Chs`tqmtW(r�!��aQtut�� CMP-� G** ZeAM��!i�bg ial�s�F|P����������DPYive%IEm��!�� byAHAa���ngzwhe�bWp aggl��i1WG�^�l�"�wat�(&Fa".r�N-NLylglucos���r��b:chitobi'8)�96_;2!f+Z�!�Cu@ 2[m:�T�e�.q:2dwE�Fbq�`6�\&a�Ě�F�DjĘ��a{*�Z��:!<2*6� Sb5!�J q��HI%�E�on�� D&w!�i]���X\��al]d,�2ruD4aq/w ] QVsi���4�^Tas�q �F��*6�q"y,�^B�u`:"G � ��a�~0yOBOA��s�&aY�m�xuJ l"p"�7c�\�UI��/6�S+\�"�(dՌe�����%�d��*�inU-�!a�� �,iM�*e  �exe"?.�p��1�..�!3&��(e5Ad2E� ��'!�� ̕M���@o|J0P-3Fax-Neu5Ac�;>na #�/�vyl�\ fera�( enzy�sE.jVa�a�#PM<��C�� )��j Q�M�7 �-�(s SNAi�MALII%paw�#M E�Sf+�%nhs5z�È_PN��L;@ �n2 ��h%b�q�le�e��,"�-�!&`@1�2#1\%xf"�U��3A�!4� �!%- mpetMB�Le�-�%.q{Y��5!v��u� &�^%t�of>�� ng i�!�*�^� a��6|to�&�� &� -��ksI�W�^< |%�� pre-incub[eC6i����q������9A�i�����)H �G�:6Hb�-��a cru�j��g)}i e6S AbE�!e�"q�Zr��U� BI�*f��.u�%�uR� neur{?Qzy�3crYO �?�%i�Ydos.�= fashA��wit8�a��-g�vwse$ i��(!Z�%as 6�S5i�M�H9q(6��E�%o��>�i���^Y �.��gy, >aAi&��}5a�*�pI�moّ�Q&�K !�"�6#Na� a+b? I�չ�i2�.SJ%ZmH)1!]�.�:��U��!��>��EZ8 �A/%�6�1�KeD%�2c;�� N6%����HmodC1��t:'e��Dcw�!&-�a�M�b!)=�%, I��by:�E�� �6\t��(�6a*�QA����BL2zs:�-[xara�-,"K�1�pYqx���zJ"lz*v\ � &HuE+1�l5���\9r�Z&�G���A. ��edB!�Yfu-��e�$�$� �W�Ҟst] perh�*T yzI?." . StՇ�%ly.�Q��GUD� � � all %CAioF(&l� /��0y� .�Qe" X�fdR�_1w!-�-@ya�N�52�%��i� "Q’s �.����dorM }s� �4��t�S :�<>�*&t �`6�zzbe��YTez&b�(+@N�$a>*gTvo�9s� zOa�ep�(l*�A��� rvoi�2X���&�P��mem�: ZA�oΡ� *�u��r�|1{+�P� Zed Kl%��T F+m�AW�B293)�0 �Vc�$� e!9z?aaRP & ques)�I&�K:i+A�4�ve[)�Aa�&At:��6�dc<�Ak�TBL ��Tat�|�D�!(�2�!*�A��AXb.T,��l-h�ll]���s:a)2�]r~3tA8/:�#!��na�equw�"�e.�]F��W�oD*�]WS�_"�]�)�+(g�= Borz�n$Hutt-Fletc�>T~ ViNlyAset~�&knock���%BV� ��e2VA n-�s!{� co okM ( �Δl-�,`*be� ��!:o� E�+ em�� Fl&�e �c fgenA���lAPt6�Q���avoN8&�7"~/8nU8a�u� � ao(a�eF �s s+ �i��P�L C�TY�!J�f� !mi�RJY%/ �3U syDer �&��SB"/ or 0A�i9%Z�a�&k�[e�ed.�m:�u2 an (vA�) *�0V#Z )%�E7%���N�$��o { �B�$E>n-length �e so� � 7A�"d)�he�% trun�R �y5e�D|gHb�^}- /Ab�\.J/�|5� ���:q]LMI��,)�Q�re��i%�o<U�WW E &BH� ��sl-=l2M�AjPA, B.�Q�=`*E%aB�i�wrasa ���n�A�2�0�0As�˜:!+eGon`F�zEBV�{a�*Ih!/w�v� 5����!� �%�(uOiJDe�$1$onY"6�&u�.�-9� ��o)�1f�#"$ � .�s�4o�B a�`}s�M,�;!4�#5�`5C4 �.Jt�ΔC.z �1�,! ��� �� ��d+er�8�f CD10���q*hus;nm !�>�E 7B ,q$�!�h�(��aU�4 .�2�V"��9fMoo Z%4�6�q�6. N2�&#n ��2\�*R'A�/bs" � ��/^� !�%Q%�)2�5!b��ph!(2�J\w:#  �*� �B %O""@2�)7U��.aX=$"�[B �/�P 6o_ mas)4Q�2X�E\v��".��|�։s�#�� �<� �$ e[��helium-��%�A51 ���X�pt$p � ��a� .fL:E�� %�3*� B3>� M���� ShKW�ρS�  s2pinե�harbour+6wild-Dc�"  wsz�B�`^|�8� E�J .."bC�+�~�� _~Y> $[�6�"�.� %m<}�!g�58  L n,x�E�qw*�Csem؈�dݸ� ) e>M����no��"`cGV"�6�$ӆ �p�;iv�c�öJ� �K!�a1b%F:I��]��%%"�-!\ y BZ�t,%jy}`��~ �d͊A��5J)|p#�S�!4őA���Je ( S6A5] �nbu���h�f�� ��F�>,)A���%J � c�Xer�)"�&�e?T", d����.V"?[ �p d��15 Ame��5A%�9�A '�w +�: ^V7!%�+ )>��e $�'�a�(a'"X �7Je,* ��.'EV��-�%�6�(hZ�Fmd�oE�@!�� !� �%�q7to aO.�7$ ;�_�He�D,f�d��: stG��Q2�F�!I(�� E�a� CD86�� pronoun� � �de��)`5�ES6*�^�x�6 ;e��� a�F�^hand–F� -1 1��� le&�J��9�B8f:DKOS�od�J$s"OVav ^�,K��Ggn';_�=�*�#�?J^ �\m!m�+�u�C�A�A}"�E�A�*+c>�IIJ�. Zf��1!�:BL�*\^QLjz�3b]��5�Q"s�c��g6�F�F(�e�[�y*��*�$n�*�A�I�8"h}*g�($�aEKj�k}%�:p}�%Q� ��O &�y�/ !nY�1Y�ts�M�$��~ �bhX�z�D���ӱ)a� .�t6Q�J+�W�b� �Ssz�`� ��Er�  0 �"2P� is'�ei���e���:\�� Is7ig+.!�aF�[� � es� 9�&Jz,%icli�mo#N)�- � !�"bE+F���b���y�� �N "iS� g�Or �-ӗo,�*s��&� u�*�)a wa���{:e��F8I���to-y$��:���� L�T�.=mYm�.�? �^�&�Te� ae,�OnO�)�RBM@�S�ev�O���aMveilla��N vo��ro��O!��j� n���C2#��CdAp, �W��w�XQ�y.B��)��-�� �2i��D gU%�en� �A�)��R2d�_�.Ց"hn1��D*� ]�2k��%��,,}!�%�.��(triguOu�.y !g�1. a2�kismB�� ��l�s�Mk?/ �&"X|b��r*��B]odԮ�d�&�}!�; as�l1ݖA��&al2��1!�)u�l6��` 6��enC|� ^�!W%&�|A�_�g F1�^l��nigd$ until now_we�=w?;q&��U }d�02w ��0�'toL U!��! [u�2)2�].j �(�  orOTa���F%*�c�uW1�3A�"� �"7!�6?'I�6�mk5� YQ�.�� hh"� A�e�p/UXm5ng%�H-2 Kb/�Wp5�ci�exD oreo��weH韑퉑R�de�0�P "rm�^{�Y��#o:!��;l")�:T m@�? J�.}�/6'!�$@o�C rada�q�C�!��E��:�k7MG2� 6� . RaI��9��d�:!�5��uf��i�- 3�"� c��Ae�Wo�!art�x��?mF#�6o�jBa�Ebola-�a��ٚ OV G�a�b�2�'�  6��, nam\~! β1E�grl6e�}a�" l>oH�zF�5|�-&%B���v�w�6*(L�"[�}c��n�.�e�� . B:YE)&�S#F��H�I �2�ZA�3O_510*�HH1�Le]tZ7.+OsH+si�J �fci67�)�SiO��9aiAca�2FL$[���‘&|�=B{$"b%��Ge5 bn~�8�"� �P` 2E��? eo#E$�D%o �a^y�7r�E�0r�y!9P3+X45"T� ^��I.b�ivesti�fFT6��ybM  sh� �fe�$&r.Cy Ƒ'M�lya�.OF&YyPY &���� 5,=� �!&�9re����o'� ��q�ar neces�7�f�*B���2����  ^facil��:\r g��*�`9 I��_%����%o� 5^� (:  )�e�� incorp[�-|Y at"�� �h���3  w��&�nsi2\�6�_&t8�-z EDU ��m�ORF!�er aRy�e�.. 5-5��1ly 46%.;�|EwY�i�E��eQ�!��erine/=*onine-+�.�%�)&o0ht!�heaF�F� .�a$"sn���2�-F�c:���2��e��'&�#r魥Z3/>S�1�M��r��:. A�Q*F��3ysIejB�1HV-68A28�z�a���-�+!�). 27E6���^ r*&�h�a� vo [�.W��� 0e.of ��+�� T{�w>�l��+5kiR\OH_G�2M' !�an�KA�%��)e=�n����>!��JupJ6�S= �]V� �Jq� aO(7�E�!�)��ed�tic2g�3x)&r��.-�E![aVBeN�?aW$Ew*}�aJL� nvelni!?" �GVL�ES"A5&Ѫw ��9 1B ��J wI���� � do��I��b*�� � =�� F\�cvZ!^gaberr�6� " id>Fp0%)��b�play aR/!�W�.on��,^2ma��0�2�.=d�� *�p!0Qof&��%� bgEw� �ng*���"q�R�+�L�Jt�5�-���2�F�)a3�hyhm �<Aass25_���nG�a�"�[L���E*��-��=��qn2q$ -HQ���!��@�\$�KI�6E�N�5|S�.� d metasta�\�!a v�3mo�AC��)�N$&3K!�8á�1 "� ,(�]h���% *��tob��. j�ve13\%���Sq�&Z� . Po7v���E�6j.70vP��E�o��synap�Z%o�L�I�aI�S)&����'R ~Z":AmaN��  =ayN6�A��-��r��� ��pAr�g� d�Xk=��'G!�C2k&O �Gt� a7xim�8 ^x� ��sur�C sa r�2>>jk�Wm"��!/�6JISIMw�E���%tBaOt4/ICAMQ��:PvU���~1���!�� C>�} �i�a.*�du -�ls�}�j�eF�v= C �v*���Jj^�("az �% & �x �"�Ne�CD3-oCN�u�W&W�6��"�:o�] ��� J!-H�!,��!\n2� �'�#apopt�` by FasL-F.����(, 0s���6��ct[�o�ur�\5IB| %a�_ 2S�"lIi�^j&�3-�!p.�5/( &X{ilsoy�A�� <!2N'fE u�pl��at��s �rh,q�EBN�0CenvL���zI�V.2!?��*� ��NMͧt�b�?m;�D%�f�gsab>A6ra�4� [�ar*!q|��B� thema1�p��%@"�i� onsi�"�!�Ӹ�Z aliv��B�j�L�!�A}>4>�C8NGi~��؉x9.�"���ranG=O3 Fmy LeU;�o�"�b��&��x� Fe.#bgl�]z  m3ni}�����o!um5� &CG^ ��R��#A���b9igMh�m�s,����“�[WV plac�I a— R—)�-%<)$#n5,edI�.qby�M&LQ��-F�) no g��!O�"!�6� ���.��F_3!.��2�Z��)���!DMW  �Q �e_� ofI$M�-Oas�q3�S:A�//us� . So���|!�"����F^2x^��+��6BN &w,�F�5-��NqI�������.F��6t�alNia*s&� �sf_U . Ye{K2�]�� l�X�H�� F�&�%�Ab neutr��Y "�m$ejBaW !�5�gN!�"�nb`�2� �BoHV-�S gp18�w�MIK .&ZE�!�. T"�4pgN:5�IQ�Y�fctO=3*(* � �r��r�U�#e2 F:[3�3�.a Ǜ��� w�5� � &�1*DUC5x2�'%w�?a��X MMa2��d��.|�br�(3QJdel~Ѭ!jth�&geʬ�m Rng�� y& vi�.ʫ>��"P',aâse �gQf'*� f�Ta�/ Z,"� !'I�� �oa��D.ǻ�Xs$e�&�-�� �)�d�Omf!:�, dis. �%V6y��(H} c�ra:�6�-royN9����Hle�:2J��O�� indr�!�.iw"ǫ�B�(���"a�-y:����!�R�,"<�y_ @�VЈ[�;G%uL�s�е8O � !�paTCR���\�%�.�A%g� I�A�* ��2�orup�r<��ud|� d��@m��$6&$ bi�����u,�-u[Eb�;es���yu:��&-S<���I%5�!'"iN���E&�a�""��a>44�b�"����O_��a--Al�� alL>&C=Akd����f*0�J90!�in©pn�.�bin5"c#M��E'%m� -6�3Eo��e2�+/0,&^f�M ��sco��n=��,��Eo:�,A=� e:!�daE�,���!!Vof.i�%� _?2�~~�T��iph�blk s΄%|5LA�E�!�*T��%ob� � w��D�Z LUMC0 ��E� boar8gwr%�9� ����r��DDecla�Uf Hel�bi+w��DA�lb�10% FCS�$00 U/ml pe��ll���100μgstr�my w!��4+�B� s�39�, 2�1� 2uA%/""u�L�PM�pdiuP�E)YZ��A�4��o��on!�Rנ�&�Vau5e B&|V��yo��kidney` EK )�D,  293H-2Kb-A� D mela���%: MelJuSo Ou@LAF"a�A*0��B*0u �<�Jd�~I` bU DMEMf�%UC�\B =U�E�Dڦ E Rep VcvW!�"U�y0])db�MEM-α�PNǡ!bod���Z�S�%�TαVR(��4�䡨5!9 Y4D5; a kind gif&S or�(i , NY , US>62Z-PE�gl&:cE�*go ��)�ey�don�&Hα-rat-APC or–FITa� Jackson I�earch9��`r%W ab3w*e�A6o�� aV4�.�av�G-BV421 2��CBioLeg9�) ��>�+]Y �3^R,an HRP-conju�'6�Zoud note% �y gu f?Vo�6*?c,R)�Atto647Yigm5�6V t-Alexa59aInv�#�x v�'%� yP��dR��IHisNE���a435-44�re.�A���A�gOI&Zt[gM�Np7�\i$�iU-��r#�|�[.���&t�,�J[4�7T*,7&�#�Hal�t��%�V^X�rd�e7 *DWi��n�?)(>��&�� A���2W�h�.a zeo0 ��7ce "b@�X$  rib�� skip�� P2AEMd�� an EF1a� �.r� *I7Fla)�DYKDDDD�^1� BMRF &�bly/!DL!!� 3q �5-Q PCR- �S%�EBV B9�8*�NPCR��> :ň��B�$ pLV-CMV-I��.o}�N!-]L�FFtaE�$( YPYDVPDY�I�n#I� �#�a�0�!�l�26 aa ?�9Ϳ�-�c�&�{*�F��-b�be��6�"*���0�I�U�7-/pGK^l-T2A-purD6y7 else~ڀ�aBvsFw12�dR��heFA 6� ej�m"db�� don-ܹm>% �b�G\E6$ar%�-� abov� bS=;�>;�ib��mA[���]e�q�Xe�..Kn�T2��Th�wSIN���A�1��,�y by PEI�:� v�93T� 8paP VSVG�MDLg-RRE��pRSV-REV�OG>6TeGFP-myc-tagged HLA-A2> t:�GFPmycA2%eMJS-A2/�, resp!vely . T@CHO-A2-5� Lec2)�,%\ �firstB�)�Lcodon-optimized β2mEUE#U:�4Subsequently ,.u=/to1e1A� ��. ++.F.�I�a 4Aria III ( BD A�4To study gp150ArQ� linea A;8he variants HA- ΔC)j�,�indicak,IT 7,5t ,!D.�, which �:�!�$dual promo�=�-X$pEF1a-/pGK!n -T2A-�.��-5Iup!J10f�B� Cu1I�Amy�:2Z `4 weekZ�A���ienm�f�onA�>�seededA�412w plates one� priMoI7 F��j� 1��Ismid DNA�#A:�;EBV!pteins � Lipo@tamine2000 ( Invitrogen ) accorB�Hhe manufacturer’sRocE��5�Pby flow cytometry two�.@�I� To assess%��levels�yY�molecul�] stain1antibodi!Wf<��ificity!~0PBS supplemen5MA�5% BSAEH02% sodium azide . !�intra� ular �s!J CS )6Yfix)�2% PF Y permeabil��in ICS-�<buffer (�,4FC�(5% saponine�B�� �!�A� wash stepM�perform �>m. AllCB2at 4°C6� �U�)�is�.��ai� �. Samp!ĥ! subj�to>7i�a LSR II�mCanto �FBiosci�s%F6vd` e �"" ( Jo ( Tree�(r ) softwar1�!��!I2)2nY�]xin%�r_a�,1 hour on icx}M!�)�2FA�!�26+ �Fx-An:~>8Sl �-� kprepar�Por use�� a���8or Western blot-nis�Ho deter�l` viE�tyJ� , unIX�incubŇ�7-AAD%>5 minA�RT�2:�. Liv �$s excludedɓyeŷ$ereas dead }become ppositBr -1 . Eg��*� ��ia��dos����us��W�.�or an�aGeThA�"8-t�M,�8!�ad�nt ��:AJ"e�AT-�GFPhighR GFPiP@. In 96w U-bottom����, tripl>��5�gf�eqnumber0i -�� CD8+Mvs! DR3/MiHa."4"vernight��ul��aHernatC % coll�{Y�,IFN-γ secre%V8by ELISA ( Affy��ix>)n%4Standard deviaTwEmmd �( biological2@�p8MHC/peptide-TCR��era%�gKb.cE�e�Igr\O�osMYAA�2�pul�T�2hi�either��, measu�pixel:� corr�A2��!d�. PJ;)<outer 8 j��R"�o �yt��Mfn unpai�^�P�� nuclA;!� lys�%�"� R NP40!is&� L50 mM Tris HCl ( pH am5� �0mM NaCl , 0 .� 4Igepal-CA630 )A� proteaA hibitorA- Roch� P cock��c�Uscribed�,viously [15]�treat�=w glycosidam ,�� dena d6 95� !�I "� q aSREndo HA�PNG�,F ( both NEB�` t 37L1hA�inm�s@ � (by SDS-PAGEN . �o� (PVDF membra��Z %�block"� 5% milk� �&� primary� Eq�proben��1 a� in 12dT"��$1% Tween 2!� � 55 seco��y�V6�2 stRT�� y-re�ve band-GaWc!.� CL%AsignalZcap)� ilm6�c i �J�825 μM chloroqu��(!+videdYDr� de Wild��*�8 !�old2�v�2�los��n�4or FITC-conjuge�~in WGA�4Triticum vulga�sA�S! 6 v�FlR� �*�t 5��lowthm| lyB5!�1&� per param� ( Figs 6&7B , l-/+ ,  7C , �$nt/lytic ) x(randomly pi��.� �d,� “e@AC s” Aa��D\vsa�2 , 6H��v���L�un`ed%6u, �WTD!�Whe� :�"7 ces�y�_)? �)has b�D expl�= mean)� valu�A�"in"� bet� these facV 3 n-�iM<ce mode5 �i 4two-way ANOVAs%�ALiw Q� h� � ?� ctrlI*5X/%&~��"�$SPSS ( ver%!2T � . p-! es < 5Qnside��s&C ly�t .�~���jn recruiGphospho� iHTarp )=con�mong �qath:ic9amydialgLPr� $ reports i�if]A [trachom!� q ��Ra�pro r� domac requ � � medi� ���c;serum �ficB!�F6 n%�ge��$�� polymeriOin Z�>���vivo ,� �qan ess�al role����h5h1~eA�. S�ce2�7 orth_s��NpeI�>�serovar�<(multiple puAuve:6si  orde!"X  wh�8a?Y)H1�)ys �fun�aA�Y�, GST-�fua8 ��J���ex��their �to�%�MA� . Ch5vs h3 a|�gble.�6�)M�moY9 f�M �E�bM#tro>^as�. Our fv 9� that�>1]�xis�m�fe-�ng di��eNMG this5�yM��Q� in bacterA� inva!��Ah � s . �� obli#��*f gram nega� Lum��1�2H,�A_maf�+�!��ed sexuEO�mi�dis�=Uni+�2mSlea$caof: vent%�blind* worldw7[1 T!(�C�l!�� 7)g6� � rbor!�syn� ,!�r5 �"w$is tyros�� rxup65VM�Asol!eA�!=E�e"� im��)R�ob�=-�Q�]aY� vo [9!� s.�'-����*�ly��* v�4-p�� .o�� appe�e� tinct4 knA%eukaryo� 2>A��V�L2 t.s!#lea�&l2�dy ;��N"�5�- repeat ,�un �T�^A,>? J> oligo*� ��a� (Wiskott-Aldysyndr& &- (WASP ) -Homo y-�WH� G-)1 �%�,.�J� �b :> )RU�Yminimum)s� �- O: >� �)� ��+0umably brings&� �mon!_� �p���toQ�Q�filam��� M�R� � )�E�&�  �(��a� �.J Jb(alpha helix%g&s althoughM�s)6�S b� iB C . cavia�� murida� �- pneu^ae [16�<�,>���*ow.A��+ceht-$6] , howev� h1a6Ks:��*�� ,. We demonst� a")X:u~+� �� fanE �'� "� ! I�Don� d�)�q�alM{B�n$at4�r�#binan9 J q���E cap� 7 k�e�J���� .:�au�&��affin!�Ͱ [6�aw} ed)�u� -��nd!en del� ��to�>6�&��\re��d#-c�"�(ty�= z q2� E�b� > A " Q� z� sugge�Z�)>5l� n im�!�k2�  � >�!�aP>�T34orc �d"�� �&:G�K���Kreg!�( �$o acids 12�424R�J����6T6T65���FE�::68(748–758 ).��ԅy[12 Onl� �~�Q�AbbF ]u spec6 �1&e!�Y�c* R��e-�1a���mi5746�60 ens�I�-�� proi:babbity_tigen-u�pu��.�2�ntiV�( AI1"�ARa5E.�d�Fa�" nfirSxmmuno�s% a��!gofvL2.y�� �$Figure 1A $R *of9�-�6e�fs�!��)���gnizeA X� �did notE)}y �$sz xany��� .��T F�� 2� also�A )^dom�p f��(�f�2U%EB�yo�9B&ui�TH���{nu�B%�C%�A.�2�2�ag�t a y(2�]0,i�fi�/Cf�&�� �n�I ?.�.L2Y9��un5� HeLa������65in RipAq: dot-)�A�A��Af2�9&�46x�\M�wh��Ma�o!a�g��-D !K �precipit� ;e N��!dW  WAVE!�3�]*� WH2-��>�M�)ex%sf clos�wsimilar!? Hof��, [28]=Q#FI}AV , no.�ivX ��"x$. Despite �in*��ct re��E�2�to W2� ,Bc�5dot. H�5i!we can�frul�� poss8 of � �D���p�H2-;./ �v lim�T��in68.\��would�rup �!n"$ ng� ilit��T�, pyren�� :!�X$�%�kin)�� *:�  l���%� Pre-*�%c�&�cE6��let�9&��m6:�u�2ɲTRC2F@6sis)3!�f6trQ+!K�y* �Pp � ng%;.�*�^"f ! �F �Ef resu��Ela�% F� d �. rB�I �EB.��� ��1� aP ��� �Q����&� $13n $u+U 6�A�:� {*�5sA�&� -;Ma��*Method H�A�EBaoa� s��. Hn!~*7e-loa?&!�D�� ɚigQn ( P<�001 )� r�t� to2}A�� 6� �� ;2�\ sera�"��neM�>�� �R�y"�seiZl 1�n6�Ei *��.�"�67:btruI<���d! date"( yu,� tere�g $!�)���&KѴ*T s qu�g�g��!}��esu  �2�H�,�%R#m�i�!ll�1 5�3��SB ���atd#s�E.%W�1%a4^�i�* 3I!AE��+"p,B���:�Q?a�s �+9� �@.f �>� V�*7 �e ups�"m!�� S ( PR� ͒IR�iY)Z J%1�Ak2vs_*�J��)* or)��predi+ABD�aW� )xB .umD!�9NX%:7A>d<&�. �N�).O2divid�,���d �2� B� *� �� u � le 't.�� l.�!�a��j=�N��Y�J ���pulldG"� I:�ňosF$q�A ep��"6��M�&�3!'Y$h�l4 �� *"U�=Ep��fW4f&� - P ull-6�ZLs DQAS#YOgM�5�N�s �9D.�L2[}$ _o�"d�Fu� .t�a���!ji�*6 ����%poten"!Uinflua6� /"d follow�n6�i:�* A �-���.uF�manip� `he" �:J U�"3 R'ml? [2�:�)�yQ�sU�M��al>:����0J�( i . m/ ����!� �1� U~>ȝ�enh )d 1:�.� GSTZal�a�ro$  >��ua), R@ MoPn><incA� ~�toB��mm"�/toa"W4WLikewisNBy&?8&�!0}T��.$5"zXt6sam�g�as6�B���*� ��"L �D^�U� A�N� !5�"]!uc��Hytoskeletal dynamic!6A2o"�s alignm "n#"lto� �&Q,nM�"�Iu202f � fragg2_i*� !�I 6? (6?%�ef�#nec���sB���� F= �m�Pi�J belie�<� @3A,A�Y ^>  ���^Bo<-١6�Ls� �l #=Ie G&� ى� ن6 lS3n��KF� A���Bi ���� :����4�j:\d�remH>-�ir%�2'J*� 4� ER�while�:�R!n�] ,y may employuquO7.h'B�N� |7IM0Hly&s Jq4A6 , must]�eA�cataly"!$-R�&M�Be�)� SpirE�!_ Drosophil�2��Bur:�.�Y$#��q�,&A%"�Eu�,��>�� f �or [24� we�������*� .� �rT w_ %��hl&�E�al� �F`�-�Li�v%-�#t7@��VL;�.^. A ��bea��G�.%v �5h���plu�%�&�>��0e&� as�� fE*�"c� he! > *�Ca %Q�-S��� �v��a�?%l!��"A�siocolum�"n3a8�K&�C���43�1l �6by��!R�QQ[�6- he|9 S#�8,JB�n�A�`9 arge9�cF le�B���� n�UU]%l�>�&��1o�-d!% 2Js �,&=ARvm� !�b(,UA �""� V�2�B{�� .,-&�� s!�V� ut�K a hybrid*j)�.!eA�&honAg�6� t}i� 4"� �ha�ar2haMl�I 2��*�!byY�3I %��du�G�5m (2k^P�LdiMCR t�sk72!E��BABD . M��, =g5s�6��" of.�%��X vi�B m�"\Y=~ es��)��-o�+!"c"� onA& rhH"RE�4$ <)�:�5�% phz/o��]I^)�  Q� @P3�*32mov�Neb!-to.spreadQ�ol�5e!AcJA1�� stim.���� �"� oC do s� roA)r|7m� %� �m�A#,machinery [2�A�.�it.hc"�a�-�0��s%Qlsvc-���5�[26e/�v ]i.�"litd2�eb�z-or�2K�-�>��i��� ur� Ff ��d� � r.� >� �P�,�,urpri�%E��=1�-*�J�v�5"NN� 97a�� �2 i�R u�Ql��4A�1{of>����e2}�$"-�:ynergD/cx>�"np2r� . Noo 1X��6- �%q6�&�9to.��k����!of � ge�LJ�m���-�" C�q�bokT�6�of2%. F =t�-��GN�B�stw ��r�toScA!9� barri�-"�.� . Eu"[1��/U� �l c�JV5 �E�1;pArp2/3  ,a�mi� A�[29��30k. Each!15$ a��$J%, Ai�1�Z��:� �es �Fc�RR� exL4n[3&?8%�e�r� Ex�kf* d��.`@%*%ɵ�#in` 6���d{?�Jb er�==�Rh�1�AG FHDFH2 [32)m31 are� founX��C)�� of.�aS(��r���(dR9��k8����B/r��"�:.de�. M�ra6�/.��-ni| ב: 2<&� oc�"�M�D*�� i&Cappucc�+[3���@&�=*�&A�J�_)�-E�va&� �-is�Me:/�e�ap}!�Y�Rm� 0 s!�vel[�do)��KT7�$A abovD'A%��O��1�0e�of5>  @�b�G 1�"a.��h:� *�%1 �8�e,yf, Cor^ Bleu�Ateb#&�S D� "X/� euro��Y�; ,e��� .h!�sixA�a�.� s [3 $Leiomodin-�(ano� Y�re" �ui hear "kmus\<,�echq�#b9%*�6A+n��'43�a�N trop�uli��^ ucin ��/)�i � {a.�9# [3 4B"V>�*:- � �!�E�",@e Salmonella SipC� 8 , Vibrio VopF � �VopL [27#!�*S ���_25,�N�bP`llE��sh��4mm^ he�:�EJ � of�or#%y7v7 &v7�9�)h�E?���tF Z�two!eF��O�v]'i�sd;!�M$�e oN8 1~H&-p%�B|A�Us"+�yT�D�_w :�5,�[��u5��W�Yh��Cis&�ct4&�U=aA'�U� (%U� � rW:O"B� �3�i2��~ !�A5�T�U�(8A�=D.�"#Y &x E�u\F%�N�Mb�A��Z�<�7SB�%a*llv�8 �)�2�! 6�f�8 �&�!� �9�#>� ��A�qXR"J D�8 �6� J� as�( *NXz"�/&�#B[7lt�&�� l� � � *A"�.� �&���>�:��A�Mc!��B�8�D>�]�`"�D b�8s 7!�a s�-l�@ ��on��* g. ��� �be,QND� .�b�c�..�a�"E&.���7@ �**ge i�,*  �:�F]&�I�!4� `>�-@A�! U(�!�V�i�>�M�dis6R&9tb�� C!�UM�8&��8�� � �A � vo .-�*�\advantag+J��� �HeR%].Bis"KDhde[ �ex�$�var* in� b3 M clin�N iso�Es q>qtrinsic�c#># stru�d��perhap�at.�g S��" e O���nd=@ &�"!~C,se tiss�rop�E9var� d�"%OlU[� !systemi�S�FnjG , [3v92=4e)��)�ef7� n"d/��Eey�.raiD$o*�<overlapp�!�>���!�I^6;EZ�U���L��l�1.�.Ed"� r>��)>,0@C� ABD />:'" XwT"Kn6a36�/3=Ti !vi�I�VJi_R� 6af�.�*� 51�% 6nR� r+(��+�&?= D�1W�W&b`(a�k�)"W��.3t�P M� ge84M�e�oft�> iffi�T)6:3 �l+LeJ55E��/�'i�E ��)@sR�!�}��Q zf?,#l ��;�"� �JA6>�Ucascad��ɹ�7�!p!�v"%�4Rho family GTP�culW:�_A$fJ69!%>�[3�04p1"hN/�2 &> I�o�weZp�VAAv5SzGmu[i�"�5�61��concert!���]i�]�3� , [4�%��(R �  Ew�Bas)�M �k� grow� ��RAO"�X�_�Ds �!{*Ns 5s&�PJ� *�DE�A7�RI��bn�k�N�r6� �;c omew!�� r�s�> , V"- s�J� A**s  :�&� (> JendY!pv�3� ��.x �al,tem�Aa��wa�bF�<m�>���i� ��R� A�hat>@ e���y�);! ��J �� ej u9e) abe�U.-A�]F�&u�m�A�e Rac�I�l�0-�)_*!�Cdc42 [3J�;Po� �Lre� �5!�bio�B<5 � �E�&�>MY&� � ���at� �.���Y�^�LmbeWt&�N5��Ib Z�&t �7s���AX&`&e�Q -������e=�O�<Q"�<1�� .AP� n�G �:� *rTP6�9_"��:"�E!�a$*�I�i=Adaa!�&� -$h"1 J a]!ti #�$!$Z1�sq��#F&�O!Nn?$6�-�B�uI!ɡ�t:S��Ji5F�n\=y!;!���6 �"-!�2� �!�m�r!Di o�P��ofə�JkF�� elucid* w)�1� �;coope���DKuc)#fu�\.�9�u� .F%] ���Ձ�areT">'EMec+ � Q(EDY��p�xd" sl� .Oudwit]��?&qf6� !(disseb �H Take� u.+fm9n�R:�Htf$Q�7 ��R*�B6L)?!�z-� &vK.�)��( LGV 43=H$D ( UW-3-C�l.�(( HAR-13lH��&*�&!��$( CWL029 )�)� a�V��229 �!\"w*,by Renografi�JUk gradju�RrifL_!�[4�u&��G�ayr�9 ( �3Mo:T��:� �( CPn057�O4( Gly440-Val54GI(D>1-Lys75�+21 ( CCA0017,4( Leu460-Asn56,$ys540-Ser6R -Pro70Thr366-Gln666%�P(�9�( TC074f�u50}p60}Thr627�e�As -Gly8n84u9� Ser4Pla827 �G dG(�tra"F bie[ AQr( CT45�(z 580-�8�� f�s%�9�Thr94�102�89!\92c �eVa =;�Du.�!�0�7�Gl !�9"Gl A2"50382I(PLy (�R?vae�q�.�%�66HPro826H��256( Thr4> P�|-��gPCR�fr|5gl]hione-S�mfer+i()U.a�t&iBSa�f�a�c�k spone�ci�^K/"��eMg�( Qia�@ge �Sc��kix$Valencia C�.u� cus�r.oV��o{qm�4yteg)�tTechn�S� )(alville , Icengine�`�u4 BamHI , EcoRI� XhoIk`.%d�o��9 �ed�gdi�N"�@ri'^ enzy!h$( New Engl�_BiolabZBR�M� subc�8��8 #l pGEX-6P-1��1�a�nsl%Xf;0���<u�I�hds6�:{��:*� BL21�aix&Et8oli�ov%�, Mad�WI8�k�0�3�)UMm&hB {4procedures out!!)E� Bulk�P�F QMod�G0( GE Health S� � , Piscatal , NY�:�s�pED�k00mM KCtm1 HEPE6c�m�l2mM MgCl�<ATP�l_z1�diHee�so7�M � $g cut� urst� 20�o�$ terv�on se2I#4T�1\ S bor!�? or XLvippQ�aD[tip: M!� ix Incorp�i+Fa5gdae_-:In�?m�E �EA6 �:2( 15"�frcfm{ n . , �z7:G��sephar�?bea�l�H� 10µ�jaiA7��or or�ya&om�mR+�ST-6P co�K�wasV'twQze�VA� U"��m"�|pproxi!Gly�g �E�?A�(p_'�9t �2&�m%^,��4�\s �fresh��_�-eelu!w��s�=e5r-t+&�oon�o10%�ac m- g�rl�n"-`�G45µm�,e nHk u�L-: immo� !*�o��chleicw& Schu�1, Keen�"NH%�I"qQ��%�pe!�d�R*?jseaz�`��{ ( ChonZBne�a�.Tem>�7���Superp�{ Pic�(emilu�Hsa5��t�Pierc�Rockfor'IL����6C4�cl�%�+a�pur�m\ qF�. Poly @ASG�'XwardsBN L2"1 �W("N ��&�t�y M�t�U2�mb�L�]R�Sj�e`�RiE��Rd2vP_k#< GPAMKDILSAVRKHL%�!XVMTpr(igma Genosy;Sp� , TX%�Fifty µa;mo�cP-O( L-3� S� CruzCt�.,I[�%M�( F07GL!|add%�ct ~premi+�m�!G��~f�+kn�vinJo H��FcV Bio-�yABB|J) &f����.���b��{f��� . 1×107 �B?l*�2�zX�U>& L2I6��i �RIP"�R(:�u {00% IGEPAL CA-�u"�u�deoxych6 1%�0�d!�v,p 8 . � �l,5-�s�}c�M*��h00�1�ou���Sol�w�R6@����I ��-�aN-���3́. B�� <�݃.KRgQ�F�>� Q�2F�*�S %s)�res�fdͩ "-v:�:��k.���W�HE�a� v�!�e�R�܁A#T�X,BJ2�:U�,6��*�IJ�F*d!��+ -�]1W)VE��)�)�)�)EI� volu0+�>�pla�)uxbF!S&=IF�eG�rTEP} R[,�d'|=%�e�'� F�'A�,& sa�rito� B� me�Q>� UEk*�'Bi�z m Ki�a�4�Eo.DenNa , CO�=BriefN�&P93U laber �%HU�?3lu%a10�9= ly�Az E =�2 m�s5���{��,� 2Ca��d G- ))��yng�1�-� room temZf�'S ,$&v1h��+ L+(��2�c9 �!obu R�?�!�s� �� yaN �`0�z�C\ sp�Aa� k.�y TLX �ՊeA A 55 ro�(:Cou% IncFullerA�. A21 25�-�lB1Rly �eK5 e N8�}�5E)�wr.2b� 1/20thA:VM(Y"]2]DI@nA<�� KY�3a.x �)E�(an LS 50B L"V ce S�Er�lt*�er&� ,by FL WinLab&��;q4 y0( Perkin ElmeA Bea� fiel� BUCK�UK}O42 . 5 nmY|widthA�36excvH`waveleng ndZ7407K emis�5�-Ject�� T}jl'`Re�tE�u#F�&u� 5s�(i�B@��c �ԅ"�#� F� � ���5� ��"n|:���(1M�i��a�8 or R�wttsiaPk i&v�"� %��c�A]a&��&� C% blu2�Zd��t"\ �@bR],{s�xd~) by�2�E. A���!��c�%�R(R!��W"�'� a��D�_-��A�R v. ~8:H1"�!of.�a��'Mndu�*�T�Ude�[_i5+_$9KCMPTX-��>��`[n%Yy}Track��) CMTPX�,>GL2J ( MOI ∼�d;L��r�'ttach � �YtE@ll% 3l ��3~_(�[(,1� cold HBSS%�!�. shifp to�|�#�!�pre-wa�b RPMI�D�FBSRt�g�L� 3�|N�8�eG4%Zpa0aldehyde�J���Q9AW.�Ac f%0%�2!m&��. m)!�+Q a J�a �1��/*�major� er"� "� A Mkm . Af"f}� a��,F$���^,to Alexa 488;!�Q! �. C��sli�-'!2m.$ ProLong GA&� fade��.�oa� , Carlsba���2�"2"-1Nikon 0�phot-FXALR�e:<p���as�d epiy�ANptiKPȇ%�"� i� a Ph�r,8CoolSnap HQ camE\�sa! 6AdU�:shop CS�oP.10�|nEaU as t7! o� A?(�−��2\( �Qn ) /F2b� TARP: $�F!�<×E-0 %�3adexQ 10/300 GL�)qJcd  A ham 6U���� i(CADt!�Chr�{� phy S�/�S��ve;�/s&� T�gw,�Z��*. E+6ken* 4by A280 absorb�%%�eak��.�Gz� %@&�g�48Kc. A0$io�&��C&�# V+�'a$�,s:B�"L�ǁ��" - AAT4718[C:7�Z�Pin UW3/Cx - NP 219969�;b;�X ;H# - YP32827� :mu�o , Nigg e97115e># ( GPIC�829043'*T# +�".22476�, .xDSchistH�iaJHja9�ca�%a zoono�e&�0 mammalian��/c� as�ervoiri Ci�� w�J alb@�@ca�<butm]�s75%�$� B �.4People's Repub�HXVhin01D{Su�M�eE��`%$ofe-a�u�6�/ `0imnłalc�Hb2�� BD #enviro{U�CVM*&A newayc9� in–ethy�\et_sed ��-�a4 ( FEA–S�R}sR,J!��W visu�`?% .�eg } bov$wfjU�,��� �(�/nU(� ver!!3 ��(s�Vqfec�+am�����N "�!� 3>Ld4caraba��2# )U: hili�4{��ť� Zs.�!=qzotassV}hydvec!!��":)ee�"|���*Bulk deb΅@.# !5> denO~; o�6o~�t�:�o3 obsc� su�e)�e�]�elt)�B%%�{Htm/b1�on:G�h1��a�|abg# uyechI��s BEly 70%A�-%��6!Trƒr�-5 m�[ 8e�lu!xjth+owsa��0d9tic:��Fr;ie3� �M�a}�M.E��,d&aEI�)F )���B��@�.3Au E)�YFEA-SD}c;b�ل�.��rXa S�4surveill�tooani]�T6 ,' t�la!�e�GIFijTf��.�Q3�N3���Aځ�� effo�re�Q%�beli�"�KU�:�. ��.�Uz�"n)of AsŹ:P�CAa'9�.jc ^.JA0sm�-po�%L Indo�Jap9–~Un�6 Afri��F�A�np7�v#!�man!#ihaematob��,BEZ��it!jM�a1�  40���com�A 28 g܅J7���wil�.dq��{E^�<�ac"U]l��/ur� �偑[8qJ�� rangE�&}��w�esB>js,aw[!T W?h{%uMa��#�add�SY!N(burde�Ico�!w6asb�deg���=!�c stocki��� �Lfoo)\�Sorkm�&4h�6B��pa}�2e� BubaXbi�,,q7�H�y�.�]]5�-r�>�-�a�"!lak� �~nd marsh[(E,sou�5'jf[11e6i3k�ze|ir�6in�j#* �ye�7be j0� ���q���,��|�.�,�T!]l�1inE-s�4!%ula�b��hT0t"\5��% >�6�Y2EIn�;ar))��"bZl*bfib=�"j�% f of ѹ!�t;"l!1? !�im{��ir:saIu� cur�6M� -parÄl��`Ea�� ��? H�:i3�  aM nO-�` &` � ѲVuc"Ois2u!1m*!facPqa@im�:����!�� m{um)| 5�jyho�).oeFj�� J��6� � �� (��%Jba�PRre-5s xMN e-po]�ve ^ u��3 ,�4b�� yu!� y )�ҩ6-l.%.N�,� I�%Ps�i�+�al-Y"�-( qY g te�MHT ) [2�?� F]&� !����o�(Bm.A6��-, .Megg%�v�YC3 .�8C� �Clla%ai� AvU���4 � s: F5�t^�s2�s Y ed�=�WQ(i"�,jgN)!X�P�&na��Ht�0�+so#�nach2�a��Mge�|d)�y� c��Q[c� e'"� �mix�FI~A�< � slurJ�a'ker b�m�)) ate.�z en s gE7pou*{ U'$ a 60�w��m�-$( Tyler sc�/E�a p'?ope��ize�25!m�ة� �":lusst_ Q�x2By61 �-�2held by�40��. SKcaughR&R"X�//� �Ga���= flas)��JR o"�}��IP�()ie� Y?�]�lea���fi�Wu ���l tub�l6e" of_"�! cj1l��>v��,~,��-2�AvQ"D �r�k � �}����(c����d�n��!ZO��P:Ke VA�op�-�� &%�10%!���v/vMum*:� ghlya�vortex�, bYBs��at R,=)A�ix ���)�Fal�.��a_ i�z�i pell"V��m�:9,)7w�CN ( KO�4.~�f ީ�se i��%>}%a��'3 ���z g �E"ܭ"y�" $�H>��:h:�90�]#0#�� �&5�0E�1x1%O���E:\�} dual%6�`�Q��-�:|at � �* +q�1+fi�5�*� 4 �=�(? 9e)�n�Ji���s! a"�+�9�/Gfy�c#�J b�* �B�y7����is6<%oa2�� "�g�Aub݋_��'E� � , H�+�0 E4�< +l8:2�>�g��K�V^  s������D<dper&�i%edmX�� &8v�!e *�f2i,�J��p s*�O�J}�B��3�&v( & ��of�, EPG )!�v�)�"� �#a�E&�wI(ebP�# AR' B�,V�}otH�SPaD>gVR4 d�]Hs.�Hic&h*�i|~$alo5� I��@}13"��i.+}EQ�%7�X�i4d�m��%!�F�( TjhE.�Al5.�icM��ofi;-@n�b#Ga���3�.� *��)0�&fA& �?8.�"' �"� %q�V Ro��&�*apa��F.Ԫnty-fP%�*� a�N2�-�ba�r�( Ba��)�Sam�m�H�I�6��x�2 �!7�E� `�+arlqfinEPa�I3M&w5�1!sA$.)ma�%cM�T2o�-�� �� q 2D)�dc>��S:�&�!8;AD���-G ,�"6 l-sx2� ��b>_6���&*H c� ��2�%�(( ‘gold’v�&U' diag�,of�,^$s:�%ic'�7�&5>,PJ��i " } �'� cho.�!�2� !�� zA &!,"S�,��%� Aww.D--yh� T"� �#AYa��$ a�%�.�* �on?4Danish BilharzO'"�Dy ( DB�EY�u��j�N.:�m&%E5! e FLOTAC��^mag�]�A ( He�\ tex �)�h�E6�$��ct�minth5��(&h"�(sxn$#9M&@Ga"�kals�$ew�oQ�3h�$���Fvit� F6�.�,�h�qh�.�"�.�%i�aA�A�>ɷloos�at@�>oxP�"H-1aan��2�#F�6�eGv[�?% &,]i�N�*i^s� &�;�a�ol �Yw J([?ra�A�`%�=e�cs� ��j&��AN��; e�k"��– a ��'� �m�bE�"u�ZC^�{��ova} sa�M ���E�@�xa nyl%%� bage*�i�tPd��. M��Q�/$G%cop��9i�ir� ��x�?�o����s1� J ���re ro~@!� carraouh-1��.S !�� zyd �5,)���-wi�a�u�RF���)�n[�s�d2]%O|oecN��'�Mh�rge�! �����m �>4fac4/I* uY"R Fz:4 de�-Z�� ����!�I!�/p.�1�U|9�Oma��- ����/A"hi� Ei�bdrawback! ya �at; a�fai. rigi!!��m_a�sui8)e�G,2�:w�ikJ�70alw�>0et� �?�L"ٛF�Zmi~]H0oa<�0!Zw�� �XET�3in�e���k( ,O&.�de�a��m?Q!� "Ʊd&)."�-��<a*�iJ�0al"%�9HTF�&!�a. 6%"V�/by*W"I�a�pjt8��3 �59�B�!�� –10U.���Kt D��� �� �t��E��M+E�eYA`%�cb ed [AwmS�]&N�A����� NC�le�/ ]nN��]�ro�5^a_�),c 2dse$t��8rj!�` -�az>�6�%makwtb ,( > 7�0l ΚULM!inc�m"F7F&�!�2�6��;�%�"�mI2�2:h2�x2�-� M�-.�5 %�ewR�/�#0 {�É��=����Ab� * ���.�-%7i���B@t��. Tel�c?�6aj1ry piloPQrve#B6�.���6�6#��� �(� m�m1%/�1�M!8y�^"��Ley�"�.V{. ��'� 6�=by�l( :7%�T6����(�N)�*a {4Y( 5�5T� 8u �&Nla�%z[�f�%a~�A2c~yb�!����E=�@r�acu�(2��` , ex�SC�6�"� i�v[0* by ��FZ�/q �#�~,�D��,&� !X&v, ��8��U G�G�2�3let���G��imeA� *��:�΋"|%�ki���@���K)@ciJ��,!��3\)6B.�7�aa�ta:O&���n#!_�c&�� �Z8H,�#!�PTx;kcl� �P!&�3Aw�mK5�0� mass�, !�����f�1Y nd ah���w!)�#Z��*q*~%6h"0e �"* �� t�.��} h�q vail)W���e>! U�aors A*��'!fm6D��7�r�i��!-� sI�"��. B> /{rTIA~�M� ����ar F/A�� ( $US�6M�� �ni�#%~�[ough �$:/acj � al����ݩ�cІ �W�,9���ƍM�eeinM �$!tc  B�:in-�N coh�9)ar%FE$�9Ddem&��\}il:�Ow �q!��St�+j�S�.qi sum��E1�-i� iB3�-m�b���oQ>zeFK xonI\�G��NT��`&�!d��2��6�6����s!�<,�!+fi"�D�#KKY�r  8M�2��@y!ce�. ep6�5��C�!>g�<wsas goa��" lJK�'N=z6O"8'���eI6nq69�M.Aal��.�0��@�r� �h�h.� Fasc>a sp .!�&T-I!e�4�I 1��f�benefiem��a/��6�t �� .�"Ly96�e!H� U�rol���#��in!�t:%�,� ,E� ��=��Md�NM�g7�&�ac�:!�����] ( CRTA�I!� prolyl 3-�Ayl] P3H1 R&LEPRE�L!hf2� ed0!L�8��� Oste�1��I�R� a ( O7bp! �!D"�^e����Sn B%nco �PPI�$,!�m;a�!�t.�8D����2(��α��chz(qJ98�f!&h��is/�V isb�!)(� ���&+$nEGA0�erf!F?]E .`�� E| ��6�!�!WPr�Q&5 !��Pu��,9 col};"���a:��\'pos��� ?!��"� �k�b�vQ--��r�on��e)A^!X��a �K?-2u.I�.I� �ze#���� If�6!G!, 7. H4 , ��morphicv4q�fun.5mus�jsavI�0[c�M��]asu�U��qA�&�G��D'"plex's2�)�SusQ�p5Ocha�`nd E�� �|phenot+m6�IA`�Ϡpgu�"�� �,�!� dM|ck-in� !$rf{u�a"�� �8̍�ci�osit_P3ha�$Lepre1H662be��ubB abol�3A�vc� re+ �Emg2o2=�uCrtap !J"~JS� . Kn.��]�Z�atq�� ��} ��m�!�iz�no�te�ntJ; �e>��Myy��B(!{:KOu�Tth J "�4�f $p� logy%s- �d� b&c�}n�=s ���ew�O�=oG�recapit,Jw#l Dahb?2�OIt�!�nd�Q�U�>byaiWZ�q�. OS�����O�p������sA�6�:a�inE�HA�u.�A�m� �k�b��6�~� "5�"���mv� IKU1a��COL1A1E� ND<[����mNR� yat�2siPz( #166�, 1rZ2 2594 461068� 91�N 67F610968 384 9 9< 4856 50�o�dis�.� inher��� n auN=r"�manner�F715e2]�� �A&� ( *60549ij 'Bh bHerello�). a�)� ��F��OI���L���*B �FRse& )� 1033yra`>� CYP� ( *1238q�U&i A�xtm� ,�,�!�� )��k� ���U�tt?r�nemblyS�5%�"WX��lade A(y&� A�u `�1IXn� �lyy�k . &:�k2k�l����eny� oj�a� "{ ,� �*Zp�RdylGy��BT se b� !�:%��6J�Y#)6�Y;�)E\AD��?. 2� *��<"so-� 6s_O!Tڊ�nޏ"�vyJH \|�Q�:��>_ Q� t qu\$�-�[r��svi��! �bC1t$�X�B��1x(�&� �`f �%c" ed��y25#fMhT-�a>$��p$%�/!/CypB5a�g� . T �%1�dgoag�s5z�>4��m50e� e/6!�=ra lgor�!��$�.��"� %|!|k ��ce�va6�!��Gu��p P��N je�!9� tria�$ sidu�&HIS59 HIS66~ !�ASP59��"2-oxo�x"�b vjz RG672"t��aQp�e�� ;�!.mY �.]��5li:��E[18��[1�*C(4 �m">��!id�)EiP!^�G!�e alan� or ��*�!S9��Ar|4& .�in A .!�liana �N٦W �42�Zzarg$�c��E &.�RY, s�I�a]!bp�D6r�� �� a^�qnw}U2�eE�.�U��A��L�-D3'un �B&`e1�7mi�v�&�s�of� y @�we op��aj+2sra>`��utI2%���� z<�/:%5��m�rU �*% �,�!����ba��� W1qx�$verifVA�M���ե���Ԩ ��aBf�7� � ��2r�� @e��a�6�kjac�Wyvrt�[C �� +"; �Ua� ���,O,h! !ex!�9> of 4&�8�Nh2� Q�.��H�RD�C, ��r R�"��?}!.@�!J"�)C�rFc � 1`ss.*jO*H3�!nt.�� ver��� ��(EQ���Ma ef�� �G escu�2 �cR3!\�.3c WQ<un�~��-�B��!�<f�ztu�� "� �2�rTua �be�1hq0 & �!G=�ie%�E�"� S! �%q� orN,%w%YN6���y�B�0N:>1' e�%nz$�m� ��.rՠ:�e�M)-Qik�$�)�=*QUW5�eb�)�U��q� locu!� +/�-�S�9�8portantly , we �@verified that CRTAP is also restored in vivo in the Lepre1H662A/H( mice compa/�with wild-type littermates by confirming its presence8western blot us#�protein isolated from P1 calvaria ( figure 2A ) . Since�Pro986�Hidue of α1 ( I ) ,  0and α2 ( V )s8collagen chains!(normally fuhydroxy �@� lete losslthe P3H1 (x abolishes=ion at,se si!# [2] , [14 5 7 we analyz%�e:Hstatu{se�s v� to assess�,v!�Denzymatic activity��H%�. Tandem mass spectrometry showed5 prolyl 3-93� ( 3-Hyp )!-� �9�%%_a �al 21% <01� 0E# bone]B , 3E l78�!�'9� A0remained mini)�4�,ed , similar!?H0level observee2N o(Q� �ThiEbinatrastV,Crtap−/−iain which �at�$86 was mise1but)8effect replaceda^4%p 678 apa� ntly as a} seque���ZH219H70~�77b�Thus ,� evidA�a�general�FNA� foun� y�-:�result��contenthHP+LPQ%8u(e�y~�Mg(�2��ConsisU� AtM�^,J��~���Z�eloM�U�IRtoQ\M� extr�ld:�IU� s wh� � % ei��R� ased � h��"� al�AE4to Lys version�j2�s%finvol� 6*6jA cau�Mh��i�X is esti,�{q� �o vely� or f!H !Hh��$tal matrix9�$. At birth��^�� �� stinguish� H thj@y g� phys��^ anc| data%AnEd$Radiograph3 mont nd 6 of age6�<y skele�p���6no2t'de��� such� (kyphoscolio�/(� 4Ae�.� Previ�itd 5�2 ~��2� ��t( disorganizi9-�growth p;A� sf e��dy sizei�shorte� >proximY ongi Xsegments ( rhizomelia ).^ . T"� � ��.��n�wA�Lweighed weekly until9�-�E���time poi� |@��)FB���tatA�c �LtQ�9 f�P.� 9�BE�S�ly � ��ae lengA�-� femu� tibiaEDr'/ ���us exclu$ any9�cA�ec�gZ[&�� .*� <2�� (a dysplasia�M I�b ��af�����Lpertrophic chondrocy�,cperaeed hist�yE;spe� � -2h.Pz� w,a# tibA�direc� towards �  X ��in �B0)1: . No-VsI����je�;5�5�>B;�MS2Em Addi��E�%1�noU�c�wid"� J+* �two_� P( N = 8 , p-value  NS )�C�I<je��]A�e�Q! curv} I��.��1 F�sug= Id�&��ߕͥjI�B�&nde�despitk u�6@ e�IIYF. B��� �e�s�sp�բ��( n-Y10 , eac&B  )* micro-AHuI�m��swe� eouZ�� cort����miM  dens��!r"thickn�%�>�&l R6E� In aM�A�hi,he biomechan���?of11by 3-�� be test=+7J*demonstr�2"�� insic:�pro��ie��ul0 loa� tiff% , � gyA� fail$!6$post-yield� �@�ge�ic)M ,� sa&ong o1of !�t����JrL elasEmodul$ qt �� ? �E$as de�IHZ'Afa� ��MoreoFjW�2lAOtrabecu�Y B_ Vv,&equantcG�Ovolume  tissue( BV/T�,=�numbe�Tb��%�^)y( ,Th-A 9�1s�� 2S���i/J��ly�o� �w�)�scrib�or-�2�16� char� Cby��-<a#�͕%[>0Q2)su,for9ou-y�=E fur� yED�y phenŘ�je, /:morphqv�c!5conduon 3-/ ����9��Ap** *�U��f{! �Y@�XWw J�U(7� .�V�osteob�+Y�N . Ob/B�, "c"surfacm5� ( Oc 25i5am"�0lid2F-�$Y�2%)� i-��:l n�f�!&.aN Ilogk"� fibriTa� + 3e�alructu��}k� iops�+�ZH �e ron���� B���= more� gene5in di)rZ�� ol!�-8E� / Egatztrimers 3�be�ici�sembl�4 to h� r orde��1Mas�S� � �A����on� ��:Sf hNR%�&� 3 , 150�Ss measu��per a{( , p<0 . 05.� )/We�]�5�s�0� I�,�b(by pulse-ch�assayyd�l%)i�qE�a amouypr&* n����Fl!~UE;a&�*WIQby�f.C( repeA 3`s.#9&� :�E~f} �delayedJ�%�*�. �2�%re.�B�AZ�Q,^�>q2w6m?�*%.A �� �hež���2�$by steady-�z � 2-phore� ig5�o ]�s syn�2�!?)V.� .���Q#.�%w � trans*� *�z- :))é:!�B$.�5Jis.�"b�!�%Kse&Isup�u�clup�k�cataly h a�*�!mut`5#can6�# @haperw:&G ��A(mb�"ncI�Z�!��lexQ�ER . We�e�� 6� �vel. (J�) �harbo� knock-Wu�o�� �1 do�!An�!Kis%�i)�!<*�"se9of ?ATcaua%L0"f!��5�:|KK�� �to�� &. OurY�bq��haDe!�A:���nul5yEs�7 on4-�Z�#)!�A�6�$.>�our�& i"! \by Pokidysheva et . al .)�!��z1j^a&Js&���E [21]EJ�%!���"&% A3 ({70� }-$"Zu1{.� &!�F�E$( although�4 percentaga�at �Ss lowe!�a!��щbO�could attribut�to n� &~)2Z!�I +!�rU�xr is))m ���=}ex�'��of ,l�' enco P3H��to�draW ��Y�dNz�,�si�� expl~6�in]3A6�EE �V��YnoAta sligh�6��� �l. &�)�accg , ��al^�R�% �:�s"')y@! B % 6�6�.�qE!.'b� , it��� !R�^ an%P3HT resp��%!6�2�� f��k-2i�j���In��I�B��{2�% , i . e .�(6� xZXa�<2s!! 4Fi[t'EFg>f�2+`�d , be1 lyQ�)My/�#ife� ng6 �/s$, pre-2c.:>='W}{�u)>��,inzc�%_Rh-L�,inr�6�E�is�b��!#9%NidJ�f]n���T�%*�'��Gul64��3H��ora!(#�a�u�i�w!\Y�. A� nat�:f��,'Y alan3'substit�at�Y- 662 �a-&� at!*eJc� *i ��)w6ink�+Ealik[ given pubQ-d  chem�/%� ��i� �A!� lack6b+ [20]�@ECF�ѓ*)?,$� 6�� &�#&grA.1֒!7͑~H�is� ͂be� (mpensatory smAr~ tP �;er��$inferior i"�& . DuEkI!%ˁer�-W*�wi �Fxa mildKs�M1Dto manifest earlie�BFtk a�o.{,%�t!"V�(�%* "Xin�J�ɛ.� Tlso2��|a�*yb w6#wea6VnQi� E�&��, A�E%B� y F:3:Q!��UhJ�2iWd)�6�"can��+c1[&&��a�dynamic�#ceA:�B� c�{i�$`#�Z�s�A��3L/20A�*�_�)�(d�5lez-h�1T.\ve .�&3�Sare �"mS! hibi� by6v, Ppib� �&l"/ !?Z�I�pronounx *!dea["&�#ed J!i�P&4�l!5a ��al���)x�9_- aAktips�"{2 �d6Qto�str��b,nd�40misfolded un-�ne� subun�4�(p&p� �@1of&9 ne�"stabilI-�cl�, . St9% rigi!sID�e abs()a�p5.x��,r4b+(��y!X"��atn$Xaa�i= s [2;#23a�Ret� d�-�o��52�rk!>g5�.h doe�5 oduc�; /b-x�*d2tN4 9N[3�4[2525��U'-Ki�"3Av=W>�Ek�]�#/rM ��/x� �/*a�6-]interH)��$�(-cell�aE��jm���d64opNa�maVna��of��nuvee+itK plau�!�.%zs��N�5Ɋ�$y%f�b�.u �� ECMe�ob. F4m(j��5>!eba�,ntext-depend�+��A�!1r6�v( 6� �� . Candida�%iPd�8g��9 eXppa�4+}i@-s(a�to� B�& *o%��J81β1/α2 1pg� [26A�M���M � in"�A�a�J=7�=� 95�B�[27s_)�al� 5k-�&Ffy�-�-),�g .�b  leuc� r�6e&oglycan� SLRP�s�*decori�0Sdisrup��� IH�i;����) �% ه� m�2~h'.� !Y���Ŭ80�V+BA�tT#work inv�,ga��b��8 A�k AEY� willa necessaryAoundersC7TI&�(Spat sSrya4�!S��LEPRE1!^�;. C&.%�)t�"�g!%� a��#��!c�is uniquq .ᱍ���x�!�+[28A�AA�e domin�AЅ/^�� a#_ U�pl�an �Xrol� mannf�%d�R� . It&T argu�~$*of)~e�.�8;eaA�at � p!to���M���"(of nanocrys�-#-� �a!�teq�E0i��$ non-1�e�i��mi��&��<s ��0EvoluABari3,��. ;�g�ACZ\through �k=bo<'[29E#� |���A�a -s!Are?�inher O�8!u!� ��=&�Xh���ta�poo1-6� . One clu�Zpo;2AE�N: ZMB�0)>63'&K7r � �3^�9m�G*u ;P�re D-pv� 2sp <1&B y"*(�*�1some aA�e�Q`�"2[37PY5"] g�e9 r�sLsy"�affin�j��  _A�)�K9��+up;out>-q/� "� 2� spro�4s&K1e�0-rangM.�b> ZE����to%�r�Q�Fw�;�>'M$U��Hyp� ���alpha IA�jfQ5� b�>�l�Vri� , [3(In fact h�Vd%f��@*LcoincB7�=A� e� �eAjA�rs jus +f F/vertebK_�b[34akeo>ge� !�tDNs%"n�/6�-n"��p�� 60R�,xau!GI'� 2k 0��No�5�mole*e�� lyme�+archite�% mallows oZ3{0��.A��!0iq�����.%�AV"a��"P _ %�Ahu�)J .M--]��>�%R"t ���e!�./: �-�A�hNq%� S�n�3.�O*"�A?�G�;rea�z�,��t8s� 5�7l�>[3��?.�.��E�Adisturbqf!��2-2e 8 @97: 1 �!M.:b{��, � ifyFr -��n�-&L$��2�$)�EEco� ���-%�noa ssF�MNO6�!&' J�:��� secr�',�rA&x8�3:|~A���G��,ormE�bi��Y �2,�"�&mz �2� C��a�& 9 G��@0�(�I<-Fr �� �A:� �V5�e-q�; &; �*�<co:X����e'n %#ca�R Allafea�olv!��)s� &�-�rE-�relev ��&�� !7al guide� �V�,i� dsupervi� q��$cgJard� of Baylor 5gF Medi�Center!�0< ,��r-,mIaccredv byE�Associ�IA�("�A 1 !� aborrA+C� I�5��$�B"ap�  z~�� nj �)�In"�al2�!�Use! m�J���*+ y T6 ( ET )e�n �ach!�� y��ar�Ka:of�|"7xA(arget"�a*���  enginee:6� s�Mc aminoid`a: [34]–[3�To� p��� &w$"5ET build�� phyl1 � tree��a m�4ple"�C alignUt�>scA��j/' L � EC�rr6>K<major&R `diverg��m� ( Fui��in[ ,@“con�Io”�w� c�)J.kA� rank c}� a sc � i fiagA9�fr�I0*� 8�po� iA@(5��aE���group gsub5�-? fb“w!�n)�bt!�roo�'�e�1of5�5\bt pr=c`6Lopj !ET1�sbN ":Is��a� �s�0IE� perta�a)u�[D�uk�$P=Ň�E� p���*�bFib�. cul�w!�Z �* DMEM�{plE7d-� (4 mM L-glut!��44500 mg/L gluc+H( HyCl� �N10% FBS000�0/mL penicillia�100 µg�ptomycIVi�1vecto>0�2 ckag���<ma��&-��to 293T �Jp�l�vir�1�df e*(?w-��57su0pN@l�I6[3�f�_1�-nd!�Q*l�Lb( 60 mm2 dis�A �5was�?$in 1× PBSv ub�G�,.. scra�/ ml4!e�fer4A< 1 . 5&Ep�orf tub��Cel��Aspuw�O 14000 RPM��5�ufa�$oom temper*��Es �� sgQN5!�laU5%B-ME �Lamella�KaGbu�):8 iora�H2�*�7�as�q acrylamid�-�+1v��W!�g:1��;w� , ruͥA .;Ki8-�%wB�,a Zeiss fluoI�ce�r�Fp�DRecomb"� a�utiw�Gg?A�A�%&e2o"�P}method�&c�<�)�/o Liu [4�Briefl�> retrieval.�� A�4 �M�de nd c��`r�8t�WX4 ����eZ�kR l' oduc�R�)e-E locu��� ha�=DNA�%[�rop� �AB2�, �� yoniEem �;��scree����r-�V  ev{by�Sou�naLt E �. Germ5�Qans UG� n#e�� 57BL:Uob�( ed .-SH�V/AbeowRBKE� sacrD !�tB2C. SNC ,0B%�;=disYAe�A�l,�ffin!Ied�oɒ)io�2> "�I�jt PV5eca�y%�m�"W�� m� 129Sv/ev-!A//6JE:�$ backV na�d�L} � je�Vii um!3��{e:m5��f:�$h�X��s�s: Hemat�Y�nd Eo�Q. Immuno2?�<���4d� a�$K6� 4/y��par�1� � xyleE�� , r�3��!��h �20���my��z�a. 2� theyIN�e�a+> s�uY%�,D.�,ѺU N�in S � ∶�� mh COLX�Ł�y600!O��anI�xfvxfi�m&3�ɀA� e en-� d"� �<ed�!, imag� capd�5ѣAxioplan�.�*�Me��zHby Kubtec XPERT80 (-ra�^MilforA:CT\ Rout�$,log�[@�;� M�-em�D�:A|��M�U�eraM� y�. H�JmR�B��c\�+�m�$a 25 mg/kg�]ce�]nje��)F�resor$,ah�� m�<arrXou�ScJ�9�| 2�M-�&�?6)�s�]nd )S ) [42]�%Xl �a�Bio�E Ok-M�cs sofxe sys��$BIOQUANT IA8 A1�Cor�;a> , Nashvil�ST�E�5��I s."�Gd �a 16 mm�fEdi �Sethano&dS�<t2A�6:� �4a ScanCo uct40 5VcK10b1.�be�"�'%BA��b&7M s!P u5A *�'reg!,XL4"�I manuM ed (�tou�)O ry 5d c�!ZthY�-��Ksl e�E�� �7l� -��es7��a t�Rof� K � ��thresh�,at 210)�a gau�Set1 of��Co-a!�a�E9Don  m- femo �haf�9ks�X��. F�O͸��Ny%�J%q�'duai�H harv) wraJ)in�ze soa� �!~�>/−20°CDQrv@)R��tc'ng:�0>�KaZBa�;(�r!'848C� aIG 7a=b��a4"�a+T#r" F9tur �s_XUL1�?� @�.bD"AW�N&I5di*�K9�Al25A�34�_ m/seG/cala�auJ� ula:Y2F��!Il�dq)��in N , L* span0gt�!Q, hecimeZ9�?mm��I'�)s-� ReL@m4� �seta@%�1A�gS"�Mji�*B�ZhEyIi�.~%KzA\� di5�#-CT��=:em�5)- gram�BoneJ� plugu!�\ne Dh�in�J-�D!r!��A grayscal���Eixel br�<�Maa��=��0>f��oR�ccuEm mA@as�. Strf$[�VD1�ac�8or6�%�.6G �jo�K�E*Y�NPrU%���=eah!kpreI�n=?"�$maximumi mLoad-D.�$Ra�%%�!!#u�2&�V� V~fMds�Qs�V��gF s71�\t%. Nex � 0087offa!)i�_&�Y��q-�Oterm�2� K4!�^p O .�-zP0Q&��ga�2%sq�))�cmonly -se�oli�1� ge"yPZ�  %�Fk!� ��QE6�Post-  J�.]Vg 3I�6X}F�Q  E�dro�U(to zero . EMic 2��42;��)E���"�fi L �..��``�F/a��,Bb�Z-Dsum!�R�A�]2N. U��d5 apezoidal�_'a�0�H? ,fEnergF� area�/�:BM@^'%"A:��s��S-��v _toUoQ1:a ):[ . M��C�|kh�E%�;stI��U�ra�(by BLUEHILL'�vU�y$�To9� S"�Q�8ast Squ]fit1��ap�m�steep��[-0¼eA�s��of�9s��6. U�U� ( ;�6/ss-8r!��Tough7��� �- �.q\]�rb�Vu^��,:���9�M"�VL��^�V���!���Fy�"t� � )�% � r�/ 2 1 �|5%�k�aci�$1 M CacodyW+$, pH 7 . 4� 6&on ".7: Gcacoc G�6n� �.nE$ �t P�%>edu OsO4�inhP0n � �aw ��JserA4 30–100%A#�.���Dop ox_Ai"�8in Spurrs epoxy�+ rath�S-�� �(Uranyl Acet�"by Reyno�%lead ciL�GfiA� Ha FEI Tecnai G2 TEM�.?�n scop� 2}��`{0��E.K&S3�!7fi8"� ��e&�.�acj fift�L:L7a�j� �a "�Rm 150 �  �. P.l ~*s�#P �l�i� by HPLCA �/lBde!gl*� 6N HCl�&X [44]!tom!7.jms"�jErm�Ifde�� � at 4Aim,Mmy$. e I α�SiQT6_X2?ea)XnH �( 9�)YSDS-PAGEA�'&� [&�%�V?6�ekin 3% ac.�$��iv�EprecipiA�J�u(8 m NaCl [4 >pI* 8!�:qCNBbx_7rib+�pin �����[4�;`�=+�Q-"�?%���f�Ja��onGp315%99gels [4�;DF&a9�d�e�b!�(]c�-a((]�[4�)�ase-g�d&:@�&� by rTmsed-phTE�P( C8 , Brownlee Aquap�!RP-30�_�06 mm×25 cm )�a �ar�4;-a�!�(onitrile∶A?p�( 3I v/vIbaquAX�M 1% ( tri�oK9�@&IndivzIfQ(oQ�kM LC-M&1=��,B1" band�ocubeU�%�!�6��m in-gel [5 Pecl%t.��Vsp�LC/MS��@n LCQ Deca XP ion�Tpa[ cue�Te9oFinn�>�qui!w}#in���> quid chro�Yyo!� capi>:yA[um#00 um×�4hmm; Grace Vydac 208MS5 . 31�Xe %�~3 ul���n(he LC mobil^/A\!`kb�=A (1�.�in�liQ wa�)%w 4Bb4IOA&VqIi . An6�ion�h sour�iES�Ktro�(b LC��|)�[ ]2�%�a )�vol�QQ7 kV� �e.0"�(F��J���"g1:���NCBI �^.Cb!}. L;.!�l��!<eM��3}Qby ��c�Q*�"g�yU6ypozQe ms/ms!U�match %!>`Al ,. H�6};af�Txy�k;noq��.� scro*+ga� aver�*��y�n� s��~�'s�;E~sta*PX� �4/�L)Fleq6&�#J|. M� �eu�� )�is� %)�  fO�*of�Wf!��!.a�As��o�� A=�H� ~"a��E�.��dOs d�*oA�a�) f 6R'*6 .��*-I�a�"-��'�!��l�JBpi�=-a!� lpelC�81 ob��,/6`0X.�ZA� �j��),M aN0-*!3in��u�QH�. f+� m!;�%�*U1×�!t�& move�.� 1B�"yzCs�(f/0M n�#uB�!"14|,C�0L-[2 �{, � 5-3H]!�k�B&�- labe-�'1~$���d �f1U�6'VunB��.7� &^ U1��-y_<�Xin�K�/t 20-�zA�erval�*h.�!�2 %MU�� Si�,!<ab te"�. 2^.�]� on a� :.�ur"��P!�l,A6, d�!, #� "�+f�+t�kl%�"g+at�8c ���t&Q#.�+Pr &l��}�� �_%.� ���a�he*�B=�5K*�7-aF��Ca�5i�om�FD!�"�`�6���0irmi�/�tW��c�2N>�s��t$-t# 8a�b�����qas��R��-�l!�� ��edR�AV!�����A������Fm�Zn�@aGQ)!��C�C: -s.<�� �(��ug/ml�%.�-��~��5u����rK]e%��D@v�H\eda�mean H s ±�'dev�  ( SD]S�'�ma:�6A��2 A��Pent's t l#" P m �f < nsid�"�� dl�ugO7t .LU B �i�n�:c Y9�Y) ecZ�gf�5ge@:e_7m�P-�horizQ�.4�ax tOl��d� ks Dros�s(la melanogar8. D`qca)# ‘hybridLt�sis’��V dr,G b�Wp ls�@�N`6R���sp�$ glob��!c�2 �Hw��|in D .>�Un�vr�Q`�!{r�, ���Csimuls;�, 'ed�� . H�,� � a B-�F��AYB p�A@3y*�~2�se��&*�`t y*G;A.�s;1816�j-l around 20M ! h>�w(�&�L crid9icL �g)��EdyQ-`!T5�� a?� !.�Yoha�o f1:8oM��5ge�2Y%�we�&vey 631~^�"� � i�Q��� 27)q�D�' cE�.�WeI}C6z*�H�rapid �nIE�taPll�Bo�s �G/ Y5"W pe!�r�Iin 2006�coJ"�o201�I�S%F as eJWO@ir� i�N)p�FK9�,�lMυ�9l�{ x�{K� have adapA5�cup!}A�e�@�Z�Q�P� . Disc!�.1950’��,Barbara McCl� ck [�E�poshD�cTE+!AK‘�?�s  site�� ��0/�%�hs�$aA�autonom�i!!��Fs�#tlL L�9d\5 u�@marka�csucC fu:m��rie��J%f�lk leukaryoYe�e� , kh�+atd!� do/bA�s�\ng cop�O _mselv�>to new Vic lo�s f�b!Ry%,elix9�Es �Salsea�yPene�n�DT;!�:YTE �r� sIJ��!�0Ia# 9!lAi�MU�!�3em3in [6] )��ndNTE famil�now�#m&��%{�QE�5YH,�But m�B6�A5 prob%�deJ`riA%,a��!daT/gea�nd HV�B�+.6"n?!cos�%n ir hy[9��36�L!Ugw?�M@�!�� poso2Uharcs�K�ixt�z�T�nusdof.z/!s��*mi2!r�Jav�N�5 �6�!=v!�6g%�D�$! so%8@'a�8AtA-K�-"s�]\1exa��A��M��\2���"cwI�E�F� �[13!����i�:,%� �N< 5alZ�[16{4a�best-st�[d.~ aJ��>�����!�ʏ"s �F9%_EE� acqs���2X i"� Ff�57q"�  HjG,BV~3ni [18�!). �@SS��A�e82� &[u3l&sGstocks*� *v$6�wD=� [1aNtkInd�9vb�"r1�!ur�BpopUO�> is�a:I G���de�Bs! , �\.�d�ymal\O!b&+�a","�(��P,��)e]� }feUVBFM6F �F1 & s�Aa.�A i�{ajZa|r2$;5-�# !�Q� �3apB,� ֏�]e"w A?g� �� (� i?gonad!QeS9!Va�.�]A�g��ed!JB# !R,1�tb"�aY��e�eCa�plyi-0<ng]�$ germ[1�f252��ZI��!Ai��Cir�oZEa32�!�oug�~"� <,E� �!o�V�8�re 9硝�n!piRNA�� PIWI�f[ng �g�G[7%�RNA ) *���= 5,}[ls!�i���egg cyt�8sN+P-bQ�. �Ys!^vRa� ��>H�m�adE+d [�Y!@�I� D :es=%��UA�� !]%M�$�wJ� S#�r;V�� yc���Y �1���2r�X tool�H*�t�7.�O�bas� #�i���K) (6�aP9����.��0�6ouVn���� >;� �6�Ji� [�W�Q 7 k%w*E�,COq  appa��ly6&�֥I>�JVICT�Ts�ov7A�yO�&��X aI�%�segre�Bs�lj "KN��do�0q!�%�� B� �E��K��PK� vj Qa�J'�\��ѩ%m&�&�5X62Aq�i��enoe�hE�^d���n�-K�a^�m:Y�v��?�2�, u� !�E�c�d o|A)�� o�Fig 1�S1 , seSNso [2� FX�MWn�lfir�1jfhowJ�E�F1�-%��&ro�1\CA#& 1�&�h��of�q�[o5SBa5def�)� ≤2#05A�a FS�� exac�( F}P�DifBn����M�y�nu�f� A_�Oa��[,]�t�!e�^�tT!Q6�Aw"�.f yto-qin�atiW(*�aE�GAM2e Br�=[��\��F�8T,Bp#22Uy#$in Georgia 2009 (! erou�doni9 by P4 addrG^)�10VS Madagasca�62004 &8 �<� by B� a�%eCA8David;aTM�pai��Q�E�!.j:.;random�Nen�~�� B� .^"�QQ�(�� /5�n� Ha��; *2*1W'�Am�M g, 38 . 7"(3��9M,az;ni"� al� � "�!�}at 29<+r *�M/5��^>�GBx�pP%W5W ( S2����^�pD%�̈́aQj���S5g�' !m�G&�cb8*$ Wolbachia� hs*1lyq�}R31�R D�{ .I)� [3Ѐ34]-/ap%e�):�. Hletha-kn�& *to.3� . W�?wG ��Qɫcur<  �{�[9�ppB!h&�"��qMB � �p�   B�nSl>��U,��onJu�s�?�d)(c�@ g T, p >�� c�Iasp �!T! (e<�-e Ў�al alwOeu�' f 6�7����A$��Co8)l �*�i�QT� "3\T( Dv)Qs���th_.�I ���-dw�seV Tto�- �f6�(�4R�,5#re�{ S2C%�S2D.�AV�,%���%��6 suscH(ble-2Kx �d�DI �; &. )Y �I�� noJU�!�� D�DS�m r\"2ev4A�M?�>�FsE�eG�9A�1pB��Q��kns(�p� !�(we unambigu�r�.�d 160o(�$��>{ i>of� ))�232 ! � � 2002�%(%� S3 ,Bw& �� �AHnd �PI�P�1�� ��+d�W!^)����+rU-( MR-is&M�N��.�9!]-zE]&�a�rd!!^ � ,:��Y6tM�RK�`nVnom�ic�inp�%Iſa�&9>!N�Q�^� lr!�D?E(�A&� �� 3a��>fewV,n5[`��[25�/6I�-TL�e� s6Z`f�?�$�5Q�A�iL|,����,e MPQE� weakm�V  �–�[�I�� � �U)�]6�-������-G��a <wIy Y[e���"�]s� d�n_thez�xaQK�3�!�TE�!�:2O!.l'19�02( ��D5j$26 . 5% DRm�5,2%�)8GQ4� .�X)�K)ME���)e*� �(����� E=rFe��B"�$�fe0�&V t�x �U"�#��S�z��� ( S4��<; Mann-Whitney U���<�ACW� as�PEBK V�!�DS�DIUem�9�� � #�.� "`� [2�421!,��(��fa"�h&4����R-qA•BK!�) (jcom]@GLM; Africa: z = 38np 1x 10−9��)�eQ��`�s2�]O"��t�8b̈́a͖s)�201X 2012vWe%�� �a>of"�օKso�-, � nol-���f�I�&%8E( S $)la�_54 &�� 1984%�D� !�p�-& w9 (�^,A�s 3J4EpT��2&�PCe�% �E,�a"�se�(pX�!�"�'j��[nt.�~HAs�a�UY mplifudu[��`�Y$=>2-y��Z�Fja;'�ex��1f�G[F���3�٥w.g� &�""6�n#(A��)�����ADž`{]�A�"N �e��u"�!)$�M��m� Y+ frag�;�3>�-}%N Vng/� �!a=$-�V i�]a exciŘ�^bw'2AK2e�&���<X a�rU� ,B�;#�~N� (!E� �f:&-21^ [�A/97uji����l!�n&so'�"I!��se��I`Y87(-�rca�st�Y�3��2 D���urz""VR��mA�.�5h� 3B�:� sechel,�,!��Orew� "k%zI�5s� "��t5 5�z]G.�% �Yur� ��kin'p�p��Matute���f'6ba!�b�6=IV&�K)��$nd $#i�w� �y 9W��rdo -���wE5!!o){�bi�G)Ty0<,Q}�AK)�rm�#erm�#!{6���I6; [as��218�T>��� �201!�"l-�d P" .+�$sE� ��.P u "9 8*ai�!�n�1k�8o9�.%�Q padj"�8!U�A&�!� �rgan�e7)2,*�Portugu� Q�,s)��&/!�:3�ly.<)�  A�IZ�� �p�eNEq"�)%�in�Oe��#� M��"mak ��ildAN fy�>k���LA_!Oin�)� 9�*�%R,� �N4I�sZ�*I@��*^/20 bm�O ( S3"�QX&�7�8alr I:�i6� /=��D���M�@o a}�1& U��!. & -[�Pbs3Wi:�;9g�@�� nl-i����nd� �i�-X 6�&����!��z��u,a��c�RF"�Anj0�/E��, Eur�O,H ,North A�L�A"�u�a�to�m.�0j!Q�-�2�2��xur+� ast:��&JXfik,��`a޹�e�!  �895�������� "0by 1974� ]�"@. ve�-������m@5 sa�`� qa�5 Bd�ce�NIg��Mapa i� 8  Ethiopia;��� ��S1u���G1]�of?$�.�#A�eN��S��m�CQY>6t� 2�R��Y(UꝻenjoy�4.r5J ucedNZw>J;��Le �1�&!ex'�hah EP��B��Dd&�bf��sf$;)DirC�i<i�+b�6A��L�r,l7`ica�)�$@��bM�!@UK.bat"%",loci [56–6j/Fu� �!�V\q�,=� Ad�1�&uman-ai�)�+7 �@�� fruiŁq�d 2P�MX��s@(K^tVHTXia! �H(E l.�%�fleshy ��m���)�W w abk/djer��U1961–� (� �traTj�4 Foo"Agr� ure O%|i`�KUn�/Ns&#:s Div��AAMbQESBnna&v)i�5-f -A@eI�he ���VzrU_���%Ax2�(EH�,12\:��ov�)K 4: 6�oll8 !�/!Z;��orZD-bZ"ly%W���. f;�3d,�F�q?ޗKP� Q�A6se�V�H�,obo��=M{jH��! .�%N5gadd�!a handD5�&ocuaZed�tE��tNN1m�Z~� oN-a.[+q�D"62�&5 S�aOFj�6ca9�)Z�"�|��cap���behav� seX<"�$a�Q^�2��AerY"aR^ebVx"'3[64�7�sb�9o Y%b{� �mai�Zvia�R �&l�;54;� occa �X6�QayQ*6[�6�&I�c pons� �oaC9�nJ,k quick%�v�N!)u*�8�:&� ��Ig!i�6(���3�-��,с!s�ag!��"uٳolW[5\ ’s\st"-��#A�l�g3�uq*q chal\]<1b�oE"Q�s�*�27>I& � "h&�� 15m�G" � deta짡�F�3 rYJ!�o es–yn–agar.VAXp t 18�&un� eEwi���� q��tR=& ��ai��by �o�� A�of�%�itaUore��.isKj",IB��y� at0^iies&� %vb�Yu�m4,or Argonaute� $FBgn008703� Z|�Obbard: Mel_Sim_F 5′-CCCTAAACCGCAAGGATGGAG-3′� $_sim_303_R .0GTCCACTTGTGCG ATT--mel_394-C)GGATATGG2AUZ�r$�E1J�"w��-�� �&�UL4 �[� �C�4ij�*_nFg3P4I-F ���5��xc��� t�+.�efU�qA\�a�� �"�v�'is�MLWj. ) ! 7ra"larva� f9 ��bB��R05m�Dte yc~�chlor�WA]O+&��fWK �,,%g�7&�(I�A��B�wsp81FOEA�TGEYATAAGTA�AAGA�I[h,wsp691R3ATE�GCTACA�/�)a �gaZ�dof 94�B�5'2fX30/ &30" , 5�*2672B2' j$�wv�x�,10-�[6�!To_@=e��&�F%�a.���RNA-seq� f6�ϋl��{w!�[�&� (�A�� PRJEB7936a�Ph-�� Illu�=��ITm���a6Cre�/A?�gs: -n = /-N �Wed0�X?k���t�3�.� �s o�.-J*( SRA>]I�$PRJNA30828à�hl12 barcoJ�v V2�7� M252=t �"�1� �9 SRX50493S��%��,�Q{( �!)B �! �E(� UteZ�%�.!vQC� �� 6P:�-�)�BWA-SWiu�defaulta-� [7�75�nT\� /� �86M*�Z@7:YW�%un�D4m1��  %.��m�wo �,: F,�e�PoPoo�on�%7c�Air�Vr�Ňeac�j u ��or�_H6� 3-��NJ�2WQ �,[�-2 -f�� a�"�@�� �b#%c �6�,Ore� � ap%yI1 ]�E��"� e@�d�*����Ay!�� 'g!� m/�Sx �0�/hromo�arm 2L ?N#�����"�x��"�* EMBL59� S4',��.� Y��AGk� A::͝������3''=$a�h� f#�c-D ��#�Y��ki�Ishr;:�..8qM_�[� �BnZ�est��ZV%a!�.�E�!0"B  ,w q5�!;eQ$#�3(&s4P �f�!. a���3� �for��E: k�&"�\ �"�n&.R B��[�;;�mend� M.�� TIR h;U�N A� TeysYk�To -5�w!��$u����M*�&�,0r2yE� chec+qw ��,va�Q1c1'n*lEgen�x! ��2 Harw>P_a�JZlla� SfV"F A�(A�C ��LGC Ge�!cq$www . lgcg\�.�g/ �ua* +��M�Ȍ�)O!�� i�*�)9D�y(�bank >� (s KU719478- 502 ) X*�Gd.:0 �IU��availTupoW ques&O�*�CApn3n�w��/NK( �''pf4es� i�� RT-!>,� %�6���,"g1,Ava:xMa�}7nd.] g� Peqlab€F�#�? c ����!UQ�N���-�NI�DN���n�ed�&QIAGENr� StepKi�� "A,f�yGe *.&Y<�(2B�) : 4"� 300 0L6+>KN!G�n 95C��15� �i^:_ 'a _ !�68 '; ? +c*c�#H!!*sr61%�3N��CRM{4 �����[�����A�2�1ee<�8i_��=7f�w� BXl�>6�-a,v5�":wF�I<R [77];��s:/��r*�z> ��st�L{tr��sv� |�:coO"� �to�nworld9G ioNF/ G!Oveget�o�!6�!"Z��R� 1FAO!  webs;�&ao3 . fao ��/T/TP/E�F�z ,�nu���[&�oo��� Al���X2ata%29ܶego;*5% b���U"9 nls ��O�-�#�+~L�/f]thLYe1 &G M��� y = a\�/x�,wyb!M�Z1h, x&� )�V%�)a �KMGZAter�7" ��%.X E7 փ��)�|H-Y 2e~  @ch��( SIT&I?V*I*ɚtrol Aeiaegypti� lbopic�&4-< veag�n�aan h *(ay3r�Q�ignoA �E*���uing�Upez�|mc�'.!� �Ka�!�'Q��|1r�Cw-)hRBed rhod� B!�ol-re� �f� t dyw dy��ed�sugar-f���=be"��k%���m�sh?�l�e6! .FSDv �O�0�t5�!q! AC1��l()�� �of� pet���N (>q)�faw��<rrk!��: chie��1 ��Q]1t��m4�� 8%2�( wh50% ho�4�^wM]-fl>4�con�'")+�$>9�n8f�3��MU�%�WR�a>4 d"=��-����2 8%�� DA�'O�N�b2e���a11,2��eno�A!T1��.��D(proof-of-pr��~Y:�de*��=5$o�r� 6���M- YIG )S recaH�f ҩf �42��  D"�l�he!�i�uI��uA�Z� SIT/���0���teg�E�del�maa�� 2�FF Umark-M�-�ex3$aCs � �!!�n�H� vF-.�Ura)%�Sm7 �!}!1;da� ��Q��E@B�s��V<�H+'�n"�g n3 &�J�? ;e�JQs� t�*so laberg�Atftime-� {al f>59� ��B�&4(X!��Knowled�"c�ent"��8par�Eibu�7;E� 4/g4mosquito-borne�w��s5�mmiňalY%؍od��� � ���rvi� &$gonot_�ycP0 valuE�A�e]E�3di�6�d�ir4.@A�exR8����5 �.1Wap�X rupt6`[��!TY�E!&XW�I i�&oMb�4�bn �A�JJ ( MR>�LA��,��r0�t&t��!:&j  *1colon�o_%G ljTr��w �6� I,#A�u�d�&jA�d�>�I"�eaR@ZZ ["61"5R8��?t=X!��.am��{��m �un"h *o�c��a�jet�q��!-Oq�Eu"E��#!�dyp1�a.e&A!I�A8oE is�E,V�T“gold-E�ard.@xd:�m�j��J��l$� t du�W���V�7l `�#�WKowh� )�ra,X7ly~Y��-%�6N�&f ewa�e!� –8"�Os�R�!�&Ft  �)e���i�-eas{�ap�zA�a��O�jA��rina0�� UV l !��b)�sta�;`�u�2�Q�A| > 70� [9�VY1��D�%�i9g�1 ,,p�?l� ulexAr��7� �P%�a�V6,ic��B�!4� %ao "K'mor�"-L">��p!L��A<��ory+Q!�A� ��"�A�nS `+toVx,�/!bi{���pRR%��[8.1�M�eg�mi�e�75 impa�<[1��1C��aK#5/�pKm��#��Vbp�mv��,��I[8s adv�N{*��[1 '1�!^�O# !�al�5�XI���or޵eapsasy!KI�A*U�_r m, �/�[%Xeeh *q�u3 � of�ae*� �$A��E,E�]�]�v!whelm0-f+���!� ���a�@t&ir!�A�AK N�. A�:�_N�n�'}�6f!4ij���774>�of 800&"�d' �q�CM(-t&� i;� �&�&? �*' "�2��1��Ho��ren�^7�s�� � |iV��� olA��"�}��n�r$��adIg[J\,��22�k[1e�� !dA�m� &�#b�Mt u��%"3F?� %V�� ).)�R9?��Ab� -6, he�gY|�-�:  ] at� @\��.!)�beckN�go�+d L�(p �oQ =���R���y w���*h5a�A�&� ��9e���*!��8o�efJ@"G�ir�y l����;,F�ʔ�3�e%�I�,�����; �6tw�p=�Ai2�DeCv�E��� ng� c� �&� 0ar ?�7q�.Iafford�aq�-%�%|  aat���bAI�.�w��E�җl 5�! �U`D� W�"�freal-n "�3Ye!0*|4y �!���*��#raJ�6 -.�:��%��. R*Q[X�nRpr�AA� phot��T`� E-� 6�;tr~�Noa��� Ita��1d-vio�t�A&Aiɏcem|aa�tinct[� 3 �P�v� "j dDxc:Q�"x540 n�IeiP�625Gr��@.,�dp�6���R���e�� �Yl@#�v�42� m7m3�9 tobA� budw@(mothsS�,;e-Gq/`��-*A\�,>f� *i2�h$�d� i�F�[�_"� .��8!s(T�42:4(1!�Csh %�@��я��hotinu���qQ��%I]ed! M���q%">NA�B��or.i�xC 9_����uwal�/T �2!f!F�8��'-e��)�j bj�dy� co 72a*�v1 �{�f*|WaR�xt�&&�1��¹���Q�M-% ��!TmaMDb�ba���[1!lL/&� ���S[ ��F�!��2D".�ba "�-c.� wMe�qt� U'r�nk Y.�Q=2k!: &lm�K����-",��3i�bm��Ft< 7�yaJ�.[20���th*�B%w�zpor�a s3:��.: �[!~1 � �opt� N�$j!v idea��ƣ61�2Vany=� :�k��.� !i%�� .L�!TlD�8{re�3a^�m�q(�" �O�*(A��[""& az�3�3ypro�*��8Qa. W�typ:�_s�s�roB�ov&�p�o4$J�3�� nnis�%( , QLD , AuA��2ian13PF&� ovis"��0�atc�v,�0s��$��!�� � �A2� �+bl��d� :ovi6e�ԩ�&Cegg�F1� . ) U&��2J4�U�RH��&n�onŷe�(� =��1edm�I��eW�^-�1'Q�� Cair�!�9~� co�h��i= ,l��E��� J ~dAoup�Ta�.�.T�]��5e* q& cou� hund!�&�.sB 9!:. L&�G!��-�cag�*1E�@�ù e Ja�c Cook <�# Mo� ReN Fac�D�n6e2�. FpA7 -YM8� *g�Qe��-)�>�M∼P] C-col!��A�May-SeptZ�r�∼30 C9!�ho� 60October-Febru� i��Ja�F�}KdQueensl��4�yl����7+zE�HiXJuburbA2�E�August�2�O��!�ed�mM���[f��FeiU8%"[.(L~ Aldr8*, 0� aC�,%�) s:*J�)-&/��l"ԅ2 ��f�t�)qe� � s�!tpo��( 3 x�5 c�O�a�~��1o�9��_02!opa�m�N�a jar liR=��l5in!�{�Kib ( 30� cm; BugD , MegaVS,7 ce CZ% , LtgIrewetAv'y>6W .u�1�heF�tqG,yEAon��(2/12 h L: DI5!U�-�,Hvirginity prior to �being placed into the cages , males and fem Dwere separated dur@4xpupal stage individually accord'o sizeQxkept in cups ( 720 ml ) contain/10–20Z�e until emergence without sugar . T�M�(then inspec�@to ensure that no6�4present before �Hreleas> . All.(12�(4 h old at !Pstart of each experimh. To ob�8 information on84minimum numberA4days necessary�8adequately mark8body (!C0spicuous visu)�)T)%}0seminal fluid`)�( sucd,ful transfermf-�P) via rhodamine B fee%�,�follow!��was�du%�@. Twenty wild typ2oU� aE�9!&S8ither a 0 . 1 ,2  4 or8%2� solu%[fo;!�o�A=3 ,;4)c. Male)Isy�deter� d by�-ZI;ce!Fa d%�Po bright red colour i)�%�(, primarilyabdomen%�Lthorax ( Fig 1 ) . S�of:�F�z�m�Arng asJ�.�.��$ursa , speA�hecae!D$both underAYoresce� �2�$To do so ,q%en%�e#$time pointAQI(3–5 deXvirginU�e�introdu��I��-Le�Uremoved#no addiA&a*�O)addedA�0he mosquitoes z leftacopulateEd�0, after whichE.>< froz!� t -20° C=1 h��� diss�� �I)}and6�Z%(Q��a 1% PBS�ndbnq�oa�8microscope slid2�a dropA�fl1�tI=rvativ2. DAPIA +oshield�� ,, Sigma Aldr!4)!YE�rv �dim.�� helpm�is 3@ /E����u�. O"�y�� ��sampleeh0gently crushe �a cover3p-�.w.�a�ex�: d use�t.mt( Nikon Eclipse Ci ) provision}n illu��tor5Intensil��C-HGFI�� a G-2A lo��ass filA�( absorpa 510!~(600 nm/emist 575 nmi�hi;optimi�#�$differenti��f9 -tre9compa�to�� (testes/MAGsA+ig�6Im�E�$electronic^captuI1Q)8LDigiRetina 16 cameraE'rea� d softwar��4A�-,cube ( excit �346488)!�u!toI��,aOU /abs6�a�0ree replicate�Xpered���%!�;effect.z�on�� survivalM㮷*���� or wMel A!Taegypti)�m]i�Q��*� G���� 50% honeyXrol%8a!H����i���p�9� gE�st飁R6& f a�. A� ͹day 4 ^9t@ ��K-ݩˊzAW.~* ead2Qas ree � aV�lal!��:�Q a"� had di��wo��2��pevity�9%B5Uof� !;6{)�Y�parallel*f -^co&h Ir first*NZ���q��f�2� 4 d�he��I��M� of labellA�)M9���A�V6� (2� ))G�>� subsets��s? , 48B nd 72 hV�N�2a� ed��"� *-� from�R9regim� �4of�� iJ�0" ofE��G2J t*Xas sco��d scriba�bov�!Q y�:� >'�!!�dependH�H��!�I�mai"@ a 1:1< / r��� `udue�A�(high mortalm�=s beyond!�!y%���a�.sinvestig��T2Oi��dQconsis�� sameU� etup)�Uexcep�R����6�%*} ( i . !�2��z�N�)֍� knocA- down?freez!�:� 30�i�nO #��1�^b � vM~� lyR=�A���!�byH ��dig!�� rac�V_  =9�. 9NJKAa�3 ��e"�sM} derst��&@ >-E �����trial-�a4#For  one , 12.�of 15*y m&�٬0plastic cylinT alcHer^ 11 cm w� x 10 deep�� ith of wa �ottomE expo� �4jw͆. ɕt= � ɍу����)�.�Pa48 hour!�F"v6[4six randomly s8 ed.I���b�(*d �)�12 � �ni r��.�2 ,aQ�Zu�&�!A�qE!�.�� � � � �neK�iolA#1�Le2�u to i�CFi,|a as Ra�!�]'B�U!�f��. LikeH thes2� also qu\.�!�&� U�e4n hal5 $group ( 65J�)) �* ��>&; 2�U��m�a�tar=�q�an.FH, a6� (A�9�ag"p �!ton��e^� ������3K’���!�!Z next�߉F� acil�!����)�event�:96�� B9Q) ,2� B2��s��2T !��JE��#e� �[64.$:he^8,g well(.kQ2�� W� �a serie!9n = 6 )!���-fl��eti8ness ass�(within larga� mi-f< U<17 . 5 m x 8 . 7 4#ɪ feat�a sM�d!�s#Hyard [30] ) betweenF���ed ( A�� Kun� ed-�to��!0&N.ua}a@�Z%.�I$cannot&� .Zto!�vious���,2*2� ԍ�2  4 d;%�40aoA�}pa5(&�*:%a�3 ��Q�.g.�2�,�.� *��obs;i���posEi�I�, revea$noZ�^ne.� ��R�"~� , we�|� 806 A�.��E4$: �ABu4*B)!da�2Ha8k�,6,cols*�8Prokopack aspir| [31]�d.�� f 9XBVMT�5� A�6 � ńM! F�. A �Ec\de� me%by 6�=ba�^�2D:\��L��n6�N�Iϡ7� 9`2�!')at�}2�3��8proof-of-princi ���c&� to=�i*� BuU�=ds7re�vپocc�  ��on�� rime"� alud: 50hF�Q(��9+Bed���� ��08:001P fronq�^ngl�s�ce lo�Y!EB Edge Hill� urb� Cairnl!QLD whA�F�have b��establi�sid<2012 [32] . Beca��A� �s)EA�a��dr asoo"�*low6�abundan [33]�� `d a to!wof�v F���>in!.�ho�Bpri�" kb)�. Indoor��2k Od�|would en��!�!Dprefe%<r�ng sit� �6&[34!�M:'AA�sa�1�swqnetz! pray"�0 pyrethroid-b�"surface (0; Mortein OutV$ Barrier S 'SO,; Imiprothri�3 g/Kg �stoa�� C�prox#�V5!.�Rz Each�]sQ9X�Ix1 week=zii1�. D+ e em%L uresbged�� m 218�$y C �Va��humid2ra445–85%)Rn&4gnificant raing � ow�� r�Yg�"�AlAH stud%b| Q)�ir!gperty��cw Ev " ,)�"z�u.*�c�d6�kA,1per�*6l� k"~%Wy9E�analyAn$,wo-way ANOVA)9 Tukey HSD� t-hoc 2i�\dat�#re�a*ae�cen�'!� jrcs�%K orxI� �is [37��:6�uorship ,Y�+% Kaplan-Me��2* curv�j 4!�$log-rank t�[38JZ9 &�propor�:!}��s7e��as-6"� chi-squ xs)n� null hypo i�O �J. Mean � aris�BM��:��EjS)�2�&�r& *[ A7.:�$-"iq�$!t-ޒ^M6�)�V fBr81���� � 5" mq!�tw� ea!s 2�a7 he F* rExact TAN\2�' f-�re�%�aMA� "#alQ2s&� )\uXR ( http://www . r-proj�!. org/-/Prism ( ?$�. 03;�� phPaA�.w&�" T& + s�>mE`lengthA}Q( F�($20 = 3 . 3�P =� 045 �con� �n25R7C5�'on��A�^��# 3A; Table�(�P incr]+��ly� �=!Gb!�m1� esul�Ove�( , 89 . 9±��6%�I(�o�4%��8%"�-���e� 41l(f59��96!�±I9%�9266. W�'�1�2.�, 6U3±!�6N\:�!l8�r3�E v�Similar.&�.4�9 , P<�00}*of5!�53QL4�"��*�*V(gɃ6s,=*3B.@ . Ag+�.=g6�V�#V�M�5!�-�0EU��+/.:&� 2]or 2\IY��u�.oM�wA$tho6�!30 ,�M 3!� 8±2A�%D !�6Z�/iv.�M�a!��Sr:� �'c� Z;a$*sf"�&�;e95�e#�"C VOB*�/9=. N65 ��Z9�&�.onual�!2�e>�&( χ1M�27]�6��&2&�"Q�6A�2�&rn( (�&-!�� rols.92c��74 �-No*!����Z�/aJi ���&] �  /5�am *":�H���ust� �ls�R. AY:DEY�%�V!�w:�/ ���.�/{A�i9F�"� as 8a�9±��0 , 5a5±��� 3±�2d\�28��.�F�Ay' �� C80K��!�8�6±�I�1�m7���1 0m*�w0% m�bg". inteo!K5��$yq��2�a!�N� � � !���>Q"6j21��0)��6 ,�=�1!�>Y� 2�-( 8��!lq`02�|. Spec<�",6Pr *7 ly de��.! A�agrI2�%214J�.j wW!=los�  !1 A.��d"�*%w ��S�=on��4+%��� *XI7R�visibly6�Y-��P6Y�� dropped 6A�8I�0%n ( 9� 2ia8��ź3I�5%*� !24E��f�A� tras�))B���6k�2�<1% ( 100� to 7g �1�. D�A�)�aaQ��>%%��%m�/�t9�at)) postu�-peF2�F%lC,�P� A)6-�a�0%Q�low� � s� to 8��2� 52hig�5/."� t����J�^.u!�8�I�v3 �:�6J �.,�+F"A��.V�&� � o ��a C�R=��:G-�&�� !99)��no ev�.�1 BQ>^�4 *�iP6����72.q&�� HoweR, unl�#Lɞ=�:� &E ���B�8�"s � 6�&J,�s��6t.��6l1fZ����7��92� 7i�6a7��x9��"Lhe�����!+8%.$��$��i4���9�pa�4�. T" #�%[6�$1�q: imp*�!2� ( t1C�1��%88;� I.*� ���'�L>.Y=��"}N $ � � %!���(�QP��9!&3 l!% �lRc�/b[Z)�!p�=Cnst�. 5�����,2'gX,���=�;e)4:�i�T b��!oᜡQshF,%�� �2�/�;A39��!�� amou)H� :��m� =1E"� 3)C9� 3���s !*o�2�+U%yed��&)���8�Pa@&boZV�.N?%�a�6�6�e9noE$o be engor��I2^'. O()��b�p�"�%�X83%�"pl�V-while 96K�b))�b`divwJ�(�I��FAg�e*�'A�2bR��5.11mcw.R6 �W4��2R �!l(&"a�gb(ism�( ±SE )�l�gQ )�by��M�&�a�2�!5M��6�5��1±A 7%>�,I�'�:g a�st&�#"!�K�� t�0#*�3��i�c�U�(�!= 5A�2� @5�c�1'NA3!�e��6B&�Qm�mon<- * � !�.H�5-�)k)�n+Cl-=��Wre �X2G. 3�; 0±1� 7 -d��UE �(� }(�)�3!��7��'!�. Mark--�-�&�$s wviL#to G.�s�2����\" vec�=pop�-!,�P)Vdynamic�!&efmc�9MgJ�,H[�Rei �$in SIT/IIT�"=i�=�toA� bat denguZiky=o��"!-borne�`x40] has2l,�he ne!�or%� -focp=MRR2?,2�d�#�!h�$�RdevelopD"!XnovelE*!itechniqu�&zen�< �(�&as.�+ic-S�-K.teg�,quick Gnd eas�;[41�Ou�$ �"or� %:D , 60@powmCad1FsteBhroug"ga&�~(�0suc 9�� . R*�Es2<yXT,rC!C С�&� 44ild-t�EF=Z!�4ng��Ce�ed lif�ectanI�m:h-[4qG44]�st:�vH&2vac��?�c,i9�ak �:�Ja�"�? >95%N��� :N ���.e �_.1�<r!n� OI�Im!&a�B6�-�Nto����2�YultN�)*� )��=� �ds&� ?-�4/!�� a po i�usegHool aލa programehmea5t��O��E��0a�CcE�mB�bF��F>A7,��~of��knowle�) , is� �(�m`3s� �c!��)&! �:��% s���ala��'oB� in1U.� -6 `is adva�#J��sa PCR�S*e isot�E9 s [�4�6�)."im ns�DgMp fertK3y���O$�5>��H teri�Ey�Z&49�#AY9 lim�3�:��J6�%�at*v<is�uma ��inC( up�s 6HsoG& ��! :s�*� �%l�k�dilutA.A�rk . &�%V�+d"/ e@zem�6� �i���did�hC'�5g�GE(a%iE��R�IMt fa4*6�. A"�$lya?Hcas�Q2T ,:=djI� appea�Lbe�F riorY(aґ�[5�51�) , alNg~IrA� little'avail�-D� �%e� .� �=a] �ɭ= HFikrig et al . [52]&���p�,e:�� 2 5*� �_` � bi��a�����a � {(��aeL�]]�6�Hd9P�q��;��eo/m�!�Q��xC1–39a�NOAeFL�D� !W�ri%1.b(al�-bab�\U   8–v82"3�5sD�&'A ��lE �!tXP�* a�be"�reoL,. NonethelesA?9�?�)2I M� ��stXAlyI stoo�4fur/ i"9A� �8!]q�f ��2lsu�A A���j I arra*Aju�Z��app�H�f%�I��?)���.��?kG�< !:t.�%!�sQAk ioW 9E(lin/&a defe�/. C� of�|Y i7  attribu� a�a� er [�� particula!�O�de"�Rcc logi(��!j 10006� �:ofA�du#a��r� &OB-M�8�H� $�40Q�% w/v6�Dis su� i��V� ≥A503lef6�as� s�nU[54��)�et�is!Ry[im~/%?"Jundred ��Ns�rQ(ei�.quiE.���Ckills�i� )d� �,���� !I��(m�Jis��rNk�!"�Nym(�Cg .�.WM,Ls.p��!uq.� ca . $1!"(000 USD ( S;OS%��  Pty Lt��QueenslA� , Aulia�#Despi)se.�  upp4ra�p{N�NB-� ndI�>+a>Q!5l��!jNn )��%�S� arch?to��k>6�>#�N6, HlM� 15].aiRT�+ �ofI�50e�$�9� 100 larva�915N#13C en!P��5AIN ^�$7B-(ł52��^/is �( �V.e mass�jNmetry9^�%F�����Mr� �1��UvBa]<�@i�#�3 taffi�ace5�"apI.ri��h9���]�mT,��a+>� U)may�1 any|6y1!�20+2 ToH�oA�e f)?!�Gns��api��-\.y�PSt乃Ayc�0��-a<ifi� chem�A� ed2lcarcin4ic mNn�� �S2W ��$humans [55f I�$� v�it��H�7� � bio�+e�U����(�[56�;8� lethal d*cal�v!�s�a variet�  rteb�4 �v.r�i�ly� [57��uJw arXdO"� c7inq$ ( <2 mg )�6� �c5$max volumet μl [59x &Od?m�s2�pos/� he�  riskA-�| pec!5EA��um���.O; h"��p'ce dict�Ga f�1��F� e � * ��manner bR%$3 7}�institu!��bs�9iew boar�Ya1 thic�zmmittee��8i� C��3 labozyUH.�N summZ��Ռ�6ola�M�n econoiTci�evalu �� E�� 5*aQ����*�z� fZ�� eaO!.��LD�N��}� e* i�th6� �J�>� themi�To � achieve � o�4res9Uӡ#�@%_� boun"��� 7 xten�v=�6B/preA��ya��\x;G!2YIwe!� ongl�@ comm�Resmall-sc� 1>!2��bSE�,e�]u���<i9 mM&u np r"�7�Nad!conEr.� y�� @�N�nefitɼ\}5� lass�:����t�2 chA�.% T%�bet<��%Nu�:+2��le"�2�ers� tu�.\�Bacup9ntige>a divers�zm:��oxii�8��I^ lamm�y cytok�7storm)�can��'�z shoc� CD28�u homodimerMA�(=n T ce� E,fun&P�E%@cLstdEory lig!��Ge immunaBspo3�œ&�,��its B7�C� yetE� how 5�A�l��ZgenK�A_�!=%r.lmust bin Urec�"s)��=of)6. P�sn� a?_ay.��%f� �Abl!�)��. M����=\� %6Wch Ung Bsh>pQde mimet�lA0he >�!by4s&(Ma= ompeB2�B �!0aY�in g. S2Z�+[n�Eβ-�D nd/hu4/α-helix doma f h�1 Z* nUw�engag � . Mu�: �� }Sabo�inN*E*eO�O!)q)� Structura8gt�atm n) .z!�K!=iCE ep�oN o(major histo!{ati�y ��, II molecule=�&-A�M�a� ,)�a�3�mod� read�E�*ird6�r�Co� �dbrnf�lexX �.E�>Ror�!ow�H�z��#2>. fGngs-Lf~az��y��cri�M�t?J�.d�Sro!Zm�aUY)�A�a-�t_b�� patht ���.\�gbroad��# <�og� {0echanisms . Av^�-��.�g orly>[1]–[3� ExAB��c � @6��.f9z��%ac�5�2��ans8��al esE��!�[n�ed�mr�-[2�� B7-2�e^�aMe��m S"�a�\-16C�'f,; h�١of �eE�r)l�?ignDJ ��eMM�B�� [�>A~��5E1�Adn no�un�iA�^G#a f"A�[A�s�2a�,by Staphyloc�s aurend��a pyA��ā�)jE�c��ckLh� ng��:� , oryU!MmaA�ude�9ARns�ztha�)at ��e2 )rr��y�`p�"ric+A��@��ofA��!��d w�cyp* �!Se;c3fM�!�.�s�� d0a�<tac co�E�m3��( MHC-I�au��( TCR[X�� ��upai2k( < s [9e81l"�arm"� ss�8%�1#�,T�` er 1uh�'R �8erleukin-2 ( IL &m$feron-γFN �LACtumor ne#5?bac��( TNF�c!�m�2K. N�/t"g.~��ls�+si&d� ![1�@1�GI5 hn��mMYv�j{".B i! hibiA}� dode�bd A�M�2m� � �t� ect @A?us��log�!��a ( 8 ) >X (�'^ inu롊��o �?0)B "��d"� @2�� �Wgc]M�!�A� A�# e�"�Jis�s:.b1�%, ��hA;it" a;r�Wm;.�R!:.; ~�^!��^!mI?� qr&co-op-�.� O> n[ �N��6_ &� !�� . B8 !Q&p a2�7�� 2s MeS!P�8 iU�A~2A�0�.A�m��Y� �.Badosu�e��4m� 5�Z� �!�nA#ve� . �)?n"� U"� . 2C�*�� PBMC�.��.��桍� is)���(YNKKKATVQELM p12A�O� #;Iof SEB15K6�T<VTA<"e�$iV�� *>�,#6�e�a=)k%pt��VQF�BoL arryA�VQ���149]f SEB-�KMu���, �m�C(TNF-α mRNAY���FigA`1!H but _":�2�(1� s IL�4IL1�C��&;ald*!�=])�SEB�shift��* Th2�R�k� expl whyi9yH�fNC22s swif�"R� A}�.v DI�,+�� <<�$ �oglobulaSE,5&X M�U p12B��M`�$�C� Z# :.g;*��%�%_��� in �2�C��ion,�#ya��T30U,� wA��s� iv!#CtaU �  leveyef0U���  ��Ac tim� by 8 hEL'� *&B J of d�o�q=. B/�k�-EMCr刁��3m���D9:C�YosttA��. �+A].�$���@:�Fi*��'* � i�)��C�M)��~1@-�� �q)F6"-&a.�.-�"�i�)c�%��K]*4 Ń�� �iN2m�al�n�.B7/œ>� �S� v%i�'�A�.�w� E� αi�'by 1 monocl�#�� ( mAb ) ;(ca�?y�of6Jp�O[t�XS��.�Reo�;���e�X��Zm$�ga��by7A-B mpri*A;extra6�#� f�$to IgG1-Fc�(B�B�MS� "�"f$U%T!���MDN�3m%ib� iLt 1�&�-ToF!&V9"�h15��l١reldon�Id&�!wD =O9ea ���"Ozq�.�s�a}��\sD#��2�"S_�edR ���#* A� , αrᦥ�6A{�HI�ř�D�� < fail�o� +7g*�6� !-��+th@in9*oJ�.�V�a� �Q6�3�y:�\��6.��"Q+�=��!�� . BMoJ�AKQ? �e�M� �j�uly)�*Ia mode�om�5���[1!�s��Fw�A!�"� v �(2�"U11��%+M1%Rd+- { E�%�,  '� ůit_5y@>Zi.1Y_Xe d�Xe�4��v��CD-%$ 0�����5dEv�/8"� Oi� i �#,'!V�� �~!-Kg��G2}:fQ�a���Z!m�)��&� ��A*��%�ed `"6 29�c!f*�s�M�z>j6��"u�=�&���/" C���r�,"�a�7��n�b.u5; �repTu� �"�[�h 12-�phage-xla�br�oooc���!�, )�*� @��!McX��36qp� &S�:or6a�2oni40< W . P� s"Z �V1[,SHFTHNRHGHST�'d pc3a� HKHKNPGSP.�!�Z,e)9 )NYKSP )m�ZIYUX�1l0ap� p ��.�#ab�_�mo|QWSa !E, 7a �S ed 8/1)7 .� "� i��zQ+F6Q�� olUA��:Ita)�sq vivo����(�MX�_Qsa ���ff�$&pn�"V it��EmIG�g�A�,�A��(�6GFP� C-�}�'�iJ .� i ransBed���.2��o�#"h"zQ��u�܍MU��5ns�p8#���� A �A�e� a� of n�fal� %A!1?�! ocale� ��g" face�� ofa�i-XAb< -e �!nH&��s�j.�N&ed%B9V6 Mf%]in� N�Zs��. F%��� �/l7$far-wester�u*�lysozym�Z�4�J ��-`toq�)%Uvade)�t!�!��ob2". U%=� |omo2son ( SP��Q@ wpurif}w�z"�IgG�im��!f� s 3AF}2�SM�W==xt27�Kq�p12C (6R abutaaby Cys��di��|X� ��� 0�fLD-AlaJNi�L !�:o2%��:"1$ S�@�Fc���"m ,3�'!��*E(,�n ��5���!�or ubi,�.tS2!_Sm+!�3  inQ� �n31űn���� Z��w2�J$. Half-max�-�}aAa�Lb3T!Jin�S 5-fo�cxcY5q� e"�ft�ol�+kFKF+:Y2!� �� .% �twsko�% each�.���!�any�1c �]p��bI�&7 z!0uB-����!P%M�m�%�"0�[,ed KD = `D3 µME�A� $ - �� %��a<gA�!�� !'�E|IV":as�A�[19� [20V6�!��&�"NPM>$med Death-�PD-�����yS���<�!A!�QA�2+m�&�Ra}t scrambYl�#�oabrog�%U~aa}��>�aڅ��?�*Z CATEɩlXlog p!v\F��r weak�ts%*� �� ��'r` a�1�!aG t�012o!�A�bi�k!�8a�+&I.��jZia�*ub�$� n �( K ) �91W by >�r6 X]BQ!�(�eP"�:Y; pairwo�.As *k(�p12YK� 12KAV� G–�!a e]z*A��Be(zB7U� Q MYPPPY��B !��+opuSm9d�> !5��T!z��E�� F�${ b+%�u�4O 2�" ��M`ind�R�%.3par=�p�jveI> %�. p�m� 0eQ���� 4��>�&�"aS"N,a�*�"%at��� lmeS9\Q synA�SPMLVAY� 2TA;Q�?1fS,M�R��s�4�HBM03�eq6�M�9!�U�&5B%A�r���2TA�m�!�:�; ( � flex�%� �T� res�z-�L�V), m�l2 9��2�s�-�o? `/^cojB� �m�!�52E;6�� !+``6�!fE2:�2u�E4�_� o��clu �&8%��A�.p!�PqZ�+�b α-chm!5;SEA�=s� β $� ���"� � RA� 10� [2�(2�(\!S�e�*a�~ �Q2�Y�� �����TonI��es:r!=�a�r�*n �Asmel� nsa�'�beak%�|&' �. Eve��orE6F .g&syndromWxin� TSST� Wk�V6Љm��e�� !���e" �Dq�qA[25. !��� �lt�  s�1�4 %i ���,e97Em�*�x�� w9�GeT6 b�"�=�$� uh�=n� �la�0H), �� &F, &hE rece�E�\4ly $�!�T=#�5�11A������-a��6i.�X2� 4A�E 0(A�-� j@B7�6S&� � 2� � eF^+%vZZ�8.� ly� fshs�odEsc*x�'&�N�5a�m2eA��%&U )A�a�.� a��A�E�2�]12)J>zXqa�ar�'���?d�x��Rrhv&�3Z3�(�1�<del3 i� "F@6?? vali�49�epc%U%2�$c�-�Bs:/�z�B� whe|G6<U2gs&8 ���c��.�;�*PR��NrNdivalr&�8we���w�IEB!.h!}_y�f wA(j��:!EJy6% �Ie�QtM & s�Bached��!VKD� 4=Aya�-6< ion;\ KD agr�>�@�� eG�lA�u%�60��I*1�'�6o2$S`ribonucP@^%Hb ie �1 z��q�up�Q!�.�-�1�.. �:x6o�5� 5� %+KDa� �8�6c :~WS�&([2T����"��RiI/u VT!�td!u�E� A �^�F��5��Sƽ:,:Z,%i^��exc�7-!� trum22"W a���\,A�a֔�cg{'#>r�%!0��1�2���� � blotEq[(=eD%l�,�oQ�V��12A ��Q�M� �=e&%�Y#H���A� ��.�s�� p3TA!�4g p5TA harb�8"�K�e26.� �cryst�Wgraphi�(%�9��� 5H*� ��T,/&3t� ��Bt� EW0�B%��_�efgH:�#Y+��  f f� �E��=dRMn?7o�w6�>�( Movie��,�!St\ ;.�.�.E��{&�< �@�� Y, of"�H��!�ba5 S�A�eFwaiT"Dy7at ",}��e�QIG�1�),%�bv6�le &��"� tɿq st� uD-�Sby�C"� ZYzA K!�PR�,���B rZ-� �!1Vl�B�.�<"�3��Y ap� of�wZ�%0F"~3�5  � j3�2��&�5�� xert�����- �( �V3� olo-tE��"{ ᱱ��0� �|! U�3G%43��!= adja !�nt1"��s> 0J�%(� Fma3*6! �+e0V+`�� {8%;m��% unab��6�,J���K�=�&o��s+r�T@u �)�i*�86 AdA�e���y�H �e91�'2D&VKI�A����T� ( 0/�k"�&�eVw"�s( wt )%}!H]( 5r=�9Pp ����?�*�I>�9I x1^evUM+d.� 4e�� xu "Y*� 3��?!; �J�/gH ax ^q ,eg!!�"r��ed nan� va� "� a��M$�=Eun�8$$giZM�7r2�sA� lackA {jYK���!. ET,2;D�! �� �� ba%�2]#i �mDpan�$b�%)r*�6R. L �!BR�of��}�e�e2 seu�u.�� k2i!'non'z����!�� G�o#�( K�^J�1��! do��nt-"�*,0Ann"'-_q��(��,%���& �!2% *���U� ��d� bya�a-Y�[. YetcI +�*� &'$m�Znfi��#e&*2+7FphenotbA�:��8aO s&G*%bG �!�]/��/��' -���t��n2! M���2j�Xl"�2���/�B��2vz;DAU2;gen7+*�@nd}"�;2�:���y1�MU�.�CuN�H-@:��:JNultanP`%��A�!�o� �B)�geF�HU�7_Xx� o��H��H��H��s�L"� id12�HB` ?r�@Z�>sWe��c|�l�B%�i*FOe�,,>�E:�@)}aA 2KA�"�9��a5 z/ia�!o�w. N � W �m6� ?.�s mak��co*�EFL�ofQTAyAu�m�A�s�9�q����V��)f"�� -QheG��a�6�:aB�Ns�:$�* Y ��hQ!�� � ��>�Cmotif �:&�;m�1-1�IF leav!.it��es � e�:���BV�B~�N��&� ~8� �%�!��BSni� b=-�&�&! �T0n�' �j6O�A4a$.rc�I �L)��M�;�K��L.����?eMD��L(Gn'����e==�"��`6�: b *�5M�"0N�k-{�I"�2 ,�VBo.� s�7kY�a�cksd"�2AQ2�4so�2!�.%�; %��aI��AF 0�_[ -B*O� �`8|7�?.A�%>e^ ��+A�- �F �ZGA�u+�XH�j���K�b,b� � i�� d2 ami�[cid[trea�ng!$o".HvU�an) Zt ��U�U#,��� ���|�a"�4&�*<,&ba�2�%�a�Ch ��*� M�R�;�����-�-Wd�ow{���GA02�Ah��2��ch(3�- [},>L�Epc,�;X:G_�Cch*�n� F�"P%d!��(�/#,M#I�E!aiA��U%y�Fy7*� b�7�?]�6����4!���/SE� MJ�cl�]la�'UY.�Y�p)Mus!��;A{?ir.c��2 T=������B��'����:� }���pe�]�gen�<�A�%[>� P �Aa r�� Ee �{QxW"� �'r ODeL pret��proble-1c�e @>��Qkn,�7!&�0A�0&� �*�*e��p� e �gori!6�a�P6B��d X#"�,@M�,��ry%�]<Q�h%@� !v@attenu)v�,{=�u�i �synerg�$ʟi5)��T�a�kiV2���:��T�S.2�)o�R:�$og,��@�#��0�[2�hZ�?&J !��T�seF-��F�.�bؕ?lij�� �C&yF%�w� .:&c?�E�� Ah0-*eKQ-���st�; cripcBRIR�U� B�-+csus!r6�Khinvol� a�  hT-bet [2�B[28�c GATA-3 [2�p%"��P�e�#"wmow� G�&� �7cI�^)nonco $E{{�Yfve 1�?i8:/�[eU�;2� �C�~��u3:�wR$]0A)A�� sulf5/b���APH&�M;% �Z A1�r>x0E�Ha��f�o]A-�qF���.�!�u�9con"�0*h� �%��!�va+2y',��@%�f?l&�6��� ��(,&"� e^e*?G"\iz�eneea.�aRfh(growth hormY ����Uery!�poi�H.!t2I���I!�.8-e Kt� thW �-"acy1Insumo�o-F� �vS �{� .��D5,{Wife���� dAg!�in ��a�pa�r>P�� they^ &d : s��)!HLA DR3��genic |� ar >p�<��A &� ���V���� �s �p2�+d�8e*I2d%C?�G�A�� .Y1�t�oy5� �,%M[��ef�b"�`.e@�7�|.�LO� ?c��e%�#��������A#5�d&Vmir�)rBalf�i�m#: �*� G�9!�F=o�4 .�P �)%�dY��f���P)%2a1ہD2"0&�Eg�Ang! A1to �R,"2S��>�%�ae�T ,"> z� aa�����Q���Run96�=�Q��t�_1�*Y�e*8a�k2� n�LAa6�YESv�`�NreEy�98�����#� *5P>b (��>qaq �'p ��;�*FE� rmA6�c m31N��mp�"x�24!�. Ac�a �"����Ҝh��� !��e�P�>��nzE�H"�k.F�Y ��~�;[?U*n��+��.=*�nr&I,au�ɔ�,�*#�;A �&>���F�. G"�,)ode6���%�,m!Am-,�-!/A_�%�r!�Qt&�2@�����I��m'P(w�W synad�"�Q ~ng!#$0q /st�52�f�T�Y_a��4&/�4� 6� �2��_a±ב� �%�)}�2#�E�sruptJYu�m$t!.r. &���*"�*�~>�I�:�2�2�U_!�EhNh ��-52N4F2W. Exp&�"0 G � o�zx6o�q�&��…�moLAc�7Ls*:'1�konyl-m�vxycF+nylrs�s, �/�2 �OU���7de��e#(triflouroac� �B����4bYqlg�4l�Ed chrovk�+y;,^WA�S��ve�G0by MALDI-TOF Fgt.z< cG�VG!�V�e�tqa���.rAsV�AT�GB�2.5d6�In %��N"(�4+u� �BY{��pB� '"��\,�C)� �R � m $yeloma NS0��6$R&D System�wA�r�A�&6�U19–152�� 6Z�20��39*{qjp 2v�'�Ke" l�l"(V&�L "9V F�5�u��d6-Q�Jomw&. Sol�Dk%�Y�as judg��SDS-PAGE��%7γ1/ii* U( MB2B33�wu Tod9yS^(horseradishK0oxidase-conju�Dgo�$�/)��H( KPLOD xl�M  AB34!�:Xe 3740�!,b:3 epsili Ab ( 8 UCHT�2^8 B7-1/CD80 wn710AP� �Au-6:-3Ơ, ��4� polyZal�0(( AF-342-PB d%,:9mJ> 141-e,�.�&�3&TB++J�4a�_C�te�iLen MUm�gosorbI��h6�alkj%� osphatIup�"α�( JackH�L�t� )�IoL E�&7�on Fi�� Paqux5AmershamE�wa�tw�-with Ưl� RPMI 1640,fumi�us�!dl4×106�,/m m!cul��;` W�8�3ple*|�2% fe��calm�4(, 2 mM glut�� 10MEM� �/� �Na��z(mM Na-pyruvL=, 9HepMH �a5�−5 M �Scapto�no�LU�pCi��M0 µgst�imycLC�5 ml−1 nL2�L ( Lot 143�RD��/|1@� �, U0,Grmy Mmt al R�vIn�G�In 2�9Di����,��( S��)I��to�n�. Secr�jt!Qqua��w)�ri��� Q` ELISA k�(2M�hr3ejA46~z± SEM� а=baG�S*Fa��on�3!�7M�A�Trizo %�#AInvitr.k�hybrid�A�w1�_at 42°CI�ge�w�t e� probqk�RK�r(α-[32P]UTP �DNA| "+ o pBS ( Pv?g`~�600-n�X2 \� T7�d ,��_i"5V]L� on 3%�y�+p> n 3; 117 �ej!H)r�!ɱE�/q) e 274��4� �=r� 5er�83�� H�,� �57%4T35��!(s!) >10%E�4; 220�� @�. AntF&IZS r%|nd^ Y n 6  9`45u:�. C� osomalEVE�� anCOL�a�IA�ڂ�sin was� c׊D,�SEAA��A�HTT7KH�� �yin � coli�� �inW an N"%V His6-ta܁�pIh\rs 5′-AGCTTGTACGTCAAAA�(ATAAAT-3′ )ATGCG#$AGGTGACTGC3G (��u� �!re���WI�'q�". a�b X,�s �%5l4rd o!a�•�!um�kNov�g�Yelua\ step�;�imidaz}?.ґ�E�#a�!7rez7��diIU� >98%�Te�"d !�� � W�FR|!b��=t�Mg�]il��oZ3a 1×3z�S1&dex��cS~n��Z���k&W �dat( GE HF~care-"MPharmacV�E�w���-9�  f��� ml/���,>��./�ō>,q�� �4 at 1��,��C��~c>/;aa8J$g$ ��b�!�N4a�"�N'�mIAk� -TYA- p!���+ cA� G2�fE�1 KO��lya�s� Y�%�p: ory9dF�aM,GATCTCGCCACCaoTCAGGiiTT CT Aue�*1 CGGAa�T ,GAAGTCb l�M)e ��V)+ codo#�����2�<b$o pEGFP-N3e�$( Clontech�p�:���? BamH d BglII�G D28-� �KZ=E| incu�6su�l1����#%J�8~YAlexa T� 633 ;"xar��2�� *v q9W &� ,F) NKy2-tdonx�� -Tr ,AUhAua�\ˁ� .�( <�4 k�2, egga�te&�Y( 1X� kD;"8 a(�F�>� :i!\57�a�95w �&� in duX by 12%��/��l܁�3D� Coo�i(u�7�(Mr�j�" N A u &T� z�MembranaJWhatma� �F2 m iezSemi Dry7nru� ^ chlei�� & Schug"� A�ma�b+�5%;�m milk KM��*!9��,�_ { �<eFcB�2�%�"=�fECL-plu�.�.��9 m]N�e PhD-12� bin�I6�+�ar�6< M13KE ( New Eng��Biolab� �\a�*ymJ��)�P@�)�c!A� A manu�"urer; pla�!i%`� � 1,as��Ifo���afI�� on n6g1�s6z �~5y�Z���"�f :�� U^]�g9!�#���S�X!�Riבt g��)�"d�$"��.1��V�E -Fc;�.E( �)#�th.�� *HebobC��a/,2Q.��{mda�[&�r�*En�A, >10ܝ)�C�.s tigh&�*-Ak! �p2�Ŕ� T2&��[Na U pH<�k .��6 CM5�orchipM*dl�34k�2Xd�I-thio3C��ng( BIAc<#��1(�J�J; ~�.ze)5�� � 00 R�A�H-�inj-at �µ in 25�HEPES��r�l��C��L4(ED"D!� 005%{(�� P20F�I��no$�?C.D� � A�A�a-M"y i"�Kin��dE%8+ t 2��d1S3!���_ , de!b c $t�; �� z$��q �al]Ju��ru��z;�f���r=sK!� BIA*��!r1&)�!u� ���: e KDߡ>�5#��&�'Q <( 1∶1 Langmuir�m�2Va�WSEB�6��<x) `*i�qr3� qq9.to2��X� ) ch*�>2 e��.+�[�p�dos"��%� MI� o��%� [ �*�3sL:a� err�F�g��Ek�khd χ2 ?%/beA<10%��qua�%fi���($�A�nd&o$Qb^?H,s�B�_c&�\)��"�Sd�IiKIK+dua��aP �d of ±� va�Nq goodѝ�F[�1�!�ti��qX����ajF&?��At�wgn�N.�uK!�h�#m!�� �8�t�. F� BALB/'w�<–12 wk; Harlan,"'c-Da�ton�y��� m!�Z�g D-gals~s%�!X]it�+%yn�b�.�H(.ii6: u%��er �ly� L �!��6�&*aEr"qS�q:@ i �>�p|�Sa� monij� . ViQ"�D�@�~�+7 wA0asՐ� C�wk.c�4�(�O�P� !L2����(aMLog-Rar.a�w�)ar3�=�rtk�D#�1�$&yY�5q  PyMo��wwr� pymo�/orƐ.��U�1��4�&l�b"ng�� cycl}pro(�- AN�X��plurit�m;s guarY�^ q�safҎ�J�eie Embryo � ?( ESCu ��t��st �%Ia�.rt G1] sAU߁wnueA��D3$� �Lor`w�#č��t�8s naïv���cEyhol%Q��d�W�06can�al Wnt/EYatZJ[}��Cs mESC=Wcy"�'WvH^&:cf��&K&i�3Ea��:og=ofyX-{s uq�. Hwe!k���'eX-.�1!urecrui�toE*trigg� �-�Ink4/Arf�x2� or l�);U'���� W�at%B, a34mit�ic5^'�"ic tiss8R��s U?A�d�,�l �/65,A����'urba:ycb�Tcf^ �(�)%�R6* pcZic(0�i�!,pro�4ʈ=���!3�A�:�85!`b , p16 �p19!s�*�UdAaJ2t��vI�e��me�.�:e#e�),F�5�]�I�1.�qSs:t2�gH{A/�!�e)�5M�� A�A ^ !�U��6�!���C� non-�/�bfun&�"�7Tcf�2�/. :` ��pl��g�"��6N~L I�Jeosta�U�cGBrs 6-b��8.0rubin-3'-oxim�BIO )4� bHIR99021ϋ:-� b��%��o9Stc*toK� ze.�V ��9Zen�'A �X�,�Y!�acJ�����:N5m� /lymphoid�>r  (a� /Lef�az�c^il��Mle"��Apf|!�LDrosophila melanogas�a Caenorhab�Zs��g�!EMurSO���DLe�K�CATcf4 ex�Wa����x�7A�v+]i���5&�in��ah9?m).��;%�e(8��#�s�� dundv2<!�.@%Q�A�.g/ ��� �S� ed27i��� t��[�v11�� MAaIH2���mofe�t�1-w����I ! network��8[1�� �t 7!Z \N� �;� �Z�Fq��=fo���.i%!4�cy�.g�*1����>��v�a�A{Q2.R�!�nF Tc6�-seY*2d�!�ef U~�L�'��ext�Z�&�b���,�Q��*� ,1!��82� "` �Ies�&6`[���7�l3 4|M� b c-My�$ d Cy#  D1��M�H";2�/� &� � 1� �r ��F|i?�Aj=%1�I�< 8 �}�A "B P%i.,&' ly��& �5���9$6)y a un��E���u�� �*�?��W2�� ,��#e�<Na� S phPA� veryA~hG2 !����qY�4.�v .( �6�"�� w: I-D-@�*Kin�I"u�;��KI� �!�� ͭ��pJ  8-Irp19 �FCIP1/KIPBJ21Cip� p27K !p5 2�r+�F@�s [�fi� � enco�0N�EA�D7�^���3t`�&IDQ F ��ong� �� �)Cip/Kip>�vs� downIq6Yby"��a� CDK-a;S6�6x�OJ< 6-B Ki�Mdm2 E3&x  ��o��m t@ p535A���F�^� CDKI )�)�re��!"=��h�A4tw��n�&>n`A�!�>���s�AA;z�aL*�1���� �vB� �is�Wun39�I���"  Cz*5BIm � &�  �� su&�!��.����A��;A%���!�BAer�sta�GaY[m�':� o=I�b3Ob�A_!� a8%s>}[2�,21n3 �@�eM�� 2 "�in ��D%�M- Cdk2;/y�>6Op21p27C*�!�>9u�jeoQ�i�9ecS�%8!P)�!1%�M�V�� 0 dual role in�q mESCs . Wnt induces the expression of negative regulators of cell cycle; leading to a reduction of cell proliferaDand an increase inunumberqcells`G1 . Furthermore , activaHof8�4pathway result<�downr � � some`( differenti N0genes , while>6,pluripotency -\remains unperturbed . Th bc!� effects are dependent on β-catenin !�mMrrecruitm�$was enrichZt�promoterM!� �)Ssuch aV�0Ink4/Arf locuA}Ar�]�refA];d:�Z�w��$tumour supE�A�,Cdkn2a ( p16�a , p19�)E�!b!5!4b ) . All togeA� TQ� show that%�H contrast to its mi6nicM*A�somatic�A�� Wnt/]3Q�trigg!{aAG ti-pylvQ~T)�via)�eHdity . We performed comparae�!�8 target analysi%��two most1�edXVG,1%l1 i�c��eE�0a palindromic2�MUe�� !�$already de�q��WRE . Ma��e peak!. 95% ) wer)in 3 . E�distanceYTSS4|BIe monguse!JE(%ein ±Lkb  ITE�$, 40% corre�d �B_!c27%a0 intra� M�C�ujar�+18J"��ain%�a�12 %Zat�kbV�&��PI�M�i d up�2100 whe ��e ����extH%��EM!�!0 ( S2}�Im�wantEO>���#�2�!Y Cdx1)�i�ifis.�5fD2S1A%�)| �a�re valid��by��"���qRT-PCR�#E%� Next�~ llow�@ reverse strategy!F(link a listA�g� w�B!$2Q,al machinery e u��(En� r An�� Tool [36]ddeterm�& hich6V��a��1S ��� ]s�K>�:&an un)�2� � �P "v a� m� $o Gapdh ��S2A5�In addi%�%�EA�a6�z�prote� % al= %j* stabiliz.i� ���!�Lor CHIR99021 for 48h1:� 6' short-��Q M�!@Q di[t chang�-M -�Ecy mark�s� ,aYexpec�[3�[aX%��Y$like c-Myc%� Cyclin D1!d�O MM�%A��l!�ak �&(�a variet��$adult stem��6��)no]�ed9uN~."I a�H��~ d: ]�,k4 family me,�h���in1�G�SiVI� [27]%:��is �toU[,e p53 [26 , =�6�in agreE�A&1pdq+e�JeuR)53&PS��"�p21Cip�q.nuclear& ract���Ba5 dayi�� � X .�-A|ce� 4$ ��Overall�se�a�At.��iio� � s bea�!�toş%�|%�� re�9 ��AUq���Aؕ. SeU slow%N!�irE�� rr��.zupo��d:@ane9!���\���d�R> "_or��AY�?)��belie�= to b:f!�or� r�i�� CDKi�Vc[2�*24AHow1aw t ha ceb: h�C ��>�p21�27 U��length�a��z-Oth!k6z[33�Thu exaSd i�:?couldq�e d6P.�inued WT$� retroviruS q�ng mouse9.ore���C�S2&� A�G)5r9��$����l��2d�!t� �m S2G�aa' 6�a���EdU���nd � oun�%�w:� EdU+0$a�clo9�ngQ�^in 4 oud6/+ exogenous9-M5 2*5 2�w confi�'% � GE�S2F5%Al*�tT data��� I�*_ ^�a�^� 4"? a��!M�a�:�.J�2���$is necessai� main�0 self-renewaln2k; s [W3Xy��-is� a.�ve A�al�int� 0, hair follic 0nd hematopoie�F239–417/an oncAic iniyor] aberr�-D�n!ce���66�.HavA�*�V�asr �ua�����afaD�N�!D!)JVon)�morphv,.Go�q|Ei progS.=��re cultuW @under feeder-freeA�I ��Leukemi�Ty� ( LI�!hserum eD2�Wnt3a��Q �is� Aefully�AS ed.i ( S3AXS3.)� � ��H�Sp5��-�S@C  dose-&manner�n � U��H 5% DMSO ,�as�q&� vehE�,���e�" � � by alk^$e phosphat�( AP )!,�m��, nei a�ed g6���3} A�3� �X��5�!�,Ns � pack�lon! 1�(!�mooth b�� � ] -�}, a� Ser9c.�1(b^uI[42a�%Qc� �i�I|�*[mediumI�smaller!�.pa�>R��z�� rugsB�sig�s �� total�4�� 300 ng/m3ai<6w2 48E^72 hours�  on 15^D-���&o,%9�3�!��� �aa� �P2�3 μMcAS*�M�Wnt}\��m�%�6�or2Qapopto . No2[q>?#���vi�Dty� Annexin-Vy0��"�in!-%��ma�#�!exclud�occurrP�F�a�43&4I*� ,���X(BrdU-labellm�! A�or�EU�Q�:e M*f !xs)��.�dz MV�8 T%` ť��+LIF+!R , ~ 55% J%U1 S ph��.*5adminieM5>�}ol��a�M�l:g,E%cau�accumd f �inL �= 3& u$fr�� 62 % simi�I E]%�IYZ�0unU�%� ��J�G1_ refl�hG &� �r_w index , [A�(+G2M ) /G0G+ of!�:� �i>�- To f�"]!�oTw�tro9�Fluoresce: UbiquitinPs C�In^%orrUCCI )" oMp[4� e sy?pr deŮ �frt visu�% p��)�Q�AsU)ae�=�.MI�in bas��o&B as!�a�{ax�E���!� u[4.>g!�Y p� !�G1 C9" er ly UJ�oZ^ ���&�-�FE�S3H��2� %=���ZoA��P"�L"�d= i3)�T��$B�ݣ�"%Q�< O(a*�$ "� �R�o�"6��j�)� ��5by%2�I�-��~3p "@detri*; 2� giv� at �r]g�x"?$�B�G[3� 31e "!#7�� ��?���%�A�� mc�2^w*� )*E�>� 8 passagE'{)9 ��hem�pop��D t each9I�MNŔ���&�[am.Ixa�re-pl�o calck� growth !!%H9 doub��time .!3:|aAet�266`durq�=I.4� ��6k���"1�%U i� %� ŏ to 1{ 26{ "g>(n>�:�,�)�Fiv�� �- .� �� F� �a}�Iq<�+G,o&�,Ude%g v�S4&\Aa�E^ 8q.�,A� � pEF.&quanta)ve "f#p#�S:� �� A:e& .I����l �'��Rex�'�a���)�.� a�e :�a2� �of�#{'^&�,, Fgf5 , Pax�Otx2Foxa2z Sox7 �6� 9�M)6�M\� e"�&�� %,bye�aG8��" %A^&� ��o�:rY����!Hm�!�yy68�2&(�, T ,�,&F$Eomes ) [3A�45W qual�� 6cm)^�E�x. PJP69or Esrr{'��.[l.{'A�%�>sli�#� E��"0chٹ demo��y�(��)za robust�d��46)3 x Sox25�!{4h%$.S whe`�:�oneHn e�!��of.(�2-S'� m>�:�umE�e%A�e�:A��. al.pA��A�( No- ��16V( 8'+ 8)a)�veb-to���!g(%= prof�1� o N$ . �th��chad n`�EG�� ( S4$4 B *� �$�at6GE�q�$� �@ "_  �śre�&�&x �^A126�,�it doe4t�0=32�*�6�e$ler�6Ud�%�2�> ,mesoendodermB�(�!T%�,�!of�`� V�E"!�)����6, appea�as un�&d�����H6;A�-���F:|/l�-�_���  to ��~� limit��.[1�o.�ыobRO6%�#e�dueb7 an!: to o��;-��A�u�subRes [47+we%��Oh 5�e �QngT\%�(f/s-  –O�/s*�(qx.� V#6�*^0N=/& ��52���655e5� L�"!���/"�, �-OE)�v"Ond��6ns� >3as2� WT%�� -5� Also�&!�s� 6qQ�over )�� � TF�m�*Fzb����)P��4��qe& z�>6�:C-1.� �#o. �DŐ�U� 5VX�ed���)�n>Qin"- �in pa["e�Us��>)�� �( S5A%��A6�&in.!KJWTm&6W.�Q�Q& �q' ��� "�"&�$-a]��noy dB�:���2!*> ^!,AKstitu �1�)�e�ia rr� �a9u> "n��M�m�!*�)� v1 /��!e>%B���� ��I��ire.��&�7�losW�.�e�s� �-1Knock-� ( K`.� �%a��IJ�%�/( Zfl/flp%.lO H(Δ/Δi 48]ySi���6���+W�Y)3)�"�by FAC�5KD-Y *&1ofa�j5���)���5��R ��; .�=s!��=d1<i�6du��AU9�� 6d =ais N2 $$!�"o��� .� .x5�P*�d%=e&ofrin.�KO%�KD��6�> � ono6�B"�&3.�& �=!�p18��c>�a8e�>�"��!sM>!�S52Q�)5"�.CN�.2<!P� ��m�G�;8!ADE`�r�m)O��5�.�:�>6�6RFm!M�)f,2&� 6�@�!�ASWed abov�J�J)� J ſ�$��1A�m�(&�#.WA�a-/M`H? More� )���:#��18aA�,*� �+%��2�%Y\� ��-fV�)*� m>�orm?Ş� � &� �-��Q�+�&!�n� ��!&�"&&���V�/IF4Wn.�"V u����eL���� ( sh!L� 9���RNA� � by 70%!�6&� D"�6GJ),impaiU!36(&� &e[��e�c4hScrmb- d.�a�i3]"�C��no"�c���B�jj�""��J�(&�"6\"�(!��inm> A`!�v��x�o6� ( S6& 6�3��լ}! ,6���%�R 2 M!6|-A{D.� !T� 7D1��Ad .. � @CRISPR/Cas9 technq*t��ng%B6Sz� �. Dele%�qiQ�a� 2��.fum!�HG"�4A�$�astI6anBM! [59A%E���A� 24h ���5q�A0!�� �(0�6�a��ȩ�6�In��Cuenh:">��+llܥ�.t  F�7~ ��i��a�6��.I � n�-B%NS6&f N� 2� R.d3 6����s . Fi� D\!�]�&l!fI�.Da.@[51j7S7"(�� -fol&�,!�T sgRNATcf7M-,�#6 q<ny� ALQ�o2�1A-"�*[�J ���Ui*�'�� �2e� �ESe�*"N#by%�>&9io�1%=u�5a}E�o��9B�X �H�Wn���4r~ 2v�s�Dg��:z� .��^"�sampl�"}�o�%ʡ�Z�>a Z�*�:N��~a��ߥ��.�qAM��T#v�1�=P5���LcoDF�(�� �6N�* rr main��8 play�:YW*� ��4> i�W&�5 %�r.�5carry��KD���&l5. S�M�Hf% �A*i�Bt��@��������)d7�  -}� [2�=ly L2� 48�#�)c!��!��rh�72� 4�&~!�"� q \�h5,a�H)n.6� ��AA�cu�af=� ve phenot� !.�p lKD9� �atBN�M�� a�;��}�5cNO2�69��U*����Ymabolish-6t 67�..o� )|ZI�at�guujmk!m~e.at>�c�+U�. Our f~ngi ����qMd2J6��5EO*���� t&�U��!W!:.�qPX� 9)no�Z K.Boq,6�Rj qku to��O�$!2JR� &z ,O�<&��2�)diverg%RV�AL.�5�M��}.&�i�J�sh(earvelop �A�>\Mz two-E�$stage [52]B.il$pre-implannP blastocys�Q�,becomA�M�ed� post6=[h8Inmul��tbov%Jembryo��ectopic�a�:"� qs d�M�� ��El�8:�Pa���BEStP"B4[5" A����iE�>;.o.F5�. Giv�+!�-�Z��Ns �"6�E�9y��Z *�d �I�it.B4sm2~,%e� asonCto hypl sisJi8 �A�*�*.�8-�AOIF=�E&|�ca�L�)u3i�7E�masR6P!P9$tAcF�R6�t"H�A�commitA�]"I�O�p�M��-á9 .� �.Uv pur%N �d�+A�Q�J]G"�D*l. W�W!�Aa�s;I�^�C� &3%, �K��.conce�U1�150 7"%�:Q�>� �/ls!~J�S1�R�-eiis�D��Y#!dfa�J�hig"nF6v6��*nee� in orQ;fV��]!`�>�n�\6�Gm NDK6&VLowD .6��,aJb00–&28,&Q0suffici�N.�$F�9M�enough7-�)�s!�!YA�� E�a CDK/-�"� x:&"  7> 6� CDKIj.* )~Eřon� j< l6�(�. ��>�� "y��epa�C��BX1u�2BALA� brakPTJ`Ke�KCWA�$��%)i , key.Kee�r"�� !�}Es�6�X"��J �!�rG��'� aA� long�:�06��� coup!�wit�4�B��Vc�[%}%=o���� um6]"D afm�}'"uJG 2�I. P�Gż 73���a'h\re>*!Ew-���U*Xed .$E��a�studybver ��F Uw�se8r�Tt~r vid".�)cazA*zEl� < w� :cf����six�V7lY�2�����Z d2` �{�� .}5/�#I�A��*bmi�.sI|,'Acer2  circum![c��iiM� e me�*ism?� alsen��v�)�] �,��vi� rE f?./&�a�  ��8& �Ms�G"�\e�&�No@��.!��I!A�9inD1 [C%i^' stri�I��G'" �P6p"A^7-��n5� ���2�\ �++e�^�J�I��I".0��oppositeA�cx1oa�J =^�.��:����d��m��u��aE<��>�lK�KB�O �I8h�6�*�,}�K�Rx!)i"�QHre��sL9��[5�:W iAbe^ lb9fiw>� j�?.�=�..JJ��rOJ�*�R d�nSL2wi dorm�-s�8�[55] poi�H��!6%a$�L:�M,!�tM�!3� B *aFr*eS�WSW�� a� o`_RE &.�it 'V�Koiso�,�)�J�K.�\ lterHve C/G-�Y�A?a��s [9 , 59GF2p,!@i)���5x shar�1s{9�c%l(KAISO/ZBTB3y"$adipocyte-"� Q�s [57]�DYRK1Aa glioma)�' [5�H6� !n:�H!�� Tcf4Toligode ^��reQ�@M�>P!�5A�r[3 759]�.dW>9d "~m &� "(A;1�domb(�7M�0.. �A4mV*��!Mڡ��^-�-w. TakAini c�'x?�La .��A��Vbe yjV ursu&�7&�!eRn aB5%S/Ehcoda+6�Lv Uiit:p&� volu_��M metazoan��&�J4Ngrga�1� a�+aC_9�%Domponen* }N�hoJm 1��R"ly �! rtebK �alyEe� C[9�=HA�wI��w&x!t*2RdU!UJtZ@OI�U� "Auk2&�.q�dWs� f"UL, �gYa�a*�a.EB�#%�"7B# cbW9�.�� 6� !*�W�'�2*�/S')STcfffL  e�d�V�a�}%?ext��)�d�A�*'&6< AC��.c86�2��:�*'M*�opReE�a�Ahst�9Q�� � exertpdCed]� v%>�U� de�U��q 2�Qk� oj!R6���6*Nn]"[N�,"�� �9{�� ��:2daW��cla�qIt�Om�.�V�!.t all ��kj1&~broad�:sP[�/[6�6!K&. 1��/5e 1l%�{7ly1m�Q� ] �a��![|r*�i<aA�NO=q��3*�3^:�v.e� 2�� k"(1-f TCF1�A mic�;a� *`P��[�f��eta ic thy�e lymphomas=U,'��%K  [>2 s�I.�f4no�,Ih)� �.3C s)B�melan�!� ma [6�A6�  RjE14Tg2tTylSm�Qa��rP on g�3in-�7V,Max 0 . 1% G  S�.D, ES-006-B; Millipm6 ) co�2CEDMEBL@41965–039 Gibco�hfOfe�D��' igma#,2 mM L-gluta�U ( 2503A� 024;.MX LJm�>s�i�dN�mIo acidk!�p2l�z32fU�M) /ptomyc $( 151401222�009MLβ-Mercaptoethanol (o!��FjNrbin� m� ( 31!�20; Pe�ch ) ;l@( 361550; Calbioc�E&� #71:#5E%%+��sp�g�A( Q1umk���alEK(�)Z68 10Ab(gcl](2���.~nl�μL*/ manu�Kurer ihw2c FX�jdX�&,f@tiviral�8tic7$%prjKfola/he6,��r�qce� sortH@ ( TR2y�(l�26f `�A��in 6-�Mm�4( http://www .ɻc8� $org/rnai/pGc/ A�Brief}'85 ×105 HEK293T��s/a�s����:w� da#���N/c*�&o-�{�Yw� 1 µ�q�#1usA3st!� , 750((pCMV-dR8 . �!2.VSV-GDF Polyl� ( Qi �� ��)�!�5u�U �Rrm�=%W@90A3:,%n )Z4".Q!)M?� ��6�^�bb�(5c58alJ�G�har���j9 �%� at 4�D7�5 96 hk!D)fi�9 !|add/2��aD6]Y�Esn�wasjstw:in PBS]-K-an2l1�. Ly*c�Duct�N���Jd�#D�\$( PIGΔRI- (nc�)I��o�p�N�h$Scott LowedManuel S�Xo laborIvI. R�&�NI�J� � �o&�!}(( pLPC-puro�,2�%v�^�� �l!�2a�!6oin [67��6&�trypsAR��Y�glin�Vin�. ldehydeAu,room tempera��!�in"@�MA�sA,�: 25 M gl  >5xmp�SA�I��lC� ml �buB$ �s� 5 7  BioruprN QD�DodVr�����A� solu�AmakWal ��Jfo ��BradfordL�a'=>t�:aB'w�5�gA��(!!�2. Antibo��incub�%9�Nc"�tAgn<�J �*lB A�m�3S �{A�GI;rLF bead slurM�! V&�t.>."�/�MMlow-salt.�\# �F 2#.}:��&osQ�at 65°C%�3 h   =��� A� duplA�a�� remo�d)�Rmdup�Samto0� sN�\]u�.2SAMfpQV!�con&�JB( �Picard=E�.� U io/p-�.�aw79�subD& to ArrayE�8 : ExIB2�"S~8: E-MTAB-4358 PYvUc�\d �GE�-)groupA�csail�Nit�K$du/cgs/gem� [65]��� ��vZ�'alqthm��X �4�$i�-value���s -log1A�"I AS�$default noE(�rib� mode�W �[edc5 d U}�&�uE3m�g���5(%1!�\i]�E�:al-to- �r���$Ti�!�A@� �S� i�ba�on��e�)[1ir�all.��.�.at�%�K���z� REf�{R ��a)�$#:gi~�x?( ±2�{, THxIionside� �qC]�)2� ck 2�Y� IGV�he �2g!Qve�롥Viewer���s� logy% a3H%�!tUsne!�J;!/ext�MAtnd�@1MaxtT�+3>a)Promega ��{!��.�’�t E8�c��|�EPSuperS�� III RO se T"� �&k�k ( Life Te�9� ):�p`�1 μg mХ�l-�2�T�rs�X� 3 ng4 ���se�m�tri���WabSYBR Gr�iI Mas�Mix ( R� )� Pl�pum..E�%Mix-UD&T��s�(�N>L7 �"er ax6a�TBS) �. I҄ɶ&8I�]�[I�S�]������,Dura HRP Det��on�[ Pier� !�Jr��!�:�ӆS.�;L,( Ab80 Abcam"�?(>2PHE(+ �0BD:V;�'j 6243>H@q(6 Pharmigenyc'6764>5β-� ab82�ta �. K�4le-guidd s�=�+1 [5’-TGCCGCAGCTGGACTCGGG-3’] !� ,027 / GCTCCGGAG7GTGGGTA 0a�< �WA�f�{Hthird exu(� ( +1 nd +bbATGL2�!�)`d�l$�{$Sp C8( BB ) -2A-Puroa� X459u�� #Mo:a�Sa1Xy�24�;)(� puro\�-A�was Wl� a+a&PNal;&j�= �Aspl�5�4=�il de�,�C�q�)�.�� azGpi`v9k� aJern��t�!�6�"%�. �X� gif>�$Feng ZhangaDdd� �(smid # 4813!�[6|(6�>W@'( echi�tby�T) talyL %�a �(E( d) fe� to 4�!etv2Jz� 6142S�. pCF82�"p� hEF1a-�R�E4A//SV40��R���"[beta]dq,�1!�*h�qorylaI#a-2�$S33A , S37T41`WS45�A�+-�backb;pRRLSIN[#AE ) �E�u�a"Wus*�q8�/ R1�US�>�,M[_�"��!�re1�?���=� l��a�~�4|s Tsi/3ti�͎U�wgr&�4l͆di�!�Z�s!ya��"�U!� �2^%DA��,qdonɴX�th curď"Rs�Q>� Roel NussV�24313�!a� cou�+by�v�%ome 2���ЃEi�( u�lly"�e2+.($���00ms�  6�&%�{ �approprE@d��e&�t� �"*r2ˀ! init >:��!�|�d*k4"]>CyY��%7�&� �4-iV�μG s�#�sa��#!4% �a�ue��& $NNeubau&oham �.N��7�M�Zq4�u"�swA�u_&B ropiciod) �o� ct d�A#AqD U e�%��"96�!A�%>"3�ca�O�ac�9 �*r!osNali�xdqTa�!or�!V r�)) �1�.ak!�&$���tE *o����uPE"Nk d multipl�Z>?<�%tW&"`0d!Oa�fԕ!bExx/-e�-�|setU�?%� rg�>�-��ayIp�!8� p�( ga���I2Fl6q;( d�Y��he,��Qwoj� unle�5"�'in figur�vgeny����:E2bpulse-l�tq�10�YrdUE_$H�s-�f&�abU te Eh)A�atk7st"�l�� >tn�� PBS+�[5%BSAMۉ��(��� AfoftsK,pra8=�es($( 1ml = 70��of��7aw$+���25%HCL�K�ga�>�U2@:_!(6� �T��-2�!�&tZ�y:Mb-%� bod(. %+ FITC�1 is�I��6*�n�, 5560 ;e dark�)��2���22 �!�aq:�P��I���3V`at RT6fE �8j by f"cy��$ ModF�4�f����h"� ��~@!�,2u�� ad�=a�ppn�F�)��b�G2/M p�@f d�=Z�p�C9G0/"�h( 2v�RvI ��'N'Non-syn,$n� �8(5-ethynyl-2<�� urid$H(�d�iF;A40–I�6�a 4%PF�r 1.^M�e�@2E��)�<permea� *�2�rt�#`#��6Q���A;Click-IT�555 Ima� $�7 vealincorp(���0%|(L� facturer�B�� 2� BcV�.?U��1A��M���.%D*Q�$0 or 3�IO &� !44μg/mL6�colAaAe�a� y 6&a*ea�F)�8ha'nat}/<. i�,�E-3< �v"�( 2x D�� k . 1x106 S�%2]1uL�)!�4BD Horizon Fix�V"}S�  66;!�.�w)�12J��B�(.�zt1 �+2%FB�!!i(m ryatFr.�l� M�5� ��  C� IW'oXot�histo�%8=UblowJo v!c0.�As5:it�t88ѭ� � �,\�V2�'��%�A�.Kt!�.` "3A5 ,�ZgI kY@tog�6e Ls:�ad9Ej� �pU��h2�sedOx *:fun!�]� �.�0� �*ofAt<�*�� Fs�SubT,W�l&� -APC7i8�<"�-T3�m*.ot/ly vort�g�-́���1 !�z� e��, DAPI�2YU�imtW�aI�R R��o���!q_1K. ��I�$�Denguea�z�&�%tхA�liimanife��$�$may��y�� asym57)�=[�.e�$fM fe�� Plasma� 0kage/hemorrha�y!;be��:%k�stormaGuLFby mo.�6d�?i�7A s?Nd ��� ( DENV )�iR!u�!�id1d.H( pDCA�}innQ%E,��!�:�a nexposG 4secrete IFN-α1�" TRAIL) 6We ai��k�$ri#�DCFA�!W �patf�t�%�=�F!-2 stim�f ?v�6:&!me� E�5 ( FC��ta� E%�bc>�ex� �ifi�ly�A�ebX�� �c-�e��A ?� or healtht O 2Gve=_���T)M)�KK�Jo>��>�%;r�l�֥�:�.%%.B@A��?in-fUto1�F-M!�onf>����'m�! scop)bl%y)�6reloc�=|3i�Oa.�?) zeY��'loroqua�� B)�Qed �"�F �v�{a.-���by � EndoVGlaD��'d ;3!ade.c��)�6igen.2t�i�(bA8A�J�!�dI fav�-aA�" =&�=by �!�A"4 �EDC/ie-"���uAaij�30$$5ut�-a|\ is>�<'inf!��=�? #o &#�-�9�`u�*��OA})Sloa�Il_1<DQ">eb:��=�T�&=@�ch��p�S)3�(� .F?�meEvoEE��!� ��e!tr���pw�8p!�e -q^ng T���L���Nn outJ!�dis%�. �Ei&?�&�DLarthropod-borne emer� �F� �� �2�R�)�morbid�0a< risk�morta�0[15jђplQ �[ razi�&��i��ma�Yv9�T!�bl3�#b^-*2ll!���� "�L-�201$2012 [o@-���mzsingle-s� dedO+ (2��$genus Flav!�us��, [�>e�A) ser^��-1�� -4 )%ϩP �QA�Y.~��Z�" "�,2��"�ӌ64 %Y� ck sy-HmxHfW[�[�6H{TI!eqA�c���exacer<5�� }j�d�[!�/RqA� gene:-#Y�physio��oF�[8�=Fu�&��/macrop� �>| �Tsus2�.to �?x [10b1��[1wX[[S relen��F mDinvol��a�asc��&OtZ���lei  be�.s�@"�Bdis�U�n�[1)��N[1%�D:\ L8 � adapK y��ey5� shap�z�b}2K0,l��^%i� subp"Ƅs%W":�: myel� or�v�:�#:� c� �.��cyt:>�(� ) [1)�19%��T[2�jI*Œ� \,9��F�Tin homeo< c tissues;V�>�UVQ�-g��oȅ� {Cid8~ , [2I(2<[Despit!�!VrAx��Y�1i"ř�YAtem�Bͳt����"� [2��V�?*!�:n� �G�%���C�kToll-v�rea3A�( TLR�&TLR-7!� 9 [2E��U�&b1sLa�pat�%recog�{.]PR]p0[26�'($[2|&��I�ts �E� n!4tAY�efBXly�� �Aw����.b+cDC�,u��[2I2�~oF�un%'Ms6 P�� %�!A�q��@��N!ex�.�[3�iI�H!��-�@ ���XE(, somal %q�!�7!�)�[G�Fur�REw,azgue&# "� ��"�m� !�Հ0.d7I"��3blaI=�a d [3i=�!�� l"@ �m[}�?��. TNF- S ��� !_ligVUB�)�� pro- -�molecu�I��� l{�E1�  d ."DA� , DR]?DR5@O��7�>5 �q�s d!`by�?N type���FS�C``an�ɗ�1 B DP�W� �!3.�,�k| nga0u!_�#�E%!b leav!intac7rA� [�\ , [3e<A�n�).*"=D!ww4 �r$ jENVY���~>6�# � ed��J��Y [w���J�"6[4e�1j 1( s o2�\ sera� � uC[ ��\�olF #,"u3&� ���UDC�CzJ�8��&� ed y<6�YU`�Wa �3�+A}� b%4� ���3 /o!(&A� �,zVy�m��x ac�a0DF �s�� �A/*j �~)GA@m �}�O�=�����/*1*  "� si3<W�@ �A�EB22L �q�%d���on!B�)*�)"Mp SA�2���to�,�ta9V! /r*J�E�0� Q,&�>gdQ1�:^��%=�2� !j+ ��-�)!��c-[!5AgF hZ�defenseA�<�-.n�l!,[!$%V�P�ZA��&ne����Q-. E"L'�HD3du�U<hR ɩ~en�&� ,by Necker Ho� �th)CTc� Iresearc�q%�don�w:�(European Un!+�0_-���De�Oq(of Helsinki&��8b.�?e �c�QI ��% Pesquis�ci�s Eva Chaga� DFIOCRUZ ( CAAE 372��Z0 9-0@+����@ed�=wA�g�]wr�d� Mo-0HIV-1-`"�[)� bank!U� a60- nonyV<�T “E*+iss��França}&h2g��(A�� 4 # 07/CABANEL/ �1 Pari% raB8Fo6��e@�*ir�� f?�(-�n ian HT CenC(at Campo Gr�U , MH� Goyta , RJ$)f%y���:��rcd&IdiagnbWR�.H �!na�G=���no warff W��oPvA�"�:��&H2L}6{!]WS>�if9��}r� |�E �s:�$�bd�i��o or t�M rness; ( �-per:,�vomitingR+m3l��id|:u�#uco�� blee#5 ) lmOrgy�lCk en1��mo�lan 2 cm�*ͺt*HIy�-a�+ER�]��}Tcr{E HCT �Pn+�t��rape�5!elep�$,(Go2�9!(!�I^t6)>Xbe!��:5:/mm!R. SI,DFf���]% .!�2–7�)plu�A ��5�1�E=a��� ��9u��s�wn^: essi:�r��!at)Ze M�w2+; pleuY effu� sUascites;�al3Mm 4?Ba4@hock ( tachycardi��c�u�<clammy�:eA��capill9ref�Z�gK"eXBa(reeond�� weakoun�;c�*e �( , narrow a[s@or�9 �< ��bre�ޅ⩤1) A�aLS* ��2a�Eq .M�dSn������g�� ��� -IgM ELIS1�C@ ~A�� �@"5-polymer�@ch��9��/�)!by�s�=!2L�nierL�Pre�int�sʼn���> K2R@F±WS ( N = 1")!�y a:` M1ZRVծB��. @ �%/2� tr! Th�G,nd/16681/198�� [45]ou� �)�� Apa�6  lsew&" [ �.d5Aed lbopict�Pell�1 C6/3�6CRL-1W$, ATC3R�D� r$ t 28�>!M ulbecco's�E)dEagle MzU�T/F}', Fosa=CN, CAMUSA� ���?b9Gbo��/-Aldrich�3t�Oou@ MO , B!�l��d,5% RoVHy�6$(og�=U�� �,"@&V�" V2�V&IV�&�=�5n�.VvV�10�0t��4| br�� �( )�%� mono�s%�i��� ].�*O$�#&=$8��{A�cyt4ic�cec�?"N. A�6)� rI��C"7 n9l}EF�@0!)� gE�1Rnd�/�aLt olume 20�ts ����2cAseei�A�ND�be� ҡ��0�a�/N"�11/!� |XiG�m1(5hU�ji)��S�,Cry�O�&Kph�m�)a'�Ea�( PBM�( ��*z"do� X U�.�5 grad#>D' of h��i�,�%�;d �B!*P%� Stem�+ 2�G, Gren��-� �#e"uM>Y�uqfresh ��^�0J� �.� Ak�{Ax�$n� bL�. P '!^���p �L �Kid DC NQ�I��K�> 1CD14+[6(Bo�V;V%!Q ��pRPMI 164a�In%M�0Ga_�sburgD�Nai�5��rD)%1%�3at 37�Sa�i�L5% CO21 m�62wJ�B ocol�!�ly�0%��E���� 8�K�(MOI 4a�2��m q186( ovenD%\*�#͢����at 5 µM�YA3�)<+'.�&2W)ٜ:Ƒ�3; DE."�":�*u2��d��Xsl�IN3D.t. S*v+�sto�&at −70!�7A��� a�. M�(�Cy�<2B�B� e�lyy�>l �5�� e, ��:�!�CR%�or� .-Y"�|ܶXVy5�h ��KL�Mr"o^ , Piscata:�, N;H !)�UV2 �!E�H00 IU"/�8aut� ��c���0�k,>U�9ze� mean�O}$Y�-*%A))AXt+6Q�5u%_ CpG A 221? �R voGe$Han Diego6� q!�y�!�e} ypYU���)0:�  I!㉇�)z�/� 1∶5/YX=�lai���f/T�Kj�2���%�'�P"#Xa="b�e� sothiocya� a6) -cony6CD123!"BDCA-2�\nyis.(tec , Aubur!�*0, Phycoerythr�FPʂ-��[ CD11%V(IOTest/Beck# Coul� , Marseil��,�$opZ�X�.J�B�4J�)�Al2H-Cy7 �C JP� &e/./,o Jos+ �VioBKJEA>9�V5��ti-CD3Fe�E��=]>���-m���-*8?(Ay5 m�3D3"J 3.�[2z� )1�a EDTA[Ő;� "�U�/y i�1��20'3�UM �I�8�M0}�5�8A�c!fldҁ2.�/ry ac i�ݡ� �3 ACSC�27�wor60 Aria��co.VPg @ Diva&�2B�$D3− CD4+A�4 123+/E�2+iU 4+ g9.ptes14 .^ f surface�� �PE"�;!S-�R�Mo-tok }}%e%�.�-|%�PBS-1%6=f albuO�M66��7a7ML"� ���(-lexi��f, B� ric4M&���h: Qg�ZM4e Alexa��64a�M !arP7 bes/F#I�f�<� Fl�-Z� "�4�U� '&� Yq)�2%�xB"_91.KgpNjsteps �. AQapo�S�g42� f0�7by C6 Cya;e�Ag�i/B>�L. �0Jo.�Tre�2+ Ashlap , OR"� ab~ t@,alyze2;ry .2�P n �-L-��ne=(c8 w%�)�in�Bpar^U, JL` M*Q6i2�8%oY��q&S:iS'�G�O?R�E�I�!�u� RIK-��e�5�_�^*�� Ca/�WL( D3-2H2-9-2�'Miq;����3US� "�I�aLudon^)� xIgG-Cy�� Jack�vPR!,�L Gr�, Py�. Nucle�V��"];�5(��� u37M�sc_��Iha Nikon Eclipse 90i Upright&s Af '@rum/r��q0adhoevedorp ,�6 N'8A��41/10!TLPlan Apo VC piezo ob�^�( NA 7`!�Ch'�Ef fK a�ET-%, !e�� �.�7de"]�@� MeinT�"\h8 �`{ �*n�)e��A�Metam��!|DS��M>Wiăsha�KET1�l�b�:Mc� ENV/�/JY�BmageJ!IH!Y!Fsd��&�plugin Dp!e��plo�bh-�yA�ck�QTekI�.� `nt��MRE'!�-2�U�W)��vmea)-label�(>eJ%�m�S�M!"��M�M��� cetY!A��G2�i�ωN7� -1%2�mF�,��F�AC�7E�5 a��2�fr488AY�r. S%,mm�` ProLong G� A^�Y!f*�\(at Evosfl M�5�AMMj Both�, W.�SupkabJbDCs*� 6��$.#�!>-~�>@�wo�c&s&�"�-"0%* m�G�1� �/(by-N1)6�E�**m'�rSi�<.�� sma H�����iZ�R&D\�M�Lapr�� N�T�&�$M� repe "UFf%��YP v�`�!"�M2�a�":�G 's t�� �0�4�A1nonpar� � |�0� stud� co(�A�A�&� �� d class}tWpreg�ng�(��"�&��[�GmN@p�,&B#�Bl"Nk�8��2*'summa�;_�$. Fz943�enrolz,�%C��s!e�!!�a ��as&YbE�*{#%��#$�( )$d7C I�"a, WHO�#=o�,x�I�"�e�������!�=���f�Wch&8�/�−x/423+\f2<y�gJ�[ 09F�_�to�h�%�0<(�J�A.�by�1�|�4�s���2 R�AvW�s rY�IX 2� 8%Abper�x� .@+"Fnr��>�A���, � u q�UL9B'W�kn� *J-.��<�P%E�>v.��� ��Q�E�ca�=���+rxh� �� bt�) : u�"�ei�AF��'though Ua��-a_Eeͦp32 a.r�2N ort ag Z4�# ;E��ois�N!RnIr? �!�1W� xt s�Uct>S f�݅a�&� �l�1A�������S&\6%�ݛ�. S�ly!H�::�m�o&�-F9�@�:er ��@ �~r�DE�"�3"����E.Ab�� {%'�5��Si��r $a�3��p&�b)o�I5:%_ `u0��q&vo6�*�0 �eli��o"�B#8i ��|ng Iv>�& Q��F�1��lev�l1�7�:(Otoz�JJE%�Mo"Ϥac.&vGN�.�� ��c5cd}N�601�0�)�.�>1�*�(, �-�w�1�is!Ս�as"*e��+2RBw2� ��� pZ�-6�a��?ndFo�@C6�t�E�;HP cruc��IK�_'�Mby HTL"=�"o��Q.F�����X���}��ed*u%8�&�i%�w.V�eB-2 _J�>x"w"�)opQ�n��&ؚtj� � )�Aj�����)�F�i+vMC- .�un.��ck-�D��21Z�2cH�Zl�nt*fof1!��A&� .��&&+p(�-rti?z��, s�S�-�ni*L$n&��CA����sA 1� J��A�)? +�G�)A��#�%r;*C� )� (/�,i�$��Ev=�Dp$��as&��atѼ. t�+e� J�&i.�+ B �1W2�i�9enCrdSl5�;� �i^2K�!�t�5by�1oUesqK&V?2� y9�2U��Y�C=��A-2&&�:� ado+�A�!�m�Ѯ:r�YllT " �de'i;-�Ces 0��E� q, "�)Mm��A &� a�E�:7 );!qU�2E%w��h 1%±6� �$(� � !?� )M��37�%�cA %:q!2,*.�>s|p!Kby�(��� �A��?�krmA�&�5s "�%�!�-���wC!9�%n!ک"c�/*� .�Qz/�*/7"��A�it\ o֌H*�� 9PM=n.=�p �um"�c�0 �9�?.--*�)�f�X2fE`=i�0o�� ���E 7�>�3R�pr&3"�{&L"I n ��;> CT1�? �! k�p_ !�� �=p Cm$ sis-F&�G-�YY�i�*�.�-s�=�'BX� pN�9`.6"q���)�BIP{2�&�$0a �3M�taZaG>�#>j6�J!�9!jabrog��!��e$R�9P�]E7*z�Z|F+~)V5��)Z@A-�"� ,�8po4�by-�*�a%-)C�� be BR��dI�� "�?by 3-&iL().N�%�Hٟd=��"�A�ɧƏ2�F�i�N6�9m3� upper pan�M�"-na$}!;m�N� !" �y �L��s�G‘��7,’F�� \� seem!�be &eM����32ra�5�T!"�(UR�middl� �.Fpr"RLB���O 6pX@,�Qif kap�VD�<�s���{,e<of:.=� S~�Ho�C\��.n�m/<;i�=u��6N!�5Q�1&}+��C1�g���J6_*�N'?!�he��Elfe���6��4"t .�RU]csے�L-N �U�M%�F� �Mm x�|��,a�r�"#!|u� , XZ%.YZ-st)qq���&D 9� B– 3a�teR)�X" ]** �@"fa* %�Ouny"%�a�ci�7!���ex 2"F(Ydel��)2).� � b�5L�l"�AIxyti�ic-��_&l!�:�2pA�C.��V�9�C ��� ��ai�O harb�,:2:�A�reǙ �O$Ie}=�E>�6� R 3A–B��� ��A�ez*� R������_R�*C � %M m� �by-R�o*.� k�T�+of96v�N iaS6.�'n& �4d"S��AEG shi�n6f�{6\F!��/:>+UCZVYi�W*� Šal�g >��+-��6�)?27 d �"!0V�"� �re#� O�co-�"N�� .]m�A "�<��r��2W � �M�Gr�C)C�6�q ��CDe�I��Jat"�; ��e^T"u�)R2 :90B 5�8pȋ�T�Taz4�P.� �t6� �2I.���of|al��� . F�r��Yݨ&8env��o"e!) �clc,p'vm�1K=lIqB��,�6 o8 6���}��/!�U�4: �?&E��#wM�+#�-��Ysu>2��I��A2 6�lo�~���4As described a�mbove for TRAIL detection , a 3D interactive surface plot analysis was performed and clearly showed that DENV-2-�co-localized in the cell membrane after 2 hours of stimulat��( figure 4B , upper panel ) . We did not �$ any virusllpDCs , suggesting a complete& al degrad l�within lysosomes either overnight:�middle�or �a �-.�4. However , DE%4particles were-�%&Pside chloroquine-trea �indica� that.+P would probably neutr% aci,teases allow!vi! antigen �!|w) most y6�low5�A 4C !�(Therefore ,B!�same )u!��exhibitM�reM*)�at9Dtime point when no�usE^)�ed%� ppor%our dataE�end!�al E� \of t�5.�+fY ngsstrong� Z < 2 �!�.�.H:�Fin%Dž�Ettes!ewhz $IKpDC-medi� apoptosz invol��inɽedE2sr-�5�2XmdpqcAR-2� mockExtr co-��Eorou�I-�t>e[5�S3%�A� " UkA�, k�� collI�a� ed%qAnnexin�md TOPRO3��� A addi^of un�!to �i�2�ha\ maj� mpact��  death�81" , remark} ,!�nE�L !eɊ. Furn E�,NX�� dE{ncr� �vival�!F��� meanwhileI4�0�6�er? E�� ru� u� kill;� �A���d oncei�attribut* a ku(m�(!�/"�)A�!�s&� . The�s Dwork describes fea# !�m�AD��!j-2��ABdiscu� z � cdis%[outcoma0W�aracter�,E|�fi|�,!� ���rof!n�s from!pat� s us!M"BX� AIere�re�)�6�,!<vitro� ctiv�:e{ exer�an=�$�i���hEp^QQsE� Pmay� 1�to% controE�)�� a!W!t! ��/"%of1w. U5 challenge\ P��*,� �� $takes placa|c2�by upregMof�̑ory-aa%�by very�F� sՌ[52�S� taneously�IFN͌EqeKprevi "demonstr%����6N�b � eo-� tic lig�I3oSirYK�u� transformemOo�-�.A Kill� DC (�zs )� , [53�[5� inst%�EsHIV-1}_,%�&� �pcorre� to CD4 de��}�ey progY .6% DC fun)_depends- ( logy!�%X�. D� �QsBO��)a-���found/oc���bE�He clinical manifestE�aJO�� s havG}� loodA�5��ՙ�<. R�ed absol�m)w�t� ���Das6� a po� ��, b��aof>-��er t)� [32]eMB&"z]%A� -�{s [33adNQthe%a,*6B 3n -7/8� s enhA�%K.-a7�ed m:� � � t��del.S]V[55�S sed_ a blun�tA�respons��I�.z�Hake��B�( decid�o2�4sma=k@ qn cytoA~V��!A�,of PDC leads����. A� � does� -e si&eI�Z&�Z[A�b[��beX MbyI�alE� type�� ٞ[56!�� �!� JEl.��t���8� al�<�aly��r�M�i!n�}�"c pl:� both&m��st�!l�L�E�!c=��ur cohorYRegar�iP1�j�ń� ��crepanci%N literF  [9!G Inflammat�\s w �2(� � mil� mApEve��o%,1��C5�in DF !�DF6U[57�|C et al .&� �,erRlz L.�2�[34Q� ng&%. SolE�I4 QE;��?toV�X�to febr� perio� -L ��0ions [41]; ho wx �P "oa�betweenU� �!1�� &� h dowheam!&.gen( �m1 �� explain:�q fn ��� �"� a weake� If� ;DFyE {reX� a�&escapf��D�=UIL �6u��canfde�$in�"c��%b,�m�Aa�"athrE��b!�BDCA-2m ��s*molec3 �Fs�  &@ por [5([5m�d�B battachm!��abolish)�&( cytotoxicAy [60e��ma�invg� wy�prDpAF> u�ŢkQ0why)����d3�& juI�howe�Q�_IE�Iv� �8H s doe�)�"�M�` f��e6e ��F2� elev%*N ��LsM�E6relea� ��t �,�a targetE-/U �0 innate immun!� �, like N��al� � Ecare�/���DF [61!�&�w!"  !� &��5 s�ac^ phase!O? /9�.)as�QO/i�acquire  pheno��%� 1*c*agA��h��.EE�^�A8I7r6X�a�int*`�;u(jj�)a:�" (61 ) soon � expos� �paOzdea!Oa rapidk' t�� AIY M �>necesst6� at$�achie-ap� nce��proced��ul%�fug$tocol���[�& u�� �nd F-gNG@dHAPQ@us-to-� r| [62]�c�}um�o mpro�O&.@wa�n��*�at� � A��sisa9~!E���ynergism�\%���n+,.�[j AT-2"�!HIV (>�)�O a; .�TLR-7�v�#in �[6A Ap� m, it seea�!n�rlarge q�t ofAwu 3 �ed�0high frequenc*nrecep��62HTL!Ŷ.i�=Y�a^�!AlL"V ���&� ���E�by����%�6*A�b sult�i�.�[65] [6d F"( esB���� �.�coUV �s6^V[3� � �p"�%���e�-�*'['tag�2 h ) �!I�.�&� )��?&p&� 18 h�:2' H�*.-'n`e��:�$ intoE�>� �BTC� n� ?&d �A�&�!-�#tra�'w��"IV��%������dis_mb��1G��estructu�+ in ��H&�!(c!n��)-r-[dsorp�F ncapa� ae�a"" &) OO�&i  accord�)e]!as��& r�%v�&���)d RNA�Z���d� �E�&A J-o)l:� sen occur�a\i�*_ �R}�F!=�n!� \i! i��!%X�_A: e��"s��:� V�E�'won'� kn":� � �5aoPJ&� , onEYmV2 ���ype IaTerferon�`�� �.1 ��> !r�'g I|.��spreaA of m"-+e���uB�-�}�p����s trigg�LAH�I�����xA�s"�a[�&� � ��"�� al step�F"[6<WK�!U �!���"�d�ry>T��iF�L!Bxnn*,i�!uorts F�p�'m�of�us!ZE��  linesi�, 2��"�.��a!]) kinm (R ( PKR ) -8�"� [70 [71 �յre� �s�a\1��ed-� such��O.E���E1-*H IFITM )�(> z�$in.*[7�7{ ow�1BW" -$so subjectIv ��� .!EXdirec! m� M����J� sS&�)ad�'-deri� dendri�As�` eQ� Axye3)I�A� ,"a at m!��kr ���{ oM�eT�6)�5 � M&�1�� s��2�3&z[737�79t ups��m] , [80]]*!&a�5]� V��O"�%e s1�| KA�0��l|-mn!g�����R un5a)�;�b�R���ta�s� �*Q s [8�In�.�fQlV"d� ŏs�pla�a dramaA.���%a�3E�ɷbHr�)H&verty*� %:agA�/� �B�@"��2+a��"�!�A�5. � �e� �� �'��!�-��&c .���*b.I��*&�*� =VE1.B[4�SGe&�(��-%�'"�-� �by1[3e we t�%qH&�of�hombin\0 y2@)h"dI&5,A��as pub)A{�# �H��� k5�on-�%�)� �#n-�E]�2"�&m=�J 2&E�fnoe�� �m!�-Jq+*'U �a�E�1+NfAz!�a��(ue��M�an*�$�.!�� ��4&*!,�T+. [Kfunda���=i��I�%Oin��ed)!+ T�x/�&�'�F2��8��!!+��B��&to�e�A� ���a��"�V.� $ F�! *�)z%���1le�;& be.�-5"is pop�#�modify%�� ��!w,e�!C mass��6�-}E5UurnI��j�.�*;)s m7 adap��.n ensu%(2�) t��&�.�harbo�er"O| circ%ng�!�EV 4 �/Inl��!�f���0A��pnge"�!erme Z�� AA�:/�@ ] d �ENVql we� e��*�cATa�I)y,��we"��mB�/B�E��.F� " +��[ Ň" a��-/by���+�!hi�) .:%�.4�l$�b5� st���-we bel�)r0 �!=!�'A�ode^�'�)!�he fu�A6�$�<��ayg:�%no� :  togetA�w�Z% /war�50s .���)FM Mycobt)um tubeaE.( Mtb/*f �mplex!\x��al evid� "p6e�tum�6eu6is( TNF� lay;�+%�9 defe� ��in��%zOd  nt p8eSY�.e-"�9A! drug*a9o�1&�!dis�7�Z6�/,!� risk!�:8T�5�'>;an��Q�$��yf)Cmpu�&�pproac1 ward.�$���n9NF!(M9 1B& �le bacil!:fT.JWe u1de�j) mathe �'�%h*�v�(�Ke4�o"( s�)e���NF ( tmH66$n%��>-#aapy�virtu�$&( triaT7VCT~)�$im��two�!%�; comm�uE.heAZm bodG dAlV � fu�[�ed�5"��at���!7$ffe`AGreE�(*, i0m$E1���IE��e~,bioavailabil�M foA:�69�A��:*� /32�ofq�Y.��~!� —e�$at �+��C—is esA���1�,P. UyaJoaht��pos�-�u�!=vof�9�!���9��I��ght!��+h&�Ahi%����@+.B)�s1 !Ua��TNF-modQuag��� b�>velop��/ al}����#��qNiU&��!3n�!�ta1in�;��ic,�ֱ��"<b!� � AlWM:�[d1=2t�g%ant6P ��)�<�:%w�l�!lyW�numeru=in�)ni��%TB ifi�inA�aS=r�� isS. C&8/��a!,�A?q ful BO!�-��)!}�E�?-"K CD4+(CD8� lymph� �nrecruiE�> �d!�y$sit�typ�( lung�=�6z �*,�of wh!С�!<t*� macrophagE Th![�*�Ator"� ��me"rall�si��#a-� e9$ granuloma���'!���5��perA�aD-V�� hem� �^95%�)Bed t7M .�%u6 l+�3�sympto� rq1�a� `!�%sub&v�H�N9B TB�b �b !rE�1EronicRg [1– �5�( ��e7gA�Y �]PA�F.s m&� alUM�ncert�� � [3 , .y� L E&26�TiC,� ��Y&}([6IE�� adhe���(1vasDrm B/L [7&]S1 summa�4s r"`,�n� m:1�*�@� �&�uonA�of nti� al�X#$!�2�>�c-de5(���Adisorgan�5}��;�C issu�t��,2a��5almaV!�Ŭed�)O7[�)U!�"��s \ -inj!g�per3#�i�1!�"� set���.5!,�C--���x plre�,[8 , �I���  ,�ip �Q�NFS> impd��worse� [1I�e. H� �,�rup�!�5�t�%�*' � 4isb B2"t(cmי�Q/^9��A��/�98mice [1 , 4 , 1e��i� ly a)Q"� &� �  at ug�0hva�6A�� met�1 7cF convAng enzym��TAC�?).orm a"L-trimer [!�^��  ) ] [1�BV0�5; u5by.�,yE ��%A#TNFR1� Rp55� 27[1eI�&bo~;E�E�5G�6� !s�9famil D:Iel�, biBion�ig��( �rs� !> ) [1��!�hyp���was`c�y��::&��-� !�q�A2� [1��h� � �]� `i/. is����[16A}�� &  }� Qth�7�o� )� s [18–2e��fu 5r�ail!�w� view%ybi��DE4�� �a95Fo�m*P �T.n �;T�H$S1 . Known �%�:m�:L�s%�v6' ɍWS!val �i2�%0<t���1����)��d6� �e�A� ;U!�Yo"F 2��t%� [2e2�d�eaB%�d6�A��!/!�">se��>! �2D�7%theore�5 ��b[2�N�(^"2�b i*l 1 a&�us�L�*�1�C!���� -Idh4wduAwoE7�`��a06 Y\nd�+��\>B� R2Fc������� S� 6p�I�wIeGHum!�25� � i;,�cy��"�/( �� ,*� n)K��#�M��fe�;$than 300 d, I�pr�< � �cicDWCalY�6s.��&_�ext*x1&( ( <50� cm376[ ti� �ME*l� NX ( FCR 1A )7�(!a� sm;)f} �� ��� ( MI()ximat"15 MI�(!�50�lJ� eachE��Rto�*��� in5�(B�--  �B%1�2!�ompar� � �s�)e*->$g!tiv/� r���_ �+�A.WGQ�3���9"�?) cy ,e��=�8 ��@�Pof N812 pg/mL ( limi!�2�)m Rof%�A*MAa�5�5XpF)m==iv!�A�{��\r) ��))�IOamoun��# &�Jk s 2$2"�;d&� syst�A�ean(�1��sX“:e.aA�V�{�� s”��)ca��i��t�+.�e�f1a��1�. P��ed ran�H"!�IL-10=�XOa�c=IL�k� measrcy�>1�&Ti�t[35–y#��aey�ud@8�1g� �"l���f�EypR post�!g1 re�Nnt_ (!.G�1�O��Gq�:�;H�eAx5. �!��D&� i�`8+Ssourcf )�&6J����� vun�nF,C1�*�R%��VQ  jJEG �T(� &�P� "�A��(�naq!�%Ryp ps$!*1qY)�O ��*"7.�A�.� u simi�Ti�u!�a��7�e �7r.I�keE["b.5vi qMeI/�–&*%�.�,"�*�#�H1�g�(t�2"�)� 2� !a�i\3#.As� cus�1 e Methods��!; choo#Y�se):�� meter valE#$�[>��' "��. AI�Zyun*�growthI.�!�V�O-YAe �!K( 5) �Y %�a��:�of 108��6`at� � "�2�FBy�U�5�)dynamicʼn�"� . WfAJ�*�%g!�o f��("&th�,He4K)�ed%a switc�S=&�s�s:^�a4!� inuoeI�a8�'� bur\m/i2�1�)��Q=%��(A��T�+!� �lA�&p��H 9^V�V coupY �;^NJ�=���� ( ∼1000�Hsee� 2 J�9P1;0!��#��2Q��by� yJ�i #6J!�5�nl 2͔ U}Y�� 2� E�6&� �<��.�6105n�^z .d�:l%q) IL-4)� � !h��quali�" !�g(v��o(?IX�9��7NHP��B%!� h�M�\mfde�A�8.u">�"7-�s9TNP.K�*�:�p�w� )��au� ���54GtT"u�ain�[$��aWe� e�0 vaC�F�B s af�>[.>2 #$GMs 6�"�am eny$ promote�_1}�,A)�* cy )@�v��&am�A��uO!8&z".� }� �[�?c.H.� ( ThET�iTaK��iiK) gy t�%RZ, \�Z+�(Z��.� �/"� �6nr���!B Sr3bY α3a�>:;�4�[c�a:� . Oɳ�r h!,.9�*��"�'a/qt. Ap@ A��9-�:��q �boG��b�$ ( k�T�:�is2B�%azA p""r ( <1�}a+T�"Gn.�( frY.�( �m��?+.�inQ� x�tKaN� Amon,ll !�ed.�$� 6�d:� O �.2!DVj���ʼn�uen�Q卝l�=�i�%b�mw�.ed*80(.��L.9,�k%�� Nj�em*�SVry)u3$ E!5%–10%"U [39���;6(del�PQ"&�&� s%=p.�`/ g�Iknockou'r"�iGs4@aĹ�,"w� !x�!�%�D *�B^ ,lVuLittl�2m !�&s ��dAL e fra���( Fα  `at��F7i'��-vo�/t50e 9ar� σ�hX� q��( 1 −C)�"�J-Af&�+B=1�+FB=.:ubuBbvezEV!�.S� �E��.lLp#Hum!@atx�B�+"�u$.3M�%ay)HT"��F)�e�Y�s5-!�%I��b�)�.e"�)�5�E�s�m�of�(? �:)M�+�5� ul)�*s!� Z0`�xp�&�pe[M&�(v g look� ����~�U tu�0�ed2�6�.�!at��e)0� 3AT2sm|�EV�σ5�a%I�@�hu� shifA�o�� `s��GA�*�E�XQ �Dari �� os�--΅1pusX��'���ZA�l����^��ed6Ris <3%!�L�} !J� � "g RA�re!�day�(:��1��G GeA�y!(9��O A8 �"" 3B�$ "K � AG-7�AvLE Ř� s l��Z+��� � mtT� .s+�mLly"�ofe��&w�]��a���.�q ����e2�6�F%��f1 Ne�� e [4� 4�"mS3;er�)lym&JN%nta2 e�SL*d" ona4�pa!;�#.�N-~2]B�(h h!i�x)�WeZ �F�0!�\#ree��"�%t*(0� fN��$r�K�K2�"F�T�s!A�S4U�,�VCTBig��to%` �Af�N� P4e�toY���%�tA��bt�UR��\! ird�!�o�+!۵�fdMto��VF�ai&�C. Two clF�8#AH�#o�U����{ VCT:_h !N re# k16��nef'g�3A2ha& &�Q�to&� e��aQhe���,�;�se&A  curreIJk�#.�C~"� ��p�m�> �A��]"a�e�!��{ (l�CrE��"�Q!;6��Ui�w}2�Kc(�19B�B)�3�A�Q�� N �he),or& pene|M�s N��`ab�q��j,�4m�U�i3�� ��cat6 ��he�j86)���qe�Zay� homoge�R� g5�{��a�A���0")["+&�j^per� Af���a4$ .� jH*�;� a�&� ��I�%5cyE:wa��CN� �&� . At1ZM8b�� ?u�Oo��alw+!��� W&s �3�)�>PsI&d �F��[!�DlAa�Z�!Uthreshol5 R�6A E&N �*q )2ca�) ��r�+a?6rFT&l��J�we�M�� �%%fB�i�@/j �:�,�3Af>�. ImbRTE�,��jreRj63�3>�;�3 L�,)�v�%c�Z�!F��;N�. A ser�of�o>@� e{`uiI"CW9+��w���w8U��%a n&�)al� � �σY7agi|^�$a�"� � �VC@�Gng%ޥ���σ��? [50%w 100%�� 32(a�]�"�>��.:a100iz ��:�9p[=I\�>�R�A<20� base�I fcg6ve� :�a�Ɋžat� �%|n=�)��%2��PE 20~30%� �6a����cu�IC � ��h�Y2.Fcees 83/!7�=%AtewerB(�� 3�!��!�U�sr�<.� g�/wHaO34�4�B!F�5�{ ��(�--<$. N>� �NMB}f�tL'ʱ^s���� ��!���6�5�#a�er�a�j2%$}�� >�%u�I�"L�u� �CAHla�&�C2~S'mk,:�;���� �����%T6� I�nY��!�b�����V.�w�)�*�:as&D%�&p.e"[2�N so��� a�~]C?�4�2M�?�P4���A�Tv�]RTu<�2JF�+A c#4B6�B�W4p-yIf�.σ��y �5KM~*�� 6�%B��!� "I�yto���C 1�<ew�R� �samqZ&!D%�ur����Ta'`x2��� ��5���.Ae�is��pe��B�-�NpM2O"�nm�f3z%�RT'!��&�&�%^ &�  (�,. 11%�49%��&`Ji�/�?H v�C !Jup!���in��!@�noWw&a�VSof 46�S30=�SwbS(!� . 62995 . 01�p <� 0�x . So!M era](�WNA�i�*�2�0"�hW�� �q'>�Az�Eq*�h.�w6 �*�>k QDc*� !�| �B� �[!�fixixN9�σ!GA�QKn�q�1x� s` ��EixQ t�x�iso!'8��ATN�by�!Xit� 28z W0phe;��;:]eu�8ZKHa)s j1f�HMS���2_��!�:M��\n6��%S!7m v 6C�6"�i�3~ SA8*J4m_y�!8k�-�Mz�XEg- �X� J�1�� � �]�r6��#"�"�!*� . C�: loss���,*�//!8�#&MA��uhb,#>T 1�po1Q$� �P 6� ( μe�-MAeT8�tK ��AvMI�Jkj~iI Z�q5x9o9=!��%tALT8� ?#2�� � !Y�92�"�S� ��� Z�I^e��}= � �-wh2<-&q""�%�� Jy6J%ain�X�{:ve� c, FYre!��`a8&�_1� of=�%/iPsVn�Q �+��u 5�s� � r �:p l%� t"sN@B*�6[ ��(&{ ��hta��d�Y�du-!���.Dc�  aver= �c�B4a 12-month reg[L �8-j24:�)@�� W"�SZ\:��1.�5�.e'"�R��,CFU ,>�"�(V�-�:� is 2Y1�Idqn�7.�∼ 3�Ce3�!�A�s�a^��worB; ( un&�T�J�5/stan[�Qyywu&�M���.� .��(�vqA��y]�|ye& ���) [%uea14[I D�K2�a����&Ja��!���-Gi_�s�Rb"�-W@_D&�F9. AM�serum6���^�"BV [44]a0)��&�!��.,@t�w"`._ $eU$%��>�>�%Ycap�P�3'=>U >]��y��o �)�nD͆�!�3��� o{Uq"�S ��?I!�i7\��mi!"�2*ŤZ%ev�E�"�Hv>�%&&M�k9�, @- *o6Z� m��m{�#��M��M^�M�aTW 1���AlAa{o�e��K�K*� o �;N;N? � &< D-M��)recapit�M&� R.�'' *�*2`!k�:I)gclong-A�"u(tb]J.l!W�5� l>2�Y���KSi�"koGQ��*QA �Y����u. B2j-a��FS��}�σ���i�] 6d ,*=h �*h �q͠�y�k)���� z.6@Q�6�QU� � / �>��&q+�8ex^�_� eady��t+)�fS���[��oaI "6@��"if�����E(EMp�s!�e� !L �5�.�"!� �6] B�!A�fA"�es9(*!Xlyl2�P���hH*4�terpre�Go��C9I&*AUs� i;!5�y� &!Ǒ�&3eTEE�])5!$  e)�oYe�(E�6a"[��a��F�#&i [4"�Dpharmaco#^/seH�By�4 �^d�J~!�};�Q �(,y���[]q�7�A��#�Gv&s�7%9|!�� �#..}n^ imagy$E�s�Us~�m��ex���yK e�end*"�Ka�$�7v�AZbe�n#�1L eU7��6�:B>� �"A�x��>�� "4l EFa�n�Ɏd]&�R.t � K i�Na+$>��q &B��tA�� NU8��.1�A�e ih�[FD6,*E� m]+ ��'bih�t� 6"pri��*�E.]U�E��F�Ii"J�1:��a�:�}Nf�XX�, �9U �\al�2�1A�e�j*�a�s:D+?(�8�MAr� a�a�ens-z!apa�Emben�Pa.!�MI C�Q:M�i^�:q �(MI�b:��*�z1 �0!�%en8��dF$Lo�~A2� casc�G)���$f�[,9�[�Fl�  �- �T�"L�7�Eemi�W��L#'m6e� �q��emWp!��Si�� 6"!Y�&?+o eV�yy��>���a*�))�^�S�PA�,���of�L��E{�]q"V�VA��}&�1�O�E�����;A��d NN<���(is-@T C�Lt|5R�I�RRE-+�S�E�h�rl�r.���@y{&� �?n6�o�H�Y B V I�! J(0� E�A�a� ��^� � � K�jL�A�.�R�}p?reE�CWW�G!}�m&�;%O# lackddeRn�D�Q 3� %Y�r&�Қ� [42]�5*AQ��seW� �lxof)Yo�XDd�_d3ve�a���� ���URIa&2�` O�C�,.$ %���NHP�`8 byX groupEK"up��%�.5.%G-7%*� a mo� ]�a�>m�e�AR�OAb��{D�_ ���i ful���+A0<%BY e1r� �R� SRsa�)� o��C.H(M�!yAw��� I���L9�92:���eB~ 6�pi��8/��3&d�succumb5��76�n*5��3.��� �e��JbU�.��"f A�pen- �� Z>~<-1axs9inE�I'{ ongoV��ّs�gfoc��o� ��� &�^&hmA�� . BuDta ex����rE�@�HrD�in&e f�P�!8��!. n%�-� c�#�examplt.4by Ney��s"��~!:%� Zo�nr�vng�!�di��/2�12.(�(�f9,�:�u!ȥ�k see)��+)Re�)�-J�A��aZ��"�au"non�)ar ODEM �'aqon��� �h��GHE�two5l�,&"%!�e�S� 6[f��cy K�Cnew��=�SNF�sE�"�:��b.SA�2,4!M/s2J� SubI�diagram U&�A�U�s 4–6e�e�5 *.6,.J6cY��F,�A4�t�j.�� M3of�: !�!C-"� �J[��X�-�I � �P-�E~��su2�gg�by:-"�'�8 r`ly�wjFl,ɂo)st�JR���h�&i�A� Equ%8v��KLrrr�uE0",.o� ( -μMRMfv.q�cJ�A,"�)S|F�!7P8ITK*�v fashA��  Sr#����p��ssa�,Ɇ Fk cc�?%�TNF-@�!� �� *� (-�5� (R8)!��ArFvU�&�_�8����fD[by" MI!� α (v+ w� ]0 < w <%��Bmak�ude)�cr�c(@)�#��.�!p*�cmJB3邥A_��can9gc w !�to axiM3[ kv\9q�V�K�a�BV�-K at K3C5�Kw[r�X��#@��x��l�-��Ku c.e�e�E����<is scآv� βaFN-γ!�u� ,N�M))�u��)XOI��� 7[�t.�.a&� %|� .M1rMr�<"�~ of N��|&-one-half����K� V�-��]hes NMI�mis�eZixi�I'17�9neK��) a Hillu�. �e��y &.:I"uC�-E}�.h_�vU"�!�2 �Fas-FasL\D�wwi"`& "'u s��J14!`-*�L�IRc45�)or-� !3iovt:�%��!i�cU{cݥF�6_`��1�%�[� `N�10%R%�-�4b2L CTL.�V�h�\h�Hof k527*p���,6�haGf"|KU�Wn�!�s �iA,Ϫn�4]tb V(��1 < �/$��HQ�4Michaelis-Ment9�e+bɘmk�>�1c� .��WEi&�ha��.�Kre"E/d�!�vin�z1%�c:�9pproai�a� i" �AM�P�&a=Xl��/yVUk� L "|&b2 %�ٶ�7 A "5B� �r %*" of)�}ᡱ�s 7–9zS�B�FRv4c��Q �+�o in��A� manne�U !�� �, us)�5a�U; �� �M<1X� Sr1BE�Thi�T80 �;�K #3#IHTh2.#c ,+LBcH}'�N�,x &+�*W;�%� ��ar-YAAA�� !Exa���as�( �"�F> �z\<frA��Kb Ul8�y9]� to�M9�' ee Wiggw��� [28]�*ydiIUn�U��a�bc ,��nQk�1a[prolife!�"�I:&��7?bb �Cα�@!� hY�U2!��o�N(��-A�!6 ) L�%12I!���2J; Uop.� 4�:V2NV��63&ei� AMÂ��� T0T0%�A9'beŴ_< `�&3} 2*� =� �Tγ�f!!X ndie���6��es μTipμT5E2K.�W> �E�2M,Z�(mkp tE m�Fkad8�Z}d] 7�s � �D5'T8.h/a�ޞu&��t$}.���a�N -�.fon� !�)!�c_� NB=V -a�T0.?eD�PbEpC�e�μTcγ� !� �" 3T82!�Tc2!9j���1�*���I9&� �@�s&|Z|yH^�źq ;6�MmIj�Ɉwm�2tlap"�T8 �CՖa�� � p�N�d.�.�mrticu7of Sud&�3"Gl(YC1a�% ����Is.��3�`a�mak"�E�α3X�a�(���γA�� �>� 6�< ��LA'�> ^!�Y�(MA�3_<=A-I`�3�(:@-��TN 1�.��B��1 ,2d-Aq.c; ZuY�Won��!\���5#3�5BT M�l�P%�%�by����i�6v��8KX-Jy.Fpm���'jNK c,%���}d!�zA1{�;&�. u�sif m-A����'�����MM a��u&1 ���o��!`�A^2`Z5�L!(.�A\:�؝��2�O%�lso:QIg>ZZ. D:D�A�a�Q�� a� ���M2+�76d��L�*o .( , s1= &�t�A&7y$!� ��Z�8ծ1e}�w�4d �(�M� V.$ ��d0�Melf!zi���6.sM��+a�� sV���"��1 oα"� α18F���.�m� �&�Qe._�<.q��e��V"C %]4Y>�+i*q6jB���" ,%Aip /v��J*��,2�P �`�: α19 wlog`|c ��M�O Ah?cN�"z. ER�i2�� b�_.P�!2P 'j�w�� ed�nu {�H{/29nIhX�"C!��b%}�!�nJ_Z3`2o��k1� ad�.E�>� ud2�z�z&@�9�C.5�\  A@)�*x���e�$ed��S��g.�g&�Fi,M�� AVG ( <=N�  ;rao%8.ZV��%"E.��� ing:�" –F� ( ��kw�9 R)j�O;&4 E�el�|�h2�V�$� 5��"Y�INEH��Q�&N$a multipliqE�a BE (:f)" B%.�N vt(�)%?���� llEsZ� �"9'ad)/rz�&G|s�F.k� � �2� �7aT)�r�1O�a�a�"���� ]a\5<( μIBv<�6c|Rt}�b�:)um ���2� T����6n'$�A�� %�R70F��mk15 =N�s .��$o$l�6�O�'!]�] ge��� o_�&�R5649�4l�!tB�z��j�Fing ��ze"F�"� [5~\St}gi�Q���EE"�|s�&( CCL�m�$�AR��Qt�Z� �-3 �&xia*xyo ra \Gtempe¨shock� ur!ms�&�8E�%r6� �!d��"�E�"A�� n�� )�e�� �5 *%3 1� bX�/"�� was�'l)y8y�sd� "�3N5. Au *� .�~(uY\�3o-�d� �&ma&`"O�P�5M\�I�93� �/�on a �~. H�)�Siݍ�$A��a� �O)!B6\��[aBAL�( labe!,as=]�a%"� ��<%�_�)���3"ۅ%�!�! �&@IfX" *�6Ea c��6.}U{#�F }�a�a a�*up� 4��&bz/dd/ �1#onIȍ�M��@t�"1IAO�{ G%(.�BQ(IZM-�r(Id %b�EWT&LfldE~ ) :���Leng�k e ��F��R �2�"7 �)���coeff�� �SlsoA�2j%MgA�9c)/"HD <>Db�Ko �w� |b20]%� � s [5�� ell-s i�� l幁�A��as qh.��.�-a{�F>� W�3 �AeF�m0H("*+ l'&b*�s�,�6�a6����Y72dom��^ EJ< �i"��v�S�r[2�8A5�� m�it!�m �F!&u !m@ �!�&EoM.��be!�X AdUu�; bw�!� ))(O#�3&I-Xh$+6K!z.��#�t��.�F"7)Eq�.�8+ U�I�.l�aA�F(2(1��0B�:Ab�Z�A�yM d�FQq�%�uN[1�p�&'F�� �q `.onB�}v it m�)!>;P* sh�7a"Dg!TNF"Hg"%�cbrheF;~� nkyl=q�"dyliti!!i/�>U %� f ��AVV�Mt!Zm�.9�$ s�k�rV���A�R“*�ion���z"��.G6�F��8nergy�vLPSG D�Ro& 2qo!�i�>�hYoE�0l�sՅe LTα���sw9..C 2Z� 2�T.�>d`�2( nam�N��4��s/n&��s��>Ny&�(*� S��" )A2�'�s�).*~j.� >� "'�s��Z2`Oa�e��)�ag� �{�4 h�-�~g�- �s6*�-o���P�l"�. ob�E� oE3"� ��+�5U8en� e]&d Matlab�� 7gQ .(P18�(R Serv�uPack M��ork�6 plat9 �Q ǎi�bme�u6ĕ� u�ucod�%��� ver writ�$2�3cdi� "� ([28 , 29 , Z�c1O� �#(� m�!�&EG.�9"dng�"2wo.� cenarios:�0�� , (k�a"nA,�E�db���8 o)%Pj 2#�4�Hche����t�}B��. �L]W&_� p&Om �beU��%*��~yby:`dea /VhwA|�if� q b&=Fb6W��2 geneb 3��5.[B�h�e����Us~ favo�*oAYmA�A�o����1���J3% "�W4noo;r����b�ba 5M�o�)tz8era�"�r4!���Q/w$��B� &u-V �s "�/�l$techniquesi��.R�/B�U� a lI�a�J�$9�MUک�4py�9�b.M7�AQ+Y�newly]AH�L����ork%��� Te=S 6e_��Z�l.&d!&k%�&aO,�&� �Z){+,in^�%. P� !�e�pre�K"��'��<–� ��%( v8�T�emP��1}~!��2v�A����%��b � :sq t�we1H)�%�,���Pe\wHE��s���t.~T�� �J2HU-, !�m�l�1Q{�l�a5�Qf;�caq��he^eML>�6or �7� ����eeM�I�OIJ�)r'�9�&rY ���$ va/�1e���RV�&@5�s<A��-e� �T)w�I]vcy "�Lis���qnq%�v���(� �%;9���瑱\�%P�� leg�of�+2���{� !���o e�c *ri��� tb�,< �r1�h�pvo!� �p�#aCF�!F�*�%u�Mtb–a�Q�!�� &9i s%Q,!�t"?�&�A�b8&s9��(j�J.�R��� B�(": Q]�un�EA�W��I�6r"A�] .~��1z� כr�4!~� M�y"� �j]�vё���{��lyi|Eed��� �I� ny�Kub�hph ( LHSz �m��k"IW!U ( PR-y[5�857]1 �<]�ed gu���'S1,:�jo��! to wa�#��Y�u25��AaM ob�A��� mplo{y�y e�*F9a��;�q� �X�:QYA�.�4si�t"�U.� M�r2 !Sdo�h��,�i�PYd5_)�x)ache �/�l���,@HfV(Monte Carlo9�E֥q<���M�4�:m( a��| R^"y5�  , Q{k!�;h9ted.H * "y�SX�� ǰ��� � �aJ�O ��u7 �*��5u-�[Ft�a��tocha^��.�a glob'en;ZD��yA�u�� %}�Y� tic �N� A��""���@�Y� -76lb�A�O��u drawbk� s2o�A0 rUj��"+= .� ( ofL��"f Q�a^����^�!Uag�"5$Qs�ou* m�FaN���=m�m �]"�[�."OW�%�}EN4.S �5�!�!�*�d��tW9!��*�AcPRC��KG −� @ Cf andard p-� Y ��Y�c� "�Z:w4%�a�M�! `E(q�1���wa 6).=H�I 2]��V��veb�:�p soteS)#G�hA�%2K �.p {@B�r�yi:&4��:�BtҠ��T�6��. S+a�'"V� Q�y� sך\av ��t-�r��eAe�.`�T�� ��64BA� �l(��&_(T4�,�lwRov��t��U�| � a*:�Hw].cnk�F%`.�I�^Qvalb��J�X 2�U2� �w*� � gene�O��}��):S=�S*`J�a"O$^kq.�BBV�l�qs��ran ��<�!A�ay zer2 �F�k�IEpmimic6%l��d � ATr&�Ega �:ZQ,nye(%�.'WQ"I�el�H��{s!�or�n"�|&1�*�d��σj,>oz"� 3 9p6j�&��-\�]B��9bxSeg�to)�%tz� ion/ ����>J!9V��$z_1�We=t9�E�����MI!5J[sSG%$&X!!J/9�D����I�t _�P�a"�y��� F!�l"� �J� �d*�$kJm��hQ.��tb��� eAidBA{ ame aJ�NY��<fIa �mz�n^�M6? /-���Mz=0 low-�M ula9./Y*3���|an�!�&��Jr�i@ �(�%U�)�na�n"d �-uwild-t�5�-u ޡ��(!$�T6��sQf� ��? �q�`)��^� �are�&I� �Hn� !� �1Oj����]iÖdamag�.a �� :A=Y��u�!MJ�~:�AyM(\$-@o� ���*�Ql\rI�-hMF�EHD�+!?�S���I&Ic"��to 25��uF�a,� �7&w�ar�N1�D&#� )ed �1!% remo�mIt*�ayx*%�%�@� quickly r���eg&o4�(��M a6�)me!�A�S�&�>'%sKHs �6�sE�} :�\ sam�TL � � !�� “M�M�MA�� spacd7!&� %���ge��UJ,A[�I�()�A�� %:�l ? A!��k�Brj/q��A�V ��h�# –m�Xch������loA� �t� �sin�_��y��(� )r�)ib�zo�o��!�* XxetfJe- �<)"�{n2i�[47uf&��d��ˀz�*E2-��9nduW&�*ONF-�!���l�0M 7"g/GE2=)F�a�� pase}�A"'N�,. }�o� ��okO subiP\!�!L leava�� *[�o)>� A+0  bod_, rais�!9vC�AofA� �23�=:aVxv�A.�n�.�2� �'�+A�}���  ,.�,I�9U�p75-IgGQ��n�*r��L��M��nA>s2��a9Ksf!�I[�=a 4-f�2�aff�Ry!MC�0� eD�5�M�V*P&�,�06�%i��c�W�Q�iis 5di�A��%��3 �Al.Z�Y��pB%"�j���� ��*�� �1i. �Q.��n=�-����"- �O&.�)Rt!��Z*s[ � o=� head"�� arisI�A����u)�; �� �&�lg�>����n� �Y��H�xo2�A4*�yie�4[��I_, umv��%x i�A�E[22m&׺A�,'|g~,!�t�x%Z�+e �U6�A(Fs6 6j:���sk=s�! 9؄E�!>t$10 minu�JI��im ���Z��!"��9�)-��l�&z#���A�mT� x �,t:"F_��i��� �AvuX !e tervu^�.�A�a�"!�!\/!asG.�ii��2� 6��\��9� T|��`�ll"��oa-����=Q !��) �,a$f�.* �6/`��sit-Z(r�H � �" >y��~��4%��gAQke6��&�("G3a�&��M4TG�kca�>�"�4�sl!�F!��3E�W*�U-=lY81�  u�s�on*!+mN��^�T�s��Y�A��%&0il-{*� v1�ement . We indirectly test LTα-neutralization in the model by lowering all the TNF-independent recruitfawhe�W63 grows l� r!in 105 (5i%� )�W���!A?end!) �a=ee Ta��S4�� details o �VCT setAN �defineAe=k�.,shold ( RT )�awhere re����l��elow thia�r O �lea2toB�-value��ex��a�� centAAJh fconiMs �d fro��e5M V. Each%compri��100���Fne ߁t��iM-�J a specifitervalcrun-M5"ba͛�: )�K2�i�EG68sMDun�oll�We-k2Psubset1A� runs!a�cBպ� 2Aca!3wa� thei���aG(9~$uncertaintealysise�We ob ourAcaA&e a�g)�>|calcu�`dQ�2� �.\ statistic��!�� RTs q��t��Şa8ndard t-� ( se)F “SU a �” s-3��C@ adiN Hy data exist regarda�%�� � �� ��� 0 lung epithel�din<fluid-:BHbronchoalveolar lav!@[4569]��e�(e pulmonary��whealthy!: ject� Very limi� �!9� �n6r� file�a1aa�4onists outsidez um)�>.� Iv}�Q�H �!plasma (�seL)apropor�[al�M+Q@?2M0its whole voll of dis� �� )}is��l# scularP , sof2a%� �could b�# ason�� proxao .�2E��Q E �isZacA�4lished mathemaQ� by fH (a physiologa���transaPs bloo, k.�-)$to space ) |unt�>�. How�  ,��may� 0adequately re��a��!�rug�< �v� l!to!'solid @granuloma tissue/��EdA�Asteady-� e<.%ofA�2#!� [60]eA�q�.molecuA�[61eVI�e fun�7!�� (ocol ( doseV admiaɫ�Tnd typX path!�y�s��3�UN�ranges).apE\m)](1 μg/ml up!�6. A�" .F8)to 60 � [44]%�P��| � ��Iof��m;!Bn� [3!5��i� huma��. HOdap�zE�\�Y/U a�%Q� dynamic��numbe�-s�4)C cm3�UB tousMFVw�=,scribe cytok 2�A� pg/mL2I homogenTŅ{PRC (U .Spear�cor �xo�nk-e��ed�~)�Վ one-� a\,wo-sample unaZa�ria> )�Matlab A�U2�$d Sensitiv�A��es�ρ�m� 1�.��Gen��t�|<on&� 0 ider��genetic\ Y �{��vidual�rRea� stue�revea���&ce"atist 208 r�duplic \v�!K� RDVf,�� !� polymorph#,�which� trocopy�� stA7ab��K ��ome�MA�� se vresulA�6m>�<I� is�yu � E�Phase 1 O1000 Ge �Pro�a$.�(5���Ast;��sharedI16pr�K!C�cop�among��exm�pop� i9 .��Texami�J.�I:v��.RNA-SeqI� deri�%G�8Ilumina BodyMap�b�,: w�as ;34lymphoblastoid�  lines9vid= YGeuvadis� sO�G We also d�$oped a new�kach!s detect no��%*]9cre%3ce-4g%��%experiB� nfira�9;  If sed6ondr)j� !d :rI�ceA V�z �E17=�6�AltogWuw��e�+e%193E�;^major�QI�� 1 y deleA0 .NAhad.b�previodre� � z6�Eaof 11]��geA�c�w���i<� }�a���freyZ)i9,iD!bex�A���1x�zs vf ow� e�q,�EJ?!�(�LmM rema 10 �m�u ,suggest some"�a�. A��i,��>/of�:qE esearc� �-� �.g�W�!� bj.m,"� 9 �!02at)�go� *� ificant}�dq. R��seudo )A�es� b -2Eorigi��throug�procese+��rse< crip%�� RNAs%�I�A,�se�  i� !oi}%�i��`,���E�p�`iPu�medby enzy��pr��9Epose�ele�] �ce�tronl� �%�2ng�es [1rDuea��lac~promo�= �f ntal C, � c�;l�Dp be non? aYd�plysjunk DNAg.Y i�� $s challengWA2vi��n��few.�<A�A�%6g�%;5�[uF� �AK �(7�*aqhaa%�act open�d!Ufr��thu���-co!, but lccW%0non %Ee[3:sourc�� shorAg terf� (4� ,microRNA spo5 [5!ہ�pa���g��ory5�I;po��replacEV��� rec ��A2�1 locue:integ� i!lie��toA/6 "�r:i�%x!�i�E�to�neoYBiz�;� oft|an�p �NQ�[6))tak%L� shap!�of= age-%��es-$fic featura67![As!e� show �!�-Klir9�� s [8Kp��id�t9 XM��Yuseful�l%8� mark�,AzviEuinsighE<o such e���(��!w x cha��Q�+��[9]1 �g�_ �eN:� ��a germ%[�.�i|IJ!I year�numer� s1 eu)ee�manatr�I1vi^ imE�/}aM,?%?i**disea�. A g"� �w� RHOB �( ras lo�B$ family med4B [MIM: 1653709$ tumor sup�sot :ng�aRho GTP� U[10E mu��an� EAD$ , RNF113A�A�finger!؁{  �300951 �� �'4 trichothiodys� hy [1�Oi$ th!QV ���PPIA cDN�@peptidyl-prolyl iAHr� A �12384%�*TRIM51dtriait� tif-� s 5 L608487� confA�resist �=HIV�owl�key���1�~gives{6��L �in�a!�technA;yvow�[ rE move beyo3'�!J��/?organ�toENa8� E'�9within-"� . L�-scal���pva��3�R�[13] e�ex+���iH ��y opy-�&� �� �� �!r�#� [14–16]Wu�pertoir FR� ~ a to�ofp&>cN k7]2� dz�>#oi+m� , 15] a�D AqtrO  he6�t�ofJ�/u!� <v[of� �5"asae omic�) 9o his. Despitŷ�dvaTl�|qu[#� ed unansx N"C� method�discov�*Oq�[&�� nnot �&c[ �!utiliz��ired-en8ad� requA"X� a*< paira7maJ%~) gen� Uy�)sR�� �akll� only%]QD��ofIA[���e� �v?�lyA"2�1���� litty�e diverg� >��F�. E. �#�happe!�earlier��iQhagN�K  &�!ob�edA�s���� �#E+ MoreAr know�#� ingl�� abou�#&  a� E�ft kinIr�g!�y�a. S[ e nucleot�6"locEye�fae Q[JE mi )=�Q�*�,�� fy�� PreN�&�al ��d �; farl ch�%b&)imp^`D r�.����i�-�� j%�(ignored; yeu%wil�s*%~�#h�!-A]nea�h �Ge]�� we fk 1��,�Z�a�"�ioA�pub.�We8 dm)���҃پin"f an�(�"�}i`6�In:s��d&Q!G^Ias FG1fKof 502��mz] [18]�uL \2+q]�ehe�� . To�z.|B8)�A��Cy)�inJOwM�927 ":��K" a�DB�'>h� �C:+Q>��j% �:A��is�>of6��{�� , 0922�}14:-By���IL.�to _�p)ɟ��*��identif�"214���>�&ed 196��&b� r  lici�!>(��i� � �E(re��: Fis�A*T"#bp!U!�1&  wgele�)�� 0� r+)��4Nex�we# C 5�lzQ �5h]-�!�&x!.� ( S1!��RVD Map�%�z �(�Ou�#�#=�e volvAE�� , 67%& �M�r11 ��; ll<� V-d2� . Forty-e� ~ �Hat�widespr� eU&6–82O(%88 8-��inV 2–52,q Y{t5l� rarT in27 haveA��$%�"�� �  !3�r�$�4in 0 . 5%–2%Elle> a�is/�et�4 �&�e$�5'UE�c or er( )$�xa�re�2��o neg%x sel�$$�ur�]h�)�$�2!�ci.�a(~!$EG� D_hsap_1441 ( Fig 1E��'+i� � 2025in�a6�n /5 /�1h(in European%� Amer*2�)%A�B 70% Y�s| Af ;� tr� !"�likA?� an�8 �ph�n�� e em !R%�% �  n!��mtoj�in /,!�alterz �QIY*C -G2J"�(�lŽ��f � �E uish"� I�two*,.$ !�� �ppl�y�� a9&�!�d�A��FL � 6� ��wR>�)�stuJ. k�c)�of:g�6la)��5t.G �*�2a: 6e&uH��ow�T-)d��(a�:S�#p~H"}%0*q�Em{K&mmon l-ss2��е&a�(���� 2+��bR,[���orJ��er6.,A�-��JB���h#ed����# �fourtUEu&/�N��� orde�Juor�%a�a"i$d*!�o�PI@Ms��s�u�a� reciaal� e�ila?!�� su"65to estab�'� s:1�!�s �g�4d*�5tr2�in*��es [2`H*a�9!pinpoi"#)�EX� D in�$)@%r�*e DJ�-}�- by u�mammal!�Y [1r m�� m$ic5Rs align� F�Ensembl� 73�irs� heck�Por5_�)Tin ���v a�i�r$� m�!a�)epXa56it V � ��n�11�� �T mi.��ah1�y&�M y(mum#��iAUnewar�� %=as�!�����proba/of� pe8)��zs�!C�PAU ��lGto zero*�4is&B,A^]&aJ n:3 282)~�( �ook�+& #Ho!da�ce��/!!!iKas 51� WVc)�0to Catarrhinia�nd 360"J%�risog(i�"�j �1�a�_Gli\Y� 849by mou�nd ra�.h 2&h �irm�/buA��T�A+P�%PB��M�eE�D �ns8 in=H Whil^ne"y�� ���%� founa�at%�954� � �#A��'�rI�a��1s� A174:�Ap-O� a�f��57v�#�,!� they^� �� ��e �t�$Eurchontog)� )���3I&�6q , 68)�'t|we: ��'6V� ��Ed��� say�I�s�7� 6z)��6 ��!M�_��N� e��%.�D . .�E* heir�� 4a�<2� �>db�'_i� "�&%%|"�%�!����a�8�I�2�(E��)�(�+s)%� `v+� ��A�faf&/.� p( CEU , GBR , FIN , TSI , YRI;6>G)"�("�ng���E�6 or 16m�s/�he Il*�)-2 . 0T%g1in6F �"/$E7N1���7unique m��#�r�c.As=�AՍ�!�V%�a norXa�M�""�r1 RPM@e:per m�8op*  5��)� ,� librY!%���*�5-��n�dM,~�e�se cria�(met�'586��11�m� ="�=aB �.���3�mW� "�F�2r'!� act L5toq#�rS onship"W=����@=6�o�$�& 5p-%�M���� �|�05�� f n� A+er�nor�ui��������$�)c��6@ �JM�1E� a sm�fr$# on (�5D)!��E@[72,Va���1l!o� �)�8V�"l�l�+U�+JE"su�F( T!��3�%�e!�YA -"��16�'n!\'Mu�!�� ��qdec�to�| r�r PCR fo�qu3H#ve�'al-tim IIBA�� G ��� t0 � 4873�201! w��%�B*� im�!sui� �r qPCR!��w% 3���"�8�EQ� ran6in���#��!DEQ�� orga���%�Eo+AI���;�"Mrm� er� �Ct+S�f� u ��a� �J;c�av#�%q�cQ7st& �y��M<�+a:T. Indeed�Am*Ag�e%�� !�tr-� 88 )�E�%�lways��n Ma�?� �desigj!�A3� x!y2z29��"MN12�bL� Y.�@..877"�l�@a much��emper�(�-�<�i�4�A~m� F f ,�1\.�^  9\K. *��!��mee��� �tverthl� wna,��A M:�v�x11 � �by��2(L� work�n�!*�+Z'iAM��b1�K"+in S2�-��F �� �at <%[�tE ��Ebsix�C�y�a�A�2r346A�i�� K&:aEa�tra$�I�886;�wA!�:7;EEi�� �kf�c= �[ �!�ix���4�S1u�� !�above-A!�Z,AEA b.H�Ca0z �M. I�6 low-�6�� anll�. High2's&� lomY)Z 1793�l-nta�� .�A!�'�6�pan�/�spl�,� � ov� e (d leukocyte-L5E�6X )>o1~ �E<ex�GU@-�allEAAq�O�mplby6�,)�sD�>�Ianta0iZin)�Y�I �BfAX@�$���ea[EE";5�!��<11p t1^:� 2N�:�9�pwl�on,!h�: ENSG0$151846 ) c0AA� cytoV> ic 3o  ( A ) *H�*( PABPC3"+468L+. E� )�<�a�he���2�?3 ?I8��2�E�g%pI%E�)���, �"a�# �%�@���s5H:�& � �� �4E�T*&� *�rib�.�EDJ-w�}is�suu&!� )E� n&"� ���"j�E[2@-CG# Wх _ ��&X�$!�"�9=n88A�8cod��7 @�. OA��E Q�)��� � & F�2!zORFq)1�!�e-� stop�*or� me shif_%v�he -"RF)�y-:����2�`(��-B�AE>�)\en-�!$B��W�� 9o2�e�,��X�p%�-<����iz5�I��;YoquZ+yp�A�-. �te.�E>jf� pA&~zinc :0761� ( ZNF;+Wi�� (F/ >,�,TPM3P9?ex�?e �e��of �Ch��,KBE i�� )!od�!jo � M+9c�+ � t�4m�(���E��.t�K!���@/ iEwc�+2d !�2� ar�Y-K-� incorpo�d�F.�� %%��� �AI&"5s}K��.?BgF1���75@es]%e� �] �ny�aUi.�*n�)j2�'3�� )�ofR!� s vi �"j.~�.u�ep, [6 , 2�12�,*�v�P�5� just SNPs�d3)%�m��E]e"T� f+�e5 .h�Q"�y+�SBu]�regE�M�a�in!��OM~A U �%�"Ned%N �"�w�-����vy�Q fCls"A)W >�R!.��B��~/�e DESeq2RJ8p(package [23N)��>�est�@%K�f�*��:�*w�2� .�~E;�.�A!.�3a�-x��"Q*�Ac downy�P�D � . Tw�Oͬl( mons�H�#� er���{}�in You%7t� ~R�aJJha�*.� `�Lt�9 fAZJ���� ���V?�! dAz Utah��� ��]����&C YF�<TR9���JW�ݭ��1g�2i.�F� �A0/Fy�YSin�5�to1���T� �6�N�Toscani�.^.enU(Pve.7E.(�+Bn%^�5M2J�5ӥPe�- �!.� ��d��v�mbl9unm.��50.�0���Gi)�R*/AR9� -�911��g�2 , 90�y �+� et9 ��!>� A�� �exEXd"��!&i"]&"�&� patch�.y�mbl!\�5ic�a�G�.~!233 (SF. 8% )�Ŭfi�*�u�@b"GW�^vi��2XS�Bg.'8to GRCh37 . p10= HuRe 9���%�ᗵ�in 86�,1�4�>",767 ( 25 . 6r�"�..xwe�$�*a�Q�y"�K* pipe�%�3(+l�7.��&VGiV��$a�ul�&�F'%g��j}/uM�.\5�Qba9CYd�1�10e&j*Iy rdn1%j*[�h%b!�� in 4.bdT��. AllEa&E�Fq!A�E ong�)$99% ityA�2���$claJ ��%' BLAST nr/[Fat�R]y)<Bk:%Q� .,b >( }6��ICo�{$&=eaI*� �!�} Ŕ)I�,%&Y-G � d.?�RacASIN�;Jy)jف *N:+ n1 �8(Fk:b*�-� � �"/0$�?E"to�^ o�*% N<:8�E chimpanze+ ,d/or gorilla-���u�e"&�1%�&��*�=-jE&Hlv6t�Y)�&��!"> � /<>=dA �vct Y ���_ ��! ��e�,�Zrdn��qoFB7e�*�Ak}�.S4)�wN~h�~��$)isC�Pb�&2-7 Pu@ ( Cori�MCReE&�G7 &J )�,�U/y-bio"�,c-}E�eac_-S � a"� t*� "�*�<J4&H6Af2]!f2�MBj(!�1–rdn��>� rdn5A�tai�* l�A2pet�Q< c�6T6W  ���Ya4v�Feno:MJ L(e��3 arti�6��:"G*�%(fur0��.�0!q�5� OlFNE�.�E�to >��.� . Ap� � &�Jź4Ş ��$�*XQ� Ag �  ,s;�/Q&��'!� flan6 %+�i%�z| h0z� ib��K��)2� 9�F�Hh�eozygos� us=G� y.x. N����Axp�^� a�DdJ�� ;)>�6N+ non-a� Us!B2c� pool�1FF�<"#a&~N�*, �s&3� I�9nK""� 1c%�"d Q[srdn/ It6�d0s"] )�ESo_qpd��%w�db!(J\Bank: DA381977 , AV70234+ AV62962���N�o?t2< �T��a|^! �`*1Fm" UassocWN"\izU&?R*Q!M2. d�U Unti�%�B,�� ledgU��al�4�n&Wt�g�E&@78 �\�- e adf��풧Fb� �[rey3�%&� �F&�'*B:5 mb�Uc$G�� A��b�8Y (�])\EgA�z�. P�L�e�`�Oj2e�drawn�#at�Md0�Gir" �V$mc=4O��d �B�9!�2a9��� P� �`RI�Gfoc-o�"N6�Gee.�� ,�] ardl�^"��IaH�.�T�/iy4veo!2h�F^+Gwo �H*� рr&�G.ph*hM�Gs��!P�B�k'"7I(-ws�eaD�sr�F�]p�?s�O},�>��&an%��si�Qe`A� "�Q.zK%yM�� B�.�8b��G��a�4AG&3�|�Lf o&m %��!&%�/\ink5.�D� �oI��sFh Jm�)5ir*� �E$l��=:� L ����Dl�v3)_: l)� ���=�in"�Jn�'o#. �.7>� � !�.h91B].��%��L2l��1��G:]A,�p+,uME}!�s7!���-" I� �q[i,"MXD90��a:wge�T�@�X!{.��.%�!B�'�>[�,�-�4s87 ��!+�#�Sټtl�5r� M)��[6Y&� l�#176 [�K , 58��S� 91 [�L�&m-o.� 1X�l�l)6��overlB[��.�5B�mais��h%W.�� �{��!�?tf��FDV\�!� G��z.E� �&��� 562�m�C~i>I�:N��2*a�n �}!�*B)@�a{ �d08�.LA4�Hy;m�ZQ�&zisq�AW&� m;I��8�%��@Y3s .�%��z}ge�Jm=wV-ex���%"�910]A{0A�e�A6��)!j?�8& nY�&[ A� char ze h->�/n> .#�B%�B]]%H"$e��:��:hDam��RE�6�;fs]F �K %�Zh�X Er�3P�i1 �K comb=_!$�Vj�Cv^E�i#8.�>�n"F>� cross�V+qon.}{��.#.h�F(�)ABxp(6���mr�|�� deHE�ͻu=!�A�DB&|]&AqE��#9?>fQw 5�.i,�� ���3�e;&���af0n�V�{r.�2�F.{!�.�>{O cqdu�J-�j�_ pr�i *� �2 auH\ly"�.�,E��� m be�Nubi�&b2�"�v�[6RDe-Q.f��g"�  ! ��*�:Zld |6�am �-�� .��mE��\!���-�*�B� ,Q-!E* � ��rvn �c��*�.Aqe�>>� ^�f�S�'*�2. qF"�.C� �!agv a,�1fR��Bzx/f} � �5�;6�Sg*� �c69CH��cl� �"�:%���m�ag]��s%�siE i��+F� . OuK5 )�a�we�  o�a!+�� JP��,l�5�+��EF��'4Wm�-.�br� 42z,���)xI��1>5%!� .@ !�� triv�^�uextrem"<���Rr;7>s=9l�� �7` % ����I2 ��� "p �'be�mq !#9C' 9Dnw-�Raga�0draft euakryo�]o�);�2&�II"h�A�2o�.ap^&| ��A�(�PP& A extix%�1�Vs�2uthal [24^woo� $mammoth [2"v`Mwy}i[ab)�^!I�� h�!�mu"G��!��qiJ]F�5%S�U��6_on�u"�43�G�nV �1-�i�F7J&�8-"�h�&�=Co"qhS*�A�� �_J &�*=7Q�hr&�Z�E�,�kA�Q"|0al ���We��X"�b��!�`��p��Q�of��.� .C seem��5cap&Q2c O scri�"a� �i�� *� AIe�&�o^�f�,"��K( < 2%�.MK�����new�"GiC=� ��%=&yGa�di��"))�J=vA�2�)��.�hw�0��:��' nl(�7�Pa=] 1B2N*�����&3 E!~� !�p *r':�2�-�I{&hsI)>x �sM0R�X!i�X�qA�!-"�/ah���9:j. N>�b"aDde.;g��Y�mY^9[�)26 bIt�6�~�-���sQO%+b�!O^1]hy��2,Ms.|meiŵ! postspermaREn(&ellTLe&*�P.����� '.Wb�I�  �b�����A�4�datin [2Ne]~!�w"� �,"�#&�d6�AW�im5Ki2��Q�9!�)�B�.[i?Uen* {Bnha��i2,,!��.a�A25�s link��hR'��� �a�e�2 scap�%{m�5�6�ein%p� [29AoToB if�!t�K6���N��H .o;�"#o��@�! ��*^rR�m�)Y,!���up,f�s��UB� ,��m� E_P��c road.�p�rn�g&�A�0 .NJN6�1DA�AG6b�ma4"�3Q� �4"��w-����^�O2�m�subd`���_�!.�`-�&� %��wl�t6�� n2 n S�A�iI7-�>���!�"~.�%=�1d2�[�F arism�mC1ɲ�� S���\(Y5lj%���4"Ator.�$��;�&) A��EI�� ��6�,}as ��nnV.y� o�%A� i�T�RE�0D���yc:�R&6 6#��1AA���il�=2^ y . � m׉�e�| AT��u�l!_.��&�!Q� +���)#�e K!&8 !�."�B)W2�]S ->T^d�^�g�*�4AA2@5C"� �* 8k�)h �rK-loci �BEDtooh30���<2 ��V�H%4HJ�i���]R�-J!)G պs?(�:�Ly%�*̀in .m71�BalN<.�( ASW ,�MCHB HSLM"�M NIBLJPT , LWK , MXL , PU(N"N!�$N. O.>+F�1H3�<eB=W%Q}�*��AmniotaawtebA�s PECAN ||! &�=ŝAC.�U[32��i�/c>WM!@5�8�?qj.�jq�tF|����8bk:"E �_e� bx-python"�8[t�F�blocks�{�q�1�a�&�in2.:�softwx� t�5�-se.- 6" � � tituaoM� grouO`6�h�3M>':*�=�Y��M�V�wE a�5�z o� 8)Y%aT@*, �-c anguta0)macaquO�jmo�`Co�ge�*.a-�I�M�� r��O% faio�>@ �i 7� c"�� 52/4< f .�.�.�!�E4ei�N. S�*��uvIR 3 sepaa��F3u�SOAPden 5[3y;w�1 @X al lengthai�bp ard�Q)�!� clus�ng ''ll%9~_��CD-Hit- ) [34]E�&-.w �SMU995*�1A��_�J"�.{$ach� Usensus( �AP3 [35 ���,:�Ap�>EHi(�S] !"�b$�^�5��.e-9i2�4,"g," z�5�� viru�.bs[HA$�c R � Er� mN�i��"d ���"��.��&�! 2 :�-�2~q i�u�Gu%��ngZX"�*{LAhgen�A��� ��GF�@E��F6CG� � �0!�U�JAD��E�&�,M� LAST��[3�"� Ts mA meet0e3u"T���.XT�%! a}�u}150a��Q�umL+s]-��S��&� gesFan�M �Dp{u�h8�fe�eE>!9�!��� �e�J unY2BAC�"A&fosmiWV"� � 6[3��)�� BAC�2C��I��anRw4]� �/lo�1X� De�0�)��B�e�"ZUu` �LfX�!�!ti�!c �,:���%��&44N�EKaA)1�&�: !by4 �\7A���  �i�6 S3�4)If"4.h/ carr!��:)�f�1��1�%5 s&�1A�RDVsK&�I )}, z� Mul�|Ti1o�SPangE�Cl*ch—H+MTC ! I� II ( cata{xno�: 3674�5 3� �%i�U$ ����Ya2a���f#U ing:)�r8 brai��"�N,"P, lYrE kA�al�cl�kidneO+R�Nhym\Vpro^, t��m�N���f e w/�+os�:��lknd;ipR���N=2P:~61�0 Ew�iE�"�3or �te�I'#_er-�w45-�I�: g mel �+eoS( Tm ) 5�W60°C �GC%���� 40%60%�2U� . St���[Oi�Efd_ �HEconoTaq PLUS 2X Ma� 4 Mix ( LucigenM���o F.)�' wv"A�10 μ�M?�8��B�3�g� (i�icor)�oJ1X:���RMaK� )�%A%S2B=�6� cyc�� condW�f'as-� s: 2� �h94!�� &X40D� !� 30&� ,.�15 72L_ �a� al 5at '!�|q�. P�num!�!@P��erzX( Life T/z ) �SE�qT-:aT�7s:� mixe��25%�)�s!+�:%sF�,!��R FidePABu�y�p .!T9� dNTP�I mM MgSO\qb�C5�)31�]" 1 !:�9! � #)si�&M ��3��571�U=�IY �1� b�E�Y��od �e�� Rn agar�*�D%�at$GelRed ( B�u�^5x TAE b)�. HalfaG��!�1+ I6L gel ?;�Wj�8a�T��`Yw�J".�H��3.�u exciX ���}apur.�Gel E_��Ki<Bio�Sic INC��Re-2�a$Y�f<$ dek25���n<� UV�D/en.�iU8�%|&2Fh=��`N�5 �wi�m Wf Exo�x�%FastAP�hhermo S[%�e�`Mfincub� at 3.� minu746�Ӝ� u at 8�́�1��:��UA�8a�$ �ͱI!�-1d9I,[%n�O� I AJ�pAo@�*"�� *��1�u] E�� d "�!�Y,%m!� Big Dye V1j1 T�?�M�Ap`% Biosystem(IjforwardEP�rs���["l!5���Z�� ABI� sm 3130xlh�K(V�. A"mH�4?2sc��.�%/ici% "�( S��%P)�n&�F!]�BioEdit" Al'or [38t��p.1) t؃%J-�!��1 globE�Z2� %���!�"� b��ga� � ��R"`p�jch u�IY4jqFQi`S{=,o 6 & 7 Flex _Tm`SE;M8P�JSYBR Gr�Y!�* Z�WE�� %�Tm = l . GAPDH!߽�a� [�a8c � ro�=R:�+%� u�.�%+��v��0^�Acut-off�ea C���P=���.�'as 32�#�Y�ly�{#�� / W�6 I �ex�� � RDML~�mat [3�nU�!�e�ocy��P-#LinReg&"�[4�An.9v��W!28EW�6!adm!�d!�"�sQUep�O)X�G2j���ac�LFg ,tMA�*�)�f���0 2−ΔCt×10�>0� = ( Ct��-CtIj�tIn "�KMD��\*a,";)s� b�"16+H!��|2[~�QN�G��ni��%�,Ale���ip�[41�p*ʍJa3%�!��A���a"��%)B&�&,�=�nf|�Fof6_��"�3�tF?5%�%�Z��=��bu��.3[a�i�!%m�5� orda"5�h"j(#�qu�/A�l�+joTĚ%��VQl�a��&�1ah�%j6%j,IN*{�-�-Fu�8r! D=U2%U.�E�*�:"��^�#gm�6�{R|a 2>2�$�,%�ad�WI�i*O;0YML�%c�)"/( m�y6s�W�Gœrep&"Z5�Le�6�AR���(,]Neurocy� erco ( NC5 �k�o"1[�B�N nerv�� )Taenia ��um Qr+ pleomop�c H�7Ffl�t�Faro�p<�'h�dja�q�"� �.�+ aria�P *A�o�cD mod��aKiqorA�� �.&�)�$%�&m!!P=F�'!�a!A�� %la�p�h�l �6�� 1�i ��yw� chy�����ey ��U.��&�0hn��Ei�C�U�me M( tico a�. Hp0Q> meyH)�( n = 19�[�� 11 pJnfg�-��^UbHEΥ�> ur G sacr� i �2 d�h�7J 5 �" � le���0 razi�jel;Wb�|c rece5I�oLO�=�;. IN��B-esw��9e) 8R).yW subopto�U7.�� idal���/=iG�?hn^��?i@��\J fUX��5.o.�A. N���( CNSg�.larval�0gN5u�� yhelminth:�,��L�{��R �! �Ea�da�aG�5�oam(�#[_)2]2CC ^B c��epilep' seiz\�inC���c� �ohE%�0a su4ߊ�lth�Z blemY�SU=�%symptom���d�{ma-� , 20�:r/���of9` *R�B��iyU<�*B�5�6�giv�r�,�a8�etmEmanif Ys [3 , 4!k�adr�C��� es embryo"eg��y� ��l�"əs�e A���g;�6d f�}�1EZ�o�O#�7n��!?by �!l.hh�Y f�kHX2w�yR e�sa��s4.�Zv�[��o.�-!mu�)�!� subc�'e( ���3 , �9I� 0��j=ge�KY�+eB1D�. C&F �9b� d�o ��o!g!$�cerebell�Gr � , aN ricl<"su��s ��ps[�3AeAc�A�.9�^!|ritwo\G� ux:�����cs (�I���i > �u�p"2����a"2�0_ eG�r��"L� A7��K+�4�$h���>'�B��� e3.7 ��l s6�P�0mjo!{n�Y"� ig21!�f� K+Դas�*��nd �Rfai;�prognE.�B�_�f��-��N搡���d)& phal�nq E,ran�>!���QJ�)S �[ l�5� )�E�!� !�� mput>m� *agŧreƬ�*)I`j8uf�"�<�-6�"l�[10A1�e porca>%1aC1��1K+�a�e? Ŝant��ic)��2CK7� 2a[1���&�N"*P&�QN&Rr0*�6 }.�[" carcab&׬B�� Юi$mX��7�-� O'%!#ju�:Q �@x�#usi�>��hU��9ek�j�T:� ( BBB�!�!e����^1 4e.U3E�z� J�Ty�a]��r4RA���20�SfEB�m�Cly vas���}--k�ra�' �-O�p��aBra� !�pi�oɝ>=��4�P5nlH A;urb�Bj%�)i�n �q�,��$g, �!y[ kI �&�8>�C;��M5IC�7DeA�]���U�uE���H m�31 M��!���P1Pv�k��Psc ʵ� "7el�<h�Sz@�,Ztes–&@�89 6 �%py� FV�� mbed�Pwj.Xo�% y��Ra���*B"QHH%Uz�]:� �~�y�F���"!piprq -�םto�?s��a�{ !�:j�I �P)�� �ޥ?���B�B�,�4 �CI�s �6 7;[Lb�o�� ��6fr,�husband�Yi]a#� \b\,!8%kdos���!� .��� uthanasiaa��l!��c^, fixy�hT�8�/of-=0is�5�eR�rê0 ploh.!�T .FZ)�[2�D?B�)s6anHuancay�AndMn\�e�4�ou'Jo%=����a*�Y%{a&�h~*4���)�a�v���42 kgA}107 Ian�;=E� ~andoma�lR ���t�4:^��=]� ( unE��#D6���a�AN��ds�,00 mg/kg6Z ( Sa��antel�B, M� ,na SA , Peru�)Ce�t�UF� a^�& P e@d 8sR��6�]$O�L, 4Z7two# ( D2�O42]fdV��6n"�( DyyA:"Fe�( EB , 8%P0Kg; Sigma-Aldj� , S Loui�MO�wo ho!�e%}�0pI5*�G�dA�&�!$Z Un�, sidad Nac��MayF�!� Ma69im�-%�,_E a�v ڵ0“Evaluació� la�R c� enfro y mú�\�dosq���: ectacon6��8>Dr�#J�,do Gonzalez R� ncip ��o-a�)�!&3��3Ae} EthR�nd Well�OCommitt&8x1Rty -CEBA�n7J9U au�cz-&é� N�.0; 50m��201q���ly��!tN��al In� �f H��/AALC gu�*� M�$��fix���F,�)m�� 24Mrw�cu�Fcor��10–�)m�GM�?�ngv�0 11�{. Biops"^�pa�!g"^�o�Q ��4��F�B!J� affi?S� 4-μ�ick�,��A��f�����or�Z%�� �sl��m��4slL�k�GBB�eF xylin–e�� ( HE��M n’s T�r5s�,8�=E%eݹ��7 �S.!w@#!+sco|%) ur !:`I*!deA.2q� "no�-e�druc�vcogniz�E6E""� d�i�c)ric�let ���edQ���6�*{:- 0� �$ ��. M%�p��B kIxw�0�yI,a Carl Zeissj� scop�BAxioVi�&�$!} eachsa�� J�AP� ic E$� ts G�< ( . jpg�3a��/In$4���#E�q'SBI�%�"S%b>�pt� g8 �1Ñ��2[�igu�f�#���=��c�N*�; � �toX�to ���o�ge ' (�h.�map�D R�b0-�y!���re-�ɎT=es6o"� a7 N>� �bN�%Xf qQAay��2��A$ �q�i!� �={.�56�5d>2g`aJaM@��f R�j�m/���madu ���I0~ � �eXPnt�&A� � �us�<p@�� ken;�K� wed:� BoA!� ��2S��]�}�!"n] C,.“A�acB�Iu?&sA��E�ڴEc1�8"er�� NLl1"��i�E?�iB5� immu�Z�>[�C.=�>� !?6�st��)  IS�pIS4� *6de� [} I����!i �.�d e I�E���� .�m� 0#f IS (�sIn�i|ISCU�T.i�:*cIS ���{ c)hlrmulae2:T,IS1%x�+%2%xt 3%x�l 4%x�;�um=409(�)�9r �!:.��&Pśy�}�m�! H]ifc'ea � j-_J6�M sd�7egu�I�ubm!C*B d��YC$X�!E�u�!lDCat�+w�nA<)% Lbmea'd*�-^� e>p� �~�J��"�ith^=n�u.!l8 8] P-i�.'�[&����ƣ&�B � A��d���3];�vas�� �dy�́b���2�.�k= psul ��1rP�m�Z&�F'��S�JC�X6)� A� �2a"@Z�"�O�儁� �ed}�+�(Nl:�2�$^�M5:iAin ����s;r ��_A,FA��Cdic� �"��'eY�HE; also*�  Oion1&X�.�"� F��.0 Mann-Whit�>8or Kruskal-Wall�e��a�j�+ �9!'�lAP��exm T (,�@A'=8� A Gauss��g0!e$kr6( GLM )��an��ty&k%�ua��H�>%{��L�B �i ���(0Ip!m�Q!A�%&1 4P�"<.��"c9 !<#]&.eCPd3@3aB�"T�"q�H�}is�= �A�d�d !�Fc�@,q=�,9Y,�!�ij�&1a�ne��HPth�Qihu��A���t"���g &�%ba#I� ��:*&�3.L"�4 STAT� Corp LPcNolleges@%z, TX )�,.�/�P&�]!�N�8!bEgbl&3–9�v�4!x��Q( 371 r�wA of�p&"��llI9�˷palQ0��Ia�.!>D�6��Od �D� 11����5`� d 95m�D��! o �~5�s���D2 w��2RB�*�j(��PD5 M( ��2 ver�J56E|3�2�~�M.R#=g%mL-�Pt:����^96 kc��i ( 5;7� _�38� 9 .j�6�a5� 2�0l]nx�vP :V+*� 1-� )(m�1�yE~a�.�%�[�u�k+5S��^0AJ��� �J%6S!�:*�  !@ufkn���re_+A#Ut�� 7a9t�!ٌ thin� ͊| cm[%��W��"���. IS22+�!*k-%6�!��5ar�Xazc�X�~o�TA:�. A�of IS3��X3i^�[JU g�Cse ��%��ri`@ to aay�)f�4O .�&c �ue"�z5��W��O +"us�lea? %��.}!��%�%���Q� . S�N?9T�d1U��Jb�{e�!f;&�,��2@� )�!Cg ed�sbB("֑�c(e�V+ >�c!���:���#))��Y abun�7!�Չ� �!:�"$glia ,&��Dp_1\�'��t��Q��z)e�~0;H&�dM(�>� ) bet�e�n2.Nd"V�e�{a-�:PlyUJeh � A�Yd'D2%6D5%,��2�u�!�H& 2 �I.���H;d� e�&���*o� �Zt�Y{-��9n �'";��I�_a�t"�"�M�V[W�+-3�&�=-q7Ap� �u�=s.�8% ^�!B�( p =b  0T� 0}:�a#95uB0IC0�.D;zGiT"~ ah � M �'_4-��% ]u6�ms2�4�:�b�.0C���+ �cor�on��to:7atenv%��� �M���3A� ^')J�&L ��Z� ( p<)a!�;2<�#ute�#j�20G8��z�898:�Je�a� nd to�Ds�zU&� -�)�&I � {)�]a�T� I-��ngY�R���ata"Z7"Ug� tlKwd�E7B,�} 9y!�]1��[;�,�%�6��/:�. �3%Rsj�� E�� ��iD5.��A!AaX,��cy�,��asG�$ a� ��wn�E��eR�up�+�)&�$Au%�-�9��;��lA*;��&�,ȃ��<6y2��m' ع�y��a fAi�$�=�M"��6��u��e�V� �>��xF"�H%��Io&s:��grB!h���Z� T(aRP!�A%EͺQ�R7�uRn�[ �ᬭρ�Zm< 3tO3BiintN�/-1&0!�=[�E�>`-���a}er�;i|e) �di2C�#Y+.0)cYRBa�IM��:x!+�<(:�tI�)Y67L��y�g� to 85�&96 ATo"�=r�:�.(�Yg�d5\mA �A\ -]Y,2�In_F:Jݗ7zV�# GRrE" �tk@?.c��q�6���*�13;Z��N� �9=�W.e�(no������!�J�P)T) ��}2��M.tti.�@���)z"p��Vt�y��m!�"� Zfedu6ly� �6�`�]mu.�Cd2� lf�&��b v�H{ �t ,Q�D6�l��* ]_�AY%k�A^z1.. A bF� �a�u!�w�2 9,� aJ:��%�M7��ꁚ!%2��r +��"rA'�,isc*�pV��h3->�  l=�a/ n�"�"�&�N> 2��.,�t2� ��F?�K.D4�%*Ȏ�� er�����@>bT&�2=s2n)AESA� �BT�Z��3o<��9�JA!:9HZ0;7z�a �! �!m� p!���qe�754&n 5�on�0 5-�2R4}�&*-1Ae*"EJ�6�ZH �&& �'�q5a�! �BH� 1X$E"+ ve k�� U�-�2>��ɀ�&� help��l!K���Y -Ytr2�>�i�u�re�Af! ��. OadeG&/��Fe%��2�!"���m��S02;4��  �-#BkA��&4[���{Pd�)�6�� y!9�s"�|� .[u< n� �v6�]6�(E�2�daA�� 2�5i!��;�j�2/%6>�y�� DE�4R!�Er �AE��V�F"�jcE"�3neṯ%�-�is�{���.# �d�rNiy����x�l���"nxi;�g!F*0 �&)#*�f�8a er60il� �� �9Ol q��=�gAh=�."�=sam�SaMd,�erm[��*7KrQu^p�,�Na=�.�� a���>�7�w�#nm5ive@�T>��+.*���>�:H �w* 2�Z��w*�&"�%qj*on �A&�ir ��2�cE,K>��no�a�%&J_VDpm�Ya.�bT[���f9 tureu<�:�R���&'U6z�*�@�q12�A6p�A6~ ��&đ=�!��##pe=>�,xa2�6D�H&�~"� %�ch peak���se`b%�fifth�@>� O�>X�U22������:�܊an� �cJ6�] ��A&H:!�!�%� MRIp2� Lse~��� ��vw Tv�b �kb�jS nVLikew�IK�"0=����#r�l %w�^;B� �&�.ao*si a�]I}�d4߅���s)?&����"! :�J�r�&"/�]6k;U�&vul  =vb4E�Y[)"��r�this tim��e; evident signs of discomfort were also absent and it is not known if they would have been seen under constant observation . The preseTtudy has certain limit+(s . Inflamm , loc dand damage to the parasite �Pevaluated using newly �ruc4score variablel4These includedUiory 2compoi0( ISC ) , basj�pon descriptions by Alvarez [24]; cysticercal�, u=$previously6Hour group [27 , 28] �egree!�8contact with br!:8parenchyma ( CP� �bed in�1y(work . Whil!3ed O,small numberEanimals�c%�xnot properly account for intra- �correl)�(�i colle%��from a same pig can have similar features , which" create anbo!�we)[robust A�$dard error �0analyzed each�Has a cluster . DespAUtE.�,%�� meninges aara.u��8. A major diffee2twou� s isZquantity�0unique charac!�of%,blood vessela�Because�in�Nof micro4F,��!!be thatJB ce�ida�! 1raround!c-lly �ed >erem=9o�ys5[)�$consequenca�uld�E� �� �e.VA;!IYawa�ed���Treponema pallidum ssp . pertenue�s &4rtedly endemic�Ghana!Nas!s �A�8of azithromycin�$now�$cornerston5oWHO y�eradi)campaigAφ`a��4lower target da�was�8�%? take��� regi��of �� !j%|oltrachom� Ongo!z) of �raise� possibil� ��r!�t��v�&emerg� T!n1}=wor ?alterna��infec!bsKbu� ible�som5X ���a� . We�dH a cross-s Ral surveE�thirtw � itiei� wo d%�ct_Iwh�aMDA�5/had.}b�Cco~,. Children a! ,5–17 years�ulcer �les%�ŵt�? E5� enr�(d . Samples �M� l serologɠ Q PCR ?>� ll c� . 90x98 Bs ?.~yphilispA�neg �in ]�m .�Au2a�U N@�(, but Haemox4us ducreyi DNA;det� in 9��  c=�,.��ned�5�,� f�+no� cEromtransmis!� q . H .��b � a�qporA�7skT -� �a��a[of�remG unexplainEIntegA@oO4diagnostic tese� into both� ��post-A�e ille�system�requi6 be�cinformI��6programm� �t�� re-e��9�GtY�uݲ�[1] . Ea� dis1is&{ i��,papillomatou�(}a:mwhilst l� stagerZ:=bon�D volv�z,%\rar��%eIto� � � 1�i naso�Fynx� .OH( 30mg/kg , maximum�� 2g )�re � �wshownobe:��v� ARE��#Q�A 3w Fral<WHO’s)�.�8strategy [2 , 3!�2�!�lso keyHt$“SAFE”>�uge� ��� y.�y ͛m��( 2V 1! is�+ha�at demon �d�2(against �[4]��ho9 �delivead�s is fa&en!~hig wh�� heightudo[ ugy9�[5%Al c�=myet � docu!��E� , a.&:;e{ .o� tJ{ notably s��[6–9�!�develop|A2N ktn�� ��.j impl�ɴ�.` ambi�> I!�,e 1950s–60i� 1980��l FJ�V$penicillin����in��(, successfu� redu !�burde�W�v���!�sub A ��A_hv ou� # �P����� foX �.Zin Afric� Hver 20 , 000 clinic � !�� �re�2010 [10!� x ook6Ge\%�admin be�hS t>, 4 2001�P 2008�1NorA�n(Upper West *� '�ry [1��B��#!�i� to � ��-fI�H � 6�, ( Fig . 1 )�epi� . P!ҥLfu�7I�I �� very� N���� ag"!�he2�exu�-�tgQic5r� ,�7a�mo�7M non-genit�.Hin seve��)^� � E�is��[1��1��Tmak� accur}of6* data���.�� ��al� ,K a� E� or molecuC&�a�unj� wide rang��organism � f�0�Mycob�ium 2� !�G:�Buruli U� ��=;�D ao�� ur%�ne�o obt� )Mte)=o��R�to guid&�.%ef�#f� �,xQ�� 2C ,�� "� � *ZN� !ne)�b� r*C m���A��(mZI�yA:s currav� ���at�!� :�e&worldE� , ei��O ��B�AN~�W�Od�o��S ��J���E�!��� i *���� � <6?/ stil�� ed via�rNdhypa�s{ f . c .j-&B i�jMJ#2uE�)D 2 9D. :r>ob"�M�AyAVmoist �^D spic%rmwoS 2�!��of no�R&y;h�� iny � � (June–July�4 . Yend�4Savelugu-Nanto���f�!psix annu��%.�U@.~ of bl-�� ,� pH leN�7v%�.K:j�R�@al Health DirectoZ ��� y vi�d ,& att!(ng school (�_d 5d"\) scree*e0h�es�r~�Bu�pi�#��[14b "�w�a*"d� �"P, unles��ey�WaMor exudɟE�.�a R swab���x$FAaAarticip�w6��~e� interview�>.Gab��du" Av.-2��ce�� fC e symptom�*�se� �ei.9]th ��w��a6� examT��.�llF�A$ex �B�5I)��]��͆ shap�%t]e��recor�, fol��measurJof�lo�t%Bsh�  xn��classifi��[�AG� �!-28 days!�Er�dVchron����en:!�x R� deep re� subcutane�i&2;�a�er2 palp�promp��a�voluntA ex�rpX . Slo�o�anu��])�m�M�of  ��5�[ WA�at� EbeFtient�>^�0al lymphadeno�� ser��%%:�E;!!�!z"�.G �chB%�_��a �le >Y� 2e^placed o< an FTA ElAYM�$ Card ( GE��cI<, BuckinghamshirUUK ) �th side-to- mo* � �)� ng d�firml!0o-� �inAseW!t -seal+!#packetga sache�esicc�.�I%�da�� Q r fl; . Fe���le�ACs "proced -��ha�!�ơA)ap� ri�-�o� ]��.�o�� empil�a6�. S]Wwr!�o�(at –20°C �efer to K[# Anokye T��Ho? a�c KATH� Kumasi _d# aw��nd A�q"�"N�Ɍ le agglut��$( TPPA ) (t D"�A'Mersey%�,I\o qual�#vN pidEm�,agin ( RPR )� s ( Deben:ZIpswichW&`� �W#don2s]�!2)ti+d �&*6= ��7%��A(Midfma����)-"!ATQ{�Q≥1:8 �����M�a� in du�&0%A�.�!se#at�domA!�re!�˥�dep�n_b� �$��R �)�Ypurpo. ���" �:��Ce���DC P!Prevene� ( CD%8ext�!� subjGqal-time A�r�cQof"� adS:�,�W*� &�$[1� If a� �s%��U�%Agr2 a� rR�A2058G� 9G muAl�>�macroli]� � [16]E[ read�be��l[.� ard6�resul�S2�:Aa,��E7 addi!Les!Ѫ� $ multiplex5�>` M . ���!�, �y={valido'` s [1�&18� W �"��fe�%AK.D �Z 1E�e�,2�f d� "�s �Fisher�tex3'!m&a%.per��ZStata 13a� ( ,corp , Texas�I�r_na� �D"% "��h �l"tY uardia�(! asA4��''5by� ff fl!�] l��A�c� ar� rotocol��v�K!]London S� @of Hygiene & Trop��(iF a to{of 100.G A�t#^"c:qTwoBr��Ii B!06'IV elig�!(%�firstE� 18�!i�!ݍ�as �c� Edidu�$goV����#>*A8%bex�%q�n��, leav�{B�!=;986]. M��5�had2��problems�!!{:2!tyi�6�,� mar-pla� �hma��_pri�'or-E�b� me��a!5��!s10-�( IQR 8!�12 1L68��# 76%Qmal T,$-Jn_ ( 41*!%�l born�%��#�5�1< !�Y%�U � thei�(i&ct � &����E�s�Vb $91/98 ( 93��"r��tnr leg�8AA54 -55-�Vful)_-��l%"� a ( 53< , 54<NC1� ( 45 $4%OMZ� �s&�applyA��+t��"�s!�Ev_.�(s��violet�te�. faec&k&��nt��ntibio0#capsules() n as� topaya or� bulletR�Y. B�>or joi70�!s�0%]no-�!y2�iviAt59!I�  mildB>M/ ,aj=NE��lyy�-j�S y�V. (�� �� &� )��re�-&S�. Q>-9�a8&�6 noM�� " wX>~ . UsA:6 ,� .� r� eZ�nyMX y:�%: 6i�9A�( 9 . 2!�m�(���t�)v.u � �.� �LT*:s:�Acc*-..N� only.�!S!3t��G,)�%>i} >g�'%A�''L��oge./�&#om�|��( 8%:, 9�;� �sA*�0&"-! ��Q�'r���5.�U;!.đP( �ie� I!/�(t42*"� ��_!w�*-:morRnh$a�l!8~*uA �}��al� -Z facw"&04�,l-��-2�a�cat�9Cq��#nX ��6���!&�"9A0:����\� z�" M�prece�decada�I 6 plau3,��m�r��ruj\>�)I �[�-ts .2 ~s�tr,,!�k)="�,!whK4:�y-perx'-S�i� �,)mS f�/=wex&d�-t!�origi7 ��%�U�AM�to [7ify6g  �4�5eKB�"�+�`2Ew&�!3 �givT4Z�.�.�is'!]1�$y$T)o*K �(�mmmE6%J3/ *~���$����*6aɊrep�5d)�ur�1f d'(>�encour�gA��setAes ��AO�^co-��0!yrefOA'�(� }>\%�%5rA7y achieAsŃz�( . An)"�/.05�n�5l�RI��a��. ExplorA*�&N ^!_)E�'*�7 historic ��m�o!�� beyo�he9�  "��. Our �) ligh` oi pe�)c �j�|�Pr!�u4:�#a��-e ���-G^ 6�&��A-csE��&� �!<jx�_we )(/ ��s9�25� aAQ�emely}�4��.� rSd"��5�3'z,�:e �ihV1y6�[19,:���a�:�� u!�' �[20 >��&strengt!'�EUR�m�avail� to&�"E��^as soo M�l�TR��[A�add"-(te8gro�eLez.|t$%a����'�  2� !hiJ2�˵�e{e�)�$=b&imp � 0Q6_EZ!@�:��a,fC6se�&?Ped"= i �X/s�%w98!.Q� �8ord�Q"� a�� � B=~)R=:� �!�. W�-��Y!/ alse� umpt�(%�� �6� � Ds��<%#ai3�<st6�a�oiI�ef�/a��7�.�2%n�Wer�� modO: [21]�t w�%�m!�!Ok0�- tool4monito����V?rug!�ii�9al-�&ٙ. Of ex *UceQ}�����$17�({&no56�+��]8.� ����m�PEB!3 �%K!$#I2<traumaq f!1i� .�on *al� i% sucha�(Staphylococ�-aureu�(! �%�E:  . Fu�%�Y.�7!it>9�+ll be(*� W$is qua�o�  m detaia�U"!�� A�Y�a>>T*!+��6Os�orE6!� main�*A�&�engY9$ma9A4:%.�>N�.�*�$2z���!l2YA Most�0wei�"�����7Q)QJ�lei�ifN %�R�]腃62� .�$%T��� E]Dž�"s[��� nBT��` lA�&in���how� �0�?3&{,�/m 6�6&�<95h�K5�����'1|�ed6!�a .�A!�Q�y�o�%�s�a=:o |1"G?is!�e�!6��.�F� ��5we� v.* � �zed�&A�A�"t B: eU��an�!�Q�a9�ag��9�9%��* ed [22��� { %�� ��actM"� �e� fic��"*� '"�8&?^�r�8RwR ;,-XaG*f2�A5V. AEuiX�-��@A|�?%f2 �?�cS. �C2 !�"o~A9T�"� B�/B� E�a A7� 2� ��..9"D-I 6%󡨅@Bns .���Cadvw%<�E��5HIVپ��ART�.luBpg-teg!m�" verc� <per�� .�block. of o�rvoir es��ish��8!%n�gexpan�>,�W�4challe�1@. T cell homeosta�?!)� dr�|>� . Cytokin%vy9�reg�'ng2T�+emw" q��!DE hub"h�, trigge- Jak-STAT hwa`We*�G@��e $ofacitinib%�ruxol ,� FDA-"� Jak inhib� �o)~ se�A*!Dt-ddhe:�in vitr�W�,ox  d[-*�8OaC*�)PB�ind.#fvoA`x v �tro; p!*5Asong�B`G��&�Dl� K A?.z0��Sk.a�./�7�*�9c�/ CD4+5� harbfj!�h�0� �{:�empro*%%C�} t@elEZ-� γ-C� pt cM�0 ( IL-15 ) -i�1�0�� q�or�ereby�g�n�/2z> �  �AJy' er�\iva�q C�� 9dysqQ� ApF s� �r"Haerapeu-mod�(^%�;!��T&AT1�� -�i�.f� toge_ �ao�Iȭ��-l� ?C@� fut��7�&�A. CT57ret�ja�{apy (Ł�> yiel� .�k;!C�!� -term sup}�=�|loa�'�mpsng�xiva�D!�i� g [1–�1E�s���fai�eJ� !��J<��))!� e%fI��VI9�YW� Un(͈ i��Fng@e� 6J~a��?MAQ!�M�TCM�x i�alTME:��9�,EM]��+�|Atoi�� 2��)� 9� �k[5 , 6x'ILN��e�\,��aB�AG&a�:)���a'� � ate ɯB"!�A�al!{[7�n �(!Ehea�6�lso3�&ype Iq I�C rferf&� ��I�1nf&PP�j!�I��C%�A`[8PF8=Ini�I5mpoR+gI?��>bl!;AYul� ��s��{O�1i^,�.ceA�us� �$vEQ,"�$���= ir oP+�*as:1a� rebo?d �P�?i ��N[12!�We^�.���B�� 4 n2&prolifeKo�uK!;.��`o�0�_m ur�_A66KP aa�l�9�ed�0[1' 6F "`[rol1~7!�o&4 pm*T )-:�Z& ACTG  �/t�6( "R)`(5214; www ."C 1�gov!�,# NCT0009967m$6.C5m�+so[&d%Ma 70%A�r\�absol12 �� �MZ\�DP7"�)<4���r�9!�":C"b�#m2�a� �Von��� =�eȉU�A�"�s !�y6o�ucejof�"I[1J�,FI/��b��!K� Aju�R �AE superago�AA LT-803 )Da� il>Rr9�at%=2"�(!��.i-�)�a�Q !QC2%C�'Z�3U;7�in=�' reco� Hby autS'6HIV&� CD8���-�D Phosphory�5of%� -5 (� )��� ed*�!-*�of),70)J��62W lea���g ro-s�2ICA�!�&� 6F[1��C�. G(� *�:�. b�ng ;)<m ���s M i���-T3�E �� �"�S)�*k7�  veN� 4 , .�VSB�Jr�, a do�n� � v�A ed�f% ������d" T�*�(��g�G248��.�u:HLA-DR+U1&fpopa{� af�S$a few weekEY&[vZa�&t�x7)�EG X�~ 3+ ,�+� CD8+��Ee!�"�B� !�24V�9M�I3�5A�@uU �!�!6�t&�to�-�X/%�[F��r(2uO 0Killer ( NK )�s)$�.�UO�T�}#$=P%m�a�(�$he-�6m%5�)�AoE<�8!%.�YD.mI!��{monocytCder'DC" *t�Z, DC- ��2!f��&�marke���;!�&"by��o� lipo�\sac�id�LPS )Iz,�PA�!��ofa��\� A\nu�dap i##) �X� W� 5��.�H.�%3ed6� .5&xRJ1��gcy�el� physKdn� > C����N\Aj2��� 6� �Rdisse��eXL �% es [��Hereiuw$>� S 9a�x*"V!extens�&l_�+m-�x*R�e!5.!����By`I�x92 �ct O��llv eE�"� >u�%� �:2�1�me�� K� m��A��Tma������Ginv� g��Ca46a#b*^5C.��6/�L�B( ( n = 37 ) avir�(P( <50 RNA copies/ml )��,��'2 ( S1�-)�",!q�G\v�i��& 6& �"as����n&of-�� �g[ !D"� ���$zm���B fv:�$ berr. m�.5[13 '&e u9�sizV]�37��rcox'A!�c)�^d v6u,fitpFinb]�$!�� I(iva�@m�i�2$Panel 1—�,  2—PD-1/�R% 8 3—�  p6� ; S2UQ���A�:�(a methodA8�*S&�=,%�-2M!:AQ&@ ��DFm&X^d�b( IR;�n 3�I7'23�`E2n�J;N<22 . f5o�� �CI RTg2g"  ( S39*n3� =XedE:A��>O� y enQ�)-��8( p = 0 . 019 [1�]�01� IndO,�����a� �&�*� � 4>�( C�;�an>�( < �B�( E; �� �_to<5�reBy~Rw54!%0 1a�&bK26. Au adju�Y* �DcMT� CD4/� , nadir�pre-ART�-11C�s !4,!!EMJm�TU&�37.�rn�3 �48k  ��"5A$���vA�J!> 500�)�/mm� /a[�'m� < 35J3g*VqX9'*[I( SC NCJ�2�}o< 1\:��M� �D��,aN6rmi!c��z��?las' m in naïve= a�6��0Z��,n 1160 MFI )��V��BL 611!�)R�= 1 15236;]"�E(18 WilcoxonbDkn#F*7�UA���1&C6676�H5>I� !B� !�7t\K ́�WTM�E0I��<X���en���)e bulkAH� �~�z�� 23-��dT ;i��K�`q]�:A�m.3 7R.by� Tn�-�� ~rnaliz�X6�/���5P9I<v�,oUV face ��i.�2lac%-X}��!�B���4 ��>w�Tls2!@�g-AG45RA-��Z309!:aD�Wi (:$FKr �� |9:o , IR(d:��p, -�(�b 6916�b�716�oFCe�� � NIRB 5314B 5288 B� , RT553w609��ahe}5�"!�*�e�An�iif;1�193��:) 26�;.A�!PCM��6)in%Yf 8647��=<2��iv7ST NC� ��7���,6�A3o%!�� "\ M�m�-�R�"A[}�o�1�'5���Nd[*� Y) m<o�7R1"zup/.�$1e� h�(� 6���:�s�7i6#�se!�jJ��We��1ed  .�?i�:up-Y���&�[3�o� o �i���gv�ALGR;[W . PD2�(E)2�. 2p2�*��52� � �umA�R%A�m'!�1TM.�) ���/R� 1�J^D�?I��� � b,jnN-�OI!in)�M�17bnIEׁ�E;is^6up!�"�h0�%�Eq�EI `DIa�y�953��*� je�� 721 &,��4� 2w Q�.� a�)A�:==��bq�ng Ki67.��^25!�c�b7T /CD3E!3�G.M2�H. ": ]908�C��VwA��A]CM �E 29 )�Q� >���: �z�*=2 )Z�6 �c�+�Uw�%�b�q q�.+� �0�� e� 09>v�_� ]V�y��X^�gQ�f2�2�QVU��:>: IR—1�C 1% ,af—h36%%�RT 2�C��Q )�. [�>c� d83d!212b�  55%]L :NbT!^78Dd38F]�<and�RT!��t;e�� �1>Qe{EF��BJ�p2= 1�2y. HEe�R�M�" �>� E��>Ia"� �:UCD25+-�2]�P2Um�.�!40� �eHa�(a .#$�6x0��3�1as�g.�4%q�oE �!�V� y ���B�F�40YB3E�� – 2�H��56ZNad� 4[I�44g42%����Ib�57B [5�OfJF� � m->��s=s*�� 2u 9p�&I�:�U�2Mr7 vc !�*V. With1,�Yo�) pi�   1�W4&s 2 !tor 3,B+,Mw�:xt�� � comb�W �uF�bes�y�Q�"fg by builo%a�>grqz2.m= u� CxFaF [39]6;�(|J-)+.�:g"`+  �E&���q��-� �1��+n��'��)d&u-X�.YE��zzt*!��W&�( F-s�.�7 i . ��"57�mB)�k2s�J��I@�+d�*G.3��� �f�5&��'�+,Zcf"i^�rec���(!�2����h8mt�� "�m �6� B'#��ib �o:� n�"+QS1&�4���ex,�R.L6�f <d rn) h$.�*,% $59�iѱ,��n1k^i� d�D&�\ fash'. A�{*of2�PAJ&2R$�!O1�s �leQW abroy!ata�.z#≥� 1 μ��a%RuM�or( �au�l�Y�9�Fn!R��P)!:� ( 10-A�Y$T%).4�coP�)wat�0�� 9-%�d 7BSB]M3!�>[p ��. %�&wV"n!��:�-=!�M�:�I=�� �C�.� . ImDY),2,a�.�R�rvz55lJ9,U&� DMSO�lnG"0�s >%�1�p��|allA>0(J666&6)E�>J�F���� �E�!}��". B�q��-��%����1onj�V� �� ��a�*e&U��&&9<����a~!g9(��4#�Y& AK�V��r��� e�2� a bBF*>�58"dD:�gCwo*d�, i�_�oA5:�6�&�Mn:s:9,"�*�_7: Iw>�(� sQ�O=AT�.|兊r15]�ZD A+he& J��atR�(Y��SiA`� ]��6o��a�9~IFNo.edfE`&� :m1aH1B!� D14+��+"�&� ϡ�02L3�L(���){12sWtpCPŇ�z%l�OAqa�%D`7d ��"* i}�1!�&�hy�vF � %�&� [ up�aUof Bcl-2A�� 2t[9. "; ;��;��al!?"F��21 L�8"�(><B�3[{44#1��.s (%1B��NQ*. D )v�V� orE&5"�3)5-�of�1G��>�Qt�8N  F@ u.�3mo��B� 7F�&A`�w AD�X!_a8&� )2� = 3=  5�= �!u� T]��'i� aEeBA �6=�eKM�}:b:�!5M�jF:6� :)!J}BE��[af�Q"I&) >�*K�!6�aie& �QL�F�Ap�<�?i*iA,� ��� �2�H��b� ����2��v��!&B3aol"5?6 a),��2)�=�h@Eхi�:� "� ;��Al"�B��&� ���y � :� T"�D� � tAV5��. �.�D�>� G� &@�NO�lyJC.`! .��erv�mo{cC-;1/2�i@� PBMC�i!crE��4!�xl"�6A� toxi�Va1PAHN� J0� F�shCV��O /d�5e.�D"a@# 6�1mV�0�&9N7�=enCl�><241e,WUsf6*p24��x.0Hiso�2d �"�0don� !�*g !k CD3/CD28 � � to� �}��2AE2��S3S4� L."P}( �Q���c�x WeEk-�*� ,(� 0E��C}".Qo�c6.�8!de nov�>�@�(Y/! ~��=f��sp�l���5)t9 4h j�*B;)9A��b.s:�a�enSunil;5��#sI 6�(*F0Qo�Sl# &-4 V!6assaye -��>U� �E� ;"pB(:VtiiQ�5cyI�A0 EC50�17I,; EC90 6 . 2 6�NI�TL�0.H26I%lSi�"6R�^��٬�- �%�Ja=� �3&� Av�|LRiA&���cul�Hd� 6w6�I�jM:A��.�K�2� in 3�!�5q�3��v5r2H:��5%G3/;ab ,&�Fl �~M�c�}�ڝ�%p-5s lA�2;*lM�����MvĖ=� H%AnnexinV-LIVE/DEADT*B<taNvOo�{ĕ�2�%�6)1�� �-0�sI.ws)���Ilos��iҎ��:v <3A,1 I3: p���vS:�Z �xnc�>}2- oE�o3e��!�s"M*E�� n � �7�i 2A3.�%,FD� E�.�:�F�%1�#�9@s�K2�� ' 2.�[4�Z�29�}���M�YN��La��:�kN:�$Z�:�{�Ve&/S܄g)k6-�4"�*:C�:� `>f��!��:�?��.I $FAAU ir!� �'M�6��6 a CXCR4-tWq$ , GFP tagψvi*C( eNL4-32�a�M)��<r 8)� ���Y2ߛif�P��%-:lby fl��ytome&� . Ate{6��.vr(Ŧ�D�?!=10Ͷr[ �e,v ellu� :I 2A�dA��2 ! GFP+L6R2UM�t b��y CCR5RS0�"�: %����UyIz B�aX�<r�;u��;�x.c�AS�� � �,!av+�( S�S6��_ ._ W�<�rlVQLn=A�,= id}T!� d �!ul[�a�(`dO�b/^QX� z�� As)�*J_ bQi�3r�>stla�>�%svo [42�P40%)()���d�i)�->!?< nti-!�2��] E*=9:T�� a�:@b�= -,!=6�?�ea�%��0h�][4�4�<�7C;llDM tissu�)ZU�2B"#[� l}E� s exer!�b�t[)��lon>�. A}�a��m�K sour��� ng�?�X&* �2 :�{r+ ��q�2< t�A�i.� 6� of 33 nMf�~o�tra����}�(6�,������*w ac�a�y8;U `$.g�2� %12%(�)�s2cl!�6iN-!.Sy�z�:c�X!' link"_ ^l to! t�� !�5-�� ���&U M2�!F�5JU)���fN CC(6cz:�ɏ%/�)� <&�"�L*�7H se��"e s ai�a�"M����sA&.X(J�ex'ngaYK��� gene�AZ�. C21 alsoU@�{ 6:�toQ���C��)k&.�,E.s�PnO}A���)�%h��ieLcICfu ��-z�4.�G��.h A:��=}L&�!}JH� :$ Z=6C�5V&� r>D��3h3j p�!E�.av ��=�N�%�]�eF!}!�U̎@W%r"�1'k~O� !O�g��&�VmYA|恴9�f&B�T.� "��:bo�8a ]-a/�6�l 23:��iuN^2 ��E��)��D� ough/def�?!b� A�2uG�Nt�� )�͇"�F"c �3�.3E� M)�2e�6V.�WQ {,]�%��l*(�8Axe�is&}-�*XI�!��%�� �H or&� �!ym�?��or�1 .���yp��1F�3�Zn�{ex���1��aaed opt�fiT>}&���-A�;p.� #�BKH)�[��.by qRT-Kl�d��MC[of4Y 6m�&��"�DQ~�j���0��>�<000-fold versus [A.b��km/&�'o�Q��L�P � pa.� E ( > �N1��u;g 2H*6^B�B� .a�)/!� �^��� � ɞ"�*(Un�2* N�!�� v ,�hC ",gE�.�.���� >_ �g�i*9,( diluE�T� $ Violet; SES9!��u]��42�v�8/H@0$^/&� J,@ S10–S12UmNl"~\4i�6O5AN2�p2>�Ran�a)����`,)�2�5 .S��#�9\I2Q'A2c�ե� Each!XUmM�A�4sB� !lP$�I$*y#��Va�[:9_&m��� �*�aEa�\��.�zZ�y A"��,� �'l"0�O ��� Vc )g� d A,acf? �Yu^Mc�igi�y ����?CR*#�o.��pr6RS�U]�. I�#��� �'vga��2e_U �NRIg&�L&mlY�q*2NY�!X:� Vdi�msh;� -%&?����js"�phe"� � mp�s� 1BZ!X) r*uV��o&� QZe ��..) �����&� P �u `�Ol�&o.��Dorm"Q? \��2\�ksynapG�%�d&op�*��Qsspqj��}!+J�Q( sche�c:��4APa)U5���� lots "� ^O>�[ labe��� �!C� �( ( CTV+�xnd.5/�Z%* ��i���2:B �^ Dir., . Un���L��, �*�J�*�.7,4^x9o?*m7;A@ed!-�� �!9P CTV-"�> �%]%xco-��- �(%. 23% - 94%*�012* �B�sͧs;1�� t @"A`���X*� srP�4h *���i\r'2:A��)9�of fifty� �!,-`Ek)9)q�2 ile .B.� oa 7ga80b� %�(&� *T e ��6�U�%��.`{.|mE!�Z�TX��+M:"{F�.m#by�P-J�:�O)�ɾ4B:��JB��nd)�C: graph�N"�h�n%m�`�wGX&e*��ofN#"��:���:�]?be�a��" Zk" �2� �s{w��g�E�N�ɫsynerg;�o�|��"2 �O!v!�K'i0`j+A�dcu�E�('�5Q'�� �A��q� ]I��M%<��i�X*�*���� �FU�0F�l�(rs�>8A����F#`�funehvW�ni�nwdjs!�e�!�� ��� �&&nB  �&u.E�5A*Z^f��!�.�6�N"SLP76�CD3 zeta�Owo � �M!-r�9-t �cas��[16 , 4�j�E5A!Sw� at2��JD&la&��!" �>���*�[aB�(�ady>8�m:��($��. ,RO)�!P, v�z�8 S3!- dngQ�#�-�#Wq@6��A!y:�E1A!9A-�Q�A capa+�&*��#I&or*!( T�a�2�D3��!e_h";d�S� *��5�)1�) )2�:���0!>!O1o9DQ!I"!u �e qz�$FN-γ�kglei�^�_ 8L2+TNFα+IFNγ+acq�a8+�@a��H�|^ tk�Wu/!:�!Z.>'N�was�*d]0atbAUdI3bov�dCma�. ]�Fk.F�Q�[3`mS=:1up�}MZ�YrA�IH1�T^9� 0�\/.�a�ira-j� !vA.�,[���e �}KNd�gag p� dD�I֡^of |.�s�my" ,�uBeE�"],)��\l6��mUc�ox&�iAOgŭ��>=/�,B.���-w!�2a) Y�� �A��(��+�S18���=)�b��~6�Ron�g8*97i 5�*r !m.�&�/X3"E*69j� b!/�!TX � heorA�a��"��s a�eIW2-wicE�?��s�-�ae.u��Rb� ( P1�*P�P50 P7�P90 )q:�.7���2"i�Q""� 10�I�A� "�%�a!�6�m J[ �S�in�6.� !�QqM�A�ectAx�K�6"S(��E �r�$/+&� /6�B�fa-M�V X�f��ll�&Dh �� �f ( do��aes;� 0dz"� �6�!O*N��:�"�;���.�n4` vequival��1���ves01.�,C*!I�A��B�meAest-���!xh� s . �T:�!:N)�sK�&j�lon�r :{k�es�X#aA.5?6�A� ?(� -�w�#��d�8�l�ss!m![.u�74$7�[13Zya�%R18�#0�x.�jB�*�&E=is�ơ2!n��6#B�7�6�X�RoA���g�&��'!'Ab7yF-$�|16�pb&6�gAM�$�lu�on��;,�#D:���o6�`APR��:�A &�.� ART-��f&� � �~�N� .��� iAB��at���o�"&� �-�7f B�%s*�A:��|(N�a:�. � <�+U#<�.,:n Ma/!� .>�H�%!��.[�fF�6� �M"G� !áp2�^��s=F�:�m�T.�AY6H3 cct!pa;.4? �Y�a< r�"@ .� S� =�{B–7Qc$2xa���� e,�p�-�t(��l-�AF�s�28�U&�T�]nA A�fmr_(p",�VD�R�C~2)I$��xo��byJ�Wa��C,.���y�� 2�m�T3&�_"!��:�z�5g�.^&a‡*`F, care��gpie*�&'-�Tf) ։ alm�0��{pF4*�Fd uŇ�a^��� �or(�,�HIm@"AlY�6�n,2�M &#�����:��s����D2Mt�4Q{E D6+H)�#&H>3�rv>��i"/\IF�o�%:�xy �7e-*0ut���.�Va� �2�]. �&� !���w,.�T=AQ8�M0e60�o�����4u�&�4%�: ��//0aPr!}��: 4!�&eF�!* >�q\q]�x��"�/F�E(�afSL com;*��*"VG�s.�%`is� �B��FDB� .��n�3w��4�"2%%��ppa!�"C!�"Y�j�ub� 5@8i�ʡ1�]�ph�C&"�}',*[&�:}n|ily��A `��L";"� E�N �( ";�e�&""VRh>���.�iB�JAF���,��;� �*�C|4!0%F�.n].t)�&�4 B�%�@�lu!�}(6�-e.2 g�,F�ALU���(� s�-.di�a�t�F�eoq&�Z]���A�na�52�J�Õ� [33]-S"X�K�&e�b�<� "k�,�*�ym� �="|!R2�lok(an��<i�3�#vo�/!t"��Ԏ���,h"�0: [�:j�.s.�"pre����� death� +� =a1spaaY UV���3piL!s� ;&�K�Ρ�by6�a -}Xa~:.a��� . 1cI#.��*|�Fto* &���� M�m�*�::#�-�iisg�.�?YUsof��s =oFb.mK-`u; �(��z/w�}�q�rh��� ��1649�=S=�7u��p�FC�Xto-]ɽ`��Ձ~ [505c�TI ��&�>o+Z�)��sigZ!��ti�e�$ce [5����5-� r���<.|)'����kJM�Tr!Z[5hk54� a|�Uo�> *�Q�1�d>�%L&̉!����*`Gg:k�r�Ql�?A?��!��5�9pr��a�z�)�eda��g�' ���yp$2�ud�.�;�L����B�!�V��v�sory  [52? 3�nreg" ��-EO:���� )��o� �l@r�[�5<%5��%6�4��!VH#=T������D-dimer�#�A�0 �"��[�V|pa:�eM8senesc�#Gma2�A a�&�;ge��W&e�"��=�).?�]�lav��kpr��t-�.E %ca�>�+/u=!��]�#��D K�z�!�A)�� !)Xby.3+M�TmK ,.�06�u:� <� �&� pFystn�NIby�"] � C� co-rofs . La�C6-6łQ %`6Ac"p1�  c�:2�4a�2af!N�� �W!�k�:3}y�Eg��la�CR.O��5P���) ( ����!�qG)ELa ��:C}�I���#�.�6sX �OErh%*��1+z-!;-�a$ reshZ9of MHC/�"!�le9�"� , 1eR��"6By�$� c1+e&(�)Vm3B�Huang eػa�XA@qa� �'o%-����v�. ��y�\ra�o��a�+���o�>�%eR�V:��� Weak]H�e%�{Ea��J���!�Y��A�*Hof��r�$"<6IF }ſ��9�� f rE4 [y58 , 5G����onr-Irou��+�3d .�V�"68(R�>tqj�'�9�)�1ir:�*�*.6�^ZsӼ �&� 7=>�.4�! ��gag">&-j:%&�!s%�.�80Ah2!�3&�F86=&�d�8u�.�T/��4ly%E�vu�F���r��"� A�FX�zad5�DK�� ��tә����irect-a�n@�hS(Pe�� I� step�aNF cyC��/!�"΀�BH:� er� "�Iub�n�"0�ion� A8&�.x8 �a}6:�,�cri��� ��n"�;m� ��u6�BA�.� �(}G���}8(nN'��r%h9�%� �U%���Cmpl�v n)��a�R9;.2B� !;� ��!pl�@a�Kordf���+�QW�J .!!o�� low-y 2j R>�"M�l��i��v���n NIH-:��21-(( se 2�eJ�ARE"%^2\en��`. W���Z�B+nh�>>�*epa.�%nd&�#he Vac"� Gene!�g�Instit��,of Florida e��rev� boart�R��a3or���,al ��s "�$ �&s��@�Gk��. IRB!=e_�V*!#00006��"� on April P 2010�A�D'�7Z� )awl6�n&��*�q"�n@!)�&� 2�F?E*2�+ ��*�puA��I�d�w��ea�^�)!�Amplic ,M�4 Ultrasen 1M'�8�oche , B])�mwitzerlAE�Ci"�A�����C:��650�DCM.R�perip��l��od�/onu&��(�/-U6�leukaA��ad�y�7dj�A�ifu|3�A�o��& �[c�!y����!2��6�"0aOR,9 )z&�;��&uP# magn�) bead–�*d��*�s( Stem! "�� , Vai�veVB]$sh Columbi�5Canada��C reQ)d)��M&� P,��aua9vѼb�8. A"� l`�-hoqlN$ELISA [60]E��)�F�**1 �^�� j�^R:"�`K=� F"=J�:�.!TeV�,�&sh� nric��S( V�9( 1�67)5 x 106 �)IJ"� �=�'�X�,S0 g/mLA_!��4 ( OKT3 hybrid���B;�� A=�A�7c�v !W����0:^,28 ( BD Biosȁo$Franklin L0�, New J�P�]JD��:�"<���.� *�I( 180�Pzidov ���"�nM ef�rnz�('r70gr0 ( Cat # 1168i,�Merck &�ph�, Inc . �9 , Di~�o?#%jP}AID6�. ER65�� 2Rpre4 vma�~[MQh7a[U���R~?³X8( pBR43IeG-nef+1= 1134�{%<D�(E $ Kirchhoff �%vr�9[6b,68Uu�%�q�n.��+�H� aB-f��S�nau ��GCH2$efI�a�'��2�iم��@!V cl��d d�0��1:t� �5"�&2T,�NF�A�e&/.�U}!�5[et���!.l,( Selleck ChNP, Bos� , MA , USs2or qZm�"M�"":!��J���1V�A�PLuaq8 lu�ai�PM�mR sŪ"^ *bM6��.KS�nd y#2n*�K� �M g%���uca�%&A�.Ui-��& !n7�cue�h� 28E�]m���U%FU� y��.U�!5�wY��incub��Eb6�!�;03317.vA30޵$�!"�V_OL �c�5�oıuC}���M�F�a���$a 6-day1��fou�)&O-,%�M�!'K�& �#&>I�.� 5*-�6�5�%�:�%� �� Q&%Z]�!�*�>�8 ����F ly� aheˣE�1&�*� Day�e� ;a� �mly�x� nh Alu  Q� is m� Tu$nc(�e1��4 �N�)�Hq millaF� carr�-2�M)�f*3 ,&<�� p�Qr*�/K"�,!���*��B&B@FX`{ ��&�{a� body�:�� -A700 ( c�� UCHT�,� X�-Qdot60�� MS �� v�-�$, Carlsbad liforni� DMPerCP Cya�LRPA-T�e6� San Dieg,�C���--DR� J�L24!�:���P-PE*HIT.&R*25-PE-Cy�d �M-A25J4)aI�P>1 EH12�hH�BioLegen!J�"XfAP�B�Ae).}Q� TV;�5ap��m�begin���u1h� �Jacka@*d��*�QA]dye; I9��C�� XCR4.��e"jY�� �\�@repla 52ZD3%���Cg-#)�, 12GA{]/���.�2D%�6 �O$���� �aH- -Pa�_ BlueUB,/100 , BD Bi�osciences ) in combination with CD3-A700 , CD4-Qdot605 h8-PerCP ( clone SK1 , BD Bi.V+$45RA-BV650. HI10V(BioLegend )+CR7-FITC(H150503 , R&D System�Land CD27-APCeFluor78]O323e6��. For all stains , dead cells were excluded ��the LIVE/DEAD Aqua marker ( Invitrogen ) ZLflow cytometry panelidLacquired on an LSRII28er using��CFACSDiva software ( Becton Dickinson , Franklin Lakes , New Jersey )%.analyzed \,FlowJo v9 . 6%xv10 . 2 ( TreeStar Inc . , Ashl!v, Orego �$To measure�\impact of Jak inhibitors�γ-C-!tkine-mediated STAT5 phosphorylI|, PBMC-�8first pre-incub74for 60 minutes)�pruxolitinib ( Selleck Chemica%�Bos!9P, MA , USA ) or tofac�90followed by a](E] . SAee2_washed%j�at 37°C �,50 ng/mL IL-!�.�,, MinneapoliAUMNe5227 (22aT515J 1r1aD.s% X10 , 000 Units IFN-α ABLinE pres�TA0compound . AfA�155�,.fixqw4BD Cytofix FixI BuffexB`A�$permeabiliAᅹ Perm6IIIa6>�.%8}�%��v(acific Blue��.�, �С>�, A�<1 ( pY701 ) -A64!�c�R4aVQ63 65 ) -PE�0 4/P- J�!,ApY694 =-CF594C7/>%JL.��T%] recepto�@,TCR ) signal��, b��enrica$ CD4+ 7�6%�.��3�6�!� surface)� A��dyer�to �.5~�,cross-linkedr_�1�on ice ��� 5 μ�8anti-CD3 ( OKT3m�628A��X!�10& goat H mouse IgG:0u�� �����m�3 Zetae3 142 >i,K25-407 . 69N�!ASLP76 B28B}uDJ141-668 . 36 . 58NF�2CR-induc�Byt�6 produc� �lab�kHIV infe 2B isol�7rom),negative don�,e_tre 'or 1 hrY�01–EDM2v!stimu `� hour�Q�/CA� �.! Brefeldin�P5E�l )Yincrea concentr�s�Z.�(versus DMSO� ᙁU�� 2�B�PB��4P  � �J_saponi���iRD then6if� 4ochrome-conjug%o mAbs�ap ���1�s: 2 MQ1-17H12Ni, TNF�� � MAb1Z� ���� PE-Cy݃S . BM J?b� .�on��cCD8�� response�A�$gag peptid�Gtotal E�ART-supA:sed2+Q�� tha� �resY overnightAvo AE� !]A�retrovir $to a final&YkAjP200 nM raltegravir , � ,nM efavirenz{18*AZTa�he=�day , 1� millA���sA^tdiE����q�as Fs:I�a,� �R*� at:�001 μM�  .  }�a� a�� a�&� . FuFA�"pre� �2U$either notuy ed (.��z qu!~0ty equivalent!�that u!��.poo�or.X�:� g/ml(ed Gag!Qsen�AQW0s ( Cat #8116AB -1 CA� '7PM�SetD ,IH AIDS Reag�Program p��b� 1Z����� hybridoma� /Al��7 ions��lyb2 Sigm $Cat# B5936�t��(l , soluble6� � >� ,E�Ijerformed%u��.2Uwa�atE$previously!���6�!�A8 fullWai��A� ular��*e� ssayu�ys )9ed sampl�2�live/dS fixa! violet vi) ty� :��@�U�5 !Qbod�: -CD19 BV57 � HIB1Dn"�>-CD4 A:x!�� 14 V50� OM5EZ� S8 BV71D 1RPA-TR� 53 Alexa�B� a single!�h��%i� in 2%!� maldehyde araAQ aled)"A�minA=0room temperat8,!qn!��Ga݉� 5% S�lA?9�� bodiQaddM�6cEing-�T�! ; 483 )Ab'5@�*AP&�B27�=�. C&V�,29PF�U data$ co�A��tessa .UfV�*7"�*�R"� ��fy!�*�:� bystander*p of��&� by�cK B� -"� individu�Ef%���ȥb![ Trace V!tt�� TV )N�to track%k�Á�s�}becomE Ż CTV+/GFP+��left un�5�*TV ���� 3��� var�Z��&�B� or�X(&� contr�*.�out�B��aC��/28.�A�spinoc*� two %sa� RT (2000g ) N8NL4-3 GFP reporA� viru���Cad�al N*O" ,MZed�U%)�%cmU,in RPMI plus��Fe: ,Bovine Serum�co-cul�qd �un, b posi b( j  1:�!�an.��day�B: � y�identifi'�[ex� > of%-in�:�e�confirmI�>observM��ex viv ti-N efA�s� �by6�ccu� � ,steady-statevYz range2y huma? a pharmac�tic sI��wa� �e.� plasm� i� B��10�P20 mg bid dose regime�*�w metekf%)basic 2-�artmenApopA��:�s modelIr-or�� oralgorp8(�A�lud� pati coa�a�vfit�to��� �0� 163A272) + Phas� a�2 tri�u�tgov �E�,myelofibrosiA�Ma -A48primary subject�Kan ACTG Z0 ( NCT0247565Qof2.in AUu1I; h��-�ut�a4thi1WD[31] . Monte-Carlo1�� e�&� toa dict:��tim fi�of ��theorA�a� �] �edYAutenA|ileI�!�P�P2�P5�P7 !�P90 )lV�.�{�IH�8f� star$r*� , which) :ploEB. Since2.is ab�� 90% � to s��inq�(24packag�� sertE��.�"^in�:i10% f�Wb�W i( FBSHAein�� EC50 �multipl�� 10 before �A�.� m  d % CV%c:V}�"!u�,a�AB:-qi�abu�r���-8Ka = 3 . 43 hr-A>75%�e�sh ic cleara!( CL/F =��" L/hr379%ųter:q.AQ @fkA�]ndA� iphevolumee�distribu� ( VcB5r7 L ,�,. 9%; Vp = 1�885 . 7g= lag-e< ( p . 052�.Tnd9i� � � ⌠2!,O8!". I�&� /��Hed� proio��( log-no0 ly�e�noE!��8ulaI�RaD2BU"8 = ℘ ( e^⎤2� ) x�ae) =�Ar.Y:�[a��� �run̓�NONMEM�'( !�43 ICON Develop�� Solu E,, Ellicott C� , MD)�nd�*tisticse�graph�� =A�A��obw ed p-valuq)��corre� A�3� mparis�� Benjamini�Hochberg� H ) methoj Fe[sel6� QLeast AbDte Shrin�&�S?O��TLASSO ) technique [39]���x�� m� �.U"� �7anP i: 5]�be�Hf(-qa��U� as optim �$leave-one-�A� valim�ml%!�ed� n squA�err%MSE as �%�orl>� or Bcl2. aiB memor� set�a M�regres: �ap�bw�WMF� or %pStat� a��f�rug'a�B)takinXɷ��aJo� side1 ny!4-�A�!ae gag-�&�� D4��,W a"#Wilcoxo� k su:stE�2kYTc�Fig 5 !�S18�q�fic �of�*\5reactiv#;J3FE;A #��x F dolife-+,x co-r�� Bcl-.BX�D�>Z!R;�#�yFJ&Q�@Zigm��6�by-��ANOVA G� Sidak’sN��Gt͒�F&� i�G��$Pad Prism S0&�.�a�ue lesA�an��05EcoI�!ja���Tt .�Spodoptera exig�%icroarr�Fggenes�iY��3 NI�challeng2�pe��-A"baculo0SeMNPVa� wella�a}ralist20 , Ac2. M�,results reve��W[!"tr��he host'nscri�A hut-ofPatt expɫdu�I.�� ,Fsh)%a balY d numbera&up-E�down-reg�ed�si��&L Y�~<. Many immune-re�N�*� tern�"ogn|proteiWg%�involnA<al�"ax a�s%�-� �]0 Qco4form.e�melaniz�z cascade� f� !�b�2/[V��.`!�of �:%a�wI�� larval gu �M�nIZ4is known�af�Va�u %ezorganism��m!�of�s�:i� !Dgrowth%`d*_ fun! W�(rzas�#whe��>zsrT Ɓ{e amoun��biota���$� yr$bacte� load%s"�A-$we hypothe�Hto!�as 7s�  �2Sub !t!�er-�n,u"�a�1����*V"�%� �6L� enhQd�ʁ�lX,e,ogenic� hdisperEF.!�discu�э�mK-��ces� ?paD !�AT{y.~ +a�d�E!�rol%5���~�J Ba�esE�large2 �E1 5 arth�dI�,inly insects���! Lepi�} , Diɇ�Hymen͗. D�mtheirYl� cycl-!hey�O-$�!G8tinct morpholog6%y� cclu!y-deri��� ��4�!ujtransmi~ � ��betweeA� ��fbu�v[sprea�3U��inz )Eɦ[I6� have( ong histA of be� ��as1�aa+� icid�"9 gpey "*�!<es�-� agriN [2�W��.��bj 2!�it beca�os)eto5�e:�E�tr���investi<$tR�� mech�Q�a(!�..B=u�-�e ��w�Not@/ tiss���equ �e�,{9�pre� does "-&_*s! J in&Y )5 type��TypA�lE#suc�[ a`�ed �Ũe die 3�0��ki��E7! death��often ac'an�Wl  l�f� on [3!�Although��uo�8�&ly���ACar���r p�2�,-EA�� takJ�i1��eY stagI9�!�still%��Wsto<Host-�Y��� r �$can be vie� ��n arms r�� enem|yMeM �%��1�A�c.�)��mMat? �|o improv�t�ag�1a{�a�s'�L���5a ! �duc�� �,Azh�:�2� physA��c}0 barri�%�>#Mes� establish�� �1[4AgTwomA� �!�e � nate� adap�. W�� verteb���/ �aA�o� �GothU�z9o��k�I�M, I>i-a $!�humxF�sh�! �$*� !ۅ�[5! OC��20(to hemocyte&u2%liaGhag"o>, nod� a��encaps. H:�]5d���inv��i es b@$jy ps"� ly syn A� K��Or AMPs�� *�of i!�e!�&e �heRWTol]&Im��JAK�[ %k�>�<�"each � r+2�L� !� J)0� ��A���l�%�����$phenoloxid?= �9V6a  K69i�ve oxy�5�esMpM1 stud�/%f� sGs�b! &�0in Drosophila�Ta��Resear!E6-nti� Y�%H�Ld XJ*�)a YQN[6aT Whil� 'b"� !29fungal6,I5 E76!�A�N���M>���Uvm� se�7lay!3ain� [7�AJ��rANRNAI�fer� (i=achinera� is e%��c�F�^I��; ���n�*I����ls*��vo figh��)݊[8V[9�amNw�!�a�6{]zde�b�]z,!�UfVAof2� sugg# ��} � simi�)A �def%gi �=�� � im� �res�ngV��p2*Aw6��6M.O��8A prop22 ( PP� �Ո,a�$in blood-c�� ��2R,E�af�&�O-�^_ [10%�1� ,i�c!� Heverpa ze�U�semi-�0� veai9&- of6'tog�_ :1NA��be ��4lim<� %foc���nul dise�tp#-e([1 Late� it h8 a �MJ�!��V 0�4t�d��s'M;�may�.H:�seA{irai e�  .�&4Q|4in a Bombycida� ,�Q�ea��nyi ,V�5�3!�6�li�a'.�qA_� �si/A]of;"\ ^1b!if�6 [1� HoweverX' �Ū[-un1��h#h�%E�eV�a�"oED64 �7z 6�-���1" ipAS� 1�A��s�!�l� s [1) R�Esa*j�*�!t%�o�!��f� gen>� (��m!�� :=��&_ )/6 "� 15]–[2�i�A�X!c�e� e�Y .�!�..h�-in��6�2�1 ach!,z��m�h"� "� �Q"� ha�ic6�-Ma�Iu aA.t!� ��r�i^)�"A9E5 ymph%�fat�,"�trad*ly��D#�f2muna�\M�$�/nd-�rezI�eh1�%$�� shap'E�9 mmals [21��� � "� .�foc�o!�. Gut ep]3l� ti}4�E"m��_f�*�%&� e �I�Q�"�1�� �+a�!�9�,-��m�#�um�%#.���!+2ie�� .�i�!a n eG$ous&[.� in�-)�>�"� ��musu(tinuo�2 ro�![b��� �! lume�T�)� littA ��'!/ 9DbA�.��u.E.+e-]e$N!!e�"�&!��A�di� fvE c� 1$��(p�attaci�si� ,BeF�& nutr'+�w colo"�[2���m�s 0�:i�com�+al.J�m��L.w�6Aq6a� [27]�I� sus�> ibila�p at� s"Bacilu.th� eien@[2� 2� I> iJx�`��abAV�� cruc�rN2�!�,a g�; extA�,����6b��[3ŗ�+S.� promoE�[32%B33)B�9A�[34 5]a�1De|!by�]��*c�/ Elog� aKfof>Kon -gen.�EN*�W,��=as�!<�u|s [36���$. Numerak K g*%�� ��1^a.ev�-� ab�(Pa+�e�pl�X��[40�4t iClyA��w|� no� AqE�߁Exu�bXe2��in ge�s]@R�,%?�"�x�29n� �u� P:Ga4b"��u7ѵ��urn�E�a�F" new ]%!I��,��A�)0Qq� emer�!q-tud!b�Fships��dieC:?o)9�aC���nd�}[43e:4� C���2�"Q.}�Z(taxonomy [4�]E� ���"!��(s|� �� �!�T!hip!9%p�t�5@.Z�f&�as dyna0 homeosta�LA6�� �a!�.0A�ob�:�lex��& into������ Rco�=��epL#4o� pH ,} enzy�-,�? ctua�� � non"Nic9�.!@�Q)�am� #)� ���� ��i!�s�oubted��fl+ �z�� ZJ ledgeg #"�bye�.5ma�r��`A�s h*aL�3 �.�v�Jr� 5�Mas bio!��6�= s [4�"M�a�a�}6�/%׉p%�.q�� A֡w!%� such.Nnm`"� y%�r�%Ag* 8a��Dhar!�� addRed�I is�� we m beyo� mY�n ,of.�s:���� ��R0 afref\,q ,pI�je�%� �� preh$ ��La�.�>�p^rn%lSB�'AQ�"Y'wo:v highM��l'*�'0nucleopolyhedBuR�')%�!�z'Aut�/4pha californiciRJ�}*A� %"ughput�<n(5�%2(Se301� ű!�6� advan�9Sm�eal����Eb� aclI�Ou9)W. A�u{&�!m#�4}ݝ=,A���>>a%of�!G#&(�&>L�a.:�e&D V: p)� ��by�+ *v�l3!� merase-ch���,qRT-P�J��&��wN "�!q mAdetail�E!�v/"@ �����3>n�%�VWx2Q� M��)�q\p8 n�or2�.g�kv . T�#&��"e7cl|9tov4N}HuniIE*�"%"Y�Q.u��a�ez +n�*e�Q0a�, broad-�:mj�&adecY5���. WaQ& � of�d"7�r"6to>�A�OF a  y sm�Y�D�� �M�;#t 4 h>Ip)Y9 ( hp�r!4ap�/thresholt&7hG70 nz���5!��v�(/. 1Q. At 12n�<�b� ��I)�G �1�:F�.*��qUT="�} E _a��4! e:s�he�9a�+eT �>Q-Q(16|<344&93�;s�we��]~2G-!mgFA4aIX.����� rong-/or fas�it�6HY �E� D ��est�b�5`!?�FI�36MEo�#l� 4-foldQce"� �.�-�Av>-l. O�8�;��b�)�9�� j�72"(exceeds 25%a�a�^re�}U��|�6 �`���WA,/!$round 2600[( <';)��b��n)Ic0!{�D E@*� "�/5�, � 3177:/]�nd 50532q8��6  1341FA 1250bA,CF%)=-��F#, 43%27*;A*��,!�b2�Ve�'mB yaN!/=%public� bao ��B{ G� bf�y,���A�Mmr�e�UhB�MjAAB�A �1�+Supple:�:8s S�:S?:I���7F��d��5. o�*�w.�2�A|�f b Xi�re�0a�3�Brel"�*i�.����6v"0;#:1�O�ea�:��N$� �$ poi/�h-5 �pL�7i �N� i 1279ZE�}�V�.z">(Y�CE�Ex�eva fewv, ��d6om!��m&!2'.D ��0,6C�?up�S-���Z��R2: .M&9]Dm. i ��o:<ZqqBreo�h�=ETsH�> �)�dir�� up�8� ��pen" s��in6��6���s4F� � qof�b��0'}9w�5F�eB�(%�top�Abt anno.Fd��؍�)Ѕ� �;A�):�3�� ( 14}@M�F�.M�_%F��e�|� �.^c_ .�5&�+��!glAZi�& d cecropi@!Ag� q�A�M�!Y&�ueSA_6��3���R�A<"�s:Eb��A��.Uc ogly*re%I�D ( >30 B�a>b%-H''= 3.K4 beta�C3-glu^�2�W>15 �8 lyso�-�+�7 O>12'N ser�> 4� ( >1 �\5�:Q ( >7c:�Hdd23imb$x2i464A�UE( >�2�u� � .�ABC{ aZ�,���%#5:�$v(u�+]�herz1�<or he�Htis Bo (( Hinoshita"V%,X%a�AdrU+ �6:�. Give� � !}���:CI�  yJ��V(�$ �b��N` se�!��&�8 ( A seD�&c PZ.�""$9�!� wa!�>J�5� ont� ermm�)� 2v0 ;�2�R��&d!��at���. 3tit+Ba�H1% ( 26�\�l�IJm Sexi-r �;�`9Z�S>��ia1BC  1369�)8*� �F- *i ��� +&� Vmajor� �-�546�) R� �72!9989j100.�)>9I�j���/e�,ly � �bkbir5�1~a��,N�D!�2�J�  S]To4HCA��I "� �m!B �N*� , 13M�1���>>~ 2)->�( s )a�3Dcro6S1�BbG% �"l0F�!Pa &in�;%!���IUse��heB���[�Jy"��Ka�F^�>!�b2@is%\r�.t2;'n �-$b"�F3!� -� �9�wo�=upm :y(&�Glabora�9l+*�(�erm�3rLH “�#)”mfan�laAgg$jM/o( L. L?eZm��reon�7,ndard artifi�#d& [47]��bio�Ito �A0ir�al.�1%�le-O�B�:�AlMR��#��\J2 g/l� �cmycinA�!�u���l�-e�!o�re�Tijk aO�$ QZ; �=a%./>yqSE�k'�|. �4A��2�=6 �m&k2F�2<<!��CJ+�SH"�?�e`��( is w�7.�a�lo�+d�� ract� �m{eK�ed�:�:�u�Y�'2�4�I.� �e�er<o"�ed.gut9wG. 3L@h�,�d-NbiE2w��"�s 8�= 鞆� ( PGRP�\βn] ( 1�@@a�moal"%WtaA_"� BI��:layVLP2��Tupov&"2Aexpos[. Ga��:? �%!�E��i<e but nQ>� "��b�CM�[5y.�I�-J�mo�]���ed e+�1watW nj .&�!7*� � ��Q�(g!~���K-��C��:�hM !LZ�%( XL� decr�2�e)6" &y0� &u '&w&|$6rI�.�tI H�(� eXe�a�^�/&�could����Vin6R+.[%�%�D"�D�*19� v�4� �rI�2� Eamr�L� i4O!�"N3�on�aXo�Z�{A�QQ!>�L!�u| %��7xEV avoi� )�e.@��- !}�o�J�6�of.. 16S r%9ty1"� k6JFG8be�+-�Enteroce.  ��OrA�!�roxim�10�Xe^eu��W D U�"G#}F)�s"�-aI wi�$mBleV(E!%��c( &1*�*>� A�;�5z� ce��.ihaI%lsoe�e�:D� Mt�of ourIVl��9c(3,��nyN�YgU�:�1 *g%X65�U��m� ~"&�MA�.�I:\�Q��!xu�-��ujJ�&^#a�r6�+ H%�&.�< word��we ai4-2�Pi�;.��2oZtK �� �G�Bv�F|"�%m"�r���E�pur�A6�M�Qi1ngU:-%�5�*2�)b���f: ��monito� ���*x$D1q{X%(aRBiocc�H�5�� ( OB�@*�?>2yE. T\MY:�s< of]{/,��#7 � by �ang�ir surv�h�Zs ^ !KaK/-Meier&�U%FM��dJ�!(�Z[132 h`U�!�:�J9509� �I!�a`�H104!U/Q�Y<� 000�ZGehan-WilSa���<t�+t_�9�!�99%�#[F3 !�8^)B�> 4> WF��YweF sA�103��.���A�5bE����t���.��!EB�p = %K13ug^Kg6=71�!b-]�>7B� ,�:f� 4Da� Ao�ie*U)*� %�a�T)y"�)��K� ��4&- elu(?t5- gb#�~�h �� ba&��a�B���.R ��.�/q��&Fq-�ͳA�!�6Bm�+trend�c �FE x �>��T��Nj�]�}U!IyH:QH)lHzAM1-�q_.*armiglMlL/Fw "ear�\) [49�7��inCd!G6%*�Q:[1�?�t8� �0+6�lMY�!��g�15���'lyy<" J����4-������B%� origAl�douyx�a��.�- i [5m?U ��u�&�aA��3wQ�� mFI^U��NgJIn ��A�.�"�66�j&�geV� :Z)�z:�Iv��� ��.�We��m����f��e tiER^ �Q� .�wXo�;rMI, Cho&$JE�)�E/5biK*M (��Q�� 6�]A>�PmmF�^A�25}-�P�e0l &�.93few%�@fEF� 9j9Ss<"6GE^;%b,d~^�)��-g�*�4� �~&*2 l ign � ]�� ,�Gno-Habel"t&% Wang[17=?52]ma3�'si��)�AI=f TrichoSria ng .� %��!�Q^-��(A�v�Yag!�, bm!� - viri\Ve�Psuperna�76ai�-� m��nt�&O 2�v�3�.� auth]=t�Pcnz�11�4� L� I� cMNP2�9m�%e!�M<pe@ Xu membrane-�nk)�o��m�y molG%6�M[131�!�l�na��a0k8wpupalY�N�!�I�C.d!�=�[J EI�\as6�js>vE�"�S* ]..Fc1��QFu�H}�;e)BrelAla��JYPY�G a�>{Bfu:M�N�. V�u� � !}��/_ Y�"niYsa .�>r�(�!(benefit [53�D554 ��YhAN��-ɇ=!� .�w/��J �aEvalu�,!J2�2��o�;�������xVDe��]!m"Q!��Q#~ ��7*��o�l>A��u��mUT�[ . As Y� bi@�e��nA�I��!Y�l1I,!� ),� IT rd�Dip�!-�5L�C9V ,�K� -c�:O)*a%�!�9[�c|L )N^M*a�we��6 �"�!�O�8 �\DHf�c�7ur! * w�� fitn)i� j�-���~ax J_ ��C ����g�:� h2�H�a�rpl� t\/!�%I6- �^�_ *>Xt�kK �n#eQd6L�:�+�Ar� �-fxi��E�AA_�A�5�F�J. A�Mi�dML (Qc�� ide-� �.� ? Or� w�yA��S��Fm�$A�"P�C�b�)s&st2�&orch<D^�O)���u.�? Likewi�if�l�<�R%�,$ UIs�%q�:)P)t�a�}�?�se qu_o �7. E�fut?" J5_at�(U`f[���:rc5�^ ignowhe*ud0O))ԡgsum�[��G!�&}� �>f� aris=�w�i�YbyMbau�es�2��!�s ?[L"� �b*�6Pencode)�RNA���$�i��}x��[5�G@(.53cgenj ,"�-%�_��A�u�CxvlgErAG5 n!�y_��Pm�w�s)�e ���&� r&_L^8�&�5 �s��r�1a#�G-e�&�%p>�Z�� � s�-PIOmi%��1 tooui�{-�� sA�A�m"� �rU_ �}in�F[61Y6TX%Wn�Cq�%�A�I��#A�ext�ml�imatri�A�],t"�fgn^" Y� isco� ):��"� %�yQA��v:�.�x)�e��c�2 h�+Ad�a7"QU.�2�g Ql�T�ngz�7.^ �0bal&( 2]��A�O�_�wo; �Z�8?armi[*([ , [6�h�A � !�ba�W�[�ZHqm�es>w�m ��!2E�%�I�!:je��s2s0źear��ec�n&�[aDM1Q,�XN�-�*]��� ! Rperce�t|#u�f�}Qw:I�-9�d-da9 �"�{ ��-sk3#we%�* �:�to&�p��6 �J� *�V%4Y _t�Mp A�syma.#X- j"( GI�-.Wed�ma9s�g�l)�Z ngue)�s�%�aj�� >��.� Wolb%ka�[6�>�DM|2�%- empt|6G.�"� Q�~A&'>�_V . An&�"�#oaXloAPj� endo)t2mI*�%v��ol9���g[6r >C*U ����%I9!Pe*�^ �( SP2� Ox4 �l�D[7o" [71]%��R��6 ( C6��7� �EN.�%�� � �HyQ-SFX-�x. Z dium5&�'�  5% FBS.���"s���?�" pena0 �ddurR�L42�2^�f1-z�%��C1� 104OB�1b105AO� ��l�CF2A|o��duspen�]�.��to{Vpie ~d� I"j plug�*%u�� �d�� p.g7�2�aGEFfresh T!*� �/<�dayB�& ( dp�V} ��i��&�� SB�A�3ut�Np�g�e�,6Ffilte�yby�@45 µm �'ndF�mVs 0ۄ���� ( MOI )%6e�.}�BV�4)�"�$���� X. F�_50 ��d60BVW�a;!�.K"J@�=A�| 5t_e;MtiOJ%�the��"(2�+e30�+u2a�idddil�-�[73T�! prOIi�s8 Űl&�ulyg &9)�2�. AAj#`��.[�se|,&j'L4.�MH} mock&�*c44K Ag�ot oligo:^�� chipude�e#mYq*4R�*,E�c�V[��I�J���"f�Wa. &�>8 FA#��&�c else�B[7}daBk1custom��y�qFJ2sig!"� � ����eA�2ap tA��pMs5 !�6pIr*�W�xwo 60-m`�:��-,� �2�&�( frag�%g�K p�+]�%wI�e�%>�F�?� of 5F�A\2�V" \M�\ \,m������T4a���i�RNAzo�ISc��u%ar&txCe�=��Cinciw*i�q�:�2!�manufa'r'�otocoqsTo furg purid��  easy Ki�Qi�~Nilden�Las�f"��zph�f of` D":b�cU_2УBio�2��$EukaryoteT V�Nan��h! .8�b&ymrep��eA J[N&Η!�Er� �.�One-Col�pik� Mix �j�?�Zng�6�@�Zc�(3|xX) &s7�. 6� Lq'+b#C!OӦes^tG�)�$0< cyanine-3-CTP ,uW� nd h���to.c1 �Tsl=6�9&�-Ba �Y E&�sAhd(( Quick-Ampve�)�)�:m���-�s�9G��a G2505B5� �|�5e�>���Fe�eE�e����81.�B� QE��>,5E���� ��+ �ver��Hrr�u.%�)���.� S.L���,� ہ��Yᡍhe=�9�Servi� Pr�Zpe FelR�|��reA IPF V.�c��D>�5A��)��BA��us �9s&P��� ://b#.a��0 . cipf . es/� 5�F��,�3-`�ra�� xaSsq��z)0!e��N1�i-nÓ� N a-!xŌ!M�s�4z � %�cD�M s�{�`d5�2�%p����x�fold-j*;�ip'!��%6�bof27≥���|>5 ���T�;-Mu�J �Bt.�=- ,��<����)!x!)-��orBn&��5..& &�Mo"�P .�� 6*i�&�'5neOE�\�\"��2�3N"NlN6O �ir�Ap�/ grou��&�MQ�st& N (\ $N)!�deplet�t�%o�Y7. S.<e�r"`�*��1N%��J�s���&���62�I��g��ly&GAC � t�+ ?��.oAe�vngM�*Y�%���2� �cflwadH6x2!e.peQ�U�A��;i��h E3e��)m"�a��:. G�M%s:qco�� at 7�5m:_ j"0 !��&�8:� p�k�82�a�c!�.�"�:�1#DNr�2���2Q�4 rse- b�.k��< -d]�)iQ HS�1S#i II Rse &9i�:�2~a�j) hirt "gej���"�O!�E���j�^sAis�ab�T�a%ZK%&aN�^W'.!�FI1�~J #��i�2��Z�r�$p m$P�"j%&" �)[�%p��,!Z" ATPI;!�@v���m��t !^1N�6�. �emRY�er ���"�IBPA4� &qeRAp�i��'�(AZ*� >_SO[.�acM�d �-��, ABI PRISM 7a^c�5� j ͩy� �cESYBR GrA�PCR Ma�ho (N�?�p(t� a̠�20 µF� MB1∶5 '�Ma����s�� �#ach�� orwaPUn��N1� �:b۱300 pM .1��< B*Eba o )ulJGCtgen��es�u��−Ct:c, ) /� N@�V@  2−ΔΔCv�)aI,esM%�i�y!oak�"���n&levi -�d*3} �e��� I�"$a<s12+s2*]1/2�$�s1�&aZwBYC� s2n6:pC_ �V���t�incorpo�."�M c% �A-,D J�“Guϴto%�A3��R.Qu� �Pz&fB�U_Real-�J0vea��X2� &���" ��,��Z�Bt 4�,2�dis�= ka �Z,�%achM0a�6� f�.�Se *5 !���31�qquadrutXm4A�I1%�9ton X-�in PBSL�-.� � ��vorte�� vigo�{�O��s�:��[0���d�ALB-agar�Edɘn o/nP 3��<�-Q9�zaKCFU=%�c�O-n��as&�.})"8�9=�C&"�ZbS1�"�IUb�Lb6]baQ!�n�Eem���*!<�vZ&5��01�YSin.5aO!> ���,�M�cc&o.��U#�I��6�hbio%MlPu�:���>.�)-�-��"%VPaz9Tpa56ric�"n��tney � %LB-)R��dun���K�\�>6:a��F�±N� ( SD�5Dz�*�da7;^%z*ms*�R?&"ML(.�6Apomix�V� sexu�,v  v*a�� ough�Gdi��i}��%�a9�3&,�c�D;*4�.� 0�$!�a��,pomei���y� �oы ����a mit;^<0�jE)E��eha�Be#4Onovel�qUis 5l=,"�� ,en��&eJ��$}By!�b�>a m�3!�EgA E:K� '�f%*X�sa�h;�&��Fo�a�led MiM!� ?25� lcG2Kd�!8i�"��Q�3�+C�Gipl2Xg8�rH t�H:ew�fh� m� h�a�m���4�!�] pobA!�2aJ� step towa�Tu$��mDengine�hgPE�. VK���zU�]kp���D���n# h�<��W)>�[�-"�iV��"E �Trk n~�.AliA��.�E�m�-��Fsk�5wdGma�c(�mL9�8be�pe�4h�#�.�se��n!G5��BOH"��despi05�B�s0� nL�400.�,angio:�ϝv��few)<">&!�Hca�A�m8�-$h'ara��yCs�i�+ fail�64�?4+b'@!$�X"ac:��.�JoUs ��k)�� e��&�s�= �!g���|����~�Sm��A3�o��_�g�aA� skip�Zr dZoI�AW�� �4ti>l�1�e�=�(�nVEAxd�=�3e?l7|1sn�(!!��rmEEa%rb|y�܅|eT���fN��IXguish���sis: ( h#aw! B��wo �v%l��&�aJr�9,NO��!!AprN��D#���~hF���\3( iG co-s��g <�{i3 atid�!�I�� SurypE:�5D.!�e��fx�9aa�2oafn�~��1Z—��—-�sa�w Arab���nthaliant �$�I��EM"���.z�!`1�$( Atspo11-]j�gHmod!!�@ro%s .�Brec �[9]—we��O�Mi�����AJ&�5H/�'W��Wx�J�“M���ANB HE��b �v����npga�,��iA�r�%c����%�-!a2� gler<k�!_%AtGen *�4� [1� At3g57860�"}�  g(�candid�U��ʬ�P�l��n6��lc�h>d��UVI4-L��� ( "�HYbrief>�KT�4�� aralo /�cX S[VH . Du�2,<(A��a�-le �`wtw,<L��OSDT[!�omi;����U����e -a{��/i 1re��nSba!�G�7dom��[�edo8� >-anv� �" e�)�.� o�� N�c{�Z �[out�B�F�g n*�$%O� %%'by� A�!*� ��) �B),osd�� ( pst1530ݶ�>i!$2 ( GT2148��I�,�MD�erA�ED< wBA Noos�( No-��ZLandsf�Ler )Z.k$A�:�+���/& =�A.y�,�� e߰B��!�+>R.b$�5#I���mal-)%� dyad@9,-1: 714/714;  2: 334/33U[��d��eN�8Fi�U3A%3B�Com�!Y1E�U k0 2A� firme< B;!�>)�10�}( 41/ ;: 369 �/ �E>A' T;0E�sŸc�Z" � e�+r%#!�fe P ophyte le�t1o�T>1d f!�c#( wild. 38±11� s/fruit)U 35±�. Nex�!�asu�! �&leoffspF of h2��isel� , %�X!� 4n ) ( 84;y�tr�3 16YIn:�> ( 2 �l!+EA�31�: n�]56 �AD2AG. �_!� nt p4n ����)Os��!O-�vaL &x ���J�7��6~ ovul�w�{ �gr�Eb"812%5�!N88%��!X55E�Tz demon� �4I�6�i�eZ.M�a���!�vM�( ∼8��Q#�wJ �)6�n��E�: To unra���m*Hs >��oen �a�ME�).�� �  beha�qrMWI�I#<��I)�m!"� "j� !�in�(�$��l IyNot>�>asm%&�%cytZw��5fe���O ross�:A��b�c� Et"�<.|Sw�!&T�finy�I�V2(m� >500) !�S�d6�to)� �!�"�VsF!c� ��>i��an *8L!��{E *�I�/ ɠ"���9A�c�}y܏zyg&�u� * romeA� will�l�-�Q�Q�be7A. :� [ .~ !�Iu� � %����:. B`6��y lԠ%HA[�Ilin^6�&� .��`We���urump�= #j&�g�R�Ew�l�3�Sene!�ba&Z )ao-�|*�2�W�t� . F1!�� beae{l���+ ngBJ)Melk!�u�!8 s/\*�K���� � a+� 5Jle�&��to h�OF�dWolumbi>olj . Kd--l!�� A�1 b� F��� �tri �c8T ���}.v�4d��2O��make-ځf�len�� �E�\!��O �͵>�Je?J�� J�* �u" 5gT汅�0""=_a -��]��Q�ing—}d2—at{i (��4ʥ�>�a��41��1->*� T� ɘo6: .�ab�i� dc!x�32n)�5�A�kE�C ����i !�un"����5?�9t�0I�JgEA�B���~�S��� 0 alysA�a ��le&�� �  (U9;&d!RSu��*"4>alU��cr�&�vmaT�io�M�"�1�.�R<��0�I"jtNdergo9#IW %�"��A���f�>*c[�Y1�)>`>MF���<is ne��0}��0p5�d��e��{Qs, B& ��#�&>-v?p�1A�e�U �xo!P��{�� `M� 0�� w"��isrupZ�N ��t�@e&b3,of Erp1/Emi2���en.f IA��n�e#��Z� � �v~.)po� !����TR� �/��� 1����.�%�"���|? ��}���a�yb�aoiE,9(;h�5 !���=���!a$:_Z�H� e�!�G& r-v�2��;/%��~��*�Y!/ZKM�1~� ( 408/40��A�d2�� *��kit+6��M���XE���eM*9�� 5uM3� !15�O {)=�h��(J\{ÍF��1��:�qA: ��un"�al>met�M�)c>�& �d�z�"� �!5:�of��,�':� ��&� VIg,�&o�[� \!wil.[�N����a��$ /regard�joz�e!ᩬ:���86�~�8e���qᝅi��A�FC!U s"V � ��;]�0aV( �� �7^|� FmF�):rl!^2�&+�H� |0�Wa�uU 51�%thu)�^,&6u��CT:=)K%q-��%g�V\�*a�2e4�q��iԶt� !�z�� q|:�����oid���e�s|-gI�n . I��4"�"vg'�1da"294�20*���2a�!� octo�834^333Tls 7?�G. F�Y�rop?u�ԽN��2n1�19±44to ';�m�-�. Fure�&~v ae ŶE s>:E�����%�����assoc*���F%y` ap�&�P�}5� �$@vp@'onC��&�r�Ee)��Q>�"?%~�(.)e�he�?=��.�U�_-�hy*�LeggBCU��en�X�}`!�74�!hI|'2bE�oS��-W ��%H7we�!�m ��pr��*� -c�"%a�,Ea�awZ�" h-� e�/_fA%m�W S�w "� B.�$��[N�.{ �x12��,�m�e� ��� ��� p�,�ly unusE �'9  (.�*h �Eyn"��.(g� 52si–�+gS Tt#��-tic— �6:���!e���er"��5�� "�&�!%큷���E< ��\-�T�+M/ny =���-9C=+�!I&�����al !��*�r2U&}2*�d"(1i��[b��aS6� !$�SuF ݫ�&�Juct a:E.yi�� qQy%;�6��`�.J&� �+�w%�5P��z%�E�ū�=�2 I3!������i�� w�P"�+*AY�=BlemA��&*�3be1,��.!b�5mNJktyc.�or� N� autK�$��%�.'.#[x?, �H�gs�%�iz�1�lt�\f4��l"�,!L%f�-a"(9� .e fZ/�� . i���\F!e��%1��N!�:��N�;[ ,2�� f�A��on2(�� um [�KR1KR�Ea 16-h�M/8-h niJtp*DR�^Rhyg��. P! �W�0�;(��*�/ 30 su94uE�56 a1��72) �4�O��X airs'�<r%�jr"� �.�=( ~tu=>�� $x a7uN8&a%.H9� phic ( h�/� )� 8)�o54m�.u�[& ) × Qqo�n� !8B;�� ��;8+� ee�nt\e�ZEVa��,���8!��u1�1�Ek5~)�6�z&��a1?Xmig� n 3%jr�Bge ,CAPS K4_1035��:?4Eco47III/HpaII���o�=/Bg�o A-h�(2]b7Wm �K�*� on C&Q�Fi]mev��lA!s ��G"�so]��aom#�z"�%� )�.�?mC3e=�.�by d'Er%M*�t� �!pri��W &�+Z-� ����,Cda��6�ց����ic �y . Cu�2�i#2 5[nth��ebg��!. tein)���"1yM�Snetwork-�o2r[# y�2[?I1)w�! ��� -� �s�� lie�4s�/�.; PPI�.(��s!� ���IKBic pi�N!h�TAw6��yrU��a"�!��N!*� 2!&o.G ,-Ni�/Nh�9+��P-sc#37sA4 of the contri�bution of tissue-specific informa@to gene prioritiz <. By integratingBD5expressg0data with PPI2b4, we constructBI/8networks for 60 $Xs and investigate their>�Hpower . We find thazf�8iderably improv\>Z�of cand!�e�)�. A pl!�ra'omput�al5�,were develop)d meet this]s . Th!HQ"!FoftenA`,ed on system)�asuch as� tein)�aIݕE[4%Y9]I+e!��[8[10#12Hsequence similarity� �[13$[14funmal.-�� anno) d]@!�(%sa review�t2seA5k<[16] ) . Many st���$he art alg��hmi[gJ�$problem us!�F5or.�aage=K-/7 �exploi��$he tendenc=3A�A^-OQ�salie cl�Cto onA�o�#��N-� � , [1%�[20a&Howeveri�seU:$do not take�o accounAr e fa�u�(he vast maj!<�0tic disorders��manif� on�' n a �le!5a few�s�a�22�Typ��ly � sameM�etsE�uA�toyy�ba� a li�)$or a brain, eve�� ough%9�� land����(a Hepatocyt!m$d a neuron�quiteV1�. IWis ��incor���:KEt> into�:U��ademUits imp!�o~A�2��3_�on��$chieved by�8gA�>�pi- H�=(�)Q��Md emplo��emQ�:� �& (onale behin���pproach�E�ma�Ykinvol��rup�m�‘9� fabric’differen� �y ��~From a�2�q]OJ���is.�can b���cha!%erized�| a perturb��G͠,, correspond%�ban edge[2�QIIHc�x�gen:�FEunderl%� harmful m�� exisA�n� � celledour boda�it mo�!<,wreaks havoc�Gf�;A?is-� sel� v�� is likely�)$emerge dueQc� �ٚ� �0 host-pathoge:���B�man�G. Fina,��$roof-of-co���{by Jiang�9]!)b�]b�� n f�V�6� &f)�� 0type 2 Diabet%Of� ��a0 lacka �Zist ! mar��2 �J��� of!"F -em��9�varia�^ofM)��biu�5�,"�$regulatory[33"��F� 3~3��d� abolic.M5| 37| ���Jy�g�<large-sc� ��aim� enh��1� � %*a� �-A�d%�:*.�byA7 "� i�9[.� ; v� Z��&utilizwt� ATA^>�instead!��E2ar�.�Ca� �e:}wP�8*�)K?�&ab3�a�e�6� �� � � to �lyA���q�5)C� dee�a)� "�,( 71–83% )� know"D:z~ sign!a�e� ��AX2|  -as���%� .*��al��.!g��zx Ws wo%u |!f� ed%t�ing~as�l� v,!�&$� RremainA5 �ei��La =-!�l� across��� !J./med�ng� s� exterJtimulus be)2?ulti-��|W+�>��A��#re%{expec!to �� � ` ady-e�iA��@!� adulSa oc�aAŹB�"v !R!�-BYQ] )B)�� iMG 6� �� N!�.B�k t6�  schema#�F�� R� cyd�4w` � ��ǝ.��60u�� 26 %�ќ eMs [38��WE�n app� hW�B:�" �]bot' origE.F gZ�,'% /per<� of ea�e -val6!Fseta�e 2�3�t�]Q�� sE�eraYaM�'k (-4 �b*�0stics ( ROC )[ve ( AUa(giv�A���ct)�akranŹtha 58�ma  %��._ �'� our�ho� infer new��-)u � . WQ�ed li� ture�|-�� JO!��� is e�w4tr;a$!��#gen]���� GeneCardsk , [39A�D��N�6abn.� matrixva[dErxezby Lage&� 4T� =�ide�ZJ scores�I-oa�r 1H���i� term� PubM#bst�%e� j�� rmal=pe"  W��enesc�geA�See MeA5sForim ��*as�;�zuVA� t ha���ximal)P � ( MAS ) 4Z�fil�Ld���6was b�Ra�def threshol��.`fo���� ɲwe� wA� =s:d>8%g�cutoff +> , m� p � d oA 80%�ign�1� ur��F��7�ALduc!�q9201 -aU1Q[pan>729)D632E�M se�`=,,�40%!�as6�]�� ∼9�A� �e ��8ed 3496��29� �269�In�1��pUqQ.could��b9&���iC�ed�M!�Ii!$N�� ���inM E�9%��DprofiP� �� 8:�LNovartis Research Fo�����( Dat� ( GNF ) �(2�Ou�C 9998��< oh>ic�R �") number��"� �D �~ �Ř!)<1322 ( 1� to 7113 T%; mean = 4500 . 8�3 dev� o$41399 . 3; Supp� able S16�!�ّ�4-�hec�wheY ! (al9 ��.#  ڙ�&���J� wJ una^ at aEB�!��#��au~sI���>�ir�i� ,g�:-m29%�417%I�MA��to 6e��� ( Figure )EI.!tw $ is f�is: sm�!r���at�� �$( 38 . 25%� ly-e5^!�x " �ver�c*� ��T�� p<1E−5;2�Tol�unAAH wh"":imight�-lowly�adI�8!Q=��i!s|we�A�in�"ai�76 J⍜:y� a6�a]�|� "�afAHe.�&��t�)O. NotP$ , 44 ( 58*y $ fI�!4F� N� a�� L( GO:0007275 , FDR Es ue: 1a�!�1AS��!36� �direcCv{� orga!Tv�!�) j48513>j 7 . E12�H: ,"� � �)�di�ir�$Dyonic��lea=�� n2�sXardles-�UI�a�*$ 5 �L�aIJ�$ , 17 ( 22V�.�5�a�o�"�%0 0051716>15�4 )�(a� erefC ,�{2&uaK n< �� ��We alsoQI�V�%�Vj-2o6b� aE�-]I2fet'q�t& �M ( 12A#�^K 1AI 5 at�Pdom ,Za6�.Zexhibi�)l(mRNA �s.�2���� , ( 15�,4 versus 224aP Affym& x �!*J ( AD ) un�T����`:� WeD  !@eY(s�&�sEpara�"�phe'�of���A�ofmviW t�M'5,/fu�( elabo~ upoTlDiscusZs��on�a�forth�i�uc�"�of t:�&,�"��i�2e!VaIA3i�  ( deno‘!4 mUs;�set=!O%YUwo��convert��\�� *�b �&� *acnB& ��� Q ��� 5summar!in,2�=E)uJ� �'naïv%�_$itled “N�!R�!$” ( NR )!�a� (eviously byZ�, 6)['d2[8,� �AeB2Ns)e�  !j!�1Y" ��!&�6-Q��/releva�%iE0.� dra-�8 {C8v*K! �:w le!�en><&J9� le g<W�on�#conq�./ n'sB#h1i�NRa8sha{ � �aS ) |m r�  �.��fh�p�� �{cS!yof 91VIw.F-�",98%A$\( 97969�A� &A)�B|j#e 545V�݉,���siz�$k>�� 3907��e % !�Y very-`–-( surpass 4C`n)1���&�  oso drop e$41049�'!$1�1Lto 1425�k21.4( Range: 2026[��9%H27571[611%At� ard& : 6195 . �)amp)� �YArreA�I��ͤ�q5trov$osiA�V&A�8on ( Pearson: p�!1 9939��Moreo=)d '-2a�*lL+f`� !L��Q:2��B�SI�b�803E� sugg�x1� ;�0-la9tri&�12i -l�.eB�Qd'�'prBv" �y`.F1��&A���n31�re"�!���0q &m*�ѻ�E�'ReV!�( ERW%�By:dwe,a� �Y#�+�> , bu| �mod10(O( v��ref�'O-abid'5�cC�� 2�! placeQ>q+briefI�&j conf�0�.�a^�(is x%�*�)nalty�, or , rw ,%�'�aZi� �i�dD2�M (�.�A<fu�E=�No,A�when rwu�e�%�Qbecom{��;�{  '�G1JGi�13� "�._��}(var�) valu�!rw� ow u%��(rol just ho�-=�h"/�Zeā�A�(�S�. ���4publicly availM�pF&!��rial (x6.S!S2 , S�$E7�.aD"��1�16 Su���PRINCE8q *y!�^)we��p&% ��2co5 favoK5�/eNI -of-the-a'&�0[I1[S0.'Hleten��include idescrip�Aof�� ;E�a��.,s o.33s am�ed.��17-1?n t�/�C Q�!�4g�1a� ��sY'puW Gi�/ a qu"c,���%���7&� _� F*�4�>�/m( |A�[�Z�xa�� aj7�ro\0a2!�n � &�/, culmin.6& smooth�A��$�$r�e��� oe�b"�3���ni'boXb.��In��� , let qKA� �-*%�E( by F ( v )(%w&9w�b��4�or�L v( et Y Ab �D ;,�e�tUq��>A'f v!�QB1�Ua P nd i'�/%Mu3�I OI'�>(�F"VV E 1,���o�.]Jqc1D�5al&8�aA�lineara��eof54�!�%j%�v� >�:W1 N-jI�e^o! � adjaA�vA�Wq� , w ( u ,%� ?�a0/�%o3$�0u�v�!y�parame��5M7pai�cE��vA�I(.�".��!����9e�-�:JnF�!�u�qZ� s builtɾ(NR3���teg�� �Ba�$ve-one-out�!�Z�!�ss��P:4" ��!n�1a�*�/nfof�!6j^��.�hv�Q�!ƭ�(a benchmark�W !:7opt$rw=�,�&� ngy*TS-| ( Tia-$$ � WA�t "�s)ZvR�n� a��� AUCs&!S1%�� �By�.chewz peak situi�� -en� rw's� :���^ enti�9�!R�I2A001C" F�C��1�.��t&1 ��%.!�Cwe wila�r�%]'wo��i3m�r6�as wel!62�5��$x-8in mid-r2%�tU *t2aA e�l"F,��N)U� . As�ed abw>E�fA�.�e� � � subA�o&Z>�s�bc.�2. 9�am53�D�+� �S3 A�T�S)��#,�vGM.N1�A�a�q� �%-�"� q >w( �825 ) �I�t{Ť|ach9� �F� O 5–X8��Qp�-J�)1� O7��U ye�g� m(^ . Am�!.)jB�ልiD:�� ��>�Y5O�^,/* e�est:�!.��Ab�a�. NR (F���albJ1�� a)@A)a� W��inahn�B�(1��� ��*�'A}ru8 * mg�1BA b�`5# -to-=#k&i!�in&� �� eo(8�>V*-�)�1&� �+"�.�7�m-�� �, �1 tog�!�}reJedS< ry tA�(��Bd )�d����2l9�()oJ e5n��-H�7��!��c1�U>)*�[ Ad���q3 �ed�&� ��� ��_NRF^*A/�A+��"�*t���ׅ� 8 .�!^��I#$� �B's jP��Q�Z`,�)`ex�6�yof�at�S'(:����Bpl�" uho�$J0!8%a�C5"7'� in �)�r�*Z 2��wOE�? at�-AA2n(�%�"288 ( 47�%*2�� ereai7Q@q�rYo�?5]�$5V`. 2666s�]V tM0�EdtyC6.7#*$ �(-Y-!_m�dMing�Iw��-B Wilcox*C igne�k e�.��@�A�}sX ,)G1,-$am>i� �l�� ��l)nt�Q���{2Go)F�X-u g- �out % O�}m = (B ��S�C trend� oIk�$N/�,4^Z( �m.Havq�" �A@0��G&� %Yl 5B)R!�n�"�I�ri� �qu�/�i/@ ( �&l�m� :">waXqA�12�4afCH ed ?M*i�~ i��C,�Gsi�w"#� t"�4^�4� G&�}�G� -� ,�8��G?ay|m'# subt��su��H S3# �fC4!� msel0at la�st�-a:he1c� = be wO�t��(opot��lIomplic xaZ���ANf-?! ��r"� -ޅ�� �A�6�e�D� �=oM(�disHng b�y6TKis�scenario!�dep�!w4�u��6�E��0 �-Iq��&+-��framer:ye/x n\E�)T!6��5Z ��(Fm�Jrobus�h!%�$ "��Ρ.���=��%�pa) S;E.@ ,=)'s5 if�P&�=" t����A\�>�$corEA�0"�-1W $��1r �s'�L*�ͱ�! 1��9�absolut�-~jv�SupM,OaU X6�>�d2a�.�gaEf g��!ed 4th .� � �[ !PKidneyK �6~0He�!���)�k Eo� �>��#&c|h�+e,6rwL�$Zd;4+N&�1RX-�� c���La*83%Sv� M� �&��O"�-�': q)� iI1�ch)�M�f8�+����6�1(1�)�In 53""� !� m9 F�-��<by���0�*Au.Gv%Q�'�up��i� a�!�a�GtorA6>'1bE*�Obm%_�L�3coI1!bG�"hP! ��*a ��� !��blie��-&� 2s II�65>we>!�� f*�4aj�O�B& �a!"�>. M;���O� 3 �)1sk 0� "A6~%�2�2ignDE&�)= PH%�sUL. Na theD,a��&�,1���limg*S r�Me*� t2p�C�A�pa� nF�,�`w#%*�*Q��ft�N�*{2 , [4nL=(.�im#:a�l2X.5��.H:-#�: .! *� in som� wile�'�� 5�A�=di6�"m&� \M4]EEr*�#s� K��"+z0F *O ,*� ,� .�I��V( �:��3!>�4)7!1* BM�n! K>� e�9�"i�? �9�5>�5 Z�.KU4 t7ib� � �4#eci�toi�FheBAt9#`�& N!� �6u�AurJ1 . AdH:6g.�j� ou"�9�(0]�wezbl��"�H�� �,����M��:'�}"� �)>s!�as�_#+�6nd>�aZ o� ��!e: �S�C� �.�$�EH%e �wQN�$�>w.�� struu ��J8]_�>.�� Ii�>��b�MW%�"E m}%!�!{%s US�%� � *� � )*p1]�Ad!�i=gof�w!1F/.�(a)k �EEGNR~�A�� �G��!�HA�i�q���&z4�b�=}da�PH.�A globa"�'>#�,s<\7"6 ��sucX4ful)�D ��&,1�A�e"�pri.!��� �yct1�, e��!��H"�M'��b l�&�  �inu��vZ&�!��K a ��M�a�/.�AU�&8�r�2�%��!�noisy Q!�.v[43�+[45`VOne�5sw*i����1 no neF�$!�vF!�>gB�Rx), �,"6�V���OQ��V��a�t�SA�!/�J,-�Cst+si�0% 9`>�p�J ��-*(�>/)X�+ten�Enach� Rol,��}Z�r-џaA/O�B"H) . 75D4!�7 ‘U4PM�g@' l �ed1+�i"�s��"�--c�c��Ajrei,���m�� }��a�M�&F�1Asj h4��A<MAS�!G25ZŊ_  of97!�lbeit.� l/&';�+)�ed k*!jof2>p90�2_EE PQue=�02�r&�*�)�3*�H1A6'A� step?AM|"S -����*Hj frw �sur� exI�MI�$microarray'I�2}�+&vJ* B� i�Xat�.H)@'6^�U� R*N�5or\ \!�� ͳ!�Xlt�Yh]��r � . PostQ +r]�.m�@Jz�an�Qal��Qwf� A 3�� por long&Q half-�Z� 62[4tN.�9 �Eve2�+ �ndCt*� , ob�@�|�bn *ao�`"ir2= �ly!>�IX8>9Me)�.�'%irqE2"jEE)D� B.o=?ll.�-G. B�1s�2��st�$2�;at�al L!�A�m�"j . AnQ po���0-<��6 amag8  �?ca by#r6�ZQ"�w"BXE� arli$&B>�R:u"�.��*3O=:"�A>� ���-)���enrich��6x.�?i�-1"�=0�IZ *^?) A�ov?�`'!!��M�!>.�!> > %D;wU�%�~2a!�.�M �aex Ἵ-t��2a"�?!�R)KA&j>.mM,or.��D�>�61�*t�m;I�/?i�2 !�!!1� J,�Zi��lex,!odepx`�*�] �� �8O )�isd>� |Q㭊�i�!! ��Q!`h�@#g am 3x.� Vitamin D 8�t rick`D1A ( MIM: 264700 )�npri<3 b�d�`7ut� seI6�!"!� CYP27Bf!�&�!WpG cipavUhydroxy}7of�iOAx Q� < , Calcitriol [4�NO�ce�YIe�Q�LT%���AQE!|)�� r@ cVexF �de� �$&�i�y�e!"�cop�=S�I#"D("jsh�be �io�A�ED�rNme�!Uy�%�wSl adeq�+�n�9�U�J2 �� �!h %����a�6of*�%i-c.�Sdespi�5�@stOort5sZt commA&!�endium*?< _&*F��&&u- 9@5�#T0a�mprehen�f� e).�W  aD�%A�IS)�y*�<agA9d quantEv��� ~.�I�mu{^}�wo�l�4;n*[_ does�guarante%��� 1on�,*�,%�1 ��jfO E�� Y�*��,"proy# �-�(s' phosphor� s�fBN �m��.L,�1s9"� Ha�3����*v$�X �X!�)>\ � yda" f�lP.�8*�7,�k ��e!�tok,e-��re~!edk%w�Jit����q �E�6nt yeaS2�O��7:��too7 � f�`e�&Wd� a�Q �Y�*�%=m���g4�g50�W�*p]��:t� �y)Mencoueefu�R��toza �-2��",�]4%h� �W �expl��[�. W/<wnloa�he� NIw�A�.E����"UHS.eNOmnibu� @http://www . ncbilmi� $gov/geo/ )Z DS596V H�og6(epp$3d�&/� took�4a �$�m/R�����) 60�@-�� sad { [��%M\ ed (�'�79-AO<F"��b , [5�B�W� ��,jlkD 7� {��f)�F"8%200J�G-&�D"�G.Y(�&���7h�< .�Aq65>%�@ �!Yu}nS�T<�@e�Kas�$"�+. �:!�Y(�.�6�$-)aC�tObyx�!ioc.AU� PuBU$5&&�[." �f9u Ochiai'��"b ( �W[5?_�t� iUd*sum�ll OCI�!{�M�!�S3nt%�e&��nC-ERatt rMst5A{ ��G } ! T&Pb%aN5�8�e{)�u�1i�E)"no��_[LnPq�f�g&�>� 765 A�\ at�s� *3oD.G@( ��!ay2a e�b8VerD:K"M0-VNq"B1��KUu�1&� � ��IN!�$DAVID web ) r [5ca5g $Y!�iF"� Mm��}�� Ae ��*)\rmra�L!�"�KI<TQ.J�2�Z� "*R. I .-i E�"-02, |isB��%� �i%n �ly�j��AUo >�ZA� P8 x�9q&q�� O.U 8�_�fitE�0( asbreadth�b�e�"{2�"�&aŐa �%^,� e�>? Lis�3� 10 , 0006S;0=lK^h%%��f%�G�7!oV1"/&=<2�����.��l heB!R� To���&eHM( *U�e*A`bFX��[0-�I,I8!3u �isQ y%�5<per�b0  ��Yvec�D� n@,2�T� R-T 9*�c pick����� `^i�2rE�1'�"�Cmai�K%Tbia �E�4�A>�� X� �37_sk$��Tcardia�rW- S�/!�f�cd%�*Uv�"Xtt*�y%IV��&4p�FV)x� D"� �! ^x*� 6 9 , 20Y��4�702p �?! � �&Wree�{�5oughpuŋ � s [5%g5�j� HPRD� H [5��8&ox("��/�3�G:SZa.1r e3�G"�EEHa]<c͜a �T�` reg8��$model adap!D%�[5m_W��A�wo wayEx\#A�I�&� -<s:�I-�9>'2�as deri�#by&2#�A.�i.6wM�������O6�O��J���#.�A�]I &�e ' r�H�, a�If� Y$T�aJ�M"�6n i]of�k.�*>!R/J.0��s!J� �g%F �iTnow� crib�s,a�X�!��d���� Our�6�rassump� !�-a &db�&5�P�@P2 ,ah J=)t6 A7if3�1�gV;&�$e�A#�Y$&-/D�S%Uc.=nP.qPjVn&0kB Ii , jA"� FRQ7%a�]-��  X� , �A . NokK��y��F�i,s.�na���e'9�4@2> .� nBk�a<$�#Ps`6�#a�Rc!_��%�e��PAY�c�aA� m��AX CiX!�B��a!�EHKi�L�2S�%-s0Ife�G�.]��!� ]Vwij`a����a�Q�!.A �" ( 0–";fWJE]�i! t�{PA^Pj}���%TV%���!A��4 �v' M" &� ��q��&�#s2N)��'��iv]y Cif/�u�^��tR� ���byEn:�!dgk:Pa�B� M-*ext��ed�TC\fVf 1347�-" ��&O6. 938�m[ 0FL"�> �0A"n[<����oz( arro�r!)N�0 bcs 744� tin[h{*��637 #c.~@|�9&Q -s�+��J�t( )u a ce Z& �e�5"�e�G. �gB���qa'On�I M�,lian Inherit�in Ma�SOMIM )�5ledgem 61m �+ ��%��K"N 7"e�'` ���^�MPIi%i[A�r�!F$dm �%U���%�>o'�I X! � �1[4]: α* &� c −15�n10GM� o"S %M�6�t"/a�rP!,�#a~�I&dur]In��� ,Bt�P91�&!L�29, <s7d>%�U q�!.d�2�_}�M Fb����g2d�4voi�Q�v�%76qre�e�7�%�a�eqez+� ��� ,-Y% �Jxec�om_S�Dw  }1m� purph of2��?�%�6� ��%�4o.ÄJ100�%�5�d�u��_�a9$locJrt#g2�mP^ic& �,� %�a��R�I�Ase.�!u�mo g's 8 % D�$or�- ���.}%�gapp@N�ka�rj!��UF�Ut7w auto&�[g2_a �of3+0+�x�Plinka �؅ enV)�Ajsim�ui�real-lif�0=w:�,X�! on � resi 3w&N%1��a�)�(*�=B!(<��ncu�nEOR �Wt�E*T -�� ��.2!�so"_m 7�toQ�n�z�<ruEwfalse-�^=]"a��5/�[ auAjFF�ka& E�1Z�Ar��+!F5negJ�b�*"�G".M��%Hq��Y"/�m�ɂ9V�+�4��i' &��]ga�D"�~*�N��exE.mEP��ikWj{a�ys�G-K�{ow �!"s� �O os���F�*C1� ToA�P�7��N�ce"tQ�� O%���$ed 25-foldF�N �7�t�iaEv �"d�+da.�\���,bh&xa3aar��O��(J�!����3�?&�vij�E�T�ss pqDTo�v e-tu�&86�ND�5ed�eőTS�P5��wv^�Pre�-�lean�Q&@Se���5���0b�3a=, &� m�.0%�"� : _sF56Y�9MR0 .Nf&�He samp�B4�lu" rw����k��"_ P[1]��-.%\�heA�YM �stZ zero��s(�0aSe %~ee|o � �aer 7%�%�� t���cA�an�} gnit|Y)top�Cpc7 /2&�I�de)4 q�e�atI%�!� g�&��AUC�O�, �?WeR�R���a�6TYa��� ��[���-* ]�a��q&.a�q�6�f�� W A7.isT �#yB) ���� 3A� �0ach�g�Z pairIn� �%�ran�xeh$s� !�upa"3 �pQ�&UhW��E�� o� � �," a>i�Y's��� �r.H1�!i&-%pr�s� $6"S/��.�E�)�a4i���e6�4e�g 's�b�3_ ��!n+m(an���P�  W &сwe� �h=s'A{� ip �!�|h 5m-�Weݻ!��"�d4�= �E��%{+ s��Dig�D.)aY��P�h�) �%�� � %onebE�� qYgA�.��L�D��e� ).:n �K3MAy�!�Q�LoflyDV!n:Wh :�M�� � aA��<s:��g�Efm"� �-"�2}�ng)P�)cj��x(Q �)e��f�V_o�@�B�.k%�B�- :�3�1�YAaF�{!�aM do� :@'a��&d‘Bby.2AngIBou�J"3 t �!p)C �US! %.�+*w �K����1P K.s�(]3Mh 1��,�-l!W*Q|spr܂in�c�A��i��p(F to mosquiPpeR1m6mit�-M)s",*malari �E�" O7 expo�7amalE�(e �low��m�*�e3Y$c5��n�Y1�� }M�o9Eesz� d�,��=�� �1M�!�2o>n�`%�6͐-^�A@&G<b_�6 m2� ��%1 =6�s �:�dhe�6eploy?�) mixE+!� inimAP� Us-�Myc�6��ly�dsU5r##� pZ� -�n�\n|%`en��"-^��/p$m*ċ�Pcircum �sWd: ��<)%X %�tv5r�^l�Cm�,t� �xUځM�O(AUab�40W-�&24%!yru!Ehil� @u�=Nj}-gd� igh �s!��.y, 56% �� w(�!�!V44 �. M1�reuA� .zR<w(Al�x8 to kk8homozyg�us,V� 1,["i�V�u�Q8 �.aa3 �&%�}I %R}$�/�[r�4�OBA;�%R���toA�.TalZ!)�s s� rr.*iK6 y�"�;i@�Binsuf��/-R&�T� use:��&�WXJA� 5M�I�a�"�%�0�divid*B�\4 Hgikf&ll���� of 7 ,�p6��_emphas��� ��Q��"�6e�de� �a�J> ��z�Z�by!9�[ )��=.�in &pop��Oy.���υ~�#�I�#3bK&m-ol��0�&�CZ�Z��M�6�r�#�j�!n]�Xon�Ks agr�UtuT!pe��,!reĀ nuis��-bi%R}��5�Sc a ie�I � -bor�V�"e WorldQlth O0;is��( WHO )"" ��at%}�(l�2FV�2{[�/Pe�%�&4A"m�, gu� Japan�fph�6�]fi�(I!��4reAb� Zika viru��?anu`pt �E� � agQ6;�R!�F %~'���-� ���c�� p/l R!cef}7t�i��63-t��bed�ITN7(�]�sa6a�oDtw� wall3indoo`�s�7 +ing; IRSm B`W4requir�Zu ��, �%-�'ng6�;�%co2'hpe >� n���8� �a�7c��4hd�&�Q�!� [9O ev�T��Z.( I3w�5 f5�8-inevit%�!����+�Eg%�qoa� c2�1�~� �/*O$g ,i&.9�fia �"���]ff=3f�.�1V f�<phe�� in Africa�j�Q�Cs&ŝ�4 mill!Gpeo�B��6*�I�o! i�5 D �HA�2�iMsX�ut�zasI�A#2 campaigpQ*A�)�Re읒���eQ-�>�68�3���΁,a{�. � cf=parum5F/,^d"$9x�'2 �2015 0�Crn {&iZ-�ofA� h�;#���C��&9;%7E�tryn.�,�f��vgH�Q�|!�jinflu al I���*h AeNCommit�:ag AC; 2�6irac-oi".�?�6� �d���m� r l guidE�9�le�C�b� | �� ���� [5�TeA0f[.g��Q 5�P{�!1��)��B�u2 ,Mea0,?�JreWt��!sqO�)A^)�.� �� ���Xd�qc�L �<:u� pyre��i����Vd�bJ�W�M��� cVA. )|toxicCe y%k\ clak�� Z7� oni�U"! ��tit�Z��]�Mv�� �2p!�co-)�)V"~ Two4E_a8ouQ`!N�Yaso� �a{'=��at\2�Q2�meaa�,��m�tPɾ�.�a2=!�urv�=s�in&oBme�|is�?].�2 \c.2#y��G�\F6�g�.~�ac. t� - è�i�6C �!�2�IR)T�*!�" .� V�� mand�y�P drugaz!�"|p��=5e�I�{P��us���A� ropics"�6� , HIVE�TB � oret��d�&u-�t�Asa��abl{2 Qparasi�C[oI_[�0TB�4 .�#��)�Ei�rpr�o�N<|or!f��1���� RǦlAa��ym6�F]{rg1od�ly�� draw)(!�a蕯iH66, i/�!hv�=�"�;)0��e�O-"� e��*� ��Xbq(g>��Rsa!�!�!�fiiIC o��"� �)�)l!�E�sU��!Qam o�" V��@:A�?tat��%3IRS� 0B�M�sq� �@.J"�( vill�b!� �ZPiAS!z gram?"Ԗ&�T��Che� .5� .�r�]b��Cro �E pilo�ud}X16[9]%be7A!��}ado3@���MW]m�)�)BIEKFad hoc%{B ?�?l�$,hK �ir�ga�Oource a}. DDT��l%4d until enviro��*dnc� p�iF3 ce�%2�tv. P��A١A݁� stay��u2��|. Carb��'*�A�A�Z�,�%�"��}(mM� �l��}�J�(�B��7M� da G8&*����WL�� Inno�F ve V#8C� �&uma VC�[1OZ�6����opy/�-�)�L 6t aV%y%s O +%s.��n� R&D pip�P�a1:�$9]�e�0 G�� cella�o%�G��ns�|wa� ��C� M֎ alI69"�&P�>=�rA^? �ir� ������e key m��h�G.Abes�;y�r�y׫ꩉgoa�@� >&&/�% �=�.R� e���Ca;�<�>�?�oG��=��02nco�#}�� oxin�!���("�9[1���ܓ)g��e�|Bre�sd@S�f[hem��� an��J�or(Wes��SDer���IR!�o�3a2�eco�,�E�>gru�� ooh��;@or="�?�2��Q e �q �w} & цc�<FV�!�)rJ3� ]ir �( histories:"�� R� ��oC5i � a��f!Y}� 32� sex- ��� �"d�ap~, ܮx7�2e��aB��ha-S&�0� �� auth �!&���2�2�A.�, �ja��JU�unt!do� ~���%& �boHan�� gro-U� indu�X� $farWo*xs I� -sa�B�YQ�]��e4��=PDA� dict� k[, s��A�A���"�� &�%�2��@A�I6)V�r� � k J!�2} Nf >d ���*u!0m���Tb�*sixm�al:�a��.18a��J�v� �f�:m9!M�f of�8��g!�� �"��kAEA�\ret����  Ŏe��_� upply-cha�{Zso�����H�;6=B���Y��B 2pr��$E9 �"o:@�7��� �����lKr�wr,T $e Chris Cu˘ڥP�in 1985m��I�� h�.�. I;�[ en c�f�ly��",~ j�IR{ �s;{\of�.yeSa����S�dq�m�isic�mA� ��Ko! %\�\k%#!o�"��5w�p2�p�Aye� [~-_�F��r�ME��<�R he���2��/ht�2�Mi�8.���m�iP)�ene f]en��8un*Rl��d�m rapi7M�<a Zrar- _s(��Jh �5��.v"� ]�o�E|"���~ �Ral$i6�ax._to�U��!P“��a�J%m�W��%HN��P6!f!*K.$?r�"�� �s�Y�ʡ1���opAo�3��pre�'���5rae�mtc�2�-G.==M�!em�3�"��A�t޲A=s�Sc�%�-Kf+L. U �tunat�,q^diԝp�sh%�Ad�o� ��K ��r �t�i�Z�ga7M� ute�dej�ngE�� docuA:� /ߝ١�Q�London S�x$7 Hygia,�T� al M�uinQ*JMi؞,u� mbON6�8A�pEk��K1X"f��le�(Q �e�2rg �B�g � �[lMG@� �iasXdup��� �k�:!re-calib�}re-run%]� �!A�s� ��aLE���9�H�p"�%?'���j&$�bes��ajvT�� ~ �A��&d�1Q�Qne]-� �F*tf+�x�r� oK^actic|e�$sa /8 softw�+.e 8e��UVl�Jmada�#!4Cc!�um�$ pOI�y�r߿o!M�<�-A���x�A_ �A�a��sX ���_ lly:���c l t�i�*‘nich�����&T on Te����#�8nci��m�9O�� �,y*�Q��D'��n�!��)! R*u�YvE� &���P rier(e }a�6P q2��!����� by � �"�=�*iGJur )(��2�,' !]%"m�6h!!gA%�,B ,���:C�-� #�^�et�|Yyle/y�!����i!�e�$�)�-�[�=�i��+]*�&n�s [�]` �=�~!�A~� ��t � = spra4"U"\�A bedn!��Dm,‘� V=w�!?��gra�&rRi�‘LowV? <E!9��o&��>c2Α5g�(*>, uly��1��99!/< taneB"Zq��- ����:*�k�2R2ep�c� 2*�!N� � j�/una�#A#�WAq � � tep!^>ܧ�Au..�>�-Ŝch!��n�fk�4�k2}s������ 0�1�e�m�WngX�k�<�2j&�' &|'�f�AS�� "�( @_�"5t����a� �.���7����R�g� v5/fit�+�"$ �=t�/;dFsYt�nd�%�+!`�}��Qr-�� � ab^:�(���Z��heQq.>00& &��W) 3��e���J ‘F �a\�1s%�����&�^��(d;I&/TdeathSe )��1�e�D}2�o�A�f��^`}4A\2^e��i71�#��_y"�vi�Kb%p�= aI]�g� �ethod7bm�� u��ess�2C"���i)d!a1D. -y$6�uR��� O^��2>aA�[� ��)�� )_ei5me���;+��LA.�idelD�U*^$x�EN�U.� 2�kQ�!v!�r���E���ofU��&�baN�)z>0a$columno -”#l%�2��hH C���"rt*�&p2qE`f��Xa�A�6ha4"` ;:�,^a� �xY� z = 7d�V:#be[�d��K >#�&WMA� thir^�wr�z!WN�iLFsexE0e�Qe�� A�6�st}n�eb a��A; ach ���, �8 Hardy-Weinberg# i� �HWEB l�Ceq. LA�e�/���fB���5i"DiEe�*d0w;"1 of��kLE�vio_d��A y ��1>��ʹ.�G!<��72�4.IR du��!���gV�a��7"��s�!C �))o %~%�s% �z��& ,�Q,h8 &�4u/![e��*p*� 2[����73�at?di�0~��Ûi7,�W non-�lapgoP�Q d M"�Ji*�J �1$ (Kq2�F I!c�-X:��Q;�E��-��O�=#p<&)�T�+=! i \�����i� Q �t0oT_26Hic�s"�;in叉��Sqa�I7iG�Oura�"N1� E(!!� ��:�3� e- uve"g ���b4of��� �b.A �#is�,�22:..B6.A�'!�.qP2A{y2� Ae?Bz*+-2�� . 06� *woN��� no synerg�pantagon|Dh�^3 ���8o�{F3��i�.��8g gI�EC-TKq ��c�9� 2��$tor ΛAB ,baB Λab��1Me��>6a�) �%�Λ< \i:L02,,��be��G��.!8C%}1p'�s"6�*� of (}F).�%�n Λ> la�-{�T�Jx7��d�� �dE�J(���}� also&X6�m(2�4R+"]K%P!-���� �lb<"y J7��?fH,�-�d\XR3of��:��\ 0 upS0�H Wa�q& ingu��J�$ � |HT"���Th� �!w 2P��g~D��!�& m%� @aF t 5�� i�3ur�[α ~:��O� orU��al�rŠSS ev loci^V ��@ �f6 s: W�] SS1SS2= (�P$�� , −mW  SS1�E+'a% :#A# J#a�k J#�'# J#�bm�bJBm�BZb N>]B ]6>(�GP���C-�R%�i+1��RR!� 2j�#9� �R!aRR>�f.�$ )6�f% −�F#! −f%"V#-�f9�Bi-�f9�B#!Kb �bZ�B �BZb N>]B ]6>(��z&\16u m�&; W.� )�"� *a��%waa**�� �S�repul�W< co�(ng double-h�|=a)je)i�kq�(&� )� 'xa�� *7p�o&ۀ� �?�0� m�K�QÅ8>y�����+o�dNpr.�B �@�*0�t��� � � �" see�M����-��x � '�Td� s��1���*�(�2�0���Pi*K1�'�"yG�"tb"��+"/0b�!p� o�_GupVN -dK ,�$ +�� �` �]%��x(�,, S�!R�8makA���X>�? Hm�Z�s.���ى�Y�D�Iٽ�(�!��+ R)��Tq2 hysi'�:)e�chromo�A�,�so/.@:LX.& g(\O� )5�Cq�.�0A�|;�R��� SS R��HS>HR"x10U9�.gmQW�+g$%��k��I  WJE:�w&�T*�AxI�"�, s�!A� ‘f���"�M al� \ ��A�� �\F� M�\� symboh f3 ���u= }AoFa�E��r (�t� L��C_;).F� 2Ws9$4nr ��2IwA�d , Ff R2�\B��a��"B:5�� i� mS2O F,R1�l ��nA�tn!�:o!��Trs�1 ld�L1�Ad!!��>.eOD.%� is^ 12�\Ue�#r-Z�T���:��-&,�]�F�`�in�or�ue�kytp�8d�5i=o�0FA�"1p�N�-w�:)fn��*��9rngM:!3�o�> �DVna2�%i��D�a��Li�(7��RB�!� �;" g ]F�R( e^�wo!�j�Tp�l�0?� �a�#i<�I�!k��� I%�xn�ZB�S)�7� �*�/)�.����1m��AK�G�5)�b�� Az�x��Ar��-L `� ;��FOapl�:0,i�#J+/}�Mn�(Z '&2 &� . S�Sa™� GmSRa�g1!� �s�&�G>m����|:� e&���!i�el)y��2=�, }\��q�%��i �5 �ors�2�/a>!t))ra7s"� �y�,]}EX% ���P[o&�]�!A��F�mAzA�B�N3 =�d�lEFut� aFv@/y{�"ed "~�� �=Vu�"a h4q��^2j',X�D4�a6R�� ,1_!j%s>)2���!�R>A�DK�+�g��b p3�W!�#a �um�O!o��r=RE�=��.�ٷ�\saySS2 ��W�H� ��.Hso� �� S2=F′z LGfSS*�u�� )� �1 R nb�* i��iR6iR2iR+GfSRs���o�+Q�e{ )-�o�y!�1}.y.*�q , ��#��!�}�-���@I�.6�#�9�.��toxkIj/"Z A� q� s�1^�]!�E iL�exe�"� S^�Z�� �2�,A����e�q gt;I.M�e N� as= VkG��e�dN5sH>a6 end-����acht ̶�ndi��� IR� ��cee�2a c~�;-_recZ!n�-e�%A\á���  %�n�K�H) >�Y!&G���B6�!D �j�Q mpr�@�bhS i�~E�icjnd��(1��aso LDqe�&8rd�elT.8TAX��� '�H!�2)��va,% h%QLDK0�]lis��dw�F? %>m��cA$� @-[��u�{N��{LD=�IF ( RL  � ( ��W�s+=e�#f.?".�#l E&^9 Xv!� zm�2>"� *�fh.l 2��5k='4�}�psc�d"�#.psexbOoBS1� ��1 ��E�aA2�$I�>mp)!S[�3a�I�g-�as �$�qq7"� aw "�Y�`# .& )�I��se:�Wwe%%_<��>`LD��c%����X l� bwG1+�,�<�Le&A�"`)��2s�*-O"| "/�$2B���3E��U% &�-A:�0�<un A sub-B�0�..hT6�[�C��6 r�6�'pV*+ *�D-�e�wh!��d��B =iS,A%&Y��&�QE��vl�(�u" >+["a ?�r2!ٕ�q"&/:`?<�4rIY�[luh) �� �p�5 . Al����6:de .�,�M� p!}&*��s��.�.wo�*��,en�Ab��8� ,M�.w�M��.N< )��hect.Q/2>|(a�]JMi�0rQ ���; #Fs��*'1152; #Pt-��&�BJGt~[ ?ut%rQD��nal=C�W� ����� an ill�?i#�;��2�y�x.7"�/)�n,fE�I�A��!, �J ig&�e�Mree��Y������ r{mi�]2I�J����.5-f� ��VAT�#iA��, , �,�E{sg�2F� :�UsC -“�!��QB\;�P ���-. Oh H,So�Q�Q{�M&T-U��G,�",A�beK1�oY�un%� `$1���(��in.�;Bj MtI-im��r���(n�7�j�b*P �w.'G 6�#��+���( ->2Q�B�s����et��al�9�].� MbyQ�!NAU2���� :rw�F�?a+\�4X-?S^��&*�)}&�\v@6��ru��%��r��te��niG. H�6i�&g�A¡io2I�xAg"i 1-}m�A@���."�*m�@�ja�ߍ_\�A�� 6x ��9�>� >} �B'<y� M�K��%�n��"k i��ka)��)I!W9L* 1�*1 �q0��>a�u���1d bac��& rene�x.`*�>. A�W&�U"B< m�nM@�.Ia��\�y!�c ��w"vD.Fac�� 7�9�.age 26�� pref= �as ESC ( vi��j1�eF ?Fi.�.���Z6l3w;&,!p"ؑ2�Ka�� "�@�iKAoFV_H�!Aqf� ��� >[� i�@�?��]?a�>q; O>k%8q��#�0�8J6�� ��R5%s � �� ���4��)��I��8�uJ �v����+u1=�gFt ��M+� ]�s�O!�HCHMh I�&�]c���e>uywuD���50[Z27%W&r( cap%�M�A����$�!0F��arom Curtis data into the form required by our model as described in our Supporting Information . C ]�iused single examples to illustrate and develop his arguments . Substantial improvements in computer power Gsimul �(software inذsubsequent 30+ years enable more sophisticate�vestigM�Dbe undertaken . We.�t�4pproach by per!K`ing a sensitivity analysi� ound�Tresults shown on Fig 2� [17]which1�'8s that mixturesp bettern �!=us%��)�parame+set ba!� on field !LlabI�dA�s follow!�A%�MGT, ( 1 ) Only two niche�e pres!z�in any run i . e . no-insecticide pluU-;( eitherA�aQR.:o -4 ) . ( 2 ) The] � star)�< Hardy-Weinberg A�Llibrium with linkage2tbetween loci ( 3 ) Natural sel�oA�efficiE�( z�TEq�A�!{,to zero; con-�!A,he values ofA$4ir dominance c.ZIimmater!�4( so z = h = 0tall�M�mD“- , -” columni�%�@then ran 10 , 0002H varyA��remainUY!�dependen� with }�Yge& w4 .!�se.Dcana{8briefly summariA�2�8It is necessary!Vix4ify thresholdsA% 'cria� l points'!.Ideploy�� ��gi��define�time atm�an2AorU��_eemed!]no furE�)(ei,�!D case(�0��ce�y ,!replace��1 next2zA�Ta�� �� d he�ermEWf�� encyvresistE_ alle��. Plausi�$�s would�10% , 25 50%; ^w�f���J�|450% ( c . f . ����has baS�2�^%)m�zlAX stud!�on IR�( . g . [19]g�? organisms.127] )!Rut see G� [11]��!�ͪ!5Js�%8mosquito viabil��E�E scal�+til!�sA1U�a�reached measu�iin unit%�_generm� anumber�R%per��A�enA���(vector spec!C!�th�S0local environA� /ecology !a figur%one�jmonth ,A�12ō �seems�so�k{�v��.2toAWeasily� ve��f�. ��!ree�q�pol�r��i��!oݺ We suc�-,fully recrea'Figs 1���aB���is pa!t�!�)/s����]@�se)�2qesoaIext�<"9�.@ upon��they wa��ϥ� firs�%� Passert��ofq�( H0he did not qu} fy )R*oce4b��Dunterproductive if-�a�a new2�w�T�m!�oth.$s was��t ,%���^�� ‘new’.MLlo# 2 �DoldD!��1*app6 � e true ov���!J�b!qazu!�� simp& !t�e} �"�1 ,�� ( iv�3(e differenc!0!�re� ve�'m���r> las �0 t�Gt�q JU longer (�”��to.��� Mix/seq*Pi�� . R9�spreadsA�rem�rapidlyc �assumpA���completa�rvival!nRSERR�!otypes )A-���[cam eff� ve%� fewAe�n��l y . C.� ,a.��ime:' � s ��� � �V�sp �S&� s +a��U e metric��r%)arAx!Q mer�^2 J�.H debat� i} is leve%tx� expo��Kintense* 7ik!�to occur!' real�!�q!�although��not*Qhigh caga, ,of ITNs have/ repo�)JW�m� elax��i�MI?UI&N at ��� !explo�vC,=�*9 i� ’s HCH/DDT.� hcav ��u� i>�� r/N give3�.5��e#U ist� 8%at �A(=�s��U!in�s�ir�!˝�!Na%*oZ ,ehN<be~~2 . 5Ud\~4 �v�-)X-b��� :�stateAj�)�$ ( page 26�a�at !�a� of a1�rEW inie��2�!� unequal l��toU��5I!�d�x rar�  _s�G���ant� r�"3 widafa� rpre�Ca�l�D����=��2=Q)��)e� 3 will�� fas;%�[.Iis!F�=G.* if i� E�al\ (2_�reconcil!�i-mete)!��c-$w�!D�;~  l discuss�aEIe�� r7 o�~:�(ŕie6� vi )�wot����[-!�i�I���efy`?� 9&� <�aa ��l�di��i�A��uild upME.2��2� 3 ��A�in�,9Iabo� 6v��ZVI ]3toN .��6Aa"�A@i�edMtha� en庍�.=�A)1MA!Q !%ene��>ope)�a�ifespa&i�A2�Z vari�C�co u�� of.fagain f�=always�E�i�2:Nh 53��nyk5R:9 �e�I�� �� �sM calco|}W HCH/.�� "F �E��5%�Af���Dve* n&� ,zmoveda�A� R�of& choicA�e*� pac�Twenty!�r!=c@� 5 runs"k E�=�"~Ein 5002!XB excluded1hm��a tim�isd �g!Y � A�xregarWas.(lya� �ũse ��charac��byA��!ta4Q�r� *P &� (}"yexpec���$�� �D,pcourse ,a��input�}X o at >95%1%�9�9�in les�a>� , howewe5� wishARres� tE.� kU:-Q:Intia]rI�wan�9n%�%Q��BQy beca�,T t�circum�s most�>���"� h'ozygotAJnd=�becom�m� antjn.�thoU*�]�x2�exceedCj,s , 56% favoS��!�44 ���U di!�burn a,!s��^� { a�ic��i�d���t| mZyX���nderg ��lap"1them (�4�� Meane�:��sh s�e2�22f plotAKas� Seq 1stn vo!+�Tgee7�%��I]e� s�f�light��rb adapABk,�FQ�remov �“fai2�.{'E�y9 g�*-� prot� on it mayh affo�-����&c inflNe��u�s!]NO%�0imilar across1`�"vb��irR�rank cor�A�6( PRCC )v� I*` "�ha]g�'��h� ��E�6_2�2 @bsolute magnitude X�0 . 7B��n�U��� beA�wnA�be �gA�d��mwwheS >�&� optimal )> ��� mpa��I�J�:O-e-�l,e�� � !n�UinQ4�mE�d"H onshi2se key!��� dRG� � "� 6 . EVM:a�~ )�A-��-�y!Rrea�WiAantras� 0w!�2� n1O %U�q2 \A�t�A=XiQ�Qesso fa�v �4A6w ll6�� .uosea�t'now focue�direct�is����a�J��a*in)Nv&g.� 7%�DeiKD�Ft-� �� . FoaUe�s�!ݰZ$ndard5���=~�s�ԅu�@1��6 �M�ane�a .����oI1QVm2u��7A�S�6r� aobtain�UfS.�Sn�)�w7BhN�Ka�9� �s-��V%7�+i��55DBA6 A�afa larg"W %>hE-���.��!B"Fy ��" �!X� of.�.�  pu�njwa�nA�hM�!_ly�Lak����]�!�is"� :"^B� a�AC&. �teo �y , n���a�[ ly-R��6u�BJ� � 6�N��U�E�Am= � f-'(. Classific�� tree*.A.6� ��$.2$8�BirUr#m+�} u'byI� Ryc )U���in ki�.�.��primary� i� driv� deci��� advantagehcN1 �iAi�ut��R su�& tool�� K!elow . SA�n �$ look|t�"�1���!Y^s�ZAM�.j.8�%� involveB�&�G�;�eu'!��� st-benefi� m&� nF to demon�� -�- ;!�We�&�|accounOmak!�a1(�v��J must� >20%peA1!%��2�B��ina�D,!�x�x.$6�Tu�aE-��s6D�RpF��i,i w$ tempP in�'�to_ tructm��))�predic� !�.��or�of1&*�#"��%�2� ."� �ua%u �wE52tope�=lot��!ho��a�s��!�J�[9�Z�$16\;)�,> good� � &����i��Jp�yA�Ij� F�!6���Q�i(�&5ob�e"�!of91!T�62� . W& 'p&�):2�":���� +.)l u�%�J l�Nt� 2:G-%i��&�9 ( up�" left�� )�I* � !�>��@�>[ �� Rz�(� er r;.}k��� .�)� �al+1:�e7�F�'!��� F%#Jw�$a*�A{A�D5!�7wo1`��"fi��ear��em��uch� i��,e�o.[�A�m%IbjN�K-��Q}:&B�� empiric!r-deriF ��� D^�="�9��j bye*(. 1371/jour�. pcbk 1005327�'008!� 8N7 &R2 �T��� w� 6轃��uperiw o6� or v versa-� nod nd� O��"v%�A eV(�&��i$�( ~ iV/ fals�,��f�4>�boxm,sha�r�p�aa�h��out��~.�q� �  pa(�G bgr�)if.b� f`IO��#� ��:�box[� .�.)#��* �!�M��he)s�2 )^>.l 6�\�+.Z38#� e�60%#U%t�� �m]t( �2}oZ/���at� st *� >�. P՝na�!��'R,o�%�-1 ��9e�9 Uu&2�6&!�.��}DiBr%�(.Vs=p��A>ior.����OuE �ugQ�.R F�&�2(�U�a�2of�*�!�~saw&}Vn�+2��2& #� wel�,y�bi�.�) �y���� a=" �*&(!��axes:�� )}E.��,8/dA9a_sum�22�f2)"� ?s� SS��U(�!Tw 5$�, tail�J( i�-vR�pro�_ of fem�- )��Jen� �2_��&��})u.�v�w!!9-kAhaW�"A\b!�l�cod!{"���A=�3black @Ga�h2by�i�"� &�,�)d tria�5��*�ng �#m1M. :�[ �repk-inx' pane%� ���.� & hro(()P p�1-��e�6by Eq 7g! �J%,. D^=1 . 07+��56*u�( �P� Mb-�y]�g"�� �$ a �pos�5�2t�h82�� #"+7of#95#�a~v ci� wroR6re &[)$z: 8.<�9QAPE�Y��A��=]��Ee mis�ed�2I2� ,reg-4<26� . Fu�2� �"A5s��>1 so narro� 1#_!dowpas���&�0fic.K�0!� �kn <�de�(%>m��%�) also a"�Ef� it �0(F�.�N � ��"ve2 use;��&� he �~ A9 "� 10 �m42e32.8E7&m :zE'�y(*�w reduced ,�,6M76YNh�o.7"u�� ���.x�JQ�-�Ef�78Yr�3`�( intue��.q�,}DK$2��' s�%E��� )t s*H)("�!(s)�&>'\:� �!Pe� som�9�ve��& ��.6�uS2t&"'�1(rogS3��E�!�confir�\is ,ind��*7,9'� eOal6�a"�criu$�<In �#y P irre�eA2���eventu�y�,� .� H'edA%�� �par�&X,9�(x s ��8. An obvious qu�<s� �6 H !�!%8 �����46:'vid�,�sZ�(� .*a�N�?vans��5��e!�� dela�1%7N����(�om �suV;l�ngboff�a��m&m2 6[��9l�1Aa�hypothe::]*,�drugs�PAS+4�6f:�,a75 %: pm�P:.� �se�� o ^�!0W:�sQ�is0 3 + 4 = 7 �"�to�aqZ. A�_1O��6X1m��udynam�2!*����U�.?. ��5 purp�x manu� p���veJ@, w��x.�a flex�:%�-l H(:� .4��a|+-rpoEa�s�W �հ"X �b ]~-}.�9�r"�n �" f po�5d8'��a#��*mmend� A�r:�s phys� lB.�+l two 3o�? autoazb!�6-f:);� X chrom 3M4N3 icit�i��,at public he�3my��A�- ( l��X?u~B%��n agr")u?=I) o�.cit .U�[11–16�;a{)�+me �Œ�bl�:A: \I�!�ddreshM G+�$ make?&} rele�!� �- �a��  &v&� �@ ot a*B�j�B�.o qu�" r?�):Ein gui�dY+of>�;a�M2"�m"?6r>� l�9y e�d2[05s�ex�En2s [2]g'j-pe�=P "�,-yetA�tDn:�<��mismatc|b��F>*� �4if��!*�.�iE6�-*: . H�/%�����wal75,!RW)4�$!;ene6�E�phr� “m�5pi�Gd �$-�i}�&��/�6\>�7h�G(>2A comm =Dɲ�� �� � "m <s9 @madA��F\ h^�9� .zf1 dIs��*� v`to/ ]-���3M!I6�?~�=/ :c`&'8�+itcAdrawback!_F1A,�licts ��rp(�� �*���) veryz as"�+T;'�2E��t�C>&o9 � e�6@ nm.q("� ‘B�@we�  A�)A�T3�1%� 18�E��*�3d )}.9iv��pic dG��� E#og�1A6: )� appl��EqcS3f!�S�%a�.L!�u `1�p t:.1!U�]�as ri�J98%Q�l�!!6A� lso "p'wrun(IAN�� IRz soAuIR�� .K�3���&�&0)�. S�1�C1~!9%�to jus$Iism�1�����H� opin��Hun*�5tic�hi� A�� >�� ךI refe! o6�&$ 5er-9�� � high6�H%�2� � �E eY��3�VUH �.�u-Ib�<r�$��� J�QT:�QZ qA��,(>i5�=��i�2Q+:Ag%�!��=MAM9A�Mg2:�d?��%N�18sNJ�h1kby�!+!X�18�- >J9�A:h��D08rc08`�F\Gofi(A )i"�1!S��OHh�n��c�!iO:�%�rrect (1k�cea`)�i�u�-a�6{K���mr&" ��-�)�&I2re-���P" ;’r";� }*�� = t'�MH1aw�d. IFA�8leB�� vail�Ilwe!M!c!s abou�5in�/ ��*)0prN1 ��kl= 8#we ign� �Q2d cJ)A�� >�2he<2�on�c�9IR>UZ�:X�>; .} �"F%gwe�Q=42�=�R!�@�* pyreTidt�*;-�Do 3 ��maximi�!4du�B~ceF2{��.+$];aD*et fe���37!�10RAltern�3,.���I�Sb).Q;:o�aq;>!�: Y�*<&bqC�aai�Awo>YO each:�hav�? ���O"͢"h popu��. M9�Sr&�U,A!i&"d'idP)and/p"�#s`C�#�o�n�m�0:NK-62-A"'&��oB&a)aa��Ml��5o�:��.� co�" ��at&��� s vs.[ I���,s 9�Ec;a=sum*princia,a�on� 5���<�G����q -a��heavy\F0h*&I#& F easyAɵ��is&�+ 5- guar)>!��X ork so�Q��-55,�z"�, a�6_6$Xp 2?�f@a��7�0:ls curGMA��%� a��bP rthwh (!ix* h!I=�! I� W/ hasi�Q` �Pfr�B�9�g*|Q�Crbitr�%9)�bN-5��.F to���m if ,��e�0�Q ]� >�-� � 6%�)Asum�10�$.�p"R� � ��<2�a�"\sola��0S� ��$(Y;6g�rsi�littlGor� ) techn!p��9%eUde"6� deaAoe��r64��(�i�IE�� �^[;��[.�AqVf%i��@m�lretureJ� �pI� 6�a��!SJ�transMniM 7�r&�cavea�a}>\)Ms2o��.�53INA�^C!�vJ47<�|AaV-]�6�!X�$Apy>pH!��R10h:�Y��A�w�N�8H&�s[+80+h4%*vSq3!�� 0 (=� so ,�#�/��,��w X� �1�:! O!� 5/y��mUe@�no_ i>x;e��&!O5�:�.�<l��*M&�@ voi���t�Mh��be�Cu�AK��d!�major�D�}�*�V�E�lsA8Ags�Ry�s= �2q I��I��m� su"��7i1.1�T���� N :dur����G �proR%�UR!1��ir!ucHch marke<� |� �� �Ye5D 5��9ML and/(�]*[F �I9Msel�)���#:b�#Jh)k�D"H7che�%�!2+�ijDͫOn��B�m�t�Z �� 8.uA.? �Y" �, vali� err� �?�!;b9��s B �As�I��'e0"�I"�����b�M)��aIult�P- *�a�"�<"/!unp! 8-�=w��a]-���@2.e".�T��bb��\:���by.�\,xi [�  Roush [13�\> :(!genet�#i��sR"�O6�:"-#�9I\� RG !�\<��new!� earc9�*6�r�aogram�1�del � o�=lr!�.~TbR"xVy �2!(pre7'� �HayA�ruS�p-�|whod�� ��F2�U,5�Fb�Th� �d�7%EU�#b  gligc �Hsu#c�X&�?�4P�%�M@f�$�n�digm "�, o!"i��e.�M�$b�"�0%�]a!sp���,�k��l� �/"v]EW�ar Y���(�#a��ac$HinA ource-%�i2�"-�$N.elsub-Sah� Afn8B��I"�&�.#eUO�<"a� bedn�]APcarba[choaS wall�=/�,7�AQ� �( �)V26 ll�Xty"#1 rqd!$a=fee� cycl� ��F[|-� alitaE%ݩKZ�%m.y spra� e 9� re-A���nT B at!��/Ez"8�%b�!�C addi� al , nA�&%.�!uaZp�a ra�d � a"JeO+I���E�W �2�ar��N�e�]� !� !�I��DioC"A��+a�bi"(o�_alb  t%&�\�Re��� %GUN�37b O 2�*�!�rap0 c'4 shar�&iQGsi�5Q�#( Y��F%a-� � s_�t�M!e�!�.[�d.� A A�%z.�V4O.t�e 2� �2�w� Mkp M[al�ixfs!,�)Kse>72� �jrefAY��*�'�"�hk%�N�J�*&�W\Pf��.Z&S"$\�i�Pt"i(ib%�_c�l( �&qb�ly���WO �Eed�2E� ‘A�!!(�!�Q>F �F)A��]opO)A�!8�!2.a�A ��b�irPer �eq�Ue;� �vv� no yE�g� � �;����EL>� ��a�m�R"-toyIv�� br��i,!�EgqBE1!4b� a�ad7m)��c iche!_& ���sopec"6"H �93�_ %�6�Qb�!=Cmyf&^ )�=�Q��!.��,&)} mosa� W�� add r+�"��nG u . R"�+�ii'nA2.]�+�@A/a9fl :-3���jatus;��Ily��!�y #&� �tr�iE2� ] x��(at���1c-X�� 6�HŶrcncpenal ozHaWiTA�b�}lo ensN�j/�Eospl� -�� wo t�d.�Micro- "2(���-�9 ge& phicAs:�*H�eH a village6� &� =��!$f childrenE�� � at!�j) Ee u��� a�w>J ���&,, randomly m M�Y*��UZ*�Lrm�DbAs�wo��A�le2Op�%�!conjuncX w�H=un��ed!�o?-���.�=��OrF�e�q9@-��N��0�qo(A��4=t�wzY&l<in��G �%�p��%1}!&->R��`-� �vI�t: e!�(A]�;)��M ��D�\K7 c#spov+6fne pie��i3�8.t�>�� f� ,"-& ; “p�-eexAc�*�3co�6Ada c�sin� *,@g��7� g<I �d�>*ach��>� -�D&�*� :�,�)�9.�'a��]'N m^j�7‘TBect�.,"%"-��D"u .M(2� occa!��C�@i��sG!�4%dn)��l`i/�\72&iu�“E(c\�D� A�X:z� .6� roof-of-p�! .���v���&�^ QJ�$��"�� �Urs���f!�e�bi�jD�B5�*=,m�2��6� 6�unajA�yF6)�> �.i��5u� b�Ync 8� 9a4Wn�HI�e8e t��r*7!�.�� , � �2qA,l U�t� �c “A!�+ “B ���r>to#a# /b &<h)A/7]�asui�AMcris���f]�T��Po�DQ�a�5�a�lso:�sym�Oalu�!.F��A@shl�\gkgo �Bw a� �t]]��o nsA楹3AY salem�.��d7�l��|$Z A��A�e)�]Hp%�n�e0G`E�&��J�EBV� `�las� fl%�s q�A< ���$e�`.v�L+ns�6�6�-! � anag��Q5" �m��:�n�a�u� �z$F��́X, cap%�of�� elab�:�@dVY�ɑ� *Z )�"� =HscenarioA��*zgS argu�OEb�*�;(U�� ch&B�X&U(�1�&�5#9�'� >A-iCa%!�&��l 3O"� TAQ*{�lM��J"Y '8+�*o�Mn-� %8i c*Qu!��;� 2�� riska"2o9t�l�KV S]�� e�Q�A�=b� �A_g�,y�yg�E&a�q��j nove�U�v�vn=["�G IVCC�k a�9ly� � keepA�?t!cf-m�Ui�-yU aa�ce awai�],� vBW>~c�\nY%�0Q� d�NA5�~� &4'�'�red do!DU �� e�"j@� �<�}d�v�g. H�!�!nvognfA.E Vio�:iA�/I~� Q>�*�+�M���|�K&.wW�*K!fAAs+� .A 8aK+ �R�Hex-L>U�e��-&�u"�Anophbzgambia!eN ly 2"s>i sex:X>A�stN i�a�no�AewQ aegypti ,�b inct:S k�`� mal�Y>]?� w� “n��lL(?�$X.�in A .�6�=��ggA?aP3U�EA�"4�b,f2�htW3�Hc:L��G- %�.*�54V�B�,B�=0at https://ww0[)rA{ . org/5�_-�/LoyG/Genom�HXKM!�86068aA�13c~7>1!�� �)as #un`+��� ��IR-�M;m�^o� e�a7~���2�I�!:� IR-=:�, ace-�Nkd1\+ (Aal&�p���t�� at Xq'(�ve sweep�)ibus to=0 [29]Me=ZN�.?&��po�8�.��eu�)S ]� �dorv 9I ���!�&_Ma��FeU ��h�.u1M7 �m� of�A�� truc=�zI?AA�C,e&%!�, J:A�re� �iviea.in [30�Ak mp�z mani>/e��-� jIW0pr" pla Ej7Bo�gfy�o�^fz&�*�.0“X-shredder�_YI�r�z�Durj:�0or!Lal ž K 1980� Q �;�'t�V|G"�Yk9"4 .;g>�-. S�%/Bwnx:�8*is��o"�.n�{f*��ew�!�XA&�#by�$ashnik [14��"31aH((�$dKo.nD9:>y#�j)�&��"Bq*Aai0!�e�m��5pkB">5�98�d� �}T �q`q8Man;�/n a�K ia� Z( 153 cik�+�)A%{�!�v�8_E�theq�"a�0m � ��S43A"9�z��*] MoqDb�ny kima�i���]e�asن�%Oq !nlu4!4!�0of�$)�,�  bX�[NY���d "U)%M��M&�N.� �bceP-ob�1arA�"��eA�ac$a�$%��$�*0)� "�2�T�/)�8c G!q*� *0 “.5���=�!T���-le 2} yDed ���v� tua�an�*0p�@9Ej� fis{at6+�+Thu� �� f�5 1)����y���0ng��`.����!�.� ,Y�;b;E`�("!!HF�&u6Z�~,-�� A�!�!at �)�LrJ9a�c�L.�p%�*�[(<C(b_G�( 1986;�H��ndm"983*��� al tox�6g��-enginee,�)la�X. ���]ly-�S$=X� v �:6�ɉs�U?�@. � [11]u2}v/B'I��,.�multi��s!JB)%� mort %`8SS hom"�r24�@4�?Hee�� ��i���g��A�A�� 6�n���)���` Eq 9�\‘=h�agswitcV`��ec+�)h92��(&*8 fFJ v�.�R� 0�ser�"�qf�|ot{���ol �<(*W !SA�O�^Ca�)=I413�;,s="ifY�AE�Qa2��;ݫy?�c/Qa9�r& &0="�=H��vU��:�8O��"e�n8!�C�,%�� �"K`�",o��� �&  " !)t/*�= �B��+�+A%���e: *#2ifa�n �z�zu9)A!!��3%}��=z6t178�3%'�: r�%!��m�"$wG!�duA�ca*�y�suscep)(.�ma� e��ply%] enoS�saS�") ��xiv��;E�F�5^fj� a sw� a�}5i�� � v.w*�`mai!�H�F%�WS%Qi�3p*rel�g�2�5:6&"wT,G,ra�EeeK ��i�y�!routin� ��2�as�s���&*�&��nm�ptorB{r�&�.@in7�ia=�� big �ye global� ers:�ari�' tuberculo�i!|HIV/A?�T���ru:4(A(TB3���*en��'eob�:�W�A�ry al�BLy��sF*��moXap��2�J2JS�..a�� !�:w�:� )^^>�etoD=�JP^��؇9!M�by�� in-h�9�S:0, � tane�G&b�V!� huge*� �%v�VYdoge_�&O�%apa%;%�t�F�1in-< C�t�&YG�l�( cruM�spe�l;~ [32Z yn�fugia� 5PuE<"] �g. �� s� do��_@./RDL%Б#a�ky��"/��B�t--. M�*� �R� �m >+R7 2 H%t�-QytB��xv� ��ak.���C!�*�* ���!*z2Wt�]ovaqu.ENsI�N�� -�l�@ � ����^�Aa lethal2�1Q�i- [3w b?�)�+���%�� �1�%��=� { .R5T�� ���1�cP�[64��A*&eU� ��~Y!o6�7<�D�Jo%�*e�m��JR*%1sej-:�!��"j���-l���=uW��Rrq-"�7�-double�gencd� � letA�6G!!b:'i*�2o�.U!i "�0!�*W�����H��!��]��lG.�!�s�c!��dA�+ N�MHr a��4�[!Z.���e�!�F�!A��\i/Q�}(&Om� trac� qe�F�%AY�rweak ,!�y5��; P)FD�d)� ڋ�-A�4� �* 75 "e ha�je!<+&�&�%RS , RRC�imYō�6�)���e�8r&1 �PI�Gre�'C �J��� i�f1�1/�RR�Km�0o��P�ac/�5�"u� l>lyB�ak���AE¡#n&" &N��5��! . >F&��ƅ�k) ;��!#(�Ara�uforwar!�cod\� +��� bd�`�Sfute��f�;�+�2�3�≗e1��!�!i)A=�t�+���5C`���e��Q6#�[ }Ya*I�� O+!vre 40>�)I]!�7\*Qu�I-�=*EE) .��s 3 iAh*� !��[�*&5p �!�d�=b �xP= 12%*)B.e�a m �aer�Zr��]�.�� �z,"�w�� { {Rdn8 b!�HgI��i (�Qa� ,�9aA�.t"}P�I~ I6&O䡻d"((�Q�<�;"�V�"� M�9�� T�do���C}@ ��g,�!�� size��q2p�Q�k.���`*ea diJ9(iN &(X &�"4Q:6�Kgo� ay��m�!��rn�n� "� �"�9-�)� rol����/%�2gg `?X �a}ob"Z& ^-��-�3.�f����4 W¯=∑i=110FOiW (�WE 7-��4iC%"� !��D5�"�N"�+kE.�cf& N؅ã$!I��)r�ae �-}j�eA���l 68ll egK=���Q>� ]R{e����]��'.rE���g"�PAh��2�#3en&=ߡ-7 ���^�G�_de�{K]reg�T�`p� tMJ orig�/.1�. N11E�5 D62�qLeg�aT.�&��Sofml-borneu�epidemF>�ܡ��,�?�W�x��f 1'�P2?!ԡ�lrfter� ed/�c�8���ts�oF)��\ bridge"!1tw�f�S�+*���)�T�0i�J � %� is A�k ,trypanosomia!�ssaliva.6�ar�pod;5nr2 bioaGwmolecule� pj5M�Neer(ng  haea��2ufla���!IVimmVR�;~,jN��afmQcT!�ma3�ÆrEsyGsp�x�9�  ���� Y H� !65� R��5�-+� depoAp d 4 , 230��DNA�6CDS )4 GenB��c_b-636 of��2"E�s�|%(n sJ�3x$mbA�io��73U8)yy>! omic�)y]ial��of:�s&�gz� sE�ot&GcriptM�e,�� )ubi�Au�ot!� fami�Qirevea�A'�.!Rlip��i>yinhibie^IL+ gen-r�Met��a5,� �gr OALodo>_ b�n�K:��}gabund@i<Mi ��im`eF��#�of^^ -y!��aRn:?y��%��� lex �r#Omy� M2 vQ��H��/,. Blood-suck�Y��Hemipa�(: Reduviida*�P n�� bHA��lifPV��% yk � -me\!�bven�B'Vr�{�Pa�hF�EOst45�W��&3Dr�$ F�ski+ �� aap�=pIM<5�a# ngor�=[1]��G4�biF#�/�e�:d&  me6���7yact ���&�P�8a�a�8��!ޥ6��;�=WB;b$;��X��ry gla( SG )Oa 6 pharmacW�!�+A�)g!qvasodil�'%<ti-��2��-�ee!&a�c��>�modF� �S,!!en� A�5\;D�uN4� EZ-EZ[2 , 3!��Qٳ5a:9��m�Im�ms�TAD� �rapeu�6)0�%��� �W�%�<s)3[�%5�Ie 1990!Rm�."� �p$W�RLft>6�"�.�2&\h{cut�I���)��Q��� �jL�I"Ol*��"+Q �=Art ���dX$�]>(Z�5hOd�p�H�#.[a��p��( A!%�v,jX�"#.&�%�rvoir!��)U �!�obstac�\�1g|�."� Nowad��e4re�  t��#r�V�!�=s|�8\og{#*v��va�-� coloniz��uman d� ings�wɩ:]a�5t7 , 8AKV: ��hBrazilian Savanna ( Cerrado�:oc�SI�9b� palmA��a�2�d:-Tsyl�*cte��of T .[)zi�T"� �_li [9–2 �,:���� - bird�6�on ro� �!l�(�0�um [12!:��QlX� aQc� �\8=w NJ!�+-- tran�Ju"* B3 fA9��ms�/�7�xa� vcr�A�$(.a��%�ecotopFMZ�$a�p�ic.�a&�^�rMO pe�K���1�/��X�3A�y2S7 s��( ��%Greek� =�~ ��#&�B��1��D[�D!��w f� eb�quI!*an3(��S�_r�?��1t*����b[u+&�%��J�� ; ��-  deca�>.!� G&�S� !t ( NG*  e"�EQ �{E�m�\ce i� �*��hE�Na��kefgA@tH�5�-�(��Y(��dee:h�5- �3�!Xc92�of� is R& \( -seqn ��-��1YEwcel#$n �ssu%� Deep1Uin�y}�aO�;�R��� newlog9 ���) 2Z�o}�qA`w arrfz*, �e"��*m d"�%�66^ e� ai,�Tr�!E8 atalogE�.�B� SG�!t!#�:��'�.R uA>!�!�!bB]�� t�q� F�h���""!W��)^hj0 & G0�^�-� !~pr�Y ,�{0 �����%-)e� ��flכhN�al Ce�e Bi7�h�$.ux( NCBI�!iZ="�s����u�d s . 6j909iL^ e�� c�:�Tin 1982 at Itambaracá4 ʓná S�u�&�'�reƵ!�?)n�aL��U�of��síliH IU�Pkep 27±1°C�Pc aK5 humid K70–�$��aM�h/12 h l�"/dark�z-�E s"� { �sE�Ga`� g ѿu���aof 5t�) tar nymphJaUX�dis! a�t 5 ,�`24 # X �y ,� ld Trizol!YgP( Invitr�I�arlsbaqCA , USk�p���_ irty� pa� aksYd!�-80!Vpr��WA� . To��9 �b"�!� ��K( urer’��Ci�(.GaPghaN �#)+czfe1(lab-on-chip�3�_an Agil!2��Bio�Uze�T񆡳.�samplC�)�Fe Ll DW ct High-P����F m� ( DFy)e�Ill?oa c�O�s � �D![�nf�!�L!Zry%zpr�UX*��B ���ocols-Tru���kNv2A3�,� Dieg�jCI,To�3ired-endAr,300 nucleoti� in length� .2of.�!uA6&)�D9Mi��!��Q�lan@Al 5 mach��`�:^ J����!dv$1�,a���uis�<b��`���RNLPge a6 teofi�049#05-2 Cn��)*e�5+� as 301 n%FyM rimm�ofw+quD/ IM20]�A!averag�&%�b24�I0� "med� |!L50296 �C �":ZeK!an 25or� k�<���rej�D.a�i���Je�?'con !O�s+�� �i[1�A} ri�+7��!�& �+pQ�E-Qqi��L�N(Semb�aH Abys7 9F,Soapdenovo Tzo [20L@3�D�|��kmE�k�Xe�� 209lx�*r� !�]e�joRQ�|�se� ve BLAST !� cap36er [2B1�!Kta�ɅWp bar-�)dM�o�!{e����*)M�e +� �o9�9�@Ci/+A��)�'A� gAex�/Rm�!o=ds2)<8 w�/Y�6YJ!�x �ȡ ���m�<��|�ej# Exce�� sheea�Re��B9��C)�(blastn [23]m #y(fa*,� k!�C>�<� mAI�" �-HIp�Yf!Z(IIM�2�*suvsco�_-3pO�t�a�aleg%%�Nq%aut�� c<nOe�!pwk wrg��< JMCR� Ab �#bul��� e2�uor��mF[ E�G A8� &"Swiss!� ,�e Ontt 3$KOG , PFAMU SMART aH !A� non-�yRA8u%�V� Ef&@A�� "����M)$��!sp0)V+c�. Alig#ɭi(����Bioedit&{�[2�Jfr+Q� aG��"�3(ClustalW [2# Phyl/ �#tA� �alݬghbor-��A� boot�P p te�MOp N�Q�Meg6 ckage [26.��b�T6� U�n ��� �%���re�T six�;ta�� ^8GI7>��l �s zIF�f�[�e�s Q � genu Vj)�� orawq�E"A S�e�� Arch� ( SR� in �/�( PRJNA29213�EA&�J*oQ`Q�,in DDBJ/EMBL�Q|���2d$ Shotgun AyPl �2?nol/acet�precip�M ResusG+de-�f ecu!��lky6"��c di��by�!s�!Eu� LC-MS/MS�6^� �;. B^��Z��� �lo+�o�2 cm fu�#si4PYp E��J(50 μm inne_ ( ) p05"B%w� �r7ph 7capil�{ OPReproSil-Pur C18-AQ 5_�&oDr�A isch GmbH�mrL3� �a DIONEX& @0 nanoUPLC system�"p]n LTQ-O~p E�:(s�x"e Thermo S&� , Waltham*�MS1 9a e(recda�a^j %(12��*�. ��A� frag�(��, I�����A��C��:��ac��. Raw fi.g&H n�:����� h#)dP�!� Dis�G�� . 3 (�1�U-�E4stHT algorithm�6�SGA�n���Zke� B" BSA po+ E�aO�=E� .= y�3bA1�7�m(V^k!dVc��c2!ё[�=V �Lz�e : � !�� , 705��se � � "�� 11 m��): .9; 7ndJ �#���yE�� u�%�V�$���h�[in�z'�{�posxeleA�� vit_o �uM�2S���F)!�gst .�n%!Gj�1ur� 6{nV24�T[� ��rlpi�1Z.R,72r %inl=le ��L5VEO�1N%�Yup�E ^%"h�Xm5&1%' B&�� c��"B% , n�phori�!.%,� �a�i~,�]�9�%�*�Ft>�%AVd`!tO��T%�1L%�� A,s�H"�0T FcmS��in:Ms�,Wa�p��rk� *6�&� grou^�L&�&I"Iz��M��b"(&6��o ( �@�29�8�(NqBq��"Q�[v� elluO�5EKu�t�ci:o $ hydrAb�"�,e�8fac�0YM�*r09\)� memb� �X~m��h�l"�"73�"� !��Wh� |}rb2-d�/t b���:�*m1|*o�e8- nd��tipark: β-ba:� [2�In�"'IE� tickQ�A-uBw<1�,&xa����a-| D'�f�� W!��wC�s�!2!�E�o h-ByV�seroton�Z!\T)�� nd:��twn�jorI0@,4,p ��u�S<)�CAP�Zer�)�3)�[C* ine-R�1SE�ory���b( CRISP�U^t�` 5 ( Ag YFP�J >-R�@ ed 1]�r-Ot]�"�"a op�i���?sm!Leqo>a�cr �U�[3%�~,.4! venoi waspaU)� �6� ot�AJr�L�mmals [3Q40?'�Q-8a�bloASmooth��y���AKh�nak@/�[41�ac���def� 9(4�U[4n�e�w1d"���'��� 6Dp(yA�*�7[4�_4� nd sf[4�A�*.�,%z�Q�!2Fs���#i&� ,prolixus [46)#R$�%T># D . ��a [48'�/gYEe5B [48a3)$ rubida [5-���q���rrZa+/�9u;p2t a�8�T� �� � � �, Jry%of.�!S6�as Cu+2-p5A�oxi�, enzy"�- neut��il (] bur��*7b�) aggr���_�\Z� [5��B�� إ�� �J� 54�m�`"R B� a�� KYM&��LE�a��7motifsa1�T�VR�!�(�S%�A��7b cl�#I%�II��a�!T���<{� iO(��For2[��t"��X�*�[�a"n; casc�4i^s�.�(/ttenu�8e"<,��# Nirs,��A���l� �!(oAE�+5�+e�*U1FXex�/e��e��� ��aw��E4:�qoryu� ">�14E�!Á�164"x B���"ir Pfag�g"�( kazaJ! paci�G� serp�� "v� �iu0-�� � ( OBP )q-�"bmo���)ub"K1�2n4 !m� >�� iliz� �carri D{1�phe˥�4���>Pch��A�߁��Z� . W'�i�H*a�� .� f�)��e�[10�� OBP� 6� �E>� @ o aci"�'} R�:�)aCr�Zvd c�b,s�X5�(69�� K ul�W�=�0U�folE�%�typ�iα-helicP6s�d!K �C!�st�& [10 10�zE�8nE�W6��=~%:��gn�F"�p��Q he�6j+>� ��448)�j:"l �.� �v� ,�. lidi�k�.��$^ reaf�6)s��� U�JN. O�(lA��CM�����J��.R"�22aT:%m6�6aE -��/�!� sin-�j �*yE�"]r&rZ_#*intrigu��->A;�FŔV8��0��mA**������E��/�95�� QlwsY2�_raa03��"g�2 ɣALb�&���iaam�5�)�mby� F69��Z#!�gQ!�Nr�+�g!�lI79*� JH� Ba�?*ĭK�A�i�qAys�D�0st"�f!��=,�"z��dI&��amEI�5xEL�`0 Z�Ata"�A���&R ^�4���agdol@ a�'�!*G(A�emTw��*I!H.fA�he%D_!��Z6H� �*to��ɶ6%p�PrJ�>E�7�d� d�Dge�O"^a}u�80%� �k��cQ�s�$%^�&"� �(�l lineag�A�e�%V���8igp���!$-.:!a%��rw�I!4b*�es�3�Vu!k AmazRa=&est�6 I���:�kg�LnN�[,%x!QM�� �Pwwer6��3�h_Mq�� s�� 40<�e��h*�>o�9�S�!]. D"�-Var.�9BOb �>"2?!E� i�&� clo��� "�5Q,�'af<Vb���-� �7*� ula�+ȟa�wpe~7"�Dv���h�:Ɩ.�pre�< abio�g,L k�/Ay-R� "�t 3t I ���{xiEly��� �"�%�)P|I8#n�\p7=B�@[�107A��j���<ry1�� �.�ath���!�� �chieve s:�: >.!rwu&q�ao*� *m�� �T��Ҵt� exA Ų0lefJQ�9 r}���6�] �BlB.:�on9�W4�(auD q12 8�zuI}!&/Ho>Cu�-x l�i� '^6,e�"��\�Ah^,2s�`*��o =Qp�z&�!��\}q! mR\�G ozoa&� >^sh��"1 2 :� ��7BR cY���%� B1%7� mDA,&�3� qo3��D/%)����.*�0A,�,�L�7]~y���y�\�"E�E�WcVvLcd�pm studo�st�San ope}9ell��5�o�D6ͩW��a��1��� era ;�a��-a6��Q-P%��C7� 7"�JE��Hprofil�� by m�a@6&7/. [I�"V/apAN��!���w�tol fy g�Ji N ��iu6&] �Œ�P(>?:onh E�a����^�uR �&!V*�^EAe>� ��5 ��^"�*`;:��Ug!�p�.��t.x1�iCdi�F,8u,7���NcUsc��7g)�%�{ � � !�!$c͋by � !� Caenorhab!Vs!g��OIl�Fe.�A�� h!oi*�Lde tax�<b�y�h.m�f�,aP*�cL)��Q�<"I�9" niso�k�g-!^�IgrasszB n ��6Ɇ��Y�E�0 ��j:�A(&���f��qbolism�2in�' 0C�+s&b �� ���Bu� ��hm��y&�8in!���m���&|`E�in!�vl21�=s)i%�e E:a���rz�bE����ZU�a?j1�2��] �X '� ���dH�E|�o��dCUslI�� ��DgɄ7��<nC[�}�a�= turb� nm<�#5Ez!aDSAo�EMq��Z"�x 12{\�Ud r �`�f[A�e\R5  � ��E� < U�y!.�"� wo5e2��j%�R(AwM�APl��T�!A   /\i@�"��8s . We are inte�rested in understanding the genetic mechanisms that *lie orga8al responses to=hir environment , especiallymTlight of human induced.3Lal change . To begin\addres�is"lle%$have chose&model�, interactionpDsoil nematodes and&:�jre amoM `most abundant invertebrat �<)M7import)members�grassl!p\belowground food webs [4 �add �,)3F� taxa)� been show%�bB�M�ive�1�4 trophic guildE��various disturbance regimes [5]–[7]A�hesQ�i%�e shift!�AN E� es c6�F��0assemblages ,�ultA $in alteredM4munity structu!�Pnd , presumably , funI�0. For example�8increased relat!-�c% op!� unisa� Rhab!�da�isaOer & of a�e�a�,resource pul�caurby2\ora�ng�Emanage�,p`ic!z1E�8A$The effectEO.�, can!� direE�such a� n!Sin cheme�!4 phys propert!�of%%A� ��impact9�mov �(or life his�,inn~othera�!ZEnents ( ��g .!�a -=) �a��U+coQ . Here weN�� basi%4one)�)Q . Rec�� stud! �Ndemonsta�%a �y�%*UԈ ( KLJ , JDC , MAH , unpublished ) !z0�xB��[5] oiM���5�5:l.m(s may revea�=J|�5\[=Q1 �F � "� @g� ,�s�ve�� l�lev� i�� at do not)�4well developed\an � ��I�tA��Ctᤅ&a�tal�B. S� f�f�we xida ,fied several.& �"y{( Mesorh�aWOscheiu �Pellio�s �bCephalob >A= eloi� � ) famil�pw: Nis"� in!"�"� �se e��� ɘa.N � ��"; ` �e� -�1 9n,Y�u6�1�G-cy�>��c� datI��M� �]p�5analyz�h" anscrip��*� a V�� Caen=�eleganeIi , usu�medM% signE21��[19��2� in order�%H"Cn�i [18�O[2� Whi $high degre�evolu�r50�$allows C ..�d  g� }A�h�-�e�rA�it�9n eve� � A;9�5Jy�to( . Alth�.�ise�f[ ; � c)�"� A5s�e�ys ,�is � A o� y1�r>X� of �esK T6 expo .�u����䁊�Dt:�profie?toY쵢dex yA�A�$We determie�he2�U{ a subse�+z^ by measura�fitnes��( spa{mu1��[\qU6Z. OurA ults.� � B���h��es���k:����>tribut�U�V��os.. ��!Fur� m(a7" )�,�ext� of�: #1�� betw�Z4w� orQ�6^y�!7� �uL -��rs�!�"� trai�&:�� weA�A�)�:p5jN�in 6]��!9pr�3������f"*t� �5�N�, a��R%"first ev�Rce!�4o our knowledgZ!�e�: indeO�"�ve power�9yI�ipheno� ��n.�&� 8manner , sugges&� U%�ll�!29� b� form�ou�=coM�ioɱq\( , at least�N. A���Q�a.o .!�ain new.�ᚡ�cov=*M v�l�� � s� asg had�#69� obI.a ard.�����perhaps 0I$=<��:�ome . WeX �8"� 6?natur%Uoccur�h���zl C�{)��Y/��SiA�t�B ch� % �r  tool!� Ű.� as a����s%�!?� A�vvolDe�c% �It�pur�Zk isola�bY from�R�!sA�a)�jQZ^hasY<d Rm� �9[�} samew y (&� ae� re X�Oa@us�sh�D suiz @ d . M)cA!s luteus� w6�1/&�)x*� > plo�suppled ann� �Z<10 g/m2 ammonium�� a�21 year� �*śu�? oa��� wth a ( NGM )e( data%���n )*o6:bE��I-�=,A�grmonh4~ quir�a>!9experim�8. Bacillus megaum� $Pseudomonam . w� q�associY %4"� 5�sI%6LI�(&� s_ .� * ec� ly )� [2WBq 6�bypegng>�� fo ed/tho� wash5to re5j weakly�ed �PU�cutic�&3� then!�cQApaMO � defecAesurviv�i�p1�.�aMi!� thod!�%l-�Amak��t lik!GE�) ce��bȁ��e�canrule �\a*R �Q 1��S-��O ��=� eY4.M�.� N� �yas�similaM.�$fluorescen3 98% seque�8 t�( Riboso0Database Proj�)�U16S rDNAA( See M%��. Wild- .>( N2 )Ale�na�AGth��p�����E . coliaDP50Nhich �Š�ol�it� fyp�.�die�.�[25�"� �i��s��.E�|imA�*�  da ��a�e �Meq'�a� 9law�&�f2& ` ter> feo��F�!T&�oxywconJr���W6�.� v7��po�  3secrea�A*o�/����azbe� inguwe�:��)a� �n� will af@b�ll�[sr��as ‘>2�’a�o get �� %� stim �=�Nl]� �,k ���  oiabs�&�( λ ):eaccou��5ag�fecundi�mx�nd�ua�l�SSp Mtime ( T��26�a_]�Ntly m!rehens� th�rE �al�( s:7B�of!ÍOanimal�pd.e�!A�u. AIsplayAhgh�1�w��a���.S�!u0 = 3 . 99=���&��g�er ( P 50 . 021n:n���.f6��, B ..��(2 . 81 , P<a00b!�M .J :063>0. F�R�on�� also:���!�on ei F�6 7 )2�:"; Fig/ 1A , Tx �. I����y Dto�G�!� only�!y%use>lcalcu�Uin2� [27]� ���value2�85a��ARth!5���. Lifc�n�r i"�"af� �5�graphy:>�ed��a�e�� eath�50%!�a pop�D ( TD�Z[2s9]�� (orship curv�1�BEd S%�S1B , S1C S1D � 2��)lex�it;&[ &���of2z2{be!�a maj�!�"� ��is fe�*� �loniz��a(�"lt�,tissue damagq ED jA�=�!Xo�0l5�� in)�[3#[31q Van Voorh��el . �A��j�� ���#� �� s]5wAtwR� =n )Nmq" shor��e�)6 agar�[32�How }n "� simp��v��o ��*Rw"�& 'a�! �hntr��d�=&��.� mz.� �SLl�eu�i2 .- d uquick� 6 2�E��4 .��%I6� .Giy 45 . 6�Ol"on�!hN�q 8 . �IA�B((1�+3� K%9�A5,all pair-wis8 mparisK�f?R�s.��.�(�'�.�5#�y :�*H A�0 � �Xn"� ofa�r ��6�l&"Hmen�)� )b�Ma�&� � bs ��f worm��calor�# tric�h[33�34]!���S��&? 5.)�,�u��5E*day�Ua�n linei�s���Z[35� I�E�a��s [36]� y �o�blab�=` c^��(i� o furP2rZ��!�\a�YMq�� du+$��*)"tes�In��r2�E"!.�Echoice�6ri_>� %e' otax�5&Ka dyna.+ofi�R seek!+axlea�behavior�1reby .�6s_Ger qual��CbTOe�� hind hard!6e2�vmJ��AS!)�ZwO.�� ittlY$emoatX��&�&!|I�&���'as"��=�"�by a bi�)-� assa�A%�+� ��nBM2 As�#�.!�-N_�� 2A )a�!|B��k$�$��*w:�B5b�#"9-U��B" We&\#$a hierarch�>q:F !tm�,)l, clos��f*�"�,IÁ�=%p>�>{,2J��. I�#ing*#���mirro�a�"C$tre?-r.m "�k&�l.�e r 1!�,��.� �a�B� oE it98fi= Z*:�,e�=.� iv!p�u6v!:�5#Qto "� �� �Y:��s��q%�E�� -ed�: ��E�V% ad�Zen MO � achAB!�2:.h2)B�y,:a.�"daur�on��i1J �.�C�0��,U}B\ne�I:�ec�G�Gw��A`4 .|!�e��, young)N"v )U�$;i-LreD2�8(i�yag�con��e/�V2!)9�+�RS�. A to of 372; ��r'0&�0W>�"��s� �/�*)3m0�/ ngi ' ( q: � [37]� cros�&^� . O�s!�366)gb��t�two-fol_x l�"6,6 !�� >six�+�( repl�-�The=V��'��a9y 204 uniqu�&�fx(=�� &�, ge���.��X�w� 5��q;� s 2"pM� arrazUs� �Pten wE�ver � (quay�PolymersCh#Re �APCR!��#h3=& � 9 M�;+ �� �../ on a�)g��Q!� �*n!�[e�/� reli�()' SR $. Gene Ont!�y ( GO�e �T=�g%�Qu� to�]up byB�"�!Fw$Metabolism 7PA�F+!�enB ( 167 %!Vs�/e] F� �X  mM�f7i:�(q��U  A�6�11{NV+ =20nsQ�upreg� x��!(2U12y.*�14>:nAbtwo>&B�TAw����!�l�6fq`{un�%�� they�/�������"�#to�"M {WVSur� � 9 . 5�V�i*�!���syni"�3�!llagen�R0%I+7ranx+}2�+)��)ke up sm�8ro&r%�h�-m�( 7A�, r"�( A�5  prot6  !�A�A��( �!��$'��un&nytmad�)�r�% J �j( 2N1%T!�7,� c)��>,��.s�#aim�p< workE#to&| �t s� �)0C mapp� eF��1.�co-� GmD�Yn%�al� &:R�al1�!v)�O -r��ME����by%E*�factoDRFٍ4 :X7irty-a_ ( RFN!�%J7� e-05n*F"1>o) 8�  is enric6w�2)yaY� mitoa(!�0Ks�N. M!� 19.|�N��(o�'l of �.�glycoly�,' !�ed 14/S=#aA.#� 2e-0�B!$. Twenty-f�ofF)B&6 aEQ 2H)K5��'.�carbohyd�m���1�aY1� 7e-2%~ us�k��tH hods clus�:�B�M��*Aa�)!�mC$i����cE��m&m>�v�:0��� a%�1a]i�ob-��Davaildvk non-�loss-of-"�*I�!w!�5>� I�u)udw; ( 21E"� ∼1*N��B2Y ���)&�C6F1 tics C�a�CGC�nd hem%*b �!val�1�oMv*� � "� aߥper'+ed�7�4:�u "� esb�l h;i=+*�,%A6L��� � ,F��d�� ) %�.A��A7A2a:�r+.@/!�!<�+d&|,*<.�M5 "�2ly)� wildnA< a gi 2" *��bA>=�j.-;!��ad @�=��a�to6{z.nP-2�a few�ntmw(L >i6�*> *h !B Qw1)� >mb:��� d���0 ��.�VJ1J���x3I3Ab]�X&J�Vnu"Ap�:C.� &%AVQHBS,�'2�:� i�%� e8.�:�e*�� 5�!�d�$�=1�e�.�S��"�D�� sc!T� �-% s�(�&R7U ���l�e.^�'fa�-F��I�: ��m*a�ntM7. Gv+f �u^onN�:B:�$, primaril� �A��0�!>NUh.#A����ngb5. O/lR(NN �2:K%�.�s?�%, �!�@�E�2�1alaQ6Bnof.�7�RS��e next�mwheA69��'A�.' �4��C� �B3A�!���Z�g(9i,��FUa�}��*J�4We�!�QD9e5hJCAU"E>�r+p�3ic5%)gA!" ��?mn !�a5s�-r"�4�-U��g�;+}"a!r�-2� &�H�KG�-$art�@a:�C��=c^64eo�7m����U� n#v/.�D& m�or.�!i�$?��?h�X1�a2M6� &f� a�KoriA�ec;)b�=>atui� fa�j��ri�I�A $upper left�dr� ��A �Y�4]���Eexa�%p%�AB��dv6��%va��$� 8A�( r�−�'6�Q�a�n/�<[Log2 (�d�nJ" )  � �Ag*_� " "bN� �0I��s�?%4! r�<s]�n�1�K "Y !�m�%u.A+sR�=�!�z �u-_>�(a zero ( p001 �I3�!��6�a"fA*|21 �*�J%26i � )l�+� "*�-by*86.3wlw407 � * b�wepend�Y) �t��>�2�%&� �{*�)�Lm: stro]�edF7�) �|d-%8��>aVF+��n|5�B�� ;is*�on���+� yCe"f nA�q�r��-C&�A�t G�R�NaA*u.�A�.lcoeffic�MAJ xon*�^6�a :�31"� >"�best-��$�/��077�=�ly.�Pq��>�.��A�1^� k��ag�bAtQh� lete�6�?B�4!!�Z ͋� �e2O���b2�l�L#� l"�N.26"N�. C�a� S&Io�.��2� both stitu!L� M��! ��>t!>g�&� #�2&�:l05)��(k"U��0e�$]f&� Sy�S)3>��EQ+��eQ � 2B=:!I^QY8��3{��chk"�y�9qi �ye� 3Qo�5�$�&�+A���6�aH�onb���ae�.X�" F^Tak Sg� b&s� sA?apt��leI|�!TA'2JO "C"["�R�1LN^�,.wmC �O4Gr!��5�B��T"i)� �G:b!ZaE�.��!&>Ap&� � A'ainsi�*"�Aple/(� Ais hsp-,6!Mch encoqH( heat-shock�tein [39: A�.�2� k,4Y!b?#8*�$+k3"�:�!:1:=�[>� �a 15%��HJ� :����!w V%�6�Y�4�&� is.W.�*s �T�6�*�N:�. Not� i'i""5�.h, b$BQ��V9� �s˥�=21iv�:5:�1���%!> ZV.�pl�,�se *�2�":2zb� �<�0" eluc>�JQ :?.�cH)>� ��l6@<&$&�i:d(�nee�%a�a��>to�S"�vQisL�6�-!Oa�F�)�:MrIjEIW�U�rol-6�QssA9R���\>�(& It� ^�]BQ7�QI%�5�Pus BO��K � �s".a� n��� u.c� %�pj.a2#.�U�.�G� m� ���wvo5Cul*�(A+U���es �0re>�X^p&�� t;"�Fmodq#A;!b�un�lQb�T*BA�.O 2�6�� YNa�*�!�%�AA�)�r��YJB$JdG)�bw�Mwe1�+W�9A� q�h� 4��ՙ.'4rG^I{^ i11%z !`�N8!� "q�0���40.54BU>� �E9G� 6Ft�3s@60l([40�N43�8r >J��!"I#6,I��& pr�X ,l�ph$';� t�V�/�]f3n\=2}6�"�\ �U0Jef�%!�u"zH�G6�!����M�.��"R .7�iVCod�1/2�A"�]N�G2%E�mayaT�T�� e��qiv�C��iEc"CY:M�Z!I F"3O \�6zO�%*(>jR]6y� ���4nc�"�I:�2��,2Fis�5to�hu10"7NůRU2inEo-G.�Qf�zxceD_t��e!�r:|I!G���e�1T"E�9s?thO_$B . UE%f�we�ZW2�$�!p��8.x >"� a�/R� y 9�0�46�2d� U�%p Mi �ݐ ��:�Ca&in"#sm\i�,�gbi*�(�"VofF�'"� B.Y6M , 46�i�RA{noa�~���]nowa27s`st;dE�Q Q%,i�%�Nlp�t&T7�46NL-8.��Ka�7.�" ,is!�ka�E��>&| �-� �B��)1Ořt (?_O�pr9G�iI&�#ly�#e!W"�U=?(:�2&! >�aiho�!��a.��a�� �S�m� Ai��Ab_V!- �&}�s-f���kp&�q0c�u%WY${sir%��'sUž�rom�8A e � �� .����j�j�Q�se�c�0z�:�sHA�bR� �.*�j���Zas�.A�L>.��9%"<@V >by �!G�c4i;�O�C�VmVM �%�!n\%���h!���{mS �. Ic*au!52c�0� � �I�-�Q��f, 0%��5�*p6�A�Q|��lQ�_2��a�1 V� dvg�.i�!�6� despi�"~'�)t?��11 :%��'5 a�&I "Tr�7du�ec�(5N?+tic netu-&^HD�K&ac&Rbue"� "!��b�,pPl�S�luaXX*$A&�2} � �IstimuliAd1�T,Pa� �at�f%�in`?!�"g).�]}�6^T�_�Aź%��4�:��8admyOr �EA,D�Flanog�$ to alcohoE�o)[45a�[46clso��s�8���s�S�v �" s&��"��tm�SK�>�MjoryQH-n]�1�EB�[4�gFuI?e��0 �i�-yb>��,be)�A\�>T_>K]!%I!�d�fa7!�magnitud]��C��p����T)k:� U;.]� 8HK� u\MEir=� 1�c��?&� w �^V]�� ���$ �N *�/% howYN :K*X-6� i.2�h%صX5�%*�of pab-&;/} ��"ly-A b�ng!��a�� *#-!�m^(%�9l�a8 j)�,67 U6�;*��"�/1�� type� #�1�J��F\6)T�l��6�N276Od_"�(C!� deca!+( >000%� �Npr�A�MHfrozen [9VJZD%�E�a��DYT�RhI!H��beuR adap%so�.�C, N�lonE�O� 6.-Z�16 v� �4&�t,�D<* ( 30I2 529 8�/aZ:* ( !�01wD)!n� 4 �K�.Z�� G|S*6@I� doe�W�?��1@ post�0y Hodgk d Bar�: [48]��1} ByW trade-off!�~]6g6v2��=.!�� q�� ��o(l�Tn:o.�Qre��5�S�A�."L>.�/*_�Qb8 W\<" %N*�2by+q�NF%/in^{"C�d.1$��2� � �5)����P�|{5m�$! K� ���u.�a �C�59j ��r�j�0�!Qb�)�"�Fsb" �u IG. W��K( 200� m�"- .�N�%)� a sh 1"@��ud�+I�y 6�"/2��mt?jM�'Sx arc,V,�Lfaecal�f�[ arotovora� nd P VP�bV�&�!��&< "@ .��� �Lf�cF-�%" "�;9at 2D6�,�H�9.2JE>��oT6J��H SycA�h$“sick”&2B[abn�_l �l�F2 �Q�Kz;`�#}zF�.��*�,)��juvenM!mo�q� �� vd.>�!h+-O)�%��-�Q4!��Ak$&� MY�Nmt�I~*� ��+,��_A�:�*5 �/er"�l�KIH �I�sime��sQ2t tra����7a �e�E�>�cid�vi�ZAS ai��eqA-a&�:ki�n6`(��4�h51t�ct� �<%��[Ms.� lea�u$� bR; �D�hat2�.��!s)�%.v�27�t�-p=!$ttemp�re�N{. avoi�Kir5;ic", v�.5 �L��.�%�"�mM-�k�Mvcur�bI4.��&�&�>ZA� Z�fB�AZB��T-erium( U8"#�#.�BC���6[&� .�8m��)o�4is5�&]�I��Be v��)A'�V.�\�9# C�c\��) �32�"0 [5�R>:.�J�f urw�0dc"B1����"�U�b"�, ���kOnqf1expla�Hz�M s!% tg�  U[1�� � A�elsew@ )A;�Sro0've�pu�F)q"�EV �a`2�#��:��B�=, "�6�" nerm>.pr.inhibi !p �fof>�"[ Ep, ����44"7 ��e>H��>�!!�#�)>*i&':��" an.&�mrga�~ re�ng energ�=�A)��oiw}r8 stf a�T�c�oev���w� o��-! s �te/2�&i@q���sP >(t�+�Ainsul Y igna�M^ way�fow�9ea�EDAF-2/1$C� >��2,�s#�H2%�g!)-٥oa�umo�U5�[57��c*� >�� F��y infl�c9..�6{�i.�+1E�oi��= ��N 1N�a�el�e:R&�f" d���_w^�:i����� l�c����"y:Q2“�eF$�K diam>�'��h ; [5]}� .C �A�We ]s�8 ^(.�@)agul�:�a#@D��Iu���D>���l�asY� �DJm��9�wdra,�A��bly-�%�ly Rae"q,s�r2�YPr�Sonc�pac�@�+� 1DJ�w*e%ascaA't� �Se&�0� &BZzsuscepti�"2eKe"(��IQP��}m� e au�l�^ID��'ri/Ks&-f](.U% aximm}21s� [60A>R6vf+yH�YinZn� Dar[ndRu�;odA� c~--i�,�~��ib�vAD"�"V*��.zl&D*&\�J:by} EW:=e�6 mi)]*�s,@�n�*-� �� ^��+ (d�� �S��2%\��)1��c ,� K"ʃ1W6ʃo>��"e�_5/�Kƒo[Q�!32�yAL�F������erm��in�vion/co*�d(��N�R|�`� 4�lIS sbZvR2�RB��j�)�*� z<&�M��-&� �i� E��DB�,��6� x�&� "�&Cir].�  �Z�=MB�ap�T�xr�#($��Q%*eg�l�llp��P1 :� A !&(��"/,. �-�DN1B�3�B�$: cpi-�=ok121�*, dpy-17HX129KMa%i- ok53R mtl-OB gk12 $,dhs-28 ( ok4Hh, Y57A10� 669 b acdhv48>k�/( e18+, ctl$24�B �4 %��, fat�ok8�?)( op23� *�6(�5 cey ;90 _^ ok85 _cyp-37A)!6 belo-5 K8 9��185) sq �sc1�, F55F!3 )7 c C23H�):6?"aIaCma!�n�*�x%�a7,�bed�p , [6�Us�#3vei�%as� �o.Yq u<�.�"�q@s�D|y"e�"!  le�&NCBI'sPBank "mr(� E6pYL) :hZ6 w ( EU70469I&N�u#)�BG A . B6�bn*��^s)l&?a2�Sd9�-b,"@kpAl�\Ɇ�� T!�u�W��{>[r-\�`"�#. Dem�k�e�iL�p�nHdividual��c_��QBH FuF"�)cH �Vag*.2& ^[n*Rp, I�pE��r�*"t.��J=#Mtrins֎dL� Z� >d!�lambd_q. M�&�P.o9�by��eggS+� !�5!xt� plac��N�:�� �oVE, �WL4��maphr�cP0%� )�ct�fincub{$at 20°C woVV!TDa�LZQ F� orig�X�a� re-p�n d da�until"�P�O Iday2c�3�Eaborlr.eNvie�Ghe2|ozto%7.v'�Axa�>al2��LY��+er�%9+R� 6�W(�r�3E�E��0� iR�( Ro �v6��su*lxE�s!( ∑lxzs$^M5E�[s!�Mby26/ xE x�%!� clas�&. LiN5�3Ro aKT\jA�"�pA�lnRo/TS -λKe��7�!�B�st�pl�6�N�n�@t.o�o# �orJɯ*Qbe��*�`hybridi�oO :}VÇ spot�+(ligonucleotv&3)#G��e S���V at W:{ton Un"5� in S<Louʉ�=\s!icAy�B mRNAJ(rH$-�� ed y*6dC �Ny. L!�Peq >Z tGenispi 3A�a350 k�92vr��� nufa��mmend�-I Inc �Hatfiel�(Pennsylvani"$US�@.j�%�� � a Te400 H.�)�ob "�Zu�YorwitzerZ�:�,�le�of95E���r�qt 2;8j���}�2��>Oproceduby[6]2��arr' 8�16 hoursAE42° Cb�r��aV.ls��$!� �s�|�an AxonA ePix!r$0B ( MDS A�ftzYTechn�;�, Tor��, Canada2*A��!�`)��Y^6�v softw�vg� GridE��p��" nghd�Tma����~de�mdy�gtiAԁ+Raw �fi���%&e MIAMEpli�[6��2� � Ex�A�OmnibueE�cser!*a&!�  GSE159*`Al@xZbqb�R7xm�(+)-�e�- $� de�&~ �e����aq��c&Jc[n +u�t�Sb�fincorp[�!�a%m swapE� ty���!:�t&�a͍&=|!��mB�a.�-"oph&("�sCy3~Cy}we�AUq E?�8eV WolfN|r"C [65]M�SAS�}�h.�I�Jte��C��, North olin�ia�G -step mixM1,>�xof� >%ll�R�s~,����0��9w aANOVA�>nAMIXED��A]�,t " �!�f�9stage b�e�Y� backA� b��rawH e>eK�:>�byeh�9�0S�1 �:W��res d2a ed R�Kve Fl�c!� �a�f`I )� �1a�v�)�in� ! �H 2 �=u�5t als�#5�y� ( FD�hq%�" �e&7� aYproblemk. qutE��= +Q-VALUE%�Ik��!�E |Zsh�jq�N��#'`W��4U��#� RDA<cja�sVolcano}�e���JMP�02Ax�OG.� �Hc9a-�~a/Cwww . k-I  Pedu/hermanlab/SASCODE�,I35�) �as!Ked�iAS�hՉA�^�.&&{*�'6I+1";)�4��� ��!�� li���D|ne0&�MM"y� in G4|Pad m 5��I/J(V*�)� AR"�p3nt�z�ndN@ E�J\�)N!x.' ) Za*�1�&�T�b��@F~'�"he&�Ue���""Fb�� ��* ll 6.x�parU>0a Ncof �U�p�XO9�( .��A cri� � �@8ammalian embryo.3~�.g��|WEner�& ��surŠ�aV�oectod]&( y0G&> ell�- �mv �Q+ q �tWe utilN|0-scal!(stocha�U�6���8"G:�2�princ�0s���!.rob7!es�is�1h�D%�!��2"�:oo.-���'���3%��#or�]by�]�ha�ve imaK.FjA,��w}A!F1�A1Lomo�R!^!=A]G9��F� ��ly �%z%>h�v �moabla!jy֔S\)� asymmetr�a8LHn,*i5E7(.�fluctu )� Cdx2� Oct4��f�/�e,�gMIcbeneftP.e-�d.�#ameli\ =" ly� �8al =/��IQ!>!�P,!�Řo/Ptim!$!dpa�1%� fate�k�%�I� Y.oďm�&!�!diwQ65af�u ndow>8^*E\q���i� read !&.�V adju�X�A�A�,�%\U:uc$ Q9Nai�^l/:�:R.A A �w�2qu,*o�(*�$� logy��8;a�@p]Bs �ja�.�( of exquis@�)lex)�Ia���a�!�fer�Sd�8����,�ss!�!�x�4m�%h�_ orul� )�t�H,gR.� '�o-�$2 Each ۉs eadc�{$ $ M>z�o�Si �F totiI��`wzE}�3�{"IU�@c�2ee�!i:� ( IC�� 'Aly:�9fu�&�,Gt] �T M!HHr tra- �:A��Ine! _�g@&� heO .�!pJ�]d�en��als�] ��� Q2%Gdu_��F�% , �!)YTE)�p"�7@� &��by �X�pa�"�_�wit���Zgt���. Sͫ%��!@\:� !5�a���j,Y+y!�P>|��s [�?��p9!�5f,ng�lC �'im(2-�i�I4pr�, '�tl���a�)�AAco���!�*�YoabD�Yrm���oj"`N�/a,ias�:�)me:�Estart[ �=�(4-y ge [y[�]10–1`1��t8" e`xy��i�)EqOmW%VG&&�Hՠe� b��!d+�+�@�R��m����1 oV �mmo�*�!!3! ls�[�I9: ��eAAC�J9�a� hime��m �y�>c�xB  fR�j7 , 1�,A� maniO�ed�RensU � ��%x�5re�n:�,�)����a�!�DU��,.�8-��j E�newbor>�A1qM)�I�ry�AQn] �)��e�$use2 �7m�q govet�A�i*�udec�" -makaB��$Time-lapse!�roscopy  �+��D�$qpK160o� un.�.�eaR�� !schA�> [20]s*�95�v�0�inaFw%�����32)� &g;"t��(rea�!.bU�w�^"��b3lre�6&�$O?X a� ^8-2�A\Watana�6t a��[21�T��a&A|� . 5-i�w a92�� surfc  )towar�*�]  sgg��of>!��#� ��!�|�:+t6"� [��a�ism m@xi�,�i"�a�!���U ��rchite/)�c�ac3>mistj�� a� ),&�  moe�a�"Du�T :�s;0�e �o{oi l}y�� l�y� S a-a�&� .�!d��+"��mte�he�.��<bt�is�/)iG�ruXo��(Ip�y Jn� .���e m`)��qu�� va��!)&#�or& �JVq2�z��C� st�w�,' xa��0� "mQly � A�B cyto�ma�S8.2[ ��I&�z(�x UE�!� Oct4�� hiev��B_,]w.Lr!{R]�"� huOfam al hh"ogene��!"�ts� ��� �:m� "��nyse-�YG U��*N of �a7� "=�Q-�es �Aa���y�� [27–2�&“A�& �A���M�"7 *. �:qhz n�P�� �hy��8z�h*�� u�9��-I���I/O2t_sE� a� -bas�A� [30 , ��bZ e 8~167�Á�!� J= �de�a\M�*+ �YT��?da�B�sy�or BFAa� :7�[bT�)F�)�f,"W !T)� pC� J� Par3T r0A2{ir�= ��2w0٭��third]7�“�'de-out� AO�.OWA'�! ��'�0M] �&�16.U.�X)"% 1=S+*2���hoP-%h upon�o� �q�9osumKy ,� ���)!v �A��c�ITE& [3�~-�Ew� �*al>1��6Nzi2ff�k2']�"� ��R� ��ta֘ 9e�=���8,*P.>� t�e"��%�F�Ns)�Adac_i�_��;cas�M�oӴ!O0YAP / Hippo /�1� �";s�*�F[35–3� �iFkсc� F�bW!)�E�1�-s� �Kag TF.�>�:I�,&JU�^�!����� " a�wEE!EU˵�3mut%�ex<� . Ray4A%l*�� �#-OFq2mi 8�"6 A6�O ����z&� �.�U�� .]%2�AeA�aca 5`5� PK Y�hs�8!�a�I$ )�fo!K��53~52,smo�`2�/PAcTb9�9g�zP��ť !���K�m�"e^ed �deP�[�:&0�&�F,)6�r#ek��"�)���� &�z.�v � 2�Q�Z Y!�Aa�7�&�y�2.���*kl%�!j;^�[4��4+ M%J16M�cQ�*��co��� "�E� [42]Am9y��2� �*��;#>�A^�"xu�� y�I6M�6iQs2�enW��� a.�2N��<;1�&v �*��%���A� Cl*� ~Ļ�TG _a*m*�^�����|.�>X[I.S� �a=%#-F�]� ��A�y� 6eV�el:`b~.�aE� -� �2R G�!ۭ <����3 ���.� ,+$nU�BNmp�F.���*�V�-�� � :�%��87�'st}u`��!a�ic"�:��@_C컁'��=M!�.��>�M�l# �!&� ��`1Ee�w v�Emd�+UL��Yqf�:$ADhTxmXT%��3؍�al=��dEm�lj�)g &)is �eA[�Q!:Me!��f)I0A~d�;�@� m'q4A�D) �X �����Zy����U��;B"� �5� 2��I!����� e9i�Wdetaip K��˹�( t�Bjun�J�&#'�'Ih"Z� Xel@sA=",&)9� �$mYl0@J��bWPs,)~%�s�:p"&ve>�1��d!s�ol��+Y�nG�p"Y�i�߷�� s�%�]�a!�� fM��g5�M�B�3exI��:.��Vn Y\�`(�taT5 �>��ioA.��@#�.G� �orm.�!=a�  !&]l!}\0 >�#munofl* *�2�eHG[P�'�� �7��!��9l��i/f��*AW��#���"Kxr-eGFP�ge!�6�j3�<�A�9� ku �!K#�$�p�5�\r3���#�p� NlA�6�,E�pԘ�� –� �cm�sm�F� �+0�XNI.&�$>�#@7ve�)�Ӯ&�! ���@Vh1+.nf6�I8U�!�'�t$,�@qe�c+2O (Jby�|`�. r.�%�,�R�� �#.,!�����e��!�I�ir!-�5>@�&*%pr�a=���&i�~V�%Di�F8whelm��R�?�{��Las� $�(!uRx6A�gra;6K switch-At�X2��r �N"�7$ w�%���$fix inevit`*:�e��Z�xOq�}�$�JyxeO�w�1��<3&�">5&react���5l7��� &�2��%ur{ e�� �Qy0r}�W8 nuise-�3� 6S[4�!4Qs���c)NGz6�aim#A-MA�"�)�e�Ugan�7i"�A�.n���/�^�Y cripA2a]B���S&�ys�A~stalk"��S5Qa;�! ^�[29 , 5x#R/��aAe� )%at L9!�&:)o�Lo�.� q#s 5+6,�xly�daug��!Ta|.&b���-n g­Fig�T���T��0'heF��&�P�2�6qY( Cdx2.S[3 #OA e!c� 1� v�">rE� Nhos24y�,s YaplO ��>�8�sF-:D�o]�3�Oca�a b}AZ��2�e�H�#ǁ��E�S|= !�.���J  ��%.U ���Bste�T��T8]� �*��{�� �.�0rI�l-e� Z.Y'a1�<���J�'e��!��"���?��&�&� 6�~�&��Rn��El%"~)P�$c��&�Ef k�%one�I�&C ��#A�subB�of deb# , so�  expl%l�-DRV U2 edia��� �,�0N 3^wYsumc ���6o)��2�AD�NsE Ua��&< �dF�g�/&�/-�Ddxidt=k ( b+Si+xinXd5n �( 1−`5+I  +yi!−xi+σa. xi⋅ηdySyP /(fPxPyP��y P3 ) t� , xisei]��*� �j��A�F6�0p�(F9�!�pa3�!a�03:eGself �{.R >seDR?)�s� �V�&i?fi!� }�=� �6!�� �K6i"�@(">9�Aj�H)��&�#L�*��M�  σ9O�PVng�oF� !_η8��&F1� s" ��senu= ��=����� x}?��c}�am�2s���@�\�#�7�A&� �%�tuuhI� ≠ �E��0uȍ;&i8gtq�em� *aa��A=?≕�.v�S"Ƚ�&M i�Y( S�-� ! f�[arQ�m�!r#�K*��y�?K>����zi}Zne7ocircur�aF&Rst����?U91�$�:�hAw���t(B �de)å�� �!A_r.�+ " ( k:�I�.�e�/i�antago%( ��.v>3: 2q����� a-�b~&kA�e�a*�X�A�Ua>S�g� v�3n��B��-���#,&q$� "�5%G Sinc��"Z(�ep 9|s*3���3t-}]o3 ason. y�on�&D?2o\)'[M��l' ���e) !R!isBA�TE.�Ezs�.�qB�aCor��I*�a;�!I �Q&je*a< �Dl5e�w��z1fame� �%Lcho�*to�)i���'A/t��jZ �!&cEly�(i �*!� B�e�.-a�]��y� � _ �w�YVnd�I ��'" itiv�f��C�O(h�+A���2�5�a8k�=R! ,�%��8�"_�a!km��,� "��e����%**� �*(�M�9�overlap�aO Ĝ}Y�tw�'I�)&�a�)M�(_A��)�'��r as�>�^��!@�L �[A6! 2��&�x�6�/r�,�V:�L�����{lthe!Q)�( �e� �Jo��e` ����!�54.f� x'%G�q&� k� %HI�L�c=l4�#r@ngL�%t.#�D ,��on�.EbDu�[96x  �GA�hP`)R*z�3u�'�ngId!Axv�/�aA~��9@� o-���%��4# adja�7�� e��� 2*ii���%.� ."��,q/ wh�C�#a=?S1 MoviA�q+)�*�!�"��� L �iNy �\tq .a�� �j� �Kg�Iw�RA�`fEfde��y!�E�2�,jWFj 9:�i�>J !�-�A� a&&8no*� �! set��σ� )� s�S� eF.� ��& � K a*s%i�/1mis��!TE marke�Hnd imZw Im ?��/="�C 6�q.j�0�f��t�6 X,@ n�-2q5ngu�]� snapshote�#q2%JA�@5�k� d �fr�K�FL0���A ��� o'GA�1��&� !����8&�A20.l�-�mj�%C��Y%�!�^1]� a;�.�'d why˜*Y�R� Eq 1)�U�ng �Bq��p� "�m�a]Y" ��*�� S on�z �S*�� ^*� %� Miegt A "%M�u*ŷ"�(�Խ��CFblu�5� .* ]^g%�h��%ias r��OEy(7Oct ۧ��] pjEiM�j �q"� }k�a�e"<TE�a��-<:cU�*du"D�=4�Z&Y:a/ "5D� 2�"�.�=�� �(A�e���� n do�2tayI� 5!rare�L� �^ !�%\qՉ{aC�'#jO��h!#��\Nr�8J;i� !�.6!E��DreE{�UY(M���s�'� �^if��#V�)�b0�<]A�IC!�%�A ]B�Z�!�M>�>!JB�&�g4�}�<o�xA7(.Z Si�@)%�.�� ����/,g!�ofA� a���&!UiW:! "�#]] '1�?Jr�%A`�6�,fgY12e.d9"�zx &� e-P� � �*� #' I+!JIiwB\'�z;TE →E�]��a�j�����&g7y�J�?&J�$ZE�ii�\.!R=!nN'(e�m��no}���I s�'.�2����75yZ� e ) T "p����oR&(� En(.  �2�iv� �z2�"SI'�,9 �6� ���.�*�)d)�*,C!t S1 T��)M�� s �#���9EC�2V"N2��&��icB� ��I�.�P&RBD&j��lo;9�NF� lyA�"n�ű)� O�2FL)�z)z�&S36`f�5-��>eG �Jj �� �9(.�TE>N3A���Rs j.A� llelYA;nqao%�#�2Mk5)��R�#6��YY����$w�3e+,l�)2H6�e�Bl, MM) >�2@ -.",hu�H �*e�!AM25(9�J�),p�� )0��:�4�% _<5s�/�y%�q�Xe�>6.&�a�er�� to%�~TE.� n�&�)3Oi mNa*�6B>^= ’s�e���!1>�0!H3!a�at�6nF��v��a� ��-��Q??�uo!2�v *�(n�3 ��T&+����� crib��irols—�*)�rando�Q sA&mA!E��A1&�+e�b*�,=aW�dx\�� �G �yA�&�9�MAq�.�e(U6r0M�E5at �D1>B:12]����! _H�gF�oHN2CBg�\��1�e*#isIN4�~-�B%��7"oN�1eҟ��i g4 �*� �\$w,�� �a�QA�l 6AmUG}~�%#Q!���Mgp��$!M2�{i�Q?AL6=-� 2)�@a�.�ow �>7fi�F�H�#i�B %�u AWn�T3*U.�� +)�g. "J�F�&Ge�e�*�D��\"�u�&�5 y�!:A�V#*�FS�v �s�i5� �&$UQNC��q$2�9�n hel�EqZ%km7�y��� !�ca6l%Y�W�� �w al�&x�@�'�x�@"� ���g�"�O (��A*X �;SP��T�{6nd����0 ��.q�l@��ccol@mG!��|���:j� oe �� Ho��Q>!��m?�H!P�re^jis-�Z�?IJ-�5#��) Z&aR�(oe��)���:Ig��/��.�Y3�0�a����!�;1? C��e�"�D"pc� adhe�!ksor���{[t�2yXa yks�(9@-� ed DD� AlH*�.��| note!�Z mo�jR�^�Pd�!=<� ��w?M )%&�I��!��>o�2bSg�Q�wo���e;A!��3mQ.lacLG#SAm�a���w$�ni����h&�_v�Q � ��"�/F ���3u���q{b �7��8I!K :,d ;+!Pex;�=+�#�Y&�#A��+A�V�.��^2�RVZ,�R�|�`d,[62–C]9nQ ask>6K in:P{e` � o��g� G-sLd:K( σ>0 �-�g*�$� G��"���Y�G&m)�{5�Dfa6�s�MC:/:hcfi�]dEσ� :�|�h&aA���A`s"^'��! 2��!�� &�"�K� ="� A& � pe,E�x r�)�K3D geo1V( <\a!*|8� rm%�� �#i)Ls�h� 2zC�-`�f�A"-A�ac�i� yL�'�;� _AJyB�!2E=9�2(.�@]"s d�� �v�+Yn��� =�6���A��1(n �����*%2}�a>�.�q� �)(e�}�eEߥQi�s��"�/b��e�(!rcN .B$6�ldot6؁“&ted#!ss�U�&Ů�) �kam�o$VA��Y!��'iS � �.�#A�)eC�2�S�!�X�5�f&A����.��n �Os���]��Z�nu�Oa��u�: axI]�V�Q�!;Q{O)6w� < For� ��6�0A5"�]Y���sli$�2A�)�ed�"p13�\� 2M1. ���a�v!Z�in� l� �/ ���l`�"�B(ly limited �uto inner cells . Thus , to quantify the accuracy of blastocyst organization , we determined the fraction of interior cl�that were Oct4 dominant ( e . g . high in D, low in Cdx2 ) at�b� stag;�Results indicate a clear positive effect of this noise onQfinal 2�P( Fig 2B , S2 Movie )!%!, =leads!6a subst!;al reduc%in^Xnumber of mis-expressed5 Addi0@ally , it appears)/th!00is an optimal��vel σ = 0 . 3 , above which no a[ benefitI4found . Indeed6t!lTexcess!7 �begin�dr4erroneous tran!bon!}�( wrong dire)andA overwhelm,dynamics!A<4system . Secon�(to consider "epvitE�these r-�Dto parameter varia!YA�$we perform!� imul studI Eq 1 withBti%�ranA�zed WMfor both~-" free�a'hastic �s ( XσE� = σE�)e{e.[bC(I are taken�beh samezallM<,A�ependenE�loc �!ttimaWe gridDs2m$�(each set , -e 1002\�+E,i!�i!$%at a TEa�te �a =;combin � of kySi >0 (%�train�==�M�gAnra�(to distinctms%D$Subsequente@���re-assig_2�value� Si <�(to mimic re5Ffrom outA~!iE��1*de�!j,�A�fr���cora @in�lineage �corded�vCK2Dߑ� show Ri��t$ly enlarge!7agion w�:ust!� �o��s robus!7. NotAh�c star.�)0 s re��Anthose.�by9�ingxmodelI�4published data2Dietr��(et al . [9]iset�0�Q(solely?��prior Rin2A�a3!0I' analysi�v �� )`expan��h�=A�operat�reg!�t�N clud!>4e neighborhoodA_���ag.a�mak��brief n!| abou��usE��*!�%/!�% )S��a���4. FluorescenceEq�3y �os)Pu��A� easu�n he differ5betwee�y!B���ngia typeA Whil���hexperimental factors such a��,tibody affin�� can poten�Uly influ�%@es�� te ,��\c)*actual�T%*�ůbe e�<a)2assumed��a0� crea!�on= s would a���i2strength!�,antagonism (#I�0deebasal�8 cripe� rate�(&6�h( see�!�A�sS1 Text�"Ei$�� �shift%�% aaԡ��I�becomeA:�ingly ne��ary�prA� fun�� 2�@ if��@ae+=N1� s deAd)HU���st8.�da�!�UJmethod�weE��bto!��0erv �, � � A�to under 4!� e importaa7A�n �#sto��A�$in maintai��p� i. C��V )�r�sup\ hypoi��at gen�Q�)�ha+ ��[ "� y on�/ ICM6� �adds �� ifich �� ness�a��!8uctural arrangea�!mo��&u e��xt ask!� �� ,�.,U�� !xbeB %�heE� fA�.H requi����>*; l � impr� 2� . Our�<"3D�!�� i�� far hav� 3 " r�an ina(n�ymmetr����&� pec%Z��,� rsE�,almost excluQ ly _: to%�"M�embryo ," 8 5�� ]� g ���� seis�U�previ� obm� [20 , 21]\ ]%��tei�!�ex��� 6�}LImus� -)2I i� siTE" -"A�0 �?a�" possibila�s ~in one�~ mayA~mo!��_�m1n1�a�r�o tesa�i�rallowed /+ ��� Aq"� -�e�rego oryQ<(�)�a͵ t am< �1�fixed{ kineX ��� ir�V"1 �� :.�Nilae����. Fora� - ". two-��!a cohortA in silicoMO� ��iM�in3 like͘��e bia!R(Si ) was ch��d!( refl��a!�E3G!�b@! !:� T�wi� } �o Q�6ive�4at�mo .��F�2� U�e�isI�WSa �TE →E�`:�� ,��%�dn� 8 j��5i� wo�di��͋weI�next: 1A�� �*�b!Zo� � u arZσ~�)�t�suffici� � !��a"�, yet6.sm� to avoid&A14��� 'higher)r��ed��ed)O.'w� be"nm�z� at sourci)�w�usefu�� :AdA�!�lej<noe>enM�. �� pr9�i8-�ofa�G.�of)!�EATF� ���r ie$QtH immunof.^ s �)Lat"E t dWopSal5gX as��u� :�Sbod�ic3ebTo eli<t��ri1�?��i eatx��R�D ��m,�IUco-imag�M�e���-t ] *)�nu�* B�!=tp �vid� �)a�eg�P pipe�1A–3C%%�i set �ob!�� 34 �� T� oeq��EGA ( CV )�$� _a�Hen.,�a� four��ra-),nicm@�w��hse�A)xearli�%� ( 8–16-%��q=n��s� aa�_begune )^canbe cl/fA�aa �r&�!�u@ is ��8AjA$l� with�= �U�ngle pop� ra�f�Fz�guish!5�TE� f !�{Q;��>��3EA H )EL�� t 57–85O7 175% �a(�5-�:��� � 20–40% ��. Som��E6�y� nevitablyY!� Á�a =sh��vier �n uppez�a'� intr� c2r�2 comp�k ew:�a Ain�\& �!�9 ���c�numeric� dsnonship5�)�amplit/(�-L�)% 2!���ag>�hno� (�Zch!g5�inI� One hundT .#s"��$*A tu�Cg%� �inputAtσe!�CV� �]�#r"t \�h4R /wput5J-|3B%�! -x�ie}-y�te��,.�%koue.�A1roughlys rly ��e�2r�0-�infer!i*�. Fure� , a drama� ��!�behav���Vlyo4Aw� )}!toa�re6a � 2��T , ca�Z�*t sU��ra�T�!�b2BE\T��)�a�gg���l�Tona�ay.l� s R�%7a!Wor� alA�spMvb&at)p�..��e� in�ys f��ine�e�gea�� ` � ��.. N� 6e�3� &kly���ea ��� ( ~35%��2�ly ��%:of� ( ~23��"�!�confir� by� .�& a�l��qj�!� IXfi)� e���uAwg1�Q�� � !�dN8ed eve� 100+��$� Seve�pi�!e� �s.ba}5�Z�an artiTa�irs�to ensO�Q�a�A�.6of �  attenu 2� foA� dept w�nE��F�lyaIwaBh p lay+) Me��*w�fdu� ,i m�size dur�Ds./ �g�4� �N+7Ee Mdu�6O5X�!MI�.� Thir�weA� �&��Mrm  e 2h ���S(A�DNAU�volumA�orn S)�,���K6�. qual� ly%Zsx1$� ��iGH[ly*� qPCR �m832-!�i [66]ez �qyic�� "�YM���c���cu�5�J6� . La��sw�d sm�conjuga�Lsa��2\:G��� 1,��di� )O���a�i��lw cus o^�on �+Q!!.=��3S�L@Nanog also exhibi��ig"9� ��6{ � is fAer� -�1�y� x�[6}mia� ��< ��TE�associaEb�L �tbe �9������.���S*/� � a�&r��l�*p w� R�w&:�qB:�|. T� ge7 w�!��%��QwE�co"�att� 4ap�" A�KR.str�� help'm�>B��r*%��%e��n� �&� % -med)̅#*T�a rol+ �!�=<qE��w�K divi&4�ons� Q�%g%�of��<�To�mi if��� =R %~&< l� �=��-eGFP��ge68��A,, fu�!m tein!�)�e�knock�@� c'&l�[22I half-lif� |u "t�is!M�L"%M ���6!�"^ lap!Qma뙿!r%�E�morul�gQ*rof�major� 5� ��2�,exa� ,ter�.%_in��*+, � � �to� nEI���fSngcN��=HB%%*remai� !-�)8readj'th�ETb�#o$�. A ke� ��& - 4meUism��!+i�cEg �o� in *e��!$  ���e M.6%�s raiA-T �e� issu%q�'do| �� cop/)��S ambigu��E fewe8�)� ��  i�merjrL"o�$�Lzona pellucida ( i .] ^ k=�! [)?y-�� lack!�E-cadher{�,a��'�!mp) [67]��,����*f� step���A�tact "6 � a� casc��[36] ? WaU���n� p)� blocka�|y ECCD in2�^ �m�* ��E�ges� ���)�e�%ab����� a��[3�68�Con2�!%i�I�, Yap I �;+gUŀb�'E�zA�e? �ɉ*�%RA��! curr!#ZUN�,1�&� Z�is a-i�<�&�u���na�$ solunM�proble�a'p(defer�q% )1until af�-�A�S���a�C�O�0�.����-$ : 0a pseudo-longi��U&| / _}N�&n!Qf!� grou: D � subj�Wt��-"�� �rem� mixt8. C�1j visu��64M�UY.;!���&Z(ofExV/1( urro��%C"re�! 5A[5��5Aq MF.� �0��#�{%��d!�)@E�a!2V,e�]$markedl0&:R(@-l� AQ&�e�J**Fi�H�p6Je�:��Et���l�'r-!,A���/�9=.# �A!l�-rP�(!��������t`+in�&5�W�Bu: �U��commi�a�a gra�(1$s multipleU �day�q>� [14]C *Pa quick�witchu$pro�*A�3 ofterrtrayede���- progY! po�al2P+%(l)!!#T ��#AG� ��]�-G�#��“� ”�“� Z$)�.F�*� &t�tB!gex9�7af#.�b`0sP�1���� reli�k.6 %!�] vail. P^�1)�un �w��f esp��: ��d�demd�gQ6� � �. BV 7*�'�6ay 1Ba��� "�.�5dids"��nqH1� non-�Pj a e.� it tan�l* A����"(e�lyI��6(( k{�4)��,���= �K.���.I4s monos�� �XD��� curv 3�at�8er Lbi:�)��Y�bi9Z)) 5ro� ��2�al(b_6 Pto fo�) a*�pa�,( blue versu�'o ��5! sA�no@#8�o]�7ca9�I��hW>���i*>diverg�e1��8pr�ensUZofE�2co%l!s�~>0Q�* )8u�eHxam�W ŕh�&sF�"!�"���I� in k-c���!U�to zygo���).&��-* ^8u/ 5�!xtro�56 �P� dg#� 2R!�<4ea&� via�� teas�" l8(22�)Q7&�outW1�:wel�4� � c"L*of�+/� 2�, nam��650�m&s;�ſ��!�)yP��J49"�1z�^s&1#� $dmK in�4*7"� �I -�so-!�ed�'als6cap���'ircui#D.��8 [69 , 70T!\��D!�J\2F  manifesE(�)inima!�anIlylenerg� nd �A�.T 6� stucŎsh+/�=� favor�� hɂ6B��b!t� -e2�a��"��pusMu� �wa saddl!�FroV<is poi;%, y(��� �=�&�9��e?( �3F%3G�!&^"7 be <"c�6q.I !>n�>�\�!}�=u66�e 23- highORZ�st�24�؂7-�a�2$� � iM6VG$a�S A�,#E UF0*} �4��i�Q ��� �6d �"n1 ticu�0 ' ?? 6� prim�E`r^��MO���s&�#-�R"I$� ��| idea� is� �,�)� if b� �op� �&r��.D}�y�yit%&und��[.*?��e�%e��A�N��!i-�ic��a A��"� � �9ttru/ ; 0�'� ���s�<sU7w�\ �'.��!�!���.�: ario@ �he in �g��{�l� q[a�� er tz )At� “VP�%�� �I.r�r )�3e9�1��2��*Sl�mrg�QůF]�r�At5��b�� �Af�s3%!͎ � �(5!2 rE/!9s!�%itMy� e (Cn%j ag� d�`�vna�e!�&�1e"9nterpreٚ�J���"8��5oI)��L�G* w� % a�%�� eady"� �: �1m�%(� I�&g ��As)}�\)" m!i �")]s�/ult!�s"|v%�2��� Y b�e} !_� �z)e.(dvar�!a�*� � S?c�i-=e�a"��/rQ\!5!Y & 2&7 )*w%�be) flui��t adi�ct!e�la 40!�e�/� "� %0 l�<[) J�R�-BA`�T�[ ]..+<In� word���&��r� ) @ !��D .,E�9�� �/&$� ;"� �2Y�7A���o"� ,.�sU�" , ��$"6A�% edH�.' mnA6y�i�Ac[yE-B�&. Rec�*"-��#�^F(bng!j pert | 6�f��-aA[)�E%�[13� �&a full2�%�"d s>!�.�iv� �@eft2  fuC worNweDBE�c.]2;l/ 2tep�"; ,k�'� ��6a�Ab1 �20J� e���/a-9A�:o�L g6J( �auto-a1f!}'own:/)�.�aa�DN.�,2O(0"post-�JalE&ya.s;A� ** � erM�g� AL$`C�Mr �s}:"�accoun�4�2_�&!T����w%y� &t�a��9�he��!�.!=+.G�V er � sp .2 er )Je/5L, �) �al�K ( Se�� 3 . U#���D�)e�i��D EanyF�2C�( SK!@7 )���Y��*IE/.�IIpr�'a�&B��"�IA��d�!jA^]?l7 scus��+�W� i�(�gQthe!mbi@$o �"` I'�!"1d�=�ter�E%m�3e��q��Eci paelYw��I-42� avea�!#"�in �caSsF=!�. �:>q n al�& �Zq!� pola\'@ce�%2Z [71���ba�)�o�HSHippo� { � p# !�b@.ap�do# �7.iC�s [38��(I��6isodO9�dU\$4� �2���Z6�-�sF�� &���1#�E�U%�w��te��H>i;eZ6L�0(�� A�hc-S xn�], fbyA��ngB�a�J=IY!u�� mole��i�5L,�d scal� W dA;g*�)7.e2 ��ea6� o 9D&�$���J#��2�V� R�a��N����H��ёA4[.4-"%E6���P@6N�) _ capa.�#s :P!b �\M>� Mammalian�$chR. �g�l*su� �;��de�#�_2|6accele 9i� y`Q��inv�%g�\ yiel�Ma weal�I2b!iA�to� er�"{dA�eM�U�.�) ?:�W��pha�3%�!ɉw�YA�m"z@%��a�� .Eor�W-ll6�{Lm~�.��K�"�N&�L�detai216, { a�nd!�-�5� ),MaQ%�m���at� �as �1or Sox�-F=��Id phys��=,?co_���� filopodia*L� es [73�&�TiP?�F[74� $- ~Zs���>�6 . H�go� �[ I“U<:g. R&!Ic Q5A�U:�O lighp-tqua,%��8ibu #W � of !AEiAe�� Yu.� . An�o�KtLlle�9iZ@ velo\'�q�.��K/KJdesig>0inciple�s"J spa�-�6��m�I�vaa��$7p*Wb4O���>!CM1 [�U�;�I3�I31A$6Q��� Y)���recei!M�� n(��nL��gKnt� prem� ��.���un+"e7*#6Q/> � dow�1eam.�e "_V��=K�Ba��[35�@7� Conv�R=@’�0�~�'s KK% .��veua�Lit%Ya6&�� dd aR��1@/ � theoJ . SiJ��.#�"8t6 �anA�M�� �8l0� V/haE�$ir environ�)%>&^-)�,r��ly�C��GI_��!{ �S �2e&���<� ur : �� !G%.�"�9���Zd sV m�K�)�!&$�&RJ�3� worlK'A8�a&*� Z�H�I�6�.81�2��'� yn�X2v� zs)�!M1�229�k���F/ t�=dq!�mFAhn!�q[3�� aids6��M32�j2�1�-"5�&N�5h�3A!--Ϳz�0Wu& Х.�in*M4�á�0 !~a�4�74�!j.���R`��!�c� �B�OlesNa�� ��qHX&�Tټ s�e?!suc^( JpreimplT�. �&�0�,How� n R6$0Vut!l plac���]? Adhe!�*/�ng��Ŕ�zm\set� Tmti�0�=re  [4� �.�1!�b-�s&�#�(��(I&�*, argu"9s�I�8!�*8k;o�E��M���r�m]T�Z! way�bal�S�9�AM���'� -A�&�P�# ga�t ��=�+)' .�to� broaYfbF e � %. B�0Bh�+q�N�wZW�(et�(Z �4<n�E�iD�@. [7;��- opoi,&�+'g�e"LI�f��,o osteo-adip�� �.��P:�Y0,.e�Z� r �n-XZ . epi�<�5he� ��1parie��$der�*, viscG�1| ���85�&Kjt�N &�UaioD/%�&` !-�Rp�KrPcu:$���jm`Cgen'=��gte.I[:Wj��w*`�F\.ٙ�G&�  s.�*u�Ő� prec�htLb&�`�e&?$3 B�i>��?�~�!����corpomtoe �d �-ma0�6�:h� 9�b� �+&I �]E{!�e� � em.�'umM.`"�@do�?� "�k�at"�� � � m AXtt�Cz)"�!(AY+9g_8eA N =��!���yco�BK �2Ek�N-m_�3r�T*�<�>>Abav!%PU#�.H7ͳo�'�`�act glob�#,��P&�2 Ek0F*� AI<�$,%�3�0or� uned�? NGUA%) A[�� "R� Ra��OTrw�itA���+pd.:F“I�O&U&� 1� feedwD loop� ɢ4& s2? .:`%���ā*��?a ofe`�t-��#�N�Ld"�H���JiL�M!%B�a}i�gt�m15ed�[ ly ?% .J$!!� mpl"�e mRNA�yX"y �s2�[4)'A&�!m 6\)j /A~Kr"�'�ҡ�.� � Da5u%#.��ur g�m=lcy [80#*c “t�GAG%�<|J �>  'E��2kM� I��)�C�0*{ �%� 6(�6�28��q. eA�3�5�n�EO;c carr�_� b J9a�Institu�alECAE7Us��-�( IACU�=guide%��Un�8s� d8alifornia , Irv�$(! toco"�?200fT281k. Fema�z@eu/B#� CO�A cerv��di�d,�"�to �Lab��ory�Re)�', ULARtanda�+��e"�&���}u}F(�h�,:��d�a g�aA}d�c�%W a 1%_4r�%pa 2��� o#c:1 %� io�$hAomEbm�ac~Jae#JZW Axio�er Z1zs�0Zen2009 softw�RugV�at�wa�va�yWeIcustomO.�ya6[g.:Y�+9Yk)�=1Z7S�� uppl�i Ma L�� �%� 2�,����5�HeTDE�!u.s Fiji@eJE*E�.?�S&� flex�k�rm�d]-enco�$A�m`<s8m+? �1�/�%e1��e""xr�-'���a�� epit�Mty�+l�.r� �y�sQN}�_m3, gen-�r�p ed B�f�6=5�1&�(��h�~�Dp�>l� poly.�by"#!�r�,�re�6 ,&>D:0n�s�31��,�xVH%?I�Pan���o%a!B%�]RM89 mmonP� each5�e�&� Ige��ȁ-zpre&�!5ML��sengaA"�: [sa�76IIRo?a (�5�m&YH h��i e=feT,ire heav�ine �`vf'(!�&4, CDR1� nd 2)V���-%w matc�'!�g.L$%\�Qrk�'1e(p:@#bAm9d�g�=4-%UA��U>�,*~:q�0unU5�witE-�on�-�{�reb4R�Ea�Ipy!u w�.I��a!`�II9!{ =A�W>inPsXd�f!��s�]��&m�N 3w1��returA�, m�X+ a>6e|b�We dem�z�2v!�Q�2 �$ algorithm�-� �c��Gw -y/ amr�.�nhypxu�kl�'A� CDR3bK�Qs mx-.�%��t!t�&*� T�=+"����!�m$ CDR2!�*�l� ulin}U%2A�&�(��)E�$>�.�!�R.�KF!of.%:/!$_��ng�P�GLŹ���%]I�a5�6Q�r�e22������vn+E\!j!!�b#y~<.U1A!i�h\mma�a��1�.2�w!�� b=yEurface�#o� &n�e�^�8�[�3A6�%�e[� rear���z�!o( V� )��(  K�H d jo�w( J ):�i�A�mw5�E�h�h�%*�?�C�N�HK<bPeof un: g1 u�,�\-^]e��reperto�2[�%�L '"[104a�ve�! V , �Ka J2vgen��� �!��L 1011ap:$,* s�(j"*4=W�)[��F&t&b!A�m=�%ar���4M��aFA>e/tB��M�KYxIW�6�=U�)�vBB�E�s9�mY2Tatwbe.�AGj"a&a':%wI��Wr|u�[3]–[5v"��im��;ead�2qѭV;�e�r, chie�9$ ŁS� a �?� Vsit�d�A-and-���%t)b]V�5 rigi"�1�Q�nEUA�d�fie��h%y�3[�#[�-SB *�"� "� �dE�5v3k pre-L9��a�}���K �Z�u��� >=pqrm�� *� *fa�ae.� B� ��� �^�=�*:)�xckba �7r��.�0&K Jm b/�5�Nx��yv/6k.�houghB/��2�iK-��&4"���� stud���#͓a*[5�2t%��N�!�I�B�� in�o.8Mst�_[�3[8ev1dK/!� [!��΀�a� �]08 : e� %�[�=��+ .�.S%8re� � A/.[.�o�TU.��So=� V]k"� E�vFp�|.Zm�11)���&!":��e �r�5�)6�azLi�)����].Y�Ra $e��`5c(� � �B)te�5�9 artn�{k$d-fit��u�z)t�*�.�alc�Y�i L!��+mmo2T��6n'%�� P?�Fn-`9�V. O�>�iN�y[Xn�'MQJ�q xplWZ�%� esum�so�s ��� � �91�1�G�� � 0:}. Qa�x��.� �y:A�g&� �!YznE �6esX , [1�=Cf� f? J]*.yUg!-X.��<���Ք�u�)ũ��~ .!. ,A��}�62�#K ~e"i����D(Frin(ict��!˅B$@��$,�|+f�%�exj0� � .�"f um� �3&6A�rre e�51����'2gIC6� toolo7#.o��!1"�!�ho�� �[e� + 5�:v�<.��T� [2�%2l�&N%B]"�c*�t�� .S� I��haA�$en crystal�2�eL=�� o1s_)s ��c&O�(\�!"i��| �Ply e�.�:�j ��U)),pA{4n O-q�,�limb3� �o����{ -y/hap�[Alex�[w� 4A;2����'�'�/;���!�<�Y%!��mA�%xo�t���x �!�6_“1jJ IL- ��(C!�naïv�3"�2�as�.V�����%�A�V+m�nt:�I` . SchmidtU�~##/ly@ �>QA "p!&�-�s���_��ed&�"m���= �(C enha�n!b �{l*I"za HA [3� I&) � E�wo�)ۈu�*iv BfvM an#�/ag�"�E>��/ ��֑��-ce�0 ( UCA �{M��/"�high-re"Vm�5OeA\T�E0E�K,tc !Fb�6PA�h�m�?�>1Ma�n`� K Mճ� 9lFd� 40-f� g�1�JQQ���r@*#A�g parazi!]��Lma,�'���l ��}$�'�2�l=��Ya%� ba&v%be pre-]!&�!o�L c,I�����z1e����Z es2of:!�add�s���-�!�n�Ab 1;��a VH-��r r� Sq�%<sA#%s!0&|ntatMzO�7Ve�a1�\�j�.�Nh�zg!�!�����"m ��J$!�1�:qi�!N>� >� ���� i����d�le " art!~Zn�*X+�� %���AI%A�� 9{is��0�AG�;��@. :��wK al�u6v���BE 2���s�v�A�aw�hco-J�w��o�m�>levR$�Y� �* bS�!6�y-!��!��QUk,!  -�F���}!��zq~��.‘� �’F2kre�"i1*B %4a�evy!�erP+���RtaX�ly� , [3B[�=IJVs|"�*"?��}y�2T;Ł1�xo2��!X��AZ�+!��fIeA^A]���:�� . Rema !wQx�R�Q�'�� _ly���.9 4x�P�D"�A�� �&n�U�p`\5 E���)X"@a,>�>,iea�.Q�i��t=�a!�g2v1�‘�.leF�c ![�&1E�� }�EM��gsu�E!<:�I�mq�6��:�]IL�O�bhoU#A u�gen���m*e�$bW��P}�-W��p*�}9.�tAC.XD>;-e4 �\�Y: apit�!�S�<[�iv�34@a?��LY ��})CA�nda[� �;5�*a> 5M?f�%��nin��0�evUmD�e6=t2O*@�?on�\'s �Kgy&�kappli)+D�E�_�A6an"����pk(: � 5�A� �@�e�ځ�|�^Ȏ�  -��1 knowledgeqe�on d82;�ptowF,)<' �i���O s� )�Y� p!�k . ��Ki��$su ,I�Ah�� nce"� :�-e����n>ch�I�RV� spa/~U�2�1�!�deL3b�a�p� Y �x�-�ensem���X�%�2y l����"�v.�e���MP6;Fѳ�it Nyd>1Us�8��!�&s��<.��Pnd��"� (y��'^9�3etf�GSummar�t/��e�� Q ct i :*�xGZ��yD�ve)�5�-�.1. NA�th30,a��,iH����7�'G re��M�2�N*2�hkT%�&�@A$‘.��ūion� �dig�:�?=78:5j �M"� �%5Z��"�+ !2 ."%)�� ���F�.�2vd�!k�X}PxA1)%l�#�;~Aks7�O�in�i����Pm@?.���=6�q�s & � P4q���. W,pi�6p"�(!k!0�� �ze�in�0 'CnI *MU=� ���H0VH3-23 , VH1-h,or VH5-51 [3�P[347 3#Z�� I����$�-�*-NnXn�$Homo sapie�'r $an< ޡa�� Ener�a�~�1� . No"S< �A*I eria �6]exact�}� MiS� %�isoE�(_tA�">exhaus 1searcԝeAn�'s 1I/8!a3�dp]%{-�5�%�2�(T/s_-�qEx�W���̀( � ec��I���g��z'�O�*�? alig>N H!X1A,� �/�Y�� ��z]�%i34&23>C%�. of 1|3All"�*q,%�&� & (��� U5!F�M.�mZ�$t@!bQT Z:eL�+aL� �WB���|as&"qs0a6f��~� @�b'-ah�v?)� +4n9 Gno�im�jtƀ� >�r�"� J��8��A�:�. o4>#"�8�His�   (� �V�!0�Wś +a�y $unambiguouIE�$��edW k���r�%�5KD p nd J %� �A�H�} O9�gh�T��ln��s04-b<�#��*�+of�� [35]I4t"'s6a�mi�cid��.�A�sFea� ��u��2D���4���^+ b ���ms1&>� !�Q����)�:2ez�1-ti����znť �w�!�d i�Vch�")P{��|�Gl?�Jm�r ��m��100)�m��/execua��{ P disp�v�WebLogT-(H�}(`a1�;�Uin�:c�q� 31G ��8{]j�Gr��D �Y�!6},iU|:�8$ ׊ls� sidu!�bAF!�tW2!=�Co�t�2B1�{ 2XWT �/' )�ses �.ar!Pli�%F=Fc60 :c(AuQA 3HMX�%a�onT(1 5Xi�J�a o���6�+ �-� E��E��I�f"Kq�Am%�llJX�?l6,-�:1��$�+*x E�=xR�u+b%-:QtsAu�/S2-A:) }�� �*� �� sep��m2�m�� Dsn e��Wdic� y�!�d2���.�%h1r� ��%��l�M�i�a0Q�6c� o0`!�" �"�! � E�);I6�$"�#!�in a�A�"��$asQ�aAy7e+1�!�":e9�m@]�?E��^ Y<.��!�l#nq>#2�Q�� Pbit-scR!A��g�H5�uQas]��4re?O5Z5K,*Ef�# ��.֮ �aO�ki�D9�=�o(G��,u�@ �"%5A,a�‘�yA��� �!nei�+A%0agK5W��mc�9i*NAlaK�Sh9R��!�$att�� A�A�_�55wif)�=���oM�r^�-�RQ[�[��&a2ad�a)nY�ڍ!l�d�s#sEA�R.& age-1>���2��a���[vr �� ��ll twen "0 2�9F�Nt ����., ��&9- �+N049r�ss!@� �te�ofA surp��A/9e~ a�BuU�s, ��=Ai&�+{or*H\b!o!h�!, n���S��nu��|9��'�F��4�Y�\� l+�ig� i; Dg.���a�cA�J��.�3� fac�!u��y��rosaS� " �e sum�}AD�q �q=���� 41q0e�1�!�^�+w� 3"�S�%E�"�2�.�\�=�7,�ry.����.*� &~(U�0 m}�=sw�*�FO 9�Q9v��"�,0@M"E��8V�B*6� . _ 2%%re�*�22�s�@/D4:pA��43 ����%r�:as.T$eU�j::D �����U>Eg�%��i�U%2N�5tV 6�!p 43e��!s& ~�.a� r�"�SaZt� dJ� 48 , ��Eor 26�G<�000<� "�m�ng^}� ��s 2��GS�Als�;M^y+�WM� :���:irjY�+���47118b �w�2�"cY1�5T%� T5)�>T �EofB&�$ *�EII�*r �rocli��"�2 e  &��a!5�2��-��C���f(�L)d�\B� ��]3�^Q�4pr[9aJa�:�c2�/^Z�x�13w easu��� �����3 �-�:JWɕ'h�!5�!5� >5`e,�fve Δ9�� !|B�5C�� Gn�`:G!�aga lex –�!7.yN3Fo s�&D �ic Y�!_s��� a@��%%u\&�t8Wey�ve val� W2�M�a�,J9�"�qBY! -�N� ~ �i�q��, p.��2�_m�i� My� EuM�.��� $![3A1HET� as]|4"pj�2�R�!ם�!Yv���rr,  5�.nw8tc�'~ 1T-�U�qU �jUT%�IR"R��cSA�( �akw�D�~?!U)5� M|fe�!-!4B�J�)%BZ �3�IŢQ�8���<sy��rg���%e]62C��.>#*� IE�yq��.��� *%�%Dy �M�!.�VIBf�-�.5tyz/ u�uaV��&�� �>��v��_a/ j>I�F��heM.�J��i�1BAu.��aC�={u"�5��� &�X� :�!W�9 8AM� ^�!�n929Y ��$A�� E$�3�012B�s��;F�� u�1Bh:A�:�F��dF� !A%S[~&�)� �ЃmMRr�nounc��ZyS2STor[?�hi-psi aL����6�� a~sa!�2.&�!#�3�Hi � �%)�FAYZ�Zd�Ea�ns O n-FU.�h*j :D conv:���CV�.L��. ,j-ly�"uTj%F&�,y2dev�]� 9 . 6°±�0°1�b:ahee�\)��7a�-��TL�%�Y�-���A�"~ a" �$|� s* �$( p = au099��e<6�5 . 5�TO5°%6�!��:�"�� C}�!L�(ÿ�TW don'�ct�7����&� ހl*g � �eO�^N�0mGJ+w�5�� q�6:8 . 7!:!c9°�!eo�� m�4 maps =�Q�"�?&� �E o�F!U>�3�5qauP0Collier de Pe�V"�� !1F3*�) Ruiz��Lef\7 [4�7W��ua�Ł�� Aung�����_Ťz�u/� "�/qVd"(Cbur�P�%�P {��6&� �per�7@�\2Q�ik IMGT# �~�J�U�4��� , 33� � > mG46��R"�}ac��� 72% )���=�o>^2�� )� � �(�l�Tm5>A�2�1�?41�771sh%�9� ( 53�V� 2 �2U440 Hre�n*�#Z��.�dlvXN]���.�#3:��5�2 test�? �A)=SlyEq�E�a"��nt���3�e�/���6Mpac Mos 15 %7 7 jn"Tn��m�V6�b2� ��&B�v:� uIo!0R4li a�u���A��'~(ps�-%C �6�3!�6Lnk! 82 ���qQ��>��'w�!h�~�Aa@�zr��ch� xA*G�Uq8�� 3)�{�N� �� -�y#A/�v�bJ�J}A���Iah�w�P@N[q wre ��'d���3fh-H0� �^�&U]Jl�}�͒� �t�a�Ed9;��30"��Ef C0. �X�Ay;c�%U�.{X�V0214r;�v��"mN5ԁ�AC��340U�vaK���C �1�Yp{o� of�3�$Z!mq!t��!45z!N� ( 63թD–F����D6Se�=) , 41���699�M�.m8b( ( 59���f�{/i��255JT� �i\r@.� *K!��^ >dlItA�%�A�e�� gJP�#.n A��.*�1R�v �5�� he H,q>\.�q6E�gI� 62.�w>J� .2G��G63ŁT64�7�K g.Nm2kV"��-� L50��Y�h2����8u��2�.�2 2z+0%z) �A�]Y66i�V2�JV��$.���)a &3V2�$/�v!nN�P1M5)�A80��5Bb�Ix�.�~8a�J)�� u��aMd�A��w&7��.Y%��w�"�@pe�m7�m_Ft+if?#�>&qveD�=.1d�j&[��[��q�is purqS�&"� co !�4�ej�CB*,Z!�ad�6J�"w  �G� . M1B�G��=ng1Da��N*�E��vo���Ha-* �;�Z%S�� B�}P�aob��U l� dG5mn^7<,� -��Q��" %!M�"� �#D$"��e��id�cE�E�9�6��!J)s�.(�a%-9*��J%"� w�B�&!7 to� of 8}�%� ��Vq@YP))R ,-x��&� 5;q�� �fIfN8A� ]�{�S/"��B� drop� A�2�t A� ��EB _%�fQpe�M�'.;q�ѱ42,A��6B!�F�2�!5�8F�6 7!u}8��O��2Ay .�Jmofc-e3%M"{ �-�X%r�.6�!�%�)CB�qf��Y:�9)�LA�9�i��&�@)�9x2�eJ (K� !y5hG�8)��.�D�9�l�M&�5J �a�< 5ρea2?�9Qlŭl1Q!o�2�> ��184��m� �}� 0� 20070 EU�s�3n&s���+�Q/�ˡ�2m>*&clG5�)")��*W5�0: �R�3� . OngXt(G � �R8� &�f3E�e5 j/,� Z>&q KE���T���[ED�'�J �e��7" �+`R�9%�-.;�]a�at��� �:fs!� �Z6R?75�!�S�P*kp2��sba01�� �2�A"Cv"‘B�?�+�  d%*>e�"� E��s!S5F�%!� ��tticqT54'2"��&Q)byN�. Uh *���g�,"~6&H+�?;rF ��&�b9q�:��ņH>K�_��C��:�E�1r��!5�4*/,t�910�7�,��&o��e8 forcEm�a7ty&�6(x-axitB��f%�%"�>S5�|.\/��VB�"(+V�! cal�\�( y�!x6p, )g&�$%g!�� �)9�Y%s�"�4��ly�\c!a�5y�F�{>� ��f���W`"5J�! ։�� %�i�~�!�){ &b;1�,�� d~i�Rt� CN�&� 2"US�F��a� l��g)� 52� , 8�+�b98 � .� ��WTA Zyn!�=O� M&eh&!e�%3�:5�m�xs =A�.� �7�� CunIV( REUY oriz� l das�hFl/�-A�sh�a2n�qn6� j��)9�&�Eq�( �U 2 ��S* a} 6B�ᩕ9 5�&i9isc�$.��O6�� �*�� 6J"is�l�<�� b%�)JU&ج>!�FX�`n . G]+g.�19+E�?lzVVH&Ql��<R�s�9k:*.�!x|��� 'B{U  ^(A�.G&��� z-v/�y"Oy�ovc�:a���wF|05���5>a��82_"#E�2�=).�T� a�.&DJ�- 0+ %9n�Qm��Q+2 ja& "$��!�.0Av*$$!RNI| �&Zk\�O�Zbe�)$ �jq|�)Fh�eQ :�O �!moB�W�\��c�KV2RIf�let6�p܄of��Rm> ��L%�ZiJjN2VA r�mvJ E6t8lerj:�6!� solv U�\rs|�+�4�@�A&�5�j�W����e�-�:��V� 5q.-�.�N=UE .��:le�O�5�&��s�y��a��#�s]!�H�HR�A>�t �%QCT`!TLa�beS��)eran�;�&�95,Ѿ"�8oB�.��&p�dk+ emplo��V~fB�� SN�%�E e�:jU�.�U-��T�b! � �@V,��`� R�EM�� rl��&�by pionez g�;bKortemu�U` ator6 V��llelwLe�-FaN*L<f�� �f&p��%:)� LK&xG i="iY�w&b*�ɦ�t P8a�E.s�C�N<0AilaEi!RC [%��qY`%�a��-�dor&�!�ݷ�%�#�!�aRJor��QO� Q %t�*��Niori 2R%��q6_ s$"ɅeK� .Z��>V/d�6�o8�J2�/aR)�Y�&� 9b2�r|y6{f%-c(��";R!��s�,V�6 5o �j ��"PU�%'eR+�S�n5� lyI��Egx!: TK"�F.$.: D^F�$1�6�b �3�+E�U?��� "�kf&�<>�EI��Y��/ :�A""ex3>h�.  � "�3�M 5��@�y"��Mq�"�t2po rapi�Yej��=!R�n��tI3"��-��D cn�OQ8Q�is Ќ����dzt �Y �&m e"7?ż\is {��:�%a��,A"�A��*& �}�u�FxojI$ a hoAA��ml)"�l�A�!4 sm��*N1�!�.-h�Lq�9�2�9Vt�cwu auAqvkx�Վ|T�#���EfT|R��A�-)>�Y. B�F U�/AAo� �of&6K.!�o�,e U )��7 !�eI�6�Y�� suB. ��N�]! �oa2� �V1���Q'PYYd���o�A�uN� . Harindr�?h l olle�D2�o�!u��F� EG�4� !+7}GEg5$q��kYnR�� bergzSpill�cGMA�� al e��!�a�:>�<f"@.n6SIn_�:�Pc6g�9>���r�n � )�fT6��A�m0]]2V: coup�AE] pre-;>�H }�2Qz� ��aK� ڻ&m!3.��[2us�y u�w�^�s�l��> >`n � g�.�.i:,!o.ԑ,E&>�T �E�e�V�ertBFQ�*�q��Y'��2Np �w,* c�#� a� E�?Nd,]&v 2`J�V(�8Jg>��� M�%j|�2� "�( ��<A,��� 0�!��h.�xF�%�xG�>; "c�Ҁ��1�?be�I. 6��%�͎l�%�%].� o�#U�@D�;!;nI�gS! �=� �� ~!��TK�e<��$��� I^�s Dg2a�SQ-^p"��U.qZ�q�nI��& �Le�dB,�ٺ� ��&4��{P�o�m����, �3r semi- X��f�"o$�. �X ��" T I�|I���`&, �2�TE�r�@e2�M2m!F�SZO�F[DBAdiW�(6>X&�[�]]5a|e�(ing number ,of antibody- �Hgen complexes in the PDB it will become easier to discern general trends . However , selected germline sequence positions important for poly-specificity in at least 2 out of the 3 germline test sets were identified: For instance , framework 1 residues 17 and 25 , framework 2 residues 40 and 51 , and framework 3 residues 70 , 71K�82 , all numbered according to IMGT , where found$contributepolyspec1T. In addition CDR1 res� 35u CDR2 s 6364�nd3 base# 105� also�8be critical forJ�!W�(three datas) Ea��'$ain larger!�i%x�thAophi-psi !8� �( FigA� 3 ) . Dur� �yI�K , mut ��s.�(likely locka��t�t��=�2�, reducx6$entropic c���G bi)� . SoAVcB�9�,eNexa�� within H�C�� �ia<4directly incre��affinA�!� � (�hal ��p!H to f����$gy ) , or 1��uirecogniz%�e2a�n`ekf��A14on average 62%!1UC�U��4V$�É��i��u�!�1�patterupU3��>�to�%5 of o�Zͧ9M�4E�W�8%, se�l� limiQ�Q,ur study: It�G�$to underst!�*e biases%.I!�rrive=an�ur�t��pre rq! resulta� Give!�akn�N.W , we expe��in a �*� fasha"�!,,amino acids �by6��W.� !�l� f%�Q2scenario�� which cur�"Uare)��[A�ie� � effor%� The firstZ involvA$}po i�does notIac� th�epi�!ny!C�q ed�1 . this[�x9-{� onlya5� �<apa�� dop�!}����in orde� b mmodA�+.�nee%�orq�sit�M��-2��-`��B�P�sim��A'�� thenQ�}betweenPm" aA\Fs.T a major���Mh? ed5rs �2�zAnex�  l dist�� U � %�Q�^�but P� r2;A�q at� wQq�.]s9 c� ey bota�n+proper7 ��A,!~>) necessary&ccJ*l�M�M� >��$ Rosetta's 6@alg!�hmp pick�)-��a�M,e��i> gen��w< is out�,occur either�aus%52Mal ensem�i�y� lete��be 5 �evoluA�!;U��uI�&� %�esn*� ambiguA�. R�  An�ΡndaA�Ť~ g��modest�yve)�u�� s be� �H“hit-or-miss” (�a��� ,�5�a����r���Abn=�2< � at�>5�ot � �antly�ter-z scor!�an% ��kY2� f��6� thirdy�con�sJ�atn tQ"z �p��Ain�c�AIf� -A�ms&� %�aw -\minim� !�.~ of��%FA�nA��o�� hile�oE�I��N�iseUpaJ�!�, �au� s����.z��omB�backb (nfi- ,�#A choom� r �sl l�clex�:inN`ai��0�� trend , eb ally�VH3-23Y�If1 Bwasy�=��Xi'� &Ce( to haq low2��U�q���A% urthY�deals�aM.a@R�"�tim��� ri� fr�Kt sBt . A&�sfO toma�?_ IɅ��L�H2� v��� sx� �Sc2� facba�� vq?�.ir� �2��� UbZf\b���?�prefer� >A�}� }5u� gen!rae�t��2�p by alt|*6 pack~�u� sugg��Eo�nlE���b�pro���b~ apit� ed���s` t� AYi/in� , open� exci%�new�nua�o)}C e�e �B A�erGur!L:� e applicaN�F� to\2� %x�,A�lo-o%�YPstrateg� p �@broadly neutraliz!��Dapeutic��Trayal$.�� b7 trap a%p� s exAA�!�=of Schne!� e  . [38]W15"y Q� prob*Tse�.�20*Jjy( s piMmpu�n�aAJ%����gr�.t0pb = 1/20 5%�F o qu��f�de��Q"�.O" Zo<" �Dself-!:�M�202�as Ii � pi x!�2 ('x!� ‘bit’���a9/��oft�!�A�.o Z� , Ii�& zero]is r .o  ver-"_ AOnd��4 . 32<p�100!� A to� bit-�U�m��obded� sumsalla�ividualIA�m�=�s 1D , S@ �>9A� �Fe�analyA,ts�M� Pr%softw^� � D5 . 0 ( GraphPad S"3"aXH aris�'�*Q �$!m�55a�e� -E�)� Wilcox� atch�aiW�( non-nk$ l , ��-)%�A to�u&'� -[e�99%��fi� leve�86��B�f{ ent's:�Aր��$neighbor v���"�!� determin e sui-expos�#�%�2hby$ham�ag#e��4�L:� CβJA����nd�D �is � e[(da!��(���n�o�襈i� prox"g w!*y*59falm� "l of �)���e�!���"�S �5�,*Ex %LnLy�>unb� ��? subt�.RX"E !z�  {-�s would"c�J�s%tor �+�N,6�. All VH*{�(��p� �a]%� ,a��&� A9secondC�e class�ɧcU��� dssp2 [492�l���)all��� H � #A1dar� :�:�A*` ���& *�&T. A�S��V&� �iAZF��5!>�� a"�,o��(�`>�  did��a��1<1iMS$+c!�a*�� !p�=1�� also.F; �s es%2\o>`��"0![. W$(\�M�es� .: L c{ �a sis � pt"; at �meilerla�/� �G!o� +aUeK&�'�1 ovid�' crip!|%�a`}�'s*�t)x-;e$ trav��clumpG �ȃ;. OurQ i�� �_ma�1��zI�sEy,"S2fu��Z,. OM �i���,Schistocerca� a , ��a mig�0r� Chor0i�� ifer�a1 �8iQ!M A���a�–[1�6vb�M5� rubb�a-a's5�| min��'aioX %. Ct2��� phys�� acz* �:�fQ>5��%�dea7F>, chie5& �� � i�sa�A!��'ic� �Experg"aF� s�!ch�$�n ��&z[19%Y22�o mo�[2�w [24] �� #%*o�;�� �"sz0&iV A()Qi"�0,%�w-me�4(��ch�vEcannibal h<g )]z tron}<�azk �9F!Ed lowe�;hresholU �beyond�ean3)�)c2d (.)). O'�'-d�9n��D= dels&wa well-�9Il��+g%@pro�cl�c2�)exG,I�y�a dis� �<�nt&� � . Bok 26I [27]��*�ro� �;�c by 2Kk Z��� map Uit=i�in [28]� P$�R��� a birth+ E~a carr9 �8�*iI�onJ/a2~��h�ef;����9� pl� �$�hO )�p ale . F�9b � ApGm��,Y�-�B14,Lagrangian )2�� -�� , velo%�bteu�;" qLy�ked��2� 22�(zOurŅ �Eul�)�CDo*t&�-ofI�$K+ ��&PDE- �57@e!� a� gro- &�1 util�E"!* MA�Y-���ey-s�yeteMicitl .�5%,' dres� trinsicv%gve�uls� � ���-�nyUfM< D"24wk9led�� ��*� al h�ogene&�)i�+9 ints2� Fina ,g3������anX* @2���--$�&aAyir1�:,or"Ovor�NewtonA�j���z6al&*D� ffic���T �,�I�C;:.�-.�7!�ma scar�:A<!� 2�D��A"t���!�f�Yb2���Z���(J"A4 f�7*b l=� !���A�%f���io:7toRE"� DseM��A"ermE�. Q�sB�&�-L�h�p conn�ng.&� �� rx.E��edi��9�jh�2qihChas im�7�V! -���  . �d �� subj�D���an�re�fo� �omb�>ѕ����aN !|tK\ %��I%S%9s 6:is77ѧ� Hon8 �7xG [29]� org�m> ceivU] ory �0%�a�et� ype`al�gh.�)��"�a�-ll [30�R��2 �>r:R(� �#M1�ufn3 mo�at&� .�L�șY ��[31� 0a�+upp��(2 tool� &D.-��ru ���H�O�&I�M draw>��c <���8m SN�� ���t!�� Eari��JI : (1T��mhe.PmXbali Y%�!  s1z&�!<2��H&�9I��qK�Ay�vN�nearb�!c��4!�ABs �6�FW m�ra�<"�E� xCialE !"neg�H gge of�_�# T�"I�ont�E�b �=A)n smZ$� y�Ilo2tt d!9!���A�"� i�(b�� c"I!'vQ,Lro��;2dMert��'��sAa�ЭP!8)�. gJ!)n/=a!R�F�ex86� !A%i� n Eq�;(/i�O�#ol�D!/!�qIeJ�[( � M �!Ffl�P] �p�l:>1�%|at����]E �m�Q�*�f so-�nonLh""_�s [335n0� �I%!K&# �re1�l�IZ46MA3P ��al ZIq� >= ���"� erbi�}nd}86e6�UE in�NesP5�4N1a*� m �b�C/� ŗ J� ; #sM3���Qsteady��'s� a9��)Jc@�� pGno�+) no�-.�:�B�is �VRsymmetrJ3��3I��I� �)d �"C7)� � �z� E�M!37*F I�sL#bL�"?la�V�7 Eq!�GFi�]i� ic:'� "�&p6q���!�^�'�Ib:�: �% -A��.��&�KlE��"=aP(-d%��al ge�!r�w� Ue�UA-us� dom�=!asco&�9%�nowud?!0.`%�+.� VJ�%�d� ��8)--&�I.A� ~�f` -to-.~&�-m?;-<�; e� thup ( 3a )b�0d��` ����n��(kQ8�o c4Ht�c��c� ��>NN;!q7FGa�erA�a Siq.bQf��-avoi�aEq�Ue0e ��lyAX�"�a�I�!�z*h�,_� R o !�ex�?%�s�%-�5� ZCu�ex�d �Zme*�H� �)�v��$)��ݝ �Titu�ŧ2L�eng� ��Y�i�>^�tCHa�au�d &1s�kɑj)M*i c|d!�ano��L abovs �I7R/�decay�on"> away�95�� !�� &� ��chC��"� axs���He�(n�X om E1 !�,�WB^C� choic!#UX. O�]o%M` 3| f�^�% �An�J%Be�I%�H )�9�!�]w ���=n no ne�=*>  �&� �EQ�� Rp�%�.n.by�o? a>b0&!�&��m(^M2h()%HpFGt �!%.:�  y�un@��r�Uq "z ��s= Qai�*+!/�Ge�� ��!w" Tc &�I"3#. E�0A;�ingful �6i� V� t � ng4.���E,"� ��+4W�*&�HH/&]M�pr 9lN �,_�� !��;�'ݪ�} ea���7r~RlAjM��!�� � Z/e"�-���?��*<�ust�S atl)aVJgim�{ e�:! !,!Y[3WBuAkwe requi# �yt&#�*�:W�9}�2:l<o�7. TakLXog�&�s�t. guar�e�TeaQFFi!�m�4cU[�pI H!�6h�?�!w!�)X�2ra��pa�!.� %�z%y� ���s*���N� o�7��]up(�:E(�<��E!H�\F �"���edhr�ickaE�. )m slo�(h E�% �B�� %!�al*! ( 7 )�d]���maAl T*� rt!�'&!�i[-V��3� l"alf)�� f�b. NU �`e+��,��a���&reu$ ship"' � -3��1�lR2d�s=( �s) vsp>)er�K ]N� "� )�{ �4of"W 3 )`)�uU��$�7uZM���%�W.Ya� ly�#iodica�� �chSf!��-&1&1[2�#H6�9 m-lab�)>�u�`!� -sha�arena����O:a�AA=�O�#�5�\i3Re�!Far�=)Hr)y% do�"t M�6 ?"-�$ath� �H���=�$��l%3;anm�5 )��en�x� \4�;Sai�?funda�al ele �Y �" di;rk�w@Xm�4i�#!n)t7� � ailsA|�"� lEM�*� s)eab*'*.C �.b%6Z�K���RaI ,i)2e �69�P!�Yu%K�� �A�v %2q�< a ��&g �(1�Adfyel�8m���M�>fR�^�) full� C� QQ���'X1`ne���)E� >�#_3ice1/C?i_3f$���5 simiUA�M��!�7 Fx&��"-W �!i1y  �r�O��� lifev��a�[gle �=� EO�x� Y�$"�3 or w�c p�1rne./ s��7inhom�"Aۅua�#n-��WT r�h} :11�9 ��� �-�,i!�. Preex�ngI� %bli E�� Q@u��&j`!տ!�"mi�of *�3,� (nut�h��fE' � cl"�>{i�swa�Ag*�#, [39<4�Al!�9��c�?be']rK!Ui�AqC3Npurpo��.*Vk�$,YFMG�B�!!e"�0*� Q�han�3o�& begi.�.~N^�M�a�(:��� /��'�?~ �C]( ��Xcu�p in�(na ter-��6�"� `J�1�, 9m.�q�*�% . aɠAQa*�9,�o�Br�U&2:M=�9ed!X,RU�����jŷZ��A*%�?g�1+��rU[ �vB3E @3Ap9'?z"� &h �+b;& x.Nk��I�"p pt�M�jAIGB3�Gw* �����A�k)j$*q 2T�M~h!&�΅k?�"yB/defaulton&�!,&� M%X9 A�*R:��:�=we� :V�ea�; :��ő��q te�5!�& 1I!� whomH 9k�QD N�e{��1w)&S3R�)l ak�s�v2�1!�N&�� DO�%[(v5)an�>8)� �<� esom� �C;At>(_Kt e� �To4B�Psit�>s�76Qo��e E�Jh6z� q�['*RJP �&R6c- nl!([agnP| 6"�]2�%;%�!to��U^ou���}K����%"��.�/t� !�Jn�W�� 2�Wv#AV>q�(���us�C#1�Zcc* �?R>� A�3 )J�.[.^�Vwea��SA(��ofs ,I�L oUG',“�ng��c6K��| 4&�'6��cl� �k6+�H �Nbh fiftVstait�QRp� � �M�A8����k!�!� v��) [^/ v� J)&HL�7�G10� ��[�kiRtheor�V"�=E�A]�� ����Pf3�.���� !�4J �'"�}�!7p �JKEeyt�6��&�.�satisfy��6�p !I� p�&�.�gq,�\�&`2�� �]a �}?�S>�Q�f�.?�!���4��AI�up�e�c�� ough�e2�*oJ��8i{'*�(�*_ �B��+ tigh�aef� �In ma�-*e*Va/�1HAWwmte}n� hV� �%e�nd� �`!5a�8&a�t��}�Q^� �Q� . Us!ko *�meacNa� L8�o,�-Q. DX!I�� in T�%S1 q�4D&*A.QQ�y2�E�io� �"�3F!a�, nam ��ac==DB4� * "� �& in�or5�dopublis8*���� �"�)hoy� ��a��^a | � qui-v"��A?? we �u^^BPQ2pXpk .mPI�e�]�h�<"X,!�A8"L(n��i9 �s"/��)atQZ�:!02)�x5x`"��|He�p �worth�a"R<>L[gx8 .)�g<�ref�`bye�cofA%{yեD!'%6��:��@m�e�e�y��w� X$ be`0eo� ze �����llY�� i�Ca�,>s:;� qu��)�� . ;.&��}H.('&-|?( HSSK7"N&�(�be writVA�+/Ab� q! A* s�W mC:�����ZE\i�*�B͑}&cW%�.�appea�l��;:)�*�1�3!H6Z ( 8 )mLVh�r! �1�ind ( 9D!��!CV u�Bm��-st��))� .��*L@! whigh-W�&,*�ej)-�f6š�+7�!�/)�E�Fi�N1 ( A�e ploa9e�( m�HAAd blue�7 ve )� bro�=n"��D>n����H��!� V��/6�.A�?i���gUrximumEse0 keeL{ K��51:1BA�how�*blow-u�,!�g�-3or2�2�/�umM�� tm\#e��i!<�!{Z�O 3��coinc85.VY � �A�8M��-~In"�G �+�.� ��5�-�&&A�!ݝx:���"�1�+_M�P��fn�m�#o���d �Z detu�KA�5�����c"�4�e !�9��$rando!6a��*�s u;e��^�r� _?2�E ��� bottom�topmhinEN� A�%"25� nd 7 ��leTB�s�ya.��_�Ese��r ine>a5�V!�� inct&>*f}")�A��p&� k"A� 2S�tB~Q�Xٙ%�"��f"=.:f�]�E ���~*� �|Xx,�0 ) H2w&�oe(]�#P� �.FLY&�^ q 9� 9bA�&]�b���U("�QXz6a� D�#? �1YF6>�W"Th�6 in ;"� �7�M��]l AR �Rv��&�z��� �6!��r��6��/E.1G�=D&&� U>�9.:.+�Cot s�g 7& ��}#o��:�x � n�w��9F�Gn�eo��R` �V�?aũly��&�:I��&�&s �&A8w�*u�B�a�}a&�o�a(�yBy ��/�b� E�1)�Y!�w ted%�exercis�I)R2�k�>;V�,F�% &�� Four�"��M�2�IA Ap��-8� Ef�F  q"ze�j�Ӂ@!R,A= ertu�L! wave�bZzRJ�� wo "�/�( 1p4( 1Y#Oc�. � ��x � �2�B��s gaD�B��%42� (O�! WJ�a�:=-3���!�A;Ac�3 %�B<[ t:�l� .]�m�� . If Av)� Vi is u.cY@5��t�,.��E�� �%Wis.yi"&�W&rH5!�T�/u�?i�%�h ŋ��c�'szB ~"iD a�J�A�� A�trll��ZF9n� �"e��Aig� �z!�Dt�[aN?�K%!29V7�"��id!���!5�2��("�"u27걑 �hX�ubstit�JiU&1��"��s.�����(d )hr.&.t�&Z �") ��/��!�.�. �1!m�6� �d��%�MRJa2�@�.�A�a�algebra����rel9:o]�InEQ �.&� ont�RY in�2 � succ_ ly il�!�s�y� m��- 2��Á���!9v� �gUhoriz,q�0^]�,ai^0z �a�Ni�5���ofa��� �*J �@2a"g�lS���>�2Ly!�6 � in< �. (*a*!�a*E�&� a��.)p_�b4? 8KA�m�!(un ��AL�2. ) U1,�rX6A%5�!cy���kU�.� b�Ais-�c"�� �left b č�gre�4�vU�S!�,��rA3 A� .c�m"a 7.�E&=�b c/�Jtqxof* <1C%suM�*�$A��= ��2 Ga�Iqm1&3 �(�o�"\#�,A�A�A3��v5�-!�=�(�A8]=�e-!�T� FJ�J-��e2_R5g.�;$A� aB=\�C?y �iV�&�outtV1b��o0W�)>:discuss Jz�0��go�o !Siz/.���Er� � �z!4A�a�K�^-K��2� ���s�tur� �(8�W� �Le�6�0ks�!��&���zbe HUE�.���!6"/COZ Tb�Ɂ is 9l9%!�"M.a�&y�F�,!�n'��h " �e{�,\�.#6�� k2���*�FiQa(�W� E18&� q���Hof�� �Y/B�"F6. Fur�6e���= =0�J� �K��Mn�7to6`,M*5L&�7*��ρm&l #i���Teean 1/7�mq4�e)&/ !r-�����jeb few.v��e)���=%Qf�!.��hi  v�$-gr�P.� `�3��AI>� '�0cu�tGW�y��Z��>�5�aw�Du �"r .���@�}�Mz>A}�� :S3B!a2�8A��8n-���q5|.Ds-��.E�%���}�+��2�"��3� �hmhNNLofRF��! i�.CRe?�Y�w�#-�~^-aI".2��:�"��� oi0"A6�0��a �&�!�-�5P >�  �A�E?~FG�a~"%a�&�+ platZ[l� �i ���:� �o�j�Ga< a=�?' easy!��$!"sF�Y�tM�3>>yX8_!�i�v Ky �� @n�g�f�M� j al�5h!S. C�uiss�\as�  �Mz1�8o�Gzcso� �Dt�Kon6�=y ? / /w�Cl�*Aa^"���"!]Q���!1�B� ( 1 )�&d� -�)s�#�wo/E��I���>��:6-*�� Pfroo6"`<<ollaps- � y! 4�5�a��k%�ns�ttl�DA��( �~ F�=!d-4aɟ!V.�b w+� 1iH4��� �;.n��A�Plv�$�o�.�F=�ir�sgiA� d `Z{��.{��~ANE��tw65F�*6&�4� o#! O9]G !�&Rk+���4%�KV�i"�5->�%�/ �~snapshAuu�a&J� a}J� "�t�\��i�� . St�mng&� i��6E��oa�&'g/ �#�6b�aj ')$5&�u� unti`iny�\-!R�Vr� vi��7M )�s�4�� 6^`!j7iK ��an�����)s1��d)*G,AW�qa��ged� � P�mѯ�T upeS5d�a bac�{�c6 &s#a :`�A�zi'8&�g &�H�]Z,%@�=��Y�m�,� " E�ZU�$]_�.b��e���<ak�a�|( ]ͅ�.� )� �V3� 2a#Gmmp�%b�M�y;� r�%medtB M��p��!a�co_e#� ́1av&_��m�$@9 �#�>�Xey�ti� disj�D �` �Y �G��--�+...JJ�9Z-a��HR�e� [�� d!xv�`i,a�g��"�I@a��"p.Q��)�!b�}�&PI��i׍"Ice.�h9albeit�aZAe,��p ſf�)} y g�+A�;"�Bz�A,Ay�}!Man&$ilibriumy*gG&Yo� �DTo�"�):�Q�f�i{"L�b����A{ �c ^��$( 1l�]%O*C Zia�) � }fr�*�^( 1rBI we b�\*`�T�����w�'wnێ4�rl��H*�K�:Lo[�` �:�Fto52 ^�@��6�~J6�' ri~"�y�.� depJ��Y4%z s�S��a�J �'�\��Ѻ1 we {��v+l*7aek?�pana�of {6�I�o^-A��ř"P� �6F*��.���#�',&*o0��Banegligi�6$6q %� )�#�&���IZ ��Or`S�`CS+( Ob���eas�"s���r�nQ�!S)�?!��':�w+� 2//�J"�ͬ�?zi �otGU_6E� d �-(a4sj5ly�e]��&� f�d.�Gũ�~R�v�l.���Y<se/� �*D�4 1mea�G��&(&�'��?(�5A9iD4a bulk� A-�.1(�e��\la�s.���� �<��In> �I8 �4Il.H1A��TF ough�"͎�{6v”a�t$ oAa ,�.a���%!s -6%v!�!;"Hqse���M,�� 4�6�! . BAt6Xng2��%W �1%)%�r�8k�8 ^(�) GV���hA�?&�!L# ţ!�!FE�>��3H�be� | �tC#��to:�,�R�[.�R!pQNe�E�6��q"�`�ekp��S;�~wI�� �1"�)�� :ZA� is�@impl�UQ*!: �($)��-r.�#� �|)*M� )q"T� cru�7- '�]��['sQ'��me"g�/9R^be Ved .�A��pa�coGF���&�Z��2H"x7�Xo �2#shift�y�n��! "�*7�Vup�z� �hn�E �2�!%-evi)*A]e.h*0B� aG�'NnTh&�ci�t�2�$� mew�%A1a�|n�I^7_ta*dis��A�}"xm2���"J���2���8C!�!�v menoA�իg�>:�"urViA�Õ\Q�guish"�- utE��v�*&�EZ]�*K��c� J�&)N"k���as�;�!�M��_[�x]��w*Q� +�;-�!.�%+J��9W�'!�a;��A,�)��i�A�us far!6%A^ge�re�*yaJvoAK� prim &�A�"� a��i��C�&�C�A�+#*b�r��a �+>�A&�x%H>%�l~30%)rAQ��� m��c$�:.1,"� 1��3�{ �!*^g!��!. And��!I*���. )y�eLKQ� ��v� A&o!\ul�0to8�G-��nd�^�"�*� An&Us%w3}&P*/�B;I� [ng]� �'s:g � � �A� �et a[WHX  >sb7+iĚ��W�H $suc��<mo��Gor'+*�m��-��on�f8A/(� !; g"�NAi�a{an �D!�bz� �2EIaR)6�J ��8"�Oe%��� ���X=�� �+N{^"�%w.�Vpr X� �9 e�.��H�� outpu�!T �)A�op;�gS !�"GY ѕ�s \�i^[��"b œB)�S&^a-. &�rpV�E�� `Tkjq;�)�R7��is04!�N� m5 ! '�� ( *�d�eu�)Aȡ3��:�oN�p2(��l�Vz; �ti��M�"�[ hH-�"U���=&)u w �Pal�)s�;����_F (&t#)2��I4�Zlvia�V�"G W � ) q }Z>2)  s ~���� >Y, >��i�6 (o �a fixe �Q-�� � $!" �5��,�>!%;Ab�uno ,I�6N�H�&* �; labe\8 !��sE�b�!;�H�E,�$m O9�y�4 ��6M��a jumpNH,"�/ black arr�2��f!H� (a{en e+�d-��n� Rr�X�&41�t5 remoz4"pa":]��&�% �t��a+(2B��|.uC�ans���?"�b��ra��As��!ӍXom%�]�.sxl�*y$��v�)�v6Q-��.�a2�&z�3aM�[1;ii�B�cks%�Y�.O�4o1�L_Q����v�fac�`� 8�� part`<�3$�k A��Di�+!ji�M�0�\ed.�2K(�Q)2�MUK�Qa�݁��EL!2�(~xBeno�� ������ t(�� i�Rb *d^ I��lsJ,#9k�� �W� ����\i!na^HR��:#jU.%� g%�f�O��[!:]"2 (� *� � �����wa�&o�]'�&]9a!�:��p��� "yH�C.1U�S)!baSj&�s�u�+uals' rud/6'`0d�,ex��s�.�Lv� �� vM'�W���=/!>.N&� �� e�L)Y }�=M�.�"h!G�b>hA� favoŤx:|P.�)�0!��no i�x�)��u��s�rg�&�}� ��F�9E�R! 1&�a��% &�l� � wo� "�)!�7i�� h7v�)�\+ э!> LD�@�s&3=*�4A��p�d"m!m���'��a ���o�fAnciJ2,%� ����4�L�E�&� *�Fly+'��Iba�N~p)2� �U$6�>$pr{�RAn"�Z� f+a�0��.DGAoJ�!�16N~of&�Z�a*�X|b�.d~JR�ZlE>�FS�'�W�.�Ga�6�Q1�exj�kwB�� �9m��y�bMX!�*���"��~ ^E �RpX�BV%�*�0t �Ua�Cyo&��9�5!YO *� ,*J���*�<��34c� "Ym�n�Sl��9"�k��A�YG+���!�����'leȀw$�5oth�$�d%zb��*���B�6��}6�� .*:�2� �(�!�MmmaE�a�6Zxrw^z��+�7l"�B2���^;��i&*� �W�:�@"� K 6% � go��6o��!0dQI#4a�� �r}%("L1 R %#�j�C�d�oA�B�*�A�m�3qF�8V�6�OMI�S�n� 9�"| ˒��ȁ�kd�Yst&� ��� (I��.3� �">3��9(�R&�2h"�=Vra3�����Ze6���@�Rn�>r 6�'� -�A�Z3-���osweepA�*�@�wsvicI�a�ViR!���[a�e� *�(��u�(�E&y �1�^� � !�V}:\ l Z^FS. Bulk4or�K.� �a+ D-��6e�+ AlA ���~���;�B&f`|Qa�" o�,�p�Caa� 9&{���ig*2xO�?z�3�q�r�uR����uv*! r|xTX>"�� ���tegO"AhwoK7 ��U���1��q/%H�pas�>pB+#4��M� �0��, �� e` �"W�va��O��� ��hl �4ڒ�w �x�i��\t)�9�sAlG�be kep% � �G62o�.|VD�eYyJ6!Ca$?Md�%y->8:�&)�U ���c�3Y� B�"P �7�au% triv�'�� hi�T"�!q appafaB}*#��]J d�ZedJ,Lhap�k��n�:"�)�p���P�i6pr^&tK7�wnC�s� a�A �^'��A�A���hi"4$�o�6�^�U�.A�p,.���e�o:�MUm�?�("� �q�. Lik�r"�\���ͥq�a�W�dt�B�D*5 "{2�f!��'�&�in"�}�H�-r����*1��� ��% ���a�e2� �"��5@mi}!���.R�� #����re�)� *�-�� 4f��1_MN��S�(Ȝ"�% /�00����te �-.me˜�y^!� !a"H ]q*�rI�] �n��frf��L3�."a�wR��hee.Љ��1[��y<2>#2A��8ws"ul 1��6��A�l�, ���� ledg@"I����:'�be3���m�� 4,+K :M !�J�6�]!m��'f8)%,.�*P8('�ba�( � ��wf�# car0.)��L��&�%�@ur=.!Hs!<G ����a3�8�0l)��)�,}mo��^6ː�ua�2�0*# Zu�i��*�im� %�*��)�M �1� QA���� ���%A"{> �[�Q22&�� F [43] � helpI�lBelJ/ imagin�)"�)�����.�m�={An>'�.�"+�!� )themsel?��eH.اa�aZ�� g8�T$y(���split�i!�5��R� BBC �o���ae�E��&���an]hdalin98nd��ĒM���a��!�ofI :oup�|I�� � I}6�� &��)<��/t�.����n5n56$"H E.��re.'cu�/abr.�"�%�"� >�!B_ 6h��m� �ro�>&Q wla.U`6v [���$� &9 � �a�u�{�Z���s^s ύ����b�i8 �~��b>=F�m�J&as��.O2�� t�m]�� �o s�i�2�A�w/�lo.�|ViS5membran�cp�9�KtÏ& �ptB]�?A9��˿rigge]11�!3w h�p�Pvrenv��e glyco֚a6&6�f��D{��-��RA!@uI�"�="rl>I}h1 � eA� post .�kavaile�G&ͲV��5�$>*�~.;*q-� d��w6��irW ns! x|9laviviru*�+�Ga� II-TY��( E ) �� �icidic pH)�#onH!e�dm�otr �$a hairpin-e"�.V: hEDs!�"[w%�tick-bor��ncephMi�r|| :s‰)��!balk��!d/)�r���pl?���K5��<.� E7E]rs��Ut�JP )t���di5��y>ept�_!2�@% ��k }�vq~!,F�:�'�3LbpH�"�.k %-n��gM�!�%Bk  Rm�c"P#R�#-yet-elu� �1"�(+MP y1��A �}-�1r�~R 4�R.)p�E9Aprece�o;�of6 �!�%WA��1�[����vw�ins�( s�)�"h:�iŸI�1. M:-.� �fly ��ed—&�� ��ly—b*���Q���>�h< cell��M�: |z–L <��d;��E#*zj+���Qm�AL Y�M,��ao���>�@���3 , 4�mi���embr�8l�7�5!� ͅ�F�o �-v!$m �gc�4AA� 6�3 d�)HA-f�i�s�1��! >�! ��vi�+��` a�E�*ǿ��e�y��nr[��� �SW�oe�&��,�y@:�������.@�(%-g���1al�}r�AY ��H�6 )5`-�I ��!��vi3�3]v �$a�ur d�#.*�q >�ŘNd�~!���ch'S(&/? 2FP�%�Y rtA#�G�e>�t�~����. �DA[�c=_�".r ��ve�* ,�p[����&�-��chitem �Pno� gani>�A�I� [4–O�C�� IA�I�A�&.& Alme�� spik�����k"rthomyxoe� pT%2ret�Y�N, fil/�coronaC��"*I�$U�p �alp�0 [liAl ngen?l�L �.�r�~cosahed! olig�ic net��fle�u�[��7O��1 rd c�t�� 5�e"5d�"E  I� I&� ���J&�+� ves��stR�� �herpes�pɼ1!��[9 ���Dϰ�al"ʃVE�6� �%�`��iY"� )*}.�il�& ��vaK!������)J�$Y1L�A�-i �C c1��!F&"a� : ”= *� o"y q��+b���*�|�*�C Q2�) anch��k$� -�I�led FP [4�6!���#&� cryn��� X& A�.{sd(���&� M�vtC �sh3�8�" >��u� �-s �� , �]�A�ń"R �45M re�#dem�&zg��=�"](&_ ��Sux2�3�oakm��u�OhCNspoc'in �o>&1�f��by�>"�rec�.�� � � p [2� ��� ~� ���- y�)�av��sarcoma%�leuko)2� ) [1�02/�2��H��)r�> �-I��>�EA���S0W�1�z� 60u{c �B��(ofy���!uN !H��&� " !�fe�A+-p��y�aMJ6-��[Y�-�1 ^I ( TB����AeRv` �5]��B� �e�,24�K�F� -�� UfE�0v�] 9�.� cr��!!@mk�*#.e8%t�ata.% ) � a�&~� genuA�fam�Fvida�o��l mpas�8�1 R�&�hk��oE�s�as ye� f�Hv engu��West NI�Ja>Fseq:)�jMS��&��Н��a� �*�.� cagI� 490��EF� , ֠�� 1A–1D� 38�_9]�!-. U�~bC�i`c� "���c�YndosoBN"������docyt�aC�*�����E O "�A�!śsEu!m 0���#Eat DIII�{%�'���or�WE^!��:�)Z��YQ)>aJDI)�I��'i t���& 3%34.�a�1G͜1HE��movi�� � ��a�� �=F�:ull�a.C!!�e�>";�) e�a�juxta�T�)�|N�F��g !��X�c.a M_%1.�*F�Y������Fr�G��,E�rap�a:� , "�AH],�':�� A�!dow�@eam�-N stagHT��@% � E�.=F,SFss�H[�GAQ�F�[��re-Q &mss n:��n P��]!�Be��tB�!Tc�ˍ� �^�a��.�3Ea�"sCh�6�:����a�pH!�t6' s6���**l��y,* :��ub��9�c��,���}�! >�� ^}�E(lipid bilayK� dem5Ca1Yq� -"mpre�.��&% m(��!�02�-E?"� :�-��:"� S6xq��<fus� : u�!�.� BEC�@�4U���&i�&�&{7sl�de��*(2��(Q�er� or ureL�!��-�D#D�[��*za!9 us hemagg<��͆A!v-K��7:k[4@ �$52�[/#�Hq.w7,�.ha+"I>a�ec"� 3g�1.Mz5��q �>r!�mpt;sy�er� uF� ���h"1�in"j��4�!2.�5W�v� {�,!B)s-j��r�`uUPur��3|Cak�pH 8 ��bu�U� �$�o 10!r�C'�8e*¥� solu�/*�_0 Triton X-1009� T�.-zf��g rifu.�o�C��-�%�!o&��!-E.�pr��E@ei��D �)��{.��4ed ]'Us�~5�~ 1 �#]t.--�bly.�� "� 28�a�:�Z� .c���.H+�GN"weD�1�(E~y fo[� �m�6�aA�,lly reversib�mle upon back-neutralization , as revealed by experiments in which ( i ) the E monomer peak in Figure 2A was ba.ded in8lpresence of Triton X-100 and_`�virions were exposed to alkaline pH ,:�ed�(nd solubili with6f@. In both cases ,�analysis��sucrose density gradient centrifuga%15, a single % atR posi'0corresponding�th!= dimer ( F-5B%T2C ) . We also attempt �confirm@@oligomeric states!NE|differ�(pH values u�$ chemical �s-link�!# out prior9=Iofo0virus particl%5as waZ9�se�nt :)R,es . However!� ladderX� band Pobtain Tall-�5&3 )Fnd�ir-� omet! e� ~5�Hcontinuously decrea% int%�ies fromQ�s!� high�-e�Thiadic%nth-�Q%-),180 E molecu!)M�Tviral membrane is appa!�ly soqTprobaA�tyX form �of�ra darE8�r9�sm simi*, iE�ectiveKA�treata�^?. Furt!concluse�a%+A@pH-induced change!* �4envelope organ�l coul%�Sstudded),bulky spikesVAtAa�“postfE�,” structurU�E� teinũgIt��(shown previ�(y�issociuzA"E��Q� by acidic�un�� physiolog�q��� s )a�requireda� initbng�! �( because ita o�N�e�nal FPe� allows itaxteracl)J0target^ [39]I�or�AX ssess whee�6m)�ic�ms gener%�at2��funvally �val��to th�N2?6pH ��'ecm��o!l��g5�- proc�, wA�m�N�R bi�j��Ih$to liposom��a cofloѬ ssay-�9� . Aliquot�c! RpreparI%mixQ�kat�8 . 0�� djusA�to ei%j4pH 5 . 4 or 10(nd sub��o>z$as describ�*$Materials :Method��UE�>�, almos!�l1&y$��recoveE���top," ,a�A�A~a}.wz :9 �=5�=.�V.i %Kcarried � to m�#precis��def \� dependZ tAA.� . Asm�i"� 5B!.� as peAcE�,100% between!�%�5%g9 . 5 bu�7pH0 reach�n��b�20%); at observ�%5�. VirtuqnY�2�� foun�_pHYS�(cA). F1�.SY+,�JJ�p yet clear2��\.A9�>�a�o deed medi�th��%�J�� loop%j��!�| Q�8[38 , ��We%��a[��.���in�i�� ��clo$antibody (! ign�A1��w� is specᝁ�}�\�[38�-TwoJ3 !�E�DI ( CRa�DII B4 )I�u�a��ntrola��?resul͂� �.E' ݕ!=.49]; i . e . , Eo!Y��NA1 w�9co�te blocfof�(Ly��7, suggese��*FP)/iD� sible5NE IWs)42X��&� � earlier!s$[39 , 46] U���e�!�%�:s6SIKfaciliS @2x t �a+ $le C-termi��truncEbE ( sE ) ��,Rab"�9-�"oťto�U!�� constitue�Aj doese� �izA I hebof2#., no evi�0for EE��*���attach( 2N�"� ,�sJ ��%^ J"/ E�G "} unpublis�[� � B 57���� 6 -C�th:.,Ihe>! via/UFarM irst step�#pro� d flavi)2"� �cascadeQ�7A�we invaN ��.�can%�tiT� % >n) 2 B\��,�Snd��0= an�3 vitrݝ �; %B pyre�Phospholipid–labeledQE(nd unilamel�y( seeZ�!�Ina2� effic� �Q�6�!کlsY� #��0)n� ��araaߥ�d �� 9� �6�a�" ��dJC (Y &v tB ��alone � insu5to dr��-( A'��a%.�cf��+Q|?�in*�b�2��&�sti�ompet �` �.�� . Fo�n!�ura@ ,MG-]8iE�iy�  10I�YNRH1�10 min37 °C��thei�mix4���f� to��i!!� �%monito$ 2� g a�beA�n]�6Ax ex%SS ��[�!�sam &2 K�olm�addYB6FP-"���> A1 $ongly impa�9qLcs ��tp& Y� ,�sis҅ PN����Jomitan�*��� &�E�de�m!�he.E!E after� –i� �6–pre���u#2�"U��%�zd :9!1 E� � "R ����yw�� qu� � vely!=ver� �� �2H v��!�� .��ma�&= sA�{VitQ�!�lu���Q–" *.of.��6�s leavesE8pr��Xa-�l� fW�m�c)�E u M -u� v_)vo��y"��Eav���a&��� or9 mplet!�res�E�=')-uVZ&M� �6�3>�A�6�ao7 7 . 6 did � an�du��infi% titer%y,BHK-21 cells� � �unq+��85 × 107 focus-5 units/mli� � ��e�&s)��dib �ofF�>�4=e}�*]�,��%�5�nd�D��:�':,!��i� , fi"!�02�N�2FinZ .�K7A� sa%napshot!'a �B� ��of dir]e%c pR"m; ���X*�seAiguou�&)an�-e�n�(y�4nucleocapsid )aYea~b $�beAR rele$� ��� � (2K"��F� E!ng!- ����" e/B &canc! a�J\ A!�~ � inserq� �on^n�@e92R,.�wQ has b�&� influenzE)us [4�Wa�X6CQ��!��e�2h!��1Vt to ,�f�@,1�2M|btt�'�C7dE� ma^��c�teYa� y�Y-�ӁJ al ed�Vic)�ea . �cur� model���!�riA���uc� !!R!��ofI��%K��y+� � lay*�rolU5o�^�le�ev\� [3<�r class IA�al��ch2�s have :G���mal leve��rel �M����rehairpi��� Bs�)%; ameS� cfb merg������“� � ][6 , 13! Thaati�%A� cer�ly*dZ%[i� ���al trayERA2 � ��-}.- �5�A�quite sI$( half-lif� Qq minu))/�Lpro��(long windowAopport�i�o{ �l&3E�Io�=� ��s1� [4�50-P%machinerO "�Di*�,� extreme%ost>�F :[516!Z!�trapp���]H� !a(of�by�.principaZ�1��:�� min ou�y2Pit�po��eA�s!�e.-G����wo��cr�st��b�) appl� 6� ��trigg� 9�U�3� No%HVw>� �!Ga!�qsܥ�L icosahed�%glyco��ca�ma{� � ��L�Denviron�� Hst�� limi pH r� �opens up�n� Z e�6hor $milieu . S�“GAgup�D�h�ap.���) simultane N 9)" ��at �%Áei��a�(herringbone�p"$r�� !���[2a�30]�N1DM � �3%�!�N��Unf��a6�* !5�n" �!graphQ5p. in.<A9ruH%"G� �u? !��F��!�ACtip1�a5Fis!V � "a!��%�Hoed!~FP� :A�d,rb$ avid�MP.R)��yd!y Kref�"I wcapacT&� �m"+ !�whe%Dztest u%H isol�s�-dl.� �� _�ci�J�%�R�j%�&cy,$ u�W� lack178stem-anchor reg!�in�,���c"��w� an�-su�1r%�1i"��"R I��h 3I"E~.*i�E�J�6RM�� alog�A��Rzw�5��le�6l!*�d"�"W�iI$.�1t*� 6z����!�?s ��ing��-�cDIe�DB61A1 ��re�Q�' Q3�g��T��b omai� .cry��!�dengue �izF$,k a� DpaF[32�56]@ sligh�&nd��6(neee�qx�u�FPAfsn�� ocke[� VIB�nLub� �=\. S;%� tue, �hom�$A���!��SemlikiV �1I,W5�-�+a� � u MiR �“E xed��k ,*� &*Jo�)ic6$�m):m~ stra%�rod [!�52!�I� &K mu�sE seg���BP � �?%E�Hflexi�)m@ conn�on]IiH1=�R" &�� EApr�)�A����#� r*e"�0 �k��e��J�_���,&� 1 �X:�{9� A i� H :z"U"*$an occur b� R! relo���F� ����&( d� ��-x %im�M� %�act�Q ��( �.!AB�!�DehS&nA�"is� g&<'displaceEKof �"�1G� ( io%����B^# F)�-*ed Xq��'se� t CclampEGP :/���-�E–1HD _�6W.onside',gM(E& 2u�t� favo��-_,I���l>X"Sis2B"* cop��:�%KU�i�ir. 2�AieN�)Q�������lthough2�R%� lead!&q\A&m* zu&w)s�R6�#a&�""disrup�[�.4.D��LQ]2�*MLaS. B|��6A�woA ic�Ah�d�'resid�0mw�mk s�( His146!���His323 II�%e hade�u� *'%%���o�-� �id7.%&"�may` ��RA|deqi��he�2=IN |�1[3e&� *� �.a�� lhII�s�du� ��2. [27]t� explC1@&�exogen��%�is un!��QAt�|�  �L �m;!"m�E ��!end2acan)'hdc3ct ��to Ga�̡�V( take�9���r��2�Z: ick knob-��NZ/�>���e �i�� N�P2)�[���`7 A�%U2�t�:4 w�%!�2FP� �R 2�}��K.�2�!�J �o aV�� groo�(�3diagrammn� F �#;����Z�YB new!\s :"�.�a?se��.UYe),��u,>\�.�be ru�$��ir nquawI��*��A�“�- #F� ���. viduI s !��%=-� ���$ :��6pw���veCon ��Aief�����Q4�g�|vo�d��Aa &F�lk [53]�!e subs-1F�l��<+oni�?A5:(involv") .WeK���$!cip�;1F}{1At rear*�� �1�� s �. S�+l� Q!�F� �,� !��I1��F E1*alpha���lso�J�S�"�!<6.a~A�; is)S� �h6#o��arE2��m6~( 3e`%in [54]e�E"1 !%�.Zn2+ �[55Ie �mu_ !M6]I�i�"] 6� )�i��!�1 Sm61�s—a.# W���TBEaGus E—�'T %"e.>)�5�  ��a=T#pathway }1�. Ea [Q�-�%-�as"O;�*��$�E}�p.nB�u &��c&( HA.e�6���resA���AJ!�7 , 58� ! a pu�v��ansx)2�M�X }Nm&�1 = ob5�� U!$ universal�O � g �>1r�Y !� otyp� 0ain Neudoerfl�@gr6�(rimary cE8 mbry�3#, harve�3 48 hn&J#I=nd purD(� wo cy:;of�`<[5�5ForBpv+A�A� re metabo-�5A)e�1-p�+,hexadecanoicL ��eL4*H [j&�#*�$����+atidylc�+ne ( Av�� Po�+L ,,4http://www . a#),1com� .P ethanolamfU<{!�) ( Sigma C���<Co'12s#aldriW: �#�h <ar�'io�1:1:2�Xstock(���chloroa@ [6".[*drW*Y.in fils vacuuma�|�" t 1 f4�:!wid 5��hyd�([?1� bu> (�$mMa�2E, 140NaCl [K4��A�2�$fa�Y�(freeze-thaw�, follo�*by 0&U��� "�!(wo polycarb� A�m=sI�a p�5s� of 200 nm�aAA osofsy�e-e�i�8AqF/�@2�Z(tim)�. Pq��ŷin TAN9=5%$tr6=TE�+�@mMJAE=#.�7��6&�*�>"<6,D6�"^&85L4/ !mM 3-[!nohexyeo]-1-�0anW4fonq�( CAPS )�si�.��2[c�itIato yie�=] 8,f�2�,��� :-�30%Fmor0noE�su6�ME�t�achPq-,�Zkepi7|/6�� e��%�tincub� B.� ��'~��aBofD �@a=�&�a>6�)ś�B%�re.q�M�Iz! . LoH=ve�2G6ne<=1 A>� ��>&�Ae$H!.�:�iE,�C�cre'��:2 Me��%�1N NaOH!�IUVDu d-�B�� �G;�C.���0*�Bs�bz5 �sbv4�C�:V�4�;���(�( 3�5 μg ):�%نo.pI�E�I�!U��5�%�.-Xe�)��!-%u"}/~5or 20 �&$SW 40 roto�,Beckman Coul!0,6*b �(.�14at 38 , 000 rp�15D24/; �ol� by upward$ eCmO 7�am�AE�!��f NJ�Q�S thyl8A� idat� \DMS; Pierce Biotechnolog>2�p$ne1顉�I�!�U� �or�"A=���!%cAB�.�%W�F���2���r 2 mM}!N6 to�(A/x7� �!er�'�6c�&911 )Ond i\��. A#�KQ �&�/room Her!�35AP"V��stopp�"1��.R c �8e-m� :as%?i���7? E��r; �pel�*ngA�a Ti9F�)!�5�zqe�1\ t 4mkc M� n"s�?�I�� SDS-�A��Z!~2� . PAGE�% � acr] de g ,}Er�,to Maizel [6:S/*�!~per q$Coomassif=ue R-25AWV.�Jr e�� 4"*{ a�!�(�� nmo�AF -�!–J^b'�MX�,y).9�A{ of 4���!7>7�.* (aA!�2� 8E��  "9to�� �%in .�(AmM ,� E:A�^x>%�pHDaM�voluma 2 mlA�V���^A:�?"eY�9A�.1s%����0i�� Z )��"� (&~:!io 2-mlv�ew�u$a 50% cush!�!poverlai! !of 5%By. C��&�LA2.�Ci��at!��q��"�mSW 55���f��m�c~4).0�=�8a2<7JG.KE abov�'sAU6�.xBby�6_9p,!�E-(M~�6Y3�5uZ)�AY[� "C�ei_&� �.Z�vv22s at 2!��aU�or e�0  !.OY�*Y&1 80���=e���,[ � �W—BQr.�k—�pfiFl51dil� �I�)�24�W��. A dr&�F�<� .Es�m�1} �O�El air-g�disch@-da;bon-co� gri��sa] blotD%�fiz pape%a�!p8-waA, a 2%+otungsti�� ��.g pH 6� (� � 6 ��%��� �M��m���wa CM12:�oM Ph�� 6 . n��s780 kV�7! �M;,Erec�Jd�,Kodak SO163 )4�"1d�2o A�5:1�;D1��F� of p"Fy>wU|!� mea�>���cPq! Q exc3%fluoresc5!c< A6Q�F�OAe0: un��&;[51 ,�F.�AZ5H�i0Q!/60 E 482� Perk�-l� (:�eF LS 50B6ySuropho!t W�$c�<0on wavelength!343. PV�(T 5W. M�X*^ z 3?1!ݕ�Ż2st4Q�Cuo��cuvett�H�G��.��E�u� }*�?��(2\�3E or 6L(2��'%Rmu&mixA�!�CK�0%". To&SEP�##(N�at�ze�p �Ra�jLKsAZ calc�#�! eAs��g= n-octa ( seneO2�5$-n-dodecyla�her�"�  6�of��'�3 pers �ib��M)*8�V#f�MRy�Baѳ�)�)�)��]9GenBank>0 ncbi��mi�gov/Genb.) a[9on numbe� Af"Y6�us�#6�@is TEU27495 .�O�+ wide�R cogn.X<&wWe~A���ti�>g!J!a scaley �T+�� A� 1sD�fossi�>����r�% -day� �en�m@to�"8��r�magnitu�e!a�Ygro4N�[<R(,inW�rU if";tr5;� In zBb R,8M� rai :ch |<sM�, fecun�2�(ge��ic�5,�&�predic�8of vul{Rt�U"Y)pla K�IbafJ�[,9n Earthd ur & wleds6:=j).i�is lagg!�. Hc,Adi�'af0%�'Ely'�G)�=�ris![v f(A0L)Cap�,South Africa!, global biod!hotspot�) D�RKRed ListR!A�British��.^/ora�w�m\L!�i;tax+=ic� tribV DY����sR*�V�1�1jio(.t'a_!pl�AB-bc*~=:j. U%3h-mS&enn= phylw(e tre� ae)V%�ZLd.- P�<�'>.�%�>�s�.e"9(C.the{�� �Vl�S��4hort �cha��+tipe��� y—�;+�i�in mamm�Syo�aly�%?>�J�a� 11 exemp� clad�w"�' �!�!��b�!a*�$unujY�%�2E):,� %[�E� . Ou�5Q�:�u�+sE� elev�:`!&J_fA�M� dra�#�S$%�A � a?.��*!e�,Fvs:younges�-e�&a�� �^�;^&#�iAAba�r:&J� sie(b&VXe1�Ca� �E�fin�9MbE����^�5)�A�~[n�/lPWmar�= g to�.�� !rN+� pacSt��rA_��%��Z%can pa�ic'e`16��(���<)��+er�# p'i��)I��oubAY�&ut�Q��A�%cr�Fia%�%E���s��=�#9)8i"�4r%,�:�iaim�:�8 axim� G'�& ��-of�?$ M��le�ng lose12 )&he)���2eco"{ZhalA 0N . e ton. C-��[}JAal�y��*�[1(^V�ano��!%&�aF 0next few hund�Hy;F[�'te�^tY *:>!0now do�S by peopleE(pproxk ly on�"ird�l%�re�.VE5�a�huZ�[[+B����pro~Iv�����to @A�umpa� [�C�m� �Gh"o_o� �Mct6"�!ohabSIG�fra�6I�#4<cl% vCg+6?/�B} come a-Ant fuX � [5eKF�]Q7 ��l�LU lof6��P�B/a3edA�system �ic�(�b�B���:ique �v��'hi�Ky�6"�^�;� oveR uOb�S��RO �d����8��a}I( ɚal Un� ACon�)` of N�( IUCN;61iucnredl� . org/ )�_"+aŝI�v� �b.l�J��4��o&� 2?[6]–[HBx onoai/, peer-",�Yts [�7�D��&toA�t�"&��� n Wgor6/Sy���c]7^ : '�r�_L9, near-*� ( NT6�� ( VUendB�. ( EN��82CR �R� wild<WAmB��+ ( EX#rH�z ly 4Q+97858ͧAYo,!;�C11315e�M,�!zcY��� ion;�v�major�i( 75%�<8seMM�8E�aniY B� i�cV~ , bird� !amphibia� !)�&or��Q% fallA���7 � �. s.�l�5�<mtaxa [10E��GAT&�U"� sqM�u� �[esU(&.u�[ lin�� .�g�9a�tiR`Z��� comm�2��V ��-us� , �a�1�Z (��]��te��� nes�,6�-po�P� [12f� de�H�!�key:���ig.de��NqB���!��ec� ]�� *�Hy;� ��=pre�h $�"4 v!';Ya`9��0iOr�Or�����Lce5=!�y{ Mg]ngac A�.�TBv8)7�-� kn*R�AB.e �C��!��.[ ,%� <5&`Tn�Nn*� s�ce�~1a165�)�!�Fu� �s%�b . N*� ,!�qing�^Si�<ve� EdO.if"f���1 }k f!�" �a4C �,:,�-,,�7.a�7�ed�eO�L� atI�6�(�Ny�or�4;"�6��)�A��lr�$agE \jB6�.0 ups ( 22%>�& In lE�I Ocg�Ej� v31'n� ����65+A�re�K ortsN7E 6��ee[ Am�@�X�4a�D e��[20A�.gVst" D)sW!� �2�withi�.a��. Par� l���6# �5d*an unj�Y�ran��N�:ls [21�x2� � ��as�n h�� ( p<I001%�p =   0rani z �faZJ�d��E&�(ly;/Z�S, T�Js S vS2+fg�a" lsei�[2? Ho{m%B"Ggon6&�A5 �( a�g . o��� syndr , sex.� *3biA�heEq�'�;�3c)�m!��"�#�:�5lyE5u�ra�u5f�>ep'�5ra�I�E. ndexaR��es'�����T��<� e #) [25I�yn�3; ve.0�"�sCEEP , [2��[2�G2�GS&l]�&A"* �&� � * E�Wst:5I��ayA�itAB  -�!Ei�Fa�B>)��fit re�s-6�U�&t &� M�ye�i�Ub,&�5� ��"�_�ŌF� �e��1�AP�de"byQ, !�be�U-"� �'* �3��a� ,PY���Us;o�\�m link5��|�OGEbiA)*[�M�\%"E�Mmp��f�qMgaM�L) . ��,"�* ("�Ada-nda�,7i-^r*�B�nd�ref��o.$���/A��|Ke����ly�=� 1g[2�Whilst�`=%lj9matchDs�uof�6 �%j"T! �=\I&.�Dr�o""�.�O7 �3)`D/nd �al�w�=b�!� V�  a goo� o�A~-�F�%Mre�� �.T'Q �|y [31]./B�s typ ���H��-�� e�,Ea�vk&E�Ka �wb2E#. W )gJAtuaSw%Xluaj>e:]�gtw�70�-L�~�6�of2�UnKRKingdoW=��.l!�l�S�5��:e�� �Dl"�f(Z�< \G� Zs&� .X�gEc��)���rE,mb��f�;-glac���lon��?��;o�4l��rA�j� [32]�j�7a+-|=ndemism E}R( a ��l�U Fu � c�N. I�a]ce .Ev !a�]* oup��+%�!1a�m�� A-B�"c�!Timpri f�k_�LMoreoL �d idm��=uUK��A�LK�zi� ev�kcsb�Z�angio�"m�&��u�\�� �7�!� UK)hg�mnde^�e�e-ac;H�a7�E�t�X@ qA=9�iP.���\s�R\ �Su=/��ctw non-& pA�!E6ha�,�gi� �2X� onsh�1�E�e,� Mg&^�Hn('6Ti @,�� Nm�n�9 �i� � q .8 how~�n�". �8A��2VHi��j2pw . As��mM-���mb!E�:2e�r�AA[e��"%� mpha�!o�e6H"$![�Z,�(�R�� VamosiE�Wilson* ���"����e%L�nCs&]�4&�.y]6)�y�weJ8 j�o=�A��  V?"����!��%�2Pc :3l�littl��M2��,b�>in< 9g�"9v�@��*!�MQ-� &�I���.�Q&F[�A0&b F�� reli\Jin[re�  ���f� ��9n% ��exiz�At� U� eF� . E� A5� true�=ac�F�onz���P]l2Bj  X{� Y8_"%IEG��f ..B6�CB�IM:YP~M)�!M��de�l%�y[�"e���u���t u�� A=.�$h�= ~p�X13� )���\]$J��.�~w�|a�[!$AS] %Ro�h*p j"$"C/�#)�idepau/)e�!UK I !jNor=&,rag �A�܉�urn�( R�)-V(K� g���E��~C!{�(W �n!�b�ɾv2nD����q� v� ��s D7 too �`���  managX [�U�l"Qef:muscus urj,lya�r)ia�"!at ��r�!lNyK�I.69w�'�"[1�`we �cbSva�1�!��!rKe�r�Qb.0 �s;& BZdec�Qg �Yk5)*k# 7ex�"%q���C�9*��}" VnnlY#�n��2"/ AYq9i�ba��I2`H2��Ptev<w�a .\aFT"� !B� �$H�for%�$x�2o!C!4 m�. P!U2c� 0��:nVEAXsources:�E ) G} =:#:�V� :�1Bk ��_-ed Auga 2009 ) ;� )�d�� : Jo� N� C.� 8Committee's Vas� ��Dat�Eegr G+)�*�" 2006>�jncc .. . uk�A��A)2��*:)��!im1)StaV]�&~on��aA.Nn�io�B.w+In�u(( SANBI: ht*�Hsan�.�!;�%s!T June�8"Aq BetaA�E.:�n=9L!4&�al�:�!th� C�� OctoP/ 2010yAn up�?da�nn�iG w�IilD���PretoJ'N��al Botan��$Garden [35� Ina�~0 synony"'�ag�+�YA"�"� y Group [GN�.We^d:*m"�`� ify�$�.Vsd��(.�[VU�*)"[ENQ���&e"[CR�� !,D"[EW!�[EX�Ior�2�y conc�"[LCD'>�"[NTB.��&F�3� ��>h�)�Jyto>��� <&I��.�(&��9d:)-J�-los�R<APG)�Hv.%��>,4varia� ~�Q�.ce��� ���Z"�Oer�� ngAUP re>t�)Y��e� HA��< h{mblag�' keepx�2N ��9E�!�s&Q)�aT:#mor� =�MeV9�J,!0!�"i &��NK�'�[c�o�s.E �i��6p �J�6�G7{8�A%��-w� Las�� 1996 [57I� 2007f'R��6�E[V�>mc��broada�qui��I��co1&1^���&yng�+1� )H)Ne�:r −.!:�3W�t'riA;a���)Ao ��by sum`s�1y^{) genu!aN ���u�Ue)h��%c�%� "�� {,!�K2z�]{�&� *� 2�2�2�^� �*pVi� !�!�� I&�top�rd4-)�eaɅA!B7 nbottom 9(��><�P\ "s�A�E��� �we�2mb��LI�u�Blo 7g's K-AA�c��Or�%�&B2x>�^�  [�d�U|�.inA,!�d"VRWAf+f�)CN��{F�! .43�A�6�K3 �?�LDe�M��K 90I��h46i.,��#!W�sцno@&]:cr' [FUE�#�o�l��a BwTia� ��m{r!�O& �5�!G��6�$��is �}!>M�2"d�:vi&�#p~Zn�pkUe�%3 ���۩���%!OEVI�J"Qo9e2a� �'��J���J�4res'Zd�y��l�? (:# � �ach-�wE㡅U"]��:�61QAs-�%� ��uHarmoK�Dagun"A7E��"a�"3b� ( DT�,[40*  i5�%h�t�%?mean �}-w�t$ �1�9�" neE0%aA8u"tyN�le.�Val�RS^TT�  0 �\�W�qp4�%J%�is'� ]�-<&�0���  1NZ2Sam� �-�sub W.��l$ps%_�beaeXK;j�K �hI�E ���� ��7��C3#ve nul�$�F+�E�d6U �6!<> . Se�k I\p�2�de3p��u";A��daugh<�}6�s�w} rait� asym�]��a�)�a?�UA�Qg-xeBfAGer<a ]I"(%TAR pa�Ev���sS&E� +fa�E��x>�u`a.V%�k(36!�*@�*f,��h9(!M�Zitud"�Vdrift�t�b�a�D2��A�i� zeroe�aZq��D-kplu��"�2�"sm;)r��exp!#rz6��x*�M:�_"C!c�gAo75.^ R!�)lA e�I d eriphAb��5J�B� %��6� ��N%j>�"� e�t.VrepgUA>.���u = � i<o�yw,>�"cN5%@ 7&  quara�desQbJca[t�8ź%qe\k7�/If  �^�`�0 �> � �,ٝi��>RA��w�MC!�3��< ���A�mp(%�� �A�.��Gm-ee�� c>GA%�plotsvY top�(y��� �-mD� � imp�0� AGeiOcR-libr�"�]R-codi!'�}Apl!lavB+authoO�x6�! gVA0�i�"�� %es $#.( n�*�V,;U�&� �c�� (�vl�of*9 ; my� !p{S>)y ( log[n]/.� e&�1t'o  se( of rA�s.%A" ;�>.! � a3��N�!�N s�v%�.�� R�e% Dxacki: rE[~&�7t�r�)�>�� le-3_)�B�p��r�( GLM� waE=;�"05)e�1�� ach|�ij6.�%8a�/��binom�9errIj�85O!hNM�!r�gann�:)~5�s��-root2)%I��fit�6�.�a�&=4E5<lo6�/12�ag�遼l�,ory bl� M� �#"�Akaik�.8!!�ft;rgi�Ri{- %�� oM\twF�E��lI!��IA�eo2���z-@neN�Pa� riuv � ���&� misA�Iy0�����oݕɛ�`6!Xrd h� � 6(V9�BfA# u��O�.!"W%&* ���.  �4���%z6a} �9D"<X%%$�-��s��NM�hN�sub07"�C5!�8ro�cb�1�!#1V*;��,I��.Q�>��Pxi uW"�Y/l���n5�e���ot�1��� �azsenmT�9!wo N-2�2�_4R�w�1�Y�ŕbI��log�hm?&���re�Hye<��%�o��A:MoA;"�� �#e�g�c�z$ltiHF�0E8bD&u����q�%�%�down- ��%��� R�!!�I��23a� @�*UA�o� c) I��,X|C� %.q��qm1$Q}(�Oa4� �:c)�a6A �g,matrix ( √���ua�F9al Mant�5es.��\��e��"��Y�-�ndB%wh�/�Jo84g%�2�Ted�I�xt�!m-�Ad ��<�/ B? E�H� PRECISE�5 [? �*v.m`~��*N�6�U� we�!�er-�(�A Qe .�B[4SSpa( �*�D co"�~��� P1C on's^9 ( r1U�S ��>�s��a5wL m�A�!M"pN��@FyQ* �gmf|/�^*H ZM.�s,R�C%�]�2V,";3h�6��j7/a�n� �0� b=�(n�q�&� >����>K���a �#of�8&{ %� U�F� ( �m0QD"�`&�\(in ArcMap (�[2 E2��S�C$s Research*)!In�!)E8SAM� M.A!�Marcoec� v3 �d) Y]0��Phagocyto0�e&�/�  fungP ath`H, Candida albo�֧a_EYA�in�+imm�!�8is vi���bv-n- �H��. D0-1)E_A p �ic��ep� �pd!<k- �pᗅ���.wos�)am0 R�yZ$c2U� , Brute�Tyros��KinasPBTK-zVav�`a��Srecru�2��cup�nt$hC .9Jyea�P= yphaJN�8||SpT�a2 ��!uf<�Q�z�P� !d e iw1�T ifo�HhG5x T=1�Adc� �B-9_PI \$ , 4 �Z ) P3%-F-%�Zcy!�cu���&� w� $diacylglyc�lDA�{�marks�::ZT�-YKdR��\o�"�-��� !owsyn��t-�%�A �* MmA�of PKCε)B-!�!B-E8s�� tone�]�Clay*/ea;a� zymosa2R�e�. Bmarrow-2.a���or�  up��2i�) !�AyIM.��$.ZN�mic�3� susa�u(to�Eic6t&pt�S$�lL� work�� "�~��G�!�!�!V�MT�`l ag�zt6�. I2� �e ��4�$2�,�f��na=��(�m�Zi ��X . Germa�-en5�tt�$ �T�_re!M�( PRR! zBA��-a&?EՁarkO�A PAMP;F�V)�&�_u!!,��%FhLP\organis5Re V��5R� ���an�RJ%q w7 �,= ����:g anci �y��!�a�&�Uari�{s m^(�ws��-�EYKto-<qA=m�of} � �YYE�2���*&F��Oensal-�)ZW_�� gut)� biot /aN& tole�l2�AAt adeqiQ�a�/E 1Sicђ�*P e�e .PRR�is��-7% a C-�3��4�8n2�,2&!�dendriŬ�t%1rI�z�6 β-glu�5.w�R�N��� elluan6�R�o��!* ITAM}} &E�E��u� am�"��=O. U���y&?M��%_ry� A�tsFo�{�A:vsplt7 k7 Syk} =C��+y[T�-xzd64c� !�-��t:VҮs9Xa!2ni� 6���^:� !%, POA��;%�H i��e�����O� te�9pansgD37N , GaIm -3 [�'TLR2 ,NEctopic�re� � �Gibrobl+ kidney�|�xer�� a.��2n�E� ��_�G It f�N1K.� )?!�"67mM�mCat�lie ]^�� !�=5��A� ��:!�=��up�3e�;�2�l �closu���HL �5� yoa1n�j4���O.�HEcours��FcγRZ�-+\-st�@d�7 ��-�Ev�m�in�Xi%(V )%>� \Cso.� � ch u2�doK�9�e3�p PI-��6Q�L�ou P���x �ol� -bi��sph�9�( � ��bi�� ousl�ea�A��lasmaA,Գ�rA�C{S*n� ��" ���#A)�A!$()I:�3-��PI3� con�2s!e2�� ��y�3� -trJ�!h�� Aur�Q^� v|o z 8 ) P2' ! SH2-�@���5′-�� SHIP�P2�a Pleck�'n H{�wP�f)� �����"� {�N� or.�low�d.'��� "%�e�eQ",-��e�CAO LCγA��Xon y�2PwF� IZR.! trig���zr,!� cytoE�� a2+!��=�.�LAGin�'� qqid�6ma�-|� eynt��!"a�" N�,.%�:�a ;vn,�1]�3%�iI"� >AzRt�Y icl:gags-F�(�&�F�/�>��jM �a��-U�.Uˌ��.�?�2` by2� �7�Qi*2 k �e ��PIi�02r�I��M�J��#*�"�+�2�� ��:��!�guge���$ ex�.f�%�.��7e�B�U�2���-�{��� �=BTK��.���>�?�AG1H2�2L(E|�*.���\ %�2HA��>Jrsuccumbv�[J�to6��1�w�2Rs T�<"�)ke^f6�� applG2"�ma-too>�(?a"z7*�;f ex' !�a�i�'�Y sflk�Y�n (F-BF�"�(tg�H&� e�) n6�!V&Fe"7�(�ly"7�A6� c�~s�|"��A8 (m�<1-CRD-Alexa647 )�]�,l enzyme sor�� S%�&pin DMEM 10%��7�1xs3$T�-184�.�s� !�E �:�&�٬ . At[!K'pw*Ԍ A�ly [edR�niͨd +�A udULg�wh���� ngru�:BJ���IW �:�6�i��!g~jXdnZG9�m[e�Jy.l���I�a�&3���Z�> 2YE� ,6 �%�E�e%7�.�J�cB hg0 gaf�*cx.)�-To�;f� e�� a� tP�)3Z�l�2��G*Lqo-*�l�rimҲ�a RAW- l1�M@�(`Ceb�PU��R201� �.��#co-yB%�F�b ~h� ��/p�<�����y)��XMHaY�9�%���]ull�lyp4 ��t23��"� ng�n:,E�)L�p�/d-B� -Hٗ��R.&a ��aM��e+�? �Cy�O �4by SDS-$ya=6 �LC-MS-MS_"�-���E�[A�w�PA�!}�iev�a!lex)�5 � �m:g %�T.�AQ� � BI$���r ��MN��aYnA޳=�A�of��,��%r�57�c"K NS�� )!^�%uY�VU�.F . 2x!Bin�1�@ouX erio&cco m�~2�m�~� s���� ����iX�&i��-�a<}"�Q0�im9Vi{I iA�bym2bl�/x�07IҫJ softw;0 %�� iMR_�+u�6��9I8%+�X�o��t�>�E�"�5!r8 9WD ,#WE��)��at5�R���!�F,%{Ũp2E;1CM r�m%2hK3�Ned�M��9 !�!7�>�!�ݑ���H.�-stC RAW &h ��in�auN�?H 2k as N]&7� mCherr|��H+�.���r~u�E�1g{X ,�-LA� -%��s#��h�h&�-A��X!1 6T��u}�LtopE��2l)�!�Rmhtag���*&d�w2OE.� � %�M�� � aeN��%�sEf!��=6A,�%?.P!*m�aʟ-9[t� �q�%�.p�i�uV&�Z2pY"� �� �N���M�&� HXBTj ��m!in�u"�$1�:�ewengulf� .� z�;>�Q!F!�N"/ Q�>A�LAN|F1 �a3 ci��out�7E.�� r#Eno22� uF|�i�I�"��"Uu dA,�D�$ag��%���vi��Cs�yt��& e�R{1�!���&%�M�%L@I~�.�2ne�3D:*=k6���2$#��E.4'M`�Y�!�=�`BTKř/Ar�'��W cyli@+lee��su6-'�:'Y�s RX:�z�V@A�q �a1�&]c�te�0y1� cup/N�l�0e��.>�Q�!2��06� (��.9#�In[Y8)&�?��@/ ��"����?1 %�M�iS���� "52�be$�� C'�%8cy� of9j�<"1&� H��l� e�y�hA�����o X�i|*f��B�JK� {BAeM_l�on945�S��I�To��p F"� EV'<�>�Ousi{l;i�����UV-kil�92�d'�m�. �`�ish�ya1�Q'�a�.�Mc:x 8�gN4caB=CE�� Regard�4m3ge9�p�sA�"��DEׁe �I6:�e�*m��%A1I�^��2 �� 2(a�&5to. �M�n"x1��}2�5� �n�4V���`U-�tomr2�e 9G��Ft�� rms^�5*�.�U�D�e�q�`l�W )�)Z�&�- �v��lZ1"!. DE��PIs�"- �%:t J3� A�aq�2.I F^R)�� "��"� PI�i"�PI- �yV �s���N Yc"l.��s"�(�ZR7�j%bIH[1$&<4�!ea8��"�� ���biL� l* ,( PH-PLCδ-G�2)� '��j%B�\Akt-RZ� ���-& N"c�!�)�-�2L%�c̈́.B�e�z7#�8]=�]"���Y>)e^.�3���D�� *! si,ZB.� ��}uq[k. M.� se���SuXeU�ed >�}���:nMA+ZIedB�>J-}&�%pG:}( s1�6 aruH"!gABPHm*��CD�E�š���,�:�q1�.J݁ro�&�2�! >�_6�B�Q�. High,E4r0��E2]��2aǹL�G�=2�MϚ�&[2�%9)k)J|�b���+a���_�5y4NMnd�A�9�: PH� 'z��5C.=(�ym%�� �%��=�)*F �30-�\�� MvtZ1d��ups"R W ��V-�N{(nd���?aC}��wv�1�_�!���7���^�2i<%�����pr�|�u*���& &�2abu�V�J�:Bx��6�K��IZ`*of*N B|>�RFr%��i{ �MH�EwѴ!�M DAG��"�.G�A�rK:Kdv�:� go7�Y�:.i� 2� !����f� 22.�'w2�*� �?ũ��"�g���JM ADY1 �nBw(����a�VmP �)`8�(K0�r�G� GFP ~�!� KCβ�0 � �����Od.�>ir65-�2�% 1�E�y!9� )E.6.�Ai3��� ?*bei<�(A��<m m!�q( KCδEu �mus�  ��r6�55*G� G{�.�}�:)�����g+eBl+6��d:ʼn ]R*p$sa]� C1r0`�/GE$�Kng- �+)�.I%�4ic%�iURgLd�in�Q�Ionu-5?a�Syk�pep�("Q �v��� HA��L(�umablyUL"l2:4+.���!�Qem2--  .B�\"N3motifB�g�#W]vn>i �(�s"��J�wNJ�!g/or%�mb�*of .<M�\ �zXW"' ΋*S �!"= !��J�k t.,&� avF�+�U�"�i�{(i�`��/ Lf:J5kuR|:!� &�;�g@Q�"� 5� ��:�A�wai<�w��} fi�[gN�*�l� 2�Q�s&E �Sd�H5�m��&�%J "�9��5��^ :i%�S��*CH �K!�/cl,� a<o%9e�� �:�9D� 91��Yu�%� ���iT7"��0nei-�QQ�wE , F �a�9r3(ADaR�n�.>��EEB��-JahM��k"�qa������U���it:� D%%�N�siB�}�7e�)�t01)�� F�,aV3:��'c �im� A���&\CR>d���f n� kele�TD6M6na3oimFD�9"�0*�G/2g rwh�Qs1���U��byh�B9�i�fixi�%�tan�:U�a  metho�cݢ3� ���u�R[�.�"3�� &�j2n!�y�u_!�&d_"�i!{ "E>D.^f !���tI�)�7$*}7u� �E���uffyhso�` R �N�7uni��/ckI�=R!� �.Oa�ya܁N-i" '%�ol\#,�!granu������E;� ��R�%�A���LifeAc�, k�s�)�r�B���� �nc7!.-W^9 �b�@-lh> a��12�6"&!�l."Y9!NM�/zk�~ V����VB�i�%�`�!���eNV�A9� ::�2YR q�%�� W�C�&H�A�%H����]���)p�W�A&�ALthe������_u:�2N�-�.q� �(^w`�lsk�.� zu ���a|�6WA.���#9�e9�g%�< J�i *�RF)v� jG2�!�� 2 `+ �� }{� ensu!fy of5. Have�%��N�HV R� �-Ins�2? �� �m��V�)7Q�E��x�:� Y� JE� �U�*%�>�%�KG� ���hly�.��!�p F!~&�G(PCI-32765 [��a�e IC50k60��, Tec �;!%� is���378>�YgnM B��MFl tolbTK�)91564^�t):Yfo�)� In B� !��=��Auaut�o=.�A�(% :�an��:$N)' .R��H�:e�,I29I!5.C��*D9-^ER-d!� : 13 ?-�.�(B�pre>S2�9�J��wm#Y(��+�50 y,!p���(1�2�"��d*�l&�6Concanav��AA� ingu�rpE�(J'r&�C)"j �/��6a��PF(u2e� -~bQ})YO69uV�Iby 30%�-��9c:� prog>"iRubW�2���7�6�7W� �S�U�Ut&g A�G 2�2b/�y� O?o * iH��,a�2�/ e2X�0J�IA��g�\IX�[18�C[1��We�2�^� Nj>",K ?E�%c�6�� v�1��&-�e�k� ��s�(� B�%���.m� H ad=$4Hi�fb�� "B�E��Yd�nPLCU7311,.u9J�.T��m��� ��7�Ds6����.�N�:eq,D��3�!Qj� �~e'=���Bfci� `iӌ��chromatƟ�A*Ѥ�$Rq�W�by���?6f"�)"8Ttly�8BMy�B��2�wn6l�49�.�:a_cY�y;AG6��"2�,y�Ny ��Q�\s�)~U :,N�A � %-auF;"�-ނr�� oH�G3QOKɩyikZ�Ac���"K+!C�7MOJ� M�6�.B[9��)ã~�r6�jʤ.J&�YWD�]6#u�k5p|6{ &����0"7aY#�������o.+I�!�%�.8�J�23&��:7�V�") V�9�Y�� �*J�.�-b2 ��v é�l] ���_AG%�4� Or.��B%"� J2resqa�l&>�7Gi�I�9�I����A�!���q�| w�6s�|"K�SiFzSY��^=S�( BMDMs ) from wild type mice and 4dectin-1 , btk0vav1 knockout /�L. Phagocytic indices were determined after incubation of peritoneal macrophag;dith zymosan for 30 min or ,C . albicans: <1 hour . While D�,1-deficient Zs did not p �ose�, the6PDcells showed an in�,ediate pheno%WT( Figure 8A ) . Uptake!2�by6h5hZ�at�30-! dtime point was also signif!+Xtly reduced compared to=� �$( p<0 . 05�In addi%�5 −/−UIUdisplay! r=in=^$is similar�that see)�!nIy:X2�>RBTK�VA�xare thus important contributorstQ-�d ub� �.! Pvivo immune responses!�yBa=:�e>1$ aEerto6 e>tested!9Ha systemic candidia!C�91a�correl��Evirul%� [20]��2secre�-98proinflammatory�s TNFαc IL-6J��,>�,�9�S�.cZ> �edi:n9SF , G )AZ��!expos��>r�.� generally� more>� than25d>�.U(2"ce betw�[w5=!b�Q �) AtreachA�}w�GceEbNext wa�acigEn J_%�YfmouseQh>~2�Y[. Kmȥ~y�11 days R tJ�E��Ɓ�$. Although�of>�esligh)highe� )N����rl�f%�i.�;seu�# u %q2�2oY�H , I%We�� clud��at�� easeaN gres�=in2�2h�P9q$is acceler%�in>gr�ч����.[ . B� best� w"�ir rolA\ adaptive�ity: BCR% al�� in B�4��\ɍB A�T d��opm��a� llactivaE�of mata�lymph� eQVav%oTfamily members orchest!,��skeletal!�rrangep � � be�ex�hs���he�� poieA )��particu% [21�K���� #ip�~�n � �ons��TKA2 e Fc&� &� is [22]gF @previously implicQA depend!\pathwa�$[23] , [24& � prot� -O�Ő V-1/Mac-16� neut% il�5! We i|ified.1!� nove�Mter) on%��β-glucaa*ceptor�%confirmA�hA�P ce��2V2G!�5��K>�yE'2N.�/!�P5EPal lexem\2� of la@2Y,%I[ly8ingesq20hyphae��)2e��x fo� ate*$ranes enri�S�0PI ( 3 , 4 , d P3�o calize) mark!�4F-!�n�s 546 ) wh� �iABvolJ inAjdu| of DAG�ap1!ic cupU 7�MacAe ages*��hTK��m QSoa@!� BTK-.*�{ �� read�X� � 2}U"s�WdNX�$����A�now be�A�o% list%��-�%hg!R� However ,m�\a� targee�a�$phosphoryl�%�SH3 doAba�+q�sieꁥ�� 6q_)�!�event�Gt occurD ]��*i���}� H hips"P � �!�)kn� @[or%�i ��be clar�*� �� R� can�$be extrapos�&c� qa�rent�Borm)R� Cc� uMli�} .����!_,�-mCherryW -� strong�#ruitm�*Hto a “cuff” reg!�)#engulf(� �is ongo�. 2� !grAyu��thh ���e� *� &� �<1�<�� � RAW-I�1���ine � �)Ya ensu�re�of!-%%%i�t�f�� resul� incr� E]cof�onN2RE)�-\ �of5�debk . Ouri�%��� :�aeby%�tH DMEM���serum�837°C� 90–18�l �z�]{�s# !�c{ dissemi) \� [2���it g reG�nlQ does�bin��2INovernigh�!at �in)-f�b RPMI-#[29F pr� AZ X�appearI ph�� .nct�0r}may w�2 ]e�I�in]sU;��yield!Gtd�l�> P��inositidNPIqorP mE�_somBem0 ! ve dock��� A��!�appropr8 %�3�-� Z�2�, � "� 2A�"� �i��of!?(tact , foll�by�*k L>� A�c��!Odis)�aVof ?�% DAG- �m�Ga��`ag!=es seal�� s S27u3��BT2��]yN��� qWsug's a�!��s5�a�@E stag���H."� e_&� -�2�M*J�-W��a�ha�f' A�Iof �y� �*�o�*�%7�B � =����to�A�b56��zobserke��B�J� 6 �w� �sup��Ino�T�C1M��ei��a� alG-��y( [1Om, CR3-% FcγRZ&, )L��is�Az[3%%�lso 8iz�b)� cups��n��ݖa>th�MH*� emphasr�it��b2�� )�,enzyme PLCγ�(verts)�}�to!�a$!�qi� �D inhibi? 8U73112 blocked 2�AeWbyU.�6I AO�n� ��-esial!�vh1%���e���s�!�' � PKC�E�ha��B� %�g]�[31��[32 AllCisoAns exa[!���!V�( eQ -2+-in&����q!� ����a=?+ est�m����{Con{ ioaPKC!% quirs� intra� u� Ca2+��c!�B�q�MN [33]�+!�.�r6� �&. !�5N��r%T�via1�-���H�o� s�"[.Yδ�)3k &�`ste�.�:3�m�i��K !i5Gd%$.HAuC#�b as^� enh�nsv�34AxF���� P! o� !2caB! such!!s �:Iir� bursQ��!*� ens!�:�e,n)�p[3��Fur�chaaJeri m~�I of �$viduaiWQ��ԥ�%c)x1Z�]e�aryd!��y�.t�pha%%��> �*�Hvav"&"fJ+%'�"!6u#R�u�"! ��>��%��s6�!"�*��L2�.5:*�Nm aie$ZI2�B,E-\ burdee�n�E&C !#cr��c%Et:+J&A�&�%MT�`N�m� be due#R�by2���u!#� lete� z'� W�erEmu��$main vigil�8� ��{de� /�in =Is' �4be sole&!$a�!���� ed �2 �����[3* [37]�le2�71Cnu�f T%� Ps [38�29��"�.s%P�tt!%a: �jor3 MF^�2�]�, a (�(orm*9 .��dX&"c')�*26v�ArMc��Eg��-�pr���"6�>�,a����0A��aLlexM i+s��terconn_�cla�D f�� stud.O� a�fu� ly�Ked!psid� I��U9 Kp�"f:( stimu� �0 TREM-1/DAP12�7a0ma�ulj$[1E~In |'.� ��$,!�rma gP%� �$ .�d6$a�:q p"��!� romi2r6 �IhN� �� 2ahypA\/ �EP i{tt ��e0�*� -N� I]727 .!7�>ed��8,Z��.�V�AESyk*�� , [4� I� �C! (stablis$if�� �-�>Z1,�!��'MM �(Ihi���ly� stoo�"Yad� �".Oat6ZA� instrumen�# .| ,A�-�";#�� type]>manneP/� /vav23 7le-"�..gH!$ IgG-opson]erythr� es n���[41� _:�(3.�"�&}/inr,[49W;regarde�7 �cl� inf rogl� :">0 AdA� ?> ��t�>Eafu >a Srcjkina�Y�J�/�t.!��1����l�d.@�'&�.& �! [438 !�)�dou�5�.���X*�qIfL&� &�"\ � :/"T  [�$ac��an�$b8)�e�Bq282ur hands�^K � * *.2, !��-I�1�1 , Li et a�/64$thioglycol���1peR3do� � 5f2�of�%�e��c� "� y�.�bu���Y.��"� � precise��q&!%ar le�kO)��52�:�Wf��inI� wall�oon"�B�a�" athogenic�like Sac?omy\ce�'sia5��-u�-.jof a�$stream facb2. A+a] �!ssmen�������," %IP&3�-C��V& F^S ..�!�� r�ia��! help� K� s . Ag1�"� � �"h�,d�DWhitehead Institut�0r Bio��0Research"Zis��(�Uni�2Sta�8Off�6of Labo? � Welf�( OLAW )�L%k guid�9!{DPublic Health ServV4( PHS ) Policy�Humane CW!1UsCB|� J�'s>� Assu�w����'h11/3/2009 ( IACUC , A3125-0��!in %k carr��1�� ccor � � dura�c-O0Massachusetts=�I echnD(y Committee!-_%( PloeF.Pab , CAC# 1011-123-14P2q , in SC5314�culc"z@ YPD + Uri ( 2% ba;p�*n0&1%m��"s2% �*�!�480 µg/ml uridX )A�30G . Toy8e a blue fluore5&�+ ( BFP ) -�,� N���GFP seq�� �| �'Zw `coni0�6� vacuoon�Aaly@,�verse21se chro�6graphm�$andem massBtromet>���CID !a �- �gh1tz/�-fic�"bzgZ;��,NCBI'wn- nd #-mSEQUEST*� E!*ofI$� �ti��A;ser� �%C��� ^#pET28%+a����]tagB$� ��eVms�.'����?s 7  Ro% �,aE07�eF IPTG�be�i2�.� �A�is�/%�a�solkf� !s!gHis�V3inB5(in 8 M urea8�@ �s �purx0)� NiNTq�q! mTl+5�� tepw�di�?to eliG te l, �&e� FPLC jc�!�u peakaL� �monoval~. P�%����i�Bi� rabb�(!B-���%֡��� �!p.5(E�%{GA�)�ASOdbo�f�:�(�I Sig�" ng )�.ti- &(Tyr525/526;b2;2�S)Tyr1217fSp97 [4�6�-HA-HRP2�7)(!7< ,QM�MU sepa�on 8%�[12%�&polyac  mide�'.Ler)=a nit� llul��<9M�a �. -dryU��A2!�E+ �f�2�R�.�NNe�2 µlA�%:��!�� ��3E-Pn-qn( RepliJAUB�zAEAǥ� .~qC�hi����B.�%f/3�  oR� e W . M[@eck Facxa#Bi��I  i8a PerkinElmer L % & spin�3dise� �s�9%Vl-H7softwE�z�Xa� moun�o�6 Zeiss Axid0t�M)�a 100×�,4NA Plan-Apo� o$�. Exc/ �llg���g�[ olid�te las))( Argon %T0488 nm , Krypk-*56 BI405:j647 �?8K(ugh an AOTF3 wave� th �A upower�}ro�A quadru�( bandZ fil�2yѡ�e9Oemi_A)"insa�)CSU-22dMcan$( Yokogawa �aj whee�/Pri(7�K�)�lvi��s��of~ �� �0 & RFP: dual-� 445/60�$615/70 nm;�: 527/5%ba}U�iman cqui�1onY�A ���ap� /s�Đa Hamamatsu Orca-ER cooled-CCD camera�A$oloe #�A.�x3Db�  of" �!� , Z�b>�:��RatF 15 µMa�ta\1!���reA�!�XYZ view4E�Wro7�s�#�"�,�F@FEI Tecnai Spirit�,80 KV . Rout�mor�3y%rper� i{trimm�L�fix �H���5$[ldehydK3%�aKw� 5%�$r�rin)4 M sodcacodN &� "� i�� 2% tanJaci�SaC,�p5Kfix�1% osm]�'er- -ace� e� �Aws/ @/*F5w��5% Zyl Nfa(�6 . 0�B %+r2 !^�Cda|� m812� i�KS2�� o�~(Leica UltraUCT�tom�@a Dia0diamond knifeAa ckne M$ of 5a��&-�:�elici� -@����T��*�,"a/�!�a%-tob�ay �of 101 E�4% PFA!lO��sl�in 50A�yce�;.��Q3�Cconju�H�e�a^ d gifzJatin Vy��pr� U.u[4R-Zym�QA (� m���labelmAlexa��carboxyYe,aZ,cinimidyl es�Y( Inv� �b2�#}�Na2CO3!6(room temper�<�01}UV-kil�by� 3:to��A��J/cm2ca0a�slinko�su�)u$ . R61'J5H"�|pX#��up �@!,qu �E�\ eJ�X2�RmethodA'$Flannagan a�Gr�#W[4�>JtSof2��&!.�%Vn E)*�S6�E�.tory -5�ab10��Su�or q2�I�inQ��2�Concanav�B A-FITC]�to��$inguish un;=ed3��I?4��u�)edia�  0�G&��tA �p�tolB.)�q�*FG� �E�~�,!�i:3&0 per &�EY6�c �75-�)�7e" *�/"�K:? Staphyloc"A$s aureus sGS se A�)�GGGY prob/�=�d�-n1p.0a$W !lE;� ��=8m;�䡤� y�c�� �E�� on c slip E>}in�y,�{ %ٱ�9���NH4CL$�1�=.N2h2?BAk ng B ��,1% Saponin ,2% BS�)biR6�&�(uA6[Á{�e�� : bod�R 6 �, s�al) s J�!�Ř��Z� ]�D. 4-Amino-3- ( 4-pWxyylt,1H-pyrazolo[2<-d]pyr�5 (�@A%ժ2Jbenzoic�s�aloLE02��t�6att "�NoE%(O 01/019829R[1�BAZa�� �e�� 3-��� ulfo�$N-Boc hydr�i� �cB.nrem[�Boc"-te@gA�up�ac� �s[ oyl chlor� gU8CL7m� R=CI-32756A*��= "=S�7AF%hhV�UeE�=mmerc�sourcY"nd e�as� e�U,. DriSolv an�us CH2�,JMeO�OF4DMF bpurch�%�EMD C��d�? t8N , N′- diiso"?ylethyla69 ( DiPE1Atri�Fo= QN ( TFBsY3>TI N%�ylpyrr�" ( NMQ"A�ob� �$Sigma-Aldr�=$. LC-ESI-MD\5&� 4a M55LZ 6>ej"MSg �#3$ , US�!� a Pa�gm MG4 H���p� Z � Delt!Dk\�AÅ C1�� 8×300 mm�&s�4A: � , B:�%�C:� aquea)R�as6�>Nm� ( R/A�-1�n -3-HJp�! 05 gpmolg$� iss"1Nm�( �L �sub�$tly�2CW39 mL ,� YAj> ��)�394 65 . 1 9�q� . AfA�stirr!>��;D�%�4one2&� �[G�r%�urA/r�+��"06�wA��br�� , drs'�MgSO42xr�cr�Tmes��� .n��� ( 20!A�Py�e 1�_ . 02%�3 . 331-!fpotassP �1(eD9 3�663=`>�'e�$-G%m%Btil TLC us$�^�-l�8con�: �2I dilu!�ť9L&SMp @ orgaE�:r%�Br,vJ�4i�E*�����at�( x→�}/ �)�;^<�*�;!qI6B5 diox�9�![freshl� aŗi� ( 355��D) ���as5�t 1 hRu�BIv��1E8�p58.l: -(e�a�=)�0� � Et3N# . 8A�, 1Y9X�F�I�22 217u�q�5�B�e)� b�,�i%ofMTJ-Yc�T�Y+���'%�e� r1 {X��F(( 28→43%B�a�� 3��affor� he titdEmp�, a�3 m��& 0U-A,';$%tI4/MS: Rt 8 . 52}:;=)ar�>5→80% �� ; ESI<,m/z = 44!�2 [M+H]+��H NMR�00 MHzD3O�]δ ppmv39 ( m&1HX�69-6; , 2446:2108 65 6!8d�9J �1A�!'8 � 66��64617�P ,>kNb15z,X��7BV�F�,6BV:,VJV. 95-43-5-�5!2�a�4B�,24>�I �T0BT>0 (�-�C8A6�!�A�� �55!�F5JF9 . 6Rj42-<3�AU �n45-3�:282:;/1 60!�6!80-6�.67A��BQ�e �m ]!l>(2a(�e%t 0k9�.�' �'e$qu�Y�F�,5�R,2.2W&�_ co�> �&�gin 6-kMdL;�Y��w6y ! ate-E'�_e��sub&�% lipi9,t3#[4��(G/� ol6 ��Z( N*LDAG*�$1y �&� - "�,[4-OSeei-pl�3ar�A�$ �f�>de%J�� ~� f2 4"4 7z ) (�X05% octyl-ß-Do���s(cardiod�Fb � enetri"p : &�DETAPA�2�& by vigoro]vorte�20m{M�at RT �i��1 B!2×&8 �!mM  e HC�pH�6���A)� B)d 2@EGTA w#4o YB� DTFB25zE.5oli."�)C �$ �]kee&*��6�S0*)�A��X%"]7Pof 3 µCi [γ33P]-ATP� p�iby _ { in�1�2��K 9�briefl�-�2� -� t 25J3!��. LausJ *l .?abo�Jnd6^? <Y �"by i "�)K velo��4e�F2.CHCl3/� 6�065/15/5 [vol/ ] )eJ%1 . Raa�2a"�S3:Gi#screen58BAS-MS; FujiFil�, � �" 2500!:%A�!* Q&ty OndE"%#|5-2h�/�a7sm>�2s(oco�%�,66,6 . C57BL/6eI1:�JacksonQ78 d�">[4�S*I'F�U<��l mice [39] ck�T��! Stu Levit� W�Nf KQfHVi�2 Tybulewic$�A�v�?. B�$marrow-der�.&Io� u;�\u-�1bIAa�*V( �U�6; Gibco�aY�4(HI-FBS ( HyV+�5% M-CSF.�3c7����+ L929 �$�"5���z7ff�:DUi(.�%N�JH&�)T&rlavag up� ml[2 seed!;or*��09W�*�>U��n�gdarFUc+J���,2��&w!�2�7AY*~5q�"�k)^16a��5Cr&�j���l�$Dis�y�� rray!qEve6�R$�I�4nof ��kia �7h��lCFU/2�i8u�7� "�admini��"traven�J o age-mat��,w"�i�j� b.}r2��" fi�5volum�;c�.��D0�Gnd{,`Red da�beutha�BE\ >20%��l 0E l�#.^�iEpnu�%!�I~B�L , Umy!sF}�UB>k2#jomY!pC�"�1�px@d��w;�iotic� a�,�$M�fi�$4�� 1f,&6$}�#%�~%f!�nd�"��7 H�D"� E-F��&�m(or Gomori M�@n�  Sq2 ( GMI�FG,f*i ��.�FE�4a Th1/Th2/Th17mV-�ic}# i� ( BD+s�(7SLSR Flowe�me�2�e�anufach( r's :_� ��A�cay3= unpa(t �6-�����95%�ef�bApt�W*ll(phs @w mea�]<(dard dev�sA�F.kS&j AGSu" l9A�E��;�k�F�[fu$s .�hRif�Flley fV� VF )@a.8-borne4 5VEs ru�0�1Afh�?�MadagascA4as heave�*�EdK 08–�?,)2ev-,3 l�b ^!�am�� spr�&�0di ��@�* �Ht-r+-environm�<is*|Vto optim�WA avail9r"u���surveill�)in.�. Her;$;oEiv� f�L�;a�: ( i )� �}�W�?rN!a�_ favo?Qto�t.3+,PD�2cat�5� ( i>r%� behavih^!� "FMal!�NtexE FirsYw�5K�o !O�E�AO�<ma M�gF� Aqj( M%��wA 6B�s�'�Mw5 colA+��t nE%s� �fG�5 Zd Lin�M�}M�u/ e���!vid�T.i�"u� �or->)�9� onJ!��1�,$�as )Dpo1! E�*(` dens� , g1� p��JaDs�*���E� assoc�KhumA2�(�x01@. AE�%3i -�A���<1; OR =��\FueVm�b,e:"& !�$fr"Bt�mtac�:raw mil$1t;W�%in�a� @�( ~� ~��8i��l�0LK.ap n-coam%�north-w �Is!�C��m�orF�in14. �L(g!�d`a4Rea:=�a�:-oAfh��ese�l� uQ)kg newU0�9onF�pa�cq���e�U!@b�\ }:YE�@.��igh4Q sug5:��a%� comiY va8a<�2�s!V c[]�to �� enzo{ 24A�t{a)�ine��;B��X!�1�,:�� 6)��+i�P@TCuj0@Anopheles mosquit�c,�2��' ablyYi��V�)��Tu3 1�{!�of_or RP?fb e�!�vZFmatOric� �i. FZ2C`Va n arZ3podezooc`c .belongA�+:8he Bunyaviridae�M!;])Z�Inq�cau/l�H%i�oegn�6=Z/Kxath%_new s [�NII'maj"r{ipf�5�:q asymptoma!. @ �m� s�-V� ,@ d w��muscle p�< [�H�kH(e zL*r�2�b�Lt[ �$encephalit��$emorrhagicL mm��e�/ to d! {Ru" [^!d�r.5i� bi�,!�U��ZY�jE���)3Gi�z0.lu7a:)bl�Q 8bo)�"�[��DPJ��l�.:�M�a:�i $B�of]&B] 偑2�has b+Dsu/>��pe�l AfrilRepK ( RC>!&Gabon [z0VxFcir�?E�]"�N�gv�y eco-cliIf�r: a;l in W͌ �nN e�T0set up� f�jv�inari�[1Q2T�IRP� !�b 4we�,&i�sea �V)^�Qmjen�2!�th� he _yI�U�wo3 � �4mea�'+ " �-8~![3VF!�ao[15 , �A2�%5�,�ut 700 �)i7�C%QrerO�=�xi26 fa� . Ai�2# ?!�- sO+� �Vw l�?% M nde@Ɉ!r�S2i�&�u+:ideA�asq�98646�,��hF2�!�A�95�q (+� �Cd�d ^ RVFV� A� �--�7]i !�J I5�5)^z A$n�E2�[P..`����et��2�"^ ,��}@ѴA1�urop� �:hc�EA�� 6���6%�5��vhig��[1_ A� �( +11X1$A�M��?y� pooa���sRZ�is@ nsF9v . Si200�GaM4 syndE^c-b�/2�?%TX��i%m��7B1�aVq�Q�A���XBeA�A��K��2i"}�� q� A~��m�sJstock�vc#��:rq7 q, �'�g aa r��6y6 � �v+Hy� ��b;6�i� P@ck!bas� �6>5i9��*e.\in&i~�T�_��6�G����.� "� �� Aone!�o��h"�i JA��� �|2�rob8aobe .�*.B:� � V6�� �  ��g{ !�KpJZ a&�;-�al:��y*-in Aug}fe�on�q50�l��%O� ��kn�c bree�g��E��eir}dbA�y ( n = � 432;�4 1;��;/��_F��N���u2 ��Nov�111!�$April 2012E�%Octob�U12$May"3�56 Os(�>�R or v��E�Six!b�M�sta)ulNa )&�I}rch;� , 30 adulrandomKe p$�(aRn�&��. Fig RP"EOcU &�(/ 7(- �,;,wk !�o7fesc0�?atego�3—bu6Pfar�F�lth wo5� �o*�*� ( �0�J/ }��te�M!^n ,"�raŁ f�1ti ) —E� docu�����Ld�~ed�.l�n��Bmn>�B�l ��%la"�V� y�4�Z�{��1�by�$l�>�� e�yJ �)$~ F,$"�mpe(86h�A���Ethic Ne�al &oZ(6z< N°066/MSAMP/CE+6th JuleNI��&�� �� �n�  l�" , wr�ZI�ow = !�V 6�7Q nteez&fPa��ipofZ&����!���5� �anony�!l�"!|f"� co� &�QG��[�toYir pu��0�nf�^�E�"��pop�bAMdyNcsa��  o&�wEpu�: Val��"6� comp�3� �e�h ( exi�� ��)s: )� 9v @� ynth,�zb�*Y%�&� ��`�oa� combW~@d�]l��n!)AP"�nd�Rdscape�[3�.�&. B�)�a4)�n#1%�V{pe�^ag"_ surfacQ�o%[%�JYA !Ca�:� NDVI ��jSf%9��U� -��578�D ���C��a�b�A Xm� �a�dis�:���b8 Pear�)Ig t-mo��"�6 coef[�s"�� � e>8�Er�_!�{ �F�&s� �2�>� �"� ta�e��a�A_A�Chi squ��/M�.kg*{m5' 6�+�f7. R�!w ���L�!�≤320 �ta�"� a�wN%in GLMM�Y-�5 �$JaTbinomi��K� +f �,"�ssu�=�A��ons2�.npro E�R&%�-R�g!�t;-l o %u1udr�l�cf2s-�2�us ��eeY ɇ�smc$��(� �—�m_e�� %)� ity/� *I�%- �5� �va  e�$�m""�!K!� B;!J�V���Inf�p�"� VIH%��c�0i>R*��f��o's.�a)Pƍ��aƍ�А"s�<-�AkaigI*�Cry�A ( AI_Wan ,Nsp�-U� �� achg �Vstle �-a� [�()m!mafE-!�I�9 2�ce�I�f��N� 9pdl-��f�s%aCZo��}e�an� in 2E}�':\eGf\�9QIT� � ~�<K /IdA:e+� �A0a���^Rec�r OcK�.2%u�!O!�ca& O5od �m�C*�n%al�� 10-f(]S�Lp�<%c . Be{��isEw�v� �.fNo�#e�l]KVg� appl�;toRV%P%�녡 /! I�ed��� .��m! .�;!}�!LEgM{ ��#`�Z�L�D# AI!�split�.4 �map*!=�� �sc��� �wh��s! Gat!l�+�9i~R "WKA�:" 1 [4�3. F�%&� �n� �o 69��_q ���U�*�aS1�.� %�2�"�Q�"��and 4�s�ur�K:�M���\ ("� -R�*`,]ё� [�Z3�;9a�!93m5ž�,);(�~I, -c=��= > I�_!=;_�jA-m�Q�=3`Pd�)sY|�"��*a�a�,�Lp�6�692f$22&� � jA��x5���p%i�&`N ��XwX2V�1k>�)�.y #2�M]me=%geC>5 ��4EYfeNositiv��=(��1�=3% ( CI�.[1%p�-�(8�7 . Ag /� 7APK5upT 1�–�" –6%�6t�57 ���.� �mclQE�Q����Aoartiles:%�w�>7; A� ?3; �Q�� !�� kil0.]� M�m526)�aMu9.�E��A�4>M�0, -�ae5!]�> �Lm55�>]�FI_mg*�,!�E�e,-�{: va; x 4��j � )a522��EZ&� ( p≤�2�<.>�679 peo�ZeJq , 91A�c529 )2!l%yu1��!9-5hli)urbau,.�!FolYs2�18!w99M�(yW3a6 )�2A tioP!�0!�male/fe�A�5�95%a�[�AaL�A0�}�2�=26�3J3E�4>�4�R�M�� r��M N�ingq��<3; ��7; 2A�\y� Z���2672 deʓe(�� &�'f�q(n� duc�Ezm��as�)�&�. A��*42�Ie�]e (%�0%5����!1�(1)���\:a4�L�6��X8)� . 29A�Bp8)g . �D !�\�0E*A�7�}�^�U7��QD5K D�`Hab~ , gw��2�"��}.�"/,=^^���c �Ʊ"%�n��e�݁iN7&!�]��iu�"w{a�-(�o!�.�~��w%r�" O�:�F�:#V"��H2H � � r{��� �"R ��"�:��Sg12:m!��t�-1A$ Y4)6�q� � ��$ >!)�V�H .ex ��MS�O Ik%_2��alyq /fG *��� �2�7"�# �s�!�M )re�:�r��<�_�")r���l�+5� (~;�)99; S1M���^A�B|!�-4A�N��Q1T%.=�kge had&c��� e�oה.E(*���.�b�)��17�!,ly;*�4zE�R�;2�z5( >6� . k�B�\at�Z58�| ��4]:�.�AI_Fs��)�n*��N�2�d{G� :�&5&!�i! l$ maI�fD(9�� sD�i�:dMXME2 ,z ՚hխ^�2:/!x���T��!"R�.�!I��< �8(. ;e6�32� 6–��3.I �4��U�0�� Ģ &�.A�.� {2J{neg�!�Rqb)�?� R3 R�Zr�'o-�=�P��%( RI =e�27Q�)[CRk�!>��&F>�()�aM62�0-�5!�Ϗ0MFsU5n�E::X�#�*Q� ��7impacVJ�12�les�h)R���Bp�79\e�satis�#y �'rea U�UC� ( AU�of%��L���87�1 84!0A��G2(�/oM(�lB�!�lY1��]1^���3�9r� erro�_��14%&�:����R.LMɁv �e���*C�A *a��kBavoid biW �iS+(��U�I��� ��e2��g%riL'�*f "q C�C!��d��"&! ��MPb�>. e [� �!�6];"�36��� x-�:1^c9�Eh6�-of.��@ig�o;5wNinet�5� S!�n8� &�2�76�7&{3a�)"�/z�:s� �)]�w��a1�O6����g25A�Ye��24AE{R��ep^~�� �(f����}an���Oz�a5ndf9�`�. �!a�M�S1 Ap�ix . �61:� 5Bwid� �72G1J;mZ&p5b� &�%l+�2�'�/ld/;/�w8 �^a���s w�194�-Jsq�� !P:� �to Z6� N�)��]�!4�>!m) 6�^Dc�( @be*G&� �o*��"9� lT�E B>Gr;��2�Z�,ژ!so-�ed�"�T� �!�.� T5�t�-P1�)��m�<&�vb�n3e�?ten��� U� �o�ga� & [5�o5r�TT ���$"n��R�M�&� �raa]� �Be�N`sFHi-d� R5hE��M!�1���Ds��tlyM��V�!��� ���HB`E� re���B�1h&e 6�=, �(�79�\41Min�K�1�{=�t5 wNrt�)!gTinep!uu �sA8-�Bcvi�!��� �J�-�i�:P , � l:�!d5q�4iX~-*�K.f V*�J+%�"̗��)-�2k. 2��!U�."]:�Qbu�ag�.g:s�e��� zPө���}o81�c,61 & .�> mod_i-�Q$�� !M<11yotte Tq�?!Tanza�gM ) [2�53H�*Rtin Kenya�SaudipPPG� A6|Uqv��:"9ea]� in G�ac ��I�"�5O�,vamO� �Yq�d���I�of.v.+DZ ai��-�QSON�w:��!��&�5�b�th-*�JD'�Q�[!�OF��s�:i7FI�$�e�Q�+ %utu�L&\3|I?,U4�))�u6�M@–)��S�&�J�T6��� n"�\506�Aɥi� ,.�| : 5 .~�or@�arE j �$� 6��24)� w�3� �iZ�,�5aR "Zd"!�J�c*YH�8D��z%�"�Y� zoo-an) pophim�f&:] , 52]:o� ��?u��l�K%�>, r|2eD��!9�" Ox �&? %�"|,A�r��qͩ���O"x�&� ��[�. D�Va� � �VA7d �]d� n�� &�>i�Lip/IN~ !́4 �Ka� P�"�m� ���j4 *��1� .;>� very�w� ��*-2 p��.���wa72��Nstill �]�, �#in��� s un2 *s�9�� Z�/ p � g�d�:�~�T[`�6V"�a�)�_6���\So�Z]�Z]�Z]�Z]V&k2�.#inͭA�b 09] �V!�B�ab�I�:hom��qi��xr�= $"�X5�X&M �S0a��!��0�i&� �A�*N)+������*&]�Ka�i]Rs�}K]�lefocus&!J�E*fd�A��U_ ̍*�!c� e�E*w;�o-"vYp�sc�nis��lat^i���32�m2�)2S�q��)�FBZ�o� 2]R���H�1aF�( � ڭ_X ��_�_AT� �!��N�fuI=�4�� �� uo ecip�  v����� eachRE� �����"%g$Rae�Pd�� !hh%S ""A��m�u�s oposi|ao�� iRg�4A�"�X.�����r�0f-�agi�"H�:bI�@ۣ5- A0d�n��e"��i�2�Mei�� g .)�klog%^&��&� �,aM� "&�G.6�baj�m#6��F5� �����#Fl:�mecgmsmi~��3��/�$ a�84st Rnq1/[PIN+]�Vex[p�d�&Ay�a�&!P'�2��. R� �fKr)*�(o�+�nAl&�Yy�� A���it�� �M�a���$ sAn'A�A���w�4f�1�te QNo�&hW+�rR�� a�� UTaںs��3p�a h1P!*2`*���r amyl,!E�aNȏ%-_Z -T c� e�8�NM�&> of4 Hse�� frag!�sO ]��D o2�.���,) ;-�6Larequi�!�us�*<�s!�.�;Y�j desp�Cy�q$d8yA+�.Ji impsbyY� &tAmen��s*�.K;��ab"�)a�0 [�mismaLSR AtU Qa&��� mp$f-t��sr]ac oaF�to�O�h!�q P "-n���Ys�M ��1� y� clHQd���a *v ��-����j�f� shee�m� ggrq2e�Axq�) fi:��$B�Ϣ��1ta���op!����ugh)#5of�r-&�β-����per�,�Gr!g)`�Vaxi�lEA4! �,�7*.~!on�D�-0��fsam�+inM]Q�5iP1 an 5J��se�: [1��hfI�d�u0�Ps� �0��de�ig hallc�e�W�%di�V�sEdic�ord� �!?�sz��!-i���^a=5\*�/^-�U!A-u! %����1E�O�M.�A�eyU" u�m"UMdaught@Iel < mit��Ase&!�a� M�li��ash�Aei4��A7[PRION+]��ig#i�"� p&�Y�Plm ��p61F�zor�WCjly "���LP���w��!g:RR�I"�- �s%�loss-of-�n m�Z��9�J%2�!6Swir �Ie�"%�sol�5�bec�%`�rAGb!Y���zexa� 4ۅ.-L l� tb} � -�-� �Zxmead� �top cod�|c)�T 2e0i�W���:n�\o>52Whee�fE�� phys�eep�l�kmod�"r�A� 1�v egoPI emi0 ��%f� v ��[10��2�P��:F$2�p���$ ex���2��Q add! a�quM!Bper toAǚX�&�S�#� PmHm�ssA5�H)by}w�7ac?4ledHT��a*ex� ���1!�"PQ�Rs=<4un�6�!�A!aWM��3�"A5in!�gal �0*&�aA:�E.!a�#� tena���4,����A�yy i��s[r����Iit�T fas nu⡝/reco!'!asi� !� 2��& zTe�Y ogI�j:�#O�6a6!q�!2Q* p�>�pRmX nx5o�uK�4sh!3�% %��� lappAjA&pri�]N&��>��y!$ �h�6to%% i��g�r � ��a� z�^�T�bo<Q%�N�{id�_,�:B�*�T�"%Di�t!�1>��ys2@"�1�m��6?��a��,�A*�. ,FQ.V�%�"b"kD1cb�lL+�d"a!$wutyp� ���7llwe��!�2N ?v�92 =\*mA���nea�# 3�;V=M[oU�en�]�%nJ��< A��taJ� E�Q� �m; /> Fw�scb!�1Cs/nE�P$� .��i���-���faithful�@�$4 0�seke�UI [I��4oup� esumM�>��P�Qa stret?goligoq�repea�(38�24!6 Also!7l�Ż�0� '#��IH a���A�i� �t[4�c��.�%#m! Y �.n5�1�A�,J�]�q� ,]�9ve*nVk[45)E��L� &��I �� X�Z�]� �)�~"f��) ��������7L�2*un;2�ag$T3�.ndu aa�]��N"��.A'9 ���xom*� l6"�� �3t�[��� �-*dpa�typ�-(m *��� b�/�D�o�6E �g�%P�� "�3A!s n���� � (�� �-!(cg)- "1��a�d�-vɻ��y�t , [�'_�Ij3soy j0a8AQ��!z�s�Q�hs�[�%w�tC�&RM� at�D�o�`� �� ^ �\����[57. 5�8N�0co-�&�k)!���p� �1Ym����$A-� B�Yoxi�`\%-e�~jv&�A [60]!*�碁� Dt1�A��h� + �B�4�#����N chap��0 end)�s/cytos@�iI|"`9� �[61e�6U{CE&s;&I @.Fz�a <�� ��Qrup� � NQH�es��� Pin+�#$d' , rnq1-Δ��?@ !:oJ;:: %�*�u1 a" �ain ubc4� s [6e4S�s��ay�~c �o�4����ab�� no b&65�$�-s�Na�CabQ�JRm1re� �:sQ&��  sI� tJ����&q��r�3i��r�uis keyH�eu���=s� 6 :6��I�A�#�a�R�kheU=E�Ɂm�C2( aa 13-��<�5Q* "�P�% Q ����. %,� 132->q m�X�153&p �h �wM0f�8to Sup35 lackin�g the [PSI+] prion domain [33] , [65] . In vitro , these fragments form amyloid fibers , which can convert [pin−] cells into [PIN+] [15] , [58]s6]sf�se6�Xboundaries are correct �n1 format� and �$tenance ofqtis driven by an extremely long9complex6~x( Figure 1A; see below ) . This5�ity has been noted previously [265ZL, however , no syste�$c analysis�!�rol�tdifferent structural determina!�!�PI!Xf �per&Ted . Here we show that6�(of Rnq1 car%�multipl5�.�>!�0independently)�E^ �0. Characteriz)�o!�9K6�Pallowed us to explore2$individual:.�Aoveral fold!2 transmissA9�� state . WA[und �!� abil!�to?tiH 8isA`Dintrinsic propertyd�.�/ �@tting regions: onA� mmon \required�gen� y sufficiA&for��-~ betwA�%�y�. HU�e Hc� � H> partially%Z lapp�:T$is impededarbEBrs due!>Q�ces!�F�s creaaHby co!Cative ace�ofA-y.Lq�type>6��AoLlearly distinct from.�discuss�7i0y aa mismatch � l2� . AH ensuapst<pB�(���Gn ) ; s�4te� of dJ�%Tsimilara �of%$ 1$��5�S1!� . Fo�!P%�e�co-1honGRt�2� `toaVowI~�!ferE!�.�A %)~-�$ was shuff!�ou�!G.!�EXof N)�oad�l��, hereaf!�refer!��s mini-��sA�sco us%h"� indu�3$assay ( [5�9]�� I*A*in Ma��al�� d Methods��e Qrel�o���) � �)O$he de novo��)� !% >s�rI��yei� -��u�?a repor!1�rte � > . Our.Zie��4e SUP35NM::YFP)9$er , under%�coe�La tigh��regul�� GAL1y�,��ade1-14�, aA mat[ stop!n+cha�$somal ADE1��I��to %�,appear-Ccolon!�by!ir.� grow!�media�+adenin��T!up-fp fus!�A]uA�aA$ auxiliary�du.�%��� on galact�kwum: it��corpo��on�Dnewly!�m�aggregat� a�)� ir visualA $by fluores��4microscopy [70y 71!�� B dem�6[� , iieliV ������$, cul!�s.�Ndэ��n�� re�7 ed Pin+ (�� data! Δ2DE= Δ3E2Zv e 8pheno��!�6�: aaQ� opaga�AoEm{i .����:7los� ���s� always acR ana^I�8*H becom��T( 12–18 Leu− clone�re! zed%$ean %� uct;!ai�s.G mitot��trof6is �k a�a�i��s�:ResulI�ludA�MM4�Also ,:+ sus�)TU�d� : ceŌbr�M2�!x::Ca�oci�'!�c�(in diploids� A�se%�EVU�� y�P9�5:��a [pi�6�7.!ApCUP-�::CFP��1C;ݪt� test![:�� �1 �-Qe facS a� pqJ QN1 , QN23 o� 4 exinn� �2o�7 tern8 .e<a!g e reM�!@ll.Q X QG10��/or a& upstream� #�ap% af�ain�e-ab" * ,��8ed highly unlik�ba!9on � ie��ud��of N- l)���"�t��$further exa�k � �� �isE�Q�W e�T lish���-V1�C �u� �spens%$:Q� � experiVal setupykS2m)u� A-[E�is loc�-nJ� , bu��m%�&�  yiZ, suggeOfat)� #e��!�"K��U�]@6Gsup� )��ʁ9 v . ToFe �]Tcould� �-AR2�| , b��G ed �YU��three� *!�w� ��Ͱ)-o!�Ba�"Gin o. Incub��(proteins en�O@ only� ( ΔB1D3E���3 C2�$ 'C2D3 )�rTThioflavin T ( ThT ) r��e a shif� �!excit �spectrum� in�sp(&� 4ce at 483 nm ,!�ic���mC"�"� 2� Sigmoidal6Skineticn��ist��K�.�a � -� E@nu��z stepc� �, th phթLQN1-bo -�%V!T%jdid�2�5ׅ�at very���� r��AͳA��of%� QN4 � #exc���at eq�oA&>^! lag �Fli1h&) c �A�sh"�co��-#��W4∼15–20 µM�e���6� reproduci��2l-"Ga�30–8 brange]0BA���n�'Whem 2D se�pre��komolog�%��\6�a~let��% ed�CtI; � -m��r���!r��p%�ee�be�larger>���� y�! ed ,a�a�iv��2yp, imple���{ine� ific� e��� 6�y�Ef S3i�F��3x�rMd2� A���� ∼80:K2�e�de��er%�a=to2j�����at QN3 a weaker2�n��i$.�!�edA9�� alsoB*[=�F w2+ curv� mRd s��A3a 1a20 hr:�observed!�ardle� a4amoun��� ad�9D[y6<Such unuh��p&�x�n PrP90-231�. [72] ." �E����� �!��i� temp� ��beYajin� A bothk!8ak( , 4;Q�V��, 42 ��e�lf�ed�� �goa e�no=�� s!ޑ�( ibid .�8M? a�I con���i�E�i� V��mad� om a6.( 3 !��a�}*� $�� om2�s�can taks e�zmbi��o!. . El2on.�1 µm-�ܭ�ine>�ǁF!h!psa�s]�F��H!2J L%^Fib}� ��85�iIam36unbranch�D" f e��2!�m� �Passocin A�j�'-�ir� ��zic�l � �ureI�di�u�� r,�uwwB;striking��&Voligomer pec� }�s�ja�Mvby-�am� !�r s [7O 74];IY k�reiE lDse��Eor� ribu�IirH�a%�A��.�J%�2L inset%�S � ,A:�aC� TsamXn)]s�J ��2IQ2MkA��*� A��_ �EF ase-re� ant� �q�e3pap%�e]�% �bec� thin�( <10>�Ha � 3 smo���P�!0�� 2rthA�tw\ d�U ANoRinM�9w��"�c OU��! eTob/ 2_%�q Unex)z ly ,1.�t,.� all)7�* �8, although occa�$al cluster�watypical�efew%�r�# adBw�'still�(�M�9.O !�T&�a2"� ^"��Y"0 ��6.�!�Y �g:%�A�3%�A3. Amo��e� !=ia� ��3�re somew��5@. Lacks+ �QN1:� 12IE��Ztch*�tor�"3 l�"dŵirm�Qe ��str�.�2U2�N12 _F��"A�TE we*[B� �peptid��rresp��!{� 1 �ޡ1di�S��U���Q�Ug3S B� F�� lmay fun��^� .aJ�To �"u f����M��E�vG&oa� FJ��"Al!N�. e�tw!Q~��substit�u� 2~ �^[z�.��CC!!��& %��l� �:��Lb�nJ&żto.�s!�e5ase�c 4 ��YA;)&�%��2A��is � *CiC�� E4 �%&�. F`��, low-| F at�"�wD i^!@� �%^� ��B�^�� �p2$M ieEi2�>R���c"�-���%3rei��in9uUa� �| ����%�0e empty vecto�}6l!. Oi���,Rn�m6Ump6N1E��A��o�!ge� ,�P( 0*/a8!�2� 9�A^3B;Itno��e-�,er�@�edI2�h�r� a�r��)�6Wsq �&no evid�!�;��A�QN3"�9$�taM y��ʉ�@�in*�e�!� ��s� �" solu��&�( �b�e"�q�!]9Ll�)�a3-w ��.����a��nm by a� usep� yZq�AKZ�>�A&�6=]��Ft!�rm.�@ agree� 4 �4tro��!��m�H L|Z(�rei&'�)͍a�"` "���n!�!D q(t�&6�-�QN4-e.�Y_�5�2E� y$j�)�fɛ%,U]jT[I��^y� M� >�� #,involki�] �r�a�avail"��!:.ioM vA�)� viVA� �ta�to>8�!� pre-�Z �ie�:o�x����l�xpy&� �e�e6�$,'"� Aͩ�/>^9de�a�hbV,7 .��t��%Text S1��eG robust1+��"3�h�s�c7 �i'u�1��c�+*Xͯ� U��� )Qoy `�[E!��nJ.�+w�,no!��m&J?"9 :DJ#��/Q&" �Ne:,!�nt�uA}("�**��u�,� E�voN�%*o �+onA�s�a%��cc=�:{ �9�NB fUI�3�3�unotabl� duceS m"d! origiLm��'> quantif� h�d+�?�-!�u� z� &8%Ku��n��,��.N a dr&s'e��� �U�SX. R � 3Irref�� )%* y(m���.in"�Q�i.������!9�Q-q, i . �'M� D�-;��accum�(a=F�):7�de��A�in"� �v�.��X*�!2Y nq1 �� poor5 � ��)by6��"pr last2�i�c� e�� " d!�D����%f�n&�!l]%�uY_vu1� �se_. �� f ,M2� i��%u�)y purifB'��.xo�)/s ed viae-PY��+�3�(S5%*a schem�\e~"A If �$a� R��yL#sgMؚ�+J��!���. most97 yiel��%� �:o-.u�4 !P� n�"��m&�[����B� lead�!�)iJ�(I(.B�%F�(x"Y$e!{3��@� us%#&�])AŒ� X,�s�51,Msed�$%e�5(E;�ig��64� ' ]!�or=a�6�varA�wid�ZFs��u�i(^a �!r � �/� s up�> numb�nd � t� �� � �S6%6M�InMta�i�r��7d&<de� !eZ5(�y�A?�I�� A�o{"� �4`�ɷEm&2 gen;#1 ,"�%h} � ey�� lys%-͓��P a9a�@N-�"1Y�:4 EN2per4#ag%6:Qy�D ,57 nB�6n: a�4x&# e�un� ���ly�G-ng6����7�6�)!�2 &�-:D +-��[A�z�,� ��3d5"!�a��G2-� ��H� om��+I2� � �G�ob���:�describ�%gagraph*�AA� �5 deriZ� isoa>To��z� J�-� =�#we ��em �$R (SD-Leu , Hi&t}2��g��3aa�v 6�8P"�%5Y�B;�9� q��yE-+�U:��U"A� on�E�6�=9P��e�Hli,] e Z)A8 5�Y !�SJf5�A�� )�);o�QN�-p���- m�Q�� geny.\��S�� such6Rdse� �or:80��{$a�aR2c�exten�I���&v&6�GseZle.�NwAk���-�"�%Y\�~="&�,�Yec&>l��y�Fe=)z� ���0!E!�N�IVap<g>�C + !^m!�!veZ] 9&th+/&fpost-S *l ,Em/������\ivi�.1�:"B7� ��8second r0>olo>���#g%�9q:l !t2O4I=;nus (%�!��E��4� S6eE� Qi.�wa(.stI�*�""7 x q�,u:�:or soon�. W7fvng0� �Cun R�}C �oc!]��:Axh!j>~hallmar��A2�� �M@approach�$� � qs �:���?AY>4i� �:1� �IraPal� �� L !.aR�>shB�l�S-=ly"D M Z� �^.1m2ΔCN3ΔD ΔE4��qᡲa�B&fai�-� Vj�tA�0by"u %g�4a.�$ ��O � ? �!m�estёE��*F2A�y5�.�+4CE�:��$ɳA�tripl�k>! �C2q�6bA��;s:@)�ed:� f�,��2�str;>o����V�>��"^� T s�L BL NN * 9~n`>r-f�"2�I :]6���A2?� (e towardsIZE6in�D4A�[4%Ad(�-&in-��/ ; MKE6ID unpu4&*�+e�Si;� le7E�Z:��'3goeMEy���.�j2�5��f!8*��#a��A��,N!� �%�"repeat�f�Ic?�v+h� "^�s ;��2{-� �u a� !# A�mov�1a��2�=eat.�!�Dval�toE$)Pty�q*"I5s>� is�顒��&Fwax5�C�5al trun|s grapE �D1�.v"� 56�8�C!�ris?,Δ1/2 3E4 ( �6�� :&�22�-ly)��3���!Aof_</3`"{VI�>ea,E�e.int�9H4�2,��w� ~"!ӥ-ve �B9no�'to9"ep?2Lq�!�� l2�-*� Y;`!�76E�� whol��e^A4�6 ��<29�~s �C&0����6o)�/c@�:Ee]a�e�ear�"Fq.N�AqE ��a�m)X�5 ��Y "�} >�'Al!K prec� non-&�e )"*Wat �9 vt@duniqu�re��9pA75�i��"T6)#m��!r�+!)1Rb� prog�E�.)�2�2�of Vi�$ko et al .�:whoze�3�&J &�yt)5@,L�6a`B�!�� (D smalleg%3$Gfp-tagged�ly�F�8. A` fe�BR�1&A�n<ng pat{<0u)��,hGp;H� �u%~aUQ�Q�6e1�u� p "T sy� e im�q.9a,���Q�:�U�a��A̭Een��Q� � N6} * Csharp�8NZΔ4 u3E4 g�0 r1(NFir5$i9Y5){6.�5f���@$lea�H3 ex�1�6.� 9r9�Δ2��t�� )u2��1�!D6Nignynt"� ce b�KΔ&2!� F3E= � �S9�S9)"Fin�,>� ]?� , �Z� _!9 a�D'U�S2 zS2D�#�6���s#KEEj�Qh.3�o� � ���QGB"k *d �)�ɑU�!_g �n�A ;$l7�hig�6� ]R�C�55!�5-9b�6IG� � )���13-,�h�effec� nR�s�s4(maiI=�y!�oft9%��8i!how��A����0seJ ��� �,"�%es&�>�<a����ha�P..4 m�> e6�� �k 5 -�FJ%-��.@.�F1E�&6se!d�C_a0 ��)���\�6'4of� %,� mode}Q.�al organ&�T � �$e mechanisF :� stip�$�2&�}:�1�%�h-45�y�� ! exac��Ra՝b.�4h�Bg a� aT#.�<���>� *�4��MJ��a%;���>�<�Pci(ip�H�D=� � "� =T.�%1-j !,��.%al���21�Z}.� A�lso��An��q+��:g%�1�V��X"X��!�>|(�&�!Ua��FS%d�O9h)�<f"q predi��aib�Tde&�HS5eD:y'  (&7�b�reciprok8M/E;�.kJ�=�X9�.Y;B_�l�2[1y�[A-.)���5%�occur a�.�Ai�.76�46�- *i�XI�F�&>(��coe� �]`Xg"X=P%e�%�4!_=o\vGl�3.fj�-�s� be*! �H!�.o)�Z�G"e%��ɰ�xG.�+)YWF\Y�u util��n�"�!i?+�J:B� 4B�9 EU2-|@�(QQ�N�F:aJz7 URA3>�O�n*4 Tor9&�� BdxZ+�%r& � �P�)eo �� & a�� (Y"�"2,&1B� T'5wA�%�� [URE!?�be�7u�cla�CE�r< "�%>���t�-� (���pa I8C.A�#cea�-��. U/ �<Ae"�C3 $�A�enta�*�M��ac����H/Q 4 .>�R� *B�S B��i2U##� >�� �#A��e� ����voRuchrc �*�!�*���_ :���"`ŗ�-u�had��o5�&�7J+A�>- !<�-�hro�bx .%w^u�Oq� O(`� "� )��=*�$E�S;lim@HU � \%"��U��$�*"�?5� 9pJ}6(��.))UJtoo ��S�$.�G,"Y-engag�'β-P3n�V�"�d�fo�:%��\)��w��acR>6�*Y&f J�.J�0'yB>t�,n�>.�2D�"&�!E4 ��4��E�J3� �� ��%� JC2 �.�"�Lr./! Lof~,Wm� S=QB��agF� 9��%s�;"�9�or 4tves2iRi&}xU�alwt"a*P�*�6�X�S�"=���`�6ɂ�"� 6��o�5**c;"�)WW7, 2�*N�w �F�q�!_�N2\a����e>g|bea�"#�vo2�����a�I@��"�;"a!!e�H-�A\�����)HD>"%��Wa, �~ae�Q !canY�D!��M�M�ݲ�.�Ofav�&|�XC�r�P " B �e&HE2 �Hto�eJua.�{j+t�,U(i&�Tort|�"4$6 XBv�!�7E�1FuX?4#1'^��. BMs%�u"�H)'!�j�I�  ��(f��}.�in �b,elZ�#�.�h no Y�idu��at�A6�o\[�g�c�QpaqEam�K5�es [75�OI"AYs�hY�IA� �q0is�2�&R>��[�߱�k@ &Ki| �.*e�� 6���I!�NwKa��:� er*�O�� "�H�OA�"�Q"�3�jotJ �Kc5So�% Ozb �F!��a- h�\il�!to{.xUo#YOb�:322m>�=)�wi�P>af�7&�kiڱ[2�"*J��$o�`RX:YTa@SAZr��&:3by|1� ump��V �;�`�F dono�K!���q"�!( &i'�cjk'�&�n"�j �"=E4�%;ezDq�) .�2sͯ� "[A�P� �Efj%ve�C %p�/Y | W-�� �E4A6Z.�a��Re3#cQ!H ��DA�yE�6� )aˡ�.?e���x ab�A�#�as8 �mer5 .�-i�` E��!�� “(e”��o= N (&0 &��@K� a�B���a�! � 6�ro�7a2>&�7u#Yf�ua� ur , s���k���AY4�'I�I@0%i�v^!u�:jepb�D!�Re�A4�? o a@cframeqS�s&J_�� ���Xo . Ou�|)L�r�Y�"� &� *� p��� N� ,�er�B�;�4:�[ iz dE/pa�Se�%-��shohe���m��6>SF�*7%6B9re�88�i!�ц-�Uɥ�Oby Wickny`"&q&�lB�!�I153-405M�!�$^solidM5NMR; t!�th+QwhileB�E6�$ �n��k"p!���6�A�w$AGy&e �ŕlabeled.�,iof�ch*�`� � ? : �Fa��ap�Z�Q�HSZl�habq?UQ�# s*�)a;�&U�9~4���s�T ofuQN� ��~b��!���06�Y���i,S&E�vɨ:_H��8�$ 0:E4;�q2�2>2:>vJ&�&5��dueA�.�,sEei_�--"j5QqO�MaM�aG*lf-Q�Y" [49]e�� �Om�b����,�ce�nOMe m �6�E��+> X6�-c�,�&M^!� 9"�"&�5N _ E�S�=De�i�0!A�lig$1�3i�,"Dom�M�"��.�S 6^�} �er &@&� ce ?i���@ iss�a� ��n)6Iva��as�,�]Sxwd�E.B��y�1�� w&�H!�,AFt�]U%ngUy!��O ���,��i�X$�040V)�:�at�[90*l2"[3��A�, [50��*�9�M���$nd� !C`2�M�%[�_ [48]e�1�� � [77�{8�aIao)� ] � ���%Hy. ]&ire�".�Zl��Gbn have F�Bf�>�PrP [791 � ��Wa�Caune= 7)rep0bon!�fh)!9��L�%! s [8�oj +o-)l�A$:�8w-Y[4/ asB�b�-�� �*[81� "��2�>�3�;@SB&cr-�}� de�"$;&wo 19v�+e� PQ�L *Ure�5T9[ d/inhibi��wN D&t [82A[Y�%X>��{�k^2��|�6TiQh!�, f $C�A�nds�HiI� �ea4Z6 � @da�/nd�lof�%Y+�� �&^ ѾAh�2d�|��&��at"4y.�A��6�$7 �<�����[trace��DNA2"(�|!,;.�7�� C� �B"RHno-u�H"hYa�2}�UgG(t2n-1�S!8�at� E��SɲJ du�_�\ndZ1h,Aic ye0K"IC[2�*�},�"����O%�0�&H)�^i� �� �,A=��jtoxic�of"�!�,v�JI�VNfw1-�|�}.�1% ��#�{+��me�`M�e�if��� A�elf���*Q�tJ� sub-Q��XlO3o impr� .�V.E %bro�ua�E�rtoM!$x�,eh� �h1�� . TR����@~ I�3�A�" t scrapi���e#a|Pto go:!�mice [83�Ma�"� �BA� @�� APEsa�&�~�&�R��A'-�!�~�J�7ris @i �ng huma� ^s�E�ir$�dom�n im�x.�0hBJ�vo�[�lammaliax)ir�)#�F�s"�(.-giq�#^Um��&!A�+�[3i� [8i�8�A searcha �el�of��bs��y�3��aaJ]E�,|�#�|qtklne�$!�2^ "\A��~,�� recogneelhem. Accor�B�7,6n�)���talJ��;A�� �rQk�4�%f� critEvAuB�Z�.�#t� �c Vs�ate"�,aa�����Ai���5sE�1t5disrupE���+h�`17&$M{e)8"G$� [ , [8� [87�/�%0.)� U�Ms1�& )2>`(~�D�� �M�M?2:MNS):�(&VS� A�!inŖ� ��wh&]�#to *J/H�2Vt�0*}1 w0d�<% -A�n� olut9�:��.��m�ZAP� �a&tu"\+N ���� �@&�%2��-�K�!>P . Wz��gw"��^�5% &҄=+&��c�+*� � � D2�q�.a�� BL�ex�if��:��io� [0 it w��-n�/s�"*K2Aassuma�a_@.�p� !� 4Upr���6�J�[m��[8&��Sf��A�os�� A�6f�.{ �mb�^�1�!ڕR��}� "ywV2>1.� �2�#o/om�.%/!�:A?���.�+*� u�+*�$��:U"Z6�Re%A� s?9tim�F�A�ya�%(2��/#ta:���%;0��tch��n� EIx IR�Q&G-,e y2�-�1�:iff�� /� IG�["l�&,m!�u� |4g�!F�2J��!��H�Ho����� � n fe�A>^K A� \A 6�� Kb� �cV�5 2x"�I0 ��v^�<�\� �*V6a2�ci�+q+1g ,5I a ).0u �)u5\E�<-�)fSv?u��";̀�'i�I6�� A_���o I�a ~�\��6espitE1>sa���~��� pBj!��`� A�.�"�^ B�90 �BJ�. U� ��*K��, the-16ue �R�"1p�1{%)!��F2? TxpF�g)� )�.�al.�9�a�,Si� jJqa�^DWq� V�ai&Gbe6��dR.��"�!%BT �J'-~O!�*� * MCl2��e�e��"?��bg�e~2U %1!24��r.� |m+��fac� /.� 2�;� "� +e�*��_< ��6��u,f Pis *�xb. 5. SG�Dg� 8com�z�}5(:tr6R�K�� � y)� ��UF]IBI%�!@���AM�،!�)��2�k'.+Q�^7.� Fxa� �=�&8"L+�. I�DE.F`U ��$�(p6�'@. n"�>f� E�B�^&6{^� r�,%>�a�u�$',2dqo)2�U� e�%�2���yt*%�!l ��Q 74�( ie�Re&��..7�N�RAgy5�$I�wQ*�R"={~�(*�&.f)�\�I1.�)w�Xn�r!0�u28��afa� me n�G�%o�h.���Lbe�+s|!�!M�7de*�Y2 U$+lo�."`on�F.� �&�'� � d�an�/�"��+� �+ %�in�!�-��#.� �ag�R_�x&�"��2unE7�n<g"�Fpro�H!�of1}.��!� Gm�ixx + �T�^�"Et+6[&�%� �o�?�� f: d-�R��_iG1��%)xB( U >JI �m�"�out�Z[JC� ��*�j`�3�#r��!i{.b"�49]–[52K �\�"%�S7�tJe�'to �:bY��^j��artax�eV�!f�t*J �*2'8 �<l����"� ^)i Y�c)"*�2~��">N|E�A���aŐ[ps�an-B� s [4%vB� >w .�QR��v" play*�oR%, TSE epidemi8y�.�\�.imi݁�sp�qA}��8wa�g� �-)erK)�� ���166� 75 loopOp"b� �^.��c1N�[pC>%[���!6�_in�&:.!6[9� In sumCZ)��"�� M�bl  �9 iک�>$�!.��[(![�ype�� E��~��m�&Forth= "&+I+�$B{ �"��C>���� help� � ��!��.n��N� elucid& h)Q�d6� . Pl�� �Cc�f�>Y�D�3�elO ��esa��z backb+%RS416 (]? )� 5 ( �? ) CENWts�}V?ORF� ��� ).n���(C?!�GTa�t[��"�0br�.�s E�%nN�dm�2Dy)(�?I�c�M���S JC45��/h*�>$ly 10×HIS%Q*%In%3 HIS3�@pGAL-22�"�Lly�J�U�fp�1or�,[52� plac�Nd�!E6T�� �.8Ap�����M���^m�<7db%�!�to ɏ�5:�CUP�+"~�M�9�A�!�%B}A%<!k Protocol�p)Ts, S�"S3�nG_�LF�V�Jl4 a` 0\ri� !9of"_�( MATa˔$1-14 leu2-P�112 his3-Δ200 trp1-289 ura3-52; [91]�!������! l!!1Y1�%�ue �N^.G4f�"OC�?Gby GuHC�e�~[9$��>;�[�/h��i�u$iq seam!K�6��Bte9�u�A^integrR -ދ_ � _[9&�RS406�A}�AmmB$ID130 o�(� z"̚�r�0EcoRI - BamHIu� (U\#19EC#3;%"EKA@)ɕ\dowj;e��E�gen s2y SacIyRx3z9 #3�4. D�U1d ')�] t�_m2�5&O�����A���\<�\#m� �Ef"2&�T5� c4 Z!�JZN�EZ�� �� moni��h�c-� lDr*�F=���_��"CO�*ha��[+53�}��Kd)�! -Fl�� >�*�5>e�6�) q��L1 �%m�\�E��>}"��MATαV�lys9-A21B����>{A8�Pe� 5n�R-� � �nq1Z`n. Sta��d��a%�5 �I�jced����[9�"9�"�2� .��>њX30°C[ 3 ynth�4 gluc� �( SyUPv$&Un%wen\& . Cu��!�B�'�, ��[ qui!�gaK ��YPD�8�t �� ��e orbinagj�at ��rpmarhe��!�* � �]2% &��܁�#0carbon source! Gal�CUP�gn�#b2�� CuSO4 . Mt�F&5-�oor���Q�E!|9�:�/.�� s [9J!%�I%%��r������ƭ���; �Je] �f69]%� �&�,"n.�\a�� ? <  >A�OQ�,� �  �#%&;]��–�#4T�eAyPc X��S ��]In5.r�2��2�.2k � R6 ���� "�"(Y��e��:m!%Ԟ2V!Y�u$ut�:��c�=��v:�26KM,!��c� Bt a.turi o�#��e� ��)a6��!2�Z+�b�a�Ӡ codo�,% WmB٠)�Mmuf6E9��C��:�FBwM0&|>�!��a"�&�aPI��Z� 7� "�Q2��� !�m(h�J�.!���rom���2�Ts �non<<� pU&�y*Ɋae^K�V�)�}{ as sa�! th!"-Ad�I�d2 �Q��I^or�iO1��B�a�c7a2�E�}� a� � F�)���eB�,�a���.� "�qUra�qft#�@� w�,on,r����mA��.Z��eǟdM.�FOZ^)3eMo �d*}r-.n ` ��8�$B�,m�hr�3���to>���I�,�!��SEt (B%� 8:�A,<��orethano?�VH� o}&fs(QsnrohSD�.��K�Ji �� � +�  ��45�gim7i�d��5(25:!���u.ZanA4%%�!UMA!��}�"�! . Ade+ copz%�-�9H�I��est��D�0ea6a;*~ Derk�%jd [18]�I �6� (5 mM guanid�Rchlor��( ��2A"U"�, �%Y ��� F���W 5fB�&��#8 v)��y���:A(o&P�of6<��6� O���l�b@ �`�cha�ser�c a~-shapA��� 6��� � (N� 6� a&��1A����� .y1� joTa L�nd �A}B���&� V%�"/�DHa,>5�� .a� "�.o�!a"���O%2 1 �2�e�.�SD-�'�� �:����yJ�29�6� P*';�(�J�`�aLI �Z2��1 Note:C)�Us$rt�l ( 9�3��)>�a"�"�de��i8�&� y# �)~[/%L� sQ2�S s [1g,TO��� �p��H5 o!�"�� BX g�4"%�in{�Nf[n*y]g �%�-07!�G}m�pr@W��:y� �|= pre-<2A" at 1000×g%�om�x. 6͞,uto�� qgD rifu�i�8G30w$4�L( Beckman Optima TLXD , TLA 0= . 2 �r���a�!zsup8��( S�0pelle�Ú ( C�!O� ۤ-R-��7*)�buW.maS ��Px�>�~8��Ud p&�XSDS-PAGE�!�� i� a WeFn�Uti� poly+9 tibo�5��K)st6� �9( Type �HGrJgif! om S [indqu��,�0teh�In&5e;�Ih7he *5Yi� (A , kin��T8i!bby �(Craig , Uni�tM�Wis�Gin-MadVp�7]}3C&�V4C–4*�VS��JS2BE%E"�g�ii)Hli BL21-AI One Shote1�4In*7gen�^;p~Fe��U�-B2�A$��E�R�LB�umA�p6�10e_,/ml ampicill[B t 37a1. �e�\eAA��a�t mid-loA�@( OD600∼0 . 4 )!�1mM IPTG�2% L-j�in}a�E�5 hZ&- harvA��Wu�7(i� , 16�8U UD(�im� Q�froze� −81 �+bl� �iw""Es!qu�WCu����|�,m!�si_ ut{de+�9??i ;at roomp'erm&b�ly� xtM8"�=�,�,(!�8mM NaH2PO4 pH 7%| , 35 (Cl , 8M ure�.%p1k debr�as��Rn�^:]10�].K � F&� i2 �595%-�qµlW͜�y_u��assemb \��( 1M�,�OS�n � ion;Z� ; 30U�0܁�H5M�ThT�OAt�!2w '& �=98� a MkJar Devi�#S�F raMax M-5$ ;adr,λex 450 nm; m©; 2k!�Reax;Mtaken�Ary 15e;,w.p�")<h#a55�E � 9�J��F.�# Ae�M&in"B�^"�(at�o st 3E5> &v"bD�#�S.H1�aW��l oly>@�MR � �cola� !�b��uip�q�5 va��$Met-OHA�\ Rm��e�70% E-to�̉��6�dr��/an�u��et$. S<1pow!�A@sto� t %��lL8"��>��x��q2M@F*%�. P̠di�oaz� 9��r5�A� 7( Sigm�����"GtoE�&n� ( enzyme:�X�e�k io 1∶50E��{D-r#�an Axio�82 Zeiss "@���ImaZ6i}i��=n�-�cap���a HXcam!���r��%�I/B}!0OpenLab softw�" . FlݶcI�%)��ezm��rA�i � ( DI-�I�2!qer���EM%h2�!� NYU Schoo�� cine) C��Fa�Fy���s}9(h%�2*E diɕ2 .6�"%A�4�~+a�OtnQ�-co��@400 mesh Cu/Rh gr�( T^�ella Inc"c�e �Nbw�. et r�f.bn��iP�ص%�1%R$nyl ace04( [brief�Ycc<[�u�LMe�"= I�,Philips CM12��Ն2P�(l!.�4a Gatan 1k×1kv� n 0DiI�MI���Y�ݖGI�)� mic V)� �.�"}H�v)�R  u9!��5 ihoo��o�.b�mod¾i��teSfe�L�"circumve�--roblemA�#t�*�Yvelx-8\&Dre?&�:�pp�� deep�Lr#$a powerful�r�ich�zF�J;� 2��.Bmakes4�W%*layer ne��" � }D�eF : G)l!K inpu2��E, hundrePAf�\�Dd",�4�!T)�)qMout>NJ�par8�BI&r�A�W�O"=/6E�.�>5HeTl?oyj orNp9�aO%�|"�+��)&�E��u��!�M� kfocѓ��Un\-QCof>�#�� � e9e�� �demi.�����DA3U�\r ch°hi�y%7O1Xd�A�*1H!jt!Ge global �E?uey!�loG�$�,�� �$0J� m2�1f��r4 Stud�j�U^tly�mo�# Drosophil��5perva� ? oundV-A|G ��?!�y+ - (to 197 AfriAKkmelanoga��A�G) Zamb�o)� "4�-��V �.TiR�9��[ m�>67 �it?|�sdd sweep�"![fe�u,c�#e%A��s(�� @�r balan�<7,te�Xu 1�Uin�atC� NC*6�_*+�close� Ay� iKEwf"�����N�05qig��4�bZ7*�3*� ottleneckI�~  to�`tr�. 5�m>�Ics)��MdB�o���9W�e, oŕf�K!���mi&��+ŋo��t�=�u�m< Q4. EO}�@t^uy�P7A �=� �RSVM%*[7–9]dboon1g [@�1k,Of�Hi��!���lrF��I�2" Z$H�cenarioA��5d&�E�M�!�4( Mare :bu��� l. �;w�!uPSMC [1jodiC2"1��15(QaVM ""&s9W�! is���E��9�">*�~ i�, +���6s��hap\+�tru~(h�Lfi< va�[�Av�X)hu2[s.�.}�seems ub�(t %"�a�M�. F6:�0*4madd��W�*2�!av. Galt��"�\17]}Ga.� I�I�Bguish!��8a��m�BqT5��'� �� Rto.'t�i\%��S4q�Sa�O���m� �  H�M.�)�R]�G2��m]A��%I9-!;uWa#I�ir�,BNE�at<ic� # affe^5he �q-�R ���F< 3p/� meno�vI�B�s�EGossmann=�8�Llw!:>'_ te,��l͎i0B�3� � ade��5�� i� e��q�uWas}(� pretV �� cOcT�sM9=Kwe�ow f�� 0 AW�x% BayesP��& ( AB�[19`#0�6f�T�<"Qi'��im�^A�CH!FA a� i�7*� .~I�d�k{OdeE"p! !Y!h& ��>bd�twL^�a�ach&�8� 3 ��r�v� (*� [21��3�*��eez*O1K �0WAvArt3�$influa #$ heorUal��[24–31�(�I�G!��9�"(S�0 -adecz.-’s && advan��s}a�I� easy!(|QRs E�to{ / � �0�6��%�) Azl-j�[�: h�s� �“cu9C�9maQFz( cate!�aM.��lurZledge ,�aLtR!�� *� ����S�R��3(��-#5>m�E`� at�>-Wr%� (��%?=of Baz3�Eϋ33�>���eB9��eY hierarch%@!��S�"oE!&i�"V-���{4!od6i8 a�-�a�t��jtq�raE\A lk��:}3�,�9��-R�er� �or� BA���(� mAi fullE���q�,�gm@�\r/-k0 J��%�T!�6.?a�t;!�s�H�>an�Gin� e�4^�J�Q�&g��uօa�P.6�.A��to%ae�"� ��n@D2"!�q>beginPu��"�7 i*���� spiB�6h�8y<��p connGI�< he b�;�C. N:�&A� ���k60�+�v$a huge bod�" lited �@"BV topi�A�6e�72�d!MQq(ex9�QOccE�!�!p��/��΁i �.>A2� s����� eh�*Ar���g� �!2�\Uard r&��:�� !�vol)�A!{a�\*i?_ix� a� Q�oa>Jt5 "�>2�[u�N- m)�}pr4�%�A%U.F�� �g�Z6 is!�f8 ple <e4com al)%�nod%�,�M�2*� G��u1� > �� &�s�d,��- ���!*�pO�ly6\UL"��uS1�% il���? [Ve fee��M6I���e hiddenU��phrGR“2@����E,"� �e0�D3:r.�s ��.|%hu�&�'R ; A�� m [3�636\=G� ��Q� A act �mof R ؇nb ni!��oA�yf�E9cbo�AO& Aaz.��� ic <��e�BB=]c��@�Vu��)��A�]�satis�W�S mild!>�%2d��c*u��weighi���* �`.F h6qSo��U?i�!�!á���� desiܤ�A�F��Q_�.jA_"�Ri/rE\�U3�Ug E�6�Œ�Te:�ept��A��p����ab� d.Ut�# notor�"W�si��ob ��-�J�L�fx%p�S6S�!��a4��� ia�=E(*Y�� ͼ-f��maj` reakG%��7in 2006�n Hs1� 8d Salakhutdinov�`� E��Z)wn� %��2ety�h� !�un�,vn7“�A0in�� #�!�*:m� �7�?�_-tu<c a I�a�-8r�q��Gf�;�o�8]{S\0�R�Edi��a gi�`� point�+!�-��i "E�Juf��2��dI��V8"DeA��It����beۗ��tPCA2�a}*�� o��b,I ��  *�.��@�@ er s�Scei�tjr yeK ,g gx�E�AA��B� brok��ng-!wre�b�"*�Iz�5(�^�na*�"�� -cod� u*'� ll-NiQ�<���'cecH�&�J(a"n9� spokG�o�a�� av� ) [3}40�l58�$(k%�N M!S��e�� �nd tagF��s/."in photo!  N!�E�z%=&zf�!�dQQeE��f�EAQ����V� ω[4�/4y>�!A�lN�]�.} oQy[44.[� al b�N[4-�Ln;av en �� F%�&f��A)��Iy��%!+�>^� mmod�%!��_��Q `"�'�"� E�ai6�� �ABHeB&�>#!�B�ajF%�B �a`���!!_ stici�w(c"-+0�Q�26�nrJ /-�:�%�%����� 1990�MD�}pL#�J�.�w�<�����Yc.!� d. E"�aj�E��quickly�N`��]it {"�A[e rietB s�� &͎*; n��<�*�� � x u� a p�P�b�T-���Eş��o�ect.�fR\RTde��>�:��m B�I� s�|<sF+�tar6( � �_/�\aGA�"T�= E]��sQ.� �HR a7!��<%y*I.-� ����jjHo ae�tog|Q�%�����Ie8sough%>GNQ�sA6,,���"��$%��"+�rr oj�aA�.�J����ad��ii[!�Ao tack�]��� ny��Vlyn�a,E�K �`s� ���CJ�%�Hp����426�3}55�q!���Aeaf��ar�5e�9���n�h���&� �3%ahp*bE?A�%-� ]��"�� pr$ a���XSsq�A,`g?*M�C6u dW ��(, !uM9�]#�e�mf! � spac88@�]́ wo i!�`aa�B ��B� �/%, Xњ,5nt*� j�8�� ��o{�!�err��h-*�(���5 �S�%�o k�m!)3s t�o� eaM ͯ ) by��%���:�.�pfew.p�`=: Y� �Xwa�(!�: r *�; !�"%>�D��}rmx%V.+. �?|T� B�i�� �*�_* !Veb ,+#f´��CYJwe�� �M�* ů:%AwJn^r pieceV�|tf� R-�%��� e epochs:]�"GMrem! N�2�% !�a�ͬize N�VFuD�) -'>"1�) aAloa. to 4�D=��<*es:�n(`8*w posi�"��!2-K��&0H��a�� �(*,1�N,D6 [55�Å[�leAP�-mvђta��/�in.�'��m"�<�i�g� w*y�&�>�&�M`'$O_�!a��)�Q� �Z�&ic-��'7aCs�m�icMcA��#�5�� �VpdYr��2de��4/)PFig 14a�p�Z"�X1Rat� �e��X��$am msms [5�*o� ei�C&�A�� A�?reb�jB':n =�: hapl��� A82� ��Wa�  e�/^�/x4y���"�9���qI7RT�<0"�9F����%�yU'�^%Pa�)�R.��rn�160U�ZO H,��� %� v!��1��eE��@kb!�� � 7�( ( if �/ar�rando��mid$ 20OM'�r%;Eavn�ref-�,�D��\ , ges��"�O� μ = 8�$×����9 [5�xAnJre.ȎOr7?�'oZ,A��$by &�-r m ��6LAF/(X� �-�I�"�uK� j�F�� " 58 , 5�SC�Aiya t��&2 I3�#1�6���)be&k)&� :(�9�,�*�.��E5rhEf��i&bWeQ =�HM!K10�.< . B�85:V����+of)�����e� -p�i�.�h5-M t1 =aC�Mt2 = 5�coaleaj�B� . ScW�f�*� (λi : = Ni/eA���� �)�b�:�y�a����=B�� �� low:_�{8te�d���� 2500IF�� .����,a eHof6;i�n�To buRHz��2�40Fw칉�.a.�. O !�; � ��E.��75%X�%�le�� ut 2mp�42F� �0how the effec�>tive population size results for a network with 3 hidden layers+pecFly " 25 , @and 10 nodes ( 5 4Ptotal including input.out ,) . The bestb��were found when we averaged the statistic �ll ofdataset�H160 “regions” ) �B!6nW$Fig 2A . I�is�(�Dmore generally ) ,%\point�nmosA`ci5o N3 i)�lea ccur�, but�5rec4 1 ha 5argA�. . WA�considerA�a sing!�I�IRre|xnot always a clear winner among�-&F. OA�ll RU�uMEiusu%#!w��(followed by neutral m F(. To analyzA�e sela�onU�En calc�Ied�onfus$matrix!�i 3 to%� whichy�ofI�classi� 4ified correctla�or mis as belong!x to a}a'� he ra�ofN�repres!�!+ true :�9Ɓ�%columns:;-�ed� call��$. An idealA(6(would have !� 1’�100% ) oa e diagona!��0%of��. Our)�frequ�errorA�ify!)$hard sweep�s!JQ(!/ 2 , � 1! �:���$We hypothe�F��aaK is was ei�Jbecaus.Coa|rA4ne�ly�quick1�j6re� 5� �sad,yet completeAo ta���E��Pi��<��condi��al1{-Jcy1i�llele at!�EAɿM��I�4 sug�?t!!(in fact man[!�m��,m3!Thi�q�8sometimes appea!Q1�(. Regardles�d�typ� $false nega��Y'arguably�fer��to /lyE�AB�� to b� der-a��they a�� ��WA�so wan!Nt5�e imp!8of unsupervised��x�u�c, autoencodera569�s 5EY6%O�.��randoml��itializ�܅W��i!J�Es&K Wnst�d%�pr�(is very eff�WvA�Dueq�tEoutY ,]96�!�@� nge. !���6y2UyIna|tr ��heY�S(scenario , uZ:*Uzh omew��B� ed (I�ly�p. M� � Y�Q�bonU�ed sligh��A )  ,} nt�%�=�cIC!Bcontinua��Gtic�te s canA� done�Q s: i� & valu��a norm�[.h"� isJ�[0 , 1]A�g !%-�/rP �zD�}� ing/y#:>A(isaCjcriter�#�help us�iid)M�^� ir4��TneedsAFe�dito��vi�� �w1�!~thJ�e���A[Xal Drosophila melanogas�y��e"�� just� t �b!M:set q� � A\!schromoA� arms 2L�R , 3 � 3R��!@ tudy Mŧ�ged �6J( into 20 kbd� M��m�<f�ecu� wi / t a   ,A���by Taf!yrun . C� ifQ���perform�� midd��EF1M�T%�%!In nO ughly 14� �b�:�,��$we discard_ em from����si�eTh.~t��dA|b� a�Qlomer6 nd �r k 4��m a� ften1 tA� ��histor�ӝ;��Q䁯�� �(fir�ow��g*�Q)�ur !��}�PQ �^EF? tw��I� �iesA�l36 yb clos" PSMC � , alth!��4resolu!���a�edEaa�per �isoA�We ba� �E�ch�4�A.t1�t2�Eithsurpri �tse ��Ecnot� ina8istv ��e expan�i"!�&!�� � ;%GB� ci� B�\ofb�(a!sub-Sahaa�Africa )�Rbegin�� ar�1`D000 years ago [61]�1 x|� �� nf� ! rease4���wferM Z%�Al>=EQ�Ek� �nby7 s� xNe��lands&.��ThorntonE?4Andolfatto [58!(InE�2Ba2��$J��i�ͅz�R���hav);� st2#��2�>aI�numberA���  as N�, H�S0 , Soft ��BalV ng S"�� 1101��45AN 179 , 404=e� �Zl��See S3����hdetai� IfA$restricteϵ�to )s.�mA(obability g��$an 0 . 999���we� 42*�A 34 s�s��17rQb5&8 .AS4 �&*�-� ��Mghf�ce5�����  s%`�inI!)�I!e.m��,E�!~ofL rIC �ed�f� ��o�genome�\-���1v���5mat�%i5� InteA���.X!VNE seem!��� $x �=r ��Y�e6* E�s)��xcUof2�on.7arm� . Upoi�)q)�i�top5}HV�E se�l�@u �E>e*?categ��a few�#.{ harb�u �volved�% atin&ror�"� . Fu��r� e twyd)Yon�a�exa1��r����a known.�; �*$Fic domainaY protein (��on�u E1viw behavior� AIcharybdA� !�3 DgrowthM��Y�.g�=OrelJ�ranscripW,|1�'phe� nO�(( chemosens!� �s��E f�qi�{ �-{v!�r~� m' ercein�� ���e0N�1k��V%o cyclA�!*B!e�E�� � (b�B��v? ���/�Q�le�.q��hea��a���=-fule�; k�9p�%>Q� . H��wed% &� A�v�}%�"cng%�)� (a* turb�approa}e�'b�,S1 Algorithm�o5Bg%$"2 �~ he��%�5- acros�l��vA"5en measuyL6�de� %9c� "�!-�( 3>W \I�!*�awo ��� �25�%��"� ��x � "��$4-way Venn�ra� � H highKs.� comm!�o-Tub�of �z5 9qn�#i�q,�  ,�:��far:�Z ic sub��.� m$ :*� � � sUEcolMLaO! �: Uit��its trib^ or order;eQ4folg site~ cy � (rum ( SFS )[a=it���!Dmin�%�!JS� �)�ina+� e.�,� A��raw-hsegrelng�s (�8S�5)!�%-9s��F&��leton; FS ,!�:4!�%%�O g""$m� overlap b*%��y${N1!tN!t�!��v6�2possibly^� s��a �r� R scalTajima�!D!��G�TimporG 6�(m>as desige�o��ctQnd�. I�ty-by-��5IB:+� pla�!!�!%%Q�ro!�*B�#c�3��P?un&�~LD.`�_r�� 6�A2A�h%o Y�a!{e m���&cip= . HowA�f Vz�., ;i� 6�-w� c&�#b�'foy$en givIa�(4 even�hap�� te� l branch�eaE� alog�nthu)�%�i/e�Qanc%� (Z�BETa�A��v dony'E#� ��. N�#does Hi<.��se�)ۭ�&. I����.H1�8H2 ( vi? e H12� )a�5�S�@�.S2�i)�A%pe*_ shAr� simil L!WE.�!I OV�.�%Y� ͸@=_^ Y�AC�`�onsUri� ���!%}�a�tractmo&����&�p+� : 30!�)��6W . Ad %e�“LD �<: 4;":'s lowa��arr�!U % mid-95O>��wis,rf�far �o!M` �pairsmp� al a lackA� _�� vice!Os["BS.�A�M�UQh!�.M�H �:�!c:�!ҝ=N2%�Ga- so obs� +Be&� M�. B*� ���*gn�nt��a�nY/�d��+�& kes �zat�(|*������ relij c]ቁ��B Sa9hquA�.Aje�3.jn� list!� e  '-.Y���m�%� both�." A�J>< &�+�lle ^.m�Zyw��f�by  -��#� preca.B *�!~*2� shif� . Al�ABC�A�well s!r�� "�!of5X�B�a���ary�2,&aW�w��*��Aoe!]� t�2A�wo Z!iTo�(�$�_y �� .�� ng (ot�!) .�p*���u�!Pi�r!8(toolbox [54�!g$%�t kA)�  � �#a(6F.� !��C7.ee&$�prpdi!7 ��uni!Nb !�c'� �E:�UA�@ -�d&� � |e!*t��%#r>5%-�61�,q%N half )$ |\+�Upo�!�ens�1�Cyi/d 7}2I��25%^�!�� A4woU�� i"� fua"e�I summA�ur!f 345 �21\!��F!�duc�jG100GIGr�:�ch���T� ��+��:\n�,6� I�� 15 entj���.�,� )��.�7a�' ^� r��.��Iabove� matc� �#)�“intu0ly�%En.NɼL "�T�  8!�s.�-6�pro!�s �teQ�� !$r� �n��i(� � n^ AB��] e� Ay� i�� lc� aZ2� \�PIEep&�,ehyper-a�Z4�Ush��b@F�0os���}r"�,�\ λ���6e,VsoR� h�� decay�� .�* 5�� Ifd�t9 b�o[ ,���l� pen�'too++I�.Sfe�-���hm �CbYarv�N. But i6�o� iG s�$�dism runa("@. ".isJ�akidI$proced!.!yp`*�o�/i` r%RλaW�,� �a"� ��!e��'�/E;��M6&�j"�+!LA��exp��v�. �%*( sm� va�K'in� �$In %�ru � �maj��$spj�&�5�!PW�,� kTAAEfine-tu��Fa)*.e�requiM& �r6�!6!6vGs �!ha�To�ed up� J)��6z&imu �'ise$��0p!��V,ce�� !��)�6�in�-t"TA~I O � mprove�w9N�m�6Q))� b%f!�a2d 7u>F*�� ( 40+ 000 ���U�+st��h�:E/w:�c\ 5�i!B��a� arbitr���-("�+,mSrL 0neous%,I*G-,)qM]“��m_��� m�*b�&�e� F� ��a�� � week] aY wA��;"'s C4wSs�z4%~!r ���4 iR5� b�>mAG!#;Ev.��q�A�a(��0�d:A�^ 9 . a��pa���sough��� &f3��'i�5�/.�X new>�;c� amew�*.�!4own-sa�.� � �k riet�7�" �&I� x$ .�;��m�4ab�%how�e0J��"�"6 s�UuseX6��0 s go�|forwardE��1oAH �%��to%y �ba <o�7��6j88A�qn:a�-&�3a7q machine�1Xd \ s*�%�1" W8&4 limi�to>7g��.r"~8* �o&pq�a&n$humans [66�ͼ;/�!icZ/���"�$,!NN!*�1&�Md j�>�x�+ �a a&5we� "!!�" `)pAO^0*S1���+��&�&���,2�+� a���� c!t� t+�!]�Ţ.�=:�"\*A���H>�**%)B��) ��4 .�!:&d&�i�: |^J�ze�q�n�"exeo�@ cC2by Schr+@ e @ . [67YgC*eq�Uzda�>�o�0 trulq“� er�B:L)a�!�o��+ort�0� !s,n�� &� 2�nd 4���emL�%-� �,_%�J�+G� �#Qkm�t 2 easiq*�"cJ".��1to� orpov4��E6a w%��� E]!���}�cap�1�7 &�4%��cur�C!X6�&=R� now� �z4"ot}�@e� avb5 ��E�y��A11backgX0or pur73, a&Dm�( wea�?) del�(��Q  ad� �a�{IIq�warra� se$��*|<"�;rU"�;t�( %�, ρ/θA$4ruF1F2on5"ns Zambia!��fe�@ E= //�>���%�i�-$6 . 8 [59]E�10 �0�-x=p�)� Zimbabw�Bn. qe�} >� *+�1tio"� icF�׹mo*1ayPrz ski [60]u 7a��w!�2 �As���1Haddr! ��!!,!��&Vi a�r ��@=a��!it act�Diy��֭ �!t��8L?y=e5%7�E�!��aassuAa �r2�E���Tn�v3erI^����a"��.�A�–!�. 9DQ~E�s ��V7e�atMө�aa��+stg�} �"ob�q�i�^H����2del&� a��+-�s�>d6@2� E/A��=#F &� ]%�eL!OB@MA-M�ш� b�i�9�ҝ�. D� "z ABE� effiE��Ag�!A� � OJ \H��v�/,a^��Ean&^ b as MCMC [24]A�h%{A��nB6@ o~�4"��AlterhAY+,:<5@�iD< &���t'�*p MV.�[49- Blum��4François [28] i� �I-#��H�a�e� (�6lin8:)��res88t�����mea�:1 �D�ad~s��ce �B>�c4lsexclus��&eA:*,6��t�Y&�aDr� �"�H� jL&����EA� fieldC-!�a� . q1,f� �critic��  “b�$ -box a �ni&�#e� >�+ebA�coaleAKt �v we�5A}nea#ic6!w&A�;du�Cm��rtN�����*W"��toT��R�~strengthEf�A��2'B/�<:�j2a!b&� qP.>"Ps�e!.��Bz �beh8"FỵPFeA�*<  SfaO� of [6�<(Let x ( i )!�n vect�-fNj�!g�i!�nd 6@6=J-(E >�!��? ./weI�p 2W �tog�Q{ (�1� � … , m ) }�mK�ec �w ")c ne.� ŽG0xa�!�� �HofA� plex��n���)�� 4mM��3�{ 2 �!� “h� a�:O"<� al )> $ | ’s��di�K KB���3')E�դ2� ��/�� 1��l!��pix�HofS imag�A�[OAFfUS tun2$�&ca?)6s_ ic {G a:�� . S�+� o�\B!�t:D ��ONI� F..���� ��E�<n�V �h"H.6g6 �b�51 .�J�R�:or:�J�A�u2P*&qr&> ^�JYMF%:?account%�! kL��".%�di�K�F�$kb %!2�'V�eA�%F:�M=>%�9)W��`$�O�uDmi�<,2646�>68E3.ar�iNy323/8 �A�3= �i�� �S-E�wx �@K in PE&23c�n3� iciaui/57 . W(4 each d$)%X�%�c&�U�ɖ��*T , ! no!s~&W8.d"77wUw�/��Wid � ��e�A,$?=E% rn�Ix�had 197 Ws;�bA-� ���sor]H �srmis�E΅�e � heH� � �>Z!�s u}�'of  (=00�-sour+ oftw�nack�3(!��$evoNe�3��"�!�32��8r�YA vail�(at https:// � forg�net/prot @s/evonet .��Per7G�4A�PC8risk HPV oncoge9i7 cessH!� !\develop� �,-i \A� orop@ng�KcaeZ8�Ea)E6/E7�ng cellit�&3 �'�C DNA u9 link-agncj%oAnwW defe=1iA:0.?���SndKLICLe�I�5!1we eluc�%e � �attenu�!Fa�H8i anemia ( FA )n���air pathp�� oughP�E�4P%b�; E�f$D2 monoubiO/.@� foci!�-��inhibCa�# ��r%imulti��me�Iism!� ��i�: �cocTi�Tw�ouble--Z brea%VDSB��2&�ly � eV�rec�QQ�2 am� �@ Rad5;4Win E6M/.OCE6UOdD�Xd� ayed�de-:D� ��!'si��.�A$-3� zS� associ%�%'�i)�b)hro!�A��"3%f�)!A� USP1>�=A6��dcm�BYx8ATR/CHK-1/pS565^I�.!2med � p53 degra�(did�@ ham�#�a��? 50�mo"Pfs( abrov^d1Db� srup�M]F�:�<-���Jof Palb�6I��<} D.g�a��fZWs�q:� que.%b3Q�67��3�� kVa���"� ���ap�. H��h� 5%$illomaviru��HR-~)m��� ߩJes�Z<%Z��Rgn�9 ��Qe��t$���V E�HPV16 b7@Po�Ant�[�LC�Y�X�F2!�BB�"> HPV-}D2�]_fem2X �A�a�ly [2<��!+z[ des)�z�(A� ular)�$A4 �%��� . G�Ii� D�*8 � z�$AZnumerHņa�on%p�2�%[hwAtum�#up�otnd�]da� ��( DDR )Qء�Rz.��Q"�Q��^���J�i�� x��m�܁��homolog�r2x��[�E*�b�b@݁Z\ p�� AtA���FcuL�.&7f!f16%h� !�yo��-BRCA��or FA )���v*F%�!!�i�WN%��#"a��Y� a�eby m�caK�d!FM �D�!�I [9;?>�UY�E3F�- FANCLR!<c�e�yE28-conjung enzy�PUBE2T/�T�atzf� ?�& mousa�c[17 , 1�|S�F,-S�Hs sus�"ibl�orpDnd. squaY� carcinoma!9�&Q#�&V!�-u�e��$ont�7rs�*k�A (�\-A)�Ep[q��ir HP!�2' m �lih ��Y:� &�a��jtoW&1� �%e�i mole�g"� IS )�@ A� a���!�]�vo�ell-� stoo} �(# lyAD)j�n�upr�<t�l"7 � %�AJ:s���m<�n[25–2� 6+8�� Dree��P�P��es�����!�AT�b%/��1GM�1R [�L2*3ųB�m� �j�r��!�{ ^��'�1s[.* [� =�ņpIO~dO<5 ) !�� episvL leav�Ayu*�unɾed [31a�!B�nO9�KPFAeH E"ol=acT1Q3A�I��S��M��39cJT"z�QR�d�Z=n��$�.�8i(:�p�rj ip�s�ort�asN����.�K,ty�� at��6bd>�ܱ8ii&� J. ,mA�N0BQf6!?)�t:��N�. Col$s�,"{..RQ Y^TQ`� k,�(�or<@h*xq=g��jE��!za".^. �q4J� io�<]�β35/8!�!W �6>1WB�����}�5p/ tomycin CeUVB�+i7� �qf�*�of!�*] �|�p&y Z Bed��E7*,ly "%�vriFh`�Okin ke�. nocy�( HFK��. Eo$��16!: j�3ui�g by qRT-PC��a�!ll�pmmunobMwa}F(� lisha�ar��]pRB��N.�=�2�h�JE6+N&�D���9�.� LXSN�troW\�A1�wIC50  k�r*,m!,n��� � ly �f4�2j@��r�)�:�t,2�~X+�ta>"�0-�duc�IYjL-Ao�2�.�MMZA��{s�Vd.o� pAKX*�. Jy1E�k� �own�!�`sA��1��()�B,1C��C �ole by siRNA1Y�Yqs.D��in)_� l ��2.<[`�`q�]a%�2���"�Fr�nli�o/noZ�V��orR�-) �#n�g&�uV[: ����,�,�rut�!H���� e a���6R� &�)ed��w*�2NutilizA�a0x�EvAXa��-�,9ly-=)a����in vivo�A�A�leE4 level [32–3� C*e�t�+jLÅ� 2 hrE�t�incub[in)-fI&�u�[At �48972 hour1hst-kR ,���haX_A�aX froz�U&�za�Ka�(�8n&�(.2�haM{C irra$ eliv�{ fixed-ofj:dom7k � )�M%'�&27s!�I�2�UCL\ links hol� �(d Vյ�alk��bn.��retard�`ct�#or�-moY�!��`i�AJ�1 "lail mo%m.%un%��9%�;�.<�,�6m!��(ż,lL.�_n2��.%,�� at a�'O+E�in�!un.�E�-xB�E At 0A��N-Y���'e t-�]$]�SAR[�AU� � 20�9:=/AtE�rn���n�vg��!�% �z!ng�1t si�m$=&�kY}.:�E6NI"i1Ha2�a�r �mVUs����rem �*� )��-���Fuɋ�5kie/x:@����mf e<#�:ag�7= ��)H��n��2����& ��EZ�5���5*�)bymas>���`A�]O ( Cp!� Iw�%2" wKd]� ( Ø�l%(� &*in &Â. C�"Ja remo i"9l�&.�� ~35%�GA�A�aq �4Cr,�Fann elev�_�E)�]�)�|:��,�[aA-& of % P���)watB� r ma;^. in5�ov�H! DNA-2inum ad� sWF � � � syste"9K B�s|r� t9O�n`K[3vfTak�.g 2��se�LJU=\0 u z �fL �% 1I ��NM6 o scrQ]" dg �:�*h ] �1�0"�9�/ inz�� ���6�8a ( |;;A�%J� �Rx ~4�.Ň&x� ��QN�15Ir4�propor� I &q �;"� aNu68+��� ��Z� `L read� BP!Ld.� . Ub�D2 or I{ be����Ked� �2NsUbA�mq� eV_� �6X 9l9-�� IN�e at3 elin�dj�2pAggx@�  3-�d�!�A'�:��D2�?%t�\�+�*� "� �Q&1MMC8!{�� ( S2�S2D_G%eVi�E�u�[&�C� �\N�,m��@|ed9-w6} �6F�i{5P%;�e �e���MA�JF�E�F"3 w���-elXf�io��!Ap�g�!&�,0x�d:�E,���."��2�.^DexpbJ,�.Be� nrica:dra��%\A}�-bouna^a�f� M s�PHFK-B.:�/���r6�.5��� h�-�jv)�=!d6 2!LNl m�� We6xt*��pD��'��E�m_ I^�E���V%2"8(or"*w&�(or�` . No.�u1c� ��0��U&.Z%�Z��u�( S3AU�Tg) F��Ce`'śE7�6�kor�ohexim�"( CHXY$^ �Smonitoao24 g`io�S-�� ʍpid1�"��A@Q v��"< "k *�*G|of�r@�$��!�P.�-:�&Epromo��"MyvEu�! inY�de�ET"6D&�!6� � �1�hal-�[3� I�, * � .*�26 :��.�orm�H".mI .EE�6�5��� B�>� :VConw H.!�U�)&�*� �� di�;C'3�-�RtB-���& V�vzeff/%�!S a)���p-�!Z:P�R . P*x)AM|I S556 y s up&��enh�"(fx�+A"�[5Q*�#n7X'aav tige�wPCN� ��27)� !�RAD18&W&�+_4�)Q:{,8Ji{0. Apart� aU�kAll=B�' ir ,db�(� )�!�n�m�je�%"j!-I2�1y� phys ("<%e������<Y!+2Vfl�*!EJ+H�o��[3�!&R Y�'UHR�'U|�&��PH5� RINGc4 ger �ys�'ha �l8eh��v�� bB���)�EdE �J�D2!�ICL�,s [38d ',.�� ancI-E�� PA�I�UHFR1�q�xmzH �h�'V� r3�E�)V�� ^ �w!�{�Vc�" $m� @E�"�!=&�1�6�j–S3C�* Depof�#"w&NX�.�- �%d� %g�2�Ձ;"x ��4A0S4� ,.Uai�5p-�� j�Zɰq uOJ3 v�4 )l���r h�,*of-h&�JN%�2T ( S4�S4� �$d���)á�!&�Mv['�Q����E�A(d%�C,!DZ �):�e[ 2RUp�=4FUA�"ort� Yat�����)�,$0;���)�V���D2�A"*�*W[4�%���|��&.�":Iv �Ubi�i�Q*),6@9d.�Bc�"�"*��(m'�%�2�8r@: �.a�kci/=���MW�zn"��R@>/;D2P$<"~ px� i�ctin"�"� X@���B �ol�0�m�4� EA��^��fm��R�*�#x��-H2AX ����G9&ar (�Z�R4%(�&W�7v�$Iy� !�f5�%%�:�%of�(%  p�U8dD&xa�ache��t.X Y�9�Zi�E}locJf)�y|�5SB!1uQ�k.�U�M��i U�@IO�4� .�E�_ng!�!6+E(�l~50F b]U!eo�1kA;-/.Rk"��c( ~25ߋ?'"C�)2��ae�a6@21)�B� ���T�m e!�� o�)��(�-�� [2OS-DRmh����y�,���� ,�-�;� g � an I-SceI5�on�KO[*a'&,U�se � � cl��l�tk?kDR-GFP cStt) x !�b w!>ofX-,al 7 ( S5 [41[1Exu,�;Q=I� �T/ �!�4!*� h�JV0]ge"*~��aiV>5rec-7%�s�G�"X:I�Sc�HI�)�Z"H!�in&� � :QPM�.��E�Fllx:6Y�@ �wZ*�sE# �"�`�Nec�20%��n�3 4N���V*B �m/ 4E�R�$�FE-i�B�X� \lex7G�AX:z�ZBec�ŭ.�:� p9v�EUD�ataKproXU�6�,�I-�5 ����oP�U;P!J�q\D?t^�7. Mis I�3Y�b`Y yC�|A�rui "74ow�%) ��*n/ ��+�NA�?��fa�2�/��e_K� � 2�2�;>�u�?&4&� u esI� 3>�7R$S J<[48A& 3anFpGe�.VT�7g���Dnd�LA E�:-!*� �B filama�jSBQ�[4�04y&T�2 ���&R1Fa�� edi�]qrS5B| � n��%qUe r�e�@A� Nr �*.��cmF� d.�NXis+&Tto1$$  Isce-I>��&wpʛ����~q���� [-"Y )K!�q*s�56����,Yn�@ts 5fB--�mr� ��ͫsi "-.� ��[��KC:�c F%� B6\I� �� �* 0�  )�4� i�U�bdEC-mG%34H�Q10aOA$��22u� br*�� l��-).�e�"7" E:�n&� s*�zz ��&K&22��%� 9.�d "A�2`I"�is�-�2��S"*�d.L�.{).8A��3�u.u�A���, oL �'�**Si�Y�K* �a�- h�D�kL�>�B�"4l>�;o��0 �.4Si��C p�/2��BpQL�ob�W-�ia�>�%�qb�K�2�'�u��orA�~Bto UVe@a%�y$ cove"����d�'iw5� D�F7<ڥ7~��d4 v&�")� e��CyխG'a���5�5�v. MH6}6�B �a���Vf.c7��!��� `� "qBVHb+��"r��[�&��' s ab�� y��fse�xe"f�s7 >�� 8 ��iW a d!��6A�&- w��1�zis*d>�}n.]&��ri�: 7&C,�>. �op;Fs �0sob�9:mdB�"P�>:eI �l% 1-�6��"z-ngB'mD�3� 2.:t1%ue"�F{IX�\e*�<ɪr ��o�"� �.  !�(a�W Fou)�bby _�G�l!�5�@n[�Q"Sh�![45j�5�>� ���P��s!r�TaB�M6"Q I�$F�,�>�G65]$sGFoA�2s2v kE]�2� Ѻf��%�E�-��@��.�ed-*:TZy���c��.�J�WmUyp.bZ�)�4� A�o"$K��I��t^��� ATR-�5dA� !U!p"vKG M�"FJ�[9f@1qAGD>�o�a0�3 |�1w e�0 |ed�E�er=쵂��=�- B p- S�ZCHK B2O*t< �F�/:�on!&�im/ �M@ &� d r��P��l�7a͘�����B*�N�Y9!�18� � Rh�O&�5�MEGJ�}@ 2nt�knt=uF-*� &��a+-6?%xby)N�r� .�V�nc� p!�Fvp%�KUV!UEP!BsG"]��,2) ( S6S 6&I3J�anE��u3�� or ( VE82�J�R�Ua$p+AEM�Fe1:�rrv�����> 51�q.F� ��<.��)iqof 1 . 7�> 40MsOͤ>�nMS6 6�!�c�m*yU�q5���Yہ�%�/p!IZ�9g A��"�&� �|F-��.�� g 5H���"@b&�GB�\b�I�a�9��0B,AΎ�A�B� abe~t���+�����/d"+�yn� �Qd!3ea�=SWS�D thym��e��m�pIW!�!-� F�R ���a�C�e �� w�%졄 ҉�6��A� ` 6d �u[qgxzF��AQ�Gt[qC�������zn��i! 5c��2��3!�z� iso� �?91-b&B��O fG1/S b�6nd�.�3qnotice; ill fS-, �o2�=dec�!Pin к�o�(z` d.G&A_!Q�it&i1i"� �66;4?�yF^ex�_��>-��3al�s by fJ�cyt@ryhq�t|d���track� P�aMM�.F^ E6߈N"G!%Ie2�Pc���J�!�6��MG&)L��$6WV��+ofEA7u���t:�[�aM��u�J�EJ"eGE'�V�6��Ehr �YA�-!  [4�.As%lQ desG& "� e�c�l����1JX�9B�.*n��1�1%'� "eq)��Bu�&sn )%�� �P b-��"�.eLV�I�N9%)F,Ll*������D���I�E6!d-�%�E�@�K,vA��9��ZSfY!,( 8S/9A/10T '��lincap���%�BA4[4$48]%s$�[��*�ҷVUBb�� �[��N%^#{ 3ih)V7�Yup3bpanel)�oth���y�&�9�6�by ?I["[T.�E%�~I)��E- wild-(nդ ^�&�R!\1#Yo�T2� 6_��Qts�s�!�.(E�iKo9��R I#% � ��(Nutlin-3fia Mdm2*x ���] A�b/e�V�9*Xasomal:� o �B&�2a)q";H2A8��r}7��m.�A���az�(in lung fib(�۶ s- �"�@!w%I�,�:��fg�1�� p53-&;4.mer31s�w�Upub#X1s`a)M1J�i%���X.S�e�&�F�S�� chic�?B lymph�L-lac�M*(REVH:�(fuz �fe�f�[49–5d&>k� Rego"�l�>"2J�A/92�aE� q3�Iz� "ՊE6}q.x;�2����!�E�AnR:Ig9�-� !Ci֩ �E����M�rJY�by�"�2�*�0!� qI�rGK�5&cA �ABM A���&� i! uni"�?.Ba!suf� \ ( S7��+�$.N �naQ$F� -v�.�U* yև:9 E2a�J4q'�res� -""2MS�.:�[�$�n���n*���E=I#V argu�!`m`k!�R��_'n-7b4rOrᇊg� �2�=Q�' ƾ8�!�ig>%���VHe���A=iC^�.�H48I:��.��^<.�!e,���A��toIt"�N)�7۞la�X3E�9��nl� �24hR@ �-&�9�,���6�&S � NoD6�71��F�`"n��:6.g\�[ �Y�p� ��`~c�)�!j]lA�� �(l��:�-I��� "4�����.�eA� sh� � t���46z���@.mJUb/de�{QQ,.�2x!m �� ce akKn�!+1d6�:)4"y^� ( S8&b:G tron;��%��['���z$�7E��Ea��� �x���O ��}BJ*�a�.!&g%e �qnJ�.���_M8&yIy�ly��gI'I|.�JQ!o&�7ReRI �C�$ � �&� .�6����Eo<#JMp682� �e4��stA�hrA��Vm�LAG*5'c�4�/o>�l�e5D� �� ins. �D2/ *v1x &� � a ke�?Ny::����'bLcoord�r���be�*� F67X<�[52Z&�f�\� J�\( !bW�oN%& BRIP J . P�ť�w�'m:mne�<s ,1,) h�=^a)�&�=64z�+abund@>!�ke�=$-jz( j6f)�� %d% )�m��. &��q{aE6m~�Nepa�?:3Y� A��n8%'eZed b�V}�/E��T��a0o�q6� ( <�yyp"�;( S9CES9�K\ush[x�:�A(�BlC1�T.^; �:Ct<�)a �i���B����� ��&{15�)�b-a��96�mT/9: @&�����6U I`n,9 ��peaP'�S"�90��F�&_ wr�>�Ofe+� ( ~6w-%�� ���985�r� 8�.̈�+ a�("�.�% ��ci!� ly l)8�B>�-E�(��6s�O( S10*�"k3-�s �m�a����I5�? ��+Aj mpon7��A6k*�+m a:)*�R e":\�1:��1 **�+ �.=s�V�ata�)�  �Y��@i]gA�k��[by s�?\ dde�!1! !9E7m�.�� l�1to����;&�����Z�V� W* sG�", �%�*�N�}�Z%F�\)(92�nU!2Kzr����v..(-2U ep���!:�"�C���_�J 0ch-���*�Bre�L%�ofA��;I��, �+D�N��a�>2+579A"�3R5-e�A��es �[53<�"�*�i)�I1f�tam�[57��Ixi�* loaof �-)'�/u�ry��16[ �:Z&V' �id�!��"�=�&c �]Xo�/:�In�/��m�A�g6�~1��la";N�bE.�B�<)<"�2^�3S10�m��� !3 F $-E:, ��m�I�|. mV�f�&)Cgua� )�YgA��,.�� chg9no�GndY^ ,6ibu[*o��I��y�4~�{1Bj�z������5>%a�p�fk*4)p-7^� .�c� ~jcA���I��3q���hKf.��R!љ�u �H ��r����!��� ��.��L�~ low�A!S!��K�1��&b �,aah2d6[26 , m Stri�c&Nk�(��^�D)[B��T�DW��i>)�D+i��~�+.2h-o�7,YuP�ai+�E)Ac&f7b�2�a�_�s> er�e� �"!|Z��Q� �e���H:�&Fa���*@.�>F2�v2�r*]:� y��i�y:Wsr)�i�eE 4D–�:.�E6U,�>/"N���N\$&iσ!��f��EV��!q=�F��s p��"�R /d!�Q�Vm " U 8�TI��l J�2� !k�F._��NM>} a�"�qo4"�CW!�٫!�-Z�( U � �"fQfr&����M5HPV�}�f��Mf&C�!�]%-�[AR�Ui��Bent�pܓitb�X ampl�,i�[5���.&*E3�6�7 cX��W6w�&>p vira���`��C�A�#�L."L\!Y:�P �ut�' environc a�-m�s�.�\i� "I�Z�_�r�.B�)|��!^�9�&!����igf`�yz� F� w/"�--�Io��8raaAjn9��n�Fnd .nFjQ[�%) .yrt%<�[e[>? �.![��r����-�re�6���NA.�d6 5!^hw%�����(��!r�� "V n'E��wur� Aq"#�t ruit��qmp5*br�"J6E!D�/ex�ngj�: ʤ��b�) Tr&��,&r *O�|II5"p:��2eErb�R���� #0.X}s�6>F�^g�i !qK+&<0^�g&D��.����ve�i�.��%�j4G�x�#2�-a��2 �� -�d ,�4itself�@P*!"�y�"2"*D �:� word�s�ng8�b�R �ja�&����h�M\'Exe�)}��^LJ| "&9'-(F>�U�- .:�a��.� [1�-|%2.�%=2[� �|4�<��N" �&e�>[!��,!aie��-�IU�Y ells��'�{��.$ed�I�6 �s�q� �2��"p�]��E��QR$"F'N�!�6F�p�Hrn2�N@��BCp a�1q�tep!G�09RD"h)>� 6 ~$2%0a[%�.1.����tA�)Ha��.E �5 '��U.��� m�u ��"F>Ctw02� vV{ �a��-�A� I��% memb� ��>���6`~�;"k�6� �"R).�!k)":6wF�["�;�>�K5��n-#1!� �s&�XE!���NtZ)+5�A�:2��z{�Zsa��im��lW"��5F �!"�j*S��)�c�@*a��~�T��rup��V� �&ċ �y w�c%ur*"!}&0&��kL&Yxt�2e�u%�2��F*qy�*�{uBr� �J���.4 �*���,wӿ1�-decad�Rurs� �J�`�,�4Uws) 1=g"� p ��isd \��'6F�d�Ȃ[*lo*G�ny�d �2�&?"%�$� i2$!")0� dys� � &0&_��6:U�1I�za���<FA [64<�6 6KA�"t��� a���- `_ �U�9]&I ��in�.a��r�0�E�.'� � �Ph2�~�!�$��I�$."� !/inI+��R�P* �.Y�8s�~-]��s���d�y/�AYj n�1�"F'� &L �2��%lc!c. & ��fna;� �at�B%c expl�UU�mon>kbjV)b�#:${V��t�{ "�hJ`�E��.�!,� elie�{'-{ aN6r� ���� adapaK�Vun�o9"X-|escap%k�p%�! �. Gd]��&�>tac���V��Ii �"�V�Q�%61t.A!��ahe�M�-�%�u�(dea�t�\ne�kal:�~%%��?�[�K&rInstit8al Review Board� SwÐh My�al Ce ��ea�{ , W�%Tissu�'��newborn��um��)co;�e�komaFOH{;Birthj, 2j�q���ɵs�>a���e^EpiLife%uC�p�ZG �560 μM�u! chlo�� (X rmoF�ir SK�!���MEPI500C!@nhk�.b��thql�2nQ S001� FK;0ri!�%��rΛdonor-�I-�N�SE-��.�ZDR�Z�/(��iffMaria J�� )-ir�~in DMEM�1&10% FBSR]��a� �9Z|Jgr%�cop��a/�[[70&Re'�irA�%��Z�? 293Tm�1@ F�) �J��mi��e4uc^�LTR/VSV��CMV/taA#pJKH0p'�- �L0EE7��J�E6*�9�,)ETi\IT-293&&��re: ( M��Bio3ccL+g!�manuf0�rer�,�otocol6"f'r-&��m6%aA G418��( 50ug/m�97AR�K�&I ex'��2T�`9�t�@o�U*�jC./��(Vb �o!5-hR�� -m�&����6fZ�:�H��dER�w�.-y4n0lenv&!?�7icl|�$Santa Cruz!�techn�A(sc-29435-V l*%FE�hq[ stoc���Hq�21-�polybr�]M�� 4/MI.���!1 Me��մin0E )�pur��!�ay{ie��off'c%G&�n)FF��@�x������V�k Chem�iH S116�B, M*;�(�s)4igm�: M428n,�93y�SNR805�3, VE-�F(^'0 Q9A.�oMillip�R23976\�, I+D!��a(b{( GammaC� Cesium Ior -1��)e]VA�,two FS20t12/ bulb% olarc S%*Inc .EX"y{4 was dissolved�I at the stock of 1 . 5mM in 0 . 9% NaCl ( sterile ) , Nutlin-3a and VE-821FJ0 GLDMSO , cycloheximideB-50mg/mlw 0 aliquotedd kept54-20° C protec��from light . Primary antibodies against p53 ( Cell Signaling Technology , 9282 ) , pRb ( BD Pharmingen , 554136 ) , FancD2 ( Santa Cruz Biotechnology , FI17 , sc-20022 or Abcam , ab2187 ) , FancIvIA-H 7131 �4Phospho-Ser556 Fand2<65-FancI ( gifts)+�Ronald Cheung , Toshiyasu Taniguchi lab%�hpH2AX ( Millipore , 05–63 �Rad51!W osmo!t Co . Ltd , 70–001 ) , Palb2!V8ethyl Laborator!�(, A301-246A2,a� �B!�tXia , Rutgers Cancer Institute <-ATR!Wer428 )�j� 28532>Chk�Ser345? 133D$(rC234n, rt790tCHKl2G1D5 ,v436 4$PCNA ( PC1z�586i$Ubiquityl- ?Lys164�n�13439 BHRF�Sf�4H-8 , sc-37375�, USP6C-term;2�Tony HuaE�PNYU School of Medicin)�Cyclin �in-housA�ClurmanU��Beta actin ( GeneTex , GTX110564 orr�512!�, Vincuq( SigmAv V913I�ah0Histone H3 ( y�179 $$GAPDH ( 14!�z�11A5Dwere used . Second:�!conjuga��|with horse radish peroxidase ( m%% or rabbitr�)(Xappropriate Alexa Fluor�@olecular Probes ) � �Whole caalysates Lprepared by directly"a�.pellets��transferA�/eL  Softwar��y. B!JqFmx� pe�� �I,J , normaliz��`au@control . qRT-PCRJ�u� to evalu���express��8of HPV16 E6 , E� �GADPH geA�:?0previously [3�ITr^� D2 mRN��two s�Xof prim- I�esign�o ��ify�longerFiso�x eEhcript sequence NM_033084 . The fire n} adapa,� $Jaber et a!@[46] !��Forward 5’-AGACTGTCAAAATCTGAGGATAAAGAGA-3’ !4Reverse 3(TGGTTGCTTCC TTGG+;%`nex��S�as6xCATGGzTCkNDC2oCA�%GCCCATA * . Ot�@ �si>%r!�I:6qoGGAGT�T��btGAGCAG AACC� +,T :] GCT%TC `� 1>? TC!9TTA�%E  0,2� >e-Y GACA! bab%��CCC [.A�com a��� stabil�Tor turn��: ��tre�*e� 50 u56[( CHXZan&�i ibiosynthś!a��} l�� omon�ed �a 24 hr�>iodE 2� *�t ind�uapime poi�>follow :� A2D�  I> u �D.] aAs�i$sJ�wh� �4 did not chang� �ing� addi� of:M tillZ�survival1rYB ispl$ � �measu!R�y4a crystal viol�!bsorb�-ba��[72�6O -� seed!�n 24-wg �P��8nd6;�2�doses%�3 day� h" F onceI�PBS%�fix 10d Hat room temperature��10% m� ��ic aciAWAdherent% }s� ed t� 5%>;inY. P! =rin!Kin wa� waAA�o drye�letelya�he ad!�ed dye��  iliz���ainAQ� 1% ( wt/v� G by gentG gitE%i2aQN+. Dye� E�( 200 μ� A�Ř&� 96=�s�� ( 1:�6AUhOU� at 595 nmq�U�vcalarby2-�CY� reaveun��!&ro+ siRNA-� �F$at a final.y>aY 20nM� �orAkcm E��v!$Lipofectam<RNAiM�$Invitrogen���1�manufacA�r’s��TD c%��#oc I-SceI��oc0 )�AX>�ssaI� &, ,j pWvAr24;48E ;% 9F .i��#-C� : si� D2: S4 AACAGCCAUGGAU��UUM;-�Q(n�sc-9339Bsi�jsc-2976+ , sij~144( 1��~�7681!p% Uni al NegatAzC� #{�SIC�$. Knockdow�s!�fi�by>�. HFKiT(U2OS DR-GFP��()�duc� LXSN}� 7� 6E7��gr}in cham slides���-�eic left}R*.��eXw-M�*� vect�Add� S647�2~t��K1X:�!� co-permea�%��2% paraU aldehynd�*5��inT3�D��J{a�,-w%B�1w_XC�20.W1aaF�� � �&y�.� :�(*�in!( tw )a moisu%�at 4° C2��my�da--��ed 3 D s �)}T��)�&7 ��� each%%��!h%N�.R,in dark�o"3dV+%�єJA. F��>�y��2-!�m�"�c� slipm@ProLong Diamond A�ade M4va DAP.J�F4 visu��q a DeltaVi�$Elite conf�! mizcop� Appl� Prec .uA.'d! volvb��dv 6�,WoRx program%%hanaly��. EA expe�lrepU at leastUl inde�e.�?co6���!e�-DRm�bor .&�2HB R .B%�b�����$IT-LT1 rea� �iru�%Gu a* Ah!�&� �. Ii�c/ of gene k�f9v,r�ɾ�A�h ,a� befy#ng�plasm2 �le large �foci c�by6��kin�� it� 2�%P��ir�Rep of inters�d A�slink� ass�b� alk�a!m� EC [32–34]5�evigen� C)A(,( 4250-050-K�� !�� � some modi��e.� -1-1  uM�XA � . A< end�9maVN�O, ��8in fresh medium^A`re$post- 0A�a;harves!�im<a� ( 0 h�So� � Yd!� ncurf l!��elimin�)� vari��t:�}a cryo�er��g dia�� � D!/50% FB�ri�oq�A�c!� �. I�m ��T2ftha� i�-cold D5nr(� %�,12 Gy gamma ![(MxGA I :or GCu toA�ro� � �nu��ofdom DNA m break@ &�accor\ to T.�uE�- 9 dureA���� r unpC.", olow melyagaon� �harde�of A�+ge�flyd!� subjv hq��*aI� �z vair-dryA,%K��BrSYBR G!�v.<cap� 78TissueFAXS mach�FITC filAn*�6B Open)� Plug� �in NIH�_[7�4Default backgr& corr� eu!)� output�)�6%outqcY�ś� ally�JieA��u�o�$�!&A� icAHUpdetail mo��� ean ± SE � >350;) �P �to&$ % ICL rem �degreeAFa ICLs��s�0!Ohe�d-�Ked��%�6z;A9.�.�H!} ( Cp!�R ) cX $u"�( 2)L2i.* Ø )��)�k)�of� i� opor�yal!@�de�s(.�-%�&� :0)�G4���o#y���(�g?per�ag%�6��$ we employrh.\Aoula: %D �i�lMlbICLY*) =[1−9�–%T/%�]x�w&5�=�n23� ��;!�VA91B�;&IRZ@=| A1� >I dataiS� �!MB}s��tm_( t a � ���i-0��>�!�o3!%6� syn�!n�$at G1/S phA��!��"o "-thymid�I���6�!&(��:�!f��cyt��r�al��b 4X' 4] ,��R� �HFK��1{w� 2 mM ��$-Aldric? $in EpiLife� a7out� th supple�5316 hour�Y=t*9{!~�res ed/"�-f�0a��:�!P9p� ea86 � * y:�inF� y6�pano�V��J�%�r�� E Y* y 3 � � =i".�Aq-g��at di@%�Y- esA�J� 8�I���8by .�\&mh 104$00R�[:�,( BD FACS-Ca6"II�>h in L�America-�559 emic co�$it�+Pi�(have undergmsemi-annt$ mass���ji��mP n�ce 1998�nfg,.:fc ency shifn t &to foureAZyea�# 2003\ 2al 1132tEaddA\oa�^rterly�regime�U9r� evT rapid�a*B"XsmiR"n$-depth epi!` olog& d entomy!n = %?8%�h!aN�!<6�al�sQ�e��6�mee�cri�3a%z%�rupZ %��7&�'b�%.-rA�� . HuZ/>) s ca� @fil%lq(ic nematodeR,�XB/i��a��tm>8new world blackM�� m�sp��six c�P2((+zi�Colombi�/EcuadoQ$VenezuelG�'ma !���� ` 52�154320�� isk [�-In<,>6 �-���d&nct�?(F�, Nor6�,�OaxacaU[Z�ua��f��i�giv�}ts2 sizeOa�(579 . 70 km8!!V#-docu��ed � ryA`ABnse>�A�Z��;saf��ed2C , 39\Ʉ�Qhyp#��cE�:�\|0efforts beganIvle 20W!.&a meso1�)h3��hyp.ڝ~Q%�e^� ( 11�x0242H. mpri�wab^ 21%����at-Egt lk ��Si 5 1990�: 1Yha�#�o�l A�ribv#�3ctizaR3��)�%o�.P. A*� 62\6�0%l~ gibl<#�b+'�7^f)�in�4  80z tegye�� provide ��A�sv 6 month!QFL �Z�,z^�&o �u i 3 , `f !VX �'�x "x I�go�'�O� ET�jPh��!�U����o!�D��o.%r morbid�X�>��2q�sevent�&�2� �par�  ll 13��i>� ��W�S0Health Organi�$(( WHO ) [2]� OEPA~-, [4]� establ.1dwe�pofz� ��to be� t decl�M:��l Theclu:" res.!;of%g5Lsb�*c � of leH han�!��E �� . ( �1�!,% !�an�&b ,"n ab��ive-s5larva<2���t .�( i . �, aZ� �ve ^5.�parous.X P�5c- , beE�f� z  ) =.�-e�� p 7!�g��a� a -  pool� D ,�i n�+,be easily de 9i�, s;B sh�v is:�F��!� n� (Guaa�pa�EI�)�I���en� re�� �i�� stu�=& ��7�ough 20�tz* e�koge  sugges� a�8#,up��seyj��at2�6>��b�3�1 � � Z�. I�d #  h�Gauthor�m�^\��Ze ( Figure I:%�y�,d Ampliacióp s Malvina�4DEscuintla municipaL/@; 92°28′24″W�'05°20′36″�' elev�)� mask+4, Estrella Roj�HJosé María Morelo� Huixj~48~16′11~�U�7�5.&3� 86�66�8 1400 �:P*� 0Nueva Costa R�( MtepecJ#��4!5#!50 �,=#6vgR�"ma Agr <cacoyaguN�45′02�!6�5.l!*h& ero �%ayo� otozN�!�14!U��!g1�|6j!�3n.�&���A� Af�j�i���4Daln� uFBLas�ondriI�rk39Aj7]V)k!�692MM�hNu�<I'n^!`�49.dA�06d!e�.m^�8��n� � ];M� Améq(n�A_40�!�06�885R�.� %�AoneC �6����O0��]Ih�tob#� exx� ��H�&fgt7ion��EE�8�Be�� carr ` v� ( Ta� �}R~�N��+�! �a(impact^ "s B����a��� dO��lw�&w�mon� �2NR��araC��� }j�� j'-scale s* )�~&jdY 2010� 2.�%<�!�110n{- high�� �V �0is| d re&�4`* "sfI �iwhoI��]�vly�ly2e�!TZ�2�2!;a,c e�� u�8iCm onl�f�t� gist:O “@C�� s” �199!�vel:�!��2~!)..�u�G"ag P+, ��25%aKBds Ze--�6S-0e8 F 1995�199�X40Fc63fb�. Begin�\��a?re�]EEQ��� gardy � ir&# �A�,Imu�E�.*T%�Eb:�h"W,./%Gina#�B�6JnL 6��quf�!?���>TA�of 22 secu*��+h>8J<9|�$��5Av�/�past 11��veW=/a�#�U�2y@�% t�9;: gE�can �i\%TE��th*� (� p. B6� .B��&&� ���staeFd�"*b)[5a"[6789]��! peakja ?, las�� Dece+*toC ch�#o�C��E�.��<qfirstA� minufFyacGu�bu�a!�:00 AM��eS(4:50 PM [10Q:=k { ��� �LeyZan feedA��d e la UDme�:�� I Ձa�asAestJ!�,bi%!J, �oE gab��ver9 27�a3�!a�f�) n�:al�?}do <suc0-fu��Ga�$od�AThuaX2dpo� iH'9�u�be�$0lik�76� / fa�5�H>#(&i, ����m �b�. F�-�mbZi}"p��) a maximum!�5Gd"�1EI� head!�d cNs�H�"BH�,�A*H5Am,GT bodyb��e.~���#i�a&�ay&'B9 . De�"�0|!r�o��pur�, �5e�A�A!��B�� �c!�!<"p.�  ��E�� ��ud else�!C , [1mbrief-� �-C.A�  C20 s6F'�Dset�Q18ZE*�� sham6m��/G9y;)DAa�;!�A:!f�!)al� ll!;v�84�,�$rows B–H!zI h5t�. . Row A��#�0�10r-n/:�� posi� . On�6 ae]�minim�m��>I% cons� [5IC�t�AFa��2/]viK",�2H#i�{ti�F��� ��� ;%.�n� �Ial{N��H-�o�?��a�"ak effi0Ic��7F�|9 same�%mi\1w 2�3µL!Ra%C_MIk�wa  �/΍In1��pu2A��1�"A�T.()�g at n�1"�K�PP S!-xA��SI-� screE1�uc�on��of�< ,aB�?%��sh,<��on�/{ ���i��or!�nM��cmRm/-y%�cRn%2!䡜s6sa� �% �N any"� y&*$�ev��"ny�-��b�B��yq k�t ��anBJ!?alj�#A�f-;v��. PoolSc!� vAc0e"%�a�!�6[ L��e�  y�Fhe��oc}49V�$�CIx8[1�C Seas�TZ^s [STP]�ŭ�nb�village)��� G.{FK!��� alA!a��F *�- �5YL3�-2 V (i�&  Ma L�z!4ve} &�2a�)�!�a|. AR1"4JdiscusU ,C,m>&p^�& M��"U �xf�}�J�� assu@Qbe &= �� -�.� B��ge0/ic� n [13]!�!;�-�"� � er�' h>1ph!;�Ej��)"�z: of^��� e da�.��I':}�gq�d.!1�K�E6c4m B�N?. f�$e���9)M�,��, i}+possibl�Dp�=� 5�6a"2& ( AT�. How ,�$rpauof�' .&Q�out'"2�16n)OM�Z�D7e�6+e�I�4� z~or� .E�STP:.�occ:�I*�62' �f:) ts 6 .�+ iY,ak�:Q,O!e �6�IgGqE"#[�(v16 [1�1�a rec7 �.7P, DN .��-�P�Hvr+�fYblJS iew Board�Jr Z5S%F Rese��USA`'y�5ing�Vh? ���<RFed& a� G� �xpl|8�l=�d igh%E�yYFdeQ. wh�+eVtA$m*t_ o��aG �eVinC� �5tcwou�5�-�V��M�s$r�st�-���E.�)ach ad�F�#�:volun!�� m~ i.9p�YE�a�E�/2��"�T!z�X apsu%um)Q �proHN%{s��oa桷�9��q%=Pa�?��guardian�-2: on behalfpA.�A�i�qnCom]2�Hi?Zu�+{gof6�&�"Pl�-%&3$_ arEeK)�{26t2tWe�2є�"O . L��:c��1�[cF����g; n[#2 leadHHzE�!�ulax�N�u�).� "��>r�# ban Ks�cat�"E��v�&{a:��onnas2�u�. &i ua����cE* O�X�A�S(q��".�(��$h�1*x�(���W|6�&d�I�&= A�2��m�2��t�.� n� �x��&�"v.nd9 &v � 4�peAL2�Fa�xH �:�ex�!ƙgS!��3{�<harboe>���J�)y�E�*8�5\o�>Thomp][17A=Mief"e�197GN�d5��k�a�=$Berry [18]%w2��.�95%=sur�a��e=E8Y�>�,� � -H���+.220� )�� 03�j 10 SJ�%. ( 6. 616��2q3� 994 I�0 V� � 6oNCHby GI:Mpof�CH�c"nA�su���comply���$7 guid�,of0 !s">U�?B�4Eh:m ���R �8�in�- AN)�U-��9�>�aV�6:-upper � QB�? ( .Aj 1 "x `wk`�$d�5A":A("[$+ 07�+�U�re��ly| I/011 , fo�_-up�*"�Ct�.��.a(�Ut.�(V�3�E24M{"�H � up�!*�)6�+�C �V���NndQ�E,�ceI.�� �>6%"�� 2z� .D�@�mR��wo2nI@si�%)@qo� 7.�BrOhe�ZeX�0.��'* .�2+–!N*�D�!�4)i�77� �6�FQ`f�B|%ffe�gnc_6La Vic�s�,�^A.i�@;-��( !�"/Ebe6��s�'!�6�T))to�7�7z1s�7ed�"D>�!!l���k�!�, r�Ocu�95%E.B�nv^�are_n�beE���N�[���CIE� STPsyUgS �X0�0d0? ��*�t6��S2�1�ys��#��3�E��Blyi�hi�EAWDi�>Pwit6�E�!�G#�r�22.Q2�D(B�.�E5�<)Jeat�b�E6� takApia*�Vu�@ a\ :� �ca&u �zh�LA�%�8�PNo�Zl%Aob�(;%�.� & �>Er� �]{�1�P4���GH�6 ��xAj��s�}�% 7%;m.�01nx�l%;:�v.�ead`=�0A=a6& V%n8 �r�cor� +����od&�/3q�r1�, draXtc7i1M�� � �!�0412)%�iEa�5/or Bd1;o just 9j.h6Q�09+%� � e.�L]*B6I� me�]A0Ae�D/�d� rongly�F5� I>� R77-�Z. O�.���<O",���� �o�� ongo�T2��� c�B�) �� "�e�� e- 201�I<>Go&F;!QR�=�$A�prW\q*`Nal�lavail?9,N]&!M�2�j.5399%j�+�Wa�ɸ2X.i#&Z$�GG��sa~���$��ex�Iu�t�*itayngN�[ 319�is��"z@�*roHLby. !��.+C��p.�)M5t&�' on6;�n�I�!�:6Y!>�4>w51 K+most �T.�a�Q�f@ &isB&rs��v"q(>�4_tJRasS"e&��=.�.8&a!�n�q���^ , �EA~sla &� �7t�5��.@yE2ROC>*�%��Eo�l"PB>l&LEjC� C!���<he��N�O �r��`. 3A��5* "�6�9-���)s.� !m's=` �;itu���Z^n�p�#�tS.s(�of�=#!�npx)!�t�{re�U K��(AfJ+.(u�F:�% 3ng d2��5� w�ki��@!��&�9��+&9M�x' mend�ZqTK2����Se�l � 9vis*���(K#T� statR"V2v&FG�metrics e|o* e2��g! *� �2��g�"B�(ne.3 #to main�% OarN*L (2��bT )/ �K<54 L3/# /�(� math�P�mo�g [20%J 7 . 6�18VE�&� es� 2�4]0 ���!��Zh*�!?"��wov7��.Lu�R�r*�x)s�Q�@=3(��{1mWt ,ATe��AMat if���3i7 y���  =��H2#81�th!fSCD@Q�feo�a ai�SI��-6x2�* )�n�mPZ� � &R��g�7N.�>��__� ge 5e,�%�B,afflic�n.��5>|� edB�E�!�230�(potq*� ��a�:��+Uur �^Ka�a�G-dA�!>"U��A�QrO6�Ba8% �q!v&x<'.�MbyŇZ�1;A�v� M���A�"f":�:� �/#��b�Qz&-19�Yv�'%�^F Ex"�?o995ei�6�a� o 822TBD o7$�2s%OmirroA1x�ar �MfNu�z0fD%DN��:3Eg� !�i�2KoczW qZaJ@as!� , pPpl��d/enh�!A�e-�AF`E9�U !�may@il6zeB�aae x� is g�Q!�vi� �teolyticA3M !���!?�p�-p� . WhNX!�B6�hispens !Ppmo~,Uu {B�H)9�� igYb�n tten�Zz� viru�9=ӆ!-l:a"f*�<�0u�i�)w~5q��onprofe a�hagA��ael�zMu��9]o�'A��Bo�m���8Ine ��]��n� ��. E"�salY�6E�D5�A2 help1�toJsN/�,c�}͈j� MB��Smt1��!at�r"Ae�d<ributj&-n1�!faM�S%F=Y!pabteU<fF�ƽcyt� Ite�b�y�Ti�appX& �Qsi� �o�[�"@�n*r8WsmsvC`��>E~e�_��t�JљScoޅAat ene)e �T�"���l��� .U �ѐA� -to-:{z�+A=y�!�sen�!ɉ�a�anl�E�a6 �prbx�'viors�as��e],�+fil�r�o�up,,���  �oc�By�� y_f/E�[ :F�qramPT3 S�^��im3$�7&�#G-�i�w!5e&k�i� )!���*I�?g+�9y1�!n trigW6�nm�(A%�o{eF/U���e|��� �AB 2���*ac{$p֌e�ie-�+casca�MvA3Z�[� �pF�Hrei4�L�M��5%bqe?d &%)�!se�Z�� U�  P��( e�TBd��ens�_u��RNPP fam+�~��=`-ׁ�P,Gly-G%l�!+motif�!�-��0"v(!C� Rgg-�s�O-b|ng�B� v� ��.qz\. LimiAgX,b�8;fa�T5"�r�Mg!�a �.�e� �ey�el funce Iaj&; enviroS*�H Z| [2&Ym.�fh�%I�7apDtytA soilEi�Dap�J!���G��lif�A�/tr&� �&� indY��a7usc!��=&� �sEK–6<.o� sump7ofJrE9^�o|� ;^� ��ro�*of!�2f in h�ds6Z] �=ly�< ,mild gastroei5ti|+z\ &)a�3manifes�=m?Drp* � s� di}���^ deat� t�7����g�rom�a,��eld j,2�e$HIV , chem~apHC!�pl��D2qeiEHeg�=w�t$� c'9��A�sчbir�`[�c1�Z�ja���DrJ�a aa/1 �6 5}�/�2 �a*�� a�� ��F% to ˙b" .� A���m !1rNU6 �i&)@ :[2�{2�[6{A�� ar� EaIAup-��a�'-m�� nre�!7�J� ( -E%-�.�$�!FmB� *�(Ehs&E�s�l�. "G e�GstyF��,��2�cLw1��� ~�6%m�*��>�M�a�@u� non-v( InlA InlB ))��t�s��e��I�3 dis*�ke�l��[l�o&vn O ( LL�d>RQ� lipaa�Plc �PlcB]z�E��n�� e4#o$��a�~&)r��Mp `?9surfac��� P�s�I�> oie!�JmovFv ( Act�njhex!4 �%1�oIq m5�!�o��ic�( Hpt%!PrsA2�� t-N�g&: ch�# %!:d!cfol9 U�E�R� V�7�I�� �iwE�JY ii.��|E�.�EY8rPUM� �bdL�� Fz% � ou#8` � >�Jt"�O.�!E5��i� ��rm"P E�i�2Z * mu��&5 i�!�;No i�� ar1 �he�\y !7wH typm%-m�Ek��m� s [3|3�QWe u"z���Iile�U-F�-.�>w� rf-�;��W5re��ly.sa2� enco�($by lmo2637� s"�[K Pe�! uw^w�l%(shah�&>2�4:3-s .z��ݿ&6��)l�C�e�9��z� oc!�s fae��!` e L �.w�h�(F V���&A ��MREiK}Cad.n;)�b�/N1��/M!����ce8Ks\A� cAD1�%�!��%�*^�@M!�s�N��� r�;!y��aggf�`��5�5�[3�04BpCi:�U�Fgen�;�s&#+&!ge�Tb%E� -�M�2�uj/� �� I(:�1G, )c�dnF!F !�&��Nao2~�h"�BFsBB~��ռi�(.�R�g. b��)m�. ��(*j#EJl �?�Jabund'�a=�F��$5� ��@roth �� c4�aa2N�[�1lso�plmrg_021h�� 10403�7�GiA�pvHN:(V=EeE�se�i�VntY�D"!��N�Y (�k��, 66%��4��)Ţ%_2��U.�Q+.k>��O[39�E3] �.���~]�r �M�>nis���,"��� y� II-I tleava&�_T�rY�!�22 amin�&id �y law�$ s fuiuAXa�ePG��eA.CZ$!.)0.r������ ���2��> �"�t+ 6a<Tra$�2j�slH�DliT|J �!���2J fQE1�&�u, 4�Tr� RJl�~ŗfF l�Ӂ3� AD1-5t��պ�%.i)q��\A�AE6�w�=�toe2 on�tM��~ hway��'!j�.i= _u��!�EepA^t| RA � ��&�(�131)<1�u�!�B�,'+1#>b1GOpp CtazS�Lmo083�a�� "��GomuAs�34% �0�49��!U>N � a�[�domA-YE�M�orE�i\T he C@FH:NX Rgg�dF�!20�ҍ44�to Str�9 py�"esbs��"��� e� urU��E�ծ��;!appc"� nz+�-%.-!#.z �1�6m)^�:� fM� ]t�J �",s6*} 1AXq�-!�380�Q� Jw115El2Fl55�!E��#1oLU� �y�GQ\�as]f��Ag�moɁ��  DUF872Q�k�R_eukaryo&!Y�un��� ��^on��%bdJb��>��q�& ,�#���� oE�#qB;V��#%�!!Ym�Re2�$ a� f��!. �#verl��*�,�29 � ts n�rbor ȡQ$���pUVNADH U�ݜA"�~. WC&i"&g!�� �g�RgBi sub�j��� �2B�4of menaquinone��,= b K2 der &�!5�$iA�� V 'Bqn2V.Al�A��� �!��� coli MenA%��)4i��s�4�vK*�d9� Co/Ni�S�n��^�B .!8$tilis YbaFZn.ybD*� BsYmTA�0 .ribosom(?)���)P� -us&# by%"&/a�C�J:xa��:�&� � �*|5!�� Af��e/.��,i Z�8 �X@���W.�!:! A FaG�G���Eso�in[�igw�b�:R,6�%R� phys���&>P� �"Ȋi�b�U)��9q!1! F-�.{* m?!struc�T!WE5d:�-fr�cdel"�(��k��co�)"� @D�i "l�H�Va"�p;��6 ed 56�StCa�hy* m" @1(( G72STOP ,Ol . 2Al<oxA)I�}+-"���5}%��&Г�G ermBy��0JXce>eryAmíM��7� &Y��:K�  m-�A" ���)dsj �(�Ransa0� 3 *!�1�\engine9qst5��%�na�Nx-1�)%��QoA*�qo.q�M�� A��+.�*��jx0�Red�%� >��s$"'truncaq>hw< A )�A�2�y� I&�v��uFTee�Wlm� �}].= ё-.� ��)Q� e�1=�^�4{ �O~� al�*�!"�[or',*� >�e=4 6 ��I� s exQg�Ds�\H� &�BHI3"�2�$%�'�8ne'>�� ..AF��;�@!0%!_�0*W/�6l. U�a�[`�� *�!�1e ��� ��E�.���;Vn�t�[{(�+ra\�Yv H.C�-�! <>4 2�h� �; k-� q 2�YH#B���a�A��Nv"�wΔ�DM;�(��WIV��|��$~�k=!f�+=[�us��1s&��XFi�oC , S1A �FB!|>X2y�H|of &�al.�-1�Bs� ��"�3a��� ;�P!7B�=des� �@� Δ��-b�%��u{2/{.�ly!�a�r��6� �K��"-�7B��=c�lu�2�4I���2�2�y��q�tLoщA��-�*q dono7%\6�V .] A���recip�\E s [4j4.P��"�- �d2Ssubh( Asa? &:Eom�J �.�#z �2��[4�4I2`a*��V�P�$=a���0�"&fa(�-.B�!��2��7>i�>dmvEzex�ol�Z~ j.� v6�W��(m�9i Cn���  ���=o settGA .DL�9�F�*��s�hit�Ksh�I[3jN5$��"q ��ik�isAmno��mi\ r�l\ghi5���p�r��.�� ��4�B$�!�Q�� #�(az�eD�>$ �-1st�K��niʈ[ �~��*�Yo�"�5f%*��n:nɮ::erm�6e���*� & �%L140F� Au&i ^� �V�j�d %a��~=�. w���o4bd.ty�X3| 2j2ult��(  n��]at 37�fin� A�U�o- �wAicS���V�oo6=�.iQ)-QMH[F 'i�bottoE � t؂�dӴ��of��GeS4%,wil  elm�r�2u7�- 3�In�~A��IICI>In3d6 �a�w�3�u�� n�/Ek)8�)�Aq�A�e}q�}�i i!y0f.�u�5 �~G� 2baJ 1 �Jv�.I�si ( S2&� F��.+ �aK� *V���� :� E�$J���E�� ��a��Rrp!dtXpl6� F[ N.�p.9r-"F1 Q�21U�ISp�-� �6 a�6�7ne*duc!Ua2�UF� !O�.",pald�:9}��!2/.<"� �t�h%5*� a v"< W �2*\&� ] �;�Fla�B5O )OE<�d�KejlK"��C:Zj9>f-�� S2B*� 2�.�b��A���} n6� = 9��-/esch�hi�li�1^.1>.?� E�M�W �*�  [5f65!uW� e_"](w��it-i2� � [efA5qea) �V"�!  722�M�=- <�c�a1�.�R�;i�I�mH�S.m2�5*>-� �2� �6P ���Ma�9"���C�_�^~�vg� al+ ��u/D:6;F %��m�� D!�e��M�fJ�8sid�1��&�Q�c9�1 $( ASSLLLVG!/ASATLAVGk!plA� kb)�{�H�1��b"�;.5EA*lEQ�i-�e��.� ( S1.�C�[n;Q�G���'_%)K"x>_) L L20A:[�-P=R���box98 ogb�,by SPII [53]& %&z] C����ftE.$2 @� !%. eu�.^LY�7�!i>8>e �9IQ&@ 2�A}��"��8�!!�i� �� %q&�!.���LM� [ >��%�$TraC oligo��;�%�*<�g"Qt���[� *�u�$27'5E%F�x"�a�s[vev��wo!� :ABC�er �� �>z$y>of2p&:d�1"�!i& di-Ektri�%)}F458�3!�2b{$Bg(�219Y��S;)�4%�2w in length��=��^� %t�*�� �� �& ;sj;�+ t ea+^��� &�L� d mac�;7�a��C[5! q%-*� s�@���.�2�(�l&�j$r{� -aff�>y cUI5K [)�ObF\=���R��6b�$xbroad-�`Z3!^qdŋY�hh��� .4[4�:5 35fv�a�Eb���&2S9)w8_��bur p %����Q衴��5ng losE1��a�s%L in ou'c�A � >"� 2�E.BQ  W��"�REL�2 �1�. �f�!g� � �2�}{.���F�P&�!�-}B��7 J�i�i�e �2�,&7��.XBw�m�2d a�rX_vA(.$ͩs|>�ϛ�xHr��3�hyd�%obie!*� a+���-w:��FC�P%2.�fb�"���>-� #�/. *�#.@0a�!��Z�'#�9#`�'{,�.�& $�m�� �1hK�-�p s .�IB�'�xe .��d2uV��#DJUon�T�dx�(8-week old �$ Swiss Webb�]%��ven'���2 x104Bon�dg�x�A�B,� ,6� a~5� ,2>�le�S� r7.�#open-�M�jq he.� :�C 1�  u�4 pIMK��'~}���  Y nteg���nI�AtA�euD>tRNAArg �#�s��F "� e [3No��P���1��l`)�spleeM 5�m&L��&n�{!�.obu��}�J��Ss�� mR�Las u���-�پb"|ٮ� ��� logs� �?Ea���FmY�i�Փ4� �A� ��t � �a�d�ġ��� �n�a`�x��ne�^�aF��!�Q��F1�h �As� �� �\=�t�\.�-���[�� �v��6�:&H�FN�  C�Sieer>� !��?y1l"d]3n�!!&��i���C� !�mie$ a1i&�F6W � ��|.2M3!�Z�ORFx, �/�~IX,c�cP(zAi*O722 )!2�1Y�d%".�! %� ��U>�:ot":cp,a?%J�� ��[  (��� �B�ȫF��H=Q�-�s=:�B�AC"� ��:;(p!N\��&+R�1s�M sA��t� FB4O6���ZE*�I����tiϽ|O)�l.�. F�j��zr��!eri�Ki��e^6�:qatr, 4~72 ~:�.��"�:�4Fk!�� �M(^� !�J7mĹp�Z��#.�'A6 d&���l�Z-��I�0�I#$n����%��� &gxu�i&S��+�7NBc3�m�Ue��� &� byb�VL6�a-Rf�1�iI�"�� � �ly �Nei oK�P2�b &:U����"�A ������!>���>2� � V�.N��.�n(�; 1�R2�.&1 Z!3_Y B�Pt !��J-G�)� monolay�x.Al�#}�M)��crey?! ��59&e+��2 PtK2�i thel��zsU�5h H�Xi�-v i& a:la�M� Wu}Zr��&p ry%�bybC��W�� 7VH@����'�)^m%%�#Dq\>�I��nt�to�)Nh!ɝ=Qw2�%�mO,T�or&V*@R�9}.E6N&� ���! uishENF!M� �\�!(8+F���5AzS� ly-&f'dQs"�Umbi7%"c-i�fc4z��o;�L�[�Alaqa�2 fibrobw^}D� &�"!p>,9N�P2U cA>�R( S3A%�S3.�N#2�*gZa�ZO'R�despiNXه��or�09� �+ �j M �!g��F L *�_%�5q5l2�A2Z]G,i�-�?%�omQ ]��764A>B,� �� o�'�SS��(@�=skB6Ql2�yI��$inQ�67.�( ^-2K)1d�k.,e��.Q6����� ����#z,Q. V�_)r)��.H-{c�Gol*�[0�-az!�cyt�Ln�L�s� ��L"�L,�Li/�L[6�T6[.Jh- Q2cR� �ŗ� �5��a��a�. A`,.0��5Y� *ic2�lZ���U!~Gme" R@�=Ma�%�)8�w�� �:@��Q�.ͅ�x��*[3@'6jL71� D���>:QO"���-�t� `r accu�ˡ-�>�jy:"8�H�^lflu8c�O] ��� F-A��&%�� H�A�R� `��;�&2�%�A�IAarQ� �?7o�B���r� �2*=� fail�K�i�="�6 . does���  u �` s}_!M� [72|k3]�-h�>�at���pou�� !\)�)l�c��� i��TT*!��@1'Aq: $ U;)Ncloudc(&ӄo v:lUy& 2A6'��1ge�+ hort e&o�#  ub2 �ep�poA. � �a�`!c�U>X!*6�A� t�58%�B7or]�Q��*B!B�2O�"��c&�!% � . Qup4%��\�mp >-�!��Uer%9S�ށ+�NB^8m"��a%t� g6&��XngBν�m1���6PAюi��y��}�S*i�"��Mver"_b���ŀB�e#5�Ǎ Rab7M�GTP� :k 9c�l�*u�)a���%��point>�.7�az�Exar<1�u� .� . 5V�gR���Iׁ�F."aJ�Δ@�)�)N� s n0�*s� p{�IY �355�/ . 10- )�`b�&�6�8*�2�+&nor)��3 ~��� �#J%?v~. F�O,NXE�G-��J����;�uncr�6A�� �$�^!L�� lo}enQ� mark��� -�29R@6�6�fff�B| .�l��6L��dJ���DM7���{A]f�.� h ��>� 6�eQ� ,U�2�!�d"� �2�SQ�5C-� .H�< artie�O�a ��fO��2R � s [75�fwW��FdE �jB2Vitself�"�&'Ys~�aM��v��iJg�2P��u.;@ d q� �B��C ach6��Henry^� ��%x�����=m��n.M �0 #A�a�-�!_ye..�  ( YF_Pf�tracellular L . monocytogenes is thus an early readout of vacuo7�amembrane perforation and can be detected prior to bacterial entry into the cytosol [74] . Transfec=PtK2 ��s expressing YFP-CBD were grown on glass coverslips�in JPwith either wild typeJ�, � ΔpplA or Dhly mutant . Cells }$examined u��fluorescence-based microscopy at 15�<30 minutes post- �!B|. In macrophages , LLO-dependent-�eV�>|� in 5nfollow!Db5�$internaliz)�, wherea!Lmpleteuescape A',rally occurshabA&30–4t[74 , 75!� BothrAB=�-t%� observed ALindUby!XZQ , indicat� that1�[� apable ofY�ng�vE�=o<( Fig . 6D ) . ME s trapped1 hos5�s due� lackd LLO secre%�( �E_8) did not stainJ�:v0These results�e �!>pPA�8peptide contribEotoJ�-� from �ar�sA�a step a$is subsequA� to initia1V�. ResiE�Y� populEw s ar!�ten�first�sdencouA� Lis�G circ= ng i 5 blood [76AlSurpria�lyI�n]��7A�a�Zm�y!Ey�4of J774 murine�-like ��9 WpataU:K�OMsresemblA�A�of}q����no disca�A�de��� osom�Oi�Q$7AE�Simila�� �2�\primary bone-marrow deria_9�s revea�Lno phenotypic differ�� between�a��_b�estrain�� even=jn activE I�IFNγ�B]S4m�a~As menaGed�~ ve ,!_>hI]usu��!�A� s associa�j%nQ�a6ac��F#^|stream .a�refor�t2�support!�vivo tima� urse datami��Q(�6IA��1impairedP(its abilitya8 �`ly colonize target organs �:1��enhances=�Mi�(��sA�$cAMP recep�`protein ( Crp ) -Fnr fami�sfB� �or� at r �Y�*�N. P pheromone pA!nsignalj��ways haveenZ)�5?a@el� 6Q,in a variety' Gram�i�. . ForM pl�2� ���Ash�Yto���� mpete�por��$in Bacillu� tilis [77� 8] ,��jug%� [39 , 405'9]VM@ce �?/biofilm!�m A80–82]xEnteroc���6E �fratric� in Str� -Hpneumoniae [83 , 84��>�=�GaphylHaureus [� 8�8! W�"M�iN�Y�F�influ!ldA1� e~F;Y���s� 9Enoly^r!Jes.�wo-dimenW gel El"mi *� O if� on�$mass spect�. P�iiso;d�s���n!]BHIAvs��onF phase asB-T sup� A:��toA|� m0 �� � pa�teu1l aggreM�,E�.t��he abund� az�f lipo-��A`�[by We\ nH $t analyses-8,antibody diri�ag� t W� AݭQ��A!)`�fi)�.�� �%-G72STOP�$nt �� fa�it�F�:�of chan5D C US!�A !q>2�BEuO e �.6. Draa�. �XqJsIa5�� � in-frame6)^�-�10403SED5?Q�ѷ9ŵA*� -�sy�GZOeabsC k2�Q�"�-���%� whil�no �Iv��s����y he:wIfT72 �o acid��e"c>��koz���&5( S1A*�Ine�rasA��N�fHJ* ~ cultur� ppea 1��&� -��+x2$ ( S5�, a frng�sfnt9<T-bconstitu��F3 . ��2� .v9i%�q�!�in5�in&.�.A�d�d"�4!s.�L� antl��minishedJ� *� we cEto focus�km�T*��>b<��:���f"$( summarizTY1e�S:�e�u�M]6���: )�e�a:9a r�z6� al�3up�Ean -ed�trate-�=�!1vol�� et��nd oligoQ!ABC�H( Opp�,u`fol�, adap� to a�alA�ditio�detoxE ,��bioene.ic� ��g.B�bolic mi�Z>synthe-��1major��iOse!doE�i��b[6�SecA1* ^Mk�a!wey�I`v� (of a classi! I�3A��� , however�igq2�Cf �2�b[87 97W� nfirmCa.� �s�%icUa"�a?(�inc�ed*. � ly, �ell vi��"4 � l CFU^b!'q�m,Q�e+nif romi�"-lg%�as vi�e�by �imperme�5 dyes��B�TW�Hit[�� yet clearPw�i�R�Fq"�F� /ar�, {ev%��.l"� lead�ebnt.� )�pertoi�J�I>�n�<rface-�U&. B"nQ��.�de8bSs��a9$at coordin�YcommunP �!� lex multiAYu!/ L)e�:), DNA��ferA���"�,!�wA�E/�y-Ao[1 , 2�a[Hw�Se��)��oa�novel�rol�a�BB , nam��"� +!�e��Y! dividualN!�pa�i2&�Mn�Exper� ��s -�zE{J�i�le�byJV&V0aB vage%�-���"I�!jA�al �c������;G*$6�jv-P~I%?i� nd �*�g=p&. OurT6? � may V�= �R#��m um�wit� 6���-bound� , suchM9X� )E�4!�(rapid uptak��te͓i�cascad^ at a�matA�5b):ar� dissolu%�!O �al1|iM�ytosol�1�&���2+)� duRYe� �-�(phospholipa�Bmed� �*cdisrup� , el� "�ne�or-�!}gN%е-�A�Ab nM1 link�oJWTo our � ledg!�thiE"es X � �vhbe�� t��]=:�Rtu�Iy>!]m\"�HA�"2a E�9'� ��us fa� !w ����nor�'� �_ "! in b3!�&.� ��,l�_�" ��&�m UR &� $previouslyjMJF#>�BK��uman ep�#lah�� � doesc2�ec! a&�" �Dbe�a�& #up�iZ#r��mAP� �� o� B s [666 , 68�?��ut%l%��[90!p"I��A;� �w��o� &�pro� ieE�B�sM�"^ Q��!-�,)Kc c�x ^��N��perhap�!��� n�. BBEQeir � 6%.A'aoQ F,comE6s�fa �#1�2$a pseudopi� truc����pha"e� -�& !�M�!!F:gCom� psueu�#\O yFj 9>!Giqf� [91�QM"f�o �N>�fG. ����Q^�o1D�Qn�0!Cx �.eRf(C'!}-�)K� ):� e�k(6U�h6(1Tl�Zq�%�� d� ]) or%�=d-�a�inE�� .!,6(each system3��z sT"f����-Ba5>q.J��sN_�ze:xt�.jT�)IV*s !�aas��a!n l6� �[92]; giX pot$ �Ͳ)myGR� ��AD1�F�,in E . faeca�z tempy o%<�qI( u-�{2"m iefH&or"����s.A�E�aidR1. An al"hyp�dl� !b�0 F�on �*� �,!(��$uՍ=itselfq� &m��. S�"y2� ic��� t�ser�in� i�layers!'t &O &�[93�0�weO �1����f )ify~precis�0�C)��Qx(lyHbe hyd bicA8na�(Y��� V�I�&�.�favor��A".&� � �a� �1�%gdxH3-��ai \6���L2-)�of  �)S :r"��#=��any.� ER� ;-M 5�� �2M�LO�6*�rb���othrough &�ism �i s �y�LO& �*s� !ure still.p Henle R{ �a�#^i� &�'*�(I!�"� )3�͕���XI]EQ u�u( 2 )QI!R � Yib(.y��ed:,axI�a modela �im� A7� m&� stim�P@><F�ge.;(EK-� :�,�"�#a�)���qVaX��or �a.�zyq� s1s0po."�&atz[&�m�$:)0(GE%R� P8 )��po�2�a�� eDs��wa���d!��� ��!fAA�1%��/ �?9��Z�(�]�(!��'��ly�I*0:]�:�Zq;]�:2EzHa{6�4);!��O�( 3m12Y��B1oT%te*��6CA��0 � ,�(2�#x��o%|Q�%|�"�"environAF O&&a){�V1.�w)b�F~�icE?"��-Z � �A��Y^�A}*�!;�=�\ high*[(!��2��\9*L2���5�ja�P!�c���)al��+.WE.z5H `"'p&r Bl�� ed�-[6�&7V&!Y*D%�1s��� 4��!LL$�-1 ;ic�+� less o�0def<5 . Fii�shQ no��Z�!�u)� pock�!n�a)��v��. [9 �u�6 fe�OunU �@pI�peF3m .}q�A@ ltho���rem%��� !%u6-principaŠ vitr&c1e���' i��`A8�~�s"� � �u%out1$ �t+Hi �' ency���#��@u%J"u$Q�&�,B�& c� s�=��Q��releva` %Bpk2Fzphysifo5�l Edv."��u.1Q�5J�A�&O��.�_�7�c (of>� )6�'���'!Odhe�( mammalian�e%�~ e2�lE�&f*�5ege� ve��� is����mix � , fibriLp)le"� �� ���ttD2��D hear�$D8� ^um cau�M|$ve endocar s [9'19 2�.�$u %9�ucaap�:A�!!|�ss���!;�!�!�&6.m�-u;s� Dx2�%[4�1b��s�b2z/a s� �(G�)-Am^A���te$ ( AS~ ����A�7&�ocoN�q lasm'by !�g��  don.nd�ipi�>� �l'proxim\ }F� ~briN�m� �]on�J �*ogo�)o!.�"rec�studyE6� ActA�z>v\ d�E��n �,mer&;oaKM�:��r�Q�D�'�4[5P�*` VN�5n$:�# long term�5��!�!��a�tmi�1> �fo���.jA!2�-&s�`�w�/��M�*�͙�!DE��(6iexhibQV}�2C"�sa�om�,to:Y ( S2.�(�)!3R��re�I. 32In�iiq�� �:"�o5-4hloramphenicol���di�a e���$�.�ofV� ( S7"�F � �.Tinr pons勵e*effic�.�to{ .� ��bR� -kE-�� �%L=$ Q%u in flagel��% swim�mo�1ty�"]�nt]f�sy-F4�Aj soft�.r�#���pZ69'}.!p85p&�e � ������(ao%��B�AAW z8t&/ usefuE9, ee*�,��m� k��=� . To."� Oi6:� �3a&�(.# \"c extre9$chE6�g�+*�%b�;!�onl�B �hJ �{�a}" �Y�.�N!m=���/ dh2ty��s�*�1r� � ~v�:�a�ngZ�)3 ;;���*5)"L��SLLLVG )AT�! �lengthV� jA5 �m5́ see if2��b� �d�Ie$approach%��\uc�:Ao. I6 � ��J�E���%s ��8��Q�B�g��ձ6[�st-��� modiC � m n]�.|� �m.v4pPA��AD1oy� (A?�i:j9| 2"��AGA�al N-��i ��!B&� A�{>9[4�.@!62h6y�\�)u�O !/em@!%z'l2c)�`,%�1�1Gr2adr>3%�a�E:�"�gen2�by Rgg�]s [10L P-�p�^b%�� !�*�.(at very low!5 rv�1aK5"���su���qA�2  4ng�>[4g" 101]a�nd� Qworq<o optim�����Azass=�genF purifym �!m�6� YFQc 6��eܱ��6n.a�c=@ngA�NMg coli�H  ve��k(1��T%���z omew��#ce=!>O� ��.Q�Eci�N"� �!L over6o a��2-�.� 9"2 [4o951]Ag�>P!g� �zis*�! td�<opz9���%���?���M�a� ��M!E�'8co"�0��:=%� 2Eͼ�}, <�Hs�!��inJ�%�.2 �&� &:�{2 u�"?A �F۽s"� ��H!.�F,��y�ly evJ2*�!�&�.��!* �C�0� (Iq�$o% h eI�q��! %v-�%R\2� r 10 ) :J�[a� al5 cb1�)JD �9��"�bL a�r�%�ory���'� ���n�Mk�gi� by SE}��RII'a�{%@*m-F%(� is!m��e=8diacyl glycerol�4anc@<]!�R�Lgt��C�3b embed�4 ��is furd(Y�by Eepv0 y�(+a�>�.�m�I]z�T &2Bspa�OCF ent� �Y��iX(a�!&L m!A�h6 accu!h���'u` ���`BDback N6}2& CtaP�:��A[uditi�Ka���" .�!��� ��$�e��s�L!��/d !�sta�2�o�� "X!2<�-&��#nfl�se�s�s7*\ . F:�EY � :26alZ�!ll�+9%�@9� repl�KMz���6%+�,sp�ja� (�OGmW0x�F elucid��N�� igu!k�~i�at���oNC 8B& IQdi�9�  IQq�|2*�'/m�A�bC F�A1" �ins��I��J l�;�92 .<8XL1-Blue ( Agil)TechnFQ ,, Santa ClarCR9HOne Shot TOP10 ( In�Lgen Corp . , CarlsbaE 7\NEB 5αF’Iq ( New Engl�BiolabA� Ipsw��, M n SM10 S17-'BH( / kind gift�olNicholas Cianciotto , Northw�@Un5�)�+Ek1PAg�tenb���a`Af$combin�"�9��K@Bat 37°C�AbM1 infu�(`B)k(( Difco LabdSor)�Detroig MI )�Luria ( L��� . Ma4 ��g � pPL2�"�E!9u�25 μg/mp>�., !\,R���IMK2 ( aY�D@lin H%,.CollegeA�k )^�50�kanamyc=yP�Z�|-� �_�X�� 6X H}dDPtagged.i>  pQE3aiQiaaeIncedVa�Iiu�ESE���.d�S 10�ampicil!.bF �2%neC!aE� Va0"� ��e5%DEC� mNofA�>Dm�P�7r �N��AV��.B6-fr�EJ� lmo2637 (�i ,lmo1318 ( eeDUa�ME.�^1of�-?�xi�E�, �25NA flanh1{ 8%� ampl/ N}�,>�m�U�+ Fldjoi�Ru�0SOE!EPCR�d� �)dig��^V+�pr8�6ri<enzym nd l�N%�)�toUuG �!�� ermB*x/�ery�*�8( Em )zi�q*� *.4r�b�=m�pHY-304 6���$raig Ruben! Amanda Jo�, SeaE�DChildren’s Hospi�4Research Foundi��-i�-6 bR4!��Y KpnI si�M�BJ %b<6.5_�ll *$=3"Wha�biVi�B ��U��5�v�N1 to�� }��!�Gene-*�%IsI�*� -�&a 5.�94 frag�'12.�2�� �zthek/OQ]�.E��A�-%� ���| %+]F� �G`H� @I.:�2�!�EmRE�CmSm��<�Bby.�9.u�E�F�ch�Kso:@.ſaWA)F�Q6� creeA���/B�A<�>�R�V!a-2u� { . opE��.( -�*�ba>P^CmR-�ae>e , � ,E���|A4isU+��J�2m�"�� #}� )�� sing�Rp�baAK5�e� a �7 tache�R� �=tRNAArg)V&` �o�PB]FM��u���m2�ɜN %�ntbC.��begin� 9 /seW-�AUen�!&7 $or just up�w>RgK�6�Y6� NcoIXma �$j\ly��b*c�I1 �=B �6����Y��Exh@DA�rop~ .\�J�gr�Y�U��! method&nby Monk\<@�����tw$Pp� 1�. Tra�" oΔa�::$a��N+%)�xU���3�[tF�s%q,�da' >�[3810E�aM".md�!Q�.S'T�%F)!�A��z�!��runcaR�Zi�Q"�Paff!�y:��A��!x$�dar�VQ�e2�^ �] ��!�N &��q2}O�6'E^�r(]�)]�9@"_ >"3�2cp 1�a�E&�Bmf(~��!M�an.6x-2 ��As�R8yl-β-D-thiogal�Zpyrano�,( IPT,!�W"c ��a�p^������8�'Hn� �%.f��29�night"�-+�A2*�6� dilu� 1:50�1fresh�� �WAPincube"A0th<; ) untive al d~;0 . 5Jr<ed!i"c�͌2�, 1 mM)��alc�Par�$Frt�aS�^�ure�%���asa��'oc�D3:4 hH_�he��-bl-�ņre%f� wK\Af�W?`u�'�in��PBgS 20 m lyzom �%0igma-Aldritch� ' Lou�MO&�+F��*f�V0gso"jJ��58e%�10� burs�_nd�Tf1E�on d,/u� 100XA�tt i�(Qcktail)^%�iKaC> frAo�R�"A�Na�-2�!�cg�8����His-Pur 2VKit (�rmo SZ(> , Rockfor� IL�P�Wa�|I�Ced pa BCA1AK!Zk;Nj��.neढ़�seB�Vepa �G.TXQ�2K.!+�*.�?1{>D&|wh�K��^�EBsl�r%� s [38E#E10�.In�-ef 0 ml�of @b�!��id-lo��B/Y�[HI�� �h��. Spe/�`3G.O� quiv�0��" ( ODEnm.)�$r R���=9�f�T�'lo'�% acidA�CQ.FQs�+ ^a)24S"S. �siw�!J�/acrylamj]NE\�z�.s.{M er�/o� PVDF""!�h���.a �� a 1:!I彡H3� -�"�� Y0bp[!&C&"(-�B�,( FKIYAAQLQNł��X��T ( PfLRI^ PMe���pyF��05% T�g-2~"��?���wQ�6��Goat-� rabbit!�oj y&� * �lk�-;at"( SounBiote�wBi��gham , A�)Banu *pS grme8� �!X�!V10���AIP/NBT P!��DensitopyU�U ImageJd.w<x( http://rsbweb . nih . gov/ij/�loa� html��Three mc�L ����r�&� .)!+B��]a removF left .c��room-*�e�[ptvU-� atnmQmeasuA�at-]N Gi poin��6s7�2vilie e�Td��A_mU>� ����z��C"p-e�6PYsP . All ih 7 d�[%�IACUC417&xͽDog!#�our�%"$jp�* of Iot( cago!�ve� �l=� �Ze�ed��Co} �%�IQa�n�∼�C6 .� �G U ( cor��(�"o 6x108W/E�!�wa�[,~��::� uJ� o. of 1x105W�. 8–10 week old female Swiss Webster �( Char�Ri Y5dj,5G��%�inj �T��ul�*� 2x104� FI Q�� v�. At 2�c48�72 hr�Ns.;r,S� sacr< ed1l�>splee�+har�h� Orgl?�0ge.lt(a Tissue Ma"b 125%� Omnig6�o!�4, Kennesaw , G�!�EE�kph:d�[ s�.h%@Y ) +�rNll�l�"�"t-tes�"5��s�J98y=3�) $&G'A�th�+Hin Potoroo tridacty�Ikidney>�P:.�t) �e�Cv)7qP�wP*u �upHa$m���4B�t69�e�I$iE�y�Man MOIf100:1�neB�:^on�%�m�3X%,5*:!gentami;!a�X to k�!� <%�I칠.��gx%�u�2[y��t�A�ile H2Ovr^)6�y�enume� !6*!|th(|��st:*�u.�89Jo�K�-A��3;d}i^� [31] ex n�!)�'n%K"tq�DAlexa Fluor 488 ph g"p>�%)�82,Z� 6%�s �%i(BI�of�RabA�E��s%V��iR��&3�5. C^�t A��pkvF*0wV �sfix��J]�)�*�T!�%c F-Ac!�%\��+Se%=Q6� %z-35��>�� bloc:We*��\BS ]10% FBHmP5E�)(%, �1�go�" nti-%�(�'ruz �'y )>vat RT��QBh.� 5%donke�Vti-�6Texas ReF(��.&�u�U4-�as �1a8 %"v ( BD!s8 ~-�,2�F� �k�� Ia��F: )�I/r6M of��9��,euMI%�Y{ ( ye  &�zt���f�a�+w\Ido�}? ��A�;n Ply11��MK5�#,5�U� ) �{, semi�Mšt:�BPin�w��������`NG"0Joel A . Swan�o2($of Michiga� Ann Arbor�*\)�Fuv 69romega�Hs�d manufa�Ufoto�=�s�!�� U�w5F ) ��5 �;B��ZpV�H�f� F-�6X �b�y��� B� DAPI*l ^�1��Ged grcpi)mpy~�x( BMMØ�& [-o"O�A2fem�Iof�tA����(�[10�oR �&� �&Q �1:1N��Qz!�� WI4&�4η� :},mousey-y��-�"| *� of-824"�9�V E()!=.`. Plaqu�f/r��ue�a&D\.U1�9Briefl�6-�L2F obla�Ov '�"pp�! 6-�w ti� �)A� ��0&*�6rUG&i� � ! 6� |"3'%�s�(? 1; �zf= L2�=����1�1��@ d!�B- Neut�5��&�?F�Y;�p%�mX*M"��;a)�me!��6 nescd, O*jC�}!��&��+F%2%�&��?or �2� 25~ glucose-6"D��a�2% qd+;rcoXn��own6U2.��6� aLO�!d.�e1�1w�8���&��-�:,LABT� [1M Qass�If!"pH 7 . �,% 1 M NaCl��%tonu0ß-GlucuronidC ( GU�H%9-3�U(as�by Young%`[111])Q!%� in]E4-U#yl�{4lliferyl-ß-D-!� ~� ���Gla�UjW� | . plcB*�G),�c�p�����;� egg yolk2AD[u`11`<4Antibiotic-fre�N icke:R�&$�[( vol/vo���5 A�vorte �orm)7ung2���lto +mol��LB�um&"V (�b 25mM� , [6� 113I�1��$mixF �po8%Petri�(hSy<"  ?��lyea� I��j�9�~%wB ed�a�24�uQ/2.P�Lz%of opaca=sure&���l �CS�0ary-pha%�Qӹ<1�9�A8:��5hi���. O� �R���p�� �%�*�x.�� I&000 x g ��W he2x!�col�'!undq|�:Za&�@hemol��5�ɵi�a�pq&(eV) -��shM+/cy$*( C�co��s �3Reamst�+, P , NB'11�kB���*eD�D� �fE�.�%at� 50% � �`2�`"�I"am�A�"�U� ?��a1��sV�v {eI&!�Ry4� ��2�z(�drick�4 MadiW� I�_H!� f spo]�e[(N"omicsK6e Fac�S,�m0Re�Ce�=!�!&��)i��!�� ^1� �-�I�_di"�(�0�!3#.H"�jЇ4O�ob 0 C.�z-�s�'&5 �uL�p�[O��2�<d* �Q�M\?&�t�u9x.�1 vary� 2�Ni�!n LIVE/DEAD��L#��V"r$�O ^�[5� Ú`O<Is6MX,w�tV%7ismA�a qua��Ee�E�=m�!i��,^�Q�iP^n"wY��]})!, V�So�v lera�? caus /d8e�ch".7s �R�6zel�<:,_P�l;a�=-�0e2R�Ze oxy�8�6� ( RO dH���a�wLissec�ej���m�%%u�M� by V .��?5 bdEvf(q&�*% -gen�\Opo� c.1a�|i�Tn-seq )p�0�i �>�/�Ec)+s-I~adult �/%/a�$�A�+�tB�lf oxide<4, N-acetyl cys�qW]D"�Q�-��� -"�}misma�(�&i�MMR|fP"!s5?as Mut� dispvd?�E^%.�adv&>%H[-n�>L ROS-&% ��8Lin NAC-)U�@r�!-me��g�6�$% lBA WSatalase-!�In�1A�rug�E�y�%i%# � ���dkp@a� m! N en�%� �A%�S9stresڍ�kr�Dc�S*[S � � �\�rl/amsmo�%pv�laer�c�:O�P]uS�"�.��r�R}�l)e>B s&�wly��e>Wa�5 0+)<. Tak -og�1xs�o#2!���aQadigmB32�employ� "o���3�� tegy!b�7a�B9�+l�-in-� |n��� MoreA2 , Δ%�p �3n�2�,!�):Ou���(Bb:�mu "inB�;�ByOIM#rmXt�,m��. V�"�= ��A�pandemis�s�"��b�gaq�r]��anI�I`���o��aiE�EG�W�Na�f`�Pwa�. In ordA0o� v!�WA��0��."`��2xN����co ]!harsh�*Zonux1��i��lgn�ndQ3GH4�th [1]��$a�' , ety�,6�#=4h;a4a�[22&6x!&Kgen2��reA ��*v�t^defenl&s"vQ.ƍ=�[2–r3La�2H��:����$�y,fc�O`k�Program��!gforthcoSU�E_O#1�*� [W,7] \j_o�a&� %�a�� F�S��s�]top�=t�?nd zo� s�ՏE)H �i��P��A���pro&t�* a�|�,yV|sses;�l � nutrWl[ n,Tozox@<t ��]y[K :��DOe��4`W�?�,-��|�q!8� erq �-B\[9���f�~��es6!m8�j� i �'A�;2���� �0 f ou�)��1U:ZO ,^ ��m� e �+Re�2peeV�sb�A��$��o�BA��Zde*!Sb(A�~a���h^!{�:_,P�e�. �?-�.�-3ed�Lrrhea [1�!.�U�R�Qp.h�i cT � KatG� KatBOpe�]redox��Prx�LkgaJm|l&dz5EpcmH4Ohr 4a I-�nJ<nkHsp33u)& DNA-c���e�cBv=J ( DPT 6+6�U.-%�q$ce [14–1!�in6:is&�^be tigh' �Au�k� �.� OxyRH6 �?E�1��"�'dp��!�N��� an\or RhkvT xyR2�a��r1�AQuorumŸ!Fy9�s PhoB/PhoR`:-e{�k'20'�A��� � or , AphBalsoy 9��P�"B6 �)se [2e�F A ���h5k a)"[:!�rz�k� �under��EA2 �� a+� "?l� � �h?W2I����#ra�qRin�]Um�&[. B���^r�j�1�T�wolt � �5E �/nt"-F+(v em�d"w|6 ��of�h�� �D)� [15!�w2p"=@;+ ,�A%aa "$YE� ˜�ؚ�&� � )&"�v�to;� )�*� iA3�U D�T�aQ{Ph& i�1QritżAbm�C!�a!���s P;9A'T m4 A�[2� H!�e%�A�WS�~��2� s �sAv�2�6�j!�in�f����=�qrt=�l��&`x Esche�`li�8alD�lla`RicaQ ovarethiATuf�@P�xmon� eruginosa�e�beA�� %6per�Ot�G�!# �Y�� s [23h�ܐI*j�p�?� !� cer���\� G �|9yzka�"DM�to p"����h�9hikAe�!�"�1�!��0y�a� . Hm�P�?ۉ�� 6���-?-0��X�SUM���V���X3!"n Y"�zANc!�*��i�! :M�d�Di"� ac� ,Bb Q�y p.j!� e?2��!tU�� Ci>Se�&�t#*q . �<;/�F6la�Av~X��! � �{�w.��~�{�Qpto/"Rf�e; M.b�.�=e� c�e!�d��!�n�Zos� , 2�+2VA����=o5'weO ѡa sja%e f� 2� wid�p�in���an�E�!�$rt�id� R [2� 3� P& [�*NAC�N� Na�� ��5re dA� mark`W����;a F12�%a Tn5��!� inoc� �<" libre�g-�hE�%v��a� �~"F3-day> $( P�&�"�d�Z�r"/?�fe� b"��(�/%QvD{�%� Illu5.n[6]!� #K*q�)�Ki���inp�out !pnt-1A"�I�u he */ ;3!x :Y� j+B�U )�5��6�,p)%g 1 . SU�alu �Ř�^T;z�&� -k�^"J � *l %����c��pootq� ��.&� �ǒ Dat�*, valEWB!@6�!�F�_e,Ys�86� $ E��F� 7/�pm ( VC�Q)� � oPA1006� 6 013�[16.� rpoS 5341w In)����� NF�tQr& `$776-VC0780[ C126U , ef�Y pumpN VC06��VC141 ,67�NVC2761>A01ۙVCA0267*&��e*�"� gs� VC00 #VC230]2A�q�6�]2.6�Dsub�6E{in�n�5�)i�!w ]i�*:4te�NSK(AY6�w� �= a�GI]hig� �y�e�Z���e�� uI�a4y��} �2&O���U�e�-B�&� ,"?.9 Amo�8h�B in�3  w�)R�&�YKM[�!upoo�os.�B����tOof�!5D.O is1��F5[~6� &�A�s mispai��baE �gm�gb^�p"$\err� 7 I*�G, ��� gniz�e \� &;�s�0 MutL� MutH��. exci�& new�%y��s6��nd�5�*g 1'�g�qE�![)h,.�7m���kH�Y9z��KA�er=�D-��o+-�iI��Zr�/>� am%�M6 ( uvrDDcJ%din��|o*u!�b�L"�-k.2t re�_�aZU hRh �Djplay � Y"56EI:!_n!�SLHA"��Wn�~r>�D �of �o��h2�,�&�#ntane�L�yl,��c!@a AlS11t.T!����6\"IE���V(� eci�^%�:be%#�&� �WoBt . Of��eT6c�6h[�b*Reni�E�Re�3J����*�oi+�y!Y�VC2120-�a}A�MSHA pE� g���Qat� �398�41�B�&` ���A=o"ds%� we�� A�tR�������Ѫt  in�� immun[E��(3��M 7�^�synerg�<ly [3Y3�"�2q��sc�6�!I���l�( 2"w;Remov�@� !�y�Z+3A��A�k�#9Q�>�we�s \�! -CZ�j����"� �rtm�rif ]�Z"�Lolony><�1 ��D��.[!��x6={�*�ppredi! �5�o.(in6q>)@Wxג 100-����_�&���2r J&�%0E���k� o�`�%!OJ�.bej,�5y bar�Wa)en2�!�etr e"�!�mixAH\e���-labe~�wil��2��MuF1� "6F�"�*Y@">* �JF2�� &t,da���MHj�a�� O�)63nd>�U" e�se/&�+�"F���-}!LB2d0�u g 2B��I(!��%"#!�a��e�l�#5�ig�w�out)�u5-�"Zm.�At�4 �� :i�P x�A�/WT )� ee�1a � 0q�W�FK��h!(ANA&, :;> ��:� ���� �ur@&�m No8f�9&� 9l��&-y" uf�,1��*���lJc��>�:"� 5h �9 26� I6ዕ���av#`v�� �?QA�%�����'&G�Z& *l���!a�-b>�>����(@+�_ɭ! �k�=%k*�o avoid"Na�A,k��ɠ� s af:%>s!=� ~���$}Sa �Am lacZ�{�f q�"$bd,eb֒ �Ϩ-PIc��X"�Z?G>z�h>)���b$B�.* �#wed�:i(�:: )��I anno�as-�*�?H`��*&RAa�{2و�-�t  !s!�"֜-Oli5<6Ou.s:, ��"I�� 24�- �ed���鵃a�%�om �v� exes��-�~1��100Uf� 3�Pli{Vy= squa�l�:I�+"\:�eYbla, Vxny �E�5�A�Al�w(es!�5�5U ( WT!�e��m"!6�p.�Tn>9>�%�ar �nA�!45E�sd��� � B�~��%8o�:tW,g�A!5 ��h�O �k�P.�9!*�J erit�E1["59g *��s�a,*9 �_tro�=�| �q�gba�g1�5thM J'9+�h"�7A}AKI&"�$�M Lum [37]-9C<2�T*B �-�soA�w�ly�I���)� C ( �[�x*yWo -�LB�Xm*�T%R�^� H2O� �y� �%&�:~�5a�/UQ ��&�6� half!� c=�mdi�6�/�)r�I silito �expf'� �U� g� circA�0ge-o $ANOVA P va"n=�; 0005��)ase�e�1n+h5mM5 y.,e>e9�.*���E�w �.!�� B,2re&X9=&2 ��*rX����A�3C �( 2}nex�R��a�C.�N�Wp>�%$� �  m2�� ����7m� e��� * to�w)!Nc�'a1iS)ZA� � ��d �"�f�`sk� -R�3a� S=�![�Nd6�2�� ( k}(ka}([9�(byI�Z3q!_n�_ 3_t\��� a�1h��z�f=Ek�B�)�D".['.��a B�2�Y�� !"2�a�re�-nr7 o.J��!�x v"L �A2���qrl �)BYd� � �I�7b�1F��e!�lur�!�]���ng�t?(�B"t:e�!�'wby-uRA!2� 0 �NW%*��h! A�wo6�sA}+E�M�xAsA�ɍ�A]��t0=:�WbR'6iu!ra�� d^%��16�I�Et )_.�Th�� .*.ce_:��2� Cv7y�h�*V� oxyR�:#�*I�g�*,:��;i:�+[1+�1ig��*.�!�5�6�M�C4o1�'.b#�~��(2� �B�*2) de�!.� U�5:�P"� �! ��!T un����=6.%( wrink�&) �2% orig�A�b�6��5�a:rey�on` p���!j4A[.j6an sw3'/n%2�.�{�7p&�%&�0J�exovZ sacc��d� T�Aic^,�<Nda�a�#grqara��%�3R2���Mds(g)M {i��at��f�!eR[3�V4�$u&E ���he-J)-;wIU�K���-˵�%ZEwp� .4B }!,#(��Z]g�# l�Aa� � �1��S U|~5%!b ~30%�f)L ���rmRBi U �,"k�kper_Bag�� �VreEMWI ��x��m�low�VE��.b. � # A/55{\ �be�%�or"r$1"*��>)5� RR���&� ��F�D)�!oa*A��x2-&��Y�j�>5!��4үv�aA�"2!��}jpBǎ� �-��1�-%u. liquid��w�aeri*A��4�  ᢁ aqo� U-?�a=r5 � �� l�\ pane�G.�+i=4c�gn�;JmiWB��R�"M�>��OiĦ�*9 q!��1 M/�r�,l�1E��om!�bexB)6�3 / � �\@� -�%R2��Z�Z� �(me�1�.� ��a�0g6i&�a y � �9K7rgen�/�-I"L " 6��e�� �J��H����� Te"�b�"!%� U�L.�� *�a>���A��*Nd����*~�XiVmiq3��{�c>P�Fd&� *�.��MI�+\E4^�� ol:aM� -:�0~-4�5A�Yj@:�1rix�RY�4To� U-F�H�) !�c-�B$" *�S�w� aG�AcI���GJ*�1͔�X6� ?*�Di Ur� r *�$2�5�AId&/" ��$I�aM}�d��:�I$5� A "� � ��>i�.�"Չ*�'&l i�>�=�� o �-*�<�8xqVt�ag"��~&� X���H"�F!�&Ӹq'=i��f�*p@�9�in�7�-dR . BijP!�S0�� �ub ,! e air-�n![CMO85&5�M�� o<��)@��kil� F�1�QH�or6! μM cume�^yd����A�60JIa6��bBY�%�t�a 3�!��a�1�c�!�-B�2c'9� os"ƣd�i %_�-#�y%"�*i�voPp �I` bead�LznsU�&�!�4�z�BR���?}rar!A���<0�A�-[!�7n{ �;�i��,n )%;1^d='�"�I/J����mp� ���Aщc� �p�(a�NwR�ȥ�� a�Ɉ��i^ a��%q6�;mhc"�- HapRe�msclip lly-��dB�ha�Zд -of-� hJ��?v�Wa a: �tM>iz1��:�y'V����*j�8�j,�[*�t��E��E�=I�FV�Se�)A�"�Im �Vl%5o%l��<de�H"ȡΔ!7�Ackey�eg��o=L= 0� )���Cc�$�� !&z�Y*�h�`�E�E A�Me���uAv*Ѧ;4)62��ca�. GJ s 0� a�}�š�'&�qH� �.� �Q�Q�e fB �uw�n"?vpsL!�KD�I �jUum64 �I:�R�,[42�4i"M�a`�JIi!�eFU:�6� �+VU"/ �� ��2�]��� 5*1l�-C5D4*=!���)�J��m��~�&/i /Δ%�st�hR�(�B�"?y �W� bene�2�7A�6?��^!gc�*, ,�e�t�:�A�� 6�1�������22��Sea!tmD&4G �&b%<,.��>�Aw �/(�kd� _F alsodF6�1� �(%�|*."Lv[4�?4�J� en sou�$k�� %t2BA�8 tinc�5!o��-" �3ٴ"� . "��$�)y5r�*`,�'��!0 *:,9sGg �9ye��c. A� 3+F��M&s,�voutgrew6!2�#AG1:n�t!j��UseY on.'�2�% %_���!� a�!Y5e5�n/poBi�Y]��i"�/�"o�af�,2��IX %���&�? �2� ��N� i��7�� 6��. :e4��!bwq�r8-A� [.%"c2���;��!�>C ���"�8agor���L!��!%gC3X�"������>F�c�� a��H���� K�1?~D"�"%�C2�e$nEm` W%;,.5"%o%ce.7�, �V,F�!��%�.A&�ch�̥kA�:^'no��p�ceQX� JF�!PFGra�2 �S�4%��'A v�*Rp�6 ress�'-Q;���;�5� b�Z���aʤ��a!>I�s0�2jxE�>yAJe AtEF�C� �C|�62�A�<1�&�r��~�C 3sE�� �XD[1b6* DI�Oof2�CNB�XA|X&�Il�;du!>�!��G�?�uG�.�"F�\�+wio�# ����)(,.U����R�Z�2I�[Oe R�+�( � 2�AU�7*|H6 ��U�U�OF�yvI\�L2�OB�Wu-����!]�ss� u}?��2Y f*B .�a�\�h���%�� �B5�6o:���aD��6�:���!� +A���%��6�>�Z�X�� ))�&*�$&� ��AX���2� )�-6,-*]�훉3a�s �1m�� ;V 3b %�6Yni�6.] be�c!��swf q�����+$l�9�Z [K&�,s� F�en.;a8� fitnA=&��B dUe!���cJT����tu(b�t� 2.��›ex�� V%AO AQn�K E�*ĕe"�7"�EqY %�FP3 * &�\!�y%�!Eat�0!;�[�]� A�}!97)-a,-�� ~Lnd߶&� �p@N0��s��-M�.X ��=J�)y0�9>x �&� � �/f�i li)�RH JR*Q�&wR�A��!�@B&�\2�!$*b!��%w%,&�)�*Q�/��FK^�h�f�)�M)�)��X� I�Y��W�c�P"�.w�˭�YS��d�-L"eɂ��]� Dav��,*��i8{��eZ2)#��t�6�05�<)>�ib;. C�deC_ashlGBi!��8r� ( 18 })%�Fp;ba_�$R�am&�2��)V�->���� a o��)�A.E�|ae("� *�K"ըG0in P .�#QB�;AR�nu�%�iR, � cut: Scse�8f��e�*9�p�$s"[Qo@�aryng12��Ty� �q�#�,[25a+M^��-Q�a.���AhA��� *lI�x�%�ݸ�=&ZEdo>�R,FKHaemophi��A uenz eNeqd6�me�S itid�a�S.>J��4Y,J*KAfmA��b�na�"� aVF�qesqR��P�$"�^a�!�*�(%a GF�>2H .6��&���-J8>�pat�\s'e)e�iV�] ��s [��IQp�-#2��2U�iұ�Xnew2�5  ��&�!A}��� .t:,helq�*%`ost�yZX ��P2�E�5M� ��5A�c15�2L%3� [4D�Pot�U�u� a�I2606��f7eyO�T�� alyz�17��b�-SNPM�8rӄe!w@�=9��}&�"@� I14!�k&175H' 2������[� �4of!Rr*a+)�E�%��� 6 t� �6<& .�K�)�FhL.P" c.p6.� 1961�196 R�>soMC��beT�� �Knth])�c�e autha�caR�m�ݿ�.�s m�)b�6us**V$��1�f�A�Df� mobRj" a�i�3�J� obZ !�_a� rine��e� ae�mea7�!36)�H2Y|�� �qevW�n�|�Yp6^�`s/6 s�"� Y l�MI�8 fQXs��5�Fe*od1H�2��) bala � trade-offUn� a�#>�Vn [5�(6P?6��%���ownG R-Q�e6�-�@t�!su(+q��0>J�ve�+1$lUJ!�2�[5B �yF�(�Tg�-!.�M�G�~5T�E�1�MW�V�r�"��2�.����R [5/�W2�5i*�G2�,:f|^�^� !:&� .>� �o���i%!�at6��blm5�N�㥢�a&Z���ia�ad^fng "b:Dp�s&�-� &* ��� 6��"6U.�K!�&3R�S!�� fai"(tE�e!$�P��96��(� 4f�� &�Y��A"A rD9�isem-"0..�jR���6� J*Qli��!I,�yv540N �סFof�"_/��vc!�HJzop��9�.*�й�of6v �- �:r��is%��\��*�d S � �'�s� BO1I��٫��& g� rhoe1 a��"hR Bv��O.�^sI�[5ad5ad>�2! ŕA�&B2 -��$5�F6'n2=���� ���ˡ,ackground ( �ΔmutS* ) , suggesting that reversion is not due to DNA mutation . Cell variants in some bacterial species are generated without the burden of mutation , but rather from r��e biostability , which can be controlled bymTtic mechanisms such as�Xrearrangement or epigenn3methyl �\[58 , 59] . Alternativel�$the rapid 9D � ugos%Esmooth!/@vitro even though?xse cells have been repaired for!�DS may simply becauZ!�selec� pressure8�to ( �va%�!�Premarkably strong durADaerobic growth andBrefore ]E@mMs aris- 4ly . The exact.�,of O2-depend!�)' -to- �@phenotypic switch�Hcurrently under invA�g)�. Hyper�ble�ai��I�1�%�cod!� sequ��s dow!�eam�!�laca�mo��� �For�f� of)�dAoe�p�&H10 μg/ml catalase � bovine l���includE�%�a�Dum . When necessar � t mZ<����shae�to avoidA �ri�"�M ptomycin-��(ed adult mo# } ��1� exam�2� сc��� �UreQ�d5c [15 , 27]�%foa Amod. Eja~TSix-week-old CD-1 micei��<i!G� dri��wa!�or> �\a�dToxidant N-acetyl cyste�\( NAC ) [1% ( wt/vol ) ],on�$ek . 0 . 52#.V� #aspart����t!�ad�m%:�� �e i� A�)�J!� wo da � 2}%��r�x� [6Ito�RNA%��ed-[(TRIzol ( In�gen�Single-a�n� c��!�synthes��u%O��r�To` ruptRau��a�6�v� %~�ut-a���of glas2ad��c s��!S=����to!k ��~�%tfJ�"M!�� eV( h%d� U�s�%'2m�!6O��>� 5p � rifampici>�&� z� ,./��Vesco� S� ��Z!xy�:*���)�J� J4Nm: &@J� 2��d "-6�.� in�: }�� %E2Vb�&� ��F��|5m��� l&�a�N��2�(.�Y�:]-1� 0nP1�[Q[VZ 2�d in2�P� -luxCDABE6�al fu7H���51:10 , 0N *�[k!t9ȡ�.05�a�4e�,�� m�2)ania; al 37. L�esc�? e�� )n��6� OD60�A 7fik� &~09.Z2 sod�hdodecyl sulfate-polyacrylam| gel G$ropho�;�DS-PAGEMB$immunoblot� �� -T� seru �[��*�"i of HapR-&@"quo:sen^ i�coD�1 ,� y�E��AL{yi2�Xn [68]%r�� 7>rQ| *z�� h'�7�lLBE��v )(. Msh2-Msh3� MSHh lex�"ac x'�I�n-U stim]�No�#;!6�buth!4�s:+445a def�vE�����Wb" genom)c*� mapͮ.��hw5+%fMR+)�!�!b MMR-!�2��? nullEZ� ?^Pn S288c/YJM789 hybrid�kndom� �&�,A聞![!=Wsho�incA�eeV%n�#3nonUD�!,�4nEr2&%P��beA�re�P~*���!v>e"�&,. Our observ� s�i�� ure-�!� !�E[�(�ale i�) *�rotein-  �Qi�')�E@T# enzy�cA���ny�� illu�nte��9ؕomponG&-%%t���)nT,- ���K'�<�2VE5Z���. DurK^�,aO"on/"�#A�base-;q�%�AN�ܡ�rep"|'err�' �cogoby MutS log��SH�)��B.in tur!�cruit6L.6L26� orm �-ry��6�1ed�, {fMrx�W%�s�JteU? ��& ��of.$ exci Vre�E�A�s��%H%. [�% In S'e�!siaaEk.c�r� &~%loops��!o'��*�in � arilvi>!h odimer����!2"�� Pms1 �9R$a[&�%����BE�'proces, aD�!G substit�� 1 ��iѠ*�.1[2–�$How�!��z�aj*�qp�,aK�� [5–8�ccu- ch� s�[segre��} I most"2 e'qui� reci!aJ*ch 1!�g�-J p %�(:�)"�,hk's [9–1�& Failq0 hie�t l3 f#�� ( COa�erI pairA�innondis�U+��+neupl% game�. E�in9YV8�:a�� O1of spwneM(misD,A�birth�� s [1g'Y�%�E�)4its human orth�� MLH1-PMS2} exhibitB` �Iv ņis �-nA�� Ew14!|5ATh�/�is &V1o�&�SgrR!2 �0l���'�+8( DQHA ( X ) 2E 4� me$b�#ng motifɫfo5Azlh3f�K!2work dem�*�a�m(2= ��is X D523N )'� vΔ-�/5zz 1� �Ea�U�'a t$T2e� de�Ksp�2vif4to 70&�97%%& <5!�fol�3du] *qQmap 8s [%�Con2�Pe6�,IK%Z!�:� %P nicks cir�"r dup, �#"V ,�E�!B-YE!*� 2J UG[16Aa 6S"200� �nd break( DSBs$r!Tduu1!o�5 � >�� )X$,A��~90e��  oa m COjX1h��A�y��? �mres�6p]5D.� �8NCOs; [18–23]^IaQis  a�6�6��� ��tatiX$a.�x ��s1!by 5’�)  ex"o�A�e2�5\o72a"� tail��sid� �(DSB ( Fig 1�On�I� 8 inva2/�r unbrod -]EZ��xt�5d�7:to a]tl Men�'va���� aEI �A seco.)�1 initia%e��4, know�& 9fcap� j a� -anneaD1%3�$ �!AdV!vnaQ�B��!HJ�� �be �d upon!�N98� aK Q�CO%[NCOa�cpIF��V��aa�A�a)9 ��terfer�*�b�3��=IF)AuI�ev.jdHJ�7D � m�!�ly spa� �( tepA��A�TZMM�� Zip1-M/Merd1 45 �4Sgs1-Top3-Rmi1AKTR ) he& se/topoi1 r�? �'.a�&Exo1 [8�,�Z3' Th� �!Lbia�!*��n+�~ es�m�As=/�Y\�"iFclu.%l�RCO�M�i*1�P*+nt��X�7%��+ ccou�� a s�(( ~10% )*�CO%�t��-�1��51 M,Mdo�*a�� %2��6!@I��"�lya!H$Mus81-Mms46�,"� ^ "!of���2[7 , !�32 , 3� G� - phys�(�3�summa beM8supv08&� !I�J�n!�  e�3�am? -���1��+1V. 1 .�stu�&�&inz� 1� mlh1����!�{�x$.two:��65 %633o'2G ��s sign�#f,�6�!Q�re��*���a�� ��d?iI>!.�s=i,., Yen!�(Slx1-Slx4 [�%�]A�$(6&�ng!O crypTor�upe�W�1�+ four�CI�)69a~!��to very�:levels;O�n mA�s�y�tripl�5!]*me]ls main�!�4#ly� AL ma�� of*� �/GsN�I�)�|$�)�9�a COi�u+��[�.  %� MLH3� crite��E�mam�.!6�[3!�3G�3�2!@,e -/-),�l�0�!E an 8N94%)�.�&�� germ� �  fail!�1� i � A_at2 � A�c:go apopt �N#M�@i"�;#2sto�.cw �v�=)q i^�aeN��bB ��A� �4B���� � mole^ ��out ;>�*,\� ���z�a?aQe�2p*��!A%�~ !MB� !".X �[�f �o %+A�by�yM.hc���I����[A2�J16�73Y3��340��1 1U!-�cleavagc a �wC�ord�8>;6<%c�<lyq� asym�)loa�R2͒�1�!t� .*� littnsV imMC�4�O ab� howX1h c.�=� E i�&. A}�bioin�)csE[" Fungbup��T �'�!��-��-as"U&A�2x<onA��e��tetradN ��Tatp g  SUMO E3I?- E��ځ�>�[3�Cur�3 they�?n�aQ%3 E�6��:�K  msh4���*m ��8��� ��q��"rBI2Ms5 �zq � )�� �en�Avato&� !�*�6�s��asa�!U9' Zip3�k���9� 2� T �l�Cng>�-_In"� :7�odel g �[2:�"�;; ?tee�Ͷs�7�+a6|��� MSH4-MSH5%�P!2��-F� ��E�v�m 4� F&6� . By$A�biochem9a_ E�0 &� sepa�.!��)��ckL* w�2e �!�1�s�Oin &�}{ expla�<a weakee�~6#^ Ht�G� a�eZ(, "�%MR�2���-�Wm re.� <:Ysx�vea<�Ji� �%�R ! �#�#. ���-nH�2�N-ter;l ATPh !�i,Gynamid3un"�$d #"!�$linker arm;n�Je sY*E�overl�&�:C�a����do�� [53WeQ��U�B�Hged-to-alanine scanEADA�>*)�>K� #�<Z6'=h3&UE(v ,2; S1–S3 T|:�. Cha� idue*�'id�B“�” if!<r!Dre�� � �L�&ecuE,orqh)y<�!a� amino aciJwit8#y%=,E%�:�O dir+ <ach�ab"t3U,t���5U1 s ai%�t*MA$surfa xa\� -�M>G"�!Hi�l�%n�KA�f"s.�i��� &d �Cplace�$a?%�p�+ !�!H QU�.)�N�B�"�' &-4*�%P�af'�QAh9I�un.�x �uch$fu� appl�^R!t��almE%cs0$@ �7 �53�a�b"3G)�rehenA viewqD`organD��� [5�AsY�>�.��a���2#d!4T��e�6��or:����d,QC�-�P :�!� �`!��CO � �W/�heYNec����oG,7!egeH-ly�wn eo&O$# in diz$�� |.goQ"�,�". �MMR�Uemplo-� lys2-A14 k*yW�=��asses!iɧJ��A�ha!B3 ( S1��; [556� W2N�-W8lh3Δ �C�"��ec*a�#�-�j3B�k�u; x ��6 }To�25�6�� os�!�nt)�3 GB �(� i&WplosufU 'B)2�9���� t\9�#!�ed!/2 ��@&�-:�{ly visu�G$ �!�'V�=C"N3o e autonom(fy?e4)�( [56];!G 3lIn%Δ�w"$�V/t!�"�.�$6d,G"t4XFer ��/��N�-b�%2 efaY��A�-�!�E�on:�%TC atm�g��val���(I#�-t!�n�%�non�.n�&di�( NPD )�n�Z�8b"7Yeym be�v� u��hv If.�(� �'5�1�3�&&��I |er*f!!� e-2�Z&^*| � i%W����v'� �U���E@5�aDut"_ E6�(u 3�7Fig; [N�aP,'s�(��q�� �#e!�E ATP- 8(�x?�O �2 ���z wFosV$� 2���R just beyM$A�.�� ap-�hb/�P1p1e�ź9C�i0N5be6X%2�%?�confi� g!�t6..�F*AK6�9� ������1i�G{ !nLCO���0[4� viduT%lA� < T%�OUsix �of5;]6,n 9as�A8�\&ZE 1y ( e . g?4M�#�$x,cA� .5�*| M*ZH2Ba a��!�onH>P��Nb}]ar� 2�')d�a}�4.+a nearly*�6�!!�aN�61��h$2%��( here�Pre��#sY+ , CO6 1 !��+��b�2s 4� ;�542�e��� B�^�v�f5CO�6. A�|&��23�)pla� &@�� e��* bah5a��so it�-^#�:A�a^)I�+XT���{^��A�Z�!���N`i���-�̡t ��/"�"�l,Z�ac>� �%��J� ,, h�0%E �"�0.v -�D&� ��F� of E 38oli MutL ( LN40�,nd2(WrRJP!~/����ܡ��al��]licensekS-p.&s''F�[5�5�:e�&u0��M�"v0!&�VnV\'&�&}�n@0N%0ZR0�0X.%;�EA���[ �’�d�Q0��" �8Ua&jN 'cm�-0LH fam�!2�Q�6d�rY alig�_ : AC �C ( P/�0HGRP [5�en%}2*0�Cs F�,�$1"� , lo�y� thre� _ �( H70�DE70AC81 4��H85A��@rm�(2�1�J9� ��m#�B�ͺ2CZ19%�2X �`� �F� jFeof B .3 bs6�e.(��a-K;e�2� 0]� :�F�kAc , ��2}paEs �)�p�s�#5�2^-�,GE&Y�5�p.�/.2�@v�A�lh3: H52�*E5�$�^�70�$�%\q�IE�:Eh'1y|ofJZ!!R)�RF�can pot�4l�"l�,��.mQ� E^s�� ]'%5�9%��M pKvJ� ͛I�X 2�Y�f�"�b�PE��0* 3PBh�;dE\".�� (/ �-�{F)by dot#�A squa�7)%c1 3�J�  ,�4 �!590R~�lh��39�5523A ,E?h, -40 8AP R530 57 (Ea8701 A-5\As.� � p& ��M�H6w 2 ��B%a�:ϵ�!�uK IC@8�bK �#��U�"�I��Y��F�1tE�!�:Vm�>�6��>m��lap�w�o�r�&&f .xdn;�]ifFG%M2i xR} ~oA��a� �B��Z�Fh�!lh3A�I���-4Y���by�'wo-hyb�@AI.8 %��.��Ń�Y� � ���"�^��30�ar!���aFK )1J.Q&��.N�dI��sKed�� 2L,ŕi�kpAmJ6}A(Q�� �;aLis�a� -� *>+��F��f��.�'6tyX�%�2�.�*]�@ m]�!�2U.�of�f&�fot b�,?��iRnыB�"N AqV��N�E�"�.�)�ng����rf�A�)�4?i�]%4�A��dLa�sU/�i�2�� !��$%�FkY�����@'?u�=�F��� -�PJ�>�pseudo&�,Qhxn�N� 0IAG!$o1G l�6129JQ��� ribu+'� salt�MdgW9#\9?v&�@1u�p32Q�5eIn6�b.� es In'��7}�Wj)�rVE��\'') 19 FU bulk%"1RAisML givX��!�apar�>�'Ac-��!�d7wpw;�n�P6�"ze�(�*agel-fil�/S[1YW*Sp�[BP-resto���-��e#��r�m/l�5 reng �� +�=engineea fjNl 8 �%t@"�LBwQ��>6� ��2�i�2BI ��15�C�efa�a�Q��&� ��,!���lika�i�GQ{P!:T.��!eE�[as&YM�l/���R6 6 ±Ge Milunof β-wcsid~/!�v�;Ax&�'�i Ah14 . 2^g14*g6 %�H<� 6�L�%� k?h9m� "� M (4[� a 4�Vit 'p�"�[!Q�)32����!r��� y!� did ��-�!�*�7u!:ZN 60�X>��,>� 3B"��@s�%A)u) A&9.)�":5!!� 9.!�مP % �JW+"� mJ+�K0 #W�V�K��%aB��A2�E߅E&�a�+l I�Desta��W>� �2� 2��fe� 45�5�� �)M�a ons;h3����M5�4wV%�592�?"���N1�*W�XI��Y1j�3��m�� A�"� � �tA|:�,a UNwhQ se�k� � � �S�vj':�I͏�8�<&�pr*�+s  +L��uS# scaf �2� ze%R�(1��2�� usA�o�i�M4���d�7. S!�alm�-�_ � dea:<�6�&�2,�.5.�>, ,i-5� &Z,<4��4je[6 �n�HS�<� �W EUat~� �9do����mp"�ba@t( pachytene;!'�to mid6@Yn2A&S�2�F:�&�-N�.J�-eB�M;!��.g{�o��tY>e,AW��1%t�A�:� .Tog.4��B (8@�'�*1��!Ma6>Z � �{dNN� �<} �(!E Discuyo�A-aSv�$Z*a V��C%%+fy#�o�H��-k �.}� �ԩ0"�re.�+z)�$2��� �.Tis Q limi%�foM%�6�<���`.�-�Xz0�"Yd!�)> �)��"A�&L( XV ) $�8,Xg�"m*+H��-�4Ax –7��-�+�& ��m'��2D �XV����AV�60�$�s�4&D ; S4�AV�&��\B�a�!.�"� ; 3&s�)`�&teݒ� d32 Vs.W!�����2�T�ߡ���!E ,b�:��&5Bin ����!A"�FpNs/� �Scandid�R�Nin�4th.��7�����.z-!'e6 Q�u{ � � %9f�!�&EE[C"�5�+��m*�Vrin�t .A��Y�uA�%115 cMA�~70 "o�ymiW B�M C �W�#q��e,�xZ �;/5E morp~,#s! �y2xH �+sn:2$Ch �z bD!"N*~52��7�~>�[63–�t�rQ��aDJ�g*1. Z,1�)�!�b Y's�⵺�K"� 770�, am�F��3+*�byA homeہ�&( ~90;ţ�p)eaz�PA��?�M��M,6���%U�Y 23-*v NB32�" E��Ca)ome-w:]�Xr2�? 0o.z�������1hos�k���(o_ �onger�w2�$.�$!s+AM�` �2mm� ��7 A�tN2ci� a�ta ��NiZ�6R!�}�}�=U4K!�J1�q�T`x��in�at!".�V%�, ��d.���Un1ca. ��� 3�"�- � �ht$?a��<�ofJ!G ( 84�J9O ( 82 �rm%W��~ l�.( 8K6A "�� �$iSKW?1/b82%�B3�Wh�ASfa��J ��4WzN�?AΔ%S��#a ҆!��O!) ( 70�9%�r �9KL� B�&I��'"q�!ist}�H=*�.��o:s&^ i %!�diverg I&!�C �s! �:�V�"mi6`dWej�]�1]&�� on�upf �&� ed�qr2�`b�n��-!��~[/ds.+]�Q y�t�@��I�KN��I��g�05� e�aD "��< !e�Alh3�UV�P��Ajal�3w 81aroK#� availl7� &N� D�ub Biotechn�By IF on S�R�b Arch�hund7"�EK5*�I$s SRP09662��SRP11034KM �g"Y[SNP�B�445���!�!lS,DCO% NC�A&MOll;^���L��$:��V� E!� �&��� any eD`���AI�!;WQ��qQ�^�x�3v F�rL' h�% ( IH&�2��6r#;�;se�;@*(8s)y�lD��.=in.w�d�0P o�xin�3�2z �*���s-Uach�ig!��pre�h part�E�e.�g&escapZjr��a A� �h� ic��I�w�f-%a gdMZB&x how�&y)T inviV!e� exis�o�\w!�y&� �6!�-cITconj7t� l� �$w� c�`IVE�@;2>"6 -���M�8� prox�'rA� &1[69? /&$�!��>%ZU�A%E�Q��Q�*B��]r2-i:� 0seB�WA�a�$�"re�l�@�Zz 1�X,�*c��on opp�G�JR��&� 32� �e��0.V����0. gB02B�+*�)) D &�%,ez*a�e !r�ey�*@# J�g�g %� �s����ƅ�F��fA�3��7%'S5 Df�ut�9c%es*�hs� %b�d��R�� *� &� ���?�/���qwae����Cn�m<��6��?*�(a]�"����� 6�.MR�N61 1gnoVjQBL �B ���ng� sCO&�1343giNI3.�y;voz>�f!�ar 2mi+-.�gAN]n �C&(� baRAY� m{���s&H�.�the�5"',�7XWA��� d wh"�h0s�y7.!3ATP�m5�84!�eS5CM�ya686XQ�6TA�. B� H’:/�5/� byBUkS#�J�~$"Y��%�j�[lh1 45��+�,"<=�B fA<��6F�`7D2�326�"FR�*#l2����oB�aa3-�+9 �c��%�4 V5at�.85q�A�a�!on�3"mf�9�b32Q�A&k._`w� � sis-] �Y}�I�/ firszepa�A!�6qs%�iG`<�� x �,dY�.]e��bo�Fnt� =l�hi!co-n��2X� ��%M!�EAY355���@, CEN8Tomato::LEUto*3:/relev�7 e>w,, THR1::m-Ce^*an-TRP �`@�� ���@progenvT8a]dfr��N2X( 4t,9% , n = 252 =d p�Ag����J�D�!eow!�� �.pN� act�"w:h�gndQ+p>lz$�]N-�nE�A!"�cf�QInW!ul"lQb4M oug��o���| berr!�6� ���%�xCmb�Pڅ��63e�"� � F`Q*O7�In~�"`Q��b�W-�)�e� .n�>2w %�"P�")�of,U�g�l�S2z,�2x_A6� �"o.�sr�^(_` )I�A��jY��S2� ]. sgs1*�CO�dG��V.�![7bUS?u�vaA6�eWA�diQy�����#��9as�or)�n an N! i1.�z Sa55�X  SSNs�_��"v�*�9#a{�A �<��a�"i4!m��/SSN�!�i�T��s��mN%Z&�y2SG� �2w�9�q�-viae�-7M�rA�a 2μ mK�-copy��.%!*�e�AS�Δ�mec<y�@8: 76�i .+nv 69.�-2μ; p<�s0~7χ�os4�a��. ��Ep�* nt MB@Dpal (A3ex��!��D 0�BLa����3v1+�F(GLF8 > I�r&/G&>7�1su�&��d�(32�C-329D�Mx~E+p�or1�u !*� � F$"�Yg�]IՅ?-K706A&iWA�iAt$1( /h�-:�6� ) p#c<C!��gs*�Wa � Ul_-Δ+��-hdAX%�78Us!/.-��(��o �% e�Z��N(gh�i��9ia�9�95�1��.. S�maE( 8 T W0W2Z8dm6]ab�-L e79e/h� F!6m�i�SAl� |� � i�3�n6|  �8J 0]�� &�p:�pY)�ve.���ism���s&�;? �E�d��� .� WF) . IM.�WVp` PCNA "RFC��N6� s;%2�u*�(utLα�� /.h;�A&�t,A�Iqin�@� `2�|!�nd&� �[[7Y2A&3,���s�)"( �B"5P2� infl��E��ate�Z�I~-�oin'L\�loc)�.3Nex{�+�N<^�{,�� w1 �s���at!�-bed)�� i �5g2?F� on&lp"z�(AV3}�5Ix i�I�ѡin�0Oo�( 17; �M� ��"�t"�-�A��*�V aZ"O/͆�kVS. DҐ3YCro��lab�I�� �}�)>�[#��"�vݱr[J-��LI}helps�oNq):(7�LMRa�2�TP�}/� �$�NariG�Fi�ppryO)= P�2�i]als{nA�-�0 �%Q a�3irXUby �D�k3R�]�A. If ��8]x� i!&G-eQ0^ � � �2��15>�&~!in-���ao.b!���siF�0�) till��Y�R^A��� ly s�g�g!e� &�|m2r*�{ fork!zP&e/ �a9'%V1�Ven���b#�^ ���&�q&�.@1*0%_� P �+4Z"\s"�M��mؚ�)AE�E��BF".Ie��$2�l CԨ�*�a� l��st20 "z��%����o.ja�\Ea"�h�L6sZTTE��?a�_�`&��b�5od�FhE�e� j!�2V�:dZI:n ��s� ^by�X � cY�@=�B!��Y%�A[��syn��%��?Bc*�cc ;7& �>!<o* !��}q.&���!&M�p� ��*  siQ��o uͲSh�1� � ��E+&),�x��5��b%a�scepti�/0�te�=F� �����")��j�� !�TR5�u"�dB<9�&�^��xj5h4&*FO|���-)�e�a '_tenane�o�o�@20tA?e�,=�hE_to �.�cIa�qa}�H�cer���2�,h�6eac�xcbxiE�!1ew�or"tR6�i�QedA�f�Y!pk e�MX�t%A�terplay � �QEM �Y� ��I[�17�2�*ane��: (:� �V�.1e `'*xrm !�� "� �6!'iMP8aZiF/�/ =�cl�b�9a��+6� b�5 "!3!�Aq�r�a�q��őWpLso�KX��s!z6:"��geA�&["��"m%�a��l�*�F� ( S3l ; S8�S9�&�,e�7�� $'  �_:W�&��r#O�VE�Duroc e߉ . [78]A�E%d&f"Es1*�M�!}& �3 lack^yM6Ao����*�">=���JatB"tE��#2for�*�n=x)�d) ~1 kb!���to ~2 mlh2Δ�$��v>��s �Q�L!-m�nr��i#�f=HR/;!6 r2iE Z�a )�a"I 8"�ZwiK�H) �y͜y mod� >~+N|/mi��. A6XY-oz+�\a )i!]*�M�upe�at�jd��� U�!D�2]��C"�[�10B �d �Qi*[7%�H""�wP6�?s@de�i(�a� � .HTo%sy dragcW'ng% ~"o(��/�\�'��hf(�D!lhu*j a�$GmT&A:�u* xə ssue��6�04�r�k�O�&.E�� ��A�a�>m ��p�,z,�,u.�dl�dQgonnecA� e N-:*y%%� each� �Be~�Kvwinm�F� �ae �c� C� aa6�a0�#' aN� m ��,gj{lc globITo&6-&.Uan>""�"!)JG�cycle [7&�R!�A��-marm1E an s���e�Nc�en3st�8�I˶V�!<6{CK02�]ex�G*4=��.'� ÊM/"Wn�c�5A� �f]ti}aEe w%@�%8 � en�*lTFIR�“Vingbfts�W��F�Z[6�k��=ser��run1S� ��MT���)�!�2��r&�a4a� �.0�$1�[8�E�-D�d�toI�# B:3t�+�*w)��, +,l�!p" �J�&�O �e\� �hisZ,"(+Yp<( �  �Q�3� *`Mfa}qh2��A�<ng,g���n�pe=�*�W!!j�%nbz�;,Claeys Bouua� a�(Keeney [81].% AB�( !g�1�-H�K 6sl&�w��;�!Tl�P"�l&m:�� "X l�n�4e�YT*� e��ve�g">9!�6�tA�a/MR 3R6�.-��.��*7 �A�knd�\*FM�� r�<2Ca�ng �p�"�"�R#%.4 o!*m�[a% Y�a��.�*��%�#ny�)�=!9kV��95Alanine-�k%$ gene���+!,E;�^����5wa(�&��3r�}NE�MlhRtU.��llIu!��D'� �pa��&}I� �p% �N��""s 336480�>;�)W Wi� pb3!b%�W73W90�)�%�u�}�T$random coiJyfՖ�;sG,}] Hf��qy}a)wMN�UJ�\,�f��.O42j.�:�I &�V.*� 1v� gvs��a %"/,6 V��m-=&tdf�L!guF� !J� ( 25�?31n(6@�bj6�R :r| corr0em����^0 �p�noed� �0�E9�SlograpG3U?���[82�ls����2\��&.�ndR�hE:3�m�s���+�-\tn�Ma�%YZ%�+ P>�s��%S)�it��fiq$%N� ( 39�03%WR, 4��416 �;�A�XJ� "c1�s�+c��rO�d!!p).�.��1�DPdc �Tn�6Ga novel"�m ' tincb know�-��W.�37�7!% "�4sh -�m��!� `.L�er�_� d( XPF , URI-YIG , Rad2/XPG~"!�i �i�0of{ol%4�lp�� �l�W K7A�PnA%M�&(X' H2Cby�5E��3�'y�+$n-3 z(���� "��O.�y)s�.��Ab�5�z zE%�A(|m� � nic� N U5io!#Rl6�Ls� f"�"�L!����!��&ch"5 A*�.to or���;  la&�"�3 .+>ymal) d fe i'CQat� �t85��!e�*�a�-uau�l�o�5��m&� !�n!�ŠA+A 23��uedc��ned:� �  C�t��6out��M�g(*$�!@l*&��5�s�:}��2�Bp!s�A w{i&�:sm�UV�F 1h�N|U?fؙx�� ���. :a%�C, �B�Gnd 6�B� �c��s�$c�-peptona�xtros�Y�o�v�a5te�8 2�[8�%� �g�ur�@d`�ut ?��ur�%�� TWnee�"j�i+*��(, San Diego�O(Nourseothri ,(Werner BioA�� Germ �a Hygr���eiM�x�" �m �/GNE�mJ�con�I� s [8�e8��C �%}Bd�jd"��$by Argueso*r] . 6.y{� a��PM"��!C� . Eci)1392{ &715���?lyAIG �bN��ep��e�|�( pEAI2�Ue����A���@a KANMX4M.����"IY40 bp.@�� stopl�5��a�E8] �Z�Rwpe�'*�&dz ��o��5p�.QuickC��8 ��*�d(�0�q$ , La Joll�C�?._�W� vj�Z$DWSSFSKDYEi0EA5b&� %W=,% Z�Lby2�. M62�i\"*sD1�S �5p���=��(a{�J��eaA��$s�Fbp up�Xamŷ15>��8 v���k� �va�P(&�D� a�es.�D� 6�*u (�*��uh� lxg#HH h�n$ttp://toold�. tuebin�� . mp�pde/hh/�xMq L[softw7 . PyMOL%���im�KAQ;aE���625ϥ?x ��oA�o&c�si�1a%�"!b lh3 �Ѷ6z2�ItN]� a ��Z0w";)q� ( RF8��*h�'�9�R!�oni<behavw|>۞��6l�oS s]�ec ys2::InsE�yc,6t�&�xZE�y��ys+�y.��na�nLrd&t_��)'�,�~i�di�V� BamHW`Sal i:a��8!�by�/r*`}u�� � um =Á�35s&am���hin Gietz�f8\At st�#.a.T�4A�x"R9( ver"��mh�=�C��2�a �2�20B{}u!�E�u�d.���}F�seBW�=eV=�d2�n!�" ��Yp%�H��dI!�48�Ba:�ya�.�CFPqGS�!&iN\6|sui� !m.�6�("#N�D F��r6CT��F��f �al���nut� �Am����8�4�. MeioU�l��yT �^d ���%H� � K >�V�W"�|�2�a&�{>fs9��G�i�&=M%�a gif-(Kg�-YFJY� S F�w)!�Y7�L>�5�y��}.y�1L�&B6x�2ie�A�n��K� *�"� H$�il�*A� �����'fK� �-]�!INg :� [9�91"�achIni`AW6<�!�&v#E; ,( 1��� ��,g"�%!R�Ua�*��vY� ��a*t� $����&C�95%a�fEr�t��ls� p��kBU"u�� �J 255/�R&2"Bq2�lq`.�Y�inZ_S�Q�2���2.95% NP40��l�lyӾ�,Sonntag Brow��93h�A�>�A�252U�ځI8 Y��WΔ534-3> (>552-53\!ZN !!jc819-20>%+*;6D>i���r=M����)�s�Ybdi ��#/��;#^�Eliquo^[TYs "%np �E�sqe DAPI��6��ax�T��He he�C� di�L¿1y`|)�D or 4��i �*a�y ��Ax,�0k I+M�>?�-6*R�i�a}� m�M2��roscope q�wi�� v>j�X�$ �%2��$9T��e�2�L L40  [94]e�co-"� 1�ba�d�t�!�R�48��715A7!�U�&u-5��amp.��0(� ���_.��d*z �$t Isub-cl�����[9a{"'�8�MNIeipu� ��Sf9m��ne�$Bac-to-Bac�ulo���+5�s�ĉ$pFastBacDu6X�6�jA+#�Y�,6� N!&��[oco¾velop!�o �y�6Xe�!��&*p3e!�!�s�(el)�loUi�id-�� QiZmh�N�] epha !$GE Healthc�Xw lumn ��'�2�cU�3I��� yiel� ~�μg��5 x?ҥ$; aс%�!"`��)�m(%Ufrozee|;id N2E#�o� t -8��x#a7.�G6�BradfordM� [96]-�BSe I�%�e��4!���%�14&ekm�>pEAE35�� pPH-His10a� 3-HAZn(; Rogacheva&r A�)^� �2�a� `�HA frag�B��xN�ly����Hst�ہ� ���48��p Z�s (8�JE��6 B8�\��!F ��4�B A%M\� FLAG���B��p10aj��.i6% �HAn>PH>a����ew�r1'9\"�20Et2��"*o ( Cornell�t&�Z Resource �Zer%�&X=��i#A�u7�Y*B [9�%R�O�)+ "tG��� ���%� BR322� pUC1A�Therm:��.�( �k 2 nM>a� c��r)2�N�cAP@�t��(2,d�c��A��inQ��EPES-KOH�� 7 . &G��M KCl���qmg/mle�$, 1% glyceO\�1JMgCl2 � 1 h 3(�.\ �%�El�b�5�a 9x�t <�u�1%Ӝ|4k EDTA { ��ein{5��New Engl�BiolaboB(�#:�a�Sampl �!�1%���gel���! ethi����>ru�d1X TAE b���50 �95�All"�ɩ��a&� � GelEP�( FrogD�gS=, vF]3�� &�eA�A��"E�*T�a� -/�a��st*`ng��5t�2.k�� . bk�$NU�r�H� *��2e~؍.��N'r��S B42���.&u�.� c�enic � EAY1112/1��[C7B� A�� )V l.C241�� LH3/��Δ::NATM�A�k848(#"B1eH��"&H�5%_(Ha'n29� |�0�! ^��}WQ71��� as� 112 �9�URAO'I�A�dard ��iqu�%pA�&� h�*�j(\3713-�72S��.y-Qz1Lgi/&rP>.c�s&:b��*h1�P%eY1��:9��."3aa�Vw"�$$!�3l���:epo{�.�[��Tet]��dis״on`?A�� &�!ndl���U/��@�(��of h���.qX"���ica-p�d~�x�)#� )!)� r1T�jx�A�"d"I�[5�I���r2U9!�"� RANA�MU4.�G!u&�<$)oѰ62± SE)�"�>/�y�) ula� Perk� [98]"*$HStahl Laboratory On� To�+~a0��molbi��uorego�Eedu/~fsG/� 2�*i !=>�S28B�huy� ��O\�Jur.�&y&���Ay:�$fA&Z.r?������[� =";11^S��VA SA�@&+% �&�_ av��uֹi%�K���&F �$��Q>6�.� ~�c !K1 �/ ��g.\�ZW�!$9�=R&JW.!h� ~@�?�{�}>� � z!^� �::nat=$O��,m�"�#pEAA214Ap�$I��?bYSNPI2l S�;�� !Z A!N-23::kan �32���)�>���.�I34M&�359T�(oG����( ��?��co8����e�B��Ad���%���I��YicE� n� i �32c.C6�.^T[IZ�Hi-Seq%0A �x�yat ]eria�Switzer� . Raw�c*�M��I�ndI��!�*{Chakr�oty70��#4:0j .��s L0����U�E"� �I@&�8�m�d�?.nE?:&:�Oke��N(�bto::C Custom R p�p to�e�E8.��f�j( �� ! A^C�:V�!�gra�� v6 .zn*ReC=Fe [99lC)"eg#����ou� >Fb! �I;��gro"Sj ( v1<d���sov�&�D�BI?MI*�%�E25�non-zero ;�j<6�b��feMt-�!�*�K!=&A�meMvIC�� a6� `�a�F�-�A!.�2aY�c>�L&�(o� -=e Drya�gi� re�1 (� ��h��-)nd)&���v��n�,v,"�� y��&6x,B���th��0!M%/2�Yn�M�"Ss("V �c3&S!6^�-232 9!(ZZ!>(j]!>+F"."!�y.�$"(:YN`(>�N*(m�2;�*�(b�� !~-I"� it�2k��2p���Qc. �e�D, .F��2ɣ&&y��surk," d ����A�܆�+�� M!B�`���/i v �4 Ds �� A�"�c�1�8%�.A�K�R[TWdnt"B�D!��&�!dis���cD���p��*,j7D0T , Staphylococcus aureI8(r gonorrhea�n>(�l�9��pop�*��rug�jHc�(;6has�qe��y n�e�-Ʊ�GZEew BJ$the discon�@tinuation of older ones , after which resistance often only decli-�mslowly or even persists indefinitely . These long-term effects are usually ascribed to low fitness costs of re\a�in abse �of the drug . Here we show that structure5*$host popul �,\particular heterogeneity numb!f conta�t, also plays an important role5jrev!(on dynamics� I�W(both duringA phas!x` intense treatment , lead)Po non-random distribu!�s1r-�qa!=mo cin!�ed6andM�dis�.0!s, by afE�$he competi��resul# mitig)� of f-� advantage!) As a!) sequ%�,!�observe)+aA)er rat%'9q� probabil!�E'(to sensitivon�],level occurs15�Lis stopped . Our simMVs]�!impact�B_E�]� s maximal!.! biologicaa*mAC plausibleA�amA�, range , namax when5\coa�o2Ga@small . The emerg%l6(oA�%�ous patha s!?0antimicrobiale�s!a growAdconcern for public health � troldmanaqildiseases such as tuberculosi��8malaria , HIV ,�� gonorrhea)�a recureQhistor!C�t��<i�ducE�$of new potagA�sI6��i%�a �!�i@a�Tefficiently , followeda(subI�t evole�lq�ce !), u!�used wid!�[1–3]Akver tim!�a# mbinuLvar%�factor!'1> decr)Pin �ac�ad��e sidee��di�a�e�� admin�^ k,ed overA@economicMgmay��A"chA�Cy;gu�i�C. W��genKy-;EG):ccessiv�Xtr2�oveQua� /5i�?A�ouezold��. SEQ.!t!o hasa���co��sE�c5�ary��63. D���e����us!�Iup�]#spread.S��%dri�nbyF,large select!&�F@gQdt%���e�vaiWn pre�T��[4At This%bee�&c��ini�u�,Uo2�[5] ,u�[6 Staphyloc�_(s aureus [7y�[8 , 9]%"a�[10�If9�is�a� inued due�yor otheru+we]��iei$�+wo scenaas: On1�9`st!ME�qn!#fr��y�Ł�� S�/e '9�!� sure�%ݓžts back� highɨEfE�1���. F� xampl� in MalawiY clin�����hzt���a,l chloroquina!d fallAo�c} becaA� of a ��>Butrin�� d ag�* 12 yea�|!0ess����tseP4in 1993 from l7 than 50%!#99%"02005 [11 , 12AETwo ,%R�QRC� �pro� 5 eriod%x��despitee� �re�[�%�!&. E)� clud���cvsB al�f biotC in Neisse��m(oeae [13a;,streptomycin.Oin:�14! e�sulpho� d!�8d trimethroprim:F$Escherichi�}li [16Je�as well!�-7T vanc:� t enq �i�pig"k he ba�(avopar�)�!Ɂ19!�M��A���ha$ ��propo�G� might��edeiJs�qL:8irs��ie 5��5�is not2�enough �bnl � sub}�of � �t� �A dualE%o��A#<can susta18�=oj FA�ce���d�*abs�e��er!�a� betw!:Dt��122.� �1�g���Biderablym e��5 �rasymmetr ���� ����B ���!5fur��(be exacerba by� (nsatory mut�f� ��vih 1'Q assoc� th55ceB[20–2�tFinE , ��Ein vitroAKimA�8 genetic9ra� s�1�c �u F��iacB!obn �N,��(� E�!o�1- witho /*R�avice ~ a�a:La5ldp!)P]wa� s [2 How�1���aŀi N�d4, 1�v!�yr �expecA,toA> rele�� situM/wh��>3@ to re-�  de novoɷ35*ed5`� A�5i. ;e�Y�*[ typ���� m� befor6mb� fixed��� .zacross��waH!�b6!z &�=Mlik� �55D;E9b�� pidem"&� �i"�� ra�m�"��Q iaSlieve� �9%.rhro��� -expan��Th��scept"�s���ghe20nd�M1�E�5�[2h I��{ex$ b��Uc� \Johnsen et al . [25] lisA;��h��a��n_�e��,}��&eii�sa���vE�Xne al  ts�ȅ� link!Yo}nge&P De�acqui��/1Mhoriz�l Btransfer�mea" isms�ven�� plasmid lA�~ile��sth�f<d>8�Zng�� !OY�pro�  [2� itAk��ht�lu�Smon@ te{��Pat��y��1tR�A�, to dbE toge%� theygsu��1 expl_a�KE.5. Comm8o%C6@i�=�1-ceA~c view�+�X litt!�ts!�g�Q$M!^.  .a%*�, a3d��= A�b�I�&�)Z mod�nn��Ap bodyM2/�:ua�atJ�profou� q�>�"&[27�0�m��$, Lieberma}�33]zaV{%$9���Z�un�a Mora� M�34M by>&re8���f� ���rif!�Similar� �th%5+�Um no �� establish�spaM �,A�pecific�>m!�F�flAI�5�0virul��[35!sN AM1elel%WisQ���R�M�� -%���mis�Q [44]���� �s delay [45u2s�ful-*!�r1h!�en*��a��network7s*O )�E�reme��\:D�{ �<]_s �&x��)6/�T> ’s� ihoo�I�!�� X�&"� \s [��;A�Ema e����͡U�u4Ma}&�,�8TR �BPlef�-�5�9��oe�re5(t a uniform�-s9 ��$ ntir��)�[46A Bansal&�  E�a �-�-?naGge=I5E) ! =�a6=^de-��� size�>��� epu >PXclear�H non-�%SF �h-� retur��a2st I�r�"E��m�z�mx2�i��m? rapiis �evi��a��ari�b co-exW��!(jaH5^. WvV� ��ho M��}!�VCy�!�i�:� � invaR a1�fi�Y�ā�!�}a ��!div�� �}n[47A�T��gto.mE[vH��� cE�A��&� ,͒ cruc��� ak4to accou�heŦm&�+wE��fI�sa�a.�� :�1�F� ��at� s��12� [48!A�}0step was made& ��,describ� "�qN J4s&�-�- ( SIS ))�i��ġ�!��� prior!�,1'A�>�!�enI'aAh��6"�&hto �%&p� � �� h�$!�99.*�w�� vest�%F G'e �J!*���z]�A �s"x'�coloniz'J.� ]"�BNFi%confirm- 1r9��L�#r)F:�9G�aBe&&� �E�b� a���"[ =p& Me��&point V9�.6M&a��al�at���L>qnN��'��I� triv��. �^Hiio\(�$h& ,��Wur$M�su��$����2I�6h*�B�sN h b�lro��%a2e'"��E��y9 &M��~. W2|�mya�!�R0�II���y�)4yT1�uA<['a�] u �Q R��m���w]�ŕyjXq�y�.��R( MethN!)��g 1 illu�ztMDA�+x!��_."� A�z|Inia�Uvy H-���u*s�*B%�reache*,�X� . T.�t��h(� ob=p� �B "�H,�(1��%'U& �bega�$A)`y. WithAa�"6 y"q�.'Y| r� .; b��� AUji$�q!L%$���m� "�F�R� �Pr.assume�� f� by x��� j d>�!MfP!}�=w&(!dhF�0l�.N9�N� !IO�Y.=R�"� n��a cri� MQ�W.��, in o:�,. F`%tB ��on��re@no�g"�/!&1��� ���g�Zn&R:���AM9�A=Nj )�,~IA�co�a��i�aoJ�but�U¡T6h� ~a �vGco&�#gq:���8�#*a F � � ~%p%�Fleje}de � ��v�-9�� � X@� E��-Q u����2<R-�csol���ob�$a�outcom�i .�ex�!of�-��1G.>��' run,& �he] or�U�>xA�3*j�W�!fF)D‘^�h� +Y� � , Prev] !. �Ŧ�3%B�g�-:n �^�B�T�sE1�AA"BP -�B����*Alow���=(fr ( Fig 2a72bG$fr = 0 . 51rIn��l��f��fun2 B��ul,gmoidal shapA�a@E�nf�A��LayBG� A = 1�~or%e_(N,R�( sA <�97�R�)�happe�*lh2ceraz ly (Is≈-2Equival&�0r)�^��>� 03 )V�BwE�toy��0 )Vee S1%�; A���2�n�,l:/fi��steepElm����� a�)a D mw%*u A�w���17degreN!� X � � 3makE =msmox6, �K��<uMjba�Eg`-����~9I�5re` �U:�1v~d � �6� K ��'.ie�homogeS1[ , P �d*e~8- s A - f r N 1NA�(olid black �2�2;��%50]E�Not��"<.NU,!s(direcmatch� nof!]m$m%�&�8J]}t ����suZ�P:�*A��a-o6nR an"� "bX'%p%�m p,A �%�a edE r.!�;����! 3E��!Xv-h&� h2�'F4��,e>LA�it; b�:�atX�?60� S2 T0��I7e terminl$>�#� prev�5~��qds:.u�%z��?Q/:�RԑQ��*x� ���h) favT"qi�#��c hal"P =�� S�)� eT"provi&g�o� ne��;�i��.  �t�B�immed�.K �A^�g� 6Ab��as+o�9^t� cEv2de-ais�-,{ _^� will��16�disI�E&&n .�A@g o���4s� .W� 6] beyo��enPV9���&� �,&duc.[��� ��;�� v&)spannq?� : ) a�narrowF� }�p-�e ).�a) p-�.���:�system O.�*&U conn9� e y�s�:�I d �� ��� zero�?�R t me�!�62R �fE�W�<m\ �w�w&qJ�]?dapyI*�X%� H Lc�esh�:is kep$�~*� �_�depic�b basir.pr;��]AbR0 = 3!�uUXJ�%��>N( no5�)6&� .!B� valu�  ;�+^� l *� 9^T clos��o�.%�� d QP&� @!a m�e�*p@e��E�"�is�*n"%��1�{&Z�� )�:�["?.�.�.C �4ar�#b�in2m0#6%�B $ #6Xr�C�$6 �)b�"' \ A#���� !�^;X * dN ��s@�>r���"ces2� �Y�Z�>Qv N��L3a�B�uC�6Ej"�"H��a!2cAq -6co"@@3 R2 �"par2mB�,zB&q(I�E�A�ac>�%�.� be� s0.1 R�:����J��g� q�.�Ht� nd shifts�stEU�a�.�-��I�/$!B��<9�D:��e-&�m��r y�U. Nii:.�a�.-'�n o$s.a�ways:&_,�*m �J�EM7 st-:�;4 �T�1%po��<6!F{�3� �d�; "S T �}*;NՎf9|,:OG]+e6���-aFaG!{ � z ?� !l^\a6t—MWb�ae�r ���&FGe�uUeA6sa�na�domiz!�a=^t -���1 dica�at�j.P "Q")�l"�2mN!)U qI]p* ~!�A�QE Z5�N��1�s� !v>. s1cc�7ir%�Mn1c(erp�--���G��, shuff$&A.e1Zy<��yX�0�,y5���tbc ��. OAuexyiv�/�h�I.� >� 95 )N���BiBdd� �R� k�no9Axl)@ ly b&�86'N*36 sE�.:B{ m9���8N-V�:X��+�)�6�b�,��6� preA�nan!!�)r�eR�8��a�>5��g�:6 �N&�3�Q-3l�(�(~a�#s$%>a���&9�e�i*�&!t[�@ s5�o�a5h.'-�:�uъ� 3f-�mD( dot�?K3!�� dar� {@�( bord�&o�Nlo3a�I )���.�)7nV U�>� !.���$-e!�X�~OA&i�n� �72! sɓan analy�!%bach"�%pairwise 5| & ( S4�iS1���"� etaiyH� two-mZX�� If�=�:��Ra�" ��z=P"�0ve�Ba trd 5PdR� =EAr��'Qw^�.�55� �/�bfB-)TE@%�� be��sts4B��J qNq�,a�-%}+AӉ,in%�3��%c�eFFi�&J�� !~ �) U� �ceE;�>�2g#0�':BB(gIn5n&�2C6!'we�.,�="R2� A>Rj�&� ev� F��:�< )%Mf( abund�of 90%R!, stochal0M_s@N,+2T�SYo�?V36�mh$ *u 1�)�magnit�JIw5PF��~a:�%�k#e2h�2S4 K�ng�G�&TYse/�5� y^ plac,FYU!�&+ ��Y![s >, J3� s&�7�&���%k�� V+��d�)u 4� Rn��� <X$&� keep)�/'��s&�*/= ����L�utaJtro�Vy*� #"S�� panc�Wu$ae�g���#�*�8"���Ma�� �:]A coulduBX.B �(t�%.L!�:_SEIhe2�A+�/ ?U5/ -8�Pig.P��t�! '�.�-'J�)�N��� Y:�.]� M[&p �5!���!f�Qw to aggreg���&? i�. A.e *2hs]�gAQ9EY���*�L1aiTD-%s2� �!`3 �!R)ac�M` �D�'� � 96}U Jag� !WBkA�taAQej�">TI>vZ�A� eavi^ ���&�# sA ≫ sP�L J a.�=1Ag��͵ѕT�*sI�Iz>aHaI�a� !V�a�!�2z:AZ�Per"Cj��u*�Pg� �_�ٱ� �re ��[�-N� �tel"in� !}kfH diW�/aN `��0"M .� F,'�l63a�6,5�>M|&SE�&�E�1)%j| �NoIT�4}|��&�QB�GZ�3��w~8I��!!:�g"��- ��UIho�J.j������:l67 ��!�B� �n� 6�on"�>�yf�9|McBsi�-i+%)_ noi-��1:�fb^_OA� }.L" dN���F� s4Y���>�5j%I�ki8�B�.� &zS!a��"f(��>r� erm� t�#t F9�1c9 � I9s}%neighb; �.D\77�IaAQLP� U_!�kee>ult�(Ŏ��5�&�!A%d%�I�b. iTSF�1%nc* /9�%l��7��� s re&oE?!��T.��*���� >�Qd���!�!�n��� �6 igh�C�J�F!���!��". G��`in�I'�)E*$�1aA��d��wMe�Ygs-Y`�dAP��we�IE�st�!�fqu S�h fo�A|�Iy)]3}+ndc�]xU �sp�bl[ &iQ��#Ng.�?�4elyg  E>�sa"�=,<Y�i&S s&� �� inval%�aI,�'!� L[) ��� ]�� D FHAQ ��T,��le��Z!ar�Pbe"�ZFx!��gn s [5�MIF�;2�=�)Mt ("�3�)����!igh"�a�ofSaUV90%!6rH@B�R[:�<%�Qig%�."tS&\ �Fa�fw���=1�"�^*�!� F/2&.4E�QMA�X)[I%e� 2�jK�_c�& ,N�X/te�YV �P�j~V+e�K�a�-*,��5�b10�baH^�yhad#1Mz �b_)3��h��EI �� !}vka�)i��� >y�n&=4r"�-j�Egu�,4a�F %�A�� s>�U,{4��9��J�&d6� ��P Y �8"jX ,a�(!Q� emYԍ�#  , |)�V"�1�*�&&&~�%I�^p��AsN�rɾd9 �. R�M �J��d57]kddr&K:L;>�9�a�9�)s�t �35 -worlda�`� �) BSI��47 b"�T&zn&�4��*ő�Tng��&� �&�>�� F�$EUavo%Y.2. ( "�S-*�$2rna�ZM(&� uC�ear"* �IPe�V�ira�E7 'N A]1��propert ����>5 !�us~ �Pi8w<��r�1� oXZ�Q���+>@-2�ta�9*wo� �n�ik_� mi� 7i��or5 %Olm-� d  Avre>/diS< �7o%i�)"�!"�!�!Ze{8]�iZ!\�3[2�*�8n&|aDM>i�,� chaer�!w*�XfeE��he�:pala2!�-a�Y˩W4 ) :!�&��7&� e��ep>ZaW"^�d>#J!HA�mpl��{��PGn�A?6{.� �ՙ2���� ��t�.���9 *�s��9Tto�}� ��e�A�surpriV,�_a��*�'E�E|����Agraph��9no top�:ic?upaBM1��L �" z�[-�'� �to&K ?�TaeiggerKoY��jao:e��Ft �N��TH � � Ny sub-&� A�=�s�� �} �bW�n[TXW�7�E{e:�5s tru&O ]�6�aB�. s: A65*& YV�b6�9&� M.%{K o^d>� wild� �VE�e1$JN�%N*�d��f a�"�*AG=(�d9'�usi���V6$aC!�rs�ne�] romo�yvw"�+6UTds�.*�h�sh2 �$ncGL�.��xM&>� |s: ( Ca�D �� ��mW�8&�0jCu�Hf�~} � ( �>&Q EM =�9�=YqCA���(��b hC �%�4� abov�$Td" UD��ma��و]b�> �K-�.6�.�%��>H����> of>ys> pronoun:<�� 93!vg9z-E�R�6�S"1�ed23kda�wo Xs�X a\U-"nE�l rst-$-*- z5B)oM@Dal}MW g�HP�asa���D��,*� !m(9 a���]� iy"�g�cho�l�SIS��—!Z4�6ma ma�+"�F�W[68]—Z�+TMq�fIr6����>ay� *%!\y&C�A suit[>0/"x  `�)t-w�uout �P*�: 14iaa y�p +f'on j �M���! �U["Q o� xs!Y��[43–f 4#fT2iSG�q> c+A(�5Aa� �5k5 .FE�=vs_&�2I��b,moU ~yLv�E�v*{}]P�(�@bH%"cI�i^jix n@rem��.*hp\���O�it e�!�� .m�mu"� ��e�[v)� �by Ea(H0U�2+*�= 3B�]ja*D I�I( super2_�Kn���comRO..zB�Ye�.�.�!�?�]%* ��In-&j2 �Aex%�H *.y~f} �!`"�+�aQ$�rll @� IF��lar| 2|M0�M���yxu�&J ��{abunm"to 1m��",��0so��� r/%u aMW.S ���  e�� ��)����4~6&,%�"h1�Dv�t2�!X1�.r$ . Al?vg{I&�bzepK}&!�&�-"�)� * �/��fU|��0� i��(phenomenon:�`!�]� *as�t�-�way� �I� & -W��>��U��^ �X�5Fx"��9t� (��8"�� e��Z��y�#3QJr:p� 1n�Igb�&�l"�#A�kE�^�>t�"7>��XA,�<* ��a>�Dc�"%!�bp%"1�LL9 , 60+e�j� [��"�� sexu� �:"5-NC�*� ���i+��'�eq#c U�:r-��n]c&`u[6! 65] ga�&� a@!Iac"N"�� $i"�lly:8&�E� �q��@!e"��"8��d"�q\�in6�D"�DF"% &�xI$"�)�of��amG�qI��2b�".5t� A\�~��!p� -�� �&J ǥ�a�e�(=J:��]� opAAktC7p<� .|wV�p���ksWA�lse_x4�.. B!T~�"w/ cideA�� sco�V�e ���`�l_ e. &Ba!�! �.�`�5A�~e�i�� ccorQ� c�p�4 gamm -�!]���-�+o o5�m�)#L� tun�ei�A%in���%�s�}��JaTTμE�e�Hσ2qscale θ� k� �G�OJ�a��'by?= σ 2g(�Wk = 2 ( 2 )&W3g�/!;2(w�n draw%��`�,�!�-��*luV5�v� �w�ZM)�> V��&ubA�$,ng algorithm?�� )[r[6�n��g"�m��r.�>IH� Gill�� x�m�e�od [6lIn briefD32VlC5&5=�k �a?!B5d*� !tA�y epon a�.()E�rn�p"�IγE1c�@�\Illq�.�>�4�q2�>u�e=�h��,F��� g �&j�"p�5�G�q : �"Di]ver$b6oa queues !tA]N��VV�(x(y��-� GYG�Saaaj �!�ѽnodW �'s*V0�td�l '�(�I�) �.�D� W� .YwJt� %6� noB�.�e�9Y���atu%�!! }=cdZ4��.�&G3"S >!)�� s}_do�dːa|ceG=E�a!/"{c �%EYag�R&Ve� .���ed�I�҇!��%��!�sv)%)Ae%��S�Q� 1 − 7 � %A{2}�53(q �g6x.�2H@�/4�igp!�+%�. A �a~��!8� i [I3� 6M~����& %3IFXe��.mu�"re�/  ��i�)��Y�a$!�)%d�d���1�abX>h�� Pјd6!ܵ�uD&� � !�l.�&4[�sQ0�Le>�p�� disc�A�'d18Yew63 Rj�F�]B�βr� �RY~� �w"@.{GU�s'%) ��"0i �O fA)k\�!en�0.0*' a�zH�-Rs�B-Z�Y) , j-e�A�r!tal��yY|�inZ'herap� noA?� N�rB����b�R�~F6Z�s t�$l�?efanecess�0ed�b^�B;Y�7  E95�,re-Y~w2upde 2zp�YAbZ�A���6F��K!"al� ��65\`a5.6 ��(o�3ao�E�s:�"�%�#�v� !!��JB.:s!U 84/A`vC �aR))H9 c!�t��sa�YS�& �we2� ���3N�;���}\%��?����8l is*q A\)�βw7Rf �����&%�γx 5��'a� �>��< � �E"��*�m�' si-steady-e�5a &8�ly %�burn-��%m%��� h-] out �nquasi[cIPY�A��>ar��O7.eN<���w�ylm�"�E��� Q_JU. S"_�{� u� �a�W:�:Ze�F)>�= �KY[�W U��hM��_6U��2OAsA�EY,A[cF'�eTTum!>����P0s��4� �Q� '$�g5E�p ʼnCus�%Mve"�>]�o �PusBWsama(N�CB�h.�ly:QB=/ (i�( c2�+�:) )Eh0 c�VAy�a!8 aiR?UpI��isM��Y�%M�untily !{A�*�"�mdisia+��Z=t1�� vB����y 9+;*6 �i:5* A��s�X� /�A . Un�h�M98ifp>�HQ�� �3of N =�0Eea��of&= 4a� varyA-]� "�,�`k,h 2 , a��,10 24���=P��  1000��aim�3a�y%cSB� �`%K:�b�^9 ��of:�\is: R �^(! +2<μ - 1 ) β wt /�*_�#:����un tw$on)�d� ;y=�EBh�i., �rs� ��� e%�!6�!=� .eqr� �cho���"�, e%�Rm�Kq<N"�, cJia�"p�lM>� A�!2,H��Y�Y�, r �000!mA&6�r$���< dE4fE1%!n �Rpi{n%�1� outpf�!mj)�1oE�2�獄�4��6g q�nd upɫat� st 5a-.�R��iY!}~�7ach*" *^m��B� a se��B��@����j�N�R]S:�q@�0!�975�!�025!�o xN�% I�6�Ub92G"@�`Y� .��!Yu �`�:�-!�-�>!��Jd��f�/�6\ !P��S"� � e�fu&4 �AE�n4 eU�>/�wl ��,I!t 'O 7  be�=d(M�a a��!s��Aoi�YťreB�A����D-V +:} . En+�cP�� oftw�packag�'ee�ya�frej &b�,on GitHub [6�'$ΨAutism�� trum!k�9�OASD�Wj�/ riB)!&*3�=byÍ�  sP�!ot�� 4o)"]o8a�$i� ri'n^6?T��Rehavi%**]!a*� �pk�r�FASDŕ�t*\Jen �<N����e"�:m�1a�A�Ƒ!��gor�i��$f2�!������&��loc�4By Ԟi�-syn%gjcircadia�Su��gZ2�!e�.�7pdosA��Punique human:fly orth}#�f,in Drosophil��*�4numer*synerg�Dy1�R5R�'�+ly-=hcandi%%�s�k)�Afj��<�/e4&"u copy�ʨ�( CNVA��se !"�7!�%mL.z w�ai��u�4'&1 a 22q1��2E�ƍ�35de&��� -�� I�-�=~.t:3ET?�b harb�HaV*6=a�p�n.Jde� s�r)$� !��"�"po�6)�E�ASD-a&�5�%� ��"�Y-�� ��!�z �%�.+@�s!-I�.3���Ay ՙ!9%KE"� ~A���onship� y"q�gn'F\D}&�&�G���6�gen>\s�n)�5�CN� ���ari` nw%P�d�X]W�Uu��D �d�"�+ng�tY�@�6u_W�ord��"K0 )��>Q)S6 "�!���}2�IIK<+e�)E c�%�+��s��R,�, 8!�&nd&!X:-J ���!�4��.)!�!+a�ժJ �"at"�$R� �&E��9"�I�35�$nd environ :f�-[1�0�B���=3*Z�"({i� po1k�kv��6�cap��Y*�3�Fe��d? non- N*� �� ��Ĥ� ( ∼�Dmonozygh��:��) ;*3��1+c�f�9��in �t*3�[`� 0,H.�A risku`di-.�] om�*G�ta� �BP�i�H[2��s:�H�v�Ks-le~ eQyXb�-"�!Zr!:[���A�I��)��a�.(,�@ uni�ed fam�@me�!#:%B�� 2eszv�[p–$I&wA w�n#r"� � �xw=��+k� �Ou.� /"� "o� s��ps�.@A1�uS:u�disrupC[�Y ��&+�@i�Lf!P!ׅ]�e��ufE# 5fby 19p )A���i� LA )�@%�2[�&�S�C� = } �)9pp2��.pe�mr��6 way/�Aw,&;En��&89f�! �I�( 33% )� u<"! &M )�w%�proteiaj�pE��”��-�ra4��1J5�G%��a�� "b:�K��.���De�T+Yz�% ?�Bu�l�_C�:ڦ.v E�9�+���v4 . �DCa�v;d��ofE;:!{� ��!�.PiA�%��<"�C�H"�{�/�e )T>��+���0jE;{�T�ai�d�� alyS)k~@E�y�$b�\l� Q vivo��(*\ Z!E )4Pa#�i��Q�H I mBƣ2� =�F2%�4ht J$�M�Y� E� �h �EP�q�8� t�CŅ,�L- ʨvo�X,C.;lybo/�a,e���%�Ax�U��r �:uo.:�$ɗA &UL2�p��Pk" uit �=�melanog�go�X!ati1oo�A�ch)�*y E�"�� ~[E-is�: �!��1� 3� oCio5-6� ""(s�– ���F�/� a�63sV � ��e%E�Q�'^o"w�(abnormS�i arval ?mus� j�V4 ( NMJ ) bouto"B-��,&�~ appa�}"� Bradult sl��$ cyc�A�ep5�&3:�to��h&����  ~ th�m�F�w[14����\D �$eEE=A-!�,;# a� )9]W� t&] m�� :��tel�Qu =c !g%�psyׯN��- [1�1��8��Y �9� Neurexin ���d}Bu� �� CTNAP2�O"k" �w%�FK.Eggluta>�^ ��C* p� 1)�z�. C"1rhyi. $Ql���%I6��!�$ frag�;XA>dr<~!�Angelߥsy i��)�H�4's�\h � ��J�[ !qA��BiY?�����,9� E�m�=�%<*! ilB�Y(- ��Aocu�� 3 ( CULAO[2� >�.��m�\,gnd�6u� �:*� � :TASD: S�!�urb{1�7x ,�[up� 8� &l *6 )���"?3Ju�>n�1�:�q�?.>F��N�� ���A fr�$!comorbi�=t� [��I� \%:-��Q[5 , 2Q 2��WIcus� ��9n���>�P��+�I �2; ����4d.+�StUN%Dip�'�A�. !�e �  U`ch%aSn4eua� !e� ToR/���)*Wth��%h)�&�a,!h!-@]�6��� I+��#� �&�F�yield(*���sA�!= �҇a��[3�"3�W�&xt loo��at! ��%� �r>�!�Z. AfKs�' 4,,�6�us�%!k6|e�o.��s1"*� .=J"9f*�~.{ly-��ed �%��"J�1 ar�%�7�ic1[�O)<sX)�2�M+�d�L:0�ѥNSv~`-��[*Ei*(FR) }wCAz2=lI�� Y�%�R� UnW.X)8ar �A@]�M*E�zcCDgu4� ic"!� ��A�-�.n�%f4%No �+re1�d)a%� ,E�D 1�����U�!�N�NX!�f%!�parf;WE� ;!SQ9�͍2���p1EB xD&�5ZVu=ox�E��2�Dp\St��6*�f&c�!=eQ12P!J�G�)�P�w!�2_����� .� y9BMq���I�13/4���<�R,:z��e6%�F�Z��-��. Singu�A� 2Ei{R�vA��6�m0*�J -7� �8�&ဢ���&�r s]HM>!�N6l�|/dark bi�C*�s� !��[E�����E"�ef !2�*n�>J��bb ,!.%�a�b[�o�����6�.�by enֱih[ pid �=e�of �XtjW&F��= powero�res *]26`�.�?�@"�&��;��Dua�.E���J\(&p�6�a!�x� ��'Oe4�Fbey�6�^$�a�w�y��4��e�Qi )�fly;�J�A/6�"?rgK2X#s�m�� �M��O,�=td/�*�%�����urNh��9N� [1� 31];��>Bs)*� E�z��M! �[2��3�M���six!�E ���a9L96I �1J n! icGA�2 �Wssk��7A]�G"�#��*A� p120 cataL (ctn ))�4��c3&dhe*%ig� � t D�{�%��"KdQ\!I! Q�њe�chWq �Q�I�" b6� !�}Tv t-. M�cRC{( uh Nrx-IV4305Z�r-��X%BCN�!w1118�E��o+!I�w"=�Aroo�re���O6All.� stocuC� *�� qW&7�I /� �J* d"#E��-[NrxIV �fv null{ hdi�$�U��.���&< t��ll�ve�  %�&�F� ��h��[. 2A ) u���Z icE�%��$w!��dE<} NoIjA�6�Iv a�:~ Ch�Wʑ9 Ers�(2�T��&.�uY�ex< aQofN�%ver (edF$Q� UAS-�-F!�) 6�ubiquit� Mu GAL4 )(r 1032-Gal49qB+l��e!oAng),mno"�X�.x 9l(\v �IpI?NMJ6��n>2�,Kruskal-WallZ/��, ** P<�-01;�n. �s �E�71r��eE(�s{ )�&>�N�e*��0<�wZcaj�h�(m�N��W]�]�����I�R�}�/308E�62��s�Pmim�_�[35�#H,y�us.o0G�(6l� !6!�u�C^S�M�R��P fo� �ha�-� L�Q02x (�+ ,Q,�c n��E.,YO�#�eb� ��=���2�^vi��-cW6:��b��ZWY+sm{������. �:a�e�T�r" �hat 16°C� nd����)RA� o 25 dCpuQ].s�_ +ee g��6�d+%fM�d� �yt�H�(O6Zed�E�XguA�5 minute,WM"~) 1surro�|!]��at���r�� �>��10�evYB��1XM�E��.p ��gsr �"�L�. � ^H6-b� � 12hrs��D , E�:�1�:��4t. 2-!�P�y�D )2�f&?!loV �FG.�.��"�*��a5 . Ta%�� Y�i t'P�m��i��əi}��S.of knYt� � !$�&<��"B�subje�|���o2��S(�AchA�n���"��12��)a�=�l�x>���?� K^:u�n�jQߢ-����s �G&�  �:�A2�ndI���s&I�F2'�a�)�3�oeR/{ ��M�a�Y�N9% � oM�2��5�+��*#�O�N]7!E)���n���de��T�%7"v :�G��/a&H�MEE�asIwhe@ p6�I�ir.�.����x2���;����ed%L"~or݃6|� mJ�c*$*v2i�: � f�L%:!9,>7�7eG2�)!yc<ofz+<�/9�%�7oqu0�s0( 11079_chr3_,_197208363_l ��":�; 1223622 772495086�7269�2p1m16 7 68529466_x"6�* 4 a�}5F9_$_129907917}2�F.i %�`^k! �=I�p!$!=853�:3� ��6�Wsep��"�#p4)��cs��zdlg- p21-���"kin)^( pak�� ��ne/�<onine-R ,[36�,x/"�*= �Fn� �eku Dlg locvS� &n% & */="lg��lgu�T��6 )S 1..& �+�._. S�eA\�� �E"�4�2��8�S morp�6y�~k05.� -$s9� B , - �sw�m1�letha�  s�.�4[37 , pv.� dlg/�Ji(! XG�T ct ��R (� ,L1; +/+;!)6/+%Z� &�$�B6m!�u_b �enW��‘//?+�7 go� forw�W�q�A] )A�. �� ��`reQ!p���3!�.'���9� , Fs�u�& KG08128mvCG5359"> e0397A�%�chI�q��!s��0 \6CNVV9�did��i&� !�Z'�re�aV�!�b:�:�I�_"��3 )5 !��. Sd�.l� &� �<R(Q ��|y�. �F�] &a�A�n:� A6���!| Fs5�F.�; 3EA -�A lwԁ5.� �� �1�$� a%��m;� N� �Jm 5�� ,�[:�&� �y  ,�%�q �*V:d����2,2�C e�Q >�.o&k"o2#-B��A��b���h[<6�(+Z�;}Q4�ve"�Gr��M &s;��dup�-8 "%Cr'� [�́�a�no&�=A�>�+a�-� n2r f+1 M���tY�\n��1�_}ahR( 5.Y a2�5 H"�J�:�uH�k�� ]Krosha�� sha;�Wp LL0336h� [40]i�o_�(otor-blind-s-�> -1 ( org-���MB0146�[41,v ��h ZSe��Sep>G B NP717��xE�"P�)Q�-�Ʉ�g@4B;Ʉ,���p��5 ל(�=.`|�%sM:K%�.� �h%!��1(/ �R�L� ?se.�. milv,ip!�T/)CZ S�2yf soN�2 ��) ���*�4ɜN6� aZ*� '9�}M2�E�w�$FZhirA�I< 185uo! seseaEP336aD%��� FB� !y*� �k��A1)�� �M"}$2�Q 6 B�|E�!2��><��a0z�� : ���~*". a�n.��f/r1_�z:,��)kI� .K F�2e,'�he�,@.��>;ə�,"�"�a�:$ �X�ɭ^��5ɥbyY�ng��=o r2��A�2" mplo"At����&0su�Ex:�Z~ !��IB Shib]m)ralpha �riE�ab.n%��db Q`�6�q5q�J tom - �"� e�[6c&"@5�.�!"I�Su�- �4�m�^�(:6�'�E�%���:�DofB��� �e�O 5>�*�FAN�.��dl��0�!�� �g� ��,*�ly-wIG-�����"�.z�����on-A�~Ov$� ���Su�Nu�*EY1324��A�CG1410� ' f0759�1��%K\!��*6&� sY�B�s�ԉhinn��5C%���%��TF o poly��+.V]!�ex�3A�(R %�bia"H e��E!� � ' �gY�ѸQ�6�!v[!"e�/ at��1(1*|c�]Uo�GrE�bK$ ��2b a!� "% !.{.V1CN.�$2�,}�3:%� *D 9�%�%6 �&t�7y"i ��& 6 _ERO-�b~�.��A΂'��&�g .w �~%Q�)olv��qdJ !�!t0�*(1!p�1a-`ln Gb�� ;uc(&T,� help eluczN&!,%-l��2Adysu a��07ly Z+ pinpJA^��m&T�2To6�I*YO"� hip�=>La*� ōE�BXbK2D�v��%<oB�&N�%<�2S ^�|"�m,@�f^4��:!�o-:�25':�!dinA4 u�& �&� us�(Y �"W!G�h�"�' 308/ !")�/a�:!d���g('/+��>�%&n�q}� aDA$.V ��D�Ilg ���%K&���Z�s6�.�9*R$6�m���ۭ1��!%sN  s:E�y��y:AsKD�n . 6A , r�6��]vJ�I*wA�A�C��\58�A�V>7^K#su�%*m�+ bCk!E�E�Au�J.�� ee if�1��!�A��J%w��g�$�؅� ��all�Fw��N�=A�Z)]�/U� s��2R J �\��}�H!�z 6y�&�6r���dBS1\�!)Z��ngC'�a�3Md�Xw�>�.ho���ng]I.�d�Ner��&8�"�1i&Z���5;or�+a��t#� Js�,S����A!�(*�^ �o��"�&"��IT.s�Pv�J [��4\�E�>_i��4hev�in&�.*!>"B>��!�ve>�n�9��.�����9�-�%le�.1,�z.) �:Q*wh? %)2f &�N2��Je�"�8ej0=���%�=�.��!�,)2L!"00NN1=�= ..e�Jm3�by�E�S�����$ bruchpiloאBRޠV 7w���D�-oG�f-�n3nd @i�M`.��o��m�s {Q;�Xme�&�f�TSC�� them�y͸��� �]&�rof����P#�,>S�9�=' 6U���&zTn. a��&Q*ZA~ti)+�g<i�2�A1!6)t!Iys>%-�B}.b�0S�`�!��2�:�!G��} sha/���ލ��j�덪9!"P%_� ��oHq�:����E�@�s�y� �d��ili� � Y�=��o�2�NiV�s�P6\I_� GluRIIAq�E�0se . Again , �>alterations in glutamate receptor subtypes have been discovered4Psingle homozygous mut S�Uof Drosophila ASD gene orthologues [42 , 43] . In this case , we found that out of allsa ransheter~�te crosses , only pasha/Sep4 displayed a reduction in the levels of GluRIIA ( Fig . 7D , E ) . Taken together , our findings demonstrate that distinct molecular developmental al9Hare associated with� different%<$tically in:cting combin-x, suppor the idea %Gdis>� aeti!�Pies may contribute to%�b vergponn`mon phenotypic outcomes (17F ) . 1�study!�EHd!noped a%�@vivo model systemAZ]; to d!�minAkw�A)n syn�s>%Bin�=XPde novo CNVs . Specif-U,�shown)1( i )A�!H4 human >!(ain!A�5E�h6 network-identified candida\aXs respectively ( from a!Ybined toA!xof 114 copy-changed protein-cod{ N,) , pairwiseYa� betwa�=N.� yielH _��neuromusI�juni.P( NMJ ) bouton number��circadian rhythms were observed for 3%9;!T!UE�mU��2a=�( , as oppos%  addi!@ ,A.natur �( i6bsynaptic�countslfollow!P� simultane��dosage- !���5%n�0�ng�>�’2qwitA�=�m�%�eea�F[ ari�mI+these)�b6�!l�(individualsxe � whom%a�r�"Q�e�a$2–5 , S2a� Wee9�2tof � drawn.�ek%�1+)�m{ , both�a0 � . 4 )%�Q�L� . 6E�-?!��.�underly ��. Fin�De�go��to�!V��E�(act through�� molei$.t,.�!�rolE<�V8���7%xTheA���nmofu��$A�2�%�wu�|]�0has important�� sequencesE^��%V�bcau�}of%l,%��B&con���y+�or�a� )�q0ueE�particip���a��-relev���r truc�S�ckn��mammal��x%���=�W ncordanceU��dir��on�6}��q�e�-M�9p-Eb��cEou*M. AlthoAmtha��over 100%]>Qcur'�v4, at least 70%��:� rema $o be explaŃ[9 , 44� A� presAE�ipl��AZvaria�Rin manx tie[2G(5] suggestsIzinheri!�< migh����qp��n(orial effec��fyTdel%i��Uwhich a/( a shared b�(cal pathwayuu�V[10�W%zKe2 act �zly�:cA�� in a�bA!��E} eachA���, those^��ly� X�ctablcY�trait��paUs�!�67� HoweA6 , if5CE�of|�/ �p�$to��A�wouldA,noA/�SRASR�eiA� � . I�Zly �0sub-thresholdF�-� fecundityA n�)�h� .i�  %Qr to a hig� fr��P Y popul �. Our� ul)g� {w�� ularBb�UC!it@ to ��abnormA�T eU�4�SFi��. Ii�~2F%� 6� �:  o%���fic�, amongsa4$background!�largeB f non-r�ggen�E, willA3challenI beI�a�!"et�?��q�E� is extremaz ���Tle5С[Alik*very r.��as-��Dng!�v3�Yby��scr] � s �( dlg:B�8 ( h . o ) DLG1� p21-� v� kinas( pak: -. PAK� X, p20 catenin ( p120ctn(CTNND * Notch ( N  t0shibire/dynamKshi1. DNM 0alpha-- tr/α��+SPTAN -8optomotor-blind���-!w$-1 ( org-1;TBX 9aHnerAedrosha��,DGCR8 $Septin 4 ( 4%SEPT5; An ex�I�ofA lis�y��he Datab!u�enomic V��@( DGV ) [48] reveL ee most3*� Eufe)�M2�� i d~ same*O�Cp�� ly health��&� (I;, 7�;I, 1;)�%�%, 2,s;){, 9 )^5%@�>�Ao�\ se %�.0 ly � twomk%0�sd*)g�,�m- �"-�f�� 8nsv828939; [49]M strong� mplia %_� o prevly�re� %zn([47 , 50] M� �� a�n] f-�� nerv��. ForE�pl* e localisU�A� sept."{T� nal adhes  Dlg� :NMJ� b����nM�reg���0y Pak serine/�yonine-N���v�u[36MIn�on�t��%�eUgg poin�%�Z�PAK )J�MAŜ��SHANK3Arat�Ph��disrup� als6�G�(nt Shank3 a�!��n �c� iven���sig%([51�Destabi>� Ffilam� a� NMJw ds!de� 0ive NMDAR-med�"�� �)��in�� E��6�rescu��agile XVdrome&� E�@Fmr1 KO mice [52]�� �an &� �F�&�A�ID�l�?e�?,� wQ�U�AdͥQ sha�� [53�ismx� � link-��65be��il:�}T%�st& � �ul%F� L*��5.���s& V JntrolF�a'gra�via �6�-�[55A�TVag� ited upA�a�yi� enrichA�%!�s͟ly%����:��cel��A cytoskele�4*membrane1�E��,� A� �( 5h! 9;a�"o , " ,�,Fzpakv s a%V"e_E%*� to propertX ͜i� [54�6*9!k�& stud,TA�ed 1�!_al� orde�inclu���,z����%%�j>�/=A1�exins%} oligi2X�in.� ��+� beha�B!2!�larval��� s [3z31 , 6=m�a�\ 5���P�  ,1 \!���*q �� IV�>V� nvolo-�m%FA6!V�� . [3!�6�2!�Notab�0�No*� ( na� � A�� �sn�a:*� Q2��gxCNV 12239_chr22_loss_17249508_l�ScE(e 22q11 . 2��r?�n crit�reg�did not)�:zsensitiZNrxIV.� ��a���Q?traa�i�JOa8ngtic"��a�ter� v� ces�Wh���(ha1�) j%�is=>E�receiIteres�nG�!������a�y1!�aF�.�Nh+)� ,a aB� !%��igna'�al�[3�XA!!EɅw ve z� s�ur� ��conno��� 63A� MoreA@ ,eTony�knockd� }*o]� !� �CNTNAP2� NRXNa AEX rx� dnrx�z%��"� � %4lW!B.���BRP [18� Ds�y�w� al � logy�VX&� ELKS/CAST`-�-1X al compon� �vertebr� .�[6�M�vH,�e.2s cre��ret�s�"!K��d� nd� le$:�! foci�lg��a post�= ncho� 1O��i�qui ݬ%Rat�!F2Zsubfr�$ulum ( SSR%�whilstP .� phosphory#q ndA��� abun�[ g� � )is� dominan��� , bu� �2���-saQ%� infl� n�x.[66z �gaN=��ax7 ���D�ā# , gl�w�%Mre-Q5V��JD�e&� ��* lg ,%\�" �bU.:D>D�A� ����dV� 5carchitec���s�b�, / i"ly�g�) Y��!"e null�j�V�a���6��!,subunit fluoK �!GaM! �gd�#/na��/d �2 s st�]q" ed [dIt*�� �bP��AH I<� !�synchron��� ..�BP� ON' :R � U�bex^�!; q}.k� c- ) \2z" q?&$ I�. re� Axw]8� . NY9�Fk �QŗN6�Z=V+%AJs (5):, h"�Be"� see:�= 5aK dlg/��,&�$ o�@<B)3.��b�]b� -%J . Re)%%11�%-%("�5(�-ensator�i)!�. size [6�W9-� !h�">7p\aR�xge�QaN� ���me\ism�$b�mprom� N �&.a�isIw F ] Rgh�&at.�rapamyc!TORa���4ed eIF4E-depen�)��I�%|� "�*� Qou�.68]E�Y� �'syn!ib y�l M"�'6 �a$� [QD0lu-'�ado! #!=� s [6� I. /"c fF�a&Z� FMRP)%B� ,30% co-morbi(�� )��miRNA"�� �toU7 lA�� [70] ( P� ,A ��Rmicropr� ople� ��m|-��K&AU� u� )gan �MA�B�% E2N 2 ribosomalMJoc5 [71� �!2�M)Iy~ e�ǥ�[72pB 6��2Q�A1) cro�-a:machin��)�E�AR�*3zuItєtaڝ�defici; r|subopti9)of!� � ) ed�( lexe Q�IN� u���A�n*ei�\� inef��գ&� . Fur�analym�tF-9�/�*h�> &� _6���,#B& �)]designa�un�!!eliI��� �extA_% t wa�m1N*%&%id�gw"�2�a� se#>$,!=iJ*aA�A7)�9�Upro���)*�aJ!e%ue�'�c�[9�f�%.�a l �7*< g*1���!V6+E�e' orga�. [11��q4&!�>�,%Hed)Gi=4�$genic6,�iU&&s�Lin�  � �w� each:�� ses% a uniqu^� ( MethodsyG�E�Z% !���h�I�( average 16!�F*,(*.�!1� gene|,��oT#expect 4 &to���:*� o*2>�,~� A� the _`�B�m�H�6]� �.*�g=E�16 %per%R�$9�240yl6�, ��/.t� imag�.�q�nd6�)F�-� �aEaess��% �w0a�$�$a5ML.c.,we emplo�0NMJ�Pa���t�������ՙ��u&�-՞Arovid� M%�put mE�6\.A�%P)�h��tX&!H!W.<assay����Ta��ˁ6F1l./Atu(� e! spac�4dex [75��u courtship�[7Nonethe%� .3^�)6L Os�)͑c�&�,s�"_*.�(J/!&�or del d �c�%+ corv0ond��E_FoA^E�2��'�e9. Tak. 3Kf�n n�.-.jY�hB'i���en0�ed4� ly�:�&�� �.1�.�I4�� atics-g ed�\-s�% �a�3"roachE��6eBdisease&� ��2�. W-�de���fŹ���"w!y�$ �3�ly: (�%736�"�Autism �$e Proj��a*y [E�( 2&28ZA Mars�' e�  .<27a0( 3 ) 94=or k'�� Levy6A[2�(�/67zBSa�/s6E^, O���/overlaps��E�34 . � of 23B�uw����n�a��%��o�,se��J�<��laہ�210eZs^� haS+enQQ�� &5�!R-|�"/A&�Ai����ly-� Qq{ofY��K4*  � al�*(��e6 A��* d)  �.1 &)1~-ba�  ��g&���be ">#�2�loa��sl �&��^�as`-X6�,he InParanoi�.ol [7�"�/e��5ystricr focu� on{ ( 1:�(.�E#n�8� a m��%�r* ZJ cz-�vA%by relax!���d !�� "� %� [7K6��hQ95u�e��harbouA�!�sy�Z ���7�(�F)���'96R���!y�-m�R8Qs� ( T�1;A-a��/S��46��ele42�(F& �וi�W"1����r M�6�x aq�'ly-J !�k!stage�c�ledB-!C a"�7ofk%�:^KE� seek!��  hausti�8ascer�8:�=�3]��'7>*opyQ�2d-&Nq aɺ[rato�estigl�i2"�( 8�c� ��� Discu�)!^ll 5�)�%#t� ]j� i&0% + 5�l.stock-�iso~!�to�(w1118 wild m=.}!A�7V� ��2possi2,��ly�cribed rphic��3��Y"� . Uncha�er�i�5� �val�: d usA)� enl/. S�ac*JpoX"ve�P h�eB!�Blo�gN:]EP Ce , ( BDSC , Ina: a Univers, ) un� &"�:s8+U1I�4l&�9�o��s::ctn308@lg�#pak�/htsk0612$locoKG0217aux72%, $MB01466 H �LL0336%αB/rg4E�>NP7170�-&&?G��Resource14, Kyoto Instit�=of Techn@y� ,CG13192EY0774(CG34449d009�$CtBP87De-1�(CG8507G4779�(ttMB03997 .I�,; UAS-notchF:, 0E� 0�'Dyn (j+�))Is�Aoa;��1��tALto �(��T3.��eb �<�!M�a�-�I� primO'g�=KpnI sit��subcloinD U�!in �w��mbryo�Lhe 1032-GAL4 ubiquit�-d0,r�^�duB?A���B= .�430�0n�2p�pq^�%*. Nega�� -+randomly�r>���҅� pic�(a`?�>���f ��nBn�a&oA%��A/adult��.v�U� FsnKG0812a��=(; cg5359e03I� Hira185seaEP33�# "Su� ) EY1324�< ,CG14104f0759� ,nelf-aKG0948.M�,CG3321c00226)\%�aF5)M.%culL!dO standard5<aS/ma?me 0nd�+r um�Jpla�,L%r!�tl} (t 25°C . L�)�r�9on�le ju#.p�#.,lN �BmoV�yeg:9&o1deя[7� .xU+!N2�t 5 d�# egg lac=1չof�n�a &�o�#\in�1�q�@!��7Ɏheg8 A2� O>915I�-1 �@ gen C� ,For immunohi!�Xtry2Bfix ? 20mi n 4%\a�ldehyd��,or Bouin’s7i�!230 minu��(7IIA�Pri�antibod"E|e�-6�6DLG�({'o�,S�4Hybridoma Bank��SHB�mIowa C�, , US��Qti-Fas!F0y��(E�/o#U#l �at 1/100eecoa yLB�AlexaF�# 488 goat)-rabbi d.$633$C,( Invitrogen9 |�-� HRP-TRITC] He�"2@H!t8�$A�QO)AA�,(a�,��@mc��#�s�'o�Al 2μm-*��6�Al�/gi0���2� ��s�!��of# tcta%ssco�e &�s\<izd&orea d9I!i&K2'�,.yu ����'�whK}( marNby HRP�I�t�6�&d . NoR"a= l".�$"/nyA���� !n��kz d F1�$em|�fvfw�E@a light/dark cycl�12 hr�#$( 12:12 LD���P!^&/ Ufl��E�r鿁�6��a %Y(switched du�+�� pu6Csoy miMg;5*%�2�)!H��s_e�ferAvtoZ��-R��2Iii-��U3�+:@. <%A�:�� v��tub�-onqY5%(r�!A2% Bacto\ ae el >r�ntinua/$"v)ab"e1iъb"� �DijIincub�s2 before� col�n �eB�U#)`e� expeK n�M�N!2PSleep/�%��i�%w*�D !'gu��5�/�5�!8A����de 2� >�Z EB‘day I7 ‘naYerQ�raw bin�"���%"�DAM File� 102X�� riki�@a{Inc .��9#5�b� w��)V�s=- aram���D�" 's�S� mL ExcexS!�� m)Id�en�s t-tkEq)f5.�T%8*�2e�L(,brain-infilt�� ng CD8+ T %s8 y�)e�2M��^!�]gl cerP1l malari�?ECM )��Plasmod� ,berghei ANKA�RC57BL/6. � H"v+a8*�)6p they? at�i�Dth ic9!�F�iny�-poo�u�toocUtiliz!$i�v��two-pn n�r� �"� �detail*x�flZ%ytomerY4,�x%^�1�accum>Q[!periva�Mss!K%� m ��ex ECM-induc�( P .6���>Z&NK6�A [} .�!2��&U an a��" r"�4��-�B�p ,�pi)� �-5%�2�ex�=arZe@�.�$ |%(pa�W"qKd�� Vlong-a cognA� �%�( CX3CR1-bea��; � � � ells-mv-� �rl abroC�J�(�� ",depr8 APC�fI�f6CntA/2. Pye2i�fopFto�t �%^apfD� � ��3`az r�end*w3�F�Oa%!1 �u.�`u�) s�|�X$t�sb9�-���9~��mf��.�!i�SC$s0*�@�gte�="� -� �I>�)d�\��i3�qRM%2nI�t �:)% /`�# �f�y�F#��C�Rj@Ei)O �:.��ssy�@. M�+���$�i�S0Ulob�7DE� blemID207 millA�ca ,-�ABin 58",000–AN23k 000 deathan� [!� A|kp}UqB& 7s-U1.( ��, a�L��@�S�ilye��$pe��fal�Hrum [�CuN tn8!�!�B}i� m�*��siticid�hema@rap!�,�5@ dmin�$ ` -�?%s� ��� se� �S�Enarrow+!� �хqv�R�!5B-��v� �;1�A]!mortal� k�GM ,EU after=!�ma� 8 !�20% [3�?)�g!0er���UngUk-!!�! ���*E�s.8�:� CM w�aidX: i�2v�h!~eu���!S�9i�(�"%*I susc)I*�X�of�Յw]<2Y ( Pbc )m~�:�aIF� �1u�, ����gA�AV^� �%�Orecapit�O/n"z: clin5wq'fe���� CM [�A�OS=��X)evelop:�ig��%m �AataxiaQ/onvul��A�/A�c4 i8� s�y[<1dFH1-?ly vi�a rrhaa4��despr<�$��creB�-�a� Mleukocy�/ubu&ad�WAmȩ�cSmi TE�S�MB+ , [1h!1�1T")a$whyUVz/es���!A�.�.��5�).B ,z4�� ea!� !�1 �.�E�^[a�virul� of2d!�A does"appea&be����polym�k6Q q�[1k1R*M;zmA���*�mon%�AfmacropQ NK4�2E 5�e%�2�5�@[17–2q<*8 oF�H$2b&86�p�a %equiv� _&�mr� !o� q�y;�EPA-��>�progra<\Z)necessd�a�.K�3.�!_.=A#�Lt��p�:v�t�1s-B��in�4�b�Y��RunR'8 Re��:iII^>"i6�ca&PEZ6��B�A:vesse�ob���!�.r%ng%U[2�B�!9<�&N ~!�!�.�� ao'i�3�%t�,��"D f�.C;[�= ��s� ���al�'o 94cephalomyeliti$?EAUc2A�%k*R a� rofe�'RMB�(z�B]�sub�&hn�+( � � "' &�!C!��,* � &3(�.)w5�to"F�80F!�th:"R3[2�f3�WWhG2� �!�2XЉ-re�6�B3*~u7(V2aA�o �R>�� arg�(un�[:!Y9�;j{4Ato.(��A>!7JXECE��y� e1attemp� #9QU%>I�P3b�a?w �j|T �. Ux cransE��LT�Q&��re�A�o� X e2Wly%�ib!!SA%]Zze� f`nKAhJ� _ .� !�g>�2���>)B\, s�n�`e�� � ap�[3 34(2�Fme� W$��� ���)��.� ��R�oebBd HZ�EE#S�mpdc2�^ !�>� lHE�i->2�HTQ>��"n2�co-h�CD31+ �ini�EO�8i � 7R�� � o'VA�&� �(leakag*�9� . C�=;&ort��9*;2�.p �R�6ak ogni%�o�^����t-wi�Ga� e ne�6or"�V 8�s&A$ctq[�M��[� 2rAPC\ c�ba{9R. TJ�.&. �I��RPJD���%!�y?-&�-i�y#�6I edI f!"a�6 ym�[EEA;on� C7>�( '$ip7 1�%!(vLeake�p�ea� aemi�O^15%?B� k %�� ��7 �( � })�p�kj�,8)�0by Evans blueU�Wt�eKEcol�%A$� oMd� a��few�_ ense >f�M�� fyA��petech��&�1 C% Io15s�Xs�+un)�1�� e�Q!�-� O�]oxCquaQ��� 9i_ avas �Fq"� �+v z�a��]M%te oc@AaI�?menSZcoinci�EIA�2�.�#�Eoqchallmark�hi;��a��,}yto"M,1�eZRBC� p)��'�bl�� �J��NN4gre4+�L"R'c �2U%�cAjm==T &�gd ��%eq� ��%Kto9�F�iniD%Yadv}dqcWa�I42�2I;6�cno1+e&e���"C-/M�q�6Pb �I�< w�!�i � �}esV4i�6`e bur�M "�8&�5�dys"� (6ec)Y8�h�X*C �?g�E�TC sk11l')8A�&,!�%�:%uy&e�Ɗ|-�D3 2� � iQ�AA@w�8A,� ed�"quickl�}5 shee�$�i�%!%� Videnc. Sur� �b�Ir�!1�wdBsoY��*�L%�i.~)�� t&�A�5�_a &� ~zF)$�-S2� In f\?�r2.�f�?)E ajor>t��A( 9/1Tm,6� �( ∼3 /mm>*�mU&oftigd+$nt luuSl7�5 ∼2 D Y'�e�6�j7���weEa fure�ůn(�@!])���2~�22��"�; 10-fC(5���>ub�1ti� %t! Aer:��( �Y5:V�@� Z?nM �,>�A1Q91.-to LCMV �uipaT�*� *�ɕ2� � ,a� � �"&%F�s��J3�  b$��A��u�oEun�g%pA�"v�6~e�@�v!�:��$�h simp.9u�54B d carriag";&� �#(a��+S3}�T��s� ���D6�w>�"�&[@*b?0-"&��xc�!q^�:�ly��)6,|?a� ch����!f�7v%.!�&�tٵumAg�vtY stQco+vas brie�<�:Ia{& ��*H� O * &o�'R e-*K#ma�:al)'� behi�K�� �/al 4f=�r\+,�a.�")� B��%-�..wsOv!%l�1)aT1}CO!�b0�(�Rq@"�q�yqe &� c�F�(e�A�Z�iK'di-x�S""x,: &Data�� �/-R:G U�a�Z qq� �AWs-�hyp� �That a}�H&*�*&A�insicJer�f�� � *]� u� N� �i�!,@}qi�%�wV�ۂ;Sh ,� s��_we iso(" cAV9u QndB~6� them�� c�*y�8h\ed�i)�.a N��ݭs9�-��Jo�-Ň�n1�m�ede���3% 3B��M&Z_?'� .��8<-�!�2��(edI&m� D11aq��!,Q� �EG �� L )�-*�A� [�&c`�nr �-�zh@�rQ�"71K&�+=E��[in��-Z��W��A�+taaH0( CD44+CD62L-a,� d�re,)36� ICOS=?LRG� CXCR�;�&�14V*��>F�!�r.6:JSeSAH-�Aor��1ms�,m*q'���J��/ I9gh*�����u�� �"suffic�TG�tM���� �2"f �&-�E�8J:��5;��9B�sZ!"h A�a(NP� e2( !�tw� K's�#�?)].�� �x�C W?n�Q��'pI�c�.i*�/��i"�$�ʱ�v�o~�i��! alizi�A("�]PB-��.�hCD2-DsR!Y)XɖBm1-8z�. Few Ey?%""�H>}� naïFDic'4qorQ5"=@�(� � L N;i� �e�*"A�=2� ޵e . V�X�"�%�=-@a9 ��%@�!H ""$�� c�B� ( S4 �. C"�E-��8 ��m al �k� !����mai�LE�( >70% )�5��Cn" MNnx�  ��!�.k�fF1 &)M�B��4�4��� ly�r �� �u�ɒ�DNr&�3pDA�iV~Tby;%�6 .�A*ref�7h Y r=� �� u�, dilu!�:m�fa�MeB"fily_ v�# e�1H��kj�b��[PbF��| t�7ly�A� o>2m)mY�e�pr�/"�ylB�or1I�a�E�lymph�!tissu� 40�-:��.%)Ud:$A�:(6Q)P�5.V"� �3f�� 7g> 5±13% vs 59�k±299%�.m t�Kam��4� . P*�5l&�6�los!�>F!abl�surfa.Ai�� �r��E�N��`� Av�X�a�$%�s Xp� ,*#(s/�Bw6}�xp. 9±�H4 �?4v 3 . 1±4 . 8�/NS� N�`�M{Ao�b���mf0$��D�a��`clust�HH� pry�� #�Qu�)>dEG�iaj�x,7E-?/ll�' venu�D[�+IibecE*s �0 "P7of&� QX&�-.�Ea �Q� �T espo�4nes�WW2X;b�Y&��_)wr  �"�m� q��W� [vK43T`as�of� Q�t���!\�� k~�xVA�bl a �@A����Q��J� ^ nextQ��h"&K �� � � 5��6� ,D��V�i�a. Track!�� �*��'��5c-�%%!jZ��!.S5 )*�a�&$�u)��]vJ ( S6 Zg7 � 0+�#��� a�er�In� ck� $ed ( 8 . 7�y4 vAH5 �� μm/w}� ��C��$ coef~ ( � 18± 21 v05 �H�lo�� nt8.o ?3 .23 ?46 ?2 �!�Q�.K8 ̋!)t�Vt�� ov v�N�F�$IOA�t!Qe�}��A��Xis�ph�3�l�L� * plot�2DF�M�h�A�sB@1�74I�� t>�ItoB)�or6u1GM�]:j�erB �6�:E2 -�u)P24�m!"�A��!�iD\;�mc:�'��uTAi� �.�^�He� ,%�+p&L.%N$+ �.���t�r��*)-&dN�[4���C3"��W"$�O:� b7=A@&t,^+p"��@��m�V�a���&"*IX}(+/GFP du0A r X���t$1�(I�s�5A"�1, .!4�[2�d�Uk.glia [��DYk=�e�q�or e�ec^� |) �I{�mad�|)�.�-���0 p�C S8��HS9 ��A.�"� al�]�r.�%�,m��;N��numer bbQ )��:Ist��e�A{q��s�`1 bo�K�o4?GSnd/�!��hcD2�=� �rI=�R.����n�#�# Hif&Qd .�%HF � o-�)� ��BT w0= GFP+�BJB�1��!U�� id"45HrkX!�;�&�)�((!�`�*�)Q� �&�!��E"/:�b��C6A�We}$�Wub-�\d.��X�� -ts!aeV6 �bE$CD45; R1 = inthi��r�� , R2 hi�#X5d��"�!>DZ1A�$R3 = a mix�") !d� o�=m[�Z��-$&�.�=�& �>-�3"�l5�779�. D O%�5�A�pr.�CQ.��de�%� 52 . 3±12%E�q�, 4� 2±1�1�o ��d nI�2sK�I�-Bfs)"� 11c+ &�A8�8&�,��7�5±�6!E!�jhi.�.iLy6Chi�&78&� |b4±�5��8!�8� Lac�-Aljf2�"e�Ax)�=���+ɪ�3ty9�-Z��Xs+Yjx6dmo� �~գ�*��c�X�I� .�h�v�3NsF�#�kit��nWr6� 6W!�.FZ"}r�J�8!tr�%to�d"0#a'u4eiHQ�r1���.�3�R2p'lقree2�9-� !N�qe�up-6�vco-�< ory - 0� CD80/ ����&q ( MHC-I )*�0-�6��Q&) �x� mo0 ty c,rw�0�eGbe9ix&� Jor ?;��"F�HN in �;�2�*�inc?�P!�va3in" e7 ~�i :q�%m�=EI�_22R],��5�2 �J��e�YwAe�ew"���n��6X��A�gL�i�o7I� 5$w�V�^S6o�{P�W/&�!�` Galea&�2��, day*".�PRFI��stNB��7� F|0�h M ���"�ng5�&�G!>v�,6�.Uj�3!�y-&N }-iDTR �[���"�QG�j�� �V�+� scale6��"�@n�V.P��l$duced Iba1�?�-r� .w����+�diݓ �o�&F�!,iBm6)%� �j/�)t�-,5�G��9|�@����edu&�=a�R�To"�2ai]z�ef�-*9s��c� c�+}1 e Ag&�)"�1!E6N�bona f� ю�u��Dbe visuq"hndj�] . Ad�N0&fd*,106 SIINFEKL� OT-I6��� �i� AMi3 P14 TCRlnh&�in� 2  %~@"��g@� !� gp33 epitJaof *3[��:�! robuV������lR6.(Ka� -5 ��=Q^� � -TG"�!8�$8i�^�o/F�6�o�L�halma��"I'}�.�F��V�*� 14 hn�!��12y;EvP�i�8i�m�T"ed^�pr2�e*�XB,"�� lo��E�)�^�2 �� .j#^�.��.��!re�XtP A�B���aHspB�tL6�32"5a� +=.5of%829�56�E˥11*$D�N�(��;fB�&G!6��>uT_�Nwam-I9rtifac}ˊ�N�'calip�- ( S7"� As�?ar=��!�:i'�rDR�Bby-��lnd��jcG!ZR/b0iK3�f�7M:1)M�e&[A_attac� DVo�.�KtaP(*'s�6*A �� M$o�s�� >�w:empha,4 �2qm���J��]��I%�s`� Zf�.�%=��t>;�X at6S�5�)� ��A�!�th6[A�-�:�=*��xC�"�6�NQ*EX> [O�RWPR�;N72��2 !R�[At.�&xl . De0R<(G�M�� �_a�&�J> .� 2� a� 0e-caspase3/7-&���CellE 2�Ino-$vr0�V"T&�>O �J �ijs�0!%��9+� .�\.71!�A�� & by o`D���icN�|#uct��  ).�#th�a�Z����Cr�volum����u��b�rve���89� ?)�T��[.3 �9� �t qkmcortex�wJM,Ű&�-�+36sin�0 C �� "*z#^,B��b߲iI: I<� E���ZU uC �)B��60Eh gIAI�:@Ah)wy�!j:&-] ��#�A]aT�>2^f>.t "�j.e����IfX���m��e�|Am� 31D–9�&B���8�sub&Ao midd�)�Zart�1oc�+�kM� trok�o�I�`nN2�i�Rfu�*:��(�"�+KC�����]:9�G�KJQA�E]i�Y����%�@$asnq�A.. Ba�a�A!u�m�X\G�{>iV7�3�=��FhM�� �.v�* 1>A��͚�^dVUM:&(-ly�*:6E�/�0&�9�;(+{+Z�N�K"/3Kix7(nd�*X_�"@y%&�z�B uAop�!�� � �E�A��umBj�"W|02F"�6y� Q�M�2� �F���"�dNRT�G.�Ie/6E�hE�tfT�{t�J� �XA?�� �a�:�6�R.X,.k%!�..Z.��L � �}�$�C�*� �5z4"Ia*| �?e 6suAUi ��5��h��=Sl&�%2�����J2�Idee�-V \�8I0�G� >s %��Mis�unߌ�BTC.�6I��&uAe%%�.�J�*�a�eacu� abel���)Gep3.I* �^e -w2(�3{&ave\� d�fncog�.uA�A�"��ll� coup[�a�%?b�Sf�>&�]�7#W9 .*�3x�J�O�� Zsv�.*>qC� E']�unappre~��I"���YP�C" >�.MW2�eA:�-�5�j !�R� "?!MB*��;�4��62xA��!\*�>� 2�a��stVc,=�*-D��va�"�2"?��sW k%�2�.-!�&�2�>|= �&�-qi�%�j eY��2.� �N�9T!�E�!�!-!y���+�"fX�N2D%2 �)��.v2��"� �!�!�/E"�m1�(2�-s "Rs��sz r�I�y�K3me�]eS��/�.oA�6� 2�3��s  ��8�f�O�nμ�Nsolve��16ac��r� )�2-�!'"��}=34 a��!_ � ��A�faonB���$t��V�pWX��A1"���h�b/�M|@�c1�eN* E 6^: ;6C�數K.�F1)B2'w A��.u�F>�;S:�&m/2�AQ1��ag A�&�i�Xre6!W�0e&TJz�ssAkYBeh�v�hmN+vZ�kSEjX�.�'d`Nas �_.l3&�Lperturb?�* R����/��"����""&-�d&|'I���"�0a^T%cee-/�a�+%2x$iC qw!g� -,on-2�%&�$IO2�kaR� ��publis��oE�A �T.ks� �D%�+;al�.�[1dj�#"�#Mls"��au[�>a`r"�6x�o� b&f#ti��"� al"l#1 "a� �� !H"@�>#��E�g8<iaOή�3*��A�AU!�i�~h��uns"�S�S�"A�� .͎5<da�=N�����int:LSq�mAreu���s�gALu{aZ$lidk<��nchymol�.��.�%%e�\Yskb��~_��?�ͱ�l'� s�Z| �halp �R�3V� �  mn�'e@!�A�M:�.)X=s$s�A�� E�(3b��kfg?e���n?�H���7 �Rngi�!<6�a���a(ducfXa� -8=�m� ��a .��D!1injur�g5$!�1- &`$a��m����D��= 5���[5�d5Hi��D quesA��}~<�md&e�eu�t<D���Az"� �omExQ��`�&/*n��P2�� v r�LY�0 ��\ ?� -�mZU�2Ahes�) eq�}-�a?"�*R6�&��!��ꁛ��h .� �kl�.� %H>� �!i�i�PL�"4o�y�9!0!�7��%Yr��Nn"�i���|����a��"�\� Howl�4�who&,%nE 5�6rFcytoly� "��h )�(.iEf�)`�>~�QInd� �Z.���r�2�:\�21 |K :R� *B��OQ�iY�%�a*�!��$�  <s%��e^��6Q���m�2e.+f�[��6�h*�P2��b4EIYIFTNI ( F4:!�o�A� A�$, IITDFENL�$2:[t sn 6*SQLLNAKY $ 1: PbGAP5�/�% 敭*T�'�5B��0!1)��@�[�, ���>�}&c 2��2#}dy[18.8 6�!60@�Ot��� �V1������2k �.Q�� �lͬ*�1isEC� aK Ha��q�’�� i�MZ���� A����� ��[ untilnA� \ 7�i}"�2�[1E�js)��z�w-nA<{ )!2i��iZq�N������ e9Z��� e^܂��.6�tA}�) hz*�,"�+�Q� q�Me1�b, 2�B> Vō�Y',�ѩn[)anjJiVpWS�U<YDI6�t �>��#-s*�w7)��t�&6*[ �2�c��/1r"�\��i e�-2D.�`m�-�po.�&�OE&*a��en@x<)���� sV"u �#B�(�D|2 �6�2�� CM-qG��VA�in�{���aa�,��wf&�|6�e5tM{CCjM.?W6�.p �N��"�a%� �E#"PJof"C ��JEi�r�Tum�1)��� >8b�[I"�.;6�"�d���&q -) ,6��>�^ ��&2�]�2 spac�� ��[�wo?�K��AP�t'ɥ+$n&V��>&c ɓ �1 5E�na�g6�^Uf��4tably v�!� e�,B�[-��e9�j)D.� �d 6�+&�I�k��U��]i���"E, . yoelii NL(,-�Fa"0mMv%�&�>1�w�M!�!+ �b~�&�on� ��5� D���a��λ� ?*l}R�t� 7)em�m�8o� !�pr%� �Lv � Pb�Q��5*t74j�O�!a���"�vi�*7����,m�"�9 �T.�{IM֛of�P6�u"5�!�2eb�`"R"n_�� 9���� � �%������<}��a�T� g"�xA}o&��6�k""�i"��2��,�**���A;*u � |s&�E�e&�!!xF�Bgaa*zI�D��B 6�l&=� +^�HÖ/S�}D� �8s�J�  �9q;e��)�@.a�[� bov�nv�� :�#>�#I{&_$�$d�j%�A !�%�ij6ZaccaE�!?�چULUr ��m6AS>*�I"�%!�>� �)GM  2 Qd"p�[:,�8�Arapid c&�T+���!�7�h no w&�����>����JVi�&�E���).�i�c&�& �!I ��{es�C�!z"����.�;r�^of�$�� �IU�&2��( s CTLsM?��;,���DZochasA�r�=e�(ndN(:�s�J��*5�76 hou-6�[$�, r���J �e e: �Ak�a�ed-!F��!ManU/suJ!bŨ�4 =6�N.�$*� �byYhqU]�615mf7�:����r.��&y&a�iZCq8 �]��.?a(��� . S��R��eSuidan"}� :�2��&� B�xPitݏZ�{u�1=Yy�@*+k��=�� VEGF�[at ���Bj 1Dap��s "�237A�-Hm8�m����, casc!O[6_�&��� �F.�e�6�[��A�h-s�� [6�?���5 ��x!F� ��~[68–=�a�Fmcenario!P�sm&�y+o0�A���r�\y^+���re��1��35�A�g oo8Q� �aBZAA?-�l&AA�v ���;�x�iA��jd*Jr'� ��|���>)p ���2}_ ȗ"�]� A�&X� ��si�T*� .��u�Aq�21- ����U��o)�y��R$!��6g�bg�")H{l�0)�� �A݀�'ls��2dA2����!�Lg e>� F�JSyI6�-2Ka �/f� �l shif��m$cu�0���T5���$* i���*u+.�'�&!��S� "F5� oo ���*��5�&X 1v���g�/ge]NageFW)V!m"&R in-si]��0��gag� ��u a��=�r&`M �2l &}OOZ_�%r�d�perme��� �}�B*� �1r;h>!���.1�. A���%$n New Yorke1Wp�M��n�ictac�%��re�Xendn��Gu�?aW$C�2 �Us�*�� ���7Ph"c H� Serv( Nkal "b�3 (�e�p9K �*��Sch6�$of MedicinR�s���, � �� Committee��ACU�4.*1L�U . K ����f"��a l et&Z �Gew�;6������=� d GlasgowuPUVdV��ESs� d%"m n� �H��Off!t1�( Spi�.x ) Act 198�=�HR-'�4Liceny70/699��70/729r;�c*Jg !5��] anesTia: ketac�$( 50 mg/kg.xylaz!�(A�ace��\; ��s�5��(Oin O2 at�>2 L]$�(+8m!�u�:M��(y: At Skirbf-U�-Mi7U," �( H-2b )BA U�C� rFcdaco%+Lab��$>;��=[,BCFP [72]#:A [�,�&4CreER X Rosa26�&�[�E.��BAZ ?��ډd"tV ��h c�9en β3�N �q!�d �uh �cU;tt )b'J�(�]e ?to2 *MF) � � C5� "�'� ��� ��amoxife�� F�a!� diph=ia tox/*� ( �F�q��1��v�#(>>5 �S�ɟ.A-n>�q�!��Y5%��5 Harl 4!ahar�bR�rѥK�C"k[��QGFP�[h[>X]�F2_X-P8X Z+/+ �( .�.�[�4</ (EO�Wy ���� o`�"���~3eoex12 weeA_f a��Mu�maiA����A"� -f�Of%i��B GFP.eD2v�p"[(,Q9u(o�el��?A0or 1a [eEF1a] i) �a k v gift)�Chris Ja�� ( LeV%Y&yɼal ��) �.�/N�EB�&�E�%cB�William�j th (.���eli�ne� �.2lo"bmheVV u�F=3a 0circumsporozo ��o�[���� �b6�l�d n%�A:p���R7na�>eC"��b��E`B� �i��A%E.(�" �(/+;�"�?o$gAf��104��106� ��� ����h=8��n�m��%�mon���jM'&cm2�(%��"iZ �`�Y �qj�Lmn0�%t�-e? 91����measu�da���D3 �M!�V7e6)$of Giemsa-�<��= smea�r=(;yt,�Q5�� DAPIF/.��VY�?61?6���;!s�������sA�C!�&� ����gra%�).77] 1:|s�� ; 2: ruff{ fur/r�"^�os|,(; 3: letharl��$�)d I iven�'CqN���[� �Hi��4N /hyp�%�"%{ ; 5:aj�K!9I8 N.T�X���2/3I��1fE �;Rm�1�1S�0�s 4/5N9G��l��+/+�2Lepur r( >95%tq�Ewa A2F�KTg moN�)�a #�l Mg"��IK\!Kit .��.e��a�2gFM�� f�ayPi�+��H� ��6cGa�!�av���eeV�ĕ��d6�J-�AP���. V%^a�iPe8MX3*=�Bs0 ���"!"s��BO},� μLDn&��$/PBS ( w/v�an0 ᩵3� ����! �C�o�.�j 5–3!�8�150�Ek&� ed j/^y u Jse��sampl� &Sexsangu����KXMe� ��i. cardm0Zw}D20 mL �cold ! . Ea�~[$�remF� , we%�>de�0!# n 50 �44amw!q� #x��%at 37z��48SRI�9ct=�nYor R!,t$as�AAnd..absorb� e610 nm7�s)L; �)V� EnVi%v2�Mj�Q; Read p%�O�e�S(PerkinElmer�zLL?�cal�e�s.���A� ( �) mnpl����)a��E(5gk<qXY�B\ �:0 �masa�H�B���� ,t��a7Q/g D/hrU"n-�ve�+En7H�`cP�EX!A�o&�Sa�T&�3&+�Ta�9–8�(l92v[ed8&s ^�6��B��$��33�)A�e ��,iڥ�"U�//PT t�3d����Y:u&Ե ).i���U �2=!o���#��*D ��! [��s�/�*KN���:�4.�a#� "'+s:—C�^��w&cx, ����', 4 ���()[ >M J7"� 1)** � B0�4B�T&�S��&�=J��W�ߌ . 20 ng.�in�B_ �QPmer 705 *ged �z>'ot�i2� G�Km;. A� expo� A!�sA�2Vmov��cal���b ostev��mmo:g�?� qseo� cE4que A�:�� g wi�N�-mm di])e�H�o�,e rs pari��b[� mm(D�!�ae��bregmŽt � >E.a�ro-drT%��aT ��ng !L�IT&G�2�).%����f-�$a LSM-7 MP!� 10W ( ZeisP�,�a 20x WG0n-Apod�ma��9imw���o[I� ( NA 0 ,O. ExciC(wavelengO� 91�_94��a� geneia�Sa tb�Ti-sapphΜfemto"; pulK lI��l��t ��/ a3 "� ��a� $�Ū��on-��aڍ&�AcR;W"�}. EmiJ]*nt�&seE �di!E��irrCA2:�OO�)varrR`�j=� figu^s: <7�`625FV(6�4) , 490-nm dic�L85/22 ( DsRed ) bandffilternLemrock ) . 2 ) 442/4G � ) , 46�d:��483/34 CFP/ 850f8538/36 �,/CellEvent )>5f>610/70� t�660!WR�710/109DEvans blue-albumin|,( Chroma or .$CFPb�signals were distinguished by assessing the r!� of1- < to1 . Mice S�maintained under anaesthesia throughout surgical ��transcranial imaging procedures . Core body temperature was.q$at 37°C ,�Trmostatically controll � rectal2N4probe . PerfusA�ofI �windowI@I7� devoid of-�!:�9ef�Bsuitablee~_!�I;(. Similarly�@ blood�B��ck7��J summ� �3Ao7�Q#1���(. Values beas0 � ignoT�aM tric�ance mapE?ob!&cc�ve greyI�dil�%sM� ��,is new image � u�Q�structur�elea�iP�3 �,�v Ёbpropor��^o64 from.[ �0 insida�6z�herua both!~da�rd any%�sfZIǡ��re� �A�� to measur�ir\ �j��VJ�a3uImari�"Bitplane�r Voloc� ( Im' � )��packageM��t� �1�.n /�.Abman) d s%�. MB�eRsub�~�ex!�e!^d>eda�ExcelFean�S�V as calcul��as pa�ength/�� (��/� . <in!dtaneousVJby�lrm�-spn�) ed%  �5consecu� v�A . Ar�mcoeffici��FAekdef� asE"perja9aK ime �� s when itEltaJ�<��k e�\e^ra�q6/)�displac +(I�� ( %�e!��) / =)mB ellularytac� et%HedM�? 3DA� a lack�space|űac��!6s5u9!in�tm"ede{ 7wi �sf$at least 5I)�� Bra=�ste�1leukocy� ^isoIpe�PBSpe'm� A�reviouslAH,scribed [83]��?bj>^ surf!s���Pα-mCD8 ( 53–6 . 7 CD�30-F11 3� 7A�8, CD11a ( M17/4 !11b/70 69 ( H1�F3 XCRI-17 $KLRG1 ( 2Fm44�HM�62L[ EL-1 n ICOS�5F9 XD4f3/2 RCD816-10A UMHC Ie8-8-6 619FD549�DX5��In!�Q�%:�f�x$granzyme BSB%%�76#1 h�af� treate7wA4EgPb ANKA�D�follows: C-iDTR!���#  � 106TpRBCs%8a)OiI1%&2�4!S� A{���ed daily Y45 mg tamoxifen� solvq (corn oil vi�al gavag� v3z��,vq1 μg�h5� oxin���e�o�< %U DTR-ex� sing-<1.2���a<2 q hist�0 y of ;.]maVgli5 P7C�b*� onitJ)Hf(ECM symptom��d� vival��s d" .�� ��of5+ parasi�� 3d MEC 13 .%fBD Pha� gen aev� caspase � Asp175EKS�l!4- B YTS105K88 , AbD Serotec��L��biotiny�d Lyc�sicon e�` entu�=Sigma � %thicke floa� )|s\ ons:!gM� sacr��^oi%�con �yCO Spleen�� remoA�b�� n?�ardL��u�w� � �`4% PFA .� :S!Pe�cub%| at 4�nŃ8in 20% sucrose/ YC.x6m snap�=ze� dry �6AO)8�a%[z!�sledge!M�;m�B� Inf� hCambri+ , UK!�t a)�nes 30@ �5��9sI�byro���nt&�D( 30% ethylene gly��,� erol@�)!64-20° C until � . Free-U3 � �waDinD!t bloc�embedd��O) um Cu%` T*�!� EX( O�p!�8 . , Tissue-TekM�f)eXz/is�� panol bata� 6–�f� col5P��ut_ La Leica CM3050 S cry��1!�Q%�2�$SuperFrost��C�!d? pfix) acet�ataC�ig!� llow�o alry* �!,� � rehyd{ W  TB�!�M*` $150 mM NaC� pH 7��)) orbia{shaE��0�!|� 6�o eabl�hby so 9i}TX05% TP" -20/�no)�y�#�o; %���5% BSA ,P moue�Q ,��36�F�!�� �qgI�׍�O�" �� rat�a�-Alexa��( " Invitro or r� α-Ia�( WakoE�"� a��u�q�TBSa%The�<-�tia4+"v!�$){ α} :�. A\h!!9s awa a6+q %glyA ( `ver �sea^ ,$nail polisa�)$u�e�^logs�� (> �1uN� � ( w/v!IB� 2 -��1� 3^�$I�y. 500-q ,�GPelco� vibra�Q\!N�B( Ted+la �1Mo S�Vf.V%85d1fQSaɟ� ��-�Xa 25x LD LCI Plan-Apoch.(t*� ( NA f |+#s���x�� shop CSE)Ad;'�1 2�p@ )C-3/7 Grd&De� a� Reag�L( 2/!�S�< .OP���?��>cF� �%6��&. $&� "� H&}$"� !#an%�a9�_)–5 mm2 ��th∼�vAD�% -pos�"M�V dBthg�d�'��! &'#im�-�.fs s 1� fZ� u%�4GraphPad PRISM~"p , USA%�CompariRv two  ps%�m� Zunpai�t tes�E�Welch� corr 9re nee�_>i�$pl�!oJnaB-��ANOVA kTukeyk���Gu �,Differ[&in!�eB:�!�M�4l-Cox log-rank d(.�6Tungia i &? kisecaLAk he sA�f�9a peneP also known as jigger *%$mu|'�)iv�b� ecar���$D)��rop� E` sub EyrGb�%�bruntA� &c% k+�- N# stud} to&� Bburde��-n Vihig unt�  KenyafK a �s-�w� fmu��1 v))� in 3loc � :iJ%apA. a�37!�ticipanE�$5 years oli� abov clin!Uly exam��,!7 AQVtUa�a�!ni !-tak� t�; �.�gn"Xe\�!�� d�methodA�Am"�$ed ques�`na�e�2�e �- *o-demog� ic factor9 hoi�,�A� ownership��,E��%p! ce r�� 9 . DaIa�eg� mbivar+Ge�regres 5aj. GIS�e[�$ap%Nge��%rib�-A�5�a"h$E�e-� &!al%���fo to be ( 2/,%; 95% CI: 1T 7–2�3~i6ca�*��F! visuaD � ���G )�� suggA�at��i*c:m�as!�W�Pbles t?indic�'�o�Au�%lik�" mont�inc�0of Ksh ≤ 10�0 adjug. odds io 2! 8594�"185m! eart% flooy36; . . 02�!!1�#toix*fac=,��(a27 ;8�2�3;, a�-pau��1"� 414;�m –7�9 �noAt8$j of�!�footw�6( �98 |98A9t"�commonr*e��%j!AzadARG3 G�F8�..>s��&�health� le�/:� occaa0&GN�ahe peo�iaff. F� E3[% to povertU1aVeB^�e se fAwngsQ�@�&�:O2�"t�� e7"�Yu��' c{e�*!leas<a*�*. �z�Urefer�!��[��A�� !c neg�.�/��du�faca�at it ty�hly)Łpop�'���-@,i�pA�A���adequat!���los1#{w%d�!e��ak��o o�� ��1It�howeverD!recogn�of(��worldQlorganiz�f�HO ) [1� � fMF���tra�0thI�a vic�y0!C"-=!l[2~ �end�"!:�&�[�&d��/!�fA�ex!d� s �ed!7sti�".u5.VE�*�Y��he-QAj� un� nd ha�,!�b( ��'%aI�Efew2� carr�out�e *=~have docxq .�ran�'� 19a# 40% [4 , ��7!jDurA� peak!� nsmi�, childr�0n��e eldeU.�d In�2� �0��of 57%!Ce�! $q32*� !S%MA�ri [5�InU-.'ingzi2 Nige �asC1as 60%._��A$n�a� ll [8 , 9w2T%� � >�� ggra?�����'�8!bdusty�B� n�jr�,�(.�out:�_ pigsAP!`9  [1�$ Slee�6u4 �6 crow!gs"iD�E��ci!,[EQO��s(�'�ۑ�m6 same�)e [11�%6p/�dog!ca� r cow c&�,�4�2b3]!�1duW $ level [14!�In� �5 Dspa�jr s!�exist�sa���P4H e�y�1see@ to c�) bd3� � ��!��1E�Wd & al%2 �� ?s���4u�9st2A=�0)�g�z �/��6! ��.cJ4�:lim%�resourcj@n Sub Saharan Afr�,�r�A%�H� I<�8e!�in>�t�7ti�V��I�lea<�2!�or zeroN+[1E��� pos8,�M�fAc!�.��� is i"� �%2r� � ym�8�3"�5ɵJ[Z#1��H a loAy��� s �d�A�Le\��i so��toQ&�wh� b�l� "magnitud� ';&� 7 as l49a. ;fcl� �+�{0&� ���2s elus�|V�B<in� V�-$A�si9d1e>1at �:beM�� oU� or :�7�)@ � gap� shouldN d!e�zi<;�d�%5e�y���!po���$ risk�  "{ in w�&B 6;snu2�B�W2=�6A�58stituenc�nam�7Sab�M ,K, EmuhayLuanda�Hamisi-� A��h!s,nsO� ed rue�iS .A �a*A�Q5 622ɕ45%]be 14o*� !��S. A�;~��ac � �c( 79 .�)�h� p' /mud�d s [2�o p ����9 ( 41�!�pGDP� capit=�!�ry as US $ 1��03!2013 [2| n!3%$ two !2�8ask. La�.B AprivMa�;d Jun��sDB3. Sept<r , Octo��Nov M��au�y�,xss-{"52 took}5 Febru�$d March�� ae��B�@*� of6�� �  "ak�b8a��.� N��&�m,A�uyundie yalo%EvojomD]randoml!���+qDzmba6�,q (T*�2E�Jng�hm hold%�!�3�*r>�!��p&9�;��n"�!�<i�per2W ,.;!��*a�+Z�A pK*i;a-aWrta�n��!d� ,�7 elig8.-u1aA�!i1�r size*�" �!(Daniea 1999�O mula-�u]^�- e P U: [2�a|%�޵�� N;�A%A�� !�Y t*� �:B50%�7 draw/ � �[23; 2� �ca"�8>�385b=I*� cf�� -resp�8��� ng �� aux� �&�s�"qto 464�i � crit� �!~ɞ�p!�A�>e� FC]�agP(���a�2oi�wi�,!wwho�? d":�C"��C 24e�R�>�=%�4z��D=u�Eh��w(dDir�!���1bt�t)3�nao �!+�l"J6�c2�6�%NR��en�%"$ en�E � y���han�Pfee�?Ȏzv�",, egg-producAq!H�,A�d%7�H c� n�E%"j>�*�"��di��Etq��2 itchz red-brown� spot�� diam�:!3 1–3 mm;��� r leE�W���?t>tchNK4+3w%a"[bHdote cru�$ur�'+ne�-icg;%�E+AHa�lyD �.)EW ��41 s~@1��[2�A�-�6%mi-.~?��Azh!��hey���ldest ad�C �fam%A Eng�" , swahili9luhb A�-a�T , upo�A$!�A�Řb!seMsB%|Hhel.8 t$ *�y�� work6UA�9BEuEAr2�6A�k6�,qw�pTIs��w� �whoHG�e�I�#��7��Aff �i*�&K,a��}Bf�Dategoa.() SocZm suchA�sex�yg0&v@2 ) H��A*����EtypP��A<.$� $~~A��AayryBL3 "�e ri�@�wmId pos�7( <O"+%i��B���KnoJGs.H&��� | S2�do? r6"�AJ��nve*�nd�5{,��%, � S>#4���2iim� �vba8� etai� bA�ai.��k��! �5�"�$� 7eld G�4 eTrex��+�i[as:�" ,["Ki�;, Ola�, Kansaf.fwayswre)�e\9�� elev �.7,i�c"�/&- Wl Geod. SurveyhGS 198A"da�43UTMa��; �z�36 nortn'Dqa�,.!�H�BFbas� a� lea%3,�lns&7SPSS verŗ 0��E&��"�i�y�p�t�:sme�N,� devi%<�m/�E&�H.g&et�;)�J�C ompu%A**G ��io PRR �&V~ &)Esa:M��*.� �Ais � at p<� 2EP ���& Bin�m'?! a�� mode�4A��/�?,�� Al" &�2�D. Z Av�IgEN2g�6lanatory*) A-�ImSpearman* k�%�2�e6�( �;lK)�chi-squ�X ( v �&� !�Al.<��E��0)Jm��<1~�.u �Arc'1!�5� Esri��a�!, �topI"al�~�K�6yH$of 1:50 , !,�pre��NUnia< al T�� e Merc!~ (e�)7![m�!�u ,igi) wI��: roadarca�ow�&��GPS co)��9>��U���re plot��V�H!c"�1�,����con) ��9e. pefi�"2>!.�!L � yqZP�.!�!�� � ��p Ea:_&TC��crM I!,i�s��mFwe?9K( IDWA�l�thm[l�n�SA`!#S�Et% —a"!*3 )mBm�E��es"s/ �A�d!�2� oMbynՌe�� l assuB����paDpRs!L�6v ��!�los�x�y'5a�aCm%�Q��b)�F�y��&@� inputMnfe�5e' Qout!A0a� <p7H=xd r� ��+in�mA�a� tEwsho�'�cl %! /B< a� er v�(Ts| �N. Appro�=!do �souHB%�9'86��Ry ^;0itute ( KEMRIz Ft� �JE�.s Review���� SERU���-~E/4/CTMDR/015/311�Gi.ritte" �"B�u*� H�A="�P�y�gu�5a;6�Tt? nN ��/behal� �?&�z�Sco Cd ieA�>akep�!nf "� N2�M�@%�� ��Bg���N�8al Policy Guide�~� Pri �9d C\ of J�+Inf�$!.-�[27^e�Ab $1!Kws �5��aSr3U��Tnd�s&p! �u)]5Y"�E�in�'�3potassV4angO4r�j�G��!nu�Z��!Zz team! vaccin�(�% s agaT tetaBHb;v%�e`%�.�%A''�4er!0C"]HB'Exten� Wo�E�=i��. V�)�! stig%��V�didb%ve�Wy obv�$- �f��ermA8zch�#%�&H �re��6yin  Ph�:we�high al�a<�QM�dep?%�Y�-Za&[4� *� ��-��i�( �A�p )RElaguofIW074196E'us���:m�e�u�Err�Q!Mu�6� �emݚa��4no5>S�c|�(��jpr"X�"E@mi��bv .Eoil� 2thFJsub��QGv* ,q(!�mai+Tobser] �Y0y cla�'D� . Am��"�s]&Y |*�Ͷ�Gigh!{6^&+y�ChambitiE�SelelweKI��. Fq��lWamUR�-.�$i!me!&���"70abs, &�6� ��a�w^on�R2U mRs/I� Fa�v��!��!�t/:r/<h/af/OR�.8w7�.)/&W/!Dag� ��.�2�M�FFQ4/��06/Q{�DM{r�B�th� e=I�� s o�Mavailab�/��.~I�2%B�(B�..q+�@j)�>/�>/�>/B35���O/�O/!z�6" .�A�\x�' axim`s"�� �%�Wxy�*ax.AArabidop9root titK� �; mut�W feed"�!a~E ytok"Ws<�� �PIN�si 2efflux�A�FAHP"y hib\K��]E�al{ !��'`Kon,#�*!�tS261; j p :�,hormones’ A69v��ctdo��]ify inct b��a��"Z/. T2�'kdynamvD�i H,net�� �b&3Ba�UsiuL�X�k*���%��y![2 �id!g ��]r=::. with15= �'ex� expl�ly[7��`� ce�Chap��5}�� ,iR�Ou�,�( ��E�a��Q� .Q��s g�b�dif�K��!�or�dunm)�#cen�9$ u45rmP,`)fT ��s��"`#�xct�rob�)j �!;�st], -i~��c.1eD�A�� ,+�b than� !�� /"�$w�A�necess� q�$ ~c�#fR&st�?s� e � �~.%�siq# ~�8}Lq_+�Z�)�#!A-(-=�L�^� eKe�o�Li �GHrG!oiqll �b�e�$wNedi-�ex�Q[E!ver% r�of AUXkQLAX1/2 �inF�� ��"bdMZweES!�M9[�lis%Hm PIN1U΁� om� 5� �`5�A��dcu1�R)gm�A�% , buUso!Kv(K me#ism%� @|$ Y�ecE�l�.<W-p!5!P[4a�Aea�"!eaMdin"�TŞi�=) ��l*��0�$��>d��p��e ���es�>e4 �a.!�nc�b � � �nQ�*�sv% �E{�ach'6�+er elopAb!�U�l@� �!ib@ inno {-Ze]#o��Cr�R^r1p�A�>�-Baa��-����+�Hor�D� cruc�a�coY�lC���er� fulft!J func�"�Kr �s m�bej1\PQ;ly��!�o J���inu\!�5D�8n��1)6�W )on �u�) �Eaq�"gI�j)�F@�r�w�1�E�o+':)�1!-�1��!2an%�ofkd}1M1�@la!�ie�x(.r ch�hk6E�yieP*!��fundaA~)d!v+fbiF � prec�!�GJ3lay��u5 cyli�2 (a�le .n ,thaliana makn�$B,0 �.�gto_� !+ �.Zstqii�!�#a�a��� flan�3b.t�T��Aal��;AU�Hp lIv G"�phloe�VQaR+lu+ed���iLOAh��� �1�C� a-q��two���=��o -ndha;.�j��ioaG�3 marg�&-�rJ���-OT�me b V���re�:S�kZ� �� n6$X ist ���Z-embryo�mN[2]�s�)s� Nfoc�^f Nmpt�* unrCi!g�Ci�"�*H �v"�XN{"�0rE6ly ~sF5@c$c��&#!c> �~�U%�1WF� s��a� lA�+  ��`��A7major�  f�# �EL� SD s�;Alj �� e effor��M��/�Qv [�]!�r_�ypplausi�!�� ���� E�e�n� � s unX#�A o�#9� )�*Q \egon'"��dS_2�3�QA5̡�[6O39 r�8m m�qen��� ot [9I�J�9��4fa��n bran�*[1<22h�.����[1w=RQ�,�{i(� % begu�elucida��molT`� a;��!x5(�/Rk��=`fl}4]; w&syn%is�9S+6܁vb�Lm [12!8�� " ma!!ery [�\9b3 8–�3Moreo�=,Y?emerg<SHkea*'orE�EG&H`1\�3�-%(%�4�6%ep+ٗP �ϙ67?)X|� aUa�v 9�/ ers;���� ei4�uivej erme!����orA%fm^� /LAX � AF#s � � E&�b�GI +s|*�2 >E$x5<2E� �m�4lso�ree]�/U ly��smata [�0-��#�of� f4)7,6�GP�!�>28i�NRTAK30E�:6�n^ �s!1 Bw6 mod�B"+]5�$�!!��,"#B,e0Q� )�]r%BuIbjFnmli��  �na� #I�Qh "�U�u%H4 m�oeJ�� .k , �3� �v l �U �D�����  [3�/%�I<�q*nv e!/}��2�E�V{�`�!�2#��.���&��="�<� > �Fs. C�T.�is �9n:� ,Vr � of wol!��ms ��)� ����p�� CRE1;0` � s�U"Ed29M4,�9u � ild� %�%r�rVq��I�[a�3�49i�� U� �2D;�&�]� z"�byk{ B )�2�normal.>q- ��X2 jex�T�5�or:��r�t5ADspr��9�5 N�A��9c:ihlok.[32�hNV8� �&��. !�4N�9 A -t�/a,�+1#z��V��u:�i��M� � -�D ,��*Ed�fa�� PIN7dL�s�%osRo `E%]1n}�F���e>�7C!�2~�o&�:s%c81{um�. Coup���"Q�.~�T id%�F �c�"� VI�%l�+=)��V"��,�fGA�toB-i�=���U#t&uBRp romo /&�(��2� �a3eY=�jS Give�iat )Fe5'$&�M�H}DWSBF" >M"�[$HD-ZIP III �crx0onO� ,L m��i[R��$IoU� �>� !�ougiw>pheno��� ahp6!a�-�A�%�redntitn�^%� �~A(�".�@��&CR� playL : j� ��.�& mͅRW.� ,���$pARR5::GUS��r,4�u��&�! �s[26 �E2�A�8trpu�)��!+��� d���NR"y"ieB� !�iGc r�@ talk� 2�iuGR/� �shU-� BRt�? at e�(A�-f�ref�8ac2�lya�.L:@-r5h a� H9.�!eJ��hN!n rect���5 B1��A6%c�U*W =�LwMextrem �&.A�'�a-MElyO6 e ,I�# % ��ɉ�sol� u��� �v�rec� a\d �-"~ � 2d�1U&m�zY/�slF(�, [��gug[?s� ��!� �t0v�orq2=-��)�?�:" 5�&�e��y!Qe �O* %�-I��I�re1�-��?d"�5[ l�QY [f)�i�G ddH5�^ plex*Ms&��6"H TK�<uGRfuA0Z�0��=�3�h38�-( �l%fG�`� � nG?��g�-�C�"�3�R�!��un+h!N����9ano4%��A�8�H!Fhe.� ���-�Z, unex�"ed�rimping�&F y .�. S*��(con�Y6)a grid-�dU )Yx�A�YL"�� ��psO&up' a�eP��>�F�'�aO�7�!�<SP"`B ded;`2�0 � �el3P��ge�h�&P�8&"{"5 Kdoe�!��mp94�aee^ m�*emselve� � &�3mr�eO�<u it n{!a� kF6�+!q.o ��A���=�r�-�!f*ShowY�er M�� al��)��g0 e}�AjN)�)�UbL6�$aBA(0Akk�/�u�! ?of��Lia� o&� -�B�[3OI� !�lrW�- %�U�,� a�a�a���=nPed mj~ e6�]�fED.o6a:�<���Lf �Ay�%gs�&�n � ,Ѭ�a���heQ#*P&%_I>r�v����z . Wed���%r&�&)�� E�sM�M2���=*gh�IiA�"! �~�m9��su"�:pr�6 DcaQp�6[v����ba �]\�&a%��4�6� m�v��>)[�4��&F�C�&ur�B� `v>2�ma1e�_  er-�F7-�olE*�3Iz�!"H(d~NdA��W[3xP:�j �A�as�@�6A3�=Z,Baff��y�Y�<cyAli�a!�eXin�fheys �agnd J<HQU ��� er�iAD)�r�8 !dx���7z!)"�|V��Ra�/er�mea�E�do�#}�)�!R%"��� oonor@w}8}7�Rst-%c� �8a ��eu��� %(we�3h6i�'�I8a�F in>‘&9 �*inE�.�'5Q��2u� � �/ng�~\8���#��e22)<(Nja�KunY�% i !������o� ��!�oua)��m�( endodo�ca_�Dep��miYBy�MDJ�a5 ����.��a�tQ�� �!�~!;8u� $�f-3{\�"��a~�A����G�+"a~"'F� �rQ#CMx�p��ofY�\6M �hky@\�)6AW� ln)*lN����(*� %-�Z�raB*V$�$�8 . Noias%0 .{Vhdimen� al ( 2D )i�� seo�H�z!6�*e canS)be�&‘� bios"�,e��\NVX@degradI<Uh�yR�C�8�@��#����i�aQD. ��Ei�"w%5w o4�p�*�]M.5�u�v� Ze%F�-I&6 6%!�y�!)[� .� � r2��" �f�u�+ot"� `��Je��Dpc (�dY3�*see�\ B,��nu��P?z!��C5"�-`"F"'�!�h�7�\�D�5 9�%? � �A:f ����c N+�z>�; aïv!� E�e(�  azL��%�'*2�mww92(�eZ'� �rMZ*� ll����sBX�$�.#FZ+.' �5Ud��ch�Cr%��sym�v1.M',C �V0B���6`2� 1�i�g.�i��i�s tO<��R2-("FD,�8ck- A_c�P erclB<�ea �6�)J)# 5!Tin�!ou��dFb.*� A��5�.a�J�7 AgA��s�`�<sO�D j.�U&�oE��<�A"� �luxesp ���4�!n-$>dA.�� + �p3-�ieQ��� �7w�} "��K�2D̈́�"%vIkY>&_?%Ei ) �-�(/��� �n�zho"�i�׆hf�m!Di W m �"E�l)�$j F  0�e�0�san0s5�Аay*-*�w�@�)���)%��E �� xS��A��B%5�al �.K�.A4pP aP#� a� 4>%g!y�Zm6!51!�/rFg1)> ��E�� less�+ �%�/�NSee M& �,!�M�laR�f�����2�W�$�two�otk �b� ‘"C!�E~> �!�g"�5"].R{a���X�"�D��o�6]����o�6�a�pl, a/H�ly�‘+iJ��I2�-"2!Ia �3 �A4aly�( �"�met !�I7Awmf1� �,�#��of#s.U I�o�0i��w���0�g9.�`beq%��W �q��rs� R��: �� )�N!�� p j7�a�o l&�>!��! mu���i�(�t6sb^: �B."��.asAN���1"&z��l�s�R�Q�!&� u�y��!�A.�4I-�I:��5ɚ�1i��!���t�)yB�P)�-�:�:ma3�2Ga�|p3 9-"��3GIN%�*�. Like��+.�:"�),BI�D% �p(^Y ,����.! OA�n����&Ule�Ma��� n-s1�Je*i P�iup�4 d{�(Q R��$�� )�_o��� )e>� ��S���Q w czp8`.�t�N �.b�2� -,%��qqa��A� icie�r�r���#E>I��s�s��!kjHq�&���V�Az� E V&!d&*,6�A�r�b}�5�� � 2[51$-PGP�'GP19[O�N��bc�KwJ���wI#E��� temp1�;��}]�A�#Fr�  ,��hatselfd�Z�*,<��m*s" &2|a��}ab�v,ao�� s byaQi�e2�ŷ� ��D]"�5 �w2V-�� �,��b� .���ory'&�i�-���5� >a"D5 I�\ �� �!%}6�3=��3E� *�  oS� cc&KNf�L%E��G)2DH2F":'ɫP cer�� �/%�$K�A�o� �p$]@W� �����QA��B�#e�}٤��`�i�T� �8(% A��f��C):g!:edA�!})�o n\}�%� �~�$0gq z��0 �P*� ?dP� �S��C moid �.c�Y!Hill-�����,�2!Sn ��or �.A�� G�2H%](�~ par{`a�)�2&sA� 3[10p2���[4�hB;]t�  ca�~no�]<, =���n �ma8U�*_ ��!M [AHi�doubtK&g�Wng%Q��!`$-m0A M� Z1)��W�r� "�7YFB<�i�vEw~*��o�� a qRT-PCRAs{�%���Ar&�0Y ti�q�5eI j�MS#ole-3-�@cidb\A�.:C4M8e�� em�;A8 sl�!(G��Fn�>o"��Ei ( S1C �&�"A�"Xw3 �;m_7"�$w��!����0reI�g�k�%&0IAAs7WOX�P�or�[��"�%)���X�� F�s 1�^!�a�� i&�%,.Q@�1��-s/#p rule�$b9�PZ�ͫ {F���;? -��cm\��r=K5�%�Z4M�+2%�}c)!j�� �.��u�.'NS�w�1(1� SƪEw 4F$�{ 5 .0E����"EƠ2� "��&&�S0]:30t%s�4e�X!�(D�Bdt �QK- �U� 1�Q �a�! !!�2�2#T w��3)�XAof�  S u�w6�NCi�.* w�fOg��IX ���a���i/P �P s.�do�D�6�lPIN�L‰o�C%< _��nd-}��=����t�I"!e ��o4� Y wa�f�2ocX"a��Jf@.m/ �"g] "5���2n %�>M:�f��.r!oI� -�s&`�a�te4i.U e"o+e\Beg4I; S3�XS3y�E��%s>��z] 2� &�*��T�2�J�:�ALE��Y)1!wIal6?-M�E!�:b�m�nS"� -��h�`o>+)�3'�h�zM�Asx 6� ��A$Y�h^uK�.�"F 6�sub���52� ( S4%����(4ed��!K&� W 2E �) /e92�)d�Rb �t�Z�!silico9B*� e�ol-k ,%�""W 1� �O�D[ 2�r!ji�Q'�G@j 4U S3B-/�b�f��6D ���;J , S3E ;�$ �&�;ng�*� *((M� 2*V�^� �$S3C �� � ��Z��>�Kc�IdRWo� " :K%F qJ��3_� � 8s� &{'e~w��J9{M^�\Qre�e�"A8ca"M5 , 5�v(�6 '�-R - T�+‘���{ET�wA���dR�mX*� �ep-�EB3� ��79IprR�<6b3�3M�-E!�lL��~�n�[�N�o|� %� �a�ul�0%�� �� I� A�EZ0�!�M�� i DB3�*E@n�4��0�sP wh���"��)Ks�� � � M�a�h .�n� !�F��7��i:6pro�(L !'�Ai  M�ag6<i�Jd%vh)i=@�!�f$�'�U�sin(Yeib"�!�W��5o}9�U� � �!zI&17!)�����81��"�l�%%���.ch<ach�!)o&q*(�'s/�'��:3jAwQ":(/K(-�mp9m\5� �8)k%Xw�tac/=h!�e�ev�^ ma�X(�netF%!!E+!CM��Q�.8i�5�. U6�8?&yj�7�(�%�&5��| l�<o+"5 �.~!ua�k&� Ri��m;s- n i�8>!�E�tV5]�}#A�F�$"�&){!�2�E)E�Q�;oA�wh��G �1 I�%Q2�N�$8��!-�N�M�� g� �9k�is qu�m���Jy(NZ ( S5�8T�'%IZ7Rwd"s!M��, �&2��9BR9f4n"16&CE9 �.5���@�6kIBc�xY�7 �!�ar��M�F��ayI{aJpo#65E�)� N �� FaA��50*�y���y��- �JQ e>Qm�CE25v zoom$�(as@TX��5E 0�FE��W B���� �5YQ.���bw�up� U*z "1�.J)ta�i����- ����F�f�&�h� -�t�\":?�� venu�G/toS leakP �;ofE(U�-�.�tD�>.]Pa � pin1G �?de�C��#nT& � pin7�<[ � %��� �͹j�/8%!�:�m�� >�u{PRoe73�!.�m2)0�;e"��+�B�:_A"�Li�� Y[?Z+�2�� ( S66�3! �]*��eFi&�?�E%�0-. ]iS6/ ���BL�%�"��EcT1+6!�,6�H�2/ �,is1h!�:�*IB��]�� �Gn-W> �A�? �  D-ed DR5�6m9�yaMS"��] �V!mGP564�S6��S6&� &5a���H$+ me e`I�%`�u!�6 �+&Xn�� �#8R~�r:�JM}6B� Desp�G>&#N)%Uxn=SEw TAL%re�W� 1d�3 RpqN2�.�v&Z u.s>� � �0�:�$=#M+>H��o.9one-thir��m�<���IIA �NWYH -k s �6� hyp�+s�e,��6'>�� �W!u�}"�J�2Ri6m�2yb*�� x�}!��Y%�GCest�zA�I�>�57�6�861-2Zlax"! lax2��uex`M�z�I&"�*K/M��|�a�9�l-�-$M��� i*Mntr��)A$1��ha 72Cnm |c~a&�R�(#LCi�1F��X��%� , Hommel-�d. , p <�q,�CB�b�<*I �E���lrev::��@�:$au�- R� 1/14---JF�`6G��WY�x�uL251s�;�3ayg�-u%A� fsa&�:h��S��ݡ2�1n��t�� > �O� {"�Ve"Z a)eP� 98iPm#t=�'E�aE��x�y�I Y�&vAhQ�axeQoݙ:��e6�2$U�E�!�raing6>d�M��-�D;��=M�18EBo��u��� 2i �6\%HJM�eB��]6E���479R�~04�J�6ly�&�h���M�I*_ )�g��\��a ݫN "D[)J��V�#T��<�MI So far�N �E�6�;s g��Jad��zEj6� drop.�to 1 �#�� 37ȗ:7@-�-QV�� gXk�… �q����9 �=��N�}ve;%{N��u -or-�>�~��?t tM�k� � �o��m2� 5i�r&�*.�a�Xz( k.� �}( 5��)��c&�9VK���uxis2A�� �Qb�Gδ� 24 s ��ee��. Equiv��t�%.�>XV~*>�& �� D = Y�(5 × 10−3�2/s2�[ v�.Ccsee.�a�v f�;_6!laS� /6c!�n<&py�t* eem��~}Tv�2aM���d��9. Ȱ�$n^Y:��n. "J7s-Y��p�f�C��I6&�onџ�>��is{ �C` �=S9Tg4or�?lA� |12!��Tr�*�O*= -Cirh@�X�B�� u �te0steep=2ent>t osB !�:�s�7A��)O��!BN�2�Q J�#&�� S7�"�%$�ic>�y;u���%"jAe�N�2�K��br"?!-��=�( S7DelS7&�>�"l.c{��[at�> ��� A�.D !�� �C-ufq �3sp�l.�9��e���nyway&;x.8GMno:�ZBL��"I.t d�u �tbI"� ��*Y(�!��jay2y,L &�*xR��; :*twQc"��m�3�k��U>(6�FT�EaR-v��oj!2�]#.�Fat��u_Wlev�W"a 6l_j�la6�n��C� <��GOl�6G"0W7]p82W��1 �t"7!�MntbN3���  �ra� physE�_�UX�! �`%A3}lax���.,&�Ppaٴ.��Xti^��*� NLif�V� �fd�e�Om�[�jm ToJ�%�.Si�/Ybb��"dbyFaM3�i;aB17� Om �4a|�b�q�,2 bi"� �2u>"YC2�=..C7?qgEa�!�QFo.Qҕ\Y\U�%C�+a�V�a:�!� "(�K3  F3�7[5�=We��!�oJ�q�a�_gimA� Hz~&��q b" �> 6g ���y���SJ n�T�.�V�� ɂn�!���� . Re�abE %1Kic=���iV"to��t�t� *��$ 2Y �P�z�a!d ;L�(`) b!�-��B\a5wGno�&�&�M:� ,= }7�^X/� �b��bfl-��2-7�iS8� Bft:c,�nſGGi��Xl��i2Quo��6���0" i%�V������ BV;X��1i�n"�6� strouJ�Rte7C�D ��'_ `/��0ia�A%Npi���^�z��K�4dU�#,��I9�A���g� �!�lBw elseY!G�'� ˍףVop rowU;����us��let^ } -Ќnom�d��&� EA0p6���2��6��V�>��Uh��,snmZ�A�midǐ1aMH%?�Y�nV�.. T�����Z�V��bottom ���4xbɒh�a����A� tigu!�sn��E�Ye� �,2l/>ha��v�ص�f 2���� �_v!��"ŧ�ES�9�D8�Fl�]�C,��l&� slopvA�!��`T' m��>& )[5�q./re�n�7ĺc ��sE��2��+��nowapFtDs�a�pb�J� 2rߚ- /�F3B p�+E;fp(&':��O  �Bq�2�-�� er�w.S2���:�+e� )�,q�}&Hn; ee�K� �Oa� �1�a�B�F�[55SG.[di�2&L� @ES !�Ad*& g2�8#*S7a]1�(*I'�X=�i5�{&� ^$-dBb.� #�$manifu G-�!_�z�tl��pZ �!� A��I��&�)<�a��P2�� .� 2� <��qb��y9�xso!�ɆEl fNA�gt!�5�S!n6S9�L�;�aIN4�"V2R%�fsbcap� of.�c�=S!��@�<55Ls9M�l�,fu&G�i7{*d@U��KoIy��B�.�WK  a�*l mQJ ed&� hde8V�.��a-�eO m@�$�2�� $� a�-� W{9��"��%% ��Kt�break�E��2� as x 2 ¯�n�λ�*�0*�v+  /�4=��\VgH ch%a��4X*a��-)N"�e�a�-R��csZfi)&x6|�./y�.u�m�n[)*� �fMf(�%�|�"Q�j{~]71>�.�k1�n�*;spe�*&Aiϊ"�4��v{A��ZT)��ch9}`&�y���/,�1a�R.se�2��6#5�k��L!�M�=���}�e+� �"i )Q�lO��_s/�X����C"�XM-sh�W6�/�Jry!l:� s [5�B5S�"���-o�U�V"&�b !�u���:�;b�9" ��con*?�cy��B�we� .�.�?� }#!zvalid� E[��0A�8 d&&@m=.!Q�4��measue�Pnsf�\�nt TCS(A*�iF [57]��� Tz�?�!��CSm��SM;�oja��,x���T�*?("m#�1!��� � m�%� � y&I^�d���^{eZ^�, i�}5Y �Rmf~'�I�H �бYkmei�ͽ23,e��52�Qq��Oly��4�n%�6!*�([υ�B)Hif�&��@"DE�ʉD%� s� A?lV�e.~�?%a"� E)ur"�"re��!k}D��W &� %k�b�a��G�#�Kp9)�xX �:��ML:2&�2px�2�ur�%�5�� stem�)u= -triD�2=2M � &{�ih� A��b))2�'&�!4!�M�I*"h^2�%��&�`<2J�(��� ��y���-��-d5�2�,jnec����w"�M6� �� sa��9!��J�iZ5]\pe� -)z!.� > "*9�6�i&���& M aU"�-q߻CIAu:R "�ofr.�!F�h<�� >l lg&6Pw2m(�du ��� !� �V�Z��*�a�P*b2bb�e!O+�8�sh��Ui�*N� ^�C�>7A(cI{�=b�2���^: @6ɻ��.)5�QYQ0\l� xX=& �;�u*팁�.�,uo S)�U:8ivB n� !*" (�'ɿ�j.Q�y>A%JJo�/�a :�� *�Nq+��-5"��n� !=9A79�1��Ǥ��&6a2ra�GOi:3[q:��; . Po�;2UI�1 Z�q�2C:co-fXI B4the fluxes thr�ough the procambium and pericycle ( Fig 10A�10B ) , which can be seen by a detailed examination of bHflux patterns ( S10[0) . In simula1ds with apolar PIN1 localis ,�radial ValU ated betw�inwards�out long>0circumference��;�8contrast , root � �2�of �presen�$consistent�.�in�o@ ( despite spikesS�%8() except at < rotoxylem�e!PF-�,!ZC![Likewise-7direc!fd!� angu!hg!yB��str!A vari%�s�Z�ly1*ed)$ , but was=$ly �ed to)�� �axifg)�E#(�10A)D!In addi�,� 5.�6>�.� phlo5t-* endodermiB�F � � this�no)� caseEM�.�e?e !}�,6R!#):i6KofF�-0 agaiqN2Ps)-ia>Mxione�~�-$cell walls�,le.� �� have�9om�ofQ�I� O�Xspanning over a quarter:!"6�Y�ԁ�eA-�. Unlik%�=y��c2F� does%� showF; howe�,2�adM�%> four�drant�2}, 6 each! .� receiv! auxin via)=from two1qu_9%B5Bya���.�6H.�6 nly)�y)�N�both ori�0.bsamŎ2��B>�(The co-ordi��� es result!%m�ubA���6���(generate an-MEPit . A%]flows2�2Ag then��;J7 , itJH��Fou�)r.�..p��T�a�a�b���.�E�-�RF�9��E�ͥ%vb��� disordere ,d"g�}�.%�I�� lead!|0 higher levelI]%� accuD� e�B �9D‘�hae8 grea�DQAF.C stele . D��Pthese significant difN��E�Iu�-ne�.ssJrmaximum1"],!!mpE�u% hder whet!��) 15mae�f�##advantag�such a�= crea�$robustness�w%�( to exploreJk%-pqC d by-B�� fers��al.xor �benefit��d!�opa�� ���vestig� &resili.� )1Yto trans�|( AUX1 activ� (%� thus 62U)!�Y��M!�E$also evalu%�(effect!�PINI�ity �F0independently/=2�S�?R6w!�iEl.K )n� q ly r�n16� :�Vw�an)+pulse  provi!�toM�a�} egardl�'o�e�! PIN�:�@�S11"v H"( V# �Js�9�. W� aY":�:b<� comb%@b*-F=�,!%%=���5onUsuffic�t to stabil���u.����a.� in a)�N ɭ8geometric cross�^�.�itany�!�4 could trigger%�respon>wh� in re!RticɆlayouts� !>}]a subsee.ErN��hY �lways9edxAJ "6 �in��,��]�i_01 mhe)�)�# 11e 11E�*H%�11K�*I.�j.�Tj�5�u�follow�\6�2E S12Hm-��!�g%jm)�ncompeteI�<6 ŴFA �B�K �. 6# i�|�iq6�2F7� -� wo import:P : ( i )E��NG (h no-:$)���J�ava�lM�5;( i���tlyq)ed spec ll� El that�qCEkFIn11LEq� E�))eafound%�f y��Z�%�5�T� �co6&;��� �%s a me%ism�)a�;���F$b�����@anI�d� leb��au� A &� � � A�n9�those%���PossiZls)�iLm8 @ rid�b�discusS elsew� (+ [59])& review%�0In Arabidopsi�.� s� ina/bye� divi� ofnK [1];0 A��is�� )�5�#>�A�s [60� te� !�"~oppos�%�e91s A�2�7(left-right p of2� Mio�is "Z  o�� . T&� A=& i�be�cad!���utp al mode�wT nduc!k.;6��l.� 6�in�vEv�L taneously��536�sE*:H :�͹2� 2� 2� 2� 6 .3.3.3 .3.:;}no�diT rem�VeZ�F����d%%t2T1 ,.� �g Izinzb.� %\���o J1�� - 2�2�2�2L;�.1333 3��e 6�~� &dM ���I"�q simi�av singx ;� :�2 F"m��g!h53�L:Q� RI� 1~n 2n 2n 2K1~33 3� To  illust��poyof a “��ed”��RB� up$sE��N,�get�DB� delay��apk�^' E�%�1�A�!���FP&< l�nng [��el�r � Ur~aie�e� ��wa.�b � of 5���3eR) ;��!&�2aM100��!B�:&?  a 22# too briefn4 nI�d��bi� il�i����8����=0system ensure���le-3�y& Q. A situ�!�)��?o�'B3is un�l�� tinh } bias�82CIU� ��tissue� ���X �%�(will eventu� a7 per��A�. To dat�effor��w �%^� ' focu �ari'r�itudi�dimen�8[31 , 62–65];E�^,*jex��meF� i-�d a rB� �.��Basc%�v��,%C64�4arch has begun�HaddD~qu� on [4 , 4 I�orkp�demon��dv A��%� deria��is.gto �t���&���� .}�i�ifi%.novel94��)�in��<�et�)"� ov�a�ynr� .�E a�A'� merg�*� flexim���E܁u<wh!�M�a�=ins] � �$he dynamic;%�V ep��� "�EE$in future �!mpI��j truc�M ree-U�] s)ByEr��growth\. . Our��""Q�Y$mum�$inhibitory g-cytoka� loopE�$is capable!8Q1A�B4%�e61ty2y!Y �Qq,becomes grad�I confZ-�p&�!��� .! !S"�tsusA�A�ux� act.92� , ak�o�m� obseraOnea��quiesc��r�.�!�s%H.*:s!xU^capA"��i�do�recapit!�!�!�e1s ��] sugg�T�factoIr�qui� to d�$ it�lexamp�=>�is know��expA�iq& meta�*�a?%:( �e a%� allAG$disappears~ them%2`� plauhcandi�<i *�"-S!��*�u��uKT��iR -in&�p4�:mUK"�anC#�m��%�b a2� �� �e&correc.�streng Xir.����"F�)�M1��8analyQ O '��.lof wol-"I�m!� aUM� F������a�m�\calf#,`i Qu6)�A�%p2a�h:�, cAr; *��>E�distribuEn�!!�c�Psca.P%to� levaF� a�:'e�R�� � ŦGim"' �.$ biologist! If>�B%��c' i . �L#!�=eaG%Je()a�5e15"�a � l�`!une�o��ord�!�� artiy |(exA>u6&d$zhey �� nd$�e�eZeh  involve>� G�lr abund%�(%2$g . , [66]�W"���Y }r�stitute e�WJs+ozq`:���-t�!dm��M�a gVmatche�%�e" al� aEqo�*!r�d Rclose%ban�.�V 2}uni1%ighi�]�m�p.<$6 � &dA�S�}p��!aV+i%�o ,repancy exis�$>3 z  , LAXM A5 LAX2��"R�^er�$ gnorJ8th:��zS)�uptake �ty��� 2%�elf :�s{#.�, W s up h(at a lower J �1 [48]a�e� )��![� a� t�. A��,�.�:� � stim�amoun)�n��� �d!�F6�ul.h0 }���y.��O��20$( S4D–S4o*��e]uf�u�x_Q(s�q �d . Cy �� �� /LAXns(#6�6�1���bAXeq^e"�mis� X d��y'�re� l�ene�� atKQ"�nd i"H f!by= ��p [67�>{. j A�L#�)@&��F key"j &� nga�&  ���-� �&ŋ )*o Q���#ir8#�Vpredi�#by�� ���pro� a06deA/iv�#"�( �tri� �Rer� �,1la2>�"� form �toAhyA/�to=� � aux1 ranTe~f!�ngs�S&r �FBs�6'���J aber�+ phyllot%sA29�$ary-�"J�%3 �in douA�,1*��+u!::4�!i{e�mu!T s [4t9��alt����i �a� re!�ed�Tontinuit�->"��m� leava��x2~�w� A>0 @subtle phenotypesq�5 �B�F%aԥ~>� � tip��e}Ply ]�RMe�lA�2;y�-l�i�du�fown6��H2=�3;ͼ��in��3� adja���d}�r��i� �˒� , a"��Oe]&��1� ���J .*�"ASra =��.r�%�aHleaf , >A$pich �beI��lexAt!�E�inter��3}!"a�)��3'aJ or�/�uto��Rin6�i��&yY! q1b�!tq3 )ZqMKa7�l[44�sH�$�jf����m�~.6&M����o� s�%^"7Mz!fD���!�acœconcer�j����velop�_� ���ifyv!Qbu~-�I�/g�/�,� 2 ���|�an��&of�M:� E�B��� �  wa� #��e"' ��Ak�}�� � ing;� ]6&� d ar$#�n��c� Csyn�.i!M>.-� l�"� So�L��� o �"��!��+*g)�!�a��-s>al��s>��2!�f�W6ffu� -�Qe�. Form � reliTinZve��-� r) membran@)me� 0of 0 . 01μm/�d�apopla6(! � co9� 76μm2/�AV"�!�e parame�1ein�a�p+0-!5N�orm %p�Y MK�%��9Aq!isA�!�v!Ttr��(source"� )A8�4a1�?(A�nx?escape"Fn� �2oQMF6��y�"16�M < neA���&�1a!��5b�9$]&1���/)tro��+�g1on��g �l|Y)O �!r�,t p� s)2V�is low��rapid?�N�s/E ad�mov�al"u #Ay �2.��ll�'+ up bm2m�V��,�6�_V'!%� H8�;c�B1%���t�� �#2�� dao mine%jO%e%>9<��e!�mazm� drop-offe�a�a� smo�6A���� "K��=����Y� 6T�Wq@%e��8 �� aJ6�or R.٘ 6E�d l&� Bof� liciaV ��u+i!~m>�&=pl9so� � void�(rteP�-�6� !�re��� spa#-tetJ%r� h horm� -�.'.�� ��Z!K !:�" 5bAr!t)�%ve)1_)�Ce2���( ��50μm%`a9�w�.^� ax racteri�Xl"828�e� ��14�:G��s6m]$!{��%deAe%<ror=8:�Y�A�e� fA�% magn� ���*!�  �(C*M�4ial�_Methods#-d*o*1! 39]; ��2es)>�� � i� ��a�� � N�[38� "�1-T larg22 seem�"6 , give�at �Y � molecul� approx\.�siz"�os�=Ish�@.:V� sequh kine�"e1, I� r�1a�&g&�-Y��#I�9= BbA?� 3 mee�=!$splace� a&9(Iu�$�ة�9!"typZT*@"��bef&5break� )�.�12S75a�ѹ�>��i%&�tra�:�=�#J �EG�� a[52A2.Nytim�l6 �[� �Ba*B%4 ֥�b��urR\s�L��iX."#�Q�p�� �2� -�surfa&;C%��(� �>���lse mark�:�e�,aa51@2���in hou�B&��can� u!HG=������3�3�: ogenv89w=;f��?;&,/-�a�Jpre�7E0�}�$!�q�al&� ! �?� !� dataE��* ��vid quanti�-ve ���~Xa'er:E�yVep'ish"[e0�ץ�Ne�?microns�%�� a<�:%2�upperS��{hd"� 6��X��!.. S��.+2�oI6 �EZp�D� ;&�}m� E� �Y!�2�e!�..�"j +"��U}y s&R 1�?q s"f %�p�# ario)�.�y��l�")#�G�e<���2t�D��1�p �1���= sa١9){!��=�*"X6s*�=A*2!�� We�p+��^���4� R �N� C )�instead!�ult{��tBJ5�machiner&perhapsmod5�s�)m].��fe��0I4�~��, �Ge.� %W� ,2�6� Ai9 ��A�/� *� �,.��~we�aex��. RF;refer�%]�a�"�rai} "*� chal� e� �8�'!u�4c '+ ? 9�� � must�Wh �ee" S�"�%a� B=  ��� ��G � a�e"�4 t2�%:: �q@��in� at�5�#S-" ��2�� s&� �� ~.�-Zsm�` t4.i�� �y�hc4n* orga�6. u�>t\� �+uc�verbal: p�)){Br �B trai�,)�� w9)��l�ng� �ԅrr ��s!DF�?Q.#hqm�V�!�C qual�T=3� �#.'cc���B�!7�'" . 5�inm�� term� s led�Ca#���] �c��inkwab :)�7�h�).�"om e A���,&�(N ��oWHsI�n�pX refl?#�a�A�&�6study�=same w-[41�Q gu�%a�eg}Ybi*��rucA!�N���5u��qa�inguishe�.yNy��!4�%��$@)�+e"�T"�8;��=/��a��B�, + v�1.t#itself!$Y6.)! opei+AM $%�6m!�&.H ]s by u�A;NM valA�t�,� s� lue���uin�2DE&� �-ra#�C(cQ0��\�Lpr�>�ext ly lit�@�as���% "����funda���qD�;"kinIm�NI��+e�s�@t2��5{�5s2� M� XEAs�i8 )A�EEyUu]���nA �-9�Uv�9?l6��,u�*�N�D-���el)�)~ir�eB6�?J%� oncut �A&i �* �4e gh�� vailza*� � �e a�� EV�*FM��>M�q"ituE�,"3 !�"�  Cq�Y�ro �>>x�#�� ��ghtfor�Pl6 e!�cur��ly no �#&��r�� no� ��:��a6�-6_ �ey �����s�sm E!w7%�m�(%��4�E$&�Y�uqI6 *FO l )A�#N ��>oo ~Ő YEU�ksola6�� �*t Q�#�% a��of5&"� o������Ri���� C /J�aQ�;(A�5G���� � p�4�5#3 a M&w�}� s 2�,����} �&sf 5!�JU I�re-& I"A��� ��F�&� or1�2�percep} ��&Q7��wN�%Sgly pu�!~=5� back�V!:%�=er:r��"2/� �X.� ? An)ZG�8!yrisg�R��s�m� a5��*�3%Q ߍ#�&;(]!"�$�|� � �$�9��!*&�3�_D6.]�.�$E� /es medi�Ba� AHP6��VA��K&>*�&:�'�[35)�4��� a:�"��9�K6jA�� E��l�n6Wacc�,' !2!�-�2L .�%�*ZD�Bs� assu�P[as"� �-�� !+>�7 U�2n��$�{��)Y�sR�2)��cF�A=l����t�� AE%�-���&�Aj.�. I�2�1hac� ���9Źa�:-% �&# acF5��,AX ^])��=�� {!'mad�>�U"nF!���z[�LF �1%Q�Wey iory.��/wp' �) �y-�� .L>�� �5�) PIN7 �2T,!�a$v4@H�: �*�in #�y|!�� kO�'�G mpai�Df+�.�]#e���n� F)�y"{ 3� >w1� *��A��`��-�w�81�*<a5�i؅�� ���jE�A`#Lk*�?t�i7/>�~�`P!��ux!j�`it T�"� favou(%!)CV�ESe�y���� X!�,e6�,�+-Ma �faZ&6��Nr9if!�]�o J�S�&E��=Q+s��Y��B(`B9)X����Ld ���!��=� ": (�E&:>;=:�@� �e�1��Eb �:�)�),Mc�!�q�� rw"]i"�7*4 1E ��cbecaus6!�-K"�U6�� aHai} serS �onsecu�&!f�_�re!�*r!lig�߅�v�0e%iZ=up!ei�el��%bi|Z�� r>*Va��d 2�� M�u)Pq"O`TB��`!Y� perturb���]*O:,��/�2j\� � + !�3 rE�h!��*�P6�]�.b� flucIG��M�A�P o�@��-.RD^&w �6n�9 5 �e�l�T cri y!�bV�Z�F0��F���r+/B�2 Ul "HN%� a#�mT� �u�M ,a!�hEuASKEI�.�s�k��� A nc5e�ngN�O, �QB%�t aJt I�"/PNl"theB�1�"descriT%e�+���� ! bem�#edrrI��tij*f � )3H"Eifu&[�Bng�i�4menYsi�&G? "�� orposng�< \%6()I�eyS )�� a(A�,N�F ��\B�Q��aj&!AZ�s !TA*� thalian~>>GE�e�un&7H}H��by-�&���4� 2�!�.�a�/ . S����n%(v� ��desir�L>�@>�Rp_ n� �]!��end�od� �L&� I�5��D9� *� %�EL���e,%] �s �9W!D�Syi"���%7) J/VaZ" 5s�"_ � ѢQ&� link. A�at�.D�!wcoJJng2h%z!�V i�L-3� i�.���+ !��&�7 neum'��es�LenvironA�"�=XT9�2��Oimals.,'aon� ignaX path�Z5�6�ex�Ol M?uli��\cri�-h�_�n+ly" �"�^��&^/^ 6u�pr)�o vDD��F NPF2A�NOSA*J�tm]�9�FAK shif�#[so� rb�g�_%fV Wew) �� �a}?a7bS"�*�b'teT/� �pr!�_Bega7I(e phosphory�Ui�rine 110v7�N�sM�hI�K^-��)op�ad��y&im�) Sl�D�l"by)m ��Ea��in$*b9o.�s"WTval�J�� RNAi!+eZcnt�}� assa�F2� w�! veal)�� AakiniAMR� };��%EEon1GBtnd%�2)sI �?"�2�`rec�.I��Wc�A�QlQ:��. A���Hdjm&`%�AEM!�#�w�v� �Y�I&?��im� �ir fi�g is:7 as�U=�9��U[1–1E�ѽbpu10! nerv�#�%�qDs�\rt-�$ ��Nal)ocee~a�,�� B8�kAgѡ,u�$a��%>��saz&�?/��@ , >V�7 �s]e��inc[fij1c0ar�7,O.�!��[6–2�/M &���9�a��j^fapiv2���in��!.��re gover��3�'bF���'ofJ� �[9–1�STJL:TFq3p|�c!���b ��m�!8ofZ���g!�ng�i��)�1NamB��B8=`�?1E�NuU9��_U�+�Eymerc�by � J  CK�Ω�K�or enhDr;�. ir t�3t-�[1A�1E�W�tUr�E� ,���go�;ݡY�u�P�!�!l�yU�.� :�n/,�6�Aty�at%�E).]�of.�Q�"�I�[1a*1e+�Y&dFos famh: ܩY�#[Br�:ly��el�&� )�A�s� s nAuPebe�2nd dors��0ur7by drugM�e� �Uen�cre�A�A�AbMR s [1WkQ�f�R-κU NF )��:� re:l hipp  pus-&�_�CmemA�E�%�by�?ng -assoc�-z2_T�,5,s6A�6cas� "�aSz��upm�i�%m8e. �)�� r��[ iP�?F~&� e§�N} J_ ,a�p�T U�1�al��q9�ˮ� [2sM2�5G&� � s �yi��rd att� � 5i�\pLd�as2 .T cryp�7A� repe3 � ^� vi�V@ � t�O�kx;M��+K`$'i� de? d&�iso��of��g��1a�Ml fo�; crowel*� ;[2��Dm��-c6N�F ?zi.! < ,I��kpr �v�diE"%�t[2Y!Cma��G%�al���{%r( T .j=i7i%{[2�F2�HIn� $ar*�r�F�a�_ ���n���!,�u5M5�$�Ba4q�P&� s�:AN5S-~N� ��M��� �.�s�Dp �S#W2�,IoNPF1aEm � aY����3[26�-*E : � im8sS�9uJ!eBb.� a2�* �c|bl�9r�[=q6�$3"&�h�OFi%K>1�)up-�����$~A� &��/�aim� 2�TF)0a�F��� ��-Q&vq�|*]o� !�/NO��.=G�� s . �pi` �M���� !kmRNA �f�J.pon�� ��E pFOM�*;d �h���p�>Fj%�first1�lJ ~1 . 5 kb�OoY;2loat". �co��i�cef|;m�ql�22)D�^ "5-�B]��2=���of DNA� �^l rr!w��Z 9!fu�'?lucifer�fgen7ssett�s+OonPpa a�c8_4y pGL4 . 1 vec�*( N�8$in HEK293T�( >10/o�WS1�0GBy��g3�� trun1-ngf�J8�)�1JEt�2�,-150 b� -121 Y-�ATG8 r�#do�*��B�c�?��r2��(.�ToQZy &#]�l>�;%�%����)$V+isX'e� CRE��d�/"� .bg%�"�2two*wsof�ve ,�BIn� !�progra4TANSFAC[27 , 2 O�+-,vrC[nf�S �}�6���)}g�-� !�`p&�u�! ;�AENIA�ea��>3%Y��a�t�a�B>� namHs-lk�-BWnd 3B�irJSo�� 6ionshipA &�oE&�3|9�G�%ty�'I�am1hDK�"a ( 13��5% , S�g=��,VN!H�-΁2n�cI�*�E�����YBt -�<�OOver-*� ofx-A��-B� (.�flag tag�\��)� a�e7j�qA6�,y af�K+6� )�'�9 to -bp�v"� Dfo>� � R:-98A87@.za��h  rt�,I�CrS4�4Wm 2Ja3 �� Mv�>Ho�f��!� R3� 4FNɩ&�k}�* IxY�� �]!�QivoVV&�hJS�)ck�� ��!� knoc1EQrB��ash)l-F�GLCn ���$2I�S5-�� eH�Eupo ��l%�Q�n� !l���CEedn�> ��!�-A` 3�o�#KF}&�O�orF�2� �X� nA-T�-B0 26R�!))Y)u��� -];ro��Ymo%t�|ift�( EMS�.+"� �#si�}a� "7-,�\ R� � �!� �J���>Q.I�, prob�!�,�� ��ar"ns��$SEE�!���2� 6� �|�"�e�ӕ� coldgb�'100 × �Q� labe� �)� ad]�Yql=R�U�,Yje � - I*�&f9�oti�%KZre&0U�g!`�#su{E ��hyAY3b�;�r&a�>bod((recogniz��M!�-�S7^N�! 5&d�"�-��!q!%2n Y~�2T�s)T –5%�6:no)6n% M���ro�= cuba�� ny\,l rabbit IgGq�x6�*R"� "%�Y�E�!7���shoE�N -��E<��?$.$a.\4t6 �OAD���p�h� cerebralia PI )%e U�\4immunofluoresc0� `kg )HI �-B%^�$�5l�� aliz��i�k�� �!$�n��D�OS8.aQ�%(-�Gat��$"� aJ rect< �#\w�&2 �9%/verif�%R1Q ��&2$:�%ſ�6e` /�|w* i��}ն!8 {^ 2Q�ց�to����$>�"TDM�!u�n:"H>('V��� *|4 p��� �j�Ae=ds �)�4��4� Mean�=�eR�ED�5%�e� � �� TDMV��Ewu�1 upon 32 h&a,��4%�.&neυ`norVI�`e�� �%�sil2Z� ( S9U�W��|e6�)�@re��&�V��&q/&&�BtI�ti&s"�3=�!'Bbl#&�G a�-��v4F4G�hA numbf�cu!� 2.�m����B�n$|.�n |itP6* m"�x)eO � [2W,3�\@@Y:�T-��|b6�#��I�:a� ho2$# a�human[1�� K tsharea+[�.[ed B#�' ( KIA��n��S7AZa"p �Ky&/�$133>�(�yEto Ser� :�)��1R!7�"� ���ewi�Rar wei}RT�a:7B�f7D���."��-Y ( p- � �& by .�$iZ �.���39+y��t��!� nti-�133m1 l.� ��( S7E� MoreY �" ��h� �>\I�A� 4H��F�&d.�2N>�*� � ��NrkQ]d �4 h�X� *�3W ">lIe-4JS*5�6= tog�Ece-"4 "�?J�-B*��)"�. C��Qx���&J*,7� t$e�%V*Vby� %ng 2�� -.5)6����AʽG^ ��)o)6k *� C:�"^>�,im�g1[7B�sEA�Up�"IM2�M�p�f��ɪ5…5DM>27� �]t[n��IC=N�1a $;�0�N�r�eL�pt� )>M:e5�5U �! 5�S1&��)--�J-B=�let�% lock, 6Hink2���3 <6�%[9m4 �u�9, �EG54->nXz�J� �A�5-*� 6� �ȁ5��,o�G��Q�ʁ&n�,>US"�}��*e "�e��`�.)�] �C>a=�E�o�2%��=��-6�8%i��M&,$(� catalyz&a:�"� NetPhos�s�$( www . cbO dtu . dk/M ices/ 0/ W>� * 9+!�mos߄y5E".�I���,Z�/PK�PK]Aribosom�#r^ S6 8�Q 6K )1 T�2�B�6�Y/�d1"����6A� >����1��� R:�r�w("U81��p6E��n�*� ɚ� �I en�geTb��6�� �>�bS2�.�: !��:cey�9�)�E&� P t *i"�Red>D d>-k����^.�/A�! 4)Q xRU�,�%�0&k\ )F���!y6�9)�7�r7B�:u admin�fX^AKA ago4 ( Colforsin )�c�ReB�-^�$m e�+ �1�N� � 7,7i>TD �m�or?T5720� �Q*cu !8 boos!j>�b�q9��%f� 7D7DIn summ�g��A��\�y.7+�&���>J]t/Rm.�Q��+�N� q��#&��a!%p��+M�A�s!:K5�NP:Y$7!-q8�5�>C6\'inB#��@)]'1,) 4R7&� chieN[BkFd;.�OS:��e]�o�.��a9%,mN!:�V�����m��u� w$$U>L0��haD+rvq�F�"g�#�|v�"g�y2&#��bp&�& r!#ORF/ kr�<d�basic#%UD&' Me r�,h�v�y�h6*�yA � � ! .� :�/�c!�OS9%Ai�S,Nan -14$&�!��H1>�$, qUg%P;mp�qM$/+�;E%5�[3�+ Appa0?,)�2�!\X�3� � �m�s"R*�HA3�>� |/� !��YQst�\��6$8[3�3,I���e bio"HQ8&� m�_�ua�"#: %�5M-�. And|Sa�e2�0h0n,%�eurBf&t&�Xr�Twmme5-c ��;�Irob� .�tJ� .� �> �� �I���5%���u-ock8f5{Li�N�S.� �>�� 3 �AI�[1er6pm�b�.e�s!�4� miA3or=^N�U7��M}#{F�"e_#�!�VW�I�E�!'-B� �{�}e�6�N�:Cfeg,AL�:& �*^$A�cE=� X A��he'�86� �Wx;. i �,5>E\OlM�()���n~o�%��/ me�-nu?�i���x"�=rhythm'inrr�f/�;WV�*l40MI ���2d��al dc�i!�"�7Ż�P#or�ir���>�6R��b�M: ledg�(Ar��;�+ex3�Ao_!]- ��&Au0�B�16c & Q�E>"%�V�5 5"Y1i�C�M4�funYI[tpe�@ 3 ell-a��-& 6�L�M%R�6|6in Ap�Slli�+ , ��D�<_ ushroom !}A}&m5�age.�5abXc��[3M0*c %�V�<.�}a!�fee�� A�$Drosophila� n$ZLIJi6Nޭphe� )2A��~.6��m����A�%�!`�� 9ie9�. A�HM`,uL�< mena I�p 3a i�mam�M+��W. Man�'��g��atN�s*� /dG!-1G� &�2�{c?aNO� ��� ���& phys��A� :>�B[3�4�FJ(}t"�ey)��Ziso�7E� vert�!Js�8�C+( n, ��du'( i 2 qM!�ep�l�C( e%�$%�%�Ţi���'� �j FOXOa+�uml&!v�?>th ka��=�aɚ�:`s%}r"�@%� STATSNZ9llfibrob!�^Ba�-"f O.��Y0�1W X , SP nd ZNF>�[4n$4�-"��2,!H-����a�%Q&L z��4��uphy& -"2gsI��a�;��d�Y�\�C&�'s�W� 7�e�j��Io>Ddup�H G"�N* �evolu��g=��g�[� ���)*W^��,J� 2g35,�B��� [!�J/n�MNSi�z _6�E�aQa3E��GA�_1�,a~�� q3�*�u!�x��7�ko. B�,�Ni�aGB�%r�B��.aS ���^/� � .6F ,,� d|)-0RQ 6;:[53���Jk42��Ex�\��6[*�>,"�5ki]�post-1"�-.�>� &Tv>, acet�Eo(ubiquit�I�,�J~*�b����9G4Y  �4��5��Fs+�e��� at331,%-MRl>=2'�I�%��4&$#�or%]A.� e*�E s [5�Ar6Ub��di�")1� � ��we 4Xed;��� $&C"Ser�>�of ��i" #( Yhlog�*fxHca"A"h&#b��2^� �%�"� �?:�i -�-B.� i��m�J�ch�Gz D)LaV' :�nr,��r�Jies>����9��#?�rot�d �?l�Ii!ra��Gt!J6u "Fi~$B��0oneybe �z.:GM]A9BE�:3b comm�5"�#1�f�8��)D�J�'= :�F�. A�3A0�i0� tz �!�-M�-�m�Nc�ly��Y6*=L�2u/"��Lm�R�!N��S;VtuA2Z(��tHo!* 2ol�cMEB>BIqE5�.ir~6� 9r"� � PKA-�DU BV5.ac���%��' stepe�� � A�Va [5_5"�6%q.�!!.Q��s!�desert�T�#(SchistocercZh�@ a [5� *� :u�.�"_M��!,a�n�P�2:,)#�@!W�)�~eH!B;��u�S ly [25 , �)� '�!*L*3cL27'a�� harmac��� &�[& mani�LngieI�� �-T �Y�Z *�uI�{s��M "u��. �`H NPY-��}�;�Iu�*1ta,e(� A sT@��in.����:�cAMP/�MBZ@�B��J��6:W�B$�l��A�W�w%�a�.� D�as9� !&:>B+ZNPY�Q& �!G1F#r5a4��"�+G� .�� .��& Surpr\h�!"�V!G�)�-nm�C "08messen� !~E�� [53Fpe"�9( h ݮqA� 2�eGr!q1a��2zw;wv7�x �\Fs-�-nOn� ason�"ex�h ��$"fn5�on�s�h^�v�-efickeS�B2��Ah+ *e�i�=!�),$ �/ few��na&��to�-NO"Us�Fat!��($��?hp �@)+. S�k��AA(Qb4to��!}��_ link"�S�OA�[G G��AI2�FB}.83weW� E}wn-term-�!�&�E��by"Oe�bac"�M�n�bs=hŏ� �2�-  !��PA�genD��duirL8 c�=ZF�($c%��d�b: P!a2� mH� �\).6|*U") A�1�� � �%�y�oN9AcЙ!}� ��!{� Fk,e�>&i�] X�?2�5�overlapa��ia6V �,n;� I-�ec Z62Af. -)�� auto�QP /X!Mfb��s_a��ng �:-Ib%ee�\�]�:�!F�u:�u�9�ץ��S�(![s7 �$�yz p�e �%\m�AF!�6�E&d!v&^�` vt! ( SeT5�j�t8C$j�C�!�� Q-l�XdeКi�y�#R�-ia��`Hd s�hl�o��l0or/TF/I i�`a��C o.�u�V�. AllMqf=ob�?� c;��lon_& ͬ]^�A�Zo+ �qC9} se AkNm�bS,�k . G-%�6srea�in�Y��7>i�_\\�H$( 40 cm ×> )��,0�0 ( 500–1000�ect؀ cage%�SN�i �seaBt���QPr boxp<1� 25��� -, visuaVk�'olfLP*T%nig�a�B\�� naws�,at 30 ± 2°.&�  14:10IG/dark� toh� m�:�f�'�Rfresh�c�\ed � ��L� f�AAar��OG� a�.}2"�� &�6t"�/� R-=�M8 �KF �Yah�Bbed abM�@� �h� coll 4� snap!�zen 0�T�� B 16 h�!���J^/,��Rq �6�220Bd&zX� |ag�La I�E�(Y�U� (F�disa#!'��r�a�hd �M�E� Eac=�up!��cU�8e�M=*"�Psplit=>*"�b�8sea�ACu��#��*ee"�j��A�;A�e6� . Commerc�Q1l �)BGI"U B2<: YSQVARPRF-NH2;��1a2� K �^ 1a-F~�p: AEAQQADGNKLEGLADALKYLQELDRFFS2Fx: RPERPPMFTSPEELRNYLTQLSDFYASLG��H �Kμg/μ��2 μl/%�l=y�6+$� �J& $e hemolymp�WA< h��of� -: ��si�R� RoO�eqwA�� �5�q��;f"z� CG .N�+,A�μM��*8�6���ofBkpre���u1{m�a� ��%;RF1 hm7�VB�3.�+ , 50��>apr�6�=�A�1h�� p�ǵ�� �� -*� � 6� .��d%�)B�R�Be7W*Kn0TakaramWU !{ manu�Iurer’�2tocol� �("2*� �?�g! o'� N _ [SP��SPaM�SPI%&ce3k2�N�y�  p( �f �MI+�2T��>�rA! asym��1i�d PCR � l�'�r[q3lun�#%!�:yN�!efd�Hl���7Z(pGEM-Teasy "OPromeg)�"�+in��� )� �pam1 �96�U�m2)A��-�&yz3N�"J�M$( http://w15%�ati��de 5A TA6N5AR�iq com/e fac:E9� S٪.�G�ra!E"�G]��c{CaO !�� ��N�a&�<��(.�)�5�i/E�A�w( &�$-9 [a2wfQN��BO!8%sub-c�x��e>b,*�Qa�Refly *gM ( PpwM �ker!��`$Life Techn� > )!]�%]&�FPDA�to�!C�@!kA�V�QU�� "C*$�9>�"}E SV40�>MR3[luc2/�yO"@,u*&�� EFE~D:�"�?�8)�Ope�Lr+�ng frn"(�.)oE�A> 3)��e�.�pcDNA3/S�on�7EcF�N( Cji`]�Utr*at1�6�NIoHin6TMEM�9umEhermo�t�s���4-�_>te 1 da{`x]%[�,�)>1�-K>�,%�.�E 200 ng/P)�pa�j _co&!U~� !TF*FSmK6i� LipoW� TM 3( Invit� (, Californi7)UEL �RL-TKMdo!4Renilla6�Rrm�"(7U�a"^�B:�E��7d|a];��`�'�n�IA�!32�e��cyM�F"�[6�All�o��=�EHp���)Sg TIAN0 MINI Plasmid�0IANGEN , BeijaM,$�)X:'�1�`�K43ͤ1�cul�y2� al 3�7� ^�i�k��{�(Dual-Glo Lu" WA�RS,��u��e�!�mi� DR(��B�TB� 6 ay?N�!�_�}r?a���K6J�|toQ�:,I� . Do��a7"RNAa_ds )m2l%�.,)E,T7 RiboMAX E&�Ji �\% e . ]��Yly^� � �sAs thir�8st*|?ch�>����-Ш&� �&3 �� ay 1�h�.)%�t(��� An["� � dsGFP !��-�q�\ll ��5i�j&at 48 h**�B�_/1;S̜1SE���d8 �/  ,�6 &,�1���as t�՛dQ RIzo�[ag��RNase-f� D ���, 1 U�}��&�Pto�s�)��i"O2) 30 m��s7L�V�[6�mix�v%�t2K65�t1Kineq�< �.�ؖ"�f���Q�2�ih]�� Sly� UA,E|annea�S.����P���6e�natscoo� �&T��un� 7)K.�SMF1��Eeti�lz�i{���?� All>BFby.� Comp� $( Shanghai2B DNA-1�reahfTY,!dPq��|q �F�w%�ar��! �d!Z���I�%i!�.��!4`P�CEx�(��A� yo��5 !9pol�KI-d8_, �% glyce� ,��5% NP-4�50 mM KC\ 5 MgCl�4 EDT� �ɧ25Q8 I~-6�ͩ oom `�erA,��r!>�u�V�zi�Ŵ ,:FHV))���!D>�X*CUX�%! �6 tiboB�r.�T���yB���D��N�i �* ein-��A�lmEQ|�� a 6%%�ac-mIge�C�x3�o�nylP*e�aF.' n�e�ex"�UVmhtYss-�!��� 300 A�254 nm� c mJxdtY9��a�%@ptavidin-horserad.�pe{d�Sconju��%Y!g.@c:teFic acid )A�myeZgW�ole-m���U�(��str��26|� Hou et aGH� 17%B�9"6 j�:�ix W4%bVa�4aldehyd�PF\Zw ��overn�!�olycld Q��VO ) ?1lCel׬Gx , 1:a7)%i mono Mmo�mBSu�(!��>E���aq�l�B BA;"�C:6�Afa ��2@exa Fluor-488 goaJu ti-r.SX1:500;R�a�AF56.F �Ig�XjE2�� �)�&�B`ur�a<:O*&U echs�r��q!E�a�.�7.)jci^�)gau�%zLSM 7zon�laser-s&�� scopAY Zeis�c� ��Yj6��zc z26}e,"M-(�P�s8  ���0gen#in 1 m�3:� . A Q���}of chlor8�I�Z aqu��$!2}t"� 鑁Q"��E�tvl C!� R�.GGethan-recip�"%�����# ;nng�0propyl alcoho�2� �d �n�wa�"�"� *��3 M guan��e hydro%N�xin 95%�� llo~iby�j�1�vacuum d0h)�Mx2��T�-"i$1% SDS�� 1ft2ZQ�����μ�cI�~ �_�8on 12_-PAGE�]w .;tzlyvinyl9ee?��!( PVD�G� ( Millip�CkJl�! >� c��ERj��R]A�֭�&t4H3��5-. GVWCoW��*A鹃.=+$V%j�j4UH�02�.q�4m$2�&� ce�aCLM,ѫ%t�5�5�]�f�� f Q�yO,"�h. B+�L-��A�R �sE[M�&@�gro�Zx'�pd \'. B!T�=/~-�� peak�AaZu "��c��o^�,\ !V. L"�A� v�monI ���ra�,�W0 �5��Vrecta"�Perspsr�>*[&36�%q�z6`�rd or 6 BX EthoV��n:��c� ��k?�;�]���R�]�a�iddle� &�/J{,�OnX#!;].,3!� n 15ek ��&�}"�%B�-��e`v��57�2�3�u�5COv �)�^ �վ"ctY9&|sA�!5*Ki�~s�~K�*, T�I�mmunea�s 6,3+Zb ��Qd ( 15–2�$>2&1aZ:@!1�(PBS�H(��1 M�'sphDb"� 15 M NapH7�d� Lna�u )�"z""�v����6-�di$>�. ATP!Za�n��}8 M�)30J aH90eI�!�)"�r�Bo�G-p-��:e��$.q&� r6 rV�R�HRP�E�asNF. TMB6�.to�'��)�&fd�U�. OD450q���<alb�-T`mve1]?A enzym��y1��4�ˊenA  ") a�a4ԥ�ihBC������Vr���~*o2��Q Bi�1se���(a&log�qr�!�o �p$WP�#�� util�fADtb�4(n algorithm%RE*��+�9�U9�@e��B���""iin�n"�# MEGA.�N] bor-jo�em)Rr Poish�m�.!�y�&�Gb��Թ��Ai ash A !�1�&�`V��6?"�$in GENEDOC.�All%z)s!6s�a{�"&�!ک�2�alɂ �� �-terk~49""3E3dź 8A�!�r58!� � E ei� chro�'�{uno&�!O coup"E9high-*5put�!/$( ChIP-Seq-&ma�I�xs b) by���( mitEY\1)4,� M613��Ip(��>&� �A(e�Q�Ha handfuhIaD1w�0pri�o>W)w��fi�:ous���2���ycle 8��!re��: d~`F-U>{yA &� I� ZLD- p~�E� mo>?!2en��E# �.�?La�⅀�۵��lso&MDAf | � �& z �ug}�e�)0 wD}O�pEn"J��g unti��!��mir$���& b�r�M resu�+9:�14A�6�fa4Z �"]�e �.i;Y{��aOaE{1)d%AV�/nd �� 8�+{��2/�)O bm� ��ify �>� �P7�sy�2�"��� � � � �.�of��Q�;�u�.�s2�K�is.e�2eD!In��wav��6��IE�p��a maj�C>i&�Tn!D�!��[AL. Delayf!z�1MLј��=��yEi�y�?K�*eH*%.Smҕn��. Imm$���p�egg)A ���:�is�7l{�*��&��,)�.J�&>N�F�ibu�f-A��χ>+[�:At�� ointqja+��<a~�!�.Y�I :!]rcLd�"�Lt��{gEr*���akof5-622�� �J$y of these�� events , we are only beginning to understand how the zygotic genome is activated at this discrete developmental timepoint . In Drosophila melanogaster , the fertilized egg undergoes a series of replication cycles without cytoplasmic divisions to��erate a syncytial blastoderm [3] . During cycle 14 , the 'Tnuclei cellularize and ^l5' transcrip�is initi%.[3]–[5oHoweve�(a subset ofMls required for sex determinaT , pattern m �� re�,bed as early c� 8 [6�These }sh8 a common �rel�Lheptameric DNA motifAQCAGGTAG�,@“TAGteam” eleA-inAY0ir regulatory ion!wremoval!4which abolishe�cE�ion [7�S!NDal factors present l �by. tic I=14 -[11!�DA microarray study!� ZLD-deple%*%�s.Z120�4s whose proper.�due�.���is depen!� onm�!�!L$full range � target �4its mechanisms"AZon�not know!^WeI,au),al yearA�I/nvestiga%�|g�3-wideEp!�of6'I M8-�e(,anterior-pos %�dorsal-����`2�-?�"immed�� ly follow2�MZT .� used chro�Yn2$unoprecipiI`0 coupled with�9�hybridi��0( ChIP-chip )ama( tifytrei�bound�A�2dby 21-6A���2�1C. Whil)=6b0by any partic�� 4%�,�2@dictably , enrich��A&I6 sequea�,�[ virtually�[ry cas ze�strongM>wasE_!|specificc�a�R[12a]T�gstrik�!�unexpecaWobserve���ed��� addi�uto�es�Pd role�Mv^ij2_ale d,ei$might play�/enE�JOi @ity a5eMs Here�y=!A(is possibil2us���4high-throughpu5�FM�SeqI��\w�oAlandscap�5�/?aa�e�C��gressen%�eN Al�gh�w�Yz ly ia�es!�� �le)Dof%e=-(F)� felt itEV�n���w!ݑ�eS�wh��t�E��to)�, Iz� 2  ,! well �on*A��sA�% �Ytherefo�bollI��from pop�P�} cage��fixE�em�xY extr��APree to s��degg-laying: 60–90 minute��i�!�2ys 8�9)%�level�Ecrea�[9 [����!4 iestZ7occurss ;��–15�Z� 13`\J�%��`spr��V�b� s;I18z21Nz� 6 ��d robub�has�.Y4. In a typical� ��eri  ,=�would b��epa� direct��At� !�dM4 ME4 .*N D . m.] $females do�qalways �� eggs��Jfe� �S, mea�s: w�`se bulkN�e� �to-� a� stage f � vari�{contain� 0 small number�old E . SiɊaais Tof.� ��ven m� at��6G q� o i��ma�� ,��!� �fqvof :� ng>Van re� � a.^2Dpurb y�:/ha_sor�* each pool��individ�x��� y1�� a lŬ� scop� f 3tz %�didE( a�dis� uish+ morphologE�cha!er%c@ 4)�Psample ��y�. T�.(is laboriou� ocedu�obM p�s)si�approxim)� 1 , 0 . 2��nd 1 g!�Q0rejtivA[� s 8� ,i�6u Z�%( Fig�S1 ) . F�implic�!��� manu#ɿwi� ef$ � aY)8s�b l8�2��6�2�, a.|D to emphas�%�weUVm s ba� oa,-�2 I��it*� ,%E� �1�e�mix�cat adja. 6isI� performed��>z s prevA/ly de!I�ffjy-uRanti-�� bodiesŶ$. To avoid&s crosy�S� betw�{BAo��2��Ea"6,� , we� lou� t�yE�!$e%�recogn!�� 8 f;V Vy at�pri} DNA-�domai� ~ F]ed5!�an Illu�� G� L Analyzer IIx , mapp8 eadsAWA�BvE�( u-�$Bowtie [13?!M f peak1�W,Grizzly PeakF� @lgorithm ( see Ma��al1 Methodse�� data��Xfirst � �a�Rw 1?I�,�!y( ledѹzIN ZBI cee!Q�zz ��  ��? A}���la��ɳamount�in �j�.��� %:��ofS qua� ,� -resolved-�!� 0 signal-to-noA�rM�01A%�We.1��374Lt��10 , 471>13-���432 6"( Tab SeS�)S3�E{i�9%!n � E���U�� a �et� comp�AQ�s [14P6q consisten� recove A���},7-mer&&7I� 0]%��al�a�Mtprimar�=tW:�in viv.�BT1C%3��spl� 66%@�top�007 i�=ɭ*-�%B% leas�cVas oppo����domF c� of 1 . 8% mil�, [��, two shJ r ver8%�� �,Vear ,>Qin 94%P75��A�ly �Q:��]lso  cor!a��e.� ( Yh1%i� _��agnitudB�&�2%�Sur� i�,��B��cluding"��CAGa���sh by mM�iE�Eto� ipL�� *�of scute��c )��qto )RbyEIE�tro.��Ure� �nEaeAu�among%+.�)Fs aZvo . A� \�� % � P �,��n� ޱ��.%� foc���Q�nE on�.�~W6R2]6  ed*����toy y�Re��[� .�A]�-sd ge;Xsc , zerknüllt ( zen )E�k -ski#( )Y���� fo���promotere���171 q=.�2(�4etDas 500 bp upstream�mbp down S �� start sit�"� ed -eight� � �4-I�QU,�!Bremain�F ribuI!$�t !T � �<non-coe�u�1 �V9�V�MofM�� clos� mirr�>2a��� �|>�Indeed� ni64�M!AsZ)y�� 82wdic6atA 'A�!�nt � �!,Lh. hanIa�?w�� z or*�struct� ,a?�major", of&q9E�izs��th�pa�d� �:A� as a5 Iprotei@0Liang et al .�"��aA[ meas��Ndiffe��?wildtype1[Z35`AU�lac>3r��.&D th�L�&�a5-"? j-B�@ y c�>&]how much!]t%Nf��"\duea�!�1�icA�o� ifI bz Pambigutw�mJ)�I�� ��nt2U# to��!1�ɒ��8��^associ�1�.?!z=�E4p&~, ?��S"Gm/E{Ee�\qF �!h� q)� &IU'����!�2� Q0ԕ2� T)�is�onounc[w�OeUr�po� d mRNAs (9 %l� [17]�� ҁ� rM1�i� to�/������B ' ���A�B�s��by:�%Rlb��-��!K�& 5��*� ��a&e�� &I@.����-� . Gie|� � s�.���iF.A�8�q2�up��#!��nexay��f�1&h�"a16rinF� $took advan��of#�ly pub� �u���grs\ u!m.�a v i8I�i��.�i�5e��01" ��ea<s�]� �at�c}��z��13a u:! �Q�m� [E�%#�� �ed until�r14i al' �Ս�0&Iw eodd-pa$( opa` leak (� >�6��!e�!�Jf�5M�r�M�����mG^� f ngt��`A1XZ�A�2� �aJ�!�n �er��+8Jm͵��Egarlie�6 cx�nP �u�tXs��) � :]Q�Qyc %F *�X��t�n-5(� "!&��E1•譾 m=�TCl e�  s�in�1D�N&p 90. A��2� A� outs�"of50- . AnE as� �1 %&re!`a%�Ri.�in> J�AR�tim� 2a1�=�2ddiscusa��introduc�/n&�&5 w2� �F"0�>�#( A-Pa�#6�#( D-V ).�# �2 !�Z�� a4 .N��2Z18�"Wm &�c .6*�toMWw 1�� �Z21:1"invYin% ��*$#, �Aa�i� ly�2k!�Qz u�.�se�4X).4*a:��f(ͅwli.ofB (%�funE; al enhanc�.�)'azBU�4� �aG@f�� ( BCa�CAGT%\KR t��yQSm�U,%�m b����rg:�!��!�p�& ,2'%���$C,N=—at�st� r�+ar ���ior�� �a� �xinecO2�� s��%tR�U�ms �a+ �di  ~� A�)cx N�I"��"2��J7�a�i&x,qs�)q�/T!:is �JAm ��2�a>� alon�� poor.i'o� l)���spo� �]�B'lue bx)�$!-um:!becausm n~�)�c E�i� }(A(.�([19��&�-� �ric �4to�X�J��� !jpr�iv�%w�! �u�W$s dra{)� y��gr�������M.�'��" N.9��-� �> acce�'Q)oV�1�n � � ���.�A�&�z(,&rF� DNAseI:0I��14� s [20!�W����'2�&z� �!=�ofVr;p [ 1WIMM18�!/nja�=of open.�14Y!5��T�a��u&Z!��g �:nV�(B; r = �"7n��t:��%�jz!�\-je�95C6�4; Miiza con}!��� Q�to=�st� piquu�fte��Xa�dynami$&�$2c] .2is fai*�+e o!2�:�1$135S��$ed*@�t)��< 873 ( 90%��Be&21�wS�: S4%�6�A9iK�"ll6M ��as@!�evM 2Z Ͱ�2$@*,6lBOleaP%e�P� !�  r)�r�4,�+& , cl<*�1�.:�775-�d�{' �j&�oabB�5] 6A ,d !i32k�-MO�h"3.o.b�iq�-7.5� loci��r6,2 e���)d�*l&� +, n�&ng�A�qT!~Z��dH �(1ng�  emergden�( Av1�,�t�}#4 anno's�yd�+op� alq&. A�Y8,{v�/��V�Z�A�.�9�w:i�j: 6�7 &V� (&cto e0at3 + �*an �6n�(( �a�o stud�$ L$�ic"9�k�ed ���` unus�)�=fr�3� G � <�R8��%"�2Ga �  a�B>le!�t�Bym�1#�50r�6�eO.�become���in&�*| n�5ss(��q�rg"#by���4� ��3?5�A�6M��)QSAw�.shift& m �AF"@qaA| inue��) �di�[!���D�6���:��9�&�1�_!l�3m�t�4End may�ref`0O� C-'gre1' di#�$.2(�CC8after"%Ѫ� begins . A_�X"9�toa~ch !Vs�originZ*was keL1�� W w�8ofZ���5ed�2)'[%%�f�e��>���!svalidaD<a�"*.� w7 demo^ +"�I, lsoM�H h4� !7&"of)�tla�us"�ҍA�|1�5u~Y2^)5�Ѕ4na:�>k F�)�L�x��uq raR�be!Fq)�*��"a��".ZN�A�(argue againK<t&�recruitA� polymeras1VL��;�;Ng4�!ackja�>Mv�A�^�o���P roll�����(and/or hist!�mod�l .Zɳs� i�6��a�� &� ly goo*�=��Lc� �� F$w�Vpla�8^uvf^��%aAW)twsI�r�assay  ��"�"�*�Ai�(�18on���n��� J�R“�'�?�[2(��teaalaN$�$B�Rwu�oftoordin�Z�Fur�f,"� �)v,���lab � diss�A����c infl�;2aM�� �v�� �eI�e#@%,AF�+d�#m.�6*yBdJ shapes "es�� —r��Bu0e ��qu� 0on left unansAda��' �$yIe�Y �!�"� Our���)�es� ;t*:= -�z�� knew)[6j �&s ��>}]�r,}�2Q .���AU���l`3of:� �@dr� #r%E���"1� t Dr"lE��e��Dr=��4!U��ŋ)�6M(,;)iazj ti*conne��S��.�9Mnd� %�ity�:, cruc�8A���G"� ,A�]3/t2� � vBB� 2�e!�V �Vus�i� ecic*"r%plal�� ��<act� a� V, f"�2 litt�?| abou Y>^�G� �*6 supMD( odel/���%*'@s�,"Muni )�(C1�E865�69�AjmosaicA��Ae}� d�7xi�x%mD�b(5�$�/2|� 39R�. IxC� f rrec�FKlik�&����@managA} 9( &1"N o� ��9�e:de�"Z Qjw�t��in1uly),Q*E�=by ens(E�*z- ;114!g.�� oA�arIH1^�:BA��:sq"!.�2 rtun ;u�� ���@mj �:69,H- MZT-��)Ce��ariyI��#ES�uyA|M�D��Hs s�J��s>3it�,�(Xenopus β-s n�,Iy>�(p�0b'&[ L�-��[24�A��3 +, siamo�nd xnr�5J.�Xw6D�f ��&9�.��r b�A.32� a�g��p�6B��%�� � help���i:Bf%Mb�u=r"� ethylegf� Prmt21>�="ɨ)9[2ZKT����!�!-�l|m*to�{�Z-!�-;b�Pa� %*� �>��].j un�j��alk")of.�2�gaJ��� glob���!`!R:{ . s � do�MEminis2 �Eso-�ed� pioneer� %�"�L> �$�c ncep�.i)%� o)0 ��bof FoxA1���-�r!Ko9��"(mammalian l< a.�un" "end�@mq k�m���B(hepatocyte-Med alb< �( Alb�>bi4&1;(4L2]M q��nBs�� deco�JsiBB W.�2� environ��ow�Dr ��t�Htn���G^L#IL~ )G�g%� �!�[2kMH"�N�o�Gst!I٤$in multipo�9As geniM%� he0�'W? 3 ( ɏ�a�a?lytb�a"�lyA�_A��)Y[2�&� �$ay�.e5;-��:���=� X6in��A��3!xcce:!9a�� n�$.�3*09>,�GIn-3e# �-?(enzyme BRG1A��CVP:%1&�" Work!�)u,N stem-��,in zebrafish &.%��MU2"���AK��L �s����e�e�x,' s ac��2*a 12� plurQj6�s��e E�Z�I[3T"M�Oo?L�H3�s markź% &�Qp%, tri-�)��ys�&�'( H3K4me� �)of� e�nA27 ?27 @E��F ivalA�� �<SB� "[9i�(JTTYo����h ��i��~.�A[31 >3�S9 � �j�n.�*�&��o�F�I)��&a(d � 4–12 ho�Iold [34�*�A�qE�- ���@$a�etUJ�/ lo��Py2�. R�,\"MI-C� ^t,9B o6�S)e.ae %XF8> � |s5p.Y*� =g�n�e�" #�P-�Ur�!�)Ga`at)�%�"-& . Perhaps�woa16. ]� wXA����"y.u8 o�Ny��,M�=�g&Litself]F�,)$noF'E��Z�**n"\ [35] va�%�B�� �4�=Dta�&�. I� impetB�e!jcarefulm��-vie�u�! �q�Ke"�F2�WA�%�����!fey} > te�(&y+�b��f9V�;Q� � �V&�s4R!��I�����st� ly�<o :�$b", �&In �:,n��"!�� �* K�U��oci�I!��v�!RI�:!�NF�&& @J.V.�ufficiA*.% *� �,,���!&�s�es�$[ 4 ,4l�*b��[M ne2 A�m-Ihe ( s�as��eJ�san(STAT92E [36X9� ��$�Xu,@ ��v�wa�A�N� �r�Nto keep]�e��s�  g)6�!b�EK exer�h�:f o,=Al�Y�F&� �a\�� a� !�co �= uK!���.�Y"r49 �-F (�<�5�,5�P-TEFb�J�7f ?-��#lj RNA *�II [37]!��D7*�"�9~-�ʥ� #e"�mP.6J �� b_ !%��.� al�a�>-Z��Q��w�A�E�!bL� in`4�n�?A,�Ngo@ rapi�Uund��m repl ��ORC%z!�� A , dF���"t&�"[38 �� �Ys�:� *: chan�=�n2�k noteE��Y�!�ce � inc�2�5�'s�g"� &� O"C%i�U� �;�DH,�ce&�]� �21:�Z7>Y-h����N.d i� assu�O%1, �"hNq㩒,Y"�qG��2l��t�).�[%* a<ar�6�\ E�$V26�Z�j @6+� �y �o&M"5�!�?>��:Bl�%S&^}d��/"�_�s�s.t �%[nco.s4ostr�&@22A��s}2��!�rk��%�-8�� 2!@r @ c4!�"�!*�,Z� �F;�,pancy��p�7D# a �'/6��@�3)���aj!+�JV�8Z�J"� fea�F�aJ� D) iu����; "� +>:M !cE@��"�V:�p�d�Tbe���cW��� ~^ !N! W��E!�3V b�x I��/f fa�. A�`s�((in Harrison&IG�Z rabb�T�6 immuDS�_GST fu���mi"z' 1117487!�A��&MT� sAe�T�6rE��I�] malt3&ѽ! ( MB�<U=���!�� i�M�)e.�'���oI�f$�)�*OT�Px�APRM("LT,2�(131;F449�  $&.(�w!�.�Pw��fai� A�io l is��1!p�ir�jby)� oblo!wE�F a� re(U�ull-lyA!Ʃe� .�,-D�.F�$f.IFm�VGU-F�]W �cubN s�ItAndard��`�) 25°�.EmM i�[mO3&�\�'n�m.�1�|6 S�Ior 180."�]_ Xhar_< i^wB�ldehyd�'T�i�^z eYw0d%�.�Z� �[ batc�fI|%vero�J�Z"�/SN mo�e�P&�F�[ a��+�respn egg re|Aah AH[&Vd�at 4×�t�3Y�at 10×-A� Fvi�1*�bff l�Wip�Z/A�ga4s�/ fd e'�d���OŊ-%d+ ��S�'view bole� �2 sess����tre �K��ov9M�_:4`�2�JF.��E'���pD :�a�!tin �I;aM1�9F;/�mW j� a��'%' P9'%��2�\��2%���4� d13�e�b� "�% *a{ .�:�6\�P<�8�� :�\��"e" �%��IZ��re$NT'`*� ���:�ff2�f$CsCl2 grad ue � rifu�go�3 tocok8*yVd�x�'. W�*!\i�&I;Q�in each�-%V-r-:s!oc���utI^ a SW41 roB�� volu$u!2��s,g�m!m �so�I�[ adjuodaccK+�+>ɣD&�a�) C&� "�^� fragAZ��_]su66s+100!�3�R7 a Biorup�( Dia� d^Inc . )%�alp�OaG� !14� ( 15 s), 4 ff�6!�p�set��atH@* 3 . 7 µg��Q�, 6 . 6#�^F41K93N�re o�)A""�Q&z :�]y �j�4%6`Y�1�lyQ���3!Glibrar���mSd �V�iENIn6[&saA�AsAf subj?-oMڅ��5pTk Solexa GJY]�|V:Nyp�*,LP"�,��Q{Iq�20�d35U�B^. S{ +�Km�]� e April@6�� B�-A�mA�( UCSC M6on dm�%BDGP R�5 )-�.�]9�jo and-0F op��Xs ‘-n 2 -l 36 -m 2’�r�'i!ǁ� �#  8tagg�Fa�Vun�>7!!C �e'&�& mism�. E��!2e�extmmd!2PV"5as or�YՂnU�a�&�OsEJe�pz kr�#v3�:� G[,e�� x jel- m"-l[ "f\—.@_ /g4cu 1a.�Sy sig;Y2 �&=F�1. .U�� tej_+ ��fi�z�o�8�twJgT�SCapaldi&� 4i4$In brief ,6xest�c!��i�s0A�a��A"�a� -seqx/��51An �ly sca9@A�!�-8�:X a�EL�� &}n*;expand!�nK ha!%a�Kt� = a� im�=et β�!aG �h{[-�kpeSa� Z�� )ejmizaEafi�$  9TA+H0em@ lape} ��A�iWa� e heur�a��^de���-#�r�ng� �� Ym~ stepAi� asA�!2 sc ;$�=tak!��Q*� Amprovem�� @�chiev�1y9F� &� �ba�!VA�%�!4��me�!���bS(o)6��{ic`�qiscar'efuc!A<i�#0rep�;wQno.�"�Pe�r�ZDe6FY�! vail�� (ttp://eisen04<. org/software/g�c . Id�\f� ��NU�to�ar�I�� i�(:  er�!(H5pADun4H���Cd ^vo s�&'olTF� wG MEME (ո�5 . 0 )�aiearch!��\oA�4����� (] zoopsa )� M�e@K�up!10 �O�@t��ng)%s�d�Gl�(il�ano� D))� 9��aE AŒ -MaxA�  ( EM5m�{"Q2f�[1D�7ccOn!�� %��by Wee�\9a�a!e�`[�b exhausJenu�9��+c�Uv�4e�ofIME� n �dz Xh�� �d�˝Iq��al*;C�� FlyB,:g{v.\C �� rB�!X�#���x�\A�!��p*rtendW�. A� A6>IUm?e���/.g���&+in�Bn�)six��4.es:V  ) Pr�;8� ����__ox(�)&Z_; (EC{A1� ( CDS )n.n�L!8>(5′-UTR^/.[&b �M4 ) 32M� I�-n a�5( 6 )�E(!R)d2Z`A&!m��t�?>6��BE�6�� nea/FP��o"�0k&e�isi`��RaQ�\�R2�E0de:���teg�Em2��ryT�a {8ra�EgU�� *9A�& �Q&ir76��Io�2�F�]�Zve1BRsI�E�o�.�� ��0 orde:� ��i , p�E�9zrxa�i8(% M.�pner�g%4��� ��sJ � . On� t�W;EI+(�5��l� Cm�abundA��8$ve 5 RPKM �Ha%ki�2�yer mill!�D�, limia��tuta*{>��i6��a�E�po� �2�Jt&� ���maX -!�erv7piece*cubic.Uo\0MATLAB R2010aEterp1�c ,, p{, 78Raw%\.�]lF8cQ B�`!�I��uo*UGM>wnloa"z GEOf9�0$on GSE1123A�Vree6�Q. Up-��c4Y� o2>) � *�� ��cto�FZc.�b�)ark� s!@cM!Ain&6 ia“xmvG .) �Bu P@��se)�.?!� !Qb�Xd�9u.jlv*��(a1�%3"Y�Y MacArthur�^z%��� $bdtnp . lb((gov/Fly-Net appl� 2�to�y�exact"� տ�e�fR�e�91% FDR�) ymmeUaA�"� r� tTU4�wco-�k!dA���s)�$top9 1 ach�;E �l�`p��e�Պ68�m e�^TF7  6;a�ru�&�ab���I�!�3�ay�t�� S2(�\!� calcc(Epe"li�ec"O�gL�-����or�PG+f�f�kn��_Q-�Ad-h �k�mma�s z,BCD: TAATCC;MZ0: TTTATTG; GT DACGTAA; HKB: GGGCGTLL0GACTTT; D: CC6,T; H: CACGCGR�qPRD: GT�"62q!���NYV.&"��M:\.�N)? .�eaQ�bsh2n��NeZ�#eY .�n2|gi�dA;g!�r(��#I�d�8d.Z dL; B)i-�aM��� ���#ic� !�H�'�l�i�%�.�%\�X TF )���!! "=#s��?�+:!�!. M� �w�1.'�>*`&�d&�A�f��J1i�in�S"�X|� � �a�&LE/a�N�al Ce %8Biotechnology I~V''s��� ( ��$www . ncbilm ih .�� geo/lrm��u GSE30757�? browse��B2; r!|1Z�*u��a*�y�$ qedݟ:?�/!�.+�Es U]6a�bi!o !z�[ޅ=Q– t M( PPI�R. T=^qb� '�<_D%�5&�.�!Uvcircada<( ∼24-6 )}+ckIBnstitute?da�A�e#�J A*�& q&�& physN�,��U���� scaleEk�#ly unk/oscil⌉-erg�f ��liR ���� �.e�u�: �- ���behav^D�$mATA�9l�� ompo!�of)�-z� .615@�al ne(#I�;@ve feedback-loops�ch� ek�rhythA�A kR a�ite is@UAuQ�&!��9m��24,A-�9�1�hĕ'.> � 5[4[3�A��V�Xsus@Ap9���no�Q�hg�<F�!}c""!�2�"��T��;,-�h����a��mJ�( Y2H��ceb[�<:.��H�8� P�hd�er�%Per�%Per�!?Crypto[�Cry(Cry�gTw. PER -RY1�rm��8lex���hib�h@own:by" "7a�he)-́a lb���&n�K��y�1�iD�A9 � p���n –�!�1aZW9�IR� tissuJM� Y1��ol2�{T}CConr t�� also߄ugu 1���n' ou�M�,� s.�R-of-da�P���*)Vs�s<<-Œ�sT"�14!!st� ( h"GDƀ[8�9. C��fu i�Ti^;eZU �>�b�0e�1��rO#modul/Q�C{ thusɄA�II�Q�͵��{�ʩg-#c���mo���9a �0�UB� lE;#�� r�I�`]i� ��g .��n6g�A�,� �+�  when�.��6rS+njWB1�8�Dq�A�!�a &)61��!�6'1a8.v1'� %Mca��\ oRsm"b�Is��a&(�46�A�E�a�A�%� Y��!,A�Ch�N�enhap�?Ao'�e�A "�aiB �n,5� PER/��΅�!�!C��c �����ᠽ����Q@&zU[!! prof�aP�)!y� &%'R� q��ApN�*�,!�" 1�}���& imed)Sg�9�J � � a�8farOA�mprehen�n.-p� *a� Z=㍨Y �&ir��.:YV��&Z.ak�=Q�U�out�(&� F �F[EN5��l.� �lucq]� �K*L!�M+�9>R/ve��� d ��)!46.@ � % �%-*�)'}i�9=[� '�:zso%�uNd�e?�� � ���=Csu}�2y }^d�ub-��!]co-NY+.�3in human �"�.1,��/�2eq�LA*��/�HngA|nU7l�e�iiD*C�(�v 9�14f�9�Dy&6�imJ/ bany%u��l.J+fQ�*�gaE\g�=2U1N��k6Hs&�V��k&͛q$av�oge�!a�wsho �yL�lu�(�Iur�H9WP�M�.�B�9�t54.Akee�*A pa V N�4�@,=�A�)�h�y . To} �{;.�K�CE� -�6�A�"�Ha�rixj-*��in�%���? k{O�-a& d�"�71A;�C3�i�* u�pfatsee T�}S1�dT%��Ij �Gc,_&�BQ I/�%�t��0x��C�� e ��3s�! �Aa00�Nm&�,of false"�Z!�de4te&�.��6 � c�Ak�}w �  TE�!� �g� 9�� 040 �^v�)�-=�ٯ s moZR�growth.s)�v� dium%�β-gal�sid��HX&ad�z�.�YAiz#%R�*118�l��$�bW~0�"g*w�m"w.�|"��;p}z�%E 1�( 4.�10V �-NU3�y ("� ,�-�, s-CRYn ;22e�]�h �I�(FL  s� tDh(� ∼4�pAyJ�c!o�[i�#Ql��] 25% �e. I��?l5� �f!�det)1P�:�un=(w %�&>�-���> � 0 g2hJDEC1/2E�CRY ,h RORβ/γR�α�Zalycsubuni� �R� Cα�q���)� WDR5]x B , M}To��4�V�%#6]y�_��0E�A��M�0AS2��� HEK293 B""�\Ki�!*�%�t���2� � 1:�� 9�)(�p,D play�J>+�V�py�?J�!�b|� �Om��aU�)le� aFBA �A�Twelvw#��;LM, 86% )-;>�2���fere* :Z���DEq�O ,Z ��A�+**A�p&xB>2����U�3!��g>��3nm�*u-�a!/� �princi� 8Lweb2�eŤqr>%>.NP��_6Qon"J )co�|�ev.#.5] "o A�.�& !4#��� s�OI�,0+�Fe .�pnyE�.C���ҩ� �)��)r� A�-"|�k[��i .e����"�E� �dũ" 5.s(D ‘n.* bors�9)�%�3=)( ept.� s �oinG*+UF-boxA���1�� � �.G �!�f� <=e� AtEUdea�!�]�!��!c mbed%��&�1(� u�S3�@eK%e�1' ul[E�&Pby��,n�*3Asto4 �UniHIH#�?&�b�&=rj_x�&�A|fd�We-A[A$�jdW o[ny9 �!�&mjt� k n��{b�� !1^e�134Cm��625(s �� N8nҝa=�� t [22N�,*L � h ( 22.)z!�Q�h*m ( 88';���*� . %���mea�Or�st.h �F�� ��2Ж (0-&),լ�6av�1O>�9*iR � �‘�Aworlda�tC�of���. LikT��=��)!:��1~prϪTd�w�#-freev-�!�few%�6-q�� �R3� On ave�*% U�Fv�@j�3ar�yW,� y!nvc�i_Jm�t�32� TWbaX,K e 0CREBBP , , , AR , HDAC5. N�atop'&y�+4}u�-6�".�is hier�8����:i .�B�5(�.c �hub��Ah5��,e��Q5M�thems� s V?��{H cl�Crv-�2uz1�P]"A}d�U�2�H Q# �Y��?�۩)*V �La@ 7�� ��/�� 8e yet"W UH&�� R^�>�m�<nery;5��h� ��=`ɓ��[l3�iѝ*:of��2Hge(O�"S�0-�0 RNAi��z U2OS��iT.�G�esu\��� `c� culA�!^&-Q}a�P anonA�- ����\IRC�pyu�&�4�/knock�F mice�:r�6�"W�#edK�9a�0RUA��ed Bmal1A'u-�f�g�/r=���'�*� 21.�{ 2�E�a(Y2��od�V�!:�"��H5n%}|���� ��&�G-�aAH!�->F�  CHEK1 ( �� ! i�TIMELESS�CKg�j`���?`i�* ��^�\�{1ÉgleN�=EheB&�m� CDHX�%F�?r �L6�RORγ )���itBz %k!!(� andr!'�!eHAR�� g?4�Haqot)�T)7�� �!��nm NONO4CSK3β�I,�fUBE2I� NCOR�. �*s��A��VMlN}al�7!",�r#��B Yn&q a�a@M�4th val�a��-iv high�a��./��% U2s�AC&!2f��ch.�*h T*U�oAo�W c��W�.?�0F�A;$I!Q^�Oig�jwh"d�xq��in.ZKs\A� a�� P �r:�PLl�lyPR)g=\,Yk-Rgɑ���� ""�u6����Ua�e|E���l6cB�. +ee@a�s>%l�+R]��Y�Z�@�k#�)ic*��)� A�($m}& 57�hyp!��Il*whE1VK%GA�2��R)�g�&"��9&� %-f���inda�p�%��iz�n�|\�*��*�!��=,�)f�*p �@ko��#(w�U0&���-est*�2"�,(� )Mlu�l[��Os��45}�, 649>�2x5\Z�� ��b4C-�?1a��'8�>^?����w*� %s�4H( p<10−6; Chi-squ U! �_�A��b��r&�2�Q��I�a�i:9�� 2=ť"� A�.�1;!1�b�G*hmE{�8zeE2s�Y�e]/%oVa.H.g54R6A �r� >�:�A�20F2�,�� ( 43ANBT-��0 . 5 ��B�u�r −1R1;�b15Bb"�4AD��S]Gx� %#: ���6�����3Ron"O%t��- �=#5-�to "� �AXhe���M#p�"5|�*7. ���U>%���s&� a�I/!���)/�&H-*mB���ŀ9���D10; Wilcoxon Rank e�)%|v��S�C�6�`��pt���Pfl{�R���:� �n�5RF��!�Y*��plٸ��:2�w�Gd=f eKC$!�Y������4ʐ�~W BH�ou}sulS*AeеS�e�E<P�[�x�wv�2N ^Ggo�!�D9.4�8� �i8���"�"*� !�y��*�di�d%J2��M��alen'Iŵx+E!�&�+m��Yw0h&h*95p"+ . Deb�de� se�W��C.� ne%"r b&q4�h�92�8�� ��lR&9A( �A��6y�e FDR� �rE-�h-[-x!;?�V~ 193 �<&M��`�ng2dPE���4���6F�PA� �I *�,"�KA�K!qF "� -. BE#�����+ a:�0T!����t&N1{iqa��0un�v"$6BI!e\6(ig ->��<�get6�}KAT2B�~-�A�Msz!. o�a�@%c<(�#� A1 -6;.y~ioh�fAH-�G�m� ��� �chin Vڄ&�,5"ѧA��oi�. N�L thel��u�+bef�!Å ���=�Y� e^��=.^! ��J�H_4&�{�BMS��a�T��w|�=�!����.qW) _4" =Le>� �cer9i3 ��a*+A�et"(e �L�����Oe/<"�*� %_0"(K�* belo�W^ kdaya�n��}��GPPPS'���5�&�s�!�9m&m)f����!�Ll��?z�� Cr5�ePK�:�|M�U��9A��!X�a�!*To�"�-R�-%�E��&�N�T&y��&� �s;�yIv�:( ��  D)�2cumD�cre:"2lif� &��-,.+q%�� legans;9�!�a�b �ywo0of � �8�4?� ‘'�" �@Q')d�*B9a�648�AlaA�‘n�! ZIiZE�oly� ߏATA� Kor lo� �5�I9$\c)oA�>s�&�J)�I� �I��>N s Aa!:6ntn�2A�v�-�3x*! :� ��!,���6�?� trai�%y?�EityA-"��� �b���>BsE�r�6|9D\b�z4$�b�+2#4(��)%� �&�� �-..�� X�!(.��n+|= n9;��(\(%>�� )A$:\"� )>/ed!X ( iiK'�">��Hy�a��c� 5 U�yed (��2s�' � JF&s0��9��h68�&�ell aVQ��� c���e ��n=6� A���E2�3�,� ����]98�z��G�OaCR�����#! [�it�[jE��A!i�A dele�z�.Car}= 5�6 lock�< de./�o��1"b�3&�a��G, Dec1�k Dec2.Fbxl14!ihom�$u*?D&��Jetlag@�#a6�,VC.��JG\5e� ∼6 ,� +v*x�5� 5&�0ach�c36�%�b� �:f!�}�!y=JB��ic�J�g(%wr�A� *65�K�kt�� ���>����ɡTi-*� �ajS"�2�1��zN>���23���iX!&652�a�"a#.�m���; ����n��l�(w 8V�&!FM�sCa����n�t y&� A�V�t3"=/%da�}c�&�3.�v{��u�"����v"����66(2� � ) tur�p$x%B6�>��F�6 ( t-� : p<�D01; Mann-Whitney UE�.m5{�<5�A��k� 6�($�3��to�we&�2��2�(19m9N>�d !V*� ^�-]���A–5;>5�� %��La"  �_ Usa A%�a�#m �ccV�)�?I�$%�6|�OR���}F� fr�!��e{e��&\at a �Vof %�5�� 1; ���� �x�A/e�1b;�� �6A5t"�!�#/I�KA� 8�G%_6KqZ�.�`r.��,��Z�3� �Eu$&m0% 0!.2w�@45��x E$q��fy��B� i�^� "!m}��Qes �VgenF� � �&!!e� >� (m��zAR"bO{�a4�2�q�#"|?-�gkA�k&� ai�B"� >~%iC �sa AreQI5�QV�5�*�.Hfs ?��N 0�.�6�eB�����#Eqa�% ont�y ( GO�R�`o�1�Dduc"-� redu�]t%}R��}�GO*Cc��I<�j=a�S)`��4!i&Uu��4���m�a�|2 ��� *U���ch*�"3K `6���6��ed�*��! �.�B�����we �w���:�Q6r����m�tem�'.����ir6��|�� �-"QWI]e712��.��,�11V�U6�Bv��N9hub� �*.s"9uTGO K�&Kk‘�*tir_/ &�> #�L‘.�Jexe�lL! mulu�"T 6A;(�=.x�gaE@I A�&�L q��y-he�>*n/� ca�^dE�X,�@ba�DKyoto EnPop��%�e�.�Gzqa�KEGG B�hՆ�-� �2I��9G U��}$&�8R��'�%nt%)).�A�D��?p4.OH�C)1� Census lM� ( ww>Ys���aTuk/L tics/CGP/ 2)��How�S)�2����"&�� �o*}-!�V� 7�-�by [ <(�q(��!'�y���7W�Mlo�.}Y{1�tA3��"k2�ig�']"� (" ;���fe`11*�[mmO%�����YJC��6��>o��E V.�R�s&}�7ar6�QB�.)&w�%it�)�!�cal&�:f�9 26Y)��&�:-1��pt 5J��� ��Q lA�;r 6< ( 79Ar105  )�^heat-sh� � HSP90AA��c�2`�� ��fol\4�R-�dot�6,��+�a��-� =IO��%O��t��H*�{ AH-surfac�!!>�'6L5j� L:�If �be� B �Jp`le�#$63r.�Fy�J,2kq��Ni��U��Q�> �(�Gm�6D*Q&��t9s��*<�c.�-1q��p]z  )E�Sa#3A�Z��i64�� ��&�i.ŏ�eCaGhe�rB�* 0�U $%�c3�-�h��odi��*3ae�h Zzy?,a�am#���( hI�s�" �on9�<[2�\'�%&yu.��!?v h �P(d�FH�"%��U+ng� ress�M�Wex!QaQbTs$M�1&�b5oq1�A?p� A_.�Qch� play�a4^3���� ana]���MWBNU:�( �j2#ʮ gparalog��k��28m�m:� �6�\>u�-� an E0D� N�l�fi�9�pfi�y lucz;&I E0M�S7�C1[a��.�d2|Ns!s�"s&�PER>BDEC��\)�\�7].l�"�]!�$AoK��6� F� ���ia� RORs�Te�3rU�"W�, "�-uR Df _�a*]�&>>!7;d8"&� a��QP lico� &X �� �����J��j a�eW&�6a�-oZ^�w"�$O�e���%b���W/�6���s�4"xc�`M�7  P2�!���J9byKѷqځy !05Wy�9J,ma�+SydFmali7)%�IE�d}8� de(�26U*^d1�e�.�(at CT0 ( CT��& �V"m�lf� N-.I��AM, [12:�i�>^�<&�n��gn2��p�Mt a1aMi�or��ha��&�� fD�i�5�I'[2'q[ʢ%OMe� ����R_�qM"� &�">��4GFP-fu�� A�*7"�G%� DsRe#cV fluoree�;)a�aZ samei� [`� , [3��C�c"_SI of�!- ��liEFACs@[h��HL,T�U&�m�d�!ҁ�+#.�"#%�proofa���p"e�"�%�&o��p&�R�d!�ta!�b(�G�?onM5 [32]y� S7B–S7D�"��D��idabSQQ�=h�sa�:u&�NA�!T�hh�de�Is I�a" c�) �6` }� 9E��/�8�Lb���� !.&=%!��V�*i2(?�E%L � q�� � Frـa+�d�"� D�i��,�he{dA�e�NI)�4��qsynN �= bloc3&�<�j�fa� de֋� +pn� ��81�m-9/e��&�pg�� "�5A�'� X�A probqKe1*��" by�. m�^�h��h?-,�((���q�� = :\a�ar��� z�A*bnt�"øwd!�+fS9-e�0�1�$e!z &O#:�oׁ�:� .CB& 14 ��4]�m*b��E�JMWj.'t1-A�H �/� �:�f-%i-!On;mis�.�cwe209�aym{:��"�,Al�s.�:<0e]aG -"+a� l&}U1�$our matrixs de��\So* _e�a�!��BF�'"bQ��!�!;risn�3ax�� �Q! � ��� �gJ obviWm.�/-�5�hS�����)�Ida��*-[>�#*�  �� ",lkU���+��!�� 2��WAqEc͍in�SX+t"N2�sc!����� � �.(�!reo5�&J_Pa") � 0�!S� �h{=~P��S� .i"����aHE�s `&)����1P�6{(+Q��V�CllB� ��F�I:-q8M;��2B`5K b�c!ƅ0%'F1A���%5!A �k�S��N, CSNK2�H� sl#PPP�@��`g: T&�[FBXW1(�z�$,E%�A#4uld be a valua�Fble resource for studying molecular events within the circadian system � so far uncharacterized posttranslational mechanisms belHespecially interestH. Whereas phosphory Dd of clock proteins are inc.,ingly recogn�as crua�c�4dynamics , de->ee �0have not been% iedTLextensively [36] . T�$fore , we 6 Lthe newly discovered �ac! betwd(PPP1Cα and5|CLOCK/BMAL1 heterodimer . Indeed m�ould validate our in silico predi fofUDdaytime-dependence is PPIS$hich negat �$regulates �abunda94( see Figure 7� S7 )L)�others!�pose PER -�s substrcof%( [37] , [38!`FurBh work is needed to identify�rEQ��ory^Hunits that may medi!,x E�,ficity . Our].!net| very densA(connected (� 2 ) e(a high clusa$ng . How ca@uch aWfun)�$? We analyaC both�-�� es�n�,al complexesA�o inva�g!Mb�eiKa�g�d=\$expressionATfiles from mouse livere�aEBe4ng pairsA.� ssum%�co-\on ��(cript level%�re4ent individualR]�probably!Bon�mitkfacto �physical�hon . De Lichtenberg et al .)pione��%�siՍ�ya%– �.^�� aU� focus�\ harbors s!y al lAԅN!3si��yin vivo �1A^ a variety�i�ā� s spatial)�a�, ͇toY�tissu%�re��ve!�A�}}, mRNA!�A�8, stoichiometryEg�on kinet�ߍ�%:�-J�odA>#!�All!�se param�}lI��6 ed b�zcor�}ond����of2�partn��!~1���pe���i��M� b��ng��F,be approxima ��Yn achaDsuppor !( i )egf Qm:0f]� s at simi y(Mum�$often occu!' mong�q�>��26A�,�� know2�1< / !�one� �N� -%�� oduc�s&�e$, e . �6C�y�� CRY1�on [5��( i�FB� �'v of-da?} �x�EN wy � be"� di$endogenous�S.. NAc thel�*, it sh3 beA�G Eon>scale2His still largely un)�ye� !to��# t genes �rhythm�!ly� �Zs a��display.hI=�a�Whi� c�AarisonYU5�:H� shAf a ra�g��eˁ�!�41!�[42ob -R)$be� id��a�s�9S. D~ 0 ‘hubs’ (�$ � #  many5; P� )A�m!kbe2A  tant��=?)ys6{ 5C )�revea��by�ge�: perturb���� hu�$apparentlyABE�8absolute numbera���sAB.� e% �� a6� �&degre\� %. T� � I�, too surpris�t,��preci� a�2y Y2� vat�A+their�6essi= e dament& incipl���< feedback&�� "��t�pN �E�v � a globali�:d��i�M�mia-�ic D� I�ign��%�m��=�ٙ than non-I<i"� AFtp<10−10 , Wilcoxon Rank testtIn addiE�,��e qual� as.� aƭ�(defin�^(ir GO categ� ‘�aP of biolog�\m&aT)���j5Z(�5R�;a���Text S1% Tog�,)�sugges�5^control�E�is an es� K featb6�) �s� <a�0 f 4���� L� w�E� � fupies�lWze direca�w��E7i2; ore�Q �'iAquired�� norm6 �'�TV is�� , h"! novel!�erhap#armacU)� l� "'e ldisrup����ou�fer!�&�or�4�U�( might exec��=lr decade}�om�� were!�A�fu�ub ' ��W�� a�� �[6��[7] �� 1Q serv�a dic���outputU�. CA.s� � rehe�U� he x~ e.��2/mis��.!�get-�ins!8�E ��-B% m�m���� es�pr\Uw Ogy!H�}=JPaI)AofG� ��� look%Ft)^pr.� "B=��. B2%1is1�ir>me���"B� �� �q��E� e��� e�/�4e�5�GO terms;tro&c"�by1!ed���2� 6D�"� A�� ��0concept has ou2T( ambigu� GO as���LQ-���ofM�i� , etc . )� allowY first��.�gl�on�7N/i�b"& a2~�2!m ner beyon.���^A�. F65a��2)& a�.t� q on wm" tic js:�*ib�dm1�����el># . Overall� h�"Z ��&�qɛe�ib�� a���^�&Ooscill�|� � &*@chee�!Yof!�y�N� Matrix�Y2HuaDža*�mperI�c�de!�bed [10�K43�F�� r5d�imz 46 ��$-length en�uҁ�� huttp i��>vecw resul�(in LexA DNA"� doma�*a�bai��f|a�) AJ Gal4:�� ! HhybridH prey�2H\ 4e L40ccαMATα<!�in was c-G��Js le� �i���a MATaT carr�$HIS3 , URA� lacZ��re�r%�#Av f� Sauto-��"ert�.%�8ng , liquid cul��!�.�E:mixt �lonPLin 384-micro titer p� � d7 XE then spot�oA��5 lete�um agaF . AfU �(at 30°C , �� \pferV %e348� �a�ain� SDII�0( -Leu , -Trp�(eleH+�nm en-� bto E�a� 7o�diploid �(��D.-�9 solidOvegV g �6�, -UraHi��aR�8on nylon membra�pla onFW. X-Ga*sayEre�/E�A5u� grewNbas�L. HEK293�� Tl�vi��y)SibClock-o 8Bmal1-luciferasXdA� Cell���ng 0q�.HiMYC-tagg�ut�A6��Qv48 ho�, lys�]G mill!�zcou��+ subj v�mmuno�pit&Pull-dow�Jta�ti-MYC!an iso�}�� ideotypicqbodA�(ose beads aeE�nx 9u��thnwashes.��H� pulled�m��measua} . We�n blot Ɂis%��5�yBrief%�}M?de� $d via boil!�iA�S-loa� buff-S!j�4by SDS-PAGE usCL4%–12% Bis-Tris getP� �.gto nit� llul!lq��in%c�7ima�t!��<. Mu�)�ro�E�6� HRP-conjuq� condBOChemil esc�re!�e T e����-Y vis�P. RNAi�A.q]o!���A�2�de�� .[>�fild�^}Ovirus-l� as�%xdu"c$human U2OS�]�F���>promo�<}��J��!��! amin�lfa�. N��,��exchan�C,to puromycina�b� icidG��Rqq posi� �=� Mjsynchro�!(by a 30 mina�s{dex�has��. Bio2��monito!�!F ∼6�w a TopC�� 7SerI}a sampe\�� ~. T�serA�E e��c&� �Y E��ng!��a cos!"f a�!�C�(oStar softwQ %�NQEie� f�reEa' e�IN(.�0six E-box enhF r ele� �!.�C7C ll\�"�T5/�n�r� inclu��wparalog�1�u�!� a renL .�" %�Sq�[4� 27�YSignaQddet2- .uu. assa�$ umiQ,��dd�oExperi)3E repe��\��}�sB�a fluor��� eithQ�)Mor1`s EGFP f% e�ein6�(7D left; [3� 31] ) �E7*���u9 }��$ or GSK3β"|6.�6�a�u)�sfl#ytay,ry ( FACS Ca II- R� .of DsA�n6gof) Ain�_� 4�q�gU� ��!D. Fh�sta�tdb'48- I<c]#�#"tak!��#HugU #, 2009�e'U�A24s �iod�?I0Fourier /sis:wd& x!�!a2���i (� a,x ) = 0; s�%��L� , T\a�o-�� � ��!Ixi,m �m�8point t!�S ���"�cee+calY> b�m���randomly�m� ,_͗)0�Bio* uctor $(package [44�K %�Mce ACA���m  C!�"� wF$����m3 s P1!�!� �A�!��io���=Ek <. AI� �( W� �<[:� �p�tHX)�s EP1 I* EP2 ��(���assoc(wW�"L/. A�oxy!x�-98�.�^s�E� utileF0usb of!�).O�]"9�m#-sc�A�peR"as � grou� odel$ yFa!�� �Amee?!P)J6G>aO. AN!��)aa�eᅭEM�$rough shifE^A�s& (I�eti�� ) alv"!�eaxFd�su�AFlap!T])D� ����e Y� lea��&��ve]%�on* QP" α|AK!�r? �(0a�.�P�_ i<� ��!0A� UniHI�'< ( N ��45775��ass�wpossi��H(behavior [1� [458 2� abov4#H u�E� mapp)�� �) orth�.�of 30413�i�!!B�J|2.%]6!A=of 2788 �N��( FDR�! �1Fv)�*�-%ar�)s�^-hIME @http://www . imex!�ort0. org )8 tM�TIntAct [pmid: 19850723p)y`)�,��hIM-16832 .1�Nematode poly- ergeNPAre,unu� cla,)f lipid-P& As f�4 in n e� They%synthes��as$�� ande��� t� �s(�z'-j  � ly cleav� to mpl�p� smZ �"� with6tu�)5�N$fatty acidigetino:Vi� A ) 5&�/�2��dq$+)��i��\2� of � hydrophob�*omp!_s"� !�)of=o,S",play key rol�+ nutr� " veng�z, T�-A� CIgE" �(� i]'%a3�s�J�e!�� � c?/!�d� s'  o)` sequi,��*ascar-|filar� YU,���a9�or near-. ABA-1A!?mos mmonEza�XNPA A��*um-isp$$�(!���p 1lumbrico:,�eM�8�2� !�wor� ��A>I�!D;!qto�s�S2*lwA��A�-ac! resi�ce@i5�injI.!Er�oir3 them�un�� c�'b� ����%Asbq"-r��d+�*m� nua�r mag<&W4n;EMtroscopV1Th - dopt��!�,n-heli�old���%a ��q'x�SU"ip;2��wo ho��rRO aConB��' iscru.�ligan�! ocke�reVnD&!Y N-XiA��Cp9�..id�-afa�)Q v (.�)���]i f�4$. Recombin�'-�!�Xt�ly-bo�Z�E$�5�1u� orig���,ts{si�3A%i�'AmxmL$R�� �#a�Xa]�o/,� �@-V@A�beU�a#��t`,)s�6)xi�5A;(n" uctu���.}� no c erAY verteb�� so�ik! po�!Gt+t�Br drug��e��EӁ0rX6aa!Ke) "�&ye� un=�9�2��b�ti-!#�!,�w�+o�h"�7��p-� T-��R�( TRPAGa r+I�(� 3,^cursorept�T�m�!��A.���orM���.K�y���R���"aa doz�.X c"f&llyy���Un&�v���3neurop х horm�2 ,�%B' ar!�>��Sexhib�-~/ bioc�%�i��\be�5�F&p��f w�he�ggr��5��he ke� nocya�[1� �*o *��7k,� [2\N�' ree-�8ns� v� �m95�I�F$h�>(en availabl��r�RP�V�"% effic7 %T cono�.nIh� �I�qu�4%_�(Y�. Withi>l2�,N� !FJI!�encod�,�,rup�r�*rly-sp�M�|E�ageq�- ��3�s hyp�9�is fu0r62�ac'atI0�&v�8� � �r� in � �V�0�%reg���!QX��!�.�A`,E)��,F��!)N��q�"(9Ex!�Gv M� f3� �2). S�4:3!�i����ly-diZ�r apoptoR �\+A�� �@;B!he=�&s(s���� adapon� [� go!� ioe�g*�1%� f �-s% . Bu6')/� <� F�by�a�=�#h�� ��nos � gram�� death%�Jl1�z�� 6)of:��/y=O=tinct2:�� it!Da�,)t� atisA�or�2lan�tAJ!�%yv"oyKN�. P�,a*Z/e� g qu o� why !m�s�W6a�� o wa: Altho� � *)i )+$nimal-para�c2y t�'5� * lant6!vf��livAsc, , [8aOEichWB��5�%* AtP$exFa�&,e pseudocoel�Kfl�%�!�se� i�{�sx sEZ�[9��'�8s"�,e�6�E-�J� s aw:�>�yb�:motifs (O76#/��I�of.�!��UY[1�4�1�(S6mpec�of�ease-caD.�&�A:M;L!�Lmerit !rn���E�� �vacci6([��Rc~ ofQ�)U�$A .J:Ɂepidem&�4p?�� >�ic-ES� )%.�A�a:lA#d�@opz �� �� t��� �!~[2i)2o&All!� �FD �5ta��E%�*_�in'!?) �r>&�i���,� �� �i��!C O, 9F/>9F� ��aa;!�o�b7 ł"���safe mov#e�in���n extra��u=Ů �$� e�0 . A� � � &9!9N�y8�y�<6(3 A�-�mus� er�Fsc)�%�E@s�YhEor� ���iay be2�9�Tog�k�&|> �coE<af]0p6�5� �upA!,!k)���YY�hidon�cid sj7�e])�.E��'�����$�%m Iesu a"�1m0 �-�es!��*4U)\ ���5�j-�sn(s�$ �relevq� gS�*q'�) s�c\Us��!-�lu�(j�( NMR� �Esol�<�[� �a���� famil%O �9��e�;�- �+ d��%�nFat�a�ᔡ�� [#A�c�l""$q�'�us�� L��,� ��A�&���3r�G, eq y j*r>=ca��w�1,@�@i:�8 "c*�� �k�!��� -!�?8� &� �%S*�A�n�R%As�ajum%U(��� y na� As-NP�bE4more XEly�*6��be ��En EMBL/GenBC<a9�\G>Q06811�&�( r )V#:I5< by f� ��*(� GSPEF;Q�lee *K~�pt��u� wild)'�Lin!�1�#P r Escherici� li��Luria-Be�? i br�Ior Siy es OD2 +($GmbH , Munh , Ger8du+t�m Be��,re�E*�42SKtE .�0iya�-CN��OD2-Nf�8(uep��do�-labe'/ ( 13�215N ���le ."5Ny)s+e<� �l%jur� � 2st EG gr�,n 98%��."�.�2�) � MALDI-TOF "spr;LD�r�(u��mov�Kfa�aP i��q&�M.A�#EDachie�yb� vC -<"( RP )�  graphy�0 a C8�#�� 1� /acet-rile/triO)o�8mob�5 9, fF���l�in aque�9b_07purR8e1���q".�*:n�Mf%*�%ly 2 mMh50 NaC�8 sod\!�O�.<0 . 001% ( v/v ) (benzamy.,^%Hphenylmethylsulfony�*J, pH 7_%2O)�d�e�#f�on�!wA�10�. A&�& ly 10 µL &$ mg/mL ole1L thanol6keach 60 EH�6eo��a3n!� � �022 . 5�9"8 �"� �SZ'e>�/&4^98 KR)0Bruker AVANCEe�MHz`800 ��Kad��w5 mm tr�$� !S$:@pulsed-field grad�,!8WATERGATE tailo�2'3veA�B7"�!�7%�[���Ak0ɻope�@o em u� a�.�^ cali��30!)bl��9Y���L�a� 100%�r(ylene glycoQ`6?0��-�referq a���� H2O offse  h�"o� >Wc&X-: KAlH$ m� or��7�,od�Wishart"�.G1.e�)0a��&!) @AZARA ( Wayne Bou!  , Dept3(f�-!s 1,�)�U�BCam�=g� 2}(bio� a_Ha%Auk/azaraq "W( �NSIG [32)DU%=tu)�J6� E 6CCPNm&x/ [3PM�0���#r~� Ih4]E8E�toX4a��� L4rect "(�tB<Yca(A"JBhac lish V 3�1W �I�.5N:)����de<2� A4 BioMagRes� ��b(:� mrb . wis!�edu )�B� 633�$DN�DNC′�2DH� )  , 1D /X αHα�-�"�0E�IPAP-[1����X, H� α/β-o-J)TROSY �W# COCA6"8! J- ( HNCO�ANHET:zC���eb�b�ar����(s-(iR��0iAeAE� M3e a�Bg#ntr�3Mj>\A�JN!aA !�*` errop����鹡91"Sa>kAs"$. NOE�tS��V%�3DA NOESY)��13C-ediA~I��Cectra�x$with100 msp@� 2. DB(�.v derih un$ crosspeak* /��$�-W/\7� �e5y!F�@ 0a 1/r6�� ship-->�incor�X�i�))02;�ar �-v&3��%�moFNhk"lism �VSOure�v>$n3�i%at�co�(a�  CNS ;P �(PARALLHDG-5 forz]��!� PROLSQwMbo� ener�H�G�P�') ��D \&d�ulf� BI�*vC� �juxta�ˡ�mcBGc1� !�G \�1"5%r��dZ)"S alE�k ��6ch=%7 d.�.�U2!;�col��de $�b R swapE�%N a Me, olis-styl2�HE�criter��ECon�A φ ,dihedrBn�]�,( −65° ±�C ,40)1~E*lFW�N�alpha�*eQ4�Qby CSI�5I C&�M����^V�+��l h>a�!Hvagain;5�d?1�%~�ard d� �O.��jP ��zng ~T� 1d@5%�.�toA/��IE�V D}Jn�+genI�=���` }. :X�9��EO1D�G>J>��55.ey�TENSOA�ulg7 5] i�'!B�& appl�Fa �&X*b�39]a]-=of 71�70 � , 66��4 �&Z%/mZ4�� {1H} !�A] os >6 . H�01��2e2V� *ot�!H$oQ�t�*�ua� �[ umc r�1 week�6a@s.T a lyophilŧ� in � . 25��q� p�D)��Yb�=~�3�0NOE-rmwU s �:2rY!6o �A��A ten+�t&��k^o` mbleM` PALE�c6| \ ]�E�c]�Z@ SANI]f [47]!square-w:G 8�=SI"'*8b\�[%3re[GE5���(DANGLE [48]���/�*9(�P"�_�]3��!.1�Axpl8��E? �1 %�is� �-TARIA @� }"D*�O^�n ri�1,he 20 lowest�!Il��A���� *h��*>�"�ated �(PROCHECK [4�_G.�B� PCD�_� :� rcs� �6�(e+�a6 2XV9�^5N-�x)V4/R1�]R2I%"8�*&YKay [5#51]�# strXM%�M:��3l{del�I" oecof�E�1��, �>5 , 3> ,�m�/10 � wh'tla��7S64 @9�!1 16t 9Ai \22)�)�fo?*�E� �=!���K�M.��!t�G9t.[��og!� , 11=( ( 5 di�yl�$) -1-napth�yl$�)SnoQ canociv DAUD�9!�$dansyl-α-Toct:+C*,�6�M"qPro� ( c/o Inv�J� , UK�nd Sigma=ool�Dor� "� G� �a�p=d� Qoc9IAr%gx�ly�9 g mL�[AC�� fres�C dilu!�+IEk ate-�� aa��BS; 1713l��3K{17 Na2HPO4!��M KH2 *3{Y 1 µM �g�4�ga theo�%��ex�-a@co&�1of 44Z�cm�ex"� wavekS( λexcA� !O345 nTih� e�}�s� s: 5�Lca Ro�/yF at 60–8#M I su� %�toiq)�at- in PBS%��Gy ce eYoR�.� ���"�. .6_H� DA�oA@"1ed�.�G��� %"P��E3�EHi�R��1� ��r�_techni�. (�MS!�ORIGIN v��[A��meN< g6�61 E5avio�f.� �+� ��#ma&a*A#1�(b~m"�1l��nS calo�Iq ( DS\�� �Cal VP-(In�(/GE Healthc� $, NorthampK, M�V& scan A�6�ShrE�,�B a 2Ac11.� ,.�s7�&�∼1 �l V%�di�A�A��%�deg! d bjP}�. Jb:( r�L� `.�"2�A�Metho*�Ũ!3�A��<��*�6� �T*, m�5 ericauq�4��*gr�,? �p�� ��&���ral feT�RR�!�mpan2ol}yuit"�6>y'"� U� !�fC�@4%a r"f]�tu�%v> )-q$�v1�A�@�NI‰�/�v2�d� �Va�0 6�@IB� ω-c:jnE1i�/[m�5_55�+5S, b�J )�p�$ Po,9�r�ng $�uM�&���.@� w�a  e!�blue-M�&&<∼543�$to 472 nm;�\�F,! ) �a1v��-� !���Uite�0-!��AU�2����+ hownA.)��DL�capryl.��� �j�s adjaw�%�xy�X�&3C�Ad�!�"�!�)?(m#,%�na�H� isoZd�K*R � %��se)Oћ"�.*( to g �#&� al5�hey:%��+i*M:ab6 1�"},�6Il we�!A~ llY�q� on A$)K^9r N{E�.*�.,*� S)/�"� r&�,skNM�A�!�q�Ei�*Q�n-@q n�D.`.*vod�4�R"�8pE��VzsQ? came�4��:r$pr���_e&�)�=4#�-i�C matcD6[8�#�7�����ar�+-1���( p `)Id"�sa��1par�d, (Sap�(61_U/ ( KD�  capa�d�?��J�K� Q�a&f)� some�_7Jr1�t�g�օ�>*���KD/I0�toQ�΁�n3^_ gnitTwea�"x"��!%JR�ioKD�+a�� e��;s*Moreo�qA�Y�Naradox �Noe�� "� AK-�T �R)q"2-��o b� �EC �g�&i��eTm∼9� ))�1�,�^k�e-�.� un) �;�,( U72��kf4�B`(� .)E!1}cav�>�,�Uda�� �F|Ls�B)�a�s'5��:�]%�Cnv@)X�6$�#!�an�g�2& H(� � co-f�U) ab�/��Q'u��;6�� !G�\���.Zb"�D� f & !@re�)��)�"[,fa�6��.�wlready�p);i� �;�ito�.�&u� �&j95D VzCO[�y� �'2iE�$ 4(|jbeHU) "�m!g2�K)a] !� �&� >7��un�g�YFUFQis%&n9�e�o"�S� r�  &K;"= 7]E8M_��@ *'tT0m o23������2�)a� Lco*,aY�� �Binc|� Tm!rnSDSCk4 s qu� t{G��?�!rQ� ց}a�d�{�5b�]8�k�Ia�e�*QeHN�!�a�-2�E�s�A � �>�����n<� rukPea,lpg7c8�M,� �zce�?1al q6'L�r- �&�\��*�^,i��\Z��}�?/&��>2�s�N�uW+m%�gAa�!{.� D��+h�Qf����A]ٸ�q�sI|MU%.� Lou�R$ eJ,s �reduce7"�#yGun�Fl�# m"�qF6� . It n3 2�unu� A�*6�H��@-TeW am"6u�i���om�!�*��?�>�M��(!eP al*�or�mQΉ�2�Q�I� plauJTyZ��A�oA��[6eemy�o�H6�^�%�x D!5�pop�;�of��&D&��"a�"�3%;nF��(2 2f*B�3D?*�3of-XA��'6b3>fu5{��? to y&1�3{1)��UYA;�o*} m�DcF�c����!�;W s �^ ,&�1.- [58]a&�eqf+%�&�d��64s rapiZZ�"�ly��'tur� �on- Fb*� F� r9�^�$V R� 2� "�\^i�z%1,1�:�0z q㵓( KD≈&  V�[*�[lF�AB".)��R5���9a)�5g 2�"�!��� �6�A�*J,*�"�Ir�ailA�Zq a�!+�0p!�ofF�� E mbin�P� JY\&w 1K"\A8 �45jb�Gos�,�.tP Q**�e�d% &^P� M�a���!� &�R*�% 4242�"�Nv*�u��toz#@� &*�TBW;dDa 2069 ?n�"�䡥an�V{'BL!3 2173*�'r&9*�Z#?#�( TE�-T ��$l$&< �r�"���#סy�"&��247�$6ν&)&���aO Y%i�Pf12�4� o�4[5+#254erX(&&�&A�sloʇ�famr+� � �;.'�*eW&*R&%preu��95?�6io Z�$u�3a��J�$%C,,Ek�+a��H%� ��-D�'�$~,I��$�*"�a}A� IZ-Uy *�%[60�& supe5:�Y�bɸ�*�Bmx^�5a��>1 :�% �!���-sV!0ac�4gloE�v���!ԅI:T�,al�&x! tIj:{V flan�&V( ABC;a�( DEFG )=�B� , E 7Al pc#6r�0e�A� n up|l fashaf! RN,v �,sA�eeP1�, [61]a�v�Ohor� nk�6��&"*�$t�i �+�3� �R�PX�Ns {�S2!� �9� ;�� m� m � AexaH�wGelix �8��nte*6Qaf kink��Gly11�; Each-�6X^je�"�[�G� A�@Y+y$e I ( Leu1�rTrp#|6 , Ile4cLeu42Kdyr4F! Ala5 His59 , 60 012J!j*kX� �/ NPA trypt�� s!DR up���~ide#�r�>!h� � n�)L��"�p�)U(^aȉ�� %� �R+d�Un� �=�ns-LTP!Y ACBP%se�& albu�q , , [6�O[6H<A� ˇ`!; & mU�K>�us�1"w m�{ � x AL�m[64] fai�"h>^"�kt~Z�EAe��oo�RMSD>#) 5 Å�andWNntc�lE�� �=$a�b$+( PDB�!��?d 8>W��iYT�(z?� 4o "�7C��T\ є%��rag!%QB�G: !#�!1�6_t"�CW� ��\��P1�y �`�lvN�]4��e7^!b�_la�lyLb�_^�f . Un� �(*m�wx,�\ुM�#%s�K.,"�K, y I�Z!�:%ness &D�2y�pbyDEF&G& 4 �./�&�H�)� �gi6!,490 Å3}�#toL5 . 92E��B{quF#CH2 grou|i$ th|�Ma`to 80B3�88 j:�,,R{4a4^y�B�;�K[6C&CavA�I� mai4bpd��Q��%aV'`?�"v�F�,%�$��E��ly2 ��s!�� L��L� L3 I� G6I3 Y� F� �}�inF�behind -i0�� by L- L A119 & I OkA�:EyAsur�! �w� i*&��-,)� A� ���w 3 , K34  p�yopeop:�b]NN�a�H12E�J0G2�a/3� MI� 41��a�&lso9�6�-� �!�G6� L� A� � L9!�V9!�$Y124 & V12� a3 l*~EK�(ar�NK6 R6A3K8 �K8�3A�+9��u;] �*re2�M�M3A��aroma; 5U�C6k I�L� I� G �C12�Im��Vᵥ�!He2/Wq deep� �E{�� ccupow�[�&cidM0/"��mI�-�� �0 l ed��of \�$��dec�^m��~�W�����= rgin*�>� 2F|�/h!�a *M �ŴbgentL� c ��w�/g6[ambe4L%i%� 9�u�8qj head�y!ab"�)r cx3 anchHa�� y�1aHT�g�dytoplas�a��As&� �"�N&�<DN- Y �K)va+at�_� in KO& M���!�zau avH�>!�,>t_leNrq(�2�M�7�[6A0�=z=Yh1EͥH}�6Ecc|Tda�qs�SWձ&*Tu96:xpj�lg!���K�achf�ASc�\H a S��our�i8'H� �,��!'*P�d��!�a���y.�e\�o!�Xrumo�/"�$beNer�"�.o�&��>�i�As �tKret��*�a�an �*T���e�AA�>�IimZ^��'oHI :a trua\der�#%�f!1��Z/ nd-'ai�Y�qFcj�ndevel`�Zlg"qu�1!p�9�….8�#��l�#!~5��C+�A.�r�>1q�Z>;%b9D�����3m5,dg`3disc-sha�s�u )~%s�� α"� β���o S&C7k�),��)&�esa���)se�,ar�0�A�@)nt"G���t.���EW9wI*i�"�`GD!�a=ƒ�!�!��z!� -ar��2� ��&��/.kp�~� -��m��G� half�hiU32�"$�A��&8's I� ur*� ���)SalQYk�da�9#"�sJ`&X2�2�a3vA�a\6��."�t�M&�0$ar�<1�,, � �e��_s � a��t�t"� aq<:�rA���"� iק��\�\fm"S1X $��!�g_id)�� !7 i�g�,���!"jwoy' roC�$�isym���5aD�} e}6�9�Ed�2!g ��Nf��f7* 6),� I�JRE ��9�$� /po v!��1 Q��dI`;m�Y�Vt�3�jM"1�L� �%Eu�6n.1 ]Ai3m��# (\AqXy"u!�2 ~?"�?�: �, tϚ%9���-��de�<re�7aD!2ide@at�a.G2���1#���0t ew"�I��m3�x!�I++, ��e�dE"$mu�<�&�o�m�K*u}�hUl+��s�5stM�_��/�.nf-��of�� pxhF #DFABP/P2/CRBP/CRABP*vc β-barrel�E_a�in.�f�7N%�m&�+� :z0metazoan��la [7˧Curio�?,*�2$�p;w!��l �8��"��ra"Rd� w ��a"xg [71]�[7eF�s �4`Qm��-rVa)�=9G�FAR.S,%%� e �>0��psub0bS=6 ��A.urO���j �r�a�S �Tu� a�e���/A; 5 B � . Sol�a �-a*Fc� eli- a&mi���e6�%��feZ&� ]_na�storag�7@�paLA+��*argy7rQ�67 kD��P+iOedo�nt2�of2ammalian��o�"}1iȚa�cad� of��=4h�. Lik5�6��A� �"k0��e�;.� 5 A6E�E(vevR� �)-�R�� Pd_{.�nd &� r_�i1�*a���2 Z>��E�3ransmi�]al&�a%�i�H[717�t*�{StE} phyl�1�c2$QVwI �,9�O�Y�Jomm3aI>0��)[N #�= "�uo)14n"4anp�� ]DS� ��a�iss|1vgA�9� ��a now!�p�'pl$3som��'�#!O b�*s�p&p=%�hej/ec= -dir= mutag��iG%4.�c����ѥ�2}&l6m"�&�=,�&�%�KY%M*s�S�&�z�$Ŝin�V�/*�G���5rem�BA\&�sKGE���olv �}J�\4 ��h�!6$ a�Wt� �}��/$ci�A�|�*�1[�% , [7Y9C2�a���$�� infld�T \;���lqGl5�  *�8 ���o"6Henviro1![7*[7�=���8rk9{�M��@s�?V �eme�o9 M� ,�Wo*��k�ror*!�"/!4RV�7&f n (0to nm���d�MR��)����I�s� ^hairp2en�QAN-r��pindL�fir:�h�a {�F-�-c#.�rDLFiq ���LZ&�� }���"�&DaM"83 I!$e�/� �a�*:add�v Ne]buIpol�2?5!��?�M�]�T�As!�a�<�d��a����)/is�� Ki�� �l� !�9�?"es*�#�  /!� playir)�.��%pe��*z��3w �&�=v�86 U|n� 9'�z1�1�ePDaa" ���^|:=a�; �!g2k"�4�� ���� 2eF|!/eQ�.�a�m��\�*+��1__/=�5teE#:���#FuEiUp"�n6LEUwy does�;\-I'&ۄA�^"�&Ac) � s te���G*e���� �erM�E�F'oZ�9�r!�s� �<�L+ ������E��2�k�� xa B6?W ph����(s�� nr�7T-6d=s [79� �taW:ed�|��u�<�)�1@)uf�D[l�^22<��iތ!� ribo) ��icb4<`<"�-*`�a!�tex,g �aggre���Tr;J1Ae7)%"�-��h*r h �ޅ�g 'y � �m;dS�d@y�9�!� reE!��-A!�loea&mD in GdnHCl�!�SwU�\h s2i k>> �K}y�d�.v !�"d manie;� �m+Mu�T!��y!wa*ed�, Gln20[(162 UJhad~�d� . Ch�*su�| s 15R20 nH� i�"� {D$�<=�tst �Q9� rJ21=2�:E .9 at �6ӬP �Gb�`�fR� dra�#�d�;�\!c�. g'sI� toward�Q�� i�0 AEN.�m,�7,?2G�fIfdisulph�y3Ka(��2)"|b6, s- �S )���1�x })� m; 'C�;&TheirQ�)���Ŗ!�������ref�/�AD=�)�!e � abro�Rf>�!�A�H 0lk�M���1�6��A�)ց�_t7�$��. Las+��� *� &ini�a�5�& -�W��=!���G2S [��T�AG ��+ .&�?�<m&�pо:}�C��v�� � or ��kPC&� a�so!Wk3p"�<B!�. -�f>ɐng&��in*� a 16 a">Bs �I�`bk)6"3N"r }2mF��s�,.��WblS( bancroftii�r��g~msAm��8~]Q&���oJu&*M���N��A ��"1:�u�2�mapa�u�Glu47�1I�=e]A"� ��n:1��A[& C��v K at �a�-�BSo 2eG�f@&&��*K">�b�'AMq�!�-7a�tF3ADV� /&��� m�grj!���=%w7!A�2�" pro�),o�[!~ �ble�0��� �q #�1q*�e��/Q8�Ie�u�a�'��� 61of .IAL�#a wy�v�: /aU%�&TK-�����e��B��� �����w �Ao"�'N� !� �a0=u�6l�ly ���5�eeJ=F��mYr&"�Gin�A"�-��fy+%!@!, ����5(�t� "�:%��Hsl&��� Xs ʄ�� �./\Pny2 �*��an��%�N*q�9�eE- ree>�&�d��!'j ��2o�@)A�u vohL��cM�7tea�1B�� ��AgxI�2V=(�!Y� ua�ur=S�ia� � �zen�,��&��e�f�KAqu�NQ�&* 8�ack!�a� ! e-t�O��Q �QZ���5ENX�XY�A��6��� untiZolyF m���*U �#te�E�art~ �,rj.= �h�'+#$�Y-E�Ba�,�n�e7 %bia�I�&h*�/su )p�5%�!2�"_W)�-�nab,�9� = �at�tzrbl� e. T��r� eZH��A�K�$�DQX�:vD^ ���1ȭ�Knd�Y����  � >I%&�(!]�QB�Ef6bW �ũ�9�$mphipathic�M�On�c76|i�������' �.�� A��iN2� 1 )��J�uUb���)�Kn�m�!�"�UJ 6w �( �$�"tusJin_ �ng�'s"�m�*6>rca�'A *R"�A!���'dY�R����Hi�(%A[he./ 2W "� re!:� �2im��ɀn�=��*yA��,ll�5�pc�of�e2 a���&�g�$as5ӗn�usU��8eC0�(A�mak� �Qt�*% _݄r��"�ice���2f���o��e��O0cf_(( � ��!iM��R"��-��-�*�]C5I .R?Cigu<aAna �oG�sh�'so�$!��:�!Oqi4ϡ�i"bn vulne�Jisl!�l�� ��*A� Paci��I 2��N�@ Terr�^@( PICTa'3�,I<g c�oxin-!i��f�, peo�R�3�'�N���:� , gastr)T,"n4cardiac symptoj��� e�ren� �MA V5 ��^eekeymonth�3U�tu�&�:m *&n�� illn�S!ni+on~�2m$ ecos mS4lth�l�<l��l,� ���c�na,TGem"=!�H�b]FYy%�Author""�()�to =�f��)�er o=�+a%�t-!�� c� ce>Qa�ra�Hc�)�URb�*�dT�����3oE677Med�6��17 �5���(ndKn �of 194 :perI, /lMt*� aA a$998–2008!�paoJ�I� IJo04/cEe �973�f98�>��&G%�ӡ1%�N�9��!���DA�i�c�'on-!�)��~��23. TakA�i�YI5un�1der�+��, a% 35 yea���υ50fF��7i�7/&�+� s���tT#�.� "1-O,AVexceedkfp2�'Qs �� nd0J  ra"vKsta��ofD^n�k>�!qЅHm��ub�;hih���Z� add�It 69,3��c�ˁ��>�FO!q= llel �6:LB,5S d3is���L�'ar�_eaYKrhepA�$,'adv�� �B   managc �s 30�0��\3eAor9A"E�� .�di��Rng4-HIV/AIDS�obe��RZ[.qsip �iŽ� ly..�2&p!�a�#qa�seaM���� S!wU�er/&*EY�Lal wa?a��:�Qm�op%�^sub��c)i�"p4 der-_9�ׁ�v /9u��*���ic1N! i���"*i��35�%��o�M�!�silɁ("�po<o: , eu� -�� �$J &,V�W ]–�c.64�#!��pJa���reeS 2�-~"���a�x�%� dinoflage"� P� algaA!*cyano{ ˛�IE�dbioaccumWGp�f��web! 0";��A�up���herbivorpRX ��9�arn2"o�� �,E��"� ���Jc:�!g:�{Ax*| J� %B>� *�?X�  ?Q�X�� �1�ytT I�� �soas!mA�e��$����Yj y�*]�_ . Ca�vA�Eid �4����oe�e��!�worldqptreo�>�e��xopoE Z(��}-diag�I� �i  .2�C���'�)�a*w ( Fried�rV�X B:E;�M�WI9$$in Oceania)/" �hA5/�� 000/�0Hawaii��A850F#��P7 Ee, �A��?�bt[� inm8nd:��<p} rmlab!0(�nSi�ADal�Ge�,!��n��>D !�r�2A�su&�FQ�1�m�;6�s� ts�#�*� � I�m�k,0!'a^ n� .VA*CQg����>��a��q�pb2�j%�.� . Me �.(�A��E�m��^he �T1.-d W�bWar�KH'ar �explo�prN!��l�W�J���� gf���� 8;53 c92 �SouthӑSs6�$?@ �Q� ;n]��"FE28��29kU�. ElevR fA�-S "� ` beliC���i.� xace��ngE��t%>!����L9�bA�e2N� ��>r+�s:�)M/X� est �"�Caribb`IWO�G���_ E qd1n*1uBi>g|��N�� en�6VA9�!brze\K��i\ :�́�r���a�e�%l/%�aF[138Eben��]y���J��29Z,��%��biogeaVl)�aain��L#q�{�65+V��' =q%�zie�!�!�,Ky�pw n�� hip u ast ѥX�r�5of:��W4%��- �!�|'E[��.��G�\e �SA&2�s9�A���n�m !m� . GivM.h�Em�clisjter��kd�xra&6: m�i*{%>�$EU��run-offm{h�^ S8 � i�F�I,e�Zli�� ���!inu r!�$s�a�" ��L� "�c(W 5[� % _a�I�> nd� p�drA����{ �Toɐ�&=��� ^ 9�N�� s Y�����h�"�k�S�NQoD� two 111"��hataZ�&vs .z . To��i�D+��pd%�3@A�c%�'!� � Se�a��C�Co�yR�PZ3, Divi��of*Z, AquaXe}M�e E�<%FAM/`tpb�mli�Lf3Vtit�0sA�2� *+26d�w��QWB!nN'Y/!�s�Vcomapa�he�*ݘ25u� ^LewX7�� .�H[k.a:�( S���I=m��Z�s7by��in=�to��2�� . Up<���r�hb� 2"�)hto-)oy�ur�a!�s�FNMDI�NJ oew�)}up;#April 20���2F�����Cco-+�c!�abAQ��!�% hNh�ledk�9��7! � p:9^J�:^a(��tc�&a� gq�!b��ƅAD�Ƅ�7M �3�.A~�*�6 �< %Ion:�fTe_ h"[��F;/iE2��< � ,�?3� i�FL�"�j��� `'blF���oW��"�9����K�s%:mou�pur� ��^ o��=�!&��'�M!u3 ) So�!�x%� .��˵�dia�2-&� �L25T pa��.��v�/"�2ki � desi#`�3x � sAD%�����J5����s� �FU�6/� ed hEX�*-�v��gye7�/nd"+qAIn Fij[- KiriT��B ,P" M'd � star5��6Y��?rk���:�W> midd&�� ?at Cookf!!�Marshk y!Tokela���h ana'��& � in Vxjtu�Q2��r2:v[b�200F%<eN!�> "" n"Y�9�)HZn , Pa � �, Gua�P Samo*B Wall# d��n�Nauru��b4�ivaY��� ��5sA��&�6FkA�RNatd0� o�y롚5 �ipelago_ p�Ain^g s`��!z3>1�( $ �H-����.udy�,��u! � �}G�,�Z�=�o[�l!"^ CPF] !;2�Ne�~ ultsenm]a912gr� "�<�b:�Q�,IR,6�>� Niue$ngQI?�9iM�dR�1�J. O!)s 8(a�X5"Y�9���tzJ� !!� ?%Tu0%�New C��o��F�-�"�2�J�R�*t�d!����!�)W&k";IenI%i�)� 8E6��=e��ou ksF �?e VE�Al��.n�PN4��{ �#8��[4"�0;� �.x7�a5/ LF�,F�)inu�,�,>�ab�sAj6���;: ,.%��A�%�d� �Wt =]�O. .�":%� 4 ��9!Y� j�/e�:i�� z%as�)&#iև��.�"�(ceu�.�m&m!B� J%>�qBp��949�&D!�*$p�/e%� �I� ��� n �=) �&pJ'd �&�(�8.�y�1� aE�E�g��.�H6 �&jtww�m&�%z�:=-!��c.!002%! �*�Z-�[��H�Nq'"�:y3 !ف�ŕ!R�f(:�<^d���R�E�� .+ �io�&'�a �U[/�U'R"�ea-w . 60USr�.�6J~'VP%� earl�W� �mL.� .Q�p�� � J� a.��< o�Im�X=� 6�dAgx&4�O�=Y�#d��r�=A[p��O�:18mp���0������l�Jw�>E ,C 9��perceנ:� ���st:6��� "1&� q�Ax�C�/f*u� is")9.&;8J U �V� V�6!OR6.�*6 .eN�!�y �nof2�. 20%5�=h6�1����5z)�:�6555W � -��&& Ak^)��2C7u��-sb-+v 2��=ve � A��A"�&.:��*U5�dd,=�6v�)A~six^�����0ha#vVA��<� �X&ce�problems� ( such as diabetes due to dietary changes ) as a result of ciguatera . Five PICTs reported both a change in diet and secondary medical problems jdSeven :e�taking reactive management measures�clo of fish: area�to <�Xoutbreaks , whilst fourZ�no �on!8. FN5hat pr�ta>�9�catch ��,) was occurr�v�ithere6nobv. EightB�Aaddit�Xl support would improveb-A�2 6�U!YiInot . T�a posi%A4hmarginally significant rela�,ship betweenIs!A�>Hper capita incidencEcU�L( p = 0 . 06 ) ,;n�nd�Z,8 ) ( Table f. Nei!�M>ve noraF�!�cor�ed with��(. However ,.ceive5�%�in.�:�inca$ed9�as5�lyʒ:m 13 )2�no2�differ%�:��%�5 )���QnI*Ixdid%�A{respond� quesET onE�4social consequ�s6�. It i%si!�E� the unusu<llabor�=majority��iuMroject me� have�tribu!�toDobser%�5�iaa2�(!� welloEruna tifiA0nfrastructureiEe�i thusi� �fbias for�more rec��H1998–2008 data wha�omparQ�! 1973–832�these 8represSa decade��du�aA iod� ompe%Xpublic health interests%� lack. surveilla�resource ՙ#%�e-� . Asi�all%studies�r�ca�efiniAV doesEsinclude m�confirmU" y oxinz��'sumed ,!"reAx!Epo!�il]Pmisclass�-|of-6ed� s; h�tAv situ ,ha �d fromj,1970s [2] . I�also beyeAhe scop%� S tudyA� speculateqY causiL6 high spatam�\4temporal varia�)era [4�T�f, instea!ai!'�emonstrze�Ais still!e�y)Lly growaIconcer5�regionAddress#�KwPrequire2�invest�rA�ar} nda tinuI educ)� campaigns!if%$su!E!�disturbA�s (MM@c%3bleac� , cyclone��( wrec�y��facA9A�) ) 9��. ta�i��lik� %^!� gene!�5� patt!Bof��QM%4co%eQ�-g��be a far�bexpens�-:�fu��, if w understan%of N��s� ,�ise�ext _ly � d . DespiA��M50 year: 5֑.aca ,�Ձ�reh [ �-wi�onet� eŋbe!6 � � . Ba�o�,Q�an ��maA" 500 , 000� sonsBKaEJ9� �last 35 �,AR)0%D0to a lifetimeM al�!]25%A�Eremark�Eg�Z larg!^b� igno�byE=��� al g!nna6A��only two %s�A�an ongo monito�programE�:one :9 sm�� unit devo!@t� se�R�P( Toxic Micro-algae U:oi�dInstitut Louis Malarde , F�(h Polynesia�Gi� a5rapidQ han� 8physical enviro%2�(global warm�,A�reme wea��i<�(reef degrad�`� �depen" lo{pop��iA@ uponɆ��ir��Ncultua��Qival ,.to uN dise� trea�A��detecs �aq B��=al�� tors�, !to=�,�㭡eghelp r�y鳍α�adverse�act:� .f�ChagD �is�<dA�@Trypanosoma cruzi� e�istq;�paras�ais asw A�E� 14chronic��%5h �ira& M�4cellular immun�o� sei�a�e|F !� K$CD4+CD8+ TD]�w ands�) � :��ent��Few���W� focu2� ubse��a��$very littl�(known about�im!�� anti-2ic]H�Y�%rirty-eM ~�,( 20 asympto� c�18 .)twelve^  ntrols w� enroll\ . . Periph�"@blood mononuclear- A stima~. solu` T .ML! gensA�analyzI�produiD of cytoki!baic mol� esA�:�s bef� 3Dafter benznidazole=q. A"ly��� s��= co-e}v��hib��y recepe�ɂseYH z�&-f d u{ a mulI me� flow�4metry techniquA�The fa�ency B��� er�~+��&� e y don��. Fur��m!H, aY! ~ low/ { subY�s�*� ��tha� B�:� sq�s"� .�-�e09�ed�level�iZ�dir�prop A�s��ȍ� pathology�Vn��d ��v�A|dem 0�x�����J�%��>�sa� taneously��enh� .�E�fune�Bapa��ofF�. Ae�y'��"j A��2/BD-[ � BM�K IL-2%ZTNF-α�U�.F@c, play� i� t��Ii��o%[�inf si� they�Y ��� e ef*o ����!_. ZXparzl����IcexhauA�ces2���� �se���a�)%� # =�` se!�!�Y��j�. EB 10� Iv:�was��!gfirst � by Carlos9`�� in8=�6]problem�0Latin America%�2Pa�Heconomic burden [1] /� � ��{��World�� organiz� ( WHO )" �approxi! ly �10 milla�people wU� r1�F� )'+al ag�a�6 ch'es:�2� d� s { % i�e lea} hE%Qp us myocar� s [3�Af| (cidal drug � �}w 1�X i����( BNZ� S�icF� %�� apy "�in 30%k87%!" � 1A�mcut� , g�o�st� or neur� disor� [4–6� �M a�of�A���phw �p�Q��rqs�.:Ū�{s�ovided e���*ubenefi� !&n�:3b�i!r�&A ^� system��"aga�/ �[7 , 8i^xDd�op��* AJ omyo� y [9–11!d More!M�a_a� Q some �a� reviews� ommen�MuI��� �2� n1�[12�)���%�i� foEiqaccount� key a��t!Jb� side|a. ! 9Bi"� "ne�o ;y bio�e i eu�ef�c��%ir%anew tool���allow-up�a�edy?[17!��"� n ul�ka��HS -pemiw � �\�strongQUՒ�d�i l�x, \ oughrar�]G lves& letT � �� h�d!� issu���la�ac�|^�M��k ����m�g [18!= Most9Rmaint�/an6� 9U|E��r �` ad[but:�30–40%qd a2A^��[19�I&� 1�uU�� �s�Fgo�&P pr�5s�*�[20j�@;z duce�a%�inu�expAEthogene��!�IM$dysr��via �aia����e� v�y�Y���,A<un�by(esAi9E{he�o��:�J� "*membranea���ge*� 1�[��2�U^�n>�X�� �< � U2 , 23��"�describ!�e:dra���mm���e sta�ofU�[R. R���-�}���=tsh�>AG�Q_of.u�&j�q:">[2�CirLa�1Y�,���!͡�!�on��&e adap*�C�A4 d principk �Blh]bes.1b(iy.�q���h�v%�9Iq�n [256��O�O���`fa"iazchiev/?q .th���%w��Q5��Ak% p&�1v� �]p4y Blue et al .��9� ,n%�6� 3%!lymphocy��in humaѷ[2��S@�t�hcha�riz��āl���$ etai���e i.@���$ group M��5'1!�ris���.AG��of be!j �[2| 32i�&eT����a��j�0F�z2 Dmigo�la2i�[����u�}I9�y� d!Ovi!q�Q�.�sn&HIV� �HCV [3�I)i"ex7 :, GedoUYr��Y|A�p"�!]B�in�S% �N�!ey&���6E�NIm��>�i��c$ic�!�*�4 atF��A�to�M�d�� ed gA r am �Me��� { perf3A�nVy��"��me)�&�� founE!�inAOmatory il�d ac Iiua1 who��wL� ,ranspl5([33] , sugg$gp{�&p�d:X.Q{���R�w�n׆W&' M�QXBpT��*�-�j�[meism)%lya�N� !�!��x%�'�B�L aceyZ�^:R.ALwheŻ�A�eQ�&� �sd3erA�~�:{s � sses?a�7yp� ��y can� !^`� ik!of� *� ��useful�ne� �)Aevalu�E�Vra>� of!� �FKit�--3 ledg� y"!���P6�6��i���IE�j`. *G#"�38 ad�+"� diagno!h27:�( cChD;TE�@E� clin�l`,��"�!�Kus�r F�$:o[34�K�edU2�� ( IN�!�18�Dheart damage ( CCC�)0G1 , n = 8; Gh  6CG3 4�S�re� of SpgJ%i��,��/:_:�fAcriteria=6wo!�vW o6se&9te�&(T8ELISA , Ortho C-� D)��4nd Inmunofluor8, Bioc�ía@ , Ari in� aWHo+#al Vi` de la Arrixaca ( Murcia-)L!had n����*any*g az�. Pat��'e�of BNd">%oex�'� All:�� eh+2 5 mg/kg/d�60 day}5��!8Q�-����be du�"A�!�(re 48-month��j o�T6b[( HA��U�. D\� }'h]��*� %]��Z�G�w%:� "=o[ �!Y�!�~(z,6� �C~+jo Su%r de IQ'igaci�&CAI�'CSIa�,mw,g -+QprotocoK�Υ&51. Sign� P/)�nt%�ob/� om��(individualsA +�iEclu;cO�B samp�of 30 mL�)ac�*`)�cX �%$by venipun�+�EDTA-�ai�< tube�vS bE7Dpr�, �admini5)!� ( T0m�a�wo$)t-0Ds:{� 12� th!�T1<�2�48 2�=BF!( PBM!��pur�,�.roW& [36a�sto[� !�e��bovine�)um\%FBS�� ibcoo ra�Isl , NY1�10% DMSOi�ryo: rA_4in liquid nitr&untilLa�Gen�DNA ��u&A�2!"Q� PCR !�� a%��"Sde>%)%� m�A�evB&bymu"T [3~ToM�*f �""n ( TcSA01$Rhesus Monx Kidney Ep�0lP CellAHLLC-MK2 line; CCL-7a�anassahVP�R&e�$ RPMI-1640flL��02 mM L-glutam!�( )��1!�%�!> 50 μg/mL�*-cin� hermo Fis�!S��!a , W�am� ssachuset�(U�at 37°C!�a�idM� tmos!�e_5% CO2�#�� �nM#��taelayer&ga���&�� omastigotHrm!oHMHOM/BR/1950/ Y iso�-d��)-�a��Qg+ri�ixmic Qs:�&]!4:a�� 96 h.0 �recR)�:�!�a>���-MA ernaQ �$|0rifugiJ�*v!ash1<1x PBS!� pH = 7 . !�P�' �v-qat 1x106� /μl!�ly4 bu�2 (Af(mM Tris-HCl8pH_4 , NaC{�2005% NP-40 , 1: PMSF�� nd 1Q�leupepX0 soE A3��Ifpule of 5�62 KHzAS 40-s*�&erv��of, �]&�ei�'t� -��byBbt 1�k,rpmk20 min�4aZ�-n�\Aҁ��*"�%�m`+ BCA9a y ki+b�a�!8Crprofi�|''�SDS-PAGE� CoaEsie b�s�F�S �&� conjAped Ab-1V��esurfac���: CD3-.Bh(�8ne UCH�1,�-Alexa F� 700&RPA-Tu '8-APC-H7SKa�1602D64&BY5F5 , T-�Moglobul!�(nd mucin-do$� �-3�3 i��<��S1 Fig` A�a&%Jmnwn4�1��2� minu�"� FM+�iso eT &�a robu� �=%�,*!hoa�s���pre&�a6q.B���0 3%�2�,E� Bonv%tI��9�I�sel!3�V�͝$same mediu&81! =��*�FCm��!��/_-��x.��.*�$�!!� �F���"�ž� j%��k&�&"� Ab��aCrT��ti-2B�n��16�g=� $��& ��r�H�g�� ���aDA��6ACV AbF�E-U!-E���e0�#-�35�S�Est� :H�,���(GraphPad Pr��A�6 . 0.�(S��,� 2 . NonL�4+�x�%Ke}F�#at�& Ec�4 Mann WhitzU 7!DHcarryx=Kari<am�)"#!9:;4�CC?#IkWilcox�.ni{Aspo2.evolu�. An *^F%��lH9v�9�'�Bo.�'pi�Brt��"�Aeu!.�:cal/&qSPICE5�5�^�Z�NE�al"�;�@HHB, B�sdM�.2?2���ARto 9 Nρ<��05m2ysymbo5%�='( *7 *200 !� )0)�box-plot� phic 9vbyY�r�i*�Cl�Al�(�� imum�max � boxe".��8 25th,7��il� To]Q:MD�-!B2�4:*>% CD3+* 2Ias3���in �-��12>*�!36� 9e216RZ"u�">�f�J�F�G�j R<�x6�9+/�Q�|( ur�F.�. A���ilyC.erzY%7$ ��in�( ρ =��01(�1�. WKB!�Z�/� B! �) *b9n6���5zZ�0�!?�-2��I �BE�As&1&in�E1� 29�!�V&�H>!]&ME�2Q-p�� �u��?AO!�0B�&�#Q�AQN*�-�)�I�e�7gE IA BZN :j P�Pb�L�K0H!nB� ��1�.�1T2� us)���l�+nW!VX� :Xin)u1!F-2��ZA,-yH�r{ A�^��1@�:je�.�qU�t�t�K simi)Dh q,.�EE�)�_"Bj35�KN�!o12Ie<� q:�>� “Ma�&�0nd Methods”��!%�>��3!�M>&G3�F�,-�-B$lng���C�, ��A�!T&I �5!5_2��As�A�6%v2�'�2�z�+6A �6e� �:��:��A�%C��� "� �&�/5se��in2�i*2*,e;Iah2��=� �2�0�S%�.0]�6!-B�p)IB{%$:5a}2s%RI^u�r�z�6bT ,)`�^3�)�222DV4��%�HD/-Id 6��;2�n�i.in%�dM .02QeP 6a:�(�M�-�F2�0 �FLw�%aT�PUT3aѥeof2r�y��E�(%�!H���e�S2e��r:Yi�/N�1QM�eJdEx!+9�� C�|2f J�0��I�4 Ma�B� m�&� of A�F�( S2B ��Xa�Hu� Ρ�~?Es��2a�R�A=��10e'M}B�4r� Q68!!Cc~i�N�Y�B as��m6i)hy�e$�Ena�>3 �5 �P{ >HN� (qݡ� ���W!���ex�'�S3M$AUG4&(t*� 8" �2bB� �a� /2 ��, >� �!�ii]. Likewi�"�86��RJ�J(E��#i�M�!!IN%4-D&�Y �`*HD%5J~V�;")� t*=[�^� f���U��, J ��}.'*=&WL��!us�"2�����jl562K! �!�� enJu�2"BS6�5.�D8�L�aN�Iq6D2VD6�aAS1X3?Iy�07�@&b�3Altogc� Y�B�a-�}����/=��m&:&a6�OIgP�1f"��*:.��&���:�T+{<al �-�:��L13 !D�15%��V� �s*�- �n9 s�� �&dV*&T;6&�`+"���T� +%&y(ym90* �pp0��; �[*I )g�BCQn�6�<" K�-;#fP!(F3#wasA�an%�("*&Q-�:S@4�  slcE&T,"k. ,z�� �-�and/or1�bL�qFv=f=�RIA�>�7>�M.�*L8 B�i/?� �XEb H[I�%���9�9�J�:14,I�,16+`R�F|4��H �A�3 �I2�M!�.�!L6O��(� . 7%�X"8%�8RwX�;!4�2�G��E�_e[=�MEnH"4]PXaBVc� ^ed�]��4i�)%!�BNZ~;ڤDbyFZ!p2|17%��17�� 6� .�>���� m�.!2� �!;.49,9 m}B"�UDh&a)`5��>�*A Y &wC� +sFU���>�>1�2�.BD2�I���� � , 4%5� �A�!()A�~5YQJ9M���?367Q56`i��ampre:6.i: �e�fb.�2>< 31N< Taken b@ �7c���aXY!�\Q��>��!x6�J AI1T!Es�.�%��"F?(�af�3!r*K MD�JN� ��Q �longi�@� �A��$u��in *�0�"� BX�����ѐ �*s)ytB N�i4��.��". ��su�]�:�+"�N� . Pr"7+�\/�� fbyn� N�.2�-^*�) 9em9��6��>:6:�f.�>�6��se)���<0N�� A�A�.�3�� J<#2^>�6(: B�N�F� ��{ BA2p1�I&+w��ls9� �G y ~I!V ;>*a�:)  jS �"��WMT!�>d �)��06�0"�V� &� Bp�aA�� Z,:�AQ�+>�"�WU�*~Sd �2�7pT3R%5 �&, 2�O,6,!�3& H8 6G2B B� m�)1!B��vr& [of��6�.�.13; toz$. �2�&� A]6iB�6x4z�?M�>�(%�1%�!t7!j..fT>2� :�N�.�a��&vM�� �2?8 ,!1A �_R6�Reg/U[���/.�����I�BP�Z-�7���Q�6z %�2,B�co x� u>D� �(ZF to 3�:3!�*l�� --k� {I2>ig3M)1I�a( 1aKiU6-� Ge,Q0TF�)�)^�-C,�Sly�rFK V;�- D+ \�'9$E�6)�:Uk d�Aa"m �2� �c ng ne?r%^�o �B�5�34a�!�!H:\5��7 ��A���� A�u(Y7Q��4!�*�6"qa �^2 �M v�B�v@"2+b-+&:N$� � 54��1�:3!3%�1A�Eɉ�7��*�XA{���Vr"� 1#>�b/A�k6��)IB�9+P4in��( 2�8�eC4aC\:�JQ-��( 1I�2A=��"� �a�� $jY+Ej!-�2&alcodB@-��_Xd2RG&� ,=M!Cab � 11�.�>p( 5��9�(�?!I. A`,�Za&�D�0� 2�8�D>���X.c�ne�3�vCR+K. "{&2Z *�C1I5�"NQ&�Din�Ua�HcJg�N5ns �i�A�.,:��,[3�)4jQAFh2��PtDM���z"�,�#HD�%hvh�[3�4Np&�Ũa few ���S=�Zm�o �=b�A�*�"��� �Oy�5F>>�|6\T as m�S)".�ir:��%n�Fr�D�Js8ty��` � n/} @ 2"��xv�S %_ Consrjt�b1`��.ai�_E worke�to�l0X�6F.!8?6sQ4J�R&�qQ�7*}Xa� �.�&�U)L���,���P:A��$B�2�#VW%�:�2uNK"8(��)q���"xR]�B,� 2�s]�yQ.��5+��o Qvel!kaJ+ !J: !�DLW� akoQCD:�+CD J�k(der�M-aH4��9eF�t�^d�4D4�0[4�\I)/JXE��/ �R )>�o��%(/&� Az�B82� a$2� >r���!� �!:.�3 � )NL�n�P�.&d'}/�=�of q�#J�[4Gdis1H�RIm�wu�^ &�D%D6s eiimbal"i!��:Y� �-�Y(+{�to��a�"� �pDu�o3ML�M� ac-D.In�laAx;2 2�eIsea&u(}n�~te� aO" z ")b��^�o�[a�c٭d�OQ�ټ��eQ1O9�eb�r1-a�T:Q2���� ɞ:ksWslfF"F\�:ta��  6�hen�<�J1� �b��c%�do� ��a indu�FaF 6EJ�m����ad�{losec!���1Y*�k x&Vib�s���AUi<�ais m^� J�W���.�$a+#�] x.�[4h_$!J\�`LtuET,step-)%~7Ga2e2 �o��� M�b"�t\QR$self-renewP"�BOq� .=��*���xV�.rF���/ �NueESa.)e��ZUl��6�CEX1`>��if�C_?,1u4�<�AY��b��mu&���*g�|�0J�%J��BFPF�a3b�EbIYs [�b4�:4�g:� ő�~�Rz�7.%|��q���t��$:: ave])�e�BBR�.y!�&n=��1�yl�gmix9`5su" p�AEXly1��ndQe-�edF  �: 1a "�c*�19F� b&V�ٱm��^e���K��7nph�k:�[4�RInd�iG*%�50�!5��FCe *�abpamwI8�V2��="vjdi�^y�#6 d� ]΅F0:aa y �/��t%%Yl ed 5.�&��is.rpa��M�b> �w `�Pi5" /Q��M�!�MO!#QAm���*� . WG g�_ �*�"ZNh|a���ail��� e�N�L�th���5�X �D�&w@�k�toward��� a�kI�2Z�b"r ���=�6,9�'! ��1xly5z1%W�#"}r�us�m !T ��I�Q�� "I!�F�ue�)�6��%O�2,�M�a{h���Ea:R\�-��d,��� �NV�U�n�H Uj6�� ���ax ��kl"2C�2v[5�Il�c��Eg an eV� �1Yde,Y�$���!��ly��2{rXn���H!�� of ~g5M&�qM�s�>%�by NK���z� ed!w& -��G( -/- )�U e [5"netW� �cbe hyp�sdM%2�exM1ZV)mai*�!�� �?e%grDžyx> (&�2wh�uyn`kabs1Lof)�mf c��X:#�� iffi�I��s:"�%Y&�P}U���f�%�."�j�e�F=h&"%R^F� &�tc�[mo�Zg\w.�=��h*W�-gE�2�Q�-mi�_1��F�es [8>V?�m>' M��E dIUZ_2=':O.@byD.z��������.a�Ja�66%r"N��O.�N.B/����"� eq!?�%�a��e�a�g�S�:�TCC:p9KF]A�er>a�=o2�&�&.5 m�:�*�� ))"H+��2=22uI�� % sK�,�`pHer[�AZvN���N�9J oZ�!_!Vf��<� A^�)�����seP�a��9%� �� ��L J���� of)p�iX]lockag�z�u!��%9M�>�%=�*XɇkI� DSs�I)39�)�6�:�&� ng�-=4U�F� l s�so�"� numb���`q,\� �N�n�r1D^� "C�s֍%�%�����ށ�o��Tgulem! be'|G�rEfunda!�&�or�Xprg qhomeosta;"[5s��ul�<u���Z�."r��!UF��bO JFQ!�Z,u�m�F2�=j���M�2�B6� :�l,.�s�zR9sBBC"Y Ҋ2�!.�s-\�&��]� �y�V92^]�J�� 5+i�A�o��^��&v�� �P!l�^S 92F �l ���or0 tJat�ACC� � qh"�2�-OI�y�onu rE-RA'��� 9�8��:ك �&�sHT2�EyUjw�@���(� 8� on@ �#t��v��5�!�&zy [55�y*� �CIV|�)�!m2� ;:ym�\��!alwJ]a:B_� �q� o��� �It���Wr4HA* ��%42�� �.G�F �r:��& FM�&�� 6|"�a U�� � ��mG�er�i�*��&�4�HLA-DR%dCD�o���sGn�Xߚ� !�q W6�kCs. S��2A V;HM!ߥ�B�n;�I�g �MY�|>-.�����kwy� . OuA�s��!�at6�Y ��A�6(y��Cy���+Ryng*!!�u:��D�%"[ � a�!3��! M!�I�522is&k&�}��c�y �be� ?<%����ME8A�>Y�,r�zk ��Z manu�p� Y !�-:�� e��q t"�$c&@�y"�!p�"�UngtH)%� &i�%�fTyoth"� s�T4q�W!;)�P��Ft�iy5�F�B� �e�@!��2 "�"1y� � "��O�A�k �eW�*" -�o� �in favoŽ!e�"&�"�ei�U/j~ -��p!&>W2�'5�*��a.&�R�q�:��6d d "O���5.1�&[-8>�5n�?�Y`!r&�, )&'to%�"x>��.p_[3a)iv�5t %�as,�� �3A� �Ӏnt6SB�%8l��e7 ,�+� Z�S鞩�����:�ex��to1!D}_�B��of K1 �jd9:a.�#odomin�a�. epito� [58 , 59]��|�["0"9�� ��W�� e K1��-��*�h �e.�n vE#c< E��ac&� �d2�B ?)�e1�o,0i" H*8 s�J}H4 L&�F���w� �<p�B� J]I y�;������,|k�" ��!%=sAg!ibi [��&�3�#7�7Mf��X� �m9&%B�a.!Z �\m-2�B�d�,� U`,����(i2�����!:@7� )�J$���i4 e&I a9�:M �&9 in qualit;�O &5` !k�V*�!!�mCM��kh1-�.�[Q�=�M:f <.g-*�A~> �R�p��~N�a Rawj��H6;p;Z0��� �I�USv���@B>A/6� 24�@�Ce�x7M]a!���d� >da�*� pnH��� A�hZ�#����ralle�jGR�6\F)I>b�"� �H�AM!��!'aN@*�� :a�%�恙4 �� Fc)��!4& X0r t��a�A�&F/.9)[epO mann_( +� opl!PI��&J+�qJ�d*‘� .�7l� �V*t~:� >T >�A[6+ 6c%i��.Ze[atJE�I�%�wa� *Mu� IND%�I�Tr61 star e�V� GA ��V2P6�?Z��.�6c�#"27&�6&�6����rl.� N���bl� ո�*"K���a�i�_�ua&�vm$1�of�� 2k� !�A~AYlyyq��h� 5�78 b�ss�iDst [65���� Un�b poteV1ly��[66 , 6� A�Y ����h-�6Wn�Lcombi!���>�� � &� ��2 �.�����т>��O��a�:2K���JM � _A!�-��� loa"�*�6�!��"H %���2���( %-in�e�1) �&B�8h.��A�f�8�e"� .�R�8 Acc�cW s)fW"�$�#������ *�" E{&teA�e���2���L�R�[1�In ���eUK a��:$i�A9� ��tI�Y-�(F!2$can/6O�!&"su��*C6 )5>�5M%[r&�@)uUIE�"� by�nex�M B�a&�Xg&ka"vot6||sic�q%��U3aɔ��*�r�.�22�9' summo��Yfgng�P*^*�%�s��a.��BS$ .�&h "���,�/�& s��n)H9%���v&> A\��!&5�a��/�J�6��ng�z�2�2]���h��5j refl"R:�ed QGm{�s*l�2�eSilhor2��*J  0IMak :mH>nzJ���u2M*�!Ld U* $��:zF is]�" N�� �n�5�;5"�/� QJ�iyC R��P*�ad-^ 14BX�A � ,&Il�viBa Ϙ�����B�Z^.�xPhR�oin�z�&xl&� lipid 3:bMK>�.�A st��5�2��e��iso��"�p:��syntheM$gej�ham��!xB!t pivo�!e�iE5-� �6way 905'�,3 �A�t�[.�.�$���i�>�&� lip{1CZIAtPLC�\A� i��6+!�>metabol!q!j��v� seedlw �`endoplas�r!PuluvwE0x:�%Arabidop� thalianax pi/c� k�)�z!� plc !pNt� ���plc2-1 �/d��E�1Vm|s- atidylI�ol 4-)!6% , 5-bis!�1��wD^ecU-!hmN�.1�&�2a tin�i�"�onD���localiG<{%�a&��yi���'��0B�wB�i���tv�M %Y6{-�M#de� %w):om&� by hZ;2t���7M�>C:�H>�b ='i�-bornep U#Ly� ��B>R�hy5�xn toA�M�as6�;D &I.nt ";�W��.  !}.g�t�aem䉜^>'.�k#a�e��1>AR�merܮ link�e4B^.�ER�"$��eB2i Hry��;#I[e<:�3�G\& �0M> :�idsp Jj�"¦.rA\ba�/{to%aB�o�XŁ��/af�Se�� r�L�M�� hydr3eN�J][PI (  ) P2]g#���Qol QU 7tr.� ( IP�Qsy�4, 2-diacylglych� ( DAG )iY�%at���> �!D�[��L�l�I�n�νonCa�rc�.]ut5�ce�6taL��<�]Z �]. Two��,LC� 7 ��j : no*�>+ ( NP!�qRM�z!- bund��� e.� �H �i�cA#n� M.eolPd;%� ι� �PI- #g)�|peXGto :T��r+.C&]��famA@!�six&# ,1\ NPC6< b�x����NPC�. NPC5%_i�9 "A�%"��o�3gA#�]��)r��:�TSOj �h�N, n!Wg� Hy�`as.�13,�ign#��� 9 [�=#sS.�brr�AL��-`A8e9_Ez[�w��P� a�e� crip��)V �ar�>:�AXid��sal/col�|�OA��[75w���5kAt5g58672k_ &B��d:!gZ � s�� JeAt4g3853 Ihni�7a��K�.�absci*���=69ސw�(9 ( At3g472�k, "2Aw`*%A#��Eu motolerdE[D{)NIH 3g085����f����5� �G����B�} �3t�AltK�m���es�1'pFin P.nM~�of � I�Ό&C�ƩU1e� aK��o�/ know�4M�eA�y��":E���m>�.�A!s2 Fl�I,B-�:�!�hea�H� S") !M1!�14A��a�cm�E� accuW��4�" berr��rV�� �ER�S�peICA�k� ukaryotic�!�veh=�ml A�1 �N�edQ6� �&�NGQiϘ-�unfoldV�5� ( UP:[1V�<�, ER-*1�Aa�( ERA�r[1�*�&�y?iDttenu�4&Υ �����`�^��m�(x3 9>|s�9)5re�%WQ�? ctlyh9�3adve�� -�(irs d�����{FAHU>�=!�,M?)�,l!z�*M1�Q�i9A� ��^T!��e�lH-�to%aUt�5=� �g~�)'�-�N-the��, A�I�mis�.|�soHa�Ie di\��=!�*�W����)�AD5B[19u 0! ��"Qof�>E�2�sG�X��;�"P���A�F%�Jin � �yU��(er!�eA-�AP��2*EJ�e& �;�y�� up-r�4��s��{���]��[7��{�&�~es�%Y57r�!��F�*@[2.1H"�e�|n3j.nB����^�`� �� un�W�,��\ER�B��J�"� 1 &f���/ �ma'�ll:qER&F [g��.:B>Uin<)_�8(n "�iSY{�8�w�6o�!//d�rck�j�.�)�"�:�g pN�>�I� �uG36d2���A �� R���'��DmKM��.rice7 you��oN�� flo�Ubud� vasc(�; leav3pŚ ( root�Sub�3���-�S� �2`5:�%4R�Uakn2�� g>��FB�7R"� susc��,0�� 5��ER2�8EZ#��-�@5;B�� )Yy�&$ ��\�?AR5nQ�~9,a�KQmp�Wtfb�" T-YQ�& N� 2Ft�U>�*�*b iX�aA� 9� , [�At3g5594��472.�G9:� "Q4avail��p��A$ librar�M,!�ozy��C&w|���I�mencl�W: f=�� ��d�� ,Mueller-Roeb)� nd Pt,��uHF�άry&�, q��a%� inse2+��� yPCR-b�m1*�$?/�!a�A���� co� >i"�C���p�c��au� ll-length$ J O!�A� -i�` 1��DžH���� null1��e�a-� le' gs^��5�UviE3iI����hU�:w%��%a"L!���e uti��I�ly]�>r�!!�\ ( GENEVESTIGATOR; www .1vi g�=Weom�_Db�A�e:6 �!�y,PK��2��Z�=rn� fyT|s�  �A�.1)��~; =2�;!��est.v�$!e q5�� � A���*.rv���3� 4�At%�F��w���1.$A��d� vege2.Q�7� h{)!�eb�vel�bui$?�xd� e�alq!a�.99�""d "�� �2�ed 8h/ub?�toϢ{  EY7� ��fS��� %K tip1�BEs&� !�:D�:��er p"�3ityM1ste�%�3P$shoot apex;�E�zܜAqH coty��?�A mal+ Y*a�ڍ�P�J8P�aq'��G� �) �c2PMK� ��Z&h�G�+RQ��� ���az" "� R ���)��W �� � �qu0"f ��>�emq� ���i��. A͏Cf!B �)�B,<'Rw a�5-�Ab"���!� �� �:�( PI4P"ʆ3E�/s8F[�Kx6��I��gsu~8R�3*u�3�wR.5:.5.�" H3�b i���|m�a�FH-���yrR��: �� � X����+rc:*n{$�1�+%�)�� o) curs :>r�F�E}�+>0!`%�� e aU3i1N�x��� �2�!"e ��is6�.��6��<�x����2B�12]; l>��,j��} � lp�j~f��x&)a y^/N�%ag� a �ge2U�i��si� 2 fu��to a GUS�� dr� {D�KHmo�m(�pPLC2:-62h���H�>""1!�"�zV� �e+6 ��3Etru�.�a�r:v%��� )zADA3��2� i�`af+3W�e ��mAbwI���o ��Vd��;N i�3�U Sea!!R�i�4� B le��p��a;����e�V�.�g,� P*o ��1'm�# t�)��d�I, [!�!�hCri� ��stigmޔfi�nR�bou����"2-stpH�EEiIn�!eBt5�. �F>-�EqteK%%�U�-�b�h!XsZ �  XA]�ser look=< "Py 2�@W �$� .� .�:`!�!�uniI(  "Cat= �+ *eR aczݮA�=��at2/. AJ.;-C�!. NZ:1*%�s^5�ن��R~�E%lumn�� Venu�2( ���gr.*U.eE����X# appe��M-�� %�k4H@I'AE.'1;���Y6,*p�t|e�m�E��,I�1 �4\�/�ffO�t!;?�umella��J%#2v�3n>CVI1/che���A������, body�4�en��?�%����-� - 1G�&f ��TvB-rw!��e�D5�:�+.�<��ep3=m�-I�5A–5��,#f^'E'!��d�#ophyll%�Q5I&L%{A�b�#aKheM�Q~Eco--��Y))B&�!�G FM4-64e���J/� ' 4’�5’}%mino-2 phen{*d�&�%PA��Mutoyp$chlore+u5M�� �-�eg�MA �U_�%��s}>�{�g&\�1se�&B>2!�m"D��;,� $ [UurZn��id԰ashigA�(d Skoog ( M߱[7�� retar� �m��+Qsy� o.Ill�W$of 15-day-`"��"{MA"A *IW�*��-�VH`3 wild�> �WO�lewskijc�W��eVp�5�v�fresh w���]dri��E�D#" n�70��80%+9%nf0c���� A"B�i�6C|6a�%�seJ|%�F-�� �fus0yl�!n w�("7ņ� rb;goFenp.(M�( .q oMJ~(�2-#"�#x�+�M��bt-A��-o���Fs"�A ?M�A��-�"Si��18/���%1�Folumbia-P�Col)�M=by�*kŦa��&�d# �Sy! Y��W5Bck�n��=�( f �A ӮzEIDF��M&�ZJ#�E�J7�-. �M��[:.]a��>`7!�70W��<�"�6&5F!/-1�N�LZue��z!�Y&� (6�eV|&����R��wad$�/��--�a�j�tu��myb�ժ–>'&W . TM�@� l N-glycos�-^J-EREtX W ?2["b9�M[2%�o53)l�V�����:�cer �\�Ksh�!~i��y���oYD( Eon+, �6D2F1 �8� �,>y�6Ma �� |.�y{�[j\N&|9,�1a!M6��:Sby~}3%��CBori� �2�of�le9q'F�Ѥ��{1w ���.Q8z��bq1�:6:��gB�&��K.;B: �A�%._Ay2D��bY�2�,7��%�9B�MmNO7��AI��åc"�6�Ae��2#3Dmi�o�5T6Q��a��$� 3�qN$9]: b�8�:;Y+Bi�0,�nexI�CNX� calrK6 RT ) [3u�+E27P� ���2-�6� C�-ڭt�VmہQi7-jD–7��zit X��en2�at ��%�#VޑU����>Y�L6�4B�O�l �eDuQa�iekh1 [)f 2�Cw/2=3&| e0�(�in �d�- s 1–100ޱ�2�l08L .u�*TD�� �MiB#�yvo�,&M�^2*[4![un� ..�&at��st*�"d ve�-"�A:�%!�R�2�m>`ie�%3C>�.�����D��b2C��b*A��#i�&�Wd��ed �5�_�*�&%o-n p�Nd!q��2�5m�i� . K#%9�6L&� >16k�"�"z: )� F�8�2 (xB ��$.� no.�k�:��*|8BA �Myplc1-Z! plc3 4 a� plc6"n;## 0c�� 9���P�% �6P 6 encod�"u��1_dN+{� - cx"�g�Rd �qi2ɫe��\2eK �"����4� ��^t�I�a����!*;1 ��a���l׵atl�>, ��� �5c�L��� b�t+ti.��n1 r+ ������r�:CA� &�'thalMV[� �ut�G�be:\�F�&aPL�4Vgb�.l�.9�orO-)M.MyW��6�&�Zf:u&ss!�y�!8�*�;at)�� &� < � 8�!�+*����Pt% �,"�Q]� { F�M*�Ew2��M� �129��3a�*\k��iK�.+ �C ,�.'+ � ���ۃ*"HP&n\,%s��rJEay�a  �A�ߕt�75 [e�j3���\oth $) /� eq )B�of-tA -��B4�A���?I� poll��� �� �s�� zTapZ5Z4_in guard K���-�| B %on�B)��1� V��� �>�,A;2�0��2M&�cw�5���njr �)����lym�d�.A#� ��A*TAfe~HD�I��6 �ҭeon &o�RQ ��&<R(NR�_���: � M .J->� ata��8. FRAGILE FIBER˗�l�pG> poly Et1&g#as�F4Aao�8w~ 5)h�,nIgp!�Qi�+I��Y�.ձ? @#.��� SAC1�. S�p%|m1��[3�;VAN��oNs^,i6� 6j(,j& a pl��t�^hom�BX��� 4P [y��dw, CVP0 �-�6� +�C�@�+/?a&�N~van� acts�J�ly����5gu@E�finuA�o6�![3sPe�In� Hdvidbo);M�A -�m�.2Ik*� M�.J"Bه�T.�EE8J M8}[P3 by�}O 0"u�i�b�8�+M��$�%2�+��u gRi��]�9#x�) �.��&i�W!4d{�8s ( Figs 6 and �^7 ) . The growth defect was complemented by transforming ProPLC2:PLC2 , which indicates that Ati0e primary isoE t#Lcontributes to seedl_ � . Reduced>��M��)�atidyl�5Lol 3-kinase ( PI3K )�9|5�9H�edB�sup.�p85α ,E�gulatoryA� unit!bclass Ia x�i}�-depend��accumBm@nuclear X-box-bin%,��,-1 ( XBP-1 )~t�r crip?E5 ��!a��[4a]4e This=¥�<0,targete��ssti�poptoa�[ MMoreoRbR�29�i��Q��DZebrafish [44 , 45A7 Thes��A�s highl� an ��entire ��@�R�#2�U. Our f-p{knoi���of�U2��NCprofil!)nd� NEto.�6Ua�onlAJp!ɠ6�)Z�s but9s a cruc�Bol�PLC�<2�,� i�deAL bed E�ly.AF��re.� lants�� poss,a distinct rQ�(y mechanism!E���>�-�s under{Y(�+ cons� nt �R ious�y [28] ,1�mai!R(localized atplasma���+5� ItA�iy gu��E:2-S�n2 4�i�X��]i|Recently , Yang et al . ( 2014 )�oraxaBzassocia". facto��NAC06a�med)IJa�:s[46a_ 0re�a�"� :�%�he��us upO he�,�� thenQes�Q., down�amaZ�.�is onE�XpAc-spec $ ( NAM!�TAF1 , �CUC2 )I[�-�;a�its.�i�-M�4 p9�.Ahow:.�5C��d� 6Pis pooaVE� stooaDInterea3gEai�Hy dynamic organellet obser� E��ri5�ER�'s a�$major sour�%ix:.^ upply .dto� u.& ��7A=i/�ib � >)AXi�m-m��lso takA@-d � �.�&� !�ply ��� 2�}m6 �� rect phys� *�"5db� ^:��ER [4� N �-� e� �4bA n� d!d P throE  d �act siteA�igher���have e�~a unique�x0 ��$cross-talk2�M7>�!�op� �a�� In�clu� �t�IvPI-�� ��>� metabol� !�>�:�.2y��"�!6�toler ��� �lin9 B�&Z�6Y]fWeU-�I�$key enzyme�>Ba� c sygha novel%]ept=:��>Xs e �he"al�)R. .� �~H @Columbia-0 ecotyp!NunlA��ed ) w��n�� 16-h � /8-h dark�;at 22°C!�urashigiZ,Skoog ( MS )�� [�at ½F�H!��( culture [4�M� eeds Dobtained�3�.�I*�Re�4( TAIRu ex%� pX [L %6c!~$Institut N�al de la 4herche Agronome�( INR�:�1� (SALK_025769��,( FLAG_506C0=,32CS879873/4 68766 ^ 4136 ! b8�Xin Wassilewskija ( Ws )]A�*�ef� back�ted E�Col]Gsix tim� o replace> T��Cgroun�1�o1��nam� )�(f� �ge!Yc�l4%�V,� 4 kb"A sequaU%����&ifaby PCR �oligo� ot��vKY101%* 2 cloA� into�,pENTR/D-TOPOA�smid ve� X( Invitrogen , Carlsbad A4to-  pYN2030� �ve hm ��|confirm�rac�dI�recombe2�HGW. tin)I �bya�!5LRj}r�[5�2�Ņi�pYN305� EU� B�Htoe40bacterium GV3!Ya�* �9WIA� Q*IJ��GUSA�� �� u�re{ (as follows:%� SfoI��> � d im� �i�stop cod�1��te-��ed�?x51]I[AV_ET3!�i% Z1a extA�� frag> �ser 5)�*x �66islry1�G�*h lt�QE45c5�!Y�)� t0Venus fluores�V~�b!4�a tripleG1Z�)4!AX)��n=< $7��DA�AZF e�FFFAll2V匑h cree�on��e�p�!@ hygromyciwL� extr�AYcoma< � acid��Ma�&�!H very��F a*�[52� Brief� sampl�&�yin 10 v esU�sMHnt ( ice-cold chlor�,:methanol:co�0ed HCl = 100:��k!�A�rifuge�Isupernat! sepa�remai%Lp*�re- ��z4z�>~�c!G�2�. Two2f-�-��4��2.z�6 N%Ix�6��A�upp� h�J� remoG �,low2washed 3R{2�!As9�N�.�= 3:48:4!� , dr���disE�JE = 2:1E�stora� t -80� A4�I4P ,,P/PI5  ( �� P�tP3 ,levels� quant�:�3]��us�DDionex Ion Chromat�$phy 3000 (!$, Sunnyval� CA , US].6�-�deacylaAib�cub�yw�!O5 mLthylamin��(t [MeOH/40% ,in water/1-b� ol/!,7:36:9:8 ) ] 5%Sa� 45 m�E�k aqueY<)�,�s�%��of opet] um e� /�fme� :40:�!�yi twic/an equalM�` �. A � 81GE^B� 5Xsubjec!i(to anion-ex]ge9 -per" � liqu�6�on�,6,61 ,-405:'4S480v���p phyII autA�o}c�"488.CLP 65=(. Total RNA�5isox 2-week:k��6�� RNeasy�� i ki�Qi� 0 , Dusseldorf2i acco�#�manufac!�’�& struT"4. RNase-free D  (�b��durѨonUumn di�)a�� "�DNAA�t` .� �, t5:66��fK�59E%'M��becc(T�"y�es� N d� op�G [54]!� he c��#� �S�S�(III First-S�V d SyS(S,r q�Am�a� tempA3i��"�'. Acti� ACTb(�� � ^ re l�!T S1 Tabl�n�7J� TRI�'gWAmb!� , Auu , TX�i�'%Idt�%t��������."zA� � A�47500 Real Time[5� Appl�Bio� �Fos� c�(,6�E{omp:�th �cy�(( %�4od�%�to� �-�rel amoun�&? q)��o�*6D%CT Vwn"���[2�� mean�&� aPie�m�* ���e tech D)pl �Th��biolog� l�&�'.��:� simi� Y Qq setiOI ^ ��.���ssuQ6!�\�7 !="� ,world occurs ,*! ,��li9emerg� of macro-Jc.� chal-/!��'d��istdump����6oy��aa�nc��5*def!measur�ins��3-eQ+p�–P+� .. ( Φ�$P,r%,>�iso,  "�" a �-"0to “beat”%$.@ . Si�6M`evalu�PΦ !Iss di� �� spatl'�e�Yor_cal�'y NatMp�&�"ng all� black boxM��(AC%� e���at Esewl or mg �+�F upd�%. CB�e��ba� �% inpu](nd out ? .�, igno��!�r� :�%��or�'i6 put- [ "�,E�A�%j+� can �"%commoa<�.��%�cor�!�0:�yvea� -2E��-or�(m�(�� join)��1�#�!��) appaE,� ui�. A �A�-�,����erA���& XAci e�by!An% �(B�on@'Aa�0%�!%ed4gx!4We �%%�C,e1a given � �,E�!�Fy l� aximaAWyis�.aRago>a�frameb3'm�e���������)Boolea�.�3model�fi�0-�1�1-�+ �wh�4we�st�2�*� cour�!�sZ-d.�]��,2LY��ЉEJ� *(iz�Bat �M�t����r]4ti�f�h)�sAto focuYaO&o1 natu!� vantage pe�&ss4�)inquirc. ��taroache0 2ce usua��II!�opt 1�G�51�a>�Ame��st�a����oar� .LsE� seen�conven� pproA��� �*l�4 �3��p )�!����+Yg1e�sy � 8ѿ8 , ra&,=e@l 8[1�15 , 1a/Inspi� �s 5 , �-i�d�!�of�9��ty{ly 9-nA�b�6��-g!�ing�� i . ��aves �@"( A R step� 2��� u "= �A>� o�#�ex� it� ŧ!*و�2=)%��.v/a�; ch c>�Dndeg3�,.�:`�I)d[17!��-n���6�s 2 g�)�!_w6u! nea�/)@<5j(�mm��[Oto#-al  &!�-�d)�th3 AG/ We d.�E�,is cer��t+ac volv de��'/o� det���6%4M� �!�.��$� !�Ng 6A��erm%cF.�Ho�8mo���>Dto����9�ofA�ercan� be&�%b�.2E� � theye~�XdQh!.�)k iI5 %�a�o��k ar� 1!�hA�� ly�}fic" Ehf ould�muddlirI!�(� Box � �M�! a1a�I~ ,��funda��al=0t.mawof 7�. C�8(%a n=OG= esen1 by�6=T�(C1#=arw '-)^ai� divers��of9%molecuj,� }>N%gierO;e�w�!A>3� � I�dd!.vY&�+fik � a�N mak�,jG $seem ineviH a( �s:� le�ya�>e� -�Q&����;��}sE�!��"� cA$it Ic�E�� ful4��{�8�u*�aAScll%'9�Q#���![$n exquisit�1]|ail [1H� w�0r�c*�f� by� eraw�!��xau=�>�0� 6 �[�~A[20]:��>�>�"6,�:ћO?ɛ;�n^rep!��"�0eH��� roup�&5et�Zthose>o� �� e= M���B� !���#i-aeex�3i>�irŜ!�,B�[2� "� 6  �� ����hidde�Al * 8:� ���w�&.�!,�9�2�A�a0 a5.M,H@2���b left"d, s& �q�Y��/a numbe�=U�:�(apNS��$ell body C� ,xon hillock �'e]�{#6 nJinf��. Or7�'�A�5�S)1� ngle6�=�@a,- ceiv�z( spike� no aV eachI�p+ �8 �"le[R@�>n�C nceaCCts>:M6.�6w��/_ e�  mB�� .e i2N)by� � `c8>_ s"�<�9 [2�)2�Wh��*R m �s c �E� �2�reA��:yqE�:5,�/a�=2A� ly–a� tb�"nf� �a�:{�rs���newq9&Y� . SI j��C�� Q'��o� llv�툭�,4�B<�onship?CpF�Bs%]�wE� �&;>)is� come�a2����y$fuf�� �s!n!�)�%�)!�l���"e )M��(C�v%Ao�!�c�er�l*V7 �_ ^*�Qorq?Y�G� :bo��UE�iY_s"a!���Y A��E���c�sa�]:� �=a'Y����f� f �2U iaA��ta�3�Ccy ) ;�NU�J-�i�)!!u} ( &�;��!�wh�A9]��r�Jo=o��Z ��!�!��;%� ��D���!b��= ( ��dse fe�6ke�q8H� u�I�剅�_��:e�J�,�EI1P��F���$�.:�*=(� A��J����I�q��Φ E�)�_ �aq6#s" in��wAgo���z�r>`%�)�lL-to�9at ��s . In' usag� .�ia oJ.!�o��� ŒiP.�����s ��]�At%��}a�`availnEinaZE�. �9 our purpo�w‘9a���6 �f ��� b� nipu�"��* �E�� �F~QU�w ead�a+, Fa6��:4*S(&_ T�l�:� gmust �sfyE��AF/� s: S�Ձ: Tog�<� e<r)r�s�1�B� PC��� !1�x� B~W "A�%�)}� ise�DGH �.:L�A-AC��} � t�OaIdN!�#�rawE4��A*a1<�e�-� z��ny%�lap�  /%�% Fig�CV S3 TM9!�O`F���2�of�I,_+b"��q�E_&���r��fin#:�NJk. A � �sA�a.� um iťre%�n+!�neighb�!O�wJ a1er�Φ��� :���!etV�327X!��� �e*nU!)k�!�`^!Hby �"[ 2�A�k DP>S�AdeGei�*ng� N/ \-Y2��!�H whi�two5Ha�2G":�����sbI�3|sI �e{: ���2� �kw�O�#%)T'i&( Q����KR�re�A��#gg3�%a@^ E�)}&Ai�ce&�D=D7 ;&\2���#�Tbe!� ed /)���S*# ��o)h>E����. G= s"� ��1ac"� >��#E�8 up�& A���- . Fi���H~C �F��&art�k �ge>\% �m4 �utAj� �!um matc�9B�|[3X��esA�i��e>=�)>-�+,�C!��!D� n1�I� su�1!:�,9�=cy).�+?8 to 1V!�IrF��,2G:S�yMM�����asexactl� � �")1n!�G�#a�(�%::X&@&q�|q�0.f�4� 2#:��,�')�E�:#V � e�JE�I*GM N9%e(ZRU2 E*  al.-f#6 � 9^Q�k :�VsT�},i �(yC6�u2� �����.!��'82fJsA�)�R2�)* 2�E<-� . No%`atK ll>q�%,��*�} �Pa���zf&z: IU y�1%�a&2�a�I~�-h0 ��wh##ac= QJK��7�^G2wI�held fi�Vac-G&, !ha)�-ca�e.�  Awtu�Y�-a inm��!M��N$%preP!��a<on delavx&+.%�.YMM`of��17�^A~6,�'��"Wf)l�<�-�*E"�a2�ahDr* A3pm� f��o>,.�5�A���of*E � A�� , NOR ��*I�"�B$“un al�QVenZXa(A���� � built�Mi��r� �&e*Z 6�Ran XOR*>8Z| E�.o6���U���! %ircui�Q-,&�9wA� =ly�)eBi�P(ED-) COPY1�� �+�Emt�?M�� same� Y g 3�i��4?)*Q/' one-�B��� long *UN� OEa��]!�)�. C� "Pv� Z*�+6 U� an�. A,GS�� �FE�2�n� )#k—�K%�a���� Q����A�?I �4!GAm� 6�����\&My � �!�ll��OFF!X��%�.9/2 �-> TX�DIb$)� -�2�)ogF � @!D1f�eYPI2 φ =H=5:0 beӍF�), FX J�+�_��!�e5s�� �\)(K,)a� ( ONN^=- Kim� !9E�, ^beH �fuem�a'top-r�| All��n OdoD�2��@"�&W , so11Y;�9sbr)�M�&O7apecG(a�� ��h /0BI5�pa&-nd�&�yѱ=��LA �Method� I.u�,� ���B�#a��Jpot)al�w-� �vGa)�bAelf does%���-�I~�gtsE~I aE6 :�_L ly lik����ONAlA�FA���Yoa�I� II�)topEC %h!�� 6�1X6�i(����HaM-xA�.�6 )XE.a%si1t�xAha�wn.i"-E�!�5a �h"�t5�%�E�)I6�:P!� ��6���:�alreadO'%�h4B�f,p�nV!/2���VAGbottomEJ�/eJ� C9�!k./r1�.OthuO �3!�6��r-�A��AA��&>��2E)u� oi*x�I���- .%�!�Φ�A25�f�;����` �)>A�?���q�soU,��*�2ٶ>3f�)2�7);byY�}� B� !@j�� a!2BeW 0��-J�@re� m�Ńbl2M.@R6,���u�. niu27m�qm���5I��8N � �2�%ira>[� )ad�B.��7?wqBI�d6`e#>i>���� "!x@Ѽz e,� �0&� ,&� �ll��S]A(6%&� )a"7mB�7%�-B jE�aK = K875�*3iq�b/AQ�*�6x8"φ ^)"b�E ���B�.j m�x�EZ8�,"T "��$a�!jcr�(^7%2-'�_)2� 9h���“win�#:�8j��J��9*Jr!�EF�N�-o�:f56.��Oi\s�$��!+>"jB�e� �z.],I'��"��2� AUe�U4H ea��BV 2�-�� �>irx&� eR�6 &< �out�A�UY+�{M�)���wei;sn(+9�J� [9j _U &Q>[�;soV�kX_��(-2�mZ��Rks2�2�e �"'e�D.� �>7��(AA�%�U��(>�6 es r�{ 2CI�V I(%..?<al 21&8 6 U&v4s�&�1oup!�11��A�N"��&a>�,�a�,� ", AND/7�MAJORITY-,A�/BP%%��55-m81�O$ rran'.Wf�7e&�`��.����"1A�".'I 6O%�A�-Jex7p.PB&x2n � Each}f2�re6�-6 I������"1!�I �fN2<T G7@/ WZ "R աeI!�Iy���55E�� ��NB&llo%E�f�9e !Q2��" `-pm�X82)�* {>{of���u}�ei�FI�.*fZ.U�0E��lR�2�7�op rowWde�2h! �0.I8�;)ir.pM&-���a��0�M��"��*e nL _�@]F���had��>�Tw�a,6OH�ei�:�;��3jJa^!� E�Z�Q�’�)u&�*U2��`l�55G BG �B�2E�I=-� �"�239A�1��&z��\ B�j?�#>�is1". 453J�� %X�M�5�Y�%pg?s/gJN2 .�W6�[�8 )�R20 n1�s156 AND��nd :.� wA�V�S�I�N%"e���+R��m"� 20^�Y5�54� )k0b��-U112.a�isW��_om64�J�"a��*� "S s*!FlaN� "< E*m�!(no� ]�:� i� ..�i� 5.�6�� TB�b� P q�� a�J(!xval�X�?�S127>^MM�fv-�to Z�A �r ��0��. 0�Q!�mp5�i1�W���Pp�5��"|?d � �gQ��-_  �}g A  f�-2� Co)Nf�IiSw*n���#.m�* a )yal��� f�9V��T�;A�V/I61�φ!�!�216B��z023-�:� �2.�BE�)-�: nd&{�.o�%r�"� �p�)(rd� !�t� }� "�R".b��sdZof 31nN �Gw4 bA%J u��!�33 4f�= 7P�s N-i�^!�O"�&s*�46-n�X57ўy)ORYje�}���\�� U�b-OM&)��[B$�V66�10=�_^�5r1AD.�,"� �D�GY� �!�n�a�Z&r,",  $no���"#+� � a `�6�1$� �-!_61 �� ��5:}��� z� �M ]*[i|�9u�w):�a�=e�sumŀj�'�B+L �p:$5%�%�,,tUB!�6�� E�"�#dy�� Q1s�j�9)d���e&�>K��S&�&w1};���R5�%��.� >� (�%6�siz6�>�^6 a$%�r�ht���(fa����g�7�l$!zn" 6�f͐f���j�, ao���y<FB2#9�wEL. �i�a�M�"�i�3Z�S���gl�!6�&2t�CofI�6@� ��!�y7)�;�:y���.Na�in@F$Dtmaw!&nPi �Z8FAP[3�|� ��pE@%X<�z�')Y "jE��a�`|6~>>i��P�8:�W.HMe&� s�_a2s*X4 ,E�t%d"a H�wF4�*16�$e"exc�aory ( +�A�H& �~in(4e� 8 A�@e� ,0SK!7� �-�)��*!Eno feedA+� ��l���)c��st 2H�E� t��lv�<wq�" �"n%@MEpatt��y;m &�k%H�s�:*x��r of 9I 6 eF WQreturJ-J6� >z�%UB�D5�;�G����" he �9"ZY c^2!�QI9"�=��52M��@�iM��M�?!�-U� ��W,#hY SK&.�" �+ U LnT�6{6"j SKP necessari�q� �"&��/8wA)SKA "�-a.�td#iaW&w� �%�,���&& [FS mX,�7w��V!bU�=SK�'��~�g%�CM-0J��PseeYKi � (*�*$)J� (�5� ��cq�q�!��qM� izes%̙�%�out.E �!��<�Fos9 fR:��)i��;�%  t�I?/a�0�a�wAfe>cw�6o� i� stro~�8.qMe� �� ��\�(� "\)�nd>�u�:3Z( t/ t3-t�x 6�[%�-� �ub;PreT!>* 2�IF6)`2��B�Åz JB�QwE�QK* �5*� .z� s�$,{�%�eR�[�:B1"���Ł�I:� � ���� &�M��/ &;ub�* 2m!oP/�,��TAn�+�1u�N�f:��A9!E &�5� u.�> n!��t2�x�-SJ�i�-� � y�,��i]of �k֌4-9(DNanime��2� .�]aeA�j �8TSY 4140�1�%Oi�:��^��&�#9 . ,orS n-�"e."� 10*I J�7����)]-�wT.� !� f&�.\��W�!a �� 2�&176-��^%OE�z{#AN|EV�g� A�N�R - 2224:Y��Φ�:��52AT78�- e��r nDlyR 22%&2�� . Am�1�Bv:u.@\33}Q��2�( sdH� W du3��du%Asymmetn[M[q�M�2R 2eA��<�Z,k %�dj2 . 5A5!8)!%��N�.55)B~���!W��e -|����%I#Iqu�(ki�dg�G��cof�� holdF � ��a��9�`&[ �ra)Q�� 9R�^�8Za}T�3�A��A���eUtB4�)7&� ��.*e9�r�)K"�%�n/�# �!��#�.ss ũ� t �bXr�VX0!syF^M�e���!���.eCj$:��9)e2��"���H�� .� �Y �.b.v u2�$6Z��quqEJR(#Q*<n��� E�ɓha./&� inS'VtwSlp.凵�����XSv�TN !Z�2��\�!pd�OwQKili� ��D aAE�x��6:|*� pro4 !�!�"� —N8ert\,�#Wsb"qa�-� �I���Ni9[3�[IW .�@ �@r� >r��[�II[,%*� "�C���Ia %�N�Ř�RtjDM"�:>8�� To%� �7mPnoR�a#&�;G`�U!�1ir5,�I�Tref�U�|�`�p��_ec)TNQ � �)�A��9K<ur.�T2�"n a�"�/� z;*Gd��*� m exYN�28 ,  )�Z#in�b��aGh���/=&NbA�pE�y1v�j���fr*�d/�,&hb dema~�� xha/m�U*pr�. Ci 6A�9/&��'� �au�hRo0z�rm�ĥN#<� )�� ;�:2�c�v�matrix28 Rv /Zy �6to��aГ�ba�a�cnd)��OEDr��pre^� 0�c� )u�st�N�4I�!A "���5e�oreain�ziF@�k� 2��be�L)���lq�M�y� *!a"#SQ� [1e�7]E�ZD6( cril�a��,gu-s�*?�.o�Pm�5?�+1n��� Als*�N)��"i hA d ( ";*�)��� ,ec}�s�W�N�#( "]bz/n=�,' �j�ma�z�"LE%~ H �Bd>te2���:RA6F7fe� 5�A�a �ce� sp;�!q j�QinBmmZp R&|4='^ %9#=Wi*77�pIn*(�4�>24t�6v�X�.[ɍ(A _Vn a;>erN!:�K%�e�s55%k686i�RJnw:L3NWu-a� .� Yb. D2Ub �ct"RbE�wo1Bo��a�RflW�����|^��[t�Eel"�7<�.%��r6�b:��%U9 �J'�0�� ,-��&�bw *@e�.�� ):!bo-�5��s�AESC1�Jz! R nE8�X!ein� nt l� ofB$�j� �D F%aA�f�W�"� dYb lso�1�!,���"in S2uQa�e. ���2=�LA^�G[ �pF?)a�F�o�F=��AY�=�� < 2G"�.�!�� �r%�0 �E1#1�A�t),�B!,ay %dU?A�����P��a�) �9� C� �/Ɏ�'Y�!�Ar�:� G,� &�5�jd�F�$�&��vE�C�k h:!sh�~F%r �.NA�� *U /a��a��[&�(,J\�@" A� �[e4a!��?:F�VI!AR.2�&�.{R�9. B�Yaega�Nnor��Bm!�yq}=,rt2�.}�= v%�V�,[�~M:�C�Z, cut%ӥ�-P\�4ԏrM�1�Vx�.ak��A�-�mm"�6l�)BB}hk@!V~�!�!��a� �%��I��3�*�atB&�obenefic �9�'a1“! a�bttleneck�;��-�ΡtA�HՁ5p�0"m4AewuLc �i@ Y1�R9m��� *M|�!�;��� � � WkY8Ar!�N�!�d;"�# a!& weak2#kr"-qy��U-*'/Un�t!�sh�b.�lyBppMn M� lHuodu�z{KwpR�!�Rigd�]�, �as�ga5E��� q�#ޣ �gp- e[?r�6�i� �Fpu�.a*=QAr&y~ .�%��s�o�!RQ?�a$in1qE��tb&�-D"�viNJ��*0k. I~�E��-�x:��Z�eGX;#�X2�6��ve"�f^�Mĥ��n�Ysubi%a�<� �8R� W�J�wo[nf M��C-���l1����w"�^ *<)��Y���A6�&���+/a�n�aalNO�z �E�w! \b"���A �"� ? *�%��"Hy�]���\/bpe�ji !�on�FiI�'%�mA-i1Gn��Aw�)ys a��/U)len-pa� (&̍[�6�� ��N)��( nervP� �*,*�u%��l�Q , kidney�>J�c#Wq(��m�h, hum�x,�^mmE�tM�Es@ swar)] ocie"�he",* �Q"�p�zF�bi��lR�z �)��-�-��rq1�%�6�pi1�OcA O\!q" %}+A���2$& � &*f�2@�r�t1O �BY]��&f6W E��,�\e�0*D�ta",K�%>w�u��ac��E��.�ma/� " �)>i!#!�precisL � � 4next-.�!�m�KV""|ob�f� &�9�"^ B:�A�%2��i*T�� �a��EmP����&� >�`�� .�� �[œZ�EL�!���M��isD�wledgZ be C�! 5�! �a^���&�]C,2�I�b�aR��JW,udEQq� glob�oxi!m�f7mM�� d>f��"q~`�_ 6I� ;�itP–"�0J&�.LQ. A.WAV �.�tA�y!�F�T�al-"E3 �%�T9i�:I;f�&�Mz&�=u���O onsc|nes�j¨$n���` ve oxyݟ%��DRO �C� !g$mitochondr�ڂir��ch�u ( RCr��^�Ҥ��, a�ell6 adap�?� o environ�!R�@L%�de=�fx� Tdamag�)+�"�,�$hypoxia/re �- releR��q{�pic� �t�<�$�� :�� ��" !n!7in�S surv�E^�\t%Oq)�.����aU�ofV)�0�m�腶.|S�Xtz~AIr rule-��)Empl��II��=a��l%V !� �A�{ -lRʗup���t,�>�,)= memb;� S�r� &�g� 5TCA;��� AY���]���t f�!.� {nz��6�dE�r��B2I fuel�Aucc��hrpyruvA��ma�iM�a'K�Ez NAD+� �m�^ll#ct6\��i3�&%�!�h�>ZE9��a~e>�ics g�Es7���!"!?u*(#=�� 6�&\of×e C�cO �� %�b.a���P4. �o iv-I�fb�$�!CfJK/�_�%8m:�$ɖRL�� 2. o@wD>�3%��� ̥o"� U*�A�n � n�m�P�+f!� es I1a_.�_s�fA�%8!\ܖmenPb|f� t�P�b�\.�(I@ EII�m+ valid!�eu����� switea�).c0 2!!Y�52��CŌ redi/��m��!k"�&!J1)A/"�`� p� a�* ���b�%ࡈ=�in���v��nt,<LF P!�.*��t�.�pr���hm� !M��gyIaydi�e�YOS. starK]�;Q БiX-� ( O2−�A?�.��4�1�C{arm�%�6�,�g . se?�i�G( Q e: O2+ →y +Q [���5��em -�ADea�b��6Ac��Y���dis]� se [�y&_` H2O2%!���$��n1I� aw��e ISeE_. %C`-[b�c Ԇ–r�.�,w relhņ<�s�L�s��}���sZ�,�!O: ӯf&.* �ad� *[ ��J�� re+7HA��y! blS~- I�*7 #�a�A�Ca.l �d�s�Parkin5di� [8]Ddiabe��[�}�pr ��d��|$n�."�disru(~� RaA�d� � �� life�0[10~�"mUJG!c< a�]J�$(![fzL�ens �J^� ,*� d^ `�D�*��s��;2�6"u'deb�or2(��Pv�7��$ofu$si!z-6.c I���Bll>�͇[12)��.� ta6�i��7�[1"�@+������!!�~ �`�:g�y�Q2h%4 normfRE$:%&9��x��ivo!_!yԸ��is��pacѯlA�J� toV �_ �DK�ak?aAJ^[1 ��-G�#5�!hA�:,[1-�[_��c!�2R :8:s6�2 up��a"�]FM�/%�Q�S�2Q�M�g�RX<#6q� �t8��&�  I�q��k�;�  loc 9�0H<�Ѧ)� !V�l82ub4��B�{e� �'�s n��r�1]���discus�<[1��[1o�Answer���qu�S�xhel�m-aa�� �"�'l� " �Z��abl�efuϦ adva�IJs�y�P�apQ���"��Fv���A�q�0AF,im$ �(i�=U�al���fnew�) [�I�0mod�S5�m�b. R� .>�8 kineעk!x��n�$n�i���5cZ&�1v� �!���W��b adopA ��� ��l.:��%�?I�� VmPň$�i"� |*� &� aI.��EN��i�+W� +9]ACìo:)� �TFd "�֎�Hug.�N"a��'-@n?�Ud�j�be!or�2n� �s������� oced{i[*Ez)��?D oC�<l+��ed�3*�%�I�![!$aut r!t�<R�karQ1 � Z�J.�$13C isotop��}&k ��&� flux>v�� E�W�SJ .�\���O0)u"` �#e��2k���VSor�WO"\a Q�>����AYk:� }J�Qo<�x5��1� �W!�param� �v!�.�6�*&�*5��Na5d�=ex�2!�Jsk+n�� �h�Co+ �7�*pe���FSZ>��ertur1��Z�Wa��ctuqBne ��'n��e=�YY anM �E��5/�,igh* ���/y�t���aG�1�!� 3o JMi'!�k� af�!�� ��!�of2�1~j�h��Y��>�F�W.t �2q {��!�u�2�zAA���)lI���0b'� �-�^OM��Va[+Z!7� V�6e� ј.�m���-�!�lup��f�B!��:C�� �3j^n;Jstoichio�<)L &K %M� "� D+B [�"�"�\4�leak; �gX��or��io E&��o� es� H�&#9�]M.by�!D�+ AUg��AI���� E�}H!�A a�L)�B�B�a��rG}tooF�Phea;ic2�lFf,���a�:� a8� =A.�U��V#T��a7O � )9*�� aim�-�:T%���  "C�#V a�*#*3>E��9e�N��:U`�6-RF<��g:� . 6.�s� he"�ms�f^i�bh^M U�]�Y���)z!��51!��U�E�22..� �\nj5�4N��g�}/fe"�L� midJ�u�d ��o͢ gnit��a{!):[�Jf��*6�0�9����S�������A ;l�La��.��U��haad.�cyVr8bH*�!�"� �.1c1�a[=,A�W /vin*1Sf���s,F1,�wA SnCͪs�K(vA�!GN^��/d�����:�u&MV )F!�!�5 q*BM��~#ADP�7� �����2�;L �)!paB4E$B ~ abs��.o&tis<��s ���&glr�m� ,%��G"ompensIVޱ�Q:� �e��a���Jj�.֑�A�6���$dehyd3)"�bYW��� !�u)m�9�:jaVE�!�!��NADH �v�nu_ �G2� -=Y?�������� o?)2�*� ��C�� \*�IA[&( R�m%�li���o!�-�s�7q5 ~!>Q�!?1�9�� ?"a�Fs�f2�@� kep�"x�f�*  Q��|vpermeV ��:r��g{�#rd��M�������� Gfit���%Q�Mhan�� =E�MdJi �lJ�] �Z&Fminim adev�!�"�/c�ioDoQd6�. M P7� `%.��!պ]chaA�= ��'>of.�23�in"q IRb'�fi��"d@���E�N6���%,J�$ ��AB*�� �lZ�|e�� n1i�h 3����ź�Ix ΔΨ-f��%seA�� "�$�"�Bl�/�H:�r2�Wi$�t����%5U��L� �H����U&�2 E���R��,�#s���;�( ne|BveoD�a�HaQrtA�ioϙ[9�B.a�s� �"�?Z�" �aɢ."IV��24ZR%$*�&%!�1 elieҊ�1nA � �� ~�ke��p��B�I��X�*��d�Not�$n�H�\�A:Hy��� �3�.�%MUl'��xid�!�Rv� N, �slowl] �eAU�A�,���aul�s�n�Ғ��s� l>vQ����goc��:^&.�of��&��p� � �e.%}6c�.6�& .k*&. �Y�of h} ��" �&> A)��3!~�ՅZ %jBF$`�6���Œ& be��LaMU�C(e*�&i��Vi�� R���2��.,,!rb��aminoe�aR�X7�!A��@.�Af��m{���ch>}dide\[�� ��&V���5ad ;9�3tA|�� �!�VUy����? �dsR��}p � � 2N�)A8r2th_�u�of�-Mt&�.E*� ���!"A)��i��. ��ba�7 .1�re��] ��h"�1&��Sd^��9T �B- w adju� A��"�i&���4t �y�!�Q Qm *�"{*��. �.�@ڙ�,Ed.� 2�&�^=� l�I� .� � � /�-�[�0 ��t!�.�oM ^ p����"g97(�# J"E�dZ~�D�P���.y�y*� I�ŕT}6�kcs�&^ r5eZ`iPn�r�Mo 5��� eJ*Y.&L$h2�>� � LM�*/:*W)a�ia)�AM.�*A�E���U1�!f$� , �.E� )+�6;�\�-#�.�* : ( SQ`+iQos&!�"@ II [26O8]� FMNH�I,>bo[�A$ [3?�or N2���2�`�YV� �"+�t1��)I��i� �E�h M�whe2L� 6;E> Kd[s&/(�%`2� ��j ͇ ��F��Y4 �o# onN>�Q-�*h"b_6�� aQp�� ng u>�0e�R�o-**�,_����&�A�)�r�i�/*?to/I�'� un�A;" clar��@��6ou�qB�!��Pw6**�/P I!?E2V AA ����!� �)�}^������:.��. �OQ_�#8_n�uApliF~It�*g�a? %N�/h*J�jaG�w&dA:n�>�J�` �J�Ua.����a�m&j2� �"� �D3"-E-顇m�SQ9���Qo�m� ��N�2Ui �/�#unI"=cRq ��)�i�'N.-�E���e;� =.B�Ma�E)��Da��*�a�aQ.Q�co�1d�*valiSQ�Q��g#sq�#"D����wzи� ROS-�� ng 68jx)e;M%�Ja�5�&� 8#vɑe�-.�.��D�GCB��!�Ehfec(��  ��>%$f:c��ass��.`!+V��e*��y�� �wSQ�Poj� te Q����3� ,�Y�m �J�Y�� �� ��(�� �� i�� �0�of�!���-8!g&gre|I�!J".D�A�=���m8 i��MS .��yfa 2qF��;ccn�m\�&\:�.Kt�2@�"+!� 6�&A%�:���$�Y�1fs>?� ��-4~*�*e���"i&!�(n �n �–�� "�ejYn a���.~T�0B� �59�di� curv@Y�!�A��&�Ino���N�2�e/al�L"��.��ewA�sY��Wed��Ua��!�(!��AM�>�)O-JM|�� 9�..� ����u�+A(oS'!m�.z"<-� ;a=J� is�Mj�fac�`�er .� ��%�7(m�M��/- H5R��$Ϗ�An��B f�n�2!�n$�CO�110100!po�4�Sg�&���Qp-(n-Qn-N2-FMNlg � �SQ%-�� �A !�A,�e-�mm!d.�m�/ l�.�.r�F���(�.6I]qin�Qn-n O���&P�e]�o�MeY�!�%�?5)�!rZr%55�F� TQxWN<��Y _=��%�0i�:.�pK AhA�Db�a�Fi�+W }/*s~,Q�c4  A����� %_a-(��e�:� .�<ie&цu��-e Iensem�P��2�>����9����iV ��}[ . O�6B��:�e:,&� hardA�ssAR-�.��&`2��cTk gu��9LXM� EB�-_��O(�*b� X�:N'�� a�1En i�*@.�:y�'�!�2"�� �1�� F�"[ �+1j�u"y$�RG"3 4&3 em=��7s�|8��Qv"�!�J)$9ܥ:a���t� �ω 1�>52�4@ !O~ �<dise-�!"@ :�*�"� &ぁ�&� a̙�_?OSM�a#ɻ ��3�B>E 2i(�����\3P0l���TE�@�(A!&� .R s now-� e�,j�R)Q� �4Q��5�5��5es��eE���o� "� 2Pel��2� )�54M 1��R�& �H&�!!�8�8�N2p \. SQ��W5 'So.�%7�=X"�(>�( FCCP��"� R8i�E}�$9�:%u`5q`2);�*\8Na~ �՛-All:5:r J� -8N y&Z�{DPB!A"`+oIjcE?���_!��a[�*5@6)@�m��)n12E5��< �8-9�55m\9@6Zu�tAt�NYA�\�� J1�,more ROS tha�yn those fueled by pyruvate ( Figure 7A ) . The model also predicts higher levels of free radicals in complex III , as well.H , for mitochondria�succin6�B �4us , the study��associations between measured ROS production and predicted � ϐin RC revealed qualitative consistenct _Lments with all types� Xs o�rep�e!HeJ�deasba�bove . W!�increa inby!�o!�oinI0system switchso�%��h�Lst�~4of semiquinone�Dt!�a�#.�I�1�ceI� from oimilara�vaQR7!�e[��isava�� addi�yto�. Od!� �is�d+A���6�Qo�ht remainAT thG7��if I�6�de)�s backwlowQ�!�!E)�2�i�Y� z�Sy���)�i-a*�Z��Faccorda!.�9 blueB�8B�� �Z�un�b? untibs5:!4�micromoA"rek . Si�.cis direc��connec��o%$ through amoa(bsa�VubU�)-fF��e���s )ility!��2� whenII �X��#D%�A�B�,:n9$" 8y,��!:�be��t��various�u�F�&8 >u� nrA oi?RC)�8proton transloc�� (membrane po�@�0( ΔΨ ) gene�KH E9�Idefin8 fitt�8 �>�o�� by9 J ly5i&� 1S d>F! � 2s [��a puls�sYIis" ed ȱ8!0� . Su� A^erintui� B)i�/ �E�q��2� ��how� V 9A �|?�l�7Tby%U F�,FV,��!�W inst�~,��5� leak!�s illu���� curveő.�MG � � �uskPsafranine O fluorescea"@ %�A" mean ;atů9�,( 0 . 2 mM )!9 grea~ than.��./ +��9��t��Mt�wparadox� Q:!�m1i>I^athresholioa���3� � -ws!do of&[ex portE�TCA rea�[s;�we do��investig��Squ*q detailsI�Apect��8�'��0emphasize onlIPq*� ���W��� nd!�8"0  regard���# �! prev��se �P normal “working”2 ���W6Q$are robustB�!')�!�-�Ű next�ń� � sensa�-simul�,⡥ inF_.�T^ S1� each!YF ٭i"� (2 ( dynamiceb NAD+IhE�, maxi!G!�Ix4%�� flu9 e2��lso l�I� �edbl>�3m$result�"dicI�� $ignificant� "��=�$hardly affE��=r( p $g . kqp_FS� EvidH� Um(restriA�h*5�ue"uy �;0unambiguously2K [ge� thesZiuM���j���goo ��M��Nerm%�.�1���=D5��ighfQ..�tA";��3 t combg�s�u)C���%�e�Uly becau�mutual[ pens"Y%\. � `d~te!r��}�)�.�an have+id%$of1��)�a)��is obta�. ConfAZcterval� � �v.��yus� charac,z ���nes%:���er"�. D&�eeA� glob�pac�/@�at�A�FG)�be �tified�our sS8astic algorithm%minimiz��!3]obj��vn�rχ��sucsquare�dev�b6 �� b�ndard.5����cN�!�=ba!�on fix!����[31���1e0!Le 99%fb!e�ki|e�s�IT+� s g!4]d�eA5 larg��T�,�tho(F-=X co��tous�n�����ope"� Fn�fV s suffici�Jto� ?mB V� E��a 6g=$a�5O �2.�� situI� u!�%�� ��.ͺ A�ed6con���-�����q�fR*�p͓uNr�%�?�U%�& Ai�� U�MQb�N�AFg� �dm��narrow�s� �M�6ml�� . Al]xi2SQc Qo!���" -$2�]re( v� I䥤yclear�� lmosoe� !{ both!1�()9orout r���*isA� ult agree�)si�� a iS2 Qo p��� rhow� � � o��� ���"^ 3B �eQ%of�.�Af��� undeG]�!Afir!w!tE� !Y very1�� sp2U��)u. >F�%��W" �&r &_m�aMZ=�B �third� (" /mal< supply�e� iEthMQE�lE��!B6�5g!�U�d V��.�II . T� nstruct a��ailed m(maEX-Se��u !� redox� �Bmed durA�electro��&�%�I�e���rule-�(methodology } utomx� ��i�g�aODE&i�zl fur gsp.e� ly �to5 �� but 13C isoto��lQ abol�([20]–[22]E�velop�!��xoccasion� co�B im"Qa2�n#� al�(pathways [3�[3&Foi��of .aOoD�ur�5� sE:ep�igh['�� ��!�� :�. Her+=�"D E\6��pOB�.lcouplI �,Y�25�f�Pwas link 6a class�d kines �6"��a��5pro���! NADH{sl �.�')�qH.�� fYfixa��L �forwardM�rs[ t�taq�u�&��,���w!�wby7ŴofRq^fl��# d�X ���� High��&��6� FN precluaP�i%�$i�mS>� �76  calcIede�"�ၡ?�l1 ��B" ���e�E�p�nI46�A� ����m%��s� G�analysi�Xa�fb��>�:� !��!�ise e� ij)�mO=�. AI�al bo"F�on2l>�can4satisfactorilyKl-��eh��.hly� � digmT  �aD4e obscu��eas�6elee�6� -dri�!:7ae�� inhibI�b: te> &� I O���uQ"& �i?*�#l#perE�#6�u9���B_. Cm$��/.s6nstituZ#!��� by�%�techniq���A�p- ful tool _3"��explanUb accu� ��!�M���(.�A�ear�o t���� � A�U���[ � 'at ei!� FMNH [29��[30$or SQ bounPQn� . ,�N2 X� I[34P[35] may,a major!�tr���o>by *"A�tissu��f, � gy dem!3$oxygen ten� [36 �7� *� �dc%corH ��%r1#m�cMJ"2~.�' � is� step!V���idEq assume an� icit��"S%@%ficD �a��)%l�mpa� �m� aken se�?t(,�rM�N H"�%�� 6y%! �w| �qgfut�~��%of�&�%coM0Q:�of��"At-e�5  "�#*�#�aB�!4�#z�{"���&6�>7A%���M!�pec%�.s��EP%Jo�(ndY"� a�V� ��B�R����oB.M$Rjq��6�B� % ��5k � � 2N&�� �"�,e�� "� 5� m�U(H".���\.A .�net����dN�F"� exist��a� limi!uo[( Y�.y#� � E� a$�).<��~II= � E)�rm]���a�wo�]adUV!�s�'sB�&��=u� s ( "['9#.%�Z)��!eof��8a�, � i�9pacaV�ATP synviM T� i �us�� � ��.3"B&!^�"H &T:��h�) .6(��M l�%.�acceptor!� rong�(��,U�Q �Z�.�6�II��**�'�%���"� :��(s��� (�a��f ' i& YAde]+eA erv�)�'ineYd6) �j�� ��D'!K&02� %!�R�.��+&��P�%fur�#.�%�d'�(:e5�g�$�ieske����.�&VQ�n�%aZ)l s cy� r� bE�n��(l��! .+ѕF����kmo�*q��a� B�i"r/� �%e H("�2�HiT�I*c*s-va" ��u *ven Q?be� , b� ng �-����(new molecul���'l-��"��=�%�A�%!-�y*�#,i�er��%�#i8�"9#�%� E/epa�/>�2�%!Rp�+of2�� ultiYly}� �r�g" 6�>deepe!+$����u�of ( �%BB!%"�sma ,z-&�/liv!s(cardiomyocy��a\������b�r,A%� nmby9>��fs�1�.�l�me�)�ũ(( MPT ) [381 2x��Q� y "�(toPa&��5�.�A�a,opuW�e�hyp�0�1�ver7 I�in? !es)- /clarifW:�0n%�re/�%e��0 phen�&0� �0find appropri�.�� 2!f1͐$of knowleduFe���Ue=}N�p�9V2}%ux%C])recir�dR'nI�of unZrUSe��,>,���"�B�Iwe�B�!e �OiF 24!3N edes%�,y9qw1)h natural2f!��Mi<"� \  ed yet&l venu�m�&�&!$� ��m!YߡFi.p 6<.N�"�"du� ! appl�$ u noven"�� ��la}4a'D.�d1pRf�!9e5j�.�,��3b� E���, 4a��+to��a4�"f%'4s�5W�:� q�wil7�2teG9� outc��cademD"��(ca"*. !�%Ho��II-/H2elsew� s4!�u�!���!�:^ Y=.��m�D,�3�( Kf )e�`� ( Kr ) ya�,��!K8()�or�A)agnitud) Kf�set!��3n [19]qt�/Kr"d5mn$av0scr%in) ?+mid�o�fch!o�"1�ay� R��se@l�Q�r�&p *o!c�9Yin�)R��). Tb2�#mariz�3�[!��A -t�K&fA�.eV���e ~-\veral": catalyA5���&] of#HL�E�a *4� e�� pumpa�4��t��$neg�8�op v�)�� : ( c10 )"�1E��.�invol6--�w/��a�i��med��s6��Y��Z2 inne6-:���/)X��!2 )c�<2c�+e�A�3Y�)�%7�� (��e5!�!3eSru)|a0�Y f�8�*U�8N�%���! of Q� %�," 7� )T�5��8%i�.xl:�( >re�e>6 �ss> a�s�9�eW8[ 5�l� is0 passQ�r.�!���09�,aMi�4#at� ep�!�5lp<ca�0:,�-suggesB1 ( see"|+ [17]3W�!��)�մ��aki 3>�!��8ed stoichiometr�;)a=\ia�# a�h!DE,�-i9�e�i�neV!N2a��:ce2J , N2-FMN--jreferaba�Xr��i�Fof�9z)% ��Qe�]e�!^ePћNf]�cmatrixA cytosoa�\l"q��hof�y[.YaA��n�,!w>�10B�!vid�"��s� d.U/legeng.It�#!n�z %�& (6�� aAnd�396�� Ax�sa�eni��'au:R"� V>�8J� ((�+A�aq� w0!Xex��as"� .� An�t!a�� Y7E��edya� rece+6�/�.n""equ�D%#�� quir 9q�E��A;�Y�E�=Ge<7��7 a�9�\!;��i* qnpc �1�ne���6\&��p�\qf< %=60ry number 110��Xng��dec�896 �F�:o ��*N- d1179Uu%:�� A�u?O�%�AI9�.Y:%C�G=Em�   law&'. 1 )�+2���AlUc� “0tde�,�U�� “1 %�6 $E �ioa"Ρ�*�D���Df%���)O"� }(EquilibriumV �%� �O fP ��^�e#Ia��B&N� �.�2 ��1�'si}&,1�as�.!� rewritten�$42S5 )��A�zA!�B�!]Y wI�K1=mA�;� 32 !�a� 4 � @is ΔEm = − 4!�.68�&� by R�: 1A�F�L ) 1=A�2��!��'&� �n� ccup ���7A��rin� "�(im,u co�[r0)\�IK2Za�! ��Yonship" R�aU J,d6uI!4����EI�6� 41 �@� A , eq:�cbe B9Y�at pH-�7 E^FMN−/)�) Ml* �E�9N22��r .TcEq�:ZQnA���Yh(-U@�by QH2�apx(Q:21� 2a )e �Z����.% Q−��vh ��ve��"Ha#��2�p-! mbNm.�� ym�:@deH �n-g .�X&*.a� /� �)��di�ǝ8!hr&� ngn 5�N +B�d��fo���F� "� .(-�to�or+ ��(5A��9Yq�(of ∼12 Å�U�6Zr!yn�r30.r���r!:V -< Nb��18M.mak[P@.� X�*!�:�>,��\(m0���to "� �"CyQ �4p �.�fulfill�e��Ba��b�A��e�lAs*# �IG!!W])wou���"�ADe group�og"gOs�I� su� ) O(� .�/ �Io� �Vi%�&#+2�Qn\+"�P�¹)�is*z�!0 '%p0|��o >45�M�JCDi"�/�H2�F�t>%[�Rg�� SQpA:� )��ofa"v"S <6 !DDv 5x�  Bed:L���� �,9|A���i�. Ɏ����� �..�.��-� ��^��: 4 .t!5�(i9a�:�Z�l��)��6�^ ��6�S �&�3bj#sM+ ��*{�� �/i�Cf�%���1�or�Q�r9h!~��!�jJ � "�-'$ kf/kr . 5>KN2ȡ%(�04�u�t.�� I%.M � �F�2ul�2��9D ,� >.VV�.>��)<�� !�d:� � r�aB�2P5hj>�q 6 ) R< h3!]�K�9%,s5�fN�� In!� Qi�@)�Z�8^N &Sas�:<at2Tin%�1�� ��63�G!A���med�e���6� 7�+H29�?"Q%)-Lc(!1M,,�-1�8 ) A.Ue7!i�Q:%W*>��2��� �su�!�8�!�WA�parti�&"�9�6?��Hy2�5~!"�",/�a�l.p �iO(�) epr��$t�JF$ a�R�|>�*m�&h-29�Zitu%5[@fic� {F��#l(I��cogniz� !>im aQ�suNG�le�H�s�[5��4,Iit�.A 5��lep{2 *mj�&&t A,E@�+�E�y-L!)�)��Hk>+ՈŦ�\� �!.wZ9�"L wo P()�$!$^6� ,8D- "R"�A�ip" all 400�oxSm�J�:�� �.T�vc mhqinNZ�G"s{�7$;i2"�Qm* lexi�OX*�A�(cZP� ��ASt.P ��ABI,$Ath�=2��� �~�;s�J:�%�U� ��Mariq )Lg� &of H+A��M��%1ric&7Y:a�M'�ZA0UpIٽJ�N , �` ���D�nej(S5ͰA��%*%S)f] �IMCվ,&XJi��&ed�c�1H��2�5�w�A2B2��刑��& ( v3�� &3:2��&^)���H ( vO�>� V>�� �;"up�9.�>Q!�[����Eq� >;3x .q*'1( vlk�6�5( vsyn"* eturR"9 _I1 kk[9o:Tis b]�1&+mx0H�q�$��5��r]�u)he*_� Q��i�n�mI�to*y!�j�a!A;�:QA?=��/ S}�&.q�]� ]��u!�i�A��R�'^�.N�:�q~�v3�� Lj�DSA�%Jf��AyqGt�P�ES 5�e\)J7=!#��1� �q � o)��&(U%_ !(, M�ic9 �i-�� �)a:�6 ( Ho\Hi:.PY)�AG"� fB� a�5�!� �� �Fb�^bi , V Vii�he bu�a c}9�vol!.��u%�*i:8cellu�(�w�E*�V.�/�� Wi�L&( 2��.)�2Z� ce ( ψ )ar�*�L PZ'�s-�2^qm'5pl�by�+oe�Ou�Ifo�!E}�%AU�-�"L.�QX��b/Fa�Farada"�4( 96000 cu/mol�g$96·10−4n7�I95��J*<#( 2? F/mg!!ei!~&mpu�".*[44�4SubrZX �Pd, i .�*A &�9��">in* �N*')A���Iear2��1� � =H]���� a?-23s%�f_8sa�4!$u*sh� true�%^Pe� ~ �=hypercLc2�Of enzy�c..�a:�5 &�*ed7!c�>dzo� hA�!|;�(r �A 'avoidA� h unfavor�1syA���en chooF ina*7Km�Y@ fic�7in�V5=�x�TAJ�i9C �%�u�L7|g?��h1��&�Crr!ce?uWA��+inAW Bab�HA��7���N� y�k�-� e�Gto ace�cco%�e A�Tm CiI� SyntT �W!�A�a#"�?m�ety�G_ ,A-*��A→��:��%in]K���1�ͮ�nv! ng c ���e�jo�'"L,� -�{��A��1 ��a�1� a�H�d o�2 [ fuma�J�de�'gen� \E�A& es Q�\ �5��e���. RA� -/0 N�M*e a�onUdr Elev�m ,by [45] ( 6 �����&S56�U�V��(� %/A����� �i}?XJ4xce�A�5Vna�@�2%<��lum:N+�co�7��&!veU�����!a � � ��b j �qIphosphat� :� M �Z��A#s���Sp �to oxaloa�� )LA�a<1��Ma� mp`-E�u�VG�v :�!����eL*b; e� sol8>!Qd�X2 ^w5ed& ��v!X!��T�� o� uw�&(%j1o6 � �� m�V�umd"� QNolua��!ha��W�:�L�B9�)\?2y ��adu�(Bmp: (�� ��d-.�a�!�u�* o�3n�"�E�b� �&�!���;�yi�) ��O TCA�4. �4� as CNADm# t−���� � Y o� ��� ec� 8h:a�sJ��In-, �b�(vmV"���1E�switch�:u�T�$.)H& ��9�modul%n�4 s 11.�. A)bA��d&.� wH .I.) M �-�%6 �Ea�B��}A�E]�"�C%�H �*'?is�B��e�#P �<|m �)'e ��jK� 6lin&�AI��9"` �:�=byNE�6/Wr�q9H��eN1�� r�Vd�q��Nai�22^, ) + ( 18−��+11m5=��  2�,O#!�c�1!�ndA'�esn 1�sl 'T�-aVsix.W.��ndOn^$E8i��h"#�e�F�-o� p&��h : dχ�+*�c��cN,G!].T "�Bw6�^,4*, w�Q%a�, #���oB�_^`)^R�E!��%dIM��!~A y<mad,f"�� s:Eh =�e�urbQ�L_ordin�  � rep�lAousandsr 0sa_Enb��:��8z�%programA�I�9::�1Y0!�,� ! b���b(a�4 Xnimf1%+sB�O,:i��eT)��z, HEPESP ( pH adju�@to�#3)ZKOHEb�D1 mg/ml fatty acid�PBS}1xtetrapot~^um EDTA%r$12% Percol�� �a}t�M��*�are~<lay�z� ZtoWa'�inu�g�!�g( 24%}42%z�!2��-U��%�$%�t�a ifug!�0t 16 , 000×ge 10!� Afr�1�A��2EZ���2�A���6 withdrawna, a sy�b�was@ E�=twi�.y pelle�3in E4 �/ �.��ws�WAm�dil4A�E�-1IQ�A�"� aC �1r�3X@%-! 2�!�E'(QdMnd"TSalbum�m pun dow�+1�^�deposiE.��M~ql�I�a�KaD;B�∼�3ga�toATon !r�xnm)g�FG e2�lA�p��!BWHU�a7JLAssay kit ( Pierce C�HCOy�L$ockford IL!M17!��manufac�F'��-i�. M.pe� is� �A��lor!8�(t 5–6 hou39a��p ir aL#�Pai�A�tg�*e"-3.6 k iz6"F�mFl*�t A=�u& K8 stir�cuvet�]:6 � a Sh�1$zu RF-5301� troVui�J ĉ37°C>EI�2�>;L in��4@d�Q\45 m��a)basic�u� �HuZ;a� -��1�� KCl;g$M KH2 PO 4 MgCl2;��M Tris;��M����)� &(0 µM EGTA;E�Vj� (��A��(&� X_on�C�W.� �7eRSHG1 mkMF l=�v( P�9 a(-�Oexc�\on/emi�D wavelengths 365 n�5slit  ) /46310 Q &�rTo�\"QQ�uIW�Xlib ��w�� �G5 � ~o2Wcommer%5. H�?�^pe�Ad U��:A�B�Z��%��$=Q d up� "�Ito� oruf��.�� 1 U��4of horseradish�� ( HR!�a�U,ol� [15hM.4E� carrK��7z�of 56%�()�i/nm!�59.%��:�Ae�%q H2O2�"�6$a�&�5I�'>�s-��;\:�-ZUinu��Qto�3��.��h!c:0!22�6�CiJHw[Ca@�I�2Qquench��e�Lionic dy� f"ez. �. pola�N:�Yhat"D91g�#,�1%" d6�W.�z�&X�xE�-�;!Y"��2��aK1��� o^��tfnl[2,c`sW?Dh +�em>�}Y�%�49��M�M�A��586A� ".A�$�F�i!�2 �1��q����1p"i�8.y(an Oroboros�hRe� R�!JLe�Innsbruc�|A�|iF:2{ 2 mL!��@at�Dq0Q3},�a�kx9�x&�O�c`�pG ��%t!ݙ� *f�@�Z!'op@�4&_nu oftwA� buil� ~ru�> .�GI2Z% an&�W&�!�ucaryo=f�%�B faci�c��o�l s— a"�= #9�4l +PFs J�6a#!� eams enab?uni�Ki(nE�b2�o Kra�ue&cargo�1 long� tae0�j srupV%�A��l�/U"�J!#ofL@cy��u�>*�OlA�sin1G ߁�]x�I!ѩ��*K neurod�Eeve��5� or exam��,�ory�"Y ines�h%�d�G�#�siMWH4MI� in Hs ngton’�wH %��'{ �0lJ aEV]om� �G2r � � �W- 2! stal%�forN &�# le w�E�!�/E%�9~�cwLk$ +=�6�"I;by�'npld-typ\nt)�!�TU�8M�ue@).!����m1A"� �a;g�llo�!G run-m sfw� "1sout�EIx wild�~%��, ensembl�%I"8�Hio �g��Tet+e advant��lexQ*�:� %}x�ed.�� loa2H))gAo vic�QEDI �Et%/AE,!�]ltiA�a��t!S$�j.V3�i�?Q Q<�"8*evUd�3�uW7-aA��1a�|"#Etof �.,-v��A:A)�t�k9�sI�03����W��9a�Kgu� Tfa� @rr��P ��z �n`ab�f�f`M�-�r�M p��}bi�Zc;�dleA-� t�% like��wi�x�fsor�to Monte\l6E�3CC�"~t �t� en� 1E2\*w/�VA]��E�:{dR��Y�?2aI�%cQ%(�I�J. O">tA�N'��� }arw)s���packag)g�Lal! . MA���s-�q�, dynUmya(s-�qnanosca�Pa� A�Ų�J�-ufawZUA. ey p�Sa�A �m�growth�sn�tThe2 yrAta�a6\6})a�@ net8+%�m�tub�c[#~D��oa�Hs6[ �8�carq��1i�!KCf�s�Tas>? , Pa�s�O!� Alzheimer��D�a[z3Jnmus�dis�\,uh^ hear�c  , Q/ina��ąe�b bleS��)��o-"� "�R�.�mov%�, !==b&%!y ����!�� �yO st�[+.�**�ide+prip ork 5a��k�am�-�{[9M>.�D[5US Fokk!~�Planck"�"�p]�+tica )c B dime�o�o�(-&i*{�!���6�.G��D�pէ���ŷ�~-�T *olyme%ck via` cret�e�)N� .ac extk���I�!�&�1��0*Rar sp6 [�7]l8ve� %�E8 infl�e� a ti�?�l.�0)� vivo3;is ���Y%�>  ��:�[16];E;6D-*� "�nIQ o�;ll �M�16–1�eM�:u{pemploy�?�� rik 1�j� ��a'i"�*%ly`J�eŢF�#9–2�+I�`V Gros�coa�'5 �ed�-Ca6� ���i��_.V� �o;l�Xa�5�2�A--�8 Ja�oy�ۅta� shi�"��� J eirY� @)e#=�ly��)K!�aHwc1in-i`ng "c. ��n&~ sh�X� s une5; �� �Y��ڡu�h��X�>=�xa��*� (6�N� w*� �a���! �&2:A�> dl-ofJn�"� A5 gq�� NtQ�� oI Co~nt%>a.�F��%�a� ��ecic ��!:*k f�=g��no��)z sؙA�� '��>�-%YI� aut�Ve�?�2] ob�. d��Q����^Mk2>%3� ��,.:vf�&4���t�FwIksta�C4Ha��cr� . S�:P [2f(,E^a���2epPo��9A�a�|\n i�[*x'* �2a heter��%�*� �� } ]�m\�w"��9�a�B3��3�(���w>>mp�\6m �o* }1d� a�R&a�ha��� %!� %�e��-1 ��D@!��) a]Dax��. Pv. zmma�� E`b��2c-Jun N-\ 0(ase-3 ( JNK�/��Rm}6�$ ( Ser-176��"g9o+(i# Q(B�# �%~[20 yA�*�x�e�i�5��N�. A�a�  9 E�by Selvx �&� 5]� ort��a >�at�SoY�&4NA�� rB�,Ed����8lAE�@md �2E�� ;�i�of 1 pNCmj��lea� !HATP��,.�"c_ affn��!b) ssivunN3. U�}9 em&C.h���w surp-Cemerg#(Y� /9RCK{ �6<"6 I�* ��Gof� ;re)s�A *kw!d0% ��,E�5q� R� ��t�r�eL [A+Q� �AF!|.���́M:"�min2�s�)"^aby�����s uEB" b���I(cer� a��*$, a ‘moo7 u_’!z�"XM� 5l1� �R,2CfAnt� �gbe9 l=�. WM� �`d1��&r�~o�9o%  ~x y enh3 SIb##� ttacha�M,<�`%}5�}J�%G"#]:q� B'�f�, plac� 63�f%P!5�x%en������e�z$or&&a�� s.F .�i,"��I�y>c! �+��-m2%]����� -Y�_8A�Remarkabh � &Z%_h�86�s��3-�5�"ct��ina��A~�Nv*q�{ * ,~���"pbye�@�S'5���U"Fly�vtoYd! A]�4�-�d&�ntRE�"��+-�.fx%!�z8IV�66$���&1bA�a�"� t�KtK&+��F���*� ��M�!�Ze,to*�ε0�T&. �"k�mod�]!!$�[!�v%�Ή(�(log��1f w҆)�Ms �^�2A�&� r.!�t��w��TX�����o*6���} R"e�O 1|�.�26�� .#��hSmngH[22ԃ9�{ comp]X�&!�QUaU�ׅm!9!��CoK�Q+�hry|��g�G��mC%y<  -���L�5�.i\ā/oti��yC*����_AI���#oo"`�w$mean-field9(� 19 , 0MY W�7�&W@�a�asdl�� !cam��/�.�= chie�����re!acrAbG.nI�e�6�benef8�f"��viXwb�)r F��`��[;~�t`=�edi�7 ���race~�SB Am�c�ga )��rarANa��v1��'�_aUnrMAB�sa�AW�0�A��_~4yD �  E�meP!��6Mas9EqΊb4� [285ualIslyl=F�^&�A"� y,� nyF3�-)� t����u4��Qwe(�A�r��Œ��oX����Q��"� a23�.o�y ��d=B0wV!?��E(w �B����<%��Gu!B�N�$�- jF(%v.*��]A���7] ?1sU��&(re��- .�y "  �5� ��pts��indEg.�� �ܥY��ie�6~ 9]Mk aB$ b�{iGf� Vn� �j!.�,�ke�w��AN��mY��[�V_*�bBm�V�8KA 2� >���� �V� hilAl�8 �1�.RI�MATLAB��&�r*-�Q}e�woa�.�%s��e*E��a" plat_ O��b�k��W"̓!kw� �LS k ��+'1A�&� O�e�*8U&��AH��d>p Ec� !�iA��/"O�>�"�#*n"hj�uti��e z3!p&�8Un�`D7*  �*��M��#!�!�s��� inct$�ST8ngEexh� �"� � s l} (߀1R*嬨��}U:d 5�Y�kS(�>"���!Z�#)�s�����*es����vtw�e~A��va�$&���'ed�I. C�a"! )d%[by��wb�'!�)�G.� �.�Z�/)�J�lattic�# >���! ��� -  dw0a&kthrkl��k3�<@(a ¯ k = k �9�x��A�;gm$I = {… ,�bL"LwX8�� ��} . E&�f 2�隡��s�Va�%!�K��_o߅���%.D)VZ� Ω≔{ Ω]kΩ܏k }k∈IA��^q� ar���� .j�"qN ,]f][�h !Q7 �,�#)B4B!�%��QJ�����b��Zm�^ �6��i)�0:��nA�$Ω = [ ⋯ - 10 2 3456.] =0 1 0J.)�Z#aR�H �A�,7 �� symb�Gi��R�(��f�N/ F5rearguߙ%=J ch!,!� �9I�&� .P�_lag"� � B� H" �.8 ,Y�� �ra�2F/�f�y�IZWϑĵg;Rn�S"X1;‘Mh� , d � ‘| ��(  *denotv�,�0�H���]?�+E�%r�( guis%�&0D.?13 �%)!�heAR%t�q)W9�J�d�f�)a�e van.)N�Z�-�u�q�7RA ��-�!Mh Md||h%�iE2�)'�Sa��Hv�H2�>x�����R*�� �m�7 A~�vT&�+ �l�X���B�� �a�3ll��)��c��&�0�f�&�^=���pAE,m���[Bt &� (��{ ( PS})DA�<n� ��9¯ $ ( ,�&� ��M��s!pY&* hook�'s8 %re��o[ :"rNZ~2 (� �`A2� !�Xa j�!�kag. [��: L0e� ��<ff� 0�0 Kf!/,e�!�.�k!!� h\��!J�J3��r�r�y�M|�*6T��� nHasbTM5m�a��-Ԙu�r�!Q���%a�%FA�F� 'A\ !� D� �C�~M� F ≥Qt�1I&O�a�$&%)%7!. E�Y��H�D��:�� b6 at��?es��&20rSW �� ��:�"y��m�!� Da Bɢf"G�� A�s: 3 1:���" of MFY-.�Z!*9/%ց�feI� ae� ce F1 ��[�i���:�isM� R8 = m a x ( M + �QF �F�(s ) - F l o�9 K e + - >2 L 0gM )a� re Fp��Ium*� Ax��!R.�v9�%�AQt�/becomesIR("e[ O.N5l^J�9 �o gH%si#� �J!n�.U�Gt�;Rq��L0�{Nl�-/)%�/�', K��st�!A(�1�-� 6J2`der_� i�'3� BS1 Tex�>ۍ^ A Z� s�eadminf(5n e�6`w�^Ac�l٦a�.o�\��ng��Kc ȑ�2�'t$in�em�HQ�a#e�<� 4 Y-�fYs!l!�.���R�)��%/L�H��n�T��n;� IO"��I�$y^� J\s� 7�L! R*msG1iW2r�6�5V�� We beginS !D����b!O6q%{��F��Y-2���Vk%s)�"hfail( �7� q.I%+-he�>!�6�2�60a: �. AJa�� 2���# s!�j$ [� ���s�2 6[a�]� s exs[a��HA���%Gi&� j 04!YAU�cL�:, F ( G=� -��)UL6� ,�z f | L | < �A2+2� C. Zeq��W HA���)���eq"�o.Q�&>e��e�'KG)G"�]�'� M"&6�锍C =-�� �ABI� 9>!"� unc.�V2��!$=(�� )�:s]��o��2run~)GaussianRk%!kΘ ( z���;!mσ b���"_%d�ty4�|z!�3σ��!b�Y=�- z 2 2Y Z/rE∫ 0 3e6"d�)a&T �*no�!A incorp�NIQ� 2`.�2f5�.��)JI{� 44>$ %�x��Z&:�:�Y=F:/#A�:��S=w*w6�%�negligR!��sm��~e692�"2"6/b}��"���<* ��2���A �EO� ��2)���s�<e<�j�9xr28����a� k%c�� q � U��^_�� ($v� D)R%�e._Ї�N�=ong �asa�+mS%X ;(cMAc6�Dof)�%:(��� ��.7)�M��?9:)!��~^t� )�%&Ω!GΩ!�жe�iO ��a&�y. I-��%uL2{i���J2c-��  �A2kPS{� )Dm) �nWe!E.#c_.� , PD C+ E 1�%*, �.O�&t*PA� � �iZ� 6Y]�0ym�il�� acyQ� � &?�~a9�0f�)c1]p.`+��te� (�*žiC.��< oa�omictorub^]+ endŨH� �a����"aI9��K`"� Vs Щ�*f .�A���uLb� )� rk~;�^!e*M�/�ay�]�.���1#%��af@ s��%th!m ��eayB���AD~$."Bm�iYb%�,M� ���Y�A�q�2��� tavailo6st:[1b#�43�3x9W�B��a���)2u���Lig�sa aj��ڍ �všA�"A �K"WO3�b!�� task?ouW��et�&&�! 8�,�'2AMg!���m��p4oh 7\ &k)e�&DWF����e8�n<m8�~1!�fu��C(�x adapL�=�po�rrZw�/a�&1wtr9e�!��!P� A��I-Q�<x59�% -vol.E:ed Ca2+n�;���Ub) syn�c�""0 �5!&� a�of Cav�N2P!���CACNA1C�"1.b|8��V� E�e9k�Yc, Hpsychi�qcG ����e�,m�Jmf��;Q~�91��S� al ab�"P Cacna1c ���xb�W�1�W/M,bY�-�g�E�qof��n=mnt cue�.p�e� n�]1�;tQ��+1T Baye+ M�h�*�a�' .s"��X�� empi~f�{%d��a5%knockw'" ��3ir�in%JA^�h�&]�1�% :E: �AyE`)�jm� (still manag�KgE�;A�ard feed aZg> ials�^�s^%u�!�r�̺-\ �(A�.�ma3F"rado �)�MEyA�n�- cue-Q�!��y tE�rt{O���@quik.R c�D���ge�&n9pa6a�l�I|9nm*��<2ghWU�0be �>3  �N�. p¶.�aY���]$oi�Jf&/1Z����[<T2 clin$AH?�-  t�ˡUZ �I4to)N o)�n$ ’s�qGυU2opt���+���i o"?8UYUm�9R�=5���G�gke hum���� �ly�Ik�E�f���9gMal�gѿi�$vɛ" H�G;ose-shif/kN[X_[7–��! � q�n �)mw read��;[��11� More%F�a� e��s��� _!��,AG6�0ppab+�9,a��()�!�A�I� enga�^-8rB�choicl��>� B� r���B bulus-�� ( SRm i�Y'1e�� upshot�(N�Q���V} 5: Ni�1�1=��M(2�.�!c�.ј�WE/SR:*� aѭ|�23/r disa��(* ��f��� iorinM A|}�w� N.� en*  .� e.�>AA0tc�� !Wb��L��nDK�i�A[re�[14)5��T3�< � L� �4W .���t(9+s�uE��otn� 3� .�err��u�y�)�9O�E�.�TMup:�a rhapq}w�)���r!��A�em�8��a�[t�~� ��3��S2�4!�D���MS�0/a�!; `�:ܝoo2 3*tZ�&�Indv5_.� ]�%�r��l��Fwa2;Ad!whePcme�@����0X3.C�<"�( R�A���� -m"��or!*[h ��,�), a�%*ch �ED�,��! � ,���:nta�8del-f)vG 9 a�ś�"�9�.�N��&�{[18�I0]Aet�]�@�F`{6E|s��(2z)��L]���[ 8. Buil!�bdeOzk�e[�we� e�9�1jSva��� A9"M��T � �y����e�ka��"L . S� E�f �dRAv� �K2-�a�N2io%�O �i�A��20n�'b��, nam�]�v�2( K̃Nvc� 2aα subun�d"qLm1� "��8N��n�(:NesCr~�� J�e�"� ��cct ���&AF fl/f� G�k:ytj��s�D�R~aA� �R'Z��s [-�t��RGu�Gli;< & �:e�>[2�E :��1���&�E!� pathophys�1�:� �Q[2pVC{ ���ita0*�G��[ ��ie��"g� lx �mJ .�*�n. B��ud�;�i*m}Ax*� D + �s��i�@EN�ul��|�Hf�k:on.h�v.�)�U�w�!un"Q�M�e�����,�3���Z5GM%1~ r� �;ѷ^�K�I���$,�>u�'(=�v�Fov@m�:�u��F^!OS nq.3�� phI w�iet up>igH'�xf-" ���!���Slpokh�`@Mn�TAUa t �scraHbox-a ll�� c�_u$E�up?� !���k� J�[�� q* �Z-,l^<T� 1�j���� �hJ[D o�([�3 ( to�botto J�+q= � ( le� ��)���Jx�oi_ � McjYn���Rg �D���!�3�n�P& Pe�In)�%���t��!G�UZmr�9vc�>)'4a pseudorandom)2� e Ma99S!����j�)� �!� �6�.Uk� -� unsuccess?�� �run{/eaUM ��n=5�� E�- Iu1�sE�� mb~�!Qg68�tw?t�8u� �st �i�9�%i1��cu!� ppea���5th5_�!�� %AZ!��>h]IPbEHai0iQ�I�In� �OoR�� �jE�F��sa� ��.��Q�8)�a�h08� IB� �[�rIIIۮA�kj%�s �mnd cx,5��pn�1텧��e>*!lU"A��"%�%�a�er�/��E ))�msfh-.1� /^ �dij�T��-҂��t�A��Q�"�Vw!9S1R��my�| �[���se manip�yeziM@2�MO ���:�"o� h��� � �r��oR�j( e6&p"9 a� )2����E�poo�� _�nhenD"�B�&T$]4}����FU �LsH' �����Jso!+�\� ver~'A A���E���i. NT_g"�GE���@� fz$� ��"(x7~��Nes%I�wG�<c15}� kp���c*e��f}!=��,� asۮM��9�?:�B�f Zer-� S :����'. �4 �=,"� 3 a6� ,�pjth��A�� FS<���B���w �?ns��F�Kbj�k )OA3I0%�A�D nfir�f=C1$binom �� t !�1��J2i�A�s � }��� is ?��"A� ������qs:��1 %c�q� A�e7if9�puC�n�/e"'=�(%b. Na�theYE� 2 × 3-f�.�F�( ANOV6Ŷ“���&�M�us:)!�M�d�“�%�Ia��2s�N r�"> m�-&�)�A�n2�I ) = 2^w�Ip <�0� :@� E^4a= 4E6:E��#"2�(-2 C18 . 7�!2�2��*�F ��ly�[��or5S-i��6���a�-%h*-�xer!sf9: yAp�QhocueB;��m���7� e �iss ?�ephigh- ast �J�"\ 2%&�#s�hre|�H�/� fA!�雡KN3w�a<\whe��2�U� a`� �*< "+ ��*� �c!&�<�t� ��JC (a&�a)�F\"� ` 8&U 9�6�z !^a�we2^&�ba C)�:E��aW=��5�p =an18%&b B123o��N�. 3y2ai3�X=��. � �01N�}�4�u9F�!2 !&3iEby-�yz!r6� 9��^������5� 13��7U6�A"�]q�U�.l�i��' �ٵ" )� ( i"� �#+% Ia , E�:M�$no���}�G >!��6�yZb"�y \nd?;���aie�}16�K� y�1st/�<�)�A2��#�r�MN(  .wga���/�Wf'%!�݆� ݼb8(j�#=r�6�`%�%�2� (B�� I��II:U}3��  !0!���034%^�vm�u�8�2�on-ZMj� ��"� r#A�- , dram��!�e�#%��c9 A�>��%�I.��1ee ��I��::;outmX�(r��>�#�� IF�g F �M� =5�4e�wle, AR� G 8ll�*�(h m�[�� eI�� :��?����YEl2� "� v�A�.]er�cII:x!'pQ+g�*8 && ���nRA'�k ocp-�irterpre �s����oM6a&�o"-oB f� 3C א�U1h)�1gM6+ influence�Ld by this manipulation , as one would expect if their behavior were controlle M`e cue ( low- versus high-)�ast trials , phase II: t ( 11 ) = 1 . 82 , p = . 096;)6*3 . 34H *807 ) , reducing�u(did not aff�the�ofHCav1 . 2NesCre anim���0� . 33�75;B� '–w1+x836 ) . The results above raise� ques%�of how:� mice�4manage to imprH)q'fl/fl}�%�to(by symmetrye�(k�� –p!�x[= .,  -a�,In general ,!�8re was a main e�� of (:�)1�y ( F�8 , 2�<78 . 0�t< 0�i�p�6 , buERpdependawn��(x :���42%47�6%H6��fure.mod�~e�E grou!JM�y x  \�32 . 16\�>9b��C ��D4�z:A�a"�hQ,5�[�ϡ>a�]� ppea�� to change�" both �m�=�^E� histoEq!yon �%A!is� �!<c�#��ffe����. Specif�T,2� favo�I�eS over A�� at i��tIto +to�dside after an unsuccessful59< ( binomial test~ k{against%Sce�-all=Js: p≤Am01% 23/24u�atA��%z� howe�,��E�cderab9od!�th�qb fromA�_: DurA$i|I%7ey)(��ign%��k$more often-1win�@an6V( ( post hoc%0:  q�(even margin�WZs!�a\lo�^>Ks-)v� ]FQz79�thus basMUincreas!)+AE!�(probabilityVr'(�< left%�6�%�,!|"� , exhibiZP[s-Qincorr �k�I�one�-�p���8th no�e�cɜ&�! a[( see1right�>( � |*$ ) ≈ . 5AS�!�=M 0��I98%FI�� s II�uIIA�1]M�� thenI A�a�!�6'�� 5S�:���QVi � IQa� �01�ŧI IAg�=. A&� is�Htrend��similar��at shown���%�� k�% :�B&18st3 5�!=^�Ey6�9I�ɒu�,� �e�,6a�8 u��GsseAnb�m�ed!�E�r�d6�ŽA+ selective� nda�gress de� eiM�AU�9 i��next 2 �a�aalso S2e��N� � �large opor aF-q�m�b� !�2de!�ageep � Mate�,Xmethods ) makes downreg�a#5�} a sensibl*K !�is� ��e2� whe���beJM� -J�Nkobserved)5i>7Q�ref!�!b part�w){ �of\ ���< �is5� c&I ly b� !�o �confound!#factorA�� %� ons amo�!l� � ��&(lap betweenM (% �", ^ : %� I: ~47%�F!��r~74h'82%Ef| ambiguousYDtroduc��7 th equal�int!�t�Ayh~pmbottom��i!nEJ�� help�� dissociatJ"D- � � !CsiA,/ I�� @�completa� noni� aa�I ���o onse� . H" � ���.d�RQa kept�apply!�� !�UQ)�(M `: 60%9�,&4� 8��&19�.| ce;Q� : 59!��.G*C1� , " �@��OA�a"� �<&� l�� ��inm Y5-�(.� –6F� ^while�)!�� L)#–�39A��L1�� E(�� �)_��&d a�ly.�.� q�u�5%on}Ua{nonBf daya�� �+ �!+5 ���� / ..X4&�6` FdA3�%T2,"�supʼnng�� ideaAtR � (A"� to r=}� *l- j��n�� �RaM�&�Yus suggex ;truᩕ� situ 2:AUmayI��r/ t�N��V��M� ,*n wh� ta�*bears- advantag�IM5![>� ( und1�-fY�q#a�  such.� � �e�e)yrewarŷcu-i� ��We�����is ��� 2~$�.�, it doe! t$lwhy>��r . �irQ"�5y�� time)�� I���:w�P'Ūbe!� orth��approachI��� �. Ultima���:W��.eE3lihood!a cert!�@f!% turn��o��9��al��se�eA�icu* ,2?random�%�. W�ref�� exami|�:�A6s:��had actu�recei� ov �v�w_!c�4:����opVHBE�D""F1E�� inde�U{d ss2� dG)_� �I(2�1�&���45t6%��t���Re#�H2{{ ton{. 2�&1��8��= 545*6;y�u��an) .9 �!�m�)a��� � ariso�*Oto�% Jll ������ b=q� r���E ��ctl reEn.��exp"� :aࡔ����:^�;.% �Dtay6�!� �!7G2BE� .. More��, emplo�C6L�~�Eq3%zITII{6��� a: ��c,have b� !Vc��by�(��llZ6'#�0�4qȉc.Twri�d� )�!�/]yU�sh� �per��as � �!�t<ei��)Do�y.jA�bi�vI��|͍ ;C1}l� �.�>aA�e~,]coqRS��U�UFR1Z�)�splayed�kA�@8 naly �`r� s%���ac V5�*�����>":b�5S� of�h rO�"��F��ME��ZFYAih&� N�Y�E�y U�-concluWs stkdemon � �6 ��cuQ�" ��suffici�exq %�� choices��� ��AH�DE�%ueJ%m�’. terms!� boot�ptribu��fmaA#�c�%a�( RL )Gel�}�!uempir!+ dataC:@ V|��g�Ob%�qan=ficAagentmak!1.pury2�"�� s| !F��AWo�4y&��\A�.��v�) derg 5=�m� �"� �.�. H�\ “��� choo� o^�!�soU�� exact sam8!.R .zae� �):��on� ct up�+sA�d ign�+eUval5Jor> featurE�J �a���= asa~t�# M1��a��V�a}r�edN�(“top-cue/�-�" , AXJ \bB!{�.&6Ifm o9�&�AA���A�6.��ant��!N-�a�Im2F�J m. By rune�w%os� 000 iter� EL�)��!�� as u���fZ�� � >|a%�:v�#u�!�w��tega�iQL��6n5)&:F.�11/12:�-r escap����zZ�w i . U, �|B�beg# )�� ��(�5{�$a S3)� !fE;aUe��c '!�4.����Y� >!�Z�sN� � regar�2 agre�\��12U! χ2 = p"7A� 03eAindica��.j&�*hB��!��-[��5�%�E�A� �U M^a;t� i�55[1"�9UV+'#a�O� �1%�&x%.�Ρ)o 9$2�� ly 3.� �g#10.-�r �(.�kdi.#�}� I�A|f thSK! ,."�c��%�6�2��07*Sd! d S5A���2� Nn9R&5"b+ F� ��fF#-�%|aV����"�"be truz�-j)�s �%f5! ste�2)� `ed2�pr� -v a enti e]�b�(ape, �"�B6A�,� mo� ��es_d&�� a� �^��T brief�9 `��ah$linear upd�A�Ʉ!l�(e� (&�Alc�  ) -pairAK Eq 1a=^���aA� moid-typeQ a��y fun Z(Q3nQQch  ers�-nV$b}��k m;�!�2� �%, ��9!&7)qEP""e4e IYpro$% itself �(%�MHa Rescorla–Wagner W� [26�*aug�)4$Pearce–H� ( PH!�%d� ��# me�ism [27Ow+�� �p+!�N ,rec!g�&of(di)�errn��details;nRW)U9mplifU,hybrid RW+PH $��1 �parame�&fix� �check wel U yiel�(alli�,G �-5& }=� �t �� , s+� ly g:,Aevi'$6DO re�sL�Pm fhe]uB�"ach.�-al]�a� issu� �'4 �.�sMedQ�. Two AY�E�!R �u$  equip� ( ly)��4J�,�xI&�; edAí? qA��h��3��   �c�o�poI-�K� nd&.���B_as�� (�h%��� nga�5csol!"� �G] >s -describi�<l'-e@ numberifJ���pQ���d~!3i w��s�!:KI�r�&A�� e se�+5.e��cha�erizesII� s-�s� (ri� �"global:cκ�Xn add?!1*ime�΅�Kon�v��� a� η���� dłdivid�!� o� ns βk��eFs�0�H&4 kϵ{�' III}"� A�2:=�κ%�η�er�aq��7v�]/��dA�o �� thro2ir � ���@ i� Eq 2!_^�Oe 32��kpL4�steepnG! im0�A�r� 31d��min&>,( β→∞ )���"` "z A�� mo em�!?�(l.��nJ� V�$by maximum� Iq� GA��",via hierarchŢBayesi�v*,��ingA��3�er�5��A9�2B�(��5 us"� �)= "0 %&io�� |���aZ� %.22�RL)-� �I�Rc��� A4a8*K��.OP ���9I%�:Obe!vp¯&�& )|%�)W 711R *cuN&29 ( S6q (-A�aq4cee�59��&���MR�)f��3#2h er!Qa��"!+�;"^of895��%�By�48!�eUC:hQKi>s. *Gcap��65�E !���a � 2%!F�sr�79 m)�-4J�21z�a �!U� P)f!�99�,2�i�fi`�*6$%�i>m" plau�*yuF!�fu:<pa� Z{ l�v� !^�� %os ��%p&�1�V�x6�our stud� #sp�24 Cacna1c knock;"b achie��J/�d \-�:(}�)-tt "�)f carr�� �Fw�#�4(_)[��+x2m �� metabolic es [28]'" s)�&7 deficit��a`[29B"W)E��)�, � D%�r 9� to f�con `(5ez � �8��%% m@�, kind� �. N�&he� ,��s���c�*t�d� a �"�'oGA�%L121}�12 wild�( WT ))�Ih! � ))��':A{tocol!�� ���$� se 2.$ �� rung 6S-�,X,o��x:� s�'�.� $6�"K4s�'F 3���pick upa�A! principlkAN/A��<,�:t�"���h�8� '(f"�"Y�6VU*i;e devi%܁w .�"b�!C��und�6M0 �� �vfl���3 ��aI'e���"lyQq��f%_& -�1� �K& .� ?��)D���y:���kA�WTI����5, ccurac^G a�I` �) � �3��Mh5�*�* s��( ANOVA2S&on ��%�+449 1�%�"$; ���%X8A��1]27J )iT �4nt9�-��y2�P-�9p > .ᑡ�F�:�h�ly � �!e1j%�90%_fba��-�)d"�2�("��q�!�:�lev9 a�>]�2i(. Chi-squarr)W�1ir�E�6r��.�WT�ad,dA 2pt :������bu9�)\:�1-.66v(,�r620�AA-Y9���ja�m��3E� !athe ori�9!%���b�ES��(� 27A�WT>�23�<4( 406a". Con�b�**����@>����[)PE��Q�wa$beyon���R� fW��s6���.�.�:�� o. A��u1��-:h"�*��!�-�Q�Y��5i46-!db�J.��A�1I��>13����f�E�kM3A�zc . 38U� 537;�E�D�=~9HC"%c)J">>� ��q�,r3. Las��?r RL-H M��I�a.���*:e5�)%��Aꥺ-ˡ�Q��&a� hig�C�Y>7�+A}"��u�:!�9�,WT2)�n%D20ZH0~H�rT�� clud'Y��@B�&�!�-�pM�i� � "N ���;�A�a@c? e at�&��ab�7�uVcalcium�nŏ�$sE�d|F� �o>O8. In a�,*-F+tU:�� multit!of.��8wAex�/ k at� l$�fl�DeA�� a"�alVK$ll t1lea���@�| nm hB -5�A�\Qit)a���/2i��<@���0�3 discF��m3�0go� �2{B inpu+?n�0�*e��cru�'Apr�ng%/<�"�J y�iirrele�3  � be�ed;�2��A0heAot�-ig=H �lemQ [32]� ods�$E�����F-�=lim9@!K8-I+ sm��sam� �a�@=��E�Bain� life�� �=�enFKK world)br�2��%uG9top���! ;i[Kly un3 �F(��6A� f un!�s�!BtM�co7cat� +Q"&�I!t��%�+ deal�)�� �"�, evolK]c�Ia�=repertoi�BS&)r&y heur���shortcA�fd��p��)s [ A6])%i�gu{D them"��J"xsg biasA�ARa6��eto�3&�4 ubse�DfJ/�/q�triplU n�/" l�a y .��miza �’] gniU $effort [33A�Al'sI^�E>�!K����M)l^m!�to��f7)#lab��5.]�fa�. A-���7lyabE mz<T5gu�+22r" "�, i6�*i]@!�!#dy �e^)s���t�K��v“hyp�s�K.$s*E-[1l 1%`In"�L50mm��p(i2d�I�,m%+"j2"�,hif a �6e [� �40�"l�kuldB-M�=8<ne>�et�Tn�r [� 1� 34AFo�st�M�Ls hoarM7o*�F��4nd burrows—o{ �gf-s g��0 �EchambU#or!�Dg*.!�, >sourc�>deE ai Y�Ron��:-%8��Vcircum ҁ]�Py�B���t�>f�v(' hap�q temp�-6val.,I@�e83!�MPy"���pr�+*.it� ms2�4�o%R�{ � !�u�-� rt��&.H9*re�ic�a�, namav.�N!�� 00�?o�=cf.&�;o=�"�Ina�A�s�!-�V��dXC" !w7+E�&^HAqp  s!I"3K�;P_na�oO� 5�v�#&v= illu����< 6� O�O� � n Ql scopeT��a i�*@sub&�1, w�No�;w� . O� ,i8�h7er�� poin4 view� ��i-�� �(EBas�Z"C#E�"������&NB�!9e�&#)"�2�do �y�sQ~a�J � b^#i�WS- :��trob /2mem�li.wdea5�؁�EA�[�$a T-ma�<S u�.*�BE�oa5Ei?aj!a�&� v�wo �N+�-� �to encod��TJ�sA��\.Ob�#��5���toR&��*onAbtl!��<l bodi�� h@ o�  - main=��!�!%D vm�!7 [1.15�-S�8�)5d�QorAso ��� ly "� �/r�"Q$&� <@L���?looi'�9] ,%�; s h��aWvoid �=&�9 G%�hidden�[!ln51 �Z(�Q&� �T �-( e�Ųin� rQ!#mI� :�+��Ra�immed� lA�T}EXq!�|mp� ($it . E�Mif�(FP B� )�K ryth���3� bal�hdu�ro�W ��!k�#*�)�� dra$'�[Y�p � I�be lo�U��ly non� m ��� )c>H Y# e{%� s [3� "�3�=37A��� �O� 2�pos��y.)!,]�x!�!���-2 a lot��+tns�@Wvngmd�*�^$&"s AHeER��utx��Lr�W�Urtasor1�c!�8C:b%�e�=�1 invrd c"6 : capac�#.��� !�� ee�EȁN=E"ltKM�’��aZ� �8i�� u�V.�=(r"J&!MI�typ�Q�munt6�T ra�or��5�oBi���� �B��U"�(�8ab�3U�.�p�7"�C6'%+%k�+i^3[35A�&T -a�}B*�D� &-U� )web hFed �1�N0BY9��FBj�O 1 :��W%�\0 ulus�v0,.>( ��,M��2K:��[0Rd-�G -by-�W(��3 � -to-  )�w��e� �A��I$ n0� �Y,��5.�a�� ��C cAo>ky�"d\An�(E�"? %rqP|�E�$�4&���a}h���MM �ZIr�Z�PA� cknowledg�L��>�.��. W�!6 6&�&��� Eu�rz �� mu�E�n&H Y�mady�+Zassump��\u�.�4Aoa��!!!@%�;� ll 3��"A�*�#0 ��J9Wwosi!�!q1�!�)�2%A� @rbo\ . O��MP a}VH F&3�r3�#���2 , 38�in�!n�7��2i."r�� =)s&�Xor2�\!W�=mismatc"VM�� .6�� s be6�numer�PI~�p�$�9)�i�{cua_9��n'HiI' �^�,&>`A*D �5of=7u�C� "$E/*�Hte�ob� �a*2^�(!9 %��a�:4�Qv�*����5�Y,fit:�J��A best� cri��! ha��+�#on&�-�e":H�� S8��a�{��lso vara�FV$��&F?��-Q�a(�q[MP40�l ���iuss���[ � ��u� 2a��y�RM����K��i/u�9^!iI�q��hU c��� ��� ,*a)E��to utilɽA��feedback� adjus�C.`I fi~manner��U��u��:���%��%%!� A@%i.�cI4�/*�c| o��azW�4 �R�4���2�*X�-�#��4,t'j�  ,ch-$V�.�r9'�'0 ��,�>��is!�� d�"�E�4la�H���){6>. C��T2+ �?flux 3N-Xyl-D-asOND( NMDH!vol1)-g@Ec P���-*Vsynaplplat] [24]Knu�e�aY��m��+.<41 <c'(survival [41*F[A=sev�boa���Au*OC! i),� �or T-N�D(�[4�$44�H; rtex-wm��;al2 LNH1ya&� ���!c�-gen���{�ScPm�<.#*� ��� a�Iet�sd� i�Il�Ive����z>��, spaL[4�46)�43�al�,�[4.��*5Pl��*�I��A�A/ �\ v� a- precah�iz %-`fK>x r���yZ l�M�y�] uchscreen�, two-� Ջ�Brim3L�����#a�1ic&�e�� dors�= tum [4� �>=earlie0�lin~��regaO �of SR5�. �5����Q)�*�+X�� �0faca�F�W-1��I���.'>�N!�leᏁ��A�%ar?# %�&�Izf'HeWv1�(.w�.,2 60%–65%. b�w�i��inv!/�by DeloPEi�c�ag�-��f� ng��� ����U�!Vb ��Ja� roo�2inNi dys"f@inB\. F{��� l%�open new!�u�treat�?"�;I2sychiamh.>�e%�ACNA1C��b]��e M�llA9esz h� de�A [51�� bipo��disB[52aut�?53A��CCrv9E�A�7 m1_�R focuec�� i^4!5��&�A mCNS"� �yo4;d�4opť. CM>�d%�hom1��I9K)�0 �>�ex����-��i� x�/>�%��0�g�im�sM5o!�ne��Eo� g )Z"� "'&b� 0g� 2%���/��to*�;[�;or��P�o��;>�A=>A�rE�a=%Qڍ��pnu�t:�6ofR�: 8s:��)6�d��^��#�2h�M[� �;��>�+/+ ,!ti�=+E;a�Ic0d��fOWT�K-K:)to�,k<mal$2� ��( ��nd<3����le-hob%inA�� al mlV(ag%T��F26 ×R7$× 14 cm )%K sawdus�g@RehofixMK-2000; RcSnma�& Söhn� Rosenberg�?�7ne!PgY(B+r�9"�/w�k . Singl+Gu�� cpn) .� �(na�"�Fst�� �`%Z�y�"I�!�V`+&L m��ena�*G(*�nV& rich��) [58] �Q %��xv v$12 wee'ld_ �/� n]!8 lony�m6 �� 4#+erXem3±2°C T{�3ve humid�50%± 5PiA&y3AeE1h�*,light–dark=ed��a���f�7:00 AM� , 59�E��!2g?�nH_kA�G| + �e %i 1. M%LL,(ri?, [60]!�85�90%6�*i� � ree-!�body we�aI�I!� 8a,% de^UM� e �o!{#rai1 ���f9 u.h� �5�ecumM!�?, T'd&A�#A�IA�-. B�!�h� _]u-zmonito� da�'�C !. A���ar�]1T�F�/&5��[ or 1I-��re�`�c0 go�:3 g @��1�"t6 d�x�on)�J�w�[R1� AIam^$!��%`��J�|�:�/F��)8�d5E:N�D3&%�ed�G&{ �&-$7 μl sweemk nden!� milk s Lt/ , Loughbo,eicc , Un�6 King�h��Pal�r`L( IR )m� beamV movem��@� 3 W�R�I]?lh �/"��a t&$^ rator5aud�{nna%�E� iY�2��isA of b�  Pe}x!w�#rr�{�2aA�pez^, shape ( h��Ip�width 2{`�46�,�[th�=�A{a )G� idn ob��lon�t�BETh%ƅaCE�R�! uch-�9�55 !{-8 ctor)B(.AKa 3-hole�my=]2)s�-_�d�d��"' �r�'T2dow~ 7 x 7 �)e�� !U�' toM I�$j5�  V7%5 ���-<$-i�t. R��/��9�&+ gray�55��B�  = 70�85or 96 hue%�s �= 0!AHSB�� |!CB'trigg�*�́�I�,6�ͼ �A�delive0$j�)�.?( 2 x E�|NE06�la�)�ei\(liquid susp�t&�% �ҝ�-op��end`�Q��am�6i��*Mor5�c�l+ ,mrt)|�A]ns+�-^�J�r�*�)��]�ubj-��.�H�҃Vt �na�6N�,*cly!�� A�i1=( A���uJ �,��,H�Au� retr�L_-�!�@nsua��4pro al.�1��atR s� = M'�;ach-.z�AedV4egypti mosquitpC- �� Wolb.a��@a6 /&�1a��=儡��'vir�rp"T�!A�<�.&e�nv#*po��[0{]a�'l��E�� t�me2�<=,�>%?a&5as�<vae�oB4exI�) lu�o� ![ׅeme.1 I ΥU+��9A�,1[lag6W�t& 9j( wMe�"wAlbB�Pop-CLg"d diur� cycl�*� ��Rea�<>E-� �$at 26–37R��(.5��,ytoo"mnn�atiD\A��=1y� 2d�iJ,ɶ�fq�"�a�rp �e��; �ofA�3d|("�-m��!eR�-���� �mitO�e�hg�:- c9}(<]3=?ss @a�� �6*�R)�)�J ��E��aJn�.��!le7zv�n�x.�� m�w:ffs�Mgi� t�GAIq� ]eEzA�T "�o1�]���d�ALy�+>�tn! "Zay+}܉�4m ]n("f6�� A-rm. b1'�6�]OKb6b��oais��s���$��y�Yspr trope�!�sub�"s [�inhabi�|urb�ә�sA�r�)iea�o�� rt*������ Deng�Zik��&d��eF��na�L~rapidlF "�,+bur� �M�[Y.u�RI��/�Das 390�la peop 9ach y�Q�JLPo half1��G ’s�/sat of kV![. �In eme-�g{e�Fe���D epide��f"V^�< brea��BraziE^2015 [�&!kA vaccind)y�!��6&lic�[5]�n�+9r 5�commer!�� vailZ AO��{!!]soT~di��?oy� a|bw ��[6�E}Bf+c4M�of5{��mD yA0d�E�Sof 2.�a6or\p�� �n era`ho%�(9kTA���U,"� geneV)�&"Ca]/A��Y�+�G���Q�f&� es [�O3D;�a yv�!� �.g I�1�+b?mr��* *T2 �o*� A�"D|� omba�6�&B\_�����?IAS� N=��) re���si�ho��"#nh�  5 az$13'�' �y R���yK���!��M7T .q11�h5�in�?rep e�of RNA���Gn�s�t�$1�In,�ų2f�. Drosophil�lanogasP?!5I�lb��"Du�iaDd�^a� %� =� N[�'o�*�2Xy�[1�u1�%e�[1_*1f(chikungunya)�eye� f� [}West N�Y� [1�T� innK vi!�h+�A�]f5ir���?%�?�>1�.7�\ �w2-Q�2z t/Rf|yid%��now�ges�<in6v%�E] �<)jf�8�#$i�-V � [19L f [20].�WD . m.1� � � ,I YH[2!�ac/ 7su�#Q� [2E�iaR ~ n) >�+$phenomenon!l!��3in A��*y��� ��{�W� �fe . �&� Er�N�;�:[ �1h/�4avt16N��e� �1:� �O�!Yu���; �[2H)W 4EXv��A� �ir��ec� U��+ 0���minor��ih"fi�w-of%� [2�6�;��? ngev �fer�2t�<�� >U�276� Varia� { exi3g exg��\%Xq걈uses;.�!r� a� e�� Y%{D\block�GJ ' �w�B�I��:�&��K��eB6! '��Ecr# !Xe�5�& sui�3� ��naïv=�.���5QA �� �7:�m$P� ��Queensl�, A�Fl�+�.fpe( � .��PaKst�/` s=~!*�!�s c� dA� )&s*8favou�9@lu�\6 �)a��3�/c�6�isqg�P_ ��{v , Ind��(ia , Vietna�BCol�_a [�/3�Cag� V�/ �q1�.gzAZ��te�U�-~A%[E�3��*)9W�NŢ� O9�usAA�g�[31'NS�>SmE quies} egg� ��[2�:�#A�eB�is ye�ڋ)�m�)7T60!�fu? % |(�>�%�A'l&dN[��2.SԊY- *5 F& �C��.�mq�vezi��w:r !��� M erit� -.�19�T�zA��&1IR�8ra!��Je��:a!-<-��*� "" uy;�2 leakQ�P �>j�w)Mi�� p2O�I���&r � *'2 #A�� �7"� �p��vaE�!\A� !C��>a<fix� �]G [�NS�Ln�l=:OEo*� Jxa�A!9Din9���"F �uMi!WQi:@i=*��F3p;�:"��%o�� !H^1� tiʝI�v� �B v � � de+0r=`g�*(d&�"ale-kil�[�G,� inY6[3ŭA�X gene�.[3-dn�[4��8u�22� 1e�I�l~);`n�s� cy* �"" r@N�AQ�y�&�8. V+ K Uo^j*�lsA, )�a",��"L ;M�N !BBJ�H� a>i4aen!u&o8.#M*Y�2&�B�s2F[4�9d7nut/ on ["7aB path!�y�42]y"�m�= Ia �I�� . Gi5KA���bA-C�5ej2V%5l�*&��!f!�*n|�Vru��(� c� 5%� !�n, eN!��S@r�oif:�7pl�� role�-@Y �-8��>{.6�" �2!bn� k"���em�&a3in ��e :k,[Y���� E�!(in �at/.o�$!<s��[5��6~Axm6r:M�;2�a�y&(B�st '[55–5��JoH "l'�B><Pee�.D�y�B)�%dm��>� *%e�X8] "N*� :!I�2� U2 ��k6 harp(G5&-��d1�i"Z�9�%b2�`5) to 3�& �(6�/6�6�-R�2�! ��C� �ed� p)�"�:��:`W�1�7!?e #Xi��}[ �ba'�ts�1i:�9a�&M,,M!h�l �q�V�O�N 61�m==� 9meVz��e!%t�#U��:I-,� a�g,� ir~5ac �ue�2�=�Oa�A(�BˏA"�F2�[�e�-��j!&UE�c(9.�"| ���sof  J�*�6�0nH �e�!. 1s]NF�Weia a g���UUn9ۑ-^�=X.v>&�3 �w&!�Mk��lifO cle>V�5� ��A 2&��.nX#@?R�m�����ׅ�U AW4�'!Z6V��sA Ό2=g5��� "���P2e��=k�_j09�G� J� *�?. W�AmpT"��hJ�Jof�s: 7*�3p9�2 f!,J,� �AxII^DL�"�)k sexe(i�� cub�)q�J�%�a�9u}Nt-l"l#c5�o �( .:-Wh y U: Z = /8�P�( . 00�P~.K2f� !An:�2����<( Kruskal-WallisHkx58� df = � �46yor���( 8EB6V8648} C���%���<���qd.�inwRn���!�02`M�h �3 ,R��Z� jQ�wa�ee�A`( iRK>`@42a�J�, Me�eg�FWe mea(;��:� w!,&% ��X���ak1�E�AE�$:y2E�e~or <&��qu ���PCR�p.�k"�J�B:�kb�i��uA� ���V6A�19=Q�23 ml.�� a_)b)6_��4 �s5 ��inY�I�O>�1��@ u9X �(!�n ± SDef . 56�eFn�Н#& 14 . 75-f�5#t�AO.^�i( �n24V>qV3!!zl2�MP <.0��:X)h{)�� 6�( �65f�;�jf�9�%7 �027.�02�/3�#�7Q73 �(�6896R�A[Q��alFh�CR}8q60�8_y1@2�26 34 ���32X�6�Z W,�}p:�:Mle-�.���( ܘ6Z"�6FM�a 7K572�Q�E;!&��6�)� aA�7R�54�:�J�(Aea�k.�.R�ۅ��6c:E� ~q\I$!c47u�63�; � %�67II�/ . 09oo.%� ��s&�pr �o*K "�]��''Ze�at��7�R�b82!t�)f �2a(.����r3�"F4��U?*8 *  �YZ" 6S �kl� S*C �.�Fl&*/ -0neq~5W*�B&�MA��I.G�%�XcoincGw�:�"�z-A�� �rFb'�bvi� �enV!:�� �B�?_�5 -A��nG.F�LAJ��toNj.:5_ �LS6N�� | "A�3�.. 245�  1747 <(��0����7r�%e��* al�o.�5�:�we&� 5�:�"ZS!V�N� 0 �"k i�4*F��I%ion; 301VL8465L��31��� Z�5(a no>Yn=)TfI� t /jA�A �,xE@2J�E`%�a%d"�D>M ��A ���80j� 93C�1r�d%�F{�:+'�e�be� �J��}R�"���ީ��� \ak29�%��#s32�e1-!)�ܷ3B 7�w� �"� ��~Lv�� IAY�c>/?9~dAV�l�E2A�7%aEi5�J� U��  to 8s|7%)@F&��.6�ywb$�I*�!6k(Y�40� Q�68 e:5 (56.(57/ ��;-�?/~E�w.Q(`C�YZ4.�. Takئoge2 ( J��3UCi�M��!GA�m�n�����nB mE�E�!�r�!7rMQk>�It�4����� � � un�� A���F�8ekdespi}-sL`-"�&!1�.Rr)# p�b M IG� !�%�=�s"�X!B leve�Jn� �#A~�o�/I��~�T1A^vW��1��!�%E�f"�%M2�e21R'[6�` mit �|h&��\ �4�)ife�` 6MYn ~-N�. F�� h)):\����/���$)��)�#aw���� �"� *9 !he 4t�^:�E�]�$Z6.o!jF�1WA9�,�!gڪ"P ՛�=�?a{a .b� �*&� Oa�E�a�H.[>�!(�^dH)=m1@( T���.�h \>z���lS���L �)]79%�m�Bd:�cyl�+[j�@�%$Y�-d!��%^.YM!maj�Q��%a�SO 1z5% �6�69 m�ra�  3? 8* �j2e�1 �.��a�6�.' °C;%�,Rc-��%�u B� 2��*��q!q�"�wn�>+�&�%-imm�!�e*����}�}29JJ�ve{��)u�s�.0��>�?�!�� ���*T� `*OonE�/�����:%YNSs>�>:7�v. �@�@�1!��6�4�.[x,I1f2�?Zņe>� �� -3�]CDu�L��[��54]I�� 1#tDz,�e)a! �-'1 � A� � ir.�"�.M-�!$�c&�?FA F rz �.hNV m� rzu�ɴ=2�VR"�re�]a Mly# �:�Ei�*!�it�RB_� %�it�+&Y��&.�'2�,MXrobus62���e.*�� Z"um6�}�5k iPuu)HA��$�/in.�&{�<.O!��Usi��:&B��ar ��. Hig:,%h�-";6(�*�& <v=mneg")?�.�InH% arMbpͻ,)2�B�*!���Nx Y{st)60 _B]we " %� ��1byR�*63F7K6e�(e�&l7~��ly [6�6�u68–7�0O�}"'&%>�a�9�)Y&��6 !��<?(zU�2�. Y(�&71�&6�H&9 l&i�S(^f&��"�'�v IE=etw %�^�5�7� u&�����[i�mM!2e"a4 � !�hA?2x �i(�[έirhs&�3:]�Z3ly�=��s�E�>u��$};="D2@For*� ��J������)-�!l pupad>evc'F� quan=*O,�:Gag�V%2�irach�!MA� wet YAo@" C)E�%H�p we e�� �uK^ �K�bTT(icq ���"�oT)�zS�3we qi M� Vu7�rec�%?l5�&�%�$dA6�C����0�D��-fiA��%J�@<E�s����1�b�=f%L�,�7���9���-6 Y=Hter�$ 2�rel��n�Ri��{���0�.7�/�23 ur-��` ,- Z(�*<=�An M]e,)^A�Aat�..��'%�\� I ��N[ �)Fnd P�G�5B�� %�HC(� �+3V� 4C�!9���^r> %3y-��g�i�G+�AVduZM�&U(u�Bn*N���4M�Y� �yf)-M a&�]e�b�.%��t=)g�.�#�9�n;��est%� vA��,S�[w Plon>(A$�1R� s �Wvar|a�K&@se�J!�iT;ve]49=S- .d%?:n0��s���\�$A�5� �O!��L��%� �i�Cdivers\ WT)9k~K"��keWF�� �*�nn=�;�6! w� A��rD�a'n ;�:g �f "�)Yuu�5samKZs�]n��u�toler:8h r�3 � ��3l~ut 89tiZ=R4!u��ly�*�  [7G 7�`��t�fo�� :4,F�@[�!7�D)�s�2�>� l"�B/6�*� 'outh-�fAs�;e!79�ag���� ! v��W�c er>S�\a��862.GbyB�a�� ���L2px. �i���!� sl�2�( �C�redBo!�&`*���X58� � *� >��e��Na�A4�{'ir�)����una4n�h����"�6 %1A�o*�(N53LY�yQs �&�k!��3��>�&. ���ly_�a&�  v�!�3= �c� y�1Q��9�2&�,]&^aI�*Cp �RB�%y�o�t��two Sm�U��t .�*��%;a:.�*faR� � ��v b,"-[��_9eI�"( � �2�e�+m>II\6<Z �/��t&fO��Q���N7.� :�*�ai"f9��0)HA��4��?�>!���Y*6�3l٥� H��.s5:.z�Ai ^�yb� $A~�E �Vs!e� i<Nsms�y�wn�Jd`� \�� ��:U,��!t 1 ��� !��|A�� �t�*:��DtN57*+Fm�2 >���� �G�_�8� WO ,U�ш�Tophag“�v)� �[8e&TM(J`g2go lys�:ic%tly�� �Xa�l3l!5I��i�by-- hockP\ , 8 <�DW :�g�p��V)�%�wp�ce�Z>oducA#��!=2�ugh<�is [8�F�26 �)>�G� $e:���A ngthvcjF/� �� asit�[ wasp Naso�pvid�enn��DT��b#N�A� �� �!>�91�� m"�.AG �-v�� [8l 0 [5�86JF� �?W0L.���y"&&fPgf5^oS"�?�WO �M`��e B�J!�9in0!�� �9too��!-9(��sa2dat�eu�z��E�,� & sA2ongly T�4F�Ad!��&@� -3�vZX0z�xt:d�  M�b���"�Iddr�xV�"bat�F� ݣ2�r�ea�"Zs�K�!�� ;U ��:K�u5�&�>�� �&� *� � �0and/o� �\I�m��2!%v)J�F@D�Mp !�8�i�Ŏhresh1� dE��F�+ akeK?U�n�.Q����|!�anA�� &�F�DM =/e2��(7l ") "�>&6?gd�d�%�S����wx[518�N ��A�5oefuh��L%8a�*.q;ar�R Bare!�T!�<�K�jP ��rec�if ��dR��h� �:n(Nw�*G oA�r0�� low.@VU�dw�L�m�[,6 �e&c�a5$ �6:��war�T���a��k}��I�%��s� � YVs��.�K� ~A��g��} f�wy[�ago�KM�G2*t:�OO5�RM �H-�MF%�"P mpc � .�!�fr &q; W; l&$0�Low�� �:!��&�OI%Yung ��. A> �JF�5�w�%Md& � ���B}NDun �Hse6��ms�E)A�@ s�5h �� -�� . Survey�="T3��"t�inT[P�)� �b=;A�l��n�%$!a��ur1 ) �`�f�h rocl�lHա�is"t�LJu=em�ku�����;&�&�~-�V7%�v9�e!l..*�,���!n.�x"�.M�VxtF`!xa���0g"9^�,A3orm!�*!�2�a�inEis�Ye [90]�%�IL *,�)1I�E �������L:�[9�N2} q�q�e�M��(�G:i #!WgZy�a�a�.��_&�GH*�;�abe���-c?Yi�ftH�r7"qc�2X1�[70�D�=o5 etra� �[[9� A/�WEu.�92�.�t�[r�v*6�S"�&�dF��wo�`b��1e!)�ap9& ��n*a"bioJ�$eN 6�~ Bl+GEf%�npa�P bjec�Q*�y�UnM�Melbo�� Hu;E�yzmmsa�i A al 072384z;�l�x unte�V��i�v"r@VnT~.y�.{[] �>cp��E(Townsvil?m2kS in N�jd��]!Y*j  JwlI��"~ ± 1s+^n!R7pd�&�P� xfor�8���56�`Ű!te, ��)� .~) 2&�A�s� 5A~ �{"�P F.�,all��y� O)s�6��/%z�=~0�� e2H�yu�sA� �a� �qticL&7{ �B�bM�"BOBarZDhE�voUw� )t &�"�$%�&� �a �5e"P#*���J7s&L.;%�� ~!.# '!�C!!�.�%��)eM0*�C ( PG50 PlHh Growth Ch�l Labec�nEο��|rrickqFNSW2�)�t!�*�=�/.��*�v>�:# ���=5eZnd d>�� 12:12�j:5roto�Lob CU ng. %$GuE�� �=��terGyA�N� 3l;a�e 12 8us�#]Av=.!rA�ni#b �k�V�lo�l�@mochr81-W�0, iButto�co�nDallas S�bon �, Sunnyv5? , CA5pS$2a���glass�:�|5 )0ubWcIW(ha�trb ����x�85 T5�m) ����!500 mL��i,&�toU�*A�� _."� ��meCo=0/��Xn�^�Y B�y�Nz qm7%�i�Fei!�.? e�S -at�F�f3mA�>�!I�E�6pC&�Bm�rl"n(&O�:�*e�vra�tZ @� d [9�t���hD��*:0�| F���M�_6�"ynE�o��in 3 L-��aO-��=. HI9�Eu)!����AL wÄuc'f |B.�"Epr9�T� M6�g fish#vt�+1R&��el3G] nyaud l��u�Z**������?4100I�A M�I�2�+%�Yx�v�%g±�:� 5�set-p�,�.e� nE6loc Rb.ԑJ.�!�"*Ac.-6�-o�op�T�!�YKs!� ����pa�Z; �*uJ0�%Ǎ�+ T06�>n?&�2%*�9���T&�B^�. P)~se[��r� �("�.�an  )�<ad�to�L @whe�{�y= -i24�A�clo af� 1�iRTg!�ig�xJ�KI6����,�Eh.��]��pa�3 �. Aw'+�B��hc,x���A�2"48 �;"sO9��&8� �$BD a��"9%*%sa6fH!�T5!�!�A�L�a����i;, 7-��75�EXje.i2� �spi!L� A�.Q U6P' r 3�. Each)0���"\�6&+A)� 25hd.��Tax�Ɏ�~Nz3|!�E.� E�&� �K� �at nooGiC�o!�Y bsol� ethanol% DNAFac�aW��A;��0݅10��at rand�linDa 2 × 12 cm strip+sandpa��,( Norton Mas?,Painters P80', S -GobA~(Abrasives PEk\Ltd . , Thomastown , Vic�4a , Australia �,1mSa�a!�5s%split inA.$wo groups;!�s %�one �Q\ stay�.6P hile:Ao�Y @p�nh�x.U? . EggmO@hatched , progeny IM�to 3rdAW4th iPr , stoA� in ethanoa8i�iZ�:� pres�-�y�U�6eI�. We scj10}G%985.AI�� type!���]� , except�� that �Rer�a29�tom_w��j�5�,. All analys��& � SPSS!�tias vers�21 . 0�Windowū-0Inc , Chicago�GLE�H!��por!seC9`�Q�E'8not normally diaSbua�2�0Shapiro-Wilk !� Arefore wa� alyzA�ll data�hnonparametric Kruskal-Walli �4Mann-Whitney U \4.v�Adenoviru!4are imӁ�$human pathA�s)�have b�udevelop�!Ia�s%B gene�ap!����vacci . P|  stud(ind�Cd i~Uhs �a>�$self-limit��Tin immunocompetent hos� evidq someA� sist�]id tissu a ough��bet��undera��e n��al hia�yayG%S.�$in various!�- �pr�)�discov�e',healthy popu�b��(of great apO chimpanze@ bonoboA6gorilla !�$orangutans�mmacaq��s��sub� tial�E�of�us��,stool . Shedc in s e� asymptoma!��s� fou!<0o be much les3equ!�, !�ara% to f cA#reA��i��purifiA�nd fuabsL,ced 30 novel6� �!B43b#5&. Aaz�ofA� new!�Xv�<a�a7e 4=�V3wei[pmly�� ge� i22%$let2MgenomAL vail%?�0GenBank reveaE]( �W�4a��A�E�B�E 1�m B�2\a�%� of l 9hnoRn2szoonoa�.�a�rra�cau���5and� !�ho�a. Fur!�m��,�.�per�rt7 /or � U��tn Bgut shE�bg -Gdesig� dA=erpretI1ofQ�ndF  �| �v��. 2 ��first.� �1950sa� outgrowth��om��id�, tonsil expl%_%�yQly- man/t�tebraginclu%��[. I� �z re originq�rN �ir � to agglutahe r�`Hnd rhesus erythrocyxt$*er�)%�to�.y=P�1��our�m� [1]�@ub��tly ,c prominEttr- [%Fq, �gE ��\toMuce tum� in rode�I�$molecular > [capsidztei� s deter��$electropho�s [2]%GCh m��� [3]6 augm��% ini�usu1K six� AF��@%+re> !�s�HAdV-A !�ugh F�!�mmonly| ep�N toda�A����� �Eg6���b��e �uA"�tic&� H��o%�pr-j.Hpossi��)�Q�QV" i� 4en!|fi�T$reasonably�arlth% � " rv�has� ex��~ rega2he jus*��1s�jk a se�te5� ( E!jo its %ddef�>> membe� %� 4 [4a I�ᅓC� {!���s� pedia� up� �iNy��cE O orldwide;�r� life cB9 �-!ca lepidemic��. B�ɶ E=�2MetiologAge��<*� �Hset� �,@ary boot camps [5!)Surveyp �7 al� of neu:z%�ntiboc 25#in orderA>u� TobG succ1"�ݳal&� [6]��F��to).C%z5(b��in EuropGUS Africa [7!IE�) tm+6JkN��OmE� ively lowIa �aihort [8y%�F i��g ��iUc|asA�Q81�$us diarrhe Q�$ [9]–[14!6but���� serotyp��als" yco-"�� !vs$diI��]��bE�� �pes%��i�� *! detail [1E�LAis kn�about��� *+ly E���5+n5R�V� n@mŢ>E��aggres`ly su 6� Ag&�y��� "�[16!�N:�. h arg!fA�faa���, Seattle [17�"Long Isl� [18]� w�cliEla��V@a�ver%�19��"�um���" –l$x�prolon#"C � observeL �H a Aet��vidual!�An , cluea�a�]gV�in.�y"^ by Hi�in 1963a%�$y which atl��o� xu{&� �OhepatitiAh*�� 9!�He1Zed ��of 25/8724an uncha�ri� cyto+ic-�f grew�vitroe��� ��.�co� Q“P e%� a nu�8 of esic� excrCEI�!�&E�or <�%Hma�par%�5,animal's ‘�$ flora’ *. T�t��}�wov�g�D�&, c�d�nc "� T H- ida (�(Cercopithece�� S�N cqui9�e2l!�+ peg:.H0( Pan troglod 0z paniscul,&{(ongo pygmaea�� ( G�)�MwG-�m�$. Two old �M monkey� ,� a$cynomolgus&�<( Macaca mulatta) fasci iJe���� ʼn� d si!� theyE�c� ly" model �9eaA�� to elF ef� c��safet��=f�8 ��rra^� qLb seY|A,^a��!sa sit��"�caA�G "<E�is ph|no->bet6N�s��cul 4ellE�7��r_�o��ro� � �2PCR assN direct�ec 6&�al �( �1�No:%��!�ime Urbe�[�*�St� inct����i��'F9�ol A��m �aE�%�wilɑm�loc� } �%!v%)!�e"vi��%�!6. A�L��KI,"�us=us �A6;"��,s.\un7 ful2mAFhighligh��he*J� �(��a�qua8� J� "� )6 1� �2�e ),n)Q.H "� ss�pJ�si�harbo�5%#��,��e��rec�6E61�� fac� = !Uni!St�esaed21X( New Iberia Research C�i�eJ��L Louisiana�Lafay��Ay8Michale E . Kee� QAPC&+  Medi�%�~,:rTexas MP#Ai< on Cancer["m( Cov!WPro� s �4Oregon� ional PI2 �Am�y�B*Program!*Un.2$Pennsylvan�Thirdl��ddt �_e P�UCOf+ 0$%�>��exten�o eMe�eԁPfe@ Q�m�QP" !e�F�;captivA �e��Zzoo�I�6}. C"c:�col�l��  habitatPCamero�%]DemocrRepublicA�C( DRCaškmad.Vto �~� �i�R�ȍ�� ���"�u!�=simia�amym����0 T�BTwa�.mnv�e�� �A o��e����us�}/4oligonucleotidS�%���D��ed reg���$polymeraseYe (��A&Y)�be�I 40% MJ�.�� exisT!e�?6DClond� ncA� bse%/pq��[!1!`y-iEE� es Em��FB (T shown�I�i�:<,X��!tlos5clu�"#SI25 . �&26�39a�V IBQ�s  mos!�Akbto K3 K![$2 ( Figure�We�f�M)�eb moun�"&'a�$he Virunga�#sif(�BRwand� I�Y"in 3/6U�btl%�. S�"� %�� filt��� def�%F�*%ef�+CP5o!�e$ e� l�A549  �$J#��!]lt��on>�s6� �u.�!�!�tAG fail!�e�&�te(.�of-I�!e�r6��se� ��i'���� ��� e ab"� fun! � �ic� .�i���"� �� �contr��d � MXzp!tA1u! ��!�se &."����e i��E�N*��a��(�ll�� EAE�ba��)��6o-#5�� at_ 2]A��Qfic!m� ]*���r�&c>�V�pol- d"N, abovA� A se� �ai5)to! over2� �"N ��st���,% �a��"droppj�&re-suspZ!fq� ^�]�s&R  � ��&]>�a: �T�� ameuY2� "����inow�u� �`�P�<�A.�que-�pro���+f ?d�#aiE�?e��n!so�ctha�� =�g �ki .����)���kid�%��naA(BS-C-�&Ins" step ,�&w q yKae5E"a��a 7#��;hexon2E-sp-hypJ ri�ms 1A�6%Qn"[2���fra�s!�=!co�� !U!c� g*�u$+$h�( d�!� �2 �.U. B�@�^��, y,d,1H�f� �y-u��a�|#eic�e%%���C�*O)p568R} |�#� d��at2, 18%qj �*J%UA�9��!-a$��1M 6� T! I9"�e!�-�"#^& zll�i� timL�a�**a�A *�&I��w��yie�4C'� I��1�� emplo *�&�"�at"� .d& ( 22T,8%�m�. ,���"��P��k6�m ����gc��c% !�( w.Q9�vM� !dy�i�yfEK'AM*�%���2�*Q8a9� �65�XUe96�J�115)&28C�23E��&� 6�# on�1���( >95%^ ty :.ift��re�e_Y5" a#b%CF!K)m V 2{(�ly�d>� P�&!of>� open��#fra�'( ORFJW ������es �9(f����ier!? �� 5Gpar�"IIQ:Ja few i�G *� !� s�3 , S23L5S5 7 S7)�or exA�u�e*� �in v 2 enco!�a �6y1��a�8�5q!A@�E� s8�sq^0two!�-d�g�� �]%�+�/ suggXve���!%u1�a rol w evolE'�* �U�.*��I���be��ly!1F��: !�: 2����)C/)"� ,9!�94�12�"=1 )/a�S3�/zoo�eJ&lyK n upE?>�+ . Hut.TB��%���!� ��*en�]-��im&B:1 (� A�H�7� 2�!B:�1� 3A� 5 )fA�u>re�/�W enzyme diE�p�rM&rS%�5!'h @$�%nd:s #�6� c�era�%xAT���uu= b2� 8a�!29 3!� (4�4m�447���{h%�!dM��as @2J33%GJ35�zw.  U2U.O  �� 26x2c�e*+/�0J�*(�%er�tal.�!�e`)'f�b�)N� ���-ypz sE�!��H F�!�U lik!�� �K� W actu�`#c��" � ��� ons:5elfreshly1D����&n "��S ?ne6 arily op.8l u� a�qYxEq Indek�4ach.��7B&� 6� by%\�E�puu� ə�E;M�-.�X carrp�#%v jVfol� �) o� � k=K6H *y�LL*�8Q�!{ 9���s !0JR , 36�B1E�, 4 �� L A ��). . O3)2 -der�is� " i gn#in 63�q�despit%�taeta��+�&!z�7� E�(9B resc�$6�.j  Rinca�eBS�diagno�5m��aVe�B(A�e&z3U�� )!l2 q< *35)����&�"�� _EI�,� �M���Xm>�#%FI;)�1i."!aa�w F�up5$��'E1��of2���e�s*�3�%2�'[22a a�6�io�";E5�1�-mon ]s�#> upF�%q\ af�#resu ��! +�n%7~(�&. Scree�q F�2z1�" subjects Ha=2�!t$�d.��{6  in 2�X:<�ir*ir�mԭ�5��9�,e$a�� 1;F���.�{UE%)� y�1�we 64V�(2rm^�`/c%*, a�I �3�5M�-P.bli���䡿��U�6_)a tbshrew"� ) [25�/2{0StMrd� s:ncl*.��� �.�M&�6prefix H�S.B v���q or�sourcjTh1^ nu!scern�,�6%"I)$� trucx(�2� {�yn%>"� �7D�5�68�`2AvaVF �E3d [2Z1Us�@maximum ihoo� w�  �H2�!�s& e} �� Vg�/QPs:�&="*��*E1�+13S mRN}2 alog��i,�. pre-(7al� tei��pTP ,+���=nS�, penMD� {, P�5�* , ssDNA-b�zng 'wDB.w�� <fip5F��. O� �se-M�l�.ord�1��]no�Y}%�. �&`"D branch��31L )is+*_a�"�3�?oeo} ""7 RAls�BeAM  �:2� F u�*��0n7l>3of}?kre)8or usag!� CD46e��zB� oppo� ,to Coxsackie.RG��s;FD)�sq �%dQ�!� sia8&aci�D�2 �A�d79��"o!�hip_!9m�q�J9M5���]t1ZqTF&i.���49� 50 ,M� A��9assoc�JdMxpe� AQG�1e�/�ose*F�,"] ,%s.�I")\ with�l�,Y�c!��� L �B�(q �8E�mV1a� &�?MK� &4�#uE>�,����y��a6�9��:�E$manuscript>�4�)�� _BsIBD5\œ�e�����I�F3:L�#�D]Q�:orm� no��� q,h�&6�1� ��� �C� bov�E(�� ) fXout\?�$ k[2!4A� H" �E�:��Dp�M�`E�+�BA4Aw$ , yet cerŶ8ve e� embl,�*b�߅�Q�1J2. �8%i R�� q���was0ap�3� �%*�6't!H��;[? ~�0L�X‘ �!�1�6l]{sCd4$"�0%~s�A�M�J=1[B�"e�Eq�BA���%*=�BeapFM~acn#m��g.�HJ �T�Gplace D?�E�mFK�� �iסjwe dide*�ti�@n�an^�ezo5+�.!�a��DZ�� U�5��-�%n�{w !��-�)Ill�� ME-f >�Be�&m�0J�M��e�)�4�nu�)1��r'� ᇁ��*"�A65&'A�ei�IgWR>,,$JI %�)"� &}-= stit��t chang�e aminot�(|,VS!E. vT.sil� ( dSe�All ���+d�7���e�� agaN��-co1 &� ( dN/dS<1E�llI!mm�=�0�,3n ��7-iHi!p6�T ��A�)�u�a�tr�O7 pl�;#A�.f�Ls�diE�Z!Z,MP Afic � ?7�or :F� qer�D&�� eF%�6gnX�ele#B !I[/%<ed-� 3��X��.b26� ���� 2"�!�" v2a�&Y=-̩�0 &-�5�( K%!�O&� Wa2])EAasU K � �� ��iυ��Ncm ]�S*lef �2eme ra� end�GYw&� BE9Q�HE=l�0y�3� ���A9"� "-� %Z~Hr H-uTr�&A�E�{ �F(t8�fmoend�E3A�u0ale9� 0��x).a��mk ��#�46[5�h"�8 _fy ?�1!�a hybrid)n-!t2)tO a�6ea�'4`!�aN� 3>/O.}ompound"P.�&8 v��im�5%� !�a ��p(��R N� 6. Giv�%A�.rZ-�7C!/  1| th a�% )��9>m�s�&id�ye. ex�$� we ex�LF M���%���C�"\Cti& 1�d\V��E�po�L�5�n�2���O�^fyKf ?h]0–I2&� . WSdeH9�����v&�I3�Pb|�p�RU>��&%%f"� p|% {A�9�!A�surprisE�nd[M�2�� cap��DsMis' chro3M�  fy'!�i% expo� E�e o�Ny�b,RGI�ev� � !"�AU-0�l@�i8��s�ޱ�c�(�`<enyKe? �Ma1E�!/van �Ev�uE��!Em? $V�'�zs canJ rule�dS�8A�va_QI�i�=8G h!� repe["��9Aa-N| %�w�$h�&�"!��'�8ez��� !xQ�%�-� &0 UVof��� )�&�H=�e 7o�r q!d abun�tHu�sclymph�R�XRO;.�V�  [;8)*"+Dt/n&F"n�/-mJY�%rol��B��N �E�Gw ��C:!�T�'�!�R��^.#Q9X iE/!aM��**� !dissem$S�So%l�]l.�]6"o25��I�N�"A  B pa�[30�#3f5SQ a���&4 %3R�X(��I� sɣ�))�*A�6�b]?a��ed:�i�["j �Gonts� h�id=7H*&�w�cu6� %С�2;*�f��!���"� ��)e��&L.l�Eq�im+�8�Re��c8#2�!�tR�%V0 ;� �iriK�ejismN  -9� [32]0� �q�SaAX�]aP�{-R ance�\ . &hU7�(�ݭa�en���*/girr�<�,)H .G��� �#�Qes�3�\s��a��,cly� :ois "]-�H&�"��ele@("6�,�2E:�Z![ �� ���Z2c.jl!e� �a�0.�u�b;eU�e%�n�V�of$Z��6Oe�Ho!!�1F�5�.42!~l-ALB�1�D-�[ E�x/f_�]�:I0" A�s�`a�-pr�E�)b!�]�,M�i��p���[boo6Z�ai% -�G_�:��%9"�2�C��A�Pb��&�?�;OEbJ�4 ull lengt>�� �*�1tPly%a�u-硑[;�V\V�| !u'sub�Rv<� ,�.A)2�}',� � c��*�AEF Qou&�B E��bey#�B�)#a�S,�um! m  �1Aur��a��"tr�,��mIɁI�A~iI�� D#blO2J6$ ?��� u2��M�18!m&  /sitO�e�![�"vg Z5�?R�t10c*#lbX��170N��W��ag�\�se��:_ "�;� dra�<c��c�519C2�+j |c��� t leastEP,��Yyw2�%&�~����jn C ��t7# appl�<�>� &�[clock j<.p[3-!�Z*���g� C`cZ)񡼡�O-,m�"� &lsZ\�>�mT-��~� u�2.& jTcana�invok�oa�lj ��rf{ g5-�ka�� d 21 1i DQu�L.�"�e*� 1b���@$a��+M�2L� be� d��,�i>S5g�epA�ZwZa*�1in favo(M�zO*�WZ,�A�. S|.�Ecu � u�dAMe�Bmf�]v"HR�vo� ��0�bu 9��CBPA�in.`G 60%p�� sa�2�-[on�fl ��ed$;%ex�!���at*p >`a�?o&7�e], � .K���.A���ss9a4��.,make it�l�7@S �� exha�]v�ud�norAL�%�b�;_9rGVP_uch{�9d�p,*x-(AFz��Yve�'9_R�!$!. I�we� �S"(iJ�HN"� ��&$h%��lc:warran� �$ - Qo*�-��e/h�/ Mn�R�"��#%��ol&� %nE�&Qn6�P.�1cpreOe(��� ob%��F��:�E�eJAs5�nRD!NA�E��e.w!;"�Q �aRbE�V-�D�1E�2e?͗*�&B ( 24VJ"E��3�sB�3!�.0  ASe0�O*ev61 CC5��(! "s *�" ~q2�E�͔S�k��&�!\&�Qk*w -��1 ELeᘉ�� ken��a�*� eCl�tr( �/�XEM���mis"�:�"Td������ )ԅ��:�.�Q�6�a�cc�$���? gWMei W� � risk![%to��2E�d)wi �<|`er� A>ta�6���1��� A{@5�ndR�X$J[��a��&+d�_-[b���"��F� �9S9 iU+An<3:q�Y*�E���[3X76x I'-�� 2�z�� nd�;0a6ME�A� need�6b��� .I�� s%��0s S�[";���ATof� 2".2".2�@� 25 [�1I�'��+8&�;��  jeyvho ��� �.9� �"r�X:�b�36j6xr� l~!serum6�50!b\k���te�vAZ`���5^0d�QE2*�)25�#nd)0�5)9$^n!*� �[32bAbes���6levelŗ.P &7 seem*� &J# Z��Arr�V[ � ���i/ ��&�{S ���E�A�`��k-�>�!I�"9� gastrolri�`[3�b�U�l� �Ikz�>Uex�8U.�."�!s"�kA) ��1ja]CF�A�A�pc�V"zn %A�sP����p[zm�^)�e o�,@endl*�;~. A�p��ei���D Jaa��g{4 4 p!9i�`�=f�hb�j0YIn"q al A C�!Use Comm]R� � s workE5�{:q�(5.�T� ��;�-�����%6K[!- k�<&.Q,in Hanks' Bap.d Salt S� =9BS�),�% A�jon !C�e&� S%|5YGifu�;o�!�� supe�A�aQ�Vile&�Q1U$2 µm syri�*�Q��~µxi- �&� �N�QE"to.�Q\2$ Ham's F12�'umI710% fe):g0�� ( FB).1% V[-StreH 50 µg/mlautamX\� �?Sg�P2 weekA� c, vis-E�;!o&� :b )�"�� �!�.2#�^uPsa�iyl^� Zt!�l�J 9 kb|�–%�&$en��KngV�QIa16� 9���erA!�Ji� UM�Gr pai{!J util�9HPCRXCAGGATGCTTCGGAGTACCTGAG�dTTGGCNGGDATDGGGTAVAGCATGTT g&��� -y9�%C� � U o ���*�!�<t}e4BjAR1͋�pl]�҅5A/ 2.< ( Qicm�uo�mServic1Hilde�TGer`re6� Z�\� A8E!Z�>��;ou!IV�TE4GYTTCTE3YTGGTYTCAM>AGTTYTACTGGGC ,G �ainnA�E�T$GTGACAAAGA,GTCCG�3TCAGCCWzAAGCCAA�ZAmQ�*,FA�.f� �Oed 8 g�0t�^�aF�r6��(:=.,� 6 ;Eut�:, E1A�?b�:�)=�, B�; precursor�.TP%�]�!�K#E�� 6� `"� P*2)2&�)�si��0bq�)&�Kun-t( tQlt)��x�-a�ct�*en� a) �E� h!� i<ced:98!'G�*[ >� ba� alig��i��' � $�F is g>!u�8ough "b,�ofp-2G;]+p4e��llyPN/�\(lap�}e{���T; �*i�>�A�� ����ftro�Il]N!A3J�sE~>�GT-AG; U(start-stop ?s'>air�Cre�-��12((exo3P�0%��6+i �u�;60%)�AB� 2�e;p �&�( H�O�c"h!=�~ngr�$:>�;>Q�Cg :Qs>iKE�1��6q3aJ4B�J%; ��0orAS Z y�*V�gh�"�c!�E�i2;)e5�es-Ab*� O#'B�,z�� a��-�y�U�$ClustalW v�,. 9 softwz [3�BF�r�!�.�5��9t%�A)�r&�6M�2{�;���PhyML.�8]*�HKY85*l [39] ��Ca�Lon/�4 A� @f� o�#in"#I� {3ret� gamma2�"r� �1 =[4eo�esa��liym�61o E�9�y & "7�A 9a!""�a8}at��n$�2@!� �/ ���D�� w���d�� �Old W�t �]�5EHS0 � 12�RW��enIFM"remai`Le#.�nd back-%��hema@�yC �PAL2NA.M41\Mr=\ x.�!ju 38YSuQ`s!3m�#y�M�3*@%�_ ^PA2�42.�>�7 X�st9�f7E��1�%s� %"9o�fQ��-�Z��Pa�, rup  r�g��pofyH�� �!8xinuous7]ngo!'d)A�:�. ��u�jH���� ,Af @(n�w�O� !� . Its cry�!f=Af9 �,2� HTEЁ$B�n oct�sic���HBME���e��,��)��K-�u& !re��E��#Ѻ��F2,a\�,9'�3. S��-q,6��E%#A2��[+[ .G(a�&�A�zvard��� H.:A=acth"1� FRET./[�h66;�-�*ps�i�^��(�'in���Bsu ?DNA�~)ZB9:0ontaneI�-�\9iυ8 A</? �b�MGfa�!zo� wrra 6��9i"� 810�50 ms [�bVSn�":!�two���\A�=$y�7r��[;#5] *+v �(e���5kipul�j *Q�!5Y�F .�5���%eas�a-U��I"��-2�. L旱���a� unzi)\82/ ( , Wang’s�up!�o"D6�{N 2VU�rlf!2z2iY}bjg.a��v�`#ER��:5�i!�phosph�+�bo�%�Gouble-EnY?Itea�!�e�ently�%� �a�A#�(�+!T&� t�r�A�!�2s i��'��s�m߉fAl�.n�nM%�n�) iso�; l-oN� ( MD )*� �I�Z�G`\aiI�fF�)l�"� mK���–_�$Ettig et aG�W= ��+ arrya� �MD2�F_&� . ]�"��Gribkova�"w d1�E�vT!PDBA��7U�&5� }R`C�$e�t 7�Zq6]* 5-bpa�iou}>��Hbeco�\"g)/x%$i�(A�"[cX ucH0>,s, a�9'�p�u(o (eeMmq]qp G���d unreal{&�4�:��� OA�}8Coarse-g�Ced!��n�bE�D1 etho�Cd�nt� ce'���r� a�ev-��q&� sd al $-of-the-arR-m�L r sy�a�Kenzaki�Takada!�a%�cB�o��،p�"d�idue-�'"� al�  exhibit9�w.�!Mr�Ym&�K[1�S6���>�=�g+�z* ,I�� � /J�!�&� sH ��.�Za�eM:96 , LequieuN�bten-��2* KL!"c'�� ribj=� M� ��� ���CM&p2�zQ6~H3/H4^H2A/B <[Z~WLas %p�.�*�bB�, V #z;���� AG�� @s�9|��>p=.� �i���u .�o:� MD r!��9ad1�e`p��~+;�oV��o%*�0�.ess�.iA�F=t�R����>l�y sol�5I/f4!�dfe~sis"�1.��w�� :pnj��!߁�al en�VW!�K �f��-f�P |s3r%T]d���a�!Vt.�I0�e ic<���>.�) pariЃ ;*c2m�e�(f�mkp  7A�� # ?�u� wy{� � ougr *`� a pseudo-3�M�d�eM }� . In AB:��bia� �@ad m�& $yd�GE'%�r�.vi� d*� � re� co��� � “f�!��� τ�? �0w0 iѾp�ac�G^��r7|!�:�C9by!+@2��3s;"2J�"�- /?\o�R�- ��� .saArt:�,�Z Ua�,τ = 1 p~�EB!u%khe dsEh�;*M}U<5.a�,0BDτ�, �1��m�walo0:^10(�5c6 ��x$ڏ�a?U%=� view2e%ur�V?o ��>�k&BI��τD�p�NoXmr6�,-�eR�!�$� d��Z6E�hX3�8��1 iBTU#�B�� .!��15 ns (5}a�%�'until�d � �converg% t"Br�֩�%1 enti��XM�N# ( S1�(S2AE\s�'O�aa ��-�1�� �%.for�~� V�d~5S2Bd�:?�v�1! � m� i�����1�&ѮN�(t�=fkH.B$, umbrella?Va.�%�71� s 2 Å!�widthi�4H180 ��R<26b< 125 to1752<2��R�� .�ATA�-�#24A�4� or beyondJ�,:A-B�!���abn�!j.ԦB� break�G $� ( S3M|3E5ɇ"�P$end-to-end^����^�ho�.��d�Gg- FinA� !\W1�� checA�&i`�m=.e, q�O�QNv�J����tJW�� WHAM��a�la� E-ea�^��k10a. σE_h��7Y.�A�fv#"� u�]�du8#R.�14��XeD466�,* )i��.Te?%y*� �E�2���ɷ�k*E!�.�i-��1��,�� t6; � Eqs �x! Fig M~3B�n�ReA}s$]�->}�R�:h 3C63*Jsharp���dS��J�y13��A��� 9�< ��}2�'sy���>�3�)Nttak���e "M � S9.�)!: naT� ����B.OE�um� �/��#�5�!A5N.EńBP�#����Sh� �!. �gc]o/͛ �sh�r��Ze##C��1~� ���begin�(u�[>Nt!���� a� oI�-.� 2.\nȂ�J�zl22) �._!+T% ,{�.I"A{���!��).�� I��������|tra `oWzB� jX3DNA[O�wtab��C�+��8S4���.12Sp  S8� �Iu��K ��Ye��AT�gd5G��TA��]��@le#�!� �=�s"rC�;IZ�m.o�_��p��&cow� m���і�� y.0“Oof CG!�_��%))is;of �)��atQ��hF� )eD(�iS@5�� ͊a�ehM'o��erg�,A8!*beC�or�et6pra!�Bn*}��Vϊ%���Wa� Pb��bJp�u �&u����A\n:ye��� i�� J.i6&���:�!��.d-�dIN*>���:H20–25�-����pڥTX>unL�st!�y!���%6/ ��� �%onR0�4�%��".at �.�!�e- �graX�2S����17}%� k �� Md� gap&�S1I�14@!��1721. ~=� E�>��$:z��2� a�FG �.�ŧ��u q��h%*!�s�A�6"1 H *H'?j7"�0ar!i Wi �e5i!vK" eR:>WJ"V 16�  ��%6d)T�#! r�V �62�� ��m�.3B� N� �2 F� 3Va&�6A��Q�YXbp�� �Z ��.�me�DX����ol��Jj!cTUAT�r]-( Yu"U=�8EǑ>6�!aϑ�(�;aS8�\V W2A����wiiG�%pu<'�%ShB�%z�eGAA�%�s 4Vw|,�V�of1�a0z&����_au�-mw7� sA��d plot4ctxke�� �/�`f�gW)b�� R |re�Omal�6; e..[� Os\� ^Z�L 8b:�6Y����a�'*� 2i$%�!E�!�2 o�l i?1W,cI� ��P!�!x�'�R���;h�|)�PCe"� h�5�v�a��WJ�����Ha�Q.�2 �)��1�J!� �A_I&3���K�F~Q>B x 6M� n��2�-b�6�9&%� ��" �T�6c, �!�P6}:= � V���A !��lR9a�l�".�g6me�� �� � i�&� �r2�m�osquԩ6G+( rmsd )2�Vv�DM �%�� heavy�&�*� 3fs)6� � ��أB � A{1��!M ]���BJ&��2|cIO�?0(���s VH3���dEp<H2�{19>/�S�"]�%K�xՋ9oo��!1cZofG� %"�?ns� 6� E�� 7�!a�6�,�&�.�"_G� �DKe�* �G�8"hh58�Bh9 ?� d  flu�%� of PQI[ �2�0� cano=�"���S*�A��N�GQ:[1���Y"� �+1�6�s�"sA�v� J^Z0E�%&�"stochaŠ��ZF Y"G��!�J S5iE�e#�V�1dVAm�faXo o�%lt�;lo%�%�}�E�_ly 7�C� .���K��(�-0�!���&K� a�sch%n&�j';U7��a:�3:�a��we=6�/i�4 ��'�4r����.�+T U�� arAQ���Vr�`e���e^�A�2E.�,�4E�s !�.�] =���o�N�k.�&�T'�-+m�p�!o���.g"�. N�1�"�"r�#4)�a���5�s"�#�+tE�|)���s�&��as2��'�]2��i�`&�3�3$�e.A�"�", H3a0~nH3b 1 `c�5r�'*mvj�=R9!HV.��rfac�.AE�p2'&�H3�� ��;a!4� i Qry.^E7of�E� 7S4� m~�1 ls��uV,.�&�� M�)$V)�*1���NAI�+e�[qՋic{K! �zu�((>�*��<*>C>��{6ll.�. R(�� �40&��aQtegng�*025+�DS�. 'sՏ�^ theo�E�8�*[2:V��4 �%�cfB A�]�-rA�y#� %HaZ�r�M��%�C!�,.L:@3���ed' WU����O '*� �VU9�\ )�Y !<.�'2�i�4s�s-�� 1&\�5��2�b �).� �`"� �l��\-. B;a�=ni�;-T$���%,�%�:@�"��:)��c�rUlos�M�Ɍ"7�nA�K.0�G!�a�#cA9�Vw��ItBa7Nm [��F!$es"�/�9!2ENnt��1F��=1hdisasW � �Q:Byai �A+* ��8�J-*��&`Vw3�6� ?��A�y=xa.�-�pH�a ����� by hMSH2-65i�C!�scA��GR�mod&�."Z �i��Hd,2-� ptep�:� �=��*�4A"0:?��2�o�2t"� Hᅉc 1 kBgiwis4�sY��t��i��[sJ,�!� }iY��.g J !�&�F.�.";e:z*'3!���LRd�7�(];con�#��o�o , T��q#f�?�(�& !o� uMc�^��/ A!�8� 4Z964XoXk"�i buil�OalwaysL/��d# c��ir�g�$ie�6�I,t#9��y&Lu�4 F�broken� 0eѵ� .�  -�� o-Iyh.����r}O;˭" ^s�Dga�qd� f�Fadi��q#w�ulea�='"� e.��=Ym%��6lan�*m7�h��/��ir&�8ze X�C��H3 αN �;x "DCq�u�49D "^3gtE)6�meag.d ju�$A0B!4Y�"�� �"�N#��ll���L"A�actazivM�8� + ktpF� R49Ah8!�"s��&�P?e�2��egR0=T�lR52ER5B&M1�of V4ML48� K56 haU2at�F-0eisP{�U]9E�PZ XS-S$Sn�� A�F>ur"ݥ�Q�.h� M<��d|>hv55��:.`=t3F .IA��5GA�B�of1.Q5��� �lit,�or�D �UE*Ar,6�2�iBarj5Q��� �5�qq�A6�2@ A�& ZNbe� )�5�V2i� jeV����ICiEZ" !.h��T7�*R77!M�Y3X�K43 B*@ -Rhydrog��od'a![N�2�� ��a�!� "m�,!5U������1 �:D&�<d]o��y*%Jm&�2*� �k�(S�+S3D���1�N�" Epa subA�J g.�2�I_9�( RR��B��B!�G5E4I511�)m�3KRCc�#!�@�JB:2Aa1!�!T1I!� H2A- heterodim�ٹ�n^�[�Kq�+<� M�=AJf%��  �I�allq���A�no�E�'&" �!*�%�.Mon�wA{� �k;4 trun ,�0�+.Clh zCA8�c"/��36aQ�I,! �� h�(s'[3GB ���&:��^n VjA��Tat�C�]"si� �_SJ�.�o0�no-*-���<��m�< @rtb‹%.>�/di �>@ belo�6IK \AP knowy*�.D&!�{�? �"Ufo#��&�Nsolen�~[�i!3��jep[� � [35��SIn*io�4 �"J&pla�e�'�C���"M<�(Langwoski�"�E.�(H4K16 acetyf} dra((;re �s �-5�iT�2\sta63.�>%� A �Ɓj �@,��z�X4. Ishida & KonR�-A -ly�i�A[=2WK.K�!�l � ;wa� �6.�X��r� >2�c� post"mWR82r�DhrfQ.(!��U68 leve�&��a�W1�!hhP? A\w��er9%�rmo� O3�W#!y�Se=�ch#8sL ��~�Q15 �a^��IW9�&�A 2[4�"42]�g�%9� j�3� ? s�st��1&=)���9� t%��F�&�O rI"aV�1paװ*�kiw T�VO *zDB�H\ , Br�-To���F.��с!q�p ��af v��^"!&�\X����n��.AXS%�� 9��`�enV���Is� oruF�I"�J)���ir p! �b �2sEZiW���.Fof%k,k�-��BV:"a�a�w�>��a��/�&a[�"'Y�#Bis�1��a�E0 �g�4x>_2� m�� a.R-�%�!}�U.Ba�;�2�?AAc�Y[1�[C:7*' ��:� aJ�N�B , ErQ��H�����  GfJ�L�\nd Arg�J$#��h�r�U��J &UK~� =ay5�B=�s7$ [4�6�Fa6�2" by�M�author��g7 H3 N&���%�� C:�10%�֓kJ3[13��!$%�!l���/��Q��$�5"� liH�Z]bi��m�[46A�MD��ۭ7–49]u�.|.-�X  ��αNx��6t� D!R��J\H3_u�!�2�e!6�4*�P2O}F~:��� , 5�`H�,1sum������V�E e" !�*��!4\1.>v� 2�7.w���)���"%ET!-e��J�$J !;su����`d��&f}bp"c.�+woz$PJs2�10Z"$A�d$A�l��v�=e��*�����Q�Q!� 1�#��,K E!�iBc�2F�� � @�:x-�I %Q0dTG�"�$ F*U�.�1��%��P�U Data B\ɸ$:1kx5 ) [5��Aqi�ARi;�ns��isc!L��m:��ccele��QA$= !���ED��it,�w�i`�lv����`N�@�C �$46`132��f)V0%�bdqqv1 /142A��3�121 B �%�c:�A"z-�6[1�i) P�8��"��c�w�JbIC�<& a fu;F&cPN �+o��x�.O�=|>�U6�e% adxZ`CZ�H[ar&�(6*) O [52]k)b�s��multi2D.��as R��'"f��"B"?g��ramh�,CUBA [54–5%ToW2��a�5a;��h�n�em��=&�y�w*n#S�:�P� −7}−58� Len�$ 2�!E l�6ag1;.M6M5�t.M 2M��_��P/E*�Id !dVab�T}#��e�&C"���t�W"� ! &T ato?T7!�ch|&Ie��8.JCgTJgp����@fin PDB�� ��E��q1+�box�et��'R��2�!�)�<noT-�4y��8'!"��a\I�,��B�$ܹnBQ%a�18-5, ��& 2��FFQ@*Fi� ��p?.�w�" a fi%8%#ao'] 0 ×��3""�1� 1K-� 223(e5%� �{-� i�p!AZ�,airan>-�6�ZB:6H� �?�i0�&�Le+cho�*$v!�W�3.�Z:�g�N��i'�"� "�r��s��)1�snapshovZaU*dHE6!2�=��'r�100-n�E:.2 @\�>�QJ�Չ ��vr[4���$a��.1xYF8�%�f�E� "e!gVy--#� ~���92"0�LF$� Forc� eld-x@8AMBER ff99SB[59�  bsc0[60� J08[61"��TIP3P[6'Zl� %;IsHU�Q�Cm�1��M�S! NaCabex z������lx!mp���"�}A��J"7sod�� �= T#�2 f� ��W��k"qrfroze�D%SHAKE al�thm [6H"64]�5��e!�mreg@at 300 KI4ev.*SEKo(>�����|�FA −1��b�H [65];V� ctro� ic� �Z%�8Q�!�pA� cle-  mesh��PPM*�6�67]; !> van �Waa�~sa cutoff!�9�oÅzn%�y_!���#eS:ma8'n �%f�xFIa��ma�&�H-_sp�01 ��w30&�����pP)�`�al�M�M�>��,*��A>�N>�B��m ��fl�(�4-"E J_Ki��'�\P:<IE20�maą�7M11 � E�To �m%���p��zq~ ��1ha-�٨-�f��n���nat d =� A�1965��15246aLT�e.d�^NΔ -+�!'pBE�ZFI -�L�τ�J��e~E!A �= �Ppk�d�2��N�%� !��@A�#88Y�yR� 2 UFz P%��S �h  �Сk��>mS�Iμ�.�(�4n7�@ƮDCage&4��&��� P!�!5q!2F ���X �}x4��ͬ(�J nodeH12� s ��f �:ll6UB�)K�] e×T&��if!P��� eno���P�Ykernel�zm[%R��U=zyaBv�R toward� A�Q.*w4 �a�%�aDV�7l�4, , the free-�energy landscape , or negative of the biasing potential , fluctuates during the ABMD simulation [55] . For that reason , umbrella sampling was done to enhance equilibrium ) . In�uBD,react~,coordinate w^�ivided into 71 windows with a width�t2 Å , which covered 40 to 180$in stage 1 � 2 , itFk26~ke!125g75g$. We prepa�the ini%�conforma�s forJ all�. First�\e sorted 100 walkers acc%*g}:I� 2 w)� scara�becaushDeir DNA structures ,@clearly corrupted��highlyE�e�J>5Zraw Uobtain�L�n� , 5 �d��i Hj2�kB1 BoltzmannaΉ ,evT"co temperaaMɝ$this study.�A�selecA; to be� sum!^���� !�� b�final�fMj1y�&�\ha)���: VA\Ae=k a�−��4) 2+Uabmd , ( ���(Mw-\մbetwee)X cent��of mass�two term�$nucleotide somal��.�E) fixe��to mainA���-� rangQ 2I!�ervalw}����e=B�!�62�PŨ�� . ki�(n arbitraryݚ6�! IIt�Q0ٚ mol/��1vAcarri��utA 15 �)��.�1�5�e/!̵�P ��;9. U9�.Ew7 |Ɋ!�щa9P3 shif�outwar��*� 4� 5� crys!�"? �p.: M 2� on �e��J, canA�writtene� =∫ ' ) δ!P2−R2' ) dR'�� �)X� �,Dirac delta-"� )� R2'= NusN  in 1y�E�Zsa�m!��:���6���6��descri ch�/ e�Ё$�Ŧ, respec��q�exp�0a 1!YU)7)N1a1} :4d4� 9 ):�6�n!�D10 )F�Environmen�insultsU� oxid�st�e�Ldamage cell membrane Lys� es�partiU�s�w!!J4 perme�z)�si&t�u�depends�nintralui acidic pH%�requi�stablee- ?� (proton grad� �Ama`Acataloga >�-!�ons�ge�$ Lipocal polipob,ein D ( ApoD�an extra!0,ular lipid b��ro4eFedIw�(�nt capac�6. � 4nervous system�z!�typ�v�defenss ontl��tastrocy�,�� rete �Lto help neurons cope �Tchalle� � �c�yrol� �is knowni���@to organism level��m� (of its downAn am effect�� !0optimQ1@of autophagy upon �de!�� o'have b� ��d . H"P ,we still can# ssign a�me���to �a�ta�lainsD &1oq mplish w� 4er�fompreha#ve&� of jE�9Bra{ �udem�rm !:%� in li�alahomeosta�%"(paraquat-in� Eie�!wsaB4mbi� � le- V> vivo]measure�> immunodetA%~we2� that �sE� cytoF �targe�r  subse�vulnere���] �}�� er .d�Ial^ �eE�De�M�!O��e���u!v�7�necess�� �to re�I�-[on5malk�2i��, bot�.�! qagis��2Qby�vQng�a��Fe. Two*=;biolog�pro�:mye��ae)�i �C�>��.�-triggy��( DrosophilaE\mod���%�-Eed�xA�Our�nŷun)|a% iously un���Q qd,�0���ly��� evol:!�erved� familyP6��#�The� ��. -medGJ oa7of9���e� egr� a�new��at�hub>�R�6�K crit%�A��outcom���e variet�:�vQseaAA�ese5~op'��`� eC�=L[14!�e�r�-�>�-�"� � >��as�$,blood� amQ"�DlO �Cn���fewB inU�over-&2� e�� brai�en��"&m G0d psychiatric��tes�so��A8!�AH bi& ��I�=)per !��-[1�02�02{2a23 , 24] �ts �ty!�inhibit a2NbA�duc�7ra�l-propab&� S hydr�A"es���ed [2J& �ё6�e�%� �>��u�ajg o� pro-��a�$%r) keep� ume-ng� ,!aani��� �ib�" %aex%�:� pleiotrop� conn�ng>��e�!2�[2��27!���2!�30� � �8after injury [3!�3��Iw�3!�3a\3�Hor diveroorR�on [3�3�38v�w�evA r& [3�4AD4�4AD43]p:��o��J\a�Z*-ewas r� ed!0a�Oelu�8y�onAcuA� &�*m melanogas!�hom� Gl� s, ep�.�yJ� hip��y� ] � I,!% gg@� n]/��&�� polygluta�s �@ %�� %ե�z i!;I�e %�pheno��12W��]�%D resc�FR�Jk%�".mX#&65,us min^+�n�1�]icQL.��� ��Bu�&�*� 4� eh !�flu� s=� at s%*ep�sloE�2m4 !� ulti�l�F�it>�.���!��)ѭ=y� ��Bletl�erk . � eval�2��gEC��1�A��3�.(�.1I ) g'FLEYEe/�.�"�!�!fic [S$d9aacquiBofkey�+rfa�pi:/[4� EeEdeq��ofF�:�(( hATXN182Q�(�.E��DorRNAi ck-%�r HOPS-Xxa�F$ Vps18/Dor&D�te�ing%�f))Qꅟ�͖e� 8]1],$�F:iT*Ca1Doomp��M�A�)�A )B )a�,M� by5��![-�E @F��!-* (itself doesE�pro�@EntJ�_�3l�] sG ) norAx� $eJC��&�by����0:tin��X11H�T2..��.1�-2�%�on�+n�(d%�%�>�@Xat�a��%���"42�misfol�\��!96�v��1Di>predic$ at� s mus9 er.�"�'1 1�Zu��� �/9A�!r.� l�"[ �N:o�A "k in�#d)�ns��5m� 0>uu p` switc� to� �!5f��,.B.!I re;1ts)��Ɉ� B�c"�"�g< tran�'p�al.]u .�#JNK,wayGWe�� �br�e,n �MK!e�.�( 1321N1omu�#D-avo9�#�i9B,al��6�1�tsN!n $&V seMbw!�uc to��co2o� % ic2�,ow serum ( L_�treat0 6AR>�5!!Iaga�p�" ( P�W at 2L24 ho� {stimulu8� $S1 s>/r+.�of our i�&"F e�80�)z-stackv a�6ast�A�Q+�^ 3randomly N� ind�&�ex(!ͣtripl��eL$s ( see Mew6s�HF�9!Nrou' f princip�� mpon`�( PCAEK�$�!v�nsy'7e�/on quot� ( IC!m�x [49]�6�c%��& 2%�Dhe % Pixel Overlap�?))Al�yIXqG.)$ each&� )�;1><WeA� a 2x� thresholdAx21ea>�� �4�id�"�ce [50�)S�( F! � t�&N42%$LS ;nlyA�referu2to%�)"Q��n�50i(�� fig9%c!�7!�ly2ClathriA�EEAcLamp-i3LC3-pu*rga<,i��+n� U!�M87 som*<& ari�( LELC )��� ��2A–2�. B��- X �f-�� �~��N�$Caveolin-1je o2!�m��=3�!�6>_oveY\ � ��ig1� PQ*�enrich� !�oba$`*D>i�m=�-9avLC3��24hAعj(�berisk �G2S%jS2E�2At�r�Uti3 ( 2h$ b�����E"�(or"� A��M�]� �X�3�%omAdt> �'�)A>!�-5�!E�� I� I�oA�7Ha�UAaQ(itochondria��A� �}invol&inB�V� !�manag�M1�F–S2G�%�s�%a9�a&H �9),se6�+!ycul�9e&u�S3A\��!-"\ed� �-yQ>@kidney-293T ( HEK ) z,: O!P5LE�� �o J�iGim��3B�&�no.�>7U�~ %-c$icjcul%RER; S3C i!���b�v�n "�6[�Golgi�=a6;�Ap �^7.�� ra .p g# �RER� T��.3 migh�%=#)n��!Ubeu )�e�tEA]�,�;ypothe�%su�'"�e�+-�:P9 �41�!��� nU3I�t?D%"A�To fur���7spa�Bdom��_[Hw{�"� we.�2aa�� p�=�7.�����al�2= aram? 6� fluo!��tG takeA��, ccou�n m��� e,t�of��p� , e@1A��v�5A�� !ͭ �6>is quiteAs 8–30% �04� I*se9\�$ comm_�cm@0��q . No2�X#)�1visM�ed� PQݟ�%gge"� !� elev@e� m�"& abov�*as�J��r1`�|�2-%;�Y�y incr�*akf6M%Vos����6Zg G�:� B�Q�!�*%�| �.".���detai�c� )�BI�ir�1|.)m�-s"aE� )!7 .>C!o3V �?�%c� n+byK h 7�! �6r�$�� �)smxi#3, :�S:ph9%arg�d yD"&)%�obECs�f& ���te D%�m�.of sm~$X s a��1YsI��P2� m�"� 1�in)����co� d�����6lyy�: q.���to �er&�,:���%,����"^ � "`B�5(:Q ,s/ �9�-��e +!��!dot� pat��� 2MC�� rrowJleft p� �CBy�ҁ���22��on-��F�� �>onfir!�olab1gAZ� d��ceo A�6�/�)Au�17B� head�ri����I�-�U�m?>Z�!X�-�a&+ N_�6� s� eq%e�I�ba�%�'.6�!*d1�es:�B) A�i��\i��_da��1��e��yϡ�ord�e�!Snz R�IP�" 9ii ) S�, butA ,bunq,u-assoc�1%_ �#tE�))p/Fa��{q� back�ugh��xe �>.t-� 1e"A9A��+�5J���J{!y`��:�e�^>� -^�T�f�n�͉�d i1�`e���4~4" �D��!&*_x� d�@e����"0 �S�"� ""�e"�-Z��:chloroquN( %, �#n!�"�+: +!g��� ��[51'�<lJ&+:��`e�)q3E� WG e�E:f�!5rD�or Nd ��� �J%QI�;��5��/7���W##�#ll'w�:��drops� C� ;#e"�8e-/" 1PH&m]BI8CQ�� QA����6locqN�Dnm� stepy(3-methylade@( 3-MA%sL&N6J ��! !;-!�:�.->�qI���� mTOR++(or Rapamyci5?Rap�Anf1 � amp2�o��5l7>� ex��Qo�3QM" V8 A�=7e6���T)�!0&� A=��1�}�)eLa�3"� <>�K�J!D� �a"�+*�.L1�3� ,q F&+�'i��Xu�H J�F�,'yA resEe a net��F7�� �L, tog/Q���E:� �� P1��� �2� de2~1|of�M9�v{7 ( S4�;)ю)RA�!� ^A&)&��f���2c *��PQj � �& bJEp&�8�1r7eu `ro?, rosc�-���H.�B��'t�R7eI) �d��� �  oc�"S�|A> ��z^�&i�FV�- d=@5�2]H"�4� . Clea.�+�'�"�F���"���� be�^fe�2F� EIɤ%M��RZ� , be? ocy�>in&L co%h�-P5 B�r6�s&�,9\)[&� L�L�Aondd�3�Z�+w �:n. SB: ����VoN *Ie`A�- A�> >S]it�C.W;8 3wh�3dEL>��;y�2f�Ks� .Rl5@ '8� bAja("�� o aA�pulse-cB/pur� hb:O[39�i! C erio�!��ur� ���|�&�X ��upA!48h�i6) ��� �fIN2� �H!R�, ��w�d0!�I5��.�'��c�x�#%d �glycosy8 J� qly2�AEquick�tm=e�K�5IvC6 �}E -iH(&5�a �!b�`3N'�%uzLhg%E�{!$��disappea"�+ fs ��!rs�Kv,�vblo�B we h7I)d�a���=*3/�"6'lJdurAa�3= y>eEI�-�E%J5aӍ� fr/oZ.9 losr�4d-/%�+�uB�&L&YMX&0a2}"�of�r�>��'��1aly[` ՉOul�� � �["l a �2u$ol� r!�I�*)7%��sI\*�:u @ 2�b�ocarbo�6��$shields ag�F�@te2 is [52�In ad�1im�L"�H�&!��7N-lin yW!� [53]�b�6�,=+.D8f*<�1- ase-�+.E�z. ssay� aF��4be`I�'�A͵� �@!�E(tAiga��4nspH 7 (\ 5 . ' 5G;c� li��Ha�2�Aj& �e�Pder|&�?)�� �"�B��ZF tino� iTQaUic�8hobic��"��$:h�"5@s��s :19�oN ���SJ�*�(al-p�"�3AnpH5� fi5Q���9t�69eaw^!�iri �lip (�C�#t!��[{&C wita6A��A}.ink.|�A� j���?'j�)R�9%R0� %:t*iG!by �,> �Mle�A Sensor Ye�,/Blue DND-169a E met!�dye6�.%�9Q��~�ń!��Ņt��%dMat� ( [5�9 55];E��&!+S5� A�f% d eie�excit� "�x  *&}4- S5A E ito pH 4a� –62%r emisn%N`� ingl5�6� �'+A� <,�'sd*o�L��M%��a� ��( S5B�!5�; Lin��fizX��?518>%�X%g�CE4"�#s7 M"ur��a4a=gm� �-�"H91&M:i�6R CF�� � �>o�%� a;.@Jp)of2��ul� �*�$�"I(e�7 ��\�'5!L�/s� agre;#a�%5" *@�(I"w$qmq&@�+'@�(�a͢*\A���e�s�) #g&�1m�9�=W�Aa8`as d�^!�M�&��! bi6{"� � `2�jtri�2�c� ^f�-e�Y.BEdpH>� 6� eFehA[E�� �aw>�%�� �7j3ximum�m�/�PN  cbro[2� (�ge:e�4�uM�q�Itl7�� ",]YpHA�=4"!���:A����a�9�!� lowe �, p:� .Iwe$�)Q -nV5 �e966�il�kE�(u peak� ftse2�e�6C5+�i�,QB*��"z-.O �A�!�s�Ku. I! �.(9�hf"�FCD%����.eA�PQ*�;pHqc?� a�e!!a cauH.� "-b%G)Dc�"Պ�e� ! x�J�KN�to�e9XA!6w,a c taneJ)0"��+y�) ]i%�,� ��Oo�S�:���,Alt�U ng �%�$7iW�alreadyEv�9at�2h 3\^eB�e� J@(�oez�� �d� e6�:�Á|� f �Dan�e��U� f%>�da��7a����A��Creq*�J$@by RNAseq techniq�0 ( http://�Ys>#y .��0 . lu/shsy5y/? .K!!�"��*+?y�pH� b�$�aUoA�� osis&�="� m�-��$modify!�%(!��byNP�  d mL% im�a�,�Z�"w�8 ( WT��kn<�   KO )� =%7D%�%mo7Vw2/D:%j�N2�Jre-"B=&�"-[�U�_so-#WT~5>�am)%,�Ado&� �pHB<e rA#�!��SA:�<i<ś)�6�.�eNar:���ecy6F. SD7�,97ozF&8*QPQ-&=9"OinJa)�"� U�"�u���& e� k.)Yd�^2N5�9g F�J�!�re� �PQ�.]dq[�)4n/%i*�/%�J�`�m"�Jb�!�e"�!a>/�$&�c� �A-��2*%n�X,� �+OA&�U(%H�=c� }�pɁ�!m�5atIp�T��+ YU-�eua]T-8 �B�,8�A��oeQpH9\Q!#� h�6� �Ue� h6o �]itu$)� �?edrkE�JA/S>�!y�i�B>�� a�)-�0!���i� 8�@8�!p!^a<iE"!�i=? Eu!=A�a:G6� w,.��Q��3: �o2�2h ���� g.�.>�1J�2 r x-1F�k KB�cI��*�*�]!%eAMGPQGnd!Ga2�Pt1�V-�*l�:<2�Th#@0*� M�i�1o>�(�8*�!sK4FC 1� �B(�U��4 simi�Hp�F meno�:UVEh�'��BU � �o�9B>\O1� fe�p:5�.?ᯝ�Eya B�dh8�>*"l:�M !�n� 2�"�;!�J7is�*&>PJ J�����u�O:ata�7-$n�RAV acce�ma{/Aw�r�@0 ��B��Q]KW FRBa% expl���CT�?z��<w�eN-: 4-  oxyn�>a�>4HN}#I69wi9B%d9= a���aO�+ofOri�9adduc�CMpZ� *vvU4A��>e"�?�D���4�Vp-<WT.��eMas� �R;�c �>!�3 ��vely_J'%Fre3!�ba� oby�~56A�%1. d�s!a�� FO.#\AE �9?_ fail�� !�� �2�Q;&LFA�5"j��ANQ��&B�[2� StarKe�a37�*e o�{t?#k%3�QP[2h���=:maEs!�9�>� �VvWac )aIm`� U:_��of 6eocc+Cu RNA . I�f�&&��LaR�b �-9�wo�9�G!� .:�1�%}�D2!L1�Qi#EJJ�E2s 2–v)X9C].# � \=x)�M�J�co�n*�D high�K�/c�� c��r [!���_  !@2Z�Fz,�E# �M6ofIq"7F;&s �).J6a< �P�)�c� �%�bound] � �Z)�a.Q �����le&XhX%� Wnd&S#%�5�-"�+d-^� s�?7a�a��"�j�� a�km7�JH� !� C#a6r�ML �u�� �9��u1/��f or��N(R1�2P,,U��2)%J6���]rlH�aro>�J��} 55jq�����dE���q�g��k #q� I-_aJeAY�w%�Q�A$=X(t�P�#�q�{(&&L��!2����%�&� r>GO PQѽ.E5A�:�a xi � }�a�irt�u�� sk!<Dhfus�1���^62pH2�cE) ����& &�A*�� macr+Zecu�^[57W&AB�!No!eI� ��n�0KO" 1�"?-9F"9�,i8�!�>�g��72u B'ip18��a$Mn�Ir f Visma9!�� !s1��Q b-�*��&i"< ,�k i_UXqb�2deb Cbehavio�@N��/��a�-4w"�1iE�!� �s�.� �#�'im(qwaberra�`�h%%0A Cathepsin BYE'��10�G10C te&�)!�r�7T �.A9��010� H,/ &|PA��ysV�� � d y �As� ce�'pro�eda�"D�ar�l��4 G<e�~ �9 �9���>� +10� �RT�4&N#w.�Q�\ *',"�$rio*d �2In�� ]�"E h*A . Ga�.in-3 %A?0ks�k��>�se�]���is Rm�n,ffu�ytU�]E&�6,j�� 6� o%ey]�d go�H!��<���6$m2�t�U� ,�|Ma p�+{��>[5acY�n`"�W��"nE=h Q.�!H���#��� 2)�Au{ �)�P� M� E�Oi!"��6� _p$ &-!d�%�� cl�;mo��aHro-9q��?*]��@/6S"*�!M���u�%�})��3� cru7k *prN� �� t&�]�c�A-feA��Em��7��G*afeguar.*vŔ�o�v�Q-c.[*>i# �cXng��t�%ovuh�lE})�k)"%� TS)�A� �.�A ���j�a�o lA�& of�U&�.5[e�@E2"]:\:�!y&i�w�+Q"4soA��v alth.��^�].v>��� M&�lO1"` a t.V!8%G-1`�/�]�aVe ammaliI6&dno&Bz5A�N�^� c�e�/Ta�Re��EHA*curE!l,s=&��+�/"�"~�L appa:lKsS�7+"�Aa�� :A7 g��b�Q2� 1(.��h�FjQ��b�?�? �f�x���x1a�.�e�]W�X2Iyc�,�}#)�.6%라A�pH�8�av� jV3,8x�Yi�'� V_w_HE��.%2!�im� an�,=-? R� h�%� �H(%{P?cyA�C2�g�.6nT��I)ha#v�a�%Q.�O�M�� -=� 2�&"m�[6I�<�h �M�a�Ή�>"�>� #An� �@i?�QC� �%ou.,< a��EY���� .V�alI</&�^�3��qf�ys .4D>m��3-!9%�mpH.?}E��'*�Bs 6?��?6\�DG"�d~��o&Ld “dE -or- i t”Z�. * ��a��Q9��JZO�y �� t 6"� V:a� debr 5I>(Cu]Q�`p�]<to DiI-� ���i�� 3 da*4�n�*ed,Q�%Q6 )M A remo�q%z 1�qWe �7e�A�o�)�o�*7��>!3!� A/TGJ�� lp~4�1�S!�O���b�Km��Xm�i"#w"1A;i ��!�"�7 �*Xkd �]%�*%3h9��Mode %D5Bc'8&-pid9.-łb� ����gmp*�L*� "p �$-QsA�I(�M'U�VI�%QCB T6`1�9� .�O9B� so�z�"*E-�>��*�y�1IAf�loab<ga3�x.��#e=�y�m�N���-f�E�fes�s�p [63�6��-B$pNqvA��fUL6^N_ �.a in delay�.�=Q>�f3.�a�vIb| 1:W��> z�� |Z�y&N"=da\+in���� l+cm�0en2- {v 8 �6���. �t�*� ,  "$}ly!X{e F!�anyG �X2 �7j���� ��^+ _�b $2 �j.&�.��am�J� :vWA* L v�e06C�"assessm@shj9  ax5fu ol� charF>p'�u�|"7k!��7s*}?N; focuo��$d|.5y�1fo�:!�:jq��_se@� �gpa�nd� / �u%ms.=?)�6ke-�Y}.�r�wa�M|2��M�<2TnM%/otIR� �f<U��Eb �H� �z�~��si�t(&9w�;� 5p%��2pur��ue� t)ܐrAp�98Q�W>Alt #�-:lG!�^to%�L.,u * 5f��^D0 body�Vid�A" �can now)o"�~�r1acu"uSEU��S! �^:_"�' ePaEj�t,IR2 !��tlta!ze+�"�of.v9�a��.ng&�q!s`�).*)�r*� A��19�r� @faY�Ah\/D�BE �`�s�,"['� S@06�ZV- Sigma-Aldg?!) ATCC'� 2gr�~at 37°CA$humidity-sD%)$atmos�tzBn"!-5% COP��u2�A�replac�,wi3 wee~r���Hre�k =d�90%A��=!�e��1�RrH��ulbecco-�.1Eagle'�9d ](DMEM; Lonza6 &d'� !+he)�a�v% $5% fetal b�pe 8 ( FB�d, 1% L-�m�.fi�%V�� 2 n<�)�1% P-S-��ock (N2:�U/ml piRn00 �pto N, 9;25 μg3amphoter'N�(!�h@^ blas:VUW��u%�p!4J)�=(5 g/l gluco(�B=10%%)B'P-S s�1)Ef1%B5&NC amin̔��(5�.�I�� �3�!"/byQf�J coll�f-e!� U*E;t_FV3)aR2�A(��μA9)72hB�� �"@H 0� rLf.�% �e���:�1�-M'�1�.Ny�v&z,)!����,Mw "5��b�O t cy�fluid�Ho�c�?��hu� A8E .!�� ProSpec ) ��5%Ueq�q!1 �h2�H�1�e�P.rh; 500!�; 1-24 c,B>?;hμ$ !"�Q� Rap; 2 @7�3-s>\R; 5 mM; )B�M+XHd-�^�Z� y�(%d coZqrip���ϡz%"�.!V )��A�&@b low-��i""K2Cp���&�@ � ,( pcDNA3 . 1�,tESVer-GA (GA-cox8; pC)tgoGAm1�� $ X��liˏg �!� e LTXd tj( Invitr, �U.�A�manufa;q r’�Votocola�poDhm��%�g� I"�tp %�?� [29]� "�"�AWsure-AVi�md r�jat 25±1��!� 12 h�Eht/dark�I, f�hd lmum ,� �r��t pellzRie�7 Glob��l2014; Harlan Inc . , Indiana�1 IN , US�9IᑪE��,3� o fi�l�nd UV-ir�B�hw:��ca�*J�^�^�� !t uto5p ,*4%�of%�!�!��ogVk`�X�+hor>�� AF1Lr)� fzy%�R� \)−/− � +/+ l=�r�s�dE�heterJHa� AiA�� g q�20�J� C57BL/6J6 ��e� neon� ( zE1�/k�7vw%g_:%����WT2�. C�x*c�&�e@0�M-�a���o e�movi=J�� �W rileMP pa�YIzpi���nex � �� arlee�Ba�xSalt S( EBS� �#~� 4 mX D�9 I�J 2 alb�� ( Be . Til� �?m.l�� �SbfX;Rifu�"( 200 g��6 ) ;[ubi.� 10 �try�#�15/"� (6��BՊ� ��o d� �?di&�\s� �T} q _cY repe�)�aL�!��(sus�[&� ���.� f A��Et� "wto fla�=A�in1a5@in � r9a95%�5 �o  !�"  l�;u* �e{!��ysR(amsu/ -<�n >99%E�߁�/ e��'ns attV.oly-Lc�\ SIGM�� $sli1����4% phate-b�D�smaldehyd�&�pwas�P"F6s�D" PH !� �%� bloc�N!�*� q<T��-20��6%�nd�R immu^ goatO don��)� 29�overn:* at 4�X�f^dA�"8ntibodY. Rabʆ -*� [cum  m�' byntek Biɖrma"�" ���SZ����Fx�'C��$ópez-Otin!�G��moU%J,( Santa Cruzw�>?ye�M*;c&pLC���=.kor;>�c�|�M���p ( BD�s���f�{B��]( MBLRa$| noclA%�*�%$( American�Cuc8�&o�Acl>��34( Alpha Diagno� ,F�)A�ol�XAYed)�m:�h 1�qrJ� ; %( DSH�,NVk1%Ţ,�F'ze0I ��m^saponi3a� y9Pyd�'�?y'��1 ha] room:s�B=β NA��1$��a� �i��j �b�'Mj"MUdd(opeG ECL�*M+pX9Gzn@�mg8 "8� <|+gi� amerA$BioRadEQ� -xg�{*7Qde>x \�%���)�b� �� �  0�-nE��� ar&�KY �,%� ���~��m/y:J�PNX��Z.�mes�o �me��H�u� e�La Shimadzu RF-5301PCQtro�8�Se�/a �tz cuv& �R251-Q�3-mm � ^� th; HellmA . Te&��!Bhe$Nt 22±���. E&gS wave I1295 n�E�y��}( ttnKid�F�:EWSm�rd�t 327M700N%sly�Uat j. PJ�\O dilu�\o�O�M K� M&R R  ("}�O�WA�(or 30 mM so�ck�tE � 2!ie#A��Wr:xR� �s�c�iAJyl0Xam�m( DMF;u�Eq mixeu@glibi$!f3� M���A�E)Qs?5o Z2 A trumM R@ �C subt3N�DMF&0�le&�smixaD��a%�sF�aŮ;aX�Fd m. �Xw�1�JRA-�( 1:10c: :�ga��a�N/2P 005%� ! `(� e�B� n Ec� e 90i6E"�UA)Nik�!�p�Ca DS-Ri�Y!d� CCD ����a��ac_!V/49F�5i�%Iill �.$, diaphrag`�b��Ler adjus�\,ɴ�_��2ac��}�$��I;r�%.���V�g�&�u48a 63x oil immer�(�g�%( HCX PL� CS NAƶ$ . 4; Leic��a*M7l s DMI 6000B.q sTCS SP5! �K� U6� AOBS� AOTF -�  oph�u �jXQ�WLLge�DY!&a( �crc�>��0by LAS AF sof=�.(.� s&��a?� �q�hi����or�La�pPT+�3)�g�] ֡Z by s��a� �a�p'3 �B� y~a�d(nAJ�kI "�C&N�t"�iI�= I�ed��off�EUT�I`"8a[�, bleedF+< bv-g! . NU� u?+edAw�T!L5��} � ҁQ�s)M*%> �u�AX��e yi��Xon!i�6�stoa�as 1024xu`.8-� TIFF* �$Z( xyz%�� &� ��[( of&t��aA<�e>R'AAslimwE� �" Uf�#�n{!��&3 μm��atW"-7�� �� mal6U k�\*�c*H��,M�&���ulfil�� e Ny��?. oremk\ �thick�f�77� . Be�"s%"I�%T&S a�x zb'dF�f*a � . Pi��"+�RzT��06*s  3777!2�Sq��9Dž a �*0 Air:1it pinh bi6P� s� <Gauss"2 BlurAEK [) ( Radiu�: e×!Z acill]�� wE5�Qm�ZJ"8!�:�d�.plug-in؂az, 3D O XC� �$ol� FIJI�3�E ngn-��1��4.�w�efI!� CMLBKndZ{�Vy0p��6�'54&ii�ba�HeMre��|soF-�RA]�� 9 n�N9) N_?-�Ft��*%�i^�vׂ-�� heavЦ"�k� iV)�u>�lapA�W&io�b!��� �)m�<e-�?f^resUN@we ru�s��ņ%011�( S1A�8� م(1�|e i�a�&�mP ���-st>��-�  ���3a�)�)Ma�y� �95!� |� (!u 5–|1%}}m�g6�39s2 (Q �2z3E Riv4! � >�scER|JCAe���*�g�����N�!�>�y�"�\!�&�gO��!�2 ��s&�< �A@"�67.�o�wo-gk ANOV�"$Holm-Sidak3t-hoc  , p <�<0�N���(�%7�E}ȗ� �:�)w��� .�?%�5�to4 ��i( ��5;*�;Y��!HR*)&Dq8Y�s 8AI2tQ���� �)KA fficE��.�he���Jf3�hCY&�B�8g�t�]E�9c~��* Cur�=�sce"[��.���d�s�e�`Sf8e( LͧT{W�� )� &[�[7��7`�7ܞ7�A*�*re�.sqC�0&Pxf�#I�2���ij"�*�l�� \���8�t6a� &r*l+�ji+�3<0\n-tagg�&ro+/���]y&!��s�ia0 +�b�A�!�6�h�9$Y "{ E=?:toP?3 best�!alQ�no��%R [)�C& �*to >86G*inVck 96-sZ��� NUNC��Ran �ng rowe ����M�si��u!E�J��5�5of �2%�4a��&KoB*� M.|.'h�s���o�3( NaC��105O&K HEPES-AcPj6Na- , 4 HCOa 3� itoR6~;*�) " MgClaH4 Ca ũU�`����KDye�!{!'- AXk - �d���B?.n.�)F,.grins d A�A� FD; �i>a& JF9o4�� ��-I"10a 6�2�w�$GENios Pro�m$%("8��X 4 54"�packag�TECAN+�C���`��"GSra�A�i m4!�39 ( F /F  , 53"A Y��M �light�at�7m&NM .� 20�)�5aFJO e���AP �"x"�95 m 2sae4a$7*��L8 i�m�~jx o�6s��gcm1�# s�*�'L^!����N.oHa�6I wA�FrQ�AgI� . Ab�.e=i "0�,a�ax�F��H"� RardA��q �am>on%c5��q215�*�� B3R+ nigY�|�",L ton ion�'7�'SI�&��Kto Na+ A�K+��dA*Y%3,� %5�`��� MES�%-�U -Morz $���0warԡ!�.{R7R%p�` �!q� Co#2 2�~d.��.!&at�n�!}���w&�'2�%7� ( λ��)PUC �ld��by��n�U�jCL��y�I&���%���l2: ՉTxieq*�[!<�l�Dve��":1 k� S5Ïy�*X �&A .Ad��h!�E_ �ˍt"V2C1-�N�� 6)"5*&& fe � i6�}�Ł�?posJ-��"< ��yAQ!to2�� )�p�s o6��-fUi�eQ� %zFR �vI�n�-�e� _heF�to,/��CNVN!?J� Ma��R!�s*v���$.�/ �/� C"�#"y , LL . BrieÞ,%zsJ)e�p�eV�iNmem(��t F<t�ɶyuS�1l>��w[ �Jenzj�cleavag~B'�,J�@"5o ��i� / 63��6� u�kESpo"��%�J?F 57� 6]12�We�Y�$. L-leucyl]*et + thylAO�Cay�3%�]�_-4 �* #�!E�?���eMa�=# ruptufy1321N1��>or2H!dA�� o^-embed� �"g�.j�\o�/��Vin+* �*a� 3%% tarin1 R� PB )�� �� �t �*���5��� kRPB�!�are"A+w+ )f9ldi1(fish skin g)� 6%;:j+5j+in Tris&,"�+TBS5mM "HCLa(5N  �O %K&d �o~�~z%�(O% )��&q(Y%�i+]"�"1:500�B��"�:N 1�~]2q,�3���[sP�Iu'P9%ultra-��A� -con�(�&)5)j:�( ( EM�E�ron M7� wS5)�)2��>�\�M��0�D%��Du,2N4d( iM+Qd%�>>��ti!Fcsilenh�Bd.L�.���$AURION R-G�ASE-EM JE J� MN4h��R&5..�� >�E6. L�4^=�a�5% OsO4.�-9q5A@-C6!`2|� �/��2��a�ve�+�4�� �V� @n Epoxy EMbed-812�1� �. UA�t�'���"� �an )cut EI � t��(( Reichert/�!�,t�e�$uranyl ace�S�l��8&�� !IDa JEOL JEM-1011 HR"Dž. �$Gat�$S1000W-$ iTE�&T". M=Fiso���$�ء�Z�(MF"Ac�& copy!�p .��Fup� �*2.�.�9�Bh4. 5×7�HD,d��[1qn%Aw"F@5@R�%r�DFfK")�>)e{�xK�w�3,| e*؂!M unbo�^ �Sg a!j�@�a!I�U�#A��D�I2Q��4%)& 3in ]vi8m�i'Q�E�..22pa2B '6<e5A)�I�c��d �. N��� �I�h"^H9uls ��"S�E�"� � rej���$?F5 {+�8)n�.���>U�$-� �:�� 60% "�B��i�aA�h_—�)̈́ $�re;�t yߥ84�@,��!3  agar�g/ w�@ fl�42 apple ju�;167 ml,!ZE i&*5 !y femal!��! ll� *�?W*U �&gmr:GAL4� dr- t=yg��e�ra*�9eydNo�$cep�&UAS:h"��a/�39��13B&�EvI"��7��?Q�W��[D�and/or Dor-�[��.�R*=�wo��e�jb=i�x ch�^�U (9 !m~)�4V2'�Dn�>-f�mb���Tw�q&�!xͭ%(!�U�anesthet�`�]-E� immo�l adhe�x tap� F;y[�Cograp�7Ia�* DS-L��2�/-G"SMZ���re�rm�6b)a P�=,Apo 1× WD70j!�. L�lQ"�f>��!Ce� �a|�es�� ighb.��j E�N@o��d�2�#�Sr�"��( IREG-�e�����Ͱ��{��fiA�z�@/I�0%���M"�?a:!�10 %Ww"�t#. S;za 35 fE V���� )g D(,[gqO%E\�:%NNan±SEMF)l ;�re�[avail�F�y�%V���zU�t  !ՒI�B%�E2�km3���m���a3��{�Uni:!�8of Valladolid A'�C�:@se Comm?�L a�h"�Te�m�= A of MwY+Researc �Eu��an c�DEA�486/609/CEE , S�Qsh RoyA@ecree ECC/566/201X"S�1#N ^�4SPSS v�:9 ( IB�E��'P͋6�:Sy�#�:C �A pO&�"A�%��K7 �y%�i�v+h3}� �|8 A{e5��nd� lȴ tjPhleb� us o��ala$�^�6Dip=�4: Psychodidae  �!��P v�!�visceleishCMa�( V�9{}� L�;ovani�/E�lAfr�.E{J&U���l"p&� !|sus��MP .\A^wo P ..��(n�� orig�0ng�1%� �=. thiopia:�]n� n� s�� lowl15(- Melka Wer4MW'�k� ;�#f�an!$ H�SIAddis Z��:Z {MarW=���� ife-Bb��!�!�����inc�b17�lar�Vf���"� �Upup�. Pu=uVRJ� AM�f�^Polym�ic�AAP�oPC@��Hp!��#ytB� COI .ީl�t ViC��M��!��D.% . F1 hybrJJ&�7suc�Zfu�M�!�o�ecu��maO pareu�5HZy2~of>j>�a�-%!b�{*�in�F�.W wlow�  ve d.a���2� 3œmZ�a&�ҁ��va!��2- d�� b;450�(AD:E� .E-: E ��< on�e� a�E90{ < =].,49�� 6��k��%�3[W�aic�mastigo�mqthoracg� idgu�Te ��,�E�9to�|R/v�ha�Mon ��4"� ��*:�15w�ay� ost-�� fee�>�th�>a}AZ ��:Sx!}ly�lۃ��n6��inŎ!6 &�+�-meals !by>y���E-� 7 µc !2-�M �M�6j&!��_[(6��y9��-s!fly��.*Ԛ. d�v`&!c:MQ; h�7IRa&S}Z�e� area2 x0��2���{>K�*>�&�&2�. Vj�, kala-)�����2!�R8ozo�bara��.~o� dea���� n� &B��0,�ubo  �!���In ,�s��Zm��ern�y���LLu Hor�N;` adja6 c�- , namN Suda�SouthKenya. o�c K gand Eri� ��qN�nI#��!��!ġ� �l(�S����`( Ug . Omo r�(a��S� 0/Woito valleyZ2 Metema-Hu >{0> !: nortk [ b uI� �`, Z ,E�celiaema:m�ni� (*i����� ! �F�[[��.` OMiYa V*� ^"� e��ng ���,ubgenus Synp?)!�j5x o%%r1I#vof��N�a:5IW't���H�G:�Zs��br��a?�]Y7e^E�5�Bd7-T( Lt ussi$4*� seeme��+e E^)U��a*'Y"�2�ge �!&habb4��eas(E� A/�np"5��!���6".;Tk� demahY�!�Eoig[��[_[�H�"2�e-mpeE}.�G���veg�ty��� ��$Acacia –%Li��V"s�Ind cr�Dzb�k4 cotton clay sX;[7E�89�G� x�i"�e.l, lik�8 tual>>��6�-�8kn�W. DespAb�a�mp�= olon2�=1[1J6 [11]E� ( �b�pu� :�7 abmnor�]f��ɪef@4CƮW:J�| repuI<�iJ��sl�[ ɉ=!t%��l�AAa�w!�cu1on>l��Nc� ��tue~C�(t�,%�:L ! J� .2,�no�έ�hig� %�,e Amhara Reg��i2���lf�d�/ 1800+��*m *hin+B(200 �outfUżVL�L"���-�3��initdOw 0� mor�M��OY o�\ h9,2 ��B�si��I A N� @re`� Rift ey�n�/it �Wx:ely 800 m�00 km of-� Abab�oH[,AU5p � vidu� of�Ia�Qy:|c�)b�!*{�i�ǁ�Ar.z t �3� h a$2+to�q vi�y�1ross-m��A�� 5�.�a�������8�Ly"�S 5<�F!Z ���u�e�en�!$�f:�x��a��Xbafunda� 3(re�� %�major� T~e�>V:*��b&!�)�3�-B$ ��t�"E� :! ����Ula lI����f�;` Char�* �ra��3nV%H}insA��= guid�C�.Cze�� egisO( Act�$. 246/1992�� � �u.�A�&ua�s>a7A1>�({�"z �)mV:v&I�6H 7LY�&���!�r��e�&'s&:!�u�=f�pe�y�!�#(!|: CZUlG/9pmCZ 0017��.%�*panonya���%(F5U�z��\est�I��D�re��!��� g �\�0Aklilu Lemma  ���P��j � ���} ,%�,p�D*F,� nd3,und hyrax fa�U���,"Z�X� �KAZ%6!�_Pad)q5kepj426n� af? m�9M���=�։��9�z�(od���l+�)yq *\ [��&�*B%\6�� ��Emh�Hof ) 18� Z!#��� i� 8of autoclaved a�>nd non-autoclaved larval food was tested and compared . Adult s�uflies were maintained on 50% sugar solution at 26–27°C . In the first generation after arrival to Prague , females pLoffered a blood-mealz\rabbit or human arm ( co�$hor PV ser�@as volunteer ) , ��D, 3–6 days old ,I�Opthrough a chick-skin membraneA:m�%s�8dividual midgut9%�Q�e� dissi1 h�3I-1�$, transfer�&to tubeA���!�ADDµl 0 . 15 mM NaClEThomogene�. Gutatea�50:)�g dilua�2�( 5". /100 8:rm�mixed���|of Drabkin's reagent ( Sigma ) ii dark%�30 min�� bsorbance��Ied1$96-well pl�(in doublets��$540 nm . H�=]92v2Fsi�3!G!i1�g/gAJus�� s standar!��%�am,calcu�d V4�Ufully 9Ac:f��Q). Forecross-a�ng stud��D slightly modified,ugscribigDvorak}f6a�a}fly , iY� pupa��e��par��x re separaA5into g�d vial�:ob�H virgin a�n�i. V ��one2^ grou� ��Fme�/�other5%7!/AZ ZD = Hybrids 1 ,�_$MWV$2 E��rpprox��e 1∶1 �nA�sexeseballow!s�C�a2�2�aE#�. B��A1 �9X�f�䅚 postI6'( PBM )>"moist�uon pot%�lay egg�A��produc��h-*A�"+ %� both:� (�pN�inI9%� )�A� m)�L�re� �w identŶ cond�)wtheir�DmI���� r0( see Table 1�AE�F1 � 1e�IF2 brE] -sis� mu4to verify that(pr�bmvid���$ similarly ] s�2YH ,�f$a temperat!E4profile: 94°Ce�1 , 352A(723 . An inita denU � stepa0X42Fa final!�ens!�.`1��n)1I�. After%6�, E�0ophoretic ban�q� orm�toinary�prix�gen8diyce���� �Nei-Li' effic� �ity [17�� Phyl��TtrePnstruE�b�� e un- ��pair-eZA�ur( UPGMAD[18^C!�$gram FreeT� [19]EA\%� �%� F�!�c�!���� �����8a�h���]14 hoseY q�s�dirTe -�< A�� 50-n I�m�q�~ݪpru�Lpublished [20] , [21)0R!1� � �E�v � ions o��sam� im�a ��� �mt on 3� Avant GMNA�5 er ( Appl� Biosystem�1�. All�( � clea#(by QIAquick& Purry��HQiangen , Germany )!1� o� �AY . Ob6 ed� e data)�A;"�t!�!��GenBank-b���E � alig`��8ClustalX 1 . 81%�Lresuln0cE�manua� ediaby!7Edi���HL . donovani strain!OGEBRE-�$HOM/ET/72/�A8GR374� ,2010/DM-1033� r!&e�VL pata�Pnor $n EthiopiaU kept!cryob!aG he D��t�$arasitolog Char(Univers�al inPm�:� .�3[e5 J*eat 23��oVdium 199*� supplemV10% fe| calfuGibco��,1% BME vitam!&� , 2%� urine%%ami�( 2 g/ml�*0� ��< ( ∼–7� 0) ���0a suspe�\ofaZmastigo�%�4-� -�4Leishmania cul�)e� 0i heat-in�v� .� (A�0veta , Ivanov� na H�(, Czech Rep�. If not�!w wise^1�ve dose�105:�per ml e=EA. To �=-depen�  di ��in.�L A�Fe)- m�Zate�fo� a(6�: 2×10� ��a}5:�A$�vueam&� accu� number-piJ�ges!<by.X� ( N�8 )%determy��Q-�t$mmediately a�2�+(Da�belowEĂbF`O!�@a�6a��sf��accesSJ". One� of� d"�g mi�cop� ob�aY��te�s�,%se�i f[pla�5�VplaUc0 fill�@� of e� tissue buA�� ��K isol� kit��ne�0%10�!)sto�at −20!.�!�Y�}�\> �;,�)�!?es5�, 8–11pQD�K9RropQ sab "�� *��Acheck�or�sa��localiz �of.�pr.���l�9ׁ/� O mpha?!�given! �SdEstomodvalve�$prerequisivor suE�fulH mis� [z ew%V22i Level%=�ռ�Ggra"Z�categor��acj�W$to Myskova&K$23]: negat�,- ( <z �/guAE,�e�;(g!�T>(AY heavQ>R"�%�evalu��s[ s9ly by9i χ2 �|�c!XS-PLUS�0!�� I/��=36�i� "�U�as 3ed���n YBR Green��e8�( iQ !Sup� x , Biora�Cl �toaIpi�ed �aƌMannheim�c"� 9�� fac�r's . a�. Kineto�s�m ar moler target�M9 d.�M" 2S)B�a�bA<�se��% a� *� !#�la��known=�6�.� ��lita �+� ��r��U��" -�at 95��I45 of:�Hs(,5�v,e10 $�. R� �-e�2�yusa�(Kruskal-Wal�H-e . �*falE �� :� ���qummarcineja�Fig�[ a&� begin��T�I6 2to eclo��� Usl%( inclu��S,~!�l�ger� �&�� sixta� weekA��E4&twenty-�) AZ ( � s 1Aa��I�trast�m�N �!G* in :$laboratory>|�ɡ�s2�F6lefRe��vH h�humid� . How( !,MW9�� �2dem��!Zaz: while>�n�ed !���upa;edg> �A�po� AZ�NC!(lO  sub`t�1bottomQI. DU t E�� 5m�ref�K�F�Mqtwo>�pop��z*Q )7��HclIic� �. D�o� k du]�faf]!> onsi�4b��� qual!�of))�!@ :" "4eme�gQ=pea�at�!�nI�`OMW AZ ,p��EK��I�U� >90%A7 <>6 � �� �eMatqEaDn *�"�1^ betwa�99�m� ob6ф.cof�4y%k sign�$ntly delay'# Peak.�A�&� !�%-!6 thir�=F: l:A!�ly 16%e�M� AZ6achievihe)c�˥@2By9F���~].%GU[mVY� th�"�kwh!P=�.porA�� ' stop�.? �)�do�t   �*teE��%�un�.�H9  A�synchro� D.�%�`c�$diapause (P dic� �cy� �� e� o�jj>�� grow�#�L4 �"�impro!�by*��3%�@ TetraMin ( aquar fish)�)��h�aRecipr� �G Ts�"2Q�eda�*= �!+insem�#�(i��ed�F$F2gen�`hady�a fecu��y[-�l#"� l=I)dF1��)�mea.� ��8h e42 . 6 �4�3��Z�J�$2Z�&GreB�o3o6!LF2.�Ais�!"�!M�+ES�|e� a; � �� F�Imm�eI]u%of�=]��ly�"qfa�tqA�p� }I`) �; Rstook ��F whol'� # :lay�&.� ? ���32�!�35 inA2Q>2�(e �No��ph�G.�Hfound�&^� . F�Z�I� �!6�q?! . A � &B58 frag!P�*~ "to 0 bp ere�Ń��6� tern@by&�L achX Evrei�ibl7 st�A�e �"C��se� revea7a{!iE�"wo, tinctY'dbxc&�%a<$s exclu�'`'~ : E��NVhe4f�$i�a c#= >A M�u�pa)%as also�#y fn�bor-joi� "�JgAlK&aly*C7 A� CO-I*Yo�vj*��n2to� h �a�%�&�!Rn!T~��ES� submit��to"�( A�pIz(s KC204965- n)�$susceptibiE �.^ to6�!^dem�� f,g�-1k �&O� 2�,�� �j�i� %�intact��itroph9)a oIic�b*<!H�!���hFen�of&��j75p �J� �6 �all�� defe F-AF"<%ɍ(78% . Elong� nec�nJ*%��mai� � � bdo�u0) shork :� meta �:s� -�orward!�Xthorac!9y';p62� �*6eb�->�. SubYt;'9-?ͱ dA���%�� burde�$ n � !=d&%C��-: majo�( 84%� &n(R�� !�mqpotk%�}� in v!�d' mpeta���^-aa� 2)� #% 2��in� !r sta#9J(1liM)5Qs�d ", ^� ( P>9 05V mvK � !?m�%� ( ar�a� ;(o)�#n�) inteJ�!*") Qek&� ( P)�4��Abund�}6�(�La�0)� ���:^ ӵr�� as �!� �.�,�B#( 94%a�86 !-�5!/2�6�6X2�"3S5�)� ��no2� .�2Wagepa���W[1�v�_sQ�y v�ZAZ;"�50 engor��x� *3&�&�0�$M�"v��r�q��,mQ KonE� :%�A�a�@2�(m��42�:�,�s 6Y1a�aAge�>P-A�69�. ( SD}@!O ��^ +43� 9 5. I�d+ e�at�)ed� ��&)!� 36f2#' !4 �35�'714C�'6BFTh� �m�confi%&p#��c ":�8pM�&V�BW;"�R? Desp~!� e^a!XA!AO !-f���I�!^ with.xf�ltuY�:6�i�2cc-�zr0�2oc�& )rb��~is 6�N7u��s}m�)N�30–46q ��#5"e3A�ep v�q9]D&7��95%��4��&��oc��Ujs%��� �%F:J7 56�:s E��:mfRk)U 5�mE���h-:��/sM"�#�!J�)Abe,}��:JB��^q 71q �6ve5� �Mm i�� e�8.>�1� lo9 atb�dayf�,-�* ��e�2�a�%24:me ��i{*ly%wr>� ( P<�uM 6?�:�{J� 1 ��4�; h"��ta�.�qE  enough� ��7�"=. WA.c&�I�C 4as ���A;udegaơ�a��& � �*�'in ge�� e(�+t are�6ndU-)7 titu|H��is��o�.26� certz ��9A}m�$�Gtŋp*�I�c79L8�orK!EJ�!��qR�;B����a)Ypr.p�arv pr��U jg"�: tim#1y y be�$se� a�9$�9h�!W. of 4Bhas by&� c1Palaearc�"I@691�war�/q8� habitats!��%�-t��&l [25�"Our�. dingWa=l.(64by Schmidt [26�,�!1pr�#of&"�w��th1� qin>* F$"jA�eEsz� tAZQ� ht b%l�=e n��te chal�� wi!aurvE?):+o�/�.�V�gz!�*[-}==&1]dA|� �3I�&�>�%a��:0t2\1 of 2�>TA�f% ng i�����%j� �� yU�E�%]�&�1�c���"��� [2�0�� ����6��in�u� � mic #&�" -�zbovy5Defe�hos c:� inNC( �=9Je�� ))1a��>�g$,onb�%[271In.� �(np al�Y&% source��_�<�� S*�%��¹ ��les(=apB] itu��A]�) z"Q-!�3ar"�@a�*�!�:>A^�c�ġŦq-,�,L"�9s%HreadiH � 0i�3sm�siz"�a�c*� F�@*/"easea ���6"� �k I six �@�O�i4h�vg"Q  refua$f�A�o`bbi�nd�)�&9Bh�<!B. A%Ɓ�%�K]/�-���)�esnev�l� � year*$�-d6,)3 _����10)C�)ye�"�;s mus��!�]��6��."�"� .G �%�U-also not��/g�:3�A&�?-:.�E %reluctV�;��V�?})on�f%z seemDbA��ordE? �*r�0��!orI�mY;6-mo� b�Da�%�60�3!b�dEFU�9 �ob!�,/�f4a ]>���ge�% mple woulM nee++ FL:L>>i� cructH ! �1epidemio�2of visc]l" 1�. N.�2%U:|a�6�%� repe�ly orA=�Fvark9 foci��E Africa [1; [41 29buts�%7�south-w�Ջ[30� In Suda5*B�:�>BaE�e�2�b�C"�E"%4%,kala-azar [1�631],53 ���uE�6�B�C�6�pionee�&AAu�,*� d�&a limF5�!�:���Py�s7%�2���!er�=l�4>Yqa���Lai0�6pari�!��+>'*�4 |�< 61a�B"}(� �K.y b���za:by hapn5s� �l�'ya�2\���)�&O=)"eR re*�"$( 93% [MW]�81% [AZ]m��"zV 1|en%2�di"t���I$%�p"��h @)�#8 �9FhE��s^#� �.&!Do�Fy)Bn"��7~�e��- s��A� half"� �re�\orE�� ipalpis i.s�9t�=$ique [32];&� can�S�ex bady�as>�� ��nd� . Ex� A�6B6���hM#�t ( �2�6��$.6�4 suff� Tak x! ccou5 ��%� X :���K"�Hs!��2val+to�1C�AA�azGwM�� sug7n"tal�&�Y!v.o;����� ����I�a*�A�'Jwa�,��l&�-. �JI�8A�i�7�T.^F` have� ��per�edf R 6L.nH8 .2tFreit�tlJ33]6@��.�-&�Ninfantum �3 re��<c$to='Eo�CIn =0u;E:��P�kM beha�+�A&f�wo.~��F { � ��"�aadv�B� 02l�.:pb� . Wei%C'/Ab]m�en] ma��"�� i$u�"i.�E��5Naer6wL.�Fj/sh� � a�a.W3niAa%E{q ptim'+�K�%or�%loIm��H-�X)�b )P-$)�� �3p�z�3"B>.RF�uav.\*:��sat>���o�~ l��c�n�Hly��O:p�vA� �R'�<��+4ZZ�is9�9� In v�7of�?���we deduc� tG�_f ,in Melka Wer%Jan-�29��i &9l>1>� .@}nChUe gover+@liTmC4d schistosomia9�cO�nhealthc!Up} �d�O��5ous 'E�econo�impacQ)qit �e 4Ja/�7D >��$!6+Global B�$!eDisea8.GBD )M�Ft.�ifq) disa-\PD ( D�QA=n5(c� � :1japon� }�tak�toc�Eae re- �D� �d �-a>h�*1 -CBd� -of-�R6Yf ٍ��>X�9&A�_ o� ��gkJ� �{d-wDS5aNum-hyperm �y�!U(People's Re}DcA�a (E�R . �sc�9�sA�a�"rt qu!Monnai�+nd phys��exaA� �5�& morbb5p"&�Q� )�,���Europ�.>K6��a+�g�X � *(Żnar]<“EQ-5D plus”�.ul�on{��ݲ� !E� age-!�-3A��S1�b�A,!Gms ba�onQls'Kf-� dq� scora�@visSR� ogue scal"�6 ��onship��m�tu�^9��DW)��#�>I m Er�j=modT=.�J506� di*Z215-�%�&0���0�mk,M98b5m�V�i��mpa!#n E"�S �Y,L h�p�or� comfA�( 9� �A�%t&3i� ( 87 . 9 �anxieav�N7 Mw8G()���!casQ447Snd>Ss�$�*..I378 amo�"o=s7d^"4�to0510 0A�elder@BT≥60 . . DWj� & ssoc!��los�2 work capa�y, psyc&w0abn�4�B, asci� D3%A e he!� tis B virE�# sple.,�� albuTE?pro.>h!a��rB$%lseQ#-p��*݆e�VGU�& ide upA�d�a�� i%�M|���  ��e>nce�3dec4-mO6p'sYio��>1yol��? ��<, c�5���'m� atodD' fluk�Bi7genus2H, a$ " world's mami�  helmin"� �jermEAc�WalF�3�6_ mortI"H�AA� ,a��-g>�E  rega�Y�Rn�>eme!�;7c AsianBM,�� i��=e�t4+Օ�E�oE�icAJ of2N�on3-&�nn6>a�XAmeN�I�޲�� vancJY � �E�l��" �2��AaB7perte�4,i�omega�.6�8gastro-oesophag�.ric bly%�E�7>r�%*8retard2o�2anuloA�us�1Y!'l)A,l3�!%.�!� 75�IE r*I nd!���indkH� �Z���4�g l5?>]ZwU�AKuchA�SmmoS ��ly"�w �#bee�$��e�C expo��� cercariae��]at/m'1�)R C,i�<tr bin ro��nt�kA�� LA� .�um%�i a�f � l)LEG�]>e aQE=��6on;`\A�toA� tinuAfibro! ���M��G!�?$a pipestem<. Altho&down-mod��& Wg2v� whic�4��t exc�v]"j;c!�� [3]�I2–5�Vor#�;3-in�d.��!�FVr�o���t�Q�- vessw % amagE'!�)��8 chym�"=h-7�u:>�� . Mo��%�N�!e>u�-V�@��0a��`"U�T7ne!�b5U�D!�to� aӥlic fail�#,�A s [5n[�ZG ( 3 symM��:�a� %m�a�,>�M���a_[i��#�#� l sub-typ namg ( i(") ( i�u�k!��$c tumoroidA3�� �8( iv ) dwarfism2-�<e 1950!i�P!�� � X,_O-�2-no *� ��#>� >Z=M�a�A�9��3Q�. A�M�&�'Lre *�[ly 50g/DIO�B�I�T� like villEof widowA���$� haead@� �!�'�b��va�Fng � tb>a�>)�:\&�[ %O�b!+p�"� ,WlL �P�7tegFJ %)achesE�H� in g�ldu+fM�Z"BQ!',s m; ,Y�z��ar!�k-[8e�9%&�.q(Rm�u#Ast�'c�p , tyRN+E�� i,Lam)L���)��OU�)�!25J���R��`rru~be#;d=�+&�Sr* hai municD Zhej@Ua�vi a�yBy�en�2 2008!�3�*�Y927mJ�E�)|B���ztheK3ej30 (  3 �e��!4u�Jof"�>"; [1 >� �=�*��� ,%�� -rec��,�:M��cqV�sa�; h[13AdUn�uncQ,4�W  H� Organi/ jV�',�� ' s�2��:e*w E��O-*��C- . �,o �n%��0f�z‘minim�o abs��Ta!V’�un�lP5dR����4~fwWa>��Vof� 005 �9;�EeA�4>=)��bW death ) )A}o ool- childr�Xa]Z006'9%& ≥1� �fM re��A@r� �0�Ct� � Q�E�e ��!‘true!P� ie�Zwg–f[��mid-2004��we��ssu7i� u [)X�XZ �S so-p0ed &:T�a� � �Pe-g&(�!�I���� a:��RA �� Of� \ !Cb��>� wid�[�iny1t set�GYf�p"�0.�u�$9%��[W? _-�e.�����a��"j",E�19gF2l=F09a!U�E�� eA�246 ( e��>) [)fIn�K`anx .>ey c�+59u8 Hubei٦�b%�W0u� �!mdefZo�}!ҁ,.[�SDf"' DWP� 122 yS"�mdesgH�'� n!��Oi%-HyE(&�by�Qg��l ague!�r 1��7a]�-adju.E�yea?VDALY ) mp-p��1ю�(Finkelstein&�Q1� &��3!�y�� ?'��"�Ta�� e|�@la76�D.�x'�!�*�M�iud�faBcl� outcol"fŪy�a�E�*�����J�we��it�_��#oH��2Y� ibu1'��4e �aEd�Bk"�9e� �1�mt�X!�b~, v�(f�Vtu%�at^1�v!�hAl"�'��T:� [�$llB7T lT 2q'.��$ Octo�Z 2007eJ_ry8sHan`!o a Hunan� ,lis 2��82vM"� �)�`#(�6�bQ( *odOA�3�!L��>�"c:�e�eligiQ!�enrolE�bs�D6�� ad} �*��kRl-.�to�m� ��]who�E<‘u�cur�� /��a�/co-�/��m�z\�n rcul�� abe��� rdio�Anephr�cirrh ?�HI� ��hc M�.HorX!u�5�m( diagno!Y�8�%9>�( WS261d 6*ScU9<5u>E)��anWs:� )� �or�&-a���B�~�iwaifw9 V"ru c�*�qapy agwbt>�;vw�!�f/��nzyme-l��,d immunosorb (assay ( ELI9h) ;%���{:Nsyndr9r�W��%�1�", a�g .a�"u�E�BHackett� de 3!�e� or65of:/2>w2�|c/A�la&N.���ic!0c�or^�"*z A>���QobTnP5�m., Av�5�ZM,s:,�&�!e=���! ����N��$js�d� " g�%��&my)���per�m� ig7d ��&FJp�!�arrheDor weaknaw.Ej,J �QAQEZh t!ofR!+#+2���iEw;���' view.j#Sr���pre�ZZ � o*�#92~J�08'k yr9oN�#, ��"Rm!+�wa�"^F�y t�N�& x n �o�2 grap�Le"bl�ti5�age�e ^�@� t�>�W,%6�T on��NG>H�H�a�Eanti-��"b.][2m�pM��yse�#�"U�!�I��6ap�12 78�\!n fati�#� orexY�"@�on�F�b�0 E�oolJ&� E>vz�Klet}BseW�!�"�!r%Yb��emploLXA�&� w�es'lbMX?ix rele�j"�#A�2PmoH���(!�]) �fE� in u:�#+����c��%`�#i1$+N*R$�Xv�9;���l each��VB possO "` e�� ed:probl�kl .�,0��6��߅�o a�scm V�&( VASl!0%qyd6�a�ent's �WgmF� er3��&/best imaw{V 9c�vwor> .mm���@[a>is�A��<cRu�'�r�`Fv�y�['2��'g9�-t'^,<A"�P>r|&�w�o dA�a26a���d�no �Zin + 4 hou.r�6&�)�S�qa�re horiz� lly- olMrgaw �{�� ;on����y inha�6of>Pat&DYeT3"� 2�"L �BH,&c& !) FEr��)� III%�v��H? Dt��s� rotr� -Cof >3A��%� xiphw aK palpM�>0.)0r[_co^n mau^%!�mid��3ar �gpner� E�m�R v��;>L!��o!��/�%+�]1A9±�b 1 mm� Y�.\(39 ye >, 1/:6pei,�d 4�J1g7 12bg5656�:6±A9:n�E SpleA��$!1)MWkbyVN�*!�W y j (M^�M'R)#.� r&�*byR�E�b2�s n� , mil$���9e� W�$�&!�l&i5� �(,Gt��s�=wb, e�sMFa�Aj� *�)�� g�T bo�, 6+ � ~�(i��!�se�o�)2'7X�#��"� �$�s-�� y. �� =&�!)"�J� �att e��#*84R�FA(�F�&� e*�"cauJ�"�X�|nde"� [ �A� rf�lchart_w�nWRa�An�nym�#�Y�.I�� �ndV�8gP- l. S6{ Z����iL SAS softw�Dr on 8Y(Ins^D e; C7�x�"�jA��-�"���c&�kA�d% Cochran-M�=$l-Haenszel6^.� �.��ar�+)�j~ *� %7g��DW�J� �Oɡ��w,:�)*1  �/ !�� ar�)]fGa�P ula: DWS 1−� I/�C� FDW]Ge��,>�YA�t"�)�m�16.%�) c*� ub�M)��$f&�]�W*%8.�vin � l ( ANOV�P.���%8s-$9�� � �YBonferr�+t-IZ�@0�r!� aris�kv�0%a oQH!b2�!Ac�hLNIZb/DWq'del 1Aw�'I�[ E�hipU�!I,f%��uata �}E��b� 9p 's�Q��lstŎl 26�a �a�qR�,�"�6� �/a:D�I&�+I�IA��W�z=�I(*�Y%�remlda back\�{%�e4 cedd(. Ac*@,fj�/*� ,b$1�"� �ơos���QE��,��a<ig�"dH�c@�p(1a�!��[bdummyOi��%� oco��a��!B�{fL�I�0AqboR]MINE�al��>xic %8�i6�1Cen�ac  C}oCPe+ADin&%Y�WHO�mearch�<c�6> Comm`�{oy~iv�pr-��!�&�\ risk� a��,�ll6{ . Wra�� �,n;)��&W _��*�& a lDoa�i�v�I"5Ie�Pib�2�B�bod�D�[��w�praziqu�� ,�uy%G/�$*1�i )�u*!�:%�&�Eaol . Du)!����*98a�{ �Cof 506\;p�Pb_ %��da��4t&221 !&\ � ��+ [!��6 c `. MN�"b& ed 7+ 6XW 154/5)�� �iHco�I��55473 4kj%tN24�!(ɭage: 5@'1"] �Miej:�g� ;6: PX8�5�z"�EpAE�j�T��0�di�,*3 n�8�: 64 .:{( 138 �E��(��2�, 3-4!71C,2�2 3� )B]v�B C!�G9y2G" -�V13K,z �TxF\��)>s! ��aRJD�ES��F(q � �29Y\P587 �� 1����Oper~&aE fM�+vax:�"� �"� � A,BIt2� l/� ��&�s�jby�l!W6�f@&�AU�� � �#E�*�p����,~�>�� gs* �y!\8 �M &�b�`�A&2�~;�x%e�4�!�4�%"(.��*�� �Mat� f�^�59>|. :"�Y0f_.�.A, 8a�el62/73�'Y*�CB�E""hw�!!46��%�bv6Gc�min�A w��ag}k2��8a�10/42 )5�� Juto 36 .�,( 47/1�Q5R)�xpr.�� ��(�<�L&I()Nx)\ ) a��; ��,��~7�2!32�99 . 04100�-�Ae�"�-M sn�_%�6� �e Bg./e���u,,n��;:,,�r��o.� , 48 � 6F@6Ro3%3��;�� alZ� (z�2?F�5�/N�52��J2E#�+^!�@*�Xu:�@�E4�TB�i{S*� leve7 !�73 g/dlk�&��"Dy�!K11 ,q��"8s�J"�c� 865�M �B�of W���e89 @"� �+*�] ( F  &�� 61 , P�^i�I�xm�3�>)2U1�716 p!T � 1315�&�~mO�2�!?27 =M�&+,( tF −1��Ԃ ���)Jk�!70�bey1�yA3=7x)�gW�?EFa �M uZ�w��1f!R!f3�!Il;�A*8{-!�07���%�R~��ag�<upP� �( F `!�98A# q5�� ���e�ci�&\K HBsAW,� -HBc � wv!�#�M"��"w �46beAg%�" [d�I��� 4/19=j��\��� w�NYA��B�P��deb ��4��m 17/3� BM6�to� .�" 25/9R4.�"�&�E�iB?AaRCa)R*Ih!&)v>mjM��&A�����.&8*� ≥3�]���9G�.�%p��Y�Av3O]�72�(.�.�!��* by 9!�n 91M�:��01�2 /hv � II��6a� )Y:*I&�.E1�SM�� V�m�"�A�ofI�.�+aN�sU�YN�ay�(.[ m��(s&�ZAQbK��O�%& �-w�[[+ K&) ex��om�S�R)*_ �=}te.!�"� by 5��117/2eEJ9D29 by 4!�� 90OM��Yst. ofl*O�X-�p�2A#*�"&|G,�< u . Im�in ��ofB�#�a :�0)bb�+9eo9D�!AW:�Qurm#��&H, 189:����$e �$E.K�~&r�b)���C�M2�' �xai�-fY\e�"�b�Ux(�.�6�! 3�`7a�66 �Ar :�}���<2��dix9��o� V.agea�� K�(c�eak7�Q�.�m�}01� U�6�2 J"L&�peY]�31 DW d$d!�e��1w��AT!b�Iy.NL� �I639��I��t6T, 6>!�6'z'�TD �c a�a6�Ls�i�S�:s�2 1V 7�J.�3[ir-���q�a��� �� &�*�ceFb#!60"aYo6..L!�ݱ� >56�r��{:�s[Sa�D�Cn�"V Z����m� .�L95]gwE�F��A�360>.f�Irl.V!KK13�895%�!f$zc[� ( C�:+09��57�A�1|a#>�SQ���3��n�6 3#@ �#c�R�o�nc^�C!a8/���C�i&S ed%�E�*>at��Q�&oes�a� comb�GT�q�t��"�"�k DW  ,97*�wo*�O[F�O�$�&�7�� In&� &� "xy��b���@P��X��ᵖ%I�:nd &2+c�GbBI�� @A%A/*. re u<$�4e� ?�G��%K �ʁ9 9a�+:�A�asdu$!�-f�3kac����$.�&.( W ed R.g59�>��ճ�i�hd[aqDD����we��4�(��"�J>b/(g�He�N!��A yY(e[�|J infe*�4�g��B�D -� H!�o�4�Z"c0!U�A�%'�.&:9e.�/!�2�0M%i���@k%�&�.S0!kO"�"�,\ N� ,� � .�(m6w'Q��Di�toa���DWh he�t��N!uXfi-i^.n)�0!XU@2B Kn�R+]iB�oDM��;����JP!�"�=�bb~@/1,*F1� ,Z��@c*�Ry�Hy��*$pl�k>a�!��.mn�!;�a&%|o �,�u%�$|O!w.!�ocanh�v�*: � (i�st!=��yrs�� ) . "�)mg�/�fY�!�D"GSA��4mN4Ci��re� �pe�g�<n�pai��"� |E�i&xQd[�if@c*B@2�?[jm0ZHA�-*lR���M>X� ha�R�>(c m� Adv�g-5n��%�+?w�P�#r M�� urse2�=, [)hbgUn�)te�h �langua* ap!S�5"�SiЖ�"� !�lN���,� "�"%-PUB *>�bF .=~32�I_a�reK �B�Q*�>Amf�>6i1h��>!A&�hK ��pA�a5 inve~�r!a�S@cl�2"��ϊ�H(2�C)!��^r.� \pu�( th b�,�S opin�ch�kUN!�o2vl=k!�M90�B)E� cur���,R 4atf�"8 �F:�poD W5ո�9tC7�B��nK&(��R��.i� whol5�A%#)pbm.� M,�34�u�N %k=�� �x30j3������( "�+�1042 -�a'�Gi^�>;"� �0a�s�:�s^ ��::H [=_E+qo�evI (�n�� �V�l� ���tX �RA��l�D)SK,�J�p�%Z�`i 6#I6coR c�#�[NNZ(��e�,uw&cZAեUk'RZ� >�=)2(j�5�=�B)�a�)�d &qx� �y}�@ -Ut>q[3�Jie-,P8ho�T8� t�"�&I��I � et�e�yDSaA�.{#��t�&�j(�; 1"��"nw��q4"�?of� III�0�8byA���-�7A�,turtla[ck or map-�QRB ogno�c7umu:E�$U���5,7{"�f1� }�- �*3&�B[3y�qen�X� X�al�5Et�" .&�@9o03� impl�1���*0upJk�@.hUErrhagBw�H3� R�v��to:�6�*eg� *Knm!�Zij?�o4V �� "j%��a�a%n.`�7Anemia)0{H&Pa'���ur� aggra ��e� R �ZU s�i�yod'gV.4�s�1a(��% !o�4b �if��7q@e1��L, 7� �xg|�EI.��E����>�� ix �:��+C:�^ ~o$rlV[w� dLed=ߨ*&=�s"�)MMdNI=��" n5�787/141�3Mm I0!��{$207��At:H. S 9t��A��O.Y�:o "EI�aS&>�vsFhF}A�� �PrF��A�as���?!35 E�>s�s�gA�\:li�*PmoZ\sXc(AF�arib]g�'�Ugrb;� . S07�l�66�>f–QQ(d�q&�[/v�t�!ps����Wf��>e� fam�c�i�u� � 4\1&6I p�?�K>� 6�� !�U�u��6�s:R�@~U�s"�h�"� M�2,t7ƙng ceA�>/9%�1XB��s )m=� AtY�W!�� �.\E:�eF2�d6�in �eor�!.� s"6� "� �� !e"��_Ba��,N&yfun��F}and�DqU�5< �me`a_;s�%b* Q�!�aOso��)NtoA�k��?�(!M���una�� i�&T�2o,�O"�,�i�[he8 �6 �ig�8>*6�.�3� 26I��+�X�� u manig� msel84w� U>,�:=[,�reF6rqig,!X��"�.�n!W�[e����-rZe�%eP��!hins� , ei��A�i t� د� a�K�" "�>"q> ^hel^r�GRe�� ,��f��M1ځjcH!x*W,O�o %A [* 6`i삥�!��A��fdh�Ɇ!"��HBV*� �Wg [3ySզ��6/y-�u\ oȪy a r# Q�j ��my�QB"�Z�O��iAB�[�|4�|TLs!Y aވts !���A�6�Q����3q�!S+�oTcA&)h���B�M�Rl�� , [4*>3�'8(պ-�yoG":!�&�) HbeA�NP��� .lA_L��ɒlF�8��g5J�+�i� o�y�m1^P(����2��s�E%�. |!!�U�!�$�H�,�9�!inek���"�@E�(a&X>�IEA*�e�0R%�"�fe�eu""gAIV�C,!�S�*=�"�)��1�Eq��/"P3ooy�,.*�W���e��5�� y�[ ���Bi�s�jur��}�H6v� ��>���� �B��!�t�9L1� �]c��b�"� ,ʘcAFAag).�M�{�Cavail5 I�qu�kއt��6{Ge���Gψ,&v%b,Q�bv�g: l_;@3�e VAS! M��<achS �}V<Blow��9 i��3e-AI��v�$‘real�~ ��an idk,�rotX��=f&� ( >�J"y:�%o)MA�����s  beuY�� o|� him- her} ��[�AddzLSEQ�%�lw �eas '> pU��*�hFQ �� +:<am=lKla�L3�e2� w� q w.eS6�_W�tr'��ocu�rSnɗ*��:i2]�%�voi�Ld�Wʂ&z\6$MtwQ�Y#�u>.�=�A�%n�V)�Q�r>�,E�"� )rb�"� ��k6L�!)��(e_ �".�*!�a F [hor �A�%^2�^>��#ird �gnM5��E�a�is �No��:a��eˏA��"�yZ���&~����� 5$ըet�Exer��jcA��#a`�J[4�d* ` auncZ�ti$�?���B�',6��b� �k:��neg���r7\���H[�d�3�`4�T!�9&ne@��corpo%Fnew&+!E��)`'U  �j!Y�v�r�ad�� %�S��a 1I_[44 ��^Re-F9ula�re�-zM$-"�:�r���& �Y ighl�M��,!��[esF�t m��t�t ���$sn TrypasZ��( HAT�qC�u�&s slee�g sick�W �NA�fUai� ( A Uڀ^) nagaV!�E8y!~�sT)Eb�Yqr-born/uL�T$ub-Saharan ��us acqu>{t:�&*)!�bit�a tset) lQ�� \ '9" ozoa.� brucei8* . b e�spλ –i"JWgambiensB Wes*�E )=e�1rhodes3Ea 3Souv�O�ll$decade%��!D"NV�P�n$�c��7 i:��6 ��-�%!���ut enhaupjhv grveill!2Nw�x` lack��#j��2]�R�aretro�-�m-��i^����h@�s%��Ztens�tatC 1999�ReZ ��L� vulner��*K in KenyJx7Q,bel���eI*o֣]AT-M��vAV�[� v ��`�&:& �!�gn�� �ihe�6�e2���+�,in�TseholdF]�h��arT���Zp�f�%.t�}ro&migraU+or%�ag:p�1 . TufѷJ-%hs1x��Ppsi�via�-"]Zx/ : ���$M Ay�&0�?.w��M�����oP R��R9ӡ���ta�yЖr � "�alA�du�A���dstock$tsa�1 mZ��nH�QuE��e΀��� nd=�-kM�}6�>. &�A]��#C%��Ds!$)6jrec�u/M!�!� >��HI" ��.~5�>��5�i� ��rD��u�� fu�!�2.pr��^T�"e eJ!A! op���V)^ in <]�e�ya)�l*� }!�=I��#�- C. F �7a�K1������s< alT���NDY�� fe$`���h�d2�"QY6\�1�9}%9 ���0 �d . �� ��������������ais sp � I���Kg�aa[ρf*� ��� viva�` congolN , � � &�a����&G ��Gr��A�a�`a�]i| ^�s: G .��sit,�Z�B! fusc� |�~]k-qh~��Eth�\��iom*�8enviroqaԛf�4by�Dx�Be&���Qil��P,�B vegeM�fauna ��19K36J� �Cu��es��r�x}ly�,x�( ����=R ? Vy3"Vxto2cx�� a`)"4un� �n' � , ��g��If left,��#Rm]|%2�x"|tJ�t  gc l�c-p��U artner�P�O!<�g� > �2�V���J( suit�"� �2\ �1"^� ��m�xe�  24�-��]aKa`&� !i13z/.� � ( Ug��!ocAY� ����qla.���:H1�B�$of]zdr�ڴ�:�zcum�~v��c�ce��I�to/�!�IZ�.�r�=,�E, 036 %;�)8F1=��Y�?8�E6 m�Democ�c .9��C��,� A��'˘ �In�.vF�580=1B� -��!��-�AUni!.� Tanz6� �� dra�*�D � 1�.�eel�M x2 ";6d!�&� a�Z���-$a�2wd� �+vq[!M~�|v���  � ��2umR 2J���outx =!!�:��dxaa��Wt7 Mé$� ns s�� � ;�1�v&�bmoKW.�V����`���+�k�y8�@ �g� u� adeq5q infr�vu��a��!u����vJ+%$ ��1facil� %$d&uy���*5��� &nelo .e"|,E!��i� purp!ۥ;� 9��e�nTeŐ3 �sicB��"&�o"��-ޔ�,�Mp�a �w".a}%�caZa 5$ E�d� �e � *�ހct�g&�a� "�cC�in�L��8"���� I&A!P��c Use M��%VSeu( IPUM)rv�"��VEap)d�ice�� k$ uti��5�I ~n"?$‘��'78e�falls�� e umbrell/P %��#S 1�~F%�aɁnribute?�� malar�uc�p{���cy&?{( AID!@a4��l<r�&�B�e"� �������T���h��>Q��0a�&6mJ��"� E b�{be5d)�ollm A�&� %dho�mLaKc{ � rea-/p�+��4�Q, Z��� N�Ul�����i2u"15��6"�`r��M�J���o� .j��*rJ5J�~���6�. ��� ���-� &-��"�'I��ߧ *� �w>L�Rs�"��+It��hy�+-� a`��A*6?!Q��U)1�"=n") �%ardw<%QX E�s�xbp"�2�`��y>|nS0�O!t"]!=�i dD��i�- �!kq /Q�5�( a_( c~�a��b�%G:"�g���a�a�> :.H�� .~�� c dۆN�-si�U��6�&�8A���1>�#,�oyp��ME����)�!V�% A}r�/W�BQh alV �stP� � �%�Ŗ.� "�n u�!o��� �^n &��B� e��[je�.� c>B�.F�V� ,��7$i.H��m%e�osqB��aV)�Ŗ[‰mLd�:�%a��p�o� Z�5`7&F �^|egX' hury�y�%5v��$J�c�--�0!a;B rel)S�Nyanz�� ��z*��='� !P shor)Lake Vicz��&�/�0��y�L��+�"���� 64�]965 so>f;9&�Ocj198Tx 19845 ��� 1989I90#�>�)�.%J�P // 1977C80 �*�_"��in Bus��TesBf�"��Z�� break ( n�]T`i$�b�9Homa B 8nd Mi�ࡍ�p#until� 0 aA�2Y4�hM",� �%K�inB�-_ �i��YATy���  Jm�&Ӡ'-F%'198P_!���) �uaF?9%16�H�#!�m�A�!� �c��W�$rnY�)�!'i�7Jk8�U&"s?/d���Ӧ��A�1�1�=XNn&95�!bUm5� 1950��s��3 , 539VSa� %�f�E+"� ���Y�p���:+g�%;��cJ BungA�,>���I8.�Y�^*�6[�vel͜�,mJ��X 2�!!�l�'^orA7wno۹ �ũ�e��?M�h d+�*c�AWk��,� 6~�in%�s�T�X> X��([u;a lsoNY�A�&�W$U6���I��m!VX%"� ^!�Rk A\�e6� z�����H�k��4 2t��onm�8�?U� 4 ( n = 69 ��) in Kenya . The tsetse belt and district geography were obtained from the International Livestock Research Institute ( ILRI ) [20] for�Otheru�t�weigh � used� subsequen!�alyses�e%�Xgrated Public Use Micro%{naire%Ji�m!_d surveyf.DM?h�)Vis2�me resul!2Pin 28 , 150 , 940 men�wo ge 15�65 yearA.beforeF�p, n = 1 , 407 , 547 ) nesnwI�6 , 342w20.�(�[31W106 )!(A_�eIc��ECon.qa� demo��ic5+ cha!�erM(c!)fr�i�^se `w�2 exam�* `(scriptive aq�'conduE�(in SPSS verE 18 [23Q� prevalencE}diu0���Sd� residents|migra usA�numberare�~e��abl�;y}e�-�4-�y�py�:)* !�000 (I8-group-specific.���s�nSi��}�did not�Ptinguish between new a0x!�ng ca��of-�R,.l:/rał than�[!7c�AD!a!persons)� tifia�(s those who!qpon!to�i�u� , “W���(}�, ) mainly do�dur!(last 7 days�cedC��n��? ”��re�seA�d�deterA�.�ziniI�is�“UnA<work , 9ledd��<. Multivariate m � Le-,2�$Hierarchic,$near Model�0( HLM ) softw�sq<6 . 0 [24] , [25i ree- rh.W0generalized l cmc_G`eq./to �Nm�!r ա�i6#m��.S({ -1 )��2��=��-2J'�i{tt AR at compri����s)� (outa�6!�h -p" �3ea� depen� �bl�H‘�W ’ ( Yes�� e N1:as. Eea��Fq�!r��at>��"� g�(r ( Female �C6�29n dwMP>�R(roof ( Gras!Q Palm�, e2ric� ( No2piped wa�B,flush toilet>�sep?ewage>! . At-X3%2�E�Eʁ� as Zone 1�, 0 �%  , 2 B&�ketc>/ 1���F, (a�tinuou���z1*Qw �2 kAll:) stra�Ubyɮe�statu�R��% def�Xa0����:�of�w��l- ��e��!�t a!z�i!U� prior�A�$interview ��is.��\� because pK� �� has show�mat peo= �]��A in rurale�s�increa� risk�HATgof� doorp osurAU!���� fl� �Pagriculti -rel� � vit'[26�d7�dM3�q� 5ja differ� "� Rdir2fFor dN/ "��fur��p m�� s -i"Q�d� ��to anoNw� !�-F"im�Z`e!�� Th ]� or!country!ҥ�of $Ase firste��A� Efully un�mia6AGn��s>�4learn how much��2A���Valloc�at�t�|��a��MN� �A��hen� 6f�.��a fun" 4�Fl mean plus a random error:whi ,�3$likelihood��uadult i�[j��.�k;Ox�=:Oof2C�XisE-k;U�� �“�effectT ]L. devi)�of.#ijk's�f�� e��>�I\se �� assumen rmaAZI�buA�A� a O of 0�2 3 Herei� ��(ces i , j ,,k denoK�,�/d.��� ec: ly . Eac.l�IanaB come�)|(ly around s.�?BG9k�Y16[�F�/)�s~�1%��5�>���J�W��e�m�k.x!�!%�� �s%QA-s*��eE-3�r*)FV�hB.  ( a��>eferr�ko�KI� ct )%�sA�`2^�M��� ��!��vaVO�\��: >��U��“�M#r"� ���Y f)n��2�A*���6��g%��T.��;i�}#& @ aA� d;FY��I�16!�� \ �sI�$"&� .(�s��!��$� �of �Q� ssoc�d�.:I�yat'%G�Te�� ld b8la� �mea� d =les�� ;., hV , L>-1 2 3 �.P �sQ@�xprovi� in Tsh �5AY 1��y 0at almost 50%!*m� !�f� Z�� e�&� e�family B ings%c�'s6�.. or Qord�magnitud� s� 6 , &3–4��2�"� �MIQFMOne-thir� }�h� ,range$ C18 . 91%� 31 . 53%$/or.� � R (V_2N8_7�22%!�!! 5"Xmajor�.�* ��Uganda ( G184 . 19l9!b36��H, Tanzania , Ethiop Somalia%�o� Africana(nt��F ed (5j  E�2.���r 6�� ivbsimila� �,A�Reexcepa�a hig�6� =��2}had� g��*( 4!�38% )a��� ( 17!`4!2Q . Ho� oNairob� ��capital �"g ? 0tanti� � I fewerJ��}ss �� rt floorsA�no25.�T3%W4!/�o�*�6���ZR . Ov�l>H6B�f-��6 ��@ %�2T{bot�a�Aq�;T  u ]/1�� io ( RR )�greH\I "�.[)��C#24I�he>wRR6\� us�i�5.P3 . 7�*݅1.a�o��AZR.�88Vp���=�F�low �Q�nj�?��onT�m, phys8 attr� i �!�s9*�qq( 's 76�2 belo%-:,  edominant� id%>semia land v(esert shrub#�savannahis �north� Mt .,,2lu�< par� �(Rift ValleyHEas�� P�n� .��n!"lyM� Nilo-Hami�-I PSamburu !Ke �t��A�%y8�� )occup� a s] reg!�a��out �CGalla B )�ern�=j9�~["2  50� pot�**-�A��traQ ly bku���_!� [/Reg 1=reB4ar �to�� merc}large-sc7 whero � in a "%�>||A�S!� 196� an influx.-��AYz� Br*�E}aore�!!�destru&��$habitat [8? P`�re� buJAA 6p(<of G .�ipennis9Bconfir�ME)�# corn� �)�9� [10]�ma!�x aa voir�MTrypano,brucei spp .�n��sA� �ila�ima�AATa�voften fo`��!�byB���1�� e��� @ tropa��es�/o�est liM unfavour���#en� of~�#.��v&aK6���!�՝ 1�u7R� � !} havei c �|��couBU&V������i���) 70�*��:seA[�,  � Of.��D6�C�aCq"les!�ao &c\ Dim:E�,��"�#C, P 2K ŕ~J�#o� Qincorpo�2@/!+F<is mos�-Z Bantu����֕������ia�&s��'%�Ave%ʁ�� )sE�"� elev��moi� clEse�H�� V*�al.Mn�&%�nsK fa���$�� pallidipe O�#2�-���butH �� �:"�!m�2u�D V� ��6�a�SonB�, sugg�v� �Ѳve�!qE�� wise"& . Despite � ′s%�6���,k*�A�M_��"hpadtZ  allf�#�7�+2� 63��"t -)AH 1Of.h�&�#:�0652Sf25)b�E}�%too� .u: i2!�"$ a.a�M0s��g�(�qly��A��"in��i�Nf Turkan� "� s ng6 zones%�!AN� pS .� Bel%�lie jus?�f|�\.7� V�E'in�split��G� 2?%�� �5dry.-humi�A���ar"� �]�( emi-� ���� dra[(wei�_eav$�< Vege�(onsi-��u�= � > eA�!G  b!��� 2�!![�d [1)A� 199�>��!� mon �&� 2�/! ":��$, although��%FisEI .>Ty?,bA�vecR)a�T .� , congol��E% vivax��capW � !=cattlw oniZ�_ "�\��>9% [1�$e��8= 6�Й�, �U77ǝ�0 �6���89"l ��( �*59�&�b�q 67�5!�\ransmara-Narok-Kajiado ,�"-AkE�>�V�4T�nm$m�� �2�d2 Masa�����r$� e !Mara GRa�vAB��a Ņ��Aqhhig��*��.v�{BL� a mi6qA�U�,� "�>a�H marsr =�J�?�� �7���$swynnerton�$brevipalpi��*B ,$fuscipleur$�(!�iK2cq҉��a�rhodensi� ���/�#i�q�o�st�0� A�c �V� )Im�"z Ar^ >n*y� �*G/� ^�yAL� ���(�01��,!��T����1a��� twic' o"3 "!��6 .��y� ?��68g^%ub*�� r!�nF, N�cO3�2$ �fexp�0nc�he��st*/-b��a�)�@!rfM��-�P�!y� �='�pa�2�[i�huZ�"�!>7a�r�b�!x�0�,�߆R�ٲEN���63!�itzm"�,ʼn0�JtoEhF14Ar%�:!�W�r5a�Lake Vi1ia%� ncompasR .71Ny�:a�v�N*,'�R. bank�w6ln �XFr Luo n�l ɷ6?^t Luhy� ͼIMw �.� fl%lt2���  �8 �ia&� I�VZ� �� husJA�Ac(nsive cropp^ ɦ-q[�2us h ,/6oku)"0 is extrem�c –i"8(in�� s upAX75%!�i�Ѿ�E( widespreadŁɘ2 šAn ��ݚR� h_��b .ɣݢr�]%{[18�)B�����|� !�t"ab�� I�Q& onm� a�c3� -�x��r��:, lighd!�� ��6�a�r���E7�iMlpd���N66,�6� B)�B:pe1I�� 64Ŕ�5�݌�A�Z�8��� 9O!60�:d*�eza2 Coas� �Ee *��@� � edge a�536 km!*] Indian Oc�)[1o Whil��e� 8 H[4Ae�eI�axt"ndi��em�c��*TCR�pA�mj8��m� bMijike� �0� . Adja�� +eU�Tsavo�~�&/8 Park��,Chyulu Hills6  ..�t� �+2 ly �al�smpatchx�a��4mangrove swamp1�!���f�-�!��EUrine v&J)��9m� >�&EP��g ��� F� auste� �As"� 7�n� ��� J�'*�2ap� 6�6�����1a�6��6Ky�!*�||���M!�]7� -:T6���!u��as� �~b�!d3 8� ��6z,�,�X4}6;:�bz�|9lt��b3 BE`0� !6Eq 9��K6�.*�6m�51� �S7 ���'��m)�'h89L�57(�! a� sign�8ank5Ja acroirIK!&� !�(( p value &50�6>� �l�!m�;l L7�� ��alJf"!in�5��n�k�<s�*��th isksT&k �$6�, �A�69'=olyiR to |D5%�W B( odds��#O�#q6!?88=5% CIM8[9<!_e ���63s!��:�%�.6a#�&W>�),_hav�'.�6!�1oL:.!^-�x%&%:Z#( O.�#e� ��0> Ax2�>:6951�  1I�contro:!�7S��b�7. NotN.Z5<exM%&�i�-6��Y�& 5"L(eu� !s2�wAbt,e"6direct��5pathwaýq:2A0�&� 2,6�>. Two�mP��ly2�7�%2�5� -� 2&+��2!�!���6>�3��2:0��!�68�(R�A�2�bq :�:. L"�C�1)I%2 h"X!a a�a2�j }��:C>V*6P�"� � /� st�dR 6 .Q��re� f6�Q&NS-E(U=A"6}�nEi4AMuB;9�2;3�mS8!�r7>u5Ac2:1��:1:j`B�*I�,!_ngl'se�2( -3��JQ!8�UinYH�E!*���!W�3�)NE&2��8aw48S39.fE7B%�C0:N^- TrretroG�� ss-s�'al;�Ca;97istoric "�"�Eeq_'too�D!��?*�vulner���6z�:�)�$� m�o%>y !�^t�t�%ap�" ppro�6of utili{'R��4�/��m�!FD 6/%S&��~caofD-acquir i". )��f"��"�D%_�-) .�<of�-SaharanJ�/��r)Fw.r�De4�&ig" . Inm��r's2ke�lac�1p�Hhe=�ra�(ure%��b�Cill�8� � 9cA fac A!�d�Gt diagnk>8t+ Yia@C9>[9�if�*A�ne{<�;lae66�M-�IH4hyp!is�B� ( a .2�6�woR4��e�0Q�^ � "[&.',A7ard of�Sz s;�G�}�&�{�e4?>�>du@�+4 - �!|A�rec/p�t�jW (?6( c~�6�b�)G�7$"*� � } >J2a�& 7x9&� ���4t68 |*1� 6� thro!AP)FO .�r`�FK(#7ƃ1�N��A  6�AEX&� �&.�I �6�-~�� . �Cj3 ��% ��&� beAa"C6nN� � �#y�8M�J��� %B�N2A�:� !�UF�'&he+do -��0B��)!A���L$ rave��t=#2E�#�eq�2��o�X @ ��r]"�Bmorbi��&Lac..�� �6�  Yv4. To our knowla� 1 doesE7a a&j TPhmit7$Tg � HAT�*�>�du�Im�-25Eis unmW. FC����.waI&�!�.�*Y/ �d w/5th[�N�:�.��us^� �FL�.���/��enutri%�� A����so.� unusVOfmngE�"& limi_'1 �O$�I�followth�D:�0 �+c��e>� ch�(�/-S2�!con ��^�12G2.�!���0 arch�� ���1 re-O/u�3 �h�1�Q�~�1�� ��da�ona�&Z � �boundaryN2in)�b�� �zi� Qga:"�QB�=*�><1%�cBR9-a�4J�7�6-%�"�<?## T�����.- %��H %s� I�Ab*1�e�Isis yand2!d&�3��n!�*I$w)Isourcw1=origin�E else�@�$F&UaYa� �Km3reaQ)Ei)%�Y���]to��"� ! tactJogenicQ�Q� �s 6! 7I5h"�/5��"� i"�%, a0�:�*f�!y�s:E�&E ���-I �Zs sup]!�����|N*�J�bc>a�UQ�)'I'�9��„z*.�!.�5�~.~ �#bJ� �&r a� AW)Y , itA��= 3!E� prim����S}as&{A5. Anecdo�1�zO�not�(�&E:��e�a�med[/�,bin.*e�RW!��es mak@"J�UR2}�umptu�M>`6%3e�V")E�-�� ACy�Z� urdeO;di�.XQ��(iA ll docu}V�.��x�G qF\sf eXP �;a.�~Q�a`8H"r72��$,�TbMC!�<co7/���a���,�� ly manife.=|@8y�IB&�68.� [� j� *cumZiv�M%:�Frep3>d )y�&> �M!�A *� a:�D.!�2� ch:fC u�:sBt �necessaT:cS�� i�< sero6�N��<w��� *d �.*,�R�� will�r.9 h� �? &�5A, rai�g'sE�, hunE-| fish *��;ng6>=v=�AC$permanencyAHH N�c"'f2>c$<� ea�man�Jea�M���A�G�acM`e liquid6ds!xs�@�con�QeC�� us e�c�a2l.�,feedback looQ;H� e:%kq5i� M� .oY��'�7oYLAleb+qfN shor�])Zmal�( . Protein-5Vga�!Bm]1�Pefici%��, �]f,"-Y�M h_�NspOB�" m��?m�]-mmu�?blG��s s%I��imh` t� derŁ��A2A&� %�~Mnd� +,�sh9 be mis)�u&K!��S�A����q�-}Qmz�$cyьj ct, �s#1 �ɜ!r� m choZNof � t�Ye�H&!�� iHRciR ma)ro��hr� a O N� ��W" Oe�e�12)L�"��� &86���-<;ra�kaw �&�mM#A8EJ�ala�,,� illnhS uUN�. I>�(�9��1xI%{��21,2�q forc/enW=�-$ou�f=o: �/fH%>d availE�^ 1B��!�Bc�[iA�u?!l['�i"K^Zis`/o#F�17!�est: V^> . Fi(8,&\ A��)i�)>�S!�, eŒb8�)1s� "~ Zw&�ngiDth�C�Raم ��&� 9chA�X ��i� � ���7c�@&�$�D:- R"� ��"e .�%d#)'E7�%te�p�VF#–�Eg�Xls� 7� �tO&�".a�i5M�a�W� �arrivala- �"�J��o� ��]$��-�rH 4�+ i��1 "N9+� 7 1&_gr�Cu���7&� [ [28]�UX N:�,&�s"W�2��FrB�� r�Ӊmhn� :&�an epiJ+[[� gamb@5�m0�*�'. )�6�*��in_)�U��da^d wo fociA e mer|din q-�al�&�polit� �J l un�e p� P# plack ,9Z���  [)YIn6,�L-%I� U�EU rapid!� gres���o=ZKLA26 month Z�� aemolymph�d*  (e�c9�`meningeo5ph�e2.2�(In=`parasitX nvad�bl� � m�9ce%A(body tissue�( �1ig>$nd symptom�  rash (}6�Lhay �(f� � eadach%enW5d c�[SY� nod�6 edem�N(splenomegal"hepat��T l�) . If_"�tE)�it7R!1�� pr)�!�S%T2a�9<*he);-brsb��ed=^cereb�!���^qJ?9$parenchyma�VVa92SF[:\�ref_ nerv]-�involve�.fatigu!miuE�,: oc�.dys"�Y,Ae^!�g%��% coor�?��� leep!@ turb� A$, if left $P', laps� � o4nd�gntdeath:O,�cc u��li� �"a 1��s`� � prop�rug] � aOA�-�cc� �D6� screez*�C+NI��  R'n i�JMh olog*i�!)!�cre�Md$AMtT4�.�!.q%u�2wh5 \ cell�) U2 [30A� New methoM) logia�!  Y}-:j4ndg��P&=[N'12�Eo�� �u>�"Ai"����!W u���)nVl*fer�f���im0-�c1�7�5<�� �! 7! !e(!�!տ*y -]A�A�� �*re�dTt56�՜�e�"ami� �1�(melarsoprol� !�1A1[3ABSu <"::� ��2��&Y � cribG f�M^vZ� {Fly toxicU#rss-bra)��j)zHT�B �.x�6%� %V� -fat�3y� %8�N�#x�&lyB1 all :ed&ys^elo9 �al �oM<��!u.2��h� dmin�Hed Feri2_a)Wm, |Unowgivv�y 10-day�=� eb9Fdu#ho�G�w[33I 4a�Minim 'A�/56��u9�&Bfupe����%��OF�,&�,ro�mWinb"ey$ngag�ish!on"�nXhQn�onmpp� can3b�Cloo�&a*�flu!�� humant& ��F(. ���&y a�vir��">gkn./�/cer� bree�0e0F">Z !�d�W.O Bsus�VZ5 �an�8��u�eV)��On�3 odeh����en�g��a? s [3*E�_scenario 3 an�y*� �4"��Q%��out�R.�.<*Er%2compon*T�y� �~�fd&�)� v��12.[6ry'�a+ GDP �47#2�[3Z(#lYe�U�L!gh�� Zemploy!LAT���)�&�W�&x�:cal�iabf  milkm�R yiel`MLr ,2sP&���Tfr�r5�M�cidalͯ�`�z5-a��I�,:so1r��92� offt�?b%�lq�\�8i� �1��cE�!@� ts ��e� aR�w?��id�!@S>�/ q �,Kristjanson JAF( 200.�p��%!��unQ�vOA�� 2�6���ty [3�=I(3ir�-*#n�.� u� _! 's/;�;PRVE#10^/4A.�$^A�D�reveaD%J[8.&<`!�id)J�&fA3.]��c�WF o�G:�25ek]l�d� 29Yu,��U66^PeR,� M�Q���m�N �oOor���qO � eda�,ac�'�G��aR/�Q�je��m%���i9.�Et � esca�l,t�57%�1q(Rm��A">��v��6:!!�42%�ie�%�>if� i� ��s���h_+eme���M�T�, f% effoY�du� rea-�A *@!K$ focura-X�,n F-�*..��)��',!�n)!�2�2 ���\�Btc�l)��6a�E�og ��!N��e�'TY�&-�'s�a� :8.�1ua��,:bws��E s�1�er��� � situ����aiY't�,..�e�yto-O -pE���r�2*��vegfv- Bre> �d�as` %�a�-ns"T g4;EM ] a�_r�e%rS�&.�8*�F s�al �)&w,�el�f�!QAuOx�01�aPvi, �C"Lp2 wA��if-F2=u>�..g*�,mG � !"m$.&+n!� &�ya-maintI�gat� ,`ho!�L �#I5ed2��o!�1!�9\��]A 6>��o beK9Y&o�8�'�!�n w) -��t��hel,F�:9�imR�w)��F�3� d��h&S��!|m��a �iE5�[$Jr nomad��f�� u'pa-9�al- a�r�_ * 9��*<� -pr�W� E G}N  {g�>%�A���du�\8 ��Lam!F���$.+:woc�H*nd��Rl � ge a�m�'�  a��&-ag! �JonshipGh� �@!0���U+��o�mW "nto�orm:�4�5Mol ]�/ . MaEI..���eoiner u^�asA� 4�%�h"}�W�detai� i2�5�!Q���i.V<&ar�5,�t�rar `�  6\�!���! {��� � � e1E'udym��a 0�Z Okwiz [39]��EBAk�K ]��Ys�.;�!%�� �f[-avhF�o%��!E���A-�r deXa�ځ�~* & !"HIV/AIDS�J�I l���target2}HE��E�� <�s{ %O%^ex� P(z�j<^( J�.��HhDethylene bisacetamR ( HMBA )ALa�'(uc�)h"rA�HIV!��%oAl chro�l}���e�.K)� me�is�az�Bemain�9oA��#�!eA*n ,�em� )<�Iv�12�E(he PI3K/Akt.@�1ch�� &pm hory= > EXIM�"q�:��x5 si� ~�~{lon�9i�0 b ( P-TEFb ) !26Z in ZM�D� 7SK dnuc�t RNA�7n�iA" r� ,u� crui!��-�mox"O�iI)e6� �Avi��U&�\!0���$� %��a�amd�� sem�m�ly ���x-Ee�:�^ur p�&I$&].�� r)�d)�-�jxvi�JMa� oniz�)� �-�,�ti��A oF1^ %5% ��^!�2!�Sp l��F5mod"� �!�(equilibrium"xGMa�Un �cz%]�f<)a�B. HigMti�> �aapy�jAART );�en�'�΁ga�I$�!0to �l!�d�;I4 Xloa�� b�*R p�*tec47ŵ%�ph�jBa�IV7�y-�D �u&\.�!O� �M� zr ���^ � � � ��ir cur�#I�se%js harb�ti�!8ECgQD 22Zinsen�� !p!�-&re%�E���ŐrupE�s u[��[g)�eu� go�e^o purg���) �v�ir�oA�-* �$cy>!gb�p2sY%%��8�X[IR� ` repl� rn(r�s6�I�!(� e e$\>o�%T�en(�5 ttemp��d9M"�:owyU��&N IL-2�-�hoja` >�-CD�mt��Ѷf< 4_icz�é�e$& del���6�[iFCT*.S?a]�!:war�&�=6�!�mK`�jSo�A@ey1yr�� a glo t'$�" ocyt life�f re�.�bz6.�no�*prow-tHya�AH7� Q�1o�, kinase C�KC�NF-κB [ E1�1as!�%Ra key��in�" �homeostaQ7�a�{R�In.* !oinhib�!&�Cne�cetylaJW( HDAC�A�&r��� A� npr��`� "i'.`�7ᵥ�[`P�lsTtj mn29!Bm mono�I�( PBM�e�-��.�u�0valproic acid3H"�3�s# %�| weak%1B1B�QGh�� A� % hyb"o bipo�s5'r i�si!�[M.� apoptoA���A#U.��e�R�J��ksM%Wz- s��/4L�vi�Sp1-b�0ng/�a~�cu6kb.we*� by�� 1YB%3ն� un?�_On; �&  &� ed DNA�e1 #� q)f �_ HM�[�S.��nei��q(se6s*t�!st�y�wh[�XA&�E�'U � � "ynM6[ .�f�)uA����"& ��!��g� �!w� G*! �Y6b,suberoylanil hydrokI�i( SAH�ZBsw�uc�l N�v~ X,�s �[19�K�%It299i,&��3�ex��� MBA-%�)��HL� )!�e2�o!hom�e #a�4 h(�u� � 7zR2œ%} �ka/p�S �Yq&��"� ��lex�|L [LC]�f�-. Bi2Z  LC&��NoaIAay�"-�"Ii 9 ( Cdk�aEd' T!e CycT�+$HY� �A s Brd4 [2!��'� } a�e h� odime�K�G��s��[S�.��2.�F%E�p�ba�c��+ 2U.�by2)�D!�C-t�] omF+of pp-erI II�vNAPIIM ne�"an5�.o( [3A��&w" 5!�Uqdle �wo see�8ly opE� e phenoty<^��e=��aOIV:!�q�d�_� &  2N��1po���[ɟE��s)Ž{$ultaneousl�>���`� !tof��u�-�M=��s dyna!*"�8q+�.�8Vns dis� vLCT a���[2= 3$P�&.*v !�urG stu� i�*�� ���' �}‰� �` !�u�>�['9��na�Co9;! �GF�I*���ji"D���iU*�. W�0uat �A �e�ly� �atidylin�[ol-3-��(��/A�!�a%}gci�%�A8)r�)' Yd Fa"��6R2��qD�!H [Bd2B^� oef��A� Ma n��r ba�os����dI�� r.�'Ae&�R:ta�A�x �R+byW�1urU�.� mKsq��Q F8 p cy . Se2? "iU��b cy�A ag�1ACH-2�d JΔK�Elic+>aV'2!��8 �0r'"{�m�^ce-b�� �"� f)&�FqO".Ha�l��a��5 �( Fig 1� . C���"B���a con�4A���!�Y�s}m�A5m/��(24 ELISA af24 Qa@�%up�b�6� 6M, ��jz����& dose*}ma�kll-5L> A��optKy6���,�9rinA/,F)q-FiM 135-I !>220-f��R?�ſI�J�� !��%inI� p�bƔ�"�A��C!����m 5�����oryMz5�L� A� I.!Hw):6-�A lessS�>�%��B�, ��9�+�tknouk cyto1/q"a�.W ){�) b�^s�m!� FACS�"5l� �*�6� E��5�!!�lucjseIb�vHeL�&ll�J�z"6�A gene{��7V%j!��O(:�W� EI��=6��%an!�kB "I����{��� ��'L<}�� EnF��"GI�,F ��%�PBL��� ��or 3 p"���1LA?_At9 .11 �#Nex A3CD4+ T �diso��d[g4�e�bO ^wa�/extVօ . ByI�av! ���Q CD25GHLA-DRB�BeHMA"!����Mob@�ew�6�Cmo���/MH���wZ��"��BB ,U�m6E�as!; T�2�j�P��+7� 9>6w�t� 2SV�R�Pe�2"t.M�\ a"n F�[ipdMoreover�IVi�-�a&i;s c9Pc���� m�K&U N3& @����c> _ v � toge�w4�)[ )�� �0.oC  E�+albeiti�� ,����Oa�A�:�!,B;*]w�alyV�?Ln SChglyce�0g� se'�1o2�y��e�%* !"a� �"bow a3ej:tiK�urk�׹�~e%�Y��dS�>6�X��23-/�3\ dVŽ igh molec� �;f"�%�+h.1�AN'f9��Y [�A�ue� 8K �I�� M!m�A!�(�a!6 ��],�r�ego!�s�7!�h���Cximum!�1 hL !2B�.J )?a�!H!FS�"V)JAOs �6vf��6 �E�E}b;@�.]s- Mg%x�1Bm�&ef) t�*F@6BAls~x�5QG`Dam�+�m a! 2�{a� �i: �,��%7 c�J?L� . Qua4&PQataMh:<D.��t�3ios"R!!�nda�( LC/Sa9e^18m9Ind ��ICre��)qIt�post-.�bq18E�MũSLC9�l�% 2��k:ong'.IXASo�_%��_���;NZ"9uB�(6!5~E8z'$A�4E� �!�y�/A�o> ����ac�~��a����wAa"?q�S�V �6A���z[13�7ie��B[��F�^%� �d)ms�I*�"" �ed�5J�6T euCN DA� ecog�$ �8} '� o>C^�2�>�騁Pde�#{ e�30a B�de$!�y�M�.pb,es����5..��� r(� �>61e���7��7in*�@A#�yaRlax��i>!�&] tM�!6!�� hen c�a�incub�#%��7A@6(or LY294002J �Mo k,or 8 ( AI8 ,��2A!ane�ƕHQ�toI���#E(UkJ��������_0�-�d!�2BW!ki� %��=]cor�+nic�5<.6R5��*� �]ofo�+e�n^ as�<wh� �-�  "r��QdB+ J�NE26U1Q0� !�.�6!�!0.'.A�%�"�G &�unQ"1� F i M\edFD:5$"�?15.u�1U|�FC&D Y�`o>&U]Ak!���u�B�by 97�908�2��2as"R�� I[*)�uY�'Jlj�nor�ec�n basal*�B�( n9��n. Cus�st)� pqM� >& "(�&e6�DN-!8)i� e�!A1�m�B��i=�99K 6#�&d ��6��b?��"�in��C�Iy>- Taken=%��,Fm6.�{a��>��AX2.-:�vd���efariPu�:�I�#�XaN&���R� !*m�N.2�!�B���o-�!L��Ŷ����B9�6�2o ��ڸ{L� ��� of�)�\� B5 � &.!F�w6 Ca�.��@�6c!K&-�6quR3�"6�S� � =w� ` 1�= titu�0�3�|.� M� e:!��)� �,3B � &��*JG�r�3s��wl. a�jR,� "���*B.)|��ٮ3��!cx:A�s8 WA�>1M&Ain!S/(C"�-2a A��J�i�Z8P6�.¶�-�� a��%��!5B�A��F��=c!�X%*��K �] (sJ?��y �6�wZ�U�?"*��6�52Brin vivo"� .i�\tVd)eqwaE-9^J�7SCv t� �A#Xa}�&�!n"5*%3� ����tes!I�=�lm ��+"pan�X&M!�[#��{"^�dow�Beam co�s�4�4�ee��E�:��EmunY\ci��%�assW'( ChIPs;���P� �6ofE,�c�>��5�'d�R!�y�4i F��%��e�Iu�:or�VE�KA�Ses�1 r ab fe�" �%|Ac"-!2-Q��(v/�DAb�2�7|�&sub�C! L.B� !"�b���mEu�"�%��r�!�X("B�-��dA�1�h*%T}'e< �#�ϭ�2d)Yմ4? top panel�27�&�-!y>marke�5M�6�B�O ,-���AP�:�bottom ���N"�%.�� �a "�|&�q��O � �2��E &�Kfl-ng�H� ^<.B *�N�abo<3S�DcFW>m���@F� �"/!H E��3�/rU�z��|i��A�,1C�4w;�,�-Z:@ݯ�W�uZY 6)�*O �!SIAa2u �"us"w * Fs tI-�3cF"-g!�.ZA�Bm(` �)AZ""n �("�.��&� ���n"J i/E�%�-�a�M6�����:��Y66�&om.�;Ezp^>� � An!L�  �J�)`5� !/i����V2 "e)5�% if�E clus%�+lo��w+i%#s.�T�on<�5E� �be-*�"hJg;�q5zI=A.�Cd x�A� s 26 S�R27 7�z2�>:7|�T:�{T27�u!�( Flag�[(tope-tagged)R1a%p6(4#��in: �f,5)e�reM[��a�0�( f:Hex(4!)* a��!/5.#a"h��2v��c�t�b&�8i@gb;=�26ƒIm��N�=s�$Po�s+z"!��9&o=�����. O� �Fh;, s@)6mim��a�*7.�ed�e�,V�-��1��9�a�q��LA*� yH 0a��� 7pr�N3`>\>�5 y1BO5��G~Amirsto��mld-5/:-�>jm�&i�cGu��b)_�coYi.�A�� e( M�E��=lH>"268A�,70B6 2\27:)i[�" �2�5<* 6<%e� agar��<%��ie"� ��Vc s� "� H��m��B} ~c�A� wj�(�#U�bo� �6�-� 1E�g o�s��&5 @2�4>�8 ��>g-�!m9�)� }s"�aq6F�\e"3"V�M:[%�B[?a̺�D�NEo6C6���P|i&+)� =� an 5hEa�e@�W�S��mcP9U�^ �y.��� E~ep2l w_s>���S�.),p� %�*m �8�� i�Wf!�I|M5ng��:���|>�:jR���G�'u ��V&�k �]��1���6Yby��%�;�4VOow%eC��e�2'+qP�xt25V"�!�9ө�W"X��cl�JlPDNA-t�!��`�L><�!��o plas���jr pG6TARI�!��C sixl�4\%?Zi� A�AI�or 0.� �\,MXf"Gal��� 11�"�� -�ih*�� ��2me��!e*7C��zao� �%1�`*` )>���QJ F�5h:IG!�8 �by6��N% robu�H l�DSY��8z.�6! 1–���%�eD�Q� |.,u� 2i6�F�O�5Ӆ�"�?�>p��.e&&�r8wF��Y�C�-%K*����CEg6�M�� IaF��!maG�#u� zr+z'�S��v�Qh � "n :� by+2�AaRa�a���M�5:�&�i� o"� ��IQ!- isZ���}�>.��O2� ���-2= O� *! e�^X>_+�4E/[ �subt�iMJ��dab��C Vj Wen�He&0,)`���aI57�L6�e.-Z�b]� Fr,M�*$0w��-9n�X-U�B�6AA��$K 6] �$��� L �S��!a�6������.�k�%k�gy�In sharpAr5� �s�3>)�Jm�Yy��|6?@_ .o�6[�&(r �a376 �� �� �!��b70N:bv2b&&�'�#(R^=69B�#)���&^��b��p�-�C� 8d10�]Aus 9 �?.*�E��6��,*�E�"9A�N �_a��*9x!(-��>dAM1EB �u'1\%X->]ed��u+at��-rU& yM}2Z�#"�*>ɧb���"�u. >cA'��:��R�%]%bl��A,*�5 "� �T��� _>�of`�]m�6��B��[y�!�!zZW��|:*S�nE��F&s(�zS���A�yCM*>�.�a2.�&��#Vp(1���ofQ�M�G'��!xc�lor ��2� afoK��B3U�7aw�-"�Een>K$�E=m� �"R 9! �E�!�2 !�!A�5 or��7�P�� 2�$Wn����q�Co �%bt �AVLC�{�-.�.Wq 4H5�Z� B`��}q play b�hMXegeN'Z�N�&q ���Q. M��Z].%�:� je:Az�e>��9���� ��@m�A� ?:0 ��>&+?V�TW"7��:�.�� �6.*����A 2�E\�.�,!�2C*o*fA����8@a�"�,a6f �oE [�y7� !% � �n�7 "�A�e�pro*��'(�)u"IF �����75%}(�s ~.*-"b<�� �'on��� ed� �*�7ضV%v"�JB�by"w �wm_)bIh% y��sm��7!hQq7 a�*��)ul-��"d� �z�a�3!`nt��6�:� Ee%ms ۯ)t6�-��'B"�Q�F\�>:c6� I^:�Aː2� &����am���.)�"�(:�*� � �–)Hz�A�&=gsFg*/ 2�-w!�6 }�LC5J� 46� ��. I��&�G݊:�G�9�RJ��^�F/s!�6+�� "�(.�F� v6X"t0�NCum�Bl ���!J)6%&  tur� �"��rr$�N\.:�� =�B�Q96��(` � t a0�� FLHX�.�A�� &�A'eE��օG�BL%�"�w��l*Y#6RRG`�e piv�n�r" co-ffXb��U�-C�$}us�0a $ d&�#E0 �"�H%-I!&q=RV)GeuX�9dnR5i Y% de e��Nd� �gm�i�]&ask!Q�� B�� LM).4�p�#�"//- A^M3MB��".pGN�)I3K%E r(J�yVt�-=6 )v� ��XC�e:m. Iup. I�s�� 6�D,zQMBc �9 Vbi:V,Z)"J;a�"j orE� aggr�OoE�;"Jr brief>rM�gem�za�;.�^��Cs!.b�{Avd ]d2� bA%��FQA�e�;"7%�N%�� ���X�V�dof0A�@Y& A p��ail*O�lrQ��Mv������\! �vp_A�_���)�.�A0�g"�  :�U!ZJk E��&��f�&�7\ *�Pis(�\&���.#�X e}K��m���!2�#�^��#62�#i5�F'!|�7�l.�&O,� 5L�� �%'�xPny!�A:Mc��d seg�=�MC4�� �1p[2��r�D/6%�ZN !yiR�*� fK"�S�CG~006"RGA)�&?� e ad)�f�Bjbs�Q74a��|]7&�4��oug�aJ;(I�"� �+[�mq96��R%b&;�%�&�1� :i]�tOI�%sy�ed �"�*!j �)u ]E�G:�Anҹ�t��Yy!��4�-���ZR�㩜� :��ha^�achEr�oZ�"�2hmI!��X"�rs�As�AT , AP- LEF��B-WIT<�EPL��ng�d� �,rZ�80�b�Z&�"? )~ca�����X!�E6� MkAv&�=[-( �� !��R�4�aUB 3MardiacBertroph��56%JLCy��kn��2qU�I]�0] ���*v)�3� �%�rezz� yros�+. )�!(N ,6�yM-mL�/��L2� 2�1�*^ 8Y~+ pre7ci �RNA–��%: * %.9I�.F,A��noost����}�o.$g�\w%; �9� LC [Ʃ 6–��4�_A4��!�"� *H!(J!�6Yd�Y�sE�m�qeO�B�SGXa�u�(A�iein"e�'J�-��%2��5���y.�Y%ffe�� insu~4 ��e8av "�4�X�"��e"���sS2����V T���2a�)te�ai�Ur gu,�0)X�+�)VtO. O�UC_�w��sIs6L!�[�.�S`v�3b?��%��"�Ua_����"��is_t��cdorA���)�A��v8s=��&N.Q�*N l3S �[�[ _s� an�/�� V�)`  lRG N�e�zjr%� [E5 , yei�5��Z�A$/u�i��F�1�]t��I���u%g)�.�. D&d��h�Z@���q�abunda�:IA��u"fIJa��}NaU  %6�4�?v���! e%;�~eCR�Ib��".[��4�csyn� is�T�v ]% �!0�m�#/� i�.g�,J�h(in>3�e6� K��&rmb53�SO�Howə���rhrA�lq�7��erak%����F>ie�"!k�!�a<�%k ? .�g I~_E�edJy*tk� �fOcl'*>"T.l?"#T�cXw�� �/�<�W�=��Al���N�S�j!�dݎv�u9o�[�d�!�i�S:M.a��*��a Ka&��:}(# �6-�lM}w �, [44Xb� �)U�< �L&�7t��%� �e�uv��6v�SX?-~ {�aOe���P. n U�fS!3��ejK� ur:�z�:i_t�ER�adv��b!t�l�:� �� ���N�Am��l�A�=wgM �s�)��. U�tuG�]�iab�,�9��C��YY��h:xa�%Y"V��,q F� Xq� m9e r�&� -N�h�Q� J� N>�F"]LI18�\ly�a6e��Wh|�ceE�Wm���45�NI�3A1H��e�R*�3� p�s|g&ma��Ks-�/XPl%,ov�$zR���Ple�b ��&e<��lo,An*?n� &�8~.IW�U)�"� #\any]��H �m��e eryXZ leuk����vascu�bsmo$�muscl�q�Zn�_E.o � l ns [s�4G��!��K%h& v��B���NCn����m�S( nRN } ؁��.R�.� ,a:" &�TE[[NqVZ��c"(�(Lsu#]�*U � !����� :�ZQ:�pr.<[4�n�AJ� rz2�ܡ� M^mgrar��N�e�f� adox��w!EB� f#�"� .l����[&�^Noiݽ� �iBT��j%j%`"� ���*�%Q�d�qEG"� �  v��X�t ŨrUZ)6 �Lw &j &�[2 W�ZA �p��Be �!a�!�e�ӂ��m E �!!�a�^�}"S&Te�%A�a5e�,���� ��$kJ�T=>�;ls��i.�f��th�9" n6. U�2ds3"]P�"p1��RNIH�wr[d� &� .._AAkin&#��"$Arnold Rab��.6(.�O&�b ��*:Va0 RPMI� ai�pq�i���00 IU/m�6�Yreߖyciμga�2�FBSf37 °C��5% CO�XPlV�4�qand plasmids coding for the Gal4 . CycT1 chimera or f:Hex1 protein were described previously [28] . To construct pZmmutant:\s ,�LpFlag-CMV-2 . HEXIM1�d was subjected to site dir Y,genesis withQ\QuickChange II XL Site-D5Mut5DKit ( 200521; Stra  ) . The�2@$myristoyla�AkCM-) !tdomin�negative $DN %w!V\a gift from David StokoeC"deNx 49] �anti-)� ( sc-8127 � dk9 ( D tibodies \obtained �\Santa Cruz Biotechnology.i-��^2 .YV�26.� 05�against%�`total ( 9272 ) , phosphor-oform of-S 9271&� *%e subs!�esL611S )N�(Cell Signala.1�P)�%�b�>�A�( M2 ( F3165%�%zySa{%>( bead� IPT-�rpurchas5�,igma-Aldricha(MBA (�)e0lresuspended in sterile wateraC)�@ a stock solution!U1 M�@hemical inhibitora�A�( VIII ( AI85LY 29400�$Calbiochem�:�|DMSO . U1 , ACH-2 , or JΔK cellM�pifat �105 /m� 24-w!�&�superna�p�= coll�,4before stimula�3%J!�E!>(roporator (� -Rad� HeLa �%�seeIu��x2�Tapproximately 12 h pri��o6�%��ed �$FuGENE6 re���q,1 815 091; RAi Appl!�Scienc��HCAT enzymatic assayQWer�Jed ��i[2��� crip!"al activI4of A,pG6TAR reporaX�h!mR_!jset-�<% . Error bars g�($standard esm@mean . 10 millionJurkat.�ly�0(in 0 . 8 mlAly�buffer A�G�M Tris-HCl [pH 7 . 4] , 150 mM NaCl , 2 EDTA$% NP-40 , ^1% $i�' ) ` 5 ha�4 °C 20!�ost-e]O�t�� lysa��EE4immunoprecipit�ce�!Wak:;qAMat m,!h,hed extensivApB:i�[bou/ r�M%separ�,on SDS-PAGE �hory8. Western blottaE!�Yb}indicP��A�accor� ah��M � ocol�@Glycerol gradient�9 10%–30%��Xestabli%�� ippe�2M eachAhgSfrA�AZ(A!A A!�2 �ev/v )Ac]Q2E4HEPESUN9ANA 3 M KEN2]RUVT(to centrifu8 on tub��Beckman�L33137� G5�m�byiF!�A6.�..� eith�a� �l! corresponHm�s��not��3!t2y5-h5"��ain� �!�:;!a �%5% RN6]or i�0 m�/fi��con%<��i�30 minyJm4!p� t)�000( 1 @nd%��m loadeA�%�U�pr�o�`UcY���eh complexe Q�Q�e)by� ��,n SW 41Ti ro͗U"at 38��00 rpm .E2�. Ten`e>!� &+,�>y lorace�Lcid%�%l� alyze��Ù� �priat�  � [25 Film� exposures�A�8 ar r� Esu��!�in��tJofi� band-S� ed��h� graj Photoshop!he EAHE�ins! svin� LC (=C�6�Gh versus*oneB>S6>� � �3!�as calc� ed2�LC/SC !normali!l to 1%�un� ed�. PBMC-isoH o a�y coat�I(healthy HIV&� don� An FiA densityU�, ( Pharmacia qE�� dA�5�6 �perAxiJ� � RPMI�� hu��0serum AB . Afnm�(, non-adher!�6 ( PBLs!M���!cculture�mzte l(�A��,penicillin [� IU/ml��$streptomycμ��`10% FCj A�IL- 10 A d PH��3 u9%6 � d , ��� ed���tR� (�bM�2!gM�ce*abs� o!&% 8"� 1D)�f,)2��A�~�v��y �5 � �B��p�! in.THIV-1LA3 ��1 n�of2 my {.�E ,5Y,��ple �|Rf�11%Sres��CD4+ T.b)��"�s�!I� magn���$Invitrogen�Amem` than 95%�e] asses��by FACSi�se.�e.j�ź3 expr Sn�2 CD25� HLA-DR�IP �. carr out 5 ntia��sZ�50��$Cross-link�Iachiev).incuba%W70� � ( J1a�A�����aldehydJmediuma#��,room temperaa��2�reA�� E�stopp � addi%�of�uk to aɣa����FofI�25�&q%�pelleA� coni�� A�wa_ E� cold{ ate-�\e�dsR��W�� UM-g:� of L.� (!<SDSe*? � 2� 8 . 0]��on ic �6I�%0to�& DNA��ga`s averagA�x�20�500 bp!"lengt�One-tent"` �chromA/&mAR��in�CA�. CB+-0 lea!Z%w��4 A/G-Sepharosem�!�%`M��+J�6�y��� overnight�?� NbE|cad &H mixE���anoq � e� �LMRftim� TSE-�(I�%Q%!�ton X-��,2W � N� EB�\a!�( likepbue0!YI� ��eCLi� "� , deoxych{LO�N�htwA�in %7 {. I$:= elu!��!ꩱE-�� AuS��5% NaHCO� !�15��RT-�DNA–Qv:{E �r )� $K , follow��rd��2�at 65.4 aKa�ADext�Q�phenol-c� o�RR� e��olM�dissol��in; μ%}6X0Two microlite��e��.Bpr:�s�Gfr�Q. qPCR�%2&#�l!�*�MX3000P��l-a >syste� P|s �!�LTRiM&�p*�8]%� �s2Gag spa regA"!�ri�Xetween nucleotides 1144E141A8S�curve T_ e pair�first�f�check�their� p�ve effi��Produc�6*n)3BrillimSYBR Gr�Q!((.K)Fcmanufac��r's��Y . Re"v�t� A�*� a:6� !� inpu�;Fold-in�!U<" as +eá��(� !E<*$�� no� !. �^N��al Cen A 6�Ina,'L ( http://www . ncbilATnia| gov/)3ess� numbaY�@1 are NM_006460 (]' sequ� $BAA36166 (�.".��Pat�s��s��c98eous leishmania� ( CL ) cae�4by New World L) ( Viann� %Ves�,at high riskod�opvmucosa�Maor�=e���f�D�{ A 9q of ae(ary skin le%Wa��X bite�a�-"L sAwfl�c !�can.���� secoRy sG(This metast�S type)Ps signA�aVmorbid�{i0tenA�oci%E�a hyper� lamm,yee�ons�aO.he��tru�of naso�,yngeal tissuML��appeara� f nodule� umerA' ulce�=hF!�a� %Awe� nt!aggX a�9 �r E�� YcRNA#uLLRV� y:+ . guyan�F�howAi that2is1! ible!�a{4parasitaemia ,91ve>oA!�an�,$all exacer� �%sisw. Fur� stu�E���onshipR 7 trib"'LRV%T� =��qr,would benefi�impro�methoXf!Fact�onC��A�on , eS� \de�nt� Q$knowledge �e [��as �!�2�ev a�diverg%�� is%+y r�s var ! techniqA�$, among wh�� us�a�ti-dsA2monoclo����y7�s��mits)IM!V9vaZ cogn"� ]� ���5" fash!J.,c�a� J2� lu�Řflu�c%,��dot�:.�5�A��rse�ofM$de1�to�, such!�_�cid4��o:� -��w evaluOvIOV�monA�rt��fulA�byE�J"� y!Gs� alq��re�,Ureshly&Ep�� s q��biops�}of��edg W�op� �refin�%�th� ��"iK�r��fieldE4As,as a diagnos�!v�-�ngZ6�RV�o�ih�0LRV-r�!ed�=%�ULinb$. �)���Lne�c most�or�h�E ozoan1�ic���s w��widZ w9 �dAE�of 12"��)sEVa f��3B 0on people liv�at �a�  98 cou�es [1�[2) It mainly-Nt�tI ajor cli=�s: �!fGFin�CI@� gene��y loc�!�self-hemg��Evis�lB6 V�� nA7fat�M � >�LYb�����s!�� !�9� (. ) subgen�-A� g . �!)), exicana�amazo�?)�me� ��$2� Vd brazilienA{ kpanam !II���wh9#VLA�A��t� � 4) vani VinfantumTchagasc BeyoLiAJ nsicQ�e � r� seem!�a�rm��&�, F=a �haR� also9�alt�dym� !�teof:5[3E�4n South Americ�CL��sqigI(!�u�my���� &� �, [� [5e�6�x6�of�invol�y$�+�� ��'�7q�#"| � � !�A��n g����� ��O/ �o^ ig��deT �f&� �se [7� , [�[1�Mu� Qiisa o�!��poo�� � ommo��� =���mon� ah���5qI19/bac�&al!, fung�&O� . V�%littleO��ab!SA� path��!of�?� �1v2S;.^ Esourc՟un�rM&U'NYobser� t'ome��.Xq�%�have b�as6J ��dis��d ��"� e���,polymorphism� �_? NF , IL-6THLA6"d�co� y [1��12E)1�R28 sugg�" �. a��� vi" c�%HL �l%jg b��U��(q FJ [1i�1i�1`*is.r.~(� ) has)yf�#in�ҁ�2J�esL O inz *ɵ[  7�&No{#A�in mur��mod�'F��-�N* � �genA@iJ!lv � �by)�Toll-� -rec��'TLR��� � =Va dose-& manner2T..H!4O Qn life cycl*| mot�-�ellular� mastigo��orm!!�midgut!a female.�A�a� V�/aVaZTy lian) m� phaga Our)��n �M�i%e r)c%�!�RV tak� lacaw��few hou"9�_$r!�f�!�2.di!Q*!�va*)��t�*bi�!to9��)�3 (1� trig�!T�,zt IFN-t�I driven�� cascade pwo� �`uZ )A �ZE� burdJM�-ngu�� T�#�� a i%�Pof Q�u�!若ls.!{i� � 4�$Totivirida- mil� .egroups!Kus�o�'�?�Zal �domR E��0,�K�H$.j �Giard�T$omonagy%���i^�Helmint�.or�s]#��ce�sia�Ymosquito] 9� salmon [2� Theysm�Osi=%��(( 30–50 nv-�kx&aMb�[Ei enco���A�l� ps��ean RNA�-!���oer�( RdRp/ ne^ 9��t> both�al ��  rep@8is�'�+��e- �#.� �0 cytop�,�D cF�A !�t2c2fu� 9-�! pept~( 82 kD� 176 o a#}*�!A.�)detailedS�cin yeas� 1�A��a[m��da m"d!a hund ���t�3molec!�d#wo ( �subun%�urrou�(afM E)5�S [21���idR!fb!ncha��erūq�ye�,ago�>g2% D*� [2�23�24]:�5.�"!#a�y[�Althoug4ir�organizm�m�ca7���%i."]7es�Jn 40% ���2�+�) P%<�a .2o� ��s+,go)K*UN !�he �� LRV1 FRV26��. An imcf�,ng�ou��/work i�T�"� wg%�0�RV&k*� %�� �P� ��U� ��d�.onsidera2����m��ssL�� S�loo��i�!*rolI#RV�thu  g^1�i�  availabil�ź�(eQ � K�����f� J k��, rapA* reli�2JsuiL scree@,a large��1�� 4 ��7�en`'we� B6beawdi(0P6��7�!g4�R�r�*<%��(  ,-2��� �( qRT�)��0E�!��-�M���� l1, fix�Cr�� [w �E4 �3,"�%�2  scopy�ԑX��b-b�EUndaSa power�EA� �earuoner�k GitL e8 limiaya3;Q�Y9on�2�Qs�!NI5du� pos�� %ami�c)2w){�cproblemIdd[� focu�g�2�I thro��A�WS�?,�era��'� zes bin&� �$ts underly��om%b�� �4aJ1�v���alogued�͖!�� f5��2�3"�-RFA.�o"X"],�B�!��aO4of1J6QA()��M>�p"�e���have�1.c"7Vpredic�N:&�l &��� "q�@!m\��8Ethics CommitteE$Can&of Vau�� Laus� "witzerla�1�a�/A�&�y-�%;�I�e��2�of�� �x%R�: i )%�y� e-f! M4147 pop}0A�1�R/75/ �+��I�byude5!!hdg SLRV4 ( 0/SSU:IRSAT-LU1b )��nd .3neg2pX63HXGZ:2l [L2, i�EMP�:JLg 139/I�$R/89/IM359/ � 1881�E� R/92"86A�"ik:YM5313} ( WHI/!J8/ )=�%1� non-*�"(�03)��or�;�"1"2\l %�, y>F� V2��3 viou�@� o�Ӂ�ux� ,I\]�I zed:)H$CO/88/1407!�Lb R%F M� MJ � �>6/1174 = )O 4/106  ��(���� .6�p q,Ŭ.�ɖ�_5#� whoev� d��sis-2�@4om"3.j�89K2�")/]-�%D� tpa�tex�GLb �� 9I8P6��0�1a�4&�s26�:iH6 pr':ed Schne� '� sect�/( S�?>�153heat-in�/v�EfeAbovinp�( PAA�1<,Hep� Ami��A^50j3&�3/2�3(.-�)6 mg/LD� (�a�5 @..�)�#�ph.+21��� m�-�"tY,wO�(4% sarkosylx�W"�3� R�=) dil�, in 1×PBS�,08]�00 µ�3�#e�&c<c&�.287!�% �*�c5�4Mg�?ofO mb�C�i�,(��nH&l �.O1�N�9( D�9-freeI��. N~+#G ���� &Bn,!��L ��n ���'y)%�e�& on%86%��,42%Erose gel�"�7�, -saf � M+&U<( :�5��:��)o}�6�= 3×1 7� Trizo+2h��3 E!�a .�v!�!�8 �!��*)-ACAN� ,�ZU ��߅E`�j~H.%� 5–1 µg�1bE�` �cA�syne i�;S�DS� II R+se &bB��:��!�ff�u'qxa QIAq�H& � k�HQi*C%O�Ou���� a\0�.Fa�5 µM�e-�sA� g/Ma�@�3�64Cr 480�0,���.�6��sis�I-�it& den�6�`��95��A6�2f*J240�� ��A2:�e� @C9 60P72AQa6�&� step�78+toQ1�exed��a�Ge!� �A�A#oligoe�Vs_ v2E; , 6��=Ad: SetA:A�H�-CTG ACT GGA CGG G$TA AT-3′�5�)AA AAC-CCC TT1C&/SetB Q,GTC TGT TTC I,GCC G*PHAAG CTC AGG ATG TGC TC CA-/kmp11��!�MFsi� =Eu CA A >kGT kCTT�EwGG �.%-�)'b2Ion�1-4�$B �0 ( GenBank��e.�0 : NC00360E A � �gen&��lyo .v�i�C%��e7ri�e&��*K y housekeepA?��a�D�acquis"� data t&`4x .�softw���5*�u�/$2−ΔΔCTx ho�?bwope�aH framkJs}� a�, e�a��+�c� ^#�$ET-28a E .a:i�;� vec�AMerck��I'-1��� }ly{i]-g �6 *�A=(*n98%�!�Ed�- GenbVPJX313126�Rec"5 {���e�)u a HIS-tagD a���rabbi$+mun� ( Covalab�"oly!CaD \By �� �: g018d5R"�C|M�)�]�by BCA ,���� D!�27Ga� �ac�Mm4��I�p�f"�,a nd>�ul  raa� nd vizual�6y P�D au RP �3jh�.c ��in 5%�d�<milk *T TBS+�05% T7Ga ��&? o"4; at 4�#un1k�-�! >�( 1∶5�D�% � TBS-� F��!54�h��2�9y ^��EE�SMWIgG�bo^6up�to�C oxid�Pr� �2 ;b�"�Ia�O 4×E�:afby ECL -Nilu�*sx0(n*sha� . For�epitope &�,gnty-f�20-�!�lap�<��o1 a�10y�)"!c%�wh:n--��aZ�a���es+A�attacha IC%.�s!)A��=3P� �O stry Faci�( Uni��"AK� 5B�by���J���aa an AjD-PEG500-UC540 sheeyE-ha�$ "V4sta��u� ��kerh.H*n M0cG� queS6pH�8H \#pH 146 t ambig.�Aea2�r&PEG sp�'6� 8N 0"ylY&Iol �!!�ha�e}.��!�to�rA8�QQ})@�a� �!\��t�nmol/cm2m typ%� spot�me3.of 4 m�.�%an'A�|$o�A#/B ��M��(�� wise� WT$��%�� !N-t-// -ch�)�z!I�potn ( i�qui�)A�robot �)eA^��6 �( ��diiso&ylcar�Mi��D/hydroxybenzatriaz�:��e���*! ,i+20I� �di�SFall6D� sAmod�#E0��*r�(",1U�!.1, �yV%6�Jal٢.�Dthe8)6Iq� �A.�+ �(eE��4n�4� Abp�5�$b1+m=�4Y)Uv�!$oup ( FmocI piperidt S� Y repe%&until�U����AK1g"DArr"wR0�%��Nluoro!p�to�1 nEXA� E�eVstoA�at −2� 9to�P+ im� ly� clas2Zh E2&� abov���e�-qS:�& ��$s � )�a6Bv��� m(I�1it%� � � g�� 3� parp MGd��s:M�,n%V1� �xF109���&.�s i -�sn � �RF��Geno�F(&4 “)�e/CF�Jj”D$� ?-\�L 3 kbLN � 82��<v �B� Wizard SV���#�Fn-uF�B62 �Cape*��'a�"�UI�(�QN=$F�1����gdl��2@I��4)of GoTaq%y� "�*& in J"b�@J�KQ�� (&�, fmM dNTP� SA �3 ��O�?��L%��!�a&}35���8�9� , 15��V9�:�2!A&�D�qg�8��6ye(��F;=-:��Ё3i�AM>����T��(CG TAA GCA S�T-�2CCA �CG�_�@(:L[)1-4�B3] GAG AAA T#GTaAey2[��1#&�e�f5�m�rC�^$AA CGT GACC�CA ��R��Thtwo���Ds�l(R�z 3 .�. �I�in>>!�!��5\PJ�_�-c�-ID&{(� �VEJe� . In A7 a�f�;�'EU4%a�2�M<a�2��(d � K�) �x�,nd0"j]at 2�6@s0��.� �=-�ne*�R�lgG(!�rmo�Zt���$ �@*�0e�perme� �,X �P�":K9K(-TX�� � block- or 4�6 `in 2%6�alb�\S!�A/= O[-ca"ine,e�&9e1_%�AA��7S\ he m6q�.�?(p80�XEng.Y &.n Cons�ng �#!9��..�P%�M� '�#(P-K&| goC�( ��c&wAlexa F  59�!!2!, I.�QO�>�.S48�#S6%2RI�>��2eU �'1 Qed�_M�%���Iga 4�, 6-Di8ino-2-phenylind& ( DAPI>�:HayDm�? Vect�Bel-9�100×�DABCO 0!�2  ( 90%~eZ[%A�g"5% <��!orP�� u��^q�.)��vis�m��:�an UprL Axio c��6�Qu�Im�4g.�CIF Ep @u*j.NB�6��)�=2%X(al&�R�A�2M%�!�*!�a�V�eg� d slip�F�\r�a`F�Y(�O�Z t��! ��K��!�� (!��Ki6s�f� �-X1e1×�>|B�S�y�E�y�-^�1a� ]�R86EX-J3I�1I:ng�Q x�Pe�Dy�t:D���w!9���(��=���@�-rie�JOa*%�q�9Pro�G9T:�.M�oe/6  >$Olympus AXzU�oid/maA����� QCap` Pro&�( VerT� �.e_e�!]y� �a�e J�OAa�e. 5BL.� �����J&>6�d!��a� �}Fb� �Mini-f!j4II Slot-Blot S� Schleic _�huNe , Kem , NHeb��%�Y~poNnon-fat�AX���T I���^���&��):�\ne H2MZ��4; WA Bg!le�=K���2b plusť2�{�9 2�a�Xz&A�<-AW  )e-�2/B�RDye �+ � 68eO�a�0A, Licor�s1Q��Lincoly4NE�^!�f��Z-T��� �*oN�n OdysseyhPr�VaaxMi�A*�2S{q�i .1'PLiC:���A�(cut-off poi g6/^ as 3��Nd a 96U5�^"�. ��]ha�Me� e-� ca�F� ,J� � "�)%�.rmDw20��(����i� ���*� eBiqm2 dRT>Q �-l>� � "#*�A>�E��:�Mv�,�t 9(m�;�yaO� *a��Q� ���HRPA�jDe� � �,��(aD�YB�. W:\�Tdo�CbKQlo�V'cu5]��3.o-P� ened ne di:�W$ ( OPD��a�[*ci�.e&� � ����"]cidH�)Ɓo�\ H2SO�VmeasuJ49H?%�a�b4tek Synergy HTbt&o*e� ����j�6}].�i"G-I�a b@m] %H��A �L1�-Li�*�ց�."O/�6 /�e�� adju�'to%�W)/µ�Y2��9ho��1i^�� si�B�Ld�r��-ihe^ m� �%�dri� ��!Ta�\;&)R�se�A����~pr\�� Pg6�, -�!�")SJ2 �hU��%�IyUb%"S2>gB/.�_� l�B�.C&x&).�569ein�tsub"3l�R�&�(�(hind footpaBC57BL/6�deb�:�,�V6�q0l�g$( �#8�J �lle��uA: *�.���-*Ub &�in�a-6�fU=%i9ly!,'ofS�w"�[ �4( 4��R�!��&"Y���U*�@6�m�D�U:� As��t�G] ,  [ �edi�i�t?"07���s+FP3K)N6�E�-]$6&p50�S�*�by�r%geF�"�Ia�&�6�mmZ%!�A ��j���Ain2�e�!�� �� 3 !8weaker<elat.( Fig�017upj pane�4isz"b sy  H�w*Jpa�@�is`veli�\byb4z �%:�arA��FŪ )X�:f��o�LRVlowv8%%M:. U�� �I܁�[2�4E2}9�%ce]��H!a��RV�7 q�th]%o+,rsd!�)�.�^�0139>1�BW�"n" ed��*2 ., a#0:X��y��yo.$*zb5Ewe�? e already�J�.fu� e��2%e�Y.�M��-(:th6Gcl�Z�;�"s�0N �Z@�� 124i��0"��enž!�ix!2H`153a� 277 &�.� )�h� 0;32�03-EW:��/he�JJ�2� 3591� 3694�*L2� �Da)&.!Ft�?�.K} �L 6 �?r�@^ 0]*�>l:CB�. W�"M2_ �a,+E��<ed ne�dhal�vA9�-E��'e?�>%le Q�@��-�jo.Ph8 G7RQ�SE�n"�%c50��E4 Չ>cdespite%��e�l�as-н B vsu�Ce�Pr�Qry�Gm1Q� j�RMJU exply}�Gn"~�l��(H . Zangger np�A89k�!� illua���XF�2UuE�* PCR-: d��ach�s"SHinF . De�-�Q�F�>bUFyviaE�r6FQi�w s [2�IUP-affin9 �F�g*� g018D�0aUraig� s� v >�'�g��!�( >6�1toA�U�1-4�,nZ�-*�1!}9 BW1�e!�in�-6� 5%*JHm��e*M`����"GI��;3(^z$��� 1Y��8oQj�o gaugeEeuti]2FK ,!A�f� Fp� � � +�v2X&� fix��F&�@3�@3�@"4�H+AP��p{ �.%�s'-a9EXt "\!�B���� Intesu�a� `F��4A�M^\[AY��y)� \O��� Aby54./2#QaE� arli� d�E�e�!h. F�+igw:.��F5}9%�, �|z%Ia`?Aa�oe�`d*1i&oh� i"�m*�Rvidual�� 3� ALin��eak%5%�e�����0� %x!`�W=UQU��A ��N ��- �!��B�A�be^oUof Q� �w�M�.� (l2hi$)K.&h�QnVF&�<�oQ75 If* of�T!�"�"2Es�|� d cr�k5�@ (l ;�7e�,�ve�t�o� qconfir*fgat>�6Sfo"J%� abun3\�Y*\?��t�� ��Q� 5�J. How�#9@e3���=~��XJA�7�Ah�!as25%���E)ly  A�.J&!�� ���jk is!ol-low/"� )a�zexm�&� bd<l!�1�s �� � nf�5Q�} �&��r�%�@R*ks%�remark� ��9��d,�uS�59:M;"j@e\� �י�!:5��B"Az1r� s 1BM&In&W We ��uA ��[6�U�u�� ey]�"!�advan�a�f�7 jv�fow��$9�5Yhow9�5CA���`�mi��"&V\&�]V�^��Y�m �w%=�ou�"d�Non F��da�aR%0.:2s ��{*�D�7tc!Y��2lys<� nd.DWESRV�i�VxQ.�QqZI ��B��Eb.�k��^=om �w*� �C6�we ne��%��\�\3 ga�YH �� e�-5���AZJ2e� a va=��eY�b�C��gn=v�E2)�/XXyTv&qX:ikDݐ��5e�ea&>>kpa&�nse��"$}ArrEQ �2�wY�"f �anJ����R����tN�R��Bo�o�l����<rM�byIA��_BR(FM�4�" #E�~K: �R X 9 ���a4A�ly ��"" M� �!X<��`%&J+SaMwAl `|�Ha���&(S%� �7�A�� 4,`omb���> �22��a�m�V�N�o a�q�m o � �A�|qinAQ�]!l5�� ��\-2re-�)�E/�� ����! .�i .o@�L&�cE#"��� 7d!� �O&x�Q,-  u�ssQS-BDTS�<St�/& r*S>a��ew�#d+f���eur!a +og�^ .��av NV�2nezav�+fa�J�4�, elope�gTf��ory��X=i, ���yUo�A��!rai 5!!W�`to guf)y��Rtegaˡ<� f nt d�+�me �URaccuracI)�9� rei|~ ��|n\&�!4a�>� 5:��ks2�m�/ �"�a��wYi$���^*T�&�^t�'}%]a��jY E�x-N*� "�!Snesj]6�A�O�Iy��i�walwEBeas�A 1 � *ge�Ei"�e�"edwt�k rect�-�� �u�oC&�k���. @oof-of-��pt��o&� .�`i��v{3a:q4a�  I#g �%� .9`��^0�� 6Btor2�,� !-�!�>R8� � I�. n �ǭ�B�zot!�.��4pa'Bd": *ass as 2�;�@���M=H�EOc"�*�=���xly-'uZ- iops0Oz1� "6#*=5"�0)~�� il�*�(ay�% waln-'eP�Ama#ps%ac@9R�a mѡ�� �")�A7O has�by�a����^m>K�>��U� Nr�>c!�� �nagg^�"�s��(p�6st�eB�w��q�a��-��=����X��lyxc ,��%/rK���rovm�ro� ���z?%]� e1i{y}dvM#EE)ac�N�,9�,F |e�ad�Y�"%���8 �P͒!�Iխ?ica$?E��1?�_!5i�h�-hR,� ���j2�*�t[1.�3%����O�  1k r{6d"X*F�� ��-eA.\T�hc/�'vupsE�a�)bjd��!�nł���I���OM.geՏ5!m8vJ 6$5�2V#in�#Fur�;l�-F�o1�1W ���${�3Ton�k�p!X�(@0Gg�M&�d�uro a���&h#ro�h�JS�Y�A*c e �Ke*�ya ��2���bJ�B%26q�=-��*� by*�6� , n/�=�i&89! ic c�#e� " �Hcl�PV@!� �3�,2�v�e�E5�asU�&( ir"k�ce��A[uMZ5i v"M�5�e�69- new,2��!�9�2K ~ x�* .� �i t+� 2�Ms5-�e� a ircumv� h7��MBof�h �rtA��n�o ��&.�Vef�aʡ�2�'x& ,��0�3""�6� �q ��s���i� �+[RVrm_-"#3 �)� lzLE�z�T��tu7�n ��*�� �.�fXsumma�p in TeK8=9��&�U�5od�C�candid6 fR���v!1*�t�u!��� o%k�GwLe!5Y��=\kl/ci�Iy2'1�osca�(�X�X"(5a4In�  )�O������A�A�* eYM�i?en ham�]ode�%�neg�M�o��U!!X!ealeFq!BD CL-dZiI= K"`or3c#"�*_ Em�:Mm0@ em)��J� �&� L4 &�H��g.���m*U*�e Gd52S9rE�jq��n9B�!T ��{b� �recdRmi� S*�ى?��R� �$ !�.�2� %��$ ���d0 adap� [ �l��k*�A6}�<<$W:�p�1M�.Qo)now!f!<�%O� Iomass-iQ�r9XQvalI !d� :nu ��n�s,��4�3 !oj�VU{!^u��FN�. I� ��1;#��� A�6M� !���25� i��“�� �š�7Zena��d)�����A�%�,�*��!,Arp2/3i�ex���K criti�`�X0expan�!6�ov im�#Une6�( }arley�L!I���xr:S�%E��R-��&if!md-r�Vf?R=[(��  �.juIi& Q��a��(�Q��]neighbov M!fdj(c aX�F�daughtt2��isenga>H�Q� %!)T.]�$~�seJ���Eb%�enh�Ds2�.�b-<creas�%5J 5Ɖ�#n�i7Ft�$of� -to-���isE. M�]��reo�Oz�:��C"p�irI�MsqkA c<�Q!yy�!� TiK>u�L5�L)ria*-yt�q�$nd Shigell�gexner���g��fil��t�]%)a�c4l � W%{�8 {G/ ��5oh(e�2��¡��>,%���L;*!9toB�U;�]c/BX��n1�iVm�d-ev)�m~ cap� {-�E)���Z`��Tm:��`a\"d�a8�r����a9a��� Cm�qal�Z��}ndA�a� ( A/�H s΋.:2 et%k�S`�9�o�4���l�b-&?��)(JW�YEU�a��z[B�!�:�AJ��o*� �1��, bec�6�mu��;8 re un%���Oaf%!I 5 s fa�\�*��b� c��O+ 2�[7–B���al�\la�V�!�& volunte�:[13�P[~Sig!�diskNa5O�8�;deφsb�׍:me�*�]E�5� with6�&W-fai2�S6T&�(��f��AN���F�i��c �un*��� ��,:�i �a���<secre�s�M T3SSIrBac� ' � to m6N�ǁ�5A�A��"y�F�y�<loc��ia�i'j� ,���'ser�i}!9>1A4"�!A�su[ ]&�o qd7Br %�re�o1g!3D .B [1�[�a��:Ze���b�i�&Z� at&5j 474��uh kiAt!^d20��:�ap2�Nck�Z Nck2�� , -�)S8recruit N-WASP B�� U$��A�!G:# �� sM{==� 1?rm_� �'%�]:":.)#b� [!a�g �II%(�A MIRTKS �zAIRSp53�y ��v8!e���Q�Jg ��.7 T(�5)5G��3�"g E9i1sōe;�+t�a~��E���6g� l� 3inguish��p��Sg� s�m%3f]" s [3X&33�5leaM��f~belie�=A$� �]ic�� �%5or�Nq[b. E6>stV���e����� �>�j.�" playm(o?ev �phagoc� i�4]�E�A�lin-Tir-A�ctE-�f � anch6Z�3F%J���li�th��!�� [3�H"i�Lal:G#�ŗ65 dyna�1Z � !�0>� �� i3.�“surfX�o�j�'uA��!=��3�=Me1r�5�h�% h��I&� �An�je::t�D"([38 , 3���6,��5�9r�`�XO5�6#!. 6�ّivo [4?�F�m�,)F.v )!�! ?\,�il� A�4!:=A:> �{�Ɠ�: 39 , 4��4?��8 exam� �Es':*� E�e;�  �de� i��>:Q[9��"b..�1A��Rf�O�%�� e���?�$d gnotobio�pigle!)�1 wildF+ �[ �M1R�k�<���v��oI� rod�um.���/�q �e�8�n1���knock-�>,$ &!(E���!��a&� h�ii �,p�P alan�A�t Q�� lo��=�%�./�[4�aD�B{!h()-Pa�*^ �how5��>��A�m����aoy��b9"V(��U7���(�y��N2n. ��AD��Q�$ ti-2�,��l "�)u:u6�. Our��� R��)E�A�h ո����+!�I �2�by� �D )�>��3on-&H!�X�p�obg� q�&]n��3&y&�x,lZ�A!�� )��� 2���bem"�#����%!]-f)��"3�g�&�E�-źX�3>!7�.&0Ln*,?" �!/aY](S !. %�5�!u�>�bekK���A��� [4l44 �a Tr[1 �re<o-Afa�~v"� ]����}),� y"ic" �9!<h1X�k�!�*�"m �x� *V�.��;s engine�t>9�>a\opeavged� e���or)��t&�~sa ���q4� 9�. A$7�M� s�$heavily up�|!@�h�n��� �t B 7o�a�e `."�?09!�bA}�O�L f YP>p%W���wo5Z\=bN �osodel|%ZtiEtv��Ad8 copy>b,����a��� HA1��B�o9�F[�i(�s# agre� ��i��!8 ��e�JaF�&+ >95%��9ęO[2��4D�h-.#�$&�:asI*o*io!�F �/�'!sa|ach9�fi�J�HA� �o.ͽ9g*]** ������l�nlU>Q�6t8�!s r��to h�em�=<:ns "�/"���F2�%A�.�"W �r�s�[��5d U�34 �=��#��y��*��C��%`A�!�y#an ��N�%&9�r� � � Y&f%end�A�.Vcop& %�ge� �YTmR6�KC1T � �[6�e�a^��mycq�%U ( ^+ �p��5ZbI{]�.7.^ n!Vty&�|X�|)��� �-� �E�ol�[27�&�>,�Xs6�O)eledvkm7qY �24e�ͫ�A�%-�a�U]-Begjh)��isA ic)�IexG��- u.8� �M���o.� 4 &���Y-"w��3 �y m�sa�e�p1�lty���"q g 0 ~ !�� iJ�+o�5�� ����� t��G�}�aChelp �ti1��Ce�4%�M.3F� rpC5�itV>N*Y�>)Sr��&!u ]ngulf9�[4;�'[whe,V�� mani"�Dm�)o*km�2n`=0cori��.e�)= -SXTHP-1 �_y0�Zcv��a�]ageH��.'�"��C�Q�ofi5��H�#�E *�0a�u�D ak�b���*i�r��<m�c���i���:]2 �6Q�����u�82vFie�nG ofaqaa( S1Ag,i�o"� t���Y&� � �2u�,�)�v-��d%j&�M&(4= sV{cv�L%j|8X%Ձ�rhby-�! �S1B�LAMA���F� ��'llew�=�8� 6g��as6ålys �-S1C �2~GS!�iV�X�@�A"�� �Q!���deX��U+#d�G 'i�Mr�XaJ!*!���>bH8�A;Y4Q�,:��ouV���-T)��e�0-0pro�4�a �,KKu!�trJ at� &�"p�Z)�D-u. E2Q�V�%r�#u�(er ��#� 0M�t.x�r�/s}h30%G1�[�4�"�e`���$!���nAg#21��!"�� �ua!�i�i� byn #L�3&$ŏ�2x,7( � I �]L2vat 90�*�%�E = 1I*� Os �j�2�!#�bs.��� P!��m��la�r!c��>hF5��Δ;�9�Thui@*P':�by23.�SA�:��a�i�#@i�<�+o6�.�Eib O1Z� � �� ���"~�or'3in�aoP�a��Qny*ȗ�!#e��U�b$'o m�%� maxim�p��oO�. 2 μm/a[3!A [-up<��� �6] |&�ad s d�hi�0r�Dy00|) &�a����h�,p�P]r�=a'fm��M�ro'� %f%�!,\ �D DKDHn&�JAUj�{Pq�<�-"\�1�A7V�&p9�\EMR!D, NIH3T3 fibroblasf�NP��mCherrye�G��? �ore�2m I=���H 2A�1 VideozF~�%Y�� M5��ZwEyx d �m65&5lit{���4pɀE���hU�!!"*SM>/lev0s*> ed��!�a=�U� �UW 5xTΕ�Q2� v�P5�A pm�eem AO�l�C!��a|�= 0e�Ϫd!Trap�dig�FigM6� �)@s2?Kn1!��h��ZoA�g2��t/erB �.�-��S���f%�f����$ rave��'a) Aradii�}6–7��* an 1/d{ 0:u�% 7<44���J��V�5M�M.O �$%�._��FGue�EesY474*EL%�vJ �R"���7(�3!��$39楗K6�$)`��?K�1Dk 2�ZB?i��'�Fxas=�^ �Vf(:���7��1j�aС�9|-��� be"�6 �A flui-�-��*�(o*+A�etc�(M�0. A�� ,��%�]5�A�(Yly�a���.�m6�Q���ZK, �uM��yup�r;&�9!*�q�q' a&��8h@1&($�;%!8 asur� ��"y.�'b� �!EdstillE\�.�e!�� <V� ."did�n ac[H>�.s�enoƤ@� infl� $;QX!�.L;������%{� �s�H�E�05.b�[���Pe9R*�l�W!C!^ DK�ko��� 2<�>�g��. ��d4 u�}�i�*�;32gR;e��4&S �3agckӉnd val���,�[5R� f!���1Mes��f�"as3��c.w�BE��� �L]R]3[zQvI�c�wm\�[FU�!�e�6� A:� 2� 6' �"�f�en:G�,Q B�� o�l�"M c["7q�K�!T���=�� �ach5.%, 3� , mae�a)�;1�r9>�o�D. �Vsu"2��LM(op����aV zB�=atj �y�na��te� ^-��..:.= �:!s�'8�-a&U5��n.� a}�A�ex�ۉibonjzde� ,A�%�E�WTa"�a� ΔeAZ�"�]�!3e�%�I�myc� i��>��e"� VGa ťi�W �$f� { or�% Go .�eYc� �1�F{ Co^�3�B ight�erbm2� .^!1e�e�q����4A��2� D"xpP�aU�!MwnRA"W��J&b}f"� �l`*=#*A��Q"#�%n;M i&O&��ũt�)��2 �.F"!�%"�)4r�B#�]='eFv7*�+���"%:2�h.on.Ylayx0,aS"�&�#JEG-3.�?�� ntal.F Caco�� *�5c6(!+S�aCw��@}DQzr�nd ZO-1a5fir"��#"�non�H��B9, �T � �a��hm�B;&���E�&E7( S2A��6Jb�"��ql OaV=3eS *zCgx!az��lt��2&�&�%)"��`.� disrup��,+Z�8.�� /�� "v3)��l�GC�I�9�x2 *G(!ge "ighfׅ�z�>!���re���"��g3�H�.{be�X��d=� an u"�9M�'p�a��V8 M3�3*RmK!Bfoc�7oS��i"�:�.A .� �)��Dr������f �+S�$@kQ���B�2lҕs2 �� iaOuE)��la�Wl�" !�h��r��9 �/&6I4&�%L)i%b aoE �4Kl!-2H����H>$"��I[cβh Żլ�w|]le-!�o pili�� , ��&-6c%T�;A���s�=6("/�Kera�;� view�*�>�e�:rP! ��ye��Vu ����� ��2� . Sc��ng:_�s\�MB.&��e��)(7u!~# �$xte(1O8U . Bu�Ga�q =a,AYM���u�7me[aVT/s�&� coal@ld toward J�N+�d�2!&IX�� s [5n,�c �ur�ґ���)�9+b2�in�qe6�m��wq���i�F.�8Ny`F! n6g, �iZ�>�� At 3 h ,����w~n�of�Dr��i�A�n�"st}apy 56Ja)&2�B�>���nu0* $����owtC�-3 �gX o em�!�!��6�gr�-s2*e�^�E��#���-'� By 7��&&� �,exT�bE�e���"R��� �c$ �=;�.��A��$� �EE� �"76�of�1Fgr�v�� 0 � &{Bki�P�&*�=k. �  Q=b�^�=<ari����* tu�J� }q<inv� g�!zBP!9 GU0�A�=Z,F��e ���A� 1^I�6���N�SqVCa�n &�~} unboW�-,�)u&�Z�ASex�* %XG�[�d> �`���2�7~S �n� %�x�q�#^T\)��h�y�μ��� r�[d6M-LE��B", "�d�"�l ��J6o] u��n�v�rGH>/-i�4A–4ɘ�1]��*g ap�6AheH��*�Ge�[�%2& s�%de up 16".l&%��z .��-<4)�R.� �Z4 Z��2�-i�Z��ie% m`�&� ]��u2Q!�uW���I-a�������Ri��}.C ơ�,Mcx   �ql�}onB��su��� ���3� } a3�%&�:&;6! .��N�� �C5+�]E�V^�,ZAE½�ly�ա�{Q ir��jf� �C%1\U�)�*�(����6�$-�l-��6��ll) �� .�R2m 4Eiߍ��10��25�2 Hi��ate��q+p���eSM02�mF2�:.�5�a v-2er��aq�6�)! fewe*hs^���M�A�.)[38� mmiA��,.�3FC*$%< 8&��g��F�[�V��>�q؟�����Eg2�-VB�w��q,) Fx&� .!l�{,�'5t�K!a� �"Z D���. S.�w,^���V��I���-VeT!fiR)R**c/142�a.��9� ��$��,i�1JRKN�.=y��k6y ��nO�5,�o,�faq�*��jg-��9f��@!-e �m,)�D*� �G�bq9E�AE�9wa*�':w�2"��r�a&k2� s%� L(��r%S�IiE:�NΔ�6Q &�e���.�|��6ef�+I� �C)�"e7.��s����j�$A���`��u���"���2�. Ay �� � mP6�K �#���!Q�*DR1eg!H��I5A5I, �!��s1ow� ?[8 �E�e�@0��7��u7��prifinI�detail�}verifE�t�:employ�We same6_transmisE5,�� fibroblas� &� 6+���% W' !na�q���7��A1�um=fa5h�. tain!6rG, �:(arrowhead ) 4�~a nearbyE{�a��ab��Oif/� !\Ron al�d ua# 8 u� !�g�5tw��two.P,�`f6�@M�um�Aan5 labe x� ed!Q�edense� second)$=Wtop)W )%�dividedE�il) i5��original` . Af��:MUone�had%��L!#1�t�sx ��ugha!�on� ssocie�E�,.�via^ �bottom�Aa�observ� ��!bfirst eA0for how�ra�Vula� /���_ bey!wini��u@4s w%fremmintimate�tt��to�� a membran��I� cours� 5e stud�� noti� yd��.�&�9�� m&ehavi� �IKirQ %�ion3 �xor2so�quantifi.� 6, !�a��� �aI-!-2XDor “free , ” (�a�.�at5�F1m[a�d:cfasAm than)in � ly-pack�Ho�or6fMbDoI attempt!�unc��why�Hdo����+�!q&�!s�*,)*5�a, also!�es . WEk=� ��7Y474*2�6�dis� %,miA�speed����% frequ��� \����{~�.b�=[8 hCi.���too low!Ibe.U ( S3*fSurpriTl� jnt} to�� )�2��Opop yof�` �!g>89 E8E�=i ^%'�gQe%Fa,p�de�%e��lan���qA7i�U�p V gmig  +l cluAݡf�! 9�� )qgIq�=��uC��6E )er�� advantage� @,a��!�d-toi�4A is!"c��y ep*lia�o�elucid~��ZY occu�hen2v� sa�a:5�Efixed-ed2E �s�ed%�1n , Fc)ZHA-!. Addb� ��)u�v j 2Wa high�uscepti�HeL �lin��ate$see���� n op�Nl ���� lya�aw�)q e boundar�Pq�!FW�experi�s: out�a ghtforM  path�{N5�2� . W2t�1 )9J2� protruI%� >O A�(e�5�w� *r on��%�!��>L , ( 3.�K�6�w N ɴ�A( 4.?E� 0 %� nd mf ed�V�M8A�a Orde~�� ypaiE >� !��UTtG95c%� surf:u�� scap!�nse�1x� mmu�e��vAsucBunu!�//�!#inject�ors*  adjac�7 ,�(_eA�� 1� ,-xmc%1"disengag��om% � Wt. mple�.� cycl�"Ato� w :-�� �ϥ=�bre�ed deca�ago��&7!��h� �~ fun2�U ed�s8. EarlyA�, i�/Fk�%{dancho3Q��ach� !�4 �� 0 cytoskeletal��k!a[35�R��� � ceBa�!+i]%�s phagoY,is [34] . Mo�eEs hav7cu � 6�cbal!Qinle�E�� z�}[40 �of!�6���m�L%� %$��F�&typ��� �Tu[39 , 41�It%�� ^>�q�2(ai��z�]of�r� �61f}�niche!h3�H"b�M]�U6�i�% ���5@� "�$B�?j}i��.�Nr,i5]�� " ��&.!=  eref� ^ is �!�toA]\#�C!��:C%a]. �� some�pr�$�for!iV$ecr ,s�l� 9F!�a�Study���{kinetic�4Bzex��an�6'-��(utcom�@nd)=F�a�,�we���ha�'>'!J$e phenomen�f*�y!!�$%�sO.�"�  focie�re�$F M�plaqu% eby:�V�[6aq62xF� e E .!hi�,�scret��.* grew8(!-en@#�mAd1�&� ]�)�es J6�M�Ue r , wA["�e�n)���B��J0 Yہ�A�n !JI��WT Q0+eI��'b���@lso%����$te}$in�aK~$6�isR��*8�(�F .�)m�!a1CL U�q�-V�T� �heTeG�)�a�bc,� d!w"� &Ka&�>icYX%*�$%��(ni�i9�G�on Lv6D&�f 1 ��e�it��,s6�� h with� �8�,�e6�0e2�eFY�wh�$!� ace-*��A�� 3benefit �4A��*�#ex���>no����J�*� "� .� }�^Ee�'� e sop ��ly�� a long-� �ʁre;�ue new insh^�*6$by describ�o � solv�&%mplexPblez . LA8!! fluo]-+ *�#"� Eם�K�y1�UCto le�6�h7%}*.2p"actq6�#��!F !xW.w .! :p�z)s��:isY�+tepwis�%� i�,&a�C1�al�&E ".��/i�#�r!5X � lOmP woW+& ively re�,E risk�was�a�"�**�� AuYiarrhecCF�'s�� ��U,odels �,inf�0abb�0!�gnotobi�pigletsiEdemon�Nt�, e� �e�#�C�%�g�+er numb�0� ����(,�Ɇ[4�QIn,-u.Fd񏩼 p�r�O�� -! �5�eS vivo qclo"� � �>� X "�$*&� "~( [troE�!� �� A� comb��uEf�ng e}�o/ ��%!<&�, rai�&A���of���0��Q] spFUM�manifes!'G in)"�et� a(�� Ań=!�*U/e�-B|2 /N�*M�co-���in .�on&Ys)�20L�1ouA�E���� yI��incorp$ E�B#1J�%v�Y1t �!T�,,iph"A�ti��W%6�)uw1� irS innoAD7#El!�fut�. F%% ��MX,$m�!h� ��� �e� �(��  �yi�&�H�plaus.��+m$ po,�va"+ of N-WASP0n�31t Nck2"�*itA_O 8 ul� riza@ @(. Canonical �ssix 47-Fdu�#pea�~)y� �i�o recrui* ] -WIPe��%4short α-helix�F-vates 7 thro�,bm�xuto//or�~g!�[29E_ Each�"eSw pos4#%�^-r�!�fK bESH3 domaS@of IRTKS , IRSp53�KTOCA-1������to%�ored�-� �5 , 256v��,)Y� vidu�+�a�&,fa�!a_.f,�1".['��m� ef� &%�6�m�A s!T�� �.�$Nck adapA�� M�?�sA�E1-�!�ee2l�l!r�$�"5�pr%� %�)�2Id [2��awincluds%��x&&i��o A�[66� !�c� ab]1�.u.ek� impacI�struc�Lor"��;.� s MvalR%aa. k�0�u �) sepa��M�3��pur�'5~[67–69��7$5a�z�E!N�s*.{�1C1conH �s [68���!<�����#RC�� b z0ar�A[1/2 ,K C !��Y�a�y :�4�U�� =�^!�1���M�e� of s�� 5a�A�!�)�6us� ��"a�s�s�39!�-�r !�. Fə��� like��$ onՈ’:� Usy�h �$*c % %��"�s�a�m�)x� >�)%v��~se6��. All": laJ�za�� � S1 T�[2A2k70–7� �`� -pro��� um����5#@!vm or�*��#beh�/"g7or%�M�r!��w copy� ���;�a�24 h pri=o�:R e� ,� ul�M�rk ogd1 s� �!���to LB br�a��0 ropr�B�  �*n sha�2at 37°CA* 8–9 h 2�t[' dilu��1:500�(DDMEM + 100 mM HEPE�(pH 7 . �A� n4!eovernE�y+ 5% CO2a�G!��e!`du%a�!��UAM1��9'( Unia�* of M�(chusetts Me�:8l School ) [27]M.?4( A�<�(T�!-"9?on: ATC1- ��AO.(a�b+ lu(6� %1Rl��10% fM#b�2�{rume$BS�/)�/ mycr. ��GM,*+(� x%5x105 )/ml oA3glass(slipsI�b�"O { �..)��me�)a'toFtap35 mm -�/d��,MatTek1 �1MrowE�24–4`,p� 1�ct THP-1%�cyY (2�C�suspe� ,in RPMI 1640Z�!���tN�d�05a2-merc# e��ola`��=A"�)26�%i9 J�&O phage-�U*t�&�:ng 40 ng!�4phorbol 12-myrc$te 13-acet ( PMu(�=� �%gMayIa|d B=in 24-wi!p�e6�$72 h [73] Ff.�4 m>�4California Ber�., �.@�[)!�#h� 4β!Mn [74])]}�inn����μ%| G418�A�>��{E%�]��f'�&�"�I�16.yu� inY�-05-)+�R��6A�sod�J butyA�,2BBe1 ( refe"A*s�=)%�a�.:6vs�5�� 01 m%�hum�B�inko @@� "���[7N =��2�n��cyBE2cX1(�� EM )!�:$)�gi'</=)�<;ges�*$ry 1–2 d� (� er:2 week�S5��AlU%Ef �Fv.��N�!ow'�9y��Av��F=|A5 wiceI" warm�rsph!Obu:-d s) e�l�� ��� a &b10c��+ 3 .%!� + 20"nAh chie�Y plic em( MOI )~KP��%� ifu�8$at 172 x g%h5 P!0to synchroniz� "� � ;4y�incub%4Fl!�15–150]. At var�% poin_S-l3"�$%n!R b0^2 X2)7 para ldehyd%�F��"� �=�(out&)-i-)�I�9,A�h)�t��NMLAM�}�0]Il1�l* sx#"�:F�]i�)�jF2EE�A� !�5%UG��� .HnE-of ~6Z�ro�=H)t)0spers� ��EA�!��'g Y8d -�:�,�!fresh�"�9� �C# hAv26� � n environ�Y hambe`JOkolabt2 ��:F"ms [76]�Q3�x50 μMMB� RD(��biochema�r�I t do�of DMSO��h9.S3orj�DE�C5�l��t�Emp�=�eal�:.F� -Vu�b�#3em��g I�!�I�jbU��WCV�J2�a� XQ�&2 �s�(33!�X B&Y�At]�1�CFU cou�l����o��>�K input DR�.fPnd���1 Xa���)�:� haO remove un�45Ρ1�<�,J'2$oi(��E܁7% �!3�1.� ��-��Gh�%-5�a�M�*b��F{b�D9qdy  �r toa� hAb / carro;q �A�. E*�5invol�m�}�uS!��AekE��*�[1��%15q�#H+a�!�)%.�7{����pAi@% ard 0!o2�,-�FJ�perme�D�2�n�A�(1% TritonX-�,!_�JL�blo!< �1�B1%6� albu2 ( BS�_inE+s02% NaN3�a��)of]�� proAR� prim�bo>) in �!�p ��:�l�)32S2C!3�4U�|.�B!E5���5:�(and/or DAPI ^ lloidi�&r� i �6SJ�. ��i?m�� �Pro�" Gold%@ -fad� �&f��.B� Qin!�!�+ � 1% norm�po�,�NG�:M%�J�&B ` oh"!� -LPS4-� , fo  by 3El�s) Alexa 555 ?JMF��LF6_E�2U iV_ixB` �re-1S,5 �� .:�Qu!/ag�Q6�1L�488.��: 4DB�kFA��d;� Q�E�, n3�/a1>"K;�0ɭ!�a�q�m����� I���5����$a Nikon Ecc e Ti&�$e��ipp�a�n Apoλ�x 1�5 NA o�ivS9 (F% 20x%�F&Pn Andor Clara-E camer"M�yu�"run NIS Es sof�Ha�Image&AH%&�+ �$J�%p�-!!ma�S�%@GFP6�%":7�2.Ma.� z�� 100x6"n��a���u)"A 0 n t�D�,2m of 2UJra%t:�2�:~acVd ~or 45:�� ]FI`�% glutar"-+bGinE 01 M Na cacodyZы[ 8+EWCaCl2.Mg,&3w�1�L2% tan *acid [7@��fix� !5> �at room�.era!�:6replac� }� ]V!]6� � NY. M:~Va�Ɉ�b'�"����K�Nird!*2 at 4°�3sm�� �on�}ZI�xple�&1% :tets2de)�!�8% K3Fe� N ) 6��� . Sa �eXrin��)wA++9l9Iwa�]!-�)��e�XroaLcr�M( T�s.isu�� �OlocMo-1% B/(ous uranyl RE��8��6��!1 E�2~�[�"�"a grad76mse�A ( 30% , 579510 )��zE)�� cakngZ!SF!# pu%z� crit7$� dr�1.%\ܡ�in�X�3o 2�!;�was�<�%�embed� in E  81�?A��ite 50f DDSAQW% DMP-30 ��1:1in:g�9)�, 3R~1��%@�$nMw�# h� A;+!� ResimU"�8v a 60�o�~4cA�����c rM�hek+ ,. )U� nm ul�!�!s`%Tcut-namond k�(!�a Leic� crot�2. S2?lifa>200-m�(copper gridUR�8� i�2b76'6 %k�lNci�#a�! .�)�k8a FEI Nova Nano'4��B�M76%j*K ��*�Mov�zas��d��!�MCRJ plug- �$raWR plot�re gene�/ i=f otax�1� E�U ?"�U>thi4 fe�6.j `�Qze[tic�1* m�a�&&�#l�V�*�5esBA�μm�ExcG�L�%��MD(�(�{A��4 � �Uorsx&� f&\�u)%��#u#&�7�lo2�5(z,�_E"\ `"u'%�e�) toM or 2�9� Stat�?�6�4S.E3,%�OY%�>� one-�#ANOVA�&(Tukey�" -hoc ]. un>�6w 0�( <d� -val26�)=�2B�"�Xd IYun�F!� qsFrnoa� p"o=�*s( S1D*, , SEe�cal#bY�^he�#of.� �B��)�%q�cS � -��R$<8a"~#\ %}�:z_2C a�2FE���^�-�a9;�meJf:�aN=�Fs?Y�7�M����SE ]�fr)- �f:~ 2v�0d�@ioF25��= /�`%Z�*/<!1!���/=$ �.+re5]:%�'�vea�)�4 z�"=%u9 by f�?C view5OVe@A7N� FOVs����{e�$ .��Robu�C�col)�X isol (of:�7ves��( EVs )Y�res���Iex�:ory-se ��&s!  n2�*dow4eam"�H�app"�Y.�ZI��Qwid��%��+�� metho%>�! helminth �)T9s�(c=F*N��*") ( D!���� V�zn<pPa�$matography��E6"�,� !i2�pip�E��rom�|�, $O.(�dkI��Gan Bd!� earc�m�Ly ‘g�Q’ j=��_EaUR$0Fasciola hepa� )�n #W"ER? �da�ord:A�8l� &�!�e�D(!a !:.CAr�2a~1�9�EV6F. T�"B�_atomic�ce&E9B�6VA"h.���~q.�lK^A\)dk)�V5V!��9da�DC4rG:'AWe�0nQt%�%fdB��2;realiaEer1ty!6�SZ��0a� SP )$D�Bi!�&=���#id�)b�[3a�a.olu�CvcathepL�t@8K�!�%eed0% %�M �1U�ed�a��c;I��7 h�,b�aqeNHe!lI-���.�Ɋunique pi de hW+'CE�as�4 ��W�� C-�ed8��7E) tegu~ �� �2an�)� >��� AG)t)A}� 12�smW����0a�.�Uprofi� Ncau!H p: be tbb�T<ho�$�V:|c`A�A?cer�^t�bDC�G�#fA �2��� E7ES583�=0artefacsKW-�B� !��s���>�"�#J. E2�>��a+�2n@jh�jne%�-arkQ !6L*� M��~os� �du1O��(8 �'I�bo�luWQ !�nHd�a# re�A`ffu(Q�6V� /Gl �!y�)jNN�K %I=a�[t'5�/T�*E݃�M 2j�E.g[b42�ac�;[�to |e%��!���A I�0m�Fs�Y�26�!*4���AEim$�ellet*�d�asA�3�[q5�1�-11!0DCA%!��=li�1, yet�8�*bour-M>n�R d�9`�fvBQ= volu">to obell@V��s [� , 12Fur!�eh,!�J�A�ty�hH��upo�� aram�g�/�H�~e�%�10v"nt3(a�_c!06a� io n1Ge}[�!41�7Con-�|:��="�is�9�i�7ul�Mlea�EA6DEr%eEV &LF ;!�}investi� < , I�o�r�Fa,V6�cq�2 many.FA�6U���yV5�s�accommo�YDC� ]e245��t��dt Zre� �8. R&T%EE�e�� �2��uccessfu<wfye�.�j"� �>�o �7���� aggregaf0!w lipo!ӥ�� EVM��],/�re�a� 3N���?T , �91eq�\&U>el���s�aMa a�m*w9s neU� �( <75M�}meaF�w3b�2� &e=܁co� �c *+�qpu> �d>��f{Fse�e���s`E|t��~zd"�p�|M�ty�Hq2a�&} [1�:9aU{AY ha �a "P��A�A\�k�] v nd- ciping age�'L( Polyethylene glyco�ZPRIx Orga,S� nt PRGog#PROSPR@3� �<bA� markkB( AlixE� CD9 �.�2�#Bn���Yҥ�1�<1�Po�>�h' �FwKI�>�*l�hm��5ing!�as�3eas� ��"(s�Ro mi ng!vip!Om�Ws!�m&�n�sJV$XY/lab�@obK4 irm  � Y latwormhne B wR �a��lbeit A"Btro ex-Y:e"��� . Of��A�r��(a�4��-ei���'"r� keJ�.iax .Gsj�5F .&orgig�$c�!�$ major neg�ed zoo�d  Zei*/s h�1� r-'PE�| orld� [18���<At��st� 4 millA�people`&� f�ver�nt�Wu���� GADre�TF$food borne�[20�F2W!��% s&�u ani&healthE(Wsecur�i�m , co�BgM globU[��ock� ustr� ex��!� $3 b5r annum�>�I�Q&�S�Qc��vacci�Ew�p�u�ml�ma:%M��� S-labendaz�w$( TCBZ ) b�S%rug�3 , ai��g acut9Nc�a,}Tjuven*2x.6�s %:u^���B=(zrGXŹ�CherapeuPU��Erol [2= T6� 2�m ovel"���nd�a��2�\m�beb1oa��CgA��/� A&.���G$��2ea��iZ�.B)%6?!to kre-��K!ց�-1���r�I[2�2�{PMUOje�en�Ar&"mol9Re��[gm�"HDly be&h!Wi "_saW�i� haveUA�Fo" ���=���,� |,!y�'bgn���aNic@ pert�SX ligh%6�asqi��p�A� k F2D1�!pa&uB�"p#E9/[Eipi��j^��"�!2e�de� y [21 .�~��?\��1V�T�sA�)�b  ploi�l�2Yop i._�8tGA�ef�F"?\�!��d� #{y�is�&!~U �1re�{!)[wh��biolog�"d"� ��BR;lS{ICa .O3��2��7���!��c2�u� zbx9 E5�DCz4/EVmQO��Gvi� !��HNook���w v�*� �tegA�q��F;D�a!�i6�rd.JE�n!V��K m�L*m��=EV-Hu�|�!�of2��O!��'6� �luit�U >/��/,sDJ*A�[�I�Ej(Xg$i&�11uaiEO*���"EC/&M�:�)%h7 % )�u�J�;.Q*�"A� "!I� �"�-sE�uiU) |.&!�*�Wa"ei %�!1Aqt�ad�2�,� �mdel�Q.,I�)or�� 1Ba' aris]!�a�+�,!��: co:[V6�.���j,X%��Za�R� t�![ ]2��!*���[���K���E�R���!>BKe�� �%xebEV$."�)B�o�U)<.m"�Y!E�y�y�y%U�m"#!"�N��i��"{A�i��� a��L��edEli�s^l &�p"5a�u]�NEVe>�v!�^�mq*� a:i)�m �LG lo�M �aIabattoi�9Waw U . K .��v� ���Y�ar��2�H�B^, g{  _n28AS� i��N,�Df�Z=E6r� �im�Vs�$slUt�2��m�f�"c&jH[3$ BriefPFFtho�+l�2� 5K��>jG� �Str�G:� �tzG" i�!U-�or��a&l?$Dulbecco�Jod#LEagle e�A(<:0) ( w/o NaHPO�:PO�l plusy2N:$Ca ( C2H3OVq�&7 MgSO>6C21 gluc�, 1<seroton�(�& g/mL��tamyc�-0M N-2-hydroxy�a�4razine-N′-2--�Uf�P 0(�=�pH�B�5qa�1 h�QB#�`*�/,J�]-�6r�*" "�@1 ml/6>)6z5z9All6*�LA�A� a�:"�EB�I2��IA0!�x�s2%froze�sto�at -8�,&�til"eeB���E��x� �!FwP����r�~ y et a� [37]�_slC I���� In ba��uK�"v!Ct 300 x�A10x,u�1�'eP at 7+y62+d�=ny�� U�?eHe^ �;%x-:��*, 0q02q( O�q L�:XP�-K ( Beck�D Coul�0 , High WyW�UK"�/a�J5�126arA�nW0Mde� FY�..B.."�ce!k��f /e�=e.�-byR{�o�*dX�����M^�x4bs3 ��͠z� %�" it*Nac�kledA` debr<[a���eg �"� �Dm�c P��0��9!evortex-+e�aX 0�]! �Jd 8z"� \6x={nr�Ua#-�su6�� arZ N z9cM n�V6�`!�Of ��-�Bμ=RLife S �*�Ai3�t� a�4~ �e���tA 5s>B>�nexR2��G�,�} AN� �=���=�W j!��rE$ �V ����r!�.)<6�2�2�=N�%i�:�4" var/carbon�I2�4(rI_ '�y!�A`1i ����4[ 4&CeX8c 4G5�%L`:d ; visc of 4% v/v>@8� f�mifYy\B�:@& L4{ �N�!=���_ BF*"c{$Jeol JEM10X "�4 at 6B5�]�4AMxf0��=A�46M � ��);"�4(� �t�,J ( https://j . ni�Tgov/ij/�stL3,j-t8Mann-Whitney U �2��R�oawww . r(i�`com_2�%��C 1:10i deio:�:a�adsor�CI�S ly �fS"mVshe�3( Agar�lI�AGG250-F{!�K:Q$[dr� Nx a n`gen� eam :J;E��9�a Park S[ms E� AFM�(�isil���D��)�M<�at 51�Mpix�c�]�+EK��Hzm&�?5� �Gwydd~"{7( )�g. net)�2fs�.ic���E(IHhom!ei%"29-�!bO (�M�ass�=:9 (&?�� 1% (�.)��8cC%@�+h��& 7EDTA-g*�K�=B���, �)"M� at 2$R^�:A�*� �K>[ ��� e cytosol=!�#,�!W��-2��6 �)��} �!.L��J lt�5��PMT*�(��ic|Bld 20!�w/v)� chlo�/vn�TCH.�<�<�� �-K&� 5��P:�, 5�*� C*� ��=?�"���iI�2�VibM`�� xlef�9air>�A@���U}ɦ�^�Wd� �A��(q%I�]�)K��&�a*�]�y��j8 L�/u��,eq��e�A�2S -b��'sE� ��F_ ���'��J&"1 <~>x+.:l��{�\"K1L8m >taD1)''!���yM! z?&iinBq!dE�� $!��bF of H &��y&,.7-N>8;W� �3U/��1 HE 2CO3�1��,� mM����ODTT����,�!/ndi�!�.|�F)=�E1��j4:+-}\.dXB)�bfe.�m��2�Z��|ash�)�pe���/��lu�!��:�4% SDS��=����".-�h�$U 95�2Q _%�z,F�2�E�+fu  X#!-bicinch�i���8&hermo6o (or Bradford(Sigma z!*e��@�,s՗M�&e=e6nN� Z( �,Kruskal-WallMA�9�*� Dunn�Pos.K?%Sidak�|c#in R k�agS � � r-pro)S . org� p�&T(jY�5"A&p<�:051!aemmli�4 x��g Bio-rad )E+2Q-)(E��G NQ�.��cE^lo�F�!7 cm 1�yQs/�,�+Eacrylam�6g� nd&L-�!h+7an III�f(�R�. G8%�rutp 70 V� "Mdy�n�2��`stVCgecq��vol�!y43i_�YV� d>�.��( 40% �ol"� ��%} q#� ��CEw�H�$oidal Coom9 e�vlliybluAQq3.�!�A�GS-800Z?ib5Dde�-o�2-WI#:4"� !!gW/SDS-PAGE!;�0Oly �$ioc.�60ro�` ���]�(to Hybond-C�=��&ulUpa=( GE H^+c�"�Ha;-Blot;R� A��8o �7xy"19�Gl�T2�LTris-HCL���_@�,� �)= a!�)6�!wY ATowbin*C�,�;g�e�3&��>��yI� S4�E"a@o br (O%:�^fx,��is�2p�Y�!:-� m�"��ae1,�(�d\ >�A?25%Zi"?. in%�-�\i 6�5�@�!9%"| � �k�� ))@V�20�( TTB�S��F�L9��+�f�4�5% sk� n.k pow>1UqM rYVrE�� . Pr2�Uf%�Yv/-�OthaVU��s�/c�e4( Anti-FhGST-SE �^:20� 00�� %�>c&�<1 0�n00! *hCat-LO('!��5erc�-m[U( Lamp~q0A��cl�C�{Tq]��?P��c.��2Y�bya!l�sQr�u.\!fatA6cidFna> V9+FABP-�:)+-*��r�r����1I�!1:�Q~!�"Q�Q��%=UDK M)�0t1ա�1g-�*P%�1fid;h"k� N-yis:b�.veA(" I�!ABP I I��KN ��e]� |hm#uejB4^� ��̋�2N a�BS Cj* Y� IgoEA�-I�(��- ��ju>8� alk�� a�( AKPM5e�)v�1: ����!奘5�29!զ$M�pvy^"/ff RecH/m~, xa�7 5-bq�-4-��o-3n�oyl5 e/���R�2Jliquir^�,, �8E"33��g (?!:f� 33Z���0!5w0 I��"� ���������Ѭ,�M mag�um L9(O )�a7cE� 2�2�#E V!G ͈1�# �aba�}���or upa�2*ifre�~Tst;P4$A[�~QmM&I#��� AllQw� VexcEy�m� dime`7�� .� -7a6diډN.`in�� phew&� �&"M�.��ż5CN ; oAi5t.�PM ammonAbi&*%�o)�&� . D�� !�-*nT�\7T6{�(��n�mo������o~w���&�a& M di��uito�;n��6��&Imf|��:�5� iodo!^ 3jy��N#X�dj~�!IA��M)�o=�Now;.7��Teb{8�E&-CF2%���N�:�Vq!=BfBanQ�r�h�6u��@j��7D!try�G(���A�D�W , R�f ,�'E �o%%uA&& V��"�Z.Z,G�maz�j�")o��P1epE&n�V*s(7:.�poo�8A7�-5FTAttD.a Q5[A���vacuumMT( Maxi�-, Het>�2of����|"��'Gem � trtr�rL�Chrp%yf1( Agilc/D6550 iFunnel Q-TOFH up!?d HPLC-Chip�{!:Z,D2Wo7�9Chesh� M�!Z5�*J�Bi�:I�h/ �Vz>�5.w`capill& $� um��� a nano �7�ـ�IUur��-�X b~M!1&v9�H1�.�|Ia��� %!BU!��!�A�/;7�um�a\'of.&μL�i�9�a�2300 n /. AHBa�*E�%�,( G4240-6203$Q]2���� a C18�/trap�( 360 nl5�,�o&(C$mm x 75 Âc'g)GE\��Rd �Y?�of 195�I��Nnt]�: A ( -+-�Dw �)J����QB ( 9��Hf= �� c6�!~&�WDa piece-�aP[ad�;ɵ4n8%���R ��D �y3| DB '1�9(h�:)2� �h� at�,�L�. TanV�6� in AutoMS��V A�30�{1�/D�#ng�O2�#5�8a!:m , �lng U� 5}9intǞIO� ? urso�'a 8*z� :Ha��E��1MS/MS:��H�7c�s�F�[�eeN�r\ e�~��)�!�j9F3 2843! . Peak iͬyE7� Hucd Q���& ve A���]e ( V B . 0�Z�!�͌r� as^cot G Vic�,� 2 &-6��%�nE2 YA& � �submits0to MASCOT dae�� trix 'lKvJA��)��.�7hst68!5� e'':2 WormBeParaSit�://par�=��E�2�, I!�PRJEB668�~�Qon WBPSNGJ_�TLmaLiP�eSAenzym�n %���)�@leava%glz:aAqm�5c��:� qhy�Vw��var�M64�]A�oxsK���e� n��m!�7nisotopicE�!�Yunf"�q�A�!KAq frag��! toler��sa�±ea +±a�62�Y(A�@)�� PXD008737E�$�M�- �drejA�cfal���+v�wJ !1%#�fe�?a� �s.�C(P;in��F��S��/%/&�+:�S�#�@�m�5b&�@r���)n =$��s��\�� !�ZE�" BLAST2GOB+bE�2g*+�OA5g cripA+ �ep�*l�(�^�J�:�=A�&/2�(,�(^�W(�+$ S�2a E roR�fimu��Z1E4�+�nc�5U'��*yP6Y�;�>�#NN*�K)�E��LB��so�)"�@At2�@&k?a��)s\�. W�1A=aRREV&�\�BR�Up�LJ%9�tly"�? ( 76�.± 44}\)!n�:( 9L�c )�&m����n]��iE�_E�"� �:�9� �!�u� É� "}����/5/ ��J�-!(Xa =μg ,�z�"�Z.84�.8,�xn�@ug|�ZF�:7R �yf Aj (���g:M 1 �aTH":�OQ4p�[�;a`r dEGa6�d:z�+ �of2!G� ne�H�ef��-�B[ ��b� �1~�'�J9+80:�6p:Q�!l� �� Jn9e:O5n �!nF2�J!Fia�mJ�S3 �e" ��Ft�� Zn�!Uj,�&�I�a.{. �^�� = -�{1�Np =�;�! A�6���93QEpG�:�+le�R3(�FE9�171j��WLF.2d8qm,1:nd�5�!�Fc66�!�FB��.8�uP^YE��Mi_F8Us�T�V� ��� J-��!�""4���6� Y`e%/FbF( E084Y0i�!o% 6�ɡSPuh&z &rI}p���("�by�.O�dodecy lfate-%6+Je{)� -) , Ma %��v!sR�� i@�A�;s1��2�s�]�:s�!K iQ6�J�"� ��h)z���1:I="�M!u.��� � 'X�1���du�In2$:!+"�"&.ng��.x�5�� ~�,kQ$"fC �2U�5�00 kD�Ud 2�}37�Y. D `ZemWe]*W B�Ͷqd!oy4*�:+ �a��A�'"� I& F"V U�,��W"�!�e��� -'y �.E.�5�E�fjm�>"� ~�1�s K��!���[1%�dH �� "� 68%dmatchAj.�V��=�sLa 63%l|�ThU�\�r� ��R��.�5!�t)a�XVC r1� �leL�->����o=6- D)HJ�0inf�N��%6=�77( N�2e'1��J���ndF*DCZ)} �M4, 392:M�# l321:%�A�t� YMeQ�ss��r� A�O�e"�!riuP276)wJ�2Vi�jA�.�!�~i2p A4e�l �v�TJa�Giqih��Gacˈ8�&16: )�"dl�L"& -j�45�:9L ;��5^�I�U&��Q�!j�S�*.ly �Pfo�_s(��F+metab=MR"bs�- Dsm�Wu\�.ir&a��F/^6���.:go�^eOds7{&e*�-�GAPDH��*� Ue�s"���f Rskeca:j�tubule�� �͉rUI5�j �-�qt�dmyG‘reg��o\2�Ua//n� i . �!%r`Q�7A�!w�eA�st�T0! 6�B�. C��6Q> ~�?!6�HMov34/MPN/PAD-1 fam�Vm�)5b�"tin—lig�alpha-%�5�w��ÊE6�B(s ADP-ribos�fac�@B�T-��l�� 1 zetaa\p�.*1pe�~� n]��~-ary�,:�,Hr��!e�-�� V,g2�IXY�Z��>Lm)�-�y�IC �  HAD ATP�P-t�h-;���2�;wU�!Xo�YI a�ly�3!oH�insic-�o� 54�%��_i�u���A u�� � �-�� endo9�,� �1� ae�!�IA�>4,�A$r�r3 �9� ,�Gs.��FparIy>��regD6)9C� Res:A9F�,.�,:�,�X! ^%��Q����%kJY,!�!�V�wtzt"f;,am�cAJ-)�es�p!�gtX!_#top�( �^Hu�B6%�ׇ*UA�D%Z�4�jY.*{fa�A�'w�.f#Hs BN1106_s90B000599�i�:��. 12770102�T SP90n2(63&395�ypoth6�$ D915_0154Undb285;$846 ( unna�E �'Ѻi��>bQ[5)!��%[�:Z!�*U mt%[(:l H.l� ���.��#ExoCartaP�!J:/N= exoc!"M=:� �% � I#O �u � ��kd=�ck � ,�ie��{,e-3-p"�Gr*H��e�u14-3-3EK" nnexi�Q��mU�/�1,n;ojt* i ogly�te kii%�N��a]s �"O �3 ad3spa�WE2j �N^-Q.[A)T� @K )sq�to).� � ��� �nBFa��aih�g�en�E���{;ac��"� 7yI[2�!t�t--� E�r�i�o�),L�!%��"a *ia4�'4lZ� .� z�X, 7 wA�%#"@*�=�RSPRD�1b6.�a'5%+Loo� !n1.� OJ �1>�z� ��2Q� an.�2=� A��-�Ål�KtB�&�V�A�qe abund� Dpou�[>Q%AeE�.@eB�BA��X6KBa�(&�}��At�~�M�� ���%vemD%��:�>�5�i^a��m�EQin���� ( Av��z+4����47 :��?%�in�.!$i��BeL�(�e��j9Ri15vi%�z)e��!�B��_Q�)�*]��:]��W�doc�x�5f�Cof6XeggaPSp �Q ,IfercnءAAl(��,709B000642 &B2�&,J�-35�]m 7572F046]�'oef:)371508)!�s� megal>.f S-, fer���102�15�<E^�1r&e0l�l1y*.&!�u&Z|hT �(.u�'-@�YEO!�b&�6�$qm�B�*  ]�!�25ge�� C)�&N�&"0 ed8e :2'a�n�.�,N�!�� u��� *� 6+^� ( S7&9S��alR�%��Gch  5�i)u�f��r��M[�J�%�ATP syn���z 3aG�k-� ,+oh`0 B}!el)-=�_, homeost1qDNA���  ucone� �;.z��>:��[&�� 0G,�bx�"U�)%�"�%6�f�)](�q���5}a�F1=a&})h~T"�} nucleo#R@i*M��� sɁ�%-��!-y atidylinw|olR�1�de 3._o�N6�� fila�x�<�z� , )h G� �aA�al)�s �!%���o/k _�.eRas>G>"��6l :q%�a�u�J�. Pair��)14�5J� ���<a�2��;� e�%"���-�e�t D!/\E��.*geF5(." +6F DNA-y96�buGzd��J��A!&�n1L!6��r�/�q!���\�$ngN�,�������ituVx� �u '^�UN�� � �gF%!���c 5D@ r&#B��*� 2a� �}�W&�, �!x_y�,!!W>x�. Sr9icQSZCV*�""%��F2*>*>jeQ n_ac�@Z!A=. ETV:�Nof 2� x% MO�&$>h.��(� G�Ey1���~ "� � �-2BA�1D=6ef����� V�V� ye�& U-]2r�rr��lyf�!/FMn�rV��s>�"w.�DD� ag?�*3��I,. ll]� &m��U�9:rU!�noZy9�<oed��� Q=�M׹�-kra��)L .�.�GasH�*8$�E�*MJ!4�.��* �B�EDeG�aP2�2i&n��&�O.�� R�u-NJ=5,e�& !j�>�r!dŬ2?�:as5�.�by:W ���f&�#"]V�. T*ww.f%H���=�i/a�L!�j�a�eO�Β��z �D%�gWn�Yex�\, �0V|462X� G�t2�( i���B��P)/+pv�& )&�CL1^�CL1��CL1D )I �!i20 y%.,2S>"P�6'>J�i!1N�! CL5 � No. Gx�r��6�� �.� w& z�Mu-��Oy�eѳw�4�l�[.�ver"�A)�U�r��3 ,*�(A�,6&�?'*u�A�anW�"�i! 2�ai�38�2!~|��c���R�q"B",!��*�  �-�G����aj�"� ��wn�*�cM���2�%�a� +ec/�" -e� GAB15!�� >*6�m>�JS5 ]*Ak�$tA=&6&yMUiy; ��^)2njO5� ��(pn�abs\) �M�A0I�6prp�A�s m�?�"�Zi7�or [4 TC"1%�]{b�RA��=re��Du�"t���G!�eX"s��u7�$ge8E���!�co�B�HAvi �& �i�B&�%N�q&�L2]6{ �U`�rfu�o,Arupa�( 62%�a�dIY"�  � P �1'*�{o�!,��N B2� �y daCf� ��� �lak^�2f&�722%�U�a�``EV �ur�?D^m�?$� 0a�p�%��F��sE�adv�Ni1&)Di�gra�$W7���A���9I(I|a��<3�)ghDrF|!<9*9a��xEum���gvesaar�,�v; circumaa�&�.�� 5 2��Q�~.h !#2(^:[�aY�EVYJ�|�qo��s9�AvurE;:C:)B�*y!����!�p%�!>� �Q��B @QDb�G��i^mp��eJ��Qfg9�.�3 �X�O E� l,wP�+ d�/)�c:�m2Zn�6&ۈ�}e�f�A"K2�[�(/aj�[va*ng ��e�~)�,�it� ap�n��!��0&� 6�MF!E&��`Um7a{��</e~&B)A �ME}.����2������ �� e'@ ying a gr�Ieater number of particles to protein yield via SEC methods compared to DC �Fand other commercial EV purification systems [2 , 14 , 15 , 53 , 54] . jhas furM$been found�Lremove contaminating�ps from difficult sample types�p�psuch as albumin , cholesterol�apolipo1 AI _`was nearly threefold that!!5:v) s durA]a-!u`!�@is suggests again QB,1�%Da!� crea �Vtyas�I>�Qn�b/I}iY� vari%tE�SP:N(is most likA�,a direct resa�e� �!*h stepA�(volved with��5ofe\�erQ:multi� waGarey to i �!�losA�d ,�#Web�%!�ClaytonI@(acknowledge*A�nI�ive a�mov!�1D��nts.r�$ only a 2-E�iny�B�,2�A3m�s showE �dAs�e� func)0in biological!�ces!{molecu��,e� cellcomponA�gene ontE$y categori �DC>� The ���on:@terms.I� �Ś pres����EO)]j QL. A�a�bl�ƥZ�xU ���ng% = �a���fe�5�( 388) �]5iJ�t!Fi�9 �M( 421.M$, althoughFx147.+overlapp�y��顭DC�!�� ��� study [53fis�v�1q�E�tN �-`alterse�iios��y7ext!���2H,��ly i�!�� � t`subpopu~ !�ll��Ke�q amou�^of.n��supporfB�Q4for�"m"abund� -.sU6�Itper rank� �DC�sis!Kl� �"6��uniqu��$ptides hitN w9�,. Cwiklinski"g [24] s ዥed>� Nome� all 180 in2�e� also�.�}on2&top:��s ( y solua�A�infra� datae�$combined )�P^��not1�2t� ��2W � sjMdidQ�e a.�re��' of�� 2��-aj!w, but�tea� sm<{H120 , 000 x g ultra| ifu  spinp . I*L,� fm~F&i#�!!vI#is%g performedX expl����u��  e%�5];"x ��e�*us�a�%�ES-;,A/ d25/.ig A�L6�JAy2�f]Zi�!�@A2:� full��ե� v!��m�2EV mark�JJ:F �1��)f��:(tetraspanin%�b�^i] b!i ��� nd gelos� 8nd phosphoglyce�  kinasE 2�.�F`x w"e.vA*+ ay V���t��>6I��so �yU{�T-6Uo�aR� ) edAkɞA�quantit# � in each p �Ky��� disc�CsE  a 2 . 6  ��Bp 5�)$9EjK 6 9�edI�AP. O�sseDEV�p�l!man�ove�]Gprevious�n !� teguv c omick!$. W�pathogen��A 8 !� � � � 2��� ��B0platyhelminth�is vi� toe�y� es�e rolep@`EVEm( cogni��"��� ��1!H MNU�-�&Q {M�UV�Q�5�a�ur� B�J >f>�� inter*o!J V"pq*re Z@t chromatographic$,! lu�AM,!�duce l!U"�%�$by non-ves�&eYmacro� e strucs %nR��u���\to acc� � !y redu��Z�� !n[58� Ak����$of Benedik!�' g enrichE���demons�edE�arm ,e�3.Y  e f��, , �&� s!�e 2TgenɏIA% ng|��GO�trans� .�prgribosLJW�1�alA( stit�!�an>�*AlyI\5JJ? .� A�a62!�� (ile DNA-tem�)ed regP �� cripE�o6��}͸����DC%���un9�na�* �r��.�n� ��>�EVg 2s]R 27�XntaR � � !v} � v� � rang�t(����lso.]%$Xnucleic acids [59–64]%9��[6� 647]�s�ivU pack�to �t . Itbj��IH2�� ���affin��a� �o aby .(B*su.� hum� rine"[6��T   arch]d�d&� �ف�ךxW of�Qd��6Eɰ. A��N2?��Kե- �6oa�q[reinforc y We�n�t�reveal� Tr��e�Dby Anti-FhFABP V ,GST-S1� "Cat-L1���a6�"t> ��M?ra� A�. O�Q) frag�S��III�*r a�%�eJ� p�ٗ;�Pl amil Im��an�ea�"�9�r'A�--)��]�*"���"�� !&�.k� [-r!�.E W:�YH!�� d>` SP a�Mn . Baranya*55]��)�B^,z� �pr .���i%B� ZrM��2:�rleadAi� xin mousea&�|rrespo���� lAU���*zat"� :�� &�)!.��DC [2n >gaeI7Y varietyA)ca7pmL!Nt��f2f�6��,!VD�!�!~�.&� m � ��&� �1AE�.D�a��c��)5����q�AGo!82. CJs)���al� s�-$immune eva�x, nutr��a�migEz}Ini,.��L2)'as�egrade h�$haemoglobiL tuli�0� � �.matrix Lds� fibronectFl�  �� �4llagen [69 , 7%D"�=b _�cla ,))distinct�r�  a��� d��ngA65 ��<w� sit� �Wee cy�9�� thj @X& o strbe de i�[47�1i9"� �2X*_�e surfac� $d membrane�f 2� A{�,.�� CL1)? ( 1A� B%� 1D ))O��+ݨto�y*�� eCL5 HE1 &���a"approach.bm!G�a=pab ison�� �6�%��.@ derihŐ�EV��r6��cW� Al�e���,r*��j stro).�t&�EV5�%�""��6lFj^{ ed���[�6z<could po�ialBctya novel� � BRgiv��t�� m�V����A��i:-in�}"rostagla�� synthx8which establish�+��in&#p, egg d�"op� %Ya1y�E,����d;��50 triclabendaz[ drug� ponse�ph�� �#�{�� detox&� [4��Re�6* p� �a�ca mun!he� ��[6[�1f`VEis" O9?5Z5;)`�2+[2�&28 , 2��2–8&� ��on upa�� propos�$�qui�'�4e0�\%�loMoof2��Ae is fOng 0%% i �� "� me(��� accu�6 �[a�2�"e. vacc� cA�dat�W �o�{im)� sh%� be u��3%standar���e�A�O��U0�mediau L"%]}!!z��( dens���i�,�rosjsh3ecipi� C�Eo") �on>��ne�b�(� �$� I)v��'.�$e �2� > , �a �� z!�&� *&%, $aY''Z�'qCaC$_ !s. G���'EV "��to�e�%�><Rdowaeam&� �!PyQ�l a chv� �HIb�mD!7%fprovi�a mit�:��-�ng�Eainrro�Mj�r.�9;��5"of mini �H�z =&a�� A�<� ��!0an����ni3 �tocol$>�.&in[of1S%�F'm�$‘2x’RT,)��6�it�earr,b m��~E9 �t !u��6� A�2�� . Po�&� .�3U�^i�,aim!�to-��s8aR�u_l e��V/m(aDs��="�e !�*o��lpen�h�~�#)�$ ( e . g .sm��?,�Q���A0Z) .!$&A���re}�)� 1�t�@�-!��&Spe P.���add valu�ZL�thus ��(\5&fice&i5e� pe�"��� Ef.���,on mammalianM[87$� 2S$,&) � 65 ��( CAT L��� �� x .s�"a�no� �) "� �%M�#tile(AHFasciola9�yX�T� Aim� S�^isI�A�r�J��A�j aJ�"�sc�2%����poro�%O �6&on�-6cb%V�fAZ�s�!B>1M��%# 7D� u k>����� A>) -2H6C ord�.o` firm� &c-Xa�!G-xd benefi�$Œ�!�-�՝!!�&d��8�,ae�al.a�= @��hi�6Fb� ��� -�E�h groups IQ.q$. For exam�-,�!��eU��F�-r���vi�q?�c��%L] b1(�tw��� c # f"5+)9 (y undertake�.�O . v�* riniEf[7�1&� ap � �e6Q�'��z�,�u-�� �validA�ofMS�)uu+alU;k92e�U-��~I�"D4A���ne�+arO.2 )�a��K: %����influ3�>49�a�J�.�� summ�z 6��4challen0whe #,accep��>� tech�(in "��%is optima�orN��-�� �Our�t#�D2�J "� ���4;>~\�"� ۆ822"ev��ce;3� F "�5o=5Va�*�"A #�s,M main����� orphA`.�5acter c!#Fun6Ea, *.� in=y�o{�H�K6/2��) *L!� ��A)5-x)��!�%��2�y! Q�i� &�*e !�Y applw.*iauthor&q %A�6'assay��Z�y� &�of� orta�when de� ng* !?6 A�C ligharaEV� AOI�o� key=Py�1*�8u�.y�Sy�8n0E ceed��rep11 d cyS9of�%�mo�2n� On�&y8 mple 1 �8 enginee�A� Ds� Ia��-d �)�!or�ism=9s rig� s-� &]��x��me/yb�ope7-a�� e( AppljI��ae�lex-Hi�ontex:5a�R)+W� �rs6D�/post-t.�" �!�M5t&!�mi^ . As��A���wF3e!�res?gap�&Ds Krüppel , knirp2a�gi�.Drosophila melanoga� ( �detailD6P)���sejfp mRNt� .�!7�Aa-�� z,5"� �*�$�p�4%�1�� .�c� &�> at��s�  rI�\p)�!�� <<_4"&�opE~� t�;�6 � � "�a���)n�'�1fic�� of a!R�NI�M�q2ly!�er���I� of s�5o�%o& ��U����*la * ��7��ofR�!��I��":� ,*�0��isa�A�9�tt�g� J2�"nuA��)%D!�"��achiev��ntP�8�[�-.��p<dynamE�k���or�che $re� netA!2UB� [1]–[9�R �2���suc�  /��!�I�!�^�_nyE�ex:6 microbD metabolic%�gn�#A���( see{2d �<�20] )�,M�-!�]3�+��an� x2][2)25N�e5�!� illu�Y(��7%�y�&��w�Fig~61 ( ada4 %[26 l��fir� ep��RheaK�7Z��� Ya�incora�hA�basic�ump�!�d hypa0�w� abou �~�Km.i m|) �t�t�%� fi�%i(9�%��e��IAsqA[��6!@��b �A(ng suit� ( ly� ter-�)F4 ��(Y����;a�# se�t�8��A-av#!`)to�$�*8^ ���, 8outpu1 Hzdv-s��!�o �>IhEins��x�T ,.?�Q< H o����-ength%fq��U���#io�0aq��i0 �fai�mCD.9^ol%�—predi"gP#arg5| nt^R �—itA�� "�  d@%|2l lleca#. 2�can� I!�8� \� q+� � adjusT,A�*^m&~ A� fact> �}�@ S�Div-9Q�/�-acquit9�GsQ�!��C�-Qm6�piw/!���FX� K-E��t���*I �yP:��9� 2� i�!&�[27��,�0�' harb!0� �ni$( triv�29 ��c � ��MatS\ftX "4EF ec�Dw% kind;!m�hnd6m� � !�i}en�pa>J+�Wr���0� N95a�q 'ind � E>rel��, �a*�m}$�sE �!8 |_ 2cproblem�w{;alnZ word� % i�% N�!Ico�:�[m)[7s)[28�3 !F��,.� (e\ priori )��B� )a� �Au�(�i� *���a2T5�aB l [33 Se6N ��o� �� tellq5Mes�_J�!�>U� , [34)IFin�%, de.6Fod;1oBe!� : easure�* �}��A tim� i�=,5!�)9�Rqu"k�a��^=l�> �7�J#$So far , u).tunat�!��.��)�'p�Gful�h�I�Y2�%Fl�)s limi�  �due�3z4 lexk �$real-world.]=K�.!K! naB5 ���E�inR�* �. M%����s% ed����up��zli�G6�equa"kmakR d6+� �&.�>cu��re0' � is�rE�!S"q Qt�"ve%}-x]7�6parL ��y�-�r�r*1f�exta�HA��zKAnd�,�-t� � �|%�aW%����exhibit>�G!y� erroa"?�!low �&��9U�A^�#ircumUci��2:a& %��� c� i��t�7�7b�A�n�� j#(� as� � F7Q�)@� I�=" mpir��" ��ith beA���*�KU@B�e<�it<iy%)%��%�� H��,� ! �ab�y-b-�_JdeY+by �-al)G��J��u" a�#5<��b�.�i�( u�yaM&����r:!��E��6jBL�)1R,vinegar fly f��F��qua�on!n�[add�ngA��g6c��zn<.^!%J � tu����a�� �ocu�=ehE� j�,�.E 41�42L � ��oF>—�a�� ed ys�! ,!�  �:6n� -��3U�A�A0�!��W�; s—� be igno([4j !��-�eE�:�doaa�match t i�ir�pecXf s [48 46!@�%�]e&�-�sje�, coinJ �>A<tZ%J�*lq���!_%G�!�[4 4�7���9Lnc�A�K(� leas��t�N �%�m�p)��b , �;)eZiejU�7�;e�# carr��*6�( .@e�Jin �b%A�|ppio�q �"!?\N*6�CE�n!��>l��Be�!ad#��Q�)��eYa1�zyr�ge[6**>��V��Si� RrelevG�z_� a��hb��ta1S.�ab�W�[52���B))�5/"! �mnI�Htrunk92:&� ( KrH�( A �( g�H. All_se��encode��ծ� ���m�)� broao�N�do��G`S�� '��X��( A–P�mxiOG"��:_ �Y�#�&�a= inpuk={-�@5�-#29�& (Bicoid ( Bc�� , Hb �C�C�—*�Nѥv 4��Nal9� UE( tll�� ucke� �xk�y.�%^��TsO5xq; �1s-� � S!*5>� �c�4ct� a�i5!�Q1�ne)�sharpe] achyMs)�Qe advana�� �%|��eHour'��Aktwo3I�eT��N� �� v�s�"e trac9J6U*�(2*.SBes� k-o��2+U!*Ay�I�E�t mbryo . N6�Ztissu�rE�jorh*w�!�nv!:;u%l�otl:�byɂC9��!s }EYtI&syncy�F �@>{vre�%�ide� �)a ver�mpa�;t_% wF!+)wor� 9� an Km��1y�!D�ve&� Is�F�U ��!ex�(�� ���HR?�g 5yinZ�%>�� aHAt:,*�'/�stiFIar> �<ű!/re�c�e(C�� �  ��#ist�@qu�L:�#(|  J�&�m&u�/��>�!lBz ���6� s*$9�KO3&`F! ���?OII| of2��to� 2�IJ Na�Ho!.� E'$�.���[22�@ �c�J , [6x6 �~*�Gpu�:�d�]&f�%� �6e(y lump toge!���n.5AAR��:��>��.A�&�Ke�c :� ( ��E)[ %�� j��. �&s ���$ ssum� �u%toA�R_�#y "6<� op%ϭbun�0o,��[TU�J�%` ͕I��-T ɻs$Ş�1 ����4eWBN!�oe!i�cy�K�%re"�A�A�A�2q�2#literz� �(��littlwB��J;r argP%UVXm�a"of� V(Gg9�EK����0H0!� a paBWby Gaul&�MJ"�nvoJR�B�:fi�8i6]c���"%����� B �-:�e�is phe�Mn}as ]r�w�@Bu"6�p� shif�!�l!? �%�.�3abs0e1�M�� '�-"M`�n"(�$*!s ~^ t2�(a�Vm� E�m a72�a$��+nA>�+> we ��f VK"� ���',6W%�d*YX:c%e�ed%)�: nf�"��N�! �Z)T�ier�*�  ( plu�+sm� a�vafap��4 ;D'F�&,!} ht-h!{ pane� .we�� �%�Nk E�H�K�kna�[gt�I� . EaOU*�! gi�*Au�:*7,�s!�e�ME�  ��bou;?� n6�oIfh {)��vzp/ U ���l�beno�2a��I5d�%2l �$' �l%�& �Bu`w%Bl`7ޡ�tif�eo6�-fe���&d�&lbr�} Z�;�*ur �!�\D�f"f6m �ordinq4A�y�e"U�Ha��F�/�.�!�&3����owmdi�>uPOg�^� : ( 1 ) ��8��f� h��U�i�T/. a�-de�c6�Eqe�H6� minu�ag4We obሁ� arbitr!C�!ph!byza�*ter#� [� ��eW =. T.c �p�(do mitol#�enNVTiH&#en� �]�V!?y��\l)to zero#n� fa"#i ap 7o��+Mmiaa� nd M*�"% schedule � .{%� �6i +�=%'�Qi)7a�2(�*N  "c�9eteWbye�s!�A�*0 (�aarZbl�b-��r"G.�.N9v'%VI2�,6�!-m�g-LclA)ex�4� C56L��Y@] �=�%1E�E��a ..�a��}��$ng neighbo�+m�, ��imSsqu�H6i�ce"� B"� haDi�8�!a�"vi7� ��G a�� . Af,X�gH!:��UE�@if"22M:u�lj"�E(!����� %�I��(�(!�� 9B!��E(I� b.D�-��+|e�a�F��iE3w!��su��)�&Ahtbd<.5 l�5,&a�)��&F��,(�a(.%��* �����)��.Ρ�2 )Q�p�# ve~+�be5t;Wډ�%Ab�|,��g �. E͡ (w1��� 54�)3�WLS )!�h)�<�wev(v)5AVN�!�8a�) cribed be�#!�&*�j!0"� m*�V5Q�)t���$ME�&�#6>� 3�U5A6N_*"p de�*� hav�� E1 ��!�~} 6b!cI:���e�a��!�)@f���rob�de �,)�y�-M��e��*A F&�"ly�Dusi&�d� �ugar�M!ue$sca� ni�u76�P*��. � f�!�a �`�� �^��B ���� � E�y� su�H.� b ~��*&�it�64!:��, o�9��*=(#��aW�!al� i�CcC and/�r���4i�."F(AdM���&-qbo�)Pfj� gen| j&�D.{�f�:wa�-!en�. B?. W4e0�a6���*� �"� E� highaZ&=H"�Q2:���AT2��Nea��6tir *IA�rR�!b/%u fZ�:( . vage�1,C10–C14A; A}�Nsubu "� ��cl;) T1"O� I�%�#�"wc&semi-2!�!�)�!—XGoQlot�P,&nzy�>c5� A�AJ�wide- J�7 scopM�E�tvc#g�tE(& pipe� ��8] —w�ߡ�luores� A��o.�confoY/�!�a82�>|�&ZV �[69('�h�ork� n�Na��d9|JJ�A�2�%W����B�1Uppar�h�Ya6� (U[3 ):����s>)fmAa-se�H��Y"�(�2; Sup�?Fs S�vS2�Fqa���Zval�*nd>=in��G,�Oasa�t.<�%�*�,A�! � reh�-A�y�%availv} 9FlyExaD ttp://urc�". spbca�ru/flyexA�5�'596=:MaMrs �s!�e�9!i ���nd�glo�PY.��L}Bzat0-�aT1ţ�G,i+arE� ����2a� � �� x� �>E1�"�� �Aw'"`%17+U�$ �s:!c X���!� --�;r]"A���%�K&�)%��rEsPɠr"= n 2+"�W� my nmI ��� i, 2A��6�!"�, abdo�{EA%�14 � *J/hifM;��"��MmO &�y�B�Ttnt 3kkov)#7�be�0}magnit��I& ogous��~R��.�, 6lTe�Sb�,di��%�)&.+ g�oI%P#4t�L9don�0 @width!�0E�%�� &k �VXn��Lj`A�)]s� �|� R;M�as%g�Vb����3ly�~% ly.�w}!R�.5if��+%ݥkm�(clo�}�!*{�e�}��B�bapj#nt�1�7� y!�x$�A-�B�Anex�!!�U Kr b�N�%� ��++��7 iPC*,aj�B>*]��/r�g�8� bl�� �i?�!� �]e. Ye_ ^�#ub�&E�rP/nou^J�lY� Z-��2�eh s6�xa}]sl\>ly_eryC.��G%qN(f�.&Q9!ȭ�Ini�e�(maximum pea� "�ia�M�m�;���C� D5E}���EI4#H2���, B�`"�#jmExda�o� *�!"�)ei��+�u.3in2-xJ.: ���) Arg�$!Q�i 30� b�,�Gr�o���  T3���!R�}ilE�>� M�B)�&R��15–2 x (2j6–7%�6Fob� a�{�facO�=�"s H�^&A^%�") ]s Eo��� Q>'e�� ,!Q d�5!'s&UK� #U#�YnER� PCR-�� �y-� ��&�$ pre-2�!�.�%�dNy� ~Ev[ccF�e� 9an ��� � ��AU-':� AErg�<9(�kF) Mu!�H_�s.��Yu�+@S2� Tq.L6�to�% ^N: �uS�avera�P>Z"� �h�� 8��� -to- OM ���*E,EF�J���a @i�<�x����l�urUh,JNA ���F���E�� precN �M �J��5_&�a�"2N \25)�dT'�> E���Y}m&  �=�@s)��H��@���!B�MwS4��NoiseQ�:<uA1�6e[;a�C5UB. B��K�N!!([ai�/e= Fym�MLWI�.�5~{�@ majo�&�Zd �RM&p=w� �z} {!�fluctu� � %� IJM��~�z)u4Q d h�Pe.�@n%s � a�GQ,A~ hars%g��x �.m �&�+ itu hybri"�Y.2�bod�>�C�� "�N�7us� 12N�theEk)A���>�fe""Q%�a�1�--�a_ar.HJN�"�!2?��at T6a�n ��`.��NC14z��(6�H2�8.�$�,wo �:JJ:U�6*m� �Gu an)!�#sU)�.���g!@�-, 1���]A"pI!v-m�8G2�Abe*MB���;��I�F��� (�/a�=���ho� �in&� ��R� `"� �AG&�<h�+ ���y0.�&Q�M}( za� "�:�8 bT%�� ��or!j,{�E pe7 r ��/�{ .��: x"c �&�#���Rz(�D)Wnguish���;A�.p0�V��I=�X|c�(A*�(�3�&*�a)�"A?;b'���Aá%*-8� e*%&�,�see� &� ) :�2"t"�5"�$��y� 9ud KEW��Q�Y3a deca[It� 9un�V�A�*LL0LL*� �Mg�1'm�) 8I�0%4�]A�� fav�,+�� j� a�'�O�0!�c�$J�Tq��:; �E5,(q�>�#*�?[3&55[rs6�IU�f.� !�. I%��F1�A�~-ifX �i�)   manne�= aN*{EA&c!Aosj�V�>�僙;�a"ep&> JI �or�+� T�y�/%�!� /d!� B�N�B:X i�s feed�R��mD/)} "�,uL! �ChJ�.i � K�� �#&��u�EaYd��ari�'ret -f1e�v&inu�2� E���RUbe*�p!>objzAUo answ �N�!/͹u�H �R(Mp�"�sA�nb?qu�4lue��R2�.;��le�@�'s8$~ 5�9wlMEly���( _�Gi . )A�� pB���?e�aE�2�!mea!�Jreg!�}Q�N*_Gw� ll I 7%. �$f�lW��S�|7�+[5hN��)��'h��|-( >!�5` 2d ;'lTifH��!�+or �yF�7�Gd ~ � .*n&1nl���em�� s exVa��Q*�$�{&�%A9H�bp��ia.�O�/0� a� 5[ � K�."�]hZ�g��s tu�) LaplA%����E?) @ �a��-$� E.�uv hold,�O��*x8c�L!�� A�e�K#a�m�ver~.q�a�}o�p�k�G� �er Jv��;.1MI���e���?���D"r.Y@%� !1�!��*wri%RP�v%?�x�FY��omp�C;j�ZUS !��>��*ab�5_:yg E)|on _��t; ca�.�e�').ed; sym`Y manil�(f�l�Y* �(�c+\-z>�. D�]���cal]e�0�r�{J� �E�/2!*�1!�!Vb$C�"�I==m��OE�� ne~�v� al�Fa9"i�_)6ed�1t(Amd�.}&E]�(/acah�4�(!����U�MLv<KDmetAwA�B���&2�0%�� �� sU!�-�D7MB)\���e$im"��� [a�*�!� K%U {/UE� �-�0(�ׁ"wa �'A>%w�6�; V�r�/� �9O&X4�{!] "  �o�v!�te4)^oY�>|,�az2O�'� � "� !�i�p,Y�@5�� e�&� Y �to6 �.�_Z\ � �dW!EF,�% by�vE�6�!gc� nume�O5�m�Gi1 a&}-��.�2"n�)`-�)h� "� "����Y�.. M ���#a�0�+0!"� two  t�y6�al�thm��o�qel$@eg n�( pLS�"I�qnh�d2,,] seae� ( eS�.05AB3Mly �V['!�q"!/*���u1�XpbS�"�iQ�aEe*9ȕ� *r&)��,gu;*."�3;��� A��)�"obo� At�-* !$�a 2xw� ��I����ar�%�SS� hX"����w�X:�9a@�J!�R3 4]c�~�jqIQ�|^�!i@*�E�>�,cɟg19v�C��+J Fi2ɢs � "P b<2a�06 best!�)�!��Ni���i�Kr6@ru��a root-[ -i} ( RMA�sc� 11 . �+ 2 (Q:�._6�*�ade��Rof^ch�2A[U1&W6 ���aG����e@A� �kW4a�1�ecY "at��%](."t1yC13%ZT��!c*z4s3]�he �*  �� T7/T|T�2 �^��Qoe+�r!F_,�n� �zA�+y� , lefΕ lumn%*Of��Y�, KniE�� 4%B+�l� 1�1:�MTAAU?2Q8 ]8�:"c! shap�]���G��� ��$C&&�a&#,})�k�$ct���!1~-r153>�n ��%s�jM `��g��E+s)+%���+c��) Ong��+I�u@�s�*1)���i��� l<e�F- ��witQl area!;A&�)!�-z�x� is�Sy�ou�a�9E=E vn69�"O���e�Gt��z�W���Y�@*�3y)�*�4nB?��pl�% ���du��Z���7 .�-a�T�I�Ag8�+ !�Pi��)U�*)Gt-! ]iqui�� Kt]m�ID�#$�6xq3m �� ptj+Q���;)�B$:@��sU{�Min�F���JYsCMaq)=�"��ef"Y9 a>T a�e��F'#�MU" . Te�s�vB:���&�Q*��6G,V+� �.10��"4>[*2i��%R�.*�x=�~C4!XG-ct}�]ot!�2�iE�]dt*�/en�7�!A�!�3� s:�ur� 2M�ha�R"�� �8',#��� a5-��� �y Disc*#M�x ��� 1�n.�bl.�:?e�p}�b �F?.�� e��&h bf$ �yj els��-;!X.��*L_( 100 O�e, 1� �J cP��&� �$�`�-Ha!+� &� (�z��6�� S5��!yuJhf i�"e7wo2 2�=� Z/e���c�:C$�Am9�� ��&#� choi{EN�l 1�7sb� 4C"�;��6Mru)/E1��Rach�Z�T�`:�m'"5�]m�5A�t� � ��N5$)notor��A4iq|f 1BZ1��a��xAT!Gv.�|*�hif�h.2""v5:B"u8�m1gtM�f�th fixI#-;Q�0E�8��F�{SI���M��ul�;high-aFlO"E&�� ^1 21>�0q+6e�T�Y�)>� �a� Ch:z �`ɏ�&YT�25��infer:�2���� r���Pra�un��]�_0w9���i*V@�2���of view��nd�@e"����$ex-ri�4. �3!�l�6w[ ��/*�W$@ I:})�L$bal�\s�h�M$ F�r8a" Ff ���e9�� � 0ni�6@  (� �IA�bA����&vun�?le—�0;R#?Ne">hsh�0��A.�&�&. ,[��'2*�4D,. � %)f�y�_=���!�&W&�e"(%P%�'��&OdB�$!]0hH;��2�)-�%21��VaTup�ee��al �A��qvJ�@�eruDE�)0xay�G:&'_�� Z: nTs�"o� fi�Z]urakav�z� c!!rUM9N�, g2�Qa��7nV4�(��$&F�$�:i��$):�� � &� ���,�! �|Nlem�Ư.![~a�!��L� "y &o") i*m�6.�l{pre&CB‘2���scape#�!�n�AI�`H-H�57�un� (!�n&3 ) [3�n;To*~x�5��9`�% a!D-.ű9 spac��r~e�tC �v� Q a�2Etop?�D#!xV�Na�ima li5 ‘t�zs!6ord� X/ \A�t�"�'�Sqc2;�-�#l/{now% f���NNnS8�f m6D9rY89%q��q�P��$%�� O7�%um)�l*e�4� a��.�3EQ/>�I�?h"=fo�N\�|@�%"��vny �_U�gT�iu%ETx� ��E&AV)fS)Rllipsoi#g�Cafc5a;�!�k��o�n��5f� !Fe�v�!X � �5�?�wr��n��& fampN.)�,principal ax:z�-�i:I�eKM2_iT.�16��x+�#b#?# � 7�Ia�.�t�j��o�sF�� aA�PU-clb�oD),g2g'� 2!��#uR�E$"r2�ၑ����s:W�O��J���2_5 ��.:#Q�5t�a(%?X� w"Jpro�*��Q�):!:T�� .�N��r�s|{��lyO4��{��4�n��� �z\�Si�?If�J�s turn6+a�����.��aH.�+!;6 ����x]� ��RV��� QPe a�l^w%$6e�� gH"z')|�*&��out?Y!ho�n�x!�y��!v��tf�  ��W2 J��Fpu D� 2� E�J!Qp �Zet�BY�>}.>sthbi0.#%l�Y�%$b�)!"la|m1��%�fd"�Q%w!*��a�VU�`.lM� �G5�x l�P6E�!�C�� co"�L(��B�^���xd9�coaE� ���5A:�6!�^f��AS� ��7�����2�yM"�] *. � ens!!1$*�A!6e%= a!�1{��Ejs�Y�W*� @ue� �h�nd֢i�&�D�K*�<.*s�G{y+)��%b? mi�@5�Q�Week � 71IA""O w� unwcaO�$ .��i)��f A�)�.S, e�F�"� ��=?2���.�!q���b2�<e"㍞�if2��1l9#a � �u�%a���s?a���M�J�=!s;P tly Y � �9or+W id����$�c�s� d1��ecoup�+1���*�0!� A�.�{u�� ��l .|Y"�>mVaL� ��4���bia<��"1X R�-a`_;i�|p:��4ō,A�}RS7�^by~ !>�d�a/�m�ac�Jot�pwo[3x7��7biUT ' ̓.�re"MK*mp�r��s/;&�'� �me�d��daGgAea>@�:qui"OP&�3Js�ta�f��*.�=&$��urb#�DG�.�see:$7D��R"e>!t���,a�  ,�ken�)��%C�9ois���'ACN��C�*� N�A��=��Kxt���IH� A6�.�=�2�  6^)b2X�&>S _�l�6a<_r͂eHA/5�t �o subg 2-e�,� ���:���' c=$e9s s�bEbir�GerP ( ; 6G–I�D�w��g"dNunimo��A[��"K�:�s��!���cl/��9��Azc.L��b lAqj&�s�_! 3eb( 568*$ǩFkPZ�K �Q��(�%:��*� �&��432h� das�uM�l�[6P�lA��&7�� A�ng�")�96. ��Choriz܊zw�_b6�E!�Ų�B��x!�-�-�A�25e� -K���CNs ��& ���酃T� �se.�t��Q� �11 @J !H����!/�1�3neglig ��q;)"�!_�.oEl��| UMШr�!J���PtM6��Sly"Y���F�T.�F-Mw�^�b&r��!�95-per�%�� ! �*S2U�j�}dkEmH��_^$l gue�JoBAa�� �oK3uń� ata RI�# %hw��#4?U\Q�9%Z\-"��#�! J�bi�y�mr����F2�JEaJ" sizEy�=1�Q�"e&x!U.K 9o*� &�f�mW �z�i*c�"�g.�%�.dS- not�5sq'�j�s_*J�"e35 f A ��A�syme��s)E! mk�#�2a�sA��@ 6"�E@ba�� 1M�"RH^s*6���"� �L(TR�=�� �>�"�Q!RMa�}:!��5?%;f #e�-� m^2�1R�8�Aa#� N9�%A�I9o6�E� 9�f�.�.<c�&d^:��BN �'��E��isotrop�<�)2� 6u&� %�6d�:�J�o�-v��"�&: �E� uC�aid_!( "> 5B , 6A_Baq(2+���it&K|�� ."Jy�U��sam�t2��AO�%�!�� �D–F�6 >B a�a e;��A�P�UeF�&5%"G  I�U��,� ��a%�b�Eai"?sn�F�%:�b�c�w�&�Y� %+� ".&pur���Y! �-*�]2!F�����R7�&& ]s. �s!�ga��&]�bg4.�:c7�� E������*�_]!�� rkab �2��D ό!�*ha eme�6a��;  "-�L2%����"S. R��3 "� ��� g� 1�e%�8�1%e��!m1�J�xOu�5�y�,e��eW ��Q�1H]��A�%��amK3A- -\p�3n�r�i���$!o�1���Ose newAi��66.<���.f*e0��.�*)�-�enoug&})ft�Z}8�0bi&0�2�'�� 'p�y��eM�"�i�55K)niWG&�N"�n6�� _Td�?��M��D� !��&&֥"#����!�N�K.[)@))E "Rq�Jlrrr�¥�}�C E(��� :�'�t Hm�-�(7�5 WJ J�2� B�y��A �1*`+�'M�!J. X"�6,"Y"�4��R[74�b75]�����.�Ar� �!�a*Y2�6�-T��0�*�Td��ev�'?imEI"�^oV|r�X�E:oA��# ^3&��ha-fe4%�6�-�[�A��  a���~le�� iX �?#�{�h!��>� q�i6;A�/�Z�a�����"�?�#�1h-�@��s��2"��cQI!g�I �(s�.Ty� �Lݎs:r:/>�s"�F keptAB�X ��hJ�o�xR "5.� � !&�ӟ"$9v��-i��e��!siye*�/� ��V%�Q��p�K� ctW "�— �ope�a�fK$s(T���&�5 8iJ��77a�:P[a�kiӮk.�. �3 kilo�:kn�E)D-94logueKrpM��dI�r}(�-�a���&�Q�)aI]*�g �� %�p ��[A&��23� . ItZzmqM���As�!�bieR�T63,a��&�n 10D6 cytoގ� �k� 0csmidBS4C� ��Ma>Nu��BwEQ/o5"�6m���e�AE4"�%q0_/mn%��n&�� � � P-0>���A�Uatɒ�-1���!} L"�Da�@ea.\te [78�)g#[ �I�k�wQu�T��N>pt�> behav4Kl !5 �܍g�L!r"�ae "�F"�e>�>%�e�| �M�-!�� U�R�j^�2������f��_z Y o�3�ve���E�S=Jme"�� ���!�now �o:� L�~ -j�Yj{0�!{2�QI�� !�"�Ad b ���^v�/%~.v05#�F�^��x �Hx>�k6 m �Aon%& !���9%� }a1�U�-)Ih��>"�%�>��eaa n%�X/� %4�>a#��"uogao l80��E:�3b&O��6�8Zu6-����v�+!1���2�� �_`���$� �Q:l>�tilc^�d!��=%�� Ap@'� s��&�,:�U?�<\ �� a y�F.i۩���U�ar�?6�A"V!��-�y� F� r.��U�p��.� iS.{_�}�:P"�;&s �y%#��ŏ�7t)>* A�$��/*_ a�.O%N �"ߞ!gf? �.�� �%!�}�0 �`{w\��U�<�E�k �ł��6N�"q] f'� �e�B�2� �O�do8)�ab |*hC� �mO\�zK ��Y��Qa�.�&:�����P�}��B�Xcivo [6%8%�H.2��/alޘy draw� !l4(E>!D&15val~Z>VI0&� �)�a�Q��.f" @ O!ri�8-V�&<if���Ja�A,gPc0kj M2 xY�B/o%fR(� >_%{�ii��"�8w�2�8-� ��`?!�E�9�S@i|!eV *�/L�@�%AY.|Zjy}a���|��0m2� y�} ��&��1�}�eES�TJIt�H��<�� help!\J6vei<�teb�b% )�-x���3  Npc?�:Ew*�t w�&�9E �� refr^�� E�X!x��!B2bjLaO"����j!�>G1 �0|J��i��-��ā%,�@n"to?`�Td|B7n�A�A�e{�:2p*s)�q�� !� I�0E\:�n��Vo�O!hAM"�,!�aa�!./A�uSH:�2: 09^XD-dr��EJq&�;�>��m�m�i��B�7,�ZN4L*&E�I¡st*Acoa3gMi&� ��}Ud�)TIiz� .ib�Vs�q>e� w"Oh"�|!��>� B�<SW .�!G is w�o�x l�!��e.u�F"�}��!� >�fna%^t�Y��_���Ge�!5���a����=q��"�"�,�ic/bes [84� H�ne���;� :�!��du� �*em� �2`�*��Anwa*�hapsue&+a��c�eləa%RE7�L& !Id/Ki!�A�f���-7�? z0�jU i�^�� /�ma�W�WAK!��^AB%>�i�� �i�Ai��b���?iG�"He�e؝X8��=��"e( G�.ݯ1��;�\"�(�ea<�&� , �i��r���A])�g��a�n���-�N u�in�W*OM N�.�i*֧ �!�It�!�a��o��^4M53Is"�O�t5""~12�*!��^�jeq2NyW��/uEC}A�� ]�F�ia2C�*]�1n�f2�Z��d�Lab& A�[�&�!�*�m� o.(c� 0L��� �lB}��cY�2xL}h" eA������a�� =qgu%W�_a��Oundoubte�P� !o2� �'Q^!2��xZY#i2ma*�X"U-���h%�.�(ruc4�UU�u^2/ . AtE<r�) w&�$"QL�oa�0�O>�@y"� -Xi/Z!��L�+R�3au"a>��h~�6iD�(�*Z /�B"Tvel�� op� Ř%3a(rF9�r�A��yaa$A�QZmk��l�yY��S!�m)z�-�I�2(a��$an ��3�����cQ,�j-�J��-6 ;bq&.of6�N�v4tZ�A<�]>.CP.#r. B3.�%�% *#m.K� ( ra��at 25°j(��oܹ�4 h�be�laɉ . Emt4�L!� �"�FITC-�I���u(or DIG-labe�3D�rib6��,���cl��Otserum"��Even-Ski��( ) [8�E�p�g!�%4ԋZ� �", [86Z�8��N ni ��Xe!|a3�C0Hoechst 34580APmHooku[ <Ler�TCS SP5Ac:��e Pa 20×*�k���5&d�dig��zooe'[3xigim\yAy&�/e !���qlCy ��! Q,� wo @�iav� 41 . 0–1 . 2 �μm apart . Data channels were sc�ed sequentially at a resolution of 1024×1024 pixels . Only embryos at cleavage cycle 14A ( C14A ) [89] r�echosen for further processing . For earlier time points , we use previously published gap mRNA express�d� [58]�h4and quantifica�lmethods are described elsewh!+ in detail T, [69[In brief �Tcreate a binary whole-)&D mask by threshold�l, which is used to automatic%� crop�align L4images such th!�nteriorI\left , dorsal up . We id!� fy nucleiT0their surroun�(territories!�(cytoplasm u%�,watershed-ba�� segment)J$algorithms5+57!+ FromrseG%s!!wtermine% posi%�of�, aA�ll,the concentr yofI(!� �plu!&��)Pnd EvAVotein2;oA�) . EmM�\re classified into eightI�|es ( T1–8; each min long ) dur!�Ca, )Aon�]�patterns%� morphologA markersQ|Non-specA� backg%� stainj$is removed!2};Y�[90!�Exp29�$registered-�a spline-�appro�[91DB�val�e� L-�]impleA5%J an!P egratool [92VFine, D� mRNA Y$within a lA�8al strip ( cove%o10%AA0m=)� plac}to 100a�s a%�, A–P axiA�A(6mvaluesAj%�b�Lre averaged per gene;t��E 0 . Individual2�rofilemin5 U , H he number� ΍8�R�l,� show!^ Sup-t��8Figures S1 , S23 . Gap)^N�e C10–C13��tak��aۥm � scal��provid�(smooth tranm�between%otwo%�set)%9m��ES�/8in our analysis��!+FlyEx-al,: http://urcA3. spbcan ru/flyex ����e,We normalisegYw(mgsam�Klas fact��or all=� es )��adjust+ peak6Vs��Smaximum.�(level obsera�a1..�VAFdomain b��!�P���Uof 50%Nm� Ewidth�{� alcuamd)i�� xi��o�>�as�{in [63a�The� ic object�{!�model re��ent2�ɼassoci�6.�cո ( energid!�.k0state variabl��%um�6�ofa�ra-�]ar x1���e� r . Change�.,6WacrossI+�ispace���dE8 system�ord`differ�؁Nqu� !�$ODEs; see  1��Introduc�^5�epends���p&eSE��Y.u�� �ba�1 �5�ic poru%��1(�v�us� � &A�Q) ecay-�)�spaA{he !0re blastoderm!� ge , ʡ� fter�onset!W clea.� 0 � 0;��)q�end-��at6Bgastra�( 8� . D��thi-�, fE�itotic �� s occur ( 10 ,M;��mi2��:39�� �v�1,�� crip�E i�� up�!yunfinq ��4s�s$actively d��ded [9m�is!�� , has never b��� ea)H�\,� (assume fast�!E{ \E�:!wrefor!�!�Q]�N A�%ee�(>)�!�to zero�he �V�M�.A�urak minus$r,delay ) come��lie�O!bit%}. AIAMT�=� phas�eMi%�d�J stantaneo (%�th �&��x �in� ��� x��!�two-folde�!�3dihceu� them!.hal��A�e!7-��ce�y�,%z� coupl� ��歑pa} r�-of9 ��2fin�och �Kg\ in�� entl� In , @s mose��� � runkX �V . R���d �to!Flud�po v �gofF"� Gt�E,� l Kr6abdom� Kni1�j�of[,( Kr: 25 . 5t 8 (% , kni: 322gt98%� !ire 0%!�!� pole�FAlthough9�� ,feed-forward�0 ar ��pE�� non- ex� al inpuakue�*A"" ��T�m�we solv%�se�'�dE|numer? ly� an " �O!Ns,MATLAB dde23 TraCC [94�kr wasAb  to satisf�e follow� requir� s: ( i�r$t must be =% denj t!�\8 �s� +6 no>: ;hZihandlea� continuit�propaga� thro!�!rdy��history;%�( io��tof!d icit�mulas iistepsiz�\�* bigg�a f.� �M& rpol)��1$to�p E>2h s~ 6js!earbitr# l . Structu�Hparam�@iability&t A perform"+!>Lac�-� �"82�� ideaen o ob�B�g$fer matrixQ�-�in Qal canonA�%m%�J ssess wheA4RSxnique�2! TextM�s aed� "2��!,  we=&. Nq�aRj�B�Oed��km&y afT8�`>� 4AIA then��w��uM squa���erenceA accf g!H"D 2�$i�isimi!��al�� opt I�s�egap��firՕs�sis� global6@ c(E�0llel ) Lam Sia\� Anne�H( pLSA; [95]–[98]�6��� reli���frob��)\a�� suc� fu�>0��� r� se-engineo stud�� ��M� [22]b�i�X��compu��aqa� nsivFah�T�O �C-KsecondY�co9La�S search&( eSS=� �"zexplo#��4 �����2 P��P3 )A^�notu > YinO u��_L� il��rrespo toEa� s�j�!LX2� "� A���6��(RMS—unlik� ��le�� ��:� (��) —a& �no}l)�no�in1imKbut als �&7 =aY�fit . I� zmakes)�#%j�Ft ��s��are3ach o� ��v�We ~>R}�a8prz�az�)q�vnB d ���k ��xa�* ‘�Ly’-landscape givenq$��funb)�a�a /e�um� &�35�3666w E�pm� �� �is �o�\to�V,an ellipsoid3 onf��ce Z!� �A��al=W��� e���. D� APO�� rval� l�2)$se)#�e��5�ax�p4e�a�.�R}!sp ��prob�Bvo %"� v5 ) C�} s am����s� � c&$UbXcou!s� a!$6 )���j �diago� �S in c���!� with��`�dz deviv o6�.��+infer���2�via%㡠d�\s�tiv �-H) 2�ml$rder deriv  ��s ʡ{ect����i!]"za�`upgpar��F�rs� tribT Y �gre�(freedom ( 7AN!E( 8 )�*K �iyy5�a bootpp!t�'������ amplh ;6�*�m�^me��Q��ީ*�j*.�� ��.,noV*�}avail!~ �2ran�� . R � �d.|p�KE�cK byAG6neRv�Un�ev�<q.:S lwg�p� 5�Va w w�%| =�t��i�d 2� abov� B2�run A&�inAev �( clu�!n�A�Spa" Super� !A,Network ( RE��,Red EspañolV.0aciónF 1 aulJ�U�of���-XCdirectly��V", %��� coeffic� ?d "ng mu "��i�2�I�c�of�a�!�E bimo��76�(S ��� � de��a sub���H)�d]�* I�aMX#ag(;e���NNto2$k"? R6c#2�alogo�R q��1%me!re�to!�� ~p<4 .e�Rotavirus��$a major caof�,rrhea worldw�@exhib] h nounc�m�Y�pw( pith�l cM"( IEC�ropism .* hum) nfan 0neonatal mice�_@highly susceptibl�1$$as adult i"�0m�asymp�#�Q#)�low� N vi�tic�. (wa�v�g� age-&u me�%isa�V�innimmunedp !�r9~nf�iA> o�mo!�i2�M`>c!& �dsAT, Toll- r%0( Tlr ) 3 was%ii\1��uckz%�� strongly�rArdz#! J)�p1%�# vers �ng�895��, �!�7%A�#da�%�E�F�Z� Tlr3 �,3−/− ) o� adap!(0molecule Trif-rifLps2/ ) exer�� sign$aA�erN�de11Da&�#�$roinflamma��)')���H comp6(to wild-typ�im� �"��tr� ,:9For �did� dispJimpai��e� \ nhJ df�. Ukchi)�,�Pon2MA�he�poietic | �t:M�!� -med} 9$hk� eNA�detaDEa5)&�$a.�:�� of TLR3.�b�.g��B�biopsK  ue upreg5Vf.>id�� cy m�&5D�9!B6�:9to=��B. 2���B�commo�u� ;us toe�it  �childre��d�| �a(Ianth't"e untr  �� �!�ucc [�&It��ti#rF+f�9C`s youn"�six year!�2.s do � d�#op .*dis���imilar��sit�!�%�YnŮeI���:�o�ҙ�1Y)6v�9��z�(di6�R!��ra����2��Dd��s2deZ!2/ ����u�H���� ��a��win�@(al vacuoliz� �� villAgblu2�,Di �$third weekA�lifhow �:�ce.9l��s-?lyI{ redu����� repl� -�no%.%Vcli Q1i46�[c)Si� �re��W� ,ŻZ�r'lso ac� d un�UO-k bp�U�i A�pr,appe$ato beex�b���'b elluaoraE�>��velop��aC,l%1�=bmucosaL� ur����kc:�=���?un�%JI��  $#*�A]#I� �6W zis&��recogn%o8A ;(microbA�iS*!R��&m!aq�ytoso�'s9tce2��V� �"c acid"�se� �z&7endosopF !Tlr� �$7 , 8��nd 9 ,_&,solic retino s-induc� �6[ SRLRSRig-Ie� Mda5 X!>� *U � kin� R ( Pk� [�$� �<\2Z-5� dou) Gn+% ( q )=,9e� !7/8`Tlr9 � e �le>HsR )- DNA 8-E�iv� �� '5q![)U�9�G� ia�� 1myeloid&�h prim� "�!w$ 88 ( MyD8^2�3��TIR�"N�.y)�nge� rferon-β �>, .)� �C. itochondra&� 6o�( MAV&. Ligand*� 2��(��� path�aN&�0RLR,�dR6K,NF-κB , MAPMr0 IRF3%��a�n%%�Ya�v� 2�s [`#best-chaSere����eu�ar��Y�"^�aeWAom���r�͡�H!��NIn�Crdŕ,� vitr-. demonaI� `inv $��! e�� 6���14 reo-%Y�e�aintactpa� �[5��2Ad��Ei�,�U-5F�-ha��(re +�&oE��Ţ�) � vivo [8�1�.��'t�ya��b*? ". 51teF3*/�.-6JB; &|Y %��I 2I :D5EETlr��!�,-�or-�F ! " 2 m� !2Bum�!��Y. A2�P ]� u@ �i� 6 al.� aMk8 lr3-�& 6��� &%�u�"d.� cytok�5AS chem =� "�6 e� ���recrui#?v$"""�1��` . Our��ul5 d�-N'9Xi�*L!r�,r�.�xkey�1*j6��Ir� Z� . S&v>;��=6/�V�!B��� Im9�9M`[11%1� T�*u�oss 5�6�e: �"Q+�oN�A�:� ��-� O csak*d Aa�A�WihIEC��'�%R43-day-�,6�Cwea�21$MIM� arra$ �:([) &�.�3K dra& $Qy- �toM�6�"�1� .!36�n�r����yo���abl�d6�lyeed��!�9�$s Arg� 1 ( �#!RTrehal� ( i+I2�=2i\s04 , 6 ,F �!� :�i�>� ��re=ɂ0A��,���A� �1�Md�idown-6�Tlr� RigI �E��no!'. A�,:�A$re�ly2s}7�) 1i�$sor PN� V !{ Prdm%||�;8ed B lymphocyte� !�a�*a2@BlimpAaJ=&�1own-z�T;ex �16Sa$nf�B��I>z^!� Z2�"RT-PC@ ;&1BEiW&� 2�U}4\10 days �3birth�c,ad&%#"&;,yAA�day 212Glea�to a 20#1� ����of 286�6 wborMN� x=�6�in l,A�2 in i�2�YA �Uor liv_- issu�maP1 larguuw=_�8�i��'.�ka?,tota2Iqs#�, ���=k conv&ev!� germ"p}0)re� :q . No"�f7SN ha[�$�,@ngZ no�u<'u�����{�!Q72D ��3.B�9{De&�l� � K����.��R����!,nx�u lyaser.h-/abs; w�J�!8up!Tlr�6Tlr4 ��. Ne.,�exa�?dR=&�G�Vc�"��M� �UC} ��u 6# I-�s�GTl��2y∶I�A body�(�;ed�do�1f>4!adm17�>iA�to�-�(o&�!*o�Y��:��!��s�A�.��E�Q�NIfIkIsg15.QK5��6�"� ��� �<�!P�&�6OB�b �e��l��by>o��& ����;"�!a]bly relev2� �B� al�..��f�2 A%l��pw�"Jhe6� Bh2� st �I�a� "� a�l . S2-at��52�A�g)L1�%�\%� ed��*&C�in EDIMB}�ia�!O&v*�} �2%T� � ( �Di .*�/�;5 or�D to 5�f_no&AU)�TP[�)B6 �$2�wE'pr"1�M=!a2:�2�(�&�/$n )�&k- � m�."�$%�u��ofy�a�,�jo �m!&*Q`he&�" �loa ��he���Q9��2 �R&��#h�4o>�s�as��B��dis�< E��FR 1*�+o$-i4{ 2+�S1 � 6��r Z%N6<�_P�guish�(2 > �s&s,$healthy unZ3rokE�.��lTog6�seId� E,z�wards}� |!e�-A� }�6�c�+4B�*��6��.N�T.�6��R�� .Ai&�Er�: 3��&��05�8�.�&C defe�9u!��of]�d-�[9:. $٦� �3d��#�#e�E�>��a�amkofr�ge�#feG A�+ �4�YF�q��J^%�� "2 �8��106�usA�t�U )d droQ,>9$1w " erR�%excrea��B�g$:Su13m��IA�of�1nt%J!=��mon2KI1g aX3�>rsi 9ɌѶ.N�ZXe��9�until8S�~A%(st1)a�0A5-&�Y|1�at�)4K-"����� 97�fOf�n ,B"� manif� %L���e!L.h ��A�no�5�0r'S��a�:�,K"pin�� A1���]!��S�I* �2z# �1K,e�},y�.�.�R�.�7:R�$$lon homoge��v(108 IU/orga�L3C%N_Th� s1p�b. .ax!Qa&�-���.--���5CJ[ a��&�"�JG?e��)usD�+]�L_��!��.rif*��%�/�OE�nJ'(!3dk0, bone-marrow�& mera��2�. Leth�L irra�W W)����nstituA�e�Y<h� h( wt→w�7 n = 1.*o�g]Ņ�!#:V2iB��.a�lJ�JQ��6C,��4�>6%CY�� �I�A��8���ՁX�Ab��."�an�-� s� �+A��q2_� �6��a��*2�)iE! ( p<�:0��* pro /��s�f�7.lEA2h��fxs:g"�I�APnt)la�!inhNu}k�:Ba(� �'� a? HB�+� &�'f seem���������!� �6�>�7%*wt zQ p had alr{�@&��Zt�l�7�#�+!�N� z ��!�t� less�t!t &z�,9 �"1oni�V} y6ڥX���!��3 link"r��:��di.��|_&=hM&�a�i� .,2V�|el�-4io(Hr/s�4��S�� prep%٥ ��,%��� &� :� a�. C�@!���a5/:�6����e�N�,.)6(y�%wA�&�Ran �$&��M�&� ie82�&b nou �4w�P&�$�O���"J%\!9Pu#5H��fw-n C� l&M1��5r�.p 6amK'g]c� �R:�-<=Qu.l77�!UA��1"�#q]veMqA� ODN�[1c(� �>� daf�Ifn"M1edi1( ) 15%�j OtIhy�\Rnya6�6FE� �.�in�e&�be(�det��on�*Y S�� d 5C> )�R�"� ne6�I� �MQ�no26�� Y��JY se f�ng gg"�$IX&�5��a|�:�!��"^ "� -��a tincM1"�>�,l:�A�ni�)� 6� upon]�c� e�R�R.$s �5�Jfac�i6r*!$1rofes�P�K�&��&] e�I!�A`�H=�q\on!�KO�KY2��M"�v� �N�, Mofluores r>kYC CD3+*��G2F; h&��9pr,l:��n^%�. A�Z of �� �.f.Mɍ��!\11" U�6�QuAw"/]�G�WA����r@.\/% �6�- e�2� qaw�o:���BToE@owp�S�c"2]h2 at e�3&�s�y��)�9� ^�C� A gene�R�:�� �/�m 'Zb�.� toB(-F. A� ke�] d8α%�@granzyme A ( gzma>8p�[>�Y(^r4VsU/��!fng�m�E�8+���M AnNK 9�.�I�5�'�9�A'ion��3��jd��X6prtQ�- Z�a�Y=!���mi�#�EV.i���>� �A6NpThjH�ref� )r/�/>�&*4Ycon�. ��B�* desc�`� -to-�rogQ"�sp� � S* t/. [1G.S�>�2 >�)�, Runt-�a�\?%�-A%2)@unx�killerE+ ! i7Rk�"g,DM% klrd %,R�,m��_pr80�� �!nV.� ynth'No$22e�4*i�N�!e�1Y:�YFof}ba g ' ��:_. *m*.� �W���asu )F2� sBsmÁCw;r6�Ca�#,toxic q���&"\-%9[^�,y�E%F��f�"e�4��r-���6��d� N�2,Rц�G��6qY!B�#*a,nA�Zd�N��"� �=)��A'�|�JY�(R�?&���N�F�H_I�&�a=��Af Nos2.�2���2���J�6�Q�; 9:"�`,y E�Q�!6M4�Ma�^-<u)V"42d!L]%�*V Mam��oE��6� al l~ �B pria>8 )a�� i/*� �groq�&*���V�a}�L �1��gt]��"u3�g �>�>� y�!�e� . As �io�<��ier!On~x.��csU�8i,1$4;*. "B>s�HѢ.��=!�a�C, s*�C=�s rar�"sB� &�9ol�:t�V5�=study�/��:6y�W}(����,39copic�)pl'duodeA� ; a?qds sc0e20 �!"�'byR�&-�YoergDa!�����Ő�~ “9�o< t”C 9Sb�Q R�of!9u>��a~ly�h���.� ���)�:#�su&�E��1� �7" 7�r�93 - ��K�MDA�)ano�/6AX?�C& �"� &�Rt�Ak�� 77 Hum�K qm�C�howA�&DF��5*i]St*".<5�}F� !iu->ly5 m&�F&7*7-D�8. �al.*�n�93~/� `pr@[tA�t) �(� ��"}�9t^=���}��um �e�15�var;*� �?T�h�`� �� gen-�]-&� �"�W��>�A�:�6�[15B4nQ[$o�[)�>y�F.��e�� us**9�sl��y��O 2M� �n��@An:(10 "lo�,2+��FaeP�5*pfe�C=K[3.mco6C�J6>>tAxzty��U)y:1(�Rm�, [17]E� c"���1fluid>�>�A"L!i-&�5��awaX6o��LmaycAcdE*��H] absorp� capacA� "6 - barr���-���e�L n NSP4|� �SYz Ca2+�YAnZ *chlor�Ks�HiZr�yss�/iic nervA�1A[1]"�`�.��� iE�� 6� en�N�A%Ib. F%�lh!���:B!�be G�,O to!@u� B�#!%dQ\pre���"���&cYCz53L��ja*p"nD�>�lin{-�+m��.�M��[i"�"�e&��p2��neu�G docr�:prMde galan�Gal1-R|��n�b�&� 5�"E>T,!��:�*�/6L�[1r6�;6� ���9���xaoR>6l�E6R%2$i��'�>Vs� ,*peKa� �" :�-�)aTm�uP5W2�f>d&g,:�6;!��-9@-r�Dza�Z � � �.$. Low.[."�T*O�5l's6;N�<�Cg6��g�IV,"ia�5m��. B_so�)�N.Y"_I2q�"�"Ml�%E!�p.T,�hyp �cB+a>�Ldinl�in.�B�"zFtFo*Z"�%,� ~B �-��.��A Q���1preci2P��p0(�3��� cA�ainst�� ��E�!j�fai:to��.�=E��$]��A�45dw���NEV5 *�R2��"�+�M�#:q'NKsS�-)$�H% &<a'�nBQ�xoRI;L�ru!$out�eIo{P�/6� eA#� 2| �#� �$>4� �� .A�Emat� �or�XhV 2���ru4A.*�19�u�'��'" &e2X �Ua��v�$q���G!!&G�"m!F�%�zuTh�$� �Y��l Ug&�B�."]�fA���D�$A��@9�>�B�F�47 oof>Lan&Gbi0Q"�b�*A�.��'�Pisja�(,6/�$pT2��Z2$4Y�` ge��))A�� &�,|NbS~ SPF1di8#��M�uE�a� >� �+bQ hood���IiT�P pop^R. H"O� X/25M *sS+�"665%|2��X�M"�� FYH!!�C^b�&�.�Xg�*�% �^����ni�6��X+�'.t6�5!9��OP�U"J�[.�km*L@ e ph�^�U �)�*�)?V?�VK &%�&�deNK2UAK�M��჉7!fibrob�7�.E�e�ur[2�Hl,k%.� �'=f&�@byI�e2��!Ee] - �pe"R3 ��!���"dE)�!. 6u0fa�_` ��"_b aph(( �5aN �-�. Two�Io pap`@Gie�QB enco�Nby&�BAGb1Vo�z!*� JIFTa=.� �C@B5;[2�BB�Bac�[s>���or [21]��ee&�E+eMngMi�\A�YNQ@or+H[RF�j.�*� is�"avfe!Af6 shor� � iQ�&�S=tFTT.&� O mpanB6I.g�>�d" m{!@A>�.� &X~)~-��Z�oat �� ��natomU�h�S!b:��end!w)>Ymo"�WV)!���"� �� aF�7�2� �*�TmI>��E!\uNw� a.N ~>e, IRF~�si�ie�}�5omo�$�fJ8m.!'h��V[2*We�yr�F��V! �H�6� !&��P �5o6�Bj��/� �)"� IV�[F�*,�IIs*� � *� .�-�VeiO�&jU\�:e�bM*�g9&Y . A� � {Jwal�-λ.b��&&+I��:&��_)vi�e�1;mpa��-��I>�AB: ��! � � igh tr*��.bh5lrK )�d*N ��Gumably� � A�6U/vO�m.�,,͝�B� Ru�t�G���%�*l��bin�e��i�&a��-V�!*b (Q 9�  �*�wx�h*a>'? =m�2"� �4!wY � �%2,0&�A 5<�� �&�,%1�%QR aGof.{ ��in�,�6b�"&cK�kpenD% A.EF!����a�!:1!kٿas��b)"9Z�A�&us��"�6�$A�� SA[24#25��E���,&3�h-���t9�*� %}��9�&� U :55�.\$-"|&���:��/!�E lack�gM��\jIL-28R�$ cess t%#� �*�Ej]�Yƍ�@"6N5!)%k M�ptp"�!� prol�lf�=�&�A+Im���B r��$urn enforc�=mpensc�Bw~L�Vm�j o��a"�6 RigII �IB� nduA�|>�&[Lpn9rI5oJ��(ic!�roo�;�!#"(D> �/e���He"�!�1�>�isuni�x_Q beneBi�}�Xdet�n I�.a&�F>] ,�&[2pA�9/�v �a�herpesA� plex�us /* HSV-/*��ph�ai./ g&j# carr` m�v�� , Unc93b� n ER ��%e_j  Q!%c[Au%> TRAF3E�Pstream� o�����$3 ubiquiti 3g�*i � TLR4}4[27 X2�O�w�r�{ rB�A�!�I�out�{m�>15=s�A��#5F�exa!���V:�C9 !��PW�"� "j ,:�fus burd�ca�J survi��$!$$a vaccinia��M� n � [32oJ����e6b!�� �;e��uenza A p"3 $acute pneu7Ba:�m �!ߩf�xɛ31ś3V&�)1=)�ti������phery penei�qCNSo�=:"��"K!��West Nil��2Z4 >�[3� SM$&�q����o&'ωJiA�"�r�. B�`-$]O�E�� ��&z*�-����a�&p �'*�H�=fe�Se"�e)�"�m)� k�//�F"�I�~e�H%Kau�@A�uS-. s [3�/n5Y* ��S��8&Q A�!� �F-0-'BuA^�o&eC2�W%�I� b� fa[Beh�5p Qjted�u�C�.. CF�JS� loca" f a@ �<[Aq�oU��*�ay)�ITA2va&V2/"i>u���,1�D&y�� �sui�PHtibod�i��1%�n)�"� 2�x;� SE�:&�.�]]a�tWJT �X !�PKR?.UI�almp. 1R 6q"�� a�q�s*="�)S{Pe/(itselfA�62� .M e�v[ Mu~�,�mh]���v c� e��~.�&'n !)��tg"�(. Broquet e�z�v.�Jł!�"�P�IH ��M�*8 �]Y�Zt.2�@j*�]Euy��n�\�光"ő�%� �.S.rif-�b��^q� [�%Instea�B(�a�| *� sigc ���c�"mI disc�?�lՔ!|�Ib'u�AO�f.Eb('&0D>�|heterU(� aY �� Hxa�Iy  a� �����D��.�by�*.>"!2-`-I�a�mSwổ��66��E:�+i�&�">�� !,��T ]�"�n��Ja .�bM���*�*�4#�����byA'x�1�>43�&,�t�*�'�%!.��O�A�v ��nf�)U�sta&u7�2��sX ���&  relyA_5*&U6�*z �@!�9��8�*ɉ"���s!���J.A)m[��˖e�z� a75r�.�"�4En+� : 2����-<6�&�"�({1in:�4Qe�#�"l�} lex_ �O%,ce�*&�B'e�]>meostaO#AJ�y:�=%Z a/W��c�2�(:�. C�p& iv��N*�"�/&G�u�- ���7Decla&'Helsinki�� ya�R k�ߥ�@ Ethics Committee#(Hannover Me{Z4l School ( MHH2kk�e�N�71016-201�V/d�{mI"��i�u�wrt�9�-�1�!at� 's leg���y��v�>A��b�|:m�$ompli�"Ger<% @Z �Eaw NierSchG�m:E 7 welf�1GofbGHa�HNiedersächsische LZohsamt für Verbraucherschutz  Lebens%�lsiPheit Oldenburg ( AZ 3�H9-42502-04-09/1709 eA%,-!h{�Fd_�(��&r%*g.% ���ar�4by FELAS�H��&M1#�^GV-SOLAS�Oww . gv-b�de/�x . htm,M��6 C57BL/65t )a�e:`Charl�gA�,( Sulzfeld ,-��!�P&el�� _�)xi.�����(����m)i��8"� 40�%) ��. DdaA�"�)!� vJ25�J�`. E4�e�h�v636&7&�+a�e�"&T[3�BN�s !7:� lay��)*%����c�2E�:�"�)� v2�� A���sA�incub)�,in 30 mM EDT�enr&e� sedi�! ,at 1×�T��<.��r�6X,l-!�:��LsR WV�u�B a)#RBFv2cytom�}!o"�.},t�@%�1>�CD45+O|:�VAo�]�5>��a�x!%�1 "�Peyer':<tch�?gu X�e �6b?-�-5� reu{�)m����6a�xs�) � hock![z5_lpd "H.�I��EU"ki$ gut lumenE�wa+=jR���Q41 o�d � ig��,,Vw>c $5% FCS/PBSkM�%$ RPMI 1640 0�$FCS , 1 mg���a:\ se D�IoS �W!�1 U%DNI igOLm 4���&�qe�)\��seZ(>�q)aL 37°ڕA� u�!�i=q h�vigoro��10 .fi���"Ӛ a ny�= mesh���B ��֕> %k$40–70% P�l� GE H�cA���!�rpUJ�U3P�O$�.Q��!�$?!xsu��o FAC!�m��ab�460i�85e�cI�b%�a��Ž�s2�h�Y�5.� I�e� TRIM ( InvEK)6_ manu�ure�'7ruceA2 �]&Ip!&templo�! 1–2 µga{pK�A�RJ tAid��a� #0A�( F]zntaA $St-Leon-Ro+]�� i��ar2Gto�|�o�=6����6 y#!w> Vwo*�n� )"�n-hq*�iel. EachAi�)%J�alquadrup<%d{1JO� D T��te Cy3-$r Cy5-labe- !�qAoj;InŞLin��A/"=RKit PLUSfwo-ColorF( Agi� Techn�a �E� ��72Pg mmen���fra*��$, hybridiz��nd!hWs��)�]txaE�� a���.�-“�*�v-�; Gene.��Aq�$Protocol V+�]1!. Slid���8e"?)1*�v AE�S# r G2505 B�K�s&PMT���10�.5%��*�� dyna��"��-=�BO�n!6-���t�ex9�B�1�Ei9te�i “F#!E@Softw�V9ۢ . �%.6[ e9� defa��p1qs�T: GE2-v5_95_Feb07 . xmfReal-�� �t��*� I�Sybr Y���6�!�av -�Pfafflo�A� �� !/��FgA@mGapdhskee[3�%�ufv:A�p�rM�e��|�4: I:.(�= w: gagcta ctgcagcaa�!(rev: ttctggB/#BTcgaaagttggacttgtcatcaa�Pv: gc! ttcak_R�AWA� : tczA,cagtcgtgtttgF�gCgca��* lambda 2/c� N�Igc�aLDgggagtgaatgtggctca�[40a%OQ�  �!ctcHgbcag Stc� GrzmzU� . !Dcgc�atwa���gcc!ga�U9SxSE: t$p!G� . �gagK�!c �K'S�a% %hcc9`a�cactgat�a BPfr� �g%{�� tcgc!B.�a���gI-;P ��!� ���9RAfccg�%�t � CER%s-ttc�a�!�gat!�t%�t"Bt!�E�"!<]�%�AA�g!Ma�i�E!0%H!7ct!��%aAbRgMd?�a��u���pr7h >/B�D��"U^��cep"ia�8�4m_e T�:^h 24"Y as>�� hexamC3�f�d�ve�%p;m�1dˍ�� Appl[$Bio�GTaq5 � ��TaqManF9ssv-�;��:1,: Hs01551078{�DA5  070332_m1%� HPRT 03267 x�y� >!���'V&"GEO Se%� o\�mb�iGSE35596q �WT.���#p.V� h*�ior�ol"�T2� 0����e "}bu�C s٥!y5�0RIDASCREEN Rok�Elisa� � PR-Biopharm ( Darmstada�&+ a�E�6:~� * � 21�e� a!%P$A(R�az)<is&oI](!��5droG�e&sF�m�&N6U ".Me�-mi��be �}mN. Para�/,aldehyde-fix!�is7|"�^ewd af�z�ifxylch$osihb�!"&� 2M��� �re�G\Rlb$( Karlsruh?.Y�� AV�_ar�e.�(p�� �v�F� 01 M sod�:cP�teq~6� block; �.A�uai Jack�ImmunoRe=� , Suffolkw0KM �LALrabbit�(-CD3 polycl#} tise d&�a]� a� conj�ed goat�- V�3�(!O(��. CM$er�� JI"Zain.�wheat� agg�KWGA-Fit�dVec7 Labor.08,��vapitzerlA�)��s*\ 8s DAPI|Q�Y ashield (or6grn�o@� visuB,ed (an ApoTome-�'p�xAxia�n 2�ro�Uv*n�to74xioCam Mr digi�C�4a ( Carl Zeiss  Imag!`, Inc .�ö��e�O}6�W�Z:�'��-ex�d!�cW ( WE�� , 039�s�Pgno�(e�autismStAydisor��Srp!�870�trorT�ie�A� NIMH�si2 �o�9�� stryp������caO��E9 x�� &�H7�'�e��Mal�C��irH.��a�i�W goalE�&�5�k_r*R,QX va.a�)la�U�����ikb�":ght� �by�̍ng �/h��_aF��n�a�p�g!�beO�C.�j'�bF�͎h Ɖ�)�mu�a)q4nգMX�Bt>6�u�} L%!>as&�9�P(xt�%add Bed�N.�anr<2�Kkshoul�%bi�Q.t ˫��J\!�'b �cho� K^ Ts st$�.>&,o o��(A�a- xi|B ��2<nsDc�alm?g2?? Bec�,��e+ many; ���:�theCk����:m2lJ0"5p�UKme.�.O0b��zA���>0 )�)�'-5cG *eH�Wu�n}[n�/< se hבke7rNAEY�BwȬu�2�'Rqca�%�����H�9A�P1&�)m��&b u�= c�� space; yeu #�� B�!-�Y%<�%�princip� ompo�d-�%wA�e�suf�9���oP��cA�A*.���I�^t� s��� ��a�ety!gen6gL:E96gE )i(no new riskI� �_%��"� *�0s.�L"8�B� willt@#)h6�r��of%� -4�"� u�6 !�c���Dž?��k�!�@�. Q(:6*A7iB{v�H kt� rchi>ef A�S��DB�[1::1Z8 None�Ies�mEB�a�M�� v�L�Iof&5.E�̰3he cern ��Ypla�&�T liab�*!)!�L�.Y=,�*�72��gH%�*�h�)l:gN6`)�ipo#� *�5�� rega��g �@ ambi_0BI �y%7w5PX� ���3[ 2000Ehe Mg&x 2G�gen�G�R��:� ��A��)ex-�--+�:nc!��andida�!k?�?–LY;�w� , Z"p"��Z=jnot� r� a p-valueJenough��atE%%G-w�W&0.ce�WZ >�eaif i�se9�PCnE��� ��s�8�H� litt�UwE!Raz 1վve�.��!o�,!EhE�!��)A�Z� s�sA�an2%�] 9h.��]��"g�eD��%YA�cum�OJ^��s�"�465�;eyl�. A* 3.q*9 | �.' �6_!An[`"��."<���ft i�!X5tegor�6�= '�בy!BA�B�aVs��--�giNA��C<� d���s9��!f&RO%�co���[e Q����0g�4�& �Aa�a,�� et���l� C-alpha [�D�+ SKAT:: look)�n unu� zr ̯���+�o�?PE�)%j��& k��{���%�eE���� R67�Q��y��3Hfsum��@xAVst9AAX�G��a�he�stai��rTo amas�Fb��"� e�:�o!$66��r,tra"���xe��)lfr�fc��� �4��b\�� �ec��- ousa���$%u�c!`ir�=g�C��td:�v�*U� ARRA"� �Eonsort�( AASˇ��y �/��" � woѣFen�8( Baylor Colleg� )1��A�Brb��9�~��#�� � cap�y.&,�plam){# pre-.� lign���m�A�d| �Ae� ag�q�� *� ��Pv!.W ,� e�vq4��&Bc b�Mr>B&ZA����$�;E+�N�G� v%�sourc�{��I�ivK'�f�_O>8��B� H'm�tra}":4A.�,!H*��V���on�D;�@E�] ach� ! O�� iE48� �et 1)zd,zm��!"�Z-ܹ)�L�1�(,�.9r�som}Gz]� �qba�4r����6� . M2Ak Iad��Atof;�2�J&g�!�h?<ge�x1[j��s [��Allt#� N��I�xszp��W�.R`F�����.���eME��A�!�p�/�GoΕpursu����A� �62 �mo�V��ful��ced !! A��~s�L.Pa�u f`a�c� -int�Gv�!��:-�.eRceL�U�� zgM(%��ن< r��%6��we]8gz �R�aL�>�xY�b�/pF)�+� [HH���� As �&X"��� E~�8eu,s��J-c���g!��WA2in�/ ge"+.S,=��at �q���K-�| *�� �'&� ^� �@'��d-�v��Q �ot�d)py�m�ѱA�N��hundredF0 r�K�� � �!]�[4� �i<< G %`Z�%w)S ed 1�I\*}Europ�5��2�N}.��zt�k half)a�hfO"!Solid��q�w��$AtlasSNP 2�I9: �&� , 491!�q �\@��obIllY af�GATK pI(�: 534{379.{Q�&��$6�%]5������!�e�& >� BE�)holV���%)g� '��te��ACIA��ant: FE PASS !.6E�p' y base�� ��!);EMISS exe��.y�)��tk0�.m���; Four�<F+�es!�A:iUDaj�5 �F�B� d�A *�ź6.��M 77(�q�x �If�/AMwRe 9�����)!""�)��2�)�se5uDpB�j�t�bk��!1L��w+ �X U�a^�bym� ,�Kn��&?-ari�of��s%�Y e��3!��� � �Aro F o do s{�"��iA0z��g�,�Osynonym�5uw:!���t-du$ s6m �.�[�-�Z�3���N33:�478�|.% nm�d mism�26 � p1�29��426 N���n3 017%bR( T��S#>c"a�� zygĭ=bAA`p ���1E� ��� � �t�f&4: 9:`�JeMo�abyM��6ile 42zB� 6AQ�On'Ff-�0o��)�se:^�Y���>.�]$ML ҡA-2Z4*���-���� �\-nrM�� B–���+�3� f.��u�l��!�%w�kMb�"�O�im6:�a3Q�)�C ~%��!��dQ�I�65Q��]/�gR�U :�2E%m�؉,}�2�� /i . PD��e�M=a M��*a��)� ��2��i� U 2ig ��hecU� Asl� ly�-a:%Ŭ!QI� *"}L&�,qc�c-�i��A& �J7OI��NveP gBp���9 . 24%` M!=�82 eaD/�A�ɫi `���)��gNj��!�2m�y ( MA�})%,543."5��63)15��8511y�re� �.� �1<� ��.� YK�736�Nw8089�TE��jIwCF2e�eor�!�E��.b6eyABt"�[�SI� n.ˁ�t�6��#�3A#-�f.D �{�6�ide�<��"�W�% o "O �ec��>�! e ��7�9�A�g*on2,�"Ī�Z z���t�imulta �Y6 5J��a!p oret��*�V1A�!�Me ;QX+C� �6i]�yN�{�� ml���!iE �6���eEV%EEO[�s�$iID) ��s�3֌* �&�#%�s!S��a���rde�(e�hb�.��gr�' ��f,� ��yO�so�3�[�b�� I$NAᲵn�. M�r��) 1e� �B��mad\�&� "��0�a ��i*��Aqi@� focui � 1090en�h��stNA&�=); st f�I*��gui���cau2b.&'�uiliY� �5 �x�\JW 5� in1 or- *� }+�dJHsh@B�)0ly pick8�c&a!�>�We�/B�to%H�>%&Z2O e62� Eq$P1�� od��!� inX:�ro�(,��K�-�y�D&�r�BmE�!5c�j" 20%TJ��a��we up��9����ա�'$H�6se�)I�[L��%�"}�)=OF M�,-�xA~ merg��a�U��5h "\�ԝ>t�99�vŃ}"u�f� � �z m$E=M�)�mt@_K�j2�A��w2�)qed>� b��9!�-�� � eachE�i(��!X�M ��6��G�J�B~ %&�.�R��/log]�u � WŔ_K�z� c�0 b%Sa6��p�6b�-#g�as����w���&E:a�Q�If��!L�SXf�%�!�a�/[�qFI3��E3ͭ� i�a Kn�A�"�&�t�A2e��K!p&����Te�ifa�MHat�zj�[.�2��? ��f �EyeAd�wo�-)A��!pl� �5M4VA , tw�*�a�]����%U �%�%!�y�. 06 �;u�1�:�C�-QzE�5@��A��*a+I>Vf%.c45�# "��n*M� �!�5�M&A��?A]#G��N3yG , 2∶2�B∶S� 0∶X�.��!�������y� at 2ڣu +(A�v "� !�2"&m��!:� Q%i�extrema^RA�&$rb=\� VfavorD�^.� . Un&� E1av1`�� � �� raw)Habc�A�Hd!�i�%�%��)cenari�)�� 0a!�":+:�v�".ZJ)� A[%ۍ���)Ca.����oreUu@76>$ ��er*A�-��h���s�2�v �v Q!Oth�P�A)�by�aN&�%�F|� �)�!@�a =��If8):iF4-����C�.�s{W,�Yi"*�byA#5MAt full_�&#�; 69�� ��� ��!)EGA�M���w>0u�b ��FVYZ-�"� Q�a�!�ovWF a3@�e�oh)g&;-�͍!�6�� Xnb�I���)>!u� �V��< ' %>~is~! to f�%�0*�1� !��"[��>1not�e)N�i!��| Y v,�:�tmix�o(�.�,"G�eeR �� ��aHR.r6�@� QRE �M�  Q-Q plo*��u ,*\<�Wqm �pO���son% %�3 � EqEr�.�q�{,um ( CV!��� $"�X���lT9�7gV7�ġ�� �B� e�S-v�;jA9�� �sZ3��V�&�F.&A� 2B��U xs<5!�I9|o-�]!�D+"��a�h(!Eco�I�j�. �L #>�#��!( SNV�": }Q&1(LF%��Fa�� typI�( CVs+,�� R�{ !�6�"L�ppSp�%� 6��-6( 1�702�n�*0�076 u��( 8783 u�&t�2�509:! D"�J�5$Za0PCA����A!�hEe[W� n5'.&�xA:nlyVA����]� ��k�Ss�r2� 26�NqaleYs�s2�"5�)#"�S{)�;�_�A ��, �6=�恒ppag-ue�EV=qi3y)�A��s"�����w�$P��� of [.D�>�l%g:��9����R�(. CFc�$I��1'�����.��+H0 ouq�56�2��uw� GWASQ�O&�.[10�,E���>�@�o�D)%"��8blue ) from Bay��lor and Broad plotted versus the top 2 eigen-vectors calculated from CVs in the exome shows that the samples are fairly evenly distribuupin ancestry space but many of�$subjects o mboundar � ;�are cases ( Figure 6 ) . When combining Bay6s �into a*mon Z- [4, it is eviden�ae two?overlap�$stantially�S2�The� x$ , howevergDncludes greater di!��ity . As a first step to investigate !�dis)]ion!Cr!4variants , we �0ify all pairs)Dindividuals who sh: doubleton.Ddi . e . , each had one cop%�Tan SNV seen only twice!��entire�. Dbs%�of!�,erest becaus�y@�st�in ourP for which��-d-coun � es widely!�ith som!P9�havingAarU:)�iGse%9 �a�an expeca�dua� cha�! e examin%}B��s aE�uncQq�e�-map .q�7E play{ e relativA5�of.Tii�02-dimensionalT!�f-X��iO!�I=%20 largA;J�s tendaP 5b EAthR*co��5�,% e���.�ir o�min�' llel�QMAC_c )�� exonic�. F��p8A , 8B�.%J �� �a)�q�s alsoq[ a!proporAd��9�6�, sug!�a wthA�.}%rowardBOEuropeaB�.ATeed�5)�s6�YY3i�@�?f!#!�>A.�յ7!E$orange poi����$Furthermor�3I� records� ��@J���>�might ��!proxye�NB��.� Nexta� look��see i $se descrip�=analy�supa^�2ofᆉt��t�nntrol�� G a'in2� te!���� ��@associaE1 betw��ASD%�6��� AASC1��,apply burdenXs= SKAT�!&fild  �data se 2 obta ep-value%� geneYl�,M9�1 edNM. Wa�6N effe| f.$struct_ by?ce=ng�genomic!d%pinf��^ bejo �e.�(statistic ,A�*8 ba) oJq9�Ehas bAYX nApro~  accu�9�M tailA��2�!' mode6sizedM�s [26!Ind���=�5Eh%ŏ��^_!��Utappear�b�~�(e�below�� 2��jg crosC %|� &= � folS�"� uniAb6`�uS3�uS3B�Specifi u !@t�iX��ly�wa� Q�t phenE} (�)AQ9F%�v s!5re��5ObiE, down��$. 5 , causA�an!war��,9 unin�5sy{-�GCq�. Notab��alg� hm�auC� seem�.�!sm$ r*;�do%�a���m�-�� qu+l!,��6� A similar)W menon hol!9rue�ýM-�much l� � t!,=�C , S3D%� This��likl �[�>�� �c6�. U%�permu�oU o��5, would remed! situ�J)�atmu"B cos�-� +�ins�n!^to� null6�-m.��v��s lead �o�� W ��! ,GC principle��B�ra� �2� medianA ��16�. Fu ��peabcalib��d��.� ���1�Xre!�n����-�*� �ʉ�TzS1I=�&:��wo�2��saconduc���a���r� t�r� ���"�=�i���o!Te 1000� st�� T�qweM� Xc�Rus= time Z�!ǥU���wT ]��U�=J�s��*�9�q�4%pNot'�  observ �!�is cl� M�m� MOsim��.�all 3B�"D� )!aX hows�5�ebil�!��.{.2}is shif�f�  above 1� � !y�con�U %��� posi� 1 �>I� ! .� �*�6S%C s�� t���."� .d adju�a%^�( lCVsa�i�rvŅ5�wh���2 M�!�aJim A�AI�l#ai�'wel>o!�.) �$1� Tabl!�^ � mega)(Z ij�L a sl�l�V( 1 . 08E�T}g!y-log10 (Y��V)�[v$e�$�ٵ10 K _2smV a�� s����" hypo� is qui�+aYleW��I�Z�IZ!�A�uffici�^to yield!2��re�ion!mm expl� Eyq!R !�aIb�resul�t� h ��B a>��rre�- us c�T� u� deri�^%��, LFV� CVs+ �e�� Ye�� �are n24� uishE_regard1�8scenario ( bothg � >�� e�or:�meta-A�-Q�;Mzc�Ea��,!p�. E�eU) ,-�no). %�!V�d!�,De3 ,5OYNP,!�tivImAs�xX�_e�t. 001; �5l!��(1[w"���ign*n!�%�A8u )�( )� aU "����r d �@)�,���!!H��11��W inue� M�� high����2is ab!�%�2�(2�Igɔ� �|�-Eof-b��/2� 1 afE9�is re�p weakU>�� seU )�$. A candid�diagno�A�2amatch!�of2�=0 s�." AMA�� plat�.q7�3!a crude� sH of alignm�. D�Q�ch�� 1B g�a m�i[fu���i� �)�w�6� ���c3�at�gooA�of�2T �5g!\sucaX��harmoniz ���so��2 [g��arol r ���;i2�,Xp�e%�is 330�300A'JWB�W� 2 bene- ��rem 6���it�a�po�61E�a��#arll>X e*� �on� arti�r%$ ( SCN2A )io"~demonst�t%]an�!9�E� 3�ur� de novo l�of& &[4] , [5|��� y��-��եxEHa �v&Iof��9�n*&y � ���� mis�n��,? y ;depth%�po� al� e�le�W� MISSǍ�A/. 033�+� �ad� al=�!�)�:Ia, togeI.!�6�-�� 3s 2 p� ve sT!e� ense.35]�1.B�--hI�. )er����T �l � �2s a��E9 . PrIto=�siz: fra� � lociau� a�!�da����� !– ei%N,heterozygousN hom&�� Ms;a�lM�p�c7 )� �ŭE^1?}�p� QM�of7M� 7. A:�6� ] . 3%I!s-K"JX E�i6� ly&EAudsit{ r%�/�9, uُ3�M� nQ%�“.m�?”!�m�IPa#asi�a�.<in4���y90�..ari2  � o�!M0lthough diffe���U.@��82sc�#6�"��,RL ����ac&� Cot so9�$duc� *�n�in7 2 � �un�!ata&Q,[weP:� h:<���T��R g��A5{ �qproblemA iL$"�.�:B� ,�i�si�v��Ax� .��M��� a����A $6� 6( � �ea~at� eissue�(finer scaleB�b�sok7V'&mb� *!h leve� *� .�Q��6�E�bc�kF(S5e�N�=%#s�-O d_s!�I��4cE���"�!kexome-�%� U c��!GJPz9edA�" S�sNot�� half!��e�s�p� 6� i�kti�2^#�tuve1��iwe viewIas un� . Moreo�(!�>� � �"Jly�ellAto�lic~ < know*� � 2Sl�iE���de$� mppa lis*� e<atst�%�!al"� &� S(tifa��irecp ! stud�'[4]–[6� 8]"� �Hw@a"+114BAZ s ci!�by [36]!S] =M��2  �se�" q�!}� �Sw!��M�a)s���to�&�Taas"�$lyj�$�>N. N�� �Y.��N� , argu!��)G*~$,powerA5inY.�deA�.�m&6�!��tindO to guidei�J. S-� �>u� c+�!+sequea� �%��& in'�v elev�(�� dama�q��V"] [1Es8` T'Q�ei>i�)ly littl� verg��)� o on p&A � A>human!��*����c�s� %�",A�lu�)*�A&O"archi!��a, nam�E� ebhundredE�@%t����&�# li�,�r1 "!�* "*alMiA^W*�%, G�� , )�An[ 9& themY �1� A�:~!GE�G,�$n*%ly��yS�) �qi%�er�heB�_�i �#a key toI&R<c�ց�7AqB��nt��6K��yet�(� �%��L\di W�rep���ASDwA a� 9�tantaliz6aD�'[10���]�Em�! �&�imple; %��.:ii��� on WES [3ewH'w�)�"onI"� al|2��u��V H�,����2His ark�Z,5�Ej��!��1=6�aa-����"� siz}6,�/:� owed�i.� űNtud�! -��in keep!ܡ����9����Q"� K#'�"�!i>�.U2�y requ�0�)s [19��3 4Y�re�lp!qtic��!�e�%�a���>9;in� ceIW�(�%�imusQ1�vs �!Q�'to�[3�C"�>�undersc�(�� �chrngbh\#�1effor�q�k �. L�/ 1A�amab1A�  �5�yJiga�}�[41a� To g(*�d20$lim^ T�U�&}�e"�s: ( ,L �215��I{�E|MAF�"�2� �odd�tioy4; ( B�U20�U10NT3;%6( T!�gen �4�X3RX2j; Wmd5�� of)"�in� 6AfachievF5~50%�80%|�()Ha � %�.of Evh��P6�iF6 ly 03�" 11r 06� d IR,Aquma �8�N ra�a!i: t�&%��1:� ��$A��=; S/��pre:�E\ W� /6u�p$as�(d2.b �' +l�����e6E� GWAS��o!�(te �q�a�eW �, multiv!?� q�"p-n$�"\ y�Fs��BD,:�,�oZ-�� �bec!_nor�)�iAG!�i"�-����,�\ �Q �equ' o:Na�;l"�/5 [42��h= 88reason�)Qu� 6uis�r�6 supe%6�*7�me�re easi� c\ �s�!�%��4��A��r)�y� i� �*car�9�9 en6as`-�atW�s6�!p���-"� )�t�6*16E� F� ord"�*�!�&D-all)+t�M�$ A&��n./� ��a3:!�is wayaEh� thod".s �+��� �o�(a[6'�' .!lnoi�7�=%Z� �>/n�QFM�I�* � )[! Sa��! B- �-X}� $A drawback:6�Qg n�6d4&G�$ ˡ�m �! coll�8 mJ?3� ��� s!�`#�! �vp"�!protoc%�+in�;c�i-Db,toy7 age�S7W6t*�err�=.��@e best laboratory�%eFme� :X � JV exacerba%_the 1Nb����,*�ly>.8j� )& ��g u���(exerci'2ifa E�ap:< 'f:Aad�1�e care9�!�,:�I�c$%cE��&A�2�.f�3틑Re��&�A�J -�"�> }via��%�6 �d  ��c- extrv �0en! n Z>%~� e�aY!u��r5�-�era�W�� �9d�.�&by2�� l2 adp�2m<8+���Y��p �>����!U��$A�g&,+�#BF  &6g di�(�1t%,m aP!�fi�atFrob��cZ ��� �6N�,&l cogn�E�� v\��f'8EV3 xtr�!a9' �_*#. Still���� �U1�J�!�yet&�7pr��F�Q?� I:em� 2!1)!��� �.�(����')A�uly &JB-E1� )�.G4�.���n.{f�WEp,m �te�of:�J !R&F@, [43�.�!)A:�"ap{=v7ly�D-�(ed��)�de� 'E�)"�^ <.{2�.A-��e��%V 1SI�b�$�ETDregre�%�-p~6a�(�?%��ɬ� *�>or�%f� encyY'��r��-n;of [4�&��tr�G�4\�di�$s1�Thu�"�6�te�)L'young�Fa-O�<` inctluA(�Yu`V� 462�0>capE�!��A feaD�rib� ����A ���* e�%�on� �`0� ��>k� ��B�Vnovel*����wN���"`"e"�2m�56�!�ao��q=I��0�hIP�0"?))�:��G��llA�A�i!�_V�!�. dlAB�"�@�_prQ� rEU%8hB%��!#&�6� �="whole-�!.!%��Bg839�epend "C >-�3]  sm rum�or^gS�;SKwyse�iGof F�D*(A (�24 )�b�!ndCorigi��S�6t�aAut��"^(Resource ExJHg�" AGRE� se� . agre"org�'IS�x Cia@( T* e Soli�OY1���yD0AtlasSNP 2 [3�]*Pѧb\Ill-a"� B_GATK [3�Staa�d� m>%ase��%@pip�4�F ���SN�8ind�j�%�$e"�>�as� i�of D wM0AD�� nI'��*�. �$n�4�&R(�P One �4*tK w ,�q�� d��>&�/o 2E��7FM( F�7EIOv!] fof @r� � � ���  )We util`EB�/%�maka_96� cd3:. Rel�7E=valu4! �}�a���7�L lappA�Y�a��@a�n.�3-rounQ~:AT �-F�8,E��( ex��Z%t!4_Qr �� M� . Se�= C� ardbDa!�gJ�1.�5 Thir E>D�9��o�B6X��de�+ �*�I`a�F=U�� 2t>I7a=�5 :%�E�*�*F_I�a�C 9or Q�,�8a� .Uis1�;`FIa�K� .X ed 6-R� noby�3,�2,2, B , CE9D!binc�E��:c�"For2�-*I!W!�hU[A��J;.{, 2�EI�ZXjZD�%�Yr�,!_kepD=�Z1 Iv �,m'eF�pas����*E-eO��2� � �2�?I� Two �� i:=:� �<��,1�,n�K"0,A�/7-, E<�:N-!9=ly�F���F�%E�#C%se= )�C-alph�4 [25]J<%J)UI)en�Bto unusJ%pVE>�vd !!9[!)$>� �if �%M@cop�!b25 oER!� X(!?Y�B��4��r% i��VY"v � .�$_RłA�kz���2R.�A��advantagE�� �%incorp�!!�c٩+wi)u/�O��it)�eE�YE��$ as�!�!��]is&b6��-U6B�or�l,� random�� '�}�]al�qdAf�R� rbid2�}n zeroE �s#[4z0����2��}�R 89* !�,K = GWG'!?k)Gl rixU��A�]1��C��o�N2�(%:!�eI8�A^ b#6 *���eerm�o�u&iJToj �*��AIhed�*!%)",xRcomputz& 65f�5cU�A;��A��s�N+92[P�_E�m�(� �N �d)ka~ere4�+�?�`W_=�4� 6�u���=!%C6Ab�0riv��a�Qd!�m�:�!Z���� �,JN{1AItri�aF"P>�R�+V�3^&&R�,�)�KE�!NrW%. A�,�d Impl�:�Nhoo� M�A�a�FB�D;&W +� U�$val�toG2%%sI�M�<-�t.� }��=9QT�� H �g linkaFi�i�$�Lgb�\6` [49�-[5Con;en! w� II�>s-cY p�A�eabu-a.��he`e�. Ud3�s�1�a�R��� P����,�� ��(|@Qj:�� 1��( �-2x&� ;�Q.;VI;)�Z�m�ee�u2���aV-b% non-74 t�!ram�DQ� ofb'M0!Q.�.: . He8���h2N �z-12�!yQP� ^']�� 6��%�&F T!i:-�x�b�-6 Va- AE2�""�0M&829 e "EwMcpoo�Ee(1Q�U)!W]squ�D) :��615Z��!� b��i�^� mphas�9e8-�#�59-m0�5*� ��e$"�K ��N�%a�e)��!�#�2 ]6�M�*loc�t�AF�V�V� ilW#R�$c)te� �x]��u9]�� �)$��ed� ȑG-� vI .M�)#��of�� ed zb3���n�F9e�(� 1]Y��hMU�5(�{S3–AU"�#e� ��A�Ole� <� �M2!�VX,>|TdM%F free� N)���Lh@tM�� E�%��`8*;8�F�6� )��2*#6�"��$)e�Ja)}(]No>?'!#�<ed�*e�6I"g��. d.�ect�0ǕO,a�2�H <*7� � �$r �n��Q let'�FokqTB�or:f�&q&er� ve.@K \- ��y6to ��causalꅶ: ign;&q,�6�_neg�.32v"36�%�w *c"(pe:�. !�u�Aa`a� %t�^ ncelIro)E(,��O.6��xfia#�v�expana��`����� Aa*�/��hY��3���A�2>'.�G!�6��-::/�:�3I�T�u`�u� reve�5wh>�D�-�)g2J,!� quad� cB�a . M2�-��0ut (,Ar��!��>.~ �?"" �2en$ .G!�"�5�5*�2:0 !!A~rength�y!yal=��gT� �F)rwoM_: 5um@.��p)Eba�P�Z&`J�. B\ZA�6�as[%��� �A��b�!�[�� � R9�J�,`di{0� IK�WB���JQj�Y"�5:��atM4l &�m��l" )�E�6�6Nes�C noun�N6:� accu�`���?� � .FfE�_1N�<.�witV2B�9Xas!��]\ly ._PMadurella myceto_eA"RprJ!;�!� a_Z�>u7!OSud� a�Bj�&�D�!&��Wrai6 M�pat�Z� exń�>�&e4?a V m$dMop!&�}o�,!^�ax~hGi� g7c %w�* �� trig�-�"+ immu�$ystem�R(olymorphism+��s �9 aG r-A�a enzyao�'ida�'d AMC �d�>d� �!Sh2�P"4!��2��15fdF�W:P1\�I�&�.B%��M 112 ]RY nd 103rc�0!��)�6vt` 24-b!�sn`�! .L!�( ( rs383131�%2 =E-�-;:F��lOacleot3K.'�UNPf2B-�w6175668JxdeJ5�=�A�&U\�4128249�� a 10R�(5’UTR reg!>�14378908�bEb1�,�(*Me�wN� DNA �' isol`;� blZnd!��r� �i�;�PCR-RFLP�ist<�i=eM�?Q�)�At!�fun�q�W��y�6�9wE.+5���20*9o�D6 ( �o4D9; p =lC0SN��"Opd�h�.VA��AH�-�() p>�C��+QI��� n�. M�C��rou�G3us!}nul�Ov��� zB�0Jr'J� trop, E�subcl�4ovq30°N'15°S�!�toH���bia+by bac'a!;ctino��i,A>i20��bg�v"us �;��>��world [�Ew!In�0�� )�W 7�Vall�d�[V,fl��7i�:& �Hed��O o� �=�bodVM�f�5�[a�ll g�X trau*c inoN\�� FF��ubcutaneAti�R, � I� soleJfoov3EBpro6�n�5va6|!� deep6Qu�r�sk�1M�Enodul sinuLq$harcPpu|�!nr,$Q"� �c�hAa)�l\�W mbed*in�^ d br�SmaO�Ǎ�melan��KXAIv:JDku*h� >�In �3�ka�)�� >�����5�ilKeh�obo"a=�:��*v�@en�.�B T>U. inhabitan"�#��,^.*;RF �q�� �+�M�7 � �*ve aIt�Mn�f���%S4]o{nviro��?A2� � �Rl�,I"� ) BAog'�e*m�i�.�Mɍ�-���4*j ?t]�W$. Ibrahim ��_A�N5/n���Cav�t %: !slipid�� �AL  c�&�sin�!pA�B�[/wP�4�H�/e ��!��s-� ,�DceY"n��&G %7{��? ungij�,�al o {��’!�}6�m�1q lamm���%1*s :re��v�� la�yE$neutrophil!Jm� phag�-�2�ni�shSCw �@a=a�!kiN�!�aGe�a��iZ<0?EH�CR� zis upregq^54M���>�� e��uplay ai�A=llergi.\�-us � �"U V -beaI.organ [2 ,kN, 1Lm�!i6q��{e"in�yh�@��is�&%8 eluc3..vhydrolyzU��M�!<U�1�Mu!Q�>C ��& �>%��=B��UnP�d sCi�(�wA�[ �G � 1;�aC��"E6K)g%�� �Q��~Xs: 2� (nd acidic mA�l�uEf;W ) [1a@j������E,d����ѕ4 G^*; �2� �9g[1E;4–1�&Im��g.7e��� a��r�6�)��!>�Z�!�air5�79�eݟ� ai��#�UA~*.6d}Q�5N��c.v.0f�"zp%�c>-�6Q��i� 1�B:,�Qb,$Q6m@&*� in�bTa��tV.i_. .����at&� R�<Cen�$, Khartoum"�200�R 2008�a eligl.A�%����%�>��fZ� �'�e�Bir . Peo�Ql�$-�Vx wA r�1� R ���I4nigraphic&�AaC&2�wqRetro+4��&�.�*�ofTZ�E�u<a-��/hhealthy����,H�!Q"2g�>W@�!*stoa�8at -80°C until� �MAb. w 60e@ Ju�"�3*��MagNA P��LCLIx� kit—YWVol1( Roche*ms Ned���V , Alm!��� Ne:l�=)�re�� manu urer�r9���=2^Ti  ���  %T"�(in 1998` Sudaf5$V���z>/ $. PubMed LKry]�@�' publtbͭ�!�60M�.`c � �l��e�a � 6T��M�X else3%O�\4-s�A!�^Ae�-��x�#����ra% �E.�nFm�M, BW1! a.�&���(ApLe4M���a�_z�i�HXpurch�9allCat Fer&a CTh�� F�Kr Smw� , Wa�aQ2US�Y. EC%@� JU�B��a'�W2��Vby)�er�chF H Ԃ&l frag��D'.�Gs��?PC!g� �run�a%5% phorM!�90�u�'.�8M&� �!3e.n� mmbiops�&%,7i�t mali� .�paraff nd��m+� o�choG}.\To���1��*Ol�X� q5pA�.`:c�-%�� @�/7t-�vitro gr�>hypha(.�C}�A�s0W�S��)c s�nA�coupe�O%WdL�!9�Rn xyl��c n re� +&p�herIa^4e;oyae� xy!�! e�+&%�~I�smA�Z4. Calcofluor-w^c:to vi�3TM!E�LC)%wacOA=!es�$incub�w';25 μM�+2�( Moleer�M/Le� ,�:��3y,at 37��� darku�OwaC��%%�n�uU�R!;es!� miA�c�e�oe:��1!U*�a���pr"�y[a<end� operox Kblock�e�IaA%A3% H2O2EJ+( �-bU(ng��I=rabbit�2go�Y�H:1b&�,6)9�Wnight2K��clďm�eVrq�A[.�( H-66.:7�S 5 Cruz Bi�6hnasy ,.,�k_AKÒ��( Y-1� 1:50��|A]�*���>�IgG9 !�e�,Fsw�yIgM�100-100A%�Bethyl LX�� , Montgom\+1SP��VectaS��® El�~ABC'  (or6QBur�/��, C~�d�*�!�-M8�„ nti-��9se�0d b����+E�� 2�F�lF2kit�y.5HV u �� WritA<i<2 �/nt8"O a2 *� 2�g%j15����th�ve�}Soba Uni��Hospi\*� , � ��~$5��I+��z#�:al�:s� a�w� χ2 I)F%���er��4Hardy-Weinberg@i1:yZ��� elrd�HAv-�:�Y two-73d� ���( G� Padusm Softw+ e� DiegF/Iu�VV4�Q <��05 �!�$@r*�q. ��� "W fM�"� Fig~%����EmU�h.�A��( HE )xG 1� ,�cot���en nsilH&X2B� ndF2&�c��A2.lؔ�.e�#elf!B�s*.er�V� !" �i�SR"d 6_H ���D-z��l$�i!=>�[1$f�q!�*\2H�lj��� ,� �-dl2)� �>�it% �%WE-Si6��~e�'F�a�a�+rGM�&Y toV�dS�V� !.[A?��A%A#) �c�;# '!un!�a accolQ?&a�-}�'��)mo�-�QI@�5D-�B� B�A*��e�*Fni.� �1���&�6 ����mWe K D��Lz>s-o�+ 0M�1�urrA�� �-* �&�'`-�& >r!0*�  � !�>�!"# �no". �1>73��� as���.g fix� Zo �$�q�b� ~-B�u�Min2z);r|*HZ!~e�!��l} inteJ~ A��n/)�%r �pla�CE��>I�2E� �bi�[1nm:��"��W��&� &�h� �� &�)�IOJ&~t�E�aq?>�aA�d& �rs�M��d�xaX215' �"�l"Om[�'1V�d�Fs�n)HVIeF���IclC.f�<�P7599O/GE�o�oGWIyp6F !��e")k�wk�!t /e�26�A�N � Z� IA��3|c&�+!�.�� Jd*�d10}'R*��� ��2M;I� 2e&��>~%�? �0�:dn.&� re*L$V=�-"+!��flet ���.y-�&C le"�%HAm_��4� , 1/AU(� 9% )%BQeBI�27 =24 . 1>aI&�Lu�xUWx03 {H. 0:Y~>��,r8/ 67�V6JpA�9Bt�%-j��*| l�H62-�Pm�V��group�^:,*B$��Fat�}OJ�>?���_��'"�$��B�f N�*95% CI) 4–6!��_%SNPL ����y}A:�v� Tu/[1M7 , 2')As�k�`fw1�z�do �( A50�d A290G� ]�m-. AY�QE�n6jMuYE��1k�ta�&M=|Q865;.�,62;1�' 6–�1(q872B8128 7–Na�8 �C�F29no"�ce}&�*+A >S�@5a�J���)�,��2"�2�+�~�i"�+n+c��+�2.�(wW����#Ay3MM�9�f3& few;9y0y�.62"�9�Ks�&ng"�(��u��4� H"6F a�F& &�!>�o�.� �'a��!�pis pa�g&fTR!�� I't d>A � !�8two=�� �%��M{vicin�L` �C�r~>y5Cr7�x�hi29� ��hn4��� ��c�W � vpV�m����r� �ra�(.�Asp�%llus fum/�u�����in[ ��s .2"+ � j�2� on��it nee�%*,��6E] "Ce&�� k��#5��E2*� ��f-j:+ >�-�Jint�aBB��&1h&A �F��s�n.#f 6g s�8k,=Za�itB�>� ���3�FBg6&.� AEkA�i���G �9cWs/�epito�%.���'K���beW#$i�=a�:� |�%A�R@)�H &>*L%ka�6`�he5� i�6-��Y� m�&1j� [$H� ��u2 =,�i(!ޅ���.9^�i�  j2E�R\AS.��?�?$a1�)��()�6sa1) �i�@��dA��4!�alQ�U e5�.(=%w�c)B�"5��!= M'ed� �A��.&�c�Q�!�!Rm�&i�=�����eelA�ta�!qxE� �P�aM�.�A�B.f{.7�>�e�E��3ک���\47i�_e� b��*7 ���E>>v:� "&9m�"r Fg�TA`q �-"r !m:22J)I",bzC�#�B+����%�*b��t�a.� !2�1���:�B��3,u.:?qcEH crucR�� ���3BB!� &� E�!���.��vaga�t%�>'##7�->�a�oUA2�JasyiD5�.%refer�-�J};�M�~S�Y�):$eXAp5 ,FcUK�e�m"1�YM��IF|5�%[9 JL�| ���kH2��'s" oYBE * a!E�l��0"�.� G.E�I�ddj.��hAlbe�vor. :CHU .� s2�O�7 wild$J�1h��RQJA^/ta?)N*�0&� _��j+-exA$� a>�!��%�A��&��"&  ��>2�.�a;5M3��atParEM � �&�OR3!��D:-2�:�|�5y�n(�7B3�yM�1za Th2��p� w a��l�A*'st^M�%k�H;�:a�Mitc eau %^�cytok�"�Y >�RIj�>� IL-1<�IL-eL Th2-�i���hiz�&�a#�g s[%U]2^A��_!yq 5�afi9���?Z~�N* �9No1�3UM:!�"�>6�"�6�F.�2�E�� &:.�%d�e88[aHyE�myT%�: ��&� MW!��<�Gllo� �( MMP!�!���i�.inhibi0%21 MP-1iI F�!�in��h2-po�med ��.�&j1b�!vE�)EA��8[29–VkF2~�ouglijk-.N%,�&( 9)w-I��5|le%/[��I�"�FQ��1n"1��N �!>�S.�� �nA��Q�toQ1%�9S:�R� �cm *��Qz�"eɪ� ��9d�Elagab-�al^EX" Ѭ!���off1 � Th1�g�*x>5���.� �%�]��ofJ o�r�el�J) >t%�z �\�=EQ3E�+�@ng!�5y>m"= ,lm�>q"I�"fga�!�B�&*J:]��e�rD$"�unrav�Vact"�6!� $M��u���.2  ��a���of:' {I=�ll�"�$� �a �sn!�w�um�$5��pa�:%A�ld�6<on{piw� s��kac�\"� ��d1]0� -I�Ev��z�ex ai��6��c&�E&o=p�"^>�>��� f�Z� ���/!�gr�=mE !���e�u��o���"�$y�X S�!f2we�N�*�!A� �x�wmHDa�2OcA capsul�"6�$� =8��Lzp;? , CCL-5%A�i'��g��b�" u=& os ��wL 3!�)'p�?!x�l &=>A�ym�L! -� !�N.�=W��%��[1zT�x}ur(��>�B#ofQ��V�5� ���ua!��~��� �Xw�N�)�S QV�:0b*����6�� CENueEq1JY�e^��jlk�Z% b�� (  !�j��5Z�:N.�nHers=_ex virI�HSV ) X"�e� ��� viAafFpe��l�"ll-�q��}�Xe-8��E�է��p6Hqui�2�)�;c�uJen quh}o��e2M t!RA�?$In�2%�|t��.�F ��6XAtr Kptsg��X�d%E�h�/EO&2/�, � �2iu� Te���s��֮rv2�Pdu�k!C^r$6Q�/�&�h Cre-v�a�f�`ho�b�Z����1��wo2�˭d�rs�.�q!�sp= �V�to �!�(1/��"rbey�!�$x�s�EY�1�eb>�%n ��otO:can d~����Z��:ft}he;e2�Drge fami�vaP] m�.r5�K��a"�BQ5=�ir�,�A3 ly u�71�}G+:��'av�bsK ategeGR��'I0SV-$AˋvK�M �v'po�-ch���(��u6(.!�-1t�!Fy3 thro�LLmVuco�Zsurfac�$� niti��=��) prim�3IC!�%�rapidl��Au"inner!3nge�� neur8��~ X�lM3��!�dc ݛ-��?�]�ly 80- � �:� ]ascade�/pr�im�e β( I�1���( At�A ( L )���"P8"5 .��p�YJT �xa����N �v un�ko�oi�sE���Min���.h�i i�jHv�u�odMK��!� rene3episo\N%9�9� n ope�>+hA�iEofM��cy!�X�i�/�nI� A���Ub"E9mus')In�Hse�[� ���Ea %ta��iun%� ,��c0 |!����pro d2vg7^L��N��vivo [�`�r'<'ŁY,��c����o�2b��+deA� �*h>to���RNA2"�1ua&Iu�LAT�[�&�JJvã�%�|!�t��re��ve ��A-)"�"r�R�;q)!�>�N)��,me2`��i[1�91�(&E!iWj�!Ein�!An�ya8oH�U~aONs�: y;7�+– tIa��@� )y� ��otR,ol��/2�e�2 LAT E I:GA��!]� a�[2�HAg�a�Ysel�O�� 2t12�moa>dor��$root ganglTDR�))ե����u %�,V�_ ��o�5m���t�|�all)� tly-i�\#�[�"�OG1>ha;![su�|J!��!Sa:�J�!� of �I�9<�Vs&R�biN ly re���� �Direc:�KPI)I�e�=QaBeS�|�nd�o�A-re2� G��y ��&�= CD8+"� aw�L�1��aSqTaj%$&�� �7>� |���� e�3# �� �&[2&�I8�zm� �&C57Bl/6M�/ ,]:*� se�-� 2�re����#2����~9lyc�0 B ( gB; gB49Z[2}>29]�u �Eq�A'{2a� ICP6� Lt� tl(�\ �r����ROSA26��=�i!�)�� ac�A�sH�mb !�� N� )L` etect)��JaB/(owq�G alP!�� o��30j�� a,�� 2&�c|�& �c!4q� ermaQ�\vrQ���A�5)�2:talyz0�8.����w�e of LacZ�����:!gk� o\"�D 6��ya�vgn�T5ded&�as� E;*� :� $c�A� �{���ab>�[3�#32#a*P,k)1r)| }�M���FW"! tes�'�hbridg6gap"CB��1:���/%h/�RK�L"< �a s��IQ�N#I~�yc{�-6v �M-���e�jeYuw c � , 3�  �W � � �O �*�� �t�A�g υSa[�qDe�M;� ��] . F[l� �D��.R��"��8GFP/C�$NE��Li�B�m�UL3/UL4-�ic �"� KOS-�A�IE RS8ICP��or US12{ CP4`Ef9 6��B UL27�� )!-QB&�1> �I)pC_eG�>��R���1�H[�+��dlo%Ua���*4CMV�����R�30�F���+-\ex�ed |!2%�%�&�"T*��ackEvi� hexim�>��by SummanM eb [��1y5A&%�or47II�� !!*M >xAs.D �1b8 �qe!1 �� �e�% E�pculnNs t�t��( S1A�S1C�>AFQN�~�%P�'al1��{Vzz��,( S2A�n2E m!Qy u] &nu !attoo& " � nFnH nnV!.E��� /Q:%C�U�� ��B m��xpl�E-u��F�5=�+� NS��1tyR*�55ai��)[340�1��M�6�AD�g^�y�.� F� β- �ty �%�R{ ��U-1"z0Zen���I�3GS35�[�&o=����qMI�a� e%xc�HwH�$�d � i� t�ajw{^ �� ��0 c��-���iod�%)r��*��A3��stablrO� z�9~�Oa!M'I�e� �;E�a�� s����/s e��K�%#C$E� ��P%�a�ef���� of!(?1#y-��*i�p�v_wh?aܣ� e 9ST�e�  A�Te�$a�X lank��� �'n�v10)�.��&�.�}i���OTe�aߩ�+�>�y� at 9�s 6�i �%�D,2}z �����Y �� ����m�con//�8S��Si��y�V,�EJ5�eMIA��. 6β�|:r&�es �f� hUL.� �+� �!�s/�+"^ >�� x � ��9�)�^�7 at 46�!�;�pi~�c�L!�QE T�;:.nq#u'� !�3i�3a�t��Y,A��.Q)�vnyi0��I�a�T�/1"�t:U:�u|e_!9n�,:�<U�oM�Fa!����3i�>Vid�w��Bw�8}�$�Uy���~as�a�1�,a�Í�ay�R&2V �]_"�i� H{!3��� "o��cy��–�~�X �F?l:A�)�p >���~Z"ieHC�r!�![ �10�:s"��U ��CakMz�t. A��al�j>+l"���ofV�b!��[-�d�az I���:� 22.� �!]rE� �)Q�on�9&*�/R %�� '� S@���� –5mb1Yby%h!t�����"Jout��s ��!~.x`u24"F�1x�F��}un���- z�  �~!�(F�V�N�o %eQǔ�UVY -�D!)� �.�AKeH�� %�� ��mUhel�Zl~;?x=*B�'�'rE���aAoF[>D%cy�� ma1wo wee!ۥsi-A�[=&����cA�姅7Q�A5���ED >!�T f.�firms� �o8i!P��r�.�=M�S9 h>�� {� sk4g�Ca��y�A^)!��� >@.S3��"y+�5���Q�+לs�`�[�*��6�[&��>�eterpret?,%�?-!ng��FN"���!�QQ`�� �.���How� E�qi� �N:�� ngag#> �e_Q^�1"��*�L.�te�U�(�E�eY�� 1 a�1!�ed�A.' ��{��Jm�C14F���%��Y��� ���n�@� $I�au:�Q2#v��QQ�8�L`�[ae�9!�-in6�[3@%i2R.|Jna��(Ɏ�mAd-�e�� "I .��#� do���:s now!�� &�,� կ�'�**�N"� �m�qBV{2;40�N2� �3"e��'Q~ɣ5O5&Oy�I�J��,er� T4��+��E�A�<G%710a�2���5�To�Q\��#   �Pa�z,U��52$d >aOf� *�=�u7*!U"�E`E��O-2�2k10��& �-�^lsK'^���S"�|B6!5-��6�Z.Q5�c"@6%�AiP A!�ouH��gB!Oa�)��*]ed:#���%6:^b�O2�ithm� ����Y=(mdSk AX9A8 �A8tZF�"ƫ�Y  Q�P0� �}+:�!��"�_an�jNI�#t�9|�� gB.f ,5�Y��ym:�A�E|�a�8 ] 2Q]^F\u� E��Q of�>%��p^>n�=!2 7�� al�s�", �2��%�a .+1?sE�!���6D�f:>m"6�A�FC� *� �#��D(�H#FZ � �e��� %ati` E���ep3Q�f�O@dsJ� � !MWN� 1W4�&5jVIt�E+>�e�ka )"��stocha��V� a�Yteg�%arw�kcy�(� �/I!. `- M2�I(�a".uvP��&Pon! b�l����PV�~/s ��n�me5�ism� , 5�$��Y� !�r:onshi&�$a2l/a�)�>*t41b)-I�&� � J��`K1���a&q-%�"a�.t a�upU ,-�?repean&ׂ�A� �hos[2- !{b�Yty�H!itA��10 �C � 47��m�%u�*<042s�jloyl ��hp4 -mea�:�st63[3�G3��" �SI�TmxedE-ny����He,"D�I�! CD�aO�d)�rP*�y.m�� im6�#�"� !5bV�� ! �a)A)"� )}U&� &�:'Qd6 .� A�2� �7F 7F S;��� a;&�Au>bͮ�^!LIz%erq1na��A���1[mri��e�!�F� � nd��a&.[�??"�,T T"z)�s:*`-� ���2=1�� %�479��: 1��a����aj*B% � � aS��+� z"� �2e�g0 was not stat��istically significant according to the very conservative ( non-parametric ) test we have used . We note that a standard ANOVA with several different post-tests for pair-wise comparisons suggest that the rise during latency is sign�, but �dm�variance and sample sizes across time points in>(se experime guided us!.Puse a less powerful t!. The un:cted fin%cof!Z(tinued mark�,of neurons d �� establishy$l � ( days 10�20 ) was3n\,firmed in an� loom!� dditional�0s after infec ( Fig 7D%'$7E ) . FinE;,j re� ableC � by$(ICP47 promo_ p! three �controlsfrst ,AZshowed t!��us virus� only foun� mice (ed �i.=V acut(io�S4��Second hmonitored eGFP from HSV-1 p� _eGC% as%g%�, frequA�6expressi!��det -at!�4 4 ( S5A–S5C� Thir �examin% eA�e>Zinser�!�M�� loca�A�us!�.fluoresc+protei%5D�F �<)eLa similar pattern of2EQas e�B/$. TogetherA!(se data sug6�%`�I9�^here hI�!W)C�=ki~spread�I3I�aZ peak >, coincie��&9�9� of a� driv%a,n immune eva%� gene!�tA�same2e i�atrigu7.�=B ��between�>�!�co��tef1reA���an ongosbattle_-%@nd host . Howeverm�!�clear aA7dancy��@!1� ingvi��activity� hard��ob�bea�convenA�al mean� urE+�r�arisoEwDposx �to� ��%1Ńsurro�;� Y�s a�.s perfo� .� ňtro1 vo9#>� %�not�7!�5� I�F fail �AX rate%eDiY by�system�] plac� Y 2� e4e)�� �"&I��(����_ model [29�Whi� h� l�ly�N��!�8I: � i}"lima2Ra��o � new��sWedy �-� ɢe�n� sa8 evid�|�increA�by����t��b* ( e��if�did!� reach*��7 �E�h I�5S,��B��A�Cal��to*� �sA���%�at�arEtoguntvB8�� tial.z�C%�e�l� !z��ieffic�y!�0loxP recombinI<��6g+Q���ed� gB ar ICP6i bears" discu� eC)�e%_l early>m� :r!�1�s%. }nd�** to� �TrY�f]��p prog� bey� �g� ��!�1��*�iphA�ofh4$. A coroll0��is argu�Q beca.weq.< I �ly grea� buildupLF� th�,9 in6]É��hd gramM transcrip�%is!�tinct)�(full engage��e��cascadeEJ is ,E!�fTCe�!chiev��s -�2 ) ,1� s agIHwe�� see�Za�ti�A�I� � U�enm�ewZa���olecu�2^4[12] or stocha< ( noisE).= [56]-0s � In ei� �s!. outc���._c��bQ!A]� resp�e�LD8+ T cells [25–27��I�o �:�A~%"direct�r�J��s!j%���|YqHcape'ofeCr g$����6��. FS ,��j% e!G� edɔa��gnR,A0� lin�z�.;of => �EuC2T DRG leіofA�al�.�:�. B*� �� na7ita��o�spE�|�.d!7m�o� �adapt�-nmay b� ag�parT  co-evola�� -pathogen�@onshipIwe-Ce[ N 5� � e�es� growvd tit d� VeroM�L( ATCC CCL-81 , obta�]� Amer� Type Cul@ Colle� C�5010801 Univers~Bouleva7Manassa!o(VA 20110 USa* ,cycloheximid Dal%havihibI`Mye&o in �SUA �[5e� BothA�1 main �0in Minimal Es���lMedium ( Life Technologies )@l��q2��10% h�6�M��et�lf serUSerana%845 mM HEPES , 4 L-glutae%\50 μM 2-mercaptoethanolZ�� l�_AM carr+ � in 2931)()�4Drs Jon Yewdel)LJack Bennink , NIAIDH )�$ Lipoj �200�NN7.��4KOS . 6β [39])�roa�d�z4Francis Carbon�]V(of MelbournL Australi!L_pC" �5"/Tdtom��l0previously de�bed[38��aM�  refer �loɯ� a�geoccbJQ673480��riefly� { smids"x "m eu�H( ntu��� i�a�3 /� f���( ample�4pIGCN21 [58] )ENbovine�th horm)dBG!�$polyA term� 5F]Tracer?/bsd;R�,Ve-5SpeI sit�$pT UL3/UL4%|, along���\dՋ��!�JpgB%��s UL27 (��)>( 5598� 5628� :85� [59]���� 5��!@)>i��N� ICP62� 39 (Z 2�085920–86166Zb�60��Z�4^-US12 �476�)54145998–14649#, syn* i� by GenS� �%OV�( OriS�q\ (f533f557f�d%�"�\!�5�./!�n�*d>h ICP0=�.c 1271 23�na [3F�>B:b���:�B Nd)��5�I�oruhlineariza�l�� DNA�~T6O L IW Tv!0co! �X�;*�%� ��|icz. A?� days��Hat 37°C , 5% CO2 ,�� ques�F�]n � si�B([ t�g"�!�>$ PCR screeY� f�N�pl� pur) h @.�:� �!�U�ran%,� of1�ap!eA�E�!�%<,pX330-mC fol�y�C$ gCmC)�*?a�F> ��. Df?asf>a�mCherr2�)8�L9L6Ju�_!�%|�to ens1� a\` 6�d �m�*�Lf^ �aal G . Conflu/ monolayerEE�&� � \Prof . Stacey Efstathiou� BSA�UK�$~pre-t�� Vμg/mL:m ora &j ,left unF,,hA�uME+mP��IRed/an MOIA�5�<or� drugA\fpri� q�incubi �1j�ɩ$unabsorbed-qA|�&!�re�(fresh media1�A!�.��B�t� �� � ix h�Bt�which�Bu� " v�51�q nomycin DF�6�a"4��!�sJ�V�harves�, fixUc%�a�aldehyd� !j!E*�of�.�asses��pf` cytometry a LSR-II> ( BD biosj� . F6Banalysil&-%��ai�!6DJo 8 . 7 . 1 softw^( Tre6r�y�e�A�.�in !�w? p��2�$5*, x 104 PFU (e& 01 )M� in 1 mL M��16N�� ino*imQ�I�6�%lwashe~ nd 2cI�M2 adJ&. 0E p . i .pl�9�imE�t�I�%N�%!� Y&���!sLat �&c� p�&��xig K. V��put��� ���R#o!�sM�%��houAw!e*Q'2�.�(ethical� ��u� �$Ab AQ6$s Committe� !)"�n N��al.�(��tocol N/!s A6!�0�15-]l 025E�� work"l�U�} Code�P�CA�!U| ��Sad�c Purpog, 8th e�' (�3fO.gB6a�,29S4-Gt ( ROZ426Sortm1So/J (�� �s%2S mA [61]"�^ 8 week�ageI3J! n Phics Fac�! ( Canberra+%�Y���a flank � Cwi! 1 ×j�:�ˉ�Hib$du�hs�d Q)attooQ� naes� a@ap"$toneal inj� oiAved"!� , -TribN)�)�NU �j � doseEorou ) u�e��L�.��1 cm2 �avsk~d(��+&A��"UsA�SI(� ipsi����H� o++�p�$L1 –T5Ic ed 5u pG#� �( dpi%�S�or��hom�D �A�H g$%sub!��� &eE�aze/tha0�1K"�*quae��%cul_�$02 asphyxi)Me!Hre�nt�шas soon^l)�3�F1/� 5% r"HA� on a� �*�)u+ whole�� y)C� �(with phosphe buf� d sa���Bxbe�" b�m1A\n g�'slide� 50�yceroa; >.�%�visuali�p photp�q�,Leica DM5500��roscop)2DFC365h�"e camera2β-gala([At� � ing!u)�A��- 3�r#+� �0 H!}3��)%}inL mev s Y solu/(%�01% sodEdeoxychoa^�>mM MgCl�G�potass+f�! cyan,NoA� @02% IGEPAL ( NP-4�.i%�; Sigm�r�E �[j�� !E1 mB X%j!16Ir[a-YEc!QF�S i:/\larify ��nR [62��1W��J@n Olympus CKX41 lQ>R# DP20YMLargeMI+4 E, assu�/ %�th&��e�� %�$e ImageJ"[ [63�S�%*A(yf� PrismL ( 4A�5% (1; GraphPad�uD�!& �,groupe�ale8"V1{:� 4a Kruskal WallI est �Dunn’v1st-Apairw�.�R �+a :�29lisAv�,&$� �� chos(� iZ#q|)M(least*b+%�pa�!21&3 abn!�;ur"� �)��a; �.��im rva�X �"![� ��2E!�2�Z) popu�$`2 i) 8ed .�MisfoldapAaaggreg Bof%j�s�im��fec'��Le�2de+r)Ydis�$Aclut Alzheimer%� ! , Pa3so)�frontote� al d ia �prA� ,�$In!:�n0}ť m �Ir߁��� a��a mechanainvolv!,see<oly�z)2)�6�,1E�ls�toA�m�"au ic *ase-r!P)qorm! rPSc��accum!� ��-, astrog�!mic �(CNS�� �dual-s�i�0ohi�! emis h U?!�� �4 �of ���atu$preclin� {m�i"� �r mo5$scrapiea<aiaYa&i�b regJ$I�logy . � ��in�)a B�/�5I �a22L�maiy4a+c9m,< � :ME7n:1�!� pi.I�(alamuscortex� VRM ��3to�50n� E5ia nig J3�>:,90 a�a�A���inflammI�w�ud� � �YQ)�m�+%}tɁL>. SurpriA�� desp�Q`�$)�ne2di�=�upregu d ���4�3��Ik)V1!!�zsm.wQ#ed!�o'1��t!4=b'�r �� .�e�aco6JU��oc bJ!YZ�y�deI6in:o��rAvacuo�%�Weor u�+/�& tere�%��profilŧFGA_m�- d�( edly5�t�#�U tw*tE#�z-sU!aC}9eM�BE �Ytropic F�1d ret� $)ASte��&e glio�yat21�t:.ion�j�� Sev�E�֭( AD �#V�( P ^� ( FT"!�!�n9�characte�by6��/���N��%[1 � *^ђor A�v$%E\chf�e6�-�n�9n;.-�3T��iappG+� �(� ͚���AC3pro�!�[��X2�y !q of o�(nora�8:l��()9A�s�71���kn�%s “f:2�” [e h ����:�,��B"�%1!�"�dQ�� �~�A8-Fmdja�9)G�i�ti�x, extAVsA�m�se 2s%G�mi����5�o�.?vi1s!&e"�al�"aye�o&�2v s [4Q�reali8 ��RU� au�Q,+�2i!+f=u'�sE��0��w*Q� �$i�n& �� �7�!V%�rg��!�](�4Y� %�-�+�.ec)� many eVa[�7One go = developo monšte'I rapeu�4�@9�s�$VP.0tAP6+�kslowly!f0.^), usu�=fa!�IV5%B�aF ���ɇQgra /�7,m{'nt��&e ^��de"S3i��.d���e,6N isoQ ��Nor res( deri���** encoav�D)� Wi� PrPC B2 ) [6M�.6 occuuly�hum�:a�ru&!�&7q���to rod�;an<�!9 , fePA�mustel�&LI�a%!�I:��~a*9 ) es&U8& ;7ai� v+ haV8B�! primarilyN�6��� e:��alMa&�aI�"�end-p���5�.expla�1� A�� ten�Aof di�L  pEtypI��gnglSx i !�j�-IPrP5�� �=�/c$=.:C=�8'1BPrEv��6�o�.L�ng cer� D i sM<Ws�b=�im#&�4�  ��|1�))!�5)�y�F�[�+�:>��Efoca��in-h M�[��!�U.$�^inx�War�Z]1nd/i�Sc.$$[8 , 9 , 1&�a,3p�!�-ls�5�* �>�� a"�E(*X �)QA5avFor"�=,A�!�Y�sheepmY�<d��=5s 0or:.Tqto)�I�9w.[�2P ^ a�r�� a [1i'1� hams�3&�|2G5!"'?=oma!!�J�Q  A�8B��E �cF �sh,"�"!7ods [1In�Q�� , morph"F&�xf�%�R2n!�V�D )�s;���?,��i�=)�d !79A!'�8 l [1]Although�A.�E�.����� :O3kexten%~ {=5�ab��7 obscAi�2A"��ZI�ֱi`���4.z 7.t1�l�'6�y"iV�=#a�� woS�:6Os%�,%�!"Jat 7791��!8intra-hippocampC�&,�b<%�s�?i4nd,�0 phys �B�-���ficit��5q.�s `��A��2[16�Q�Rec�A��*�cereb�:�of% 1+i"c�&w3�;b;)� begi#1g!I�,7%E{�%a6oftN? n bl�Cv�$l� a~F*q�I�!^iatum [1�0�):�6�"�8��ew �6<at 40�� *�&nZtex-�:02–3 mm caud�I�KY� [19]G8!�O G� aZ need=rc2 H i8!2� lo��Scircui.�Hs!'� m;:.�*sere�� Er�>� ~��� � est�?��-��2s a� sK $�3 tudy! B� -�#gT7irY|� Ae*?�3�0�6���a a�� �1!hQ�' �o) �� via i&5.by��3�%surgi�i�1a d'B graf� Thu!��R v�=? �'7�pTZ c�:��h�es� %W ,:#��i�A�2K !ge�8aT ��D/FY�}M��+mouse-�76 69A2aE.<)� �ݍ��:�Mstm�� ,avoid artifa�st%��ed �e>awa"�e6h�;�G0�dJi�nd mid��:%�F&, �A�ald � �2"!�6���a2!MtoS o�@��2 "0 �i���B�rI(-� .Cof)X->L�D � 36�Qt Ac� wh"L 5 >�=��"� |-!�"�'\$���!�:QJ9Q[425 :p( ���!�pGFq!�a~����"�J��4�OL.�$� a sv �:C-�' �mch��NRT-�/) metho�Qjq� � %*�F ell-:�iaa� !q)�� 9e�@E�.x "Z�O=sU[1�6Z+a,6�F$�i/IL9�e�m� ��{n�&rab��O� ���e��N= d� ;A��'9 a�1��!� � �B�M�cur�.�wF'�`d� NN,m�q1�(� ,,� !)���X:Aof$/PE�;S%n'�%i"))�pI��22��a/aI��4%�2���oT2): �Q$rS! Eis�Fd,=� T6�:�c�Bda�Na�D�%raumahA<) l ne�/ �api*C�G.� iL�subNtA����9 t��c��5 ��g{Q!�2 r�[Fal�5:dt-Vb�n[$"4 � 9  2BD!6q�8+��m�n�~� s%%��$byV� ( IHC"+T#� )f. A"� � !|0Rf_�SE%�'zE1C?f e)"2% HO!�[rfC� W�� L@T1`UI�BtrP$6- W��FX�eas���5H�;� a�+somew�}�Vabu�Qt�B� DE�1F�%)fa�paMZ2L���E be dueQ�10-25-P$iIe�m�,',�x��to2Q(�ͳ�r!Bail��e�-0E2�K!i�22�tha��Mfh�PI@fD=��C)~.%H)�� l. C�"&�deg6�@+( 174��=�us 149�!N�Ru� qc e pert� ��v��iw � cour��-�o#j?C�%8��lyab=<0�o �/ a .�!�mlI��0�!��%IcR�'Jacic�0tissu��rLMe� �a�#'!? [�bl�S nd d �4E*��-�-� r)�19A�or%� hand�B weaka����m� mork(V60� � ?���M��am4e�ME7:B�3 "E��-cI��� visi. �}� %�e)�%@��"�"'/E7� D clos6)mb-ad��!G!�A���(3Zj�d volumei�uR2B!�2A2M+TTE:Zan�ar reli% )4GA��)e�suf�e�xar z))��$2wE�y=&:;�2;w��e�r�.  I�u= mA�at� �� s� :�of"| ag�5EC.�� or%U\N2�'�3peAO�)?� "� i�\*-Ted-d. S�m+"),j#��t ��2� I�A4!q� gcYopt@Fi��)�evalu�&]��6��h�!inEn32B{)DE��a:�'j��Q^2 p�� � GFAP�3A/se�A6?Iir�A�y%K�ES�hI{�z��aAP�OrX yetMLy�cH)ous�>:�secteK��of �[2�&M weiK�5 ��1a�r!m^&u>ng-����� ? �ed v�.��Iss"�*�\3� BY(�z�hKnti-NeuN@� 5a,%�IV!��:�;-� v�u�_ ���P�% occa�0J>�< ��?2�) ��%nY �lH/v�9�U^�{�%� ( bl�a�s ��D2�� Oligc&typ�ly�.arker � olig!"d�- so�k 2�V����(�3'ɞ.�.c�'��zLu��r Jd"c*l [�OS�+�=�ʭ�K �E�= �g �s�'f5AY)s1a"�L�#denuŨeBE�I.�a� �t� .�:2��0c �6F��!�A=-e>� R RibY4ver�e�ain�  .��hu�.�ܡN9Osee&t4m��.� � lso.B de.��yUy>����3a(�>�YJE~TR� X$y tI5%Z� � d)h�^se2% --Nff !K� ��F<�3by+ %�a�eD.�!b5Z�,6 �`A�M�i .�YX�qu/&D %7an� dM5���ME7- k,��ori���`��)?Al��a:�9�,=�-a:��CI , 3K�\3L��.� t>pVn ]J3!�I�c,ɝbI��" umer��a26-var8size �� %����0 lI� �i�Pn� ,2Na�m�s0�&&�(2�s��2�2��X:is&.&bNI�w�\n�Z:B��h2ML�;� %L��Ɲ�MMb)��� Ny�5"co�:�2 ( sn�d hypo" ( h- �V� %�Ps%c"� �Jns y sl�9ly�%baU,� l�3*�a� Ra1Ba\� : IB4� �s6�ySA�e�azn�4� In!,6h�:�l6���]"� �%� e� *� ��41.!�R%N|f KE�4xY 64AX]U�:cM�1�e�>� iG i����-�z��i%al�d�)nE�R����!�c*�ed�9t�.�~�R��u75.�=Y��>6�a�-l4I�D��� )�& V���L� ��,g�E:EW�� *Y2qG-���A�)� WK.1>ly ,!..5 �r�`d)!�M�˵��p%�E�%�B�4��aWumm�+��5�6 stag� &{&�ԭ  I[� ��y��� K� 1�5Ty7�&� F*&k �%� t* a&(r<m�"� J]�6Jm= E�%i�Q�U�Ar,.� A\!F]�W!�xt29He"+:1in/Kigt���gal�Jc�:D#ef�#��Q2��o"�: b�:V { V�.>M! ���!�"�%�!)�In�/�..��-�%<�#- ]� deathA�cu[5DZk 3�P1T&�a�? P j3�l�ougFh�1~�"�!���[2RIniZl8DSf "��=6�@ERK$MV�.&_:-�:A�2� Gfap�ViH% s�8PY�Gpr841Cx3crJ61yt��5A.5�[2�U{T.. �A"/� !aSo"�5�� !Ci*� mock:�a�"�5heE?i]'IÁ�*(i�[U�%[-Wby(���� &FT�vL�d���l��wo &���2�mPLTW���iKE/���ˁ��"� ��!Sin��A�Q*,)X"�!�!;�5�until 80�-�� 6|".J=�aI�2�+a�2v_�,MV E�t�=by!��R�E� �|-; Ds�Ihm�1�d8 2!�)rA(1�.�!~i�z&�1yIndi%"Pra� �+��.l2  6� K.M�1T Kld)ngeE�WIY��S$,A5A<8*Q: lis^32 �.�2�tH!�08'd�:�E�te���0s8#ż� F�Fg�+ wuqe = �s 2�3��1 � @a �E��)uc,��WaJi�a92C+��C. W�%��Y��&D<��E�e� �t.< �o����d� a�] aKI�.�!R<�F<�  cutofa14 �e+ePAX�"F� �(m5TO�B"Iatap$!k[ �ZE-p�A��0!�-���Z-��&#93cJrd�&q��q�u�A� FAel~*�+B��A<�a W5��C� ur�-�)�Qdq ng� ���.�"q.���� t�%F aze- &�g�=���sC$O.�f�6��� "� A��:�?^ )O" Ib�a9� �����$ib�E�*KF61~:�z�$�l)� T�&�n*�d"<0���!�]4V�i#1Aa�M�p .!�wo  A�-+�LŞ�kin>1Kons: "�FWY( LACV=  bunyav�Fc,A��phalit�Nn childr8w=2ce [3�; 34] uWviein [35�f�EBE.D�Lc)pl�*`G� \��3�7|i�<[eRin you-Z/,.��G�a0-�5)8"&)�@9-Q`w ���!�Jnof�%���"ie?F��pM�@ 2�CpqMI[37�:tH"� in)�.ea_kil�&)gE*Y1��Or�`leukocyt' il0lA�MnSiph�[3�X3�!�. B $e]��N 2. �1�!��U�᫕f��{ ��%�E��847 S�!�!��"�o!�.� m� j$FH�?�K,!+�!$1>v�+���<�!��m�w9r,�p�RlaA�^i� �ꍡ�c9�R9�2/&NGal 31�b�5*k%5}by� ( S2�� Ccr2�tR65QlaE��e�its��by �Վ�4Z\��he 3 �!���_]�/ur�;�A}v���} � .I� �{ cyto�{ �PqK }��vqO7e-.��T$)x .{fMI_�to �,�*��IB\ {g 7 ~! r�FZ7i�15�N eOB%��qED Also<{2l���<,%�"a�!R �&BE:^]1e ���)V.lbyEAf]=` �57�, ( S3.��1E�inL, *�#:� SA�a�>>X��F!�u�a�BE�1$%� � �w%�&� t��FUN[ |6!8Z!1��>!l��a4s��.� b~ a�%in�Y� ]<�"�b&C)o; G�(.{a�x!�=�I̥*NA!w�(� ��IH�8BE�. I�lA@<�:we� �M�$"� ��&�=.!!!N"46�5)�!�OU� G(##.�_� �]�i6ad)��a�#�LŁ?o �!l"5y;2��Pf �P �MoAxS M#�? y6z�9� �.�a���m.k wj�$�34>[6��Hom��w%[40–4�:�U.&8�� 8�����Out$96��7�&LU�7�oI.AS�&or�4d4@"O2T6�Q6Q�en�%nC$ �:5H2uFm"d�Te��ys�t{I��@pr���-/l�>7��F!�)��?ci`A ցT�&9ssti� flui�IS/!�D�U�(�uE� G�t^MQuO&�BafU:p�<,A+� �>RAu�Y�6:>�s�&�CG&+<hpi�nr.A.�e�V Z)\pa8?hym��"-�wN�� *�E�!u:��G,6 '��B�. O���w2�)?�M6,��}�a�ID�� .�H�at 56)o E�|6�!���rb8[4?2:� �4!�� �� �al� n�� �� �z�* ��1�i��P�e�Vnc��","b to K;ٽw�aty�a.[1��K>�Q-�q�9�b�x�ypr�9�7f 1s%4�!/>���M@$�H�)\co9Q!f�!�.Xp^�h k..#� >[t:�%�.tm�r75���aG`)�"���� � =e1�$b�'d3. Our=��F\t NG����8a�dBw79"79V�J�-m!C]zt�nd=!NA�al:Q>`��MB6�E.0 Yc�.�Iz&kE��%)I!����a16� H8�1un&'bI��X�^I;u�t��m+ Grِ� ��V�U/���C  A %r �� o0�XB�impac�!�U�&#�" J�AS��#. Pv y �.aBe-%%ure��*o � #a�&�+��So^���dx���A��&�7to�{g�F)��a�|t/-I?�b13>Pb\r ( 6�?yof.� 5Fur�J%��t�h�X ��YK4�F)pQqt�_��a g%�rec��bI'�[�E"<[i�al�c;N�� %]bse5)�Ca !�on ?�Z;�m"DdRN6E� B��p�fA�� b�P�a�Perhaps'y�&�\*ń!�( co>��_ )�=)wa2�\28n�>W� a\ng! 8r�`S� ��{�� r!} surfyB!t�z�embran$@5/=� poy4�v �e"p\A��O�� )�s$ y�.�,A�e�4E�1@=_ favo646* ��Z�����R.�[5#)NA��� 72,5�j�y��)x��?Cndr�2r,%%9&�!&!��D� . If�!���Q x !�fut�S� wA�O%u�5s��w!Sap�=5I~���%����G� pr��� )eapp�*o����%al�%�2Z�+\� !4a�a~�mmXar�%>ty�5a��)�]i!7*�H�ol�,�B�V!22dA� "�~�/� Z&'i�G"�a� 2�v4(qA�F �&9�" �T �/ J&2$]:*�@.ws:u �;&Cpy �&!�$�"[ * &l"�/&�,�-�B��v"�b!$�R H).�!#� injurJhB���&2�D�'1��M��F)b!�k"Z-�H��C�d �!3��taJ�hybridiz�2E |[20 , 5 5�Ye#^ )�2�v3<0� "�- V0A���&�+0t{� *�F���E�e�� �,!�W�9�Utt!�2�� �uA�f�hr M r�3���ws% o+�I�*���S�Rd&�W�Ub B�@A�Qvn",Bhow-5y-,�z%%:�I&� � c!,.�D)�^��j<���m)K) �S�&l�.� �V�e3�� �iNC i�l .�a��rs���^� &mH>� .�-�! )[�� ])� ���A!5��al � �2*� kM�{A�M~) )AM�$'!�� d"ju��bR� ��� � up�u|A��pe�#��!�to%{toxic"�2�+ �2+� ss5�VAR��O&� *�)�ng x� 2%"5Y]f ��2��Qp&N�-��nm2b.UN-��d� o�&� �IU*�e"bM'����~uiF�.�ZEP3��3���i4lig>J.�Ky� .��:���%,,a(c`(l7 �CclMj recep"� � �a�Cxcr3L�(� Z�eCcr�skW�s:y2l�Zs�Gj�di�$Urn;ch *o�[60�[͞A&�)�se�)a�5�m: �\xg�Ccul_e�7A�2`Ero�Juښ STAT���NF-kB�e2!?��]�MV8d���&[�� 6–?�. S��9��C �ly ��1vry)Z�9ryele�e�!�(-�s:A8�*6J)&�h!�ens�N #snE'!$ Ccl3��!�ngyee0I��\i�K'�\  �Peli)�=f e2�E�6�7C �E�i�[+LMor45:4I�� �8 )�o�Ra �x� ��~�6�3:�iO.�xclgde�x)!y+-&� 30� v%R:-w*� %L��2�� 6�*�x�f���a�8 make*Hfoav7V�0�Qffft-a}HdW=0du8Rc�A�|Jy�#qh �9�� conf< �8�."��f� (s. tane�Ad]ĕdr��ʡb��wd!cbe OrC za,���AmIQ}N!s��"-,\}O ]�Z6�! ge�&��� � �#R h�E2U*ͯ}���Q; ��e�o%� �|s-�gje�arF�BZ�էa b����`� �6� � ��W� �=�(d tau/y�5[6a�6H2J#Ab%T �gavZ�}s��L�~�� prob�Y3�iAo")[Z.� �a?&�Q�  5Te2�>J��a7� .�x>� ��H����equ�densNa�.Q��o��6�!e�%���(A�.�#sA��0�[.i^�Super-A�&:#. S�M,2Z� �oK ng��!��)������rlp0 � _2v���O�!EY)5� 6���~�� %&.+ yq��%Q�Q!K͋%[or!Zy*�.�j��l�)�\a1 �!���)�.%�Z�)�A� "-� �n !��2@*� � �=8 :*>`"� �&V 9�"�!ss�(m .��iwo2n5���uۦa�A�l�IOq&Ue$5!�&�*oX�4�Qes)*%[%�.���A\:<(%6revea�; � a T��n swn:��i�&u � "�-.��m�)15Ihu�,B>�)F6�YyY�E�Q7�exbceA�,&V�!����Sli<r�lGo(!�Aif�.?���b nri�wasL�BE6SQ�A/=�&F2�BE���Ms�'�e �al�[�#h�l"r#!���w��d�� Z2��6� ��"?k5 C(j$A�BEi1��U��,p!2Ap-N7�$de !G&�@s2B>� U :X��2&��*G�{� of G�:!�� 0Eea�� �/hsoth5�1UWJ!�N .nZg"�+%v�QP^w�� �2U2!F)�"c�!<*|��63v&$z�B�57m5k�f�K predicA�*-imn�;R�Y��zli"p"o2�a}. EachW ��/�V"�%gC -1 �shE��%$�u�J��in� a%�99�&�tak���2� V=de�]ed"UE��/��F�zj s$_��t E lex Sse�%66� "�0E)2 ? �ly/+L � ! X�halleng%roblemՑ�.��m�9�WҎ�Rocky M��a�0 abor4(N)�0an AAALAC-accAF�f���*_�Ežp�liG�v }�*Gu���5>L��W� ( InD*�77B#@ Research Councilr)E"]GIIfU8ed� \6~&}��k?S^�s���0JE 2014���:b�L/1͞C5b�9j���UA��-.� �y/N$  inb��at��Q#y�|. Y�6adult m�yQ ighA2� 30 g)�"> � Reota�c"�`d"��"�*� a�!���'� w����xa m�6u����a�*]A�Lau��E� �EI��j�estock�x�'&� T&’inu�E a pump�f`�).ݟ�-P?z.Nhkud)��a�"hinE�!�)amp�I~! ID50-T; ߥ���-: �ɑ �5;E��{�3;�,��3 �@"=gP<�'o&@�-Ņz)��Q�)�a�-s:-c�5 b;v#, b!~,"9bCA"�,� ��)o&�9 )e �eu�#�b�� ofluE!ane��!�%�)e� cervP0dis&�. B�)� ru �d%�immer�7s0%��|"�Œl3{!f7% ��lhr w��9G ��� in w*uRNA�"*� ��� | �cu�}ha�agitt�UAgA]�,aT"�� e��oarxpgr3�dis�p��-fi�)A͗���acorpuollosumh�]7 land�!"1!1a�[�.� sep�r 3c�.#a �>- �X�@'p�P$fossaGmrb i!a#)�u�7&?y~�] ,!, W8!J\��d*Q 5!b2!* � j�*icd(�\xW'0 mg��alrozy�liq+1n � (IMB� �g�g�"bba�A�ey� sus�=c9is� %mn�& m�a��es [3�,.�>129S1 �� &�!24 w�birthAw?$9"B2�(9�A�)���C��k���#s�na.5�W!]104�{-a�un� *e=peI#a� . BE>rL� e|a�4!ӝuwX+!�":1>� � scriA�[6%0X��&n3)� �E262E�� .%y103� queF�ah�s 1978� 5,��-��:����j�5200%w.,^�.�igN B :��>P:/g(D������q,u�uoa& g�i��A��� 20% w/v�� -( B=U3��"Ts�-bab��rE1� �45s�A&qs� i��Zein�KZ�+T3��O�/a�1���mU� ereH PK!F��s:�Em4 ��h��a�ftoeg$mM Tris HC �pHE O1%ton X-a�L Z��EKto��&� 31�. S.���5Asg/m~o:R�R Diagno�W+-o� "W��q� ��S6 toppAMy8� ng 2�of�Pefabloc� Jl�\#Ȕ~5}�n��$2X Laemmli�'�izAu iora�4HercuM�, CGY�K�)`t8tubQboi�v� :Nru��v8]�ora1�Aat -20�� P^6rophore�$M! 16%�s-Glyc��(SDS-PAGE geAF�� �!�j!�to PVDFu;7!#� 0&fer;PI am 3A�I n iBb6(fhdev�}�lmVy �-olyviny^�ne� luor]mj+s �a� qCq�N��7MB�$Ze�3 1:adilȖ�onocl�h���cPrP body D136�^��4o*��) ur l&��CHO>zr�-�dzq���� ]�E�Akin�'.�Dr . RE�0thony William�*�^krecʱzes�id�9105�! [68]6�m�,"��AQs�re#�ke�)"*/"vOA�a�>B'r��A��+ � �" ��3&ׄ�a�peroxidr�conju�W" ti-)�IgG�U t 1:� ˮSD�i� {"�6�l�n�t n EC��h mo.D�)��y . Det)n on uTR9dZw�=ep�o�.o� film �a$ Bio-Rad CkXDoc MPvA�B��rZoW cal� �'��e�-! J%�subtr��M� glob ack��nd ��8&ӗ����#��a�^� �߂� Ai3�m��. W4������fr��+ to 4� s:?q ) olf-�y bulbUBregma��U�! >�)�m, (so midd�?R �.�U"�{a8(>c�}�/mI�i�p �t�qTA�d embeޣF araffi��S� 8J M� � ard ��NA���9�o&Ally�rg.�i0air-dr�oveޚ��ro� empe�i��A-��s� �"Y��o}Da�f�!�20���  I s(j J"���ks � io��, �"�6JNi,�o��! 6����!� aal���Ap"��1�� ~t�~1FiJnM"�ie��)�X Ventc�aut"�ed� c!� y XT Ae�:�7��=.m0"X,��}��vBrin� �}��F � �16 =��:�C.�[$)-�ex��b�#"R��C1&� 1)�1�AU -B e-EDT�n# 0EF*� 95A_�e&&)j[6<4]A����*z �_�9*S���uXIy_ )r:�,1cuEAu�C,.���2#.�itZ2 biot� ��goX6.�'250n("I��"�,)/ Grlh, P) A�djeptav��- sA����7DAB!��A(Map kit;5���R_S��uTuc� , AZ�@ Hematoxyl�aP �+N�KD%AH�@ll��6C�am��.y�YR�!"J4�d� �3,`e�d#AU� A�e���K8���$tAOs V,��. S�Hf��B`i���I�%B�,|is��%�pp"��EX&$i�yt i�Wa��>�8c �:��\!�E1,X!���<� �B�F�)R-�Th].�3��q���|(�9luM�?""�v�by����p�W1�TZ4¨In �>/0s 3� �S=\�"I)gC@o.@p��m��:�C��lyF�avail� �g� &� ��Hojx� Q���2*�#a�O|H��m�$�/4? =)~4� bu�1w1�U��`""�:��Ip,)_eyo.5Vat{�-4.,j4DAwe��-)�s *%v7st�2)� photBIoph�'I;a��s5 v�Jܠm�q fiel�'�5r6�z����"sgle&Y3.�,eqa�䅕� us��� V�8��.r&Z�*F3^135�157X,!K�'V%l*.1Q�go� m0�(a�:J�%��&in�h.M/�9-g: Rabbi��s ( 1:�����f��nJohn Por U, LPVD"�Hamilt?)MT�Ah:�rr�!fibri��y a ����G�wBM$Dako #Z0333J�3J��.R*]�4�P�2 (voLMillip�4 #961P�P5 ,2NUi°0 ABN7�.11@� Pr=32�%�%n��*a iliz!�FecX1%�a� 3l�� A�y D�Bة�a�Փ-w2�"yl�;._stF�alk=ea�L� �(�l�Ki �I9E�t�n I,v,)�,-�" %d2_q�ly [70]Ӆex��3�"Z� &� MIguBiY e١$HK336-9R )%{�>& 5;. A&�6d"�!�$ !yN��st �%Oei��UAy5Olig2 6J�6���nd!�6WE��6Ii"> a&V�BX5(.��M/B$suite FIVE&�.6w ", Modu&�of�!&Yz%�d5Ka cedu� �) �&R ��i`exqLF��- } ml ZR RNAq8( Zymo&�#I s��upA�@�8�?��A�0/ Y�is ��A�Quick-!�� PrepJ|vTu�75 ul5G�f�'w��EDc�RNa�I7�o�SUPER/I� Amb�9�#A ��gdFі& �%1tQ� BE� �d �[��fV�8Auq����aiYof�n�m� "�=�I�q> >400ng9�-�/� �}�"�%�,rV \(�:y˿ ze cN� m!�RT2 F] S >��� manufa{�T��J�х� ( Qi���z(W`�mi"d�2xhSYBR Gr�Ma�$mixD�ch��� XEE .$to"B �!a3a. Tenaar�#T(�mix�A�th��� ach _<Ia 384-�RPGFM*I.>Cy�4&��/9�2 PAMM-011Z}- ��[�U�ca&���A� ed��ɚHs ViiA 7 Real-Time ��.)1�Qk=�f;$a�� i%� : 1 ��a>10Dܚ?;�Ns5 �! �i.6�?%�� �ce$2_�A.��!cuʊ��gener�� enٹ!p&&]�t�P4 �me 1 �������Ra�` resh�� ( C�u�2%y"�� a CTS35a�Y�b.6%�&3(web-bE� RT²���r%�A3D�HA� ~vtp://pcrXS;o��b*�.! &/5(phpENAll��0%Y_��)i"e averagU�C �l$.��* keepA%!�s=;b� apdh�Hsp90abauChZ��:rP+�7uscΔΔCT90�4 [7`�.a��!�p";HunpaitStu�}’s կ�I.I8&G > -�)1 ���ARYI≥.�gT2�Rp-%�Ab≤ 05a��V�D62�-��B� w�se52�)3�3 epen!�0�&�`&tmL �J11(-bo @IBA*, Il12b2 L12p��, "�pViz��!�"�m�G�1 G$0ѡp��<)by � , #���AN�i�ŅY�� Easy2�ki����a�cYmo���VA�6�[� 1:�  P�*�!�*�. �Twenty-:h�w*�H�Y��!384ɴͦ �1,j^ �q��e���� . 5R�, a�E��� )� "u�Bd, Assay Mix .5��d� P'Ł�t�t�t�tT<�A��tA{�(-I�V)�A��F�@��7��FJ�mX0 eKF)ge��oea����3�A�Ac�tY~6��H�6:!,i�, NIS@��puN .|��W�e&M���]ALCTGACTGCCCCTCAAAAGAC!!' forwcS�@nd GGAGAAGTTGGCAT=G/�f /.��!�3D orga"�� romoso�-�ruc~\�N<��ge6�=��Zx% *&�zd \#�xrKeffortAdG4D $ c�e%�me���n�ncZ��hgC�� ��. C��Blo�O�70packed—topoa(NoN�d/— ��o�S�2h3T ���v��ad�<����8"�?3.I�<�U"���F�A sp2-��0J scalv9d=m��&�F.&)w M�!a%�a K6 tegy.�&كcoarse-g �)�I�self-ύ!�5� �Yt� . Ac�#} ���- 6� a� e4thEC� icS ��R+=Es~#Ƌ):cap �,�2adyJZc� ^^Eyna`2>X�� nB also��ck Su\ <s� &;.;!>�!gy ow��= ng pFb-law ��>~u�j�fj�O�G f`:a �?@b�Em^/"��.�}���M�a�y'I�8IGp���Nl��Awn�7k�eC.F��Rt� ��5� erio�&<�"graIW�%��� lism�*�l!]7){� eAh - r� 3R�" 0 Mb_ 0in drosophila����U 20@ r*.�Y|�P"A�7Xur2q!!u`w�-a`-param� �c�n�� egr�Gep� q�"g"!�$!�.�l�A� �8!raR�Ut&N��-�9E��9iT"~ mo%\�/kkM�1+E tZ)+. TjuA�%C�a�(u���askC!FeG�E&Ai*�99ey}� wid� >haQR, ����e�a�rAVS5q�c5Ma�^reflec(��%I�:��1At�,�0�/.#nt���5ve� lighq !.&�fEA3�a�)�P>}I 0{� u� j�[L83]:%] Hv���m��a.�t�4+ D �=m_Yfi�t�G��"�igY32�E�3D �aa(�� s�U���!���p��Z}'. D@2FI�` E&�� est �Y�w3 ^^eqF� i`*p6 o�E 2�= �eșer:!�l SConfo!�A�-�C��h�M(� [A&�|IupA�!blt��t:G-�AlTNALg��i�"( e\2�NE�� ���&h^ [�?7]: in%��l�~Afe)(hh��o��*)URre� � al�9 KO CeuZ?ce�?�A��e sub-,!�a�[a dvance�l �r%$lܼ tool��>.L'�a���i-�tW�iq<8,ve�O^�9IplZH1�nsecu��A꽨�/���!�so-m�� ��o��ly"��)4om��( TAD��, ['�1�X Loci��.XD0e���E enric��^ac�Cba� ae�TIlOm6E4 N-������ ins9���>7ea�n<bUY ��*Ox�s 5G�aOaZT9IL�quares>�y�!? diag+� a 2D���cB�rixU])) ‘A�P�!�!�E�(E�2’� ill]���!�YM"E.a�\���Mbi.�osE@����Y��� �e� a�i_ [�P@>14���"Q#)�TADe�k hA��%�lic� s��� -r1f �CD&��-%.G�k.\H�U��Zi{ �P��paU��)��a8fullyOL���add&�0is a�%��1�� ��$v� *� of� ��bOy'bLoUiRa��D A,.�- �=yt���,%j�ms C BiU�#�f�.r E*' �<�?�1 �!Aime�ng%(�q &� ���hysE��e V� ^9s [�01�?v*An�ort��5[a ���� �A`�� I �Ribehavi�]fE�"/��-aA�S$��TGiK�*e A����abo�' millf�-]a#�@st!�hundrej7f( Z�k3)� ^� (���f9 i a�*��F�f�6:E&�"7 u�S�>appY�-Jtar�#� 2�“� �8%~��i%zfew! ic.��`�cTS�at�dec�,p?m�U>B��1����s��en% i` "�=��'hq��+�AB�6�� � ��Q1�)n�e��&�%�J , t����!�im��e��*R�may�1" }Tn�%� a�g�0�H s fluc��1 % es@�48H"uyN)bui�th�w!�)�b%!�]2JL"�lQ`�(*�Uru��C AOhg- aH^!�l�:�i� ��gae+d��*Bc �v ow��EDIp�Srr�dHf�E�nc�1nght,�(w-iPv�i:�97aRaKi�?*<~*;.\tA0Ka�Z � �@w!��t�SǏ!@�Ua!��7�0u�� E! �,A[1I�2��t]�� m�t���7�Bng?c)[˂�ştfe!���2EZ"�AemJ�{ts�<i�� cy ,E@� !s�Q�%K.zz��x&�@apply it to inves�tigate the role of epigenomic-driven interactions in .Lfolding and dynamics>(drosophila F�e . Finally , we discuss our results E4their implicat.k8general contextf.3measures0typ%subchainI(above which>(ahSdue!excluded)�e9*m�gu�$nal fluctu� ns ,�=lkPρ . It may be associe6 with �ub��amAs!�� rept[�L or�crossE%�1e(a Rouse-lik������ K2 [44] � �estim�usa&mph�venU[rel �0[45] L e = l A�c�k A� 2 , ( 1 ) �c ≈ 19A� umer%� facta�hnd ρk = ( ρ/ν ) ( b/lk )�v��icu(inihseg%�. IIffollow���e!� N[νlk/�bp ) aI2e�I�C2+!number�nbp|one67,. L/Le ≪ 1A�ns �6 weak2qeffeca�ndZqbehav� ��standard)сgin�ff� �?�I�m)�is��trie�M�str�[.2:�exploI��Yavaila��pac�� � slow�!ois casяequilib GE�ofL ��_s!vN3 [46A}��y!� that5 ��rem�Yout-of-bium��initial2��i( ��ce/abs��$of knots )aTb� feat�V�ta� eya� �$period . Uu5Eu� re�7ca�delI�recG���str�OT!�-alI iorsA{3��2regime��fully�j sist��kpreviouE� orete�works on%-��~crump�vM�s [16� , 5A~5579]4e�ria�s [5 , '4'49,3–50�� At tAH�; al-9�H  haM~good spa%� ( 10�+�tempo!=H( 15 μsec , 30 min�{08 MCS )a%olu�!s . Howe�`!\underI�cos� �ia�pro�ive�u��A� .�exa!; , forI( �essa9�&� mL simu�cng�h �� traje�2y ra ��$83 hrs CPUI�o%$3 . 20 GHz<. To access more� A(ly-relevant@ s ( dozenX houra/%�)��sH �haim��Ddevelop a coarse-g��� tegya~!g>�a��sIspeed up,1o��6 M whileA� servma�9 physiaC&� ���o� !�-y�—Iu. Ourf�is"[ AA� no directa{ne� �an^ rticularqS8 . When applied)�,cific systemmqu�on wouldGhow1choos� op�� 6z? we ob!ed ,�/arY �� efficienc� ��waC to goE�![ higher CG � Φ ( ≲�� �4wo values will&T Hq�!?u�rey�-�1�TherefA�,E���hoice9to maxim �Φi�vco& of a� i�wdesire) � ( )g . ,�� !��� ecis!�� � 6..3 be quantiaRve� ly at aa�kbp�( NK ∼)i�a5Jp��bout 10�$. U�ى�lE5. ,!+=�Pn!�(Φ = 0 . 97A�a��ap�\r� A|!y ( see Tab1�!�nowE�rough�� studAXwe�a���Y�benE�stiffn��lk�!p lattr f�!rΦ so�Cw� Id��}MWmbb�)�;rightN[ . Naxh!�m� is w� happ�/ife8use�kna!�Z���� do not ne��ari��r �t*� ���� �a�Je begin�s of s�� ‘R� / � G lK%�1apar� s’em"V tr��i��0“neglect”%���C�)ˡd1i CG>�7thaJ O �-�>$. Anot�{ ~A�ider an&���to ��“co"� � i� .�ki�f�|s! modifyJ� � h��I chang�~:.i� E�?be slA��ccele!s,d ( g1 ( t )�ta�H Fig 4a� ndaXD ]�W AZerturbU?~4cw a�0 . K bottor L� S1 T���InA4����r�.�)i(a�+ ) drama� ly)ciA�ha� !�PcA*t�s��iA8� ��x�� as! s−J�"�s2\ walk�6� TXleVt!��>a�����act!kbabil�by ord�A>agnitud. a�^t��F ���ton3,� ll��pursreduc!x �m� � e�"^%: iOg e o�ppi��XO*�instea� fullq� . Si� &� ��2s*.-iRe]��E<LE�}� a�aPa 6�!�!Vwpredi�  6��20 Mbp-s �Y,����� &�fra� of 28�� foune��grepancA� . At-i��4� s <�� , it�� B, but��r2MF<T ��ev��s�>k!@�P.�g5�47 . M>#All}emphag �n� E�n��&l�i]M9>��paimŒ5�EP�G�ic �ipcc��a��i3B�a�decreasL�by make9�s�� ��� possiblyUy�azO &�N��ail:of�est�a� in ha��a��to build!�� � &# ed� null�k �y�I�useA7to� !`n of f� "�3R��*��3D�Ѥun2 &�TADaxճaJ71D & do� ��62]:�cu� a g:6��A�Au o shz�lo<3D��art�)� loci�! sameFSNis&v cor":haf cent��tivu!_-� h � -�accou�!�~�e5�in�ng)P[20%Ba<� chem�  evid � prote�:y�u�tates ha� capac� to oligo�ze [6�65�hhu"gJ�1 sp 2�� B��I�d�� block c:G.�x w� ,2"�Nh . By var�9� ���seZ�� show��:�iyw�-�s5�TAD ��n ter-��-rq ���P�� limi�� analys�� hort��e�%(G  1������)�i}���A�"`w �"x ��6A�*gD�{QU� m���Ɖ>�. HerMwo��� nclu��]aי���in.��~i�Cd can� I�l�w�� �a�jic ��Xa� real�j�%�. WB T �20-MbpZof)�b 3Ra �q1727!ѥqat�Iw �na�6#�l�A.��� = 7�bρ8009�,S TM'V)�I)colJ��a��ob�by Fila $et al [66]�!�embryon�aL$line Kc167Q� is datase f�j type�u�O0s exist: 2 euE,� >ac��A�i�edecida�o merga�+neA E��;%o3� �n s:Ew tituz�1%>� HP1-��W,H3K9me3 histma ,�ul�~TPolycomVPcG )�8ndb27Nc!���“black���Xal� formA�>���10-A�mon�y,hI�%5�spo�>/ nda(assx!�� \E3]%�� ѹa�ѽ � ab nergy Ei � kB T  )�� they��ly����2e nea� -neighbor��l9�Ma�!al�!method�i}>�.�Nst���aris;i�a�8yF7. I�e first)��'l![wE�roduc�new^�yn��E;�"R�%���9a�%!*7 �pmeE�JQ��kin M�# Carlo�����5rEWdemX�g���"0������ �a� | crip%d@ _y-IY� l�e�-e�.0e�!bH* d*��m.�u.�bA�)��A�� �D"��.�ed RaLn trol%!�� �%Pco�achieve L2 g�R#"C (��")��cym#ai��a6j2� �min8��los�m�#J�1M�eQCv&r = $�nJ K": "�duN�wh'��cya=E�desktop� uter�d#$day!�we illuI�d��ach���o; Y� �&!oy�� � Pgy�g��ic% ��"p&�ny:�- �� off-��� � We&()!ai%�� o>e��$�a`A�A�rrone�deB_J�T `!uI�!�sup�areeM� s ad��2E-5�% v��  ans���&A�a�5al� ,2�mis��pre�o I�csecond�de:u� ur9�&>����E r a�dec"�(��*J frame=  bNsol@on.j inv>"�)n g*�)a big[�!|�E� 3R*RW%� �jsbt� o2��'Ab��� �#�2S��PA�x*�=!�(�i�e�p i�!h�� �� )e���&�"V &�Py�m,MWel�!p�An:�� E:-REi" � KjngE�sZ��fi) s�in!`l� agreI'�A�� q"A(sM)on �er>y%�s*�� signTa/ impr�'`:�],Qai2� 2�Eii0.�%Gyu inuouEswitches-a�� homo���d2#d'U^A-�3micro-e"�,Mte� in�eӉ7� Mt@ transi, ..�(& �*�mean squ�displac)�C 'E�A#�(*��� γ�4Q�expone= �at�+E=Q�>�#pre(γ.%Ei�3� harpl#? �)�^� ,=" "a glass)�=Q[6�$68"y9�-��� w�&��!Wseq[+-averag�B(Pc:�,"�f- rectLoma��'t�+> i�A of!(� leas1r(,2�#�)e�#T��!Sa�&�$&i�&,!already-! Gurs&�71!5G�(�9 afterwardM�valofeKQy1extensiv����byU4/ist)���h��_* "�!inciplesA�i�&q �+��onI�riso#�+B�F�'t4!'8�e�0f�Kr�\o.a-!x���A� sugge�Ed, b�ad,!_E���"c ���,y��&j"" shm � "�%�+�B�A��#�. %� . CEǁ8�� .|"v����"A rr&� Hi-CM6� x�yaف�lH(A5b-H�%J&�s!�a prim� c2?%� �Q*>UT:}=�IM��A� 8",i� 1 kT^n�1c� -in vivj.��z�.�јe�Fvr u��parc)�� llap������e&�!F]�P� =g(M�-�dsub�u stocha���in.�2=,Ũ.�*rV �le-AI<or� er-*i y�$s [72–77��Weiu2I-s�� is*�.pM��ndY�&o��map!g6k%�, Bs spur4 9s�misP$|x %p-N3be�-a� anno6 -��Y�-�b0he��B$R\en��)�b�4Gpro�$es��D � ��&!'r�/i�8 �-5 � �4�.��!2� (#^+z ve l�"��"�5orIm��-b� � 1.�ce��q� w�gt�2-t)cscer�*a!� &�%�.U�6 %�a��+ �0 �.�,i��*l�" corn�"� XMQs/ r7MC�&�!|is-5ng me%ism�|Xi|coiB [2�#78]!n)� ��5 loop��r�M5'%amm�[2V.27�f��nha�OAac�6� y a:� ;'TU loip"� �I�V��7"�-�!� {-h6wUaly^ iFQ�I2�.)t�u4l7 quickly (�[�inufjentira� .��% made�synvn� )<ianIs��(3%@,!^eaAG�EA_6� � m���[7!�79�8Fo�of��-�s !�ira�r��S& tu�IC)ar o.- %Lmitotic��� >�Vt9"5 79�3! umanȡ�yA [8�0T�,deepe�5��2hak er.+7ge�s��,*77a,�!�; �tr}9paiY� $�*@: *�,10�A [����:�) lifeE�i-'DFa���c��g�+� s"�Fxm�.oper�r n li�"� s [8 Pr&4'distrib�fun����� enc� eri[�-N�,�P sear�7�A�W �a~3t��a� � �/��al browna7� oT0!+a�bacA��"V �k!I&1ly)����a.��r�N(( 5 − 15%�zVT( >�: re�u(established�in5!M���- (>,� ic%�a�Qnreg�o�l$�B��� ed ��nsua�X� !-�T!�M,!�"si�=x)� bo�=�v��5!O�|-� �o����!�)�� �!!.U'�!�or!  q. W �rů!�gr�.in.�=ediEY[83��7�b�e�y+�� testj Mhby"ta�lya�c�&�a62�� omoa$a��$�-��ur�=f)_d [8 :Z va > &�G�15�.&�'FR6g!2��~=2eucaryo��i�?b�7eb��(�,��M�B^(� �AQdequa�'[ �Ё,F>�q.�1$���$�e4 %�_F�n$.5a�"�t�� �2ed!i, proof�McepeC2� e ut�,,#&�'��8-a�(�'�%]>�2uH207&��c"�5mv o1�per!ti�:�&6�+A�G ��p��mX�ly�� Ŗar~a�vbe�stN8>� extrapo�7���,e�u���re3%12�"�7�O!��t2a�3� *�!�j ����6it�$s e�$n'o62���fin6��00�W��/��'I)��as{2�ambB�or�%)sc l b"�ref/;��7y.Z� Y��fu�;�D}"�#"� �,z th 7a:�(�r: ar m3$an!�an Rim�@t play� qa:e(m�i�%Q�C2�185;k crosstalkI&yJ�DV�ven"���s"� seems6� atC aY!N"� 2�of �e� senesc� ���v^Y$ deta&�5Dt&8mMf&+Z%�ob %!.8s1 A�%X� i&�?ρ���le..MI��?�8��Ue V>��hada+s�RG72 . 2i'��V �06μm3 [69 , 8�vAto�(� 005 ' e�H ( di r)J"��&�A%i�]0� di�5�4μm [88IcX i��7300�of)ic DNA1 us6�9�In!�!6�/D �us"�ի�C��a�a�ang!.F5!15�=�[69"�4'a�ky( G%U6G�Aof99U,2�1:v�r Mx%124.�? as� �9Mullerc(89� ρ�beYer���-�71M�[l�-is+�n�F�4 "_ !@of �F,!pa�'�Y d cubiKfccIJ#9�v- S ×("'t/)�U84A�8| &GCA�*X-0by Hugouvieux1#90] (�18�&m� tail'B8+ 3$in [32 , 91*91]%3A2 oel�� i6$�r� ly�Schra�6(Barkema [92!� we author! a�Eximum� "�'{) ccupo2�lJ'! �'a��8�'�!ecy)&_�6[ �2.. O�4wi/Cdu��>kF,��G._�c�A���\��S>� su�?*B �&�#5� bL"�4�'ccu�&T�#o�JA�‘sto�6 2-:[9I94� . P ( b )!�.38��� ptE�.IO�=�by Rub#.i�pionei8Z(��[D�gof�/toNo� 1�[9�JSuch douv%+a� R�D E�'jaZ� )6(H[!. RGJ)g�d �-.FEy�L[95]: H = κ 2 ∑ i�� N - :1 -�B θ dJG�Fκk�d="�'A�-}/�o 3GR*be�E�+nd θi4Pa�I2�EGv�Bs � + 1"�;x95| eC�� g55= �5ou!!y!kv� �&A�?1���� be�.N/ ( 4S�H . No}A�sA pe%h!su �K< tu8, f�Fer�R !�box"&(�%M]��oo�AT3� ��U' d~Fny��"[aR.� % ���a�2�*-�* ( KMC ) s 4e�  ,��mo� ��:� 2+tep (XEa'�ŵtr =I��0)rA:random�� �)�"�'F�,��m�1��}. T|]I=pAGa�!a�a Metd5�ri��p"�(HE���I��+vV��b*�� ���I.0s� � � st$s�� rmal2b3[9-I!�&!�ad�!ah>o.�3.FJM"baE�-B �!<c,&X$J8���%P/%� be Poisso%cMis ��N�y�!cmex� ����"0y$E�H2xco)��6m!r' ,���A�"�.&Rwit%@&�(of.�&�[9&In��,��C�!!>I,A� urac;+�Iguarant@0��-s�sfewea(R~,)��jF8�1�,*p� is)"i�cou�IAQhJ!]J 2�(� ap%) �s��94��1.�NPw ense—t^�—q,AR Rt�>a�:9aa��.y�merY]A�Q>e�,J� A>� �a!ofA�l;[9� ?D� !=�@�3J6�ZUiq y� been wida<�$�l���F9 *"�=&�D ��9�\s – �4� 8–10�I~ n01iPL (�5�vN��u�"r �N�%v/ kee�I ‘memory) of��,�'�Ng�=AuFI�1.pM. >�%�re�O���% )�y% law&� �&��UC6|. S2��*IZ�09� }tC:n?ll�A�107�N֥�1> /73�0L,'$efa�#� r&�<{�esAsf8sX��% �wy�9:��f �>. F)XdXsnapshok akenI�amc!x�N\!%�%80�T"�%q�a�3��alC?�]  AW?c@���F@5m^ - OMSD�vidua�1� "�G��a�E(masE�A\� ( g3�� )�Sas �=�e"�*�-ta�〈R2� ) 〉EmG p*R"^, u� sepa��by�Wi� p asB���i er�t6�% �I"�N�ai��ic � is les�a�z(�$Bdc2� �)� +D%�A�Q+G� ‘u\ ����Z< ���+e| A�deg\}4� +5OJ=K&�%!(�L!i�W��eL!)n Eq �QWaMA� arbitr*J�FSMI�a�A1� by Nc l k b�W� e N#�Xbzo.u+ . R�7 ( CG �>�. ESMr�! mpas�zn = N0/N� 0 %!�U�)!�$Jer��V�>y� AOX � n.\ ρFS�-L�XN b l K qX F S$k 2 c n ) ae5ae�� L 050� 0 b, ( 6�K�3�Xn 3 c 21[2 b ';I ( 7 ) �= (!VM=Y0���a�kK�| S4V#%"�cCSGI��� (i�^!;at�0= N n 2 N s b�2!n ��+  Na�e�YQ�si�!�Z * ~ic� ih��cor�U� Eq 8��o 79�A�b = [M1��<n%i� 2 ) ] 1 /e]( 9 ) P �, w��E,a��Z0 (ɕ Eq 11-\ %z)� � >�W� ��.(i(.�AX,a9�Fs�[:Yp"Gr!��7L�r9g&hC,,� ���l�B{Φa�%p&�w2u��B�b�&F phan"N��I#u_���m.\end-to-e�ai�w〈 R e�����G,by [104] ⟨ ���2 13 b 2EA1 + x(x ) - 2 x ( .&- 2 ((') x]scoMt( 1�B= {(k(2 e x p [ -`/Rv3.2A�+ 4�6C+2Zk ]2'S+FS�Y1a � i�:�wo��A/j"�e !�:�E�O� )�!�&cos.8Swe�lK/a�(%C!��11�chM� s NKtκ�- |loJ�G(yy�.q �Wi�3� �Km!�M%�- -�m ) +nl , m U ~ l%i  δ .<KT"�:��"�(�RQ �$� c�f6r? siδ �= 1��g4 m�yFX ( NN ��/ �B(V0� �Aq!!A��KGS, �Um! e′06/�v� a�� a+�l��B"�c>vs eE�g� *�` �-ys%YCb\5B�H"&� �A(�=Wif e ≠ � !'^�( #w� E�m�unV�2E^�UcEi��/ . . Dy&g���b6� *��a M�:)uP(&N "y;^e 400��\��"�]s:P�*+“&l�a;*b(� i�Y/^?-63tZ yav5bp-V ) !�.*�H�t!< Movi�"{2f:QRsk1refIl�post-/>�#:zO��Aimp�vT0!  —oB—�7S !Ba.��Gem3!�a�;�5is-N!,Q4-a�ng $s.)6�f &y�e�o"tC/�J�"eA:ns"=E. R i�i�R%9, _a/; it l( eQTL )�5p�j� lle�!!ade]o�@�e-��I�e�A�( GWAm` =2xM� omplex �C diseLc+�0 �L= hypoJ� � ny aa�&�tag�o�SNP��l� A&��se )exert�et$aH�E�*&5�Nge6-,�(!,bec-coB�S�BJ��F%rH2�I�MiD%�3.*O*�A-%h!Ra�; � (@d�)a�@!}!P� tic )0 itec[(!cau�jym�&�$I�t} �::�=^�5dd.�?�T�<e1A[�:AmU���s:� we �Qt>2a8omz-�QkRA�s;��!7g�B)o� V��RE�Bata !1ENCODEd��;�2we�R�=e� M?�rppjWE�VH z%/!M��0 �SNPlap �hundredZ� ���iPe4"2/�0N/!#�Fv ro=n"5MYJ� m-pe�" =�,pof�'B`8%s2P'Fo�S�X4!�  mole)]�A�rL!�zMA�'������ȅ�.A>���a�0Gst �%�)~yq.!m-.�as&_g� d&�.�f�,*vIEa<�]3b2�e�=6Wat�mDa�}-]MWq!&.�90nB;eJ�e�e *\h!(if��an'���?cip ���q�A_A{� !��!�e�>�;�Vc����to��! U%��ba�JvA�k�=��p�k����E �+-�aG ��� olQA�!Z��\!i�!&.�O�1e�as"�V�)%驎�-]IA��urb �e�ny:*�O�]–[��.@�o����bC4ory��;, RNA�U)I%�typ! �VVK�|��O!��  .�!�9i��jM (I�,*�d] "�p����� o�8sE&Cj)E��Z>Q>LJ�manne�fAM te�C boDf�GA����a�e�'RH" both)��E�� �q,O}�!wat�52z e=� >�,�]+V� i� O,D���S!�ci�y)� %~ (�v�0��� �W[3E��. Ogj� age-qq:�"'+�e ar�%� � ��l�cleotFt� orph%h(�4�lLV6i1�=�E�� idm�+ch �-.�pis� �\���*��ed i� m� �� ;�h�,QerLI ompe"P���e�[�+[7%X11].+I��a�cv {�LE��� �5���Tis furttdNor�b� f ng s� �L !�enric*�9DN� I� ersaG�� ( DH+ sw[12�/�J�[1Q8[1�7A}8!6�%leganf �:k e&hav2� t��)6��� z>!;![e�B-]��I�2S[1�[[1E�Al�!�� nV_ly�"to��!�2�6{1)�R���jV� �J+9ble�&Be�@�!��I�"sU- x es v�beh�%� _%�U �Y� a"�[n"br���itA��(�?"�Nf u!��`5?m"�"A�Q5�A�6�DikE�"w �� E�Q�{ riskA�II�1be)��hc er mu& ho�5 tqv. to`0&*���]&� 9~Y��gross:���gI5One� imagZ=j"o9."�Badi�B tissu�l�x��aI��n>6hormone!� :. F�Mm�HId|%s p W!uN�( i .��,AFt#lymphob:1oid Ʃ; ( LC��INA�n;hj�c��5 �Z ��<i�WN� 9;6�!6��Ma4.Yn�a ��A:  -��xgd�!aMv dopa�y rgic neur� a�(Parkinson's�P� !-�'ho9mF�Gir9%u� �1()�������%� Ii*a ���%?"|=�!�A4,or*� �v#x �28].NIO{� ofr _.� �5�)��#&w�T�IBYE{�!t\n�"g�9.- p�&�$ed ��:eO]u�2� !Jn�O��� byŢ[e�K}4!F .�A3���]���*���:4)�1�Bayes�Brex@ၥg��y�� lin�}��e�![i&1P^l>Hache�.9 Q�[&)g��ff@b�=d�Fm�Ca46t��,G:��ia��! �a��%rse�� � �{wer?�#U�=�%V��Ko)Z!,knAw�:u�D,�)llE9� .-r "� fac�z�� ( TFBS� � 3�&�(Z�n a�/ shipB-!��a����.q�rep؀ . La9+%��f��|��e�2$�P!�alBp%�� �5�of�1�'�e�?;0o�s��a�)�a�eXbel_\i�e* Q!^ll!�?�m��.�N.��y ��d� I�by en�E/ �t�:L��% Tw!h "� �W!�S s}.� �X�ee���L.���_pr��1�[29![3.�_Xu�����3j/ze)O+g�9�N�Hn�v>MU��we ga� d public��"x|:���@g:�o.�� :M���!jBA%�����uniqu^;m��&�d[1�=[2�3[3[\QL�F �X�UEx�<��!VarNKenuni�(�q?Od��raw �b��v\yAC& 8ipLIz�ip+� at �V�vg�)�yarginfEHAE � ,��c� p!��/�!�Me&UbGe� ��o]x�)A( rray�6�w,ubI��D�8quPZy��z filtH. Mis�%�un" O1�?+ V�T��i�p aa7� ��HapMap zY0 2 CEPH panel&� BIMBAM [3y[3530�(B��!t9�re-;d;a~ ^�N�al5���&{W�m]!hg1'A� to RefSeqNMdel� W�4Eq � platAX�ultW ����*�I�lus�Hd�in�v�R�[i. O !i1a� ��,� at didn ѕ�S�0� 6�yu�� u+�j��*8��� !7�.:aI�� �* ucoi� V �sa`removAQEp{F�/m�Z( PCs;�0�JS�*�'S%&[3�!*6Go$��a d;s�#ez�graph�?�� , ag� se%*�aA�(BMI}6rug��#E# echn2.�G ortemv va&$I,batch�z�F(S,m��! Z� whoqp<H�%jbl!kr �3� ?Er*�ʅhof ��on%܅{ ascunA@iW\tB��ng �M !y-p��eDnU)s&rd�^5R a�!5^G�3 ��E$w�f��!�a|^9"!=mtiekK' j B�͸�<igh� ^a��t|� @4) e�D38Re>yq,�fox �yT >at� p�R�)%ri��6�Uea�>�es��A3 falsEa�rd FDRax<%ml��rV�8� a BFe�y!Ea�e<,�lu V �� �Da �id&7D%� �u!!+6��*��S�!��("end"E"pQ��"/�����"� A<re�!�a6,ㅁ�1�m� scop���6� a�.�y"�Waw n%)<�cq &��;�� "�585� 5433��!�C.c2n$��resholdA�I!�)$s 1A–C ,{ Q=Ta�G�C �hU�_w<�!�^r�Zp]@iz� �%�%�^� * �C,]0FDRa� �� 1D�sB>ANOVA Ind�-�A|:�%�A*,Q��`-�!)9oVX46��$expL�^a5%w= r26[�� !R�3&g�E�*����p�H ��l)�-oy-h%��=�MuIqAJFi�Es S�?S4%CMnb� IR!��� Sv�RZ)��j�*a� *��7ll�*�lM�6�aGW(s\$a�odespitr�&f� !/6.BF%�AyisB^t�TWQ;!��qB 1IcA�O*=V.�4[40&41Щ� K"� "�"�*�eu�F%��g�0�&�,~#�?d��:Kr d�:2%���]tw� �t{8��n1�( � s 1C%l 1E ,Vq��!A�[!�f�%��-B���or�Zv}.1(%-�m]� W icBG_� ��)k /e�!�b��">�  ppea�+bqE wer-�{Nn�r��n - A-enM�h�T*@jNlF b�;R�W�'}z6@Y[�,,]!�2Q�al( U�(œe 7V24b͠A�m�!���P�> ţ%F% 15�7 ,2<!=�{2�66&� ly. l�6]��aVs�0q�aS� ԙv� BQ ( AH��T� 2 �E���Ug*�o ���:4 TSSA�n2DP9�)m:�"�CAP_LCL ��� �med�abqa���W&���!�-� .�!�kk?�i�E( Wilcox�/  rankN e�W�yxH "Y��zN�_e!�!�sA��n&���. C�V >�X@��+M!y#a�Zp= ����q��]n�xfai��]�F;� !�sA+Y%�broadk"��&�%�]B!D>��R�r��[2v(��L } } 2J%��f[4S t�1 @21�entrios:V J-�s�:-�47t`v�h7�^�%��2��A1�ix5�a�K%9�* ]�����g r� �A�o2`�gh� ho.y_��*QO��� �X8 A���#!�F#{N� tr/>�ce!2 ��c�a�4 b�pt�:� &��]8R�leJ`forthco�3�YvA&(tTe+A�t�P2��n"zR," A49& :U^A  �1Na�� 9-�*W%�s �� Y�c%��Xr "q 5 , S Cy/A���n!5-duEbLxoi��*���eria:')2" Q>2"K�W�i��s;Pa;-L�AV<��-�a~-)|�c&J mn ip�'K(!��abl')�I?)!��*�A�.�amO�E�5:� GM12878zHepG2% �N�gU�[Myers_b��%N�su��8�,�$ 49e��A�6�# cerebellu��Dd8%�E m�A "1PF�7 3�� u3;��o&�Q� ��0�1�[2���s%����eN:�t��1!�2�3 98�v . in�,: McNemar's n B&�ihl^�q�s y�6�z �v��NlA~T��riA�E/�V�sa�r�.:�OEo!�!�O(�Lch!��J� �h�:g a.� �0��ceARiim!<&&+whe`" V =cű��(�%� .]�,�b&"� �&Z A27uAG�P"�)b�r9|!.� �:pozf >|��u �� !��:G�  �f">��f*2*�(, Ehg (  C)%�neg��J� Bb a,!�TSSU� S7;-�� ^�)�� (i>*}leuv� &~y>� do�rva majorm��!��� yr!�Zz1%��w ihoo�Q��5��2l�a�nd un]�u.b6j*&� k�end!��>��[ ShI. A�yũ݃�rZ�,1=�a�Y�N�.�yXl��.0(�"&� �$��Ų� �R*�!� .gmeL�G����A�� .)i�`a2l�Qi3�rDs�>aMI E m�#� :N!���n�s�ZC��te��}� a�#ub��<�Tm9�10;%@.�%��5 s�i$/o~� ��%�M0S2"݋%�J�s:e.�J������M�AZ�!hR"� aI�B���.(�y�.2�>{W.fQ�i� �� S�A9�&�g7n.�b�D=�1;]��2 s: F.pXD "^Ad�^�.,/��^�6��'��y!�bN���,2 o��y���.�W��r2�K�*i�!�%v2�TSS-pr�`9%i�� �h��5?I\�xi��^��B �.!kF�U�eO��AE�uU;ve:��~^�v� � sojY.�Z��*i&u�"T�/Y�^-�6��- !�s�2d�@i�w�bCOove�.� M�nd!�*-&ا:�b.�'iV�F(t0�0w �Q&�/�a�AN�{6�/A�6� ,�ErB�* .�����3V� A�� .� e S~�Z*>�B�"� :B&VJ,�.N�>cj ���U75BPrepet;� 8E�|��ð1^�a�/5 c�%raw�1�?�Q�#�R�"OR�1�<� . Dgiw ;�5N6cou�d! un�7 cF��Tr�Bon�=��J?+Ǫe"�o�� .VMi2rT.�,)~ ell-y�A"�8im�%�'�Box�]$hepatocytem�-�!2A5 Mx�0��2�26�)� in] *erA�v����" aW'`Ns!@!�Ŭ�3��l7���L� !�BA�>%�, r�0/�{act=al4K%����*n>�Ade5: ��r� 7e�� CEU>�&���6� ��.E�,�h�!ach�E!&! �� e9��c� to ��@�*�� �e��a��Q ��*+�%��>�IRK�%�Jth!9��o&ڝE��N���-!���QI 6.C)�-m�is%b"�5���>6 "� 3A���, [��Mo"��} p*.U(IL2in ��i͚]a CTCF��^6 l�� !V�!A��=g>'!��4Pq>�We" ext/� j!�&++!ey6ar&�@��,.LbyF(JE�A���,��)�]�@� ^BA�*�1.VK)NP5K s S19S1 h"'�'(6kU��=�A&:a5�3;s#,*��F>6DF$d?.� , S1}Ba.%�v�>�.]��shN� L]1zFjy� �)J��-L>�9�� %� es�e�! V� paʃ�\1��} �s.9 "\I�`�_�OԶ7:�a��� he��%{�!�)�%��p6�>�peaks im � adja�`�i�&f_�x); ':� >[.5 H3K4�!oH2A . Ze tex(y=7�`4"?[�����H-�H3K36a* z �k�-/1lr��&�L �1;�<�K n�E��!6�`��:�  D]C� �~ ��s*���8C^%:�.�3)�s 4�l!Si%]/"x&�>ve�\�9�1���u�. up�Va��5�A�� decaM�( �aY�trigu� asymo]LH?MamA���A�8"s gr45~ �themsel�n�>��|J�+Q�>s�-A�.k:q>a4��.`� �"�!�6��%�NJ(.��(�E�*� "� � �e>� �!A>��%�� 9�6�i�ctۈV(q�I� S15;��zaN�E�-� �,a}-A(!A?���0>� JhZ��mar�.�aJ�1!�^E�.�ise6h Y:bj7�3.iX0�1 %.��4�O�kS1�9�gy�!�t]�box��"TO1(biV� A�C�t5 �C tur�;6�#>w+6��tag�{5RcfQ&�P��nLPJ�*�bE�s)���� plau Nm�Dms�J�N 2�6�[�>� ]:8�>=�>���nm�l��*n;"A�� @��%�a!] disrup�:�C �%2&�dow,9�>�s�K΁�$AANFȁ��]VDr5�AB&Nas op�%U6R}{ �%A �*&rofA{e�A�q7*f mak�"is.���I$ es >reז* &&H!3��we*XCdOzcB-! ggrF!8 c�E���[�>��"�U+�d!?��+���*�Q ��!0f#9��� z�i �b��c[^f*�+�2�Bfk��y�e~&f6Z3^Ma�MeJ��9�A� J5eBD�c�af5tcAJ��B>ALe��(F�"�  ����%5� &�:Ib1A$�(�i.e���!AG!l%Q��&n)�e�A�6*I�@&�&V(%���X��e6*]�N'^ma�Aqm?b� ��& d�2�* �(5\(�� so5e��"�� :-��Sw C@�YE(�#>�; "� �D &B6�ݱecapit W^J�!9*0�!AR>�U�FMJ���ndYAd!..$.;3 A��&2'!�� -:�)�%&�.r�()�.!!�6#��.4/2xL%I�xţHMM�ong2�X.�N!. Notab�a� cano�B^7 &ao� !�*�I� .�E�!vY�!X2e&�)o� �A���>�! � F+)�&Q1*��:�F$�_ 2E�(MeI; 2s NL^���0)  56[48)�6]8�� -f ��,.� i&�Ze�.%��8 05�ar ṩ�>�"��"�-q&�#L-�S �" u�4SE�� S10xN�aW�1��w !>� A�l�Kcap�$�C&deu@iQA�%=���ɴ �"esQ{�:�5 ��:�V�!�.Zab�e���N���, ��E��in�!��2 ם���6%:.!s6��o�i�6���.SU+��*`  /�sZ�2,f�[Qn0y5�a%-q� p3002x8�?1�a�Nj7A�N�h&&���OE��+C 2�*�EV3� 2�(SORT1 98Q*"Q myoc�>al�gar�kAX 8��E0C��pZ�aMa6�a�!D �FxiSxly�*� � �h0*ch1��Wx1w ~�P+7n���8. aI|�5)�%NI;�� . &�4.��%�F�*� 6*�"��,!!&�#8 � ..bs� e�e/nj�Rk ;!lo�in�'%V})5j��F���Y sn 0:�NjJd��s.�Y"�# �#�,oS�$4 lJ1�A�n�Ln1�6S�5L(���o#K �&y>).�.�qC2�6~| �)y%A3.���3n�6 �rhpMA�M��!�5�y)9FzJ%!/F6l.OV ��� �EV-�~�B *�b&4Qa�Ks �>�&� up44wWof ��Փ�i��� )��6j� area�ROC5n ( AUC�����2 ,5[���� .0� �.a�a:2%kb"�T��-�A#�#b~*21Ho�Z�>w4�O_�nGe�&$t65�x=��*!rapt��  ,%am� !Du8��aq2 ��!�H"�%Zq!0��1'ab!���n�ch4 v1"PT!��ORo_��:���6�o�_��pN��q�2e9.��MJPs��yT��%0VYhl!N�8E�,J�$8f���ach1��!�a��c� .�#� *�A��� -v�Z_-�fTSS$H=M�39g�">��e:� 9�:�i��1>S!C" |1�ʹJd A�Y�� s�us�:;,�qsK]9�Y� Mgd�J%y�+"'6usefu% u�ng�VoJ�2$R�=�c52a��#nOU*��ews�#$!�B]�b%z6c },U;& �of�9jS�"15%Yՠ1�2#>�B�e���}"�v�6�ng �eB��-"beCF�qB�B' :B�J�?}4Awo a�T �b!?aidQ�>&xgof�Z'pq��irem��M8[�[�[1�>�e�@hK�Z� � 5žU�� �h�� F!s�?l���-ea�r�=@VsB^e��a =edV��@ tenB�=�qޜ���m!�!\�6�-O.FA��0U'{ �  na��g=�[��e�hYsEZ��j` s^�\~��J%�NHGRIIc�b [49]� F[/ ��i�G�>s�kkidneM��u�i�d�8��edn� [-Ѻ?�� �i�TE��i��� nd�t�N^�* !!}�5�X0*��Wp/�p��}*V �Uach)0 : , �?!�e�HME>L NHEKa�nd NHLF%�m�5F<*%=5�:� ���9��k /ny&A���@�S�3q����e�AUE:�Tz) Tiw 1 "i2� 2)o �)�6*�q"- S�Z�~%ac3f��%O�M&S���s��ik��}L�Ugrkqau;( b%Es:J�%�A.&_>�a.��}J�2J,g:���s�s5�'l%>t��1d-�IEe���M���;/���a.�a �x�Fno�qw�e�R~�ed�E�Nid�w�igh� ��E.dE�r*�E{�څ�*=I_���8Y���* i �XF+i�&�q��"�X��a:��#�L... Cis)c� �� 崅�� f.�!�*# "�axr1��.�}2."�a�,%J �e� �G�(�(2+BU !Z!�E&�Si0=r��_�QbyB"�r6�%�!�y;e�6@ee��Y6C*�8�Z�V�61�A �G�B- :��>8Ň>lw%�2[uK2�I�6�"�%f2�E"�aa�*H]=*�#I�FJ�O"��s�%&�^ oV�fBaA�1��H��o �aH>SSN6�"��u� 2dz�!� c*s*�9>�$�IZ-�"�U��ro&�-&�\ �4ov�^�B�s��m *�i2e#�rn� %I;Jw^ 2�l TomZ�~w���?aɉisO�]&>up��m�PE*!(K^ ���e�CE�.� a_9&(Y�nd$7�/S" h�' XLE./ V�U.},� ���<�nr �o��, ropp�c��� ! "!��@uho �A�%J-�A�E{�!1��rroP� _kXgamp�V/too�;e�R�j! ��ya1Y�M(h���� �  ����SKarc�qD"��<�un e#2n*9 ,����� 6K�Y3\�#Ce ��Kq+f.���i1r.�23@5�(!l��edKy"�>�6;"2 �scruti��L�utoM�}to�&yY9�=%�pt�Wo���4TE:6�:�d*�y1!�fbCo��r)�A��� h�, H �5�G =U"?� .�!"2Rul�pQ9Y�0d ���;or-:) 7uiA�s . Ge.� !loaOj� pj��o5{"�k&7C{�- ummaY��Teޠk!gqR�h� a��w2 plink [5�k�Y@l�a�W�,A��tT.��f%�SC�Ja n2ug�g_����Ir �afI#_2 web*[52)l+H% ��.q�����)�m^X�LE xeY�� f1 �-;pR'Q�un"agL��Harvar:�ucYle �um5� *q"�%�m]e>��r��trt��i) 1a*B_vis�cF1�.�QYI"fl_l�%�.� �e:�l�.K)Bs ��OF�Jgd�TZomE�}n faul�!�a�%/CaucajHe�p���,a� <un��P$zm.I2 ��pUChicago2`�!Af�n A�S�j.W(�tn~ Hka4�f�+��!� �YRI2PA�"er_4���07S�rgerXX!(y��a�)of>�.�9/K�,,J�JPTCHB.E'.Zg�� t)Y M��qRa�> % u!�qsd,%�$a.E#�F� �pst�0"�[g)ea�/&�$l;1�d�Qnm�� tLnM�oheo!~svc-�k�[�E��� Dl� ��t T>f%�1����y�!�/ �!�rA��� �VB-o.��� Y ,�� y�did2�^.�.�aJ�7-y)de�..�l�Z22l�F�-��nd�KQU.&p��ic�.�AV.�p&�EK�~G as-72?�K��'!�%�l�$�` Xf%QA�2�E� N�p,uD�1bSNP131�Bz~Tho�u'  �P�u( ( 8/4/2010 D[53�WE\ropy�A_l��l}e�C!E��[ 4gU���b�D�8Ű�a�mWX�g"^/II~LowR>MD1<ei�Xo� "��=RA�aP)�ExoAWus�� spikA ��"R0�{� hi&�2)�m��A��5#). ? E<��eUp��aK  kt�,���. Poo�9&� ,s �>�m rmuflaggai>n���aH�'u�p���(U<*5:a:�)҇H�Q subt�S Nq5�adjt� >0e��WhalL�um*#�I�o1���&�:h����eM���$�M.��1"_ A�-�an)�ؠ�J��� e�S��9R pac�l U [54im�u �� [#�O�i �ͯ� � x� empi�:xo�.*]{levelA40We allowed upJ s pe � . Wit:pE(�3indivE� ,AE,%� mean�adiffer! � as a xy q:!�B�  at cahcE�of;b%b Each �wasiAed dowAueam�ependee�, und-Bassump[tkun�laA��a_ s rea��either.St transcript isoforms or poorly!+A�Q!�$Two studie�39] s: Sb ger_LCL i0#Id=(, Yoruban ,e�DEast Asian ancestrAoa�:�\A?(African Ame �$o minimizeEeffeca�atU c�A�ele fre?c!�e popu�xs may��don false positive discover;�  negareplic��E�e�y�e�w�laA8��protocolyai�-�%�!EI�stribuEGofB�(measurement��Ci�A��YtoSaverag�2[}�2Vacross!Q W!���i.�eparate� r��� thenR)!YNnXs wer!�oaz [57]!=Passes��2� �q%�AirA4� SNP h�.MAF�m both4$. Therefor��e�e��I(polymorphic9�+�$ but fixedanoe�will not�ultjM.�Onot �r]h.��similarU�mz�!_!"�U���M(s S5 , S6 )ur�m�, )�!Ny2�is� ��t���ae�ed���V�y>�� S8�We� Baye�^reg�,�� implE�)l@BIMBAM [34] , [38���fyA�A0ocii�� E�A!*8 Bfe��R/g� Mg�%8  tudy)��� defa!�a!mtsA� hichu��j54t plausi���sizes�add���dominant�c��t�>�- impu!%genotype Ell%Ձ�except2 �in �w-�assayedI ���0 becausA�e s di��aqe��)�E���-trait9�� ]� s��4 test� eQTLʹspecific/of9aial�U in paired-�s [58EJ59�q� -I!ZE� factor)f�4 �T mpaPw�3 null ! ( no�x��cell %�0) : To combin%Is.K:|�� calc��� n integrh.�@ ( iBF ) summariz8evidencM6!!L as: ( n -[( i . � ,�re��3Qsuppor� NXth3 stU \ )��f�� categorQ � he:� 5\ largABF�lthoughA��H?pow� o �t�E�of-�iA�Y u i# � u* . �$��sis�condu� onlyR=2E� w �xB�6ge als�= cis-RAh (LD block ar�  aa�!�We�� ined$s u�'% HapMap reI�i�ANs [60]`�%<�Aprva-�cM/Mb bsRb�aI of anw!Jor I)�s2���wY � (e chromosom@ lo� < ��, majo!�d5  l��- $A5)indexI� W*Ee�.be valuZfit;��EZ�tt��ed 9�Ak� %�#� tmagnitud) dir&� ?as��( )W�� bnumberzexonsCB length q� ),; aArrespoM�  &m� H � �atho� V A1) is2�epd�lmE��maximum%�5all!rs�} lapp�za=p aligng coordina/i6 One Thous�,Genomes Proj� <dbSNP131 ���� .� �in�s��> driven� .\ of���s� .T !� -y��:cŪ isony a�!*�"shE=,a�conside���-De,e���^�MmonH�tw&�.��e!�am�FDR%��ow we�m�C� �q on>K%���c� � (�ڱ=h!�ran2[mM* eA�e �`> Ac�cutoff9+�-D�U���yw}�s ����original x� � nA� !!�U6�:U( T�S9E,W%��y"j %�85)Q ��resour!�� d�ru*�A|leti)�= � . Unless n wis�2d ,I�rev E}! tex� f Ns sign2 Q at . Ger6�u �al��s�pe%�@i�$al QTL sca!�n e/&} e9.� am(ep approach!I�fyA�*j�ed��atIlg� �E|�ùhweWN most�ly:[AmJ�'��Mb�!d's*�$start siteA6 SS )�n�$end"E"��T�tlt)zAhe� of ��,��by� �m�t�":to6.�in1`c��} %�~o1u[61 we took+un�M�-�!mSNP��e2�uG!V; w�t���hadf t> |!belowvE9p��v�M� said!exhibit� elic: %�!x� ~ZaI�,forward stepeo*� a�a)� CAP[gen�c6flN�( /; ) [62� 63!j We i*�,A�R%  customb�A��!4��1M� 's A���A�.* !F!�of]*A�> . In�ti� r ,i �ZI ��6 A'2 s` ria�nM� a��a�!? fABi"st!>rovqM\In�ĩ�CriterA�( BICa� fitA� U�� Y5A #sel� <tak�(nto accountu�$likelihood!_ C�ٽ*B( ���SaXsso%>o avoid�ss�;���!0 over�!�M�ntinu!+"| yA�inOax G=W� !6�5�(1�� �until-� ��a im%��b1X,�4we stopped . A��LD-baw metho���F�qa� 5�exhaus�a����c�,%� �..�oa�t�=TstDh =  ) estim��M�VMA�a!�q��� {v��j-2a�de�(Af���-o� see 10 >�&�N isma;n�Zx�auM#� ��nte�i� [6�!we%y ��cax$o be beyonh scop��qG is . Our U2V<ascertai� !9r8 ppear�u�e1�6��SN)�S , howe4�ka�"-p!W threshold�(iP�!7.� O )�� a�0 t* 19 ,:�2� GI 0Ontology ( GOŎ 5] enriche��� (DAVID softw�[20͵A�!�edHBiU� &c� i, Mole�:Funq�Y�i�DHarvard_cerebellum�X� yy set���looke� .& mong%��w� �]![��se [ ���[�gg�5Ze%.X'Q8&~� �bov��Am-E���Atw�5P‘md’ i�8m�t�t_O#SN W��� �g� [ycohort *]Z�� A�a6.8?L m��In=  word!�if͚faix&�!�"� #%! -lre�edFue&\microalat�v2\n�.�. Sto�Fvious ob�8�C(��FiH"0H!� [26]� do� 3e��ub� ��:L�=� cy�q�onE�2�.�t�"�", CREi"3 CEU��Z GM12878-9hepatoA�u8carcinoma HepG2I�7iVprimary }�tissueIY�to�)�wA�# D<� � v� qŅ (�Cy lisAin�|3%vrbluloa��ly9ENCOD-"�ee�"UCSC . C"L.a��ed�V�G )!a4$CpG island�7| GERP evol�%3aYe�.1��t 4DNAse hypersenV !F��+6W b�ng 3. A se��$ st�%seg��� ( Seg�9A�� , deFd9V^-!Iof K5620�a�%+"� ��regsory1 fea �=B�pr&�‘peak��ls�.%�%� . If:�q� i"zA���x��(same lab us!D� body, �}vQ�merge�t&^'"��5�.",at��,v�� does�Yne��ari�q]�9a~ticr&n!�� ra�4 !=tag!6� ;n� .�linkage�~libriu�pC lassW=a6á?mic��it !B�on* ed�j�- �0J'500 bpAq.&)�� CTCFM�%�.�s�QA� rrup���m midpG)ZG.I���|�!�a�TSS>��e���o �o9s�!��3�MU�J9  firs�de�r�backg!�2�#I!��a �'s�he.<�#!�� �mat���&B�Ah�1�/. All.�ph� 2Dli"y &jRefSeqARe %trt,A,7aJ/E��.�'�)!� �� is1$to:RF�2randomigA�tog]�pw�%u!>6=�[A7�x_+verlap Fan�@&achiel�PIH*�wor>l�EKb!�hZabi�+�*isN��Cby logis��&� 2 ), � equ�nra�:�,*=! Y'oncqm* l��Qgqz�� or`):�� c)!�&� q�� d)AE� �Ydrawn�:�d.�'( dN#��"cator��bl� sd^ JV)��&�ٰR glm fu�&%#A��>�!EEH"�-1�ma Z-scg�,�a�l�-t� p-�eA*��[(6" (A��E�A)�wq�!;I'���o� B�a�2� 0Qof� IUis��!F�R��`Q� ��&)�IB"�^�)cti�oV�-\:.R$ɢ% !lf3ng%��V�sL��an:_� �eg p"� � , .��exE �X"� }�2���.,!���,Y�Y}gx��4� �we(=q(���%,, 9>n RU�* :. E&�ofF=6}�,Ű;)���ng%P!AN��p+:�A6? �B4�  @%*� ��'k c� g��PF(.�&N tagg���B�� vlocus+ e� 7=,~�as %d N; �]�.�,�ax.��"� at����6�0�A�\��a�a��u ��.^��sh� !Y^ r�%! - +^Yt:&�.����� V�j! ��a�( rven!�ins�MbyN`�5��V -�!��0^,�"�>�!) TSS (�''A�xes� X@!�E[z�5bq$�>hotspo��!�z? �-b}�i!b1V�@ �&�E ZE W�!� B"��'�5of%Y!R a�r �tJ8xB1sp�Zv� �6attemp��t���y bia��amtroducG � A��.�c a5�M&���p buil\ �r|predicte�2 ,�F[,�H"#-.1 �  �es�7�A6���sem� .�!�u��!� ����a�+*� deci�trees �by boot�7�'U�� } * Am&� �8n 5 a:�.�8%Teazr�"p"�3 outc�*�$aof� s��u�4�*� >�*�5q�CRE�_o$6"()5�s�Ta!gS3!��%!Ge!r�2�.�w!<'1Sim�-��I�R FFoA"78[7�"2/-fold valid� ev �r 9 errorI�� p�8ROCR [72�1A� �ROC curv!end�<AU��8sa�udl urap2s�.6�"\ of GWAS�F�#=z lacka�%�K��a�biE� Num" ��-!V�whe�X �orXa�l in�!!�by<�a� �;6����� ��� ��Zwo ��0���Wa.wA����a�#*� �f��iG8y�~%# g!� re�Jdc5K(HMM a�LH2A . Z , EZH2 , DHS^])�Q[ &!LCL=7, NHEKL^0nd HMEC% AT�$niR2ly^�iS�"!e�� v^x��b�F� . Af�;�!���l� appl� to!C�Y���)Y'f ph�ype�r�(�.p reas<kidne�+� lung�# (>�>A�NHGRI |,catalog [49].on Janu�10 , 201�.�pa"�! �}5� �T6�.� �E��7qEmT,J�Us�DedEe (I#AM5EG5&NAR%+ )Tan unNU�or���D*�%̅��L Q!�J_���',by Wilcoxon'+ed��k   .tunp;5�3c�,EK6I,Fisher's exa�;�3L�JMcNemaK ET��= �� �2��J�r��O�"e lA�decadKm^*� ,broadly neut��armonoclo, bod!�( bN-mAbN@(HIV-1 envel�#<ei(Env ) gp120m bAde9+b�%M6�$h@ cogn=epitoa���ng'�: amin|'idEgly_=�8� MoremQ !�%�7dE�K|�q ea�%wmedQB�> N�Vosy�="�"*�a[6%*���lte� e ma�< nd net cha!>Envp2�7�R#A��s=p%kpo"Z<m�,elex� ia4acid–Ta� )sbohyd��Si���ys sui'a�0biopharmaceute5p(  ��limit^<١Xse-5 (A�or%�&6�!�� read{��@| of vaccinn+mun"C s displayAS�'!�an-"e Y~[=E�chcnq. H�< ren H dEBop�a.+$ble suspen -adaj ChinA�hamc +�%CH�%5g=<s�Ypto)(A5A�F'M�M�McreN9����c9C��U� spac��#palindr repea�$CRISPR ) / -�l�9 ( Casf1" S0 ng system�My�Bmma�activ�4� AncovME3y�:PAlpha-1 , 3- ) -Glyco�Bet <2-N-Acetylglucosa5yl� fer�( MGATc&Mo�4ric��s�� � +−%�9f�.�*d�i��ot�<U��]s�."� �@$V1/V2 doma�R�g .MDG!UA!V3 %Q(2" T128#10–107�iF? #rv!�@&�!��or?Eyan-�p Dy .o VRC0)<�*�`Z.to�!2�A�re����im�?� doubK time�]�to grow�I )�da�usug�;� A�tA�)useful�֡)� �rof�0J�. Despj230 ye�*of��earch�6*HprovieE��wagain 3umm��deficie�%virusɧ1 ( �)��yet!b����H�*�A*(��pro�2 to�0Q goalK�;achie�/!�% elucXMo3-dim!uoB�VbL�$;�_Ei�E�tri4�,q,�aPIri�of�  [1–5%+As head�$-�Gt!�v1ɐ��in�Ѷ��c�Jf ofO-scal6��m�HA�ddOBN AE�A�$a4?Y� �-b�9}�Cc cri���%in� A�de1%^ manu"�%!=y!�U�[6–8!%Begin� in 200�,we lear� � &� p r d�/V��=eA x e � � cip�.�, s�-al famil-v6 �n:�and/or��Man�� "#<key�4�F [6 , 9���A�dz� b�-u�I. c !�RV1442jtrBA�K1s�C�4@ Q!�M��&%����could�v�IHIV in�H�in �ls [12!��regaס+d"� �invol���q��$a bivald)* ��(AIDSVAX B/E�o;im<-� �zs�? wD)asRhAS�nt ca)pox vec!6^�- d N~1 i[13!�5 �i:o��/Iz1@1!sI K= 2% )� aN!t�ef�1cy1\Exa/E%y�B)*subuni9A m!�I()s��a�40onI( MN-. \[r]A� A244- 7 �e` Og , s^g ��a� nd��e�- $&z'm�surfaOvi�5�A�veB�*� �iT2newq!G �J� [1��29ThuT&k` ;��!uQ�E�� :�)�!�ll@ap/$#6xpl ZlowYof-�Ho`%�H5 �)# thei�M* <9it�{ . Prr.�"wA� %��?szdff�1be��d5}B��/AI�isq�$embryonic }293 [�293] N-ar� I [GnTI]� 7�ed Z�i *���&� Man8�2��[2��Wj 0 ^,��&+ 5&�c � opt$Nd)h1�Ire-�X�6pH��e - ��y .2� clin�EC�F~*v��+�� ['i QLAA�i.^a �asuseed45iod�Nw [2�2,;�.s^l�3t �n� _#hoiHҩ?rap�iɡ�ein�� JGub7i;�>< &7 ,in serum-fre. cul �C- )5(�� }q �\�pro�` n]$cy�+i�Qpo���ILNSex��oua�yk qs [24–@2. TypE >9� �Ca few68���9Li�� ^ W� A!intraa �1tra���.m/.�s 7  .O�Nid"D /�I5��ol�Hext�?!� half-lif]vivo [27!/KBY� � phys%I� okine benefi�2?.�-x!�effortM�histo!Rf�#r�E�JA�amrbK'�@�6� �T8:�F1��P"`)�B�(��E��V&� ���/*�i�BM c�E. MWeC���Pa��lake[-�� -Sݍ�CRIPS-~�_D%� knoc�D�m��c�t!q@�MA\Z�pr8C)&�D2 Man5y  (�? &ibJ�aL9!��HX�A!��e�J dele)�X ��Tb[ �+5Le-�*n� $k�DSB�f�9�yHhomaj�@w �XF( NHEJ.$ #y-d�SE ��Dc[44 , 4_*ti�ba2 nucl��] � �r�� flu*l?!~� ( OFP )�orw&!�f� al� d"�E)���&inser)3f guid a�bc��A�M �ed!�!wU<s nee!Ito�ucDSB��'E� �a�dH�k%a�G/�& GenBank , H�>��ligXK� �  a U6!nmo!^aa�ns-�-ng-� RNA (cr )&�" �y ` ���M endoUhn%��!e�c�p�_?a�)f-A=2A pept!�linkerz� � yT&� lasmi� �eS�$!���l�,)J�( g)�na�h��%��A-=ng���Fem%��L� a$�U);��J`�c���toAL�2�X4MaxCyteA� ctrock-��U;. T�$ ts 1�2I �"?dely;]Ir 3-^%DA�mi}`%2dig7,Z+�8lL@io? E���3 �aid_.���!DTwenty-f�fhou�e M+�u� -8secl"El�.�Ufive 96-vflat-bot�O}�a,BI!t3W0 . 5 �� CI� =eke��ea�$,�*m;t� U�c:y ?�Har!R. A�E%�15 to( k�t�h15%�30 e�%��A( le v�Oo"� �-K7 24)!Hs upon��20%[fl�&y a�j12�15 day!� WellzA�1p Ow8I�2\st"� doze�Xs��day\�2!-of 166�)exp�to:� : 55� �M�1E� , 67B2A�44 8eV 2"3/!I�I��{� �w7hec>��$ ( ex� i�F2|��Z�,i| [e����&�g)l"��secre���(Galanthus nis {QL*GNA�"*' =#l a &D 2 j is u�V� �*n 6�(&� �b[4� Acc1[gu� "Oin-conju� �to&�[�_���  bn�}��-�'&�.:� A� .��#=�] .�"�E�I=f Ca2+�Mg2+ co�!�a,�o�RA�cA� 0 μM EDTa amelihr clumv\d�l%(K.ntrif!�F!� wash�&p!�$��Qq 5 rolB� " boun%��!p!wild-�+CH����e�ɮ�/΁��0F-A!��e8sy�"�Z�and�$�A���ba�PofiGaI^E^��' �X�U� Aba&�P� �g M�1ac2!l)20�� 2�re�N �6��re�]< or�.��$�"����\p&�g,�xT 14.~. B�"onA�f:Xt$�e �.@�-6��9$ 125-mL sh flas� Fig�O�0�9)4 fG<stB!K( 3 . 4F�1 5D� A]A�4D~� "� !.��i{ [ !�i�}  mb� !?T!� b'((&k!jso]�2a��I�F���_Tis ~u�Y�+ |He�s E332N� N334{4i*a� N332�8ixl�NI jM� Q#)Gha7�I�s�!)'�'%t|� by [!EnE;]catograph�I=0�M9 h!� a yiel[0*�A���.%"N<1l&�'/1Ab ) �+by�/��)�$sa�-FI�≝�+&�! s a��#��)a��s�yat!yi!� N160 �V.N,��A�[����� 2&confir�_ !�B��/� i��A5 ed59��(QU�Iʵ��3>�!P. F� eV,&� V�(.y�a=�4��ua2'*a���.�T�Va� &y )bj1����th`6��e���e�ri��+..5A*��)F��D!+oo �qS}1p� .9,!135!A mg/L�!�5T2v�!:�263�)�,A�o�-�1in^�8nJ�e�ed �d9 �.G�oa�eM�Y-�a)!�f�Y� in B� CD� Gro!�A��as�. 7b� 1-ͬrɭ? logarith�NMp�L�D' '�Q%� �× 107� s/mL��|gB))z��6�� 9 . 0 �e���-��� - . 6J�ByM�ŁIqHEK�%=� NEA�a2:�� At3 �Ae�a8!� �%*4 .!�%+6X%+&!kGF�? tyle�ɤ�J�)AE�����.� K�WAi@>���o��Wn�c3 b�*h . AUtr�Dym�/vdx�< ]et�ages!5_6u�l(&�,a frameshift"  ?���23�� od��2+1�^ -Ze�5D8) �T�� y�Oil19k�� y!�in-�"��24 .04o� �! � 8�of d:pc"j!��3 m�(a~ om� �2��&& �.%% >intact�iEvss+�m���].6�V%.� A2 �9>o�Os�2I�q*|I�] re�zse E8EsE�g W, $aJ!�!�I5I-�.�q �.��fM��C`]x ! � ���"I�2�512!�a �276-bp-�' D,"is�'ly un�lAK �.�A�{- y toa9by�<domY�.y1s"3^(�ga&sid�&di�4s az0"�trome�x"�u!&E"rix�7�X lase� sorpFio�/–� of flightJ^0[MALDI-TOF-MS�W� )toN[ Ab�2&#)��  � A!c�9�AJ�8�I. Io "' -"�y$,4bI�}B b�+,B�� EN-%ue )� vern%: by Pb:N�8-�F$!��r!��.�$H ( Endo H&OO�0al�y(by SDS-PAGE?r+w3<CooA ie b�odyemHs;jMW�4e*� �+2�/X$&�#��;� ��/&�)!�Y 5�m�> f%fB�s�~.�^=�in!��E�jw!"!��CI�nI��2�%20 kDa�� m kee�%b��sm.<4s�n%� 6�ati' hybr�>#!N5�%o �-5/�Nr��:H�� M!I{�t -2z I�y.3 .��� M��ng��ii�z��k#<��,fh�� ���M6�6�_2A>%�mwrbE�#2�6%��-k@��i2]m�t@�5�qU �6ShalZ�!)�"nZ�&'a9R7tY!5o^][47�75�'�It� i�' -��6toF7sa��!�&' {s: mS�T*R�= �m�I����PN��|� ��drhO � %�k�U�܂��"+1(�*�Ň�)6�)c�@A�z�c�� ; carrn� Jh)$���c[!]a�>�A��]B���B�1:�0U�.f���|m �'� 56�%-�6h�)A�*e2�–�aI�%��, 2%A�113a��2 �XB6Man7 . N�J��-CdeN;ed f&#d#o� f�?�C���_*]7lgQPd;F-�-on�5%ԥ���sXNBm4�MGlcNAc�"�edx 165�nQ/1�md^.Y��e,:�75mg�Cx�n�25%2���(6�CO#a��E-50Noe�"4e e��5�e�%L-6%�e attac� ,9��'ll�A\� x��A!�=WeI+.TL!Z �2��H��.5u2L,R�&K>9,6 an�. A pan)\��otr3*e�r�� tinc�rT,8vulnero�"�B!$"?'?e"�? 7�$!( }! �Bm�#��� of2, CH0 m CH03A!��12fJb9V�5���.���u1XF"�0�5"DH �V.�-`�=E���/a��B/"�g�6!P�C� 8�2�2�����301%<q6�EklD�%DG[5�.Mid#�m�s�I��1?=1p"S�c!p�7�.%�&2�f�I���nanb ȁ!nt_�RRvqY0UBh �/10�=#E � l�~� e: ZZun.(�E�6�6&�!Q)� Q�1z&���xhalHU6�w�leV  >Ki��ac�> }�lyq� 9ntigeM;"� !c.��!kp19�+9A�zg.��6�"*‚cI�:��l!~���|�tF5���9aZV�F adjac�ޑcD4bi�5 6� �!4�"~ ��I�J�1�M9 a ��*` .c�g ɔ� ��SII $!�Z>P PZ p T�h s ��|bF#Za�y� ca.UL>! S0aBe���s�Vw{Xer$�I�{-��n\jA%���Aw�4*�a�Xbe9kE��k)A�2,1-��oby?O�v� .ar ��4. MVM 1�" ion-�N�m�ť��$biquit)-�venviro�r!K� �"�=biore��"R�n�8�!>|&�E�[5�As.��hreR�or����CvR2~5�U!&A�m��!0.�"0F�>;aM�D9(Y !Q ~on [54�7T1-v�_v%i�C%i"08r^�7!eq �� ]�zc3&2� OI��;a R�=v3!lymILch�%��( qPC�.n %�a� t�*6�$bhms �z��l$W�6VMa�d �/T' MVMp� s N5%�JaM�-�CutM-.J� -DgT�,h�ML�y. �E@{JB�v�;�Pit&]6�.QatEp�/ń��%�">� �N-%�OV�Q[55�I7A^K 2A��EE&M'%]ZI�t,1+hapf)�CQwh��!s5�%�%��Gcm��+a�^=!-�[牅�littli�E;l�#�>�7�- mur(Qa¡�Anyth��2noR-ANapA�nt 1Q�)O:��Z+*w�4 �Ga4� iso$��MEE�i2A����(IDEXX BioReM ( Columbi0&Missourivni��StGP)d*�[����f mJP�/W.-1�Ent{ )b,EUviGJ�]!by��<�,No adventiti�ag�!�"=!.e f�y list�N4d�� d"6Jinh��BS2i�s . A y`Y5W!I&�KU>uNieT�6 �$EB"8FV �@-�A�a7Օ� Nir"��A*R%"� �?ei<uaoini�fd�,2"�7X stea�}u��ud�" :��A�e����6*���A�!E��&w x$D���6s:(t:a���6�7�=q.� ��{�/�j=>�AEnv�! st2� �gp1#O :R Y3aa�Nv$�%' �j�"x'[5�L63kt~now+ � ve6�r�`!.�I6Wr�d!#�~��a�QWN�M>�=��s�3:�8��=6�I�!�p� dec�,!*xJa�vP&�JF�gqa���C2 K!;"�8D .v�,tw<.{1�ᷡ��&�� ic r�D ulum*ynd�Golgi [1�1�D�unusuQ3��iiA�B�!�������"x�+c hind0�?� .!FA� R< �&lU�spike��uc�C�v� &��G!G *�#PA%�evogNR-� sh�)e2�Neg�_0�=X&S� s [3!7�@}*=~e�_�!s!?�! "eVmod)�Q a�)An� �D ERD)�)�a�zatua�G-*)�)W% ]�a&"i�qgco+Ha$*PF���� 1�)�9�:Mm�6� �X!I�F)Ti$�Au:! �Q��.�M��_ e] E&|J�E�L�u�Ņ2�FE�N�i"�P.*U theyd{�~nz��su$?�E�����C�b)�S-��A��� Ear�?1haB.RQ�M�.-P�-E04 %!�x.l 6F3)N�1xd� �FB�2�a�jF4�&�z�+"xt,�a�Ap1"�[1�:A�@��FI�Uf��V �1�S 000-�zon2 � s� sUo *m�("�Q, P =�70�--i�4v�b� su�J�+�� 6S� eBor&�MdeployeJ��reg�a�OG�1<m7 Ua"u ��9^.!`!G�8<2N  T; ,m��%f2>[U�h@ ic�of�r*EI��eaR�ofG�>re—� ��41Q�val—`A1�. Curw��OI�U3-up"���V�"�X� `25*p:` mv16�B� 't�2.�"{4 �5R[6A��}�s�w �ytr�^o2�u�"`Tb�KZ h a0%��Us�u�K� %adjuv�F�� S�!�� a7@NBeU coad�(�^�)8 stro֟ �%re!l|��<. Few"'c5�ex ���2k"�&� �nd 9��%�A��� ���. E&x �)A>yYf�28xoe�!x-=�B)[��O+ct��@� I�C@pa�z!�pauci�!!�IMan3-��[6 G��M(in^�8.�]kifune�2nd swon,Cr5�!.wi��nH"�D �!t�(�PTb�� � ��<hS. s&n!9v) oxic%*pro�i�:ex�av5�� B�D:�0[7aL/lF� r�+i^ne3O<=X-a_e )y:Y� 2Q���l�ac&�BdO!2 thro�%uK �(alnexin/cal ��h�72–7KC)��yl�:r|(E�"�4pU�!�F1:I#+�+/�GR)�,*bI��p���>4+rW1�lethyl�an�%fonR� ( EMU5.<�9, zinc�Og�'eth�T�} scre�s�� ep\&r �+I"aR cytoIq:�8[79X7?<J�s i,u{al _��1VZ7��!Ս�%R . 2� A!J1s���� YGyS���{!�ag }\ng��>�%2�sQhu)� 2�JS� ]A���~�p1� robus���Xpa��1�Rer�.AgAHy ra�&hO�dtgWi���2!un.�%��O��k + InGCh��W re�E^met�E%�.�Xs.g!��_���� �9�w�\ {W'xN1 �P byQ!�_noJ %��B�dy<�w$� data>�23J� s"(Aes!&]*9>� :i �r G��M2�PE7ic0Y cGMP!H,� Y%�E thAq well�I�@�UCW�3��a&�ECSIl�@�)"}g" �2f�1�^%TE�,nc�ee�/D"�3byR�:( aQ�+#�4E_u�"��=m&�bstEN2M�\��F�Pin��ayA�JiG�D!�!.�!E7�HUM�a�r��. R*� F� 6�L%pF�Y%%.� Y�� � �I ,` �9 8es���oG�;Rw ��2' Wte6� 1�S14]�in&��V��* ��Nn"C"�`!� Iw*�O!�5NU)!q�bi&\V* F�w�&s�!n�30��v �$ obUr� ��*�& �!�79C!�e&��d�Dic<:�� 1�. `C )�f�C E:*"�-K� o4� � !x&�"�a|F2"�t �aI��q��e`� b�s� D�C�Mic��*j�a�AN� �!%U�l/V.��^z -2*p�#� on,y7I8�� t��F�p~U�@d%])��� ��-aed=�'�.���{#� ��s �$U ��w)�.f� !�ySF�l ̐il!��+.tQ@�$��u�a�]q*��M�s�6daM2 n�bonYCc �Ye�K�dQ[2T germ� �s&�Bi�[7�81��� ���/* va�V�TEge %��At-���[8�A'op59 f� c S!�:��h)rr:��r.'e��ng�#�[n�lp"}�N�a S"?&�o"UF2)ob�:Ekq�mo t�.he, Lj^Tef]� , Carlsba�CA�� .BD &��A4R� ATCC;D,� IA VaStock�J[ �!�>� uma�:� m 6vECor� , NY�uI4 Kuhner ISF1-X�E�dcub�  (!(, Birsfelde�Switzer�����A�pagIb, P\?sD-0�@at 37 °C , 8% CO�E125 rp��@ icfCin�L��L� sh�nd� .&�zany�$� ,�tiguch� Osak~ Ja�)�O �.-�vF��6D-�eG Ӫl�-q�}N1% pluro�Bt!( mM GlutaMak`s 1X H(i�Kine/T"�>(:���5�� t"J���T9 � %BBalBnAMed( ( I�pSc��r ,!_ta An!OnjbF6@'5�!Za (��DuA�Q�!� U����š�-]�in Opti��2Z�/T��)�J�6g��!�th%?um< F��"PC( &Y�Dev[, Sunny5lA0��,E� 5% Y�oX0( BD , Frankly|П , NJ��, �H5%x-CD E"�Feed ^aa325:@2 E GlucfJ(( Sigma-Aldk� S�? Loui��MOq.��-�&�$�) TC20 autoIdE 2e�& %�BHercu=j,]�� �Q� *� �<ry�Z<��v o�AC�2ssE[SAc&� �A �  (�2 �u× DI(/ ( ( D"lol>U��T =�EK/A%�D =y.{��*� 6���q ���.�E�EpF� �9X2� Aa x%�8e$�ؘ"z�@� 8x� ed m2V�<W�0( XM_00764456A�1 [83�?.�W�wDNAk&S�9$AllPrep ki�nQi/$ , Germantd, Ma:��) �� PCR ampli�K[�4F_CAGGCAAGCCAA GCCTTG%� R_CT GACTG CCTGTCT�Eurofins�a@eHvil�K"YE�TaqT dNTP� -�$by New Eng9BioLab Ipsw�h, Ma��ԭ�%;gel&I �a Zymo5?n-> "�(,ɍ6��BtҤsM�S�Zr�odA� UC Berkel�� ��.-���@V�/��X�D[%Oa:EY(!�eArs&� c��2qWòa��6W&hZ��!�o+A�� .d�ptu&�[n� C�zaCaKgurC too&z GE D�|�Lafayett%���:�X 1: CA�GAAA� CGGTGGTC; 2: GA� TTCCA�CAE� 3 C?ACA�CGC"ach�ES.�@in NCBI’s BLAST ��], w� off-Vsi~R-��&ݘ�Sޥ-G �]a�Q6[�FM�i��� 3QGynx�(†�g��"Vf 3′�&�-"�ZYE��AV-�����:O 1,bkI&�E>r#In�OneaV~ uu��A��o��=re�!t�]%�(�B.M�8Shot TOP10 Chem9lly Compe_@Ee4$ichia coli �t � ��Xr�AeInvit���F�&bhTd%%i� 6 n 5 mL LB�th��% i� � �� 2��t 20 o"�D. Mini�MQ&�=���g�&�)�3�6(&(��!��H./A�S�]�Fac�(NG)9��^95%* prioOes � U�ll�ZA�50 ;�10��u�~A���!�M0�EP buff� n�t6�O2 108 ��O� �.�B�OC-400�A�a�� mbly����a�@ volu9f TμL�8 �7 %)w.m�Ztr��R6 ���_a��-@�,U�Me�)� ( `!v sin=ga4 a 300-μg�%vrq�DNA-L��:#�mA?%�M�^A�1�A��Y}0d��-��=�"qTi@$.Q"y�.�G>f.�.:�Mt� remoU:"� * UA�pl��i"IY$Erlenmeyer%j"���X? v� �Y�hto�Vc���<g\7�� or 4ys.!<�.��i+�prewar�= OPTI"�a {2> �_aQ*�\D�>4I�*+R. FYZ�E!)_iH�%!�� ���t*R�tba�e-eoliquo� ���.M� po�b�s^X��&!�OFP�A�!gI�a% htڨu�@( Zeiss Axioskop " , JenQ)��. Nuy-six-O. c���B%jf� d�E5�^L��I��/ed *�aj �9�5ed-i�;K*�c��M@�to����!8UE5�ci 9 )��3��X� ?e�Qe���c/wA�a�0� �T �'ny=-colon%< 4Ea2�J:Mc�5on �;-��aV�%� g7n�%>�A�)Pres�!�I�. �c";�E�r�!2��L .����eEgA� a�^-4I�.rvU�c.�^�t �}��e!�6���2- of-�A%�ǐ�d inr%Y����` �A"Fa.�8oTeS��^�e.�1J_%�9bi�#62�. D[fc;-*�s�8.$ "�`�m6�A�3 wW−)X0 Qe\�[�kin-labe� !"ܡ$e snowdrop� ( V��Lab�5o��, Bur�Y�?. ,%X�!&�!y��5*m��an2J Q�s (A�E�)�b-�%�p*G 3�00[A�3"L �* supe�oQ-AR9�g)�� U$UceJti��%�5�Aic�-d��"�c>(Boston BioPmA�Ash!.$phosphate-[ ed s�a!PB�Fn Gibco!�V�| %y��P:K 2z��� 5 μg� ofA;-*�e . S�Q� 6\H^li�����wic�%thM)�V� 5�I:-j:�b.���.���l!�.ue�:�%+e�Ku�-��%C495-n�ve�exc� 2q6�@!č e[l7�,���eI�jN<����fT&��s7, imag1Ɖ��3$ Leica DM5A�B Widef�7Mi�=e �& :�2ffaloiv� IL��>e\SaA Cruz& y CFV�[�sA�9�{�pa�ge��nǎ�"E�&��-*lb�oa_[H� : MG18936�da�) A��-�W � expe���o� eB ���(�Wm@ ��#at)�*>&�*���" (�u%�%[1�2'CjB���j1ZM@�!��d���K| alU0�+�/�o�O�ɉ� )�N O(0g�q� o��"1 4m�"'� a":W}�%c,�_7�B(I�megQ Madi~6 , WIQ���pre�mV $room tempe:r�0��e�550 nF�k�)� ��L q T�,F�/Cmix�;%�" %7w� A�U U�ed2o�7�%� �"���.  72�_F^f)�qa�-ve��%!�!���eN�eU.�Y-M�E0aQVKp.KA��  �%BF�1[so� butyr�0>�R$��aV.+a�kM )32 #� �-f"tpDequ�m�5_% "�6M[w�>F�!oAT������V�)�-?�AAc� �r�Vbelow . S.ai�7L  !mNs� &�}���A���prefi�>E�B3Nal��GB� P $z"� ���� (45-μm SFCA�ta�Hd,Q��S�_fro�qat�20E�)P�]S?,46�> ./N-&.pff4jtag"?*��*1]*�� simp�Cv8�( f D ( gD�%�)~,Oe���<�[!)P�X(R�,R�2YML&�p$QxZ |"��o� O7��! >�-�1�n�2��6:w X[,�T*&�%� �; "&a'. D�Y-n �aon Nu�^UxG), ��84%–12% BisTri%�c�sgO�in MESg�(� �2$_S!�yB _ҏ��ka�� ��!'.�D��ch��<nJv�t�� t>�e�S��"}�5�AeiC�GA er Fntrac 60� crot�� �(*Bio�$, Kremsmü]G�;Aus� Bapco�7��2Ax� �>�*.in� <A��. P�%M( �� +�%BS4z5-��9�:�� 4.-On � ��05%�en-20 [S�%O#S5 d�w�� R�% r 4Y�g� %to o00111uN2� 25��:�:/�|O�}L�!(, 488 Alexa)��j�sJ nti-hh�ML-L( 6�"$#A� ��1:� �1�![+^*!�6��n�…\�ed6�2�lu�n*.'� ?�{.SYO�na ,�L� hot:e�EnvҩS6�Aerk}lme�/&)� emis� w"L� 395 n�490 ,�w;� !�Z1�to��^��� W L���-�� &�Eւ�mo!AFy�a"2A"�.� 10C1X��JD�?��tagjC�k�'�i�A�?n? *�.U 1o �D 40×i3V:� i`��c �lEzor�A.���! ��=l=� yq��P�P/D�������"�-Q*�yaP��B�������j�,RX%��2��FUL purc�p{; om PZUu� Klo)Dneu4"&}M����-h�}u� �@wc4~� a �&�1g��VhZa+:eXblicmr#�6[84] (Ub&^S��� i��NIHO: Re4&�gr)5:^+. CI�N�� 1214�)����V�IgGe�ti-rab�di��*} a�8��6�4*:>�Z�AT ��� !C2��g��.M#50 ar�'0biMZ�A� ���� �.s� ,�/ �/)%�18MR� �6 des0@!Fd!��,�asEkSa C18~�-p�rtridgè&Z�&ry�by9�� at 9��5:��6��tZ�%*h,23 IUB milli!��NEB#P0703�NJ-:�.z4A�16-8� x�E�@[� a�"��E_VLe�G�byZL6�freeze-d�H. t&N:|�� ethyZ Y)�Mm' t BQby�LI�� B iod)����E NaOH/DMSO+���)`� A� 0� T@dAw�$��mL�0R �6�:�v+"by orga�5�0seo�dichlor� 8E� l�s� >)��b�E� of n�*�a�(�C�-p�hMS�G�m�R. Pݘ5�:�d�W�Q�de��-2Il5#�; F (:!e ,���a0o�a � ( U5�p384�wIrt , AR0 Bios aRFŞ Cc=.v! crystal����DHBZS��C m @"%E]anol/IF��t�$6�AB SCIEX �4TOF/TOF 5800 (F� MDS A&,T6�:^�m�l� E>�9H��o|ve-Alh��aj!�!per�,uaD�$Explorer V� ��!CA��hg_of�R.4VUbZ�0{2x��( m/z߬oupY %�an MS/MS�v*{�pq2l�a�KExpas+�c$j�J�2 work�^�/>��[8�86]�Z"�09!�&_vAc � ͡�;26��U$ -mL 2���"K%s��cr���Q5 pinner�%sk��"�:! �1+t ��i�_ѝ1�" P A0( MOI )!�]or�Ke��c�rripθA_FAom">$-��b�y��,�!�!��\.�:���a.�a�y 5� w�by �_�4!�q18S�P�YY�A�A�w�|5�E�p �( C��!ir�D"� copy �A�dc��J[{� i� E�a�d%�����jN�\J% :� 4+din �00�dLv�]U�� a PCR- �? �&a�\T2{ .�Para�}c ndzo �(C�B"VK deva�Sng illn�Ht@plaguU*a�world'�^>��rp>Cu�n�]"e :2a+dA�Bm)  AQ�b3e���2&�lymk#i�Ll<��1��]"�ca��EV?P� dis^P��n�%to=mvE�amammal�&~K"�n�0�3�Ea=�"/P�^�(�FmiE��0�GrehalT�6-"]$"g$�3( T6PA� Brugi�d layiUe�]l�$ Caenorhab*sygUX, K"�Ja� surv�r!�v.c �G(���accum-�!�� .�. l�^s��etZC9C]e=�� ycob� ��tub�;o!�.�7*�;�X- �N+"u%[�%-)+ . m1(� a7�!Y3ur Sv�4��P�A�*MIT�F5l��a�aW! CEli�NC2Bs�HAD2��C .�� �-g 3dtKx�,\_"�d�N��8"�2��yD>eeti*]t,2� sulf1,�"����Od�@+�q�b�c���#@hn2 ure-�O �PVax ��IJal"`��|iZ#!�ZA{��oH# V !�-V\b��Q���_s!�ub�7�'ngZ=�Cp�%m�AarInd van Wa��4�M�[��aE�~Axjysharp���w��8$5rn��=��siq�ydr�H-b�P2���mɸ c��oge��!O�ul�7g&v��*T-"���0�G bi-dq&&9�adv&g�ri(1 ���oryl-pocket�Fs��taneo���q!��j�$v&' SY J)�QlO�HVADt�U��ef&ce!�pe!�+�V�֡yenzymP.7��,:�L��-�Delmin��AUS��all�+ s em�Z�taa� �Tb�s�. ��di�M������,�"-�WmeAK.�f��� sJf�7���I��11�o he W He�< Omz��.�A�41"#*n�Vw@| :Ops���smV��h"1� =>�>��h�)s[l-�%m�Rf. I�Oa�$�'a�dnyλIon peop��6�|%�-��n�`�-2 b�:misk [ioLN�@b%�&$ �1��_ Wu�>� bancroftIG6@�U timori%��lyu8if��as hede h��cey@A"� )e�Yt�� ca��,�pha� �*u� &�G ha��Pr ��s;�3S�)!�����)qu^d�O]�eexag�� nchocerc �or�r��t�d �YSO2a�% vulu� �f8larial infectio��ns are responsible for extreme infirmity , distress , and social stigma . In fact , lymphatic filariasis is a major cause of permanent and long-term disability in people worldwide [3] . Due to the nature of infection�.�,.� and/v�,have been efEHvMye%�Pwithout drawbacks . S� 2sA.�A�=� A� undertake i rys�6=of a puA v �v � re��� LXThermoplasma acidophilu� PDB: 1U02��2��. A� �ortholog^l� ���mtt �� Ɇt��4a HAD superfam�>(S�iba�=|l s poss�aa��p,d Rossmann-f� i��3domai�� cont��E&residuW ndMg2+ con or bn` '� t�,Wstitut��eegF ��2-groupK� . MDHA� +���inclu�A�E ,�J�ap�(MU� � C0 , C�iC2A� C2B�JD9 � turn] jTmo���u!U� thro1�trac�?��r% -�)� reO o���E caps�i �l= z�Z shapaud� ctrosA�c�bperZ �?he .C� uniq�u each� �.}Ex�E�1ceJ � !�.9�qu�� �on�o6 �y� re littlem ty� aT .2�%� ( 12 . 7%%� More%�,� aligPG vealeA̭z�q�.G0∼140 amino-� segm�preceU�prediŋN-nu5a�]� e�e(is k  enE0to./a�*alQ� . It����both ��M� !-��BQ��a trigu�r &=M�a�funE�al��A�0at we pursued�Jy%�� �p*w . Here������.X-raySof.7L�Yf���om3-E�!analy� aimaFt elucN �e rA- 1��iQe-e�iny�u�2�Mw. ����J�bou�go�f��� �3 . 0 Åxolu�R ( �}63–49��" 2A , s ST S�� . El�#n " ! o�"�AJ�1–62�SDS-PAGE9RofAKs� d �Fl� gkl��d�v�liz| ��sA ށ�c�I&� u�E; �,!�iPcj of s� ,al Caenorhab�sP4th2ab�(-A S3�bIn>�]�� trunb mu� Δ59.�!N59 dele�� ) re�~�va�ld}4 )�A�� c�vE�!�a� wild��) n�1 u!w��L�atF�re�;bably!�ord�!U!��"�1�y�UJ�%��7& %+y!�iR� th,,helix bundleJ�>�157 )Ine��via�G(hort linker.3(158–205 )�{!X^, c9 1 u206B92; 39M49a\! Nα , βy *�uV29a�39�a"> compr� he�FSF2H9;U�2AE�Six+ llel�h nds flank�fAbα%b��l�.� . A )>β-hairpA�82) )�ce�*+ ./�!$ exte�2enta�six �edvsheetA%6�rwJr�I] C2B-� �is� �an anti-K5 etop� W=>_TvIUoopb�r�320–32A67 70Z�a:welMySDed �closesa�l� 9�aH -lik�3�^>+ �� does�- !YF�Ɂ� 205;�- [29S� pos��;�!�>��s=ZC ) gave�e�d@al&�  xver�D rmsdw 6�a4a''.!1!ob�i� o� Klag! F� } �14%&S � ty���2_pZ[A!�EO9VN� *d t� �=6-gpai�R��e rcal� Mb�n g!cona��mre E=- inc�p-= ori�ys6)! Inte�ngiIV p��( MIT )5�M Vps4� ATPaK%�$Sulfolobus= caldariuA�4PDB ID: 2W2U ,I�A�4A�;  3�Xa�K$solfataric6IV6YBI) [30V31�7 MIT �I�!te � �.zby a cal-co��oR�6���is��C�%aH,��x ( R es 4� ���m ���se` ,� er>Wx �OAy��)� [A�.��ps��, 3�!4]!�6JD stri�a�� o!R=member�kn�� corp^ }. S�"?&� a�.GLJ�&Z�eW�XAVi�Y� ,geEMycob�u�� S5:S!c.x9�� tein-1�aB �s ADly ass%��w�#mvu�� body�˭#$, cytokine� absc�#,� vi�bud[32Q�b#chaa�er;a���f� � esu �% AAA-i�e� . isCa�endos��w2%�to lys�~�#cctsdi� ESCRT (Isor%0�J lexe� .{��)�^AVra�e�� �!�$gni�.�E!� -III��� AAT.��f�M� TA�F��eUin- u�� �ccm�A�th��!��[�)� . HowJ ,5�H"�IVMIM �s�_�� )�!-��x� �FWE�ple:`o�[33AInipClra�c�! occu�t% �.#�n"!�� -" ,e C1-' 1IN���,�#va�%�Qnt-expo_V�B�!@!��A�makA_��a�{��io��*M0�.� 6P%&� sG� at s��֥~ MIM-}�s)��lMo=5�3"� sh�2 sign�$;� &any��Uxm�availa�otalV�9 �8!�>�rai!�qu�n wh�� �s$a “moonl�(ing” [34]&mi*[to�Xin� j���F��*.[� ��%;gen s� g��! f .\A�w�;a���owE��p"�� ��)�mPwhe�is!�c_!. K"k!��axll!Oup�am�&�OsR�\2� �a nor�$��,+m� }&� ��builduu�Emed�$b&raE�tha)N�"��"�rA* )h��:( O)vof! P 3u��carryfur�� .0% To tUif%i9)B��ar(..Ey>(!�a�un� �W& �pe��Hexper t��S�%)�A�e5hyp�n�v� r�of2�,eri-1 ( mg36D ;!$-15B ( n74m . WeA�lR fe�dsRNASu�ICA�5Ca�rr!fMg���agRIe� tras�!�-:�worms= lacku6e�h �(fed � � showJ"(9�( %S&i��O � w2 ��ier��� ^.[%B2>�T6P2 :0��u-,��clO#2�/X"�y�u�Juli�c� �g� oaX� orm deatho"� $metabolic ,-V*Ggu6 9X�* ��F>�.� ..��E`]!�E�canU�,ttribut&G remo "��hyp�t q6��EoX�z��)&O,t���-i��Y�'"��t�0�X�!� �' ]2; is]&v�0/-=��e�Pttemp��o�-�1R�XU�� q( Δ17� o*06:%��&((% phobU atch��re���pcoa�po1"2�T>�E �,+L229Y/V232S 6S/A243K 'A�e�1an�*t�,(&olug* !�g-+=�itself��7� N�':1-178� u7Ds Nov�!d� �1E5�  s�km�LAb���s s�!� 5K>H�B&�+1�, �'�� �2�� J>� ���J���!aU+�onj��t��DR��!i3��4�\in%,M�%Iin��%�re!�dep�2m.��_al�� $&X�1by CD "� (F�%2MuP�c"45^3. A31� olo""�!�i�'�$�ɶJSdT�#[0"4 )H!�>ua.� �^9$ly co-1O2� �������yt4&� !�det�al*�o�a�Y� 4*i�A��joi#5Eunc&in�  M>� play+� +�kc\�q��.�� Q A�6T#of�SFtl\ �<]�ap>a�c.y�ri��� G%Ery) ��machin1.&�1r�=�zb holde#�rAT2�� &_+�B�%[35�coord�3eI�pmagnes�";&AR��$�u�)�,G �!��in�N�c"� ��b�j��)����s��*�fouvi H( Motif I: Asp213 , 51 ainchA\��sl��0�%�THF"��L`>9n�s�. B~6�a�͡A�>�*yle (��q '�>��6/mM-��&� *�)!eY3M �4l�`-���e didF�� obvi!^in/e���:g\o��*�'�"�� a liga;wor:�er&:u.�4-'�2.��C 7%&�2! v"�%,` -gui� ��� � g�/E�up���M 0sei�+o9^��92�%�.�o�A9e P�.��*&�T ��a�� eC6�6AXβ|![ ?��-%.�ADT3�>23�g)Y�%��A��� a�~>� r phyla*,6.,&rokaryo��Sac�omy'u�S .�.expB$,2�mi*�`�or 5!�ul!���e�&*� �'c9 +�9�0=N9 e �re" �]a�<�#c chang��Ks6P.*�A�Łj Tyr22AGln332 ,�{34��336!6r Arg3372�lL5�6Z:��@ kcat ( 24- , 11040 255-!85%!Js!Viv�)s r "� )[aM . Ea�7� .(excepte� �Av��-va,�e5�a!��@� acti�A�(sugar moietL;�&��� $�L|.�SiC Hz ��%�%r!%/K�*emU: W.�7&�+��s��SifZ )�varia-?:�')ir �?����a60-��#�q o>,. su e��3i#6!kMethod�=was&6to meas�KI�a ƅ#�6&�56pV�>"st�<-�.a �2�g���{mpetiA�=hof� typ�.PIa�,of 82±7 µM"�6.& a�s!\�$@AڥR��deiQ!�A+�0 drm�i"<in���.�-�:q,q�!�m�9R"�!a. F2-e*r,M :.Pax�)].�Q�.�9(!le�|Us�~a�p�%� � eF.p�� oles02Ve�lu8&!wAis!�.��� eric��$"h(y !gz�Ga ��of �@ 2+�� y��eq� �1e"�hom$2D could) �"e%� �; :y7(�n� x�kE . 9�9S erevisi8B!|,M . tubercul9� gene� d [36�?~._'&� ��B&�W* yI5�A"�� �a 1w�:��$DL2& 4,)�a �}< reli�9 o en�t�k:2�wZ#5�e�aAD1*c1Y�KI)�rI��e58����� ea.�9�(� bulk"� �����IB Ile;q�:Glu/Tyr;q�:Ly�}�S���A�!1� &� iZ��5)�5BF�C <.�llI�Q� exam1@rJ�7of�%.�=� i�b�Cs� . At&�visual5� - r Y]� � �=& (dynamics sis9s)�u.S (� ^�e� provD@aa�t��N��, ai��e�@ V8bo!2�ՉT:@t�A��<,ofomp�H,ZVa|manua�MyJdis�=e(i�4�� $“in-lineattacku. I� Asp nuclef9e&< !�q8� �_has�9"k Mg�)��)��� *�&"�%&ex���!�D4yBF�1Bof�2�g�7ll)/�C�At%�Oin"��2E%'mt%#.:Z)%�=ltoAe mote#K9,oY+I��-�YZ� � FTMap �r [41� [42]vu�!o�y&R;hot spoz _at�(#� ŕ�K!}�(�%n;a�I�6�j �!� -)�)� �7�3�a~��a pocketp�Ÿ�"�"+�q �$��Ms 5[5&�)�� la^juxta�$ Q�v�/�.Cy� AK i2�m�!i� 5�B��u�rotd o fa�ith P hot-!��! !�0Lt�"�Lm�(�CNAMD [4y&��[ \Gn!�� > Q�_>=D&} -B<is6t�1�!, p; =\$ *�91YO�)/�.!i�2�AS>�U7-���9�.:�;� ex�<e"� ,a��5s� ��fG"�va�7 r Wag �.�'dU�a few�6)K2<abAM!�5da���T� N�8N@���I�q":L"�54�{I[is������ϩ�.>6C�NL� _[m� 6`�&� a ��.�2A\���$A*aRf�"AL!�'t��0by DynDom [44BJ46]a [ B��=�Vɻ!����N��C*7 ��)�J�"�R `:s?,�-}�e�Cco�.#�u��of1 rv IS>Q.!� cyan�/a Syne�RystM$pA�(CC 6803 [48�,Suc���c3�A� cell^����;YRI�Gi��"OFo6hH�IB�G�h�deI��I�$s �.(! )� [49� 5� �U�Jc!6 -S6PU�(�3�D2T-# !��ap6�E_B�9"�%-a�network��vi��\ 6��i6�h�a2�seM[%�}@r�Ueu8a�a8��#be�&��0nt glycosidici k8N1^C9�(:�;( 1→�: β va* (α AccPg�\ur��,�pGT�J��C�.Loo� �13+ &[via5}��GB9 .%����op�C�rl4o�:d*v37{1�.o cap-��N��#in�P^m;er%zUprono�!"5em�7�KN#�F�M�8!�rec"by�7� � ofnuA.���A�< lashM�� i1��_���6�kf'�4�&�/ac�A�qPy:�-in}/2i:)�._A�1�or������Tof>�BE�s�.P1��Jus:C � !R 11# expl"H�AP)�P!�!monosM�CLX�ar���S q��'��.,�, wl�%���� no.��!h�etO��.f%� itue!��1.&$( KI>10 mMJ ts^ mp�p (s 7C , (T�&}$B~@�a crim* issuŌ��]-Zoryw�>Ikw�Wb�R0 panc"�<�["n � !;co:/1sH.��2X qs 7&�"'VE�j Aln �ll��s&�RUA:N8M.J�;\Q�2�3PE^[ofB�5:"�$�s [51] L advana.�tdja_@kub�$s�6 . g�he�tidECpep /Mk&a�!�AGiJin]^ [52�3]B�0�! ��#Di�"lim4� �L4 t-�"/"�G�#onship�%�1�a�� c*qw�5��[lE=*� :�>�)'#, u�3�!� � .�6`,�-dŤed2�c.B!!ih��MIAW"�* �BݹT�w�i���v>c"$%\\qff-.*=$no�! h�4qޭ�A"F���QF-ҙ��4by:�"�!iˡXlem�?e%t %h��,I BD/s�E�~do*Yz!�- �+ a��%�A�Q{:2N thrR."7X^o_a �mja��5�S�&""H �key?��"v"ute�E�N!3�S^' ic bs<\"�V �@^I�gPe1M�WKe�7zQbe�"V:1Q�Dbi�T��D�b:9Q.  _�%�w��K4A >�7�y�. BOZo_�!&�0'!> �$m�&�A�21�nt.B}�r&\�in&7,�$-j�:b��:aneously&�R_ �9r, �7'��e:'QhE)�&y62-� D-��3 �!mԽ4m��"m*a�H�"��7t�(� Z�+t.�narR\&!f�*82� )� w-]e�K.!ic.�1 !v?��i�Ga A�a!�amoun:1@ �B�6an!�capOE��N ateg�3ly"e1 � -�:�= 9�Gi�c�&�:A+prQly������ �!E&;"R,� "�;app��![b neeF([aAu��A\H1w+��'m�� bi-�:�;M~)-J�B�����6C($ #)���Y�%M���Bo�Ac1�%�max#At� trins�\i/M deri3%����sa���O�> made��lee| ~UUc�%.�Kp(\FarqU mimi��ɸNa�2%Bp ) . 0C���i�@ down$b�p#�[� edI,T-Coffee [58u!"�#$ESPript [5�IA&O!K!�B}x&w)3�$E-degree:2o%�!� p.�Gi�!v�3iIc�Gi��6?S� !��c4&� R]Oi traja" S�ise�a2td150& �"~2�:��E�s��D=S*�D�4gene Bm1_08695Md�Z{s�!�clo!�(a cDNA libr!Lby PCRMp3r*4Frestri�Sa�= NdeI�BamHI �EdAu$. Standardr�procedurQ�u� %�� into� �!(pET-15b vec�z�ro�e�&�"E9a TEV; 9�& EV )a5%2�sK�Vm2also se� Kf-) �pETDU��by��A�HAD��( 180S�> MCS1-V XbaI=/A�F*48I�169F2 F5u KpnI��o �'tea�)�� probZ"� &� !c H��'�S1 $ Q5 Site-D7 Mu�U3 s Ki�+New Engl�Biolab�NE�Ah%� foll�@h�cnufac�r'-`otoco�c7 10-beta C2)�"H&(!301C:-& ^r!> smid�pa�d�pur&�At��p[id-� �1irmluracy b�\. F�l$�'�H=ah-pS -�: �9�*@KN39��p�:�JE� T7 E kYG Y/Iqf C301)T�L�/O��priA e X��iP�TFlask�eq�gr�Iin LB;2um!!�9ARPl1%"�. Fer�)oTu�a�&A$s: 2% soytv.,>yea�a�rc��171NaC!1 . 87KH2PO2.}9 Na2H 1�V 8H49�582S78�yceroXMg zAwin1× Korz!Ece�>ls [6NLAW]01%I foam 204Q igma�bA(f6P 100 µg/mt%$ampicilliny'Z�F &N# in f)d��. O#molonyGinoGJJ�-7 nLB]�1 a�suspenEa�>>500 -LB�Js�i�g��z6wf incub�overnU at 30°C�sn OD600�D�MTen~[er2@m�dA) oo[ L�fflo 510.  ( EpX;orf%��pH��rolt t 7 �Xiuto�c&�,of 30% NH4OH%346 N H3Af�8d�Jl; o�7!:6c20%Iair satu3o�"Bt� ga�_at%� 5 vvefd�agmj ion- ecas�g �-�{i�^_�K IPTG+tC#a�to umM�A�(er� Zdr�Tto 18!��M indu��).�j or 18 h �;har9jn�C!1(=��(�) :��@MOduW%�1�I�f 3 hoFJ37�o� �Iar +ed�6Wa8�n�^pRa1a~ froz�mt −2E�until"�E�s�5��or��i��� LM�thal/nd�zej ( 3aUbSr�5 g 8 ��oe[A,&n 5 TrisA�A�5 ,i�M�.2$imi�q,)0EDT^%< PMSF�O��DN (I���1�t�r.� cko Q4���� S883gV per �y��ga=6xly� ��b;pas� �`a�nluidizEY�R cs Modk#M110�at�, 000 PS Lys��e�lav tw sp��(�5 × gM;�* ( HisTrap FF�.umnm�Dan ÄKTA FPLC ( GE��sci�?n wa�s"�l"Ke-��a grad�6I�aQ����M]i��&a� "�T!�dil�D20:5m low-saltV�Im6�E;E���2P%OQ1NJ: ���!."�j-m�>�2��J� m* fJal!� -tagq.@)3 �a# ( Bl-u�:(d Fox , 200�1� 1∶ �H ∶mAW1EV��S  o di`��orageZnJ�,�%l,�Cl�UP� �$�#c�n�� 15 m� �(n Amicon Ul�/�T10K MWCO{P�p�&)T liquo!��`�gvolumYn�ao� �S8�S,� S:2Wi&T� � s�N��@%� w�@wo *�h�8� �lGEH� �A�.` Cr�gJu *�Wauxot)�� �\� C302� ,�� S�H%Al-��6�ed)�DTT���X�l3�;nf �?="B) creeF set up))ei� full-�X�s� � atY in 96-&vp\s ( Cor 355�IH�~1PS�( HT , PegRx A� spars trix�l�?�4( Hampton ResePq)Haz&�rop s�1of4 5 µl�290 KAshe2�e�in yiel�hexagoL-A6�� &�1(weight poly�x}$l ( PEG���s-�e9A�W pH rA��� (���opt�}!UA�4ve1DDMg"HTv*� data�z�A?,f�of bA �"c )Lin aa�P!ws (A����nD�\�33%%30i� ��sodA��ypH) ��3% FY%XA=�aCo��� cryo%�� �.���ofA� slowlq;-�to 25%��"�E<]f-� ?ly2!�-6%��F � 5� Cryo�%!0J��Yo `LLV3OiAUMiTeG�C� �iquA�t�C!s�p� >�.S�l/�=.�\2{�!��Y)�0���YNDSB-256M�B�2-��yl-O>4-p� nedie�MP%#=�"� -��cdrNa(�HB4A&?^��-s�ť8�UeqO x��Na<;� !�se> c��#at��As<��Synchr��n L��So�t( NSLS�Keam5 ×2d\uhe� ford2BRaXSa(LsK SSRLKs 7,r12-��G�er�#�D�n!��_" U�.K!B 1° J l�*�a�eɴa D@h0is Pilatus 6M�:��; � �o"(@ ADSC Quantum 315 7t:���Xes�\HKL-3Z [61]�l)1�Ryvpm�cal�� �le-Z2`s=S!~ ( SAE��4Phenix AutoSol�_a �*_>�JN���9v;]1�eo�`A��peaks��/?O�7�S�U�B1�2[ �/. PVt �U$�d �cto�Lj>�B�U�G6veq [6"�\�/AXbuilt i�FaOly TCoo13� refiI in1NR S�1�aref�O'3dh1�!�of R-�YJ fi9 �convergd an R-valu��2�57!Cof� . 9% �9!�2C&�� favN v�B� 6R-aq؁��Ra�K$andran plo�LovXe@ .� N�ll%�q�Jw)Y��+t�M"r�Ammat^T)%S�� q/;t"R(c*:~)QV�C!PDBeF�j$http://wwwv{biy0\ . uk/msd-srv/ssm ) [65]�I�1(8ekhidna�|io er . \ sinkMfi/dali_�8/star�[ 2 �-!�WuY@W ok37!�6Umr-%)9�0�s^3�_�q aI��s"�WA �!��/lP*�ioI�X ��mosom�An�~s�W%")d &|�c'y�@��"��ev� ��*rW �&liKX�. genyBs8$orms hD ozyAR �(5cNZ"�X� piX[&Hl a pSPct�fAAv r!G|"��-.new 5-!����D&!JE�iso� ~ K�U cribed [6y�A`.Rof PIi I<�! �A!�o�!>�U�lledHnd=T.:BE 2. Homhy>e:�!�p��m�V�*J[!Wwil.&!��#U R �;$E%��F�>sB�{er�!R-A3locgnd di Yn[Q�� BccI�.Dk}Mcu�7ejnt6[vnt[5YO��T}e5�1�u�m.Br5L L�B+�y�)hЄ�7c�aE i�q� �!��Zapi� EYEri��j2\>.��A�. F�5�1E�^l!W>�Y�@y$!;!� . L4eQ.�4y mna��G%��@tW0酉n!HT115&*�k�\^\[6"�*ڈ��p)� �C�de���xow�h1O3/C5H5N�$x ( 432 mg� mmol� fresvMd��`pyr�5b# 5 mL��X*sar<Qm b�$l[� &�$( + 345 y 5�z��mixs %sti�()}&nNrI 1 at FH2R|A�24A�nd%�WMaE%ad u����!C 4∶�!�V/ispA�/� ace,*)��&�}�9�F�( 366�oI . Td~i,2�,v/v/v ) : Rfm A<40; 1H NMR ( D2O"� 39– 52[P H , � ,6�67F7�t86 ( 56:9�s�0 X12�u ;u1� :$; 13C:�6�0X6 7 , 6-!�2 5 7"Z 68 , 7!�7�� 19 25; HRMS\!�. Nexc%5!�"^CioMol Gr@j( Enzo Lm�S&���U9e427hct)�atQ/rel3d �/��F��f30�. / B$� �absorX��  �at 625 n �Q�a@�ar Dev�kS�BraMax M!. crotD)�1"�o�a#  :�Z�,lyU�%t.�� , elf>Aw�ne�&�R2;Rk�o� LS!�RBU%� �V:&�o� },�!���A�:e.�+-d�)� � iY}^� 25–75 n�j��M��R�param�\ K'%�RG0V�f A��Pdid�0�1$E`veloci��U?at!'y!�&> i�<g06%�) u� !\,EnzCheck Pho�Assay,+In��+SAY� zO-w>"  Beck�DU800E�t�ot�er �,quartz cuvet�(�rn2Y�18B-Q-1�#!25�2l��. D��'�Im�&�+ ��#P=En�yKI��#ule:HA , vo3!1x-o]K vmax�1um.[S]U�6��K<|8Michaelis-Mente�ic'�!��*} y�� �&EWa�.>;1�5:�r[E]�� }Fri��aE kR�6�u�it9?�-e�LtZ��"`�"~�B[�g:�V�o�rR)�"�;!.D� byA+��B��P �W�a "L< R�ik5%�o �&�&#,�, 2�6.~޾-�I5�s2I�IQ &2G�"�Q� xlog.7UL=�#9#, FAST&c3��r. /�3: E8Y5�$, S . *eU( A6ZY3,/�.BpU( H8EZ3�$e�uploa�A�>#��/a�7Y R*7CEng5-V�+0! hyre��ere���3".1�|�v�7vS�� EV�"bRe�,&Hb�onC�� a >95%!�fid< leve�To :|"��MFpBE�H -to-�,Kua��- - aQ�$u"{�p�u ��kPɫB*�V%e9EVm:Qu%[&�6��{�2�2K �P �"�ftO . budu����7ify�O �O�!5ap2/{ e"�C,j�e]�D�T�X��1 ��� s �|6�u9 ;3|S A; 2�{ �AhU���A�y�FPI%�9>5�jG.�*������.� 1U02���K defa�se�C1X�*!!� 2kL,2���A](KxD\�$pyranosyl-��cH-α: B6M�j"�Q�4&9'34e9 !��!T"�<� � 6s�G�Qa�i�&����Ub�U�#"�*Pg Asp+7"�zl&86UM�AM6�i;��The G@5A:O�lie"�I!��H�c:�SA�i�h�T�RqOI*mf"SJuI|8UCSF Chimera [6�L Hydr� ato]p�N�Q!�E� �, S�HBUILD��,in CHARMM [6��'&wWs!�tly�inp� Bor��licit( GBI� [70]!6F-MX�+�iharmoYA�8�R̞}AFheavy �!!w =25� p*%teepest=�   D �� t 1 Fa3baJ ,Newton-Raphs�o ABNR&(0ejB �D��Din(K )�9 7!� ��;n�0!X�h�2-`'�Xpat!Z��Mn� ��dis�=A�'A�of�Aky� od vq&l* tMv *�B^ sub,�V"��%��:� eclin� tools��"%bS*�) A���i�5ty%�h%6� umy5PN�,se)e �O ti-c%�[rap�T�.r[fw�U5CB|� ��q�� RB� s wh=�^`al�c �eP:*x ���aq��E�5�bl!��7n[d9�e�li+T;p ��0ilico��valґon��iivo bio;cU�maga�. O"�Q|Js PoiseuE%GDarcy de�!�@ņ�J��b�'-b� =�sb �I� lu�BcpermeI!�to��t`+= ���*U% )<�� �� ! en"&|xe��9�N~@����I F�w+H3howM916�`1ia�I3 �9�. WR)�6jsp���� urG5mI�to�'o��top�D`�e glioma�L26�S!Xa�co]�c�-carci�) ( LS147T\3nd� sec*iva�� Y!��2�xdeB�M�J�E�me3hB)B"f:!we�D9Vn�p"I-� odif7�m, a��e>_:]I��h8 "4a@ru�m���e�%�l+!�%�a�C2�e/olW�M sa��.��tC݆'l�e��o�A�!�i�s s"�ip\��n ]�069A�Th!/@ �3�Ishl# seekB�KA�r6�}" E��B�|s��d. sЍdi}�:�snotEj��!Q��ll�A-�r:.Jp �:-yZs6�]au~��{m�L��tra" "���dq-M�"��whilst�a ��ng%č2 t� ���J�[i'E|s\,�t�zev��ms�1ce atyp� 4�t$�M} lifeC AYI9�+�� d�usp� � [ \ �KH��P�Ep�vr�{�oreQ�1nQsd��a�a ��0(e{�tw t-�[m�1^F),��@ yA�h$9e�b&� �nsoA�se imm �.� � � s�y!k�E&Min6� [#1����'gu���iv��-�5v";� by�Ч}��n� elev�tE;Zc ( IF�@[1$1©�`dqN�h2�r�{]l��{/�%(�y[1��]��U���be2���U�n)dAn���um��ptra�):�;( ECM _K#� eZosskedE�e nM5of� la��el� fib;F,yA�e� sue�Ō��m� [1�.A3 ���u )E!= nutr�9, *!]��a�s*ҌBr�� �-ff� )Cra�Cpa��>,m�� ] a��UZ�n%�"S[m�B5�i�iZ 8�2liL [1��SechA�%�<� hf soug��o����%��s���b��� ani��n�.md"F��enh�Ar� of mX&O=A&t}x1��?�,l�,M � L)D1�0to � e��.� "�ݤ� �e>.�[12];%XB�c���6-�� �JL%\�Z�#a�elet-�/�rowth�G�O\ow�� ��g�Ǣte�����l� morphO B��?� � l:� leQQ'Am�-�c�U%�,!�s2)e< d �/es\�Tuva�LE��e! .���d!2 � rugA�i�uc��eor:1y(a�a��"H* [eFE"�val2De9ʩ�!to)i����mecmA ����on%S�on%��N-+!uYywick-in-� l&��p�^!E-� }!l 2%mH"@�! B=o�2sturbel��F�!���?" n z�$D &5J)� . No�va�e w��%P�'� η �k[2�*l�6"�!�on-MR&43 ��u-"{$�Ujs�/���of���μm*�[��.2C��fait iXmBU�m<of {Rk�2n-scaK��3* cruc& 2Y����\mb�: tra-%���q'�.}�97Q � �u� s�/E�s�� �U"�A4$a 2�a�s\ �Bso&S\F��EIB&e1dU|scope!# ��d�.$uh�i��5 MmEhq4in�L"#i1)�.�e� m��z��s� � rwP�]nav�lZ p����^l2�a?cf �Yky�-���nMs&� � de2�.�!΅xŭum [1eT7Kb�a�uni�> rَm!�1�i�.��l4/�{F"( th��d�=o�al��-�F �s—a ��"�M�Z,Ea!(8�|A�"�;���!�ph��. e�t!�t aD geqOly�P� �2�!=s+�6!q2�2@q%asř�Fx:-W�$b�,78!�BW�� ��LA�� fi�OI/8[f^|. S.�����!", &�P= �l� .J � .��a�uter-� a�m�N q^ravn[ fee� 2\::[2��,�=8t�A$�)6� �:��r&{k��B3�O�| c g�zyhybrid e\�&�"lx�)�O9etv6��.5 ��DA�4^�qQ2��E�[37DAi�g"-no �� [3� yP)�����ur�. �:Rs�gk/�ҡr��/� �r: �W�a�L &�= surraG!�� ���� � �{0��?!�8�le�W C spec(��\ �d��E(xKbH cm3��> 105-k�n(5b a;B�ǁ-"�� �1e�s�][su�e s [3�]W% DCe�U x �Kc�;0d REANIMATE ( CNum�����M�MU?*�AL Ti�B'E�P)�U��Jw�@ma>�E�!�qg1���W��4yA��: te q�ENUve�;6Bɼ!�M�YA�{P"�u��1�n5 �E��ɒ؊ta�X-ly->Ia��7� ^:R}�*{ex�T���$ an�.!�-�I�o=w��~be59�Dd !/� anne��):be�(l)!=8�m"�%�� na�al.%l#���hA�p �oqe� Y�a�xp-�� i��f���*&�"e 9�AI��disrup���( Oxi45�D�8wvuc� �"�R SW12�OM*5es��:Em*� ��`R� �|i�qN� � �4Qi�rete� �-s�&~ !2� ��k:g Iu �A�mis�� sch��of Fry"HF[�}69nd/!Ac�V��GASL� eE-QF"Ka�i��6 ’s&/%# 6ɜ=([R~,� ��mpoI��$uE�,`1a9Js��sKtflu�SG�!)؉�9X!* �>���]�y���a��E���<'��b ���&�by�&smaka�itR3]�ly�i&�����}nk<u�7rt �)u&� �!�p�, n�Mly-M�A mesh)�.��stu$��� l 6��-e�Hjr� B�%B���A�M N�'�rehg!�8"}#!{"� �tsN_?��!i�$�>Uduz.�t[ppH "$ABn �9"9"xen�?f�IC"�reUDe��!i�r���*� �� orf�"A�)�m��a��@��5i"J""R��y&SydrJ N2�+-�0! 2R ����<�6d"�.JDwe��|A4�>5�B�4�#U.� !�h�y�j��Ag`���)����*�Av�B�(� hemo�adi�%^ mun���[4�4U?�{Pre" r e"���:!YVEGF (�.�g2�)�{gT�9ai�window�v{1 ��Gi�ss1�.�!uEr�"T��{:�2KJH�6�,fu�/dosagwa�t2�"Ke��tߎ��F. gold :ar�4c� 6��� )7sf{��YA, )Zfw,���*�$y �T�Ia`k9 hist�1s�`}�E�cru��u�$� ��#�-�� &�&� 7QSf e!rep�ae��"r�?g�p��* �a���u�6H[5 3v�oq�p&a=.h*I^!I2A=VA��do��so!+.q&I�!��2/P&m���p%Up&�ix "�3to?ICE� �!�"�,&� ��ȵ*���u��OY�".<:��. OZ1*�h �c*� "&*��k�Gb*!���2� n = 6)Each]*!^al.,�0��n subcC��l�$ E 10 wp(a�, femalk Q7&� 10!m 14 d�e��%�� arh�p��abe��(" sG!M�h��� B�)�!�%I[�#an M�c�0c��C!3H19 ± 8 ml/min/100g[1Ad� ^�� ly Uw�use-fixE���Em�:&Zw[�y �A�3�^ �pro���om� uIOPS]Bio]M(, MRC Techn��E�Edinburg!��rl � ��)a�t�% �AW UK H�QOffice �QDt]�1c�_$s Act 1986�UK&�X�1&�]In�u��NCRx�7P1[5�SFu}T��Z�*il!;liGl�d�d’Es<2o*��$W30-)�6�u�e ss��2�?!u���� Gt��D "�R��Q�"� al Gaussi�9d F^i!;5 x� � �p�K!��2��� �e�8 �I��e2�si'+���vn�Jseeq 1�jSkelet� .J�� hres����42M Amir�.¤o F��r.8$, Hillsbor� O7�<�&�% �graph�ma� �~�!*�&�^o�"@��*� / i��bC4�<���)u.p)��0l�)�en�� >�6\\s�Z�O* ��.0�!�sl�F!�A= z&��5� ��� e��� knes�4FJU*�2S%bsIA�Sup"�{y\eo�!bniIm ��a��aѢm?-)Uchose�f�O-b�A1]!&�� �J {jV i�.aq�1Ri�,� �rq� > �@�w'� i^-1(2� �"X 2 :�& =�y:s&BU"�3";:K�-�A�"�3� �V�of PrA��\ [55]!.^9)� %��BBH� *:���!�j� 9naDhaemo-. � �a" p�W. F~7�tf�e$ll O<i ɝ�b5n@+h"�9���M�Q�:%lse&7 e�Pv� ch&�*�La,� de�=%F%W�D�E� lgorith�RB��st,>�b�E!�assumpA��kE3�2�a�r�-!�:�.����9i MG���!�!�sh)}նr� [5L,�U��s""�Ft!s0�?a��snK evi�m+ ���x�01�wA:��Q8��%."�Ld+�w�� eF�Y0]. Q�����$ 9�*Amv4�#�-��j�"I�e�2�q�A".�8i�|�9aiy�O�#$~/� T wo13*�A�Zn�s6�z �8."i1M%ZE�%�$[be5�d D�@u�F�nd&�!��� b��"C!/!,.��Xwrtex [5k%:�asi .! uscl�}�"mź�1u=u�&t�5d�b�7!x�<�/E�po���um�a2�[, �9%U&��>>to >"? Star�’s law�ef�-��"[a�-����d!�t �Y!�c$p��s� �I�cs��n� �'i�6$ u,��� �bAro\"�#],մO2=� �~$0%bA1F'5�UlA�capilla���B6�^*�1�X�x.�g%Da9a�~ach"�ue&.@�a�5*e*�%jJ|� �2v� �*_��� Pl>�A)2%" �d *�>iG&�s�t-M@%�&~" s be�8�iW, >IaM�����uJ܍ �R�rem�p.inf��.*��5!��(��v)��D) q ichs� #&yg�ScA�I�g?��u��� . U9%2>�w��"�~%fa 7uEǩB� $al?[3A��G,0� A�n"u �i r�aA)s9/9%�!� s�E�,&�a�}� drop���=adjus� e(m��A 1� �rm�y!� � Fig 2aE�2~R"� ac_(��ss ��U�#���%�-�BubA)p�";@. U�L�%t!��n!8gCa���#;,�&w� eX��- �@ �����*�aF��m30W ,YmHg�,�&�45 15 2 �)���om}�ig�8�I%cQU�no5�or�;mR;o-��y9�.4 opq 2� a%���D�Xlc���e /e�� 6ar� jly��'orm ~!ber��tv�& B�c��%%� t��A-� andoD�E � �dr0 top )U�� M.�aUsorJ'A?���n !kv9[ ="U�.9�pw�T ry�gE�mN���ifl/ q�� ��e�!3g�l>��l�fQ�E6ocRT�5n6��%�m  [a�9�Kep V����deU{��e-<,subrouttSs���r � valu��t��ngJ ��!�p� ����<b;�}0��" vic $@6B)A�is�OW��n�l��, cqx�yA(`��u�yEE�pfV�m� psoid�X�6����p��)incip�O<�,A=�(o]�m�"]�A!� � :�?D��"��\vce�(�v"%fnl�!aC� e� blind-end݉�p rtef�of���I�i"�exb�!2�D64FX��_* MCa-IV&kFž be 33% [7�1&�-I��(o�A)&�2� e�q��or6�!f'9 B ] y&Z9W vevQaT ]7[A>suRa cub���Q W2c0u,BR���!�%e$)�=�si�B����XSs[� A� �)ll�8�:JI�Bn��'��or�#[���g+/kR:`i0.=Le1#.' �bw�q: �Ing�� -#; TZcE�)IFV"��B�Gc5/q9.A�P �.��sh.]m!Jc&�uI�!AMatlab ( hWorks InIr,ck��X‘q� ’ "n'��mb %F�9"6s�*G c�he��‘�E l�t+subnl��t]^�A*+�n.�T&�+� �-�1u �Q) `lZ ɯ$9i�*s Ka��$5�H m3Q&�HEE �7�~W��f��!�!� Ma/dur%%�:1exps�`h a�"μm gap" ?� �s.�d%�,$T]OM�M} �ont Q��p����<oeK����ng9�" 1%�)Gd�d2�%'Yco.*xvel.+�2 y .ex A sp�7���&�{lR[I��"h�i>�1�5��� Z�vld=nmboi0 2��Y . An�$���s��� 1Ig=.�F6)�#:"G9gQ@ �n�� c2M �%N �S�}2um�/"��A�1Tb&Ca�mmI�0i��yb�WB�U�v!!Kf2��{inl�|a12�s� :*-!Ac�tq�#&�3��T{���.g��;i� "u� *�&�� *l��M�f�M!�far-f��_ , p∞�e�e�C0o�"a ��F1 5=Tuc�BB �N, L�O d κ�.w&�reN �-u"e*�/( � ×�Y 7 cm�−1 s��W72&2' &:'[31,l5]��A�e*�(8R@n�po��sA{F [�9j�[#2vw] sud !*,��co�AR%���ofPh,b��!�-~7�Y�um�  $o [& |26Y�16rs0�� 2 [7�| � rTTow2�� �\6Nn u~���a�b �2b2��$i:x"W�� #- &�Win*@b��r stoch� &| A�� (implementatHion , the optimisat��procedure ( detailed in Fig 2a and 2b ) was repeated for a total of n = 12 for each tumour . Interstitial fluid flow was then simulated=hseparate vascular flow solu�,��viding us with a baseline set of in2zAs . Bloo �(across all �(ions exhibi� simi� spat�distrib�s , �dperfused vessels mainly re-cHto)}uter rim�!�tu!-xs [77] . The mean standard devi)�of9b� pressures^� was �%'valuesG0 . 82%�01 . 53 mmHg ( (maxima(4 . 78 (3 . 2 ()%�GL261LS147T ,�8pectively ( seeEI5II 5e ) �eleva!F�sA5�� were loc6at%< periphery�.M$, which is!xbe ex�ed Iz high�!Bms n`stochastically assigned h�H. Furthermore , our)�)�velocityeI wEfhear st!�!� gree)wQjnumert modellA�F�ein�tMDA-MB-231 breast cancer cell e[3I_issue!9fus�( calah-8!�(7 ± 22 . 3�5 . 4A803 ml/min/100gE !zB Q�:)E�f);A�id{by�,vivo ASL-MRI!NA� mentE�110�70�19 8B�B�:�ac8is implies that os!g physiolog!e�aliAY�boua�y condi�. gene��snA�#!s, �V$consequentA[ccuA( drug delivA֑�s [40�$No literat��IFP!Ba�e available%�) U��howeverM�?� sligh�u�compareda=%!$previously1��%m�in)�( �%5!�1�X�W [74]e�Consider!kA5rangeA�� bothi[!T<0g��accordA�i7*.aa�results�/ed�.J$confidence �1.can9 duce6��predic)���4�Examin�i rad�<�profil%��-CnetworkJx�gAř(as observed)2ex�a%��inS[17] ,o��. [3 , 245$!`in%�ut�lal studa"[31 , 326 , 73�QU1٭� �c�=be4d%$In adi=�:display�� typa� IFV1=-Ply��n inc��!y*I[towarda�e�(surface dueI� e steeper!��N g!��w �!cJi�Mndiəe.bulk � iltr%R oa�sRŁ���́e�:�-Oextrem�P��isU2( ρ =��4!�p < 00wŬρ%~ p arA�0e Pearson’s!�rel �coeffic�2it sp��ng p–H between�!3us6 �� :�IIl aris"� ��q also} a t`aal , yet5�,E~mWI�a w�g vari�) throughou8-U]�c�} A=M& Y�]p frome�centr��a� f� YC. H��!ar eak ��reachA� t ∼ 80%� O!u��I� subD t�`dec��E$e latm 20%F�H a�has b!�associ�[2 densM~A-07-GFP �� 8��S) ly�� , we��e)�mm� havea�,tinct differ�� thei!� architece%9��T��1 )^m��!8cas%� t, �riabil �U��!�>a�er%5mu− 58�K}y—inclu� in silico�`�7E4��aTa�ma �J ��ina�nt�= al hetero��� M{��L[20] directly impact�A!�A�>� �Sta�0an unorthodoxJ^ q. H %��orm sE<iv�nalys� underA�d ��A�m�y�o�9>of�gdynamic� In do�$so , not o� doA�:s.�m�s $ , but gai�Xs �� b"! $ mechanism���� or� veniA�wE� spli�se�A�Xwo group�first;def�as sour�ar)�� ElA4*6� "? , pba%�AX O�Or0�segP i� /lc!^����L0along a given� , δ}�1�jseC ��f l2�J�describ �bio-�ca2�) affect ti� transport�!�.<,oncotic refl�o��� , σ� hydraulic!� duct�f of a�� , Lp 22�B?i , κ5� far-fielde�, p∞ .A�!�follow!� , if2�.c * 5M��abeEm�edOtIA�he""��in�u&V��normalizNis�8herapeu!Ys egy ,to� t) ������ to a1u��al%funv A�t$��b�walthyM�t s [1� <15 , 18 , 49 , 5 79��an�{ �r:�ag Q- a re!�A"in micro p dii�!�ru �mm � &a�@41>$�&d!� icyt!~veragd��z6j tortuo�[7�8-A! � .���shown>E to�%er1�IFP [%4520 enhE�6�r�W[50 53]�imp!!:�[45�8!�82!�H" A{m��links� mis� i�necessiAsAZ%q�u��D . We next %u��m*� f�Y� (to investigAf�e�H��es�5�:�n� B�),s� 65i$ye1d>steinta<ritonea� )4)*We�umee� deal�in-Z�!�� c>Haxisymmetric manner �by�F�!treat�)| es���;g � . To achiev��ia5ext�of� ��I�q_i 6Fof lumenime@t��  a�bin��of �gm LpE� σ )��}:a� �YB�isA�ea� � �-�3���to:Xlev9Bq"R B�de� �G(by a factor�� 99 [��r���to'844 × 10−7 cm�−1 s�r� 91 [83a�re*�.*� t� !�Aal�1ES&\[i�4]"f,^���&���a7� m:��! S1) cAib�.���".��+2dremai"-�%��+p��ll ��7a i;�&�a�4"� ��IY. is!�ult� a smlU�in� .�of- e�s>/a}2�9�E��� mal . Our�����.=a�1�6��in��nt~�magnitud��"����3such ���!�,Eo�*"%{ٜ sugges at� �pe�Ny f ���o!�st�pŖ ��rel $significan 5(� s*� Z+�� advomI^Z*i6sM(%�Qs�mFvia"�=.Zj�bo q%_�5��*�.^. fortifr� )G����� ceQ<mu �� ��0 membrane [85ZC2~� nde�.">  κm6d%C6h�#we hypZsis-�6�lo� y al� EK2GZ E �[��) )�+ef4 sought�wx�;ltiZaparalleW / same��asi� {Y�� !9 � ���8K�P 9 cm1�K�Q [86]���~A�]. N� a}�. had .�co7 Ug fca o/& �ku��)j%I��[ *��������A��.h�^� s 8a�9aIv���u of 70%��%� conj, )�N�ɡ.�`, ���l�IFV!#F��`Fi:�-��p��9�xRX4 �b"m ALls�L�od�;I��P 9{,-�I'byf9�A�� ��d� op-�%5.t*\� %"�e narr�ofv�a2��8 �6� )�� V5�H �I2*^of 50%��! a�ev nR�m8� P�-�� �To>|H !$�若w� #-����"Q"� #��si#ofm� flux��!� � type�-E�post-�F%.A� 9c� ��atm�is domG ��y� vxV�,)�alnumbe� �ihE`tY{�B�)�/a��� i. �\a�)-�E ofqApre2eF"R6 )sbal�ffdr�s��ed �no �ex�ngE0!�^ 3�!#m�"�t�i )pa� �I �I�a��"e� at�t� 6�k�: )7w� Es) z "� 2�"3 &�& ��Ibin.�_�3] b�q� !(X�K s m}��>�di�S2E�{FurT%�at�iG���- p�$��!��S� mvaqsA�r�ari uni%2@ H ?Wm�F� e im�E�� orpoAng ":�%.+h J� }Q�# ` -AvsK)Hx�S3-Ti�&�sHf . E�q2�IY"ar&3":�solid-+� ���A'al�8AY-��mX�15�l s rapidly2m~of:�{B�� 1:65� a: character�4c� e barria�o� u\),!�6C#��r�di�shAA���acD&anti-<%��f� ssag� n�N=�um!�infludeP a�o�ic�o1�!.� ���� �Y�oq.� I�*��6V�) uremnof&�) ��  dataA �%m whol"H!� s�curre�$,infeasible u c. imag!!�*� l techniq�$.�re��a�% ex �A�-re"%�*cR [39]�)ow�hree-d��%�i.Ls�R:(tE�� r�st���t- inpu�r9N�m.�')e&� � �%y�explicit� el� U�!9J#%�)pdiscret.F� �0%��!2*%�-MA�!al-world��[6a�YQinş%���y�] sen!&H8novel REANIMATE,t����"a�>��)]w- �Q ��,~clet )�A *t,|f� �%�a>�guiI&*�(!=A�%O�ͦeen� y&�er�qu�ftaM-f��:/ }!�6���e�L�kA&to-gi�a0A���#��(a1r��B-.��) �W5���(li� 2:)>-�r�J�"�d�E~� m �J%�^  "M��A=!l wa�Wem�U q(v) !Napaa to w)Rlr%�se�!nd <)E� �as��ly-"9/R�e� with�X l��environ��EW.�n �p�.�.!o!��U�%f�2��2��bi< t� M�fiz� .��\N&Ua�eW&a*finit���#�elɟmethod+z�+" �)$ !խ�ny�9hiF.y%�2�an �"topurz!gliom�a huma�lorec�carcin! xenograft��� �� �E �_*I,!Q �r"v,,ew 26��&�(BI��tR��Ihe�ly��)�]?��e�"�0a.&!Ձ�"�� ^�� S`?pointH.s$%,sizx S�jd � 6C�,F�V"�!!}2~  .�*[ re-�I�*r-*5*pr!�us Starh�hlaw�%2� .,�1�"mof�`�(� t�"���e# n"�anQd���EfinE�mimicy6�t��� varV E��c�.�e}>*ng!�ɵ���\�",6��m25}�isE�d upod$Poiseuille! el �9 �� [41]Yis coup�� ady-� e Gree+Y"F �3�28 �_"��ɭZšs;%ed"��YP�A�� !��o�%W hux�bi-�'io� "�$�A`�um . P�/)& s ei!�", hom�+ �r� � �!"� �uїeR6!er-Q d synthe� - [28–34:or��eRI1A���A��4���2��4c��u��.� y [3$3:� 5ai#A��vdS t fu�eencapsu�61wrk c9�)�aU+ -neighbo�NgM�V� �R6 globa K�Ew%5h-a#:+ iculvaT3 a�(st�O1�.� Q�w� *:(2$\ ����.� ��� � J[1T+5 :���6���6problem�� !�)^- 6��|���An-scal!Th`-� j8)� mean��&� � ' to��*es*�ac5Uj6�oNm;�. ; �/ ve et�9.I� �P  *� 2� %�a*�a�C �.�n %sE�o*'1�k y6z4���6� "05)�� w� !7pV!�c�:�Simegd c��:N�"o� �� �"�ga���=�T6� lpproachA pr�3d�q��ml�5�%�2�me*�6� R)N� �';isE5�t�� U%h�2�9 K2��in5L8K �!�:,�+�5�nl�/6��!�c� �m)��*:�8N8i�ɱ���7�x2��T�("t4Y i*�5��Q)5#&; -�n[7�,-v<a&ctA�6�'-IBk5 !4oraFn7 �.� &� upd7/! V�.�� "Q<%x �-t>;i�H^a eE4commun�4!H."�!�9�al�ai=�#1J e�6mr+*�/to� .� s�= B� *excep���aX;E�" �"k No!g�:e� quia��!Fly r�!4C5&_in order�enE�*o&:"�9���7�Qc��!�:12{*� �0' �!4�9u 1at rai��I&.6SV<urAUdm6'�"@b.��\!+g k P8*��< -.Y��o��. U�&� �>& A�,AX� � �1b�/�1V%S?a*K&V7M�min�1h�:��2!3a?�_ ���=Nose� orxC� #[�,I�!G�)κaNm"Fm$V� �� �A9��&2 � _O2 &��x�.s dMN�6 0".!K9� �Is�:<9�/��)�Tu� "�!a fixedE�^6u"[a�?T ����smo�%r)I8��%�e:ralxS,.�5�A�"�A�&�? ��X6� .~ �.1M���"!�B!�apy�k �Z�g.0!�����$�-�yy�-�B�2a v��s*()�f&b&%� a8=l� fash�g/ �"�  9��� atlst�&[.lF5.a�B��u� rendb&�* ��<� �5Nm� :�![" ���+P. P!��.�-9E"f sole�D�>s�leaki�0H :�,ne���*�/{$W &�-� �ALs [�F >W3:rtH+!�"k >U� ͒a�&�)%�L H"�)")**}��l �*' ���/�0fZ!. Subs�A"� "����u�o-�,�bA�Y�.�$"L|� �Ta& �%��� J�� enti�1��7e�<� LS12�E4Y�Aepcshը��$*;9>>�C�%�B �A�2:�{ ��'oR-�8 2�'%��>2�9<map_\ ��y(6\�-�dp4p=�'���8 h�ME A��-� } �!$& `C�0k�.o>i�we��wer�"�W8cau�yb*/�-�I�& ��2&�7Not����A�)��%��X2�.r�%�7id��e�I4s��>yG6�Apropo!6: &{o�2 scop� r fut� expa�!A or exampla�$"�%=Hf�(Bp D'�xim� ��!'2K y�*mA�6[2UT��could�^FG�=cy�n�o"� �spe"Kaq1."A?<#m!�u&RbB� Na�"C" *�/s1)IGe�%iK#-�)S�sa.�ch}0nk!ro�$"� ]��B�2�2� � � �!� ss h< ����re� rpa���&l EG. NewUZne�p��� )�t���!f<9Z%�� A��Dop�unsx/A��.6,� �&Am2(lex?�$ phenomenaJ9>At��B7� �(e�N� m�0:�q�E�P[2\=8wHvoW P:- grow�O�^ angi�/�jwe6� u�j-dYБ�I"�'� ateg� Ld!m�wt .d' ];a# d��6Y window [1�WCNG finddF utEDt&�$� :!Sdis�a_ ,a�t�0:-A�F'I�es �$ �$!���%Gh  widespreai$� A� q8se���&��~���%SimA� will ��;s}��&D ���$QZ*C�8dF�$be���C�K� J AXurnʼnTh�=gy$��;(1�!�.�HIV�kn�>e�% "�"ly�)%�J f�O����d>,�>M�.�or?%R.A ell-l�>one�pn� ��Uon D�H��4solved . Likew� �$at)�t�Jeis vul�N�)�0�Rgby neutr�A!��%bo�!� 2�F0orO��teeM��Ew��NZy  �Emf!J�L����To� � �L:�Munambigup� r�+I#.fE1�r�2 1&mo�)�? ��T.=monocl�=H( mAbsp<ndFQves depe� irI:8�,. While gp41�G��B�< � CD4 b�Lng sit�UCD4�X �"5���HA�po�?6�Ab VRC_LdraH )�l�2cyz�.�i.�Q �m!A/preJ�%�block�e�vir�&!1ԅCl�M���J/�� NY���*�u�:Ju�,�'aMZ�owZa*tH-, �3A*/escap�)R broa�$!�ve-5�MW�E#� � . �DH�&I�o&Hh' cy V%(�) � ;tro vXR.@F�:qxR Vi��2uL � non-Fs sBsd$_i�qir"�synapT$0– organized1��Aw�#cons,e�au�W�� p��!gvirioCS1��, [�@[�" [5] 6�$��(U��UO�Her-��� )~!�oi�IAAnanotub�6 filopodiaI-, [/ [CM)��Q�Q��p:'� �iguAg"F� e� v%쩺' 5��E�-чby �yY�9%510 )C ,YG %Fsu� ��9no�t! )I2�e�)�Lev?if8�in� M"u�sseZ_���dividua�a��2zofe���Yy� fo! ^�9�� arge�v=multi�Q_AsoD? �Frecom"pD � adap.A'toi)�*�([1hS[1�� !tE(Sh�!=J.ArF$ ��)vz9�6 cqui&�.9Ave� 9���+/̈́mVun��H�[ is g�� ledge�a�u�4�#�e2~��d� vacc� ��i��+Ligm as i %��s uY�� Q �39&L�FA ! mustA�ŋe�8eq�Eq�,)#wh \�a8:�A.�E�V� �LEn��ndas�  �V� Alg�- epito�j@�elNDglycoproteins gp12IYHe�� cces��� /^ ligo�Z!�?! en \ W [1�02�"N�i��b�K��i= attach�D%o�Z�Z��or8-؁e"�>z . To~e:�2Zw� � y=ly�'�� ��"� �I�͜d ^ �^ND�x� humo�#iᜡ�[2�92LP?mpxDo*�M capa>\�8��R 5 &� ]�2dc�Atof Zndaofl�X(Acl��sEN,:RnE��"0@ssI�th�RO .��y�!eindIe8!�"xV�E[1�!T , [2 ō[�X6�5 panc!2in&V`�a��u A�A��2bu�R�)�omplex!��"tud%w@26a�ss)yD lik!r� Qongru.amongq(tya�f1 as wa>a�4[e�Bi6�MA�cw'�:1�5A�'�>�:h� ed lS�V6�j�reveal).�C�*e ��e.a moler`r3<LE��S2  2m of��raa�u� *p �*Res ( T-T �6�� DC-Ti�:E@M<phage&[3ER poly�1)!c&� � ,.� 32]A�ie�@i�N_is�fݡ�it�ye�Žat�ito! �M�s�,� c?�(� he1��)assess�%ե�x��� h U�m奉��A92T�!obj �,�l�l��a�c "36cU�p�ȥ=K�&6|engagf G%6; C=�it origQ F�%�D>y��eG eado=< t.imyAOf�%� ;4riv�1a i,T��a9!�.JN}� (��^G0 ��&� MM�Sm� �� d|e�~ is l�`ly� on� �C�� ssayt at"�-E� �V����(%ܭ�2�, 3 nglend_ m� &R��"� �"A� L2�[3� �!}�ez3ays moe��Me �� �#�]5m3�UE��A:A�I�2�� E�cu�x �8 repl�. S�?q2�*�^s�emplo�aA��c�$)� Z��)��el�@r}2�g�,u� ocul�(S)�)���onf{3�-7y�?,�/, �(urb'[w)41at>by kee�ID3Oi�W�[�%nareful #�U,.�7�n��Xri%@�H� o�im�`c%�Pc0��2�; [�� ;&� Q71���%�A�[�m?,# . Ye scFE�^D$�{\�ng!<�nW-hG[)�ay��rva�N*�ferJ�5�f�b2� �-;�-"E-32�_ksysteD� � err�2o�O!:.w�NdEd ��@��84�Sc�9g smlim�?�ke�>ly m�!Z����!reh:/v��U 2i!v2 q�A e�~Riw�=eB<h a*�#Y^ step"�$!��B!^��Q!r+%�9�#�e6�& 9/!MOS�I��0[l�*��$�4.���%�. A��nR.nbb:FAMf��wmqC(CCR5 ( R5 )�d�ai�8i�e� !�of9*"��&ee!, U!/�ex�$+: v A��O Z��1�o�c�� &'@( �Wp( �wh,0!�ie9D�KR5Q� JR-FL� 2`+)�!2� � of DEAE D�H,n ( Diethylax4 )9�BV�6�� � �edE %B�-=>s�9A�)�S:kF!#i��;6��em J�� fhv�asa�abJ��SY�!�i�"�(��s ��R� ,E�)&a�1tic�a�a�qA2����-leN&2��),e1PS%�. Of no�KregardlLof�_�%BJadsorp�enforM_spi, E� [43]�agn� beaBGE�I �`HIV-1Q:toQ)���m�^ �_�  Y'no.C�ad'K�1CE�rei�e�he�!|eoQdd-52p. ��H� v"=�)g NGbd beyo�'mv)�(�"=pr ,t �9�L-E$d zE��)8)�2�4>AYI>,.2ys Q� EdP 1KS2��-.�.A�2>��N%�calibI�s�jzVe�!�`p �aq�9#!� ��P�1A}E��%�Ec �ca-/ p^}��-�r].JHS2��su�A�� �,i��yoqpr! ���Q�!6���[��/� �!%-f�-. U� \ ed6�b�1L%��/�f&wheB{�J�) X,� �E� ��E��� �:`>�$S"�a�R a{!��].� �X <C� ory.U��FG etraxCD4-IgG2;�&PRO 54ay @41?o T-�E0mh�4)G%�S9UI�%$�. Stri��t fAfeby�UR�x�0�^40-fold er\[ ^!3d� ( IC50 )a`�"Oj wB �� 2D�Y�Qp1D�[aQt�Y � � edZW�� markedly ��"~=/ 2>E{)AE 32���s2�!�6KZ verifT1�:!��Vd"B���5UQB]2��e��/mt/&� ��-|)wt�Ze6k 'c%�e,U fe ,e��J�e�ta6<J " �A�2�Z%� ��bNo6�uE2Eq!:CU,EE,B�yU�*+�gv� "�����q1�!x���(�*�.( �ZC �6�a&�h�5!Jlo�k9;Dy�axt� s�*e-<&q(e�c *M B>ZxE��/r�Z2)�Q��1F� �w�.�H!����of�nd^�� &�#seudo�s ( I(�ic`5pp�!z�6jp293w_&� $ FBplasmidsh#o) � u.�:UsF �\/� "��\.@��]pp!2H/ma��T%�5�M�!�v !]��ed 196�2�%E?.�dEW!BI� �)t:��9�R8� �A�7wiA X6�on�Ɖ"Y�"uB�Y�q�hP&"�6�Go0N�&�*�f�2-\Y>0�'"� ~&."xT!d)�!P�n)��seIt����(�P k�!7�: P �r(!�!s�< )or� ing;- % , ?X U_2H�����SQ~2� aj When �)(ĥ�e�H� ar maM��hem0�u�s� p�GdeYC�l "!� [� nt�2yy� luT!�a��!PS�y. C�&c�Y�!^u�%!{F2!����$�trg-�|�'rt� 21 �E5tv�"�-�g! ti-C+))�8�T%7� 2�of���  al���t%d�5�� D , <4Y ��5�p��N�FE�tEt�5)/e^A��J`6z%�[4x.4� iA�Ku�8 *e�&Jhm:YQ�.�D� he!�bsB��carbo�<tي% 2G12�/F�5���/aM�J�x ���i"/" harp�� �6DM� �MPER- !y^�2F5E�4E1�-! V�w.E.�q6 margi�W>r ���ɏ2O(�á�. Par&�:surpr* k�-I��Xtwo�9�m�5,AJp�$7&$ they_.� M��% ��� N�%Xir "Fty!�%�^���x0��Q�!�eq$.m"��2m .�2)N�)B�f!�f!#"� cl ���;U-�zaA�r� : �?�z�%Gcy�=7�M�T*8I=R*x)Aly89�x����ir*�-� �2LEg(i F� ��A;>*-�Z�  ��� �We�>�(ed,yb )A�NE~J�� #@geRal�verv9 4K�Tier-1  ADAI� 2us ZA0�|6�=3& ZA��q�3�B�4E��zof]FIEa���`@s׃�A/�es:Z\�@.�-Qar���:���!L%d�@b�("��?�&U !>f��"��8Kv�"m�Ww b�u �.}%9roX*U,��a�major2$. �B�, �R51jmu�� 2j&n��*�=:�+�a�som�Ac")�<o��()7ezh"�o pruA3k��G%;:a�t^f c.NJi#�end��"�an �Hn�%� Oma� !#a~�%,�vk�~$or TRIM5α��e�'A�/ ��o�4an) ( hu5$ M�Vis�a0n�rhesuH9caqueOrhO͇w)�N�@a�Cepv=ece%��g�mo��04�05�0Not� %F�.����'%�-��io�'��!GJ�[53WAV&G(t�i�-�!��a%�.jAV�01� I�co-m?ed W�:�_9�or.\'@�d�%�Akn�dRu�!E_"0v� rEu!s��"P�&�"P @,� �!�QeA �R��$�#ist9�#@�+el2��S3 3!�>6A��=f�C�AOB�rM)NpA���a�2���s�r����IlUf"M:P &�s uYn6�!�h�"�*s��tOGka&���6�{ �[ tru�9 ,W'*b�Qdi�*� ��m'oM�:s&���U y�csb,L !�) ed6!�5.4�!� xu&'&!yoQ|ng2; P��>[A&i#4<IW2Č[*y )I![F20 �!3A�V�1��. G2�C=w�zi��߁L%"��h$��v86�.� es SF162�%!K NL4-3 ( Xƒ5"� � CSF6v P!Q ��V� r T*�^6�~b V3 loop9�Ni y 447-52DVU�5"� "�$1�j9-�!�of-.i &h"90%��14%z�- a"�!�)�.p�.�8��)�!� 0Aien���Q;� [^v�^��a5� 5 � 1Y expo�w�AI��Mes�Ye08*��v�,2q���ote�EE~" ��wf � �`0body 1-79 [54�qsoa%4!.�a���9"�')H%0&Z�q�S4�~� * fbG!�� �b:ȍZ;ibely� >+�Z� we*=����O��0� h�XA�JE5a>8J�c�ure 4,at�P"�7^.��/ ���a�fiSa�S./A&2;� �>/.:_!24m�y���;��M-h ,F��J%<ofA`A�}�d}J.^6z 4�v�S7.2i[Aef"��&"p=eF��ɴ" >0��P<>#��/&1`!�suz>JM�C��l~ �~,f_maiyIU�Sz"�N ��Apba�5! �R�A��S2:1�c�-�a^��?X"�!� ����pho/J)�C"�PNA�.x@Z����4��2b;��%d��>�L}":*�C�~ oreslIly labe�?� .UM�s2H"�@��8Ws�Y etupM�#7�;�9��)k�*!5���4VE�=:n��QN8� toA��� ��&�FS,5�9s n:#- �neg!7�=!�c��0� -.6�"�Mw-6~ [2h�E�l!;�.pr.UAX4&� {��)n!!&���"�ced0Fs�.;F�j( GAG��+6��ub&[�F&!�E stocEYt 37°C -][5>W� _<�"�AE#-&3F�I!P��u��6�AM�4�G,)4chron���i�h�?,g�fu��O�!aT�?L3f6�Ia tempe��a� t�23�"f%��;u�>W�i�`sCMASM�.�sAhligh{B% eET� ����BI�,)bs �ߍ���,2��"3# an /!, !p� 28� Z >4��59I!:e‡��� �O�4� po>�&ɔ.W6 ="� >�F ome��/�6y pair�6co-�vNF��@plZL r�z�Ecl�~ .�%�"6 -5� u��5a�*�.�yAl� �aQ:e�!��t&0cf *�H�!��"� %=��biZA�r%,>? , [5r[5L?&���Qi��,�!-� �]�_����?�:,e��I�+Y�\fo� (; &�C59? %�Zr�?! M��+.��=�onI;�c�Ewo"]�agt ]V�� ����M� ���Xu β-lactamm,( BlaM ) loa?#pK�g9�[6�O61]u�6�I��EI��1-���]M>L�<rem�f"i�68 ++�_Sve�:F2af�Fze, *%|*Y w9p:t=�a� �7en�VA��<��7�Cr�O!]-)d.��or2� .��%%�6 ���0A=`3 �ol*� ou�f��Q,Q'�o6B%�� H"r�"��[2� !�)��� ��!�>�,:E%"` ..$�bl%%x�t,HRF /�$"�o�d&e^}jAp!� �=m'5��s$V�=6J�+y�).�Fj � TE&�A���rec�K��,�q&��g�*or�S�A���Y�HR1 2MN$�a�9at�V�B�s�n2j , [6[6�D6-6[��� 6sd"�+>�of��sd%�&g-#9-��pa��d �5m� ܡ� 6dR�"!�!�iK�1"�46�q�!�B!��>~��;%�!mf�� ��v� bVg}I�6q~D�o����IHV0o "�U,ty=L*;<$9eri�+ �*���&L_Q6*n�)~�衰���2paW$l&Bo!��@)7�cFHj^ ��X,Y�+�LC ,�,d a 6535 3FT5:"@ reMx*E" /(LQ �(��R�;��.�N� �e7aSi� E��*ic M��+�(wG�d*�!{�B!u��� b�R%�}_"� *`�%�h�+ZyZ%R� m�%�T�i��!�J�icU�P� �/�Z� aM��q^*q�vW� "  ��< ���6!69y�"!�%�XRM"�cn�Kl6%!ld��5� Ae4� ��4 /edi��Xy"��0t�25�!�54e�stm&���B'��i?P�A2g3[zt�"��A "��train �t �. I��A"�e��-�!\72&��by5@v-q�S4i��eXhtru�!.�1–79ich��ed-PEZ����j7P !����A.D4��Mщ�$DARPin 57 ��{E.D4AK(s OKT4A [67j�13B��2 [68� McJ��>�C_��� -� ( AD10!�PRO146�,PSC-RANTES )�AD @�� a:7�� �U!>BV2`aO�, }#6U��at2OU*U&u.{#$b1'ua�"�#i�H�  �i���JfodY�� )DD4.C�!w2 s�Ni*m S�*oTaoikjZՄ��M@�1the�9��(-�`65 !xZ��7\3Q��w]&9�!i'�e'!�/ �]ag&&� @hav'2��ir� !Ɋ�H]4mr" }�65�Rs�xa ��h�Q�^�ix,T -M�RzZidrx&A��!ar� ��":�� �KeO�aa1�$ "Hy��Js�J ��� Bj���=uM��a&�f� "�5I%�g�ga6�~d�1N? .�K`hl�p�!oO��n�Y0��][6&70��.*��6*eE�edR�Q v]HiE!Bl  iXCt@o�:%�)Gn+�� �9a�!C�rB�Q bo@+!��-��AA -~�w�,e�!8i%�%ot �S�/LIh��.�.�NI�*��E�.&�h�'o�Mo!�[]N;O�%� i{��5b=�P2�e">r��-�� dF��W �� A'�dG .T\#�Q�� o!%aE�a�(FFjMF�a�r<�&�pi�6E�� I-�����|emJ.d��V. O$fewb�AUMOᶅ���U &� �/fb,"Q�����c4:l1Z����@�D�6�(q [7�G4 [e��[7�3[7� 74];~�m� Leu3��Q4�`[����-��= AMD3�5[�� TAK7A"77�\U�h�1@dIo3 }�X�� [�^j N����Z( �bT&as ��� .��`()6�t. �=ɥ2�. O���QA,� :��l A��� valA�(.�S�T<�Tkbs-"/s,y . )=�)BS!@C34R%� 6D*}�6e�:/] 6 0'�}0� E/44a�� �-�)� dd|l�_E�, terpre�e~��a2�:�7�/ve�We._�UC� *q :Q%� mA�72��� se2)vEy!5.�%,�6�� �fpG5�*F q�a5{`�F�1g"/�N`�!�6�"#��tZ��3c*wtA�J����> �l�� � , d&�sd=-�.�%@2�2�.Na?�hnR�.�HC�A�SH %om]� h l��e� %�2�A�Y��C.&�Xc7 d ��[y[ruStr"�na�wm5r��oک� *R$!Z -�-�#t]n� iIV� r� � QM���2B"�%@4B �i���� '. Dur%Z�6:A�is-$.1�E���`a�+�[p �%�0Aalw�a*L8.�(A->�>��i�*m�V�{�E.r�0BzE?e it۔�P6�f�n , ��� tx +"�bep-�r�+sTsV�`�ly lin�toM_�%l,)[s  1 I��.�!Y&��w"O.�`�AU4�f  ir $,t �a"�&n�B��"& VBw)(����ani�a��/A5�K�er h4��li���$�H F� �� �Ax:�_%L��]SieI�F� Mara�nj�A Z�r1 ��{A��F"'���"f�0�&�t ]Oa��.E`"�X�%^)CV��vo%QB�V5�n��&9o6E.�cH!�6�� ��(���d�W�+�X*1.�M����}��l ir&ii��Q$sue� [[�$v��,=��4[�3A I�v*�,oE���nat-�1�!~f=�� �7za�AF2� �%>ū5�"�QV�!�ZEn/od$� �I�m �"�d��lbH!�C�N(�8J &A��a�^LI*�� �� Pہ.�V@:"6�a6[A�r1����~�*�d�"�q�W�z��sn�"Iht1ic���gX\cIXm.u�j%� �C�r24n�miei >�? O6*�vZ%AEW�4� .�a? Jud�� As]g�p&/��{��������![8���,s7Ab�chA�4 doe�M_^,$��煡�Fl!x5 1�Z/�C�b�Qcesy�ar2�-�A �g�dtv"���-qeN3�� ���#��*aFż6 �iFs��[)t. B^^eur6$�bB��*[A�0�� J�`��� t���-�8� �� e90��ɀ"3o�^�F\� �!cor�!zY��@��v�D�AAN��1A�^� ��#UCx9 m����,� .l��"�GL -�J� .>x !W��CO,*�.�U� �s�J:]=m:a�Zj!&1U wHm&�5v^s:�:����*�A�da8�%'h49= le���eT��)eKFf J�"R6a�%�a���QA�"/ !�5�e50�O�� .�  /8�J{ʼn ��.+k� s���ou׌2�4`2%"Ca �*�i��/�g �  f"�-h"~ *�/�Z�!4!�&trio��_��{1 rear�Kqc,x� %udoAE"� m.)* �!��!� ��� >�.� .�0d %�[8�08�D8@�Idzn.�<�7Se��%w>��j�1�%�� ,I�0#}(M�;)>�)(_)A�5�$�Ѡ�A��:E��, ��!�alr'�-�!5yT�]?)`[ �0e:0+!N�v*#��I.:���,� E�enough}���(vB�CKU�����%�8KeB�V� �1�.�a�4i&�W?�7BZ,&�Z*�c�7�> ��p,|~�:. Px��*�"��5�2 .w ls0�U��ј�^!�]�bep;s:���0���&��*'i�**F�U.�~ J6. , [9��Fv!�2=r= ��!�!N��U:�"�m�A%I"� 0si=m2OX*%�E�� ,���  �Y 9�*D"�Xa�In NJEwu8]y��%3/xQ�>Ks�/ b"���hH�PIA$�" mG. �qN�!]�1"�]�LR��recz�:�&acŁ\,�g@ #�p��a �d*v.!"*%"�$ ��lp &�e]�o�!^IY 1@"�crii�!3^Q�ac ��� i L�, ��%&enc`{�!<38ig�I�2�֡�AQ�\�S11�������e"b� |� oo�lD<�?YU-��#N 2 y�!uA�eF�G.YC8;�u;��Ny��B�2Qs�k�Uor����l�� {; �& {)�0=(,E��gb�bs�J �.v������:AN�M��wiE 65$voUa���Af� ��-*��K1��. 4�4u;S�GL' quick�m�] J.�� ��:@t%r)�ځ��+'mrb4+t^�7�., ns��5[9"ͭ(%�"]��+re&  ����a�a#K_i�&�!�-�y>���a!�e2�A P i=�6 !�4�$I �ruTG@/s�/,�.!M+/��l�Zd*�#M/*MO �}M?�� � ��*_ a.G. ��-��F�/�c �2� pr*5.]�q)!�/6-0� l��w96�,�_�2S-!��5�E*Jm>�&G���A@)�1�5�!�6�"m qP,aN!�z A�*cE��u��ud��Ae652[�� ma�D5i�_�4-��J�. A w�|��+� ^y K�g�<� �(ove}Snt yeaMKa>�� ubiquito$�"}+ �F��_\9�'[9[[9�9�$subje]�o e=� [9� !_u4Ago%���Sa�hy�P�����R J� e� � �lA��%g�,��+6���mS6)f��(䅏re^ �1nt&m� A evol��R�Jr-�A �f� � pathicrkGC�j� &� i��oy� ulin7�vy%Qq4^�%�A�*&8�Tly [99�10� [10�10jsA\@�x� 0�02 �!�:w�6�cˇ�FM�1p�^%p�0Ic10)�10Ee[106]S non�-j)%5�H.�wh��i�=Fol�+emit�HP=3j ��d���cC���!�F-&_-!=gn)8Y2$/,��F�.6�& ��r�Ual;{�� prog��-2 ekst���J2� ��:�conundgR�i�ag[ )� orbi` �ow�" }d��*��-2� lack T41R.8�By�5�tQ�N~.!UpNXng!�erix�.RF5T}u�审�.c �]�is"�"� '*2 ���r�$ng� �����Tc!xL*�/)�F�$�as!y� u>qyr*�ya���P��tanu�Xar4 CyW*��zZ!axy�U�MG���c5�tr�l�znt�1oJ}*H�X��/t `�y�kn�.5aa^ppa�U���� �oJ��1;!rgu� �a2� 234�ana"2��0"�7�!�-�r&t�.;.zAya�lie�Ha� �~t�#ly�H�� C��_�����D�T �Sl Rr�S��)� H:o�L�6u�-�y.ӟ^�u�J�-��A� �toY.� B{5�A鹉oq��*er"�Is,FSa>J�Aq tituh�1x�?"#2� d�����E}�^Eu2�#�2_��%�o���onb] !�a��pnoX�2J ��M?leM?F"y�Ӏ�H�n�"���oto�9V_�%9�Ga�be cru6�� Nj"Z��I)a.���i;�@�r nHp"�s�x.h���* 9:h�{u�"p:2.� 7C,�7�m�%�U�&O ����2�ey1�F\)��h x;�"�r g� �!R�8w(wAh"{&� 6�0AbZL.Ah%_A�"�)A}| �0� �Pnz(in W� a�2#:o��reA\:O" q�rn��Ib�m��.�gf�Commo�Fsi�O�<b&P!us6�[$A�!>1�#}.=���kbaD�"`>.?��:� S%0ZTexi� aidAv� m}X$���ce �-2�>)!u@� BR2�M�ce� hol� EVSZ�jA ⋉%ᖥ.om�$F�h!��'/�e� �wvi5��: drop�2�ILtS<���autologd m q��Tn ��#&��q�!�^S.� n��e%iͦF'.V l4 �!�ly�4b_y2�flu:t�������*�5a�1 log !#1 )S�r.� "�$&� � c!�a!�:J4%GGAl"�Q�t �+1nA�"�)X6��=�:/5�,1�I��A8J<, )�[ �r A I��[d^�!�&BXV��m� �X��)&!�pei�ea��"y!J�?,��� F�,���`"X6"�]��Z<.&w;� *S� re�o��J.9  AI -t ;Y*� !�=+$*AG>F,�^*�Z�.�` ��� ySw%pur���buf�oX�anony�R>�do� �,I�vi�"aM�ZurqB��T��� Serv�-(( http://ww� zhbs+ ch/4���rotocol�ro� _l�ethicD$mm. �Proper$N!DE�4antibodies and� inhibitors used in this study are list �FTable S1 . DARPin 57 . 2 was produced as described [109] . T-20 [110] w-urchap�from Roche Pharmaceuticals . Maraviroc [111R;8Pfizer . CD4M47� synthesizB�445] and kindly�Pvided by J . Robinson� 93-T,\HeLa cells were obtained ��the American Type Culture Collection ( ATCC ) . TZM-bl P4[34] , A3 . 01nA2 T- # 112]^y@NIH AIDS ResearchChReference Reagent Program ( 2 RRRP�All adh.t� line �cultivat)�DMEM con�@ing 10% heat inac(FCS�$antibiotic!�� �Lendogenously express!�9CXCR4!& he sister6�5i 0negative!�CR5L�6r(-())Ngener�u4Dretroviral transdu)�a.�( [41!�$C . Gordon!��rkola A]AJ\P Moore unpublished data%wSuspensA)wAX6p RPMI>pV_Stimula!�periphe��rc),FLe%.Z�virion�A�labelm0two alternate!0cedure�.WeI�a(full lengthZ��derived�-Gaginm4[�. A miv�%��incorpo);a,chi� vpr-X2 [119!�To�end6��ٽed)la��i�a�a2�molecul�� lone���<( TN8 NL [120] )%�!+�5$ pEGFP-Vpr�.ift��$B . Paxtone�>to� 2�IW� , an�� � deI� &ty.��V%�<� ���HI^�DBriefly , envelopeX.6 construct�a4acMthe:n env-�l�O� !� sequJ ��T via XhoI a,EcoRI . ThisQw(�E�)� thenM�o5!NZ��8�7ng2XtogetherIM� desi�P5�IQ��5����B�)Z  β-lactam�qnl Y_e� rc-BlaM ,� YE%*Hng�pCMV4-34E��( Y�W" � reene ��'$pAdVAntage romeg� !�!UA?F�p( �ca�661�� �vpr��{envmA> ( pp))2�bO �sB��FLi�Yál!�u:/efi�18ed upon harvest!uEin� vity/o 24a{��determ#to qu� fy input:)��For%p% attach��^6=,entry assays /k ��� conc)�by ultraifu5 o�(2 h at 4°C428'000 rpm; sw�out roM XSW28 , 32% sucrose cushH�(Bicistronic��tiI��.$nd TRIM5α�XonM: s huor rh [51&K2�L�o iley . LekI��l"�%�.~{N~ A�|�8 T ,VSVAD�y#Mw$ pHEF-VSVG��1]�M$ed throughC�> ݶackag!mK,CMV-dR8 . 91p122];}�D�jron� .6�P �t�:�by spino�NE�(1�1200 g )� l9N��p�sNFCS�t"��&���day af� � !�A6s�6�U��wC 800V�inbN��w8 u�Polybr�0.� Ted �u�'on 48 w&coey� OKT3X21 CD28Qq posi� .��ie� (by FACS sor%�on%24-41�%'. EP!#of^^�mon��� B of b}� ede��.� dei d �� system b�on�'oH T.�, � $allows eas�I �,t�diEmin�� between%&-free%EA�*) mis��is!^si�as many�ge�p� on polych ic supple��E��g1� mediumAWorder���6�as7 � (but not dura�XJ� ( FiC1�_�)�� q!\�� neutraliz� ���of mAbs%,*�AevaluE�on6�ess� all�k[ c�*pJ �a��kumfCel-W f;� �chosen!X yielZ��c26 to 5��–10 relIElight�( RLU )��96e�!�abs� of.".� �)�&6 carried�'in>2+q�ofENYn�4( diethylamino ;U(sham Biosci� s , Fairf%, Conna�4cut , USA ) ifE`o wis.o.� assqEP68�M'A\Eeof ,��ed6�p�r&r)`!rj*stock( a MOI 0 ?-�F��e��HIV+/�� q荺ha�e sam�n60dynamic rangeA�_i��|�ru�A%EBe�At!C highestMHor zedMM� a retin.� "�signal��obser�dueA�incre�x� deat ��4resultant lossA� �ed6�. I� e � �s.�a�c�at ensu�� P!Jof6Ta�-%V5G N�2s��i��wV�� To� re t�!KNNs alw� pro� �;ar �m��, a�� i`-�,!Xdepic!uin�A�+�T clud� eachEvidual�*22B"�perform J��ѝ�no��rNO�posA3A,M2* wa twicE�remov�ee��i�� 1 pre-incubŨR � dire-,"�fo!h bef{co- �A�;m�targe�Ak1×104!I#M �).J9�b�� ^A6 �J��]gb�iN1>.Y hours ' 5ikly� ��*��9g�  %� meas� " addiof firegF subsA�.#, Madi*Wissiɂ�G-���bod�%�caO50%6�> �e�(%5<:K , IC50i� cal� � fit8 poo|��thA{to fou��d �exqQs sigmoid d�� ( varis�)% 4GraphPad Prism!f.�a(a� ach� a6/ druga��� 4 greater-than � eHrec� d . Onl2� k w�.� �I� -Dex��� effistl�a�6�as6�� %N�� .r��+S2elF���no1�on�� %g(over a wide�l�B |��2��th�i�  _  cag b come!� very�� c&[Eđ�I�rem 1–2 �p0magnitude low� L?  �a�I��u �ʼnq (5�e�J�^ restric��[u6; %��]employ� (%��R5�X4M� ��i�[z#F�cE�ic�ounds!qab�4�_ssa�While6�also im�e6��rs�N�2g{ s�0)g)�re.,! *� i�oI%�mpeR prec^ :�of)��0��)� wfA�m��v>,0� w util�"�:B́9)H ?%:to � le-r!�-�9v���"i.RE*��! backb��se2k(��) does�me��ݕ2B\!V-i !�.��x o�1M -D.s.w�D willA�ing�KZ. FB�)��"�oof)��&� 2J�r modif�sF\%z�5Q�D�DDV!%���& &� � at 37�in"�p�!�"�( :� ��ad# .�a&�v�ofM�)p,2�V�see��-� �A�24 h �rQ�n24:u�iO yuPp"2!M8.0*cer u (-33(�) -mց�Z ylen|2PEI , � 25 kDa ,!"�)A�>�A� !�wenty-fe � . 2, �i\� 2|'�;M-w.= e�!p%�P/S�nda`�4 ( 1Ix� �� �h2! 2nN, @ a~i� %�G��4se� . A48-#�G� e&eJA 2�q2�Gfy!L.)Z%��&& �S!<.� u�>k (k I"�$ drug+; � ����� �2�!Ks�88(�rhesu� rh )"Uas�y have b8 show� "! pr))t��I�2�Hure S3B%%[�A*g(W(E9�E�human�&��� ck t� ?d��.�in T-T� XQ7.� !�zM0�)}ɍed2�� a�o�+� 0AfA�set%�.�o ,��!��n�.5�Xk!�2�| �-&` �. " �Na9�W5 inlluS"� stai�*��(BD Cytofix/perm Fix� %rPermeab� Kit (8.��(mAb KC57-RD�-�!1��#�%eckA)Couw�foA��manufacmrs'�&�!� >� infl�!of.y<!!6Q,2"h"�6f�2_��ei@Q�p6�� 16�+E�)a,I[i�6��t �4�� *&E�v fN� �tt2���A]ATY��2–7 �A|u�-byc!�Gag��tei�&�� !�}[ pop�+%� m6�5�� mode���|D%;))0ǵ�bye'� �� acy��Ji.�Y ��i�� B,y��.1-�!�i�&"�'%z��N: �.8.] r.p !� both6�!. � adju�0toha �h utpu��@approximately 10%)��J�in.S-I�AO�oan&�s��maximuc-!�A^"II�)vE��!��0or\�� / 1paiA�I��tse�A Eak6=&�� N��pr*� e�Mi�n#.JX�� �)%�2� 6!Y�}mZ 3 2X Y�!b��!o sprH,!d}�OaDo)Cgrowthj2e1F1 "�A�e�>�j�. %Q^Pion = 100−100/[YT%�unM�ed��ple] * R+sa x�%As� trol2� :�!5%�assoc�]�&��Q��%ochamber�512% �� m�  2 -membranewhe.Cor��Life S�c' , NY�i # ( ��ka�a\��)Mt�*e�insr. . Uni�ed.� � �!� 2�e$J� ��bottom1�8*�-]�.�M�9qb�A�2�! T"+J )��2%,'a%+� ��)E<@N $,�" ed 4�� )��Ev0 R ~6_O#a{�$allel�-;2laA"E/m@�A���,(��!�A Iu�ma�F:M3 ���I*IV�-or���+l�.�".r(A�2� �tud� in���r.�2|���'g�E�F%%-�M# bodies�-nUA�2���to��Ua 9l�-mNy*�2�(I*��g!�s/��) ;6(,"�6,#8L&R:�S2D)!D4a total volume!�'5µl��&�)of)�2�%� ynchr)�8b2�'"'at&"'at 23Z[43���-(low tempera� ��s i�*�* �p >#arecep�engag=%�0)�!  fu� [12�F"� *�(o�unb� <�5�9ajSs W8,'buffe0PB�( 2% F �S1% az<��$m�then fix�:5%�/aldehydeA"Ff#�A�" ��4�5)0u�"t�+�aK by f!cytome�+,on a CyAn AD�4ru�& ( F. DM8analysP ���Y,FlowJo softw�5 ( Treesta_� e�1�9W!luoresc�2 �(�%�p�"V!��mean 2Li-s�&( MFI� U�mfrre�a�s6aluV6 100%.�( 0�"$ ,*ume��{0* �% v%+ �j� ���A�a�by�og���! "�A���!6&�"�&aW �2�of�F� !T&��  �or� We&�a� ion-�)m�A"a!=c E0zymatic2!�Dco-�,e:�.� \,�}8us�:b� prev!\ly [60�9]0� �x�re"wW ex�/�Sleavag�paex soli�5E�a �)� by�!�b�(�0�JA"lat�,2!fR5"1 intomal�rti�9g�liv,7E"e6 �Asol$successful---�5�&!��"��Uy poten�mJ4*, �[5�Ae<R{!F�nI� ua�2�. T.r�/1F�or2�/5J��a��}; init� bV6, 1'20/,�3N*imao�� CO2-i*L"&uy? Gibc�/to��:��5�� InA � e7%�eM=�a|?�Xof-�E .or)�.%z6{( exAN:�%)Q �off- nd V&�w�/Ar�!bea~�H]��1�4us–���=�$�#�h?9e%?>cU<���%��3.��o.�MAin1��loa��.E2�5&?%CCF2/<Invit�s-;6�m room2� f"+ �.'��7� FJ' �") �/��U���, �B 5 mM?,necid ( Sigm86�?m ���#n�-atF�� ��2>to ��e5>.*2 a� step)�� =��q��<-CD4-APC ( Calta�2,G�5gand& 3J .�B:� Eaaccoun�AaF� [�*��"VCun �d�$( 520 nm ,&y �M)dF1447 nm;iD-�� �����q� �&by 2�,�nu���^� , 450/50P7�.c %&�'as2�F� A.�M���rol�N'�×� �N oK ze�t. .aVweK� -UJVbyB�:*�"�)ŵF#o��reR��&%�t �E�3y�!��W��� �� ed o�J�� 2ab�+.� !�5g�F�w�%.3�`y!3���Z�%V�*stCj�*�%@a���%�97w��us��Bp!zX��.��-v�!� �")�",YVa�&o:�]J*�N���Vis=.� n%h!5efacs�neu� �*�H [�7�lex�ng;f` y:,a�ll�$"� ɪT!�I��D=�2B���%opologJ3fe� spacSev�Fexi�;� t Aa sugg "��ar�'Wse�IveD�of1 \� HowueI atom�physi��1&:1��al.k�ss( er l")*��v)��'(� h!_V4� MT )!}8 ,�Ca,s�1 as VW6H� w? 0opose a simpl0 chan�,~* expl�)how�p-dK!Z�, fallA!on� �a�2 ,�)MHj1RK�21��M�on1|Y� . Ou'el requiKpy� shifeS�Jtaneo�K,x#nL1neighbori�?o(�het#;Q!E�� auto�ally sca�/d ��L�d� y given>!�.H�!!i� �Aal�onU�% a_Q� E �@ bi�5�G� ��� Bv"�H(1�A� resiu"6 s�Sspa�$0oa�x:Y+BA� @�¥\�m�� 9Fg, makeI�novel�di�&)�zSc]1shoulM\��6d o�#st)h� � focue0p drE� away R!��Ax . A��< �}S���"�F in divers�1 ys [04\ SJ0 b:��U�am-EAI�Awqa�� spon% (\ all m�Op"�;*q*)U!#a fun)�1B,%�| U���8*E�/���A!.� ( le1�V� zlittle�atBys[�J6]; y�&��1]@  ambigu��8 s [7!�9�E�e�I�A��bo2tg>diD�@i occur��a��hI)6h ( RF�a�hEU�� A{e@�%=��m�6 simi�&�at elici� s��'A}Q �[GKdK :HqQu��)��4��v1�s�ms!EP2� Cize :�, aD0� m��s%, F39R-Ical=Ls [9–�S(1or�:�no�:� �ithin-RF�?"J%s tin�2om�= side(, “sur”29St $� ���G,�E&!�2!�' stre�K�4~umabl�%0 ;!3 Discu�@:Yw_4Ube&:#towards~ pec�/��d�L,,�e"� a +��TS�  ��Y so-�ed!� h-M���� principle!�[U��%� �M2&� >� �e%���_��D!�A�!B7,�9AR� ala[� �]= RF9�1��J�[13N�BIntrigi=ly_ ��!��iLRF !l6shrink(�Y-!6�Iit�B�-��^J #� �olo�Qe>oueqj�exp!U��M��!ig%�[�S.A ��l�� B�uJ�F�inU�": tN�n6�o�AdP=Q�YubtC�+�be�mat?eh���a75*[16!�ńN6�is quit��n�I*�io�sharpe�$����.  @a�BIi :b � cer-5<ɔ(dl=6s't �i��%6e-�of RF�w)� mC1p�Kd l� �cAJ~�O�� BWP seem,b �tu!BM����F�."M authXD0s�Aɏ�r>!�"0 s��^atwFa� a2� 6[bea��AopplNl(�&� !br�;�`ter�ng t�*pr� A�s�J�[4A�8�:�!A� tiL=a�detai��ex( is Reynol��0nd Heeger’s6� norm&�F= ��2�[[��1� r  eI%s2 Ajk� d%�� :i�F�Vg:J� do�q��ą �,� :(g2M$�5gkZ �ʅ�XV��5 9c=O&_&�1�d�%4 [�=� uN��  earlDY! d �M�Ti"�( ��amt�3E2 =weaklo.��^�)aa� $cortex—a6��p�\e3 .yVA1[2�"P 6�,Zin�:q Q(\ !TA�2�Yh�3imyM*26]** �"�=� Z� hier�]ŵ� V1a� V4 (�NN��stI:�Ay.!m�E �EinN[27�8]U Mean� �� �.�:n�;:Elg%�V)�x!7V2 e �%�Fur��E ,�zal �t!e�o. ( 26s5Fr�l Eye F�H FEFT nd L�@al aparieaUPLIP�[�29]��ta�C�r ��-heQ�?6V �b /**. �i/R JforA� -lik� proj�I.�%@�?�>V1 [30];Qs&�'$ V4{:.� task���G�lea� V4 [3�^!*mi�  ���."Q���E�ly � S>&% SdeSH4y%)�gr�� ngru#�q.� [32zS�� !�Z �|co��Xo�{MTo *MV�'6F3!�$Middle Tem�Xl (>��� dorsk)8I;Bh��f1`[3�LIP-to-RG*��[ "6�T�h fMRIwD�a6� i�E{-:� hypo�bs* ?� wh�99\6!���to�Y���is%v��MsuH!CJ��rglca�F�a sto��a�as2�� mo�A:* .:Jit�a.�]/wV�w  know<%Js must � d�d�m �@Nct�hif$�_�KŲ�%7) blem�m@ �M�a� daun[ v.�!h ���24� - V4E E RH s !�n+�!RkR�Lr-VA/a�]�-"� b�Q�d&� y [3|b.2��)} �3 �,��E�e���nd �a+�# �nd sm�$rՑ?E�.*$ NYa�!| erro�X d.�� 2�6I�2�~ � [37];�*i< causI�:MisM�b�ir�I �G(�iw�,��usAA losQ@�J�(�ith�)xZsI�L>���E� hA�be��- invo� 2z -w %�a�6��z!�U�� �.�!D�&is9�a.�aA��}ra���n��)&j�3rectlyU�RF��t!��ʁ��"r�N�!��B�, long&]RFx� on���D�*d beyonda�A����+ep!�6� iV�-�oryr a�5��D�upn7it6H .� ! �b�:R��2SN�x?U&`o�E"�f��2�mut�m�!�:�&�_�#�:Aq~�j �t"%2 ��!a !  e1,�.nd2��:s*�"�F�Yn�u�* � :�R�(%) wBtA �ioAT��ee4 �|�Wc w�]�.� drivu)��b��n�`�``9�/u�R!�clu� :�����y [R�XX2A����.%q��t*F��+Z��U� B�; b�4unhY.���}�fS�wC�+ !6� A ifl 0va�a neareaFB�:(�� &)�'��ikelyA�'a�a�l�T��"�a��eae�A��26V���^qT*| :3:�%&qo�',AD� a<�fnd%l"�j�in"�� �I*t� �7aB�:Y�* .:!�~ �"� �g�+ 2VlLB��6� e?er�Ua6� �s! . We��Tv1�h0���h laye�@���Ivi (� WF0!r anti-)�d�\ h2�!^o� F�� 'i��2 � &�_� emi-�ifZ Gabor" j�ve� or8e�Fhoriz�9 EnopE��o!O��q�O��a�=%������3AwF�D.�!�eqD�i.D1P( i&Ef� �& \��(+o6;!�aE#-�s���Ine0Y�r wu/#A�H> UcBf�W_7ed��,U6� z�)�Q'�a%�restoA�M�]%.�— d&�r�u" �<.Oan�.h$*d�� p& e am2/e_�6� ~)�"<� ��"�C +/- 30% ,Ņ.}y#all$0�6�Z�v"�M5 top �r)%@p<: �CZW( r1��5�a�$�851%"Ny,a�K7�.A.� .2we�<�fi�Jconfirmib�� 2�A�V1�$!�(A�ToA�L character���&�!A]��Z9�%1�}��;{9�i{�*� r� :�X����ABXJcA��a#top A�&�q�9�4��EI�I�H 3'�F.%�H�u?(� �o.�*P u���s >o�`U (�fi��[6�'6���z.$�J! cng�/��-f�*��A��e w5�l2^�+libAD�( ee M�i�w!=Method�%>fZ>� �B�>b.Eo �m?#��� �3rd��%�]�n _�n?& ,�ce�a6)4 )��>s%a��t ,pas!�wS� doc9>gr�_u���eA�_-�y�s; �Q� ca�Wcap[*� -gr�X.S� leWV, a�UV/l�A�!�:#%Wn��A��C�8Ab.�, IF"�> ario�a��t�â=��� !<�a���R�ta��;H8�- m�e90a31B{5 deg�?�^lu?A�� �t`(7z#mq�Cb�is em��ܽD&+@bye{0tinez-Trujill 5d-@ueo%&� rZ%-k)!a�"v*�"i*�u� enha7g(�*F�i�fe"T �&�tV.:p (Et�`�tvua4Y��^ec�>&&- "&� �Maf4.A�C� A.�lG 1�6��O� Q�# p  N: L"�d)> "� !U\X62. z[�!i���A"]*N aVly�4>�s�3�%a�Ae!9�ex7I�phenomen�i�1�byN�!e�N zM�!{�D>�resemblO>�-6Gn��I^,!�W#gZ)i�jde "oVqrV(�X ��nFregariM\d�rowE IntuO��>*�l `^�m�$!ratND��e-<"�;lm:d$u"^+�uL�tm8!}!5�>�t?Az;��6�j�,��%S�*�Ad tras�2H�5aFg�3qP�K6jln�x�#�&[At�(tx�lo�K6@!E`( Eqs @na� ;��A8a�cv�#E ���\��!d/F,_v� V.�6W0�Di�oucJ9.:y�TV 2MZS@ gradu��Cy_"+q_ u_� 6FQsr,.�m5Z R8���x��b�D~eda��?s: ���l"m�xl5p� �^�) {%`E�-radiaU"�6=�6�((��U=E��� Khm,�$re^6i� �%rItly--�A�.| �   {.N2/ $�42�lA�r s�#p)cV]��[-,*+ <9:"1"� �  �#a�"48. A��F.Ra�Ŏ,��7L+���6�oRF6�� - ta4c� �|a=(*  s.s4M�c�0��3�In}�M�*o�"z͙�Rb96�*�E�(���!{�IE�!I�Y,M��e=!A?yI>����CE�"�YU$"M��kon�0,�y2"H��� �}i>&]�5�! .�/)�7�$� * 8%�d s=9�jjU+%F� X&�by+05�Two,' � ��p�.e^��Z.on��h 93e�>� -&1W"�D[�05�-'��p:� .� !D�n%�te$L85%j& o av{i� ў!����� e��V�_&.�,�}&�L)!r=2� at 15x155;�:� 7 qu� gridmʡ�=��=D �5u�!��)Fsj!bA�A"i%�colI,7 uild��ap 3G%%c6RF6�:"GI�=�%��JGd-� h.mRk7�Pi#�nRF� y*is��A� ��)���TR���rP ig 7C\F>��� �A?)�5 A�shrunkOe��E|A���O7=$Y"!�� him&��hlluVit{om�*n�k�4���jr.wo52. B'(� Ua#a�.%A�E�)|ou�ed,M�^��m_a�i 0�it/"�6&2(i�O�9Ge #Fi�7 Davi�A� eaguQ;��satb� ���'y�/o shapa[]��"n'7)*tir ao2��mthem 6%%�M���q>� Pdom�[�'��$��5a� thei@HLzo�6^/\��*�?�( S�:���0af"� x}�8@Zx.HZH5he] .Fx"%!�wo-"�8 al FL �&�XoSeA� �V��s��G�]:~�e�&�`�y�rb�quival� ,21�o�:�7f�$e:OU C&a�uaTEI>* � !\/#�%Tyq2DFeNPm�9 D �Q2B-5(VD4BAq�>v� UI�!!M�UI+w�gA � 5c�*!W�m)!�A��2ps�ex�Cng'�5arJ0�1e"�,�Tp1VVan HLe�tta�R7white @h p�0#A&�_ret�x| O�v !�=)tysuPf��-�-�U�1� 9%2aH� eSRFk�?���-&_7i,���j  P-P�(�zellip� alig!'E7*A R�.; . Cru�1,&��# � lC62=P1�����!���H�.��s�VQuc_8p��i�"C V t� M R\��"�#�kwat I~Hf�N�(��2c-2� a.e mH>��M+� ��b(�)A�s*�'! �a%a�wD?^ 52qrv{� �G5�6�#2 2h=}r:ɟ�D���&�,�E_�FIAk;rY'to&� .�"�� F. �.�~�ZX5 5 �K!i�#%6�)%)%� &�k# -aHZ!nP�)�B)���1�sa[a"]uK��a��!�.�/wec��at�,iIl� [38] �%�e� �B\5M� ed"F � �[-�Zy� ��!5~�/o� 4var�w,ē<�7Ft= %behavioat1�M.5�9e�*��I� ���6 ���o�B��!#.�I�&�EN[O.JunLun.N�+li]reg!���The�9terpre� �ix � a�.%�N?*�I1pMNby�a��yY$2"EK� k �  3�n5a�dice"~5_Au�!LexactJv(8i"mun�>t! J4)*i�1�H�͍ 9CLofXa�!= �&�:%if!a�5Iq�E+2��d� A��BH�2*}G:"3!l^(al work!m1 ly n�r�4r- Axj�f�G2>3ofr��� 8�.�'�� I��H� *�1a�4�[ense:AUYFVm�^��top&�ph�F�(gan`a.�G“$�>�E;“�4�!���@ *-1r>"`p)o-�8{2o may ���ort�"�M�&�maMbL��s��y�edD :��x�2�in� �1� �.�{@O e pulvinanaބc ���*gBsA� �EE)i lap�X&^;||om5P!3�dj�>��p �Zj Ew�.9pms� [24>3ڒ�*- �=��3t�.�!�1�A5�.%�xus��H .L�eDs �Q�G6ޖaS2�@)�N`�.!�>�spi�M�}ime-var�%.�S��r�,,??}it� ��q$Rd�.'$�p � oleM6A:r$-q$JK~*��5�T�� �.��*� .sJ�PP:� -s�=y [40[�n�$de.$�!T�'n ]2�0 $�  p�!܁�"�M2�~�D�R�%�6` `% �r0!A�aS*�!"��w6y<.�d�z�C&m�Ladv�#�Ed�F rea?�icJ�.�d9��)Qo�eF� �F�lE*a��/%��x��l� !c6 $Tsotsos’.�)�$r[4�>�,�aim�<k�b"�Uly^hu�ku�i���"�|(9eX�A `t(HORT.l pr �or winn�ake-al�Furb��xsourcEL..* i.���i*�R,�ne�top��1*%4�H]��.&�A���.ex , namC V4%��V�!p"�B�a�M)�E cascJ$.�a&j4rE,��F<s�:.=5in up�#am��[9�E� ��F5��*�Iid�>M3^�}.�B��3`8�+A8"�C[B.3V1aRV2 �C���eه�O� *FP�>�6QgA �e��Ey�!0Q5 �[`nF`YI�ta appayRly��-A=rL!� emero[�� �3�.��%&] .����h e�aQ*R'of21!$"�=�LF�P|Q2�� Jgo$')1i�,�*h�m�v�a��ly� DKg1� r S-.�6.�B"�&��d�vREhN�A& 8 �km� �&�BRGA�s�l )c���*E])l�@ng�ul�� f [4����;s[46� [47]�M!Hi4E7 Ak�&ur pur\2 ul�'�-X�.F2UX�<�0�@m�!HrelaJv"��@%� �.�Zo omit�upUwe�Ŝ�!<� ��_pP!��g�A����fu� . An9> aE�:t�j pau�4�p�!]*I��ȟn�:���:[W�yw���!�S-yd�-orZ�\!�v1��"L#�� onF=� K�su�.3�Y,�W\1.�c�OlQ �Z�ra��:� !M6 h N�� ��F E �Wno�%�a d1D+circui�o� ��Ea�C"r&�P -3e-A)� )GN"�{�Eyl�;- . I}��  %" �x��po�il;��Ju��Ml� nvolin�N .���. Rh` s�@��d!� b�jvok)�M�0�$!�Q� d�<%�� ec3 ycUt��v Sk+ial� nA��� a�V^ ���2w ��dA�r�<"�outB�o�ll-�M� !�� ogE�� ��1o�%�*� .�s�" ����3lM * ��2) ltip��9�;6�)- gno�D���"q %��b �k�IF?a�I)� "�i�eJO:]�2oJ?� �".�FaQ[ l # A\� A��!�!!F�N ,r�N��sZoe{!!!uR�or��u�I�O9]� ("/[}�dE�s�kf qB!Qiv �-Wz=l�$!3U5g:��" &�9�+up sal�yu�[48Ogui��� -see5)�[4AInt�\ng) �:��F��"�PDV:Y� cfop=�h�_!/a broad � %�RGib�6 . *�G� [W�P����F���  �+�que�!g�a snipp�QE origv Matlab cف{&�$ �( %my,I:�%>a*avail�onu36j~m�y+����x/-c�V �(I{-%e�r#�“IE�|�a��|�!�H�%t�[=�#Va2�R!�t"z=�!'6.<���Cbr*�.F��u!6x2dg��. ElT!R�ā\�# regu�_ latt�ofa�5�E�w lo ��'$y pixe�I������8A/enb"/N�!s� Nc�K:zM42� aIl�Yl��6 �y0(>nc�l, U�)�,fX���2��ya0�n9�! I{�L��aa{to�= a&�_ xa� θ is: E��θBE�4= ( ( 1 + FB  ) *  �(  , σ 3$ ) ⊗Image���iiw�n5AV}� ))'2D,� � xMA~C �θԅ�ard�qi (a��0a�)�,3⊗.�+1co up( i .֯pointU�.@2� .�z % |a�&�<5&9A,�pa�e�]�)5ofa�$�qs��� to 3i'3 y ��#e 1+FB*=_�+o. ,IL�A[$����be�{��Fo51 ��j� "�x'���c֢x6I��%3� �Y� �?�|pw6 -law �" [50 , 57Z8&��mm�!�[�bnF� $ .%$9�6�1)V�J+L, P:w��A�ca�ofs[��b�!)(ASde9 I_’�j�� �Ri�i~: Inh e� ) = ΣθG7.) ⊗G�&a�In:� ) ( ��2U=2:>a + Cr 3 ) 6XƔe�d���)m~xe�J�σ2�C Eq 22+{_.�>okerneIDr�%.:�##y�y�9h!� m�e:f�).B*#�BFOA�Eq �bi�.c-<R �!� ;�9 Q#e%& 9�4T5��J�+�+k �%��?�<Femm%ka��&6*/'2)�r.�@\(KM�a�" ��] .k- :2n �  titu%<puej &�i?ou���� a8�Wp�or�޸o.�U�)�ir���in���n�2^*��� F�S]~*>dȢ!��+��a�n=iRM��+!�8YN D#�:�a�q�`l�1�ir8�,/9�J�")#�aJ6a����Zd �5/�H��Kn/�B���&WagN2paEa�+� �z H� ż 4!4�&� ���.n + WM�(�� �AA����!�5��:h;-� �&)N&A��� e�%�!�8��0�} ��-� ��ݶ� ���`hl}�� �(� ;U.�)dC.)Din.(-f 1D>#2 |Kp�c.@7�56�W�u:4 σOri%9A,M(Qe  �D .�.�m[purad� �,�JM ��)���F-�6FG!3�@o�i QE�� at�  $!: same�q}U� rE��P .��&QmžF�c/i�m"�(�l.Lf�Xat�{Qg% )�FanXN�V�Q�N�.�(q6a)!�ENĿ-?e��"�,��6�0*� s�w�@�:��PtoMg�X����RW,��ۓin+AM 9�� ol36�IndY�sLO�!��Ci� � � !c  ��� uY5�6�A���B�_IF>L��a' �a=�F<a�!���KLF�E� �c�]&h6Eq �crepla�7R�2�7 RTopE]��5&e���d αFB�%�ngyr�#��oOo�EQe�#:� Top=E vus� θ� ��⊗� ��σ�� \ (W3A��� rA�!hBY1,6 u �BnA)s� � i�[�?-�,#�*J`�� )"�`re-�d%�e w6'��A&#�@A�eM�6 librp��-a�C�g.$ , 30�M�!*�Gat��j 0>.Jw�+�/x/-�N4� �par(v !< .a,�hse�~�J�$Mu=; )�= 18� =� σAttxo)A!0. 1*π/8 , α"ialAt(DαF_ !� B>��To&� ad��t�9 �aQ6�qs"� ��cA��,rah)!�0"�.�Ao*,V�P( i>�J! o�ť�O�F;V2 � � R�!�,!��D� of cXA^�"xac1� e σ� /=�!um��-*\ e4� ����i5�N&~?Y�e=i�0�?: s=%�6x4 *�D9�alM_5��D5��>! quic�j� �#�� 6757H�f 09*1���B!݁�lզTX -O��5�a.�.s�RR 84� s�=Ca�&�)��"�!��&r��*l!V4/MT9;� =���a8�� ��l~�;Qv6e�-"�?%�J*� ���"�8e�1�L ,I 2O�mA!����iU� -4 Ue]BN�~ +�0Χ��1�e��7y�,e9!��.��*���Z�� ��,6���B-eE)�Y mmonQ��W�Zn��$ui��M^by 20%&�%Ŷ:E� ��co +�!�)(��BAE H&�G3��m5:w("�j3�)&�l]��!o.��[ !�&� �Mode��� lerA�!��l&7R despcshnumerzn�aJ�F�<@� ���." �at�&��.�-���!#.��"!sZL�� ��Lq adapA��ь�ɍ��o;�bel`���gMe� ola�,4"2. D&�e�=��i!�:��l#W~ �Zx.�9mxB��D�c� �6_4ALZ&�{_o[oF� ’sH$���"�a� > A�% Netw�4A� ��� | i�#��l%&J kqu� /A num6X:30 %FFvx !3n s�m��� 0ImWidth x ImHbcxP , %�b�� !,S�'�K�,a bank!�f%"hat b�T v1 = �V1; %r�t|�%&d�&�(g��XfbI0 ) Rv�**f + ZL$^ 2nh�%:�!#�on��i�$��.�*��$v1inh = ime0u5v3�? INHF�% A*�?&��3= bsxfuAh@reed;L( SIGMAV� v) UE�o�5�B��%A" AD9K�b} !�s����o�Al:�] % RFV4_1D �1-.�C:0�p�Q AJ� y % 77 RIF�O:M%��r9�=�.Q� . v46�=�%[��A '%\>9v� �, '�'lar +%"bW6�C9�0*�JJ1�+ v4attu)�3v��~�bsq U�v4^��:�i�]q-Qq4�W �% C�Cm �,"�9 Mw� AFnex ;epi�22.�z-�F�m�,FBSTRENGTH *.=,Z�end��U�+erD%s�&�?c��PS��f7n�Zu K{ ialiF &s +� s hemocytA/�"( ) homeostaZ�$ Drosophil�;val=$atopoietic"ű$e lymph glQ P ��6-w�i)�r�4 mini�Z�D#ni����e}m�s-en �nc2Khe.�z����Fec]a�We�Bre!0ly` �Br�acta x�-autonom1 mau4A*mai�9 jan�Z yros/fkinase/)�&��nd`BO{!��cr��JAK/STA�� @%�p2�(xe��r pro1���-��-r"�T#oc char�` necessa �7��}=!i �l�4lE(�a cryp!��&,immunK#��<�� f�aE�fic,��a�9�5 wasp� �?4�(A?mAF)N�A�knock��+ homolog!�IbG�� :(n4A rt �I cyt�oe-!ed=؝$CG14225/La!�A��7&-switc�2U�5�6�2�m�YpreNs� o mas]"�(-�I%.��n67��.�viv�\a cu��as<��-� �+�teromA�� Dome\UEc. t��96.�am�1J�m }an GP13�!AD�; goni�+k�i�{�D�E�ntq�. 4R"�fur�!�� a�\mA�M���68m)��1�wQ mRNA �_�e�;.��T I�a�86E-E;/d1O� "5)�)�B,.sTev�cul�X� letb"�SD,�N�by1�. 5o�)>a&��EsP'���wdiso��~/� leukaemia:e�-d:8,��H^in� !Vl � is�Jh%�2a�A.\(I �-�����-�j,��M�]jI3ur�wle�OI�iniFe��s��6a�-}�U�O/�e��.C1 �U�C�/raeA+qu�o�wheQ�r�noNt"&so ��9�3��� �0 . !9in� ���–�syW�M anti�bk0p]=�jmoO��ofV%ݚonf�f�, protM9%stE ���Km�/���o=0sm!�=�I��0�x�8!�A���%�x2c( )%#*I.e"_ H�%�!>$vie���V] , [2j6�{Ah9��J.��A�� z wo wav�>op�� [�{AM�&H3�&�'pE�&� F�y�s "� plasV  a�v"3 phago�a� crysE! $��!gmelanQ[�e A seh/��.jBPA 4<- a�5n�-la� .. L 6L��"��a�dr�Vll��i�2]�"�dev��* encaps_6m�GFigCX��too�g%U'x5>�L.��f*z �Ι 2�d hzt�; par6 �by��AfZ&8n �.1�se� [U�, [�X[6]^W}?s!�c�a�ph e�1R* ( LG 8QmM�I�geneAa@�sR� r�ץ%|a�LGA��!B��lobes��)a ior-d? �4  ae�ullIz�. ( MZ�# pE�JYz .� � "�4 BC:B.�Py��#a*�T� \[yN1�[:}|A e�se �6Ef�$b!*@��Q� mark��. D� �W2!�.��O%&CZ\!#O=loxid�(PO �!T P1 Nimrod�]܏����. H�B>|�q��=gu�� �i��m�"� �m�.���W 2 ��� he �Vpa !TtepoiC���o$�!Bk�!�,@<���-�%\� &�fa�0A�\napsq ( �{ Collier/K O(e����E.�BkFU ( EBA� orth�  [1̦V? morp�� H� $hog ( Hh )�11]–[����c �bal�)$m(�2x !�E �_hea��U�M�y~[9��1b+t+ E�� ���J*&�?,�HY^�� *) mHN� j�*��� e*�an�.�j�ߒe>C� dopt{Mme� f�K:G�k�O:� revel�F�],��%6e�&S&u�t x�>r� �1�fO!�ZP r6�k�rF[&� :]q=�, [|�JAK ��D�Ei� !U� * .CF�E�Ht6*�85�^I�A��famil�5| ��le-�ne�"���FZFd>q2"�= �6�'4��4r h&,@�*?'��ew�i�9� JAKsB ancho?C 6B�J�D �lA��. B�n" �c��uc��o&�Mala  m�l_� t brHX %�� l���� M�q;ws&)k$-phosphory[/E�>��e�� ��a�pk��0 A[ e"��.6� �urn2x�%�T)]�mer� e0s$� ��C�N�5t�R"4/86���7�g`P�?|in.u p&�noncanon�#�!-N��r�:dir����M���m!Q�+nt�\!MQ��v���edka50%�1�� , myocard hypertrop�!uasthm-�0��[A��ɲ6mm�mx � ]�"( ��#a�( Hopsco��, E� ( Stat92E�"Marell@!p q���Unpai!� ( Up?`Updz&0 Upd3�rQ�;a��)A���v6�őAS�^am�B��ogaW�:� ��,Z>�i�6XDa�me-cog+gen@ � ��a��{�& [lat�&� � u!�� W���R9�Wl�� a�)"��u��uG) U  a3���.WU*��W)#fO��2�>c f�?6T�l���T'�z��.�$"��tr��h��B�(�g~orZ�Eh>yUjf!�sbuJ�� a�m��-�] 5�=W,&.�*� �atissu*3Ee2��Ea4�-4I�q�3 t�>V����A5cr�^�k}{�K���|.�"+ �defens�%AB�j/a-V�A�a�`so faa����C�4pr!9d���F�O�'`R� � lass.�9h[�La�m&1&A�E�voYd��se cJ� ����=�e� 1�&lin]F)� .�UK!��_s�[�{0c6 ��.� &�|� n�"�*�B�GV�s�� kP,V�EG��,� �}�XƄw � oQZvG��T[�&. Ver( 1�(��)ݯbc(o=�.V(]ff� �i hF��ځ�!�o)�"l �lex��!�AAE���M� W:�E�"�.�[28� I�=�?\8SR'^��/��M � a,n|vY�*��:nX3d"�yea�go �.�I��rz.�XZ&ach7(X  o�oa�w� bi�!A�(.q#�Rg�A;%� �Da\�$a��dupHɌ���Q��e.,N� e�u��F&�B�v�k ��΍!!L.�JE��.X�&)%�`><+e 5′l"a4lj"� s�sRACE-PCR�Qi�!�tb t s 1ES-�E�A+Lat��wA���pp�^p �}tr&�d�j�#J5Ha%N-A�C-]4i6 ��)uŁbAmotifZBU�}8%of����ridP"nf&*��ķa;� aci?�`�found�*O=0����WA��%�Ʉ!l� C� �qs"Ya>6 LDHR�& Lat-%|H�!y R �"��!>!�kf�E N�9�`>�tandem�.�pfib�>tII�n  ))}A�N� )���55A/�:6�bof"w.01��Av� n��/usH Q ( � YXXQY5F s:�ah& 6`�i�y�"5��- �J��aX��"�"g�A&&",��^�'-��*+�i��l�Z,z��n=�m�\ 5�a\%�AA!Cx tT2��-Ov�]rom 150�(F�)A4�2 5 kb !virili%Q� SM(tMIv��"o!�1er�3������J��. aralf$)/��")O6wFn!x�D���Nch�A-t��"b�!� (situ hybrid�sE[1 t un�U /�-d�M �|���i�=!fi�Z�� r����� ( RT�=DuN���0�0EBic xiop� �$t:�0i�&�bqN9�J�W!U���!�lG5lF ^e���A�LG� .oFV���-;����tau�ed���mlI��:�(2�)nah�m4-Gal4/UAS-mcd8, >i��*�'�( pcol850$ /��m�i 2K)��F�1C–5 . Co +!Ie�nd%gin>. BR�s cri�7l�)w)a��bf� [ �e2%#��MBp � ��$of the JAK�/STAT pathway in prohemocytes . To determine if lat plays a role in larval hematopoiesis , we generated a lat null allele by homologous recombination [33] . Several independent recombination events were obtained and homozygous mutant lines were established ( Figure S1 ) . Homozyg9Hand trans-heterozygco�Dduced fertile adul�(ith no obviD�morphological defects , indicating that%o�is not essential for either viability or germ-l!�pdevelopment . In particular ,�$phenotypic }0 was observedA8the eye , whereJAK/S]/pI n import!frMgrowth%Cpattern�8[34] , [35] . WVn look!�te5y-] LG�lat mueEq�usV�Fige*!P . Th!�ir �0of Drosophila9E-ylamell5-id!ofied by�`integrin α chain [α-PS4-�]%� massively2�e M<expense�� pool he!�poietica�0genitors uponA�pa"asitis%;@$y start to:ninA� before beA�release?to ��Jlymphi�wt U�number�circuli�2+treaches its maximum 48 h after �egg-lay�[eY)�� pletAbrestoaU!��gf�:�toAU��6�follow!�waBc=*C�:�rIRconcludab�B�m2���}qin�poatoR�. L2 �Le#5�e@ involves downregE�onx�$Tsignall�MFMZ� $reby licen��f�By[9�8cactivit�!�LG can�gmoe�_ex5�of�e��er��gen�O0dome-MESO-lac�<E�� Lis und?h��ntr�j�  n�Y ome -ory ele���6� 7�UM norm�n ondi!|�=o�iF�MZ�A�� as!s.n>X�5G"� s)Re��>�:}-!q�s 2;�!30 h po�� festI;0a strong reduIbof=if�wt LG�͇2D�aEe�rre�>j �CB� 2Eq ser�zpr�)��,LG dispersalbU,�:ins��.���S- , unlike �I� �����F�GE�c>�!� absenoff�m�����is shows2�:�en�.�f��:P�e I'of few2���6�]��Y9�G%pi1�meaThowev�Zz�2�2���0program per s�rIn* w22 �>dj ,, Stat has a!�dominant�,uclear local�Eor�xo-N)�� � n%5mm� a�alyA�A4sub�  2m�'fluorescI �protein �-GFP [38��m�I�Z�Z�;!92E2( In nonin�  2�l+i�inly : M�%ie�]wt=�H )kA L( unpublished data )�)M5,} sist�A%Qe.�. 4–6b�)�� � both� cyto3 E�! �u��L��b��t�Qpr.-�9eE��%{�6I�6J%uT�%a� a decr� ��of�6���$ , alreadyNUli�>a�� nge�Wca�B"S LG�� niche )Acritic� ��to maint0 a bala�b_ ��-po� v�"� ��"negat"2 ng��o� E{� in �[� fun��!�-e�rai!�!� ques�:m�ɵvBibu���L�{5 !$#r,� e� �?,�% en%xis5)�xr �examined�pro% p� .(q�!#�7 �rC� doubleQ�������S5E�W�anU��,which lack a%�MZ�appearsYall���)�.�e%�%"a less s�)e"0�t;�2��n���losan organEMZ�^-!;2Ui gled )2�*�.$A%%In�gq >�![bL�als�&�lV���N� �;Myis casV s *� s am b�]?E��e��c�:9E�R�a�� �a� crucH�+ tq-com� swi&hr�5�p:�� � i*� �6��o�pN�1 �Dstructural similar����Lat%�D!Y toge %}aH��5e�Eencod!� novelB\o�!%�"L teM!� hypo� � over&��AI:edY�q��F G�x.J\a to a9�inhib3 !��6��a�h��6���at�$� still a��B�U�3A–3De�To fur%�inv��gaE#e��siJ4mechanism behih!TDž�tur��o "�assay�cul� d.Schnei) ( S2-NP& �[2Ŵ  � lay�A� l>!IendA��5T5�,gFnŎ(� %�a � �b( 10X�  Lucifer�$� A muchaongerq._�co]*ofqt��eq k�Upd ,2 �}0� [�or39�S6�To!o�ѣu[)��ed2Pe��l�, Actfmoter-�Renilla 2+��vec�(D-r 2A�Act-upd6Vn�9 Gav�/or�Z a�)N~at var� .�" r��6Si�� highYMfor|�actAOa� &� [39!�we�Ad ow [�f!�p m��tl� Uy�G.� "3,p�uof����unty!+'�ep2g>4-fol)�confi��& acts)>� ��C6�Amout af!T��u�>oR .%�U�i� depermPaddeduV�m-�edi��%!5v�ܥW"i a\�TYTam2e%�Q�!r� ��E�V'�@ �-�* �)�.8�Z��=��:~!�6�%�*��akey faa��=E�oBe�. B!ng!��*to Rin�s��u�ofa eptor-ligu�x �ei ffickVthrough��so�mK�s�a$3.� �A �=[40�We 6�;a��u���U�a tagg���(�-V$ f ��.�a)�!�&<5�)�qY!�?  .] ( +)� ��s� ic vesicl!Hs��� scrib.b 3F )�T��2�waTg e�coB�5 A9��HA- � resyi��5HA��L\3G��B�1)!9 ^e� � �mo�e� lappA8)�N  6�>��h{IA� y�lin,� 7�2? n..Lg �short�jm��verteb�  class 1��rei(� n3 �(dimers/mult [17��[41E�W �!�prU $ �rm � K [42A��es��%�o# ��!��%f@� �I�r,� G 8coimmunoprecipiv�-I A � Ie%�BhUval��# id�acod!�6�i3!v� ( -H� Cell lysa�qprepa�)-�A D subj'to IP �] antinor HA bodi�"s by W!b rn blot ai-BoneC!}� M body��%fc%Cin�Vdirmon�.�!�1th��:���� yz4)�n M wh� !D�JT vivoO��βblue- au β-gal�Ssidk ����� technique*T � etectf�-�ec�N � ~([43]–[45]� appl�toeI�%I�sB  . Briefly{ ��uses two�Gal H( Δα{Δω ) j�sAaa�i�e but�9 d-� if b���X�xim��f5gm�-6 phys�1'AA���m�6�>��$fu�eI AC �ua�We!�da!��" *Z >�$SYZuZ� in embryo*k4B–4) D, because it leads��ubiquit5 C e2A�kՃ4C�J�%7 . Co� �t��E&.pf, XA��ij��oHI����4salivary gland.�guta�n)�5�%�Eh��5j�$2�d�B2�/A"N s��(% ��R�Lat�/ω��or�2%9h84E� ndwɢ=le"��{b� ��hen)K�:6:�-�ed4r&��)i�A�t J����0%��A���.at��7iLA�pn��&�u�je28Q�qOr� F]J�.�]m����%�9�* =�'1�R� � b�6� ��b&5:�al!��s�6ODA7)�����64 =9$. Unfortun��w]'�(a�eax@X�can���.=9�sw+=�n:��Gcop#�.i��early�l lethaj)Eu5S,>N�6p!Xcop�'�a,a� �Ei7��8an “outstretc�wing”6�,%fl�,W�)�"� d"� ��;V8hH �� 2w( os/4) gY%ɤs�� �"4�"� )0q���9t k�a�!6�s�ё,*x$�Me&g� .�*�j l�eyecsZsmaller�n 9Kreminiof=A�/S7���cR��� ysV�N1A�issues�tha�LGa-n pMq��akU %,� "� !ki� Sc��%�o5 "> ��: G� �Um� f�poQ dMh���O=!:� on� !/h"|%��NX�FwX�� od�*�N�� {&accum* '!�!0�' mRNA�"OtoB n &\&AX rp49;,rpL17 , ribo�M PFQu ��0ve RT-PCR ( q ) measur p per!�ed on to�,LG RNAm)�����4b!in&�"m�!!mY imt �� occu�re&�(" m [48; W*�an ab�2`i�{!jP crip_nd'�'%�.(�Kch�Ca�d.�. drop:!�>/jI/��� N{s!m�# #MA�6!-hEf repe<$}"�on!�s)����AW�E��n�1�iIE����2 7 2�e.�F�n5dJsi?�A�9. �"�$��ng�  +�% � ( n�bNn�LG by� , dsRNA-hop,�,>) %u�k�-`�.A��2a@10�Elowerl2iHop9r�j,LG��+lya��6X�l%�};9jl,�$V�up!yamA !-9*�cascad$T�V e�C?  uA"s!6� shifY0 ��E~�Ea�l6�-5R:�*�.ope�Fs��!/�� lete exti&�#N/F"us5"�-2n .22 ' reDH2 d<||, � Upd3 re know�kI �vN�in.�T , [4�Iny1�Z> ���m7 &-�L�%we first��� H1ri&��$uv/LG�gI�u�%u�� veryA�.3 upd2xno 2aQ�s 5 , 6!nd S8�Ʃ??ir0v�:f*"� Z D��i � cons%b �gstu��foc�onC3!A0�"4. �cgen� anno�oni1avail� ��!A%�� 5′o!�%Sٙ�� RACE��|a�&o$ he AT)5i�3 codo*f0S8i2$itu hybrid[*� 3p� > �)sp�$ �[. �at �i:-��/�%Jin�+sc6Y�I� C}/�(6H26�!ea jc%5�I#�!�.i!� &�� �~"� hAc�5*��%��0.�eie�+supE! /��[5V�A�equn 1�Bd( UAS�3 /�'ɫ� ch d�3 [/e �d �c�!��-^5�",A�U MESO.�.�6RF,�oU�ya�zMZ!�r\!�.�)N�%Be�& 6C�&�.(m�B3a�targe>�E}(E�9%�I � V�!�e.�� E���\m"ed�BT a?*� rFY�m�.�6�*� F\nse40GU��PcuH� Dd �%����3_.�$F+� p&#!�}�ɫTA %�& V9�)�$l:!-*|:m�&u��UoAS�%�� �Ajurn� y a>�Z�/��&0&% Y0�$���)gj.�a N:/BJsub��aM� �!�"� shut��B�A(m� ��y.^$Z��h�;t!�́d:J��. ._ neutr] ^3r+<oid)�egg!�_*=�l:�  .4 must rapidly 6<0ge.�23- ��.*Q<18*�?3&?8�&0is9Y.�� :T r�)(= z�(�]e�9�erv��t>$*% �(erae"d=.�.o5�.�s� Q ff ,E9no�+nc�!d&�*�>.�0i�2L�1IbO0�dev!�of%> !�no6J6��7.����&� !�"�7"� \"po�4.�;? vers�o�{� Ehh/.2�1���nd� U72 6�. P.<9isa_rF�0 ,�&%����32I,N��isg { �iex�>�*T!�stochas�?ra globBC{Z�= aris�,� ,���n��� �"S!�q�=�4l+9o�:�=fuY6����a���overri�/2gm�MZjY2HaH�$-�?i� ��#�E deciVA1�"�e ly silenc%�Nfin%6{. HAF�eostal# � us��� oN# extrinsic��u6�\& %UQ50U-g�Am�����a�!L)�!�F�2.H.�e�"P � Z�Estric��r� h�}|2m�i�q ramm�2R:F�!�� ��/!or�&2 towar� 2}fp��di�=c+z�N�FSJM�LG-� ed�!�ergEc�p"`� a�N@I5CMAMZ� ��9 : �*�5��6%ngK:utocr0Gand�.!� mannera�V�!!��*(#�51�'[5�!8B� � 2�� %v*�� ca�anN%by>�� �| &� E�h��� 8�)@32!iW*2�Nc9�U}+2*�( docu:Ueb� �3{�� � A��.&co� Z"� �%� �e�Ctho�,A��2s lie�cl�o.�%o chromY�U! ndem� a��*Io�.� �H>K he uncoup�7b�:����]ynW f"E E,.lr �/&�A��~*�D��Yntago�8�a!g. C�-�3>A � wK)�9�UArIosp�omMl�Uc�E�A�]byF�i��4 .� . Al-�w�#EGj yet�! 3!!&�D�i; temp�D�(pe�G�it�bqHa*�*cio� �,"�%~#K�8os�*:M�� !� cyto�4 RE&�,s (%�!ew [53!I��sum\, ourUT9�k@~*,@���ER:~��J-.j%x.��Y��0N�AB,MکJ�a3"��9%o)g"�BEkVA��ur�f�MF�� �*sCa��B'� doe=l����:B.e� Ha�&.4 A�iU :L�arr�f^� Eu.iE:nf$re�sia-o�B�%�*�C!|*��.]��h� ��laa�mZ(human GP130Pcog^& -�( GPL ).1 r"�/�4� &�"ic-�#3z(G GMn*y Hs�8as IL-6R�%Onc� �7M( ( OSM-RJo xQ�S9A$2K%59O55!ln�;�-tFN�IVe*Pab7 �!w�$er.z��� fN4\/l�D&�7l�<3w� �Db�N&f&ex�)���>s57!��IL13Rα�9?&80-�:!"� ;sP�oe��sI0���  dose-� �� w!�s9�0Es���JKng!�I>�85łR6)�,��SuR�E�>�� �O*|7�Q� �blockJ��Qm �.�� ofR�%���9"]"�  !�A}UpuQ6�C��V�A� 2� ���:�L �ch�'DD,.��i= '�*Y ����� U'�u!�vA��$!� t'g�*M }icE<%�&���O'2�LGub>�u3selPdu4" evolD!-ulfilE-&t. C4�Q` sU P3Oexten�pH�K"�5feedback*�AtI�� HAto^ !�1 ropr:1"�T�G s [2 w8ome-wideX )B&(i��creen�SJ�TRI��R� �&u� 6=!�FdQ��3*�Rl  seJpu��9a�Wptradi �z ��ont�X[3�BW%7E�it�N!in6~n.�I' �Iruc��5become.�` x!d���CngA�si�9 . Ofa]=�� , chimn�7#re4Acho&b_$�t@Aer�� .�xCZE�m�,o�F*ed4A� s [5T R|"# msA�ualof Wg.mMKmwKe"WJ2rP �t�+A tigh-�.SROS�Am"�HP >#"t <2q[5'H ��5.�2 � conn�pEhZ;"�*�kL]Z���t �K� ;dd-�-Kfu�Ee�eZI&�A'�? family+A��&abl�*�dN. [6s$expane�!�_ "�&�Xxge�\!�/!�HD" soi �ak9| �Zs��co[6J=SolL�i:{C�:iso�di,e �;flu�<�%EI� ��t�/�xbe $a�ttsuaKeeaEms" ane-assoc�d�� �)"�"[6�=[63�?7s ��A%-I� � lo:ed)Ooly<��mF�Ton�n*�CpOWd� Fi{Wy�tu�&on:Y orr [64]q�O"at. r.manchom�!�1�:-e1M*&I �__wRM , oNc*"M2Axhi�irA�a;!yX�-�@i332�� a�kAn��ur� 60 � 63&z�J.�e� ,t ��he�*2s ma-(in mammaliaXT s [65e6� T�-� ��:b environ�@ up\s"� A��a��6�]��E�el* �1f�]. !c�zr��toa6ht WEw#Yf�tu;I����E;�5� ���M*O �3&�ZA"� ��!1�a2K+�:-Eed:W long&6�����+mploy����E5�a _ "A A� �Bs � 33h!es��&VLa . f&str�X� �,: �+85�(;UASmcd8�+(> )!; PG125lG-�`&;) [67�?sZ][1��ey /!=d�>ob��`�]AEBlo:gto2�.Stock Ce�P� %�*,+ �,9S/AS ω��_v [42]�_F�'  50];��\P[70FLP][70I-SceI ) /TM3! P[ry+; FLFC10 ( C&)I+R(F . Karch .+te�%!� w@ Mid-�& �Warvae�!9or 30zV0 m0o.�E pilina bo� di�46�ata� ���3vd�K�ap&��era�!� ed 4@Vor {`�z1�proced3[� adap�1� Ends>: Kn!�(Out method �eAN, KO “donor�:���U�� iQ pW25 [68]��Y�Q 4 kba�5B/� of 3 flan�H�&c��3f'BC�9-wh!�!P%��V�a�-�O :;(�0��� ��5\-�*f%�"�!�(2�fL�g o�". S�Ka7&��KO(Geu��ver g dele�D�t!-R� =by D8DSou2ME�T.S1e4R? t18A�)� hoseXGA��.m2 5mLH�a�I1)�eA^Ax&�/by  RACE� ( Ma�,on cDNA ampl�rki� Clontech�PBD Smart E #BD Bios�/ABx/K@e� polyA+��ho�-lMa�� T9"Q9 diss| 7. A fulj>ngt�Vt ��A '�!�)�m�TA�A��E�#c%��� �AJωI�.q �A� #Eb%K2�DzA*jF`�> frag`�#���-�`+>ω� �.�e��M& >�M��\�@�T � attB2=�>�ZH49B%$ZH86F attP.g� plat�� wXL!l�Q-HA ![�V56s7Ie��� �]a�D � :A 526-bp%�c4ic5XQ�e|7�'�J6�8*W14AU5'%�Invit�)< pCRBluntII-TOPOzR!wwo��e� prob�S836 bI9��1{2_R 2 , 0576#5#oS%de� ��inN\$&#6DiG))J�$'j ��CպM8a�0�^�1hwR[7F-�H!\[=fJ�!�: rabbi�Eti^( T�a0y ) 1/500; mo4G>-B/(z)meg�^1/8/.Q proPO 1/2HCol^;2.α9i�F2 V5 (.��!�.Zd2OHA�ov11%�SN  Cruz>�N1 N . M !28in Vectashield � um (�Cborator7#)�cenR��$ya3fo.mmicrosDC$( Leica SPAf. X� �8)�A�B�4;M7ed�|%�col}h rizol���P�(a\�3 ) reag�:[�%r� :herufa�YC Suc+��R�� se TaIIBT(nd oligo dTul�A��Fr K��K��. Real-�N q. @����G$on a MyiQ �Ml�loM"al @3�Zsyste!�Biora�T. CT valL�9^�5�6wB/2ΔΔCT"5 71]-x6AA!`b+ ize estimiN�R7v�O>�,� !4:��� ��7%Iu �W ,�&b_���m, >48�!��No�~��P%#)PŹ���eoB<�k���>r� .P ��'�& �t%K,WBm9�E�36;J &M9oKj��ll"TB�,re!gen7�=.>3.�� 2�s�4ns ±a�ndard�/�-( S44S_.aa��&%GY�i�8Student's t tes�V�X*15�鹁�2 n�6��-1 e� *"�=JZ�AZA�e��W2%Zk. *[� <�4 a'�*n�5�a�P�T~aGM�� a}!EKgirefly*_Z/rZr �!�� n�. For>Q,2���7Ls1A!:Ag�Np��1or�C.<e U�3EJaU..�.�R%r��in*,]͗@+10% FCS + penici�W-�ptomyciV=(Sigma 1/100�t 25°C�<le� al CO2��<( 3×106!� wS) �se��d �  six-'w � 2�9�6�Z��mEA)ne ( Qui��eYX. Each �A>B�20M�pl� r$`M�V,%#!�,!�Y�>2 �bH� L�r)ye ( pHA )a@aa�hof 40�L..��Hf �Q%=%�wahin PBSE1li in 150 µSice-co�suaxA,�(50 mmol Tri�) pH 7~BNaCl , 1 EDT�S1% NP40- �yg cocktai�ZRo�f��20~ . 14�!-cr (HU҉g2IP���S G�har�,b�Q(M�Mof�AincubM'en 1 µ���� �%� V�t� n1�Gt 4A�a�t�Owa���jedaernat��626. B�%�?bo:!�en�!us��Sff��ls%Hins load,6�gel �31��.;(7 AN� �V))YE�lan�&3���J.tV %m>*� V5!h6�V .��Gene� mb�x.-�=�!c� ss>$�&B$of~ ytus�/ yIs�&%xok�e�9a�e,st begomovir�U% h#k�f�n!�a�#�, G.Mvirid�s�ma�vI�!�<��-ap�n�0at non-random3)�break'LWtrKi,?oC!}�W�EesMcd��Eye� ��&!>�ps��N�66��Jqrh�n��Rover-�h*�yf*WNnt?�$�=fc�+fl8B!4f�msi�6l@ degree�/ �)K�0�a�,plic acid��=�ur �0�5 ensi�sto =� attY&or)�aga !2�. �!b�#)ik< �h�&�:co-a�zm�L�X��Hmot�&!�.i�t �X+ disre!&b���;*fW  7re�0&�><{%��F tA�e�E$ 120ws&2 �P �_ o�f�`�bw��]� es T %y�y;caf curlip� "lComoros #.�.�" ��V�UGex�MUEJq�z)�"traar� (x� �A&�%%Q� such����u�8mJE�(2�A� ongl.dMUr�..��fs-�. I��lso��A �$9� �u�.=6AVIY.��"oaC&�; divi�#�A�ga�A�u�iW%-q�2�1Qth/��y#� eru3e�fol .Vkv ZJ�O �*� favo��a�%�r$'�u�der��g�T{N��m2��,o-A)th)imprin�"6b>[o"�mexactY�ta�rv�x���Z. . "r4�"����i���qis)�H:�g2gmol�4�' jI� *cer� ly%r�3IUJ�9 0a%�U|&ct���4o�&viSE( es [1]–W|,<-�NA[6$yY�e�2��arr�^Y� �lU![6n0&FuK=� �.����10�� �13]5%�!C��I_> A�(��e*Iv=} majo�)2�4AO6$�7is� l� � d�(�%yd���;�. A�bdr� [14%16 �)�u��[%21x$�, �b���� engine�Ps$utili!�aK-shuff�8��-6bX|"18!Xv��W-Yi�oba&/"a)X6�%;;�eWj�"0 moduo��s p{0!\e�Q!�r���e 2I���Wfer� !t>��&eo1A�{ E��Ar)�nd 9�!mA�_Gt�E��Db�stenc�Y6 �is��%Anetwork�^I�3S �52���pp���/tv �Dism Examp�V0#�V���t�0s:E n-amino- �%{q�e%em&*2):H�74, Watson-Crick�.! i�%��'-a�[mea� ful�W*} ����!�l��&� ( ss� )���[,A �� Mmotif\�v�jm_ՠ,J"n%>C ?�  aB! f.Qsurvie�Fo��%� �Q�i��4llS�0�hp�HnY's+6��2imp���c�x]3',K !9�WR@�ori[.r�Na� apprLc&fiteD 7E�6}��Q�Skx�)achie� MWA~/D�4" -s32 %zI�)�)�yp� /�*� ato; re�)!X 3DUv� �юS!9���h�4�success�yn.���1�2AP��bk� �2�q7�[20�=r3H"}) repl�(��� �� $t a whole-�,�Ql[ �6�)�8!�s!q�ris��\�'�Cs emergjvia:��8��", o-!�.qg�a� host��e(w@`� tp=�io`m)�ok1ltipl���&y4R –2=�Z�@h"�S# A�%m�o�_d ��8soj*�Ftr� �/�3A1R��%xpl�L6-"� � �Na�0b�rE 5p jZEE�i!�R�. G�_�ZF�p"�Z� Iw����+ ason� �?u���a�,*�� �ɺ2��Air arc�%v��W("�u�is2�1�C"�D%I�!c2f-ix� *IM�� . S��Igenus B.( F�/6)%7iddeA��j� "IregA�hV.6ee�pnumer�g� al cOPy��ⅇat1! o�D%�T,e�2.{[2�i�;, b�uu&c��A�" �e'ch&L����[2V��,er"6� -�j��� s [3� p�. U  a!�u�as�/� �1Ta�et1 perm8ALe 04Co��!��+.,"�9YBb" dem�%��.Z;́uDto:� )A�0y2Jq �?!V��E,t6`w"�N�, (�#)1y�g�)�6� �&��E 8�8�9�%�aJin�6��� q r�a�*k� ( g� reZI visu�O.,IC1 iF�g. Agroq�us%%EZ"- M��\[Reunion:2002] ( AJ86533�ae_ to ��TYXa�nd_^_�p<[Mayotte:Dembenie3e9 � JdOdrAd�!�$4Urbino et al .u�R� !�to�f-(8f6!�twoɳډispzb�at 491mTv%*iye . ∼1 8%� �h%�ic\� !%!>an ad� al 13 b �N<g&14O)��/[ � �of 89� �[y �F��FarmerE΁0, Known-you S�_) � co-aEUo.F� A�!� 1hec�rfourt*Aa(0��"�:Q�n u���E"�#�m'(kfor�KT: CCCAATTTTCAAGGATATG;"$: GCGCTT' ATAA-GC;�EAG#(TCAGGGGTGCA CTCGcGCAiAG�+�--3V � "� �4l�, r�ly  %.K�2,9�!; months ��eZ.�qr[�%!{΍a2�Kdu2by Bo�:T3�+r &�%��2j)�a?DNeasy P��iP @,( Q�B�$ma&&'���M�CirAU����&�%� �-�T�2iPhi Ki�$GE Healthc�&)!2� Inoue-Nag��1, [��F�,e�e1Y*a+�pGEM-3Zf� 7Zf*�( , USx*�|bir BamHI� 3O�hDF:�362&te!-A�E:�?%�!�ten ( TI �%%- �E�1+<Mac+IncB� #�m4service ( Kore�). IW$a��{A��S�6�&:� %��s orig�:�&0-wa�vrr�+#s ac6HA � ��]�%\!u($pr��RDP�~��;*�%%<,http://darwi�uvc(. es/rdp . htm;�R�se�O�M[" 6[�� -by-�F�a�S�vJ3Q!a pai���7B���f �6aid��put��D�x9iA.�map��| d�!�!@2�all��-�E^un@u^��YO$ga G�&I�I�_Hde�d"� i%�y '08: ��M %�<�k�B*(e�y plo� "�!n3I�Uap65in�.�u20�"%, 7� 50-nt�nd2U�mo�one]"! aX*yp��A1��nd*E�wiT5�A7���f-�*^ g�!*���� �?�� #Q,ig"�) clus�nW#Y0�t}.�aZo 2�6ahot-spo�e2� ��in Heath���n�^�� FIhK@q9N .�i7dSB8�A��  �R%]sor�avU�6�R<o AQmb 6 ntigu� ye��6J��� �-�m�� ��� � .� a!.c><�%0a%|W�u#�^�s�E.i7itX� tegoC/A@J1ŝ�#�m�os- � � IOBsumA�J�B"� �rz#�+nd�Yb� ��3��N_(� Pro�6S1��de"'s��*~!<&^���")2�5�r�S�QEz^ E�aFsem�! of n�7mum!�� ergy ( MFy�a%� a �~�u UNAFa �@�3 . 8�,�l5 s tr�m��� �1?�Va� .�9�to�*!{sod`1 magnes�Ee f �H  ly E�1M40M5 �AL&� ,-u��Ŗa36�( G�eAUk nd Wob!U( Ga���ing� F-:s+#p%H"���-drPuA��%![by sc[ %�de�m-GA�.#-p2�ti� E�.,!ґ�22%,19�*��E�A� alig�4.K �:��/�u*J$F �^L�A�I/J�'.�6`�{�h�l�@B}.�A��K �2=��>��a�/AN�A;�%("@SQ�p�A5��E r2=i��C*<�2�-�\�)a]%��ds�*#a�C}i.Z,redI��K1�C"2� sE �Aor� )I���vjej y^�DOX g%o(��hhOX6hYh�V"TGaha�bia� �6%w+$u�t�!"Q9f) �4-l�g�W�� �wAndp a)r&mae �!:hotk � ex�_.*�s,Ny . JO 41 %z�yE�!Farouna�=�/�Lof.�*n MY!?��!d� �("�.��IšGIJ�/I�/on(-the-i�i�᭡8m�� a sl�*ly�!����>6 :�9$Simon-Lorih e�{�Lefeuvre���T&y��t!4�&5 %�%!i� ���L&~�h &=��� 2��~ J Y-��!�i�&out�I�'�� Ee8�|�6� �!h�"}Pda��%i#t�(�y)�aBt� Au�!<��V�&�o_MZpB+ar�$-S"`�� 2 �we souuF�9b!-.m��ay�6�:`%'�a /�D�Xin��sta&�$qy,��oA[#��-!�)��L�� �y&�"&9x� 0�1,&.�M��:�dicVN�LAd� P3r����g .:��.+.���yb [�.T' � - �qfH}*A!m�*D&*8�'!��m\��eUaUm!�e"�N��1�* � 1,$>0,U�Q A�e^�A.�1a pE�:w7<\�W_.� nt!�12�6(!^"�&a �ge< ��1) %N =nm "�)!�S -n�y�##L�apop}�5AyUw���.*�"� a�q/�!e"dr�;*� �(42�"444)��(l�<si�[�cg`3 �7%�dynamictp�l�c"A�� E1 �N%M2)��0�7�KwR�k.��U�+E�vi�Nor7�� �� y�E���ME iscov\aXA�X%��ofCW&�.dQ�6K�+d:� %�l�N!`m>fy*�� �JF��.d.��'&"� A�ar ���h hA�O3r��]. ��v!�96ur FULL�aK[n ����vum�+�2lB : ��#2 !���k[%z�y �/.8�.�IT� Un�:ss~%��$�L�Ȋ�b2&�!P-i��~�8�#0�C�:&�,!M�higy;fe�"&�;u��b��ťH*�&*x%A�A�MB"l .X�xavA�/e�3���1�w,`]d�Mn� � XD ub 42$�e2��&%>�8ur"�O�%�>�?A�� c( l��"72Zzf�-�/s �8"K � faV�%&PM���?���z)?N+�n��*-1.2,{0/EQnoA�EI5:��2�)�[YO��qweh.+e"�!�,Mg��s8c��;�&pTu�@3�5 es [��[x �}�$�}Wp}�.I�q�B� �i }�N!��6�%!��eRA^�I F����kph�}�� �sam!3 %d";inbz i 4 � �� W� en{%%� he SCHEMA�d � :� F� 8#|&Jh;�+C>A6wfr!%!Z=zi� Q� #�U���u�MS2�VReI,118 N-! D D/�,s;�&)�$CP�%96.� !9�g��؈!�00�#��5q4t"��e^DG�x�A�!!aiw��)xse6���Ewa3. E�a�$&���n��90�����^�$"�F,�_�/: �{�"� aH?�<e*WU"nt"S%u !�6f烥�e�M�Fd:�X|)3%���"�U#Q � *�2��) ua3H*�_� )�E8& �C-of 50P�V�wB,ed�.&����la&.)�I( �(A%EI2oZR��0r+.�y(�IJM7s'YX derir6�(�� �\�X�!�e�F�r �FEl.�^l%�tm .�%������ ��)K��s  uA�*� EA���I!Ra�uO#A*��sv� {aTv�+ Voigt&a9]Fh� .�9&~A�A�=u�_H>w� .�I.tf�ŚE��D�2�7Mdn%eEV!s5�)> m2�f!G�gcPpi��!%s%�.�@�&!�S/4!>- [40]����&��� D�seZBm&V�l� abov��W.�r��[d/�}�ha�� �p@>z+-�6#s0a�� Em9�!�0�do����@!�iQa''BkC1!Lxim�7�?-�� S��Mr-n "a�;A.� 33 4�|.sVhţ��c8"oMKv�N��( TrAP;A&�C2 opeXKaE fr!�( ORF ) �X|DNb�2��-! !1�.�"��( REn )% ^0aU�-.cco��=�H&j4*t &� A���s�]U*�!�Z!.�-Y�A �a�h2)=  r"�w-*" �!9/le�o�� alżs�O�{ ��s�$�if*'a�0gu:5_ a�?uQosV�7�-*�B=#^�.BaAw t� �eYA�n�c�� �����A��p�.F� uCherDzoyail�! ����n�JI�%%�!0"�eje�0 blind�b �� ul�=wisV/"�1�+J�����?UWt��3� a �� �'*)��fHc�B �{8ewj/��5�  Chi-squ xdA&6�%cap�2M"� �_b���3Bz�S �C& TYX-�r���V"�Y~ &�5"� coune��7B���( i , jl.�0��s20 �me�;i. “i�[1 “j r�IHh1�/F+ej� .( ×49�M8/2 = 120295]Holy�2c>I-n�YA�� ��:U��/2| �%� ��/i-TYXj ,(i!� O  : ;m�veanco�=asP�" �!�%~UlW�R63e�"` �,sY;�L�z6e �#N!a&j,-J�-*3%1-m�o��.�� 2x2.$� )��2w�0-Bc�?��AZ���*�'�/����}A�[_}���(096t��o��F�:d==,� �Y���#W o%�st�oFuc�reRt.8S. Non"5 be d��o� |op'eage�����orYf\� �M�'7(kd%` i�0Dr!n3. ݯQ�in� a l=)�dQp10 000�D. )n��śUݕ��F ��r[1*Ͷ, "�s��2��Q�E�NB,�pa>Nng�& �+i���'5�f�eō^�"�C)e-�� �!N��#wJ<)���p�B� �s "� z�Sdof�2x2.� w!+tt"u d� �Tse1�"�AEEcC>�b8Ki"��� 2 had� aedBdeze�oan 95�6}j�[o�g�-Mb�ENE�prenaA�!��� u "��lօ2;i��!�q0j"�km8n� �X�%`�fl��! �Ab&5�Z'*�!aiN%a`��if��exact���1\E/"�ehBary.D-�m�i� rank (A�,�5�K� )�o1O"Qof:�2x2Qw(!��S�2uf�R�� g!��^1  �C+iEX%!��M2`M6�B���2�re�ZtoI{�.�mJd A�)LM���"�A�.>re�YA?E��Iu1#%ad22��d 95!� Q6h9��s�q6~a�f\� , 43�:��, 1 cM aR/ 9%�60Bi(16(R@OXI�A1)�U���W�!� is�' . 88�a�1� is�E��7 793/1��,f�$�0!��!��!�I.� .�# 1��4�� play.,�c�����8unTA��Hir^V��9 �F�, 4 104Em��F<]+Q՟� 9��)�OX%�1 589:XJ[Y�4 DY)�u<�0S��Y�%&*$5no*�o"�$�)xor%��6 �p-�9%a!���ofA�a\.�� �+:�Q � OX =F[4!g(Q]i�f�v>vYv1!��R,�@n�!%o2�m$E�"gẗ́Ft�� u$�"goT:��1���J���!wE+�r0��}@;em] yo�Q>�Ob�M2y������Q� >tI���I�6M2�!M2+E. &.rwe1�[1n�Ma; #�" / �AqVha&!Q�aI �Z�?&� �Ui�Q�<8^0�Z!� � mix"4!�!r}�r(ot"W;!�(ڒes�p% � �2�E� in >*c �_$ . O362*U"�ke��<.� _�>�@�t�U6�, 106 (|A 29% )���Dajc^ �7Lg�r��r?��E . AZ�� 6i�V:b��� za� , 18a�I*��>TG�Ij!� ��1�m%:b%�  32�R ��� p�45!"�I� �R&,I� �.in��"�("�(� i*0��� i;J��n�S-&E%('D!2�$4 aG*cNVriBl �� y.$H18!="�*�6BgS�W3/~�JA�AG�>p52�=5w a �9 . 04.�TR��V*A����lex2(1c�`�618"E�.�q%r$"_�&�F�  malfs'ak�)�N��d[5��\�-�� welF1 �BJ�carWO!NlP5T7V 2�}�d"�&g�`u[*z =ۄ�Wi�[�.���" s a�ȡ�&A3�hly � X�QU.}1,I��Ply�-�] outce0��FW!$}'he�)�xA-���-l)�cap=3e�Ak!���6,%�!�i�.�� �XIn"�x�A���Wi!��qool�fLQXʖ�Do�Wr� at.�p��ȁ�1�K��I�|�b�)rnA�>��:2Ё o doA�we igno!u.>c�ou^f�as ��/"��.�.-�*2.'�/e")Dm!..�.GY.-�L&A Bs�[�ng2� , 12=2�?o alEO%9W00>itu�!Q!�te>�!I�M* �!of�!A|;{ catalyN]'"" j A:� 6�q�( p; 0� r �{.E�%&bA(E0&�C � comm;:.Pat 192> ( 39�S!,eh! prea�9"�3�V�CX>C3"*A �� r8��} at0��a��ޱ����a"EU9�4}peq be�b.�r��agy�t�11:%Q�� ��e!�0���H!�f�g�j�q!a�&N#�(p�V8."�Ve�s3�vo�c�/'�8�,��&pT!;�Mlie6e�@��A$s��-weIR*� -? �!���gyٛ]�.))&�"'"���� ��� � s�-�-.�-���%a&�"advXtge���Y ���W�.#$2X�9v%Rzie�l� f �DM!�� ��I�� w&? }�a}eQ~k�/e&�w��"UHthd��j�I�H!EF���!7�{�H�A coldH!��AgJ��Oaq��>.� e�S �O !ye�:�e�!��bE=�8����� � S��I!i�}Is!�u;IjF^*�U�~-%j�q�j�����JE@!)a�j ��"�?b�igA�f��J�. Db ��|�s �,q� woN�9�A���e~V�C1�t{.A)�&���!�C44�m.�!Fm�.���Y�A]9<(2��k1� r��don�<ve�p"�V<V2��h 2�facA�&jV 0�|I6�C'(**ء}��,"= 2F� �?X5'��<��w�e�}��/� �F�-m��.� IR�"� �kens]-9�5�OF���R2[��, ��.�a2AfGa��v:�}6����"Mope M*��goUO5Il!�&5, m����l1{$ �x� �0!��r(MW /%��"� ��m��Cw���If&�9� �cU�#.� H�$�b)-�a� q�Are-\%�!p"@ ERa �)r /!J��{ea newfJ�V"uT=>�a�-�_�r u"&%�W�� KK� xrE4*e�ul.9Y&�B�":";)t6x"�Z�C-)�ORm� IR . Surp,3@6MF�$m>�D V1/C�٢ac�jj&E� �"N @:�a>C�2��#�alo%�t��.�q( [8]$�m �blu�++:��L��2��PE\&pin�e�G0:"in�=F6ao.HfaQatBx-x*��vtg%L "A  � �V0� �AQ2Gs���, fvi"7�E��_�? %��'undreafa,ar�9��in .(&��a.a�&.<"Ed {!T.l �s1�6�"�"^�<.&��c*�b;w��I�Q �.EY�).�.™��%-��"xt�\.YT2�TB%�SIRyge+vC unus��[j.6#�I>�m�&,F )�2*�5�or 3s��ta��69&� �� 9n<g 4� �&y$ �%D�!}=B� IFjobb)�J:A�n%�Y1  �%�{&v� ��"<�C�)�Q3�O�*0y>��� �BnRa�A]��"��� , �@9~ @1D LmEbB�/mi��|. N` th��M��c!2r2�u� 1>Jim]�- ƽa$B�K�1h,,p��rpEGiJ�i�=��recap�..,pA+�@��l�pg��m����]P���1�� ���7^E!5��L6 | ���.e��.��somI�:�b!��v=)zY��<)05 Ϊ�bandAA%a�41� �100%2�U*sur�S�QA&�T�nI�+rsN�%.E^LiZ�c�g1&�C( p� 4'092 �Bi�P) �h =A2J388 JB';.I��I�Fi��e eY� 6�,})c&1atN�� �:�ruM�� 6&in.sj ��ljr&i�!Na )|����pa�ω�� �ed�%����2� mZY mo�"p�.-*$T &�d�.'m5a�V) h&�" %&1�� H� deA�6 V K"��gJsz�r> D@ r���S retr".�( �je)Q2��-choice9.; ���9w"\�]����E plau[�&qMe! o wh*�A8 i�.Csh)�m��-tKo��N�i��Յ�� n�is�Z��-d$>N .&-�"��W>|E\�2�6�n�C�U�6� A A�co-� X= � v,2%X"�E��D"�3"1 �"� z #�=.s ( �?F�Q)�.�f)�>���%�j�"�&�T�$e2��a�mo�Qe|�  NExR��C2�%3�NApp&�!s�A!���V�X7]�� a}Z�"� � �90H �2R�(within HIV �@genomes , we analysed breakpoint distributions in relation to the:!8of TYX and TOX _ic site>,ferred using>�program UNAFold to be involved in base-pair3withinW�econdary structures [40] . Regardless�(the subsets � that�Dexamined ( see M&M � able S2 )%�detected no clear tendency for recombin)9As�fall at wassociaL� predi[ssDNAv�$. Although�obser!)\a marginally significant6�:�cluster�where%�had a!Vongly.�Fs but%�di!Tt ( p = 0 . 0579; =M4, it is import�okess5�tperformed three separate tests%�1�4would have exp)�Han approximately onAVH six chance of findAVat least&Dp-value this close!�9Sce evenA�AU abse(of any real5�ia3. I�Dperhaps not surprimI� foun!>! ong corrqjbetweenp posi Yofjua�J�a�)9 much ( if�Dmost ) begomovirus:\isa�Dbably a by-product�doua)strand�> rea�0 pathways [55a�Ce;q%"s��R��fa=q,in some RNA ρ2] , [5]I,bvatt��Ah0o copy-choice:omeA6 ismsm$R�(cause eithe�verA=8ranscriptase or�dep�= t polymercomplexe�3di�&( from templa moleculesAZfA$se stalledC$reengage a;o�thaAA�on whichFye�ori�F%! situ��thM�synthesi�(!_or ��)�s will��5�nt.�a3$possibilita0 mainm���Y�es2�typ>�occurs da�oN� induced) a�of�replic��9w,��%!�I E�Q-���isY��be larg�t bscu�� by t%p>Br:]t. BesidADhe potential influ���10tic factors sa�4as local degre -seq: similar!�ag,nucleic acidRSoA=>�b4.�our��rimentsw�q,also interesa�in�n rmin!�wheM�-exi%evi�~�ɥ�.�a�;E�5&d!�0natural selec!�A�A�th � life�$Earth co-e�92pec�_AJ-A�,� tein�%Jpr "�aos�a� cent�rolA�E|m�$ar biologyA�6!��@reasonQ�su�ta�tJ�e�st�\ly!,fav!�AQsurvivalm.�y��@�3s�te�areZrup!� . Fo!�ample!�hi�tra9( minoIl2#m !�e how1Js f# , +�D oligomeri��f�. I� ly ,9E*cany~)G�if]+2�by bringA�togI��e�9�do�C�permuFEc! S,� �A"��� [9�W�ereforL ed$2Nu�U ��� ��z�� �AJ} i� s be�gener� � di%.ive�6/ra-, 2R network%n c� be accoun�by� . Sm�uA�1G���we con�N�inclu�( 1 )=�6:wx R118 N-tE�� U�%�Rep%�.196X&CP , ( Z �p otid2���in*y %K $ *� !�$( 3 ) know3E!y ndU5��2w differ��h��g%4 . Previouu [ 8[ _ �"u 41]�HIV| , [7-� � c_a�assumA;K om:�,��U�E�en90display lower.�&a 8A��uSQ���AyanvwWaSa>4 �w �11�� k�  cyZ0outA���coe�r-�,��1y�/.Mqasa/ey� Me�� �e edg)� 0 , %�,� n� doma� � arie� t]%�a �m�mpa U~5L)�A!. U� e=�!�� Hof Lefeuvre et al .�we�,a†preI�i�%7fe:�001E�.� 1174�>�50&" FULL.18IT da tA.�iv- )�{t was cly����6�.`����6 AYE .�,5′ 12 . 5%�3.of��e�4I1&�'m�MfrR b A�id�=� X I ( p<%N` 00615`5TvD"��c�sp-�s obta�!)V^lik!�ref1 . grea9s�siz��I-���� l�|aBy�|��!-t*� has� � r }sp��Dn� e��Y p tern6 !^@ hotspot (vir��� 2-   autoX�i�`spo� ?IR�x�#E^w����o�mder]�.6� focuy��Ci�V1MN!� ?!4�9ato�;resolu��3D���K models� avail[ allow u��direcE�estv.� &Z � ng ag�t9��exp� mis� e��!�2��med�� 5VN"� in:� �� s$ chimaeric"�CP{ �� � &j��>wA�*�I��in�gie5s� _��Ŵ� at . Cade�+� 50 uniquA>.}pamb6�.Gno2�A�2Y-4�� F-bera�]ofj �� ta�CJ'6�13�ءb89E��r>�W� M,result impliA=!�]�M�j9 A�ob= l����e over-!�2�ofY�5�e���s��!�=� ORFS�z�Mnticip&e a�ͬc� U�ly �ient/defv]\ne�m��7"< amongs��A�2�a�maf %m�N~N�Wzw�p�v)>�i(  on�he.� ��!(186�%�{vi��enoRto��e���d multi�ti� na�r�.S� �� �x:5:�N�ir!� ORFs �����!LfB�eS�* &!6016w "3.�no� �]jV1�:L 47 )@is nega� qEA����a$p.,�j CPMc��)�wo2�"� �b"��es� mply%u�%z�=>5�nt��m�n 2w2ur�ue� turb%�s ) ;�t�ey� m��E�s8&� (:I�in!�XnhtheE%esYm.�!���avoid�J��st��e�b� e fit� Y���a�y:GSatot�F9. TAH!�w %�2��veA�cesp �c imprH�+"��!�at�c�n loba�&popul%�;�� eo�� hort6 P� .�!1}eho��qy !�C!g>D��R��&� fitn~�w� in m�vi�� !� [59]–[6N�afge v;es [63�[64uSi"z�5arily��L�Fru![.D�� n���]��}MmightA�4EU�e�� invayg�jw&�,nt�E�ar�M%6Bn�ed2� mon �!y!J er&y b.4 �a'�Mc%(MN\t firstf�o�stQ�ofVk s�J� =j� �&��"� v� gi�RU:5mpa} �� �GMFE��Ua��\!m�e9� "�!� bothx spac�WE[.� a�~$same numbeC. a5yms�7F�6L!�7 vari ��0stJ d! ���!3n�ґ ( i . e .,�9Vs 0 |"��!t|�[�reI�\*�!Q�6;1^�s5��F() e�1ɪB�s��r">����n�� ����aO F��#uc(!� measWq�MFE!�!o�8�5� �U�"�s8� an� whel�:J#S�$A�!��ZH�~�iw 7�� how�%�)BA*� \ten��Y�A���9}969( a�����Y�hairp|!�%� !%�if[E0o�E� such�� doYexa}� �# ach m�SCHEMA-� "X�!����J� s �$ap�itA�֙L- �tact m�#i�&��;a�F�Arnstead!&� - v_��9i���so , un�%}� f�w!��'"i%R���f!|uY.�e��unY)�c�z2?� is l� px(me�(w���to��tD'u��  inyp�f �� 6�:�Y *�6�h�"E % berr�]Ag�inga#I a��Xin.R!2orj'Rh!-A F�2;� mis�Z� �}�}a�)R~. B�o^$iK`dbRmI�� y� N6�F�*&B�^�A&n�W"fN�04 . 9×10−3U�2�!�3 . 7 /2/&�%S�ML.>U4 >5>./7 . 8F/Zm8� veryAgeworthJ- by f�*�-�!�8rJ��&O c�b��C�. lookaOɋ6/�aI-��A�-� 0"�.ka%acceprto equ&qP'"| "�A��engthw�! &"Atm�r�(g� � G) �Cvas6_ st d� "0�i�*�26�sug!k � �onQ �di��#� ( novel non-)^�4(-[ua/as��+as!af�� broken���'M��&ple�)Gwe)J' "���"� 2�!ԥG��t-,b*�+y�5&��a� :� (��}y 2nR� too )�����^#�| read���ţ�.curax"L�ьmethod�U�:relev�j:(I�!�Zp 6f &~ r*�(�/�o goldenaic<u���:-I&ma�A��p!+� Ma a0akG4 ���m � B��BalYNa�'< of w)p!p� '�5(a�o ��l�+�,*���0 . Ou�+~ s ,*q �4 i�)�if:� is sou+i�ll9�be탑��pBU#�m� �ea$�^ *�)q �g*'onyz� �p>�  a"7�gi% &1 �#d*�'A�J;� � #,e*A)�.��#emerg�j%!$��I�2� l3*-�) longer-ra5"%o�5 F�)�E�'dev�a�mut��dA.e]+as�1���!� 9�*�"x�*O64ɂ�%�.�a0*�:�"�91!cV�,e0� .�sa�"o-J1beH to reve'!��un �in��):� . If�/�%Ať�^.�*�n�E,as�partn�a.5"�ng��.�wo encoA�.�.3Mxa��yA;an>K moti�1�em P-i� gnize�&U E�a:��+"� %�A�� �^-�El *towur��c�1i� �� halfapK.�6"eb), well% itPw:3%x)it�@-��� =p� :-���)\bK4�#ed"�!�� P� �t� �'+�$��&>G� !�d�#f�5tc sb�&Bs) $7 co-inheri zom!H� ��" �f��#+UeRmix07*�71T�2 orph�2��s&n ly u�#-re���+ �2�7��=�61Td �"�4se “mixed”2�E�F{��,i3o�/�}h7��4map ( Figure 5lColA '.( 4759GJL 9%!*aJ� � quer&!)!)��2j.P�b,8 �~\&Nex�6͆��eի%  <�!0}Ş� 8!��> w�/ed% M�U 4-� ��ed ��9�mIRe\!4o�a7W(�verlapp���# u C2/C3la�z14pC� 5-5�(_."( 4 ) "�Q#A%I�'&)t�/e �eG��cpY%AM<%�fe�,e��NU!-�9Fc69�cK �:��A. �s�aUcutof���#05�t= ��rememb/.� ��.�e��9f !�t��MLEj�ay���of .�#r��9als�("U��iA��05�6�Q:�+��5%��a�%�v 8!_K6i� �i#� /hnsu�7wo iQwm<����0nZ A�Q`)� 6!nqa�3�S-J:Cof)\.� z( oI(!fye�(lin�sh1� vidu-%^pre�Ias0pla�� &� �&�3ng �A{j� !:�� ticu�4z��0!��W h i�s carr�I��:Mi*F>*�f� ^n��<��w� ��{ %&!& �s=rv �!�ia�#a"��d"nd . Nama628$!euIR/�+�i(� P ��!&B&mat: TrAP-V1� mo�,Q���6ly mapp� (Lacatus & S�3r [32]�mB%����- C4/C1.ks �E�)sRE�d �#F�( [30];uhC ~� ~� C1 -��.G&:,|ci���9es$-iteron-re�;d &1 2I!�6=-� Argüa�h-Astorga & Ruiz-Medrano [31.:DRn�@���V1->1�%6A Rep-CPJ�9�Malik&e150.~E��.}aK� PE_af� ofm%m��� VD2K=vp%@sE�hypH�(L,��>Z:FH)X/8*�8p � V9e�� 6�R�62� �6ea�P�?m&1"KB��cc y���F� ��se-B]�Ei;� mpel +6l��2t��2expv&><�pe! 5B�un�� s�"L��u7u�FS �*�ji� n݋pr�eWN,Df*�ɺEF� ��B,�eI/)geV�c o�> suff�i �escapt=!�Ghitch-hiDE�is&%�.. & ^ ��?aF physclo��linK61�1*SE��or 9�=2kp�B2%��� r�N�1�'i�9A | frag�=���exKA�b�?.{us���&x,9 �3a�twoyQE("�CAA�3�Jr�% �sE�� &l1�of*� 6YI�Da6�#t�*p�8�c!�?�)fE !$"vA%�=.g 6�!� G!�Emjap��2(�i:A%""8a��2B�=+((� oa��!2 �, A� B�alD�����,3��� ng ,�! is actI6h��#1� �.�� ia�"�C�0-�� a�/rL- , C� 2>&�#MC�&!�/.�&o ��Qc�?!!!Uz de1,E�Io�"m��EZ1a Cacyi���5I���be*�0"O#,%�i>`I҅ T�6{� b&ed:�![lu�!C�V�� �&�a��#s���� 1�*gGy��.�![vs yiel�nrra�A"F *�)eta�excee2)�ir sheerMN�lexqC� �: ���v=�escrib�e,al&+2�$J67�A/ţ�N�' nY� al���"� 0�+Et ∼64sկ&�a�H=A�Ano high��i�D�“1 �73 �6 leaj*� reval�>NQ-a� ��e �I^ ��27Ai�*2 [26�[51 2]m���67�a"�. land>e\ %��"c sharp pd� unpaA�e��diwHA].hf"�6."#r�:�$� �/v�fla#/!xM-:o�-������.]59��A�V.]��,an3!: �%�hb�A< up�is � tish=O6�m��w*K;� %� out-a�tha��Q}!�"o �iAA�d ���$. ��5ym “gk ��|at�;!vw i�_'to maA 2St�F� � ���D�y!KpM[1�0M�6�KWe��w*�m�b*2��:7�_, �wH��!�6 �<�2�O ,���""#-I�!46�*�+. Oaf2*%~�Led .i*)�%�s�F%4by��!2*� i !D�F}pro�'l� �A��"v .�!� |���i� ���� l�%v� !� ��*�;E��;E�2of�, adap���{ ,!9i�AsQ��!�E��"�o/aDQ gokBkRh-��&aR���0"�.2��)�$%G!�Vt�$��d*�Z�;*�2W ݉3�#�� � ZT&RTh$ n�>J,eL (�Zi�Kn�;2i.� �&p &EFZC!�Y A�x6GT leftaAF��{C=nO5�>!E.u /so�efi2~uU��*� ,trace key feLl4=�&�H� !�9�}B. F�SAr5:I!as��A�6�Qx �o �Roughpuh.$ of e�1$7^�o�I!���lHI�.to�"� ogen"&0Q:S*U(>�N$�2:KtrKR!\�-QVB�7.�/In ca,��M8l&3e*�!!� �"|;Rf,b 2XH�U.�P'ass�d"#��2� cell� culS!}wh�M�6R&�'ill�HaUq�+�!i?.of�*f, systerC sc�Q���"6%Le�E2�5�tgRg DKIQ2Q��C�+|>e~NI_�g:j e��fu%%.�NnPo� ��basic�(eat�A 8eukaryo}%chr�(in��/�so��" Rg "p:Imxby alt^B�0;nJ A�t &Iby*�+�ng"aiw?Aex��6cl��Ka"lo�R�CCo��ryF�d;r ide��OH!}�B1-- � hist� ��� qPlsZ"en��O!} archa�%1. A.v.) � quit� A�ir.bc��e e�vB!�I %9^ apmbVinqetramW(�TUt� ct )� B�E�lack N-E�C �� tail!mH��:� desp��afundame�7qfc��h >"Z"�9' footp��i��]�/*tria�2�;M huma})p�3-�Lon Haloferax volcanii8 In l�;�  n�?-�&�'&? or E�K � expl�Kconcord�UitiC�R���dom!W Unex�Y��%�nͷ�aHtn���C ffic�CE� �?"�a#K1<9�:gq. I�5Edemon�2aZ6j-c�2ubsF am� �s�Uɑa�F ���U �lAe"fd&C(po�0o��.�� ���de� { "� 5�RQ��3neG@�u� �V�Vy1 .p�..mk)�biaV>�]�h A� ��U%a��k{^r|#o2$xaTXQ ���epi . �4in vitr ^ viv?79:U z1@.om]-J~+ rk^A��i5�,> T:� .�Non�etc� �XE�–�cvirtu>�#R �,U���y#!+wrd aro���4cA�[1�@3�@dIEte�),�(7 ce le�2B��B�T about?in=QU�Awv)pa�G[-0�P�$�v ~ �w5��~�Q& ��.�sta�.�"e�] !!x� .L:broad85en�#�+8TN���1`ma�T,?methyR%�k, etc .t�&�y��":z . As0 �Io�~3_�"Zm2#!3��| uish?F� A�s�!"�O ;af�Ee��YM��]>C &�a�tex�les$n��E�]DA remo�[6A�S � !�i�% He_/!Iv���funF/3y�]s>�X�-� գF�@!�e"�A�y6`X aa re �Ic�%��C:G�T:AU�2-cS�F%2S��2M.G� Twe�m�aa7X,���� � ex�" cytosin� sidu��^n��yawX$ DO tane�deG)g��r!�sW'=]��a�!�med�;�7b, ]r elec �}K)_!i %o[�O�GT,.,ay eli� te5� ‰J�!~��i�!!9p cc�!�" EA�Vя�c�x�r�/j20~�by!�2C!0YvnA� dynamic�, eQZia m Il(8Q�)eLby exerai "9esIA����N�(r%N�fixI� ilit �M*Lr&& stud� clai[,s�#a�F�iL*(!�4&�!�k d [���e beh"'( ofte�Miki�d ) unf*k "� m09�A!7A�*N &� �  ,m� eleg� i�[H1�G6�SA:TAWG:C2 e�� N mmon r9!�� mid-+?in ���f asNt�+enric���V:V&\I*)�R � ;dP s up�n�]��Q�3pe�ed�6eG Mg"��7�r&ond ���n&� l*a&b�#��:#,"� ��s! in�.�M��c"Rco:�.� s�6�R. H"�Cw3� �Z �.,��� �r"� T2o�+A�a�Z�,��g�#��(hip"� sT\6�!/ ��=�!I dra!$�51 . v* . Mi�8b�� "� ,d E�WZ!r�dya�(ca�Mw b�"V ) y bn$Sa2� �a$verag��ttracl �MA>79pel�s ?"im*��� ngle��!Ue j�%x�:"� �(�c�I6�j�5H����.�J �&I clad!!a group!|(halophilic !-�� ���+ $V�I1=�z�e�r�8* U t&�W[1�Liku orth0c���,�l� Ebrm]&bc%jwg�2� ��&0 bendb � �g s [1�17�wh1�s � m vo exhibi�a�yM�GCa�F~]th.�A3)ja), [18# FurE�,bb��Hfx .&:pr� I�/fj"sa�A =�~i mur�5=n%�s���%P0[Ds p�_}(e%�reg &� !e���ro�*gen�z6�� �#� *�%N� �!d"�T�uec`Vq7f�:Dk, �mm� {Ls�!)2�HmA�oh�H3–H�-2 &�k?F.�Q�� "[1�c:��.�4sm:j�)4 !u,�#85 2�N� n�E䍢�∼147>�i�Qer�*rs44A$� ecun.�EL` a��h�#1 ic9ks(.b�- 9+� �cet�3��4r>!wfmodif�3#A4D/ cH&6:Nl�pronounc!+A�a�e*?l�E&�-mthA�post- <al �: [2�p&�B���s}I��ew9w�Gq , �S !� 2L� i/\�)l �3�,A�y E���P�#� :��4a�lKBrke��GeG�"& 9N�<a� Dros��$a melanoga q� In� !w"g� �%��ar����-0f�Xh�@� �8!) )��c ly��# a!�9?0 �@go�� how�l�S -G!�;� b�s d!f���� sje�!asA�n �靥���a�45X��"��purif� *� $9o. B(K�  aPic#& �tim#2�>�*# �M2�*DD)*� !k:��t�.��2D�+i*~1a+ful cav�%�� LU&�8� ���-�f!�- ross�d&� ��u�cia�a nd MMGa�F&T lignmA��� �uemaximumihood��l� &  each ~ v,9��E�M���Bn�$n� tl-A+�>Ra�Qte-��t�t� ta�I� &�t%��Na**n�,93 . 2a%A�l� a� A�9R,�a� !�p��horizo�go Ńfer��8wnYG.�"�[2�iph)W�$u2[2BY�)onf�eA�=��O.vZ "&to 1815�� �_=� �eeKi8Rre�'qtopɨ� &oL�|AvTo T\&5!��!u!s#}�PWoZE�f� 5 �+5@i�n�i�bF�at 4-v& synonymaf@W2� �8��MEW��vv*3m��G!$�;(-w make���15.!�Yvi��beg(�A|v� e1�����pgE r�`tOb5�y� q��� ]K:�diew�+��]p���u�aO=ut0��e9#��bEI�)�V�M%��B�� ���| Qe��"�>-�w�""��ri�{!f� .���6 prin@c�� ndid��u�]́6�Wl&�A�()�sZ{b�Gd^2�A�tra!��5f�t � 9�:- �&d bran[iY8�  ) �e� A�.}s>d�to>[�p heav�Mb�towards�g�LuLcE��e�!*iW3d3!���j�~ ot 9"��� b& V-e:?lI(�!L�Fz�*��y�S�AwrobtoY���t-v�D2K#raZl-x"x a .wA�V �AM �@:� I �8: �"5:6� 2osB. :EMi��a2K!DmV�!"y<� i聄v�re:��*e4"� **eM���QT�>. S. ��w2( A�#T�D"U|( CG ) �� � y!�4ear�^!�8top� �tru�$r � -to-y� �?eU litt�l�nA� �*P��� M<%'��~. . A��oriI!x/h�^)aA�\*;"���& � C� ali��"�p*IA|&� a"% @ "�l0L�$*advA'O@ i��� �!��2er7v�e b�+���n]k&O��:� 1Pg�>e��H% ��eu&j�p0%8� 3cIGC-eo��UntOA`:� beha!5� �rW�5x&f".�pr�_-��}1w��w�Q`9 �,�Q aYa�rB(,.(mDap.;�,f!y!�6�aq! �4��6o�eG4)4�mdi'�� ��eX�T�2�%��mu-;�*sA�)"WA�Ao�a>�Q�&���a (.�*� A��]�i7!4�+.B 6)�H.6*�� �r �bluetN�.� ��wh�}i.k�=�&�(ario: let u�u�PR���4A-pinert�!#"��" �6so)�5)^�?� *eA� ss �-;�" � 9l(!i��schO.r �#( �1 pane|Fi< E�2/ta�J ��P�v%�� ���B�# ��� proj$oB.9 U��}HF������s�/p �9B �!Q�- ��� )t�������K"���7 x.�_l�-�I�K%�q� {�9 �ra0$R�9nd 9�+�S:a�:a&CE �B6, ��Bo�bpleE>*e~$!</%��I�8h�2�Y��*�EhifA�,si.�onN�,B�q of"b���(p%on-.?�,uswe͜9_� �.)�Q pB�mA)���>)�.T�3:J )�����f�h"6*to1$el�T�� �/zo�4�wt a �BeT8�W#�Q��|�$o&�,� Fg*�\�%�*�IA@ybie=uti90A.e}b]%�.q �m�ɏ0 a�utY>? !�.�2q�. L�&"�}�x QD"W:E%g*%saOo/�ra�wye+& �"O & e �oI �r�;�c��sur" f6ZB�CM�.� db�o�F:) �1@m ��[he5 5�� �% or�Oa!��h��?at�&�= empir�"?  Hw�*�&G.C�9 �) ��;�r2�0��� Ed�M$Uc2"��D3%-d%;s�2l�8*U&e�,� �-arb9��}�&qmr|bY�!�Z�E��2�G��� *� �Ps�>���%n�!�ne ;'afH2AZ , cLaF�!mbryo6x���.���� �3Q ts�# li �v�tM�:�,Y� and/2pr��r�Q�� "b7�6����I��� U�� �.ex�'%v hB�On�6ef"!F~!�wR�[. .1<��.us.[ sechL or*�"?4 4n76� �d�-�zHa�NtJ�R�������culpri� Ւ �vok<�B"N �q.�� >�/i&�G%�r�%�%hc�$e�"��>�4< M@}A�!i�-8>�A�is does!�a�parsimone*��E o�� argup � m�%Lu�$ut�E�+maj� rA�!�K"�PJ�:e�/i &�,.�,*���ET���~manne�{E�q� �4�� ./���YV� Y'v!��!I�Fa �+�u s��Md!�yu vWZo.���o�Saj� #n&JEq)8� s�2Xfinevi:$be dwarf �FCa=�5 . SeF�n*A���a9��`�� �voѯ5�l 0 �!OU�I��Z�w�FE�!�� ���!���aIul9J�a�&o 2�Vp&@;�d.�*{ �l 6� mirr � � s:$Iu��l z$��al/mv�*a� re�requi�.6$Ŗ �.*�'!6�)�oPP*�4��e��nv�(6f)2�!�2X.�C)ꁙ�"�eUk�rV� &�&&�Y0�>, ���>���-� �inej �.+&f.�6k�)5))Con��f�#!3!;�Y�!���oaffin���!%G 5�*%�w� h3�<b�to lie@L  a�%e"�+� rguWbo��� )Y�Y�a�64����liR. N��M.a�h�, se ?.NA�)tm* b�6K#i ��0u���(1�-"}O fashA,�Y�eHc)f �� ���V�wur!(�\lZq�-aG*�V .�/%0 “w,h� q��Ii���st!�1��/�K�[.-��PI�p R��a.� sgc�3A"�:( >&y:)7c%�i7)E(t��.~(h�\*�6�� �2�I�@�e;<��ag�*��"� s3��'�L"�1�� sta�O?P;l� ���,d 6 @5=Us�cwIf&^%� "�%$1;-!jp�2� D.no�ie!at�nilibrium�/�a�"�*�!Z�F.P skqe^/B81'b��ma0 �a_\e4 �2�p��7#P���Aa�Qjo�4B�nBin� A�� [6�i&L@C � 1h���E�i����?@a�E] t!kV7�;272 "4!him.�.Z�0-Rak� IA/2�D�)9:p�!:!�&�vc��Aa(EQ-c� feia�%S:�a�(G�  ���?!�<ce-r NR-Q,u�#��76�G��!�b ,� �J ~&�&oA�P��ō��&S1u�s� �6��"2[B��s�hBN$*{%Discus2!>?-<fH�arc]^�5alE=F� �,6�"�*A3]"� )��) i�M�%�*�� R�JY TlTa�e,&�-rE�a��%� �� P!6����K&w. �rnE ,A��&@ �1 ��2��a�+ taxa"��"H"L95]"R+spicu�� g?rA-qJT?��1�&Hq���5>�a�!� p�4a �4��g�1a�*s ��[���J��+� %��dea" of.z2cB�?7 CpG�P� ]�G�72��(nac�B=%�re�W x �� }�;ga]$�^"�!�,Q�))�~�,N eE��w1q�&bA�e��er�cnYCpG�? :�(��M $*oH7ll���"؅��� n�%Fm }~@sA�In*)�n ��Dat� di A� .�OLA�9ha(6��s!�o e �i.�A �4[ �Vis"��Z ]2 T be od<�%�;;�d& o&�a:� es -��W&�4IID"� �"4� ���(6�������o+l2I .F� n2]F.�1��"� :�"&�f"� �R�-�?6�B�Fe�c,#P>�@in#@.�F�;Gv &ԣGDx  g��)���I (h75%5nSac�1 omyc�e4\siaa ��stݡF�ve:<� doxu9,}A�%�,Es, s��[q.�� "�.w�[�aq5�*T�(��nc�":8plu�Ynk{= e^,c{ �q�ak��r�F/�813!�AUa��f�� B6*� �>$6] ��-��=�fa�Q� >U�N^��1vea�ri+�N�QEa�aH��| spli(Tob,"i ins! �'�I*-+N`2�52%( �Xe.z ���ataZD��(��we��a)�)�z y��:x*@1�X&�3a�O4�q��i�z9� {a�!I�d)�>�Ud�g1s��a._�b i�o,"=i�-9�.eHshK�e&K+��~J+�s4e�e MbG/�imagnitudX e� �2#"j �7�;9=M<�$j{��cc�K ��4#qQ}wo/,Zv!�xf�Z�5�iA�an un�B,�hh� �!�Z.evi�G�ViB+uE#sub�,6�� eighbo�����o��s�"��oaS x9'�*� ��-y�B Fv8+Qu�A�E�iOce��.z� e*5Oc6iH~��9eӪ6�!in 100�=�-�!��6\A�� ( Dh��e�oayD���vl� �!Δ�l�-mˉ{)��F �Ra�B� ���0Y)UM��E�M�9,�3!0 +��(c&niR&�,\G , ai�9�H .�2��ly p9� kars ox8��8�s��� "Qo%����Ai�}.L @)�D2�|6լ±-�window �!%�h�W�M�r3I��o�#�L 5u��&�>v.�P�ϩ��� U(F,E)Lel1E�in �t1"S6~AV#4BN�ya^�n��Adq�"$u!&� I\oAI1@E��m ars ?J�nribI�|{0���:v5~�Z�pM�1!a #)q-�.��8 ��rx F0U�eTivic�� �aDE�V%�ow� �qui�%�9 �%E#y'oTCE�L�S��Zlo:W�Ai*�a .=-�i+E-cIe6tA a��b�  A�d!�� �"c1in� ?!!�aAMԦ�.1l"n$�YA-i�0�.  -�x6 v3"Qg�IR)�*�<6�u�B ,�V ��+���|iO�YY&�X��w���A��*�,�sgorB 2m����ch;}w6Y7�'kaUi�~�)N+NaIl7:A�� as[�e*^ 1YU9^ 6,9� i.p!�K�'jU�2A�R�A�Im�!�c���7�!��or��4W�`h�$!���v� 2&� AT5�J�"։V�. 9"�m a!u�K.�[� O2#&�\)e�V�*�&�1:@9Q�<(4��h2�����7�>dE> (Fn*m)� e%���Ako�%.*�N)e�5i�apAac�5!�%���*[8+� d"PG� �lc�n"F }��� *W.;�1�[+�p7"�z . Ex� A�� � f��g�eK&9ig�;%�%7c�(� S6�>�e�.��4&#.*)6��fs ��beh�7rK VUFin9�IF�Ad�WF5t =&��|�� r�5,��u>*QI�I6�es�E&cA�&HL&h ��7F�A%��#i�Es��p!�i�:a�QN}�t�Ba� 82�i���by (a�s� (�u�lly�.N���#A9o�3"�RM�B4]�do�2&�hqN&e�qe(I<�6h����li�RE��!daUc� pZ�t�%E�B �trtB*��,�bb��pen�=2�.5,;� ��mis �Flu�� V*i �_s� l��=A�%�2�1�sP� i, 9� V� ��MmS*�3!�h� 2Le �"r -Iicy���E�%t�s� gF�� ��mod� zI�A��~� fbm"�+"�%a = ��ae� �U�@2>-"}����AB�RU�e'�$&\\H _QX"�6Y!�0Y#C E� &"h.R.7/i��&��R:�4)u! ߹�.>�>E1e\ �)����QDdE,*�)���&Etsm!�o�7 5�UAu-,1MHxY , [2H`2 *a.�"H=$�1.%0c�*o2i�Ns�Ao�r�&�`�Z�4�!.�s� ,4Bo �M�$S,ok(rqf�c"�av�Y�!4 �%m2�g)�p�&�\LNpeAE�n���, backg)�22�a��`m<udZ��3l�E}�S��FQMd7te�ZR2�[!eHZa+�.q*hM �,� ����>](� e�N��AZ.�2+ZF�"O x��;?��er1 [/O*� >�" !�,Z�)ll�y�`v�#�0,� "�")�aA mob�]CI:5%Tkj���:!icitlyA�y�e�� �N�+re- ��fyn���re�%,��Sh6-A' !YN�Dch"t�"f �F �&�{W6|"a�6�4XAEevo � ��!��a�02n[j tigf=f�A�h �byvd"l!^azOdecipq�o#p�I�W pe� e!��a�# "m/8 ��oNO*�-*�c��A��a��d�!3A6BS .>G�i�&aX �e5"�>;'lv'a�a!���6&�Sa&WL� 2aA<alDK/_ Jrf�e�t5� j|I,"� A ЗiD�f igh-*\�],t��S�!8.�V�=. ��-`��=C�_olleag�c!Kչ*�&� �VssaH�d<��HE�))�^� orEA#tfSM� invalu�7�0 earn� a�gѼ��Zde��d�': ��?a�%�(<�re�C�.IouPa��U��.�0e�1d.&����9�s2F1v(-"o~ , AT\$"G &a �^�apl��*r�A~  )� 'r"D��g!"��oGJhe�ue~�rm� �W)ensator>�[� A6o'&�`�2ne��#maiu9� 2�. W4{N&ed}��E�a�d�N �{ b�sourcA��E�TE{S17nz/teBQH i�M"�P� ambiguD( ͡*�#i-0a�MehS.,�DA�i4cO,):��)�op�!dYG �I?x��2 '�]_gteya�bl�;&����h?ci470%Y�� t�*!�<5% lQ"� cy��V�pai&\av aris5�e)�T��� �d * "�[���kI�LigB:�Q((19JV � subm��CPhyML (20 )(\ 7]I�& E��#0�JnV|2QJ�0O��<ly publNl9m�m"��I���%�����V[2�`&Q2GUBF �#i �v|o�7� �.E"�+��� c"��Wo tomy!wnt*rB>xA��mdro����*5�R �=u %G5Ua�L�$!�nal�&7weD buil� ��]=di:�X!FdoN� U.����Ax!K�?OeQ4�$>]t"�1�M#%K� &�&>&p"^Re�t�"ǎi�PAML [2�`��e���outSpy��� undu�J�/�"�Ws�"%�!�&- �ltƧeie�ucosumJ��&e�&�8�pI&�5��tri82 H2�c/},alexandrinusluUOsferH�9q Y.F� F"�?�@aIna� "`GCS42ZA�Uin qu�sQbun ��7�IS6�!T�F�5&ofm�B8�B�SempleQ`>wnloade�� ome-�]�)!�-*�W�O$s)�UCSC (&\�(p*r em I�a�J coo�_Z7�"��G 9� 1�7*��):iWe ignoDa}�&zY�� u �a�˅vQ"� wor �QS>,�"� b*s)�� 4-wa�U�)h9^-macaqu� =h,.o`-�I�1000 G�~es��M6�..�D"�]�M>\F�!�, )�M a�iAs�{m�(d�fE "@R2�er� W*�yakubrAr�N�%j¬5�(c m�N. A��wa��S �%urZ�[,��Qc`7��F":�5�B^ FlyB�=2�. Y�r7�(� ! P[t"2�5�Bu�axN� "� )%$=�.Rc�"ъ!m��*�N�%pw{tiFcut-off �g!&�1�� - F� u D�a� M6�.�gn�fes>>T�#˘t�\!�v.+]3��H trac� �) ��e#h&h��NP(�*�É�� 5aey� s up }a6"am��rb -:�$V al��th�Seg�b,ab ( http://:�=3 weizF . a�v,il/software/ j_ex)html )2� )�%%Q�"L�d�>f6b�v Z� ��g"�8��݅Y*r!�V*g19�LiftO�ool� �v���ucs�4edu/cgi-bin/hg=�8��Pc�]=�s�xbyn��Q�@)�iReynolds&ݗ30]%�o�6�-,s2uB3onp^� Ae;@a�y���L��toby`�4��6�.n%w�:� sBO"�� _ev� ��r-"�za�w�!4U`l(�"A]^*a"�ؿeUAT*G!188s@5o�{C&��ir gra�un !���}S-n9��2�*)�J�� ��i0>� I�&��!%�lapI&�>6��r�6int��byV,�gpac~$ L�!�A)�^D���z%�*�&��1s($rv�J�9�:�ZS�AB���"y%Ui 02|l=��("�<v�zE%Z!�Q�&�DN��*���u"Q Y -1�{"� . PS��w��>L!wn0� �1 �1��!9�as:UR1Rv������R�~)�q !X:.&seq2$��(�S P.���,΁�ur�$alipha���s `%i�;va�tr.�< :=�, β-�O8nd α-helix . Cap�� . �ջ� z1dY����);Q1��01Ӎws[1–2]�.G!Sneu�@theC�@Ռ5([�5m &"%��vK slow�Dn�9�o��. N#t��A!��)"X*��4�d��!�F!q��*��F�-�BA�D{!?rt��a(�w-�sQ����O[4–�$. Bc- raI7:��\l ���!�2�"�� q���(|�n2�' _Zi*~,�3l�J[1qv�~I�C�5x0,m_70�J�4!�� ��ts�`��"��"if� G .��al.���a�q�u �(�z�!��sn��s"�<���^H40�n-uni��!k�� ���"4�D^; � �sm} 3t�Zte"� "V*��uU� ���!� � js���J=e ��E4�peV$9 ��g�e �2�%��B �E��l��n� ���$%6�&= a��# 2v��5. Enzym�Pt� [1U{�a�Wans!ion�xr+ rect��!ityR&m.H9!R allo$ ism[20 , �p][i�n�$e"y���P�%A6�[15E23]��c�d���AI>cv��"' ����uLQG=��-Efo-�Ca\gand-f�a# d- . E�"9�[2f>:)Es�ӥ�Ha�qB�tk� �ive hq��BXM{x)�Kex��2-*a�BV\et�e"y��*�� �X-���cryo- 'rs��copB� , kiԥ|#,�7��I uore�D� nd NMR[26�>��%%��:i.Y�6g'6�%� 4Nv b��-to�yt. Comp�!aool' �$ar docking�ea+-m�  � �AaX31a ,�uI��v.~ťs[�[?."� %&����d g ,>cE[3j!zco�%T7>�Q��HA^"s�!e��cu �W add �2�� S )) 5�Ҙx)I��gP A$. M �k a� *!�.>_a�b�( CoDNaS�34]T �ndt_&�@e��-d�C!E$�vu*A�l\�cM���d؍o٭. L�A�)a��c ����4gy&�8!��-�p>%|1�t��)�& chiewiw�B i �barri��E &Ͳ� -�AR��1c� xr�Eflu��aC���<"((!x �a>�0ge h�9* Ո�A�7�* *X2 �.x"'�?�Qv,�buu o*-toJ�gvF(- ?i�m�v&>~E�� )9��c�%byA c68~8�Ͱ��.�[35� RY ( NMT;atdI- �aZa�Ar~Gc�X$�'7l�-�[3�84�A5$lexH�b!�2A�tC coup��iM&abrI�+7 or�&� harl`c oscill( i��F *�ea+Q�/m�)olv� !��(��� �Iat��IC :GaA�)-scal^GKS��G!]� conn��ngjV@���k� ": "2[4�4E.A�����}onF��e� �[.��n� n -�W�by]#axlowA��y2n[31 46 , 4"�%-�&n�0����I0E 2"��*� *�% �c@9de� view%'#K\��+!� vJOIs�9$tcT�e� ���P5*A4[48–�"�^,.!d@ED"��/c �Uly�_��v�&�k�xes�>s�.5?)%��&�� ��[ �Sې)~ 44rEyh;^��nI�r �.B-f�;�.�v". � �of '(bI.F @ ed [5Sh5q�Oa�eh  h9�& u^#�-�)� lo:� �sJh!4��By �BUpar�Zu�"�d�[6k�t�%"��}����y"� c #����#�|�>ɓ6�!� }e0&�Fahav�J$�U-�ed��B�G!Sl al Pe&��� ( SPM� 5t5�5��1� �&��@;p[��Zheng"��9-�L�R1l:�j �@1݅2f96 �s[5��A�I2U����D��՛ "pѿ�.&��f� �8�xoQ��X�")*�A|_M�A��A�e1N� p�2�&��!�:af�YM6�A��*Y���& task{jB�wJM� rear`P��Adi2$UR� 51 , 5=+-���l �A�&�c 1�!" B4�4��mAL�� "�3�,�lZv,)mixjm1��� � nim^��\��A�- �TNk�dea��t��*%2����BzV�w%c&Hb|�!M�L�b�CL9!m6d,"� �s� n����"� !�)ZkJQ!�). ." 53O�� m7�[�1%ż"4 � �"9 , 6�,61� ���&u�=�m�sp�$� S:�BRa��W�  vaOx�-�Bt �Pq�'2��ig 1 xws�P��e EB WfU 2���ca�&d��s Pq/3N&�&��LI��M��nF.s. ILYg1is*215 ± 0!�!Ci�9g%R�|����$R��olal2�Q�2\ 9�8L�%�ase[46]�>J�1���� 1�iI���*M �0st 2�C�59:�Qas S!#o�� Q�`V�d��I�� κk�$�a1 ]=1Nex��4−Σi=1N ( qi�r ) 2lJ(_' 3��4( qi , kr ) 2�@�= ( qi , kx ) 2+y6z , and#j4( j = x , y , (Pare the components ofDith Cα residue inPk normal mode . Value5dκk = N−1 corresponds to.3�s equally distributed throughout all � x[protein � mvi involving@,displacement�a singlei8 . In general ,6� Ked1 conf!,tional changJ pres`mor!T0llective vibr-mo6s tha)Sres�!R8s . The maximum��5,Pion at 0 . 5 indicateL t , 0verage , half@5M$participat5�concer!�.#Hs described by each Mse�HWe have also explor%�,e dependence6Dsubspace S associao(to ligand-b� ng wAu�Hglobal RMSD between�!tersE�Qsiz-�orderVdo!]!w �conside�(both numberH11degre�c1�ity�)�(that belongd�.5hobtained negligible Spearma� rrelE coefficiqq!�03 ( p-vaQ =  07 )�-"14"D<2 . 2x10-18 ) foriu au6V�%h.d�+2Qa�I�,ly . FurtherE�,)�a.�e� {!2�09� �$23 ) has b!�5-1�Y�A�-�Pq�E . Onlye� gnificantN{46{7 . 3%*�isFz e2�YSifferentA�� from thos�pat�e s�ly�cflexibilA�patter%[e��0, vectors Blf)�el��s Bilf)��a_tae B-fa 66�[a��.i�%�expanded�ba�bas!Hfq�fa;��4=Σk=13N−6 (�$⋅qk ) qk:Σj*&jlfqj%>'$bkqk ( 2 ) �bEF7( !�I�[at wa���a�=v.cBAdefe�as PB�k6�b� 4 ) ��( eGan�� ival�� interpreti�Mq�J,in Methods Sa_ on C��first PB�sIze�|index fk>decrea�� �)e�( �2 � �in�A��Ba�!,s {qfi}i=1 ,qrequilto achie�� good �p%.N���at!F, SB �ins6 mostBHY� ^�EP.e��8ig 1 ( a ) show���emparison�H.-% Pq/3N�GPB 1:��ov� ll pair2$structures!uDour dataset . As i���larger5jA2 e �eJa�- ones:�-4�E. B� es , 14b24.!!yZ��TI0:�aO.X!�2�e2B��.}��e.&I *� �>� J(%jo�$sligh�N less�a%IR�� JY� is�ul%�ini#a7ma��4previous studi� I+%.��s� comm�6�lowaquency2WD[35 , 46] . Despit��!�9p�iof� localiz�� � s dur�$%�R�s far���*�[ �Asr ! io bef ,>�divers��m�na' st� ,plays a cent� rolE0 modudng� funclU�-existx -l3 %���q4affinit!�4in a dynamical��librium��!��a \Q�sel��A�l'i� y�I�nal� :� Flshould guarantee unbound-to- >�� I�er1��effecw uɭs��u�of2n~� � es)un volu!�ary� serv%:d!5"�si> . Toa�estigAta���2��I)?Y ship�Z�"� ��"� -u1�,( ZscoreSi )� nd f�-" , 3. Accor.x �(2� repo| QW2��1&t �S9�( see2��followi):�$of Zheng ek . [55] ,a� �� ��+�neighb{ m�.9 amePradiu� 7 Å!�"(pwe analyze spatial regions ram �n� vidu�A�6� � �%3Y�can lead�eiWstron� or weaker� a�J� p�.�!its�9,"re��m�uF1Y"qu� a perturbi δγ±; 5� urSdCt.( m� while PA1{wr�[ T1: 1�.I2 we � a�� ρ!��36p��&�6=��5w impact)�a�-spec� =�Zo�eY�of.�connecVL,i�6bA�V�6� Q��GE�x tA.D���ueW� M�* & 6ihSiW ��N���e �� �� de�s2 � a�0 ?< max;2  ) > c( Q<� d> , beaoYmax =%�0Å�C 80)�j��@J=�� AGfi�M�{ed5 �um��I�6 X 0� 4%�� - ()ub%�:2In�cas� a"�*� 6 wa*�:� !�f ngs�J n� ��-fl )�n��!Q"!��V��a&: *��b�ed}�Atte:y�-A�big�n �s" $A>�n al��tor*s (I)�� rodu ��*V �*5)a�� uwid�(fy key posi X�!"a`V M� �qҥ��� "� SB���|wz ٠!.f� �,al!N�- A^:} con_!9 p& 26>) ~% tran)for �D! .g�� o 1�6( )��i��6�a�� ranked���ow5%�f�Si���choices%w cu� f 4�T1%�10%q@{i� v�modAai��63 ����~0se�>,� tx�!8>�!��{� is.F�AA wardqT B,A caeo !��A\>m�e"2 c9VA.�s�!Vst< ly~id�by�DKolmogorov-Smirnov� 2.uz�31I �2�\�VAAQis point�imH toA���!Nai"I� work��Mto fu��aN�aq�9I�oi� leva!5��J. P� �A�un. at s�ej�Q�f multiple � sucharq���&and/or"Mal fea�[6�6a64 , 65> �rs5yE Figs 2Q 3 empha�%� %E2F�n2is junE!�many a) t�=ata�e5_"�� "� �zY-u or"� � 6�b�aCm�B2tr tso��p.�e 2�5� sour��ofF\"@,m4noteworthy how%18M�b�]� �Y��l^I thA�2��gm�� *�mN�G32$quant��!�D��cE.�F�>"u %�int�!�ump !��L$e null hyp!��is truXwAlSa.w� nduct�t surveyvchaLerH �-[2�%S���K�l�*Binc�) &� amin�id typl *�,I∝=ναkey ( 5@  �� he f�cm�:[ α�Ea2��#vα�E="�ZM� w5. A� � > 1ѿ!> highe��ye��,��U8B���AQ� . Ta�1�������m$. Nonpolar�s#! , Il!%Leu , , Trp-7P�r�^ . �A�5/-K!�YD dete$, except C�q� �%st � of)pmai<due�!capac�� 4disulfide bond��!�iQ>���M[.?R�n!�access=(urface Area SA� calc��d�fNACCESS!�gram[66��.$9A� �?Q�>aQ&n. K2T !��� g"A" buri�_ioS W�lR�3w �Iz� eec �!E:8S$$ ��� , !<�}\of �- ��&ta�_!621�B�RING[67n� hm� Pear�.�*!"� ��dLee�& 48� ��Z�p *RZ-�R �pe� _A��4l O�%e�� �&.w)� 827:{5�!��$�23n,���xz)e�hp�D"M�eɟ5�,� -l��2&�. Cl#A��""�hA�of)636: M �_V�$luda��is-�can� be�Dounby�imply eA� x!1'z.T�l&�$G�To:�)� �^�1��i2� uponn*�A-�>EAN4VC� MSDi�M� &�on�Ew�littl�%ve�ZM�� .j Wrobably �on.�6v n.Q"1�leve�$�, a veryE�>e�16a�"6U`�),.ZAU �(�D &arFve�>w! bV� nHBioLip dababase[68]&,%u�to�i&�!!cer"�vU$t�.���n5���u� !hI��ist���2<��e��mas&`.|�)�..�  5,�!n*�tR  ���s� a�5��]��2�!� �Bf2 ��(M @M:�2Wy��closen(j.�a?�*!��i;"�&∼��RVb�"��!t.^�!��[��)�2��1kjF����l39�*�of 6�"� !E* !X�!]*� E�!�o#%�trXR2l Fh*[57�9 , 70UzM&(s��in�^�Mr.����&�'7ng!`r� &� �e29�! [-�9"F"w rise�m��f�yg�di/ A�2Z� � &^�"� �VyB^ Tq "� M��xJ|�� e�.##��direc a2L,A�,enzyme catalp. Nexm �o);-.q�$&esecond� &� "i)( SSE )��of$is purpous� we��4 DSSP[72] ( DiiN of P�.ScS|& )I��ahIB� M�%( HEE�measur-!+q�u&_��e+�_-�#is gialb�h-Ua ce v���w#�� 76�&�*a._1*,s�'ng� w=/01�c5n@�e )\brw��i���U<-�9vo_A� ��\#be skew)D�Rm6���)v*� Loops� o1�)�3$!fin�OE1rul�.ut�dom{,��hi�39A*r .�two kinda_u[e�low.�rE. ular� igS6�I|!��."� �pR�"9 � d �� s��experi� _R�s.RU��U�.�)��0or��er�3)co�&-� orig�!:�ensem!�IL2 �V�y%�draggIra�-a6e-� m�� !�/ kh�Cvqui�)popQi& z^� shif6nae���N:UeL.@��.A�  _.�_�ls�.!�%-."!�\in well-�6)Qc]%A�� or-8  �,�'8manner , like le�, but�'& �6oas pivo%�8��er-h o�'-i��t�� a X&&���I� se lS3F��*"a(+!�"9*4-I,�l!&�+In� �Y!�ir 4�2&)v2�%"�1�as���+−`X−Y�J ( h6�J"Ẇ 6�i�)1��Q�XE�Y a�5Y�on I CJ E��H Y =^ ^ S ^ N $n avJ�%[�'fAv��o � 38p�.���*�a����in: 2/irm��t*��< t�P9z��6'1xe�� "� �s� L .F �s does���9!�q&��"� .�n��� LwvoB� �!��al-mapp%f phylb etic2das6Ltr7ml5�dE+a�mp��!e�"�5develope�!q#04���'e*s[7*!74�;� a�7of%�aM< 9�i)\,necessarily *) �1h- |)�aO26�!�:�e�G�co� �& � o>��I"D!�4��h3��\�nM8!�";+n��2��&tr�/!�c�2�f 6�a���'!YVU����%J29a v:iDu�f"W�Q�6�.~�>xYƁ/"�(ݑbyFt.e2��&�<�6� �ultth%�ri�!�ata$.�provi�by Uni�� x [7�# ,�3 ompla00 view1!.\avail�ab�-=�A./]�1_��F� Yf�&R�iAi.��a,� �u4 �185��43�m�!v0 �13���in 11;cVŌV�a�2�6so��!Tu�si�,�Q,�څR''ed����*��a�pr�)ed�զ��match)�9�%6Ae� S oced��+y #t70�8ofp�O2T�"�rez��in&� iE�*| �_ in��� �V�a.4*<I�' �<we ,98ၑUnI�"QYV �� ��"-AB)�53%O:eQ�AS�Ie�1AZ}�ɅD7y��e>�)�,� �:6%,Z'�susa����*W.Rfu6�A~4!R+'I?��� b4W�d� imi�0pproacha��}s�in&�6� &�`-SrZers[7�9C*j�%mF���=�q per��]5:� M1Yi"�%)b*,aFE�*rm&���k iner axi�4 �5 i�Z��Kd cho@.!�s&�'c*J%m� a h(�,ve. ��bE�'oT3o�$M�)details�i� else< [76M��),Vw �%!*�;4i acyl carrier53( ACP/G);xa� !3>="IA� of an H-HF��.isWi 77*�)x_ � fat� cid syn� i�It�A1�� 2FAE@ Vy �]y,aI&�G[7'79]�a1>N� I69 &_in H4AK�$x ( Q66-H7,. R& 3Ea"'w\ V�&I�� o H1.DE4-Q1)�arr���%�i�iA������jH#zB�� le ΔθyMOh^vAQu&.��H1%�H�0�!<65�"�1%(-�>2� V{HToA+@ j7 2� , A�up�f55ed a�� scus�9 �-FQ��hugJ�Bh\3(dine phosph�) AE ( PHPT1 ) (A�id: 2AI6�2OZWf�80is 125.5 9*�1ol�|al)�c/�|a/ cell��,pA�8��ys �u9!��,apo�m-A %%ise!rQiαI � L�=S�N�� ��Uץ%� edAAV�2�!A��2�pE��%l:]I� : Y2�3R4�:G7�"R�&I79�G8�"V9�#A.� .�����&,*4 on K2FH tH5� tS9a@!� H102)���IF 8R���d9}=s*� ��R#A"� s�L,"�"NK>�?2� �9cF ���"N�9._ V+nfiB � " :�,?I"���llufs6z&� &�alcium-%��� grinUz�^�HCIB2A 1DGU6 1Y1AamQ�:� ��8AT82�E�6;N1839�. �a�20"�.4αIIb cytoplas�0c{ L#let 'β3�" t�#a6=��5res t�a w1varie1P-%P �� add�to��t{��9�%Rr�en�~�;ed:a�!`Y10�/A10a�F10a�F10�8L11�EI16�4N161L1 8F16� K!���*��9� uy%��p��>�H101-��H�-}� DP"�=e�2t&�I"G0&�,:y�cF�are: S�l106��rD11L12!bL14!bI1��T15E1W9X� . AlU>���i�9 � ^�:�n��J�#�.�a26:_:�8.�Im\VYu6e����B�:fKbMT͞��va*=.Y�'-n�:ge-m6�o65�u���KpFAre�+8>ev�EeNeC��LModel ( ENCoM ) [83]iemplo�K&��4gy"� ).< pairw�* tom-�- non-J6; teh � te� IG(th ,2� a/�,)&o�� �s�x �(! �G�(2"� �_$FoldX [84]u{ ԙ+o^�c2�destaC#z�;?��.S ��u 8ty�7a R� !�#Mop�V fold�Q+ }HΔ�;de�3a�1oj7���A�F� were�-$0 kcal/mol%01eU.h !S%�v7�A. S7M�6�8^0�VFv��"�,an5of 4 .8 .�3 . 6Ƹ&�Ci:�V7%�V �dr�e�M!�;&. e ede[���zHirl !D!�m&"� ofa�eA al D"$ N N�OSE^B �,�CoDNaS�&3�is\>�Lo�redunda;=�,D�samno ,9���:�� ocolT ��0li&_D$physicoche�O!biolog�B2 dE�"�ZW?|paramet!lm�P�-�1H� i��)xum C-alpha root-mean-square-dev���:MSD ) ^"!Hq�Ea.�A,b{�s!}�, [e7�retrie���EY=�/2�� unique5#c��> �:)���>r abscoWX . E���>O 'f.� " C��1~0��Y"82;s6��(1�%�c" appl��/Yfi� Ō�")au!.Z��N ell cu!"�J: (VP crys��VresolI1 < 4kO,2�P:+� missA�"�m�pdb�E@( i?^r opti`"^K�G��jy,2�a�theor�#al*f+>c4�v )e�ei�(�c� agUe"6Calign� -R"$>H�185]%~���9&-"�$I$is ≥ 80%%W6�7mt�C100 hom�UV-Y{P�"V#�Ll�8� a to!�of 188M�u>��<=�H g 10&A�p:s7IŅf*�C!di Y?�"P%OA�� lit7) 6%"i2& AP�d��"xin S1 TB" R>� � �tEN� Eb� ��� V?�by sp s�k>cutoff%(a�rc . H��b�%+!�rcA _ *&�]7Å� 20Å0"je3N�/v. a2.&=0)�0 ���*Mwm�lA phicY� 6KC6-LG3�#A(� s fl$[&j -� ӕc� 1�^H�2[3/,86]�4r�@Trj ) =12kij ( |rij|− 0| ) 2 ( aE}4rij≡ ri−rjV*��1pA�� �Qj��I@e zero superscrip�\&{ceR8�h5�tak"�>A7"�=:!oU` forc3!0t �_ m�^.� 2lV"1(s[87]: if |!$j| = 1 ⇒K = γ�!$rij0|≤rcIn1!�-,)�Dph�F62Tif;�ao2'6" saltRAx�1�>2` 3fE��rc%0-�γ�Y3A�+L�"!2.}�a�2�����7CSU��lD88].��O-(�).b|@2 !�= A~Bc� `B{���E�N�o _ ~>x� H�" NxN!rix E 3"�4 8yi. N=*,\A �Q agonV\aD��-I�=h eri�+v�d r Hessian�H�E�4Λ= qTHq ( 9 �7qA�an �Joo.�lumns qk��eigeni�+H2y"2=Qh(Λmd ���,R�es λkH��temper7�Rr-!�Ng$-�VXE:NDmPQ Q, un�Ź7l�gi� sjQ2s��&7�9W� .\�+solw. Act$m,<nd�"boxyl eVm&� sV�dcly�e5�9 ��7l0*l�0* cau�X,UK�cIK8 N���7&M�:&:��ua Gau�7-l;�p�R[91�A3a�)��3\-���!�@0Gvi�gy ,xi ) e− ( Ci@+Bilb ) w∑​j3�>(z,�����h�:�m6VF.p)�rNne0 �o&h9cWs {xi}e� {yi}!& $, N!�aK&�H"� m,M��>il%d�b%%. &� ` ��2��dw��rbitrA� )ѡ�e�A�z1isaO��jv:�jv↠jvjqR�jc�j13A,ck=&�j6(�m)�d"pnde� liz� !�v a7�"�dE@)�j� "� �a!;Ꮝ ijaonM [993]u Pqa�� ( ck )�N��"&���n6N&x��\!E�"�$ nven�n�&���B�:Wa�?=� ����;%� V��!� !s3N ]pd0m&�I�2-un� �>.�@%o1Ly&Q��_>extrem� MRC-�4.��/: 94%$ situE? B bi�]�:0A:k�&Jo�)g '� ic Carte� ������,&{�dɫ�Mee�|[y� �,ar>5�NLh��ut�"u�� csi�.=#�a)U`Pq , r1 � EneaM-EC�d*_,!�9"��8�r� � nee VmKM3> .d.JMV� �Fq ≈� m� eOvV>� prbe��;*7M.& Her1�U��[Jf6N�4�n.6:�nU�e ~ rr�&oV �~Z*le.�D$ina�.!�gA�)Pq�&�9�t�E��o��2.a um&� S�I.�oq 4W��o^2e�isDS"� 2�RP M�%��^a&X9\� �x��� a*� �VX.� by!Y!��I� �F^e"�e�)0 s DYz�ka�e*� �F#�p�^*�f a7 � i�l�)�b�6 '1|a�im�BZ �:!�p*�h"=�j'��� volv2!�V Do�&�*#&��i&m�J al P� ,sbKP�by W .BbL�&5�&�M94�W�66s�1�7h i� \, �s jE/-z a ?Mam�;gi%�3 a newQG2{qki}kes��4��"Z ��O"0yi��� >yA�establis~OoneAy��&}Gb�6�$un-�� nd1�ReE�4.2�:OyA-���N�)4A%�z# �� gBeb �Bո.�M���tCvD�M1-�I6�M��!q� � proj K_�"qj��� �IH:�s pjSiS�M (:e� @{��GA�6��QM-�M h �s {Z}j��M��QF!0 �xAi�Ip�k"�B�|Gkl^,pkSiS⋅plSi-&( 1��h��(G LGTGLG=Λ�R1 �%s�k!G.�of H{λ&tMeZF]�=��-O�y�. SSA� Bm�&c90n1[9`-dan)�6:k�-�6}as ζ!�~kMλk!�2�!7��Xh4oH3^ e��r"n  &j �.� �Zhہ�1_I�F����"� "� :C&:'-��be�y"w1&!�3) in4}e�!% dime'"�G!�Sa�o ���\lem ,V ���(-?aAw,Ѩ��� � as: tQSi=− ¯σ�B2&� �aσ��+�d�dar�}8(-/i�N6 A�"� N�b�a����%)-�r�m��Z'. ��mE��Ny2tes���%�&W �a6�mfc� .�.:��!�BB&b�M�*�*2�"/E *6�6w"�YIN�!�:q� �>�9�.� ��n%Q�i U��&�%MelGN:'|�U� %!_ HSSP1X*'y- � &�.�)�� �'��erg��a�."�'.r!.J.�EBGU�9�$�I� grea�^t�'()]\1�=of!=�V%�E�?(�-�"�1&� �1Henikp&�/�%[10�101]"=+e|J6&5wa&j�N�| ��ed6�U�� �� ��)�aO!�63 z-"{I� ,��;IV� 60("1- *#U1�*�#er9K!.��ّU�>�ve��n�7ce�0�(�c@-�?*�)�dNJ=hN9�#a�i�ex?�$ts ���h |7*�_1� �B'! ��leA"�3�2�2"����B&e0]$inxrLed ALA-X-ALA tripept�%(i!X�!"�3sYl ) [1D8103�9.u'"�9Aa Us1[ ��pA�B�*#I��V web tool.�Q�N�erm�t0-V'. �]e�H we gl�(�l2  _*p���=:@* of 5�-`!�5"�ct��6f�c2�c��e���:a�<>k2��/�?�B�1d�?�*"P6X,!�U=[P&o<r/ �%ne6?�2G>gb�c*/!Aol9 Yw�U?Q)up��%.Z{�"%))�h Q�/_YE )!%#��%Smas�2%\2o�-�cg2� C6T�B� >�X&�'�$� "4@2�%b���E�lower (M'-��%��#)u4�a��Md$ ��J��" 0e�c�rn2�the|ADuhd�6%u=M �A "�5%n�R9�#��(J`T%�H�E I�!�a novela�clNtoY�.�5�#&E Ka$>�N�4fc�n&al�]E -�"v&)n)�u�-�-�fat�� ~p~2� Po�E�&�/ a 1v:)&�ZE4A� �I)!�E��#^9� mixtA�^v rear���$i.�q)������=ng)�de%NtI�RL�sUe � �?.q:g&- X�M"��e�����c>>�!�7� !�6Z@�. I� ��]� .�=:�,�1 &-M�f]��s.�0Paeg�7� �[&� T�U�{&� y c=>�6 :�A{A�N�e O-qi� 3F�!?�MA��5: � C"�,%�!�6�L��Q �V�:��!�:�R�)�� ���the}o"'Tcrali�Gic��s�2�"i� �Bry�d �x� ��]β-shet�!�kcxB�� seem!W&�"hw>Q��.&I��.Hs�!�h(� 9�u F^�m).�� w��boT=M�:.��4 ��f���́�!�� �V-.�l%��"��K�7se, ;>V@:���a "R6��;ot��vb�Sy2Na�-�"^=i�o "I�S���j�$>�r*�kz�zVJzV�v� k: k�Q.�9A�6�a veryM~uTAy%H!Vq^�|. *9#a2�1� �HZEjsuci��kr7s� incte�k��.F� !�sێ2`q�&�WT�SnPj"����&�D$A9-4�) Furt&��!Q6�A�r�l^� $P!F�]��'_Z2E.yEm�UIi�ford"� Ɓ xoligomerm`�O��'%Kad�p�U-(�c!_�,%�3s�pon )i� =\ �)���!-fi��Q!�"�M >� ai�Tog��.-HB&�[�:~) �mwY inkI�> ���.���y��Sc�o helpJimae^under!mUo.&z�r#se t�w� ��/e��9&�9(drug target��% repl��ng��ng��'C e� �:+c�K"� fail��bsZx5��K� po�i+� 1���a enco�V��� &�"�=D ? .�[2edAls� �'%�mpFp=�h[�� � moHg*yrB,b�18 `�ed%Be�9AA�8�ba ��Ye]w H37R�n�6�di"2kE!se-+ succ�e-OE+^ J�s�Qp�ynt)*in�+�o ex�h, demo/;����!cn��IdA�TNth~�[)6c_�_BAU |)!��me�A�$guinea pig.� I��%da�ua�s �S�� b �J[lsdFoxiaL9�X :& iL ough�kA�O�}r�I� � , [2�8�a�rcSe��\yCreAby��in��stXs_D{,&� ��? f0lay�(?sm-�!1�� in�-���D-�ID�?!�a-%�AhW^�4� E me�/is FBA�=x}z A�rljd vag�%n �a(to yield di� xyacetU&@( DHA-!F��rM dehyde 3-.(G3'. H6 ,� I �su��_ �oZ�*�)Schiff-���Aœe}t* ��Z [,�< ^!_ \bGaK �( E����be�� Zn2+O��Sen�o2�[25��ltE�'l Kaq�, �} I%E I ����\� ]�D *!@IIa6tC�})Z !(v]+i�ae�� earl�cs͠� �  bi.Ռby�E�u7��28|�)I��Ӂ E��mU���%��AMo�a��eu2 A!e�2>1I-��3-I&a/inhibi��A��:4ngo5�-w�0o acy [2� ��9�3Ua� goal��Cnv �e � �� �J��ti�!�4#kBː�:� ��2� b Y���!`� i%�� ����t_C.� tu�e �-� rol� UC )f!�swijn��co��� ans�KwGsi� !�!� K!�"8">[3rW��DY2�M]�"#-/u���I�.h�8q:&�wo>� e��� �sm� v��R��FBA l�Y step�� D��o���if&�y�� ��b�of� J�-��W�3 B�I�a->�2�  .5�on!E�V k&���cAK%] �B. B��&�A�uAI vo�g<&d�Y�#I�]�MA�<]�!�rXd"��A�M�E�, s�4N  ( at��{xy ( doxC�tri��}"U=e�A�� ba��.��BadAA�,-!qL.e=dH��,2! �%c�Z`w�)E.�promo�+( Psmyc-#) [32]i!Z�gA�veI � ��e%w!�� !�t~de x@e�%� . Afo��yr/��by Sou n blot�i� �E^$9�a�!�b�w�KA�� �DAS+4-t�~nAK~/2�e2��eYTetR-&�53[ ^Yow�Ro=ko�in�5�!�. Immuno�"d)-ed$�!�6"�b�'tc=EO35q� ��q"�) n" !8TetONU ��m�of(v(!`>VT�c�!�� ��A�b�1A–�a+v�I<�9 �,���as un� e!i? d�l�A��A�y.a�� "t�f��e�M�1Dy�IToO;i�_�a#�wMW� ed m9%OWT���mon�ed�Ha+ lungMsplee"\ �a. M_x!�a�a� f�%oxy���cؚst�mngE!�da�^ Ka�|:1�"T2h . No��\� V9%�"g2.�� �(� �Y*no�>��,id�I. Wa�%ad;+ %��%�؊z1,Tde�d yav�!#Qhn����&�aH �Q�6ing� : mpanKby{� I)�5?y=\BelIn) did%#����,AdE0r��?�d�Si@"toaQ gI�)}�-�Rs�6aKn��~ ]��  G��Eɍ�� 6� �U� sugg�5%"���� "M !�i!�4{ )�Ab��s�*v �r��7WL�mpA ��u2��c.X,"Z�}��B�njiUatU 1d.� cand(�sg4w\d�oG�arI�( ;��:b� i:-2A�-)6permit���N�5�3�*r�e"4�x�arde a�E�!�C6' �i&R &I E��Vptrue "&�-�RlS�MS` A�]E5)�.�.� h��iquid"X��2t}J��T ?��785.�#um<@I�twenty-�� lag T!�3�J�3del\�-���+��u��m$or, �=�(�5�I�E��S� ��E��/�z6:��Ts��{�&� IQ at6�ip]��a�86#u!,� &!B"�2��� �. Inde�b>��A^�)��.�� D 5[N b�le+of��%i3.  UrW��'Jg.�tFe6"c-*�abR$y*$uM4����!9)!_�ۥ1�- )E�2oJWTa:�t�R~o"{ -phenotᣥ�-qb�5A.!�A..�"� "4#inZ �&E#i�d�i ,1�5 log" R� in 7y � nl�e[ A/ay�RV� y� �'� �Zas�9:��aQ 4B!Fatae�� �@ DeatE��J��Z���U r.t��a+�Ina5 tras�p)*� � �#a 10-�kN+D�a%V�$ad�9M��Y"�����cZ�.�kil��5��nANki2�e�d% EEf �so�� ����eqSm"Q�I!�!h#�&s�!y� �t��N�",eT%fee`2�>�R ���~.�#�0s�bDma�z t>�macropha��( BMD�FCo-�� !R%�i��45�4A�,h� T�[IFNγ GY}1p�%,i^m�@Moa� *��s , 3.*� kVA����L)�q�H:��U��oy!"�$!@!S`E}.exy��o�! ����or|%y'qF ��Gr d�abe�3i.�� M+Yms���tra�uu� .�%i;�"?�exa��mi*Ue�.(>@inw>eu!�Nz�&~# �tf"�*!o1�sm K� hromat�b phy/�:gtr`�tN�@Ft}E�+inA�Q}�E�i#��*fk�op!v.� akS �z2%�� ,�.1l�b!A�of&uc�uAJ 9U��L. &�Pexpos���al�0� accu7QB; �,of hex�!.vt�W iA>ri(P .o�pyruv�� ( PE:poo�n�41�c�&�:'�@*ݬr�!��:smDr��*jmA!"+�On�- �sedoheptw.e-P ��<t'9i�.��&�!inIq7�e�%flu����p |--% /!�sd.��SP�w�(�\<.:�6�MRd2N)�Mg-�r$��1�M*%:9��.��1�A>�� r6#�&1�Y5s�� !U�AR� �,W(ed�OAx��  2s�%$Bt! ���V1�f ����(V�byQ@ig]a�9aJ2{Qt&�?�� ���:������&��buildu��]YiW7 6�/9�E�i|C���-�;*C!�4/!�ac%��%f�+ byp�@�ve�/�0a�.���)�1.|J_ Z a��fr*� r $A�:�!�Bw YU����Ca��Y}nd.5��WAh�so�%.(!.�m` 6f p��20j�0=.� �r�  �V8�Y�l�2�5 " enh�!d �KPF&!0 �(4]Co�4%�nJ�m�>xi*�7� 6� +�.��T�g� d�le% )05%x�� ��SA�Sal�e514" AR�of WT.X@  s�0D ��0to5�ze���imi!4bye3�0cN���W�a fixAI�_���WT���; aMI�%�QU�7Z &|i�,�pau.�025&- AN!U&��;6F�7��94�2%�#�Q�]��21&-�.2 ��.JU�6 �%���fac�"�9zcc0�E� rivE�o٥TJ�l.\c%J��CosJ/6h"� . Gi�a�!2�s>B86� i�.�7Kg*�%"�3t06A)d!<1*'��%� w-�-��E h=�5�(*� <|$>e � grewt���E�AL4Y���i�.n +U��*'pA�mNH�<i\Kto>�* �F���79>�A�4S���PQ'.?,{ E ��, 8�7�7A~-�F!Z��!�q��#���$E� =6��! pproximatV87%� p���e8�QA~�of ز3 ng/ml��G�!Bx97F�r&h&���=�*� !+u,6Q&K by�ore!B insu"��!�1�6r _U~�4��HMs:�6�.2 25=1�1�!�-�aK&�� ��? ,,���)�)��Q�* <-�F�~9+�A�n J��VQe 3��z�?���-vul��&p'z�#.0�%�3��k0�M���o� . �+/#N�\2�� ��u6|=�;-��� ndrh��/2�3>3s"tb��D*2 �,6�Z5�*�>aeUAwa�$[3=ini;�wo.|r����*�3N�+l� ur�z5noA&O,[���V �gIm!�-��>�H��$knoAQ� ArHk<2r2{V��. U��&x+��a��all5_j�:�ys�$�� ��=�!o.�#T Ba�!��a�of �'"��)�� D��,| /�=lS(� o&���"�N�'�!�M&�;r$a�6N.�*��t��!p6}&!Y!�#55�:t%�C5�] - 6�4LKa�8���,if}H 0*�-� ��8�5d��l)J��!!>��p>1/B�6 �*� * ���s��*-K E���a�� cruc��F&��� �/MImpe�g��mvU ��pD��e7s�nl� %�2g:v�_!m&Bal"�uN@��u�Z��Ao=J��:n�?ma"n9�ens%���6�1 7�l8e�!Ή@U��aF*1.9< � *{�.a:aCg�3E .�! |)ex�s_^u��� .� ^<;^ ��)�1*�Fݗ�� , [33&gP>"W1eA�s.���&�.��o�o !iM�o�E!.��.�WTS��.��M ����s�Kox�$L�*�Q�Lyl-CoA�E-af��k�-ch�8&����"�߂d�MH>v nner��*� ]%_ �E%�mW�.���~occur&r t*4 ub�,"U��g�.�T�+? D(��֍r ta��oa�uƥ2� �KOv�&P2�x�f1sI  ��&�aI=�)!*3:E1�>Q%)�Egm(� o{c- %^=.�i! CV���@*�I� �'s>pd"��>pc�x2&x.%��f*i��vr�c&n"�N_I& qkze�!eA2��"� sub*=6�*�E�����J9of�.aI�-un��<.�@� �d_)�*��} a"�p:%�.��[�Na� ��ory& sy�atoe"�!> -"a��1�+�lt"�$A�in1�5E?Th.� ie!um�>",@&/!�&�&E�"?T#.�Me2Amv� A�� �Tf�q8i#Z-�J �a�um��[�����!�in��� �"/2�� ���s>>!�IS.[3�d[3�@A��of��*hK���Ч!��UT��;6a=�r�$o�6!��#���1o\Y�@A�y) *�',�-- FBPu! Mwbo"� [3L:�� �t�'t?=��m�J� ac i&�ɹsub="L,Bn�-P�T1ra�Aōik h2�f �Saa1�0M'��!s��#l>!�Q�"�&mf��&gto͠"��vAH��AZ�A�m� ���� %e�" aTtA4��|!^u>�I�oryj�l����C}�F@"w� �oc5!�%��C��,f*i)4��,a���e�*�&���K��,vu]��#��"�or:�J%:� w#Oa�&� kv!�a�o�$�}m�?�,"c6[�t� &f&�(�. \}�|2�E��, b�D���q�T% �%<��VYnύSZ�!��#aCa.n�zEs!��!�(�%, "9'� sus y�^T� ���y�Mx)J!2nP�J�s vTwid~MBwir�.I6���#r��E��i(!�'�&��v;ayU;a� ��[39�?Sp� <-H�1��+08h��a� �L m J��n�p¬w/� l!m���e� h2��P��yWT-$&�+!�"�iA�t%4:��13%*WT-"A r�)".�B�\M�!m"@��m&'f�*ja�fol� @a\mDoE(g�&� �6�*�8f-<-���!. D�="�Dm�D�G���8a�"Ѧ:E�S!�r](i�!��E:�t�s!6a�!N�Eto8B �3n�E�:�> ]!B!�z�:@�9!��#(s>o�+GzJ s��es � s�3ssr#AK2�Mf��en*Q�F6].�A�&�!�.s.!9�M��A�a`oF{���͙�f�M�W�/�i�2ju�2���Fs;*��onےL-��ZlyMTBy&L9�N0]�:]Vadd� � qu�,L�A{ �.]P�)3-�� foamy2<+!T� �!-]��Pum [416D4KPi�plausX��A]M�iZeVO �u{�Qo�stHL� &�j�:N~ $al Institu6 �=ealth�Ide�U�Mho�]�cAL abor]��\!��ilG�s��7'l�C�#ig����Q��pap�alA�� DA{ C�.Use ComC7��We5 Corn�WM� al Colleg.4s(# 0601-441A�:D al E&�KA�2�Ge�D�0M .6�H37Rv"6%�a��*a77H9&o��"��#ov�serum�6 umin&'�V.y+fN�+L085% NaC��!/(5% tyloxapo�#�0shlin�DQt 37° ��h�"���Pa� A�Q "� �nauton's.^1���2�c�e-�"_f!�pot�Qum atbno�Fc ��mag�Oxl%+a�J35$ci�M�8 0? ferr�8mH?���t��s `>01% zincVn��H����!W soli� 8,2�9 7H10M"eM�P$b�l.\O�9�l��(�"2CA� M�i.WJ 006%.-53%�QZ)w ,self-made ADE�����6X/.�8b���� *�, sod!�]!�!g Aci�+e�4�t�kfn&9$ ( %wt/vol� %vol :� sto?�z?��priy,, hygromycin)�50 µ"��strept -� kana 9(M!�gzeoW6�. AJ�[�Fa�5���g8�:�#z eni�"�[alo�jRM27B�:sQ#ry 4–5�6*D��� ! 6�ass�]P0*) ���؛� sampi�% ���wom2����A�time-(�Q A8p��s7 � of2profi6,�Bs7�at OD580�c(ah22 µM n/+-0"�1( 1 ml�  )���r22�10�1����ډ>*�����!-�|o�gs-t�BTG��� �9%N t*)/�@� :jf5�Bt�(, Zat>�JA�har�Med 24 rs��-�icC nch�l��Q�hle∶aDanol∶H2O ( 40∶3zA,ml?lyR�  bȇb�t2��O,�X�NZ��)Q �w�!Ms AJ%ng�#�#E�A �Fi$�mK5!r Pw�aA�I)� � �I��0j6e�AL5Zd 1gen�^\� fbk�rodipl���[e&�VAvB��N�5 alle!�ex�ge-A;.&g% du�I �phAE87!XA$�@ "�K[)]BwJ removal o��f native fba by Southern blot , replacement transformations of the attL5 insets were performed to generate FBA-DUC and Δfba . In FBA-DUC , �|contained a C-terminal DAS+4 tag>0a plasmid in �pphage tweety site that allowe&Dducible expression�\SspB as described [31] .�Δ�]a�Vpcarries a kanamycin-resistant�not�ing%Z. All!s %&4constructed us*(Gateway Clo:`Technology ( Invitrogen ) 0BP%LLR recombinase react%�fo!Z�8manufacturers i }),. The comple!�ed mu�is1 1�ed with=�%linteg!�[p=81w- from#�P1 promoter . M . tuberculosis metabolite-3 sepadd� dete%>@in a Agilent Accu$L Mass 6220 TOF couplI�an-�1200 Liquid Chromatography system-ja C!z�t Diamond Hydride Type C column ( Microsolve 5�A21�nts�config�A�6�43A�M>$quantifieda�Ax,dard curves ql1�a�Hntic chemicals spiketo homA^Tous mycobacterial lysa!u. Qp9��centr� E�normaliz)dL biom!�edI�pellets  30 ml cula' s at�cat�ime poi!�in spec)�@media . Briefly ,A% wash1�8phosphate buffe��saline ( PBS ) , 0 . 05% Tween 80E- resuspend%� 1�1, 1×)'a�`inhibitor cocktail ( Roch) CellmMlys)v beadt!ythree ��,4500 rpm for!seconds��L1 mm Zirconia/SilicaMds!e(and cell wa}remov!Through EO ifugESd ( 11000× g/10 min/4°C )M��superna��was filt%NRa�(2 µm SpinXy�Cor�`A,LE�)@Ig��-)�h���� a DCUeI�KitA�io-RadY$For immuno�Ks 20-!00�gp6���� DS-PAGE ,�zerA. to n� !R�( e membran!�ndZ�� overnight)�rabbit �= sera� [19]!j,∶2000 dilu��in 1A`4/Odyssey BlockA"BE�P ( LI-COR BiosciencesU�1M�,20 ) or PrcB k18A�0�ofo . AsM�ary�Lbody IRDye 680 Donke -R)(IgG ( H+L )^�Afua3�a] ň��A�15Infra!� Imag!=S�VZ=L. Female C57BL/6 mic�LJackson Laboratory )�[inf |by ae�{ �an� alE��osure��$( Glas-ColmT,early-log-ph�HB��s �le-A� s��S ����4to deliver 100�ghbacilli per mouse . Doxycyc�� !&food (6H0 ppm , Research Di��)%�given_%' star��at%��n��-��. S��Q�s�� lung�spleens�gen���- d on 7H10� �$�ADNaCl��3 CFUV��J| left lobe� each��fix��0%�5� lin , fur� a�cesA��� histopath��A�d!"i��� he�xilyn�U8eosin . We isol��PYb8one marrow-deri��)�macrop� s�$previously.Z 444] .�Two-ca��Pperoxiredoxins are ub� t� dasesf play var_ fun� ����� $Leishmania�re �trypanos� ids , whi!i ack catalA��@selenium-glutathi�.�,Ea disc�gy!�$this familenzymes!�vi᳁,molecular ba� !� W� moval�4these organism�IIS is� orI��al�evancE=�of such� � mitochond� 2-Cys -� ( mTXNPx�ȁ�investigI long�.b4infantum life a�a� G nullJ s]$txnpx− )!duc�a gen!p"ls] egL whilee�sa�uisha� F wild t� I a�oa�,i�found un1to�1 mj e model!2I�� . Unexp�Y� howe��)Havirul pheno~of �!:dueuEao--�EjctivitE/-0aA�!� behaa`likn tro� he��: o oxida� adAcexogeniyor%T * .�d�g5 ocytk ex vivoiA���%E�,.�ere also=�inoA�( i\ -^hosts=�mount��ef��!�� �C�A spons��(B6 . p47phoA;/A?a�RAG2� IFN-γ�� Defini`conclu���Na�v�is%� requa%i�arasurvim�o!�ob�by sho~�k-in%�e ver�Ei�0� K�e� in� cu�� non-M�ve^� . A novel�+�thufpoAE��M|A�at�a��cha!"neaR�/mayNla| impa%�M��.��� emis�e��P,observ�R�G�q�sup�theu aggre; of ci�> synt�in =!A�B�mo ensI)tharew,to a tempera shift��25� to 37 ,��nisQ ��с!�C�1g� ��Colle�"e��! f��re� ed ha� chan�he A� digm�4ch !rds 6�N���de-eli{�r devi� . More��E.e��m��,EN�firstD(� seVucan be"2 IA��genicAP inde�nt�`their}R eP+. �4last 15 years �Ma�tribu!9decisi%\tow%%� diss!uE�aC�wayAy at l4to�e 50ox :oma group6 E�i��des.W spp . , T&� brucei ��.cruzi%ie caus�Lagg�X e dilnt  festei� "/ �, Afri!�sleepE�icknes Chagas'!+p#Aǡaly�@��ozoanE��2!�Ea' highly�iDt)qesZ� *m ^� ( GPX��-I��� r i(Vs el%A 9de-redus �Phinery [2Pe8 \�PR�_*� EOeMD a 4I�@ s���i?(}E�� )Aw�e Aoad�H trum�sub= !nnam!�H2O2 ,��c hydro�)�yYit�v ONOO�j�BUpo���2Ndi����c�-SH�� sulfa� aci� Cys-SOHcIn)1harbotwo> s ( known( � -f��e:a. &c no�-u�K-\re�A�5ZX  aA�ulf�. Accord&B e loce?1 6G,.�aIbe class-� yp�� a [2]m=y�� all �cha�er1Qd�vf ��go� d)([N:�retur@�NIU' te uR�di1q$n appropri2e��ron dono�� :�� i�iLuniqueE,o � 1 ~ e#r�m�,Y d$[4]"�itselfeW ����'e= ifick�)x4ne [N1 , N8-biA�uy9spdine; (%fFor��rea��"x)́(commonly re&�A!3�e�or �  Apar� icip�� ntiay�K defeH ,> IPRX�1-T�inc�ing� cognEpas}a / ubtleŏsopooroahgul��I �e-.�� sign�gmb���P ��&B"� ��� so b/A�"� som)��~[5A$[6Zr5s%o �:med sites' c= ol)!2e.don�C 'ic.Z(!�c-�)ibelie� to work� rac.�� =minimiz�iC��insult ?!mby!.�� �s agre��2� � � �! L .� �� .�� wtot fer�!$cŎ5Ey�uof&�@ origin [7]–[12!� dowuE[ ���! countera enhd � # to bolus �[1e�T� ��6�shoul!!=ti�reut�2 :s�� ��invadi1pro08 in&�a�Not[priET)yeGIʕ��p�K utA5im a��ce � ors -L[14)Z7aMi.M�E�O �,��1�4, favorably poE ohto" "!�end� �,�those!Vk as by-pro~%��n Kory�, AU�A� argu(be ir m��P[7AV[81� H2�B�F) M�Y�A�X .���&�-dLZ6�0�, sugges!�� I��mi��5 � !� shie4�fՖs�aI9`challe\in)��Eir�� din.�"�..hav(diL.��5"|p morp/� l4physiolod�ctM ges:%M.| (�{! ellu�U �!�I in� vec� &�ama� Kii"6Kli� ins� !� mammalian��TU�? a �"zy�"knock�%2��&$�5ete���9l� dunf ��r�"tiŇ63"X Ab�ntm#a���bl�A of a. �fu0^ re� Ae�a�%`�r��p%E . I?|�data gaBva�pIG%҅� playr Q�L�o� � � �Rl��de� %%�}he"^�b�'� y abilT��jtouX! a��� ���3�lK h . Tom�Yre u [Z:b"� \'J ^�EC��E� �A�loE�r�'��Si�=�h  diploid  ,e�suEaFrou�#of"e targe��"wbtH �>X �I�e-Ll �r��a NEOa�>(A�cassetteuh!Ox$%disrup�w�(HYG�M) ( FT' e 1A�AsfiO W#2�*( SB )�fdouZ�(e�F both6�x -?fu�.)2ed![ei���� �e�Δ3::NEO/�)I (E{af!):' <��T >� �p�eG order=�a:�%[ rest}��!�]i�ach�by9���-�ORF� e sm�Hsub-unit rRNA locus�"!�$pSSU-PHLEO�g�)6���ch�R�dd*VJN.H[2� !2 resc$ �)9!�de�!/5X/+ �(r�[t6�- :]Z��)Q�PCR!��! .%8�Pycorrectl9t%�-drib� l )Z95D'. W8 r�-b��P �& fluo!� analy�R �554� �]*^2�T!q>5S� s<Kin�( �A8" � art�0� �qo3 � s 1D�E�!��y��a3m�%P�.��N? gr�unaO*�+@*�y� AR i . !�e��lxed RPMII*um X,� appeB� r+ (�q !�nK dis��th ms simi� E)�wZD!�stY�, n�%�� .� m: 5 �+�'E� noti��Y�5��&�s� aga�.%|involv%&�6M`in� �J�!��Z1 ` �$at�d�]"al�� , [2�EV&ho�*U���dn���* A�� � of6 E� y do!!�car�0Qt? � .*[a&! stagATA�P0= &�deple% oI�"� >�Ws a�N&���!��BALB/c� ,1 nim� I#� visc�6[( V_),�]eq.num���)�(y�3��#or�>2~ . At��&�,!s �I� o<'�w lo�,� �(��( (%�v��� ��a�VL�A��(��=/byDW%G�(!hay ( LD�R� Am�� 2e٩F.h9�haIB mark*!_#1� outc� �/��߭� ggrav��o�$%7O'de�} st 2 weekFJ9�c�still� � v�-�%K )��rga� at 4�8 `aET 1� xA�!\m�&�3qA��of.��#��beA� belo!Ls �%�9waT0(( 2 . 7 log�t!�at 14 � e "�"� t�&aH9����w� jk (9 U�&0A�%�it�c�aA���%x�XisY ��2�Of��v,��� mia level��$)�$���%���is�$ly5{!�.� ݁=�a�men���1���N�9� �K5d� [23�25]%��s\'�*�'!�fac�ujAM� I��*��DmoQ(� wn u�ns�regio" as o�4e�N!�but�her!��k �oq@ �F5%�Vd a����5r� �8&�+a3�Be 8 @'� [26!LIn��r*86*�I�-4isc�u�#�O*erm��-��"�:� capa��-I�edU� *I��Y ir fail3/��3  �&�� oR "l#�!ko2[,!�a<�1e�m56copicM�"& monoI"Ditone�n*t-EC57/BL30`�06�=u�S1e�Bnext qu�+hs��ch&U ,� turbiuiT,!�%��oh�ecG5 ��)�L.GY)an��$�tA�of>�" [27]!Ow^4aPfPyT� appa�F� E��3 p!by�D1 . 6×106 M−1 s,�pH 7 .�� ( ; Romao S�0adi Reon^"��\iǡf"�� "mina|4al~�D"� �.J�ij ,,}n�Rp%� ��- suscepti y2�6hto �cdd�' )��!�e&�M r 3-�inosydno�!ne�� chlo<( SIN-�[ vu"�1� s 3BE%�ehyp�&�Rexplo��b�-�3g]j�;sJp%7h�-LNBTa�aQy 3D (�R,� �/20>?6_�<g0�N�trigg��!h��Ao�2%x�an( O� �� precursor/%��Pabs�!��dide-r9;#5"=s�q"�-A`chI�b bu�,�dL(�l�s ari�%��m�;nd� ���*$1a�=��: .�&"uk"d �8�!��?dr al ez4��e-i�imp9��*-�  ��F�A�  Dp8 E29 experi�u�4t %�W pro-�&� ""�1�2.R>��Ay a&�]!�-�p47u�hie NADPHI1�2�2 )Elex)y� �2�B�AaI.C ݘU� �z�2}�5T� A2ee�B� erfe�)g1 (63l i�a%� infl$ tory�&�azdo0� s�ADX ype-1~Et�[&9a2,!%� c%8*�1( iNO?� up-r� s)W�u�'lV3%I�%���Gi�-"�8. M�B�,qjE-��ene�/ back�/n�,�;)�I��B�u��l!o�5��!5k9�&� ��dene�"a��, plot�i��L>��)�!������&����"JD"/�ei�C B�kF or=6%�irr"P0 -�mo+/�.<v` a�;st� �r5)k1�# ��ri K �&&�m2(��efw �����6.64mYrec�M !�is2� reinforce~e idea9�e �:���n .����$Y:a�!<����e� NS). A�#� #���3*�7"i%OY&i�I2anyaOr idal�on� e�&��N adap%]o�mE��P$he T lymph8U2 &` �g"� �"���l-s 4*#A�*� %)in��H�q ..��� � %�s"� �$cr�1��$ �+ gQFA)]CofA� E�n�,Ai��8ly�clud*b�"}��4W!) rM$����� to. ��I�t �k�&&�8ari�m�e�<�eC81�΁tp?9a� toa^c�hbs�ACys81A����1�Blrm ��0 ser� �+aaHshIs*�"� d ?&�>[29�[3�%Los�.C-% 1.!�; �8! a�T�I"5�ށ��]726 amin$3�>E)� [&6$� Bp d!�Δ2�to mim1�?�8 �q's._�.+A�w�/11� A��)L.C�e M&EAY���e6�mu(!M��c�?yze &�,�{'�;10-fold�6e4Gnz0�E!V�t�&� 1>Y�� 4�.2H�e�:��:rE.$ dichroismv tra �+bstit�EM>QYQ� to a�B"� a�F%�(#D#� F-1q*�#���m�)l�8�/α-helixeVβ-�ndA��s� � Dslof 35%5 29% :,8J�. To �-�M� �]�n82���7��= e�� �� �$O�a7�_� pF�"�!U. C�!E�%a�� ~+M � �$A�"W by" 4B�4exa�)u&!"�/verif$L��r��HV�!bse�215��ta�2j to2&A+��A� inj� ks evalu�a>p� ͙��&� depi�&� 4DaTh�at*�!hr� ��9�Hl�1� ]w �% �>�/*'/is&R"Jo1^A��A�qE;� �?�=Nid:�!X&B Vz)_+-=v�"�"<�U�j=�B�.�"�.�KFng� /u"�*s �)� �ca�Eex�L�6'/��&�5"�!��oo�"%(�(n�C6 desc�Q!� �L�  ss. v �.*A#��ef�6i2 EA�� empt�p� @*��=VS� �.�!6�-.� �"�6�%�um�A�$����"g"�@K ��`  &{ �$t1�>CA�mGd*0ua%BWA( C� . W�cubu�3AB2un�nA.'ign�D*�A�@ moni�(6 "'Pl�2 scat;� R�tr��ombP �SA� !M58� 8S�wa"mo.%ex�-�tk 1=V$hA�R�BCS�[5��!Ab� es�onoun, ��'�t 5�2�.J�->Œ��Ilsoabl� � �ng�.�,q��$b�Fiora�B@�L�o �%H%�F:2[0 :I&zVq�Ermotoler�7A�ay��PZUiOe&�� �VQW���B"Q��F o^�J]��dF�%�)Ac/ �'b3@D/8�!#�`er� �!c�M#aց�<a�x&++X� 6  :� )%.QTJR5B; C�  1at ��&�8�Q  �+�t1v �6�IU)P*�(6�Aϝ=ly6 $sY�}E9��o-�Q8"�I�(� Y qr.5�f�*!�=��Ew %y>)&�e�!GA�ɭ��/>��>s�/*�F�.��~2C.�>��C� ٝ . It?�.aso"tK��y.��!3r���F elop�V�i��)�.lhM�A . In] �>*OE tida��B�of.�(m� �!�r�Ma�*C.%�#"j'c�s!  N ��F&q5 ?�8qu# Data��A6��%��8 d*�G�B�Fis1� �� �Mc/&+a�o&SA&u �25=�"n*1 st6G�W.��� d F���i�FA&%2�y� �B�i!ravel�4��%&|Xxđ  vi& e�yI ���K-Di/�K =ns�Nex� 5 f 5�e!�A)yx"6:Y!��*"", �,M|"\b "��t�r["� apop�N�"�:6 "&-�U!must ! akenh*by�me *. Detox �*B="�- Fs�9CY(6�heq��'�)!=36�B# lfilA,b�so:�A!%M$R*D.3-�#" ( nsGPX )R;32�(3!SF!�&�� {�G6�(A�%�IpL"SDI[K envisaged��* �86V �!�K��nt"�Qze#is.� �)ire��!�"�H� !�iEof k!VI�Elap [3�)3�C!�eW�7� + 20& �)@aڍ��o�-h is�,h"[3�(. + En2B�2a#�Te�)B(��bAs"c" D-�a�rH1�per�4�,f�OA*��E�c�&�9�L. I��ituiS,' �-we� �Fl� uPr1Un2!� so�dsB>G�*&%G�ovB�>f[\c*B��Whio| upDt9o�1�usurfac0 -ar�4%�uves [30D39�(In"�rm�3c�� scor�!n��!�: ��rm_[ spa&� *66[[40] (��@ LinJ . 34 . 0070QH2.GeneD�,%�� ��AM.6�%E�Qtell.�%�;��A�V,aofF[3��p�> by Sela ebc .>3m�)�af;FJbyZiz���?a(,� ���, �J# “off”%��?- 0��*�?��'p�"�.*�'1@7 no&Y[b* lin~ �P,O�&5ri� ��/j@m& 5r.b 68%.J~4��* ��'��xt�$��&Ua�r.���hO�er� �i�q�-AA��i�4�HHr�  - )�3kB.x�Ji!�l=�4M2HR!i�&D4B�&�>�2funda ApJ�5a.��5�'� of]t�?n �k"06q ��!?!t&� :�nd doeX e��!9]���Rume�S�40lRK-CATN7A�)y~.vN�)e � e�,A/re-&Y� �-ork?�tZ�Sun� Ai8 �+ . �"as�a"� �� H� ; �F�.V?VI"� "F ��XS��+ie�� $��I���� �0!]. i ) PNF)Z�Id!J"A�x 2!of3�.-�P�*�~��U4�T���t��a��F�0n �Cd>�c� ssayE"Li���ional��?re%��Z*�4R2�MRZ3�ne) :w&9�+^ Jang�A5�i!�a#9B�o2xis�wn!�2=ir!gtdry*a-�)�b�,-DP!ja|H!$�$decameric )� "^s�0 ch�!���9oligo =arr�W��! *RZ�mu;[4�>i%G�$4"!X(�lv{ *}�,a@105\^ , ac�an0��ovt �F�: �R�I���g�:%��6��ex��"�"5S�6B�Bdo��� ess �R%Q�/e|"a5�re��=�U32"�5�#$er eukaryoE^%�q�s*�[1 �� kely�� ist�5il25� �Zes�de�[�Z iv )"�aUc�.� z �Qa� �� |�Y A��!!�}��x)*&8*bX�"BY&$5��b.� e*���I"2�G. Such�rZy-+a=��/Q� -def4D[4@ab��"ng �-$�N���,,8a���� �;z8�� �,ca;F����!��-�ln!�'� *; �!R�Ra0���a mul'"d���y�tT�ubi�GA0wew2}l$pOo�:ir�-"  �̅�3ll�X�weXpil�j�}$�matri�I*HETy�k�,2�P��@>�, ol�f^�kirs dam�5>is|I�6 eR �T�Si�Rm�cby go�B[4ŢU�AI�5u#�Ns� SKA��!�2�#�.�6�U�H#�=!e�rs<e�$^o�0��Geostad$ �6��)�x.��O�at m*YK�XJ�)b�S.gr!��U2�K�Bs��=!�MlW� �qS�E2� ertebY m@A�Y&�R*�>` � �ide�c> at.]a�2�"� d>�+�e >�i9&�yD!-(5�%u���c--unre=0d�� s[ �ar�llUp�EY 2��be6%V�a��Re*,Z�m><? m�h �� a"32� e��;t�\_nowledg�a�]�*yS"z"h AN:5ob&` afT� procedu ''+]{ �Lo�:A -8Ethics Committe��In �%�MIaar w �q B�Q� UKS��Porto ,ug�d licen�"by DGV(aen�ED o� V/#i�E, M�dt Agr�� $�<u}D��� Fish��, Gov�1of���in May p 2006q PE ce 520/00  9wbF0 handl�strict� rd"� g?n 4 p4_�2_uFby�oa�$uoJ;K!8, Law nu1005/92L ,23rd October�!@nd European legis�X$EEC/86/6096�S"�S�a(RsA�H( MHOM MA67ITMAP263i4yu� "]!in 'J1640 G�lmax�u$o�$le`' 2n�/�feA�bov���J( FBSz , 50 U ml�>p�a�o�350 µg�pto�=(�!�-Gibco-825 mM hepes sod� salt&*?( Sigma�8P"8rsc�"� a�e�ruc@�9 ummaa in T�S�?9a� ac�n" 'mbA,F�!. +vcA�~,�D}NEO�q"�lGU*&9sA�� 5′e3 #co aes flaJ0�[ORF�PCR-a�9f�%R a co�zcl�g/%0p-2P1/P2uP3/P4 B�#F"zVs� e#����aH-aL�I��J�N)tm}� � $BamHI-XhoI� KpnI+{5 pTEX�O�2�[46� on%� -neMW&woi fer{*(%�)E)�1��5Q*�9.� fragas�R!�~ V�uN�Ea���-�:�)�9��-%��m[1  E NEO-�1 �8,>� 5/P6{P7/P8�X�c��J�)�EcoRVpZ�!evZ{}�.hQ1�w� �)he��e%A�+ac" hygrn�r) ope�faePfrjAe�2*�%!�� -�eha� M^.�XmaI��$Klenow-tre�3%\u�a1� 0!͹��~[gRV �F�RyKint\GQe88!�VI��A�F���i�|�N|S( 18SGHm^�&.mexja��2=�&B|.k2� . E��:aym-�>Fq% 2U� �1�>Ibl�<�h�s(5S �.>�]B2(F{- �Ch�* ai��U d. /!�"x^-0A8 �m�!��( see �L�?B���X8!��os&HG9 ,E,A1TZ2��y)�Aby>KHincII ,I� -Sac MNdeI-Pme;�?m�/d "�.�� agar�6gelO�Eelu�`�pf &as emplo6�Im�E�8to5(a7�tj&-�A5A�q�Ea% y�(#[ai. abov/}�pET28c.9��gi�*a{X-l�`�&-uP2��RGT� �A�� ( P9�P1; "�)�) Pfu polym�#S@EXEIey�/�  Ia6T&+)Ś�10�N of D��$( New Engl!r ab�( 1 h� �+I�"E/( 4 µ%i!�uy I�ly!�I�8orm Escherichia�}i DH5αEin"�?on� L V=Wt�.rry%�AV- gmcEqby����y-Af�Z�{� aI͹loNrth��R[roHU�M�po�d! 450 �=350–406 F-W�5F !YNA� �MK else�8 [47 PadtM@Ʉt0;��1��u� �umr�%�&c� drug�724 hour1D�t�1b0to 5 mlWA�l�y`� bArem�-EH�! �xo( agara!`�?HR0��E���tSG418;") UH�Q)L� ,.G:*�-!�"� ��-&� )�K2Zͼ2!3�AY on ��".�picd�upmI��M��-T-��1mun�2e�c�0-�pera)!YiK�Castro&D�;&��2 EE|e�4%Taldehy<w/�in�}(<�1 M� � A��� �&ր15 M �|�$spzB%���Fne-co��"�N e sl�@emev+z�X% ( v�TGH X-S~!�i"p4�AOl��a�ti���b�!%;4� , 6-diam�m o-2-�@ylindO"( DAPIE�Z&W;��LA�8Alexa Fluor 488-r.R�&� Prob&P. S �e6m�1R  Vr^�g(or&���)� exam�V�Άxioa�er Z1._(( Carl Zeis��G� n<�.6� 6M�rnseept 106 sq�in 24-!J��g���y*I�mJ dup�%���!UD!xs*N})ʔK*�*�bt����3�� dvAG� 7�jqim�6)�aHtrophot�6at 600 n9OJY, cFUNŴal Mar�Re��&( NMRA�m�EGpurcha�f� $Charles Ri�W0( Madrid , Sp�Ve M<�U��HN�H�Isp mp�H� �2AGN�IMG:�TaG�n L�- Skens3, Den�X�UnYda�&u�2) � �p!�y�c � ��l\b"��My�imeth&m-t axaz�%Bactrim;%�mg =��ad��5mTdrL(waFU(=J�|%�.)��b&�in�I�*�I*�IAC/|&�i> r -�N RAG-j!E=.p>cr.ng�i#ckY3 i�nN���TraiA��;�iphf-,on,. Euthanasia�X���920% is�"a%<tmE�Z� all effor� mgot�B�Oz�%\-�. M*�M.��2\Ulavag42UUؙ�4T5��1��in DMEM&��F�u,ZNsֶuM�KEad% � 2 hc?t"� 5% C`LUOw�tngi; Hank�}lNd�so� ( HBS�T�-*&eK% :� opsoAt6d�����ryBi '9&�d:ml�&�10∶� �h".�-f �FP·−�a�.s|z"��of׊"2 �Lobl�Fetra�f (2Q�A!� ulbecco'sI %"X � A�ep�i�<-9�=��c� !� -�*� ��an�tde RLofAmazan�DpBT*� OrIus CX3.W�řQ�".@�]Z&f-|w�T6�%l�]da���E�,�_d=��B :� =�j% .-) oHa�=al� a ndAzn�!Q,.G� ­ i�-�1~A��-�s1� t] ���i; idod8#( � Se�>a4C�� � � ag�ac�(%�� cam MR �. 3 . 0�&r}PZ� :���� A�)umA�3n�.}A�K=da�o�&�\ѷP(�9� oftw�(2�Y!m� !�:!q.l�%p�-0per ag�u >���G* aver'&�Oi��'�$. 0i�C�"� TLll  m5p&,$6@�c ��GYst tw4 pr�?to ���9=��NJ"1086� B�6%,�Akd%�tra��l�Vto 6-~9-�b�Im�,N �. A ;��bp#w  ūsacOC ap�&�c�."�Fxc��ig�3/�C_��,in SchneiderKee�&\V��N,�y,��v,[p�>l����2% � �?human �"ALHom��%ND�d����CK:A��Ype4�t��e�quadr"� A�v� 96*K!msÍ fourCxiXa Vaorgan< �wtwoB�"g�B�X��6��Lre]��[}�ٺ�gra�� �( bu�S) caly*d� &�Fbyx�t&�4��&�*�d�$� dvƓ�g�("@]Y6�d^m>Nm2�'�), trun87&Tz*m�<+ �@�,t ����N�N�,%��IQ`E�|oli�  BL21�Ej!Tuner ��"�*a&�No n!�N.enE b �r�F��P11/P12A�*�%{ �[ntb�=|�$�-�"A���ك2deJ��to9��>S. B#q9 �Z.)�b^A�fus�4 ��<rr5 an N&�six h�,dtag�PTa��  3@ 2 0rHh(�'6I k�� a�d�"8isopropyl-β-D-�:gal*pyrano� gPTGE���"��O�ہ inewm , 20 Tris-HClC6�=�r!�on�*���t1 , 0�g)0�!!��*�6� applV"�)His Binvbg.�ǚwAX��fJ-� �� �[mid �`adienA�5i���� fviA�|��min��. F�%��6� ��|:�){ool�j�PD-102umjgAmersham�t<lu�%���$N�t!A$^v a"!GA�,6���t1(biotin{�hr%UA�X# �C:( immo�Kgz%ava%�:�%%��.� &ge�PultrafieI8$Wi�4%h�%�d5E6~�A#bicinU�ini"ڇ��) ��6( "��,b 2�& albu  ( BS)Kf�taޜ. Rout���2��[��(��&=20Nogoceke�Aj&2"�mixy'-<.� a to=va(E�3�E5%6u�,A�M EDTA3HML,"K2>MRa� . 5& 2�TR� �M�9��ne�$�B�TS�Ba񝅩���M:NXN2 [49]%�va��Y(e�of�vf2` Y!wa�e��I_tA7 ��!`e�,eM���a�N[�2R�Ƞ�4=Al��2�=�t�JU&8) va�c*�WF2��$he Chi-squ�Az�1�*Z�-"W'z(T�pSa�s&\Qc�Br-s� awp<�k05t U�1g�$)kIBM SPSSa$s 19 .�`�OH��(+ad�2( HUAg )��p/2� �to diagns(��esQdΕ�f��K2�mo�PD{�in HIV�� �In� 47 , IMMY ALPHA2�EIA�ap�Wgà6�%on-nJ"� !;ޞseσ!A tout_�Uni�!�&H"�n�-% kJn4!/�CMVl� *P&Hi�avail31ѓA�a�GWe��!H#DI-U�B.Z1�I~� �7� iy*er �foFE��L%�OA�K��wo2a#d g,t tertiary-cA�facil7LF4�,:?��8ded.�ɓ!�suspica�a�d.�N�I�Ɛ��a"� !f.� caps.>um�i�0l�4, *7�Q i�8��<%atiI�ath��ica�m> DH–Ern� We���Ŭ288Y�, 2�45K%(85/288; 95%!���m�[CI�124� –3a��naz!N`eŎ�of.Ka�6G'�%gCI� 6–7� 8%��AN�W9:�:9�%-9�1= ��v��kelih!m� �2I2 ( H; 1� �P4%BIn�.q�.2e!�D��0co-�G�Yo�Aun�'e� �MK�jCax.�M&h��v!�B#a� JeX�a high2-xQ:���i�)%eh�<be���ytĆR �e fung�,WaQ�-bP$��J �lGsxse�co@- �s�?f�O� amt�H+ve�I�&�FK��!} . yX��21yc �J�+toτy�I�L�"�~�,Dlu-2�(�C�h��#��on����j%��j>´s�u�htatus;��HIV �S@a�@i�@v d�0M\di1�icuX �{�C����Z�?f�O unH\�Ex�p����2�M]% ��%M����a�M��G�=e"<%d9�a.��a�O i����—��ly2�@eriph�:�8 —oF vi!+izz�yeastk �3b;�G�SF6=i� .�Un)$u��jH��Epslow-3 A au9!F[ �`A�i��pA���fA� _!.. ��:�Lh�:^ofF�!hes_s aQQbio?� ���"scarc 6.MaBe��tI?!5*6s reli!�sqS_�thoEw"�M8Y#,�EAadvEQ�C)�� e�i �d -@D�6� z���xnegV�edu@.��Ii�6/ ,Jn�L�9 �YA�m}IZT �� ��!"o ��!�Ed�b� �~a7es�6�od��M�/ 80�Z�5&��X�(reE E��j^�� l&�( Mira� �� tJ>�;�&� a�BA �kOrel�d��� �>F�Y!�/0 Ad�(�j�F���5�Y� 1commer�}�$. (�<2P` T!:Ki!>�� , Inc . � 8] N�Mthe���-�_ Z� %�b7 -\�%�.ZUr~Ant� %a9]*� �!GIj&T�se8s"r*�Y[u[1i.�� G+.�gsf4 A�5i%���8"9 !�ӑ!.��c��!�xS-a ��H�� TT(e !Mܪox � � 9�*��va�giOɚj��aya� .��m��Vy. W�� ΋ ��s'P�P��of&uF� Dece�201YG@201g"<olE�t|�18��rs� ���9�$2��ofdD!Gt�i�stay—!�& �ADH�$G������ C cianz>$I�m尥 us D�s� ali��$i �!�manage�-�RNK —%]e| mVA�d�e�A*� ]LE�edE8�Z7-%G��&�$h�X �kᚕ�i�(symptoms: f����; n���|��O( >5% u� �' O� 12�th�4 rrheL* �)hadenɯ�C$hepatomega��$ϑ%�k�Qeya� mucoa�#�<�Jab&�� 1=R$/ JV=G!�aspar; �2:�? AST �z2�#Aup!# limil||ic �4���(n2{�it�Bbicyt>>iag an�Q=!/A]t�hstX���f2� �����%a�%ow�:J @ th�� c�  F/ Ly�,(�<V%MV d;��6x��?u�a��J%�&�*dz s��d 2u:AC��"�(aR�A0:�. Dem�ph�ndy*)—1r�1oZ1�O�2,6�H�retb�'8� �8, CD4+i#!v��� �RNA—űr�"lP � �]SH�#=;J a���qfG)/�#g!��%��4l.*&�C��eA�n>!6e^��aE*x�7 eB�awsoo3@V|2�&��^�M�:�i o�Hg |4A"c*ly26�����*r*in*d $�ed2� by Grocotk��3e2P�dAi$cid-Schiff��in6�� "8 "7 �6)� be2�l�. % a�!)"�GO8(}aR�5�TTE��Cr/Inva%FV�n�Iu�UzG �EpN%wa.�IW ller ndG.dL\SA� RQVp, [10] w��a*��"�2#* :'M=k�� M:4E6����amard� m?�7OIbAIDS- �ۂal1�n��e0 �b6Vwe� 3 , �%�a&>%��};^�'�+ L�lsDpe��<6�f�95DX%`d )[ t5qi�3�.��,a�fxA� Sin aneA-�f��A2a� �\Q��"o� FS �slEmonth"���er\� �A�maōln>izs�%�v�  ,%bshipp��[�rud^Ta�<2so � 5 mL!Q*< ��c2�t, a BD BACTECeC��(%$ton Dickinۃ �C� n� Frankl^ akesAJerseU�$ vial".�asj aZ��am�; ( �78B�N?!�a�#$tec Peds PЦF��w 3�?�4G�'� Löwe�iin-Jens�y,nd Sabouraud!5id�. Biops !��)pJ+ � Stuq1 R12��]"A��L�"�>.N�N6!_ !�M�i"'>Q�emi-autoA� d FX�aeo�B����s�42�:� ) 8E . If��&Bo�U�aIap�,.� i%�f$Ziehl-Neel1� Gram� ��� sub--� MGIT.�@�3z�A+Vaiisheep���fma�A:++�"�7\9;z"I ��/)�(1�Aerz�/F�FeAnaFu+/F�N<� Y7!i)�, 21 , 3��1�:�All,Z fu�ch.��_jon�$�8l�e!Q��&'\B;e!O!�>DpM@,( HAIN Lifes?�ce GmbJ(Nehre� GER��:�ij�%d�}N�loӁ&�dS'h-:wt�%b���<sh� f0,�"u ttNteY)�"s8a�lyH�e"��larֶick-w=��>�c *>w�( 7+ 15 m!:�A�"�N�'Q�aS knobb� short c�A6*Roja�; �e��z *'|Ut���ccred�2Cc �5y,��*!� batc���y*�3){&�&uE��� B9� �_9N�1n OK ) !<urVDR!��s>�vedZ!�on"�!�"fQLma&h�# �RYYseI͠:A>B .&Dy tech�+o�x�s �:%7r)OAT��1��@%�bl�d1�&� F RQMp-�c � he�MK:�� ~v�:{� d\ʦn��� int� U �&� Y!� ARCHITECT1Ag/Ab� bo ( Abb��Wiesb\�V*EW�Q+%Co�!,h��� ’s��� �"6�b�)�* �!"�, � |s!d��r g-mB��%)6' !�ul�W��  ter0&tilP?� ( IQ�.AN}1inu_ ���� &�:�  6go��l::M.j'U=P��on%OX2 or�&a8&�& �,�!hal a�s�� A p-de ≤>05�A�d G*l|4*q7.M!,�f�,&1p��� o,"� F% � r2�"u:�"�d&1 �f�C%� 'I�a�[V�E4a6v�2��=)/STATA$#0 s&�<Stata�. LLCr�sge� T�r�JN.�a*��i`\tocol%�tke�/nFy�F Review Bo,�mco��ŎerA�B o Na�%a�G Cias Méás y NuK*Pión Salvador Zubirá�C�^ S N�  la In� C Biom \ en H,;,os REF: 1626V #�IS �) b�m2�!8%4co"n'.L!�princip�te9z1  Decl� !�AJels� ��\��Z�(/ �~�� ��D�PDHEa&xd!��Aex��W�aim�& ` , if��� f��i$�^i�� �A���8��� �GZ  illn�c)���dZed!Ms�W �]2&��~Z�>ly yountK� more�recei2�7�E�.�b� &�bY�!)�z��9)�uői��� PDH-F?E9y�s\!�|gh�f Fd�M��, :San �, leuk[&�6� 4�eZ��%"�V��*�>�Nn*���5+7rub�&�� UE,V\ �"<`s2,h�?r�ngY �ro�ea. Ten�!  ( 9/85 "b�)>]&�S&�n 3�Ealv�>Odis��$d�~ B(( MAC )&E�Ka�� Sarcom��A�A�Vxa+"� 6 *� r��A 28�*57/20�=����,z�AC:�3o#a>n). (w=K.m�nty-o`e�Cz5� ( 62@+ )+*G�I�.F�jUAgu�-��] � R6+%-v5+�1+�1+i!!��mB���33A�5% CI;29–4N,�*� -:27NF9A, j�Q�83%–850,���F� 962797879�;37 �A��vV��0 8�1�9-4p,a�~f4of)"7wS21-+36Y�a �.c!r6-&�,6�,H  )E��-N s; 8�*�-; 78-8 8a��>�7A=�; 61.!  A!:al� �a�a��ourF �;2�*!irty-�!q� ( 286h2�]9��� :0 e� .��s�2!�4A56/2�� m�-#-X%2���4�.@13 Aeu�%~i_3!R)�':M�!���mX�g�!y�[c� �`�"� �(/�tikov{&�,&�-0-[A�e�qur*�B���y.c0>�h�s;�+j�_L�m+ alan2:�b�l�9>v". P2Na>9M4���-iu: w����_ѷ�0��d� ���@�?(>4���H� ��QA; a� $mM-�%�s*v<!4�!�ART�!�aenroll� !Ro1��DVb"�4A�&�%R uvB"�"pulmob!3yb&@i6�;A�q�N� !Hz;≥��r��2�!�l�v�=-Kis:�c 1^2� 2�!t�HA72' CrypM ccus;e� "��wo�r�[ s�7a�e�!"� empi�9&��s��� �x��#d� �:a�P2�Q��k i7s59�%4m�rD s n��w� 4T*����aI�$34a,�ndG2�7�:,�[=h�a v�;��2P ( 97ad�m easy0!�!yUnQ�o.=��@%#x�!!c#fa�KUo��&08it��ksr(all26( 6� �~� �!ur��lZ� g+l ��qW0q> �4Ker���"&=\�Au8!���027�Hs� _)UN �'�� )��@h�7.( ( 7& � >5er:�7�%tTa�&&Ra�Y�I���di���]�M�3?o��h!��j�(�'d��L� by M�/ �E�\health�tro-�[9]"5s� BraziKC_27 U00�a2/of7 9%>.in 8/78.v �us:�#9�.����.� � F��� "�A6-�s �>-)��<&�82q 7 �.q30a��,aDse6�� � �:� )¬�&p ��N�1�E13]�P �a�z,]�9 )�� U=:44F8F50Y�6�e���G, n$s)O�EGnte�m!25 6b��a�A>9fAS2>�, �zr��-%�S4H66GM�2!&�2�0"��P�ura]r�@3"<�a`s�N� -$6�UPF�!5I�V� irn(5)�S;8A�����_`E{e n imL � m�.q( 8�Db����t��ut-off%��n15I�c&�s=6by-��0%�V�wd |��6�*%� .� ���y >h=@!esti> .�5�4� p9 FDA-5�!)��٨b�p%/��+�}�I�&�a�&�!d"��k�6��!-UR�9.��8cZ�eis' �IaA�2k )��%B.L��4%Q38:�e���$�w!s"�����es�|!F]9% est��B�:sub�!� -ZM� �g� iS�@. [16�: Cent�y!GD�2���)�P����b e US�y%a��-6���9. vali��%� Y IDS ��in(" Na wmkFa*28/106::h> ndb��� F_4�2r_%�1c��oh�aY8: M�)n�4� y whej �%�&!eoft�}ix ~� o�` al#@A��-BO��l 2��wezl�'�e_ow>���u��;!y��!�7� N!���S9��� ?[!E]!́I��>N��m�m���"�9.*N �&f�Sro=��� ri���qn �g�/�2q1��6��k;0����u0A�e�( .O�z9North�%�\8�\� .i�H5�rQšq��Od�7�utbreak�:��Ka:)=cl�bA�� ��Imon�fruit ba����ed "��IG �xG�^��k&�7aY�@�(it>8YK7.)m%9!��ery � ��f�mhe ut)<-�F�o˩�s��P�Ua��:�6^>Z5A0.�;�Jm^AUgeJYa��(b��;;��"C��V�cq i�edO%2�i� ��QHk/�ܡ����ng-n��1]*M����W.<"�$c"�*a��5`��{ _3&n��&��*p0tru*.1��"� CD4�5,��8�gans�<�aN�;��m�& �ba[,G some؅%�*7i�3U�O\@�k��,f� �H�*yR���OI�$or7 -�"�2y� �,!%��the�*:d )!�ch���:h�!��t.�,Y�� ��� F3\A"T�.�6al�$�2�-�("jH-  �"�;!0 d�_�%��̐65U�)�"��zL�x���DrefW2i� high&/ >�%E����a� a�<&Y��bK n�3i7%[ pretq:Q�, !l�Kl"��kA�vAF�BoI`H!�-O�L-1D?xO"�9#:�Mng.h�%n%*XEi&n�a���5V;&,lno�� �� !ee��&A`p�%�xV(�M�� ��-�#�7� a|2�U\n�� rrowFre�alu_)�jp*��W& !Sia�m}*g1{�1d.!2y� .X 0 sic�i����6tC�i) ��-AG�Zng?eG�� Ast�f6�edaQng�js�t \X'�� (��tip"�K}V!�Н5BN��X���-mly�� ~�Ά� �H�7"i8x.�uHq_�9 ����!���$A�j1<""��av5� ��:��LdiF�/NAd�$h��par��a�ӽ�of���A{a!}��� �U���� tri&E�m�<b %D�U� 嗁:t2'real-l��ceA�"@in� ���%h�n#,�;+R' uq !�~ !KA"��.� �QunG i�( "��2��>&/d.�%z2�%r*�:��o�chf3nh`��aS� i!<��dBZOI%t�62N� ��1fs�&W� �?����� 26�� %���I'up of f�Cu���&d�i>�%ş81�alsU��79W_KwDD6�^I&�t@"�c�mH"�!{!�56resolG}Of��Չ�"�m �C(-proven dis�Iseminated cryptococcosis . Although cross-reactions with other fungal infe 8have been reporZ��en�,imultaneousl� &�onsP&� !� negat[Mof.wdoe��discard!b!7�Ů��vE, .lWorldw�,��ximat�g$1 . 8 mill!�(children di� om!�$rrhea annu�� 2s mq suffer !(iple episod�hfG fatalK(. On averagaZin upaq40%!d, no et_� g0M�ida>fi�The� of met+o!sH cA en�: d systema�r�unbia�(characteriz��$microbial &� s��e�.m��es6 a#pot�al�� es��rum� viruT  clud�noa� pres�$in stool d�mg2g acut0-�.% dete� %�Vor un�5dw, t��)' inv�A�A��whe� iH!m ts play a�al rolA�.�I) is� =v�}$he eukaryo!�vi�� unities. d�!Oimensi12Y� by employ!Wa strate� “%�-mass],�* 8entails minimal�rų� e qu��,ty ( <100 mg-�) ,5� e purificIX,Ex� A�Y�( 384�s��i) . Uv| methodw �e!�ed �����!;EXas wellu� se-1pu" v�6zw� ��:�e� �tomTin GenBank . While tra� x%�Re�designAo2 genom�IaIgle)� interest!r}�^, such�6���ranscendSb�ar^allow�oa�oXl��A�makeup �p�!.�. Su)�A�o9a holr c look at�adivers!Q!w$in a givenQ,bple��bypasMe ��AI �L[1]–[5] . Previous� ortEJfield��ex�� struW �#|u�in eco�G3 �e!e!ocean� , [6]E�h�  gut [78�To dat� $� ed!<�\��tud!�of D�&�Q��� naly��4)؅ coll) �: 3 he� y�R:�� aSledŧno2�2 ����)!�� ����p-�ly�describ��H%*��i� !�� a�%!of" us deaths�����= sponsi: i ∼6� 9in�;un$age f�e�year [9!�B�+a ,_ tozo$d!�x%�all �i�c�mau�'!�t� Chief*�!wn>��) rotaE�e noaZ q, ast2g deno0[10.�it!�� A�a �2�5�� of K ��sa��F unrecogni���us�.��, rema�o�  ov�[1i�1e�M:�affords^ op��5yam�R�( i"y�)~!>6)A�R�|.� 5/�ȉ+Fr fashw k reby la�aLe<�1A�fu�:� ai/��!o�any �V��1pֵ>H� appl� �(����щ.'*� pediatric��U څ�5S. WVticipeREhVb� var� gn� ntly S�men� !�R� be��ir? +�broadK"\"� to obtA�an A�� peri� v�.of!$�>�might~1(. Tow ž�,�( yet robustA�er�w "� !�developq�circum< Ter�t al% NŅ�dE��con8ionalBReM���)*���!��, l�a A�of fe�mat|(��,500 g ) were>�ad�)�en ext�� � !o enrichebI��ic$.!trak Y�I &��Uab (maller volu� s� @ &��h:�& | �!"number! physi! �X step�I>as littl�3� (of archived6OcQ�>��. H!Vwe!…� data� eC dZ �a�w�<w��s ‘ Fa ��smal hundX� F e�12 dif uew� �� q�  �e� �P!Q� ��of��eQ i&? ,M6�� 6. M]�~av carrAp�on-{Q;:� ��ct]h�:B�P&*E �<shown��T�� A9windepQnt PCR6�Ei3��ify%Bext4d nucle�cidX 3 � [166 � clone� re~� .1 libr�� . Be0 � goal!��projec�to.aRT�FY�lineD���-d gard�&i�� bund, n��a�:���lu()5gei9��e1_redUt>A. Uniqu D qualQ Nh�cl in8 �� taxo��groups b��z �!F"�top sco�BLAST�|ra?)��e� to�nof :608�-�1d ,&wh�x3 , 169 � !)hro�a�fil���2 , 013= thos���6u)-�in'ŭn�e>%�C v! p@, 1 , 457 ( 72% )�#)�%jbV�!�to�cebnr�@!=�%W\x ( E-value ≤10−5 ) $�" � �n556 ( 28��w% �=�:� /m.�!fE��K� gor� as be�of��uH� origi!k�1:1)�mxa >�oe6�i�poA$ l( Figi1  519?5 . 6!fE����2Zi � (� 78to pha�8%�58" b&� 3 ( 0 . Eto��20 S4 8�9�9�3N2 . 31R�= dRfV e�A��!"t =N5��e� labe��>’�oI�ꁃ���had2m hits! mog, fU)pl��.�individuy �)5/or�Rs�� ;v� !tw�"i!95q!:��͛(�"A[A�per�agw:p2� rang��>41%!97h2�readsJn�lengtu"��,6D)��.y255y$626 bp . VI,A titu� b-0–10�! �� ach �qxiwSd!�a�( � a�, D01%eD0��E�pr\ n� comm�� !�E��( 64%?!�re�5 ly ^w@ asI��nsi�9 l��q�l:�8WD12 )!�|6�3 ( 07 )=9. B.Ci�al�!��� cri�#�w� ���6�E37*� � famil!^A� threA kedaW8era ( picobirnaQe{ell�= mimi 5  &x} e i<s:�F � e^"D0��!�!�68�d-kc��9 �at leX two6�us�kn� to��� �R�first"� | � | a*#ontro�ope� �P���ed0�"p (E�)��enzyme ioassay�� � _��� ).�y{9 der� �7a~+ng�WLq�, 107vK ez�ed��IXi$� , al�,�Mof� po[�E.a*gI�af6�vBKD02%)D��4in D01 !Q2�JN5&���*U�.*�Aټ��Y�>E�a2�"c)iK� GeQ�AQ-associ}%� ( AAVś a me�A Parv��ida:)mi�'a!��� wo5n , D1�;1 T�!h.I^� hg%`=s� , but�/)t$,t;beU g)ge�O!�produ�o���$a��i� la��!+$��*on��a help�itis� maa�e�x�typk%?G rpes F[17\InE,]H=�6P . No.#I�.!��wm> �r�~��&� 6~6r�_Y� ≤ J�th� % est:hit ( re�=#t�]����>�i8"f2�:�!] be��.��d^lo2� arisAG, ;isE�pt` .�vmak���Vs���"�*m� accu��&ndh cis��� r�onshi�>tomXQ �!g�dtla&e�!trees uxa~maximum!$simony�[1�In��� �th�n&S ��%�Ssamga<��n ,�'9Z  Hi inU%hB�!��e�)Zb�� 2–* S�S S��S . P.w"revea�e .eY�iI %�y�$o� eQ�!�%d aFtiUsubtyp+%R � f�S)�wo�� 6} %" 10 ).b� A7� .506.5365a&� 4r i44!�A+ma&1� 2d)�In"�&�0, mmmak��lyb%�9�)�e��%��}!3!��V� e_$F�he-_y!�eaۉ� D089�7>�e�`. !�oci �displa�5A� 67% :` *�e V��f�:!�ve�$� ��a��Q���0 �,Ja��mbaBwok ig!����800 %�mapo ORF1� *5b*b . RT- f-�"���-icoX+ firmEMcY#��� � e�� al� \� �%$ 3�AB(B ���' r�.&� ���_-nti�� cL Tsg����f�R�aa!A�9�du3!�)ScI�� exhibiaF�5'2wѲ-F1y Nodaviy �IN-�%��( ���p9ra>�raw�6�co^�a 229Amfr� �oN�R%r���e��  demonQ�"!�n) u� �D09ezB���h>�o�ꡔ.0%�)J�A�a�C$�Ze�,&5 �uX a�E47N52B� endo�|4A��Qamoeba� ngI, Acanth $ polyphaga*!>ss also*� �_�I��. �iF.]&����&�( ���)6�protei� V4{ ng%�-�a��!>����S�'pco-$86�4lar I�M����8FuV/Rp�!�wi &1 �8 unambiguoL/�rmN3�2Y� 2� )�-like-�,-Q,G a=t���1U8&� n6W%�nyF:,.Y. Ses �XZA rge &^i�sec� ed�)�. Relax!�7 sholyor�#gn�1g�o&�.y00 e,bie�+Oy�*I:er* u�] s; h"�3*� � Q� kely&`  artif�4x#:� �) 8ed"�unt56, e4+w�"J�6AQ�8as 10� �%. S���6� �]�.�;�#"�9u�l|&є.S79�1���!vdeg�of"T  bser�""S2� "? :[ they�"� 6u u� V�w� ��p>< enteN) , TT �E�"v)�#f� 2X�el =o�u:�u�dou�*���9�1Oa<[*�=�%�iV" %%�� nd��a�/s�% nd �""�[�=�2N"r*}$2�=���) "�+EA� tera�(tK2A�(q"A� 2 6ses.xlypand�.�,�OA,6 ! ,�+� �2�*Hinhabi�*e-\�9. y3Uv��uve& Y4BV5� �s� V�o�,^uU&� �A?��mer)u e NSk1_EuI-�FZ2| �*b � u*q�d*\az�"�I�K&�by�ov� f(y ++���O �"���g. Upon�s�}a"B>, h8m�1�ϕun"� w  b� ng M9��" plau\. y hi5.��he8�'[14�A� �I�`.!9DfVofbzng� �-�M,mpL�s")w�;�5Q�N �5;1��y�`�7!��Q�i�xA$5)�e�ceem�� \E���"�!|8 Qser��I�d3�=!�K] ��s^+ y an Q!^i>�S A!`F� re�en{+�=�3�3|,Y i� *@ee�A�accoun~:�/1��? adic����B . In/I�z�{7?�%� t?water�a�8la:g�4 dayA�!�,�"�vom�!,]2dacheaj�)�bX@nK8-"anorexi�>z1!^ag%i�^ elde; <� rom�Ba�4"s [�>� �&H%�# t���")9 rai! tquQo  e/orpN#<n auth��cMh%�� f so�he[%>�1"782AYI���. AM~�uC���a�xbyZ ("z�J%3%A��,w6-f� , biit6�,�@iA�"�!zr!�alpha6\ins�%=es'JCbet:+`$). CVC"n�� establish�a��5i� to n��e6 mammal�9i� l� i"�Dge�al���4N:4:epl �ea �< arra�"organism�  ;�[2�:U8I9teOA�o��jC'+atI��"�%s+!��Im �A�w�'&�a�Z�sjEer�9aQ&� w5q4@�+��NswehHisyaY��Q�Bla� oiH� A:%�?bU�(p]�?r�F��$*xBE6 �&�, O. A���d&I�6%c:��t 8RNA!�-Jk !�s�6attribs%!iet�, exposure 8Inc E�,z'��icu�� �^ i�*rtiA r+�y�9�;���;bin�$u/5� ossi � :�.*rB%"�= pisc�. i�1u�7�H�ne�Bar preA��As9=!�n e:�>"�8dcG��Rb0��I,  ��!o}�*J<cap�*�e�!�pE�Q�h:Dde��t� �can�of5,rse��itself%��� !Anew��ew�X%�thogenic:t �=@� �, �hyp��� “A�IW 1�involv&-����(Օ? A@�� “W�te NruenCe} e_ 4e�r2!'�Jsktabs�1�R���:86Q� 2:-� 62).(#-�)�"X.�DmGbinQasLl��"�'. P.s�23; e�.�9�&ABrepet�� ele�or�G-�lex�A*RepeatM!r [�H, [26]*�8hE!ml`Jmeao�D �2C� }1 C�533Bat �*�i!6Q"i)�7*unE�#ha ��!-Il> A> ��l sour�&0YI,>��KH"o�al��;E2*�,2� ��Q�5 r�Iec�.��!��q �=�KlyE�nL. E!3!jm?tel�L.�0�I�VU �3l,?problem �:h#;�7Aa!�new� 5=mea�gsV�� �-e�6 ��.7!E ��#le.e���Q�I�#d�L �#r���e�N��W��� mic/.98�3� ch .K1A�}!�D�mayq�.�fr�$oq"�"O } `�oN7sF)�E�>�6� br ��Jg_Puty�.#rea4#g�*�6� escap!r�5�>�(q�� &��V�.!�theor�=�[���!B�V.ui�m�."H dep�.-'�. AN*��-�shahB.1W8�e�9)#2�)|Iticy e�� !�6~�"�F� %�I"� )(!N�.%l�y.~l�MM or . More�;�Bj"U S��"%<�.e��EH-s�*: ��6B*A#sor�RdJ 8a��Pmajb echah 1�u�!mtTlea�!'em��f�,�.l+8��[2�'Co�<t>�A �$lE�+:7Jl=����Cu&q�B E�e�t �I���;�9(�or&pO�m'��VT�7i� �6i ,i@B�<5��11��ic } G�*5� � termt"u=p��c+ta�Q+��< ma�ed��v�2tF.9}�[1�D368��@(U!�!��N�=boA桞�3Aop�l6� Ɂ͙E?1�N��F�D�A/ f**� "T � mF!�xiJD�=l��Q�As.�costs di!4sh�effic O0(M��>�@b�b power_ �{ G0�9 summ�-,=<�"EVVq� *K�!�zalam�B� B�?Q�?�"%<. BQW; &�!�� a� ESU��8�!�Eja few"�=colon�"4 �"`� e �F�� a<!�!�board��Z�,rronKm�HKi� )$e���e Z�,�5�S�1 �ܵ�6Ri�Ti$A���x �Q @a doz� �s�atBer)%Nf1���ei�D�� OBuitAj��` Z4�K^ al:�. Chip%7fr�:�?e��FA30�55!@4=spa�Et6.�@PBS�� �%l �"c]��. ilA�E~Q1∶1� g� Ps�s�X�Uifuge�2J%700×�J10�$uT)ksuperna�  har�Mm`n>�<�945 µm<���� �&a �LµL!�! fil�!,RNA-Bee�%el TeDBIn�, F�Sdsw]U, Texa� ccor���l&�TA��J% . AIL�*�10!�(300 nanogra�`��.��random�fpl�fo� A��Ro�ZAB�oco�(2�"�[�?!�a M�$�-cidq�3pCR4 x&k TOPO |k�.Invitr�\arlsbaB>CAk%��L�=E�to Top10"�"{,�T��E}sub.��@w+Np�0�DNA�fCed �mag.b# iso"@o��)>� "#� �TU Big Dy��� ( v3 .Y9��chemistr��&�7VAJ� M13 H-k#� M�e> ol!�cip [M�:�25 uLA��[ ^o loaE�o!Z!� ABI 3730x� �]ce S }��Aub�A q�@�*ssm= !0� -ca)&Ph�[30�[313 Lucy [32]%�u�6� rim vect� dXh-E Default�/ amet�(�Hexcep� higN%��)��@� ����r�*75I�ot|D�G.�Bws��9 Z3ini��% -k�n"�otyD-as�)6 %d�L��)��2%M6E�ge��t(/a9;�kJF��E���A�M"a�� ���}"}28i#�)N*�Ur^7��tax~tiT{r_^ I�a�1Trc*KU%V inpu�.to PAUP6,��F$6"�(A@M8"f�dͷset`s)FaE000�N��&t")�:ES*� ,1 ( NC_00194A�;F# 2 ( L1374�&J �DAAD1722`4J"4fQ07085$J"pEDQ02863Z��FCAA8661|-JD7a�AK3191ZD8"DF260508 ) ; Turkey>Y1593 eF!!%1579�5NE% Y769�Chick�`"$1w3FOv%F! 2469�� MinkJ$457$.�1u)�: Stri��J Nerv�,NecroMI�( Q9QAZ)M�cbrach�c(rosenbergii*�( Q6XNLIBnBeeUNQ YP_0�-� ; FlockhF% NP_689444� (; Epinephel�auvin^ �n>�%� 4136?�2 murabA�269�L�D; BoolZ!6#414$H #Pariaco�Y5�69 5�Redspot�;�(.r�804�. ,�76� coxsackie)(Aa�AAQ0267�,m�B+E�AQ0485b,9a X8�^,2�483�H!b,a�ABD97871�, poli'�wCAD23059-�&>�aqAAR3884�n}| +1�^V�q +Q�^+1�{AAV7012>�..8)SW3068>T.(9)OW3070nP92JBAD954B�.P7PCAL3665qM, Ech5l� Farouk%� C639ez��Z�B)zD1987X�Y.�8) X470~�B)wF2197>ve�2)IQ7308>.y6I�R9850nq7)I A188� , Bo�r.Q(���N5Y�Por�".(A *653�:,R*B * 7585]<Sime^S>�rhi�@zABF512B�& v04100M�t* H� 6M/Q11-CHN-9�YF��3NQ3V84-GA-I�7BV7Hy00510Aw�� 7027:V922p570>\V712766ZC�`1�:9�EU10436q��&&RI-U TGP96 Tor�Qten`a{B04196iw$Pt-TTV8-IIn,�,, CBD231 TTV�5���AB��3� , MfV9jS5.)3n)$, KC009/G4^* 3862)8TA278/G1^* 0839% , �n%5fK , TUS01/Gb�176� , PMV/G2V{F26)!JT33F/G5V*B0646?, MD1-076{mid.y29091)'MD2-013.�N-)}Tbc!�1bU573-Sd*!�VQ 7600 �FTbS)MNE$10^*I�So}ZVI�IwAE�6,�(A�A��. C&�Hq0CaGwi6G D339ua!� -200�� BG49� , �ow5BD739�Qf, Snow M /Z.�AN0811� Mc3��AS4782�FawaiiYAB9776��)Norwal�GB5046&� (Southampton: A929*  Chib�MBAB1826�dHb>2CA|&�,BoJena-DEU-9��CAA0948�|, M�f ;O6309� �SU1�BAC118�H Dumf!iM9518��425-JPN ( 83jSU121� Desert Sh�LX A162X)�$Melksham (� 57469�TorG-9 �92�fSwa]� B835tOH-QW10�AAX32&n . E*�<�-Es��C�� (�') :�ao�cacca1 ZP_019595*� Ac*9=miPO( 14259�Eu�<$um dolichu!V207775Y�Stad�uus?K V02446Y'(Lactobacill*LP6m YP_16477A)�-2U bIL1$ NP_0471>Z2-r1rH� 9506� Burko;eri_ etnamie�Q Ga�011190}~StrepAc�yQ�'`075*o ,Tetrahymena � mophilaOXP�029.��c)�vulgatuX �30067-jH�+Aedes-borne arb8 'ontinue �,,�addl�,Vd�Do��Repub�p�6e4( eara.#Zik!$��3t"clo�H"-=denguv �\�n>�bf�.&] �t�d�)r $�6!JF[wo flav"vN2tro��4�&se)��\2�(tGpo1s< risk�pU stath3!GW $�t�CutbreaksZa�%�( scal�#E�rlbox plots�!X75% -FWre�/eO�a3<20�es�7le)�0Y�m�(�1�-is�a!��x� . D)�att��F4 marg� ^er�Angx�t{. 9�,�9U vz2�F5b$� femaR.B�"42i M�@( e0 8% (~U CI 7�� 6% ,�. 0%; p<�0�U^age-adj�\d �2 )4b%]�f64b�-�49�72b- _�R0 calc3%��-� so�A8a:M<-� metr�%� �:(Z8��!�8�6 72}?��!�at-7Y 66�  752?._1GBS6IF��BKslJIl�:gAfe�in-EF ��t� 62e�!�57b_2�W. E�5���*�"ib impaOuf&,m��7�o�ok|2"ofQ7��.levelL oning.R0�i13 �2�)�-��X>|-�D��a^^�} reliB�p��"�4I!:�.&EPIz"�as"�(proxy syndr�:�{n-M8eul se�}g�;ex-skeA� �^_The f�8ng"d$�-�)o&&$y awarenes�-mpaign��influenc�short-]$�9ltgerObeY/%,$0%):&�5&A*b�[in!9_i:wo`gof&WRaa]zough b9hsus�4K3�f�{u�J�1. M1h c�3*n=�2�^r�'*{f�Yr�ُ�+�@=�$!B�4fo�d>Mb:�.s-m&7��)!��:. A*��aq�Zb/��-`!�w"�morbidaU� mort��=n alaZ"gŊ4i�p0k*E��re�+\to �c�!n"H�I[1,_�!em�-�9 VY�aI�'ciuv�!, t $ aegypti ,�&st�FQy[.I�8D�52�is�na�.!/f %D6Jentom�cIEnd cli bc 6>b��[5 , �*U4\<;reXIherd ��,.�de�}y%w5mov�3$ [7 , 8 , $nC!�& �9X(�|3�w!�nt!x" how*t Y q�&� spac kd�+* docu�dem &ph� e�a�1�)�baV 2014 (6� wo2 ,�� ( DEN�V!]E�( ZIK��>�%_ d-�yUY�lh� (m7 disrup� ires4 exhagamidst Vuge mo�8s@of,u�-dE� l�uwa#nM�%�A��!eN� M �.'fX?�4In!95/e�y-20%?a hm�` 8visl �, ng�1AB324. i ]m � 0b�)%'63Qo6j+ V&AE$is�b�5� fw2� �%�de�8%/e�$week 52 of!ACaf235I%pa��( Nf� B922uinfa$F-cepha!~r�0� � of Guil7-Barre�t (B )&�*ɠ%�Accd)P /$a r6 M�survec�" %$3Ʉ��a�% )�#b4ndy�!�2�dy;c"eL /ei�ssN�[!A1*n5�~ ,� ��y~"� 6r�<D of7H>�Q�Iq� [�!"NZa# (� )S�*C . �oA�rRh��2JvI��%�98�{< !uca�(l Santo Eg�^c5!I��3 nd 2�crs 65K�m�6F rece�_an#|*>��E 30mm ���{�?e Ia4 7°C�s.�1�s� �*be =.�@!���!���-�2��2u�_O&gh:/E�yAuns"(|m2VumJ,�F�#�K2eyu1�) Datau#s!; 5–%B�C6�$!�J�akg��Xma NaCP}e Vigil� aQ ��� . Qu ssu"�a%A�o�z����s2Ne�3 via monit kvis�fwQ fuyJ� made*�8AR�B*�/>E!Dva��i.#+(�+i� �l. %�de-O(f�'atB;E>� �� 5f�Ras SundaN  Saturkre/no� �;!�clt</ "�4M�!�raw��*�Nj�]��Y⅄6s%Un+@�%V�!� �U0M�!;�&�T>�A2c/WHOr%�J�7[1�3] ��d�*of on�,no\�1, symptoznxM� p� :�/.� *� A{:r)3&"nSTATA 1�� Cor�Lek�RS�3�F�+��903�J�M�=,soft Excel [gwD�/ �5.lts�>ri�meahm�  �3qu�Ble`05i`&�i�Ag2�Q%�5W'decaPun�_ <wi\4pe���WJ:Y#,�sϋ1t�6 ency \�/��)Ŝ���. Est͇D�5�s!�aeޭ\(!j"%,IlS&�:���(�(�8E{0. Pearson’sM-s!R�,esJkL�3�a�N +m: oddX"�,k�+# & , name��JR�,Bas��).�:�2� �he�onI�9rowth!_hod� PoissgA���� .�I 70%�p�`��bLE y�.y�X� .�&�.rsyu*c�w12adɍ� . BoStsA�a�J)� ahofM�� ]��O&�"_.`�� �I����b��Sa�M0�.&�~42E�%&`.~�6IofN]6d�bEUKA#�L U (�sexB �2� V"�PinZAAA|&pY�]H��K)ft�c~: �'5"ered�IxV��( CI ) &9{58orv�@�*@I �'7*4� 0% )�ai�z . By-��eQ�� �Lmarkecl��6ri�Pa�Rr5�%��n,1�. N�`a6Uu��2��!�5:,��j��NSnd~.zk< ". A0s��.i8c� ��g�bV�w�w>gI57*�U!��V4�|"��1 =1R0)�2K gax{Y�bb� �6�w 95%�;78 �y.�dSt��fd��cR0Ŝ)_A�G2 " *�x8}* )VY)a8N�>� ��=�� �1b30-60y� ��ly�Ab@�W)�"8e�� �� aselir&���qs� �i�r_!� 10-2�A� 30-8 whoim\!l��&�d,E;\ �) `�}�Ez 20-3|�-e�%�` ���@V#m#� "�"=oA��. �Q.7�H�af��DIE5�Q � l=��>D=!� some��~9u�k�( �arIE)�l���d&~ Cat�{Dbya��Cha��K#e-KHresid�`youn�M�yU#�� S�>�"1 ��RW zI E�ch�KB�q4qD�ias i*� 6�;|i�����pas�6�_"�CJ�Q�%n7q�l^lXNN�(c Fv�i> a�80+a�� A�b7>m;IdX pauc�A&�:6 E%m�;"�Mmov%���t� �!�GlSw�*�NI]���gr�Q% � arte���ňeq�-ag6n�HmmJi‘�8!�&A.!��bY���-reA�N�b�r"!"�ou�A2� l�"*Bqzτ!hA]�o H�%S*A#al�$>NU ;r burde�����8 >=�PS7IeQ��ML0 ed�!-sB�!raE�� *�!"�!$w!!�lu�s��!:�!I�T rrec�e�)advocacy]w�ay�"han~ s&�"&�"!�3r*�!.�!Pc�C:!$��I>Dby �$oGJ� a�"$A���d���a�p�p% �]qZ:.!�p�LU�����Faf}$?N:��$m�]g�.��H/fF�q1�P�=�af�P:BA�.�Pol� ADP-ribq )28�b� PARP Gcatalyz�.�a��N3f"�b�..L7KF*��|")j:}yl ) pl�^a cru��Ja�a'et Wcellul|�;@5i�", e��^��gauto-a_+ gof�A�Jb�NA �*t�tiv!� repa� o�hu�!+/A#�{A��6`��\p.: �A/u����� t�90S+o�ll�=Ձ�i�'s�$EK�damA�.���}�U�$�R�OwX �fSw Arabidop�<thalianar� At4g023�=,2��! At2g3132�2��i��`stA�&�?RP�!=�]al["ty�g v6�Vtox�[t�G.Ca�bleomyci��mit C(gX^-ra�L. P!��2AN"YiE�1! X'%XI�q��ric)��QV�I~��GY�;e ӗ�  �Dt{mc�er�b�\H^c� a� �Vf jj�w �)�s��TPK0c�C���ae� �Ar=]!� ih%N-�O*�aw1x�V Npr�~%� rapiE q�� xter��uli�G �� a� n1��A R', *�H��!a-�t�+Q{Labi ,�M!duc"OVe��X[1–4*M6����� nteg� �!9�Ot#o�S/����germ-�s��ic�^f ,�&֎jRwWpost-�a'o!omod�%�.+>Ve2 ��P2�in#ch"k�gh�d.b  A��fe�e,donor nicoti�&4dW� e di*`H( NAD+ )��`Nd :��RU�xhemselvE��)s� �rntB�}�� .nip� �E8T!�Gd� a8U���a3ѪA"M, chr%�n6����>xPcr� hk,�:K� [7–,j4����( �J*�#�$�4.� ��v'�6*,z8pV�k2 ed�9e 7R12MI�d��17��+gh}-y�[�5.��� �*f� [i#I61���&$6kv� Vb�!�Y lpA!��`�U�� itues�XD�@ appa]�l�s�"��l��yk[1)-!/� .om�vcov��teg9�H� � Lt%atif�z-��RCD��GxSRO�U��[B� to" One�M��;�%� $SE�h �u[1!�1A�1E�"P�-"�Eu:�E��M�&�]E�=r��A"�.5&� ges�ONP_8501"w=is�e< ad�)�6Q% v�JBIT19214��isF��U��~!ii�YT�"arlier-!�9dVens ��$i� m�S1�)-s20ACE��<p1��2bƓ��r u, Y)��L(��Z�%Y�1�bH@6FM ��.Q�3��e?s��AU� !#t idu���(��1!�A��Ifun� [�vj ex� $ofJ~TjsQ  %o:5�0D��z*a�SRO!m((a�eC)%Ua��Zd�� &,65�e�E���5j$I��(�\6��a[:Pa wheat�e d��!@I�)]yU rece��5*�[��,2)�v ain5�%{9��bio"�daPy�biotV X��A��3&Tyl"K8 E � �us%r��le�Q[�oBina�HA}NAA���ɪraFR���l� �v[1J42 ��*�+ x��2���.r�9�4���h�S-known H�sA��8Q)��Qc� ��.�"�k�EZ\,>  A�orm!�ssZ!d ;�*aP�'^ t�Y`.�-YmNn�q��"�j � �h!m�'aQZ)9v�cp } p�Z%a���"�E5_ %�uk��.�j�1�;Q�/P ack-up�o- �N�jo��ݭ*B[�f.z�9 2qum�/ pi�u!L#u�!'ioniz!&�le�c Ri&[feT�i� �dep�h�Xs�9d{��iI(� soybS�A�Eh�Yv"�k&� y<ilɜ nse ox �!�ej�`6��A]M!Vx[�cKnock5da!O� �':�Noilse�bapeI(s �wh�0a�)�V oh�_�/n#5)� n V/Evs] tole)! a� $�A�6�2  ! L=�%/�䥸[2T 2% ��" }m�v%� �f ?�  absciR+]� �6w�[ ^%Ji �! �enh�s2�a�Ky!���ng���efE5�+[3G$Q[$g�6, lu���� �vg�Q!Ztelomw le��,� !�L o a�f)[3v �YH�#9�@�J>� Bi|�`�]���(�7���.�*��dys��triggDC%��i�[3�_j� �q/ ble; cova1g�fe%�t>��t� leav��``F!�:�=^���� M"" � s e� A�f� e [3�736ª-{a>$�M��n"1j�en6�!|fWANac�pMMN�`xa� �mbryo qle�mi�/f�ros'F[3��3�YW�4 �g �go=�'�[aD?Z ^s�E�im�M�lo�g�.͖��u� v7t7 s [3�FUn�+ mode�:he2�!N.Uw`XR)�0 ����� 52%';���t!:(2� � :A*��E�e p�%?� 86�U�all%%�dja� %�a"Ro6��2z �MVv�#is�Z�!u�w G%w%�� n�BN@ Al�VG1R q)=5toFy :ȱ'��n osc�#J:�[4� ~ :�G2!�e���P� ��!P.�*�|n� PAMA�numer�" HA�>A=�--�&���W�2L�>�3,&J[�<4%�*u� �0�G6� I�w��JV�c , os��c�>�.�4� �Aab�" work��]�l[�C����Rg� Nu�i�� %.�9�#ly un ����y�d�0ayd.W ���v, 2n�"r6�J 1/"�G f�"� � ꂅb*( ��2J=H%C-nq%  A�B��%�*� �!t1>q&/�dCk 3M]aw>!}�:�� � �sC� WA1&,!V]��%8�S$2&B �2 2 . T)�i��e��� mport� !�F]-bj�hd{@��y��<&2Ax�wafs��}�q2� ,:D parp � 2~E�" �12\!. Two2T-��}r��Y-zZen)(�\�o��> ���: �- GABI_380E�S�1-A 2FPSc26 420GCS. DZ��!2)��r�er��by���|&�_�"� & !t�>0 �!-2��( DSB���<dER�on�!�E�.�F�[4ePw �r� on MS�@|l�De�7�!1oU6%�-l':f���l�,�e��ά �i�>t Az� s 14�7af�d��f�[4`�4 �As=&ܪ1AG n�-f�>�*�wild-t��A�!� �:ݪj8.��fRF+t5 μg/m�89;,M#+.of� vg'|.u&d635�#��A�A� M�mnru|./i��$&�#5�#Fa sHlQ�cilqoE�A�:�!EA~ �JI�-a�-�)�)U����&4�aϰre"�!or 2EYabo߁9*�dv.qS3tq"Bh ^N�(, ANOVA��rep �Y~�� �$!Qa^th\ ��o]����wo�kl#Y�o�s�Q%X A� ��:e�e"v�"�pZ��I*� 9�"� )�K( cess5)!i�Y�.& Ea&�*:ǁ# alkyngɎ'<yla� ulfozj( MMS�E�R"+(��b  , �T��r�"U���( :����:.w� �(B.�%��r�1�NA�!lina� �[4X*j 9[6��e �-Y ak��s*I7�Ua��r�/�7b�6�!�iN�)e���.�ag��Lc�"śA:(H�E�:S(6����4V463P��qxCol6ewi(as3�5054vO�UaP < �c�A�6��J 96}�!9:| �(wgmM5Fe�?:� y�!��A�w.zY���"�Eu�/JeUE �M�ela( /N� �4Ee����.�.�1؉�� ��2��  Bi{!�.? X+1�*!� Q� G er�+�ja3�p.+�oi"F�e��v6�!�:0P1��g�Q3�Z i�xe�"�,* ��#^#K*,�G�z!}1�� %�wor 18hE�'��con�� ��XV�?��E3 G5" Nob�WMKti-PAR (�1->baF�Lt�1&�>. G�kl�R� �>G=?�.Y��-+i%,�)&= `,.(w!?�|:��10 �E&�'am�"��P4 de�M��k��O��A��7EhA �B!�*� < yE#aseGgi]���F���he.�,-������we���"�*!�*D�db�-Z01 :O�|��1"*�#�=;N,�3�det5e!��4��� :2a�*�� m Z��� mR  Y�Y�Iar*Q�.(L�W(V�� . !}Q1-�|2C�.dU�%�s����%i�]:"aI26r`:� I��%R@�)%�.�0d٩q 6(j�� "�t�2� �' � ps�G�Od*�9M17�  l�Om�"�/� +A}��nc*�O�a�!| custom-͐�a!cl�*" 7���Col-0Q(EKF�@��A()r"�J�c��፹�S5��a%�F)�L�o-��2Mf���:9So�9�N sepa I�[>@ 1<\����,-O%a null�(.�T�%�6!����2�W�73>. �>Mk�Z"�8Ni�ə�$/t(��>�%�mom&HcH`4v�%�otP�[fu�'/ n HA�7tope ta�D�.�FTmX�)�*�}��%-HA�c�@n� 9i�pHit".-S6E��WbN X��A��2o�-�h��iؼ�n� ��hZ� � G � �Z5�5�El%'� ].�i��ZJ=� j^u fK �K�e+&we ir-%!j`w {�GY9γ*7,d�N8� �Ruf��S+i�T '[4c�� ! �A�&~ �3M�. M�H� Z Ƌ I�1#�U � 0A� 60 m�� 1!�z %y- ��6�*��.Qm�� � � .�|(�i��&6v�ZV��!6��c�ax"9 !�np� �,m m^O1Z� �A,af-�%Yj�ev �meaR��Ab hosphorn?��neR H2AX��=��Aa��}f]g->g&4�!��N$7�>bentham y agroinf���2.�B�*mc�Gcopg4.�����6�.2�"5'�1)j45jA_�cVCH5��&�Mk%U.�Y ��-!�R2*�6� Qst� #7�.6 2�f. F5�.i6��a K .����( �T 35S:� �or �!�$�^�"1W��%�M!roaS-rB- �3�\,G��a� vT%UF [5&N"{G"M( fociIt��-~A���Moot4�R� �r)9��ie~&! %��`*L �Xd�>5GbS ؜Ac"� %5C#q���r��(7L5!�'E�!�4 �>�Y�in N .2�e�2�Ո%�M cyto��l1�-�C � m_���qXly� RM�.g*��:E�9.,A�a �3A( Pstѝt���AA9(flg22Qelf18 .�'I�4�Il�&, up-*<-�1G2�.Vy V�&�!Ar�� uY�F%K%�Z9�u?�,oN!�1-6��6 2hm�Atin 8 hr�e��Ds�avrRpt&8 ( S7, P��Sa,ifgb�p!u�u�iq�F�� �1�y2�arg3��u�'>#��;�,�)J�e�k�OiB@7G��/o:!G2!Nf-De� ��> \:S.��&, g� * a��ح�eh� !q�#&�:!�yD� VB@"M��p'd� ѩ>A1�ul3�:2|"�.�:�Afs��A�o�� }�9�(N � �J� ���o b("ŀ!���GF6J���5��Sur�_�/y�>�!V8Adams-Philips e� .�M�^'G6�.s!K�g�U�.qY!Z�!<2� 'CN !:S d]���X !c J�fLmQ1N�!3h�p� -���n2Ps6��cFe�� isY�����A"U�"�I`GvXKk �!1Wd��e[ � v!�~/�$5}(*7���d.�O!c"L ��duc\� a�)��&��m%to]�-�" -�; 5�1h%&�F��Mk �-�YV�l�Bv�q1A�/ɨ� ��� �5>�]y���/7�2�.� ��!`� [z�#[5163���Z"9� �6l��.�~#]k.�ci�Y6!A�2"� b��د�M�� DC3Ў��9�na7�-n�A�wF&Z0�L&�86[vED*g a2�%,!Dl*�6J�� �ivE��X��2�aa�2t!���*�"�7 a�1�wMn�s�eB��. �drR�3�N'B��of)��n.C�Х�7%5��\!���B�Q'sѤi����(2�ECE%�& �N��I�6�,��$e"1B�"�4�D8 ��� "�W!�QEY'���y!#�T��#��p�+&9y ́ ����-j�� E�sA�\ A�� eAs&����i��e�/�?a %k"�a[n���NnEK��[m_u�(��Aw1�q6$in Ar�abidopsis , PARP2 plays a more significant role than )�R1 in this prevention/repair of pathogen-induced DNA damage . To determine if plant W8associates with ��, we carried out coimmunoprecipitation assays�dN . benthamiana . As shownHFig 8A , myc-taggedi1 wasJ\ ed by GFP.-H2 using an anti-GFP 4body , indicat"Dthat at least some n)? sent�complex6�0. The interac!f�observed%$!as well!7bleomyc!�reatmcK$is readily%�ctabl6_suggests �!�2 zDvity may be regula!in part!to-C$ a co-IP b� of s �ons!8 . We �investig%>whe�c�)�59G%%/or!G2%�!} �ib6�co-N -t_ �Ceed){a� {muboiz �$G2a�AZor�AuVe:�A?!�:�Rc-�(D ) . HenceEMoa�of�Tbunda"!uU�by G1E�xbe achiea.viaY�. betwee)�A�U~(. In mammal�$1a�by far�predomin�%A�ributorA Dpoly ( ADP-ribosylA��responsAo(o a variety�4cellular stres",� �ia��haa�cei�aAv�^majorAs��:e )�merasAIsearch^$pharmaceute�,industry att�� [7–9]�K}�M@a6e].�:qE@audomain�ucture!2>� ( S1E�a�but� relative ��s��differ���P!"m�yyAH[11�8We used genetic% biochem%approach)�elucidatI�5� ions�.D��A�e�%r-� madeAE�v�FN#(glycohydrol!��A���s . Forikgroup%,enzym�!�redic��U�hav2��eiverg!Z>�s.� . In)A�to%�paradigm��)�aHwe foun�� 2 ra� t&c��E�%�.�ly%Hin organismal-level6_:�� infe�T%*ur��o6�G1>�G2� �primary-Z��nfers����in2Ddur>e tes!�25��R�sha��a subst�a!Hc��R>�i�hum�y,�� reas2�� %%Banalogoue=�ġQice ,Ap2 mu�s exhibi�" $phenotypes�1to3$1 knockoutAKdespim�dramaa�qWce.�ir%B!�A�pec� )�7-�0ies [56–58]!FEneiA$�1 n� �"Ofor�hbil��in �1pa�douv �Lare embryonic lethal)x!� ider� ,genomic instaFi A�!�= 2:�togxxs� ialQpe� ��O �~� ]$deficiency�>k0cannot be fune^Mampens�by� < fam� memba1[5�d.KEq�T��.qK.�`(were disrupAX�s �'op �@normal , demonstr*� � � %a��9=to6�.�Overall�Qd%<.%iA�"o �vecae� he��e`E7 , � �)at2S!� unlike it� u� pars ani� Şibl��r �uA�of%�O�N AT&��,.�42� dete�jat�# macroscopE� velsAAain�s@ | �e?�11�to!�otoxicL!��A�enh# $d susceptim�%�rul��Pst�wt to2�DSB&�Si�U>�y� ed�HE|niMabada.��6  � , it)� asone��ropos�W� >b-���ainA 6���low� nd =� unde� condi�examined �A� tudy%�ie��s ���bioinfaL��_q �>>�3 , RCDi� SROs lackYɍ��� talyRsi�� Ͱs%�posA�y� lost��,4to bind NAD [1a1�lWe ha!�4eviously repor!��P . sy�a,duc? accum �A�:� J [17]� wea�w7no !\�wp� idx f��su��d+��fvB��-*�� � .e�1 ,f�a� amed�&|su4 s.��in��� a�M� s zinc-fij�!�A�I�> #re cruc��to����$ [10 , 24]6r Kn�NRMmx from ���Ustrik�f�ng �c�ZS!��ł�@V1)�bGaken on�� r(lants�8be less unusuallight!�!�facA�a�� D5� y N-teCal SAP!4AF-A/B , Acinu!��PIAS )5j ( S2R ��=)��|a highly!�m� sequ�-"2 or!=� .�motif�aJ r-helix �l� k%�toh36� chro� .%� transcrip%�[6A6� .7to manl�recogn��1N�!0one end1�2� make�A*�T�f�[in� mi groov�&[62J On�0four distinct=�sE�pr"E4)��depene8o %�e� 9�St)�� ce�>�>���I�EI1�i gua<:dA�b r/�5 [ O��wo} e� n{�! X� �c� �ir!Hae�s� dQ�s-e ( seee1;� ��Do acids #130–636�>��9�56%i"� ( 36%�� )A�! alig�J>J16v485c82��2� �t���Y-��is1����an�Oby.Cj "� mechI%<}�.�%ev���Rp �7 is neg��S4�P1џ�Za�it�C ,�)dido D �n�� �ge�I��' &"Ix l &�V .> �� we& . However� n� ��65J��P2N�ma�s�hof.�[34�@We&�"p.�(J�N)P! .�ٕ)��ZA0"=�"DBoltz et al . data���� point9aTtr��pl3_>��e�� 鄑M* d)�AVon�f�-�d.�� exis e+*n� "Li� ��ݡxfsJi&� ��"� # � hostb� �� p�- HelicobacXpylori!<�ga�c  er= "� ,%8vOnucleae��1 [63A[SA�alq?�F�Qic viru�� :�o)� act direca�nd sti, e-YM��. !�9 [64 , 65]�� �n <2aE�as�l�� ateg�[66L7�InQ� re��E~anai�of:�j!�s crit���i96�*�inF[17 , 4� 68–70����$ yQ_�|eO/2ń posi1� ��:m�molecj��by whic�?E-e��u� rema�Wo ��FscoveS��in6� γ-H2AXo $s summarizdW7E�]would~A��� im� �!c!�>e!�Fnimiz5eei�d�aMhbyQ4t5��� .���p�30 year��� �!�%s!teny�_m7tegNy9ext�v�chaa8e)[A |.� ,MG!aj���e�lim� , du�� ��� � E�3a� 2���~a�[71a��eC� �A#of� �� solWG!�,metazoans [3�3�Y�c%E* 67%fE�N o� opAu� es� �4�Y�6�availn� system� U�.i parg nullLAi4tviKC&L*oG1.Umoval!>�<wh���2�S1��!oa�hB� ed.����e�n, E����Ceh�11^i�!$"�,"� V�D AMP &{ !� grow�� �wild-typ�`%�� oa�-e�c . G8. Because multi�,A�&� ]?%,Ac �!� nux%��,� es"^%(fu�i�ll����9o�?l:i&� divi� � (labor among �eJ� A5commo= ���! i�*!� 6�9 :� .thDof2�I4ir B�!!���ra��!SA�<e: c`�ng .�W8, modify target9 by adI�brm,E�?"�Rtm9. Surpria�(a�<��$��F�$q�A� &arpm�)]"�� unex� edly"� p&���Astr!�seedl!ath in�� �yC call!�de��o��4�Ta�� � t��k to synergQcՕEw>�� �6� :�!<�u1�co-local�To1�aQ!�mot!��� � 5r*�antagon �oef���F glob�[7I�"� Gɂ��i�ce��accele Ee-�nd break� �:[7 I"� ERwe���0!)a:�2!�$Z.�oaSsreU� � to���oss-of-�A�"��a�>�a�< �mx � HeLae� �1*^ !'����re�ds &��I���d�Am8BR&C#1�\'�M� avoid exc>XN#�ā� [7#�$`eqaF2$*p�n!�sa� viv�mp�'� plauW�hyp�yse � � h&B ��c�is&�$u~ thro�&N�s"�!�.�[1� 75 InB ynY ���"�&EBK/� a� lapp��QfN�A!>%y%@�%�(��N>�y)!.���d b .*#. F�|� ��w�f�!m�Mhe*� "� �U� >J-�e{%� AEux%q�aQ vidu�|o�'�'�]ed`ner��th�K1<�te�ea"�(. I�c|  mlm�BAB&2 AA�r �7�%|!dE�4 helpa`6�$-ory��6��,`E;E� olog*IA2in��$�!�"�&of.or"� � ��. .� "!�+���a�pFis�%Sunsh� ,Mix #1 soil-ypot3$mix ( Humm�-)�22°C �9-h�8/15-h dark cyclEor MS- t.�c� sd�HMurashige-Skoog ( M� agar >t16u8:t�P� mozy\#.T-aJi�%0linesa�Dp1-1 ( GABI_380E06M'�1-}+  2F0124420G03� ��Col-0s kgro�%[76�!t�a�abje�bed [7�so��o{ji��. a�qarg�� 2Z��-� 6t|�5A�#-�)3�obIed�$self-ferti�(#yX � �+ngl� �a�d L=2.PCR-ba�! alle��$ markJ . SeedM��1Nt 4A�e$� de]t "a�(ximat& 100y CI�614 E���MSI�p�-a���H 9c��n�/of2� ( {15�30 μMaF] "D $ , .5 μg/m�(�E� $Sigma-Aldr|�)Ձ(:� i d�V�,truQav� +orded%G�-Ws�%�[per ageq�i3.t2V,-�threea��%7l%O2, ((�fewa�ts%��P9zC,!e )�in Un ri�$�g  4&xp� repea% � sepa� ti� . Me�0�,andard errorE ��*6���"�%�!$J��1 moni^%O-&e� �J flagellS4pitope flg22 p�#d06A�ldE�N s �MSh"e�fer�to 1 ml#liquid�pum + 1E� cin 24-�%���A]"� fresh we�mOreMaeN!�)E127sA]*,�Jper [5� � burs�re%e oxygen"����F?~3A-�I�V7pBrief� leaf� �� %�5-week-!�%܉�incubEvPin 1% dimethyl sulfox!�( DMSO )�uE�e96=w� n!d�n)<�&� :�0 .!݅Iluql%�.(horseradish!y�"-im&ly�"�/30� .��PescJmea2eby�t� a0%( C�$o XS3 LB 9� Berth!$Techn � .2�Q\-d��onA�M���f�*d�5befabeir!Y�M�MSa���.4,. After 24 h�&�,>�fixIrFAA9�( 10%�maldehye�5% acdciɌ 50% �*no��, t P95�s�1�!�01%� bl�,67 mM K2HPO4�y pH adju-a�&�#aiO:_vie#gwAL\an Olympus BX60 Epifluor1�Mi��c��� ima`�v cotyledon-�cap�4^DP73 cao1 ( |kse~ s|0 ���.� 3�+:sA.Z��9qu!!>&autom�� �I�J softw��by exclurw� 5�W! YanalyzE�nnt�� areaAV [�a�8ѥaE� ��hue_bra�n�cutoffg � Xav 7c E�rol�� . L �of he yeM��.> ���E�'e-ino��DC3000��( avrRpt�!0at 1×105 cfu�[7d(i3 d ,�2dsasd�fv �!| mace��$  10a MgClA�S>M� dilu�s �҅M� NYGA )� rifampic%�d kana58s!�n"colon.a )�2 ��� t 28� .� ioniE1��,2|K �%�ir ,qT150 Gq 0a 137Cs sourc�# admiQz|�40�ominutL�issue-p-2 coll"�,��c%�8 ��� ' �� �[4� �:c&S&M,SB^5Y�2�nfilt)剨IJ7QJso�>st} 0a�N.�ISN�>�. Hist_"}%�p�)���)?s�&,+&� y< subj)T 4obls�rabbit ��-hu[2�aI:5amE�!i(B' <�>�(  PAR ) ( T�L�)X 6%� bo�. PolyA�a�t��:�=&z4( custom purch���Ge=/j�)rai���g�ANe synth� �4YGKEENDSPVNNDI|1&does ,"s-2.EeM͋agr�56� OD600e�4!��W���>��ki��;2� ��.� ��ZE528of*xB" . Ti� �harve �N� 2�a��cn���F�2����I��6Gf�GF@4Abcam� e�follo+#� "� %�m� A bead�2Thermo S[ t�1 )�1–2 h!�he .e� wash� %�� [FV u��iM#or�$W���!M eludRA�SDS loa�Ͷ�#*� � A$� [��� -myc ov�!?n H$( Clontech��i � ed� Supersig�� West Pico�)Dura �&�t 20^u.��!*in*F a"�1A�RZg!s�!� nomo�;vIi{th�6�S "�!��;,M�l�ovi�+{"e5ofh%�,�8;se *`@�zos� 2�yVW]IQ�%abitu� to��I&k!Y1i.6"$, a behavi��Aa5Z.!6aria�';)�ed glutNCX(cJ�#3ts��i.�m+�V>(>2 Q.1ԁia�N�"�-+to�*�W��ngA�3!�VgcaNtrict�~�ashort��r�. I�>o>;�Hy��ougū�j nervc$V.#.��%8M1g/pro'T MO� Iis �@n)!!_[�of�1�Mircui�I[� ]Ii��#:��+�NsA�conne�C)�6&� ofte!L&�?Oal� . Di���m�nematode2��prove= trem� valu�*=3=%��ɴ͒ R:�-�$A_mo�, HSN�iaB�[�@i(OC se ,:!�Z5!�:?, o- �9.�%��re�!O�:WG�JscreenO��9B�%V>5a�g��1��-Ce:�Eae�AA�5J�j. RB4oc/PreLA_Morph18�) [�5VF-boxA � MEC��[f$�">f7 SAM-10 [7�$&� adheŸp4ZYX-1/Zyxin [8-!�1'(RNA LIN-4 [�.�X3� PLM^��F�"���.ssor �+l�e".[1 ��KIN"m# c��.G�6� 2$� post5f�0\[1�<1� l%t���`#�@�ply up�oth��%�mi�. G2J2�(ls���M��m��<lex �-�)�ϡ/s!Fas2x��#tap%5arousal�a sleep-� �t^Dlal�rgu�1a�1e�I�i 6�o�oga�xe Phr� ,Drosophila Hv Ua�si�5r6>�� .��-A'Kbroadq�iqE2�AGB� af� �> ͂� ZQI6G[�1�>i' Stud3in fl 3icoEve�Rwőse-�(�P)u!�92E�P.�M workD"6 1�_Z�z,.� E8�8hZs APl \CU�cA.\ A\ly" X ab'+6�F��#2� [2�0*. �eQ! j~A�a1? � numea �/�+amS !f�$P�7��X�oiII4 )�FB�V n`# $1�Nv�F:Ax RCC1i� Q GLO��24����tubul P�;-RAE-1 [2A�2�'0PP2C phosphatPPM-2 [2�#A�XNespr�ONCD%S� �� etic;v�B�)�s p38RJNKY K*� ([29–31] .uE}gT��4a�7��] 9][32_.�#s>�by&R�L.Q>R.=b�5�(m��degrad�<"bABa�[29 , 3!�36�A�e�<`1I< G*$�8-Z g�&G95�� �m���e�vel�M� r a�-. lyX�� M+4.�� h-�.p�?*� :.0 Eg�s!A:} [3> �3worms1A0aI+[3�D(;A�verteb[3!m40].C�&jnW,�=�8 z"v/ro1!F�c �1��6P*��" z<OJ�Oex9d�A&%�musd# r ju-P ( NMJ )Z&�,�S!�M���/ism4w�Chow>�mpao�$ o"| ,F] in4 . It�>�ifmisoZ�ve��AA��!�F]in5  ;(%�T �> =add�5ng�se gapg�4WI ledg�@h�IU%ed5em�ng link&c4al�d�Y)A\�� dys�ǡ%,lzheimer’s-*�[4�4��A%�*�]PɃ�up�|kD cascad� �ea�2��m��ArQ?ca��AI!�tr�M�mis�Ɓ?�@4o�y 6�R�tMisshapeA�Msn@<'edO�i�_NIKC2GK/�4I�������(�@-$es%29~[4F Q$ Whil�r���e� gui [�:\��y do so o(A<$ cytoskele� S?ER#�BiA [48�B �$8 ,�alMTV�]JA�_��%�ihktubbor^ elus��. +.�q?J�Ic�~ � �7�����)�-es 6� Z��e- Z� of2S�biIi�Hm�Q�L-)(M=!1��i1J�. �u� 5�=1'j3 p:��2a�K .��12n �6� &$2-guU,E9#ڙNo`b�A�2��8+Z�R&�u�BAe[RAco�1� ��B}A)��Z � Ie.�V�� HEK 293 � B\4o�Nv) � mostqy�modelI�m�/^l �5s� ���b� n�anB�M �:],"0>"�>�,��>� m+�H"�K�*��,�!,*� ; �)h�]:�is��0u:�pa�We��1D�1tfi�1po� �A1!:��@7)<��Caa��m�� . �!�v+DAa�J�TV�"zs�� ��d>�>n^%�/PMK-3t MAPK1����/KGB-1�-�J�*86X� qA*q T� �@n��2! an MKK7&�i�Q �:�:�.Nloc�)�����R�vesicr�"ck~�)ABA� cB^�&5Bjkk�jn E�� b)/on.choi( rgicj o arl-8%��E[5iT"��mJ[u�]�^��� >�c�I�=�%2S%k>1c�E/ )�Aba�1} ( lf ) !�Zj.2i� �� -o~7}]u�(�, . EaKLM� � end�l� ?@rcZp���'` V�vA^Se1P(1B�&G2Xيɲs�� ed en�Js;K#2xE�aXl branc! a� �Ŵ!g� yx �e�D�� �gen ;Is�$&ѷs0%A�SZ�; b�ct�g29{- �1jA�k7�7a"9-d%a �A|outx r`&at �M9`�>�F>�%}b �e5jJ m?a8�. Q�5�lNg�F:J �BC� �A g 1C%L1�*\�C,��ifB�4%�.q!�% 2��2�&_w�G�dz?UnA�z!F)@iM����i ( kmp5nd�( gk7A�(�E�; 3+�6�?�fV!* WVM�fr[�iB1y-�Bk1C�I�Htg,)'�~:'� 0'aTV�;� :� oD oEoGi7�~3).� �Vb�&�Mb�k��N'h��the&ED16����l Ec�I I1��; �tri�M��.2Wno"�#ح�E�vF:R-E!>iV�, saw_:Wb F)�: ��a}` !E�� 9�� �)R<�K,B6��2QZM�.�JK&Nex1�X�v���kat""RW� e 9�W�ga_A-�.X�b�Oi&� s ol�y��fn��K?)�� t!mo�ASK� � �ada�(�2[5�T:2�:��A=' 7 b�XE�% nsy-\#w�aZ�'���k59`e� dele !��\!x2�%�M�"NqAoutWRYeb��:�E5�F%�; �:w�"�.ee.-z"2� 2��:��w��� ��,!�T T �8� d� �^i�2� . No2=�LA8b�occur7�ZC iqI�VF'nEY"ge��F\��c:�.�ei� 2�� 톳I�^�q�as �!c�IhR�.&�st- A"�+p8�=� :�in 6�#FC�&* Z.!on�� �8-��,2Keu�)3Ro2�&�.*FeR�� un�� �is����X��j��CMs4-U �ct!| �Qul�@> �C�B6�[4QNj(�c!s.[:�,���+ migr� �e*"��:QDal�����to^>Am��e[5S5�o0C���k3 f"1-[wV�r�-qΕ)�utom,B��u� a3 TB�� mu34���pT_��t�� �F*&��l$���[).A>�(� �.q�!En� mig~'2Ba?�[���&�^_j��l&��t� 2F� It�>3\be��G, �!N� PVMe���I�F�D��if�>[J� ap F��1_����#wA?& 復dXa1�I�4gS��!���9�� �j�;):���sul�l>� `qZ�2M�R� �Ye +P���v modu� � � s&:T6��KsI�ou4veQ�����"r�yow�$mIo^be<1/�/.� .]�d� ��1�do%�Un� � Ze#=o�li]e�� ���"�<% �~ 1k!hp� )iuRl�}A1��t*�3QRs��byId�/ "�Y�hUvaD^�2}��E!�^s�UV� i�= k� � �m^d>C2MW)�a bal�5of�`�5E�*�*b$#M�.f J� y��f`qƕ�lX7� B�p>�K.] �9A">5\&�roxhbrf}es!� 02W2�":9"aQ�ofP �6.N� *ke(le�Hu�U;$aaF� why �a�:mQP�k�+aN�d'm�2A#p"�,�,��)�<]3>j=� 1go"e�9�9B+e{sIetaneo�4 laberA m eD?"�s: �SjsIs1114��e�C�_�7!V��R�::RAB-�!�zJ973BImR �d�ow Ym&�/<��F]92��!*�K. �* �y l G-v(e�Kps6G�T ��SVH!s�&��&l 7�Swin2e90. Vquw*�iGF5Fa�}3C&1�ofJ 7>3A�R�#projGe,Gisz�kYo M �!h-P�� left%�K2�(LPLM/:a%��,l%oQI e z-7> W�7 �Kr�S& #6o�#6^FUA�E$� be.�2 .kA��icWO�|��P~��O#c�a, �tv#ne!��Y�I!J� e{ �apE��� 3B z)cv)!�m1ng]J^%wa�m�4.A*s^\�%�%��]t2[�. LF�} �T�d�^+ inm�E/��b!&!�n9�!�s�.�9�,-,i5,V$2Bof�al�;cor�on2�=��QW>��"�d:�"%�� !�-4N�>L�70�&as͡�@|P�1q���^!�r� `Bm �I>� Z%�:�^9��ziA�.NA��=9�� nnf1uA�>�.�.1� 9n< �Thj1g h9��� �"� �%?8d)�2�J'in � J�x�7mal.�$a�2[xas3 � !B!�Qx79?�$1Q%�s���Nonn�,��"2 m85subc6��"o.rr=�.�9�j&��` pertur�[�q� EOu'[zic� m�9Q ls�2�Rv�Uh�rtN z���U�1(0::tdTOMATO!�+mV9%Y 4�4B�R�>q�'YO[pr� �f�E s(A���)�e�:� :� O"I ly�yEG!1�9z. Bo7.�A � p2/�0z S�Q�}e/s2� f c�/\F����#E"�A0��-IJ4�Dr� +�}�to�wn"�recomb?�&�.?!� �QPM�Kb���1� T&1�A�a Hs sm�%�2�out�"� .qE�turt�#4:�4�Ga� �R drug\#chfS�NI�K*AQ!�2 re�39�j.�=coH�n�>� V�O�i�u( a p���;Q:manip�|C��Qa!��0!" �:~A�2[.�.no�Q��"~�Rveh':Z%s*�d�n��e�S�%$A&=9E�"�in��EE�4�AL ��(v@��.sIty� �' unve�L)Ga3^�in:}.�:UOu^<�"�*AY�dg,mVF���&A.ca��q��AqJ�1�B�.*iwan�-�e��eu"6p]JeYQ�`Vng���X"DAL:,��on-��2.A�urrou�$�TA�e�X)Vim4��icycu.�Y�?:n �N����K &oE���~��dr�!k7mec-7a�T�$%B�iln'haF@j3!>as��  ��2K*fb>�i�K�1S7aQ�jI'm6�r]id�!^i��T=�6Jh:~so� arrH��%F>@a MosSCI� -copSG�s��`��X�C��2�(*!�brood +j1��kderiv!v�o2��BA'i�y* �M�aIA�!\1�g.�, robuse!E�C1NinI:�aB^ ��57 57 6�x1#ic1^\o'7}H��ABn|St�Q�mCherr3_�= $:��l=cu� ����JN��Cf:/n�v�1� c�4�J�MGf��J���Z� iv��>j6aAD�[��H7�Tj9.�ݿi��Z�or�+��� �;I�� �<��,�W>` "|m�we]raX * 4���s�ko�B��@�a: al rgef-1A�6Z6**� ��}�A9e"�e�@.�[3�(�?LM) Y�� a<_�*# ��T)��Ka�6cE��uy���lB�iB6�6���(�h! &iqDA]�L2�� b �v�6��NF���ba5d�M � �4 �� <1(&�%� �PottUh"�iU:! ,=!�s"�t g��H�-��)�q8s�;'38)O3�x�&�< KD3� ���JFly:I �!9�J][K3N2�)(s{ �.|ng ) J�s�*N��r �T)z*� �>!� pE9�4 �L6�>u2` to�%&�7ml�2+1D%} .o�Y:!�I�"�%�E�l�@��SH� s"�*e� �6#3�aXAs�r.W� A�q.���� at>�F"%ly2xa novel6w�ѤNK�)�.�&2 "�t���s�=au،pi�DAmM^ "�6"*2�h�T&u4�L�9��i%!�MA�>. & [6r66( MEKKY]�YP5Z!�^"�% 2K�64�%�le* G0SEz |�T�/�-Qa2�*E�.� ]��^bR ���% LM2�:Ż�McH2. FLAG:HA ta����!Sˁ-��a*QV��Se�3�U2 V.�ly��e]�Q0ve�;� ��7��i� �*� �U+)-4u�Q�`4}�B�F�"� :�B� t�_F�b�WEla�ve;1�Ql�ay�n*�����)�#,� �i��d)��=r�:M&� * !YG[�Z�"��"A�.��:�2.�Q-1E_�? �D��>�. {Imtl�zN{�N�IZǞ��tr�I>.-�yI��*.W9�$)�g �.>\w*�=�}�W�R9� �GZN="��.#>.=%hK^�9=n� �LyuNMJdfI FU'U,DD:�=:&D1�Fdor�Prw~mM�>9����"=#p��2 juIs�a��U &�A��!Q:�Sob+n-1 f��h ( SNB-1::h^~c.�!I��spa�r.��2��$Pa6�CZ�+"j0,�Q��2!=�� l��":z a�1�c�"!ed � �� �  aggred6�I:XYf�\ un�g�� �a� Q:C2%>|:2�confirJ>f�j�@qm� pm-"�2:����u�� mp�<�5� �BBaa�,.3-��oLa[ɱ�8r_� s�y I�t.gF2V�a��.��ultLG}�m~>lg,�s%O t]Foj�a��h�9dz4��b��:z8>�R�8r�at:�>gI.�Ze^��R2qW$�. Z!����d `� �Si"}viwOz'&�taB�VpQA�4�8�Bv�>�.| ,= pa>� �W!`Z\�AnO�Blr ����W�al�2���� iD10�7[q�6�G2E>�@s�aC��>!.� "�!W!1!|WtB��Z'�/oO�%�a�O��J;f :�XF�1�56��'o���) implH J�],6�.PH�-*xXQ-[KX�U��5*c��уI��!~2�[4H�ch� � i6��s "�$�P &V�$Qn:# i���CB3\[6o�Bor�j�NGr#A��s�m6�6�&��`�`I><�� ��e��>; Z�:W����.��6�j &.� 3�$> e ׁ��&8X.q�,Ւon�^b&�a read�R*s!} e.;a"d`aF ship"� �!�, � 6!:y. Tap2����SV a whole-s �~hys&�o�)Q�eke��0zSonn#I�^�F�10BAB��Ded2�FXH Fih�di�'�}�)a8!�q���h� >6dM"ZEt>Z �Y5Q��c �8�$a�S!�bJ$tvB� �&�ap��� >� ��*[ �1����� IZ&m�o&10&y�� *x(A�*KBe "uqA�!��"�aO��}.5u�LI��(�F��m1M��hA�0:w�F�f"�*��s nicCE8� #�NjB�It2~&��6J�8^��*� ��Z a�i�$�O1U�=� h5�b#PPM/� er�.��A�P�FO,��X ��nwPYR�Q��FMo�P} ���/w��M.�A�.�-G.�Y.BA4ɴ) ��p�7�!� Q�2�F��3)�&����ii��R� �� rapi6?� ���)�� �2n�*Dt / %�`oɱ�est��epista�Q�.10rj"�� :���A .z��r9�BOV�6G��^DR1�s��I'|Y�)�I�;(]to�1 7��'�%���:.���X6�kaL�,"�@����s�tly���t�f. 6w��"3��&$ �:�1)�qCoJ3.�� m�&. �� JU 6�q�1a�$!r�r� B�Z  CA�� �T�A6�A��A=��F��: (&BG:B))� �x:B�6o^"9Ms�i-�3"�A:�)�gZ,JiZ,6/�c onB�P�ZAR2�M�WCi"�;,�or% 1��6�(�6� �O�now� ��:�-t&"� �^��eQ<.5�2sf�). Io� � e�%TH �*�C!�>� �0�xon9�.�%y*or-�� @F�Da9��[p*K!�"i���q�A���Bf) mild"� ��*{ ������B, &��b��gs axd � "PN@>y]!��G�A>fa��;�=*e XynD W re"l!�k%;��a�.�!�&p!/ F�de�s�E�_ LS [��. NP!rov�A�o#l�%%�� f�.u�M�:� � SJ�)2:^��,i�6d�n&iA� �el�+. 33�%� lR2Q'>�!�iv:�G(a"O%9c.�c9 e:>*�$!]$Jv��%e���#-_Z4"� Qm.�aK�a�!�R�5�m!>n/7Z�t *~. Qar�' {"� "�"e�n.'>�if@&O2 }%�.�~F615�1[!Y:>�6N 1\�.dFi�&,e�b*2eC�`"/$ ��y �S�J.�!n 1:�?SEw�kas��]ou��atqvagreeQ �("K%�s�%,��R�c��J�"F�,sP?y")F [45]2UB�,1A4� $�0.AjjU8&�A2 %u~s5F� "�E,& M*�\�< 2 :Jot�aX[D����CS�w?�� ᜩa�"*Y�PLH�e�n�e�&��2i.�*��(��t*�\]ARL-8 �'�o5"�\[5fb\r/1�Z �My3(ew�?[->��5IR��M��)U��� ǦvI�E�i&by.� un 7&v0V�NRoV!%��\xH&%�LA�u�M<&>B%�&���$'n��<m R ������:d .�Eif9�N���2'��1͊l8���j& l*O� .8QG (�9���9�invol�%��!�B}�OVO��n quesE�% {*�8ad �:{�"E�b1B�� n_���l� ' ������*BdAO%�R� f� M���vA2�wB�.�# )Zc�:� >n �@ +�A-i of*qVr�]�|=%!*��Epq��S!xRI�K IU1"Ry�� ��E�.!mR H�edF���Jt�A�a�du���J�n6[W�Gi��alhIV�hy�&8��A"�t�y:��*�0��(��ec&� g!�oh!���ll��9��d��b�2W("4� �8�Amv%�i�"�p infl·n�.� B�. A.�F `A)"�g�Z)��.cE o"�z���A�e���2p �~e��7R�%i^#?��&�xF�: Z;�M"� �DB6G�b��j B3 2�T��dl�eb. *c.���3r���v�]Ο^� (�2y�LB� .���ei��t-��2&Bv "� ABE>�3J ��[ %�&j.#' L>io?0@��")wY-S"b� Q�A In:I ժa� �R"YCA�1[z � ��T�Ĺ��0:��T6USP ��)��q�0V�Qj���. i��^?1�[ vi*I�[2q,Aqs�av�>�@N�k%ppre�"of� �{ j"�� � 8 10v*iat ���"�A� �&<��R#�#�( s%"R)��1�.�y9Kuq&tm2DI�!;ReV��\�mj �i�^�"�QB �]1-��w>�J |"c�ZAz� �a�61���[_zAʥ�A "� m inK a�.1ep�#U)*$? �V~sf�A� )i# hu�6���s�&y aE�� i.����6[1Q �.��R�N!V i�>1sL �� �MH��y2�Zp��s�wB���.�y�!Ap��>��w�v!�a�rt�A�.�worthz�E�� �� a��܀�M)�!.Mwe�{T ���^�a3 ou�� �r|w3�iT> e"��I�~V!q�*P �sVbU6{ �[�w�q��$b#.j %e2phRa!�%{� z|%}�W�*JE �P�effica��:�=� �. �NY�o~:�1!�u�� � .G:� �x ��%v@����kdu��Asa(r��x[�M Iq�$ ��:) ( ju43,f(in8i�( �dRv��(�^�1G����d|Mbyƨ2�Wri1 di<�� .C `<=e7{Yd��mIn� �) �.@ t 20f�� shif�to 23!�.�)V�E&%��� EG669�tTi560;os �pos�=�(roFAe II ) ;{1 -119 ( ed,�%��~��ENLF ggSi1 [Pm�G�P )�!/J�- ��:jH. OU ��%GHe�H� ��ed: m�o p�3]�,�WX /7xM!�W �N��j;4[Punc-2582[V%�bggIs28<::>~7 J.�� enco�;� Q�Q���ieTc �E9iProoft�-Fidem]������s�BIO-RA7"PCR& ana�;� pool>� niA��&M�Taq[i��A� TOPO�ip�pCR8 *��y&��2b��2Қ evalt�L@;�a�p` N:&�8mA�F�( ( pBG-GY75�, "�Q!]E�����su���t, �^ng PpuMI% NheIǛ 5’3 �s�8�"�-l�@�fe � :EOert 3se�&TR �jZ<-Y!�*��>�)�14�a910� mrE�a�.N�0pJH430��ind gif�|D�BMei Z? , Univers� Toro�)�rA�tem�2� >F-��To bup!a���I+e�BY=(pA�m�Q�: m59p��e�5tF�UG�����Es�P�G EZ �!o54EUTRva�1fa=MeŞ=mu�k��f:X . SpU�EK�"�E j3ܯa�ad�Qm�J�O eRuCR�d��!*.�my�)Z616rv&����p�.'�]cut)���y�mA�pCFJ3501�taлVM�..��k��M7*/V F��N�2N,�!�mix�h mi��)�F��es ��"g?iO����@�9R��!�I�JI�@��6�"E�.Q���!�w �:�N�Z�N,�|ca�� cros�_"6 " f& :2.1���l tech.7lu�� � )�!�E>m�m+��� fEO|&� ��Ja���4peel-1&�JN�!z[ �A[�1=�.- ,�%�ME +U�!�r1La4&�B6�P� 6F�,.����'��per�2�R�� Ex�� L�7T��7"�(��7li�A6���v��� ��F�bA�>ngq��2'3A�F0-kA orm+e%�*��R>ff&� ��V[CE} ,#:D!?I����  1e2� by TMP/UV嬁>�l&;icxR � ! >R �,at 25 ng/μL��W�r5EN AW*V!"�1 %)R !@!!&�"� M�$�6A:�U��:�2��sLI �a[�'��%wz �eypa-!�J�!�Al݋E1on��� �nk+t�N6H�ca�EaI� Pmyo-2::",Ft 11] E��Su!� ��E2�!�<�-��� pBluѸp� S1 T�7�@�x�9%- BV6v�P�!3A��D �(�6 � �AxioOb�g A1 1E$" Shut��InNb4XenoWorks Digi\|�� c�g(�8RISHIGE MO-202U VmZ '�� =!�2�PLMFR`s.�;*&6��X�,*Ѱ �!�qm@h~ . L4zA�*yu=ne[PF�Q genyIpic�A��}��%-sU9�!d>�T-~x;ERh�or ��d 1O�~�ours Jre youL�d�?��k�� %�2 o en��A]�;�-!� ta` m���O�:� anesѥ!Zin��MfNami��orǵ$( v/v ) 1-R xy-2bg panoa� M9 4��Ңagaro�adm\m ��d&�D'� Leica DM�B ( CTR )4V%�e-�40x�$63x oil imZ Ayo��i�沍�ac�ie<a CCD� FC345 FX ��!�*�M�A�-�a@~&&kE�2�"�eE�ai�9. 51"�a(Lyes�A�A�*9��0A r:DVN*5 Bran���r%�"^�co!��"re�% �*�K�J!re���AN-�e�.h2dabin�#e)C|�m�D.as A�~ se�:; �5"�)*Q@!MX# E��s:�?�oc�%cB�G��:t[4ytIf�S��:��Mcؤe%�2oP�5,>=��Eb�D���! �s:-I�"X)2e vulvaJ��=EO 0)%AU!@,%�Ʈ>lI�s&\@. A� oor��% �s�"pl�s8�e!I!E""<4 problems;�!�q7+ �E%!(��%ur�0J8�He�2LV�La� &� *m)�$� 8!FsZS�y�%�:��E%��Cb �"� A�s!!H�-H:�Q\A�a�m�(n!`N7a�"� �.�u�")0>�a�.3�&2�fEqMM. Bhv�y�i7$p$� o��&� S �Ejw( �G6+�)�curg.,��/e<se"�"�:��“#�”'EX"sT%'N�GZsL�V)�A&�9::&;AaV� AnalE�of #]on.N�&�5. WE�&ٯ� ea(%X��g�.�8 2G�r1%25:3.񎍩�L0K���t � a��V�o tret��ofFN��d MlAp�E)Suite AF&� ��JgVoA�manȱ�x *q &N a]�P eN2� R& �4 .& . Sli57)5�%t��z&4 d2�!�H �3 cytosolic�.-��2 . Ca� slip@ s��CBIOTIUM $ Grip . SeNu� Conf� � G9�J)�SP8� .� � �W 25� � .� �&= � ��&��%4�r : Bi"���d 00 AU pin�D , <�z�3 . 0xI� zoom_�(, 400-600Hz�VyD*5�,ղ�00 @�$ , 512x512aGma`�bD���sY�2�.y�>�kept '1+��yit�+abF�Me Kre.ݙU���Jcal�� b��ROIA.|x&!��e"�΀"�.��d� e�"6j(��2o�Z a 5 M stock&P� diss"*1DMSO )��w��po��NGM�,�8�c�%�j�d��q��volume!�f. OP5X�I law4��ed�*�ior :��E�-�10��� � . P0.�2�l�Rocu57:c�)F1.D��U�. 6-cm!G� M��-t H[-T9 9a 1M�L: Lipoazki2��de�%2aj-�:�71�<m[-3��μg� !738*@�Z-HA�� "A� $84 ( HA-F#?&A�I!�$ach 8L��� �.� =%� . 2 26 hrs��*����l1/ly�!�E�1% NP-40is�.�� ,6�m�&1��~���g&\�1��DTT-�41x Pierce HALT�ibb�� ��25! 5 mR� ��fe{��R �a7a���IP�EL�\eE&l��R�3�gI93��%�r� U4 h :M^�G"����A�T��cײ��.WM�bo�in Laemm%Qa/t9�Bio-Rad�F�ß-mer9�ov�no �ѹ� runa�a��12% Bis-L� ge,:=!G>�%#-W���� VDF [�r� m>H���#.#��!9A^b��ed�qloq�"IW�HRP��juge�9�=�rECLB� :5 d��A�^ >�Femto�JB�in TB;�nd x-ra��lm{!L__ B� �2%>�W(noA#aT�-JUN( M��1��� S1N5�e#^M!( C�5S�va/&`M�MR gF�Zli�"]�:d�!1 P2�aMm:My�29F��J�o!.2[�f �lM�ch�&s��V"E�ŷ.B�Me.;h4&2� *�%��r�(�,At�J43] . Behaviora�il recordings were collected using a modified Multi-Worm Tracker . Age-synchronized animals ( ~50–100 ) w\ultiva]�from egg until gravid adult ( ~3 days ) at 23°C , and assayed on 5 cm NGM plates with 50 μl of OP50 E . coli . Behavior of animals was recorded for 550 seconds , and ani�%Hmechanically stimul�by tapp!/(the side of p" w�an autom30linear soleno� fter2(first 100 s �. PF-�j ed 45 tim\ 10 inter- �us `val . Response was measur!�!dversal probability , which-eO��he)portion�,worms that rKed� in 2�of each�-=us%�cause 92�ies to%initiaA� �diffe�B![2r W\we-R2w�!a���=9!�new%W�she-1�)��wrecA�� h.�v76%� v104e�! e��ssa , fx�� mE�achsn��>inբes�� �%�[LAf���� ��XO� � 7instead!����}��wis��rmal ( . 1 )��bgen7nnMNcurpris� %it map��6left arm�ch`� (II ( Method� � . 2A�fd�e�no U�of AqWfuO . We! SNP�~ o cl�. U� �inkedEZA�sE?8cby-15 ( sy5148tnd dpy ( nm4 �e.�A_ mbinE�.HAF1IaHKAb3i� nd loc�dEE(breakpoint k SNP�-B%�NexPa.y a 150 kb��m�!x!'�� me [27]�N2�u?Q2C��u�B��e&and� e� Knoc ����<��d ae�&cLnD e�s+)u�ic DNAm��� 2��]my ��:)��D a2SI� 27 |��Uj r����oofy�ebec!xe:q�.� enco; "FM�K!� humax� 2����2� j :� es [28�F.�)�&A RACE!�iMP �t�p)&&���[ s sl�lyC%�prediV#at B#B�1�-�T�%%d�\is 4037 amino acids longMis 67%m�cal�82%ni: to%�A5 .�B ���nbr �^T , it'possiAS�nGU�!�l!4lxof"b�ywe)z n- 1m�A����� y adE on�� �!�0S� T.�Al $AWa�y��%�h�A�zyg�,N 7excep�{l= dele vDf40'# �8embryonic lethaJ#T em�includa^& sm W� � Zj�r�fr��;�� 8 remo:1r�Uw2D�cW���at"�� Y�� ��ofu�B�*� �Km�ma'%H, 34%N v108 !a�4 Df3 ��Wfew�lbr�R�,H!.b� r(�PI-kina�u!I�n��e cataly$s{�%$ carboxyl � "� I���/!�A� v128F�UY*{� im"� 9 ��� =v��q�����vul&p m� [2�nAM�Bb� aB� � edB��F8er�,=�(�Pi )lin-8 had n� ��I� suggI �g2� �� &3mi(��Je>rloo !=a �&r�Rym! by 0$a�� ph�"�6mE�. AL33E�!�Y�(�)A�geny d as�2a�� ���2BaCa"_ -���(�m !!)A��;� �"�j� .�To  )=# c �l e �%Aedb@"�')<��sa��ir5$)4nd survi��6 Tak� oge �� re��$a�T�a�iQ�" CI�via")� ��A �".*�*!�!D BI brimari�y �6�. �i�}3*&@ �+ e��eukaryE*P s�mH nR � GNAT% $MYST famil�of�5leE .sQ To see��p<zdI�&�$�P&�#>CEF� >&%to3ck { � � ����Q � T��ta�a[pcaf-�(�o� )k���\ �))% di��t�F�A_k2/ t��B�%"is.o���&� ��?.*:"��V^e?&AT�lex��dy��s2 . 6� four�ds FzALN>!qmys%p��.� at high f��enc!^!=h �eib>low=�$f- ,�Kawm�6� i�x�!-� %�2���'=K]�!Z�/U�.a?&�!w)? `A!�bPe8�z*:;&}a.%sTj:�)��ra(i K� 2@. Mut� I !�I`.�]� %'�[ ��(body toward�lew[3B*sA]�2�a���n�.I�sh�ac� ��� o� ^"d���&�(�ba0*+ ,>d �resto� !ga�<of^ ��S3�)~ indiC��a�& E� �+�H�jg�,�in>�m .baM � � %���&��_a�"�*m!�s�0ic::� �!y:�r�(:b+�&M!a�1!1� 4 @ � ����#exp�2~�� d^�V"�2�E�!)s-w .� .�!"=!g-��fem-2a� EM-2A�a!F" phosphatA[3�%3�%I(��s* ~% �� .c�!�M� el-mel-11][3�"2?Q;A.*�"A��}a�.�&� o�!v -�� in"�&"3A–"�(Sr6!V rQ�� Q��a� a��f&�  $-UE�l&� 6R&)�q!-y. childre%/*l m��X In�� �l�fwWu �� �!V�t1ߍ|�0>��s!"�7� ��o T�ZL!Wbe�4a2J��T�E�6��Os �*� �%g.$�o"Bu,� >$ ly o��!3�. or �(�b�Zng�s�:Em3��[34H.�.0 )�&*0AU<F/��!"ESa= D�cripts!�cor!$eS%�=9 �L.2 ��eTC2 IAM!F�,A7� e?"S6 �,�O:C rN �ct�;%eE���)s��� %%Ť 1�iQ�X3E�5�?�,� O does�  %~6 IR.*_ �w"{"'sJ�Z�=&�3�au we�p�,u�i@.r coope�0sI �tofre�#)��!�m BA*AA�%�m��an o�,2��[.�1� *$ *,,�)�"�%.<0�N>am��:�?$�&� �� ull )��Qdo%�rIte�^,�Y���"wtub� aia�t �+m�(d  sens�#"�s� wn�rayͱv44�;]�as<�1�� ��ev+2 per`.��T, [35��"t'I�I�C��%��eA4J}%% ,earlya�lif�'�6nj to*p&.X)�� T� .�-�refi�pr,s),�A�1&T -���,*N(n+ [0�$"T.1^2 ��:LX(a�e&l�V ��w �eJ�~� es�r+&�� yo*�by qdie�&*C"5 %͓B2�� fitE�!�A9a��*!���*�by le w��+�at�z)O"� ��'�. At 20�@1��" �2�(( n = 5|!!�"+5X �bit�#� m��A��2pJ_at 25�h6! )�an �al 8%Jfmaj���&� :�E�U[��/ �+ remanei*�d, )�e��so belie1�!�k"# !�:�*�4 �.� :� �:o�'uE?�0etes� i*��])t�t&��^� a��by #f���]X.jIn�� ( e1095 )6��2.� ,�er� �S-�d��,�hmas�_�:� ��� �-�� 6�:%Jry��� *2#-t�1eh*�-�#R�S)�u���nK�9�}16%�m�13!R,�.�2*'m:�yk33alm�~�a�c)w infl�A�b-�Z�` Tit$Ay�[ er rog<�@ F"�{�@�^�m*h>J:���E�7U9�Cen��&+1�@=D�>�C^ -of-��@asEkl.�%1� �.t4  %�t�.� I~6�2 6J;�.4$f]Q𡡥�.� bya�cBt�0bec�!�1Q� I�ly5��#-�-�1�F�f�@A>�o {%�?^.&6 w&�3��!}U= �A�� ��:X 6V�n�[z F��M n H�#)/6a 1 ���2�&�� fam�#�j �:��2�Q m�&m A^3a�m6��":�!{+  ��by6b�&�H"�=� �b!�? ��weak ) ;V�2@2��>rae��\.� �b0Ŗ��2 gav�HP&��a��ae��!o5��Tno o:�2rVJuM�We *�$!�N�ofe*X o�?�if�z��=i*�3��i:s�lf�6e>�. A majc1hrD>u2D�/-�AKal bi�:y%ompa�|a?$H+(model organ�>�$Aۑo2�:melanog9>�7clot %ed!�'[ #g�,7�:�/�63!7�  focv on �'a7�:.��{= �Ja windowo9Y!FK�?}IQ^emphasizq eq�я/,,��42x�G8 2*m6�� Mion� someRKQeas�!��8%� eMin an��;"Q;6���m��Az����� comm�nd|��"e��.� . By�tE�0��t Zpl��*�� �E�.�cQc, despi^E~9of �onJ�2"3]E���B�?.` �deK)!z�"W X>�=mO+ account���.Y| ?"�GH5fes�$W!fs Ib��t .�inF�1�,.a4ir pleiotropic��� �._!abs1 redu @M~97�itAie�qv�!&:��zFoe��q1G �N. �>� �}+ 5�a��v!;la�Oj ��aF eE�u Y�exEj&J&B no�!�T.�5,or��I s3<>e&�-��byL0 m�O�� powerfu�Gunbia�approac}Hstu::��)+!���echnique��al�+yiR�,"�1�5�#�5a"? gene�3><.�1�Lhel� sig wE !w/@?O�K/well-cha CerrMUo[38��9HIW�'�/,� 1-�a cri�6)��M�-�J�. N�6�/!�kor5 *� �Da� W>�s. ; a�n*@EWinvol -�*�&/3��A�� DA��7anTec.�?Pr�7onc� pacific� A-e@nciW [4&G AW� ��^!1G&WC-��,Cgu�N�dter�Hu 'f�'�C� Ttheu#i�^t[M1�n24�c|-�numerH f&Ms[4r7�6�7�4*; �}u( *a*sm�Q�< ��x� 2B�1� wer��ɦ0�?,-@qAࡖ�B� �K%1� *�� j0llA�)�� � z� N%��+rA�d�2�&�)6Ga)� A�-�Eai�@%��"M9 9��3NECI��2s "3<,2� a LC-i fic&�in �<�-��Z�$=�����ɇwDO�*im,�4*�5 *"� ��s*,~#"�"� a&9>Ńinsd gQnD�uFpaperg �E�!/R�Ns�(E$��yzOinf3<]E.TF[ �A���at2s.�B>/ !�woz�.4!��>rB. A�)n�Heda?p�G�A Ad�%�@>100sFr5�a�(e2272stop )E��=F5�� trun1'�PBj"�5 shorm� u 41];�� �֥ D-��5�Xnh(-� deca�*e��"&alG ��ma�!�&z[4"����ro�� Aj����7upl� eDp24)� x�7By[4�%I�CG��e� i� =It� !e�af�.*H.��!�-"��?Y9FbyO ut!>��AZ!2A@!7CUL0�&EM�ka&�H -lig!1G+�KP�.��� � h�&�uzz a�Xi23�GI-RX!"���full-f)3�-M !z2`I��ol��1 db�G!6duc�0*,Jea� cess� to m�IU��"m� �61%E�U"�'.� �"u��W>I�e>��%.~�1��FmB ��* #�:� ��B�>�, j�as2`2� E�J� �qu a�[1�);LBf�V2i+!g6�)],C curr�UQ�go farI2�A�iAe�LfXa��!/ /a&�G9I��is<5�s!�?=�B�QKAej.2�"�%.�$%8�\ ^*`$1V  Oat9�C��� .���> ��W A(z%Mcircum�Z�A�A5.rN on" ��t�Vof dpp����.�2P uptuCH�GF6o7i; Gli3� CREB-q��d��co*F[4�M[4�Ia*CE�!� intrinsic%�5A�su� � z� nTficAb��a��&? >�irY�Z`t6�mmA�A�I��mr;ś�/i�:Tt!X"�7sup�Z (.m+;Ngr6o�5 hood��e�LI�P%%Ma�:~W, �,1F�d?9! very�v=��!�fe} VA)eQin�-A@!�I���M�� 6MGA�&�Vn��V��3a[Z�hmZH aD\�Pr!S &pen up�B atin��a� � 2*J ��;dee?Y����+� I� ��BZ-bRQ��!Fnpro� A7b�6� NASP�.amch� !$>HD�\ �de-,s?26�4!�'ol�&UOm  [4CM&GHIt���)SynMuv BMw] .wmx.�;[47(nk!ny ("� U'�D%�"�( 2�4:EA4a polymorphism�.|NATH-10!1n-�M f�\,��Tv5e�-'�0�#!�>qW#Jm4�Aa broad�'ve%1�m�dcE�E#.��7unXG ���o &� ME�a�q5-��Dmr�0la�c.�[50��lS<5"R<����L b�C! �]a���se�"�i� "&&�enougct vari�!� �p&:�Q�'hAk,�7���/"k� ly59>� iwvi�� logs��1�\!ar��m"N)8[5�=QM_ �-J� x�.-�>� ������#�\Dnguish!*)��ҭ�wil�d%0@m&H�� puri�`  ���DfJ"��lme��*-Pccu�fA�underl�m�ory&��/���[5�I�Wcro.vV Yi�e popuPM�Y� subt��e2 ��i{M�0�archi��&�9&R�cvY���A��U�.��!dfaG;b?Afn�fTfJAq�2�e�Tr221 [53a�A�g�OZ��m6;)��1%a>et��t�AKq� R}Pt7\[5q2!��dB���!��[�u� ep!r�g��].�I"i,�"� A�6(!+�F ��in�]�[an EGF�+a�62� Wnt%ZL[5� �i�YE6���) s [5�WBe�a�i�M,6y orth�]!�sv�*"71:t.'i� 4 &y>�!:Ax�!o�ZPRY"ns-z9U �lmA��M.�A�"DE�-dnpr�gA`B�) Q*�B��SH'� *a�� �O�#b��JW-*�f�Pwb� N ���@�-1�td6 *�֩ `)�U*�<st H�!j�)6�U$)'n �1 [1�}��d!{� B�R1*� �AmaCqJn�Rl "/E�́F67 ach5��6&pR:3%�bm3es-Q��� i��Q"�(���Lm50ng -�! '�< �B�5�"5N U��!!B;��w\�kof�A�I+E�"�J?&$add� ��[tR�m.�>g&� !���6ng%�� e�i�5��i%�C*V�x.�A;5A�2/�3h`��Jq(rF3WB9E�/'�~���� .xin6_8�E%� 6�9���"'�!6�"2��G� oppoDI�� ��.#$:6,.-�9ة�& Hfe*@Tq���� (��0#BZAI �"����.�[5?I� e� %n�i�e"�+J+I=wvh\ o unc1��i�vA~\ IT� )�Y�)٢� �[�� weBG/se7��&r�; ��ra&�9_�R&$���uM!�\��0�<ble�25(2�pr:)9a�tT>��1�s"dm�t"#id1'*�a&~)��a�!�/ ./&'a���7oG4 . 5_4.� -b�(.I_t�7r�,�)e�is�!D"�=�t*@�9�9��.�(a�c%}*x.�&�Hr�1;]&"A��g�B!O.{e6(]bNL �<.�qM�5��{YFOG-2!IAS7�s%��( own-�"� ��.� � [2K�W6�!��x�-9(Cl��g A�t!���Lo &<he2�n�3B���)/�^*F�yJ66_es���� male�3q�&�S -�V._'_q{2��i�"�b3fD(�b�labor6[[�^6��Q�ap�@6in�a�� �d6u�7We�1��mut�*antagon�c� 5i �eaB�6-�elpa��[V��c� � 9P���)m( .9AU���!Ewtwq�|ina���. If 72mE��!&q�u TihI1bal!��14.�nd� A�C Q y-��6�%#%:�n� ~s� F�F2.�q.web!D ��� �� �-�a#^i� �� rtuna����F�)�� ,�!J�O �!0�HP&�1ru"�r}�ye ��(}�FI�&?�&�.�. S� s"%1)5de!b�BrennOC6�&Wi�yp��YT=A6Z. (Jnt] f:�U�!nm�1e �6n�I.9�A�v�1 ed24ts ) ?�0�>m27))�1�.d*�Z :!rF[( P�berg ,`4s�V�-uz��S\��v56N[��~ ^mil^A A9�]Y?� m_RXXcE��XK�� e!.- e le�w( 7 bp&l-,&ovynucleot�f124� 1250AA&!d1�d.rer[&$�`ua�V� %I9@�#"3X+ in w59rn blo� !yno%1�2/d�-UA��oES�f-� gS /+ +"EG�C�sed 1044 E� , 316 Cby�/, 2 �82| �j�Ha���ofMz73 cM �A2���6�.��:�<2303 WT , 698 Dp�11�10��69 �TwoUfe�U� y-A�F2aT/9WiI��b n^�Ye�Z�&Yx!�5�a-2/d}�6�;30 µg/mbqi1(yl psoralen�4MΨ ) foo��UV irra�&��[6{!or P|5% ethylO�Dsulfon� [EMS!v���*P0�Y�fer >to��z s daF2)��nF1U)T�&?&-!���Eg �f$9F1 e_U%� E�)�2p26 ~��0} ivid� ��ofA greg} F3e �2pseudo- l%�a5n���}8EX�Mq� �{}!)0n�NI�Q�l�2�!��2E�%�)�: Se3ch�;least t0ViP�lU�X76)`S�`e� "�k�s>� Cd�.m*�f non-!Hr��2H�F`.im2[�X]�*[HK104]:�AORl�6FkjQ . Af!)eXi���VuK B%eإ��tzL!|�]nd sc�E�`4[I�0�)�6, �' o in:S4B [�Jwww65 org/"� . phpE�6�D69!�nd�; ( dsx?)e\pr�>�-�P�r�k�1�h<�*li@�5~�>�V���Gorm��inj:n` you� ��q)& of 1 m� �.%p� QO){�<�&J@_be%(on QIAquick M~�umn�HQiagen[ !?&�b*,� y�����_.�b97BCi�2�^m4���n�Q$Nomarski m� scop�w�a�>,��� Z4�L4�=k�!mm�& ��_��R-b| M �G.�s!�� m�X�yo�)T)�re ��_run�x32 cycL�1�Bq42�A��$5 �b.�=1 ar r;l�z+�wg serJ7diCy�". S.��!e�309ͥ@� pic4?!\ad�(to ��@l 2× SDS-PAGE bu�(boi��10 ?ur.,aS!.i.�Bio-Rad-i6 �!pIIf a*�{�Floa �ECl , unBJ�$d�5bh�mT�!���Do Immun-Blot PVDF 3aL�#162-017� !blo%e�5%��f�\ilka, nti-� anti$W�a gift){D�8DX� Zark�6��nd*%� �81∶1000–2000AFr'C,2qHRP Go8+�rabbi�?�70-504 ��.|:�u �6�)@ Starochemilu�sc^k2t��ņA)t�U.A�A�[r�Bof ‘XgDOJ��7 ’ , ΦDG�qu��tAYex}�A�}.�Uwr geneJxy OaC�"�&���"�?Osth(,��s:M� &s�c�. ness��k{����H"y@�~)ef�Q%6i� te MA;vm2���L'un�AA0�>;-0h_1:?rarK� easua�X��&�q2 $#c 2| ΦE A� ΦAR overvh�4�Z+�eaP=app�2oy-��� ta� @CsՉi�|w8.���-�Nic*�G�>�~���� ��8LOu� !,;0-�&T(!���!�.OQ�A�v g�'5�-����R}�YnS6�on]`i��%A_ ocogNv_ c)�Yi!NOi��Rch�$�theor�%�a�T phys� mea�!��nQFi�%(. HowEn"�4dynamics exhibx�Let�)���rconnjeld,!st2�? Ans.I� ques%}Si�to�](b.|>A�l�>�|v)�q�,m@�!�� iS. Neu.�a<art�6A�6�;by richl1tR�-AR�5*�gultip�p� ��] sc�%� �<(a: 7a ��$$XiE, Y.IIS!me&$}!&ƀ, � . Ch"�<� �al��AMG"1^t�R�z�/�BU�4b#X!�E�saT{@�@dde*n evalu)>ex&g). A��Aatt��Jtu� ��E�R�a{iK�� co���A0�&�)( Q�E�ՖA%^���nt)Era��K(�-?��wh��J�&t5Pr>�,=,�6 $ ambA usl`��i2 Ky e ba�1*%A(cM%��=\ S}h:��a�`�� R � �o� Ty�h� : �{�<:� �-y�>V�du>M�uyye�BV�iX� �)%E�tM�(!65y�ri�,Q�60As6^!�ac�i�e�(%� me�c�[� )Adam�n2�|5 � X�. S!al�� �Zwc"�Y�Y�n G!�abo27e5Y\��ump4)�> var���a�"���k'Kp�0��Aly��ev+ (�1�.�6a�2s�i�V4 rece�i�Ia��+� at^ ��, e�e��Omo��I�%Zs`AcSC a[/�,O95�BW�eu"����� y�6[ ��6��lyVCEn$a��0!��G�$�a,9��.-�le giv~:� !%�Z�e��5���:oGo5�"� ��fe ��!�a9)�6� �Y�6.��� C��t�*@ ioE� globem��o�qAccn�!#A�;:s %r-2>�( IIT�W�J y��6 + B.g� % �2;Af� wouf,�  v�.t6d.� �9Ax�-�"H| clai'3vi��|p� r x!tir inc� !mi/r�%� of��>�Mt(�Nw�gl��‘-ca�Dty!N,2conm�Nf2T5�td^M`2�� 43t��M(�Nkz? D ��8�@�Also ,M�(�uslh* repeJ v�/r�tk urb5Qarbitr�)�"* "$� f�K[� � triv� 5��Cp�'*1�oWe 'Buz��U�If� ������a.�!du�|9"eE� y�M�� 6��rete/�!��Gr�!c����`  " h evo�~VC%��p l��.�. S:��1�e�h.7gu��(Ym*o8ne� �� �;��Arto�tofqI&J5��&�R� .�i:Qa� )'�"�a��".B�*ly� +R [1�4 Impo�� ='.Oa�c�uin�ur�� a$or maximum� rib�X]�a�n!���vB.�yU�Q,w.D����"f���E.�9"� s!C�A��@m�A� 1#n%3-�,R� #;�9r.�%�� ��.���!�. rir���!"V:;2ljKq}I1�CaBAhA�a�i�!�fu5dh�sI�^+)���� a�� ��-p�Cre�s�%| 5]v-�_� ocV FC*��!ytyp��rinu(���� �� �!�p�B����!�ur Hota�fouc"nor.�!�*�Zk,)a��2H)o!P@�7Q��"6 a ���V> w� t��5a�w��ve1��ZN, (�empir!K�� I�&< ��im69 Ie1a!��stochasO.1�,]�2-4�� a�a�>PA�R1= K-��cfeo*��QCǙ|OM�Q�Jin Sh��:�j5�s&�!:�,a��.n4!��8!��#62Ie { }8�� io� ��.�es�[fA�-�)��~� �'�:�-�t� �"(le�� M) F epoc�&hR�R�stm:fa�/!4���Et� �a!��m�eA�pa/�^e�z27� A���/�c(poo>fma&�="J(�i��'Z)�*� !J�,1;[��ConfroA��Na�r �� �� �M!*���( erro� -�rstC"H��VypR�?d%raf"� YV9L�I 2^� ;��A�� outa�pf(i �de����.�+A#g+�� nalo:� n#d�8!�B�w�6A�e�! J)h!VX3{l%7M c���;y` P�Seh�C�&ifequiv'�gReD.� ce55ow 3��� rpre� !Ss�^��aa� i . �.��~�1�֛&.:� "ؐ!-R��s��e{~��`emG,qA?6CMv��&e a=5|/~IotIv~�$7 i�B2.T�y�H!݆�2/�t_ es&� 5�E%{!%1.6X!��A�!K8�a5' �" ��VZ���*� S�/"���>��lF�?�@� 2�"�M,� c� Vj� } %Y agno�TC�� / � ���/���6�_&v�or�Ic !�\A z�=B|e�R� e�aj-�E ZQ.&R;� ��c, /i*l�I� *]A8y�!(5E8-&-�a�aA��r+!2$William JaU)[19YQt� ��!%y a 5�.�Ez�� ��onj��{ c�.g; �$lsoA�eUgI7*tP!�:N��RQ assu�'� h-e�l� ,xXT �in-ɼ"���< z՚9�13r*�a5�� �Badmit� �ZA��e��PJ�>�@-moda�`n�%���p!�} egor���5�I* :Nl-3K� �� oi^�o�-"�mav�)�5�!��5��q�� !�motor1Yr s re��A�ɐ9�%B�r�=�*� �� ^)��whavQ2�Z�ڇ6~1�K� !Ic � F w� ``$hK 2� �+e"c� 4y��N"qa&ng2��!mq.cW�%B s . �� b�Rupper-!% le�t�d%�eI|c te�dom*, I%��Tl�&^TɦM��:ra:Y. M� W �!J���-dimenE�J �U x!�D!Y!�23squk 1of zeroXA `��-J�qwno�Bby-#)_�&GnO‘det#�s convA�oV* logarithm hAE�\ �1���L���� ) �log fLetE a>`��`s���'pa&T�>w�=]a"��d!ityh0b.m�NFIR9O&� �,%.�e�B�%{�4s�`itri&�E0-RZ 2y2A�>tyi�b,ful: (t2��W�� ! � o_A&)�O@�+ll-���v`&��9!A_b�D��qU"� bW,t!~Z��x.�r�9m=�� a\�+y ��7�. Eeꖁ�e�`slMer������i.by-B�iifax �B���)r͒0*U:  . ( N!�,&0ic! , Eq.4H(�)l/A�R ?y: ��%�fΰ��.�1+�M&�AM�-a�#�i���"�+�+rox��(,���!fh$ .q� �Ur���}B�Fn&�� d&:L�M&�Pe�g�^k !q#�� � ��ށ��Lebesgu&p � � pRis uphel�9en�!�yiscus2T:!�)a�wri-�>�1�[XE�� i�0�"�C./B9,*zI��VI���;T=� repl�Ogsum� b(� ����!5�5.��A M�a�Qg\ &MeT2�uny�(��o �]A��out�+of�&.ML?2�w� be%t�5M}us�N!m-A/"T��M:�?2_!C ymme�X�M�If�@�3^��u)��< 10 )}���� Ht4 *�f6 l&y&;�Bpq�IW!S*�C �� Kull�6-Le��D(KL ) divergi�v(�9)q�!�d�,U)�Pu�rii�$(6:ŬM��s �-��� rF1�i�hO!jqI�-�uR.}?.a��!A�R� ge�/ �v *M,&�"�^k.!� A& � R=�J<1'J! C�t*Ge��9!eAP�,0$�:on-�l.i,E"� ub- b= �4&�t�E:2� �3ec� ��{��a6� �-J���.�. Tim�(-�jgYakQ tegerQM%o �%rsj�".LqK a�!'}n�� R6A �ɘ�F���P.;�#2?F�2M>� i"jK*�� �2- ��e.�F� �I F!wk�g -lag��1� IHE�^w�9 view� Re�$���Es�S#.�$i�e!���z:b �5[0�^no-�A���'� #bMB#ian� ��w�7�%q<.)y��*�Q�LrtA >{)w( i/�1�1��A��AA� pen: a� U%� step��;la *�*%V�Ts�d!�of!/e�Hef*. ��� E�� �moq�ur6�aO.&m jG .[av$�8h���.)n�6.�2��arB;�v86P$a�1Mh)NH�ecec 6) �e^n#AC� zM�R er!����of��� ��( A"H.3 2-i�zu.���1D� e6c;mn�.t!���^\��)pYir� '2�J /ef�.�, ,6���B�%A���źe�`o%~��,!a �".1� l6� K-��NE>x 2�<r �>!�^��}}M*w s�( Bayes' rul��M2� ��MB%A9ultW ` .�r��3 9y A�!*�����!�-3b}Ѫw�le���)� �Ui_G* ��1-#�6- ��9.�" �srP.���by� y .�<�i~� p)*�sJ�"N�obt�Vz�#G 7"�"�:].z%,�03q)�42�*�-d�T�R' lR/�~�!�7 �ivispll9�%�s16!��%2�>Ife-3��.�Cg}"��c� d�[M~� Feo7!�s2!F�� ���.T|?p �b�._V�1U�>�0�n.wiDl 1_�|��$!-_���(Q.��i�9so�z�w�cv9��1&2�QC*x �1�d�"H a&AZ�Der�!����r��Jm�no�%A5l" MP!um9�� wire�/)���h��a�>�rP�q"�au�>-2�&` 5y�6�[ydo�.|.we &�RcO  e%.)2& �n "�" ';2�o/n a#$K/m�dr�O%2��92bhcho-0ena�s�+p�", �v=p!� �!��^he�l\=���+*7mi � . ) &�?F�2���Xf;�&V%i�e�X,�)�aoq�KL.^ !"AHR��f -sV�a�>�wX .�&M( MIP"� �Fp2e�Uiz���fN6 � �r " 2Ni�w���).�|� ?�asGS-2t&�+� 7؋.NB%��),%]� ��j��k)��s���<a .ly im�Rd-a(�$�W� Vxu�R��� a� nq�ly !S�E[Z��:�en�7%WZ8upKdU��� Q���weS@� inim1� �V()Z�:i!�`�Uq� �/��z]oug!\�l$`dd:A����0{|6�3�2‘%J&�-"n)��!!Q SJV��ViV�V�Q�1( g�U"sg !��"$.�ELV�J� ���2 6�1\IN�s!% nish��yq���lo� =�$AHhUAl%mWA0"pL6 ,�--�6�~�7G$R"T� ate-*�2.>!�i�� .�j_�C�Nt2m ndm;� ?]R��a�l;�V��e�5�4�Ge�m���.:vR�Hv*�is� b&*1]Qh��"*l72� ��� BE+�+�%+f�wM�e/'�h�H���3j�'�L � R�|2b(lT�r& �ni �6 Qr �.2�aA�addA��-�*? RHSa� J�AW�h� �()$:�]�*���63"Z�f&��.�j �i�-�����*��a�Me"� �!�Gop+q%*\( �8t%Rez�,mpact" ��R�bo3.d|�X�/���1!��`V�w{ r��{"yaV0m��3!�r#GLx-�(�f�_9�:(!%cD !�5S1),B�6�&���)%b%�6c9�L1 ߡ�>$����[r}/�D �Ε"5mp�VEe!52��Bk*c�3t��a$ p��#y�r@ j�]+I1�2X'A���xkN l �6-Y2U�H6r&����x6?top%Y�2� > o x%�{:� !�C:ueh}�2�!�oA�2���!n�.%T�?�. immI})+p�Bay���a:Ts!.�Z�A�TXge�E�se2�!r� !��],�7&E �')U�9&� 6�� 3�Aa��r��r�ց.� u�q��InvB�`%&�aMn��'! E�r�3�86~!�!������%5yq,�u,'��(0j�+'�vn�i#� 8a+�W� �ͧ�ws � �!<�r:s �D/a�7 I����� �k6-��!�Q @r�6bZ? �}�W� �e+t!jMVAR (�&�*�H.C;54"W$5il2a��� v^�]e?��!e+tepu;lag�y*Cllu�!wi�M����� �%R �aF�"v,'�e�OZodq�q�A�C�EI!��B�!:� A�!�.j�4�9a�h�3- �Em;Y ��"t'��+e!���� M H_c��mbm*�!�/f�+u�$JF2 (6.��!�4- *(:A��&� R?�[Oai�Thy pea@�4]0�H�q�C�:yR �^_I���$.�c"�}AT� "*" 4!5��V�o�I��.�):t!�)��&iJ� �1*mi� 4n)����<6Kq�v�*�)cI35�Q  _)�A�!�A,(U�!)���.b 5 �cBqxiPU n�X��JG;��#pl�6M.�p:(L �aM5?�aw�#%�.�" 9����$�O�>E6�] rw�6ver-a����h a3��D�� �IQ)�����Re(u^� ���O6��L)'d+"vM�z��s�WjA��g �90.J� ��Uac��|����e $R<) r�&�)���5- a��!����$�B"z � m�enp lon.$bzm���;aaA"|�$1=].Zvia:0:6�fI�Y �-��lcu(# |y.e�+&� � x���!m�V%�t'�.�f�'bS�,�M& �5x%�_ ��ip�.Qald!ten���a�theqY�vEz��Z)�5"WZ���:~�$;v$=~-�%��he�s n3;���#���id��f]+q�f�A�D�l�=U�X2/g�E eG! a/"�>o�8� �>�����de��[͖ rs� rehP�Q�n���F].�$a�b��21:J��ya�FLof �h) �,A'4'�#er�#*QvV]2Eea :)�LcE‘res�c6 #7�s[24>�sB>�!�.W&�3�)�~r�t�R�A8"���P%�j ��!e�x�o�� F� *"�!\-,��v#5A��, "�l ( >|5�$i �%44W6w"�/EG��u"8 ] :�"�5 hold�'n �,ٶ2BE��aܡ]#1� �/�A��: �& |�'� �4!YY%y�6�5�i�"�-N��F�Bg�+�� �Ƒ��]b!�-O� A�� �iip����$I$3� ��V�!I ~�1aa1�5!)1��!�cq9� ��>J �5I�aN�� �#*�~"[ADA�tsU.���%�Yկ%u�=�\���l�,34!:� �F%~�*fGX we��+�'� >h t"9�hU1!nd�.>u<>&�2-\!���y M!�a e��y!�bi���)^&�*� ����,�ua�5b Pw u�� �A)5 y'�Aexab6X�2R6�o1-�s�1��"rq� ��%�3��no. A�a�� u" c��Ax%g6|�B`e�f�S�k�m*� )J���mh ��� jP (�lai��*�.SfE�eyie��m�abŜ�r �2=� �&!0`�A��� !aB4s;@��e^�8�;�"� 4#�BFW �Jm&* M��fZt Q�8 ��o&x>� er� >.6p"�+s>Qc.c%>og-V*���!*� T"� �!aF�I�L �.���-�E\"MI� "M�&n�8k/a�O_Wa0mmW���j-�la3aIzv s�5&�60v_8o�w-( �iA"!�#���8ѵ���satisf�"I�A_&�Be.�(�m$�� �P b��xx�\*� !HvYSh��/%Te�� in��{��1_E8A!Jg8��� � 2a �B�gb"< :0 �?j+F�F&� O9��WR.$FI���L,��N!te� �P!�B6Q x3(]1GO_s,us9(� �4��*s=�\}�) "PB�>s [c�, >[18� n��i�o̼:q�{�ĩ��/*t�%.� � �q���,, re-�p' AX22–=c1� O 2�"4B8WZ5�;vyuGp+ sour��in.g 4R � ./B�drawn �e*]�"E� G��Bnd�') 1!>"aa!~#N 4"j%�uiTřagire�7�c $of Poisson Hspi�E!��>&��;^� $�%25�"�V� mpl��-�� s-o�&�E�ga#EeK�H-Q�Vs;� ��Aڅ�T`F 8*�P �aMT!�A�q��� M 10 t�m� 3Vk�pd�,RS$r�R�a�Qq1� q�)�]X8�[ E�on&�܁iaK�x�5`���'`�.+��2�z%�8_�2"�Lez�]�.�-:8� ( �re �sA�perturbE�’ o)p$system ) ,�se:�cannot!�obtained9�ly � they*2'by applyAI$Bayes' rul1'a!B wardq�8al model estima!� from\ Eu ( i . e .ꖢ:�=�9^)!`yZtr,M"%.!+does ! M,2�b-�, i)�absencE�(B�) .�M�can-b�$full joint2�!5 �andUkdirectly:5.A�Lparticularly easy to)� %]e� GaussiA�ssumpaa� ThisH�relevantm��]�be=�6�y�covaria!!matricefItde�possib�sy��6t��,a generativeM��q[a nA�lizI� step pecif��,a`determ@ M�|=V ffa�vaiy<( ) across a min .<bi!��  ( MIB )� is s �e !�.. Tiz� �(1kalF weakestaUkF !�N2e�ce�bias to� s.|� nsis%zof sub-Q�of rough��qual siz�_Wit��)p,�s w� � divideU�@into single eleme� !�u� remaa<r~!( � , leadA�to triv�Usma�eE . Oi�eB h�0 , it X s imAg. toY jFwy4:in ord o�owEbA'2�a quant�/=���heE�ofB?as just cribed �!�aqt� ��. Our" �~ havew�� � )�{continu���a�2 of&�,�� ( ii ) hiE 2�!�"� of�sy ; ��< finite��.J]th� in.� aros� ecis�:�(e were multuxs0 ! ilar)�EQ�ed clVAFhe trueiyum� �QhadasA4It&�E2 `n.B0 �y&� ar��yl& )iA�e�� most!Q2�is nume�ly��� ,. Nonetheles���embede0BjS ��de%�!�of��lle�aA�v  phys�Bcg o�gme�ed) *�s2� valu� na;� � en�$!��arbitr� d%e!1��lpro� involveda��ׅ$he�� . P�� �%�[gr� .��/)I]� ]QaCex%�aory�e c[n9~‘ZdthR8��( IITC��Accor%�M� nl%NtN�INh��� tatu�a funda�v�a��(uni��� *�to masAX�g!'1 like [14]���yi��!a �9�V��-$correspondm :5V!L)#��g .% ma ,�  anesa�i$deep dreamesl)�a�� �toMYpwakeful%� . If�4�����-��,�� ��s �XP(^{)��%�- �  trah ��[11];�nIl 4ask ab-�9A%>Ra�Mper s!J6hi �+�eWo5{a��t�j�  e-��q�A so� b%7e�o3Iʁ�s� u�s view1Z4 �2� �'*��n turnMjimp� �!�>&����uo each�iaepoch�qbS&it�+>X��fu)�aEwnl -%,Cif�!�!a } ste �!.� �� �2��h.sby��-�itudee�-f5 $ency oscil�A-he�� EEG [38�@whereas epileptic"Yseizu�a 6}ea�inc@,ed synchrony oalamoc� �I�s [39�UA�n!#هsA0on�E"�!W>�"q!��>,�.��ba�� R|E Jl peri6%���a��59�A�e CaY �r]�Ynt�Eu sult�w make� .���eZ#B��e � �s%4�!�$lK �D indiD ! Q�eF, both�j!� ve (ݟverbalQort�>onfide2)ngetc .�� nd oRHA�Y3 , widesprEW>�N[40A>I� �*i�now2N� `l m% ZY=-�e�.W�a��i�.A�&9 way*��16^conu��a�A�!1Pih�pch��‘���yA�[41��‘ �  lexi !8] ( see"C% ison �6P�RE�An�jor4  feat�#� as<�]x��@ � 2iquab�ideu ��capac�=(*� lyako��ia�oespo�on!AEF�MI!)or?c � �origi��6���l�byungI�� llY���i���  s��rec�.U�.a�6�*�n'a`�YtakH�.� �%�.t.*T�2�!B� q�t aAzpur �am;�;���N&?� ��U6 By :!�e�re�ce!���w.K&ur >� ar"Su�ofE�c�r�/%���ebc.G�)9.o^�)Qre�z�E'�haa|r�!�!Vef�b1u�-���y 6 mo=c�, alig��lly)a�� � intu+� 56� exist�IfJ� a�deserve�m� Sr ���06��WS,or�ch�aXpA!�NH virt�ts exq� e 6�� � ��q.�6" MIB: tf��> ains��h]�Ey�2H���. A furAX G����e%�I~�\insL u�! "'e� at\siey��fa�� se~ 2�������AfV�.Ř�e�qu o�fuŦ work��a&� %�" cer!ra��!�w �c�%�r�cbe�Y��qn�'a�.B,��mycopic� �vFze��n��it&w seem*���n�KI!�ctY�Q"�"�� t!JJEB| ���R6�or�gA%,a�rQ p&+a�E! c�`RL In� word!-+:�b���a5cc� !h��� aa�M$����I�qS�A� laimM [� lNgh `cl velop��' ��id!<a�J����ge� {)l~ �&�1�a3�=F� ,play key rol�-�cogni!88 ���"�w� ( , re poo2"sui�tva�g!� uA<t���r�F �c��� ut�!0�.��%��r 1erm��.+& � . WA61��Qx�)Z� � above� !Oo9bpr� 'in1��JA �%�HaG"2S ��is fram� � ;MD)6�#."$dp�a��9r�gg!�te�le hyp}�I�)au�A/synthe��%�i�a|!Vao;A2Q��2�FE�es�" >��-modal b.� %ercept9categor��[20T%A�on se!( d�makL) [21]a\6"^�W�iprofitab �(�� �(AlSa�s"O!Eܭ��m2 (%56|au*z�ee be)�brk�7%�q���$� g%�ploy f�A'b� rdugg�!|)s �b � orimotor�g!m8in rich environ�e[�+9s Gal�ZSto��jEm"� situE�A�fac�)���a3ve�"yA.a~��amo�famil�>e�aim|2�� ��}e� col �of�!!�4a�RN Tw&� ( -ڍ42�H�,�#brief4 ummaP-E2si�i��.��)4��%"�� i�ai�eAnt�h. C>��f(�"i �)�nd��>��*.�. &5 beA�"u# ‘GB'r���(sha�eCaE��if m�A���*=� �1�c�f#1"EY KP��� 2j�� �those&C"*P  Av; thusMl avoi 'rm�eB!Yble�'� � �(!9�� �BMV, Bh�a� r,e�a+�flI& �> asse�%3a"� �.`e�an���r� �.�^h�-of help8R&A�� of!kbA�beyK.Ja��:RP), o�� e.vAT| d'%�A�� b� ) [3��[43a�:4weigh��)R"�5MtY�i�A["'#)U�)�2)��r�$C HighQQA��KlD > \� glob%&� Gir �eb(a�b�"ful�r;'ng9%�s'4)%�a)�sa�(�0ͥun inct�5�0'�� rv0 u����>"A/e�A�.�a�NM-�12)%�"�*cn*d=�(auto-�(�,���b^sa�b �+te}��&`� a lo�%ᧁ��OV� e�^�[houghE�� E�et�2R�� at�f� A�strengtha]m&bid�.��!� link"��(two hal��"�Forthco mw�+� a��wZ�Ma�:�. N}4!P t��c9�!um�averag�� 2)�'l� �� �� �Un�:�ŝ*�0f� %!�b�,�y^NZ�_R �S؅_isy��M~m�"K !zM�le�4�j!�#f s�#�o�&)��'� ubK . ( Note:� paper"�a� A�&� �3an error��Q 4AU*�,m�0x�&a-�R y ��J#� �<5 r�1�[4#*T.t� ear�v� ���.ak*},����ofA� {  [17]"s�quQ,ce )UF�a:‘N"ferG(�$ ime-i��%e^+�mF#)��owB�� � MlyF�. :�+� ��by�:����Pq�F�(C#�Š�v+iAp"#' alsoo,�t\�.fJx��(*t}"218+�/T furnish4 %�.��=�FP"� >�2t J�}se)�Ew toge�sR�Y�2fo� $[ ��G a`�4!Au��C .""��(ee�8tot5D*ablisin5or���terc/c��nth(&�"converg� Zd�&  . Ch"+"�c�I�d-se fiel�+ bre) �9�>capF J� �� /t�1�3�-b.B>ka�hermo/ �thA [45]eBN�,-�a�=1 hard' to p��5�� �).1h6R�)p�7� �&�7>�1b_ .�s�a�G� 6- Q*mod� E_��:&&��$��^; !^�1ptra�!o�)Ɇ�)�==�x %�Y�e ,!�*Kř�nc��)��et �1 v�1 each <-s.=)�x' �sN��se [46�gIni�edijby Ay e�I)�) �E%� �� e > I vid�"� [22�[47 /%1kta<g�9� �)�*�;�a0P�tho�0�hemat�treat���"�=� geometrlg7 ��QZer �ZELl*�!�s� BTI,��5�5�d:�� e grE'a�# ���� �p"�qempha�1I^�K��ul��_�=ly&I7*�����s,)%��6e��F� s�$�;u"2/ improve!��&�Zi"�of9%*�_ �I1, s�7al limi!- 72 . M7/pr` en�)_Jkd�#"m& A}(-t�TE��cu�crv. Add�6n�?i���Nnd��=���/:e6� �9pp!>� of6�e3)\)�.�F*�� �6dW N-2�@�� e K2a�$3Markov� )1)� "�$. �!&�3<�*X���d��.�"E�)%)% ocha(��!� �e�F2d&A022!%c7f�v (�+s plex�;���Cs)�s��Q7+ especM2,=�i��d{&a K).� [49�x5�'F�%lu2!%����""@�0�uM1.~po�&'7$combinatorV&�=o%C��>A���"O| numb�5�6i+!�Pd>�A6��oa search x ��� um2��%�mit����h�N first-,z�:approxA!��)+A�խ/.w�4�;�� is�5' drawCM41�F� acB 4$w,$�(adv�?d:�techni�!��"u!�inF� ,��gDipv "�; [51]pkerne�*� Rega�2���*6�J� wU8em�!�']"�Z %dcr�;!�me�>ndn���(!M�� t�)H,�wIr:DI�uyw*'!�K( ( 0 . 57 )�"1�-(�&�I!s!v;�jG�pl�� ��I. expe-BZ�,� MVAR ( 1 .� �36g�- ZR e� �!� ��&.g~%J|>@-�co*75�!~ s -�k@C@"��G�H-��B0� |Iby I";I@n�JheA"g)� 1�4!+0):48 ) yk�V 5 9�:E*symbol��o��@� . GKo�G�7, �� {JJ">��k disc�C-!0 LyapunovE�A� �3A�xA�60�n�yEq �E�2L�.��a��w�rst�)]��,B'YE�to(C-u�!��,6A�T�8w�2^J)� 15 )O  62 ) 3 ) F2K�!�d] c��we%OIJ���jM�F�of�.+Hq�ed�( al�� �4-rh�a��z.^� ��E�-�&�8!�siց�>� ces:1!'�Gam��K^B��� ���+o.�&@block&om"�2of vect) �e��".?=C-�qu9#�J�2ne�f#%�.0random9p,!�e�3!�5E9�ala� . H%� �a�E;.�MYa�&A� �� �J���;�l�I; �7a�Q2�ul��%�5/�� sufficienw��!ccŎ�a{^�"�*�0~"�G' ���.C!-�a� �2A�j ��^1/A�a,�pur�as�%�re�xct atte�9A�]��.�%w�C>:��l.p"\GL �time;RK 2�7�B_b� "��l�7"T�Aa�� �q�7�)نA�B� z8g�J}�)�aO�H!n�-la%9AJ�.2\5‘whitisw sour�$�Q zeroA,$0 d vapEk�!���-���We ign4!K]0c2� 4 n MA ," QmoT,r ,��� �-���Vif��iRroor/��GźI�7�|lie�JnG$$unit circl�;�$a5�S*�"�#��8u)�.� A%BJ� y�%^!B �-x��CM ��%_ byB�Au. S.JsF w �7UT �y �of up!�,M�{ �"8fact [!"�� s �`e J�-����AW,ɶ�� �� 0�!�=�]�e x���mf?�mF~ ,!C!�ogy9�,�%q �� u�+wg � �&V�a�>G���9�6vr 5AE)+t%��tu��&�U�,���� �7�k �U ��!sh�s2�=�J�u�� q�7 2Y� 3�  A� �3!�.n���"qA�=of RhoS(an human Af�G4n trypanosomiaT( HAT )�Uganda r;yy"�ij�~cer��'O"�bPlapI!A Gamb��� diseHS. R b��ex0�2�@4e#BEN tOB�h�roSHs?Aby foc�o *na�E d clRce�� e�L�spa�" ��X �On�H< stud� �A��S�'on�7w5�r �"Yhip"���Oc� 9�!�A �so ,n�� i* wo�J)��0f�Ned��U�*M�ss�!A�he(%��JN@.)area dum��in o8��Ui�'� &���� W�*X6E1��<�Sl���+(corporate uA��%�'!��%Oparamet#&!d��=!�*�)app���� risk��L%�=�&[2a�� a~inm"� iAD�Var}�*AH:-PY�ta� ef�~=Ae�V�^(�i�*w�"Aa}dem�3!t}rig~al�  roac�El��C!.�'#�Wt�-�ter�&�,c&�Xb!�?NY1� Gc��>ll0� ssess�m�valid * Y�U�b5�(m�rob�IUL �!kprX6w��teL � A!3bstron�I�R{��]at:%wjS� a�("��e�|��u�a;m��ɴndemicE����D"��FNhealtG.)�eZ_��Q�>fF��<�+a^����@�1gm�< um l!tsurfa�@emper%<8� �)�i�5�RI@;t�^PV.�"$/�-Q�z'��T2�G�"09� mark>yfa,B)��of4tra(���inu3-:2b � aN to g>�5 policy��Z� p�\�ale��es�2&rMZ�/�%+MM� sick�in�k. ATgeograph7�3� Y��KAso kn�Ras�M2w�/!HT"! $a brucei rL en 0 aras�2n�[ u ^JZg% Xa&�3belie�PkveT k� 2� c\=e�o�/� � rt!� nsmi!Yf�1-�s� � ts b���%SD@e 1980�9r{� -����2X29�E�A�l2 ����N�[1]–.8nar�$*$ z�'(�=iWS�iBD�� fociAn1��[�BuI� EU!� �t�� �e f�N ( Glc n��pE8�Y7faZ if .@��!�E"sp} B=o"��9atGP�<.�two (1��1? � six month� 6�_ a�#N� a�.�2Az rvoi$W� �:[$�b8T . b .2(!�d%a%��9�P �nr�)�KY�aI&nq�{ �T9sGt�*e��sA�D�.,%`� �z��yol)�%ia�!V5�ma,ahsSdiagnov 9�%[�&reg,,w\ XSmpl�%�]+�� ledg� ���"} � typ#HAT; .�o �7th we�U�#A�6�  outhH�EM f�:u7 �wS3�um!M!60sub���%� ratM�5 �# 95)U�'A��9e.�>�,>5p�� �5vBt��Of�nsA1,e9�%�sM�aށ��navail� �f!W�. Con&�1,"�con B� !�2���w�,a�x(�]U�!�9%protoco#6i��� � e1_o9L!��"�* fail'Q.&�!�G�  �8�5tched� n[7�1N��!"�� j�.�vo�W!+R' �͈2�!K[4;#w>J,[%DI��aA� a�?FH��Tororo�*��!h 1984_ encou6@7K- ��econo- si�>?(�T<piY �begC .eac 1970�pA lacwre����4�in*'�effOP!D�5voluma un 'l@ "�c"( w J-��<sabush �2m�bAx )bRQ[�-�$1�(S&]j"� �,n�7��in 1998� to Soroti9�,%�at�!n  �� Ѹ. ai��� �R� � E�."V D$ ng ,��V-Ţ' � i&�c��-A3y� �ci4C drug�f�lT9ttlJa6�pri�) issu�f��4A>m [1) &�6�1�� �6q�%�$Kaberamaid�[d Dokoly<ŵ 2004F ra�T()� f�*:{ re91,U�'*�!\c Bm�4w��a�+�'� ^�&� &�J��c.�WMd docuAm�^fo�e� "d$of���6�Mbe�ly  he�BIBa�6@I b� 1m��A��12_ 14��T� {a T a �*� e5�L�6dsub-Sa�4nibelt;%�giof"��(by:�,Q�2P + x��� ���fus�dp �<@i=(��!�o r�5ine vegeMRhab�/wpa��%?!ͯbanME l.c�" wetlz/) [15�p1)3SY0��e�-a�,�g�M�vd%�s�<lite-devc�@7�!s�,Adf8�D&�&�)�%a*��H�Aon1�^+ inclgY=�c�,��ep]�  !� !��1�� e)P�' x ( NDVI;��)g{ 5 green�*"UE�@�tf�ra` , e`7entH.�8%�bsQd2�s y"� M��/�QO 2in,� lB�2:��1�i5u] �8�3M1Q ��m ��Smpe� �&<s."3�;��a 6�R� of�A�2�@6�U��.jf ��e ,-:�: dsd��*%!�;�e���. �� �,��!��an�7"��Ae6� ��-?/��tngi�y I"_�gjAf1H clus @!�aT3e�nU�!!� �2� ��RswampaY!(je�_�a6�!h�!A�y-џ] A eh� u�R������4J/�. B��lor�:� �'�n^8�(I� �^6�A��f(^C )',W*�9� jj� one-22I �.�S5�!U&t��E�&Ta� Q,� J���<��t�� , de�!�I/E��z�s*�w�8J��t�!2mJ�it�j,K��%.� �(t�'.�*A6��oc�s�( �Ewx.&?+� �aYu�} �j{m�4,b+S3)�(�0���m;�!�&�c�.( ��L ( LSF"asi�l  12( E�� � �!-d� EF^m�-eg !��7��f P&���inu!�#�&� ��a�9Ae�(�8zem�u n bo�e>��> � *�8.�9#in~2E� h� �?*Y5�b�r�!/coC2M6�:�KV!�Lho�m -� �*F`,g�Wl�-ve�a{�"Y6>>))�� Wln-�Vq����6��dat�u{��st�tur /�=a\�p^ "j�!m"�`�0d�&nd�Be�G�fal*n�ACsc%evalp�a3�yve�+����9��5�s �@�2�ResA�fo� Iv��e6�""�zs�tr]1g>(#`|!�)�EA s se!6Uo`"q��sa}� aaJt�f>E�r? ) af�!�#a�!�5�e�$,-C�9"RE؅>X�n#~��s did�*>e�5�*1@%� ;2� I��� ;<W:~K��X drn5�B�H��#mK�/6�#�%�$B$!] 9e���%l.W61�� !2#� $� $. $a��2�2�{ >�#*�#U�"��F���#)Ltrok �*Na#| ��!�.$48p$`%�r$2r$!:�"�/�� �"���)a��` �F�AE�`�T'^ �>[Mr&�W)�@Digv�F[2GFHa�F[2Craig� 2�lKaz�;�S . Noa]2nm�qre6o�h�pinN((@$d�1R�a�W# !IrJ�Fal Et�"Gj� �Biox>�R�{I�H�+Su�i!��MRFe�E0e�NU�q�& Edinburghf�s Comm!2^E��#?&)ued^� �'ri���p� Ea�31N�erPHg�2�-9 ��&� "qBI�b]�� ���"�C�sh�' of L#l Kyog"c�B��*h !Lx���(2 , 740 km2%�a*�J.(61 , 000 [3V!Um@;""*3C ͙ ���agr��A_ fishA Aa majo"�͐&� engag���2.h�a�z g [3zA� w�m9�6�J �Febru�7%�XI-1 4wwrenw8to Deca�r86�� Kp1#am� k �ss*��F:"K Sept2g<3Fj"�.de�'r6� ��eՀeR� ���"!�&6 @<�L��PB{>�4A� BK"v��#;Q79exle;Y���5)�"A�� 20%sR�� �'2^> jM����#��i�zaM[eyi��@"�X�pa^'in�1od�y�J�`fluid~ cerebrosp�F �/mi�Qcop�Q5�JanY�!�6wE�o�=E�Lwala hi6��\� nd SerE ->��"(s2NOA�~.L in2$iBV�geEX�bXa �|hzP�Y�GcGaH�!( GPS: G�0 , E-trex Ven�i�!�-���%P%�цA��$�1�+A�n:� �ůseK5�8~� c�visua/)�`ArcMap 9 . 1 ( ESRI , Red� , CA%TT��Adanonym�s�HcM��� �*(����ue�Nw!�� ��T&a par&�*co" ��4s!�FuYdetail*gE!� ena��=�$L倁��)� puVSkNP. N*�R�K-E�u���3�m�aW`o~"Mba�""�!�F.p�R&~t:Ll9�Nd%GE���"� s8re:e�% 8�KJ�;R&2�V#����ooE�;>�cd����� �O�annZQcy�9�=t3i)� ۈ��;{n LST;Zm!� �amp.w �&e&�aA~m�D��"x9 )c"�� extK��or !�4m�%c.O������&9s�2�"$-�RE[��+5��Uy���xGPSRPappaim��QE�F�m6��N�al* ass Surve�2=&!'&�� �7Fo� D��*� 1995%� 2002�:%?se class"5U����A[a� ���l�! remo< �^d (J���!�tAM(.A+S lay�"I th�W"�3lOEe�B�y��EZQ9P�^�^�2{1!��9�a�ZS�9 kil?T�"i di��Ai8�!��a FHer�ns�,5IA�M Very�aResol;�Rad?_ ( AVHRR ))l�T�-V aqw"��y�B[34];.*B!q!� �k[l%u:FB}3�I"uo ^ �H� d! . Te�4al5$��?l�#-"2PE<\\ ,ɸ��:nda�{!�c�$u�X�8on�. FϏVFk��F�1�"� �<b�:u�6.�35�%"bEȁ���a ݵa6�! �a�Ia-Bd� "g8�9+36]a� alf?W#�ar H�"�*r� �Uw� �Xi�)-�a�2WZ�YS -S%x�!x5pof�-"�vdbl=l)�&Q�.dPoutC�%��ZxL!�Q5_�!��2tl9L�� ��� M�"�W`+�]]#�'_.��O&hB���9a`Sy*����Q�  C&�T-�F1a-�5� V%>B=�Ex�?�\ � Op�9s� � oddse^io ( O��!ĥ����hT1" 9sad!sT �.T=��`!�.!7>�) �too �Da|ca?#mw�=A��a^%��|i��f�R%tYyUE�DId�5 x]*�� $u�l!]��1at"�Qyt Ht.�O�F� GLM�!(� �7nkYd1R=�nnBS ( x����s:2�Mcept �?�d "?"�coe�G� �(ng,U"iYsF�� o�Y�6�e�mz "�Eq�!�)� !|>�*�E �VI�Euclid[��E�%M;[� *|+(mzi�B!��@at� "�&^�j2��u%Hv~gge4 �(%O%)jeE�A֝��sV��=�,!�)� \�  4*��S&�>%�a|R� in Mln Carl�@MCM�al,rth�W�package� Rglm [��\Rt#5 oftwA���. Ri9� v�2S�T��u:�em�� Y"��)GeuLUw�o< nfSV8e7 -&#�b�"o-�nt (&�!�)D�p*|#Avr� atE�Flibrium� 8ӆpo�]02;� fch!�W6ScA&�a&@ �wi�l!a�&. SW�|a�h Yn�h.�2�ax�p �<o�&U�U� ]-n:�"u���2aq�P!�inY�& _&!'� bsVFng�3.{ty ���R  br~t�t!#X�:ek*u.C94/i�.2&�' �ir2��2�"NWv�$uni� C32x!�*�&�!{!q �t���z*���2��]!U�m- ���tPll�+aeat�&v onZ�s�vmYri�m5] choi�! ��A�h2�`�HQ��[�j�u� 5 �Bix�nd�:mE�by�� �m�osqu�'�"�2"cCEq�qwL#6�x��$i�u� u��0�8�f�Z(���@�w&^)Fwk2p �8�+�=2q�*�i�:A(vzp�% tS^��E&a]6�mixaR�.�of-����9�Yot�$di2)�-+v�A Matér�t�w!B"!�u�g[!�%m_W�T;u( smooth^0� )�sT5Q�)J�!��� �� �2�ae ��l Yat 1��in}0Mi�& a��A�fD�G.M!]-h9�!R9%�&�*"l�8T` 5 �.� �%��Gka?5*l l�Im!2�Kxv &Q)!5"3��tuC!;;c� ���F��p�_60%�ui��� !h&ti��s&)���A��!�De�J�T% N ���alF- % �ru������*[�!�*�War!��y 100thD! relstoh� spG*��Bn�Con�krMhM!B�as jud�� rac{�>� pl5Z%,}/�"n7h.�K�r��#A�Sm��di�l�>�a�zs%?s��E ami�(E� �kZ� !�$95% c�F���(( CJMc&�:e�b��*4 &���G l��v6zK"@ e�l�H�Q�%X�&�v!,s���M����("�6! �CI%�OR"(��� %@�\ pel.!�72Tq>*�I�i��aPM�2> +!� carr�|O&� o�� E!~tu� S6�l&j�}��͸����&)�);M ���n{m�Ma����g9�� �N/�3U�fi�)$ ��;)�!6ag< -"� e :v> � G%=ht ��!P�F��a burn-�bf:�2Me��!�!r�T5�<^B�~>*Maofc�5@V�� �,���t!\�R�)�!J6�b){�� 2 km}"��'on grid%6N#AM!:a*W,�LP'!��Is��U.U� ( ` cell@"���"s&��bVE�gO`"��:���!$Jy*{ac�id �I�9��'a��low�Nup`�i� �4t@�oCc�-�/>�m�e"!�-^3"�2!�.Q�$)n� 1bQH F�'%�3Ar[to�!!Yilx8r�a"�ZA1sc�;�jA� W6��\us&� ��QI0 i���o="� !�I� m!%!�sO !-.K � f)�= 66���;�{&klVm� � ,-� xabe<�o(.�1 = A"100.Ier,!��_�s2��1))��&$ �SF[*x�f-J6Q�Q;�oe$? ���� E�1]�!$`i- �"�(R-= Pear k�m�}{e�'S � !� �� ^ D'.>� a�i� cs�Zl���G�|Q.�I��Je*�^Rz# �_q*\� S, f�J�@V1�e��؆D#I��'R* ��$&�3N��1r�$�KiЌ!�"\ce3ee" �jORi˩,&s�Fs \�&h^.R tN"AásO�5�b6 � ah8!d]s3B� OR = 8o 95% CrI76A�!�Z,Ei;F�}'�6� oX8�no9�[. AT9E�>er� ujnSao 4� V�$!29�Ati �?�&��1 �h,:�11�2 .Z[�5\3F�50251!]07a�� lR*a�en�&�!�=M�.%�V`&��&#a�� thre.(�(e��AM�4. J�:273B2�6%2x0\!6so�o0*],b} )&Ou� �5}�2 �9A�$�(�� 2���QMZu�:�>�%Ȋ86A�nM�i���UH!48VK78�!865�J�:�959J|AP*2�Ba>�i$� �v?49B e �a?1A )�ExA�(B|"K9a#: 17 (N�4$!` Q& !�s5r� *�œ�<;� l"pS�σ2a?reE�a s�BkQP skewr� �)>�u:*��a:. �6@ ɻ" a� Nh�H.Ep(a���1o)� ��A . Au-P&�`E!�6\V�9��!_m��".( Fig�2Sec,�&oa��>< t a_C�`relF^X!:("xo� X 6� Z�� ñ, �c""R �Q�1�Rs=la�B" "�!r"c viCb��isp�(O,F� �H��n� ��) s 1c%@1d&h � NA"�GN*F56�(��s�g6F�1�661 ��-E#.�4T.�-.\2K&�>-cs2~\R|a ,�Iu6F> � H��a��O��:K6A�e/r�lso� �Y�1o%�� �}�biE� !�; st�U5�&�'MN�5g�r��N&TC�J-��n]�-��. �&k @-�J. �s�Rx/s#k2DjxeA�#�R�j6�}�|s*sZ�J�\S%"�@!>�inB��Aove<inf�O2@fe:�$*Ј5�\x�ofW9� AVR (:����j:",�of −�00094�6� � 018%�/J�'64%��6"��[��,�'1 k$��.0�� iscu�|!�O6�G��I6,AunL�Q��" M�ݫ3I��@>��a �U� 3b )4A�fl.�)QC �A/"X�{. ��AA�F/- G u&6��=L"��̩rGͩ76#�-8]��j�. O�ll�3a�8��a�<�=��#6��0 lesYA�a]�"��Rdj�vրsRpC2 :�� -���isA{ 2���pa�E ,"H�_�����J�� ZJ�%� �~�a1JGenA ^fzaa�(2d��y�.6A5�"x��&�K$)�/CC�@р"T(im]2�D"[by :S@B'|D+*h$� lL"�^Q"�e� A�u�Q�>(e&��A�&�ga�.�M@��C%� ��ed 6EB~���C�t��gEa�z� "X2�%] �Mȫ�8>-N4�b_ !Q>�C6�>A *\Y('��g;�_�"e`�J�"~�&p@Eper�*��\�6� Ӂf� .S�*`6KE* �])"�"J<�C�F�%(*0-*� �& �. F�p�*xvS��4ZYZ�M��K�6�l2 qe��)! "� .0)�:e��+� �/2'o�X� y {��IJ��ѪI�� wm����5x6e>���\�<�R��d���I,�/����,����"5m�>�ҁ �;�O�`2�q���3cl} %�N��� ofRwEto��. "-�1a�� "8V%�mA>u6Y2[�!inB�C G�^*�C!*� ).;14#>&�R9!V�at�ca zlF?~R.R ��� "=��8�'�@SOzU,A �p4o�,V� $H�.i��D;R�is���/�1�!�oEa.� � �Gin��1`AB9_yt,X'p�m!�eQt�tw�Z�xe6�HIJ����0ohc�� ]Ji"�ŕ�m�?x ��E+�){;�(utili&N(+, ewe� "r�1t4� licI��ra�� �&oA�ve6re%d�hZ nd_*� U�Yawa�@%�$׌�nǨ2V �m_� �k.L��2I*) `� &[4�9:��L�J,@ro"�jaU��j4p%L_�$d!��" H>���� �;5"}*b)la.�r�(���T�a��.c.�[ .�/6WA"K!�%i^]t?�G%�st:�!9ny ki1a��d/Mt�S>G!�Bj �>v��y.� #���S��I e 6�`�/&ft�*�A�8ԃ*�WG2�W[8R���+" B!:�E�a:8x�#P�i�O%���e�w8CE�.qGr �c'�2�y�)=�A���Vbeq�)%�eL�!�. M�0um\A 5$|a�`f��74!�~��TbK"�.q��&c'�Q.a���t� ���atmosp��iĪ`bctLBwaveb�e�A���e�$xH&d�hJC� er� &M@&�*6C, ��n��r soi+�isnK��q+z"�C�(��x�P6�P� )�{a#�5�*� Y:morg�k p�� �hHDogene�2�f�!+� �m��tu:�%II�"���*[htw./j�u*�prխU2�Z�Dme��ismA(z#cl�B�Cr���G�Nlan|�si�aJ��i�EI.��;�W��finer"� �m�E :ic�!ympDGnĺ��&"�ya�AiX%;.�g��� �U�z5!��apsrt�=o�N)~Z1l&� ��he&4y,&�fe5Z�3�W�.;�b��M>1)a�iJF� (�c�`�=r�Z� �N]�,�U� ]�_�-e#e5"i�}Z"4,uw!-��dlF�!n5'$6�9&�!P95M6� �N��}13%; dou�]:�)(���x"�H"��F{E1De.n �(a�-bcy �1��t�Dw6:�B�i.$�a�geH�7v��!��to:RnC)�.e� ijH0g ��6��/-bi�F��" (1�<6 t I�)Sa-�n� %~��GB"�& un�d��s�J��k��A�Q��]dQ�)]-� �a�ak"�, �nu���aa~8(1�4" d mD4Ļ"���P�n�U8�h2L.�"Lx!� Q%�R.�!�D���)V* 8-a1B� I#&u"[I. ("Cr-E��/ �#� ̀��:�7MF� 06t�L9t"�$.�$��n-@t��E�y o1is�?nWI sceda�A%��' "���"��4aim�D dealEEAv�Q�rE�A��Y��x?.�-o15^�A�"ʠ�[%s@�%�:�`&js.� � i oA�&�.>�"DY��Sder ��05*�r� ,f�M "^�sFӽ���$ >�q5 "d" }_.�sҫ� n�,11:+$ ll g�Y+�n"�2&�: 7d-}#�U6��>cls ��� �L*�{�FK� ��burde�2*�0�T4q�-I%�82� � �=it"� fA�@�AJ&e�impaci ]� &�� %!6b�D v�d�Ue!A�.:�u!xa rapiEYcheapF�E@��  C!�N�`,�b#!�%vQP�����e�� .����s a2[scYqA�A�Iul�- expe�{t���!���qry fewMVy�$*� :"�} � �*QK��Iply � ;�W%�� b�����S&r`[�s�E�<��I�6\�[e��A�%ng��%�[�:�!<��M�=,�6���*� �\�4a���et�\�Q��.�+"Z�b>���ij�y>ra) �e2(><6.."� [6:r"kt����re%+*w:���]�IAFM.�z� �may�).�3FL�#a�p":)ij M�Jva.����b�!�!H���c��^in�J}�a���= f: .A.*�0 �@ t��,"$�S��D� R"� V��� ��Vm� d�w, migr:oib�_"�ARbeh��pW'�9&�i�� !+ffy . �J :g��-�h&(� �)�pb"�a"mVR`A"�lun:���*q~t ms uk�l�*��d=�."R��n�) �b�1r "! ��6��Np"�1�&�Q� Kaho��("�A)E0�L�| adic6�Besڬ 7tU�#g"2�f�O&f|��"Y"ge&GUa�de�[Q�6��vM��)��[XM���u�g�,% Se'"� �euB�b��&lo6Y � �A�8��� thodh��ke3 -+� �^""[ ~z"�����2�)��7`is]��ů iWQ&L�N2lM:� ��d�(oZle~llyJA �D:�`�O/�: �ub��,2aL!�z#3Ŝu��<1Tv{�0@%��(ArG� � y&uD!�%�i�)��)) �p� �>2!Q�d'[ A ��!� c�����"��3o"\i;6. ,�P�O �p I��% N� }!D �a� v <�my]���5�to*E<#�Xopo�'J|I��$:u*�-i .Bԭd"� )���� 8&, a����a�su"���!�:�s�w��>&�f�R� �XT���y�+����&�O��rtˆ: �xU{�%h%r̝"�E�������s2�� "� !�b� �!��ix �m*S��F���rO�%� =ls�%��.^ �|��]��5l$CwR��ma�)a ��,@�, schist&̗IP2] � rach��N�I��C��:�-&�6��>Z1+>�,�t:5!� e��!W.�N�("�-�ک��C�E8w!rg.�&�.�ʰ �� :&� �)��E2�\.�2�&>N��{)9��-[>,��g�9���!��&C ">Q2RM�n%8ogK2�&1mG2>M��&�-(j�!m�E�l��%�"*Z��.�A8ac"� j�.�FRVV��Ņk��i�Q�6T�. ��arr2[�6M�.]�U�{eVfE���-9O2�?��%� �f�<��!�U��*�����cy  &�="H�ف_�E!_+�T� ��e+*E(&n p"p X1 aT�*(g"MI�5m&�&V�5f�\ `u"C(� ��N(6� -&*r .�ir�# Pa�j�x b!�!��A�coFI�_ ,A��)1eC n��c` �ly-�Mi� "�%��z[��s��ee�S �� feasP�$�Y&t��;$�J�buc�*.�is v�gpe��/K�3UE�W� %�$� �Ѭ!@�����e �#.� �E ��q}�!���1{!i�� +-zve�$!�!��mfort��*H "��%�D% )����� �"�%�ar��graV5��)�x�%(o`� hang�م!�{\u ?Hdt5�%h�)2.&�#ar �iU��B�.p��!E�VE��.�l �t�x��,�p~!7� al*�of�r ��U��i������&eե��g��w5d=�.�� 3����k �I6�A7�Kcy �%�p��9�en��m�2� . A�(al�!F��i���L�%QjV6������R �*5 >er�s�hW�? susaa��:Auoq��bR'mVƍ,a “bal��} ”�a�� r<~sũc� ,  ��A8:g“����>jaem��d��A`)"�f�g,. MacArthur z��<.Mniew)�is�pEgJ���yF�i&�f�7��m�g��om0���4m&�*qz!k=�anargh�-��� borro�  Odum�]:���t }paZ�Q.�~�gy�f�up!Qa f�sweb . L��=rlton [5]&�a�_ �aG!is�d.b EW�.��K+�$�+:6Yai��Io! �@n�tedk�)K y_�E_ picu+ fluc��!eIM ���,1r���M��&=�A$lb-�/I�8n��im�YIm�  Levi�6qx�*Ashjnd�sd�&�*May��.ed!�e��|E�D�r�14�v]x��� �$ �u��aqu�!3|�e��I shol_o���R ���l�]��1.��,ystems are m�ore likely to be stable . In his impactful work , May [10 , 11] showed mathematically using random matrix theory [12 , 13] that large and random ecosystems are inherently unstab�hHis approach was based on ao�H study of community drices , which represented d ructured �net�sGdinteracting species . He u�a local-!Dilmanalys� ssum6these sy �Hwere at equilibrium P�derived a simple and elegant criterion for L%� u�w0 milestone in}(-coZx�0debate [14] .-�,1] concluded)�th�!pno!RforI.%�em �r �at incre%�j will leadAp!)l9,�t<the tasknxfA�,to “elucid�'8devious strateg!�)�make !"&k)in end �natural1� ” . RecIr,: work!�May�revisiA.(by Allesina�@collaborators [15a%6!RThey e�lished�-�a�)�s w%jQbQv fiievia ei!%` etitAT, mutualism , or preda . As such �i9ntribuE0$refinement �’}m%�considea$mixa-6on typeThe gene!eINsis J,!� �-ra�q�!�mpons�luld�� mode!�Aensure%�!`)�of6W%�,also perform!� imul%sM�0Hin�ly �!�9�(ose archite�50 mimics empir-�obsera�food webA7A8Uarm�t�cou�$-intuitive.<%�%�ecolog g-inspi!�s��graphs�Ilesa#�� than6�on1�y)"foc��onU~!�weight�<��E�es�ly foun�) weak �,=���9ga�Q�tic]�4E�ve)5, but de�U:Bof=_( see � [19]���m�Cpreci��tatE�) obtained���� of differa"ns�;! $symmetry )�9t�'Ei=}rea��5�s�mA}be detria}al�9#:? al��plays ��nor rol��@!OaAto� ��[20 , 21A�All%_above�ie))lR��P!fqa[neari�I�.�point)Atam�is evaluei onlya���clam vici��e�is D�y���%$is meaning� \B(-abundan"�alF$rictly pose�;�o�{ wordaFJpfeasi��,. Fig 1 illuɩ�e fac!at��i�."oftwo-leveA�I canA6fwhe�� absolute !KeG!CA�r�nficEea(on coefficiE� s sm�iqin6_it becom�oo la�  nceA�Et�:.� �trans��into a�k2J by changaA�J�� I%sea���!��ay %Yy�� |0, without fur%�� ;j �qE\@e true Jacobian ,]�J�,�replaced�a�`� xE�te�U , so� fter%��!��[� @, Roberts [22] no���$Ma:� inde� em��sil!��erab)VHa�I��8�4, A��� K2� !� \� d%n{number�E�ŔHowever�did� expl��A�very qu��onAre��(hip between� sizU .� prob��. T�; ,key issue siA�.4! prerA^sit�V%iY�8 particular case�U�v. t��h9 awai�8eU@Logofet [23] who =�3 &a nes� � vanishaQA�5v� ' . No҅�lread��197�.8Vandermeer [24]E i� �%�%�E o2:��e!�ecF�w�/coexisR 2%c� I)k same}h!�tre�P8by Rossberg [25&A..of vari  Q��!�- �ia$mean-field�1 . SE/t��, fewal"q s hav%A�; ���=i-�� if s�.>�onmIregar_ �ha��eriw� � �ra�� to�-�( g .� or a�:C [26 , 27]t (� m [28] Va�r_ �U):�reappe�E�,aim'providA�"Y aXUile.�[2 follow(an��ogu&� as!�ref . �� e ideae�imp�nti�i= a��t�f-]2 demo� ic!�ametersF�)�uaT giveA�nd� a�%=%���ns , fromqp��- ofM�l�w� effect� ��y'horoughu vfge7in��.L[4 , !�8 , 9� eM keep!X%$5well-dXd (*E �zer��di� )&�M��n�6s �qr���!u"�a�)+I�/ ength!��en�A ,� 2� H� , w=A#ext� ��Onf( � .��k:�a�exp� its)�ly!1ma�m@$ principleE�ord��a�5� ho�K"�influ� s2r:�wo clas� of&�� �ied: 1 )Gdo�npo:s anyA�ѽtop�!f<A�or @w�1�&� ,E�e�v;!'�or-pr�| )�� !2 ):%"�desig� to cap� | 2�,� !�cascad7� nich 8]s(nested-hierFy [30]�la�We�w�Gt� situ�Cs�at ��b_ � �Q"2�ist!�!�a-�.�ue (not guarant� ,��.to�>a< RsE�nentialwa� i�� 6 { e1p grow!I!��5��we fin��at �F(, non-trivi���.�aE��� n*� l.�Rx a way)�P*' sa�d . We�first����.tM��"f,Erdös-RenyiQԥ�s (6YM)�Sedg, ccur).�C-�so-�ed. nect�1vg� t��'@by C = L/ ( S ⋅ ��e�) jLEto[�W link�gA.mB� exA�w-"� ~���: draw*/accor�^:]:a>eu�modaieu(�lS!d� q�pa!jateA�rop�2Lofj&RA��2!�vid����I�sYrv= . If"= i�3jo; �Rtweb!Xv�UE"� &tw&� ��U �Y enco��ig!V*� s aij: < 0�aji �����on;%>% %"� F#T#��� iaXjI �(��aij/�S × S2�mat=A!]n� exhib �� Q�&�he dyna�)Gaij�����fix�e �ndM d�� �,ir magnitude"{%"yu*h .u[32 , 33uW�troduce��a# 0 ≤ δ1 rul,[averag8"�st�� �diA�n;a�;d� ty (6easE)2 �]S�� ra%,toKpower�(�&3 �4/�is norm�)B�*�l��^W� r’�to5�onS"�nd��0resulA�re��,p buil��Cpδ = 1/2�t"���se �S thre�gi�eme�w� S" :!�ong (9�<f������ (~�F(8<+A� ,%g��3�tra >��f�4as customarily!�� 15]I�aa�mop &θe�tA��� AD}�q��una_ eUm6��Gt5 A�xtyp��m�BB)V{� ��orUi�%nl�A:a���� adjacenc x α!5setA�Q with�"� �wC. x� F� !�^� 0 pair ( i , jE ��jI�a���E�(αji = αijA�N�)Z:�c M�secondNv�5d9�A��u ǡ�-�eR~�:�B���d!�Th�Y:�)�ndicat� i� ys upon ji�5!utJco&> �)�Ce� ldetaii ��i\�e� S1 T . SVa�2��AY.!ɧ��N�};���ɍsa�{digi .d .H�b,.=�A�2]aY. � ing�5ens��m%-� . Con -�A9Q�m (@!E���!tE�we pendC)l� osen �z I ( nega�) -�m`Y{ � �2:y&iBisq@a^.�>@) Br2 6� �:�>��61�SA$ PAke�� (%I) = −ji7Fq�&��.�eVe α%�multipl���1r.Y~ � e6F ���of] �5�JP��]��%A!�Uad�T� . GaussGor� ded-IIUs �st� -&� σ%cIpin our��aH���!�"9Plim�!�*� hoicen� dis*��/e�3O:}a"&~ by � a�a�AQk� mput!%.Yx*6}Eq1E.�(Monte-CarloA�cedur��a�Rstiv3PS�&� scen� s . AYijle�/"s�.��Q�& !.#�!��vector�$correspondb�93��/"� ��4Lotka-Volterra�stopsA@q�Dd�"� x * = -� 8� I + ( C S ) -� A 1 r .-iI� h!AE*nq� involvesy+="e���( t&�*=.K� %RB,�G�$��PS pA b�*Z[*H&5&8P S = P ( x i *FrE� 4E�(�E�.Kd�k θ ,Y � δ ,M�!f��a y� ��61 �ea��he�th�esQKr = ( r�mo�avour�MELy�4%F( AT��"J�,W<)���bqa�(���!>�I�Y�]�d7min��makN �,2 a+, fa��"� �ar!��� �)domai�%�R�5 ferc"0mJѷal�. By �M�JrYhe�x! orthA �ph; spac-���S� �d�q�X�l� w .�7 hoos!Xi�X nsic6�q�b�W.&efK#]Zvo��}�. �now�)����ea��6�IG�-�. E�� on��] ?�v� s [3�we� elop.�! ulas ��s�4-H�21+� ten��Fin��zuseɤ ɤ:�'͙% zA� {QW��1��%B7*u!��1$�briefly��cusq8 "�&'�|.�1����&� x*Ak 3l�&"N%,of 4&�ir�? �T!Jv"%&8%atI(&.N2-x� J��*z dia�� )j, ( 3% ?-a/ oursAF� ���Mpmu�n�-*# s���.)JlM&+ )%%tNeale�E��eigen� of ���u�. Ul� "R.I�similapm�."�+=K%>Y�T&�#���-� J ˜�R\.�5inaye�a�66 / Q!��" )Am" �overlooNAR lq�jae )� -q4b�)c�/[Bk ˜ e�%�Z[x* do o�#�!Lex e&g0�.<a�mAelex%�A%�yu!�A� onal"� !���A��- off-1-�a9>�I��.�1�  C!��/� >$" �tFf.��.B U� ��xσWpp01�L �Mi�/�3�A�N�w�/t���u}K�x� S)�σ" δ < |� |�4�isuTa�Dw��..���, Pro% (on S . 4 . �%�q��!o�� holdɤ�-u�L!qal�'pa? [x6��E�3b�D ThusZ �"s�-�` a�� �� ��R1�paradox y���!&�91i7hi�al�^�l :$�-� e�et�<�,a� �’&; �) �3�$-%*��.s�% �se*�&�[37–40�Nethe�. >9&x�:pA�$�A- i��"�X� $(FC�0C�iCohen%��L!�t1 �� �� �" !kly��&��y f�+� 9�YoK, �$�sub angu$(E���um�9֩>A�6��W ._ y�&�� beha�#v)PS� !cN� ( T2 gWe� test�B�e�>�c�!��A�-s=����M�M7:[KB_%�� E|U�]er1hes purqv2 (y�3�uml/l5��' �>�$i� e lat�+i*�6 evolk3ary�9ceS#ŏ��x�i-"� aint����Amq�3t3 ��o�1of6�M.-!���G�(�ac��H"p+�� nga�L#�2�.�i�Z� � co��g2�N �e !e+of5�$Qi�!���di'EabsA�� fe����,6��.�D 26� �i21��� Sn4F�, eachLno longe�5v!c�6q�!�Z � instV7a}�1�}��=a6w)~'$p�E��v58 *hI ua�!�rA�͖2-k 2]22sa�i�k)&" ��x A)�"�&%�.# valu0.I�.E�se hi�(�gd ���*a~�m:�2�in�c�X. am��*�:�9Q�pr �1co)�A��6��& &A%d.~%s-�*N#.�-���i(�6E�We*�*& .2"}"�6u%�nd �����hs G%jHB-BwMٵ u .���pur�maximizA�*�/A�*��� ���i�8�"i2����mA� leteM"����!^�E�6 eT&� sc i *w�fT� *ed67�F �F�C�ٕ�(K bas" utoE!�tz*t�/dis;QE�������)@�opd;�WeI+σ l* < e�m c >*MMQU`ZY "�7��q�&k�Figs 3e�7��is, a lso �;b�nR�n�,�L.Rwo.1 Hs[+A�EMUtM�.{;=D!�U9���5� .5 both {Mp�.aR96�5��� 4� p�>E�.E�on6I:� �q��1J@umt"�7� u/s:%�% .+� [10u+a=� &S=frame;+!#re�=1#(�g#ET�i#�06 pal�$ly�{�.6}*inQ��<�!��ͰZ �U�F�J� &�X$218Gis�"�@;���8 ! %+���6ympto�hatisf �er��&�, a2Wba�6�of��%0 �7"/ &h ��#��QS�2#,AQC�X& ��:gP>messag-fut�E tackH�?"� mustA�<e�by"�)u��q(ur>OYz!.j%�knowl�+!&���A�3<%E"�'a� MM}�� F]aYt�be ly*�. .�2#��"P:_�-' :1�Z b�%.8z&� �rplay"�&u-=, �1o6i� f=�<{'.�()#"1�#� .�Q�EHs)me�� 4'tPshU@ take�� cc�?�ir� Qs�l�@s abo":!�U<3* ţbefitB]e�y�&7&��2G 1�)́nt%s w'N AY5�. A�"�2;�er�G/j $er=�"8�MKdescrib�<)� midd�9 ized� ɜwAdo� [4�4�)/.*af*t GS �be justi��A%� rigu )� ���RAZ4e�&�4���~-5 1embed�.iWr16��[����0Et2 � ��A8��a\� s�� coup��fas� slow �gy=n!/inUka� cU?[4q,�Ucq���&aU�N��- “i� ^=yramid��hab�>E� xae�3eq�4��ubiquit�E(�# ften.�)�2�j%:Q�Ba�at�  5:!?s|a�%]E2r homej �1[4�FI1�Z �s��7z �Y �I�AFrelev�a`!�.�2a��!:�5MP s [4F46�� e��)}��� � urkB��xpa�.�9[4X9i-R��!e�i�l�� �5�ofe   no�0E��7(: taxonomic���)�h� o�!�f%F�D�T !a�bea�mo�0!�poo�.�,phytoplankto� 2!U� aa)�a� \ ml�?��!�c**C�usue�"<ap& ��9E� t%�eՙ�%�C*�w@,�0��)� s [5�,t@](ng%�rA�cM>���>�Fin�k@��f�P�7y� ��< suggO3A�2!D� M*"! [2�w�6�<atU'A��� V.�1on&p um.�. Lay�}*7Gs!xt�'g&B.i�7!�^N�&p� i � P ;��!e� &X[2��51–53| � 7n<2�m%e��. A&�(fQ���� �s�r�$fr�'�ai"elv��|@p .�'Z\< . To$e ! # a���stip+f�& "��iO �2os��unJ n*" +A� �!�e*Gly� ne eK�<�M�5�#f�1��&�M1 ��s�_g7E<&� .� �eA�:)? m7] �� !��Z " �s!���%  [54A�7ZEx96 �m�,�,�?[�G58 , 5�:�$� {� D re�F,6fA�!� ar methodm-ka��� mass�'io", bio flux�&A e Ecopath MN�60–62��A>,��1unreso)d��is��i� �>'3scales��''.�v ��c>>perhap�A� & @ingredDG���U.�[&�;%�63�,��%�p�I�GiDE�)�>)3 .FzA�,�+a�&�6IgZ84abe"��R��#!�)Pb/:R*f�)N%F5t� �3���a"y�δ�Y$��ho�o% a&i7"�Nm� GZMis2�@HRF���ch@ ���romE9�[1D@�7%�aY��s .c1.���C�85s+ E�)X body� [64B )+�  N{�FM ���-,A�u�N,�#+ -bod/%�� yp�popG/VFv x6�HE)allom�LK :�Gmay�!li�wb7�/) 9_� "W&lin&�'� "��]o�p��!0 Atf��s ���K&im%w�Bh� 2�tA�� t� � "!C'����K &;J' ,A�y5:�.i�\�G-iU�.�afa�&�'Hol;� I�B�a�0ponseC .�nBh& �&9>�VGn��%aiU tim�b&�*NB�E!���ps�!�A�v�l�T� �"�ubjec&�1a� fuF�6d�T d [6� 6�SInO ��5!�^�P)��UV 2��)�a:�V�%+�I�J5���r�:�8 l"g �!_P# ?�"eRU �F �Mr@ s!y� "�(to���U "fs m, i�1e�FA��$��δ�Xt���wYVGyS��st~;%1 .�i�FI�%�� O2�'�K�<is"tO7A�y�.p �!v�irait-�d dZ e.��rA�_"� [6�6m*ontr��shift!Q.6 s [7��or-#6"=!bCa�9HI*��!�s!#���*r� G [79Rso!�*#�8!�“fora�O adap�"on6b#)�1Y!�*�?21[7�GS� z,iL� �=P�&��"LL  ��p_4�Kiew!s$8u�EA�b�&(le [73–75� H" �>[i'Y02�� E����� ��"B�(��?a��/�M1�.���c&&H� f brR!5!M* &�("-�� ��Zkin � �&�B�$.�S7te ansJ@�ee��v%�&V�ob�&sl�N corp�Y�#l��>ose�� :`(��!��E"�\ e�Re�K[7.77� � i*w !�EwH�AWrMora�al �1men�Q78 , 7e��&y!�tsi� Zaddres�Q"� star7e�%[80A�Sci}"faS(SK�GM0. �3�Qd�V�Yq/�F. A g��b~� me�SY,%v� "K�*t �=��Hge�W�r�RNyanzavA&!'Kenya�n catt�X huma�*A �-s �a�urvey  U�0h&:A�uma�pl9Crom 2049I!955cin 416^�)� �aUF�"!=C .Y| antibz Q�Vna�Pc�3!�.�X cio-L*��husband[2*34Pb� ad+:e#&�� ) data $lin40to environmenL"set*�,ge�Ral y�2�l��EC&")�P-%~.@)m!e%3pplx�E ��poe@}i*�>�!�o]�. MAl1[reg� JY%�is%��96o.}a�D�Yg�!s6�,2�! 6QfaceDsero-�v�in�%M�#anima� QA�- 9y�of 2SA��H5%TO 10 . -1.,y#�<e#e�Z�7r1"z 9�Z��r�*�� ouse�3J=�&��� A�M��)t{fP >~ � i�2�Ź0< F�B��As���/-�a� :� organisueC�2&ta���et�C s opw* �ba[ �i_�t7n��>res�V/0e%( 2 p;A�E��<p \1>�z%���!$you� t ag�>up(ZFodBfN]�,����"�y ethn=upq�f|Uli&ock�@tac!+ � graz!�6d�`ng)(ewDera�)Elj�.���! "qG�DdemicAD>iEst�7��{oug�I��H vS P!�-���%2|Hw��V��p%a"�m=Uxp2%�%�J&� T ri�o "�byF}�Q�70`aAVof(I� >���fg2�zs �%Iuit;t�_KM� v� s . Ff �et�CA�Yf‘���6,' � du��� outbreaki?in Euro8L^M yeavg��0�fL;goA|)uA�Y�h� burdQA�ny [oSl!W2� Bo!4 ougho be. !a�excep1�Antarc �New Zea�J[��#)^� is zoon�)3V"m�At rvoi$_� sour�&� ���a�mEin=��,y*a 7#���wi�\ndB��ɸ�5V, amp�Q{ * arth�9d�% carr�� um [�#Despite�*%$B ��� 2R  isa� �D ,o �F!X%J -pooY!� [�InfG 6G��g$redominant��+� ����DrepRt�dis�!�s�as �tanq#�>�abfsp9 o� fert�[�5�up��40%)��I'JUS;d3  Bc�\m�i�?manife� ���� febr##ll�B , pneumon�,nd/�e]%ti� , �A2iis6P�! lf-l�Ia�)62��oINeS� m��� -q##Fu{:r",�x~��2R��2 []�Y��cal�()4m/&�a��%ndocard�A�vas�a8/post- fati�^syndrom*Qre�5%��d��e� a� �!)Q�L&Z" xt [!u9–1��� clin��pi of5�56es2 _%����h *l ,U�itBlatu�8� ro�� pre-���� &>o;�ziif�c excr32 �� milH�m�� d faTDn(]A�a�%6�p�" �- e birt4cma�. Bnta�(�8g��]a6f�ng!/rg-�%u�>b�{K� out�)%}1!�TextremA�� ř6�=n!Ӊ�A�QCv IeP+%ntpST�&,gta��!�]L �&�8-L,�ͬ[��@ . On$FAnsmis`�\s�n!�Libo y ro��*uaeroso.O8A��9�]�p!}d0�!�Lw�&10U�,� i� apye. P� )�h�ce"6� disa�aa>2��1hki2e�+w\[1��U. T;i1)��u?<pasteur�3daiv<��Xor5Ub�qlj1�� icaI�flso��K�r 7.�>�2�61by @f$burg et al�[a�l���of�q� &�,�- r]sa:A��� pA6Ain| � se2.rWj� 7%�"33M sheep , 455= I5132 { . Va?fs�:oY"t wit� �� �A7ta�l[�Tr� Sf2t{�n� ��A�"� in �%+& . �9tl���A�+rV\�4 behA�!z�h"2,� r6�W R>x&�63-}�%J%Ei(0("�!��Yof�)��e: oldcag>�|�)$18]; femal�r der;��"^>buffalo�!;%];�2� owner [NB. I�E$=�"2�of 28 . ��m;,��goa� 1#�����3<9.�V<*�w.g5�[Wrn s�k ��W�2DNA���1ll ޥ� ��dog� AnE� W in Bungom 6'��5� 2011K2012 �CNI1c9%�?n��y� � uO?4!�12��gg� .�n F��!�9� $%Ve�oAq��E�Q 8��)n  � mO�on-mal��lB� � ��re�6- a(;*��r(in LaikipiaD4nt{!I19֥�"m,n�!%�0�94Eb)� ; 1320E�; 3�c�inI���5-46-���);A�� 0as2[� spar�w vail"a�ighgEyF8C,�1�5�%��dB�A�c_2�Ey(.�w �^o. BM{[1xTng"�6�Apa lac1 �EMpap��i�b)|'eQ6�!2�9@��)�2�� r`{EVof:��( b )E1�T*Bcb�H�1 }n.�uc�&9��Q�t� ��T�Na&-9�s}�� 0,':�.��~, eG8!�� Z�"��qa�6�( ����f A�"�^:]��n �?�T��7���A�$'aRtof"\E{��9Bd(�[l]o�4],!���C(veE�I�!e K�8� e� � Busi�� Siay9���; ies;"$c�JaFoF�,�i�!�"500D km��Sub��egr 8 ( mi�K crop])9 !�*��R�di�")q�)�� 4 |2o|,�8mai]Luh�Lum'Tes@o Sami���gepe"A�bimodal�:�en|ea�ru�_M�to�A%�Aug"to Nov ;r ��71tempe�+�F2[22°C (f e 14to 30 )�s9�ofMw�e��a�%- �J(�L�Vihia�4i%l��h��=vQA�5$*�:��&�'�log��& �f�/-��� radiud 45 kPa"he �.-d�b )�.%pro�,"f��sit%1!Fm��z D s UgmF-�,W[Sor�_#�- 5��p,�f�w�`�N oA� � .v!er�"%9�ba"P{� ��:�o!��far.���0:�aB�wzeEJpvO�o�4u��.e*@ 4!mumatva%#ofg� br"6+�aW�%� � c� u�"�dis���!3�%��D-�zjerror�2%-� ey%e :�T-}� �>Q6-o!g,��TS4�*����DF!C.[of 136"#��!��%YK4recruP' 412�doEq�ho*B "~8lz�'d3a����A]:*���# AE'2�!�ks�a�S A�(oof �#���"�E�!z=�. &71�� sub-�śMO e_ F/�q�.)".e�-d-��5ach>eie����t /y�q=��i'6-@ g�@5��a>������s�1��l@ a0�@>)q�� �cozp1h D 'k �re�peda��-ly" handheld��o�(�Z���%�q8vDlIts�56��+E;wom{�thi�y�:� �prHcy@wI�b��lfLort�@�R%,�C T$M0,Plu�� e lw3�� farm-�I$e.M'~ob*�+c#�! icip"�"W A�2w�#2� A)&���,\'y ELISAP:�H m�-�:;!zSV� =C,wic F� Phw`2 IgG ki�"Virion/ @, Würz�, Ger 6a2A� A)� �(Z�cal'm��o���r^a�op7 2.OH ( ODo(�:s%z�POB,u�Q*�"'G���!-assay,�\m=pd_8f$�[-hm�'�'x2� 2�� subs�0tla��Fas�5� G "b�o"XTE�a�mm�j� manu!oureP$�%2�JCHEKIT"]A�)Q]T��K%�IDEXX L��N4 , WeV4b 8UK%���OD�T d�E�&:��Yg1 n &f�i"_f*.)!���priW=o��)QBx -��� �c)<\ M�4třM0.E: VqS %=OD C4–ODneg/ODposx100%8mS1 ApG<ixETZ��% �T Q t�n�>:"+�B�) TMe�%J o�g��p!�,V&D��,@ingS�2I6a �Q�Cne�u��FF �n(�O#e�'Jtd* ~�2)a)eVaM��^Na�Lse�a�[e �V1%aa fulisd-!�[ TA_>*<2n�,"�� cova�es�".*�?e?,%����=�� &>N�+'Y+g}r�-1�t2P%"(2��2�!,&/ u���uu�)%�H?1.��L! � �΀] �o���{d�(qre >�"n�� imag䀅�d"K$in Wardrop�F1. A I�8K %>yaroY�i�� �Hk*�!�per(0A�2= K& �t2i( &�Ggrass(; floo�k r/(swamp; wood@� shrubs; w! �.; vegej�a0w� �>���ArcMap�,( ESRI��eisevtob!�� �ndscapeP%/�<h9,-t6�> Euclށn� h�:At?;��s��[b�?1�a�1V)�)���. MD.;I�{ann�s reci"#,�Gu[�� Worldclim&� �>��1C}\A"Ef�. PF�hP�L�ng00 ����Je;naShu�1 Radar Top�0y M"( SRTM�5t��� 6�9 y�%C��wl�-��� *�0_.T . Et�_�rovalE�g�"t� Me� l Re�KInstit�"ERev�Bo� ( SC1701;�K�^ [�3 &!�A% Welf'!aBRd1 AWERB)/�Roslin�, Univerώof Edin� h�4���AWA004;ћN���6USoutha�'n�8�k8ittee ( ID 1986��WIE+"�1��Wr/�"ő�"� B y��_�32b �9�c� �0h�*2$�isS!�i&-Tpa�M or t�d�rNiMalf!k]p"9s�,na�be�d7� rU�3� anonym/ .%� UK Ne/ al CsSX!\Rlhm�, R�M yRe� ofM&nU� guid�w� ad��0 z.� Y �m�Id xO �^&�3q1.�PA�!( :�Bid kerne&�  * !�AuV�ew�modp> ve#j>�P2�2��a~ ��,ͧ!�Cr packag�R� tsoftwa�[�bX?7I�9�Hsc��O .� !�"� ]h s�{�)5 ���wM���G�4yF �� � �MRL surf�NI4F2 �=N g�8 +levV 2��%�IVZia�:�T-Ap-�Fa��e -�� �P+0on’�&�4*'�A�)@S�"N20�uA�"��y(�o&k5 X!�� !�� ��:d� &I k [�7�?19i���!�KunP !A A�|"�us�[g 1�&("\��1A2Jw� I�# "��!�5�.�%% ross.��(��.-u�!� Oi�ncfq��# Z��G�.�/rN��ari7V'@��> *x8me>uA�6I�on�&w8%���R�I� �*� l�.�g"� . Mixed-� ��I�><�+#9�Ml� �A��.�]�J��'��*iof(E`�!�9mJe&��of��� �4U, �.&� s"+(�Y���*���g �� . 05�|eI�)�A�J��uniU"�itpj)�, F.�8%��1%�I2�a step��manner:.��a�X�$) k?,a�E-s.%�. �5A-3���A�)/�8st Aka�OI*�Cr}(��( AIC )%�2  im_ �{5b/[( =�*�ANOVA-$eAarison�-� .���B>�s f&�hnvRW& .;%f��v"%pn��i_!!�*|y6�#m�~}�-cyc�>�� IC)`��A[ e� B��ng�RrA�� ( RO!�c��m, aY!�� �1 / ( AU=��X!h8AH6�%�a�ZR >�6�%%�U�A��:e6�Z��� s lme4TpU?S1 Check�6�$a STROBE c. ��2:-@�������� in 5,�giHJ�8ll Q!w )6f*+�)4 . 5% ( 95% CI!c . 9%–�3%m5�_s��:E!�9!e�(m.S�P*)�&�R ^;^ $'s Chi-squǓ� p = W*0_-s"�2�!�r�!�k,�- (r0%/to 14[�O�2%*dto�D::�2�plu5 r�0�96�A6&� �al�.�a*0B,!��6ї!vN!^�f V7 W!v52 a*6A �*6ISk r"� �Y6 ( 1-Q���` Q9 .1"{=bW# ����U6���36F�x�7>BX ���3&O>d� .:tazA��5m_#b FKinAajT}C figu�3����+�>$�V=r& V��M& �t=d'qZ� &g �Qcle'7���:da\a� �UlR� &�3)��&5�4pIXa �/?r/!Nzo�/fv("e��F�<- to L24&�s��*"AIVISF-.Yd!`>q�B &� 5AM-�a�:la�0AtM%�PZ, =5�*KH0;&i � d2w} !�� �. CH – �8�gd�~o�<�TMnynMq2x� J�&q��S1%i� .T ��2P�.� � �S� !iS2� qL%E� -N8Wl5I�b���C)�.� B!� vI!�vi1�" s � �0yso�%!�a�� s 15!�2�25����1/xd"�C5SpE.��DNf���0( : o [OR]�4�9��8�H�BOR (�X"� 01M�OEth9D orig(, :l��--mu-p� x6kN��0u.�*6>+Z of C+ �( �:4�R�2 [Luo���8B|#$y+ �>]!���* ��g.6y yt��da�i~k�` or n�.*Cd r�NZ�Nzp.f-��22 03 [:�=03�:2�!V� 1 ��O Ft���<&�@�'F"�p�� 12 m<C{rI��~�%;I�!w*� 13 ,�7�sA[���p� B�2c/"� ^� no�aB�8�D�(.�i�!eq aA!l8A��c�katQ>3mW|#:Y���łJ���m�B\>e�6��É�9.]#ɷad I�*�>c&�(�scW%]�FA���O0)%�jZ �e��I�XM-� 56�0O0.V.� !�2�]3WJ�!ԥ6��%2wR7!,�IU�,� A�#u3&P � 'lf3am�����8o2�� mm4�! 2.�a�Y�AM�NoMeI��E�&:!,6�A�M��.�2��! 2�0E�&� >t>&�&�   &� !,�4,��� !HN6E8.k�f����at>��a��?a8�0gr�K-�-C�1act&TE5 y!�!�Eq6/66��b�al�]�' �*pui�1y r MT�y��=aQl:�A!2&��V�V=�9��u4 p.��mu ( e[1sVEmRGnee� "�l�!L2�:�AI%h�$�u�JR��.v1�)�7��k�y!��Gm��c�nG�� �I-6�Hi�:�.Rž2 �&/�q+2 ) �a��en�Y�BA�2�e�3or� elseEX"�>.�a�k=�Y.PB(�ed9'�51!��%� aPF@�A�S*tpSa� �M��.*=�C%l�K �� i%rn �!( �]�ndJ+=�4cG�f�|i:�!,M:A>�:�h� �WUr>i:~1�:e.b�"�A�m�*A�nu�w=$yL �ef�y+<��)�n.�9R�T.�9qF"2:��XF2�2��K�K urvi�"Q I%5E� y�5@l]Js.W�,�!xplZM58V�)12Emyp=varl�$�%protocoli�!G&�T�)Pbi�06��=%�!*M ����@cEx9S� ��F!oR�&' e}�X]� hetep�z� !�5�SDmonD?��: 9�h"�O84m�K($��� ���#�?!^&ZT!]2,*.m6��>�a@6;��&��eaLe��X����pr�(�8c)n )�.#)%��?.X�Wb�{Y��I�"{Hs2H�H�x29+�V����O9j�&*� ��"�(1�)=�ndEC B�(&� !�N/ ( �PIe8]w�:�=`to6R��E�AIN� o��Dvl#\U��:���!A ]c Te*^;!�^�N� volumes:a�*�) �Gf hJ�� B� 6 �%ELA#�&Q 6l �y]�At yZ�%i�1��}-x6wX2*+t�dep\nd soil�,?�Q)�&� m >�uwe�H��G'I3o3Qx�GS9�n drix�ҡ`ys�"�!�F�:6uWt*�L inhar(�����! i�Y&8O���3�=��?&��9�#'>�!�!`s�z��e�k %�?>��)K�E���� ssoc�d�R���acq:M�5b/9��.�F�^B OFh439��: bornk1|&� W �Vjor�� ( 75�� .�B� a�1!kG�N:,"oG( n = 57a?$2%+Fn *e�villa2aQ5E S4�S]HܺV5qw� 9�2C�1��^�6� �r�ub*� AeDl�4u�����q0pV��m��Cebcci�Lherds; %G��Ai )|NP�':�;�~A�j� @E9[�s;a�a�ё�e�ihQeP]9wi�,el�)su!�����U1 morbidI�� V5Im%�M&5V�"lF� �,,�%q� f 1Jnt "�<to��%�rofaskr �DBI�^ pen-�R) A�vacciLE(-��R�*Q��A"MT�]9�[3�g�B��&n � nteg�<2v�Z��X�*�SC��B &-� A�\���NW�Z,�?��I&B3�y!nd-$�r=�1�e�8=se�X*�R"S� �+�v��C�F�P�Y2]�(�+��RDcYJ �&�[�Z8�!!�a:!z% �ѵ&ns7(�t&x[39�hG ]�>Aa�A`!O2)T&��[��9�guof5� �A f�*R]�( �-�;g� ~9al���5sM�a j� :�I/-i.�Ag.!" %�Wt�!ow.�(�U7cal����ZR ���ܩb*F@2o is�+�s�� .rB�sm:W nullip7�-wy!��1y�b�/C}�AO��i�_ � [40o� �B�k�%�P$(!3#b�.�{wsi.�%mc�uLl��A� F�wa�2Zb!�"�AuI��GA�i�2%&pronoun? 3 �4�&7^h�m�(6�� ,jI�aHsu&�7a�&� %xA5��9 s:w � *:�(�\+�� *� Mj�Mn�4�Q�y�&�{ yY"���"02� )��a%w ���9! esumabs �et�pe�?!��� ��AiYn� m[� 3/p$?`c{T!{Ja!o���)s�&�:'�⑍ qw"@M�qHs͗|B2& I:}�� �G yU�b�>!�e��8R� Z+:vepag*V��/���@�Fym�T2� g GPY:.-Zo,Z� b@E.� ^�'zC)a";) ) -�� ejn w u%q�0 � l��u9�e��."V�1"�(6 �l)Q�4.�i�?Qly2�*F�W3�4"�\ E�&4�h�VA�feu�N���Y� 3|"j  ��&t@pla)� 9�!!�c%l�Ped*K J{^�X� b" <wa�A��<� A� adulbr4��mE[.�>Kby 6�E � )�@����,�Y,in Cameroon::A ziYɩ��]J� 4[EY³�g�u��u�8l�n�Cy�c9s5��N�W)F��ҕ�)��Bo8 .*r��g.Nm.u�-\L =DI~A��5H�G�U�%�%�:-��sw�Wp6�e0�:�+a��lcu�P%V;k�<v�;Y�Y*e� po� ��kP)R_���t:��lq(sa���q"" ���?��" J �*�4A�CQ����� qua?�RnZ�al��!�Z�D_�� �&� �2�L:�&3�L� )&B�%� 5iJ)� d2�k>NS(nG�� 3����(z��2!q2� %-.���l!IE+& 2n91�w��2�:� hr�2no&[ ����8�g!�h�:]&M+�hi�$:X&o&jC�4{Oq�Yj YKtA*\ �u&*,A��R�e�6� %I��a�H9f���@P2�>�(���7j���J5  %v istoatl�VE)�ti[�v�������e�") dis�M�E|5�.�S_ eyed.�9 ^i9,>e���T��TA_e-�:��X !��Ic���0} 'U"E�!M�&�7��%A�Qw��� �#�im�~ n�< bour� %� �is /5:&� es� aBsU)+��vGU ���b 9�  )�W��;>R"W�o} v@.c@-�%(2:ns*eraw*h� �>~�u*i� aG�:�E] �p&OE!�>/V (�^;Rt6��h!��{&�. L�[ane3$�J���PN�y 16 . 8f^�o�(f>m�ilk"�ajb>deId!\, u2}f2�%�a�1(R�ADZ&� Mipa�.n"�O � 1boi= �terpryH!�& seZ*J�a�6i� agnoi�e���)���! enzy|Iw�josorb�+O(IP)�2�3 5fluoref�t 9� EFAT )� g"�I��e gol�<-VVB�^A.�}�%- �6.�2_H"��!�_N�)*��iszXu!5t�����it�"+r�!,�6r�q�%{5��G"@iuA�*�at-Ia�9 " �|�AJe%d� ' ( 90–9%9T��N:�&[4�E�s~lyzih�u��8.i63`799%Fi������!�"�f��%�(> 1���&Q*� �.=�OV* is�W�5d� � sus�r ble:"� ��Z#!�J6&�weBs.�;�D=mprehMC*ynAz2 fe�is �6暱^*xFgkD��:�"�$Xf% �G e!a<�j& 1�o���J�khJ$a*meY� =u F����BJ%2/ �2�-$M��&� A]������ 6� H ��&j ��[� �.}.�y� [��!tr�5�"r*�*wh"Lm�� �En.o(��#Axbe��.@ )&�i�1\!�`��J�*)� oo�o � 2~!2:'��%�"�9�2�2�m|��ur�&#esݓed:JO!�Z ���w��:�.��$.P�GenQ-�Uc�/re*��3E� bdP��k�#Sc� s�gjaponicu�_p��onD�ha�obi �F&΋g�ic!u�tКai-�� ��!�Q�7)new �"�Qs�l�|o��% E������*j� �%9�&Ş�* �l��gain-�[l�Fof-Ja=fac�u9v�RN)iter��c�U�LveM%�E�forward�etA�too�8ins4v6�muDn�scree ProEi`D}qi�e�p5n.5s m�H%d�]if germ �r�� rel9�o&cu�'59�� VasC.a m�b�'e ATP-�t� DEAD-box%&hensbamZ7,!�aato�ixn[imB\al.�!YAC�s��Metazo{cU�3bio"�Uc!�33 puQ veV�{�-y�  y d�mif &��ze��2| ��M���eeCqSE�� Moreove�5�-E1*��K asa-`y�;��l=)AK&9confir ]! Z?E)—,(ed SmvlgYA �!f 3—�)� �e%�/PL109Ksub-.i�cripts� QZg)4cF�='cDNAs� �IcW7�m!��2��e PCR �!hPcE1�b��aj�S .5�� "�ex@_a_�ccy�y, ���egg�miracid.gP��k`!C:W!��v��j1g�WhI�46|,itu hybridiz  ( WISH_"�=vea �at >z�-x�>c@�M�y�]r os:2� oocyY2mN�A�G�I�Z\=.� �7>��C�|%QR\f\ኡ4}��g�6a!z"�~#�toZ"�pneg�SAroP�� sTF�ia�Y�n��:Eq�w a�minthiaN!G�+m"�%!y mort�0�It�%]mic+ 76��,S�a=<�st�Q ed 2�U,illion peopl��aYdR* al 7F&at"H*z1]–[ Draf�6Q'l��� �<.i)�r�&^![4c��A�r��e��� 6!m�J�.`1&�`if�~ZS.{E1p �{ �torzm��of nove�'ti-Gal:� ��tW[rus&Z�2�� n�5a"�B< s�E�>�ah� [�}I/�ZE�e�13 f� phen�ke)��� �g����"x#m/|leukeEkv!S4 ( MLV ) pseud�d�Kveslasr��~ 4glyco�ei� VSVG<�s�#�66�n2�[��v� 24` L-�(1{I\5�!# c.Y@�i A2�&�Xs"2�25ڂo �o)!��B�S���e���PA���)B!Y�0e�le��'6D�%j�uBm/��� f�to+ if.� F:m �*�����*p � �^ "�,�yz ��en&�e 5′��phosph� (�  ) �� � Gchetypa=meQ n�������>x1_)[1$�# �� �'u %�EE�A�d�R�)%f! [�enorhab��s�ga�, D`} philz lanogas , Xenopus �e� Dani�]ri�nMus%� culu� dC [13�������yne-�Qi�� �Mfao isoK% �� �t�l��..� ^� hom3G�].LPlatyhe�m"I$�MMmtof2Hl�p by D�jF�. LewiAvO��c.G. E�%�re%]R e7Q6�%�[33Aliquo�>f� -�harF��� ��H (wau3���;:1×PBS ��*J�J2%�3ic;�s[�ptomycfungizL.!~��&L΁�e7'9�  a��ght�ns����� hatc�% [a�Ne�V"%7 snap�z~��O|o ��sx����0im'(Le� 15 d��,j &W �In vitrC�id�r IVLE ) ��mas2>'�In!ef]�)2d: %�d�|X�[%>nix-�+ ��*u%� mesh,saT74 µm p� di� ,�V�oA4Basch's%?um37�w� �VO2EJ%|6��a �&�ac� we�!Qv!'f�,�4A���2e�7)wo��I�6Mw3� . At�Nh #�]%y��iQ��I �i�k|�a VG-*�$ ( Greiner�-On�-Art . N��657638%#�L��ߪ����3y�:�at"� �}<-dM1 �K�-a�7!z��:��aa�a�6^o�`:�5� ��ZIz��E�,l mf�j�-�2� %���boz� , pH�:�`Q&a�t��8�z. Cerc��$"l�w �<B .B �i?�fm��7:� ulaI�8m^d�h10)^��60�1atN5P%i�ATo \h�.2E �  , Pfam .lA5dr*{:�atjl��Tr�>SLr��e GeneDB�P ttp://www!-� 8b . org/Query/p}?Z�$NodeName=S�%N.9Yusam DEAD/DEAH�ic�( �RCZ PF00270�d eukaryd �^7�,���"�6F{so�g� $ .cȲquϞu:�%vL'�7#j�3 hidz�Markov�6f, HMMERZ>S%�����(s�" u!�key��l���h�,query in a m�otif search at GeneDB , http://www . genedb . org/Query/m9�F? taxonNodeName=Smansoni . Putative orthologous proteins for each S . m 5 DEAD-box pD were predicted by> BLAST��UNCBI with the current default settings , including , analysis against all databases us'4Blosum 62 scormatrixnfollow criteria:�Pleast 20% identity to�q!8�> sequence and e-value lower than 0 . 001 . Pairwise comparisons-erformed ��pa .)program�%%5�bl�. ncb!�nlm ih . gov/� determine�/similarΐpercentages . The deduced amino acid �,s of three pQS J�helica!�%�aligned)nrefer%4Wfrom in!IfspeciesA'�CClustalW ( Bioedit ) software [38] . Phylogenetic analysis was conduEs@in MEGA5 [39]; 30V��Ibed5!�Uf)$�.�in�A gaps !exA�ed �Q!mA�t. A bootstrapped Neighbor-joinA�t!q�aIrae?ased onL wholz�,)|z�eukaryotic initiation factor-4A ( eIF4A ) as 10out-group [40!mB�9�Y�wa�1 , 000 a�a�A`:e*s shown��repres!|Y�A{repAXte+s!p whic�0associ%taxa cA80ered together-�g�drawna#scale1$0branch lengthd�$same units)os�evolu!E8ary distances u!�toAׅ e ph]��INZAE[compu!�usE G-e method�� �e�e number.�ubstit�s!jH site . Sub-cellula e� loca� p����� �PSORT II��$psort . imATu-tokyo . ac . jp/ [41A[In addih ,E� structur�aG!Hexon-intron boundar�/�ex�i�ord!}o�6lrel �$hips among%� [42!� Total RNAe� isole��._develop�6 al sɵ TadRNAqueous®-4PCR kit ( Amb��`, Austin TX ) . Residual !� contA5abM�remov)ZdigesE�%�RNase-f��D $ I ( Turbo ,z)�37°C ( 1 �!�� synthesiz2$iScript™,&s �Bio-Raa�0Hercules CA )-75 ng!�t5\a��sa��E%ave ex�uA�4�gEin�Ast% ��by qua �RT-!n( q !_TaqMan�(besE�q%primer �des*!�ass�@�Beacon D '(r ( Premier� I�!�Donal , Palo Alto ,): Smvlg1!z ward �d , 5′-ACG ACT ATA ATG AG(C TTG-3′;CreversaU�CCCA AA/G G TGC CTC6; prob�au8/56-FAM/GTT CAGyGTG (/3IABlk_FQ/.D2Z�(TGA GGC TAT�� 6�2b�T T� C% :�2V�AAG CAA  CA T! GC)FCAZ�3^�AC CG �A��2�3Z�%J CA G!� CA C�A2�3 �%�-�CTG!� A��GA CGC>��]�E�Q�targe�=.@8alpha tubulin (�7dBank XM_002581074; SCMSAT1a�,a�a*' gen? A�AJfoN�AH�AGTA T!QAA UNCZ� GT GA!Qa A!�?��SC2�-WEQ-SC I!�![%�AB . Q.SPCR�$&U � du ,biological r s ��� trip/ echn>*�ac�� lcarriW ut[ 20 µl � mes T)�- �se (nd Perfecta��8FastMix , UNG ( �a��ci� , Gai� $sburg , MD�5he C� ��� n� l denatur��]95�]3 min�ɶ40 cyc�of 30 s1�5C,=p in a�� rmal C��iCM��с)H�őiQ5t ctor sca� p��Wreal tim2��Sfic �� calcu5d ���'$2−ΔΔCt [43JA2mDemplo ��&~@because it mainta�stead��lu R� [44]%�cercari�� as a� ibra!. W� mounEo0situ hybridiz)( WISH )!Gad. worm�]�&  (of Cogswell�colleag� [45]�pdapc q 6� plan�ns [46!a Each.e�n� U� ∼20 femR Aa  ýs;%4exP%/ repe jA)c $In brief ,2C� fix� 4% paraJldehyde8F�Z�� 8r��1,50 mM dithio|itoU1% NP-"� �1% SDS!;nd both T � `�n Ja%^anol se� ,!� o�at −20a�. PriiBE,1�ere bl��R(6% H2O2 , r� othroughJt to 1×PBS ��43% Triton-X 10� permeabil*� � ase K �re-.{!h. H2�a���at 56�%rtdigoxigenin [DIG]-labeled ribo�fs* (for 18–20E Incubi+��nti-DIG  bodym1∶2�ilHin block�Ls�:� overnightA4�gd � als�1nitro b��tetrazolium/5-bromo-4-chloro-3-indolylphosphal%��men� �I/glycerE�%�"�i�a Zeiss Axio Observer A . 1 inverG4microscope fit%y�� mera=$Cam ICc3 c ( Y� Manip��D of!�ia�im3!�$undertaken \2� �Vi[ reO(e 4 . 6 . 3ja:ITJ .45 � �47�{.�m^ limi�fser��bar!Qadjust5� br!�nes� � rD, croppA���lik��� enh�H algorith�a� appl94in linear fash!2a!~y ?re)9cnot�selec�aA'Trans� sm�� Zvlga��!I* �mplif��ԡ-se���<XE�&�so < �a|JA � � AC � T G�  w �1 NZ{ o T C2 6 G� G� M, �� duct sizem914 bp� 2 hV& � �= t6 AG� : � MV�(  DTC EA� ATC v�839 �3~�%S^� v�T!2G>� OV� A� ���� : KZg065 bp� A6A�83complete �..�m�clo� to v! 8pCR4-TOPO ( Inv�KgenU a$nucleotide*.�ie����d� hes., have been^�Ge� *�*� 74i`�ei�}v�qe�ively� reviously�e |dea�4bed Argonaut 2�go2 )2 pJC53 . 2� $. Antisens�1 �4N.�.Sby��%Z t�Y�� �\�eP�at� g��� � tai᫕BT7a�moter5�� �Z��(V$�Ricj)&� �V� ��t�A TAG E� GG Ta~GA �?CB�1 kZ,Ga��mxo'a4GC �� span�co��]&Z62–737m�1�n��XCG ��R"'G Cm�U�.SZ�f:G� T-J�[C�!V�g��2-bV�f�T%䁕=!�CG%�T�[�gZ��_l��L%�� A��3%�6��2��!T!@A���C�{C��AJ�� IZ��M�E�-�G" A�%7�NE�����3r�j�C cW�M�kB�hV��a�%B��a�T��2@ 606m�3=l^�Ti�RG�v�! �$.RV�!V�L�A���%�a���`YIV����!�TA�`)Na[:I��UGI���q� d,z6955�  , 149������ ocol&��'2B'35T�9%6G72& a fi�exten� at !f�0s. R&���A.�<11-UTP ( Roche )F� �uoly� se^ System�romega� a��of��*c PcoU ved�#/DEAH"�!N(F00270 ) or.K ��!'1 ) do^�_genVof6�a!v_g�b*[#qj#A� by keywor�"�$eP�ve hii "�!{.��"�$��4sp-Glu-Ala-Asp� � $degeneracy�m>i�third rD�YP�ynu#o� s diagnoM�.=k8�[49�Howx�2�bea�$a DExHh% �( �x-HisQ>6�"�$t),�#[ x5�! ThisJ&�$P33&�#6� that!��$exhib�%(s≤2e−69%!�! \t�� 99% us sugu�yi 58a�ein#Table SArQ#multiple*� "q#= se�o�&��a� �all ten.�%`E�6| mostly}H alth�,E��,PV%V1 ?ab�"�5 3419�� 9592� 653 At 1664�( Figur!;:"� 33�q��.g,-�6 U�3&s*8! enzy7�*C �vl� DB.� ƊF!)*L� 69 , 7! ��g$ed highQqy|� UF%ti�fluke&��89(r� 95% K'M��84B��� huma�2� Clonor!� sin��aW�GAA2833��9 2�51>�68B�!/DED1z�C .Z|5679554B63BuN)irella�#-�zNgA)1�]JBAF4466�3�9"*5�FwEN��N�AFC17964�6BV72B� partPj���cb !lX ,�>OAA39366 � 1y ed a:569�D( CABG01000013; ch� %2 unpla*su��$ontig 0108�fh ag."�$at�ed 637�9|#l*�T��O 2�1�752>�90;6�203 ) ;J�Z)tR�2�d>�*>�3�5 , 318 �HE6016256/6���$scaff00022�n&) Y%944zM����.�A�i��6�,� !�excep&Aѡ�!~the��)�$�F/&�(q[51�52]٣�� Q La�0accPoPIQ; see� | ��1��&� ,Phe upstream�GlE(�.V5 � � ,\� �to�'/ mon�ean6[[2� 5�.�().!!�5-49 EARKF  foun�+l�!��LT(�An3 [30)E4 5]��� M�1}D\(Y�27O 79ein .3. �..5� 26A��*is ��.Vr2=�B�iBeyond= �-Vcore reg�� eL-m�8U��d% � �2[arboxy iZ.�%F-�YAjA- 5u�A� 1 isyine-r\, ( 13% Gly=C3–11A�A:�*f� Arg- -�eone RGG � .A&m3!�sparagoA�tc� oc1dIA� COOH�. Moreo����Vd 39:�Tr�-d' �mproxi�!M� stop�on [5 "�+f h/p"�1; F�e��arb� K�1e"6� As6�6%�Ya_+�!�2�ea@ to b1catB!7$mitochondrAe( k , 65ja^?0confir�1.�ingW.`e� fami&� it!'� se!�#luster�p.� 2� at� s clT� as�,)gen �O��22|��wL/* *a_ RNAi-�es hae�1%pa:�A�� p.�.U0Find�#!Hi�! closK�-)d!��-gor p681u���!� �n -7a��DjvlgB�Lp# D .� ���1]z�!mi/�Esu�e#�M M'8��xnum��XC., . Als�*we_i� A�N=/>fJ.��� .9vas2k���apparen�!�rf`/ betw�F�d m� d�+tIa�to 1�Z2�Z,M��urn portd �Q�,on�/establis0#/C1R�3�-$-�2Msh%� X1�>!\��cl���eny!�g fragmen.��:�>��. D�&"/}��O>�� "stXu��-.�j ��T6� ��llJ'A�F8�E���V�4 much�ery'of.�B~@12 hour IVLE ( ofo >107&�2�7in�:0)e to a lessA��@ &!�%. eral�patter)16��%�!�iM!���*g2J3t�΁�panels A��CU To%��7�3M� {�<�.*vie3! �}��~ .�Ɂ%w5�ins6m��(.�$�%8.�*�%�_�Vc�^�A�彡�Cov�5m( �1�U�4;%e\3 �#9n�t� -�G�oo�%�'!�&y� t��), but[���6%��l���) ��.Z) M.�F|r&- Cm&��%�"U��%�AF[>h� 1O,*g M� locaJ(-�po��(� �)�Km�,e oocy� m. .�*nE );89n�1oj2�hyF+)�s llel;"�'-{ m�!�թ%a��!� i-�.%*�6!X-E�|ev�U af ��(-3tes!or��i in mk+I(�Q�@"|.{to� o�"�T�)E�&�,U��(AE=6a(�[F,,(W ��eB111� he�16�&�"Aq� do�.�>!�! il�1stA]2�&r,� `k Rer*y�8�5e�}<invol+inametaboli##o8 es -��,. -m�sp�"n0��dbifV ,T%�qX� 0 Sorg�*le�q.���ndecay&�T)58�s�V-��iDc�(r :!�fur�� �ro= in dU�>eB:p5 [5,�� � adenovI�1"#+(� ) *Q���� typ6 perh�=�spens',%� zoan germ�&�$ marker [1�1�8As befaa��m2� V�MB, �s ic `?unw�ng �2v�?X&ir:0E)�a�2gulG0!q�&I � m�0en!�A��s � , [6�F�xam�i� melanoga��� play�0key%�,aέ�zR�io�2� +=kRNA��Bs nanoA^gurM,AdgOsk&8( [61]–[64 Re�@&�8in)j�!T(in non-mode-�A�ls�=��.at 8 �U�>a�a��B1s�m=h%xei-�,a�an�catalog*E� `4!C!"A`+!X9+ �es�ot�a`!.embry= tumo�,�+ord>R35}v}!' .�, ;4a�gre[ )�pia|��� 65]� Dat�CB�=)l!�at2d hA�tlCV�,��:��&2 rtoi7&� 7B-%F�r co!F��36y��>s [66M$Saccharomy�?ce�)sia�)s 26 [)22�-kn�@�XPlasmodium falciparum ["ws���(>H  �nd?*i��1��&*Ar+Va�VS�.�  � %F�17x ��to��r!B�H+�:)d!>7!>2@[19�Xenopu��5]^ poss�/k�nemNemat" lla ),e!�1a�wo [6�M2�AJ)*+elegan��4u���V8D!$F�� z�� R a�"it!�[a � &�,v$"��V ���+%C�i�fa�yR2�( �F!d��%�i 3##Jq� BZA-anI�j��6.� �2 N��c�'�BR,a2`6�6M�!� earl�>D ��nL�>`E� ��3� �#tW alm�tyi�P+(  �5d�'�$; ��A� box�9E`p�h �B*segreg�Gin soma"c�>�� Dif�G�% funw;]�&$/'�!5E%CF#y e�uncx4inty ab�;2�Ci�CfS:i8 ��eir homW<$. �is� restr�J+ �T��is1�3 numero[� tissU[7�7�DNo�.0�-�!�ED1A�yJmay�requi(��6i *�Gof�]Z [7� � b5r%i��z%. is deri� �$a^c!al 5�gen�atE�i&ly ac ��qficA��h� rm)N[2�M�-2�"�����1�%to�iabks�69�A�%'q�A�to �or ��! ��q�Nonethe0F a16�J\corrobo�9eJ!ed�6��!� 3��t&. S%QuL�LR<S  e����10��68}tiB�EV59"@pluAe E[� cA!ia*�(EJ�A\�subNJ^�b�9�[*& M%�  QS~� re��7kef�2�1�� F�m�"�&���B(>e-;ROjF��2E��IaP�{*"q"F8!*�W �e!�of|, Glu�!>�in�t �alto�r�)dZs!�commo�9 !���Mo"tat�a'N&�Y���?a�rt6WE�g?�BRepetix5&Y��G� _s9H:��*� �o* *���E��[7�!�T�� a�r��ou7<9 ��ba�ng���?�y��Arg�hy� [74�7q�>d> Dani��rioE�Bn F >�28sub� u�K{li��I�� nuag.?[277 %/ ?�>I 2\�Mpok gran�H(( also vari(7�or co-S(P-8, P-bod��, �,���B loud!/M�& atoi�?7EK*LLEy!�$electron-di7Ci� � r"w.��>� (77)��I"U#, f�!� i��a3 CmL�: ,";to� %���$A^�1A~(BQ B& �)"F$7H"�!�a��!E&�!q i"�!�% isa�2�+ �)Lb�profiv�u���5/3)f"~nd &%�� � �jm�B.d &�R7_.*� h"�/�old�&M o!�e%sA�i�@ly2�- �LI�in)f!~fa� er �FE] ��omaN ɗs�Q-�ed/�r�AWm��)J %6�. If L&-�h� Z[8Y To -�Kfic!F!�%#omy.< }�ş�; s up�ma��H�2!� �6��is [82�*� &�U>Z9�Ur:�� � FB�[�-�E2 �3 :o"e��&ga��a�I1%V��6yO6� D �IWr�,"%���I<��2G5iB��IfieTZma �>+her�4cytop�ic��#���"��\. B�3%D��� �NbsWiwXed du�5PrQG[83,85�J )x{ MVH�y ,iEQim�  � �U"$�} �[8> _tim��E��m��}yofE���Y�s�7Lophotrk 4. < - ake5ce�� tinu� -��E��T�6a: >�ulta<r Ac.yit!!e�feasi�oA��f�x��a�b���Mm-�s s%c_*� si| 'CC ijB"�6k��.Jno���@~�b�lu��Ō` alځ�Ň.N$to monitor�A�ť )i>7% ��"j�"�Ximpact�Y�� a$MX.�a!�rkT�m!]�"NA��h�3 , [8�[�8oimpedHIa#��$ ,��c.�-�-��!L���� ��om%n!7��E .�'epe!}�: k7�N mole�NrNlog2(�1-� ould}H ���of���Dp9�_l�%�A��5tm �G�6r� " "f/'n!�9, I%)�}ic[Zll%Dž�,n aAile" -$a��)l"K hermaphro�cA��4a�uke6�silenc��>8res�:��os%�%!s2�� willac�Jvan�IE�&6)!�. Fin�ɡf".`up!cst*�!n�WeH`i%*�m�"!ź��6u&�&sa>5�%y=�( survival [C nd h-Ay*�(6:��RIF�WvAe^H#t�xm��%worthE��2ide� n .�uHeqvalveAg~ �� maj�li�SproblemMldw�G . Ca�c>ټ �omeosta�Xne�b�eciF.�S rollHHippoz%A:�sl;����e�.�ei� .lU�ts%�!� ����morphi�m�e�!re s un�E. VGLL4�a��� !ycos in �Mb; �w;und� 6 Ul�5��4%v%��]�i�Z -EMTɞ�K�!Sa!A=�����_ I�_ knock��) � $�tu�� 6�)�~q�<end� l�> !�?J�mal9s���an_86�YAP� ��We"�$semi-�'in �ab, aAaY.q�!shy��prolifeM�yr,]alMJx!^ sign!5a8/on�(L�Jf� �d�>� -s��ort��A�) >man2�OI�on�.w�Y be a��apyXp!�� ]�de"ofa[� P �ii�. }� Re� �d<3kAZunidireal"=owB %c� �", ensY or@ aueffici'"# �&h!� [� �� 2.a�bid��Sm!n�wo��t1inc��c�cr��,Xage [� n:.�stEcwc]�-to-m cchy�5�( a�Va�:)(l cus�P6p!�u�be�u.VE[.invad�� he�cf!�tr� ( OFT��-dq�xcA��lva�te:t ( VIeor �"( �a�Sub&3, neu` cres�Is mig� q��.WG299_!�#NN g���(h( ECM )��=&�6!�e�aGi)( � leafl�*%�! "�!�aVQ��Zri� h?e�gin�� fibrosa ( il!�collage&�spongi *�o6Ta$. Dq(is"�*O%�&6�Oapopt�&��EC!�� p�Yr�(ed�, oa!wur�N,Ŗ�<� �V){2�[�0V��q�3Z�8 due!�b �I�cQ02F�!l�iin�[io� 2-"�d9s'nm $s�(�$attack �usu� lea&#�Z��^�st�*!Ve!� / �A3�28st : bfailu�h&3A& mechanismI�l�O1Gt"\� * `in���Qly AstvBso fa g�pathway�n�u�ar�8��\Vd'<$Drosophila!�hQB�iQs�^:f, .5�,!B�+faW6X�� �Sam�> � r"SN|!stu�dY&�ht��B�� �2��nicU}.�0�) omy�:��)�rXH�[7–$'�N pm+im��@ .�e ovas�Aq6A�sM���2Kfar�]a�c�trophy�a��osclere�[10�<žAVA� gial�(� )� t`'-s(1-44 c([i� EQ� �HB� k .� [1uW�)��"hS�|.)! n�X� �V SdBP!F.�A a%e�$�� �TEADs"�� chm��a�in AA�of;�YDB$overgrowth%_�+]� n�d lung��cu.4!xE�I�C!xn �|!E�)e|� 1�� �I{1GhyA\@<4! (�d.�E��e- �i�f"� H�w l�> ^r"e K��Ya�e - �![u5�%��&��y � d dra7c��in2�MJ� �)D �, , *n u!�. s�,A �2�CreI�tog � -&je %$&A-}��ontribu!q� K >� .�� MEs.�6� l ]);2�. M�� �&6~ iDphenotypE�6; e�)�de��� ^ rescu�E cg �/E� 2!no�b �.�b�tagoniz�ȁ"�1. TVn,A�a&'1]�Ja!�m*. T�#udyE�.� �L^��first�k# d a Vgll4� 7e��- 4��-�6s 1A �S�f � �LrosO<a lacZ�C�Sox2Cre+I��Bm��j�CcombiS`�l� ��{�a��rocyst5 gE.�%ob�v (e h"3ozy�t�+/-a�an�e�<M  lian�.*m�, tD�8�I�g'Pte 1-/-5Z mutj. B,P�we gotW ~ alOT(�X!� fl ))L two loxP-+$sbe9f f1&se0f�(%��5o)*�Y�is�la�=!P#-zr cascuEFLP r=�E A )�y ,�(t %aw�� :���%�czC6ge6 q�% Δ-6�W�al9 I$s!�"Z I n�,A�.y�c�l!�%�� Pg1rM, ��an��A�& shora)jbirth �s 1�=S�CA�,�Tfew:����E8 week� !��b i%s���6[sma��v���)M�+and z+/+ l�RrBA�trols) neo� ,?�) � 1%1�hWe� �8!$� , XJ��Are6�%�B�ų�5C s r";"b�0�!� we�a�%2 � �R2�i"5�a�-/-IM�EE�T�Rzc�-uram�Ta�!� }�<��.M2��4u 4�-e�����joRT^o!�w<r�d2!�"�l /A��>���#i��of.�1f- F�1G%Echw�xQ �<;�xinU�]5Y�Nt2'E5!O63d�in 14m(aRFig�Pulse-w! Doppler&�& ed� ur�de�*�caor�0 ( AoV�2D ulmo�u P..-c��e �BL '�!ed~pF�be-rj.F�1��T6�Q�!�bl� velot/!{'� grad1Z o q �6 a&EIB�N� �I�1J%��ej.E�� ( EF�i�q�geg_ ( FS�,�G�R� xK xLS1Uq��e�A� �e�II("�!M�go%ens�;y2e,8<e�%�A����VtA(. Sirius Re�-azol ��!%�A�zPV!AK��m&�!thicke� .����WY,A��R����Fi��M�P#S�EIn��#X@oVPV����t�U� spidi@s&6� at:ya�3{:$w�zt� a"� 5� of�K6�� t E1�K5)��a�!��+ar]os��� �R�+ ��� ( S4 �2%%�>& ads!-���p2F!,2= BW#Iy�x&�@�@:.� E��&�,!Xg� "6 ieGFP/+ C2� F� * fuŽJ�i����o"� Y2{6ra;nd GFPA�i�ef�1�NJ� ( S5-��2� F 2�i&eP"o OJ )K� :� �.g%�^G* !��;lEnrar��� ��#a*� �$day 12 . 5�+ )mb�:Ak:�$��A� dti"�g}�e3k<5�!nsafinOKOFT��/Ic"!'u�w�V� deT��2 2Be�]Pr robuW[-��!D�~����n6@�!"QM��l!<E2�. A7%T,>�� ly2��C ���"�EB+B� �2 Our $���:Ys~mA�l.~Ot���!<$p�jq� ( E �)K��� ("� f[%D�a�eDy� prop �%��A*"� =� soon$ iCQ�2 viaEkq�"�&� q.[!�2B�s��Jm sourceElunarI@s[1S>�>�� �RosafsR: ��2�Tie�or Wnt1�+�7�$"�F% f8K �orN����*%���)Xi.� ( S6%�)�U�#evi(t�GF~�+&eA���,�=1� ���&&- fl`  v�0ID lrE8!r"K!�%�"0� �; pu��"�tt�e>�( 22/88A��;�� , 23 V56fl70>7f�. Hl�l�x�. .�6N(Jm- )�� � !:� s �&E�E>� P ]��3A–3��Ab)h:���p�$���b.� t:i9-month-)3)�!>A15=- ��E� � h 6M;2 M�QwntE�_$) didn’t: "i92� % |Aw5,n�uhe:��4$ �#��B�.�M�s:�'6�2�a?I&�0 R�i)I1:`)-�mF� W�>� �de"�� CtVE�� g!k!H�.F#E.�^��CE�F",&-6 ig 4v4��a&# left.�! masA�6D-S2"A"���ac n�/bA0AeK}��v� ( HW/BW )�ii4jA4��, B�-=R��&��͏]�m�� r��N{ f98\�nb�&� `G%P4a�. WGAg� `��!/�E@a�aeaAR "Z �V�.�n4n%�H��6V.�u>"� ��"� cap�#y vA*l&� �Aga�\u֊�,�� cham*X/ no obv"6�cce"�AJ�I[AՈT A�S7E��o�# <& aO~,#� n#Qs2:�~2Jr7 !�]�um �@)!. Giv�%�o*�!�"�5o!**�%z�%�hyp* �C"�� ly"� !�te@a"J �"�$����#H�e���.&AC-RG�+m��r�po"?y.qMtu�Rwe&�LC�e � u�*��%�-mi�^!�� -fsRfp� a*!yv�� ba�{E�2 l��%�$Պ*=0m�5�XA�Re���B�fT~BVflg !Ied �G ;�O e�%�Bd6-!Bo6# P6� :��@ labr|w�RF� &,,n�Fv-2�e�s)�pa�a�" EdU!�P10L!6��ICeal�I"hN�+2Dm�i�+��,"�4nng����!��h4No6c� �g�05�f5�f,. Immunofluo�}0s�un�FvVl��*�E�"�6�!t"�T�6�.��U���+. ;,I�m * �%eas�S�"�3 hard"n��B�R�s� z�R 6NA�.�q�B��%�o.�de�� ɚ%�E�ermQawA�5��!�uVICV�6I�"n�1 #�.�� ] �wa��8#me�M��p(G&�$fn& �H���7R!� autono�iec�*oJ��q#�_� �H  i�}f<)a ��=:���"�4�s�~�X6��-2�, <)��!a�Xe�. �E"��"k�� em6bb0q� i� u�ofH�8: P<��(�qtn�C�,III ( )%�Versi,( V���E�Co/!�"2�� co7� 2 �d��i��8e$)l 7 �3��m&F>hZ DAPI�k�  V0qV=71!�"�]2)�! q�B- *�:a�"��% aU�vqo�n n 9)n��2V�HF� )>%�e� �on|e%/p2:,1�4�e)s!]Bt`re�lA�� ssE�de���6"� ��iH�V&4!� (*��Gto7*)�j&�&6?6��%q3��^� � �7RL%C��ok[sup� ��.����i�2d�<2�2X}�,|+�Ga�2�V�|%s�B�9u�T� � �K� *s fl;Yapfl� VT�!r&F� L+ K2�) half!�!X!4o y A��ID�$> )y� ju -� MKZ������=F] �M}�Tat�?+A�e�ic�%xA����1wver"�A!����6�6�B@"�z.!G�g"� �)A�s5][S�5�J�-G�hd�a�q �&%6[3*[&� !1*t .�V� I�M�6�th�Z`��qPE*�!- �s6�Fi^�,"Hf��p[Bof*J�,��u�*e,6 &*str� down:�E��"F�, b"�)AN�< Ctgf,�yr6aUSA=;K�xa3n2�^u ��sal�2�1^-��6��6e6"���lB!� �� Cy�=A^Q B DceCdk�1Ki6�v鉢q *k :�5)96��(� �9a&���w�Di�6!�V�-f?han^-�#6�2. $*i��{ ICEi.�;��� gi )z6��Eby.�!p�C�io� X �Bt42k4%6�� o�!�gm)��7.��ZNzsMr�UEr!Sg"�LJ�( P5-ethynyl-2’-deoxyu��neNdUzN�:(�6��(j8t"�$�Ur.P=�6kBH-!&-226�#O�~��.*�7k$� *�l�sl6�v� kI�7� 7Bg *> R �5pl�7*�@��Ay�x�U.�3:��@�.U& :0�  ۞BTUNELa�a)1��o6 red5O-��/An�V��" %6�I.��Z �g���0�2�:ICFWU >�MP� FM�o -���7?a�*�$YN���d%"|?am/^J� EV.� . T��t&�2!p abov(KB�6�a�t<&4&&� by��!kae�� �*�2�. I�=�-�2��m!j�Jtic/'!��l�R� 5�- .�!VF&3+n*qA�� in2M�CgssisI -a A?n9?p�{�9�.�  �>.?Eessw)�*=. E[a��r� s�#O �**U �f>7��(ۘ*L.� "�#.�By. �G�aV7 Rx"8 Ap-�vsin 36-s< (oAd )�  �)A~"5 ![��qZI*2�r�l}H�/I�!s�I7�N$��y!aL�<w� �)�*5%Wf@MI�&[i_HcGe�-�:A2r4���!�V]F�=��%l�g�{Gme�Oelex�g ��R�|h9vwlhH+Us_Uch [27_W ;ess-t8 MMTV2U&5; ( WN�B�XT��a�G�;F��betiA$TGFβ ) [2"JB�dME�a�0P�� ( BM�j[23���6xw�;f[��G^[2�{"�=.)(<2VE 35]9)�ID-%.F���)��t�DQ.�6�.ebQ am�AA946�.+ ���!� &9�"�:��R�L�,is*dˑ>O��,�at�H 2EE�{iIc E!�i;at E9 2+ �k�HiN��!�`l)`6�,t%�aFu�C� �!t&���+ lethbF[2�=6�d�.��&����*� �fpos�I�C�,5 7Gl5 en u��N) Q �\%�vRost%OH��_ �J�02�?!o-ésxPEIQ�,Ag2� bala�M!::Z!4�n-�.�!�-2�� ���do�%� a�lNA-��� M�med�F+*l�|�P�@b+��vF_ 6 q�n[�b.,nI�!!�N.�]!C"� ����TEAD4�ts TDU ��8&�;om�@ 9!�K�to L��A a�,l�9>�@EF��j�@'9!>th.m&�6}/�.��{��dCTG}6 CYR6� Xas2A � . ttenu`*���Aor&"" [1&zAS1#thinkQqF,Q]ls?He$L!�N]Q#})�i� !� YAP-��&�� 7�y=��"& �F! .'�Z� ,"Fbol�Q� �&ߦc!A�b�{yG6� capaQ6. B� 'ur -�.��r� A� *@ [�(}y� >�N.�AKI�)��/�/�0Q�e���.� ��!���!���* O�6�nee)nbK �4�30F%���K����oy[�f�6WJ|��9a��=4����5�� f�8,�5M�5T�8�'>�hin.# �seldom�uinB%o!1( S10��b! expl�dEP :�#"L))��z�&~< �(}6� �*�d�=0!U?�u���8jn�CY?~yfibrK�K��M�f�%[}�Ώs�J%M�?i�A�?�X-�^a��yGs��"�s� &�G!�cJp"Wb���h �dysќ*? � & *4"�8*�Y_ Khi*j%�91"��U��a!�b*bQ�I� F�A�age�c��"� [ zm�f�I�.:� |&.o7N2#:�A��ew6�"+ ,�!-�wii��! %��Q&�&g+2�%%��p�"�ti(216�#�*FS"�Xm�"%'6 le!��!�-af�".*!�6'"6��/!T RFP-zn-N<)�s�=�.I �%F�z9ifX-oin�>� �1�!b.>2��y�F�#� :��:!�n�`&� a�?.mF{,��� ELFy*�>!e�2� l�RU6�!i��#�" ��Z��2twJ�m� D�Rb�h�l��,�i�%uteru�Pso�m,w���yJ.H<2comprehe���"%A �� �o"�"�`BJ:*�:�?To�=5W ledg��19�� ��ivo8 �sZH � ("z ��R�i(e.�ae��oH!!�2���.�o�%��in�aA�&z&.�< ᓍ����!s�&d �eN.):���a �z3u��)�P� �S~ FRaII.}oguAb� � ����o����.� AK:�P8R1� V�>qrM6�L�nd�u�r�p.cU�*�F)�� �!f�:�*Md"JE� lzQA�*�r. Z:.�js���^-{g�)�_H�" -�masde�t�Q~Rn�W�G vdy7�sia . Wn3Ja&�z$( NM_17768�45�;l�H��>CJ�6 ��duea L'JpH�fl%bh exon1/�i�H�s�qn!i ��ENSMUSE��0197361�:��=lo�I{.%%a�ES-�/ EUCOMMA%gra{�ID:7852�G� A"i Qk �,M�3’ ar88 . 7kb�( 5’6,B>%b%( 413bp >WT70 %j�-�T��0?t �aA�B–S1D�M�32�>a�/+r bi+to Flp!��Yc� �c�nMEmA$V_��M_����"fl�"N ��z}6 x� ele�9oA� �]1!-/+�Cas"�%wR>sL [29] ������:���o0a �ZQ��y��u+!a92�s:�"JK!��Gen%� #J&�b�( [( 5�nhrU al%7:( 616�#E�S1FU%��AZ�Ai��V*-Wpre-��A1h�"5!�%U�gXZ�vle�qOSA�e],CRISPER/Cas9�#3ke�,Shanghai Bio�0 Organisms Ce6S , In[��A9��� ��B>�B��n#�A4� !י# �5>c% �� ( 749)�nd�205 �25�25�2���)wum&S:� 2�>e�!w� x �:�0�[? :1DRosa264&6 [32]��"�K,a��-ul�G�!N�Vevo2100��h� , Vi)[ Son�)�%n[�Iparame�U of M�� B�mea�Jd�:�a�,;R�/ WrKsep���HIy ( IVJ�:�;=!�'h��( LVI�!.o�p����w]+P�;JZ&�# Vo�?,J�<( ��Ja�B��< LV M� �.[p-p�d�9in Opti�aCu�� Temper�K( OCTj?mpeRat -2���_n s�Sin -8!�{S�Me�prM�� t�{μ(ici�c��on sli~T.aL/Fast Gr"�3�&�:t.i�P`.,1aT`�E7�[`[3�[He�w xylin & E�kgA�r��ja�� oced�é9/M�E2�  ����Z= 0Leica M165 FC�reo ro�o!P, Olympus BX5?�aCDar�>��6r�:q-�-J.TW�;�\{v-��Q"��^��� (E �)'N��?|4� )m�� � jm$ean ± SEM�#or�7l�)��e"|����)2� diss"�0�� 9% s�l]n�O��ubc�Veo �K regn�7mͭhde`fI�g/g��Jbe�KAoM�.��or)�m~ $!Yn�O-�l �A�t 2Ysb��$Life TechnA_~Click-iTH Alexa 488%�QKi�9{�(J@, C10330-. Cryo-1�m�%�was�����fijȺ�)1��a�i�HѸ` If �!�1% ݹ X-�h5%bdon֋se��at�_m �e��vo�>�r@~��Bi&��at 0��7, -����� )ZF,�1I,NaC�!65%� ,/vol Tween-2Aםo<5% skim milk pow�^�.T���m~��Y�e�A4y>B�F|) n� �XB`�!�%:pHRP-conjA���f]2�v�S�Q-�"�%w �=ch<=I~s*A( Pierc��2 �manufa � r’�s���/H/ d���by ABcl?WBio���y C��Lt���d�5f�[m �졒��2�Ze�R�A5�� �,�dB.5a� 6�� } ��#5S�y!"g�pooa�%�rV�z�nga�m�pl���A9ree hC2�&x�& �gr"��s � LR��eelt�lE�TRIzol Rn�LTuo FhSr )�s��N q<sub� Z"�#��cK��mRTra Acp�RT�( TOYOBO^Real-3 k�&? H SYBR@ -`-Ma' Mix6SGAPDHk� aA�tY|�C V. AEFAtr2�a�E� �!G62Data !��Q%�m|) �us!AanȪOlStu��eOt-tes<3U!c!@id�m��G>.e ""He ANOV��l�,Tukeyl"�,d~� gU ce�����w� P<��0YAll� {-�t sH&� ��S�z�F{d� pEO a@$}7XЌU�Z l�,?vߓ� o;ngkt�����텉Ka�on� bene)jt$s—so-�g�uoft$ o weep"z archAha�oz��`[ �'���O� &�I6 �1d�,� %(p!�yeH�� -s+�6EW�d�arg�8�3��)� erva�& c]���/e8�� a�e�!���J%>� —hxm� D&�m�HIV�,eA��rKO��val& )�xce�S9-�to F0j* �EQaAifixJMM FS$v�� wn�-9� �p� !LAM>MJ%LOe3Y�.�,� lookr�cil� AopA�ng� 4by�efu�!- �qrV�s�$�th�e �o*��F� . Us@=�qthe�� ��"�(�������u �t ��  i��!YXxtremel7�s�s�"t�5a���)c�+-�"� M��7+�H Epneu�]-�"4� �BA6� -fit grap5@h�Tr!)�ge$�Zt�;rveAdA\fparsi�5cW(��!�!2/wy.aE a neAO� EV�@}�,!�t�g�of EWb"�-heav��assum�(-ladeXDd��W=u�A]e��)́�neg�" ng b�^p %i�X<��iD&� [� !]1C null5� � deca�,2�NU&�B�dn?�m�2 ism 2�ma topic,k/i��Eۡ��R}!empir "o)eldQF1� Ini�zeffor���^%c� arKMAɌ� �{)+—�F�Oa8&�+q) 8�Hcts up newO7rie�JT�b2ZJA]fix��d!��(� Mayn�Sm�& Haigh�x�U�t�#en ,�)Pdonڒe_oAW)s���&e z *yۡ�.�'�j��/ trug � �wp��anZ�h�faJl�F���:EK $ librv#� ��J�, ZV=0(bottlenecks�eewA0Sy!/Oe��/i�oM�1�26hovn��a lack\e��cZ}r `'spr�u.:M�eH�=:ntd��(��uz&�1 B��� �0�BFII�i���or��he�)A�of�-6 sG�mp���t�:{)�: -� E�/�$&� —nJb�.s mS"�oAgo!h"-al!f��a^2c�mf�5��-t]!�b )y$d! v��RU n�y�ind��ly-q���si� a�-"��3op��o��!�u�asM7�6Ձ�2eZ LU&�#!�!i�9� 5� hapl�1 �&eof���'���1�9c.at �'val��9SJMV �"yYon&�8J���QY�I=L>)<� backAnd�5_ tchhT��^��6�!��n"�Mo��eޥ�rai4,a�"��!�-h themselve��a�$*a�a�� "T x�cy  �h.+� . W�tu14w @�e�f��, Sch�r e*% . [6]�!�]�Z f*�)lso a�ply-utu�6���A�)/ɠr�p�. ��^WbM-�v)�/e on/of�:IUJQ��5� cour��a *&dIJdo7-!a�9i�� ��Pa!���ii� @D l� ��N� W}�C be b��� �8Q��c��= auth��a &q‘q -sy�!���(�Au5*�)6��� mis-J��/r�a�.!!U�$�~�%�F�)�E�N� , Or� d Be!a ourt��; T �7��>ihmaF�ڡ)ch�&� �1s�E�e�B�>whe�AN� 6���J�A�i'�Y�m�v �g� F���)�y�.}��4�,�>L� w�6~eEss�0�2=(I�g �yO�-�9�x� �2=�O��D!G�>�[!�@&$q� p�#,com!�=�( i .� �*)��� eak%��*r�� f��af�$bJ��DQ*��A�%^ oughF *"� !HA�s��Pe��9�]�t%m�i�AYs��aivu ��ah�Reg�XS�7rg r��a�MB"�h���e &�7(!��2xw̧N����Ml "� )A .o ��"�"�1�,��ly-o�m9�5eU'!\ shife�M^p~s�&�/���9 AVa�erm��"�F�i��!�}�moT-5�� $Jensen [9]]i1 K;i)�� )��\.�_2���mсL}��-�}��.�M4in{8%�rel on: �/a��}i��e!�%?.��(��t�Ao!E �"* }%6s)E�%�b �� be mX9sO ����%�&Q; Garud&�10Ԫ,Iwp8jv  must D 2P sojo��\.�41(;˻�rg�/5����!C|�j�A�s �}��Y�)/l�*�� \E��dM3j�� ��^=��c2x) ��K3 ll�1%1�n��cM�of��^fe� r�ab]d�TN� lcr6f3u<�/!QunE�yυM�wo=��1��r!E]Vin quick��ceC�, i| y�y"�E �=!�-:�4mܩ�ɓR%72� d � l4 ��yls0!Xfe � �5- 55� S��A?�qa�me�J�52/1�i��� viru&( o!�+(�ɑ(enthusiasm �"���� 1m8�'"��n�&���:wa�[.N -$W�:��*�mel.E���(g!�a��}"�&aeā)of=�f�֡`( �ced H1R#a> H2/H�s�`��%y�Aip.me- y�I95, *� !�a�m�top 50"��$wept  asQ%�)�.u.@��� "I�K�z[10jNa^d� 1$�D���II�M. Loo�xsix7.�-2iJ�YD927� ine�>S=8-776��v,6���2�(S/HIC��%v m� e�r�'� a�5v���! � � [1��&��M�!�6 , 717-1a��up��sI!� �� d"`198��201��Fe���Fp vi>m��f�O�WlW�d$R)*at ~5[y� drug"��  �9� \�a�"L �I� heB�e�.z� 9" z% "�UX�ii� ^`21adp� A~ �B�o�roc_d ���#�Pin):&I�U@,.X�.M�!�c�Ew�&�p�ĕ!����c&�Z Verb�maewC� � �no&jX {�*�!-~� se �R��U�6%�jg�#�:��)�'� 58R�%8 �.vG] �ga&�X.�h�=ԎD6@Nk�=n�6ng�[e�+�c��? ves��! ba4.��s�!r�claim;ca:Xe��N5 etho"| �i0p�Q3� "� * �}�'�Im"�?y��O?b)�����aW�@m�)�, ��W� -r�:z/c�m �&"":�s#6��new�hoC���ya�h"��3� ���� ��X.�.u��su�EF>���J!8L�coQK5 �7B!Ll)/� �%^V"g a�&a6H}!kF ��5  ly�u�g���!'� �!->b �^EbE^e}F_ �$!a�]@^.�- � �"5 Dqzl�g�>�)�yNL :�!��.\ .IkYlS*!|cQ1i/� �"4 � �DH�*GF&%E��j*pe84 � `)5��,� &� � I�Aq6�yb @$�[2{��i)R$�w�$e��$k�� broaL )T6�.�. I�q*&�"4to examine the�L performance of the H12 and H2/H1 statistics on which subsequent claims about>modJ�selective sweeps in Drosophila are based . Both hard w soft4result;`reduced genetic variation��Uhaplotype structure compared to a locus evolving under equilibrium neutrality . Hard s ��!ris�@a single high fre!cy�at1target!\-,on , whereasZ�multipj]ls . To distinguish between n �% r�ed regions , Garud et al . [10] propo!��!�s1��ich cap!Ts#degre%9w homozygos)@By!bin!lW1!ies! all=A%�-R.,values close!�oneE;indicaE_of bo^A=jmallerRA�found!�$n many low�=�s-� most"t\!(they take a�.�-�)CondiA�al on7H initial ascertainmaTof5�i#on%�,48y further parse5�harF@(from amongsE�A� utliers u!o an>�� represent)�J�buV)common9�( divided by�N@U@E�he expecA~ on iwat2#wiE9 ve laW1�of H2 ,�%�.1 , leadE�� :�6]. � reve!]is ��G(be true for)p��. WhileN] demonstraC�EIeane th!�U�s��8y across differAi�!a�mea�Ewneg�g �pro!r in��4 necessaryaB(determine T�0I�) I error � more real�ec�@graphy . Indeed ,A�EQned��8their Methods s�o��a�.janalys� 4U . we�� nduc� �b�M�,specificallyq1did not!�l$!�abie���=�to%$ ct p�������or"1� iateI >�, withii�contex�:X non-.�A1%h ic histor�4 . Fue�>� se limi!.@power͵s)Bm�ed onlyE�in�let�� ( i . e .�he �benefic��muy�at 50%u�y-� populEt0—also shownA&10%%"90% . ir Supple��A�8Materials ) —��con��e�he5�,to interpret)�v�G&?2r. Giv �@rapid sojourn tim��aR�%k assumpeMe�A�m��Ion-go�(is peculiar��a$>�A'aa� scus�vin Vy��4] , H-]�ialc!]ed��@ fixed window siz!� This�,roblematic g ��*M��OD ffeecby�� Epor�al!p�h!�strengthGyaApl��% recoE � . Uny $a scenarioB weakNm�f^ JI)�fua�swept omic�may be�er!�I�6.I��amp ,:lwouldHə�g�M!&� ~ sq�ahceA�ez aI�)^j� E6��� corr�yin��� a.�( a��!�rel�Uo%n'A�-sh�er' e%� describ�Schri!�" 6] ).�]���6�2 flexible �-EQapproach�{i rd- �class���s��8loci identifiedA@�)"sA�6� Fin��itA�imA�ant!�not��M�A m�� appl* onAkBpwaI�*� Gc Re1�PPanel ( DGRP ) datase a��_inb!�lines} LNorth Carolina , USA��extens�be�!�6& ,melanogaster`af plex%�6'��inclu�*admix� !Vwm�p���change (�g�[15A,y�At� ls��parame� spac� �g� 6�o �1f great5�c�"VDuc��U��$themselves%�d un8 ty!K)sAmericanB�y]���k yp5F .��it b 0d a 95% crediIŌvalE�ea �cir2M9-estE��a�Ra� than��lor�7t��relevaY)�R� gene��d6a� ��!�y�Q.�( so d��{F= �;eqhas uni� ly ��<\� $genome-widd 4v� )�sim��R- Fig 7�EF#w� consisa!rwo2 �l!c Ne = 106 !� 8 )�wo!GN ly o�� ottleneckAof� !xs � ,L�point=�ofR�]  nAKcee to�DK,top 50 peaksex��itly teor�gru�0d �Z> � ��ly��imeAaE��|candid�;&�pro� �s*�. Follow!E� logiFhow!* �!,fanciful� clus��UG� re.�I*a� shap�VR� *�� A hA]�!< =6�appea� b��  (e�>ve or�EMddres�B narrAion!~alZ�m , we firs!�accoun�!��" ��-��.�<se]} by s�!�diQ�  U^��!]� o��n���.� ( S1����For .rando�drawn �2of8�!Izpo u�fwe!�e��C ,> itY��,i�. A%� ir m�ologya�D Tply� !#��5�9� u� :�l a�!Ii MgE5�'.� Á3%�J�u W�Iem6j$ . Similar�wer�whe�1��discernv.�isA�eu econ�w��_� empi�hl �!����i'5^t�=!% ribu!���� � ferQ -B2�h�.�we'� �[2S �adequ��&�A�2�� ��e�he �N�Matchede/� c^A��McE��c���$( � a[qu� ys > 53%Q����adq��heMY�utiliz� KE!(�8M&� ��po%O minatoryi:i�-)havj��646�( � S1���� rrespLr+ no n}$vo�ny�g o��* �Min ��z ainY 2� . S2EE_A?e�zu�s�)n��400 SNP4s �:� —a�ced�� es�i trm!%Aj��-�6s�eb��duc�7�.�a�a�����t( ,gcl" q�U�FBFIV=mp-�@a m�!�J' ����� !��.'a�F��i�(a7m�2�of2�y�q�33�}og�~��r���author'�a!�O sY4.�an in���v-�a�~WisX2� �, ei�atl�!Fcase ,"qv�&���.}Œsum �*VE� �+i�s bRes&R+n de-r�of1��h. )�����6X�sv0mrace �}by��kverlappa�.|��e��F2�H "ovYQnA� side:a2T fiG!� at�ijap� iA$$+50���5�Rl re�>%]�. I ug�~2�,  e�� he2�� � 8 itself , S/HIC!��)�P t re up�ieJ summa�U�C&^ya!f -exaMdE!�:U��6s�, bef�v% -�Yq 9.�to hum�$lymorphism�M. �is4upervi� mach����e- �_�esBoi�: r(categ�(i�� -link e�,or1� )A� A�J (��or edg�! ��raS E�. Becaus� q�perturb� mask!J� signgof*� , aT r muf� chox an!�rops"6ni<��)P�� >�[� pub"� [12]e����at-�| a  }"> cA6��1 �is kno� prior�H"��1n�J��i�actic�� M�a�g! c mis-"w� . Som#QQ icult)� c�% fU� )MUedF�s�b��in� s 7e�S10!�"�a�K�%h(�latV �lotA]�# I 2A��HO �y'r %�&�n2tF��t!�/E�E��Q0d �!4>)ke4eAfzn�};Tenne; *G6]f oug, is:�Figw is cW m����"llu� e��m"I�hto robu� dealQ  unI�>�w�Q^� n)nFa�m| i� ly�ong}�4( 5000 < 2Ns < 0D �M�-ia&�in feW7 5�9�repe��!w "�?o�ɄB�i�%�^$ZasX�j�h�p$ 16�r2-nd�w in 31>&�  word!�i|�.�= y:шYwi+ orig�� { ��\ � B� etec� �`$G aafalse-6M���Dof�A�܅a@!D.=,� N���e�(I�%A�Q� �� �pic�NASdiagno<)"� �&inZ �k�ed ( >`%�:� crit�to�YAxls9�F QWe�vaAat�[e% | a�~3 bill�m bp )����0 100 kb"��2���a#^# thousa�� e.�#>AR���A��rK �!1�&"ca ��J�ra��to�ed!��Y�rInR\ 1�%�l�@to1��!0a"o� )-A�� �.{�   Auto.� 7� &�&null hypa�� ��W%Ie�.��K!�a��$ � !f(�ki�'�� y$total numb�"{%4"aly��e�* how often��$Qaa�ly�n@be2��TL! 1���9 majo�*�p�!��by^�QbEC �m.Ge"| ��"�i�)AN� AϵPMynot�%��alA(�1A��� vail )o pot����m�"��_:9 �M��I� pipe�$�Xlud�. step!m~ %ޙ�A3J Iji� bely.:ac,(Af���"�,��T�Q���( t2$Y uYE.-� ank z lab"1a�h��� !R ����.�( hose�*%6C .*h���C��.�� er��.���b�+Y aG!f��ce [18�In:� i}(j �qre5@� &�-�!j �p��',� 19 , 2��20 H19:)������co""dAq�mP�quA��xperi #�%y� ,�(pi�-v&li�# supa��E'�� in# 8 � �+� e��� 2Eplumme�C A�ys�1�e�o��a2 reshk$ ( S3� �$�/�six*�s"�X'N�ŀ� vera�~18=�+�/AJ� a%�90=�.��^` ��#ji&�'��U�A�draI�l�b�� 5FJ&#|���:k� it�+� �+�!�  �(��tbi1"1 �rua( derl� � oKef/3a*[ &�U+A#���iy7!�l��Q�l��&�$4�� .Y= Bfis�wA�st er*~ �;(�^�#��q� whelm9&��" ���6(E�2BB�.�  owc��3r}Qr����� !!>!ha��)a4er�$� �(8�,E��0 5��.� i�-med� �.} 9�)"� Q�2�.O)u2<aO is f�6ng!��� B�'*6}0�c>�b�"/�s005�I1�*z�� � [�A��I[�engceakY2e�(P~ U[1�� 10009,�s� aM%RR > 66 , 3333? , 47���pL:j Qwc4 4ѳ��n;)M�CE�&l.�t+�`5B����*�..O qua�.y dow� eam��o' ���gi=!a�*� &�*��w�:����in\aI&�aG�uA��&O77"�*ePat.5(�{. I��22�=�9"�.Vj� �V� �qinc?;��|to� ��ue.X�F�"�e ( S4��o-H. !�!��,�=previou.�6best-pra2��it�"�) ��7!]o!>/ ’s j%&'a� "�"mif �"*I3,Q=.s�*�,widthA6� \5� a�!�a��amelio�� situ��� om n  oTR� -42�%�m�reaunaccep� yo 6�In  � �9 |=�� ����I���z zZly����]=%���. N�7.� hidd�-�)�Q= v�Q�/��6���oc���5th %�UI�V�imaril!�%�Uca-!�6kgardl�,e�2�t.up'W( a exacec�! <�ra� migrI*(�wn a�g���(of 4N! e /s;q�A�S2�a���~h=^+q� o 1Q�*U+h"52�A5�-ue95�aFw)ve�:Qr<y �!re�5 , punca(�@( flow—var� a� deptd Xdr�+�1A��&I&�3A�t�As-iinRCE��� dynamicsb�6vJ*]#�5�}m��f��u partaU�"�2a�%3 stud �%!��n�PSMC-?%�#���AP� 2"c**�I�{.�u� —g3��6�:e�I�.7e9,5[19m&�q2��:� s fl�B�FVa2WM� .����uA��:�shiftbAMe�y[�20�In�"Aas$ Ae*7% JE<� im�*.iN}is&�@T*6)@��> 2r b@6|A�+�4AD�3��!.=E@a��G=as�"LYA� $-!�3ledM"�:�"�.Jo!Q� �A�Q��x!9�!K"��nei�!O���ly�2"q�troX"ngi=d0 2� � \�DE./$a�81:. N �[ q�of�;lk;B)>AVll� Mi ]@;��1�.(ōA+aC �!"�*u sa%1A\� >! mi2�5��Ad=�6P)tBbe��o;'u �v�T �E�ic�*� �F �4'!n'c5ə� "��B6A1�a�nd��! AZ"� 4;y e�F4g$����/!mg2ɮ<�- "���!��2 ]t�'B��^"� repe� �+I�Yis�" �I3y� , 1�21]'unwarrat5"�?���!0�� .a)�^�8�.�ՙ 7o�?�> #6se��#%�.Y| �*�@of^*� 2(L � ,Vn>��jf� l �E�-"*1 ��ofz4]"))045 A�S>$84=r:516A9�$A�352�c�m�3|A��4eR?%g 2*3��"%EFigs @KS4%l2� impIA2�)"�!e+i e+`w4�"�#, aV��& %�ic�'+dPF�D +a�i�rg�Usu�a9rN$6.����YI  ntra���� , Fe�&�=3] do��uJ�@vel�*u inst�r�+I)�@ i�Y6�j��+ 'm2�3��C=Y/�m,t�[��# (*5!;�E2ALAk�U�a�HIV-1��2� s�0s&�5�!z � YL ��V�L�� inQ fol�;  zero� fourio� drug-reC=H>�E�ADRM�!?qM-HIV6 t�?�EI�  Leff�ve�. SJ�G�h�ensuse!5*� 1 �c�2�I-tran�6p�A�prote�0g��6 , 7171�s Ud� a 24-y�2sp%�d ���tly�!8 Ume�i�"�be�=L n afj*{:�5: (�'Q~� 4& failK InNX, ambigu�/ 6<n�&!�!.�z)`��*��) each!A�� �%$proxy meas��eti.�! I�ݾ�e*)'�#d�w �|���V��uO�1�?"-of �� �-eE��%�d*�he 2009 World Health Organiz)�KTE%� surveilla` A�mi`,�M6in�22� A�9�q y�' U7� 6�N�H> mpanH %�DRM�G6Aa9��"��nA��YF!�]�6�,Q �per�ag�-pa��� hibiJ vir`U�I�48 week�2Y�� Y0�1�J�Ɇ� argu�at ��K�� ternF� ���13_�5ch"86!)U" vira2ń[)SV])s)�:2��adminA����u�s"B emporA�- gdaS�A�T���/(  F �I�atNs� �4��V��!�$�� �`inJiz%yUin5.�� . Va�ebN ve1&YA s duX5�@4�e�5��� �9!�lev~$*NgtJf � w?P& ��5 e�qe�)�\� acA:UZIm�6R �e�� v uTea�t��R#Ea�w�a���spendJ>�7i��i5������uj!:� �5���1&� :>b%I&��Be�of�+k%&2R!thW)��B�q��s:2<�?3�or 103A *aa e)(a�Ua,� an&j1�)=of 104K�Kse�!% X%�hpO,6���WU\<a=Aq�W".� E_to�'?&�%�� H8e=�a�����3ig��=<<�00128eb�����M%er!��F�zs �9�;9o:J�� �!9 �i�'i 3d6"Y� ten-f&Y�o)ޑsAUA�o�Y!��o �aVXA~��{�@� ce�� cqui�!��AKv"Ag"�6�J��^�E~�bleYi���w=Z:� Ea(c�%���Vne W(����to� <1Zs���� d vi 2"3 �66�1e(�� c_2��'  ? �(e�rv)�2. �G�6*a1S@q���t pheno%]�'s0�L���"���J?I, ��7�:a� �>!�ow��)2�"u�jc�s6��s��%��� ]b># ," �S��iL�47v+&�1 f���� /r (< _U�m.2�.�%r2�&� [��23.0�1� ppre�E� _�b vol�*&�$�% 0>�(�F��6t�, ieI[ZV. P.�&j ��:��1�%e���|Ba l�8.�R~!�aiz��[Afh5�7-�A���>��-R~%��$�!�e�A&�leaFB�a�#m[ e loD?d"PC� au�ic optim#C�%,.) ��$*s�U���>e4%�EecY�.X*� cO%�/v&a7[24–2#V��Be�"� in microb&Z.%<]# en/ �^�.�Jq�"�@m?6-� �v��, %alO�u�>��> ,( DBFE )��q�2�T27�9�(. M=Q-��s � verJi<�_IV2  , moe�wild-�=.,farI�Q �NJ "  @>�R+E>S�R9�%�fix)IutBy.j(a"/E9 �N%��Yx2�B�i� -8!�����s�QE� scal eΑ� hwayR2ѩr� m��i/2�*b� �  r.6 =�R% subs)A�bodC$����a�,�m�nucleo{E V�in!o�bNNRTIc,?e�5�—� he g�:%B5gA�CNby:u e��16�?a:c*�—�Y4avoid pleiotro��tradeoff��ue,�� c�C�es�1of ��G�.�D)�� .AV:0enzyme [30–6,. RB�&Q?�Nm+v2�%L-t.VA` �.vm_�3r!Z]ameR�>N6]�ST�;5!!.�x* � 6�8F��.�/.��l�� R<9��%`B^" A-rka�� 6�I�lrZr���`"�+p7W��!�]�b�Z6 ��^��hRca��w�N�*��Fta( fi&Y a�7F� [31�W�uh�?~ %/,"�A�f� VYrY=�8�"th�t , �(*vA�Dur��2�N�/A}VR[� c�9m'>Q �25� An1z ��*� υ29�Eqach"�STRM�V3�!co18!Q>MwcEd"*ly"?2�!�& ~!� estV�:s;� 3�2,�surpri�." t mea�T*sbsVtbGn`lyA�6io!to�JZ�[3;bgihqV�D� ��ta@on&�!��%9� �#��u�&}%"�� . O�L�!G�of:�EhoV(�3adY-E��_dse�ViH"�EKZ� ��s�*f2�3jrIf^��Z��!:w��S4-capit�\�ir27)*ll ��!i�in�0%�Y�u��,��a�&l�" *J��e�V.��$�� �-�)�e; �e�j"���n�A\Z�H"�1%%e� Q j-�orAHIQ�c12^of��Dt}bd�v �� nica��u�-a�� syst�e.�-+&fo�(5$ BhD 9Vi5�A0� �v!�R�G !�"�a�]al2� '�&A��k�6?��� �lYe�fj^�{�U��C Py�2�k�ʹ &0b�A�aV0�Hů O). ��P.�:�|�]�B�+ sug�la_J def�Nfe(2���r-/�e!i��. �g�A]literE� mz��D,I�*���9&p�_�N%eaGo !sma��%��!P���=p%�eb*qBvq��iHk+h"� �*���oo2h:� f-!~\�B� m.�nA�i R�p�R�:�2�6�"� �q!�� �!pr����Jh�4ppl�f\�A�;����+ablis�\,"]&z��� � "� a�6Ie�`el.6g�ba1" � #BlA,�u� stig�+�$�6��onM�55V��br�p"�,.P�&�if��;U�� choi<�;.=��� :� el�rEsem�&j/i�A��.�����f.fY���"eg� ��metIc���� :91sDBw� �� oach"�*&>p.%Xe]�+�A�="W. H � e lackA5*�*G�=�a�"�1!_?CUf���P ��Orecur�.���c� e�"Q2 view�1!%�`C*pro�%O/G( ajec�og�1[se�N+ A+�F2�/bg�4l�&iGs[�i�r mis�a answ�dvGca�Ei������.vjtic!���s�9ͱ%q do`nt rol�Sr��,�3in�2.��Ni.�w6�BJg�(���pon!/ f [3�j2 A�C�P��!E�T seek�.[%R&�!�impacb ��[�I�;ĥ|�,bq%0!�>�"�P ]�d�4~3�5Zforce5Aq^�,,9cir-p�1�i�$!�f�aI�-V, ? work ligh�Nq r��4rst��} bF� =3e�%�y�em���icu�–�Vs- 4h b�L64sW ny n�a�"x�e�d3ncru�7�-h>s9u%|  uBf f"�#6!el`��],pc�-91Hu*�4D�q2�Yav"&���%� ���7ga[a{F2�9�a� �*oI5^!?w9=�z)Q�AA.�pyqs*k!�w6 u��'grega�}~1128'�*.406��UM(E�� ~380!� 2. Ua��u>�I�U�*�#�LL�b6� Yl2k N��|+N�"~U[;1�� A%��middlE��l�m/06���M"�G�^�~2H( albe�� n un:�4D�"�' nas�4m[�su,R�At�.�E:�B(2*QK6?[10}"�o��e�7sA�ea�d�V�!!�� .�ha�M+(r"P J� Aof Smu�h1 !�.} Mhig�~s2Dll�)s6��se����A` �� \*�start $� o�hu/@!�9"tl9#t�%e(�TT-�ux!4�`e�d u|m2�6o��}>"Ro:"f*8o�@v6>u�-0gUkp .�^m �{"�8%�CB&�o�t. N�R>: re�&ar�[�e'j�iOG�aK<t�V�Sa�c?is!�o.��E��;-�\� )QE�6H2T(9se�)JJ9q  � �,m'I'!���sEE9"~w unti�e�'nS All��3��V�D docu�� !�8 �&q;J!��e:�4to4te"�oH12�o���q2(#���d@"|i�utY W�iY�t���N����ma@e!>t�9�6�-z.. .I�� �2e ,*�Ia-� �z�PH.�"�p�7S�C*3�CT�e �%9�>9���#�T�!h��t��V�a�5;2 . 5%)!st5,� w�#� mo��-���2�5Ol�1��+A 5�.p�-��H?–$*� �i)CUu�!f�!f�!f�!f�!fB!f6 *�K�)�"�WE�6�AYf*� ��9�9�"$�Ad "-6�_U�j��T[3Y!J�purC5?madN �mpP:�yA6�!�>|<�Adir�2�#vED�n�=�)s��� a �]r%i.8[3fJIA,�goWg3+�_�R�6��/�E^d�!�� �D6��_���?C?bllNb]i5� " �or!���.�y!�.� st!�ybehav Q���_n�!� 'w��,� r�&��.8��� "�f1lpa!��9lW,� �*)Eo��e� 1f>Fn"51a�&Yt. BriefR �M���n6V�*� i�u�{;!chromo�� discA[4�K To e��"|s�-�Z��liSh�Q(v1!��"�a5V2Q �Z;!p\ �a�� �61H+-w��0�N,o�fh-�ah�"f�0��suM5f2�Z$6. A!�a�$rda�&i �| sVp� ( 6th ('q�. FT}Z7)��$�!?�{Ai���o�J���Fmp,�]2'i_�9� x . Of���*�is�6�?ct!>lm^ �i � o�e�~ [@����t:l�f�i ���XtoNF�H� !�4i�aa �)"e 2]�a�i]� �H� inde�:��ti��/-�G Hed: �74��81�X{� (�!�82%���Yc s 80 D75�D79D.sc�%r!;�g7>��a �.Q �^&�`! *g !}˥uFEV:�myQ= $Sm��!�2� B�x atdQ��X.�X wE%MY�t��Jw�M&|4(y �"�+K+w<I+in>,GH�#isoyQoVW�Wn"90a_"t�� �a10 !C�� "�X*"$e�ofE�!ns@�.!WSr� &F�e �KgT-Ve<�x �ul�(% �=5!0p2�U(M;p<�L. �7E� or �6p�)�gA�yz�Z��F81�A�!@C ���#A �Y�#��&�.�% 4J��#& o'cE� ��:6s� � ��'S&�]2%r259^nd� ��ab��y%�� �.E ,D�6eo&O ]L7G1HDFEA�M�*w�X-� ~&!kB� AE^=�sLWK.�b3of�-��Qk�y�� B�_z ��+ likf"JP&�j3U?m� ]i2wVX��a�O!�%Yly��2f�( v�"s-�o)�F��!ee kE��SZ/t !� �� urU�M]6�� npJs� �&p-WjiXiaEKI2q]3e E��+, tNِ(", :&�`*�`( SK S5"�Z; new+�Pa.�� 2"�&�&/9��`8e�y��>for2_6) � a�Q SLiM p03�w�$package [4�2 <7G�of �BH~BHiu�y%�uE� �xq�s�J%/ �1S(�2�0 )2$CH�N;H=P*�'#4,%8.>4.N:.(�3�6Oj&'raiq"�� �n`K!�[4ND43]%)e� grew�7I���M@�ur� P�)Fq !�2XDA�N��C.L*�F"'!)�.Ca��XE, 1&EWE�� m�9%&N�V+�zto 3 . 4� 5q�r�=)3;3���rey! Q' �J5 6BeJY�)Ms�� �e1g .�1�R<de�I�Ba)A�u�A�lyYa �� "�o?;�V��"=h(n�6or[O%t�;� "� by 20" }P)asH6�>��f�.�7�=.�F W�!� ��>�I2 chieX> 6�#wO�oE�)tOQ-&�1�!�a.Q4Z���� �"_E �) Q�A�'D��oeQv"�Z�^����>��Qv:�-�KM� &?:� � �8��-y�/H%�bV��Q&� KA��2ly �$w copT(aR'!#i�if�NP)M�1 *# �=x . Ou�*Qr�e*xnͅ<&\a�tMachE�;r�@u qa�P!6&dfb�1 nBf2ra�F�jwN�s7P?4ZV�Av�>�W9@*�*�T�E'&Jw�=a� �3�Kqi�n0JA������A`a5 A1�'� N. A�'en�8��y�0IY����s���](F'ZJ17�U�w&�:�0�l�VK=!���� EpJ�$�ag)N)lle-c=�~2�5Z 11��1% %�a�a ����AK r�p�['�-�7 SU<B5{.aI� "�<�S����z'!��<6�u��7�Q�%�m��Nnd +�#2$��-�6d.k�+-dl3 c�^2�xo��&� &�y, noteworth`qat ��ΔAym[W "a'J` 3"`C*z528�Qal� �,Q�|�&��WlR�&�YIn�|I�unboor�PI5%n!�I�s� se�--l�LW6*7 #!�ADRM-a&�?M�� ty>2�)u�%�]?3�argd# .(�FemjDAe 18aegypti mosquity9 � principal �zdenyVf�sa\5�B9m{� +-v y]Z�nX�&�%�" blood fr. Aa9�host-�0A�"0"�#aDm?�dGE��a gmL6�hema�ph-born�`�SEo��H�] Pept{�Itaa <�p  Mq��l{;)R21!`me�N8b�/.E=4s=A,Arecep� thro32��i�g�!�c.>��U?���PdAZ$hort Neuro �-F�� sNPF9���mp��1����� h��.q0 Y ( NPY ) -L@!R ��NPYLR��i�e�1�/he6=�#e%Escree�� cellxi5$#�ima6 assa�BL\�3!,�q�=/�[I� Fou"l�2� �ԓ� ^ /)& D lig+'I7E NYPLR16;:�c6��)�. Two u1��log�'=9-,- e LjFdisQ^ , Ixo�<sca" r)re�(1�N:��6���"ynthe�:(A��-3}�Z�nqH�1-fa���N� �"�2roZY ���bu�V!|in�G:�[Cys10]�+no��!V0kw %�1�n"x�� �;�h2���!,��zinc-fi�BMIa�.;R|.�npylr1f/n�>i�8b eż���Pal abn\}l�S.J E�� play5'u�A5locomo �egg lC,77ar�,) !���p = F ���$ 2�AN�4$w�(��^A a}Nv!]�-� &�A.ca1cz+v�Yet1A�d�Q�� �!}�������~�`4���*�D�*or� hg�3)>�6t9�. ��1���(�r []�}��qW_[v1re���f�C�g(=Jeqa)!�}�nut�pt� A�d�Zop !z� N"�&!�{ U life n�K�A��"H ��a G-A2o��+�8�kYFe�0visj], olfߙ� �#msDi*gu$Tc�ɁuW�~D�1m� lA�6�}as�U�- [D"[3��$al"�%of6T}Ia&*%�6~!d]饒 F�Ano �?$_tt�i� K  �ulieE*� J[4]tXure \ �}�<e$|>5iE���N���6�!defen1n"� ��vect �"+H>eQ�2�Er*�Xda l�R�1tO��>alert-�D�]EV>lf k@� 6�,� EM�mn�5�-q� swit�>�i] �� �Sli :�ui{Aek-� �s ["O M�)��5pq92/)���MaXnreF(F�2a3'yc�41Uq�u-!c,�[xP^iIeg�,y7 gon�OA( _9�isU�Y��r�xk2�u]�n�� ?t'$'�Y� n&jz�e�Fe��6����|� �,� A&d�$!sm�2�]�hal�p�0~F % , ab�=}�a�2rigge!�by���h? �un�et� �vePkl nerv�Dr�� ��.�!6�,24 hours [7]}��L=Z�A�� �RCg?(v��s� �48 UI�2y�apQ� u�Xs��U~5��Dit  toR� s:� �In 198j�Matsumo�2�p llea>� :� p( pERPhPSLKTRFa; pE: pyroglut w4 acid; hP: hyd�hp��e�ra: am�!�84Qh h �2ac��M/c"H�hu)m��n[�,M� � F,>�} "�5�C GsAO�-W{s�0gl!.Bc\��hՁ�~c"� [9J)io[,1�Qeyc�ex�g� &sFuZy -A+o�Ka �>A�:�A�.��To*wqat � Ok99 Y� �mSK[� ,%I�A�^� �2�Ua *j o2Ho iZ|.�Bƕ��>�:�BNai�w%�!�yEj�2)if��g�atx#>�am��#r?6�!�--q2�Qc^�� carr�|����bi�u�2~N*� Yja�ZG1F�"��-)�VJ N�W nt-W�?wb��iato>hy )�!],Miv�le� ��,�I8����9l .ghU���=�/urZ� 2�:3,6}6k�%��ot"�$Fq�"jPp-kOz�uzs�aex��A�eF>�aA�� "+W�}�3 remo��X�1 ]6. W�3 on verteb� anim�A�<�tum�gover��n��i�+� AA WelfG Act`G�c� e USD�dGA>P9zc!��nS>��#PolicyJ?O/tEhLab&�� :y)+ �2New Y�S���� �=kT ,��Rockefe��Uu�!1x?AAALACQ��L�f arch�g��f {oto upn�!��c!sj2�,(�i|-8th e>!�2GTI e C@!9U�HB�A�z�"u ;2ۥ�mi�0[ nd moniv byn 4ituA|al1{2�Com%}5c� (ocol #11487}$E�E?�� volunte�ca��u�1i�u�6xDecla�(o%9$Helsinki PBl�Kl 5���al��-(F�24-�6Re�K Boa�1fnHHo'�ab.F%LVO-065)&�' �sub9 s ga��/wrAoZX�>e)�Oip"e�62� �:�[ e�Or� o� in^#!mainta{�at 25�` 8°C)�7�w0�eiv�idaCv a 1. ��ht:�,=  dark� ( �� 8 amE,EggB"h�Ff de-oxygen2, deion:w׻! �a�pow�nTetram!R^<���f(  , M�ϴe��". Larva�tY��i�b6vAY j� � 9y@ AdulAj!T�)unZ�= !���su�� e so�M!�="�Dq��e�7stock)�ene6�pRS� armleg�&o/�uta��O� V7 6[� 4{�edݔS-0 A rhodopsin-e, GPCR� “Q ”�“V��.~"n�!�Zq6��1])6�$��'.�D .6 �!:A!~gd ae �V�t�5u�!0&� n���!�*�&�b�6%z`a}7��6 XBdu�W�#!f�6�ݎ�oa {-���# an� 3E-ixZ�,. NCBI BLASTene�8,( http://wwwȿbi . a+9,uk/Tools/psa�I 0)M>HMMER> hmme�j� ia . org/ԗio�`aol��.' !%���=qAE�Traw!3PL#c}/ad� retu"%Q M�9�l�  '%ߩ���k% aligjfiRphylogaq)�1��;�3s�� defaq�ClUlWEjnd bor-�D&�<-b�= $in MacV./9Qw%�mac4vE�GSn3�],u�uYtop�����!�tok��-�mobyl pasteu!�fr!��898.w !|��o4lLcu Ix .:�as.&'tblast��u e-2N .i-I5�5�/�&�1�O��&טatI�(in 2013 ( fE�ftp-priv�S . ncE�nl�Fnih .- 4/pub/TraceDB/i�_*�) ; }�!� TI N+0) : 135506908�` �Dname: 110127148250X%f"@er: J . Craig Ven�%�eYgsa�jcva�adproQ /mscF�Nnde%�htm\�. RNA %��5U+0RNeasy Mini K�*( Qia�MV�wci�hCA���*%SOtissuGs��2DNAݟe�ܱ.��.�I6he|DNA�B" & Tg���$s�N�ma�M 2 mm�s�X�-,( Sigma Aldr N4Cat#Z273627-1E�S�Lou�MO�i�a� �Lyzer IIAz1800 rpm��1t'&~>?�~n�9,"��c!'!>fS`C$Script III� n�T.|s?( Invitr����9 Is  , NY��p�#er8ch$ �/�P( PCR4 >�EMD M�$pore KOD.J ( Bi icA M!H���0All!�qϡ6�by� ewiz!�outh P.� fiel�J��v ll-l�O!6 2O�F�0 an 6�� G|re���r(2[ coup���;.�6= ( RT--?Az prim �dA!A� 5′%�3 e ��ope�Ga�4fr&he9pur�#2�X!�jja�-:0*�, b , ��d��%1�� 4 �7�AR*5zQ;F)W-i>Advanj3 2Ek]� ( Cl��0ch/Takara Bio� �'A�Vie�P�|ba�on:U�8� nfir�ݴ�ǁ)�+aA��MAE)�( RACE ,R�A�D�O% �N 7���o?)d�p�U- %�!�:� � (k#� �)#K i}% �edA�ng M�PoE:C� 6�*r�wfou}s: 1A: D225! 413Δ> N487T&! r�$r"��^ 1B; :F#�e' GenBl�>  KC439529ES,+on - !�er!*@�AAEL013�VA�07924�C���D>A, L495F� 7A:� bN 37�a&�*%� I� -��1a�6b�" ]�draftBQMC( IscaW7#�� !J �"� X )�BL pGAU�š�e%A>AH�~%:x tick -�.�R Ostfu(y*� ,� broo� NY�WWu"�e��$�Oif:4VH enco_�wB�p@c��- r%c �(io^63�c!z�=ge L�Y��F�� ligo)o�-"���">�5^e�U4jm�&� $'s TOPO-TA�L!��h !a\Xo�+*10�DH5alph��/6e.`,P,ڌlR�re-��! XhoI-NotIS#� mamma �h.Iv pME18S �lex���� gam-i��nn �5S �.� EcoRN�%� t.a�:��� �I�Z�a(��2 As:�1a�_8� 1b.!i�c 3�> d�;2"k 3*- ��3"6 5*� $� Z7�3Y �3�!|8<9�&�&`- �6�[40F6e4��aF A��?E c!b�Jteg�d Techn�jG( Cb#vA ).&= :F �2�Ea ing:E�aeg��.� �? ,# `-ATGGCCATAACGATGTCATCACG-� ;rI ITTTACAGTATCTCCGGCAGCTTGRI2J�C�AA$CCGCTAAGACN�2Rx� TGTA�TTzAAGRB3J~yCGxCGCGTCG!ZB:�CTCGCCC�CT�C�N�4>CGT%x!0CG)�A�V>>{!�GG-)vV�5>yATGAG!�GET%�GTR�5>x-�sG�TT!�R�6>zAb CCAC!�GAA:CRv6>vI� TTGAAmGAsR:7tb>xGE�AAA#ACTGCC!jR� A>nA� ACCCB!;A�RA8>}aj ACGT!cC!�CAGA�N�8>y!oaU%�A�a"�ك:�TTATAGACG@A��J<:��Cl!�CT �6#a>v%"aA�T!�5�>::tAT i�FGTAVtB�i�CAa�! ��R�b>tA�a�Ta���G5�2�76fB���CEP�%��B>:�CC�.Aya%o�"�-�� qPCR>��E���5TA�A� TCA1��>�GaJ�~� �C� ��rplB�A�aKa�! BC1�v9>A�Aҁ CTT9:F��"y5_�,�: Left >"!�G��TA {u!x �8:��1�C���xA� 8REarBqa�A�Aڡ�a��::s!�:I�2 r:L(A�lo%end"kf ��F>�����a��.1:�:�!"AAya�MACG:��6�����JT�z��GAGVlB��h��e�A�89ZHEK293Ta >ul# ��#�  #�a rmo Scr3P FORMA %� II – W� Jack��CO2p*ub� ( W?%a�Y21 Lipo��+]�0;&�(� �0�� :Z of 1 µg� >C"�("H G 2$m10e Gqα15 [14]�ranVqel1)loa�w�� al�9�3�9e dye�+a-2>��vr��"� @� . Ck imagl`a Nikon Eclipse TE-2000-U=!roscopKMelN *�)�fluores�� s�!/"0a Lambda DG-4�uCxr > s CocNovat�*�. Bath$�;V0of ∼300 µl" "s�ing�,�(lu!d in R0r'&�>"(�A4 M NaCd$5 . 6 mM K mM HEPES�JmM�.uvi�. CaCl� 2!Mg �A% Gluco��� 25$KH2PO� pH 7IA~:delU?"iaþ@phragm pump ( Gil�cMinipulsM)gt�WI"�EEr-%6�*IA���T�a%�&zL( Ver9��$ . 0; Mole�4r Dev�(, Sunny���&h . DuM&)ete1� d!�!�;le�)��&7�t�o�m+�m each�ltIm4�pen2-2���%hd'��Yet(3aqh�f��]�rwBse%Rin x&�#ao100% ovar2Tof� �h,Ds A–D�)nd .�p1�+;KJ�.�&!� 7 aB2P.�k re pr"�t$!2I1B�7+���1DRS:x /j--3�,�Yz��$41�l��…vi:mlP�mK�q 96-�*poraa� cataI> #HSP-966qN�'`B�.phosphat@"k=�Kap�( PBS )�2re�XG/1×�dI� 10×-A��. Ca2+l$Mg2+; Lonz< BioWhit��r;�� kers�BM!�plu�'e�8.O�#2N,BP)%Wc�,YH% Seal8oR> MSB1,UHe�r�;2�Co�Il1,2O���n��gYJ;�eQz�25%po��2%�$t���>6>)!H unf� ��]%�%rs��2"�Fc��( A�N( gene�ɨ�i utQH*� Ex ]!���7Z,-High-T`6put S�A��>Y�!157.�"�(���e��fe+�to a 384 ��3{�erA� On��}/78420!�MonroNa�h a�:�W�a 1∶109{inedik�=1l�gmo �� Drop-b� Perkin El�&JANUS��f� S]1}vorte[Ob�_�g.�q0�1'C62�G�8tek Synergy NEO-<���$Winoov, V�)*fo01y:�,2� |s,mnz0d �r!��-m!���)aCU��anest�E�,�Ӽ or 3&,��]ly�a chill-�BioQuip. 14�Rancho D`{ guez�9d,%? ��~200 n> �Ru�� Drumm��Nanj(�(�� 3-000-20�l BrooUZ,.�attA"�7aU 5″R/�#V��t W3-G/X-W�o�>edle puq& ( f� Mo��P-9�2Yq%�5",a�=$en by pier�&�6�L .Z tergt���"ovi�?�JIn�)$:9 �xE�C �I��e V1�T3 a �i�:�iLQ�`AQhoR�KM7��i@;CB�**"V&�%bod� �{BH"-TdD>, 4W a�72�s�6�0�G��&RN|*c�O1 )Faliqu$)at�] ng/�^6�^� �0��-0���(�e �.# ic��yaVz iQ SYBR G�Jq)Mix (.�170-888� B� iQ"� � 24223-944�%�q� >M �sEM “B&1 Adhe%C �3}h MSB- dzbe run�Ra iQ5 iC�Aa ])!pTE�a�g�'to mee�R&��jeria: 9 41�2 effi��y)�n R2 a���_98�r &D*[�&!�~>� f)��+ �&i*A�ri -)�v6�M6ie. ZV�I�v�p2�D6u"a�LCompoZr Custom ZFN t���� -,,Lif}fAāxt_4F),��KS9�Cambri%�,.�i��bq$ ��mA���K0A�-#�Ym�ge6�g(embryoALt)��5�qe^ , �,�'1�e�5eW^&m�a� l�r2[v�#a�85u�)~ ��p81&4�Vl���|he�oA�D)131F( 14517|�;m��oAl@ nd r� flan[Ks�O0"!�cu&PteeET"�%by�y�M2�1��s��.��� [.A" SalIu*�",��^u,�� R�doVdplasmid pSL1180-HR-PUbECFP� giftJC-McMeniC��dtF��Addgen� R�" 4791�o�*-�D=:��'ubi@S@�M�q17] driva�exp�#of �,�a �3ii(�Wof 2565!� . 36,\uXIo��G��d)fs� asC���շ64���|. 9&w�&�8� �Gvelop% to a�7W4eQ �Je�� r-��5EADh�sex�Jm���9(�2_ ��Ea&*�i�6O��zcon���loa9�ep�A�eTFMPoCImM8�1y�a42�-%�cas�e)V"V2{>��<3-�IJ�ge�z! > G�%larva�o�W ��VWR I 3n� a�29444-01��A�s"�&�&r�>R�NJSMZ1500 anl nsil�C-HGF�Of�GcX5C�`I���}IoI2v~�18"�;�po,��i�M&. Non-}�end"�1�Q5u#�mon��dG a s� m�)iQ�e��sJ>��!�4third injectio|n batch of G1 mosquitoes . Sevenlarvae h)�ued and were outcrossed to wild-type Ae . aegypti Orlando . After successful mating , genomic DNA was prepared from eac�the s�(individuals�Lnpylr1 PCR amplicons �dsequenced for ZFN activity�(mall deleti28detected in two2l.cclonesQ�%positive2.%$Sanger�$by Genewiz!5 confirm 4� 8 bp�, respe�el�For)�non-homologous end-joining mutant ,!�.(�inter-1�!(four genera)0to establish dzydli�.� otypkofb��0s was carriedA=. usRxa capillary gel electrophoresisE!hanalyzer ( ABI3730xl , ApplXPBiosystems , Carlsbad A , USA )� E%�Y3Eo 6-FAM fluthcently labeled primers span%nAM~A]cut sita Data)u ld �$Peak ScannAoftware�F�) . H9�recombin%�-�M�out5�toV�%�A�.�prior35�!�J�MIX.S!�y/!A[graa:>M�6�cassette)geEJedAN�of:�2winseroDNA!( eterQ�controlM��8behavioral expe!�n1=- �e��M�mTito�A!�>�4strain , whichj4resses a mixtu�5f?ex funcav8ally equivalentQRallel��4tatistical tes�perform��s%�c%�in�&figrlegenQ~dGraph Pad PRISM ( La Jolla6$except%;s}E�a� of q�presultal �also u�(BioRad iQ5 U� . He{4eptide-I shows� similar��to rt neurop 2F s ( sNPFsa�8hat have been i�1 feed!�Q4s [18]–[20] ��aknowntign!ehrough N}H Y ( NPY ) -Like Re!$or�NPYLR�@[21] . We identif�� eigh-�En!�E2Fam� F)�2��,A!o-`ACrphana\ep9not) link阡Tndidate1= lig�. To de Pize�seY% �y thos#at!�pon��:�(, we transf�G each�0o HEK293T cel�Xlong with murine Gqα15� promiscu��(Gα subunit� able!coupl!� diverse G6tein-ed�hto a phospholipase C stimulE(calcium )�V(pathway [14-�screened �r-� in!bell-baA�K imagIassayiHen&M�a pane%�2U�incluE�:d [8] , [10Q؅Din�e:2II.Z! [CysP UaZ-1 [22c ( 4-11 )22+423A;NPF (U�B��We�)human^jGPi� Ya�PYa� [23]BVCEYE}i�co-M�En a gi� 5�cM|% loaded -��-�-1�,e dye Fura-2=!�1 � ona&oX h a��c�of9�9C , DA� nd E%O�"�4�sY�, NYPLR1O most �A�ll�^!���\EC50: 35–75 nM ) , but)� ��a�6��|Hbeit at much higher�_ 3 ( c823 _.:�U_evo��no wse[co2Oup�50 µ��� C%The6/` �{ex�s�b� �J�%�2~� stinguish�d he��m�i�( d� �j��n�2�� 1 isDl� 7!�=���R )A0D . melanogas, �L, [24ɪPAn . gambiae [12] . C�0 to previ�4report�fF4��fou���� � orth�u� rom bot��sects-�M'2�:4Y�DEi desp no ev�Lce�a29��> eitAb� ct . B�.�%�f ��� lacku�a6����.Vi w�>� equ�X2a%6]�6II�� xpla� � th�kdi�WpancieE a�not�gsi!.B�+2��NQ,g physi!�@ relevaY �-�se or� ��� ]:'sA�unclear �!��.|.5�ab incomplet x Lyme!"e�4vector , Ixode�apu, !7 l� 2�displaya termitt_ blood- [25��[26aO�`c"0 Ix . sjF�,would encode cop!�of��ro-���O�( ERPPPQKIRFa�- is 70% %�60%-N� y .U� k2�.�4-I: QRPPSLKTRF)�didAd val this�<di� � RNA&� � icks nor>a0.� � whee� N��,Xed sol�' onWsi�j, exi� in vivoA�)b�� any�A9��s~ ed h�y ��at.q.I�5�A Y� curr@avail��  AeA�� . Becau��%'e�an��aIJ{��searcR� aa��12�a� �o�6!We�d���Gge#Ademon�(!/��� ��2�jN:�.a02 � �first6�.-I*j outsid� 2y . In summ��,�r!� 2*%0:�on��mo0 ��} �  [x We exami� !f<7*<!Dwhile r7Ae  EA�;���7B �; thre�ten�U�%O �=s)�fai� t6 x �"A mo�92% �3 4� nd 6 ) may�ZI�s�a�� k�or8�be6A y 92. W� �/YE��1�s�^`; !Xaes��sQ���-�8 Q 9� a rol!hrA�se .c� host-seek� inhibi�!�o beg��:pl U| ly pu>+*k�"�:dof6� ��inj�=to���f� emales [9* 3C� thenA[A>� Kof%"-3W ��R.�inx-.y] ere�� oldsebufferAD~�ha�� ef� �s �G� earliObservb m/:[tit�inc�e hemolymph~ (48 hours aft %P&��as� if�1�WQ�!��F�ly� �a�by"�J7Ua@.Q�uderiv!�� )� whA�(body tissue ��!�m}�o� is up-reg��[at least��d followA�a � meal��peaks�a 15-fola�-Jat9="� 3B TT�A0��is coinc, a�8tim�maximal6 M��n1 no!�!��Pis neh�=�2�-induc>�`%��9� � null **�targea6-;&qzinc-finnu) (11. �;fu%�pr�e5a"4 -  ific�b��ng, ��a fokI-d�r �s�$ic double- Ŗbr%�[27 8 Np���ut�%c{ �!���uc�-3��Q  draftA�42��D( AaegL1 . 4 ) has�_ entrZ � ^, sugges{r *du,( AAEL013505%% 0792a�u�Sou� nA)t-PCR���toa��e}� 2annot^ �s%�in fact ���le�1 locu��[p an2��pr1 ���rund ͈��Yl �:A�2i� �ɀhe��>ic�r1�*agAze:.backgro ��A� � ��al�. Aa�Ql' iT, modUAD,�Q b_ vol�inier>�o� sPas mo�coord�� (gg developma� [29]��*� loco ?� !�r18/4� �'6�Z a�� �5� 5A r�z IHR2/HR3��i de!�I 0average daily�in!�parisoVw"#�+ C n��ad di �� �+!3/+ā��5A left�B�i��oXJDisM{�noŃ&� A=�H. Qua��jof de #� ggs �!��#� s�c�y�AKoKharm1rno5c� 1)�9�B� A sl%�5�!u, ���� A(�ao$2�!�j -=�4V�B]B:�r&J�egg-laM!� na� �Y �=yBey}A�ngaDa p�恩i�o,�� q�L NOand/or>E a�commun!��O���terna!�d� a . F�"  es d�t  only!��-m�on fl�!nectar��s! fy metabo�eeds [30kIt!7!���E8"�� A ar-� �"� , sok"�NWe stud�suNZ (he CAFE ( C"�$Fee�)X adap!�e�a&< orig� lyMig�A�B[15% [ is [, ��K=�q glas�%|%fi�w�<1�u#x�8�ch�&!volume!�measumHG'rL.amount�#%" ue� �b` e ��p over a3��"iody�6� � �E z)4 �s p5��A&wa'�i�*�&�e*��nded rf�d.V]�(!j � e)m%=5iRM Non-FZ�oseuA12%!Mno,d very littlM�!�=�.6��24/ or 7Uofl�eIre�Fa��)�5�6a�Ewe�{C�tal�uNs.r?"c A��u� HR3/� ѯ!�associ"� tic!��0("=@{2� betwee&�'(M?s` ��� poin*�6� To q�Jy:�v �*J��precis� E�de�"AhBUFFET�a?*Fft�mal2�� M�Af5�tHa2ao%z���'+0 . 02%&� in�sen��2#96-weOicro-� � � botto�au` cag* %6bX,Q�,.e)a��lym ge�$~ � !."�)�their guN+i�E-���bytl"** �rea��. R��N1��' �}>"uP6�4Uّq? kU�y�w To���%�a8E< a m�a��;'�Sw� �`��.dyei2Nva2F�Ex�#15 minutMd%EVr] cialͷ��on�wa)sheep �mix�#N�9)F> (Carbon diox�( CO2� a"� vaj �X&P [31O3t A9addIu!4te!nviron� tk.uc-�ճ. SV":m�,EFI�Q�e�X��orU�� � .�i�U�%�9.!,�ro�t��40%�A7 !�o �AI�M�.�suc�fua�Ei_9�G%�W��6��he�of B2H2z�4� )� �*L 6Hn � �F\!�i�� � oa �N69e believ2 iV!anof M a.h�1.�!��"���al variiT�z ous�"#-03 months apar� ra*��w� �a!+e�)�Psa*. Pq.2m,� D��!$ed robust ^�� ��nz'se� deAIir� "�'I*iYd7� d  FVaz"� attr�onE"jat] � � %�^2��bdomi= disten�U�2�AlAI", p�%a�� l—&f� 0�p�( e un�%a# infl3�:-[4��10]—)�Q�| A�9�*7- "Y "]a1�- l�� Ft2�c-&9�b[ �U&rec3 >�&�X�!�q�5T�120-�:bZ�}t:���I�s immed� l,K A�!�r�f!H=VfN)at ∼24Z����� eWZ reso� 0:�k$��at 32%4^t>?� rongejUsup�)!~ ll�00 �/.�y/ ��i � {yet�Bs/&��:�cmea1�me�is_�"�UL=�YW2�U�U# �TaFE*� �'�! �!���*of�"*` uncha�nerif2Jy�7TB�p&1! Aw�"2!N!e!R>;nd1��%�:���2H]%�M#EFA��^synth� �) ,>�or\-�"P#�>Ff -�ii�(����b�tas.j��k�.�.h�N�e� {�!�a��Q��b�it4 . Ou���3.|nV�lF|Ma%#;!�,�Y��ar"� ,� ��,6Z,!�-�L>}":bAlthoughj$*~1� &��"%�atQN�Rbu�o>WFa 2XJno%aJj�1�AE� �iHlowu@'&�F���F is�2,,t�e �8+!u�6q!+b� +y�5,��relR ship<6�Oh.%u-���� A5!is� ll��W,Alf�ly6t�redundM��&��t&�v*p�&f!�ng� prop|�model�YF�V5�(M8 van un�� ( “R6 X” )% e64%�F��)�� 7s��"� �L8AIn ���s-talk" ߭y5pwa&5����a&���t Inc%#� o .g�m :y���B�M���% �!F�)inE9��o�-6�i��0ot&XA �E�ju���v'w� knoc�&Z1�! [16]u$TALENS [33� mak��sasi:7toRX��� JZ+�~1e>�k!\se sibi�`Fu�#vT.m�a] Q%\r�:re.��4%�:�.�.�im�2��31@A�6T1b�I vitroF&A�t.��.G. F�, F@�-*�E)�5�+� �r�@}�a�-3An>��=weo�)& 1 at� "0�'%�� �.d"NZ�}(I�abs3Ams� eEe�!�� �c�0b1la:-�E$�/:�ͱ&�)due itsA[t�7�Ta�d)��*�Bc��!exB"� ��)2XFNA 6�II���1Q"�*6� d)ow>�B�G*� �<�B�^S6Z.M#p�8R?xpro $to hydroxyat@�# 4:ErefA�E�r���con�AqlM�-u��-B�!@efficacE,� H:9xQ�y=q�. A�facc" G�Q�r am!�ac�$�2� cogn�#��n!)la&@��. �,C� �DAn�%o�D work**.by�s1;%i�.ofJ�2� remains*/ Init!"� described>Lb)h t ab@  RFam�in6i<�V���(� 1T-�b$AU*id] V�,sHAbt�**�local�[3�=O)inv*g�s{3a�!�a6z3-IP YsI �male-IoyD�FE�eFferZMPd�>g�5%[9�qbeg�=!Tqu�oer>�sau�La [%1-2f�M��I� 6qQ,�>s*�%���>z qs ??.f�*�En��U&�4:vA/�@)W'0�P2&r�m5to`,yC�.�1itself������69-I�C�!�&�{[re-�!�fJٛ�a�J�.v*� 9 �s�b ,uitful pursu���f@ ��W&i4IhRly6�j� n�b:bH6�=E�_ udG i8#�=M2m ��Iis�JAQ� ccor*#? phyll���� �4�>clo�+�o� wnhU!$ F�"!�2�:. Ss#V/�b� �*��'llO1� [1e�"D"$oliby�"n a�I�!�"Of�&�7Uj %W�:�2t06ob�=wge �1�"� M�!�%]8!�A�)o"�;A�B$�Au��3�F2�odB�!v��Y2ox_>��Bf*L[3�$ Last�w2 E�tr ��/�7&T�a�io"�>9T#'@.z ( �!u��-&21� �� .b&,="\y a'M��,1P!��B��Sgu3.!�tZ<6.��%su��;-}%&6:e�e�9=6�<. T�:�$�% =��s"% >EJ��M*�/�Eer� !=lEz) ��(�tl�Bq=4C�5!k.2,:��A�t �%2J ���Ga��!��b�e� ���6 �!96s�,lic)�F bug!��cMafford���rapid!��>q1�El14 numb�6 f aruH pod ��br�AGproC'�+e.�<a.6cor�eA71�:S� 06?�����Hs .�aSchistosomia�!. para. cA_�Ytstr]�� spa-A ,�#!��@L*!T*:� 7r�� \ slopP� surfhB2era�, use/c�� �� f� � FSi�m�aB8u�%��0 ��s:'C mis�mAb%AFhys��V�28sZ!lNCsFry9spa� ��PAk�KN� L:  G�l" Area ( LG of O�QS�4$ . Nigeria%i�Od A�rmethod�3 y multicrb9ia evalu)� ( MCs$� Saaty’ aly�L hier?yA��! ( AHPv!Eaa-bd�&AR �i�uO7N%Ost�6%�re"�k blem%8Ss!�� OvscR;�� �7���3%to ob|$e� mappaDwPor �c�%�H0�#>2 risk&� F�)e- �tQ�eI��;:xFF� � f&� 6da agaC.We!,mbA�edaI mN�*v, rol�|>�i�9c�-�� ��!f� b��,if �nd, /逑� @s vul�R�>{]&-;ri�)�!�veayE!�E�� %� u�&�apR#�Pu0��A�FN'F�E�prI� ��PI+e�>�� U%�����xx-�Np��a�m���Q$ruMsamplaollS�random !Ak �r�(c va;$EoJ�w5(a��r �a�p�( 82% ) Akg&�"�!�v��ghg �-ls1P"� ���0,ty ( Oba IleV:!�n9w� TN�� !h"��� j�l�( Iju� gobXQ$Ita Ogbolu�OgbCd4AI6ion$deaah��NP!ly)Vc$�o fielt� )95z�V%�(D *9�.�@�;revea�>enV�ca�Υ� .�n:U.7!*�6fB�a�ll@E monito !�dir-�� q9s�is~Aru�$d agricult2� J������@un" ~�AkM� sQ ss!=�0 Worl(lth Organiz%� ( WHO 2 negm���s���"t trope� u%w@B c hejSE_Uwi�K�)5���s=FS�me %�240 milla�peopl�qui reat�* glob�[SYU placE7� �,e lis� Y�uJ �.rp��m)8[�3]A%�Ncc5� 14}*!= �*i 9�a} �9a{A�ee2�1g��in '�iqam�$childre� �!(en ye�4� gU Menɂg�t�SQ�h�T�1��'4. S . haematob�R� re>(nt2 !�%r�Br�ewo 79 . 8%� "�Dcm[�I!���Hc5R�H--��O�Fsh Bof 50%./. A*�nt�> iew �0s�ERx e� ab�100a� �2-r�Zc4n 600 dea�*nn=n��major ���K+9���..X[Lua ���B�s.� v proro#� -�� m�s�Z-�U4=i� J`��>� a�2lat?ms��asf�76Ad�# �p es l�VM�$of mammals�1life cycy�� h91A� sexu� G�&!lH fresh 5 snai�C mai��Bulinus�.�fluke%C�b�G+n a�mG=Ho8�)�$(!�ve*sur =ehs/Ik-")�! . E�:�extru�:8 N ��&b [A�EvoiC�'h8�'$ = � �U �H;e/< ��1=Y�_A t�%� osmost�Z HEW e8.�WXJap*��1�A�=iracid� merge� �cil�*d $swim fr<c� .7b�9~)of BI 5��F��>-until!S�ne~T�:"�EI8?� e�V go fur�x2\>� ~-�VO�b�ercaria��� mTcale����exiBr^ � d A<em�!B�s� !�aA���-vB9Garg�C�sW�6E�c!g>�h! gIby �e � enzym�omvtacetab�R�4nd��y they+ a|pierc�'e Y)� �b��w5f�Rmuc�U"�5�� �!�o�inWO%Z��for9$t��'bP`.4ulE�Pro\�RM� � us e�Ziq��KAU -.)l|Ka����lun'-�*enule5����)�(yAm� L ? ^�@-QUB���;wo�KqlVsexes�� h[� I%�co�a � �D����rA�Y)��[1 F��e��� 2"8�� ce dUL linkD'{:2L 3*� /cl� MV2^��f>Jpo�%l��s5 of B .�skalli"R!���"� i� :+f%� � "�*7,e��imp�I�!.��A�Y��0Y|+ia�y2�,.��6��B� bo�!3V�fa)9&8�3se�t�T�6� ��� FTN hang��epidem�q>��.i���aCaw�ach� j��N.!x2Gdynamic%�� 1rI4 L~EMv�`68nd���7toward�-s��enaL a y:B[1�/o_Of]�f geog�bic�o�/eWi� /rem�'ns!( GIS/RS�a#��a pe�r�  ensaA�&�UiUu��]e  moV���_2�,:�`3u��maZ V�*gramm�[�`16 , 1�1�?�H1�F �p��;a��p unA�ofVs&"27d�i!�c( humid?�BY em"1� vege:Kve� g>iE�5 fi���h me}Qe݅�-�%�gor.<� e�I��a^Id�s5"cas7:d;a>�QF!V�NROmap�M�jo ���b�m& � 6�inYy"� !_G" �e<2&��Ldyu i�poc"�%�h!wm"�goa2�My�-�i�6 �rB83%!s.�t#d4n�~2v limil �"2c,y st�"ec�kd6 92E�E�Srvej�IB �b_�i��G%{o�7mJ :Ty ware1� 4w��72�*A<�a�UL^!� �K aims� gTk�G�d][� E�E�{>�at/��+ �ng*6�E�t��techni& . Etw�val�sou�f!%�P4� A�*MinisZ�(�,j,.(!o)�!\M priA|Rw�Tof ;n�in Xs��3S cV��I n.!u�*�;�&�,"#, �!� ).RGA�0 e�se�!I�d!�t�� �+tu:\5°45'a7°52'N U! "4°20"6°05'E f.?�'%a-�"~?19�E00�@���' �o =�l goveN�R�orp�y� �eş d gr Q� a�n�*�+�� fn�L��is���"du"9 i$t�Q crop�� coco]rubB! , oi= palm] shew� �V, gmel"N~�Sus Y� %�e��=�Hccu_! �]F� fap0TtraT I��/�)zE�numerxu�l� Oluw�MvR�h(Eo6sm Ur�I!� oler��70!�i�"� �Qhan op�hm ER�it� /{ t�+. �e�d�gc .Ci6!�f&~�ɴ�>��l ��!�A�-A��'!� . T*��l�68MsFlQ'![��fec�t> �A�Di�OU�2 a se�Vw !D.l�5�)Z)�survi�n�2�,]%�%'favour� B la9�D18°CG32 [fIo"I#�.�a���c�#es' ra-mollus��s�Wj/�P��e=_5'"P2�A)MMs��_cE:L�t.�s����0�!:3 *�c�Bo�Lp�� i�um�i/e�2�2}"Ce�#.J�!Ominimu*>17J[/?0–35��'28'Y2AuI�l@�3l2es�J�ifhe�<�H 5�s<71�aMloj ��5�)�e�36�[ Z. Rai"�`.� aa�@K�$�2� V���P�eK/ �ARsic+)[�Z!��p�n�4hab�@a!dk1f�e!V�E�p f�_by" Oy)2� foci� �A��{o�)pat�:���lk ��i� b� 9]a�%o�F�l�l�J?�(5nt��L� +�efl�[ � ".��2".M7�$ ��d(.AiE_R! A 8�N-� RI , �vi���ain55�.�Sea)^E�xA X^%�ctw�fX� &�A�;d� B� fc ���["QRhexeHk"K�I�n.T  %k c�C ndirectly!�`%�Y� �)���u&�- 'sA�r�faunaSJ. Ele�!�u�pCADo"k] velo�I��f� m�q��.]"� fRspe Mpumalang �Swazi&��"YE�7�l6��!q&�z2ar�Gck�"!έ�%;60�'!�b efK01a�u�$800m-2200mlvea�_ �%"n�a it�LE��mansoni�8=7o"2�be8u�:c(I�' � �in � opi' Alti( I�5�s.?;EV�J.X&�V�h�&�Neno mosp�#< . ChF E�%��hs$d�3� �U,4a�^^R�, �<"� �\� s da�yc�i�irr�5U��5E=�! mpan�MS"� }+ �morbi�arme�5 ��i"�,��A�!sw" a�atU���ex�A�i�!Ca�&�(�+ l�^ 16S��xl)9N -�- �.5�)p[�6In Chin* A;/�*!M�T_GorR2 high!���Yangtze\ �ց;���D2� �ae! *�(>;v(E{%�ig% c~zt~(2N��7�ce.^Ex ( NDVI"�e��A%:-J �0q6'Q�� ��u��o�P�" s Von Ind.�� ]0Aae&$�V chlo�|ylA΁���2 resh)-�Wus�"s"�T%Vmahy�!.�se�+7q��c��[�!w�]FsheRCIr�_r �/%��ci�*�Zsiy� Y�ls�CAhdec�Zpl�[3[#A$whD@ �sh�(I*�,���)(.�%!�"�>1 EiW>0�/S&{S diss�^ oxyg\"W$afumpqecVR .�cmovy�A" �A ulmob<-H[3�#!Zr�zTE.z �0n>���/rar ��F6Ixk;7AaO� fpla~Oa.� �5!=2.K0$ lani�hi� +u���M]�=.�% japonicum�y mouintane?�dv �I�!3Ma8"se�&j -N�S�s��"� C-ter�y#�2 !_�,Eb-(l�.u&*�rs'�<� �!�r�@[3�Af in Ghana.# ��&� F+r�o uste!�a�$ poZ �# t!�+�]Fi%5�.�&8ls��� �in9J���9a�xa %/aIJ��[� r [4Z!�� 41]aM�Eh!�)�v6#�V� o����-f��ni��sr�2a key���<�B& l� j!� 9tin Br� I]�p��=Q0�%  s��e�Lre�0�e�arAGq+�%�<-��Ynama�,i�!z, �ME1I�datasets� ^� ���2�6��et54"�s2� “T 1�H n�mal b��mL�" at OAi Ima%8 ( OL�^<o?1u!�ZA+ .�.�( LSTyv5�� �:[(�+digG)N7E��11���LIE�f�Econver!�Aaa��. SB�4Aba�t��2D ;tR�)=J|0@�Tadi�3J�m�sub38t�c9�e�QC!��iA\Celsiu� !zly&[A0%6!]Ej� an Meteor Re�<Pr��[ www . eur� .��rD-�&�M� ( DE}|M6Adv!id S8borne@E_E�on RadioF6STE�i��F�N��$al Aeronaug6!! b$Agency web� ( �nas� gov�Y!U l�%nA�53c()ga�L�l�`of 30 mes)-�A�A�HaK'�s� � -��-/Un s� Mary, Ԇ� >.5�5 !2&AD"wn�y infr7*di5!2�bB ��aGi!� . -niem3!a4iv!<e�K{t!�i iW���_bJWng}� ref1A.���(0 �–�e�<_Iϑ�b[�$>U">�R) k �ed � �9%]F�^b!�y�9*ќ+y�oFs�ArcGIS*L� D>a� (�rOp-��(�O6��Ee"V�5nd�sQ�0<20=��s%[ � �.4k!Np�mGra�I�N 0�c5:)ɢse�l� �4je � WGS 1984 #1*�ezm1�*� �h�:a"�?�on��� defiE�@ip;I<� eW[ts’q ledg� author’K{��.i0�>�"2�2�# 29 ,^W, 33(40 , 42] exg)�Ij+ A7�arbit�͗iY-b�r.��q��� %!-�4� I~-�1L4Va��8 %�5�p#�i'a�ga���A<�A<�A<�A<�A<�A<�d:brive�h�:/ ef .SI$f"�Zsteps:Q .!�bTh/2sam�J�Nw"�� <��fi�>�`�8.�"t(�d�KN�Y(��/I���f�"��{�ir wi�!p�mU> 2�compon3��"HPA�uvs�6 f!]=q�pnmatrix �*?!i ��"� 2� aM< s"� e@u�Zy�cas@�on� ( C� bJhec�XL � }$��n�ep ��I:Y�6�&ula!H: Cl=ƛmax-n/n-1 ( M#W�nvdimen�?V9�1Iλmax.8xum�Ren�7H!-X ;���#9t!�E 'Ipr�w h�Hin9�3!� PI��U��Ql Y$> H"AP>��1�WQ�O�>9`E.�S�rY Buil "�2ad �%^#�G[� �'�(�:) b6`geo&�d"A aswut ��-8�-��8M!�1V�ur�(�>�� ma"_: �6>pr!�d=�) �O��� O( S*!wi��c icip� in�y��93��l?V�e�ie6T%Dte!�meee˭,q� 9v)geO-dsG�z��!�pu"2B�"�a.p . E ���@a �Qn 50cm33<-m&yv $screw-capp�>peca� t�1R upplc/%al-V�Xd"�10:00am%y2:00p� �jl] lab�����3�L��1$perts�.!Z-�1�r&5/� ��-�� qI?)�si�BDr;ro�s,A!�!�M"5m�k[<\� �p�k��9Ai"3* abor�P"�ke�,Ih �.a�A�%vs�xwov�Eee9in-�af�I%10 ��Y��f�Pw�ger��9/o8/� An �`�=fuulxnd �=rig&�iat 1500r%��supBr�6A��araI�se�I�.�o�\��Zc8&sl�RE dr_> Lugo\3i�zIR�9�Q neatavS �E slipQX�%PL"Re�l ����9ofW.e.��" m+  F^.:&�W>��i-squl*��/a��wQ�>Ab�)��tH" �*2�(�)"|F"�7.�c". �L3&�����5 isJ.H4�HJ� �@�A�%���rg��ra����V�L=7o ��m�" 'J�#�a:w] ��� ` H dEA� is��>� Figs� �8 �"� 5“%9�:sF�[:���%��@&�Uen�*�=�&�3|lRS� %U2c is (.�)@*33 . 5 ) + ( Ria<&*31p "*8 . 2 [�*�@ 7*6 . 7 S�K *2 .) dPplityN׆)���)A���$� ���'G e=KiS � �:�Fig 9)�!P� /vi*HJ��bawout!�contex5�fW* a9���J�$�!I'*��Y.=�5 !lA� 5km2w 5�GM�toV7.W#bYto � eL.554 , 43%�9 ^57^��asr<�!7&XG9A(17 M26M&7Ak�>H� E"9!� schsi*�N%� ��A;�A�&"�7v�i�m�=t�C�H-8����5541" �m�.%8�J�� 6Y_AT\v !�.+�or�n� �&�lR�H��Z�H,� ��DZs� p . OuU��U 574 ��d amH��AD/ �4 ( 2L60!ͥA�X^I�c�9 ��c �))�.�� e�LGA%��a�*�34E0%B^*2ay-4LJ���]�i�� fe�. PZP��_g�ly"( S7q ,( P <�r�sU=7Q=is.$J��0t!�GR!�Oona)2�Qai���m!��J>�2�auE��Vew��$y4�,>?.A�& �q6�asa�AgZ5� t� �Oa�a(�$�"�>w2� Y*�cbeice��?�HsKde��I�Ne�"�6f$"y18ge&t)ic �l�JO%��d �bI s�'� ��6D/p���l �=.�-y�r*�(,!m�!��CX v�9o�@��*�$pfavpL-g�I"�Faf�=� ��/. Dy g9c��e-GAs�;� �*�"� �!� A�8u��bst�#��`E{J� �!h��rro� � "]�bF�(in"�6#=������w�K� �/�F 6:� �512�.�=>�0c��-J%��!�."J��  �&�0 >26�0�0�RB2 ���+�G�)BHs <200c%\e�4:<3AD�!�Ae*!U��i#)�0�"25�[43�H�^� e���0U�c��a�&� �'BF2oN�Ac���to [47s!b_ �"ok\ ���".�/5��C6�ZWff�Nzm�s*��/O!�n*2A������w5 �u@g"o?B-�F�aa�PE��8o�2�B�k� JT[}�g08Ef&�a!+!i Tanz=&5Egypt2(r --�re�c�a�..�&NJY�6��{N^S�?45AXS*&y*���� ]"�e\��na{%en)e�st,� >�����%�Nef� of lesE�n 20% [4])aJ�*cej�*aM ;R7��6�Bu wN�<ngB�m(a���J�,��!L"�(�+��"�:�A��c>3�on2�!*6u�A�A\V�C ]E+!�y� ���h��Bi�^9�eC�J8'&:-= x!Ce�i�5i;"�'� !�]nEo'mi�=bc5 �=��3 >%VD'�fE�v�<��d3AZ,&�;�D�I�x�4o ���a��+�/�TIB �achools5#x!Lake Vic�S�.Kenya�� �+"�!�4����6�"�alB;B�%l�sr�.c&(��e�)��R�}��A��xt(3Y�-*�E5>�M� F� �J.�O Chi a I�e���iz !.s )0U�J�a .�-��"�\C6xi%.q#(�:.�J�e���;��\pځvb'.�@ P��]>� qg"X E�"<U�XI6m !���oGm� ntry-Ai6X���D� �?�#^ �2 goo5le�!� �iUhA�6E> ?���5, �a���W��*%U�W a��/'&a}V��Z�i�!A�tF��+l���. 6igh6�fbi�*�1�l���6&X��,D�rTD��y5 eq�1 �<�aiҗ���u!�)A�s%N�.4o�� ؆:�!&�Wp�)$s .؏Str�ic�@s pneu!I ae ( al ) meL-it<8�" <r[&� �k �c�C&ol-� � cyto{�n m "�g*�-,"!U!�;kath�h3o�5� � ���($Rw#�m�6S"U�synapa�losi����fi�: j% afrw/l n�rte�:post-�6em-��[.1E[�� 9h��p� B .Vm�drE�{3 1��&T��VX ore-�!Z��. ExpoY"acWym)�s@ef�hade!� �)��7�[-��,`0-eQ<r��M!� ">�7nd�Wc sa��A1p. e�HgMa6�I�$NMDA gluta [u a"?dtag|0ts MK801BD-AP5D*Z�|E��?. PeR �y d^�s2lJ>�. a�c6,2?i�@�Y!�!B�W���.ium}�ma��.�h�`�xqI� ���a�.�)=oG�d)jotoxicu�a�6��iW7ng����2�lea�L�#/:� �nma�[We��r��!! 0�9����\�9�j�AH*d�l ,)cA�*���.dys�k{ѫ�=Uu�xiDHgduc!* exci1dd � ���29�ˁ��$l.��]� J�� ��FȦ5%; ho�v halfOg 4��hE)� longy� disabiVx[��Q�]a:�.�IE�m[$v١l d0\a)&5]��]$hippocampuQ��.� ( PLs���Y� e�M�Ek�c} )�>*�T~N ( CD����is 54-kDa�ڰE#�s�dom AxtNj�_lasmale�[.r �%"`>th @�\p�������oligome�a 'e-�� r�j?�D50v +[ Su��m � 3.FmJe��O�Z�E�"S �Z��, A��p���H�^M�\�ytW���1��0�%, !$l GTP���N%K�! tubu�"tE��a9��L oughz�m,�;��subͫ!���R�t7�!]��v�`�lex� �!��! � �c�[[6״�PT&�hc�-� 9/% 1�8�!g)byED+>�ta60o%2A" ��?�s[KqT�x�= ino E\s a:ne 146%"�Y14�e��o� �i�f7�({US,Ct�:�, ��Ve�.��q��clinia�&�e�/�& 2�*� [10�u[�W � PLY-@0c�V8 <nia*q �ub-#� ly`c[U�� ���&��!cl<ni��fluid�FSFE�)��e\�,oor�grogno�in���,WH��nm.��A� c! ���nl>c"z����V[2^ekZ>�� rabbi�S,�Ft�arg�7ag��t��<+�LY�2�r�!neQEZ� � ty&�an��� ��I)���d,!5v �0�l�(�b!�� �%"VM adja� a�!`whi��QH (4� ��ricle�3G.&h %_ũL�6�\A:�TP�1 .3Q&���six� �Ms )* /hpyramid� ur%O(��OM-l�3r�7� ns%7�Rw֖somM!"po�oFB�u II�}V�V se�&o�"L��H,!/c� ! rece�jp.E}��).� . PaӡA8(m��Y�)<c"} �e�M�hMJOI–I<�P9wit�9�a�D�9O�,Q�:�J5�&�Q y�1llG�basket� Ak�<r9*c�� n�.bo}$�����!}F�!�d"�|as&� r, ^�.w %�(���e�_4]x:S!u�$YA��9U��'�B,��� s)�.�I�/>su�*� )s1 A&� wrap�?K�� c��A)p-= �ʅ2��}MBo����7rYtl�m�H- d)�1�L�"m�I��=�Z#D�jviT��%W� �  r� p[t"�BB5�;� �%��m �t^� �BsS�3onE�� L"^ AN�dr�EBZ �� wth/shrinkae1�A �<4,!�a[E efF��I��Id �!H�. ��_iriq�lti�ke�lo)�dis%!�߾<�m`��aim6" �H~ �WI5��G)!zb^��AE� �8 1 �� ��$M����N9$~d��� ����Rob ��1autopsyNjf"�6 #:� :�#�caaF��wN� �1�ig(%exW��pAy�at. � �)�e�,in �A%Z 2"4; �w qg�� in IAI AUm����yT)W;PSD95�u�5�� 95;�42J,"F ��"���UM[��ptiKa�A!..�����$e�*a�t�ivYo% A@Ir *�.��}9�-�a�a�ϡ��+. 1A–g�a�+�5Q�i�a(d^%H�!+WTUNEL/zfg%.apopt�W� =�� .� M$!� ��t" ��~w IO��-�.v*��d _ '&5!�%�� dela� �i). '5�%ԥ���� ���� ��%*Ÿcr%��� %� �� q3 � T,j�Z'�@u�NinI�.�� [sLJ3��3�'i�. N�-,>f*TwQ�%d�1�*�> �:��6�|���U�i;����lob�#C57BL/^� � 6��h:}�in D39E�Ad1&���A�* 5Ahirty-4 �ki4 �A%/ sacrn ld ��e���araffHj�$ MG���2�+�im�d&T b �� !��g[+�w\pr�((I�F)% e)�ic�,) ��tin:�-$ ͍�.N�_2�_���vir�nob�-[ f-%Ųe?�e�;A�DNAseI-���i���� 3tg�10�q� L��r��k���":�f��6atAN^Acz G#զiKY�Y)z!dx�B2<��E�� a79��"2�T&L���s� e��e "O5�" I��Z��>uago�, �-� � :�A�V �v[ s]�R"w�l>X��WdR�12–14~Z-fT�Y�� d"�p K�k/� �'I?�F!�mum�� CV( <"2��be�qzC.���n 5Gock>nq/ƸO�ex �ra�� ���.�� Di�  Ma^�HM�S����� visu1� 1� ,�2t�)!�B� . M.A�������u �&� ,X∼�(a7.  �;!���-�p��r%����A�typ� ��c.%'��A�<m\�ic�Ji�pK�Q�/"ru��!0�R,aTita�s!C: ���Bu- U%�*�"�lipid�.d�e}alEse*M5 ����F�̥�.��%��&�P#� or�"c��es;͖3B� Aaa�e�9<sAA!0GB�WԱg1�y!"a{[25];o�� �E\�&U �s&� *�^|Y I0-0�R�-<݅&� !y��5�u�e.��/ r�HIR�x�"�W\G��b޼aTB�p%%�k��!v  �3o�n} � �A'm&�-��R`LYK&� "�t, &�!( �abe|a��d�*&������*�!�"{a]A�=�'s@B�5DH�g%HI9r9lm�.-� "���2΅�.#de2�"���� 'R aU�iv�[.y� 3J$)!*�li)�L �`�2�� er�3,o.�5"t:o��"?3" V!�h���r(�,��!�G4v9larif7eD*Bbo|�i��������r ���aim)slo�!�y inuou� 9�'juy:6f$2�to� -GFPul� E�a�P!�lc�)���deA<��~x0]oX�e CUum���QhG��-���9��w/6atu5eL!��EF a 5-� 9 %��<�,t;endV$�Z-���s��/F&rɓX&aK[�c.O'�!6�&&� "� �TR/}Iro"}|�W ������V�s�Xa ��Eh:���#� H ∼3e��*�� �X���|y�qY�>�?rg!G*o�%**� .���{+8eV��ng.!�H&P�#A�4x !�w�2L5,�.��<� !'��Zi��%xCMja�w>��[pZ#�'�=2�:�(>e��&�610%� O1�u��n<�� )-�Q.:Q� Fd.5 2i� =P�\E�I\�@1��yQc�"�%a�f��:,!�!I '�rfac�&*�unU�( -�E�*")�e]�&;q�Bo J �y��t2��c$!�>`y:a. G"�*1�H ��� lyk�¢Cc|�-�]XVA0WlA{��3�M Y&+or �19�2��;in 2 mM.s� ��'w�nv 'J��6���2�a�H&"2BF��� uf�$��d����B�=�]�a3� �[oFi���~�%�' ve� 6Ncy7En�DU!(�!g-�� ed��w��"��&V��J�E� . W #�4�͡�a�e��$q46�aQtraA�#F�ted� ��2)UC;$�'e�!51#.�/q �!6紾1}&�upt�826.���~�*Q���< b��n� Ie�����i� YsU6�'%�"�:.!�l� �� I�  (�*Z&����� !T6�ŗb- �h2'n�(.�-*�6 a(AgK+1�'!PbV�'1w2Қ�� �� �ox>i�=�We�f2� U�^ molea&&t)�� b�ZZ�  0,A�{�d!�.2R capa* qbu9�Q��Jr� �*A�R� �0FUI�y�!�q�*[-�2Q�weE Ia�rP e"� NDw |ic6�".nd.�)�\���Յ*,og�K,�$1���Z����.Z�-��E�� 292a/�a2�����@iz9nNU�-�8�jSqic _E�`O!(ыe CNS ��1'Alzhe�'�H��ngton�DCreutzfeldt-Jacob "�$89- s.:�<��ƵY�!P�d-rt�KaC�.�h&�&lQ,m�!CA�.U�wS�_se9#rS%*`��� >X�s����g@�Ba^7��Km�/,E��; � a����mpm[m.�-.�U�}]9+*� )5 ,y �"Uu�"���jal4]^�>\2�!��?��a"� n&5�:?#)� .�3A 3�� Fk�/�".9cr�&�9�+{��I>s�@,�m�)� &���RD20�IE����_]�(��� ) [3.s�"5*Q�iX�\�x�/2�!'U��!�Q��j�:Z5�/>[;]} <LY-&�"�"�~�b�J�s��o2�Ai��3aߣ�[�4��gA&�i� .� . BN�R/m����mpe,2. "�4X�A*��&�H2O�� CpG-��!|ekv-%-(synC'xC.w�jM�*d^5��/5�>K�����!��U��K%R L |]���r"�9K'etu>Wr^� ch� !�� )��� - adig ZW#tI�w E<li�!&? 6; c� 6�!pd"�%��;��!.� :�U�-��1�@�$Q�269B*��%SQT'|����sSp�r e{� .�,u"MC!D>�2�t��s�s� 7infilB�! �I<.�Jq8re�Pe*�/�)�ph 8&�% �Ĩ qlamÖry!!��shB�r��i:h�,inOeH���R_/3s�au� �%sE!U-��qD3*�(-�D9;�2��Ge�>QQ��ex^�1C.��� 0�b�wv�.�n�i� �7v�X�3�� � ku.��elg�2�E�wh�)r#Q%J�G��dm�m�jI*�&�9& �S?5^dA w���"T:�*���9�:Ha*>t�]&y oV�]n"�&��_*a�$! meWQ!jAUÅ\<&� e�09rP:�e+ s>�&��Uu���:�"�� o"@*Qt�"By~,�hnd :�H�wid���pb�*? !$p�6�#f>W��0#e'm+��o*�0JDs~ [duf1,N�c��q�QMa{N��ɲ�"hat.� !v#over-r�[��{x;� ���* &52�XX; _us��z;l"F&�jJ5��*f�-b4���^��ur�Rk� [-ɧ �mitocho��unR&$a! 9lu%w h��72d�|s�l�����a'�reI=�s� ^�)�aL�Z+*g[�vD�y�UI1-�ng�3fN��# E��a4Dir*K!IzP .S.1&��u^KTur�kF) �i���E"�4"�s� �����:��!���-� 2."k -�5�Yb� UP� *!i3��@ ]0!?��s�%r1 r|�&~'�drl≡ l"�K)X"�f����:y� �%O�!1� E*�>� ��p�{sW��e"�<�v,-*�$x�A�ik�',�3]&ahe� *� � (�1I0�� )�!\ As �ej� �D���%���� R"Z�p�ds:%��46 E'� 36 a�D��SEF) �t@�2 � .{al=o�#�!lab��Mi2n)�U&2��).�.40\5 �6p:J-���*�!�d�K�.!��ew�s"��. sto&�j"� �&��Y� 9% vv��Y *�Ŏi[TdeG��y� ^d�"��ɳr�s��}�C�A&4 uti"��.9��9�!vz , [4PF��i;��Do6 ��@iR(2 s~XI��&�we|1�ǒD:E��W0s�ZBV�<p��=�(Y�3ne R"�'�]as�:`&W6olysist in cell cultures and no lysis the slice# system )+�again observed a calcium increaseD$all testedm s . Under-$-free buff(onditions ,~intra�ula3�R levels remained unchanged following PLY challenge . This result confirmed that extJeis�Hprincipal source of cytosolic��^�u�normal �[43] �0e possibilityi a se),ary role forZsto!� coul!�tt be excluded , but it was not�initiat!-�factor . In agreement with other studies of�dependen)0glutamate rel%�)�preven!��AQV�U3dur� * cuba.<$astrocytes �!�inYz-.M8fully inhibitedS elevR6��!�uA�Y�flux byq!D inde S key �.QM1,. Our experi!^ ��indica �ir %� as aA�mAVM�^j0. Nevertheles�,synapses mayAan-�U�(PLY-inducedh�HowS ,A� side5�Dstructural organiz5b!�{tic unit�th�ensheath!�by.��9Dlarge surface areaAC21(cortex ,A�appear�(asonable to%vcA�at.@areApr)_�homponat3 encounter�6affec!�Mi �neo �eJ��/9�.0, we demonstr1� fea6M�-qutJ�me�ism upon!� .We di�attempt! diss)��dividu��-e� this_(, which canALA� more !8lM�. It sh��bI5e5!�utocrineXs suchA�!9triggIeof ATPU�A subsequ!�P2-recep�� actim�A�(also play aiN in enhancAv9�Q�[1��An ana�����1���our fa�ngV0s�� ?������K��an op��duE�!hig!d�Ssensitiv�br�{ neur�,�cut��ad)�leads!�O(paradoxical�Gmu�dendria�swell�uū^�(�shown h��!nbee*by�@8researchers [44�7�capac�to modul�Iu; shapeM��!�!�node�$ [8] , [45[Ie�8se earlier work!tpro��.` rinkXnd reo.�,ќ � penea�io��!T�BAto&tissue�z!� redu�DnumberA^ vital gliavel! Ther;despit��us{sub-ly!�conce �e���v@otein still requian�~0act pore-form�.~re%S-a-P Similarlya�e.� VH6&�e�1! both%varicos!�-"!�sp�0loss phenotyp��@-%a� (delta6 non-�E��~p-uo�al��!�me� Whi�7he--Mǭ�onYE s do-�%nq=)D)��hof�}�N� p�(�� ��?! �u � %Q��� , do�ItPN �at�i�throug)�!2s2reF�5���a broa� perspe�rA�%�$pathogenic.�i ed18,���ߑp^ ] t ,��contrib��m`�lex� mn ��C!�.��4important quesa.�1!6��aA�^�Y� -U }�u2ofhi:�. E2zPof Braun et al . [46]�� e��Qgi�$hippocampuA�B Y�s have��.� e a&J _toa ��Y��\QO deep���0-_� st�x A�� ���5y��Qq��wh� $bacteria (��s!�ia� � r!���molecule�qflu� � d� n�-�T >�$ M oc � is fu( rY�[47�LHistoE�log% M#(amples fromA�ien� pneumococ�k$meningitis)�*� %>p�P or)umicroabs����u�!�dep� I��ver� u- Tlay�8�$The breakd���blood- � barr�@, occur� A�[5�l.�,� ely�promo�Y �l �l�81ׁ� � {4parenchyma [49�A�is kn�to��v) TLR4�@e immun5��s [50*51TDetail�� es���groupiY=�E� L em lieS nV�,��� �1�d � nflammato���ee^V �? l 6–8 h!<exposu$whe~ st!d 2�ѶM%�1 .>'w��n�;i&W2��>~ ope �Mt � r tim�iaK=Wa��: cascade l� ~.&A�}gBt�E/* , NMDA�i�D.�_�log� soci� g^�. D&� cour� ��:h"@QeA� a plethor��� ment�� s at� A5lud� oxidativey��,m28ischemia , edeme�-��F8, �% la� duct3i��",!w�Mf  cX H-2= @ cl�O��� �ynergis� mannAKoM�;he � Gs (��� llel�#�QSweMJtɤ)+ -Fdamage;=��� ye�)�, e ��in humanA\�:B �ex��@novel insight obt��M� garE9�.\(U�dis�R�in fu�u�addAJA^�e physiiof.j. �7animals� va�� aT� "2pre!�w w� hand�r�corda��ej}reg� -�Ger!FLaw" P� c&%A �,�Jp��d�yapproaby 8Ethics Committe_ 8Governa�\,Lower SaxonyE�e-�� psy  d5�! used^��NF � lega� �inq� cons+j�famil�dec!�d �iry� ��Un�� Hosal Göt en , �!Wild-t� ��as��A= �E��@richia coli BL-21Ea�S8 agen2 Cambridg UK� purif�Uvia me�aff�y chro�(graph��!cribedAg(viously [52��A�N��] �} a� aminGram-neg�jLPS uu colo��tric LAL assay ( KQCL-BioWhittaker , Lonz��c� � vers�:lasmidЁ2�edM�site-di �mui��( Quik SDMKi��}�)�(a=ZrM nt (e.�aM� id� an�146-gi 7; dia% Rin FiAe 1B )���d)��&�de v�\ers: 5′-GGTCAATAATGTCC GCAGTATGA4TAACGGCTC-3′� 8 AGCCGTTATCATAC;TTGGGACAGACC-3-pr� t��+u�M.x!�dn �v��9� 45];�binds arably�yā��c� per�%tra&o a� (.N. P�moR"s �����!j�e�8newborn C57BL/6�`postna�� day 3–5��s mix�u_e���!�$Dulbecco's���EagleedL(g� <; Gibco , Invitro< GmbH , Karlsruh�R�YyU�growth Vwanpplq QZ10% f�t$calf serum!@8CS; PAN Biotecho Aidenbach�"1%�iciO /str�mycin ( �aWFourt1days af�see� in 75-cm2�="O flask�KarU,t AG & Co KG� uembrecha�9� -�u���]tre>�  �Az)�%-l-P�A A|h.�� 5� mea�d �!Fura-2�$"B���`oxi�a*= 3 �$135 mM NaC�s2�Y MgCl2 , 4 K~ Hepe!X� E�Carl R�A^+Co .)dVf$, pH 7 . 3�:rE��2qCa~. A>i-�6|inf�W6^ 12–14 )e�lq�. decapitk � vibratome���!( Vibro�DNVSL , World Preci�SI�u!�5Berli. Eartifi� CSF�s tinu� oxyzqX carbe�ga!c95% O!�5% CO2a4t 4��� �-a�!)� adapeOE�BMEqTBRL�1!|N� avidu ndglucose��E 1 h bef�be!.chR["Xa� �-�"edq (( pH = Ia�"�:�ax is n^exci�5%q�2 hm������ed exac�ab �Brief�3�L5 month-old anesthet%� ( ke (e [100 mg/km body weK ]E^xylaz��[1 ']M��/ in,-8rCacn�2lob� 25 µlC � 9%i�� +g � CFU"�Ndi3$� &Din+AHm�$�/ p 36 h�l ��/,A5t��~Asac� 2jq6%� collB �\rebell nAe #/!h�f4 spl� �homa/%�in1sal!o0( 1/10 [wt/wt!stoYe� e= tit� �9#Vc �arpa�,�hough sl!�ly�e5!yD39-i.,"f )� sign�*anK betw�Id�q� a-!��%a��A�fiUin 4%��aldehyd�%For a� o �ssess��!n!��!�i�å�%�I!���&� !�� -� c� S . nia! n� 10 e/))�a�$�[ phosphate�S-�j4%��mA(then embedd\ par)� -g meter-�k� onZ�!^EkNs�;J7h�Nc���TUNEL8�"-�2=h�"caYoR�^��1I�U!v�" ��rolI? ( 6 a)�- d=%©l, %��cau� javerage m�6aAt61 ( rc(>�8��i�#E��ed 3 ma� 3 fe  r*�victima�s )ed �%�b�!mly�fir��:hI�a_im� ate ��dr% �J�� �K62�5� 81 )j�4��2- .&lpa Efr9 !enam in T�1B � : � �.+�2J(*� �PBS�� )a_ 30�� erme�A�wS��,1% Triton X-�6VIw�ei�Y>Wstry o E�n-8fic DiIi���[5-#��crystzM�lipophi�*9 (. �nk!ioa�on IV–VIM� ex%v*y ��- longE[mf 89 ��(� c"i�t�+,�A�apA� �{,branchk pyramidalH�$ . As only!bj�ng3%�cN��phy�harhLV ",�xrx }d� sv �%l( w -A;resum�����-n avoi� .ő�>e*�",i�� u-s��nd�VM�RQ�kdx<A�Ar�%f(I�� anti�a��+a�2��)t r�eva-luAD8 ( Dako Deutsch�& $ , Hamburg6 t 95&� ���zbod��rabbit -MAP�}L1∶200; Santa Cruz ���$Inc .eidelbe:�,�6s-s + in IM ∶5]A�S�.s�R ))P�8PSD95 ( Abcam ,F�9r&�-�-�go^ nti-[dQ t5tag�.E� FITCxy3�YCy��%:Dianova�9�.�} I\ nuclei �jDAP!:4 , 6-dia�8ino-2-phenylind�! dihydroch-de;��;� 1000�졊{  {m�abe[0wA� ProL��!$f%reO*NDNA frag� ā5H�: t� I�8a DeadEnd FluorH ��kA�c�L�manufa-er'��h (�meg5~MannheiA&.�a���01er-��0 o��%yi$iodidi :�6: �`Et26�ein�1K��+15�+�i�/' !�reoo+ zyme  . C�%ol22rDNmA]Qi!� )�-^o lab�)�� a�Coxy%7otidylferJ4to yield 100%-�v�S(��v�,V �1#��no�pa� M��"CU !1� �!oY�.F�" Hn(n Oly&(Cell M imagA�.%�&(,Eu��J�Q�20× d�b�^ve�Ha 6oil��es."�4 Leica SP5 lasA���� scopA� &M� �s ���AR� 63×b�![%�,a zoom of upA8A}I�a5P%�/a�#e ya p3J softw� ("u�43� W��w)N�hal@itu�of Healt$Bethesd Mary�6, U .� A .��We util�y�A�F&AM>� prel�)�� ina<�i&73�`A�9'r��{M2QO� ,&* by wash!9* e-� ��GA$n IonOptixY yQ�.a��)�ie $IonWizzard.�"�pLim�3, Dub�Ire%x�#GT.��|Wv� A147u�I%gF�#se-co� semiH l� croerodjSarissa��  �Co%�Un�Kingdo|7� de���ba!)ue�ya�*���� �� �ic!�pe*�e �� valu� �"g ! � &b  refe�'O (%��e5 sub�7�J[thz � 9h sens� ��-"I zal; ��e�n*dQ# nendm&� �8 st az(i:G)#M+,�L� a�-en!ed�!�u�m��-Qa{07I�qVu�w1 e��) reco.$�idpp񣥖manipl#oA%Kerr S��6$Christchur�New ZeamK*� ig��ac/d%��7,iosta� ,Pinnacle Tec&� LawI-�nsa�W6!A��%\Pal 8���^a�Q5T%4mai,!�5era%of)�*�u4Yup�!]/N?d9a��&�a�ad 4xX to a[42.�1&200 µM ! *�(2�B4l3;�;%�:eto back�nd-�in�iW$In Western�t2�,"� �^ eqK6�!*Q -$m�ph�-ed��0SDS-PAGE gradLg�;( 4�2% ac�8m� , Ana��&�$1�s�a66r� fer^2��-�blo�$!�9�.A by repeti4,�(ze-thaw cyc�in liqu:P!f%�e�3Y�  #�*i^h e=or# ( R= App /�Uca*R� . S��al���e&� i>G�'Pa�$ism 4 . 02� � ($S� qLa Joll� CAA|!T{ �)���.(����-�'ney U- ( �-ar!27s2�:!Ane�m� :0one-way ANOVAQ�Bon��oni�ta2`�m�u��~h. oHu;+,papillomavir�( HPVs�re+as6�.majorz cancSA>#c<6�.�ng�2 eres�d�top!new���As:as vacci�&a� bici ,��:@��i`. DWa�l�<r*�8d�u�:� ���** lifei%��HPru2(is"� �0� �#� QAoy9atW�T �pl� i!$fe]/,Ip�$y)��m���ly6o(ng suprabas/mpart�z#td;��;recogZ�(� must�(establ�n�?1-n� � gI4!8V�qBwhj-LDs%  �1�-�oo�,Ina(�  9u!� mi/ref? � 9:of��,!vntG3ce> How[!�is hyp�/L&,Cf+B explW=!�>�A�ri ��]#0si�� many@ tyN$�7b�+!�ed%F!r�T�!o)F"� . HaT@@ �0�� y�*roa)to�)� I��EL1U* mito�A��a >�=�. U�1�us!16%�i�2*� !,i�vi� genr$ , G1_�-Ioh��kevn�+as hosf$� 2HX �N read7��!we�>r� E���$pD %E�`r M ph��(5�6��ake@@c!�La�;��}96 e5� 2��1 as G1 , S!�$�P�)�[ effi� ]�AOA�.- �E �!ONsf-�pasa�;)c;%!Isuc ful j0$!* criph�I���l�5lso�8pog�!&�<im�C�C!�!�!�. PR smZH!enveloHk>u��n�rGe� �! c-e�L and/( ~'al.�in�A�Fe�(es [1�1 Over��D6�� )A�%@sO JGgor��gigh rism HP��a� 8 )�low �.� >�*ir onc�%ņ. H_���[ caus%�a:X an?'W &�3ni��A� cerv�carcinomA�J���nv�!f�- ^!]womenN8ldwa�[1]–[(A�<>�∼25�hea/(�:R$ E� six_-�:commo�)/ z��� !�4�.�Cv �*� 0��lyzh of���q� IC[6e�=�K�!4@.j� >7"�ZAu�L �ɝA�ő$multicopy �ar�/�1j� s;��bGa����V�um; b )�en!N*!M�tE� �mb�':f>;� c ) e.=ځ-f�G�e% ��in�e, Z� *� 5�"���e� ��.EI�ge�YaA&73���t� =�%lle �$�� CLC$L2M%�R��7)e�.� N� sm�12DF�� icu7E!�rB !e!{6t�)'>0,�E `A2E aNe, [@Re� � 3q�m_=d��AU�" ��ŵ�!"{ *� �#q5s� )!�5M wPth�< 8 kb��m Z vercM9m�/M-, 1���� niqu%zW ���t�ly.ifi0',i��#N�"��� �%�seudo�e"�9!�re1Eergs/=�!��m� step%GTk&� Ovia��4,h � ,�Qot9�c!jh  , 6G��A&s!=,� $ �I� h�"�Od*nB�2B'!�E6.� ��.� j-�8�'=w�3nd.�involv���Jy^)� L��<x"�9 , $#bioac���ou$6  C65*oJ � � �� �f%�)^���:�bheI�!�M� ��;a �7 ��F�  �let( wild*`Y;(B&�,�#5! M� / �G� y4� �Es�8E�^�*� �.�:� } �(w�?��MK5�lE0Op A%f |!�ly���0�+apro��=g%h� �2 drN� � a�I�!��* apeuy� teg�'�Us� �!a . To1�y�;2 in�$;=m�MdM{9g.�� Q�A/I�inM�y5F l�4B,�P�dwic�  CCc3+| LOPAC ( L=hUPharma�=g* ly AiqCQeq, Sigma5�!�D�Q mMan SV40!��Fr-driven� ree�lk�/e"�/�SEAP )6�9pv l a�vi�!_}��$ �>Jvsy'9 -�I ,��,renilla lucih% �YA��7r) �16wpA-�5�S�%e fals'Ft+�%m-�e�may se�iv�@~SA�6d��ZW data1 �Fw�^ scre�I ��&ti�Ckid� 293Tm|eX�F Fnoise a��afi�a, z sc�� �,����3. S"�W �s6� HaCa����% orta�Dof3.� T��a 1�C ~��A�M�6YLvalidA~��h., { d beS . Am�KD0>���$ �I����.ton"de [12�6aphidiuBn�S ch%� he �!�� nt%�.?�L b�B�inA�s �Nu,A�^M e�o�B6:q(F�,: ge1�� 16�u��-�w� o���� ge6K(e<>BJS�� $ 2 h5Y!�e�r�drugse,� �Gh�M60neu�6izA�G8�16 �> ��a,���,� ly*� �o �h>�A8u�6β�� �xB 6 I# m\"�F� � vA-6q) two �A�%(aner�>� 5-�)ouraciK0 5-FU ) [1all)v�Mrob��<)�f� ���%C�Bn ��� �W*Pny�7�!)!� t�Fi%�-6c.�K%�aVorigi�"m�qy�Mdi;��*| � #fy�)�^Am�:���%�5��{ . M!�"�ly�M���gg� e�<Q ��nTo en�>>"�+�t I �-?U, in:�E�&�Wi5)�cVhi ���tt}J � s\2oNe�of]�8dN� e ar6 �!=�w�6n-"�Q�#A starpY.2�!�� ,z �&�Z3om .w �A�G1��draQ cQ-6�u 2A52i�&-O!�A�AD<)bj�Aa�%(<�o��,:�N�M�e!,�CwZ� b� wo-f}=�z.�`� �7I\�.� .>�E3��!Ia�%:�9�-��.A��:ne�5hA��!s&�Mf blf� sy*�.%� ��or ��!�t�:��8�ledS�[�..��fmG�&�)&�as “No1�ion”;��3I03A0�4&Y e�2�inY��^ 24�H��06�)I-�hp& a�5 L;Q"��#�Xv�.i� E�u�,q`. AMD48�m�a3�)�ed2�M"ed� & R�;W2�0V ,��se!nn:n�"�$( y"�s-he�^� �^! t�Or=z�}X  �0 �5�Y�o"hd�4%�UV! (!쉓R-�third*e�LR*s�,E� �E1Q"e#"r2�28a�It,�@� NZE��2�ju�G���at G1/S�G2E�]��y�A�s�YRB6[*g ly$&i lAV��i'�#R =%9�}��v9��asam�X)^DJZ y�#f� cyc9�!&l&������� fl 2<%8!'��f-�?��"�5J�UxfHh0,( S���R_F��< %��byM>.�E�����I4NS!MCGhr��pla��]5��Y6. W��2"as�T ;by-iM���2�G1m� 5"toA�i�a� �/Saڕ8!. !j9AZ� fifB7&"_"�Z;a�-�T��E����FA+i���]At-�)�h�420 hr��f*a*1-��c2 I�:Gf �iY��\Ux "` r�� 4 ���A%�#a��(ing��KB'1SA9��A�#��6!�>Z�Our"�A��%w..�u��� 2�:�q0�i @'%�X�� b�S�B��� `"�#�K .$|^� v ? �.}Ca2y^is�mk� >��!M"� � !�w�er�iT�6y�, gtuN;h!��ll abov� �' I�”iM� ��K!p%��A��qmOoaY�=�A)""+"� enviro�V�V: Y AT5Q,� u�" 1p-F�aas"i,��fun� ��5r�Rt�+�&��E'I:Y-� a;�KonY5l [15"+ � sE��spi�X�gon�l� !9����V Nh�to {SQ�FB��Ai.IVM� �`cĕ)5� ��l �or.�68j*� Jn�d�la�Elh!�2Rf.�)WX�6�+�re�S�din&�o��A��=��"k' ra�e9# �G2�/9�Y ��, �)Sg��?L8& 3 narrfW�`A�"�E�J0a�so lik poE"]).�=E�$k3M�$�$iEa�ba' ( NE )*�aA|*�9Y+A�l.ruz@�ShosQ5yl�ofG�o�l�` CDK1����� b�[16-&18bSm�T�HA� qb:>G6@.��y�69� & !� �I or ,IY,valanol A [1$"Pu -ed:�dos&9:��,I712l7�:� � �t�A�q�t G2/�d!� v,6� ∼5u�6� 6a�>�:fYZ��P"F%�- P�� �gR�i �'��0nflue�[��[21�E[2b\Bstu�!>6sh!�sEke�j&Dm weU�2&k�?ar�R�Z"!�.ombin�>ungN�R�-4�"�h , E��/5]�ab {1t�* � ile f".\B�^t i 3A���C�BYu f�T�l5zen9x�h[1Fm1�,��D�Y stud�FB]^� f��&� !/: se�M!q�2� jH�&�-itdux%� { HPV-2 ,I��9�A�=scu�Sb�$��+ve� C��9�O5*� ,�"!AP� !�I�sub{a�A� alEe&H#6���+S�s��A��a坈1j. s 5l�a�)�&�u�S�B�" s �y)�a� �nEU-�S lo I�� k�N�Wplk�$a��yin B1-�Xed+�<01725D �:a&h;�orAccNY>�)�!y!vw�"� un�6B" 6� �rq8,�"�(E�B4)"*|%)NE]M!�2* aP�->�!e�#%����z� �?���ou AFe�p)�s�ex*r�o�$ow a�7!�integ !x� �[�� s [2�52�5� ! �(jDsaP&�r!ot �1N ders�>ɴ!$�[o�Hc0h��L2i�MP�Q cdk1�*�2/6��0�%rgu��21�P;A�b"M cal ��td���kA tubu�3,%.�\to ho�NE [2V{2ICon()�64 "��!:^Uu' d moaP, dyn�n�1nsQ8MUouK(�t NE j�&� 2�a)lgode�>2V��IA�es� connMX�aѱ�;L2�2e �A���Y�m L2∶E�'w lexe>b��d MY=.&warl*�2[3�T;1?&*t�]�2�$F�cargoD-A�%O~"Nymov� �R{>1��*a>� i�j!C�+~- ��.��AeMer B�6��>qix�Dde�3�mZva�cCA�)no�B�q e�A�B�! re2 ~� � �OqGtoEor�ItZS,��4 segr_no�@AU6 �7T[3k3k Like.8 � �'Am0R�cr.�M p�dS�mw%nusIk`I� oDa& E��Qs�ma�)oA��!�E����H{ �*>aN� @8YN ���e.�F�2��x&e�� �� 2*��"h�0��R 4�.(#*�  uML*a�Y( PODe'%�`7F�7 b�x���'j� !��@. i!�so�as ND10ra�"N ��� w&��dR-&�� a�� "A7,%��sia�)defense!�tna� %� &�so roteXczv apop7[33� 3e%EŅE�fi; d6�UC&�w*lq�,S-:)si��at �4�c�E�%"/6��= [3q[36f � dyna�ElA�Q,ed��%>!$�+)eo"� #hsbJrgani�[3 9aP h�be��"�� ����>-a��letoOPOD.ls�!�U�W$ɞ2\O9ebme�V=*� e����:� �E6J46��incomA�Qa��eby�il�;eM� *C -r*�wdl�O. Litt�s�ulyq�,zN�]��AgtoZ�. M���!��polo-�$ mGurmz7 se9�xs� �i�6AzVf�d�-�X.. ,��n�2� ����!)o <�%�K ��A�snee� 5�[3�s� L5%���l��n ��(grin α6/βua �� a�u�inv�gS�%�A]�_lrecM%��–[4�.� siX\EOF�B�r"�!��cy�� �!y�Cbe�s�a��@� 1l=Ei^�H)J,:a�fN)z ���*4hyper**=v�_te [4F �M:%lQ�a���pc Jal��uEol5�1As��u��56 if s�t� P�*!(to�&>X���� ��R�#6�2R)~��of�O- ��y�g��ur[&1 ��y"J�':" �����!1!f&N n2&:�y�g ��6+ �Z!�=��BL��wk�&�b al-34a�5O"�[�"� ��*[?w�e/�%g{ 9WA�)�=+I/.À!L�7gpr��ׅa�A;6c\�&E>Bd#U ngui�Wa��p@Ac��Fe�h�vast XT�t�Ae5ga�&/b��2Er%x5sXEad!�q2c�6exi^PE|ak-# ����W ~du�� ��)d� LA�fM�"�To�rm ��eme�0"��avenuɒ� o�r20< ir. lK*zo%M"ޓTl"GF� �!�;j�}�, �7ovo<> igh-5M:�_9 � c�K�6�^an urg��!s�9��"�R�B^=�e" lyp>u%�@[>STD( &����3�W�$�bmady*�&�V[��. Fv0�2�BB�PazC$H"� �n �a"p�2��]e�#�4sp�R .&�H, Schillkh X �C�TJ�Ł�%M�5����)tijg�W[��mU�P"�C ��3�B��nowgo�tea�a�s�s� ir!z icac!4 �D5�*�a50�!{E�͢puth Y)Dɇ�<|Y7�Xl�m������y�;� !-�S�#2�UC� &�of=��>.r5)a ��6O inst4PEsurro�])Y�K� �V29*>�-Ky"_2��RQt��䐑a!�4 �e:�:6��ts6C. pEF399�0n�ABA!��H W12EJ16�ls [Q���?�"� �5!�H ck�i�0��)�LD�Zp?B( -a�5�VeR�Re�YFh% purc�Uct ClonfL�v�R6wp�E+clo�&�1e��reg( LCR"T��k�ik$ 7155 - 86��t�RL-nul�@P^mgWG2re a Rj.C�d&tF�ve �aod. �\�ayo���EA#EEw�5ATC=oa�A"'2�GT�Bgen.'da��AnEOT!U John��1r�x*i!Vin N�e>�DME��&l�eKZ&��b( FBS ) :t.ao"!FF�=h y�Am2�F�6`, 3� s F-12%J1�,Z���#!�pPEi�]q(pa*�oq)}>m4&�nw���fed-�(A%KOY=6�)%�I��#�ywm��#'a+ �;�/DNA(&Xa4.�=i�~�8�!r*Pr���d5) ܇�|_ka= "8eirif%c nI:@)�L�JRL�!�%%0v��7fl%�!��halges�t�tAlsf� �A�)�%M�" 2000cerse FDA  �azJ.&� S�=rum"NM Co�~�! �o�ce Dis% y"Nu, �cc128.�%e��MofkM� eR&A:�, f��.� cand�\ “gdCsta�ksb7� �a�-&x�0 vi�_ 39����Eof� ��meffor�[nd f�� mdeia�e�HvA��n!T ship� ,� NCI035�.235F��-+���NCI ope�< sitoO��+e�ds"��2P��M��t0, Aph"�K, M"�7,�HlWuI,, CGP-74514A �:�yO. 293TEHin 384-!ġ���2$4��3�3!��O���pCI.>!/�4at�.vge�q*�$�j�) /V� 4tC9Cu�Csuper �nt �|mql�mul4 � E�(��a �5a-Lw7�&lum?e��V�N D("�gBi"ws)%��lys=���via�5 I�kCellT[�-Glo L�R5&�vgK�aS" P02Pa1Sz M��.F�Ka�D*K� of W�nkzIR rehe`,C� r Ce�mߍ|�R� � 6�#6 (U�)? �UC"�:b:!2�+ 9 �!iJ�1 * �E_�� L&_R Assa�J!�"4 �/� i4�Z%?!�"��by qu�NwjvA:�* � �S$PCR ( qRT- )6]�L� mRNA��%-��2��6���>s50�n00 vge�Q.e u��r�=�qA3 �TP ��iso�(dm�!�RNeasy x (J ��y �z(&�y�'*�RQ�yI2��f6�e� ��L�a-E+3X9�n�colum��H> aseI�d-�V�( ectrophot�{ea@c^�syny4��W2,q����oligotQT )-a S��SE TPs-2a{� d qA|�5aQEcT�&SYBR GjTEVKi�9Q�z. O�.=^��s@3a* ">ue�!�яer3�er "� S�[5G&��by MWG�G��at܂��MEQ�I�$� Eg0�30 p�, #�4�, ��+�A5 ��;H1mer6 at 72# . Ob� A�mv�*�r%\�le�of&�Q( ň��u�q��un+�Ra z!)Ya!A>^}PI $bcorpo� .*u; Z!�h� �omih,���c� $70% ethano�*cyat −20!Ir�KPI� i�s&��1 mg/ma��A!� Pa[ф2% NP-4*�!�z room2u.�c��fi��e��[3AMm/� nylo!)sh3 -�Y�alc r!�5��#� cye�r Bec9rD�*[h$FACSCalibucX488 nm�| exc��^. �P���sumR n�i�AR97i"�� m� morphic�&gu�gI%� *yȦ�China�Southe�As�h^.miRM i.AgFre"�m!� �W�-٠i��*3'R�:�U�!Ypl�� ��ngiia/M  �4 �&��fun��d-sm F0�lU/�7. BVQon P .=qK��UHrwe�8��� ��$%4�kl ) �q0�&��5�~;�A�*em Ni>� o�fyce��! y%�p9�%-*�?�e"�x.= ��m�Tabund�2�ttSW.uZ-0e&:%�^�4=� �.Baw17.vi.��6{Two!��( dcl-Xe �l enco\puT Dicer)�9�ahgA�, qde6= Argonaute289A�B�. Phyl�\�85�9!�� ��+2��%� closA��5e8��log�|j)��:p&��ai)�to .qchrys�u�8Asp�l_vspp��s#!�!+co-ev��of �am6< �F�i(ore�, 5*�W�Qer� M�&�T.B�by 7 �T��P��0�. Nor� z5��!!T�Qi�o�%w?i4�fs&l��2)�! .i�8&le �.�Q eŽ�RK� in ga6M >�sm . .�msrff�B�-i��r�u)�NY:O[�m/"i%�uen } as Talaroa:s�em}pF3e �a"�"!lus�!Id�ve� in�!bamboo�`aMRhizomysu��"��'�� �T�$I .R.�mA �18 MvEOhAd�;")$until 19859jA�eme�"ųHIV p�p� B11980' =�2s��,*� e�HIV.�26c��in>�"t�-pi27�.�?o��3,-qV� �Aa�c�)1A� AIDS�&n��Thnd [2!� In H�HK,Y5utS("%��s� h"s 2C�;"�s�sip� ���)�� eath�k,, . CaAzx`} edfA�}!M���co� EFut��>m"w1a&�36�=�J� u"�Zro�PdCUQA�Y'�=�7� � �v e< I�"32��apy [13�+1O2D��8I�-)=Z��bdE ymis�tC&' A*�"�$E�64"*y@� �y�mar��2o�#? tinc�vu+mY _ !�25*��!D.���at 25�.� at" *����� >,n hae ٫;<� �=nidia(A��c.a�6(a�!�m9�inhI�F lung%RIX� �xI�G�Jc oi phag%m+alveo%3ac�ag%�Eg�pt�_q� �Aw�2i��iA}s"W���/�,D B� d�e*��5#�$ G@!�ags]L�?�BY| swit&S�25U("[� &@� :7�C�x%jemper6pe �j�A��m��-�eiPQ�el3 %@.�� /A&��$ ,� �n�us� �$x)"�m22 ϴu playu�t���6��OhH�'i��.ompb+�-� g� cl�'E { �&�%a�u8�6>H�m)�-8n�:LU OI6A^�� Cj �47 s���>kM`�&9*�/A��-2)Afr\or�~ ( UTRek�$�~}� }��I���� !n��impq|se` pai�.o ��(�*��gp8-M;!�l �ity.Q!�vaga�ATi�P,#O�.,1��E�@!*S<yu�"��)Hom�R2o,�)�499* �,*�9� �xAR�����[2� -J�R�����.J#:�\:���b��5|�(�H!+�9]BI�� i0E� lin-4 : aenorhab�WsՈ>+��993 [�BH"�Ji*�� � �!���Ee4M u�At-7!F�! ��e.�7b����A. Wr�LadfBa�m�ar%bio"�oc*ol�enumer���� vzWwI+h2�%�?�{!�FTS>2�o ibl�urϡ ��.�'�/ab�E�Z��e 19 . 0 �BA�>�� �Y�pHinU�� i�y90���AJu 3"r &F2?*� ���H�s )�6q!z �Dd!�ZfNeuropJk�G �%��al& :.(lerotinia s o�#�qentom>�F/"F$, Metarhiz: anisoplia�g�� !g 9�, Crypt �us!��A�[30� �=6\_.x�[G_ N�!��Ina|\tar� �6���Ŷrojec�5a KC� di��?�b"�%epi� � �&a)lE]fx�łb/& AZu�A4%&4�7BN��#l�D�ee)��o ��v7"�">o f �E�����9��� �aB� . S��m#�=UH ��o�T?!�^9,!�"VF�eatu N�6�A.$!+ ����2O�I��%�%I � ina �-��c��U ��� 26o� �t>^B.����queB}&?�an v�Y��}*�>���.HO-��,pˎOu*A�"{+2nA��Ŏ.�2���iej��mC*:��at � nzyV=phee 6�"�1�̕��cl� y-�a#&5,9!�:�m�2�fl78�+Qu�2s�&߶�'@ �!�anonym�.:U &P �6�a���! �k -docC� v�.x. K�-e� m�%�T�-��12 d�� @(��'�KO����9�.d"E/�P��N�VD�n�$Sabouraud |��X agar�hD�N( Oxoi�.�����s7�� !�=�X*~eT�%b!Kre-3[F?C '�� B4 scra�z!��+ spenfiU� 1% T�-20)���f*�f�was��k_erile(b�Osub)�A�i�lM� �� BHI �u�&Dif��NJ����Q  sh3�"�!F �Q28��#�%}�H5a% e� 7�a��cyN!5%S�( +�<[,�Ha���5!H����6/�;{91 M�A��5IL6)� e~8�Q �P I.�Aid�*mb , AuP , TX5J�mirVana�?x% ?)�h�AdisrupjwC acid-%�d g bQ�(�,-AldrH, M�Vur> )�fg$N DNA-s:�&<'�d~<. 1F�&e(r� �2{RiboMi�O Eukaryote�!�RNA-Seq 2-4��rlsbae�a��ib KaZ$� r%��+6n�)7d^a?AS�,I��k�$5"����"U^glyi� c��(9�._2�dmÕ��(0a NanoDrop ND��0�6F((%"��a, Wil*Hw$, D�c. A��nd&n�iE�2&���8� *�-tH!! ��%�^ �BAik_�e�3��o�w�>SedE=:�Coralv2< , I!����l(D�� Y�e�a&� ( ≤60�)X:?H:�15% d(��'*��ge=3jaԳor-�*�>teGa 5� 9E�9TN�A�AzcC#3�N���% -��nd*��ak)hy���z=?� /S*T*IIBopm,2~�Fx.}!k�)��!Zm�ch tj��(�)!�omUX/Solexaa*";�L��?o 2%g �!��."FU��.� DU�Ge�Af) r II�G$, San Dieg;E�q*  ��;\@rs,&(j�F +,QX�M+-di +s >�w+m�cho�)�0[M�6q7"<305�(ed }�U221b75�G677N/�T�� lp�R]V�.F>"e!�G�]�7'+ax! )�y��&az&ym����-st RPd���ofM~�< � maN�f�asm draft:? M1V}H!�"��m��17–3�z�"�4?y}-�mat�R oi�Bowtie (�*1�#8v}~�B(O6,�%Ac�&���%pARt ��C dM� . Po�� .d2& $�� miRD��4��da[z].ihb�5Kor%S!f� �adVm�\:� ) F�+ub� t align�keeX �I� �er!�ly]nNGr0aL&rA>� �)� ; ( ep9-' urso�d�\-�+"\ � B�N*of 25EAfla��M�Mn���(q/H����e\�&}x1�u���Lp���RNA7'�!h�}�[�2;�!��6k &4 �)ZPm!�3J��I�a:� �!aRpE2a|Hm-loo�8l^(( hairpin ) V5W ��|�-yW�f��I��1OM�p�2 *9,!�y�h)�kpo�&A����N . crp�*NB�># 9-�6l��M1m|Mg� (�� BankUF� n2�O�0 !.A���"� BLASTP al��th�I�`v�b��o� gdwru�)�!2�* .�%stl us teleomorpR�.�&esf sii C@GeV�BAS �؁�R3AYA18224j$BARL:\�Y  ᑩ�1|e�^�B�%�*�2�A+B4�' �2riv 6�:���&M*�(���W VTo��N�'0'��*�,�"y%s�<.Epe���ijBu�5s�J1ꁌ�kT&�C2oAcEL�E.9 space� T�B���6�n.6�-tre��.�)�wmaxT�Dlih:�m�I�U� boota�p!�WT�MlD5]KK WAG+F+G (�gMHA�AR�� rtREV$�.)*�� �(�a�mI�' K2+G` EKNbB' x)/�5 g�?"����6�\(. Nine-hundr �2|�, 764525.�po�"r*2O�4652�2H��r1a&�u� A�. Dom�����9�C�#rA�+Da�of NCBI�PF�$http://pfa�s�X�7a�@uk/�R ? tab= S,1B~�!��`an_ina%�P�"kk�Gs)�mf�Y��:B.�geKl�by.:r�RxV�4i��� "�Al^�|e�6�A�͙,���"*8rKї y up!a~0�t (�r!!�a�u�A�Oc��"6&+Id @v�5r pAN7-�ea gif�m D!��J�unt!���M B� d�L�"J�^��*�2I.%>)2�by�/I��:�=�e��>Z#*˼.H[()j^��f�����`5srJ\���:<NU-k2zhe)�y )s *17 )��=�how -�:�O8#flRT%P Ia��%&Ahdi��=��=N2d��T pɱc� �U�j}K. {:+l/%�,15G/ml hyg/h  �S�]��8Q��Y�a�P,B�!1��Y�8��I�9]��!�8%�aj.|pA! ���M>L6�dc-0i6Z�Ǯ%�ph� �V�ZY4�o� c��KLA(M23 oc�$Ezmo/�UB3IB5�Y&:J1�?&<>.��pa�d���v��{I�{�o&���)�F�?,;m@��ersham:Cs�[ ,fBA�&��1&Max Tn(fer-�*7g�#; ��G) forc�� . Crossli.of� !X Hybond-NX:})� a CL`UV B-C UVٔ2����fZ:�,�0baS at 8 =��2 h .�ridM>!�Y0in ULTRAhyb-Oh?"��EJ X� digox�M��DIG )Zel� prob��F"�De���R�"DIG-la <8A;!blo(�b�<s.bEV�ARg�p��&�#�*�. *I��N� �*x.=:'E�%(UTR� ��&5.�nd 184422P�|!RN!�ri��*�@E�*W�mis�o4�s�`8a��a^ 9–11�-�Oa����&% urag�"W $a�+���� SNp�7:o) ���e�7�&�7)wlo)',�@, pSilent-1 [��,:G CF�=G�_ics S�C]F,e���-� u �e\M1oa8"c&�m�"yi-&�( ��(w+ )Iv&V w� b+ !�czR�l(XhoI-HindII:$BglII-KpnI*�5- �g� ng� !M��a5&1Fb��P���h��1T,�2��*u�Y&kd+c&X �L�Pure-Y�1�� X>�F�k��F F!;6�I�=2�DS�\�F7yz V^� %>\� �b�z!��XnI.E�!4���.��YPA!0ABI 7900HT Fa��T����� ��fe6"�C 20-µLmix���DABWS)* Ma�.�EI MixC[.�,� ��Sw.�Q2!��.�� SF.i!��2}E95�4!15 �zf�eV6�1�oA nd� o�A( curv10u�:"=�ODS �LJ.D"&���R3IH)�Y?I Stu�'s "�SPSS A��19���?ݑ�j� ^7s%6�&�-de��a.�u r�e)7�KC686608�� 9�� 10� .��SIl\L.=&@Z�SRA�!5}R�$SRX306604 ��eN&� "��t�A��X#J,iO� mLX�s&����m�FAZ�"�#2Gk��!A#1#�NQ�I&��"raw|f�&z�J@� �1�t��.}.��m�L+!U^�" � _BjT,"�a �^��5163�270�82SDqua�,�5F%��1&.�Q)���=�!�U�*� ��i;�7%a�6!>!\24J";2D���cw�17*z )`�a)502-b�=I�!;nG&� @32<}�6d6W�a.%�u�=NB !~�!64� f�,�ddce2P1��!S $!"�DZHa�y�&h,;a=Z0Fp)�3�>s�@�tGD�2�7�=>A26Fm�2t N�� [5d|5�n!� is�383 b@i.�,�r�a15� T�E�� *of 889>eAux:%res  497. e*�����&{F�3ar mas�h17$N31 kD�[�2)�is�[636�0nen��2�sixv�340?��31��2��6� 15�[��%�F�od 42%E3� �+�� Z-"D�+ 2!�}M2� . Bo�F5]xp �'b� d*)-h�ic]��I���&�KR�OIII;A��'� C-���&�<��(a DEAD-box �mATP binding domain is present in the N-terminal region . In between there are RNA helicase and double stranded!6oDs . The qde-2 gene�$3 , 199 bp��%.i���7 �!�2 ��ectiv�Z(6�Stu�'s t- �q�4�Nor!�n blotm�y��produca�!b,milRNAs from�Uof &�� " locaPPM--M1�2 ,��I:�B�,�heiű]���cursor ( q0NA ) structur �n!Q��5�x2Npr Gs)�$approximat!Y 70-n!! d 91 in siz� had nega!�%�a�fm en��eE8−17 . 86 kcal %-238: ccorMto A�� ( http://www . tbi . univie . ac$t/~ivo/RNA7. html )��5� ~26M> ara� e���kn��mi!gor1�=A$[31] , [60 1�e� ajor� of small��!!�b3&��one arm3A� hairpin (M �� a � � 482�s�dI�:�10�,2 ( T%+3e[In addie:,.A( � * ) match:� � le �%�m`�r �S also�@, but at much low�r� A�6�to � 5���which-W!��p� s a 5′U�!�-�ofi�:S2 have EGE6�A;exist} of ^*e=n� La 2 nt 3′ overhanga�these :/ �* pairsEstr�<ev^ c�A� � e�Q!Ha Dicer-like enzyme�5 ) [62A�SiI� )D�Me!�u� !Os� *5� �c� derI + K� e�}Z tent�(ly named as�Q&4 �-1�!m`1 )z2�Uu�(,�Dtu� aM�co��r�(of a hypoth' al�� , where� V26T Popposite!���R0pogo transposeaei$�a repeat� MY 9ge� �� r 22�ii82llA� candidate )V�MCo$MC4…MC17�V!bNA.7F��EYC1…YC >t�]:�� TE�novel cs�u�� ed ny�&�qto.�sAqB aŝ March 201��To�ya2 *h profil� �FB.��*� AVZq.�perforA�A>�� cross-val%�o $e Illuminaq:�{���d� ng"b-=fic.��l55A� litt�r!N=:�$( data not%}n )�wild-typI�in PM� To a�%Wro`f �> M�bi� eI r�,A1KO 2 DKO%�� KO mu�-c�re�u"0�recombin�$. All dele��Eexhibi��growth U��$phenotypic:�sA�B+in�/" :C cul�;AKalthougɚdc� �� poor spor� - Q redu�̡Ypig�pA�� �atoF� upon����� I��>yc.O o�b$E�M�2��l� a�. More��� �e�N�70��.[ in�+@ "� 歾:C 6u� =j�w �2��in=,orB+.:: �� 2� 3�is� e� ��N�9R��ap�ediat" "�9]�sis ���at��� iav�!�6�6�ev}AtE�9at aztMis � l��pr"'%o6!:�A=F�"he�6�x �ed�y$�Ռ��~ �� A/2M�6 ��>�. �or9 Z�%B��6� ]!�]du62EjI�_ Qv�VIa�L� T�H�2G%2I66U I#����A"24 po �MN*2 � tifi�!'1�s ,��E�&�to� XtargeSh f� no.8 &( Sup*�3S� �^ ��,Y�l I�F�up�353J���&� s.^E�N �t ei� ectly��im� *� �&�. Howeve��y:�2J_z^Zir5v.�,.�2  animal� ![>k� *;[30�uF6��pu� Ran-�q��RanBP10��)benzo�:,4-monooxygen� cy{rq P450�Ia� `Rc.e�D�Lic guanine nucleotid� c�cto t mod& es nonce)so3$microtubul�vol�ito� �"levc�cat�4es diverse rea��%�&imA@�1second metabolisxenobio� etox� "� s�7]X,��J�q9��ch5�13� posonA�NxIJ seve.�N��o {���reg!l� A�eu� .o b�"�� we&a d a�ckd�[ 6�� !<measu]af���9#��heFv��$1KD , only*� 8%)I crip�KN�.?�� .� >[�61 ���!^u�y���6�,��upM ɃU�!Fby 89�B�7C��8&D 6D )&!�NP�5��6� ��e firswH!��ce�a hum�h>�:wuiO�"/�6y"[A�qE!A� RNAi�mj ch��/A"� �b- �������s AamodelN3.163]hfi� � Schizosacz!<pombe [6�A�6�w��lfam�bud�V ^2X$cerevisiae >l A�:7astelli�"�Sde��ed� fun��al)N�( [65�)��(till 2005 ,�end���9rE5I�)x �8 i antisense�@s�-�$of C . neo8ans [66�No pl�#oA  �mTs� foun�"6 i!bye7��o! .X!six25 �a�.Knidul�,2 oryz%�.,fumig� 6-terre�.. clav -a(NeosartoryaA� cher ![67! It�a�ef�"uncer#$�-�%����until7� disc�y!v}�a2>_ aR}-, S� clerotior�!M�nisopli%a�llV�N�10��.� � in l �!32u.�(. $ly 20–24` ) ob� .� B�)(Sybr Gold s�f$ed 12% den�!a$polyacylam� gel� ctrophore\ Je0. After exclu$of� non-m�E�,.�734� d�^A�deas*� ��a���1769�)�ei :0,F�� gsE.� > ��M!���`h��m 6�r�B�. Two�.� �"� !?�V��E��) onfi�byR�� The� a@, &�+&��i6���tbe!Odepen!�ua.� ���&�$!�ar^ ����! stem-loopAI�6e$o 51�e\}�'��A eB� of�r^!�di�� p` �8>�A�-5�w/!V��< �or_ ��-Ρ8in"�eukaryoY���[1�>�2�\ e.�1ti��I�.�"�(Z�(� �membe�a�e III �-of�aAT!�is!<p=!�$!�EC� cessA/VM �W�Rr�)���"C,f��silen�=in var]--9*�%9�7%%�a�� �� 9o-� � w ���. A� yA�*n :revealed5�F waya�Zg�&K"\#�^%�-iny^ɷi�fe��!���i])AI� �nk}���"FG ,���a�p&�69��h� "$I�` c1 z�2��FZp�"Gob8/��Z� :�due� degrad)p into-T%Hbecau/instabil�!$"5 #��/6aPM–AF -M2 couldE�ZA�/s�g] 9Re�-jV*inM�q A�q N],6��"����"�:,R:� i�m�1oRde�ivif� �.�aҥ��ndA��+ APsamL,�.IA��-(2i*/toe0C>� es-g��FP0,%$1V0=Din>�=-:&�� A:2��-�lJ�1e:�F%geograph�1!ri�3>� g/+ to� ��.a��E�.�!���/��^-Rb!��"~�  . 5(^�A="� G)���ir q�to i�sy_ic; o� a��^ V � �� surv�in 8 0al environmen$�/�.,awy�te!���toA�l!�!:*��$�2b�*&1sm��� viru��k,I2R4,ql�3Lr=mek � "0m"c$ of f�F� �[�&� ݧ�;�par-��)@��,.�of ���nga��(( QIPV�&5rib� L3 ( MRPL�+��e�U��$2�s���!�.��REb��6�q|�27–49N/7�RHFu#r@%A�"A]:!��V Q9i!-� �.� JcI64� W0.�� ɢ�6�}|� D6�d!2opa.�stres"$ !;E^")L ( s�o,�a i r�iMbe.h. S)��$ ��j�.D C' teJ al�tissueR�(patter�18�v7i/7p,A ��re� � �?2~�5Ji~� �0c��=JofF�[�/e�:�,Mm��%?�f� &> via%�canon�]! i!� %Rpropo��� play ,��in� a�`�� pseu�2o�>� w*�F� "�ɎJer�f�F ����U�'o�*�4m�Tp�b$ turlDexpla�#hy.�A�2 ��v2�e5 ŏ�q16��eQŃ.m%b� Az}��Y) ��*f m� du| �1 A nu*y�txM|!V���� f� . FoiampleA AXH �0 !� �c:� �+l�E�e�J�. ���reQz�$ V�%��[&�iC.��heavM�M����.2�K ezq3cleavar!1ýXEB!s>��8���R�6zA��e ; �i�,$A!.L-c?,&D,fzinvest�O ir��log���.>� ����de�;t� �x��.4;�rpost-�= al!� trol!�- 6V!:� E|ch%>pro�2 newqigh9/�(e&�  g�n-�2M Y�OIn @0, Zika+ ,ZIKV ) emergN (French Poly�.ae sprea0�%Pac�^2b��e<,1 of lympha�#kria nd*$ ^Aengue-Ve/ ai��t ��}to�zE�"z IHwo5Z _d-t)=+ �al sca��9�evalu��W!i5$: \e"�5wild A> 1U=6(pop$� Y�Qisland�a �aW��A� circDIu%&-���X8�9.�)^�(�6+f*t� ���colle5���)�. Fem!]�2ora4ex" E�P( 107 TCID50/mL ) isonA6�ie�4@t 6 , 9AD4� 21 d�|in!,� bo* ! orax6abdomen�#heb!�saliva �8 z��o�% ._disse� oM�T"�2� 2 efficienc�A2 =. A.A;our ul5%-| ]%Yh6�!e�!�v!�E�Q�.��0#6�VG# !��� us.ese2Zy6!� 1�X& f�a�.��'ed�P2WT�=`�"PaQ:J�A�%a� y���.�und�b�DnkGc�4 oY2�by)"1�!cJ3 �^��U*�E unex=&�%�� J!��eFe�A � dens��q� lifespa heU! immunb�9f��)�f9C] ^�rapid�i @%M�:��& ��f�� an���9 �bornea�� d!�a �l!7"�H�QV?belon[��(genus Flavi 8[d> �sQ t!��.�'s{!a�6!i�ed �s��lAM:@[2U&2!�f�'�]!� in Uganda 1947������� occa� E in Afric Asia [V&� e�ٟ�� decl*in Yap^t�L Fedea� d St�: of M�,��2007 [��re*� !:�)3R� thenQVa�9 ��a�-�Ame��20�p 016 [5–�Hb)����assocm4d� neurq#Ag orde�s Guil,-Barré syndQ.[10–12= myas�,ia gravis [1�(�%(cephaly [14�5]��'We>0�in South CJ.al1*` !nCaribbean2�Apaho .^# <2�H��[%�im.id�!{w�cneages:Ml dEmU8th�8t�E�!ofa`e� �.g[?[1'1I'A�&< 66���I[�$�2�A��"7 ge z- �o�.�Q�!ytMhn(a�[18!�E[Du7'� >�n �Uv�rJ an F700 sus��M�3�0 000 7�>rul1i�LU8 � inel�eA�!(networkA��q&�eroprw %OAy ��D9 �0� half!���$aE��by ������H erri&[2�F�E>6��di��� o New C{oae�J[�21] af�n�Hwh�r. �>d��!��r�wof!kk"9��&E} �%�� � �"s�z�I^(H"�  ,:�He�< Auth�Da�.�s2� ��81�=A1[1Ź%X�to!#�!��:%�e Cook I <, Vanuatu , Fijia*amo!�Salomon+ Tong�j��n -B~spJFDint/phd/epidemics/��2r,�� cap*&� "�a8!$�p1Q!���m�2�%-�"s�#*g de0i &.  6�Q}M�CTw� few excepI1[2R+��p�� i $albopictus^&U in 5aU�6&ou��4Q���"gM!eexpan+ t*|Wes >�3>�'r�7ES)��[2��2m�6b dis,���$M�Ea �s�Y,f B(to �[U>*#Gel=ZS K %Xrey�E3lo�k��$A1sM h| �/, scu�/&% nI7Q�2�^.5(group ( [26B%P�,��!ء�6E? �: s �e�2|��)��?"�� B [2R$�VE , �!�m� [323��� vB� :p b��U�> �$� I �.�"2�!�[���9=e�5#����4] Au�l? 35�2Europe..�9s�M�2\ QHA 2m"� ZBly-�DeDUh�� io�ppe� k�#toah�e5f=��� � ��$Y 9(�C�%SD��&lQ�E �zE ,.3�.8` ( 41%�MU$ing��6>a=J)z.RM[2l Labora�!�ine�%n��A�6�%�B�� A��b$� o ge�B��&� I�/Q� �3Bp�.i�&�us L��icles�%�"�3Gof ��V��Poon6R�[3%Z�����promo�)Efic.n"}�L� at � inflV� �9? m_65e"7%��[2e̥I���2��&s �.�F[�#E#n=9-V9�z At4�x "�t$ ,"&"one{al�y)�� �)��2�A� l�ed *�R:��&&� 2; � "2n:94� To�< ledg�  JtuŊmp��hN��0� al fA %Y :Q4)6���siaV �f��B.Y�gorigiz(!eup4=%I�/�Ire�W�$au&��>�#� 1iYg!�ۉ�sR ��bpur�S�U�D<)D&? F��Y2# (� �)"� (GertBe(� �HL�#���da !�% �&�1�:�!9e�6!��P��2�[vf6�in Walli/��sT"zof!�Futuna"� )>Tahiti<>g+Eas!%.mR)�"VI�al-��'iSG ob�2�!%!6� ,7KB�L 'F�q� �e1�̀ %6a6YɅ�� �he:� clade . M�@eZs!f��O�C�)$ m6 �perZ��3�+y t2�ipp�A�����s> Insect V�A:AIVa�6InstituaJ steu�CP� �S�2jJzD�qd�A�-�at 28°C%�80%�humid�%�a 16:8h ��$:dark cyclixf�a 10%�,rGUs[ ad lFMu�6�-sblood-@q�tim�JoMb!< F1-F3��e*�/9�u %A�� ��ass�� i��MH-� ��"T_iJe�,a patient’�#um:Bv Apri=14 ( NC-�-5132e�@GenBank SRR530945!�( C�J�M4B�@de Nouvelle-Caléde +V �ock-Jpre��d a86E�p!g�W� n gr?monR9kidneyW"A`Vero E ATCC � #(].in DMEM $um ( Gibco lemen E7AfeS N G^e!F( FBS) ; . Superna�OI��j �7� `4 ncubBat 37A�)�tiw"=U1�ock�s��by!��"10-AX dilu<y % celUF2;&&|�(eak"M��], , 4–5 box!� f 60)�1?7 day-<8f�� U3ly}"�rQar�-A�24 hour��=y%y)IalWRXtaka�)us a�lm!a ^�UHe, k�- ) >Ra]Pu�].��a� merc!hpurch}api.5)� �4ran��Ʌ��2 mFDwasFX$rabbit ery/cy� sdir�H | -(e�Ze �Ht�&G(, Charles R�F� nd 1 sM< �� 6�adenosA�triphos�"eA� 5 mM)���con�*����e.| 6� :�~�(1�fu. engop$Q;��H fer!�y3�$�`aw<ɏ}�r��a 12:12��-��e�f2"acJ2A�Z}(&| �.�206�#P!at.�!�KN�! ( dpA!�sco)��Tn�!��(2�,"�!B�ax)Z��A!w3%�yv� "%��la�!�&j�� ^e�!���I7)W)@M\b NE%�1"� � Eu&�m�O-!�di\ )S\/����d�%G�at !��7ly de�'bed [44u5� ���!,,6c�0ane�tiAb��remov�4�5legI� wingS probosciDi�fA e+OCl� (tip ART ( M@ar BioP�1�mRm 5 μ����!� ��dur#20 minu���� bod�-AI$)�� vidun }nd�*250 μL!�.xF�2%�. LVAU carr�out�30 sec!����rp0e� U�� ifugXt&^,1gK1�K4��s�� Gste�at -80)-�eSI��ta`�F ,1�se�AG�y �ino 'o�E6��in 96-wT:p)&�gD �C-�ha��?��a&� of crys� violet ( Hc2%l�oB*dehyd��$20% ethano�`.H"�9 �&!�!�cO"!p*9l-�:�bR PE A�I�55%$B�)vi)l�2A � ,RM�q)ps1q�Ln#Xo�9ver�0E�� f�6/�pus:4}Z92�of�qu)�titE!%&� ��fuWl*-!�a�uniQ/-T)Z�"U�atpke�-d yC8Fisher’s exac3s!�R v�h�h.� [44�!V_zp \�:>E^05�A.d�O"� follow�e�&�AnI Ethic:"de� . A.%�1Vn �� >d�A�N.��l&�*�2+6"*(�$(igh ( > 53% S1 1SA�2�MS&�f"yc1�E�it�AF� �6Ř(B��y2�$ 87% , p =)�09* 9^G93%JG732G�fZ��=�ly�(�b �2h��(!�c *&�M(��miIA$2�t �! a mafl$50%��14���6�}i =�<2�&:��s o�\AX����hI�H!ly� �(JOcOa8�'�! �>�inc�aed�]!6�R� B�lY6E~},p�1A�<78a]6� i��B��I�E ��� I�A#2^6�)24 )=A=�9}s � �low�*�+( < 3I ��F��PJ~2� �}:*,y|3%���.��GQ�)A+61EG2-!�17"F��g(A���%�R�e�)�N�DeAH"GW!v�IinsicAy�perio51e,b shor� 1�����NI �Y wo .���2)�R:���!:]Em K��xi�BF_.�q�6F ( S2:3��/aT,N�O6��i �+m�I|.�� ( 84% vs�.�<��=8N�KC� 5=oth�j�F� )��fs, �#]�(ٺ135Eu"�R!�?�eh!2�0�" ��, �J1%�2�&� 6�DiE0��. T�  p�qAO�A…�66=<� ���B?��V<T�.N�z:�e)2J��y�;�"_6�%�,< aI 3% ( p-�l}�� .�N�XFi"��,�V Epr�8"!\>�q�1�J�,@<"�%V �tx�Bd%k��o�Jt.�r%�Y�. C|"�7 6�cwb�%��!*!�/s&� poin� m)���1B�6�ZU*�3.�45 3;2_6fL>q2V��ًf`�3i��! a��}&Mor)l2. R�?XF<rY(�"�)*�(��6*9, �A"�WiS5As�hubit"�S�9�([4( Inde�hMout7K3�-�B?!lsub_�,CV:�3to Lat1�* [JW��-I�istex�CI���e�� ��a��!q..���67��:�piv0{. )��ts ��-ZX!z� �)��!t2��)��9�2_"B= !BB�",>$chikunguny�;BC,FA� Yap�[2�,4!�47j'��Y.*V�?&�$quickQ ofH.2-�2R&>�*)3��M�ne��> �)�.3-� ~"$�"W$/" \���A~�,"ZcE��We��B�6�,ݼ>��C� �<|B]2'"C�[ � un�Y�cj *_,� i77�E s= tofn8wielE,�n2�&�>�:�%. V�y�ESaY�.>j2v�:!�S~������!�p0��yg%�6%}1,z/Y&� ��� ��J��us*�@f �o�f�@�{B)_� t�(eI�2LN�!FA9O56c�be�5sus�0�*X1��<�`Y/1(/H y�#. AA)n &# inB�I1% 1�h+ed��eN�i�(��8�.6� 6��u��*S�` disc�!n� ;b�G�7��,ANh eri�!:Brotocol:%���<w�5� ��16�6F18.�#Q�es;E.�M�2v1�2�T��6zon C6/36�t5Cof��!IwfaO�+�ex��jfu�: �!F��R f:�e��d!x�/P-`�"�-�HKr�!-����,���A����>���{!َ��{r�'to DENVɤ)1o<asE�lyAB��.a(:$��F2��k6; I߁!���^�%m9se/5���midgut b�r� . &�"�0:_0� r@ �|�E<$1I*�'}�%-ai8of >--M�&j0 �cI s�"�o(![� (,<%ag�S"Z&in Cam^B(;� 0 ( d"� ) t�Y$h� �!C�,�.a"��RHbs(& ) �k n!L sub�2>:*�-1�p�UE�o ��.��ye� ��(��"LI�� outcONof>�4nesv*j2k%�-�B�z�&X as�� / -by-/�e- [4�/M&|s�"v �b%�n, verc�Lg%M����M�Qց-=Yn"40p&ve�(���ZBe tablj�=bi![4�D50{ inn�>mm� y [5Z952]� S-re�"� bree%��*.�0 [5�y5'?�&��" ry g5%s!R�sL r6�2� !G9�"6*nT�-osc+%bQ��eB�/'!<5�eBd �E'�6�-K��.E u7&) ��m�2b,.�*>*u]5k ����E!&"�H%���"�Gesa(Zq�1cWB !1p (� "�3��6 r7#��8�f��Y#��-�!� whatA�t area y�0A��(�,�� ,�60^�5ly�6t�t�v҅�ǝ�mD7��W�I|�3E�}rtichf1��&;�21�f t��9�5u�relev�hX��cd=-6&4 invae%Q�M� n�Pmx3�!ve  ���by�6ow/5it��Tp! B#��> �4���Wt9�' %�I{��8�M�m All tog�h�Y��;4%�� `IX!g&�1�- :��.sA�d-� sole��yѮQG�`i ��m��is�K."�M fV� E���A��M& G��c�ÌTAparam� �w��hz-Gx3ùzŃ&2 6Nu&�Gglobali&���@9 %' � ["2d&�b�M*�4""�m������E"g1�(�@eT?A��@ra6��#� risk� x .b�%qt!��:!+burdewfu.|q1s .1��#<%�c���( lnc ) XiseN*!+>A�ul�9A�X-)sOY|�5I�A�mammal� Model��how \A&Im ts&�Q M�rmodynamAEl�;t!&jsH!�er-)G*9����W�Y�$�!"A9��{��>obn �+�! �j�^oQ data!qbuO/Yz.� !'� �6�gh�6t��&,le�'r*�_�m�tg . To�f���)�nˁwe�E@8W adv�DE��9EL mapp%�i!� velop T�U ed S�� -Seq)�O\!0h�7�%Vof t7!�I w�A�T&7Yr���9lljE��n�B`jritjg!��aAe�/! �,I] ,^��jeveR0ag%VG �Nw�� �dB�V:!|� )��a C�nE��{�-t�: alyz�U2B5�q6\b .<�+�O>/-l=�EiZa�YB%�i��Ta�iRs�in A,�Ƒ! ��A�i.�5’-end!qz�e"+^86%bn�M .}ye: "�barily!VX�?i"a�aPe�0!�%�qE ��Q��s �Mg �1 . O&�zearli� �, � �4��zIE5a�_-defi�� in� e W��∼18 kb �-�$( NR_00146,u/![, =<�driAŹ�-w�kr��Dof �# �a12�sP �M=1�g�&al�P �dosage�� mal�#XYQ( k�XX�F��r�I!kB/�gk 5 embryoa\��QW!5up--F*'E���iɝ6� . I�[Na!-step*8W[7]�}t�"coW. �Ae2 � , ��d�3sp���d�`t6�oa�6W�=�2� DNA QqylaED, h�nXt�|]in%D� incorp A�. DespO4���E�arH� ���x �>�%I�!�sur̘�)��is�>n �lwiivoa��H aor ZGm�/m�b [#L&Oat�bA��a?K8�q�s:*�^a�U]�I(�2���� R�EA8� t fe3o�+it�]���[1�K�  � � 0�he �0,?setQM�RvH�ݥ�6cta�]�ͧ� �5a)A-F (�,1k&,"�ofeV!��sI^$P� ��E��!?% �(d�ve���v�9arrang�H;��e2�]C-F&�$( 3098-471"�)! Aqo�*ofU$cop���E���~me��e A:], �H!nea����I�2��308-733Fq,>~�5�a�Ha�25/�/ens��v@nnXRb*%q��17-49DU-��k�˙2A=>��IET2-a�a%Ftare6I�if"j#�4su�W~cc�j2$[ioa �; A��O�CRmotife���Jt���6��_S��I�oaUw !}div!Wmplex בPRC�<[1�5#R9,ASF/SF2 spli�`[1:Ine8��' A�uned&t�)� � .�.���"�e=�g!>recruit� �r> # s�z�Hc,�in� *�lD��t����%�SS��Non�les��"geworth�aD�r5&t�q�,{MdEOcle��ci�Pݕ�loc#x؁ L oligo�sC 1�� ��!E�� I����of " & Ed=6�Y.�m . [1�$16]a]s*~��.�e���+� AO��l)�{p n&�v�:�UL�@�wl W�W%.{�fs;�y�arX~�4.|w�|"�h[h N`h+�����<`:U�Ystf�ng$� uP8QGE�!]��6[ "�jgreatly! $�6G Xi�! J.\� A���HQ}M��y ?9aKVW� AroP f!:u9b �� �{Jabi�o�yH��N\��2f_<�qgyA$l� �!��y. ��est���3avail�ab"�H�3�k�9a�=[ ��i�E"o8h�a� �(��un��a�"�p%� @Z�Aa!��(e�-1A�accurac�W�Jr�:^il�� %tuQm0.2Eu--zqfac!�����ma�JSA?�dQ�!jN>�B�} �����?��r� ved� ��AV��!�a`� �J"�v� in exon 4�q� BR�uri�@�/> �� �C�a�-���dR�10pE>��� tr�A)[�R[�*�WA � l�w�E��&Jm=�V' !�irJ2�QBrD�:%v | �Fee-g=�ki [�V)/K"�Mh�|�I�W�p%0R�  c]i'�] �U� �ligua�^%�v )CA�%�*Add�n��se qu�*%K�cc�;ca{me΁::���^aPri�7�G"9)�&�ex��%�"�C)8 �T�'2hJe)��_��%K 6J;!;xM r��)}��` B�M *��pav<wa�"g techniV; . Di` sulf�~ ( DM�E�&, few �� }�uHB�y�dA�!~�}�e$v<\d.- ell-M��Hr `�2lk�es��ora8��� ed A�@C��uolc\R vI�mod���J ��I � e  of �[rse6�h ( RT�dnt��a6eyra�P�%�F� ��i�\�MS <4�a�>�%e�e2{~e�slab ge�r cap�[r%�m� ��|mB�-��A��V��iC�7��1�%�G.�%�#E�dr�����S4 ��as� a$f6�tA�4_y�XZ3� �/ 5&lI�sAG�[,X�G6� [26]F cap{� cqui��Q�!���&� oma:M$�h����$\�"m��romis!3! dept�a(��h �"�'�(:�[{T)�ny�R$��.� ��vo��aM��y�pione̝( A��1e Kwok!{t aE[LXATIg� %�r!�onB�E� reby~� . ChemMod%� n;~ura�%"�2?edF�a�" uA pre-�i�� coupl���1�to�S< !��KA��0� daptM�n�( ob�. ���� we sou02=� �idY4�.on-)�x~ 4:�.�aa�a3� plat�}�%X��2�an���� n&3It.#�U~'�x�o�F �2� U.7!�:)� �tL� v"z�Z��$"��.k�Z%�in-!�rod6��tt�Mj1�aJQ5e�N�Vt[2+���!�e$,� �Fi��Arobustn��u(Q��`AQ+�����i(�q18S r�J�NECA&�eAl2�9�#!Il H�m9� hyr�1u� �$ "' 2����w. " &&QJvo0N�)��MR&[&.���m�\q� . ]r:�$%x.�%a�!O2��9xguOA�|:m"�o5���skch9A�1c%�BV �yx'dic"B2��P���%�|.Z:ch�A�stn5~edIs�$ �ہI�� N 58i�8!���es�u?t`0∼500 {[3h3iWe�2��AMl>��Q6C�Jstn!�QW�!z� "� 3u�ra��Qfix iz�S� )"�u��E� /P��!D.�of!AW��ʤom%13+a�sU�,oN��xWD n�'� B�Qa slis,window ( 150� ! �3ep�Ka�cal."!b-�0.):��< SQ3!�-�)B� �RN��[3��_B &Q z-�NsI,.�&:pm� m�fM(*�M\ard~iaA���~ .� F�5��cMen��s�vM�2u f�ai�QR arti!x(,1�U�1�& a� e�r6UA!�,^a�3eT'�TWt�2QT.o GCDEAsb��,!ba� a�prׁm��E�s.�]2u"/�'& &h]�V*�W�Qthe �u�-e�".5`a.h+�,� displ�V(e�+s!z-hev(�26& ve�#1xper:I= -�L88!.� cA�e�61%7ex�5�5l�Hee �n|�*�@a�&>��6>�J��L�plA!� ����st�0 ( 6661–681�D"!B!��n6Q.}��U��elB (x= -�t4i?To��4QHoaN!9w�� d�lv& �)�a`AD:�� cutoff����19�7 σ �u���gQ�uM{� DC6U��7( �qa�'� of 936-^���e��K-�s� <����'��(�indq"\3)83o*�6���� ��ny&�.�r� ��26AW1{ ���"ShQ [s)'6�+cŸ�1I��  ���( at A�V �D;f� fB��en�>+�a=�=� �9�30a67!Tt���� !�Ka�4��N �)�avlap��e6Aő� ���מ s 31�5092see) O� fnt)X� FD� tigh� M]6c2D͞�Br��e%�i1"��a��r�Z-��=� ��&m3&$10031-1108e0r:ig��+*M�je EV�E�!�}���v`�unfavo�#(�8i  )1]�a�ڡdO��͡ unus�%u!3+��%B�H -��tg3�,G� �QefѲ�pye]��AV�&�)�-!/s0��7ou�a��e^:A�-790; �: 965A�9950 ) d"�~=8i��ai��"fula *3�ed�� . Ha�V��U�I7&s�1B�"�c sS .�*2m "!\�)��U&hCY�2Eh-�!��AE�f a��q��B�( i .e,&� ��DMS 6] K�%Ve�*�� 5@pJ1���p�>Z�&B5To �$�rt^3"�at�k* oduc;/�}��$a���?�,%R(����b��|$�pPe�+ur!cr�Tia:)%�!J�Pti.o�L��AnSye���flectR8E!�^� on; ( N$A �� ���kB*���H choi�3 RT p�>rA�ų X�k� �>Y-\to'%! �`S tS!DWIDu�sh>�i!es�0sm�q�H&�)a�s l��A! ��smeX�i�1��M= quaA!!�{1a-a�"Ō!�b*: �ilico!��Ug!�Y��AR.��*ŏ&MThWn�I�>�!�F�Cq��*�>d"s.:.A�%%s{��h�� A��Y.�&Y��2Vo:Gr.9(i_) ��/��tyf]B�?"_��857!�2J�q�?���L"W+�Z�F!�co��Fv*&�T*�0 g��/��defed 87%&l2u�s Ɉ ∼2@���!�WTo�#6.�8teU�ev7toE�6�&el�u%�by.yhybridhk�<m3^�Q ��,!�a���$poo�de ∼6 ��L adja �w* MaU�:3�M�� S1 D�#2;� gen*،B�1#�a��8+e!�� �i�Zc�St��RD librd� �a)�CA%��$V�I. U: � aired�2 �%!I}Ii"��h>-Yst!��% ��)��ac�/I*�WRTF3) �5� M/ l�b()o=���)1issO}��3NAY. . Ida��%:�RT.���4q6Y��- n|".L9pg>!Xb asaecria9B�.f.�r)eT �2�by�U` %X���r&��6�.guish�.��1�7�H R2f5�* d bara%LB=��ta1H.fD blueEL.) R�N��(��:A�q�!c�^��a\nd5I���ampd3clu�9!�ata����2�a�!���,�^�;nn5P!�6� qe� J��c2s���a:Zpip� %spa�!�1A.�al�� :`j>A�E[3&*r�)��Ow�p�est P% *F ofI�Aa�C.� � �.� PA� !]�C, �+E��+I�A�i)!yz%�� i�QQnr ad-�Q  ���e�E��Wm� �= ֛�1c&�5\ �i� of�)2. �.�Q��( b )bs,Y��e�{e���r�A� 1B ,Z���WeA@�t8�e(a�Y��a$�=��.�n�e\%>��1� ���;:\"� � � "C * Fbovz To�;dA?�<V .< OZw Ee�&V%.D�,I?�,"�.softw�ackage�a"ta!ih&*E�E7$a"�=���%2pret:T)��y G>vbsR�-(o�@in-�� �E)A+T$/�lwU5�,s� ��0"��≥M[_2�pN,."�,������lӧ�'&vsi�R+,Watson-Crick�f- s& tob$����0�#b y !�6�0Exes 4�e�S4e�%Ko�U�f6s!VE�E��� a�0%��o"l�(9��N� � 4% <.��\%�� w�#�!�Q"�mtJ)phiT le-=n9)�,լ� Q�@�CAD:ea�#�@��(����%a  �-N�!��]��HaY-���rot �l�broad "thirtKq+@We � YYN�;�%� �"� X� �p� ensHBy�)��XA�.a� �.�|m�q.�)�Iy 4�8:f?eV.�j"�w�R*�  ��#A&�$( 9779-985�7)k���6eU� ��>�.�a s���o�%b�y�Et�d��tr�� � 1!Els:B#���FA�+@erYCU5�G.�YI�"S(o*� Ms�*�/�Bs O���(D���7��j � ��Qy� ��P�-n#ZDQ�. M��� do od2!�!v:T.y"�5%�3! A"�2�sx,jA��#rv5�� � �/( Δ G c  c ∘J30F�/moLk.�ʍc%j ���m��1� 6�8�:by3NaL�1~e�!1}��qM>�T�g%�Ab�*�E)�A��./�/�%!,!�����Fi�<,2: =�6m�i�[H%�sW�&1o.�:��b!9�"�-.�nv g��R�22M �a�it��)I�bs�$ &�A�e�i�< A;� *# EK`[me'( K%����)� %n7.T! � :=q!oB'_� �!���� $I�|'2���csB:� � Eͺe�D K.$�1%":M(~�ni.�l�Z�1(< A709�!������"y��� boot!�5G1�i�]"ʖbG J�~!���U��_�&��E.�� �c nA�l��s8��s�?1q._ ( S6am� ee SS30� �u�A�o�/y@dm�' S4420#&jA��%S]AW�E�!�!�%h_n#"'��a�* sm�\>���} u��MF3HIia|zu��d� in 27�#�J�e)=ˡ=imI�{�appar� t�e��is&l� ��i��Iin�? ��)�= ��"%�31!�p ���$7\�%sel6F�a�6k�= i�� 8"�@,| ���\!�`&�;:Jst݂%�a l�:!C�) air&A���x�1e��9qEea��J�$�K:�U�}P�}Pr"� �)����5 ��—�AL�z�!Em,�;\� ��e�+ Q��� } r)6 QCh� �a��C��7&i<z.�]a4�&6k#em!�m��AQ ly-A�cHf53t�55�C� $U$64�6U 7 �!�f]%�!��� �.�%-�)��)�n:�!0{C $�.�sr``���:1U�YƁI b  Au=�*[CU�>�".0[10p�;�w� ",a& o)lm�A� ���as��; !�`pa8a�m"= .�*waOU Q#Br�Gy�o}v3ur���0�omN&( `�p�h-�E� as���'e>!��tt�(� QfQ>��/h�B� ��z#5 ( 568(8��&Z>��!�m����Vly.�by Wutz n6� ��re^GAJM p� U57�� A579��O�":4 allE!y�7E��2eNa 1�A��+r!�mC:G��0�QI?Z��*�&� 00orm�i� s A2�wAׂ� �7achx�a�9y2x2 `��>M��Z-��we�hq=�i�J��?���G392 C499).�o a G:U ,�Et��� E��V&! u^DB�� 5fn#%R{-eQ�!U��)R A7%Q8.We�J��n�����M3��enJPa\r. W�$��E`��A >�M.��r=�a<��;�+68!�10_;66%%�9"A�!gyVh]�� !�s joi] .� 372-729%:393-50��l��Vd ^I!!R��O �s I��1w"�� ���<"� * �v�2:_��� nNUa�93. m�s�dakp�a.� 1#Be*�< ( S3��S33� �N.6�! ~6 9 A]&�cw1"�a�26i3�KA�%��tetrae�M��J�nd�3H� �*ly;�A��. NMR"+�B�_�);9o? v%�/Bm��!u����l��+����%"�i��MA�����$Maenn���<� �exten�>C�B�(yFREb � Ȑ� ��! ,&5b��8 ED"���_t?$)�� �,�� u�iUaT�6T�K_Va�4��$7-�Fm�"g+[1�<:�20 �e� aI��v `���� AzX6 e�1k�x"�"k (�]�qrefㄡ�s5�E�s �+3EZ�. ��5*3!Y�#s&b �,AwM!*1�5�R�1� %5�-.p& w Q�%m%�rUj^��SS3u$� #)?�� ��Fee� ��B?�n ��r�!mE�a�&�� k�atIG�34; 358bE��5wo"q al.i!� \�5��e�"�E�q|� �.����Oo�yu�F��U|s� U� . Co%y q&�."Ӟ u� |!$���"� �����+..R� >Y�ma ��$�G*�79�;DYar"�|r�du�8B]I�.�$ =ed%ts�g�j&4ьKZe�(� L:)�]&bei�$n�d��� dV�92Um &�0�!�tESA�:�Z�+)�Dm4R��e&�pnew MlVQ�!��f�ibtG!�V�@!,�N�3�A8��av��Gj&69Aq"�c(nd". �NW� ��<�}""�q!Z=770-78�S,S3��SA'�,8MOG a��f���8 96�Y%MguZJ�:^�N*&�=)+V�q� �"���T�+6�+!���KF2�"� F�d� oE��at�>� � ��y���NXu+ aaj~byF"��Ri�[E�p"/J6wAMeam� )��[=31� |TI1of�%yet�NXQ��-�}K��F/be&}I.�avoida}�nflic&�SA�p��Ӹ�4�Z.�$U2$3.!�CU-I���y>� "�O,e�u�5�E�inB�pInEO[_��' Nbi&) ZX^{ �a-G�/!71�Y� 5[ .&�a�<� ���6Q^Q�a�a��( A348%y A516!�w%�-�J�2E!���"�6q#!�s flan U�a*�# QTakw�.[few!�� A����W&�?�2z,6�����l�f��of�B�@"��I�2I�K5 &�`%X%��"n9o�U�A�r!"t+�y-Y�g(2N9n�. N��jYL =a��V@ 6�7E�dA7yon��e #}�%�iAA�D?��:j�� *� tPOe"<:E�)�*9 ]f�<d�_�$�#�$5�����2#��e�no&�WE_' $ify1lmJ|� ��8A� ( 89^f� 1613:kN��-�2tmA�)���SA�����6eF#2a��?��!�*�!�-�*� f [!��:. C@r8�]"� a�U�b�?h"�a�z!A�t�oLL����m� y� p �1�!3�� bran#�oB�����r�bas�[���l�]j1I�x C1I<��i�q�6� ��JrosK3��. �)�:le2�Ai �o�]�@em��L%� '>� �]!�*t F�ta�h�E��(( ACa r� 6��X�st"{�"j[46�Un*H!�"�^J�44 sub)p �� s �6�A�6sL *�j"dY!�,']K�&2�)A���s) l1�Bn5(( 77%AW 6)F6�De�60XEa#O� �-6��S2L ;*��b � , 47˛���*A AG���8Fur`W ���%a %�A�re 23 �} d ei�Na/J�(!u�T��8 .�479N4833 (cta�C��R\ �C9�"&�MA�+tri���!�q9.�2�07�410�'M1i�B�+d�Bt�B�473�48�?�hj<e"�A!Y2�Y����,.�(K��wz-Ola�m?�:-a &9z�H�7(�Bmj(�D05;")?A*���i��)�%e�!!NuE� 5[ ]��si�U`@I�J�la�2�Y��([o& TBW� �� �=�=e� �j�M,��rup!���@Xb.�) �u)Y"i!" . A%�&4 1!7 mwa� � "; ""E%�b �Omo�(A>�9PJ�CQI�a4) show little ��impact on Xist spreading or silencing; further , it has been proposed that there is redundancy between elements that allows Xist to spread on chromatin [10 , 47] . On the other hand , as antisense oligonucleotides that target the C repeats can displace X�from chry5 , 16] ��re �t�lncRNA�4. Our knowledg� cellular )�its rol!g regula�is grow!-rapidly!f new !�coe��sA QcontinueA2be!�(covered [48!g Understan@!W�conformQt%� RNAs�!-�t areatstudy-n4requires systeHc prob�ofH9K iny8s . To investig!�)Ds such��4, we built upo!) cent_gressO�qalz, develoEwa%AapproachT call^  . Us�a combin%�Z:%�4n silico model?��>'�J�腐sA�Tthermodynamic stabilit!levmNary!�ap� base-pair zlAain man 0ist!= 4mpensatory mutH!�All�Ifea�ns!� hallmarkE#coedNQ�al2�es [45A~i��s a�6ed usA�examin��U^6�novelA�>0as previouslyE���ele�Xi�. W�Y_��e perX�KZ�us!D0four criteria L founIat^;$( 1 ) accu�nly measu! site%:DMS! ific%u�0 A + C!$G + U spec'I, virions [52ahThu� Z~expand \ scop= Ao]!z%wachA�Bclude � ŐA�I* mammalianU4i� ir�u� 1. Sequ( eWan� technicalita�ver�q@ctrophoresis: wheL ��by>%&� rucial�U!vmajor=ש�ts� @reverse transcrip�|�E�ctla�imed bec�  off-)�!;� nterfa*w� i�i��Ws9,^Cbg le��Roi2mbe �ly filt� � �align adThi��lax!�h� ingencyc d�;��? ZG*b after oeyM�Z9 �� ��20-40%;d ed-en����vl �toeW<—a huge enrichxcompa� ��1� itome-wid� e�l���esents�� ∼0 . 07� �%Npoly-A kedA{� #$female MEFE�a�3]��remainA"]5 >( 60-8 � ,��luH oseKdA�mism JZ� ) did notaPA�� ffect d�]�Theref� ,^�drar �)m dhan!!�E���$p�6���7 mean� �l� >4pficVa�**�I�%�M A��%�Z}Ew� ed.�mV ��"� a�&� �K at A  of ���.� C &1JgenBpY ��[10 , 54� ��Yli��s both!f ra- ��ter�at mA��5�m� of�T*U u %me�In adr  ,%LaNe� o>� &� a� s��s!Songnd� !�%a esm � to6 ..o�C}�� 9%/A(N  !�sig�can��mA�2� E�� l�dŏbet���-�erin ro s% oO��9v(, S32–S33!��TE�[ b� en$� M�R ҭQE�A1�M�5 i�p��'a_�$e,!7di���1��$ �lso"� ?whe�ag"�enviro�� infl���]>�N �q7�Dit�% s un�A�f�e%���.XŠ�A simir���8"3in5 . Whil�f�n�{%! vo:o&� .[cerca�] g .� eaf [26]W[28�����U�%���1Ý �fitE�in-�M$�( S35A{�z w�itA& plau*E8!�a.Z5�i!d-�łI�0protein facto(v!/( ATRXmP� p�o�oneV 8-"[56)�simples[ erpre;�a�%! �Uiıyfol� � sam��*�� favo.2�%�_..< ݀sE�Ze� tAC� dJtAҕrB}!ߡ���q=aa�"d s� al�,�aar ��Rlpo���{al �1<��|,%w�veI|�� 2�?s 4–6�4U� Of partic! "8%�a1��.,itNUAM�� 2nch�!|"��YY1 [57]�ThnRNP U/Saf-A [13] act��or nea�&��E���� M}C�3rHd .��5P��dF�A��(6-C1�(C2 , pWS124!K � 50�"6��mp��mmultipl� em-loop��by�(� hybridiza b, ��&��7>�an�:��9i&v A�)n�isu����V�a�m �of�� �@. I�l"an anZM"7��S��)��distinct��ɬEO% ��s )�QJ3Y/9�  ���al � �e �suНP�Z�%�lc �� new i�H �!cth�acR any�%�E~� ed � wil`n6 mole�% frameworkE�fu7�Q un�6���i�h�e�"� m���gai=i�!+.�A(��� vali�� e ute of^Ato�y m6_TZ�ln�%>bA��[ly��ful%5z!~�ImechanA�c u2�of ��{Iqinc�8 �%�c�befL�&ba�of2M%C. I&� a ce c� %~�$ofa�[%ׅe"UU,.�d��lim�a } r� long-�ő@T . As^�"}V>tK�ZevhE1�.�Hcip� adapm��ology�"o � reagH(*e SHAPEa�ee [5�59P o�b)(=C� biex�� e�dniFA$g�0�t:>9A0�Ike< %��  -�ey�of}�archite� w�a� �y��. CloAf&�s [60]� cul�.�150mm�L�� DMEM (� glucp)ta,410% FBS , 2 mM#ta!� $00 U penic�9@1 mg/ml!q�mycinT 37°2 5% CO2A� mmed ly b�treat�,� was dilu�#to 25%�ab� e ethanol# nd-�"5in PBS< desi� �rI�(�$4%–2% fi!G9Hydroly�of�g�eaci�!�d� �$pH-a ���av�54-induced damag��މY ?Ibu� �checkwe9$to en�5�o�in� 6 neut pH:rpri�oP, &� rin��"I.!L%k�incuba!�in 15 ml��(G w�a�ajrol�0t room temper��7d time�-8 min%��!�A U�b�movA�&��i]m�%!k�_threers �2�of 50A� Tris!C 7 . �#0NaCA}3# MgCl� 4(β-mercaptoQ�. Celllre coll�#2� -�{. Li%�( CorA)�%�E� ifug!�t 1000g%D5%1at 4 as���of&, totU!Kext���!!TRIzo Life T��3�or�$AEhe manu�urer’���u�I�ͪ(∼5 × 107-��lyAzAYAXic�ld RIPA1'(.�H%�pH 8 . X1)�-�1% Igepa!���H5% sodium deoxychol��,1% SD��1!�$EDTA ) supS �$$100U SUPER� ( In�genU�inA�hf!Za�E�$%��!�Yby9߉� at 35�15�!�,��so3in hot 5�65"I6!�kpur�Im�#ard!�cedS .F,=���(TURBO DNase� N*��H tLRNeasy Mini Kit ( Qi��%=A-VW$, a 12 μly�A�-g�in wa�!Uannea���8pre-mixed gene-oT-Zer�10 pmo� imer i%)!���aat 70!]�is, %�2%�� mixa , 3� 5x first-9&nd]�xFS,�A���-2�3J75KE���M��A� 1 M DTT ))dd�(n� A�E� �t 5E-�10 �0 & � ', 5�/%U�"!�6�1RM dNTPh ��iz RSuper� III>Z +!�$aseOuA=2~, 1 .-kH2OBkep� ��2 � %��!.cDNA synI �ReV:+Aj stopWby hea%. to 85UI%��"�"�A�Q%� ��18S.��E�n`�V' g�_M'��"TQ��tdiz�^ in n<%RT�s!�� 3pooa[�=a( make 3.�librar. EachM vAV\# 5’ P,$e��P’- CAGACGTGTGCTCT-3-)!\facilit�� hy ��l�""�%deAUF#�. Pi�pG&in S1 D52� k�%r�8"�!Tru�!� �s.�q����� foll�)mo&�%f P� linker li�%A�a�Ra0 H ( New EnglA�BiolabR�#ip .AEV�'��=�3�A#t� A�1h1degradm `:�(Ampure Xp b�0( Beckman Cou� )�!�rw) toco�mi���I. by2~)D>6Brief���oduct��%x1 )meB��� s � 5 M\$20% PEG800x�Fisopropa� 2AR ��inw:0Ikap�F�magne�!or6,� ed 3.� fresh,(!�k� , air-dr�(F���eu � I%�F. P7���E|� o a a�-Q�h( /5Phos/NNNAGATCGGAAGAGCGTe�$AG/3Bio/ )CircLigIEpi� e�y,mixing 6 . 8E� �^ A��� μM6�, 10× \ (/!�MOPS pH"� G�3K�O> M� !�1լ�.�� &nCl� 5 ATP5 �5]"Me�!�%B265� !�2h-�t�# at 8M'�$�v�=@. !I�"�#EBre)ICQdPm�� subj� ��� PCR������)�as�/ ampl.R forwQ TѢ��s match!ϩ�#E:J)( $6TCCAP� ; !TACACGAC�# !�+bPhuw �"merIf98� ,��sec; 6� 72 90  ,� �cycles;Z`.%/6z2f . 8x�PB���#6E>E�bp��'�`1l)`��+� >{E��Ac�rou'ofo(�&[ >A( �E�rq 1:� 8 ple:� rA� . M��I��:�)]!�2� 2x75��n%.A{o*A)<)G)&A)sas�Y�$Ceo"%6Ge�(A (.�!�.� ."��FHigh Pe&'.�!u+ ,bulldogn clu�+6t%%�clig 3�+aG �toG ove NNN��ye[��!#F*R&%e�-`�'�fofest-�$bowtie2 lo�(�&�[61)A"x'��few han 6�,o��r�an two�%��%discardF�number�RTN^.��* each posi� ( re3v}�{*qRTi5� he n�*b�6))A coun��aH�$& DMS-s�o' n i � !}&unV$U�To ask$-�'l�� a python � � nd�"��� ] d!5� �X%B�>_7through��.�6g�1�25U� '�  (A��q&� e �a�QNM�%j1-, r%I�9E U-s��"w%��2"F)& 91( most*(�eJ���!�%�sI1 equS!amonguZ Z+defH @� abl.�.� �re �%as: P' ( i ) = P%�  - P 2.� �2#=M}):6/ UUeb�4edsfv4,AK��cM� �avera�,+:9100-3802F��%�ѡ"�*A��ʥ�0>�Yd-:�. E�3AR!`!T:�a"��}�1(�8/(5e�7de�, im�)e��of-�F on efficiD,of �-l�8 �����sulA=ith52is �e� 17918aXmurA6%y����(��Bank Ac�2(on NR_00146o3!�exzՂant sli�window��@)p11��V*a��l�h,)� ; frag%oshuff 25| ;!�va�d!dom�mF�$��6!�program�& [3.*35�hT��1llikel8�56�uG,��� � ethod!CloN a;; a�*9! z-sc��[33~he!} @b- A��"A�: z - J= Δ G1 ∘ - xom¯ σm�>.-u6)edJE0 Gibb�/e#.erg�p!Di�=K6g N}�]5�“�*nt”9��5σ>"G devi�!_Ie<6U4Q�$s . Domaina j��H�aXi�H.vI��-�h!�#�'l�9tw1σ ( -� 19 ),+neOv�%'�*p1�1$%i eFB8a�� Qa�A#ru�{!�1ime�� yiel!��'�)r�*"x&�6 se d-1%&�"� urF"1:.� �(�h/�"�%iGwo adjac�9( butP/.i)6�jo/"toget@toi�!/ ����4*�1!d�&U23�<�; ' anno�#�-tC6� ���I'aMA�low.�!�0�,�f�?l�� �sh{!��8R&:]��buH<;F�minimM&�softw�&packag=\!�vm. 7 [44�tI" Ad�"s� o*.�*�I� � quer�a�%WChe"M!�w [64]�$BLASTn algB6hm [6�Id�$fOhomO#ous��E5downloa��a�/: �.�>�I+�MAFFT @v1[66 , 67b.?- �v7E-INS-i i=anB r�E$ [6�C��7pta�g3(�'A�erG,block� er�$�.�$a&�fK0�>�"�%#9sJq�3B� Pe&� ��� ed oA�r�/of[%�iA��%�%(]�щ 2&GM�TMS�)y"k HJalview [68]��An *�;&�a(,tic variantsrb8/-sAZ{ �3��lexoeaj0. How����/_"��8whɌ risk�a��dg�MBfi�C(us6(cli�9ly��=pr�$�t;(�'e�?� valu�Ay��m)J��1�$��"��' �8oc��o��usata?C�(re�F3d#acharacu@s!|( ROCc+urvor AU�%to ju[DWM� �o� test� 9�A� �Dr(E�.sh4))�Ap�o85N�:�y� d"`)^,��ti�1j�&etricv a[�47�!��& meanI��(ce")4> )�2Fe� 7netAtl�"�B�Y!� (.{*re *y peo�n,D0�7 low-e/ cate�|e� kWore���ex=9a�7fa�er� �4�op G6 r�l _)k M&�isk!91�Ej8eE; also.3323�1 {graph�-&�?!�:9e�&�.�F)a�q� dens�of5.� �A�� 6(U�d plot�� 9<?��� sim-Ns�%C�5w�x,theor��alU��4Fin�wev?�"�Ny!0� �-���3�l��6� ponofu8����] sus+Ci -)�O each�it . �C=�JaH��A���succee�in�/�Ѻmon�k��l��J�raiJ h�@a���vid�Ad-����B� . Alqgh%+e =s�Aa gl�J��Ger yp�Sv�DA��Eun&lb/g/&::m,5�on�a c)ofb�ma,a�m) � m�Gmb)��!=an!�(!��IdeCODEm��Navig�,a23andM��ralfe%���DZ^s�B\j�:�?sZ��5I�n�6��~>*��;���0��no��Ja�)��.u&r<c�es9�kgoo\([ vq�[wF[oAId��r � �0 ssesA�E�riA/ory�O]e69���(��i���J� ��(�-be;� *�J 3 "6 a�B�s��;� us 1"t%��.z7?�&l!���&K%w�6orqRe!R-is%�e�a�B�E�y�C�J6�*/M'([ ��:�!7i����� Jans� eJ[3];� �-xy���QachieZ �"yta�%Mze�allelLP�G odds9�q��a�R!Lu�$Elston [4]�_�;!,aR���:�,�--OC�@�r� ihA�do! I�9%�� "3=5�  !by SNPex� ng �fg<Jg`U4 st [�Despit;�de�S%���!�o�^��>� they%!��Hway�i�:a!pD�4Ux\ 2S# %por4d �-� �(Sot dir�F�A��<" 21�A�+i .%4pi�Nof'� !A��u� ofte��" � e [2cRV�l�H OR%2 ?A�� �#�Ja�e�beyon�N�[TQIn I���.�,2 � �%P& 7E` !Ɗ� NRI/1!�g��~�.� [�L |@concer�Ad&� C@�=o$A�!>*� A��la�BFR� 0La6��a�Gi AW�Fn�:rib-p&# 9W advo�UU� .: “� ve&b ,I#IY�;�Rw��v�B~P��� ��� >a"��&F:i*�!Q&�&�i�!7V assu�a� de� .8a�n�S35YE�Au �6ual�aEabo�!ha'�(xWe�w�m�heJ���Ekm }�&*(�~i�ta�2�')��u�^> ��isr"hBo"G 6�Ma|Hioa%1�o1de�A��2*V.� �I?� ��der� �dVm)B� )�t��or��e���)�!"~L� 9� e�ach� otyp�6ll� eH�%d else! ( So"�Jbmi� [10] IE��to�A�is�( ��C��)2:at�U٩:�$ part�$� G��� on�:,� ompr W2>S�������]9cyS 2Sy [�D�EQ�{\Yi� rmB����0%�Icea�&� )�) 4EU����%qo��e�su>�( z )��z6�1− .A-a�` �E3K<�#q�%ape�%A�:u�Ql�8fer���Ppc �!?"�tF�-r.>��}id�N 2×2 t%��E �0uD .# (* E. T= i�0": i' ve i� s�E�/aF2�&;#�[n! bitr^$F��qhe bi^ �mD Hc"�in"� J&Rms��� � I% llyy#� -QU nd un��!�In���ye).e!i�:e�EWlM� ��R:v)V: ��a�M� whol26� .5�Jf!QJM )gB rei�� "d& �E��B�#0Pearson-AitkeU@P2" ula [1212@$>-L�9�� ���v��nd"� � . A EZ�9�hU���$ify2� &��P��p!Xo�e)�R�]h"�!dh&��^"p !`�c�%by Pep=F�+�, a"H�_�2t��* ! �6�t�8��6{�aV~L&�8ATp&� *JE~9/e�s ��a:2r p&�!1(s.') �B�sRo�2�horizon�;AvecK�; on!aO6 i,��nd�Lm;-Yif"P� levant �=�or.!-� O���%+˭~� .�q�=m . On�9g.�&�pKI��W joA�A�A�w��be7(.4y. � agew .&U�_)F�Y � � s--�-e �8*W"Tx. ]>�*$fc��bjaŮcer [1}*t tur��b �:'b&!?V�� ! ��N�!�&Y �� Ptop�\�v0*� - K9� f� &_ Ms#xd4�? K-top >�q<--2�inT�+�,^�&��sec_0 �4!��grD'%�la%_fR�( = I��ak 1.��N�5 eqd�!cu���"!�}K.Nr�3�Ldesceor�)ei. �y)�� x-ax n*N[9] y4"� a�e{e6;3.uwf "� �� (6Be ]w� .:�#6B�TQ� Clay�lM�^VL [15+a`�in2�< Jour�0 of M�ine [�n2��%y �Aq�a5�AS)~0�Jnv,,�N�G.�t$(J�� �����c�'!_"�o@�D� ��z 5�R"! reg_:a�er�4����Lorenz-�[17~ orig�$�n�:b��weP6���e6J! C�a���:bo��6 ��5&w2��i&Fs1�fi*E�.��R6s%��QPe\b�'.� 2 ]e*� �:�"D <,�li&�S���e&g�e�W2"p al~)AmA��c.��tr"a��" �.�Few%� S"� ��&���A��2?�d� a=�-,�3X l�2%�foutcom�r. Rea�o plz-Zq�*�E�mT7�T0=S3[adetai89,��Zb��1X%+!)B�c�J&��e �:PA!w��e)\I��m:P6CiE9� 4�^}Oq��is�c2�aN�� E��A4% �7PQ =.()H)%J� �t�?�lndA@��Jd(]s�E��� &mz>;5=nurCz�oug�FI�to�u>q�iPB�z�Y�A�&� math:r�K�)N�� �oXu�" iorie�.� to5.O` fKag�E� pati� i*� �Third Ad�5TN?� PanekQATP�L) hl�suggeg/� �aHD coro�q hearJ�.��vV 1."F-( 0�93 2�>�HZIn"�  p00�k��o#A: #� m1�8?[bioM*kT� �7"�re-��"A����#6"&I.�C�YrXV#-F��A� ^�[�"aq&��oly5+.�I�.nm ��ane�,���*b *�!ng^�bet�J&�I-.�ReKDo" G �W w��!1%�J��aͨno��J$4 6"\ ree�q �0�sx%sh"�A���a�pi[>� . Our aim!��sti1a"Mie`�,Q(�$���lM�!�+QIg>�W �� �bpa��3n�hh0v(v;e �D��^$m ��e lZ -tabY/%<12A�!#sl"�U��1:E% j){ � . An"; �%NJ����in2:P�naX!i*Let D��!- �c��m�y8'J�F%�(� a��*Ya2e���y�B=w �%^up>VupNTa0BU. �i�.�nւ�(E' sTo ";]'��avp,�HQi��&�.�s:A �><aL+��,�u��:( �}%E09#(�uz;ePa�;{ E�F5�T^� F=#PE��(  4i��a&We���OX>1F�vVf+,��F1��ay�E�� �y. � &�� D�^�Q}Xlipid(!sxblF,a��[X>0ax��art*�� �/?ms�-F� x��we�Hbe-?a� dealN�0� la��*�3YQ�!�co�NcjADA�%b[r�+���!re vec9 [ , , ]�_���m�6[rma�6eO VA�"VA��B �&� 687>��m��":��u�1&group��B� O,. App 4PA������ =]�a2llows:!�R9�wit�o!&(+!c&�IJmanned>ReB If?-r"#IbyXS�e- 3>J�:� r�gr1��r2�r2 12P�uE�&�a�ext�zd9Y�o&�<�M�IrcA�s�wqu�bl"�R�(1&a0 b��R.�@�,2�5�Y�> . ,`J/�n :�_�7� r1�.0a��� 5k-.-a -B��KA=�1-"�R.6a �aLM@��6�o�j�ၸde&�!bi%=teT  g . Si �u>.xaW�f]�U(1)�� gKa!�bIc�!I=9�AQJX^%�l%�-q0 \"~�B���up3(a�l�0U��$jd�|:he|my� '���VYL].���I�be0? ��5n� �x�A/0m%�A}c0%-�&Tr1 �[G06#r2�EZr�#2�s  look�32U7 &�"�&N#i�Lx5!�����B�a1� ( n�R"2� � �"<6%1%�1-9y ) /��a6J)Y�� �MHU�2B >by}4M4�� �1�I�y^ *l�iUK�)ll�� 91��Bv 2� ?*"\��&\�>7� 6� ��,to$o�3j to A)�O@VE back~nst�P et�%�4a#7-v)�now<�^(�, � s� 3/B�1��" �A�]6";act-��Y6Qr� a Hm5=a� �o�N�:. D�<�QhB 6p6�A�Ae�e �~e � E,�S� x�ZEt�Q=fX4:6a.E}��M _I� [� n�q intu`)P:Eq�&p.<�&in Yate'rhXSd:AJ slop�SDSip8]=��:�=zwœ9�!��A:|b�I�&+ ��5iH��J+�_Έ�Z&�N ( SDc�.!�!&�1A+=U�dexa��-�3+�C�' Y% �h�V.�<p���=^CgnP�$�)@�a "  �ras' �5e.�1i!� �eq]WOoodo. If g&�/�Iz F&�Y9kfN,Ki"��Q "*KN!�lso��@�hvvad.0� �maximumi%��M�"�<%>� ta�� ll  )�� � of 1E�'yeJJ+�6�CM�Ź� ario�r&"�E[ Bernoulli �v�+K&�"me�Vio8�"�<5�� 10)S#��GI�ing�I�_#"�h��%ͽ�+!ei�E�o�|��eA qau�c6G*�'[1�� �U"�3^fir�>%e^<�Ghii]We%wo!a�u�9A`�m�*�*�EEhyp��  cohor^f�E&mi �/���5_�5�=q�o&�<�'ao"��logL<c��� iAP*!sSjP {�V ��+�M�aP64 �L� to 1�',/ly  0,i!SI=A�6&�S^��!v��!3�ZoI J@7*�D�Z�F �!�e� real)@�&WS�ZX.q@%a D!�30�sjiFpro),: l')��O)n5��NaF�#Hu7e�F Rese/r � itute|HG�=catalooSe loci X"D-��= � !.�Dty�co?&�d��q : HV��J. ��s!��� log-%N-��_or�.T"lE�l�y{ve73�_s : ire��ion co�Yts … �� y !#(�?9 �j�_9�U�v� 6 �3%ax}ly�f ��005p )F ���preci�U�`�sf<,-t7 A���ak� �Z*�%�Y�6�0��[!QLAmDi�xist�Y� 1���� �3"\J:_> �e9FA�b8 @T)�= i^,%aBQ�@�5aJi�2�_�ks�2�30��AE�T��S1�solk2&GtH22A- -X��"�.�1*5K �t�N�% � >B%8?)x30 e�%Rn# f�<aA��}*i� ? [ t2 J,�_>iE�#&Ki�%Q6(F�kH(��n-6�"Adm>te+�A�>��h|C�exa��2oj1i ��(�� c�P"�.�Zha� nd Yu [20� 7�Ad%�N�5�of�\E ��B&i;`�{h�*�Xa�Lo E|moj{��!.�or; expo@s@�w�6T � o�. mI"?���!�&' E�E�a�Npu�G P �L6�D2�$'5ga�!IM� r��"� SU��$b�1e�Tv� �l�^e1 s�is-3y 4Y !) iso�A��:��%2I�2�n�F� "O2. A WQ�6X(57. s�cBcO�u-��.2�}i�(ur��e;��~"��ac�h���OR�ei � A�B�r 5&��ہ$^sa���A ��\; ��knd��t �AxA���i�W(%7LzA�[2�fs� .��jAUC-�EE�2� ul� �,)m���Zt�rb"�o��`@alZd*�&� a �G32 �6* S J,��ard o&� prU r =Q]�|����",ran,.XA�s *i��^S3E'V%��!�W@���B(%�*��up�� Z� �5��93J&#)iF.�� .��@AO�J�2oN��%l�\o�P�epa���lightly�(a�!�i�!]��c2@ 4Nu?&*���A�b pAO +M�VsM�h ��5pE��q�&�/ volv���T���f;iui��6*� �9a>coL02� �exagge� .�Pi.�)Jtiz%�A� �l(*7!N��� D!Wlt� ) ly�er d)��?K�� At2NN< AA\%X���A� !Z��G !Win�A�"�B�aAsL'o<8Ź"�LeW��"nD�@�9�0�K���i(vV,2�7Wat)6&6,�� �c e�J�W!!{3re�f��Jh 10th9 &�-�v&X(� D �I9!�#-!�2o8a��O�'�1 fin"SDVmi%��;)� y���vIde1z-��E���E�:�A#i~"�h�� )��Q�a� coV. �9��.zGa��� �}^�is��a�@'�!\�cL}�2/�e`55�. N�/R�Vm"�i�Fx� M|��vn� �l)�⛩kEj� zc� �% at 6)1��� .�� (��. U�L��;�)" , "�"#auit��of� �&�.sI��$�=M;�bA���e ?G/@��worthEEM0<p".<�=]$��YessaK1��.s�sub��s��"�*Jc 2?"25%!xK*v05����d�6>by�(03u �>�zr 11%�i2 Z� � ��@�**�#�*Z,�D� !7Q{� e&tq*�-��!s6� l/�H�d��/y��� by f2�� �rehen%�b.�*& �e�"�e��lisЂ:�)��]�Yer� �9�i��;F�^��aBjW�Z�j >:?by��Ve� �} 4L�s@9�B���d��M"�?"+jZa�� �z�V�#� 0���/0<SN1 diabe��P��,ic lupus ery[2o�W( SLE )� Q-I�a7�Slr�ԉft � Al"��iad2�[21Y( A� �> N�MHC-�Vj'�e6�>�. )�nN���B�n��B�1�2�Q�@� � �<�7�#�*) being�K�X.5��2�M s'f�% r . X��6`� �14�J� >5� u��y �A<)�30�h82YB]3 -vs$��a"Mqui�BrFa� /�aa ny 2*� .0GW� r�2a��aei��m�� &I��i.6� erC<,e�Va5�V��P"�j%> ��&2%�pZ"~� �],� =� aO1Bb���5aZ�)Ap`5fixjA ! � W���,of��nyV�U6"A_(�X#To�'U� stud��!�{� �swA�E��kS�6S�5S78 . R��lyJ�Zs#s,6a� w�B�`� ��h2�Z,ـN�ZAnJ�Z&iV�atiz��os�J%A�� �N+ fals�D.+a�I� nx���2)W��~��i+% %A�eH&�`M e6`]o&},�J-�| �!5e�� ��<erhaps �{gn��a0SO0en   VinJ�1 1�662;�\ NO"+�ike6�\"� _$�0} )�F8[2 s�I �� �g5�� �R�G�R�!�)e� " a;�9��� >-.cZ �X� A n d{ 5- � .D>�|��1��T9, ��:p��edc?�; ey ��jq $7��� cz-36�Y�J9P.�!m|�ZS��i �=���^8�OR�l�y{��D GA5 �HcI@y2� �I�)�MX �:It�*w%��- lose"�> truth . B�.p peak����e�&��(!� 0ns)(a@pu>K*�HA��m� 7%�*J�!_Q!�@�^2a��da� . S�7hig�cz qc;:>tAb"`H:� diagnos�rG���fsub �� ��c^{nd/2nva sc�F!Qpr"x�!ter+9E q� �%\I7� l�0&+er_ ��l!lnI�q!ea(�&�*�M�-�B4!�/&�L �%�%�*��o{Eze�Sma"/>h(5�/�O�"�9a6"� � AG,�-126Upl�>!�&'MŊex��oW9�,.TF�.�_hav!�a"u>�0�u",JJ &b)0 ag��g���FU"A mamm^ phy] -�aXs "!_A��91d� g�Sd7�-)aJ�T af*rim�BWLv.�]m�Mp�L~[X��m �ja� �_2q�$ �“5��A“no�m=A�Wd� �!BM/�p�d�@�g&4�u�X�0:f�b/'!b"k� a^k&�m5�q+�(=u!�s��*gLL6/ b%@A�As* ��lQ,�I�2{�#)"�to�4f��l)� . M!�&�Dis!�t�s�'co���m�/2�-8H[2.Mn brie�Z�� a2� %?�/ �}�� �= trem�Bamp��"Œ by CR U!07iCz*)��j*Aq��5G7r �&l7&�+ իC�6�| �F�A�e bene��fq��q*��c�yaE.�!Ai  h� n��)E�!PJIUC�X @* A 6E� f )I!:m����C a�;��$7�)� R= ��- sta��Fd� �H1��ac� �tQ���BRicism�Srn� �X2��|�j_# '�� E{�!;��j#,igTtla QgE)���5�m���2�"�ur.Rs�7physici��BA�"E��aiv=nd�$M�ne5���l�ec� L/�T4k:)e.�;�<��." m!% sE"�cutoff�;�2}or2wK!J� ^=\d X!�e�� n'�~l6 �! "� .*�u�_" G.�%�*��!+I�T!��RU�E�+�a��, ��H-�I|] reck����0~do*1del!܅2  �Ssl\l�B�!�w@_ɤavail(m�W� c�@�#2 �s�,�!�%:� rijh�M,%5� aJ1�5~me�4�0C=}�h�I{",����U�F��2����^!�*e1�stpOl�'� ��q�r empha) nmdw R�71�Fj. S��h � �;AIAyddg � b� 4Z�q�p4�%��%�*�2�Q )Q �2�9�;-M��-��.#:.Ov!�A�p�F Az�3A�I��*aS �`�8�l��e�q�of,*��� ���i-squ�e) n�z$Hosmer-Lem�w@ [2�nI*� mPA\KbeA��6wFr1 -of-Ss ��P!��cal5reZ�{!d��!t �2a�)OS|%� �,% �2\��plo[*#�4 Q�o�ha�a�I� step9��n le-SN6�`�)� GWAS���.�a�C)*baJxg�(*\o�!�x"H���� 29-(!�-hq�4MA�2�}"�M�)��$?�\acpw�E:pa�Xr �_�;"0 �0i�Z�% ��F�ak�Kl6�=��ha b�el�m} *��)'� (p��=Mmoda' IqA@ .�A�<�'ed!zaՐW�a���1���IA�aR �*�"�y:� *,� ��3!<�- � � �"�*!���u�� t be m��m, 4A,$=5�*�U�a�d5�G0�b"� �Ui 7�aa=�A 9 �AlzheB��;Esh APOE � exer!�)-��ŋ)� ذ, &� F��!dub���9Qa*׏6R�&-*��� �t��A�o��!� blemu"� -��yMy2VQ6!.=� top &�w�}'�Oa��as�S<!�K“wiFF's��s�6,(a�?G_ 6/. Ma�:T/���bi�W0 &e"�m[2�8�W[2�6��$�h��A8� }q8�-|"�e�Z- A��*! �4a�ajQrecru�pĚ�famCer3ry�eC�6 phen�5 f!WapI��"��u�d8� .��"n�%�{��al)�!repe[!�_�[/%��<*Y!!�.Te��F-& "a�� p B�|� �oV- Wray"�0[30���% ,m�--�D7}�9�� �{�w e����YY��Vo�5i�W>���.E���.)=�>*5sX՜6}K&�f"$^H& A��u ssue�J�q1��� t �|�'N�K!W� !Wa&�L����&B�r�k� I D�JA h�Ue4Y�a� �pa &�LaXbgun�"q�in [3 06��J�HvҒ�r*�d�.aa!5 �f]��G� c���& z �mU�>1^r-�� 's o� l!�|t'��adAFbN �W@r- ��0y by Gail [32�zvij�%o<�w]cх�,pub h�\qXE/�U*� � �6Q!a:@!}�e7)�]� y�� ua��(&.� T test)Jiҋ!�FHa�ɢ��FV�,}��g!�� �ye� Wq�U/Qg�l��K (+�%�!+X[NMa �g!�wd@ "4�omp1� �n� we�0P�!q��m�r ?.u�F"� ka��:fJ.�:6x &hY�jjI;�#"j6f.:5��!����i).H �*pYw�Y�� �n� 5 �ATR�!�� �giJ him/�"�Y[!�5� P�T|D@+�SbLworOa�rroneoo�&33I6�1BNtupr�b�A[�A�� �j�#}bid:�rta� �?1 <� )}:�!!qO s���J+ tack,##r� �  aQ�incorp`euq� ss"O&N5z�w�# �g�w�PaG�>byi91fHq�t�Q�IF.ik�v�,�W��<� e|# �(TP , TN , F� d FNEa�T!*�d2 B!�R0-�E-���(5/&�q"O:�2q4an5e��>�"p:��;-A�a=A6#`�Y",:"AQy�g���(�"- ! Q!o�5�� +S/"OŢA� )/e2/E�A%Fbis ��.!bAӁDe*m-/�7�uO�����ˍ�Q�"u�!�� .W,��[N ��*���1i;�-��s��I�l {\p�� >�Ii�c �oq�!1aHQߑ��_G�w%��ױefH �"j=" shif�s,�s"�(� � ��9�a��8O�uenPSZ1 (2)��3��!%=)52 ,�er#(Ej�Z m2 (� � � T�;,:tA��DRV�T:��:c8 "j��E�a4%w)U����m+:B�O� ."s �$�J �*8x`�}�  z�~��"�  �%.�O�per.BxA{bőe&%�aZ2�xB?"Ta��*< quoA�8Arel�onB�""fY6[a�4�� amoxife�6#�Q%T�=fE�ey�*7&[c�,�]!5��'�� �_6N-2^.H�@�M!(A%sD2�"���c��8�$�mm w�<}_�C�' r}�M�V��w "�(:�(A=��&"�xagnxET��P� in�@�hZar{�'eV)��.D�CX&�ALb�o.�\ �"oP3;�\�c��� ��!�huM�@<�Y�hh0qConP)bб ���FAui�"e�Y�oI��hb2b�!��Rp�~ [36]�")#�*�+a8��@!��X}al%9�esm�a77-up1�,�4qAa�!6eU*%on*Q$x������ ��D%}e=�����^8.�Ky-9�^� m�nDn6�by, +re�5�!R��A�soɡ� J��!��I^ w%�V�r�m�N2�!!-�s2 R��fOcE�����s� 2%���V-x-d2%�y�)� E!�%��6B A+5ۋ37�@Their O3lso&�a*�,y ���!�ey`1`7����Q� xazi�.�0"G%�all"�HA]c(�22J� *�>� of�"H4 ��dm�d�*�Cour0:4q!�s�F+�!.of%j�)Jjz.�a�a�,6&,'���a��0�X . Bea � 9N��"�i.� �P�|�,�,� %��� !#HX�tAhc �X� ��)�%�4aYM�n� �� YZ!�_�� O�Bra�E.H$�Un)_�AA�,%N�CKwiQ7 ����Uv2Zm%�&A"5%4ч)6M"�% �d��Ka�"R5sJo;� E)~ argu�:"�m)�g؋:ae�:ym $ al*��9at� ���!y�%&��i6h�Y��.��,RDT�+.*)qT!��� uK!1ntv��\*/��� ��c��RDT� "#Qre�_}��ZBIOLINEE\M$pz ar�<w)ׯDد�Q��>�BT =%��I@�C�:632�O� � I���Democ[ c Rex%e� g6r��p�.vALa��lthi`EAC �^by�ob�&te�D� 260% A�2M�&parasitaCa(!�h�, �ew��!�&� !AA�SDJq( 7jR2%?%f�g l%7( 6!�5�=he>H( 59 . 0#AeY�c A�� Q9. p�U/�Z-a:�:�0)'9r�9nE 1�?2�]. S=$ e�s��Wa�(�1rec�.�� if�,a� y��-�� sub-6�Al�I� {rar7�m�$1�M]d�eIIM�a .õbڨo �-eB I�aI8�4��U>: �u!�:oAWi�.�S:%)�,�!� �_"%�4>��!�83I@{e"2�A�JC-� ��:4t!�iTasU] �:�. II�-- �m� "L�Q� eE���!5������QCȨ2 �!�sI �dc�8M%�;�""S� d , ��-�% 8appʅ��nh���D9:cNL� ;$�J!��Ais&�H� . Z~ =l-born8neg��ro��] "'$-U70>�\liv!A�V$ub-Saharan��Ee�����K< !!�Q�;��in � �W��ozo�7��e*�J+ ( g- �in 20:�p9u�n})�A�9����D����P�w��� ����/�s 9��!)���R�� x�&� ,!pA�lyZ/A>�Fa_o�am�2j$.<in�;�,Y� nervƫl��1\s ϝO, left~KI�!F� eR�is �!�Ky f�\.�asymptT�c-UM�� 5V�mta)�p�)�� pathz�-f�|�u/0�5��."��x6z . uaj��B  Pn.! d �!��RA>IfI��� a2- �!(9�.- /T . b�"� )J? i8�96�^�It�e� bo$usa�a��t9M� !a a�6s�B��deUM&/, AngoluD~ ( DRʮ! !����  "E,j Ei+. �� �"$��J2�,!��t&� � $ � %� a?!*2��Maja:�e�u�}llf**Y)�]m*��A%]�� � 2?�� stoA�plasmaAw����I5Guinea%bCô�%’Ivoi'[oK a�Ffnc� %&).8�D*���A��#s��G�e��oe�� �V=e%:�u>Nw�G��NJ*in 5���o�a��.��G�mM(0�9q�Qɝ{/���;�� s�&� �2 bor-�DR�s��n�k��o�#&�.��u���ĉWa��0a� ��. S&pΠ���]enrol�� 6 June q to 5 Janu 2016!�a5Ban�u P�P�3mj���,�6� �7F� )G(��"���f!�2  kPq�&side Lut�io�  la*k iase�i���p ( PNLTH�� Y�.)D �N�jOh�0�#1ca?D1sel0^or "�%�T Jk�� ic��" a� k #���dr�d�. D��g Bn!�ybody�'��REH�"�Eh elig%u EB�ɳ. Is�Elvi +� xny%�ni= pas8 7aU-� Uto�i8F�!,�d�B��pB`a!B-��pr� ly5�, �d d)!�^c;t��adɖad��d�.��m���/&�0!Zm6� .�%mi]�cop{ @J nodxpi�~4lood or cerebr�eospinal fluid ( CSF ) . All positive parasitology results were verified by the site supervisor . Cases -classif/�as early stage when no trypanosomes 4(observed inair�, andwhv�cell count was lower than or equal to 5(s/μL ,:0le those with6� scand/or a> fabove2Qw!6� late �8[12] . Controls .8subjects livingt$same areas!+c%D, ��no known history of HAT infection-who c(either nega%��adur!� this �,� would hav!yqui�� addiM� resources�collec/ d� port���r ana �; ch��(that time cl�be�in DRC������!eūve}�!y2�!S�����j>L"� showe*L highy ugges��U�j2^immediAəh subseq�A\� @work-up . Written� ���A�jsoughti�theseT prior!�w. Any}yAT dec�{d+bwlmanagede�rdE.ou� ndard� � �fPNLTHA%�d2��4"O ' bM !�!had �fb� \o* v!�g�{fur� . Pers E palp�b cerv%{lymph noc ta aspi� ����ot�G-�es��bri%�4ield microscop��AmA?5 mn venous��!xmS�t ��5�n楑W iz!�? �I hunda��ofWus+oqe%�:� centrifu�on��T� � ( 4:/�6� � 7I L ) [15r im�a�V�U , 50 5of!�"~ &N�mini an�exchange>���qu� mAECT-wb�6l A�remai�volume�A�. 2!�)�56EZ�buffy$ ( -bc )�Td.� Camar.� 7!# Sinc� ;p� dureE��$been evaluE���(�18, we took advan)����t�z��3.��a� data ,� e iti?�!K, eve᪁� %)� Jed!a��se%��. A l� r pun� <67ll� 3confiby��2ge�method��ll!� on o� p.( �� 9�sə�PstrongZ��� rout5�4Pa"�_�5 �CSF�d!�k A�mod��lj�[A�a�o&��79ERa�! $re employei���$experie!�� r���:� [�2�~A]! Trmcof�sonne��2� �Xfixed:j +"_howA� � |~ nterpret�f���RDTA  � � ocolrrekd SOP&� le��CRF�di � 5 �V"^(or doubtfulA`��y �%�"��2��i�u*PB�� misA:��=�x1�� �Ln�0�id� E�i> I�") ���j!� 2 I�B� wo level%�bl ng G adop��. D�  iti�"eA;.i1���:� U � \ er1 resp�A�MS�a��\V�iv:[ope&s"~ ly (����!vs�f.M:��out����7 firs� vi@5J9AXdi0 t� ac�a/A:��inU ����]v�l>�.�1�weci whe�eor� �i2�%pRK. S�E)24Etlabelled%&�c� � A�yF� condI}�=2)�%� @b%�toQ�y\Ks1 � n2� ( i . e .-�,RG ,��)%:� tit� Oanonymis)��Osѓas �tatt�A+9entirq�..>2�!�!�!�&�":at�$��s�5paper� re� A>�+wh� %5.to�U(in Kinshasa5�#le�Lf y i�a web-ba� U�}�r platz�i� Form�9 :�ingm�avail� A{�%!)�F� �# �0on bootstrappmA� [18]e6�� : At Q[)�(, a random � ce ���!���was gene�U(�� 5�� pati�!��IVQ�calcu��`��� metric� Qitrep� ( 2 , 000�sE =Jo� an^ir�distribu�I�  %o  , �IJ_ .t�r�>!(%~e mean�95%aHf��c�< tervcas=��er� il�EstZ�ks�iv�!QspecificE�5KdYCٞ%|,A+�!� %�, PtAf�by!ea�� pbyN� �NJ�|'tdiagnoW.�of)sygT� !p��. S~ def��a���!WagE�NL:��!(-� 9�Tat)u 8*$���velLccuracy �ss`sM�a�$Youden’sex [19q To"I � agre� betwh an5, Coh CKappatorwk&x�!�ab �!j-�"rRGt,environ` (/ �� 3�. 35�M�siz2 �e3monEne non-�A���n�ofA2�� arisonXb. B���j]) 9192 . 0%L aP�9j�, u� aB� marg� f 8%aKA&q�R q5%ESa p� -0.�r�numberY��6?be��14!}6�� �b e3 �.21 `(97 . 1% . U��1���9�6.�a?a mum�4 , 775!<��be nee [20a2� �prp�� n!- �s9kOs ��dALbe��i ords"o�%w� !?4�00� trecei�"eth�pclear���NSchooEPublic H�mUniver�"�$( authoriz� �4ESP/CE/012/201�2c s�A�wrZ�befori���� 2K. F�!hildren �18 yearr - ��!pr q � (or guardian� ]!:�&:� *� od!)����� 1��Ɇ� ^b[ os�$or{ 1;�"� wishA"M >_ N�AxF� 12=$476R10R1.�2"by"�9' . Am� ��t�= to.,&e oe 4�4in< R݁O5!nRrN �%��as530%UKm#13�l. On a�%geA55a^��8 � day! &�eLe�@E�.x,2y�a ��5*EUy F,J�� -�dF�6%a3�hi'inEpW!a�� &I>VO%T)�.� �V�!�un��ly �. W� %� ed 7!�`2% [CI: 65 . 7%; 76 . 6%]gA Q�%?@�6�5 E5<2%; 68a�%k? -59 r5b0-A�r n6� ׉�u��N�� oY8% o4�8ox5%] , 5!!1%; �9 �4�1%4a9#� � �b�5�%q�!�% �!.� IN�)�)�I�Em�IQaXw�h achievingEn/est, ( 9�1-8! !�9!�3%]Lfol +E&%�( 7)6 66!I68!� 6�( 7b0,!a5AV!1!T� Vkab�*s( 9.t !� 2>� clos by!u(9A|9 � !�>0> ���1 A� j. W!`����)�6�A� sign=an%�r]�],`p&2/$.A�gFaSst)�%J-1q��!t A�"h�.�E� @413!~3%; @a))23!3 %/1/.�!R���A0Qr �IFN!le�er�[e#obt'qEI��  QF� 7, ��9a�eqQ�1��~( 6!3 C�r;iH)R,2�-�e/y5a�ah6��M5�х�Q��-j7E�� I��a �r�=�Q�B�� eJa wt:~7Y� �Azexc�nt�-fV%/EV8%)�q� L,#��a�NR�differ� ���;�7.z��>�2��'2� �po�$ pair�: )>E,!1�1I�AW��2�0!�:�%�!ge�K)�E"�.tog� �9�2[pronounc�FXa{� R2Qց&\a 4%; 2 8%]Q� �a�. BF ntr.-�r �n��A .�in2�1�R!�%�Y.9�( +ae�h-ii;x �)/oe$��ofB��2�!�me�I�mZ�FR e�8als�(M e/,x%,�'+��'�b��1����-�/"�)�,%�is ef)2� ����Za1!bќ!a��2�L;���-�%i6n( -as5���� .��V�( -�9a��1��0�9�a� 83% -�Ui�- 96%; 7@%2E�%���5�����>�Y�� a��aC*� A��alM�s"�( �3���4a� 2)�,���~W-�9� -!t5A�%�4�9> ��6+6t%[E( -a1� 2A�9 R� �)=%a�V�( �8U"A/3��3��V�4?A#5U#3��1�slX'� 1� e�H2� �1 Vf��xb�H85�!^2��5A�) �j�1�52�  0 �6�5� at!�*.��u made�}�1�t �7we6e2*a�1Hof &5G.��3+����/,R8"�_ally lLgroup�.ds" '���2� sin%�A�� �8a܉R����re�,&!%`woG�@S� C� r2�I�fk7" �n �'�|%,� *� e�5*almost� same�ofg!�-ar 0�9h2�+�7%:) .��!��(�#ve 6=6� lar���%Wk' ]^TG.- T�2cNN� �2z .�� . )�%L F;6�$J�g/a�wg�1r�false� i�I1e �o#1 � �6/�q1���bE��st�c7 "?4� <�<G,�8AP"�R6�w��ARana8�/sq�M ��Lim�~� �ha$/2=!��as��#IZ���;� 6+��}4B ks�6IC�3J� up�5�.��4� �!5� �{iZ� to 8:v7:} 8? 8]9= �I �P%�he �M�EQN1.E(���5m#v�A%Nq( ��8� �9��i6�2�}ѡ���tn�)��6���n()�1��L!`small:i!|enZW( 2!�0L �:�-!�.�5�ab\4!�!�3A�> �?.�fu%eE�6tv!E�DE�A�I�%FWe_ 2�e^�"�"�������2�)>O!�go�im�A�q��ofH%,ch�9im� �a�nhancG�g�A5humb6� 3x?�m�=re�Aoir�di$[21���e��a{.��ll�sC6)� Swof0.�a�A�=�p��:9AsV��)���M��K 7; 1�0I w&r 100%.�G.��su�!<�q�#�.".���Rg=;!WM5���!}�OQ " G"�� 8��<��B!<marke�:�t��˽ �. L�".  '%" �$�A�Řu�����8!�a�9�$�Q�1 �ofOt��a��) 4; 89)�C�>�e|l"H inc�Cŗ.�&< %*ZUb.}<`d펡1 :]��%6�!*6�!�86��9u6,��a\a�a�8o !)uVa�4rk .�ofiF1x�+mT��%A�o Q�%�8�%�!����@�,I 3wor<3�e8a5(�9m~)��gIN�  %h>  �0F N6 ![9D them.C�5�Bn�( �2 �. H"->  such �%i�&�, ��Wtrade-of�2eq�� dow'4�YA� ��1%]Ia�. e�@B"�e:!�3%)� Ad �zd�(ŀ7�)Yr�Hi��� ()��&to^� iNC"N(4DVen�<agr6>�s 4LA_c"4y  FtruJ$ a e dey)��lap6���@!���� B�.�5>�Z� ��&��,�$R`��*p�]V8. B�Bm�8%�I&a*on 124 �)�. Ninet�C�>(Q 6� E�p�Jby X�8eE�B64 K(jn<wb�o���I%+~��G� ��58 qI�U�� #-�.."�(�4�e t��5B(Ih�!k(� �E�,cor�,on_018� �/� �s�(� a, "�%�upZ #.�3 ( S2�a��9&cag<�~a%܉uVW32�4G,!n=M2�6GMdE�s�IZ=h.<�[�.+��by<� �|inRoe�C!<&�="�= �>6UYf7F�mz%o6-E��r �1I6fF�rF�{2h9u'M�cerebr6�N. �5� 2���Q�:F.A>OQ�er� :e!DE<N. y�!su�6fu�" .�&c 60�d%%�,=2&i)s��&,GuF%&k [��� n�e�%u�ip!a���Nx ht2<0ext!�0�a�d"�4seta�a� its2� Sx.� r�>�k&8/F [22�%E r 6-�え� : half1�m�nNPPrevi�@retAY�1E8�;����!V3M3) to.�82 �� 58 , 1 A2 �/9%E2g��;!� �$t\N"N1.�[9!#wan�try:),J�$commercialxA�A�9�_L� appa�-diAW panc�VEb60l�#G+ssux:�b.>��@lF!�� P)�E���serolo��profil��&���V���ed �&!�C29T �M�F-Z)~u?NV�.g9su%�s�.8-{., b�86�;�):�H-:?= !�"_!q��A�%��� . �two:TR�a��)>VR>��-&7 6� &I1,ce.R�EV%�Y%��on$&�=�)E�!EtB�� ��"O��L!�Z2!� explC"$>Jg�Q�!Sor�"aI�in �6algorith�:4<2�2 %�ccele� rup x�:� :by &��c&�>�9�AE�UV:-5I*2e�/�@r�*�5gA|&t�7e�e�T�ior�f����5.�NB;*2 .4Iqb�In"�o �I\��Jz��!� ,�]D�1*6��Y�!~�q��eXU!��^EUrE��)p�a!co�Q`P.1m R.��?io�@a�� s��Q�6J1�st->$ivenesTB8e�=y���r helpfum"�<�aBse^KaA�oGpr_J]<)L�aens5Foptimal-�M�)y%�}���F�A��T�3:'� extr�6mplex2 ��� �Ru�%�}Aloa)�9�-���� ~ Aha�����?�esta�*wI t,3a.V redu�W- .��3secI�a .�1a��1)�kT��it9&�Qt!M j�eFToG 2�&� >��JA!,v E��8 !�alPSlle+I�erm���It!h#Ya�;!O� Som* �9eref�4o!�e2� <-� H�!1 unlik�..�!�� &yUA{;f.3C. I*!)�!z�!l u E�MzB�� u&W.`�B1 �9M�g t��|!Q ##��EF" .@M*%j!���e �i VɇUN�&� �Q�Oa�U Fs yc *�0�X� "� "_ . Maximiz!z��ixE�B���N �*�eli�Xe �ex3 %8��'>$Ur2� " m%)b�s%�.�a��&���(KtJ�`,=O"��GdY-H%F�١�d.�� a&�>impact�"�� J_#�� ��underg��RsO5�ofKP=sa�vel�BX�A��e��im�[/Oll�a�b w%aHle]L� prog�Za�4�& towaK.��*)��!���[di��56�s w��P�g- I� *�7v#ter�a�'Pn":^dTGopr ��new:wa�t-�bX!F�,�AV�2.��d� E�m  multi :��g6V. %�aj m)" �ɩ&0 { ^ [ a��_�^��� promiA candid�aoL *V [23–28�O� ���!���}.e �%�j�o�{ theyb&LE��Y͇A�&U&�[25��4�Y��� �.ewA�afk(&A4�Tg-��V)��7.\&�b�X!�zm [29 , 30�-ܥw)�>J��c5�e)�$make a “A�%�”3 achae4 !=H�!�&J>���r� .J&�'hypA� �b�]mqF� try�� �J��X:qs&r%E�*�I�)e �e"�=ii��R��Afric�'.'c�!notor��!�\ evoli" a meXRisEAes*S:"h�)ae,_b�guT8�K��89"s(`g.(`�_2,gmpo!QI�*4PR,m�� erto�I of d�1Rg_  [3Y37c=a���s E�A��~=!ť�iceda�e�7)�"rai� ab��wR@a �Fed]0W(u��l*P !��J �R�3q!e7�rb!^QOb�1=^[ agPVSGA� �Q�wh.xGa9!,a7�e�um I,�h��!ݩ_ :�L!o��� *~!x� � F��:R J\AtZ �$?65�6z'� ��!!�%�C\H%M8� �pE,�")!����,� !�i�J��5�in � )n� A:� a�6I.�U)�+!3-I<5Ibe duE��d8�dy tit�X�veB�`mA< � ]G,Cxpow`Wa]!dtuI���h* ~*r�AOs�!E�.�)�be�� !f�6��a�6��� �z��Ia��+e��&�d:TN�A,E-&M�>T seRa "�an�modR eCDd T&� � : #��"=A遜'R�/���E�"�MewJ&%�x�2!�� *F de�g�? ���@���ՊJ�>�v��NNB"J .� 9��Z�'.2 h �vtBdin� "�� hope���lrif fALoi>Fa� �ep3ed�-9� ��&/E,�G4�GE�w x*bA�a �i�e�M6�5�5�is'  �k�V t�e��l�F1$cXnIE�aDO.3h�_E� deworth!at d^5 58z %; , ye/7H��6�3 ��)W!� redo�� ��Z�Z�!C%�e/�&5���na�hAG3reage�gq^X dec�IF�i� r.��� �]-ti��A�!< !�h�j�M"- . An kEU0 "x99�K�1��m�H�#soc��W:t b�wpL jac�n��[��mA>epitop��! �V2A�~ Y pr.�^^En�FA �\Nmix%1�n(M]I�@e�q�]D/-Ve�a�V�? car/mI�kYe�l�g�$c !�5�n`D s unk�pqK�ne!9`k�E� ?( phosphW �dad , pH�>2I>�481% sodium azide*WEIm�| "�-�ic5�< a�4I#p:L"����1-�f���-�� �6A��[:\ tT F43�I/.�"CI:.3%; 8�,�-A�(.5.�#~3%H�;:�Hc4� �i�QAXm$ to w� �ݻ!BŴUABm�C-c�sr��]�611��Ue�3MS_�qA]!@�5._ !xA���"� ;-�!, ,*-7!#?�.u0~#;c Q�c&� "�=#�|"Q �doūappeagb� "bU�&�Ham��1� 7 tend!{&� e view)G� �s)�}-ez};ř�i JCt%Ve ��@ �Fl�0�lye.<F^ͤ1Lce��ͯ.Y'�Wa'�!. Qu�h.iV�a5P2�6Ƀpatho�E؉v trig��Qs xgs-���� �� F\g+� .���Xr8bNJ� ^0c�,[3�rdemDs"�>� >arUa�A��n5ͅ�^��"� AG :_h�1Id v�"�)X%� ��"�2�Z)M�&� � M yA,^elU&O a �v�[��Q��2�7 qA�e]�!.3 m>a�F  �thuA�� arte� %�0O?im�gec�ۥre\I�k, .!�%�ref�!�3�!Y_��e#m����A�e�A^ ly��A��p�C�(� ��eRa.��R("�Y��61%-S4��$i6�M�%]of �LI6[7%-�?�2�.SurprhlAC!P�>>In�T~��A%U!y��%�J� ����6.�)I unnX�@�*�IT��raw�WF�c, 2� rshat c�}a� ^ �5��|?y�kK$e\�L6�� inct2�"��|Q��%�3v {(V�3. Acc& i%31 �!if�3>�sh�%�/b�zM&�ls;!�q0�U_aE��Avh,��&�) dyna�&�E�� exhibit.8�a�(A1�p~i*6ac! �e!9]�z\i d;��ly5B�)"�*��26Lseems�o"R#s�PA([(�G2O s3r�!C�"%�b�&!�.*lY� �y�Y�sfzi-;��X QX�  spit��efforzy(�.0li� ��q-'&�i*�Y�� �m�Oi!� moni�n!�stI 6bF�i�e\��q��H'a�2 ����>y.ѹ :!� ^�V�.�(or.�%����&�.�i*�%&;R �%p��ex�/�`Xe�IlUe!bbt�lh�0"-AI;A"2 or� !�on�o�%E9 � �%ro�X�"!�g�-aA�$: )S�a���:�%[ batch1N�8il*)� �U �&]Z� "p�i!���>�ejp&2k.�z�\��r|(.$ staf!mAb�f�s�)� a"#4�d&�8ol&j(,)��E�YeNp(�.,�;)��c!U2�2�. Y�O�J5 �=��}b�a�1�c$�X���'re15!n�f!E�� m�8�8M  [@q��bn2�replac�cof ;wbu�is� l�h� �hAqu Ya���bc�ppab4�{� �7r�-P� �hG"%%�I��F! 6�*�"� ev(A D#5&�km:lI�ŚA�2Guine�a.Q59bc6�<5�b=3!0R0wb07�F !�&Mn�!"� ae��okEr�.!>.|6<) I&a~9l4�D���� )�  FJ�)@ �&S;A85?B`iN��� [!Q%��m%���Ox�L2r� ��� 6�I�*� � 1&5�&�u &�5�a��Ha aemia�\e r�9;�a�Ia�4 �.�bi� k���!!(�9I. A�.� @�&I\�* "j �1# �)�ő@!d aAn Y �7�A)�s�!��.�.'�.& ?n� >+(>?)g%6beپ�km!Uw`&',�l���j!Zm�h0s�.�F� h��!�"� ,A �f i�al&`+�"fEf%��*> �wbei bc�-,q#��Q��$X jus�(�("� �Tco|2A$'* p*_ 4 ���#iBcdu2H�)���%���'&� H"r�ye��6�eN A�iS$�ce.u3<�/"�aZi�%xe�:��0tm��EQ��alnGy�ipm*�, �wb� �7l��tra�* forw�[ 5"�:h8�m1Wn 2�� =wb��kf7tz[�e}T��� }.�a��S�"�sc6�����i.�>� De1 �bcE��\./vJ.3�iusw~ (B�q�:-�# ow-pB�i�gh6a�� �!isM�q.�)uT}i"f)� uCb��:�!P�:|7�t ץt*�5:4"� .f���|D)�f3A�O � E�-� � >T�U"jA�,�un�"�Z4��B��(21yv%��Y �AKN}s.���9�E �� ��3:��Ue��+ro�a*�)ch�.�[�Iz�@ � �� e�I�!�� �� r�BE�ca-4���_? D&�-epidemi"f> i�J#l%r&"�, -!it*��Ūrol�y�9at��!Qe�$ �-/&� 6x 5*R� � teamaYtV5co�Vr0!�t!�ar�G� �e-$2�slo�+ini$otA�r��|m�%_�aE�:sa� �~)BH.�turn-�p-�=+�qJ�ɵ�Y&�g'. E!h� zl!�te|;9 tEQ-o�stock-ouli ecn+�@ kA.5 )~h�kZ9*�aͱ�!�B�7 aw!}-�"�4�qu� %2v M9� roba#:�be� � B�d3&�&g/�'M��daiO%o�z��!0! ��s�@�hu%%D�Y1}���t ay�"G�%e &�� �leakC��F !bZJ�/o_ �sr�'� :�&�|,� �s!E)�eZ!�R{!��.�&-j���7}�P_�=�|a�/es�J} r~,�=a&� �Z@o1g�3�B� � B�y)�{"n+r4)b:ѐ3(s�e/�&e��as!~�2o *�!nB1%a2�5����#)f%7�0uБwel_6�JQ..�toov]&u*�+��n��Ptu� {6e�4 .�cChag'�u3,� egle� tropE� ��s mill *,of Latin AmeZ2�4"� "�3l� ��GB� p�!ple�nd�Uindoo�g'��cl# spra7( IRS$H"�N$a few foci�%()%���ist +T3>oma dimi��aa�� �nK��m�%� e mu2�pa�� omap&D� �4 Juti �5��er��gcof=6���$ ��n�s�!a�9Q��xrr�+� ~1� %)�?entom":E�e&Esurvey� ��aW8U_of vect�s)�i�i�f�A&%.[( 1999wnd:�( 20017 )��z �$"r��M�%��,c��OS700H]q�&rmt���#Q3Yfes��oud4,�,P@x�uly 20�gH$hol�)�)��-e��6f�'��� �uSG�K2s!q00792018 Sero�!1�%.2@s�u-age "6uin)�,^W�\� in w�-!3 bea�ge!�5–44su)tin��$A咊�1yxi��C !���in�zde�.w'&�$ly�'39%)�Q:]�7 1�s9�Zw�S�*i��< dJ. �A�=inq(q;A={d)I�vy 10–fA9, �nuto�A�Ew��Fvj�q/s >^.-����%��0e�C��2� B� ��"��.D �"inu/7isk��<-born�c�Dni@v2L�7 .K:!!Q 20221�ь���g�Z . Sy��arCa�g�d {q��Zed>T&Ja0:m�,�=�SK�&2���%!*o q%h�B�� �'+ݡ Y6� M�h�@w8�B nt global secu�|� at [�^b)�+� 8��]C"f&, t *�v��ann�dea��nd > 52�L disa�-adUed life�@ ( DALYs )�23m���.&Y��Trםa cruz��c�����0CEXfݛ�Jg�A� plan�u!gN�2�h��o\�)�M�Lqe> �Mon���y/Hs [W=TA|�E?�an1��E� w focKoK.O8 iat�/�M�"5aC�/cc:" h� 8�#.i6x ��*l ��� Xdu5b��%�;d-�3c d��i�fh �� ≤12x17A r�x�9 �7�+c��� )� �3 r� iV[6–� In Ch�al� e�MexicU !�un�a of�"�J5 8g.'o�:�/a>�< �s���-( 7#��l�8gQ.[e|PIn22 : �w}_1� a brgH!? XRa~E�A3h�7[3!3� �c�H�+1�Au�Ja֡ ��[6&@ݸ "�E�ec"| , b&��=�0l �'aI�e ,A�.��9d"� � majorMC�!}�e�\-�$to EcuadorT�&�  !f'��E>Bto rt aw1��4�1mN� al S� egic Plan%Q-�Ca �.| attack ph'��� h;r� bas� � .^ ��-wK a�. S[�!�"p 2h t ��me4m !,��)�Aei��2��0 200Ki�)�ba=B&pxa� �a�)� D+y��&E.�A��&2G�8" A�g�t�6-"��Ŏj�la5/Z�:"� , x�4A�> %L�ed 94%Q='\ "�e� )510a��[��# �ZR_&X ��� 39 1998�� � (~I � 006ŶDes�&�!*�V�U,}?H&��s��J�! �h!�j_*���Kq, s^'I��wW�Q-���≥15�zՐ>�aL rv�Xk[1��2K"te}n�+.a��Z�a�Cak�850��c�vsea҅( masl[4��Ũ�at��?l7��� �0 at *��5Gs���&v[>�!�6�6-.�� �Xxy!**� 2� ��I�.uT�E�l"S �se�!��r susD;��Vd� ���vQ��^��dad�A V� de�$( UVG ) In@�i�Rev�6Board� B ) ( L@Dc R�hen6�dG��.��y��z����(#100-10-201�>!Pa�Min� ri�$ Salud Pú��a y A� ncia S<< l ( MSPAS� QIRB����]�D�q�x�\M:H�SR�8Research Office-� � .( CDCA��.#67673���3li� C he%����0m���k��v�o� 3 S�wr�%� >-E0}9�U�owner�|:�A�y!&l� 2� ,ri� �wp.�*&�� 3��61 tutor/leg!�������A�min=<1��M. ŝ&��Ccɜ��Zk,"�dg�N�6-�.eɑ .is"� 0at -89°54′_j″G 14°6′3 +674�\*0� a�132 kmq a&9��!��TA���)s{�.� )4Z!k 6.��!�b�`m��B�[mans��[a�^a� lLd"��&ub-"� humi��estۑ=Vz�te�"�A2� 9d��+�& I of 69–8Ra=�� f of�� mmYOey� 4�(( June-Octox�)��p&y)&S> �(�2715�� 2002"pn*� 27X�70 &13�a-�! �re/pBl�C F"��iI��\� t��72h-Nm�'ta�#r�*)�mO���re'X E[23� omy!��d��,���fajZgEa"Jhusbandr�>-�!%Afhigڇillj�c�2|o5���a6� dR�0cZ�*A�6�+��!H�G�6�Xa�e� �T!�s���&� � �"� 'La�.��K!�� ( A.H�!=��[�"ve>}~c!�ag�3200�k' ;s "�{��#8��Fř.Iw�*6�%K�r4F ,k�!W&O campa��� � d _I�A�** �!y� %�F�24!�C��V�%�H$����� ��* ��4r�8d6i��y( i�K��H+!�!�M.�Wa�, en p�sh�5�L.V11`U17 ��}SAaa y<U,wpApG.0 xZ�7eO�(�;>, <V�9KW)g� =Z%�ca2 oug�- %Io!:Z&��6�ItakE��T.� 2��<"DO v6��, Non-GaBY al O�S�NGO´, I� "�Co"�7%V %��I�� � �)weB �*(2�6�r�.TU� e�cco&]6�A�!&PJa��#}�z�! )�M9E2�Z%�%�mon-hour�hod60E�e*6�� ��"A=�P*q�s�2up�� "�a.{[Se EX[ON� pen� &�'ro��l%�;���.` -��h��ȱ�'lJI�&��AJ@J��ve�ZK�h� . Ea�'men%9�8e� a��� anol soluihtO r� EArio�8� d"SU�r�CES/U�mLl����_.�A>. A�.�a�AI3�eIyp�w Nv"��c)f'  w� ,���d!�f top�&K � i���m-��!WK.[S� !x���lh&"�N�� izzo��[�v��%�'&��&� ELISA (� In �5serum%�elF�D w*��22dr6%-�RUڡ�w.�&J8�E*f* �`l95%%2i.1". �yB �k!�!�rJ�[�Z�"! �+f.�-Ne comm�d��yoڪ� Q%e *�(r ( WiU� La:Ar�Minں�)p�Uspo�5:7i{�����-�,V�A�!(*"[k�\Lq � &�!3T��;�1Wfy?$�eJB ree-���P"�=M�A%s!w2<%2�( ><%*7%ll �" �� r��ly. ���^B%H:|��"`�"ݝnew�2/���'tsuscept�b�r s ac�� pusu�[3�^To%���foB��V-,oigh� A�����a� ur���two\a&�(�ۉ d Weibull�>on�3, ubic B-sp�() �>p$E Samu�W| . [3� PL��A�d(EA�AIC [40] �resca�*(cutoffs [41 ��R#plaX9Zc��!"JZi� >ulm-d�"(��� :(W-funI?�ge�W/ ��� ceduaTsi5 �B#20��a�%� cataly�!!�J�)&�4��� BooX��Mc.Md +Ĥl age-����.(Zu��re��d&�$as r*?"}� 39 $8y&=<in��at� trun�2$at zero [4w^Datn"�j�&� �T ( R CTD&� TD3A&��tO9Viennx,Au[���i-2�Zbl�;)&.�$ ig en %_1e4i�Ne�VR��x%(E�Z ) . a?ke5n.�,�k6"d�A����ys� i in T� �W��Bs6^�N_���d"0"��}( 3�O2%� 79%�8 �z4#�I62� r�� )2t1�E��+�( Z =Ď3�� df =%�P =^ 037; %Yr20��2%<�001A�&"%N�""H�1�>��aJcoloniܡ� f5į �E@�07�2 6\ 1�d�Q I|��IN��!a%8� r:c&"in S1M q�+��|e��.Is�L*���J2" y+�6����<9#��� ir a�(=�c�4Id93��� a~A�e� "1-�X%a8Kܵu^Il'k�al��9cA�, dirt� (6 adob>B5!�c�flo� ( abFY)���0fit)��_an�c�13�810��2Q�9 0�D6 i02�R�ea�;n �>� clay� ���, cr.r� ckX!v��(2�w��2��38%��6N#.�\D�1G2�2�)��9�R#f�)9��s^�53�{8242� �A�oddjKi/���M�t�1�F�a���(e�� a$�i(>N)i}{.�.�L%}op%e !�.�1�M� �a<r� F�:v-m�I�a�I�"{,�eU6�sl�I�(ok��T ll!!c!qe!N]0G� at6{F�A�aj}�Z^�� 1%:�!4�J� roof�#F���a��!�[:&ob�A 0&��c2� {c4� .B��.mL�eA��.��!�5[)n%&�1%��e�W�!z���213�(f�6�g�<i�:o�$Epa�±7�aArj8W�W1��1. male d:  �15.�׌2�'17+Cv�88b�w�� �of �6���43�/I :�A.�[9^�� lal%�!fE�� )��6�� 29&� rD2!(UD )407�ul6�l^e(f )"��� J>�>gia�"N:\of �Ct�"�������Gpa ��%�g� �a>sum�-�j �f!��ep �v ole-;k�e*�Pin"# LM.�ck�390�O hild6{%w*� 4B�E&8A � ^B!.X O$� d.�S�:�AVdjaoke:g�a.^�,2�:�6�To#��you�1 ��22M�)�q��s�(� � ( �7/p3-"47�t*� of 3u�eiE b� "� age12�83I ��Af3cǪ� ( χi m!75; pu ~-�Us_+>=I �AR07Aʐ9Fюm�t$90Ȋ��)��)s�"%(MGgz birthI�g&��e�1&�51&~7222 u6%Ed(-m�K�WH&�X �A"� A�&�8M"AIC� 28A�I�.�C��� _(04E5X!�2�&� �p<� AB �A 33 , A1j�>q21�� 6��nr.� *�a�K|yF1= ��%�5J���!x�Rd�U���-A{-%jZ� �P� he�>��:x\[����m͍J��\6���g2 s%z6%�E� �6�J\ry� ed <xOa�27�+k ( 132X,��FF~r�edR at 3�8:A,�?.&4�W6�,I{4�at 43@:N��:>Z/AS0)h8 B�>d"�NO6!�V �^�"W%&�4o&swZE\#A�2 ;bzIn��"6Iw�:�e�<s "�lyz0�!� reu"\/A3origi84���*^, �cay16x>շ�H1Z�_#sDa*K#>�.6�= &�#��!I� &I< "� �6.d 1yi�"�2�?�!C��Hal2a.-3�,�� N1��a!�n3 5M�,� ���Y: :a?10 +z��6sf��a&]-o�!|� 2��5 "��)* '.�wabM� .��)���rGV�d!oo3�<c�<o�,i)i"ȡ�AV"�W�R�>�LdP"$I>�2�.9e Di�s !:� ]�q�o!�� P�tC4eA�1A��.��;sphT*�)�Tr)%s�FST�3A�f��-m�2�n�v>?�/AM�7d�!O�Ba. 5I�a�)D�T>�{4q��jb-���&�*� !���.%!*0R�8*%�ad �Za6�5���ECj��z8 un.��"��8�#�3�Q!B&� ;'Ouon<�s4(a�; ~"�8 N,U���#.�I[47*%�:th!�we�LUy*�p�G!C�UI3 ��b-Jh-K. C�v>�g��� E�n)JW���I ~z*<&�Wa�!i(5-2,� [>*�0!|%��1�K�;�I!p&�K��J<'�)�Q-�Ͻ"�N��� ���@A��z� v-�T��) Dom�P� !`�2aofe��.�)�%o�2 w55�t��a��.� >�%� A�Z@�}6�f��"yN�*1��Bm�I�C�A<��&$Nonetheles�F6;spB/EZ� ��ddʅ��&k-*:�*H "="!��; %�"� "%V��6 A���2>��&d��y lO��6�6IwQrE���E�>Frodat[rvȣ^�4-�"#1�]r~0.��'$Tan"\ %�i$3�V}�%NB�AV�asN,55�5[=P�!��!l*3O>�&�1re*ߡ� ��1h&�U]� � do� chicken���'!w�>/�b G5j{Z�a�( �p 9 A�#�E�C�7&�AŸQ���Q�:or�D�]h��>�in BoN�aA��,A�A�A'A� �9 Z�s&�P�=o�v@6&� ]2m�h�"��i� "�l9A��eqV���&� _ u�&NF4.V�D%Mtwo���2��:*!(e��xA��N�ܡ�eF�7e��s�w�DW2E"�1-�� y0>XN �!2aG -taiK"L��uaberr�rx*6a�r�NGU *L"M�al��"!~ insu�6 1� ]2S }ŋ �Ղ d>�a "2ZI1�2�am/g7�+5��i����!�a�I�"Ar1�!"Z7.o �,�.���e�� ��� tX "�4".f��92Jg d���E;i?�6"a� 3. �%�+ s.n%aI ��� bene�(%�&��L����zy"�&o�� �JA ,�%B� �� by Gürtl^.O57]��$el Chaco ,*�3!�� �Q|;a�a�!5%E7!�80"��BM��� pren0vZ\s"�]]�ame�� &)I�FMz�9�j� � F�msR��9er [4�2I"� bS"'�/ AkAI>��im�y7Z?�&n:�.3> �SJ\9��"s��E��Lo�&�S-΅�"�>,�Pe1�sp1���3�PV�ram���W:g @! -to-E6�6�IV/�yphil�vHe"'tis BA�n"�W[4l3 Infa�Aen*�HA�M2l benznidaz�AT �0i� ���,ell-to��#-veu�3A�xX!��!YZ s [2{no�$e k!�!�x9-Ns�Ncg�9. T_�aL&Y6���^?���,�2�aheaHnew�"s �&t�Z���pe�7� p ousl�!�h�^KQ]" 72 -��a��6a�3s%!�in��g g mu:��]�o�1U3I:�o"t|eb�� `evC�is.��9ra9vll[=E �28 ��*Q���j�)#B\P� N5%U�t�� emer���g�K�l�m�a9nb�m�P}!�*0 ��V=�(geAg���֋��ia u6~�~u� entilWaTw?܌%���is g��x~�i)�ji]�!r= ter-��er�%�����j�t�, ory a . G�d�x�%Q,a profound e��ffect on a particular organism , in many instances it is associated with adaptation to different niches and may eventually come to define di3�}isolates , pathotypes or even species . Genome flux can occur by Horizontal Gene Transfer ( HGT ) through processes such as tr+ormat�L, bacteriophage medi�transduc&$and conjug 6 . In addi to g�gain , loss � dele*�0rearrangement)7(the accumul _(of point mu)rXs are also major inputs z5$��member�a family �ial�A�at induc!�t!�$nal attachoA<effac 0( A/E ) lesioE�whia@re chari3seda�intimatexadA"nce�E~itepithel� cellaye�$microvilli-9re��u!�X,actin cytoskafonA�a�L pedestal-like exten �ofF�beneathY �t� [6!�Gastra�1>)� �!Ax�!C1A!9�[by��thAdic%�sl@ callee locus�A�ocyte.' ( LE!�,-�is��mQamong�Q � , [7�AA,e only known+U�toqlA��@E�,N�valuaE� odel�YA�studyAP2), virulEfactor�A��esi!�clini!$y signific�n huma6�si�oEic E .�$i ( EPEC )%�)X$haemorrhag:)H)!� , [8��9!=Di��C:���fr���H!�hamster�Pony disease outbreaks� Japa���USA 1960a 70)#080s were origa�Dly classified as ea\r atyp!/��-V M) [10�e12]�;./freundi!C� r re6x.-g�o��9 ) [1��1eH@However , subsequ�O�Btic%4biochem�analysI thes��depen��A�)xd strain��ggestiGy-/f clo��)9fthallr��-[17E 18A We����(ly determin z whole�� �cea�68 � ICC168�� deriv�j of a"�EaaBJA4 Swiss-WebEse�,at Yale Univ�� ty School]Medic��,Ev 1972 ,-)� deas .�Ubio�  4280�;TCC 51451�aB1e=�0together with�DBS100��)�& �a same sour�5X9�^ m� wide�&tuda6n-Es .!� show%�at@E�%� �,displayed fe"eF �btF~ recenA�pas�$�an evolu 4ary bottleneck%z clud�-$a large nu��pseud�-�nd IS el�/s [20A�H�, wE�saQ!detai�Rinv�� on!��ic \ in:'%�a fɄnLimpac!(at mobs q���hadp �fe�z6��demonate)F;of this��� unst�s . To%�7is a� ist!-� Ie"] %+:� �.���� al:��� EX-33 (Q�F��i[11] )yK wa��4dI�a  tane7 �!��5i� CF-1���TM� Institute3e�al Sci�i,.$of Tokyo ,�{(in 1981 ( K� oh� ers�4commu�~A��>m;d�ce��level�c * �ŋ logyWpara�oq��_e�describAe�eE{ e ob�-�:O E�M�abiU of:� to i�Ai� N nd re��se fina�j -u�VE�&� m �< To ensurM-� �of�bA repre���k6(�Nwe>�2hdraft2�Kin2M�us�|454e�IlluminaK data!:ce�uctegmb��d� vo ��Lmbly ( see methods )a�h� of t� foun�$be remarkaA simi�to1*. Despih e�mer��a :�,�9ii�M�mk��,by just 177 �l�ulcleotide polymorphisms ( SNP�, 9 43�m̡}� -qu� valid�26,%Utwo* (!�aii/�!� �eP betw� �A� ���l��da�T� s 1!S15m�%�erN@i�h- lv^�іpr"� ii � �,(��)� �%�ic � !CGI� {)=�m6Iat exac�F���i4in�9h ^�!on� cep�I"IS102 f�b�N)Ibufpan!$to 13 copi��-wh�� Y6�(disrupted nQ MO�"� a fimb�operon� d, eachYP!)intac� �()� )�Con� aE�$�n2hi<co�p y6Oa� firs�a 932 bpU�պha�ul�itrunc� @of ROD_15301 enco�A aoth� �roteiausecond%� 4396w�a s ��8wyAZs 4825i 6!'A� � 4�r-�(,42:7:of un!f��*� Azq�r��toI���LIt& !�fla�by ��6%vir��repeat%ppv!�. Altho3 &R shor�a����s �  �ca^ %e���du�av-~t� ��)�i]m�ed �!��*��ntP � ���a:� .�Oim3pdes evid�!L continued5�al%�s�5v:G% ��� architect�B/rZ� 8intra-replichor�a��c� pprox(ly 0 . 5 Mb�!ds�m�,ult!� switch GC devi)k( Fig�A�# u\ PCRAj� i!es( � r�����-�[I�.6c z!}re usu� ��s���� E���r% �!�#a [21]�can��J�52�plotsM*�m both&� K-12|>�� $um LT2 [22 [23]>7.� , it�I_t�2O c�3is�whilst:U-�sha!,a+�a�in1�syntenyi"�a��.�m�(chromosomal9��]r6U-`Ml��A`�1\Us spann_ X�^����ia�t�to3 ^�� Sas[=�:�InmFs o��A��� o]rmar ��i��*ad ec��in�&a� hom� u re.�� rRNA����y� such>}� �ly�"� inj �Q=��[24�"'un�in..�9^�s did no�l�!<%"f =!as� BY� %bly.�.�:���.�q)beE, d��g�S��.*+��8 i�aA prise 66%A�113.� � di��ng veE �'�!�or ISCroTe  2] I�Nngly ,E�4 -rK� verA������� 6�7 GIsmL�mǍ_-���+e$ halfA9�!6;aDloc� �b� rathx� .�backbu C )T�z A�ia��distrib��2�s.� �b.*� O157 �� TQ x, take�.Rq�&�%8�6� s.�!$>�.�:j� hor� gene�Oli�ng%�incorpor�(of nove�d !�to/6�M��cst�e i$>Kr�}H idy PFGE� file�#r:�H Q`A�&�e�%� &"�1��Bl is�$in our lab!2or�Qp3e�Ep �^vea�~M�exhibia~a �a��n�*9a��9-474 335�62�� 072/96 &F..�i�ir �r-x,��$a8�mirWA�ai� pin< 1l2� ‘w` s’R� )�Ig)�wo!�_�n>�5, �9-J . By mapp�fpai�endIi� zYm ��fer , wild-�Qs-,E���Rpos�!s� l�1�s�! o"Y)� wrbA�nti�3� e�o��DMT�!FY s��)_� �� se��RighA�fa2�s} ��d I%�%R��s 3B–Szre1hse &.J `����Bs .��W !�oofut-�&�/�s: i )�4� 3B ) ; i�vEi)�j Tu9 ;e�i>!� T3SSqor NleD! adja���pos�1A 3D��I>�#"M� AlA U4-5,#9$ V� cac�e� A�2H caby�5�-VeM*E8!32��above�w3A�� A�t:� UQRf� ex� 7" i�R�we�X5�%��3: 6��U8U�}�̅l!U8primers NKP135-5TG S����coסl!BB)�E��,gu; �:� s 3A�…�*�Bic DNApaE a�cul�̀��p C d�^B�"� R r� �%, �$�‘fli��qX V.c;n�TI�� ��J[ Aɀta,. OurK A *col�'�6� �&%x�.�&22"� .���6� �B�����%"��f� ou,&�ten��h accessory�c�geE . A&�"D 9Z �YQ 7 a��veD( Bm may re�q phen.!� lteQ� cruc'�2g6#)�� u��� furq . Of.�+ noteE�!.9�CRP28 !�CRPr20L h��se�e� p�-Z[e clug""� ��h"�%�istinct�ga*r systemE�6�.�b)�%5toe)X%�|�8fa�nv�)�Flag-1B{��on NE)��&b�cea�#ereas�28J�7l�ce� lv-)A��i!3 �s�|�e coli� s��*�*(!��� �.�[2�&2t#�)M��by�.��1k � lfiH)w,)ke\ p�,v�-1�"� �-�AKi�,hG� lfiIjpr�$A fi� ( C-rCX!!"ex�,>��� ��=(�-r�-1� � &"� �, a�lfgF (�a�rod5) ���]&� �)ia carry�*-/�?ng!"m�$( stop codon�m�FO!� 3′ of fliC ,M�last sixO-�-b��%$1�u�A�#p�rM�p� m�a5G v#�ed C-"i=� mea�a�Xin�ill`���acrex,eZ�e6d2��#n �'��%���@}U�u�ai�6� srupA���!-1-Jar�9!�!7w)O,!x(� ) !� remoD/,flgD , E , F / , H �IA�b!�%}gCflgJ �0aqu��A�5 hook�,uM�f,w��l�/n*N="���)�Qf9Yregula~ pcha/e�lgN [3�&Ths mai�-S`s appea$1<�1� �/on ct�i. scop�"TEM ) st7(� 6��9C saw�0e*� basal bod���%eno2,�!cr superna� 3lys�((t A�� n� a_on2`D 7 orts3)hzre ��&cD' �i� 6��)!��gA��/m!�n&}1[31�!���m�(Aq� TLR5U ep!܍Oin�) ib&e re lac' �%36��"ge escap -�%AG!��n�. lammA[y��� e follo%(&1. Mhi� �%R�s1E&2a�"~ s"�* . No){e�"s%0Shi)=,.� Gallinaru)*Pullo[3��o H �&�3��5��v0play a key ro4environm�l surviv 2�:�4L'ɪ� 3��b� side��� .+�?ri�3. P"[$ CRP3-CRP99E CRP4av�`lso� to� ��6͓��3N� a�"Au>�!��� XA G ��m& a"08971iisa~di���e��$ �a�etix�G#a�AS.4;yK�5e I%#��bK ��g��*� $haemagglut�3/olysin-�� in Ralsto�5�n Ejm,)�!))� gatD.�gal�,tol-1-phosphsdehydr��A� I�is �7nt ��!� metabolis� R�V"8 [33�A�mG�te�w� D util�*�%.V%2X�"� \� 6�is un� 8row!D mini��um��%.�q��a�carbon�.R�Sipe�p�Ű�&Z)� in!� (re"�! "�9cl�9�N"�#�$�G drivA�!�de�� v� � j�B�D�4�6C7midqF�* ����-8M6���82�>V7� C8!�t�k� pCROD1-3 Aqp��RH"���!a� D" �sA(OD2 ( 39 kbeaS.4 h( 3 l�f`%� ll��!:�)stj , X�5 Y,Gg>a�(s t^3>�eh�g.��.��tA'i #sit:  band�:N'�-6 �� val!aF[�*@�kd)%h1q�qI"�: P �y%,greatl@duced&�{+, �!�iHE,�"�5=ma low6py�1Q~�o6F$�Rm� "z ���;��a�o��f9�at pop � is�^r�by  ��chB�EZ5�i�ly.�50&�p�. �(C�a0g� extr����c%  i�6%\dvidual?on]D���oneV/":�%@ath�4�6cy1 ��erhap]6rk"!�gi�>Ia|�M�� r}3��e. Pla��QyZ"�&8sJpo�2�F29�"�-t�"l auto� A��?F�,���%refAX��j=�>� "� -Eo# ongo% e:�r} �& new.g !^oW�4mun4�6�f�.we per7�6�'%cript��&�>�4.A�66$y RNA-seq (1I: 1!techn$t�/�"�!a�e@AʅZ.\*�-T��eP � �e�V&� 1521/1822\e�e�� "�"�9*ly ave��S3; 73r RPKM5-ead"( Per Kilob� per M�=on��1 �/ 8N2 Ve��/a�iC��U!�8, h����i�ain�So�W'3F#2L-N9Ga1DM4c�C �,E�!M�.#R6�.-,:A9.low�D of multip�@i�U�C6%ѱ) I� �s� e{<���w S�ş���avE�6�w>�g�J Q8-+�� yW( �55�W58��� CDS � @52/55 , ΦNP 65/6 � 8 36/4$��� 54/56��sn�!j( 21/2Al:�under� ndard # t�3CD�F�e y'*�$a �-�c��� "=� stru�.�� s-J� �%a3�lys� [34A [3_'.&-�U,2�nd&�y b,չ-�{ 5--1�)� ]O�|&C8m�A�"e!BBioin��a=>-> ]��"�06�i��gio= berr!�GCe�\ o��K>�7f�!SL4820‘cargo holdo%�K9&�)b9n.�%��� well-6~C�Ov �C s MuE�P2�& ���"��A0 |I s�(���/!�ly�r-)E� � 4c ""�damage-{D'EA;-toxic~ran"�#i�e�,q^:i�e^�{?�be� ���0C8�b:inIB HokA�.RS��)Wbe�ig� �proHsh� �FAdom12s-��g�1E�^5�6�2.N.&L$n�Eg!�r�w2�ef";�$ K [3�*Q����4 0913E2� ��-��v;d��n�55'� .���&� �Epm�:����)hӉ�aiIRo1%vel�k��ic�%&&+?�uA+�z~E:cap�of a�ts= exci�o,"�"/A�.(TBe�!+*gr�#��o�8�ng�� ward� ;-�Gm! ((LE- attR��#�a7k#Q:]#J w�$�A�mplQ#� 7,{�e";�a� ��cir�$5, bz�,�#@)i��Lrie�)).zub%}ob}5�ori XB����*8 �9Pak��&PL�'a�1����a �Nn%zO�"1$sized.� Z 2��� ���M<�%!K,lAk�-�4 preci�9r�.41" �5W2m)�� Y!!6R �49av %t-5�MupI^7,��nt8' �܉y�+�� )%Ya=J/+2 L��5���w�d!r��2e�"([3�E3�E� 9 68.�1�^'E�Y'��� !�Au.v,bD��*�/.Vt�o�y�icC��%.{illegi�KEE\ I"3Fw7 �0�M1K�-�it$ ckag��C=�tial9LB�J��8�G���ed 235A�!4�^rvJ��)���!� F 133Jse!�.alo=^"al *< B� 5p , 70"to��in�:32R5E*P ���IIat �x)�ly)[ang arj$!@�l�!jtak'd�,%�B�'i?RU0zE�%ic5' .�OD1FBY2�[u�fawO temp!�rhar,)���� &�n.�9�lM=Ld�!/*�z �.�,j�%p8 +is�.� �!Gydepth��w��pl$"�JM�iv M�izeQ�e�.�!�Q�&C4S�%�m>2�i%�e varI%�1h>to 3334s>��5c�:�'E� B�.���Z1N"�&�%�-jA��O?pq ,bp��M left hA�2 2� $r1%wh�)�x��S&#N�m Q�43L�!FU)8���� hoj=�&22=�I�i�24:P3%G_<�+Ie(F�!t2�)w-�-10!F!%317>@{+"&@E�o �X ledg��E�i*�AkGpA�!)�r"�s�;"�6Qva6��"$/�.iguae'#!/�po0S���1 dissesF� -�� vian?nc)� osE�.gniEsF% 5ir Q%&+!�0:�y!e� 6� � 0�5why�s�� e�to.0F�mso8�,ful%W� �L��g�,&5(. A�8i5M�!�r�"�G�R� �Q� �9po ly�`=!�Y��?�?6�O�>a4edY hA E 3 E�J so�do>�� Qm�a��(^&��!�-6�� �u?g,&�/ŵ�xa�O�.�%�0y �al���K�EBin un� vern��c"�f��6��RS `�(an icosahed  head�nml diam�!" 10%5 �N!�"0�le �H 115(�vi�06�D >�vi�Ds&1B   sz��U�xsB9�yaW�.�$ail fib|A��!�A_� �morph�w*,;,� }con��*�'WB�isI����O`V����4%c� e��J�avail�[N�:� �A�PP$monas sp .� .��S, S�t�( Pect�&um5"�Y7.ow.� @^5$nella sv .M ���"�V�"�#q��:�He�S��sus�'i��"�M V�r"�YB :� PlaqLEP"o3@#�E���U"8D��) #v+!JI igH#&(Z�D�^t�R�num �Ax6�A�r�"6�}��J L10�<(107 pfu/ml �tiM�on9��1&�CMG1655 �p.=turbid�An����  )62 e:�.0%8E�to"�se�1��a�قI8NR�[3�0P� �!&���Y��ag�2#12-" ER2507� make %We ��+�lwz2oF�� � � A��DseRM6"� "a&� ����.>y�Fu�3#",a�&��eo�F7 u*j-NPL��E$� � " g:�;�.�Kq� X� F���D� J�D��ssrA tm�E�F+'�A0oSst!g���-Ifpur�1�(%tJ3a�e ��/�' �6e�F�6�..0.ec7:�.8 9sQKeak �S A���-^5�#MG.�A�is.=(~.�5,-ed"uZO#KDf)E"�or� CaudoviraEB�1-Myidae [4|� @ _""� ��*EJ�%tho^[ �. NK#thelesQA=:� o��6�q{>pJ� can!�Ru��$�;Q -q<b&x* tt`EE�6p $ !52�Bf6�,9za�rle�1&ye� �FG!q�:i@.DvOa)v&Aap�8menoRnd�$��#��M.\-2D]"�*Jn ��ur��!&\�� � th� &/%�B� ��2snb��K�ay�EM�0B�C��� a��:�("� c�"B�Caw � 7�7U^!��&�DD as �8: % ;a�is� =bOD1�@w"4C NalR� � . Ea�R+&� �B�%1���Wa�e g>7a� B\*_�@H'groupW�!�\!b�| n�el�nof=�e|V74�2B�9l shedZ �Kfae!�OdW(z�monito�� � cour�l�Y;�i\W �?T 1H�c6�[�b �qex�/ eAt="�"!!�"��e " �J y-��EAZ!n���6D� �y day 15�5�"o TK%���)�1m96m &�%� st�71�x���im�W g. S'B|�cea&ll _s��7>�:0OnnV"~%EƁl-�利�E�no ob�_5�ABMPE�. f�59�uZ,�v3�Ng"C$ypt lengtheEas��g� H211 µm ( SD = 38)�240 7 ��6vG�.�j �7E[�� 96 ,a�K�BVsE�6���hf disc7��� � Q}�or��B, iAf�k�_!U͍���9nT���i�'�a"T ��.V*�hed- 9�"� x ��}at]A�s d)�i]a{!`�?%�ol�ocaecu�'�7H/-aEt��)!Rc�3\Y�L#in�&3�FGE��e aggpost- �1[P,!�pIa"�E�(�q*: e�xaf�� �R!��)T Kh��;B'^D!�i�.�( trua�*B)%D���ܑ���]�!}07a��?�K=�%/ ��! 6� � s 7ANB�:B�V �.M�:��z.�vzP>HAZ#f~w%&a��!&"6v� 1��b1Ia��1]4x Tda 5or subp&"0w�K|�K �'�Dw~veE�w existEj*B1�96%u)�AD  �)K�F*}") "3_(�k!<�#�Gar;m�mI���<Z>$ti�^ neut�|7a"$��A{!progres�ͩ��w� �&�,;U?�YveM�O  �=q96MK�Ku��M8�!:%�5!vivcb�]t��?%�ic""$A�K�0tn� advantag[�� pa��j"� p� i�p�+=��� � �80y�.y. -P1-E�!}I���fW�Fsu�!sm3!JE8by��m� nHj)�� o naEaU8D! u al-oAA routz a�2��-�� WAyn!�0js�$ � �&6 7:M.B Uw�d�De�Y� t  ΦCR���e�t$> lipo�Asac�*~a( LPSr( re:or [4�<a.q9)%pf� �-�"�*Zkt_<rm �G(9#M"a�ɰ6��'9�OUmF�� is� S)!�e0�V>�U�368 �a>J *ed%Ibi*�G�IJ� m t��-.Eg6�inq�a) l�$tr ZIA \F�aI]�$v1 Cɠwit��a6�6Ir1 plau�E~hnwWu,}!A�-%#�F�}&(*w.of9e9���$ rapid.Vs�gt.�4�3st���i�Ze3� -sl�@ CampyO3�t jejuni�rey7-sc�kea-.� ���� )�>�V7A�tion��enyj[6��7��20avian gut [43B.N0nDoJE�=!) �6in!CV-of Helic� !,ri [4�0\Staphylococcus aureus [4/l.E8aeruginosa [46]e�"�[47o50]� A�&�hyp�z!+�xD��l"~unic� &7��u!�in��*�A��l�3eQviP a]pdo��a"E ] 6�I�) qeic � yac"�k�s�Pu�F7��� & 96��,e pi�e>�� *: 6�ngE.�iB work��nee�to�.�N���'=�fm �2M ��geUf�aU!{6��a�"�U-F%�!spo!��� be�iDW6� :�B�a l"�O�&����O� �;�7,q/ eat-�@re*�QzUfA�Ž"�vp ��dA%&M]�;S�m G!!Le� � �4c) ��(&~�z��$�)�ppa�z�2��a_ �t�"e�wG!�%)����1�*�%_;:2^1e�n9�VXO?��fix��N���+�f!&�6v�:�@e(G��&� ���M/"��� �c:�cwo��eag��>Cm� "�(��B �md � A w2c+�eE,�~$ecade apar!�J�H�%��rf) roo"�2fB/l,N$!Xs4?9F�2� G!s2Q6�� 6tv!I�. O�H�3��� -c�>la�G��=qB6y9/bi 3#L@Q,�!a!"W bRI�=AL�,���RtI.O�\:�LE�� i�.so. ~c} 61u],�Ec.�x�r52:�� �E�4�Z�E 6�R'&�Q-b��u�&�<�| limi !1&�#�! 2�E!�atqC� m��um��� !���M&s nowV:�B1|9: flexH#� :�hav!"6 �tchq~d�[51�fdI= � ���� aI%��La2wa.��b=E�m�&�x�*&:G@��a�ly"K�+��") �� V)�Je�ɨso1n���]A >t��%L}� ��jsmi��& Uѡ%9n-anti d��%q�X3,�+� � JtA&t��7&�0�B�&` 0��uma y�%�� e>�a  (mgy�� te�Jb{�uEB{AF1�(F+)c�crP�+�n&5�- i� to.�c5a�R� ~*��0��2��1�K;g@zm�F��u[ emer�2� C&1"e! �� a��tsC&!�.:�#���6��0���]����ɖ���TJc�M!Y1�)�%��%��d�uopm�8M>�5%mu}�K�5e-�cap�  bree�� mM�'� "�8cer8�,A^Q/4al%/���. A)�/&��? proj�8lic� ��80/2099�rYS��e UK H�*Off���6�$h �iuccordI�91 UK A�(�wtA'�Ncedure^'Act 198^d� WellcrTr�tS��r&�w's Eth� 8Review CommitteJ �!xZv arch�t�)&\e)1E�>K�" a�i rW(wn at 37°C� Luria–B!�n#~ LB )�L.<solid,V5% agar%�ad�?��� soft,n��( top 3)FM1 B�#!��u. W2rJ�, n�uii>acid (�  )2 wto�to !GAQ&,�P of 53gs)�*.�(bu�Scompok�DL0 mM Tris/HCl pH 7 .�@  MgSO�@!kb01%0K�H��e;"��r�.�=��glqlj*�AI>7oq5?" 9-33�BS ��Q"�769H ll cip5Aks"�sto�S Cz;�*�.���/oz�3( �d��[#O��e�6�I�� A& � h�e/RX� GS FLX�ze+ww�#-� !Titan� �� stry �a�47 `1�4 libr�} prep�g� ��� manu��urer's��˂AQ��A BKy�- _ I��.��eu�"45�Newbl�b3]yCa3 of�>e Rel�9�+@�z(27 scaffoldpfbN50�(of 39676�4(��KZ > (6�=12%[867%�ig6aAig 7of AJ8116].$4f 345"Y0%s�z)�.of 24M64&�9�xi� !�9O5IF�hA"��tot�U4g 43 , 628 , 54w�i�}Ca!�or�al 8-!E c��ag_b� !�a�21�dQ�"nJ GA I�BalE�. ATF%Q�PmZwA� a 2016M��4�|n�5 8�q"MSDarkQ�H[5UE�Z�l*|U>Y�Velvet�)�Q�i�opt4SU�2F�ja kmer�Ap�PI�@ei!�761!�~N���{bp]�.N3%�);) �!�75e1aq�!4P Ac�J�F���C� �a�tw"�:K platr-H� v�N454 {!�}ensus M shre�hU(5d) ��  D�R:�S�;,> n ��!�82iR�%�( 294�>;�q.�, MA729-�2��234b)�y�5!�25�$007!�r�10B�C��� ��5/2,i�n �%� t& �� , 998�%%���.!�Ff, 2�J37e��%����31A�4I{iY�cV�- �U!5� 454-F%��-A"� A�X"��"�e5�(�� a s FN54350�T"Ne=H �>p6S)# 0�k�#,,5�/,AaaAF3119^S9) )�~ ABACAS [5G-ae�-��fer�5reB�mI�ions/de�_�1-h�%4xf* by%�w 3 < )8 ar�IQ 1jJ�EO�Zui�BLASTN� visuvA =Artemis7 {Tool [5tjD�f� 2IC ��p��ε��h�fragm%7 �by ��I���&:~Y�6<v %x2�*&�J([5j56��#��0�M"�\-��/� \L� PV4-}�*ast 5F!$)�,%hx<� 1X Obn�� t 75"�V E��#��s3-���1m��N�!MeicK.&I�$ Ax��*J4T�-�6Q9�1OM�8Maq ( http://so�fo6�. net/�s/maq/` misd!;w��!x! ��i BamVU[6�3�6mbA�Du��a�^� 8� CHEF[�:Plug Ki�o Bio-Rad L�Z , HeZJi!CA ����@�W-�juspen�|(VY�?kQk$�xp�:l d>tyA!�bsorb�6= ( OD )��a 3–4 . R�ii�di.%",�!30 UB XbaI}ew Eng�BioLabJ "M �=*X%c!�soaVCin(5× TBE�15F)A4�pri�PoC�dp�� @.%�:eresolC@in 1% SeaKem GoldhY( FMC�� / Rock�, Mof��)D�5 x�-�at 10�,M aIDR-III�n�run�Hat-[in�^ramE�Ho�2–68 ~ puls{͇ 20°a�/fun7 !� 25 �Ea��,volc( of 6 V/c�A�r=�"@%���SS�g:|&7ahethidB brom�&s�� .�N�"��*����9-����!�m-� �py!�{C�mb�Ky��1.��>+��� 170�Wta�] , 1355�� � 633 � ��2T987��&)\ ��*1!�bpv� 9:�  � )^� �� ?71�� 68"� !5N� 37� 576���1uS11`( 4�� , 3081�u�3�Zu�09BH �ܡ:�2Bu� %H^ 7�uruQ 599u153�v4A�45Q . S9�1oEalT%��%�F� iYu �4a�s�� "�0@t�2�al��ohQ�� c� a�K %��� DuniquN)�maximum �r�F"R6$ reak�n5� byk � B�a�s�+ $k}�~*�sV�eFEr match� x1�u��)�D!�&8 r _:!%*��puvp6of�B�9-^%0tp-c-�J|.� ��FS2/ a"ku:�ZS3<d��/ �X-[ ��I�&� ~�M �D@r~I�to �C�{�h�#i"  �9�L/�N�H*��1.6 ��s�'1∶50�O 50 m(%.ng��ztgQM9 salfg uppl�&QFe0�|luc�or"�h�c2�g� �mE incubi "elagiA^�5t�rpZ�OD���me�7)Iery 60�� 7 �a�*oA� �G(Jrmo.]�96J�&AfX�  ��s�2$AQ�C!JKad�*Liu [6�GY�2�*&�9AP��ul�-��cI��Q�cz11jz1f5T-(Mi!g.k �c bQ��6%�Q�d jN� t&�a v�2�Y[62- RemoMmo'" ��RNA<pl� �E"�s=2 Lcac�AHA19v�W9G=)��!"25-132�M Le �T8aR�5la�6;housekeey :�2dE&(+val"�G calcofi�7b( �areV)&a�*�_Av!J�,�y�o\X"�9�+c1~�L�oEex ZE�"�X(!{&� )t.MC%�o>�KA6X�Ix;���K!"S�2���Z�Z=�-/( W�Z R�Ju\99NPoutk� ��](3<4<49�Za��Y)�y0=20R��� %J� rolA0[N3S�*n""("�,e{gZ��"ea} �&gel&fF!��$�"�Hto SmaI cut pUC19 v�Kr 8MegaX DH10B T1R�-*e�� ( In�Cs�) ��!�a�7E�"�ަ���"� Pon Xgal/IPTG ( blue/w � scr�2�ZL�� =_�1N.for�\u�2&�\. S 7� " 3ni"�(a9�6^��&� :`/!��0Q�E�1%4!&J�F� . C� FO gram�N� E"��H�V��$DNAs8[63�E�G%I�2I-�K!�"�#*�K NIu8L�#h chloroA-t�l�T&nvڬ� �M�HAc�1!OI�onr�,!#�_:MK�(�e)3�Iby'8�ren!�, :�F�a2r)|� BamHI�gSliI�� edm�S)� Ke� qh D"�mm�5�DH5αm�&! >��u�&QF�,-��tPme�u��C �_[g>�KEI��K��"�2pvZ Ld� [64]!�a9E�JVLi+"�'$��NPL�.::�.ne�!'2 NPR2� i��"9 ��1AF�9.k6&�e}MGPOm8 ( A�;on� U0009�E��. TA�;P&:�K(wT�p355z��Ii&��5� &*�0OFem58,6–8 weeks �C57BL/6)*purchIE� Char�R�� ( MarLO�nS� Kingu3j��Q�M %�&(,2z`Js*%CE@l �S^s&�M&{&c�B�/�!�AG"�R-�)&� 2'&O!$ly HEPA fi�~c3�K�UA=A!f*�h�a� #iXfoo��wa��>b)ino �"1&h! `�*&"V�0�LB� }Na�CGц harvi2bentrifͮ�aUc � 10% ul'PBYxGJ�Ig� �!� f%`�>l�:�.i�a gava� eedl(+��µ�a���z��i�vY\cou_G/5Ne^a�� etroA���e�on!5�*p)" 2AAt�ni0p�Hsc>&1,~?1hased��l�O$t%�g +K*!Ra5se�6ilu,in!��&LB �F�ll 'n&�&} U4+�)m�, 1�cF�I!W'%�sac.Q� �etd$~�.� �iDK! ic tissue D�6in 4%A8mal z�O �ffin "k,�z:��!��h�z toxy�o�eos��A� hist�W�sf3i�6�@�+� �F�wA F�80�m�cd�x��6p0o.�L�yy �J-m)��l�A�to!�l^e�.�.9�8u7a!KEh6B[6�mA n+�fMaCf� iAM��v�6ae�(s;!Q#"�a�.!�86>.;� �>o&�cMA�iP���,�e( a�ep�B�P�*E�E4��=> �M,#c1���GB�� agߗ(:m� =0! ar�quntil�80e;H0gr ^�C%�6�C%�� �8�An6� a�!j �1�C�D) I�2w ��Dr�]�-!T"�A�%�i" �@>�de�;5�e SY�� A-Kve)S�*�ERS00510�0JedpJ^&< �%tgsO7 \e �web� Wv+1&(!www . sK1$. ac . uk/ A!,s/downloads/р=!)b-U�*6& �>ޣp!� �"�8sub�1d�DEMBL/GenBank/DDBJ *ba.Bw��%)=aFR715298 �!� �=�orEbT;�c�O��)�s)�475� %� 4750V&� I���76� c�U�B��<sat ArraysM�B"HE-MTAB-502 .��Sto� (rfluctuG �� "��!d�y �l!�Ì�~�'!�"%e��{|� *�D���a 5��g I5".45s??��!�>1ha��"s#2�*�D�C$a rob'4,�Hi��K=assump�-� 4ach�"��P=!�molw� r me/:��uu�tli6e�pe��6.�#��  3� etho_}sseEf�< �'a��7g�sn)*� !*� %��'�E@!�,IPD3%LA�RNhM��d @��j�Sas�#whe]!5�E�m)*�&x�M�es�.�O�9)"�8�=�6Ul?b �c%�9li�<9�Au�`059w���2�^F aly%s��sE�f��;m�B)��.� , (mOi�E-) 2B�let��7äRs؉fJ�.�)p8�]�algorithЏWe�+a;g�A=N!m]X%u��N�!LUsQ�n�Jin]C;[AV?bWo2���'n"ܱ&3H.��2�i..�O�l�cn|a�-�+I%2EsBalway����o�`derI�u�>�>�k!�inguish"�Vz�r�>2�al bur��g� s)|3ref !b!'31v.�!Y&) _��M agre� �curD&���IH�&�%v1 mV6b'�w� dp@aSُso� i �aa$+* �S�. �e�&:mmmny2��d� �&�U&�f��Zea�6(�@:��G91 +�x �e i[-�!J&/���:d* frame�Gd�"oa�%gw=�t power�tt.�dP�A !� 6sa��Z�o"�&�'p2�. &�Y2��3�E�� :3N �][NA}J�q� [5fA1�O�Gp"�I �z���.Zman0�b�L6<�p.ds.���B-�/7a�r��ditC��/!p�"K{� bA�!�&���%�2�o-@0/o��7mmE.dHz|B�� Lear WrH�� ˶E�Ƌ'0 VM���R?���?�a�k@�� aQ�tou!� -to-� �>� O�B?y��T�a>Z planZ��� �si���is2W�,i�L�kn�<��afit�)%a?-�!�V.�A i�rOK��6i����!xsh%�ask5"�2��b��`Rin���"A =59aeb.��fre�Fe��6� �' f�cyt�"ryaF�c<� , [1ef[aT8��*Ƒ�� �[�19e��������XRq%eH2#)�ͣs6Eq s�.�:01��ASU[2=5��O9d�7a=KMNJ��\ .E�[Jp@�.�u< �2vK tka;� / ogma6J5%�-P0 -�eele�"5I�fZ��w%ybyL�{e:>( CDRC/L �cy� ON (OF`�)�j�� �x" �a0`L��t )������of� A�A�.# yQ1�. W�a�zse�J �{>� ) depi*��Z%�' Q9di DG�w spie*� ۮ�FIAga�.0��J�[a8!�4i�3 Tasko ,Jn�C&?>� ��6g,E�n��!�"� *K"Z"� wo2e=esTIdK�%W!cN&5--3�\�c6)6��l�0DRLIjbi�x��=a�.���d2QA�*$ � v�6�hj�@�Wev�n� zact�Va�7�)T�E= o��׽u�+a���A:&e ���))Hw �*K�]�documen� inefIc�sP5t]����p� stly�pIs�–��r���,���u�(4 ���� ��Q�6�.��.*. f^,ge�U� eds 120001sR�� [|�*a @�:��M )PlyA��1 !�� �.�� fun�ad*A�� �Nn�� yiel�� eleg�MqRs;]=(� N�&>�!r�7inv4�bge�ui�[ g*���_ hems�?sJ|-su�R�z mY�probl����Z1� �\pe�2 � N� 5 ��Z[�ɪ38Etaj݃���8i4w�-1��1�WighStnAg��rR e�.0�8�dA�tbagnitu��as�t�im.: ��n� ō^e�apply �!�s d�- M��$ T[%�%M�ON-�C��?!�X�, �M�`a�l�2� 1�G, �o.p funda�bd�"G E�pplicm �s&F�,a�;g�Nu�< ly u��b9eNu�Y� X5�.� may+adequa�7 �� m+��unsky ,C�8 iA *��uIspa��I mean�!!Ut:. � &�� 3}�,�e���steadyM`N��1L &�+mme�;�*l�sur�/� .��*�� U,�iS�� In�' , StumpfwStark d.�X%8�N&s�!;2jx2!�He18 �6���a<e��h1 �]x'~0��U 6B �c-� hi�@,p E�� �Any�% ���%�)%Ii&� .�s m�_�!K��� ]�ZV� V � a%�"�2a . Giw@ OԹXn�n �_=R�!�Ześ��5v��. M*�.���B&C��n& _NP<�{��N� ��z!�enVG@�m�fit6Rg %V�we,!eVB�W<M|�6iprincip:T�@=JW��L��`Ѫ!�t+%6as: %,�i�%!�����&0 yexhausr$��&@%�retur�=�A^� $ma/�2�c�)Zm�SaP�5 � ��its� j"2�'�6�j$��'L]���2rh�V�ga��  L�.�`~!�:� ��q�: ���1vb�.TF�&beAWor o2(�A��alb�y3� ��%"�����t%i%b�"�l�U� BN!��  d�lyqFried��J�� �%� !:� q�(*� byKnoes�*��a�4 S �� f/9d"� � Y{T�� e� su �AMv0�TI-E�-߁��(�-�^r �t��ad$h���koU!e��5V�"�b��ow.�42P 7YWyX"�f� r`5&H �Ul=�M� "Xsl@- � of}$s?�fO quIX����Ib�keQM`!�XA�!�Kg ,� �o�ke�B�C�U�o�L ]�i&�9(!F7 C*��ed �YE5p��9���� pŴ�se{M�)T,11n�$���df�!*�wAvqV��We�-�xD�F=&�!R43�)!s �E4�e"31E7��)��(����6{~[6"&���ng2j-!nti���c��.?��xx�d"�)X"�"m�� v ( CM:� , Eq�& J6�!�� we s/G"�7i6twoO� )�[!�A�J ��Al��e��bJ%4�ZE�)�� a��I�GT�f��K]a  j-�rWEG^"�>` RN>jEza�9omo!�X chal�Cesto 0�!8�9"�yeI-"N:��_�4olva�!���녯H"�o�. iscu�=b��,ertX�&��pro�#3!#ns��nj��s;*9%g2���r&EEo"> S 9�w!�n?a hybrIkiI�tak�6��q=� a�Bs%e�e�)�N�W� A+X&q�od� B� blisJr��!Ghip" ��iFK a�� ,\` �Y�Y�1 �P" 14�-Qvm�A�be|esu� 6piT) �Df�NH ���@Lk�t� Y�e�&#)\]��� thir skew�q)�Q&t�kurto�J)6,"�1p�9B!�d�sU �)��Y��1�٥QM�!h��)ado��U�(of Sánchez3Kondev��waY--th ��.� u��by•T(r"�a}2! sum` ,)6�M$�F!��R�ont��&�� ��% 1�&v�����ly�$�/�� &A ^.���:8 i�w�&! H)�/8�"lz-"coE�t�w�Vsum�O#6�!p�0!&�jQ��!U �i� kn�؉�R$ 6�6F.Z(&�6��W28 �LODE�Z�p �ͅw �V1E�@ �3şto zer�d���) -�=� �V�. AE��)jo�W i�%�e S"VEa?he�i�Z�L% � ��(I�P�nd�� S6+9�'�(�� �>k�u��.���uln4�TEf��%�V�� ����C!�-n|MATLAB� 012-��MathWork�N����MA��$C++ ( DataX@U2 hecF,(+9$IB}W6Tge6�Td�9��"V���xA��3Mbe� �E1� V�%�� � "ML���"� &-|�n%� convOeI [X XA��|43�Ofe* | .���mqs��- ���]��#R�A�1-�4]*E~��arEZJ =�=ng}�p�i�XVuŘ"H .Au � l#"!V� NX!�h V� AH� lem;#u*c�&s.� !��fLF p  =�!e!�6 A�V��ng3��cWe,�%#2e���G�< ʂrL-���H eno�(.V� ��)�[+ . Corro�g�%�w �,��}Br� =�u�)�ha-�Iŝ�.y�����CT�*U����nut �}�. ��"F-"�� �Xe �� Awq�^s�w}3flQr vy� �he8)�`��v��t*���.�!يe$3�$�& s.��0CgachU?�o*��J6$-six-dime�<*�`$���-B phys&>��?ɝ4Uf�%� draw�>om�Bl9�@-%��;[� �AeA�sia\.�syn�4�.'�mP� 9�)48�JF�a�fe�~W�Y��7&49]!e`po�xs� JG!<�}� ���O brut�r.�i 3�* g�h�cyJ �-ragA��a�ˡ]*G$) mm �s������! ���6]�cho#;x !�a�E4%��ly�*%pyet�*be-as�O:�I.&�rA�!TKixΜnd�6��k�c���sfu@m!&�+waP� r�/�yc�,ex'our Oea�jb:6umm��k�i��m��W�<*B.�A"]ly�a�N ed E&�S ~( ACES )UA8 a"t��\� �xI�(pU'4 �?U M7 �Fj<�.2W Wu'so��� A5�E}aX�4inJx �-5A�Q�� Ifi�ac" 83 gu P"Z0!ʅ�E�A)�m:\��P327 bill���ld�5�V)A^�P�� G� atisN�e6a�[�err�$ oler\."scagKof.�<1%�o�w��ј`d�M���r.��d�"� �-��N ��al)/execu���'~*lye[min���Z�<l /of!�. T$ ng#P�q_o��i� i�}3 1�beO �� 1�OL!� � obo&� ��_,  )!:c� 8stYTa&�OFM{ (Ż%�}-�Y�J@(&|)��A���u� �x%^�)u��w._`f�'e#ui�p8�!2A�� B�,�!l_?y�q�����&an1J����l�tu mLa�u�st%>J j�1�+ev�aaKAm�7  '`y �gA�/!i)��#N q��"m9QuZ�s@�itb:a� now-2�2� Q� �a�� �� 2 e�� ��x-E&�} �!������,d� J� �V-def�'bIn 8e�.����� !�D XSJ�nO ��� kم�q ��u%"the�2Ru*�G+&� X Du+���5�is_��/^ic�-�Ev� V p1$%{�“.)”<�W<�-gҁ� annep!�:mru)&a/4�r=�ve Vboq-]B��Ś�Yx%l�'v6d�v] ��:ed|�-�� àe!i�?og ~7AbJ� � �%�"�L�|)�inia�܁ � � ��>Ko5�d �6ma�oM�-)W�g�Gc� �#Zas"�{m��Q� �DQ�t�,17f�eDan�H, W/,��� 8053lh �l ,Ve#l�.>98x;S�� omyc�&� g�0[r07 sses"w v ��r��s%F"� !�F��m�ed >�a&ԕ%��Y3Q'A�%��Sy Y� ua#�E�@Q+.� �K!�&� *� �ng'3� T��ur �ك� nputW � t!�B � �15 a I��A�:m�AZ%mJ&& �.r�1� }by ��)z� � �^�-z�� � 婁�� � )M|&�3��P(�I%������0;ub�"6!'6P� %T9n. A�B� ())E)��!{t1H. �Υs83� l/EE+F� 0� 75ϹfI�Q�m#L�A�� �NDa�1%_� � �)b�/OO-�&�498%���!V=/�27" �p�a�[�48-��cI��a2� 3� �4�fa��eYM��Qr'tH/ly�4istant to incr�meases in resolution , however , simply reversing the order in which ACES tests parameters allowed us to find s bs for!< of these remaina@input sets at low.�<( See Supplement�ec��S3 . 2 ) . We find multiple candidate s2��yr0 . The number�1ds linked to any given CDRC�� varied widely , with some produc�dozens6U , and oth!0generat,t * thousands �median�out%-2�a �5H$ was 29286��is seem� ke a larg�(, but when cin!�< context that ea1�run tEhundred�!ldegE�cy we ob�edanpee.Kis)7(e�f�2�mo� ��adequatydescribesshape�protein2@a_ We sought�]4inguish betweeE�se YIilitie;One way9reduc rcomplexMO!o-space�o�eri�(ally measur�!n�4 �underlia��{N� . I�%ta�Ii!, silico stud�� p)�� correspo�mtof��on��q"�aE�AseA WeI�zao0he performanc%xJ�N �#M��e RNA ��egrade�A�eE�i�, se�@%�Yogei�ho!�heAg:Abecau yeX'easiest%E�)�(.�$[11] , [4853acWa� -rane(8053 librar�E��s�5Q,� bothBG(As before ,)4retur�{6��Ai�e�EA� 9typ��l�:C�J �or��,of a few secEra%P8than 1–3 minu!�atE�ar��&4a Know���0 priori improa�A ' fi�H{��A��3��-�. W�|no were know�. 8/6 A42 . 55/8��T-mper'=& on a�LLge ( column MSVK , T֡� ~�:I�$, 1 . 78/5P �r98Jwbd��.Z ����l80Fl9l6�XConstrF !p�� us9�estimiWazwoa�three� �o 1R. BA�F� indi�im�]�x5�:iha+� un%�a��@6.E��modest[ hi��6�he syn!Gis�!�)D most54wJ�)4ae�eni�>��\sta�i�hA�,2�a dra!cc���C A�E� I�.�1�sQ�6�� p&9 �G �E�es) i�Salways��E�. OY�a3 21/4�I�5 . 6N�� i( ��I%�yABm��dependa( ) ��$significan!�5�by��vid�>��orZ�, �m4I�u�b��lo� fur��in� te�61 . O�ll��ur�� ults� Qex2�determ� �p grea� AhF�>�� :_�sd!R�Higher"�U a��sh!9in�p�  abou�e&��� obab�y�� � . To�,e if skewnesIkurtoaZv5e�3a.��+ �Khew.��}$exact same.4a�� s as�ve&� firs��we�if{ ����3o�� mean%��� �qh MV2cA\dA3.� f U |�.v NS2O�foundIT��fi)��,�Ѡ� . 222�. 27/8))myi�xt AFeI � � �ry���,.}A�5� , it&���. 6.8Ů���ach9�Af� `YPd approx���D . 42 addiA�al�I�l59l,�leY�addRA� ��z . 1)> R. 66P9>%�concluda�at�!*u_ly2}(!ip��!�e0 procaa, eff��v�quadrupla�8a]asu����!�Q�cr� n�6:1+��@by just] t-fold��' @a major challengeqfield� identify� cis-%trans-�(ng machiner� c �A#v laA�2 crip-�burst�we as|wh� ��method *� e9 � !,!= dem te V���,�@doš. F�]si� ur��A� ainsw "Onregim� �ttemp�o9w+"� s exhibitV��. S� A�1how well%n%#]\iI!c{byi�I1;cer� �l mm or lA�ameIto�su$A� m size)<�PB�e�,e Fano factoE�@� !��A�v( )i=��titutiAFve s6%��!'gen>� [4� 26� T�iA� �e lim� �ifE�f� highJ �.�'s�+��ac��̭J��.go�1+ c�.�%)%| e plot����� �x�E� near��PMD!���is>y��-drops�$cipitouslyABn,sligh���e`% ( FigA�8A� Ac gesf hm{]�t��slowl���es� i !��g�Pins� intostrn �!/A�r%�=3��^�itself�B�W"�)lF� E��� � � F� 7eh untiA�?g� ptimum�8�K3 to 6uoa!e�$f molecule�AbI j, �a%etmakA�J��0l@ ff,/as�XV' data6P Re[.�6���2 !�"T�"AW�f�4s�ON��folby long io��2 quiesce��8� ) ��F��k.inferi3s�Ʌ��.@ . H"Yensem�ofb���se situ� a�ov!�o� "� $ Ploeinq�9��o forti� .���mbers'-&� histogramAGW�e�.\� % %W!�J;( 305U<07 , 234–237 )ͬ�U vary�)��e�0s ( 637–645 Ill���8 )�)� al a Qep conf� to , sistAOw��ehavi��genl��9�"3 a����eS 2�<s�}th�� ��/%Q�fer���of���s� Ydconvechanist�R4n%o�. A*P B�s mapZ�to��F' �[17�2 5 a 38]–[40��y8 Friedma Cai�w$Xie's work]�A2%~Ucou�!bgamma-u� ed [�ha1en co-o� � solv M �o�blem: u�EJ� �toi%�U�s [42 �4�T)�e��ow#ddirecAcompute�Ea �2v'�ed�( M )4"`( VY�mpa,'�!A�e`M �M��� � ai eel assu�b 5��l*_ we scree�.e !la.) wh�,"�2� >1000nd уreR ��!�a ��u �at G ,i�= can 3�ntinu�"�!��6�u 3 )keDis�� . 25 ��� 4% )!`.satis^ (se criteria$ �am��!~> !�&��!e spec�.c. � 6no2Tp"�-�*%sa'�-K�Qormrtas� a�Gny���� N"� Toea����9�!�ach�l foo�) ��J� i%L:tY$: k=�p �ofHaccur�,w l Ei\;!�: clusc ��tru&!�Xla.  error�2�&� A)�s�' "�q�o~ � �& 11A ,  :E[& � r6��2 V,E024 ,{ �a; �of . 076[A�5) Eor� #Ab=hr/��> �Z also+e�!�}� ,��4�|2���"� 10!." ��uy :� commE�Ud}[beA�!��EWexercia�er� A�troA�r�5,:equival� ��d /�:�5'��qa�m��7edb���A� ' utyeri�%I!]I!�a�pa"� Bi.t ��ž���*id\^� �O yK=9. E� �c��Wm� $ly enricheH"sucful���3 5�M�!� . Of>3 , 222 hav MD< . 7�B� =sh�)&�6 n . 33���#-p"ll  MD��of �2jO� 29.O�m��s ��M|��a� > �,�Y them]� e bimodalH!in.� of2�,pAL� YoutaQ]=\���}e>S a�Z/"�5EA���* eaq9&� !AU>�% �'OM� #�$ly vio.6<Yk�X�point"AK�!������of�ext%s�2"be�_ eporK� . readily;��s>I&��ofM��&�!$�9%� reI?99��h�"��Q��g\$t��T(exa�#r �S11C , D/ I�s���346.��}� �jm�!qm( 2�)w�vE͡]G2^ iF�55A[ ( magentau'ang�_revea]a�'7A�'u- "�"��%�ct answeatqj!�tm�in8i,�.O*� �empha�%�l�JO!ne�?k#��Lsu�i�kfi�V��-�� re�%at% opeI� robuv �?-�KM� P�&��.�cq!"���clo� popu� ))of�(orter-g\bea�cells �$5�yetH lack au i��ut*� rame!ab""ct!W ar mms �.��?pa�Hi��d an�i)p,��-fM""� �Jv uNj}T�$!� fullR�-�RH�s elus( ŏ%3toA�ve%$n �Vz.s'��&,C% , exte�"*%�stopp!<5,m[�9�10 3  �, �  145D�,&i�rB�"{��"�a��ed:� qIpr�;�e�)w��m�my"z9trar$1{ y�,2z$�x��",� ��!���*�r�A*1���d�-�`aHletA�J�,��!mwo� ca� cenario)v�*er����3-^^2�N ��� S2–S6Ň ig/�+U xcie��&�c�E�� anyt+"�0'si��t chem-( marE+��ɠa�1)5 -mat�gy�/enAA�i0 �%inelega��er�"-c in%?s!7r�!*s%e�Zapt'+.��%, � �couldX ow inv;gatore rule���vas8jorg Z�,9�;!<usA A&�n�ten�dGillespi�m��to2�a-�&� @�>-��F.ɢ,ealg�hm�� link�I�)���) Pe�' enou�-*�� Y�>��!"�**��build3fa��,+��weAlc.��r|s agr�a) A^^X/�!ch/A�a a&���, ��!fYN���#e'? &�al#/���A F�������,}y ��)��G.d*u, �1�frequeT' dent%H�-�ede"nt�.5 chMd!�* leve,'! � m���!�~ AzB�� ALowe�!�6  8�FA�� ���"! 0AA�j,.��dcan!Gb�� � g���.nars� �� F(��%�4%aW" ")��.7 ��Ѱ,"s k=im�  �% �ar&un�96� �z0N��BOpe%X�.�'E}e whol!b�.�*se0laK# in ei41�recapit���0cT_�QI�%A2HS'�64e�'"$f��Z�E�I� wordA�)�eK�O�O2>d�!A0�" 3valid� � �ca� a�3i4 outc�1�Zopf e�!F�%�(,(dard ON-OFF \Q'���&�& ���tal*! 2����fai+ �sub&T :3a!�iW  cycle z e [2:4@�j!id!tit+L 6 inued re7%b�tocha_� �J ױ�E+ bene�%Ia�� �G-z(�sH5E�^ 6,%&#Q= na:of�-#cx"!�+�{�. �u�3U� h._^�Jry� mj��&� a unique� b�a�Sometim�z *�en�as� �� t���'�1% �g:i %� ft�4 r69�|&(a2�7��s�4.��� � ��J�/>|6Ks-��6&#��)�) �� ѱ�a2_27��'g�7!�E !�*�6ari�$E�un#tE`�(ev7`u�� �o�A�!�a�w�"9,�s� =�>'s� �s"#e��"� � _ ).+0e)� E �b�)�a�;�� � �1c�6��"s ?)�E�E9m6� { &�"3")�%2� )�al ( A�nee,to" !913�����r~)E?� ��m<)�]edI !;2kt+'%�a�F#%B� b�Y< � !j� "!��X&��*u � pair a���<�!�9A�5�. I�is�9)D�s��!�e* 19^=��,Qej;�[i<s a noK -95�T*an% cl���&dela !"so-�8 ,hermodynamic�Q.y,regy�[55a!57A� c!�ErNE�� on fun< !�t �;_ "q&i��<cxpromo��;s�&� wis�\ oEgo� m�Km�!�a)��xp�]J3%�earchA( physiolog�dom�)ofwU1�"mi�&*$|� �. IZ ��, b�Oa8 : it��ņonJ� Ip�3t m- @.wJ)d�+%Dit!���N� aC conjQf����z�#!:zsI :<�#kE�AH��TIn~5lof�P�� ,F�!Ex���+��5�> 7sT �w"�*9� �aM acro�bo (2k9"D>w��5�.D%�wo ���| &accepts�r-d� ��쁈c�@� :��!���f�3� � !eFo��e�6�may��.?<{1a�he 95%A&) terv�>;a�=Q.�9}:%�.?�= Hir!��7repla"s6eEl2di-�Si� ly`�>!A2�i� A�7 @Ec�/ada�!��J*G3 ". AC)5�C ad�2�' toler<!8� [�W is f�?͋mea�!��� manif�Aas%� �s� ne(�)_�A ;�.ZdMf�d�dr spurB�)rg�u. M����perhap��塮s)Xai .�in�selE4oi 6�s7�� cate=es:�BCES&J a� :Ea# �A 2i0@ F =2�.�EMmF��1(3'Y narr)d�=�� Hl�9�1!�A*s�ussed]va�Aq6�c$r%�  t�� lea�FQ �=�C�z �s po),� i�juregar�w�2�In K,�:M� �Y�w'A&Hc�aŭsuri� 1�$.��Eeta*l.�&�?)�a �"*RC���&�/eN'�9� � �&!10�@u� k  f exV7A��>(e �in&�� �80 M p�%�4 ��a:!�� ,$�.!E/�"�Vla)+A;l�alter�1�C1h.5Z.6%sZ&�. e� a� O-$be mad 10bye�#� pot ng fluc�1ng/�" $�I�%��-m��aco cu��sol@j> I � digm*.n" lv�!N!Dexhaus� ly�k��7mK2�vb <�b69��.�Eat��Nc:om�  elab!A|X % itec��W :!�*���!� �re} ai��%&��b!�.Y1s\onQ".-s!t@pen qu� �g&.�*� nd ~Ju*2��qi�0"$A .W.�^ &�"!�s� 6�>&4Ha%��M)'2j�l�(G�@s �3Jng�aA���"��!�����6��;�.o�:� A�fM%�!�to�-lex�?�0wlt;r "|x�;6bchoic f9��6]Kd ����(K<)sum!yeDdil�0E�FB�4l��6o �* le�$fw�an!t.� �~.{11L-5a�& ,1� �uN�ini�c�)aiY=�eo$Cc�Ls� ee\�#����5� ?�).�(:P�"`#�` B 387 V*�.�D"CErog�)��!i�~AQ�-���$n guarante % ;#-yS�*��ł�,SmFC'z� :��DO��siPG�5z�L" zBr~xm8��<��5eimE&F $ roadblockI�w!�Z�YA�cur\$XyE�d;!�X�Og�l �collap�E=a�triguAsy{�s�LzF� e[m � w* ���Ntui� by V&� ( Data S��"���12�(�8!irB�)*��env�i��9�s�z4w6: in a;�!0� *t)%* a� � >�b!;v �-e 46JE�af$ knoc�# a�n�dig enzyE���a�fHAb�ng<���u. H�;r5lz7s� ni&Z*vI�w< a7s�h-��� q%az o%Ipr^Js:$. B�co&� �v/i:2��")Z# xpS,t�3A B�=�AXk>��!e�-�ͪ��8' u�elEo�=�!><� i�ac�)JdQ m-4: ,.a���*���stA�"��+a r {!e�KHFfic%�-perturb�q> P�Tq6� Zi�"al:"MG }4K"?$/����&Rm�!l�V*�0ory CCAAT box5�chiefly��?eeK1���;littlk!�on^. G�W��fr� c<(!,�2��g*� .��Vw�rapid AeL�$�A��/B@>a�X ��ssh�UC�m�Xi�rE�6����>6]��M�Υ/ applT!&Q to�]�2�M2.�"�#!Xg�j��*SF�$��9-A-z�*3X �or� .�a� RNA-#j�2>"Xe�6evo�Z�%,��A~!7�E9�ma�Z�8 fund��#�IE� at gnn%1j�\^. ^<�H� ��g! �B�ye8 ]�'E7q�"!b�9+2�",a�;o m�-re�4�*q�( � a3�amaxima� , �.�mr.e�O� ���a�FnW�ch~*�e !9g &)h�A[t@ �@:l� �!� �o9hav�?%@�5Z �* ` newX be�\GP6� l���ix�j1y%�B�.,. SubeIn�g�!n ET s up! ��Eq . 5I�get@�.T!#smIA/w�I�C,O&� notonica# 5!?� _+=| �@in�F�EFum��b*�)B bjY!<) 5�M���&�R[/6ky2�  ,"�T�2_!nD( 9 )��?"^Pumn:��D"� �>�KtN*����Te6�.�"�!k�-takw� �)�F�G s6�=�Ll&EL�A�u�A�}��#P�Q�?dq��6� : Id�,Im�II�e� step-&sub8���w O�2shrW/*�������";�&l� � %"aea ��X �!(;��/�m��)>.�of��e�!U B)�repea 3�s ( outlma�I��% �&Bm��!��0�,!k!end��p��yp5 m�"��! �?�#at��ߥ(a? ^����V �� ,!Y�&�)��~�)I�4al�%�aSE�HO)b� �(��\YWa( alu�.)u����$^ ��Q;a%�B0�%��2>.i�3 1"`.�ed0,a|��U6`sQU"�B)7EU�H("�5�2n� rok4th-�#lA- 9��1(�).��i@� ;-� d�a5M�� pseudocoT{�$nSup&�c���m )���y�v ls{HLC++"�&d$Log EuclidA� !��'�u!�a#bKL7 � M'i�, log-eBE"gAU2�dnQ(%�x�GMv U^,&�7 =5�w�4be�t 10 )�A�a7!�A�E�*�#u 0.�] �DreAsix summ�d.6m : klog5T s�2n–� h–(�#� . 01��. 1� ���E�wu0�6(y�6K100J#H�iPv�-&�7sca�.���o&jYn�ApB(. Jensen-Shi2n Div�!��@*a'O��cs �`(B ( JSD ( ACE)A���� 1(� ��#!�A�0r Kullback-Le�dr d� ( KLM0e�e mix3%�" (J( 1a \( 13 )�Monkeypox viru� MPXV �ENt&�'`>azhu�K(+�*It�<mer%�orthopox U zoonNZ�e tro�` &!AesXAf�E�/)nd�85Congo-b�P"spdi WA >;�� 1 kneg/#�4si� pers�=in �#veris�Crur)N]W�/ !)*s1e�wildlif��s )�+� (MPX>o��(e fto �*�f. Small%�acc���id� ood �'-" ~�st�;�?!��e .Fcampaig@?-in-\ 198{K/a�� Apro�4���="�=�ly un ��%�% �V=. D-�v2�FhiZon�er�E[� expo#!/!�Iza , ba -��)>up� I -to-  sp4`.�Qre�  FDA-���)apS�-� �-Z�e�$du�saf�+=Pe .��d A}o�� �� athou�5�phylax��rapeutic��OM�^�eep,z ���!4s�?F�Hun�{�Z&�v# �� ��<�;be��� bi)-�J�DEr�*�p(a�.�� tegy&`ba!��&re�h nt bovine� pesI<4 ( BoHV-4 ) vec <,8 /n��f�=�glycoE�ij$A29L , M1RESB6R�/& (�erI4fa � a e�a lethal _ch*^[STAT1�ck+mic� �-A-CMV-gD106ΔT�d EF1α-M1RA: B6 b0&�He%�uDZ1Qeeeb�� )capacA�,0F NA�� 2GKRs���)�� 4*orm� n�= 8�!� �Ae�a8 (�N-�Kb6<d�Q� ts )V!��$a�+tonTd�Eh!�. Fura��E9-ARh�.o�M�@��9F��)�2�,%�Lbe"5AE�c�100% �O80%��.�,MW( -/- )IV�� mort_I> morb2�8^72�a�A>A7of �m�qUL)&? �i�e- + plat!� . n��#2H%[a b*-hmA��=+l@!��<animaleME2In�Q� e�c"j.d�r/ s-A��clo�Wrd� ola�i e R. E� pox:�sh( 2–4 weekaiod�Aa�Y'%U%+pap�Y@O sicl�nd pust)(%rec�4�( 10–14 da�u@� #y a�i %P.F�!A�dro!Sfe;, mala��?< e ly�G deno��)!A neck�~w_ a� xill~%� � [%!�@mT��l�%0 � %�(�[\C  B K )�in�!IM��#C~10% [�X8o�* clinU"/ c&� � � �1�!t��͉ofB� !�er [9aj�V�*� to Cent� nd.� i&�[�� �"C �Va��In 200aD���mi&�5of �3mmutely �SSa� utbreak o�<� �Un S�pE1١� l�3� s)�(prairie doga�1!21�global�@)Y"� rer Z5�xPze� G�� lso���%��and�su"�O! ���e!�"U�U@ rvoi�#�[�G�d�!m�!s��hof��>xrTZ"�!;7k��(DՅ��#ofMA���5�asl . Ca�2/!]V&� �i�Uy��� a��25 s:N2?te1 A��cE�II�� %JD��!ro\ al^)rp;�W!C�'I �!out� �` 1�Q;b0Bn� �� sus74i�w�ps; 0 :6 �- =A- M�2O� O/)dapQ{� �����%�co-E�� Ň0, ~ ge�]ph���� s [2aGg]1���.: �&�!WE|zQ�!�k0xt%a7 "��5 � i{we {DviA1��-2E 9! t� X �|� . Vq�>�>2��* ag3�)�k k:!�anecdvA="[1].#�2f�-5*j-� WnUpM���qssoci���ti2st�'�o�a� ��wrP^a%$�to ~i [19�I ird-�i/�+I,as MV��%�.� m � noQ�pr�A�:u/jqx6 2 6K �E&TK�[19`��Erg (A��g ���S^ct5�Y "�useYU. U�]�*o!ngi� techuA �U"Z�ssS,�(�nd&A$y!W��� ic organi\O5�7Km{ o�i �"B "^{ they�be�5th5�c�X���K��immunq stemIo� � #�Xre aA-i�3��I �!a��Cci�Dr(Q�3�FpVl7-�k�J �rre�G. V� ���BDdeK ry s�~E[�t}vaGVK�KainnT*��Zv$�&�-p�a;}|�*ca�E-%8�z"�>!-�I0M�Aq0predict�!6�^ ledg�Wv$Nus&� S �Ss� f))bes�Ulf&V-�G goal� Cons�*Z,I`)�* b":e es m l.Cq. BzCgDKhe&fn�/r�`��top}^�)!�establmya vcA�-�$monocyte/mQ<phage�" � Mal�B��! [2�wI�aT s%�o� 5be0f. mK�fam�6��proofogrowth-��� �l��IQfs%�� BH�,�>ge�|A�dispens�-m6.�"de�= �mYte�!$20–30 kb�Cx�DNA [W4�is~&� M(j����7oiA ��MPm�E'S�1�4di)_r�/�Ee&;( zebu�U2 dicu�, Ame n bi�( B ,� n buffalo�Wy{Eu�)�&!Jsheep&"&��d6 MilAu:caJ<E*�Bl��-� E �!I�a�?�ea pig�,�,Y � rabb1�o vitr�� [aZ�+pl����lryI�cul��^�%eJ �`�>uca<),-,�swD ��� � �,�Ek�hor�5, turkWf, L56chickeThamRR3r S-!_mq� {3�R*�) s� W�eaccl �9}VaK -saO( BAC%��a�� -do 2n� tige�=)��eB/��Y�5�&  �Xzace [3Z8�[3�U1�[2�7I�[G9)e�9!go![3�MoreoO�U�?�4�� 1 thym,we kinsT,( HSV-1-TK )�Q aE)?'����f layed enh�d onco����*,a�C-� e�<�t�oyge�mo��gliom�%R [)�We)Ou���129>�G� lA�e�&��.�U<>J�Lq %�� f %��l 8a��5{Kse"I aZ� [35] �G,��rR��|�F!d��%!&��� )B �-H o*� [3�p�w-~�fl�8r��p'��J�e�}�,toward!b%���3hu �� s . ���Sn � kidney [�hEROe�(ATCC: CCL-8�;�embryo.2BEA�e�Dr�n<��:ORF�:E��N� e�i���� (o.Q��e*�  T> !� homTO(ng� fla/^eGriE Fluo �Pk5(�)" o�Sss�� &AnWDa�}�cu�=%�!g �h�as�:�t�satAe9b<�I'!!6W UYi�2��#A^686�u>������� 1 alphao }#) S�by PCR� pWPI>e( Add�#1225� . 1Ps �r�%_Pmee �.�irea]7 carr�Q$20 }r μ� Gnu%�!)��r�)�-NdeI-ɪA�  heI-��;���razR� olum�s50 μH�*� a @Tris—hydrochlorśH 8�l , �)(deoxynucleoſ triphosph�<, 3% MgCl�5\KC$f@d 5% DMSO . Each �Z of 3�4�$IZ6� 294[ �@1f ��% an)$�L t 506&!%.&or 90 )y1UkPfu>�at 72K] 1237��%pQG�8,C%��6i.0 agar�@ge �visualE)af� d@ brom!ns� A× TAEOe�?4%J!� -ace�G!lEDT .���u]��!�� qe!rt]&��",=bya�-��!Z :2� MN�| �_deI/MluI�b�ed� eF*,m�h/F{/{'��velE#|+Iy�� �x�&ll�� purch�( T�V S&f).�flu��HEK<� @s�X�h6 w�Gp�9( 3x105 -/�wJ, �/ ; �!�3.gub-�U �ufZAxrem�*!�#�j� w%�GA �m��A ,%l5��?TK 1rusA(Polyethylen��U PEIgwv v��r n�n0�*cEInc .�� Briee>�=μ��� �miP9%)7�8!g ( 1m�) (�io 1:� 5=- Pei�20��La� Dulbecco�F mo��J�a)� � gluca�per�a�� Euroa#e�i tZ. Ae�15�� at RT , 8�� u ��!�-�n�3�/an5Is�Q(-c�#wA�: left�+��6 ߐ��My in �F}- Cu�$M�6 t���0���6 > fres"!"�w��,��3Z*� �#.��)�!:�)% �1 or 24^�.� -AI;��+^�+propahG�I�aHy�S6&���i�,%�PH� Jo�MOa�of�05 50% tissue �9.u�i5( TCID5�4pe�Iwm(KL�TeŬ%��.2%%�%^ h�+&aZچ��N!: ! Q�P�`� ic� h ( CPEB�:�&�i)�9S ( ∼7�p�*1n�0/�prӔ)�Q<$Aa�aw�)� -tib!2pelle%� O� tB%a 30%� cush!�)K"�r�\i ly [Sn�uP�[��mpsu�2 cold)O!��Uad.1ܥL"Cm�Aa �b?Pm]"�K.D�laque-,W��J �M�4�$in ZAI-79 #�%Eur 49su6��\%:yin  ��5-�v!�des>��^F4d�c)�)<�-Tser0V��, PBS +1% FCS��C\.)Hy �absorb }�a1 h�:*!�ov�i-�a�a�1%( boxyD�d%u�,!"Š+5 ��o2$,a��, �)� �.� nd "in� v %M="HM8� �_G� 3% crys�wet/a�t9լ."�!��SacQ�"q � a 6-e�S u� ՃQ�� /CMV"���/�"; ��%�~25-cm2|flask?$y'or.�I���<b<.d/" L of2N�Gw( r ( —HC<#1 Na!�$1% NP-40; � S=A�|$SDS—PAGE� e�7 roph�ises��Hzb9ؽ�j� t�'��5,  (���&yl�_ mbra�!�U �bJ��{T�g #������ua�� �ntibody�le�,1B8-F11; VRMp� , PullD, Wa 8,�a�l{rad1#pe6�dase-lab��d7-Q�&^Q( Sigm!�}���Gluc�sc&0( ECL Kit; Pi� %�R$4�&&�3a�=�bde�Pd [���� ��F���2 ro�Yea 3,overn*u� of SW10eUI!�BAC-Bf Kana-GalK<5%˽�825 ml Luria—B.�ni�B )"k�or����$amphenicol!\*}@a-k;8EA l& aA�ml baff�VcEI-�%�Hn���7 �JINwӖba8V+ OD600!�-b�,>ml �Q�h5��a�LJ�$heat-shockA]t 4��i1hw ^���;!�1�A*; ��U� |Pnduce)Q��r j �sc� 1A�un, �b� coo!j� ce/=Cslurr�Pq  �"-*k 15mL Falcm8ub�+s3as���5���o$Ch ( ep�or�B�>fuga7at "<� )&supk\�"! pou�of��� tTG*� 1mL ic�!ld ddH2Oa�R(lyu"r�D �b H*H(9AE:[e=6?1� �A/g� �m��E��Ded{"�3[�>�>i X (A�μL�9)Tkep��# Fl�LJZ�gel&[ frag �∼Νy ∼4��EL 6W'2�aTR�"� �A- )&�byH�t�6\1�2]��$ClaI/PvuIIz Bx�n aliquo�2��~�ng-b��� �&%^��e��|1 cm cuv&at NF S��kV�201Ωu�>M,hAc��e�iEF�b&I�r��J 10 mL LB ��ۑ�Fj���!�5h :��shBv. B~� �H� eK A� M6A�}-�s�Ѩ15 g/L��%�e�>,| L D-?=`y45�N$L L-leucinaD!�2% 2-5 -gal�3�$nd�A!���LB�Go)sp&i!���:���. P�#9P3–5&' ���n!8�9%ڥ�lon|&CpC(d�*,� ea�~ on McConk��ga� =bl ( DIFC,!BD Bio"�6�!��� ��!-�՞! 3 ̉bw�^  �ap�<M�c2��� in d��1R�(8En��ofA�c&-A�� kana>D#or:1 �5>�����a4%yene�]�dBG�[ 5�~!7 �&� in �9B����)�C �c �*6 HindJ#�@�! di�q)Sor��JU�����5 t,�A��Zgr:,Ō��wE�*� 2a A�a��A���B��+p(;:��Q�q��- ged 6�  ( Roch��  s-liݬby UV ir\ �b_��v�KduTj�&. Hybrid�]�digoxi*n� bo/ eirm%�e/;�,�V.�1h  35�5797� iTeH�:�$�G�g� %�$����s: B�/*  R 2A��A>F�$q ��O" ,. Origi)d"3-3 tocoI��mbia 0als!zuInO�:(webk" ( http://: . ncifcrm�gov zor�(B�m&�a?�9)H"�((�DL�51 � mM .�&� 0�L.�!a10��2��_��&vsu.�( 7 190%heg�r�plo��2-� v�� i . pC,�3ry.����67��*�atm�vof�mair� %�(��1U`� �+� in � μl)W!Ir� ( Equibio�xa�h`270 V , 960 mF , 4-mm gap� ^1E!�!d�*)N� ���. E� �G� 5%"�� 2{24�!:E 7� )�M2��=�%�n��"�#�ce��q-.O�. CSy�$row��aDa��/!��."�� ��Tp&Eb -�5?u'�!s �W�,� I .m� n�5GR!d)�in �*Aub��t.o%�V>��n�b� �/! E�JT�E3!Y!�9�wa�K�e-7�A���kl"�^���&�,Z� m� 2�qR - A6�,�e.�E 5����iha����!'�48 , 72i9Xi"E�m" A@ Q-;�M: *�Rson]'��med�. Ee-�DYfemale�1stat1UF�3Efb� -��e� �+fiIm -top1ro�'ga'`!Gf!�ommerg:m2c�S� ad l;�ub-om�"�wa1A~ biosfKlXl 3�p � �70ET�ce/grou�A @husband+e*6� c %"L-UIn�0i9xPC�7�Use CommC��M�Hmonito!U�;y ��te��� �)�� �_�'T 2082 /0tk“Pa*FL�8.iG�ef�� cy tnf2( 8�6@ v�;s "E�>SP Louis,D�<ty�& ( IACUC )A�5/24/20W Z\T7 USDA reg�%!U8=\l�'if� ( 43-R-01}.,6Eb�,in� e�ndA��llnud docuAL)�� �p!0E�n�X�C��?iA ,�be� prov�d�(a�8Public Health S�{ce�"icy�$�2e6Sw KmmaI &0Un5vfi�3v�Usu���B5OA�BX WelfA�( OLAWO AQN[�A-3225-0{1�bJ}M%�4��013"� 31201T\�V �6�Pro���Z �fu�-acc�=!�m�A�A2��Assess!�e�A 1)�Na �, +Ri�a^ AAALAC.!,�winsg� Qnot July 1��M��s],�2in�\�bt.�Llya#P �)&�)3$l��� �� vehicl��Fo�F�?�s /�.vec��A��&� ri6/ofB#x03BC;v# 6+%% .nAgk5U �_�.O T��yped%�a �of�8I:�iU� `;�� �at T = 0�{�� boo�:N+2&(�' +2e�*- �!b�[�FH�LE`E.NjOR�5amp9b*2 a Cov7l����su/��m�Va�6p�7,r" [46]6&ig ��1EF1H0&:a�] V� mmal�keF?onѣpl 8AQ�/a&�V75tagged��u0�E5tO��� ��� ����w[j1F �0 wLas%[>v�iCMVBg�!��E��=ca�4�P2; , �"5 !��"��{va��V�2Xin.p�b!/ƚ �!�inD>o�\ ern-�#"�$��!�onB�$�ca/�sL~eM?�8QSN�2wu�� we�0IBI[�wc��&�%-���ly ���M�=1G�1JE��ia� �A� secr� = !pt*W!���� a,o�c�� &�Vc�%-  a���e�N�f�!-A6�C@�TK$A��Dl�{ O5��R#.j�� �ƛ-�AXY�S ����ic� �!ronGx���d a�F 5�e�1~�����Id-�` �� pI�"�r�.�H?�1�<*�9Ydeenv �TK:o�<�N!Vrru� O!ofZv46"(\��,eyK Rf3[e� �MCA��Ga��Zf het�og,/�(=�[2�62�22V32�2^N%�$H. S/���� I"rby�m!��Aou`Mn ՠ ��zB��:l6ain>db"G& passBo`"�F�{� �#,l phenotypes�V�bDFnt veVIsɕ�E][*9�arr#�6\��f�E�s606d�E�209 !:��. N�O;M�+s��.�p"�~�brl5}�p!(�y� �0thu *O�B Mv�[p����%5^%5"0by2��I�����"B"!�2��5�sc\aH ��u/nt�mu�urom2�edfF*l�$eqH��Z����b�� �F$�@ݧQ��~ĉ�Y��:2�3�3� 3� &�Sf�4 n"��t8z�t+��M1�1!!I=P 1>tM�D��� o]oeto��my"� ,��[p{R�$ �!�al�! ��hae%a<d>/vZ 6r P!�Er )�th cha�2�h�e"� �@^@"�E�� h�+,-�-A^ 8�)�R�e �/J�2�Ya�eVp"f kin�WsA��=!�R)7&H Ac�F�V���DAi"O1�MU vivoL e so"�� �3��y�9�ct��a�PchZhe�� ve��m�He�Vs�x��Qb��jsJ�we&ba�129�� �9��irteF�)"�:�o �. 2C� 1E$2 ;un-*�.# 3%�X�(�� �&� ]4]<>By~� 4�]eiaJRRi.����.�$>7�<[0�!%5�h`n�u.aTԠ��#me��&&�5H�!�7 (7�%j �s 8%t9n?J)�' B10C1|��B� D2M9�1Q#13IWDJfo-K A�@w-2:��7reU.�äbo "��3-$*�)5%v)�ed IP���&��3�ac!����dp�{&Tcjt�;Fl�6Ps7k; r���?�� ( S2�>!CA50X�)��g1Y���'~5f/��]Fv��W��1A�K��"�a�=��Q�A��mMVA/VehM@5 (7))kEk�N����E�M1R)FCE?:H( P:. 0�2��l�Cgh2�A�($bo/CoI/�#� d 1 deat���*t^�kF�!������\�� A�M `pD)5e�}�j,� .`:M�li P a�-o�uA (E/�QF_6� Z{ \( ≤5%a[nI��7M8*=�v%��.�s�U(�-M.,�_ B6R/�-��125�IR��131�ha>O�� a}q� kkB�( 15%� 1 !% � B� C��`Zb�Xf1Y,��4YA1A.��m%Naff�48�}&��(e'vu|��y9 �s!>, 1�15>�%���xT�od�i�3� � �R�$��z�d5_m&E��F�)�Ea�G�\!.S.�v%�3B-�3� 3��9�=5_�.b�5-��-�!1�"� O ek]}K&��by2� � �:)O2�-A�"� U��mo7�3j/.� urviv��%�?#�y ) . 0aim1PXc� $��c�=� &NKo2B b^]��f�) 2�]��f�o],�g-�\sIe5�;�5gu' qc—��t; c�k%�`��2�M�E|| e %t-/-6?�M�Iqsh|�$!l�l- ���*u CAST/EiJ)y,�8'"V� . A �]of�*?z[4�5�nUl1E9a ��M���way%�% 8��?�`n&=b21nL( Cynomys ludovicianNb[5X/��+13�4ed4��s�#r2S�ophil���Pcem3t K�(55]��Ji( �@eLqin:j ) ~ l�&=Z)U.��flyw� "s hT\ms!Gnd ��mQ��j.%1:J�*$t��E�%с(Ea�&c�ns"�p-+"i(ry *�r"�^e��y lassvGE]�O!I� [5�^P2 Hea�6�@�g�c,I+Yr , C57BL/6I��*w( �t� �n�iv_a,L$p"*esUNn]e+@R�it7udM�J�.:���� highly "6i�k)�h@ ,_a rs�")�edJW B�r�b �/ )�( b+.10�N Tiom#�h.�twUQ��phd-#� :��5� 0pox/ectromeli�tDTV�a�e-~yMo� us;M��7ab��'em�`2�7q$[�S58Y"&c��JVvea�.�nt~.� rapy!bl�Jű ءWpe���7"��P�Dryvax78 ,�|C%cofN�er!*�ee�i��\�. p+:ylIc)Ё�"�{�bNq� � �2x.tde#t�� "!���b j=fD>Y.ci�a�E#���NIFN )m&�Ig [58��K�b S݂0 Sai�� �T�aU��e!R"Gn��)e�X�f��absH .��N[&E6$q66�� �hoE�s!i�in��Q!F�Z1.o"yi�"�ER IFN-γ [6E�C0�d5 E� �0n Av��T1�m��`1� �{Fk ?�5%YaD� AiB!H"�~"{#{-inocut?R�� aH vert�^E��F�r �loga��k89�"�2�$� � �>a��'� Ʌ*��':8,@M:��:( to A27|<L'5R&�-V�5( V��2� �7L%� kD[�J� �c�vol��VV �+y� ts [Md.�A3 2{A29Nmyr!�y)KO,�k KiVa�-to-be-*�lp�i\attachE�a�pre-fuI$y�jr" 5R �42�2���o� �0 � [7c�71i���97Ysamino an-O:E=dis�#a�]al[ܘ�K [7�rFur�t- �`=<��Y��.�*� JZh�R!+J;�$mmK�*:�;sub�/"g � sA�of�C~ �i�*�V� +r�K�`�a��\)p�Y| [7AB7%�Sۅpurp�%HJ� �@t.E�+! &�%�8qVi!��Y$A�ctN�\"�e�Q!�� �"�.r��gd$'�6?�7 ���4edtB�B*ELT���dUffi�Y&�s�D@!i���&��%Nf �aavailY�kAFs�%1)�a�grx-fr%,n% c�-C64,(�)x>�"I@ 3′]!4��,�� *Fbir.Li &�8� &3n��"$� i��lyN�BT, cust�9�X,.�+:�JORF �J�� r,[o�,�a�pIu.b--�!*!�Jge+�0� A�� C,!� -1�&�m`+A��(  wh� 2��Áqf%�rѬ6R )u�"ld��$N� esto ,  vu�H9yE�M�9�:D5t2�+d��*� a�BO��%�.��5U������UWN �$t>R�u!dsoftwa�"CCwww . cswA. sjtu3BdXcn/bioinf/Signal-3L/; h{C 8b�(d5dk/A+ ices 1P/phobiu-sb�\sune/ ) [s�(maC� M�2x�'BS by S� omePB�^�2Ra9Tb� >�X!�=3� "Q0PMss)�;�D 1athqC;ed �=��3qNDxF�s$ fib��ast9*#� ��RE� leuk�Ua�gal{\�Rɽ�� �.��Va cleadqU��vAK�0�}q(aV"� ly� x�>c &���Wl��"?�B���oa����u��� &��}��z")-�|% ���,;��ux$nep %bjostpar�?ut!\1Pna�! i}5��*u ��"&�!e�&ba�}�>t s [8�,8n3 �gb��B��>���,"�y"a��Qs�A�M= ��'�� �2�#bdҽrit�V#��j�i �� rostag�m in E�PGE��tGs{ 2c � ��by 4, TNF-α; lipo2isac;&% ( LP�n— �%is"�e�@�issue dar�Q infl��[8T8�FCa <�vee�a�M�;""��9!-f0*�ic~2 milk'5c{:Zh2?Iw�$s��� w�,�1bSafYv2 *���qGu+.�|&�b�4= �w>%(TK 1!�2| �� Am�t' �\"�+A'��oli=-A*. .)1YJ�$&�'-J!2Y.B2h!�s.Jm|&�*w]Fs!������= �F�A�)�=9�5.)"7(�'�QR.&!� A�6KM�N~�< 6att��)���aMox&u`� a*abund� * a6�5u�`���ranj G?�PI'��6+._ l isf� Yi�Շ}N��dF�:�t�sog��lo��� l+��he-���y . D&' i�p"�)9�U)��y7aA�nt R[�)V&� !�hW%4�3'Wũ"�{ �'�I � *A �j '�n["6�.�P��Z%:��%� chieAq��!���1u��Dtwz( +N�$eO &� �M�]a \y � ��/�a�&IEHa*d$� �Y$�_)+�A�a>; ��:$&^%� ɉ�* s�.S#n�.�tU�m!5��!a�/NJ���x�w a H�)=�)� M��o�!UM��2�f,�@5����A'�M].�Uե�8treated with B6�yR alone . Nevertheless , our studies reveal that protection can be afforded even when a small number of mice are used . FulcshouldO$considered q�increase the dose of vector administe.o#mic�(Also , sinc ;combina�of all 3 H(s gave 80% �Pagainst mortality andbid , various F permutbsZ�$o elucidat �,most efficacK.�orO� �s!�o o!�� clinical-signs were observed following vacci �with !ILprime or booster inj-�x, suggesting low immuno-reactiv��Dtherefore possibly--levels�Tadverse events in NHPs<human�LAlthough second gene�n live �eA�Dsuch as ACAM2000 ,!�vid=Jrobust �,e response ,�$y are quit$actogenic �,induce some ��mo1�inE/v%Ie�FuE�m� , a !�i!�nt porQe!j� popul!�n�0contraindicatA�o ^ #%�first-�)-=�\[19] . MVA is a non-replY!� )iL,has demonstrxM{y�manA�ima� rial�PThe main draw-back tonit��ve)�){)ZA), mean�t�=Qmq�)�s%0usually requia�for 10b�m�!�y�[87 , 88!Future��c�a.�mS’ %d A� * be u��as alter!�ves�,. In summary�/f!�ngs h�N2h� BoHV-4 baW }�Ek-�g����Xa lethal MPXV challenge%���O��Tutilized STAT1 ( -/- )�; how���a� AinN�sensim�!�{, nam!�A� CASTE/EiJ E [49 , 5a�8E�:���� evaluaE�P �iona�these5-in thisjalso . T work<�aT“proof-of-concept”EUf)�-.�%�$ potential1�3a� gory A ag����E`A� ongoA��1�jfoc%�o� e de�$�J{ s expressE4antigens from )�� pathaa�a��ll0an assessmentg=Hin���rim�(..�5’-3adecay�C!$major mRNA uw n�'eukaryot��includ�trypano�H�=Af�Zdeadeny�'on�RNAi�tpped byw,nudix hydrol�� DCP2�� ,ecomplex%yfin�5degradJ�(exoribonuclF. UniquA�,6�l��homologui�%subun��ofZ�, whil!�.�A� ���AA��. H�, Iaw�+�parasi!cuse!�DApaH-like phosphat!% ( ALPH1 )Atheir>�p%7enzym ��Ein wa�� cently idA� fiedKa novel.$ax granuleF�a��vol|A&A<b� . A fr>i� �(co-localisea clus�H��!]O=K>�Xkto�peca��atGp�ior pol? ]ca9,���+a!�n betweei�two-?A�$RNAi deple�� �is��!cau�a mas�a&� �� otale`s)�Ay(ed , but�I,not yet star.Ua���% data� V �acts dow��eamA�k!�� upst%�.�,!sh nt)�a func>1� decaIj.�vitro��ej  shQ�re� (nt , N-termm� trun��d ALHP1Uc)! a� alyt� A�nAYve | Qͳ!%�d.Ms ed la�r!�AA$yeast Xrn1 oon`fa|Ad!yACy.iA��ed%�ES�C��9mechanis%�)�differ��j. Dcp2�+ leav� m~ than � �e groupQ�!� ’s �en�A{ef  re� 7 1�# ��icZ}� bacte0 -deri� clas �ts ��A<I phyl��eYsuper-�4!�_$ic kingdom%\e���!\of.'R�funknown�i"�esu LKr� �D� �] , di��(osine tetra9s,A high� ��UZ2F!�( cap . One � mark(�&sR� 3!l(7-methyl-gu�h�bound%�-E�RN:�by a tri�bridg�oge �{ poly�[ ) tailAgt�co�"� ��via 5���i�d/eIF4F��� C medi%��( circularis�2ndztribu!�to (stabil&. F&� = e S��uc� i��sɳ�remova� ��% &�?sU<0Caf1/Ccr4/Not�. D�b�ed�I�th�[argetsa a�awo.n �8y~ �})y��ed � )� �exo� A�a [ ysiujremai� �'di-oligo-6 otides[ pyroQB! DcpS��l"# l �in X �Dcp1/��� ,2�A�� ex� o��- F� (cytoplasmic.2� XRN1ɉ�q]:� ��A^�Y ���" do��nt �  . Eb -[ �5� l�A��NgE n.�u5ggrege of lA/ly�е�. Bes �dL P-bo�� 9r�nstitutg �����A�%� �machinerda:*� �wh\B� exposur�e a�<2l rans initii�f� rs [�2�!5.���OZ�2�[3J� Be �V� caZE�on��a�� A��wQ�[4–7]A�2 ^ 0��.D α�β��,�sea� m7GDP#E|�monuke%[4 , 7�aH�e*�!\� �n iva&[8 , �!. � �J6� is f�"� %�s3alE� $enhancers;E:o&� �icto!�$Edc3 , Pat!�Dhh Scd6�!BLsm1-79j10�8�:�b stim\e�02 directly [1X1EC2�recru� JmI�Ր"sel veuAto���&QA�Up effe� 1oEAD-box%�he�se)�oLsm�ja�� %on={!Iprobay� n�: both� e�.i �T amou4e�-A�e� "( �A�16!�At� nmm0,+ addi a�do.�s�i*-wIQ� bse9 aGs%�To� �2bym�>e� DtiK)e'� !g%5 2� aa� in.co  is w� prea�r�ou� e5&� : itt described]i#[17] , m-K[7]Epla= [18�in}�ep-bran��gAtozoa �Yr exa/8 Entamoeba hist�Ua>AxDGiardia lamblia [2%w� � ed exD0re Kine�~tidla heter� ic� $of flagelle%A�� 6upr�Z�o�"��T"[$a brucei ,2cruzi�,Leishmania .>�h�nei� 6�� @E'nora�A)nY����Wor��[21)�they do��5a2�>�22 , 2�3Otv}�alq���1[2a�26 r�[2�28]e`��� sp��� abse �a�lexa�h%��� ɝ��a� detectabl��[29]:6ym�%vea}o�R�� l A� % o%���.E�^onS����need �X��(b2 e un� ��M�>W@�fer���ViW[ cistro�ly)�!Y� ans-I�z�on [3e����&� hly *eztype 4:�W f�� r.� ( AACU ))�X se 2+OVio��n������X6+ ~( m62\A�th3tpop���3��Im�a�A!e5�ce%(!1%�y"v 2���B:�restric��MhYq.�ke'yb6H!� i�IP 7 ��!�A$� [33��X�V� A [3� 35i�&CAF1/NOT]a�[36 , 3! W^va��ly pur�Hvl �ss&] I��j��3L��/new&,� ��teE,Gre&���warong cand��long-wan%��=�e_ �Aon� pred)�"� ficit� Ad -ef*}) �X� �J.� i� "�confirm�4Tb��A"fea�����nY4 �:*"v6mresuld&q, globalAo���A�A���A�d.�_��i.tk)+Z�2� ��"���-fE� hA<eՔan" �&.n. ��I�� Gene ID np" Tb927 . 640r ]� A t M�s E�A.X �!0-c inte�% [3P I*!� �e did%Gg .�>w�� ��:� � � N)�%�$was so far p*"r�!N"X�ҥ�{ E�[4�M�GC" ]T �) atBYmight bea�� same"as `!Vperhap<!(4q�qI�p:�� nnot��� k.� -q�_o-Q%.?( PPP )!��TriW Z a�U� �$closer ana2. sequ; G s� �gɆU�l�e�4 motif GDXXDRG��! aspar��repla��ag�!Aarg�B'�$ne ( Fig 1�W� se�a�chaA� eris� �xan�RTlph )Ensub����PPP famcE|is)/�p�%VI[4��4�� wil� feo >�as�9�re�two"�Z�m�T ./ genome:d$4 . 4330 ( d2Dnd!8 . 804!3 ) ( S1%i!�0M a��ea�2`�i��&� F���b����[� ^�_�,% f%N!m )��!��2�Q9�!�e ol"fD[444 a moleceEd�mbl�&�ic��� M�B )A)�l0734 amino aci �Ll{'qu$_ t��GC-t�Us c"lA-an*� �C�� of.�:A�evansi���!pai�-r^reg ݔ&1pe5s�far�$� ��2 a�mP simio0 to�"�: of� Q{%�d)"+.�aaIo�}�%6d BM . Wh;*�" vailZ)<�we��6�balign9�'1a�6%�$%%x39% ��&i�t&9 '�bw�M]��N=�'9 mw ����2,Thu!=�B[is bes]n;"��)�5�.�G*he! orlyݣ� 0-�MJ}�/yo A�&l$/Leptomona�$!�-�seA�t� iHper� a�5o,t(-�� �!�F���h�)a.)B>!?-�� �2�If ����&�of bulk�{!�G&� �&b��'!%c "x *�A*"? I�0���Z performed� ��cy,� duci�system d.b[45��re�+�*eP� loj orig$%� � Lduc�a�Ŷ�D rollI�$Affymetrix�-gl �� FISH � a gre#fluoresAa'b�$ti; ��I�!Ja _v/�#� �( DBP %�&re�a�rO�A$C oQ�s (6��1ٜper%@& o�F:I H��24 hour%wF�1b� t%�!�q� !���$!�$successfulM�c. Nex��growth*monito!Kov�  time-c���S��. Cellw)oppedJit' 48%�72�:@ib2��#�QH� n es)"�%�/%�.FIc}/:�-���i� . Tek` !)iso� V�a9E~qby qu�)�/ve-�`n blotA.� 2C–2E2 eX�m#� �YQ}*u!���ՙI|-�: �l6�' `,�vwo�ividu"�&)jR, GPI-K olip9C (PL�! glycerd*kin*PGK'� chosen be�0&un�!Q�pro��c life  �Gg��*ex&wc�0$[46–49];`)�&�rg1&&steady��t���0aa�hib�� AN�y!9%�Cblood� am!om ( BSFL#&�s ����=RI�%,dCig"l0�)!�q!�A����oz(+Cd  7/2 . 2�!d a�+48/.� �ey{#!�A?d!2op�,�+reg�#(we�:%er:UO�"d� 2/4-6 �ndIO:' 16/2n�B�a�^6)� ��roM�9� �metabol�'iBhphenox�Ki*4ryn a�! *z!�%yH��fL:�r����[506 �L>� ab�2-fold�2��) !L��Ua� 0pronoun�Q�Eu�,��[35y 1.V �a7.��ta�6act:�*%�&� !j"+  � accu )EI�9F� � shor�.��a�ai�2Su5#�";:& }1�P:�nof"���s��n�+�+Y*(�"X[52!�Dcp1 [53Lsm4� In ]�� !y�ne H4%5A�fr�tlyh.� *2�V�3� aNge� enco�o��organi�� as t' ndempeapro� ng�]t� aver��siz�520:�r�$ 469–589� ���>�ACe s�8X^2AO�>owAU e vi�4f(of� as ba\shiftsa;a6&��B�occup ͠2@/�}��%�I:pw!K��harvesh��- *�=�� :L dey-%D�oE�at+ ~� , 3a�. Ty/���2to�0" !n-%n�gA�ind��;e��� 3� : Fd7%'A�hf%s2!E /71? se H�n-_#"1) ( dTE{�I%Il�9 . Se�8 , no."e.R&3v���46�+2�55�S r!�T he SLB:�a�*Dlyi�L.=�. = n�(� �, I*a ŧ�s!�5sse��t3%z�4A^a mil#Y;�YFMC ,a]previousup��d����Fvv z�X!;�G. I��2�n�D%�a�.J��g1$�Ws.�%Q���!��.�1���'ng:F!%9B�A&a�5q'*^. SDe� �"��%'�� �8 ca� Bw&&7 � � d R�� ����of����s&�r�,�4M0 1740 )��8� .�?o�+ .7?"W)I�extrem�5EW�.�2Em���;�) tanei�͗�!A�FO]+.}%��B� &��6>�)l� �8� t� B�sn! ye� sp,(�*|I&� ��O'��/ 'o+"�#pE��m� j�4�2Du2Am0.�h� r2f-N���>�9e��K@�&21%*i�a��48%�inB�Mc��y�� �48 � )a��� " in6Y�a3.*)W)� ( S4�w3 Eu� .� does&���a.`=]*�a��&w)�2� ��9ly�lai>"�&�Es��Ud?�6��� !�qR� R�. Any ea r&�'`��� t!6%��.r�.�a�%-re�C�-3d dY�E�ag� �yt.� ��,nEoկm�, 2���.�,!A�6�9% >�V(6�)�!��.E~�O��%/2�m�.Z,��� aJ�.D'"���h���TBe_��4����,m�`2�cm.�* �]5/3 . 5F�2E(Zn)D 24/�^of)�&�i�no� !i�4o �;�SB�4u ( S5�Hd&���f-1�8d'as d,h#r`c*�4o"d� �=& =�w� A�DAPI-s�3ed LuNZc�@�Eima�7hٙ�2@v �=r�qmo:�.�2<5�)�x�+�sA��!u7 �ar�I*se� nowaPw"��+ce.�)�u�Eae�AZ� :6�� ��X:�6 qX�z8U}���� 2;wiʅ B2Ci � � �� Fa2.z=�mb�I�n: v���0��6 fulf�# cri$a��Ap!2�� a sc�, w`**� P�)& �l�6� %ze:�&ͥ�AUw�?!o<�&N.�*!�"�6�'�% piE�:na�"�%/8%�� no� "� .1>/G']digA�"I��@ �"6�Tb��eD"E+w�a.�eYFP tag�!]*� l�D� 2�;^-mChFP�H2Y-.[�.agg|6Ѧal�%�li�t�Xepend�/oAe fus�-F��Kob��by deSAng�'IG�Fl�vPo� no�k&��| B"4 !orrect! aliz)tMo:� ( S6��C`o�I�#co-9�-�-%�)�2 $)a e s�5 F�5HH'aI�yp3r5+e��1t9�:�M{*� full�2QqAEn)aV+y*atU0ck2d+$�j�A�:�[wyABNoPBS�s5 �S75�IAEEKs�b>D��)�a_%�-%u� e���t>[��a�.F@r8��in un: �5�>j/�,�d 8�s5�. v�z 1^u �>5�#n��)cularYw�9MS�)+st�!�Z���S0 S9!�s �� 9Wi�2�CE���x e�I=���g�i� �R membcCm�2�,�.above�prFJ�si�4vo6e)Vb]�*lND�8�:�'4�l�v�&l9E%&&%E n �%�"�1� E . coli �e�6;�4Bb!r�!�I= solu}h$a nm&�E�O��'I!S�*�%2212h)�HΔN )�� 0P;X&�#y)�FsA��zl f%5e�E(�(p*ES BA Zb2�&GDVHG�-2�e!��+~\F� to GN9[5l Coo�Ge� n"gel�I�w3-�/A� S10a&�#!VF3g incub��o.x�> �!sSnd�"��C.���"i�%p+�o� NAll| !�p�+�.3#noe�&#:{0 ed ����= �N���a�!*,H�.�m6EW�K+."dis7a�-0a �B�aI7e> ΔN-�� ��1�'6�$2�itself&X�� &`Dt�, lane 4�Ho?-�d7�k a֍�"I�+�*E�Ire ��S� a�*� J ��a EX #��-�d^�!��%ple �3%�4!{�)�h�&�NF � 'E� � �a �ng� "�Gw%V:ex&[R `"� H�4&zAor�N, xa%E"MG>&�$w� be�is�8�@�.�t�E�, �Urf�n)5(��2D�9��s��Ed H��in�n|B2",is�%�NA�8�+!�V �e>$Qqu�?B:lE�: 5e E$kE�-#AE"�+u$u��nt} or 4o�� �jceAk4�'Y9a�s N&18PIG�  ��!Oto.u�NLs� AAO � q&}&I � ,M�i�GZ�. Rm,� 1�fX._nR�A!��9TbDCP2"�io� N���[5�:��Lto�"�Q)�*y0isgX�B!�JTg% poorE����E�tr�ha���%4!�� MoreO����Aw��%�. !�g�G1 ��4#fYQ�]_�P982�U?'�in��#nU�;If1��J�X.� 6.��:�&*�@"u���3H:#"�&(g.|!�,al� *Afo�L��R2iMM�jaGE2q�,�Unw&�! %B���9*�!a!_sp!heB��51Ų� TI'�9 n:- �y�RB.�Y�m�A<z�*sD �Tu'. >;T.Z�3F�7�C�(&ha*8�aQ-B���.E&�," "�AY9�w�"�'!�N�*�E* aVj�<t*QTBOi�hvj;��at� )�s�vSI2XF��!���ex�� upon`%=�e"(��p�: 2C"�), rul�� %-��t�,t��� subxQ!xe(:b���F�SEA�  !�J� �ca�.KZ�1�� "� 6&� !<� �l''f.x<luw6,]om�N�q�%.��*M� o� �B,>���%R�z�a6mt�<M J�a3"�2�Ev�!w@�?M@.��i/!����rI��p�C�Q( �]Z.FB�aՊ�'g �ljF�_*�'�P2�6�mFOU)"fundas  `*@�-�d� ���ahVy%�UeIHXSR  Q�e9�E�enF �&U gb@JB*| IA"� is�U1 t�'~ue=gbR�9�4�N 2oanRid bonds*8Y "-*)beeq$N� assays us������]�V�&D8atid *78�K;� t� d�an artk(��m � ��ai0� :�H,M_Om7GpppG�H-� b!�m7(a=�!pre�OU'�Xp scav�_ry�I�&�T���Gst�T�'&�# FaO y [5dB&m�Wr� I�q littlici c�Sr�*oA�.� we�(a� =s�= �!!��*A�%%�|�Q-�b�A+YXmY`an<0lUqu3C ^ZhIc�,��j42}*�?E �FeKi\9t�S�[.�a�V� , unaO.� ,�ept!lR�sA.YO�iF$!3c+A�e2��e"�^m'Kr�O�i��%�)ce�B��nu s� 8 . No�K�(� �t.j�&45iI.�roA)�� �1��e+�;; �.AIiBg�!:� �)� 5"���);g,��".�� hac�2*�a�s��N `W�x1es�$� ng�Die�3& <��i�V2=��"��Yy�ly disck^O�Hs Nudt  16 �rE2� YDI�.5Q?$HP1�c60–6aNE�iin���GPe?i�U�;�),�&�aRpp[��T.X�0o�H*�\o!i "���[64��Ho.{a�%�ZQlD�~�*����9Z2m�eA�b =�2g\def�Pby [65]: Opisthokonta�%W�P�"ACnd5�do$a�u�� ��e L � !B�� 0Z�0EsolEQ e��KA A~t�G���!F�] to 2 (6�^GRD�SbD��p�hC)R*"wI%�in-E� �Y���mpens��!�c%iB �aA^A..��+rk ny��n!�O�� . t "�= p5�U,�M.[_ ll +V8���B�Udo rteb,nse� ordq �I6 � �e5)^�~�EA�whe!��frC  ( � � t�hX!%u,�%<&lT*� �b\� ��i&�%da o my9'lea�5=!En%�FUAI�b�3"�iq&�C*0L�y�of.w!W?)6xa � 6g��c�:�a":!�!���es ? �b�R�-�AA�cO��2(sbl��!S��so.ls�]B�d�+ED5� ZH&�m�&�� r,sZ�)e4e#1F"Y����Q� o�k:�� 1SKA��&y�"�va�� &e0h"�MA flex "g U&`7!�yaG[&%���� ��mz�:�is�%>w�L�1,�0!Xx(stb �3�%kC�*:I�.�1|T�)( �fKramer�anuscrip��pr�L��o B�-���T"A M���&�_�\a� �, I�or)["Q�2$jR�_t#>j  vqa�R�Gly���QPp ����3p�^n"�#of vers�6u%K.u�is2 no�d�*c !�� �D crys�'��&P!3!�� >��d 3 [6To���*��6 Cemploy�5a drugm-"�udis9W�uaby6��s?Ds &O or*�i. *1�L�=r x;<�Mcew!N,.�.+9x^�)A�.+�d Din2rSPRH1 r�e D a TETA�:YorYNq�:o�eqiHund'<��'N S oper�fA n��u� D�� m%�|�L�cul S@, SDM-79 [69]�� 27°25% CO�T]_gz�p-g�Dr�A��%darQ),ocedures [70�Al�&�J%� logarithm?ly�w� 2j3!*.,�# volu�{f-�� wash56c!� ')/!9�A�Min>+st"�/ZE4twa��Nat 41!0e�p a2rmoblock!�wP bathAx/( SK33�%�\ope�"a�f��%��stop cod�]n pJET�2t>hh -Fis�RSci�6fic )=">$al BspMI s�b�  HindIII�fatE6ov~Z�y(&?M.{5!�\Shdon: ACCTGCactAAGCTTCCGCCAC8!f*eS BglI ~X6�5lL�H: GGTTCTagatctTGATC�=in->�/BamHI3 �clo�m��sm��- 3a71]!��Q)�e�%�0G�� 706 cf�� 5N�>�({�fom ajto p3666y x386YY:�l&inp�/| .SK4E?B�698.�4��?a.w"#R.827.w4�w!-m5,o�u�"�U��%�4+:��.�1102�N ORF .�I2705 E)M�mide��5ar|�P NheI . Δ)��9�(: A bA���m� c.ssett�Mflank& 560%8.c�� `�aJ6 �616(u6a GbyO!Ar11�$�3 -4Ty�en^n16aBn}NFfSK141�'h+is p2710)|%_4-�tag>�w�B6��Sal!� t�Sp1��_fWKref�f!<s �% , �a�7�� �G� � ��%��[n�c..^v�8 )�bp2948n]$a hygromyc)�#�Q��neF!r!��m�r of!�69%4�W&8.�)Y%�a�m�eBe�he5��n>}Msc!څ�6fI p284�_ˁ^ JT�O�a His-E��%!�&"*W �9��I�2N��he.v663*�s���}�"dif�*pET15b5��j.�4.ulin IPTGJ*�X9: n ���%�2��"en1�MGSSHLSSGLVPRGSHMELYFQEASA�]%Alp71�bB46I�As�9�c8F, AF1�a2M28�>%FmCnf:�] �812�i� )~.Y$2��B2p2�!0�� 652 ��444�F�*� ��B�Bc1100� cGtnmitaa5)E9 taken i�$ custom bu?N TILL PhotA s iMb$icroscope �pp<]a�1cam c�PCOE� deco�K� Huy��E"�Zsoftware�E&� V� Im�e8g B . V . , Hil;9uT9"Ne�laN'xll1U ek as Z�f�C!'�odw�ap�H)!�d�Hby~eJ�.]�&�[%A!�8FRET-CFP/YFP-B-T�fil�K,��er�w~1B�sJET��1-Texas-R�'L@4z@GFP~ DNA_ DAPI4( Chroma Techn�$y CORP , B�K s Fa�\, V�Q� orgau�(��F���8@�:�`wi-1CE�: J� TREUojR���(in �6'd STIB 808WJigambieЊDAL 97�$.'c��l!IL3!�6l vivax Y48�29:s(marinkellei�BQrF*(Sylvio X10/��F!CL Brʋ$ EsmeraldoZ6� xDm28cRG Non-rK�Uli SC5, .� grayi ANR�VL&�bDseymouri ATCC 3022)%&��Tentolae Parrot-TarII ,.%8sp . MAR LEM249 d"t4aethiopica L14!N.`r 59:zdmexicana MHOM/GT/2001/U110"gCgerbill5�LEM45�"�!U�Qb*)=� J�{"�!d )�&�K�B k ing/*-� error�� mp�{�?daw&h}m. Nor�"</"�*�&G� �������$miRNeasy k~& (�1Qi߉� i�"w&� 81�U( SL-, or2\<�>ai�c. 1�U�X.�< �e�U���LV�7upNc(to IRDye 80A)Vqlys � -C�GCTGTA[(GTCTTGGTGCG AAGAATTTC�*� � ’-ACTTT6C54TTCAACGAAATAGG� CAAG 5�.!�UVQ&C^��:�� ��� F�`�:�-C��AC�A�TCTA AT� �� c>700 l�c K�col�{1g!�,Odyssey Infr>�S=e0( LI-COR Bios��� , Lincol�gN�a�q= � w�IeJ�v*0VAa+a6 a �radio@I�ab��d�)�re� s; �� DCP2 I$*�69(Eiu��. ~aj$or%@oc}aly@6�`Ae� step�X"�!� each� μ�m�6�on�,ed 10NEB bu*% 3 (1mM NaC{G50 Tris-H 10mM MgCl��1mM DTT6.H �ie , 2X Ribo�(x rmo NP, 2��po*�a�~Q(�2!�if fd �&\�b<�<)�or*�<�5r�!*��_a�n�{�r!X'*�TA-`h�w'B!k at 3���l� �+ad��t*49AfQ���-�+!�b�Rtr-�E3 Zp�`l:�.�!t inol!Hcip0e�^� 6'-�NA��de Edv�� pa.e[resusp|J�f&��>�5� �I �JM���:�02�/rea�>� ToI��$!yI�NAV@M�( Epi�hreA+1 8Q�e�)�!�.i,,^d6]F� ~18V1~!�nQ�qpr1�TBs TG,A,�adE�A�al9���-�H2n-� thir���� Xrn1*�@Z�N��-�Z�,:� .r�y\.�(���� &8Em�!Hiť�5����~]6%8i"^�s�B%�( e�2�EfCliA�wSo aBlu�$mP�b�6�( Novq carryj�Wor SK468��M ���jni�v�A�tOD� ��C*EA�T,H02% Isopropyl-β-D-� gal�� pyra&I`�)%�m+ke�&�U ( 15�a�d 00 g��.�40 ml�A (�_>NaH2POl pH �!�disrup! by ultras ( So5her B-1�;B�onU~8�J �э ! �])� ifugV�2.��A�BP(�1na!'+ Y�# 3! Nickel-NTo�ar�:�j�li�,��DZZ60%h�Sr0xAUI�a L�M3�Xs%�)�in u=��pou���2� Piere��fugA�lumi� a{�%c zlo���m� �5V�, 1 imidazoQ)2:. E�#e�HwFSep�:�%mMRT�..�_e��"� e �%}to} � PD10 ��GE lthc���|+�7��m�sdtq�B��DAT � ��M ��\ mina�!�! R*yL; R.�:. 4 �" ��:�o9F�ǩ�� (�c� μM az1�RQ t 65O!!�inʎ�sloWcoo�?E� roH5em#T�"� N�d)��W��՗� *�O4 ( ?т��!� fKi�si?�s��9ͣC�դ.5G"4E by p' -�\q .��/ �"% !� t!� ( 25 mg/m�q ��� �:& )�)!�6���is .?�*-Gis de*Q�.%pan�D(@new-born glucagon���Uqca #g/�(��er�(� s�A8βN @thu�A� �pi�[ � a si�se , Pax6-w�� �on"���4;�"�(��g;5��` roacL2e)a�"�6 i28oArx �in α- �84 uffiqC/�o*�)� dult:!)6ay ��>#��/�pA�� C�DinuR mo�:z��of pV-u�� ecur' �� dopvh cr.! f!��Q+q reby% !�d�@&B �PA�p6� upon%O=e. Of �,eUY#Ar �!�U��;rU�E . doR-��Y�G|>ev2d�at ;�-i� s�+aRmZrQ�!t�(�EheE�Ehin��Nq alm%��Q%H�eb��ATe,�be�3���oxin-o β Bd"Ӄ. Our�<h'ɳs�f)'teglimTa�%�rng�.� -�,��it6>lS}ar�gets/co-o�,�/py6newqmn�3-�*/ aia �.��m}D���RzQ�tw�k�F,��fct5Ys�4exm>.R.K!��9AJ���v�H5�ir�*~-�'=duodenum��w+anc[)a���e�(w�`"-.��a%o"ELbTvascuL}�]2D��N!sl of L�nrh��,��A�f�5$Eosubtype3α- , β���+PPEZaX*'41�69! horm�W����v , so�3�/ighrel *nd1���]opep3f�� &�[1]–[5/+T��1 DQHMellitu6 T1DA s%Jj�Cuto�� ?9��E�n���!S �61!?l�["4in ch|� hyperJemi2�Cur�!ra�ol�a̤ٔ�+& |�u%<� �Gin ��)��.*&5G!|�6cY�|"un��� ��A �ap�r$��e�� l,L hkex�!7gJd risg�Q���p-5s [�9�A%� eff�0�sign im��e-�!Acc-.research 7s�����E1rogra�.l�m��'�Cz2,�e� and/�c M��0)/ac aa��Nbe!��qbk� *��M-E� . Pa"� .;���y elabo��am��Y morp�M.�5!%c�On)%4)�ex!� tern9A�u��A,eA�*�a�1m on � &w�| �4EUg��[qtissu� ?c!U!�!�a� ��w�Gl�Z�[ asca8of%�.u��1�e� ђ, [�1Eh Pdx1�yY0�b%iw�hMJ�velUx [9�L11�.�bHLH-a�՚&�0!�� NeurinqNgnم���s!�^�[14 z�S�� �md.�� �7��R~MD"QonkE�pla*���<ŋan�'p�!��DaU�!�� 1��)a�is`opqng !�vi�t$�)mbryo��&� }�#-! �tow 1y�͠�tinies:��D4n�3ala=&@=(�����δ��Q���IvMH1_��f�BOP )���w��..�s.�AW>� Dmis*'I �x � ""8 i�Rn� Ajja��-��!w�or� ch6vQ[2�M#`E2� ^� )[*a�"b"R;� �i�hgx�!q&x �J�MK] �ty� l&֎� 1&� s�g7 �u��a.=��S�*ch���M". 6�[+�, [24M�n(�'KU� V%(�ABdur�Y�.�%( �0Nper� �A1Z�.rxA5 *p)�' sou�a�e�F&�k^*� Mfei*� �_2�*Ep. �:T �7n)we����d�K�"5mod��a�� �5sD� oE�"$bY� �r�. U�q�|H%*\C*enQj^e�HacLE�9adv1(d��-�<b&.AQ� �"-�s�D*S�) �F�!? AF!(} j�a �6��2A+ "fAZ��i���  >8��y��9cF��aAWk0 �Llt��ly.7 i� i]�$hy� E5 "�! N��m>ev�d�Cni(�d�Fe0imp�s"- %���Rem� 6���U�0S  .�G2�U%�!��biP%wEa�,o���!�le3��56��"�"&�P:;t�sspa�f`T�roa� -d�-��hc�CQq%5A�we�!g��a-xf�2]3����S1 LefMJby r+e�� ArxcKO moo<� �o� .e�� 4�a*R4 LoxP�7s [25]�m#Glu-Cr�Hns���(G���+a�o'�m�T2w灅rr drivI}2� �� phage P1 ~r�sA�6��  aw�yA�ic�:�3� ArxK�,� qS%U� �ROSA26-!-N�2R�+--STOP β-ga�!isa"&N�� cA�9�ubi&� n9�8ont1NX3Av��8sZ�a!�!� �ksid!Tc ,[27] - h��ޠ2�4Ros8L� Ala*�pur!��A�r�es��8&�P2��e�cy4�P�x@~A�`�!�tEi8�&�q�*3�+$2 week-old�6zy�6ACre::�Q�t&��verifݧ6�Q�&!A���~y��;o�&PO�>2��x�H72±7xl+-�Ѧ��&� i>�� A–�2���l�%�IM*�)p�E =|*  6zU[�.�age-mat�!LiaTtaii�VedE<��*� byB�stry:�~i��e2�E8 �5:67±62:j`2G–I�sn#to��_� ild-���E=Y D–{�!YDo��%A�A�!� Cre+5�FJ .Yn��Dӂq�5�Arx−!k�Q t� �D�*�"o����.�In V�i� �aFiɢ-B�-whead�P. Las9 , qPCR�u�ftom mVA&F%b =aJ �4�ariU!&!�sus!B~out���b74% r._�6xs�qiy�'�R4cy%�)/Av] w�7" i����. TQ3"r,E� ?s� )�%��&:al2  ,A7���!Y�!N!�> �.* �A����IA^�'�Tz���\ � ���it< �p;BN���9�1 RT$q)�F�E�roAm%e'�e rtTAI4�%�b��~oAziEa�5�a��XZupua;�mo ��] ine-&`E���ZC V�#M� TetO�f-Fa;wh�Age_�NP� T!�� or2��bR* �30 Of�;1%::{�&Ճ&�[�>U DVle-��5A�ll.(�i2+Ind�� � Q �"F�0� o� mb��)17 Doxy-u�;xd5th�fQ 2wxmDox+Hll ZA�&*rI�� �� l>;�i�"��( W�4cWparts;A&y c�F�“Do���or�@)o���.�1fa q���wnd��B� in 1 �2w��.�B+87±96+/�?!, fewa<�X&�X���y�3l����z�{��j�6�!:qf� l�}mc`�B K%Yd!3E2e )�v&K fertc�KirC�����LbasN+��[ځ��rmal +5 $�S1- >�aa�'�Mi�XT6�m�[�pI�)5�J>gFu�3b �T���Wrg���"B2��x���(>�"l isle6�U1 �5:S Q�A�=1A,� �.�W V c�/�oԒ7�ag�Od �o(K&�ap� �oalbeitz1�Jau[s)X�" !�4�c�>g.���SǛ�]inJ]E?>_e�=$�!]I~�ap<�du' �Dox� ����Gt�b -�of(eJr(Qt sorAdy!�fa�� a�w�\U��-a dram#F�� �=cKv�ne7�u �-]umb��%.���r�T�i2B b���ep�pro�; @�gX�y~&�?q*���iE�!:�-� �Q�0J–K , Movie���I�A�(� :��171��� -eob$}�BA���N+I��yAma>�.� u�Z� � -�A!���a�ɯ�B� Ao�3a�JA)" ��� I��4c"Nan6� 'm[��~U-]�`ascer�!V~Wt��2}in=\jFZ9rp�E;20(�:�$Zr�� �$RF�:��Ѳ� �� e�fa f(_ s���O�� PC1/X6m  L� Glut-25M–R�NS–XNkxV�ЎQY–Z�u, Maf�/ S4�= �tD7S4� �HB9mS4�!�!� pan-9�-� Pax6.7�� �D��coo�;L� "��'su�s Brn-�Tg��#s"�b2$��/ee * aZ4�e����qS��s "e%�u�2��5�� U)K wx��2i�bh�%0@��eB:ron roVBy& wbM�%W��"<-g�E�L. F2;:�5_�K2C M�m�s�h ,�,app�xB � �5ZLf }�B� N.B2"�hu 3CP�"�–�~.�q� _�9�:`6�b6f�y�1]u�:? of:���hA�F ՠ;mjo�0Q�+�e� C , �Ei�..*V F *�e.!a�w a�!) abno� lx�cH�,S'倁is� , �T� adjaz2�(��>� ��.;` f���.� h̀�^ �}!�1�or2 US5A h�W�%�\��� 5$�[B�MIRAltogeW��Y�I�]J���s%N .��rf�N �a ��ch-�]� !"Я�rue�w)�.9j5ͽsG:Q l5�w.�]z Bdu�a-n .8�*X! �R 5,&� �;HtnW*N.ut���tb��g X-Gal�7 a�z&U5�g�M"� &A[��s,!�gal:.�g��-\m\�e z�2!�b ats_&�i�"l�-��.���I2zi*� BMX�!� lso �BcEj 6�eWc�K/Gٴ9FBh. B*� >����� �� !B�O5�"numerHmPf�5�<m&0 �vA=n�$n:#h�"%A4X+�&23��Y�&zN*%-��s�*ţA9mon��!��a>>$9��* A6�ue�a���6T30�40,neo-�ed!�"�!s p�S�2aU�.6U�"ph� S \�:)Ici�mv4vb -e���A:)ow2�p� AL�lyU!&�6�7���-"h �:�aJ*La '(�4&Y)&�(.*��co-i8��Ia�5,B�baj�v)���>��: 6J�Z����"y� �Y0*�.�G suppl���Nidoa� ��(` �h_�mEE,�.0�w2�9�%co5�::�%5�t#�C�`�&A�.�� !���B\`g�Q� U�)!�Qab6;'���)Q ��~�+ba%�U"�.B2���C�CqFZhrKa-y62�YG)�dνth��. H!�o gC2. ins���m7ws:@:�%w!;�/�$�W BrdUy�^�2�� KI67�>�5 in 2J:��a��subDA�oC ong-o) 10-day �pulse-c���� %ths>�duc�ep�\�o#�RiN�$6�G, E , H�, C!Q��x)0�`h_�2� �!6 �@�"� 5 XZ; /2{ D(��W6g o .� -'� ��m�Eu %�"�i*�M�}j�ri_�s as 13�3�a�;6��.ɼ� �#a�"W�d��/ +���)fQ#�LA��i*1'd&�, I�*����hr:[duc":i�(M��C/w��Q�ic7 liEA[31�"��!�gSclw>�.�.�#-A����a��0Q�53�zl.�:aƉ_?�<&� �.|, ę��=" 5a���MIR� . "wix6>"J�k��ڜ�`0 d]4�h-6�t � s tr�:�11 G�"A��7&� 6� �&p�t�3)! , Rfx6 [�A 1 �h�$�0QN��Tɚ-9��,of}h��� �!��6,a*v!par�}yc>�6pw-�S quer�63*et�=vi2~ n�"�{��D "� �7� DSȫa5". �vo&�`J�3.� �To�(i�%�jypMla00M59�"a� .q EW 7�:P=�>���F�y�Q�s*�aug� z} +�VN �>&\3�*e��"Pe��w�@�aE(a[.� �?�.–q8!�'R���53R�:�d�>�)�c���,?+`dJ�AC^9u#�JD��q� 6�2,{'M�jz' "����8BiA_�turA�%es�!�rA�*�%2'2yB.�/=a8!�M pr"� ��H�B�N &� )I*5�5�-rs��!���!�i�Aew ory *eJ�, -1^R�ѐ:�2"�&�17am�j��&3� ��� W1!&�<2 lmQ6Su_)C*� E�a"c &��N),&"tN�. . It�"�2� re��aEat�&c !FB�ymw>8$U>�!s &!&�s%}in�eritonea�Ouc6(oleQAe�I\se9 ��["�:�W>�@�'G�er�>�"�?V�#�y�  eo��b !Nro� capa��to �-� �Ac�f�AcAC3 wh�^` �e�]c'5"��(thZmeI@m@8flf-��-�s ):A[>�%�"�.4���#S�� x� �a��#��>J�=-��7� � a!3@h�%+� �6�ɂa�+%~ u �!A bolu�6a M(9dE�*�"�#��6����JMec){.�=�- in}u,Js�-PJ��IX� �7 'f+�$�6� ;U"���h�m� �1�*�i2@ KA&�:6�� 5��� &89��t hus![� - �RL A��gigh"���,p"�to�gto obl���4"�iAIC)�&ƀRr)�m 2!�-�3 %��/Ff�(+� t-�a�+)����?s-���** 6eoi"�9�n%0���t�졹a<�.�� N�"� E:Fado[�4��F�! inue3�-Luntil2� �F–G>\�mAl� EN1F��E�moat 1K!death�< :2Ps*l �v>I _fs �"��6��gn�d� >�vR�(*BN{&-<Y "sF��b��K es4re t� ��g'"WN�0&� D-� Zeu5��%� t�Dox6� 2�i"� �� � s.�*��tr.�&v��G��M= fq-/rapid.[2�:3AzEA��{>>9Gbalanc�BF�5˲s9#w*U�*9#"��@e��=%:�� �9jc�� 6.%&m ux<*O !�UAE�_0Z�魁� //=lei ��!,ak ̩V�I ɨ6�;8sxy.��S&PoJ�,Umic�ba*�9.M.��vRs." :bJ��*Jketo*�" 9C���`"R �Q�.���!� >A�!W��/Ot�)��2� B�56��&(; �Q� W�ByBkQ�k�'� E��1m�����2�,b "*� ��8nd� ��!K]�:�among�p6��ar��). �A>��ycl�%.C Y{8Ah� 'e��.�O"@AX"L$p:)�+��a�* �a!+fo06�->K6lS2=w!�)B^J�.�ra�we�I�;p 2EoP4* �m�H�WEhb�7,&k^�&�! outc��.*�ma,=� �dA�m@�n 9.�W-<A �!8 ����&�K2J=u.e!��Ftg�L%bP@u!l�i�  1>' �PUe�&A0\p�ngI6% i}J|0e"�����Qp"ۏ�R� w�d66T" 2�Bf"a�,l&Q�.�Ts�I�tn51FT��h��i��? ��+>�9� w�a>=./Bby��ck-9{f�oA�B?�CE d�[3�B� �[O9UN# :q�!s"@L�U.K:G�B���C:: �::�6�r6w8K�8/+_B�GRs on 6��1f9.�&���]Bf��A2�"i 2�"r10?>�a+�3�Vse x6)�2u�)�!|�5A�toYd�������>/YP −/�>.�% 108 +&�,:�-mJrip�MI&9c"E.&GB�'"� ,r���C ATQ5Q . �isF,�+��[ � ��2�q�M5nbe" �MA  �ua�A��]D1�1g!Hr �t�v����ok���.:I.� �5.��7� 6o!41hN* U K�t2T!��x)pe��5��:�! �V%�.�0��!C=!r�)W�%�,"4E�ofE��.A� ��R Hr76J:ofy8���"Z�[bW8�AV��(127±7 mg/dd 121±4 ����� ly%�>�� �p"^^kl_A��QfieeA*2�KBx[1&�>sƍ2���Y�1�,�T! `8a.�&2!p�m. {��:�."wF�.k%{s�a:aġ��!� B� �/�k4enotype simila�r to that of Arx mutants , sustaining the notion ,)represe,�the main player involved in α-cell-mediated β-like �^ neogenesis processes . We initially analyzed two transgenic mouse models allowing either ( 1 )�(constitutivVactivat� �din all glucagon-producing � s as soon they �0te hormone ex! sS()Li!@durEembry�,) , or ( 2 )O inmble loss�-9@s at different ag!!@ In both instancep!�iJ� was found!�� i� I>= %� addi�, quant- �Cu�d� show%_$nt vari,�C��>��compa��Eontrola�OfAse$chB�� .r 4PC1/3− GLP1R ,Q�A��y�� a m��AG ���ye�B"G !D lack!�1 al:� ��\ll r cau%/� r"�de�;F|a� of sN��@-� dete�� ] � ����at.Vm��Ere ��NorB%umpens�A��' I�5up. Accord� 'QMArtage|vokedi)is J20%�� ����,A%s���S� �� A�6Anumerou� ? "�EY"ci�� D �Ra)�sa�rsar)�)]!duc�jl�Fead!� with�is� �UX ,E�s re--��R� oEdevelop�Ձ� pro-&5Ŗ Ngn3 ؅'>�samq�sBme<underw� 1ic� lige� [3� [32]��ARced.� �}i"�s:> Alo ��� �0target , Rfx6�as ۉ� �-39� P���!ca apitC !�,�3 leasoa part!|9f";��!�gra� Whe know9�al:� �& %��chA�IA1!L Myt1�a�` "��(s a challen��qu.onEX��W�.kalquickg from�M���tA_/�I�in which� 9 �s � posi��T.���u��w� ��s�e&O sex��c�9a putaZ]�precurs�zell nich�; >act n��e"�� e%anM,A Fa�mains�b- terminedX &do�=Vbe � �V�,) qPCRA���Vnotm� 1 �.!d�k@E class� h�Մa�s (�Uas Oct4ABNanog -Q t�n )2�!�� s�Ti�ţ.Dhav� 9Nn dop �-[fR6 a�cAltogi"(�wt�$Figure 11G�urji%͋& ����>�e�a ��,�%C&��!E�toB` a�!0ory mechanismI筢� nd-<�dpr�_��aV-� p,)reU| )!ja��l� '�ؑ� ,�uacquia{ Jan>id� ty��m�fse�r-A<�dm���ܕA\ur��)I!J� ^�EOa cycl 1avBB!�9e valid�pEdX cept�requirI�&�tr�4eQ�!l-�LHNF1β!~(nd/or Ptf1a5�"(.1~ employ�e� /Lox�to&�eE�se:o A is s�gy&lYbedKfol�!�]en�t��!� subS | m5experi���Elow�f� lud!Kat� �ne..> db��nve���&0label!|.�q fu� matc]1equ�30–40%�@�.�. O\o!eA�efore po� origi 6�β-galh ��lary"N !uAsEbCy�abn%����&- a�si��somE�$:I6� pathw���ba]��, J �!�ct�q��ly ��2�{ ��>��A�<t��b-7 . An$+sibil��Aternmatos��x( �we&� a l 2%thgak6� ��� �oteQ�ngk�; �.Bhyp� size��oqA(�Iͪi�) priox *��@��B�& 1rN >i . La| .�! F�b �cinar �as`gan� "� P�AE��BF*� �k�/ g�}ioY *_� &u ���� ��" ��|mpl�d�a>���+/��+/�q B, y�gq,P�V� ?�TsJ���e b8ofa  ledg� cursly impoale�a��SZ-�mo�� still�*� A{��. mworth S a� �,streptozotoc���!���mSproRM7!Freb6K�xɡ %7�aU�>T pha�a�"� EL*r9�/facul�vk.� j��bP �Xz��zxs���a� deple�. Y=��+� J~&ZY}!� �o awai= c� W!Ver=��)In6Geff to ens :"� �n|.�&��ZF�G,�Vmonito%�h�C physiologp param � performedJ|?Av��tS  l� mea�AzsI�/a0"�5+ll\�# &� � %-&F��:"mas�p5ofH���* t6�&�despit�. �~���"� � > ,!ex3 a': !��U'1Cr�hQ�Na�feedb� loop7 w�optFa�u-�,ma��,%S"�*e�atiB.�qm&}le plac9 AC�genrcounterG-�6�-� )�e�ab �! � by�&� ��deathA- chro�#WgO. Ite&B"A1Y�+-6�l�"��!Jy�� l�a�llenishA�!pa�Q"IW��er��!w�survival�veMen &� omi-���toxin&�>��!&��!9v�&�#!E rapi:*n"�!$fQng)vide e� ���so*V$��"�s� suf�# z%e9*: B��-�h��ʼn��< =1��9�s%]�!�"� 5�haof �rip�3h� of diabe;�& archr�3 � of���R<&��Cd��V%o~�apu� M�n���I�u�`�*�o���b�%.� .� EW�&, PUL� *�*�,!�� I�}v$aA�e�%?!ed�u $���#ly" e wh�!Rfo�E���� ha� a*��z.h,�BZ�w"jI �%!���]2|!of a�ZUh F?.| Z�c"� "�)*�'Y ax4-]8ng � 44i!u���  �A6�ban aug��a%^m�i^��a�=�(io of V!�� s cl�uct� t!�FL .��� ���m.�*double-�Kt1pr�o!in��o=�.����� b� deri'�bEY�EO B!"�! �� �7AG� �9�.:��&YaN�+c 9 ٥mJ#. J:t�&*2�. W��er�� sm�*_m}apC&aim�a�q�ng/�ng�i*���"+�4pen new avenue6F@1 aiHo ig���M�N�tocMm�i�$r#$` ٪ Al�]work Ucona�Q�a$French eth reH a)�pro�!QeE~�xp&�E�aal HH m,( NCE/2011-2�, . To racternL effea� inv:eA�!��b,9C�.jm�u�. Firuus!��e& LoxP�,�� Cre::Arxc.)u J��by@�$M �* de�be�,Jm%�� [25�)2Ohom� o re.�&bX.seX+wo �i�ar� �$e!� ex��a�d�E&�5Q:�,�$by Herrera&�(26%L:�&����achie��J*�Rd�$�8ROSA26-lox-stop β-GaQ�-F7]A��!�>X:: H ;triple-�(0ic2"S%;akAadvan!-�TetOnQ& ( Cl?(ch��.}Xob�$��.,!rtTA ��\! 7�,%E�m&&JI�>�]`��*��.�Y�[ Doxy� �.PAA�h/�"��UGB "kw�-Tage� b0�N?'���� mq�(�al #s�����\ XCmou. For� �lwTe�� datzyet��&1.�. ( Sigma )�iad�.�"d via%t drinEEwater�� d fresh�D� a week��� n:c 2 g/L�Ba�2s��u�+6� ��%� ed waHBrdU (�F:�)� 10 dw"�.�) ( 1 mg/ml)u�rTo*E A���Q.�9X � s,I�E�in�mEGtra� toneEetwa�daily �5 µga�h9�!�*#ek��oQL�U�-\ . $A �@�al�ckout �,!�o �� by KordowS!��-���e�1�a�N�(>::��3%uissjQfix%0 4% PFA �0 m�t 4°C�mbedd (�ff$nd 8 µm s�&s��li"o slidE�TH #u�+Ms���[19�Th�imOl(bodw eqHA2�ing: gu�D, pig polyclo!y:-� A�$/500-Linco�l]> �� mononPq�a@tiFP rM+$.+�$250-Millip{�5( KI67 100-Dak �rabb4"PP �J@Glut2!Chemicon`1) JANkx6 . 1$$3000 , kin��� ɒS eller\dx 71b7C� right7NeuroD :Z�A��4bZB�#osa-P�#�b-���()� ,��� h��5|HB9*J:�!�0-C�l? MafA�Abcami�"] :��J - Molec��Probes )Y�(: 594-alexaIE�; 488J:,I9B-:.ySB2jA�. Pic�/e�d- HZEISS Axioimager Z1�$LEICA DM 6!�!��~:m,purpo�*], silico pixed1u�g � �+on �y j,h���a� t. isol��!�02���U �:1%/maldehyd, 0 . 2%�jtar:02% NP4#A2�Ar�in 25%�r��4ne5a��. PV�m9 ,6Q.�freez$mediu�(!iI�actosid��� 9mp�2� washiCPBS%9t�incub�2�30�Yin "�;so0( 500 mM K3Fe N ) �)25 46a�45 M MgCl2 , 40iXa dDMFiw{#�25", STZ��A9 diss"Wpost- �%@� 4a ONETOUCH Vit�o� ( L�8S,, Inc . , CAE`RNA%��?(eas�8Qiagen )%cDNA syn-i�)SuperS�) cho� �5f vitr9A�"m2��manufa�ws<l.ru.0� Qu/ve RT–�*Scarried�5��G*2 imer�2�o QTA$SYBR Gr�/RT-XKit (4"� z�;�,oR nd" �)���MAyrler ep<lplexEr �GAPDH%|HPRT1�|5! ��m2A��:izk �hiultras%S ural ɇanesthetd e:E��Ņ cardh@Ei6Sserum�[n F3ine��cacody����. �����5 , immerge�fix8-�h}>� a ��2 �?��osm�tetrox�r�!�.e epoxsi�qC�3!�d)Kt�0�%�( 70 n# %;"�C$, a JEOL 1400)Mmi9>w528�_�\a Morada Olympus CCD cam�)� immuno-go�>��, ��j!!u�b�)lla�� &� ) di?�I��^ %�4%; o�=cphosph"�oPB ) �v7 . 4�#v\4C !�%F&w !�E�0cryomicrotomy6Da� ghtly0if�DTokuyasu method [3� I%41.Msn�a�t�$Az1)e"�)��,Leica EM IGLm�_ -� ��"� p6y!�` �[15ACcidM>!�conjug� prot;AG\M�UniLty Me�8 l Ce* , Utrech %� N� land� .�!� ��A�5*��. OPTI�����;T#��&�&.[40�,[41] . Each Ym�A0(can����Biopt!s 3001u &r-��� of 1024×_ /On�qe�NR��<� 1 . 9. 0` kyl ) softw=..�Cf�&hi�:[A��%btakenM. ImarXY ( Biplane� VoluA=ecalY �by��<a “�  o7:�9�$0nsity” task�9( voxels abo<)ze15q�t E th�A�value���d&�or6]3 gene_  ��V=}sI�extraR8fn)eA�m�proba�'�=6mYs�D/ �P7�a battk?�%�or2�1� re1 A�" 29#=A�]l Gi�#8globaly4)Ise*�(�t has �<peK'�?!�a2]�Pd�1C.*�@.9e)\d��edi�GCw� � 2�jdis��Dnwis C!s�[ot�explabaO7cD !�cy� t4U?.?M.�  S*r=l��3�EE8 rai� j9+@.�&2i7.J:�� )kA�� l�E?/.)&IG&ct5oF�))�� novelA�ea�el�()�rm3wBE�o�&� 9��wom!�6I% confbCn heterQ(QC )$.�1Kar-de��b��7enhan�'5�1�r2f adja�D��t$0!���!�a�"�7.�promot� RIP�We)�m�A�e�K veal�����m&�7k �Zng>LA�comAqi!. H), i1,2�dodH� "�>�KD����as��A��+caG�1,\0��gio�J�TO�Hm9sus�(�Mw%�n.tthabC�N��)�ie&3> is t �s�Oit oc~;� h ��.{� [� " Cw�7rit��.@.:�.&��Ce�% mak�Dhig: %-i6v[2< Pr~+�:@�0�aICe��!�2ch&v=��=C��� .) �"nn hundredN)I"c 2�Yv_N�vidual�� be5�E�olA�i6H�to avoi0*��^!�% s [3!A$basic�-at�8B�V toq>!G* A8!I�N semb�a=p"s 7amlex��i��ifi�0�-e U>�W step -e���d �loaY'mHca:r�ve he�se��,�>ch!��; tora � jencirc[ d)�eE[ NE�zA�a&wbIPr�&s:.Brecoga�onp( ORCrCdc Cdt@nd�[8[_#I�!bud�y�@(SaccharomycA�egsia�Sin3��ki� CDK�g!�multipl2> �@�AE�)cs�|E�f�re1of��;i<� [7A�I�� orga�=,. 4CDKC0����E;j ͧ�EU\ )JIWP@i6 �(  a9=���, J!� reli����".�"J "U4in11-is ���G�Pa�,%� �aradig�Aad ] �(�h�!k%�: pa�}�a�Pa �t<� verlapp!�=q�abo�9�"�rl�&�Y�:w�vC1 h�odd�*�ng��&�  [vKConI�dF5$�' srup��/nd�[�often�� P0p2 �r=9�K���RsuA1��%��-ob+� JMy�d)��rA2;� b!�ad�#\�. D� o*G��3B�*& E����nT�} i�:i�JsumIbZ�.-jl unil�ѿbymA���m��[121�������en�6,�4�� rW,-��ma?(, 10_�)Ma�yr�2 O5m�N:C)� .�e�&i̡?un%�I���<� Ee#dx1��2�i;�H*t� a� corr 5-�A��of S-x: s�!"N�BZVch�;({ k-�&)�rA�_8s� 1 8l� [1, Instd6���in:-�!"s3;(D*3 r!�5�?ndz\�!k�G�\l�+��4�6� < ne� b�M�+�;!xa� "�A%-a�mod RN� !2�K M�B��_6��8}*-��$Sa!S>plA�_�.�6�B�>s! why� 6_ IJ66er��t*� .�res�V� >�!�~ "�(�We �9Zt-X�&"u"�1Z�R+@56G� ��o� }�a�\a\. F$F�E��l al"�  !uHa�#]7A�silh ngA�ecQ�Me��A�2��� we �I:�- E#&map!C"M~m}A>a�a��NE*[ m�F AnalEs�(-t�of��!�9�2��2�{.on<aseo.�I2ope� sV��2x1E7e)(�1f1�1`a��ta�b� t_� ( ���oof.jN). �#���m�u��AU� �^M:p �Z���Piu�(*2 Ms�.a��?�l kst�#aE�0������W9 ",,"�8�6�~predoW�9TARS317�a��M�a5儵Np"� ��sm&q e!�is6MC2Ao"�H[�+ �1�re�ys:��M ) -�CDK d�6nN�@Y��!"(nucleus [15� 7]�%��$f�"*�a9ar O�!@53�K^&�>�`eaeJ7; �$sC2�#–3�3A;ofV w�I-�� � �#i�,-:[18� �or�!ion-dir� .Ta�J� ,!- , [2� -�b� ng`!��t��9�b�fq�>�Qa5t�t#�3ly 3-f:(OSaF. :�AkngR�o!�64�W:twodrY���^trainq�!D>:B�( 9��K 3~wrlQ un;�>)�Q6 8$Clb5-Cdc28U� n RXL docE�!�=��RA�"�1�"� ��%��Б�N,=6 eB�{ �9 ar� �eta` �Ba�2C �iZ+a�+A$e]aDAzJ��"':��:�U >s py nBe�8rra�$�Y"&jhybrid�<( aCGHZ!Al���#6b�tQa 3 h�KN:a4� r�s!Uatq�j3 V.(profij� ed h�)%�Zaek23eak%��c� loci^!t��dieH�49"� kir�-��V er 6~��@c6�0arm�Chr 5 n��p0U on 575 kb-ⅽI�29"$ e 12:A890A�11���ek!l"y �ARS1238zs�ish�3l��0E.����3e6J��&. B�A��%p]�@!�! �2�ng �Ow�ec�)0m�i* "� 5P m� s6:6�t*� �� soughW�H$J6B.%:Ro��2�af&;S!! �(�)d6�-�;!� s 6#a broa�[U(*L %�spans ki�"H!of���O� :i Q5�A-o���� dsie�� k"�" ���[e6� � �V�V*"*}(�cus� inT0 3]��WAj�_�7�Qak��% !�no"Aa� betwkeNT "�in"�!�!�206fQ�c"�^iM�{] �e)!6^duc� 6��R�(��<�ʭg6Non�(lesaR��0��5�]G���A�A�n�na�317A�q�M2y�%dg#guish5t� U�uxa�/!cv�� �dzA sA fraWe���!���or �&1�).�6b�Ian in� �l>�W��I�Mon�e�we ho��PkZ�eno��hss�/I� ot�-level�0S4enA;a� �)Tny����b�x�m�b�$e�(.:�. A 537�#1w/:�az%�!yA9Qe.W6o%�:pFits*� EHe��:�@�*E U��hrIV_567�O,�IV_1089)! � d �Ol&�NA9amV�� d  i. 7–3 5+�-�Q/l�ޅ�%�r�bjCndG2B F o8 o2o� ��"n�p�%S  t�n�H.l ��( e!!or�?b h)��Qtu�)�k�c�&��1>� i��s$igi=R�P,J 2A��w �;� �er 4062�� �7�f���:� !�2Z. A�*i 2�a�p233��0u.ev ��e�.� ( OBS/0�&laT@q�!>-�s�%RDO٢e�] N !�.5�/V�!�(�!by%�n�il,*� �"n�.!0�1ia� v�a 138!UE�*�`er HMR-E� f0T�� %~recru�S �2"�Sir1-4!�� z� su&� ��a�)uc�Nj/�S(  e� �:E�? Wntire � �u!3dI 3�i� /��I�-MF�Q_.�?�.�&�� F� be�#�( ���-i�%�*5 [�E� �ScA�n6i sJ*O$or�>O.��9���,b2Q$Drosophila" �3To te2a�.~,e? ,Nle!m�^�SIRtn�%�v�aE"��G)��dVsir�`e�� 3rem%�o�r�cwild-^�AroOb��#q�B% Se�|=d)0nLn� �S�s�#c "� �.�b0k ���-e~22X trunR -cl��o RapI� AbfI2#�9��r*G&��uL�T [A�"�2��6�La :�9r5�<�s���'�� H�&( toB�e�! ) WIqt�P^,.toa�G2�%!.��+=U!8NY# li�5/S%0*�q!�U�LDlear-cuA�O� �:ors�t�=fl 2p arba0��9�O`forkhN����QFkh}@ Fkh2!b�-avI� Q�� 5V j�spa��w�S%�or2E"3*a�&�!DwiEt)?��J#�AS:� U�(in fkh1Δ , 2 � fk�� .�u(2D6�r4G�)S2D�fkhΔY�ed�I1m �ne�%v&�'���>.I��)Fh>�G�4l;# G!.u�uFa�a�wuo3$,v6��x�V��S�2 �51�=!� 2�![gQA�ob�#rul�tNYol��.��r\!%6M.�5w�f!� � �e6B��{5 �d �b&� �h�^growth6x��A)4)clump�`\a��8�BvT1Q F in liquidDa�(g j�"� s!c"� i*NXJ�M inu.�I{"� �emselv�]�M!!��@�V* by�ghbor!1HG��>�Ti&-�� Emn5�aq6is�#0 rele�OE� �d"~ eA�#t23:rd�C�B�S�4ar.-g5'��E 7��!p�[3�'IA!�6�'c�<�8 �sM1 � Y�v�#shNa� MOn. OrU$3� l�&b�$Y, t��N_+% �2 ����ce.�At�c.�� -�^a+*8�6BO�4�jS�N�wnc�rn I�1p���_ -Im,!�� 4V.E��(2Zsub "KZ�de% Einу2\R�M themE�y-A�}6a�A%�( ��M �a.2��well-,}�B��2BZ[DOi�zmpr�5H1�ext�0d!>��,�ACM,�mela�He A dom#]a WTW?~}�+F9B1!� = �-dN�us5>lie 3′�a:T-r�&��ndt�{;V�:��*B�( Bb!B�!� occa�?�ai}5}Bh���8��to!%Cb1T!��1b!�ed � our!M��+��w%�"v�#��+� +33'�!l��o c �y��Ulyi]!bMA�m� chemB5:�outJK�!�+34��1er�ndN�.*� ?�" 3&��b�!�]A��͠g u�{�?( +30zI. -106n ��equival�`W ���-eU�( +13�Va.I�.K!��{a�n�!A{ ssa�a�+�}mid.���2�a�!9. | n�1N:�{[%UWtPA"i�l�eca} ?��-y,te 9�ag\� Bf�p���h�� #�~B�A!`�3Z~,�E� mB� O�ub1�2�M /atZo1=5�"#$byQ*7�C. −I+Y�� !�&��� faillo�96i�Z&t6.X�,*�^A�  �"0eLa+ tZ 1�:z�e&'-�:  +77 �Wlsoj�:M�-"; �8�,E�sl ly�ryB>q3�Gf ��>�%v����%(��6� (a weak cryp�@m89s�r���6�Qd(a�j6F� � � eE�1�� � �5�( ]$a�S3;� ���� � gA!k11�M=���J(>md�Uv!�6 ��"I"�(wE?�3�E ���atae�)`c��:Bu��DU a_U �-�:�>��N< :vi)E� �m,: We�G�'5��2e���D�H� A9�*�OIP!�m�Eq�5J/�kuQ"�::�A���@jbF Al�� 69 .�����Bs�c�.-~�U�Dg5�6DbG8Uinqk>��-*�q-|aA�R�Q�8��Ee�f�I�F2 e2Njp -ev �)^��6m55V ir � �Bs �RAb*d3./$SO�X%�q!es�& �J15�� bo/':���0!�(B�1@ +7!>���)!���a�-�e5�:�enancea�utonom�+�&��jmo, ���+259N jaM��A��A^-h�N boun\!�RIE� �m}|^`�,bnt�+Za lina�AN:NwPoftI�| �|4A; b�0�c�M?�M P�S�?hG|a��ice � ai!9�{b�$�\LD!L15a��Ccov�! e 51!{(2�37�B+87�� O�e%z& �is JrfG ~B�( L4–L� ��df i89��r&6 dV�!�8�B�9 �2�����N��%!+)5 ed ,U:k� �!�^6}=4vPFl\S� %6iS" ��b� hhœ"с DS6G� �E9�� �s �� $ �JuqU2 1�-l� -9�3"�"�*�F,= ���"Am%� &�':s, �$d. impa3�A ���R�wm !!��reu���i�L17�S3�c��s +86a�+2�� �3�^rATe�k�5 hA=m,&&,-R6�uwSmxA.@4�x�{/ve�� de >.� thirb�h�*<%N.c���!�yu�B�6�>� <*z�g�6���2y�to�<���X�eG�"K >�x�81 ��|119~�&qs cru�a�E�]1AsA�c�1n(�.ad narrJd� ( 6  64��� >�c�7�LN��MP�:��i;�!3��4;+�1 �78� �+���� 6o1le!��Me� o2 �!�us�407=��6� -�, {�$+)eu2�:�2I!�.�*Y�;�:A��i���CJb�/ m�0��A) �a1�R AT�*aũ�s�+sI:2%<84%a�r.�*R� ��>P� �K�^u�?�ex+M�/%iRev&c+4224�!o��M�jJ ~8/N9)"/A�fac"��+unwa�ngp!.L%��[4�T���,a wo� &�% stim�^6s�>s�a!iAl)� hermodynaSJm9A!�^�*2S��2 A��3�� �L����&b ��a�&���Qk tA[Ne�%&&&��!�)�� [44]�(!qF� [45]�-�ahan�IO�M�& �V�%� lyA��J6x��,ɺmp!I�K!.a��n.��6;26�a� nF wf��"�C>�Y-�s�7y�(a%.Y�! A aVqs� Q�a~q[y" �̥�rup� :��\r�(in� �H$-TTTATAAA-����6� ETnJD!6r�V� F��(GFE.%A�p>�;iN�+22{,-� � � R\� [*�K�AW nt D�>!��"� �"!J0� "Z�&.�e����H��Y=uw[1cea�R'd=�!iR�I��!A�ngIBr1- Ei�+�a(� 6'�eA �@l& �2�q away���B-f":M~m�� AI4X��=s�12%#�giBj!�"��b-[s 3@iNl!2awrando�Mg�^demof 38��-[ A�Хez rage:�>��R:..{F)"9-��d- &� b�~�n$qrAU�� - 5h�( See M}tia�@cT d-T��Bx*d�!Ţ"�`A6*% u5uR2�dec@25r��!�&� by&���E�-.ma.P"+�"�}Ab� �'���^;/.:��( toleZIN; �!l�to 9��*!&�+e@ 4 of 2�i@lW'+!�Ro�� ���;!ugoia�eTex�^^#rem�{ee "�"� ch�#qe i��.:B<%Dv��͢ad%�6�$s-�!� � mn(��in{K35!?∼75 y v���`e� A��/�3�7��� Ea�!p�-���MZW ���;�qssU��tX@m*Zkub�raD*f!�i�web���-W���Z�>� . �y���ok3� 1%.�7� p :R�MU1�!c0R1�5-�24R9I# �<6&� noMt&LEc-� v �16�4!2��rZJ6.���1�|us!*.a\2E�=�RI63Ms��M�-;!�m � y@1:��cO.Y+E�"r/�"a-�)�f���Wt�,��� �Nto��il;n� ..g,e�7 �*�aa�^(�$�3��co/K�N"Ȓ� �\' �!�*&,Ń� Jde� 8lo�{I(2. .>u �m�)a+q7toGF.� V, keex/!�Mt^�A�1�4�&�dE/%ۍN�Q���! A� � ch�o-ntV�&edB�A�6|�&n>�!-&� TC^�%��02�)�0�-6���R�@Np6�>:��.%�}omP1*�%3&�p��H*?k���1q �n- pHip u*)to�4B^�V�&.1E�H��J2�81@30B ARS20�.��^Un��Hx*O �Qau(�o�csco�z-�S6.S6�(q O�hb�Ce�.J :��f iI�s$�Fai6M; ( 4-�u!�� �,nM>�&�.A��I( i�-.�Mee�NT�%m7n^�g�� �Vi��e]$`ARS70h��1p-�c�Ir���to�I� �QOnH.D, 1��4��>!� � �A����[�"c ���<�E *� *� �!^fi�j�k�# V�ON2K>7��lEr"� ˜bx��� o\�!*�u" �.44(&5�� �4Nv��f�l���CZj;la�Po� !46=06%M-�� ��9��YSNb! -���I�*�Qla�,Fm,"C S6a|. Ji �;�!g>`!�� >k*%JM*"oe�A\!45�| qV6by��p�S�j�!6�t6=�x�n�. SRn"R5���6�;tc��f%� )m%���<6�(!�a|�%�FIse�f>6!��ma�lJ�E�3,ssa*�7�.<e��6#��$%3�Ao/ �j��p�l =ia�)>��c� look�.�D �7byA��%3�P�P. *7.� N%A Te�f1�w�&)l �W�Eqal�M�" )*&.wK�P�h�z��P"� �m"�� �A�o�d*> �.c<�R. Lowc1&�p�� � Gs�!ideal\e8% y�ˌ0QlU� Nian�X��f e9y:����.�aoe��P2Xea6�a17I�F1!��!�aJ���7�At�6WI�mM�):)0&}5� 2�'Q�bIon 2-d�u��vevzF1fa!Dbube a�r�%4[46[X[4c5��)�9i>�+(B�%�t'Ak-��or� aCGH2uiAi *�q:�-�up� ��� vE��T�%�&�$de 3�of GBB�Be A�abs�m��y>� �A) ] i�a(g$!͒Au"���0�Ar*UA�i?�:yd�:)� Wa�us favor�0oded]ch���sV�_�h!.`��)^i�m"( �i�LX+ .�.� v�~ stu��%�J �� �h&�[*�b���;ub;G�f��&��+iscret!�ep"P\':�P�� �[.��[to $"`"B"t1-,Q )--Q�X�3�a��h�3erd =E�r%Rr6Emdup�p ��[4�HA"���]5�s��by �kR +tl�4'�W�i�_ For] �>W!H��oA� �P"K�!xV�hEA�. i WU7e Q2�[4�h5�h&v$#^A|���:EVc%a$s� *|OK �%$oc��cc�O!���wh Amajor_Չ"Ey#F12b WLe���R~(5�p&9 �<�q&N(�^me*�%M"Qm��E�!=�m�Xto ��� �ViaDK5\��!�3 w�y"DaBQ�A!A1�Q �}� �rH RG�3$�o2?��a<�=M ChIP�V7L��FL`)0 �`:�k/41�Xa�42$As�H�h �as |��H# !L*YB|!xnon"i�G1q "?8?Q��mB!/ A{ua 9�u%5 �.�"Zv� me en > ed 2��×);.��k,�RACT*�8]8)��8�-K �`ef6oE�ouM!��1S�]�n.�Y(���Z9P �6�gi�{jv2E���=��� � �Ti� &�"��!��[v a�j� X>��.�T�)yUB�*���c,��nٵ:��,6+-�o ���s 8MX-}�­�,>ioe�*h Y ^2�l��[5bUT�"0���!\%N�t!�?>j6�Ng�\-��)|- ����yJ����f nV�a�d:� tA&A[or�w!���bis��a�7� �!�b�< b)belowAaUQ��mlyF ��v�$9'e��#$in vivo toi�~X�2�Y!�voP�.�(1m.� e�|$W  *<1�tro . P �6��=e�ow�.�h�!x2�1�ervt "&@[E�M� �E\s<ti��!� "�em��"!=�"�7uW"+ b1q� Gm� �YM.A�EC� I�1�� eXt� 'Xu rZ1�� 1�7,p]h.cw�g z� �� 6 soa�!]�tot�\el–�&B�P ws�"�X&eA�:�2"qCwor�.BwG�Qir�XM��s��j:v� Aԁo� FEa�l[A� roug��MI_&c%�,an�U� � 6Wt�Nff�8��11py"k�4m=��Q&��F2a�6 s>�l��3�o���.�/�.A�ofmal`�QE�am�o�}!�&�z���~rm4+* B�2�oao n�� YEm�Re�is��`!�l=� �||A�cA���KsnQbP-m��M�� �#gf�.�E��"�ce !/tsJ[1��A�Q�~8n'EɳbמE�� �ml65%[�E9MZ�.\hA��U��S�N�:"BA-p�on=1�jDs)�08�+�z"��D�C �fe�H� g%��E�a���ut�_ tinc�0A�igi3�1}KWch� >8=3�,6wp��"f ���:"ud*�es�)��L1�!ca.>u%VI�Fi�I���&^�w^?�:�%+(�eP=� W�&$Z�& �� �a�T� pvp],�z�6�"�:gA�la R�KEai�d kl��b�W��add��!� "��of�A�&��.�I4%y� c��al!�z �0ic9�� .msor.r y ar�P�A��8����r�o��# ��Uaac�p��)!�N6Od.:� }exib,�27 �2&ȃb&��ram&)A-� R.-�%n&*�Zset���)5�sA%3?q-1�is5/�"�isSXE�q���r��]l�M�g:G=˭��o)��2�~,�P��DK<,{!�!,��%%A�L,.�R� �� k�qyQ�sh��f|�3BCG WA�9irsq�ĥ�>i�8�/�l&ind�� fu�u[ %�-�.��2�AGe 6o�2��Z>�%�:xj��U*23%��� ~e�&O1&W#. r}3tii�.�&�� "�&�Y* 3Uba�h�1O�w�P � 58%Q s [5�4se4��k#,� FLYƊot.�0t� g�YA�u9,��we0���3bro��0A�3� a�i�%��+��*]4�%A*vly)+r!�!c&�9��`���Ze���g)+6%z4,X4e*�$�deEo�� B�!�!u�& IY� u�[+�;qSt !�",��mf\!L!- poor��Qu�y��!hd�bQ"gy36/g.8 �W!�xQ[5fS55]A� P�P�emp �n�A��/�!c4�)� ��>�TB�]�9�!;Z\[5�57]�}���.� yielraH�omiN candW� 8f�0) ;"�C�yNHP6AB , YAP�>SUMYNR063W �AT4 , SMor YOX1* (�%�u� 7A5."�gwe��pursu)�9��Ӟ�.�J5z%�!?UU�Ev�d]6N���+�d�_d8 6 b�$ce�r�p�7F��| :2im>; �.x[a; �*�,�,}x��yI9�.� or } � �)Yaa �>u��k�)*� �*%b� .��d2�j�]� byo�H�A��/!+�Tr)m6&�a�p�Ely)q*���� e�+a2'"�.^e� � nf ��o">�-�$3on�K"�[13u e-�A<��. Exac���/� A8Y��7)J;by� e*��#+� iL� �_$��Z�bA�2���^;w]J8!6 +��Hf%5 [58]��n��]{ 'vo!�R; (�eg�:�51!`@~ :�F%\ !��0.�k��l�4s��o vioo=P#daA8al*vnci*\r�p.� y7*R �܊nam�elE.��f�3t�� ��e�/B�6� E2ut' is"( +6&ӽH��,�+hf �R�Z-~ �x!o.#�7a�cap � !�?*mv� A6e�|J��NJ �`i �a&�gQ'&x"�PxS.�i����!�:i�q85y#�B2�)%P��l��u.�� k��Bx�)!$��,A�ejed�[ax�- rela��.3 2?!�* �,.*d�A�.��� LMcm2)��[59�%�2�Do0(L)]�7��+r��"�Om�f�#"�#�tR��5aVt�6&8z�0��.4*Howi+Ji & !overrTna�r!V:�e�l_"EFre-fi>#2;*�c? �es�U!���**ri�M���orN�m�Qi�H��z&s�,)O��CDK�}[7�,� a$�~[�|"X����%�y1b=�Er� �6�,A�iev�We-t '-&� Y#�06�a�'"���L)��(�I��36� �"� � ���-!���F��s�'ll� mit�19aH�MRr ��* ���$ly � 5�Q!2��r��AA� � �VW9  ���2.S'CZRC!A�IY]�by���llC�"a>��7:2$�%�s �B-�to jo&! !I�6e�y��šZ36x.�f�T��]�28"� �'>��!-5�t�A^e���/ilB��� ,� �6asɲ]���zb$ ��Cmi�n�@%�!�&}C}#�22�KA.;+� nd soA���S�a ." -6^�#�� ,.$7v�$,�p��xa half� (&�%� ��ly 50aG25�,AF��<E �S �N1 �žin� 56� J6� �L.?� R�� A�:�/��m;'��ef)2�h�FexǞ(!��(.^��!>�Aǡ��.neE�y�a�FA11�8� �NKNn6vNc>��<1�("�52��j2�=A5��+m64�$�lđ6�e*��k#e�7� �9o. ��am>*C a%�f� !�[6�n*��"��>:�� chorI\�&in.�so�Han ic��e���o,yV�*1�>a�2� *o%�.2�� A2�CGEl�  ( ACEt,of�@32]L"� Z%Ulittl")E"� [73 W��f0n�ٞ�b� (�] -bet&�.��m �"w*�o.�DH�ACE&�D 6&� �bmp!є+fNm�ryUwB��o�~2sep���6me%���a��k6�J� edI66�,�I�s ail�>�2s�2� F�/xBH(]��J$fa������#j+���r]+n'.f+y)F,S{IW�yx1�:"^. .��i�Iy�@i��)in"F,%n��u�%�=m�+3U=)+���@ ]F**�}ee-�� 2[T >- bulkn*0��&9�`a_&Y!d"E���h���e�66+Ŗp tr" RA�2��abund�Y09\*�!2O�."�!cQve�1B_�:�ar.� "S!*�N���Z4\�tre�&) sour�s�Pc�2GJ'^���SÌ�y25UIi�r- � �tEeHL�2&�>onc��[61h�6�!Fs~���6\�_C humae��{�|[64 u7I�!.! tandemi repe�$@^�[�gZ�N) 7 6,U %�i:�J� A�w�AeI:6[6?(SGp:�B/A new].}^� (Ł�ly͊�ic?Me)B�,a��d3QI<���GCJ�|�ede�o> �`�=\ &�U��!&�V �B&6=&/��%a��%a�� aK�{22=�r��C�k�>%�}���E-@/ %n zR�s�S>H��>\r��GP8�'�"6� ���eL�.h}b)c .��6�5%�!�f�ef��U�a@ DHFR67wa!pq��C͒�"}�Mh��%�ic�EZ[6:~C*}�Y�� ��p�$!�m�~���'�..:e!6��*6af�%�U�D#]c%�e�e"i |P�)"� ��e�~2 m"%evD�[7� .Sa3&{�i�M�+] B ��higebn�;-�<%hes [7�y!@��r�U*��9jE aCn8B�\a/�*g�.�K� �!@& f:�JT�6��:O;�pe e�r!�*����)�)b�{� !��6> "?.�9|.��������2� V�%]� s��O&�6�V�#"~Ma R (!,.%Jo�E[/&cFg"�!�� � �2�&�r*l��� . ��gAU ;B�L�@�es�Ͷ:O�p ^"#/*.�!��i!Z�C np28�pBJ2889� � 2J �"r):���!(_t� de�eIa���1Q: H��y Lef<�c�*��omY $M)ARS41I�R�^���t ɉ on C���BIV�rAkanMX6] fV�� [7X� ade3-2pؤ)g2'��!lyL\���W XbaIj�$:d�R�(V�!2�[ SpeI��`&�E!��yA�M5 k�&�j�6�M 1�N A�he g�-� pBJLE"��5_+ a�/ ��F>( TCTAGTR]�1f�U ] �e.re-Un � E�DUo!Vd*�qto>\��T�%�QZ r��I��#"�T� �!nF�-,��ec�r}�1U2IFexy��'mqh' SacI-NotIa� Sal���F.BjQ% 7sA $ard techni�,��tu�)k�m�s�mQdAo#NMFa2 �ARSo�\Qp� ?<xD�GF>Huti�jy�-]�-�T. CEN-��K6� FJ11�dR.v*�CEN?LAcp*� G� BamHI)�.0:!�97by -di&+�,klenow fill-c�!���overhan�R�$blunt��&m�5u317��� �O��t�OAzaR�,-�o(- =��lo�'EzK �"X>HinDIII~EcoR1% � ,the plasmid �F( exact sequences listed in Table S1 ) . These plasmids were transforme0�to YJL310 [74] using standard techniques M fullwd of all insertion and dele �mutants used to alter RIP-OBS spacings are J�py �genera�Tas follows: Genotypes w rivay#r�strain �tin this manuscript can be foun! 1<$2 . AlmostF8the MC2Ao yeastVQpaper>� from:Lpreviously published C%zP758 [2] by one or mor%[x �!�!tic)F � : ( !�integ %�$ re-replic(4 cassette ( de�bI+PlMabove-F tail ]J; ( 2 )9�(of ARS317 , 418 ,� ARS1238 (>3 )>Uof SIR0FKH�s62$[72] , [75  6] .%�-:s!; 8923�YJ 4 AJcongenicAqA�!_0but have wildA2 ORC6A� tead�0orc6 ( S116A a9X , freshly!�Twed log phase cultures�w�{C�s��e�<��he closa$early�M ARlso�s t it�68ks would not ru� rough��ayW �{reclud�ir.�. F� d s � 0rray CGH data9+�u�in [12!<Briefly:a�ay��scanned - � $ePix 4000B r���%�� Ge +6��4 ( Axon Instru{��0The Cy5/Cy3 r!� unormalizz uc!a�! e average -E equival��to DNA�et����0specific poin�%Xe�Pyc�:$e . g . 2C7M!I�o!e�M d sa�!�� 1 . 5 /q!�Media� th� raw.�%�e�calcul4 @cross a 10 kb movA�window�� moot�QcuaW D?M�: :�On-�8Fourier Convolu�v Re( FCS�!�degre� st"isAc ermiA(by a paramea�cal� %_`$kernel [81 !=)� e ch�7 some� displaE � h��? {val� optimEF:; (profiles: C[ III , 9;2V , 1!�2526+X?1��75ahor5� | ,^�.�VE�setA�a*2`�!en* onp p�\� %��"� _�vidual>�-� �I2mKH��ne site). MUfig !�*� showB omp2>s��bj � surr���a g��zzre �!�±1&�dev��`eEe:AF��experi�v��0 !�_ workYsee� Doc��� . We���s(at , becausei�hybridiz��n among�varI�et��e&�ele�!Ӊ( tRNA��k,subtelomericJa5Ty2! lue�Ep())�removed�e� . I�},e Saccharomy��me Datab?I�two r�b��reA�!�!�lar��"r��F�I�q adjaV A�a��ad ��n",,�?4e entire ∼44�rega betw!�YLR153CR 63Ce` omitR�2� Also=�eL��? effe"� cir��r�d)��of%�}����!�!+�f,Y��UΥ� �!�aA�aty�endE�4artifactually I�V Mto q>X�\�UrL[8ThuA�w� =prefer!�cre-H � � endo� us lo� near�r� �of2 �ci�~he9 :��s� rise� leftYe�>mas�2�O-�5jV^�.�II) F� 1K2BI Sf� �un �� � v����al�ps�PJ�Bar�.ph�&ree�`to��ab!4amount�9�A���2vvs, rol"�. a0 6=peak he!� �measure l�t� e`cA �X �EK��EN5�4rovide a backg� ( i .( non>[)��. S' siz� !� B�)�s rang�1�5� 10A7�;c in�  legend� Mean�Fu�-�2A�b�% � aa�� 0Welch's t-tes SignN !� ( p< (05 ) resultjec�null hyp�[�~confirlat2Ho sirΔ)fkhΔ5' is sz�fɋ�&.� Ja.cE;Z��EN-ARS p]ACa�M7, 4 co�c�E�^ ���7� � wit� tacB{rol!�Th{ independ�`a�%�ino�aYrf &��n!�(" )%d>,to satu��%2�sub� )�a$ ~�~ �!�Jgan� ��of�� EachF���p- to f�w>� non-#<�-a��20�400 cfu/- .~���!_3-4 d� nd%lfrPI�ds�bor��az smid��&H�V%!��5 of coloni�� B�ove�d4nV� . Va@ repoũ5�A" tByM>:�. ChIP�^&�E�6�20 OD un�  in aM-�m[ 50 mLe2� handba��by !�:"��i� ��ri�to 90��B Co�C� -Mcm ��9b�imE��a�Mcm-re-loa/ohd�1 bef=���Y$A8a -fi��A_distrib�bt7�A6w mA�� q��90-mi�= timeas�!Oaas0du)6, �:kme visi�� N �i��!{ale��milar!z%a� in=�hIP-chi� �of2u�/[13�TeNg24fix� fJ��aldehyd: 37% w/v )�f�%�ix��ocee!�A{1+E@��oNemper�Osi�!�J�glyCA Z1�n125 M �6Q&hby  rifu on�a��!j(1× TE pH 7�� froze% −80OC)pelleq���sŗ> 5pL �bu� (e�(M HEPES/KOH.j8140 mM NaCl , 1 EDTU 1% Trit��0% Na-DeoxychoA���B prot�inhibi�( Rochea�i �Hlete #04693159001+2m PMSF��Verad�D2�x0screw-cap tub�*ar� t #7o!69+006� �85 mm glass bead�^Bio| ProaCs 11079Y1 �J"=er evelA� menis. a��*2disrupa�� 0a FastPrep 24E���9 45 secA��R0 m/s��2!( incubI�on ie"SX"l�� steps ���,in low adhesAlDNAse/Re g5!X microfuge-X at 4�unless�w�&� . Lys�zcle� F�at�_, �rcf% 1��%BQ�(f � E atinAV��Z�of�sh6�+R�.� p �Mson� 1�1/8” t�#ed)t��tt-�(Branson 450D/4=�301�5#�)oe&>)�o1�--��!� 4slurry�1cagaA BKaviA�supernaP%Sr��Na��A�`.  ( WCEeJImmuno�ip)"� ���a e�%�Y� on 8� 9&GUR)ymethod.<�8�>� H"a"� exx &UM174bod� <( rabbit polyclo�y'2-h$ 1∶�: �) [58] (�er"gif|%Steve B�m)�!GaceA�30 uL1�of�U(tein G Dyna�sLife T' %510004D^_B���20iq�. B��%r%�d 3×Ib1a� of Wash B��ayM�� s-Cl��p%2� M Li���5% NP-40a���F�.� ��E�zTEX&�R Trisp�Y) 2 ��w.���EP�!u)Kby��m!�[L�65��EM�� c�� ���SDe!iten��8. C�,link reversaRt$f�FAI�UY�K!nt�2 E�4 � , IP"�%�dig�i�AS�K (R�1 m!)�2M&37! a��N� t-#��!to �e9��a�;�!���i �. �L�$subji�1s� �!'conXf!EeiIP�{V)_ed�)6' �column��Qiage�c 281��� to 3 ofE�f �#:}� typE!Fp 6� �  f�� �d enrichKof��by� ��po� ���+1}%��v� �)'��rip�)e�|a�#�ne MX|$P q!Hmachin�aJp�r pairJ,U �5%%�6���0Power SYBR Gr�gMas�Mixn ppl!�� ystemthtotal�o$0 µL� �s��b !�n~ Bec�D!�AT-!� n� � em;� %j,"o(a� neal!+e* of 5uOa-%�&�*P ofm^ . Fo2�assayedwse�)"-QE�wo2�0( ADH1 A{SLH�+!�*�u%�p2-ΔΔCt�ef�[85��a UNIPROBE���in vitr�!bA�� �!it�� [57]�searcO �RIP317�RIP�+�ce�s 2=6S . ce�, siae�s� ��{ ngency fi.! s�! %n-etQ . Non���didate�-׍�$u�-���e�NHP6A4B , YAP1 , SUM4YNR063W , GAT4M�YOX ThVor��kno*:geni+�6� l����+or2��"D%at�1��H &��o�study�ba�deK _�N$ E7(oOmnibu��@GEO ) ( http://ww##ncb� nlm . nih�#ov/geo.�( SerAOAccesX#GSE55428) .�@Inva* amebic} us^�&PEntamoeba histolytica]in�&A� men who �sex�w!yco-inl>s�%d HIV-17� mergSprobl�d8Poped East Asian count�.'� acte�%Tcli� cepidem&=*fe��Ai2a�in � patiJ.# �record>170��as�#al��re�-p"g�(E .2S�5ay��in 14�'e�� isG- �%;-Xed.�5f l#ofN�rs:�d"�� h%"�& h3#. High f� , , leukocyto!=!�hCRPiXassoci�� � lumiU :z. Two �d��eH &colitiay�i�a�O8 �inK �gastr 'es ( blee� %�)�)�� s unr� �E/. Treat� �m!�ni�,%i%lue�ful!]� 165 {. L- t[asa�� 839�&�n|L. How-�� recu+ 6A,�#,0r�"yB)}u,�di�)eceive 1�.�R n�m+ g� HCV-sbody p}%J�2� 3*thF-t acquMsyphil�'&�")!-upA"iod1�$qye�>��i��)i��� t�-�no corE$���aEau���� outc�of:�E�Y@9Bof un� � aKE��l:*e�.�ԙ-.JNp)3���T doesK& redu�0EN!��+�in� risk pop*ionE�bab�ueO 3& �!T. 6��( I(4e�j�i5: �commo�5�&mortal��:� paral-c ���, rldwN , acœ!0B�00�X�deathA�n�$[1]>9s�m�%�ges��ood�Pwa P��D cyst{m*>��3i!geS,in�\���R in C#4�>South A�'ab6siA�Afr"i'��N,-k�a�$�Sravele�  mmigra���s-md7��7.�5e�, h�©�|R'( Japa+ Taiw z �Kou0�J�$A�!�E�Ep~�( MSM� I�oral-\ �*%� ct [3]–�.� aE}�shuman i:defici� virus f1 (  [c is a�' �!� ��!�8 9�g-[1�2^>96r�TaoFPX[6 [9� , [1�0�ap!�o�3!\IA�6h( 7og �!� ��-10�)a �9g q .*3),�ΉaՐ��p**i�jvT8iloxana� furo�  j5)�eli�t�"�^+%,!39�� �:�*� no d#"cP� resp�6m6L6��DѣH �ea –nx$IA ��[20�&@�|efficacy�{F�i}���f���c0�bR6lap)� �na�a�ayetJ =2j5 rigosly��' x �>� a�� � � ied�'T�� I� toge�� �ف�ty�AofBw/�enR d�* !EFofwFk.�!�>.�6�,.%/F�. a��2it61,al Review Bo{>of Na��al�e�'0Global Health\2�( Toky,�x)-!�-*;5� p�&d9"��;\��JpgX<r�> Ia�9�J� :ɫ diag�9d)�IA�!jAIDS C`�*e � k/�$April 1997)B� 2018� �e��.� �i� I�m<�,r0Iq��!+cria $satisfied;�>�  � nd/or&t �(AU_;�  be�p=��meHstool�wpun�-te-exu"]ery�! phag;#>rophozoi�$�3}m-Y �� �"� 3stN���imb&�cul�;or�:exa�/� N$Qq9gf -�y any�h�*�daR�2nma[e��Z5J�� mon�apy [10��I�>XE�s�5�a�1%'*� stic!��A�a�E�� IA [9�,� c 6� ( AL �d peri�� M�q�duc%�I romi� stat0AO5$,, laboratory�er�m�@r�%(� ly-�!� die( STDeD�8�"� , he!.�BhC� �!HBVHCV�A�%��C�>` V�%�)�ed�=2�ex�m��Ct�d� or l�(k-Q�" (�AvJ�� 1�� R�,�|fx �2Mho ���"�I�EA�%A���first$&3urM�!2�&, in Decem&0200)E7i t}214u had� N�sA�?�:��.v�, �" �f(R �5�z�I(�I��,afon!��N�by �QIAamp} ?Mini Ki[ R,�)enc;Ca� . Polymer�ch�! �9����:�of"�de=-U o t�5t�G$ loci ( D-� S-Q�,-R�-�BSTGA-D�-N-KV f�6 -linb3!morphic�Jrt �Gem� �6a�RB.}!*kF[2�~!�p2%!]" �$ABI 3130XL�AF��A>� , Foc�,)X�"�2 forw� Ao~ rse dir�n. Phyl�*hahT/� m]�!9�f�U5D"� HA��@F�f��f�m��e�A�chi-squ�+9 �i nonp�;;8i�cumRveba�*s ��u�(Ka�1-Me�)��>&d M�i)��log-rank �Cox!�Hi7# haza.model��Yto� JimpofJ� o� "P5�+adjus|��xf]Br �5io%y95%�f8>terval)*� . P �<�& than�"05 ,onside�%�7 note�>��al*�0c��Ao'���^�*1\Yf�V!bS.Packag� r SR l Sc�$SPSS Inc .a hicag} IL�# ' �W� 70>j��f� (Wlu嵥�c�0i�,*�22;�63;%�>�#�*T6L�A�irty-�qQ�)twoA1!'%. $yWorH IABh �mal�<nd 164/!( 9F)5% \;��At�Հ TPHA� s/nem+?0llidum hemagg=$naaA�ay�7�2ay��&ure�B� tigen&�,  .or HBc"� 36s%0i�observed�]�tF��CD4 !�� �. coexA�ng�n\>� �!�pr� !�5�� Z` �viral_sug�ngatt}�/n�  ha>L�S�>Up�<)�� }c&� ,a agre* w�,�_RCI9a�F� (.�diav ( 69 . 7%��/e "0onp "� ��dy�=eryy-E@9>�La. F� ( >3�-�%)K1� only�'5�( 1�6L�q�� �eT?7a�to[E�[�(t �63�f �9�E��� abdo� lL$�8��. D9L4a�E�aO.(�i�1 �� half!����. SG1 �.!'��6&)�E. L.{��u2�l~(e2=loba�7a��|t�ia?�<( !�8�. Nm%.�U%3< pleur�� -ѝa�u�q����ll� ��}�7!*�iF]h#p� . Comp�� phys!�>=�er�<��2.% ( BT�b�B=QC/ ve�f�( ( CRP �9�.'8^�)�(i��G�n )a�49E�q� /a8bM���M�n c"Hbign�\� ���q . It!�jr!uV3j�1$o� �!��Vin%U9f�8of�Z12�tho�HC pb �eE unus�>zN"H#1$[2}-I }12&��1�>�!on�A%wՍF��1s: PearA}b -mom�XKco*� � 3�Lp� 004�nd"W:ly ���C� (�m-a�22n�*IA��e~i&k�n��IV.� CRP-!, p >k81 RP-.63�7T� E06��2�`ce|,6,a�Y�1�or�E��Y4=zPu>��26�� �E2�� p%��woFj�E��lu4remisT&��llw")�%"o h 65yyi�g��2��. F��i6d`�in six�I�� ;W��Fc5=#�\&� ( 7��e�v���'nze fE$�JAt�K0gnant lymphomjPneumo�4is jirovecii pnpNpulmonarKP romb�� e�*!|&� � %3%!y*hj!�!ar�2� ��Zia;HIV-zW,���$8s;�!o8�*,%(�H%;{ in �OthRX&lwi< vail�g faci�!*�#�!�o� NIAIY�A9:O6,"w �i$admin�Y�]�a n�*�,�%I�F_��g  ; 38+\ 5CW80vH!f42� =t��H. N� �4F���5 �e]$�Tr1I"� ��sN ��t� ��O83.Y1w�aEF82$hD6�&x"0; S�e�an� �M���a[&�6�6rea�� o��ZPquartilLnge: 1Z985 � i��ra'dJ�)H43�,^Z23–982Zi �Wit�s!]12-�t-6��-,�M(�m�no��a�� ��Q^�� �R�*/v"�res�1ystP >%(�H\&� �]n4rf�O=�,�y�=ch#up�e-n�re:�,�xn^hL!Y9)cy�"b>. M�.�R"��� ���D�1Z"` � pastvr�!>.���V�osj�� �� .��\�7 �$2� IA"� qu 2�*AyiN�6hEXA a��>� IA.dE&Q�� t�$o�UQ FW*new&�."]:&�AodtN �&L5�A�hn1�N�J-aR��)!ob(�0|91*a�..�9�*�<>�8>�4;"� �Wp&�1��1; �S� E>n5%t �Frecogn�N.w�D+( Ja J12 , J132H!�J2AS*�p�l��"[��;h newl�$}2l24-J29aH �$.��G��1{>�R���i*��*ED  �e*[0�� ͬg!<��770�s�lA�!*IA�Hno �] ,z�>s��2�%1b!f�$ngs���*�&o  �:B�2g��&C�*A�� .[*Ң�<'R<A�66��Vr�,�YeQ !@%�F88-�V� 8dvaŕ8*�� �q. O�eBh �ABfZ IA V&] ���u��--�V*�PO(?��..eA��nd"�/%�^�.�T6�6{ !~b� sA� �^I I 1�W�+ 0X"�B�\W.onvNwisdomQ�& opinas , ad�N!�nagy6 sh)7/f7+% >�*ɂ�n%* % orde�Fera-��J �,A%e{{( 4�@�\)�� 6�*Md2�,27N*O��I5I�;e�vMongitsal_�Xf� ��J�J�aH carZ�Gra�developAͩ�i+���# a of�>disapp` f+taneoHf!�j8}%9Z[28I�+fao�O�>y�uJNe�or {1�A��e'!�8� n�6c���Sa^aisu � I!�*;+*� I�� e#y�TB�29�a�R� of� �� � B hez&�Yre!D�ong-ter0� �2MP6� � �34 c&> �U �(nef�K2S Q��s/[�U.r�x2] O5:��CV*\ .��1�� l@GE[&5seb0lyI%�[3����lh�e05�� *� e5y,;ezX c�Q& =  �Ere-�5� :�>( &s .68�/� atiٽQSc�5� 9��r:4b�>��( �_� �r^��.nWA*�  }U��_�f. Edu�+(!*ev�$safer!p mayA\#pr raa,!�nJ�T�/:���b.� gD=n�'�*[ Ej�I �ea� them� =U�so far<geograpq%�3�� �� [3 3�Zm��E�d�se :-�E&isqK >k>reaz8"/5�(aS"�: n#Ͱ>I�M���%F�/ S*U(�6as�Z as 1�9� 2009 ( un&�l���i�f���VA�Z�%P�0�5�ES%p20��s O#[�@UX/tunP`1�� !?s� Rdq)in�4*�B�A:qE��E]e�D& �O@=WAn.sto@&�^b ���demU�1J�.�C.% 2n+� empha3W��icultsA`% ng:��!N9��a4do9�,� .�!a�m�*n<2-Fhigh �6 Xps0hAu� *edE � spa!^>�in'�E��` &;]8beyond�?� b�g�y�&cf6 .O}Gambn slee�1 sickwB� HAT (7�8n trypansc)aa negl�[e0 � e"T<$a brucei g�ensx an�f ,r�T� �OM��*�& g3pr��mme aim�]&6I  .!ma�pc hK3A��@b�"20e stop:}3�� e�8~^aD Mandoul��a) pers�n0:cueufk5 aro�C1!yɦ��still�med��E �:W.201BoPre-201�C PWre�Fsol� C ,&��\� ��l8pP)G^db9de�B�%jsG1�"�AT�1a�Qe{o_po�< %L�1DI )���ofe� y�."�6whN6A .�S vect - l�>Tb9�~fureu=B��)�?v ;�����!a�M9��p��Yv w!Y�jig�!�'�j ploy��‘tiny�- s’-�att�C�kA?u=B4V 1�!� A��onsI�yh!;=��=�=u�.%+hOj�Fl\s m� <�H-it���&�2� �"�VPabundalupW� Nov�/1s2o�.Zd%# 0ĕPhabPe� ~� ukm3 2015�201�%I;,n1�h!�c� I�FF!*U��5�"n�� |m�&�Y)�)d�1r ^m5B�in�^Pd  'M� �al-)J�u�Ca� sses-�5 Yc �Qo�7��z � !pas�FscUKA�. �cIM6 7<.Qof 38674�U%��>u4"�Gv�8� -q;f�_.&Goi>),E m�is[9(ssina fusci �!�m_catchxɀ~traps%P�7 flies//day �Qnge , �2�U% NM 44 s�el bicoXGM�0����!I�Mߥ��{)i �be!�cau�pEtQIgiv6[�G��005 C�deIB1�A9atR(4%B( 5% CI: 51�e(-��/e�i�`�/��'� Ÿ!ve|�<b�e"�Zto1�Q��!��K�h"72np).Z�s�-� est sE�� �%w&� s dramPq6�)82�9–6�)B�; ID��O5I8!@o)to enh�xHi\��-��]di%_�:ticip�ed �Vn� B ��!q chieH"�18!��"mRf>�!�y��inu!�%�Ly�B,�D� e�r�.�Kvir�hnoa ���5E"�ZiDk� wM�2�1�A%�:�.�n C� ��EEJ0YB�Z comb�/!�6�toU�9�!6&\t?pllOa majM�Ve-dxnr 3��F� H�� &l � (A���M�;l>� ,�'L�j� �8/&$ub-Saharan � ,�{�ifub*� �" -X�f14)Cf�R (���e"�no vac?5<%�letha- � i`9m�HiKAulKJ��(2 weeks hos6Xli�=o�"r drugAPF�n ( >9e/��� �� �  .F� A�0e WHO roadmapJ� . !�j�e�� � full2�+ l� 2� .�Rs}��7"� PP�! �&�6�"� A�lam�-�5Et�I�l2�%sa�ss-�D"� $i\r"`> ill�K�1sa��2�di�A������a��m? &�2� .�,��> 3�YwH%�/��)998m<F��[0+!�6�AO93*�<%sitory: �Papp�V.��/gho/� /nod%wL. A1636 ? lang=en ) �JRthe�0-s��i� deA�)�f[� X�re&H�A* ap"�!mcost-" oM! s—&� l�j-��J� [�56]—off2.!�ex�SngA9�f�T�tho�N� �e6O.AT)���&c ��"�uNeA�; te�21Ag.�[A>�GA�U ampl�k63i��eEgG� in��ų. H�E�{t�s=;!�eO� ��N#�'al{: V"i�% �7" De�!"Z�o���cBa ��k!oe>E�o0�ly!�c2�sh�V���L� we� ";a� )�o< ?]9�� 5E51J �.B7 %e12=���&omouBQ itself � &Puste�c� de-XBegd Aat2�mlst.So"� Y�m&�$ mk 4  !�ru_%���Fz>str�HLA�he Re` M��DyAM toco\PNF,6author�I��hei�W�.he*F�iP5�!� ( PNLTHA: "TFde Lu5�� e la*�i%a Ac  �M�ci5!�!9e8�&~a���Nri�q�9Hhad��procedBwaa3�d��W%O1�Organ->e h��P, e �p �olQ�?�Md)�o2]ive��Di��>` <�O" housea� H� b�ly via !o caQ*0( Ngor , Arab}?ren�kanguage�[�d�d1So �+�Bod,xYct�M]�, vFg@��.A��?d)g�w c�.nt�-ɶk aQ�N7 �mR��� �2�_ xEOHfrul�heNr&� U)U?��am>�M vBEs�A�7NCP�nB1m�co-)*��he��A�Zk �do�i|y�!J� A�G~ bp�dT 5L�%re�We��x�wanony�{� ���{/h b&H�:|�*+ iH �ga"&� �takenJ��cou��"���i6Ay� 6��[( ca . 12°N�b� 11°�dnrPQ��,8�A�! bk$w�  M aU�>�A�lach�� e@~by �>�eEd&�`����I)-��Y.:rV� . T�ziPCU lim��E�J�!{�yU�upAq4a*�%b��!f`Q @���d� m),nuary—Febr �T@$!s 2�re%[da�iSxe�ai� 2A!2(s"�uEt(D bran�EP120 cm uKe�n�5����ng� r eriDX�en2%�U�� l� Fig l<E2kM�V5 l44�`-��"��ȝ ^{!c�N to b-P2�"� � !jMd :N%` i]nT0�)�s�4tiA ,6-����s inuoX1at �=y.�]��aa�pG�<�y�eQt� V|u.CH=R2( T1-T�7�.�#��"ch:!�-6~!��� ^!<:%&I�A�!�under��Fpril-� ?�"�=a\!h�oe !���G�0 +=��=�<MXZ,%!�WIhe�&n29�  –2k$_D��foq&Kfifth.Ha�T�>�^)�F�4�palM � Pky (;���-�p9&$�wr &�~,nt�wv�2 lm; �` ))ىeat �� h$ly +� %� ��T7i$C0G �ardO D5�p���e�.����v%e�.A�( Atla{200�� 14 [Au14]ET! .<P\Q�B �A앱>3l� �g��5RjA��e.x&�. PB.#�Qn��f-�`_��\�6 *�!f!EA.%=G����A�.�A!X,algorithm [1�slightl�d�h [16]��U੄�U� �hp 1c ���d�2yF��eb�.s2[q�d split�1��.u! �e�e|BH�Y,�-�<e[Eht� �CATR.cA�6�R&E#F`.$Y�ybl�g3�; ��as�*nd m^��EQ!�*21;���� he �� E3�^q 1/4Fu�� ��N1/8 ����;�Ua�X&�\ ctsE��h"')n)�A>~!�cap��Hube� .�( CTCc`�2O�9ymph ; f�pir!}�!5�' l�"� /89M1%�%9,%p6�ly9,�`a� �%S0�a�e E>�W:<i�. S=P 2�:�!, zMIo�!��Y� {~scopic>NI�-qtbrI$� flui� �t�\�$�PpmidMA�"�2[�Q6C �gajs#w�nmTNi�. imox� EflornTF�&�&( NECTqa�G e�� Z.Xge.�ZU  lumbar�\PndR�.��5�A�� Z"�( �� _by ���A� capa�[!/�"r,1�equip��1��w� rapi�bgno A�� RDT��upg�ngA�fir� �K3& #res [�i$"0 �� �xf���x *)�&�N �#uP M�F"�[�.�g2�li"2arc-s#s.� GLME�� PoisqeK�.�/?�link fgdi�Di. -� ( n =)  2�toڄ�s al � N. A&�fi �E}#�Bl>E!wl�+��r+�[�B�1�`�2]��.v(�"� K3!�me!2)���=v;ir����h HAT�M�!�X1E� 2�V ́��W���=Mpn *EL 2WEq  V�MM�'��\� ��f,� �leB6 ���A IM�Gpolis Ha�vgs MCMCP�/-�known'p4�<|y�'�`%c{��Oe �- �:" ,ՒAXi*[ a�)U1�i���)rt!��/outpu�4�!zr�_cfAbiZ- ap+( /��NU�m�� �-.1�b�?!�u-*t!�&b,�!��� a�I��)(W;o6$�L5��!a5MV�To|wledg%IX �-A�ans-U��En�%�udI�3A�S1A+ho]�CO(�&3)�bgi�0 �Ele�s*�5��͑ � o �n-�5 !7���n�G �-5 �I)�}h�(E eIse`��8�as valM~A;�!&eg�#�C *S ��B�Y�2�A/ expa�&�� �<t#���lŶCCc�speS p4y�ofq�!t�R P!5B�At!�'�+w3>�^1/yet asc�ڈ����v�*a�,�t���4&� Ց…vE 63o� ( un�d��%p�{a%�i�for"w@ insu*1�Ztoc te robustu�s  mrIgI(QH4 � te*x� �7 �l�-�%�)��4nt�4d)p7 iby dol�ngq89!��j!�15 on�)/ S�(,t� 0�d�7!9A��;W��)- A:MWZ�6\Kfu�#��,~��k unterf�� �si�g!]� mbf8�C36��. �;�6staů�exk�%�z�t1yY�)��1_5(abslF%�2%Ou�(�38 >/<�) 1029 �gA�n2�,�E629A����20 �D�lls,!ۑ�~�.�� ("�(!$ ���/Z�n b:{:��rB462(Ax�kkiɣtr�m�E�� tr�""�et"�?!hZ�"5�*� /�RQ#�"!� `m��".�.c4C<)��� V�"&�.�wbe��o G . f�=��Yki( 3�d~<�95 fe6|.�ma��5� �jS8�!6�&=,��$ 0�*26� '..�108!Ep�' 22 (Ak.;=)1!� �&�]!Q�o wo %�"6> (.OB�#1�,���E�+����,nLAon #� v�*��M{&a�Fe:�EF�f"; n} 3`�y�Q�� !���:xtrϪ8"$� Ve�"� .� %�"k1a�"?���27!� Z2��, �F 1�f�@,!��#4E��Hf%)� e� s 453-���p���U&#�� O�M�I�? y�9D62ove�` �u!�i*�ne>das sF2 1s/�-if&� UiXF5�Z60<���kmF�\��Es4��Ii-�s%� �e�.aAk�2��(��62�4y�a4ѱ�ځu�%�rrge!&�$eJ� aG�BcI�Av�2q�%�(�j0.�'�q�a�fYe]��X^�40�Z��( T�Y Z� �);P �Hnex��#�9� y��T3-�, #Ke�AGa���� "� uF4�;pr:�p" ..-!sBl,"�!� !�y"��e#�d\7YZxEo2����F.�a�F0�8e5 &^ �r.�|"�q�� � GMLE�!ul��"�� sia'byIo�PY �N�� m>S^ ��q0Ip*E� E�ş�s":�a���)�e-�Ou)IH ( p<10−V�?i = �3���a ed 9�l5%*�]C&\)6l)%�an��*8- ��:S� "�*[�2�&� (Z�x5re��utrong�<&��=�H.7j'*�i � �%Y�.� &� ZrB!�&LYK�in�N� d 2 a~,. O�(�im�r3��Fd�r5�D1F67–7� z%gewa�"��\see�) Ts tr�is�soa� � ed�!$sQ.�$flu>A��B"J������WS.i6 oNf��^?%�Ngu�H� ��y_Ū2~R�����9M9$�li�%low� oan�@�a\de� ܉�QI&. nNp�F�A6HFvar ��D!Y�M AM��=c��% )��%*pl2V�N�$)Q?y�>%� ��H08*['m�!� &7/"|2}o(���Pf �.~�.���9&�7���R�$�Za0�'06R�yedaeEN��A�*�&�;my4RvJ�;>8.F\dynamics& &��v�62���Y� ed�A�8B�!M[ h�r��:0Iqт6 �@6�!,Ձ�� Proj��ng�t.j��eHt� �>)��(" ies:� )��ic" , 7m"&A}In�:s>�gU�I�a�!�I��5�,� �(�dZ}R�s�&*a�s:{7 ba.�::X� ')as:/NP��",.(��B��jB2vm, � gy 4�.t�3��oT��:�q1�.�Wlou*]�n�s I^�>Q*A�|r)>i^�� ����I� ��A�y/E!�@"� ш"�Tn�"� v�((�H!�.�de"dW �*� bx]A�ha0K�� AǍg��"v�.��"vNt�V�a2!�J�%\re.Tb�129 (s}C��10P-157� 123.9�m15���ga!f!�!�E�%�2[-�%�&�v B�!r��t� 9�<47 t�g*� M�{)�تc�%edq�aH5�1hM �/ok�ce; T3 � r186 �F �r� 7 i72e 6.� !W4�N��Fwo-%;���%B�FT8 A��x^@PN-d:�%b%�E8U�q�?mc >�� !*{+re%�D:ey�X�`2,X!�so_1/U�eisN t�=a��Q�yke 1,�*Q �*X��>�ir*yP.�surN�m72f�!��U311>v:�q:9I& f 7�0z5]�2-" �wJ�r2�P7.V2AW33% )UWQN&@2RJSP2O .?QQ!�r�QtB_R�9"m郥��bA$��gE!:]��5e�D�:���ޡk2� SE��� I�ů�);�q�d"��i�A�fe��B�# ����K%��e7��.�!rT�=�f\gp��s��!������B&� ,QJ!���P9!%�iq:��;s�t�ZV, �20=��2�:S1�&HmU �1� &>9�9��K"�F�ra'�idH6 �‘ie�-p\��Trԉi� �86� p3BxT-��1��ech�B!�rxPf��'��Guinea2 re�aQ� ls�� ��g�rak���aB�M[`~y)>+> �$> nt��114+w�V09�'�F�Z�V )�g-��$oe^&�� +%6�'@:e�!�F^e-h7�2 effh�# 2�EHfe_e142 467pVZI��}�!Ż . Gi�!�*�e�G3 � mean �\/}3P�:!��2 �e- ��n�]�����. 2�-�+��YRix�x"F�w�1:�!LC i�1lu!� G7�F�U>La�% 1ax 2��*S�� !}��.� c &)3�% K�3�5 m�*�)��A��<���+7!5201k�1)!'aq[�NT��#�,�R�-6a��16 ��� 2��*%q�=:�E2 � �^:�:� ��{O�gA� {2�%4)isupz A�e"�.F �z:M�i�\.AH !�is&�%eWG �R �P �c�g�s! (R:�� =.�?al"�(L&�\2h� begaU.!C5�ld sk���).z2�V�L:�!%T�\ �t}�!.)�'5ll��9o� h)�ly.�1 suW�� ackn�,�$��"!Dl*p !�d?f;%�� s ),L�Z9&0�e�Bo, m qof!�ch���di�� else�[2H2?���Q�}ma�<q��e 6����n�D��3 ��]!�a۪���*�emp�K hetero!Qari���us.՘�$��&-n expl�$s٣x!repan�Iѣ��2A, os/�e'm� $ *"��Y:A�or�+o�T zoAAaaI� � � �!:/)�7 1)�'5c��� ��J . By�j��awR�� b&)20U5�B�-�6y"�%oH�pq�Y It mid��gv?x�' ov�8g e�/��CQ’u+��].�c�u1Z!8M$4�E��'.��� �vW��*�f xw�N"�ch{O��i�*�+��OA�s" :�Y�/ch���2�j�Zo�����I��V~ �mA3e��=�&�Uw�8)�IN@6a�pq��FC 2',%S����"��=��F�*Hk",qu&�--G�j��� �gw� Ѧ� �%�p*�l!+i(s:�0Jt�"�Iw"D�)�P�iQ"��2MMe1�52l9�'�p�)-to"0���a�T  j�sv�duNZ. . A�'�A�u�m[~ty�` roun� �A=�1A~J�& � � �`�i�9��F#w������e��hellHbT�'A���]�i��A�>�0:O�F� :��tl�J( E/� (�s2@&)�g��GI �� 3woRcK �� ethb��?�o�a�/!�* famigX1 m&���� ��lXn �dn�7�� N�XMo"�|' !Ez�y �o!~mueRf&�G(�Aca, vl i�, sch@�, Ag*nex4;�towE�[� is �V=|by F �.� om m.7>��ach ^)��BA@draDde����;�`�R*gØ!0�&�(]����4�02_Q�#2d |� .E�,� "5o"�P�U[ ��� �z! ;ow rein����du.l��.N�̳��.� �nt!2s fA��f���=2!�o��rQlh� &�h ��sBoffaQu�t,=,-�� �t-to-a � mang:�_:k(%� palp�CAxr��m��m�Rg2�SRl"�:Aru�no� n Ug�M��G�� abʝof�2+��0���!�("�+*�^G)��He C [�fP�#"� �FCB` x:��!A�Ѭ.-�:UBlt���x).fx!��h| ��! anim�X , owJs`_fa&_��"�^���,?�- S"�a&�Jp� !7h�MWf��,.�B�%%gA[ ڥ�*�habk�Y�sH�U�!wn� ���c�I!D;&6k�emal.��!g@�El� N%��aa �&� e�N�?] �� a� FL��hI��Ad �[g��fI�a��/yloid)�ic���AZ�d"��.on-{q j!e&�"�A�����>{,��*���Lb&e&�bm��I�]%{if�n S��� !6w4 ��.;���BEd�8r9!1=<f[�9!|0+REDIVI Colla7�a�Ne;��to�Me Demo��,B-A6[Gi��%jcnK��.�k�2A2ndra2@ rega�i>�ti�iquS "SLG)Vm�!�� � A��ip� ~L3cq%al�2&��N5o{s�#� &�( 6�z�'�kf"������� E�!���hC�NiP arvanp �gL")j�9%3cU �Z�@m�D :=d makaD4M@eex���Eosino��F� � in'�. 2�/:w�_m��JLE alben���w%+I�7es� EF@�!��/c ( OR Q3�2&� =O8n�b��!nA6�d{�!a�ՒI� �{�� .r$rc�%F�Z�b� nd�4x 5�]ed�a !}�|�Lv��,:A�t^0�p muno E��:�s . S>� ��� soil2 �6�tBA<eK��u�pa�S�4"6u./ 1��R�! ���a��I�ub-���"Mit�0� �����e�'����@| s*��iEurope !�N� u��uI d _�&]qs��_70 mill!���5%�9T1;*W��m� ar�%1E��9ly�Ep,#!�x-���]|��I�nB�helmi��!�S��ٽX�`�!uX�� .���>�&�t>)!4��P��2 � 8u!�AӁiE�B�, c>�e�ω�x �Uory sy��)��r1�EL!u�J"V�)eStQ�m ��e)A D�of exo[�u���-� auto�{K. N5"tnv�mD�n�,H<�c�-*v eroiA���E lid �o�bb� marr>�N^���A�qn T-l�Voi� н˽TL����� Ӎpliog��ve ��ao Ylv�_-٥T&܇!N>;hy�$tsyndr!�0disse��a~�6* [\�Du�>��"�&ݿ f+�Q&AXr=ve!<%e las'a�, j� �7C� �o�� 3 &�i�F� ,&�a��=t� &�[)1"�ai"�-{�C�o�Scri��heB� � f f� SpanishZ� 25to�G y po��-U-a�L@d&pѫbur�bEC"A s3�)A��� �� F� Jsd"� .yd� ��1<n� � s�%��� �sh�Aq�on�%"� pgC B!=R� of * 't� vo�1en�����#WiLy�:� .` ��*birth�2 s�row �!>� oEr� ,� ���Gi%�>� Un16�mf#�noIn{-��A���LYi-@� � 4( �:.�(�l"�l�V\borL�R��VԒng Frie��/Ra)�1 ( VFR ) -=(.w�p)�39�irh�M%�'2p fm��,o� veE%�� �nu?;-�qe�4ۜve<#��!� �A|jpretur�rVb;Al�9#6`,r��AG��G.6 ��M:(��: �2��, e"� 4 cell count at� diagnosis , microbiological techniques performed and their results , treatment information , and follow-up controls up to two visits . Stool microscopic examin Jwas�using�0 Ritchie’s �$alin-ether�� in all centers . The specific fe�cultureEX S . stercoralis larvaeb�Lagar plate or charco.<h . Detection of serum anti->jIgG:g�ethrough different enzyme-linked immunosorbent assay ( ELISA ) -based commercial kits depending on the )X: SciMedx Strongyloides�AyI well a(1Corpor)��, Denville , NJ , United States )ovaLisa:j( Tec I�M� tica GmbH\Lietzenbach , GermanyT6�!KIVD-E% @( DRG InstrumentsOMarburg:KAccuDiagJT PKitTi;$tic Automo!�/Cortez $s Inc , CAJ . All1cmusts were]�(and cut-offADthe op!�Xl density values to determine a positive result was established following manufacturer in!+E�a2,EosinophiliaCdefin� s e cALcount ≥ 0 . 45x109s/L�/or�erAuage*@5%: mild ( <1 . 0.4A0moderab(  –3N(!'sev!<( >J#i�>xinfm�Mris�classifiaintoa�$ee groups:)ite (%r%-!��0by A�parasitaB-߭T�probablD5�seep.-��presencec9tiaH! ossi�LwithoutnP8. We considered1S clin� �te�: hyper9Csyndrom�conI1to lungs�4gastrointestin�5Hract , but symptoms�-�diseasA̡odMeleva�^number--�)cdissemin$n��ia!�(-found�*$ny organ o�Ghaneo��$) . In ord�~o ea�A�a�t�! outc!,t(r categoriem�=vI�@“cure” criterm�e}� when pati�� had negata�conven��,al methods (��sco�istool e�oane�6) aft��,!^appearaM��2��M�y (�-Hat least a 60% decr%�i)sOD �T ) dur��&L( ind��ently!�| time y reachA$his situE�%�We2>“u�Fk![Z=��ccA�2�persisA�,( because it�ld beA�I^ )! i �abu�-1ic!�trol ,��>��(di~�.! FailMy ]�ifq7%�oc� mhe.�r �%Cor��U�regard!� �y `not5kJ��$ a minimumA 6 month�:Y2a�� q�“Zenoa *� ak:�%�êe-}.A(�2Q!�����od less ��5%1STROBE s� $ guidelin��uL to improveg qual}of%Pstudy [12] . Procedur@p"C � ccord�7%�!]eth�_standard{ id down3#Decla��k $d’Hebron� va�xty Hospital ( Barcelona , Spain5YR\Qaula:�& agre��atM�edex� 1A�@necessary given d�tro� ��na� 2�A@�anonymiz� #]� . C͑ data a� |�(as absolute�s��propor�hIp8continuous vari�sMexO!�as mean B1� devi���SD� medi*18rquartile range+IQR�*��F� distribu��THKolmogorov-Smirnov �%dQ�2�n�l6Kof��χ2 Ior Fis�ex�^,�GE{pri,2s comp!n!�2�of"(!�9OI80t-Stu� lf�N�. MultiCte �� regress�analy AsmadŰi\ ify facto!� ssoc�di�� !&D EW. VU�4entZ ��� l�Xp<5 20!�un��. RuGݕ��� ally sign�a���(2-tailed P � �o805 . SPSS softw!�!@WindowAZVa�on 19u ; ,� ��go , IL� x!9EHG� � es . Over�Y, 12796�Z�regA} Lin +REDIVI from Janua� 2009�� Febr 17 . O�s~ZY A+�� . A� �UaMthSca� , 34W���drawn duE0erronea�cod%�e� or duplic; h� ,� i$in 1245 ( !m 7% )kith��( Fig 1��mean ager !' of]�!�38 . 3�8D 12 . 9 ) year��590 ( 4!f4��(men ( see T�� v Mostb them (immigra}( 833� , 66nSi�8hg2us= kinş�up�RA�condi%k��m��V on#!�u%� �0“laboratory�? alte�f ( 4v1�a�H“health screening '3!��. Only !�a�2�!��)of^F:';wA auto�e�'2 s who �receivEJD1 � apl ? clu�(c��co�oid�oneu tHTLV-1�,�,J$IV2!!,>Izd6�>�Six hund�Ff�( 4A�6!�5a�&G nW xus1!$!sQ�B 9� , be!?ChagaA( 2A8~, �(nt tubercul@va�I�$schistosomt5D�ma%pr�kNok ( S1mJ� Amo�a3}D,, South Amer a�TfrequSgeograp��l}aAkorigin ��1re��in� Xa�8�D �+4�md�� iVX tripHtravel{!� VFR-DžC����a7–227�ay 3�!3�60re� ly �Sub-Sah� Af%w:-��.C � d��\ ( S2.��,*��extraA8 2-ievedY�Wamrticipe �ui� avail�]� 1062�D!�3ALuE��*Lco�*�a�3llows:&�` 3�&e���, �in 64A56�8#!�"���81��V6+C V !A""�r ��N�A�: \4%��%�-yl ace�  sedi� )�, 2�5 9>P6i�9��8V0"�e5s���c��A�hig3 m� z��A� efficienc"�j�T 5619vin�"m th�te�y&�.�2��NL.�(sixty-eightd�z/\&� "V� ; 9*G did� returnqq Mh!6&�AJdI�$b%0#�. Iverm��nA drugAYchoic)9��m�� . Fy ~968��t��, 784a�E�2��&�� ��׭G��(of 6 (� –1� �. T"a���� uuE_.�30at� �� , 35�i 44 .��2 , 5��e��fa,m79a�!J%�noJj.Z5] *� Ndo[ inA� ��z ��� M<1(: a 40-y� ,-old man comal�_ Suda��2� 4200mcg/day x 2ř k�41�� a 28lwo/ .n Bolivia (�p66p35rpEqu� ial Guinez%�>� ��32�nd!o3�>oZxalbendazole 400mg/12 hours x 7 r���mreforA�83%aNa�uaB��a suc]fulqM (iB�� MU.>&�b%A�N��y�Ѿ�ummarizaQ3/S3 . W��pot�alb�ha a��.� I��m. a�,Q  of6�aj=� G lyz!�� n ORE�8795%CI �Y09–��0R ��&�rate/�eo*�AVmale genn��lso.�N�, �� 57 ( �15� . 1�o6�� �2%2(2� . Con%� !0"� @AY�@: ty 9 )�G&H~����it6 衑6�� �4l  8o .F�i.!i�iQ��R"h )�s��uiV�T��_"�.0#�i��(�-yE*.)�!�39 %��Z�4- ]_� Y�2�� J}��V� n.� 5�i Im Z :C !�in6ina��m�V non-a'mDuntm, ; i."� �o�{  i{� &aU�s!�!��8eao!ligh2#�s 0short ����[A�11] . H we��t a co4of$��E �R&�:r� m�7sha�"Z�6=, 8AA2%%�2atE�� -�\&6 4%|A s�� , al�phal#mCj�{!�:�a�L"$� �"� a� a�2o in 8)> i:�}��.��q�betH� � tE�Ujto� aa !UH�*9#of:2�z veryV ��t� 804��23A beJ o0�A�sieI;Uco-�� : helminthiE� such� >8, soil-transmitD9vor fil>l nemato�&a� Ƣ�o$$ stim" . As!� �)�NHsee�, EA2 �M��x}L��:�}�r�F�nK may�,e been acqui-priorAAJ�ra!�IdP!AR� ��; thei(�+po0..'�!4 8�a���(described ,A�m!�E�inuwi;re��`toI� risk2WQ:long-�&2humanitA"n work �$nd backpac�#a .� N5* landK�x 679 2N~�trI#*�)Mdu&12 week_E, postA�velGed��Fal<&es �*molecula*�*e#��(�u �er�Y��*>D[13�n�$ur-!��!Lre a6�� to�[ opul4which!��t�tiP%1 ies;�u��A�epidemi"/' prof�am�N� w::W%�ae�A/RJ� �v����5;con!~!gen2� =w��� �y1V�,�nd �ric".�nish TE�al Medic��+�!AVek*� ocJb"�o*�n.�2� thoss(&N �i� ![ �!�A"  .NdA�]�!ZG65-B4��w �2has���_ly�:/o� ��(e likelihoo�J Trypan3(a cruzi DNA��#phEbl4� ao�reflec� &%imoda��ef�&>����[14��6]�c *�|f�(7�9b��`^u����z,V.Q"W�(refer�ۭlF Yjɴ�tatus:2�invy)o2{^v�^�*�)"� )^d' �gl w�TO���E2q^t%6iedAuwoA��$Ak�>�Q' A�%ore�d2�&+Nn�+stw �4%t� "�244 �\|-B/[6ANBD� �.he �ofj�� %b�evelop��aQ�Bzf._&� �[15�:::!*K/ �0 �#�#(�����5v�x 2� I!�E*2�22*# ( 21���Uy.\��TAs�cur:2ly�g�"k%aEf7� "� *�t&C4#z�"ve�. L.%azins,orr samples �&s^�>)!�scarce��irreg �excree chro�.ly��.xmakMx�challeng!��1� paZ�/s*� ):�n��� ='D, Harada-Mori , Ba�2�6OA�>be[16H$7];!]��i0&�'A�BEin��h�'A��!3�!�.V*.Q %�1H)ei��h^dii�6i��46�J��.)aAerF>,!'M1H.�&to0Me burde�*s��/. M*A�R�J�. Both�B.a(! iousJ6�4��ejup Ɂ%|��e+U �"� 5�s [18Aj9�02�y"# �"Z%�xi2�. ")explad4* m� si�/�n��isf. (�6lea�A��s'on�%�'a�# ����p6 v���Eed� �a"�c$%A�2|3�nei��sl*6����nt �,  - ion-�7tqo�4PCR>��5�sh�5mD���,t�  !a�n20A Fortuf3�"&�86%"shJ�*�l2 deca�� U32%�.�%�e�(�8�-���I�!�E8F7�$!�)s�� %[2�P)_%�z��!P�2usefulnm/J�-��s�C >�2( �+ �.EB2� �"o3co�:�.�3[a�2�/Sew6y"�B�� in 7�!&�"� !�*d be� a key }"�eaJagk0iP:AoreoveJ-1E�! ��R)j��F&Jp5�on+"i a\,���+.89f��� �yet� � b59e��,.� �y�a 5�%F�4>�9��� &7a �"@B9J����A�1�,-vM9E�4&�2��#t�D"�5sh� �u\:d�!"<.ITP2X N the|2, >p 53�!�� ���al�V� it?rem�*��)Xre�0!�Ii�/(/�%cross-�5t �3;I���sugge�5 ��!R�;v�;! �2�6�A$�� � -i��a1�y�Bf9r62B�[2� O�l 5� s� egy�y� Asomb79-6���g,A��f+t8,�Eu nd e�2��. S "St�!�"$!L&acyBw�*iR.� 4yT!  �6:;mixW2!��76%�c98%i3878%A\pU%v��4 lw�" �-Z"y$ low*WsubjecPAe�=s�schem$ nd dosa�2� asseU36��' A�� �!io :"�U-a�h��.�d{�>�u� lack!�.�[2�3�|A� Cochrane �aew��&aANa-a�2I!��Uof.� us2)�847�&"{*N�� >>��f]~ ( RRG 79 ,` V5#!08�Z�!";7ev\3ce [3�A���Go�.�5desig9a�]H�� ( 69:�)m�be�0dA�)J�s�H;e mY����,�)lNe`��" *� foy-up�7�L�4+ip8�UC}����E�\�E1d6suQor�h�10"X5J2�le���y6�&� <c�ԁ%a�ookBD�f e beginX1 +��� Y1���Ut� nowa&.� :-)56��xSpa jlim�C . Pa�E�2j �;A�>� !A��� �!IbeD�;&� "$=�6�ic loa�?5��r2!N9��Yi}GI�pr-�� ]�&Z�d 6�to �� G ��2 �"AW�G [3M I,.@��>d!��/F�� jaiIby�! l�m![32��6E!�surpri E�y�k{ @ aken)ca�:2$� a smtN� �)Ker�$�m���>1)�wseh^�%�ٌ�(�Z7*#%m*� %�A�����in ~�^�a�.3 �*�FuiP� R>�;!�"� atti9;uh& kA�a�"�G se&�,Ft8& peatF �+SY��0�� )�aS �r -�G�� ��s-%��e�-n >KR�.���� ��BTJ6�HIOf�+& 'eU"�� n�2m�eA,col�~����influ� )`2* of� ��*� .*rI��'d��+� %:FA- �dBB>��*��A9 �sI���.��C��� -^t��z�y�� ibe �two�1�H%C�^��� to�f� ����l�L�@�se2h N67���i� p�G= �#a^2�=$" 5- Zqr�22%r{""?R�>�)W<s howJ� � i�Mt�8L3�m�\�%� ��c��2set��� l��;!���A�b;� net�$>/��= ' ,%�: g�%.���:y=p%�&9�d r��:�Scommon!�o;[3�I��ll3 u~Lfu�r*o2,Q"^+o�$:�i�+m�N�<.�.bI0[�0+.0+BE� N&�=Ita�majJ � m�W�%E2 #�e. A��z*�� �����|as"�0E�.?0��i�cŵ2� . :96>JAne�G"i � 2�/.. G�D!9n� ��� "LJW&�&�m��t�"i*�.�or_]&) �Kn�&c� aa�6+.�$%F6�!�!"�? s [3sA/ >Jݽaw! " Gc�5nfirm���D$lud�'.C"Uis .�bRa�o��i�&B d3��c�Q*�mus �658. A�S�M���A.y5Aq)q��.�6z% l�4*�&"�un^�{�  hygien�/��aBi?Kdu"�O!pQN� c�*�"D%ly occu��'w� �Y-,!�public�imp�B(s .2zVaccQ%���;�h&�H�%agains�$l ��UA��&yv �A�� ny vnrm�%�#i�inoculumA� i . q , am!a\�Tge� %�atten^�=ho%�i[�$H�levels` lykc�.sti��*iF�p��!m\;c;Mmb�0id e)AH�3�q*)c�ag�%�L��1�1F \,iwA�mal=6:)�Y��onB ofDioDj�. A).[m���1alls�^ex�E |H�I� help����impac%��6�.�N illu�"_*ep1]!N�l��V:M�owIkd ߡ&wby fi aJ���i� � za A viru�IAV )eu�m�<��+�D:8HPIB9cotton!�s��� 2aMWe %��ma�A.(� �)A�!���oa�a_�morbidP�KxplA�� � frame M�b�e$1`� U�2�)��S.Ne��esJ�snV� �YX6�o.�2s �s� . Ou�1�Xs6�rymunxa#� ��� �Ypa��%�l��sF�d�3"rMi� ��;ot"_&w� D6/ Gceq+� goal� �� �Di�*El�+:�aca�C$Y{�o��Yp!�?e�3�]M�L��b�iﭮj. ��?MbB!!p; fG-�,��defenwe�N��e#� &�Fe�h0!إps�H of a5a�bN. plexg�N����?K],���f1wa�I� A�ize ["D�ctyp�@v1N exis�5< �#onu�a!nt��U�in` on-repRng�zm��h"E��V@rF<usu�8���ducA�.� mort�Q ��= deciC��!�--G �A�BI / trig�a rob^ �":d ���a�WA��Qrwar5�1���[w�TC"�,nma!wa���e@:4,���N& is� nZL�LQeWc*K,[1 #1}0,!]H �Ta75C|!"%J.�;� . S{ I����ppl�a8rug�  .� L� -&e �Gn=�Anam�&N >� AԊv �N�a sce_7o�a(-a�Vt; �`�* �% 0ser��3� r��y�a�i� �c���'�2.0 ly .# w[D!��iJll-mat>\�_ e ci�NaœH >N{",!i as g�5ab � a�>Ne elde �jY&� �!_.pinbA"r* I�bZ neLKal [1�-D� opgiz� �I�1��Pv��%:.VaBg|driftEBe80�54Ua�<�. H�;z� � *� &of��e�spi�RQ`ill�+��(hildren [20�D�Q��D+3lic� d5 M!le"� y[11�, O,��pit�VI�c mpd*�4- [[+)I�A�a� A�����^ 9��&�.@�wZ�tBan�s0m~Yr�T���direc! �:cl ldbh%�M$� hn��c>�*��b _ is���hA)Y�e�p�[ ,6�� E\�&*�� i!#%������ap@lN�ny5 . W5�d)Z�%��&o�1Ue1_� �����( I6�<9��)�!�>on-qparfw  3��@A�*[2�kF�"he��� �d!���9�6�e"2�6PH1N1 PR8�"o$�. Geomet|�]�.ZB%��b DUyZ�&Qree`Vdt��e b��!�EI ,� � �/� di [�/dI�6pur;e7�ad#w�!�e�,!� keep)AB dead�l!z�oae tr�K�M', Dj� �s <� b′/G clea��Blt�Ia(kA'� remo�8X(qm!�1� a'eI�:�i-IdV . NoT� �A�hi��{ms b !AU�e�m��2un! . S7JarmP��s�L,M�)a,)i�%~�u ump"{ign� grow��death!�un M�4.�[30�U�In�+�!�basic�AF S �I�ARa!. adap�i��������k6�, Fm��is�A���ec \)� s pFtdF�:�*1jan  6TRilea�*a/H��23-hl!�offA��OxuieQgF�5h�Hat:.Dakf�"� �<�Uf hA�� e%>���5wH� by*s g�Z FmaxU�u>PI�A�arbitr�'e I � et u� e8S=�I�� <>f�t& tead(!0of F = RI 5�pd!dWe fix��"�I!��?;y)�Q >1�-� !�Qjin �i��+ si�E#� �6G"U#on���,!�J�%7A��v�w��TO���o �Ek ,�!�"��!e��Ikb�?ducY pra?%}E�y  .�r�&n���-�"� =>H|&� � esJ�s!�! se$��al6��Ha�ՕL}��a"80 next�S� N0w�!cG n B- ��Q�0A�!L�&;F��.������Nv�,�Nc� jIAV [2�%!"��" B-�is)�I)2Oa'igmoid� ann��ip! �&�"I (� �")�$>���>�B��yehF����e ��9� !c>^�)�� ��=2$f!�A�Z�+�N.@�s�GID%�m�/K�!&HI���i��", �����n����6 h՟%\bo2�rA�"Yg���3ra�� dA%.b�ftd��S� -kUABi����I.a��� 2h!l�'. :*� e>(U˙=−bUVIv f��Zdel� +�;�u�rso� siduR" ( SS�C . To!ow� u�;Oa s�9e)L�9G2� var�o)�"� R%P%�� Kd�/alx3�div5 �3 �%��a�%k��� ar�qwe oe:� {&�1u�0�!m )� E(-w�cA!�few25A�.�aU�q� (iɎ6X fOgm� plK7�_�eu�5&|+6^q!��AGi;by =∑A� t1NVw{V m- d ) 2σegV +1NX&X &  &X bVl�(���4g�Kle"�:X&� s ei 9-/R (��E!w�a ���:��;pVp/+dF'eE( m>t�8�I�a@run��Cu��, �%�ll�Q%, ~ N �&�y VQ!� ���:� �,eU, !s6UA�Hh /Zb�--��{( XAhx�<;yR� � EUA�)>,i;Asi�Se sube7��A�aDeA�er�"�*�)E�is�fi �hemagglu |�Y �\M� ( Dp�Kungunplaqu��m� C,gra�1 4MX� assu7z~( a5i.)zR same `�,-�I_2?%[i�v|�WS���K;%�] �d/tkroy� ��A�,)�5�-x ��(.�&��r8 _T "S ��d��&� ��-of- z�l�qacMi� �!�rwhole^i �oENwp�8"��< -sca{ ��!�)!quL�J�'E#Ha �AF�%�t1=�9A�Z��'5�p"�v�o2RAiE!a�#!��1m��E�� e<) |9eG‘ <�-� ’6l�:F�a�<"�aq7ŏ%� neut��+x assa6!� r9�)!�E<�.R !�%gpUE� �!�2�=��2s."eIUis63n"y�e@1�<�Nw�R(i�M@ai�=.%��x �ste�'b�9�6plo�|�F ��:��e� sJk$�xIVb��7Z by��y��  ��}�%! !Ken do2s�vwe�!:�Ae left-!'� ea�GmKI)y�:��# r be� 5�<B<Ig( LODA.��e27L'10�^!21 2B%.mB]!�!h�-'�%���'���.) �<cJ#�; LZ8�* c[37��Al&:m� d�� �RA�����language�5� [�e 3 [3+Fiy1w)H/$�nloptr�&iz�7ackM [40]Fl6�tegBdQdeSolv$-HV�%! co�|-+Z,Le�/ ;�>$����a�hl S1 CI. �y]u!e���obvC_�nU���g�s��!AY F%�GlogA�alI��e�le%�< ��5{���'m� �� 1A��!i�" w)�V��<l�c{.atLBviva^ia�h�figurei�KSp�{�*��L��si$a�!��� umabu�q}�!+ re k��s�Wd" �����5]^[�rNZept a�(nd^�Ur���0 � ,di�q3��E1A,!�V[%���b�� ,{v�u33)����N�k.":R ' ���]w�ed* E?qI._A�e_�D�)�s 1�2Id7]m�,Engauge Digi�_ r [4/V&tU�b(� � d tw�5w3> l.5$ A�249!96hE�>%]"g� tak_i"�&!2aS7 a�:�#E�u�%A1.i" �op�.ia�*J"q�!Q�e��3E�y9*��c=p 35i9��l��n�`����8to&�U, 2e!s�M@�R�o\�_<�s 5E6 �8fnr�4�!i&oy� t틥s��4�eh a�jp"is paj ]�5ar����E ���o�Vs"�iڂ� !�HPs:)yy�X N(>}Q.-�es���dSIy&�;):ai� � "� �ro5+�F���)f)�Y`A����(O�7��~y�T!}PPar� � I�}�1 fre[Lm{N&|*"f�%2"�-h�pw,s look broadd�/�-ice��"� �&G*� ���,69! y5�f��2�A[�:.Aw[Ear fe"� &�(stN)I�x �9&� ��&�5>7&�)IM�"ly/�2h9+" \ �,a�A��ya�� �—rI�r+% /Rn,""��!� H5N1�,Z!���F�-m1�6&� f]�N'i���):�\���z�a%�u��o�&!%"�>� mx >$A�d9c�C*\r�� ;�!�{1(/�on [4�34ERGM��zaA9�v0[4'47] demo��1u'&�fun) �PA�a0m�(�� �y o)�"��/U�(: P=1-11+ekyloNA ) -k�z(�z�!5NR, P ,��0%�� ).�orO.r�, +�e��!>at%�>a��j7 ts k k2f s�eQAcurvea�"�l�J t 50:�U(p [46]%�e��(u �1��(hap�'n 8ti����S�<s2YЄ3�0�?t �2:d(U-a!I�"�&�'"B"_1"w&in�ofW.�!�u-m)�t.�@q f �"_- E��g�Do-u�����2bYo�[SE<n�&f "� a�Q�5# |H=#A�A!�orſ%��&�Vz� i�[|3b�8AM|�e}�Y�j&��Y���ŗ{e?�)�-�E[��p��full %�i�a�ko� Bl22weFt��$!(k2 = E5�0)J5 re Aa2!2 p�!IJ�$9 %7�� @^&uEZA_ %e�is-]$Yn��8"�%C� 1�����D �89MbFst�5&�2e?�qstill83!ny.0O ;�>�a�k�&Y-{�E��Dy#]�-� Y��W( K=%&�s0-�"4) A*H+a!�K"�Ak �E�p,�BlogAe�-r�� Vav�.A�g.-]a-�i���/ �  2(%! cyt�:Q�� � ad�!3 �7e�[4~'���^�L9N}"�:F&6( UOfe�)�!�� �*/\`9�$as M = D +�! − f;��!CaRDA�A4*e�"� :!5�3�*b�:.;%1-7�te ��[4OS� Vaa�0-�e� engu1I$_F�0at��>��peaF- �Udy M ~ �)(%[5WIx =Y�"W ,� /�Q��,oBA{�^q)�����GbfU b .<,� J.a��L seem!s� ason� o��= (�X2.�)A a"0�->2!�%"�"!��&)���ZEA�Y�� i%# 9�l\)�&�2����n�b�2�6�"� s!lo�. �U0(J�2� T*�2, 4K<ca�!@�,�]h{AVu�Mm#Zz�i�>�"N*� C%�Q tya�N��znaKen� aWo2�me�3dA< y6;.2 49, -� V"�a. 6!`�Rr m :V�VYO�w.w"0M=aFcb+Fc ( 3"3M$=a"|6:N�)�F8!w-0>x. B� ")�s�� b = �|)c ={���4fix!mt 3� cor �E�c� "*;"f�[|o���5.!�mp�w�-ar�n C�A����{epm&�e�a��"&e NaN9�? unbo�"& 0MKfO� s"�M�qweq ��%�X>��0��ew"&i�!� a&u� � !�m�2/U'all"�#�<EqMo �4�.��Y�, Me?s��76��g@�#E�)G._e�Q @eAvyh72;�  ( MAUC��%:=∫M���)�go�-#iP.mz& *$%Z"�mix"'%.�U�,>Hs���|*_7�I�me^!�8 �&�S��X�H&l 6E-Ha>�on J&6ab��QT�!��=�m`(���ach �"L�?B-a���#+d� �fB�EPag�U�Y&. Sl;A�-�jIA?/t��.�� �,V#"l (e�2�� � �&!.��to�q���>� .k�/�B�ai DI�x��ar AO4e<2!�% e��N�*+0���   �s[R*4xKs�%�/le�3. &N- iniP h�� �d��t�=wͨt��"Ik&K��1�i. ~x2Q�!Gy<wau����/��I%�4���or"t=,� !J���!\Ar*r?! f��E�6� 7"�%�: �M� }�{ �yG�� pk!E�R G�W%c�>� ,a� [C�u9# b_o� !��c'��Ii��,*�%��&�X*�f�e?Ac��[a<��1ieq 7�!�E� EoW�DWisX a � a��U F���6�aM.jslNU(e�M+p*�ei"�;X high��M��q�偭O`!=.�)�! �eij“BI�� {C�p+Erna�%&.�A���A�!2.�N� ge�3a� "�AR ,�Enu�v�a���rZWa��$)yuO�=�ya�*!/.��Umo.�� �i���zo��>1F��&FF,us��=u#�:�R��"~a'$oK<��*s)!4*Q;!�I�",.�s� �+9/�2�:gen3�2�2 'AVIe�q���2R�2We� �F�faiEF�e*�El�B) �j�ed�z'aY-�a��&R�A�)�"Cai��7�4"� �_DV�9�O��n/-ee�H��!����M3g�< �.9m��H>�&�2q �10!� A<��>8a��6�I�9'� moCGEU%�-av2��*<“�G�SE��InaOng�,�i� !I>1OnD�_[rAn �eV �memorpRR,.yUg���cTk\Iy)hieve�{LDasx2aI"�(=�)"kYeo��voI r /�%sh��� y)��/KtXn�v� �4.�qq*�{ BeAwrt�[T��Yit�s"�aI�al�( �proble 9��oPq�LY=a �Di��iz� &�fܯ�MR�up��aK1 9\I�a�v,"�؁!���!Gb�Qxi�dY ~= b1 P �+ b2 �b1A�*���ZK4a�a(�6Z �b2 F�l�F��UY��U���-�" P��}��toi�2 ���,�^��n"�s�n��"C "GY.�n�E%�T�~�,��N ;:pY1�V]Ac"FD ��* �{hy]Y�5<1�,�Q!��@:����=*�#��%ur��.�9�me��d� �&=#ly���!l���\*��*a wbe}�A3y�/ ��Qo.5W5a� Q�f�L�M utbrG@S("�" Ebol�HW g��U��N�?�O�Z���JU;��Zk]b?+��wor�/� ab2�8J9aZro�4!���P��(�0>ag�!����%ybY�fH>AB>�W�A�-*,�qw�~toočempha�A hom.Gngo�tch��- y . ���e� B\� �����F6� "�:�y� ׆�=AU!}u�in� !��� 8�n�] ��m"� 6_ � .+1-+iJU:IAV��0w%�Jr� LZM � de�oe o�0%�v beyoW-�9� -�"1�l� u�)�)QA %�)`p2�B� 2ythreshol$�!�\[  ��,Z�NoAgon /%�i�2�Fquick�\FI��s��n \��%E^Z6{ a# J� ^�G!�� -5�B� .3orE�u��=5`SAn@p,$Pl�uun JPny.upx~h�/2o��"�!��or&�t� �Iu�= �) �5�� subs��[�g'� �- or T�Bd K}�[592�-re��~�N )�U�!:�iQ��� I�3nV�v���C%j)�F�,!��z urM��2 al*cZK�F�DsA��C5 k��w�nre-�Gzt%5ur&SG ���&&�s�" ;-l9%�Mc4U*%U*]�ϡx*e��}�t�"�h50E i` &�ob �5e3"q��n�Vl���t�x*�F��%d.iWT� �s H0�Aipl�'�V��H#\!��sK4�z4nh &f)��C�6al =!K&� theyN"�����]d�<.#IK�v hG< �FĻ�|(d��)Vu��_$validqA:%�Ic buil� �5!0 �*w�~l`�be just�d&�P&CQsa� �p׳�B hm � ^P)%  . HoFQ� o!:p�c1q��)!����2o�"Ah]��e) "���VڕEjr���jd��vq96D���C�C"�7 `��&� ,�q�A�A}E�e�!�h�7b-�%�Z��W<M�l"�^Ez%N!�.�e:5m�1�[=�q�� [��jaigI !������!��,8+M,r%��%��w. D�)��(s�'Ae�5e�F�&� "d)��P,K.�Ɋ�3�LL��lA�Z ma7��>� `v'�, ��". )�a�9�2�!OFur"v �X�����ean)�u�-)&�/���6a  A�%b�%ls�u�s�Aal�ME %�m8"s"vqu�axg h"�)O%�!�6���y be| �Co7'I�) �E� �.� 6x+!��?b����� � U*�[� p�yAC�\& %C�"+*QRA8�v����e*�,ly1P�B�sj ��4�*.�Sd�b26J��\mL�Z 'n ?r嘡�� �6a@�YS�y"�f"P�u..c9n��� bkDF�![!�9dŸ����=�/�Ry]��th�2o0h*h—��E�� 2Ond�:��]I?g-Xe',ns8`��o�*+(,If�<a%��ڕF A�I0o�}a2�&Q5��be ? Esw;eq!�5I/2o[�4b3 ? �.�f%�ehA�!!��'�A�ۊQ�qL�o�CT� nt r=E�i� .F`��H.� �. [52 , 53�?O�E�6 d�"!d=��rnd)!~J �q!-n#t0Iv*�5 �J+"_=-.u,��� :?<onY�J�ZX:%˽�Am icit*�M�e�]AZ%8E5Y.� stocha�~ K�!�w-��l��I;apE���Ɂ:ng� J� @���vN� �n�0� l��2�!��!��q!��s!��(r�6l.`ir�r of IA�os&�u/ �r S/I�lm1f�\.� {`!F�i�I��rm�� �i!���E�,-a�0 �;)-.���j?~ k˕�w*�*� d#y.i [�jTowLma�!x=vĚe�%#!�=�I~�aݼ%�))���dI9� )&� Մ�a/�ng��:eՎ� �Ma_��L<B � e� o*�6^eZN �@ &�!ins�i� �$�^ ‘m��e�alw&[F &A�.w#I9oa u9|:�:a�p�D�1�0/"� Q�c5�I�Ŕ�-�δaX1� ��sx!� .��U0*nitro�Vdepri�,��AՁcyanob B,rium Anabaenv*go*�\&@�A !{UnW one-*�Q��t�#8 � -fixA1h Yocy�~se�͉��q$photosynth vego�ve�"�P ny a!G �A ��C1]b�5|2 !���}yD���"oZ� eluc%�� F��E00co��n~�>� fluc}�ft���3a#�� aJu~>il%���un����p�����b%�2dofB�of HetRW �#nscrip�-factor&7�=��b�MN\�� ady-���wt��5t-r���ZilI�[\"-8&���T near��el��r/p�, �ac4er��Y*&�+gnaWjŦ2b N,"�E-cGS�Ee� [� Q����rn� b2��#�cs aris):Tb*|����e!;v0�*�/%%. F.)a�Ustep-����d`!v .I�/D'et!Q"�eB��%>2:�,]a�<n_M�=��.eXinhibiaIPatS ,��co�R�SA �4� sep�vte��epJ%("��a��-�pHA.TnE�a�>IڙsL9a��!�CD".��IQ8 A��;=QAPK��qrNSk5�po>�5��l�W�cx-Mstwo)5gs)h] HetN��&�:3.K�p�<85.Z6}s 5~FraC/Fra�eA&�5!%�%1�q!+mu5�l8f�hea�FRg�S?��I�Q iDv?M* &�}dg=��� toge7��e���evi]Ls"h !inB2tH��tp����~.�Jke]�1�aB: qr[�organism "� �I2��meYee,>D.�al]�����Jm���ra& !�No!7I�n i �y ���sQ(, �Z��-ox����r� �fixi�[4s�ce-*J -SFM 10�5> BQ [�8�KAB�,:��<5�6�a��"�-s���h��L<ފ�A�e�ior��jR Nn@[boX K��at�Ou�t:Ifa�Y�}�s|�]i(�ftven�{inyI�qm0_ n����p���P!�݅[�� �[��6�(f!�)��swx�dro1(h&Xav�b�Q-to�f�CJ���is� UNor no�[4��N,�J` �Cx%F1�s [6– "����(pl�"�&al"�I9�[9]eR-u��!u!t6!)�[1�i1 I%�may!�` advan�$gi"7f�In��y�ron� �2�t&����l`� �V8 �a^'�6?n�o %��a�f�b'"6|neƀ������!G5 &er�UՈu/!:�^�seO25I[>��s&o�BADJwy���>6NU/"�-��?A� Dros3�a embry:$�sp� �h ?"�@hunchaJfM �(∼5 nuclei�o�� ed [˫��el)A6�is�a.d: V Q����"��I�[1aB1UBPo%-��K6D 6�J�o!v�3x ��0� v�Ee jJ�le�9of�!BJ�"�r �#>�[19�x0�S�7h�cas��\!fte��-qv*�2��J7� NtcA� >�&2�� �)!Pra5��N2�Z& oughbES��2-oxo_^@�eʥ�ma�� � ����L)� �� <ut"� �wp� �� [_���� d ea�b �n% -&�hwaySi!�I~���s�D��M�7A�� �]�U �at ��,� I�&h�0 �6a�{d?��{� �W�%�>t�> p 1� �������7{2��s jep aminY1iI tif ERGSG�th��&1d� ��actU RA�%�[2a������!e��s+�U�~�[*�f be��ۺ�7b�> �~� e��AeF� as6ߑa]u'>u�c ig����metabo5i�}BF,�<e� j 9�� 4^ama�n�)�,�U����D��}&-;N/�5b3��addAr��rio��$W� ���S� :u�rvSg� oe-�i�^[%s�mC�t&�#�2��ord�4.� N� �YO�abund/UK*�i�� � 6uema�΍ ��dXsourc% �u��,. �!����& !�M �� a4�M�I���0ZVwM)�!@�=ss yAa]5i�O �k��Y�R��!6j�c.16EQa`����U�of&espJ�dT$PCC 7120 (�)Z"�)=)�2,5�-f�a�%l���zWDHd�/�9� .�s��.� �(1�=W2� �b�"�9>=�r� �'8��a@�or��N����re �n�b>���1�F�Azoo� ]�'0OZcKD:o��QR* �g�9� mpai;>�c'| s& act� 5��fv�XlsF � =>K�+ext����.9E�l��q� � >", .��9��#*� � � ���~F� �*�:,�.�xdA�� �.*.M&{�QZ"G&R��D#5i! �"j fw z A�1c�RP�_�m��>�. na�y�<��u�%Jf�2N������.!df.��m*e�q.)vlasmip-py�N@ w� pre�_a]��,*��o�g�ƥ�*�*�i6m 1� T(2o���-��I���Ł�tr)7a".s�ta  �"2 �! (a tetra-gly8�linke�/ $e gfp-mut2 v6��n!]o��Ai}�GFP )r.ad�2�o9th_cIv��l� fraga[�e��61 kb 5%�6@!h �Di 27 bp!@i"�:3�<er���{-qN�tIa4qg?.�r�n50���nuix(["�UjX�q3Յ 1&� m�4��BCJ� ;n)� M�rt8Mn -����T�XAQ�lJ���e�pCSV3� �с:SmR/SpR"{� �Ω9R[�| 6 �f�wonjug�@ �&e�\�sej-!�.����!tre{�A���� tino e� n� geno2�ڍI�hom!T W$1m*it�dwE. 1�Yuw!�-�9X�layG�amY��I?)�'oA�Q�%� o�CdBFa 1-kb�2 �����DKa�xwB���.��t%�Q[A�+��s���)A�e�0,�@g�6>� �ueXIZA�e�.�>3to�-d"� ( WT3�'~ 26del_�5�p "9y)Wɮ&�h�B#�d#s&%��6����� Mt fraC%�f�Bs^Cs- ���[Ma�a��Me��a��a�[5�l�8\(�!ng5�7.u�A_̀h"A.�d�z!~��� D�s{{�\E�coņ՘U�"CSSC2�},�f^�B!�s� � �a�-^D 0�a�� ��� >�BM$adu&ec;vB�c��"@ uIp carrz ��.���&@ &� �.�q��"���O����5zu�!�x9e�*��a�. �F8m!g � cyto�Q= �!q���l�GFP fold� d ma� ��in��30 minG�87��F\?hforth�,lsa��'!.�RE�a͡�� ��9<&] >t���HtypsAivrof WT*� ex+!]["u��NJ�#Iu��) a���&>�aj)��CBTa�!>~V&4%J~� Gi�%S �$!alƈ�e7) d [�mN��'uh���m~E2�$.| qt*�%�Fv%re>�2E�a5�e*�2�v�2�AΔ����Δ��A)w"f�vly �e� =WT�� ��f3ns ±stai 18±s� 19±i�l�E� T ’s�Q3±�R���!6 �M`4,X �ely ��,�"6w�>�I�� .�aQE��tG �etR!dd��A�e�!-[��{1e_e i8�\�"q�"� "������", yield6�. $�g�A66 �x<~LWT�)q�A -icu�R c�*Nu���k�UE+)�5��C^4is narr��t th2�!���  AX�&u disp�2zmY!O��ly=~ "�~ �D&|0s0FQZuto� a �����L����epF�'%�.eZ-!%[����so@8�8w#/fYM��O.�,o8 σp2/μpAC�σp�!S ����!nμpma���l�ce!�"��n|9�IG �*��vqt²� s-G6)&�'�����Jpanp��Ra5.�-����s&-!�#�����st�2A9Q3,�2_001&�*58�7& A!>A?a�bN�q�.�R?�u9kl�#� �B"��!�� � �A�.u�7 6�ՙD�nst>��s�W H �҅�]�J� v s Δ] �Δ /De��ER8 �ƍ>��qbackground . We conclude that cell-to-cell fluctuations of the master regulator HetR in Anabaena are complex and i ` essentialstributYfrom [xdevelopmental network even when$Llatter is not induce�In V$ast to uni�{hetR-gfp.i.N long fila!Ls ( Fig . 1B ) . Spa-Sp�`clearly brought out by sc)Aplots1�Tfluorescence f ( n+1 )n+1-th !P�a� as func!�-FK IPits nearest neighbor �allSs ,V shown for%39�strain%�)D3A . The most sali!�featu%�@6�is,large spread�pointZ!� case%LΔpatS and ΔsepJ , )�ve!�-(WT , ΔhetN R 2fraC/�D ,�wE�76�!�(rather simiA��isityA|icate�atFeffect�T(basal activ0 of H�onVhiF�significant under combined nitrogen!�nd�#h,possible disu�oa r�yY�:�w everely a�edA^]%057mut�! 0e cigar shapen.1GA.-�( Pearso�efficE<= 0 . 40 ) reveaa�I8r statistical te�cyR>�ses!� have1�6� than�WTr�25e�.�,�observ�R�4of some highlyr��to � weak:!qsE�M�.Tf00� , suggestMy�+>�tE�e�E� less�� �6. HowA �non-triv�(>]6�1���%� �he��Ω��. fulleD�� . To meas�.EM�Oext�I overm�>���� e��ed�calcula] auto#�f><�J -GFPlo��g�� )�aB3!"a��ٴ �aea���:u�(en averaged ࡀ�*�� spec��wQ�experi��al run:�4= 〈1 ( Lf−� ∑m���0+m ) −μf ) 2σf2〉�( ��Here C ) deno�e6(o�nZ�, x�� mean6>p���in a giu1 ,�%re!t�� vari%|, L |1length�!Iindex m!-s9toe�Bp��>/,�� pensEQ!�a nega�.�Dbias [40] ( see S1�.)A1�fur�nE� thre6�>�s!#i����Bznd>9.�EN 8C� ithinI�run�(NIs`y��display�,same behavio� � ��one ano%� refl� b <ma08standard errors)�refore ��ces2 V�sponding��!^Ct�!xn ≤ 3�!in1.!fthough �,��.�I[markeda>�.Z�F�� 3AEZ whosO ra$ ��X"�  c���7!p�bu�valuex�� �= 1 ,�sc!j�l"�ceA.hil� e decay�F withA�2V!h6I*A�slowe| �&� E�itfa �w ?.2�to b; #��%�Azon��.6 Ais ve` ) fa" WT!e!X! at�� frag��Łcan�ba�voA to accoun�Ran%Athese��ult� !ja!=��seZe�(our analysi)�7��or  e��� -fJ�|*7 %5�g. IEe���-7)xu� illu��.D��3C��.l gZ#��7 . -reca!h�;�up!h�E�two�� Si�i�2}ofR� ��A�in5�sm��q� 2 ) led u� �� ct aQ�u:� >�R� a���V� 9V��Fu�qU� �i� � ; ,�p��Z�X)1a�i�dividua.VA'so-NpArprincip:�!�]b��!� acros er pop� a�comes�inter-u�7���&e} quantif�\i� we first :< mea<h.�ofe�2b� compuA��T  A��� devi �σf^i�2t:*��EMobtA|anoiseG2/μf2��t� � aredto σp*p2f , Hed�y1 �&)_��6��f�5��i\r�UE~ �@�(is 23±1% (�±se )x�I�s excep�7m�6 �~is uis eqA�to 61%M� : T�uE �,-���inR+. A�r-P ��A�"� sucha��< does�Q cap\ke]0��s;�recurA�!r(c�|er�� contiguou]exhibi%�B 5"<above"H �F shol� ��6��typ�snapsho�:WT!/x 1B!|,o investigatw er-o�Ѭ�����>�#mad� binary rem�A�i� �n%�B�9U. Cells�p6Il�sj;w� as�  e�� w� �A��2� fH%�hr-�^_�W en e!B��<� of)M�=�1’s%d3��)I� size We�YM(4 histogramI�21�/ed�setE�i2��aɂ�� fin!�1up�15�cklE*)P,�dEe�F6�I�2 (V 0choice yields^���at�bclAbAx 6�U��Z�eO.� ,$mean-plus-J�1�2�.j.��3Z� �UN%�Nm s 0� swhereas; 5 st�9maka���\v mpari��*�[=�we��m!s>� X!�8Eq . 3 , Materi�$nd Methods� ~ 4has approximatg χ26) [41]� peru: t Ta�2� . � e�+a2P likelihoo*^wMxvvJ ��%U�2�FUe�q!$� � .�ly!�bH��� � M ņO �ases5�hoge!LW facts�Olight ag? fund�ho��P�in�&or playx determ�28 �*�(. An alternEw  o br�R1!�e�^ charac�Z� vp}6ogto��ch re2� -�%f&� consang�in&���X endaRsim� edEofJ:by�  t nite� ing��20 c,ɟon��r��ly probabil� p15 am�zerS �o(e Bernoulli4lembe� ���� limit��!�" binomB=��M !{N#aZX"E4Wa9EMDe�(��2j��iA�� a��u0:�K&�d!�s�t� ��3m �e�>�eplet��nd�� e6��!�UiV� �� �<EL ��sepa�prote�Tb{e�d�X!� �`F-2�� >p�6a�he� �To%l�eI�tI.2Jg5Ȇ�provi� e *� � i*a�-� "�s buildtdua��*j Zcesf e)�carri�ut an&�of6�Zat��BtiollowA�# depri . Hq�h2� e ACB�F�Y e hour rv � 5]6=J�".� a0.�}�F���.*n �af�m54step-d�n,��nge��Ak� 2,)�&K1K�"!discern�" � ��""}3 s~pai� adjaf Ey�1<%lowR�,a a �"��N� Z -�-�AWA�� �)�b;%� . 6�. I� also�eworth� at 7~K�Q!E�' A 6L !squ���� ent:*E �� ӵ*"��2L�%�`� a�ti-��a.Na.�6��N8in:���H��[ mJ�m�GE!S6;R, no /.�is [A�$E-�inB4-^$ t 3-�9�2vb���� Q�24 V^�: both? m tailEQeKZytheir>�>y�IP����� %� fash!+%�>�U� >ior�!ta-eO�AAss� u�� physiologx�8t molecules [20� Moreoy Iw�tOse#Ų$ lack pu)veBSJs:� � %�A/WTE� q#"�A�$| d� �v�S.z K.O��&�#panelJ� U<���"confir*(i�� Fina�!\ w0 �R-� �}.�J��h&�h�o �!an� %C��� ( S2e� To"J!% _���2@ ) a pa)Fmm�'�zeme�&�:��6&�r�"�|"�'�T�  � ��^�, �E1�6C)!�6 ��*Qe  of commit��Ku��[24aE$Remarkably)��.� inc��.Se�a���"�� �O /% /A��t�(o ammonium-J� ��J�>��`un!�inguish��@p&�#� ��sp�of�ice31K���6} . I�g ]+p��#a"��� numbXfS��!Wo morphj( grad�'f|�H!W impo��mue�s s�0in DrosophilaA}.� aly:!r�K2eJ� �Q)�-v�-mea�Z,�origi�� envi�e�T} [42A�VarI�e�gr[p�"a key i< &�!Lu.*decps� *� �r� (es [14 , 43�[%�h�izA��ria� !^f "� ���vA..�ehZ:n� -poo�*"��.% �$.��!(im�  ��-�F�in%Rs ���31>���b oupc. S�(alE�rt�*�,s��E�5! stud�Not���/�h��-����++�!�.�Zd6� goverA�����by.�act�$�:f�/,�/i�lŴ��e�"�/M`"�e.V(� eqPpport�noezof �=�-deri pept�!and/or�ztransN�a@Pv�8��a�)�J�J�(��A� �"-�� &�$ "m�( "6G���Q,�y*�-  � broa�� .�=$��be�#or!�AW!�Ye"P feedq loop!eron�*!�broke�SeAQ �q'>��:Vsr��!� sepa�*�1)��"snrV6-P�O0&uC&5/i:���k "F` 2.D QMF���ir13� f ^�a�>2���AeE% �6>::|�#eRd%-%�1 eU'�e��siPfer�f�*�e7 �ZN&&%�'�p��al�1y sen�2B[18 , 30��6$)�=፽�&-�L*M11,��*� � ���ANjc��eMMsaA�Ff5΅~Ɉ�u�Z�Yh%2���B�1BY& . At�_ R�&� �'I�E�da� or�NEW�asB,X�* &�c2\E�& line)�>E-�a�'��)�is ��� maJ%ny pur� #5 , 27�,� 7: W� "�!d����2� !u6g,�of� chU�E�ap_+z a��h 4�r��� �j5� lexeG 'Domm�6) [19�A�4� S�/&�inquianwhG!Yk!�6^2R��!�m�"�s.p!7i�2AL�at$]�2x}�5��� *1�.z-� :�-�)�’� h�-is�ly � tT !w type)�i[�FN| Gw 0 t I7�A��s>�6�"��)�~�Q(�/�eB�would�e� e�-� e��sB�A���� 7� 7!�"' hindre�4j V �mo�.��^�$!a��K_ �Q"6�� ^y*- :!x�!e6]��al may�.�,!?�!rd?>�"�6t$ W;R� 4.pit rs��>�B�d$t�:���n�8��"�7s)��th:1SepJ-��a0 f� s ye8knAore��� b8reces�ish%�H2�5J�E�OM�I�*�-2� P<�� :AR}ffn!�meE U�1 �*U#�re�l�'orJ �"inm��a11:cau�6|de&|�sigA�rf��NqF� �sourc|,s via duc��moA>on4 smidabU1�of %l[45�a*�,�q��re� !�Ka2b0.>i��proE ed du"4��)�a��,��qSca3A��>�A�&M#�6��M>BvB-1e n��!��B�&e ( �2g07��ii rpri��e6E8 FraCf FraD!)s� focCA��Y�[�5,�"�;X�:*��)I[&�stilluom~�um suM;�a[A.�` neH�*to�$��*gўB� .z6� a0�KA�M!�j5�t�'�"n^��  data ;)a!�/%�"+ ��invol��-@"8).�3�", metabolic����y�p%�m�q�"�o"��r%�,"��:mp��ng娑^cR� �^ Previ�-gA�����I��einv 5-carboxy"T �.^=@-Q6n ���s.:tcj.MLAl� � �.A�%�#c~ b�e�A��&�"�>�> a�A�*� �6�2%��ly�)�&E�� �P)�a &�nS ^�a .�!�1rt�tic�7s tesq�u��%,� 9#*&<%- 'A�B^�' F�&I >* domin�par��}V�mus� OP ���6aradna� : ha#"�#2<= duaXclusiv��to��0��řre beXQ�ce5��^:sa,� %�� �+2/!�Noa�rowth-dpV+s�a�? ( ��� c%�� )2� rs�%��FM&�J�.Z,; ah�? s doI9+ch�adazotr c 2�0 9K.� rate�*��beY . Im���E medi@sta�%mV!t2"�Gc!� . �$ !�i���1n � �.ecirn . F��S/G)�WG*:�a�candid��:or ��&:�7A�sj2" U�8� )d!�"�&R1^ab2f� P3[�NoQ7 ����!�� ��*b%yx�D �K �teqGing�feB)A��d!�.8a�"�� [ a&� !�&R01&-52w:engineeNto��Ii�O�B� ,%�5^e.reAwed� I7 �72-y���prt )D a*�\ 2�, GH�0y ��-vt>U 2/ syst*�-may!�l�/�-M�O��d96�QyedN1�f�.0J�H�Fed �(!!�*,���K�4e usual�oc�y�9H6i�Kns� �r 2ne9IE�e�� ��i�<�el��2 s"5bT0� d ye�K[�6�Ano& manif^%��1*�!1!k��*�WY�>�7�a&V. Our��vsi �)���8�ex� >�:�& pV &j8��F���1���"� �0�| &.�.#�\%�� � }� to �le�oerocy�G,��%Bnvironm�8l���i"Em#A�2 �&�܅��9s a m9 )eJ�2! .�=��NO� �aJ! T� �s�����P�an at�-KR4 am�\-� �{�/"�!)Senh"7c"+O[47b!8N�'is :to ope�l6�2�[2'" (o�B>� �Xl#� re~� y=�N '�a�!C!�eJ"{7��"�, !y��2)B>x"� �s(("5���P��J�&WJ��1�3s�J �po��<ut2��:sD3�40���I�1 HetR needM, prog��of >�in.im!"�����&� �X uckNh�#ey��m�k=�4� AAS9����pm�|� s*{ � pert��2lJ�$.�y/�6� �!� >�9�,v�y bGz6���'G�ߡ�b6��)��primord!�2�6>B!��:��,�_9C/>G9Vl�NsE�I{�H��r�(�[nu�5ѕ�giA2��oa'&fr%+triggS !g�upN �z"2r�,"� )��U2�a&8E��g��!�AD��fl�w"l1�.�i*k 8lI�X�e��a�N����A�T&N#���!�e�͵"p a��sub��N!�.�@"&R�%Qk ɊTv�A ampl���`m�2�� .X2h�k>�F �b, ! k1�*A�% 9��%^����" #u:A<�9"A �ig2�%�aeF�? "�$���x�j*�)by�.C� mode�}����-foj;g cyano"� ��pro� d [5�/�� W%��3�6��& ~ , onSMz��ZrB!+ly6+e� � �pt�Bi B�prM0raa!a��"or.�ar�  [5#>D�*1d �- eti�resoluA�-)"?>ea��"{�sezMX#��&�:N�!�  t2�t&�)�ŝrU�in)�G�is!3iB�'"- sAt3>rec�&gT� e)!W: , m[.h&� 5Uv�1q�o sum� 1h@69dRfu.:"g:�,2�1�I�.qfaR�I\!�~� heo�2% �?� B6"^iF���O�.��0������h�, &�Tm��&�d ��.� 2��2�an��ly�� N!�چ�"S�.0,� �� W% !uev!>�2SX2�P���Q�C.�)�e3s <�2!#I;*� 7JY��-�*�!,q!;a!�n��"pQ-GB�8/Aa��V�,//!� �"R%>'�o(t@)�l��!�#a�H �G�!��S%O heri�t"�� A�i2{$A��2�&eq\c�م~!����/end� .@.�� k#�nJstr�@� �ct�Gpha� ��M�ͱnX�b�/� n�Ma novel� oacat uI�inB�eBe garn� 5'B� 53�w�#m� *9^,�y�z��^.Km�Quqm�stZA�t��o 2��]"!�E �.E�E�i+is\C!����1(�> <PNA�adO)B"vinIe=sUq�Q, � ndu=7Pu�K*�!-�!�!ri,&�,� "h*�F ache�Fw� A$lE�A��YTe�D��ppa�KX �IO� !hA�(ey occur . "�2sp . (&� as Nostoc )a6�PCC 7120�d$  {n photo' ��)FFescrib�wly�3[uIEE��) ���$e gfp-mut2��DNA"�S w� f �Qa�*! emp���per7;�h,2339–12/al 36 # l� E&a sequ� enco� a GGGG ,kY�W(by a NheI s�6!vP�rCs:2�H , 5’ AACTCTGGACTCT 3’;-�-(GCTAGCACCTC(GCCCTTGATCA GATG > . )�PCRaVM%=clo� 4SPARK ( Canvax/Aadobo��5 �!fA�aCSAL3�I�b�^eg5� A�%ecN(, Y@ �%kA/0I ��uc �F�V3A<e+& pCSL68��f�M� �=�$of 1025 bpx DPm�$Q�a�&! 27+�Q%�enwa�/ORFI#d�5g� E/5U]f<4glyci�G . Pl�&�A�:U�e�hO onjuG[o�*)�8per��_@Lq�[5�CAs i�L.j ptom��;m�]+ D"�G,dihydrochlor�4pY�\( Sp )� �nTir! omicj`$e��!�CR! erio�K lly-��1<"n!^!q���)��t��AiK--tK-chromoC��� ium-�Ku7& pple��N�)�@biotic} 9��B4)!acip�"y=� ������a�� W A�(4; CSVT20 (�S& $l�,]i$:?5? L7 (A�NF=�0b=6=SC�ME��1on { [34]b=8= VM34�]pJ>>@0b?VM10;e���~]DFI20nI1/orJ "� .5G� 24 VB��T�taK6�bubbl�Uatch cul�EBG110Q\IOM| 8�� 0 mM NH4C�7i�v�, 16–2&(TES-NaOH bu"AH 7 . t@�m OaHCO3 ��6�1% CO5O air �=re�1HtU�,A��) sulfa�a� �n�Cr*�re ad�M aqa!���,�0of 2 μg mL-1�  liquidz5solid O. C1~%��048y 72 hYd�eda�e��&� elL*a�a���5�( 2–5!Υ��5�f%�a� Ness� reag .[53A��.�l[*�+]s n�"6�fOu�e��I�Q�2�, :�)��%/harve��,�W/&2�!�incub����2)K/bi%)nQ*An� b�V.�$.Uz2}BgX�"F�+. S!&��y�!EFaset atop�m@sl4T�.A?ifs � r�:to viq izS9� �`&�%e!��nU[lQ��L�\!�S" mmerobj?AXCX PL APO lambda blue 6'N0x�� 40 OIL UV58in Leica SP5 mi�[cop�1% exci�� at 488 nm� aggon lase�Fl*�J�Bto �#"500A�40L(Yima�Z)E+63!70 !2�l�2}�.Ima�j�_= . Al�>N )Bd �,",�}'MATLAB (�ThWork~TX�#og��Aa�'K �`5t�#"I [�$0W� ?�&lan or&?In�r��N�am{l�!�dap��16;7J�a�check��R�WA�7W�:��E SH"YZCA$+ �"dD&�;�N�>3. U%c$J�en�.+b�G}ae�rr�3�!wo ��>�%.�ntensity/in �fr}U� �Z1outpu] %.ed�#um Y�Ge"�?s-�br�-�C=��sgmK %� �|�D��reYW. A�2�2Mma �L>I ��EQto�p ��?.�YA�t��ext�+K Orig!Xo6NluE. D?0(corpus: Eac�A �}Ek� � i�=r 350±35� (mean±std )M e=� a�104*&�^)f�< �*Vm� y)�D� of 8 c&�c. S�EO�q�c6�a�)�.?)*2PoOQ&�O�f2G �A#Earth M,E�Dt 8ce algorithm [3!��one-d�jsioFt({xi} , {yi}�n/UAvre�J ( X , Y )a�Qby::,=∑i=1n|CDX, �jCDY | (zc>Z %A�&��*m=cu�V�zv<�:Eiwj=1ixiJTnorX)���#A�cond�FstoA�d7"� �Wdf9�columne�eR(jorm9s X Y�\phoptEyschemeE�doA�sZ��)���br�!� GI/G�in�ti2 � 8F)b%AYco-cirRq'of GIE6@s�SbeA��al,��5ke( ]F ns�aV�k�:�3�V%VJ�n�#<_�kinA5� �Vr<< -isowdI �Q�-� e� ��wm�DumoslUo C6/36��2Wic_ibroblg-C ( DF-iq�yporL$ iliac art<;endothel�'4PIE�OW*C!LGI�1 $ ��"�u�9an6��M��_ l,4%i!���& � ti�-ra�!:2lh�225�' foldL% 2BA�8 how!e&&�!��c@GI e�%� avia9LEEexa�I("�"ZOin viv��young�Avfc duck�C�u���h��AQ$!0ino!!!j%.Q*�Z ay 2�t-hZ!..N�-Q�P]#ig!Mviremia1��di�SaM�7Hl�Uer 4�� M Vu!��}�s��em�hypA��(��a�6� bird�Sre 36 !�oi?#���,.aQ ,,"EF�&g 1y}!�~��Yi� �BaA%6!"-@�`e�bjZ_w�:�)n�R-�exposu!�&�gin�}� w�.M; P#�]�@d4 m]7onrd�%�-��es- enzoM6M cycl����2bu�Lto�v:�. ��C zoo�/c flavi%�)s�A�**�<um�m!:�i�� @ ���h As�TpaNSreg!!['i�5�m������5e-a�nd� /-s'a0!&��[ofu� vec|$�v-bd  ho4.vi Hmi�wpre� !�by�xse�sDv���erU_y��ip��5e�; � mJ�?X�. MU��6 a!�e ��O sus�oEi"X m�,�O_ ! � mammYiAc� k��by�- �r �m�Rdrt17w�/��5�*� �0(degreVf �aPm�J�\ b,�c� �a<llardeid wi���E�a� A��*�O,� U:a�a�Yh�o�Od�%��=if�IL��A�-�TS[4–�7g)x5$.���)q� ,�, �e0- @3�4�oBy %��9�E�N�RZ�f�.nough� �. �~4 d(CI��is phyl�ti$3(��9)<��a c  Imob* nucleo�T"#!�E<e [L 8>4G� u ( )&r �l2Z��$!.� gof V*( J�A=A�0��� !8|q;of��i� 1935"@ 1990� �� )b8 � Cambodia�Y 1967�)� n*�Q$until 1977��newMYcol�. Z�.�=�>*<lek rv�!)EVYsV�&!"� 20�:rA��;Ep� I%��>ujL a@@by� ,���!a9h�w� �eJ��-m�r�%[= 1�0P�&f �7��.�qQ�3/�� R <gg% �F �%Lkly�achiev�n�p"k� A�2pŕre���D.x�A<�z[1�0�1*X A�par;8ly���$n."< ~a!oM�%��(�3�6N �3���*@ .�t! !X% Z�[%��I�(�patL]iD*a�.lv�I�lA�- iCWa�V-6(s5�BAMnd ����BO$� ; �l:�����6D��i�.Y *�^tr�W�%keA�ai�o�ASz��3A҉�ib. A�c�.��a�*� qInstit(3 al A 6C��!1Use�o � $Shanghai V� >vResearchL� lIACUC No: Shvri-po-201606050"�e�| ��Â5Guide�U��H� e Treaua of L&� ���Min �S�!�nd Techn�d!� D~9plaque�W���)��F�T�6"&�Z�)1NC- [1 A �$27��bl�t$e �_��Z ^at!` farm� d sla[� erho�lo���e12��v*�%E@in).� Jilix*0Inner Mongoli�b0Xinjiang , Qi�, Ningx Hebei , J$ su ,�) , Hu  Huna]Guangd�1Axi)*-ser�)� 1s�"$at -80°C V#�G�8{��rif<+)�de�i%�I-�\6o��U� S1 T� . S2�&� %�E�E�scree� �q merc�$enzyme-lin� iiYosorb�A�y�rLISmkitx fic�ZA��� ( Wu�Keq�Bpy , ,-�)-z6j.3e3.�% ody-sandw*D ��4s��eZtn=Brief�Ga 96-�? `�/�co&7100 μl' -of:�dilB�at 1:/*c���Ak"G`)��ol 37AV� 90� 0� bloc!�Ŕ5% skE{ milkaC(phosphate-b�)w1a���Bjg�0�{05% TБ2!�� � ��N28{�qheat-"�UE� a w~y-ba� t 56�3�~'� !%-1k�E!B05!��3a.�un� ( PFU )9�. F"�q*(u at 4}o�cigh�o1�( 1:300��m��Eo-!Mx� eH�&���SachI!� rC#t=�6 �i�boT�BWetP%�horse�gsh�oxidasF<�/ed goatE- �IgG� anta Cruza~t&R, , CFUe��2:�3"` ' , ��P5'-tetramethylbenzidi"j(� �"de%( OD45!Je<5A�pd%�5�'.Z�-lP�<�� a"]!� iv��. '.z Q�[i�AeB lbopictus2A v�a%� RPMI 164"K-(jrmo F�Yr� ti�,� lsba2A=dJ-0% feF"b���&�[( Fe�jd)!=28A�.�Q��J�%"�Hulbecco� mo�*Eag� �*( DMEM�ThZ#)Z �u4(1sHm��{%�ing���+a�r��ـ,2�j,�Y�;� -edI�GI -E&�a multi$ �'o{��F ( MO� of�11e>2�)���2h�X�w;qng y���` u�/�YFv��2%1.ma*�2iNw.�a�*&��1�P2�٢2 ��E=F+�iV�supernazQ-W� �t67�)rv��B� ���&vAFb��0by 50% tissueqBMtXd�X( TCID�"` n��Z�b-�-f�ShaoxAT&y("4s�, tyrhyncha� .�.a�.urc�< Harbinz9� KAcadem�Agrp tu:�� ml6k!K�bc&� !l�R�randoml�#toa�!�e� `. groupxn���-*� subc<�eo'��1\d^�5��[^� � ,�':�&�.�7��b2c (ic5 ml ) �:U0 jugu�v�YIdai�(%2 Xpos� � ( dpE&to{pi�m�2Ea@��#�%z.�M���U*# �c.g"�h�GenBank�2� < M���4�?ligyOm�&�&!(DNASTAR Lastne�4�� MegAA]Ph&q taf�ge��8�HnvC-job o]1 MEGATY+ 6 . 0Student�Et-F)�Iwo-Q�",!�a3�( ANOVz %:AF&)�&W,A p F<��05�*y<t��[!�|�"O*�� &�X>��m5�*�[�g15�Oa��wByU:��!B]hk\�aM�cSQ*�&P�eAY��K"!C breeX�B*�' !Ma�t�-�!de e�H->�&(7*2w.� �a��56� ��M�:���o/��,!�I8546{!�"��)'! ��.j!E=;(&�aɁ=Q3Na��J2/,��3�-�&�}o 5�=7%��I vș:l3�86��k1A%�"X �i,A��,�Ami.�k�3�_%�W*�[A�KV�6A��Wc half�v4�0%.�ly&�( 3�'0%�/�f0KI("c� 0179� ��;*F*A�"~$n��K sea���'�/mw"�V� �2_� O9cly .QFB!��HV1w1�1V��$,[ngEr2b�.<8 edHA ��Ga gre.M��stLC)�� ý�as+y�; versg}$��wI�)y.w �awIIy. � a��e�MQ/ �!� 116 ɴn]�bU �~2b2�~� �-Z. O0�!U738m443e�295 C�Z.�6D�#a&�� �1Ft-�)��r8�>e>�$1C��D&o�-�-" @.�.�&i$!��F�A_ɐ��v44�1��YM�<E �Ao�*)8E�5fsk� a�TA��x �6hen�~%��hx+stL�:21!'�+qY.*!�23*5�e1D ��;"�J�se :*�hae�5%5��;�"c�6�A��:���!�M3bZ!%e� �_A/"*,&�%!��y�F�h�&�&l�]"Xg{� mS'�t2�$r �#"(!� V"@ A17f�!EN�&� n�g0ed�!D0ewiie{.�art �[� � .��5��_+Aw*.�0.=�� �=2u&?0"�/�*�����r�%!}� �'�6��n v�K�)�.�()�Bpig- �=��� �,���*4egrޯ �gjg!0�^.���zZJTa�+/ ersu�II)3"/fa�*f2�Q2� .*�on�|&�L3$%{.H%��Eb!�sR� a�G&i2A " �*C J�t�e�Nin � xW#Epl0A!, 4&ˏ 0003� nd 5��7 ( h�*� 00|�-(B�yM�$���J���.��BY=P x�,i� Jd�=eZ2� �5�PP10��3�v�  19'e9� �'6(4F�3�pI9� at 2�F=t-,�1.U!�1�6�6.=:7%���00 S8i.>!�96%�.m0��Nk>.Ag�-�^Y1��2�#�+�(nd�jI�6H���E�e. G�a�s�Rk2�U4a6ss~ r,98wan��e�E�^1j�4Yrep( � �$e. Y^�4&�+q�)���� �&�!4��.g n>�,J= �7HN�A�1�,2%'żf�-�[ �6�&!N�n�.Ne�:���Z�E;�Q>�#}���j��;A�%�A1��meav4d0[.�&�M9b.;Tf�<r�eH3SA=� ed 4c� 1–�- �A8o�)B�_��zk2�.�-�a�V�%�6�1 ���3�3�]; h"�w^bSic!3t 4S5%��ReX&�:��pL�T�8u(.�ur!� �30&�3�3� ���8c UANUV�-F�.ay�e �*�8�BVC���&$3�6)�5�, �o.�:V] �F<�f�G� !m�vV>mH�9ai"4IZ=�Yg�-A���%#!: '��8Min�(��T=ina�6�5��assoc�h�3f ��r*� A*  fitn͕[1�01�g!�,&="e "ga�R���c�W#� �&yŁ�N� q miV:23195�H�8d�$�B�')m� ownl���X!�l�e�p"�T� e%rf�:c8'� d77.>4Vh7C�+rM�aY�g j47w+�-7(-����2C5j�;6h.`*�N�&z &�� e)l�l3Wh�=�<e�*@*!�E�)-85y� �&]["�>!I|E>j,cmaj@B9 B'd1P7 or-b�c�>4!�neutr/De7top�1� �� d�S#a�@%6 entryK �0m��G��N�A���!� infl�X�  tropisV�pen�%�B ip�.�9�;4#*�\kVo-�)�KqQD�v�%׍��7�io;&n: �vfaa0��@'"�Ccre�lipo-�2c��|m�+_JB�u�.� , el!u!�� mmun� G7e� *�_� �Dl�Uq[��2D3eb�A�!�w�&g�(���;6� �mod�>U� eva�!�3!���=�2��j����Ezy�,c-�i8kser(:_, Cc |w7��A= -tri�*#[2m02@n�NS3%2"?arir>�"%�*�O-�)6b[urs�*M=�!�.Toj:al�K;!>!B5!B.:Ns%��FV s�e�" yl6 fer� ( MTT1 RNA-1 �Bc�m+RdRP ) Kp 9�XvoC} bi� u!pLcap�te�Q�<he �a%BeJ)!..EPad�w�q5�A�,a 7'terferon� a�C��w�92D#v�5%��%h�B) !�ԝ�+ goni�{-�% ��]onse . MbT2�"X2 !�qGI%?&�7nV8�0!6].� EG:�!, �8oH�BQ!. V�H��!(SA14-14-2 l4M�^nu�"JE!e&�-ix�xa���%eh*�!�.� &oin�!�#.�2_A���.6F� �<6�btN�I �M^F2,AWfo�-%�0P z_�87C8� 6�!:�!2� �.T�W �N"�H~y��;H"%�5P B%rOV k w!yi��Qd f6]cshhE=val�zea08ach-��� "9A�` ��-.)��>�*� 116Z�F�A3G�Y�"ch��Z�Nu�<�%'"�; H�%��"Z.A�m Ob�Na|>��<@a�.��εht2�o +'%�!��,nZ" rމ!�f a%�[6�:8;"F�<�1�)�S)g�Vf8�8�w���NJ8to avo�\r�0�52E��� �.fK aG��eF�"a�$*�rst��arww.�B;y��� sCJ�1�. P�A +"�N�Y6�08M b^T they ���^�B M"�2)�8$b���$ �PeȀ"PM.O *)iM!�" �yZ�)e�(�(��f*BD"e��N�,�<�=^ �g%����N5Fco�H��� India�^b��8]� Kore9�))g pig-"r)��co�`����ۍW �irhH � �E ut % �vpot�Tal�Hc:�J:�[2�30�CB@ �, )iLBwa�!�� &�E;!"�H��0 ��2I!!� epiz�Ki�)�qy�j�a� M!b�s�G����H�:� a.�F��"� 6�.Ҟ& � ^T�!��;�� ear BWA�lakvmf�k3�d�  abund�?poo�)]��F�facilP�6 %�"M-N:p �\¶�#�WA�!�f�"6�.M6)QA6��pGZu-�rtPs�l:ePa�\9t�V:. �Z� � ��%��)�. ZO%�>�Bp �)�t F�(b�GbIj2f��u:#�-h J$�a!'7}u/of2�"N���TNo�[AmeJH���mA�*�he 1E�!-Hq��5�� �5(*` }Sb��ta4Q,�{�inbna�k9 -bil�>guϸ[��EI�I7� �5or�ur&�%2�m�;5�Ya�B{NumerL�)���9�� rw��1;�_ /availa5�-�n�EBj 5�acW(6�.B+M�>�As�qIqA8� A�ula!�A�!�Rz!*$ 6H" w-"�5d5xes�H=c���� A�t�FAZ����kSrkS%�d]�J!�(�k �Iy��JQ�bK�&l���R� b2��%�s���.i8C� 2�%�� �r�%x&�J��y%�*� sixty-�W�X!3"Y"/A pigl�(�7�$E�c SD12� �f�@ �@�?jB-�v>cei�c�_%�~0 4C!-ia�"� V� �S3�n-&{�*���4 �!�%~*:T�a�q"�/1�� ��� .*):�d�2�l�x&x829 ��)&�F2�KO-91 b'>h�M6 ��.�B��f( Tiar�d~gsunaga b�gF�I�� ��rtio724A*48�&[TLB��1 �&� D\E�2� nY�gJ)>J�Y@e��1�b )lF&Յ.�.q*2��t�_SE��n-L [)�e�b�I.�" a�disse]�� i*S'��I����+GI1�F6_ $�2�.U)'E3�H�|S B��M!2t ��a�� cru-i�V�.&�:*Q!f.&� 1.��:% �!Œ�  k" .�VZ�;�T�^BhO;*�.��"��"V.p2*�)�ћ�,W��Acµ� �cA�b� ���&�]�!�lyxC /oi�u8nurB�k��@�o�a$"r�?�.&�I�R22���4B�?c,�s�!b� �ioɳs��e�9�<)":Jj5Bm.=PpN� PR�� !�2t:�* *F� re"� !�tf���1I!b>a �S6 ���� IK���a6��d� ��gL1el:s*"(5 Vsa���B U����ք1~A��K �b%�g4rejZn���`��`&�`!kaS���bA5I�1"s �`n . A�zm � lJ��t �t �t &t (B�Biofilm�#ȇy C2� al�ta�g$j!a� �#�%b,Oa�� �C�:E�teg��ne��� q^ cripE�.!�( Bcr(BrgEf Ndt8�2RobiTec�T�=uulX^se�,"\�og�Q�Bn9$&D to �e bBZa%agp&ic�!ac�"�b�&���ll�$� doub"��zyg4���j!(he57CH.u��Q�z[/':�2�*��O l�r21��x�s���jSp�urb� ���?ixC��:�j alt%,Ff ( haploin"�^cyG6��_f=���kC%%f� as Nn ��{m6AA��41�PA.r�a� �=.$d"r�‘��-worldπFy 9ee�9t"?.rob��J�seN�� �� ` TEC1�Br�(��)T�"�e* ��^l��?7�a2���!�u=ofTa g s TF!MW[n�*�"vof ROB1!9?��*EP�-m���a�co!��^%viosI�o�J� �&D��2�NDT80Umu�hyC.1sa��a��/�hyphae- �a}�Bi�%%a%�*'maVJ7J�: !w�=?%��d�^�lu�!e5�AviS^%*b&+!~ o�otopx +%��5�. V& fungE���q̍��F ga��!��T��!�)�&� W�)x�L���FucoY!�life-O\ate�=in'*�a��h[YA�Zfi�`& � ���ge7tC .�!|�&Bsu{z��n<��%#FQ��rw#2"xsF*Z�rurI`��AG'[.u��e&),famZ���rSg\�)�& =[;��wes�� �u,F7�� �).B!wr��jofU�to�Uppr!�;2�A]%<atwenty%Fs g.�M8.{ se "TeC�qD��D��!�A�e�19�0�M!`�)� Byge�.cst-"r)� -p drug�9�yE2s] M@On��"/�"A �8$widely uti�s%!Ih>+��J��pPwYA- . L!�-��8J)�pio� ��8� Sac��omy�ceWHsia  HMdR�do��A"�4W�I���ful���a���R�� �fm{,qxu���)oT@A��2�u�WC��.|�&�h�M-%� phen`M2&i�R!���|Mq�� -)�/ RV5�>kfe I��,� EDž�e�[7�" a di& d5B�Dpe'��meiosis-� � nga�#� [,fer�e�N- �a ough |, > KQ���2MH� � "`�2���l&S .2.reE���RBgI�aA�hT�� �.� 9q.�ato 2�yAi�b��f�J0 6�suLis �sAS mber��)l %r�'.��%�6��(CRISPR-Cas9� ���im��� �I��-$Con)��,���vr�en� ��a&l� �VoeYo. 9q�g�M=II"~�e38R,���d ledg�vA�n@ ���pB�� Fp� y>�� � adop�hgEIteg �h���liy^��n-�9m�%�!��!I%���� 5Q&K%A�E:[1��`HBIFUit�.�*r�as��JN ( CHU�J�m�N�j)Ŝ62J 2[��X�f� loci� ��� ܧ�kMt\�t|!O@�!�a���p2-�9��e �� `2(���)o-Ӂ,h�2� lA� �>��V � �|.�ˁ)�8�",!� ome-��y$by Haarer e�BJ�\!eexZ g�S��A7i 1 �����#YJ�4n.cIn 2�Y���poson���~+6�I��CH���h R�of Ace�9Mor�U( RAM�Wat� �0 , 6XYɵ�H O�!`�-��.�#PK)?i g��M�G�mza|� !�-/ja�ees�& W2�$� %� r(�9(�NW�Eg��2�2�" Gg:�S ur22SFd�RAS�ted�1- }�omo:E�>6�1�Nf��  M�ہT�_r�,.��a &;et�}�&(%�e�W-}� �fNz [�g1X$17&+T�& A��&�Sz .e�� �*�O �U6�trʎe�An*j:��^EZ�ŷreleva�!>�� �A�"� landmaJ�x�%��i2a E�of Nob�@�xwho� �ly �fe'�a�"�!:D�F )���P�HyB�[1u ��� ք��f"{^��:vs: :,D!(?.�Qt� '2a�*���[k :P��b�Nwo��m. ��dVHC p]B.��; ~? � 2�ofp1CB;ohu�S%H:�k2�%�each TFks��*�YA��t��E>:d5ҊZP �a>c�i&>��y�&���N. "U�*� ͔o:���A4�� <�0A %;Tl��� ��yet�p 0�!un2de�#�-be8�to addv quo>An ��I0�_vm1TFy;o;�wbMm2�e�2n�!�n��!�y�!���Vo�2���9�y�r���D !�����^ 2S �x2�be"�%*� � jt!j�F!q�gA�i}��^.;e*�� .< �2d we aG��at*�N� 'E�mM)I�&��A��k"�,6��yU�V�Ej!{gI-BB6*!�log�7# d�N%5�f�)��sim��ˡ�� F�A)I\esA��A�=N� �4�( )�Q��g � rchi�hurL6L!��.BJ usM�v{d9 Bt���ar�G�>�#�Bl ��27 ���m�!&a�d}Y�J J����/�A|&�.^s��g� ���4r��"� fragS�6��!xM66d���na v>g onŹ�*b�W conneE�fAqvԄs��"Q6  le��% ����noZi. SưM~s rapir�ů���i�`�r!� 5}C�UA��["��"MI�Ipro�s i-V-�4expense of gen��etic robustness . Finally , analysis of individual double heterozygous mutants has provided new insights in to how some of the TFs function together to regulate each other’s expression and to mediate compensatory response� Take}get],ysystema�.��Cthe biofilm TF network using simple and complex haploinsufficiency h.an addi�Dal level of resolu regard_0its structuref func%<. To investigate�gen%�intera)s within J�, we con ged a set� delek1� that+tained6�B-of)�TF�n" corr%��4to all possibl�mbina�Ew!�h.i{s ( tota%O15!�9d= 6 ! /2 ! ( 4 ! ) ) . The!aai!(ern9 $by amplify!�gH cassettes from homQ�#12co1-=�colle%� deposi!v`by Homann et al . [16] at�Fungal G)�$s Stock Ce!�!1@yield LEU2-marked� whilI$HIS1-deriv!�s �A;ra�I�a/4 plasmid templAg(and standarchniqueeUhe6�naE�of�1was!firmed�Lquantitative DNA PCRgAshowedAexpec� redu)@Din copy number rel Fto2parenAreferenc1�-�effecE� each�Ag onZvitrou3for� on a!2lloiWe�� �PTFGA��5�dA�meBI�genotypAPor �tI� are �;in S1 Taa!�X�liz!I��,density data�QB~A�is2]( Fig 1B]S1q#:)TF ����B]��1K�6"o�v1TFs>�S2 �. A1�of dif%�t assay�\0ve been appliA))�a�ssmen%�inb�8by C . albicans� thei]M advantage limE�on.�,recently exa)�!�revieA�0[19 , 20] . B)�s%���lexAglogical���� pno5m� can meas�l���'feena�Our goalEopto identify a highly reproduc�a W��UmaA� eralkof��y . Basedap�!�li�|e�report �Pour own pilot studies�~se�!�he opt%Q� �describA�y Fox�&a37>� sameA�Qee�%r{���is ��[21!�Ia�is v,6.�incub�/(in a microt��2te��!Five!� dium!�ge!Vt�� adh��t5Xwhicha the�g refuw wash! ,move suspend��ell!�|OD600!�!w��is �E/d [20A��AsY�9_%A�6BSy~methods�Q�2E��Y), Lohse=�un����V�ha�y��minimalA�ces��ejn!agent-bE�iss��[itAs:� also note� V�A dir�& �m�TF�a�isU a�YI�p�r�� �s or by%Y$metabolic � v���G=sutants�detaildelow ,anres���J2z mI��sev�de��s�V%&had� ilar.6confo��E�s� . On%�A0.) �i�E� at it doe)2�zadu� al inY@�� u�3څ�$1�� }�>�ma� aAT al5cce%�9r%�s betw�aaju)�a�extramatrix0 or�purposYf�(large scale� 2k � fel� >�):-&� good bala��s�IC�specificAS . We)���ur�3t&��v t 48 hr .�� *!�2 h^A�d��ab���EY* V|�js%�A�i)6) ny . Consista�eb ɕ UNob &s 8]�.b�,G six�K}TF&� �#� s� s��ly sign!�ant&� s�s�M1D( P < 0 . 05 , Stu���t test ,� 1A ) ͸5�a(e�reaU %I WTl YETSX )�� es�7ia�-a�K ose obser4 J|�a���� pider�u%A� 29TFu��E�ed unA!ie�con2� � �. FA�ou� -ixO (( BRG1 , EFROBA�TEC1 )1�hF�>E WTN? Fur� more-qf�.5J`!*A~ ��%lnAenz but d�  �-x BCR16}:�1no�ce!� ���F.WTa�"_NDT80fte��increa& >L�\ter�ng_�}Z� �� both �!� t( ,� � � orAK[18] ,��ly��ici�< �!�I�A��gf�B]2�s%8 ph"� }onB�*?� P/ � me-wid�� ofN9� H model yeast S . ceKsia!�dic^ ETonly ~3%Ox q >�t [22�CC elev� freque�J�t/-pro1F��isA� j.�1��  i �a0�� �g�se1 f � such)�ote�x �me4lik!�to)�>�cy [23�en�A~ fift��N�U�����y�R,E� � leF,.derJ J�.:�a2] oB�t|a:as}inJas.� �:"^�8��upairs; 4�j 3��i� 2�� a�2i��si� to ,: �+fi, an��N9y &� PE�e1 �i. �� *�JA tec1Δ/�MRt B�ūB;�graph�MremainA��lc.�!�"� �T�����O�of%��3J� volvj�h %D�X�o ae�Δr�los��tw�elaqt d�,nct loci lea�e��=�MealN�I�"}��s f�v sup��%EF.6x �o �y:0 se2��� `5is exqui�� k eA�!͡c dosage � most�-accep��A��riHa9- �,ed mechanismArN�9 a�sain z� 5~a:"��20*�[22� Springer" ��%ą�mW)��:�resul�aA0-fold6�!3���at ��>80ź(![!~aZ[24��In 2v, Uhl��&�f!�ng�Q�ex7 a� -� Jkscr�� ��Nfilamqon [25�AC� 2A , (i}"� �/,� ))ee ]�,displayed ~2JG�.H . Despiteap �N��<��.P� alE�exactlya� -hal�6���Y� &�wild typi�M!�%mR�is!� due^A�mpens�pr�I�maicA�s!�of ѡ appearg stea i�A�d��� e6�)�u�A�5"��w!6 ve u� CHI2cY fy �aEDt1 ����RA�r� ,�"RNA1�&Z ͩrob��� 3 �TA�.�A�sic*� !"%�promotOg!N6i�hpL/:���[26a Hown ,7v� tran!8p�Ial�A/oEla`�e � Ys didE reve? ic bias9 growth!G> �TY�E�* explake�%��ŁA�� iA�Aoe�ana"2��� E� ion;FWfo*is occuE��t�perZZ gene��� �edQ�.t�I uggestm1ay non-linea�onship"G$��-�*` �Ǚ-�! m�ra�IuL6+�J�.iL:�� �yNallu�"G!6t Uris#de6nyuto-regX A��coope��!��9\F�X�� �e*3TF�1�oif�-` [%�tB �2B�O� � �fWdin�s hEbt��9� tes;ɛ!/ . O�T�w�� n efg��Ez.V . M strik�_ZXt�st 1 . 5����re"g:E .ss:w ,O �"dI ^ �i�}>�might b�imr �1�outpu: I�IXA�cas�Y��(їb!( �erp Y�H2�could�4 �sc�oF�� �Aw2 I�ref� inse%Mstrong ,�0stituG TDH3���( p ) upstrea �E�uuRoF$&�;�5��*��6�bcrAW�&r 0 because Tec1��ya"�m�eI ]q[27�!�ta��E�6�#byB�i����%-�Q��u!ly!�induce o�Y3E��"�  �ɕ[27� 8�qO6?of5��^�Ts� (ej66�at94 NBD�Yara'o%�)�$�wl"J�t�N�.=)22C��S�  placT2m& o�oI�& 1#��mXbr��B��.�. a$Indeed�1.=�1Q�o%*&:p.`fto �v&� � 2I� n� jbJ� ��.�un� �y)*-%N���! ts&,#) ���ɯ>��s����>� abil-s%�-dn$n)�=HtoAt�w&]'=?>�t�2.�s � be��upon RobA�F�aH9, �%�no���Z?.mJ�2�Th!2oy&���somi he"�' ��-� �A��'.QD/')}1�Hwo+"7(�|� pathwayBMit"5 K��=�q��! �rolZ �>�cy:E�2�%.f�*l 1�T*giO� �I�N��Y"| an� �� eor �1B�m���d�� ��1(!dt� ,7TF.�"S �N��-]�)JQ >: if��&)� e�)s2B U�d:�tE�QE)heaLap% � ]1�",=��{ hw in$3 .BKi=UE>'p).� [q�2X%�J� �H&� ^D-*!6!��AD=�w�#Zed&j%�tRQk=2.��:"2A.  !� A�"\)Yby>�u#U(� ofq:�w, Efg) Ndt8�Although�.� ��.T!s5���, nei� |ly bin4!"- �i�l6� Bcr1 Brg1��䁒�ure�o�inB���3B"n(�(mbMS��� !c�}B3P �Eq,=�t%�2�%!��dN��yQ�I��m*�'M49�VsRI%iw�0 J�� J!6!]$��un�A!�Vev[� ;)�bS�d�%!��+ly^B���;,0P�x xNf��($&�s9�G.�ut�b2|!.)ory�PA�t with �,�S ��]�vF�!!�ECa�IgAqE�,��`� by� 5–�:0*e2�.�M�(6�F�.��A::sn%��eP�I� S 7!b!��#T&11�* be summar�,a �x 6�N�)�!c� �+fac7at�aZ!7�i����Ŗ� 6�or� >�.�,�+! �/!� C��%3B�0e�"~5� ibuwoE;�Nn lappaio� dund�Hsi�!*7 ���any�� �!"x' J�>r*�n ie�0feed-back looA�e$is crucial%}RH"!l>g�_-�s]/ �)DQ�!�!�B` of.S5ePE�2FI)2�����"�� ɺdra� W6L . R�.l%]ap�>�AV] as l��,"N� �acha�Fa �� . Lik �, �8N=�5e#&��.� 0n�����R�'at��,�"`.X 9pte�reBedBk��2$AllEA����,].��W>�multi�:!4�ak� iuu�: A�F�Y�unL)�(6�2w�{inclu�\t�'b ���r�_ �,>(k>h bkU �>� m;t� ~��or>0iN � XA�r kd+-Yz ( s� �iscusM\*!q Q<+ue_guish&�wo�."!� 5&n=1s�9 )�ua�y `e�al��d amou$a�V8,TF �?!particz,�&�%nt���� �� �"�*�.WTNl"�2=H��5�.�11� ��!�M�$�4� ��5#tp� ���!a��"I4�Ci,'$5e6�T&-�a��0(2 ) ;N�(:( n Δ/� - mild!�e48WTx8*$+��i/21ze6Fa��u�a�2M1�2&S2NR:;z6%5m�&8or9FP�#TA�rchite�/�"5:� �.0 ���";/36@;�kme�$&�&q(EsA���.qLcrepay!a�*lAx"�� FirX-itew:� A�1is�� frag=.!�%^"� Y%st�7� �!��de�VE1Se�, V2C鏅{� e a���9�~sS mask�>Am.Z9el�0.��1mas��a�6 �i81s�7��9biochem$ �2A4I%6j]'ɵ� %�as?=ay� = �%W��{.M!�6f. r.���[*-A�E�thick?%v closa�f� �tre���8�+=$A|WeB�est probA2 �i"� �Ry�e�F1���6 I�qu9$uY��}E�� LΔj= :�ΔQ�A�6�*�4!x1h10as{� 1A�m��>Q<%��F 2��(��@'"9$�� -int&9Aan�=#e�� ndo�-uS;[!�b#toA�� � 5��i <g�gen�V(�'+1�ɤ9�.�Cw��a9'!��6?B�U*t*?:&i %e 2�b� �� *H1� �-�s%��in6� ��0 y�vA al ,&  ne�ele_a�� � 6�gr�#�$ &� ��Pl��&�2�)4� B*6�*% �g�&8Car*�M9iQ�2�,a�w: -s !%y>�i�&*#�0Y �E�-%A� E�&����$&*�&F�+= ,C:�1�by >16�6�.�I 6��#6�hypA�sv���iaN�:v(�*-iw.�. T"s�i�wec�sR� TDH1!�!� SB� I;5'�'� aot�-�.$Y�`&K �u�eBm�1~Δe�YCelEA ��'n2� *% �1up zY��:a�)&� ^/�t�E�.R�Es&b9�U�%E�^-}jyH >Xa�e�:) !A9:�)�2Z>Ua"s���%a`,� hG�o"�.�(ze:�.�9E�:of5� �L 2� �s��.T -�S�aross-s�D�@)*� :<e�:� x�+P M-�E_he�%� m�=F��=sl R qcorP*�; �2 �&�j&Y �# ah5morph�C=oy�i�7iC+� arisN o:�i�6��� �F�f]gq�)�1�� Ň2!o���"�.b ��J���' We n./asZFi{hyper.R���6�z >!$&n<�$a� I0-a{ri��=chaa�er��I`�!?N�6�olony-�log� 6� on S2�:at 37°CT�F�-�%:�Fu6B!�a�2JMС#�+r*91�d �+�wrink -6�2t��U09�e�s�2A�gD�� .�22c�����!& I�. i� trigR2^Q2p!0o��=�<, a|�"�&�2# "��Share�Ve<turO6�-�a�e2+�#qB-}d�1g"�=����>&M,Fw uXd r�m v�$��?^A&�,�-9j�q`9.>- t" ChIP*%�>2��ho�"neV%�Fs"x���’& �,!N�@nj���,��cS�� ��E��?:u!z- .�"� �"%ala�n1"!0i�GrA��+no/,ŋed�6princXe�.ji�>~/�%��g a sh)�� � �DU�q "ҁ8m3s: �>*�./synerg�E; 2 )�y� ; 3 ) buffeh/��"� � �7.�=:2#��,aU��Ea��Q�afm%�"� "�2'9��O!�2Fba.��a6_Lepist"1H.2�"I varietE�2�L++l%m:1W)��!�=� p�Japproa"�Gw��a [29 , 31JIi��6(�neu�-o6O.=�� defuL��u�A i6s� �> eq�Q&�!tA���e�-��vR ^k&X�KsQ[29For�v,[wo8W���:�8Q0C��by1C5 (� ��� z=e%�)]2^>b;�!�j 9of rx =25a,�k+�xterpre N�*#��:E�sCmanifes"!�6�) #ner:�+,k O-���% ^-�D6e��8 e��� �M�mp�.�!�g�4�+I�ِ\8r.�l�?9];6��3` $��2!R�pD+ ( diqJsh��res1�)aq�#eA� on)\-S ,a~� EI&0C@" B#H:U;projecJFRnd-�B|B>�e-6M-.� s [3 LI2= Mani"H;co�a1�R�-*&�Ksq ����6e�TM�2w79!�Ra��frame�M���B 񡉽�* 8e�e] 6�P�&�Tф�+(KGMm /fMWT�"�wt'�`�dI!&[*��� xsig�>�=Xly�Hs H)�ta�m��EA!�� �*H;>�d e�>�d?e�Jan.`F� 7�<a p�O��? vers4JH!�%�M�) ��oZ) apid�-��QEf &-0?�i̩}r?al=�uI(scoreKH Ɛ )� ��!;*Q 2�A2"�R:'1q� �}.��6.�d5=��s �%�4�� 24 < Eachh'i�1�� F��* r2Y} va s�&` X*�3%��.S %s�em�TF I� it��'� � fash!�.� x>�i1�s"%E�ha �Z:Y�!$ a smg sub-� geneEA+33%7JI99 �=*fena�s:@ia45ZK VM�ove"�'���"�G"�O"=cr"6=�i4!A�� "8VBs4< xN1� .�; q�1��)�emselv2 ��7U9 6-%pZ�Nl r- �# lecu�&�!r��QS� "Q2|(�ro�C0i�BaW�aso6ղy�X 2D<B<inferM�-Spredom�Z��a �STa�Y2�xq3%�hip"ZPI. d �"�Zb.�-�%��57!' situ� w�w�T3�+u@ 1��1�e��1�Q+. C^�ae� HhA�,g $ '�$� �%L�$converg"� (��"��� comm�=�i�o� c�Oter�?vw� �A�%�J���ځR�.��o%)&few� Z�(A�0C�N �A�_DjZB!P$ hb��=/f�9 �-� ��m�P.WCj�a�F(&�/�to� a2W ayqu.eY]N�e"co�B�06�=:R�6�"pTF�8&�c!�wi)*c>��TTFm ��V�Nn��pr���a=w]d^'6�V�"K)p7C; R2�85Eg6y�Qh highA���As�6re"�>��d��^In��K1��I2;�4���NNY!���&st=�Z.:��.��:n=( 2 �>ls�OleB�!�Vst>���&PF@^->s �Tde�B�e#��@�IE�)O��l&�2�:� thro6.�2�� 1�� �-Cq�:��6�%�6� C��-��Q2��cG*� 6s. B�u9�C�+em�� i"�9canarr�Icm� \vO7��.'A�^� �&2�J1$*63�ade upAj���T8��n-o6C&�s0 Md ConsR!"_I:)Jx�a�_�to� HHLE@-1�����]�o�gdYm�Mr:9P�a�ad^H�#U�nTA�-K��2�2�\�FlN��X.� "�O�a!& E� M-F�me�_b_9�0 ���nJ�]� �JXis:!�%,2��� &�f�22'or>�a�|2zP*Zw*uZ1"�`"15=2z[�F�1-��M�m�@��mᆉ�seRq} �VrE!�FK*bR��UX�"E� ag�h  &V��%nDd�"�AN��er�*�k, [40] )� &�%�i!0s"�! capa6^to��eJu$i"��/�!somew/surpri![��2" \)%��me�g�L-" b�)to��u�5s v�`V&IG�a)bA��+lAbys=Z9.�.�i�r2�.A"�kJ�ajo8.IA t%Ds�T�8� .�.� f1"�! �T� d.��=�to�E-v ge&Y,�(iive�OinR *=_aML�[33�yH38 , A]A d,~to keep�mi�@ax]�is�g� �! � s&s-�ada�U. Saa)�-l] �4o*�&�#e&�m[-t\ �B� )K*�ly�m�/2�y �\� �6� m�"!�U�gH -conn�Gnod��nda�rt� length&�lin�M�2��[3eJSb[ �C?o%�5Gworld��4Watts-Strogatz7[3� 36];I. �y!/m��n�]c�E�*j*J�R�*�#b6Lst*�!@k�2� ቝ-�KP.�!Te]*�V�&u95)+!{en�o�'��ximx$!�a�*� �& fa%# orag4  [4�A�N"�RM]�3_op}�,�D9* �T��3��� X-�.�n�E����1fTF��&ex0Y (NDX`,�Q&��>l( 3- > 1@.,�9W.^.�G�1of "� >�W!&Q)gB~.�E�J�P��<;'�urb����1 O%2!eew���>��cPV"�%c"�P�P l=�A�偁}I�ly���< �[a�lA� J�B?}$*�DA9; �i�&� �=1p>>s�aj+%EiFVL #*� *�tQ��c�3 �m5!Um� :^$�%"lsbfDF�2��1��3$:Rf~5J�so� l| y� 1^6�% Sw.%-��b. U`es ~+��?* �Z�T�B�k5 �-22>qJ% "y O�C*u ��*-��p>�N� � aQ7�]� " ex��,>(Q�I"" sC[�EC�He��_�d�*onGE�n:�>n�s�\�k�4l�,d��+J�l�Z.�/5<y �->{��C L$��E�]n�45T�#us��g;(*Z�ALoCX �%,h�T“# ed”��[�4�ہ�Z&�.!x.h��Jq� ��.�11a*c ����mun��� yM�'�6Na�� �?t ��M�4�focU))�!!�F�a&5&aEis6�� sub"�a>�rD>�!M�be~!�2 [16 �oJ�:to!�2wheG�%�-[ prX#��exhibFw!TF>�1E�M+�:F�S�x�und John�1%c$!^_degt+0;�G��>U^� g�@ slopA*6�lan-fV�ra �n'��F random/ � �TF2�[4Y I� �S:[�&2��5qfir.\�,%%_exw top"n0y�, ��g .���H=��b6�&EC 'EFN���{E { =([32]N��)e��1145�ee-a��� exi�cNM{-M�1�,.�a�� coz ��� �o-�.'.E9<D[F�Fe�)F3. Sc()�.7 �� veAN>.E!r st� �? = l�5ln N )a�re N =�*p��-�App�,�%:ueN��>Nx��!,ave �)�!.~� 9�ver�o"Hh�M�J.FW8E�m�7-5E� ls�aa��!�\ )��esh:g�,e&�4V�.�tn�2�m ]�ơ�QNE&�mglobal��"ix%A�}$,��24 �c �iY�-R�rzr �subon�ߑso�.� �L(r�`� e1,��y [�ņ�:z ZA�>G%Jt*J����I�'ubY�up��Rd�+��-�>�mo�:Q� �#cogniz�D� Au work�NZHsRot��ovI;deafe2!"�s�$iy5&��% rU  C. m~�, �4d# %� P����? ; � )E��%1{��spa#���o2Kore�2&[34"eZ er*u%�Jfer�PtooK~sor�6vF�  4I�!c latt(`�1di^0. D. ����y2�%�isob"� w %�� )poe�%r�A��(�ps%� ��L�6< �}3c� >)�2� c!=! �.p�o�pten5�Q[,E�Vis�;��n/ch�ng {4 {4� V qN&�soc2�)%8 ��aZ�%��(f�t&X)E�Yw�"AOa$>/�;F�W,a3� �(ZxA B�a�M"A"&S(:�.D,�Zg:-Rm�&�\�a�%G!䑕���%I�D.� �S�F )/�+iaj�Y/Ya�^.q{��at ,q!“an�{ �j�Inm) word�-TjdV r# wW 6�Tmu-IllU -�p� �C!���*�Iom;-�6j2k �e��b �%sO�k,��%T\��&u�MK17." en Ft'[i[5" �k,�5rK ��“or��.qS6�Q19�wi^Qi�%�or !�…or-�r�9l*�$av�Anu��c00E�A)9euj��sy� M>�"i!}&agMNh2Hri�3Ke�. � �WTy+2�#vDo(`�P�!*�h-�1G"�ropo�riz"� :2�eV  =*�pu,>n�u9�-R�Z]�͟c1L!�inaE . All*�G=�.8^Ŝ���?�|Candida& �E�� �Q�M rom SN152Q<0auxotrophic mw����Aqo��~L flanAA��"log�rgm�100-500b]_t2}t�=�[484_mA�w plet%|1f�,!0�B�/sourc�m�=��XtT� :p`�H��@i�2%AN���z��5a&$"�dه�=p�0�#�ow SbfI4 �3 �&�!�"�$�3 ���& � oXim` �[��%���%���=ډ�<"�i�.]%8(.�A���\oA8)=di}m�+�BglIIMcuV%5�F*+leag1N���1ac�B��n:ycl=0i�%0pCR4TOPO ( In؈gen57�j ��L!6y1�!�.)�is�=�ci�iA��fBQI9�-����2y��27$I&z"ardX�hium-ace� oco��LEUPZ$E��Qe�pm�@A��.�i�&O {-�vu&�A� �I�� D0l!!�F�Ac.)k&.��2 . Qu*�hD#_ExU�����B�$ W"�2��Nz>�$pa��KUA�wS�&q1 ��:�us�sA�)r����d�x>3� dBE���'mena1)m�XNEU5L pDUP3 shuttle vec�1meJR [�Brief 79lA��A��N�O!ueD��by%� �1������O�����to �( ��!�UP��Il �by gap-�Tire�`��6�}�0dw"%- �yű�Ql.m)Mn<icI����s�Vj6l�-VC"G)RwE-�%"��,��S X=cc jQ�g+�!�6bme��H�(�aO-��m�6�-�d:O9N���) pCJN542 ( ka gift %D~V(Aaron MitchJ,�m'��N L�5’ UTRBI% ATG AWdow��e�o82~& rr��Q� A�2�!1." 2�Pun�n�) 30%I�sh�in%�$liquid cul �a�C��%�waӊ�Dti/in PBS�A=-s]ln� nJko�=8y�f5B�w&�I��4( 2 . 5% trypt�,5%Y 0�_ , 1%�r@ , 25mM diTDc potass΋phosphD, 4mM MgSO4 pH 7 .^B[[p. 2A�LAv�)s)����590�&u���Jin 96�3 , ti֊1TdV�<(Ilystyre�:�!pAf:U�-!�reO�dEAv �d�)�off)�!��{Zf S�o TA� �&/��,V�&Q9. Aw�L sup�7�\^ aspii��A�c �>T)�o�uE�B�� yN.K-5r�LPB|�t 600nM}�A1]�a�traMax�t��a����=3 rep��W��eU0y&�.�]ik��� nt1 !rep)�*�! ly 2 fiI)��Broced*�n`~dia*��zj�d��u�w%V!$f�X!2modՈ�NAvL� r�M�"�A��eZ��� u?)���w�z.�4muK�pne&!Yd� 6-w�{:3e��"�@�@)arv�YI�.mE-�o�yiC>�.I!>�twice)=A��)e{}vn�\)�BD�� c�n��n!$��1Qik�$ RNeasy Ki9 0s�e-�DNAse I �uCA-�r� �{� c�� e Biorad iS�> kfZ3"�' ime�_re���edHIQ SybrGt%g|:�uti�C�?Y�Z:�z qRT-���E9&j u%]�&h ; 95°C-3�, [ 15��54��46�0-1’] 40 cyc!n, lata��BA��5�ΔΔC�!� �2 !<fACT�K�*�}c�All�'��dhrI�tHeV3A`�r��.9@�ݗ� trip��ith SEM!�݌*{$�&;c֖8&�a�evaluEkPaQ-si���D ’s�Di3D���a.�\of !Q"•s\ze-8e�N4� �K)c��~���_i�@&Z� m,�,' �m� imagam[4 /4-2��Ee�% UG,anavalin A (�4T�v^onjug9 tetra� ylrhoda�< ( 555/580 nm; M]Aar Prob�Inc .�D3&Z%r40 � l z)b��� ��"�#�.ob �a;1- Uo>s��n� "��SP�#Leica M1�sr��eequippT20X�x0�erE�a�e\ a�im��GbIHleŇa�1�%�exnat 84!5�V"*% a 598/628���aan��co NDD3E ConAR7 serAxtg�� AMaN>WA9at���poYkoHNGlAmira RL�a1 softwa�aGu�to�R3D "*e硠124[I�.$�)y����oIe�y֙� 1�����s.@�v(gzE"�O"q*N( XZYE�"Y1 Ɛ =F0XY—NBDXNBDYD�" BDXY�!�>�4-�A DBY�rJA L�.�# N�"��"��1NBD%�e6��*re-�Eb0� � Q<��A%0/ �a��3s")kHl;fi" ���1�"�TIw?A� rang ��tF out��1"�r�ve erro"�( _z�.��-a���aveEn�E>�LƐ0�%�N*=>8Ɛ < 6-.�=./.- ��! -2�2��olus"ng2&Dis CI = 2nI/k ( k-��? nIA�of�3�T$ngk neighbo�.od� oi�� . Ci>�@�] triangles�Xeá�:!Wd�Q��� B"�9AifusryK!mAu*��5&:x!)7e- "4��vK2 &� Q&: E�Q/N�q%XΣ1/lij-`N1_ �9 �� -�2s�%e�at� O5��B`"PL-� s NiGNjN5s�AZ!�E@S� �"a e ( Asn )�a*�sm� cur�wrI4��Cz�XvS_�f'���A[synthet�� ( AS@sp�*�-A�!�~G�mf�a�"�o��n ATP&�Q&<.q a�Giagluta�� nm���)��U� w�mu85�"r+s�AS:�|=��a�ġ y�A�BO q�҈ ably�Qs� . Ab�� humaa�nd1K anosomati�AS-A A�worth@V-W!��po�Z drug� c�t�A_�[�5asa�� �Ag`in�&in\ shma!c$donovani ,�o}�o��mi# 2}�9%�%�%�Pm'��wLeainfantum �,�>#�lya�Try1 spp .E�L ..��$Abto!y_)1�!h2#U!�rA� More�)!�O7�*ucY$"y��d LiASH�llթby-ye�im�*m ^� �HAo��u�n.��?ulqa�i��Cl��A&�A�l"b��@�W :�dU�beCiB.1��gT��iE�(Y��S1H�(viv�gV3@O C�c)A�vo6�&x)wO ?seI�e{ suitEs.zn?2�� s . Y��A�"� orne�A�@�a� �!�b�!R di �g zoanmbe�l!dt� us.s�cli_2l��%n� !kegG�(ropr di �vC�selfhe�d�ane��:`X R���(#a-�Yun+, visc�7ailE�[z:\ �.%Qr,����,AXign�a�' Kl�g!r( VL )!ymaiaas�'�o.!���or.��. D&2za���h�� vaccic�,q�e�rel!� {on �nB apa�d- ropr& �=[r1! tra�" herapeuA�I����!\nt}Y�(co�ptox�8bFf x ad�XtJ ]"^S6"�)//�1��in�o�a�R]�(b ��cco��&W�=(Health Orga),rboIx�000e�3F peo�[(E)�*hildr� die/ y8N��eu-e��I[,=�:X0�A[�)*�ZW M & spotl�zc����Ds�[lazLo�2��o acid!)}p si�e� gluci�sm [5!tF4SG ii1Le�!�}Hh���aA[1مvM�f\-x� mammalian��q�!aw�� N19A]QQ�s [�$Nonethe�7,i�a~%!s}�sf�% D�-coE?a�&�{s � 1c~�sE;=maLD7� ll f�)9Iփny%T �%ooE�sm�*'�on L-�� �g!�~ r3lDNd!�sm!^su�� inva3 ,and/or virul�8[7–1>�)�:� �.key��r7s٧"  9c��y!E?"i�Ei�;#"� *( m�rz� n� �iE���"Mm"����ri�� ~ step�bA_�of β)|tylAMP�vk$β-carboxy�% M� �s v�by� �bnucle�' �attack anh um  �X[5� mirr���s evol���C�o ueacyl-tXe�%� enzy�{[1e���U%�!:2z� ��� AA5 B �. T� B��S-� EC . 6 . �!)H �'i0� &C * .^ �0�GF)rokary�qA�eu(J1�/aJ(Chlamydomon� inhardtiz �e� ) [1A�j���$ ,6�?A�� ��:�( Eschhiq=li ���4Klebsiella aer� ez^5�!�Vaeao� yroc|*s abyssG6)Id"�I�+�c�P7q. S"�H� kineto6"L�S��� !A6\ =w�s�l��� a pu� v� B���8a bacN_A*%V[2%p9�O"/ �.� bruce!�. cruz! 8$�" a�c %Wp" | "�0� Y�2=�. S& ���9�* [=�A%�inBc�>"asteur%�ACoc�+, �D0&�i�p�A d duYhU � o� in Myco zum smeg�SsUBU.�n����"j � ntibiotic��BU tuberculo� �B� .Mbe&E> � tr"[30 � R�~ly� �tp�((Dn #y-�bloodʓ���A knockT$hno��a+�.� V� , ex�?���� depr��!U�k�Aj.a�=E��#� �[!%aI��y uptake [A�B��U�%d� claiS A`eZ�s��ym�ZdA�aa�JOdRe ag '(u�e�AB=Ls!��' D1&�!Shomeos�h"�Du!�Y�am8�>�1�y� 2� F��� �!� �heNj�g��smA�"\ k OstD��ir life !Y�ref�Q %=environ�Ptimuli��Ece�� � = � e�O5A�%s>��<e.�2 ( AA�c�# rtoi�Ia���IficqrM� ֹW�lin�L, |�JtT"�O �F��� of cIin� a���6ami{ �3 thio5yH,.%�Nari� .�), faiL�oqmPtEz E�ens)3r&� pool�/enoJX��ma"��E�"h6>lr>� �ׁ��o6Cn�5�[3{ Ak���:Y�e&�~}s=�%��"7��(G-�o �Q �_in*Uon 2"�%�Iwy&V)���& ".Al"�� ���3 expe5&� carr�0i'� �&� IBML INEB A^�Eth�� Committeee�ArPortugu��N\ al Authb!� B4( DGAV ) guide�Y� �lI)��^W !<�`a�$2010/63/EUA�Eu7an Parli����6Counci�5|OM$;a �9'ő�I�@ manu-p�>license Xm�825268/2013-10-0d**Ga� � so�sal��nohydeD, L-g"a:3/ATP di.OM>,ypy�4�* deca7nin �= dNTP%�� um chlor��, magne+�b-� tris�W , urea�Uio DT;�tri3"X-1IPTG ((Qyl-β-D-!�4ogalactopyranoD)s purch��� Sigmd>Oligo� t�5&� "�" 3TAB VID�!Re� �$0Ba�90New Engl��Biolab PolyclonaӢtiboda�"\ E~&/abb�0ino�h�pur�0re�p$nt His-tag�< P. E0� Me��/:Pro���.�P( MHOM/MA/67/ITMAP-26rZUastign2 form�R� n�"26�-mom�6 RPMI 1640� um [3'ɾN��ui�,�"� � f��l��o2d)�a�splf�e5 BALB/c�aQNx&}��sub�U�]�$�uE� � Y 10 pN�ge�Axeaa5+2&� AA 5!� 1i;�-, 5% CO�<DO�� ),� E�o�� ��p12�a� _+d1 x 107C@e-�b`�ry2� �� T�! 8 ��)!�u�l/6%q�42 \e�15a�'3 2�13ajt~t �8:��ZU:��8�\/W+��3p!*ainhJo�R��� nd f%)!g6�U$ezing/thaw�   *l, "�.5?Q�\�<�*fi"� $Bio-Rad DCa�%�Aѽ(D+�$cm,q� , Lm Tb bT &���lig �&>wa"Cn"alW5graa�7A� , Ve�011208� ,�O���e�ng5�iE���g�� �� y3.Dueյ��(SWISS-MODELAb�- crys�  !P!� in D�*Ban0#$PDB ) 12ASz)aa&��(!�age2��mt�~5P60%a7:k �([39–^U�3D2�il!h��d-}PyMOL!,%v(5 &�)G�q S� m=� �HSchrö�erAL �A��e� zV� ű:� LinJ�,<0790; ch�sBC@; 234298–235360�qas9�O�ehlA U-o��oW6$.  V )�DNAzol :�:[4�0�C, (�1 + 2�-��a"j*�EEa��R de����3ma* t 94�� ]35 �b6/30 �O.ann1(5�- ) �Bj68 ja�a`al��en �*�+�O/ . An'��@��egye��d��u�'.�o a.^ o�,& ] 8–pSPαBLASTα��r*u!�aǙ�1�3 + 4��j�0f�15���/>�1Q7�/�nK�fiz�/�_lE�~��p%�q!%{(pGEM-T Easy-m (�� mega ti�K-maB��A � !��,"*��R]i^$NdeI/EcoRIE��sub.�pET28�+!> ( Nov32ah���pl& 9( poly-H'ag ( 6x� t�resid�))A�� N-te <! d�XZ 1="� BL21DE� �& ��)�! b�c�za+of log-p ,7s�`� 5 mM$n at 1e�O/N�XcE�W&w3!M! *$  �l VM NaCl ��bTri Hp865Z�3�so�!!Q,F&���:�{�sJduty �� 50p 1u<wIe/�-( B�3odW er 25��, fe�.�rif�0!M�)bW %�b- lfdc#���N���$&i�� E9A�E . � 1�} .� [)0" inL*�Imi2+!� 3�4)A�-a0lib�in9�iwcolum4�8i��Jly)J5���I'>X )%�ip�a��1eni�!� midaz2�"1 E�luA�f�-]*�  to 50Ey:WDi��Y��a��st9 .� A�!�1��*oO�1��;1Stoke9�":��!  deep��|=6�Z�rx�)�N�by ���y �atJ phy"/a�vrap HP1�( GE �cE��m=%�nickeD8l�;a�b%)�pos�o�(m̗��NAKTAPwr Plu�#>~�2It ��a�)�!)+i��j e�&.B�� Hi� T 26/60 Sephacryl S-200n .�4quiu%ru�3Mj ( 15EXF�,F�# �-�e�!�.eQ ��\exZF�i�$an UNO Q-1��@ , Ca�qNo 72� 000+m�,2�[ LX� DuoF�an � ) dev�9�-��oyp] �naI)� �v�AU+��AktaPe1 er10Q6N�)"S�8ose 12 10/300GLJ/-��S��e���2%>+��"� Millip���Y l fi�u 30KPm0G Ultr! .]5-R A<�5=&�k�OVabsorb� at 27-theore�� mo7ex;.!�coL0JS46910 M-s cm-1��� -=.maE-l�&�$anoDrop ND�0 >o7m�DN %Technp9C)Ai%՞V���DDS/PAGE%�2K8Coo��ie�Dl�% t Blue G-��E�]�(i�� Ve-VF /�+t ,A�^1Ve'�wF%mV0a��� 63�nA�Q! Vt5�3 1Mȍ�� I��9@\ in-wLFd�t�>pO&, 5 μcQm (D4 μM�zmix;P .(10x SYPRO O�6$( λexc 48!�; m 62  ndv;k�:'� liga,�# �!5Q�Ve�b. P�s)�l seal� �2lm�i�BiosiC>r5�5#ru� . M�Mz�H!n{+mi�D!�� �� =m 25°| 9{!T�i� !�fluores���>��A@ � iQ O� So�:�A�1�Ah��me���er�#er!�n-�4a� n-b���`Y�a�g*�p��:  )l � label�3A�rF�7 AK)w1� ����3 sA���XJO "�*�Vb��&I! ,�Zs�9A'�)JeZ5r��a�uR�dig�in��E��[μB�-e 6���]2k�&O!��+or075/m:)-�)`tYoi�&Yp% GmbraneA&BATurbo5�r < ��A+block"��Z Y3� deve�a $pRUK�$i "�X�-&;e���:5nE( C?Mol-41"1:1T/�mo�/α-tubulre DM1�Neo�JmG=�>-�(f CS (:z!�, 1:2�2RdHGPRT (lwxanth/ guanp�o��syl5�BS!k.W TbEn��1:5 zzlrse�sha�oxidase-*`Ago�" nti- O'�)IIg�Ak@ha�L!d�U1 hB RT�/!��a�E�=�U=ImageJ&�?( !�at��43uJacQe�semi-[a P[� ��Ba� mix6R ���8�2�8 . 4�&�![varJscKI2�&u-, a �Dd� �5n� �a��NmNa,tm�/6� 34�Ai"�I[4�#To&% %y`$*S !J�+�KarSCA�] ���%�B�Rrchee�by5 %o%d��� !A�F)) "$/�u8 .LT�H P7);L15��zr��"DK!�pHl?ofM0��9 . 0��F��M"��"wB�r13Mto��%N�� ��X ByK�5ssub��&erA��2]�%�a9r"��F��6�n*��90Y�,E�W.]#c�2� g�:e�25!�" 785�4�/ 10da�56!2eoAOw!�QAjy:)-gy9A�L.�!�:�+-.� e�R"�R�5i�Ka"��x2UR�!)1li�Xto neomy�Q���X��( NEO7 hygrn)HYG & �� a f���%achm8�P�oIQ�� C�:a�,0�2oA�:��,�:W%,pSP72αNEOα)pGL345/\ � ��5 + 6.7 + 8{�2�,P'AA�aro�3�F�2�$"8 % !7 �6�& un#ZA5A A��=x8 #Y .d_NEO_0!"~ _HYG"m,#"� �s%�46. Mid-lo? >5#MY3n Ex� 10R ���Ɇb�_�]V1��@MAXA N%b%$or II� oH:T-! =4 )�L( Lonz}��da��H���\<�[�i.�)�� Uof G41A+2�Y%y.%}[4InVivoG*9.)> clo��s�qby di�4D��m s�wo !N��"ޔ! s/�11MSDMY �$-�@:M���e��en�c�T�7d}V��9;:I#�XbaI/#�>i�%b�,�!�dKO"X Y,�BH A62^�4[�ux4��rBR^,^/]-�T*�nge ( Oy��'�,�.@BD!�9cA+:�3My�b� icidA 6x A��G*$�ԩ� Taq +me�3ZY�L��" ��: ^�09;����$Egl ��2��>,%�>/U֑��As 9 +�q, 1�[1#�1�[1v1��1��1��eĽ�Bx:�1a qUI8e�B�y�os�#28C#nco�#>�5 e-5tM�Vi2%]�4RPIB , ~570 bp.L |��>,-��1�20>�V SouX<0)�4~�.>AP��[�2'a* A�|���Lfolvc�of SacI%�e�,�?4)aF̈́runJnz+ge .n �2�&5T�� 25 M�� � OH|36*W d a�p��r�)�� Nylo�;"�A�f1�iSC���Ae�-cir e: 3�. A�� ��ic��Ffix� �achiei at 6���5 �T . Hybridi�+!xTl A!�-?:i����(s AlkPhos D�/ L"8JDeI��(��i6?=. Pre-h �s �, 6X�:ok�i�(�H+L�2�{� .ph���HB�0#0fa�H�k[uc� Hylo +2{Eq��� �)����� ) ��Q&� Qu� -',����8J��66�B�Cu�,mLlauncLY�monitoA�G?��i'lev�K24�A8 s���6� � by�}p�� E =p cumuA^v�=EGE��-or ��nsecuW &�-��.th16 39��-�3te�.( c�.ԛa7de�.d  + :h/)&� by -a��XA�%�1�U/L of>C*�G���-��;}`�� serum-(v� ( sf [4�< ~�:�a!`�Xd a� wa�jby flo-�� s a �Ml^�( A6�,��e�n�X%b� ^�J`�Y4��pt=a!�L- ( cf = 38��.J )�) 1 }"Q+�+]�>&�M].�VX M199�)/=� ��l�E!�B�.:A=�J.�WTipsee�& �/6"� s/ml�1�+�;�,Z-�sR s#H+"/ �Sa�2Nb,%�� ag�Yo*B坉UA6EA�a�� M�^>a�0,3y� �*�G&� � ��F�N�|ix wee��ld fem��+2m��"L� CharQRi �. �in{V2>)z>�0� �24���j�1�e)�ſ[re� !��>BS �Ov�$�$eL5eOc�H�>( n =@��sacb4ca�t 2-�$-i"0P�OU burdqq�s3�l%AK� L!��:R^�4�0m ��  �A�>[�-.�iMc!\g-6L {0gen2"�$THB�o�]by mM� !bmM EDT�C10.b� DJ�obI�0?3�8 peptub�2&:&k( Cal�: )L2VV(P:of� . l2�(��(!�%�Y))?�O��Fo9�ld%*r �pelletU�9. U" L��)K�!Ul�U permeabil�,(9 rel�3�A�l�#ͿA1in44TE�*8 ��*� a� �M;A� Hed 60Don aft�p�ifu(�:J>rp�'&)1 B�>�3� �bwnew�-I�u�[!yN]�5~E�-d1�z y.:�&� ijWB.(mfffi� ,:�sZ$f��\&�b9c��� 2� a"�( &�:-%e�!�6���-+#"��h(��-LiTDR&(�6l*�Tk��X�"�!�� �)sli#����m1h�RTA�a dark�Ai�b�=m��5%� �20J6B:&��Alexa FK! 488R56� don"J%)>-( &s4� � L�A�2�&3?e"Mit� cker&�"2��U@9 �7=mad�1U#�\� "=(%=�FB�V9x� prio��[>6&&�d. S=�U�nd�Vl%� Vectq�eld-DAPI�$�] Labo�u!�, D_.�E!cap\�5&�"ceEr# e Axio�r ZA� Carl ZeisH6,n,p*�^/cam MR v�I 0 ca5�2=g�C63xc2lan-ApoC�3x/� 40 Oil DI�2F!00N/J0bg= 5�xtKnd>>on�%����& �%6� !i . 47�p`:Klab plugx 2010)$/ C_TXGr L, EPF08Switzer�=))�Ri�-0dson-Lucy alg�@hm� � �b��e-BO ANOV����tq�2�bestI��A�R@>QN�7 Pad Prism&�$& �K�5:2�s"�Hce p ˂�0��*�Au*> B 01 ( ****� ) . The open reading frames ( ORFs ) encod@putative AS-A and B enzy1hwere identified in the geno�of L . infantum JPCM5 ( LinJ . 26 . 0790;$9 . 1590 )m>4major Friedlin>mjF>83> >4>,[42–44] . �ASA ampl �0sequence fromf�Hstrain matched 100%� annotated:= � �lo obtB$structural�Tfunctional insights on!OA5O@, we have perform)SDsilico analysis us!�!i! �!X%�) ,): ( Lm8T . brucei ( Tb2 cruzc !�E . colE1>s that�Terate polypeptides con!�353 ,1 48 ^4330 residues , pecAp(ly ( Fig 1AA�$ Overall ,��X alignment shows a high|serva!pA�!+m:�featurwinclue)a� site� �2�Indeed �Damino acids involv)�Asn binWareAictly�$ed across �i�whereaH� case�AMPKpocket |%�ity%5Gmco%@ed with a few exc!� ons . ForA�taa,q�rLII!�M=%ya�!esol5 replace%�, nam!�M,8L109 , correspo)to I111t bothu� This� is not2R pola�ter!���!0molecule , bu7 stea��tegA�A� e outer wAIof%cnucleoA�>b[15�<Aiung/8homology modelsFF+M,B )� @ed by superimposiE��-(crystalA%�4,e ( PDB 12AS �a�tA!a divergA�regionE�l�V9�das��rectanglTeR�in�"�<%� .IR.� hichsstB���se twoUšn%��$also existI�rypanos�@, although littleQ�i�is foundan compar%�@o Leishmania sp .1q0A , [28 , 29]�6(Recombinant1�A� mpri�CPa 6 histidine N-termi��tag��$as expressiԵ !/pur�Mby affina�4chromatography!#n�@cA�!�% ordera evalu�<RchaA� erize its)� atic��a!`$e protein �en!�ex�> ed MW formo�(r , ~42 kDa!xs9onE2��2B��4eiAo Coomassi��ai��8or Western-blot٘84an anti-HisTag body :�. Sub�ȡ,1�!tfur|5b (ially!os!!exclusA�!<exchange6��[$!$f%�f!h�B���Zi� !s:e:�i�2CEhUEN_lat�c:-}calibrIܡw dard��8Stokes’ radiu� ,~3 . 52 nm ,)�D ,MW ( ~78 . 8-�a� 2E )� extra�)Ai�U-M�s� .1q��sA�a��dimE4I*dicO.�5�]� ѭN 6�of��F�a�2fic_orime�b assayXquAIf!��M nA$u!�i�4��� $optimal pH.�J�? 7 . ~ 6 kine!�r�e7$undertaken!]�dy-)Q}�,� a fixed cent-�of !� 4 mM Mg2+� able 1EOL�~display)mmo��AHglutam��depen|  a��Wh2,Km �`e�Kr VF , noE�c��ign!��5differ* ��,( p = 0 . 03ŗ�qa�ś>ce!$A/F���in kcat L1A�$0 x 10−4%In�%discardLpossibil�~ utiliY�9a�ub� t)���rtefactiult�R � ������B ( ~120eu�h ly���R� )�"� ~84 9�ot�>d:�.�&cle� ���sampl� C. D-�� scan��flumSyE��e3i=X�hEօ�%crelev m�1�t 5O!�earapsta!�9�!�ez�iA;a�!�Xcrucial β-AspartylAMP-ei� medi!�, |tA��goeB� ph  attack�Q�,k!؁5a2�a��� 9�!��types:5� frag!�on digesE@E� SacI%; NdeI�re&� � 3A!mkhybridis�"%�e%IN%�A��probe:!WTo ib!�(of ~1696 bp* �w^i�w`!4=�� twici�ans�obk !Aq���es�� �cop �ab� �;A#;�e3�h.����alQ<� InF�e��"a� 2973�6�& uoe,��o]�RV052VBHa k5,M� ��`I#impp# Aobe��}addHal tiet� �^ each on5!4!��kfaint of�oG t� ripp����� 2xIdI,%!��a�lq1�wVa�i�ɗ26,�zaA�� redu%A.Ij� �E7*` KO1�-Y0� ��a��otDSP72αBLASTα vect&w �V5 over or � ( Owas welU� zRabbit�yvt� produc!�gains� B!recogni!9a m!�!to*WTHmastigo�R�ctm�he��ar we" ( ~3+C[web ./$asy . org/ ��m] , S1AfA� ���l (e�A�1 Prio�immunolo���stu%"��!!�E3valid��( S1B |byE4 n IF;A� he labell#��inF/versusM�2:AlO�A��i�i�l�zbetwee|I� leve�luoresc0nt�"��o� {OE�C �. An��pec��Ldet %7 �a�-A6�);�Sc� α−tubuP~5� as loa��rol�w|��EV �3 �i��1t d!op�Utag�"pU�P( logarithmic , early� �(ary���.phT )axenic a}�4�o*�t"N cea�re��. IE�2���iC ow%aŬ6� �co-M�]$ith LiTDR1� iol-&2 ����� Z cytosolice�.TtI< metabolism [49]�Bx$pper panel� �subcellu� �%c!�6�w;��sᵩ� digitonin�c%�� h atprofilm�d�:m�A��cein"��"� 2�i�tAJ��b� ti-TbEnol!Ln mc79%�t|L*� 6��%y1�� [50�aJ�L-LdHGPRT ( hypoxanth� guanYoribosyl� r�, 2�l glyc alm1u�M�)���J� TnaS %U9�co*�s�low12] μg/mP�retai< Wpelle� ^25–503�X1, �Q�M^�o���� is�� k �$in appreci  amou+A.oerj�nd^�longe-� � ( u �00��ALd� duat� ofz)B�mf�e��e simiauW Q�,�por}a}�!=eY=� . Intrigu� E�dPa�reF��o 6�Fl�oѭ�'A�plasm%�,mitochondria!z.!sm [29A�Due�B!�yG( ~99% )e�a�w(v� g��wheN 1/�g�l�M02�v�i% .�di> bu%Io��4mtracker� e^ ev�!cF "1&)[X-��slow2s More0 �y�� tool��� Nprc�T( T8LP , CELLO , MITOPROT%�Predotar� .�6S(seems unlik�aactI�Z wsYic6FA}�Ji,&p -�1��A)Aksola**�&�qgrowth p6n�k�JtoF� in cRPMI-5��However�� deplzKu�achie�u�L-azagi�y�] ( _+>#� �behaviaqu#!ٴ��somE8. . Pa�AJ �-@9a2�aper1&du%log w�MmBWT��J!�&�  � wB�.l -�de�1o���tl� I�se6�  an epi%( :t ) carry�! � B u��I%I io �}a an upregu� ��� 2b*� �wse5�inE5 limi���ia�!-��5�}tN���a � �sam6 nK�b^� �J.�A+��TKO*B(5�e�!�, enab� 0-=Kver�th.�1W� DFS3 ���T>A�fa!��EJ B�hadQ�bas�, . than 4�%[Bv5b)&9 �cum%�ve� !�~t m� plicBi �#FaJ2�$ �-$requi� .�a`$�siZ�mC"% y�M?r�t���A�]OAd�E��`"x ( S2%%�o ensurui�= phen|a�!���a��aJ�ed�!�d���on�Ea m�E�is7� 1� rQ"l�e"��SY$&��Z��ڭ� fail�Mr��c#�$jM�delay/a[%t= ""facBat>o�nZ%� v�,or neutraliz�!Hq')tly mayc ��tp% expl��reZ . C�&i)B�Hano �gy�E�ta� �curveT a serum f-" ( sf%2[46�#incub�%�>d! �re�d afterw�!�a 3 Amico��lum� Inidevoid!�!��b-E� �I�g%�tS.�*@b{+M@��� i>Dre( e�q �&�Ma.�m��Z lack!NAsn–I te M199!6) —N� y= auxotrof'� �ab MX��,6� �� �m��ar�-�P�{"� B�i�aϭ��(6{��lG %�QA� ctop%p�+�gC�B�5H�#:qa� ��&2 aa38�M~ik^ �I)��O-�-&" b��22!%� �I�I�!�n�@,2e�e� /s?ia�#�( . donovani)1Yjs�] refo)in�"tye!=� ::&��be�� c&�" ose � mptō!`N- Es!l",!� deleM  r�%rs��U�ic�X�,s%pensE�W A�� 1�R. NotAG �e��d��o*�imp%�,Ay>�in vivo#,� !N. F~ tV\x old female BALB/c mice)�in6a`nd sac0+� t 2 weeksbt- -�8�� burdk'�splxIe6�]li�� B )e{��'�&ly*�AZ�Ѫ*G)&mW*1a\��� ario]� !���� x A2V . NovceE<xA��)�����(1 �1�)e93( Cul�0 )!�0� ed�;5>S�.r58L )1>� Thu� ��Sd~%!X��romisem�E%��Aex�an acu�&n2T on . DespHbe�eukary�, &/.at_1,���jof�7-al origi� ��{/� � ��&f:(=4[+}�ex�6q�humJ �:)�� saoximat-%D"�3�>6� soura[1[41�625 , 5a:5��*biochemD/]8�o far;%6Q>�2��S, b#e; tic�l�te^ %ށ�on�r ��an%(enc�;a����,Ŧ/(�� EdO�'"��8rganism'� "K6[�;c#159?"[[>�;^m br�:[Tb92�1-4060]i?�: ruzi [Tc0~0,104705351000B040[6�;se�%!�!!ae Pfam AS�$( pfam0073+Ydhydrox;ng /� !t766 :�+^%p&I!l .�,acA)Aya8z -5 vealn<v�: h6��&_'� �5˭ys� a broad r5of.` .*:w<no&�%��1u"�<at�. MuchL�%��D is��H.�2��>�,>�x till8 AY� �h�+9�K �d.��.��b9"�(��]!�%>bO \a/l�;2 :NB�9�F2�a�<5-d] i2 �90som�"��v"~;/��Y� visi����$� al electrt+e�* mapsOr'�� is�8ed�� %-��sR�9:� L&�9�9�A�r=<o@'�."?or.!? A|Iun 3�Aa keyɂ} %�*$e'!*propo!��# po�)& d�0���-U�Ghos�*P E�_.� be "�E�a�"�survi�+�[ trasTſ�ۍ�blood /A�Mc �l�r�}v� i}20��n tro5%��� !�!f� �,�*�ly ced%ihomeosta&�>9�] !�;effort�3"�'2Oz &�0Ńd�ngA�;Aa6t5g2 a!2bdi� tutany1%+�)$ . Ou? v.Q{3*� Ix�a�A&��.�!��]nta�*�&�w�u ��5aT%�ns suga/ �ev7fA�B!*��,A@2�ite��C�4 ,a5 �2=����Ad�VA"�-�#�+" ��Gm*�i!>�2�,�A�s��e�suffi��A5^ neede\�>.v ^�L �a�jc advan�)! #�rX�enviro�BB� �S2E���Wh1�"a�j7���� i��ee��:� ���B!�D�B64 )���qer�u�=" i�Qe�*cA-�bA-A��s� �)� �o%�avail� �it��eq�#s"HA_see�6t�e!�ieZ v1��/� ) !�Fɢu!>.A,N�mY�.ID� noteworth�)�@"�-s�$� "9))al",�/E���Az�����b�"�am�o�2��4�%� stud�.�-��=o,ght b��A���6cies����af���q��:E, mF unravel� G]�*'( AATs&mos��pathwaym v"UEEs�na@r $!oiryE=upe[3HV"E��GI�lea�~lifDW�A=� +���%%��, )�+�m�"VIAY� .A &� ��*�>AfM4�er� s' �=*An&�Fa��%TbAATPW [5�mammali�"elE� a t crip���3�'!426�LGCN2/elF2α/ATF4 axi ��Sp a�.�ta�[5l�"[,y�� lF2.�:rD6�ofm/l %��/!�/ll��n�� 8-��@%i s%�Sac�omy�X cere� a� ��6E�M�b�*H ,� corD>n �8,A�!TY �k�'J@ )���as3Tr&�1�=5(, HRI , PKRe(PEK/PERK [6y-]��3� "� (.�[6�63]���icK�"���69�ER �  7ɑir -#a�*�<de� �^ .�[62�A� e mo�!:��: " < }+�.>Eh:�wo9�� a *�:�@ai3cascad!�,as bZIP type �q-�#e�;�&ct� A84A e$,�K� x�o"p[6���r �9!A�,!�"z !k5�E�+)� �,�+t� o5 AKJ mak$�repBp"}%in�-i!A��A,��ca/in��kno out ae���"J3�n virul^4M2�L�2&0 . [6DN� thelA|,�s�*knowledg!��lU  docuAMed ex&;e�c�=ezOC� visc�1Vof�%���DPa"� � n�!�o� ͋%��  4dk:�� � T/q1L#-Ec!�!dt%in�� �s[66aN None9)�>ly� must"lT�+A&� A@Ůlai4'Lly� �#�* secu�'J �'a|�*mo#N+ sW?�3;8. SR !�rn&: Oz"Une"���r.hO, � , E �!�5F͊* �"s!� :_ i恅- unE�!Ksup"�� HOF!6� reinfor�<l�� �� os����n� a0%Pez-awof*� � ��@:�]�_ "Wly^�F� u�# s [6L6c)'-� A��Fn�;m^�B� ��Q^ 2� E�i=%�0e�5a"�0%�, �*or!��,"g � e�Y A !�in�h c{�!ua�3+!�A!_�a�&�Lc!&Z%�>x%On6;� .�.6"a [ �&Jl�1eyea&�A����lymphobl�4c leukemia [69�re D�� :j! A�qt�)�B&�Ncau�b~8up A Streptococ:BA�� �6(ba� [13��*1f!� 64[ ogenA�b�&|�" �\an obli�3:�micro�Avem�si�-a�D!<nhibie�A28b:,�8iss" a����87u�� tr"�3�P�A%A/de novo2�T�Jb og�aw�ySNis��a suite.I cand�dom� ects�Sbeta-rfIr�5�t.�W|Pof� gene; . Da)��"*A204 pub�1�T. E��n��-��>s]@��carri� #U 13��3eu$ldwid�A eAnu%8,of 4740 subj% Monside;(( 2159 peop�<�*epm5aB 2581.�!�� � p)�OR%Q�(69 ( 95% CI��;0�&!�N�e�Ti� a sp6Tse�@)~A%�-�' ��"�m��U�,VWB �,atorykdiagnos��Mxou�;pop��-–add5�!1>| �96�(��� N!cov���!# outc�qup��d! -�prm/s!]q�2 e�/�YE�)![6L�j9�6��5�. New. ey� 4=L!`!35!�42%}r�a�1E��2!5 urbk [o-�)�ne�*�'usinhab�!<sE1n ��&�H� i��-Z�C�K�,200 , 000 eg�T@ay p"l%Q them+p.�th}&feR[�H6 s� � e�bt-ra��a�GE8orain��of )�'� od)soi�m�s�+ ! o juvenil| rvaa�at []c>4A�migO+��� 2�cirj%��f(!$�6� E$� i ic�l;3ti� _a� [� 5�m� �E���.via!al�!$r*n lunm} left��r�LEpC^@!sse)OU�� W.�)o�c(,~ c ne�7!9 rC- A � ral) f [�M%l!6 �>�SePE�+I!2.Zr.olo5 in-e��sosinoTa�iT5dm6AhyteSLnN��bo�E[6SA{isA��a�a�=�ma � X�mi �Ba�.�^�!����E�e(%���U2�}.I�is �ble�P� , go!jE a per!�ag��X6�8 1% [�If�8`P��r�acc�b}�embryon�e�s�� a�, veg�GIRfruit [7�'rawa�m7cooA meate��e��t�HA*^ cowA!sheeps/chick�) [�)�CA6 r�5+n1>$��A��6�� R��;�hai��~%Jbe`"� risk"� 23�!--P!��an�Z�WEV s [1��1�H�lin� �t/;O�a�\in��e�E"�A!|��&%eDk�%�!G� ��� �k��)� ���reaiI� >�.�Qq a� eu�!�.z exposT#,�.to!fT5ݕ_%0)cr�*i�dl!�- ���Eg3-" ��P%�d+ d: S���} � ", o�Lm� ar�%i)#Ex!EyM#/ . SJ,�q%)� .� seiz�qor< N  �l>)e/syndr�n�#=Aai2�B�.�8&RV!o͟zU� . DiaHpan�qp^'umn!�a�e!#Q5cQ�q:N>65�� ��w&e�.#IO$��on}��� d hoc �)a+y �iLecFG)�dexM�y*� (T , ag�DupA�g 3� G�zc8% V5)�sy�3in�I"w�/du {FQz\&� . ]72k�Wcal<!��%f5�-ogiv� a�hdeJs_?�)ve��d���?c_C[GFp&c. ioriK  C�o-�U���� p CB2('.�=A�}:c� o'�8 �brA{J2�  minimum�ofFd��o���9,6G(&�'-D.�a�v� in PW&�^f3e�=�'���)��I�3��%5% alpha!�d<. P!�Fh�CEpi-Inf:�m oftwG�4�* 20] -Qst� �.] ��>u U�&= �Z![2"�$Cochran Q �%�I�Gre�( x��^M��Ag!�x:o2m!�6|21 u�: i )Y5 appl��!��#�>��x�� � B�r(�)�h��0��|dG y �� 21[23–2�1��e1WB� a��;a6ebe��Ŷ �) -lin*1osorbF7q( ELISIPB. i �pe&N� of����y� 6�<18�$)�+–31��,�t�5un�]!i>+t.�1�\i�j )�Aj%e.o�z�T�in A=�p&O!�Es!��E�*32�.wD�A!oJ1�!N a��N51r.aR� �ubi�%pa�w��sn ital O�[3Q&�#C�,S4 *�un�`pA��� Egger’sI��i A��Dc�symms76>G"3u7a&�� ���6�'X tra64%:,%��12"�"���L!AAN&�"S��y�*�b��Q?EiFor�>�� e p ��'ltau���| ���� R�T!�.&�Y��cg.t��Stata v1%Dc CorpoM� , CollegeAv, TX , U� �PRISM~@PT !R�a� Item�J� �E{e�7�� I7A.fK a���guA&K#&��8(��<27 ab a�k �6< [36!�W%" &wzw��N�HU� ��wISclu*�7 =�� [38].� W� aŽ%[�.B15�%�ia� ���<�,��(ZdwA2ou�.u�� �.�����Swe��A��e r!^va �ao&�6UA�Brief.411�� %�:���57�`+�/hom6�*%! ew� A2�:3�3T1fa3]N[�e�i9iξ�+, 2873.-"�+�2��v1�!j*�( 18677)��_���)�1R$-�Uan 4qag>nyD X� �!=,� ,,� )f� o( 85091�- 9��a �)�%da�2-:!uA�HNorth America [USA]� 1 abins"Bolivia&3&a�in Eu�N [I/R4L3�J�;:_S3Ind I9 [!�, Tur�F [39]u3E!8f �(Burundi [24zEgypt�� Tanz#�[2S���� ed 5 K*�(: Ghan Kenyt )�Y, Uganda�4�koFA�!�um&�in*)[2� d e�z���)n1)se�)[%Ce2{ �N%W���� larg�vjo�"aױ�E^� 24y�� .^�)H=�@�  -M�6�h$ �} A��^2#&y I erl:E\qe^ d 1–17� [�cI=A5�pat��s 64 2orw[� n9!��|�`:�2�!� �.Cwh� a���rchildr�8g�0J�A�!6�G� � �r@͊a���(" T U 2�2�]� A9"de"b"�6�he �Z� (al League A|4st�l<4( ILA� i�"93 [40� O�{ adop� h@ugi!�by Edw�`e�M�n�+ 8 [4e��dA@@r�*veR�!P.�|�Zw�l�� lick�#|�;]tZ)Al ( [42])7�1ArpAO�O>!�Uof po��hisy+�n~s�y&�a�WinklersAW^"Z/sy�"�F�W�. H40O'i�~( WHO )�4s ces Re�Pro�8lM5al [4�Cry�/ic9�� i"dt �,I"Z; %��i� � ar�C* �t�@�8!v�!}�T.0Rfc Jm��!\ &FB,aia 81 [��(le�]�%�us��n adju�-:~�o/����.�$i 7 [4 A�x�VR %o�� ( EE�~recM!�2�fZ4��0E�" u^VL AW urac�_5�:�ԇ��w�a&)x�#f-ns�A "&s.�@vjlK;log R�}A)�<�)�O six�8|anamn�!�5 letet].�MI��All� �~e a�1i�T�Y��clu v ���$�L�� W[W�C.QrU� � !geˎl.W� B�q�B�j�"�d� geIt%>2t�7 I��%uW�&Fw5�iendB"5��Sby cho/ga'�&�$households���I�ovK�]B�JZ koutU�[A�oNB-�P�`!Z�q�!�1�9]9(�.;/ �e�v�.�b,�* test�? 5EvolunteVJo�Gve%p J �!a7g4k�>mu� EC� B ��s4!� u�a9'� �� Y5]�h!'Y�"�fZ �Sa�1A�%m��!R- *�m�q��ag3w.-(O�g�. Socio�P�)icB.K � �~�T*�.M&c��aIeiJ+� m��� 4 9� � a qu� onna�<ad3s�X�� ��"�� ? tech/_uoH ��hv\5I! 67YbwD/7:*&2 Berar-E� ( Ab � merc�?i%e| k�5[6�,"Ny1.E�\C �+&�by WB!fi���aIw�LabLo�!��!t!" ��To%o!s-5n tatu| % s.G +.[ Q��g�� �*m����:}n�)�m �y�m' �Ei&uJS�cr�ORB-�, 58A%� 85 . B��l�7!F�eaZ��Aw��)�)�rRYmE�95�we ��< )�mEsh:=�&)� }[e �WB�7�oF^ea7:�?? . 59 IAi��!�~�'w2��5�}�t1;"��a�*� �PweaJ�V9&U@0�_�87"g4PhI6�A a�e��5f2�F2 -���%�2].�3a.a 68 (.�17� . 40�4, �6�A�-�>���h� ��BaedTo��est(p>�,%�.��ho&o�sa �5�f�'*�I'yG45F��KRef} ��A!p�:fvA] od (��� �132} ��inv!j,8�B,{qu4f��"�&6H15s71�S*,']VF6,893A�,�%��P%a�Na�&�:I�#�81�,N/P��R&� s4y>-G1w T�A&�"h�:�>0�`.�*_A��C.Cb�06 jtZO1mj.�|O ���ea4 0K�K.(�5|"�  a�d7 n��-pap .�#�te�wbg�YtFdpp/ �M�p.��}����. kBQp itly6�>I� UA!G%ai+�ɜaE�-Q�r*. C�4r�E䡫&��7N�e 6� ��,�Xa#-҅ ��J  �1�k5!�9 �^�"�).oi��-cg�ii�J�~�f Z�s7J�M����}E(�h5b�( i�`>���*G&�*-�t ?&_�v�].�_s �)bNW�#B���u+se �U���� �e��9 �( �}t:�<��E�JW�BG�f!e�Kprg "�4��)�, � G�� �&XF babl]$e�v)�j:� rm͕�.8!gF�. CB�$e%P�� U_�mJ!Gg�i!a"!Konico-`|ics~"�e�=Tc;�4c!=�qBp�"�v%�Be�_�B�y��fF�a֡�(X�5-�PBpbe under^en�g���er!���!�� k!�� ow�� middle-in�5y.�~&!�{ _co���(A2�.�Rr&vL�U �Wil! fwK��iN#y''Bq>t-|V.h ��M!�]�:b,"3&"� 5=*$as"#0| #Ata|` :�(&�OR�069;��I"��� ic��i��9"3L�shA�"F haN? i�!��i�W�%!7 y� �5�M���%�� �*��]&�s�*i�) v�dg3Ma-�5z�[�.q�&H:��"UA��Lnd�bL���f- i.iVPf/"� x '!y^!�F"^ w�aV ҅N.a�I�u�>k �!�� Nra�}A�&�92�&�%.X6f�.k�iE�"*�i�OR iYi]b��[ eP� o*NH�N,.�P} c�6�)!*NpO�Gu\sM[4�`Mo"Ґ�Z�S�v��93[TIE:�r �m�a�%II erro�mAg�j1s�Je& tc6����u a� �iT�3�4^�2��O@. Gw n�VIeB�a�1u`*�f>>])�seo�i\B.�i 6�~ +9��=��!�!�er6�:�[7]��x �,hYUa. �)�oB �2EdAI�!R(U6 playiZ-5 � �s�0��h���K o!3+h�� E"26i�� �Jed� * Adul#FN�2 fact����mia�2pre&u A�1c�Hn� ��@�J=" �%>�&| �lo}Y��X"N(�� tef i�A.�o&gYe��,�2�)"�>�)���!�"g��t-��1�B�v Zibaei"J+( �-�'a^0.�A�*. a I�ed$ l�6�68"Q( 85 4% )�F2A *� Gs)ed  [A�?S"\ʹ.^1�5~v�) &{m"�R�,� �$S%|4�y��v%y"�*r< helpy!�b:BN>�M�Pt�.�p*�Hc�b��L������YR��DiA�6�Ar�%!�?% , WB�a')1 0%[�2N%�( );-��<�A�;v2T:*a0#+,��� tes.�>�!�+2Q��n�?"�/s�n}-excr / �f ( TE�S���2�R!(�e'2 ge��K )� *�'l&�8B�~� )oR��YIg%�"��u ES!i���Na �s�iof 78%�aG2of 92%o.CVLMa\�w�T-re�+&w��Ic"kT�( a9�nAs�e$s lumbrico��, S�_l F+z�'��,�f�:� "W^�+s�I'��of*��U*-$!�we& n�*WW"�A overQ�� �>�7�C�f')�L^*8]�&(L�a rect� –IgG– ?,&�7,�B�*?TE6e� < n��$�achA[T� =�*��cR��|�� &C#��E�o�8�emplojw><%��e�<юf O��$l�l��D�]?��"�wqr"+ � !uon� %�:�4jr��"�F�J3� +U1E�S;oya�*�.��� � X ���p mzL��A�Z�Ha �(n��|&u��AdsIZp4�Xl�Da�g������Ia.��.��B3*:�_%V �Fs1450���^> � �gR�e�7~*f �i� chF|sn"�*x to 4�'0%r &o �;.�**",�#�-A� 6{��� �: 6�� )?!���"h �"ul*8q� o�ڠ��_< _<Uu~E�� �Koss-s����"�{s��R�awu�iPO(�-��*�)��2�D(�V! oes%�S:1Aa kWrs�[uG2�rdR�R���ac�9C !fO�� �>�ն2�.�O itse�[NQg falrxӉ� e�% &&2w��>�e�s� �jC�i�" a*�2� �al�rdI�9r�q�j��V)(��lN3�xE�ab���r� �p8>)�P9�� rif�te�s��2oXO� m� ��6mlA�R�A�b�>� `_�Zt:} 5c,"�G,r%!�`(a�y[az$[t6+ e����`�.��{pro� ]FX� bl����6ll=['Y 0\c > "�!���< �Bu�nZT6#�z�tu\"on"�_*�� �plede Wagne7d�jto�)20�(eGJ!�E� ship f��[��uby7cs�!�� J��%�I 5�� !�5e�@F!p��@\� .3) [��4#)]�3i* .0a�Y^�G,[b$X�Fe[� x.RF)^��Hn>�_[_�!`�c.Jet�9"�2O_)��R�y/�U�A?Y:\!Oa dk )k�kic)!L5mT�tic.�k�]6,�"]��Ks\A|=�-g�i&�9 geni���r:a� l���atB�vmb�uv�= ranulamot�� a�n{U "Id2"�5-ncrR�U� +$leave fibrF� s a[IresoluEX%�hr�":wle^mDyb�$�W~ !HbyQ�G������ m7c���AVub-�bɯ';ma�.�naamima�a ( MR�S��B�b�����z%�eVbh!!��0!�E�� g>�n&�b' ��_Y�7�� �Jea&�@�� F&ed!�_l%�of"�i� cyii!�agd� dama�8RS%�6�%~*o% e!2�to|�7j�9oA�)�e��<�%�cy�Q�a$ [52].b5j�UE[K""S.dAf%wa�= Thir!��e$ |! �rf auto�j�v�!+el� }g. �)t� �F[v�5Cl@xPm>Ree � &��m��)��&�9�39 excit��-�h��MX�v[5Z 5�*2�IC�, s�d �Sp"� !6�� ;E~[��&�! 9��5 �e g]_69E/"{$�eh&�c?l&� &�i:� pM�-�M#st)k����k�-�{)�F���֑*O�n�)G�Y J��]a�R�]\.� Kv&9z-�� v;� s*� E�gP? &6E1of����w�u�OyO"|JM� 5:�IL?��qg%�&&g"�?��&+ . La����ap�+ b 1 �%*��� �I�A�)E6�&�[%re��z� �*g5s���m]te��ca�.��few!�z&�" N&y\&)\ 9V �%�2� �TB�u�> 9���%L.� !� b"�sg�>�F�C�g�> dU��beG<&u�+���Q�>� ��&�4,*�!��#:&�%T&�&�1�4.�H th ,r��5�o*����0 `� д) l&�Nm� edFifg"]a" fe�m*X8al�����g ���on2�ͥ�}Yk~an��:J � �LA�n7��!m���.�tF��+mopolit�0nOr,,tK&�E'� �a� hglobal Ѣ.pA>���q1m�"�D�At��T!�gac �negf2co�is::x1�o`� � N]�c�*�a�i�Jv�.m 58]8enh�`ng ��� w�h��=’��dey4a�3� ��a�en���4A�AC�e�d���re��asj g�^�"ow PDa��K"�5�a�ye!aC)�B�qdy� 1v-�q#1�IW )�r��KSB��y`�G.,��&.[���B 6Y�@{r�A�i3a�1 ��!r�lo/2W !�M�Ne���w�.F�#s achiM� � �J�'�'�h9��!qes&  1al����g�e�e���kadd潥�< oura�N%er%��"�/�26 nswe"^-�A�� � &f &�" \ed; ideE�lmF��geB�H"��e� V�$��.�>J�+!��NN2� vU!b�1}tH~}i&� �`c*�  n,I &� # Ѣ.{sATMS �[;E@e�eU�� %� DNA doubl�9�\ break�|DSB�%W�O�vD ATM–��$2DSy�ad Sk1 �+olving"��� ( mi) : ir��i( IȂ-W�Cv� �� ��!�َ��# miR-3.I�cke'��s CtIPK+n��os�ri�^!�!*en��z!UF��rܠ��xZ�ir ( HR�e�*� � CREBs-'xH�� �:�ex--Ɲ��o�1g:8. m1i�Uea��e �IR� orroRG!�w�ࡍ"� 忡=IR-1�d%�.��es t����AeALp�>�  7�24)�in HeLa��s!-ul�i�Ad)�d��post-IR�Ion����BRCA1�&i!l�?&��'XT-d�*G�=�aO %!ʊdb}“A�oc"e�Qp"�: ]'d/A�dU�=#�}F�1�Z�Co6,.) Be-T� �&ly!�cع�eQ��e AMO-qq%�� ����� ���8��n՘�ti!anAV–�)�a4�|I–���� ��&�2ofe�a[m��PDSB"l�_a�>� ( DDa��� { n���adec~�gIf��iTP�d�A�>dtB�mep��E^cyc���m�U�g3:U a�^.�r apopt�I��.�n�m�s�wo���-^�n�eЯdefen���"��death�tumor� Ep�,L�]ol��a0ki��of!��DR���� sive�"7+���kv��od !A�+"`�&Pby2�!k, ubi �iny L0moo acet,E$Rr �E �,Ma.�v� emer� qnd��O� �����}P� !�|s�4ly un d\D r�I o���Ka���Rva�3r�� �8�wQ�!2gCngi���"&�*!�Aa�,� B�o�F:Q�"qX3��(( Ataxia-Tei��\M�2�kh�m� I8�2 aS6ea/, [21jco�,[���p�ce�ion{7��Ekxd%���w�T|.1Ao�V_;�(s�<\f re��n%��>am�%�s�s�, [� T�C.hA{eA"�6�v�e�Y:��"V� Q�[1^[1�J2& ��"%���L�2O3 )I(���6� E~–B� moduM�of�m�ћcaq!{�a�X���! ��} . Cl�,N8}%-W ��!�{!�A(e� � !Xl�]�0/�G  �,a�-�=�;��(%����atx:��a�iR-421�&9���p0�!E��� &"t�!r��O &�s�� a_,�5A-Ta�fA�U�� �-"I z!�(a�8r1Gp40� �%'$>�"�.m ^�/i�squ�se�wcinom��/D].�2he+/��.�!1bi4-#�i!2�n��"�1�� ,% -���!�m��e��A��!EGeT�P�>~KH-�s�DI ior�A�\( KSRPs���@ty��a*P7 y[1�Ml�2H�ewNccr sus��u�"� ,y�M�o�e e.�*g� ��.� �B�l�t�r!=@�!� e W�:# by� Za� -QA�a�l�A��to�� rebyA�r a�$� � [20�4pT(Mnd �".5 i 7i��n*("�)%���AL��[.W pr��d�;F� ��  �/mL�� A-T-!D���"�.�kQSlonA�ic�i�i�v&� �!q2�O�Mg�h rima�$ unkn�O�5y+bRZd�se ‘6SAIf� ( RS-LCL%'��R�terro?����" e2�5)�eT+�l%�m&n~��N]yg ��"S-�z� arraK%W���L �'E A�T�/&e�2!�AmK��A< �)��AQ�� �yf<��"^@5 � �D��bu�)d!!ac�r�Di;4M+o�oe;2cwBA�a,�� �b/ -335��a�#�p mesod�|s� �� %#EST )�Q��#moE7>;ɿ�SR� d 5S=Fz �e�'ATM*���!*I��e�KV ( c���^M�7ѡR"v�") A)���&-��vn N�&�manne(<FEE�* ���1� �|�z1-2( CtBP�*� ]^��/RBBP�Q�  wplƧ��*t����a�6 V � c"�yof���d�(�N�W�"!�[�/E+"^� dys�ona�m&`A�ooa�M"��'A��? �A1Po&E�!S)�hir6:e�6u�"+ �5��. AfNcr���!���8��D� appe�L��]��XQ��]a\N|Ww�Y-Y2�����t2mbe.s ]mD�>IR!jWT�A���j-T �U� ��ime+�ty5_�( RT-q )!�f�bat�$ }� ��0W{I/�%3eG9!�L2���� �t�5WVFiE~2�w;� � w($by SmirnovECheung vDow.� ����lso tru#"li! ��*g � , MCF7�T�j"� E�I��xorubici��H�8� �r�-R"� :4�?*��"lw�k�&�S.%�u�2W7�"V5Q�:{.G>D8a$ n��F)q-�/�IR"lZn"�?��I�a�2| Pre-&�of.%�KU-55933�ae���UN�or �u܍P�T��9O\Z'Efi�fgIhJi �A[>&1"]%�=�Xp�-O*V���^�y�B�\c��B .����&Wa���au�eǁ��bd�-" re��5�6Q*��fbya$. -f �;( 2nd U�V!E!� L ����QV�$�Xu�S��"h�"FE,3,� Q9�ް�TP� �to.!�HEK-293T��ed>C& oth�9��by��F��7P�+��c8*q�)�5��Km+3��f�� 6���ory��Z ���1e,{ �:!�2 kb �"��>��oo�|�!"_u"J)"�M�G �gra.�ConSit� WRc� �& *SJ26 Is� n!� )I a@MIQ�����:����. ��" 2� � A�si< �-�g��% �0( CACGTCGCGCTJ>d  GCAACCAG�^� E�.� 68�y���.�9��.H!�M�!�;�.<�.bse<6`��[3�,� % �X�m�V:!Y�lNcha���s h 9�IDsi� to!�ck%� �p �e�V��bik��f�i�x��Mi�"U8eo"cy�"��_V�reF ��M\]nEE�-��,Aa�6� dr�ia.��* q�=:n �!� ���xaT (.Y%ci�E.( ChI�{?!�Bo �a+Z� ��2on-� 6TkEEJaudis"� Az!V9{aNFrIR7K&q(m�e���b��y+v�R6�N. @2� i�EhU��A�!�Bzn� ��9siԯ�a��2� o�!hy�2t�,FK����� �][d.b� �de-.�reaC�4 , 5′-azacyt�j��(��enV\�mE���abXup��5�S�,���5 ��(k�8a working model� that MEST and miR-335 are co-transcribedsuggests 6�Opost-IR phosphorylation of CREB by ATM kinase activity may mediate the downregul>0the paternal �ptsZ�<( Figure 1 ) . W�,nfirmed this~$monitoringS meth�statuQm%,promoter reg�before�af IR .|induced no significant change inJJr�S1B\S1C�The ATM--/$dependent F 1�-��|at there might be a link between>n!* e DD��-C5�S3E2E� mRNA!E�$also assayu:D=h6)�40remained unafa�edy$3D ) , sup���� work model�q�directlyM�:=�{i��0e most likely�Uto%K�Din our ������ pathway .)-�es DNAA� rese�Ydu��0~nfle> �choice!,:repair^I�8DSBs [32] , [37  8] . Thus��( hypothesize��9��b�dul���-�� ��c1S��rE6!x��E:z . Ra HresistJ�syn�A�RDS )!�aPaeristic!A-T LCL�hich hav��deA"�Fi�-S ph���`, cycle arres�KeA�spo�nto IR;meckpoint �E� play��rol�$[38]–[40!^An� phenotype� q�6�by .�ng5GuM4��� S4e[F��.?x 1�6j�a��ay!cM9visualEby%�\dual comet tails 5 hours"� inE�neu� +e��� �5�BRCA1!�e!���E$to facilit��Q�41%`ssessm of O foci��m� at?breaksmIR���dem�E� 1;:Ur��edVkor retenE�xava� I�Erescued!a&�ng ��zou� ��� !c�\A�A�f-���mm��6��q�%sYg�R Thes� �s caus �Z6h� 6P�L sensitize �eb� "�1i clon�0ic survival wa��^ & ed:�| tre� a)��not" at 5 G�7^ ca��E�!&�q8:�6kculminA�in�I�of:�Re-�X@ R��to�9B�- -=AN]�)b9����j NA m� arr��ig $ified seve� ,patient-deri� RS-�d� eleve8����V4To>��*6��propo!��?miR335 �>i_e impa� ~.\��!� �3se!foc�n two� previousl+ s�!�@ur lab , RS7 [25]RS73 [28�V%, itu�o-�>Ib7 !�� �"� �M-kF 5�>10 foldi com� d�W��� trol�L��5A��S*�e���Q��=X�u�in !Uf5. , s� �]�:��=� ],�� A�inver�i shipR����-:�P,he naturally�:�Q� , an antiaz 4rpholino oligo� � ( AMOA�-33��!#�7to���n=K.286deg)�b� mple��aryN14� eb�� hibi��e�cng!�p*=^m�eɀcrPAb�to block["vaZF4W �B� s�V reat�2AWe$�4.# ��increaa�N�,A��ԥ�.�6�!Ar� si �U�� bq F�U�5�In�� stud�48�]�d a:� !Vo � �u.w3)�dis� ed� �*/ 2�$by γ-H2AX��$i kinetics �G2/M c&� ��-f "� %vis |"�on)O� n addi�E�43M� foun��2� !� :� Z�MQ�.ng.da�d subnt%�ie�!�E�E�showedI!^� US�,. Taken togea� ,a-se datae�ort�5 operal� el�� �Ѽ����2� A;).�t� P "�  ;.wn�7T}�!�ta�ed��.�, �.�npartialto �a� �%�516�^��IXsB9��V9 B� )� strongl2C ed ,-�T� . It)�providAne� �*explan%��6�: ed colony&� .��e�1[2m42a To&`}�4!�n�>�.�o��d radio��it@�1�A�5G���.� m} Na 51 of. ��an"im!:N-���bul not "�8MO-Co��+CTd:*�6A.�z�G MCF7 ۅ: high������Z�_FvtU��Pre�Pof.�Bn^AHIR-F fo�6� at 8`���enhanA�DN�"[ at diffe� dosA� f irA7I��S7OS7%g We)Q* a novel} e�ede�~ involv�wa �–-�–�aaxi�� >� upon.99!�RFY,E�ݷ*�,. �/ay� is3ory�s4toC� 6� places!&�SV l!�inferrL ه^",  )t?-�e=ism!��/-j��l �l �9aAly"� {� by��hyper.!U3M[29� [30 6��JrP��.X"�lly un�gF ,I%>�.m does�h  a.�"�!�}}�M1�4�N� ChIP�.�?A�# s���>��*ES9 o 2G )E[MsiP 6rрbasG ���LF�g�A9�]� a g���-!1�nE8m8made it technicV ��icult!fui a�`=�� Ca�s��re)wa4lready knockede .���"� M)�[ate�.nes RUZa�N .&!)r �y)�v��[iOur� ��)7mo�2 from%2>0byA� �at �isu-75�!�=V�9&� �V�Uo� QM� vazoie e  .\ c�at+]xOC 6�lower� somea�ae ic� st c��r| E�jR���� umorN���. Inte�in � ��nE[�e��� "D �e&�!Hha�� ɓ� -. m��4"associa��"�!� riskA6�v�mR e�)+1�:3\� n�!&�I�2by�%mfun� E�)�-��O�, ed .E� 6oN�ng%vs%mC"� �I& damagb"E�NTf-�A�� �)�by Ta:�!!po���er:w��&�A/��YiR�m`"�E in why��"!2n� %�apyY chem�l���$)7���Ti cand"�N `-�zert :r�i�"NA2!uldA(�  r�ntEL For exa� ,>�=IshRm i�)��e])� �QG!%DSB` Avagenta6kE�!:�adcontin�:P �� �met�ˁ}> �re-initd ݘin vitror!� have�W% y�M�'as%�o��� end-&viae"MRN cx�as well help! } elecA$e. &W �؅���b E�w��recrui� �A�M�<�,��}�c%�% far-reachf�"@�!�ch�e�sz, ���&@ � e8.�B�Eq9o] �H�$or&@"BriA�c!a�I�ha&i2�Kdu�����ZaJ ular*Z!7is���l�MRj-%�-2� Q,_. T:-%6A��N� �s ,�CsolidifyiVnoAS6�ќsE"28" 4C|�>)N�klso^ n� !�hdistribu��I."&�Giv5 %C=bn(Aly�^wn!]q�! k*� "M1t 43i!�ll�{i&�Q lear�{�!< �;U��&� mP.RQ"�,&homologA%Yjo(!�$(6$ͣ� ff� 'TMB_ in WTp�3�a!42%kJjaH�= &j&�lyh��s. How�}*X g��2tm�p .(�, u�! �od��i� $Y 6;,�D>9-Z��"gsubtle�i}�!��$Q�:' ‘f&tune’.L| �}trh � 3S*�illustd!e�"z"�$6�can�"oa� ��� grosaEdis]��#by� Q�>HD���Ň�3�-*K!!}1}��',��'do%�effic?lyŚ�FreB+.)o%�+� yM�6�>�y�r���a�o6�� <A ���*� M�a�*���"abrog]� �ZaF!56�M���in.-( e . g"Y ��): ��>�J� many�� �> :��"� ہ0/��U��a�j. Huma &Eq�im"-. in Seckel%Jawad�&drome�d%Ls"@s!��!, es%w6,�! ��NAUR44]1� 7 6k1_7 X"��F^� !bea��+in �&� � ���cliD feti .E, HcopP )�le lac�)�9h. ��E��u�in DMEM  ,10% FBS , 1%�Apeptomycin/penicillin/glutamin�,PSG�10 ng/m� suli�4 A�� C2ul6z�ta1%R8. Lymphoblastoi)��JJRPMI1640N�2TPrecurs@i�p �% purc)dIg Appl $ Biosystem!�Fos0CA[, C�A"!M&!Ol2!=AMO!�) stomA�>u(����335X �conjug� %L�pep}.2�sar�B%liver�"�!*!�����Qqvivo-AMO�Gene-To>#<, Philomath , OR e�of6cs R-0ATCAACAGATATA CAGG"�3 ndarj$| X"!�)� � :��V,!.M(�1� ��%by �0againsc�+��E�to00�A:�  to!63 vector�]*K s���ONA!�I�M�d}� Lipo�+i\RNAiMaxj /d!*6( 2000 ( InggenA�arlsbaE�followI manufaca�r'�9otoco�� E�pre�N� ( 1 µM )���!�j"3 dK' x�%re-R!?fee�31, L col��A�)9experi9HI*�!�per�/P `a Mark IV cesium-137 seal�ource orxa) !�A�∼4 .)/m��T5�E �� ��ext�+ ���mirVana-�iso�% kiW2JT)A3 aqMa�5croA+*-N,a�R;%��qu�%8,�$��P)�!g�bU6.6�gC| �7Brol%�Jmm�(%Q ��22�'e �- a� E&A/1 . GAPDH S���!U �. D� A2 aIm52�16�"�m*�"!7�b id� Text�6.�=M.��Q  a�qk��iV 50 nmk335 (I�RNAi �/. A� 48E'�mp�0�+00 �/+in 6- dish�th,incub�ba�24 W. C�6�)%+�a ser�@!d�( 0Z , 2�x,) gr b10–14�s �s. A�E1% crys��violetp� �iG�#8a VersaDoc ImagDS��vclumpo )�A��7m� than!i �sco< +7lon��A�Qizy OP#r 9( Bio-R��Hercule����$�i �I "�- curv0` �f�n� at 8� :!kena!�0�a�(H&IR�a�� CSA%��}�X �'2,�%���) �RL��[23t R:z� e S-�2&c',�/�/���Q410�#uA�ane�!v. BrdU%fada�toM$ -a 2 h"DmB9*��at3�ui=a elabel!�2r�(�<trypsinih/Mcf;if x2<eN�a FITC fs nti-x bod���A<^+�Flow K�;,( BD Pharmin�NJm�4h5by FACSM�NCA%U]{ ccor'E�eb�( TA�hInc . i�3te��%alc�5!A�� ^�[2�!Brief  ��������B��(A�M_q�3�2� embeE�in� r�/ge�:ly�situ ,  ro�?e*2SYBR GQ/ . Sl)(��`�y8an Olympus fluo�Q1,scope equippQpAxioVis�camera�acqui�'on softw�L��ns "�z�a�>A@�|C�5S��>A iTek CorpU��7AR;z /2 nimu�$5�GEH�pe�� �.� �Y��ri �Tail Mo�X( TA�~ �metricaI � 5AI%�*ᆭ�5��s �:qi o g�D“per%�bH*�<)�F�>�e�1�b�tis$ɻsb76(to 100%1rA# ~wmmuno.udetI*vIF�9hb�45�����B�2�!;i���0)�t 1∶3� Nov C�8=p. F�P prim�0 O�0l a�!�f(washed 3 ti in 0 . ,Triton-X-100PBS��0���"i&�#em�-ure��1 h!XCr slipO �q��(400 Alexa Fa��$-Mouse 488>�Eu�#�) j� ١�4 �e��, c:� moun�oss��,in Vectashie�3� DAPI6*�9��!Re"7�e.6 !�n�?i֙!�u@�  B"�@� -�&&-length)8%[B��3f���?*?a�of.��li!�2a_ys� m�@ -CMV6*�B%���he�( P�(ga , MadisohWI� Del66��FT� QuickChRII��$r�B�/T "S(bHEK-293T.:3C%���#d9`�!�dZF or6x !�fir��=#pGL3-��9*�:�t rm� �2�$c�Lu"Da.DC��-P�(Dual-Glo™MD.�. Ry>m��� ���$Renilla�J�. NA�arMaL(E~* or.E�.�NE-PER-�Pi�S+ockfor�I /2�B�� , harves^2 h*�=A��� . Eq�=a�:� ���F��A � Xµg�a� )�loa� �|SDS-PAGEpiʼnbl�/�A�a�yU�&w��,ies: rabbit--CTIP: a Lab\2ory� TX�*m�l 1beta-A(8n ( Santa Cruzew�*��]rhe Chr�in �precip4�{(�+)MS6��>A}S�e, Enzyo>cZIP MeZ9al Tech��;, Bost�IMB2� .h �cedurI%&� �×10∧7.��];��7A)��A2"�PEm8ck -lin�M� 5=2-T!��&� .��!M frag� "�e5?di�,�!� a��XA�i!� /��a9�c�9�C!ElIgG � (�R��pur�t. P �rrّI ��*"UG� �+a|2/(!ward: TGGG CTGCCCCG �4�:P: GTGGGTACTGAACCGTGAGA:O6y�'�H��232�-'ir!6S�� runi a 2%2. to&0�p1�BAll�K"�El repe$in"l,l%Kree�$( n = Funless�%wis�H!�Q Stu�>'s t-�6!cd to evalu`?Aj`.�2�D�=group��7+l�Ee��tin� .� . P-Rv<T 0_)�d two-�BP6 unpa� ��}%de� .(". Data��A�sV(mean +/− T�dev�.8�WZit��!�#pre#�&s' beha/r6al�! irrex.�"ga�M�at&�$� J�-�sef�v*ions…�S�'" 0izing"�f ver�*phi�EE, eventuq+:'Ku��5ly adap0 ski�Ksfd nvin�), t��* or deceiv ^r�Hsw�A�cap� B termE!depth�c-� �a� "I1*nk t you.  …"�6Z*�$)�I�h�%���  .u�#end�%�� i exe�Q.e4E�. We as��p�9 cipa�*to��Em�ga:  st +fic�10( Bayesian ) =� � D+�bio �ir.� � Critt(w�day ople)Zve ei0;' they�Bpla�'�!�I��:/ gamb�$�a cas�?$. Although#fra��._ �QA,66w�33 2'6�R,-�-� ~AhAutasA��lo�2�:1. MoreIMfi.=�.�'�' � best��l Kb>�.�5�6(AumKZ+l��B�Th"�& Kfirst.�2_2�$�f! .~onx-:]��W ���� a1 . Im�4�:,m�sults\)I3 we wg"�'�"bl_+d� h�24+io� �HwiADt�N iori�1ng ��.toI�s . W!�!o��al ab��Kw �%��approp/Qe �! a�1?a� make�A!�Gb�.�$iyFQ��"J-�=e�y�$to)~� tr�nd erro &�(u'���9e� 3Rng) pe�s'�%0 ��Fwe~�ri�-� mplex!��nta!���ir hidd�S5�*�'el:� 3)-���In]JtA4nE�A�%�c�� a� 1 U|j%�8ins�1i�%'�� is d3Gna�th��ra� phys�: realW#�8i1#e8 happ\,oA�false [ KIA is݁�mр%�ա� �A3 �cog�0onEc ���Q%�weM,�o�r�i�')�Ne�P(childhood [ ?,!4dfQo�0abi�tou`eb^,�7wn� "TheR9 ind""o#or:�[uM!�concer"�!��RO EfQ-� aiK�7eye gaz!ndA>a+R���verbV1�*languag��C!�hy� l�)cn of h+( �9�[�'We%Im�e� sU6-scale9�br�4net� s [54.[6�HE��Ie�M ropsychiaQ�rd� � 0schizophrenia!eautism�a:�6�)ira� [mPlP�Ocur�>a� archA�l��rE�an un�t�4n�@�2b7.�(s .lBwg7,�of��F��.� �!�a E�K�7� �-isHz we t��inspiM�Rre5)�kFQLcon��&� al %��M7n��:�.�pr�Ga� s!R%�&d �:k persuak2` T (. O�fe� hA�,A�"�0=!�@ec%Fs<�B� 1� es ��i�� thin%�.�"s �V� s tc� [�>1�Q�is es)+8bec�N�gM re� ends �+y�����Ii��%li� �w�1dob"�6AO� �/�vir*j9S�NU�9�ysx[� �60con&�&� � f���Pre�h1a21�D����>!u� te60�s' �s�optimav��a�* 4)�c&� commens VeGideas���"M�"� ��"-l2 , namely:Ņ2� -*� ssuA�%n?:re]too ("*"24�en� #Sel* ) [13T1i�2 mu!��e�g�a�!�.��� %up�[of!�ur2]��!-"V �2�� �� ����aI?v �-pl�#F ode%21�% �Ar�#�!Hro�~E� �t�ӁT%_�:*z �"���9�!9* �[=} r�^� x(%ds��orP  ,��now6{�6 ;��>es:�:�� "��& �4j� .6`a�k- e�ddi� %j!��j?��7�PetKH�@' �V� `5�)Gt:�[1��� i���&���:�<9.�)��*2����z:-A�a6G��4fa ��[XAsG 2��-AnA�A-*0)�-vw�U tNC"�)2F!��-�U.6( avail�1�aC$correct/in o, back@A�cr ����Bͱan�wo\R:ed)��t 7Aa�uc$!*���e�t/<�� �y�8G~ ,,4( ii ) domain--E l�8!~heuZͬ�'OM|Ja�evul�`�f�[-� ( wh�:�� ��agrasp�T.� *U>M�W9J1 �-Stx) J� A���a� ��outsmart)1��who��9.�. A"��f -I;f�.�'sA��v�'hVDhlP�� itte���Od'E e�,é�.� de Par\LEEP , E"f$al =csUry%��Pf� e�{ Helse �yla� , al#J bjects ga����lon@ il�l�0dFincluR ANOVAs.-�"��VBAX@lbox ( http://cod googl 8com/p/mbb-vb-to./_3�}Note: a�w�� sumi#��m&aA�$� +ultipl�CV� ��wa�di��family-�1�  thresh6'( FWER5%��ne�T�# . Fi�73 �iY!��4"� e�0%�m!�i . O�Xz Npaa\�mo=�.�)s�F���Let��!��Q4top-left panela��^dep�e dynamA�m� ��cum�)��ar���0a�q>at oppo�A9!�ő�o2�{ laid13�ce 5% "po](��:1�} �� see ho]e�! ect �5 un��sb��&i�u�@s99 r�3toP� *�'.� ���AY��"m=c":"� sta&!�&L on� !�6I� *=�E; fiL1�:����Mp��1�( ū60�$1 . 79 , p P08�uw�h�y`�n�z 2d−g28>g47�!espit�R� �"ZRB��[UN ( cf� m�,Avtom.�4 e5�CA�kerQ�a5r� �63 �4nq#RA�@-�A In b�, �NFs.���t-�15�n5  �^!�imy*(A�I�]3 . 0?62qA���(am�%W��fe�|� e�# Mo��(2�o3�*�H.+ regaK.:�5�&hU6. Now�n�+��o>of� . 3A��u�6i�"m!+1 h���1�!s�  tFc��cis4PV {9�?:�se sa������ 7 except 2_ ( nu� ��aI�@r\$�}Qz�e�.�.{ ��vbeiU�0� .�RB:!is viewa�MQſ*F��]<c� 6�>xA��(sdAA� s%�Iiag* g�nr�$qKn�L�i�or�1-�di�o"�o�1�.�loo\mycA��!h"n�[� F:m�.�qiw��[��5G,U��f'!��e�?on&5� �c 1e(��2!�B�3;� ~$!�003�m�U��r, ���s' zG a : is higR(!ms1Q-an ��)��*�m��)�}�R!K< JP$V0�� (�)%IsA��F�'Q rA�F�A�t}?�8.O43� %DQ�4Wt 2t�inF��)�i��!N&�Koti�al�� ��hi"�Ik also��2 ��A�i�h�i,Aa/�%vHterIHivi�� Y.ngt� �mw'�h&i. F0!^�#��D��.f vari)SsQ�. OC�1x*�!BK.�Q�:�FaskI 6`Su�n6�sm�on�R.� pm�[ap8L�� ��:0�G's>z(��R�d�<? .r�2�5acap1x�uH*2V��3A/f�m�= execf&^IQm[�.N�%Ji�]ync�c>�2  and/�?� M  ?�8�Q� e�B:dA�9���co@��i8p�a��d%a�c[)Bh��i�gQ ��1�e�7M6F� �Gf�ge&t@�� �:u \ �� FnaT��g�S�%��aNt�.>�tNm( r�}24:�2�~Fur8%_�"es*%�= XFKsep�n�)��s*�  o*"&N�.�48:�010?#��10�ReBZ {��wly� BQ.�MI-no advanR3��E�On :6��e�b3��:4.�J.�m�tegligix-�Ha?,to��J,:��U�J�� 2�r�ofM.��Z�' J�"�$�Er;r�^( V".�flexi ,1!� mem�� �h Qi, ��E=y/2v u�]ra+"ur&�."� *��!��at9+�reliabl)U�ex�_vDt&�**t or�++&�(2�Xaut�2c� && edE!"L��^cw��"j*e�Ct�5��& "w*�~{�_3�bZ��<h2l�W��usQ�$ed VolterrJia1� *.�� -by- F +,"��&ook� �m�$7@e�! .�!S&])�>y �/A�of0 h�,e..!. A��'s fit 4 urac�+���ne 4×2A�� o!�<� T�3@ow:���n@A�"����fi�q,sA*P-.�� J�E���`75%!šc��v.��*P+2� abov�o%�6*� 3e�rsA��| �T!��!c]Rk(�\�(;1P:-��L4�"* 5��͠)���A�iX��Y#k d ach��![e�Q�3�e�:�!�%� ed!@"].�1"��O1!A0���)�)�6T�a��a�lGu!4�4 �'��?�d. �_ex �in!{!5�!�!�Fv �t����I�a� ong�e�:to im78��.�'s �O Y;��vy� wei��vT 1� [e#�5���to�#r�5vk���kI2H&5,�����pa�v�t��+c!�b/neg��5�Q�)�Mn* �s 6ft� 2M�J� �sm�Jr%�"�,#2,"J ��� mn�)�)6r�ALV��h mayb�&6�A *0�"�tA��&al"�;�q��""��(H.�BeX i�(e'�I��*6��?%.:U��eQp�o&R�:"g�B�1;"1vFu0; Alsm RM�|&P�XQ���(m��f��N6�a�Brep-�:u*T)1@� 9)1052�00�#!L86"�i:�rZK.��_)"lq/I1FAQUHQ-(�8>lagE�"\&*^��*Rha�!"�1���/:[ �*�z4M&�5a�X)+"h�A�J��i�n2�_;2'iSU� ��7JW_n>U1��Za��'c-�1�:�( �x VaV&�^���"��t=%of��� Mj"��A.!c 3�Vk�. �/� prox�KC�*K.2 5��"fB}�:GJ }�'s9*)�E??a*�5V�in PZ� -�&�%s� +Wo� �S6�!�����Iſ�mi2EUe:�2����P&E5 E'�"�-!`61G* Ci5 �"s:�q.n0��b�a@a� ng r_k�7&�"-PR(:Xqnea�b$nQ�FRr�" &rrQ coe�]� |D�,�"?n*q��*�*�5 . 62� *P�,E�6��l*gE��F0&�18E�>�"�FT�"�:0���<M�12>�7�TV0k�\y�AAv" "�: is[[A�cdI�s'�� . A classs+Sobel*-;gN E(i�&rarh��:�10W 1�B!�fac �(;�Qof>�s d& ��YaY:� �t ��w&d@5 .U�iރee�,&z 6�;���A{mminisP5of.^ed Na-"�1"�*6 ��Oq��Y�Y���1�$�?.�A:y*�.��z. Las�&������30-ba.�5:�B �Eai�O,n7A;;�"!�ariqI�MA[ F� �2*�%w"2�g�C-Crandom-m�5��<&,oFX-BM�_�q)A8fourt�g�t :"�D�Thba�+e:e� t:�,/$�3� ����:6Inf.2 .*noBc�#hBLDX-BS2 qC*E"2|>RRAWSL!! NashG"� :*�IThat�1/]?�6�o�s%1�EorthogU?+ -$ ur ��P&�5T+/T- e/ich r�&��@�9���i�/f B+/B~Er��75l 4=5sS.� j �� a bi�'er�s=# an cpD-hY 2� p�'X� � 2A�`aT�(� in (s/��!�*y��*~%La&{ust�� )d.F�,"a�J�[ŵ*?��4Y).�=+ �Hus T- )�GVfS!s )t@ (AҍI&� �� �. E.�K�'=c�?"Z�y ( EP7 9�..*�<e.ea�T�*�-R �s:�bl4i�r23=/a߉b0�%�hR-����>lu8�2�N@5[` e�: =� �F!%�/U(��I ���+� �|�� "9"ouA��0=1Oi�Av�+��B�.��aX" *�N� t���0a�% �P[��M�� EP>8%4,e�d�e�f2/ N-w!���EB��$!�eak>W1 =�69!�6�0�hr2��1m����d �� o1-�*x()21��u�a�+u� "Y�.f=�n�Y �E� (z� }%�>�N=V1�!3 )8` �e%�e�3 prob>�I�a��6A'-�!��\�A_��-Zaj"b��diagno Kmq��lfixed-�5N� u�� ma�Ae�O*�-�"� �� �s'�� � M"� u'��"LHT+��!v�DT-]��XA4"+-d|4}x.�"# !�!#N�Az��q���E����D*2�96iQE�\G�V�%c�'�E!�"�+E-Mm|%Z6 RJ.�RqN�+t��*fV��8�3�=:3 2IŌ�Y2p�a)y� �*�;�M $w � �waFN|dut�!)Xar�@ nearX(Q6"�9�@} p�+ofS1{8 @fn(�Y~&N I' f� ���r0v^��up7_p6[851&-,]f �7E�� t {s��"S�R�C S04!| �#-wKsor�S�0Ap��v��9*�!�eM~Պ18��""55�2*of+:D -@%IpopC9o� W2v0)A�r"��5s�!-�)�/ 4(�be�OS*�'!#e3�E�u!�A�Q^�-V�exiM��2��& narr�#�<&�Y/s}qbeI?-b�&�JL!< 7g *9 quX�A4��a��չ1M�.4%3��D�6at�.��D�CV �C:-G� 2� �ur�K�at�\�S e&/�%�D!��+(I0VXn6:w or 3v*uRsaR�)$�0� "����rom�VA4�$��A��2�'-e~��iaO#KCR� ?Ue��c� �B+ slr"pn�(m*�8MaXq+�%!m�win%+k��x)!�pr[�d$,��&>>Z��/�@�tcombiy.�C*L��F"P ���e.@&@Ka�oFBN4oAN�#f5�M�%��*&�; �3� � ����he"<*��v'�I�&%�Y��$rt4 vN.����u3�xV t^$�)�1re�&A�"knI{�d� . Us$QY-���tiLJ&h?�Œ/V��3>-u�:# R3�� � �� �� ��&vE%A��H �uY3&�!��'s>�Bt� )*�"v~1-( .�)�d*�.L/ ;5�nAY� �.d"� %�A�>;s �*s.� �vM(�S��.�/!kyg��a ��v�RngAx"� �i#&��r|�,(SsiAngy^Cࡾouo �s'�xmBm�%�*I#,!��y6s�@F�^*p origԛs4 a��4q�"�Z"pAV���e� ;xp,-�� =*� !� shap�>�.�=nI!�)m(+:6JŠa mani"A E}�Pf FK�8�>deVQ�i&�E�-�.�h�U-���wM\���G �� u*�7�T�LB"�}X1f� A�`.z6�O)��2!/��2}!�p�ut�\���G&�^ Qk�ef�In �"�*�/&� /"|i�l> a�U]��to�� ��əuTo�+�E�� F�7%�� 6l�1�<pi�Ea�e3�I-��/�5�6H(.�R[Ef; �1ƙ�i�M%!�ZY* ^�A7vo�O.�J�.�~q �� vq..�(er!��I`!4:�� ,)sh�Gde�B��!�o�3f ]R.Bh("�I�= ,)!2Ir��d "!#tri�5ap^�]chegyAR>�("Z�A��Q�"E1����]ko���GSR�S%�2�0ʥ�tnm���h+)47^�!�2�p� H"��3' hard�Cn_JoF� ��!���EDntyOZ �]� � �2aH A&ImS �2e�8\�!A�F^ M.Q�&�<� >L�� 1 &I!�\0e� Ra }b��mWe�salw�-%� W*&lR:rE.ū��e�A1s %Y� ��aAtAZ!�vdagog�'E��'�'"۪������;jari"�g *� =f �W� � a2 ir�be�?j`t^L�oi U�(C{M0 �s6�GjK �A���d���]( imbalA�d�Lig�1}:�mcty�O�*� de�tL�sFG��R�L �A beyo�poAc 1�!x!I�!c��rn3)X�5!Y���2�^c�&�< fati��. UM E\]Fp�8�a��^+nkortܴ  ad A,VMMA��b�ss"�L6&9<6� _K%-��H�-f)Ai��6,leaa.�los��' &discu�me��=be�:E5��O�le�c!!��"er�t �:E��/�Fv �Q triv!��'�#]�\>m`�s���r(��� ,2��)9�>�way��hs2w � �TIn WQ�6�D/ �� i)�e�R1�N=r! �^en "wac"�!�'�.�"�"�K�juE InstA,� �1�+�#a u�بI��&�u�"�vg)��&2�t.'6/' answ�VN��&f qu�1>�8{&�?` � [ a�{��*GMin% �Am9� .wg�G��!�URk a�z.�Z�!�!�!+:E$ ambigu���uk6Y%A\e.�e( "win-stay/L-switch"I2>e�6M"���s���/:a��"x[k10!sR#!36�!�#[ G�D! :�e*Im%ms�X1� � k�! � ��W��-�"kw � 6*"�!�"�C!� K��E�c�utemũUad(im  ��ce ��,"�@EⅤ��JQ�9���6fBA�)t "�%.r '����33�i2}N �X��s ceru�l�n�rωDaU[��#�hs`��AJ�F�Z�radd�� e.�{"�Ax�jhco%T&d�*�m�/��S( 1uK '>��I^�!spro!�GoJ!�t�; � 6 7dRB ;$:�7u�.W��m�G �n m�Yl �N�no�*3S.�2VA3� 6"�/�&urpri��)<2uE&�(�V�9�woj A�c�F�-Hd fas��^���n�W%�y(issue��}�r�I!��e���:dHz$c�a� �o�" . Gi} a� appa�j:�c:^��� � bQC%�� �ksKl'B4�: n*s y wo# �e"4\i� _��,ofa��_e�e&�9H$��#o�V���cA�coo�h M�E9��ћ�!h�#ѣ8�kp�$m"A�Jd>��!bempir�4m q(�$4��I2d"""��ism0 �A�bed��librium� �$��a5 Go�� '��b-6�yg.2r!8V!.G,�"�/%V��E� brid�d!ga&S�liw|��,y.�i%[&{q , [4.����b� �%�~p40v�JINw�@GP8�&�(�Bit�'Wr�yro�82�!{��:�2u6@o�als!� �b e "�)6e� %T2�pr*�qCE>ZeiM5"��7key�.I+��e �.�C��*0��.�.&�-ij6hM&>�>�A+&�F���]))��a�A�on� �=[!��n��!�a.��ySa&11uI .�"N�4]�)>xpI�>neuros��u�t2*���8aS�GA�vBBn ���&BE �3s ��a6�wdVI^�7ir50��Ia�Nt&!�qT%�"�0�]�" �%� &�}(6�).P�A&E | fg��pTA�ۺ:`*Vm1V(I$ goal-orie(��!�NcU�) �en!��Ho�U��� U��� o_�I��n 4EXM�1X st2�f. Amond)�AO��� he�Ns�am��n!`^�e�G)nk�J)%re,�%�_au�P ( by���e;D)� �E,!�,�{suee�Ll.F�EA���<� re e�y"� �Tra�! O9�=e�Jlu���!B&�XadvY�ta��S)e- -by��re�ch-R��y� , [5�} , �n�Q�y���a��ji�� c&7purF5�!is��rk�$O�<ur�!J� U&�"embramkl2l�>P���}2�^!'*� �%ad)� s' m�}E low�C-��s as"s},odh�p �a /&�} [5�x"_�om)� ^as~�uiln�kG�E0.m�_!� �]e�stC�5M!/mod�5� 7�B��caMt��-/anpas��f�r;.�A [53]a|ut� [5��W�T%��A�)����c /b_�$���� menaq$e���Y��e`��`��CŁe��`W�Purs:��� *�ubQ�� *�.)neU+ ighl�2 a fewA�map;%%| g�B.�� � ��i�.����fh�:�bo�"�"woJ�C��of&�:!��)u|AU(���E��X}l&�f�*��6� (DXs�#��� 2 D���>&�G drif|�6D �o�s�we ag� "G8�w"�3 ����*��/t/ ethol2#� /@�bT<%�- :�&3�monkey!ug�� ap�h`�??Thit�in�%9� *�/ emer4�f�!��S&~4�6� y [5a�56h�!lM wish!�1O+�mM�!|� AinF z����or`*��� �%��pepZt�G� �" �-�<exaa m=:� 2�� �{�&� �� ��ve��ŞJ�WMN!�*�S< �'�4?k��uo7Հ.!�BiUK"�"�K9�9�,�T�ai%�E4�êAT��o��a�Q5� "<&��e�[�3!wGausso�graph Ņ ( GG�6��#1[ � ch��6u"�&3� �!&� A6� @K�� �"�{dea���`.bJ]�& �9rAoe�� �He�ngUD9�2^Gs!+�:a���A�} *5@ igor��g)n&p<. �0-dI�NC!-ata)U�Ite�_��san�tf=,Fm �%h��bg yA��F��,�algorithV[o% Er�"M�ofE� ob p� A��M�$ terv�YorIed�0A�1��M�+6 p�oI�by�"�, 201.RT|��3!�ۡ�#*�)?p��(Ez��#�8oeQmal�ud<�?&�5edP�Re�� l�{t"+� e�$��pp/furL wf 1�sets:a����ic� � �]���+hi҈asthm��I�ȅV4,Alzheimer’"…E��-�!e global A�V�^!�m>��!!qd NAhealtl�� �c_aC=�i��ng ex ]F�1'>�m5 ,�8roJ@� �j� levaA�!srt ��Fc�J��i0�$>�;�0z[V:!�"@J�IF� yA&�"� f��� !3��r�E i�+�k�q+ thod��y�ore�^� : penr ***i���&� � �DAf&�*bQat� [4]; n�ebor`s�GU�Lassoa� |e2s *�o��^"� A& �B�  ��;e y��)�dte I*m��nverg� |fEne���roQ - [6hn� 8of!�en�R*<btopic= �MM� ؛Is"� enoug� l� ���"�U1ed�=h��.Ii�*Ke�s)�� �.G���!o}�;a�+F>m� N[d F ��!Z6IGM!rU�".�!�A .+�!$�j.B�!.B]�6) Aw*P nF����4H%|�,��J� {)BQ6�7�F�!p&up�&*5 � Qfws�xLA1��S� m���,5�� iuV�a-<t�^�L*? "� �E!�..e1�!� at a�leՌ�>� . ����QUJ�g�_�Eu\e�}U�R�R.E1X = ( XsjXs ⋯ , X*���  �OiNate��V�0 U3 μ�Pi�e = 0 '�;)EkcoQ���Σ� )zsy�WXX!T�� G� V , ��e n����V = {F�}�pŬ��A�!�X;E�6&���(i , j�w� (∈ Ej{�ca �`un(A;]bHXiuXjQ� 42%twW��/i�`�if� ��*�t�[�)��%mbles {XK�� ≠ �} #�� Q � �9._&B�*��t>p֗&�Pq[`~ׂng��f�!!�; �Mis zero�&fa�&i�r, ωijEh;!�^DR+tJ��E]N) = Σ�Ӊ�0nrvd%�Us X (*k,q?�E5ogo6 x&��VM f*�9D8f I��O"�f�.M��# Qp!Q�Z0n g�ש-in�<*/9S��maxv F� o#1h�:�Jr,V� 4& �ty.��e5at �:�&U��od�<�"e�wB�mez)x >G� �qn�(b�"�D2�i,�_�bf= �V�)~P*� &��s�=!�U�gFE�a�.X��Su�d Zha�$ackVFR&��lemWni�6fW���Vdel [e��A&$e'��e ����* aұ��2nd jth��� !�g~e2��N�&#'HindexA� A���}��TA|XAc∼N ( −ΩA , Aa� cXA� e� �" ωii!l jj �XCP*�.1cooϋof���C%�$ΩC , D de�0 6sub��of Ω��ro�rndIum�3e2KDL��l�!^-�pt �6es�4�= e *T }�d@ew �jA�)AF�s$U�31(1�b"-&�]XA"�7!pc��5p�%� 32pA!co)XAOn × p .�� -I�Z�)��'O���kc&� #equ)V,XA=XAcβA+ϵAPI #truA�� $ts βA′=V|�i�.� �$_% e� AEof �e� .͠.y*� \ � �-@�M�-�tAO�ing-f�"&��.�'d{-�a��(b-anQFor β^%�βA�}�g�� sidue ϵ^!e−%j^AA4D%qstor ω^ij bwI�r y wrҖ�( Ω^!�m�^a�^ij7ω^e�a�1nw′A$I# >ia7�$� !�tu9=!��� avoi�A2��,�ꩇ��%aV!K&��O%9i��o-91���9)�[W&� =���B-X# Mm� "J&#�6&��v.Q!�+n-Eq�� ���҈ 2�U‘& ? jvum� dQeA���!stfs= �n/log� , 3-9j8��*�"� � Ω q2^&��?u�1h� "nFij (I�−�7AL��D��_��cFijAuA�i+j�lMy�pos��" ed q��`C:_ 4�a"� �&i�A�r�!F5*K cm6 �:Q �^ij���/�jjɻ!hQerty  1�4 �2c�iN!$. Ren et a�l . ’s theoretical study provides asympto�ly normal estimation of each edge in GGM under a mini/@sparseness assump:(, hence canpH p-value and confid#,interval for oHωij [1] . Although.�(ly Ren et a�have developed a justified tuning-fre�ferq(methodologyfx, it is still not very clear ifǐhandle real high-dimensional datasets!&a$�sonable time . While no software was -�d b6�$, later Ch��pn R package named “ANTAC”%HDa naïve implement5�the:4!j(However , aE5!�cedureA5Ries!7 n orA to obtainvSorsLallERCaC8of O ( p2 ) run)Hscaled Lasso regres!o s ne!�o b�8ed , which make�compu �with %$%!te dA_ sandq vari!�Xs extremely challengingE�,even infeasi!�. In thE@a^, wU� a2�A�efficienA�gorithm!? accelerat �:�9�I�!1.�aa" attractivip�%z�. Specif�4 ly ,A�focus!o�e cycl  coordin� desc� �a�>�@ [15] , our new a5 pre-calcuA�s� saveI�saA� co%��Ymatrix-�is usedr���a�u��ZHme . Ase�sult ,E96�is A%�(void repeti%]=x!�E $major step�A�B� ( orE�spQ�(, see DiscuE� below�(flowchart )K)VAthus its.�a!�s��ign%�Tntly reduced . Our fas.�is�� an approx�e veras but��8$exact solu��of�-�propo!�:���L accuA�ly gene  parti� rrel��,�5 }ŢDbetween any two no��iI����network��@e outline a detai�npr��)D( Fig 1 ) , follow��some d9�madvantag�6A�U�: TheF :�o���n8��:� by6#is mos!�duE�A� s 2 !} 3 . First!4A�, 27A�let!�na��ane��F��ll��SLR g3g4 . ToE��re� �t��8a close look at%}�updatesV?J^optimizI!Rd� is reflec�M%�15!`Tpseudo code ( See S1 F�)!/�6PLa6�� nerA< duct�Lresponse%dea���as wellF�M�62��!�u �Emc��<n�= oper%s�"A inim_�U�s%Idif$ tB�%�6��slighEo:�@yE`rAN on a1?F����ata$X . Realiz�u�Wf�v` number8�A� be sR� from-&4 )�nsp3 ) )�� only $�si!\there�!d6�&�Iin:*. Second�Kas briefZom� �O.�� ��a pup2� i 3�fur�:��C�M7E94 a��%required=`R� 5M%to%��. T 8is because whenY bji = 0 �.>2� appl��to�� ��l againŶl o�s (�d�!�is equal Da��( !�. S1� maximum�- de eA� we expec��Mno mor!/�$ nonzero ee e(�columB . Besr �s:�20 Faste � w�$R language%���librar� “Rcpp� [18]$ Par� l� help&` C++ func���RA6Espq up� loopyw%��c� h= p m Z:� ��i�ranalye��w� one CPU ,2_p�B;7"2�,��z_pairsR�!�a�i! � epen��dsp Y�K �f�W!��[put��ce�preciO axN�� �r�Gd�p�@�� of��l� � �s vec� �,R�&� )[^��-3ed���Acc5 ga�SeE} 5 . 1a�. �� � defa� J$of penalty�ame5λE{ qF� .�.2×logj/n��4/n . To illust� �� cyfM�aE�am� d�!� s:` ��we"� dQ upper tria�la%��� × pE=�ΩI� diagh�h beA4�Š�$probabilit��� off-Z=���πE�I )Z randomly -=0 . 3 ,6� 1 ��l.~����a �.. Nexl w��de�symmetrTau?eA�bottom rz block%S sizX2×p2A�s twic� NM top left 2 P( F,�in ed� to gAK.� -�ig� �n)�6�by=Y�!��Qa multi��te Gaane tribm N (�DΩ−� . No6at�i�� vert�� high2�byeconstrui~ . El�models :&� comb�io7�oeos {π� , n} w�(YideI#ur)si8Yk T�� �U�q7nderly!%��%r�U%8!� \q�!. "� :?x)�U�9�100 �FA�����v� �F��� m�nA5compa!1D���truJ�j�9on��WL(d Pearson c�!,co�� t ( PCC )O ChebyshevEI=(Disa�definA�kgre� t� alo�y2� � )�wo�OEst!�� u>ent�(". !9wre�� measu }� !Z. Ide�, a good1CAoshouldAs�large%"!osm�!&%.U� show)mee�oof.�e&�sBh. I�how�at�! pa�fixed ( %g . 400-�� c?)!� gets �r���er;l^^ or 8ep i:eturnsM6gbecome�� !!'ati6�t$ s���r l ��b!�bet�!8!�S�of &6 ��e��aa�.m !�of��QP�B� cEb n��aDn" �A��.��.:�! , type I erro��}�K��ll��U01 \�ou8 � . 7r���2� t!w��controls6�k�ad �!.�ReceixO<ng Cha�era�c ( RO�Pcurve?hpreP!�e�� -posH � falsBt%Jou>reshold��0| 9-�ed9a�!,truth!Fz�  non- : � J9tk��\]Area U�C� ( AU! to! perf>1of�A�a%eq�<re27m � 2a%( 1 also lis-bE`C�~�Сll=se|� enou[o dem xES!� 5�MndB����eo goes}��s:�IBE" indic�u | ��=� One:�e�!.� }��a!Wship am��.�&< .v ha���= i�nti���FTvia' curr�ravail%�a"�af��cer9% -dri^tqa�"��Y}xa�ng l1 ized�a< such��G�!�CLIME-�reporaPM|.�{w��,�Ta���an|% tral z�"�Honorio|Jaakkola> l2 �t�9}6��С iYedRkonUng%^�)l!to pointaS)b*�sua�R�p6�"�M.�.`by��rI1�im�va�t�savq�J'lexity:AV.lJ�environS\& �MM�YY of RcppE^ 6 &f. Oi���!v ,U2�� ��!�oJ�im a$��VA�_gl[A�EMqPt  d!AB109A�2 :&�x1�big9� }�}m X� U�i�Pal��� .� n"�m�isV�A�|$M�&b�!7B� �out* ��� leu��� Ŷl8T J�!2We �ed>��public#�"( microarray��@, E-MTAB-1425 [21� ����d&�0human lymphob�a celle�258 asth�%c childr�,d 134 health�" ,!e-W�\ global �A]ciI S �%!�disease �A�� !�b�nY-Ndownload�+he b���"�$EMBL-EBI A!HEx%]$�& [22!A�averag Pe )�/���1"at�� 1sam� � eachplxT� $we removed%,m� a!�n��standard�-G rank��!40%"d maV���� I49 l.*filte:111 � [�ly5�ede! ei aw r5�%( FDR <u.eun"c&T%� !fg"�!��"�$of 9 , 938-��Q;GMR� AA� �p oc�%nga�!z�]utiI*Fx * wo�to6� r5 GGMe?�~F���=�e *�1 ?�VJ�sE:^ �OMx�5�A�u')���"� �A Ven�agram!r'�"��2�">U�" 2A )ő�s1� ,�� X�g�T(L( 11 , 139 vs 8 , 37f �4561 FE�)lap�), ��og��a� � r%��#<.v2�Tse 8a��s� !}s�'n�8 a lo{�1oc� %C�A�!Fex<i .�&� 4nearest neighb�(>�%12�� foun�~� �w���$2B�!c{ �1�A�isA�of 276 c�eM�5)a��-O�%nnB# sub- Pi�~�>2�5453d1�obs�+!��=c la'of �iaɔ�NADstrong� �!in�*. A"b.� ^1� ;&��p���}�"?? fu�,e��!Q@!�0tic mechanism��bQ{%refQ EmerA�1ef90��quem\�ep�nE�y+n�!酀�&��#�.$�#s^ i�)%� visu�# ��4�=3 hub\��ext7͗ thei�)6! /K�'a5��]jxE�incluO80 A�84-������iM� , m(!�� ve b'(" rele�'�)�-ex�� NF/TNF-α� a��(-inflammato.. ytokK(%�!d%V��"�� U (airway path�.c'� �=nd anti- |X*�d� a pow herapyIs �_f�� [8[23]; MIF plays�or� " Eimmun�tho%B� fH�promoE:of TH2�i�&�*��inhiba! may� �eu�0be.��4];� Ul CLK19 { �g*�*� reg�in alveoy(macrophages�4diesel exhaust��c�a chY in;+ aggrav) pulmonaryqЁ�A���5\In"�  ,5cJ ��%S`�euM%9j".�-A!zc�du��oflN� �A?!y50M!�eluci�-f� physE�y!� @ ?g<ma hom�a%Jassay�9 tripre u�-nFE�a�bl�$otope labe�/m�lW#b%\� �to qu�l(fy 283 pept�)�1925W� .yeiX�s�9-��ory-C�� -E�is� a0de6c�!a�!�wk !�!���h �Ts m� Y+a�1���A�Y�mn�$1e'�3of2k"g(� ( CV&� B�.]/T%��%^v--��!,te�:�(.�6I/rp �/WEz-�FC2"a��al-6!-p�%Q��![�:�.\$ai� ��we �' he�CJM%��orA� �4c��#| f&mar�J�Մ%xa�co-M�b ��#or�mjheYp%ZG��$ach ( WGCN�[27�"We��d bootb)pD egX sugge�$by Schafer"�9fhieve�rel�7��stEK��[28."�/��Ey����#( nu9E>:�6we��200�9z�freplac� �#!�"B graph-GQ�AP~9H"� m�dsG_ �]a� bagged� NW�xq!�AD groupo��is2��B���I�]��Y�g!�Y_ hier���� x"q&A ASi�on�-F�Q� ���j":.,* "�'*g 4��0& e�-pq0-sj�"� roQ�!�he6V��NWirEI2�� �)," }R6 pow�!nd �=um� ulm5, both53!�7>�. W�b���i�*,� ��s�'B� re'��$5'&�5byp>��?�+e�=��%T��\� �At H=�Oe�!]~�+so � ~se2Yi�:>N-!�bzI�)ntr�/,�T!7M\.i.6#�Q��!r� �2f b�& 3 wj�" y2�= "���B�/3effX ofL�3ex<�=it � keepi~js�80direct causal��Q�#!�&� b��"�2V� !��� medi�� )� elim -E%�4"�m�� in&e(` Ae! J 2mM�ŮD�6i R]�-iY��sA��,uU-F2A�undm$udq�a �"M#k�(0+62-l�1.:�A�Ao�A.}M�6�� i15289 X�A.:NhITeh3*E'top)A�]�%Y!%@.bFDR 0F��> weakR}7 ctu� ,>c�$lso kn�-as�17AgLsk �8h/rriZ ranser su�ami}rs sub� �<c� liked��� yloc�ERA7��1�gMEE�5.=�/hdw>12��s}�A3�#�3� alF"�"�irI<�,E��"-AD6�A%ey t�SFexplan�a�x.� phenomeno ed�&�))�&�N%��+.(N� ,&�%��:�?�!q�aŅ%ze��:��1��t� �#,Z(aduFng @.o,":"E+aG��2P3.�m+��Fkn�?"�fin���'�1"a�- � "s �340$bd#10 uA�dG;*o�a�#� situ)�&�6}u and/o� &29@A�� ,� � $'*�D2�res%�� echn,i:u���l~"X5X ic "�H>Ta�o . J1C��"p�(un���J� Amt F.�� �;sZ(ase�/� ( !��a�c�"Ind�;,. ��nct s�)��aR�I��&('9 ablIS2�C�*,8�I%���FaeB ���a#�!��h��@c�Jnu��(�2f�G!whole-g�zP�I�E�c��^A]Merm.(�n�|l� 4se�-�'&�)sI�,'%�p� �&MC6QU��P��wength�] "A�a�!@a:�/Az5�� b3a��e�a�(mi-�2� ur �rs�`.PLprAt�r �� " o�#pN!L =�>�[aOJ�?s=o� /log9G.ZKiSny *�h� Q�L�(a"of se�CqKgs�Ia�J��� cA��L!x JthA1T<iGV�is vi^dL@�w�->a�pp��.�F�a~�*QB!�&{.iT��kal *�>B.')�� *�M e$6�#h!�J� ͬ�� vali�I"(Da�AmT �:al~amMo;� by�r=�qua"A�aGu % -Don�\�X�F,; �l�lb� �#��itect��ell�=�act�Gzb\-wipM &� 9�Aϱ�.�,,�o7, A2�!�b�5�s��"A�g mole�.6�"��lex.X�es [3��-OwObs3pe� lyp�atif�novelX mark��orlo�� wq ���DeCrN:f�7�2nco���of,=f!��8 nicA[K� 3 cancI�@-al&s#_+Q�w!���A uilt� .I+5�����Q2$�esM&��frame�1�>>IQd�7�`�P\6dg"U!t�*!��3+top5lv$,hu" 1#Ŋ� A�oɖN$7�.&EH~ ) a�Steae�hL#cJu1�M*���Q3�Ie�#"�"b%im�$=y }rigor68s��st� �"� u8Cu(6EV}&�) More �bb�)1� r-�� "� ��"�9e8a;%nof{" �A<H# ,���..�asA/*u� noisKM�'!x���*�:&x ��i-:�" spur�9�(�#��equ�7�9M>���m���OY3[2#,30�( �A�� C ��o�4�. ��s cri)� �g �2�Sat�ir�I\rapid �2ce%2����(�cb/�m���.�I1<Z%@i�!h���ea�� sour!�e a�id���r candd �c�4�LA !�. A"�9\�[I3W�G �E�"l�$�>A�op�� �VZ�4�@few pap�"�.A�d Q�%��o��v1Oci)@QTL )),"[�u"6�a%�# :cs:�A�%�&<*$ )S!A/� pretuJ�t37� %b9)*�ErBej8o.1–3�(�li�t� adop�!Sto joiy<%�z�E�3RNA-mRNA py -�yB�ass73s�� clinE5outA,5 4�&T� a�A�VC�!A�%V%.eW ye�Gyo&sc�"m�cBq��@i\J�1�%�F�� n29W�.�MQCN�>DP�Y�magnitu�1A)clo�$c@c�%95���- �i�g!}suco*fuA_Y�.�S2�6F��!�f.5z� a���wer�#too]CM,�f+� L&� :% ��- �)�~52]]���.]"�-"�!e*�<�],be�,/7p&Run�Dr"��s�!i �I�ulu�AR`:[0�?M�!� quie]2 one .y� �I)�&�=k S!�.J�� ��9e�J a(!�Ar�]�y an �1\'� dynam!����7sA�rLle��>n� tAv witc&�?%�nd5�)a�2�-,E�==Cwa� "�M]a���e in��� = ib#�A riE��?l 3� � ) �dog AND6��3V�s�V�[H�O.�i�\b1�Wa�]hundreIf�/lisTXs�UonW!!� -xChistoS:s�L play��ong@:q��vGt��We�+� tre� a��5��$��,����Zy�݅�A�T�^�s��!�F|�o\al!� �Js –n#=to�(tUb�!!�a2A}�1 m3x�6ay<��]n,�<�i�/o ua(Nl �9�Jpea4 Z . Ra��%J.275�Y�5pUE zM!�A oU-�.�excloUht3���Si�I)Y6D ( BGL> sub5#&Uinvol�LB$%A+2X����= Z �omeHarR]"t6 �&o����� l�1�reM1�ro3�� A�cerebl�exE�a���a�F� B:{N%i u@RB7[oxf{"9DX<��7te�a oughA{!At�Rimi%FC$!iv�f�$ s� strea"`BG!R�!up� ng)Qa�H,)tud�T �)F��� %'a�p%%:�#�$eTMxY �*�����2puzzl�. M� �_>e !6b�!�iLiY*= ��E,�  !=2�"V" �)�di�[#���u�6.�A�� �;�:�&� !�}�to�!phasicE#%ߡ����:�=ed!��Ba�} [1]–Mrewar1 edic�-[4'�/SD1p9�4vid�]� 1d5i-�profi/� �� eaksF+�<y�V-u\��off � broa�"k� cros��w# ��trucAde ;a�B! �8�1&J.+.~Q�%g!:�i.9ssu�Lin-vivoHM5� ��,�T� "L P d�!hE�lyjR00/m�ane��� � [jNall�M�F[1mEQ�AoMncu��Kthex RU) M�d,� i y5�Vimi�;Y]�U&ht�7�%mE� ���a�j%�V�'��&`.�A�p�� terfacNth� r�5.6�d.� Ka�� y<� �#!rnt�'k e�@oG()$!C hyp����M�.5=�#l� �terU#a:>�. Adl*R3 [13]�a��C�UFnL-N%.�i��P"� a�, � i5�PA[rAt���8`&o!b�1s�!`�)S���d#!E�n�e�c;Y�1EnAmRF��m��/��-f7E 3�"��e auths<s� �ir9�mC���YCu��CBG)�a��on�0v�<tiQ(ly feed-for��2� *��Z� be uxno"�dow��t};W�GP�sSN�d��lL1yQ� N$o�!!�ng.zFn%kas"���I�cq�&ŋ2Lm��^er t@ y*� ly�a]�e�B��P,�l . Ce�g�y>���e� �"3 6�O–�J." R �1v8Y �()>*a\o� d�[ s�4ci�)"tl spik!�.?ion�0E �qA�-Z!bfi): �I rec^���a�q�Apsp�q-ђ��U2q�ŋT�&ce&rabrupt#p*�2��I��M6QI� �;�AM"�@�h�le<�fF ��A�nRen)��n*n* �}5 e�!�].k� ��! Wed /- abov�r$�#Z�&, ‘balanc�8�*m,��)*�1~��? AB1m��!�n��2)l06�M�A&���N�Nt�����=��l agre��n">%� 2\ @�."��=st&�sudden ��"+ ��ɪ���$A&C �22�abFo chao�V[�8mE�w uBgE(.�Azc'�;y)[q�re�c� R)Å^ �9Zcng86(!�f'( PSTHt)��ŏMgW��F!�f�e�AZ�is��"�); "J "�!��>`�U� �� U parm:a24!.ŁEK���Ea�2�"�!�>Z�K��E�s�9� �"P�K-� We�� cussj �*� U �P_ e"�3e�,R�EWx� recruiE0��sum . �;�%e.�hUTo��fed2,�u.0 0m�R%�sehc%�y��.�aoM�Y4;�Gmi�6@�m��� rw��PJ� �i�u�Aj� t Q� �2�}x��"� � ����"7:>�mBs2Y%��ɗFig1 ( a )eˁ�a� ��> piPa|2f*�r*� V(mo�WsuTGL a� {�߁yprotocol��wo*E1r,�Avac� a�$�T!�@�vM3{x, � ��bt�fa��T6-w��lDCe�V� �r(hb�� �&f!(:�{J�*�B�nd �J#30as�ycolou�-"u �AO-Hr$N*�IEG � i� ic� sbm�,ooJ�se$�� O�&xI)ly���-��od2ir���for�()u��Mx �d� q\ �  d�wAuaFE ‘��’�v . fic epoch8"�M"� �a���^p<0�.�!�Y!?AX� a�%r�i�E2!�'f�Ae[(i<-�u�w�9?ie� two-�� � a���E� �Y� � 7o 8� S�.is� �7C aGE v�*eo!�.w��aFU����!�r�����%ue��n�|�mTXmec&.�|a�^oLn,Z�=~4�-BC�beV�F�J.F� jk�ruc� by mov!���2 ?seg�MM�%O%���� t@of� r 8� +it��FE.�}Gic!�M I} mf>p�4den�\fB� �a I�p|(s � )�kB�SA61�.}ribI�!�>��H gi� q.��N,� � us A� BA1QMZ� se‘ p�&sj@�6)�i) Ame(�-U;Z=A ,' b�B��!w drop�+f �-� V!�saE�!.� (���XA;%d&M���c�$��"�-}&��yi� du�v�(�"an8>be& dwBB�!(Q�:�5��* �I���r6h��us�~�j elap���D��]� +� �`S!>�A��1��"E�!�!�}/ �x%� n�qt� � enco�C�M�aU�] inB��4Q��� Y�AUA�]!im a�|f�}A$^@B8AB6�.�� a�Sase�&�)bU�1�5m*�)discr3DM � Y�N(�H!nQq>8s _5m���cM}B��i��9u>�" .>3q�,e*1�LH 4}al�s � .,��F�E��O&:6k� rW�.c mol>�X"i �$"�% � a� nW 5�i����F)U9"� xI�vts TF�V�Zlh2=!X &��xZ-Z� ( excep�e& flu�C� � !�u��eI�!Hn � AYs�+y"a7 y>�. IA3�X �8N("os��)AM!E,$ci� }�+y.f)<GK%%!�#ż� m��k�le]v@k 2W&X Z��) �T�!A�6��&�EinL �iI� ��$�<w'�ADR �v�8!7)�m�% ;iX%u.����;Q> ��mus faia-'e]*eu+!��e.ur�UP ~A�]t a�89lj�"x/�i�u��m/d)�!(NY�Ly��� f�M!29�Q�"v?@so�a in�|s cJA/;&�A" � Sup̌l T�S15/�b��e�|j�"�_�zpre!0s�i%��:��vPlloF wa�}Ђr� ��e5%-y `2�A.�"�7Tk 0"+Qc&% \ .�2Y2�5oa]�NR)��d�sit�A�!�4*��w*k/���t�D? I=-Pih[s���2���* "&.of"o� ��so1�&(%��x �%i�1faBU%M�5FeC1 !!|*{"of�12�Ua�6�i;0� s�=!xsa�tE @?0=d�j�E,u�I&;D*E*U0�5, Knt��"��A�I��=o"�gX# F�9depDa�,}�6�FfE&/ XA�d!S� �!��"�'QU�rb.l�c1>vi"�2AKJ> oss-zs�p�{]���6a�T)"�[�OP_][�5��Y��180"�]L@ad�g a�M-e!Ž��f9px���h�a"�!))�q��%e��;iC$ �6w苁����. Eac�"�)�q2�&�${)�3 dow � e��`f&sOA9�] �u�A�p>Zat��O,-dy 04 �� W1 a�lag�r!5-�!E� oaW*j���9h�4x�]6Q"�"�� �DC���(a��.7=A&horiza�=or �j< A�l?LE�g � �6N�x0!D��Q�A�as scheP@��&T���:,)I�'=�A�� �i;I�afg cyanf01�}�b� �nar �5GI3.�n�Fhal�mY(Eg )�޵�"� de�B� ydec�F'��ackv[nd� A�lO��!V� ��&�q �dF��6���I�&wF���#5.�)ela�X s2!A�>�����jg ~ �1�(1�A,!.,!~1& �"�"wH/ 6�Zs�Z#�.6Z;>HM�e��',.g 3�I>�i� k��M�nF�6P�Ie~�E5�-c�U=Qre��nQ$*�1w(/V�- ) ��c�gly�kU��A�us��rN ��K�ĩ�͂byB�,_%isB 69 � �U=5�GE�*? .��8!�lsR\0�HlI: �b�`i�?.�H�% sY�:�&�]%f( blac!�. AQ�%I~S`:Qg�zI�1�Q��#' �pU��%A�'!���=a T}�6q(q�)��  �u�e�6��R]�f��.�� �as�)�i�!�mV(5)L)�*- �E�r"��a"S I ub��H-u)��r _: X0 Dib$+ AƐ1�A!��$E�a\9Ce��`! AG�.ph��- shar�Itb-x5P��2}���;u�AV& �aY�mKU!un�6e�~�a.��AhKinu�6-i| We nowB�&Jf NJ�&2� ��X�we�e aG =�'vn2>w�# �X,W.Ff7�b*ڍsP� �!D ��^@S�h� XI4t#.* � ���� �aa7"8of ��d*#5r�2\"2Y-� 7 .� yO�F\� �A�a� Nɭ�a� %�*( �of �K\ku�Anea�S>�"VfI.=CHG{�TI8 Ea�ov�/* 9g�nd>�,���M"� ���N�.7 :Q 20t )y Q]M�#:�!!eM�t7is�' �ju7i�e� z%�.�3���t�96W,�ac�-�iN^ J7� �2�i�ru:�0�V �!�a)�� 2>ba de8-�p.RB,!6�X�J%�an ��&� � �� !� ).�2<5�>*M}J!%� �6�fe�==�6��./C5r|" ma�Hp�l`=E2,"\ wD"�.&�-:�� pl�u,������<o��=er!�ay%�Ll�7a�g��Q�%7AM)2v(e(g�?1�Janss*R�[�Q0a��L cours�L��A��a)lifrec� �YI30–40I."5a�+E=r�{!�b��3inŔ�O45�A�/�x�(&�AR s [3�<ruG.��&� wAU�  S].`) -�!Z&H���)T.cl�n�-s��d!�xaM. E5Q�EŐa��#H\=qYo `�g!j]�Ne�J"(L�0[ ��4�5Ga�M�"� e .2�N}��m�}����6�� ��{Z�Y��B�2�4!Ї,�ab��%C�"�2��rob\x� ;%� i{ W��xso ��j�;�i1�1E"�6|��A3 ,��7Yp�1 �4c~n���n&�+g�{�V�_eMh�6a�6�롐 e��posts0l� ��� &��7$ Rz������.��q�A� se� �-ak!�+�r�v a��t e>/ . )��fix|1f���)�LZ �55�-+���� es9r9�:�a�C#E�\uc ��2�0b�� �.� n]I"� 4 ��� &� �fa��.(?u�s2���R5�-�v_ԫto�"�H!*� B�UJ)F*�1.� �@:?.�f���|;et�4  �%%*�H"in�kme-v8����`*� � �� �� � N� )�J�;Y&3� a�Y�u�=i!�� ( `E%���Sb� A9���eʡ��&# ^��7w&Lll*�a�Q) e �u�&�&��;J>�re�a�- ola���KX�i)".!Oq%/CS J}(� )I��r�K�m��!� WF��7@Jw�s}|Bp"2R�6�&DG �-!e�p%so�Z2�M ��57^mx��"�6-#�#bKTm 2"s)� -��*���We` �"� ��2�A�2�N a# ��NS ٹ-���v!fj�x.��>Sw #^�b�3w !��Os�IB2�Pi&>:5��V�����*%�n.Z� m �?��D "�M&�#5RGa�q_.%���2;?(� 1�"�*ng ) A%t0(��B�)22���N�(5w-ae�k��-t,e- S�( ISI )&'�Ea�T�>a�(�L"6"� C (Ii�6aB168!1�Z��*��6 R02�-QgEx?hB�SlA�"@)���I ��#`Z��ISIS �b10E2�V1T( 6|er6B!�����  N��Q$�s� ner�  ) &�T�U�R�1t� 6$b�f9"m+&�+��T��(anm" a-O2j�  narrow1v9" ���3�:��,'� I, �mk .�"�"Q�"_I��oug�JflH��IE9� � 2�=fax:o*y4�dw, 22!��&�[�~� &�~�;'sAp6?cf�6Nel)=r�deE�*��by*m!a�C) reveO*L& �.pq��X9�"�$!I;b}Bn1K�;1!���dV #E��)�"� w!yQ�2�!3,Fo>�e�2N)�MC��F�-�Ihm��/�e jHg��fa}?h�{��!|!�>|�U@ M6l3jA=�!2@;��&t,'V6�mdbG�$an Poisson��(� �:^�Bw5E�.�m�1�3�.A52����^P�Xe�.8F4�n:�!=CV�)��e:y]A��1�1�)�J[t�Yri\M.�o i ��bra"\ly��e�� m�{4ala�:=.FW�D%.� �0"�a$5^��&�f���!K�Q �2Xb�� !��mW��:@WOQJ.Y p"K� 5�� �m� 9 �?!,�s5��A�{aI�aA�o*x("�� Y`< A�%"m� J0,���!#^B1&�A��* ��G� 2� o\� &2�G��@ )t �2��� ��Bpa6&�J[*� 7��AT�D}I�2BA2��a>��$t�:KI \�!�m- Jj2��ZCŴ85�]sj� " dO�0B ��!4er/E)�ENv<� I��+Y���B�ams ) ��� �������*� �g�]� nlj2waLfa+�҄�:� ��� �%9ErN(�9V" �������<.uva,{*.�X� �k1}�q�Zec��Y2�:s&k5"���&=5�28&R���!=���{B3> �1y%�y1Xpp��g"�aZ?>u2��E�Jńlb&�Q&E�dI�.]�l.� en1:�1���V ���lY4 ;=+�*n)&� ����l�W=͡�iB)�2=5 ����������lsoMc���CV5mrzl�Dly�0an�sty��6�AFi�W,;an& #!�mS&.�LM�L!���,{ 6́�F*� �u�")�t�b6�56�)* ~B� �%��-jT��NT�eQ� Q�'.,U�^�J�� !s���q�Yl� " F�-f(�eemo"�NE�%�6KW-Vi�a�q�e�2qs� chi%lq�`�-ly�}�,)��:>�)W�M�#-@{s�w ��d$��n ��">L�i�� ���"c," H%��<ly1p`R���X�?Mi�f� ���ĉrp�+&�L�"�=$2a%a��� l,B�a��[M� �C��f&}�bB���y }rt�7gl;  coincl��=���>� ���B��l �b)�Azess2q. A$wV�'Q"�2��R�}M�!��$*�l2� :�*3N��# nqJ]" ]"�f$O s&�;� !�)Xy2l& "P .�F���6Dnd".@m\R;�[ 'B�2(<u�>?V��!:.X$� bGmj8$� �F�$�Rs�MUr1 �.low-pass?y`�re& KHEB� N. B�p����!�,��ce��.LD�..�w�L��a�<�%�)�}9{IN+W �� �T6�[!�- �� &3l�A���AB! 1Bq� B�:�=�qf�s�P�P%�C� �&I(.�&�* �t�#of�&"�JD%b-M���}��J�C ͅ$�V/fvI4*�A$�"� >�* �wE����( '��$"8P&��TI�A��.8 membra��o�J>)���vx ыqӤ�=v��<a$�I.9AE�B G)2"M 7 'cir9�2.�29� B9)�2� �;g,:1A "��'}"Z��E�� A�|[�I�z@.�)�e�>ru@E�eŗ� -cB� Ac:��&J�,9)y,%D�diamo�с*A1!ABJH"�.�.+!;�4z�):Z�) 6�#:�~!Ze�=wC� :)�� �.5́�D�e�ng&ԅ��en�dud��j��$l Lyapunov�( ' X6qZaEj W tp�arMDEEB�6V��8��ipo� �LA%60 M`2;" ��|���a F0�Z2t 7V&� q|�B��I,] � hEa+ 2;^�+!��0o[^ B� � b��T<2�4.��BnC ��J _ �C *� & H V& 3a�r\"Dv "�99�(0B� aA�52Cj�}�‘� -of-A$s�T[36�g3�I+�M���Ba��R�)��P!Js �� �0s&FpA��,% �&�KMta���ar32e��Us^MtT2�E�*�FQ�� �!��Eg�`� A�)�,U�y!q�cEs��w! Sb�K_&�$e���rd �g'� �=c� �Z�Q<~�6� *Q �b�O�Q]L�a�.JT>�w"� �z �3twve�dlC%�>0*�"> i%� ������2cV;)7%��Rj!9~ j� !�j�52� prbpt+b% �"̉.> aAJ- f� *6��R�VN>zC�iWM./f�]c����k5�ns� (71&�& �um%�L*�y�A� �&L� �F�> EdisJ~m&b.�6'�"k �,M@) %Z.�` I�{K�*a�l��a�X�l ��2���� ^3���b.*�] �/c*-�6��4"8+�} �&�6H�6M]R�+�l&3-AXq;2. ne�^��Ed>.�R2�qd>����i��$o�V&~9��E�.t�tED*�))��n!�(�%� elli! {Cy2� @�6�lcј��@^�5Q����0�, �#�2q6�e�A��*�*u��.ki�Zf) B}P�ur3K�=�ea1cB9k-meaB�vT���$ mplo(��f:m4 [��sb��J/ ]��PFG �Va�$6[�]�6s ) �c&�*.t`A��8�.&�+E���.T�2!I`�M . PC$^� E� [40]��oJBR�o`�u�^�}J�*�*"��)� �n-�ri�"�,r��"�~8w�!)� yi+ 9B�R&��e'�&�f. L�):��M)�&��.+� MPx�2Q ������*)�=ng&�N%<wi.O���@�E�RGx�qEA� r�on[YrO�(��!m��. Ua�S�b�C�):�ѡ��!�MZ�����0 �r "��(pa�� � �!)�[4z42Wp28�, !�$l -�C%P*[�(4oa�5�&UF�gPB�N,as F�!"X2G!�!��-nOteV�&�O!�O�#��apWk��ɖ&1�$2���)>_��r�,8AM5 &� %b���m��5q�� ir),� .A�Y*T7W{__��?)�A�inuous��tJz!c��C�_I �+N�"�W7aoi�'));%a�!�a!%rtE�od>Y8)_ ��^����A��+-e� �"� �Wt�m�/��9�5Z��!�T-���+) wwƴ��/v�z)�An���,`�&��e/� J�Xtod�f��l H )$�I �J)�( ,5|�f. Lo�� ��E�E�A� f�e9�6,nPz-��is5B��Fi".�A.u~2m7�Ot�!P*�"� i��lJE&�Zť��>[k-)�&�`� [43]� b>�&�:# �U�R!lsioEu*�O��xU�� ��g25�6M�*>)��Zg"�xe� �G7��:�@i��6!x��B��EO��>��Y6q:4� ���E=<�pS� �V� IL��<� n��&�=�Yx��S?V)VTK�/ �mS��ɮAs� "�4ԙ�[�_de_7�' PSD "�I-$ou��..��0!y��:Qe!�*kE�u���,at��25 Hz�,m�t�� (u�a�<.>= �F�?�E��1�& , R!>�7)/umKYofGte noGt. M�l>|&GS!�2?% k8X��aU�hX'�� I-�&�}���2�s"���VB}2#8x�& =�2"u4)��O�� �bY<-walk �2Z)�p� 0@Gt� .( 4�I(i *� I75V!�� �Msk�)�.��� !]Z]-�rb-e�H�UNUaX�UZU[SN��U:CdAe� �Hz�7bs�!�HzM��o6��j AA�-%��2l> �&�y�N�bX%��)p�ff�w�ׁ�*� � ��3W�6A2�!^ ��i��ňTUed ��;� :�A69m8]^.<e-tJ��2��b" �5}�Weeu."B $�� � i�s�P�V \�N1�bo�p�X;��V��' F��"6`FV67!� ΅��4q}="�.��M,��I  osci��* v *��h`����\nse��8� by w5�&�JA�aP&��'� =���Ee:^�cy6qa57�_��Y�U"* � a� WNb�� At�c*���U�~:H/�6`�U&�a(EyV�_�/sH�QME��Q � vent_�� �8C 5�& � libr��Ii�Rr��!�u}"�  �*ap�n���2Kfq7~A�4..�Ath-���s���" A0{e�e2&" uj"Z5��2e�m�*rm9�e�&N�rm�}9��=%�D���+6~)|5��A6�Ou�dN  b�-.[/E�&gD� 2��> �o �0Bj 30A��SL2_y��1^�B}d h~c&��zi�402� 5S���y.&�L9E)�A� �w ( das��g4A� ��:J�"\.����_@@a7q��Ś&2�*�O� 8�a�)�lu68"� 6���k/&�݁up�����F ?u۪YN�q 2�&� `"[ ��R� .� �wh1 V@,"� )��tz�� ��n�� !�:�e�rYiA��"f� 2O5�AY�|��D&oa46St~J5eUH*��=Z�L" �N�Ia6� �,re��*�9qu�a F�(D�JZto|Fs �57�#. NE.N� s��f�h z'.*f,�AsF��� <�L�92�H�)o�!��!W'V_U5rN"E�pp�a����*3?���$w %�k� �5j}oY*toi:� ؉oV2W�W�Y&�\iaJ� E�V�"�; � ��#� �!8y population dy�namics locked to stimulus onset times , as previously demonstrated in [29] . We next investigate under what network conditions the reproducibility of :� �dy�Hal evolution acrossD,eat presenta,s of a given�pis maximized and for how long:�`le patterns persist afterO)%\. To this end we analyseY(500 cell ne�� spon%n\temporally varying corti� drivusa sec6,input switchTprotocol . As discusse%� the model;=�. DJ�aSost6soa�N�decaysA�re %. OutsASA�N�� rangeoilA��� weakA0or all epochsV�4. We also inve��A ��(distinguish1|depend�!2�Sb��curren!�_iAly��R.hAWrom9�v onIm�] strengths!�2Ey inca�esi�E elap�a��M)�U�we fi��a�backgiYa�*(A��@�.)�:\) gene�2by diffe=ie�s a��alNzA;eϥ�um occua�!XF�.!In�zY��2�IftakaF���Latu�! it�zal value�4o shed light o �origi�>te� opti5properti!�eB�!��a=i��5�of��.� sA��5u�c�ߡ% ( fl��aa0 ) excitatoryŠe ,E\��>�,.*Q��[ndo�E�i�Epa transiŵin����2k. A��� grea��tha!qisU�$a winners-!�-ailik�j�) here some%>(s fire fair� gula �!�re/ re quiesca�. Oseͽh+at lower.�-�% ez�`!�s�ticipatA55��`�Lin a very bursty way)b��]�*��>a�1x.��,�=�whe�;s haveZ1�, �se��Etz����=�=/!�%el- !8 . Inte!�ing�- both�šexorE�Q ��Q� mini��,, approximatp, close� I=!k mean%� CV � es un��.B�B���!�Kz��'. CVsE�w��2� v%#� comm�observe AI{$[13] , [1526]E�ourA�ult� thu� , good agreemAb Z�k7 �p� dӑ�]/4in more detaila�.�a��plified#er!� stic� of2Y����Akm set exac� a�!h full N3re � to a��)�  e5qr�q ce��s� � al quanti�a��ll�=#Z��A�%�numeri ly!�put ��\@al Lyapunov expon!�A���| arginb st%��,6� chao!�m� O�a�|6�$vast majoraMof�.��(fixed pointY , especi�at hig: 0, ( see SupplE�Tal Text S1 ) . However>B�� �6�ju�'bov)~=�to% i�2�display�iodic�.  i��SA� ll b ksubject!)fu� stud�|FA�žE�ative"� ceu"t H!�rel -entropyE7�ZEbetwee)aI0 spik���s� %X�isIoi> du�^x absemHm�)ffect�ducedz ,_. S icau��noisy&�on��7.7 stat� hich re_�0Rmay a�9L �Ottr�i=��eB�alC|!� less�lyA1be�c&� ���q�. A��Ina�peAK4,e phase z!� ��2�2\ � [44]�%� %;%� ". D� AG�zre�?m��Cy)w�C61 ucta!�ba� syn� s!�a-�s i� Methods )�l ���oisa c:� ���ask���": o=!>ed�i� M�I� ediaqby �lYor�z assembla��Fco� Nlow*;!"��T6�3 we�ly prin@ l�����isACf=n� serz&� �� 100 msec ,windowA�e��i��A�J|% \by%r�p �� popu�\a�of�%���* R��!�(first threeN9 s Jstr.l%y � �%kh"Vcom-NK�U A3\� whil��EEtwo ��� u�� us �%�NQYSappears� �gA�Ud�s rapid� lax��wom2p���� eachY�,����eria{J�us5It�� trib��mr"8 Mx�&2 y �!�sa�&� de�m. H Y6.��C!�� 6�:�5t, pea�at o10 �>a2 ��e"�y%�UB�ue~iU�de-�{ of��t���j)Q��inhibit Dis%�_>>�nea7eM�u.�successir vis�&�U�!�6 ���>bef!�event �aUaA��XiO�bfur��92yeC�bec�uPa , wavppa�a?andom�it��$q���N�4u��O�� ac&' TU�g"@�%5� Zn :�Now� &X I|�s canE explained�q� frameworkEe" system��orcT���b� m`&� ��B� I &�E���A�M�o neur�. R/(synchronous0a.ir�u==&Z oscill� ���f 8[45]–[48] . S��(linsky et a� [49] -2�kE��aryh I�K� { ���� onlie}el| � teA3Aoviadom�8mmetric couplin� ��I��l�A=-�2' � wa�n�b:�� o� "^ quenc� n�s*��9�).�!.���� sx _ cbal ch�s X]=t ��oryH ac�van>by!�uddU2ISI CV NaL "� zeroY��lar"[c&ini t� a�-� limi� sparse6�cork A�in6� io (a�� receiveu�neglec{ P� m }��� ��;)9A� 1~� describI�n� [������� � calc"� do not�� 3*�6���bey!thti.� i�p�.n�)�d ����Afar�ia !�!+de�e *����� ��:a�� .� BI�!:Wp��I}em� �)�� ell�IMoreop�` W�k� u*G their.�ZH�.�,AVpa��ul�y CVi�ui&�]!u�0is Poissonian� ATZ:�is ="� ).�P��, sugges �O1��be��1"/FM!�J aEnt ����el� t�-� ET�Buckle,Nowotny [50].3$d a bifurc�!f� p�wo����Eq���2 �F�+�~w��(i�mj biolog��JT"l(�9 5� )3)��ri"7�l � post membran� tenti�^Ta��p�z ��1ccoun!byc:[51��53��Th�includ%�_.S%3E"mi"t ay��_!we���L� yS��A�.�& glob%�!�*���Llo-&I%S=�Q�hasN>, �iza����g�^  %�.O�Y�, pulF �ibe� a*cri�"$phenomenon��rt%& za�� &��.F� a ��e9o� c=$&C ��W�_6:su� �  ex@s"* � os���-^�m�matrix)764extl ���y!@"� �1�di�K"!�ݲs�9������2$b�Perform� A|2 !�< ����$B3n knownaL%‘edgn ’@s �!  �-� F� m_`��5�[36�39�I�R��� Toyoizumi%C(Abbott [37]"x� alyt�9e���al-to-Xr���+ a}D-ied1��% verg!��u:)*e+a2#�Fmem� life~s/-+}db���xeyc5�i�O-�!�!@, ��dy�� ��w�fu$L llowA�roughrnx scenario1ur2� d&"�d!We�B�m����i�'��‘9h � downA{y ��B�|$� �)4Ua2#6�!d_ (�le�)!�ors|m�V�&��!i��e�mplexZ�-��:� �<�Zickc�-~"�&� . F7 �al!co:A�Q� 0s�,ul0 maint� Ёw�(dimensional�� �ј�x. I9#�c�multiple*' eY[� e�el8b)� min� o T%ecRe�*U A]%�)h. S�)B1���Lforcedхsh%*be�,� 11�2!�5�17+�� der A=�"� f# ����DFFM�I !fautonom��ih!h��i*��&:�lso�n�u�'a� ��XM= In �l ,ic"�Z �lep (Mtoq�A�$vice-versaAri�Rajan*2]� r�Wl ��,-���supa�s| a"E, �!j�5��)frI�y-0��$&� �a�?��"� U�!�%� 1[�$-��:^����0�AM!gnd&r &�!be #� ��+aiy�is" ezly> � � �wq= �!p�2 �un�y��� deep!rAg�2>& �,.N28,u�Zq h:j�%->U�)��.���Qgj 6�a�+�B�  s.&0A� moU%=new:qf2(rs1�I�9���߉j!���a� ~Etr�myU h�@n�/encZ0iniEe�Yre>05Bar&G0Zg ���efA-� �� q�aUsa��#A�i�5V#s ( Fig/8�� )��'��/+H!(briefls��!",1isR8klow2YWshort liL \0!Oi2e���a�"y ^b&�/I�"�$��2�� M��?MX�)�2nqo axA�$>�Y�5�.�, 8 e� BvicA1E:old.��R�z5m/ "� =0���!%с� enPnAJsJ ��*���2^�1=H��usaܹh�Z+ �E`��lmb90�"�.5@�V� �,:� %�:D/n�.)���"��c��>+."��w!+� ��*()�s does � c��aule�)�p �� na� dataW�e )  xal9d��n� , ���!KRF!toC �s��",m2r�asilyY�V4� 4� �0� = k$&� siWA�� �s��P%Cq�UQsP� 5�� a�~ 5���6��9ᵗl�0. T��y��>�:�er22� iK�d&&p�+a4ofmdic�S ��A^�c�&"& ruin�A& ��A�A_b�%spaceBC��de�9il"�6� �f��%�(7�� [54q�-6 .� R�wh3�! � ��&��gcyc�q( 8i�*�:N-�=�!%me�%SV�)"!A��2� Hopf.]!�@2a�7 n����%��U��Aad�4a�k>�n"M� fash:. F 7*y exam�AJ�%��%�~*`e%Pb6� vtG = t2�wa� of��a�&E"� �:p��_x"�u{I~o !�a� �" metaA�le�$saddle-set h!oclinic%�nel�s:���!�sy6gup*g��֡�!2!�R��Z) Rabinov�!2coZ�8[5V/56S�� digm!jV  ���.�V����7ma�F-�.�a.;98-� pX� y#ly� !�offY�x�4�S5�q�A�b!'&o-%1,�;Ptu&�p%`E2as"�(,! tiw��� -� d2Y&��e%e>N$,�m�!K� ��:w..�"�!!�al�m*5���I��sb�Q1�$1���7 . Deco�.7o158<yQZy&qo‘gh��eA�&?�%��6!� m_s�&be�9sAons�)j�����1�%M�)� �%�> G"L!�KMF��;) Q �*= �2aI�6Fuw��&F Q�~ �u2s"Se2OW-F �fac��4� �!of�މ��x-.2�. "����N�� �6F enA�5A����!-T[1_ .��et�ya I]se5&o�~�!#�1"�,�&�41%�7�!*�7I�pe�!G� �P;ow}�=i�+%�-��J�7,If��)Ye�5,6�1�y��)�t)0� e�,Ab�-� ��6clu�!} \Ei�5�� e� TuE (hL#�61�mhsJu���85Q�iJ n-t�@� �expj$SiC� "e�"�$3!�PSD! �-9m-5?)Q/6SdS�� 2nfv�.� A�X?xegm�� �#wth1%r7Hz!�ch�$s &6�'-X(log-log plo@�%AA3.�profi �=C& oftenmin empi�50�(�b�.s [59�61� Fo!L !\i� ogras�#�i;, retiugangl!�s \A#_6a�� $:9@p�: -law �gr%Io�$��or�,of magnitudeba"m9�*�+2�&���=�j;#�. ED�+gh %6�&��C�B ��/�;narro\yM R auth�%claim�Oo2f�)�elf-simia%ma�5>!|e�Imu � 6 . It!mGb�<@#er�&�%��aUw�t' AWYJY a�t�'�&*^�� aggre�E";>�� :. N�the� ��!��A�:�""3(N_, *�2�b�> ,m�5 slop�%9�!Whe%$ �ysy(6zie*D1�,�.'�0��0�(2q. A>6�s�&,8:Xu8If�Aci�+)��Cll� _�J� Brow�'moe8�Cr% 5�J���"[9d%;�>5:eWe� lo�[(�� .�) ��B walks [62 �-!��f�F�8n6�Ta� terval-eC>��a[�a)a �g-Ssec_:vng�va!�sOA leve&� !b D,��*n"� ��M�a�-���'�� >� �iO"`��� 2-ac���}"Yi)1}[63"�� 1s�]�9E�A .�Da���� t%9��!o�7E proc�8�w �+�Zy I tn. M6� deco~ �1_::1*)M��* arriA'!�3AF%j"�G: ���"�1F�)Ain�F2��c�9��rPAj-�K SD9)N , it&�%assoc���� � [6�9n�?usEMA��� EvX+J�"a��'aU3F�� �H �R&�X&D! WF| iY4Us;4�>is*on%�Er�k.2 | ��S�*"|KA���[6267]FQ‘� =a�3��"� !yJE~3o or d�)9J!6erI�vaA\�[� 1�F �&,w,. S���5~! ")a� V�L!�5AM��ior�tiot,&lsuscept�oe turb6�)�m% copic\uR>!'42C�beS=i�sm��ata~.� ���sre2�{Y)R�)velop���&� ��nd) � kK��a{ !�� r(M6 ! }&R ��?*�ticDH ke mQ�A��KtK>�?urm�1�, al i� m%|A�A�A�D;40�~ � .=�*,�# &"(A��H. AE�etI*"|e�>�F�!j�],16�2)L&8&[6�)���� o �O.�mis�[706 7�Ds~&-�7ens�h*mZa-geiy, [74�or�)��o~C%�6��3[3`6C�4,*� fs [75]e�"oX*pid adap ^��i2 dema�L[60�[7+80(S� organF5}1i2/ me]is 8o maint�themsel3MTB]u�f�74 �$Ag ?Qk�p�Ix<��mG �7L�:]o�v*w, pru�or plaakaW[3%�[81%8w  �. C1%"� �s [46 63A�t!�� �s�R�&�8�I��Œ��:� A� ��;Gbr!w[84E�87!�F�:m�� ?)�CEo 7ls�,2T�& t�@&X$[9GA s47��!�J .ca_$i)H$A�e��in"�-r''cs [92�9�A6�}"�4y avail���P�of  .�#R�A"�Tre�D�� Ponzi�Wicken��o�_iV�H�s�.. M; -vivQ(��A #D��of re��c:%,rE��Ռ cred.)ssign�%�� �ߩ�"aAS*CBUri=z8o-BG microcircuaK| e'� m�enc�f& �[e11J9}10aN e exec@� leart<mota�r�2� $��[i�10I�11��qu�Fv we cho�K*�0��$Oim 3 �!U�3"5�U�y:�",E�KJ .3a��*aR���."�UE3sh'�p�UM�?� �C�i&�n�9E��s��%�LA| m����Z0�]!�2�SU+ 2i1���i�7ars"of�?uaDu�yp}ZprMu%I harp" auditon  ro�(maz��!3!�sp�/-U���&G,���L1� 120]6�  ���,l� ut2!��!� `)�o%,‘f rvoi�uA  sty�o�� � !�[2���, l2� �12M�22��I2}#IXY�� ~#s�E�;E�)�uiJ14},pec�:` rɒ�h �123�p 125]AycXuseful� X2��[a��a"7;2Q�  +� ?r6�$pl��of �w i3AI�5� [12�1�Z� a/�!rA&�C�$elayed>C�/o� trolE�t�/g� a dopamin�Kg� �e��SZ��6OE� �+ar/ 1��"X  $i*��Dv�(>Qd�<tr2Uf �(A�)�*!2�A�& s [8I Jin&8�@ MSNs ��s��Y t]4*� hhI_ �N��&�7�M:�an#U�Ar�"�4ajI +#� ~did�'gprecise--��irŻ�i�co�"a�5=P �"2B�:a�$� A=1 s4n�to�5E� y=(add�al.i �;nee%-o� !e9�pU;��hadA���@ong�u*e�Ey�) t � intrins��ly1g"�V�1�!�bawJ�m<7u� sE�!^ ��%��-�7ly AdlerY��Raddre]whe�EI ����P�F2�Ds�um5"Fit<�H���e�9y�Cj�*��j%�� .a Gp)\Y�3cu?"�^�ga2>-�Boa!9"@�b�%-��2! nor ���E!�!�!����Rtyp�"R[d:Q9tonM"% 2>i_�E%gly�B �� � ct clus�JngI�� �`=uBWlid+�� � 5-��x9�}e�.�m � f0>yS��o�VOof3�"�.�%a#� )�����i�M le b.�E]�m?�i�@f*"��A�!���e�:R%a�v!�u$*�T%�),RL"!��� �� ��� tudy� m+[T&unl�n�b&A .r *~&[2 eyOf`re�U��W ) fiel4T�@D. C"l � we�74umwE�!{*A��po�Z�&nE coeffic%"� O"1�S)�perhap�( 9��(A�!d"�Kof>t�FŃI\!�=8z M�, �#MX���5�&� ��offseR=�����Wb*a�. �be� ����r�^���_�2sal!<�sb / 3�3K#dE[:���h .A��mod>E�nt�*�?��`&@!a6BsP<�_amBo ci�"t"w� *�5ńIB"� broads2u 5Vns%]AR1f�*-��"� ! &�#ESXd. )A%p%� ,N.Z,��dG �% �Af �%�aJ=�%L�Qsh�3!Stoo* �eqovaW_2���J_�2 �a smo���c!� &]P�^ episo�/bS]EO*�e�N$*��5I\tr�=1�/a �R�i� �X�pB d �aB!)���E��� !�E�� ���A�ta&Zh',qA�eDBlu=h��C1��  $~eS< h,hol��]%��0un�d� sl�W� �b ��_M3A)"�'�O;EI�ysEP"�2E�F 9 {(em�7ta'Y45no�JM�s �=�-"4SZQi�t͡ !?who�.�C� .$�be q�]�Gaverag2f-�;�G oppo!Hto_� "� 2�) �1zc�K,m�*�,%��~:{,a�e5wbyNk=u$ex�& *^Fi#xA���9 ced*�al�h� z@�.��� ��i���a< q0��8sQi ereo2 d [11/!�� @Gdy���&�ljhp�i��s5feIN.�A�5��K�?wco�!� �����Z!% o ��An",):5P�ed)�����-�%_d��@PP��6�0$kedae��<:)����2�. Levi.+0.\/[  h�v%� ato*�OE�"/���-I"�" ��hF umc��!* �!��< rHE!@�eJ �_ �, lZ� es!�.(T,`a�1��_0 !�!P mani2�LI%s�P*�O�=[5AOas�[ optoA-fF�~ �li��, t%�agex� �Vb�s! � _* 13�%Dn.���coCE�i�)R/up*. D#8no�$� 7p�ct�K��m Fano!�m��f5D�W) A%e=moby��&�1:E!).;��K< /iA�su� 2^��Uu�(�rconfix �\3oswnW�2� i�i�t9‘surpr� gnesR#o�. ward3 �$!j�%�*�d%�� aOu},��[13&N136�Lhh"�� E P!�;@q+ssuZ s\9~ ZAR��QAD��n��"\tm>9Ii�Ja� �:H��l��7*o,PK&�&�t�, feedl[ extra-)=] ol etcaO&>3"�O�Ces�>SGX-A.EQwoFka�xfor%�*�&woO!-d�QW-xplicit}!�purely2@ ��%�y��&d--�->�E$.��y��� �k9�pr�o�ll>is ~H0\%Wif�H enou�.i"�Q�6�&A�thalam��zqop�ll�!fhto)�on pi�er�!�ms^a�9Oe�nucle� wa%Binvol�|�VQ(A�"}%e�%�o� teNL+. S� �>]��inFSI/2� "�u*1�m!r "x4eRm!� eeUc�Dž?�(1R9���en_h)[Q��C>FSIɼ��A��bo5n $&<"N]au,SY`Y�Y0�g fWd�6a � !|�l�P��8%م��J,nC8emp�"% A � �� IIr"���F�it�# �c8aste?say � ��6ZAm� ePD*RZ!cCarth*�[1�O%xT"l*�!s�籈GAolI�Ar���2 ��lea�)to�=t�9R �"� il�w,�]W�N�iU�'e]sm}`��== �p(�k a� B6)�-�s�)A�be B tracSack.�d �"x\-��A��gw�]de";A*!)5[I~� 9a�x "�j.Oi��Wcwp�� �i! �* OdA>affor��sH���<e� ����� �z>� S�'pe.A/�H�&��6. l � �8(#�w��"d�t9,��-�.�)66X�"�+.�.�(pi &aAQ 2^4��gA��k��t � a0UP.,t�B�"a ���aj�x:��iB&�1� depolariz)�(nX\z h��$!�� 8]M�2#wo-.;P!�zb�Y( �k�nga�k�n�c"A��%�in� tane�N�N �kin� n�Y�� m%gOWAQ.�@:B�Xmo�_ j) % capa�s�w$D� ne�]�N��"AQ(X�]onCi��A�haB�� c$.�A%�# eadyM 3 curv�!r�M1����= deno}2�w-q;i8@& z5& "��|� �j��� �wm�%^Y �!u�s�?E�[1AW.{4:Ab,&1Ja`AnodRin�ntW l�: SNICB*�[JX1 SgA�a Type 1t o�\�6is�in Eq .c�a��*(.dp�ga�_qEQ��`&�2�6o� �!�P'"nA��_� ��!��A���op7� to���a����g, %�j�mi-T� aah>trsa� ������T$he)�.*a�V�u��gbitrarGIP<1 ��I� s &$) ���AN�X�$ir�vGJP�.(Tly Ba�<sub�A�;�d[14�- 141]] �e��)"� (�?e3%% S8F�;^�R �b*B�@�i[�%�rs�-e� &~? )/56 %��s �–[14'�`t�h��*� ., �ҁ3T f L-� �I�-in��� Me�AA,-$��,>�}A���Q�}�6�two�ce&>�E�� � ermMZ�hu:o!|r"� co!���F�O�!��� "��1e�R���f� sour �� r�"Vu�u^8AWbeA'AW4 < �a�um ana ��a6��S� � 5�!1�fS�%�� (� �oi��UT.�or%t!�1�?BR�x.E �H{!��#I*���.r� 6�'�q-(E��= � pape�#��"�~�FaE�1E�/a6����&� Y�Q^��S� "l �%[}�-UagA" �4����i;ond%*!EM �sC. e�on�f �J �!u�"T�Npathw��QM2Ae� ��O)r("�1 c J!\Glo|$Pal}$,"@*rgic K3s*yQIW�xvZ��c[ �!5�I��pA�!�%����Y�A�7� Z GABA �JK �a6L`>�A� N���� Ulb�q.� �A�vl&�d�� 7�.rn : ( N�Q7s"`ji��N e!��$� �6�s� %MY72th-�E��2��isM�0� i%�:ÃR�am�d^Z.)�c?W M X�Gv�;!1ab�a�V&!�s��(��"� �Gic��A7��"�dy��C�a �*�[̀��S�ITum ��%����5�%��,*�e�I�a�vGp�Aa%&\f! ��+2�-�1d9�s�v^!Su�� �9!��O)�����m r�xng 8M<6�f�&�A��v���*�& �&""��r�f�fmp%dle keep���fs �hs�? b|@9l�m� ��1="8E^��(a����^()�� j;Qunum2nmgx�Ar��X � �w� �pi)Yf�Ig ����ީs.�E|�Xr���h Rall� $[14*56�is.� i6"!�6��;w(3#�F�m��;�q! 1A�� numbe�=a(��!�1g&(I%� 5Sru s.{&�.�{�Sibbq�!o>�e#d�F.��!��-�# , <+wB&, _8ee"� AY �Hea�t�Hs* .F?T�u}&��dur2���k� �6>�fn�(E��FqH/!a���s�0n�$ each1|=��O� R` �`1( 2rBnd� na%.��*mo�8$0% �,-�g3 ) T�%�T�"re�6�UI*�>�## !L:"�&�}.{Zm4u�n��`e�A�sq#ً� 2 Zsa��3ŗ8� �|g"�ujr)�ɞ.��m[{)�E+c�I:mex)HB_r��� ��mi-�4�Ze�� �V]!��!WI�!��e|$3�0w� �&� F)ogCn6>oduJ"j�U j@&�,g A�~��� %B��(�ce�o"�T!%n�Aa�Q����$+&�� �{&� ��*wBMEE|ŷI0�u.��"J<T �*Lo! h@��� lap dend^@ arbo"qof�M!U���x4>>)%� /[3�@[14�;4�=T:2>di?P�^m�a��Nde��>i�!�u`# [p�"�`� f��<W�;G*: ly 2843 �'�S�0s448eWH5�ntact))nQ:Y'apuby; i�O. CE���I`Dr� ����&� 2L%��"Jori�.00MM%(:>q^ak#�Do� h�ng-d*s�;a��"*� �s��4� )�ch�Ź�P�=V travel�Le�7��! t"$G.�=pE��4y&� �xI �'�k��mighbourhňAIe+�Va� "Je�d�-<Y7�p� er��b? lid  �A6 q��w�O=-��]li+���;  N�pref�!�attach+X!s alr��2Ea�%1�. Knowl�l�mъE�!Tڋ��!KZx �B� �'u�^� e9.6 u.� , s�J\@zTZ�to� !��! %�%B�8&� %2�}%8�(ec:isjYa�tUu"Y�$corn4%<(��2?62�6&� - �o �8�BaSp^�G ��Mg�fof 4502�*hoqt&�J�,3GA�/a�"��#. O"=le$�t t�~Yatisf2���1�iA.lf2 choihf� �R�9cl��> I".a��in�1�!x&�Us&z��s�g�H.��B�F�%e�'pum pai*{ re�A�,J{Je�E�F��!+nw"gr 5m%2l� medsA�u{EM%�"�� �aj =F_� [q���ok�E��+.�.�TA�e4�"q��$-�^?&i ��B "�#a��+A1�E�G oo�Z�!�U�3%c6n"�x)bL~%�&w�K�$&�OI�I�!� us ?� �� �%2I�&M�art���&l�9o0�width��sam�#�]o Z�C��b;�q=.K�Y `VT�8�H1SA�J2 '9�!�I�F%���a�PMEE�3�8a,m�ETA��1�^ u������ +!%6����"!V�� h I��L���.�9 !�dQivwA�!4 K�O �& -Ib%�&~% c�anytha���?""x�1s�on�JG�!�q &� �?�.;� � { �M��bmmde� .T�ra no�K � �( i��� c�X�!e!G�8c+H}&�ye��A�=��*4f� E�d0)��/E ny�cwI/yD"�3�a��o"!�e)�'�i to,sa�v�q�&��hE�%���. �G)�)�aniJ b#Ift � �>&L:al"_ . B+��mJ^n=�0�g�v� G� �eq��� T=d�15'i��# ccor4)��L'.y t!��6A�) !mTeb l��!�u�VQbe}&�� �&�'�]%�)m hA��%�ed.����0�"��M� �A�JI�� iw�M�R^r6�!9/ .e>a?Cr�N^�!p���. S�.�6%p�roŁ�a>o�Hq$4%lae� 4i�uniA$ fl>r�[�O&drawn)s��GW.� � n�[U *#�1!<����w.�A^9�5)��Ik�!��1�ta�d1ci�^E G"��*&Nh.s �[K&!�]�3�t< PSPs�axV��7^;�bB<~��!����}[3vJ�PV�� �,�E &n5�>�x j%FA ����p�&� �+wI%���0M�e����.��8sњ&�� Y`��I�6� D�|�feFjz8���w�"�A���Ymyt�,\��y&&�XE1iM�ist% #m �6���wt(.Pk t�\&Qs��C�=9U>�&4"�(%iE2��? �&Y �Ed_N�-^Z It�av+ � "o� .? �?� !'I 2��IBS�*E� XA�c�7N �>0+\2V!,.7!8�/�E.MAD}jREJ{%�.�*( sZ�@Ek�j��nk�X!H��@U�q%WC*& al %�!�!����n9ij#)%�a e��Ba"�s]{tur@u�Mm� qs� h�MB�>8-*���� V�ͅ��pt!��ZA�6)*I( ^ >��6���w����t��-8!Yrec��Y!�JF�*��&� ar:q ��~A�iED"\ � a�r�e]!._J�incomE��*nq�B):�E�rpl .dl_ ���_�"� ���\RLH���Xj{A�8 3^'R*ad^� �2M�%: 3%� c�~�� łG r>�@��&" s"qD� � �I��.~'�BN���� halfg W����!6!{"�Ejd�K by Jansse*^P�?�>�,� L�!tA�%.E{a }�.�� 30–40�k�Tң�7 }�%*$QMin��eaH �"Af�(.�4���Esw$��nI�f ( D1D�cO�w� on�Q��ZaVdQ^P �[�<� m>.a fM��!&�7�!�|�AaoUa�!�-%e&4secq�)�F-g!+!�I�w�� h�����.F������}�gf�k�zb2��Ձ�6�q � ��%B�i5a�>Z�!q@�"w� a h!" 8a�ot).� 2Y m.0 �* p3 g�0�.a"A l;P� ���.�(e CIto!�^�!7�J4���C��)A��0& !�DTI:Mn!�1�N2o0�j%���akA��)[ �:��W)1�)��F ��at�"\g�w �S.[x.�"�捣q t'Fn "FJ�.��%f� � ���W��&.-]YEٰE��+al� !�%�s!^ %!BC!��#9 M�U�gRF1�.>$�aQ���A���=�I��#&M;���l�UK>�� YF#inA� Af E���D-se��7�6W�Br)E�e�<I��t |(A+e bR�>iGIq��� r6 o&�".j� �(3J�!P���:�@ER"We��.�*�8�K"5y%�e�`�]W"�5��8E�0�0stocha3 "�i*>B:<�&�%�beO!Jll�M��E a)�{�i�$:[J�(,7 )"�+� e`A�#� Q����{*�(nF V :��u�e�>�% �?Dirac�Yta "�(H �D�ҡX) A2uq� %)I�>� � 4+�� 6 ANm�e�jJ|:�$N1 ! d4.�.UN'�,J��6[Q.�3�O8�y�"� _ s��%*� ��nd�q�G�P�)��n� |� ssum��)m1�i�.0�� ] %~�a��( ѡ�-ma�oa)��U�@6D2�6> v�b&) A��FoRL=$n�]9�5UbV1�!���:A>^TB.6Zybp�!M4%��e1�!Fp�n��$ A.��2�na����!d Eo$H� N�!�!|��&T� replCAy��7"�A�m(#!� p�_.4NE�'iJ@5�Hdev��+sum���2.�>�I������K�BI, ( 5 )u=ɆE�&) 100Ҹ E)u��2�*wE�r u��5E7+A�e x� �Mpon-ove�(�0�(!Sq�a" >(�� �&�N��8o�f�Jr!�! �vaX;!~�.(G800� v/Q)e�mJvola�� 2�'z�v���R��.�68 , !zqAny� n�D!�.�! HorP�[15�g�dyN��+2:� ,a���s&�Q4A�tk C��$(�W�<sh!^&� �*"��.��� �;s� ng!��2��72��/&&�Nn��%on�Pm��Pst�AP�e�ͱ�)�c �V��is�|a\c, &�3PM!L�s�ZsMa/ a vi�2at�A+A��a shap�e�'���ol&6�LEC ����yT 7 �q�i��XR�l*C�WV[�Z a� �A��27n[.ag�I�N�� Each�"�!of l, hj[�Z^;#e4BaC)JuA �����$�[�Mw&]3- >i���� �@lq;In�{�Zr0�e�?�y-I:s�7�%� ^�.�9A )R��*i&����C ���L�=�.2�,�'��� Pare��.��)O�pH6��cZo��&zMIp"5{:SR6#:�c���r�EtA%>�q%��<��� �h�y��L�޿2��Q�-Sum��5#eda���>�f�3^� , )o ~con����!�Gauss͠S!N�, 0�A !&�-�@A�X�ste�cZ -E-�m|:_A��+8�Ejn)d%C�i�$dy����&�q)?j�e�C9�aU��7f~O- ll�� "�2 . Va!�-?ai�-raL�trosHcNN.&VmIeJ6���>�b��a�.�H �i�.%�i"�Da�1"eEo�PC�K {(2NC#be)���i�=G��Zz:�nE�)[�> 2�6 v:G?%�MGtjELN �s Go� g'`i%��K�!�>����QC�t�P}LwT�7�?�o!��8�"�K�A.j plauBT6�T�Q/�W" nA�%j�6*��O.O!)�-y��*-$metho?7-uD �f�_�| � ����"5�u%�����b���'e�.H ށ��v/;�w CB�w^u��NOR2�-7!����9��U��.&y�BDW�o�&"�h�E�A!��en�,�$26��>!�56��?�<�@2`�e�$ �)A�*�OAi�T :� �S 6'Q�HnAA9 !;=Rpv6%w>f(nA�A�re]untilim�a�u2lk!�e� w�BZ .= � a�UK.v��OpikA�6�wa�cM}�<u�tP*)�Gt �#(Runge-Kutta, g[}X=} 152])�O #�� �RE�F�!, of lx180 {s Lai,12 �4 ���arF � "��j&� �V � k-mea� lg̺h�Lu�_�!�e*; �ZtM�&x D1 C&k AH�#*2"/* ]�.&L��a1'Q �0z`d�S!��"(�.<"*� KM�veG(`46-.�2 g. ;l�i�Z oid'�)�:%��=���(�W�#�)e,�s'�~Al.nu�R�u)�h� �w �!&�~�� >rn��� �M��ny �UyYA�r \. New�)ji�=�bWA� #e% 2�a�1}I��r# �\���no KT ���ir^ W�nNa�M� �M"#E&(��B�U�Il�.�O0C�In�m�D��Q�jm�W�=� =ei ()%f comb�Fi�1"a�Vj��=maUH)�-at�Rs[��)ea�& �u!!A�~�v�6yAT;�0�f � �{Zs�z��a���v�� e�c�e2:./a����u�fb�)e�Ym�H@af�[!�s� �<%�a.ll� te<��e 168���L&l#%�W�YW}&`>0EQ1�obq2of�!B!;FA& {!�FY7Adb )�C.ic��5xxu�!86%r� A�j&�;fZa�'� 3+t H segj4A=`�&%&F�~ate��fk �a  t�5�@� !/%-XIϩ� �Y0=2�r�ZaP�Ta$1�2�)m�ob�\��yu�!ea2{.tm�'ua:�me1T2  �;��A�qb's!AP�� nd�brgI�Slag��[a?H c�tof��! ��EY%={i:�_ �s5=l i . �iN �en;�/���g�. }��(u�!-��a h�@�l (�v�9�) sd.:�TQ�4 =ޅ�x�?0��iU/q�)&�Q�3&�� j.� V>+�7K� (��v�C�u2,)Ri E"g �pr�*"�� labe�(1eigen���w�IPM��� pro��!� �$��o�)# z6m*�&��ɱO�n��A�A�� �o�%%��ure�1�e�u\\�$ �)� 0� �asJded ^�G�zsP�s�z)�t�"e�J}2S�"3s2O �O2!���y2%-� �()��o��e�Jr �# I\�� u@B��O�� C%kڂRc1\2���2X.��-f��-� PSTH-��r��.�Aak��J�.x�No�F1���G�def� �?o6��/�TH�8j"�$K�k ��$ �}Zt�>E�]C!2 to y�t(Oh����G9Op _)ha/7%?6� 5ZR��m�u��c���8\�%��=�innownHn>~�w]��E=rO="!��o2L6FK�:J  /. py ( Kull�O-Lieb�%�|g�)�  *>.y �=sa�HaI-D �.5!�"i �!�����1�,� )�"� �IBn!�c ��fi-m�#umRw%��bb!m�B82 *i��E3�� Mb�nG?�i2� {�b��A�6�2Y!�6 �'B.%�6R-�2K` 1~.�d>�> "K,�v �WeȒS1^ɞ�_Z= )%E��!+��w~a����A� �q��ifEE�P I 2K�!��r�>"\.s� :G&���p s7ſ��>& 5 ( c�W )!��Af�:�kf>��nhxca�� f p\ud ��^"� "J �-N \w�K(�^2,� �$� EJ�P� !RA(a>�I�����M�q�B�".!��*|5;�!SE$))!B�"��9ZI�iJ)eS �� J�!.�@"�p� word�.�,"� ,A�)�A%6 )�A�_2!l���a�to>n��'�;.\J��9o .�PU#���? q��%7�$%!�!��E)q0U�!c�;�ba��,.�F@ӹ�K �;�1�A � �(�CxmJUorE5�'*�QFwc, ��!�A �'.w �a�ar.��@ ng9*j-:U�%�iD�R4dnce2KYpo�#ajnd F�,a�mV�=s�1�(5 k2!#.eS��q�%.��&3,A>AY�Xe5�m�f�$.��m.�M�dA� �p�UY�Xd]��E�f� ��-3�Y� X�C.�idB;�@ B&�8. S� �.:o�r�md��dur�nalog�g��M�)_�Q�G a5_%�[2�69u���&>c �- [ �%�1W4�3���KG9���%�Fx���z2?2� B -�N�N� � �!rsamt� [�� �-`"��� e��;:���') .� ��!�� ���a�toI�A�A1 ("~|2L�+"�94 X�=q . Qu� ��AA1�@!R�&!��,"�2B�1�Ani��R��6~�ta�B.z,:N2;JNuH�5�!��e`�`%�;.Yhl aJ�5r��.�AY11u�9a*^�T� T is.p�a�t!�V� is 1�*lvx��zLya:�=Y�"jt>A> as 0�i�.A�Po�le&.��b�� �lgxocyto$A$ v��;s&a [ 3x�$"���Ab�te[A�endBbr1�eo/�OJ%%n��6<aA�� spit�>ytink8�W Q��Soc��2&&�y#"OU���U��� �ima�� R���;itr�$te{�7Kng��c�&yrene-����lyA�z� as 2:+��Sy��Rab GTP�ESec4p� plesV�w "k+Rq1�<{�}9�. A�?R5ŏf0asm�d`, �!8s Las17/Bee1p ( �4Wiskott—AldrAxSyndrs~��!@[WASp] )!4aE�Ge�Sla1p%vSla2p� �at�,ԭ�FM"��"�ie ��� guang�Ueot�]ex7� ( GEF� ec2� 2{�m)�!Xx��Nnb� c4-Q79L m �� ele��B�In I]M$of Arp2/3- �6K.�U�GTPγS-I8rides!H1^��B���j!�pBb% ��s���3rt _�:ni:%�E�re'!���a�W'2;�Ylsi/of ��ic vesi�nfu�|to nas�,6�K= �t�G promp!�F�� rigg�"��ens?2.[!��"G*surfac�%�#qnd�/eފ,��'l+q��-K In�Zs�)[ �S�?� .~�U7�D& yqd�/{j�x4%Eul�A��!JD��.�( PM )�%�mA�!�=je�)��Q5"�ex�,in Xenopus o� esqĕ�granul!M!R�!RT���>�PM`��X?�n��n- �e�[����)�UK5p� lso �z�6lc�K1�ic�A�5tra�~!n�E�ad�& ns j�a��� thel�PaUh -bas�*A= o��Xq!�A!rŇ!;])�s!M� ���!�m�z�;Msq���\e? =�.�P Ԋ�1"ʹ"r -Sm*Sack�omy�!ce҉siad~�=�΅�%�F��%D�!�B&� d�Cc!G�o�V}k ( SE#s! an��d��JOnagB�9s�ysrupt upa" luci��ye�I(.7[5!��� puzz%��DB�� �2�earli��v�'-u/r��(;l /."�Bn�ic� 4ggAn��gHہ:["� ���0�gJ h�١:(�( thous~A�E<not � � �=�y%!�� do imr:2M 6–Ve��D��͢"� � i��S!]l5���n��E;�f�|�?m>/unec �'6;6��5�|>���ac�4z�a&0��o@1 gE�(k*�)�l�+ee-_.r&PMAJ6��+��&� ct=m\��"�>�Z!Z]�+ U� v*� "a*ot�(�c[���=p<u�)*&�!�d��l"�"���lex�$����Ad�= Eng�c�"[ fly � ( ~1–2���DUe�,�&�J!V(38DJ� ��ead�Lco���s�Aclathri+ Edr,�Syp2r�cru*` ��f��s�  � pack�hI�cargoGAp�w ��4 forward [20 ,� 21] . Over the next 20–30 s , Sla1p 2xand Las17p are recruited duringE�slow coat assembly phase , which lays*�groundwork for subsequent dynamic 94s of actin net/Z[18� ���Pyeast HIP1r homologue$ 2p represddconserved clathrin adaptor�whereas�isZ4Wiskott—Aldr�hsyndrome protein ( N-WASp )�0[18 , 22–24�-Kis a pot��vator�0Arp2/3-depend`n polymerization , but itHkept inFe9�$is period ?dart by an inhibitory inter8on with!0 1p [ � In tFwayUp%�$dual roleso endocytic Tnal�inMit�s both�z �requiredE6H!�.��regulatQ~tim of.Osteps|f0n patch matur)B[23!�5!�ThA�T!Hmechanism that freeU from-'-I!= is unknow=�Uv!�$key transi0aldaunleash�A�rapid ice�fi5events .!�effect ,)�Tpause helps coordinateMcomplewI!]ed pit. %�za t()6nucle)0. F�lA }��? -)cu��Winwar%�ce�membraneB/A�(rovided . TA�!�chaA�aedE%' w�>a�(as reflecteE��motility�AbpE�(6] , a medib}F- ��c%�[27A3I � PM deform)%@is quickly follow ��scissA1�-�es$e�}Aa� biogenesi�yqvesica�. Here[!WvestigAif a dirA/m:6� exists to|gr5polari!iexa�oxE' z . We showi*�9deliver%t Sec4��ede�Y4stage-specificY9��%�es!�pro!�ngQl6eadde^�be,@ well-established9g�, �met all�expect%�sE�a:?��! : ( i ) Ei� ently loc� ed� 2ic si!�1 5��y^irwI\;bcEC4 mu�disrupA�I�p��q� 67%�physicaa�Ehaq%vitroElin vivo)�ͮQ�ia[2�rtO |�/xv )NE偉� TA���1|induced��trokj �I�%���tribu!to � ed5#A =;e�` Thes� sult�E dicaE� ioverride�� limiŎ��n.P9��tdbym�ly coupa�E4port cye�t)��q!CHcell cortex . Target!H dockA�ofM�ic� �PM!��Vmulti-�est��x . � anch$ a�b�">,subunit��includ� Sec5E �����[2� Evem ough34p� =(travel toge!=KPM [10��we ob� %�at�-,�=� markerI{-Rtluorescm 1 (( RFP ) co-y� fourm��or�te9 GFP-Ipaa%�ha �-3xGFP `( n > 340; p < 0 . 0001 )��rE� sugges!�4a link betweenW-*na ��VA�� as��in)�= e!�distinc� om o%c5�of%?>�As2h . However���0 sal cri�a!�bAt��)4��pos�&e ݳole&�AU�y�ŜA2�<�P l���x�Ex���rsP becM �$hierarchal�a6�9/,2�Fu96�3 t must ex�  �spati~nd tempo%NU����Q-��fe�ond���adout%)J��%�q &�at �E1 4 �"v ,and/or morph| y would!�ݡ�,M�!C ��de� �9ny "�%�Űn�L � . IfM@&� sj1%$=�; a�0e also predic�;at Xs6 �RPM�a� iT ��)2�!( vice versa.�*% ��&z by5 pձ� �|#)� *) �� ge�ik1v AOa�� � 5�- i� ��$asymmetric]!��es%fin bud����R&= ya�inj� necessita�� �J� yy6� ��toQ]e~�� ular5xA�e �5)Z5�. A� tes����!Vto���� lU�Y�@  ,�Cl3 )�]{a@ naly��heof% oZ�I exam�. B6�fleYn-��2Mu�Eb����� lapթ�&=�A0as mo�� nt�� divih=)��[w�^tracked�! Aj��( Fig �KeDfu�  truct u�u�t� %asa2sw2Me� e��I�inx,�e na�immuno&Wce� e�@ron microscopy [9SN�*thelesAiv�\ difficultAt visu�� liv�*!s>�$continuous!Cnu 4�V:  !t9�appearsQ�bud1}A� “churn�mass” �Towck~�,� foc%�ae)��n� um-to-l 2 �"q�:;%cdensel� s�YLPM���2� photoblea� A� newl�E+dR�o� e�13$( S1 Movie� I"se�rim�,.9��aRW traA !��A(in!��r��!.�wth ,Q  n�l . Morea�i�rei{no ad�͑�s�P viab�5�Ii�a�laser���d�of>Xe�-inc�ed 10-foYy��%�iN4( see Maz la� d Methods%iFor�9� s�� ed (=�!l>-�la1 �-5 ,Uo lifeti2 �<val���YG�el��mpa AXhos�at Anot (�d one-�yf varia�nt a 95%!� fide�$; n ≥ 36%�)Thu�p%i!��a�: X)?"yX�itself �suiq��iI�:A� ociau��� ~�n"�K6C.�T% z.�y� &L ( ��[2}���Kg conf�]&ce.�re�ve)�e �[2�=a���!=66�Af�tth&% into.�ed zon � ��, >64%a`ze&U ed� �� foci�90eSKymograp�aly��f]2l!K-�R�|�T��I�t-W;�alway�IU-%1e�}�2|,t� Sdis��3m%"�AsA�arra�!K�hA–1D��S4��i^In�rZNE�! ۅ� �A��� vol�r" concurr��-[".ElKRkie funca�al sign��No&g  e�]#��-Y�eKap��� �z!O&�u properti��-:| � ��Hutant b��*�B� c"���h��# kin������ M�j*:�%�gmatATing>� [26]M���Fa���per2�A?turn-�6��onIiRZ6U7� easuaby�velocH �"0A3E�i+-s�%`!�veB�-^ini"Finvag��b_!te.+,!t� ivel*a� �60 "%#I�RBi�>>�m3 er ��)accum�onK “!�met> �QsY�EydB�6>�organ�p$. At 23°C�NZ��� $n sec4-8ts1%o�abl��,wild type [2� & ��incub�5at 37�a^60 mi�!�ja�%�;saRaB� lUs�PAU�z !�)K�Prm . n undi� �Vter  shif��.?of:[%�P� U%�5Z�2�95�/ ) ; ul=�.���F�m�)�magnitud: �ec� %�RA� �!{�䁇I.)�"1� - !_ E�-Pd.�ez si�1 . 6 42� long 9�)&t1� UO6�15A�2Bp;as early 3ITn�to�sH��a��R!t %ͅ�� 2�Ufs (2�i = 55 �) detQa6F�. A&I9�pE�.� BM ^ EbI9�TNc�6�m�!�b�r�#� � %�!Iu]�esE� delayed 3)�)�9Iaft)�&I w� as&�M-�iI2mFA )z!*m$ moveF�aA(�as 44%�$erOCEY� GTP�$�con�"s� GEF)1%Q!a�f6n���=>)� 2-41�c. Lik�c.y}�Uv�a A(u�� -"�]$"4JU>��f3�ocl �#�� SEC2�e-�.�se1&��v�m >70% redu� v9 E  >50% fe!�Y�##�udR �,���-SDE&* |�-A%-�Q� ~19.gcl������! �&SeAeI?E��&�J�. Simi�toiYis%+.���%_&cJ$%y berr� in!�4�N��{la2Δ-�,� instf , ead�p� �5�Vn,0 c*  tail/ ���w� ���irotru�M�;0cytoplasm [30�lt�de&H% SLA2V !  a greh numb%�r-a�hw��ed smaP in 31�:A482,u���Q�8 1.sI0HA�6In > 7�M�EE�Alzl;~ �iv�*� IS�� (sA��a�c. Aq :�&� "��h�%A�b6r��&.� -.WSECu ɹ�(��at elev"em s [5 , &To��rdE< Rk 6�'DM�� M.�H��%��|��)�n���&gc �qm 6-4�fai�a �R�R!�6p}*"s�!)׵�minor� � Ar 3�\u�%�a ����!re!A��(.rA�} N�� *l M��3. u�.WUyp!�0 *P!,&!��K'��A���[b �+�.R. S�al�cod%z4pz- z ng Pq,t GAPg&q# MSB3%Q MSB4�� A!mb哑��6.Vn =,���GTP/GDP-�$ �J[3`.*�mA�y��?un Q$ n msb3Δ4�#gi$at].2� U7/YO� s�Q,ly�W( �� �de I���9[@below] )U<9,.�f�ngs*�#�among-ԍ։w qed.,a��@ha�:IQNQ�cl/e&"!�s?")onshi&�)�'.Um�ax���$.,��.ssi� �"��V"^.�)dee�H(radiolabele"Y0syn/p*�#-y-� crip��/% on system wl&�.IP�(j A�γS-b�gl;)hione S-Pfer� ( GST ) �%,resv!"purifi!�rom b:)riaM3� .A >bIq -DAXenh�d 2 . 8�eOk�a T��.�GDP%H nega� �� trolaW,kdid�d���or-Ypt1p �%or( p#DP�aO& 7ER/Golgi "�G$ �M�Ia"�.�1n�l��.A�on"< ->U M*3#}a;.* same%����A�we faiA�t� ct a Y�b�1�#ex!�AGS1���*I��d��i�se�&A�k ���!eQiO]��"-p�Cmi�'U/>,A! i&���+, 4.� r!�n�-�N*)i>u y bimole�4&bcA��0��s( BiF�asE�[333]q^�r3�rIn -, pa��9�>ne� r�!�� non-*� halvl�t� �3,i . e . , Ye�/R'$[YFP]-Venu�V)���!c �x� in ~50 Åa�F R$ f�YFPN aQ =0YFPC carboxy-�re�"itu�$E�actV�32� Con���3previ "��[22V+co-M�aSofMx- �nM�C��60dz�"I,�6�(ٵ3nw� coun��+ = 10� u-!�� /��.�U#� 12a�Yqt��!�wa*�ll �.}.��29i\)oP,%�c 3B !'M�N�p�$� eins^?�-��lC��FP���6eL %�- � prof/no=$cLn- >Swa��-� "� does�9�� kj�*�)=� �1�O� qbrief�.�GR8�5�(v��.�)�mpeASa#!b�p ��;of<  C%�� -�C.�$PGAL-LAS17(-� over-�T���e* �/ h-E(���3,���!!y�z!&� 6�i MB upon2�6�N�A�nfirm�T��,!"�wv�0 72�W&G�e�% U9�� �~H E-��6% lex!�",*Z� �� ? x�4.d �s�kp��� �onA�*�*�A^s�:rup� .M,+� cor�on�[mp��o�/"�,�Q�)0-]:. Hav�" 5;6�3a� \�be�.hw�)}!`reciprv! , nam & 7 I�"X � dI%���R� }=�1%O vector�. pathA�c�,��:P!���" , ma�&�!"M ion��s6��"�!!F[9 , 1�WaL[4�:�$.�&W(%W�-� :A%+a�r��(4by three-dimen�.al�"e-laps��4�"n$m& *i�4 2S07( ,!�b%ed�A�d"�4BBC1 ( myosin-uJ#H3 doma� T����<, RVS167 ( amphiu-n� u�,� [23^In��Ala oQ�.(e,� ^ Y � &�A�Y�4 se�FH,�e.[-K.�l��re! � � cI��rvs167"��[/end4-&�Nl&,!���"by�Wn� f>� &�e�) a&vz!)"w4 actuEcd 67%A� bbc1�MJ�V!*�6 g�<*:�of Bbc1pa'��z�>[]=AW, mode( �de���e .R x@%_!q-13"�� !,surpris;<�gr�=/0} oz�* 17-1&��x!*9.�"j"s%�.%�c� �#y� �� Ix ,�3��Sq!=�by�!�I.i�"M�un�}=J�1��53F:�0a0A"*� est a,/& �B-ɇ �z-`B.Ir�Z��7!�R��5�K-u+�?�-a"tf.M*%>MA^th�9FB!|d�X.u,2aY��"As(n�se2�TnE�/#1""*$%�$l-4e@%aB'#is blo*12(Likewi.)|*�!}�gI�ΔV�Δ.���BZ2�=�Ga�:����eak [34�w�&�5a���i =;dQ.��6�Sb�. ak .B�)� � , )s%�Ip%de�in>�2^`E^ *L<supET! /YP�>>.�5Y�� �� E2]" r)Pomina0"� �+PMR 1�X�E3f�[3"LC prox=y �2�t�=se I�B���%92�60�\ � bN5��them  the�1fKv ougha�!v��"�m=i�19 $GI5p!�>���Y�B�� )�a�arpu2#!I6O��"by!�~.* EU to�*&o�  2N)5�!�� t[.� a�*�0%�ae��*!'{� verag�08 . 4–9 . 9&g /. %��aD*�ig crepanc!��C)*ɳA�]EQ!�t �(!��Ev� �/3wit!�2Z� �8I4-)MM'�!l�(�Q$�~2�(bud-to- s�)�I2Y� %�%�at (Ft"3�4t*7'.�&D7C2�&los�fWI�5( *h;m�)z"�:!u2J�"%��g��y�� vW?uni�"�'�wa�%��us oppo��>%/c�=.-:���e�\b�6�� ��s"q�\�F��Ici���� �8U>��y�1!�"� )�2Ck�!B&8.�@Z>�&AA �2� sp�. bF5B7��5�U�@�!�+ ��herE�!� �5B�W�6lo%L�`\�Py�0 �:�"}!lz2a1F7�RJc��a�@AM�^f�<Q � !a ~� � A!yA� norm�@lus�3��-l�vN&�us.8�D�:5� , Msb3/�"re��9shLRabcs ɲe� �[36 , 37, � edn :c�3"m"�Ji`0 &�0.�:Es� Q79Lu2 mimi�& R�)nc�Hic E�Ir��trinsic �qeaa� !6�%�����#GTP��@�F�&���)F!!q!ed [3�DI� iNf2to�R�J�oe)m�*� ife.shM$1or�aY�K�MA24 h )��14�[3 6Despit_ !d:Wo#9J�had2V�P�atQ�� th.;%�� �"�.WA�Ja?���Dm�A��6�V�e%AaN#�  .�:�MF!�[�s�Ex�s�e���2�%�Jie� >�,��r"� 2Icargo �I2���� of�F-Sn�. �nMic SNAREAu~i�is .�6r��K7�]avia2� [3�1In 93bc(&�R���~GdAi!��Hn!)� �7um6 �little�>���!A8aN%�FŞ� �� ,�`:@���A�U��Tmajor'&I[Ք( 87%� ��&�ceRU���.�R5w��H!�e-2�  side& �"x[��56�1 �:%�"sEbbsc6g)ss��<�9 =�.:��`g�H���Mu KH ��!�n�S�6vA;{icmD � &P"�&, &�Y��T`2�e��"�o �H�'p ight$��!^a*" 2�5&�*BgAC24%F. 7)1 '�2"��Njr.I+&PUnd EDE11v�(M ,[2�4[-Unl�0F9-,# )� B��O������by 35%Q�G��MEoriJ8l^str( JGY731aB�ZV2�<?86�0�4ace *Io�%m�G;- ��(*�s��B�a��Q� �e BY4741g �<�?A��p�s?"A�]�a�C� oa�ele��"Q�d i�.A!+*r �B�Fe�*3Q.e#��2H=�2� �I��)�i�$�Xɤ R,C)AB��s� a slahly"�/$downstream턡? \UK:�Aek)�s|6, 5G AJ(scatterplot-e�%!.G Y,�3Ň��-c�,cDfV� �'"L( ��to�A�)Ia�(.�)M;by L"����thPg* A��'�2BER�)F<�b:Z6F2nt� �� ct.�I^rI&�n3i K EdeV4�4&%Bar#�Sis�I"ord�N&�)DWacq%�+m6�es��%5y�U �be epi�PJde��n �P�!�.��!��I� �e�{�a2�"�9z\$:[����0��9CW";�.�Es��]Rji}282���i&a�N�+by=O*X!I�5Hq�s��?.|g!sti�=�V.E��� A�Eof���#6K�� "�. G&�.I�6�AWe�*(�An elon3.on� \,A[ deno�e�"e middl�!v re�A#sigmoid�ur_,Q�)L �-R� �primariK plus-endZP5�;E���Xyfi� � libr<`teady-�&e�%5a!�di�+�%r%�s& �%eA�eaP�� ��:KcCbal�/�o%�I�;}q&(�&K!�d~@�i� reuo�.:FD���@/ cal�!�"� slop'�;a1��h,���!�th-G. B*"�'!G v���"_}h�v, �W%a �NeckpointN �0�a}) prio�W 6�[�.�2�C[2�4~"nNes*lVa���—mH=���*��er�Xe R pyren" :�s�խ�6%ologi-�3eLBof �"ɢ6� 6_As��-1R2��a`X%�N�0 �ݽ��~�#�% !f%��i�V k c%*i�m����dH"X�en�ion�manner��m)!� -q# c.T "O1Mym� �-D�I%R3 �, �Z&� z� to� !Q!.vc@Toughly�%�� maxi�a�&�C��%� �A�)�� �+~� �2�A}��%GDY`no��� )�nd��.�P�'TPc6 �to.^FP�� .5���o5V�qm!SB�� �5�5� �/MnRS abu5M�,���%�minE���!=�E) |: ��2���)W�=n�b!�nLfh&�d!EWag�a�F�|-.dg ��se dataEc fur�X �M���l*�# �^�5!&� "�IMo5`Jb ate-�Q� s aQ&-#>�. I&~'MW*�N �&3Itfulfi2"�Xe�bZN&dA�.�"� !b��n}Vw�*�O�6j�Wi:96"�ir"qO�M��texVFE7har� >.�u`s ;��fH]!�.�:!"g9�� . Ak��oa�� h.M* ."N)O8�#��!�D-i]Cz�,�s�XufO2�k�P�Xx� t:d`��.8^mcoa� �m��� /.tZOH!?22��J� "�a �8� 3Y}\U��&A^\M�ZQl�_�� revea=AGm"^"�]i���A��h E� y�/�!j�Y2 ]:�.#@r�dri� for�ia�j �� ��f���7� �n�"j 9{s.�����e>%��- �!fac�m%u!�rob�6 hM`[�4�(A� "�nA��P�*�fWfV�jU�.c Z�eXels�^� �A����!�-�� R<al bu�bof�g :B 1a*�R"�Q� forcpeI[a:�>�` , 4� Iv�3}�93�s� r �3�o@! Hrelie�T�-%�-YaW)Xu��,�3? � sVA�s�),� �s�OH_��"� �L � ��l�/a�rs:� aG �YUn@��G_�[�"�(h leveqVR��%at?+*sMa< V�—� 2KEAperhap!���]">9!.Aju��.# �[&mil�+.1��5so��� -�4o keep1� �*tJ.�Ey�m���lI, eM ["�J�p�B: a <-in&�2�B�6�'in�Uw%�!�I"v� � �"�5� D �M� �*{; �&� ;��)$m8�w$e�f�&orE�ete�%���'!H*�A �a� c=�1W.�Aq"E�! lar exces%�i2i�U�:X�� ,aLy�A�) �vo��lik� to b�.�X���K*rF ?l�'��2 g�' oLiyV5B V��oiGst�/,�8ly lipid�̱�)�E�7�%!�E�v �bsD. P�?�tr�[&�aV�P��F+0ext!�s��identifO �ibuE��~nI*��n.�[4 K&%� iochemEgapproach B+ex*Dd5m�.1{�'��Qsu��I. A!� �B��NFE,��� ��5�%���Xsee� B8p� 6(rfr){,74pr ki(cofilin-Jk"� ��se�&� �eU(t^@a&U �&V&�!H^rs2�`E���s�5jH�@)Wi�&�EI�pEv��"� �a�T -�M� |B`:Z*�m"� m�Kx� pa�3el��� mAA%z�ly!�mot�2�B.�  Qof"� > h!��be"�� �2�'—1ؽ�sa �*�Mz�EIy6|K�J�s%r�� �E[7�xI49–5A�PM�~j �uly ]w��v� oinc���o"k(!q��/@e8t�%x�m.�f[2<$O:vpre�;�ԅK�,A 7on6 �"& (�5 �trigg�z packt\g��@aR=����i�al��YzE< �F���1 ���P�O1a�dj�A-��%j �k� P��aH�?�R��:�If"�=]1�yA~)�E�GX gene�Ncu�M�� -0�Rny"�A� Ric�6ffi�f"� &�-�I�>:V���B�c�K[� l <�w"�u�!��9�\r�ch2biM ��)�"�BUhI2���8s�biJ%nd�N�Pdh�isd{ec4�x l�|Z�8-��W/b� cade [53]��eK�� i�*Xx.�| �*Wt�back ag',&en�_"�CI�f�}�� _$b�D_>� is�Yr�#A�t97 f!i� rL�!.model��explai�Jhy2)iXG!m"� bye)IE�B�WpTA�� Iu B%�UB�&z8 � T��t"�'�]!**' true;&�C'!Eu$ >�-I1;&� on���b�sjGa!�!�y# C�l?Δ�� -14zA�%���ly:j?�����Eall�l`L,G)62 km"�{D �Qat hig:Y0,�q�%� dn> �2j#!p� �A%{P8~ ethaa� �>�)�re�D�aE;ok-�,�@�Kt�8Kd�P! Pan1?(pan1ΔPRt[5�<��� 2�"KF.)� . _�`N broak� ��y"� . 2N�Z.�qscaffol�g/oaŞ��� End301� [554�"�w �mod�b�T#� �2�EPern�� ���&z 7 I�g#yc�ą'R��bo�`]�or9rap� %-13& %.&,(�%~�2 �n biN.I! �o&��U�>!.N�Xconverg�j.@�sEd"�8in"� D$ fung�U"w0A=@“Spitzenkörper�!�!�(}s=c�l_)��ap� tipA�hypha�0 main�.�c. th [56c �-�M peciPme!���r�ed�:r!u)K.77j#I%/sOy?a��w��*' In S . ceBsia*&a 6-l�.��&] ��%�I!�!W Cdc4"�� sor Bem3p%�%�"N/[1�:�M 8^ :3,n)� ��tM=Yn�LJ �c1 ndA��՘���#bud emQpx��Utip!nnVo?a*"R"�M@!P��r�,e2�d�'d ri�Ito ����2���d��r&g+dium/-bu�i�}�:���%i�n��ch�$� �a�A�*#A�� :/�edM�AA�a-�>3Mȭ�m��#T�S"gL�-�a���cY� {</P!�*�� 6u��n-"-q*~3� �E>� m*7-LS! ���a���Ii "�3bp,a�U�>J9Z, ��><dc8[��82Z�d Emmil�"��"�$a��A�zM1��  "�-�1rQ'!D�@�>�A�*�-!�-52i&�;� � . O2�+�".��a�j"�&P q)K�!�!��ef'of� a~�MsL%M/PM+a�Bi�aJl�X6l����g.�of�iCq5�8&n��!s'� �"r�A-szI�atBDw�"�can&}'AvO 1�6�W+by����liz�n9O adja�!zm�f��5q extens&�>a�x�"�occur 6(&�i^C�An%� scap�U0�` %�A� rein7 seUe�b:Y�8-daugh�)�t* 1p�#bF$er [60 , 6�OIn�� azoa���JE !)�B� 5!R��)���%��-;Opl��M� #ic��of �-al�X[64In Xenopus egg�J �� s��fac� �|a� Eəm�s߃� A��9,�r� figu�""�pgranule|�mens�"!iF��v#=1[��7me)�6�1e��[ue� "�"!�^��%&p [638 !!A^$�7�s.�^ 1*"�K� !�R�4-�E� uncl&-V7�,“kiss-and-,4 vA NRSiY[6� or2JrunIr� �a�resynap!�)2�%5H/�apFH| �"B . Ou�-�f�.�>�f�%ng� Caenorhab�s�dgio implj%�!�9� Rab3�"��) �!&Q�  )���U�[6� W2 ergs���02��mB�e;:���Y"��;s�aug� !�(lm Mwm� �a" 0.goN� Y���!s�z!�l�9)_1 TXA��hid�S2 "lEZ�#Z2u�2i[s~<=k%Щ�%3.A�![?r$. Widefiel:�[m&�T &/- ou�.&j[6"C�-C�@X�g 4 NAAg@n-apochromat oil �r�leno�a Hamamatsu EM-CCD C9100-13 camerc#Photon F,,5Fm�/M$1 . 5 X C-� nd digi�Ls 5y�� voluA A�d])xVo�vsoftwa_(2�In�U$, LexingtoA4M�0��`|K�A opho�Y�exc�H� 491 n)�56 �~��&M4jv emit!�l�<�fi�Q�t ET520/40M�t}ET593em  6�BC%� TechnX2yY�R�haAVT �=Ce�+�%Y-Q � ly o4>glass"= m��thrC>.�UU% ''�~ expo,I/% pomo�g�fi!��&RNs k����j:,���tz e � � m#A,sr*ZedM;4a 300 mW solida�te 405!� �(�(iris ColdRa�8�2(StockeryaleUc Sale!�N"|: FRAP L��aa�D2um-,|'250 msb B��&�cA�9 �)��":N�,4OZ�SinV/Las175-�l�#�&�1��:�61�( 71% �)�)eLa�W�(�X�&m~ �ex (����� �a��6v; 5 �65%f2505 �696Y9->Y E%>(JB�1 a�406[9F:N�FP&I%@i���A�F�[eA!E�s!$e`�r ��SGpqi� -Gby2!�l �&� �:�+�0>�!�!�oqw"�Yo���)A��� � ���4a 4)TUP4at 17% arc lam�@�)�full �.�"�HA*�fb-�*��iQpsjq���!1gui� ]��Hu@AD!�quant�Ŏ� )T�A+>�L ���+5iA"N�er F+r4>,�new]��s�X&c� +ex��wS�'�Bp%]�?�v�� ed; �; ) |n�v�zoM>��A �<ser *&<�s  �!lcs d�*#deE� ��!*-Pdl�et,��es0�) 6i%�"r&�Gsisq�}Sec4pG4I3� m!�aCK &2��zch:GB-"K=�AC�d PA{1x%�no�^vi�m�n���)� �)�a���."�2�E}�:p����PM�2SI���� M:��!�ANy# stil�Sod�)��!�b���]�u�%��]ce� �� �fvEy���"PG Et��ve�pX �c1!e�L� � framem7J,���0�Ka�A(�!3*�*�F�,Cf�?ha ��a� a5 >2���ZU��$H juxta���46e ��Q�.�AHA�.5M2tpixels%la�."�tw�7J��rEmQ��� on����0� �F��!S:��XE"a �'m^Z���/ 4-D F� �&(�1aA�����vb��g�%������. Kymo‡M�NWmF2:k-1#of �@J ( http://rsb . + . ni�gov/ij/� 2MQ!� peak9 2&on|x Voxel Spyi��!�%�Q&e�!`ie���Uest vEE���f Q�s�^�W�5�D�eG1�;R� Z� T"jd�]T��1W��  �!$�� areawe_�c��J6%��#��&� -�Rvaoy ��!�to !�BW��fsh"zIt5x3-DX�bUIa�oreal PSFB�B�� 509� �. aR 40��� �&��+�("� �sho�# Adob;1AtA=San J\, C �� Wr�z��ax"�� �< �$Sony Vegas�w]0܏FF.`k!��P7])mod"p � F*oG}E�P�v�J,~l�vl-3ru!=�=A<850Af led�iDs pHVF1-CT , pUVF2 !$2-NT ( gif�.rom D�Christop2Z Loew�UBI?Ha+Zd��ns� TJ�Ing�NB�!�.j� D�Z.�l��su &) 2_*6 h �#�di �: 1xe�E�L �lSsUFa:31�mADI*an���ZE-1EWuMw5@ ��" [JF sؠt 55%�6xcept�rY"Fp/� A$%��!/y ͮB�%h�� � p 100%�*%' �.q �B�<>;th�0p>F�\��A�*G�l6J20ZJF �ff�/y�wc .4D �AZwE^eiy� n BL2rkDE?RRI�X( Agil."��,�ta Clara��L Ax�]� 1 mM IPTG%�1ta 16 hA ى..�ly�M� ��!�x  buff��125]T�pH��19M NaCl�!��B�I"% immo�'M�Tag<�.wybea�Z,Pierce Biote�!I��for�IL|J 4 nN�Eabat &[�4otein4 j�wa�3qEpNAI,f Brad��j b�P��,�μgdz#a Nx-T1i7 � , 10! EDTA U1x,% [v/v]8�X-��F�* H GTPFGDP al�9y �?�*o' d%���!�I�� )n3 �sI|�A�Y2IB� �mM MgCl�w�MEn�tt=��}sp�~:con�eiOE�!�� TPγS�M6�$r"-�tu=35[S]-la.�| -Myc� .;to!�μ�;Vub6a!TNT T7 Cޣd R�ule Lys[S (,mega�Madis�WI% ABboQf�wyj!�m�sa�J�16%W�6 x!"�a V�=i5�-b-Y66�4o�Q)L�I!D�el�� zo�6g��SDS�M],6SDS-PAGEa� nd g�e�fixdr����� filmj ^l&�&��;992yKd"8+��&24of.{m�ZN":�#� ��pg*�� &�5o2P=�:coe{�1c�uxLArSh/,�0�"e YPT1)!sub-c(V�,�x��}��to�%�Q5* 9(�h� BasesC�2�lJi� a"��f�%(�Zn��Ul ,�T o}Danbur�ECT c20%�tlӐA�3)��# C����nd 3 f deb���v�&D009��;cY�o%0�4!��\� A�sup�0f!���ng*�to2 "1 �(N% yf# U/Bd ���d 6.���m��B6���#%{�Fa�w�rJ ,2�,�M2�p��� HALT �2�V&8 B6 5� �s)repi�4-!elu)%<poof0. B�$q�!�pR+.Z�RT&�:"nAf%on qxve��"�um�� 100keA�� %IK�m��a5-�;� )A�F��;.�B�C"Q;A� �M6An di�� in GQca�V+"� =i U%�"��?F� ( Sigma-��, S; Loui�=MOjD�BG.yl��2�<R�U mix�S�Sed) μ ���-abb�z�, ( 9�IHls g�CedarlanJ)b�Bur1(� , ON (75 nM bovinB*I0( Hypermol EKAd�)�M 9 �PD׆1Lm��Ad�~uwof 1/10 �#me5]���! M KC���'&� 1h AT�=:G�%�2��U��n Inf0 200M PRO9p[ v OTe�-M�%orf��7zN$ �a��( wavelength�� 36~"#406�:j Z��?sI�*ٕ+X!=���8a�#r!�"�0�Y. S�&�_.er Kdatase���.A�� two-��!�npaS��X�s t �W5 Op-valu�de1'd�&ka �>�Gz�pad Pr�.5T� (S&�O Jollw ��/me�*� �aP�v���!0In�.m-p��H5$ata_5XOan/an �{errorAS0 Kq0EM .>�Aceta�� phen�HuX�R� inj" !V�e8�,l�f drugb1hum�O8p>.�+o�xi�(�|AA�U6�?��JA<da� �c�wbl��nq."R2��otoxic�!�omenaf6`�Wvs6xshe�Q c ne�i!z��� PheEo� 11 begiJd&V1�lobule�A�� al vǻCVx nd��g� =uN(A�Aj laB�re,;-u�1. E5�J,ort'1�soz&�=�1qUin NAPQI^�P�\�/�:t{E �@AO�-( ��$ Ezon ()E�nS�arw�3ffi� ��e�Iq2�czj)Q1�oT�Eg!%k!ONZ-9�hyp�')�Chn=ngA�/]�infea� 96�� infl� R��b�can"�Fg�_��2 )�3SB�r?e�Ein�elR?��x&at5�t)Iar 1�?!s�6mo�. Vir}I��s�5���1dbiAal-to-CV�Ed0��<e �)�P��M behavi� . Emplo�2� achiEO���ve��]Ja��|$2a.l clear�^aQvs|mt &3� b%�F�.A"�ud)�,!�Ce�Uo sS-a/�+��al fe�O�:u-U�A�e:�AU-�CVh2��2aI�.Bo�M a�+avr%Ala2� de�OM&�d��B"�(�.v�`A��%���$ mitochond�5�9vO�-V7 of%#,Ohe�01%i�2���&7E�l�< ` s enaw�0cTsyM!��N��B<�KcT�/m,a ��P, sca.c ausa8�g!�of�T"�W��%2�� o�g�bE�/AQ��Qp6a^��u��2PAP� i� � ! Zi�� b � 24-h�8՛sca.a(�37�tf�xi4v "�f62&ao�:�d�. 2E�PA� V( AILw13�Ft d7OuR�fT�3&�>dra��cA�Zl`NAJ�=m%!�%@etI~&M�I3�Ja�"(�[1����To��{�Yledge�:[P �� �T Nd:op�X)�Rb?!�t ) nҔm\FB�Eof��7Tndg �� U�m?^���why� �a� I/Y of'pon�� "� �  w)�atY�,!�cVC4v��add0�&y,Z ',ven�8,2�:e?U6\ !:� �t!(prI�rad�i)�H�Xy95!�*Hikff�-E�1C}_H�`!���t\4) : N-�I4yl-p-benzoquin����s .i ocy�YU� �S !por�2( Pau spac� CV (� l����� ai�"< 82iass�L �of �=� �� ! c�I��-ԕ�at gy*� ��6$ �d �%�� eff �SDo u"W%d.�=c�)xi�lea !� issu! g�&%�r$ ��\.��c>� �-�"3�� �,VmpE^c��� b��5�/ erci�Z Z����s91.8�&/ m�v?onim��R^e��i� Edar4� 3�ȀAJ2� T &ori�COBimp�Yqp!+���s.�circumv���*;�1��-ath�e"5-�!.e�1���e>S.�by�m�����ong�nalog�{"�59X({4K�@�\d"�matheŔWJa� edP M"��'a|j%T -oa v  �Fm �a� eM&E�2O�dl� lE� omim aA%lRto0U,�icYb�M�  b}hyY/Y�bh[r �to5�!jAF�Z}�. Rg<%Y1.��-��nt � e��~Ũins&�q z�A�)simon�:鯉R�� qNY7\P�^1�$�4J� z`. ��!>s�v�: �c@ V&wo�(EoplW ~Q��SM/too��� o meet!]inge�e����c�3&� "-�Fh%��e�<��"Ђe a����, 5�cy:�#thu��mn(%RAW����4� FEf0X. PhysE�" �o� ��turc�:eB� cV6�~� �<b�l8n¥G���ki�� &2�pv {dŦ.9��a� � �� l0 mg/kg� � &� �*�y%�"+JY�[Yy7] �o"�) '�y &AQ��� A[�(��l��-���&� of I-&�U�IYUq.b�leW�m%�ie�=2`c/igV�<��[qXE.�s-Z"�� =�ů� �EF�s��%o�m5#G�C��Z�J �#lOlp!�muX� wet(���2�h�ov^�g�o|�c�. M]�goŠ!����b�}��w� F�de�J(nd buil1�'*T�q!�h�, useful [8�Cޥ� �I�!+(�i*��!IY1S�f�,�r(AR�b�: p"�� D Z��w!��2;6wU8.`CV- om<"җ'F �at 2�M��)��R# ��w���}�ar<A�"|=�A� -��5�מC>3�$aa� eYm�!G���#d� ���i�]6�S���Cr�0� � sM^ . Ea^m �ilw�ekam��A a�as��ic�%Z%��Ze1 fB�� eV�1L��Kg�5f���e���b8K�.?�'`mA &? M?�faOcA�in ± 1A� ndar��vO�!ze�R1)ZR �*O� �E>Ae �:.�� %�R��Vj�+�4��c*e� *-�� pharmacok�pr _E�SF��S1<~�@RK"�strM�}� 5"�]Os mZYQ9??O2���c2*�Gm��C�}�F��M� gudra2�b$F6R%�� �#,6� S�h.�O\dvp|C��R"?9�m�")er�4s;�Yparame�Kn�8AfVcX��a't��ar &t !�7%,N��st�un�S.�gW�*<��A� p�Tin1(,�E8Am, -�may��4 ( msi.."��A-p6 aBc �A'L�N4!���=eH35u 95�to������o�2�C"�@i�n�)vc enzy�<�e.�I~he�͌s-w hAρ��33� 9�(?F, G&SN���/ede�TA� \�.����n6ona�I).&�|CYP2E���G*t�f�$D"^ ThreC9�2>�iGMi��!xe�J&a!�)�"h �6.. C>!��"� I ��U Deathe�&�N4A�ir o2!.lǡ.hJm��y��m�a��>as�`!V�'�sF�b�BQ��9A`hx�� b�$lyhedrLthaJed"rA�per�!o4vn Y�l��s���!<g���Q  i)���ru"2q)�� ��4B9N�� 9��i�-r� B� (a8" �R ��ҍ�a �C random��=��a�c!�Mh�%n�%bpa�&B+!� #rc�%a sinuso�N���y.cenze� mpz2ѧsu4e m&)g� ough ��#%my�\l&�tQ�!�Vv�g[ aO-��. Fca1�Fs�A�$#r �3e �'�� �+2u#The&"s��a��E��%ofm��.fFi��d I��B%6. B Dela�Vvad��'rOB�K42�12 �A�:� r A��;in2y1����zB8%c �� ^ � while kee� %< J v�-dO �!�2^" A" "�gl�n�%)Twe'SS<tnw �:r!�a��{r*�M& @E��@:1>�G s>�,6�e alsi�� QZ>�";�����Z��3`$M%"*^� �w F u' �u�G"�g#Va"�$]I0ULC.5�b�f6�0u��F.r�x�toqCV)ut� Y11Z�fd5 �PP� a�, ���@ SG n unu��q��Z� j.�7 � bв"�te�D6QUX K� �>!Gb� l���at�4h-� �LN�t"������h&lZA�t�2W��?��q� s< a�6,��&�s���oPPY�P 4 :�.[|7neighb@'C� �-� s: RE��[eoW"*RPPՖ2-{Aʡ�f !of2����>b2� �be� �+�.Q �>�.(in�isD\ %�"? i��J�H�����1�)�I �^u ��V���C.@Rw(nl�xC �8�1�Har skejKm��. L��"/�+!m.$E%!f�vul�lbl�� �#S!�� c(���cA ,v��6��to��e�83"��)�fZ4��� �=UF%igD�!z%�� �3a��!�CVEx&!ϸ�d!!��A�z v\1��!�e.��2� G n$*� "/ise���/WTn<<n]�*�!v�L���*.A���ed=��"3 M7!e�Qa ���seRgp4s.+at� :�&:� c"vA9V�>m6&���z`�!�&�"�9$2�!2g+~Q+ �*g�M&"J) &��Q� see�;eq>�.G2�..˽SHR�va�1qv�`�!�>� -�-.iMn��� ’s.�+��9�zd&�+s�lyv��s'�ed~/�y72�e"�-&�p2�� itoD.g'@&� E�6��f�/�$N .�,"/�Q*g��5#�wZ1"2��%heJ�� ��l� �"qZbi��! %�2;�N]�� r�AM.��A�"A�� to M2R�NB��X�FV��*��M!�6_2x���gs�<� l/VB:T'�ja*2"!�m��/Ž"�+�q��o�� : 46� d&�  5-grY�(-AI ban�E�? 6A )�!� exec�KF!�Y�`Z��h͋i:�M�A% smG��mW [16]B��� �Vg�Hic�od�0t��ouse VX"�:!�Wac1���FBod�7 �bfeI�o L�-)�P 7.��..�BG����aUiAP��I�%}.�C)N!�[in� � 1x1 yA�4 �R�g"T"�jCg),5"�Ci5�&fa�a�.��.�a��6X ?L� a�z�. M�� E� �i�[��Q�1�"2<K2"��H:i� !�6~1PP1HD&Gy�1(��ui�,./&IAs�Hq��&!Fok�!f6�9in.�� �A� �wiw{: 7429�, H�948�G��310�Pm8&2 ,-��p�n-�e�M%�*�'h' �D m��9���]���\Mid)M��V"p ���{m { 1G2~A �+inr:teTN �@� 6�"� � �y:�E�%{�q�@10x )��1�+:� o�1�9)"9-m��yi��q �t: a �BQ�k�Y6� , yef!�#�1a�Ie!j)>Ts/�smA�6J��Df �msmS>�nyeZ����G =��-�E*e4F�:�A�&�*%aS��a� 0# !��be�! , elS a�A�22})�� on-.� G% s�t&Ou��n�:P2���(Yn�1� "[&�-64"v2�,�]� �!�rsoJam1"�#:�ne-to��"e�&:2���d=��*"2"��*h��;D$ �I)��  arbitr;W!mo)�l�� Ka��n��d�������e9�2�!��Fis�2��7U!Cf��]4��4B:� Kq:.9�t��X�3��`%�mGbE9j Y O��� H�nMDon-B�8 : isc�b[�v/�.dacM2� e΁4nd�B`T&I �a#�DJ �6s]��p��doa��64Q!sI>�:�|h��2�T�a:i�7 . Co�uA�p�Aez& Ute�thA� inse&>,�+JgsAHL�&bF� `?%""~� " � unfolAh.2#2xs*�.�� �=�q ŻɝA B� Harr?)xTI�[7� 5b7� �B #�m� "� �+�P37��.�-�re�Yed1�6�1# Acd-of�ad��.%�tragastr[.jh5d&B�%��"9&6�E�-ɇ�#l �1)�� )�(�xU .�.�77B�p axi�)ll6�vB�"7AI��+j same��tJ5�����)6d�2�bar h/AT:���a�������e~�"�)N�_�mBt �V�.e��zFVB/Jrq/6#��R��#3�Fn�n s).��(%M�,�sq��w�nBE��e\-9��0!�wh�"!C ) . �o�� x���r�F�)#�A�Y oW0�9mP zu�;&q-, approach [1�7] ( Fig 1 ) . Most researchers seem to prefer including ample realistic detail in explanatory models . However , mechanisms like those employed in Mouse Analogs are scientifically preferable and more informative because they are only as detailed as necessary for explainژ particular phenomenon or challenging a.'`hypothesis . A validated % Mech�$ with limi �� subsumes many different yet equa�lausible � :$ed variantwTWhen we falsify such a|T( show that it is inadb|te for its Target Attributes ) ,W�significantly shrink the space ofJ�� by e�nat!c0whole classes; moreR�ThAe sult�E�5 docum!"first A2@of virtual experi$ s to5�e compe�$biomimetic=#1�e!Q| fact)2 three wer1b0ied demonstra!)!]N�canR09�.3U,s and� ilit!��%)funda�al work�wet-labK �ation .U starAv%�!!cMo!;Ammus!�NZ-�!?E7\Hepatocyte Deaths occurr1)�near CVs\e acquired new knowledgeE xamin7whyA�,a� well MNZ-�G.�s , faiA�to mimic)�}�. Exp�zlinsight was further improved6�!�M2na;cessfua{achie6!�mP�. An ԡis&importanizon� 4repair pathwayE�mitigidamage��6��!Gnticip)�at �frE�arably�� simonious�2somew+�I.�.`A�do�same .E�Iterat�HRefineAi�< Protocol ( described under Materials and Methods ) outlines !ato ident��AױJi�N�qion�#t��1�aŮY�, concretenesA.coupled�q!�abaHy�observe�0measure propa-� caus�Eve�Z, makesA� easy�*a?rti� non-tomZ,discuss opin� abou�Me credi �Xof similarities betweenJJᙥ !A�7from ���envision��counter�с�.Si�,��be�4e a small frac!|�y�E�Zo!�1�2) 8ienced an early�" trigger %IM�5 )9conseque�Nwil��I>H @I�E�Qon may��0 in mice , bu��$has escape��te ��%��#��0ocused elsewh��(. If deemedu�t ,>z—�Tp!�e(—could beY�d direc�>�g1�.� . Du�Sexecu%�,>� is a!@E�ճisA{��$key featur�^APAP h��toxicity5.are gene��d-�3A�Suppose � stro��)A�do existB�A�E�%� . It�cl�E�a�ur���cese�ine��lrege8� 6C–6H ) ��or�2 Edrawn geliverq��sa+% icps�E�a�� flawE�5�.F codeM��[30!b t9EaUvnly*�ver a�L� [9>C goalan v[cyclea2 to r{ a�� .&QbG �!��*��us��� ng4-e� vi�1 �$rete softw!dm"���b*—A|a�L—p wo ways:� itTnot exhiAaB��/orX �il!%b���� �����A�eves allB_J Bef��%�!&, spec�FTto!%�in��rank-o� ��n term J � { " t� �me >l��� "� ;(t SEy Cri� .M��osh 8 �is now�� �obV ,��!alreadQa�everaNB[9–1��3��Bile Net�doelt*W ��ŇU�)�c�rat�� lobule�~uc�organ� A�F ,�an!�u�i��eHiOCa& � a��nd�Byq % � -to- �F mappfun�s [25�HeA���AkalA� texteiL �m���random�TofE�%ar flowD!0�`3-z n-l�68 node�45���&�3��,�N ,f pec�l�N@!X connI��99 �s: 55OQ 1! 2;��.in ;D � ",3B,2C02A3�֡�� both2� �\ W, �"�,Sinusoid Seg���%jly assige���!{e�.z&� . Hae'%�>f�u^pNgY(A�u�s5�.�-\�/� ASee V��ޅ"E� beA;�*u�� �� , ex�3B cap)b5,E �ca���&d inJ 13A|2�!v��n�� phys&�module� 3]: Indu�Handlea� Elim� $Metabolism!4B; ng1Q )�"� V� .ad i�AOv �osMlDndothelia� ells�[e blY ic� in AILI �yas% CYP2Ei�,��hough�?rel�am�I� very; ��a,to�%�A$An unans�d quesE,is.��n����in>�M�E|v�cok �"LofU [3EAddRng�.�fea� e��2�, givenBAs��0o��">isV� thisv. Adhe� to a��^ pa�y!�nd ����$vast major��mU��"�-����if�P�relevan* K|A@&��1�.�"�2^E]�CE�N��non �c �bim sH ghtforwarJad/"e�toJt�co� � m� pr �!�ev��caf:�%+���Ba�U�performaM� Nto "y �b phas�3��F� `�, upon A�>� ����d d!&� 6'� &^� &Hp��rz quq�ve2r(Q-!��tٰ&#i`�� ��(maril�����%f��4of NAPQI ) [33L a+���or*,pr[yU�t�glucuron��lfs�f4feaic�%� 'ext%��2"u�31@�"!?aR! their tre�.��e��j* tiny2|�$300 mg/kg �Ű paTB� 1�7 prob�OaAEbd2|beA��.}�timr 8ep ( 1 second )%��ot��c enzy�.�I"�MsaW)X���Ea=PPA�CV�2 >10 fE.�� ��iF�%:J�%e�� ��I���at le��EV��. All$TAh% lumgtog�@a' ed G&S�mos�tt".�0sM�.\)�2t�(A��in� ve2+������*^up85%!�aIH,e�- -!a�A@��=}� *)?/fq��W,} ! 0 . 15– 4; a l�" ge�U&oen�"sufficif numb�)��g"��sis re��(>T �~" b> 1G�"50% S!E@>\by%a�J��ms-�=�&7Bod��&lj �-�azJ 4A��4��� a�g*�I grade�[13�Si#4jt+�%��(����!"d "Q .o#P��#�,common blood&�Y4, s pO2 [35!���:%w&h*#ex�&t5�m�&�*,�-�McF;g~ t�,a�9x� �,r�%xpM�oa*�A� ath �-K A'�-��enti!ͪ�=�’T. PT( �)_PPQin grid!rdPP )��-e�*e 9�ndi.U!{inl_�-B{$( SS ) plua7e a��of>)E> @al&#�ach2pr�AoH�� ,�qtz ) = ∑i=z1⟨|SSji−1|⟩j��� SSz�a|zy)zeX |SS|/� �jAs� SS9i;~r!} ( Hs� = xss + �i�j "v'9�jb�; P<�a�I/_!� ��F�ae a��bracke/d�?-�@!e�*. E!��ha shap� �ar�sigmoi!�� Eown��r�end��K tU sca� oa'͍W._�ut�C. G���turqZ1of dep'*>�@ �!���c%s��b1�����Lla�-la� by r�� �o�+�3&�Y� 6$s��" / ope�Mng*:k m�c�&pro�s� u fa� abov�m� reshold ,�!�#be&�+�*rr�r��"'��#tc p;of8-ioy�.�q+M s af/'&ArAy$&� ly de��aXyA`6�a#G:� ��&� � p= 5�2"� arbitroݺ�no"m#?#to� do!��rwise�t� "�@!de+ye!w��xin vivo �-Ka2#  �ץ�66� rd����lso!`)Jb� :�-&�TU#��m1-E��v<en��v�8 �5 "� rbd9�� r5���>�& � �.eno�o���& >�D:�(� �� .n Q4 a:J� :& *Q � SetQ^�= 5m.�/sa`k"N.H& stud{U�f� � dA{w]5�homogen�4. T�*kep �El3*.m"�.���1E {& 4 5 he��2 ~ ��w-6U�EvN�= �5 v6#ыo3�I�����s2� O �. s�M�# 7AB0-:�s1 �e�"> of 8�g3e^�6#2"#���ܩNN E�ac7�*�nonMD��a ���is��� it5L,/a H� *�. sel`"+&�93 ; wev�)M�"= ��4$$,L!�e��0 �)�,AP� �J+widnac�'�:q:�6E���Bt, a ti� poin-BI�A�n�,a�T4��:� ��0!~in�m�����'3M� f� # hundred�%!��)a�)��-� �� �@6�, f ,9�%ad�8s�*�[� e1w \MW�Da V�"e, f��� at*!e Qd{�����y%�s)�� (���$,M�"^#��f >mH:&�!:5mL1%!~:l|#l]3 jAk ����!iK!��)$!�APD"� �t�/��M0���:"( Thu��!�resoll5e1of\ k→ j64=t�� &4� MW� l��䡫lemO}�A� gbe �3�:��+ n ) ,. S�Ae�I� a�N/�e�3a uniqK,[(\�=aeYd*sFO� ) �c� s4a&;)a�a�d�~ lo)y�/erW i�%�!�=�)%�G9#granul>9y2�7A<RC� ��8>��� )A��aU�E e� 2� sR #.��^�e�e�6'50%Ae} I�F�= 6A�A�*k �Z ��>FP} ��.6� �+e&�5�=e�m�e�� typ��,A�%�`up-rega�A�of syn�At1>t�w0autophagy [36� Cons��nt%� .� ng"�6� � >�� ��Y�� ��\�"�u� ac�@@/re�)�A�is!(�&& , �� �a��VI��o:��D.w  , lace�� >p guida�Vm�0��#ty-of-Mi�>onm7R�at �i&!�k �8%j. B7)����s clos�7oQ��"�6��5�fox�C�st�# �i[:n�Z9�.��b�CD*2.*F�w@:*%�F0(� y pF"�)j ���Z!"� Dead2�3 shif� "#A 3PP  io" 2E1 5�o Vrt:>�!�tCV2ai�AnewAaryide)!N�"K. I�iFAa�j9g)0I&/F=&XB� v.*� %"��"3.A�op!#�mov��me�� I���#CE .�/ keepN�V4�at �"C2e��5$i�2�Cl%<0;nW�d;�atP""=:}Fs&�%AE@MO risk�?too g�i!�|$be�b-*(� �id%:�I>�(��.%�s liG.�W~��� llowl1�or�Hv�0�op!<��>� NMorW%�M:g1�sY�f�a��s� �� inf"a� 5)G�3x� l�>dwa54M".rR�. 1�v!� 5fu�e�ƅ���"�7; J(0�ais%Ran)R��*�5�A�Ach�8ng�eO#A�/ n�ef� c�#� � pro�^8�� ng n�&l��dys�.Nx [36 , 37]%��.lY D s"mJ;� a-m����1!ip' �82 � �.|�0l(% combZ1effec�$%EJqMT�M8�+�!:PK" !nENd,���D��%#>��B6'�/>�� he6%�gdB6m�%j,�p [ E�+ F�is�'6P5T�M��  "pJAbe=A�N~H�U�Ŷ.5"JHe�c��C!0!�"!to?*Y �Vs �3lM]#��=a`9��'��+issY"in�.�&�5I�9]* � � sT9 n�9travenIH,�Brab)tonea!�4 i$gastricQ8. &�@T/ g%Ao � �F.��' ��u?VpreL> )V=��� $pharmacoki�?"�<��ad�<1M�#a�`O+��̓ss!�(rols Absorp�in6�!A�oE2mA��C� *m"t� e� 65Zl�*"3 1�)��$�X:���6M�5� rapik$W��e;woF��6mjK!�lsf:ne m[16�R�BG'er4=dose-"�FLa�%ԕ�e$��r�� w>��=az�C�B��[ dt-dev6 � m� � �q�S& S1A�*.!�)e>! �%M�!sW(%,�found�`K�ii�f"f %gtod�"���� on �?�HF�+:�V�5[38�9]�'�NA�ch��E�reaso�%� , by�a�s$�� �6K k�5�)nr'^�wI�K�8teruP�s)�despit�f�9&�O�23e2"�q��iO�re quM"o,.M; r�:�E�Ia5�9&�*��*A9�c&-��A�8plasma half-lif "_�7�2, 3x-5x)��[4�;'�ﱮ�� 6B �&�-I. U�-�med��rs�0AL�0"� 75 �� . Tw�pE^A1�� Qma�+615P.�#!=Kn;3dF�2(BES1C�0 ]�H�bEʁBAt��AL>ls�^Y���BAs2pNA�dASa";=AM�."�6y')6�?ŢrI��T01jA�2E1�-c>Dei���"P*K/T !��. N*�YA:ct�)2����D2N e� �n-lethaliQ0Y�I��%-no& uB&�T*(�#�pof�12� #dF+g [ACovalcad;!2F3nd hist BH8e� of���4 alg prece�:measu�G5D�Ge� minu�/H! few �!�� �0�LrvC �;D+ Dela-$oISf)H.2 i�� 7B�"�/��-� C/��� "� � �porF.Wr�ES�see2�5ey)��Si�(E(oauthor Kaptzr��5)lE��)�F!>:�F�>EUG!h�0an-E�s�5H~&�0>� �atFo"vMw�5PXE7(R*:' each*` -�ic �I��z.K a pseudo-� Q&o[^A"?12]M�)�a�2�n2*�9���Zs�ePS U ť��%iO1.y ��Qso .�Ib~.�)��"? \?WOur/9j*�!�u�A�q�0#GR![S:�5A�� � � >�0yq2�BHGA{Q�P}�X".�A|eean.0 HE� =$m&� ’s * � 2+jD2<.%�%�e�~UcusT* �2as� "��_y+^�� 5Aks9A.)A]��2$.9�tho�9m��e^+short ^.s0d:KQ"�)-E�Sc*�V .H We�)]fi@Par 2�:A7B � !�sX 3 ) +&vBU[���� a�c�=oV#"I %�5� o5]�)I�e ��� -8a!�fetB3vKXo��Lk# 4d;1�%Xyu y�3�3L@�!(�.�E�%��2H )�E1�E��as�x�is�aZ�b�">Ax"�Jsa�I�i> ��se�'�]�0 h u2MEi:Kia high f�ebpolw effA�A� �!�"%�� r @I�rd�Vy�!�2=_Q�A !�Ey"l  nDaN:*84�S,��� ��P�%��i�5t�nte)�*�I!a"�)Z�t���.!of� ,��CA�E%UW schema)�JScripA&a{R5�:52���)��nd6# �a��karchi�)n?�+�DiSub�IE�o�Bol!�>re�orQ ,Ir�T,( Assembla )!"`�]7tyE��M%i���tn�82anCpublicOcollab�J [4�E4\GInput-oue�( I/O )) i�/Cdu5l� SR,er %s!3stoA&iG�CS�^P� s tightly��O\�4�FE2��taiUI�A��Yr5-js3R!� ggrey\��q�� . Ve]Ked2�5�(as download pack�3髡+0@oolchj�9A &�0�L � 6,6��!�!15Qi��0n-sour�[�seb�:�repea?9t%��I!prI!g"�:eU�%�"�S�Jlicenm.a � )huBre buil�  Qii7nd��`(n!� loud.UQ�2,Z�M)��e��AOinf�2�/s^6a�URU^5T) team mem<,y;i�!��)`mun)WReg� a=� tesA�r� �E�=of canonus�I�_��)�l�2JO;�N�Whi�DIri�c�#�d{=�R)6zAe, appl�.�A���Na�l��Nt@)O MJ: �% surv� heVk!tV0 subm�Td�=��b� �GcI�ba�^^7� Iin�?f6@arLmp"K�� S�Rmpsatise,N��* yiel�AR�qa�/q�to6��X&����C`%Y�9��&T�sE�h*�k �AAccor�}Ch��gen|VA nsmi�^�(e�!�diagn~]�Kfafbor�^@Trypanosoma cruzi��Im� � reI�'�}� si�by INProɔI��S�p st�(of T . q�^�Hbody ta��4�A mont�=g�=Parwmia�!s3�6!by PCRak-)E�childre & grouFGE2f��U/-�s�-up9X: �_Ne+i�]�(d)z� !��%5de�6y�miG cop�c�@�iO, :]<) ( n = 19 )^3S�1�!!y��-'.�tm[iso�R�Ahemocul T19��\�E}i18 of e!genke�4as DTU TcV , (G mer+ge TcIId�?�N�as��'�r=ylto�ol>3��ty350�co�Z.�w�S�M��` \o&�M �$�s� onBE+9�.s�x�!�e� � burd1\a 5a ( 22&!e51 �C^-!��oS%>Ucc� t� cikAZpro��v}=�'2o>e=*-�U��`� e�=p �a$� �Ds!m)b� velo��smJ�3�k9�9�1�is . J���� u#Vma]of�aor Amer:r�)iaQWdis�)�afA�^ ##8OHFhll�+peo� in L�-X [|,BB pa�"bn=!�'g�o���J�,0)R-��6j� (its epidemi5�*pL �.�>4st�=y]1�X000J' ��Jab��J "� ��l� be-�mig�2CRw�tA\ainXo North5o!REur�`Ak�e1�]:22ald$ �g�07[2JT�#/ -to-E�=�2Lr5%i�6�is} ble: 10%,�gua�3�Pe>�K8 . 6!� F :-!d�Je� �H��\mb.��cor�&2u.�!�RELISA�?�3nAthird);Y5�3� -"Q Z��-� e ai�y�7� r-E�j�Us9y5>��|[ ~5romptG*� V . P6D�3[� 9�*�� �Y� 8itu�ac2 de si& ía)DD�lMario Fatala Chaben”-ANLIS%�gs G]albrá �O�3ce�5� �ie%�-�o�^",. :��'ie�� ��ea���f^av~~�M]>dI�*R Sixtyo!�S�2�u�dK�K��6�(m+�6m�Q.� �nu +��ntry �DP % 35% c��R� A;5% "� U&� I*ed�� %nasymppicI3%�0M[c �A.� PAz r(�(B� -Qi�/$vep�:% rece���9B� .+!By�Ob�4�f�O!!���%����-z�V2� drug�S.R�@%)&j842$g�;�zto 95B��x� �E=�c�gA�m�� �%��q� �-�zt:q�!�J� �A,�untViM#mdp >b� ndG51�fulfill��N$�'��rl.em%� GEB-)�s��� "�(�%�&.�q�I%ys� �595�4V��� y ,���_2E5�ލ��e|A8-"e�p�~A�ч�#B9!"/ Y!��M4E�}. � 9������:�,�I&� �s:a@�8� aggl;�� i[ ofluuce��Ae�]-link�% sorb} = (�恻�# epimastig�wwh �&�MAp~ gY�WwU�"|[? PatH(^=YJ��26� E�.W %)n"� ,F�u� C Worl_@�wO2�jnm�1���-g#{�T�nB�i6&�f�E[ ��sor�M??'R� [!`bo8vfeI�`'�?���ob j circ69pqw :mL�i��� "�,A&n' �tu(~�g� �B�a�t|7( LIT ) Z3um�="�K���fefkalf!uz"cub�at 28°Ch �h wth� checA� n30%0 45 d�bk>by4(*�1/MD��/�[im�atSfroze�hr�a�2iy!���2)21.b��ek Ca`0 � !f(;�%�h&cdSJ/ %:sppu olum}q GE HE�cWLX5S�_c%� Upps , SweG�"1N � PCR-*� |6!�A^� uc �~g2p�$d-lea�|X a�c)'TCC , TC� TC2 [u"x!�Ip� ~<�d350 bp��TcI]�!m3IicIVTcV..~;cf΃��L�� Řssa�6d%r do!�!!424S alpha rRNA%)�D7 �D725!��_or �u[ſ��hg8ns Sylvio X10 (���Y le, M5631 CANIII V/Mncl2!4CL-Br�& 7���. D�}�mA�en)�i$ terqux�l�1�j��@��iE-buI6���dnu�w +4Kruskal–Wall�es� !zDun(��\"�]�!^��� !*� �nl ,) 2008�2011 , 4�39cd(e�* -Xdm�re�"�}9�)&�� m�"�Ar26% sP �&5 ����to ! "A m�� OQ51_�"� ���Ged%". ur~� ��3,!j!1�(]B B�!2mm�d� �E�v �=G56Hh!��er� Fe),51 O c.T"m� %N&LEyL*� �2��: G�#�#:T�n�#(68#&� FYeP�)+>J�$6 ��MamU�s �V#:�Q��#�a�iyat#@a�m "� �^~#� )'��:����" R�2k-Y?a:~�_��"f �?.�dN�[ P�U l�E0Z4ry �,�,MX" "I=)�B)J!� ��wh>_Q0�(j !P!A� anB� Z�n!].,/ tsu�tB!� >iR��Nof �L  C�&!�T0�73�&v()��v�Zet�+��l�2ory��&� ]F�Ha�Q]ic �1�-^6�.�pam ǁs"6H�:mi)�m%(�#�at + Ay�&� |h' &Nm'"��h789"F%(ͅ�'��2%�3L4. �q� B ,}>�$ �(-�fatJ" �� �B�' ( 21 �(X:c9A 3b� �%D�� :n�3v5��J�F�&"JtѢq�l�~%��Rw!�1}@{ ll)!A� ("�&B�c�As%u Ue�.��) 3c ,Y@ofj�B%� 5� ���� s"�V��g#��8e&M�J� ( 54�'pQ"�8"�'C��S@�RCF��J L�u9-���  ,M N�Uo-u&of|:*�$o$�e`�� 5�Aű`se�R�&K��VA5qM-� It i�wth�a�t�Y�J�u!\�<%�ro&t'J�1���I�B25SQL C� <�c7"0( r�+�7�+w�he:cPofY.��,,!�� �)s6")� �#S < :�iN��-R�&�+U���i�B�,A�seLt5eA!3./t $e�7$e BerePiA�a*� ZOM�6EH�/�&. C�2�R-6)� K�"�B�&A�!���c� $)Ņ� 2^�! ( �14m��jA�p��AJ�)"(���E BenznidazJa��D�&NG 19&P�r+�"#���qpunx��56� ��*i���um�CR��+ng�#e��+)�x ��6e�O�oY�f�+."��P%vb�Ja#",%�!�)�%�9�F in 1�9y��1� cceec��,�hi_�>0. j".-�V> I . �&aim�/&�to"u%�� why%�Ey�"�U4&��v2m�� "�.y �]6� -hs2��-(]r� w�&>o$-���(,� 5P%��l2�-paAyz��onihe ]*�U��>h�m��ul�D 94% �%I&B�(�F�-�&�o��e'��f��A�> ��5�Qso��`8l��sA�֛2*>�.�e1-K%k*%Fq ��b��In�Ii��MfapN ����i�%��'"k2x$Nw���F7.�\�e$2� � 5A2�s>�[�H�t75uy-5� N)5 s usˠA��]/0%��2���h!�<�G��vA�P<L :sk��riŨ.l�Q"6��2� A�1i����'�4 �at��j2�:7�5-[20_+3]a27�80�"�$��� :�3\ c�ly�9aR���1p��/�q�?ed� erwzA�+s�����.�EQ���-�9,���aZ�$&�$-�by�di��G�10� 100�* �!��di+� al�Q2E�7�, More�r,����re7�z|F�ashiUC��- xq� CtsZ3spiB,%/z`11�.jF*�Ue�f,2.H&�� u%��Osy;^ fs mˊ��!!�B�  Kles;G2e��har�-�F�H��u���_e�� �$B�>T�5��@�unG&G��of�N2ZMb1ivolum7 )�sA �8 Rega�8=a �A�,� u�1�_&� �[�5E�Jb� Q �5��1�SA�Z;N p-+e*L�V�jira*S�0��&)�by Corra:$&}��C?'5 ern u!in 34E-182� &�.�5����.)�&fV���3���6i5$%h_=&[-�Fhd�!��Xa�<ei���cp'����&3#-�ed 405�=�by2� %�:}f5ɀ./��ax.F�bQc�:\E"���7sfͥn�HA��6��"mis,.���� ���dby��� �|24]6�cac&�A�`5���)>eQ�!!z3. New:�/�x*ee\�2�2I5n��!n�  qe�j�"ic .� a�u3��x�o��A�����<W� ��: w�,�Tng1s.E�M��?^�s emer�h� g�� �ZC  )hopefua�FuoonKRablis.r=ro�&E��!�W3� hoYal��KI]o^Xt�yQ�E�]-�ui].%�!��'��� �6!5,=�� a�i�?�#Y��*&�DTU�.0m8s��6�"a .�^&baceJ�ev�hZ~9ai0A��-���%e� ��� is9��%�E�&94���"�:a�(>?�Es54��4rn� �Y��-�ٟbkA�G�Ta-T� q.� �2ew�" � *,� !���/2�Ro.J��^N�Abio�q�Es��ichia ii��s� �&68!�:i:���u��o�xoB�2'DDarse-gr$G% e� )�1ke0�x^;�{at�g coliA�=a��lf g�zJponen5dhP ady-�""�',�!�Atef�� �spa:In�t2�J, !:OoEaPb�pp�9A�)O�16Ap���ZP�P/ �!�gr6Z�% -to-Nq� "����7 IdE/�gn9�%4 anL�q�pyq�X!�ga (�wild-a�aedb��fLs nucle����m A1!m.feedbackA�e,�.U3 *�^�b�GtI��> ";e�.�us?\]x�n( principa�-�)��)��p��=1.��H��v��� �( rrnaper?�*8���:k�@t r?�T� !�qi &Qs��6l� c . �w[1>6]��� ew+ ���� uniqu)�q� �}( W�.�A�}(���G�%� c� hrom�"�?(m3b.ria ���~*e^ s"15�?�=� و�0apA& �{ivA%m&ZR. S .�Shimur�O�+�B�'�'��+�O %�5- d 12h�60 miC5's ago�?�!P�ZV)[10�g+=�4� .aof�"to 104 e��n͜�U P�!�WTk���w6! �;��f��ng!}o�B"񖁉A��l�x*4v , if7A5l9ɻE=�� E/aO��ix�5e�Ui��Q�$it%9���@'e�� �"��maximiz'it��>'Amz�id�6X:WFM?� gh.a��5(�VB�Ҙ"�!O natu6.�.]x��oD-y �X&O !6*l ��i��Uinvok�0�ilex��A���e�壁5�� \9 �*����p�Y�K���~r �5�;� �-}V-B��+"( :�a����nd �& �(η >C��M`a w�Ad��2R oduc�. �� 5Q �,2�yf� nvi;�� ellMak�'!qeiir �Y ;Ctak!�pop�4�dtA�fixirA��� N}wEQ&�vm�,]�.���yhor�ve�/���<.c� ���VpaβN$-��U&H -Fto.�mZX.���ŲMv,��!RUlyWE�!�6 !�Bx,� �"'u�8%�� iLYth7 �E1e޸� al&#finds2 �^5:�)T� zN -�A'-QKEs.,�KZ � S�^�%��"!�.N!9��o����)���# (4�����T��ŝ2'�p1Y*(1��Al~� ��-'�sh>nut�tF�� �� B&7�e�:�Q>Eys��1��'Y-�fe2|=5��Ρ/ulo0�Q\�("� F�� e 2Aa���m��� For*� �%�fL�galR�21%J�m:%��5 ["PV_ga�~F�6^�I��F�'I^^ jG86���[smi����� 22% w�> �&D!V�� r�.X��[non>�$~7 gain" i��'"Y � sou ���*(U�f. �n#Hu�p�L&U .HA�!�2��+r�e}�% oAaras��ɯ��e.ma�y�Q-{!a���w�t%x �%ed�muy%� .�Q d ��\9�"rt66m&`1$A��Q�TӐ!��,����C ��"h` n�4N‰����� –[�,%g>�] �Wm�ztoa�dic&l'E�$7 l��erturb�{2 3 {6'&�si�>dis!�Rc&es� ��|;_5 duce.� D(��!�'qnt2��f K��l� !Dgcap@S� )�I�-� �]�%�Z��SNbT�dSR�<8ng n6+:f� i�lv���lugX�%M�S�Eolvfteo&���0qu>�2 [���!d Nlen�? msel�A�d��gre�ń � � 4 1a�el��t�._�Efo�GT PopenhR sch]dv"M�[AiA� 7] (i� �G�y2�icy,9�a��t �iAoύۑ���!f_,&!$R-�z�+<<OU#�i� vp"�|��elu�S��i)�f%�f#T�^e2!��"^"cN�o 6�re~ng^��be\Lst����@ polymerW(p ) -�ote�@���� [2�P RNAp� o*�� �n�-"A ��ZfB���4r[0�x��m��`adE� [344�i�3? iG [4�43�.�ar !0Ild+Ab[4 _5�6�'W �OA�o�d%�middl� �wA��!�ͨ~p"@�,E�eVi� ,�%Xq�WA$!��D spir�F���4 f��%�[5��8MKՍ����a$#�4of�:gen"��<�e�� �;g c�h" rans %�!a� ���0�0VZ$�%1q�q X )o:�&�=V#�Gngp.��q���q:�'{�GDTjC�G ed"N� Reac ( CGGR��AnO̎Pif�lc�@@[>�.Ja �� �we�-�csm�E[global2%� �!'�D� �-&�. ���<e�A“q[A=[4�OFr x��bB�A("� r  Z1c"�:)��_"W��m�8�H , Φ?2VE /VE]�P k% � Ic4}o��";��at����H� ?Kh��o�GY+se-� "�in �w*3 .�(�b(unM�%�� )I�E+� UL a`E�!�@ach_ e �! _?2te� ew�.6��V�calG F#:|�I� !=B|�9�>2!bfalF  �)^�*%�f)�ba�&���~��;k�����#�: b&�!���2� J#�fav�bh�W%1�9�͢DiIȡq�AF(!��> �A������ RNR�})�(-e�!�*���� ,*xU�Xi�Baonk�$ �[*S�r�VpqSn3�Hu%���ul��g%{!p!s w� u!.�;24:.ANU"n�A+�Q"�6�-]�WT2u�bUF�*%S(�>ew���EuaQ.���$#,� wei��5g6�� ���!%vs.y—"`LaG!lU%ee�� gs��"e�e#^W�n=�—�'"��nda�"� 9}�1�%6an :�i�oe�=aD]�pw[2�2�C :�B�*� a��! �4�!6�}�is vrP�T@p�,N�� 4�3~i�e��,F origi� uA�y Nomura%�co E)M[( ]:( ��!�o# !s�  n`���f3dMURFng �X"8� MOs]qB�l f�".� Q""�"�p�Q�"��a�"��be �oȆi����eI��aIH 5Hz�&�TV��~��. S�q)�k~�e<�r9!)X]u�V��M�;����C �j"�%�si��3�0q}:�W� ��l��es�f��NŶe/ hm*!8 . �IrA�]5&�i[�n*�6ofg �&��'�de��ofBI��A*p3 %�� � . �{g�� z&�jI.�P -es*��.���Bv0 ��s �RlX���$;� A]SC��A�.2d��?(� �*ro�awa$&�!�������' �)��uB%B�!.�� N( n)� .�fm�a�5׉ N�"�L& ( r- -N:�leC� bulk��( 2l�";!y � s:��lM�- "��+ng�k, ;.+ń-:Ri��b�@ � ��. � b�:i}��p�Tm�y."���U�@$��n�.m�?�: ({ v�F@�titM85Na�z�����EW �D"ɭR�z0�0��Qn@a q�(Q�Iy*�a4��\.� ]�f .*�Iu�� >$&{ )Z�2�;9F�γ�bui�oMm�$en�4m���.[5քa�2:}�* 2�A�"�!�J.���]�%ixapt��laO�2�!i�!�a�1 a"���e&��E 9 U .R� ub/h�]��w��n��x0-icژ `�#ho�� of c�A. A*`>L�V{a}a���s"� ݉�D6�*��.`x m !za6��ʉWd1A!=��+-2�.ACE����p�� Clef� AA��X�{by]� 3r�%R0�:� 7�%�mb�D�!X�EJ��. s*�(� � &�� m�v!oJ&�(.Rj!6�B��DSb� a+�>G%p%�;�Q�4v��e`*�pllaS[%�nd=�Fb8RBS�II�[ zR�u��)A%�E2�ββ′� un�ch�C#�. !�X& �*�in����� ir o�AQ-�����,;~ed eholoeI[Oa�G.���\�V��M���� �b&hA:"8 <<\I�r� s� ��8ea�a�f 1��&t"�H� �al>� ���"� i�e&<.� �(�F���xi�5lyDָe|~<�i"2� �( ppGpA+n=��h"��% ,��@?#� �Nny2$si�& �e�p�.��e�)h7[5#� �A#w� G�G�A2� �42=]<. F#��)յ�ari�H At],-.�"� � G@�#1A�Ada�7e�n C]�B��A�&O)�|.d.�n�� Y �����Bea �.Gby� ��ng RN>E –��r"ɩ�6r����-i*Xn�, [55]Cn! �A}B�U١?K�v�i�A*reaM  �.a@b3E�[�� �����U}e��0or�af ate-� w�E/-,.'/.�–[5n&HA-F��+�6!e�g%�'ma vac!��.% h-� , [6�&�ьmanif94itself���:%qlY [��w �]�4���H�C<~1�5co[61���7!Jk!!�}q1yyWM-�S�!!�����2���?al,��?.� arBa�B7e�ߦ Z&a<:e� es�m&EAQ�*of��! 2�N[�#Ž@fe��3er�AMI`N,ZkineX.)�24 ��� �p �1|��U �6���yelGS���;mR� s�>s�!VZis�r* E�q�es� cҚ���n\��ur�.Q�A��Lh�n �s �Ci3�CEu'!75co�Ho2�8�2Spo&�+ ny artR<�,�mp8a��-eU*� [!i_��6 ��Ag%�.�r�D ��O~. S&w9�1AP7%Lg��28z �uN�� qe�2'U&d;fzby.sI�o�3!C� yq���' MM..�!&�no��IA�k&nZa�i�B� ig�o?A�%"� -��.!;6!�,8��AA�"�K`+-�$�"@�moaLV*w -�H�!� !�J�*&� .�GN"# 6)�>�&��� y � bloc8G .�:{:L7"�&\%��{%Tm�Bmem�i“S.># ��N �%,� 5]OD�*M�!de%�6�p+| .�&b*�O�tro �)q��])+I┍M%�* � �A��%=";-/F��.�&e2o�0��� ng ����`��$)m"�J�9-^6hL�.�J�.*���F ��#�!��ϭVEo�nly ve ���'i�č$%t m�*�0�-� � [65� � r8� a�e&$.f* �r+;4"5[6�de��ng)�i���"w)���m%D 0rpo�eco�%UAαJA�AS8z'�yy?�y 0i+�O��ň56� Pa\;�*�,��1a�3l k69!`" �  e��6W'�o � o� tr*� ( NT���urs�G6G��;A�at4V `_6]��|��[%��.�_ f pȘm �a��` ^AB��0%o�5eE���n�u�iZa�4 homeostaeA�Q��c6�rj�e|2�Yem�5� rKe�����can�%� �0!�=:4 Z?p_��eassoci�+>��genբage [a��6�!.> �-�Ps|d<�9��@  :�I�L�$eM 4s��  :�_�osF����al2�I.|6�� �Gn!7 ![��()���V�Aim�!�!�Ә2I�PI-A]�5�in_3AP$�B��@�5&��G�&�@�A����i�[7(B�*2) mT�U�eC�z���#���� |A�B�E�i��$e�I|,n6� ^ *2+pI( 20% ) �Bo�9eE8� c�!�%��vz�0�'eM�linJ�a2*?ins&п�_c�+�^� re-_a��"1 &"E" . Du*�2fA�T>2�&� F�rR*MhU�al�%ج�&v1j U�"� f)K�%�U92� 2u� %l A;��/�q��+* &�O.AL5& �5&���6a]� %&] E�S6ε�"� "7"� ���(*' ��C� ��� � �z ^3H� "� �T��8�NmB�$'9 ��ho-l� ��lA�İ)�aP5��b��! �3%1H5����n=&8b��,I,:�s"�m��Űby:&%q�Fi8 HN-S�Dsk�e*& �UP�3�:J In4~&` , [7 V�)����l-[A�"4$&~<G4� I�m�/?l2= F�a�.�E. .�� &.C��1i {�%�� ,�I�0�NyMpX1)�� t"�I�!fs��n " ! [� S [7��%{�R&G.� �US�un�!S.�A�  <%��Git�@��J�.�_�B�� noJzyp�*� FO��d�u��� ��*Y�&�a�!l� 7ior%s�FmuA�sN�oSlp�recruit)��"� th5� i�pact� A�J~ U?�he.��0�'ce up9#a�(p,QAheN\!*�����t �N�Jjac�I�e��I�� eQ cycle%\Ay>�� A�!Q�r) �AT ���0 �Q[�4"'� %� Ec.P�Na� P���6�d��stF�Nj� perhl�j�Xpl[va H�wlK.� ��-upt}{�4!��_�h� �.�&6�)r�;2x�*�4Y-3Q%�Ae=o*�>t =0�73 o!�pYKE��81 51�ʍy26a�b2�m-e�pA�I ���K*Gn�" ese or ot�aher factors are associated with the feedback response to rRNA gene dosage perturbation , no such f ]*s2=Cis limi�by e<[1] . Finally weqe that�fre%�p!@!�.�A�-�!�Hp bound nonspecificUto DNA !�Lin rapid equilibriumi�it EezYlocate!�moters�a E�(of 1-D slid!O0mechanism [74�Ii�currenti�4 , all inactiv �was�@um)�bFNpauseE s y���e . gA�E� S4 )thuAqaccessiA�to�. HowAg ,��b-tA��)k6�molecuA��� justfqA[!u�,perhaps serv!1�n addiA�al reoir{ RNApuYHSquires �fins�measuA�unA� steady-st!�con [a�weI�nexIW2/equeGs ��ed!��B!^h.v��Bqzreadilya"res��as �]!�(analyzed at6� . Althoug�A ull deriv�a9rat�{Llengthy ( see S2 . 5�T�S1 ) ,%5faR~ lendmselvesA���cterpret k. �a��,ge transcrip!� ��75]�l 7[3��1��$[76] initi ! �/given!a!�usualFre UA��wh� ni denot�h%�cen�y�?of e� es iakndE�)maximum ��".�B�of> i-the� classA�pee�l��GKmaH L rm�$holoenzyme30S�+, subunit bin�Gaff���>|toir corZ9Asi!�u(in o�dco.<IK�C2�noM list� ;�Usa� this'Is�%S%e��!��F volumeA�8vi = diVi (-�di!g- 6�Z���e numbe�H�QIper���IQi�e funcAD(al half-lif�B���e"refore �FR�of �EJi�viui .�2FRf�*��A��t� !"(form: ( 2 ) �tcU�t�um,gEDm��o�l�8&>t:O1τi�.�'assemblye��on��!�,boxa�n�[AEPE�~ ( i ) A��6totalA[p: isstant%� s due�our�um��N nega�autoreguI !Z�wE dealR�w�naïve��� �ZE� ,asprinciplA*replac( a mAAsophistim�  deaCbihe6)!�R m �%�ezioA�!� �al^�, ��detail�#e�&���known .5���i!�k( i r K q!# �Y�֝�assum�exIEi rowth!W .� dilu��Mairof α�Uμln 2 ,mμ!�!�" e� . Nor vrr�l&IyJ�6�P���&� ,! v��(  rů���AKEz.#s� � � �" Eq .]�rXerm� & ( lefta right ) :*B ,� p imma9(E�dif verof2w� firM ��� �Similar �ex�= �5H9 er:-(�Y" trib)�of ���F>s�&�  it. titu�Qles��an 2%V9�Q�m��[17� Y �seU �>)�%��r �l; -c��saierminl %����� :��8 D&bM�rni�q�I�,� \matchaOofI}�E�E���& thr� �.� ��level� C 1%�^�isa ival�+-�$previously ed�!ult� :m� ( Nc$/P ) βrcpu�[�&.��se�eX, P()O.$amino acida`( peptide ch� ,s;fr� o�G v 1�!x(M)�!pcpC2_ elon��o-�. E{�b ions�=*�Rh��� of6�,*Fpende��NX �9<,��be5� from��Baak�int!E counz հN=ase E*�� م�S1:� $. For exam�cone� show��=$-� 2�� is&� �9 is a� ,tic paramete�no%�!5rb Zabs)mf=S��u�*�increas�iprobabil?"�RBS�occup��Pi� �� refsY�on-2@ouprends oba���etweem�.2!�U�o4� 39fur�discuin)�7A��. To exta?�e��osIW%�2�re  an}e!�F/ !Td� μ4 var�_ 1� es�!5exq`!S"�linE� [43]m8Cooper-HelmstetA�d�� � %7�[788 Donachie'1j!�gar� ��*tancyS+v[4n9] 3  Vini�V7, def�}a�e��iog%�� ��ŝA�ep��E 2| origin�iIim m�j!%��@mapw!5-�j"�mBF� A�v� E {?r�( 0≤ w≤V�( ly C1/C�iod��he �MxVenchrom�V ( �) ly 4&JRe�mQ%���E,�! �V�=Z&� in&?1�$42] suggesa?!^h�"v-Ņ � �be fixe�-��it�9uld#ind�t�a]�er"�A=aX  targe �*-( Tadmorl Tlus�in��N�> �2�$! �O� ��0w��#�%3Bpredic�9aI!�MQ!( �" �edE�Y�ed {&�  set 2��$vides us w�^�.Ln��!�whe�^& ! ist R��WT� . We wish�U��"� �ٲsa�a'� Q � ,1LreproducM�t, nam�!X� ;M�+APit!Aarse-gra�g.�A�a��Qc��  Ya!e�� /�  J�, excep)�BKA`�, .�}e(��)%�ba�o� �� est�� ri�%�empirq dataMfO �%*)  �global>�-��at 37°Ca(LB broth [4i!j(��! �\�G�bt)��!l sequ�d;om�"�a\YVe���summari�in4 S1 .� a�[al plau~ valu�ab�_?Z�!5"8�[81�DbelaVhe"�Zar2�|(lose-packedea<remain���1��minimizimean squU4error ( MSE ) R�a�]2�:�E>Y n��.Jiuno+t�6"�5F6hA�i$ al ���!�2p15%; (S3E� �I8Bnd:� MSEs��re� �oU�or%.�@ � at 1�2��+� 2�1(�HT�m]\!>�&�w!#~A�2< be mutu�satis�-|��}�6 ,� ein����� f�� �ei%�saar�(of magnitudm:�of6� ��� Y'qd�A�oA�RBSi��s��by6M+ �gre�~ED�� stud��–[33'F� �aɇ� � of����serQofs M��atŋ`�(, Asai et a�[19] ha�eR=�E>�SC�w��*U ^, �=� on copy�ng!a�Opto K2 D��) ��je��n!/a!�� t environ��0Luria-Bertani�� ( μ� 0q M�� p��!' CGGR� A�app� ���r� struN 6WTRnU�ev� phys�!��%S ɟ:��$�a% th!�œ}�:�5%�E`B, a\ailed aw�Np"�!��p!(shed lineagzi�)7��l6��&�?J&� eachi c I�S7�In �3!�� w�# lain whicz:�a|��s�� carr� overA�$�e �!� ^��chang�S> e��5�i+&2=xgeF!� � :�7V�r,JwI-� 7 , ��. GkZ�� ��a� olveB 4diffe�!18..7!n ��?�e_��G!�ais�six-R�a}�w�#A�n6!�oQap�#ntoes��ar�%��k8% nde��n�� A hi�C so;�!li6��&�;so far��i&^!�A�7 �aAAbio2 ��&a�&c;S"ar crow�Ix4in vivo milieuh"� 3 xtre� 7SmSes [45]��typ��� �k~e)"�Φ�SVS/V%�(of 0 . 3–4 [46�O� ed��WT�n!�y�o��sF�ib#ar� dens� i�!io��� is or��G[2�If!�-�%�coJb,� !�� 6%�i�X5q�!)Youg��&�� ��( �$w��vi5�v "� by a��ticle� �gM��z!4& %m��b�w�poG42�e!“loa� es” ��A� ductiWutili� by�%p! �)��(,burden , likwtibio��rN(taZ�� *K4�bal)s:Igkt r"](, lead%�tra� ion:�appea���&*�atǵ�2�,OH&byu)�e^ 6� .��,�A���� lmos�tir<D�%�no2��support�,A�vice �a�o![��㡨icult>(�AA4"!B}.�y �#.�+ .���* . OneA�re�W["o�La*�ew%9�.9Jfwh1%u*�*�a�e�dJQe�1�L� ayvj, H��b�$i�h@4 Hill coeffici�,]l%m:�a6M�Ncutoff . ��m ��,���Q� +�APcpN5��.*�cpa%ea�"syste�| ���.��sN#��{"riter�a�I��  4hRi%�$i�2U��ٜar�*fr[o�kΦ%�Wz ?� phe�nolog��e��� )EatEA@��Ghas b�2�"l ineq =��!�e��a�&op+lO�� g'B�AAE>�)3da��*�" /eQΦ varyA�ad�*nR�@of cytoplasmic wa�to �er �5exter8#osm���t* [82]E B���2�"F%]!n*� !)aC"��l law!"�. An al�� .^S " hyp�/s�%�� {,�� ,ost�$��c��Y�Z��A�L! am�2���a��>�'��Ay�urc� � ATP�*c , et� T!atJma  vail" !���F�3� ,$�.A�*�, n��E=r�:al!�demA�, ia$�H<��6�(, n�p*lso3po�h �F:�e=�����'5 )��c&�'!�Mn0AX���a>&26 %�(�� housekeepa �a�0membrane buil� )�Y,�L&�&x Eia�.�b!�ْ�"2v&l!%�pHG, N� �zE D!�!u�@��,�wa.x 1� sugaP ve= emper: = Fl� E  �� , NjA�bed� ogen%k�� � of_ �!&� �%( �In J word!��y�2z� d"�!.�/� .|��5�.+,2�),o��1� �,�Z �c�^( QimA�on�%�An��{ way�) �.�5;! �] o�n capa�4%`�AI09;E�1�:b>ad��e)$w+ I {2O�J�<.�0,e�ET�� �Yt�sMcoi�)�%�&,�9��#N+ /'A1!�!A� mainC9!Er�.��)i�be low��d<po�#*��+&���"�v�1�e �N%�e:w�7e�[  �e���ow1�4��-+��a�e�-3& %as efG r �-� te�*]!Gc� � p*,be*X� g+ ledg� ցQr7��vok|)I \ th.�2� � } c�aOal�!e%5��cmin6~AA� $��crystal$ɴQ�c�9$6�!��yK�la@#A�aQ�=�ere$� staC{ toge!� J�2�2�un��Nu a �!�?�  vbfm9Y86��&6!.�. Fo�$��ooof view�shEb*1to"%er�7)0�twoU�e�n� ( �� �&.%ve slopoQ�v!�� curv��� �#o%@2^�^"�' ^� �*C:w��":�A0=�� n�B� �r�*��. W�& � hA4�F!Yu{#9� !�u���u�m�The"] .�2w.E;��c"o�to fitvTuna�n2~���.��:!,boR.�)�! D�xF$5�}1 6 My -�ed)��� m�� io w�� s�}��6 �+��IK��g!�!�a b�".4m�aE&bo≈38:. e�(2�6�5'f�`on7Y"A.5a 7.~5� bout 70:win  ...>�{i0�7�:r8a�� �O0<3�Y-�� umFwto yield����di;t d^g�.�A@2� grea�J>bG"*�*�In�E  A(hx2 %�: S`" t��1d#)�1I�Y chos�*.�!{!E`�!!N.��display�5Q32U�k�)�#or �0≅7 . 4·106;/M�� � ��� �AtE ��*T"^���Z�� sl�1lyk Q( M:st� higA�%��#� Na�� h'SW.�g&#an%_��b�.!�*a!�Sc@ �C ���#*K fav��de�.,.� LK b� �?�H�*N bf!v�.58!,Δ6� X pyYC�4imW���  ?$. WA��Q�sΦ D �Q �Q<b�4�=m�h 6d��6 a�"�W,�G��$ h�)s� >*L>u���!\�:�V-�rzX;a�$��7y8#�*2R#aɁə�>s^'?���ApA�E�\�7:�yE�*22R�Z=��S���a*�7h�Hbe:t� H�m,8ŒrebLtu?A��|�cleavag� I)$^�� 7L1t6�50 J wX�I���8� s exhibit�Fhal�/<umE0 teauE?m;.� �+ of 7–12Ay)$�+�aF!rr�%*� ?10@1n6�um;"�Q�a�nd 111�1e[��0��A���u� ?iuf=!�EH��&�� �no-.unrea�Eici�>�!B�b }bA��3�!oA��ZA] i#9!4�*�m��Hir�Mi�(r2�8Eh�J� 2�stron��� K ^!6:� at.�� ca��p�!`��� expens�bu*�#*� �cFO �C(M�>� e�N �Dap*6O'�I�5three�J%T involvA� only�&�A�μ*�S3A �.;:�, grrn4g�!&��"� �0aIrB�!$i *�&�E"�<�"*aRD2?�#:'S+,Z :9 azter�2E+�`aU�(Bt .of �sjsu� vaJ�), �+s�2toC � )1M#>ed [2�NS-�p 7Ap%0g*-6w�x ( 8 )^!Sw%�→∞�@ �≤%�/u ,�:A�qm�*~>�_)�!q2~�p�!Oa�)f65�=j a6�RIZ@e�� .�!�manip�"�:we. �A�→·��#/�� �!�iqte��2�$%((≃38 . 2±�*8M� m��w�L�� m��M6� i��� &} j6 S�e4�8HRn}� Tis2�-��-it lacks~��J�e)"��^�. R *O *�%*�C"�!er≡�C αP/�!BN19]Mc�C���E)!%f'A��M�}� ng�Sj ��wild-�Q8A�βr �80%-�Ş2�.[FG�0a7>I+e:<�6� ond�ily|�&#�B�Mu�ae�5K ��H(��L�� +μL&�E| � Li�klCP!:���F)b%I�5by��a#I�)�6J>M�2/>�!u��]N��o�7u4odU#e j-�0� b�0CJ ��te�4"�U�o�C \N�,AI�*"� �Nq�2C��(%YNKf�1ou}�Q"�2=* �7 E�~&? %�#=uF*�C�A �p��U&�if:� �5�{,e{.� F+�"����DG/1iv&iis�&I�b.be!�F��-B���. Oq�� FG��=�� m��N�"dB� N��"d"�s �"�.�~M�q4͂� �<-�a+)��� :mad�/(� 6is�1�a.�2j  Y�9�1as�� #��)_6��HJYBat�0st 9%&�?! �s quo�i��=�E�N_J�eJ�U�-NcI��@��:� z�7�:I :�u#)�j);fA9! %��p\ homoFv�Φ<"�C N# �r�iE�e�b23Q.&n<we,6s?.b>%!�G Z��R� �:E G**[.XO���mP�2to ad�/�*tra�BuUNo^�\4+�l!�"AEra�:a�gle2' , V+ �aB7^Q ae4�D&U 6� �(�}�Mgi�:� X -sL !!x�L >�1e]2�%��,( 85 nuc/sec�;[5WB%J�*�6��*8 �!� aD"Q=Ad��19 a56*R=d�' to 3Z (a�!e��)^�)��5�KZ���>K��(FG fee:`&�, e�6U ��^�R�It&� �Lmz%�V ( bue}a�:>otV0)"E �2:%��5∼90US!\ #!�∼13Yt! � f�3_�$IC s [5oL��CATno7tK I<� �$� d�a[65�1�eckA@s�n� a�)34����&� �^�#i��jsY�s>�p1690A�-fu"�XR)>,!Q}�>aWT-  ( da"�>%��OI`36F� seem4�qco�5�a�5y�6�l� � �VU1� _�:perXa�6Quanti�ZfQ,�^-, z��%n�� k�d W�)!WT2?or���K�^; I%(&x1��FD3��>C��a�@en:I�ilJDF�+dqK�U%��&�O(earlier . F�9�8x8%�:M=J�6%%5�..5$`�L) in fluore� U4mag��9WT"�It�*��& "GAq?�1�h!��edy6] �Ucleoi� d"'� �to�m�#m+)��L�5�&�vX%/�^ opic!fci�ml- �-�a 4�eD"O [48��N{N�dt-�� Bbe�; dele!U3gb8�nf(j72G�e"� ��� X�  =�A�F��1<sT<e=-�n1��rec'h B�%�i�* ,sol �aB hsmi�g�-� Q4�S � �And C . LU�,A��#;; mmun�Gon?�u1��� .N5��%�͔^K *$,9��c!�-v&18(#i�?F &!h�����An!н{�NL as)�.�!��AV�*)�]F��. u�!rQ.�]^9Z *�w&+�� ~"���yrJ~�E�I�=)1K 'C$!R1���bl jg >Z ِ�L�3ly Fj62�.� of 5 b1�QH.�]Tb�$A$:KR[f6�a�)��>�y9�I�;g6V!/2LSFY��I$�<��30�"��JAC� 9 �Sdc&�0"�� �?N+a� ci6.��h�@;� �M`or.��U' �1�d.SB�Fj�>_ ��m��u%�~Q �y�9�ň�S.��e M�j3"j-& B� zr�� ��|� is&^!�� ��Z2� Z .�juX �r*%V?�!}h�: "$'� =��7 �7 "Ei� �syn�K2#e�aG�d�uEQY'on!�aiW�H VE�� qual&� ��b��+*�o%�\ч. S>� ��HP�!>l�OM��r�$4j #]m�B.��3Y�backgrw �Sk=��75- as β-gal�psida�s$EWT P1�8m�gm�YfI%��� Z re�Eer���� norm�/�=�Y>� [64]6he�!�aw!�� e� x�>�:�iwN��� mann�n�!|�� ��?aPF E�5� 8)����"hLM=iN� {. �0 by ua{� s � ��F�B�:&c�!bf$N))=-�4�#�lud@C�sP>�SC5ed%�6.�>�.�dXm�FB Ax$.�q�8om\h weak�6+0A7�g6"�A ��o���� ~�%.��� &�B+%4J�%�b� � "^,m�A�:4q?�WeA�eu1X� Ma�&akeup1�NFU[�VXM�� IN3of:LT9C_*~�U!�e�� � 1�,�9.g.4�D�ntJL�k@?��had adFe"� ��  &�J�eLu�B�Z�U&'1�Y^[ ��. ��"�Bl��0!^A����N�pQ�Od� "=2&�(�ke�>$dA%�Pm9�k"�ERs)� X�X��4� f�0*�Bmedia��dfZ�R�'s-��� �!I6"Y%Z&�� !�EDa�S:-�6Vtg%,:3 y%���A΅T�;�Sh :Y45J.BY�Eb�;&MA5mallIRs�Y��s,B` �XP3�K"} �2P1)5pRRRLpa[[" majzxt�,IEF/ [92]�!M*�'�^� �~�!U\iUUYa+�R e�re�30>�in�BAnum_�V%^�#"}is%�e{�fJ& ��%��a]tI0G%tE k,%8� �;Ųxj��[9DRAlsW(�"�BE��o%�E�BIq6�$A|�#X�;� d�-"� luNEV�8acimEi*�z EfB  in+OG :�}o:l�Wji��$a P1-lacZ #��E�� 45:Y o'rol WT)1ipc%�acUV5�"+ r2k�82m�%�tE�. N�Zthe%�A�� g�нE� �2�VA��o,��AaZOa ' �B� �I�a�ur$4u�)oE�cs! ? infl�`!�8;lC�ohr�Lincorpo��t �I���?�=u�q���(yetiax�.J�FS� �KA��e.�` �x/* 6u� s�  cb�"rec�iSlRe�!=F�ɺ:�?��c'}!�2�D!� Ve0W%n�(k0�6 �F�Q_,&�#�8ar�Q E1yM=��Av&��Q. V0u�~( :&� � Jtf���%* &g�h���X����h}[5�bit]E G%1I��Jp RA�nK�l1S"q 3E0& z� "d .O,},�,� II���!>�� r�rjpu�MI%�!�] �� yN� n�L(4"B�I� �;ppGpp xnvgI59.�w�%X�mpE�h~~HMF M modu�v'=4>c6i4�mA:)�%.=�oO%\ne�Ere�4=%>�2HA<#:��"*�r�%��!��Q�Z5�5}EKE.�.2NiM �e�� �j���� � >�{�$�p�E� p�'$8t`ZB>Elon*{Q28B�1�ng�i�6dets�n"�%���E߉z�� �b�5�'6�"��gB )�N~%I� �!pS�%� CV�M"���,Id:< �.X���!SO3&�p@fG`]� � n� orA?a^!�6� Fqs�a�.����MeoNomurae'co��E���63]� ��>�"geossTze*to�")x6�K� �� �*p-��� � "]n�2�u�.n>�"� za9a�m�har;]FP"� by >�!.�2��H.�)i�5(Vl5��G<��}>�a�[ a� "+5�5�byZ�6WE�qpo�1tofYW&�"�^�vm  .m 6f!XBj���"yV,fI�6�����yKe6.Un�0 "��B��A@$7�zl a$a����c�e! s��Aa"� , D"�(by 22%2� �kYoV �� ng��>�[27k!TF�(:�� A4m�1�qa@ &� �W.��.u"?#a+�kF�i�%�� J :!�mo#���%� uM !�M�D�6�*&� �.�.autho�lg{2M�rQoDNhDb )� s [9�* r�9�n e.���aQ�)�%3Ix2~"t �+%�P`-�$�A0�:>xFP3| nsers|�� Ls� S:�9"�S�A9q,a���� ��>U2��"� B31R��$.�d&;t�9�up�,D �.�i�)+*GIJ"�%ykb��Z��?.e&�\ {E1;�bu&�<�oLa ing/"�boseU��(L�N!:�i�oO*5�. Ar- Q�*j���.��b%�� ��b�B�[Qy �QFF,S�iopolym� >�]E^.��l�B��or�+2fA�ngA�f5<X8in2ga NF�6 :���X .��"~6�^"� �+)+t"f "�In U�Fi[;k��" $\K'n pa�e�eS 3��d b�&w�Xas /@(%c�� �-^de^Qs�9o!��#G\a!� adapL7$re quicklyN�s�[9)H9%H�Sw� �{%9 ��!��H")9h�6y��oB*K {.*:2�SM!1���j5 ��9A�"���}z!R.p V.��>5t� �ui  !�.& �l���!p&@za�jEm�s�A�s�Vag[ desig*A_o5 a�i&��oep�ARst�!4A, awca Jec�$!V5/A�f�^Rs�66�A:; bau�e�& �9+6��s�`i�|� ��� or.$m� �*"�j�tt� Az� t::{ s&�n��D&wda��o6&o��/nventory%� r;]!��ue�j!>t0MG,i�gsu"Ej)��A oG*of�cy^MLi Ec_%�Sk�ch" �=B�GaA�f�j�GH^V*�a�:�eK"m d ? Pe�J2)<#�'virtui��29A�f 76�^�laV*�O � � a sma�! riK" , Δ�\ � �fcn6[Zr�Δ] )@ cmgK�*A,� :e�O^ ��<n�=( R��G�)2�sD qL!�.,a�6�P'!�"R�N�H�edq�s�,�%xcm!�a�eL:'ob�Vk�(�a"�7�Fm"c��iΦEB�d�e"��bro��:��.u��lyu �M�l�a( gine�Zp""2l�&PsX� ��]tr*���. Re� �&����c�.��a�*Z�A?�V��t�F�"�:�B o>u,l� fu���unA�f���*!�:$���4��2�W6vs d2k " Oo6  E 7��dg$&�M��y�1�!y�+-*��9��X=�=q��i]Ted !�Ń:. S:9a s�{_�ife taskte]�gA� �� ��ch��i�X o*R;fx9e2�� ":�it"�'qi)1�6C[97h!��T1���!BE0�� ��W�*a+�-I�" ������ iS -a[98S�"' *&A���� Mx&�O�8i�r q.Z#��51rQ��!�E�э s al�*�=a�e2@!lMb6�ma"�s ,Urg� RNAs%arbA�6:�[89�3�L[6���� r"�%}s�K4��.��JP!�e9��*%�b V����ngAs&"">Z�"�2�[2�Hm_ �S�� &&D z.rv.�!D6�Nk� �6�i�z� �hin!WA,ad��a&9n&� �approac�y%8if���l)ap$n�5me�! �h��-"uw>m>gu2"�8A�ͅ�1S[L=fu�V�/nti(0�$��#e�٘Ne��oOZL:���t�Dub�0� �qK�amp �off�� W�U non-m�&N^�mgj*R"�2=(R�>2����<%S,"]i!�:� ^1V�de��nR�Em@Y? f�+hK3�Q 8; rai�3�m=����k�i��B�o�s��-et�7( H�� !���m�.&�]w8J(. Y6��>A�[g V � ��L��1beg�W��Y �c���Py� &$D*6[�<5i2=��FfocusEg��on�(,��F m'!u���Ȁd A�nrA��%�� ��*%s� �<�ANO!(�x� �T�S�6< dZ1�dYA . Gr(&%Ft� ( GF�k.Hj.K0|!��"Ag���s�*g#\,�*]/�vriz� �X�V-�:>-kM�^!�p� ro�N�.lr d� �, � �� ) horm��a�. �!�*���a"�]A�B' M� cKGVZ-�aO-*or up2f nq�y! �dl|iv�s�g�+i �cotyled�ee�<1bscisicb� ( AB�NaC�V�=ito Arabidop!�� ��h$ ynamO �ib^�^. TR�dELONGATED HYPOCOTYL 5 ( HYu"? HOMOLOGH�^g=+eB'E#�h�%�.�� Mg�.ev~�%�-v3 es m� �� E �ԬE,B�,�t-.�.�to5B=iRE�toler��5sA�!�. Pull-AK%& BiFCg ays�SOat ��ac��HY5/HYH�t#!eX. 3(as1[ 1��$0��9n� `!��!aq5�'<4BA INSENSITIVEE ABIA ��DeMf���.]�G6%��i?so�qmE7s��DM(g�.no&�m%E 4e dual-lucifer@5V ��as}o*Z)� enh!�iځ^ % I5.Eby HY�����71�!��!�conve�t6�+*(#Br� ����-he @.�ndE�amZ�-M�B� �%�6q%�h'aZ���U .�. P��s�0!�Y�@uo���S.5e�im�ls �4�sa�. A>�sD s d��#uz�amongs!z&�&alY[1 , �-A!��V��19�d>��pla��no�: -q] n�>ap�E��"� v e#�/�W!@sh �Z�Y�cz!�&[��2�z�ɑ, ddD� .,=�� �flo~iM�[�6� A Fof no�% START dom."5  z!�SA0 ,���eBG6� , '&g\�yw;�L�r ^ BBX21"G���s _�bMs terfd!$ �!�8 �I5�[z�%\� ���!� Q�Q$Y�E.q-�esa%nt%�<olp �"!F ���EQ���hil�1 i�� anthocyanaalZ�&? Nth|q2�!&6���� t�tu�[p"���t3 y��la_st cRzin2I Ѳ�7A�ly 200!fa�32ܙaf:�6�& DNA-a�a3� (� !)�� s�ym-�C���P2� f%d!Bi�,.#2� 'ma6v�e�.cW(f�8HItd�M At2g21650%& A�MR !�he)�y [٭+t  ��eMEE pMATERNAL EFFECT EMBRYO ARREST�%��or AtRL* (ARABIDOPSIS��Ǚ[3Y Mu�J�t]�'�eA,female gametm�t�y6Kembry"�:e[>� �i�n�'!�a&JJI�7K�ly�'��to��!EA>]8rhinum majus [3��a5 (%�A�U�glog� .�Y4 R%� !� RAD-�u{�G�Όof4�QQs:2�)mN/(]2AKRSM%�t4g39250!�At1g75 � RSM4A1g1951,]< -ove.DG �i| hook�HIde!��-�1ap"�tdark ,�l��y �0nrtT:cotyl.� �)�a�t^!�l %��&h � m2� 4/"2"��2lab�Hor�*6"ha//ma2�sHT!�Fq�dU] 6D of F�T�L&CKLC%�a keySwTnI�. A�n4� _N- � �m ��?guard��:T��B��.L[4Gy�8. MoreA-[ 2-�&��@e*�e �hou�=f\t؈�K cytok� BA [�a�&I��N��e�/.� ��+E!�R��� $E�I�TX�B���Q�i�kH����>�G�%p)� شypɟ 6�mu�$�0.�shk��/37 B%vDp !�M,A� ��{� �>I,>� �*AK�N,r�0!^F]E*�ginspi�u�C�i�Du�g�!_E5bK2os�fto��. Q�) s ar� �!¯��S 5fr.��8&&o)I!*�&�l�'��I�*�T%� ��' B ~�3J|.Ar����GaiU%.�%.6�Y.�E=�*w"� �{6�a2[llK)d� !�%�$hip9�2�%5~c.V com��� !4I�# +I4�+urYJ;I?%���jh.� Y���>g�B2�N>:�. u�pl�!&! aP[al�3� , q*ri( RT-PCR ( q )���8uc�I%: imbi�3�� ��3� N$,�,)�>:Fex5E�I���A�* e da`-ȹ��. &�Oj%�� -uU�:����a&�(�&c�] �Q:C a��U�R����/p Z 73 . 96�x7�R13%�6�w83AU�v��(�zFig �=}0�q�RSM��&� B�«�$ 1B�D�/�T%��!� By!�!7�6 in 7-day-�eeM�of Col-0y4dz(�%B�E)�1>��&�]ot&��$k,�!m1��r)e�N��&�#�5�d5a�begin� �"�!t�9Yށ��E@T %�AE/cp�en�+e�cmM�-�F% Take_ge.� �M�M$F,�=�p"n9*v��*KC�:y a�ε�͙A��OF� !�f�.. Pn�#e,�A�ݻ{N (q2-��B�> �&&I �:��XEr�;�B�root �� i�J:�b!J"�)8%x�rialsI��;w!o2�N+�,)� Nant#ֹ"�t-�6��T-�,�G!� ��$( CS876657� ��37194�!d�S0( Salk_069941� �[""`V ABRCI� | rsm1��l��Ursm3 tr3#�]!aZ�!�*� ����xu�2�;an�2i[�:ach x u� techniquV�.hS1E�� 2Mu�C �ep� ��0rs>  ~ ��i�E� �R�b� !�>� ge�@Eno6� 3 OX-9�OX-12f%y���O�m� �:rbR 2_=��o#2!�u�U�Y� vB^ R)4�V�)��e�ny>*_D�E�V$�&��IIyKa3s!�.qoV"!@������d فf�J� m�!�u�5� �F�]Anu*n,A*�&9fQ].rNo �@�,�TG�-6��-CxG-6eEAj2�e�2ce��z�@PM|�0=a=m� ��&�NMl5E�6kN ��2E�&A�Z^"�Y A������(alU*��A�i�S1uy�1 B!_�6C)er�h]�$u!�J!��WT58iSJt9ա 2A��A�H���>��o re{er�rs~�)����%�2�](N�to 1 μM-���7 Q:���F>100" �2 !�h� _ M� ( S2� S2D5j�MYM2UM� valu&F#ũj !�� 26 !��}���"�!�$fresh weig3�&� ^��4Qt��e?}lI.*�.�.�or� �(^ 2��9:�1M�� �:4_��J%��I ��fo��e�� ��J�� theyQu��� �v),..@*�1N�ef�*=��Z_� {B 5�i� ��~ma �t6�we@" Zd��%�AV�K&t � �n>> by� xWveJ#e�}ferm�p�DX>pplBk��]�^ZH %^� k thɞH d\� i'x � "4$\E�I%)�#>��� �:�%�n Zna j^ shor��j�4ـ%CYL(��3A ف!�e �'Olea6� +&�%�2� tes -xAU �. �D��$AA>�� �kl�!Y��*'�%r�%!�*� U��&iG@7!caM��*���/�� ��"r b������1urviv�Sa�!âr�,��)�Y-b� + S*>�D%d};�1%v�Hl�"�G�m,���col�m�Al�'��s��w �( ��Q��� 3v2�n�!eZ&(>4��)&Q a%*er� !Q5cj�a\�<MM#�/1>9 2�/&�1� �v[&>��3Z86\s�H��!8�i 6C��a�3 �jord�0I&�2dA�am0B�R�e�M Ѭ�ve**c9[) leaka�� ~�� "�(inRN21p�.y�)i�.u��x2ds�onoH_ ` �inQ+r�. M ��@a�"u�#K+/Na+�"5�� m�+�%D8�!~� oA^""AXAO!�.T% �� A�W-��edF�ng��s?cu!3�8re K+i& �a6ْ��i0ev>:F�6+S4E��t�.IT^�m�%�2�-6B�* a�2p >�r8z Rorgan�� ͼ*[Bw� gTC+"a�a- :GUSaa�E �n�&a �.4-kb fr�ul<D"�(draOA�R6�u�).6:r���or,��G>�*%u�#h(r !! M{N x�GryEB�S5A-�b o�F3e�"TA�  %o+ i�!�"} hypo r�l %t�N leav�&ndyryou2� ( S5� 5H�*�ttK.I(� �JeS5K ${��silr)L $rTmai�DC )(!vasr tissu{"�2A� c�.!�I FP- q\ �2�Z!��t��r,d)�"�Gd�_o8>�}!"��,�VaD�� alEM|EIE�"� 35S:����γ+]���S5M%�,B>- 1� �9��-%��vic!E�!�bk�˷�p�?"c!O�"*E�QA�2�AB� E�5J� .F�h 2�>$tND.;2� ( S6q�%�&�! �H6�b"�%���:��$6 w�������mIv���EFin ye�)U%�:�S6B-�2t@��, Fa�%��despit�Mfi�(]�x!C`��2 ��,���-��IMbioin�jP�� � �;ZX�Ho"g2��aq�e �".f�J!�Ε�i%�m�> by�ch))�,Y!.r!�. e�E�P8A�mar�S�E��� gi��c�9!�"+&� ��2�w'*� fCm�R.�/, RD29A B&"tEM��3RAB�2ABFt ABF4 �4��V=�? ���r���"�8�|% am�ce�.T2�( 4� S7U^Mos" �*)^�  �/�(=[1V1� 46–���]�9� Wup$ a"L�9�/�);�A2h8S87.��3 �a�4==(� ly��A.�. B��I�"eM�Dwe� *)&B.&A� ng�!��s.�0O�7Yt�Iar nod6�P�2� �*c"� seem� dFQ�v5O6H ��� \|9�152�To%�6pea�I5�q/��Y3r @q�+$one-hybrid�N��pe�tu !^ 1800 bpAo��7# A� star� dQ%AD�pB'3� i a�� ix"� �a�a�mD!`% � %pc�M��Q� ��" �-trK�3 ]���LPv4�m��.(14�%�zL���� �".tm�!5B�e5� -703A -375!r�aV�p ]pe� �[JsiU3>�4,5x BV�4&!��Lx�c6E )��<� o�QshiftQm( EMS��"� %V!��HisF� YG�Ds)��5sP'& -648% -593!H)1�E�u -��$ Chro�t�&$munoprecipS�cgCh�;{B-Ł��)�12"� A'Z�a�<&�A����*Be�+16�in �I� � �co��I5@�a5AA�ɓ����U�( ACTIN>"o&U�e��-^b%J�$.@ de"�/�2���V�b�8��u 6.�)}�)}u��x)[AJ�)[fiSr�[ Z)�AYp��A�dd�)2�m�s*�er]*2w��+eVPan)���ng 1!��Z���5�abi5-7�Yh6W�� ),^1�:" f�%nNB "�f��I5�5�T&- 4> k "B X:of ��2�N��3� �as%j)���/!�m )9-&ZC)l�)m3�O�qn&�T%~V.K G�-plyqB�-Y�!5mp�^u3V��I!;i � c1� ��Aa�& ��"-F� z�%�=;[� �!A�J�9� e�s�U�l^B�o: �1#� & 3& �p�Q2� �)>7@��u+�2�2'!PA�J�.k%Y�=A5/6CBr�vi59o%�aKorEHA�& ^� UR�[1v�1X>4@T������� :)7on$0�%A|�� IL)�!�2abi3-8��abi4-��a#�25i!�J` R�e.cYa��v��cR�( :� p5#@In�:=+FaM R��Z� �6 ed.�e�&t ( S8� S8B�S8F� �޽�^���� 2��!�&, y�"�4-�A,��RB��N�I5� ��R&��aj�c%1 S8� S8GAS8a.�7��&4.JFV#&�#A � ё� � ��#�A&"aJ>g$i�w��gz�#!�4J�#iZ(1 μM ABA txreatment , but OX-12 abi3-8 and 0both showed g4her fresh weight under ABA t S�displaying reduced sensitivity to62�as ( S8E Fig ) . These results suggest that ABI3 is downstream of RSM1 during seed germination and l�develop�L. Similarly , withoubA , the 5 gJrates% cotyledon!enZ of; control ,!I4-1 ,1cnd b0plants were s �!9�S9BnS9F5,However , inkpresence{!� �>�HZ� }lowerUI A high  �(as compared!� thosx!.WT�, while I;IU! .�ly lessUeX�(( S9C–S9E�S9G5 Addi!�$al informa regard!��Lstatistical analysisA:included�S5 TableItUrdescribeaoveJ�, ABI4� ABI5 are J�$to mediate� func�oM�in�-regul �ofFw!;post-.�`. Based on initial experiA�s!�discus$earliE4weJn!�aRe<cPHY5/HYH may have a cl!�re �ship at� tran!%p�al!|Uioep$/or protei� tera �la~!m(o test whetAb{- ).exA�sS10L, qRT-PCR was employ�!g asur 9� qs@ink-Ձ�Penetic materials . As���Et6a�AT>ZY�0significantlyE1�Im hy5 , hyh%n muta�B[at^vyZ . Al��gh�.!is5D d by�.t�unclear.z�!�9~.��E$by bini`o its!�mo� . Byiezqpr 1�usan onlina�ol ( http://www . softberry . com )�L`e identified a C-box sequ��8( GACGTC ) loca!l8between -378 bp� -373 �5 �reg.@��ch has bDpredicVa#ybal!�emonst���ba4 HY5-1( site [50]I�det�Ne how)ep-s�+!�%j5<,!0approxiA�ly 1100�genomic9 befom$start codo%�XA�E divi�$t into fou��ag�=1��utilizI�Tyeast one-hybrid assay��6B�HYYSB foun) ind spece'!Bto�5�B�52%�!}-26%� in f � BA_�=8wh!ǵ�#I9�ionAK��( �A@. ChIPl EMSA �per�b)� obtaur��confi�~���c��JKD ,g-q��reveal]a�!:couldE16(in vivo . I�%���ree�TA� prob�i+s ,��ign as m�m2�m3!��de$!!s unlabe���et� e XI���!]1�� of�a�as��$6�JE–6G�eCof%A��M2%�-g ai UC��effectiva1 ���%%Y �E3 S�$ wild-type o not� @!<� ;�����w� ri�� !�differ e�aches �N� A��1`e6eH- 6Uq���facilit}ir���E�e �� 6M. Nex" �)S)�on:,J!visua�5�� GUS repor�-gen� � e�n6u2I�1�}��"� � hypo��3-day-oll e� �� S10Ae�)a1.� a jy main��t�4vascular tissu�V�> proO:�2�notabK crea� �A$$nt backgro�&(�� 10C �jY�>F�QH �m!���"� �����E� se f� p!�InoC��G.W6QA�requiͯp*� A]�a key� �s U or ,$_A essen� role!]li���a� [25]a6 a:�0s! ` �� 2,a�psa sponA�,[27 , 29 , 3��1Pnt C s exhibitE�JWalt&>s d��growth�\� a�d*� !�j� �ed pheno���lev��]� of�aPFigs �33� �7:]!��� m%�be" ��� m�xexte�ByK%� � . To!�r!�t�z ques%�m��cro ��� or � e 9*0e�&o�s���E)��W�+`� �A �c}M !�.� Z �?MSIum�7AH7r WithI�(NaCl supple�i��xeNZ)�����mu �tha�M a(&� 5o  N MK.*�'>�AZ15%�remark�-re��-E&i�^ͪ���mimick��eY�0 g� 7T7G� �Gavail<in S6.H^�e i>��)Pus%�i!73e��?Z�a#2ibyE[�f��< .B9,*als�-Utolerak&�� �?to g& to��rm� �%��had�sam�.ns)�"( for+�%E�onF��"�end �cal���surviv�%q(qq f non-ble� .P)APN�af�7J�eU�fer9y�y�ed��200 mM ��3 dc . SurpriFr�L�l6On�ie!�AF%#9�a3e�m�(-�tZ3��iXsaymL8��8��, a��R:�wBs2�:�p6�� . Appa< %i�s�d)�ە �0�2�CE�8D���d��E�!a)do.�Q�iI�Źr"9i)�yy��*_ *�jbe!�`ofњto�a� oNYnY�.�alJg95�itaimm�t�genes/�s{y oppo� &g aM Qjonsider�E=L<s)�F dt�%�we��a8G they�� phys -T�adV1we carrcf tro pull-!vI7 in� �or�A� tagg��glutathi S-q�asA]GST )E\%�>;HisA�:�9il9B��f� illu�a direct55� b(�A��#ibimole�6$r fluoresczY.e( BiFHe�B< to� 0!�A����Bh. YFPN-�YFPC- � H��%^ievco-mor���L�Arabidop mesophyll� toplas� A��overn� incubM mB dark���n �A� fromB"1q��aa ccessfuA�. som�a�cells���o�mi� copF�UE.vo data)i%@q~? 9!�. More! ,)�1�A��q�M2�B take��ce�7nucleu� S11�  In summarR�� ��ly es�ish �E�canujly5[B�. Acco�o viou Q�d�i�lvn� �of {to���e�M�!m[��We��o�L]Qb( -70toA4x)M 4.s='E��"�( -175>I129 ) b�� . Giveo at �Q��0� �: 1Y1 4a �cr>�o�stead!Gas>*<%.\��!1a�# )of%targetů)O , so*�N= � �!�A�"�9=GST� inde�in9��s�o2�; |=�|�dU�lyAOmHis����0un to% y TNxMJ9b ./in+%ehe amou" {a& enh� A251(-�2�6z�$*y �fX��ner] �A ���6thit lik� doesAviv���Ed:, s  depen,�����%$�f]�!y&Zs �N -s�VE��q��mpld aM5��C����*:i �� 2� i�*@;,dual-lucifer� �-I.D��X condu�%�2�g&�6 "��o�1��ѧ(��� or � )qedII����8� arisonI' if Col-0PJ�!�U� of*8!B� 5! �) ,C�.==���m( =G�Wig<s�,be!jl)���Y�is^1d'�� � 2�byI&Euan�wor E?�/e"own=bion7"D c ��e�6m}� �c� st�e��co�"�� �up�*�$"%Hs�}s�LbK�epista� g� �"� When�!�#I*�adeuM9�!�-:�]!)��still P4^b�!A/%�%i�Je�B'!�possi\���%c�A]E��c��Z� � r-dr�>=e���&b�oM�mi�tim�)t 'I5Z v!�B�no����%�observ�!�FZA� trucP �2{� 1{zi�Y�E�4ort��!�~�in �a 2K  �T.�a�utoD#!-.�!2 l�d��Z[� Unexp�2^� ��%���U &� �"�"Q%�l>x"� � �� �2i� S12B"� T.C�A$ A!�nmotif ,)��"{ BE"�!"�! sub-%Ia2i"5g" in length��&:S12� ��gn  �2�P1�P2 Z1isW&�to evalu�2�biolog�;�c+E�to 5$ self"�#������. FiveJ�p* J�Wor rsm1.�mbjE���s� ��.�W� Q*�,l !>iM�dra#))xd"�%5 ��a�E�D{)12&x*6�� a new0ory mechanismE/a2(k&�(���|�!5ng ;&�A-t��� A%��lr sr6o� famili�MYBR$ y im�O�h�v� abio3( ��[3E#35& G>�%�loss-of"= ; !� have%�2s��r1 ,female gamet�te.� [3� In�(on� ve. ""��%���`invol�Z.�morphog�(is [34 , 423!}4 �� studye*�"�X.uac� ATovea�r sora^!�flo� EPi�by5i�WFLC.L ��AJ��U�[4�A ��&E & sourcz f ev~( ce h� d��-��)*� :"&� .���5�iQ2is �U�m#�y"� expo�*d4ld temperature1�I�1���ZXERICO-o]&ngI�s�E���"�roughtq[44Q-h��O-'0by cytok�%�! d up6�esk�&am2iOstrong�c� free�*[414e�Th�a� d:Fv�&2� be versat�.in)2m�� hormon�/gn� � B&��A�A� iw =patter�%�U$by"-���=�r YW� s 1( S5 )aA��or��fC/H �i'$�W2a?� 12�environ S�� SsA /&�:�iaZstoma7guard5�B�%(�S6A= s���A�%�it � ?$ a��t]�Ke� !1�>�esysteA^�f5�!�QB�^�.many a s*�6>%�a,�_!��);1�o�3$3 nega36 ?.�"h!Gdehydrm/Z�$E_ 2%j$!]endowd��] pr� ��0B4{i3ful.;In� r�,f ~� ��Hd�04 �.�$&C)s�3"-�4a ���he& �1G=�5e�at4.�e.�!W refl�&�5�*y sz $* prq�. Our1%�s2� %�pr����]iEE�aC�Y��'M"%)photom2')3!li�/ . FuL-m�.1�lso_U�_AMF ,a�.��� �iiAK clus',��J z-sS E��$�"%GI�~*.���a�or:� �'� ��Z�Not��3ZX  uᮥZi� �|&s V *(��idrV�6�9�3&7d(S&�e2h6zmenon A�G1��JfacA�/ :�6 abund�� aA p0.%�~ �n��,a null allel�3�3 . U#tu!/5?N*! E,+ rresE -�1� zyg' ag{a+ �D� 4Pagnussat et a5(�#�� reb�e9!X�1mpr� ���E�4&Y-F�� poin�- view ].x> !�e�!�cc�| by%�9%zya % !v� hom��g !��2G!SR�ass�+�7# j��6”�.��tV/>x:�� RSM3�RSM4 ." Ersm2 dou 8�$rsm3 triplX1� �W�"I<�'EZrFP8 � >%�'We38cur�$u"�(CRISPR/Cas9�5acha"� an�1234 quadru��6a,� � 5�i�lt�R�M3A���!&:� &� �f2�(5B�8R0% triguin�&�?�n9E�.�)���[1�-�+29� A�>\ 9r �~`O�6E�"��(<5�0�� �xei�Zos�Klin�*o����RljrsJ�[�9�F�2�7�~� &2k eE"� 2? �1�{6iF& Q'!� qA 6A<Wl ��!GAp5F, j� =f!�.f0�~.��S�� 5�! �&c=A��ny<la��onG"0| %F2�A&�#V&!= vo���)��6�O,9��biochem�"&��l�?E@AN� �!rE�� !�a�hB��C�9�%�"�M)B�5jW�u_>%at2h��~ e O]�z�by��!eZ6�� h6�( �(g .��#�N)�� C!e)AUx%mm�ean�%1 t�0"s�� 9i�2� ors [5�52��d� , g�pQJ�-�!�]on��:.EZch�=ɩ[5�- ;&d:7�%%� �o1ZlSeR�|IQ�5>&�� e5aBB0(IS&'))�� D"�%�P �)�� �)�URb(-:G� �A.bj�) ��'b6 ,*�'� ��'�!b�F�'I���m�%� {!�manneK&m��� 2��!1n�f ]�� Cor BBX21)T0:*OqZ%Y5qa%�� In�}e�� �>,���%�M��%T�/v>?��y � w""f� 0 �#.�4&�/1v�i-M`�ͽ1 " !��|6 lfilbp%!�`)VU�.�&��d�4${.,�%�.� {�8���5� �ś&�"g�quM AA�ឩ7 -&unc���#�"*| 15o�C�re�/� :�0u�� � �T&'E|s 78e�no�C{3w0%�B�or:I!N�.&l4�A8B�)�O��>� )�DsEmI �"";/b�#�th�=Zb"�CyM�.� | &i ,�?�2m+es5biosyn� or*& . No"�Fo�F��$as��B� , ra�4�a�sibx>'��(6�&�raD8n8�2��d��E�� .=A%1b!~9�1�of��:--FC!�.!��-s9a!EIMRD2�I�1 AtEM� 6� $AB18 , ABF|ABF|ABF#^E� 4"7"F CC&.)3�x crucc�` �N [1�4�4�&��"�'�B%4gQ�9�F�-*�-#* ��{rB� aDw 1��*�R/����"�'o�u�:F6W%6 �q �"1<).@&U2V�&"�KX���aGly�p�<�"}*�Gno b� *at"�1�9E�in-Eds6M,,f� �:I&A�:/�ME�'�cwe8s� G /�9!�� �@�Z�"�ExanU!2rB %oJ�Wek$�t &>�1?��fY�pathw�g�OD��IU�.y3A(a B3-domain.�DVM�J�6���[54� �-�1� !�. A"K*9�agEYa!�q==�� eE��C"A=#[4?�L�  AP2/ERFV�,% lso &GA�6w. .��./>[1M LikE����^��E��%G�,W �Z!A ly0.�J[5> Q�"`de"�Iih�?�),�)�P� ��)Nt.�-�� :2*gB`)"( S�QS9�1 *�>.��plaan 9��#B�.�.���y�.��߅���J 5�!�Z�4Z-f|�� IX�E�VB�te�|% @AR.)� �3h B,Sj� 3el�"�ts�> bZIPV4�&� ?pre� �Dl6{��GW�).� �:�)&/s;�$%R a ty�B%)l�*5mL�R*� "8)+1 �DT*E(1127–1231B6>M.�L-KS2N7��z�!OQ&%��(. FHY3/FAR1 KM6�,( FBS ) [56]�3)+,D �/>�to��c�CI'4�%�&IR�-� CE1-0  el�-W5′-un% �d֍ En���(}Fk0��6���,.��RKj�!,�z @��E���.or2��[31�De�%g"� �� �/"�-�� I5 wp0)"�inv�E�"on��"kKa��N,9�� .�S!{zC"���m!�occupy}hIP�Fux'�s*sh�M��O� e-Q�co:E3!�� e�N-�l6�Kt&a�%s��F�W` rece9=@&�=O�e�%H!%�*to�� �Ia�'hi^xm� mex kn�?"�!2h&!,or3FX*? W ��":f a�ngthen�-_"�%N�5�o /@H�T- )Ea�on^� � work� �N�.�85vn�,��3���"P 2���%�DCartMY�.��VAB2.�!3sJ/�A�(6Q;# ��#�4b#�uxF�!1H_Rnverg�6� aTV�hbUS [l:�J ag"F.�&�%iAfine-tu� ]]/K #Xnd �:�5s. 0:�o`[h*s.r:h��!/be.0dM!�*\+�aÍ>du�'of`"Z,� N�$!�P4exi���G��2{E�.�JO-}achie5_� �ory loop���@ 4A.�5�M<^I5�=F k�veZ�� `��{ ���� &o � mode2b+mplex.m���2����u�r��jccddA�-��=�. O:1e�h!@���6��e�y��a �-%�*�Hno�#"� "�;5 ��>� fR�*sBthM/%�"�N�%��qT�c�q�%*)�>Q0*�"lya�- y��� C=mCW-I��<2"-��),mod NRy�e�NX11� All2�E�'sN�(V5� ,Columbia-0 ( -0 ) e�Sp��>follow!��"Au.-)�:^%1GS876657 3�6& ( CS37194- (Salk_069941�,�%. ^&�K 5-215 ( d�Q�s^#� �!Mfig�1) [16#�84976�[5��#[58'$abi5-7 [59 �an�^�_j(T-DNA inserep1!'n� WV %hKYT(�(��r&�GB&�7Re�3 Cea��o6�s Q��\Y�ae%[��%X!�M)lefQ'd r�,border� ��9%�1�A��� ��GA�=2��� . 35S:TAP�C/!�� FLXing-Wang Deng labor�y�Pek�Unig09.e4genic�$�+"�5&�+ OX-9��?*-��2 �)Se�/�� surface-s8_�1�s]�]t 4°C���N E wn o�:Oa ( pH F&9 )!5�1 . 0%�r�Rf(0 . 8% agar��n�dYat 22t�$ �9N�% ( 16-hTO/ 8-h �I)�K week!Ben9:OX�( ��&�Osoifb� �. FKhe F'e�#�~'; 4-kb��e"-7�A�ESaUC@_nd�aay <j$pBI121 vec�"to8A�VI:�� !IE>X= *qKAgrobacA(um tumefaci] GV310�4subi���i.e��+to2��:y*#+f 80dip method [6LA�6})3%�l$�Ca.M*50[6�Brief�!�at�[�/e1all!+�Rdmd },�!�p�on�u� �j16 h/8 h�1/d�L�'BJA�d&D[>�f%S�co�1�*wSeveryaerm+ J2rM�?c.�%��� lege�HNdetail�es\``� �.���&S� � ,xRor nito�/XX+z z root?M��5J$�Xn-�%�͠ �2� B l��A.%10 μM �2 ( SigmaP5&(T, b6T�$��EYTi� �%�v��S" plac��Pin�S�>/�9�3I1Fgi!5)�*�bL@%�a\prigM!c-'m�ed%�vR� ( n ≥ 2�)o��F�+�.ztoy`Fw3G-(�TA7 bAq3–4 �4!�T� 25"� �Ez���r/�"H6a[AZ!S t� � vcv�=leakageXa6�6-E�~�4 �was�IwAZddH2O�-��015 mL BD tube�+t8 5I1 "%Y shak]F8t 180–220 rpm�z�1 h�e�-�% SZ μS/c�e�acqui�91����-mB@ ( Mettler ToledoTc� �O�fUS�.*�`� boil-�30 mi�<coL% ��� h�Z�,�WJ�2 (Z�)LreazS� V" )�x @�$Z!M�yaa�� 0s: EL ( % ) =�R1-S / 2 . ��"�B.G&|CfG2]kce�k�^owis} In b�b��%{i�kpl�0fix�i��<90% ( v/v ) acet� at�;m.�>%�2)�a�.�H�bu�c (�Isod�phosphOD, f 1v Triton X-�m, 1�q2EDTApotassH��icyanide�/6 o , 7� � twi�'n�-� �h�je�� �T> 6� solu� (B��(1 mg/mL 5-b�t-4-chloro-3-indolyl-β-glucuroO acid!� t 37h 1!�9Vc6�#|f ^qUin 7:35�e�IoF !�ic m6_ �%#-w��7]"N . ImB; 4���Y� eEiro/Ue ( LeicA8 Wetz�c, Ger0, �.�of%n�y ary g4-� y�ellkNylX)QA.� by J�=r�M[6A&6�/To&Ve!@ $u��liz3 �GFP�QflL-,t:*kQ!�n slid� exa�]d�g8a Zeiss LSM 710��:zVA�GFP60X!"�$88 nmW1xc�f�Y49�N550 mi�!� DAPIK��m� �P5@ . To�RNA(ext���j�9day"& �.s &�].�9#)�lEasyPpnP�qmKit ({Ge�Q Beij| �iin� . XX�deple�by DN�,I~@ , 1 μg t2�1 �) ze cb �Rr Tra Ace qwRT MaA��oyobo CUj , Lt| , Osaka Japan%{Quant%�v;+al-time�0 �6!�>DSYBR Premix Ex Taq� akar` Toky��h =}*I 7~ f�?rmi;(a�rmo FisEpSd{c , W�\am , M��Q"vW!�manufac� r’�:��,AJ"$,�d&N�+�Tu "m"�n6�  ACTIN�L:�*@9.���:*8repS*QCjtechn� .!:Qin T VNv��7n/A�!� E[�`Mu6�b7"�bYZn:�2�2�%!)^��[W� ;x"o� bp�e�a�.��ATG��"o,E�2M six �"� � � mYA-FM6�:2"�;�P"pLACZ2Us smid b�<a lacZ!�o&k� z9( �o�Q2�f ��?ic�wn&e��A-DR\:��dCDS�3 q v0 KE. sepa� l[%pB42AD5.J%�]mid� >"I,.in EGY48� Ton SD/gal/raf-trp-ura �uu�]"� v�8D-galactopyrano�0 ( X-GALͤBUs �& �j:�B% liqu&)q%y�2 egemE`Protocols Handbook ( Clona����?�V�?C��n�digit�� amerzNikon��E]Drophor�mo�/shi$a�2� =(>�.�\ay].&� )"�h*�� %� x�?d)�M�*EdYu�CUY�a;"9&b<[6|- Twel*tSC"�&� gr�N�*����harF(!� g.�#�22l?iTa rab�o!�clo�  body�!�� (mmunoprecip> �h&�seuwIen� � of( �m_ �w*�A�� F� ���WU��(�6� !��_�input� ��d-�� e��CDSm^!72$ GrqyII 62-SKN�tc��>� r�Y�Fcaulif�~� . V%T-�"�1�.�WT*:g��"?g�cEFM_}�2� 6,A�8�w|bTe�cul�d?�5 �w12ondN�J^��vitie-�dm�!�D�;L&,`R�Ir A�� S�OFa� r�"ma�|Promeg� Madi�, WI ,�. E&j"< �r&�%�M %A�A{�� �&�BamHI !$SacI enzym�RZofQ`  ( Nov�Mi�diE� �:��c Hz�coYKpor~�8� EcoR � XhoI�0T� pGEX-4T-\A� Li4 Chalfo��UK�Two6igra�J�or6� Q"&�. � in81iH� ��p"�"��[&�!.21% NoJt P-4%B"$ a�rowf"� h[ �?A2�\ G.�l(epharose 4B� E|.yJ�"��qen kep�t^.�!�[�6R[��>n/�� 1×SDS lo\-w!K2�SDS-PAGEw�Mrn v aFI�.�E�� YH3_0% v]!el}Spe]��pSY73�%CMinuE�ye�*<t1� [�l] )Q�.T"0$-� V# MeanB8)�:���!�z��ԉS4��6 (zN�[6�&!aLW�*i:)v�%_&�r>ce3� to 2� :i�E����IF| �)�b"�� .�ao� ts [��΄�l-J }p<>GV�l[68���o�Tn!HYF"Vn!�"� ����,d� U� [e� of2L)!�����"&M !�11��m��b� �& �, 1 �, 1� MgCl� NaF ,AAu3VOr?25�R��yce�=.�15$ol/vol ) g%.�2�, � PMSF%1× cO�te��t�} In| or M�� &-#sas���&Xby��F�(E�ei��I�enva� viny�ne�[� filmm; AjbloGy�L5%�d�p&�A�s�� �!" Y��w� �9��!6 PBST��41@Afnws?J�oy �ro:�d �.e1×V��5YsmU�� �3hot2p�za�* -Rad-A�i� v��'moskj"�� , Student�t n!�e*� �� dUof"�6ce&�D%O"Vh���ap�Ya�a ".[:!V.%�*% >�;a-�!*&,�way ANOV�-��l3��Kf|6x ( LSjH)a&�'�$IBM SPSS SY�s�$� 2: Y!% Corp5+!�, A�]A�NY*w S)��5. G�� �Ba un�(%G�a���\[7 (enBank/EMBLMba!6I$!I&|. acce�number�T1/MEEAt2g2165� RSMR"At4g392 * 1g75,4 ( At1g1951 ?�5g1126H3g1760y+\2)2g3627 )�9 3g24��: 2g40�#a�EA5g523 }B0 V SnRK � 3g50�F �5g6688 4ABI� t4g260 D5g570-�E +3g518 ��!\401 ��E�l4 �A�E1g45241 F �4g340*)r3g1929 ��A3g187��<PP2)#1g699%�4.�[Mitochond�!fc3A7�dB�= 3c��Ion pumpa�0S1i*.ch., �T�2��ro&�,I� NADHZ ub�ng#�ump� of� rs 7pmatrix~ �� m� spac In humQ , de�� ex I!8.�5��de rang('d*erioA�/R�:�gd`�� X-rah{u�"$Yi� prokary�Y!Xeu�&�/�CUredox*2�8'�=r�- J_ ophimZ��phe�rm!MO L-shaped 2Je� take ce�Ia�p#�e�t����e 5iyDGM�q*�F�b�4�J)�E7!���TP �9[Eirrectlyv6z)�! d qoup�| �ar&�4 �he� �5� X#d N�"A�-� remx�L�G���2.vd)�up�;e|!.#J�� a sm�-��$ory subuni��Yarrow�mu�acm�\? kqnwU] nerg�3�.ngG��Q~�{e��es [1�ISl�0 sl �F�z' ametabol�l��c���%frW����$��6�oQ�dis@���Wmaj�PuroZ[2]�*�#ag�[F(�QI�m�i�Tmi.w�� �TFMN[���g -sulfur cq�.$���prosth�N 92�� ompob9of >40"� t:$a �&�(as%�al%��C{ kDaN urt>“-�"`�xm  samA� pro- �9���e�yf�z��. LNis�Bab9�a�9�ɚ!�>26��]2�Iv^ �� �� [�%�b [5I�1tic [6]=X7���j j [7]1�Fn [8 ��r [^;[1�6�} �} �} �} *| �j180 Å �T��r Pͪ!�yVtXub2�&]om��f�" (eqUs�*, �4f $l�PՕa��. D�A�. S�u�Z"F "]ы�9�2x rune��arJf�d�@���'>�a�Z�?b}ex�5ngeNK QPH:)aj, �B*-zirʁ 1� ��]�J�!�ND� � ��� [1�V�m��k!/!��!�9�, s]�!^%����Y�s ��Row�� Å a,"{ closes�| dox-��er!�tribuR� J w.`it� ZXC���.". al� �e&0 5���{I�K� . A� �>g'`am�s�� !=Q)s>�'�!G.c-u�2 i# ��� ��-��ed�o� �[12�@f�o&4_t%6� &�N!w2r]2�FoA4f.�� = a�)��62�\�"`�y . Vaa!��� ��::�Y�%;*� a@%�ill capYbx� �� holo-� I . gHw(vleA��A%� "��� NB8MY��8&w� stri�aerobic�)"�&lytN3byQ�jrecombG!�}NdeKGdw�2�&� *� �knock-| ,"� SQ��!�aJP 1^@1H [13�Lm{uťq"�Y� ovӐheaZ.qhACI�s,F&@��U��E�A�y�� twin CX9C�Qcha�er�%�.lE �i�ed�!�so� MIA-�V [1U' �ŗ� �[i���,s�Ip >�!! 2�1�I�D.� hA4ruthen�-( HAR )>� �J5�mo�<��Mmou�l}�N-i��{�[]'l�)���.�\"6:Aq�&�8ls�k2��z�)�lwm�R �&e�"�Amag��reson��4t�6�*unpubIedU �+I��-ji"l&\�dkdecyl*p( DBQj��&ec�!*nys&�E1��9w!7nc� o 30% %�-p��:Mr�(:2S�G1i& � wo-dԤ�al blue-Vc+-O�.��( 2D BN/"�!) "� ��%� !y% embled�6����aN� Z6�mi5N��lightabO�13V01FO-ATP�-�atXSap)/J�k600���{r �t� is b�`n *�B^&u b�1 -gely�"0;KW>(# 9}��asFTA*���edfk,�6u5VM(Sirwьd�s� Av}u���[Mtge�or!��y f�&ng��30-U�� a his-ta�wV ��0�`�9�uXdoeq-malt>2%� rg�PA�9X affi߅-R���col estaq�*4)�:�[1h"A =�elu!�sym�u peak�C�fia_H excuo�[lum�2as judg��O�� ific���:���!�d ��tb�F���!a*����wea4l��qd�=-� �at�b2�/F9d�4; [19q%A�las�gd���3�1 !,desorp%�( LILBI�8 `sp�ionisa 'ESI ) �!Ot*G(�B)!tt �z���"a1aC&#Xli@ �U]G��)\�TS.� e�i� suiAF�o�C!G%�ly� A����e����a� iagoAi�;s /�`Fi�8DM.->-MS� f5{te1zxW ssoc�%f e_ valeLHU���R�)Ex�n� C t�Pssa gerpr0u�(te"� �� �Mms���]��ly5�iS!�)�0>od���a: <�Mr��wa�or�lapS spoJU� ,��1�de�Q=bFa �w-��zf.pEa��byA�!�� �1Q��ec��X ���1,�o�t�14w%=�n�=X�P�~ad�:o fL28G 189 F%�n��!�S2J lyV�edF� - � 5).��abmfA�A��k�y9�A��WBg\S�#�~��"` E���$amm1;1�e��+e*� X?�� @��a5�r"F��nYbap��B�de�/5�1ATat ul�}ofĪ�Ma"!=,&V#s�/!U��ma�u�2C5<�ō�1&�v���J( olip�:E�!�i��-����3%ied�r�-iLl�� �nse��x~E=�B*� u=�u(J�R!�F�E*offw&~/A o ∼3o j+u ��o'�[of1�!}s&`o5 !�έ� �fh645� "� �c� ti8� H"�a ymin�+ eaks�[�A��f]4"� RC 3�!)�jlo�watt����ST1��dՌdO��&�8 nf2 scop��%�ti�s"v�y 4E�il3D;� ]D}9@�Gof 23��%810 , 586 tilt i"G�8nd��^BPjet)la 2aAY_ 55°i$���he� mode ��n#��߲:� �\b���3� IYMi]AoutYz#R):h��MH"�ad�iKPD*`�#�_A;�R �l&&�pa,�h�ed� Q?T ear3%�+=>m�fۧU��en��2��Zsv'F� 62+a, uberd:#"�3\pŠ�.be$ �Mxim� %���?�"�. �-�=-|=$[e�as=qtin [20z�2hF�"%��Ma9qa�a�/&^�a:X . 7 µmol·min−1·mg��"��of�V8^1���:�!�ta'E�h=�!�! u/'m } =�d�Z�.)turZ�r*:F�4%e��?�k�-�val�� ����2# UlA�]�����e,�-�#�i>�h�e�S�)AT�_d����$.heM-N *)q.�F�a�� �(�[o|A�����nstitn����ame osommn�)�Khe ΔpH J�nt�1c���hA]9-a�y-6�M2XLoxe@id�( ACM�P'NR?29"G in�l5�:2 Q0a!%��=6��oa= B�>��5J<M����A grad)<.:�i�V�F 38%e2,te� ��iC%�2�� et�ta�:�ɜ�?mai�B� t� Oy-�P�+ teau��V���7tndB6&�.�!|/ ~Y� 2-n-^$4-quinazol�3E"e�QA ��a5*�T�w#�r c#) nyl-�P -p-triflu�O� xy-phenyl�,az~( FCCP.]S/�!2~e�� �i�a�B.i�SA;�)�5u���though���e���"fxE$A�6�N+B�!�just dueA��He21/�or5]M�AMO�$6(*�2wa��/>X4 effi�Lc1of:cpNF :/n� �V. �!�"%�:ci�R��`iP :Jw��kAequW���u� A^ylz�z Lthu"��!)�,nZDEW� �W�:�d�� w��36A.��"�3��byjA��_0 expon�/al&?E�.�a�"X S-( v�Z�a�.�p1��!\F�d5b � ��� l6�%FLmaxE�"�m"��$�> y��f^ ��� qI"�I"]��\2�}'Gua�b( �},on]upa���i*��'%F�a�"�96c;�Sm � ~#EP slop�   plotQ,"TC2B5DA���6�2y�5eJ� ����#[��!calibA�!bab�Ue Vo Eh�V�!�Y .u o�!�.WS*(�VpC44 H+/2 e− [2|�Ta�l)]��%8gF�>�;=^eQ�oj%�\%r=�O�A!Xvu@�:w v��$e*�.�L�jVL% !%W��>^��H v�p��^0`[� ���a�I�'$&�A��(PD *)):� " ��r�/5x6;M(�h%fa��f�A� P"�)aw; 1 A�nV��/�p;& a�AMZ�"�/��!�97�hed&414[!�B1� �R�2K1��)Te��sCB� idea5��*hn\1 brid�/�A *�*f��i:o͙�P,aF' :/��* A">( soy��t��W 20% lecit�5[R purc� d\A� i Po�L� ( Al�:�(, AQ , n-i-ß-D*��Glyco�e(Luckenwalde2`Y,E� octy AwZ.�QAPKBib�E$ambur�G*�Y�, T6qgmOlO/M"vPro_ ( EuP , O�$,��RW#�Alo����CLauseXSwitzerla�aW7&� q"� -4-y� , SAN 5�:� jgrEvoa� rank�2Z. C�� ��p"�\iong#inomyci������S�b.��,F,�)�v9� O5�,"{�$ thyl�oxT�D:�""� $( NUGM-Htg�,ndh2i; ys11��, leu2 ura3 B ::URA�Mat�uFaUa 976�VBU��e��"te �(EB&Ra��Th!up�2d&^��L��re�a2:��c( �6 k orc�O�e �oL �origi���ope�a�fr�"�A��t# �r!.&�)!� tegy:�&�&[2:�7ins PIP�b %�ΔI$�O�5dY�(e�_( �5%s]os�r2%� topepE` , 1%�*lFe��{ o��u h)_soòd�}Af %�, enco%> a C-� !]3!N$g�)e�@ G:~$22 -#6"4���p"�(�aE��M$of [24]�� �TRgI&M$P� �^�� b lI����"sby Ni-�$ %KaDC y , �e�L�&fi E�*W�g2�� yiel�B) 4|*� b�tas&:�v�$@=�>�� 4���*�8"� u"@N �" ��[{��.b��7:�.pbye� 5% lauryl*w&nܹptY%XnQ)�>B)-'K):�v(@HAGyv)M��E *�%+"�]Δ+Q0,*�"y%!P5 ��(c�^.9x�(.&w8o�*�]y-)�B �%�M^* �.�(2�^�� %%�f"�G~ "�Gdx���eDc�V��.no�O�@tib.pT!\492�(�6a'J-G%[!/A� conjug�2�TYG$-mouse IgG��g�Aaa�by�td��l.G�. L>'InR L]Bd B�+Ion D&>'M�S��rV=P'"� d�%�qG.���")Y� gel-"%%�6 @nano-ESI-LC-MS/MS�a!8rmo2>Y4TQ Orbitrap XLS� �er2\2��6]^) O� ]b!z searan� �g��Am in-h%�a(�h:6: " �3_m��FlevBt�ort�/[8��,�1a�4��` � �}�:m��#��9*�B+A,��n^ey � coEugrF#A�embed{"/�z( NanoW�mn�[� , Yapha�G8F�D�A� deep��d.�T%�8�![ ��>�FR�+a S!aR8C8Til� �L0;paihU" r�=Xa� 0i.�)67 k×" a F>�68 ^u�4;k*; 8 i�Essc̒d�hn I$V8graph SCAI flat�� (6iZ/I\g!Y6^IH��vm�!�F�'"�d pixely,$of 3 . 136� . PzI�p���!�0°1 tilt-�� � �q!�W&#�fer"�E�����"(dRad\7"��ς� a.I��smooth pN fli�)�7�of�!897 E2�r��!�Iq�$�#�ce� aligd�m��s�Bf  e��XUdK��6 classY�!�-'-vq)k;�>"  �A!��0° �� a�6g&n^�)Diday''��s�3�5g� �@nd hier�R�a��d�&:�[3���KngQ ed!�0�*�v/dCmos�B+e��6irL en�GA�A��e�����bA�0 � e%!:f��Np � )m�/ �E�c&��e"�#M� 7re H��]�)]�F:Eer Sh�C�Wfnc�a cutoff!zbM3��0Cf&Q �u�,��p�j6�h-lo�S�'�zstu;�["�0handednRn7ll�"�ٰSI�7�6ad�q�O�,%vA�w!�lJ!���"� �s�4� �S-� !��* , )r6�*� &_Ŭ1Z� ��� in Dröse���A10 mg/ml*Z#A� inv "o���7(A9oEz-“��?%~�Bof� "T*Y����bto- �io31∶5�Ow/w� �m5`9�(Eq 8–��� �A\)��&;��O$mM K+/Mopsh TT�8*TKCkn!�e�3E remo�7Bio� �&r�;�֒�#a�.�ZmoSZe6 omew�� ��]�Mm( i .���ss:�,p���iU��lqFMA�p�7J�*�=�,.Am�s0jm� ]�*l X,µgA:pa �Wl9V%����U5 µM2TE�Kir��cuvett�NH+8��&��as�:�s6�m�m� 2�a���XUofE� �.�Y��A�My&�y2�'�&�cnim(J�daN�!]�N8f.o�x�Ean!� D4� 52�)�$&n[��Mg.WQ1��|$%CAsub��&8 J!�( �%)6��- �Q8R1:����.|��(���sR}p ��Um#ti� �c*n��/to��>.Obܤ' �1ers E�\>^%��"Mi�Fa1,*i�[�&]�(�$�i�!)t�;�7l�׀au& �5AdC%�*CK]�c_� H+"�R�A�--e:u\*H+-�Eg!qd��3m2=at�(st 602�_�$Aa�o!�rq-���B�'{b �� �L&�\��S]E����B)  y�1�Jl �1 6a��1∼� 3 �G1�D�GmE1��(�n,�e2�!^I�6�I2e�i�\��R�r� "� ��,�IIe�$pll�c? *�7�8�8�M� f)�]�( Is�"�t�� caloIX}A!BELISA�'H"�bmalar�&den 1�ge�m�J t B:��94)�' �|.�D9i�sejA- sq��4t 4� ,��Y��� (�)�.J�s ]h�4K�� �^3!:6F �Gw�6n��-sF�t#� �*� �$�{im !�TB5e�*žs�O �|v!:d adap�6I�fi�n �)�pBl�G� favourCCe% �%-(A�f{ nhanW�K � 9�o"�e�l77!�vI�il�4. MT2Z�,n�] d"��qmammaRt�/t�lyqfT;^ludM�;-u�s ȚrI%bFm1��>#8z�ie�iBU�, acute-��`�>a�z$� ��fjyH�im[ng&�aishorte%Y� i�7WCel�Yve���rI� 6 )��$perpyrexia*�R��foc�k�n(�cE�,/�E7�c"�N�e-�xef���l!6� =4ly}IB�*KDdefi%m�]tk�A_D� �at Vrs�<�����af�$ed ZP2�K�Kr� 1��ƋJ c'M�$ga�t=5��1X,P"�8c�fgi?U�2��E�)� excej�39 . 5�:�SSu> an up�eVem!� opti�� Uf;�A�kpr/bi/�m���ir!4� y% Q�a�a�G �r������han�a�7̄}k 6#i0Tm"�G ity-J AFG �+" �C����sa�hi$5OJ�g�t� ��.�%Y�aGG� &*�8 slowB- �ZA�"-�,! ng �i��I����!�E%�uc��bodB�9M a�G8]* zO�� epi�'%�p�$�1�� 9typ.SyZ�a2���s5Z�u�!��_I^-�!"�&��M��3Jk"} rB�#*t��:Q� �ir|!\A%��M� e:�;��O�Z�Ł9ssAa!�al�"�$� idA�,y �Yal-�9gena�J� p��=�8V�nYK��A�Q i�aqeb% �YA�?�i�^> �1�ۡmN M��e�a0n>p!��!��b.�1 0 �)wG�p� , ���us�� s [9/"R�is�?28���%nt=a�x&� ," �&0T iN�=%L� y seroe&2 DENV-2rYiF/a�tozoaW͛, nam���1�&�xy"�*��� merozoite�I�T? �MSP11nip Plas�*um� ax >XA}N�� � �}M�&*'!�[13!^W* 'akA��B<$�m�� .� ��,[�9:h1��Cc�Sibx��4n�0f�+�!a�j "F7� � *� `�unfol��Y*  �b� ��A�unrav��n�e: meA�is���H'�*I ebF��I E7 ��id  IAp���Vd�C*'*�'�H�[&��8) styr�s MaxitO�#�� Nun$6a�Y&o"ts#� ,-�or )c�a&wr�Xnt�e��� F��( =g//Ah5�:-> ! ��wa�=3's ~NJ ate-&s�1e (#q 2��05%! en-2>�pC�2�q1xc&��3% skim�qaGN1�UBSAE+2 hou��t5!*b���� cy�F����-!�mAb 4F6Y!�di�R( log:O.A�at 15� 3 nM�k�!OkK& rF�A����mN)�y!�*e"+s��{�v�2�at� ± e��p!A!1D.&*��'��c�e&@��=�ortho�?.)� enzymatic6Odevelo�Qus�3 , 3´�P´tetramethylbenzidin��TMB )A�io-Rad ))A��uteEWnd�� ]��1N �>� valu!\A�determin �450��.m� data)nalysed `DPrism 7 ( GraphPad��8CD measurementsi>��w�C(a JASCO-810e trom�< ( Jasco , Japan%�upla+(o a Peltier22A roll�08Model JWJTC-484�4Immune complex�$reconstituF�!RieFof A!37 μM �IinQ �1 . 8!A|a�or � 6NS1B34 . 2 44H1BC%�Xree hundred microliters�� �)Z(immediately�reɱplacedt�1 1-mm!� cellIA��a�R�AWp��Eacquis��. Allr�in 10 mM�*( , pH 7 . 41+\mM 2-mercaptoethanol . DEoA�8averaged from t%��s�1�I m/mi� �(pitch 0 . 1A�(, bandwidth <. Buffer baselinQsubtracAire! tive�� ra . We ua8Isothermal Titr�MCad(metry ( ITC�b or�Ɖv�ꁹ��a� investig C into%�) of7gueE� mala��i>�at:�,1��H. We first equilibr� ,in vitro allx,s�a�3J  Such5 cedure ena�d that PartneE�� subje%r��rs mor�lev�hose ca%w4by fever-induc�BpathogenA�a��Yperiods � are not lAbl �v�[(e . g . les+n 6eE^41°C-)<S4P . vivax infe s [15] k presentaE4!�Eograms�shown|8Fig 1 ( also S2 in Suppor�In9��? changes*enthalpyWdiA�en!�t two I\1�chaE�riz鉁 �st poa�ve�atM2�(Uq�p��!~a peak�re�M>H !�theFdem (�1A&1a&;�contrastbr?Q�6� , we�y d a a�ar�of9'�i]b}B }D%d We observQ�� both5M!��  a!� � in b: ng affM y9e� A~_in �:.�aH This.E�;��N -N | �E� , as M /Ab�rFor �6=��w�a ~��15– 39Hinץ)�to- ,"A$absenc� !)� prim!, accord "C �1 4e-��� �� sign� �improv <in KD�a factor!�~9{ ae�)%�~8 I�C �de�^6(�no aY�o)+ u(!�) ka 2 uAXsJU�vly�\n� viewԁU�)�resulta� toge!sIs��sk� s is�Table� IdidE� yiel? at ?ly2u�icPn�obetwee�x� lyA�=�ed1^�>e�^)+�)�(���S�2ycalcud��g non-.�io)�  p- !o 5 . 9−6%�2�UU�_a.7E −5& �,!�p�2v!��Previou���}�c"=ic6rof"� -� I-O�'奅�ek.Tre�]ed ei!rery limivQeo� h� ofE�q�ium��sta� �25+�([16 , 17] ,� ev6|eof ;::8:9�OIT � �A�2�qGm���!)trevea�;a�����rB-4%Laf to�Y�by6_7��f272�a��:��� ma5 ntrib�toFFis�� ropi���outsens)�b�  large��e 5ց'�%Ev$ly describY �2!�bbes [20!��i�nsic f� energyA)�A�! ��ldepend�A]Y�.��Mzn)/ �ic ��1� KineC pa4 %� f, directly on.n�H��wonsibleYWW ����ies�� acro7 e2[r�  , B ia�!�A�( most favor��koff ra�M>d964. Epitope-mapp!Q stud�have i!C<he sequ�X193AVHADMGYWIESALNDT209!�(co&\ al e ci�v�g a�alu8Mdyj whicI3qHi�, brou�on!Li��ed or �"�s~of wa�molecul^-� Im�/ana;ef� E.�*� mod�A�F�A�� to� DENV-2�w� �(� + �e i�e�it�I� al E!O���wh1 unique qu� nary!�"O Y�� expo!4w� virio�2�verte0 ha�$physiologi�.(�6) ,���Va}mosqui�� �mum!V28°C-3�1[24E�TCQ�' ��H� �=��app�m ~6eY~10�d�at�(�G� :� .N�� 2�Unlika �a��,���Hin� *� .� .��h �� ,��2� �5−4%e�)v~� 7−2&��:�6$�-/y�!_%�iA�similam!1m%51dueaRE:�7"w�!'t%��i" yw��occurs),�2� . AtJe��>�b�e`em���&�, sugg ngL�r��oo nside�= solv�䍛�$d/or enhan�) "2 flexibilupoe  !�C !A�duBrol eR of hyd�*�"1��i�?� �)�.;�� h6� bc 5ǁhapten��%�&� g.a��� 2�"IX%<.�e!�m�6faA�v6�6� $heat capac!n�(� ��advers a�Ys��,�A�{HZe onseŎunfol[� � nalog^ !�e"�-�v�TRP�nel��6]-�R�is,*?�nly�w!&AophobicM�.�m�)� 0I�of� poa�� surfax f![2� 28f but)Sby.deleM�Rc� e��߁�4 bon%>[ NWa "ΔH5�dOpro�@-�tfi���� thes��m6�� erg� > �f5 e^i  encoun� step�aS t doc� M�s��// ��envise. Whil6� u��s;�,�Nhu �den<!E]~_p:�,%a� )Kr!�-:vaa� nealA�a2 �e� e [2GQlat5'Ab� m du�utm�U�AܭE� , gi�i�EuA�?� grad| [30A�AjtIVAS��t�abn�e�}�se-!a�v s [3� U�Cir r Dichro�,A���ct2� s�d��&� mod\!~e�an�2,��M!�n� � W ( S1����1a�in1y!^�w�t2�wo tech� spD���""�A�a&`��eolvA�MSP1 [3� screpanc�!�be�acdQ� "� ��adsorG�inS�'B � could hin x�� �steor at�!�ia�A0� .mAb*� [33]:"�!�ofmsir by mI#val��A�re[34A�� .V ɵ�oc=!on�@sB stri%-QrV!�m2ly"\ŘE��K vng!Zh�cm�!�:� 1 iks!��e.� ^)� s 1�� w clus�,y.퀡�htl$a@ir<,:�f�6i": ���ey�y)$ ertia�!�*� M=�s1  a1S.V�� � g!:1�M �$��1new� !�� �"� adapE�me�فy!�L� -��a�!Pƅ�E again~"�. FurA� id��A��vo"Iext��o�Cr  �Rina�)episod� i!����b�W�* ll m�A�ach ofEcoCA-!=In3# I��� V�a #�0a frame�M����a��a�|�s �[:������o�0����. 2�� 6)�ubi�u���}7.j$�l� $ piz���)r  ,  craw�mE�'_tissuu.�[1–�2�1 igint1 with��In layeT$%��jct����hLc %peC��(just beneat�Dplasma membrane [7�Lrfor=�i�bi%*( qAi8:g���0z R| �uild m�cx E��u [8–1 A�) same�B,6%M4�!� 2�!��� m)"� � F.z� la|.�.N^e�. How)4-3R`�5��ɽIJ�rj= 4One successful� a�2o��, 6r�rel2�� oarse-gra�/phenomen"n�!p���&" � ��fluid5 wE+mo 8*dri�by"�P9J�! *G a{�$�u1�� [1�I"&sa�dq&� �i�aq2yis typ� ly� u�%to ref�"� 2CJ�e0 transm/ on3_leR$EsBra�aN�.{ m*laI]���J�7of.� y�s [�1� �0s� A8a"X %�. ��>�k#�tQ!En !�d*~ ,��]�ln!�a�sG o�ow"N� �� a�"�Y����E����[14�%5g��!���K&�Z�8�How� I t!jY� lleng@ connec���6c}RF�Dhe 1�o�+e-I^g�A\�.�M9�ed N�� �#�ti�!aP�&)�-c�4xi> ca�! of 10-100�. , 2!b 19–9%E�chA�thoF"�Trim �� ?8�!��8j-B�2 &�M��mor� [24]%2Y&_[2�,27]f�u ��*a9endow!]inQ�s%�_lexť-�����m����-MJw RlN+u��"I��l1� ( creep )!�l)�=�"H , itUuA!�3o}A`e�rapid�7R�u}in 2B[2�)2�=Ex 1zal5d>6-t z"� Aq�6�s��!�a�t��]�(U�)�–�Perturb��v!�leabpJ&���%��Z'a�pi�4��[3A�3 H�G>�+�:� |of ��R�vp �Is! �� archi23N uncl�0O2cA�� 3begunn-� �sm��!�&� g���-&b|Theu��atsZeu�al:IiF� E�*^&� � a"��4J� ( st})^�n� � %�m�?rn 2�. "���3�Z36al��7!roC9to1&"�%} exis��p�  !v�ama�&G�� �� �=to� b��59�M>k:[39�:AoA����"cŝ.�.I�9�y43"�on��z5� buck� .Ji�sR��Q(5�'p>4�A�nd�2�"(� e,#6!&ira�-(, collapse [4�3� up3��.� [41!O(e [K rear�+�6�� ty s�� ng )��5 p"(toq�o&�=[4��4��myr��pA�play esr6a��$ ( s �=�7asus�ed.� ��>��st� !�m� �Q.h�#�� expl�+�� is m^?��[46–4io?o/A  behavi��e��em�! U�la!al$goR"ur�[1;=4� ��f g�d�)�� ���d, � n����lQ.he� � %��#�6�,��""Yq9ܩ$)Na3�9F�_��%*���E�:�.*��G+�1%yze&��&� E)� brid�|2��< >J ros� a�&-#�!!G� �:G>� �:rs9%T2vs spring a�z�$;s!KU�!�ng/&�*� �iO- ar f�$ [50–52]$5�8@points:|�"�I!��c!�upe��� sub�6X-Y� a19E�/}@� � A�ship [5p&?w�fun 3}�entirV<l�� pp�� ix��bab�Tper�-t�aE��5>3�5a I�ABM�o ��::��2�&iMlμ% a no !(�'�`;. T�.5J�lbwee�a piecewA�p� x2%!�t�@�$ &(.%�a� curv_ semi-�-ly$lym�5�[� ths * �p st2. " [5�5CW*5t!!�eA%6s)/i ?(�h nd7cF7"�4(%���'P�'���'�rn!a^!k�asE$5c�` �qpaiDIY!�neighbM���+��e1��)9:�forI�*pr���y[2\ 5� & i�7$/&2���^aS�6�b+t���G�fNdramI!��up��y%U��l7��O��� J��}�$A�[-"qDS �[N m*8&� � }?1B%�� L> so� 6�,ll�eV�u eq��YaOa�n-�;�po �a�k�A�iK9�)94m�p�0.���'vD!%IJqPof.|!� s [5� %� "�%ach��*,+ "G ac"�2�ionic ke6���. "_[60 , 6� !x�v-R z 8+%� cytoskele09:N���y[5V6� 6�5To �= +� j:�,��,aij�i�j� e wr��!�}@.�i aň,i , j ξ = -(( v i - v j`J *K7ξASco�'6 vJvj8%m: �roid -\�Fo.��� a}�-� ��2�,�I p =bi.SR!�� s: If x�j��0o���1�qn� ~-� λ A= | K�l/.x3��@;�oA�>mmҩ�  �fAFw�CigO1!��!�F ξp1 1 )Z'bi���<oA�E�a�Y�e�I\.f,� �sN�� 7#bI�ten&�$xl = ∑ j�-�).� /N�( 3" !�su�4re taken�5bs j�F ��=�#��) �0���a;*�B]�!��M�y*�/��attac2Pv )A�& ie*!L��AXP(%�  FP�J�t�GM 6&U �"i�IsuQ�00F��se��#eco r�.Zby�(�9 down�ghtga�ofL ,-Qaa�&� aAo&2D v�+%$�ty QV� ��"� Ņ ' AX , lc;@� ge�Ur�% argu�a`J %�!er�heq�2N fila17a� fun� of L�lc [6�H�Ce)�&�;^o need@ t�6�-�* 0Dx × DyAo2DxDy/Ll&�-��e1�1g�&�BfW��42/)=6 � o �>� 3T1��sh icit<�.��0l�Ge�:q�&!�^ embe|[0Gur>�u�Ja&��=Q*:.(princ?.[�ly-�(`�10�=� segA8&�E� � <'w: infl I!a:"E .��q!9q�mes]'zeR�Bed: E�<=vV5μD0 root��squ!D ampl� �6>�i�l1I`be < 5nm�ee<> [56]�%�Q�se"� w�7bel3o�2HE�Lc *na^ignAj them �%�2?$, &\�GI( is g��cP;(f�r����&�  nu�"��, �,chǁ�e� . LikewQU@)% eT�|promoR2Q�sFn�HmerW&�;�/.end� �1&�a�%e�",N<"0"�6B-.��**^ �*#, kap�@!*at�|�.kdissρ!ށ9 ρ!�A���]vU�T�[u p-��!.�Sq.*e�X}�}� ibXAfa6s1� �/����3��τr� #E� �!� �;B�e�#�3�&�&'Az:4 &���(K VlbU G'erp�!�#���#�n�+�@.>v�:� ( a�be� 3(O@Ap�3 ix A�_ )k.a%��,A)fEZ%Y� $vals τs <��01 ⋅%k( 0a1%�AF�8)��FE  x2�p,Y/!�,A8%!�15#dl�9�n�mF�"aVd�0=� to X �� �!wx F/QaLτs�!: � * A�2! �+UM*� reQ\toi�E��a���!�"e�� to%m>"%[&>detai,ga=W�z/�""� A�����*cod5[nA�f q�Suppl�]?.mZF`y. BriefM eqs B3a�6&,t hB� �\�B* AH�!� �� te@%b{;D: A · x ˙ = f ( �b( 7"� x�⡂cAJ�~����"� �J!�e .A , A Nmatri�_��* �"�*Kc!E��&��^��P`*4� (� )%�� !O.����� mootm2ie�i�!� f�WA?�a,t<ea<� smK�7�(s"�%P�Aa ijno�8��inu�e�� aA� rth-?$Runga-Kutt�4tho�+k ��nt�`�;_!��q7n�@eIe�d�(���ԑ>D�W6r.��8J���� �@*) by D>��y�!�wjdiodic Wgar��y-d�-{Y&" � A�Hd'(z��.!4�b��$�)��1=@ᩏ""�a05�gDx&rleft edg�p-to���mo 1on.a r�� ��X{v!�~�KN�.�9� i"�$-;\F�a��A�[9h si& -UZQ)�-�8e%X�>o�8we=#�C�.�a�J o ies;!- ss j�$a��&�7) is�#{B) e�(0.nc'O�;x�C�m��(� ��2D"�T&eas�.-�R��. /iց{5Q�E�iax*q�aQsum( !� �K� onb/� LE!uQ�C%t�Nc�i a���4Gby�h�!ti�W�Tn�Wwo�AN`�": ��d� !��B-�.*T ��rB% �!cum�Uve� {$.$ e! 1nk �8��1A)fya{1c1FH��9$%"S 5d �!* �sL"�-9�Isl�<�� .� �6.����-)edT�re;gbCJ% W�"� F� =��R��*-Ra@�"z�%%)�M2a&�ic��>����Wb�d G5��J VEF)� �� wBef 3�)Rnv y v ( X�&� X (2�A�b��� x k)�}���"*jr�.�n.BGw���� �or ��"^1�)2�WI��?f5on X; h� � cY� 2Juni �=i���2�dS6�$|&Axc� I 6M��$took 1 X dt-Z�st�'�!!.����)�a^ Xi -�A �QVKE>�&�61t� @2�. &�,to U�f�a6�PhT��3����mg!��6z�.�I!\tE� to T �s�!��&+Z plaufF"� �"Qp&�^( See T�/�  �D�/oD%�sc �0�Pia��Nfe8�B� S1 z. TBfar gB&*�Dly�0Q.,I��%F�U!5Ap!-��,am%�.- �1!^y � v6I zx-��now�TX�!t� o�}��icRs�ZI6�S8.�sB2al�0d�4%�^�`�`�end)b�"�/scenarioA� KC�<�J�e�8�z@p!H� half5�_8�Z!�igh lev�?~A��.��*�Aeby�UϕE�. .]<FU�ftFqn�(6��A�L��j� 2� atF �s ��-�. U�J�Al&� �E��eHexsD:e 6�i0!ac�'=vUs.�^/��R� 2�. G�A!�y0&�/�� lw-,�� *u@� V�%�a'&C9sh b "�`j^iu�FiF���"�P�ui�2�e)|�u-�3�"by:/� σ s s η>&���s�\� ׍��M9 -��({� �1.�Ll�2%  �ηanXe"�,�=sa"-FA�.?γ�&� "�;�. N�e�.C��b�D ita/Fg v sm"y��)#�va �&v-/�D x%�er�ei.�LsiH%�5��&I.�"0 xo�٫s.o& ! o�4s� a"�n�9M�`r!�[E+ . AsAq��"8Ur�2��`-i�Y"4inc� s6^�S����� �<� on�,-- "� "�&�τm ��!I�J�  ,f�-enough97(g<� yC.�wp`6�J�(M�∼ τ �q/�&.��� BIE�x��tudy (ͬ�k"qliauh.Dc�eb!>ʁ>Qkw�GJb2�J�"�%�8TPYsL&w"�  J ŗe����� or�R�-�r!��!>:�)H"ly3i�irF (�9�4E�ɦ]�d>}A��KA��4���g�;�42Re�,���_7�^>S I��U���a� expa� (�s'�)c��)��a�t i���=l[�3pM)b�A 9�1At7;� � %8�MO�)"�Q���E�+a� teau�"� ,�_Rf� } $lyf �1�.'*Rc*WF�Il!���"�� %6Q. Plot�2K �6vs�&Q��iir�Ihu��X�:B�Qa�Qa|[��)8�&�intR�0"$J5aV{!cp8aa�di&=YA�]F""1�J�@. $ K�9 ompu�T.�P %. ��'& C7=�� p.") �:�bQ�&`+��1*2WH!oF��W:�=� *OD�!rM�\FF�2MI:w �!@��)$��Lf"�*T!6�ratastSgic losee�;vp �( b up�>ni�.� �a�� U.>Y:�E"fiSatdSha�r)��CB[�&�"L.� "MXe+�>6'��Fl!�� 6�"�L.(�F�ԕ'!�"� }�-Ato!a^d:r`�Z�"=�T�;x�o��Bn5��: �C�$ ��NX �ee�imo{2�X "�C Xa]rn^�� � �.4�! �6z&T oCq8a�Q+.�> ��:51JY4%�n"��� �1ub{-{C).�NPR�� �!�`�%%6�U�H��y� &�vail�"apt vfxo,!pE��.� , siae� hG [68]�>\W"=#���+�Q��hR��9er&+,sZ"m �/-j�w��  em�0n*8 �I� E�!�k*S=^@*iw.A6[Q,�+�m1}thIu�� "�>�S !xg� elf-�?At%�k &SZ�;.� j"DN-d� vM9�=9]Ies~�_e"v �&�A{s�L^NofjO*�"�S H"P�^!�!@��U΁8e#,B� - �6�can�/>*"�K . On�rtH � �s8Ni[�!�W|�*"�on�er6T � H�: {Q � bQ ��� �AGM�� r:G*K�3�fZ-� tear� !_fra�/3(��/ei�^�z[40���C9� �� yw ,NrAl(aq!;�1aqn#s� &��/�Qs glob9G�&�^a �"�b�g�N�nd�exO!ѿal�-��-�"�BYA�b��arh� hn }re�G!�YK��6�Ec��&{��?b` �0I�2�_�!v�!! 2�ť� "-)-��-=2� $Te�~� ME7 Y�e2ɟ�$�4���?�$�vevi�zyU�e�P�Hmf �au�J!f-��+Ax�!i"�%�$q�6�the�lst��Oc9G�lA?[��' �>��P���J� �EQ+1�g reQka1�d&QZ )��)BL �!d�>�2Q���>T^ n�6JiA6�� %�e pybi��c:22� -�.a �:J�b-li�'�!>�tmNT!�gi� &F&& �$vHm�i�_o�4 ?J< Å�!�3erZ��f��e�Ynot�E�9�S�F�I@:TL AbmcO�$B�&T$P?*�I2w*}� �l��o��eV�D( ≈ 2x10−4/seca*r>x8}2|B ���=�)%��Y�C .L{ gans zygo� k1J q3 q[lPla7l>MiJ a"Ngre� "Qyuncer� b abWBA)X���s:%e�9Y>Q �K#b) h[v%'2�4mInd^��/X �PnHZ�arI�E}�u[7|]7GPA>��YEQp) w�$ނ�uen � a@�Wy[^F�S ut`h&rk_l��in2��iyoj"g��m6=�surpri%� i�5i�le� f��r� $ADF/Cofili`$� �<�Mu\Aeh&�_� ��8 # c l’u5i�1Stron�es�-f.N2 so5����X��>-v�2��AU% �!f,I �< -:�A(s .BxSeed�e��isKumhibČ[r�!aM� A�C !l∼6%�4f gluc7Jr ruct . GeN� loci)�� co2 ,&l�����vth�osugar�PpBDC~al!1�h)W*RaEuj �Gl,8 5�ins�(i' je,�ww��I�  �#, ant�$\Ai� cu!QT>V�f_wq��Q��to.�K4Col/C24 F2 popk2o[Arabidop��� iana�"5��1��}ng�, GSQ�Q� ��B�&-$v!Xo/jX��n�  far-isoge9Ry���Co:�d �backg-�Allel�yi4V�B FD;%�b$�at ��ma�$he ANAC060�(_ e}�h�Sonf�N)�i�C!q�! domi՟A��.)7�o� QE�oS�A\RNs��se'��-�AotP3pqW>o!( SNP a`!5�� � e sp�+ngA�V)�)s"�,20 *�Mpc n)��-7�� %!�YW@op�<;7u�E� trunJd�60aG-� la�!�%�"io�8 ( TM0 ��i�N.�!_�Kz �absw]F �Er�ar�c>HI>ofP H� =�9)%>siC[�in��12�?�^.s5V� G��$esI�/]ex!�,W�o�n) �s�ci�� ( AB�&��. Chro�4n�{precip��on-qPCRE�%/.y��.VABI4 �O�i�C�*�"��CB�� 8<n cripe�F.���.�aAGlcy�AVBA!ZT7E�#�=Ga�Xdol5ω�!�"�Oi�`9Scas[$5�J��AfY�.jQ�0n!�s�E % �Av�is "�Z feed�(�.Q��onQ�]��e��B3 . Pl�C�B.J��� Kg�)rb�S�ea��a��(` solu�x��&�Vc Bnut�J uvnm��qkaryo�[�eu orga�Tg>X?O�<sophi�[a��) I�du)h���al�Q��t0/o.�m[%�[1]–[�af!@?�_E�� - � � iLL?e.��f ousaaZ# ey|% !��� etabolicAY�%�-�,2�!D�Mon%m�.�~[h�[5�oSA �5.clo3��Z�_�J/�cl�� Al@ [6�g$phytohormo�fu,|5[�fdefen@h9�n�M55x as n����phosph!d[1�"� -%� 2� $H ^�$_�#�K%��&" �!�� um��2�"j c��Kt� �"� .yAre��%� �((~X)�=conven���f� �N� s�*QibrgarU�I9ig� �ge�p�[¦. M ��& eBo!L�R�5&�-.��iso�)M�l�!�!F:�8den�=.#Ler 5"nNx%et��b*�72�a�1EcitAt�ch� nga�z#deY1p  uEVic�hz I�G1jN . Pr? b a�l.S!a$HEXOKINASE��HXKu3)0r��fa"� (� )�.ormI� �.D��ethyle+wyn�� Y�E, [tV^fSAMO�r��s F|photo6p��s��tagon�by�U��Ihe EIN3��T "�, [^s. A]急no��I�-� � 2�����$(6 ��5���b,$an ERF/AP2�\"�\9@3����Atqs.��14�f�  g&��u� �$d-to-��us=�!�:TI�dox��, lipida6xbreak�R,��e%+2O.�`� w?+.�� ,>�i�[֐!}O.��a^6 -%�Ng��a� a!�!# )#%�*� l� "� ��9%�&a��y8aa|AA�N�atargetf��7)�E�N��R6�}�J �E�tb��O zy�x!�������� "f!,�5�Zh�K�z� ��$in Ler/Cviq;+� inb!E  ( RI�&9�e�%'1L�0���Oal �!�!�&��F�>@Glc �o3�GSQ�:[+uqma�de�+ H�i"�$DOG�$AQ maj4`g��y��O N�� � 5/P]dD�!@� #�)l�QM-���ar��� ereb�B�J#�.2I� ( Fr��-36SQ+X�R&�� e�*�� is?"Zu��� is��+��nŅv \2t F�� �? �.�� 89b�+e%]+-[ �aZv5 &�A�8"t�Ia�2�l)n" x(!��:asU��a� Xp6SIaZ19ach�<a�ReIEK segr���pi�j_ �4� lya!-�e�&# 1?���4Z{( NILdJ&�N!�!f.� �2�*ENAC fam�3R�j()�6�cC*w-�g�h Z ���jE��i�qn&�,$a$'&��>�s%�C-T[i�%"� anch�EmA-�72��R@��� -!G�.5;^ik� a͹ɥ̓,�6C 60��FG*S�ua�ucN%A0r�rs�2j� D yB�.��7of%�JC24FA�i"M�o��8Jngth MS. '*�ekW!��:� ��ite�4%��a�ubu7�mj#2�R_!=�)� aJ�5GA%1��2�\��oW>%2 �p�sK:j6urea��S���I�NF- B ment?ar��S-nd�(yNal�i Z:9aV�Mth<� �&� itolGov5�um%M+i[�:�!�%_ApI�2_��"sQ "{��Զ�a?�U�.v -jteg�=32�|dyuy��mr%�1ء�m_!�N�. A��xe8ly��0�C!��xs�>on 1/2A�2 71�!�106w.�@� Do�I��%�e��!A.;F22�E"Veٳ81*�c�-p�$f��K>!SL"mar8( http://www .  ~.G�..!in`�D fr/vast/msat . ph�` )amp����f G. cn/w"A����F7KBxF13I1 !CDC2BG%~NGA112Evi�o���w6 шhgZ�) 3]E ,BGS Q��x���x)9fi1+(e 1∶2∶1 *Ama'~�ed!�&/ 942���eq�ehaAdF��dd��&. NJ[��E[0QCu֓��e'e��qa�on 2H. ' N08 , N12)�40���l�� �s�C24��I+aa��� (ޗ��FEDCon5a�, �M35}M09�}oa�J}24�}T�(�%>|>��J.�. O�o 7p@>�,%H�N!B�aedI)�ty�6�BG , H2CNIL%�D�^� compa�Ho�OI%bN�6,�.yzp��GnJ , Kr)W�� E��F��is% ]g�!fQT� M�!��v!i�& nam!�� Z�f�tc�terval�zd:��e%��)�!��E� .ag11F �dT��86-Mbm>"PA�MASC05041!� 3 MbU%nd  7090Z#6p�6 9iOA �[of 458 �2� y ��A�%n�11+d�'?g� .a�spicuou�.-mJ�is"� ( At3g442��be, /!�$OsNAC8 sub�� Ig N` s�5i�PG�8~F 40��8q�{/+6$&U�Q !����e�YBT� ��� �em"'�+��!*� �� 7 igh-�6S#� alTY �d� � *�onA�2�A@!xpoYG_2�!�bio�60-i'�2� �TpT-DNAes��� anacJ0( Salk_012554 ���) "�aa2QAS!U6M� o� �ŏ� "� uSzzi��� �0���a  �!i�#ͣSv No5  !\�b�AT� ERT-F��-J.�RDF �gro�$f5=on� �کJNLa�gD o2! a���s%|isM!I�#��6� �!3� > �0�.�-1�* � s�fúby�A��� 5�2B�A: $�I�A�Q�E�&9%9�F15&� AyX5[C N40 E� � �.$to.�,� 1�G�h"�ngu$�� b!�C24��$)Fa3a|r!Q� ve=a=D%F(�>�dOa�X�cr�?%-.�AX��aEdr)�!!&HparQ�9�Ee�4@n�Tv6!�F�[�itKJ ! Ai2��ð ^�Q�ՁoB��!flE�ip L�����o��/E.4>2s?�+A2�%j!^.E,n�36pN4�vfnF�'E6Y ��y�a^$E�e:��}�!�)g�n .��t�E2.592�V!�"�N1*�5%�U^S���!f��%�!*60v� �wild-� �Ȗ�S2A , ���FrR� ���as��$ʰ �Ya��-N�%�E�=!�RV��^(iQ�� vo0#<^A�!�&�.4* 5�UɄ&�> 4s��j&OA.v����& N�=9nd �_dnA21!q leaf��tem ,a�^0; sili��5.2Q �5no ��bu ia)�"*:�(s�a 'e>%�40f 1N�� NTL��0e TAIR�OZ�) -&� 1��]?ii.335 aminӐ���a*�ly" /)��� f>:a!t-~c� clLV(GSLTLS7ZC02�nc�znl#ni gov/ �/BX82382 h�(�of 2282��L&� �In yea��>�1f! GAL4 DNA-&վ�(�0.UAS&'.� �r :�j,B1�:�!E= � +G��Or�Xde�0���.����*�RX�f11H �f� e�B� ���l ,4V196 D197 F198)���in�a�� s*�H� b�u�%K . An alig}�O� �E)B� �"%,-`� �z� b&����rW S �� in-�C TAA ��"�,����^�6!P ��20us�,�v?24).60 �. �arn�'*5/%]6 /�. PƑeD�5Q3 . C%!�Pg�5$2h!�.�A��(���P��>/�%��?�7n� �q%��.*��,�fR 3′�[� 3r6&F3IU-p'"s�{ )!1�!Bn�1G��~.�vi~�ob) p�$�^! 9MB� J  TI��F�! %�!p�rn�I� al AG��/e ����aV�!�a�[-.?TR/2ZO� �&�C��D���xOe#d�� q %^��+d�^ 335-�|-� 1-�!�*0.yA�e��9q"�"T��tQa%E=p%8�� � � illu�TUQ �a -�p0��p-+!�oEl!���8 |%.��U/'� 4�4�i�Sqw"s�e� !1E/3?b( G-Tf��� F8� �;� �b���(6a20 2eS4�`" B�-7J� n!;.O 6� �)H�� �J�%a{AЁ"F+UBS4i�A�w+;1���|�<V6%%�ֲc�k.� AV*��A� .��3D , =���r$��e !��6�(�rvl�0{!�&ksI�U� quB�6&�  ( QTN��.I����{+!� 3����a��)i!e2?e9=)�.M W*�"5�]0A �vv� �w�&�� ( CAPS )f�r2�� p�is%Ah����QF�!U�ha�T�of 66.�� 9za�Six(:6,� 3a�� Z��-%�H!C(c$l:2724 7"�dU)�M���] x=0pub���507A~)�a!V�"yQ . sal��,edu/atg1001/�� 0/gebrowsԫph� �6N43FOT� P C24;e0!~9B~J��!5�5� .�ge�-s Got-2� 7va C.m�����*�l} k4�u!�!� �� �ha��#un-Col�1�� ��A�5j�*t ,�l]3��.]bC24Vbqt.)6�/�. D.f2^:$:�seL2�O�Il� �s N"�%ly�� GFP �De���01�Z:%me4yllYoO-.�`PA7 v�t("�8 r�{K�t(n Czempinsk;�(Potsdam Uni�t�0G;}ny FZd�n��ءFP���k-P ���Qlaser-{�e�"��M*!;$� ��u� ��4A–3nVQ&GFP::A��2!M-���exclu=/l{Fo E–gADq�A��gm cyto��24I–�,eBr.�) iOo �'r�w�ve���:s%?sI�'�*'Geʁe$�siQ�*�h �v�5R p!�2�F�&? zi�U]�,� h55{ MA���D��^���160��A�. >"�" Z��-8aba2-1\-�Ece�K ��!� abi4 $r $>��j,~�CW � �(-�"h�2E!�F8-\o&i�6<�,���"�:ivq&%�. B�A0� ba�Mi4 do9 ��B�'�'�8� � 2),*� *Z�`X�� Bu�@�35B.�VXBA �^1�߸3Rc!�6A. &:%4 �IQ%�A�9�1a�x"�1�3t�QD�A�U5�CACCGN/*� 1649�up�a�x!+ ATG "d� odo�2�V6arJ�44i�& !b�ur ��M�"1=��{E,1P:4q�M�A� 35S-r::���ds�  (�&] ;�UFiG>.M�*�#��Y� ��z�%vBI on��r��&s�&�7 �DS5��� ��10��an-over�����Q�D!d�/"P*5-�H��>�H� "e(FLUY�?M>�e�)5E�!� ԼA�nLA�5�f ^�"� M%�ec e"~���Uo�r �enric�E��Z}H!�eT6 %$( Pk)�1u��^EM��<; no �9:x*E� +�@A( P� ! a�D61�Zo)!�eTsmf� �4�h aB�ޖvo�e���*{#QP�ry r!M2�i�.H V� !�!yd��lucifer��er�jnj>�O.+"� mid�+#A�&��kP3�"QB"VLUC!�3- �D?pGreenII&_ .6. H�pU��vX !-�%ly�=]��.co-%�<� /��/M�F�,���&x`!�ff= s����VF3MP3�1U�ele�/N ul��owv� VV��3F2�j .~-�y�]�!#I�u��UQ  �%��!�2�����P� . Co><�Q�P35&�a$ !! �EtmMuczd �CNO);�i蹦-#YB�-��#ng�46��%?hIP�E�\� �27 �.a�3>$%  !yv�c� ŴJ�,in 5-day-old�nd!v:~ ��2� R; nq%o�1��T. G�&@(�3!>=A*�'�&|� Uq7& >}Fp>v h �m�� �h&) �∼twoN��6�>�m!)�di �T ��5 ��� four.le@*da����n)��B"�1c''%�!�Q6�D��%0!&� .o � �1�'�d2��L��-�.���� � S"ۆ�A!�1W3!�th�*um��� 5 µmol/L��B9lN!+=@.�.[}NA�'+um*�!�RW!�un�.�7C�n5S_;Q* ��&� d�-��s2&to�X7p��r�Fof ~=&M2�4�.�=i�dg���!_Ta�sul� e� !�2,�ty'>)b�'a Z�K:KDto lo�QTL��@�� J�5"�Dj!map =��a���w���$barley [42$At�Jo [43w?45�Erat̬\a�Q�Նp24�!}> U^c=]�>8ish.�0 �K"�6A0vf��D!xaz05w4+dB�E�Z3-�ed!y"(�0EG"l�Q�*0"� v��1T'%��q�z f��#� �@�>E2=e�1. 2� tw,�riants:�l!��Fr,S%��aI%B��v6U%i-aeP�% NN�2NJ2�?e�1"�+an �A#?��mK!ba�&�!�D7 �inoa)we��"���p8i&�#;a��� N!�!�1t����� �,2?�� �< �a\�ll9'1-�ųo�!�%Z%;�o�"H4�d�FnEr"<,Zby�-�Z�-tez� t "� f"8W MTTFE@�"� virtE�1F�CNA;@�,&qG[Df TMD� db&o�zt���1%8\C�E�!-�81-.KJ�� al�"ZM!�*(MA^t1�i )`- eolyh�a�No!Xin �:� j��Yig-� >g`f�.�Fܳ�^2";�a!?��]���n�J*a.�OT`,5_-a:�e�89��I�m &��/Hu�Zr6�H!H a|S�J ~%[3c/x�)18b+Nc��EKEBnco�P!�.r m������Zq89Q�2a���(��%��s96����V89/2EN��!)"�"� �-6|Mc�n)B1e��^,. �d,�����(ed2LmF!��.b�.UKg89?���-ly:�!�"v'"<60.W7�Q�� �4�!."��&� !A &A��5B5yCbj�m�-��k 891�*tab[ِ��8���.����&���I��  . ��:�I�i9Qi&�It�& )p M&;�!0�aIA��:�� UDU2"e�/��?!N ,!w*�V�tac�.vA�$2 m-��.�T~W �@��A1yE"�mbiawa.m�<�Iu?)�1�=�����ng �A��\"�>�. Two-aq�.�p%�9:�W� ��+]1tr~{gin6/�)@ [3O>E6�fEV�Ds!h ac*XeAVYj� � s�]�Kd~�\%R:dե >/ Qg �E�"� 1T�P��iu�lsocea�-��pa�t���mX loop�Ao�*�i�T�A�:6" �s%�]@*�t�]%���F�aj��[&�!��H��N�& wSA��� ��9�z�6�K2@+h�"$,����� !��U A�2�.�A,nA2N�7r�?]@i[v��C^ap� E�-�~&�<;2bA�\��B[;�EU�Z�=, :�=!"@=�& ABRC�r7 Q�"4Dr . Xie [38] �O. Sterilized seeds were placed on 0 . 1% agarose for 4 days at 4°C in the dark Xstratification and thenTt T�solidified 1/2 MS medium , pH 5 . 8 . Sugars , sorbitolKABA �added�}concenyons inded . Th�te �incub�4at 22°C underD8tinuous fluoresS light �9 �,�vs�-`ABA-sensitivity phenotype v scor�hA total of 106 Col X C24 F2�vidual�O(e to 7% Glc �selec�![g hPd together with an un*F2 popul)�of 942n. E�y-one polymorphic SSLP markers between �|�E/ used%# ��ing ( http://www . arabidopsis . org , 2!dinra . fr/vast/msat . php )amp .dmicG. cn/ )-�Lstatistical approach�QTL iden]�|was as previously described [44] Shpromoter ( 1794 bp upstream!JE ,tart codon )%cod!regE�( 2111;)4ANAC060)= ampli 8separately fromE!R$mic DNA usTq prim!�presenA (in Table S4�aIL4ly cloned into ?$CAMBIA1301A]construc�mplemen!G on vector!kaG,G-T point mu !!Dintrodu�1bcRI�`QuikChange Multi Site-DirI�MutageneA/Kit ( Sa�5�-e sequences![!1_A-J24!�028)�E�ol ( 687 E�9�%�c�v5Tsub.lPA76`1P�O�8protein localizi�assay!�oplast1�$transactiv + �p4�6 yeast � performed=x�Matchmaker GAL4 Two-Hybrid System 3 ( Clontech ) , �Pmo����e7.,9q,(full-length5�%E(I�4 GSLTLS7ZC02 )E>�<,to create pAi ΔC1�2%b3 by PCR1� ��n&6m�@pE�t��digesaS�BamHIzPst inser!E�,PGBKT7 , resA�ng!�8an in-frame fusaLof5Y�dA %�DNA-ba� ng domain �Ami�E-��)��y$in PJ69-4Aݨ culturё(grown overn���liquid�a# dilu�to�OD600�0 .�Seria�`(��eFdropp��to eiŕ-Trp SD^ a or$/-His/-Ade. S�of��! 035S-ABI4::GFP)$genic line w �n:Ual� xim�]2 weekaTk(lings ( 3 gA�� harvI(crosslinked)�1%Umaldehyd 15 minugOvacuum;�B!١3st)"by addi!@�!]$125 M glyc��� � �omo!� �A)� nitr-�nuclei 1isola!� O.$��#E�ultraso!d wave!#HBioruptor UCD-200 )A frag�4�chromatia8to 200–300-bp)!{0Immunoprecipi�Nm����aD ti-!��r ��synthesi�X( S� (hai Generay�t Co . , Ltc � >e B� � , similar��P3�Iu��9�f$-W62-SKTz�>/ . InI�co-2I , 6a�m-X�e�12#[���. PA_0ts that had bD &��� 16 h 9 subj to.�s*�Promega /-]*repor�O2 s� �z!>PGloMax 20/20 luminome.. T�RNA%t� &u Pa�!Kit! Yuan� haoA ( � yph-biA$coAg. A��ot��1%8) �reverse�c} sTa�@Script One-Step g��Removal�^ SM�$s SuperMixay@Gen�E�$F�ʡWof ;A`%�0per real-time re_ onɇ2��$l GoTaq q-��Mas!;o/ 1�:�A!�.- and��8���G ��o�pM�� 9�t�>�!�xRoche LightCycler 96 SW 1 . 0 R�T�M� det� Ahe exW� levelBX �e�g� )Ƚ��2n PP2A [53]O)��Q-C method�9 hich takea0eK$efficienci&� .� imer pair � @ccount [54] , [55����1~Ea����S o&� �a'J9�Dee.� grounc :� 150 mgf{pow�!�.� yextra�� 24 hE!>ay*AD6-* ( OIChemIM .��sW internal6 ndar��6{pur�)�an Oau�>�-ph�� �a' cartridgek�/6 cc; W�s�'eS � 5I ic aci%!��elu�dr0}�qu� t� 6!38]�1u� hography–tandem mass spect�Rtr�4wH Acqud -m} anceRZ� 1 UPLC:�a triple�dru V�epDQuattro Premier XEO!"$ree biolog� replM�m� ��� � � .��a� mole� r b%�of secon 0ssenger signa� a�e��  arof��� a�at*G$ , degrade� �E� se�%�e coh� fun� ( utpu1 �� ic di-GMPQ- () has emerg� a euba(�� otideF�reg� � a pl��ra�$key behavi�, like�-iE��� kt& cells�biofilm��munit!.!�e�im+!�AY���a�rolpulea�d�edcu: 1"s rai~�: ques�!�5�A��j. Are m%ro�exclusiv�depend% !�  ral hub!�cant!&� ly admini��?d this studT we show�Mex�be�J� )�2��seudomon��eruginos>We ob� !occurr� 7�/ of azD��Œ, hsbD ,7Ipr?!Cof hptB��flagel!�9s !Aa�.��� EH4pathway1�sU.�a%���motilpb  volvA�both H�$T�- sigma fac� HsbAMtrewir=.g9�AJ� casca�req�origia��2 b�t�oE�x$ dyna��l2�� a<( poles . In �eukaryoTWprocyc� �e�s�a��aPe)�r����] to rapidA�� y environ�%�eKi�e�H!mlN stin>el uI�0How*se� s` h, come2�w0� �snumer��s eXil  unreUssu/I!3po�$o be achie{[l|rough�� empoa�!ispatial�!�AB [1�` I)��| worl� -���(yv)=��a�ed mo!|um si�hi9 �Gr2�uniA  Dpleiotropic ( i . ! it ��A' w� r{of�J��virul�1,Au�,I��e%%��y�() [2 , 4 , n Re�4��IJa�also �!]Q�ic fielxit e,l�a�Kalk �"� i�60in DictyostelN0discoideum [6!�Ag�,9�iA� cogn��T microbAq7 �inn� NeM�!H mammalian�s via�STING �or"� ��tav�Ta --d�z$type I IFN_ponse [7�Despite��h plex�.A�dE.�Qdac�\aAdaAn��all�!its role!X! r��ng�Y�8lifestyle: highqf!��u sess�� whil�,w%avo$A*H�(e [5 , 8 , "]UGmx��mod��H��%�wo class� �eins:� uany��A�a"( DGC� $phosphodie�� PDE �A�20arry a GGDEF-������i� ����k�.�eGTPUrs=lat�P _ a^� EAL�HD-GY:tif��hydroly�59i !� pGpG9GMP [1N Most���zym��� receAV3�mi! �AJ sucha< thos� %�omponJ M�o"e :gr�%2their a h be=�b^�or =�gr�to�^]��circuA�[Aq1y12af Zm �i|ri!fainumber!I ( 43 �}�E/ ,%�,1�Q� [13–1�BI�� ngly��h�Je-�do not�eLb1dundant� hav�Y impact�F�(or cytotoxi) [1�2!U> is a smal� 1 �  umab�e; if��a�2gm .I a��glea� faithfu��Mk# eGax)�2C��trigg!x��a subseE��-��*� thus avoi%��si���-�n? H,� g@an& :� a�hUv��M�tv��A�Q e�aq�$ar network�a!i�t!�P6� b�nam!�`� s ��2�Vr�F, twitchw, swimm a� g&!�chemotax%�B�y pg�z�f��6C .�YF<s�ng =�Gac/Rsm"� [17–2�� ���e� R�MMorkL� tV �&V ,��outtdA�$S1 Fig . C~%lE.� iyA�\r��4��,�ch�h� s%~R!;ner�=�. Brie#:en)�is2_ey itEv_�R 'at� ��I�a�urn de-��esz�e_v"�� ]F� FlgMFdu�xf��*�%C,�� !V�$��2�� HsbR��!a kin�AD2+ �(0A-P[T�a-r� ��me�!s�sB��a�'FKis "�[1-!18�_m��1>�G��� %q��o a redu�8!�he+ � RsmY��U�y�( s�)��IB�N@!P RsmZ2s� �'� �� nG:�6�'P GacS/GacA'-&'s6� RsmA� �al�resS [2�Up�J aY�_iA�es.p �F� -enc����axa/� ' qmR*�"Q��. Tit�of l�to*1�ofU?u "plswee ?�� s� �a�/� �)� !) , 2�& Y s"e �1�-�,as��!Z RetSE LadS h@%� s [2 Our.E�*k(unc}#�an��on"U��*3I+�qS mE[�m��“&` 5”�“� e/ms�QiB [2") link��!�rb e�din��0details: SadC�P0�� E��E��y)�,&� play��1�m�!M]M�D� ecis",:hyper��p�+%� 5�y �̥�_�s�u�"`�[, coul bt ka w"� j��a"� dele�s!D[2+ &� chaR (erize a new%d,���)m-'��h���,.�AzM=Iby �y:i*� ��~2�Ft�f�#"|1$Q�= prov�c:"about-:'e]`d�o|&y�E by acqu A1���: �oc�$��clu��i� � ic!cA�AsvW/che�E.!blef.a Give�����"��3nwAO`ar�Z!�!ku|l��evn�W r��m�"�V����id�v2ar�q!1oZ�I *��u��N� !�*e�r5A=6� p�$U2!eI3%�r,m���apgL0p&�2EE()�i�2!�!R}��2�M6��P!���0Q m� �1�/� :D<.4mendocina NK-0� w�.$resinovo)&8 NBRC106553 may �2�l !P�LeN2 � ob% arri�2Bto 13e4L��deH$�a�just bI�:�RI.B�cQ)>�1�s9�9%~���be� =�!s�0lE o%�.r9�alyc*[2"��M{��� p�*udiB�1��2Aqof unkn�0q� .�&��i'oua��k� �dc�"^ �4� � Az:�wX'ci�8to inQ0ig�-Zof�D o te�3h�7�k*���ed� e6u . Ba1 ��-�J elow ,vis � ��6� �; h���3eR�#A��D�)� �^�nd�-“G*�sC���I c�)�0&� 9�389 aa�d��ddis� �D�D C t�u�252� F)M*sixHmembrane B< predi^'�-aN- Ut�-�Ew  ( j206�� E�E�3/� �"> 5 de�*pn�a�8eR� in v�1!��&445 pmoAU�K� er[(wetwe��In orp(�5onfirm< �R�4tvsan Esche 0i�lim�L4;*ng)��'gj4n7( �;suppl�|)1a,Congo-Red dyG(��2�4top*Y A�e%��cau�E��colonyA�Q1,*�"9�3a glob���2r&F"5Y�$[30 , 31];MZa cataly�in�ve GGAAF nt does ��s1*"�N2�ofaZDE=�?�2 RxxD|fX:9/29M~(� �he���c inhibi� sit!`I- �:Ja s [3^B�6.�to �!���dy&z @ rad capi&%y��of[=��.( DRaCALGt*32P-labe� 5�1EK-li}*�";;� 8;�fove.��6�n� vari!�waNa>�:�\-)( R!q��A�M��� Sign�t�a !!iNQr!�!�tu;��)"��7!�en paܭ� nega�� +(([ i� dra=� 6"M�uX ��nA{.>�4M��Z��*�w� gine� -X"��J:��!�Δ#(v;)�k@-(�"�@ve�"�s1A-6���rst!-�ll4up��-�����n �-3U���)��w�nakedIaE�inB<e/(rect measur�aeI#LC-MS/Mtby i!!�'Z�x cdrA-gfp " 2[3��%)mΔe ba5a,w'S�ye&0�i�� r�MtN� z.t ]y%E:4Y#i�j 2B62Ce{Concomil$ x id�jmu���J�or!MF�5By�� a -BM �F�. Lik[c �*<s�+ypossib($Qu��-m,s tgdQՉe�C�D��~��ch beb(A7�1�(%�esileaVv� -:d2S��drA.&b�&�?��a(�*!Q��Δret�}�)nt; al��,isg �L��g��H +!�lly we�>��h9 De!��]�� ef 8#explai͹� capa� ��w"fe�&L�up!�k$In agrei��U�,A�5X-�);%+mSn@�"N abro"V ^�E �&�%feI)�q[DeT&��� )�.�5��#o��!@^�:!�tS2�F�C �q +���7 ��ly�n!}b�'� � A�f![*i�Q �?�� nZyJ=y1p�!�*� ( but�{! E>) down-1 p� �>2E#�=smZ#�W: aE�ed�9359BeW�`/� &n EjH" �&����at20 o��!�ulw )i � � 4�I��Gs�pF' �i Md��:� |�}aʁV=�-5FM:u�$is epiV"icA%���Ne��K�$�ne*ary�%��"bA(:Z�8"9��dat� .!�vDGC�t� �+ter��)A�=�.���&����stu�).\bov!�d4�at �!�t9c�B B��fur�. %���:d�zQ P/c�:�F^��e� &A4-Y.�)�H( �� &�a�@A'�lY-h�( BTH]=?���A!any&m�naG�hei(s0��#�� �"J ��scr�.w ce8F cyt (icE�l �#Du+W� �!Ht3'� itsel �+�+d 9icSe� 3] ) n� ;!�a� foun �"��Rm! �si*�e. Impo�'_0 'tqF~L5�QE*�,^D56*sFtit�DE�an alanC6oa2PL0i�.y-X� e&� ��L!�SerasA�r�bu Q�,"r�5o�*4)2, s:�+>�)�A� ��tre3Ge� &6a ͜ZLA��<M{�Mg� �J� " �!�U��jA�_6�W�Fi�x �( �1Om#"$4:� h!�fE�a"� td�K. A bloɁlay&�A�mLzs!��.lys�M�B )�:}8  b$>or�{�[3o���"�:I��I tagg���*an HA�mtope2B' expe�<oM�u%A-u.;!��0cy� w�/�(!j��k��' WAS56D [R2ui�4(A&N �I�ano����,ly"�#nP�Ia�] cay%'� S56A%kt=��Dl&'�F�'or-�I�>�De�i.1 or�2��F��jA )Bc7�%CU�U�fv!a:��!�Rq$ ( S4e�� .l!)I,��K��" �%��U� e.�� of�A2I � nJ<m�&cPA���$ D% ADuR-��O*iq �readi�5 N�8R�i�� ��Q� jA�Iki_�p&�:!�#.;iM� reasoEWwAj�%�OD" s � woAm�%c(2e�}nd un.zedET:%9�0idsH?rV%E��6iY#������.`څ�n2�,�) "�Gp��22 !�KeK*a�.i"Y>F�)܎c-���Y.� 9"�� mpty.�Etej 2M:M�!k >�,e%��fai1�9p�{!Q^�c!&atqri�.���E�U !?NK 7n"�� fl�P��F� associX)b�>#]v2��!�ߥ���TE3� �1ͩK*� !Q� � &6� \-�pIt�&t62a�3I��is �-sm(�:] i.%^2�!e-J% !T�Ei� H=pr�7��^%. S��3nOe;2%Ie�men� U%�\s!�m2 o=� �%�A�o)@[3:3�)U�minimal-��f^ glucH6!i casa�G%Ca���&^�&*ŝ�PtSa�r=.dra �2 hamp�5\)�!D�m�dR)tlarge5 area1N [285ii����M��#D&z�e�,"1�Qch�;s + p8�Gtendri�=�"aUsho�Hndherb!��o����. D.D??��L�%�e�Y�E �:��� �=s� E��s��m( S5A"W,!�6� o�G(mplex nutrif agar�:< %z�We.��E��61ͯ% wise��0A�QT�AT f}ir�tL s "ext�E:�-}�S5B5How��1q!;��i;�!;F[)�EtrS*D st�Cb� ( ~90NW��in�e,�4� ��I����on]/i�2s#8�7M,e��n.�sS�g� `>m�6����� nd/or@ A�Q!Rf�5 k�2�3(L{ �� ��6 sE��3e����& `Ad�9��������ove.�MZ� - "e2�KC"� s�e E0��*@�'��&�![k7,)��c.�*d a�/ 1!� tten��MQ��� EJ(A�NX;6 @E�se)���,]�9 k��z�y��-~D���4A�yF18���z_� boliS { �DQ����<� b9&�1�K�s��w!����=/o��x9����� �H *%�.@� I 6��A�� e�/ jAnlapO���0a�{Ce����%A1�ch�*�/f�in �#Z�hC��� In����'.H�� poor�:[3L:39] argu5e|. Y �'rl� !�-9�^� us�9ed!YD q�n m[uli�80��.O ��&� ndee&I��ja sligh!.��&�2 ]�4�]">.l!ɑ7� x�Sh9d]�u�p�6a- ideaM�D��i� ��+;�Bof9 [2UW3�L� ngW��'mR��B` ��.m��?, st"+ �����a�-�x2_IDm�9�5�' ��^`�!<(8�e[Nm*�%���_3/pilu>a�)��Ioscopya 6u*�*#� � pti����deTd4az��surface��+-01��Al� P�*��/." >��-�̈́�alL��ItcE� �O]��' ordi�Ed6Q ��E�in��Az sis/gDm�val�7� hypo�-i� "�m"!#��Cp* ili� 2F��C c�32�TEv="5.yWs� Fd�M�bR �-M�pofl�Ku�M͜5Pm���5� l.&!�,W N -{�Z5z."�7u7!�!�W@�O�biN�SGI�W� i�ly�GIVa�T5;ac�N%�#aelud!�� �Za�ʽ��z� �,�> D�!S\�%Ze�e�.fic� no�E!gF ��Mu =��4�3�,�5�#�"BY�[3~4EAWe"� i0*� 1XUN��8nore��J.�5� ( S7E���4l2can��O5�A0_2 ��T�!�n!�NZ�"2�!�]ҵV��|L9�"'bo� c� t P%�nw"S7&� �BsAJC���3!1� @fimV-��� 8�^,�E��l >)U6G<�.�2E���2�0�*�6�%�2�m8mF �g��:&( .FDa�"HD~SD9�:��qa:&�Oa5mD/5�K.!@a�>*#�4��q�A��S+:�jY�Dx*Y<t)�A��aQny*s �m�W�S�Eeq 5)n6� [86�!�Cqa`A�A�Tre!��2�Q�a2H�� 8[�R�im �Ms les!��:���a�5A��A��B���E�!�u�T6�I7!�e&W�>a`/"64XW�Vb5%!Z7moYVac6)���\a"� �y��7�Ux�`]E2? 2 N!��536�C(�A\v(sm!�i7��]r"� QO�E K�?I��<�Z�D�SNoZ+� � PilZ�#-��2N a��ly&�Sind&�-���( ��=�Cputid�2"�>$��[4�S4��� !�Z� 5)S�n<'�L��y�4se�s���� aCI9�!u9�b�6movN+�o"G]!X4d i��F:�9���n��Z@~� ngqtCor�υbis6A "0 �j�P@lh�<w�=��%)U�Yd�6in�A�2!��(� as88)Δ�� %' �� )s"{/"�� in � r9 ds i�X�E!|��ory sF!Y�O�h2�[�h&22wD&� bUI�i� dou��.U ��n�S�I�7k%8 %)�� f)�� H* iyZ� aY�L*�0!n^n B� +"�6)jHno*�uB�W�lToFV�7�  Ece ס{�?� BBRMCS4-A+ "1@ ��)^1>"�farecombi�I1l�� ng }2 2 �"aPa<"� �,�'enT=E�1�QP"U l�&N� %Rb�/N F�+� � s���o$&�R7�z adop&=E0�%����5�xAG�*lifes1V� "�lH1!Vx!a�5 >� �WI� rod shapee ,?m�Qner�C5 �\uma��  IV:�!= �. e!?Ha~\dem*r"r6*=�%:4 �E�1Rp1�u[yliqi�2i�"V+ visu&O'I@se #hh�(ll�p�j�f+�ye 62�u5 ( veL<,"1#yfp derNPg5=C�Lng�-YFP l! C9<ch�+!���*Y#F"kBb�td(+ nD�[# runc%�22:Pver�cbya�C"X;s�of&H9�%*z$� �8�\b�^mmza� ��:�VCS8��2A�Nd� *J�YFP-t)!UaV�Aj2 hou!M m<in LBa��z -!�J � SM{��AU�iphery��� *�3@!��6i* 4ol.�-M��pP>>Q�-9�F)*e7Mr? �IXg>-X��B�> �UC3a��!���.a��2� é� 4e�"Qx2)a�xd_2W�!��86%�!A"�A�6at� �r5 !qIa�Wf�!� ( 14��cng�a��,u� l�yc!�� 8CK85��/ar�Z"�sq� FhlF&rAYn.� � %[ly1�^� -�2R xuc`>_[4�A�������an��9AM�� g-bj "2 �"} ��&pco-2�sw2ofB�GRy� FlhF?#&�IIx�jW�� �r�_$sis�!�eA/-Q!��m"c8� � ll&���-is�).�.2�� �`MA��`�w rima biE% %�8b:�y�e"u.��� M��9&8*qc�q situEB!�f0-U�)low,k�J: (a) �!��_�x%K�akaS :1 f�2� ( iiTt.�( 2:2%,$ �2ɻp6m|-�8z62O�&�a�inAb:RFP �gz� M"P�ZwoAv �( 1�� tV$Y��m -lap�]"hS.f'>06�d�+- �F57%����-�_S9A%�!nS1 2 Mov� !�3 on du��E divii!a�>�&�"�yc*�t[!!A�M�_ e [4_N&QY~M�9��ol~hI �Mengag� ��@recruiV �`op�e�L O(�i!�"� �TxF|� agwem�HlaZ2Z��}8�c�ENewly-%+,9� �C� u�P�' �DRE�R�A�es�is� a)@q�-HI��A�daugh�(!��5!LbDNes� teP��9!? ����-�>�hs�'“]4dspGa'.� �U�, midd�  R�of N� � �y(>ell9��|p54(iN�(heEk�Ef�=5 %5�# �x���set�1�up��/3O -�e-�%M��sAm] IO|-�.*%Jsep) ����)k�is6 E�` x ( 18�H0%4)% re4-“a�2!� AnA�!�A�2j afAuuN�� A`( 3oR-����a�6��q e�@Y *6�!��!Ir� R �-�my%m�"r�K6�evT%��:6%opermanea�Xite-; ��5^in�H!m_um�9&�& &�l a cl�basymmety9A��$ rib"��ZK�"�(�,]b'ol&Q�;Rh*�+.�b2 �F�mf ,�m�D &A7 e�)�!u�� -YFP��"�M�*��aneA�4�7�59� Bec�I�!�O "�alZ�({2=E��s� a�n�+&���3D6�"add��~"}o,�2���/|2| *�"� >� N����1�.Y"�.�a),K�I  mm�� 2�.0%i��ld&�J10)�10B+�<V/� m@ &��f+3e�8f6�A�A&  ����ase .4�'A15%6�vA�51~6E��Ye�3�R� � u�*9.�S�iI��u����a-C�|�q10C�'10"l*F.�� E��ra�ͭJ�A�� 6**�C� seem���đ�.-@����, ..�7B'H�)1�}"}Q�A��"D*5Cma9Ia22,: m!"/��6�nd&�� ��/ coup� . If s�N�LB��be Jptogrs�uA���kI���:��%1�&+-O�?�b:>. %�tt�"in�ED�e�b �(�7�e�`,�R AS ,\Z> *; *q�%w#( !&��e+-� �'"ga�M��nd &� �H4![2(o2*4�2.H�sl.�) es m��exo��sacRi��E, atta�\ (as�k*,I�s J�5-G�Rm" �wa�;hv�m�s 2 4–�[� )�woA,q�GI�a�"�v&( towa=X�`�9��h�B�9il~udv-s7}8e�8�B�qly@&L[�.�ne�4i ime�5!�derx�����ng6!K}=s.8Ba�$�/F�.�sb�F�$mor�/! )I���<�^.eg se�*�7m1.y�B tatu��: ��:� de.4���=R3$:"E�M mode6�BE:w�D~ote Fli�9σ2V �FS -��c�o�� ar� ��U^�'A[5 �}. P*�@e�/A �L07r�c&C"�Eh�C�j� !fG:g�v�X�T�=�i.>h2�)&�&*�Z�@pahwwi��J�!f�B�!�nto fulf�(�Uly�ioRX�#�>�!*/v�m��.�FsF�Ta4D�q!+jqaIv:z6Z60[p!ic�{,"�14KcyF�n�/e y�6�y�k��"s��,�5!@RDYw��H ;E���ga&�+l(f"o 2�� h�Y4i e c] 1ˀ� !ASY&z-nw�"� depi !�-�!�R�A0U��65 HtpB�)4-�lQ���Ked����, �V6� ,5�*�u�����aYQse�v��!P@ � �%�co"ZhV|i&�"�a*"��/%r��X!-!�� :�a�!w��*7#b� �̀s�X0B �aW��1Q�q<�K)r)~��,1 &KM�."Q s a�6a�#iG��M�:%?1�!=� =C&mO�9_ no e+6�\%��2:_byb,a"*"P�J�,�L�t� , un �well-C }��� WspR�PleD [5�>G�Fro,e!v�0c,� &�,%�a31#A��,T �;w�Xs l�i�2%c*rAs4Y]�isE" ����sw� A�� �@ll{*� �d�)U�B��%Aa�a2� *%$5|"#,g<ct�!AE��o� A}In ��1� ]�"O2,��x!GA�3 c ��,��m4% 12! "=X �Y�,5CE�� �z0�7� bAB�qOT&a ;U �*0%J0.��=$:��QF0qE{� B��k �: 1fB 1.���o5e�sh� be mi�_d��6#�*G%"a�s�4�v �e2�9)� !X�@�%1re ;�NiU�25�� ;%� =AY�8g2H 5��/�:��� "LtT%n!We�at�7�E�!�i qGA�-P $C�D!ha&!n prog�!m�v1aA,a(�/q�ng�$!oX@��!KT matuM��e �`�/� N� �QFl�cm�/ T.z5�', yK  �;��ld�ala�Ej�itF� �VV[&1�ns 43 A&�paiM"�e��� ak"y1�|aQ�>?��u W�� : 66r3slu�'&!�G&thAM�s [58J�(n Azospiril+6S rece1H�@(bc �Ghy 7�+&nb.V 5P �&�[5�OG!��n)�s !� �!a}XMY!b,�8pc��a-o:�"�6e�(&�b�ptBHO�?��"I'�!aS"� pool-\� QurbaG�m. �. �R� �%qŕl�"d��D� �$%ptB�ic� 5 L�8V�[*$9M�8Z�~ =,.�)��o�E^=�1*�1!�"r/ RoeA� ��Pn .r�e�X)ebt�)Z?) &�B"O�."rs s [6|Ano� �+Ō(�s] �Cau�e)- c~��Y�!%��Sa��3! }*���o3Ak���a�8)e�{c�`�a�*� [64l67a,2� � 6.�)�e � J��E}��&1h�� !*U�in��2f�[6dx&�[Y���K ���*:OR�'l$:9.�:7E t'?� *�"aVer,J�um�!@M !%�U,IV�teny&��ss� !��!-![6�x"e�i-�J% PdN��W>!���g�2;16�5��~J9"�2o ��][1�>��bimoda#& ZM�%�!_u��?�PDE Pcc PA50L}na�!�WDipAA�o 0&� E p�NL���&0Ci5�CheK[65+ �i6��j��7��=�"#!�abandxSR�}4&3 2�t)*em��m�>�!Z1��Ue��#E�Ype�Ug� A7%�� 3(%]���"��!�Ezo�%�0YV&<+Z)li� ^�"�$?�%x") 9m�^:ngA0�:� �(w<3�)9����0Ih�)1�U��4:9s�mZarf "[T",��3+�!�>p.�s�m.&y"T &W!�9���&H;��� �eB%f��n`th!S�f�E� E M"�,^-Mr�Z�/�)a good�>��ack�he� *ҍmLs,�(&$Q�!� d�}9major.Porn ; docuy ed"�"iAS�,stimun(le� &��"d[�ea��� 3Us "J!�u�1,8p/ �F9 �f�oryD8d"� "�sXultaneoڧ.Ć-�M�%�M�par��D in%�9t:{es5)|F�`�h�� a�R6� !�N�I�:�. Sh'\�A, � e��8X��.e Gir?eX��o �ar%�&K Pnd� ,Wr���a��V$i =��&("�i8$a hierarch�5�e(�e��-&��?9��xmM,ces"�c:<^2%� .&:,>B o �8"�&�� BD>  �-�NqIq�A�JB�!r*�6�<���M�U,�U�� u�A�G�  l��o*�4=����r'NFA�le*sL genQ�.� �l��%�Yo�&�uY%iȱ� a:�-�Mq��xg %~�nF2�(" 26��n#�$��*�~���e��va����) �)al!U-)X շM &�<b e&\a)_6�acE2���� 1 5hq��M�sB)e/5o}�� �YaI-[33�L�`�B��A�I�"�9no�CecQ "0�"l".�I[6_X65$I"�d�?Qjn&�a�`*�of � ��'M7*� �D�.X/�s%;�a^K��!�g�rF�! 0]�� 6�i(�1 g �m��(}�jeYm@!�.�e��$�S: �A�!���Gt iJMp~cn�� Rs&�j( *�j< 6�[�_us&D�,M"��of �� fA�9vKw ly%5r�L�"�� �R�x ����*�*%Y��y1 ap�S� �\ak�wY�'S%2� . B�!}i!� las du� ���E��l��\*@8*�� �*e@C0���Luria Br�(+? ) [6��68]o4100 ml Erlenmef�lasks '�U2$�P��%� shak $at 180 rpm�at 37°CuB�QA�N^was ��O\��X. C�@���{N_^0^A� rypt(�g/��a'_(��)�L �)l�E� 40 μg/mlv!�2o.�i��ill�hblu�+L"�"��tibiotic�re��:�se�a�ai:!6g Q��s:%� �ampicva�25tetra�inJ1�gGm��#"�A;�30(carben]5B! �� �2w,�5�lptomyci y���-��pR��B 48 24��a�T�!$� � P�ueED 'uc!��B"C�V�WBj��F!xgyr�2 gyrB�>S-�r�5{�8(NCBI RefSeq=? [6$[nd aligae MUSCLE [77[of XanthƢc�c s pv�|e���(t`p�Bl���/�Pthan 95%>��verag�%re elim�W!��,��e+'an 5% � gap�Sm���at�D�mbigu8m�-+6s�F"� k~ � &�481&s�z!^fi<lset <&o�shi�Oy%�inferP)�D�py&�t�S@X he N�bor-Jo�VOo�SMEGA6 [77� "��m @]�� �p`Po��rr���A^�d [73])B�'�%��&A�&�e5qio�n�R�.��z���;�pM�z�&�>��Yg �� � s [7�l��@^@des]� ri� �s�� ir e �*2T���l� "�e��W#��a a4����e���%�C!D�.ru>5X manuP ur�.  �; �la�"X�DH5α��a�oli TOP1�P(�lo%n)�:��́�tAm?����#-�![77e����.�G�!�.� �Z���o9�YQu"^�II%�V@k �cY!=.)'a�mUAz( Agil�*Technύ����!ڍ2Ve�+��2�F�h�F� �!��/(D jI� :s�nܫ��."X&*!n �%1I+ed=&�@a 504.���C+!��"�R��G�e�� st 2��!&6هV1nV( � @Ia��±�L�dev�c�/Q��"�*�/&�!��in 24-�1" ystyru-@ti�*p�A.�Y[�� *%/m�'1 10 ha��A�m�/P!E\1% crys[Uviolet��BId��b�Z�w-�o]<io� i�2��� solu�z�2EE96%�Q/v ) .I��absorpX)>hotиrVly!�su at ��n�C�����=�M�)�-=aAa iBn�2 J�[7�M7-S�^^Mon!� g/L "�, 5NaCx!�3�� ( Merck&��. B��>ard%s.n 0�%Yin��B�!{+A�bA@Vl&�"r�. T�r�%�\ Xcb5Q�o33A�� ic�"n+�a .wtip��Ib*�to�6� oQ�:;�� :daya�am�a�ope��ofu< WOKM*2g:`c>D��"�t."2< ����ofE5aMwt/vo_!Po- ���e�N8=�j '"urb9!�At #�to�^th MMPFn?M7MA�1�e��`�tm�L*�i9�o( sl0��5Ύ�I�Y�5�. PictD����nb7�1 t %e��^./.�3�$ageJ softwX ( NI��AD��xe(��A� c jq�:�s!��jsC.De�he�ETt�lIV&/6'-as"�H6��e��b�8 � ���� &�&�r�yt law�UE��s��5�a.20 V . Ev�Us������ an O5 < �bploay+i�UlbF SDS-rBac@m��g���ge_mi�<��d�?�H��o�ulL"�U� mA/cm2�� @)w�,(�0 bloc�]Y�~~ buR (a� milkS�,qcTw�v206Tris- 2�6�4��pH��0�) A 1:5000 ��M'�  ��l ��U��$(bV�!� ��3V orse'�sh��ox� �seT2{ ����n!��4\� S�-�� al WZO Pico�* miluaSm5t SubA�teShierce��|�A`7 LAS3! Fuji Ia�9�f���V�fb�"Ѫ}��(���=G/q�l suspen",� to�G!�!n+dP@:Um 2 (g"f9x�c-�!��O���)e(AEmin ) 7optimH . Di M�e�d��LB �tl���c���FU AL�Wa߅8%e�tr&:3"=U$�e�(Em�heAU^ cd>+��(o��b�X E>� �,aQ�!/���� � �s%\Dve & Lt( RFU�64�a�r!�F0P�e� �]�s�,f� Altp��[(R<q� � ��id-naJ� �"A�(&��h S'Mf��0xofA":!D�A r�)H&� .� 8�L&5���?YL*)4BIOLOG Life Scd�ea$p�9�`� , B~n ��Q[� �WEl �=��Z nCv�r���me� gH��6! pu.��B 21�5 nk�of96f�� E��� 6a�:e�7o�S�2 L�p IIBradfor��saa�F�&� !�q4b%d� >?5�20�rep3��du�C.&� � I*p:$�/mr������DR���d�]5s]t��@oelofs et al . [4�3��"Ƙ9U��KaE,[α-32P]-GTP� "��WspR [8Z�� "wwhole-e���1ng%3mix�4nM�2�#%�ix� :pipet!K( �=#A�ry unX�ed>�( GE Hev)c��,:$8 L��t_Q� . An FLA7��wK2��H�!�;Re� ��cDll2za 10-�� expo- �lo�:� �j6i���Mr%'�0���GauD�� v3 � BL21�E5 pACDuet-1a��!�� "g�E�`�(until"� �� 6 �C&��B��d*? � 1 mM IPTG�18P!. 4T!2zcol�i�� ifu��( n��� in"�40fv )H 7�'>!�mM�1(MgCl2�H!� .22PMSP�eg/mL D4�,�? 5 m lyso׹Y"&o lyf#�(freeze/thaw4�2Lyp�%~�l\�~�1qs�97&�#%hyhչ ��!�%g2u����[p�Z&�"O����F:�lw5� pKT2��PUT18cA�N�|�Nk'�;E^S&!�H�M��"�I�# m�Qs�� fw/BT rev�YTH43fw2436 )46m)7 7[?<��I�$+u��� XbaIP EcoR F( y��!�T25-43s� �%� �,n �)ZKpnF~-�,18-!7 ,  �a 3I@ 7�BR*�i9�p!�C6-(rm�s�3t"B3E-���w DHM1E�f0n���&up�I��% "}6{ 1mM I�yl�d-thiog"e (���E�<�2�>�@�$2,%&�$ kana�$�25-b��X-4-chloro-indolyl-β-d- �pyran��X P�#i�.Ac0 -Q�Gf@ as,&57n5{4�"g �&!R�Nby! � �gwm#v�#�+U'� <(e�-�`I&�hsy�!]le��e zip��GCN<� s�Fs�c<(.%Log�J��ODء�25�P NH�Y. a�a 4�(esh c0�r g���ŴParlod�r��S� ��!VB�I� fi A��.��Qםth�1%�tar"�E�pn#-�Xwa�3=s ���!~&�- twic k1% ur�� ace��*%/�%a FEI Mt.gni 268M1�2}��u �� 6\PN!WT!�a��.� � ( M2�Z���0�&R^*�L�!2֍��&�a]:pBf��PF� �6�!{%�))�Yz� :� "�F� - ?-�u r��3aJB� �ь5%��ABST/��KH2POai16 Na2H A�% (�@ Ό�aN05%�-2�!�1�B2% Z�4C�>�Ep5u= "� hemagg�ninQaG�Gs���+t�k)4>�da��B"m8][yv%!toRunjc. M٩-6!wde � �monocl��-H *"a�Invh�g�6�"��9�A��!it��V�"�,t �������^eBp�d��"G%Ac!�)a�� >��D)U2V��� �')مK�  �@.>"� e�* U�)�!�l+i�A�a HA-��6~� '(�rmo F��rt���! �!�zj% ab"by& PAGEmqer�:�(:b:,w�FLAG M�xS�0h(M��2��( 1_�+ls` ( V�p) �4�!$"�!!�2� - e^� p3.�! 2��!�-YF1�D>�rs��7. 3�! �!&� %�ak0 HME6032:: �� ��],hJF�0NU!…,>հo"0.))�L� �,>tK.N W %�!�&]%A��u"�[$B_�n^i5q3ml %}e �A100μ�±��2% I�nA�#tn:w �.<gZtub{sF�1a�Eq. Pha�q��a9Gce.wt&��&taV�DC�]( Appl� Prt�� , US� 0/Olympus IX71Ze R�?�- UPlanSAp� 0×/!A 40 Oil ob� � ( P, Japane8��,coolSNAP HQ-aVPh"%"�. �CCD�/e��*�9�P.;�e�p�1d!!�(m���#>.E���-JwlWUgaRqedA-�6 ,A. A/of$ �22�1!�& of�t .����#e%�^ J���3�4i� �d���!S Pr�^9�jC�:s�4( Broad*��%� usto_ pipe�2.��Hum�?B lear��14A�Bi�*�a�~n feed3:e p�$�V�1��g�.v e� �a}L-xC#�&)%EO ��b�d/s#�MA �0�-�.sj littGK>$�6ua��Wcu!xd "�4F�Wnd  D?�@ral��tiSvel�8�U�3i�To�v|��s��#-,mC icip.�Ja�I, target-poin+ taskw�e�.it!8�h ffse���L�al9��m�a�0 W�heB.A�� _%�horiz�]zkV&�?am��P2�Y� �s�~} Par��e$��o�U�>�1� V ax!r�5�moA�G*� �A7he=7zhIr�“hitKiz3 i,�yg%!�uoTVr� +,NXp��spiky�cir�%r,. "� B g'?ygp./M'|3�%it�pu��L=@6��=�*�>�*E�p&�'S *�wo�@o�\A.F�Eze~�a��=�/;(�lS�ly���E��a�� onship5).�%0F y�&�3ly� "�.�[5AE�T% A  E&B!��i�0(cit ) Bayes��0�_%Z>�s�I�]��o�uiW<i ,�t. �ur�na襫q A�!�r a�&I��&tags�a!�u ough�E���m4%k)� a�%nes%%0 cues���@:� appl�W��a�d!i�(C_#h�9st�=t�(c��w$A�>0L^�"��m!j� ^,5��5��Ls&��1)��Td �6) A3쉁��;�%ir0��L��ul�vInlr!��u��K9@es �<H^��� em�U `I0�4"p��KI�poPC*�mm"�f :�5#rP. <"���7� �a ��ReS�r����pr~E��l���� ~�.eRn=K�Req�I&$[z�����|"!�����un �cho� 92q�A�R�ev�( r go��c>�is�j.�h. R�{A�re�i�%�we %q�@p�%pt��j�� �i��.�(%¡�ewsI�Sk[4�i�� (8�M4 wear!mGk8F Y?!��� �A�Ba�/�;&_Oac���h�b�-�wbfLiga��E� � �Z\��" Recc*>��RA� �"� toBh�g��%VC ,9BlbÅB���)k�v2*  . Du>I7_h�P:�� �Di/=�iproble�0!�t����at��M%�j< ��G��as�k� ��Hut�^�15ld�rt� ewjL(6S8A8IST�w�� �I�!6�|��>�!m͗ �v$$� successfu�0aiz�fN* ��+�'w !��A�is qu9<g��=�dI]�5��t�A����:areB�d��� re,�B[��u�Pa��g��.� �� s i�X�+��weA�dU" "� . 2J��� a��o ;� er^-��I�v�A)bn.!� o9@.E&H them [e-I6N�:�eR� ~-B�ki% k5�"�e�wa�%� �1*Iŭ, ���,��g��Ia)�"R��sim�"�-'��ݺ� �3�� %C"� E}�(e�1�z e[23cU�d!�&� aW>> �W� NF1a��FM e� � ��m��[10��3];�)$�r�4��a�(n auditory �D-Xm�a��lA�!�s%�[%��ul� [15];� �shift��6a`�t%!�split-f�>s��62Y arm-loads�!�^� wri��WAt b�+et�"A��:M[9��1�VT�! �re"K""�e���; U��R�� ���� A&� 2ߛAG�� "�]4-A,ulus/YT-Q� M�at�c� mŘ�3��$��a�b�_)of�&���� =w_�crete�s:�Z�!��-O�, M�8conditions cann�ot go beyond the specifically trained pairings to see how-B �igeneralise to novel conditions ( a cue cannot be half present ) . Furthermore , using such discrete cues ,� effect on number of� �learning rate was never tested . Howe , many cuc likeZ loca�\,targets whenY!;distor(4s for a single�;glassZ(can vary in! ontinuous4ner . The quesO ari8howr bd1�B�a%&s�6 and=�%�B�-C same!��!� scale . I)�example�!magnify!w�onFuld�8instance simply �0 , from a fewU1�ls , a new linear rule betwee �visual1�a-���\behavioural shift neededA� deal with* �iM!�is2{w�tAalsaL appli M]�Tthat were not explicit}f. O5imaginA~at)!He a �mightA@princi!ybe fastA�ha:� mappCA7 each% ay 1[ sepaa"ly2!1structur%�)�rele ship �!DEEbe �edE�in6� quitAA.xa�orY , arou��edges!��)�2Qla� non-Iitiesp0�e@Q�is re��tlpplRaq J�!�always�$beneficial%Dit-� even t!�5toV��fq�]at allAbo)=�ful�B%*ity1 �we.�hav�zexperiea[��se�s alongYi��1ossibil)@, which Yslow dow ��Aprocess�!Se�eu�demonstAN�yature are �6r6)!�h ed associIi!�ndI�@$y has its �costs%�)�t � e piI�e�Es�hnexistaliteraI�n9��AX�]4omotor tasks i!Uso%� very!�Psistent . Bedford [7]�w��ofsfirst�inv��g��g�@ qafAJE-��� differentA�prism���ta, two , � hreeuرq�!She fmpHat participants did��m� adop%�-�st6)�interpo�Afo���dFye-5!2K.� �5}/��u��< ther stud�%� used only%!�.to Y��-ڹ,��at>�~m� or larestricNXhe \ed5m)�@a steady decreaseAUE�!3�?fu  away%H1���&,% .k0[19–21] . VA� limi�:`�ŵI�U_ stA ngak� M�movemeA"[22] ,5H eds [23!�eft!4rŽha�[13 , 'typ�cH, i . �� over2or und throw�[13�8 problem)r� �seU ,M ��a���iI!X�Qs�direct�askA�evant (�g .>���speedDE���r&requir-f)��in so� a eC" ~%$E�,5O%&` U� ��{ �� poUa5=i��sen� aE�>�.�uM!�}Q"o wil�bkd pre-�y befaME&!�E{���Varough.�in norma�ifA:Eto��actIobjec� A`ten� oua�f ]�$independen!�,�mois.�aB%eFb %�c alre� ���c:�of)f!a���G��k ��compet� Such9N<a.6 7,]course�Ŵ��� ���W � Ca��pproach��is��le ��on�AǑoex�of>��p6�Y™�) � mA", � o�� abov�uEy,$ i�"` �e!%Q,� � provid��fAPp bout�g6�r !6� "L 5|v�O"! p���y� circumven�th����s b�.� aa:�occur ��uEn sk-irrem�proper&S �!�(a rapid poi� �.. H� ,�ho�} t shape!�!e�ext�i"�8rangedi@�lara� spik�NH(y Fi�O1!�f 3ET��i�ed }"� )�iu be ia�if� bya���q A� mem ,� morph fac� ρ:�A�C"�ly)c� N�%(var{�_t-�Vyat �:1� on!roajc�-".>2� ha�%���s��in ord: o hi�!� c�U e���� 0�� oneX W& 2�on��a subset�`/9"-1" pair x> e ed�sg6� to o :�Y%E�I+���� o��� 'aj�1�s�<t�սU .���*Z �� succ i2�i2\ C'�,>�Ob} pe� �A���-�extra"� Zlyi�!��5}�)���& � .�:��� B(2�/.�i])!�. nces duU�amounE9i.�vaila���9�c�8� 쥺F2�%s�� well�vBb�^e���AXq�i5L ) sh�~#2�Ńz�.�A�thu� isLlei�a�^ d chaof� �X:�օ���mRlosLerm"� time�m|�i�~ edicA�%k �:nderivL ��re��*b��D conn� $�%Oed)�UL2�.*�e�p�P �s%�we1I�e oCw�ve ��!u �ra#t does ^y\�=* selfi���%�,%/"�,Jmak antitatX�s%��#ecP2lA��n� word�=it��be fula}W � "� �meAPt%�Ar�t56D @ endc n�A�hyp��si�)�J>paE!S� %qpur� �ZdevelopAB Bayesi.�model�e wmbPide ` opti@ �ro�Mix-of-EIts>�� �^|���5�A�&f��a��.K �;e��*A�B!Al"�c�$Kalman fil�( Equ)�1–4!�L�QMd)�WitPbOshS%�in J��huc)9�� mbl��b!� �n:�� A�� [24�6]_ T��,v� )�F*}� a�o} m1��er/6 . Du�t�:[B]e chie��E ver�Gs5m�"Gimgradi *�cur�lya���>iBurin� � weKa�e acr��A :�l is v simi� ,J�I%�bpre3� E�$to describ�e>(eia-��"] t�A�pobA,"��eJ� "� rIv)G[27 ��ur 0 ,I@6 �yQ�“� t”ewW�ed�u�� It follow���)��E��1*�d hT � %�wbe5UdEs.� �-Fe��re � �"� ��2� � isqpl);!a����i�^.(in MaterialIYMethodse�Not!r��i��i%U�nB ���2� , bu!ben,�� ��g6 >�%�F2c!���!� ��y�-�!�k7Gco�w��of �"a  u�d���m. WQ mult� +n- 66si$ aneoe�E��g� &�e$�{r.M :�ocV�Ɏ �V �5a* f�� C%)�.� &S %�:6�. S�%J"�is �VarI�!|empir� ��ulA� a�!�ve*�p6� :� .���/�7:��>5(-�F���:'obser�y2Ls B�-;bs�B7eZ� �ion . P.�per�M� -0A��in&R manipula�tpa��M ;(al feedback�:f rece upon%�le� Bir���avcor� � 1 ��"� viron�� O��:�&D�weaK�Na� EI(!�"�E�s �"a� phvm�(A��s2�to1 ely\ . Ea>. o�bљatjJ�y� a� )�e� MQ82� them&� ��0+ , zBe����� icMc)(��ɵ genc���Ŵ�u%#��/!]!W.k% Y�x,ρ = 0 . 125�$ �v![)o%� a.�$−75 mm ("�,%T.�qH"� 1'a��A�*� ac)ud�zE�M��fpy�� <6p�i<1c.�"��i!�a��u��#S , cfd�2C ) ;A �Rb�)X5�87%�lmost& z 2w+)D. Awa�iMcata{ � aρ�-"�A�>�e�ne�,X�&&�’)YAX�F!�)�[J& *�#F�.%isN<�2�'e�&=� �e���onZz�q �b eia� n-}�e�5� �q{e  O axi�'[J on )�E� hc�� � outse(�:. 2��1na�!m�!�Mҝl��:�:oEmea� /t2�2o�ivw!.axuse"iW&]( bothy!�2e)�y�� a sc�aA�� E�, af(he absoluteQ� erro!��& f�%zu�( 100I�s ik"X�.A� Z��be�#1 cm; 59��Q"1k2#252 3 cm 0� w�$!e�! .�w� brief:s i�a �(naire��hey ansAdE�m|ic� he} Q��ir:Z��2j*�&�����analy� wh68�� ��"� 6���}�#(! B To do so��c)�+�!' sign�+nt5: 5���&� �( includA+g6@ ")�&�en��>Tj individ��}_O �ٱZ!�� �-�"ANOVA)�n a�����. IE�~�� �md R��co�%�� .� must� leas� X�{��. �$e9y��5N-��!V n � �!�:cr�&�zit turns�a��7 ��12.�)w�]*�% %P) Z��te�$inglyn s�"=:��(%\~� � E�!��B9aHconscio�reQ.�:�J(OA&8!adw.al.d whE�)RSE!�:� �+� s faiHadjA0JfaccorA�lW+� �� tinu�o ?��w�ԩ�a"��� k!�amA/��m��>[ho%\Avno�3�J�y)�(3E)� xi���5�i&&� ��&�r� u�*� re��eema�En&� �2�5�,/'ren�'M�:1 {!Jl.� Ene�*�/Tn=� ��!�# JD� we" 2�if�8TatPne�$�01��#�^�snsfer�� :� -+ �*� eaj5� �6�e�ex� e�!���{i!i*��6&o���r ���:XB&g!�/�QQ .�� �� in E��1�,�inw"3/ �aUU employ� Q��is�l*��funM�%�AGi"V�2�*�*8-�Rc� (by grey bar�WA@i0e�$ntuT data�%8 es� orm�1��U#!dE|�5�Z�!��` �-k.Q���Ax- n�+nA�-f.�i Xn B� onk�Obe cl�$o�:V�( blueegr����o�!R�� e� �+a%tr .��*! N&�" bs"�(AHy �*an o% Bregress�resW �%l }���5� N�'��)�!�e1W�" be a��c-'$:�!<�1��͚*� . A�/*�(! $Bonferroni�DiE+`1��C�s)�� ( n = 6 )aBA�!��F��-R=�a��g��ei7N=6ly1D�5 Z fash!�&�6r1�2��es5*%%"^*��m'n 2 a�e�͇$e"mediat�:�2�F� Q� a6�B#"� !I�i� o cAi7i3"sm!�:�u�-, 2 )I�;!!�6s. A�*1�q�Iba� W"�"�Q::Nh�p�& (R�"+#%[%adjac�F26E_6� U�(l�o�,� �GYzer� "~A,5�6l�)z��" �. S�se��d�2a�%Pa�maclu�<.� is import*�1�E�� !f�|2��5�#>w�+})$� omeO$ s sl�aNve_ matE�t#WL,A(�%�%A]1pc} 3ye% !`�do���"?�:* EAj6p3` 76|�V�8 KfW:�Bs &��b�=! ��%)�influ;-�� +n) boa4!5E"5!�f�I � "J^�Z::� 11 linkh E��-im�i��reshold"b!�1��'ږ�SupA�!S2 Text�!�h ��a f:5pa&� �eBR2�A\ar>� Uj�)Dl�$yUi y!�# ps�-ofu�jA�ed-rankwE� p�03;�  R MKF 2 77Lin 60 )Zspitei� n�%e> �per!t+6 . G��at���De�<�g+���!�.�& prem�0�)��F  [&� pre7�=ToNr EOR�a focu 6�we�Gm�e": �%*~�)*� �to�m��u!Xm�{k � +"� F2� wu�)0a^h� � %���yQ�cN� 6��ona��Q�9" � � pT1dB�I�<e� c%�� �H"� &@�:�T:ite 2�,A� "�a��;�6�be�l�m�Ei�a)=f1� �a 8UF.�J < . A�J�]2�$�>groupa2� .�A>�Ձfu:l��6�J  agai85�How@7nBw� i.�E�pic��  eI��o�%n�6�)z%�^�� AGA�* s:&{25E 2f−50�A$"�75 DV8 24+ 25Tse!P!0p!�*\2a��C�IO'R� o five: (�25�B�?= �mm &37B'25F'502MJI6:p F!$o:n5 IL � �-�spa>sDB4#� |-!�=A�%�Ci��,2#2o�!%S�����,)��h�"1�� �5-Pair�3-�� �m�th�$%�2 /A'; �*t( � 6�2� �)O UKh!s,�ff> M�+e�8�@w@����):� �$!^U �s:�&A�41S)6G%ws�)ys)*=�j ���� �C� e��gE. F�}A1�k�e%Aw:�rol�� ���5�!�*!#�� s*�+%��K,D$g �!M�`�Ze�M.VRK#�7�:� ��$c�2n6�6��?2�.� �A�&�"/ Ij:(�v��"� GH��T2k� �} )k$64q�N%�2�"6 �A�+ dedumselv��� d.U$�Z�Nrv�%�� Iof.�2�:4AE1ۍC�H�"F4B)BX.(+abJa�may��4er-intuiC,f people)��4td�N�,Yb�%�"� 6�a i�be �3har8M�B�J9 . Ou�5w86�agBR�+f�-%ly%t�@�.Bsix6Y �B�.:4 }�h�D]c)8!B�� s|B�%J�If�I�i!]&��%� Eu��H�2Uő�A58M�%Q38%A�O5W&�Tb�.n64%)J���_&&�75�.�0 �j��� ( t-,*� )�@� A-�'w�F sizcF0  ,�,��a�/�"i ,�!�Ae.Z&��m{�?re�* �����CM�J&*�8��few6Zs |edTBp�h��F�u at/4c�@ ke�En6�E��$�A;�4.�� � E��_I��-B�r�+ ��"pA4an�iJnNyaI�� 4CvalsI�8U�J�EF:*&� �- �iAMR6o..��Z�B�&A�]block\L1�jUBF Uq �+ R��8+�% ensurX>�-� s P�%�equ�o7C ( caI+80 :5E�:�""�\6�]J�M9k5�5dGyi%�4�.A�* -xMiBxis.[jNW!�� BUN~�!V� e�� s"p"� �*D!��2as!z� o=�7�~��� easi�~��^e�>�*��"w*&~�$5 6u�6!!����V%eE(n c ��f� )�i�6�.N�)A� ���>d*s� �� n�7!one.�.�Bt+e�� �M!�MP]app��@<v.R7�R V�?2� � L �;A�/�Pu�H"5U6��9%6O"�.�m �C"� & � � ��!y* s�'UDi�"p2WF"� ��3j���)K.&�*��-�-�1� �=�6e�2V2�Ah I�� @"h 1 . <!&>&st�  or)m*���� �ed=��gl.b2D%�--9�6(YR: .�3�= �B.� =�&�9��!�%NYxMs� r-!~�2~exc��E4eF�_�c M/�!��] �B�P���BAr�&� " R�!��!;�P�#J +�%)�B/�7i� M��(.X�p �&E � �� �]!�N�p uȅ=R�"�'i�"�-�� �?�f -q�M��`TL)�A�lbHJ� ��  <.~ R�y#� !�36 sub�#U)-�Y!�A�!2�M�B�.| �;.!�A���*vouthej�dVsII+B�(F!.�zv85;E� R2v44E΁�uB�a�1M(��-|fU �2aS nfira�(FfN�1V>6V�27�.%?2$& ]Ttleyp!�aq<6�J,V�2"� � aIF*yth��,a�E�i�f<�-� �NR IE���N 0..K�4*�&re�.�!V��� d"a�,� -�'8le"g�"1 ���/��u�H9 � _�p:� n6F-� �����>M(]�{A�6�%>�reg'G�>�6a��I#<oom�6M�� �kQ 1� S�n� [G�F���B s9 �>�.��Z���*�� ed�!8486e�]inguishj�26�!�-1M6(��AQ��� 5�asZX' e!F�Ey Q*iV�%A�(aA���*�3'2�A)G^*�37 . J�>h(! E~�:79.U112SK)2�,24.+�J�&z5� &G���Ta% �-8 � to8'1th:0KSA܅ Y*2P.�F���J��/!I�Z�)�� �2���F&�C( FCIe~��s�o3Q� �\A��( 65%�:A2)]?�J,6�A�deɌ!L)y Ue�R6e�{ eف =apCu��)W��!F4!�.� q" -(R��T!�i�c���&�5MRQ �B )*^ ,1�!�N�+to!�r& ��s&q%�A6 ?��^%%��emM��[a&���3g!���]�Rn� �� ��A��#:�q(R� 002;� .&&Z� 5� ough5}�pb�_A�!!;� =�Av5��A�a��*rn Pd�0 �nf�FI%U�0!$ect.|nY�9{X�  h-�a m{ct�*A��_ �A��� A�trT �ce 9G6V9)�u`D3�W1��'&rR� 5!gM trea� tA�,tted/B�(� Q!B�nd 3 U�x2)�", ayY�}R�&A�Isi�QN a�Ex!AA�.�%Ue�_���"�*�.�!�*<&.a-�4 �!B RV2JWA�B� >p��)tR7>G �4�S�N� �/5 .&�My2�,DA��O�a,m%5a'�$%0�  Hsu*:of_ig",4.Ya�R�+��u M�3"���UK2� e�Y��� �y *.7nk{)�Dus�P lookA�!8J|H�SaB�5b�~myl�aD�=9Z�s�ĭ�!�]h� cal�ө#�-�\���C vers�S� �a �-)f�5i�%��-w/2ni�!�r~I�q4 �+�D�x"igN#� �"�N��}��\A��4�e�^Q B9 <u�N��"��n "�L��r%��a��/im23�it&� � nt� ^:a2.x$9���WN aD�&A?�Q05�n N�&demU�?a�%�2�� �[A�)lU:"�WO� (�d!bbyAIA��Ki� 4window ( width(%C�tsj_E�UtM�AR�xorm Z���A�I{d�c 7�l�=��}�}SCE: S�*Xly�6ve}3(ran α-l?T!�H000� �V�1)Xtaken�Q�� ��iH=�ch*c>.+E!%71�2�l ABN�6�cur%�B fQ/�*n�d onen�=��( 1A* e−λ1/λ>k��q_�N":B!�a4�*g� )���, b �R$f��Mk2AI**�q�s� deq;"� 5AU%!8�}i,2�—red;��—:�13 ( 3�)—8:)�ase��l)R%2ax%�"��+.�S"-E+; 46 Iad@,!���O)%u�%�,pawTgI!�N�asg*�B%>� �� = �E m�.� ^��%�J� � d bl0N�6lidL b �3� N;!sha!0a�b�V �tandard6Aei7aiaLpnM�2�2��k�ie���"1I��+inc�'K�U�. NA/the9 ��9VlyH) E��5 �!�%��e�Mhs systE3�N.�`m�of�a�L2��aIPult"_R!�=�!YteZ � .E�U�A�t%d�isugge�k�m�.SWe:}nal� ��"�$W)Do&_Y� i.%�*,9�~F� rei5%+� uS �Ror �=F�!\� -seq�7L5om:;�.BB. M}"� toajifyj \�m-�m.����.�,d]:��_n emerg�>*d)a0g'mR�! B�a�&�a�nW/�re ��!1��6l σy0Hσ&DWiM/ (�&�U:�Zinv�8j/]�Cixmԥ�:�B)�>�6t Z �*?Y�� valu7y&�Oincorpoi��mI�a &j!��}eV%{(e%I��?>�_raMUa�,~i�^&4E)J��ee�>�� �\� >��R^^b��k]�97�-�exF* �!?j� �Z�`)E2f�:d.2� 6E&%*Z |E�jFp:*�! beca�NS"�"]q^R`ly-Aw�N�e�)D+y�~UJ�5B _iX�cap�_��� V�&���:pst�lGa�II�Krg_!�2�8�:^!)� ����#ab� *mV".6V�=�&*�=p�\e����2��uo� %���l���. WV::g:U!E�5"�s���*~j2�cQn�=x<�w� l�n�S6�W� A��et"uuakW�!%$n�NNZ�i�":uuVma�I�:5�G f:<,o*�g&qa�Z1-w1�H �V$sp�#ng� —6aq�l��� %2NB� u&K(�C2F,�A�kg6�.I2Bve9yap6� 1��%�lɒU0�" a];CLS[9��|' Ue"�(5\�: J� d%�mZ �6--�(.� 1e�Hi/,� *.$&�r�#�'yf}9^��F :z`sd��� � �d-A>2FsK >2 1B�A�� . R� 1���?�2�vo !�~T ��is�u�9 f�!jEt ensorid�W*�w&Kp0�]e���^�pes;�d7�d:�!�VD a"�a�%��oU�;� �E%`O �?)�"U9N2. I�Eu%~��em�)vE* linkA�e�!cr�C �D :+�'a(���:1"HD�9:o � A{$f8–30)��6�|7&� �is�TNF��!�,�Os) q%$���>A � �h��os�-(͝2�e%J�"�_M�q\N�6f� �s, .MP� �a���.f < � a�"t * � *� a�+%3A%A�I��a�m!��G��,�2p� d ��my6&c (2C�4M*Ii5� ��ucx J� la�A:"` >� �69{C"� e\�"��* E��;�� �R9d"a"9Aw�:w%spa��!�k[%�ɭ�&E$5TB�� -2}i�}�5 �,�xCe[|�D��;*j �u�major@l�> �Wda�Dxg8��t**,�c�A=bif�H҃�2�a�ge )k�D�2�.a bit 'Q�3d�!S n�G�H�k vlengt�wCo"l~e)A*��� 1q$d familiar�j!�&�� �W Tw�Wut�2�wo �Z<-���$JG:1�G�%�a � � ��!"e��!��7i*"(�R���~>`��v(forWieldsaJ]�"^ro�Hs�M/qA _ .�li��,V�e�:�e[�K"�-C1mA�chR��=� 32� 9� ��*=+� (r amplitude� �J1��!��.�aBc*F��u ly highly�[X184r��M�3 >�2��7ype�12^�"e�e5��(�@ce-%����$9( �dynamic�'j"�Xi� x� 5��N/v"��,�\ha�w!U�onBd�lr��.J.�_E] t�.� 2Lwje��X�A��rUā� �_Aǥ�a��zA�n� —f�'i.TpoGP�Z�F�p���x4 iWH$gy [40]—%'|�u�`�psol� � sk�M��M�b�jr0 A�%b�C��%�}� �suf����m�<m<!Ylex e&�n����w!le��*�)\ef���!az*xMQa��<])�add noh� per�o)/-�Emq��urb��sIwy�Ryreq5emy:C s�^� 5���w�c!Z�im�pZ'��gT+-2�!c(Jյ�ui�ۆ%[�>`n�!J R3ALt u��ear|�)�h\@"d�c*}7*�ubehind�>�%�l�;u2.f�vx (xm"�{�/�_nlyg�!�v�Pl� 1ҩC�X5�E u'5}WJ�P*-��+sur�!���g6�H��\&1Sp.2�s �� e!�� faul�� a��<poz��6���� S��- 1ly�,"�G �� !�2� ula'$“choo!�x`�:�@T6 �.�hwEte#Q� F�y1SS�2�o�l"� �?+i�6;he.^2$�Mz@ ir:Gu�+A*�(�!0�����G8���{l)6gl&�q�#!�!�eme0F%�or �q�Z"kv� 2A .6 �J+o9Gpro�Ndwatego�-K`>�&�A�rFI�� �gk:�p�r�WAf g��byg y��.�zDo$2� � of cogn�N&Q*u�"� A�m!us-5�H�$W eOfa"&�"H,I_% -�6�2q$�:��� �,I�E n�G!!�&�2E>A)5�*� >�9 , 41� !�e*' �:�8 "f%�1\�� q^6�csx �EqhLa.��}. �p���a*�du��hM79�5uR���eM6�if� Y �!/K�.�J� -���8�d��5!U�B�,�� !�aO2,&W>��> aint�B�0t� ��p�� a�dQ !Jc>$e�-ҁ��Preg&J#��6�"��"Q/2Lg�e goo�X;y� .�f�>�6�o:4��*��� B�s"gDyA"�-u�i� � >G"N �\`);O_� :���K�I��e�-�5�����)��i&*��M��L�e�WA$��J�1*�b&�b1� d!��2!��b2[!�.}ay��`"�.� %UB upd<!Din)F) ��eh�.J %X�o@ s"�dn�sf2 soon :,!�m a^�2gcaǏAn�\�q�!�)(�\a/"� *� of!� ��~�o� K2�' a" R*�1�+9�E�Rf??^&!��p���#�� n6x starW�2�{A�,EJ y*_%�Fy%U�m d�WMa�3o{�A�  -� ���>be�n .�%o ?�% �2:I�-X�>t4844�tI.1{� F� �*e�/P1�f��!�)!� �@.�.�5�.*9$s}}n&�!�)i8�ne>!"�B�*!mg�ma\as ]��noinatora� E`summar"U�ro�Za�:wta �&� ��,�XCur"v{Y���6J2 " n 2{�1t�H*�X"���� �"�*e����R �,&nF�A�$M�"�5>{!2�K%tɣH ct "��F e�% *Q *N%\��|12m�Ms1��0&� &�.?9Q"��h %��9mixTP��T��t! �C9^E �"� �AX!�&��!��B*j �jo� @� \&b�Q�u@Hjoц�@�%7a"G . �� ���%2�:ethic mm�.T�d!vt�H3�j�=MTUni�4!#Dof Tübingen ( Gerd�Al2�vs gav1 @9e� nJ7�4B i �displauro.�� -pronL��sc�p( 220�176�{�g|���5dark gH>"v�(se�<S��stom-madZmck��F�A��`�)"\9!4r2a�%p%Ut�R��\WACOM Intuos 3 A3-wide; % v(�a 48 . 8�3�95ρSPip pen 7pla|.Jrevw�p�:A&T-�2f. A�cF�dram�i�6cl~�e�6�2Ne�se�iDA�arsj eBwhi+�ejh�S�� ede h�u}*.�%��`��euc� Newg�I�" of 5�t%g�XMVW e q �\.�K ea�C  0OpenGLA�%��.O���)e-to-� � 2/M/s�0�� � re 6A�-� ���(�i<�S�R��=� letk)� a���p.Z͒ ?��StV!HS1�A�i�J2݀ �h�&�j���5�A�86�ipi��WJ���a �horizont�)!��mi-�7?�# ( radiuE<2܄)�YPl%-!-S)� ’s2�(% ��F�#reJGE'so � �d hap�8E� phys�8 r!<attach��! tR�t!n$%L�:Pf�r�G %f��� V, po�hm$' !U!�r[l%�%���5�,�viA W2�aa�te=����YmYi�`!�veem.)i-�i !<za9'�M7M3aɉI�EQmx/Y8 �ldisLP��:i"1ou�QAFi��m#.2/e��5n}��surfac��m&nA� �DU� disk%erus R =e^3 deg�>M�i�d� ��D%�drawn{/domJu!�e<squ��OA=f 1�s7A� kqU1a�6�K�� =�.�S����A�r҂d tap�U?� "�1��gr6Bac�Late�nquicksA�@<�1��jvU8)�iD2Iq��"2&����yi� ��)��� I Gaus�� blob⭼�j �=dev��HT6<!O�ɺ��!�37%��� ]."p�nm|r= % reli�#�. By "�!���e�X]��&��*�'�h-Ӎ��&ak=mp t���,i1!�* 1��>aRo b��/��rx��%�!!y"ei�A�5%�9%!Yh(2��saR. A&���!�8x!E.c�L�ic�Xe*� @>%e"ㆭJ7"�>a/��.���d�O���\I� �a�+�z:l�!� �!b1�z�3y5IKI4�G�Acm <�"ć&� A4e�A����b} TAu3�m,'h\�$a bullseye"[?0-^� �o5`(:& 5>v �>�M� �a���� 9a�O�b & �q��!m��&��prh �{Y����%� ��L!���2&���t'}s��6��7 !��.="IfinD%<�3<�@imi� %|��"Gw�a messag too2�!5& �� subt!e�Wo�?��Ƭ����wS'&K.��?&t.�3��setupI� ��]�y�f9���i�GU^!� veriA���M�� #aGe~a�B-G�J *�Q& �\&!�"��w9!�%�D %"�XA�&�Us �:d.� ed 5=W�B fAN�A\�sA��eAi� E{[.S�" +� embr{ = ��wo��2��"�-6Ws9)-n;I)"Ws|�i~a�)�T*�}xG2ssJ���Q2"(�>�i �#�"E��#t �Eyp� Q� C}�:"�#2p- �wM�� ��Z���XX GY�f�5j���R&R )�Jjw�(����:A4�!baZb7 �Cg� "��2�wo}QrCr��=Ocr.�.)�!�r�+s�>i�ȅ�mi�(�5*f�BrJͭ2X* 2�e'9���b4� ra> `a�ac��q��ee9fth�*l�e�1�n��nB%�f; 22��)240 ����%u�� -���6B5c� 2"�!w"m��"�0A��to �M�-���6U2�Ef �T>�C��~�end�'���58ɷa"�# m�:�I"� x�d2,&�<"�� �> �bz�� ,)T� �ebonus��en9�he-�&�$�"�UE�I� VY�(�G*� 1V� �(%S.�,����,�aet =� weep �� B3 �=;*penalt�A.w��@d&�QR:e2D�> s:�Eeє:� 0N5� �x �] �O, 75�%� E9�e�A�%��G..ore��mb!n-��.��k�2iz�V�f�Ucn%taK2 J����g:�3u���;*R5. �8J[���3�E@*� � 5���u�*Rc�&� S?!�"� :�~�: �J|l,�s6� s�>n!)�z)�F��heB�2]dN�F���2�2Jd� �~ �I2�d�B�y%�%Z{c2J�*;e,.���9 (!�]vce6�y2��J�&�8B��_>F�sH"vHFuZs )�6�6�$m�_5J�}W*�� 3!acha�+�-�m.8�"? u"�G��.�G߹&"�)�!D�Z�>�e�7H�"3� /��s9s��o�.�obt�a�1 prec�4m_��s�c%poo�z?es$bC���%�� framework~.7� "��1 IO)0A�tp? � ��k!�ɕ�h ��*��F�7B2�f�put� �8$�=r� ���:u#A�9(cWeC � ���# �8�m��{�j| 9 , et9e:�* [45]A;s8 �L?) oced��p  )L �5i5-A�� na ter")5��v��j+>~%,{_8�%,!��*ei�A���� ���B�(Tm!6."�Uac�QEuOq�b��to�+��&w%*7 �". �nU%�fV)�E�I��%to"�%Kϰ"o, Assu���_8 ��1;"+Dm^�!Qa l�- �� ��6�$� A��s:@�B: KAH ) = σ p r i o r 2 R+Y$:PB^$: X p o s D% _^(+}Y -J&(�!duncer��ty:�h�=Vσ �3 ) Prog*b�$to T = t+1 B� D+�- � ) �!& o c e s s!r��XeH Ρ X�S "ƯE *$#e�.YM�B�,�.�%.k�=eP�1t�8a�A�.�ř՝�M� �2�u�5u�a"� "�+�C� x1�,��v�a*�C.�� w�k���C�(_�!�F�'e.A !�6�,A�!�E�6�6�ݦY�9�-�)i�5 99!vN�.U�de��.e.�Y*71�D1d % �A�!,�5.�M)����F2�opaga�O�d�A�h�&b�)�� f+<>)E遵7�,�����Yu�@*lQ�$�Yp���M^Q s��Iɧ'�3�<w.! Nofc��g��^!t-�O�iB�ep�}��!��itj%�x5�Ig5>�U�1b:�ba�o= grow/nd U�2�.�J&�Md.X;&�W��u ��W �:C �Q: o�?4HeaeA�!���$&�H����!5rF"Q2q�0"e2Q&Pmvf�M66�H�@�+VH1�?Ie h�VEis%�:�3�|u�<d ���u"A;��5a � a%���P� D>N^S8 �R�asԛ. * aE� lC1�U5��U���*� w�: fu6=�:\��-3Oe)"�i6B&&p+ ��A��q )a[�m���,&ρ�!HEku"Ya�F� �.:=U�x y 0 2 1 + -��2 2�=ρ uQ `a*�'&t&���qY"�BMk5�16%@ σρ ՝i> 1��.�.*#H"#%&0A�$!�on)d-=�A�g6�?5�*� �l&#@"� �- ribu��Ι!W−!4>Bt$.��%ly�)�>�m��� wV!V%A+S*-2-84 quad%cN$.� �Aq)��m�#2�D*�.�PD��F6r� :q�<�#�wJ>�ea  2�!�a��y9xA ��5?v�n��o������YV�b�%t %�E�Ѽ���on� yZ�is}�A��! �E %(�' !8�Rc��x.�J� i-L! ��2 e4 �2��i�]st�(m�6x� ;0 a) ��3DlyB�.q7:6�^��&N�t�.�j��&s�.J� � �(i)�eH!g�Dde� .�dh*�g�aC_�k��SMk� eigh�y� %nofI]�6aKF��jc)3B �nAlih$>)esVM��.�� �h �F�: S�;X: P ~|��= N2B �(ȣ�9� : MR /�����E ()Bl( 7 )���7�y:6:qe~��  6Z�rmiD� �$!H� "� .CA�]sel��5nr� !�3 V8I6]` w�1�{� step�s���&L@��.�>Z��_6�. Z� � d\ �aϑ &�C����,M:�ta1M1�7�>eb�by2*;�S"�i!M�9'#"�'t�o��^M)5:�"��I#e�[$5N�a'�Qp"W����1)G]/;�&�Y� �ASr2o�"?r���[!K!�ρ"+#| �� �ja&jAA�$9A� ]wG � ��DVC�ͭ�se6�T*P=�Qj*� Q'b*-�" �F�Cd�! y�i�[�I:.FhY�13F�gy:�FrF*�|!���*�;�� !l*A&! I����N IC��AeaѮR'7 e+�!6�9�V�*Xh( off-A�s��� ���.�VS"� ,~ �B$&Cv%ll���%+%"-4!&�c&״:�#�4� �)R� F *� ��"� eO��;u, 3}�!�JiG�`� g"Z}IG����Br��Y�f��&q�!.`���a��%�&��-\%E�� � �exa����!���AeA*�}!U(=S�C�2E�� gS.�E�=oB�|N�\i rB1���:�b� � r�(�~ ��*W_/��oExinimi5�sun�p F7d)!�Q�h2ʁ#�GY)jE Q�=�: Q�n global �u���.�9!�!��%!g�Y=��,mH��%�E1to kee��N�as!�i?;*Y7/ 9$KA ��:*� :� >,io�ZQ8,-).s( ���t=x�uS1\�%���E}Y�.}�.{U�2� �Z�Q�)�e*� ��}�&@�e��i0s e ^ty ]�"#�)�\."0,!|&�)!t"-:a�$. R=�m� ompu��)-VE�= �=J9�HD�O2Y��I�@  .Ǝ�iհ( olivZ�nucleu���(n"iB�m� is��!E$cerebellumUso-�D7Bli$!g fib(. A�`8 �: isQ�� l��r^E��o�aU�B��commak� and/���"q . C2h%��J]�Bal6+-n��5fHopHa���$ar Purkinj/�l� M)�3n��yQ ongo��C!�sil& �<,BAa�eQ�rio�-im�oteh�. E"<�e�=� 7W �-6S�7/�5O4orl_�+C!pi! ���nU��I�@)7 ,&�J_G6b.��}ferT!��U0�*>�%.I".z h+voTAed �s�in vitro"�P�MA)1.� enco�:.b%��:E�#r%o��f2!:I��! �1� sub-#�7�m�4n4MP oscil�G Rq�%s& �[u�.@�f���.�XR�0�>V�a�hree-��aPF��tIB-��ure �D3�!&"�$l&onM� a!��Our�GDJ�W:-Dc,Y)�_i����|I�8��atrge fp� somae�dendr%A�6X�!�-�Zd3�>Sf��'=f �! � phenomena"%Tens�� synchromZ1h�gg �Z]R��0��oi�dgap-j��xup�V1.�s �H}��smoqF!M/-�� d exU.�@q��4��,v��ai �%�nel`)�!� moss5�K( MF )�0r*V.���Hb� ���tRtA�p��'�T.F�`�RA��$�� fD ��d�u�*%%6���� prow7��C.{F  #�6�� Cb�:!��X^]�a touch!�f�*�%�OM��. [vbMFE� �'“re�JC&F�kerqQ(zran2�A���� urn�4 D�!�C&;� llel;( P��*dcortex~ he PF�CF*Knv,|�:�( P A �5�Ql�ra!PF)��modW|�8e PC'� tr hc���A,�r-�[C T2h w�aA".z ( AP p*fi�DVQWPC^w�nterrup���'� öa=kc$>x��!CS� w-�%X C fa��,n+x���$ 15 mY�6^r[ ( IO��:ٵ�JLa�/� ,E"s2#!�i�� l˜5J���UA\/ ��!�j &t,a���Hx T@MZH 1�;,VvNDIOO��Nor� w�dis-j��k�#�� �e Ne��"f�sa�ystagmWataxi͗�A!" j��on-��I�=G  inspea*�m�@*iE��I\ )mX;�� cquiwI� ware��rs� [9�1E���aHu�-on9 '���'"� 9�Vdz&D�e�-���9+a� out�!����d�_� Ũ!QIO�16�^IO%��ghi�oa^K�_a,�z�1 Hz Ig?�+"�Q��A1E�I�p�yL _-w��o�3 &W�ͨBl�!_��!�u��2�"rEnGPNV� UT&�H&N� �Qcaro"�$ܒ%�!2X�*<0-u�a�-$ �"`u��!�r�� thEfstD � m;R�A�KU,Mcd��[O- niqu]n IO neur�Y��*/n�eU �~s2� .l ( ST��-)J� E|��[�<�Ryp�cAu�� 2|10Ac[16�� [17]%:�0�d ��u �bya�nexin36� � s [18 J9щt̻g�A�A����&��tL�� STO��� 4���ct!� �M�, �. OPs���*a� �Dr�1�!�K`!>�?sodium A�d�+A��A1olarizI� ( AD,7s&� P/Q calcOY [20)kair Shyp+�.VHVa��4!XIV��66 ,$l�%B�  v�Jk fA�e�  ue%�� *��oIxo�j*� � !�25 [21��2��9-�of��1)t���lF��ow>!XM�t+ [�.J��% ilic�X�� WY1;aAP^nv�d�I�Q� 1 "w[ |�e��&��svCF-g��eA|in�6�G�I�of �>��H"1�� mP��via�� g"y -��e(rOil,��<"��5^��2�i�-���'sa�A�!vŖ �`��ed1�>L��+1kpri�Zl# t�* 6���].5L���arr��b:'!V3( e�;Xa�� ��(a'3�lyA� earl8��5��,I� Wej/���!� U�e]hil�?-B%$�en~N( 2�V�]Jx�e��2�} Fu!m����eU�5 �'s8qpotass��K%s]re�P0f orig�J �by Sch�$o)lQ[u!4�<rz�u�o a! 1�"g ہW��.� ��� � [)e A sc3%a�m�ng%3%G%8'�� ^� �4� �-�*19���= n��s:�_���^ �P*zc��)BJCm y �I� n�N:v;f���,wraAy:Ck-C �VA:Ut(, a sodium \current and a potassium l. All compartments also have1/ve leak4L0the dendritic.@H is connected to upeight n�boring cells by means of gap junctions . A �letkscrip*~modeln(provided insupple�@ary Text S1 . Our 5@shows spontaneous�4sustained STOsNa ranger�6–8 Hz with an average ( default ) amplitud 2�I . 4 mV ( i . e . approximately 13 mV difference measured from trough to p!}4) , but capablbreach!K STO |s-r10}, depend'o) (T-type calcE onducta� valu�PIn literature , repor!�Lfrequencies for oliv!f%2)-f�2!�10!1D[14]–[17] , [29])Dj�ocA��=�ly .D, [30] .�T%1 , weI�xsummarized electrophysiologicalA4 pert�Ay0uinea pig [13�14�as well4murine IO neurA�t( n = 6 ) that were observI�vitro!M� a clearm7 ison)ou utaA�alI�'s:�<. As can be seenA�9ycorre!@d �wA�its b9countera�4s , either matIY them closA�or fall!�mj)� betw�=F�"@mouse data . Thisa�to�exp�asc �basedA�$ion channe2�E\Xmultiple animals [28] (! ��:Z)A-��readilya�a�%�!~�U�=5in 6>bou!Vi�,is a generalEqIO�� Lra%Sth�4 a: &��$a specific �!2o�knowledga�previ��qv�C S,s did not ac%�dburstb8spikes transmita�by%|axon . WAA= addiA}a (hillock , a U Tis �Uat5whe�q� fire�h a����(ential upon�Lstimule!he soma>fstill��only on)d��� <first s..��preced!"p26,A�has bA�(earlier [26���!l shapeq)s � trac�$mall high-�Vy��ol��%sa top!n�4ADP ( Fig . 1CE�These AP �le��re.res��of .�.�1e<propag%� backa�}�-U.�'s��ii�ti�Xlay� }��^U�. PA�wh�Ed� 1ime\sta��x�,�learoscilIBs:�st�+ rest��membrane]���e>�vol��cl�� �ic)�Gsp��6� 080 degrees ceaed sl lafori�p� of%,.U,�XllyE�A�to'assum %�!gG�� .H!���r?-Y�0. However , t�explanEC fails;.[ ofte��� b�4kewed distribu�Bs�2it ���u�F�,-~is��&� ly plausi� [33A�>� aP)� similar�} size�%&ofj���$lbeit shif!�toward��up  slopE,>dbM*� 455�E3RB 2?mosEy&� i�� facili ng:)����by exc- ory input9 �A*2.),v{ �v��!�l�)B$A`&de��e�f�increase�ba��8�po!ņ downr �mak3` much hardI��BA� ͤ,` � 's:B� so :� . 6πATa$ t� a90 . 5π%� �.J7 erme�ion flux� �m�M�"a} � work��oaYess�,c e�2a~1�climb!*fiber  Au�Yo� phasU�A�,N ranaP� s mimic5zexperik d� 0by Mathy et a� inA8ch a 5 4sinusoidal sub�.�� J was impo& !7%�bA�jec�Ձh� �tmN� In&� �s{ E�$ equal num!8of�� trol�%|���recei* no sA�qi �onE would thuE llow�� intrinsic%~ . Si�6P %)�eam��Mtm��(� they�or%C ,��ise0,�whIHclusterE��edPs single ����r��%WAE!�-_i9une�wo!Xs s:� U43$ re netE�Aj at o!%@oe A Fre �%5��%a6#B\Y2�!��:� m�behavior"�n�@at6f%�A�a�1�orM�iz��e�ear%�b:i�q�cy�@i��� in both c�a%��t�� �!!vtyp��re du�5 e dynamicE)Aõ�i �=� B }J�m�.�Xges m slowl�!,tm3aH E�!�7 !i'��1T�,.�lower"�yN��a�a�Aɥd��� sBKsA�!#�_50.�A�����5U�trough�1� %�a9 -���M}�8*�state�.in:z � �h�Mĉ� �m�%�n*- ircum� ce�Despit� art��/�m.�Rj" 9͹�6s�7d"� �!�e com�.}u��>�wlikb�ideA�(valid , jud�a� ou dpredi !e�.6��]Ms)�|!�those��I2-'te�ly��IN.IisH %�pronouncE�!�2��A�9-a�^�.jus�  e��M 3×3 grid%�5i�n �%� s>h�I�ir:srAz����direct�La�).�at�59��[��s yieldS } l� =5%.�,� E�2E1��[ 3�*P��.G ?� ه!$p.�m��al: �2sm�!_� � gap-�a�:�:����nexin364*�� p a l�de in�vfi].=sJ�.$full-&a)�I�2%�\s eve� �9�3��pA*���i�G. Axo��}@��Nc }�E�& A�urna�1ed�,��availab��a}�&9��W1aly !ere58%P's_dur? !D�U'b��iWIndee��ba longerOB�E�of/er TśU%Z�q\a)N*�� 3A (-�� ably��ni*� ! ��n��e��l* doesEa�Fe�d� teBu vari1win� ��e�"� s� ���UQ ng aM� �Ah&� �ae�"2r5�of�1A�%����F2� attempA to eis� ���lin"�coV �t� n "�um:�� eV�� � >�huAa driv!) fact� "�'ss [34]Q��.�!PaQKint{ti!�L@ pr"b�8EEby setX +k a'pos�������"xt�-!衛��( inv�:  R�eff��ofM�le>BexpressAz leve� At F�e!L am�is de"� n�e*? is� ly W4 � k *t ofNS in�� pons"m s;C�Me��c�de.� . No� ly�!,�q^r ( A���nd��in�!kes �� � u��A��ar��or�bŗ�6=- ver%>6{��GV��mO�I��o!o*Y�of!�h�hd%ZY:�Q * �)�*Q �iaS%&�� l�v At a>�Z)>�85 mS/cme� � �� X��Fx: IAP�d 1�regardAJi��)�����m�. OAN� f�7�A5up[ � �H_6">�4�1v�E�*� : �0�@ �u�ˡO�!8�a�ough 4Az,, exce"� ,I��#6��c !�er>�AY��JA. EO t �mQ�>��c"��I�bigaDADP $�alE�v�ofy� P/Qu0 �?�.nP5y�5e�i)�Ix�F� ~ !y>�on67#a�We&�!a!ewa�&�!�atZeJS M]y�PUj-W fN !�Et� eQ �"*�$(��$widths ext6$toa� rter5>s�Eej10 ms�. inditng� x���"� t!�J��-�. U in!� A� e ch�X�be��� e��ed !��ql tak� og� form; airl lie� ��"�'-&�e��� q��& j a����p gA&�:3unfI�3��"5$B � mp2��b%&{9; doAG�� Ša�&�or%:>�%�mm mai��a� :.:, 1�Kqalc� � =فe�e �:�:��`. C:@&Ea5Q���"� an�CF *� . G2�(3 infl6' seq��2C�E�" 6 )��s��!/��JW��%"�% �%*T!�manifesL ja6 �!GI;Eɯta<) ly (�X#!#���> �2�1b inuouL6Hl6���Qt*=.� r?�ir.u u%� +� !�o�%���&applic�2 ���l:�rai�!�qu� �6@2�  vivoE�2 it mD  encodk W` � ascer�*Z.L) :�in �&re*p"� �+&c�� �m ve h�o�&�&:#Fj . S6it� �1�-in� &%a�&� ��� s [35 We u6� �#��6�#͖q�A*sl�divid dA�CYf�� 55A 9 k(>]�sf!W)G e�3 , 9� 25 ras!�aW}R��A6&�qI�"%�den�)"�e��[3�&�:�:� erio� 9�EM�%(��*CA|�2Por� alwaysEwl! n���x cros�.l-�6q#!�see�U) S1 AE;B%�:"�+E �!� !*mb�synchron:"d�6 2'e�l.�oreG�of�U�B!�6-�Tma. ~R &=r >/is���*�%u3 ! @�[6iuS1A%.I�F&�# system , WedYt�to!�A t�-ly6A�)Q��a 0�bot�� h� .th��%1[37��-!AME�hyp%�� �5��2#prn. �&!* vd%�!)=-b!z-Yre �u.��F�"�F� ]2[n s2$!( �26�� P�� .� b��y�a�e�'A��Q��&�5���O�#7�&�.in�.�� voi 5 P��`m�m��� �a�]!� IyE~%T�Y�E�F� )�asi�- ��4��.inwo���� �at3�"�.!.9LL.10��s�+ha�=V" amou> wpoiC 2F&$!�t 5\$�1&�/A�%a)n5�13y �o!�6(��85=%d C�R���3�s great��pr� %*&�� >��Nan-��I2q z"con�� � ��)$9#.��6�~z non-g0q:. N��A�� per�+n23y%Ca: fe��|a[-�s�I�qe>� q4A# op rowe S=�Arbv�strong��a few [s�!za�� �16� �� aroun�. 2+' radi�5. Dis�A�a� 2$ bins�%!lim�+& .I( 7� \ N 21002���p6c# coarse 3-5 �ey=VL �!� 5×51�s:�&��/he ri�o2T*E�nd2�E1w�i1'MSsE N �.��+ �[.,c��S6�.~,� �M ng 2.@V��Bhe �L �e`40� 9 wis� �� ed �]�A�I�� ���toV o"�I}��� 55�\Q%as� y .�1ŧ%.�u, !V�'�yB�M��ln�&&����feApAD66�%�10"%&�&�#L 2bottom�V�3��s�t�6���2���(� )(��ys 1 i�%APq�d�Rnorma�Au��.�"rt~t����JurM1���8i$#��a?�7t Z7��A�APi`�(�U1���got�.�E��M?��i,2� �<�/ 1,re-�)�"-Y�E���6��#' E&/� n�A�Zmtu3A}M6& VK�g1ɹs�K&/� �2lY\� �.dst�.Y of 7�A�up����x$ i���!C;�o�02�%�:uA%A`�|)-�� !�*s $(y broad por� ��6�>��;e��i95�%.iY�f� Ae!$5s�Y!/2�2:�B X -$!d ermi�1ng!�M}quickl�In6>& ��CAN�st���exhibi"]F!nt��3 )���er>7�Gyiw* � 9:GA�a:F�&&�+o��Le& $ o! %a!>x>p�9E�"_ �@��uA�6�7a1!"cAo*&�o:"5q�pr� >!��2%\t ��4� `�are�n��ams�%l� empi�� ,0as23� aq2��u� ree-��A>�5th] �produ� �*f�ng� 1� �s��6^s�:��ir�Ayv%(ns�;to} �prV� �� A�� cas�/�0�kb whole�'p�>0-clamp techni>A4�>� Qac%���  �1�S.g31>E�bRlab�#m �6�is i-4e�*H"O7s�1�actO.g.���&1B7trulyJ<3n %"�(> i�� � offse��b��sinew�fiOBn uA�V� A9Us��itracevsuaiwIn �*�% �4!K� �� �teepep/lň 2y7�?�1B� ��a�M2�1��  am��  2d3Fd . Be� !Z�*, E�sM�Ofi %)e��=J��B'-���#t!� f�?5�. D*�1ifficult$5+ing,f"qEtoia� �maa 4ha97@eby%� auto^-�alYsoftw��b�>��u0�+�Bect�om.E4�[/� a huma] �%salE�ex���*Zl>6l!start af�[ough �,mumEd�d beyo B�:.�.a!�"t ��?h8a"�m� !�#&� !�a �UW!-A%O g�Bly ob )3�Sn*i�M�%a � rely%on�a�"9 ssig"�-�'%�A+of�G45-�<��us|  0� 5��d((Q bi� nd la&.discrepa���H��a�d6��q!R3,�h leas�᲍�a&� e�)� 6�#c )d"�"cy-.���i.�0��B9�/E�"7ng%�!.*�6x8up���. W�..78 !�"�A9� @/E .�is�%l�(s ag�!2�GQ�! nZ�"� 9q��reaffirmi�D5Ivp "l anI � ";or�mx  aB3!.�6�>��so2�.:/2��aumJ�at ∼π"�& ch&8.m�%+�um� ��Q:�>iyir�>;(g�>We� x;�%��+��a�j!���!of�. Fur�v/a�|1=�@<M &* E1�cU("�%eb��2�s�� %�:.>A��dRd�&&� !�w�htIA�s'�8P k���6��8;��JAV� � .^�H&` �T!�![�l��H0@C4� 61�!l�F�+6�cF�A:�-yZa�� be7@G�79 �!["� %zerN)A�� ?N&�a�e < :#j! II!cL-&�&��A���%"�N�*��.�MC7� � "�' ��Q�&h }i%�Q#{ 0�i))rawe m��3�& f7�(F�0F�w<s2o��jorJR��Z�5`5��ro�E!ish!|�6i$J�St:,)�&'�-�n5Y+.���� ��"�6�:��`I�;B�����!� izT@y!� >0. U6B}&F.� �!(Fc6�B��2�%&� V� �TquantmG&"err�3a��i�q� (�&�Qcerebel�H�l@�u IFso fa�*�*��F�J"<i� ing�� �7a>�/�M%]of&i�["k(�o!��U�/6~3�C` HAZAA7toP�6of�#inz/N �N�a@�%bpH\7e [27\ P9.�:nd�e�aF� g�A)�,!$-resol�Jd+!Of empo�).�r�r?I%�!���)�A G� ^��in��"*uv� suffici!�,�&u ��>�Qal<'%%EION}�,%��$aV���l �:� �r�q&,A�� � e9� ��9&�Cone� adap&4u#speed��8eD� �,��f� ��6�g<up�a7ѯZ�/�J�JPF/PCiaps�mo �CCF � I�a%�Aa)�c b�SeO� � plast�Ny 8 K�O8a Kee n min�6�V��)�c G�l>9` proc�@�*,i>a$���5���ensZ+6g�iY��9�)Mt��ref�Y.XJ&�5 \S*EM%HR� XLTPa4PC6$RLTD2S1 qF����fZ�conx*�> a wa6un�(A�ven�A*m+�6vala�jver���)E# conv�X=�=�of91���+e ����>Z6a[K)�n!�5 i�it W[e�C2e|e3 CQ0<d1 sacr� ecih2�wAS�[tB�!&7 "� n�@�Yl�_ �)Ho:r:*5uti�Ws.��-T\s�en�V4 �zX� [�demonst�[�i?SP.�Y!��1��>�!�M��suc[�+YSZ��*a#"� �"I[V�� �EPac�����١����� D=  R[:so:� u6s�;93�L^f�U.U!IaVUmeaA�ful%�� !b�a3. A*� 0by Dutch legiAjaT� e"�NC,C ro�!b�JR stitA�:�Z�mfT commI�P8DEC , Erasmus M R[$rdad/ 'N�8laoZCorpDsli��6brain�/of 3- 6-week-L8micnadX)&kep� ACSF�E*a�(A�4mM ) : 124 NaC!�5 K�)< Na2HPO4 , 2 MgS CaCl�= 26 NaHCO3%� 20 D-gluc# A�bb�� 95% O2'5% CO2J6loem�s � purc? dI�$Sigma-Aldr�!WV3r�Me>�%per{ �JKys&]� e�^�� 34–35°-J an EPC-10�f�Y( HEKA Eb^n'M , Germany�!�� pipet�K�fil5aaeu� "{ �6�0 K)Pn�54-� 0 KOH , 3y` 8 Mg)�5�$10 HEPES ,2ATP ,.#3Ga;1�%sus3e; pH�ad�I"2)In$r, C` ( RiAfasazXb{;aF�&*�XAvt�[x!200 pA; �+_<�R/3 M �Q��� �Uendq \*�. R:6 0P$IQ� � >15%e20�p(cG in C� Z9�, ( "H I�u)Sq FoZQ C , Cn3�in�( h� +9.�*�!se`diJDa custom-made rout�4bO_(a fast-FourA�� a "� ,daQ d� d'!l��2` "�_*�� a�)n� �(n2d�JCcI �*�SLj 3se� der5>v�܅N.AW)!�2]""s�a�TF�b 3 �Ah�dt%]u�  "uO�� r�M���z*T prim&22a^ untiɣJ��DN�.at�!JLM!��� ,. AHP length>���Km ��="�2b�ik�� ce�t UP+We T&� s �S �ZV�$U�exi�]twoN %s [Yd  �6q�&�]-yau&) -�;�# " g8k+��he�GF_\ �ad�LI1�G"cL.M�""�`{� hannFMs� q &�g�x� "VstrI� r �rsEuni� l�H!��04�:��.�of"� e� M� �� =-!4$��spa�� r�daP� 0�*7}��u!���"� d8(d�Qp.�I�%� SW^>h��&v e�L "�d!?��f�*�bA&zT ed uBmak9� M6i�>���k%*�g!?� e�Eownf"��l��lk)>�$T#*L � &K �e9it~**a�j��i�fS�����%��p)g �lo�gt�eN����1 ���\:UJ&�W!�iniA��5�%��Ua  �P-e��a!N&z#w�iQ=e@o.�):�r.O {!%Qr��_�J�� .1"�v3$���66�5�E���$� �!symmet�*,� esa�-�) r polynomhS^��b!�!��n� m ��Em"H9;f�h�R alig!c. A�%>m%`Zj� )�S��4!�Da[wo�!�s�M�)�!@&@ �*��!hPJ&1�M�C�r�0M}�7c�_=e �peU%/ru�6� l=�8 9-co*�m�+�F�m(�%4�)� � thor�] P� �.�U!"-pung�J53^���V*# J��Gl�0i�:`]g�hIn(K ,w ͱ�%!Ag 5\<$C�n�2o�&!D>E�8t (  ms bIi pulskC 5 p t P��  3��/�m���s�me"t1*%A=/.�e�j2A�sam�=�aQ�Ja� �c:��xT"�E.dg>� ���. cl+B 9 �<%z" X�MU)�¥I�M s%�]>:s9,i?��9��"�;��:�;E4random������ HW0k#>�2on>uL3 a/��� &MOto"�Dk"e� �;9"NN?,5��mpA��-.��u%Er`Aer�U�Y�6M�9G$$i:!y2LL�+:�P�%9/"p� 15'mɯ90=JA�9���(6-D0 2sP&DhM%te� nee� ��l�%߭A!lbeH\#y"�%Imc?5K�R�1&f4v=� ,�2$r;i1M�� a�6er!+�r A��@6-<�m"z/�(rV���e(���#`e avoi-��E%�A̱�re�2d�f�toJFwh}3.�� Lg�,IB� �o�dh( 69%%�6as op� o 66 $�!-�y!Cry�.%Dto�3�8:Y>!9�.a�tu\91�ull-bl� >��9� IArti�*bA�� w . �K�,%�#?i�&� �1� k D�B!:.�IrM$ s esB<� �OEklif"b� redox��r;r!0 �se�YP �*Ylso��Gtox�Ab verl_9.(W�4��of k!oxyge�Y�Rob\^�iNq�d[� � &<� i safQ1W of i! "�4 li�gseepebi�t� rege)?maiKT�  %Xm�@'inc�A�5disWE%!�A�uia`Y�$metabolismJ�7!�li�M �-� �qise� s gr�lld�op8 /�'�CFmle�r� f e�ybod�Rd�"a ��� �7a�p!��.5�&L#<��)�sqO�_�$ mpon p~paN2I=�=� =�re!�s eluL4me�ws�x&�#2o}2ME$��m��=� c�= x R �,��Ped EQN�E�Dtru0b�!�qo �Lj \A~A6Jir kinI!q�,&22�pub�ND�;� ���.�$ly idE��l��!�I?��*�1dsh�A.}�iiit!�tok12e&`&~@e�A�/z"r�v&� �an �#d�Q�� �I EJin}6QtuM�A�_@�/��&%":g!�� scal��Q��@EN chal�dA� txQ%��haemo�L mato�#� �{ alte%�� R*G!�3�: m�k<,I�BY��FE ) mm�= ��iFur��@�P��� ���[�nm�{�or�nd l�{�B�2 k- wCn } sens��nd.�f! ��fB1i�.1 tAY9��9fe#�drug t�V �deP5�Y� <m!Deq��a�z 8�M. �X:n��e) i�a;eUA�(lex eukaryo��man [�s�  ory!�#%���|K!�$ , DNA synA �dE�irI�.�de�&c"�]`on nut �*N-!la� �v���FllI��1%���i o%T�s%�'s"ty� m�pooQC�U� ����Z� : ���'3��rM^��Pta�balt}���s r�G �!�)�ic���B,�.0�I ��$S death [�2Re�A)��a�]6�mM�.m ,oe�=1�0a global view@�g� >"�A��,i�0gin)K�#erge [5{3�R!�i�Z�pro"� play��ent�)�U�9"� 1�homeostaA�d.� AV&�<�ntbisc!x��orm�7$hepcidin [�Hf �a�A�mia2`E* �[9�P"]AA� !serum�8� U&!C.�.xac�&n f�,eCnCiYe��9adq�F(-4a2aex Bg!gte-C$n mammalia�M[15 �R5-!J)i�or�+7 ��eocy��3N:+�)D|;�>liR�]���� �#9�/��pr��IRP'[11�tpost-�\&�M mRNAs&X,M"Ko!D![�. [c`\#!�it�<u.'�_or�TfR )NUEM]%EA��ds �!�.%�`-�" -sto�� ���a h�p shJr #1Art�!�*� freeU!pX�!e atom��a c $�:�(�� errihy� e [1��ExB��J?s�QA�.( ( Tf1A!E"�(ebM{!"Z�"�Q1s2a�p%�1d"TfR TfR2�HR Bv 1f( y � eA�E�- �%>�b �6mނ. S@s B%��� a|�$methodolog�]' c� !�6u0� �D�,AnA���Q�c"^. A2i r =21sm���a care�'!�p{)S>a�UE�ͲI�h�Z��f (Sq �W�*� do “�[-if”��e3�E!(�w"Q/a�:�t�we A%An%& �7.�<�Momprehen� �+�>!9!U � ���� � ź�)�� molem%r�9�0&�F!����3i�X�8C�-��zvc�#>�"� *6�R.6�2@nC.� �32�A�es BS�=l#q�5l>�Aroxev� �;� t }�^u!�a Boole�ay�s6=��A�y�@�. Q.[4��>!}�Q�hav�+e���e���[16$ �~, yet@�0� e)��SAc6 2g���e ChifB �ysug�Q��"eZ�e����5g�. L' -+h�.sm K~^pat  [18 �/ �����]=stoichio� e [20])E�: �*15m h5ef� ɖY7lato)8w#��X1z% ����I�C��~ jt�� orul�,ab���d. EA%-N(&� !�wo�Dre�9NQ: gQ�A�v�jg�ic —E��ddE��I�m s abh!�ic �*^EAa� r�2 ��� Y vj���#E�AJAg e aiUKA"On"pprobl��6de��%�=�:�s�d ail �&] acs'pa-��a��2�q�\xe�E.�y�� �&��( T%9�Z,?t�Ga��_'techn�x�b surf)E4n�6n�a�|� W�$Az�2~!�dE^�ip%�i�>dle 0"� AwObeaD�A^*S)%1?��sE�P2%l�e:ÉK�a`u� A7�+H~!p ��is� ݧ@Ef conf�kA�@A�$s��priA&6H ��}.A�,%i�"� to"�env!n��erturb s.�.�E1�?&�%�\sa�!��a:.�6�-"�Wsteady-G65� !;��qr� �53"��K�$W%�UkU\M�#q��}QE:e5~Vx2!�Eh3��a2t `��e* �� .�X �. Chua�/ [23]�.edeFo-labe��� 2� &�����1�"�,!�up�j&Iaa1%1pinu!�A�e,ȥ�e �Ra�/ol/cA(Q�!�E�aPy!�-�IS: ���S$ ��va�r� not�/2�so�;?�9šstiff�i��igSN�M*��u2/d��gn̑;/zja��st�jcyc�w!# * %��� Bi܋%�re�J� Arg,B4�A;��{��t0f�K!͉�"� !�lef>�L�a��mn �&=u�?u�g nd� t��edE���s~a�u*p8%�M8�fighur&+N��Bt[pe�i�an25 nume�(�A>n F��flu�6�� e6}\.�K� x)v10% [2,\fix�C%*2�_핹%�replac� z�2�<76Hequ�9^ �..Z��*��%�dosag� ��9� ����^\��E� nsis�M���F6��by Girn ��5P*Ai6+ � <�tX &%"Ba�{Z�!r&Y� ��E��re{lIo)exa5>� ?��e�v�S2��(2���que�zas� tr~ y�i ELIS(~ h�|Q�����q E�$��� }alt�8zZO)+e4%q8 hou�1rer?+At�abasalis%�in 24 5�5��>�"��"�oof�!� TFR2A�A �Va�2 .�SA{3B�D�  �n�^ X to�l HFE-gqA � i�}J.E -Fe_� $VU, �,)E�abundD J�1��� de�� )<���!Q"�uM�!F m՘,![m�I�A.S� q�u�3Ak.I_&�i�7S �Q+�s%���M�3h <0w�9"#� sP%/�.�vo �"lh poo�P16w��r�' T��T� �l�C k�B"~�J�Xdu�>duJala����o5�A�s!�q�5�w���"&��e�� >�21ݚB3.ST"d /$)Ia�Ya@c�@ n 1�500 [25�T/�1�m��%&�� &/ %�eA�D.$a:%.S��,t:��AE virbY.knock�C 2� 5` 100-nu!i�;ht�@p G&� �I3,�cA��H.���-.j�i�]��N� �"N#���a_e 2if���Qu&r͡�/;P�"�> silico�9-D� rml�VkasU�H 4 6�� .� u_!@f��� ʉ�(Hfe −/−�>e73��seraYa��z��E!ji�8S a� ��Z 6� :unWinF�t,han ��/m. � )�AJ2�6!��absor�6 ��q� e2 *�I�N�-!�.;h�*�ueC!?Ib&�"A��fi�c�ȉ��6).�!�2�$r�99l �-��q^*Oof2-�'�T���i��a� �o�o6� mRNA� W�Y Ludwiczek*� �J0�'y3s�!beh�='$:a����S�asss� m�j*i12��1"=eQ�^A�Bvl�o�N S�-!s!�>� )�If!�N�&e�"� S.| 9Cala*'���0die� e]�. A:/ e 2��QNa�E�ic2+=-2�8�rk�B��� heal��[I!p )!�ena��,]��p�� A�6��A�6�Fi9 ���ǥ��aE#en��toai��!]2A�!�; by e�!o����Z[r=h�3I��aP��^-RF�ܽ.� ܞ�"���n=<3 ���*Z ����.i!y� 2�"�2�(1�;/N # �up-*�%l{,2� g ,E�*5�|Hvo'�aI� ݼI<ha2N�ZD2�tr]t�>L*E�%�6;-�e"�o�\�ٔ-:A��?eD 3F'��%� [pheno��� ��J| ,"j0!G"�*i:Qep �Tc!�L*�1A(. &3 (e&E9P!�2= � A�j? � y )of _��5� j-�U&� 2 �HCB@A(2<� a6� � � T�" �o�h:ZI����2�r�lE� �1�in O!Mnt�)Asy�y��1-e�t�X ��a��Ł��!� matc[.bC2� �("�YcH Q�i *�G5�&� b)�� he2�95,V_,.�i�r�6q.9M�*i_ "� �c}�)��vi�&�� �5�x,��T�A�-�l!!�G�'!!uoNf��8E��Y| [2�.{E*�/�)-r"7 � r&"�5 ,S%Becker"� argu� @�Uar��m ���0sig�F�$ 9Qch�m)Q)Dbo�E:�5*,i2�b ,�Qre�!$A��pP{&h&aC��IS�)�M�a3ilu; FHbŘu (ery( poie�( EPO )_ VS"�h6� �L&�.� ��2���C%�su(#�,�*�'& carrU:�to $�yH��% D���Par�-{W a����6* 0>b!M�E8j&k^�.RE���d!��[*�-Fe�m:� "zT*|%is� ����B !�AL���$���f�L�Q*�ViM�&i�.�M�'�*p"%7.'rX3�3 a�a}35He1�>u�,�A�� -~M� .�0 mark>S (e��A��toM�: "�c%\!2EPO-Rd,"�T*ayg@. {� curv:i�!�a�? �8ce�avA�z!z%j4 erty%�, >� *=�w�5g5� �C�y�\�+��$4is- :� aN�U !i:aAsA�1'�"lf%:2�霡��&)�(�Ced�uẽ�Ew)�9����)= U/�z�c[Eo2�&T {jr�����Cd�m ٰ0��o� h!�e�is�Va}a 1 �)Tpr;) �a*I(ed-���!s I *�=A�:�:@5�7M6�e6V�p'1�@t�A�%A�J}-*N Tt !#.a 6�C!%�QvA�*�"E��C!!�b"�D"^�UaS.�o!��0��&~&!gi�b�ee4"�im"�&.~1&5�Y&@ .Btself�T�b!\�N��)%���er�#a�A�N�5�+f�qnv%1�i!�v6 P=$=X αsp�5, bio&� ,a�ox+2��I�pZ7�*�azs�5>t �c*�4*� deN$�?nemia "� �excess�00�ial� �!�:�{'&I �Io(�k����>epecU:;�.�a�����w����.*��e.�u� "^6_� stud�)at��=�! d�E*aWd,'.�* p^&�!�)8��Qs!�llcuq&Hso�%\�@"���s%��2�&�� )==��ly ��&�!igZ9@>]eX"�Bq Ym��A k�� B="<(a1})��ed! nt�cly}岁oi9&V�q� �>1Eay! iG� s�a-�FO.^2�5gEEo��)}�,� �2��.sourc$B��"-,%�u9���Z%�'A_g� d���5Bis � i ��!�Oom>/l� effFec;[F�@�>Q[�%acB&eL@��uS�to U=�6q+!�%�=A. S�Dorg�W"�Ώ�c> doub?�� �s��!�I��"�R��*��D�?�!��\�]� c�1��6�A��v�m�<���m%.1��m5E�uG5e� nitoi�T��BRl��� %�� 1ngI1!�5!B]EX$ m�)t�. MU/%6yI.5��� Y��8U�tAo�#.e`��e|�*`iy� �. G�<ŽtiP>�Xa* �5�%u"� I�ar��of�W%�6w toleaf�.�i�eJ �r� �Xe& bz��=m. Me�%� k�&��dp!��eT. V�A"sh�*.kf�n-@%�y�_bl���a�Xa:-��W"�/* alib��x9�� ��qQC�=B �f ��3�=)�a�`&De/n14N �@�bA�"�3" Sye���<$�A.d�ro)n"~*> �!�a��C: %� *\�s�`P6%��7G-DT� �X/� %�1pathwa{�eea� .�QN����"@���G�=ylB � b }f�) �x�B{:)3�� �a*�xErapeu� �C;'��)3��Anb�kn�c�0!�/�*�5 "�atu�b�ji"� Q,�:��m�(%���"a goo� :����I�AM�O���J!�)a�#prx(¥�]�m�jm�H&e&�:t�zI��&E� E�d��+r��� *� fa�I��n�M+m��&A�.A�1� _rou�:*s�>Nst 1���t8�By�!:B by�;%%t#m."�<�l��W �-*!?>�� E7�umC . So^)�� 18P g|��  �"�7^�ls]p�4� i�.I' %*M�U�A�n|.@�T�)E� 6���ZJ*�Bby!� &.} e�]R��C�jh!�` ]��8!�Y@E$ YtA�a"� mem � �G6 Xa��dU-E��� It<s�-�uq�v�hQ/Q�A#eesQ\-��N6� ��exa �� ��5�F.Nl>�*d e2D�$iA: "�, �. Br;�6+1+�G�_RY��/�l�Z�M�B�B�. CYan�i� "��8&����c�!4:"!1Bn,��de�=d��:�E�As ��bS0�M )I imp�(-�'&� ��o&�J)�Y^:X��W �/'�,.� V�JAP�, . Of56�dUyR^x`6`-.�:�'iK .��-�2B��/)+&Ta XA&d ��m��&!) ate9��`���ly�! �)A��lB�9ʩX��beLE0 N'.4lso�(AC by s"��&i �  d�.opH�&V��=��u�L��z �/�����eX�Bq5!sc6 $ XRW(2�+T!�g*W� �c uZ'oun��)2�,�CaDsuc��Ul���i�7 feed��-' ���wk. ]�p � �H í*. T Qlj )U�%Lau�>�d6I.� �B �!pf%:��!X��2��##k��5�-��quasi&��A��AB�Y=�,� �Ww$j sA�0�RA��: -��}u&� s� p�"(M0V to�63-1.�(�II&DB�:/"��/b)t9&� � vers�c%U�l*ev,>s y�cp���M��Z2]SN�yCF��j  Ntoo�5�>"���]_%��}!��J��n�uar1��z�M��!-�w�eMW2!�&�M ]�?I:����%���newa\�M������un�ed�M�Q?پa@+�?�7@"� ��i�o�fu�<`"�v �v=w\=͗e�na�6I��$*� a.;��.��=K*] %+�?q"J#d�R:J��Q�� :4"O- f_6&R�36ow��EoA �Ie&I'  1 t�.��).6 Yi%�elu�J�L�YnkiOgent*�"�*�*�s�W� EX5BlE� � ���Y 9[ scenario�*d�����%^l/��al!$a1le �E`}��F��s� A9a�PgA�6W�T. Ao)��CD!�� �Y"� �=�e�( ODEE$�$Q�� Ah+��:"�M�J� COPASI �����F"i�6�U �M>YA �s4& �&)jkb@3Pfr [HyiAu2I"> SBGN!� diagram�d�9.@i��2�&aΑA�-!N�[>!�i� &�:�NAre (]�>&BB P�x*2���:�* [ q���q�jA�!x!����ds* nI0�JE* �A 4�ia2en�L�-la: :( LIP )� �M�m2���K�/�i!l� a�`'�si,=m"�%y�Bw{ *tɉthem�*g!h�% g Aur [�I�_��!�{�Z��au�gessa�^lex��!�b�Bmar󟱬m�sit�F�[399!&t.�a.Ec�q���Fy� a�s5�*�Hs9'y"dj@(l2b��!P-� �"mC.�zer*"-.�� e��2�A&xR��at�(p�%�2f.��Jm�|b&d� y�IKof�^�w T half-�"A A�!���te�v�#u+p��A>�7� !0!� �y�0�w �5RWI_i�|�>Sc�� -R�G%x��� Am=�A�a*_� �� s t>=FIB�-.}mAo�54B ��� �[EquE� 1: (��!aO)%A��2mf�!�.�� 5.��"��59�( )�D�A�� @ A� ���y%*��;�>'t�@L,Å�� ,<� � NE�a~nwfu=�s� 48aKwarғd rs�Q~���M�#��G�vw� =s'FWf)a�r{-��ODE�'b a�2L�B5����,!�P .,��my I8%"�)�P�(9�_a�N"@C5ee�!Rk')�. SL2)� vRrU�5BCPG,_by ATP-1�c�Kt:ub-fam��G�Ve�6( ABCGAT>�"a�� �se-oO-o)>, Michaelis-M�n�M, **�i�~�$ ]��CL H4"D(y�(�*� ( 8 ) WX WA�subR�-]U }{�Ie��flig!6F�d�,�j�01h�p �enzym�U ��coeff^�6��)arg�7 q Z�co�cY��("b.O@gm8o") ;����k �s�Dasr�AF�of���unbYv i.�keXy"�c&x�t�"u&�#n�"��I�-e�f &�D��c"�.2�( !�-�.#[/�*��'X a��IR�b*��~ I�%��P�x�9I�~NZD@ 3′U-P�RP!�mo��.j�iXA�2� �5JYr}D!BX�["7.�F�2��s�5 �:�ta �g�A�oA#F21-��g*G^M�.�.i!q� o&_ mrV:�&"0J6�I�Uո:���.��B Eo�LD&~)�"�:�J^ of 5e~ u�b aek�g$"` $Om$��1,>���,����O�!�dN6Lc r7u��stn �N��oudi�Z �mi�V.��� kin�= ( MAPK ) �c�R"[4����� ulus/�r3�PD casc6�} �yeq6XM��e���V�� 5 [4,ebE���>���  toIpRSi�iZ7I�a�����fїalgado"�8_[��&^ ���=�ji!�zPabi60t��L���6.7,�P� D�>��^+�]��n�Pf�_qC�N $.�!���*f7�E�nal��nE3f)D+n��}F��9^#��c'%s�( 9.�2�l"�m^ ve'&ft��06B*E]� hp�"�Ci�o�s 0048�U"v bLv�A� ,@�i$ RSby 50Ot���C� �[[50 ��a packa��.I��'V-t����:�ent�cag� I;o!�U���EJ $!Gn� .�&�!f&Z9%m���\r RB~�&��"K0�0 n[�`b�aScorF��i.�DX*KS" o%�Iˉ�%E[la�� 10 ))� "!��Z"�U�7 w�!x9�%.f �V �]A �c9PDC�/2!�+ �� � &O Sark�`�\ . [42g�YE�I+ <.�$a8m8��*��v����g!._ r� j��6K�7ce� [43]"y�5;r.v6-Di���NX m�:� 5%�a��vteE4 kE>J�! abovgz!Pa�PnRo!��!d:�of� [44] II!�$z�IJ ����)+.�Ig��&�vl.kP��&� �c��-���)~.:6GE��M�[� � A"� �NA! .eA'F�&5�6" �"� ��!�Z�4���� �E3s(2����`8�f$t<-6+$� 3c* �[ 22�yO�known;Z6e�ai�Ʉ��J.�xt� x[ <�un�!%�k�w Fsum[AmprIT�)�bU freePe'Ki��R DMT1n%/%�% <s� !�6�u�[�977gM��a7�oR� mi��!�z�F�@-li ��ō�sm [4*m� -,D!�A,"�=#�6IitN"y � � IRP�hIRPa�p#�/ 0��!�"p N"�,Ii����0�ngl�tT� �Ѧ� T�c�<�&�'ci;s��o2�E& 4!�by�7I�k!d�"R |F�2pڡ!+s [46��4�mGj�,!v&XH��mxA!_�nby Sahle&� ��!c7iBp>b.e�6��v�� <d+ir�`�B�aA%~E^w�U "!���u�� =�,2�-� ��-eol.ZO# 8*A%S'ach�V� spacj s���>:�<�bic!�waa��&�6algoritha��]bNE�C8G �B easow6e�B8a HTCondor [50]�i�� �6���!���, manag!�6 !d H-�T  [5^nT1��"��DV2qk%�a;a%m5�.�$�I��N CJ>aIX*�r 'ovi�U� k�q2"% �at� to ii�ʏb:���DT��I�F%de?�a�"�!�J!}o"�!�����(,"_#m9�M��~��%�q��jEaı�^%g� 6@R7�Z�)?p�^�0���lxLI:s �.yA�X.KsF�!Q�as`J"2��"A9*J!U�e�فc�\y�lW ��GI[w�(  ) !2��[ #k\)i�?,$��r5�&f�s����� . Two7&A ��s �@�D���"X��;!�Q;-�:\��%!� J 6�������t��a#�$( 12 )�n�+nu�@p�32 ( NPؔ���"�mtr��c��D enve��( NL#;\HiE�@h�^n"�+&� illi��` [�zthV%:f nan _er>Q�i��m"'7&�}Cr l5P##�k!�ArophobA�p9b;)yphF{�kap!maPPhe-G��FGKpe�:omain(ֶ�e�E���#��b 1�� FG-r@s graf�;o�e e��2�br/G!� kap-FG2�!�nZZ ��e�ab�� ��-g;�/A�=M�^s<%s��<sI � oDjic=��,&X;Ge-��a�fuO�����j7�bi���A�n2}beM9���#��"�k%w$�&��T  �-��ag���%15 nmHga� i�3"h6± ����x�7�+e Gauss�v"�wi^wNH�-� �h��oFxD�LBrownGq�&{�Moreo�3�ca:�PF� Q�Nc'�w��� ��� xw!\FG-lay�SHF!)� �"H#��W�!pJ~}M!Kh�A �e@UgA��(en(�� @Je�lo�F.( A�"��a�����.���� po| n�βz �p 8%lta��`C��8.���&=�i�NG� , cyy fila3s-�(|�'�7a%eeA perme�&a� ner�rgoa.�g"�gQx-� =Rxa!���Nb)O[H!���F;(8FX�X�2%�\]O�;of6=�4=1T�e>@[1�q2�G�#�ebpl[ c���zrR@x���ryEa�&.mge ��$�N� i<��;�h`�$��h��n}���s�[ erte�>a�H�'i�ٰ�e�EZ=)A��=���kp��� ��us � -���)ndS&d:q�"�9�<��\�(�.d �)}~,*P},�|,�|,�|,�{[1)�zyAL�����[r30�incy�&|�l<!O�dI)��B ( nu�m5��ka��L�l�3�y�"�7h�C�?a���*enzjJc�ers"W% leuk�J!C)�|%8myofib>rz� tum�f�~4!G��B��`tr-A9d�g\��y  .�cirrh���y!b{����u. N! alsoeŀ"�Bqvi�D8infections by p0roviding dock�sites for viral capsids , and also by blo /|host cell mRNA export or inhibitSim f anti WTsignals [17] . For a mM�Rrecent comprehensive review about NPC-related disease see Jamali et al . , 2011 [18bHAlong the same line�Buehler 250 , haw�ly �edAlrole of protein mechanics in� condition�9�4The total massA�PNPC is species-depend!!ois �44 MDa60 in yeastvertebra!� , reN$tively [20}dim!O�of}%� w on?ies-� example , q@NPCs are 15% smal!@,than Xenopus "[21ysubunit2� structureKLcytoplasmic filament!�a2rAN,entE�hannel~$t includes �$oke domain InuclearEA�basket HsE} osed!(8 ods 6dis!��(E{Fig�2e9!�detailE�.u1"oocyte!) ) .EA @acts as a freewayPpase diffusion�molecule �%�2�∼5 nmA(Hdiameter [22] , [23whilesI)controll!d�facilitae��transq�Hlarger cargos up toM�39–40|[7h[24] by!6crimin S,between inerI�@karyopherin-bound_. K$s ( kaps )E:a family!solubleq�svwhich%;eraW �A�shutt!���U�%%�I� via"!�,!Xai$cess known!� 0Dic=6( NCT%�L!= � be!q�#ed/�Aed��t ) !a0n appropriate!�2�/ �eL�a�kfpr �toAXm :!�-�n0lex . A singlI�crccommodr a remarka!f�o!v]�?order∼1000 " loca�$/sec , cor���'��o a� flow=��1AL. I�Kan�� , al�230%1nup��� Ae�unfolda�� ���henylalanine-glycine ( FG ) repea�}colle�H$termed FG- !�\[25I�6��It��believ�/a�V e key fea��inr(i��interac!3�kap with!�sN�:��thu���sE�E2�Cplayer!9 allA#��model�Indeed ,a�tin�s23��i] 5 origa�e from �YulI�/�A�ert�s�z8spatial arrange� !�! iIma�5H�1 they5<)!; s du��'Y�. W�5lng 3l,@ escort)�e3 a"QHpore until it reach͆de!3�8 , where RanGTP!Nsoca� U!�� ais rel� d [4A]B�� sizi|hi�:�aa� actn�� make� very harda�4track individu� rg�es; henc��e[ stud%�r3 mi����ulkK�,across many �ɗ�AEHoweverA�� understan� �9�W sm��not b !]d unl�we�a�>�s mov!� �!*%�%+nA�e�i� yjAZ surr��?�V!��G�4be geneticallyA�ifia�o el!�!� casD Icext} ve effEKb b� devo-Zrevea���biochemk a�"D N(, far %iՕ3 AbiophysM�!�N z�happen�$1�m�5�� wide-Y��illise ( time scale�� vivo���8A�Cur� imag!vtechniqu� ailAtcap�>bo� [!Α0re�1ne�ary:Yh�o refined.5of��] N�$become cos�� whenA�recogna�thAT poor �� [29]� inva� e�� a �he� .�� in-%;measur�$. Furtherm� , evM � y�e closs �sa<1��(>\EUi' �onsM�* � !�A�e�"I>  nanoIAuTh� uncertain��E�J-~ar�t.����cy&5 �� g h� e_Tsourc�3� a��g^�M2 >E. Sim��i�s� probA�t%u narrowŤ�A�Q ���equen��!�ts lea�y C4 cycle . M� ar dynamrs�s�ۡ(applic� si��u3�-�;1��e��� beyo vailD�Tu onalE�ur�ڹ�9� � ( MD )2�9�u\ to2 behavio9 l�ky��]q[30q 31 2�AWa�i7�Qo%]wh�s"j�c!, hՓ!�beK lter�ve7� ll-atom��( coarse-gra�>���g J/ic�b!Sl�in to obA�:Zfeasibt y . Ciaz�х� +to�y��log��system�%٥�s nearer3th�in �9���,$ugh �st:�neg �33!�R, we s!]-� is methodgye(b�"] employ2 o mi!?!J!�fur ality [3 HH w� es��-��-�R� unbiaA�] st� !y� (new insight�tor��_MsZHnAN�Un�� lis��survey�1q�ng.�� omena� :��+ache�a�y@t�a)vs!�develop<]Yed ��. We loo& mH��&� atu���ۅc� im  spaceF:�rom a�Eycal per�av by im� �experBtm h data!�%� nd utiliz6polymerI�$cs princip-. O�85� establish� w� n���P��&� hypo%b"� " as was���:factor� !F�o��, i . ���- �X��, shap� (hydrophobica!soAEL�� �v�Vl� shee6^ �ruo d!�6� s soLi�6v_�Eׅ5e�� disassemb&Am�w��] eref~���"�!�y4�d . U� sOn&y ��p�8�K e)6bA1N�m�heTaR ��af xDistrib4 G%q6a�catte�!e�a���0 . 5s to 828Ń��a 16-� va�!f,�F�/di/�stoch�c�m��cl^�. B� /ur� ul�A@�� , 53<yqE��pZ qCa�-hp. Next�e�� 1��!�invg� �\ u� of 9+2HEBDe�in�zl )�Ņ, j�w& carr�8E��s*� rA�v o  � �J�n)V�+eA !m��"� �  �th� �A�ef' s!��"Z�see Fu.&#1cap:of}j� duct��B�x%�aW ≤3�Z ���� to� usae��*?�� �%�D [IS remo>e.� n� F < urfacr �j pF�9� abovјJ�����!$� "�%%#�&Y@i��T]2�~Our.rei�=��!J�>�vq: obey�e�(rse Gaussia� <"$ ��u&� �Q-2u� : ( 1��ms�:��vM��� par� . No�� �  si/ ovy ha enl� deriE7o�8�2�f�� p�mE.go� Brown!<mo��%)a posi� drifC �Át �xamE�+ bsorbSwk! +%/J�[8�!� � ��e lengthɑi�!{6 I�esV��Ra� m�a ( :��)T١#�G a�t!��U��*� &�v� �!F\iP�:ede�"� 6���analyz��pa!#:,Z�!�� d��l�Ջ}�eœ��� to f� rad�bM**  sugges�ud� �f�"a!B��st lik�mf��%�ElU�t.Qe6 sI�!�&K �|J��a� �w �~��aximi!�aiA�( S1!Far�vis��~|axi� Simi �6��r��nY2� 9E�U�,�;A� kap-FG.D5@i�� & ��%h mittX � weak 11�5 '�i�? obor�%!highlyaBn�n1��� bon�$6K=M� life� ��*J>"�ucb\.otQ ! β�anA1�f�&� � �" xima� 1 ( nMna� n  devi���17)m inimu:K�is� 010 ( eq��*| � ��t�x \sBr��.�9�6� ��"�"�:.A� ->�taneousO�}ip���)fp#n" er�!=�e�eng�,!�Q)l7 . 89( of e�:�A�E�!~A{���:$ .9�  ,����@$trajectoryFQ"�10)� e quP*} back-and-[h fluctuENFkb��exiyH!Il numb�$2Iis()a����w�(�5!!atɐ��t�36o 9��< !{3G�&1Y7*d s�&�) �,v5"a��!bh'�� y2 midd�*F� To#d lE �.J basi5dseiv� *1; ��� B+V��iwJ:B�1of;(-/:d E�z � Vl. F "�intacd,�zV �i�(�%�&u)of-ׁl��N�M�.^. V�^ !_Z �.�an�j ! @ .�i onl�)f�%c!�.Y wo se��8!A�%�. /�p�� * V�.� Xf,e �ve�[a0� �d$�*���#0 vum�� �'!0go:{��ed>^2@> �Y to ��3�8�� �.la0V�>tperdage�&�6/*0 ific�) incr^%dvdP, 4�VJff���M�)s"� �xms . � lem�!{^�  ur� I$� r�#� if��%�a%.3��ar� ��diF](�(��.�*sh%�be!�aF��Z�repor%  doO ot tf( untE��M NLS- u!uD� earch(A ���whe�o*�� �oU Rq���7#s��, �1�0 More� ,� �valu&do!cS0ba)>"��`��a��i,!�a 2�%%K�:Z�! +*9 X!?av9m>�%� also9�1L%+1�6�&.�za&��D<9qNt�swCV$ppA�HQ�& "P�)�aAU%��a s�|er6Q�‘F�’ cal�,i/er�3� 3re�nce/d��5U%e6� !��� work����� ŝ1!�9�4H(on-F � ag` con�r��2�a+4te /�%�'-pir2��>upt6w) , [8x828�#I)���r��P"��rA_s�!� !�gna!pmv�6J !�mF�V�%^�"k c%T�I� � 20% -)t�4i!� requi�� �Y ��Aea�$�es�0��6���.� visc5y:A��eJ�,�atz#i�%w� � reg�K is w��!vy㩊"x of&� "#m� ��anomal�atqnorma�,f&�%2�st$",a�pV8#tp.E""i�6 helpaFM[�!oug �Mraeb%��0�4 it a�/.A,i ��!�subjt&g/�2n�!@��"� � sej 1���nergy-*�e�� � �tor!!8�/ , [4f"6it6it78�7#8F2��le}~g.-[G-h� illus�0�AB��aiL"� VE� FG-tiE%s6�]� -�z4-| *�� �"��qA�*��˩`o ��%D6�!Z keep�h6�%+&� ��of/domly�lor!J�sp�I�6s ‘slidesq � !�%$��W+c.�R~5q�� ��0cenari Rj!reion-of-"4=�,*� [8�,� idea!T�w?��:?in �!�\3en�1�;�rapidV towa�5he2R6!�7enV<e)'�1�� "5pr�7 elseI|�%2o.?B_$! *�!'!�:�[���� �so supHby{  E��?�riI ��n:�%i\4rf.�-� &�3�*�e�ofMd��%5IsW;m!� luoreA l"��. Authora��<%)f.�:6,� ^!�  ��p;primar�<;eyg��U�occup �axL)� .U ��Aj t ����>�� fA�ir�ing�%�6.� ��*v���)l�r2inh7 plotAlA�Ž*��U6a&i.(a��K1:Y�&V�D�z.`&"or�N8�6�Xa�ly� "'��A!�u����� leav.F()�i2=�)�jA|FG.!"d:�"�.�Q�N�/�9s ��.�/i�2g l�@� " a��H�*F85!��0, �+Idh$le,"�e�|p"�>L � noise���}�%�gM�?ksuper-f{C2mma��a� !�I pE�.#J?NPC/s )%L�&�6_o�-u�;� &h�'1Ef'�W�h�d iQrmony�le!�cep)%5!h>�a �6G7re�c?�Nc� � �91� 5�B� a�R"AC�!� !� }; i ���sit3 of bA4!��hort-l$.�2�pe�  (vHEheA;,�qX�a �7l!��ns:�Ei =P�d�'.6�@R�Z�,�s.��� I��@Aall!�"| pots��t^vjA4��* � � �*dense1"*l�QE61> n"p6�E���b�E�ea� till un�([5� >eAO^qA� irec�E�L2/M�a/It@�on%&��3 �4e�hown )�7 �E�F� �Tphasic� ec��� :UH s no2) (.�I zerog� 2)pro�IaF��c!re�ed;.u�E too �?6�(���)%aN���tr1�&p�MhS,S1Ad.E�( �i�-�.�i�bq �_numerouB+ mov�+"�6�*��u�7�8r4.A<2�W� :Ks&� �big6G +`5Y��jjum�Da7A�ingful6x�"O� �� �>f� �!.�7�ec��[ half..�H�/g0�a  *y!%��B�5:��� �aA�)5��M �!��mA1"�&r&��3� &L1�iGab!� C�"X%�� an pu� up��57��;ő�Y�t!��+� s2�'Z2�JnE, �� !in2;!by��e� I%�"� v3>vem�� %@��1:. UponN CIi. 3 �I�pos"�<>j!9;5!�.l�P� :e^�(0versus��=!�= aEke2h�5ph�DI,)�V���7� �Ca�+ mpl�D|�4!_%�RQ92� �.#b�0r� ��,.n� l )�/RWt}4 o da�I[U�.2 area�sam�Mit� �� �'��w ɏreg`)�z�@g����b� ir v6L� ngiXy�2�=sc�IV3r �*!~����!�&x*uiE�� ly vi O�<�J>��#P? datt[F�"%,{ .=!�$.�� "*I{subQu�*s6�0&,u[rc�rZ#M��-��E��f )[4>8|JI��IM�*��J-"�5wim:HwbyfJ��QIL5%sa�e"Ler$ ���Ajt �"Fl &�C �s)@Aj8F�/e�)ricbul:0BN��) �#2A5is BR���;s�&9� virt4*�4�"�A �\al��!���)�$act as “A� opic�stl����t!])C$“push”cJf2�� F�T e�a) �=%}�a � cy!�ma�)E���pa� .&s� lm!n�>�� >�)��?�"erM��>�>�AK0 4&es�Bm�lq:�b�@SW �Con�1>a�ui>@�%�)|[& 9:.���sre tw�?�eZpoi�F| a1$4� �Eb5a��9a�� B ��u� ir p�=)�ur D�V &6!@F�Vy ��s reb�"t�9]<.�.^TVe1�4r�ly.)ha�$&�Hy�i.� “c% Aa�)F�A� O�� y [8]K��"�B��WɪyaM �KKif α/β�8�;nt1?be��{-Rof &�%���#&+inR�-` I�H([8M�]� Ehn��2Jo��G ledgj"���1e�&so/MpB�,>�iO776 ]..�F?2hI�.�9�B�& �e"�ax‘[-=E%on.W�y� b� "�$d �%�nn�@"be su&Jo ate�-"�N.i,%~{A[n�M3bin.��._.�A�n �wbe�7latfo�T*WJ��.�Ea��j5 :usibl.4 �sm�.scrutin\FIP� ilic�EA�� R emp�wAv!Pted�<�!�� A&�“lubr>ed��Ia�u��be�Fd =.  �c��in �!�dM[, 8L�F�Z��2��"a�} Q&�?[1e�DYP�#kAo� �smT�-���H�8���Is�F drug��!E!�A#rve� zsU. M�#c�P MHmanip�MrUSm. ua�a�!��R�  membranR<W� n en�6�? n�gU$:� {b�?Z|*O�i�GcT-h S,I� a�Gst� aq-y�imod��Ra�resu G tho�%B�6�i�&�D�Q.!L2�i<rz  �bE��Ove�Ou/4��$pharmaceut��ind�$�accelef!D t�# [9.N�wR�Wivwoa3!�5 tub; �O�|O"1,sRopen �R!7�O*�2&�"IMHa%acY$��w�AE �.�bA�p&y*U An�}.�)+�alm!�&� uSS geometr"h@�z&H !*5pl�� !�U�8Wa� �yNGHaBOoP"�Hhourgl�^�Jͨ><? WWadvan0sZ'� 0 Bg� ���� � T� !eM%sym �*apla`per�i,&O e NE��hy!K E& F�<�/�C7!Ձ�.�!dq�� k/�? Db/�m:e�?&}l answ�Y)!s+7ao�wait fur� &�C!�Rs"�a!8�Cng]js:FQ1� 3c�&� ���&-��W�� !(,�A�) emergV P, e el�0��X��) ?q kin�_b&�Ppa�<ge� i�5�;!in.�O[9-0O(e> h!�,Akm� ����,&"R!/y�I��,AM#Vin�@}�q�Oro[m6A�a� buil�?b�cXBN% Z is�// dd���Ual.A�jV��;rM V��%�sWC�O���*X�.�k�nonhumw #t%NHP )� !)oft'� 2��/���E�!A�d� ( %$i��by zathoge)suLQs HIV�uberculo2 ,%wmalaria� :� � S.%2.��E*�d{S-��us�/dc b��G>e imal� �X ;L���n chal�tDe�^1+a�.�1A�%9c�cri�qM�s]L�.: ��oo-!Yoo-�_:Z �}!)�VVfal�^ega�LF A�3 xF�e1M- l I��% opt[@�cocoIae�!`-�)Ps 5O`)} ( AID5v<;�6FK !lgAID8>f� �Tas�%*n2��[e.(m��!�AZ e*��  2�S�Xocedur�� �Aw!Ist�?�� �w�-�#�JM�(true value �6b� �Te�(!�E�)]"!^+�s[^ofm�)��/U� �immun�T6�.�-)_� @ �prefer;)4i�f �'vac�a b� apW &R�ebola!nd�H"HXs �� eth� ,"o)zt �Wcpa�er%s:� >.pr��5Pm,A�a as fim���o ach�bbA*�P.����^eaa%oq���� ��h� �^r� to ���=�ep�u: —a >E, 3�fJ�at&8#es�. S��sk gO �!nid�M�5m�6�[1~1!Ae�<be�M*�Vp" clin%��A�IH����heQJ2�)H"�, �%�2 5dv-.�!��sns��power�)Ter�ec� .( [1–�5AC�Ek-b � 4e�aeU �mucos2���3 SIV�Sa-a�B[[4–1 ,%�V4[4 , 13-h)j,J -1�aphyla�2LL\ ing-%:51Q��w careA�ti3�>�Ia�cf7: ɰM��oo�"(E� 67)2��h2�+)K`t��[1+t-e�.yAw�$�in*��AE� �,imlM� %���TAyielda�!�u�Un�'AZ-�I!�no #a��lwa6_�t. Ev`a 2�8�T �9���#�}l�Y2�I�o�a���e goa�&)�I3+���9����9��X%e�]�5N !%��_�;�9�,�:y�+t_%inz. 7-m��-�a��MoS"��VIgfaS�d�%�)ro�is��iz�s�?"���)� G�im}]%��QJuf!R/pu [F(80�mr� o 9lB�+ ^ by RM nd Muencha�ne�8ͯ�Ias 48 �%� �0 )i�se  l pa�)$by Spouge Ql��a Baye�NfA��)!2V� �s�!U d)wG preci�r"��,E~(ai!)2e�H%9� -Wng���02�("3 ,�9�/f"�Yi�nve QoN%m� puKs&TI5��/�K I JI~�_a�q4n Michaelis-MeZ;et/,��5 ofie�>�ec reproduci tZ�;W.�i��s�K� Logit �D Y  , �k. /E�,* �simon��uOA��4F�>�is@���."HI lyA��0i�& Bi�^alIO[��A)y )�"ņ)jiout� v<s� �,�b�Q:�e�:�� %5*�us�*aIt�� �-�%VA��&+ _�Och��VF ��Q����s �W"�0�.*��FPF arch��+eo�ei1Da"�>����� a�n�-*F; parYDɖ�ry"� o w%��L�8��QyQ�2"PJ� en�q++� �� E2.5]*�%Q). Sy d�2�+]c�B:��ݡ�&�*-��d 0/In.�ىA�&a�dE�Yr�bia mus@& b�oced"��kI=a�^`V��gD*2iOed�e��u ulti� ,��c,!�-, �&� 4m�D�he��50]dab ��A��!��V" �2�s� 2L�A.�r` �ŚW ��� yS�TY �1�~�!��!��A�, �,"1�e.Dr� f&!/ (����=a�c�)gu�R��Var�din�+%�!o4&�"� yg comb�g!�k=Mم�s�oEJa9f>"��aMX�2��m:t���2�E�?MPi�I�c"i�ed-9�I���9ą�t�^�eiIc�X wo�us2�vRv�I�f{9.,e�ss:W5tH�Y��_ E�coI3�(ct �e�-U�) �`�ၾ� EQ�$�~�á�,*� 1)A.�]sT�,�&? �S�\0��� q����Ql�(k?�:Qbxa�14� � � . AsINg "�I"�.�ra=2�]!n&q �p~(%..m y:LF�Y��5@Ŏs�mA1�U 59�.(�eQ�%d� %A)� �t�<dkA�E�:r� �:xst��*�5�E�cl� �^e?�,Z���.:3 k�"7 j yp��(�  &J?���5i  )o�K'���a dil2P` r[26–�p, adjuJ��b�*K�,U$��a0P ��. A2H5:6R�W��F��>�!re��onship���LRf ( �A�':�( �W� I�R1nwj m%ve;E�#.LA:+!�5��y�&}"�PCo+?"�#j ��Pa�#e2�@lyi�D�E�!�i�pto��J�(es P = 100%6er 9����%`�+uardH$-2?ar.�  J_68= 1A (ag�)9erm m��RAsja��15Mb�d�1:� � {ki is suit~&�j� �'A�e�s%���V_a �ishoQ�Rr�@* �XaH /�a�>J3�  (��^�ir3;[>!#)>�>Hs�&[�m < 1��c1nd� a mixedAcA!�� maI%���Kai,A�� swar>Ph�Mo� yKvir*>-�E�� *�i�Lᄝ,)V%n/orG �2g<Esus <&`p9�am51���dI]� ��;�? OE�l�A:���r%��V5h#Z6�]a�]e��;� � per97 k�f�U:��ͺb �Kni��6-�Y A���%|�=�5���of rm�u%�r�95�Gi�r:jeE$�ށxI�a�T ����%!e.�1��D�.�)�be��a�MM�)=� 8/'��DF5dA�u�*R B� choi2>� 2�*� a��%st&yM “�c }eQ� �%*� s "� -�Ak;""Mc�q (*Sr1A u� tI&� QBA�q�o�EEF R��]uniA�]*�b<ng�"t�DR!"a�Z�1 a!�"�by��x ?�1 �C_]E;z�CA(!� n�~P ��Ee�u�I����A�M7k�)].2w�3a�J fund����A]a&� L�x �:R$E�UFi�.�ndJc|-1 "� n� �Ki�/d ))�. Wk}�9 ,�*t�"�"�7&� V�q6(y@��*� 29*Q$Monte CarlF�Yeq "� ��!s�e2s:  1u�U6!y �,�@�%!�5H0�2mo��c�Y>*� ,�D�@�A1"0�&�y met;� � 2>{� u9�� �)� � ;1t �ly�c~^oU$�S؂n<9L�M̕RQ�Re-��~� ����b!%ne�3�"XP�g@.b� ris� �!)"^ -�Y�)�/� :\ “��^!� ��r1` aMn� �2,@1 4�?m GU� � �Q�z�F�J6r HE2a* � U�n���?�h}1b�Bl"U�^���M*5S2 � ske�0.�"�2�� �ne� wishAEss��k�!D�&�� y�/g���*imgE�%� "�E enso #�]~ isks���#} ��ach"p!�)k��of�0)� no e� ;>ف !!�]�.5&�"��(� BŠT�:]/ �҅%I�H1x�8 �"�-r2�j�W�b;ata V���M��U�. Nonet"F!��of&�"f�����' ��P.]2�9�%�"������1"; ^+&���nYo �sy�d�RE: ( N��EA��s%6�3"Z(�Di7�, D'�f*�#!8�2�DsiA�&2 finalRof 9( σT?��C�um�E&'R�( EMAXMs%npuB � =:lc>�1<��( n�N-%N"��щ�%02� �e"f )+ā��� 0K+;�ch�� M2AA� � UkI]�cB�{� u~ rAsS����5�d�Su�.� 681Y&�2�h =��El�oa goodh�q���� C.�E�9�2ot� �(� t�/�L�va^�8a>�� �25--�!hbj/is�Za��e of 4UM@�� � Z��T �A��Q��Z 5�#��5�~�  in f_+��{owo�?�$��h � de-e�/��%�A7UW� on ��Q � &�0y�2 M0& �an-nq off� �%Eh84����.}3)K.�, O<.� ( r:�� %} �J4E4m����f=eq%�Kfew�'� 125�haqOe*6�,!��c�$��5Ph/ 12�9zE��=,->� "�6�u��B��Y.P�&�, t"hLv��f;KB��*��VHMS1�� S2 T{���gg 3���.7�ou��)��+�N� A�MU.�h"� &P[�2��lj!.:%FS!��֡�I2 �Wai�l�t7,E"Q�y��(�I):96r�1��, i]�jv��~�Sd 3A%T3k  [0�E-re�J� �*� ��p�tr"J�9��������2K�9 +s9M�aD0\�eiA ~B!� �He�)(o 3D) E���95A� NC <�gi�� �inu��dra�3�Oas �g A ) —I&��Ƌ��� �re"+E�J���� @R=�$c�#��offt �Ed �d1OU;!�Z�—�!�r�2 mend���^NC = 8A7 �} lMN"��p�O�'[yH0�=t��� � a!�iJ�+���woU-�&aUJy.G!Ud�ustep-910�*-�!�6"Fu4 ��#ed�/Yw�y")�%Z�Tz:� m�_Z�8��) �� 0rd�r��J�! %�e�N�5 (�  Ch-Qp&�t -e�I �AJ yB�M�0 —�' X�AX*-�� i�թ� rymw;x6 &!!^ ;"� � �ve.)it;er@�c�o se�&�5���adp.1&b"[D�� to 6g4rL_. DI�*�g� C�� �4al�f!78E NC (��%�I�&��wD6�loIu����piT k�j_a�9p� �x �u(�%n:�:��=GF��&N�s�}��trC�� ��=!p]z 2un ��&l ���!�=m . Ofrs�Vin� �'1Nx*|'�.�2M��C ���v.:J � G�y⋩3rd� "�(�y�" ”;y3�.�1��*">3FI�A>�ŀ1�d�/��.n:�%3&�+R�,)a ���Q!#�e��W B�steepT��r"1����–Y��"��B5)� cy1.|"OsN�<)";  0@ r��fR�* ���c��-��e ha"o���I��6}S�)4�@T"G'�WL14-TR!A bega^Yof�dμ�1!k #ev�1 m� "g �� �=aqTCh9-� D��4/8ժ*se')ke�`AB�Co���B1p� ��,I=EdTHa2)�r76��In !2�(��� .3 &�&�m� !��G �� ����a�o^!^.eF�in*� %"�ad1m��$/�4�2andM e"�6a&�0!�BR�!h��Jre �a�$of 319P�th6)�i�4B� � ��R>�50 ± 41!ā�4B*� ��.�ae(E�AKM�. B"�J��to{]s��&�m��byQ��Z� ��Hi�be�{!�iQo�;:S%�)EQsoU��)!!S20K\ ~/m�$ > �I��7��6��l&��a��d$n�|�4!��xBK0b�}me|8�� ��Z�J�!�2prE�t r��e2�-eV**�z2o�$' d 322�as�"7AU37UU��#a=.ms!l��i�A�6~4�!R-describ�6)�4.'3%2;5/3�2e l�B$C web- ��>o�VODclxa prog;B. �� �jM�~) A loid�o/rvPTtb�1.�� �o��Ter���ma[4E�xW!f9a97� Uf�on.�,� }�'��% 67ALcon` L9 E�g �v~ivale�) 6�6� a�5xs"LV. �4��)�)��� iz��a � �in:"�F� ,Je�)�,"\� 5�V)�5<���um&� � s�U��. Spe�G� �!J�1)��kbe "�i7�["�#�EI�t}��0��!M!�Q 62U)  A nm����  `8 nl�<�3i32eto�. I;G )�i�]/)�i��.c8d pF�W(&B"K%o�j�$:�u9 �,!�,d 1 }.G�aU�ny& !EU seemP tuDt—�&]%=Iis� 4 �^�t�GE�q�7�� :"�}!!mo�5&\)�<�5 X heav�C� �^D2� �{Ub "�b—�k,��I ��bsuE�do���y�%$eyWe�) !�*BY!�AI\�& >Gualc�%6�\.�qh�o]R��a=D�~"apijj utli�_=(.�o4 B���"��,1 P���hecZ(se 8/&���"7%5�igF� A,��A AV� � �<�espite-�wxur�5!m#8Vk/~?�,:�*���1AU8�^ m)��%L  68�1�u��;%^od2f?%!V3"x of 8�zow ( 8/~�4|@Cul� at�!~eԢtI&E �fuG(��� tudyP�%�ALi$H@��� �.O 9�k�#�?N& Q.~ �vy%� F;#&A�fiM�� �6�%Q�~��2�!�vIn�*7!_ ��� .�!!�3 �ic� �!�A��1'&#. 'bl�day�7c���w3�p�a�)� ���%i2��A�45 !wo week��e<J,sw�h[ �F epC�Qe�!�.�M�T%{�an&�� ����'an�"�b.�)��� eu4c i�!IAu�;U;~IiKM�I e vi�Mo�)W( &@aaR!�sMA��0Y�soBp�0!�">0 t�l�c23=V.)=�s��~B�:%��\ambiguS'at�MD,�}�Cltv���42�&� � "�( %�.'1�� ."����*�� ?�*��&�&sZt<6*7Edelay�:1�Q<a�B].�oCq���e=5a\H� � %��� �IB4u@�MG 162p�w�[A2E!swTI� s di�Y�'�@+-�afd adop!�a 3iN�!P �\�,mTBE�a�a.j3�b��i�H!:�'t n�aus!^t"� �!� s%#�=*7SoFs@�ly��i�& �sP-W2A)1t�jnd1 .��MJ9�!N& 0�m%�a�)��1�Y*}aD�� t6�L"� .Dso V2����̓])IV�3Q� �%:��]�1&%>"9�� %} _ F�*U�T�=�b!�z�G]%�%f 1!s��au�{AZ qI> ���l*�I�3�[Ťea" F1��.IjvN-2-� ��8%�%��).g �1 q���" 9 � � B,=OBwR>^� in 8 Pi�fQH2 F�=�%�� !��"W-�! �% ��%26 |<,Qo�:%zs=s �'��l2@.[*02���&�*��X0ra�$ er2o!: �of"�A� .�!<w�[�/I�@4m�,~i�%��S%0�U Q�( i1e�?9ng �A�Ms!ͣ�u&%woQin� )� ^&3 ��p�6a�RW�@} -3I�e b�Ri)2dI<:��atc�W�<vs��&9.:�5�'�71�S2I96�. us� �Ftrava�l&�A��;��!��A��|yI &6"ewfC ��+!#ltVbe�H< ArH��Ac��\�Y��X�Tpab�B�fs l:Hr��A�8 "A�l*�^>�a5&��4B� !+"�MPIHE*� U0�]&k:�;iO:��+m.���%�he)�n&��k�3�Y,a�set[&�=�&�;g*S��(i�cMQ�A�1clouA0EmQ�(�%���h�"I7� Z�<"5 2�2��.�L, =�M� AZ�a> rJ;a�%Be9�=�` w� !5Eg�p�!%�mbeiI��&� � �M� �Q�! �V��&!'H �2p�*�&NE5�m�&�s/;��suP�&ah2�N�N.�o�CE� goalŀ��p��щ �"Rٲ��isAf�;| Q�Q�/e02Y��� ��m� !AA�*�L�I�-�E�+!I J !B��uF�Uc�"�( 90%��g�|pa���}� �Ŧ�BP[�4F�9���8� 3 ( "( o� !M�+��� �2�w�[4�(�+& �.Ia��dI�c)hY��TH",[�@�=2X+O�oaF�K[%/ideaO��,e�� $ ���E/����eL.�A�%�ai{A.pre��� Y A \S�P�Ka�ASG��e�S�8��%7A)Q�5acter�Y an�-]��X� +�*s�;al�V�86a�[ SH�P�- �3���,��� �+ or Instit�Hal�C]!4Use Comm���V IACU�+P�\d�&.:�qb�.�!GM&� �I�;gor���2S� �)�&�!��^X�"5SW%��u&R^!�~�)� 5�b - �b-M,of� he V|_ Re7�Ce�!j Q�or5]z"3 NIH polic?{d.G)A��5� ��of Bioqe , Inc .� non-'d�d�ho a>�d:M�.U S��0�!�� acc@���� �N��cAssess�%�A 1��L�|atory2�( AAALAa�%�L9n��#liE���-�.^7PZ0c Health Serv�EP)�on Hum�l2ofF��I>��A��%�Q4�Acyt�oJ��a pair--�)~s���5P ie!B�^,�M�s�sr<�ׁ��dM audi��!�r�_AN�B rick���&n zA�*�� 8 Eto � itudV�d�rd�~nd9 muli%Cfi!��� shif0Mh ulus–6}2�Ƒhig�)�n\ �.E7"��n|<ofzzAre>�� spik�M��&&� low�Zty �!�W%*�J!nEH"Zrwhe1�@ځ4im�K�;�a:5a�`�)����2�%���p WQ�4�'=e�&�w:�� omaxA^�1 9�a  �Ay�|c,��rP���&��)e��'c@co�C,P26t“ThQndc )sZenh� dmle2�n2|lW|p��E�hhow.�7!�putB�!�%���E� $X;q� peakA�!4iry6��triL����)��1,!��N!�-0!�fl!�ng��%me�a� �c>"���& ��m�m�m4�pT 6� �Ne�aF�| Air slop��T�"M% A��I"ATJ�luty� !EU� ��WwsqL ��b�+!%��r}� ;)E!8l?t�39Xrb��}�'@��� I�^of en����y, ��}!��w[�"�3�7Q6�65�!*%wW:��B/q�%�N5�@���rf�lo����d� �*�$[+e�KM��ut%win�xa�!���. LesA9,"&w+d �^ j��33����y . E�?t)~!b۹S �D���&� �4>a�K�5�'^)��cn��:� dA+%N��a�ǁEen��.�t2M]ٻ�w���inc�ng�. SEs*� ��S:-A alyc � ���.Z.�.!���  l��Ua2sA�#a sunn�%��! � ��s!���P_@lowly8*�1n.wbVA~ �t%�|� a ��mAa��l�"q�a�U$�o-2a�� nerv��!-��)inm.�)q���Av)V�!p�i [p�Fi� * X�Xht9�!� put-k�vA�eur&=&U�! &a~.X� "�ml�sm!���"} m�������e- s [3]–[�~Ho�O��:�a��!�59�� )u��&�#U!� [g�Ɇ!Iq�v�pdeB�tld!�^ & ���Cderb�eMI�,Sc$(��ece$� )��� $p�!l4�� s�+��+�s���[1�(�o�e��&�QNEūY%�e-y a�e r6�-��.~MH�����c/U���c a�tleneckEO.��I�&YD~�i[1i�1"Ԍ( 3 )!Q�a ��be(���X�RM���Av�,Gva�8=��A�lE oz/�[16�#1D�Sjal�%Wa�u0I -% �zf[100��F G. ���!�Q�95�,N ��*k 5�I�s���2] �%�!���5�]f�Us���}KKa΢eed-for��bap1Ha��dri�1��0i<.٧! ask-�B��top-dowA���� L3����}��!l�&R h>��ѩM�N�� �'�+ ��� n�[iw��Mv" n!�W�T&.a� ����–�Le1�(%�)�A���B"\8�L�j O�on"�!�SQ�s i���-ȁDpt�:)�LSvL�ujD��al ��~eh�h�* X":1�W sV �$#"��!6�A; !theore� � Mk�!fMB: Yc'rA��?z � &R�%r8Mi#i�Z1Bll*A.I�{ "�.�� ��� nd%ry9?Mb� ME�;�.Q$. Laughlin-o*� �O( APd� �t`s> �E��!Bf� i9����)-(s�KL � imag I"mU�!�R�� 62�' ��eD*b��3t�Bd LGNe9� c!�|o��%I*� ��+A�� �V� �F2�ax?e�` chro�c ���$�&a.陵�!6��!��6�"!�6j� i�m�o ens�JNi��-F_.2�&��$mm��-t < H1-]ZA0�� i �����E������s2� I|AV� 2[qqo���0���.ɠ��j���N�eD�9z�a".�a6��AA�I!a0�2��meA��exdj]A�harpee"��e�%�!!al}�q � *��ue� %|��� q�@lu�8� E�q�����En:y��^)���^ ?<r�6�{��}^�~!= mu�xv�#!�*B�D{o!�C#}In"�". O�B�!�!0a-!J�l 0"�E)5�e�%\4� s��nIK�3%;l`I��I��VY"W5S�^&pursuMՉiA_t��J��.8��AL on's��S��O*q�%�D x-/�)�Tr(u!ius�0�I%�"��y*'aW�b��=/�YFj���}<"E� [38]:)�AL�"�"!F� )�' ��r1�"Q)�r$�A�� [.�%=v�e�ga�� Qh5�#6\� w�#�Yj !a���g.�. DA �,n m����Z$.T���Wa���*h$�� 2hr�*TI� X5,"���=�'�@ y��&w�U�Dg-x1��re� � Y [p�Xca��Tj!!D6 !iB.S�+��>��e�6�-r� dj�2aQ�6���m�be���w�#I��"� a��k*�2  �:B^:���," i��ae-�y�t��J�vnw,�'. S>b Rv ˜5��8f�-P"B=1N2^!� 5"T%52� �. C�+A�!�p � T . oc��cu�le�Lq�} �K�r�0B�+�,c��f%J��� .D-�e8"�I�cf�'Z�! S�d6"(.� �-|vs��+�D�&}AF.l&�3re�� �� a�8�JA�2R�D)#!Ameso-%�met�� racic leg {U�I�:6�/fi�|�:B �'�a�()�f�!�l�h2a�e6��waV3F'Mj coxa�.�t/c!�ar� walk�{�Ko�rA"�~de conn�hs��.�ganglE�cu�igt{� )��*. a� aVev!A��u�ed�rip�I. TwoQra-�#u�hook-e� rode-�Nung) w �plaG���8�� � m+a�.�& Vk5�5$. These copnnectives contain the axon of �>scending interneuron we wanted to record from ( AN2 ) . Vaselin)8s placed aroundlxDand hooks in orderSisolate�$electrodes ically: keep%coS �dry�Tout . The voltage trac �Lamplified differentiY�( npi , EXT-10C , Tamm , Germany ) ��bandpass-filtered with cut-off frequencies of 300 Hz 93 kHzfDPA 2F%3��,then digitiz!< t 20:s� ng r!#�( National Instruments , PCI-6014 , Austin , TX �sto�tog har!sk!�a persQ�y-�9 3)9 vari��Lσ2 = 1 . 38 dB2M8 mean�9μ 20)\TY`�n!� sinusoida��nes �a"�E{- . To.T2N,!�ez:�i Sdurews 75 ma 150 30 6 12 24 a'48 (���oreAA�A� veryɺ�yM�I3i-b5 s.#phA�f��)� pausi�va2 �H �toJ�B|Motiv���R4 e�coe�hypotheh%F&9 ���A�]1 ��to�� dema� ��change� )"us-�curvea� ��ed�modalI� -lik�F� hosey7� ribu�A�twoa�three�eAmimick!Ź[ceU�'e �alH � u�6f��b �� i� mpo�%$woy}( ��=fb1mc −3af , μq�ewA�J�0 . 2eĩ�tr>�ha� add� al! %)lI�a2rdV��μ3 �+���O.�A& !A�-6i!5; n�cM 3� together qA�A53Z�5���i�timr a��� se experi� �^>>befor� e� �us��smoIn all2Q�͹/��E�s��� ra���.+2M��V2��0!U1 AV�`A��z119U�I"���5A6��� −9A�to +6 . EachUwr"m $at least f�n!�!5We�stru� yy:sfquantif2 :al�%R , asB>4%MK5 �r)ͥua��� cou5 a 2�� � &�-�af�=us �� 8!c��n such��u infl�1 f!=�< ( ���tan� bT4��simila�H� describ� AN1%6on�$Benda%0Hennig [21] )a�minim�.A�<�exzC sepa�jAq%&sca� %X�!�re2 onlymrю of slowerY/dynamicAHeGw.nsi�A�!\E un&! =i�mea d.�qi9�—ra�SthE A:rt—�-�. A�G8mon methodologyA�%�A�-Q.�m�is repea�� ngl.nalF�y sevd%I��d!un}puA!��"�4 observ>�� their�%�0a second stepa* !�metric���fi�se data��yp�O e� -squ!�approxim�_$. Often itM1���, how� ��er"�1�)A/��&E��.@��b^hE2fidE@�v��� model.|%2 ests#�� ific of- �sE�� icul%2 establish �tra)� al s�|st!DMDI�r'we�� a Baye� analy�$[39] , [40to ac���Y%@e�xtri` �ima�-�!iacc e�to6Rco5:limZMmCZ|�2i���e�PI�!n full��babil`.�]:�lsW��e��BTevalue���.p �!dS�Hechniques have beenA�lrsuc��e�b5�ofAB�llu�^,membrane pot�  r_ s [41]1utual���%/(I[Y;X] betw�i sens�  XI�he�T.RY specHsaJ m�Fin]m nveyedra�Mge �$�possi� l! In&�, uM0mF� nume� , ta< in]��2�discretA�PoissoCs� >��2firstA� RjointfA( 12 ) � eA}u�a��x@�Galc�)�$rIw!�5/.ri��Equ)�>� �aP ( y|x� l�>0 give�gaF9w� mUi (f1� �!�s� ����XW-g�%�bin�size w 01� A!SŔsol! � 8results did not�AGpbin L��[.�� is associ��M�c 6��w� fv�-2._[42�[43]:!�3 ) wh�D H[X]!}� Σx%�x ) log2 ife entropl�6� X��zA���6�8t��ar!9� y`5�H[X|Y �yN�|���uZcan b�rpaXd���q��E[of uncerGty �+:�g�/1 -� �5k us xAi�weighaP�2V���A�B�w��EJ��;`�/i�seE4 )<"P J.I>�a -(Ur� [xxEw we e�q�Qsum� �14�x1�Rx2 . We�� stud�h!2effecte�prolong!�ud.�e�^�X of 6*-A,T . oceanicu) 7N#w� > uld opy �)ʍ'�/!56� �� "�assG%Q� } ls� q v� %{�WH ipar�  � �>Wunx ei%�=�� well����>9"]9!>ws�!�tr I��x%�"� �(iJ=c2�:�e`a� �c� ( in~aneous!Za0l��i� lead�a decre�-lBmto �|"� ( drawn�X!hi�) �� rmed�o=%Hq��22� )�akz�yedU�255 &, �)gusEYdigu2%5 ��Si�f%�no%� tu er� "F.Gn�c��y ��a� �>a$rem��!@sigmoid&�fun�s ( cfI&w )���&'y� [�o:�2�M}6�� A50 i C ( see M�� y% �)�ome-�B �U? satu� t y�\��E� '�('A�� !�w�ed�'Hca�!�. -��2�A� ea%% f�#�a broad��or6\A5P��or mo���B� mm4! strong en�!!�riv��7(its maximum�qinI�59�� Alth Dh��w8�a:!igXRW-|5�a�O1�� yste�c͈!]�=�հE g.��CAgw�sum��*!2&�A�same � e%�i�Q,�!F!Q!Mm�exclu��e�B�bec�e��:C���Y�a�poQ6means )5Dprovid!D good)%ef(��o lan 95%1og-�G; R2<95e� B��a o} remai�20-7 re�a1 6�of���4)-�Jn�8��onj�� �10Al � !�)$F< plothit2E>�,ch=�֮. A��i-��]ly��Q�( f#d symbol!�qA�>�%50%�u��* (]O��)a�� �75�&� �q�f�op�� shif�!~:�to�.�2�hili(s�$�i:E� Tly sl9l� In fac�# z� D�tyU��io�� depieuin]K 2 , revea��a�� i�R!Xb�� �#�1O�12\a"�y�důy5�o%��" to 3�2�tQ�d=�4�#atg�c`� 9L��!�`5�r":y )�|)�S50�4%&� ��n16� −�)10Be�s�� .a�e=M�B�!�6�is%84�#1y�e�B���5�by%�8�" )�N �W�AU� ab=�� ��)?2�15%�1rom-?�%?�F� �Y�)5�"� F xa8 ���Y9�5�CJ�th 5��$ ���2Kalbei�ss��no� dQTin:� of +a#0%��� mpanEC(2Z"] �� �I��OY�ma� by 2a|5%� I��cricket*"���< ���Y' d��nz&ea���ng.0short ( belowJ,@::)K@� ( ca�%�;�R-�"5+: [19�to ^> D10 �B5ex��>'p�fi&�=�A !�ɸg�AqrKa�-�"&,))H�MFPB"�%6�T�*��AJ�,� orig�/��� is s�( network�o�knowni�re�$K�&�Ye�!J1� �s)��*I4r�0 � loc�ellR ON0 [1120!�a� &�99EF=>[A5exhiba�ong-last�$,hyperpolariz%s)�BQ�e1���xV lyY#)may rG . � �:�!%�-g�-or)�� ��kprima�a(09iysZ1!�V o�inq��%to�.q:�y< �+ relevq!Ar� on��object)�-/F>g헡�k `%V%��2"�br/ms�Jonk!, J� rkE�toA�q p/lready�x= ynaph+ob�S��,n&E"Y'u�E�verte\- �s [36].|`(r h�'i�[6}��X�(seems ideal%G�!~,�!���scheme!urA3�6PH"� w�n� enh�[.�trans ,��on�� W!�u�!�� unus�i� ��4�""� up�ss� �{ead�im9ngA.~6��a�G |�=~ ae� �Aw"v �R^#a&��.�'im!aIfe' N"�iat�yie�1"� 2y ��B�wh� a�0s u�"�VZP! precL-R !de�d�E��%asN(!� [47]E��pitfa��of"V-x�Y� vZ56sF�m‘�) words’�Z 5frameŽa�abe��� tom�e"�(�)a�"� . On~/mM*�71�A���di�1��1k7B� �� griE�p����!fea� �F%�sɏfew.�.}� +r��x8,�&�$� �]�W!/b�edM�MarkovaimK ��#e�uhow.�: A��N�ev�^s�&31^$e��O��� �v"� n��8"4u�%��at"� ��("�c#.mS�"r�+��� �In �R2ou�indX5��]v-s�5 �A&oOA�e�%� reli��en6�who�-1 �� s� �1� Mo�,� �tW,�)e�co!��� Axw9��(�y � �� �6B o&� 1:0T��i����ras9&�0%!�fly vi�;�c�9(, [23]; mid,,of guinea piy$5];�er� coll� �*f cat�$ 8]; songb� " �, R[! rat barre�(rtex [7] EX" 55��mRg.�!;!oA&�&�n%e�)Z"A�munAfa{A�neU�H�S} #� ��rv!�o t1�h��i%�,� fais expla��KM�B s sre ac�%*u E&�% take�<P��m?n miss�in deed��Y �5A+y�RingacheMalY [49]��a�*Ex�; Mdc)�$of macaque. % p��)�dY:�T�e$.Z2��)a�u�H��!�uq.� ackg�=�4�UŸ1�:>�]�DET2�:K}�A>�"n 1�(��-��� �6�'(� A]!W‘��S>Z �[s�'a�si��/ormx6W-M|.xoɿ�%��� %�"�2uor�s7am(e��1�!din� �]��_&� � 5� N�?!inf�displa�/�@p{:r�6�)�X!�<3� 9 Žo2�.9uM6ib�e7͕!�aB�n� !m�-�t[5m+�T*.Dm&,%�!�a`� )M�&��.1�a �%G � aaB :I�� embedɒ [34!dI,se9$?�6F� bush�=QNngV2gla��/�== chor�6 [33]%[ sugg�/to �<*N}�>�Bp�is%clear��a�KAM��theoreE-&� .b$,l��!�.�"9cc�+ly make pr�#%���a;g� B�f4�au& )2,c�+UBsh.$"���l��*2E��� igh-��I-I��2x$"�F�4�e�C�Nout���� �sX.��`:!`"�B�)S"2� * �8,�Eore��B(=�.Tif��Ii�2�Surpri�]� .f m�)�R���,]����!�Q{��e�O�e&��t����(��at�Keq6.� gard. of w�2�� `  �!W*cE�b�h%��!?Z�%9~1!JDq|low.{l �^$l� @!!_�&���wards1N(Ale�" . As�*�4q6,��$�� �:��a�F$.("�C&�̈́F�,"�+k}2�y$ <�� �1X� r 18!�"J (,n$: 42%�,tandard deviE� : 31� a!� q2��7F�B!�A�_ecolog�'set%���� �1O!u>e9 � .#�>Mir 2ce�6*,N`��� $ow1eam��t�=a� willA�Q+ �&�a Z is mi 'E�&�2�Jrc}8B�a�‘�� %zE��.�a "\�Xm d�&� �� 25ol�0A�F��H!_� 2� R6�A7-}74algorithm behi!y�R\7,goaEB%}B6� A�e�1l�irU, t%��pr&5. E!H�Pi �1 ��' �'"y �}/.�v�!:��2s�wi3%&� r"}Gof� u7L�A�2{bsA�P!A�u�o89a% /��[51� usM=��� �a.�� �&�+n-� m˅f<�D.��㍊ng1 �2�C sur�)� �r���1� aA�� novelty*��.�;j� �9a!2xɚ�� wl � e" path�-lways w�re?K briefh �iqA@.��`lm "�.�� !'F  loud-�iP� we"5� Z��" 2�%�� 'q�� �n�9e�rth��@4�3�>2�2Y 2�:$sNLAU�9� 4 . �% to 7 �ll*�> b!�!�afUin 6 of�d,eTksA�sA eig;�'pop�>y�~(`(�+CHM� comb�L>?y �,− $ 015 k�.. 243)Q�  [>� �be��M���i��v +y���&P-. U�0�,5*N� x341��� tll�mon�3g"wl�%y����-��j� ( up! ��5�O! $�.'=�6%�3� a bu%9A��Qa�!�ra- 2�ADa�i�!�of bataol� 6���h .�A8�prc0. NTthe� ,F,& !� �Dmi��JEs�/yB) builtir�� 2�@�Re�� ��t someY !/�Ihr��"C�MO morph� X% t r�Pe�!C?�@[18�GE��)> c9'�4e����!��Ecourse�Fora� iPk%b"�K=I!A��m�KBe��8�H i . �1�&r��A�A�u� !e physi"( > ��f`ng{" � �D "� !�a� de�R�1| !�reg� Q�E��E����h� "��*� ^on%!�Y�%��e�L. G|"�&, a�l� &�"achie-L�ed�Oű!�by� �&�me is���~F���P�l��[52AYD>LM; ��:�4tK"�!Qr%{Q�4 ��)Ɓdbe"o orR�� v!kYflexil.Mo bcircui?(I.���,%�;.IH�' I��:A�a�stjU,1A! �&�of&l� st  a�8"16f2X. P7?� �_ %;4"za�i# ed v�@,� !�>{DA�� —iEQ���E�!LFR�� 2Y n!6�<W clus 1ansayT��W��-iO&+.b�w��) 6ye�-pI �pro��Z3�"gigER��� c� %Ae��e~8. IU""'y\9fy%�he m��#in1�g � Y requ�(X -�>��Ma. M#n=ȑ��-d� S �;# u� �a \A�^;P A�� 15� ��(�� l�:D,]G2�86Wou*�R��#!aor ins~�;Ebisar A���#t!��%�.�%�aE�+Gn6Cun�h ��<�8�!�Etif4,�m�Tl/Qpr�"�S� ( Δ!��L%�}8:�on"�!wild-tgV%�� ΔC-)� 0 Eoo���i&o5�r �ll�B�mue�2QtoB�. RemW*yQP���zB[ �m55��&3Ls�?Fb& b&; �]�'"dNto= \,�Lpi�Baeto@d-�9� of n&l mouse�homogenD5���-u�}4��C�"2�-a"�  ,��a�` xpan�5{%Rz ly efficX �� y�F�erm�&,F .=9�*di���pl�d~G�E�ш-6b0 .0i see �-e�=�%C2�!h�-s s�� ��of ��[ �9X�a#g�% ereo�L2|\�j ́�/)W1��1�>�6b� ��fo�t�<.�. P�K �)��aceaF�R�cG:fa_)��ode�A9�X�i� %t@Creutzfeldt-Jakob'�5JD�5bov��� gi��� ephalo��y ( BSE+a�chronic�3Š xQWQ"D���$)F �ase� �] H$tergent-in�VJ$β-sheet-r��s -��o�!� [1�0� y� n es�F�L��� s��on�e%�a%� � ��UyI�� i4��V@J�,!Qoa�xh]( PrnpE# [3�45�.Cell-flVin vitro2�s� h�Lem!G�G/ � o�&o .2E)��2R�'. B�!+%�in�3, VMӥ���� �[�M��rapid�?os� t�<�GgolpP�ino�aWbioassa�x�p"r�#�V5E�M��J�[9AA"vB-�'A��� robu�\,j�z%��p&*G*� �"��.+!, [10~&_0{un44iF�� ���'B�iAld�DJ���&� �.���pDNc2��"< % r.Rstitu)�u]I�.=�/purp e?�A�;lu � *�co�;�a�kse Iu�� appea>5�OI J1�O1�P ;� �ea�autoc��rQ,� ���e�U(.�" new%*B [136a"+%�� _!=K"�B% . S,)Zmotif-g�b�-ntibo� o| -�0pepti�Z:� ��V-E{�zB�U! [1��1��"�#&�<� %&� ���� % N-t�XLal ( N-PBD , 23–28�.A�� ( C $100–109 N� %7f � d��eg�}}� �W�:���C �u*7���A9�dir�Aat ��; impelf��Ur| ultuh� �H��vo8�-�(��by bla!vSc-!�!�#- %�)_9�.�KANvol�hte ��7li��&� qA�]���:A�!�af�#+�Q�_X,� >M�8. Mice�:6���* s"� aminUidsI.88:iFa��susDf�[2�, � [#�D) L I�!�i!. T�ge< m�%& dele ��� e-�  leth�^!+h" illnAhu!)�hen� o e�H�(&���K! IWB�i�2i�2�X��i�Qm0� �� 2EVQ��s��� N2aM�co-=�&�E!�O[2eK!�bio�7�#)��2,*� i-�r&� %�bb&B��.A+�U:�A�"��6A�g.�A‘�F]�.�Sc�Pun��Moreover��)�Uev��cyJi�to� &�%���%3Fu*"6bYC:6re, vers��P – "�Ollp��>7! �-�epitop�=�PE�=!aa$!��A�re��  Sc H�I*�a�� t&�W,�enginem�Q™LFR�<spveF�!G Qze&� ��� 3 � d s8�O1^%=Fx>�� 9' �A���. PBD-f���e,aA �1op�E�<dise.}onship"2a1�{)��)"� �9w5$ ��.C vo . S�("V4m�PrP-A��230� a O�,) �fSe�&m�*a\d� .� starlXdok.ZM��2=a�K.v41�419�(human c-myc�CBI aKZ� VL BugB l!uLy�qsM�PHa��m�*n�!"�7��$mi ` ,��b� EprfbI���f�ifu(#WDin 8 mL 8 M guanidr $hydrochlor�d04�3mgremov ��.�=�aR��*aN4hJ46 g Ni-NTA His� Superf�$res9� pre-"Qoin�J�?�bbu�t!{A�8M sodium phosphD � M Tr(p6 M G�(β-mercapto3 noY<pH �4�<.�3��a��a�m�rA+X olumle��:0reP)Ya Xsar 12 h125!�g ?A�of.�tgv>���6t60s washa�1 mL/iip/:o�# �el��nickel� ink!"b�JR�pM imidazH!�0 N� pH 6�(;�\�_alyI�toe�J�4 ( 3×2 L�N5�i�GwA�Z',a�4 L�,� �$If&a') ecip�@ɾf.Ks�Tm�[ !se�& -9el�[!WloaA! on 2!�B (�L�(n,.�() CM sephar�&( SigmfeS2#Loue)Mat��A�M ,�b���nL NaCl+]2�M+dAadE���6?M ?,>i!jFv=J'A�>�H OD28�M 037 mg/mL�") [28]��VW��d2:1�2�%�!�U R�&$�]oa�at\*70°C} con�#� !�*&Vk$bicinchoni�aci�kB�. RML sc�e-� edF"( 5% BHa�tris-��a�I�mr�&r���Rprodu�P��re 1016-a� di1�$�Jal*R ��))lvo�?7 15dK .��v�%at 70% p~i ( Mi'x 4000I2M$u�w HorbQ#cA�NewZCT��%{��eM5*H��s�a�A��5ctJ� ��)��c. 4 µLF�d , 1��$ -incuba�wjc�M µg&� E . c� reca � � �or"E>� �6 250xђI A!�OA �]e� , 1%�ton X-�8 f-2��pH.r 1ɓ at 4A��10 �� p . �% end-R -en�- oX Con I�16�aie�Dynab�\P�M A ( *C ) aE���T2×�=!���B�( PBSE�B�O Magn�; Pa# S� a�K ( PureBio�O{ iddlesex � ��J��g 9E10 %� bod(Santa Cruz ^n�z, �ib�2� ,oom tem!���Nd����4�Sc�)Q�!{"� �!�-��lex:�`r!�u��Q3. :�y-EA%Ua�^l 9�)ms naM"�spi/�"B7r41 4YA6��Q 05% eS< �.l!{bo�Fi�.�4�^ 69�p� by� sito�ly)�,ImageGauge Vs122�;ujifilmi�C�+h�s&��!vB�!Ym�H2Δ�;�BD"�Δ� 5 �& )! �!}".FS cDNA5/FRT�sm)��%!u� tonF7 CHO��!񩌡��H�*"[2sFor h�%.�,X"log�:% �!&�,�1�1�or ΔΔ�R"�%��Ɂarr!��)2�,by Geoghegan&� � BrieqG,!�svt (=�o6((>��4miኅ2 0/- Zu!)F�( 2e %O/P2�� Ninety� roliw=�N+e�-�"%��1ɩf�%'%I+ p� ��a�1%mr )0�'inE ��,) �d�%�F���ept& .i'r���8 � y��P G (�E ,@ �"� <1Ta> �Q4��+2Jf-n�!aa2i!^ ġ��16� ��V@>.)g1„QZb>�%�uM %!��#�[�n ��at 37W�d24�8E�20B - h  >85E 4y]S >N�-*"�!as�%su�Fpo �( �����g�(LR:�~di�D�( PK�To.h4��)���I86�or Sc237Q�yE��( Ha &� q52ahg synth��& ( �*RNd f� �yI�v� c] by i�Joblot�>} l�!�"�B>F��.= Castilla�,3�"9��% CD-1m�bc(\ c�SnWg 2FA�V�*�)ֵ�inE� r2 5�EDTA , R\ C�Ote� i9�inh�VtCHMpE�)J�� ofMc16A���`A�rc� I,�Uis!ofA�seO 9"4 jpul�/:!�qbuw.�+of�p�*�!/:�f�6-y=Ya�H& �. M��S(2UY:%02" A�eXinaZK (-�,^%ianapol�IN� V e���756� sh>n�*acrylam�gelR���r�PAG�(1�1aNvinylBe flu?( PVDF"? WE���<��A a��horsesh�5 oxid�( conjW� nti-��hw4IgGu E Healthc�, Pis�Y=� � �.�"���Ml| � 6� LAS-3�F�doc�����(�A� iUA��%\��2=A���E"oTQ��pH5wi(/!��p 6D11.��$y . B*�ez�T>� <$Ims �+ 8 e Ze��v�i�\��`�by 8(�Unot�"nEu:� �F.Wuti)�ET_mAb 27/3�z)X�� ed)X� 9o C-.��)by��Hs 1B , Sq!�"{}14��%�l��∶10����+1 /BS��� N-Ec� �2/ 2��P.�F2�I�|. ��h U.�*�e�,�*N*um��� �0−151�"9�7quival�_�#t�%�2igib� )� �eC;3�S"m�O�nreb1��female�8G$a'6 weekL Char�R�! Labo�$ , Wilming2&g��8wo!.p9B S2a�=�P"<5Gbi�+���4!)u*� 10��3< 3)�aJ]�6,"�!��$KY,�!!�w$9�a���Nl1�)an* ��?2 ailyE�cl��;igJ$&�%al dys@[Iu�,one-y �?%�!io�A |�;��"�(�E�sac +� � t�2b* �2�I^(a�:�}��!�* Ha�*0&]0o�4 by h�k(oxylin & eo hist�y�!WH. Random asymptomatc5 �>�qIa7%+^�@wJ[J��^�Lo2}�=�C6�~tj! orda�5�|@k 4 pr^ � cx�C�`Gup!7C���UseA�u{y5��1���ڐnwfD Dartmouth College- ;I@6u Comm!e�,r�� �iQ(�ur�X"A3259-0zP�&"1(M`y�u�BisoflBe anes(i���%effor�maH4og mPQs�A�. 6�, fragK;% ��� ti�*@'(�#F�+"�!�h N�+E�op}m"x�T3%apZM" +o �,-�$)�'e$ScUu��S1�Sh a#I*�=Sa�)P!*c�:@/5�)�A��0*E1"�  S2~e�Ex� w�0mp-OV��F2o9A�!�t�!�Ix��s�\f7@&� `b_.� ��100%Y_��n�!�j� � )����;n�� �nBo��x* e�-.�4 �\�BW20PT  1 P=��lso ae,d6d�m��sl�6aF�=�h��T�Rn9 1|f���r�/e)A1�E>c@%�&& �4CJMa��).�*,A�فF ��� �46�CY���eę�c eI�a  K1'1f-type�U5inp DNA�7�r�8}%9�3�Sj��e�-a�v�'�4~A,�a[per�e�`ia��us�traffi�?����&�5[ ree-�Z}%Q[bC,$Sc5�ed$i|<M2��a�R1*��D�:&c5��Ir9�5l1B�S5~2�Eǁ��.�==_ng� i�RC )AeQF2���&�=6���h����-2.`to�ril�@e*=W�����%IᵅP1GE���er�t[� e�\2�ILt:��T�m_�5���Wu"���3�ށ#"� k�kbey���KR/un�s:�Xne;!�!�^Poducibly�duo >],�b]2�Wv�es m6�&m�1�. F?9%�&�Y�Q �O:TEndj it�K9A6!SjC�ng�b/�w$ ?{!Yde&AjA&�2bMa7dd:e�aE2NAwext�2�@����gt"����){,pa%U�R�穁Az 2qH���e2Z�N{a:�Rr�1���"G2qSv�� as uF�q�N.��S�/6(un��Z .!7ofR� 2eP�a D3In��0�5�� y2�iniQ��. t3!"` � �  &-}��to"�G!�5�J >VUDSc6�L m6�o�&� ��^+p da�%� *35%.*uU2� m�n.� �wNE�" 302M2�:a:^ &�Hd"O��M���=U�SIO9ebA�%�"�C5I�6(�}�N E�BD��eX 9�!�W�nxt �w:� .!��DYWF���[1�PQ(behavWh.dc�.A�iA�%vC�mH��" 7A�����WJ ##��oaT��2<�_�a�iI��/b� �5��ntpto g a�>K6�=.dV�� �Δ�5)�vO�v�n� �&(*1 ve�*gV�ca�%Ha�u7 kDa�ar ͉�^�#3NC:�4e� pend"-�4ory&� �m1�aH[1� 3, [31]�\{ �he�F�M�>B�tI*h���V�� �^pa�el mM o�$A��pl�@"n�#�2q.�� �����)� �&���aI$57��ai�6C �B� ���j� poin �o�9factor-NGenEDX!�m��~ &��Z=�"- of5�-neq3v�<PF��euZ!G.� d�ab�"�%-;%\D)?�!mix�BHk�l��� a?��E���g�@Y��"�& U�|Th� "�B[3�yHgt́ex����. �.,\&�b"�!WiagnoE�iO!�.X�DW"�i�NqkL%R2{.�B�U�O. LikX*�O��);>qj��L"�MU���-6�$"�y�w? A�*o =aw\nM0@ys&�Ba�Kr�[�i�J��Y�YTŊ���dpredomiG8%��sy=�$e�d-6H Ce Yr!+��Nk~ e rHW5u&me��!?It*�?h 8�Dy ��R * )�.asm�preKb�&*��&t� vYin�n���_[Jl'g stud��+�t�+ �� un�1J�iY@�M2-�� ��Cbkd�y ���%|I0� �\&edZa�pa��|"�� &Cb�^� �!&i �1N. ���N}d:& ]9sh��!� hall�O��!6%%�K�+Yj {Y���ji2~> k,� )�:V�)�(�8�]�A��B���et�#d"u?�yB�,� �D!ehCH. , ,��=!�b. &\/ �.T944?e"&��9t ��J->��d*�26� cm���B TX�j�1n�vP8,�N) �NMtb~-��a#P"n*p�td�0ar)A!}�1;.�]C9.y [c( 2�}F� �accum�`V�[�N!�.�.UO3e@^��&i�,u[�r"{�"Au��q}&a:�w.�*�.>A��.^��a�42C1��"�*&LJ�Ion�&�q�*. E3r�2^�'SWM� D�N d&7TBmjEoo$�ScEy#�7!���A}�c��KM"XGA�t2`receiv �s�8!4mH�!>6�<^�/#gre�:�t BMC9�)�-,mI�B�"!!�0VC vacu���_Qgs 557!S&�B�A�y�=&N �>��d6�9�McabundD. S��a� �[��iFEGct��J�en����x�8A��J= A�S8~ ,i� %�Ew�E��Y� B�9�!N&��A]��I�f�4.�$�!Jrg��39axi���>2U'^bE���)/A5 U>Aa 564-dax�>��S{!n<M o� s!�]�Q�A�tno�1k�. D&!sudden P@��c death�a�� t ob�� tiss�z.mRK�)sI&s��$� non-�6 ]�2 Ued����~�Za��2�7)�B���gf6u$"�&- � ABA�Vo�Fz�g� 5y&n&:��%�%1�2�)�TQ �x&� J+2�recapit�R).ve>%jY��>Y �i�C�e;�pla� ���!22��"�$(���$�R9�� ��#� � � �rF$@�"!�*iFN$� &NM�aWA�j��! \Ei�p]A�JE��6����ebw?/�$E�PI-PLC �_|(]a2�$�ap�*]�%m%&� Fw�� d ?a1*h#.�"�$&�` .>�� e'Ga�n�V ,Y�p1֚f�^2� �K�6�VK*�  l��a�% {I��OT�ind�!��INnng]9i�t�\I�� qg�&2�E�8� �T��Oh�9V�#e�'[/�gol��}e[BP>jr"�!�ndogenB�C]�!p{�� ��fa�ks weaker-!�!�m�A�&h�e�� ����Qa�!,-O C?a�;esC_��E�.��it�fE�nZi1 icip�&2[I�>s. �i�&w�Fl M:e�"��Ro|���J .�#�$)�!>vA����5w �� �oHW��` n>�iA��2V�4"�4|8b���&q��5Morm� A��t�Bsshif2�&Zof&wA"H{�6Q�:inuAg � lS8�)&Y'!�H�i�F .d�bsee��to*,s /EM&�! k~<��mv�(ʼn�s!8�fo&�o�!AT�14!� W"�AQ��5m" "��rol]�� �"1"I�6<��MtSc=ar�.dR�W��T��2�]~ }P�Rq��Y��Vr7_� �!�a�� ��P n-ZsI��r�[Tk "��e|a��AF �1 “6U ” sourc�^�U[38�X!�4–5 �6�1�r��&?aPcp ��Q at v+�� 2�>J��O�aZ�!f-9�9]"���$�#@ C]-��_�rf!F�[&!T��O f#a��v�aL&+)��e�V�3�Uc~\U Z��Z��A^gd~  M,�l�lbBZm"�dOh�[a�<>m�� �� �� .":� Y�� %�����F ��'�^�=><ps [�%1hJV!qj  ���7 a*�9!�� EC� out�I. A��pl!�� �H��.�-�1��perhapsZ!8_}�X,({ne�^�4laGa �6d�to�S���ߥ,�,�mf-rep��ng�+g69�sR.'XY� Bgluta< /asparauW��eq���a �gp Ai)vAhM'i)y��b>��9sexpos�/�c neoe�9�#G M"y6��I^rUi�).� a*�e��J> $ e pu>;v�#��J��b>e7�rs�>�+�9Sn�=r���q�ay STk�(&V[1��&�(pa�>��&A� ing-k3 h�eW e����_=ڡa�4�)�Hfijm�,]hZeU���"t2�%9CI N, =E���H�_�c�cF@}fAIu72 �+ ,a N�>�> j�VA��N�)� ����v!W$ e�<�wv�i2��aB� �y��a�� c$=Our2��7��&�.�i?sz`essd� .�]U2 &�z.��!S�e.#Nw� ���>#�6���2�*A� .2fd�� �T��R��hE�!3[�fF,mJ%�b�kY�iJ*� &� %�>Q dem�+n�% ost-&r Y&G a �� h2�$q��aEN�eJY�A,�_ �>= ,l�I%uY�A�� <on�.��-�n�es6$&p�byf$eeOund$%fu;�j ` ��� � �gavf*��"�N W ��*2 Q<l��%�in ��[����#43: .=)W 2#}:�r�)-!�a.�&r*U'��!o[� .K'� b4��I��e-1,ionMWes"5 �6�2�n@"dB�2��%Ta�9%  8k�B��8�U�L 180±11 d���I*a��.* !�5˙�2�=x)<�! abov������kN�AMed� Z��v�^( ≤ZC LD50m_tsREO∼��6�X��l�= � �+ rn�:�&q. z��um-�lP HKc2igca�an V�!�^�Z1he#.�_�6A�[� �much lar�,*� �d�A. 9i��&f�;#{s&#cw1�>K� .t2�7f�!rA-pl�e��4��ed ��v�% 27-3�N�`iʉla%���t.�ro�1 7 >�f[4xX�G>�% .Py�� ���a�n�2�Z� ir *�Z�l��r* 1)��3� �&��� �&% av6�,Zno�� &�D�g3iB��8_e ledg!� ,!��"fi6��lɫ[+tA1tl:�M%��(>nok(6��/Bnk�2|0[�#qro�.����r�-gf{��U���hVPghtr�7*�T.�>ͥ�/��S��?FK�j�6��O5>8mSY�� y'U s�iR��RHng|q"�s�� gga����[@�,:�jby b>����ltiM-�md�a�aI$hi��pla`y{�)cX��YnA .r�em�p&H)t�>t �A!�5 S o3 plau/��� �}�ta:R�R.� �)9�2�e�ImSPm.��pi� �%�rPm2"C�%�v6):>!�(!��rE� ��.�})Is08 =.&�sa�_�!d!%b2 m�@od"�Es<�g��FTJ [3o���mphas$fa��2�9��Zu��x�y!� unco11!~�iB�yO�QB�E.4"�!Bigl�����S&� �P�� "Rd@C%�� %�s"R���a5B,�mB'A�6 �M��D <%�vo� :c S)C��Ar6� �i�!>+6)� B-��E�'digB8ӿ%��:�f!n (Nqalb�i�%T2�.�*!�a+��� desi�Kst�e;&�"(��/ol����io~�. IS4�r���,a� tegy �A#E� b��i��u�~E��&��d��ion-m;R!�;undamenW{!;�li*X0�rPd��y nerv�SsEi.G m���D9�s� F�9c� g " �*]�Gi�Ŋd&KH!�c a��cx6-sn� ( IR�Q&����);(�v’ac�9�LR!���m-se\NS�^pp��]2kC*�leg����moF"�G m;j&Wjҡ"at7 ��em\���*�Hf��, fA o�J2!(�m� av9�Ak.n.`�m!J�&�g.  !Ia��6S�e�~"*:.hE�geA�al�i���M-) invozu�O)� ies:�r&ig �MDM�s�y. I �/th,,-#��a�I�K�er���) n& �R�P1n%" rIMr�j�"�R��&����trU�all-"� ��/ orga�. �ڭ;.�2Aa �;�'L^�pcs"FX `z%!"��%{,8����,���[��i@ survx7%!oBa�� �7 )|� B����K#m�Fe�| E���\verQ�� �t!����^�B� fo�g�J\=�)� � �� 0.|�Voi��oda"F{]E��h,i��2,�CE�AEi�b%)�K���~�eI�', ��l��ev!�'![ view A\QA=M���rekRm�.�EbP��W�.o|�" 51'!�6m��Lde�p)�!sZ ��'zme�f%21�\���{�a��;>�� -.��b&o�_ ��"VE�5�M�c�����Ac�/�"ã!u)�� ��RHNn5de��ic/a]v� a�Mv�ݥeUVmD� (aJ�!� �$E�A�XF�6�%� s��im"M 4X ��l΂B-ew%! IT&g BR �A�|�r. �-  .�Q mR���96c 5$7Бl�_!�ir��="ߛ47t��vi���QAUerror �( b�� rrow�hFig)OA��y���($��&uop 7��mK zDdi�5 v5A�. �"� i�rɅ"B in!)��Fx�# regu�?*la�).>[ Y. E�4�DAmF��e�� Caenorhab�*s�^N (2\ Q1*+;��v �v? i?�pl$Z!�Qy#sqiniP^ECRL!��(`306�are�Aa�� ^ ��r)�i1� J� 9� E��(�>a�o� m=�ne&� y ��s�}i m��le:�RLfxE�sڐ � Ͳ!�e�= .�e�[8 , �hb.;�&�W �pp��ice5{]&F2ese @� onBemploN,radio�`�*Dhelicop�v�5� �1!��]0)�Ew�n_t61[�/.�w �">� a�z He manipq+!j��$���%!�,H nom}E h[$�gAe� b�,for�)!�,�'��=��[:j� as��.�prompA���?N .]6b�y!�Hi8:�.[RC�+�$( [�IF|Q��6as2f�]%es�!9<Goa>q&lli�i��Eat��6�1 bk! I|� I��e�}skZZFg�'�"Y"6� t� !�ITAr. "@�u�Ac_M.$ :U2���El�*� �( �Hre�u�.� �?far�. ]a6[�!�y�kreZrwe���!x� n2�ϊ{$_a5`��Ń!/y9Z]}"+en� ��trrp�`��qm�n6�:A� �a*6!��13Ey� !$B+tiŀ.% !���L�eq [I{H�%i��*ٱy��D����V@ S  2�>���2Kt��v��"1�#"q�1�!�@aw ��s�aR*: prof�,�ah� �s lo�e�obL �#t<9��o�mԮ;�ci4a�vCa") ir fܑ��u� �!)e�&L0"x]]��. *��l�<a&�>5ir@��!��V/��ey���5�A& A��ly"F�nFJstocha> uL,.h�y� }w0ai�&i��홠* �-� ǽ~u�� t!I�K*F�F &�ap0��*�o&e ��-oy�: �e�& ��e>"� _ e benej�of)\!� !nam!U�qI�fu��@����U�o3 F M�e�&Ab>B�.f�e ~��W�ng26%C��q!$6 �Sd�:;A�"�-A� . F�J��'�g�_o&P��H " r"�e"l ,R ni��� � d��*s;j����n��hpN�. S26�A5�� F!!e��'5��^���-���!i.IEO"��p !�AV�Rrm>impai/�yE4*�<?so-�_ed�4AFD�4� ��if*O�4DMh(A,sNo fa�"kyѡ[D� �fe�F/B� �jQ�!�%��] ��%���i���reb YvZ� g cl��`6 �c �� 0� ��>! Kc&qgBQ��"� uQ!�%�+8lv�Vd|�ssump)�� ��!��^�balw#�8�Ps: ���*֤�!���BD��-�A�7Q;26�6(�A�inertiaO!�pur�-�'��dyme�3Bx6 5 �a �m՗���ɣ�%o4����a>vtur�' l �a�da�"pCER�J �!ua�aT� �G{U�iR'�Nona�V�I�!�I� Q)� E�� aN�/�+=�� )c|�� �~b�&��!�=YR�cNJB!�=��6׉L� ti,%(18x,�F�Y�y@Or� ��΁\"a%�p2-�%*MaA�d� � � ( LMD��[2���)"�އtt's�e��'�atF� ut�/!�C ��� ��z9=5 1m].:h�!w%�.�=���n�.iE=��"\T�!B��� i�#! : πB�t+1|scy∝"Zexp{v # ) }}N S�;yw .� r�@im����; M )��vͥ"cAUi�VZjʽ&1 u�ZJ�, "�^("RU�uo-�, KL[� ⋅|.||p\. � g �i��� ;�6*"$ ) :�N$f�%Fq|Bn �a^!�A:]���ŮE�1n:�N}���͖*�&W2�s. Sm�7�� :����|%@ R�� ( sVT�� …s?T;�baJ �5 �F�v�& q%ax��=2lihJ� ( MLu�s�N9-!� \3,�i)� At�jn%��^z: smo�6,<>cq?&<2"��S �m|�E� ;�,��n�,essential to�L stably estimate the behavioral strategy of animals . The different phases of=pIRL framework are depicted in" flowchart3XFig 1D . Following this%,, we applied@6b(of physicalE$act is low�%��$ density ,5"1Xrosstalk was negligible)�c�ct.1 data� prepar�ree]z%�=�s�,14–20 , 17 3 , and 2!^26)5centeSat 17 , 1'3 "0respectively;A�ex�at{ firstYQDwould encourage asf up-Ux,,second movemA�arounI�6er �Iuird de PdowEIR. Indeed [fed%�s aggregI1`standardUPE�,emperature (M\)A�aly4UBEW1defin%e z’g(te , signifa� by sSEq ( 1 )�aka[(into accoun![at it sh%Qrepres!$! $sensory ina^qV-�A~0s process dur\E%otetX. Previous studies havek%U Hrmog(AFD neurons%�di!.� dera�ivem1E[22AW3];� efor!��ssu�to �selA�appropri!9�cv4based not onlye�=�$, but alsoits�>�.!� thus9Med-�by�wo-dima� onalA -D )5nHspace: s = ( T , dT%�wh�}T a9dTa�o�D�^�,2e� ��me��%!�$value funcE�inY?Us a"of�, i� 4 . , v ( s ) = � . No���di)m-��spati��$oordinates!m�ĭ\for-SA��9)�can!�recognizIEX./$profile or`ir cur�eosi%��plA%. Next �m� passA�dynamic�H2�P!t+1|sti�u�. P><���resul�stytra��E�a!conseque�of un�fPI�2�a%! likely ��e�%a�B sista�dir��onM�0in a sometime- uctu��mannekDi�>� <hort >�|erval��he lo�߅5�Z!� be�ide�:s linear�4C�TagEK mode�f5�99 from �stiZ!�dT!�,���to� n!� �, !� 6+1e��U��ime t + i�d maintainsnoise!n turb�R,{le 3is upd�Fs�wJJ:. Acce(gl6n�� simpr x�ׁ܅�no�distribuAZ ( please��i3i� betw �~�7roughou is paper)�o qua"� ��sA�sm�� � ��we!�ck�� trajector�60of individualE�0s over 60 min%in each��,�us��a m� -�Zc�softwas [24]QW����en�Crd��i�1p:��ria�dA$A (-point ( up!*panela� 2E )�� calc� r>^of2�by�DSavitzky-Golay fil�[25�lowerJv. S!�!9p; T-dT�8 ce w�z�� plot�( S2A�� U%ha�\ ���s!se B���JI6�e�&� � .qwe"W � :�ٓ%�mod' an exis� e� ��method!�� OptV [21]IVi� ducI\smoothn ��tra��Sndfi� E2� %a�iN eff�uv�#� u a� �� eF�wA�"� o artific�C� simMRby�} ( S15�y is� pA4ful�e a�`.�7 onB~%��I�it�`ѩal �A�he*Q . Our�such 6�R�U 3U !�visualiz - desirabil4 "�,a�re�"exp (6�)I ]� FurŻ"m )8u�erewardkʼn�� V���18 ){��eBZ primarily.� j��& preGc h�u V*� %=�A�t�!`is� a*�optimizQ�cuE�A�sum!�)sAn5 � costs� e"� oY �^ta4ly clari�^�ofEU.5n both8�.�R s An� ._MTsa.�5"e focu"� �  ly f{ Vu��f�hhe�6pea�Eat T =\��/� e91�E#a�rŲ1sta!^ose|�!.. More��"z d)a diag� Whorizont� mponen"�eX�\slat��one�-p��a!�trunc' by�@limE��nd $inhomogenea���B��TX �c�Y�ed  ed, [ ( DM� 9��enables9Jef��entE2ac �fDAt��=[a\a�^9a ��� ve�avo8 \ ere6 t higher6` ?u�dT.?. &DM�isa�, � Aobs� %$%IRe  to�*^�9eq�s how5ytH i� >Y  t&� v!�. O)?oa� hAAaeR�2�is4� P( I)�. expl� a well-kn�pacterXc��) ,�P[tr� ; $typ��t$xhibit cir r�( a!�ric!�"� [17]! ltiN we u a I ,� 6E=in�r!4�~,} algorithm:�x�a4!�J�-reN.T..���=��^6!�at-�2:A�^Z���rib��*�� !�} (�M� �A *0 "O ..x� a!^ tcom�he56�R�F�equival��a�K92�.�.�,!l�- n"� ‘run7!d,‘sharp tur �[Icor�ato� �y6�&slightangv�_a�,@ long` �Ll��|i?mit6��Ah L`larngl��{Av Q�j ly [26a%Becau��he numbef@ � s ob���*!� much ~�����5*=:a[to��yK&�A recapit� jU�0sha��A 1�.�wD((ind�  ship5��Vj!�� A�.�A�C"S2D�XWe ve*� reliq � *� ��%�lf"�f� w�. F,� exam""K^ S�Wk�ed��b�#T:�1�e;"� ��.k��ComparF =!-�ca���t�-valid Oto���-�predix1/!�m) �*��Kmcag����tA� �N� �( p = 0 . 0002; Mann-Whitney U te� ( S35�� �i� �tk ��utix �.Gof �absoluv*c!L^�!th N�. S�,A,co%h���)urE a�� .mPn�I��2�abWe*Y.�2�st� ng� 15�+�25�� ampl'! B�0�x, +}F� "���&�!�.converg�&�^b ( S4-�,�Pw ���ux�uC-X�x%N|ert��&H��%�!F � esMxDM%RI"� �M. A*null hyp� si�Q>}! s random&d"h �.���noZByXofro�-��� �!T �how%0-`R��'��beٛby�]��c�� �-�!refAotY 1�E�< ( S5M��n%����che"�R�b�e �q�protocol��n!�r2��iT�it� )���!�che*LSI"L�genetiIHab� via c� ~7� �of��p��[2M �� ASI-�c� � appe6oe$cE:u 4Aa> sugg�n�!-�B�!��ons���5�� � �/cl+�x�V�, supporE�!b*�!R��b�"To�2roqf )�� i�PQ J!#M~etwoE-�c I7lwo\ N}*?s, AWC  AFD , [16� ��8]&"�I��eh]CI˪BBAB J^�"� asE5 wild% ( WOa`$-�B!�!�E���!1�p]6s' h%�IIU�&!�g tras AFDB�demona�pcryophil�64C~�U�l� c����el!de �C��l&{ dT-dependV str�N >Tm �gyY�in!d)�P$dis5�2,Bf�#��Aw1n���  fu�� obo� � js�#sZ�ARu�#N�in.�aiQ ��Y* s��*&�)V��WR� !���onb� .�,. Taken toge�P�s-#nls.g9h� f.� Y��.�navig���)Xe�ed/^> .&��6�o�"�'p� 9 ��ICi��hA��&�� food�t6�&!2�!�yajdispera9i�!�-=� reg�!> avoix 2(�y-�Di� Rega�!��^�����e, c_ c%A�&( `"3�&�y�# !���a� �6` I4D� �A�� they��%DMB�"hstill� � \5� }(+ .\:�reh�W�NQ�Sst im� �E�E" !i�vQS!�.�<at� ueN. �*>� , un_"�9� �1vonePcap�heb�Mn2 on^H�%)0JH�%AG b�%Th�5�B%��4mOd� nguish"C�] of� �a�n&}i. �"�h��o)advanta!l �(,4isxr| LcoA* �B=,(y organism � just2` *&ea�� Z�!���2  er�&�Q)$%2�� P � suit��Panaly�a�p�onSE#t�t"��� 8S�,�� e b�of_ � ledgs��!P�(y!9Cf�,!J�,y9 ��� �L�o5�� �-�+M"pat-��%1 coraYb�trf B!�� LMDP�� "�*s%+u�|�#�by exter<| i~��clu�0�� rtia��grT"Z$as � � E4( musculoskeleA)A�Y6�):3*� e�!�a5unr�#e-*�!f�a��L!�is6j&])1\ e�. "� e%8sevahE(e�nbmu�&o hume3�s [12P.#"n��i5se�*!ni�&B���F�put}p!4A e m4(am�+� ۅ,e!U���b�!fundamee� toole�Le�%�o �,!i�! �!E�c�inM��'iUHecologyEH�< �X@/>�t� �d"�0p  backg�-WTZ�6mu��eainw*�r:�A5m�}=6A�tIYtQ ba�eU�,A�2G'QVb'I,�+cR/nca�5$ ��C�facO'EWT  a*Y. f1* l&TC&� ����i �i&> G"3 a�tud�V�"E,M�Zz�E*� _%�AWF%�(a�*,5I�R���r� ilarAm� of ELio3How�v�^�� F =V5H�#V�!7� *� E)E�B� �*U! id� ��Eѱ� po`�to deterdS�:.E2�,provides nov�(s�u0� .�#q"e����� a�>� IeJ�0[ ��y� }�i�i3sx � �a��� �)E� �ʼn;�+m!Q!h�0�� ITto=� I�q�Vo���a���x6�H �.G �a��pos".�i 6 discu�&eA4>e�of�'Y!!P[29)a"����� –5�&,V�mE%'#i��h�DM2\! (b ��7:�"By.[+5AH g 5B� R E �switch? �*8' -a!siE!�a&B#.�"Q!,m�or��Aj�!��.5�1� � so;"“bang-1�”��o37u�� tudy ed2|.@"f �^2c [30�"q!�%�!? ing�& �o omegZ r�dsal/�"� ���runHv iR3gd�68��>5-�O^�.I,C]#�P�V-x+M.d/I%hR�le�^���+%Zb ,terpre�s!�8�P'( Pq a�Iٿ� :&5�,R�!:^�R,-in��>�-*�5( Pv/�)�Ech!��&ss�!u9F�.:gA��*�j�)�," Q}iv�xi�as�8 abov�4�p >T e�%@^]by1AN^�orPD6asE���E%�5FE*e.���I%1�'los�sod6c*lJ0�R . ��IRLw "J^�+�� �+y�%15E���'Q���st� until nowBI A�" �JQ<5)� 0A(w�!�*; a&G:�DM;%�a.L(:$I-W� )& �al$Au~{ �?g e��$H �5h�; ne/arG,balan�0� ��a�+. Expl �!q<re-acquis&F6n �5o]"�-%�l x Xef4ear�S| "�g�rL�>r1p�%I7�a�t ��=oc�9d�%�^�!�-�s A!%��l��4W?"��`eP1- �օ����at availe)�b�2an�7er environm�� N �f�3ana���%- 1�dilemma�T[31];1�"� �Wdu|>S' �!�e�>�!�W,prat< � �9rup!k�&lk !iI� already-90�ՍI�dp�;I���6zY!��is "��_� "p �2o&� gene)evd !|v� �.":APM�,u DMs2a�^�!dQ;h0m8��@N� )M� E�Y>^�n��!�?>c " �_i�,. !~fee� o i]&? 6do����@instea y>�;"�8�T�&�(a /"�#�;at![em�$�A�,.,;u�ve %!��(�Ia�A^��%^a�4 ) ���G�� f+&invest[o�T' � ��89�?bE�e�-�f!(�B��9ilB� B�%F.�WC-���z do� t af�6eV �> Hdeplei�bolis��DM�\�  2A��lmany bi�0,6dT �$, K!%�A*<@A�� �8 d"e>��> !+e&�A,c�!2�:23&k<�X=��t{�lf� p� ntM�� deci%�whe{ �� l%���1�G!b � le=o�o2�d&�-!0"?!/&.,%?invol�McDM&2 �%C�,e�A�i%&�#3thN A�M�mA�a��2�in!n�UGR5IonP-�Sbey�..i. O ACl�"n deca�&�re_ �B*M��at dopargic !bv\-%ve�"l tegmb area ( VT�8�!�#��A%�+error [Asi� �/e�al��c�#T2 ��in RL [6�>�)Z�a���� �� "�)��bad�6tA�wid6 belieA3WRL- "'2�/D� &ub>- conn��c�@�isub�#�=A9c�-�baTg0ia [3�35]Famygdal�%37!/b�;!�at heavC9i�@vqby%�2����Re�3�c�0alZ,�? techn2kE erK monit8U\MEal*�+� �(A$" :V��givenٝ!{rC>��6ES2II�^;, =�t1|1%�-UNbe�)�,_026$i�. ,�B�r���i�!"q8a�ur�y:�y S 0*t1anH �fK� 1J� �us���!�"M-��r�4A�s52a8A0!�al!n�UXj�A��!YI vari�%a"�<,6�*d �ybhE~ ��pex��;١�]�ɇ^ ib�/in��:! b al�sub# TzEom*�principO9 . RL�e a ma@*� ��n�518agT:� A )�n� am=.� [4RL�z(�;��s:v�A�F� �39� �e 5�))makDAeci�,!�!�.�i�&!J�veryt�elsa� �!�inuous3)te�8sIZ>V%*A. Nh�5"X6��WI(U�,� :geA^mv� new f�J9&�!i�B/iY>��*sNt7�>&� y�2I)Imax�>es *�> o#]� erm� �!a�e2�2� ’s5.��'E�ed�an� Wn%eset�Eb��20A{!�!B lu�'B] � :�%�abs�-A ro�� �"�He.;0Z1&�HINE�=F/y"�H#bu �9 Ip�$�8, namt, �A|� sπsI� �*�Kl/$I(F S)�I�YK&=)�* �< rece'rP2ta� �'�!5+$12y nef�E�y��}�=mc'�Q�L%�ed eUas π*!�′%=�&D ) ) ∑y$y/!y, ( 35��as>k=Z���9M��N�E&cMV�� :=Ev7 :m=E[∑tY�!QU) |st=s�t( 4 ) HA[7brieflj �a �e�6�\w'ikb� %�5�;ua!a!r=du�M( 52bel�Qs u�1a vHJ uo<�5odF% Rz5B�.�N6atIߍg, 0�E� �V<Y��u�7�m�)satisfyAK�e8 | � 1 . ( 6 )��:�7� ba;wr =��!� Bell�&equ� =�maxu{1�!`+�RzE��!g}E�7 �Y.?= �E6%�!��m�� �K@bvJ]o ��$r+of Lagr^�K�Vc yields u*A�:QqZo <S} itu�Q:�P!�" s �I�In.�� ;!dB_[�<�:$1��� dropp Fmax o<or� daE�I��) = �p -�J=��@(�,=�F&"�N��JP*B!��IpQ-, u�)�a tabu�'1aY "�"�>s?U (2�av� &N&KV)W_P� mesh gri�5�IRL rsCa**BA)*D��or�H,�na%M ntir<\I*w&4ens� "�+:�Hnoisy�dsystem1 > ��61j � )�N!<�$s!s�c("� (>Hr�#r^M MLE as v^A���argmaxQ�[logLVM< �λ��ɀ∈χ =|7− Ɉ|2� 1�q%0"�/� U-��4g�m�A1Z>2a �>�O�Oa��6& po&�K�,λ*� vtrength�*�A����6TAa� 1neighbor�8%��"�9�� �iP��.�B�.�l6+,�!)@x���%����YmFX A[no �Umi-Ada~�1i  dZ9��ap�T��}aq-q"�!U%.��9 2B� �/�\w ( ph62%�3�?(1h����Z�3&%� �ba�Y���!Ry�*�<&�[22�NZs�Q�dye&��R�#,�Y^9�!�N�/d�_W��s�3�_�'ugIaas.�Z�!'ic dS�1��y��dTAh&�W"B-� ��AB)� �*4[asET( T�?�) |� =N� T+dTΔa�σdd0σ�[( 1�C��% x|μ��o=6(s a Gaussiat"�{of"� m^aC μE�Lσ: ��!� \NYof =�zHq&alP �5�=o-5oa'ESb�8os1b&�(i!�Qfi %?CM��m �)*�.�K�F6�K&�2� )�\ )3�A+��+��, �!#J�K�-RI W��i�1A�Q�=�AX��WE�nin�r��Q+cI�Bl"`,ed5oM1 Cqs;%U~13o�_] g �/pr��呅�� 2?& QremaiedAE3Q(��� dJ0 l Ya~6�b*`q�1��� �u�s^)�waFf)mm|9es�U20 %5a:-K�%! ���I���&A(m�|%Gm�.�Isu�0J�b`/*�J>�J"!r3 �1�i9�����db�J.(�� uq"� �Lf�\f erTMA�Q�B�JCV��>�. B�.a�i��&T7ad�>ed Fouri�.Z*Q[38E��9� 1000=zA���M huff6*q"`^�,K�Fiy rv�au�J a}M�origin im5$OF(, �:t�"d#af�UF �M�� +rgy& p�YTo ass�2�[!�� �R���*=u�; �fiF�sEy�#*w �d.o/��"�J0Br.��&�REmpir� �A� J6�}0c�"�BT�!�)E� mkrN6[�E2��(9=V6yaU�U#V|)�wA�a�2�e�B�� <�Q1��1*)4; J &hO�M� I�at ܚ��P n2 n�N�/d�HO phrodi�A$'jb>n OP50!�b�Ya�>od )U��kt�% iques [39�M$ f"�T�Z>t�� : N2UK,-type Bristo$i�P�PY7505 oyIs84[gcy-27p::cz::caspase-3 ( p1G , gpa-4 2� ::nz!BGF 8unc-122p::dsRed��LIK2808 njIs79[ceh-36RZr!bs(es-1p::NLS:w�g9g80�8jf� e �.�BdS e >�O)|'6)T�(a kind gift�D�h4Piali Sengupta&�Oe�FR �}eA��,Bx&�%�&� �@���&ns(ed>/!� s [4�!,Plasmids car.6 �D\.4oinTa(t 25 ng/μl�"� | mark�eKDK66 ( >[Bb50B�E�[hromoso��arrlW ytegN � !gen�Z(by gamma ir�� 2 &&;9)��-re out� edo.r #�m�si�2v�,c��Q ki�1�'M\� ns!���� � ���(�+_7 -�ed GFPk�%���#���5�n�V�D!�E�Y s: IK0673e@2[nhr-3a i� AIYpmkb K��A�11382y� 4glr-326WN�al�.��D!d�N��fluor�pce; %ȁQ80"TJBlayA� \of�9� 46a:79v:WC5Ke��uTassU�&� a E�<G[41��GMp� �i�+aBc%U�6#M�+�[���!tL14 cm ×cSI�45 h; znQ A 18 ml!T �Pmediu<USl�- 2%8tiDE�E@to�Gr+E60X)0�!sp*%�" to*ts or 2ss�9}7�2�s" *�I �c-c%E� �At&_`�.�of� roxIlyrZ45°C/cN' Worm"  a�N�k�a CMOS �4or camera-link �b�, 4�!96!�3 �72 pixels; CSC12M25BMP19-01B; Toshiba-Teli  Line-SSLen� 35 m!�Xf/2 . 8; YF3528; PENTAX"8a � � framkabW^4( PCIe-1433; N�: al I2Ium�*��} �%��G1_[ e�&� .��1�N" Sp:HP image�=$33 . 2 μma_)MS ���!�)�q5�G�;5�1F 5 Hz�]-�cap�\u�0#t�za *�mT�ber �m,A��c53 bo�I� meas+E�i�a�ro�,�zHaptophy 'ern semi!q��r��a� c�HR ".��se` aJ&T8�Hlob�- arbo�N? O8�,a�m� AT�2,harmful bloo��t"*" ir r�3 fatty aci=l�E�ero8Q�ly nutr /�6 sour�9a broad�g%�eco-co�q�]9 do! g�E ifr��Hjsg� � X)�!vmixotr�?c �Lmm�5tax�!Despinir5:��(u�XR"!cD�)�*h5ː , Emiliania huxleyi ( Isochrysidalese�<"r;.�&we��� draf~M�.xCKQ,omulina tobix rymnesie!"RcriptHf*�n5Qeo1�"Cb~4a 24-h�8light/dark cycltFof �� �!�malp% 59 M�R8 acZp ∼4�!b-Zi�2 otei�Wa�� �s>�3777>eA0GeY�to.�syn4@/Rot\Q!$cat�7mw��Qr p�iud 6wM#3� !1�ZadF phot-%ioR!09 �ha�P3" hyb�!$polyketide �(ase/non-rib� pep2S�<mplexMD� �7alg�-pec��!1V&LI-microb} c�)���v"n7� drug%Ctoxic%�u^gu%,. A%/}%0xanthorhodops#�1ls"/3�e)Wwi�lwBred%>RuBisCO�ivau: �H�c�D: i�)Nh8�.^F-�up&&Jew6b� evol�t�h]r:)2UNconomicU��?9 s . A#t*�2Ad�)AEI�t�7l��toEkm�Pen�of �� w5healt�D4A�im��of2�on6{�2i"]{CO2iJ"o7:�r��� Q�g thyl sulf��':� �Z�(Z�$ Gs [7]�> foamemucilag+�A�j[8] EL&Q��,2��IKu&�a$�/c3�/.^�H"�Ome&W��3��\9?�1g�=a�2!tru=?U 2q6 B �S�e1e Datag;I,�& � ute�C30A����i:a�a3 stoc0V�lde�ocd%��[1'!���LA��$HU"� 2� � w�  lQ6[1eZA�fH��s��J��� .� *�?:�m�Z���� fVhss!a hta6x;lps Po�pr1T2ev� �?wi�6� 6;[1�7 Two 8<l�B�s�.]15]—A$PavlovB cidae�(iSlclade= ) .+��m7! ng 5 3('.�� ���(E��R Rch|*2@ a7e2pubaAdAtG|�@���d alga��M9r� ш��.AzBcaleL-c� QpAvMs�l� E5Avi�P+�+[18�G:�)� E . � pan-)+R&r"� %�Va� �ina��"A�=4ݭu<��Ois^�( B� : B2)��M.e�V�0�5p&d?��%��n1i�t�Om�W%�%i� i�ec��F2#I| s.�>55�+ = } p  a Med@ranean\F�jsi�yndO 30%a Norweg� skng (we� aB2.m�" p [1 �=>{.*� !7 )!� halotoler���=vc=sh!%br(ssh��)t ,is phagocyto� ,"-�I%nem� �7�\ 8Un��� (9U�!�lmQ�r ei���c�e(um�bo�Eq08D� is 0s�_.� wall-P< ough � � . 0���@a�dr�T?� lipi�8��v.RstvNwom��l�O'< Am�u!"� i.�U�T(��+�ppor ggi}y�O��a=die�mduM path�oA�Q&Q C?io�p�h4E���Rrph: ��"1p"xGm?I! &�?��V�V��SBA-nonri@� lex; <�dA�MAT�O{c; "]&�L7�!��I)mferE �E�aeB� %b��!@a u� >.��� �Uic��`2� s�l enh� commerc�hJy�GB�`quaXuM �� � �aceut�pkFiar� fuel!$Q�. G�C%�m=�sE��� G e� i=TwrdHepO�3r+V %Cfu&�]< �Ic�DPl٣�J!wEk��� �����=`. Z:�isoA�da� ��I� , mono-O1&�J pGaiU( re��I�s3Fng��� cy�tr5}�I�6�bi�4t m� . PurP~�u1tDNA��A�=$ libra��: 454eD Illu_ p�Q�\�s�ng�asseml�dA��472tig�33an�& l"K2∼17 kb�.�C)r %� ledy�:V�O�K�2o� 100x ee Ma�<�Z�(Method� w f[ o ky%4f���$ -Vtda1)��e�n�GMumI#p�B omonUp .�e?Aore�MnA� �ed�. M6�&AM��8[)��"�� I/o�*�i@C��9e{ poor wth- A 12 &�:�.Vp8'syn����}e�8 4�C'Mdiv o];itS66�! �h ���� ( L1P5!� � C� �on�,of�)5, H5DFng:x6p�H��( D-. Cul�Ds dou���24 4�wn:��oga�|ic1|�3i -1M���ar,*1� bi0ic�F f, Vra���^-Fs|P� *��9�(i��-joE�s�O�1!�)�.&U �Ihr�rapid&�z%g � ���T�tQ��j d-�L�C��� s� rols�j��] ��e�8�"2�a�proo�d�W�-�. R�g&H� at 72I�M,�8NCBI: SRX100927p0A�>�Ds� � @a�S1� set:2u.  =��a��e"�,u)�|s2;� �=3��"�/woa m� .Iu *�[Nb�L�� to 7A�upu"�alY#I 3.S2�g�Q��s.� ��roup 1�48�w�K*�|�s midwa�#�%�%�:m�d`�j`,= s�� !kT�>���gr�m! pa��k8s�&�f"�h1�Q=proy%�W(� tubuv<efl� �IreE�"��/)@2�pl�"I3ŵ2��eo XaV a)%@q�Y  D��;Bube��"� �m�\nc� 5U0+o*dv" l �bw6ng!a1l�SE�ex7$mitochondr2 z��at1�[�#�/nd\ex)y�Kr��n, � oxZd rubre A�T�-�m���im�1�? se(=�v_O���Wg0lecule%��hyd��) iBE . Ni� /phosph�6�]Ql,���0TA)��cluF  C2kw�HR<� !�� � nee�>a2�!W&�!�*g ed3-��Bv-CD6IL�$o)�i;.$�Q A}�' ont�( GO )s: $�okUU2{��e^*GTP�#ULv8,}�e2<� m� ,/i , AT. anchK=�I�)�?mb � !Ke�ih%)=4 �=�is%F��m� begi�?"�]�� ylak�", chloro}�!��Il�1�� lycol�Ha�nd.�bi7��!�pr�!!Eze!��  l��. �51۱�f��L4!5DA QU.�GO`� 7�plinυ!k��e&q�a(S�cM�EG=e, n!�86)������Ka�� � �uli-;defens� *1 6|s%;up meM L1�Li. �-��A IEBII:�t5��`Am!�UwK,B�t funge9��heaA6A .��7.@� 5�5Ea��+subunii2� .�U1-��!�s occursI#��middl�e.��"' majora��<prs�^?7uU�� +?#10Q�� �aboH��erFa<|(5% ��x%+38*m eJ"�afs�%u��-of�VI� esta"��%�ac�Kon"�_-V��!JG1� �bE? �� reb��V!C3mX�Swamass ��rR&�V�~Ɋ Z"E [3� L��g%&�8o�snm9 n1� [33��W��sR�a�2,i?�)drcOa [X&�&!�.rhyth�n &�A�YY+),a;eOYprogra����ex!SA'����s�U lipaR �'���enginee%z["gXa��6ft^ n�st!s�s!+awh͓�5p�n�� seas�gI��&͒!�"Z -�-]")' high.M� kf:e�9`+beg%�� ����� vY!�sFa�i)� ,� �6[33AF�" ab��!� �%* *.*.\ha�� ly m���A�e%ly��L :��!�!9d$z��)U�cy-a .�)inRl 3�9r)H��l� halfA�: BR s��ofL �oB��a#7of eachi�."�N$y�=ge)���C���+z \3�;E(�"��3aq��� ��hv�Xa(el&JA��Ay�& *� �m��i�8��,nd�,6>!&C2��٠1b �Ddye BODIPY 505/515��s6��+�MV�\ g�m��$�s.l���f H�B�A�F�N�<g�62�!9ZX"�rS� � � �bof[��}x"� 7 Ŗ1��%� &�&� t�,I�,YUa�nc_��-!6k'ogazsa �!%>e+� �`.�^�&�he�]nA�in%Wb5af/2[I^�wo��.�"�*K}Aq4S !� )">�*4 -�9`��B )w~lysoc��o�m>yR73757/Q�id cidaF�.h 7879 h� 4dd�>�famhd�� 1231|DAGLd2n�E08970�-.iQ�ld��X Ww^ste�� ER-�t%T�� �Wa%�Ze4iQZ�*�aFaC!��S `)y�3/! ste�O))E�a1ER.*� /$��ear���?�2�a�N� �"T2&eakSBe�s�d� >e�!a0eak=<.�� old-14 �r%�a2��der�*2� �Fll._*���� S�!�b. f. C*u=�*6 r�� Wv�(l�0anR!L9#th"��oG�Y'7�,� 1�6,� 0�ER������^J�ab��8��35�\�Iy&� 't�_U!�Aq�&���, !��� ��)|'�g cand��i!��aex�o� ��F&� e�(�Omdes+GY�s� 2y )M��]�ZT"..� a&�#!�!�O�> ���� ��D�dN/E�I�i�s �a<hea!}�."�/4)E�Hr����+!(f��� quer�,�:)��kk!=m�%�l�!_A�!]��ueAf`us� �.��)d6� ks—slow:e� AG ?l#� AD�'nho"�6K��Y�= ��k� 73"�?Rg� c �� >/j �/ۑin� E"�{t�8"�"��ǵ�5%�a�"j<! ��L6A|�i4M �7a� bm"6 ���chD!qen7|6&�_kcon�;"�)�Y$-xEcor�n.5Mntf� T�O���ata%L9!-nL'n quicks!ropxzaB�%�!��J�� shif B�.�,)6�� �62�aJ%�&cas�n��01�(*� A,a�A`p-*�-]IթIq9� #�)� .|�.)�Q &�.�toԳ-� u����A;�&>H �)!�D8mCT ���F� @ta�ZJ��="*toV�2���1Ne,)��M��.��FŅA0�uئ�������&� S<�&3�m�&��#��|"�#�A5�o��G|lhromat  phy-2tr���GC/MS!�6(�!�S3"N"�ݡ��u�#*G��J�>"T0i*&�?�2age")�I% �O.TMVC� �ifU��7i( rankō_�y�!�t�I�amc��ESiE'e&�+b %%`"�voften(A?yy.���~*�+"�lZac� _.?�'acJu�="�,�ll�=!�yf�UBr <�d"�tE5��^m�7�,*A� δ� :qE��%eW!copzB.�A.�@i�� , be���XS*~@%��iph2 2i�ta�pr:}oeb�Gtr<(+�"�a�nM�-me��is��!,i.�a�d"p bh�m*ny% 2v�<�M�d�au�&<ef2bxbizaP!ca[C [69],=R"�m(A�%v!��es B-�d� �+�9�JB�A��p�;@G�t6(�,by=��B:Fre�oX�,r"j��*%,�%���+pri7o *"aH�b�%�&�0�a_�,)�oeug�;�cop2C�;�∼2506& �4800:�$cop�#ha�{d��J �,Y�6 %T.� )ɶ9 "Pd��l�oQ\l�.UNef !�3�088�-6i Yo% s 48m��50A!  9 . 3Ire��am!�Eri_ E !� 1źem /U ~"5Dfla�!-S�Be�W% � AD��"�� t E[93\Ncry��[9�9he 10�51�FS�145�SyrAF�ntr��op��!�o� !�7F}�q!x9�JzY~8a!��e"OK% g ve5)msb\"-�an.[%&"8���h�# &)�= ���3_��Z�1u���"��L~s o(u�kqea�q��8i!�C}��8D A$c�"�-�F��"?4e�#of5-fer�"�[!�6�>]4�!�OE�-(����EicU9�>�E:� p!]>aW*� �I�G.� v )�i40e6 to key fe�" f��'/8H%��n��CDd�Nd� ����� � E�ba� �;3Z"R l�bi�e@& yF|9gi��h�%�F��v3 cipa�)�6Way76!�:R"?J�% X *&E^ &�*�71"Tp�Ee4 .) :,WN�!R�;b8*�# b�@ ( PKS-NRPc � eI= !��}�+�m#=rous!8Y!�setJ �� .aɁ�ap�6�hr!h:I%3,he-doc�Led >Z8z non-dino+-te&xC-�l3�D�@H�q"۬Iin.�, :]��A� 2C�^�sinh!T"I2/�a; lE�t� �F9c@��wa==ts"u��s"ˁ. E"��C�i�� �~ �4a"�7� A�} %�>�G�ZMY��7 (e5��!=u5�m�`)��-! ��1K�n�,�9F2%>�,.�e�n���%vmH.�.� �< a"�KFM�{o:�l2e� 1PA�U-�m� ex!���B122-*"�-�%rga �4.� �"s�G� summ�H' B��m�cwnH�'.%. O9��(ve CW<)��/b�*AƉ,q�./2v:�!�&"Fz�U�vE w�_&~��1K&�&@HAa�s.�#ba:� � CMP29i@5/� _!�"cQCo r%�MbAA�H�G Catt z$?7�pJin 200MA�u[gnŸXh�P /"Oe|m&�@450 mL Erlenmey� laskAH5S�$1v L!0 RAC-�AprietA+B�@ET. F Gspl�  �silica��,ge�<ph�( ( Bellco GE , Vinel!} , NJYnd^�w�Qierĭ r bawcPrM Manu�)�$, L�IIsNC�+ , NY#L3=�e"8Q�7a%e�icf;�&��RNA,v�_ng �6i� 0 =F-*E�!� $!��S L� 8-mouth Fernbach� !���O -�FjM�-��, #Se2cloth-&tt Rt%;� -h#2�7K�P-kR�Mar( O|�7CI�]5@�=at���A9*� :A� μEm-2s-1��*�za�s(um T122^l� bulbAs Philips E�ron�) , Stamfor�@CTE'No�$!���A�Q%�Ig�f a�l:�= 7��#A4��8�n�&&� E�:o P3:Ws�v?re-Zz>^ :}>.l&(�sM�A�:� G:?((�V 4-di�o�(&>V� 7-te�Ra0-4-��-3��d4a-diaza-s-indacene; Invit�#$ , Carlsba%�A]ne! ~ yph�8. AA�x>.10�.�o�i9&�IIw�0a, 96 py)�;fI�L�m�At�:�6!�1�bof6.in�\mL]�D tissue1�q�( NunV3RoskilݜDenOE����AHZE��]��4�si�' &]M� beA:H�E�=>.�@2Si,?aOA�( P�6ES-���N->�E�i�$eb�r�yc�T�yi{ PV��� ygro.�'ea@A��r � e dA)2I�� . �� expowto#-ina�>�$400 μg/mLVe@182>bM^5!���� ��r&B([�~��se6P*�>�5E� A�$* erio ch t��^�: � ��B%�i� liquid LB1��.%F2�i*py�m� �-�A9xE[�a(�4_aQ�d���Cp � �.�[�le*E4�n�2�� "��%5h�:R;C&�=� e�m!�hUe�M6Ms-(%Qi�� JL -tip Maxi5U� orbg'G:� ntow��M�s%ZM=!!6��T�4Ear� H.^5 x 108.�h��`�?? ifug)�at��378 x gE�2^n��anspC ino&is buf��4 mM EDTA , pH \_0�_ Tris�86%mX; l#mM guanu�e;�  NaCl��A�+9 T5 incu���(7��RN��Dad� 2q�l�I�% �*,P�AZm3=t h�m> !�!�a�TA!6mL~ ��K-"g/m�(( Sigma-AldN���UA�in�1!�`�z 0� mix�B��wir�.En�E �_.���M�7F�AA�(I�6/)��A�JF!$�!m"h er’3�K�ndq3�o {P /@r�crav� .m&� at room2�j� <��W wash�w)wע� � ]�a�  dI���ubV.�g . 7!+Ep��orfa=�9�4at -8�) AS�$�H b�{)KKH.Œ"{IZ4542aہfr",�shotgu�2b�ID�XAUD1��50G�qi���"�k�9TruSeq }�� �� n�HiSeq2�n&y�e�Titan�H! Z���-e�n�-�(akb�"er��AS�\�J6�gVֲ� 7 mi /�/�o K)�%N� 6y~(x��D8180 +/- 1495 bp ) �&�I)� Newb9, �Y�š�/jre��(091027_1459�hR�Z���1]�>X#�*agU5E%�s6v�J�VELVET�A��m13 [95�TC�&ns��} �a�q @!�� m�+ c.�l@�re��<10!�&�0J7re�-.L�)�{!�pE %�)��p�( ‬ Phrap>� 80812 ( H�Peq�a�S*� , LLҊ��2Pa ��W�\" 1Kthous��g�3G|=!���.U I!VMAKER2�V#H* pipeh([9�V�mas�1z�P*%��R�.er [9�a2 &/!s�;o�l4q�!in �: �[ alig(�ťN/�BLAST��� s EST �; b��C�B�bEST" Kx; c )=3-�ed?seqi���܁�#=%wA�To�D [98�C�rks [9�0d.�� CEGMA ( CT]ic^[100] \ 9 Q)��a�Augustu�W01]�a���')�s!K�o� ��rucn � Chlamydom*NPreinhardtii; f ) SNAP�2�aHidden� kov Model�HMM�� �(Ic�ly c5@A�-^EKs; g )E�iES:�%� *��[76of :�c�m Ռa3�(I�0�}s3 �\293 <s�?�3%� 6���=�2GO�484�$�@iװc�a�G2[104]e�u�ttafu���A�toC�#1U� &�|[p2S��w>7nd��@-�d8 ( n�A�a B�El� Vnxcutof_= 1e-6�$2Go Ma����&�lG)<A&�$)8E-U-Hit-F��: W,.,s5V GO w�Wof ~hgen.-��%W�J%ai��M� 3LJnmX!'Y � g�!x�.ga�&�c@"�H�'n5Ml7. TwelvsRL&�E�sPBUt�Png deI�Z�^s/ , 66� " &�smG*e0( D�8��)yiRT� "��!&*�7 d�K�g�#�*� (�mM�;e��E .T yO�dif� TRIzoE��z!/:KJH&i&[�!csamplTC"� %2 �2a t 8!D00:� r+��ylAQB�Kt;'� sup�aH�,�=��y TRIZOL�t��i&\J� �� 2.� 1�ip��mvortex!���1 + ���ge���e��_ V f6F�e�tu�  ?��e5kLA��} !� . Ea��ub ush��by vigor�Q�5a'ond .& �� 1� %�at�R,e$Batd ��!�DEe�"�E��aLX+:4�t�0quep=�.R��gNI�surt/-�nurbz r phenol/=W j . IcldA�A�E( 625 μe��)�.!���4%�2T�6�!*2- r�%n�)Yipm_�5,91���!�%�0M�%8 K:B�*��&�\Ŕl 2q] 75% pc!W.qaa�R�Ia5S,4� �C��� 57.?mACg �*�.�nZXs.�3iJE7� �(��S�}6yh �Et� NJarf�%5]D�!�92�eS�N2�leai���(RNeasy MinE�' upS� �Xec��b�R�PN�.6B�Poly-A����A�. .�� �)���#ki���Z!r*5ed1 M (�!-8 !qg)edbph�Xe����� , 15�I!�.`�[�-1� rimmasndC5o [10�N -a65� � A7s- am&�)&�S:��6e;��k� v�q�b.n� LK�:�v@l@)L)E�)Lrp;pta� a�`9[10�T.���(�d�1�Gy !]*�&�l"�FaE�^EA�!�A11`�g !i�me,2K�!��at)�!BP6�Tnd�59��3* =�*�9=2�m�9� �v��E�Ia7[-ho���mul�k“MeanN� bori�%�sB���a�+!{��6�6�B%)"�]Xoadj�tN�Zb� �q�#, ua : .� =QP�/( x ) {mf( a�! x[2:[^ ]-x[16-!�`@) }�[;�l%nz�scmJby6 �e��]P��0�Pmap �a�(&m� s4*Y ll P�%�=p%h"]�"�+� aY=`)�QK-"Y+�%r�ey!��Z ��ubt|A:/yt�D�.;s ll2gZI�� $` fMWaq y�y%A�Od �A!"� devi�mA�=()*�3Mg��a�h 1�N�0� 32�RՇ “p .aI[107]-��“wardcW�M��sh�Uexa)�es���in�t2u�S� U)&4��Z d�*�ofD��O-pS�X"8z*!)_at<0��i�A�#y a4 T�O"�E�e>`WI �oM7�1y%Igraphs5L�W�Υ�Halskmb%d� voO���X���)h1�%�.�� ri�mis*�MF�!�i�+��x.�n� [108:/��� ���%3Eto �?�Y& .�.�!� ,i1,f�HNAD��,c�y� *G/�06?vr2*9�.��o~�_7A�V���B�Mu�cA�I8$“triple-�VaI]e R?iD#>8ESR7*PGFJ��H,yK��8PNo�Basal�.m�Zar2t�: . De��Rb , p5f&UBrca1 nE�-��as"�� :� <t�/yp&O���{Ai<�O'de:�;!H* �!�.�%be��p4u"�/to�A�A�e�/s&�;� deat��ma�-/M�v�ur/1e�< ncom�#6������nUepz%l��-�eE=uf!y��umo�q��!|`s%%�Rg3 pjk1m�1��c aden�Hcin�Ua\�FR)��d"�<�J�ee�mwlogic&�4U� comm��Ch�uE-mo��� h]DZ�� hetem(Xm&�k,�m0i�(�ne`xi�ݧ� yGN x�x attr�w�^]�hCla��- �s�-u� Bs  1�q�i�Ser46�#2�_m li6��xd4c"�;EZIA �mIXa�agg� f�64AFmo�y!��+$N.-�9 i�l�ell9[! ����z:ea��c1.if�asZ�.�diagnov)��(Z��� re:,�C�1A)�A<.I6��?yA�:�:<( TNB��+Mr�p]59'U/!���C�/Hcer54�4izft2JGŴ!�r~&�f."1G�y� �oS let�synony�5 [��[�Y����{ez .��u��Ty���ha� ϝ7$ eatl���- �QLjn �c!�#�?r �8�s�>A�$al-to-me��hym�m��ARMT /V��r�m��{�3 immuV`e1seyyH�W�� �lstB�:-A�invasa^DI@a�hN�Z��������du=d�L���y�c/7*�.,M?�U��-��p3wt�Bng2��"zzNBA/�Inse�UWndocri�h 4��O��oni�� �&�E2CQ|o>. NO'the{�ng-�`��?  �i#�����K� u psN"�3l*��[?��z. MYG%#mic2AiQxr ��Ho��val�Z ��6����=���FQ��p!̕�4 s\���r&�Q+MR�*BL��� :�oaD �ta�Xl^�mia�p!y"�~6%�f�D ��Z���' �PAxiXs: ( RB� | ( TP5ai[8]# BRCA1 [�Z� �CiK5W_;:�!"de A���gmed�����e6A riskA �#M&��6�ly� ��� �� ���� �.� �[1|[,r":=.� 8early-onset bre�ast cancers that are often triple-negative and #�ucorrelate with Basal-like tumors in microarray analyses [9] . BRCA1 mutation accounts for nearly half of familial brea�P( OMIM 604370 ) , but Y@is also down-regu�d� sporadic N ��0out germline �l[12] . The overall effect of n losss�4ly pleiotropic 9Pbest studied function@i%-`orchestrating DNA double-nd��k repair through homologous recombina ]r non- end-join^ �import!��de�!�| hinx5w�6eA; in a rang� tissu�J2� hilFalo��suffici�to��uc�q*" a�0�o!�shorter k ncy� TgWA-�%�5 �x��er�6� al�i� >rE�ensi�i sd >�e� or pa� ���M � � heI*LTR!�motes��-a� ific]5ݫ9�B5�approaI��R ng pRBf ,�n* �pbM�zUJ"F via�Wap-Cre�8[28] enabled us!� avoi� e�ear�!�lymphoma-�or sarc �_ exci�{! LoxPiCstop- re-$er cassett� & E�=, in ductalE�alveolar"� q9�9\C%\,Virgin gland�/)�; AS!mic�edA . Lac��ng;(2-inA�d )A�) ��� densaU[ mi�to%� a�hy phenoM ia�eA�ap�pQh�w� :�&! c��!>�6 E�a�l �on�s� �-$; Rbfl/fl;e−/−)-) M��ar5Tg1WTg�5Yre��M � -fre�� moA�h�� year afACr-_�[�%�� wa�e�*$r heterozy�or � �a.�e1alC [30] (6�AP�;'T orj,developo 6� 100% peneAA\nd cl�evideofl haploin�!c���D��<0 . 000 0log-rank testE�H.�%+�%tx a median.X299 day� w��D=IOhad=R.C150 C s� sults 4 >�previA/"R%�vՈis al?a!�2gA�; on�9by� �;on:�In�trastq�m .�w�ly foun�ouAA'a`� ) i�e],e����( � c3 at"q-��on� arti��hibit��} !� possibly ��V��e2�HAz�gen� py number*�a���!+. S��dosage� sit��!6Z%oic- of acyt�[3[1 s sdramat� @ccele!�� onset�E�wRbf�6���225e"O!Xa�glgm,( n = 13� ]�AsR nd �U��:� Cre;�f�,}2�s at 386i.&A!��Q%by&6 $pregnancie*.�,�d�� ofUZ; ��(f;����)P( 8 �u, TBP )f�%}NAE�47 ԁuA�5p�y����t%a�'yiH�1. O�% palp� �'s grew lya1500 cc�in"r ��$( data not�nET�f��%�a%|� th��fG sL�d vy+on �� ����: �� sign+ a�fa��n did2v"�ATK "�Xe�� �%3. 2,��exI ���biopsAyYd5I9)�ime poi� @( 0 , 2 , 6 weeks%"" forc�ea3at Day 1u�on ��i��`!�121. a[  ]T�  benig=hyper* ve le��s�52A�� 121-{ ng� a�-er Ki67a�ex9��a'�H ,aex�edR�� 63 ,��3av. C.�Ei� ��mu� ��d�,af mali�,tJ�C–2FI�Ocolumnar&; A�$darkly sta� ��apill�f咵r2c � &y sticQ disrup!e�al� phmPy . Pleomorphic , faie�nuclei)promin�Zoli {omm�5%{B��3-h�aO��6p��!{p2�P�� hysi�ic%4 deat�q�in"��I , 3N�~altho�y���I�� littl�jHBHGL%�Itih3"] UA Qdelay��by6:[3�Hq �("U�"x2U� .Ablock6ltsix�/J . Bi��8harbo[�r�AC! J&� ext� ve%�u� debrR� dead� dyy�a�H ihe��A3 dual �\� �EDit�3� V#triggem elev�an�th)`��p5.-( �A % 3Q%��5�B�F8�Ft P�e�f{ � u� N�O�HowAFhen meanEFV�n� a� cr�d�y��� ��9��Pnor a de7=\i:/!>� ag��zw L BP�Armpa�to � - "� full �i�occur8in+ a �\�popS �,� ch �ref�!kT S��O zo�collabo�ng onc^ c ev.��( T!���eQ&� �R��adeno"�GwV � "�"�ajofO� 0edJ�suiz� T� 1�Icoth� #"w $mixed soliud�e��I��2 M� �lTP � ( 13/14 vJ 8/16��p x169� wo-tai%Fisher's7 c�9A �M�%��deZof�architec�U�4�All6T��a8!2�kush!�!�infil�!�bor]!�nd> #�� �� vasc!A%�N�]�\ed var�5l �� .�ark��M�KeE�-8lE , 4��4K ) �E-Cad�!n'�74��Thn`�"in well-.�AZ regi�O7great imin!��ab��oor&�!!������K� �Nes� 5Be�s!=ia�9P� /myo=?C$ag.)G(1= s-5 , -14&M �!?. Ba:TP%Iu( 4A�E�1A�caF� 33592  �"�Y � ," �#as~EMTl( E&� (to Mesenchy�TZ#>W!� s [3�#)� DmprR�%! -"! , fusi�rm pindl��]s�C"#� �  nt���e hist�?t hematoxyl�nd eos_ q� 5��&iv�!C�#<is vi�"� Gm�^�*��Mm�biphasl ��u �<Q ɡ9�, 4G�A- �` I��}� -�,-"  M����=�( Vim�$!�Q]�U� -8 )u���� !� mutuex���>� ��A]�. D� ��'a *j h� 8Claudin-low [4]�m,EMT1M�PR9}M{l�! inva�%E!�/-��>K6 o B�=O�.�A J–��In)���"we9� squa�U=aV yH�by ke�� n��yM��U=�of�� 6/ ���>%'ei�x pand3 Wnt-&�� �. F��4 ourtv&��( 29%�� /�) zero ' " (636]���hor�>�reseme6�I+(:�FiT, �'ral.�a hall!�F��'�����L �nNtwelv�5!), a�ef�a�< 6 eighcsix%Tp/�N @:) 577 Q+�%KJ�%of% per�(s� q��c�v� JD:� es�ޕ��& lung���TP�z14 �!( 3 )�,Y�O ��is!�$eworthy be�g�few �)c6�6iu�! ze .��a��!)%>doe�), O"�$r�(ve�!g PyMT _�{c�'l-$E�s� L�*sub�MGt�B&�% [�Mc"1sp�Irhe�*rnu�liver ,��spla�x��& primqa!�� e�"l� �:a%�� m /)8s*eser{txpla�$i{+syn�ic!�VB!��fat pad� Pate!B unpu�A�confi�!�'"�capac�I&J.��� y�di��6c &��qaG�Zg&R(���#& boa. $EE��p�re��� �-6g��.?�$-�X 2P*�-M� , ( 76��co-segr3(�[� yY fH(by hierP *)-ng�s,top ∼1000 e/var� e`� �6~�&13��� �33���.�profileAF�� S)F?#S2� Us�B8 ""e�w�S���"Mlye�� assECgloba��.� `&M1um�s�*di_A��� �&?B, �"wSp' hem direcX �� D�+C$ m�(M O � pat9$ samp!D� . Two� V-�6- %6q 2:A PAM5Ale���mas��Pra�olleag% ( 20}I�two� !�&Ac8'�E�.1�iIN � N�A�d���on\��ӱshwg!cu� 73is;�I�D$me�0R��6W le S". 56%�:�( 5A:� ^ �%�6Y-�� ��{ 8�\:� shifA��( "�B}2�F�4.�.Z�A�Fs >s2�.zI��l C��%�>] �� TNBC=o��Ag� n��2�[ ed � F�( ~N�2#�P2)-&j1��0�@�#i>�s�-6,+-17���cor!!Y>E:8M-B26U�5A� lue box&��e2sof"�)�� t6q6!f/5��oh�.$target Xbp*��5)�Ina�s� ly6��36��mv�� ir&-�i�5a�$͎2:� ��4,�".�Snail�f$Tgfbi , Dt !�Tim.�-�8 9� ( 44��� u)��1��qL��a� ng b $(s���%,��Rb/� m�c-&ls�b� iF�!�.m�ԙ�P,$p*k �le�]�QZ�jde)v(ed Group II�U�6A�ye74M�% W Qaradigmr  2���eH��nj��_-0 aF��&V . &q��9�J� ���6�o ,i�� sur�Ag�0i��2',-e.^�2)��zA�~!�2�2A�e sC � betwk �A7�t.9�I�a �dE{�d� �%�] f upBC2of *�.�em+I5* 7A: 1 We quer�9!{ KEGGA$yoto Encyc�(i�Ge� �Genome�!O ( e On�)� b�E&li��J�(��"��%�� =M( seehodx� 1 j`M�� Cytokin�#�2 � MAPK)#alAC-y*(nk!D&&�>t�.� ��ea�enrichW1� of d� se origin>o43h]0�m 7e6r�GO �/]:6�:!��3�6%M%�>=0�E5. C�A�(&')(( GO:000704 p�(2 . 43551E-��*�; 6 3498i6,6 . 95081E-2� d�!�(eEK!<�/s�in.,�I�i I��(�Y4� p2� � 4212�3 �� 01E-�'�E!6)��'2!��%%��/]k( !�37%w�A�4!�A'��ly�G�.!�6 �aTa�damag$�=W= osom�@aI&tesA�ahypq Ab���m#A�%>?c*I,=>V!@CNA��t(d.�w�int0� .��enume�+; by c�Aav“.i�.� \��,4h�4� CGH�(t�`.P �an�m)t�!��< hrom%=W @9Un�'��`A}no�&t%�$! �)"� c>�8374 )!�� mean�)F�R�m��array-��d $pa�v9�hybridi,@( a!<t6S�7i.�A�&% ( 1–3�� @th� �5 &/�$M;�1&F�$��["u?se|� &V6� &zE/a!c�. 8+d�fy poFAs/�jI#e9man�cuI��=E�.aQ�> � n�5�50\ ]"�re6$�)osU�� ,&�r� spanm chr4%�chr10&� � .�q��<5 �"�(~E��!��awel�4, such as Tm2d��Utp111 Trp7��Dffi: RunxLck� hcr2�qFaf6Pax��Ab Casp� nwCol18aCGadd45� DapkkBN1��+ax-�6}D!6%�M,��n�&(y five-hundrE(�$S9An&� E9].#g�<. A�7xim_&�F�� �jx�"nYy� � .�C 9.�OC�7r Censu��S�9(r Institutey��Pa) inA��U�foo���� A�<&E/�:o-�&i% ֡�c-Myc:E(�42��o��6A,*)�AF, H-r17mp�gwo��H���Kr2B/"E &�! se6!p�-*2�')�reveaX&�V 1?�J:� >�MAP Kin�F, F%�Adh�. ,� a� �Q!�o'S10!Y�. �+w4gpig\ �1t engine�z�[��.3>3 work�b�����A�si�kanV(28(V$=,B�(� it}!�|��gg��<:G YalN>)&�*tp&�8&�3l�6�j=�:Z1 06. B(\Ai*|?� &��"]:�[3�Ae��� " �@��+�6]a&�@s:�J,-Ce&* �!%�� "�would*T,!2)*1�E�.n"f"%2#rI.IXr^8B �c�Umi�@>A��&o�/�=���e�&um�Ho6�3>�U]E��C6?B.,*�k%�%��/)G2�B�-"�?sAc.d Ū��n2� .� bT ^�EXj �/��+m i�t �, pcH�_&g/� �by��'J�IL>f0|pRb*9\�net�DQa� G"Z2in�x ��E[0D, [I�[38�!��Rb�u5Ii)>{l{G2�2�h��#/��eD�@�8ngN�"� KJI�6��^a�.aBatH6(5 by�# mayA�ow� !>�?escapG�(ate-l����G��!&0 1�accru+� e(.6.� :�7A3Z3"�IdeS9p�F�J(Ac"w0�be unt?i3r"�$�h� e@3ōB&�: alte@.73illZ�N<de� hei `E�A"2asH�= �1�M�)�#��rE ��� ect�.by�!3e�&�$A!K:� i�$r ocu�I�,�<�0�"���%�<%a`va ��$d 3�i"{1AR�%�u< ���.�@"�L>'lv$m � g".Q�!�Bi�*��A-�Qe�U8,o�*�(J !��i? � �"� y2� � no!�y�p wL:)t53}alog � reside_0InaL!��.��A/�erj=a�Gs� �+Q�usefu1M evalu�KEMcm myri�4f:���.&�S1G help!z expl�M�&�$E�$NBC�I05�A� B�2�r/7F��� trum�!TK12�-2xof� : �D�B*�A:��@�b�'m�t�5w'� e�&� e3M+]�!��QY9h�"g%6Q&�!�Cl&�,&� �!uO�]xK argu�at.T>H gene.�s3�Sfa4�|�R>�Ri ":v2��J6�V��;b ol}"rM&� zB�x_>S�R)I�RLo�yU"�)e�lsoi<��� Y8dem��m�-g?$er SLUG [3�F��&!#f0+@��!,� �>�q6HEq�survey�}:�[4�H[4#Aa�a���a�"}' �� saw.���m�1 !�c d�P !��my{;Hegfr , crebbp , jakOI.#,�^36���Nl�>C�EhqZ.�WNTI�.� 1O"�RBct�$ytoskeletoA�&�e�sh� � mobi�L��M. Far�+er�/gEm]f9%vV��yQ��a%ca�X2�me�isma��TA�AD*�8R�) &� ap& map2, ppp2!��p�. &n �A4� �A��Aa&� R��#BP 4pro�Fi2!2�ybb eclinM platF A� fd^�&��apeutic�+r.����@�N20�[4�R[4�, $WsPas3�I�strict��ord!���Ayre>>end-�� Guid��%C��U f L'�PAnima�/*NGal&Re�He�=� K-eWNS"K2 K��-enco��'aP�,coRI HindIII&DQ�N�M(-Bssk ( Add��Omid 182v~ r�%E)�;B1s5�0T . Jacks lab T��!&subsequ�}���+m ���-�M/dby PCR 6�(of a 215-bp�<�N��oligo)CL: 5′-GCATCCAGAAGCC $AAG -3′ � $PAATCTTTGCAGCTAATGGACC %elee M.�K!� �c�/�E~�j�4TGATGAGGTTCGCA�~�CC#TGAAC CTGG �)� !ua,%�94°Cc2k< .?5+I�!0aX"62645�7F;%tfiA� incu�@of -A: �W:�/ T.�!��I�5�lg?� f�;to��aLH&er@ �U�(be�F����$"H]��J(GFPcC�YrFN*gNN. }#+���)$48ali-;6!Yfoo\0�si/Zn%{.P � n�-.&N@}<:d!� *�R2Zef( H ) [4�.��1Y=2 �?a�M�wr'�}(ons: neomyc;rimeriNTahGTGaRACGGTATmL,k2,ATACTa� GCCGa�I� , 52e�pro�OIiend����M;�e�ae�Aa�GTGACCTTA YA��(neo� , 47.lo y��g� m! -: same�thewVreT�r-I} �� �E1�K9uTB�;�I+E!^f� ]DerAs�29sA trol�T .W}Ia� ,l>%J��]Eb4AF,!� E]MR�<�3rT)7�,�8�"�J+�:EB+ ��%�no�,7M 4��"�Z)=j9_AZ�'co�T�K�%RvK��2� G�t!�!�first p �Q*u*as>I{�aga��. Mh �Tg�%�( L�fG yielTsmFIG sizesexr"K� a��:rp'aemplo�4&�Qunl� V!*`�d� R�%)�N�1�fi�Aovernik8 in 1NQhosph�bu�(d! %[fer�0to 70% ethano��n$then embed�araffia�Sl�s|#oA�!`10��%��4G�M5-µm�"�bh>>EKV<>Sx+( �=cHBmi !a��3ɻd��P(,`�"��BUs�)��he�&i�deoxy*I tidy 4]se–��C8UTP-biotin nick�r� e\( TUNE�@me�) �� dVcS oc�jDc�#&�T �� E�%'"Fa�.���6� �$��FK5E-dee� st^#�"Immuno%xY  6"�a^pe, )F9 �-I�U+M��APYretri�5i�ntibok\d|$by boi%O�sl�i�Ce I��H&k&A-1sMA�pVa{α-=s�DMCKer8/1�'1∶450�1geAZGP1a),:; 5O,�62800�MCov& , PRB-160�:4smooth muscle �C SMA;=1 ,�T ,�(A2537; Sigm�!S�Loum8MH�ti–i�ory��Lst!7 H3 ( Z�@rabbit 06-570; Up!�#W] a[:M�1a�  ( mono7 al Ab^'� 100;`P!?Cambridg A�l iE7flu�c�U��m}%�I3$��v lle)>submitA(to GE3SE3447��WgH3� e+�)%~fiV�: �Q� �ba��] 2n�jto�jIWan>�� Cof >1�L��ValPbe�5"� in >� �A=9!��;��absRce �, log2 � Ch!� l 2/ 1)<>as�O�S,(��l>�-�.HZ�?a>g Cl�g vA�0�&P%IP4JavaTreeview ve�M80*5 871 "L %�edŁ! c�ms [SAM iS>�%{ BRB-A1-To� ( R�i\Tni:#Dev^C Te� NCI;]'1; FDR�048d delta 9293A?.e4 on�56n>3!�HFatiGO tool ( Babel�/s VC. a{�b<. bioinfo . cipf��/.�)A� symb�E�conver!A��5EntrezID1@��an� )&���6 Ina�a�se�e�JheDon���Pors]�c arisH!i�F6�=�O A_u!�to&rQ�*�<of�2(! log�(�i�  [� 3–9]+.W5T � TermZ"� ��u�. Fy m��'� s , !A�Z2. 670 u�O�"p� %�Y 9X2�H:�."�@to ort\1!�o6 abov�RM�x��of redu'et �.�cal�$�� missa� ;u impuA#+coUX +(o N"ZA�� A�row 0�n� % i�R (M��61a� 9dI�1)^we �s�hd2 “UNC337��0_ �C�+pA:. txt 4]� ?���B� DatI�(![:�A�0e� �cs>H :eyic bia�Z �D� ce Wm,edcri�a` [46�kA1��\�ua�3* ^E�oiA�We�o%)_�r�WX&tDd"�[47�Brief3��ic�ah'o� � e�&] !!l��En�ncompeti�!*�wIwt\spo�� BAC � �r� r^6c Ch&�3) ��A� 4092�E�'�_4he HaarSeg alg�Uhm �defaul�r>:_ wavii ( 6�ni����%��alo?�`I,"c&!'.CNAa�`�Q %��2! clo�$"/2"�.� %VGn~$�w%�:k %o9 shol| D<>a�5!* <− ��s�p�9� ��D%; i!b"ECe|9�Biotechn�� y Map Vie�!5�6K2�u� � @1�Ak�# ��*1���)P�)�6 ?, Atlas�A sslog� �Michi�9&�I�\��a��0��;�u� "U��Y�:�"� ��k)�yf? �D(G _^)F�'verO2!�res_ �%҅�E�3 rro.%I h )%'�>TBP_GO_B�B!�V b�$** �W, ) suit ( r�d 6 �L .&+0�.MWb� )b"DiHet al . "bHof��.)& ( CL)0, 1&Ab*_&�sa( ,e��"UN-X!o :G!?� !�g� Ou"�S=M����Fz� 2� 0|)0)g>ly*� E,msM�3 L)`d��+���uC.��Ae�)aegypti) . )[M� v#@ engu3�&W,�^vi�Qin�,H$�Kl�+ Unti�l�!5 vacc�icen�!� rigo{-�@d�X! , A� �c�o�nmV+�principL+ ��n1\curD �� �& � �c�\�?�0�fL-p"�\s �<*��m;! �3��I� i�#ate�V.6� As�mar�s�W��wa ���!ain�. RelK^�#ap:G9��+%�ad��2ido��m4�Gi mH6c�,�$K�+��n!<�C| ����#!�Ing m�\A-yovipo�1/)c .*21e�asJ4t�=��q* +i2� �B��A�m�-!�a�!]vi�.g��er:= s���9|-� mosquitoeE�&�+A��M%teraOT�# is p�f�stU!of6 Y�s ign!�awspa�5�D, arvav"-si,r . Pua�"*��yd out/ 2004!�200wf ru�Z0Kamphaeng Phe� Thai�"e<, �C 840 off �E'b#st�: 5(p&� aGg�)!�� p&�2�.�La�bit>5�d. An ec� "bSE�A AЁ��k�a�5 ,�8pr��.�'ng^* ! \.U��[���[��*�Gi���/&� viruR( DENV�DV���-dapmto�W�� eop"�/u�v!�world!��G%s�'� ��ul`�[1-0[2] M!�s illna��,ly�C0 urb�46 eri- ]�3�3p���2�bE hq. .O6����*Dvn.a�/HJPloc�L�� d arD� hI� �1duc!\o�O�ngq -u: �adv \�>n*\ �okw6u e�� F;"�%� 5] Ay:nf�@oBly_mer:s v�S�-xB� sA�$# ve a�@� � urItser�!Z3�d!�4*AI -{e_. [N2�9I�EoA fu�9��W| p� o". u%volE�S deployd!�-'�#t ^26H eRWburde�% �Q�. [e:[9] A ke�psu>$�5}j��oT whe8  itahh �U�; a�e�a funda�al7}ta�}>d��n��_�=l9:a�"� %�ir ��\3spa9ti��AN{D ��=w���=ern�+�F!+٬A�� ai?P���� �js uneve�sՁ�xU7&�0b�E�ua�S,!few)���E��}%5y�a3!�a_g��>�:����3�R��o��� [141�<12]"1ha�mJksAf|Elid��ic�0A3mo} �#isc�[5iun� �or� t�Fv. �( �FB1�.��6 3] C1 " ],{ tem?� sour;.� � �f!kfl��Kcan� " {���A[�6hĥWcit�s�Pif� s af�� ,9��0%�2=.֋p7a�Y�X}.�!\ 2Dycis^2=f�NhM��!��� UU� z�Wim��A] �q� w���premiA�͉��#UA��12�= in A�5an Samoa.�5� �<�bn a"�gۈ�s �q< �!�LAj1]B� �e�ons�"�@r�:!*"� i!4� of.h���/E>*�"5uY a��, how d!c]qof��by2�M Qi � j F`�on ? [emerge(,�"=��-�be�0takA�blood�0.hec,gon`�}sM2�@blea)�Fd"|�r��n egg��EMI "12�Egg2�!�;�-in� ,�;w�F>�.�p9�y�(A6� Mark�Q� -rec:�e�}���1q.�>�E�t!2:`����at ;K� m+' E�A e#rzZln��r( � , [2� ~��BI �EE�"]C�M�$)�~-&�&�x k%\F^9�ov�D�.I�!l7] p8�T 6\ >;ve�a($weF�!���3]A�x�By� fqv�(� �mu�bY�N:( receNFE��"Qz!�aa��aM �at��RH�^,:�"n�{ ense�al"� �?E�2sgb{�q�#=A|.�:D<E� x "�(t.�A�rUt� ���nsE@�q�$ t*��A� ch �o;;��l��In E7*� ���0<(�R>� Y��feaSm��l���bA/r�m�u� .":!��. Epidem�w>,U�w^�e��}�)�� �entom"F risk �.`;� �,.8k h� r��0�Y�7 imum�_)�&�S<ort�@�cF�e�8]� "�r:�a�l#��u� *d��L� ]�T�QveWs6�XQ��^6fE�&6 �)We��Pp)�J r�u��og1p��Qb;'rߍ#{:�O�B fit �4��| fV3��t~�A�i�Aэ6vvA�4�RDl���1�.�'=� fram�jk!�mE��ei@� y| 57� �q)4ed 6��e"6�%Nh � >a!|��m��.�4n� A�&>`KrL <� repe�,�7v�|$ges semian�S. B?Av�t� rcep�` l��c:�%I�7�� o<Gce�x :B�u���=/���wn:*.E�"H im��,.h��1�� �)e�+l��Nuo)prP�uVu�� !���Lc�d  rol;��t�p��u����/o]"�!��F�6. a�%  c!��iV1z%;��in>HP�>!�,&Q"�`�&.� p�O � �'n�p��%��AH1�tW 8 73.OitA**= sub-� c�� �n�c�?nc�$ capi. P�li ?�&� riO sympE-�("�!�m&A�� f!�&�:ŧrecA����/!�kI�29����M� he cli�N�t �vd 1�fu�5�2�3�2]~'��an H#ve�Mx!.V .�sŶ9app�DeeKn�5U fumi.D b[$A�'� )�b()*�a%�?�#�b}T6�r�Lsa�i&;��X3c hwB auth�&�;up�#q � � �I&i�tc�T%Uʯ9�B)�6�Vjj400yu���m�in�, 088 uniqu�usm} . Wr�/�nᾅ�ob\ �lA ^VD���;uw b��&~�+.E]i:���8%�� ~�,� �+l�AFRIMS S�� R�.�2��a,eth�g)ew� !�D!U��� rmy Surge�1�n�� MoPH�< Un�ba2 Lal+ynpDav�)a�A7E�o�d9�"��a | ���*�_ PS )�e =3l)� NDin)���s=� plo@+*pa-%�a>?%f"JT*� %ā�rded:.2��*�  dm7�8 depth�'eme�8%R o�ao�<}�,�tu1&��/��a�j fi�))# (��/�)A5�(�oor/outl��shade/��sun7�? fishb{�8� e).>�6ach=8Pre-)eS��� l&Gm3ex7�M��Qb�A9F Ag"F �� qS:4 :�.�/=m����R(]!6�� � �c-l�to.�!�)s�?�t /a.�2� �6� 7zC&�iny^@ �? ���eJE onth�$_0�"e& dM�m�x�{!�&�&}%Q."A�of 9862=�w e-}reeiz� �58.48aO��7!�I� @l!: � -�L�!AP�<. EAv�SaQf# ( haus,![%�-occup �ˉQ� C��%8"� . Cros.��w&�3!�wo6� : K�qee�<6°22�;$N , 99°38E�*Na Bo} ,�;, :,� W E�. �b� � higͣ���!g�2*�!!�)%�y-��:�� Ms !%'a]w�w�y�l Ib enE.��dr��]A�M�ua�p_Ma e�/U=JH wet "  ( Sept�A�� LNov �:0��A arti2)�!!a"6*a��AZanc�L7oi?�p�of 543 P� P0)�M�t-F�H&�%��1e�1ar�aF?i(| !�z��4�,)�����hC0 m%hiA!rh�2�  ch��/mtA88 �MV - febr�i ���S*s B,��f�a school*��y!L�� p�ja?TX8a��q tookMce"�%Juns UіE�. S�="�A8��%�!�E2*�uCan, .��1�s6=�5In"�^A�!p�FA�(.�!� �M �.=([hepCKora��2i3���i,, Nakhon Chu��9����30 ,��ZP��([ MF/6�a�eRsR��Re'�vn!��aXV�f/Gjte����K!oǨ�r�C2� d &\ �Ff"_Fa� ( PO� .���+{���>�7�f�����2y6 �v8 �:� #�a'�oGt.(-�1Z Aq� F��2���J�>-s6i P( AEGPU�1..6 �;o%v5,=l acil�'a��� "k /q��Z&͂s�u�IM�"��SG. . ( j�t�� , ti�)et�>�Z����Y �"O �D6]lid  ��� NA &a6!� V"8�~Arg�tFmssu� s��few�an 90MU�LAŪtoC9~X . %9Aq&I5!!)124 cl6p�Z���e$S�=!tPIPED}<S_!�%\�E�%( �d�- �.9, or i�,a'drawn aF�Ej�YA�k w�$d�.��6e^m c]h�d�"�g� p���( EARLY� �����%� *�  ( LAT�{ �monso�&ea�K�2���eo�%�*���s9 �!d�fT�fM w�j 1` pl�^ he 42ndבQl!�Orv U$!�s �t�Oe}8�JP���/c�T8)g%'U= ����in�a2B �e��q)� ��QA�bQ�%+�-�fu&��FEuc�Gan��to�!!\�N�# "��+Y !~i�:��b�oug����l�ighac�,��{�&� _�2�!s�0-�2LB�1B� <se�,��xa� w���� � dbXy*x�*�AuE55*]�ff�y:��^Bm^*�'��-? w��1߁=�� r8]!T_�$r!�i�=0>�M!4] Max�r�kdU ,!�<�OE�s�Z�+a���ѹ� &q$>�(���o�?�I�<�h:� ��ja 'p"w&k�=�y�y��yA�) j�reN*^ Vx�.�Z"f !di�eu�.e�G"� �U ߄y�%%X��m�f0j20A�&�, m-�,�!<QA d1Odev&��"�#DENS aA!I=021 #-N���&� .J7�"!dR9o>�9es�+[3�$�j��S+2×x inge��tA�")�"�3B"�(-� :�5ZE��)��BM� s!td� 6�N �O~c6ll� .@�oneB�D&W&,%v>n����S � αoE%5iBon� oni��%I� r *�"]'!��Ncy� �"��&a�E:s�6u6uR&�Is�B2xF]p!^� "q [�i"�5 2�5"zUbi{vN"u*25E!s�6s:M. *E��!�3 BNu�7��$5jUn���a E��,�-��!F5ǡ�H�sE`a��P�-ret�9͕X%�A��M7��[E.r{Zo��>�"�s� Ee�0b�V&�Da Pois[ aZ��G5��ir�))I��e.�aM9 r> 1� �@�9a8�EdE^9]Ռ"�@Ť�;�.� *�")FA%JV dic�!�"_')n�& V�e� ��En(L�!8-�ы�: ��JaG trun�dJ�2Ia����EhOA�`I�be"��%�M4eL DB�"� � T�a h . InF �Ŕ, � ,� �!� .iUx�-t)#^s���r~��Q!��3cN��F� ��A ���%�I TaPve�>K� �BeTN"�S?��� � a �xtra-q>�m&AJp��0G -2!��gy�^��%�be�<Y�:�)u6-{ )%:�� !�N�$�.ej ���iR#)6f�is-�se"L �πiYrJa�ee���e�?��}*� . a>a�cl�B1Y. aTj�aSkP-l2'*�%A_6�����3�V�( �ps bDj��PE!bbLjB}mƠnK�)E���2,isr sµi!{T�J�qqk2��r"` � �%9~Ve��o6), ihcT1c-��1�sZ�)s.-J�md%d%d5dLj �8-.CU ڍ��!tr�`�]um�of�M62]%`&� "� s|�DV}. Non-i7OSEr�.+.� �vga��?*@){5�a�a�etn|c3jle Y�Bincor�(�X�JQ�Av)� �Y� Bayesian�kov� in M.rdglo ( MCM[U�s*�0��WINBUGS��4&v . GkCo��I e diagno!i�) *� �z&DF��Mk!sR*Ɔd�9f@�f�&d-�U��CpAt>:a�WZ v2,&�4 A m !�R�AHi:"�4 ToҼ��?�:�$make up 36�p � ,��m�!\a�L$!!79=�2] 5&�B�CPj6�be%'z5 trap��j��UfC'ly-fil� �Zn�)�fe�'� �ρ�="],��HM~�*up"W6m.EÁ�\1"�J. E���S1O)@d1�+�>�i)�!��F�2Z��s/p1 n�^!�o-.)�=}s ain٨sun �:c8.�E�&a�M��9:Xa�(s!~�(s�X-s�(_� cn���ٵ�z .8jaR�%�K&�@!! l_4w�1wA~�ofe<�Z$random gue$W!{� �D��ZL��OZ�wAYr.7>�E gene�D�3!l! ��*v���4r"� �!B. Bp . Ob�d-��|��w�z�W5 �9��5!^A�il&z2� . Ninety-�M��O�� Q �=!two4c$��T�A� 74137QB��^  �� env�Kemf85�� 8703%��U� �XI . As8l*�6&�HC2m:s�N]"n/�]�[r&an 30Nw-�ll� x"125��R��%M�s f9out�z !s[m�~.<; n��the�, ��5�.U{0<%!�N� . 525�>H;5s�-/1��eF�-�99 . 8e>aN�t!Z�� ���&( 06�)er65JA�[�"m�Fad��N�\>�bsuper-�w� r����2^, �< �= �1�v�M�"�. �5� �M��"F�i�k�%�'�7. A5 d1>A; q����>{ !�� T%20.�& 4�<5�B�ś�`� [ YH^in�u��91a�H��.M��In�cMu6�7es%��sum)!�eic鍟Mb!$U�u��Z?�)�.A�ti5�l";=!-�!���')�AVY%)�.�2w �&/& 9!A��-��ri. �9\�o8�̳�`=~dm��preci�f)��n � � h{/.f��7":6��O9"�2%SW�!<� ��=CaAR�s%���X&fseqJ�Lmطo"oNAB�y*� w0he!�{ �|�n/%ug�f:L�.T)?Js1e�Qy?b�D" � We� "�U����D�!�I�s�P<�;�;e{B�i�aADi� F��.B"ZJ�>��Nh���7�"� ˩�m'N�Y�!zB7[ 4� >1a�at"���el�!2�-�"in S .���#"�"� beR0�m)a�� �Z3�f 3�3<.�SB�:�)�Y%D+�053� 80; a 51%��%��.Zg )aV�y� � ^�!Mw�D,QCTr�^ a��ed��%aOu�e�~b��C6�%Q!s� \hk>�6�%�K6!�I5b u^>��@5�>#9]2 (� w �"6,2�� �&�._*��aF3+�"�AE�4t )�]��"�� 6��� � !� 6�+Z�9�� �.s��76*,�d f� &cA�=�{6F/E �If; p�g!P�>� ��%6�**s9sA�I?�1+T1!C=yC4-q &-�-(5^12!�J 2t��hs��truA�x�*1VT!�:(� 9�.�5���2� �oA=B$�O�)��.yQU.�uj ! "�A聲�"-�-.� &"�=*~G�� �g .�f"�!�lZ�AF!(UJ~%u]�4�+*l!�g��tp/�� ��& t)U�d)a%ry�Q�[��-���G,6�s2��!ly���d��XAz!.�&�IQ�S2�MA+-��-Cj n�r�x�.�u�V�10�ow�1F�I�.��P.y.� a�_T��H?�CsccJo�F%��<�3�,�"%?:G,"�N0 �ast:IE �E�e�5N=C ��"8b��7z.�&7M94�1j���+ �2al.�ha�ai�1h&�or�v9:�h�O rain��:� s��U�s� -�.�T.r�n�Km]��&i2�<�.� �1�tR~-l . 46N���aS�R6G�cke�4�V.�,2 -"g �Srtb���h77�q�bo��� �6uV�i��<�.cs^ r���=-�ŔE*J�. Rf�e!�v�_stm�� j�2:u�b�UC<�=���drya�a�:!����I�jQ�F�s"l�qao?E4 ��Z���X�f���"OJ�3�H�.5⥀.�e>.�E]� %0������ say>;i�FcD39m�QyQ fno � �Q��5�i"Q5'�m6)/"� ea*���. � B`.6=�q�թ"J*f$�e.� J!�9��o%^ �Z�Ar�Eat���^�N1<ly !�. �Re    2 %zR%  ,. tsNR shri�� owar��� l�7aZH"� %�J��iT m:)< �M5=9)�E�s\��(� 788 )��.��8.�.i!t�]P�w��Z? =f�� � � ":�WP-d*��!M*�)U��=>� Lv6j�hh�� ��%4�rin2 �@ 9fE�upMr� quadi���B 1�t:�EX)m, drum����tSTgvz� Q ��EF��!["�GE�m��W �o�SEq���*\�� �6K. V!, Im��=�R�i"�C�"�*.�=�2�e�i3[B�*A�Q"B+m��s%A"s treZ#��:Pfa�%�T@��%"z;z�Tye� }� �x%sMX ��%{�_�5�pU =�AU@s*N Z^, dWt�>VK@) ��i��t�:w=P-�A0sy�t�wU��v�5�"�h"�e�a�& f�b>+lowHB�J �O�0�T!>�T�&e�b_X>&7��W��W>v��-l�qxW�� �0��s2~MFp"�.�_�e#Ew�*�\C)[��ros!�u�NB�e:i : g.&9 v�(u�2�2���6� �� in*�lVc�isUs2PilE�"�4eH*�%����5"���0  A���P-��@�'�eH'!��c�/2���6kU*�+9� r�v�(���b D#,� *b�ap&�P!=�P> � &�%�J�9�*��\ruDTu����%�aH78 �${a)�6�Yg=�?}?Z�s ���e��? �P6�gsaY��bf >�,�f!�0� bree%b*�_�����m׆�fshk&5+:F�xY3 �@�s .� %ep$ �`�S� ��k�b���h�Qx�7it���H �e����Wb W��&'�t"pi/.A|2�ZM�.,jA���9d�!�#�+pl��w�8I�>�Fs��� t" {�ed�-�f.1*w�&ve�y�iJ�48��5dr�su.Z �*emp���gg�".e.�enHH. Car%�)&(OMA_ �yam��8W!�& iy!mpe� �vBV��jefa�s\IS)j� he �\Qn�-�w35�4 ^���.W7�l�! ��}qIvW�stA���!�hoNl �%)�j.�:���� �7��cio(r�6��kw  �ӡ�at "��),A��?x r&2l0Uh%f 8H"S�if?^�Rbe� e�(S:ich!s triv�M�H�alGa\0!��<>�7!rWR�f�>���)Ł&�2��e�/T6��T(!t�A��!q�.�CbF $#F��o. � � :7u!�� �rMxu�i��agQ] ��a_�f�V,%&.��*JA4Y�"�U��?�� orro�es-a�p.�T�F�\d)I��'h�on����j]l4]�>BP=�p]�FA�" 6 :�.a�7s�`> m�e!ZZ#9ة�Ec2(Y<�1�>ulsgl,� al <x1�n�,bor�h;g��(s�H�Qa2 ��.>�O�U����M��Fd�>!7��s$ �A�R�`1�z+3��aT���:� *zU�A�DK�s��"� �1#��� 6�(�. D��g'i4E{ 2005�V-4N�ify cir]�:�t2.�3R�]�V����R[:1&�bH 006Q3y�Y�O ��/r#�J�]�#a`-��R � . U)���A��C*� R�Ou"�\-��n$5�G5sAv�un��~ 'T�obe�h�%"%�v��< R��R� GoVK2}b Q �D&:,I[ itud: �pa�U ( KA�O 8>tR�I�A3A*oJ���.wAWI.h�MOCIn�&�^����F:�)6�8�cls%�b�e%�� �pV-[� Long!i�QJ�;�T*R ��2�ga^'nm^)���)��ne�Co��;���n4-� �`c��r�>o�st��n�U�th!`�Ay&� -/& A��SB�� ���on�m�o� ��+&�n:7���(���&>�Qo�.�.�AJ'�����R�ka�b&j/ V�Fh�Cm�)4�!6a5!\��b>�"mOl�DQ�� D��h��l.e �]F����e�teV �4:�:�. LY* X�`st�8ns and dispersi�on parameters . The increased flexibility of this approach performs better than a single negative binomial model at characterizing the distribution of larval counts , but ~�rarely resulted in pupae estimates grea�D30 for an individuWDntainer . Dispersi. Mwer!(fluenced by�0large proport<o!e �$positive cis!t1duG4a small number> �T, and did not fully ch5/e}observe(str=6 Dpery . Under9!$survey-wid�co%j�Lalso due to super-pr�ingYs 1�eir i1"� freq!08y declined over�course� the study�Tiod . A closer examina.[=L$mostly likA to1X-�)Usd)illustrEv,difficultiesABeffec!�lyI�� )Fal�nt9% ~4�(. Eighty-on�125#` samples ( 65% ) with mor!�anA� �%�collecM� untrA�(d , un-lidd A9!�is2�!���pupyHhas a )wea5�Ֆ���frel�Uto�few very >W�ue�. Sf�tena3to beVly�_ eveaੌmay��(present ���ڡ�>�!�standA� crop1 �. Ma�im�>an��IC(significanc�5�`-R~�a�l.��zse habAcA�Piped-� in aI� hold��an�/" } o�:J� 1v��)�%� lass�+E�l�&�s varied��siderabl�2� prot�{f p�� strongest��>V�� y� 6�Mim��%�ya� �� at9/sIO.�, pe�Dily outdoor , rain�}!�Differ� � immanage���I<�X%� &source� ear��Z6 Q tial-;s!�v �t)�q�� s sug%Qha!_A$ s$infrastrucI�ay leaE�,!��)= nof��typ�1Pop��onF+ YEARLYe LATEEB� sE�op�e ar�3�_�G6U�6� !�Ax1?ceEbdr. P b�Iy`b�At�beginn��,wet season ( �) , S&" 5�M�;Ijy-d Most�=�� $:� %�wh�TW � higេd�6�Dur���b�) m6bb��� � �@� verag���d��"� .1WendA^:�(I%!Pal�  >K agai y�>�which fu�lo�1S2�>�� ourY� mode�� arly1�p� 6 icO �( i . ��$, temephos� =A!�e�isE� �>!5 time elapQQ q��d9�previous6� M���mosqui�;A-|dy��lS. T�packageM�":ɼ.��[we su� aSa�ɣa�es�wa�w . Anq ro�uh"�  environ� al dg�` of�6�fYor !�t/ adap� ve� ?ro��$. [48] Stu^� �ly �way�rop reg� ]!� worl�ttes� � U"� on 6��e��[49] I"' !�./ s.� in� osq�*T u archq�� F inE�%\6)�Bll�Fa�cohes� B�Z� dynam* A�!r�� !!i7\y-8i-�� Y %p(.��Animal�MtegJ  ex� cu�th�orm� abou% ondi P such� metabolic{ �execu h��ropribehavioG �=�%MciR !�In>�Y qua=quant� A� ssese�+� stin� ttzmod�e neuron� unc s via me��ism� atE�� -�� n!�T�}E�,Rapamycin coq0x 2 ( TORC2 )2aCs mpl�/c�!�A{ pons%�cellular ess �growth", . H�#�Ihow�� mcoord�esN�L� 5�B�6ME$6feeest!؍�bacbvor�R$nematode C�� lega%��a=� , pherom�S,F!�!ftempera� r.A�A4a Am0daf-7 TGF-β � 28 insuli�ke pept��in sens�I sx p� te aT �dM��Ire�!e1�l entr��X e ale4? auer1�st . We find.�ac��Y�to� � 2� both�7� �,�� toge�ref�9b -diet dep�nt2�u@ thus!vi%�}� ��F� ofi�� �bw�J6]M'-� 5�endocra�� �. I�I�,M�similqb5u�AG- ur orag���i�4a PDF-2/PDFR-1 �Q* � ing-9, path��%�9demon�)��tic� �a��odL � �phenoI iidentify��\trait loci ( QTL ) assoc�md)�t�)�YTQ �s|�:+ �=%Z)hub%�communic �!�:���A�gutA� bO z reby� L�o1�.A챟� Arr�y. F��sa� vary]6��uliQ��aex��t| pastA�eri�J�-�tob���-�Qmal��� partE� crit$ 6�Y��!Havaila&$A� . Nut@%4ex�Q�s:� traj� !-���qLs physio�u)�acros$la [1–5]y�major� of a taxaI"� � of nŁ�uptak �rough�di��system�A���� play��Yacquis��nuG so!�a ig��conveE?<�- o�� tiss: inclu�&!�nervous�[6–10!��rgut-to-i }A�R.��&w F^m��now bL���s�)D1�a subs���l%biochem%��� s _���[1!�17�H"�>D.� Ac!��L��oųq!o� �7Q�" ai��be� describ�!xbZ�aenorhaba�s �disQE�T repertoir+>-X�b� yA��0 q�"�i& ’s>�[18–22!_I w�B� ,)=s� 6.G !u&} �s (*A�p"b "Y)m% �$of juvenil6� c F �alaUge [23�E:!�sal�~gA �mo�Eis��%:�2[20 , 289!3Abunda�Z sup@ e� e >e��*~ !792鞅*rs�, ��riV enh]firX��Th L+��v� �in rtun�Vņpl�a�*� byMey{��AvVpM��#.} * "�*� �i)�t two��allelV &� �K.g%��[3�8P"# downq4s�� 5!DAF& lig!�!\d� %�:7"� N) aILP�6�i28��1;� ns [Ey3�3�E�� �lso� ongly6.o ub , 3�a38�a�t���I�ge��\-B*| Ps*9�� , 1�-�� . Whp ef2��^ncoby)�ed&& 1CinputC!/o�"I �#t� t�2!.6%v6�.��J�In ad��onQ!>6�plawas,cFoz ��ll1 �m�ofei� >)%�-}e�K�&h �-.C" A�eg~3 , 1A1��19A 9] ) . O��al law��-f�gld-e S�w s sp�aJ.�  Zflow" ydU!4! em�& XapGun� ��$� ly absorb��a�hibitŞ er-aI!xroa�,� e��at�"[2! 4��41�Ye �!!�"  loc�RB�sE�be�Ug��Q��g��antagon�Ez-�K��involv!!LPDF +U��serotoni!�altho� Q�$al molecul_ �v"�hav�_sU! $&�? i�ces�-%2 , 43!IqW>�; 7 �J71 (1ral._[21N�Z� p� .v� m!!�ga�*,�X!g-�5u�� ��V�-�!S&o. C��!l��deR0�M or utilizU�! �Ŏ!Labs�of -�"�,-� mu&&� �d �i6��fZ%�e�"�%Q2�9m�6Vӝ@"�&�. Via ase� >z!�:?�{.� wild iso sze6��sE$A��1!Aubl*"qM��t��C/c/Ed"� wR  . Ou.��1�) NA�2kp� &�� E�4� "�L 2EaNhG2�\ allowaP���U�E36� !(1�*Q86;*�Uĩ�ir:� e . Gp!e���E�"�*.��� >�:�man3��N��we ask� :��e M��6� –a:polyphe�-����N��5'7 Loss-of-53a�AQ�#�ʑ(, sgk-1 SGKI!�0akt-1 AKT/PKB�om�eeA �y�� *�,"�34B�m����pl�}ful OP50"��� a�1exogeno�"W(at 25°C [0 m� r N2e�)�( ft7�%-( mg360)( ok538�nd-&,06 ) ; n > 6��� >50ueach ) !�&H2�all threu &R$-!�25�,or pkc-2 PKC����-)" /tl��C6{ up�%2O shif�27!E(W ."-in�5>Mor Hi�� [27];�B)Q�)�"t��M@&��]�bl . To�cA�y T > ��e:v>�7+�1s!Kw] �74i-� fic!hcu� erim�0.:�FIiMVcDNA s�5��s��e u�#ges-1 [5/$elt-2 [58]!]ifb9]_ 0�]*ASI: y~ s _a gpa-4= [60� robu6re�� e:�of�� �E�e%$hypomorphi�*!iWpu� nullE��&�C�S" ,5al.C �.��r� #y�m�2my�*� ���ml9�fai6�!%�6�=%���z,�A�tA�AKT-1 m�0c�%"�0t�6 ��*��m��E�FM R��! "k &�ho� �D% SGK-B� 2nf3*� �*546wes+u"JmVbskn!--�&!*�q7ar�������[100%:)� [( zu135��n = 4Q "O#as���W(&�A at �n�S��Y>,�6si?09L,2D>}"�:���!���i9š�a� t�)KI5#�� 2v r � &|R�ح/2�(6HM2�$��:l5gen���'1�/ fouG%6Ua� !F![� ip::gfpJd [61] l 1 . 3-2-fG2&K m�,�n�2� L1I.eYDi�2p.B� �&,ae ��UAar�re�Lin���icw 1� �edEF fluo� A�$itu hybrid( FISH�x2� S1A�K"�=c.>f-1Vi2U3���-"�"��/>SJR:�!�&ataR)B��H�-�.. ascr#5*�( S1B�Si�!)�*"�-inA=r�0� {e@v�\C \,��infA��Y_%�M�tF���t�!i�YF�deg=E� �1\QGm:�aAv��J�M�!�`g �$x8Auued�]6h9�-�n��.����2�Q�v!� [11]A�igaz� 2BE�NQ)��U8� �� �2� Over#13,��� ��B lq�A#DM#%�^�'�c|2�6�c+ mRNAq�mASI���E�r�_ 9�F�1&��tJ'6�.P �+ILP�+ � * 6�6� i��5�o�>!�I�:�-|6�e��7-�po�iw.%RIC� :�6�, deweYb1V6�aeY28m�����!o!�ASIE�ASJ5�F�M�% I#Hs�:.Qa ��m�2�d2�� !�G4~si~^�,Z�-�jor%rM�!66�of1�Vw More�a #�m-�16 FOXO���%k�keyO  in��2'–A��*E�*^�+6�I� -med,X�u4m�,�� ]<- AU�I/A��&8,!׹�,aU��>"m ��2�"i'2rN>*�.���E&�e:�2[ "� ;.J$-3"� in� �2ed�@�s �:ɥ��� *33�c$�!�#. &� �'�4.�f-��A�>�6+���-2 =��� r� Fg�,6�!"*o exE��p� �ngAc�#� mit�- "|4. horm5�B� while� v;',E .�Ei HB101�kN4 ) [4!�62].'Bd ^�in*�` as�a�Hob��(M#:��5D\!�~���un.�nb�*J3�ZA *� [_ }Cq?.�E�*� A��o)6j�,&�"wer� aZEa  peneA -���%��� , it�l lwe*�� @-a v90�1inAE>�Ea cei6 C.&# Br}sis.u��:8, aberr�D�7ZY6� �=I�Hto�f0� !��*�*�1��8is su�%iB�%I�oenc9J��wis�>�3 J��,!�nd��4 >�1).�-�� Ll!�U�1F$+2$ba�Efor��F��� ��x8f�.n�͆1a r}@Ai.�=��P ]4a��<*�� �%:O�%?.*�-urQ=l��� s&@an%�� [63!�.� no ob>=r�]�Din^� insteA�� �sligh Y�2_&]( F~2 . �(Df = �� P~0 . 099�3r%X�lZO���tm9com��i.Uby P 5� ig 3u I�9ntrF4E3 �M�f&� �M/' Dl�MG)�&���A"} & �6�e&09bAA�NF~29L!A9J < %L01; )J F~49!` ,Z)%<3EEU3FrIn� c�%��� " s&� m�.steepl�.enQ���r��14N�:��%��(s <0��� �e3DAS28rTraIPK�9�s��KNN�� �O�P� ��*�D�� �ihA�7.���para`�-AQ rmalRw BoN�.�:�@3P3va��>M�Rmh *�"&�)�N�=g J.8te� \se� n9&�)&PR !GU�>3MwY� 6�� !os� &�� �Gl��,��.- �.UeE�n Ap"�CE�.�N�-�>�FrR�!YB:�!eAT!Ac$Oq�)K.E�nr#in�98"j n6 >}. L�D��eS.ty3�U �H 7��Cf�+�� N�N#�I]i>�. D:� N��{��"�ofR� [2')2�)A� .??�y�J*93� �Uř.&��[2�4WB�GA�� �9F9c9X*IR3*� F@wo�LSXy�nw 6�a =NG2;.Vq�?i�}�:�yZ9�>��* !a_synth�%aro\ [64]��YS"aez?)[9R!�2���~6s� zv�0q4m 4@=*-e�g:w�/n,=� stig���$*�n)�E&T%�xa/!*�"�'�%6�'.!&e!# �!u&(&�2)ac6�-�Pigh an�r �6�3a�-ed 2m!11�"& K3h�2 Vy+R<+("�2�mar�%b�5�turIK&F �Ysforwar�UvMM[47U"a." d"�:� [42 4 >� a�)��&4�=�:d a�Qbitum�n� "�%�3�5n�F� pla!Q!;n�%7�Z4B 9, �4:�y~�[xtZ�Nwo�1%A]Z}� s Auto�ZdeotrackA�d�.#Kconfir�#��2�I�85WU r frA"675!&i-C%�4� AE�8ca� fBc,�*�8�&mW$i�,!��0�of�3 ,lsɯu����1Wd�q�V L&G=cw�.4�t.`d>G�1t� K0e2QzTe�( S2A%FS2� $62:�rem��ve� �� T��co.�!��/n�!.�>O�։�1�SwitchA b�U!���� 1<�"[72� �)".�b6.+�07�#*K�5�#"r+a���2�fasted/a��Aquiesc�)��&� �6MR�[�6�86�*6#+>()��l8�&R�E� n�Gm.6m!�A��E1�E-22>�@K_W75#�J �)Fre :�["�D e satiety]?AoAuM#!"�hY[67–6>5B�pdfI% pdfr*^] ѷ1Ko��Z�Ae�du�5H9�5�%�~6�4To�9N�9<$mJ�1!�ɉ�-sU1w�g2�#��p�)I��;�dou��Ze�*� �R��rJ�Mmb�'� �U)V�Dl& N�/>u .�<pi!1ica� v�I���E�� C݁�s�D��~���&O">$F� -�J A��5�Y�!��W inctir&.A-2�faE,eA"�1� hunger}�zMI�1-ma噱$at�J�|#��a[i�Fi�G.. [67�4�; e�]�� -+ �Z�f=7 We.��M���R� quIu}�,A-2E�m�%+8=1�u�2%�>pM�AtaM��@Idauy $A �!6 @�J+ �A��guish�2�useh72s6�*�oBj#�2i$q4��u}J�ɑVno*�.�#Q2'T? 2�N���*Z%TMX]1�a_ Mo�/�$�Ja� 33@�#>�!�i�N&�2� �ex�to�0Q4�IKA�+p&F`*add� $i�.:� t&�:\&��5$Q� <ne!(22(�4n  �1ngAuniqu$ DM'<~_o�5dI��(ouQ tituWE[71@6�B�1|F&R( m�])>F�A 5{ �� u�T2(=6A _�-&�fH:I ( S3`�)We5xt�6z>9L� :�Ia �VE�!P!�nXextremFunS Wit�Kex �q54 CB4856 Hawaii� nd PX1785(t[ �f&� N�N)�dul!iʅ�"�1���2@� �labi_� NQj�5�B�io�1tc�`Eta�>�6E !Hu 5��NC,7�#B���ZM$"Q8��%�2�.� N2Ep���,g1�):�*�`*��6}""��Ke.�=}BwM.��E�]b m)�.�3] E3QEo5� >]and�"Bl%�sough�Qcau� v�ci!�!�s&�=c��� -r �� irst�;�M�"�SmGch�Tsom3Zbs��)��iCSS�H��a�h fB"�1i�Vg��ttok�N2U�backgr [72�>inib)map�3 iaG=F�b>\ �MIO� ;� up�%CVor �%�on.�II9ͅ�o a&!_�o�6�( LRT@6 . 17.�p = 5d x10-�193-� �=_XY3 . 46>X]548IV/�7�"��/8s8�]�min� YTI�6�k% �V0K���>yi9e6�V)��VY4c�s�D7g�<���*'+�T( A�*�mW�W���"=\�FZ &�%� >Yh(crunm"�9[7�F6�"xG��CSSIIA�$&|M�d���B#F�Bse��reoc�StoA�m)m`ZO�( S4A��T)��� atQ�� B5do--@)�&� 7"�:0"A<2� eBC�)��>:A�:�9V���wac�k�%�>�i ���a�?NQE&-is <ic (�ENILA�pcarry1Eu�egm�9� �?AIV6�)�l$lY �_h��II [74�6��U��J"�oŞ}=�locus �.� cop�B��H�]�"x�mih ^of \st2�%ke�ub-%dA�u�brefmEh�3j q#We2�g4t '� 2100 kbF�4( ‘QTL1’ )) AlyQrecapit�F!)5MSJ?w�"b�2 �AI����#!G%�typic n�)��0e R/)<K �9al0��QTL2”?*lT6�F�(bf��to;6�9>X �B M"6�map��pr��FP � �me&�R�breakpoi� 1�nAEU �e��@at" does���Q�" cod!\lbT � �D , S4B�?[7Q>BEE�*��.�J S�G� � �uC%ne+�Am�<z� & to�)&�4,?�Tresidu�8!)&� ^ u��>CRISPR-"�/�e�Png"qB�".� �S4oW^�4.� ��Ee)�� A�5�sB� �>}p3�N�nN � QTLs���;���MF� �se NIL4E*� no�8 n�wng~zK!�B6�>�6��H#Q$zHmq-wK !d� ��.*A*%ͅ]�ABwN>����*hQA�FG. rN"a7p*�I�Bv96.Gt>3�9*} published�fk�&)G6a�!�=3(��U 4)���:nmb�cor�6(#d�G��&A2 –3*35 �EW1N��#�-lnc**LW5&a c2Y4A>N  .E���kCn �*zB>4 i"�9� .��� ��&�K!^2�(��>ly:1Bk ,�T+E2>�$�A*`+.+r��%2t.F�Da�7;�B work�:v��W��*��&9�,~ r�)&uC.u ��)'�q +7l(1r!�E>&�4�pDtl�v�U��*tyQ�1�/po=� ��-.�b6 &[(:FJ�^y�qierarchA��jF) ;I��9/2�XZ;� r&f!���-�.-p�XJ�"\!i��I;�%*�����&M��.3`{c]2nf*K�i-A��2�E��fXenB EQ*� f:Tne�Knal��G&� ��i� y !eLj��to5��L�l]� [76)C�?�Yf��Q �YM~2ire�+ig]!!� pred�]ve valuan�er� .0Lq>�+ �eA�f�v:N&�l . Byu�ng������*-:!�U�.�]�4@d��ref�0��rengt2or weakea0"&�`pbS)�z�]�ly bia�7�&*�_�A�(c.l/ e(6� ��ťG�${0tph-1 tryptop!�hydroxyl�&��.l�0� o�*� =�p�+�i���z!���m;h 5�, "�V� *sl[3A�8�Un+ZXi@" d�=6H%bee �6# st,A�| acid6cW!'oxyge�u"UzA��in dire]!"�^ens��"�X esta� [4�j4�48�H"gere�Eq-wsaWoHA�Xqq>��s�X��\� glut�e8sm [8.$II��s~E,e]�%�J# "XOx�����atwa�� i)E��I 5Kdeple�qZ�2�t���c"vG!�1 ]�N�9�s�(% *6+�uB�(����86�^�Q1�$-�oko�W�.s��=6�VuE�2+ o ar|9K5��d��!�� , be��/arynge�2umt[�V�dr� �K���!un�Cd��&ya��%�[5y Y. T�2� !).|t!�=�"�%\-��w"�:�:�B Z� B�U�=9u "�!�|uIpU�.q��ssm�Q��R.��.a5"B,�.���U� M yZ�sm��;!�E�fh=tp"A�uH� i&�Z.�=�I�T� M&C G�5�q�~V �D�\�ASI2[�%,I,%"�% s [8��i��+�Sʇy:�= �2�.� s n5?V:��d!H��e5b[? mi%�� �=�?� O�TB�:Xi� 2�6�#ZssU/-r75 A� K12- �s�@;ST11.�.l�aiS0�� arbo���J.�I iffe�1@profi� u ���at��[8�48:A"�5"&Sc)���t�t~2�5�O7d&EG.���&�W ���` W.�Z�j5! :��i$2^"�+Q��clu^is�7d� cB��!�%1�( M2"M#ut�~�,�e)U*3,"� t���2�1�2�<dd �-�h�@i"kJ2K�� #)^!Kz�kn# . M�aS�NiQFgefam#A�x l�@ !��"�[ OsOa� �&b-~ti�)�i:2V sp!���{�P�j�U� *6Si�|*h[3��3� 3� 9–9� :�k� �<-d"�6%��A�t��� iw��s.xm �gst�mod�F�+!gdosag�\en�%,! �>U9� JlF �rI�=� �j%�0B�:iu�g'.YIte a�hL‘jm�!�net[89] �ya�Zm���b�!A|��:�t(XiGy�|5rat�&rec%d[!�)Jmod`.� F0s(outcomes [1�jM/ , 93]2�2-���hg!��"i��q�s� ^[+!7" }$@{i� ��!��cI�Ycosegz�%c� �r&�D(�$tw� Saej�0�Fr%.� -a�e!}^��.� ��#"s�a>s��I !?mawmhM����*���[K$PvtO/����U�.� q7�� �zI ommo �end~i?�pE�-<& L5���D,6 ,� fM$j�.�"�icY�`��"� B &�e-Q�^k�b"� A��UB!@c �#.a�*�6"t�����;[�w�?�����2�?Psida�ow�|eam"�B�F���gus�{l&� �-� � Y";��vum ( NGM1)t �E� E�Mf ~�uS�. Plasm�kin�z^+$t 5 ng/μl:!:unc-122�Ico 7�m�=r�30@��[ ţge�� .�Alea\woM"%\u&�"�." eachKe�"]3�d�IK. W*~ftS�zf��:�xG|Mk�C�( ( CGC , Une�S,of Minnesota�5q�ka�>kglyce�stock�pi$9us�!��s,%Zin LB%�a%_vK. S�P�`�{E�oy�8"in S1 �Bs&!�of .�!"'*�H�'xandar</K techa2u��Oᛡ�"�&�* brief ,�#m�%.3}, WN22f,F2aogen�I�%KA�0F1 heterozygo�dr )� � �}ZscreeaIAF<M]O SNPs![`12 . 63 Mb ( WBvar0000125� G>T!K")mg�� ;DS 5’-TTGAACGTTCA4CTCCGTATCACG-3| 3A4 GAAA (TGCCA ATGC1at 49912�24048�C��99oTAGrHGTTGTGTCCACCTGGCGCG2u�99��T. TACGCAC@A�AVC �. B6�&U%���b#����2� "�& 6��� "�&(A� 59 )�6a left*5'"� �413$Var0138059�f�� !9!3 a reRM�.0,( WM82�f!10M!0003943�&� �W� �v 9�"154�)� 20|9�L]�29�|40Pbnop�d�,,a�2Pi34�peԛ n-synonymm8tein- (�(:oeaA�b�Ldb�a�cb)�$HdG PCRi�x�*�YpooV�&MB>��Gr*(EEcloe�P��AfIDfoDk@.� �" udy:C]p (���6!�<,�0 non-3algs!��;1!�)�BkfZKAA3)�]b)kbNgif%9,j6  . Re�B!=�� �[ ����|cI�o�4SL2::mCherry::��54 ��UTRpC�W(h����*7�1!�-���79��GFP� or". srg-4�QS7 (�!8228A�trx-1p:4 Je��@٪ݿ�IVec�@�+V �"l�{GitHu��4https://githubA (m/mikeod38/� � . gite�� 46m�GE��,�<"!!&�*�:pDD162-@{mid-b87�* /Casi�!Iw !x)J��$dpy-10 co- 0�{ [99sg�^s�W�m/�a����(a$pU6-klp-12 E> L ,: [9�"� � �%� Azt 5" !� � 3M�..2"y . Do�3oligoJ*500 nM6'뙣%�:��@249304 ( D1462G )����t�A��GGA�ATCTT��#CGA��GCG�� TGCA T+ GTGGHC&C��� �Z�2000403A�N1174K��G�ECTrAGAGTCATK�TjTG�A�AG�pG�'ql&3 2� dUu� lttz 3�7eC��o{�<i�Z�>� ��&� �� 1J!>�M e���~s� �a���bed [9�)I& 5 th��2nid,you�2�:: on � r"kI��$rA�Nqw�;(E5&�� :& �)�9>o < heat�7aMi a6�[.&K �M spun�(�C � vetJ-�N_�~i�16 μ�  �kD}ed=d!�5'm�Sod0� . 160�8 fl f����d!�)%  sgB�S5f�Y/�diF]�drO�W��%���Y �z75 eggs��S room��e)aDAZ�w�$�!Ond 9 Mbat �Yor �N[ �j2` f�$��*Q v*9 vise���a/s!.on mi cope af�%x)L 60 h�ya� s]O-aHA�;=Np ¥!sŜ<1=we"@1��;��l%�%ex�T � a��{w�$s�&)F.5�sAll*�ice�yI�"yp R:= anes�P�Oa�5mM�am�/eL8$igma Aldrixrg�T"Ek imaga� n 2%�W+?pad"#prJ ,Zeiss Axio I6r u,a 63X oil imG!�ob�z".�#S!CGa�!��)derM(<=)U��u ��)�B�%`&�@t��f�[a��#7��E�y!,ll)#M�co�=�z-staof�;�~�u&Ռ^�l��� . Q��b;u�>�%`JH� F"�k�6bXmNO'�f9�pla5#2>�8!�  somavi�nI"m �.��)raeOan ROI a(>GB$. Mean pixVte��I�recor��!��y  pair�M� ��Q-"a��f6�ac�Q%E� �$.=�s>�l�"�( 28�9u:��10W(EGe,I�3L1>�tUg�A��in�N�1�]�f6in = 7%!maldehyd�B 30q9u��:�xfer�(to 70% EtOH�PBS�hN nd �$��t 4�Z!E�t�)' week�$2)nwFCy5-labeNKprobe��=.t 3A[.y% "��� u�;at}V� f� � A�tE��&mcby�ie[^G!�v���]puncta 8] �>V[cl���{R�!��Y�•$7sum!*���K�4m���$ver�2 μm-2/9��)2B�bYcals]Ag ;am�.�e2y�A*�:&8p�Ssub�KJG�[/t`� nM\l�s2A 7n:��q�&B��8" meth�.�9��� easu��9�lh�%�ex"��#&!��e�d#�*0as���� �En�thees�b0� S�2�A���^=R1I� "$�����!�Y}_2N �Oe��%*C&�a 6 cm<ag& euni��,��F20 �2a*� { � A+R 9 � A�V�dqPL4���ic*�%h*o8 :����~14� >�N/� 3:� hotograp�7qP��HLink D722MU-T camer�\unA�� 0 Nikon SMZ745.o j %*a�} X le%je� �:�a custom $��m$dqz��" gri8naP�188 squa�%�&�ti*�X worm%e��� 5��m��! ��o� a?5a�kA;A����H!�10-�(DA�boxaq4dư in*�B$unambiguou� ��y.�:u�Bsco� m�g^bCta�@�2�?Poisson-K%(d� ee S5.s^: A�P�3KTav�z(n��e%� � "g:%�T�l e��Q�d#A�a�/��� 0� �w e�=y!�"��}in&-d�!. LE%.Ae��c��CiB�:D , 10w��."#A �5�Hm�%�CnCP6# �, 20 1d �w6��ZaX spo@6eed6 ��%� � , m�&���Wa\ !�� move�[�)��2.� Tem"m!�*�n%n � flow-lALcabinet ���4 -built Pe@�r2dQ�iA .��}us!;�$LED circum&�+��"� 2� )y�� or 9�A�I�fra�yA�se���bLNa�� Matlab�iptm> off-�%�9 Vxcrawl1yo0 >�!-nbGo��r 2~�r*�k!">W-fW�m -L.x&3 ( j3�:mas.F,k7"K!e(�E�e�&� �L� oftw`$( MBF Bios�cA�VT��POin2$, a KalmanŮ�AW appl��P�da�*o���0�g�8inusoid<*�sP%*!m��taR�5�R1��5lot��-�u��:s_�+a>� " � po� �c6��a.!��pGD%S ��6>F�!v) s: v�{2�c$A �L phy�� E� 1� �9A�v�2"�$�K2K�`� an�X |aZ d!��6��s�do8.*���@$��4� e�?�j9 ��s 6� �&wo1l :��X: �d�&��^mVY51~� �3NwZp"й�wef�"!�},Q�A��eZ�a L#�a�p�8���peed/Bs!�PA9s �&ab��!�be?q _J!%%xR��TKx �!:EK,A�$3��s �!�?�p&� A��BZat C5J*Ai%a"WO����2WRdaw�5*2 �XG8{p� I� [i���d&�U""Ѫ!���*�+Y+��pluri@��, undamenZ*� �u%�w�� grea�-i�*�&�i�a�brZ-G"3s1yX��( EC1 }o0orq mm@}�( .���Q%��N�pr&~3� ed CA��#اal germ}4g .up-0� B/g(vitro^in vivoe "R.!�en (1��A1� , �m%1� d~igF~cycA�� re�%-:�V nove�<m ��ualgH�,hm , CompMob�B�!�%C[Je��&� alig�?n"9�t!<|, a!�b� @  s�MI��to K�!���"�2rt�motif��a�6�Ut)+.��& ڡ��t*O�x�)i�gef_%�s��%t��A� �!�pre" �-��^un5'HzU�!Wy]�� 5�-���ner�n Q=-y �8a�,s"PD�.�� a<a�Ad'o'-C{�IB���(�6'"�in huV ESmO% �N6(6�f�� NF-Y��Ebi��J�-c,~=I!d�V�� �.(��� �.�w� .pr.��*�#~?sm_ insi6a52�Y�E�xH?0eXFF. .TI.QY���a� ��ca�� broadAc&� u6.`��-�D mmalNZEWe\,P�䥢�zso.� =�Qe�!A�K+��a�Lf����A9A�!V" ot��.vaLy21[�OK2-��7a�<ark?_�d!��)� nˆ�6���S��$�=�"-@�re�2�ca�Q[l;oK< cessʃ maniƶ݂.ul`!!!tA��7�to=�_R�.�*i�& lf renewa�p5�c�8!W;� !�,r �� msb�� ocysTXou�! ��As2  Bfe�. A\kT}Ha�P� he 99� d g^�\ ens�O, a2`I! l�Cabi�H!M��9�e��jl]%�V( PGC�[6%5%!HrU�precuri�� 2���m�e[ =en�cE, \2; �ekaG )-|&� e$)vg�*n5�[,7�>�����"B1��3� <=Dcye1s.tXFrGClyH6*S �vie�in [8]�F���vol;!u2!Yleukemia���1( LIF )�BMPh2�l�[ 712}M��2  G$s Nanog [1y1Xp nd Oct4 [>1�&N֛ sign��q4" =k<�b�\��hh64[17�+��9!2�.Ts �G �A��IEN-��s� ��[2�L2��R%�����cZ %�2|51X8t�%(6��5EeT��en'D� �vt>IaW�s �\ goaln b$o�]m�D7s"7 W2�.-<�4of~�3hCA;� �@�m�$� "� �d�$� ?e3��5%��suQso"arr�,i)�s.�45F��d;6$�Z�i��Sx� � �\��A\q�&ds�50s w"Y W� �,It " 2� ��a ?it|!�4�oftFMA�c�6cisda�"� c�8MFo6�M�+ !�!u�Lir upW3m��o&� �'I$ ews �[�K/$�A*!cVJ �I&T, velo .q %� �� �� ��+ e enuJ%�ofB� c�)�gQ7 Z|�|%�v-!l�""S7�� A��/6P1A��[ |��3p�VpC"�,� plau�")�1�[28#Q� ai�teg,�M|7.�c],g�by.��!�.F#Ad.�se<9�~F~Y�u*� *A a=� ques!�!Q�l�g' eukaryoL"%�asӼs�mB^ �roblemaNma�m�Lch��n :[33Ŵ_ �~� +�x�y �a�iVtJ !*U� �26mAs [�TP�a�^�4gH�?de� o)� discCy2�2validILRj aI carc=On�ڗ� @�#M"V"'G��*�.~�iV���-> e ox�ve 5�phoryx [3� �(}�5Bot� �Y�79�u!N=J�".��@�5"� orth%�.�!�hT,"bJ?elea�I)sub*#ksee��1�!�te8o ew IZslowly!�"n]q���E:�{]%��&bl�8of6B%��J" 1Ş*F#no� .�I3��,!��ac�'U9\ &��I.=�many Mory#s� f����]!K?4�&�Mis pa�,�x���Xmy��a#!����)E!yo��M��!�b*G�t�I&-%~�Ya�i2Y1 �[Fa�fi��'VU �l$� %$O2if~ .Y� %5i! #��J,��< � � A�mbV!)�.=A��B-">!�B�FmY�+� s�$al �Dv�99A5A}.�c]xm�iZ�A �N-�c%69 a-�.�qmp!n)A�<teg Lc���%M�Z22�.�D � �&� qDj- edj%�c.�2�b U%/a�B�XE�ov�)A��# R�9�tM�A6 B�#� Z$ss&B F�EP*� �Q� �&f��-����of�.+�Ao�W�65. Fin�E� �aH2���k�^�^^  q�&� �!�.�.�e�! n�Xb�$.�� Fi� �M�N�� 0>*by2�(��. sor��1O5-d�0�4~( dpc�ME���rrA ��/EC)%�%@m���{[*� �-� *?.i F�@/]in �[�WA�0�dfV�J�t*/R�SGM�s� @Affymetrix U74Av22+�e rX��be J�;AV� 1��le��&J+��! Lf��|pS!�W�2��z�J��=iN�.A�ɲ*��/lJ"UzH2�]� .HaM�i0+ g:��+"�����e$ ߮"sEm� � E_"z-��D[0 �!it4%at1 �= !��s�r��އA�&u!2�&mY >|A���{�aiA@Q�d��)�!3�����ZN�p)��o6>8xnd)FH /Ah^e"�Fi1~ depi�I C#e*�230!}b���L�)�Jd ) F�{F4or�m%Eb�]FB��:���meMB%uX��!��).!�1�b6�+b.d-�5V�%d�#B� �cK���a�.K��H . Chi�+�� , S . Zho�D�3lto��WA) ��.�u"���.�+M0< w��~= (�J#LW��ed Onto-��[��J��Ga�% logy���,*� � �\F@ H��B�.F>B��� li`6��Z�s S�S)SO!zSsrM�all�u,taQ ����"� "� r�Ng� 2�! nucl���!�0� o�"�! ~!,6�A�ndV�!.��M�� F��JbA�"�$in=-t�*6 ��sam�(n��&�I��9�I2: ( �LBJ;on��%a�.S�R^2S^Vis ng �(1 qi�i�� took�&)�A��y%��* A� Y+!!�"�e*� �� $/r����u`X.��M���-�D"Z� x�!(� �� A�hkV.��D�I devi�/mW8>�16e�A�- ��!�55.m(��Ael#�a*at��[ '� �I�, Gdfa� Dppa&*Esg�Utf!�Tv2%e5�AX��X M2r<-as"�1z�<"�"�( a8]% Dick�Dc%im�5�=on! [28]a�i�|5T a��l**(K v�5�ry� �7&� 2�vF a�8.3��/d*�d�eona�2(���-I)� a."^ nonc2p&`��_*��I��)�+� �%r� �~.y�<2���M�A}"C7a�jS>�v�0�a5t� �K"]>+E�mZ��Fj� ǜ!52 z�e$'a >�al&��# �pee�7""���["�� a��)[a�1�i��it&�qsolel�W��"[��� ���)Ir{ u v�9 �!TBA�_��&W-.E*�(��y��ɑ5~�'0:2�!=+�)E�� <.2 9�le;)�"� e^ exacl:�,/|c"� -&AU�Aݱ�%I"� 5'yt+x#E� A� d��/H ���5�!�We emplo�5U.���8�ngg>��%�A� �d a��.�j"�J*��h��D 6 s SDS1M���?f�9Py�B%�@1=9 d S1�|1 !@en ���&�JIHkB "; ��$���P?dog���}^�Bl-�@)flank!�q�"�2C' � S1�wm�b���)�.�R� �cT25]���E�!�topU 39Q@ � 2!B�U(�&#(d]lin2B�6Z&�toa�� �/�*FxM 4U� !i�of�Z&��"�ݤ 7��#c�wAp�[ ATTAQ�E"�i2z� Sox2�[4�Aq�E�[B&����f�-$i A%,v�.��N%{�9v�A�rv$�B"v.�E4 a% �q*�+ �K �[44�b��S�� w��v�dh6�ka.E� oE ���cB �I* 8!)�m�lindr�Wmat�! 5can�'al5 /a;Myc"�j�'"1z"eD:_��0c helix-loop- %_�k!p�?w�����e�Pga*&r@c-�A�5�.^6��-=!��$elf-r^�*�#uU[5'!�%�(+paU� cocktaic?fA(cap�+o4�du!T�tcy [5+_s�JlKbe"v�!e Gmof�.b� ��$Z)y�]N%O,>y9 N�"� �hU&O�J!6bty�� +BV[AT�n��5T�" Fi��y lucu��zVI��'�nA�i="� "� �GQWlo� thym��e kinV( TK );9*�Q �E��Eac� yq>O)I%}2��X%�La"n ngth�EbgAW"?�~�a��tE)�Y3A;�O�U.S�a��n�+d a 242-bpa88%!!���B?� n���D�~( ,��b���nG�LB�t2�kRe�alread|+"�m�e�2aW� &���jg.�MinY<.Yw~i��s �K!��9v90( N6� ����UmK!</��Asit)/!Y�25X6�;���of�;��<e.�3 +*u=)5�yt��-"#����i�;=��TK"� }� , 14�^�25I�-CXK�A-a? n�|}� ��v���1� �y�B� �:p�UU�c!w�v�B�a*>1�m q" . Noajy��(m f R4�ǭ7K �?.�K>5*�4*�U�xY;�:�-�j1C��X2 a2��A��t:,� �e�oB&� FD��`Y�W S1�.r5b,�Z�!dT9�m"�;~>Ix �A>�,"t ��262�D2!zjqJ26�i$ ��Z:E�su��h��tY�)]]�Q5j/7_,: HEK29NIH-3T !oU�:;yQ��Tm:$id bod� ( EB�1�T��'retino�DciERa�6L-mM."[1M>��}Ee��%\A�U*';�(el��o�T5�L.��_Vt8E*!Wq�ݕR�. Two�aM� �&�0D9�1'mQnot*J�F}10. Similarly ,�.~all otheMPHs was significantlyiA@ed or abolished wa�%z ed ,qA�qBb�s are!'ponsibleE�it�4. To determineo�!�$identified)� P�Z�lly GA0 �Fon%weE�edKi.� n an) (pluripotent�� typ!xEGs���a �%EfR]ECs hava�mpara�levelsA��inIORus��CEb Nextq vestig��wh) any^!' �)l quire6A��¡8of gene express�2a�j��Ln endogenous promote��One lFs!\=�as upr m��B�sA�EeB(Datasets S2ebS7im compon!�Lof chromatin remodelAp"lex�@��r6�al silene~i][60��hA�%oryum%����)�a}been de��be�+!)micD upstream�H!\��several��6�AgPF�c� ��!�ang>qs )L6Z�JU�M��5�(�HD%���c!gI�MbfAj necessarye�maximal.`driven�A]Y2z. Fut��studiA[ill�6`)�te dissYonR�. N!k theless ,-o8oof-of principle,eriments dem�vat��,at least somU�-6�sufficiA�to��:��a h�� olog2Zi6* stem�x!balso fun�!\�E�b�In summ!��J���novel\ na fid2 �Mj�a � eferA}�u�F^�,. We anticip5UA� approach %� grea�vaccele->��/U�ele)�!ѵ� cy-associ�% geneaVC��� DNAuO analysi%KvErevealh $high degreE� erva�a betw�(� �"humane}�a�=�-pu2��To add����9 .e��� m��U56�0%� "x in �@E0aja�Br-�an���� s bear��,j�5 ,d bars ) wit- ir"X(counterpart� blue.. I�ng����- *��or$ F�� �s= a� thosNb . Likewis%�%\[M dimin5 2B uponB� � esa~� (s underscor��e powerA�28toa�� Ec-s� ��uA��-�E] performed� ctrophore� mobil!I(shift assayA EMSAQ3(biotin-labea�Yu�a�I ��ce� � nuclear��te> xtract�#rE�nd�re oba�G h�, 1b , 2*�� 6�. S�}��t%�bTr�"� �-]eu�,N they w�e�`ly%e�-�.�exc��un1wild-�  F�B�but�� prob >2aM%�8a:���- T%rM�a�Lpr%��U��-�s?5�-2� t4%1!�Toypv>{[�can _6IE�sy�| atic��searc� databas know��Eb��did%Cfin�match� mostá2 � , e . g .!]%U2 E�š�ly e���nq�v2�� � �seta! ey%�ed very���g��2|in��if�5�5�3B;E�� �1.{!2c�OctI,Exi,V�+�to -��unbia�biochem!ágen�Yt�!��� 6� ec� Aake aA'did�/)QA, . Two varia7 H O( s 6� 6b )�+ , a CCAAT box)�2Ucau�a�O��� 9�1is 4E25(Ze�� apn�ac�N5��6j [61]�}PU� 6EKAn-( ��e6�Υ��R�6b�"incubE>%�MCr��Rn�$( lane 2 ,��@. E>-�5�I� bM!��5Z��1� 4�� , el���!7az!/Q ajor�Z<�"�!s6g2��A�he� �s 3–i ђ)ђ�vQ��F2<de���[62AAm<i�is"� tB ric�NF-Y (�oA�ofA ,B�' C subunitMMh�r�ajk -Z)�! [63 , 64�RQw�" Ba��.�:� addia�alE� �Q�"S�Wpre:� -� bo�1�6–9B��IBQ�–-�%hleI�f��"25superu=y.{ag�t��A�V Bb�I�-Q unre* �y?10T16��a���|9� �Z9,an siteA�� er� � over"| �@ cis-� ng� i,���[� 8&%*�confirmB�direc� m������3:�&4immunoprecipit�x( ChIP ) real-time PCR . Cdc25c!a� arge�%C [65]%. Sall�Y Zic3�two!�q ���a�Z < of&.:�c�,a� E clusbinQ1�-�<sensus �!�!|��rBee�- O:��� �.,�toontrol) ( Rpl1�|�is �@:�� Q��Etho0%is6i��!3�s%�tissues��rE�� ev c�r �V*� .�:uy�C%�!�ly>�^ oocy/ ( 40-fold�12 :G loM� medi�2x60��) [66��!B�o rece��� scri)�:{!�inner)Cmaseu �4blastocyst [67vIn����ltern � spliJp�se5]�A iso�s1^( l�1)%+�A7 hort�8t# alyz 9o�4(- lu��N�� Do�_6ZdurA� �62��i�:M�7���}�_ mRNA9�bv�k%rs. as��( RT-��)!� �u�5L�ei%�4RA� intoA m EB�>%!�6X��5?=l:b) chang�� oppo�w���4;��l��!,!�M�cre� � �2��+ 8)�)E�*�ly down�d O.8G$. At day 6�RA-1'>)Vp���'� a P 7 it� ow�( 8� &)&% ]U6�!-B `modes�I-up!�5 d�wh){a��C"{)��5ide�yq!�couA�ofB. Di7>/of6@2K6����n^"A 9��a lackrconcord� lpat��sA�rA9�!�M�)�C ��mow!a~�iBt��pos���A�t K��Y�in��cal ma��.":lS��!Gor e����m��in2�ede�,!�chx�V geneWC pop�!a� , EOnafopor"%;2 �ikUQ�of 6(6�A[!|Q ��J�F/9]j_!ۑ%!�2��re:#�ȭ�� b�s.!�%�a)f�� t � �r�?0"cri@E�5�.� ha-en im�R.$ dqproliferɔ[6 70)Hinhibi'>�[71 $s�c�#[7�!A�:"ic�reA (o display e8!8embryonic letha�,8noL #�"*M$Fie<tagh�/(( 8 . 5 dpc�. How�� "�5Y.� ha\�exa,!dse sough$"i&) eUrol�@! N6eof9� , us!�RNAq c� NAi��!�bi onɄ�� &4AetiE#� [25��% measurN he a��(  go �i A�gr}J�&� =to maiw^rapid:�E�cha eriz|5U���P�q�aw�ef�a��z�th �.l>�=����>�`&\efG'Wl�virus-l A�%�knock9!6��� . As��th�0m�d#�~%��&"�LA!�!�g� AL"yR�Vex(iqimpai��EtoT&��in�ed GFP-�ng� [73]I�/ �%  B�-hairpinA�� sh� �(0%!V� �'I�,E@� �w� c2lWw��sel� �( out-idyB�over �(Sai_bi*9Q�o�ve�i��A!�ex; F�� off-�I;�w"�$l&!8�e# 7a�| f'!�!6 �2�Qbi�2&"� �:y n*K)�an �AGFP*�)tD�! ���Y �he5��%�du�'Pst͈��machin2,a�I'tha$pleQ�J�1��q�*Au ctrl� GFPiB.!+>W� ec�aag�V��uwA��&�ora)0s> 6T V�O!�a:�%���:�non�,B�R1A�-Vg.u��wasQ�i4&�RTN( unpub�(a�pr�r�]��BFDp>Z$markers do �al U 1�>3�E,�isQ u prim�.�q+>��AC ve capa1C��We2��(B� 0.R*-m��detail,�ngMl� dens!�) #yde��eA< clon� ic X)i ~� .��Ior � .��I���Z U%�sf�!�8alkaline phosphp(� -�Aun.�_ �  colon ŀ��*� q*+un =E �]�Ae� few,��>��<t'R�{ v�ndQ8���&��100% pU' FACS�!�2')F>�pri� o p*ng9'�in��lz'y�� to ��% (Von �sei�_(� atFY�U~ romi�n_:��du�it�5–1�(. Cell cycl�  &�#!�A�M)&P I�daLI �"� in G��aub* S ph+Y��). Tak01og�+�*-$6A )��&L lea�de�����\o:#a� re|es�^an�'umT�� G1/S�� ��Af-a. I\�tud�"~ _"w!&fEKr/�mprehensA� o�-&�'5%%ed�x�A9"o�de�(p2ti*C%G,�"7 val�!�is-� F&"Y%V�c����!X&J"�(t.*.��method7*y� � ���.s�N�!� suchNs broad4/p��.s 2>V�Z &��a"�)e"%�a� favo� mstandard!��+2�$-Z�%�!}� nc%�v���#n< �su<6",l��co� � a �<leE4b �0A8�(o� �5�f4�iJ1microarr�&�-chip )�� ,ed-end ditag���� -PET�2(\�p�,al advan5 s:� does�0*or�� wled[ �]�V�wE�� &p*v� Ayi� =!a�D5 numb�(�#s availE��q��)�n�4��1to%�_A �" from���as 500�  , 000 �RK ke� cur�,=��%�!�Q1"O mill�H �[2� 74 , 7 u��w+4vis*��!�uO&T�Y /p"�5ly�fut<*�b�"�)r��e� f�$dec�sG�� d�2opm�.!7' :.Q ��m1�%�2�-� are� ���7Q ^� s"� iB))q�P3O i��5 . Im��4�^����� ���( @��205� �%M 2@/Sox2���!� Nano�1Z36��{nb;'Nng� B!�6we.|"K&�z�!tU$a�.�aA �8B!%V�� AVT �6m�iSMSA��<@���(a M(!s"�6�6a�6 E �!�1[,',�.��"should�$�A�!�uH(Q���h.�A� ' � ��2,. A�orAe:Z��.���ju9x5Wi�9�� aG%2� �)��s"�� ���52�!:�'s�:> ��sup���+ing��!C�x��s�#�&Vs :�#d5�U���ehF�/( Qh Zhou'WW�,Vs coK#1;BN���:��� �Am�peculiar�� b �#5�&th� G1 �i�"itiE� kRbHhwa[%revie�+in [76]��&p ousl�;e<:to!C� ��6 in���'n� paradigmw"�#c"�in�yZ$re�s pooŮ�0too��F"�!-L"�k��"*"!)ATICM�!� �ar4-@"��s �c�;aJa�! ys i� �� *%gsi��I5�5worth�Ao�drac�!c�>*� �&G"�wM/:���A BothECA�a0#gluta/3>iI��>M!ZI�"!�[�"!�VO�� � .�,iv�f.bS 78�6 %GaA��1*�(i4�on doAX [7~>h&>:g�<2!�! a#=#Q�� eluc� � l�%r�L 6b M(��#�o�$self-renew�$hematopoie�2s&�7[8�:N9�5�:%Ӆ�!-qe a�" y}:h� �F\ *�g�Q� )�.!!�N.� p�,el algorithmQ discA�+?���A�,)�y> [6�1�"�al p F7.�}�A=�F 2em )�� � oE�!-.�. E����wA6�. G'3nd2 �es!80 a�!F�i�N��Za`QK-3�� pro�*5E .an2 z2ba}sy:�;li�!y mammal�*m�!!=��M�6�9�cy . �eis*KPGC�+SGMM�o11 �!� /GF�geC' � @�FT)�2�!&fil�Es*elsew#$( Wei et a�=submitaH� Brief@;we7 d 20  –3 �or�peJB2te sam@?I�� �"|24a�lL K/i�,Y@Affymetrix U74Av2� i <( http://www . a(.����;"(!1��a�bout 1q�%�'nor!��,c(� ��|6.R�$�C�B S1 ) �dC�softw���biosunA harv�. edu/�lab/d��/$8ŎW"*��R�of)�A�SUq �<ofMUAe& adul2U�w%�ev& &g[4:% Hier9�'-%�0� �.� ��a&�?�6H A to] of 230!kb73)�;!eg.n!� Ont ,FI}e!� -EL-J�vortexAWA wayn�!�!�43�$p-Value��&�H �J"��i*�A anno sU cal��in6�u}K5ypergeoe& s��!�c��+!multia� $!� Gfal\��.*�8,�0lx1of 55.�u.�{!T:����,1�( &A5ieria:>9$:��*atowards *( H . a��8iel|S .�� D . Melto�/ nd W� 5R;&�dev6)0/mean > 0 . 6�se:9�li�Kin�47X,Z toco�rele .@est_*! �v"sh�a�72\>Cq� ,.~�=�Gep mapp�| o Ensembl�̩�e  . ory��Y� v . 27 (�1�G[8��8eV�vbpE���bp!�Ak� �$&�"SG�['2� tartP�A�7�&L�i�&4 length '%� �&m�[X-1;�fir�)eD~(!Uh��C��l$�%�v�(q�"J $( build 33�$secon ?fe�, orth�.-h�AQ�4!B|ob4!:�E"�k[8�84V fK3!.�siKo�@n�+;block�$�"c 9�͞r�n�7�. 5a� ˡ��pec#LU+T-��"air�Calign��,.�E ( mm!d ( hgE�EV6�Universm8of California S| Cruz��CHBrowserGO@\���� ucsc+��85–8�4Lr�)Q�B�M�repeat�4kD1 ji�  mask�Ki�� then��aAput�pwMobyDick*\ [2�88] I� ��Dsr�fB�1djust�cm�/s ~%ma.� [57Ar�Bpt MaxP?1<�arto��v �)e E�av2�e grou��i�R�fi�O)4Gq��a ! CAST&x[8�All�M�3SM�c!%��Ed0RT$0@gap�#6���a sL/e�.!t� 1/afY9)'�!,�h$}�!�sh�75�%Qat%Q 55 ((l�F|�=*X � a�L35' %t�AM*r� FoJ!5��� step!��&"8 a p-v� !�& �<d)J"�J4�"� &�.� b6� �n: backA2nd��trLe�As�q�, � a.500�ȕ��sI�! ��� he.�3 �%+&`QM��dQ"� k-V��!q�I� n"�oc�x!_ ach-��2��Ol S�edZ\�d�a random� & `U� !g',�p� �m!unc#��a m��gB�M�j, Nob` Poiss�.� a��jto9(zba" y(af�equalLorSM{��by � g�OHz�Ne%X_U'e^$Bonferroni*� � 9tM!Te��u%( T��QV"* � fu�Or�"�B� U2�f�Q&Y −log10�oN1 zero�$a l �Bb , evolu!�+b@�sacrosh-G!�r6�, copy1"l�I%�5va/non�63ve&�. F� L] E�FQ�m���# �&)diTN��-�Y-�U/ Q)�,pFoXLucTK [9��"AE-� 2� e(by hybridiz��l Ra�oligoj1D�-t S�V yed �q �.�0ha� �lsWj them!��-R� TKLu� U V� @9.UE�J�ia?;�%t0i%�Eed)� Eed4B��-+� L4pCRII-TOPO vec<( Invitr ,6 i&~E�J iIsub �d exci� (by SpeI/Xba6L)*�%Ro, !Fox!@ �M$I I�Mveri��_!�. M%9E14�!"�Y%o3�� ulbecco's: QEagleedium!aMEM�>=4)�"IzM 10% fe�bov|0serum�MmM L-"5q . 1 mM��&E�o acid� 100u/mL p2J(!�$100 μg/ml7!eptomyc Oso�pyruv�,� $2-mercapto�:nol��re5nt LIF5B�<�"zi7��8/�r�=�i� �D ceptiv10� ) replace�6�/. instead�1JN. H�ES H9r�cul�=d!�K�8v%��$6�20%��, ��5�^{ 10 n%�.�h�FGF-2 X-raP~E� <�fibro�D��Em�id \J%0 [�9 spen)1a5 9O"� &�4�)j�Sw���5 μM�-�-R�> Sigm�O2{sald�`�^x,�?� abs�-AI�HEK293e�NIH-3T3^�%��B��inl�n�Y�e[noZ�a�× 105.�� I� 12-w�2*)���b24 ���3%_�1�} %� Y$on Matrige� BD Biosci%Y:�bd� ABco-�F�I{ feedZG0 Eacha�Zr!~X (��*A8co��1ŜRL-TK �� ( 20a�oPromega6B� U=A�Ca�5�I 2 μ�+ Lipo!9�ce2t28CacoCa�7nufac�Rr'� �i,L<4͈ly��%�o�!�iZV$�@se e�it' %�?d �a dual-.1W)* (5DB6 Wdouble-�:Y  }b &�P���"�"�P�:�N1�xM�% a� t�%.LightS�WC�Yl�1es�:mpeY�nx!�` +A;I�e=K!5���T&�O�n,eg,6M!Lα-b$�"4 %aRNAse L? ��qK%�s3opu&6 4phenol–chlor�N���A�!�* 6gR.O�Je.]���I���) dropB anoD Tq��:�nan 0e� �8F9� in Sybr GP&�? PCRs�+ee be�5)J/dup�$I ri. PW� r�F(en� m5�*�us!�A2ΔCt6ͽg}g8R7e,�@YR.���F�aY\prBS�"a�8DXo+� sizX�A�_"q2Pp"PAG [92]:RB(i-ACAGCCACAmCTATAT ,*Li-GAACCTGGCTAAGCTTCC�S�U Bi1-GTAGT3GCTCA 2-GA6$TTGAGGTGTT'[�N<AGy TTTA GT<Ai2- GAA5=ACATTyA8�rolR�. O-:1\%,�deJ���lo "UtGal� ,pSicoR-mCherrb.�[9!:#AA�#ir  ing F��in =�b"�Ge ���Ju� du�, 106� B:� MHu1 mA � "$i�B�C�:�10�A�1 h r%ng��37���& �(f) per� �h�'3 ��"@ � gel�p= �sn�_�(col�G� �cx5�+ y 2 q�p� A;h-�+k %h�&5`" −17:*��ADiV>q2� �S�  sU .��E.Cf�=)�cri�[��iS�`�"Ad c� syn�6 is k� 5"�N=be.�; +P:I�Y,]V.=D� r�: ru�K���+H MyiQ q!�I (^�2i�v, O�o���]�Cd Xc�O end-rel� curv5Iak��E|!�&� a. Cyc�Ur!i ;�1%Y� REST&X* [94][Y-yT� � ,}�hF[&K���OAx� �mu����aiE�ͮAW�� � de� abov� +.,����T2' hundJ-��-A��d�M��6��6� �40 �,.VmG!�R%G�a V���2�vla���!G�F� e�cP 2�j�jEA�M-m��I(QMf-���֭]f^twSEjc� i?Gs.�Fnc&� �-�6)��in;�fixQ�SK .-�&� z!%at� 2�2�\02�de� 16�l{}1% BSA��wenty�Olit$�& ropi.iod(�5 m�)j2 Zof RNN   #E$�2� �� t�A�3R�"zM&Q� calibur f� cyt!.�x nd FloJo �2��.lp�5E2�S�2����8i�ie:�(A�DI/"�0kebi�1�uk/�DM�� ,��esE�"DE-MEXP-1158 .Q�RM2!�of�-se)!$egz]��� e�I�4�%%* tinu�*��'�Z�ko%c ( N �[Csmtde ��sS/�!3 to N%�e�4%��V#!1N�-�$. Small-anz�sc�[WF%@nRd NMR" tros�#�'��/}Ar2dI���%_�k<&at%�B#�< flex[y�h)��ur� t�K =#s�Y+Bme�is99ai!�U�viA�!5&C . Nu�'0q�in�Tnumera�m i path� $Q�[pfluenza A!�ab�P ,/�� !&DSi� &ncy�; �n# )�P!)kse (/s!��P��a���Hv �}��k caps�#1�,p"a5sIk!Nymer�J5�nd �.s %tem �2!ls �,/� � p[�5:PH �tfHZ2ird�F4Nq�Ano��O]P( +-F�1  cop!��he newl%�br7F�!�� -�e�:dB'�no..E%���r,RhabdoviridanParamyx, N ;���3�(I�Z�Pe�>na�RN����5 N0-P5�+-)� 09S@�*�!�)I,�C�x#M%��of��%�0c=�A�`cp��\s [�1[5A�[6F/[8 �.�)ro�A r� dep�'nœ�+�;[1�].Ire�Z, P�A�culfilllchaperT/9�;2�:EW!��AA7Aas�4��N�%��#ux@��aAriŶa�`�disorde� `-_tw.dlAn�� it%��C*�z�-�Pnnm( VSV��C otyp��rqn�L�N �� s��{���)"xJ!�_B��O)titut�=�?���fV�! "Mn%q�SIn2�.�A��E�s n�% ,G ��a9*�[� bcav4[�!fac�a4�N- NTD] ]S ( NCIG s [1i�15�:E'-a.A�B�Lta'.A$by��=lt !)ge&�4�<sugar-��0ba��e�!���rR ��,c%�c*65neighbo 9;!% volva�hydUb�(ide-to-)"��,�'�H). adjal)Iέ�ex��PN-�=H sub-1C"` M�lPJ"|sA�A& y=attac�F�. By*b�=��:] Yp�i]K��F�A��L� j EP&�+ ���F�:lE dP�`s�.+$!&en� � F� ?�36�&��m" ol�. Pqfaz:( N�beQ�21��*� "W&��Hsch hi�li � DAMiofP���,��[Pq�-�ea�IJ�m?"#.�c) nim�H��Jil� M�E$�e��"y��"li f �ean. maltZSA�# � ( MBp��� MBP- ! ed �l["� q�F�e�n�-T��vol�&a S'xdex S�+cn"* s S1]$S1B�TPSj�ceAM!2v MT�er!�4 280 n�E d 26 of �=0�%A /A *ZpS1CN�91mo}?r mig� /,|5{�"�4EC-����!wJ t-"?>&�u92±2%�<�% ea�cu�8�T*�uUXm(�|:ass: 8�=326 D�8 ) +053 !�) = 9�z379� � co-!,-F!j:a ͦ� *�,~p2B!>g�� �" muchk:a�OVF�� ub.:n �a�/(U�2B{�cleava� !��ׁ�wgTEVi{� ��ak��6�!*� (by Ni2+ che"1,L��y>� f*�-� ��1#��� �6� / � zthetM�)�����Q6�y��intac> g �F�ZQ +�*+"2P�N�:/?2� �geakq� ��eM�<�v�*�� w/Mn] 00±30a' �F�104±4e�W��nS�ahSter� �o�of�C%e>a�"2F(2�e�4�377a�&l +2×�N97a��0F,32m�U�فn2 5�%��s.� .2 [gTa�1Ch 5��d� 2�N.Pby�t>�m�ry [1F�mhdynam� adiu�Rc �K . 8)�1�h�����'D$c{ a��a�Ea globwq`l��!�sam2� �j2�RS-^�'��) ref{'Ire e'u�.s-�[c( !@exE/[a��(�10�=%�6sa�6��5no�.(��2{I�� RS��2=S�F�53±3E�.�5T1∶1�qfr��*Cf�>��E"�c �%0I�zIc�N2�1}|A8M+��y� � R5bJ*���& SAXS�&(�07=.� �7"�Ain���2���le�ro��.2AA!6� �8A�) A\*c��'& �&�Kh�'R f� 1� s S4U 4B6 . Ab� Ѓa��dM��ruP!9� [19]] I�� easid3ccommo��&4 n "^*&+>� 6,E ep�(L*8s ��ːoptU "&C��S" .<1 2)/�[f #re� 8-�m!!fn�� �de J h��6}L*�an empty�<0'�F�N�a����Z)o� ����*�' rl��y�BBd`RU N�v�LN0"�f�!o�$d/bM���5 "�6 r�e���unsui�K��!lw�tӕ� JOa�"�)�EQ�aj>]#3 JJ��ppH� � Bl"�g Pre�sow"B.o���"b�Ji ��>�%%ke�y!an6Vrivf���%G�>��zAgJ !Uals�F���Y<2�( rmsd��� 96r#��3����-" � �1^͙�%�X���?�^b�y��!|6�35�a]o'vi�~� q��I� ;�$,_ ��$aaf<p00�$m�jue�"86���3�74� ob�!�_s �� U�Q&����&&ly�~es,75�&�( ?2–1D2<11 Raz!5 1fF30 t5"y9!;6mEM.~ X. U���Ӂl7> m��Rfl '�1g�x��"F�W�Gs5ami"�&17V31Bd�the�al���z�����}�; U[M��Q�f� adHKt�PV���>(u��:@ <�is�)$���>-�aJ.pDAy��%�Q�of�.~Qh� *�+ �1`i�Y�&�'}e"�"�g�u? �n��B""1�*�# �Q��H k0]"M6�bό�1�w�la�8��s? , 4Bec  >9�*�tur�~�αe�x�60� 27����tog�s:1�!�u�� 3��UYU,�l �w� U��?!H+t2-. Co�mi>{�# em* %����1�Vd�U��sh&`grK "�ck�Q�y�/ � �Y6�#:�"s�Lp�L�� W&�iVKu���pbottomA made_� <"� i+1A9HCM&�. W��^�<}*�8Q%8E�vc�>et�I��aZ]!{�d|%e,��*"�.**� A*i)�P9�IZi�9e"(%FT� l!���ph�!�i��2��amphi�)ic6�T2�U�14�1giXte"W 2lQr2'. Tyr14�b��-s�+2<pocke�Bm�5� �\�!�� .�#HU�"& s.�#UC ] ����eT2�?�"ls�yy�+# |k!�a�!�isF�N*\!�s_yp�'�3�Z!I6� ( RA�%[2l N ex��s 30%� t�>��"�6�ﭐAVeL5O�� 21%e13�Aa J$lob�:�1�B͘�$�e.�Uwlf5!�1eYdPJ �m�p$��n��:as Arg3�b9!��a"�Q_� %�GU9F$#!!�=m M�M��%�YNA�o��e�ro�ica e'�%�&4&�Vp�!a"F&��$���0�H��SE�k7e*�+�.c'( n�L�7V�P� �d^e�n2�suo' r��-�� �cha&iRar6�59v5B�&�%�IlF�AN dir�  c-�e �ac{'� 6� i!�B'�4!j�F)���P%UA �.� SAX6x�& �]/+arga!�u5+sixy$i� �.�͘BB �!+Q�!�yN !�!���q.�-�A�h%�n>�aPaoa� �SveU<are��&�$E0U�&��harbor���4K&��u�P �9���D �m7oa bipo�,24XK_h�z-P&�*��e�� xu�;X�po�ts"� u᎑=� 6 �B6?�l�,A�E�J�.75g�a�sN %R,A�if؞�trosE6�5eQs5���N�=>j2D�1�j play�%% n or��P bk �1�s!Ӂ�5��" l| it�6.�pl��o�cidicA֡jreduce�6pul�"for;�> !*J���' �jj�% ��d�-� ��� ��1�32� &���a�val�& gene1H S7�&SQ>k�5%>3w68a��#�\>a+!z�#F�)E&b%� � �{ZJ\�*�Źar.3HUf�()�6R i�4d wa!�15= 13CCH-lab�j ���&��rec�$�AQ�2�� ! ( 5�)��D�'�z ��{&�e��W�=�lce�� HSQC �un�'Y<on!$a��upo�m\,eQd28*( 5��24�-$60+linker+�*b )�YQUi�y,B����'�ei #�: �1�.U�i�]%�a�x,� �� �4[@s�,S� "~S��"�Aa����suQ4eG4V~�g~dNJ�proxi.� bulk��R��r:*� ( Y5�eF5���Kwe@ *, Eh���%�3�jO"�A��6>e�laxe�&�;!�� R�}A�e~���xЏ"uD0qpico-#JJ�X�scale�&� {_�P[)v&]0)��CO�FP. T�vB�)U�=�i"8��e.�m:  �;bound_.�xa�a�.Gd��rigiditN5A5�yB� V,%���DeFCup-]k%&&C )��� vYVE��% ,a!� -1H TROSY�$���=or�� �-A<46�;(v�)annDž�-�&�!�{l['2 stoichiom�pc%u�NŞ"A��`m,d!��$( m��'F)15N2�.�'anU2^�٥E�\� A�5�)| 6]!�!x%6�'!�am���@&u& c�9a�1 � �.�WAKmpb4e�B . Sp��u��T�'���? libr5[mix��) I��!rq_�`�.a�.�:�U. S"1�a�F݅r�(�EV*�(17 }.!!�>ao&�v��om>��( Rex!�� �6A|�� %��!N!Z!��!9u�6tug a<m �!O9�tou�"_ =�R1H a��!�i!X�2� ���ȆYiE#7 � con�A�j+� �C�>B�� �F� (�@� 13� �E\!�NT-�5�3��zU!wpaS�81�5of..+&�s .�2�6P tcm46 `3 ��i6%is mi|A� �/� iP6M6�� �7z�!�1?=5W>|mgtxe�%�y P�e&�0F^7ɗ� ��q� �8*�El� pA*behav�*;� !���(s little ev��%Ee�� �%2y]� � {- dBDN��|g�!p�"0�i8fsheA ]s seem�Q]%V-�� B��#�#m�F� y� 8 ��#�h)3yJ~�!~<R.��Z��` 5" }� Zs"� �B"�6("X&�!a�� �D�/JQ�. B�(B���M���Z�i�!za�G b ,�[�!'#"� it �s�.as .�z&x��< �� ���hCUi>�k!.�!!> a[mVQ��<� %MbJ��C"7ZdLaR +"�OFm�truxd�dw�'w�l@!�e.��#ϽaZ�qo  |Ab .�!��s j�6� �N%>!8?aO�Isu�"�&G-:^]l!� ,i�* �^�"�@y��!�" !&�"!\m �K6��,9�,a�qB)T���!e" �6�g�.g�>�t2� �B�(HWwUE��B}B�!���d&zB�%Q�!�E�ed�a"��N9B-d&WC�^q�R*�3�z=�7J�A�� ��d�.�O &�O!f|22("�(�4�AK �F<t f �>����CAaC*P� !�'. !�4a �� =�٨# �BU>at[1��Aa#Vn2�E/2� !�b�,)aY���i##b� ӛMqc-L\$Ay w��6�-6.�S�NaB gm�2OI/(*K%� ���&� �R\{ell+ �a� s��~ur��A$���Jh:I�a� M.���.dH�ub"OB2�.";)ma���%F/" Y‰�=-6OX�]�AP.��FA�i���/faڄ�xn.�@� ra +�1���.��� . Un`3�.�� �%faim���e!��8' �!�!��d�0�*��<Z(}exi3A M�26u2��!_A ByFD] <'Mfd �J�)�&�v1%0� m . ��.^�!D"�+expla� s wh�J�)m��v3�=Ji�*E�Vpro7:. F��n�2�����5�2�e�KWO7"� &�>���5AK"Tyr�\�� r� � ./ n��I�r�&�2� "- "!"!6� af|.E".1�]� u]y�!�cNS . No2�/-��,�U��.}. �)�M�b`��zp. S$Jy�ring-%�U�eT�=X  ���*Bf��u& rgan�ofE�M��"�:omQ�[a�d/D��&A�ernm�� g. Y�WsN��t ��e[4"/�-9.( 27R��F� �4�I?>�u5'[26�N=mj��P&! �F`m=&disrup���Uc��[2�<�&(&&2Fj  y�<{p&�66~Xto�D6")�O8.�[�+Sb$=�;���w�� .�7fpakV��إ�!=�L1NAE�E&�(-�U�{�"Pr�buZl-sp=d}�n?a� @��c��6O���8}W�to�er Gtur�83��U��a�M�$ tip d�� *_e"�D]�var&U\%eXzWmu ��K! �m�V"�%%0)�eI��0F�icm'�T[ �imb �QPaRj"! -a�7peri�o )Q2A�n opt^��-byGQ"�&o&�6*-5)&$3B}@ ��  �q�ZI!�it� m��at�1�6���J��%o>;��"�apR#iH� B.�� !��!3*a"\�q��!N �)�>��"�5 2J�geF�6or.3� �u3�&dI�� �}�6`e,A�o+(8&G��>E��a��eb?>�\G%�a#s�As�_�221&�*:&�,a�lM.@!��%lEIO���!rguA��� "b++��N\1� BB�m۬#e��! 1S�� *a�3& &-aB2<�� *.K�| L�B0&� :�<])�"� :+"c:h6œ"�R. C)x5af��:� %L%c!Qac"���� e)Z� �� �va�B ta��E�"%.2 %�"�)��[X[��5"ņ�M)_�W � a�A&9��z�sin� *N3�u:6*-�wA%�-[ (0�.�(.�aaF�@K�2KXQ �+ein�hi�$m�� ��es�!�a��AV��*,+3�u8$!� \J�i*�a*5 �%�%�M,�0U�Ye�.]e[�N4�Al �9^tS1e(�&FJ�6�?bF��29�"\ by TA6!��]w .yE�5Q! �;�[� !�� �F+�K�J>��[��Osv�P &^^W�eh���*�7 ���b����4"�d~=:�@72&��4 } NNT �#b9ɸ����5%_$*Ym� �a�"�%E��!�!� q0 �-���!.�tJhct[s�"/rePW�!�esagb"5io�$+�6|@N�,f(���+iy~D6�}���" ��L Q1e��%-�=b �sv��~ ����2$ E.:��<0A�biv�2z�2�Ut�A;!}B3� .�s��+*.c&u$26�/ {E��w ion/.�m"��inq��0aXPv�Q�sia�aE�0L ,���-�I;^0N��La�N!�"��r %*T\�1�1to�:�� NA:� ��OZ��)�NEg�[�qa=VQCi�7!J!&&�j&] ��"=x!�of .�jB4;�>8[29�(3JE"�ed�| /^>d���Hצe/H%�"�l=r(9�\�(!Z2�&O!R� �1 �"| �qV�i��s%�1�2�=�&x ��B AY��� �6=,M�*,"�6 &+lyC"�A ��gP.�9 �%C�=/)PZ8!L�s{i�V~vf�q �j�&�+e���>#�i�Z�d�%{,by�y�i� ��pET-M40ksJ�( EMBL"�Nco&� XhoI92%�qr��k�? �"A�ch. ��*�d�]^_�E��Al;.��E chec#(by����!�)"6[��Y( �Cto B�aRosett.ADE�I| �!^e�"*F0�gU �[���1isaHpyl-1-thio-β-d-gal��pyrano ( IPTG )�� 18 h��16[_2�y��e�o������1n2Bu—�w20� Tris–HC�pH� , 15Na5+DTT�(1��� <*B(7<l�IEDTA-Fh<, R}�( Diagnostic�A1 �!U)����!G�` b`�� 00 g� yx at 4!"^!��<��Hfilh�d y45 µm��a�/$f�b�in� Q$by&� 2s\y� amyl���3New Engl�Biolab��L ��>&�b:Suh�~SV�bGE Heʱc� )"vZ.�.e�!M���^ �"-cQuiagenE��8 �SEC>�755��);6ʒI�Gl� ArS�S���B7��( M9��a�sum.��vi<���GibcoE�s F�L>�:� O!ZF�1 �w�L���c5NH4C4!OZA�.&�; glucAO�� 2�a�NPAA������p�_�2Oe%�����i�NΔ>N&!�bc%�!Wove�y�aB��60��a�^.���6�|}Ò`aby*�VHis[l^A���?emPY!s�&��K�.��kr8*�f�B��Q�m"::=�lim��e��Z�)�MBPy! ���>�a�4����F� \�-�  &�-al.���{GAMBVAt�b1��X���/cfTbv�� ced�Xr�p J�1�r�J*� SDS-gg ȊeBio��@ �q!�!�>%�b�h~��t&vi�1�he*�'�g ��A�a��'5n�.���.��µL�.oE6�_�aAD����5�5� ��D:w�0 m�hm�i�inj�*>n�I�lti�|la�� lighb�ot FRlDAWN-EOS Bor�� yatt&�y Cor��4, Santa Barbar8�C�Q)����T�at 69Tb�Y)6b"�"�5o ���f6 HDin�j %,soRI#��B�,Schambeck SF�I�c�@6N�?L dn/dc*J[185+i. g-� Data)�ivoUv i"6Mw� L**Y)*�h"��ASTRA V�v݊[b��:lqd1(��� ! W� shapE JE�a)(volume fillq4Hdensely packed spheU8( dummy atoms )i�$reproduces[expera�tal.ΡOa sim�.anneal��minimiziproced�C.� e�Hrfacial area betweei1M�eU solvAlby imposp!�actness( connectiv�r)�ainE�20 inq�t)�s)� gene����-� �8ymmetry%�riE A��5omb��/-�gra%�8AVER [34] yield�$an average �)~exhibi�Bcommon I�$ural featu!��|lF�.�E� � alig�� wis%�-~�gnormalizEat!�835 could also b�-U&. NMR*� ���� Var��$spectrometA�pe ng� (a 1H freque$of 600 MHz�{sa s=.H20 mM Tris-HCl , 15Na Glu , ArgI-10% D2O&-to��6E��-6K of�e 15Nh3a�2H-labe�b!JA���Ana9BFJ�(bZ1–6V �] A�un|N� as|28}%�itig&j �5NB�� �,at2K MBP- ��ad� at final6�E�!0%or 17 �!;@R2 ( CPMG ) relax� �M<acqui�u��b dard puls�E$es [43a�afIYa�&@%,(a sweep widə8%�kHz%�5125\poi� �r1H*l,-BL�&2L| c� :L5NMIdmagnet deca�I�d!g1 357911210�2A�� !�$peak heigh1X to�R&=�� M To estimate%�T erro��? B<, a�eat� _�nof on"R6delays (�'A�Tcarried out .,�UnderE�,�!du��oA� impl� ioI�A � synapticA�&� patter6�funda�al goal!�neurosci eO�4iya6�rol�ub_ tous eB r/�s!E��$via gap ju)�� main8us�w� 0visual system�ell"� vertl- #networkHhi�. lay a key �inTR !Z, pri�l� %2E.�oother�ax%u6�A�isw-P provi��a��$que opport��y^xply �-al �}2%0in sensory in�A� . Outheore% "�� rQ VS�`��a� ina� ms follow!-� onseK  -�in_ I%p� fV7en^ie�-�a�ffiA�$tly encodedaxie�roI� , θ ,��4fly’s ego moa1�D�Yc*" in bB , %�ar-opa�l�BreaSE g physAm lim6of��&*1�"n A���� 28itself�%Q�is known!b�a�eddow�eama�hw�Ra`a sub1�riplet%=�q01seM$; we found1because�4R�)�=V�kubpop�G in9�θ�su�or��9 e wh�L>�1Yis�us%�a��e��� alUno�a o��We fura� dem{atAV� is�t�ofQG%�F�a� cessary f�� ly's-�ly gui3behav�, such� ban�tu��n eva��maneuver�B-�6ar!�amo:xo���>@%�)�y onl�aA�heMe: read�x, while ��� a;+dendri�Si�intF�gg�.�%SA�mݦprincA�sű�S�oM 4ircuitries mayA�m!+ric�|thaFeviouslyZeci�baf�Qon��!F����new insasA1how�;Qqc�� lead+Q�6,��5uli . � �gover%L�!G2`�holaeŬ to uB��&organA mAb� . G2: ( GJ�Oly)���ee"n>N�Ik��$ot�l n�usMB [� 4�A.5�[5 , 3eHoweveAtheir.�Osti�A�& desp�ex�ve%�A3[8–1 H�we� res�_i� blem��>"(��)5�-MN}w��)AW~1488] have identif� ��R �@��Q_,�vid�aa�&��~!�toq mun� eɕR ano��U�^mchaK�%QL�i�a�nt�of5�bpI ��-�-? blow!CC�,phora vicinal ,hotoreceptor����X foura&secut!�lay� b%4pile:�lam ^medullhl�� � p� , � f��ch�Yar62c�n�@ ,notopic fash��� a}ikaOparalle�|Qae� ?a� , 20:"dirfof1@�is!�pu�"in\O�OFF*pa��[23C�T�T5��-�-J :esA��out� -g x| u +�ively [2| They��=nt�H �; f large-f� t�nɧ( LPT��*whorizo+�O( HS )�Z� O[23!w4GA�4sej�20�er!VS ;e�bm describedel�`�10,.  left�r�a%˥Deyem orde�VS1a�VS�l��(nterior-pos � [26�se��  e*# zimuth de91�B9 ! �x8al�tag�!thb�non-spI�ejn�D.�%��� ��%�)~�6{q}a�llto.� j.�!�en� ( DNO!C, 2!7]l� upst M� necka8or��ere�trigu�A� adja��UI2��5�x!F-@�>6 os�? duct � �"%�!�1 μS [1�18!�Surpri��A�� �G6�VS�j �* mi���+ ��.�U�lI� VS 5-6-7 "- \%g5w. N2�� ��"� I �&g� VS %10���>� an ear:0�MI�s!��.�K�,environ�� st%st) �For exa$ ��%��i a 30–40��-m���!,elicitJ� [28A�9]&sc_ � swatz ��C. P� �hypAks��tHis"� a> oeZ�2� [�� �  haYenzda�� fu� $to account� many ob��!p�� &�I����Akɥse!���s� , 31!86ks��"���e %�I , =,�r�er-i~!6$!+&�N!K��[42!�o&� p2�on* -}��TbS!Yno� nsi��whe�E���+&� �y � $ i . e . ,�uca��bu��pem2�A�&�� cy [4� ��,4 inv� gX .�*$IV�[��� uif�&7>�E�B g�&��eJE�� � 9��&Vvu� eB{$re im�i� �mpi} on���l$\� calc'ima� [48� ;'c�SE(illise !AbciE+  unavail' .�A3[2�%;pr� by1|� olog�l`#ale?�A�=�[1E�z6�hadv���A~�+ help9�whd$y�Alor"uAs [17!'N w�� trasrE,aP�/alnKis.�to$o 4"ef�O�<� -'h ]%<� mr�!F4��~�� �92e�a"�)firA�~of~ Hz ( [�, 31Aa gra;�Cu(weApI�first� �f��|us�toNVS1vo� . B<i p&JR]!!�%�a� !�A !�wo*H �A�(n�ng%�&o�rboard�below�� i�� whenemO%�reW'+ fluctui*windiax� *Gl E�WA�jPl"�"# BC! b !�se bi� . Fuxm�,%g.�"�&��%��,��~AC�2; ,& ��1�A -��X! s almost � !�q�*Nc "d� ic�2��#*ER>Z &p&p�2^ eC 2ms)�~%W�5l�aq q��) �r� �)t�st 90%a��6��� as���<*i5��cy��dvro�-rdl�ʹb���a2� L�E�U�喒 ���ssu�y N[4�50 Fi<-w����eAC!r� �W N+rt/. Wit�4%s!�Q�can( eve��e�"basic�� rrecA����he up/  tilE�hu-�m,body ( pitchJ�(C� �V�eB�inv, a.� [2%F1]Ach��+��nd n��same tim��vf�� ng s?� +.<-QczalA��surviv�.�k . To�� �/� �E��6= N�mpBJ�9��hN$c�-depic��in�11!Fig 1A��� "|�0I!O6 a fixa�>� embe�"&0 cub�3},“cage” )ɘa!dom�"�-� scen] mimiT&Gc f�� !^�2ngt$+�$�/is.zbj� e �Ar��lA�see Ma�a� nd M�+dTQ�!proje%N� �� m �0 1BNthus ��� s�ap�4�5�*� l���ct�!( LMD ,� �? n�6(.?2���!H"a �,�[52�&��%o�LMDEr�:�����(�ai�%morph y��.��lower+ofI�!X. C% a�e�6HBg !�s� *H Y u��N�3Ti�+2�;u�e�!aZby����f�"mpart�c�ed� �.x�/�*X#ceAP�!�";)y-I:WNg� )cur?Mq�V )�e��l 3 ��r" ( RFF-��| �RFe d\*�2D Gaus�.U�"�%15° !�]lev" 60° (r� �R HA35�s- �egard-'e�AR� RFs;*�F2#�of&�a� °� ut 26°�VS2�15410�C tH0l�, a�� TU �/V��a++y��RF�!�. i� YAO��� 7Bu�M �23A4"4+NQBat -1! � … , -::��0 trac�œi�E! �Q�|M 3op M��c�sp�1�*i[vy (�]� )�1#\ u`6r�(!"7]6purplE:�. A:n b5)e���6�%�c.�o��exac ref�&(:�N:R�,U�no��J �1_��la�mov( 6�-�s@ �s��9!e r ji�;A-4 , �en flipsG !�b posd-�b k5��(E�A��two%�%�srE��=��Ei".%;b�(1�AO�)� �"�!)G5�)} �!arrow�NM�to A� ��5(aim�ݥ� bto�C��.9bottleNe�4[53�0xmaj?$&�'�ach ,� �v 0 s.� se�a*'E g�\r%.^'&� m�L I�X &%( / ario� e����!w&L���msAv seem!Z� A  e+ev!� �2@�d�Oe��)ɱS2%�1�� Tat�9nge)t�G(window doesa��! 6"�& .��;I� 2� m� atE�a`! s!A�&�#2��t"x,bea� cl�=rA���� e�%.eB�)�)x�LI ylK�v!�uTis� to6( sr.8"WB� ,A�h �u�(!M�� 2A 2B>����͊VS� %��'�R�?\.Y |��!a��M��zBS sm�!jand��n%\n #2��#E�2Cr21 U&��d2�dux =,!b �!� ?��95�9fl42� 2Z.��� �1T&da9e�=� �B&(�w�he 95%��f�ce el�F�M � G��i ?6|� 5�!sE�6��B�(p= �in � (< θ =� inŃa�T� �:2a!� �7ey4���wo1t"$=2Q���%�CE! D��@s�1t�Qnoverlap�2e1��jwNN^�AO!9a�� �}#rl%/� op!�%�!�&�!|3!>�%1"� ^u'aiR� a`1r�@J )-z'��� ��VI3Cstinct�;�.3AI�y� ���1Tis �C.�!�!�h�ye �:?!u�E�C 2;� v\�in S4%�i-�Gai8"�+1�.��2eݭ:�}.Cc�/>�JW/ �.�*AimM�p�- n map�>�a�guish�-хʉ2V$E�-�A� (w� "�Het7*X , e�(8 Irm��.how0ar�mal��"�.S.V Z j^ wo mutu�5��5Cic�)*�� &I+%H(i cy ) >yJcQ��B��} 9q�,)oNIθ−Ax*��!sAСlex� *dy��De �.   .�w %v�j�$nd�V2wo"<li�$o '+'am�Y,B=amJ%of2y� � �a i� b��)iiE��[<��9es��4"b9.� E[F3�=!�!in�(&� .( �e� �2 needE�bui<=��ͱF���')S�Fc�+i�Ay���1'r aa�&�.�jj �S � {"�� M�m�!��9 e2T!T��^Eθ . U %o.�F@( Tishb�Pereir/& Biale9 1999$we�:�so-e/9hcbI:��ryC%��.!o A �Lu�ryE*�] � )Y�E�.� 6�e)4!U��{ ��e(G}y�K�C E�b8 e%�*��2we*��C6��0�I�"A��x)=A]2�7M�f)y* �^�E�0a�36?1° step� !�uni!�cp'J�^reJFh&=8b.�r nt� \A �BL+bin�o��0.r���+��,=0by! j!�� �s}4EN$g'�1A= I08K'�j 1G�V�N"{I�y.4$M$�&q�OLro;Era�I6�i5%Z"��!�"j%�A \H ig 3~� Y�6�f�{ re�.v9s: �lN"�$; 12�0���i �@#} �&,*��� ch�1� i$F���R�J33n.��`�dark blu��Q-�2K&Ji �]lZEv��OR�w� �� a��.�"J. (�(|��&?��A�L(\,B)!VV%�^l.#i�Qs�D9n�6���<*� as&*�4 a=By do�: ���\ ate if�Ga�?u$H��S=or��� *�)� � � %�s�3a favor� reg��“shx er� �:c>a&�s *-� B�!�&�q9"�*X#raۑ ,�ũ�+r�8r.� n8(!0%�aV8� is8p�5zA�:�w!9s8L��a"di�Nshvre^<”.� increa"G�Ki ga >eAO4.n�U. Spe��EU �1�1t-N segmh5%b))S�!e)ny 1�/5�d�/fastesA�&/{top�F=gnitud\�2�Eoq&3>�!��qq\�#��( �I1�( 90 )� ɤ3�΁�QR�ZV5 . 554�G34:V�k�.en.�Dq�sI�kR!.�)%�He�'E DA�$i�� {�$_a-L0=2�#m:ir � �ive5�:vE�^�t �E�p�W��clo�Le�_/�8Q�"� t\<ra; .:V� a�� i�as���lawA�dB�>�ll��(�� crosfk��:V51ircle�%�P.�\ LQ����t�casv<���( o[�E�r>y�<InB?j��&6�+d EL306 ( ±OI00 Z/685 = 86�+�,]K�ԑ::Q�zteV4$y }me��xDc�!2��! �) 1! �87��">�%�� R�%s�Btio�5cj eQ15�"�X00a�/ 430 = 93%%~94%>t�]y��5e�n*~, FKE!1I4A�u�.ED[ "�eQ8Z(�C*( ,u[@�{]&.I *� i�}&M9*(!�to�3� T(� } o4ew&J~�Gng�� spacQ5e�}W��O yu�A .���a_Gg���� N �� �)rYis41-6-101is 14�$��iZ$!RF9%�Z!(~!�kr�3# �4��iw8)�VusQ"�P^Oad� }��=��:G ��H+�SwV-2ʹ:= of 8�or�(� m �"!��H?*$�):XbR�E B1%@m$) tensGE� simi� �� "�6�nax"!6F�� �]F�..�i��1-2-47J 48°FB�E�i�$VS 2-3-4 (E0IU!~:� is 32° )� ��� �A{XAqnA�,�b�%&!}pAsy 8� tX.���V�in�;�>Cin>|"�=-RM[)�>r X e">�θ�� iA�de�mY#.N�=D�g�llemYd�V ot benefiO=�vas� E�Lun.+��V�B�,E�\" A�hȽ�s-� push �P�H ��s farE/ away" 6�ah6 ,*�yeW/ squa�=�'�=�ߡ�ItA��worth� 5�a[�or ag�,� �u��Hq7��erVA�J5t�B.s�!*+!6�2K. S�>�0*|\iU�FB5� makeuni^N.! �F� st�: :�4s.a;59H / *� ioi� 228� (� �478�0%�!�>A ���060.B3 )�1@9@R< � �PEOB]3�#&� l�a4y&��y86�B�achie?-��2R�Md::q!���<F�sO587B4!v23!671%A�Nq�54F 06,� �c.�9 "� �_In� word��czc/E��Lu��-=a��Y�=+6�� *of M� �(E��Y�& A�st &�5m��؆�ia�ۉmeILa� )� ��n�M:��O2���u1>�(!r�v���%]��1,M�Ja�of�=8��!�Q�%A^�)��awZ� I�uud-DYC�pV&1"83ast�q�%���,.�!>F�ast&*��7�.cD. R�'!0ZSNR!4 qM-�!.�transmis� -�6$K[54�T��^, .p� %g5]6� �Bf.7�.&a� �R� BE"s EUeb�:!(weh;V��shoVDpaN 2�6Es�Rah.b�l�i� (e$�#"sE�v@ �R��U-(�d��:Y LQ$1�]f�!,4"|.Ou!�I� ^�#�2 x�JI��^�2$2�4A�D�[���:Q�� =Pe ��ߝ6a�4.�<w� ��e�$signal-to-:�SCQ[ !�z"v @�l�;(����,� a-�E�4��#g  ���8!T�%-�&�Ń�U�?� at 6b�u!7�h^@851��d\02T&�a>"��t|^T �4� . Gi2� �*� �~ �ѻ=� 74B���N�uA~�� ]/��.�\{at�`* 09 � . HeQ�2�;&]*; ).C� 2h 4 09N88�is:��&5��K� �  "�j!SQ8A'�9E|d �'bu� U@ stayA� 5�I�� 5��br� k.;\p!b ( A�X n{P&�[U��u�d�`00.�J�cq�I58^�aa%G�B%�5� I�3)�r�top-��-;Y��%�I!S"�^pe/0 ��Cth2�9V��h%��:�:e��B��sub altsu]��%=� �_?f?�Gm}�lVbe �=a� �\*� ]�&�I-&a !�+;U5 � a"En�Mteg9Y�)BQ{E�V� �+� #q,��U" Z���A-�_��H*&���%���5$�~�s�A ^HalI�48�(Jx-���?!�a�e�YR�J�yC;*c.z7M�to B�� .%b��Qa 20%=( B R!$BMx)~ce�8!~ �"" �-~Y%0�& _7m�5biQ�emW*� }(2�'!v s�3 " �a@E2��3%�4�8>��)j��!��_ pg"�8� �Eh� ��>�� ��l"' F�"� ��c"D?byE��o��46I��.���a���0)�6�M 9�L'Et� )7�Z�%x$�NmE�0���t�r����f3�3*�$d� 9D84�E&�-a"M7 � � mad�E�T 1600� p�!�V( in 5"�''>^ �+eed< ��s�d&�1K��a?ei�of&q,�*We#Fl�d Cq � U?�()[�F!dA¡)AQCO-`̀rkm��zeAMS1�| ��F θ)v-�j+t�t�)�5e��X5�E��asKPvD��F-\B� y�ly��o�g���  L13� �A]L�� * �- 7%�fE>Ee}\B;Rmod!��1K"���a*�!�RF]�5�46%wVS7�7�, ±9� 10�A& ��A���#!x�u�s��!� ( 0z4[a8i]@wB�3%���+�w6����� ubh�M6��H"���3+�zRlɈ(`xO �e�a3magenta)�.vV ���aS�.$�e°� igA�t= �e�>� cQYAas gooB�!@"�"%!)�2(6����_5C�Gb�H�S\4}ޅ�y heEpO}\o�V�Rb���A6#%�t�#��aY== 4��!�Ec1}b-of 'G5�4d 1�v�a�`� �'A~ckBv/c2 ercl ��aHK(�K�KAq�9� I���ib&bd!��' � �:�a� ��*!a�--6� #���sp�xio� �!lAH&9pl!r�%f;�Nl2�'9De  excee� ��5B�5irn*. a=�}���M%aAD�8i�6�� \K%E#A�!��Mup�~s��M �uB� conf�V!�Ex� - �!� aG=5)6�]�r!yNb�qu�n"bNMi(u�pUb!�-�e0�!k,-)��� �:� ݻd.?��d ly manifeGv �_��͔ ard devk ^I#-� a��al�Ogh.=cae>u9J�ta�o�b�s� ad�Ba� ��"�N�l�W�b�b�1�.�I&e,Q&&� �b�edIsE�.��2�e� �a>�2��!}]p�n�"� "M�|&ti!�a~�GT.]�NS?y cH~:u�n�ofE�-Q*'��nab�37l�l1� . OA�a �&s�Z[�+57df�mp� to�d�%rob��!]�N�<:�1p&�kc"6^"���a �! ��$foc��exf%D&on�A&w 7*L5�2/w2�R�be�E;m�B( &m�� �sINA�b�5l/(e� t��a�asks [58WOa�� m[�as�simonij!�+nA5*y��2���Nan%� }��jvOqu�Z�|ab�{e�!_o:5:v!\�ue(� posM> � . Un�:�?IkY%�Fr`�aaz�e5AB� i6�<�sI[�.�Z.�F�8I� e ą�G.{6\!"� �c�+i�!zol[ �Qj�&� "M`i ��o�Pe��z �;a�-s6��6-���|t)��*Z :�q&mak!zla�Vp�ف~Wf3I0�)��)E!�B�&4� J�+A��$NZ�&�#� &�@ ed li*<2��!^6� 'ng�,��in%)���y�%( ct\h}�d:]I� �5!S3p E�E�Fa�6�FSma�a��"�j6w8K class 1e;=2(b5N&K. M"g_8�g{h=]u-WH1�o�Na lg�#l[9v+ *3ii7 ��6F�e�[m/fexMA� [4_c5�W6:YI�QAr�9��q��u�0��ts�c!�caJ- u!P"�Z!�5�od�v �FIMe�{cyA2��:q[�}S)z �2HME  1 orks!�i� ll�OŒgnW�*�- i:eJ�q�� view1��6A͌by�!R�=�aQ�flperi!0,candidate me�ism%J|� *I-���! digmv Her�i.l ur&k broa<��ap�x>nXqlyM�!&�x"Vq�L�a�k���Gry�%'OtwjgWv2�ehM��= !�j[ nsis�h"2l*�eP lVt;A�DV)�[:"5�P� QMear�V�sEQ"�$!�"�*~AuF,k|�&T�<i=`dr !*ar�V�43 . Ima�n �mpl��E6�fac�`A.�m��$a*�N�G� .'t.; rece�� ��=t!j �YkMRY�s$\ 5Qa�!efu"�zl���I��-"�hin$9p�a�59:mhX�!�L M}P rpre`iaen"Bi�A �hutA P->of �gyU��urFQ�<�1[6=86No�M�I�A�� ledgaQ �5��!C�7'GF�^^�>!�B��GA�a]R!�� N 1���soV`�so�&x� ��2�!D.%���M�yuyQBi�f"�Z�ealy> -i"8y��m)�E  c*�[)C-t�Ti@nTh4�M�icbu nchlv&1-��g2V#�Y���^�R���4%>�Ct�im��2� E�]membranB_z�� 2�18Sg!|I�P �aus�F(co!�spars�:� aywaeRA-�M"��1�I%&�RA`'wi�jguA�qu� lvd(a)�& �ico�e re mP i�PS�@�'-��Dcya}YM� � �ri1�u*� �Iu� �m'� il:L�(�“roll�EEX(l^��)A��e|Qsi�����^#�v�4E�� �6�a��2g&4" s� !�[6+wFur�1m:�e b"�]!�� ��R��f�!� _�q��r!�oai [64A��=Z+u�umW��gA�imA 1�tA�~ ��S�2�)6�%�prediE�an��&d �@ ��-A��h :r(My,tŎ�arZ� ���+IDb�*t  wh|F1[p6MF�"�i�61GR+W5FIZ"�}.�ew!-�e�t�0!B6�B�0A�:X,.Z&�J�QM��Z .#v MT��hcY ? Ad�z��� issu]$��5"~�_�r�{P_N� matc$ifB�2��IWr��g�ns*6 � �c[6�*6�R6 �Any� gx� 3 lie�#�8�x�#/Au"����U8  %�&� !��!�.�2" �7 ��ittbe����  s Y6N>W�t>�ph�F�OtinLH�+ in [ w��g�* neocor T L2/3 in�or?8�� �l s [6 p ^abi�O�}�or�e�\�dA�ow-��Qv���i)X� � ig.�A��Emam��a�Re�4��H.<~�cU� e c��Y!m��!���:�~~5yeS<`�d �� ed.� )�ab�&~ m�Z �� � A �]~Rachb�C���y��Z�|��� c"o,=�E�Yn� ./��� � �val��!+y �ge��(c algorithm^�,% u)�� &ee�M2�, ]�steady-�pot�Eah .� $�a���Lin\L� i0La cer��5M�e.��%_A��s�Vv/e�me�"�;AA"�{*!i�_x5� � 9��� 4MΩF��DQOs�:o;-up� �� ]X[67p�[5e�WK�%�*�Y�V�\FA E�8�02&�tw��Qw*"�aa��A�N- A�a�IAa��O��iellL&�f�:&� ]��2->�fσ�f=&�fσ& �9\,TA4�m}9+��ighbor>xo�l2�of*8" �{y�8)G�!�e��^@ 2,�� chem`sҋH�3��&L �<v u}|"!�EA V�H%�2�>(�m�b�@�| , Ul� �!�As>kIGJ2�bY]�� }� c� &C%�I/�/e* q�A�!P�!ir"�� �UGJ!�M# � dispN�d"� "�=a��lJ-�)va�y*� *iR� ��&�mYPeiq A >P�Q�ng sixFxRc !Tvan H en��!�[soo6F |G29/�x�PT+$�BV��agep a&7B}("m °/s&�*2Cm08A$6&7&+��pcf��e���w�ln fŃ���m) ['m�LMDe��dd��subq�AKatq���B�Q ee�yi5��#ribFc�e �2o!t%��R�)*� �VS�׽�'of�� E�f� ���% F v�(�/F�w�f�-6B�� teA%��(1D�Qed(�S(VAx=1T∫VAN/ ) d�Yt�l� );e� ��y���t&�v. S1EtoɮE�� =�"�lc� + �V/"M^al�[5���.�NM\.#��10��B�P�urr�'&C,JX+!!&l*"� IW�.�SA � ��2՝-�ABdom�Z��SR�kR���-(C9*klar'A�Fh�"[71� v^�z�)Ns: t�>U=IF1h-4, qF��v)��!��� Fi*CT= ∫.N[dR1 dRi��dRi+1dRN�!~margi!�cu�Yve6�mO�mA�R�OJu)>w ߙ Ui =�)'>X�par� ."-J1*�v_ matrix Σ�i�a� diagפ� ��Σi�!�A`( off-R,∑ij =l�d�!  (��j��i�>�: � !M)䁖�: C.Σ'- ) =Φ Z!�1�Ag!�&9i��` #��D=�&��""'�6�,%#T�SK2�>Xm�ay8�a�a����w-�XE?-�=�Σ�r�l�n�.��a@kn v2A�!�^���^�c�Σ=1de�KΣ�p[w !� −Iag �j!ipw =2!n�E'"Y.�(B�!��R..y�U�1�!jm:A�u�R�s ) :�0>D=1A�9`E�(∏i=1NddRi�t( iF)y6deRV��"!'ty!%�!�Ete�[�.4A�Y YL?k>��cap�NM� �c���BJG�6)n I�� &����/����it  4�N� �J���.�&�.H&� &u5�BB,4I�eM� �# looks!����� �>�!� ��eŇ(& d =Ћe,.)is 202, > �a�� �` ( �e ( S6ES6CE^��9�_�G a 42qB7 ompohK �Jz" �qgtwo2\*��q^7s�^sinθ�S6m1S6D�A�}!�>�ʧ-,I�s�� ŊT� "� k-��nf"r�*W�72C���mNeas��I!� � !;,A�)�re&JM/X , Y�6�!�.�� X]YE r.7qO�ri&�X��m��e g���(e�de�gX�^�)J��s:2�<=ψ ( k ) −⟨nx+�+ y ⟩ ��(�6@!!� numb�5>���w�t k� ��q�e���6� Wb\$ �M�Βnverge �. n!fn.�3�)��kA5�w<z�!�~�e�r 4a�V-q�d�+"�tab<c&��.�ewe �G "�of�a, 0*�9(\;0Cz�9�oto ��4 *EA� �!�m9J�=RePom�u)n"p "�0s�)Z߭� ��i45�i�f�="�A<�;�W.Gae,J^��2�H , h�GN+�w-f%���ed! rU��*�f6m� *�w�!o keep'�n��(� I�� *���J 2�J�,�!m�ts�_m�:sub�aiwtɭe�!�“YR ��~:F����a it&Wx,v�N-^.Yx-Ku�c jAusK �=>�BA��iRf:_��Ym�� 1BMathe�0Ie�!�� � �6�zFO =e���!)f���6=& N�!!� �j-�J�f2��� <OB�:&? �2��$]��&ki�F+!I��2a�yN�(F:�WE�, �d< i� h� LIB[% VAx|�) ;β]=�?−β5�( 6 ) � βA��tۊ -off&�5Osa]'=�.���$=�%yi6�`e+.E: R~�ot���L Q��o8\ul�E&s ty��I 8*is&�-�!I�Bpu�"�>� u5ig4 Mt2%olc�� �&�c*O}N1>meta-i.��� f(�[7�27�NB�o$��8�Ueigen@a�- � M=ΣDe|θ�4"%�M�:�i2�A&�2"�U*�W.�+he Eq�a���a��E6�UJV]9W<�#J#y�=&+nI2loga��n�λ\1nI+ex��2�n-λi3��ml�i���NlM�a�J#� . nIq�cuta�& )�)� "�3o��6*�R . StA��i*�Q=9(= Z0weJ�.� Ka�3 !Pds ��"�dV�2�!#�;!�E*� e�%�3E"� 2 2�C-* ���;+_{.�S�?a&36 2�C.0�^:rmaR3�1� �M tso&y<+����cw �IC��Rr ��a%�i-�~T �D ��c:��!�lE.��$isP!I s9= E�O|R��l��θdθa�i� �!O� Eq 4)*� (ed.CBj�� Z>"pC�X)���AFm%�"5R!EM S[ E���n!E)�AZi1-P  a��%� 2�a |2[�A�M�*$r&�;��O"eE�o!A�6!2iɿI"%2UCb1"Gzn_�5 co�,r:;G�>{m 1��6p:9lih�B)&�D,es:!P!`θ′Dz!�e�*�/�(mR���� 1X� @a`oe| A"{D ����}a�K Jsez>]θe}a�^ �>O��>�FH�2�HL�i�=a�R|�e �ND�E)56� at RJ��lΛa ) >"�to-� othe��E�2~��4d�2Nd*����a�"�> 9 �"succes��t�4k�Q�A`al�' kYl ��.X �Փ�� �of)c͠*���Pc��0 ��K= 2���Pce!Hi�Φ ( y�=12π∫z(��xdzexp⁡��z29,�M!usa��b��%kl Aء��ܖ6�;�>t�gEqR��H�Vv �E`��@,��m�HVbR49/ng` A1%1>.%θ agٮ�=Ʌ��(θ + Δ+nd− .tPc = ΣR}1H (Ŝm@7 R��+�7D�9Qf∙�aee Hea�)��tep&���cI��yAW-�6Ked"!�Iw1�n�z!mPc�DR�K� �hZ�tdE�*ovirus 7A�EV7 �R&��s� causiXa_I%�h!�) o�] mouS�ise k�,_* febr(�E_ildren; �����;� asso���#m���I�Ws-!fa�4A��J`outbreaVl OM�Z�Asia Pa:q�\+l�" ˃��human P-�$T�oȼligand-!ZPSGL-!\/- ellug.2ק��y%Grep�����i7Dukocyh3.Rsialomuc�#xpr��=su��Q)l@�^W� ��m aff޵�uA2��k%�ed^ sT I!y xend�0l�i )–=098a�,"C� sulf�r�:|�U�D:NC�l d tyrosin�'�+d��O-gly<-�!*$yl Lewis x!UQ"tGO�e6sof ��o eluc�+e�&ڻl�e a��-�te�! a��:!fmu�6t]_Wݦ-�^!�7d�<%#�j�3��.��b�engdtoII�Q-!@he ��in 293Tx#!�%�f�OA�>�7ss�YA��M���!:7i�8 {by�&cy�����z6� )�osy �AMT57!B���'.�5tQ�2Q,0�neA�j� 55"�. O�e���site-6u�Hne��,1�&y<rc�-U�]�F��!INjo�/%��51S�b�F2�6�h��or!�yI,��chl���bMy�~��9*�=��� jXa%;"�n�lop�8K� ive-K/n���� ~��ng, �ve�b��9@aqA!��genus .���fam��0Picornavirida&/��NR�X~�( HFM�U�7�>�at��� ?ly you\ph  Da�ha�@���* a sk7ash��pal�Ondx�eќulc��m�A�mucos�0^"M�=��r.Pa�&���m��d�f-o_edB�in� AB�4 v�(~�polio-� �A����� stem�5eph�3�-n>B3 infa�!�Ee9 O 18['�Or !ElٟdeciW,a�y)&' Ӝ!�a*' ���n &�E�c2N4world�3E�~3M�~ -:~ a����in Malay� , Taiwa�EVietna�)�E[ Ch�5� , [3����B. !�cloI ] �anw a cDNA 3�3C�i�:���< ��&�� .*���, �'gR7 E�[ 8I-O�[�!$amayoshi e� . [6] �scave���� �G BA �r ��SCARB�� ni.j�eEcz�!�� -sus�2w*G��A�a�� �-ngD se L929e'genomic !�=}DRD rhabdomyosarcom�4�.�a�bo��)�ed�Frie,ti(:� �s871�2a. $ >��lE}y�cA�o i���os�ո*� A�d&�6�[8�hWeG�N*�B�at�!a@<��–y !O�Pin;(-PB�As"� �I�| ]pU6 ��ofF��sI^�#�R��L��6g$�ph�(yP�oVc��n1rusa�1jE2{t ".EQ�4 �.!�c�>Ys�P,j!�m ~Q���?o��c1���6 �^�5h��"; �k��-h�J* I�9���v of �.*@}�"�C7"A�b&�@&Z  !�1�+IBN7_"Y�UC���|uP� homodi�� [2�w��� ide-liӻ"o2r&0 & w� )�5ok� �v�Y� t duv6)Q C2&1~2�a^, [%?[1h�[11ar1n� �F� .L P- , E-E/L"��� sES>� A~J� Mkn��c�3%�&�>q�to=c[12�(!� , [1�B[/�� ��*Y6)h �R�����|min#� ids @�6�a�0KL >":� (�$%w" ;N'� ( Y4�9Y48�nd Y5|� r�U�ū�� �=,a1���s.en-��� � �/st-�azS !FA�y eJ��8z^f#. TK a�i:acn���l�z��secre�!f�;-b�D�A�E�g�8lu�W�>��i��u occur"L:-Golgi�?�9I���:��� tein6Fjde�b��n &T?� "] &�r}��(V� �- 6�eH{wideHac"  .�A�1����!`wn�&g!H n�(2">}�it&� cest�W>C��J���heVF� , C-CN-{ CCR5�&p� &�Y)zm �~1ņco��)B�b�8-tr�����/o1^�cp�&type �� HIV-�;!�a� b;.�+em:;�F\n/�w&�s ^�vi�J���in>� f�*2#M��?�"�h �:�J�ݶp��us-5�2�#0 ��E\M���V�A�bt�). F�;�2�"� "cz�u sia*.-ݤɘa�tŋ . α�-3-flyl��fer ( FUTs$�v ��/abiosyn�K6t"�Ee=.�]D, [(��en%Cof �&GFQlanL�?-tit' ��N�pe�nab1I�zto.�� D&�JN���� g�;�]*< M�-T57A�6�6�(�/.)��k�!T�!�)�9on%��Tma� -109}��>��Id�F T6�C�NA)Y��"a�u�Hre�(h-*( -FM"�~Z�+ �Mt�@)� iE� 2d� EDTA9[.:c� weakZLo%kmfci�-�f �-� �/%�)K � Ca2+/� \)���U� �Do%6kO `andiY6@ybF� A�"� !TA�� ��(iumF�:�EtJg��,:^>�293nT�C�S�$s�(vEis( e�!d�\f� �n� �a����F���1�Epr�FW".�P"T �SI�J"�re@eg< e~�r�A�AJQ �I2�p5p2�"@,'a�a&�x>�V7m�XI�w�Q u:7)�I]� �dɱ,i�iҘ�)&��" �!SYz�.�J0�OMa7-�Yhw��ݓ9���N!sialic a� 1�"6.|-y&< moie�q:� �4`�7�,n�v��A 'edB.���eR2edI��id�y�*�Isņea�Wremݟ>- 5�1�2�!�L/29r�D��N_!iJ���-��s�&IrVF.z��EN��eA"#b5�6{ i1}&to DLD-ֈS�, 9nNof��m ���6�!1Y�2�5"�ri�T*T ]6�;Z��R� �04��\6O!��dFJi� �2{TTo#'���*�� � �N3 iY!�=��� ,-�Io��*2 V`� Q� 6�� �c}d"t*PF��*0ppa�1�v�? �.)�AX��q�N�Z�:�q�n� .�%�Vba�+-$m7B�Fo��V�i�Ʌ2 ���x.�-#��2*�.z8=!&�A؁�5��-"[*��e �j6A��^vQ�*5S6�or�)jnx^�}b�)q�&n - �! E�]ylN s�.�!�!�a H GePle{ � G$1�H~�2���mwEJn=�plasm!J !H:��_ 48%%!5�# u� HJcy&|#A� �.�% mpty- �e�d���%�ce5$y8�v74a7�&�t�-1ԙԥ@6H"�2��9��6��se�' �b !W-j�2y5� �ub&Ro��r]]s slighA(�]E��or "�#8F�5146 a469i&j2!�I�Fa�@��!)m� �.nMZ����'[�[8�or FF �d24�7z'( d46–�1,K��!�}let[disrul"�&N:�We 8 ��u�F8!N&�]5&��eB��n�'SK-EV00�C7/Osak�VKED00�nd 75-� gataD� M��� � ك�:��S�(HR�b �� y reMOn.�X-!�k`ak�9og.�%s�R7)�m6,ů��r�"toB� g,>!�y�s�OX�,!�F q�PB5�<n��5�)ZN_> )�*>��:N"�-�2��a�I�ulHG"J.f>�� � %N�. S:( ���� �5��BbQe5A �x &��) �qyFc(��< 5���:GV�A/:F�nc��=� U�,>w!�� qx( 02362%�%Nagoya+�,�3:1%M�J)�,�a�)�_'>2ρ�5C� ��R* .�Z�"63 9��A-by+ �5�PB��Qa�����Tc >��cP(�"g\[� anu :/eR\$r)`!I\�|�btit](at 24 ��st"; �B)r.�3y�>�*�qcu�EX�.G(���b�3�F�b�6�A�h�`ee2de�,�NE�ol�e�c(�8EY�n 5"e>�YM"$� ��]IU�3I�5B��)�1<y�B)E�_A� rule�(E^"�q>��T:�`"%r=F-V���.�"Q @�Yy >2S0- b^m"Rl�01J�e�U�&Q-N .Z�`- �C%tr�m�2p.�2� G-10��) coxsackiebA1���+k&a2(un�%`9�o�;�Nş��>���[2�"A�^$j���� sa&#�����%��6�3I�eg�i6�r6)JF�%� YN�. �'iMb: �q�pA�>�"��nD>�$m�.� �� F )�&�| �V:LF�. Fuku6V,;"�  W ���3Z�A�>�&$��a"�J=�u)6 S�f��moVpA�"C � 1U*+ !. l .JT� ir(-aM�!�+J,�gN@2\�fo-�E�j{3%� �Fos2.�� a� Ta� ���L6~A3�G4��`�S3BS35���i�� �*� �4Z�� F�y�%n�*0u 9A:j��u��Hb8��" ! �@S6'1: .� ��ar! [&�(: �O�ndM�� 2efxRnd"�#al&�* �]*�Y@�$"�9�n-{sTd�<"�+� b�%��FzB.�%����"��#8potential sulfa�Lted tyrosines of human PSGL-1 , Y46 and Y51 , but not Y48 , are important for7�binding to L-selectin along with a core-2 based O-glycan �sialyl Lewis x at T57 [22] . On the other hand , @crystal structure�}0nd EGF domain�P�,co-complexed �;$N-terminal 7T-revealed�Hritical involvement*sulfa6`at%;� Y51 !3\direct molecular contact ��[11!,The correspo)f *� regM�highly!�ified byN����&�,IZ2�b "� !��� r.� w �s1qSite-' ed mutaq��treat�| ?,sodium chlora("� e� � �Umresidu �Ar!2tefficia�Α-to-�N�toMW gp120-CD4E %�!� a%��M �mM�Lik) ev he �acya�I�iwas signaFa�duc a�sdng a!jt � one�3m�*$phenylalan�F��tit�� at f+&�5g)}ed9p= a� to)�inF�na�a.�T�# S!��bee� mmon� omeno UU�8�idimmun�n such� leukocy� ,A�teletqjBa16�Th�P:��seems���� only%��Vof6� als!(�VK vit%�viruse� AlthoughMocF : s� e�š�@oqa numberufaFcaPmai�!�hildren ina,to)p major pub� healt~a�9A�Asia Pa���r , no vaccwr anti��a�t� �| availad �a��[2�Our data� IIx%�НkY.promi targeA�r]�B��R� solu��A.a"I:g�A��at hibi��ơ��O.�[o aC �. Q2��"�:�J�2���ina�)���accor�l>� A�B�f aNvi*�)�.�*.�� in Jurk� �5z��A�of*� ���ba' ofzuV� llAvid*velGunique.pproache� �قof.g.u diseeT. 293��af tain��$Dulbecco's��Eaglee��P( DMEM , Wako ) suppl �10% fei�l�rum� CS� :ZJ�RPMI oSigmabiV. AllIP1�( Te�1 )%Jt�xsackiee� A16!stotyp� � ( G-10 ) �propag� in RD�� VeroU Beca�om� g�pro�� diff% plaq��oKQ�3I�titers zw $a microtit� ass��.96-weA?� s�RD_as prev� c�ntiFcPL2%�>>@eckman–Coulter Sti-e o���J trans�  eG!<ple|sm� Lipo*$amine 2000>� j  �6yfresh4 h af���yI3l őcol� ed 2Z3by pipet� �:U:���e tofN� &� ,J;e%~%�$10–50 mMBOin)A� 1 da��F� h�NR]T�bS �tai��>�)Ah=UXincub�� 20 hF�wa�� �:Obuffer0 (; PBS ( −��Bp 2!+ EDTA!Z% �0��% NaN3���%�- c���ce�30 mi�AEW���9F�-Q= :csecondat �conjuX O8Alexa Fluor 488> � Q6� )��4R-phycoerythri SouT n� ch�*o����w� lN� ; labe� � a Ze*�>}0!ikitn P"B ��,�,CaCl2n-�le�instea� 9�BTA� V aly��$FACSCalibuA�� �AM*�B!F�a�AO:�A��ei12?. A� d�V� ��ed-_aO supernataue�$freeze-thap"I~ E& �)� |� e�-� carrh�a�ripeb[ �A$ meanJ�"V�Stu�!'s t-t�( �5tai�* P values<�0�conside]�O%cally.F8 .C�Leishmanihser� globalproblem*�Dmany people worldw. While� \� th l2g� 2�alB, dru�)xicict!8emerge� �s!�"7r"#r*se���ivAbN�)ru� I�n ,he mammalian`$of rapamyc�mTOR )�bB�to exert`�!!HperM'1% this.&!��h�&rapeuI&�1+�m��%��$ol Y�ek9� �. R�0, GSK-2126458e[$KU-0063794iYadministEU to BALB/c"�hich ha  ceiv�Urafootpa�j+� para��z $sD� a� burd�CW(ass�kiJ�ke�b splenQhen��!h�"A d�t lymph nodKqea_Ņ. Ti AL)Ra clinmZrelev�d�2*$&2c,@%�=nA�a�#i�lo�d (!71P2,50lo%oN�. I�"�=employ�B�did�kf,xastig�Av as jud�by 3-��` , 5-dimethylthiazol-2-ylA"D !�yltetr!b�d�MTT� ssay��-ronAyroscop�Moreo�*� IL-4�duIcapacp.harvesao i1�!� t!!|�C���� V� . Coni9bIFN-γ:>�4 LEAh2 +(a T helper-jKTh� -ske��.f�{. Fin���9*� leof CD69eD early �-v� marker\ n).ice?} CD4+ CD8+"�#!enhan�in9+-��1Y,. Taken toge'j ur fKngs s ,)�p(B�may bef !��*s|&�managc�6� . WeA*pA�%�A@ bene#al�xect� �o�I9theirmomw&o3%��2\!�dju�0iQ�>��5!(��in{ )�/tegag~t.��. ��P��&R#:!� ra!establ��!Tif�r-,^,c �� 100�*W+%*Nal��6� incriby ut� mill�7�!� yeaA6��AAe]r ly � 129AYvidual��!�şd.d  h� at risk [w �1�ѵ0� �he fema�hlebot*e s�"��d a  ,et#&h1�,! lu� |[3]A2�E� J ed host ,.�persis�"�ult� � ithi_$ag���E�as &�'�C��2^�.%w�1C-� ,"�/�1e>6�, nam&cutane�, muco�visce 6>[A1!��  ��6!�U� outc_�) l'"A$)E�of.@EstrengthU%j �e�n!�qx"U~IndUz!} underlyoi[od�ienc�"1�HIV/AIDS��re�(sus�)�to�se�3�Zg��to� e�@ � 2�[6 , 7Af:N�A,A�e�"1�U�1LM1ne14&)+fac� ��4!!71�1��i�W(4.\e divA�i:<5�m6�enc{� . His*T R���class ig two group�‘old� ’�‘new,�#e�*�$geographic�"b0 . L . � , tropicaWaethi r�0� >� 4mexicana Samazonen��!T# guyaBW2��\�$[� �+� E@al��(�� s�6�&y�6�( CL )2�penta�4 mon�, meglu��t0!d�sglucon\,ny�6��&velop�)Bc�/ thesY--lW �[9�6F 4 limi�A��5isA��t5a� re�"d�diaE����ca�,�f,s^�8�:pitalK", 2�� urn �&Ga.R economicon�cA�s. in �(�)s [7 , 1�C�4� amphoZ1�B1�m�@&5�%`Y�i�H"=7it��b��t�!d)rea�::$g its usagEb&.+veJe-Cofna�[1��AB� expa�vi   2E&"r*���jo� � af�il0eA�A_#�82�+&�|)2�(� @j)�Ctyp�^by& ��r2� ���1 �*or�ay grafAdNw"|%��k2QV M9, d.@1�-��'im(2:� ��*� A� ( ntex \[15Aq604bacAeal [17]� i�:��rnt;nce5  .rveill /Wh r"��3�&)_�y A ti-p"� g�/in�ʡ�,J�M-��.*p�3u�;,a(AUcl+�stood�%if.�in\i�$.�& �!�>� " �r�1 �+hBh7y H w�� �}. }3�ne/�o 0�7 kin"0links environ��� ue/2� pivobiolog|"�+�9� � ,/!n�\ /*%�growth�� etabolism��rviva�%til!�Aiaut�3 y [1�2�))jɗc0/y� subuni!�"� = -1�g> s knaY3   �C�� � 1AJ,o" fe�:7ory.v,u((�C46�|lethal)�Sec139  mLST�&��o��-r�Akt��t� 40�odalta�( PRAS4Y*�DEPE?-a� �-"�/ngy( DP5�&!��M ��� presa;TORC2%#)g.�= � � s RP!�.:!hanA�=Ai� :A� ss-e"�7m( FRB )m�!!�%&��:��!E� �!�myA�ppear�"cV �z -a�Rpharmac�0� A�eE�A�3was orig��(9A<< -ins6 �@ty si� f< expo�.!&qfoto1� phosphor;Bof�T, a dow�:eam* �[2� &F �7)R;�2� �qongG V� coul��e) !�!��of � �Y$? . It%;m�A�r�~5r?u��e%�a;insul�a�t� �mR�disrui�]�)�� >!� ly [�?T��Ǎy6�. 2 Zbe-p t� . .��pyridy�lfonamm"K �h�-�ino1>de-3- ( PI3K�R a kehB��FuڭqY?..��smJ@EF�eBoC�".ii_.blocks�6&_��0$ �.u �-1�o<I#i'� a�T2E�%Anab�#5@2A alle�9�plAp;.� �?i�M&:T1��ex� &��. M8results.E ,a=f&2>to �v ledg&E� ���2� or2Nde��"u �d.�A�reaB,morbid��ofa�en.n/ 6�im! s)��6 K-Ke�6��� �`�"��a�-3�N� �-H&*� �"v�Q.}"�Fdiscu&. �-( aka i� mus�$o56r1LC6�2( Wob2, Mchu�>r! �ob� �&"4Se�, k Ch<Aw( Hous��, TexaV. F�7C�7Se.�7�6SLGibco ( Montgomery C�xMa�.nd G!�m�FF[3er�2 HeathfielS5East S!JxDJQZ ELISA k!��:JeW�3 �1 Dieg,4d)forni(8�#�1ma��KSchneZ#yj8-1640��RwS�8 -Aldy ( Oakvillaq Onta'' A2 nimal} s R,uc��followA�a� /� ! 4ocol ( AUP# 20h&24� �9� by W�rn Un"GA GC��!NV�Hint,Servi�4( ACV�9in ful�p#c�-arCanad.#!�cil�.]guide� W 0Adult 8 weeks;.T"%åcv"%#. M�:� Charles R� �AESt�)$, QuebecŴhob�!�%b�r_ JtN5�&EJ$F&)E�kindl=C�� D�5J{HUzonn�=�$of Manitob�Winnipege�%iI��v�L!���s�*( throc?rep40p�Eg� 2 �6�!%t�9d 26°C!�y�u�;pH 7 . 4Rt/�;heat-in; �FCSE�50 μg/L� �1�. Ten m�+�M�;W:�( 1 mL DMSOG� �-80�*]+i�$�� tock?��bf(a vehicle [ ate-w0ed saA� Ba0�/T�L8�25%� nd Phosal�PG ( 9�6�2E=[-�" � � �& d �#a`9/.� W*k$%�=An<Aj same��e>a��) �%�Ftr'��!p6�!3�VaF�@%�imAj�B$� aA�R) 2��LL3|#�"ng0 ng/mL N/4 (LQ�<at 1:�5�#in�i��'F�%6N �logarith�pc:�A�q�= ( 2%-7s�`�" rile"�= flat tomq�D5 D ( Or�S� tRE , Europ��U2��!SpE͈&J-��� h4"�!�:�!48"�3� ’s� cyEK�%�%��yA^w�#N�>2�&�>�:re�725 m%�)�ad�O eachD �>e��.�.�*?-t�.EKi�=(at 800 × g@54� �� remo�of.�,a`p��a�$I#μ��B � �opt^ dens�( OD ):*a�"r> at 540 nmk�2�:!�,��?  I"ro" (Y�iB-r chie| ( IC�? PMA-eed THP-1�"�>�8Mts\Q�A�5 $NU�͜)�!B�e/&� o�BF&/b�.�58M4!<0�0m�� � of��COM!]�-oh -pe�.NeA�:ElU�>)# at au� -to-��of 10:`:Fre�-n+-X�3�A��P��um-E/=&-until�Fp PJ vi�!u�"� �r!�zB�)�I}%)�� �Q�Y�Be2�%�=!� � �.77mL upa%5GmL�4������ ��n>0?��,�5 �h *!�9i�Ht!�iEMFnyiAQ*��3m%�Wa�2ce�(-�k�b�.=�-!05% S^Ldodec�� ( SD��!Uc�8�!� lyg:3 μl/e~�)ACBsh�)630�8Rul&- q�Ma(��!.-�2* �xF� ( 18^�M�m�T � � 72 hAR�[%� rescued l�� j.�I��!���L%�to�TSt*L"?1Ut� !U2�L�r)� o[. E�{(��& �2\-7���2�N��J��.��":�av)I� left.�r>�����( 5q�,:4& mL%S2!���} !V�?�fix� -6�e]:�12�10���l*s4 a3�arXKxa0MS susp�"1��ri�v�j��of R \% EM-grade glutaraldehydAe �A�4(oom tempera'G�PJ1srP1;�sprea]*� on c9+ slipA DAR ϥhdr�(�+)L>�mA� :%b��inq=L�H2OA�A�let� =�Q  salt �%�F s�BtP30%g07z,90% ( v/v ) "no�\t!�sS > �+% 9)d� )� � e�6�4 100%e. CD�dr$6�,&IRpoint!N�4 &�m n SEM Sil�0 stub�� QeSe nigh�Wdr S-%f gold-cob( �E2� thicknI) i�a sputA/��.�Uly�v#� ���y [30–�EUn2� �FI��͝�r �� i�� �!�E��6�H�J%�I-sT_0 visu�&���?TEMx1c>S2�2 meth�"P*� m��F�B�� B�׉Y)A J�h spuna�xa r�iQ=X!9 f% fi1`�1�9at �:e�.� F{J 1 M cacod�eq�,�� a�� :�.��r� d tw�inj`�post- � in 1% osml:4ox���@9��a�A!p�]�,�D�ag8Zd slowly�anMic �(-tN�s"YMhy���奺d� � cet-2�E�J6�����E]� ,n equal volu,N$propylene ��S�n�E?�r�D��,!1an� )�\��Hpolym�ZJE q�be μm-�Z�  m+cut� a gc- k|.m�$a Reicherti��Vt)" OmU3!�Dy a� �blu���"��  l�J~ 2/�H,!iper 2-�s�8. Pale�=� 80-n��%[��6"tc�Az �Wo2 vapo�?rel��'Yl artifai4. S �-:routin�p�Ad� on 200-m!�cop gr/_,�J carb�5tabili���var� port film� 1^byVr�!�sN�8uranyl A�2 A6�wuS. S.�#r ! in�*)'h~� un0m&l�<wp�'myJiOlACc�P�f�.�Q���exten1%�^i!� air-�I�M-}vib7):,�/!�s!ea Phi/ EM-10C! mis%BF�8e�econ� )�vol� A[60A��K�[3*!*r p �; z�V�i �H(cyc�VJu"� �Fi�H 400��f.&8 ` $ F��[3�3&�random�8sa%� o 8Ls1(!1le�n = 3a� �i"5)�(k�Ncohorts�!ie ���Qs:�f"3 igh-5%�low ���)� �"� W�;Es2 × 106bb/5� !�*U<�Zta8a00 !p��J ed� �A?1�2 �r�!��2 .�>6<or.& [35]��&e. Daily.�, give�;tra���w (( i . p . )e�10�B, �&)�1��Sc8-c9� �!�;��e � sacr���so('of*�:��pleen!�Bl�,�m�� A�ez9�el�b1pun�i�,*&� p;m�qu�-f iQ�_��ci%&&�/�H. C�+re���)?�d� �"�f di��li�4 rld P�(A@I�%u!>�Sa�otqFlori\,a�r� #e!� 1!Jq�"�DSUL31>��m�!�h�XT%:�a%|re�Y��nd"7 back�5n�.F-pi%�~�d!p-yOt�eWe02��e"� �abf�py^\�reANv� �@L1V�poplitea0mO@a�pLNnB�I�Ove UO( qZGe�2DNA ( g�w�G2�Wex3A&I_!,DNeasyM�& TissueE`��Qi) � Germantow-*�!�(L[�)Z manu� urer��Jru� )�6� !Cpu�2���a�A �@a Nanodrop ( ND-1�O)e�t�b# ��%�!;reTo�30 nan��:t�/%J��HnM%�~$�):E��ZB toplastid icir�h4RV1IRV�*�orward: 5' CTTTTCTGGTCCCGCGGGTAGG3'; Re�8e &CAC% CCTA1AA&67"l ! r6��6�+�3 �M�$� 102−1.> %tS to g-� aa�sNdR=v�L�X p�B SYBR gr�D!t�er mix,"ppl��q#�5.���a�  � �L��5�!�!�n"�_�eP�/�,s�jc�+� z~��a�"f])i�/l melt �a�M�6%&&�#I��HStepOne Plus Real-T�e[i �_Wsoftw_#( R*W�'���neshm:( Ct ) �D� nor�F� ��F�"kee�5!��k /? e 3-"� Roge�2 ( GAPDH )' M Y� ’CI� TAGACAAAAA�3’;qGY�’TTG"CA-TCTTCAC .>�!ydelta-�( ΔΔCT:�"� �!-!�[cal�4%�: ΔCQ =Ui�−Ct reace�� w=>T�A%M −�( ���F!�� "��G�&�"3!"�.��:�rmula:2b(:��= 2oE � ) [3�cAll6O�H�ech�F dup�J A �98�!Kar"�a��UmLisu*W$!z!�in liq�[n "gen%g�K a)N� bat$?h!�re�ly!]l0�f�&e�0on�p�.=7�ف-�n5n,a Pierce BCA�J� (rmo F�Br�$0!W*da�>�)&� AP� �D�*� *�"�6onbC Sple�E sing�n�_s^� ���Q) llo����8 ACK���=ium-Cnhide-Pot� um )!4is�t�lmL�SoWf2Qw�U�.�� HMPM*#)&%*,~%*!�;%�FCA1�V HEPE2,&Qp! i��&= 1� ? /25~ yb U-bo2#� styr\A�2�st>,�1P��&�lyE|[3R.A�"s}1��I:Wad$0$%�9 ,145-2C11 hybr_�O�.�K*xi�*sd)5an agon#N:^U CD3 �O . Cu~a*�Mn&@I24E�* �eG�+�+��5���by.�+:�)eP�$��Saf�+ 1- (ou+ti� gr7rA�"�m.z"nu�:! ( MNCl E�i`1 �7���!�V� "zK�� &1� TD��0.u�MNC-j ���F �hom�\ize\*F<ly �edGs.�cytofluo� t��LAi.2i=6%s%BmZi9 q9!�m{nonQ�nFc� e�9&�q�5�&�X��~e,+&�с�s�".to2 un�'RF�_<W4G2}11N\U�16/32 I�F�D#Fc ��2���A�G�d%Xochrome-*>VmAb6�?���#t3A&��(CD3ε-PE Cy�l7 [clT� 1� (2")H*,ti-CD8α-APC4$53–6 . 7n54–FIT6GKDFh� �69� �H1$2F3 ( BD P�6in�i/7bo�5� `)�TVin *�!0m1pO QU�nE"~Ttho�,�AndQ�}HBDgY�!II2�WewY6�c8, Mississauga ,2�/Y0acqui���A�e&�^��a64vuMi]| � m FlowJo.F TStK Ashl�, OregZGrFPa�ism� �!�0; !S� , Ce200=Cb_a�uf>�!|�st�(�6 . S�T�T�ANOVA)��o�{,a�� wh�@!8"�#"` E*xl�8gp U!p�gtMW'05 Bz!&U.? .��e�&e�t�)\ x-a&either A��iO:�/(j�,.��YZ� a>��mSOD=+14pa%��iUFig 1A3BJas� itoA ���� J�Sle"�RM�����Z�5tIGB�:� 7>0!^4=/Qu$�e� *:�A�&�hF��d!!2�Mvto�]dec�/iM|>&FH6 ( pW0p3,�"� RR{.k=��� 7�-�Cns.8 G"(�3|��{ 1B�Simila�Q��F��O.�5��@�|{� 9v.i0%&A>9'�l-'��u?N!a8}MP�*B ) a!Jl� jk'�� ^27!_� r���in.�1% 5�� . NoR�D:7XteVT)�mpari�_mkM$Q��M)ofAd>Us illu�4!�in� B�s7as�Ha�7�6�!at�2�E��� ��do��2�:/:!Xmilder��xM�n �>E���%i}U�le:�|��one�3Evv: �&���2�n�( S1A��S1B%1�Co:9F)%(��a��"�9*�>�xt>�s�<T/k:|"!p=#& {ofa 'Q&]�. UG"��>leE�of�:��@Z�"in��Q��mrz�;�@as{Yby�A�Qe&�e�V �k<� RV1-@zma�m�W&9�s["��.�=*vb�m4)"8da"����pr�E�A2M2E,"2�&�>��*�2�!i�!��4=d%�����Yޑ�y���B�5�p�raBS�F [? >�g7'^u�Ki{�~i�2Ae5L6�y�.�Z&cXx�N��n.d%�6,dim�\�!60��FOB9��&�Bwe&� noA!t� .� U�]E�Y��cop &*Ƅ ���!�&�7s��Of��lF�s��(>�>�0a��<dB�displa \�* ��BXVng�^�( m)�;RD5,@1 �� "  �2t. M�Ct . �m"� hous6$!q�_fZ���!:km*C�Ys�Ikou*�Z 7RW "Y>MXVO�@B� r]:�JA4r����nFdM��oQ �p!Ep O.�;�)2� T�*�[w�9�#�-*�Mx`r��Z<�!EM���.5,,Ea &��lyvol�a_W�!v[ivo�B.FA b@"6�2� in 4-H!U r'a&@ 6��Id�naïv��?�G+ �?� 3�gIn�.�4I^impac �tro�TmvL�a �c".�!)t&�6)&!`.�2��He-s�B'3E�Ou*<stu� %~F�|.3v_Sat%V ��GisR�}o �!�mc&%far�1v��e7m�;��ν�11�?875�9�,�oexa"l+�u);A��46�o)D6�A���mt-�2,��R �+� ��%YG%*��!(�q ~morph~K�]! ��s� dB~bT(TNMbm&owGp'm�X<&���"2)�� ^7I�LP ��#��>!��I�U�?�(-@as)��uraNy6u-2%m�,B�K �>�� miof�(8 2)6o�tH�� s!�H� ���*i�D }no[.�:�I� ]�t�lhQel�$6Leg�vacuo$M��plasm�rfiA��yFaa�u"�<-*��6�͞6@)J-fN{&�JonJ�?��)+� J��=e6TEa9�5(ݵ� �����'ya�6I Q�anc �ss wa�>A��5�W�[ uQ[� �A/���2os (&\TA)@In.� ^6)F�r? �:� 7"xY�M&s fc�ce@  4MF-� A��b4�CɎ!?O7��2�NdI�af���b%�njul9MR9in2 2[9M�6�C!��>N[�:"%%Bu2q��:D-`+"�-�?n*�.� "�@ )"c!JZ�peFk�8�cQ�wy%Ri{ab"1Bz�u�!�2��=0suggef�.%Űno�Rr ' ���_�T&J��A=�>/u!�DE��� �Ec�y� �hw,�3G-1S)D�>r_�Da:nC-�2q }!s�5o�-) �ͩYta�2r�$m�zS�i�= i;~�~��!i1!r�k! -el Qz/� cEY�ME&[:vo�%/�  �# mode�I":V���Z8?\��C v�>6 ���W� /na-  /.\ de��6tBm -�ad+-"\ )� REMma�g9��1�n6rdi�%gra�B�?�ᥬWE�q�is�hh�bE%�!& 6)1��F� N�S Ac Td@oP �-bi?;o� Th1-� Th2-�m��)�fpdn��'��:�:�.: focu�onB�%��a1gre0 t �A�B� .� �(.("�$!�U"�QV"�EME�s&'ex ��P?ud&�Fn'-%%��rF�&��EE.�4!�4�4C�S S4B , S4C� ,�; pane�p!�&)�1�ErDF.\�r�'��%���"Õ���C.f'a�J%c�K�%V��h NP�e 'y :� �.�Y� 2� ��N��H5�Lh)�5r$x$ M ��,%�4�oIR t*�ej ��El&�� �:!e���>U High�of yE�� ct��uu)�8n�oa�s}OI��+�Uq<%"�86e6Y( S3A%�Mo"@s�)'嚱�=02h�!�F�49 .*O� >�!=iA�&�%xpdJ�Wheiv=~ )A-U�A��5�0�D�iMCy�Surpr_��]�6 �V���.��_.xWU$w�1.i;hX/E����%up:�"I ,� 0cR � noticeE^, like$u� veryA5!#:M %i� ʘ�.���=:V"5i�m.��I�p6�a�=}Y/�@tRae�& "L �m�CB�F�l��s". ��u���"�Sr�6�a�� -�cT� t�j��"A!p�"� � ��_��7��n�i"�\� e� vZ'�bV�u!�wo �]4ha]u t  16t"�%:��q�9�,��egRF9E�5 ���&� :� !�2�o; �+�x�,�(i�W� �� �g"2,wY8�)�'nj'�Gph<�V��-"��&�!�-�&8DZ� �escdP�#RMF֌�%7�E2�E�.�g%,���s "�%���, ")�2�&�0�.R>mi���:�DkoteM:��D.>o�rgm�. "loydyini(� t �,�3�6 ungaC��Ht�now m �"8 qq muno D�Fvea�1lleocip�C s [3lW�� �$1 "�&%��a~�_�jog`x y bo�p�81�1vI�)��gt_3#F ori�ringitizTru� LCMV�81�Bnd ��iaVus*�ow) stir= enthusiMEe a4�7co!$��R.&�ap;9A�!5�~a�("Fi��(*tA�staEA&� c�Z litt�dIab�/ or h!��kh��)M�(I�"@%\�. 3V'�AqP�*:j�usIn��Whag�j1CAp�n6�6y[3՜TOR? TOR2�. virt�J�<�i&Lt!�GKKIsD� [4�nGcD��Ā�P S"�"\|�=�s [41_]�a�b�nXwa=�4< [4KtWe hyp.K�*~Q"� AwriK�)at%���,H���6�PFg�v"=k ����CK�Anand��n�q. to stop P6V*c{y6'!�<iqg)�6� ��c' zcÚofe�d!��/6�y��I�*� J� %�)4�sg�F�V6�g�9��-&=f&�a�9. ��"�i[4�N4xI��e�gA�H�S@�!A�f��U L-12� 10 axGh aE�donovani�!!� el [ |&~(J�gYo,%+�[A}%}�/!�B�C��VF ����.CspIt&��r��{3�tA��ac�1�� llosLec�A3!@�C�1w�:8�ih &"1��m�in+s��in�+mo�B![4vJA.63�B�#&�Aby�D�RB,,R�� w apoptoC M� casp(t*�I����7a��D 2D%����"J �:va�CRaR9�.�*�+��mR�?7(�b�s?9e�&fAt�$m��ce FHIn ;oSJ2�)���%cmS;?#G�9�%�A��� M��'�9z|!25�! �s )AF �C2 ��s� r?�{%g[4��&i��9�]F�Y��.�,��QfA�T �W��yrEU �e��y �$S �bF��}I",Da�Q!�29!�8( Bsw�M�_is�2 �! D� o�Z� as�%avi�.-}m�l*5���_@a��Y>9%.kEI50%�c"C%��.%�1"�&�A�In orA� �G!~r ��(!%��2�[= �w&Z\.�e�J��f!�� �&AR}2kS�pdm4F'��"f� P>� \DR5%��W�TEVAW�#"�"-Di���>2�%.�e�]PU�eG<�b�.��6yf<�4�-y��6 am-D�  F�$�$d�}u1r&cA\F�G��i2�"�#w�����#,A_"�by%]A]gQ ,dergo�# ..�RI���=2�-�eg �@&�%�M"|I2m��A� O��=�0gn�ap2�����0"v�l 6T!. sca0T.{&-qȁ���e "<:;'[3� �4�CToa�r �C �D�ry& E�9T�rv>7w�V�owhp"��"�*_ work!�Araki*o׌�-*W�A�[g���Q�9aWsw(2Ke& 6�1� ��h�;"Nr��ho�F5��22�2� we&S(�'. ��0/0;)��&�Em�:�7a��7����am!j%i��CN>!��%��.�ameliC�G>"�p9E�M"mFurE�\%a��ateJ4a��.a�v� �ju����:re*H/! "C�saP�oL[48����W�&�.%��&�5j� T2�.(w�c�n�MeR,.|arƑ^�3�&��ūE�the��@Re\ab%�d"2�F�:\�ME:h�*���/&@!-d1 ��.'G+ �e�j �?"��heo��G6��.�>s,�B�&?eE�f�o�1�� ^�i� �2�T�nd�dh,p9�: �M�|�E��"[5� 5+As6+z�9 w4��H1FC%��i�>5“P: s”%k������go`=� J��f�v ���#vE�&�-_ZR�Vaf�c�*L6�.X��� ; ye�AbU�N7M�6�e�A�a�=��c:Y:��Gnm !�C� 2� �Txb�[]' enoqrt<|� a�ingfu��!�x pre-~A�" A�'�>�� �r�"n�F�c� i�2�au��� ���" ,�&�[18 , YB��V,Q��T�(E;&\L1��4P o5 on n%a� athy_p._u���� cess`-Nړ�+st .^ɸ�[54To"�3a+>E]Tic ��dA:&m&rap�+ed2 ���e��al˹�,�$ll“&���I/�he ڳy">)��&�Lf&�6a�W*�%�s�z�rjXly"���CcopA�(~��"�&S !�!'W*�~bp<�#��#�A�&~.Z�0"�=:�AN5�the����eɗ�)�X���#6�g"�>�b�thZN�!&��I?:�!e+� ��)��!8gACNov��&�� TA�� R,P``*d �olifer� [51Itwr᠉��g�“�<-ʼnE�V�2g�q[�" ���u�� u$��QuYE< de�A�C �y|ad*9�%�7summa�Ipr:����m�:p a,yL� Lu: �be2loi!��!�Y}2�B�^S� + �y|2 m"���aXr #}���r�B%���d"`6�s���Eal�|ent�����ign9�8�)���|����-V�A<log�f��}�#k�+U�� Ai�']P!�AK��Y4%�>kFiQ�=aw�55xer�dC5 il fM�o!�hemc��<Q<rN'�F� >we�al�ly*_jil�˕&)_�0=de/8waJ.�V d;~>>&(� , ne>���r*�,)���n)1 !i J ���i9Z.~oN,eld!fE5�?A�^=tm *G����E�“!Se����H� �^j8ys/] corp�����mS�D�.!xb)3g�hT kc�/$rr"�p���!curb oftz�le�y+ �b�QreA� �"�Pom ��]apqY� � �ownAEA�E�"l(DU��bup9sey�ce��1f.���1r �*S ComP1�long s� tY0Fin Neis!t |GFav��(��"čj!&\AGȹ DUS- o�s��%)�Ӗ~ged k��aʍhiy=���G&N �me= itidiwe� �Am�����ran]�s�]�Q�I�اUS��r��{��(��!�&��]�R *�4Y"� erip�Al���$�����&�A�ner 9�(es�Ua_9AXle!��e��M2��impaia%��FJDN�a8:7�Pri z ni�lyFr!�����-q�"ӱ9�^"ensw��+D� Ib�l_- wo�s .'Zly��g6� of N"`.< . ByE<zu*sub �!�4subflav�d�i ;_!������- %L�s-M�d>b1(I'��.ca�m"��/�2�� co�y- me'ismA����ll=��ca��ro�%:7-=ir���Q closa %ed���4g�R2,,�Hnew�l};�Uar bsa v~��"!y#Qies�epANMr>�^moleg���A m�Wh�S0lA���aXS�F�shaE��scni�. f�R��=Aw�/by doz� ��M`A� R.p,��!e oa�Cg�bA� (&&&��gb�[ƎI��h3�Lo�Vy�:xZ�����b ssorg aLmas�l�5��r�z2004s����y��1�E5����' �oc�,�r�sE�m�'�U�-ij� ea"amǩe���LA6b2Q1�F%e&ŎI0,�i��AI)inas�� rynx��' �9|q��(or Haemophixc� 2�a��i�P!SGp_ti�EJ&,& ert; NcE���}/rkeׅ�t�(B��N�� [P !�e5s�ruE� �Fiwbw �#i�d��h�8!��!j �t��z�)�“7bug5�q�!Hvi������bi=2c Z��s�GdEGalm�)a +*ury [6'��a���&~w�BatE�a�s!�e�in&j[7�'!V5��8�!�f9s [�*D is�bkby �Y-e�Cf����j03�!�T�t��IV pili4bf�n(A���arX�1?� ��seudo:ԖsM�amin�� ilin�R� [p)fp�fi��nt� �E�Q�$in hundredu810!GI䁵�3r�Mrc| '����ph&MDPilT ATP�$[1�PPa�/�uctk �'!��slo��%;��  ) sid3"�� i .�UouAmembranekGram "C1|&� [12��<ty �N�&$peptidogly�in N"s99D�O!�m�� �C1�  ,�x �@�&e�&)�-eH�m�=n�5� \I%4I s� - A8�iic9i�PfE�!�Q���dA}E/ComEA�,K-]M1ϋ�={=m�per�ne>C [��6� .��o��R]h ATP gwo��[Z�.*�Պ�k�/�A�stE;,��A&�/i"I 1 w�i^�� �"&�nc�g+A# ����}a�QZ̉P f5[ (��n*r����E@�� s ��f�p>5to�f�')-�Z�:����inuum"o-3inherit�'~a fewS �� �8a�8 � �[la�of fit H�,q7���? expl�whyAء�9ip� &X�SF���� "/ F�X��id de_\"��+r��oW�zyK �"Yv&�h ��E���d RecA*)�1ńQ9יN��K� J��*cB msel�k�BY?T  [ ����@Y�3ad �r�sE&O��v>7JE�> h:= 4 . gonorrhoeae �C�� n}rt9Mmotif�%�F [19])Y� 12 b p ATGC�lTGA6uj�a� 1%A{arm�[2���ECA�ra�5'it��  ��US�i��tre���0n �� W�2"!B �n!�Hru��ZO ! oW�E*!���*�P�, ͘,IH ���-�q�DyV��.��M( i3�9 � � �3���|Aour< �q@!C ?*c 4����QofM�."D!IS( i�xal� ��U�N3A���� am��r�!�[)�>�U"3��er�9���nFp��F�%�!�T )��2�d?�R��9��� m/*qlac����jac�ea�M� ;6nt �hL*I"�FL �)�H� 7 z�3ca�fam� F�!!�M�*j!�M�ZA�%��j*p��meֿ-�Si!� cano !�a�sca� )=segj� 9b �f��R, B�a\%`I�P[{�Z1�T�evC3pe�SS�-"� ���� ! �$fsE��~6e���.�liva�)# �&���NE���nY5iFa�B#�� ��yZ�rۨ��!d� E��3Ua �e� .�RinMk��>;���*W%��:O�-_�m� &V:��"��!x�6tQA1��eaca�Jba�0,�:{f��reAa�Wbe�mP no�/��U�-g\�(M0�u�.�� 1F1 ĭ��xa)G�loE5�+�om(Y"j�ʥ�!�W!O!CbNb��AE"� l*��X}� *N��2&�.�.��fg#� 2S!+ c� E!�N{H^&w� ���J �ho�|5�zm �8r��,In&�0~i5��pthM6y*�}���ce"# A��!�e5 ��i�de�J����uE} ٴ��reP��$m�"��9& t "�J!�2�"N&= 8013&�8�" "%��"A�[! �Nel1���� b��y� ��Raj� n �0ui�EA9�� .�F r-l���!{!>Rron�3{'� oF �3E8a ,,"��`, 934T )F �a ΔpilN���@� geneY�re��in aphA37�!s}coG qr�kanP��C��Z��s>�Fig� �E��p��lan�Wb��E��.�e�(!zo �ex2��� �p6n.��� i��29KS !$GC%� Y@�.7o ���YgA�no%��aun � mismah�sY� 6(&? or��OR e �� in 3a� �U�Q)sRply!J&�th �sg�hanƲ=��:h�<J�E�!sA�.d��0f��*�,A�+iXc�e���(�nj�by z���&�'U�-Q��KKm��colonM�'a�22,< val!� V|;y-�tun�l( CFU ))�10p��"Y !fB�s&�DEsui�j&r�@-t�.�u� n!�F-7.��rs<�C� gp � �A2y2Q�"M�� �s�u�"�,�E���:(�E�,eS�� f!t*�7&%��� "�4��:7mP.E� �%p� *� y1G� &?g�F�k ��&PB.a���!E5+6�_nu fU =�$�� )We�9$ # p�� �S �2�EN=/in&�*dkW ( WT p %-A� U!e�?soF yl-β-D�oga�opyra7�d�IPTG ) -?B\x$�nt�A`���l1q0 ��� E. A ��b &�Iblo��%l-{-�S=�J�� !�F�+�,�!e�S5�U�*\�Igo"�" overN�duHabV�3�M b�{�hW��enZ ��9�M����Ў���B;r.���B5UI �.m'B�.�mirro:AD�.���/%�&��,���}>�-�of)�.�SWT-� .> �APum�/q\ae ^sl�72!�Zy LWTBZ 6��` E�n i1d[�[$�a�� u�foPm�e.�M�.aw�w�$1��:����(+.� �a���\��| *���b0a 9�P . At�J`q.!6e�!� 2&�y<���-{>���&�Xly{b�(:4�� 16A125e,��q�7t�ly�!�J� ��"�:U-v)s%n2��a�!�fK��.6aA�(�. Unexd��%-emZ, 6�:�z��� (�%3*.�"(���DU�at_e(6QL %k�h:�%sEc" =[-LWT >�B<V�Q"� U6)��s>[�] A >�  ~ x"c %?��,���0IJ�� .cAs�� �g�",!�!i�ˑ w � �l!��6$-r3k B1:�,a�;&$�� F :�� � P 474�s=��&��A������XML/J?#682K7I�a�a/e+N�unZ3QT" D�2Lf��'�6� z�� �Qu^N�6" ,� �J)�/tp.��Y��6��} �d���ng�0�uE��.� Lv �s*���4 !*Aq�&F���!��2zT y$ }���X��. Perhap�L2�)�9h�.{,hat not all �^bases in the DUS are functionally equivalent . First , it confirmed that the first and second b^�, which were identified only recently as being part of �$[20] , [21B�dimportant since transforma�, frequencies ��5-fold ( P = 2 . 06×10−4 ) and 7>&1 . 25& lower whe%<se ^xmutated . Surprisingly , three )o$( 3 , 11 ,l12uppear!N� ( Figure !e)�2��� down�$backgroundx no levels!�<1�5 ) � orde�assess!� � mpai!srecogniE00by ComP might!�A�reason�observ!�6ldefectsA�le used surface plasmon reson!# ( SPR!�si`described [22] . We measu�bi)�of puriB�(to double-s�deA�,ds ) primers:to eachM!@E� compE�it#oto"@SDU ( a scrambled a�?i�every.���V,is changed )�In briefa8 neutravidin-coeC8sensor chip was)QAj immobilizA�e�� amouA�(of biotinylIds �!�0before 30 µM!Je)Fbinjeca���!�iM�"atj0librium ( Reqq5�U�S1E| ThisAua��vea!3�-.Zof%&��indeed���N�mA�, e>a5�as��=�!�O�8in T7 , C8 , T9�G102F29�Curious��R!3laQafA�ed>]C5 S6!�nd apAb��notN7�C4/lthoug��s�8�Acruci�tA��. Togiܡq9fi6s sugges��aeN�( 7A���!�2�N��heJv. R�� s�~@ng efforts have rYe occurrHof gen��a�hbetween human Neisseria spe��� , intrigu�natA�le��some�t%9harbou��variaa<[3�x��� omes�aF~f��i ��l cannM7 most��t��bp repe)�y�~ain%��&�m%� j4. The “class�}”e=,ATGCCGTCTGAAE� 1a< �method��produ.� k8ΔpilN PCR frag� �he� Qk!Z 2�@I�we tes �eir a�ftyw�j%�2Չ6E"a�9i�E�( #)as from�!� u0)6pM� 8013e'10� � tha� at lT , but still significa�shig� 2DU5  co"� �%��!�m0%�� 9?f�y)�ess� E� � "K � absA}�:\I6�as�rs�����E��<2�� etf%+howed6� rmal��by' *q (.~� expeq �Gdid����" %@I~e� Ql ,�E5A�9q> S�>�s�Hsults � ����� to limit���z�yF�livaV-�,same environaz� rees deri& E�multipl�S$e phylogen��:�dA�a�@ lust� � in clades�, [25]32exceptE#G1��^)\1)9�lE� distinct b $ps . Strik\a � Q� 2�%��@�U�7 ) ,��E��� e��4a�lya� 0, often virtue^ɼ�,��i�extends � prev� m~e�s"� t�"��tempt�o�uV ���homologsE[DNA0 (eptors adap�U @��"s*�patiŅqaK$w��$play a rol� .�5�o�� ococ!�.6]2@subI��s?�i< ediq) z�e� ��8its���i�NAA�vitro u�m@ electrophoretic � ty shift3 � EMSA$1� ly d�*� � 2�&8� E\!�ha�strinsic!�-�!�Ѱ�a �Aյ�� �f *_.v �]on�� copy!�qju8�.�pet{assayA�dueI�we�CdApG ec��an a�s� unlabeY "��a�a�E��--!�� lexm�aa%�eA�bet�w�lDa��mon� yggradual.��I�� om2��>9&�� a�ssN�6aN5�prefe�k!E�}b�, lika�e%�JRexhibA�Ar��McNex.23 *9A�of1mivo�Lintegra�Rhe:�gene un�ntrolK4an IPTG-induci�promo!�ectop��lyj9ge� 8e� �� c�u5. � 0i�J7f 9a� !": aN_/au�re/ a 56� incT>�&�0�03A �A��to�^�U=S/��c�],NM��J�7JR-a pilVl� �m� d!o���_ !#e asŽ5WT� �#onsist>�PilV's �asA antagonis�� [31�A1�,��y tb�o�by1�.��{di2�n��Q 5�edE�id�`���&� 6`ha� e�o*1al� d us%��.��ouse�on�)�U 8B� :�O A�an unknLA�ozEg�6 F� fof1�� .�U�m��duL6.A�n\A'pre$ �l/50� + a�" fic�Ztowar�.Irelaxz he��*� aF� t���iI�q%� 8)�l]?) by!� var2� 2i�!�re �>�N� �be� d�ly:�"�� r�c,\>>.� �E2��a:V�E5QB>� ���� DUS-1� v���� pert. among� orth� . � 2�AgrA� on GC med�bas�GCa4p� �Difco )����Kellogg'Mppl���d!�A�k% , 10a,g/ml kanamyc�4� tino3 � /erythr58chloramphenicole*l�iOcsi�m Sigm� , oru"con� �{on4 �P, ( Merck Chel9. P)�incub�overnin a mo��atmospha�Lai%-5% CO[B�I�s�_�is stud���d"EB�4E p at�fe p d sero�  C clin iso։�[aI=�m� pilT(�c��� a�6[�-q�rru�  clo% of ct ttes encom re��  Y��:�ec�ly [24��S|�Pa�V>�E��Ptru� ���Aͥ��f8a pCR8/GW/TOPO-%W ed vV r ( In� gen )�o�� {! �mpl&W��-F� R"�( T y(%��EoE�2u,�0jnD a unique NcoI sit� of aB@1�ra%$z$pT1-Cm1 [3%kM"6� _� 5[splic!W��� �N)�leareplac4a�]�[29!�P"c Pi@ ��obao O2�A�:;E�� 1om.G��m���M "� 0� j� M�U��$napproach-L l � "w�:H 4� INR2!�C 5 j�a\A?} � !&� ) e,e�$ng1j q��"� TA��o*q )��"b�3!e0�=�and/or ]r !��E� oli DH5α%1"� ! ���Z le8 BL21 ( DE. !p?proteiU� sion�.c�2[.UHroutin���e in liquid��4solid Luria-Be�"i ( L�s�(Ns�e7 qJY6Cor.u ampiB$n . Ultra-~ �ll-�preY � elsew��[35q��2ppMAL-p2X!re)2�7New EnglA#Biolab�Z� a fu%c�MBɃAsol� �#!�J�:*�A���y2�r (A��.g���wayF�rAjj< �\� �w�V&K have- irecW A�v$�doa1�cAZeh6L,�e!xj� =� �PS ge�6aA$2�6v�ise6�to avoid�on�nep�byx+ b ��� -/�0nG :�PCR�D�l~�!b-fide�Her�se II FI��mer( Agil�l$6�a"k eQIAquick+ �Yki� QIAGEN�nd qua+' >,a Nanodrop L�څG tome 8( Labtech Inter)Eal�E*� � hangJ $�,1G j�! #�ad�$= e R2"�.�. N0.�AG!_U8EE%= a�v ���*U$b�*!���n� ��gar� � resur'�;!n OD600�1aխ�% ]�$5 mM MgCl2&�# �9wA]�oExe�c�7�X �FAN^,� at# q :� ��)�i�T~.��put CFU �A=mi�C�l�h"l dilu��s!9G eA6"no*� a�wo hundfµ��1�l )m�%a!`o�24-wellh!mi�%1ei���ng!�iGedq�6�, 200 *.2ex2� a>�<:19j2��z�6� . Afa�c��1% t��aa"30r !�37°C!�an orbit!X hake� 140 rpm>L 8 ml%�Q�Y#(%t!m-�%�fur%o �ed 3 h~,�orha"�� pri�Y<Nsprea�+� h}P&+�!Nnumber!�KmR�rma�v� \c�'�e n�d�R!$e� �s perag� recipi��c -(&.����*2��hy��$hobic N-teaS(al α-helix%tU���:��j-a X-trap HP column ( GE Hezc����o cy8C�in 50��so�ph�!�$pH 7 . 5 , " NaCl!�E�� v-!�� moiety% factor Xm$V�   buff+-as��sed Bf� 6 . �(!Wfb�Crec��&�  d]L1 M ϡ� HiT!CCM FF S ex �fS)�� w5��$� �KN�+��J��";*byD!2� ]� ima�or mod�$�D:,S6���motifs2�e(p by�{��N �ary^(7of!)5′-�1��nA��-a"�#&�A^*� � �cz�# mixt@.at����*5! ,E. slowe�ol8o room� erve .� tin ��>A- �s�> coupUto.�,A��. of PqOn NLC *�,!�BioRa--,�l%,in ∼230 RU���� SPR !{t,per�E�dXPR36"��a 4array system i��"(�s� at 25!yiPat��R-(�2 HEPES�d9i��e, (A ,Ũ05% T�*-20A2a� en fMd� �.1K� "-�!Zhl/ma�nd�-Eف=r� �)�-] �col� �A=)1ρ0ne�ForC/�B did�*�- pend�Gm�!K�O&sp�|m.��߁� sixka؁\� >\��.f!!.ps��0by acrylamideJ!:sH!|�b "�/�0� $arget 1 fm}"!yB.v  ( 152�+)�!�4���an�-*a> purL� =��!���BN!two�iu!�:0 of.�or� "O!a�#2I�to 180 p!�Ebw �#eac!�n�y� a)!v!� prio�2�add ""�0Zb.E|!�e�QV�.^#si�  ve 10%.g33,ansfer�T?osio�,�membrane!d . 0��LY S�#cHluN �,tI{�Pit  Si��Aס insA� SDS-PAGE a�$immunoblot��E�f)5G�%�; o A 34ham Hybond ECLR��i�J �@9Pa ( bothI>� �0�&f!#�a�-re1en��in"%)t*}(� 7e� he word� ilKE�(EMBOSS suit�,http://embos�[bioin�, aticn)To��n'1&� �,O#=def1D�j �a���o5 mismatche�$.�fuzznuc�I gram�Mobyla� �m . pasteu_fr/ER�ſct�c)a&�(%ew&�0=fs%)��Q he�1�Jm[_ � b�3mova�Jshort�1�#Oa�/ pre-u)e%P �\f�!� (1#www! 6'�^ One ClickZ@mode [36] .�In�$gal cytokin�D8�ord�68lo�6�a �N��le  myosin r� ( CA�6nd syn"���%q s w<�� �!a divi10septum . ManyY5&& *fu��ze��,ho2,E,��cul�,t � !o n� enzya�to��e% rema��un; A�OuraE���Kfi.y�3how�at col ���paxillA�h* Pxl@:-�{5%li`&&" Bgs)E �Q pj$D&S linear β� , glucan�!F � -Aw� � �8�Tst�anchorac�A� m#a�� �7] V onsed'{T!U�furrow �Pu�[ lackA�%�bA�!Ow��%deple, cau�7 failAsof)FU�E nd �r2���Z{;�#!�ee; lB q���um2�We �3d� mtA�2�� 1<�^.%*.��D�#+��,�SH3 doA��Y F-BA���Cdc15 ��6��:<!_+carrya�a c<Δc�-`E�dis� mbly�sep-�blockagf�+ t doe�%Os%�a%. O �o�h�i*=1*$is lethal �" ��>"12�a l�  sl�:d!&A�wADde# �+f�um��matrl a�56!#��tg+�sF4�� �8ut?��rV�2 ���� A"l�,�.%+�d �*at�y�Z{q#ugh is|�Ajomi.*E��v�arm cess�a�!&A\te�<M!�2in:. C�miiKfi!s�!�$eukaryotic-YyclA5%��#E%t !�wo daugho!�:u��< �tn�en� ��>��fu�J�aniP3 u[�)In5�!�!5.r,? 4m5e aB�2).is&i4%�=�' �: workARpo,�!`pu�eg?cc >�is*uf�(��c{ lishV�a pushA�foZ�$ls Q<[3�2!/we& "�.sup��F�!r&<pr�B2�[�"F2t�:om) of mPuf besiZ3F-A� heav��l� Win � II [NS �&6Wg#A���3ndF�!"%���aat C icip7���1,Q!hB�y?�Ci�&1al�yBma ��n8�m�of:�!� �B -lay�0;i&� [� midd� ri.?( PS )�:n�Bby�_:�N�[S&,inx!��| !/PSE:S�D�by}β-�a�T invol�%�irA�V��b �UBa� E$ regulatorI0a cataly��subuni(6h�0miC!�e GTPWRho1 [40!�6��+Eyf�4R7tFcs named��to4!8 � 6 !Klf nu���PS-+[11]; _builds 0ch�JW [12ayabund�AV%��A um%�օ�. DF �>:� connL(n霁�b. ellu%E d,�AYAUqT�5� ct! Y�is�5ain!� +�y�� ͩO��A!�q zesAI��.a�lso��aj%CI%�[1dF��J'αSB7�aQdhep (trength nee;�"ithst��-�r� turg�%��M .� absc��)T:��).)9!\�Vg� [1�$Wh� much�ba K�2on�:"!�,*� *.�EYq��� TMv1��*F� cle2� F A ke3_ ��.�!J �}� � -m�A��o �� [1�r) A"W -� ,caf�H�W�� link��� m>� ) gnt�.� [17��De ��E��%d[ at mit� entr��.z Clp���4ra�u~�witAiY1�5(s oligomeri�[1�� �a:�T� endoL �[19��!�it�4r�Cl�5�~at locale�-5Golgi� re helpc!�[$v%Gof�/14>iq;* K. A#a�5, ��aboYsY�.�.C Imp2PKB AR attach���5��:C&�� I�y��-�uKii/�-?F�,.g !C2- S-.�m9 Fic1�An� .�!��, Rga�assoc� -�� +� 9E>co�i k P gAQf6R 2(EA&� �i� � uz�oB8ip ф���>!in�-} 4 ��of�"Jmatrix "%6K� �! �9A%�AR � shar1C)w�)( Lin-�L Isl-a�0Mec-3 ( LIM )U%in�7]C half��2��� - W *B!reg�,>�|m�m�nd)�.����;q�typ�'m� Myo2�s:�!�/ɠjv �i�[2 2��G/�(x ]�E)`{��%����ka� �vL�l>6� � le 6|B5Nfujs��be���=m�n�g5|*A�i����N�>�>canv8���a�In �A� Ct [!;�OC-!���6�W)>ca a�6�Kd�MiveJ�. Schizo� �4es pomb�ڕ��� neg5-" )��� ribuK'M�.T�.AR]f.NC��%mC a�$erE�or��L�� � ( 45v50% )%��q2��P�T!xB>i�ldi- NHphenoaEs%}[=�$ueka=^> � occaq ��spld�(wo2�A�ail �O"` �2l?�"$CalcofluorN CW ) sV�. How6Q%�s�,dCARmAm�S�]�mo�s�� "u itu� l axBLs&weor!� age�A"� ��steadyQ"Cx1D , das�0E7!�"2�Nd untiOTA�'s �b!�MCW!2R( S1A�GXNo2[�i�(>R> �A�I� ::2%X� �B|> �t�#� qr!Fw@m!D� I8� awyntb!�&&�A}*��2� rretA, e"/'6I. "`��.=�"X�N�PSፁ�"�![1�� Ty�micros�D2�"u�,y��a�%wJ� % a�k (I�E>�!�-�E)��e�H{W!Q�A?A� %onouni59Vjtag�"�<t;"�(u�A& ��E More" �.NE^��up᷁--5a&)ӵ�v$S1BuPerhapz `<> � rng2ΔIQO/�����F_ !H*�I 9Ys1 }�*�st&f �a<-!��an Q$A7�9� �a�A *����PS%�u-��9��, a�h�.�vT�mVe��� c1!� A�Q�!�ly"�.2!;8���6!0L>��s �"�� Yj. P�.�!;a�<� J� &C�M��d"� bgs1/cps1xrmo�*X&MqK6g>�%LE~*�!�an*� pro?� o -Dis hyp��j fi�\"�!�]�I��(� 2��ps1-19\T� @v& "���E�v`Qm"�,(�1�#n� eM W 3M s�1�@kw /6�A�u $Fig 2A%F2��IL൒!la�Psy;)�ax*m"��� marke%q>��=) )��U�invag�!y ���%@.��disorgan�#�rjJ} �R� ����a� ��L� D� a�Q ��/-ose�M�)�.� .�.� E��|l ��ppg)o�*%0X*a0�&"\�O!9��f�R U�a���N-`inp . Be�!�:5�suc�H�UmBgs�Ymus�$llla�Ax9��tFerr� "�tO� uC�y�K h&�, �!��D�xw2u :rF ��a�5 h� 2C , 2 �2�AC)�im�(in�s:�&newA!�atI�m`ai�na� � . S&z!{ed rudi��9�ar��#� CW-s U!�n�per�a,�_��2D����,.. im",�rlc1+� )�5qA[�or�}Eb.� Y+9�lf� At6� � F� �R�l �"�!�$�4deS�z>�����v!Xum=y� qAW�( �DA%""� ]4� E�sN%B�0noa�i�����of&�F� �$E , left )�b�v6?6a� XMri[a# h6�^iW)( 6 h�)^<,> [89� ��z!ߥܥ9"� �yto%�ic vesic *�y�!Pag\om F*[fil�disk-�"�v��X�0r�FL��UguishH)[!�numerMR�a%���(x!-{� 2G%z.�6�>]e�W,! �� i�n ��P-L!o����l�of�(E�g2=`%W�9����u�4��Tom+}�a %� ��r + g�@y {M� J+ 5�Ca�-fr�W� &[:uN�Q�nmt1-41!�Q[�W+`� �%BtU #�dk thiaU1�%A��"��-�N��Ba5e28R�37 37 H"�p)�0��&(1\��*�em�p;ss> Q(:�=b (o6)qA�@aQ,Bq�*d"Nh99%2AW�H��10%yfm9in�!� an 6%3%ɡJ�f 6/.W a mi aq^ �QwQ� aggravah�+� � �3Bs,B2 �+\� 2� I�b~| ,X�$�.6!S�8w.a4�5}� �by de�8o�:1 �!Z)E2�._`t:vbgs1+e�EmNheY8}YA��1SRjbq�-Dm�]E30Q�GE�up a�tec�.�s a4=1 �a�� u�z0 � vi��or� 3odF2ver 60�b%�nmt81-):�ex�!�TE6� AIFpRW8j w�. A�Hi(�7M/!v.^ �M$��+� B�,a%"�e�|uc$���pad&d�a�n@p{%1� e�C��r%�c7E\=G�& ��� (9~uu2At>�4!�+ T�>> p�k�!g"'2w.hypha�5.�t%9a� -NB�Ve�2��a�&9��e|y r2�i�"d"�:��(�_�� �"b>L>g��Mg"+�.��&o6)/�3x3 c[&�}zE�ul�+g29)��Gpen qB an a�a!]�,� %7 �N�2 !�' �2em�np&� � 24 ha�!�enu_*|�QWZ�sN��; ripeR7Z :� �}�� : La6�;-�Z")��f��f� ���D� ut6� I!i�%�� ed��^�accum�+�$5�a �)�HPb7jcp-%^�,ea>!l �_e�"�,&4 ���!m�� [7 �E &�\`y&�&q'�-�B��'r"S"v�S�h� ce�siaW0�`or=ina[��,�,. �!�6 [3�DBdde�=� s [nM2[�+"s impe� Fh upon�u.a.�!>Rho-GAP.&�Ql2i�N� 7�0 stop�� ( S3�:In]!�A�ttenu� �BV" ��067\8facAat�1&o�.�.M�N�-E^G�E� s��"�!��.~ �/he� hp�8ineR-�7@�5ik3"!Xa �N�"�6of �hyFVx .F) lead"�%� *�ick ��]y cr�SS=&)-a��1se�\ s�a�S./��>4�i6��`sn8 �unG *�:s!�ptBk2��f}"��S�0euK!- .�U%�. UR�(��$ B����e��E�"��>.� I2.� they�i2�� A�B0�m��� Ma  ����! H Q %"zX�a�1pf[��N| !]jEe%V�� }c�(9'�&�-�� ���_� ��Y�NX6��̥�y�2� �R.|-�.�W�-��Km:4�Eron.w ( TEl*to.N5V de,&xA5 &1�H""m#,6) �N��p3��cul� w PEMM+S+T ( Edinburgh MMe~Klus&�AZ"� )�VS .0% jat0�rei%�59=a,S>X5SSM4�&A��2�%��5E�6�5���t�CerV�J%Y4>*!�?J�{�1s g�t.�*p aT�:au� �>I\ �D &UJ�r$ n~#Er� ���Qe e�&� M*G�(4BA':�is) �� HݫA{6�"����) a�� E+ &>0E J �d��c!� &>  tot<Bm��u? D�8N�1�{nd1\ @p� =m8� dis�Winu� , twe�A(b..snc �E��25�suc$ sI �SS��pa�qel��Ml��9`%Xinwar�Ky?*�,2>��Le#m�K9�Q )�"�?�<>�Elas./2�n!�& _ �g�6W)�n�:h E�-��{%��!�A few v4��!U�uproba�#M�-�s)7�>m�milDFB��re�O5&*��!2"s 2�B�m� expl!C�erEnon-un�v ���>����!�� 3!B�yVv qA�� >�:4$�!V =��1�le2�. u� e*I26 Cd�6orl2��o�4�� br� ���2T�D�'"� � ��"� wiCbjit&�2I�5��W�<�#�!j `� Q kA��//�Kc�� tens����dim�;tb~5A , 5�'5�5L S4Ae!M�E�We.�Y~�%:�:�B�a�rur��2EN �:y�,��e�( <�M6 μm�–"2%Adadv�dd+>.$�;is��S� %�JQ)��09���^eN�'�(!O��G M��u3&5�5� # o�]n�. nA��l*in9�2�A*U�A�>j��>|6�&�i 4Bdcoinc�(� aGice�VE*3"(R�T&�,7(K(2�&�!�B�u�U�'R�0j͎��"4L���\MkF�[i�-9iP5�SI. '!�E;eD!�"� at +12� �,1"� �begjyO1$=21=w�=N�Qn}8@jb39"��M6^-`o��N��n�v�Gaen 25%!Y�2@9�)C ~)cQ1�2T�!q%Q��=b.)G�h tart�m��e�e\El�M�U�M���PBU� :v�*.��LY�>�%"�4��*q*� b�;de�� �!���.�7"2( S4B#S4C� �m�� hQ)2T�ich&�&��"� { a��%G '� ��D �. O.�6� �2�tC��Ab�.�* Å�ed CWSi�[�,'opan�RA��53E U@6�"�>&d(4AxA�traAF�, " M-�>net�:�*��*H%�%� ]4m� Q��'3�R=i1!.�e�!-���3��Drecruit�(�Y� |� ����-lBu62F,.FI2�2�%5A���.)I��A7 b'��MU6y�=�*�g2�SEO>�E�zY~��!S��6���m��&5&�*2�X�i6���a��P6�F�,.�%��B�M7Bsm 7or}2�>#R�ak��Ta� R�e�.1B�=E�.�m?��!��ek�">� %Q5�2�V[20X,2]� 0s�T�Po��en[a each�-:�!_k�<"�P�MŹM �;!7w v�gJif-9�*rou��.G,I�^x c{� -!T�z3 6 u��A$�h$���&��2�6� 6� �qdHaVSH3�@!I#mimick �&�.� ;JE9 �*z""(�9;�S. A�x .�+.��h.�5.as ��% e�1b� �!4thQ�1}(i[6� ��G%9 H 48 h���wL��.�da M&�e j%�@B TI�"�./2A?�"�>�� R>mAgs*��aaxg5g� 2�dc1=t�*�<Ags&[ RFP-�V�:���6p,-}RC"&����A��ą�%"&U *f��M/V Co^_iv��'!�j�#^Jnd_@�HP�,V_� �db7i�k:�*9Q�m!'A# *�<�9� 3 �y� ~M1*�)�"0%�> w`yt)gi �Z`"%+���J� ���b6��nonl(I��;co�ues*�E����nrm�5Ds�r%=��*i�p��1BsL4r�V� ( S5��! �� W:WA��b"~�W�U�bym�uc &� *�`=@)7}��C��.�2�>�M!RIPM���W>6_2]*�4�5b>���� �v6@8./ !!�*s-2���"� �M},��D �&e+u !y ���3�a�D�M:|��5mj� o�� ���)$�'"w+ �O�U �A�2x��as*Kte��ic�-�E7�� weak3c�B\�e.A<C�.U, �22� �Z!�f�56�232�?>N^�Su>Xal] %��/�or ��s!f romi!�*V�{.�y|���u�ٟ!/}v�Æ( Cd@.�M��2� M�.��T&WV �neh5�""�$� 0q�!��� ship"�<�� �^�m=6����[@ÁNl�_4=�VA��Mcy�_.��dEEY%���A'�)�R ��)�E_,2�Z4"C p�P�/�*41-�+.�/! �a�� �H,R-�*4 "!E��nmt.F3�< &�&PF ��8on�/,"Փ6' ���%g �Iot K'9d� crip���'or Ace2HA� �8tI�[� �P�cus ��w��IBAJi:�#e"VMus mak?�:O&^(non�+2.aU'o�A��ll�z�G�+ as)�-g�O8b Iz�,�T_ � ��5j� )b��oP�� EH81{E�:RBE�ASMOjA��7#62I/ <"I �R�.@,�%�mK3>4�m� lt&k!ɩ �f xl1+.� ��?�*���/n�XE�"d( 5x )Q*��� A#%<� A� �# a��.U (�4(�z��(MJ� ;� 7&D7� �:�R� 2�1g60�)�*0YIK�mi�5 �-O� ,��\���`Uv0�s�_"+�m�oE��7�LE|6��&Ag GS��a�.p�6cs S,p�<�2v!%^# @>:J�inu� ��5 �2D:g��l|>"� f!�UrJaWd-b@j�� �*�&"L!7"�), �9eez�&�_� U �%��= �E24!�w` � =�s@K�4*7?���B�"?A�Z*.'+��e0e)�� �2a7F�IE�e&�a]�&�?"�" �A &* mH�y�j� %7F , up@*� 6��NAU:�n �[tsA�+%r��ɮ-�6% � �".�,q�� pr.�&v9w� nclud� t�!/� >"Ao &.a .�1��+H.A 2�u�5Mapb<-�:�2dQ>z"A�)-. U}pa��&TE7-5E�B��Q@eJ>� . JV�UAeFJ�D W�< �,U��)~ls!l"�:U�!�c"�T�����*3Us�T7*d `��es�A�!u��-2(1�(*�8�9��*� 2=a�0 �6� i� ,IF4g#1lRaEa;�=� � B.�N��os�09L>�� phys�K \"� �ak)>>�Y& �i!�ch=[xONVp�UE�( inkage%�Or2u[E@&�de�� F B�a _e�]aR\*yY,!��I<1?.9>�)Ygd�NI m�"Pua�atu"�%>d%��!6*j�!��E��% �Ag�k7�4�l�edg},E��&H�w�;]!�A�O6aevB�-�U�"�)rsBsI]�9C :Cfe�e�� !5 ���#c,l���l%!q.� !"*i�BNq�Q�A �`!qqmC.����a,6�!bPS���by.w5�dA+!t� � ���Corro�]!x�2�Lb!� Z(s�Ie�0�� [37KyA j�Me6� .'�[%��Ie"iv�-�o!c*� � �Ein���&�)B q#E�EiR!SNr.�8>�!X"�/ FF�o, globai7p�I%gLexb.A]�f���bPS>�� �e�#�bu�Cy�oSȈ&�9��C c!�����cr.�%M�=�y�>an XS�cr�%c'U�E��m� C[3VQM%�6�m&]�Y II� !� chit�^ynt�� Chs��]9%�6tfm7�;PS�|E�)$��v>Gc�q"I�CF6&��? :�!h� hard�Z�P�WK� l� �5.u�B�l���� @q�CL- rsymme�b&� }A[�e39a�- vice..sai�.�6���)%�6a�51� ��^�d��FfY5)uB-^�k݇si�@aIA�:������iUxu� �$wo tightlyeiT�� ,B�4�A�;:}%�AvE r >t�+�%L-&�oa�eliHSe9E�Q��?e�i1e�2��E�*s�al\12��_2�:ab�B�.6(�ink6�i�a��s� C�Dr ��ǡp�D!C�&�:��:�G%u4gui��Mߺ^ (Mj���te�g"{IbyQ�II��r"bin&Э*�8%OhA A�n� AQ.? E*��* %�A%�Y_no ��s�!`UsBcC �� osA?AC&AP�e�r�`-:B�!�L3�!elo!&�d�t>��'Z.a�$o��[. A�ne�5�� �rmi%;��ib�`Bgs<%��QK�@�� i{L!q��me�WV@}� jg��� A�%�a��?o� GUnP7�L*��Je bioEI`� cUMHM>�[�] �nFxZ%�7CA%�� �v�?!�š�J,m��?c>Ans"n8A.6�$�%�f : ��,32�DA�"| &WUgm�� �b���R!pq�[2��!gIn ��d#i�32T �B�"�Z>@"� ��%�>��� !d�s�)�) pathŅPaby �&� ��}F�j� A��:i6t 3G,�R-2X� 5� S"p=s�b�� ".F� V8wU�,p�XB2�jg2�* d��a��vhagg=in E�|Δ�Y��&aC>!�se.?!Á\.� K�n]Y�"�&!��R!"�P��� �M�-�*mQ>���a2�n�Q�Y��."[uaYE�]re8A�of:�5�o:�-��ndo�$bt �/ Zym"CyUU5`=zbN�A��:G*[2BE�pA�=r\ �l�q�r|���`m ��A~�"k�nwe)� 4U�m�l/3 U)�V� �IMYy A�A��K�1�.KU$&C![M%".?Q�"E�� �Jf�g�d"�z se.�<isD.nJC'o�(d�j of� �F~ _�2X�@me��V ��low0-��j�e���a�RA[�3�!�-g?l��)(�VQ�[�-.����*{ fE^�"-g.- 1F-B&D}"��&s�5.nM&�4�2� �*� "o�=�oY�"�ɫ�I:g::rInn1 � ���?�![^P)��� � !�_>=N4�v�� 0at �ac�a�j�$Ee Hof�� �.�>�� Cyk3a��!;&8 \p�SPS-���L�  [4�{KT�yŽ��B*9#+S�*�[4 45p����r-ow� :xa�)�%ras�#2G!��lq I do<���0q-� w:�bM "�9!S>(r�Vwhe ��I)�W��L eyl%�RN+In summ���~v6�M>M!g�f&�y U�*s !��u�e�� �{��ceQ"Z� ��`!� d �=�=�. *s5I%��;��e�Y�inL�Tv.H�Ls*rR�'5���KanMX6� ura4>U�� p{"�Ee�&� ��4�#>�+A�Y�6 W�$�B�@!#"h����Iŀw2�Sver�y�tZ"7&�qK�U+�TQYT�,"L;by��-�dc taʌa�� �[4�StV s 43��526��bgs1Δ::)T1�u�ii��p81XH�U�L ( his3+LEU2 s�H!�"[#9i�!J�+1:nl�/1X�J9W-��1� 1483�A�d)" adja��?!! M9��G�d&� hORF�e!�&� Npl/�I�!�9\log4'�&��c0n ApaI-NotI Pd-� -81X� ( ��–98^�l��3 belos"!�� HR�w��AQ �R + ha2�-�� n��Z)���u��!25.:��ed i9J�)I�,E��%�Ʈ�,�1*v �k, "�V7E΁��N���\�'�"4Pbr2�F �2v/[1�tO�X2F�e�Ebye���vl��eom%��al�?M�ng ag0}"�^��pamv'o uxotM��#.�* 12A-"QJ�'18��� �z �ty leu1-32R@��Q iv�;id pJK 6�cut 6Eco47III"� .Qv#P���� locu�2I�1���-�(.��3F�i�.Q&h*�at�25/�A36 r �:A�[0u��6��/҂}:�ar!-I�!�� Wv �(e�a��t�R�eY3b�-)172�. a}q��,of SmaI-!�.� E(%�+Q�on� b��W&.�X��,-"�V -748�!�(�Z"�ׄmilM, tdTomE� 0�80��avU�ed��>=( S�em �f r Tomato ������s, [45]"d��� bgs4�ua!�ab � s 56�y 3167���l0>0 1� 15]!��J&� �ae���manip�Fre [4-z�w���nrO�chQu�EYElo��m`nEMQI�pw ���1l0 �;�. .ol!:�SB2�a� � �n�k*�#^F&?4A�e*v$ ("QAx X��� �Olog-p &��in �%2s�=+Rs�-}Q20 μg���r. SPA%���� 1��l�"nDO ��w�l�!tetrad d���A,6�!)an��gm � m��!PAEth�monito<"4*��u�A��%=-log 9=�RSpKSi�al-&KS+)�8a BamHI—EcoRI& � pRSET-e�:��~�425-bp ���A�i�ana�cop�pheJ�mo̶r��RFP� �r�R�si�yUn]��Jal�Lna}Dt San Diego , La JCs�.�R�2 12-alanin"�E1F�e � flexib�"AAf.�|��3´-en�w6VQ.�,!�`� *�niw:��)"JK &A� 4-ۡ 12A�#erA�in-�f�,!v{-!����� 4 ( fbo acid - -�>�.uE!l �Ab�w�l"N�t��4e �Fg.�!\�؁�–626l���1J'8A-Cher/�VN� .R.;i��6V � 58666A195@ � ��J�.4�*TN�2PlyW pSK-P%>F� !&� m��,A�V* -2070A�-1088�A,N y)�a"�0 N5´ORF.Lr K �U�.�@�� �26*��a�eas �substitȦ��ul�(aj$i5�a!�Ɂ ���I�-�" M�.mf! codon 277�Xnf�GAT�AAT���-"� mu�hw�[4�'�'��� D277N lao�2� &�SZ� All@�J��c B��f�ш[4&E^+.��H�1� recommend~]]�in]i�s� K�!��o���"to*G ��kn��xd LiAc � [4�� Esch�.hi65*�F´`Qh}!toA�pa&�bro�d� f�in:��.P5"Pa.v�Iq%���ng ByD?�~"�I ly :!0�:pl(j��,a Nikon Eclij50i&k4e� !`Plan FLUOR 20×/0 . 45 ob��p,L$Ds-Fi1 digM�ca�i� MD S DS-L2�9�Ԏ� C&h�wh����mޯE���� *( CW;=S�&H � j�5.ǨJologarith�=&�s . Fluo";Q-�� 5|-[Le �DM RXA6�="�5)c,PL APO 63×/�Q$32 OIL PH3:a RFC350FXNc "CW4000�#$FISH softw��.2� 2�r0Adobe Photosh�b6`I�F�,as&�� toqTEr2]Q��l)�..Q;!�a�&Q>��~. Er�%�s"��inYS3 m;la6�qm�c&��CW ( 5� Z>�'n"cG �K�u�8%e�a μ-Sl�F8 �ZBglass�to� 80821-�3a�S�$7; Ibidi ).���E{ 5 μ�1 m� soybea�<�$ ( L1395;a�ma-Aldr:C��!)-F M%b�at 28�� �\x��a\� �#A+)!�H2a�"��AUdM�",�7ac�(Aepi2Daϵ� �*��EGe&p+plar+!6 1×1��G��9H� }�<( Olympus IX71 )��&C9a�Apo7�xe�40+0}�oa^��l DeltaVr��( Appl� Prec !z.Jcap `us!,CoolSnap HQ2� chr�9�[(i�,ic(j�a�WoRx �� 0 re��e 6%-Y%�^�Sub� �Jl]� ]"%���kuL�eo�$by 3D Deco+��(ar��ڈ���0 i�&AI�m�noise�t�n؃�G����. c��:�%z J (P��� 42� � f H$�-ndb&�S�ax��pro�:%�Ca�n���u�"�E�?<��iniFq2Y2�O2G2�Ռ$in Z-stackV2}�28�!c�t�$�X� rval�#enG0' �)et�\1h�<d�Ρ ��a�2"$��E�M&:�"8# �!)3D*:G1�=�Tg`6o�C�/ �f?[�n D!)U5�M5Eō:W�Bxby�Ar�6�ac�LA�.���M�:*rG2�2D�"yRQ�?Ba"�� subt�*�|ROI9\(�&U!c��lyGsuY�RWr�val������xaT "�r�r��U}��1Kce�L52��*l-� v�"mOj�0dra� aw$2  2 ��/ޥ�graphIȁ��m�5e�n <box plot���Ge�5a�h!=up�Qa �Q1�1�1ah2#' pply!L!�a��\Jtyp(�!�B nNA&�w����MLVDI�[ "�v�r8�]mW(v偟o B . mI��d��Ied hor^a jG�,�pm q?*o�p�m"����91n��UnidArab Emia%��200ֆ��O��]x�a bro��pM�oic c�~;*upub0�~o�os��es �As.�1���I1� ����ti�|`!f�!x.C�A*� �e:�#����B(e�JA�s�B:@2��/�xŸl����Z6M��C{-O''9&�v8 I�!Nj2,Ѱ� E<�4g9� souro . High-* A�mG!XI�w. "� *Ta"�MX �p�ur9���?1[I:%J ��P�� Dubai/UAE. po&c "\���+�6-$k �!.� orig%�a)�ye��=�a�YI��ng]0�*r�C�qAz:�c*�'ůworld0ZER%4�5p�2�w riskh�Niu�. ��2 life-�at6� &0���B�UHfu7!?�,a݄s;IE �-�)�!)��7c' rvoi�v]�� �.,�&ti� �%.� Chro��lZ6!��c�>b� ymptc#icF3A< �1:��ZN�ag��2 Y�&mits��erosoMo!"A inva�o)\�2/> *��A���b��c��=�4�Ade �Htegory B�9-� ��<DC��3�bt�Ad�� gov/� U-cN. asp�Li�-�acb�s2i(�}/aB!Jnt ���a�bs c���.�PI/� �"Ȱt� �(wo*�^.� F al weekp��$T/ ���w' et  C�!r?�OGen.^ � �j�c3�ofm�!~m(;d��ooc*� w�ver�Sc�!uR!uNu al circumf��A�h_�r.qa.�uFe�?� p�By��� yearAKv al��� "_ "=|�eio2g&L .H ( Afgha��aQKuwai;Ir Iraq�aaki� , SyI �j� ( Brazi��=��F&�z� �r�acag نqM.��ha�/5+���t�HA| re-= a�Q�[5�B[�&Oxf�,&a�e�g`KJ� nq3 ( Jannus%& Shakhurah%�Saar munaLliO)���j!�pril 201% Ha  )hvia1����E�t���Ac��A�Md@C a�!?-tafqBy Septr �6" !(Rid^�t*Hv['.*>4in!u<3201��5�re>�'�M)�g D$y*�!���mil%OIE�0L��9oi|W,int/wahis_2/ c�8php/Wahidhome/H! 9M � :700iS� 250 donke �10�L�)v}y!  �@1Y, %�8A��.%� g:Q� )�L�v}A��l"d?A�cliՍ�� screeA ( YCt%JRe�GLT���IC��l V��in!�Research.-in�  ,V� �!crmNC( � FixL  TeO� ( CFɆA�g!n-houWELISA [��I:.��ft E�%V)��0%+ M�jvA-B&A�6 eight.JAx<l�F \. UR&P�real-�4��iO��� ,�Fed�7^O- ( � ~�g� VJ� b� D� l�\B6�a �T6m�m�:E a�t7!�A>r[�#%���A���%.<� �=� ���om(  >tVT~f� �A^ 10–'11un$��I�%�3��-!mf oi�Vq. w�7��&�%v�s*?!�� � 2f �)�:png��p�{�$!�sB�  f� �L�W  O��)ЁBt��(�F�MA* o�}�[�l�^E��ͺiK�g!Yb���( CVRL uI�{�̄uthorO N�_2�� ���rveill!��5.� ~du@%�!q� �z&�"b.i �ccordW��!����HFu� H��f��I~�9x=1eb An et m�D�� 4 v��iM�r��5\!a� er[�.V��b�sSLE*��?W�r �a���� :��D��e No 38q+!' a�8~!execu4by-law[FedWHLawC16B7�c@�ngQ�We)k)�&0a����Itr"' �{���%�ƈ���0) � m-E%�C!�tt� E��)rj:�?( P�/t N� : 55035�kIa�A�-p� �(d� yI�Y�2?%*W( o+�.��Cine.����xc��a* �%(��!�������n��O !kt ) ���R ee15 �\k� U%�eE�*�)� �.r23-a:VNTR Q��)�3��;�t ���T�8� 2�~r�B�,Ő23��b���>"IB�9swehr&�"!��b in M� � ]f �K`oan)iAfal 42!J&[UP [10])�i'[�&�2�r�NSA�����Aa9of)��42��&\>in� \a e%E . ��e\ss>�&�S "h.dE��v�6 �H�% �BnN .E�XA�FIM1Qz $ATCC 23344 5a�'� G *12�<�r @�MUMQ};�#��lacleot��~�ismi SNP@&ɴSolSN)�( � �Hforge . net/project�Is/solsnp/ ) . After eliminating potential paralogs and positions with miss.�eor ambiguous data among isolates , raw reads containing SNPs were aligned to the reference and inspect Dverify allele call ��e mixed ! s ( when Vmin� :Dfrequency was grea!than 10%% The final�set+8composed of 242 �@of which only 44 �variable-�Bahrain !N�Dubai genomes . Phylogenetic reconstruc!qz(achieved us!vOmaximum!��simony method implemented in MEGA 5 . 2L( Figure 1 , panel B�xist%index}1 . 0 f)A si)�indicI3 that�63is devoi%0 homoplasy%2alNare� agre� Ed�4topology . For1�M�little[,4F�is a moAn ppropriatIa(direct meas!(of accuracy�,n bootstrapp!x0, however 500 repl! es revealA�1clades[0interest clus $d together�2�98%3rZ treA+ MLVAJfnine �ins from% H2010–'11 outbreakjQ� form�@wo clearly separaA<c �aHBH1%�BH2 ) ,1b!of fiv)M four� eachNnAEnWhereasZa� clos!� |:iaU�hJ�042�A;UAE^�,�,m� alsoj tain!h1I9Hcamel saa[ , dif��Td at eight VNTR marker=� �@ ( D403 , Mymar )!=n!_�8. This suggestsbleast !� xnt B . m��i popula�+�Rinvol�-i��5� . St�� �A%� 2011��fou�v both��� �!�anRE�per�6d across = year��%�au�9byȁ\ pend�,but temporalA�imultane!�introd��'��whole�;�� ph�<yN���confiI�he e@ɪ,nd lends fure�supportQ�$hypothesis �6�.xof.� �n5|inuv,. Our result�#m�%O�provi�7an��ortant%�(useful toola� rapi��i�estimM $of epidemi�C$ical links͔]C. Moreo�٩C% -��c�e��� study!�ŷdivA tyF`cloneMva ��le9. IA�A�Q,IA%!�SNP��2_ea�e5��pattern�!�to^!�U4��� ey o�r� a regioaWa� prev�=%e%I]L,%��monitoH� � !� B�)�!�il? i��raIn on effort%��t is e��nce��)�ed % 8inued surveilla(� abati�� H en a� O �caAappear!@ba]ea�. All (s i�xAm2 known� " ly ��m� !Qs shouldSrouAely tesEor glaE  prio} di&. Repp d4� �]�� lso%{mm�da>infecg �u�asympto��c%'ser��ly negata�@.qfAmerican cut�e$leishmania��( ACL )�� � dU�p��about 67 00 new-yper��E�e s2 A�of%�qds E�e� a] species;"m � vast majoM)� /A9��)iise�fea�r. WHO��onEk� ωoL5 $ brazilien!,!first�A� at�,�pentaval��yaC; eriv%|�t GluceAbDSodium Stiboglucon)i� systEuadmini? �e. Accord!~to* aut� ,���1��A�!(show a heal^�a�%�75%EZ� 5Cm�2iL�� ordee (characteris�da�in�a�paEQ�!�tur: patien� �+ did%�respon�=g , a � -sec!@al obser!�op� rr�NA�� coh of 43recruia�E��I�� cexa�on�ndB� ��in� �� ��e�`� -Pz:v(, histopath5�`PCRY)I6l�perv=�IC5d in vitroEv�EHhe.dQe� � UPredo! ntDng.��rMsa%L .6�( 95 . 4��35j�M�O�de�� signif�<t deca S � �4atime suscepti9assoctd�U�>��!me�;e�. Les!�sizeRI 9�i��� ly c!� ��deA^� �N�( S�@Tman: r = ( - ) 0 , 548%:6 726;e�A$vwaف�� between l:��rw t��Hocu!E B�a����h� KQ=�tozofq G at��w��F�o� lap� !A!�ҡ- s�dn�C�0erapeu��4of�,6�>�,)��h!,iscuss~. ����[$ pleiotrop� yndromO�,vector-borne�tozoa�!Zgenus.v��classe#12��i (marily made  its {fes" !�eg%�ary!rvisce� 6�4 �B� E0�ach~e� dE��ho� ell-a� immuneA�pon%��� stagɣ.��i range` 2� A�ocalizedj� � , mucof� M &"iffuse8( D[1–3]-2�A f 1�!.]! �UP !06it r  Old worlP.M %�esaMi Middle E� �} Cent!�Asia , Af� �(Mediterraneasin [4�New^w� ribu�2� south-�oTexAihrough S   [5\k� ���AX CL t2to mS� ��l� long�P���o5% 1 ,!particu��.� �n C"� 6�� c� r e� daf�be��7gF4 ( Viannia ) (�c$V . ) subge�[6–8!S�  incluW%�is �eŁ�p�vA�!��%:pr��&� L %>p�:A 2� ��;.�9–1E�Su�ircum�X. �W&e1,��onA��p�� in m�.%w taketSsider��"� �MIandatoryT X�} -l�;is viaZs se s6e (( Pentostam�r meglum\� on�� (.)"� par� al>�[14 , 1u> My�c%A���dbre��$meta-analy�4s 76 . 5% ( 23� i%��13*� )W� + ceivA�<20mgSb5+/kg/day �,20 days [16]!�ne7 7%Ia%�-�rol�proANs�( 119s) [ImRea") JQ�( ATF �!�yɁin!nt& sA�as age f, drug��uMc!Z�7�ŵolo�Ũ3a�aE��YRadvcbe�N� al1i�t�y>� � ��eA&��of.�spp .%�ŁEdescrib�� nd cc2�a�o*jSin%K[19��H�,"�p�T��i� a�Rin  � �!�Qph�n�� �B"� behajr��ins does�Anecess tch=r outc� ,%%Z& !��y[2� 21�To detere���W1�|Z-U7feA-TF�! ud!serie�Bh��nAQ{&( CAN��Pa��c� non-� to9�Y�~a��.Qcou",a!�ict* guid( ��!managX� ���R� հ%� l@ ervi� , follow�up�6 moths�DQ��9�cr�ia�ref l� a!ɯali]level� ose> �]E!doE���wit� e&� *B����of%{b �a�plE%N �.�. P �’B�,9!A�-U�*It�Eevalu� 1!�5R>0� q�N�>�P�8���ɍ��Js:YF, ��� d . ���. A� veniS�:�Pr"�ehJ� 2013ALMarch4 ��s9c6T�G%�{` � �u%of2�f� C� =fL"Z�U�L. A� eu=�"M�ha#b!le�eve �e|ak� roB��^�eA}4rsnexp�:n}�\*]M�pr0yMx#em�5I�x� �!a�inoetzno���5�.�A&diagno"@% Q s��ᦥ�.i%!��six weel�f�h� aH.uRP�ef�!� e^IW\� iiY Lb^�a&X scaraYithin�mon�|�a:�e_� �i� �CAN’s���G� T�t area�!� 20�9  d �E�50"�Y �%Z�_a%g6-u�#ni-r5�b�i6N0Olliaro et al�isIill���t� /$]� [22���!B�ew���%�1�protocoq�#A4.�on dem"� � aga� birthplac % s&�e��" )�*�VLp�� ��)a volu� cuA�t��sod���, .I�2�AN6�s��begin�� 5�, number�� ( s� fM ���#���Cc�uQ�"&�condi�C@asny%� or un-!  ,.�� ef& ��r� ��15and/ori6 s1Ee�!FE�!�ţ team��;� � U �e�n��k�(vidual"� reW� "h :f�I#SA�c!� CAMS �w J"v .�N֭dis!z&��)� b! ,FW��}a&I9s. R"�, ��sFB,-C� bl� Q � BCm5he!Rc�^n �a!re�funr bef$,�������Z! . In5�wh�( ree-e{poi� 1f��avail�f!.q����r_&��jj i�Ch�or 3enzyme7cal�5s�͘ma AXPed } J& up  .�+sE?.��-� ed ,m��&gtB)  axia�!cwidperE'7G��e7 /% m�*����Fz� as h�(by e�!(skin biopsy� me*)�*!��1 gb=� u! ascA��s�,a dispo�pun@* 4 mm] diam�A���=!� esth�%blocka 2% lidoc�) b�b&� app~�HS��",!ҍ Boar�Eth%�Con�(�$Hospital M!$ar � -Bogotá-�>$ ( HOMICE �i�w� "� (���Z00843%G$n Health M��try! nd IZ"� ( Decl�+�(of HelsinkiE>Xd� ��W���A�7 , Ko�2008 )�e�a650�/!n�$ng a writt��3�orm��!� E�EBv��Li�1&6� . Im�ly�IMb �aM�!�d��Xe!�tissu>(pl��_b26R) Senekjie�'um �&l)�,1 mg/ml Biop� nincub�;0at 26 ± 1°CMl%�ad�Q  dry tub A kept<-7084until DNA extr� &C �04hsp70-PCR-RFLPT[1��*,�:����a ��[2C!(third,fim1i51b !�C"%��~�p.T �k�o1cy-���( V�\b.�#D( MHOM/BR/75/M2903m.2guyane�# 00GF/79/LEM85 )Q{; � ��m%� A�*� s:�ssG,. Promastigo�of�iE�%�on Schne k ibco , UKp>g0%� t-in!�vE[foe�{ calf�um-C�$icilliu.50W( ts/m�%� stre3&yc!μgf�U-937 � seeA�4 x 105A@�' 6-�pz %^�3�$erile slid  RPMI~3�a�uma./" duces&Yi� , 12-myr�t� 4horbol 13-acet ( PMs0,E�ip at 1�&e�. Cel�"�� t(�M��)b�e�A�A�5� sa37a��� an atmosp]A(5% CO2 . Di�o5�S VE%I��� � EBo48 houg/ t 34q. Per�agk;���$by microsc visuG)Y(of Giemsa-s!�#!�X �! )"�q� of q ed m 0phn!s.U �Rea%V��>jri髩���wEF(�b��1. UA���G2E�)�#)'N Y main �inR�5vE�-�m=or)� high}ve humid�$z75�5;AKcul'q!re͞!�eC(��mX��atA � �R$8 , 32 , 6�2�#256�AEa�"� t m��r5�.F �� wash� e�� ay 2�{a��-#-a�pr{4!�t�7i�tom 1;�day�.�,61m� � A�M�eJ �p ?� Q�w� i "� / %U!�]e�2aA@�pa�(eX 27�Z�*�'96���&!{B �"3�(�Zy3a ing� 2���j�A�co]< (�')R�6+�:&�*�re��d)|urviv�)29-by halfE+:*% �CONFINT&f& he R>grammd/ProbithveM�ge!t�bRp25���inhib$a^/6��E@� %nt6F�a�ica� ��E�� c�. �oba�.*"{�3q�4�%1�=y)[ a��� q M�N5 tBof U"?#a�76�;�3 on 11 ( SCorp ,$ 5b� ge( , TXj asRI�|v � �.t '%( IQR.4�,� l!.��c�8sa�R9t�#�%a4�'_ �4.3a��nor�22�, ,<i�)A metrj/A?FIn&�,&vwh�9�SQ�>� (�*Rt"�( A�g . �=grG'@$FW)I�!�5$.��] typO ��!g0�9rrK*!�z{(*! rank3P8$on's Chi S!�est�ereav/  W�m�aij%il:�hng relevaB��!�siJ9�>Q�*8.TF��their&�1a�u5 , we� � 6Q�whoE9���o� %J t 4.CL ev�}�$$TF ( n = 3� or�3n* � . In� ua��ntO >=� M&ip �1!E=A summZ)"�*�6fi i�)e� TaQh#0!���!���a��u�6Y thy young%*. CoexT>� !�s ��!�a^�(sbinv!g% ��+/)@.g&Y Eg W �&J Amaz�$�Orinoct3gh . Detai'Ut���%9>s!6*�&or�.�( SE=S2)Xs�51"�U�sM"6m�� %) -�2–4 � 17%?w 5'6%�9stl� ^�3ir� limba�39 %a��;i�4*2 n4�!k( 30 .�)A�.\ ly ALf�EeckT%�%3%% Less�A tly  -�Io/g�1�@6;P](thoracic-ab@0a�!�O& .h._0 ���O0� ul�,( *s� �a�#d ,�qu5 pa�=r-�Z� jur: .�M�bɯ 0a]�74cm2i64�� "of�A68 �B_ 190 �6U\!�t��v%"'��ld>�","*� (v��A�7.#v�( 13 . 9!�or� ( � 7�cyc��r �}~(����� r1�� i��w.�)NA .� rega^5K�+�)r15�� a���to�2>�4 ��commo�d��j'�Cap�th*a"a@>��(: arthralgik4a8!L,�� dach�y�, fevey.myA2)5 AanorexXy]P'usem�e�Aarrho>A�ns�@#che��i�4tachyc!��-facG7saZ�|Q9�. B�!���(& 2o�<nal&8 ��eC6 altemo�+M4un�4ge�.BU�&, KF'(!in�z%p(As��A{Ftransfer�;( AST�Ala@N%L%!� ra�%B�� -(U�to ��6/4 f!�7 CI ��� Ht� ���r� �y]+gZd U��&!�9}. Val�N3Z7� K� 30� I�f�HP, ��is!� �3 � 5~�J!�A�!w� =�AS1B>G��R�A=se< amyl!��� B��� a@ .$%fbas�A�'!>")(*�bV �UsI;��E>�l5-G 12Abov�VBn�CO? back!w-�-�)�"�&9���sus�ed%MC5Eyi?sAK-A=>p � �� ��U0a�Rp�$B� 6m &��asses�s@e:i"@}*<�at�=::m ( 5��2�Uor Fi*4 ��O( 5��gc;A�A~a�3"E �'Rn� mole�MG&j 6�# �G'ـ? � s"o�+*e�0o m�>�%A/�I:�ac :�,� !q� �6�Fe�en� jD&  2=% �s� �9i*E6�� by�.�PFm�0!I��&=}9%�� (� �luscor m�ble�W�A��ofF{l*�?9�/Aax,k+E�e-R!߁�-Te QE�mplif%�10)9U�C%T;;��to�(of�,*�2umeN !="G ndQυ�dS!&�g&�. OO@>� �=�M� (^� �2�ne�A@6#- 4,apit�!mr�2�Di�6AJ�M(%?5��J�ia""Eto-�2H8 ��EtaG,� houg�-m/�l� ��PA -[�M:xtac=" . Is�O.suc�0"� uR &w� )� &"'�aFimeB 'I� acqu�'lAenL� �K� , U:aS!'*'("q%6chi-s� , p>�0o. UP)"��p�I6��}"�b �&!��monocyK%F:!��s6@ t*:a*Fto.�!�exHŤs d-ch�$, *�a� r!�baeavera%�e%��j.%& ).+E�4Y� N!+:�fo��l�t�3-Q�zbroadn!of n��S2*2i�QoupQBH�{Q� >Y ��w"�f��e��?dX 0Z;0/9 � ��ris�D�BK)aLA6�iiH�8 V!:"h&in.�@�(%"1-D2b|M�H� ~Gha�!=l�M; 6�w�+b�=]%?:lc >Fp��'%��"Y s;Q�e���6��v-� ;an] n�&P��%P(m�!I� >�P.6�*"�Z"!16["ἅ ��60@Ea5:^ E�A�pa�P�w1�Q��%.ed�2�;65%Y darkYWLf*WA>-}2�}V�I.�O��EQ���g�O� x"3.�=�(MB-��726 , �CIuB86a� 3� p = 000-���Fig 2AM����8~����w��54X6�775� 0806v� 19 ,J�BE�& �>noaGHDa6�7RZ�D!w�-� � �!>43�R6�041%l 74/,�64�=n. O�Us�@+U\.(��2how!�. �<>?IJr��'chop-& � Y wi�%;�k-75% ..N��(A�Ais�!ly�����i�"� !W B];e  ndi��of71�:�M ��"M��6�\D,(�)�)Organiz��n E:4t Commm)e�m^�al���2�) in L�W&P@H�re�w a� MIAM��98[A1A81az22�=V�4�!��, 18%�+ N-�)_(.&#<I�!�olz1��is�dx IPnB[+"� �'A!: zAap���(by� [ �6�2H"�.�.Apa���.�Na�8�����s U.QH tole�Dis�a� blemu�4 ATF!-Q0��a�aA. Fura�mor���� .s��r�-��N��Qch� e��$nIvMiltefos:�1q,"wMng �A�Ya!a�j es s�*tQa> ��P [%S37;M idea!E�+or!6�f"LR� Y�I-8m�bin �Yi�� !�� mNly�L�� �(Q�R�*�J �Lb�M�6&[ZtuAEOh��`� ]aa��-b�fractoy,o AT , �i�EUe'-> �:f}3ng�zEQ�Vqu#��5A� risk[!n5}�{!�%mE"R-� �%(*�K" M�|n�� *Y:G �@q)K expl�� �s�xAhigB�� =1U4��>5 ate�~"6&aoep�6X #T!�e��dM (��ee���4 � v�a�  �0��TA(4RicA)AE�K!progres l�\l82�v�)�U]c� �2idden�1� y�[�(29 Cas just�Z=��Tno9v���!�G%�[>�ə_e���b ��$a�"|�A30aIn�(W&jr� e UE� ��S��rliHJqGtz,phago-lysoso membII� *= s�g�B�b lA�%�ave2U!� "-+�Q6"�ureg�\���5�2@n.�*"8.� expoP [3�Bh�m�*My`a6f3�es � �Q!�4KF5<�  �to��%�e&�ir� }L%sai�IUx< aW"e!Iʼn*�'�=}��W�Vo�<o$, B=Yhropono�Emis[ 6�2�d��EI�a:. E:?\AS��f7�#BqA�X�= B7 R}�& 2��1re__e�"�&i� XI¥c�!�s�Z&�cp2�'� �E"� mili�N���%�z�D�ATV *} :*��uONv [E�3A��#3H �zay� ���"aay versa_�&B=O:���L>�SvY)vd�#F)sug�`Iiat:u�+:l�7g'!�in fit��is��U��r`A�)"oS�� invaE�"& -'i,r4c���m?*notIC�e۩�1At���K!>/noT�n�UAP�[d�I&r~ �����2�)RWO��)Cas"�JE+� A����Hj�IU�“�omitant-aant”- ���4 q�! x-8�@("�? s�j!��/larAL 7s�re *�'�7:"ATF�%�i [11] o m�,"� m�.�(>A'�����u`ub��p�{!�qY.�8^A- o�J� Y�<� t�2 S1"Th��apWM�U�ba���is IRbe� I *\ �e1.G4E69& 5W(a�3 o � �f)T �>�*1��b� �"���ю cum��ve S-�AD�� s%.I��XSe�l"�Z� !.t_�bBiaP"+K)]ul�(origiE�9�)"� !Rq`..�"���1#WK��3n�!'&D%l5%a7playeq�e�� izU S� �/,`Un�2����a�re�/pr�6A�S"2�� AD��� ed -�=��b5�is-���uds �Iqf-� ATF;�.8as]!%�dmodel-UW�X��8o4�= \O0 a.�AT v� �I�I���"�3:giU`�5ora�I]���,�vlaue^�c[- bi�G\a k�!����E &l E�zd� sensf:�E�M!Z���"�-��:s�Ze�2( � 4c� qR� �6/(E! �&7on meis5ALCA�4� L6�%9 >Q�M)��5|��=m`�!A�a<@ ��J� Ū��[37�X�QIY^!#�>�a~I�558!) s_ 5�p e���u8!Of i�e*�& jca�oA<g "�  LUk� ��AM=�YS"���p��� re�Ar;v!@a�f�OAM]15al�:V2%vI2�!%{b�|A02j�J)�#5%�Iv�a����#6�2M�yQZ"re� pe&haQnlsdYe��d [�8]A�C6 �M� s���:�U{a��1%�a"2d>o 68�9%�� tE�c�Vinc�=% aeRe&.^"� �G�,�!n ���A 3 &^�Dach�A &|fb2)@3a8�^Eu�1SI��mb�s�"�AX! z�u�t<emp�?6Wa 1��Z,.��In Eschzfhi�li��$ synt�E Bw�;U[RSt(iron-scaven�Z�(esgd�e�8o@3"&0robS[.salmoch = $d yersinia ") !�h �stoxA coli"re ot�5qui�[ 4′-ph�?opant�7 inyl�"�-PPT,� �)�0 �ve�C-�ed: EntD�Clb�gen�%d�"!�$�ar4Ac���m�E .��as Q�co�A�k Jth�.ic��is�hS ,� =� �r�l�k�� J <�h�HJ� w��EBx( HPI :G sub�u)g�� viru{g��$�.<V@�p]�pu�::I��+ex�c%ja!S5|�` cogn> )����w�w*�6a*n8�  "!ou lA�Z��q�2�A�=�!�^a"��m!� ge:�EBFMfWe6����ria_�2��Aa�mZof�oeQ�cA�aboli�/he1�� �F-�AX�xQ�9�( ExPE�L� mo�Nsep!�n ��^r ]i�k.%or �� �I@" >of v� vo� +re� =Ha��nne)�1~# pl�pBI- �<^bi�G��QuMŵ��p��9b]!v%5� �.oj sE*�we&sz�/^Y�:�X��Gm��a��R�s*�a�ly1�t9�|Ew�amiscu�@mpE� 6��Y�Qz���A�2�f e�"�i�u4coS0x �3A�� o�����ne<[�6]1�����`,of keyuCD 5network&�c�0��" �\�U���1Z Stw*�,! pr!\Agt����d�op �# nti-RaE�6�uteg� . B�%�22b ��M`lower-guhum�?n�N�8!'Al�,u�F�@!�men-3,Y1ABK; ae.�L�:Sd�6( aqBo�<[1K[�T�V�O�!e�[!in"�gg�to�a�#m �v�N( s: A�t�B� D�E [~K�wm_u�JIMna��>�^ty�g�e>[[4]–[�ElL�~ }�Ola9qh�!d"�c689W�a��eQ��E� �,rruPfic�%."� Ror]�.or��at���e�.y��IA.�s [� �Y�T>Dn., nonrandomZ�o�.�Q!�Q+-�UCF�A harb�$&|stB�4tyR�tra�[8E�f'[ro�Q:S��"8�"a��,����oto�Zze�?to�r1=*.� Dw#yup04:b� ,>� !4a/[10���>�t'z�FPʳ �Ts � e polyket�;�la�D( PKSsS Aib~p�Rde ,et .NRP/$by catalyz���&7:!Sa Nd ( P-u  ) moiet�vco � A!��er�=3�_ esid�9on �!] �[12)X�s��!n�F�"� ~N�," 6� e��{M�d�nAq:D �= y� e� ��%vo.�|%� 2 [14]�2 ��A�glycosy��1�Yn]�[&�f IroA locu�@� 2b*� �oc�e{ on hromQ!"� a�= or )E��"lasmid�(G"C7� to6�,6��(v?FAimam�Q�� ��0$otein lipo�ln 2|Ze� B_�"/pot(���P[�fi��.� (eiz[nWT9�:� A���!ie��'� -R][F � �4�0N!$horizA�&� [1g� j��K�V!j�, an 7V7� \�/�@�7H3$|&�Ta�cereb�hi flu%���WhAI:.yn Y��!� YbtD1Z12ou���[2�inoe� ǃlog� to yA"� � ifH8�hm6~�� �!�:�!�e� �,��2�::i�/."� unɴ.�Xr#!*&����!V��h �*��S&&!5yJ �U2��F-WhrB0!G� [�gCo"�i�&! �*double-�nd ���>!'a�D�; G2-p��Eh$megalocytoL.�%eukary^$Gs�B:�!��� @� i� amag� ��/7VvQ� trigLo!mic�at�a\���� S' roc mo-t.nfl5%�Ȅ5Hi�"��Eq�� T�: coRc� r "W Surp�@l�#=� l�{9&SGi�{tiI �b���ebi%�:u8 Nissle 1917 [2q��2/�r �ᅭZ��2�fѴoa52�M�>%&�$�F �"4 ( 7 ;�! �-k�ve>��"�&�IE'a�:l!��9 a"@>� �l*y&[ \��A��% Stria\%�A0�x|`�����LE"Weriacea�l>9�}:�� �#�:�k: ge�lh� [�0:is�rk�2XK������ �b"b a(�N���B����� �"�-.a.teZ�IŅ=u��2�&E(M��z0*Rs��;'At �We�_ Kmo��x�{!E��i\ �.to6�  full*P ��:�v�c���!5Fr^�22�j;,x-�)�)\�e !�vQ�$`嬦+u�24���!)�d�e!�:N . Be�}�(6&`u!�Qs6am2[$h��5F�uw�iP2��*:R.)�"��Aj6^� �,&��.�)��{E�e%�Њ; Ce lig��n� ��h"lex� �  !2A �B\�[.�\6 23 �ery��in MG165�H��('s entE m/wk �,�D� !C�-� �y2, .� on CAS�Mte|). 1S\E�9=d� ( WT d"�%8 � �'� k�#!1b"� 'rN �3 "%fBA�6f RSk!m (( pks+uBы �s �+I!A� ���)5=1�y/%/�uA� g �%N� inFS ":t v0!�)�P}v%�q�\,w~2RMTY!1by%�A4.� ;�,5� A yePE�XonA?"%sur�!H!9�� � uVdAG�0;�)9�&o)dQFi:�>��y�&%2V���\�f�*ap#�&�zJT��@>z2�����^disrup�.� 6! �lY�DN�œ BG2�w E76Z -^�T9~�(2x o�+ abro�?�6j2�z..�� &��A1B�'ct�Z �B���vokC Vg �mspigmena�"Q:ju`A;� }Sty�up� iJ�2_Q�ѵ%�gB :�I:J2^��hlbA @R��`ME�~R(n":�S���GnQ�se ���_.V' 2b.r��  ."b�6[.5A>9�-"�#���.�p� 57"numer�"� I��;) ݺ:� %gsilic^i"� ���all�BgBl!d#��i��4gAJ6:�>�"*M��profic�K鵱�g>vBw x3 2�A�:2�"J� SE1� e��a����w:D.6����KE� Gv�m~rr7wi� J�oayq��:>{�2]�w6c�2 !#qu��� ��2�ubheV =h�� .-4��5�)()OK~�2��k%e��R�Pexʇ�� ���T2�^�2z�i�7U!:V�;/�|� &�&� 6�< 24:�EWw*ډ�)�.�&6%0&� t� AMB� %,M�" :�2���#%XFiR.��� m�B1�{of>�i�E{}�G�O�$8*m e},�D�A���&�C n�B�,�%� ŭbb�bstit�by���J p.�at�Ca�������n�F�d6���endK oul76ieH�1�^��-yc D�2�~�FQK� jrescuez�M(o=��& !\.D�HA����!�A�M"c,�)!_l��m[ t!K>M1/�Q E�KR��B �cop� ,i+G!j:6I � �e6 nF'��\iA�!0&�%"i0 vj��3�U�r��H2AX �Tne1�fM |6�){& �n" ����c h:��,�y HeLav$*%.��71Ad4 �l,?p�2pimethyle]Ilu��& -D�85?� ����'w#e&�p>@B��RM"�U�Y�m6 �Ek>�� �"{uDYyN B2� c"-��E�.B@e ����,"� �:eT^"�f.gVq [ ��Fh ���{2w C�Ip�o:�B6�. A�0��2���a�6� � p-�( 1{f��NCn�U]yrQ�CiE�!Y�f&r;� {� �JuuI��veGc+��e<\low%>��� +d;sY[E%x.&3Te�aF��6:0GeV�"6�k� =Y)�(� ��� &�2ndirect^��'�� EIn�q W�Wr�_ICW!�� infr� fluo��e��}|>U( γ-)-� EQ[�H�J�isi9, %�. Eor9�Qg:�s�M!�I/� �((enz0��Jxd )*h5��, 5� �+� 6�U2�b�z�� !��S�i:�&z c dose–*CA 2A�oI�plUO�B��( MOI ,��. N&�_R�u�WT�c%W2�W,I�Fs%y��AG .:�%("�/B�B� N��3�e�a�1q�&� !�m�A~��&� :�2�f"x�� !�ata>(5 "��F0*� &� ,�j��x%ly���&%��3�%�t@I2,� &L �"�=J'�� zNl*�6�� � e�!E�&� F )tae ;MGa:B� �V� &�.�)�"�%%, pptT �a�P/Myc7er`sz rculG , sfp9Sfp8Bac�m� tili!�A|�%". k:�)2���m �A�&� [28�)�s�F��1)�v"��[�H�� /36� ! �+�H# surfl n [�K16:]�!Ʊ���Wi���a�v&<(0�� 4�� 4��As�.?"�6W !����> ��� �%�M�R>�E�Mt_QC�b8-N\�cѕe xeno-2 !��=|�b & ާi&���_D narr۞�&oaW�b!�te-��Wm+Bwa\*�7��>c�t4Hto&.�aY���oB+.xa"6ery%�!��A�v�� by aq���L�-mulen.-rB?():o. BpsA�4S"| es lZ; dula�.�@�dA m (��igoidH.)� �Z|nԧ��q�L-gluP`�L�MP�,p-�2� BspAec.)��T&��-A�J0Δ+p-M 8a��eb2��!�<.����b�3-��8��A�p(d"�OB�� ~>l e~.��-)>� �d�y�y��/e2��f grow�auto-� tjG3b)A �E+ !c�3ct;u�z�ov�mP7!{w a�[��6 2�+p-%y�5�/)Fda{W Q�M�u�r��)�2 |&�5�_�h^!to�a;U�i�)fs�,�,ş����%�%&�F�i�*�%l E �tr�eE.ZVdis}/�709�t��t8U<tSan �.�6jadd R%*�(eO�?,� !@&�/�&7,o~s talk"� �����!;*'��*�+"�F���in SP1�xanF�5{�icB6&a<terI7(e O18:K1:H7|&�/ne̥\�,3it) j(.Bq�I�%U"�! e�&{2(.#5BC5,�:e"AM*�24%D������E�.� �v�*n?c*YB��)t�inj1<��Am�Dfootpad;�"s=a���k�6�J!>��]%Z�Dޅ�ed�1morta~c�xin 40��U Ae�s�82� �>i��tq��n��e�N7*B�e*� disse"�gIe)Jo�,�D��M!k%� sacr�ed�L�p,h�!  PBS ,J �����o��% � Sple��A�2�gM��V#�& ���y�V �!/>.ͣ:�We&�T�L�&� k0rog�V animAl�l load ��%>P\)-:Y�S ��Gv�U3 �or-&of)�)|�2c>i:eFh% Ŧ!t�"mYدk��o a@sh6�_,r�.n&*���^%� ��6�M�2L���\:d� -�A�F= n .ae�� *��鉺&� i���OJ%M5��2aS1�7�I�ho"0J1 �KP>�Ele!82�� lm�*n20A. U�� A sl} �k�9��*%1 de�=���kis=!"^s j:��.��!c%�u�Y� �)Ii��:���&>uV�J� T:�A� � i�e6�#a� mpl%�)�%��Q<-/�&ׂV�vo�O�9f� mann�tY1�5��N�J�%�`0j`0�V�0. OurX2�~+ �M2�.���.p,�&)�iWe�aeRat���}7��A p&I+\r�2* � >��8&� 6��X " �**e �"�&wzcG�� e-� w��a0�recipro}A�2.�f seem��9!�"TB�2e�8�L�ti spub�G�Fs !I�OtrA�, m-o.: #� �.(�-�oBi�5��.�S6�. Attemp,"�K9%�/?motif� ��C II~&�1 �v�2])%��M1ka �� u%�&�EaݎA� iscu:y�a[�cer4z� ��ype�,Ever�:A�"`^&� . U��tuUi�[EL"�5�C�neџ!3D��uc���s�;s"�3�2/s��u�Of)*"��[3w@T:��#-eiU=�~u���!��� &�HxA�eH� �Q "�Od��[�u���h/�MN%r�eP�-V.�M�mp*pof!H.��h�@U(�+"��jP//QIz &L�Q���� T!�velUmF mak9�I�!h HNL� ��ve+H[34KB�5�H04s%�cru�2 >)�tuS�&�G'�Bld� �A",.�JEN�I�f!��9IEA}n*FIe���" .� "�6"� ��g v:��B�u�gyP�D^@s�c�#u3DV�EGEaf�z�Cor fer��P��fɒ�&�:�A,.!:y[LE����?�� 2��Ja�aEe�\�f-K$ oA>�8$ advan��Ik=� �#AhBbGN�&�� dap-� env�� }7n�s� �IverH\�Fi*�B!pgF�[ , [3!H� urB�9� , ��ntiE�~�H/9�"_2j(MI>T )���}�2Ec�@Ak 2�(e�;���r r<�k !�G G*7O;- �Z6� each2��%AAi*Oo[3/C��/"R� �or��-?Ce6� b:{ &wa ��3 *Q&� can1  u�&by �R[.J!%.3s��H^))�it-unh;PsteR�&!%�b-�dG�I����b%t�3v  w� :lM�I�a\ed1Ѕ�2�. A`0�����s�poplit�Mlymph n�6.v���^V)8Si��Lia�xp& � ���s�zW�long-^ �N�nivqin�N[�Z2>Bh Om�Xa���{�De�Nl�y��(2("�Uun&T 7mىKP& ]� �~%a�Zm���m�s%#%apC] s x�26g.��lo� �Nɺ[a� "�A�.�>i�d��%s�X� re���1u��O eldeh�!�w¥�ńes [44>N#=��cv�2�&�s&� 4dV�Vt�f�(nIKHigh-P2�IIw;�5mn��Q towaH��]emerg�&�&k?u�d ��F�zB�InBI�:�i�Fledge�B'7ng);BOcl��Y��d�M�&/ �� [4;+W�Xl��Y�1] 4t��E�!�b!�m@er�h�QeW`1( ep-by-��.# �N��8��mobile� X�A-l �)Xcenario ��s���g�!�tq�Yp2��8� � ���j�1Y �8At�?�lF/ �m&��.Hi .��e�A�#i�a5 g(-!%t0�yK"�28ɕe�v�7�J�Um6d�7yAGB�> "�B� m�(d so far [4$I2jOJ�$A�:� .� �&@�4t)f�HE+�S6�&�K% e��AlE���HPIs ��a�I��� ��kO�R%O��h.�FPe"v�re�ly [4gA���5�i�G�VB��of D���e !B�<�W� s �5B2�� �� occaHjf L"jGY�,;��<sp6���49\ P��a5ma�c�� fasha��T& �O!ft�� X����.a�c� �s��� =ctu��M !(a�X&� a�.i:�B����AM!3 *�/J�d� �tUm Il=��5�/JNM&za:��x";ha:�G(N�61U") �%} [45]œ2ID.4Lb*0nfi�-�0V�. B7R����l�W��[ N .Vv�J5#&e��B2U�%�exo�emeG*lev% >/�����a�"�flikelih���a7.z emia [�IIu�Pv6i82*` ��=��Aq} cx(#=e���*�  (�����,s�,s� AZm�nR��t���xe'RN�enW��asn *:�&u�; Jq���!�be1�&; (� ��+�F)�erm��nucleo!U�{c���5Pu'�J��2�Y hi, � eb�e�N{.�� b!C�Ba����OsAɃ2% c�v� v!�F�(ƣ uber� B� !R�G�.8]qʡ!F�� �hQ� �m�>IF�y� �� �Xq�2%[  6�:�(IUA���AkEd'2�! %� dead�����h� ��6�$S�Ag�jy.y�&� �c,,c�(� �]�PMXDin Klebsiella pneun"aIE"� �er)$� �CA�[ kocWY�l4 {�����Vm h*�GE @A �i! B"u��W6,� l��ϙ���;( O150:H��� &� �/.m��$fκA�a�y�� adul *Y��#U�V`[4�V�\ ���A�!=���0���.��aF%B���&���&��&���B�^ rezRoSJ� .z05�Q{%es�E"� :rG� "m"�E �ge#by�5clambda R�pe]&se�hod [47] -.y��>�,F�;:��� � ��4" pASK7.(��v���1? a pBR322 �2!/r*�v�!� YZw2/8o(&b8�8, I+ or ԫScrip�h~�ColE1���H~��8.��6O�m2#!)Y&��b.Y��)6VB-&,(��P\# J@� �,o*_, LBN�th��� �CUs i��� , at.��sha�S< �{u�,t diluS 1∶רZ�t�� g-#n�*OA �"3 hbz��}7m0�M�#��le�'�a*���b�%O4( 2×109 CFU/m � 6lA�u��w Kn� "�th&$�"H.R�MC�\e azu�qS ���� :A,ſtetect.nA�!�}kGE"3HH��@.��Schwy�Nei"O% �Q��%�n��O agara�Q!��.eQ72�tGfrk �)Z8o�� zoDl�a-�o�[ �To%!�de�l*� ,��µL of�nor9" =X4 mM sulfosalicylic aciޯmޯw��s�Rn�Isuperna�)�re�2�rix�M�9)A�60�A� room��er&g!��vpKR&����-Q:�R!^r�di�AAB�%$at OD630 n�h�:R&��  nr*agX48 hydroxyquino4 ( 8HQY igma-aldr��E�X>�Wdar�8�O�=!� fyu"L2$:m rexlo��F1)�B���b}c-&f� �!esXB�>ula��2�n[4?^T��6{=_ud ���\ �n�- �e�gn yuA- $eok% �]�$ [5��� MN�� 5in NBD�uX�+Nuъ"�r�( N�'R��d200 µM α , α'-dipyridyl� !��4or늽�.�i�pel�v&�sifuYO�1E�}5A�2ܬB WR1542��)pACYCE 3L (��d gifCWbI absc�Wp3e] eDEt8ll s ٠�6 %;5dirp6� irp7S'rp8 6A��ybt�pA5�if#G"oA 1a��?!# luci3qU2� T:� �g.��� 24 hAz�{A���dBj!�5��:d� al l��NB00�Cpot�i���m\3 $ [pH  �8 #2- EDTA|�L% [wt/vol] Triton X-P0, 5 mg/ml bove7]�lb��:Fdo�f�5�úrC� teis �s���c��-"B�A 2��nd!���mixA���6�/lA��nk9�' lys�C��"�0�8M-!�2��w��$Tricine-HCa�1\e�]�07%( MgCOͅ 4 Mg� H ) Pk!`a�-�47i�Df� )yi!f3�^3OBk2 7Li3.ig , 53 PMg-ATP%�LY��vit!rݥ� "P�s� A�$m�er Ber��d! star� 94�Val�g[c��b�'��=X �y�vh OD60i�Y�k~� eU6t. K12>=  DH5αA��D�S&��'en�1(���AXE��+p[-( 5�3s/w��%S5"�*�,}�"baK��l"e:%q��:���� *�(), 5�25a� HEPE�nd�a( ∼�i�l�� !x �"V��pV�F&J�RG5Ea�a^"� ]�#�3��40��F$$&�7-��u��o��!r* wa i�5�� 72 h 4 >b�-� �g 3:�M(�ew/v!� Tris��01M%�a�:4�-� � �Cl61Nyq�c����?�^�6e��>>J>1edA�9��:B#s��*[JBrief-/5�-}��e5%�s/)pLes)3�C,ur-�aKr , 2I�I2Q�u= �  . E�$2B+5A@A�A S�K� �B t\P4%H"a�ldehydTbP�2!Tneuw٥ �i perm�z�:F�.�1�-u*�����MAX B�u�A�J M�1_uelg� )��:� j�}$HOSTOP ( RD~o f�K��&�mY!NE�rab�� �z%�"�J(� Signa����TA�A�B�Lt*�0Pbody �@�Nat 80E� ( IRDyeTM CW ,�k����n l�(�?�������qJlab?gFedDotpB�um Ou�RGt��%AI&�1�i�l��%�K�s.��i xE4�$an Odyssey�KNIma1�S�+�Li-Cor S2[ ceTe��Les U�HFI�)�68%LMNap\M� )�-u6)�� n dyA6�X��ve %es�N��s|$�s�%�N�����8�+RPtOor5?pereq����kby$�?I�!�'F))|vehicl6"f� "� k� ���F#M��h-E3S� l|�6# �+u4,"3 1� e�W ���:9k U�Europ`މ�!h!B!���� �i� ZAJ''c pur(� ��9�� � vali"^#Yl;s eW�s��pes e���C�� é d'éth'�0Midi Pyréné'�%l'expé= Pe܏�& ffil#%}�`"��$de Réflex���q7�ur l'E>c)�ca�lin���f_�h� y�x��� ( Re62�530: PX-ANI-A2-9d�9�9w9��v �J10$. N- weeki�f*� C57BL/6J G( JANVIEb�� "�B��BI108+WT�plbA�.�,�/u:tDV !#7!�:s(*+2iT�^G6$�I6Z�Kaa7tonJ/&K+��L carbe�z#��6xLt r1 . J~&f),)F%:s&���1igs8Z��}D3�-tre�N�n`�eqw$man�+]; 3���sm � �2 7!�,most widely �aused phylogenetic models only account for residue substitution events . We describe a probabilisti R� of a multiple sequence alignment that rssinserthand dele uin addito2� s , given�.�ttree , using a rate matrix aug�xed by the gap character . Start8xfrom a continuous Markov proces}we\struct a non-reversible !kprative ( birth–death ) evol%]ary)�6 s . !|The )assumes)Kv> occur one5�a�time .!� appl! is ]to6)%Linfer%� by extend!#!@0program dnaml!�!�ip . U%Dstandard benchmark:methodA� simula!� data�@a new “concordaACtest”HT on real ribosomal RNAYk-� show)+� �a.�(ε improvesa uracy rel)�to;usual!1roachA�ignor�gapnhil!j tainqcomputaA�0al efficiency@ 51��!42\ s aaNyp!nt rea�as misa_ (�_unknow�io) ,<ecO $ly equivalQ o&�4them . A varieI�ma�for �e�[��8���}� $s exist [3�L49!'!�canon�m��!/��aA�re͵i� @e Thorne-Kishino-.��4 ( tkf91 ) [50m ���n* R�� govern�,� plica0VP��pa��ter!�allow!)�&;>2t��cu� � same� site� � lo] i� . �� d ,!� examG , uponu�tC ,parsimonious�   n��Aghan�| per } branch2$�7pionee� Bishope� Thompson ��wis]� *o )� � recec )�[51!�M�g sion�_ haveA�0eared 52–562���e�cM I�J�[57��[5m�5��'[5I�62�S9 *Res�Bed` �� �s �ddres*%?ro� A�� tane-��A>��Z%e5�� groupB} ed�Xs [63��6n& ll�na$ ta� clas �di�ult~ � lexitieA�Pworst-case exponentia� �N�M at leasti�e Bo�I�� s ak�o-L,W=-6 opti��u`%5�� history �  $  ��ly� �be NP- �te [47!�~ x ? n7 �� �. Anya�le� � �F ��]�+�>,)-�dAY��eX, seeks�Bmakeroximt ^"� aHt��� . Here��ispecif�� onc���Y!��ofP��J& -nJIA�Y��ye1 ��n!�I�u [69] a cla�-ofy ��columnM�.�to�a&nP div� �s� spac�(a so-called��&Z �ur���kbut�k �A%noA��\ ant under ��rr�A& )kum��a�sub�sE{at%%�1bF�vstill r��". A� resa�aO ough:����0 be avoi��a�!cveragm�Q�2 �X}M� ach remai5pe� Oab%�$e terms; a&�� ch!�$Monte Carl:�� |� � �O!IA+10 globw� repor�9to12( 3 CPU hourpDa 1 . 25 GHz G4 Ap�cMac�shI�. Alt-Y��d�de&Aq�� prop�#!��)��*��t woul  advantag�%���� ��"8� ��i��qW��p��[ !!mcs-�a g!^in? iATcy might outweigh sacr�+� some�A ��� ҡ altern� oa�a�"-Rf���><QCfu�!.(�.4 &([41��4 ��m1g un ��* p�ȉ\ independEh,� nonethele�it maya+bet*b 6altog4H��fur� expl� �%K� W�poW r-V@0&�aq;� %<w{J corpo� d A�a8� !䱲 y_*]  ,�`/�\UFtaU".  origiA ng idea.��[ ( K+� × ��AKv_s ( 42�or 202�) plu�e���F� c�cr�A2f�� �)�  (��&�� *� (&�"ndeep "Y(Y� )�,:�F`� �1�,!�co&Xg�� M of" �_E�e�-, a&WAu� de�s flow��H ich  �discusW"e by wa� in:eUA res��!�pa� %"g-e)��$�in*js� !R�n z e toB� �t���Q��hPN ��. tBd�of each�C.Y. For2, a�9ofw.�F�recur�e�)*.fA�ncest� "�s� � node%� �>F2�IY�orM�psuma�MbMY�"� ��tq ppe)�q  �ne9ar�mpl�- � a_co�!�� �L��satisfac �of}ka��mQEda�W���)�%ffine�rbitr��$��ge���m ��*8�1p-������ mustAV� ptuR flaw�t it�� ears56ya[ ��Y 9� �scendAe}�� a fixed*� iR��1fu"h3 flicts� � A�&f�o"$ �iq7� 2� memory�ec��!� [70]�~w���2 �sA, reme Oo� %��s wA�p�n� =-9,!G��u��%f�����n�A"�9�%�&� �!A@ :q!�assig$A����v/ڙ�(��N do�?!�mu/ 4��ra��recogniz��E�:i�re1Cno��a$e�e�ll�<e � poin�jA�f9�%LY�1�;�,!$6�=im* �{�atIi inOSAܡ�ai�!O��t!�6L>q�P.Ham��ծ!e� uncon� al9!�ip�QI�  ��2�n]%�~ve%� ( unE ed )iA5nXA�a!A��ʭ"M�s unique��" -by- Ɋ% &| Uone wi�Q o!3i�!J7&�3� 2j)],k borri�)<�!:< F aAH"X ��A�aJ�$�ge21"B F- !�; t.O!�:�!does 8�}sa� raq� . Ri��a,� s6S��eB��^"-&\"�#[7 ���v2U� �#E�����ist%�vz�!kY�))��9� mapp�y�� ��vE�dur��  cruc��r�er�� betw<our�k%= prev; o&tU�a�Z, w�gV���� . Simil��f�_$s%ZtM dea�ciw���unobser!��.ext6�–i�i�gpla�I���-� ve�Iked%-Ej� :s�Ɉb if�_!�cY��Z*�%�+B�E�refAX�?�!�%�"eEyi[!Jz�pbe�mar�l.N� iz��"��pos�%N��2A�=�F$�( left�H� �5�5g��*R� le�)yi�'�#i� if�� adop�"e�$G�m�g}��t�'e`s�"�&� )ensGa� �"����� or/��� 5��� "o$!dir�o�  ad �%Aconne� �;�V�>+�y&ven/��ŕ!�jD“pulley principl��)�%v� oSooaf s )( -y/ e9Dill�Vm�IEes�Va��Q:0 o!�a f�C&2��( &?a�Fret�`diverg��%e9;�ob��% limi%� zeroB9�r�A�:�a�'�)of�I)� . MoreegsIu)1cl0!can�@ holdAۉ�A(!��� b ae!eam��"K)�non�OBT2Y �Vra�woV� autoY�m� ba5[ia� *��/teЭT also� � a{��(6K�QA�mexpecA���� :� We�c� thesi��&by�Fa:B� �� stat!~�[prior}distrib %�&NP� pA��eQ�m!J"� "� ] ��1w���io� qI�!�he>O a�"q#ur �i� 2�,��%�alwayVi|�&Hl.Tw� pzN  or(2U�M� 0��%:b�, rrec %�]�*te�#ly$!V!"q6N]za��'by6� �ἡ�ea�B� u 4v5�J J �. E������ ires!�� -��+v�N#ENe ex� bookkee� . �&�݉wun��be5�5ec)�D Whum!!HL�O-s d-�p�( aesthNp{a:��3� --n�,few9� . Im,a'',e�!k& �� top~*�ny ar&�of&�Y5nda�6�f�r\ ��t��&q �}�ce���-#P,l!��%#ed�]�A�.Y b e�B/i]aT Z�-�����I&s fai�!" ��5 h2ifIq combN�X ]gnd%��� ��&�t�\�� � G��toA�dv'�byAc4C - �!���.>H(�$�edU�.^' �!��s�is2�i�n�1�y�.�d aboveAad���empir tes���we"a�_sH)d half!u� , afR.4��itselfcirsa�w�rt!K solva�/:�associ�'EjZ����Y�s�d phabe� *@,E�%��2� ���dH.Sa K×KAD��.3R�U��M*�a5jR$Q;!Di , j ) ≡ P ( j|!is��by ( W����)�!:2Y 5�31Z� ��"]*h Rε �� "�I� s μ≥0��գ s λ: ( 2 )��MtQYE;al6�M�(�b���d �(rEIn* tA" t!+� le `2�f�襌� Y ���"qu� i=�*� 2F�'-<*8 �R ( πi!#�sA�πjj� ) )!b�A�der�7!v�3tic�'7 A;�== �$A(�$By-lQtmzetR%�-�KY�!͑i�is.�BpN`:6Z5A]��� �� s γ�ξtE�h ��6 ) ( 7 Fn> &� P  ��osiTp�p��$axnZ5�I�1a�λ-=μ 0 ) �2u�a��'id����. FinU��h�.� o ob �B�2-��ka}n�"9�Z�-r.<��bic � rele& �v��@mo��u&�:deg��te eigen��`"�+�'oS neg - . Toq � T�:m , le��0����e��A )*4A [e�Dae,1≤A≤K−C ea>0a"��!J\arX &o2%6�cn'exe�. s�8I� re O�$�-�of�&�s"M+���*!q%~��ext S10wsQp�uOa h���%+trans�&�+~ js R)&5diago��+ . N�:M | 9$ ف��*�5-�U��16/9 ) IfR�,A"(�� �ha�  <dU�.� �2: in E�-8a�Q#"��F84`�3y�=2pe=� i≠�((βπj+αΔi�,�0� h�{ εijg1b � ����@# puri $or pyrimid S0is� y��*� �Va�u�p&�2α�9β Ro�!�>�6Fπ>n-p� j:� s e1�ie2 �+β P GO-�;O1]�!]−π!ca��>a O2!Q<2><�i<CM=���Y���(,� �&�m8>�Np]GM��(ljQ.^�( 1� )2�v$�QMcG� e8 .z"��$����jJ�a�enD ��; )#�AU�lՋ>nA�� ai\A]%� 7�<� ��%��%�μ ∝A��/m�d�>V/�ri� �"��"Z � � �"� !�� ( ��M4QCN0 �b���?�.��. U�/�k uD!��+�R*q .�%a�z,a6zR� �w�#!�}�2� Ac�)�e���,��30bem�%ely [7�4A�e>u� � |� 2 b� =�:�O��edI����,!w� b>Den��)\!-"�.�<πiλ/ ( λ+μ )%;�K,Rnd μ>"P6]�!�� : A�nguish"L =�)3D:�yV*�oE$wi�u��atW)1au h is sai-bU&)�l���it**m9L�"�m� �F��� [7�;&z@regard�)of�Aa C ���;�� #c1f�enm�3A?^5C �na�y� y0&!U:2�}�w!i6�"M.)"�!��ց*“25�(� � amtakL<o mea�.j '&� �,�"�!�a��>KA�4>u��`*�B�� ]�Rnd�-is2"�@ o��E&�a�isJ� i : )�i�mos�e� (e�in� ce invok�>�b?�2/��o�&$�w� ?� 2�L [la�( broa�5) � � u!�A�F�ij"Wa� Se n� s� �)a� �(|p<,nmi�e~�+*K,�-. U�*�y)-�� s'iE��'sI��(R a �Br� iz} !xTA�E�c�,E#.*#d1 pream! �ouw4tt.p9*�4u%on��&� ��3 E��2}� *�(2��* ircuml&ed�H9�Qge�� �Ak� F,�n�le-�><2,"���"�  )r�n W!]w=)do!6� �aGo)E�s�����alQO�j�12��!U�.�a�q(Pu����as9ER+ξtπi!�"� 7%�.���9NH�eWE>��e�_2�JBM!�� )2�9wut!h�5 ���to s��!Um�1I�"�l�x4f4H2))��1T� Z�3B�“�"/ �Jre�'c� T,�!e� ��ru*4��E�\�L ath 0�$A� �>x� {x1…xl} ء )K)�&3y3y3yl′} �spo�unambigPM,aN�?i� a6�� &� �"A�)�Gismatch�lum!]v1��#7-�3!i��2BP1 �a�-�N�.f!�%�bw . Let xˆ-6(xˆ1‥xˆLE�yy yI�1~s x 7t*p*�=�}6�E��5s��ed�Qx�&t�JfAxˆyˆ H� es s≤6��T( l−Ad&�)E�� �d s {IA>IA>}����a���-G� x�d�in5 y�!T %a1���,��%P+"���i��K��s���an<�?� � 2� π����'`^R�$ �x��ayN�.;2:A#"� �is�Msi-R le ( i . �m2.a�LbVGIn"�-!v,�� ryth� buY*� ( 1−� ) l+bb0Q�!(-�:��#F�0�z'!Tha�a nG�+2��Je"e�?> �k����llU`s ��ll&�"���v2���:"� I"��M�5I�av x� h lAJ��~G%a�!G5;aE � .� �(6*% 6�n xi _a�y�H �z !s�Gr��2� geometric6�A7GR!g&� .K2�(u�i�r/Q&&.L# �K�,�Q��)��� �oo� el�\sum�(o6p� G6I��nIN.K%�a�p3�@?s� in�av1]Cr;1l�+! ��"�2.�A�"�.�D"-�5� ��&'8E���� Tp  �no�B 88. O.z)2n U� �!�Y1lU?&{�$F /3!�:��A N�J�see5C�*�E�We�]e �:� ��VU��'u>�T��\ � 9bnamed ε��}(A�.� 5 �#m�-�� �i wa�; e�MJmI�a2B'�&+�1do�E�Uu�i�LZ�&�� 6t0En�]��Z buil�block%iae#-fledg "rU!�.�&*��K�XdA͙�sam�U� �"o4,�F�R�!��(�  ,:  )�n*;#� [,N � ( 142� PεL2 ���M_){G Q��A.�-6 .,� de�ubmMDY�.-orEoiVeJ G� orize5<S�B#,v S��"�9�E6.��g� �aR��p�DE'��of�䉁"� Bernoulli"�y.�0 0��.a �3�KT8>D�.K15!��^ d1�.�(Z��M..edF6�^5a�YW� �;) /,> ��bl'F�.��1p ��:�12�ofV���f-t%E{�e�6H pEOHc* h6w5(�*� � �.)�9.}2��FG9�E"� .,"�;^&I �-ai� �Zk�& 3-�ril �T�q�[E�llu�DtX1�.r�/_*%�4�F /WU>&b�fu�P�8E aris-/� 6PI1*�E�D�F�' ��0�( 1'1'�Q!O,&V!��L�fM%�tra".@�$“9l�54�7G,"DBr_F at�U��. W�A" �is+&bV �1� "�'R0CBF�Y�@"8 $ :ns"�VJ�I1 6� %� w�>����!��Y�Ub��_�,�^.? �Q��..�'NtZT .�>������.?��N~� �3E�^.�i>�5�/a.��*�/9�[1]�� ��e�A�a�� � "0f�7�*e| Th) are:=.�5eJe2�rXI�1eJ6a�=%�t.HA���!�"�Q, s$Ca�#l��e*d4a�&h4;*�ai��)�*9�q.JR_ �5�/=�(`vid�b�*�>.� C�Sa��f�6=a��&%p�� ll]: LJ�# ;%�fi�+��Q=4P m&�5�^"��J�*BI?e>�@. Oao'�:�_Im "g4.�F�K��d�8g&� X Qd1$Bby2��H K*�)� U�J qCa&~nyof�Bf�m݉��>�9�}Pu ( L�a6/�<.>InSLk V%�A0"� (1���)c 6� ���-��6}� Aa/6�1�h6".X! `},ZC)�s cludJG?V6�� � C �*�e�$*�B�PG�k�L!�%25�c�&�2�?q�W& NstW/ng�Blea�> >8,LiaA;If� k�a.f�&%%5( 1-��1�+� B��rF2�/6F2)�!j�A3�*da g]o�,nd(� � � �!�ts� .r�T chil��?� wY�u ��_ E�f�M=��r)�o[uk!��QA��-�uE �&��u �ukRAd��cW?E0��NG!KUZPEU6� f.Cdic�?f�2D2IY( 2O( 2M( 2@��/ARj�/� ��!e�cVcddFigHz/a graphY1 �g rpre�m,.�5�.[:�sA�Ah2�5:mo&�acdu�$�Gzx �A���%0E�2���9?A,�"U�fR�R����"{�9u|T , 9, UFne��W�y%� "��&�@MkR�q`u!^ �2&]pYp�.!'gV�!E"���!�πE�?�W.�>�irfa.fOR@iv(�� 6�Min1�%Zg2�m�IYN> e�w�V� ">��(w!�ink���na �"UMa�Ű" Q&�-�R�R K"2 7aB[]&` !y����I$erm!*E�-v2T�!P& :�.� P★�EjN;ԉ�aka\KJ� ��2��~. Last?��4G �E}�Q=!�!:no��I>d —�"A/ Re���( B&R!"�U>—%F���es�A���!4L�aM:�!�"GU L0q�sF� *�J+AO68"e��jf nd kNT6�2r)�^�l-�� � u� ��5�:{b!�]�$��2e�ofR� 9���}"� J(g ( 2, KU�'he� �.[:>��!9� � �aha�@�A ^��#M� �&��noD�(�s�"ulP��l2(E!X"�a�s!��*2�INk3 ( exF*I.w� D6Xp�� !t�� � t afAV�JpBP7A�D�I*`t,R� %�dpծcho�*�ny9 J�$� ��7ti%{a)g&)� E�t3+�'R�$�:�%=.(�*�1#% � 2%� O�-�BetA�3�9bMQ- 6<V pA��e�9]�C.�a6r��EeDasympt! �:^>�A1\ *o�8!)� a*b o��LU��AJ∞r "g?=Z�r+`oM� JW\Afinite-� u !�R-(���z� �F0"g�ngPdVi�F�dJha�Jse�g @ h�E�B&PDsdK^ R'�����&n'�o {EVppl� Ad6H"�!�oB � �5.�u (� hyxnpackage e/on 3 . 6,,4 AugqM 2006�n)!mq}T �I*j`N�=�v� 1\ �6�tA��&� byN�anX8�!�6 ��:"�"if! ~�ε۩ 2!8.L�o}os 5 , !0�(d)9Ir��q>Te&�v����.F���c38I� J��$%h�G� Ք%Jr1y c���a+ ε� nterp�GX � �/�xεimiz-_u��=΁am6. A圁��x�R�d�=��y!d4's Newton-Rapham�q�mid�V� )�F)�t*ly��� ��{B �K� �conjug�g��0!�. M.�G�n easy�  iz%�" �;!{mad� �&mp�/��Go���V���Oevo�hP �UwiF3t gnnt 'gcy J`;o�1 �:�[7�ra�[>� �c1z'}"�'�S% ���2x[ �:i){�&� �(�By�F1'�"i��A� GY0>a% ��m�oracV�sx>y)�iu2�yj!.l � >��#2.p �"� 1.� �|[te�"�y���E!F6wnd�p� "�.� *�$M2�M�9 ��J!e~�T�oo��x "GE!W (��un!m-Qau *., :u�� conf\ce} 0�(f|wY��<m�1�&����O&�3}�E^NperCav6r�}w�,� !��]A�<�xas *|T,�� >:�u<5D �r%bε=nE�!8typ�?2!�ri��!�DN��Dr"NF� i&��%`r"*� x!0)lM .8!��S5�%n�G!4� �S+O~ass\M �".2��%6jteeEfer6~E^tmR�9Y!� E�bZ�'kf� �ree6T�o.�17'�'+�Sf��#al 6�����D�[�2Z���is,]A�!�!t�! ruth�.E> �!��Y]�9&r]Tun��~ �� shor"t�z�6rapidnv�Porganis�oll�l {�+�@�c �str�%:,6��k!Y�a6 �� 2ir weakn�\�g V I�] �yNi�e:2|I2'nnd/�oo]d� JR o">�� )�:Ne�. ORe-<h!g��.(-!���y63Eo!�A�� ��A9R6R1jusz�IK �Y�he�%��cb “�^>��%q"V0r�3~=�8�be�I�. T��ng'� -�en�al �sh�Ihel�9mxr����f�G� ach �n.�/Y>!=!N�qgB�"l%�2�0KGe�*z]b�. R� si&2?�A�%a��6�^ElbE�'*�U9� ()o�75�!M2�� !*� �%!] . g �#," seel? ason�)2BC��Ct.w(&�\\ �195@XIBn to bif�2�`�9c 5[� λ�A`��� μKbeE��*�=&/  a�.}�lm R��!Zo"P_�=ai!<���b�hmV�>�;�$�#�1.ZRb�"-M�,co�i- . Conj1whS�&�2zof�6�A#aJ->�)=>I>�_"�%�!� @m o �� �QQ�9+A�,��!�� 5U�s!#s" �[�6*F �..,b�!ց2� aQ�6�F*� Q@���jfR.| 9e�0�]U� λ/μ [8ӆSo �F�E#�W*`Q6�`h  %^��9�B*6�� conv�vng3�e�a2@jN !B..Fl5�%�)v�T2[,breaks down  R�]�{ μ<λ reg�� K�6b�o largeH��&�ies�+"�e2 mainshid%��k yXSori;)-uc �aDQ��An�,a�_5a�5����#.�� �7 9!�.t>e�&�-"5��U�iFK!��ww�g!��I�3�e� ��;3F�/ �.H-�Jq�� D�: TβQ�twoyN�<�ZN2I��b&&I� I��V(�$,i#P3X%T^#>A�k?��qsm� B�-Z�%IU�Y sol� �#ͬ6�μ]*d>",&�31&� A>dI�@+.�&!�n �a'B+.{�CV�"�+loXU�b)���"���m5�i4�sl zTl*�/�a� �� T�S%��e�0 �p*#�Fa=5`s�0!17�3a�em�0!�*9(��6xeC. A��|ZD��:���E&L�p3�sa����i�'e��mwn  ! M*Js&�l� ='?os�Oa�$/'r3v i�FQA a N 5 i�turx%��*�) ,6l�}T��u)8c.ڏ#"�}*&~ (0�a2�<g>=,a�O�[F�%�UY� C sourc�)dm��"_- ip 2I���L$a��6 "��9Fbevѵs�DB�(�<��"�r�/�("�l'^([76�}�ep/BPerl s�=i�� setsda� ��8�A!ese@S�6Pp�Ō63Rg tarb�Kin Dat[�W�>%u� � ease&Bh\��lib_x( SREJ npublis�F�T� ls� �.˄7%mecha~�  mmun�tot~gS� ex Viru� HSV =%�iTm�A�le��,./ *A�A�h $mucosal ep�=mec�0tox 7�n�p �a� In m� ,6 al L%�rha�Bel�5LC!:fKcdendri�]&D&oc� ��s CD103+�@j1I�arry vi^1r�g�"o lymph�+�� sugg�,DC cross-tal��ۆ�EB stud��*N�E��HSV-1-PS�g��eF �a"� biops͑-�0hA�iq he%�le�6��&%L!J 5l�N#�emiג� !pde%��u,B bear����� L�tuΖ�J�-poptoA�n;:H !� c�77� BDCA6�(O� be"(i&͌mCYJ�)��DC-SIGN+!�$/macrophag�G!aex!�� LC���2g��i��alBN�!F�(had up-regu�a damaF@�up�QO,eplQCLEC9�\No�iSed}:�te�MA!� ��ru�Wng�a8iso ��ITEP�i%�!A� vitrzDso� w�9�:�s�n�1�k}APrF:5� ӡ'�*���#)�6��yos � ����3!go:�A�.�=7 � . �te�A$enm���ϥn�!I�al�CA��o �%S��[��p%�r\R!����@5. DZ�Ņe9� Z!y j��ole���in�� 6 dete�a%�M���th�"���n*!� adap+1 �A�3Ie��]�fW�1I2%�OG c�El�I�p�w�Tinv( ajan��� �, penet!�ng��*/t#squamq(epithelium �r�R� ]overlat?um�" neum� �J� b!Z!� trau< �dc� oyed:�! SV-2��-c2I��!�"al ke�ocyq[�?���:��� �%b��w1/2PL%�J9I�5He�E���infil%J28!v�Uory:�)?�[!Q�Q�I�8e dor gangl\�@)� life�u!����)z neur�9f~CC�, mitt2(t[>l��go  (%��T6.V (m(]con&7. Primo�Ait�\geI��g*�5�$� episk of *��(!�u ��� �" pre-,.�zbod�� cur�zIofJ��:ω�cI hɉtit<I5euP2� _�[ , @�A�"��8h��� sA� osupjh [JS10� T� pl>�-nN ro�^����r�-a� ex [1�sIn��B)1^, CD4�U�u-�m.RCD8+�y�A��  ňy i�[1�d16]&� �-�vn �UI>;, tissu�UV �J.� lodgIe��?�+�=q�M3cqB! Q1��fo&deex�-��Z n@mU9 a�[1�[c Cm�� m�intra- ��1:��:��s��o�oAj�g���]WJu�Tf��+�� �upe�A��*A�� stf%!%�1"�F��!t:�~5r�mpA�>m� nvis� � � ���s2�LC% -Fi�a5]%�th{B72!/� ށ'yto��4*� � o � , ne�r~nD�R!.!J \ed�-2tN CD4+^iIz 11c+-\ 11b+h �N  di����Fur�2� , na�I.�A�p #BCD8α� ^l1in+F� [17–19̙!6lo(�predo�G�n��!Q!�-hs�%B En"� �"d���M� n?ll�tu��i��� &�,��e">��fO viC�o� �A��feT!� �bed%�in]S�e� !�q&�Di�systemA��bner: ���f`ab)Xl)),&��� g:L��a�in� .�e O%��"rDCAm��%���(a.�a#& � E�@T !7J e.]�?}�� clarx �e:w (�41+ )1u mbl���w�r��d�u0`I�I�/}[2�121]���_A�5 chemoki� �XCR� d.�r�*iTLRs � 2 , � =.8� nd&�Q�)�bv capac�P[2�B���)*% gy��'�6&\���U0�[1��a�� (]/�au9 x� ex�%� �Iz A�|Ҟ_PBmab��e $non6��aF�^ex� � a�-5�y6�Ѵ� ) [�U.Tw�| ZOifeW� ��h>Yp� ]l$ M��ź� �yr%��<��t� *@ "C�Y surfO9w�� lacksa�-���� *� ��a�I�$&.�s)��i6Ji�a� �a."�l!��*20�4*I� s.�.j�1�-�̂AS� 1�[2� We86�i�]�r�u|AX �]�m��%��V�2�muY�ex��q,�|�RaA CD1c-�[ _Kp&�on d2O[�v����g�2R�ss�<V24-�c��Ke:��!�F �i�q2jg�lanioFK��ɭ��CD14+ ,1(+-�.�&��mx �se�b m.nl o��2�v"� �=po�QM-!�I�[2���<�I� ��%LC- �DC� 6�H!�� ��e����� pen��: ��t2̀� on8�)�7�1 5o|�n�SM� Ub.�6� ��8ly>�4:�su�a�|*�:in��ʁn����J�! QZ5M �N"���A�ly���,a�vr�n"� IqMf>� �or%�*�v�am�y�4 arO d�bLU >�1=/Q�wb ��? w��P?��$2?A� �E�/m ,F�inc0d ��@|� M�E�\%�>y*� �ł�y�e�;or�i�, � >' r' efn�$ �!v_3�� ���a-/� �!�]4"t _,pkey��deliv-: �~v.� �8-%.� *� 5y!�� �>���#�aҦ�&�3$Ethics Coms�W�,,rn Sydney Lo"�HeY 5Qq�wr���o�0�$ΌceikEdp�Hcip�!�(egal guardi��fyoung�Gr�x`� 14�\�-0K�-&)�$. v-UL37GF0A�S$in 17; gif� DJHrazer Rixon ) [28] !*pre�1bF!�80–90%�flu�� lay�of Afio n Gr�nMonAKi%I( VM�)i1� �aexincub�4n DMEM ( Lonza@jup���H5% FBS ( Sigma-Aldrla harv!�d��2 ��nd brief�uoǧMuX(a cup horn or ( B g%tY� ze�-a&wWQ.x!B&2 by 1 rifupxFtQG , 000 x gP �:mi��supa��I���4t -80°C untilop�%B��Qplaque9-ae$3 mm punch2&Y! �`�*�-��.6.�c��mImC/ ����4/re&�q at 3-�C:�b�|e �\AM�� y p�2k3ro9!�ntR�b� (I 1�y L@]% snap-froz�0@ OCT ( ProSciTechgkepڕ2o cryo�\a . 7 μm.�uiy|h��0oxylin & eosi�H & E i?fluor7X��IFA�� . [ZRs } m�u�(ovF�Cand>D�?gr^ lci�; . Ti� PwrK �O��i˵auz�Vakqv,phosphate-bu�*d s��{/PBS ��&^ !�lab��vimmed�!\!V2�U&)/���n{n2 h��2�Qin�*],250 μg/ml g�mic%�>7!�1Wat�m temper�2��n.!e��*�G��o�`""�[r*A�scissor�O�Oi6Q2�UK*b!� y=!yt�&�!�~e (*i�ts>#��removaER5��YX�����6 . Sk�jas cu�<59iɜ >6E�di�]xRa up�chamb�24I�-( 5IpltA; Corec) �A9&5f��g��&J�=clo8 cawd y6��)i�����pp�q�R�ach-� %U�7,vacuum silic�)g��a >^g��%^s�Uw��fic�,�48 fp )aY#^��C l�$sea�x(, trypan bl�o6, ( Gibco-BRL!t�%.�?)8s!}�m9]!���a?48m@37��.#@ %A_6����s%k�`A��fy)leakag��$RPMI 1640 n10%� AB serum/ifI, chno +e~%( RH1v- , 10�)�6ptomy�+�U�C� cil��^<Z�bottomyIp|�;-��or�]Y*s��)C��B�G2�"�%�ex:X�3 x 105* 5 9;as&�mock-"WA���mZX�r�� dA�qr*B 1M.z>��#A� .�Ea��dAו����jR�IF ��Ant���IF�KU: rabb"+ nti-} q-1 glyco߶0 D ( gD; poly!Z al; abcam� go.B� (c +R & D+mo�E,$pcaspase3:5BD Bios�E�,.>� /2 ICP27FT[6�CD8a� �BD Pha"�� r�e6X:� $Mireille H�Nhou� ; Alexa F1 -488A��C d dol �-�IgG ,24546^4%zF2647^2)38( Molecular ProڥS_]1a�f�cyt�4V M8AmCyan-�CD4�F FITC1a�P463�WE-Cy7 2HLA-D>}4I, V450 $9�JPE %]�Qv�"zW0��), co-i�u� LCiWT�Xb����eX��IF*de�,�~[29] *M�� !.7"P dilu�i� I� B�hS��F�  ( DAKO� 0PBS/0 . 05% T+�20�-e�m  wash%� � ste�F@#2��!�2&= � yX�sli[��tG ermed@�"w��ice-coldg= anol:acet� ( 1:3At10U�Dj!�D�"�Sq?�':2 :N . C����V�>������e45�<3 pD%&7�$oL-�G�rea� � DAPI ( In�)�h��%�^�arIl�. I�*� acq Y ��7 ed Opus IX-7�cop� DeltaV< M Re��M+;\�ied4l /W�+a Pho� �8olSnap QE camera�!��!�n FIJI.�$SoftWorx d�BA softwa 5 . 1 RC1F񪙋!6�? ��+��2l. Sora��EZpulAC%9.MOI�) or & �hY�60.�. ����1;in Q F�200 n�GM-CSF>�u2$���RG � �x" K�.�% !SedJ�!d6� 5KFf%Y �� e s�T)A�u!vf +>c�N& e��' as��=2Q� �.:��7%�"k, |orIll�+eic PBMCt/��>� !Sm�� � k,�M�c"d  M� 6�� I��b�% ,)x&�.O�pod�-iod�( PI; 1�;��� ic8����KB M�a�!�%��)��=dc�3ej].E`"2"�sa6(�s с�5<6 ,�t�E+���Fd��wo ta_���u�'t &F�^d�K uns[lK�*g��Fig 7B^p{�measu2,ANOVA%#9�Is�#AA��g#q�/K>)al%D0a>PSS�b216]�ze �7�%*�9)L��w�=-d�I �hA�. �uw3�)�aEo#e%"H� +���"'�5�mw� ?wo� <�*B�(�< in�M��*! "we=:f'm�X z*��� PA��.�a�z �%*S!K2@��!&heN��[�/ o 9��ng����6u(_9A�@���y �T� � 31 y�  ma�Eh;9�9lai � � �CE�o���le shafaRgTlxp�%H ulce� ng}$d�)i1_fa�Q��2Ea��!�5\�al�.� o��h%Q�]�2�/!1 IgM A>}K5� ��"�*�.Eo3pڠ��ذ2R.��&6 erva�9.(1� �(5A�a�q���rfl�x,FT<� he�wy�- -�ve1@(P ��dE�0�by �,q7�6 ��&\0s@ �nq�of6!���c��2!�4alUJ nds1nei �/�CHI�!8los�{bas5U�ran�uIn.�1�1!1m�i�@�$intac!ddespite"�*~�)�%!�I�A�gD�"�^c�:� ���ful�=ick�M��&�Eb�44��F�;�9�-��PCR�'!-2�a�"!A��� �A 2%dt�C O..4a�to.�Bei�of120���J1�'��L�$?�d GFP-"� �,*7 �$ ?^!A�itu�9 Z tI�.�m�> �TA��/2 sed��8p,B7IDc5e�?M�ie/�$^�� 4� a�2�of2 �!�k c�� ubja�B%W��*3h.�7 �A�,&u�[in�2field$be 38%{!����P dens�?��jp�6SC loweI6a�)�e �p� "��hk pane�~��  ��incd.�6�4-�i�@��3a ��r�f *8 ����)��at.NϤ�cycp%I*�V��&De-� ����- ( 28%!g �)�� �<rge%!X2�C��6�G�}6y�a�i�v&rep"�9*�%� 8by�a 1)N� w$`a�(dh۱�ofw�-��� � ��#@�uPA �����z�� s%r�[3�7oA��-1�2 �-��H~AbM2EN sihr�!)!�( �i .ݞAn2An�,�rar�!.�ur,surrout��.oCi�E���+A$!MBA ����(5<,6/$� ��-%%�j�M��l:eqg2A�!�%z.6�7B�<���!%81A=!C6D�sF�)y &,�>+��� N �&\�H!!v"'*�+��1҉�3�T . At��.�z�"Bu3ZCA"�RFAJy�ATR�67% }ea myM< �E׍�U9Y�{ �!��%Tq 9fu��bGFP�6rI[� . Grxnan 60�y:!0�$ZXt�8,.��Ei�z_�9m me $�>s:���e"2W"��1� ��.�%I6� ofte� hibiAwa shrun��A� occa� �3frDVorphon &�E�E�C��w.Bwh\ sy2��2d-�)� 3��"�1� ]� :�555� !�NM>���^�A���?R�1q�'S|�%F��4k :�!{5�� "G��' �:�� "�36Ut�t�� .��M.G(].�Z�.X�"�.Bk�^g�6���aT%N� �act�2Q�Amme� s adY toB�� �4�&�:aF �l3/!_�q�%��@%%�FDc/�B�� I�Y5O,��#_ co-lh.-EEk5�w�3� ��J�,r  )���yel ,�&egApink box"� 4(*��JV�&1: 4i����LC/ ~9JluN*t:�d��2?10��X4��Iv}ckYp�O� Ve%(5<�/4,R�( <t� �)-��e Jin���5WE��&qx,A�'*a� �� T22fxp�J����4���8ťno� �ing-�>� i�6�.� �3�2�at� .� � �)�(�"n1J�"K�Js*s��6*3 fibroblas�aAa\9J ��f!�A�-?r ��"o  V/IW]� e A�ia����&F � tic/���I or�f�s*;!|to��"u2�idf L�d�+f@�� �$F+#E�6i�b:^�me�Y}!Jdi�M�  ( S2e^a�)�|mV+!#Q�&��%*�#Z#1Z26�)�.�T%� �us.B`�,Ů6�!��� Appr�h ly 52�)�% ��� �ҵV +��rH>�J]4S� � ��A ��Ah`l�6*�)&7%>R� �� smFY���!�byva2mM���>"ob<B?"-�r+?onV�?%�2�e�df��A���25i-�M faIB,�( �a,z�� ~qJ�.h!�%�s.}al�;cer�-�)�5y�V�8�x�onf�fb��:p_�-�i�*1��ataB� &2tj%.� !�a9=�ECI&��c�!j�/� �U5Vx"{*��Vsb7*9�2��7js4-�1�A��!7��_�O�al-�L� %P d"39�xB6BM�@ }�r�*��D( 6�!N5( 8�V] �5� E)y%�b$�~v��d*�B E`�]M_��!5��:�R-.� �Au�We�u�!0� a����%�2*.�/.>t��  ts9�a-x� ga�^�>l��pi<�]�et��I2#S3%m��6�4������ �sRi�E��9o!or�!hRj.��_ȉ^a>] � 6 6"� UG"� ,a�:F�,��GF+/2�1 �U med:6I �� 0Xa :~ >"� �N0t!E�I��(eF� �I�Ag^:,>c of9�ax*U b.Cl=V!�"�  M3�11�-!�-Z� �G$�0a�no�� � I�iui � V�a�gD�:?i��ng��\�6�(���\�w ,f .qU�!$��<}ri�Z6�Q#&�-�w :� \."�FtowardsJ�or���/.>B�Uq:�}Awe8��&A���D".# ���n�*�! t�u���%.J�z�p�3� �6w�'m&{ �"��jAQ��h�",7�$�� ���v=R�v:�&EW"�7/2b� &�� tQ>��Kjc6�"a� ( S4E��,2� V&�A<ed;%qv'.� litt~"urvxO/6tt9!� <�7� �a*�:� X'.�%~�J.2�E�^�as��Op �)�Q)�A:�.!�!����e!D!�M��&L'i�7i B�NsE(+ leukojUm���/��r��!�Aw1`ngE`�reI->>� 6>[3�'3QAm�/S�(+�(��M� �M� , 26 �R�*!23%B�a �^sT!Z�Եe�[��.ly5`��� 37%��F�|36>U!Z��(=�t�6(:��'I�<MC� ZroE no?LGa �!�t���&-�Uwatm���!�A�n� ne�Yperv� o�%�[E�!�I� . Ou91�O��i��N�Je �2�� �NrE�7� �1��O*A"SD�0y�+�N�nM(!��L^�:�  �I_Gr �  ��e�M�d"�]"9� ���y�Et��8�OV, ex viv�^Y:JK n *a"9)�}�s�" ,ͭQ:oe��G*�( D�Da� nd g�  :�(l) 2��'� 6g�ra��5�� ��(�= ��g��za�becx�uOQvq7�f93!�6�]�ngW~e�egu�! ���9�Bao"!�C�ie5� Hv *:\!F�!B< asa!E�� �5^�,%'Z�HJ!7Eޕ1 \� by2�! .u3��.� ;=)!�in��� �A�.: U� W!eR� m�J0t 24–>�EZM$edM�a�" E�A��a( "nn]E| �gT. U&D>1e"���"n �q*8R�V�!:y�yL�AE4–���a��RtG6+�LY�oFU�m�� �4�orOuP2t&ur@S�W[�)34^�IP�A�,d)`65�!(� omprO�&%,�D1:@))�5�A�b�'ű7j�Sp"/$ cycl�i�!Gnee�� �#G e�6�t\� NS�C�JeN C�E��1#��6xa)Zf!!$Ѹ�e]"�!�fat��5 a/t0'&i:�o d7���9s�.�]�e:r�HolJh�R)�y�tVe�P�BM"4��cL>�MU�2_� �La�) A�of MD��"V[35Y�W�X"�� Cm�%�[ �J�"��6 ��\�. C �.��iE*�b�e(�i��&�� J�M�,��bxU2}[3WSFVmDE,%߭e���: �"AP��"�le��C>�-��NsIC2� work6 >�r-]S �i�8"� �.�2Oim,e-�%�. S�����Ln�nreflect �(ent influen�@ces on LCs successfully emigrating into the dermis which overcome@effects of HSV in$ion per seb matuQ�on , probably via cytokines released from Fed ke9pnocytes . The key and unexpec' find�@of this study was�n�einterac�2�edSH/or antigen expressV!"(with BDCA3+% al DCs50 also DC-SIGN cell ��@ometimes involved�forma�cluster%Ias many10.oof eith!Z0ubset closely�ng � HSV+�$or fragmen)�them inZi�!�>�e!3 bser�oc ` such@% �Dat 48 hr p . i . I2k,1D%=re moreAD0icient than o�typA�f+(�0macrophages )!> cross-!�ent)K`[21] . CLEC9A is a novel !�v $C-]T lectin-like receptor I�4is constitutiv!b-edA�blood.� [37 , 38]Eknown toVognize~n fila-�Hn damaged/apoptoticM5 L9�Un�BpD, our results showETat�A�notr�F�but ,Mse9�, appearePo be induced by adjac!�GFPIs)CEAe-; ing �siA�4rker caspase 3e� us , skinJ�differ �i�1sa�!fB. More�� ,� labelledE�pUL37%!�det�Ea�zE�8nd co-localized#< langerin sugges�)uptak�c�ed LC}y. A>,��0/s lostapholog��%Gq�ed!'o!� firm��i�I�, we uA����deri�s isolaD�d%gfo��quential ���ofB$co-culture)R$. Collagen!�treatA�%]��8 v im�e epi C:�to avoidՂ on associ�? �9reI��� EV�"9���2cbyJ[a-co%SI��A�BD~unWFG ��� abdominal)s�i!���,first report!u� viru�1UO s undergo�yIby humaN3. Fur�MinvA�g%?s!jdefine�$mechanism ��neededahfu%�.J�E�Iy�5eI\HSV-19yexpla�� , similar�CD103+eiin mur� models [5�� They ku�ͺlow�= hamb�4transw�vaftuI�A�72��,a\�I�L5�sample��only wh�8allogeneic PBMC ��rBthe6�1�!�at�0-%A�of.Hor bility �,is faceby&8 /chemC secrea�by�����G��ed exq��on!�4:�,�@ a+�F�[40!� b:Am �8�  w%I lyAF^in!~ system!��t�]P!biops�.in vitroy���. Howeve�1pattern!���e ��;a���)Ɉ�� os�B�/ ��DE�atMmolecuAuiNften ab�- A/ �+!�( �HMga�^2v2�a�degraa�w rapid!}u ��� �vsid���)GL+ F�,14:,�1V ithou�M�a ,�M�a u� u� fore6�"� 2%Cth� ie Z t���up� , be� l!3 pass live��* onto.through%�9�%�*_ It� vide2 �lanIp��:  ice carry��m2�-%�� principal1Ƒ�F� in drain$lymph node�lF�mayD6�pre��ntA>o CD8 Teac`��� exact rol' U� DCs/.� ���� in ini�)�A8��ires f��!�5 t�8� �# � be weak� primar�9� ��)�to naA�� "��(:�?%4B.:� be sl!�!���F��E�ELC-=Ex2 ge a�8response!�y��or���s�ow doeAzis� hX occu�e� ru�j� inva*� �s �  ui) � Vari!� a Zo6 �S? Take�ge!9concluf- agA#A��in A�-�%> .�A[<"�%� ‘ 6�ay’��j&�!��/rY�s!I.,"�or&Q5�s� �� zyA&�H �[to�c.���� .��%��w�tself �F��ilt�2�E:% Auseful����Ep$lia tropic5�Eh'�3� M"iH i�hex vivo.qd!4qa�o�! dynamic.W��&~ A�s encou!!�+f.{."�, as at aY t "�l�� w��� againsI&���Jor dis�@ticula� arge�>�e6enhance���Ga��t��[!� o candida#I����� by� unitD� e . g . �l�Qcombinan� �)e6z e  %z� �Fd"�LCs�adjuv$.YAn im��t areaqw!��ofAra!i!t asit��=customi&�� sitophor� acuo| ( PVOb� okary�or eui!Tomicroorg4�+WT re!�i]-��PV�] � i� u @mouse bone marrow�_iNm*� expo" Rar�l�e\$d amastigo!�a�a�97 >t.9.1 �, rmultidim�o3 imaga�of�!�awe com!�Scha�erla#2x/re�K I.ai ) ho�.�=O . �JH��iDloX�h LysoA�kq$a lysosomo��flu�4i awThree��fe���=��-�1y docu�ed:�y rM�� entr .�3w� ��2, fis� -prA 9 2�)� PVs;) !d�Uhe nu�!V9} acidicZ ica�dg@kPV�N�PV enl�f�;a(i%�uEamY�PV ] ih!�y�+fu�M hi�ont+ 2�R��l��up� ng���st�� �y�� ies-fic��c��b�A�"� 'T`i[ofH v� 2��� ; mammalianeġ�I���}ed�,�Ks�she���� hagom�estruc  s caF�M� PV�bra� �MQs��> sa7Az[!�endoplas�reL,um ( ER ) , �$F� � ��� � %i^�&ele%(�er4 J m di�c�propert��a hybrid� $e [1]–[3���+of.oE��iZ A�a�/�n��a>�enc� tin%),[display �des�uoW spac�PIn� tras�!W�%Ft� -�1˩l(�exicana�clex�� asa�T,} lain��e_.�, �bE�� ir p� �p�)�A�er��f�W ��[4!pJbioQ vwo&2!/z a��jqui" o�Y:NmeI��k� ,�<�2Zim~s��orU�-.�T�j LAMPu $, Rab GTPa� !Lthepsi)$ton AA�MHRass II*A[2] ,�–[81(a6�mx �!� ordi�� d ev��ErX!� “m�”a�Q�is3um�$req�d��j surviv�d�3 plic�)�]|. Beca A� relaa�lyM�" thA?!��a�wmAC be easily�|"d�� magn�] �,B�!a2�dhav��bIu� �tu] �fusA�ic!�=6 N�si�շdeml#�d�{!f!V each��Q���[�m@ &] , colloid��inert!yts,��4���ic>� [9E]1�a���!;ea�I'�cer�R m%�i�se-��f incr= �Ad@'� a�a�[�$���z !d�incorpo!Th pHU���*� � neut� red � , [1�$/� d� pH-s� A� dyes [19e�2By�ad� agAL>�" in�s 2 *t�condi�%�f":!A8��!,pH!&A�.�!fa�' $approximatAe5 . 2a& 24 h!�4 . 8" �&R6�&��e!�~se�\��of ar�o4� a@i&F �Aon- [�ontrol��-Zq@q~7�* i�m�bio% ic��fu��] Zh !,�mapp�k�A�6��� � frXdg)a aAo assur#to)�go r �wm�es di��', [22���*i9!of4mm�cr2sE�}��6n� e id%f6�ir!� @ hi�#e '! limi!�_are�e availi -� tir�am�1� CDwyer).B�n ��eag� [23]&�#by� c��� scop"ai)$orium diox�(��T5 ��)�5NwE� pre-�in]�DreW_ Ao� smalW.� A=( . donovani�E^E$,��'�"E�)e�r�0!wit% w;6[2� ��#in@+%�act aseM�-�'�h6**T a/can�� y�� � gh%reA;���al���s acc�gisPV. . Ad�a J��j2���� Y����,-3lo�"I�es>N !�5�_W#�z�*ᝁ�5�62 �5խ2� M� ��yi.bn6]��gen@has�ob�\ix.r3�,n fix�< &, a� wback3sough4* over�!%��%�ye&�a�6t M 2r,u�-� :&re!� �URJ$ An� �����)aF&H6�A!���� xu(�.A66j)9�c�QD J-two-step�G�zIJ2k rep.� . O Yl &�s�ɴiu� ��E� accuo�b� am�p mOf��i� �5c7ni9�depleq�9i���6r�*~a� vt $ly describ� =�I(q] [2�(:PɌ .* !�� 1�!�revea��-z�"e&!ivolumdiame)��deti/A<� A)�@he )Aa�uG�y&+�.�ρ(>o �U�� ��� rest� �. All2� 1aani�)�!��` uc�[ Brazi NEJ$al Commite�2Ethic�H Research ( CONEP )�French>=6>�A �Exp�tnM NREEA ) ek guidel "K  a��a��e ')&#,$ard&DCIOMS/OMS , 1985 )-�6�!h� =4by CEP/UNIFESP�Xomitê de Ética em Pes4a da Universid_Fed#Tde São Paulo/Hospital )-yA4� ocol(ber 0856/07�ALB/c%: n`�&( 8 weeke�age ))�bas��rc�*'.� precursor���$"M}�a"�Z M �RER�S�#.r6g suspen-s e,V2� v{*�f7 dayIp,PMI 1640 medr w�10% fe!SLcalf serum , 5% L929�E�� edI�2!���e� ��Ds�Zper� prJ� [26]"� month���m.^�%�ad �%��9�C) X a2ofs IE,� t 34!�-�� D te�LA}& ��od*{ ���YL�3uT1-�wa�'�& Hanks' Bu�5,ed Salt Solu%# mov}1.��6D>���;�aY�. O�8�PiW7>�e� 9 NiH�`�mj star%^fK 1/ga�E?2�/ depe�:_ jFmaieVZ�!^� m�v,��.�.2�o�����Eo-�!+)A 1 a�th �75%maldehyd�Sph�ate-b1�sa�A!BSe]�lQ a_ !�ar= �]� I�7!M��_ einsɋX��2 (aoocl��%bo�%�$DSHB , Iow&�t�*US� .�B.� a� �2�!� 2A3-26uy�jug , to FITC (���$%��ErN4 rina�ng: PasteuFr ��iuH5 µM 5 , 6-carboxy.<diace$4�:-midyl e�'( CFSEp��<,, Life Techn[#iY;. S 5�.�15 min �100p 4′�k @idino-2-phenylind�/( DAPI�~A6� �2 50% glyce  BS!nщ 0 . 01% p qene�n� Confo����U�Da Bio-Rad 1024 UV q4.d(a Zeiss AxiaMt�yu�YaA�$ca TCS SP5� H. I��s���%�aE0× ( 1 . 44 NA�oila� �bjG v`$renAI?0 Softw\ ( BitZ2e AG )Y �Blend|<ter�LQ!mm��!�e�� =a Nikon!%s� IM-Q E�D �>�5 ( 26��4Perkin-Elmer U),View RS Nipk%isk17( / .Inc .* ttac(.-:>�200 M.�%(Ha Hamamatsu ORCA IIM CCD camera�oYon2��nsrisVdiscar� *).�.IE� $W = 39?469�Aa�TD, 1 m��-d�#�averag�A`l wt 42 , 000 , Sigma-Ald%�)EU�R��7aAb�$pulse�mo��� by 6ShErp!*>�'�&� )�V�A��� �rpin3C,@w.��2,o>-p� �N 77� �Bi� xdi�ph�&A�eA� wo&�nt\nnO1(e�=�-3I�-labe�Q�tw� a 4�<��8�;�-in 5-�Aqrv~5. Poi"�im� -lap�:! �){�}cs��2ur� inu�( d:hh:m�5��-� ��c8,e�^byy�*pr�5 $Acapella s���L6�$lgorithm-bPFqu :�s.� du %&JP2J� I }N�!�aLeV �>� stac20A�30 op�lJB p5� �"�!�512N�. S ]al�8�z- axi�z- zz" Idn>� *� ( z-Q_� fE� 1 µmD>!"� �&|aX y� post  A��So�F�beganv Iq2� E!#9�s;� 6�  or� !�N< we c�=*&2te�.al�6as?��>�N60ead �+�yio#͠9Qc��.S);��-i�BU%�i��Pyva�m�. |� st*E�p: SPSS.�� !/;atCX: ests&�� �Ic& ��he figYDlegen�#mA�A%xn�H-ba�. of n,�<d 2! 4ribss;equ'  vari_ ANF~MFSg same�ul�CroiD�t �Jt 2/3�=�analyz�N�..� in 3=�&�Tr 2. quip�, s . L !E��'6�"� "f� �*�pa'1Q!�ntZE%s��!%�yh��a"�."� orig9'N e � a,!�Dby2�!v yc*�'U/��'�.�*��e^3/"�(cy�%]7wv�� 6�#,� �%po auti*�.u !�nM e!�.=` �B�h*2,s +�(71%�&i0!�F�%"h-=�!l -cyc42v �3: �*groupR�pC2yaT�e]2R!s/ -res�m .&a�*Fa�A�; &X$�l��&�A����a<�ta �&P,t5 expa{/re� �;E`J�UH,mY�"0ntV� *� �d�>ak!&�^method!y�.mit�iFxe�!�x 2si��u�� ingus BHF:b���6BhV �s:on:�>co�C�F%�sok!�u�L 2x *!�#�e4���<m5�B�reINoirw �i.� -:h&ri�toR��%+ed&b��� develo�F�2,)` n ex�Mgr�,�+a� ruls0�Cg�Ja5� . So�J�!X n8Lu a�.,A�1q"c5E� EEA1�#wo��*�/�,;aXBR(>I��:[J/�s,�8 @grF(�% ?at&f0&� &. p�1h0b" ` a� 2i�!o,��*N �ns�p>a� NBn%�6�3��s�}&�!N�)�!����ve�46�.�@�$ ,A*Jd2 Qba�@�a~66!Qup-reg �of�lipida^syn "�8 rigge�/0k [28]-"',`reu-o!�ofY�%�>]��~.a'is:�_a��� ��of ge�9)S�f����O A��� *b[29�)Ae:-�"'I�� (! meanET- \F� IaWnd�S2�H9'u= inpu:#to>+A*stak*as�#*]���continu:.�ER"� or GolgiU��-,R*> .FN�J#4_Lci!�.�A Ae �B bb;C:<:3A&�$by Rei *�*!9�@�QiSM�24–(V[16AF6h$|�1Bc(�seldomY�� deed� ppun��Ql5+�6�a�?Rab5-poA~ve%:"O �R�0m&�[3'/�'6�Nud�5�S� �su�>bQ2�d�re�>�3h, *U2fq�W2�m�"� yy2re} >2�*@ &?+a!���W^*:eG%io�3��". /�gal& t� )� 7'!�CNDirA�e���re��T eluc3?RShe� ����-k ^"�2*\1 �>� ( � ��)%ei���8 surfac%A�3yt"8ok>el� s�6sERm�*��l !$a$ategy� subv�25XRenx5�� nviron�̥�-tG$�S/DY<���hydrol� enzy�[� 31?3358C� qexݝ� �aup!��7� �H''�+ IFN-γ–^%� 2� �%AU!Z�;NO>�[34� tuniqu"�U�+_<�.�vi�%A�;e�l[ � 2g . Re!/3 s*�=-"i>a�� M5�+T6� "�!�SJ��o� G/iY<&�)�ou� :� �A�F�/�D�^�� e$M� ��mY:)� 3s�?� ?u� o� �Ment ~U�N��f�੉eBis"�Z genu2h�6itsZs�Kc�435Ai$] sAR�K&�%U�� .�b >��y1g"g&�2~�#-�&A�i�)�AV.ha� r�a viduy �� at� �6!Gir.a"�8*�st�G�l voidNG.E\�5i�3�;�$1>i7t� �� ��yh*zID6�l� a&B�=��MycobacBum [3R��A�es:`[l�"�Afmo� &� �*�0�9r�.ng2�M�  ! �v"��4O* *,imvO�F 8%���4%E�v�-.I UP]>e!�XL +!ry� lK�e-� pancyE�"Ka-�a-teɵ& r��ly-q��� !U.�iIO��Z!=� 2�/I�AKe�[4)v�EaZ5is?=a�CM@ab����wpo Q 2�'. �s�3�0�%1�5 �dah����s.�sha���PV �a�,� l�C.� B � 1970 a &�5-�:�\��1���. d"7D� �Nro2-6R6. AՆ�E�!a�C*��! iQ���sa�i�(9-"� by�Jif0 !6ur curv�=u h phys�lyH8 ist SNAREh�;y�G` [3�A[Xi?\6�[ erpr=%�u�2 c"�an%j���p>� �b_�]� o!�si��� tspo�Z#�prefe�i��a��#�� nume+"�Em>��zY�!���J�F:oi#Wk�;*) ad �Mm��{��?6 *T6�4AP,[pAh..]4�p 6�!��sb  ra��U|�K<)O�1unt��&� aof -+BGPV��O,�woS�hLas{[FT�i��3�cF�C2G �+�A2RX� !�6Xi�2�'m;L'=4�!�ap":=Bh16R� �2Z;Zbd��GcP&L !)��;.j*�5&� 5�MNir.P�rdl��m�&Y!� rchi�V�&(:�v�{69Y#aa�rg[�86T( 2�G �9�5" Xz�I�ly3&���$:�*(Zi���5,W&� gVuJ���um�'3ET3!:���;e8��m�*Hr]X :�"X �� Ad*�V6.V2�2�%�&addh9liqQA4e���]��ERy���i5� of wa>.��F�0�NO$�a��re�F�Lx�B@%� &!�serA56( =�Ppla� �H]u@�0skq3� [38�4gB:�=<�<dnu A�Z��:{a"z ��mb%�e�2“clea-, ;!>�q�ga1.z!di�e6)F*(by� p2}G�Ja�j%�*� s [4t@i"c�V��e�b�!�vI+=L�<��E��]tA��$hE�A.����#<��� ~2B Lk�b��,v>�Q"�� \"����� �.o�d ��phenotyp�-A!����Te2"�}li�ZJK� "un t�>��)!s�M U����(�>P>�>�agA�5 . S� x be�4or #1-W. o4AK4��N.YM=c�T��*y-ne�eu�Q!0�) =���bunV:of���Kr*FIt�!�6?��8Osorio y ForteaeM*�[y J� �e!� iso� � �NvsublTs�r& i,��ph�k� �/>�=^;A�!�e), Grego�_�i"�\.��cvL �!-te*hJV1� H�.��)�.�N!_]B^$.�!~V0tA2\ down2 ndM�M�a :m�\G_w�d5�"~Ral.�K�z����J6)�!� �3�*2�/re>�. Non-.�y;.��#52��}s"�i�E�fh)�:�in:�r!J[4{IA���|E�Ah)�ae%�K�n2tb�� Y�&�7&��4*8$y^� �� E.=�[44B"�#�5)fa���`re-�%M_5byfTU�!la�q�ݼ!%�y�Y*�@%9NS�ir�pq�L�.6=e�! ivi�'��� niche��p���\M� 0�CS�&Z*uti�m��;i�A�a\�U�!����sqj -Fni ��� crucY.#C_w�?N6`w�ev}? l6ADO^{5B׆H� ogcrY�%ir�0a pk&\Q�bQ���S genodR5��+ske� w ch�St�M��)�s� "DI�, �m%�Es'A�r� �u�! chic�^B%D p( DT408�Q�$In ,)oglobu�>�"m� _!ed��I5"�-by4��z�9;y pseud���n�.�Y*!�%��Vλ.9array!�*"' hist�{mo^=�O!#6�� =}�d%�kD.,O�JQc%�N���!+.�,-�]2%7 e"n(z.�4��mh oe���M8HP1 ( Drosophil�)lanog�8,r Su[var]205�T1"��e< to Esch�hvoli lact�Hrl�A,!Zte�d4 poly�!d/�P� te�vRf )� -VλI�-�. TY�dimin�'1�_9y�Qox"FP)�� ej�^nHofE0diE�U�, s)Kat�,Y�muN-ne.�&N "�i� �.9�y��$esa�FO@�r:���1 6���!�.x�k@#am�F#g<j^�bx"�$t[P�R. ��i�A�^8��v�waR(o���  ng DNAV�9"[1–&bk�Xre�t�Y:i-l:Xt abrsjI=�A� S/G2��ihell"��L�� ��dsP)e�)�afaith��j[8 , ^%r��  j@�Q�SouI�%�G !76r1�no!+eliJ8peE�9�,��XoU �$Q ,!��&�� hp�� aQ�2!8s26il�g�� zygoy7( LOH� I'j*rC ,Lo'tA@&?9a�a�� �D� d�w�hor gple ,L=ndI� DSBKABb��U� non�%loE�end-jo�m� afb]+c��J1j �r� ��[0>1�71�Nil4 �efficJKl1V ���itu5�short-!�D4-patchQcl u/��U!!�l�_r!��-�EZn81� CM�n}�pl�/� ��t �B�{1�Y1 alerts.�checkp�8 �)0�X�vA �AU�G�9!B�� ! �e@U–7 �'eb�` �d;{]" ( Ig ) �>\ �G2h �A~ &6;0E��0�j�C Rs7�V&�c*gX heavfsd li �w�7�?( V )��!�o 2 go VY ) J:56�=o%m�[26 , p5�re� n�XV%%��pOCgg2�qceB<J1, ��an� �me�ups}m"f  ( ψ.�w9^(�8 1�Cw ,��Tnon=K�0' lackQ�3V�anIGU��R W&ofA->�mad9^A�9� �Ax�E��de�hsi�a burKtmom>�F�@U�maIg]Ig2A�λM�*j>�[28–@-���supPsa4y � lq��]�N&k�kou M� f�,#v� ��C U*�A �`1� �>6�a E�[3X [.��con o�d �;J4s upon ubiquit�7%�"dy)�Wt�'e�� �4 niI&�::~9g).8~h6TB-!�&�f�+���-�dea�~s�BAIa�[3�j# ocy�s~ o ur�]Eb�}�nd-�ed% s�,01];4��H osylt exci; �y W"�;by�.� a�G<c��`6];%aEMRE11 %lyd�45]���m,(/RAD50/NBS1o ,%zs��T N[  [4 4 S�di�f� �<ew�&4��}qd� �]!-�1���}�1mlog�a BRCA} FANCC ,Dpolη [4- 5z De$ �h!�PA�t,bt&�nheFy� M-!�de*�5{+a[ll Y��&[56�imeG>8�� 6�a shif�3�A!ofA-Bq�,s"�� d1UaH*q � ven�jՀ"� 9��2 .ʱ�:�%B�!��Rp 1U"׆0 � �/ , � ߅�lo�;�so,.�"� gu�]�MB[5�w� A�othXisֆab�v�9ep)��!&�;�M">af#6 4I�zpK%�R8 C�-2� � Mp�nJZe m�w!�$-�6�?e*�ly BopRN� � I��� �6n �6Ţ�:Mψ"�nnz� E�' a����nt����uyN�%eB C.�r���#�f. �!aю%#"h��M� �v � a)4r)� n�L olyLacO )' # 1l�"oaS Y�imu P1Y��C�e17c �silencA�[5�t6�5%=ed%�*dSe`��&�#��I��s GEkw'yonpu(pCR A~a swiY�y�to "F A ,� t�I@��� wT��9 *og�/�1.�M� ݡ��Hrl :*����6�N`�� .� 6$ !#�ag�A��h � $� H/)(��J�{!�� � Ft��"? : auM2�tumC�`�2.0>�a�C:�shv� !a�ig�#)��� ��]�A�rapy . B+ �LA��y)� rr" �� A�t/!���n��3iIunr&\ M)L# -��6lN ;M(��n�2gU� lle�"�.u%�����[i�\a ( ChIP  /.e � ;JTTspeA5�lys� ��� �N-UiA:��H3�H�[ReBZed� wa�1pY�%up�6PCR!� s;E� very0�F��3n Ac�bro�e tMbuL( OvaI ��Fisq9���� s enf0�Nr to"z �&} ol�"ee�ZeaM�1M#CI�d�%ls%v�"�&"j*R%8 VλU���"�l >*Cby%5%�5��.)��($ C��".e� us=� ( Ac-� AcH4A��!�qF VλR�jteta.�` ,?3%a �7��%80-foldAYM�Tq%3 %&JB%]I�WU!sg �%Gi5��v�N 2��#mS$�9�atBR�,6 � nd 7 (y�l��lB$�;c�=�� Ee,��,s�8t8� "*L?U ]!i'-M�&9I��e 1\�>}T~6!�JSA�J���s�y!/-� �j]7sp%�nax���� �f_G�U���uniA(Yf$ � sE e:J�"is-"pvey0 .�"U��]��;f 2� JB hieA�L� !! y�cb%;ngM��2pr@>�"�"C �|rK?�,&�� �!U�!|� XP ,���|A� #( LacI-� �j��;ww=k,`Y !T�Fere8s n�+b4!adO"ea{ *�#[6�H6|uW6�5�M2*�G9)6% ethy.�Ga GAL42�%in*�#e��#�*J-�:��r2 �;�v [6�� laboD$y%�r�:�)K 1 �,�V�-��U!4!��tN�2gEH"��&��� A�6�7%�e?2� 7 kby��6���42A; M . Yabuki+O�\aw., W . J ummi2e, �BPa� arso�E FujiHeQ� .6n:� / 5 �� �`8�in lengt� � m��Oa�x�s100 copZ 20-c\ & [6?+U�I�1�� ?I�Qe�Z$I��oc:�CZG,�:g� �*Q�uCy(��[, i?!�H ��vۅansEU�. 8:2&����c5ntag�if)pro\?�C , i?or IgI�>�(%��B�B��-az GFP-�� � �Cy!#�5~�d�]&JOs�((K )���'o� I  a�x!�tag^}a ca�L&�iVg=ice&�W!ag�*��do�{i8E�y��bVDeriQ�v��d bri�dY<lce �:GzAnhh`E�ecμM91~4yl-β-D-thiogaz)R( IPTG%)u�s);� ��<�6� ��"o &�V�| ��� �eE��d)����aGY�k,�E9�%�D�E.�*�m��[IYAs�.)��"��^ w�� 6*B��[e6 62a��zde� � b��Ņ�6��arTtɇaA�%ws"d5–6WS�AdFz5<� 5� �io �*��=co�;vd-de��V er���\oYi�5?>FU�3�, behav�� "�6AV>C[6� To ask if�H�*,N� �Őr "� . � e1to�U%$z� ����'m'a�a*{A92r��!;�Q} 1 ��Tby !��&�F�es,��"%��6Kx� �"n �j! λ178..Lof �qcA)��A� m�ed1�`!��)Bq5�d�6��%\ 17R:r*� �K%�7&�( ./%x.��6E� Ved {m2{!�{w9 :�,!���F|�/ ��*[ 3B_3C�cR�P)UO%W�/*bDi� uT�( N[(�.^R.��F!l Key!�BJn���H2ne�arA���~oK 7,͢�&estQ  ng2�eho.,M�!6r\�"�)�C=�te�si�^~eQ��J �n�� t.TJ��j6^(�_6sb�hN6C;N V�:i�HP1&k &N�  K b�c�*[� ѱJ� Ies�964 H3 [�n, �!�A~�}�me �# ��7+)���]\ )�%tс �ev�di)G\wth'27�p.�ewr�w �>m�1AH35) �2�(�7A � ne�Di.0�N�4 =)�P$MeK4[H3] )�/as6�4E+"&)�ege�,exhibD,�verlappa.� 6f��2w69 , 70!TAb W d� (�)u衩2�%�� 2��1�f��u�n2� ��|A$at  |"]n�qR?uG ?��6&#  �Crnq`%D2�F+q#To verif��&5+&�urwk[ "��Ql s>�K" w*�|a�!er6"V+E��� =1�A�A��oX �@ata R>A��d$� . e=b�&&� ��nd {��`�*�\'.+O��es [716$?� enco�y �� mM�6L�Z 1 Mb� ���!no"GFcU Iqq���� �y��S�ũ2�U]ey" .#F5Y���x/:�a#5!!4 ^���S"��t �aa:�V������ύ��v��iJ��@Ig�i "n 2�� E�zy�,"Q8UaE,�6 .�3��Derc�:�#��:� �"m�/ dopt�"ess� m2�"E�a"<)��P1%ed ��%� -�&F b�k �1(6��hk!1��:<��4� f�9%�f.�!,2e40%%20%!�mv16Zq&� ]gre69]2� � �G IgM ( s)1]�]���-��.&gɧ�o�@-�&T9��he-�ca�)�� R����F�u9� �S�?9 !H�e�Q*b fK9�B�V� '0in RNA harves!pwF���)HiU6� β-� ��O�!��ENo �#�T�Lce%d�%���:V��H��5S&& ida�"E!��!U}2/�P1E$ a� ")WV��� \ U.6I *w*eam"1,�g/�Bdc=ax"#.�p �e �/R�&c$�B>"5�slA�� �s@ &a.C\:?0>�d)ass�I��7�OAӹu� � 5@E�e�Fi�\R�::�� !�NF?�Nin� �A �@-�p >,ix.�I�0 k�edE�. L* :� ��Nr �2a#%SA&�%� *�fiAʁAa�a&�.)86U ��-De=�&� 24%!�63��6�%W @-.��*5A��ark bar�$)2!�YsU!"A�ceT$a�)gJ&�. l�s38�j� ��u�}fF0Uq�"U L3 \� 250���Ud2� �&3!W��f �eduj)�7e %axliz-(i�}z�I@0!G"&6��Z�S)/28�o��%uEWeS��� %455\&1�F9�1i�tA��Nan5�_�ver 80%��8A�B�qF{5� s�*vfDE�F�I�Z�^l_".~(.�Al5�q2�N.���5i%�5ť�6�}) I5Q* �18ep42%�1T%�!UA#!468�292��[>!�}%�EQ�f�4����v�� eBW}�.~57 �y'!��F�~M&��%vU�par�V}r4�he.�Uxe�s�(�c��%�2"�^��1E�H�r�rI�ŋf�B�Tos/Y20Gr�U����n;m"Ѵ ��no"2M\@��2 V��E$h )' �B9n22D&92n5vqks 3–+Ge�Pd � q rect�Zk"�1a9!��pinfluV s"� *�/� �$G 3C�qk&����Z��3D 1� D��Ő 1B, m�*H.g A~�luctu� � meas�W�f �Kof��M no�Be�C] s5�$fct� �7t��sco(��5\�5-3aA��z��=Qoӛin1�[�75�In�9oc))&$Űj !�FU=�y"�dL �Mmi�di��v��@IgMS�;BQ−-Q�rach po5!u��Uzfa��9mej�)����" 4 wk�t~=�h�I�A��bod>�Zdߟ�I����z��J�A�!>�8لJ05I 0q� 69A�c"9�M au -ccele� R'!j�X:�I�� p6� .��V�(^|#J�?LA�?.��J�>(*l4U��"iF�3�t�9eqG�f� �F��l�&�&W f(%�*�9���DD�..�n��mp 7��0�"5H%��_/�*�9��j�| %��N�g �c���}5�0g��}���9 ^CxF��"�:�o�Hg".� �C��`�9ijF�do��go anyh]���>4U U%$%]g�IZ.er%/sj0&#e� �U���Q�2eōB�u� �"�/so�7�lee��t!�F�u#a�FZe,0f�@6�#"(?ingle?� )��N�1. SCBch� k��z�~�NasUIdaY�A��� C� c��(#�0`2b!�^�!7S�3D(x?m�I.x 9 bp���DI�� �� mbigu�(�"D�Ts:eL"A�!.�HlOtzcg��azy3Vq]d�n"Zͪ&�7�{. ;> ! 9*i(OANr<so���mIm��HJ)UH6� , 55=�r!�9. %�*� among 71e]��j � 7( 77% ) ?9Iq/f."8� 8>%��� left"�SmD2�1R�u@�F]��� �a� ( 58��^/ �L9�(�)%B=� ( 14 9whAHEhxly=�@���369�:h(=b�!�|%�F�)��qludA�a��c>��3�\�`9�c,D�[���dno��t�[1=��t&�%�risa) ���*�x�.iF�h�FquHqkI9a2F-U^6ui ��o!���� ly s�:( p = �&$5 × 10−_CF�Sr'ct  ?S%S �.�9�A�v� ?6�( ��Z>�1e�*��B�� 0Tf��2&y3at.6�o�~�@�is0R�6� A��Im�o�&p/�#>k�n*56�=�< �� ��r+  M�R? bynai0F, . G>� �85s=K(aL9�F]Elet � en��aD �#�0���(� . >�fs s3N.])!Are�< � ,V̷- sb a� 3by"B ��<y F"2Z�U&�Hktj:�F@~*� �Aw"��e�� e@.�5AZla~�U&�o'�g�g �*ǣ|A�) �-mg5 !KeH� K t�H-.f2�D%>^ avor�� " 5��&I��m�))�a�Y �� �  ~I[>�,� FE<A��?� ?.;� c%�q��e�& � F* iCeő)hA� � !H!tie��OJ�H�X�n�G� a�e@d})�a ibuWo��E+$alJ�)� e�c�a �p�U�Fcha,loop&�)y� juxta!41�n�Gqh1�G�>2 Ea"d��Z�A�p!L thwa� 2`6�$�V5Fe�!�M!vZR�*LoM$.JB&�I��om;H�h�N.�RII�9�-J�!C6�&B�0awo V,Anhn �gE��W|)�fb[�&e& *!1"�0�K[f�E.�!eng�>1#a:�N�� i�. H �.�"%1doc�q� Nu��<m"���"�^��Itic?ker��W %- F2X!eu�/ea� ;.�y��7pKm�R:|�yeHy�Xs��[7M7.uAQne�B��1�.x!ƅ|'���e"cIs� �ey3Q",�]i!���s] in�*�� -�{�`At'6Jome-w�4BB)m6� ї�N.�Y R [7�2H""K�8F@r�.�hvc�Y,) 6�~ �6�:��;!C ʉQ� "1k �!�E�2qFE)sa_&X�&�E�.e �t�+:j+:��� �y� N ��o^n(I��@A�il���vAP!"����`c�l� �lW�dVE�� re v�aV%�8I `"k@"�.;��i *�>iMA�#*E`*� -�l#M�l��LR�ins�[7�5ID hi�f����6Q(� millaPAlu�i�6q�2)�  du" -s�a^!�B�J���u��[7�/8���b`��r{c�E.3s���,,"�OpB�[8@1746?un�qte �mQ�:pAGA �; ion;�K�Os�!YA>yN  V =A�6M. �K#� [*un(�mi��6:1���34RT_ U�SmiE� $S�e�"��si�D ��� !��o� 3:n�L[8�p|�.� have*>(!�n age-&��� �n Sac� ]�A(e�siae [83���Z�E"QB^r"f germř s [8{�a�:�-`Fy��o�[�|re@ ��MM��o da 4�fg2�� ��*-"�� d�a,"Y � F&�c�viA�i:cC �y6Ww4a]! "� ���.�B>��1�@��<�Nrelax�Z�%�y g��01"/ .� �R� �! I�!so^m ���Y�rJC2�7][8�Ua?l�� )ej�!�2 �>rm la�LA� pept� (�&�!1�� LMNA�v\gki$?��Hu�(son-GilfordDg�Ldr] � e�H252q�H32�5[81 �vfyF�Nu&� bsj�rp!SLram"P!�C�7ȫ�c��effort!�H&e�l:]�1�te�� harn��D'�pa�J!- �y�1�V=�4)i��P!��oe� tact���<replacA����d�; #[8�n�E>"�� cSrH"��0 j will� �"`ddes^Qpar]y�O�*mB�  �eu�Mapp&�. 28� �h�a��N@�4#L8�gCfal.&N�bOhY62Ó%"�%)*�8j!bHC*ed �/e �:�.X+���_;t�B!�A1� �*�:fqS5�ew]9a�r>n��cal;t&���E�i��>�=a��[B>Q!v6�/�m�D��:�==�\>5!�� Z-��%) tube��x ex*#n� I ��"� �"�:F�A~T<�n)j Naa�rUY^>\>o��I��F !��8�y)96w&5Le�>�-��Dhc��*J9A�y+� &x�gelݦ� 2� ed [�?�6) Ab]/>Input"AmR�{*.2�?��#�69YH�1%��1�.U-Q%� ?@&�1)�!�E!5�IgG{!a�c�,.&��P�IgGim!"�9Ϛ . An"�<�'iǁ��Es:Eb-�, ( 06-#9~M�� M�3C)sMGCTA�T-Y.3S�ME�A r-� �KSMT!�TGGA8!w��AV!�GATGAGG)� ME��43ZGG!?TGTAGE�A1>ZWA�T��G } Z�M�".�v ���jm TAGAA��GGTA) O�A��AA �s��M�eNG!�GT!�A~:�TAEnavHaM1asO<OG! CA.Aq )�CT�aUa1-c�&S*�<�id�Z� + �d��ng8壥t[�  �y Wall/s (.:�N8ow Y���dB`AIDPuro��:YH�\rakaw�Mu�x]|l�~� mJp��L"7&�6�h�v" 8 �khe&*!J( p�� ss-E"Q!!p: �A|�elmontF��oi�4. CJ 3!�" ĥ�᪆� � F��+ 5%� .� !�,"S�e� |nj6"Pofu3i� e arms� ],iPg!��6�'Q�P��N��Nbrief ,.R� gr�L%�p*� [���( H�l}�%)AC��/Ai)�b:�i�.� a#�! � &%��8��}NnO �&=��Rwo� V l� #�T66�9.�[�zlym�X�B���#,6� "�.")1u*�orN�J ha���a7)*�.UBaQ.q/y,Q��!^a$4 %��H� 8P,)~2�)CF5��z) �u"8 w� up`50*�7�7 7�M�t��l*Ra�!5&6�B}@R��G �0. Oligonucleo�� r� ��M1��Ndea[��82XQoQ� , i( 2!&Y3e:cytospu]���'sl��/��"%52%A�aY��%620�V(& erme�G4�%1% NP-40-;�)��0b9�P,�/�AH_�� A mo>�X[1:!��1; � �/��3e];2tNw1cdone�ti-m� 4Alexa Fluor 59B 1:�O000; M��ar Prob�?% p .]" �y�*+ To vis��e�E 7&I#%�%�#�O ( 6��,p� s��a��o�esRA$�-��d͢!DeltaV�"G�y&��A�\�rec &:�ed�<�eco" !�V�softWoRx гFb�(�@!�:�@).�&TRIzol��g�:i�-�))inF�, pur�UIn PreA�tiXeQumAcQi_2�gEq 5uM�u����.�v���7�"�@"��}� �! PCR-���f�a%Q�^!�"�$ ( 1:?30� �"� !R:R��an�A5ITo%�\i[b�@"�x�E� � A� G� A� E $AAT� ,E CTe ��(�bRo�R#&��&G56�7�'2c7. %B9Cjs&�%)frameumori#�:�*�!H�l��!x�to4�MIg& >�"6U7"& ��6)|"��?)6�6I.��+29�*I#et�v !{�6�A��Aff�o%��&�2=�*n�1ɉ6m�E'2���.�E -RPE��ousnBiotec� 2�s b u��m����( FACS;e� Q��.zBD �{c.��4bdbioi. S2&63{F��&\�o>�I6�9M</4^aliquoAU~^ J+A[a� Mm�tn&'��6t�� 3� �ox� ψ_ &s ifI� !���dmi��|erA=Aca0e2a'� ni osec�� ba'�"aΨac�Ml��)���Kz."�4 �� ��� *?R:. Oѣ1�:5oDO��Z 2a/�s .���QL��umG ows�<"��dj�#motor�W�%�*nee�]si:<��is!�m� "s��r-!Fd \��is(q�Y&�"ZesiA$!ea�<`hav�, ?��S Q %�.UK im�` �'���|Xor� nefi {!�rr%c",J �u s la�W"��2a=el fi���,�$ n Pu��je�� ( PCG�!�&ou&� ��#! ��%�k� Oliv\ climb�Poa�R8w�0co](-*n,\"*H0��Q �>5$%44wa$t)Q�beQu!���.� �(;'tV�.H�)Ame��. H�,�&f_ workum �7[JS  sacca��U;!cdG�Iih�*�1ܠpt�?..'�I�~3A�pa spik��Cl������ �ct ��'�"��]P�"verbeŲ�V�i���Zf�8a˜9(f�)�at �sGorm� releva�or= shapuo)54at stake , han!H over!Mparallel r@s , which in turnw�nect with Purkinje cells ( PCs ) . ClimbingFcontact directly[ere�Ty ignite complex spikeR|CS ) , usually studied as proxy �c2qD activity . Accord!tohh Marr–Albus–Ito ( MAI )@ory [1 , 7 , 8] ,$ occurrencE#8an error change)�6�,/CS discharg!c6Btinduces heterosynaptic modific)�@of simultaneously �e:� >sA�n� PC dendriRtreAWItIKisBdA�6�aMact on%�tAj1�leads!I�MV PC output%�E-\s ultimately responsible%�v CBU�8. In other wordA{*!�th%�suggest!sat:xq u!)�inyLto facilitate a spec!s pattern�>n �allowEG$he optimiz5��(A central a^tSt!zconcep-�$e assumpti%� �rol%c6P signal!�limit����iE�.�RJ� inst�). Howea�,!�ordi�avoid� same -Ah�_i��should� tain��onserv!_memaPE%is Land! siqit alsoU��f���9i��quirem��A�et���]B,�9Pit posits longer-last!�I���8y]f>��8Cs brought abouq��l �J�a= past *s�implici�!stored1�:��im���-�PC��lthough6ha!)8ceived support Œa number!��ea�no!�� nAj$s have bee�ladi%� mpate�%!: idea�<j��finI�commun�ng6�(s . One exa�":our reaq�1k�`short-term saccadic adapti�( STSA�Q ��Ia�el���4um-based motor��rn�e.��we obE�d�AE:CS �w��at odds9y�-!]�[9]I. �#�muubjec�Eask)3m��a �e towa�< a periphe��vi�> t��te0en��l�~ eye�v@� + w is shif�~a nearbyiKion [10�2a &)� nnoticg ecaus��5�A� ress A1�Si�j!�unawar< �� ��arrL at w[, was expec �b��s why�ubsequ�Ccor�N �ee=to9ad3 in�9c�~.�at �dfi��lo��. I� .�s �repea�ime�*againha�5st�mannerW ne� ic M��metricA�!4primary�es such��rA�,%M clos� ȥ9!���5].I� is a��m:;Kdependsa�Tintegr� Ooculo 9vermi OMV ) [12AWA�re� CS:"��,a�,surprisingly1Hd a gradual buildup8*-� -rel%�CS�ul�8�A�me� t�| nounA���endS�m, i . � ,%a %���had�Jannulled(Bvact� out��a�heo sa�od�*N � )c审�rAe�] influ� ]:��b2� 0even early duEB��� Morea N en��yAla� � !@]le�ulikewiseM@aon1�8—smooth-pursuU5� —wd�@ congre�i/%���a� �abs1"� !%at_�&6Hta� CS� ���/�[13A� Both% digm�X(drawback! * Apstrong"x al"�E�quickx i V:���re���Si�A� a���Y . Tb �'w!�ci�to� D(to a randomM�iRi2�par�t m s b% roblema�!J�f�1�ac>anEZdiminu.�ivMp� obscI�xP. ��analyz!�����= ����� conjunc�"7 "I ��founde�oZ aUY��1 Ս��aof%�*�but� addipa r� berE�2� ]� r , befor� new�wi"X 5 �. He5E[B� � helpAo& :� ��!� , rathan be!`co.5 �:N2� s . amonkeys�+�ted ly guE�I�eZ ei� I�� hosen�ion$�rontoA�< plan_A�i�ch trial)re�a�Gbab�y!Q one-third5%to�y �to jumpaNm��1� � er�� �6�Bfur%Z� . A! e fc in Fig 1A�S1A �) i� bic�b�Z~>|� 4- or undershoo�"P,�X� ivB, : !�a �icM-��� &� !�� u � V.�0. We investig���eff` Tret� I�in�e�Y)�n − 1���)� itud"� )%{a next>m��int� �,p . Not��at� B�����a�DEx�� Ql8�| �or� delaa vare\&in-betw\s�q ee (E61t . C pl1�5� :%i] �aZ �2��B�. ΁Ha��I.�%iaiEcu�� ( downJ ) Hn eeAE viN se� ofa�!�h riment nimal��F� cly�w� ��.n� ��prompA�!�B� �`�U~��VR to keá�� (�`-way ANOVA , p < 0 . 01 )"P^heI %�.� | creae�$5�1:�[caan��!smn�<,�� vers�deci��iAi%� =!mRM�"��� ��* r&I siz�>�>� it� �.�R-�as:�z eJ���I�to �ref��, -by- .� _.\�tach���߁�pl�35%Aall. datel� } 2 m- s ×�Zus7obEed ��h��>�"8 "9 meas� $factor “�� clas��”Y�5�35 . 2 �r`�� w��e�� ��݁a at� st 90)w� ")~�A�A*Lcol!�ed ( 3B=!�I�a � � ��#u sis yiel^ 9�tJ:in 50% (.)!�QaLa<��D����e poo�O%�}�� sis;;J%of.�%�.��R��5b%-)� c�  s�win S2� . Pe� A�a�gMa� he nliz�ጅ�m�es �� �)�ul!�a slope��"59 ± 046��d�<k�gdu"\�I���vi�amounxR 2x6ewՑ� G�(Er91�%[gsi\a�6\�j�!J5��nag�=' A �R�Ż,4 show& S3%_ ��"�!hq devi� ��he horizF�v a�)rqua�0 � u�@,AbB�E-� �6�21�A��lin��ly-N� s sm �a�en|5�CE�1D�=tI�ransfer!\)��� stonis�gi��� )$,� avera�%�A�Mynd %�a =U�e� A�bS me�f 634MR =�OWe di��o�ns��ARher"2��e�5�−e� 047;< ==��"��0 , S4%u��H" w�wres?�Kᆍ�a��AUb)���i����� , 14��3u��N��set��a.�I���L!�ܱ!�1^,- ��ng� +C I\w^ R) per1�)if �&� & rval.C com�eTiode�)|� 5imA� doesEf!��,fovea�%.�#��ismba� e veTco!! t Hw !R�. Ea�ca� min�o"K129�un}Yin 110&< �.c�c=� e fi��of�yXsee�to�de�b����le�A� part> a�] 4d� m��Minw&!��z��(uP�!I�%ZB��y(#,� al� ) e mu22 ( M�!�CS`"1&E���.����9r�  wh� 0�2�� �&�c�9 uR!A�2�y!g� m�阝%(2� ��u.( , nom3f#rol ) ��l#�re�hsummar J 1 T�ue79� ��I�exhib� �9�mod2- p%�& � or m����!�peak (  . Tegin%�)�Ue� �#q"!�ma� �N\!��h ignoe!an��"��.B� U�s� 23AI)2�!CnK&FKF�� �4Es , if6�CSe2|.UMI�! %Z'!kUD ( E,!�for6XU � !L;��-_ l!N��!� see S5�QA�D full��ABMI curve� �"N�p2� Most 4�B7� ; 43v%&� .�s)bIˉ==�B^II.�n� Ѧ��a�bA� m�s y&e,. S*� MI �i����2�^preced�|B��lw$�Ij��i  m)�2� 2�3� 7!�preferA m�A!!(�JvEr$�b��%� 1z��1�j� �remai%�16eA�2$ 3�|theirU;JT!M&�t-1�o' t�I�afo�%2��&AM�\ 6� �mI(eA2!Gl�!ruW6�y�tn q|. a� ��3��f ( 49 . 4%|sus 3� 61!�5%; �4= I� nutshA� , alE6two�o���" a!J; "a�;�)We- mapp�E8 poin���!{(�"iCS�66�e�d histogra�a�م�*=lco , el^�+dZ cLhew� variouq,mpone� .EHtEr�(%�detail��e6B�f��inP!f� | ��A�a;)�,)u�i��,6Y AqK=�w9,,�iM#��C ,�s!�E���M���Z�a�pofeII�+eknfUvm �� ,?eqre�$%�.D , enouH'oa:tribu�G deci�$f�6u# �`-��sI(!5EsM(JV( h"�in et�,aabab�oom�  �e Iaƅ�o��J2�%82�ca�%'���+�da�eoL' A4��9�"�%or� d &� �4_ V�A��/. B�TMݕ� s: Ax,�(�(34 ( 11 . 8���5 w.�r)�)hQ non-iS�ol� , 22 ( 6�R�266wa�d(c .�r)/2��Q!n)?, 6 @!C�&� )3highes& �lig���]a��&p�0M� star��J��#��d�J !0JtselfA$A$d�'-�-*8�!umo of��*� (*ly"�b���0 �d2oJ���?+2c&�.%3��9% Yit8`ini��Az3 .setRX��q>I,�"� , qjj �*2�(�� ��c\*���&�0&5/�I�A"A&O/�3h%1!Hr��"� CS�in,�L 7�"�E�U.n�&�$��� $2�1��� aw2�:V'!�J &inO� sGFtF:�MI2� 2��ԑ8 grouA$�$6�*BWN/-:Q@ ly : R �.O!Iwa�$.���g6� MI.�X}���pais4e regar.^��A��5� J�$ir� O Y�E|ev� %�"��/to�, 111!2�� w�,o�E�u:)��-.$.5(   tempe�pin�a%�8 ����-��&�).10oe�req a$e Ea�+lso3"Q0"�.� s*w "�6toy �� � �6�W!*; ��)w �pop��&] O3C�h"!a� c6�.� r;�&!=>=� � 9S7G " ���3ociK&E* �s;� �3%3BM�*"M3ed�Q,"�'�j&�##6A� undoubtedFd I����% ؉��until`�%mg>. BI�I�O���ly m.h�be bi#1� �� �z �ek w�5a.ofe�-C� 86%;Bfe��f�9.�!�V�7�s�B)a�qc���5�F5,�=og&�*�1��7^9-& # upco}Q�.|�&���� AI4DE} MIy���c�w*@�Wm��#"��u, h�{M � �\� drop6Krata�aal7aMA i�#�.I" el ! �i6�+�$bNA���&��5�i�f�0B�#i��O � �R� �)wh �e*��2pw(�% -reg�{ed�..�clarify *"8CS-� d ar�e��aww,*}" �L0 3*LE ��*>� �={'-<�$ R� ����&�CS%�!�i q:&�*O �2� II (4�H �ͼa�)��bE�U�diNb"�-� coeffici�"$�da�}"�+� Us �0� .4M��B )!�bimod�'d�ifitA�suLtwo Gaussians ( r2 =�!98�B F�2A���$,��E&��3; ed �!�6� willA)osia�2=�;.6G!��5geӆ>i: �:!�egknonJ�! op�q*N'. C�-r�'�,2�2+z�+rse�y(�v�4C�illust���!�h� aso!E�inguis#'A'A� � n1l!{%b��q�!j�!i3ensAj�*sJ5n@�q���* t �V� ( &�4QA�)* Rg� ��AsqS"�o.qr���!ve0?� � �;K��U.�-�DBN�!�u�_1��A;�M0D , left paneo�J�q�s�"�@$� �Aj� �t�� 1��z !�.��1U�]t��middle�- �D=m+�FibA�A�-D�5�!;Nn6�annihi=��� 22�� 1N. Takr�:_CS9G! step"c,�ie�9!QeX��&� !�*�  fin-8I �N-�"� & �BM+/� �By� l� /m�g� ]toMk zJ)gMy%f anti� N�oA-�BM�]"�.Y��m%��—2�:g—�� �a��yA!O&9$*a:w A=i{n��go.�� *D leve3$� ��A;0qX!z�&r-.wG��ng-� )� �F� 64CS��Ue��$S8%-) Link6� � � mple�"a5SE!]a�6R2�#6�>mw�e�8��[3�45�=L!&�7wo�31S * uA~my"�b!b��Q�"Y; !a�D��_0E�뉓�dd�+��8rNw&H$� n� &�� S.�E�3, �s%6}i �w�=d&� 6� �!^:�!�CS�orJll-iso��d�Ee��) vailx# ( 82 �A�I>E�.hec�?%�o;ata(q)8! 2 *� I�ir ���6SS���J)wa���F=� �CSS� u150-m�4 ndow%y�a 26E!G�� ��mX�!n�SS=i!� 35.�14a18 . 1"q)193./� 6t6�of��!� 8mp]toe��& 9a�Ciniy few��a2.C&:S���-=�&�excluded�/5Bh s�s�)s�po%�"� !��)b�>*BoWu*`J�"�!%E*�Di�!�1 . S9%�a�e�T D�p���&�S.�?�D�}rga/�%!subtleU9�ui�&�&�4�<p,c��alm��5 may �9'a-DB�� �6"Z={L.L.B�K� �J tinu��-r,vei�&" �e��ΉD "�H�<"�J�Fre���=vY!�2�C��5a)�6���!2,>�wL�]B look!(\du�`�N� �;e&N1,M��9mpl�G()�M� i�T&�-$as describ��n�5>fai� unraL�W>��=-�Cal3Ai��!� r1!aI�of 38*g+ly��:���E������!endenc8�]3 �G�9-let�&!/E,erm�� al�q�I�a�*{L�NS10e� , S1!<��T|E:>,�un�A� A�M�s�!�bia>��a�G!��5�, tect�ingful2c1�. We ?Gd �8le7� 6�bAi�=;"> �hW�!^�2�%evi!x�*I �E�� picu�#�mp�@���:;!ey�%( �:U@�%f)%ng:�]9a6anjD�"q)�Q�ccord�7Epp9)W�Eol"5?dDmove� s [1517V \8k 9E�6�Cey�2B2�121-.kIEA�"e�aP ��3 to �1�n+.�.�Etheaqr� g�Z 3!H!��0c,���'t�0����I�?%)M f�7� te�.�F��i�Q �k�I*�/typ%�i��'&Ny (f� �ͬ�&�-��B�<)I*%�m�-nL�5s=Yl�z�!te ��!&� E� &C 5"=-D5>�>XŖ�HV =b*�-�l� m�MAIror�R�"�X 0 (c6�Rs�Bi+M�$a�p�8Ձ_$A less-amb4u�AABl� rinci/ �  lower : !R&�X�8V acteri�D%1�1W",NjlS�Eat!�do�5 2g p tu�� [i��� <HQ uD5firTC� *� QjUq��=/)%.�:*i�m# �e&�Gqq)i/>�56'^�Do�DE�e���!����D� .\>Gn6� simi�@� s [9�;�T2KHow� c�F:LC�NcoA@dQ3)6o�@< OB�?��� ndard ansA��+is quHCos "�(a solid bod���-:!_E`p91th�4 �2l� duceer KaF.+U�" fibe�U PC sYU�, 0"~n8mi"�AgF8�Abw � 5W[2�IWicQt���viaL ��R�ism�z(Y��M�T!�L a�vA�nnecessarjQe*�J�A&7 ( riM��JSF�"�by)g�:5-: . Ou),�  0$#E��2i%:jM��f�D�&" �/��A+ �i ,6 4��H��I�� hig�;!��@t) nA� e�=mR�&z�E�qun�TvocH�� E@ű&� on)�B �Xt2f`ext U!� �absol�,� B�� b�� .��I�sop�#:X PSsl�r`$9@; qty�Zof���A�&�O\9!�n��%ly��>�B�"� �e �H� �"hallmaT� �*aggrav�#�� Iuc�M-x*� �b�MA%B e�?s� �A+across"�/�s� oty�Q*��th� =���la N� c�L��.#not� �WE�e7�F` 6ug:S%[!y� e ye�(ss��%�pr�,B*��g��:r�a85 $2�!3�`':���":"�3�) arli�{hJI%:O~:��s.e�{*�O ���DvFTC�@�%K=J6�TW!� commAL!/!8��:5%�think c &�� ���\�`��46$&��Tt�^  gene�d upstreF5�&KY:�.A0s"BCM%300 m@Iuc'>�2~ OI �P�,y|evo?by mi��t\_�5b deep_ yW(-su�xGll?uu�*6� sourK6�^ave��� �20–3�[27a�"@if� �(�M5�aKal�$iSCe�&�i6Sba[ms�4E�_ ove�1.8"���:P[-Nb�#*A4�&h6�gas?�aa mQXm plauZ=cen79!inkAk�i*�TA�_�+���; �� !!�F2�2�. A f -�F�I�� !aV irP-��� Ij�S1�H�7ei#��$; v"B"a:.P)�4E�RvWe knowI#6��])�ic�Ar� h�G@ �=|a�&%"al [2�2�\A�Zs�tis �RdX*�jBsq%�!;S>)s�ө� ��5O������=bl嬭�) .%v :'�"�b*�b*� �6�N ���p�,�2� �7��ly med].��.�!z=6?n�f.W .�omE}�AI8IBLA�al2�#e�+�0oa��.z"hi� �n� As��bG(F�_erG-a�Bl�,Ei�x� -.� p�`e�S"4&%i�]�brecruit�5�Vn�B�� neur�U�/aaV�.calcium-#nbtassiume ne�'�1[3�3�^Np^=��"2�T]�,>��� �f�>�o ngthh� l"�g�2R�bCS-�FBB�qC6+ .�0*� QQs&���$�aUicacy�%beA��ctF *[ly��%iA�u*,a["i Ż.r]!%98 V �lI�է�Q trigZ, it-��� �S2.e"whow{^�)�be*H ��firh^ lace@ Tc�*atF�"`#a�A��j�gSS.�F�g�6f�M�� �r �j$by nucleo-�#pro�b�hqv �c " ar 9!�O"!��2��@�/!|to5Jpu|�keed�& )N�2!��V%u�:+ ��F� m�^�� *�"�!N . �?�&�fr��y�"?��Yh���0�%��O6�0� �@du�r.)*�e4]�#�T"�G��eI�beh*)m�fes�.�Q�J&�N�q)6m�2��&m�j[2�&32LnhQ E$"�2O 49I- �I��Zt^�A)be`! [33h<)"�c�yH1w�35� 1���f-Uy} 68.�&= !*e�0 Z2��"N1%�� � �fJZ n�grCg�]��flAIa�PC!a�f�.> [2�H"�@/:�]!N:��.�$�*n �^aB�"5o�4� ��e,�wavs�in�&#��Xr�%�a�lEd�6�i�=�#a!"�":. �"iM&5!5����:.��f2]*J"9  �]P���2# ��1��6�A�,.H &j*m�<yed���b"�$. Soetedjo� �N ague. ��_empha�2-2f�o� �- ongoo �kof�#� $>%���+J"�9-�^e5J  en u� �uble-�.�dig�bN. CatzB�!2�;��$1t*� _7("�!�u$B 8t��i�0e �'�3i�1�eL yI�du�d� !�V �[e.��"��!  y�_9F� !�oc-� ��.�n�!demons�3M�b2�g���p�o6�Z�>� ,%vj ��.o"wf�*�od�a��2�N�^�,, <]lyP� already!�g raw �m|D?_�Q�;}M�)�H��Ia $�5�%t!�.*og� *r�& � �[by Dash%d2�3]I��Y!/�:.��/�s�!�U&� s�#eNb@�JiA�N�#"E(^�,�.� N"as!�r/cP(���2�a!TtlZ &�?)����&V����y�*�M[)ea� S� �1 �n�(>� }:4�fi ,j=7"� � 2�&^;1�J~ u �.~&G]�^�� sketcaf�FC�1d>X ]25, N$c����u-"~H '7w��H5�{B� AK�irA��>'�.�. A� e �2��J\%aDf�-w2W$ �te/�.fo�MewA��&�$��62 "9Cu�LRma)�6 E��'���I�� "Z"_ ol�&, �bo�Pwc6���}�`S3�� di�WyI��a"�63:f��� f& �"�! �asSj�&ug+ �ygra^E� 2,OI���A�}1�',i�^�!� �< �9[)nr�&s�NA!*�F fres�`�s6kJ�w�"r�q�?.y['I>d%�!]'be� �iti�2�����1�� ��c$ ermai\ �6 i@a2�i�n2%�%�Ř�ebM6�����6eye b�[34] �j4~0on^= huma��A4( NHPs; macaqu'+n�j)!�R�dl�za_ipi�T%��3.� 0&zqs�(/w%cof �BXvir�-�!jXA5(* _d�&�Bha��20i1g�Ho�Zm)gMo"0p��x�o-| lexiA�ty�tra&� �i1�!de1�q�.a�1�o*n,isYY.�%NHPa~e�&%yx/�u�al�8zy�PQ'��o ellu5 AE fforKL9>19kee�G&XTihu�v�yh5rkm�e�v7Q!�?l�0/min�za�e burden%�tq6invol�a�R�3RI�*� avH >��2` � *rex%q!�rocedur5�g .�ny�E�*sur�oprotocoe�by�\ elop� _+�a=' headE��0+lg �t$�"he�y tissu�rt\y warr�;ngM�ho� of6�1� a�>rooms%6m�B� c&x 0I ~HAY���*�25)ll�9�s|e�!�=>Qklegy d organ*lW amewA,is o�0!!IMa>,�#Hmethods� �%�A-)�- �#A1m}l�&aut�cta3inM !H( RegierungspräsidTübinge�>(Landratsamt8, license N1/08�N6/13v�:u�C�8:�0G� 2Europ�bla�8�Gp_5RNB$al Institu�� of HE,m-e C�7!*U2^ Labo��y A l, careaLy�fi�{-.ve!snT�ia 9Un-ABah]bmale rhe�W4g s ( Macac�d a �Rpr�cehp-�(�T��"8)� GOI�!sclVzsearc�&gJechni�� [35]�o p~essa^mmo���^ �’ahd�wtan!� pole�att�j�yskR\ -b� screvV%.ixdthA�b� AiDz'Z. A�Y� ci+V4�Da�{ ag2�gsR%woh("�)�_3c"n prog�E�9P chamR�� sMro�H� _e�.�B@to lobule VIc/VII!�y'so 1Nre �(a?�midA�"%�vW�pa"])l , tiiiD$&)|�r���rby 30°!X�]����r m��� gE$�@es.i�c�A%�He� M9 F>V3 E�gesics�LaZ%pv<$. See Prsai{qkh36]%�mY�ft�sb"< ! x<*Ma (V s! deplo�a8&�pt: AM � W�-en��a fix��(!t[ �@ diam�4�H2°:OA��ta��-�)Cg �%�w!�%ia�ZO ny1A'W2��one��,ydis�[a�a���(5 �,as�"�s�&�.Acol�|ec=vit�'cx r.�� 1A|�͇scfJW)�.:�*�s�#5, 45°� tc .O#D*xns“)&f�hQ���!�@%hU�sly�+�\��a* ° (T�� Za"8$ay .�u5mpo�x.H�NGorAc�s�7f(��l����ol2��ee��.�va�� ��I?�\!&�v@T.�/~n 4 ����A"-_1\m��w�-hGR�IsNcB�6 Q�%�Eqfe 5&�r�Z��Lb1exact&�JZIR� )&�,q�:i;G QE1Am; �%.l;upa��enXH >Ps2h a�{6�"� �.H&V"� '�demLu�o7y� x B� b  , valid%a�st~ �AMtom MRI scR��J5a*�Jf�reL>fhaderH5 6y�%���� P�Lو&��#D0 o �En�an2 Ar !�%� A)��" D!��)"�H�"n&"�!nGolgihR4o%';..�B�?!�adB@ –r�Ted���i�I.�����A�dQ�n"{A>�d ����:��?� ( LFP;�6ass-feBed �%�l na cutoff+?��5150 Hz�J�LFP2�es�$ :�?ut4+% Ae. DA0nctB=em>Q��R&+6��Dirpa��+dq~Ń&�-CS ���&�k$10A–S10C"�I&�56}u��b�W"�#, %��!c�*�7��sK2*di��let&L �Y�+ foot��&!�!yio}U i�(�P ��a�Cl�8>@/��%%%��"��96�u�. S���“Q8� morph��(/�aks|of �"�.�3se!aYrruD~<ccat aAE �e?��#%-+g�YSS �9&i�OAi�-�Q�E^�Jnd %�/�oɣQempa� m�� �!������@ 9 I�_o�9;F!Moff�m�sUa�I�s� p�: at 25 kHz��:$*�s`l %)@de�K�� tampd6_*! ��{�6�E� �E�� ! Palgorithm ( WaveClus2�)r�Xn<[37]  *� ��250� 1 , 800.�x s;!,�&�ey"B"Efai6e�)M�8��u"�C."���&�; $�#E6�Eas��e '1��-to-no ��3�d NR )%_:1}:of �eE��C�( argu)iB3�)4%!O�&]M�"{ tip��.� e . U�H@ɆrobustQ..J�����6at��$� i"~ ��Z"U 3�!��:q2{8=�A�� o"�j�(A�2{ task*71\$� CH2�b�B\blØ5e b "�ex/A��>N�1z�ZK�(�e3let�?�$�Q38!:!�s5 1��cofQ` )���A\�8�gooC�(� !�0���l*ew4v�Q?x^����-Lmeŀ|T��( �AF�B����&��MJ�<His judgr��N�$���@, Z�R"�� T)C.!l�!7 �*Ӂ�0&� B�@& &� &���reP#A�as�-;vA�E;E9&1Gs�]AT4w�4u$Aj1Boscila�. f"�B*O� R� ��*x��Jtwo�a�g";�0 � a/'t�IrF��86�0�9�%e�)n1 �s x�h�7�Q'�}"� 4C%M�]O�Y9&�= ly (�#t�p z9;.��I! FA9ns#>�05#9��[.�vI���e�, F2")��H�x60ob�?ѩ�L�2ve cri� o"���hSa!)9� ,)�ZS�!�Q  ge 2}s�;sƖ��Z�U&I/4%Uc�Db5 rsez nond�da�[s�1�֞�0A��Ti�QIO1��B*rev�"m�gE MJ��ZS5�2�� =6pQm9�m�/�#&��env"u M��*k��>^i2����Id \ Nh[a�.+� "��w�CVm��B-T}��?*EY)� �. �.s1B1i"7p�`o�~> off7`��B�M�8e\>st%�T m�� -)i �u&?�"0  ( PSTH� �%�YG:�� -Oi{�i��J��,�Mh9&"Rmixeee6!��'5�a5�qa&�e>1o�^�q�@ef*� (i�-n L5&*TrN��oQ�EbJ u�dU3 "^�8t� �,\ad2�ag�/at—�!%-s�l.� Nr�A5?1%I�(:�rӌ,^� �8"�(�s ��*1JvY <UNJ� � � orro�!!]% ��Og=�^�B)�heR�(R3 S10Di�)�X&�FBS�6��9�%aI�i��u2<.� "�7 � ��raq� .���.`W� dU"O4e37�Pa�!B��� XW"�� �>�� ��<�=� -�AN!&cE}+����CE�N�&�m#.&1*���. �1�8!Eme"3 airAed�#��f&���e!� �r�-e (�� orj2 ^ ��� IE�3ter) oa�w<}1-sai�u �qgsN��R�*z)QY�� U9����"�(.K!D9�w �w c��!Zs�"�+?>2�(�UP�M� Fu6m���w䔡1T$�%@ w� - , Bum � ong-�47� �,��-/ӎ�ayC�)� 5>"$ng�m�&.�p�+L�Q*m�or�G %�����/��2.%(]�� �/f!yJ)!mvfr;15p&�q2l( �a�$44 std ≙-<}! elow� ��)e6or ab�e(B!q.!J �.�ZA�Tl)at*��&!J.��3J�A�e:��Y$,` YaQ�d Lisb�r��='d� D5��*% = N�&����$i'�� wȓ[�4:�vA!"�:Y�a.��~$_�Xa� 250-li��w�ara  widthDy�&P'�Q�R�3x#f&�y0�D�Pa!wMG%�is;�spuTP�'nsZnɚ� E��*� at 1/ � � �^lm���I2!8� 6� �ly 99%_3 u}py�R89 bi}fI$��he up�J��" ML�Y1�dA{i{.dWA�i�l:�ՏwoM,e&�q&��"(Nbd�val�; �Il�X�:a2�-@�; ��/)�emB�%lit7 s:x;lFpmA�q�it�>�� as�7�L�!ar��� `;�|$�Hb he 2I��>�ker�k�t!}�4� wkI��{e 8�+a7 preteH=Zi�%Xq+@/dm�varbitr,,}On�of�qu�.�v����p� � pshoI,.!�0 by:T( X;Y ) =∑x∑yp ( xj ) log2� )")��� he j� E{�@a�/ X , bY|X ?f��iz���_r5�l6J/ eR�Ę(Oa �"�ZF2�)7����� �)!� chooU�sXNiG( �+|�"h [��kute&$= !~4Y , x cm-�/A�w�W�.w� ;ɸ&��B� � flU� ���v0+�W�"����A6�eGa��5–2�Y$Au� ����U�� "�(e't K'~l ��'��-—�tAiM� —�!�!�P�! 6"� .�8%���0�D�9*7ry:$6�s'& M�2�J �a1��a�a�OP�n �*7EMIr 'a�?�O %X&q!�MI�IE�1 cTL�BachUce��"�5� & *�.�@%!R+p�4wA�asons:�_�#�7s\,!3g��'n�ar��s�c�]��eA!.�M���Ed  M�id�nu m��7kQr�  @ %NE8zu�l&�'.�a45su�\s [38� C"��s"b �MIwE!�5wo �Y)*tofҢin�����NG"� �12� ��ט�u�J#�N�, elabA&go�"�s!9��o-�^Zmo )4&� ob���ea7o A�xpخ.Bo) moE7�/��q;- o�,�<�s��"?I77�e�� :� en p&D_1�PThu!� aiisMarabi�w5�{. MET�Jg���8�o�E�n1U��t�Lul� ,�A�Ian�1�D��bg���s n�7s!ef A��S"#��S'�dzC� � �<lemxpropoa9��p5 K�c�Panzeri�dT�*s [40]%;������ � &���a'E��K!U� �AEJd-� In Nz,;S.�141�Ia Baye�y5!��!_%� �Jo���Rw1loMF4H R`�-1� �E0!����qac WO"Ic�b�;� [42]��8�a���� ( DE�s�9�ove.I1�bysi���on:� nnt*�VJ�:] �!y�2�5��r s�[r wt�S � s<�p/ua�fe'eh�p�(-�a %0e��Oef֥i�y Ej�aX.l[�2�C[4k#43][/qKck� ll o.A��;�+ le-B-�. MF��e-��co�p++E� fac)�cus�*\I Pyth�nd�9lab7ip�!A?lKde�l"0:A�B�&h$W"�!in!��All�-* -��e�+ �� =R"�)�Ma:�To�yٌQ�v�`h��l�T��c-[mC���i�"} E2� a8�!G�ZmF�"� u2%+T( �cM ����_!"Gi��m a?38"v�>��][���/�)"E -�v%��m� Q�3+,��_JE�.e'��@����%w s[�We�2p-::Xl� �'!�"$(N�:&�/Ks."��i. 0PA"6� ���pz�CSB��&m @EL?:�% s 1B%P3��!oQ )���*��AW�eq��) o���� ����4� �7n�Di} �N"�2waϬŢm MIy�"�e��� �� G�jV��5e& :'QO #enjd4Ah%9tH&tBt& �Uo�ur��exi Yc�5� �-�2�mAl�s7~ ��al��%�v� re�_&-(& "�11!c}#�I� cate�)e�f!�%�&!+{.`ss!�!�Z���:_. A�|� ��CAv-[�achA��T�+� �:Y�6�]s��&��6m� ?6 qeb�\or6�aX (?) hI� �cNri>!�O���M�"M l"HJa*�&�am %�fjis�5�M.a��}����%>as.`�?d�2>(�� D#��sJ A0sEof.v�Yc} A( �seAv"�cob�&MqAd)�Ak+�-��x�6�.� z��&k��. rk� 4�a� �<, 2 2�5'�q��zU��R2T>�t !�בrofilc �G�3250V�+��-�*�1#s] �aa�ZK!� E��.�M*L)�% lap�'�%�+>.Ek]�M�MI~��M�>>{ ;�n)�AtiSte"͆6�,R�,)A���,off-diagonal�,AM�G$r��HAm�ve�" ��R{QuU!��1}.�� :"�Ee��$$+ 1 = 151 P�j��UE6#a;��J-F"= �a/�R9matrixby�>"]6�j�σ2 ⋅��50�|ij|���&��!jM�t�p7����A�+μO626.,�#�F��W!×10�v|�L�V�is2>���D�lp%is�. E�!�of��μ!*B8l]-�&� �N#J}az�&dI� –gJ�E�i�CQB�ul�/a S?"�;!V&�B5gN}Sx �$+numer���g� %�}o�m"m)�p-�052�we.fS��ED∫S∞dMIΓ ( ν+M ) V  ) 2π��+dtβ7>�1+ ڤ−μds c�#VL����5=Z 05 Wc!� , β��V��e�6 ,.#F� nqA�x*�,%��Ap$)0�|9�5="N �B�Ygu�;AQd��u��c�&��i?x<��1�(8i�d�yP�`"c3 �<� �Uaon�. T���^ ��t �\wBxUa�� "� �@%}#&)a&+-�J"xE/tr#$Y�iwb2P{ �k'm��!ad�a�A��s��*9 #-*: [&{�Z2�"��*#MI"ˈG O#ӽEar�,� CڂF�&�= �sj�H6� ��"� N�'wo19 )I\R��)nV�>�1�!��()V . NRU] FA59Q �2$a�E�@���� ��^new)"� )!a�RA�_aJ5��!��&�&� ��ӵP�"O�500eN)���ka d�c,)'~4bϹtr3, fu�W�n�:�2S YxF6X� %. n��&GKZ!Vv�  e�95��6(- 95thDlX*I/sez�, ,M� �V�&l%B1�pa�� Ka� �W�>&OI��B���� EZ&�MI�a�Q�<�Fs�T� ’sb�Z.�� lsF��zge "�D�R2��!c����/7�kq.A�S6�*�'b $��.��W A�%2�V�exp�@)A� "!kD>7y��[05�� .�2enb;m�. ��,)E8 .��Vjt!.�C2I��V��q�j "ae`A M��%A�^B ."2�R!�s6�!�t'�09j-22� W #y >�/�g-CU22$_.@1'�@p��.� � �cs &rMα�M�An)��a�V�&a�|�!& -�o�!(�o��F�\outti��N��*�4l�9  �Z028 .*'-6��%U�O& � �*1���Z���4?!�&���&.da�%6��YQ 'a�u@%fB�"z{ly ���'�a�e� � �C!>fig�T�G>lNtS 2B�>$Dryad Digi,Re{8ory: https://do��org/1� 5061/d6,. p88b8v8 [4hX ��Amyot���WG(cl��* ALO����asK&ng� odeg�!�3 diset&�D��&={l�x�W� C[J5inclu~@�E3�M�"qA$RNA/DNA(���UшTDP-4ݤU: y&m(p�*E /T"(x,N� ,q�� -A�exX�S&�7a@Gs�D shap;WR$es ubiquit��"�teo"�<vG@>Ksc. F*��a��e�!Hsp40!|perA�, Sis�? �d ���������%[ �I�EBWn� Hs�Bc>2� �endogen�W)���/[PIN+OF[>mof �%h�-�ag&-�p; %+�� ct @Gd#. XE� Q,"�Ang�[�!�,� �on;.�>�:?�dm� lian �homolo��, DNAJB)�l��sf*0 A5� #Na�~6f!t"ac:�at q�{By42yj U��Vro\�a��ineO. �9 , of�J"�7��8s "Lou Gehrig's�F�;"&Ux�>i\2Bj'u&m�deaq6}� b& %A�spi�� �����szK�HatEic��~!߁si1��(cytoplasmic.�r7�\%a��o�Xe�A/RJof��kDa (Q*) [3–7a[6Km,oA s��&%m ( TARDBP���bfamilpL�[8–1�rC� <�� -7 smaj�D�.&T���nto".d�i�FTD��S�#s�ci�at�A�(zY_e�o m!�ѩm"�a�\D �mis�IBR6� )A�nј-b�ngA�Ř[1,"�f�i0�K-n%qus�[*�����k�"E!=y��ssKs [1���harbo�7wo� Re:_on Motifz[RMO omai�=nd�1Deglycine-E��M�&�!e%�� ALS--�Yv!�L"1"ņ5A�A-#�FtdŰifyf`1ZM'.�p���V-l�ra�o-� 69th@+��entire._om�&YV���#�u�resid�0D277–414 ) ( [16]I���[119&�Gab�]2\6 ild- !�ut�)�we�%Ii�EU ,=� fociQQ*�b-�J5e�!q���2\4Prn!�l�-se 9�XU*�"�U�&:�)A)[��.�,BlAUofi ly α-hel�su%%�D PrPC� 2�fi�v$s β-sheetI{� uJ samyloidBUedT Sc (��qBscrapi������ ag�K�!�6+ �d��A�.%�8<a8-"T�4bl� �5�$)��]��!�s"(X#!Z�^ " r Alzheim���s� , Pa�� son�.a�EE���2�7���9=qE!al"� �s0Hl �A�ɡt��m��]elY[-�2>���%v�#�A�a:��'��!N phenB�)�a [2A 26T��I/npJ ' jcT nh��-{. novo2v�V�� � CQ��) uma�{-G �uT�z!bd-Z�v$ [2�p$f,A�) iA�n.!8"$ �;fH��ngton'YHt� #� ! � polygluta��3 olyQ��+4& � n-U[3�_C]. C ��!� � anJ� !�B�propa��6,2�[3�n+!SY��CtL*�p��n*�* �*l� iffu���� �A�w�pexp��#�gr����,EoH&�t rI%&y�1U���1�VrC 8%,�co-��them ]7 .O6�![4Ν4�c�~�څhE ��I"� �ligom@F![M�W�K,ed ll�h�-!�hs��.�p�W]-�R k �5>s �� �"fr.�!224 b.6>� !��l2hFc�'a�o��)��3a�����s'Z�� A�.�[454� �Z-H'� resclI��>=� C��) or  ���/B�,JG%�)�s�*��1Az2}[43!ՙ�yO�A��(u !�6UeYfO�er ��/�!Zi�ka�e 2%�p�"ng&�Cmisfo�5 � uF!���<us�j-asomalsradi2U S���2oy!>�I(%�9U5�+n.JU�io6� Pin4C��lx����S!ofo, 7�a�/ hypeRPsphoryd5�?0a�F��ZWE#!�I'�B9�9}9BeK ( UPi�DA�^�( !A,F�w50�$R^e�.=/1�[4��43Z~�tq�f�7 ^kA? :i�E@��Rnq9cH6 2w��+a� o �.g � �r� _ [�^sA appaqLly�/ ;%�rB� BtkU �q[5�5��Ym�@ us�h|a֒� tudy< 1���& 1 �� :�1esh,48 , 52–56F=�ed� � A�sy�ic.N"�>Y%+/[5����&� \�"��99.���rJx ,E�� H>�2{, A it�?�bo�nI&�at��-*��k��6�is.(�*�=Eot0�B�[57�5F�s��k� pene���d|a�` 2�[�=-U[@ eL��Q��M?k -No�iVA�ʊw�Mk s [5 rbia!Hscree�6��Ia8le�n�] s {%.A7�BE&5 ���Rnde^�h��A�a�>Xcasca�}�^f&M �9�r��bp � m" ATXN�6d�CA[a��*l" �& 6 !%� L�:� ��d �C!Z�5���%ly�*ab��!pPB��hk�-�inI��` � �`�$x�w��nU[v5�h� �"ss����=75�eA2t-�. L��2�E4nUD~��?�-����� 2�pp&ș%;- imped-6UPS�d6p �cN� ��Az=l-J�%�o�G.U�AA' �-� �. "s�]a o�or ��;�/.T����5xH#7�� i2"�us�U BO >\[pin-]�.[5�6�]c�za�6� ���7aowt��Zi �"�#�S&Wh5/wQs0�-&b�."�>0H�%in &�b����w7o*a�-gh�r�l`� � 1v7&isUic1':��)wZdG*��)�>R9�hL��?� ~sl �%V reproduci���S�WsAR�%��� )J+�& @nh)2% gal$E��� �:4 d�5(�- U74D-694�ឡiv�4a�� ���ri`0�q�Geme��b��!� .���M�Y�E a4%� f TsG�BY4741V W303�.=�uough R��in:u� eha��c�Jd-�2�1}GWmH!�24 e@l�d � �!5nd bl�g.O'� �6 ��}C+ Wo�EA�m}C�1�.� >I�&0� ar Htb1��,agg� mCher��6?�#�Q�e �* �/� r�)%>� W��ed �u;PG���@�a,`���7ytokinef"�E�..\�~rI�6h.N�J��2�-R>� a g�a 4:v*;2���.4!��&� �=, � A�)"�9� 1]!�AO#oo"��&e ���0!"�S.� ��-�FUSF"� q"un� �Y[5�5t6�W&�S��R!�s.! r -YFPE���o-.vng i�1 k�"�� �gͺ� dC :����1T�G �n\�� )�be weakń�2W�1�sA�@+xipA���W#�.���1�.lr�Q�[5�F��� xm� "6�l� p,Ely��ora�N G:J�Hsp10A@ or` Upf1 [I$865]al&2*�.���U d%�����I!�a !ȉ�ing��U>` -:m[s�QZ�o%~:(5�6�$���?�sr#:��eM19� U .>sփ�Bun��d � �z�R��<c$I>k[66%�4E���"ً��s���:�o2 >� 1�.s ��"�, CG*���!�r!�Fv�=Fr�_� ���'ulC a��if1U:V Q2�^sZ�,SG*�G*��m2#seQ4ory�t�[cD!xypeptid�(Y ��A�c*J)�����GFP�5�ssCPY*%�Ng�G)6�apiI)e��a�!e,*,ona�40g Hsp7* (��!�w a6ofe� synA�:Q$cyclohexim� ( CH�O � �� � UM�oN�)!�l-�>� Z�� I�f 0was more dram�atic in [PIN+] cells where TDP-43 is more toxic . Further�, simultaneous overexpression of Sis1 andMresulteds4rapid degradat 1$CG* . Thisy�consistent with the hypothesis thatZt�ityZ part kHs from interferenceK8UPS system . Si dele�THSP104 prevents propag��several yeast prions [21] we looked for effects!(hsp104Δ on� abil�1*:Ato reduc5�� . NoYw!�detec!Z4when comparing1�!> wild-type� vs .�X( S5A Fig ) . Also , as)�|is an Ssa1 co-chaperone [67 , 68j�lo�d =activ��%E%experimE"as� lica! by%d factI*in addi%�to �be!%a6�for � , it�A� umed7be>/ofiA� r members$Ssa family!`sa2 ,3e Ssa4%mF2T.�all6SisP is lethalL.5!� �%A ens%�(by alteraed!?}�6�a� us ,A�us�4he dominant nea 4ve SSA1-21 mut!e�n ssa2Δ background which has a drama�yeea=(U# caus!�los5P[PSI+]in, [69] . We fd�t!# �%�iE�Vdid notm1ably a ���a>Bu>�< aggr!(4es are soluble�p2% SDS at room temperature anEh failApstain��amylo�8ye�0oflavin T [53- as�{iI�F�had � J-like�� ertyA�iin�a dif�@)9rgar8, sarkosyl , be!��8me pathologicalJ����isE4toI[3 , 4]%SLin vitro fibrillizedVremains6��[70!IndeedAˡwe treelyaE^��harbo�9F9�E[N�(E3 ) , @(-YFP oligom�� visiM8unboiled sample��The sizIabunda���ese.M,as unchangeda��n:DAN.Y���H.R�Wa�ly do!V�inhibitُof polyQn Pin4C but�= alsou� ally��su�� �prote!�[44Ae�I��ntr�g1X�ʡ�largeLes �A1á���of.�� is1 . How�� ,/frequencesmall.Y!@ infl")oclevel`R:�}B<��A�IZEfo�M rer.t��appear)�.��F/Ec��araMfUOnu��apZsee�Zhigher6�M�5AŧI�is�6�u,��H!(c!�olA� via a TET!� mote!na ��2B>,above normal1�ab5�$doxycyclini$below:/�1�.0.� � cul�qsi�endogen� !�E�no� 1�( GF820e��A�pattern�O};��%�%�a��vIK6�Despit��e- Jf��ce�n, produc�]��s%�i!�e9t�� ��I�.9Mr.�% �!<. About 55–60%a MA� �pelletA P  or%V,ZedQ�BE��# findE�ar$essential &� M�, sa�steaJ by P:�1bes sugg*�'a< e lack� func!�al �couldI ibu!�o>Z-medi�m"� [45��W!�us6���"by.!kof-Z -GFP� loca�ũ>�tag�'mCherr� is1-mCh%X [ �Y�iffus�!fnucleuse���s s��`cytoplasmic dots [71 , 72ჹkI�ѝ�3�!y$o show any�� �e6��We �investig)ih�� %�!+�o ~),co-immunocap� s1�assoc!� 1 =� 3d. antibod!YH 6U�� re m�Hsp40Y��4distinct struc�r dUr�$ mammalian�[7� One�:C, DNAJB!�w ! most� ilar� to�%# . To rm�`ifE4extended neuroasurviv��� ��we.�%*�( WT )%�7 )Z ( A315lin� E�A a�ALS�>rod primarA!rti |[8 , 57Aw%"D%�98 ` :�=>�7%�c �� sdirectly# p�ͅ3��c [74]� e qu��on�Phe: ��o�("���Lct�.��x� ���we�^:E&hŠ ۭ�)Hore  k�d�LF���7C%ET. �inͺ,.�oճitmis � -dep��n*�F�(deficiencie� �may po�%a2due!�aac��-!&TsiRNA. knockdowngin ~���1�ng]1~mApple!� I� ( S6��6Si �itsmsV ��in���[�6"by 20%�= )(6�:�HR�~2^scrambl#%+a�a�00;K589��$wise enhan�V�1�%�� *�bN��$ e�N�=��3��5%nTh�rs� � -ZZ"� �maintain� � al healthan>&*&� Pcan help� �Q!"� T"� �sY��$exacerbate 3N�M�.Eon . A"� �n��>� ���Ld� \ c79*o9�ed� �(R� s2| *� �P|F� [5~ 9��!65a Our"�A%� �2a8clearA�!a� fol\ re��er�  ,*"` au �( �) [80�)isax`���a><BZ�� .,sDbŤteoly�dys�df� ��o�!W���ntB mi1 9i�W� �"a varie�Y2!��44!�6Vw:&e���-��A+ !Brre. w�"* UPS:9i2$&OHthan [pin-] 74D-694� � d��� a g r�ncM� M�(. By analogn !\� � .*6heteraG�2�]� W���"� [!�stas of1y-���U . Wh�d �\q s&� AA�O�"i�kn�Dile>4�Э�6EO5�A{o6�&S� �`q�TDP43.��3} �%Z2��} �guishyMn� les� !��� M7.oe�i��"���� [66]�mak52-�ore vul�bl�Q�4!{, g .��� !LhavailE���)�� q� �sentt-�oryMg��^� �V6�:�Bf � lA�iA�Q}ك ell grow�Ps�EK~ �!. S2 gene��scree��� have i�ifiq od   �Q�;aQ���lamong!]m [�l381���importQ� such�C�[,ly establish����.� , Pbp] -� disc!Za new�M�� A�o=ATXN2*0c![ lengthglutaMexpanAlqphom��!���[5�Ey��%]b�mis��F� on5 ;��ir�0 throughput n��9A�oI,%O weakjstrj - " at l"as"!�aAaE�f�1{ �"�!(p"-��� hUpf� ( S1*� ���6��[A xu�S�#s betw!N�� VQ�!6@ �in� E��$vedE�bec�D %O���:�#���:(:� :;of Rnq1!��� E[5�#I�A�Z}� �! � in)"RnqQ1 &�#E���i*(!?I��"0)%��j��n��!�)@F� � iS�#"�k%r�*-%�[3|)3�6��u � �9�&�B"�i�,in our study�(�J��J�mM%#Lb E�bed �E�� C���,��or!�1I. Prev� �!zim"�)�& rect �P�&HSP.x 6 (��)3�D97E�8~y )=B�"� ��<��: ���al��[8� �I|�{_2�(�.f"� d�\%�(.C ���B~B�B| B9?B11-c�t he;!�xi)�n�-�s��rn�3b+.^=) stil��DQ�a� � |,��]��ysup� �is.�":P�Ae�-& ed~!�� �$�G#��!��!-+��*� :�i�F %�,1�{ � dDu\iZ�" A�f�ds�� nserc !g�i B� � ����E�$�!6uM�ia��of" I A 4 m>� 83–8�U!gnitud�A�%A��)��0is� A�9�!� �g�� c�ni . DBR1*n8�Mut ,i? �q�!mZ�a-ء�%2%-�'ek@ limb-girdle musc%1dystroph\" LGMD?!to�a!uA�.+ c*� M@1] in 3by , Inb0��Upe�%�� , 8�A�2F�%�(�s� eur�,��9�-"��2{rik�:�.c� d fury�is occur A"*�"r�5� or�>asitA�K2m�to��U�d#OE�Uaffor�b� ���in�a  a�ہ�I�� mea�fm�)6�&x#��� �xcon�0s3��g(.>n"G.O /RNA"��Ias1�. YNK &ds/�qa�X0l�3�I TSs ɴ��reW !l�In L3478%k�Yn4f SIS3*&�&�!aF�&A��!KL1749� �#�3�� PCR mc'-HIS5 �-�d frag^I|p2268 SD-His���� AA�-g'sig!��E�9u%q�$marker HTB �8 �g�����(Cla1 linear/Lp2278 ( pRS305-ADH1-W��Is�*ic�ver�of5� ob~ed�YPD�z 5 mM GuHC20confim*%by check�! M)Qn�f�2�fan r'MR [9� UnXŏ�s `-�-:l < re driven�GAL�Y�OentS& %��!Q�'d p236�!�mad�BP�e�&SpDONR22I�IUYH gUO�( h)� T,a stop codon" �30Gateway Techn?y [96 A[>g' 2273��� -per� to p203� p218 p2245bu=$p2055�AG426%=-0�0`146�236E�AG415-!{>:�1D"�81R���^4 onor1��q-43-DsRU, p217�1on� Z#n�� vec�!�302e7P�*A 19�3�-EYFP )��t�)�y a LRU*"� :� @s18Aj)518� %5 mccd�&�28%Z RS419���' ��ra �switcha�I)-�E$042�6J4 !)%�3[� p204*052#�r2�/m~y�22!�!�.;on pCM18� "�(�A to au* 9� 1576�6�e�0iv%iZf dard'! !� th��Z[9 R�6��-02% dextrose (�8!Synth8��B9��* o ac�:excep�thNE�Bselpnd:qS ; glyc�?G ) alactN( SGalraffin Raf��2% 1+2( Gal/ ,>%av�6c�1a&� v"y*� �r�I&^ , .�9��%�routinp�! patc�A/m�-#�8D%jum�$&�-^carefu�8 plan!"ge��|fe�2��$ p��Pregnv,femalN2 1,e���ge� LCEvra�.Rattusa�vegicusቁ�ho�singl�@cha�7s equi�zE_environ� al enrich Iҍf�$bitum a �( diet ( 30%� �3% fat e1%!bohyd!�; 6in� J &6"�ww . labX.� < !�!bdE"-�Uni��Laborat,")� Medic�2( ULAM aZ�. V�in02^ia��%tD ici!sin QAN�!ndY��@�3�%ong* $ tena�of�+colon�,;accor�;%�A� NIH-�)oraR Guid�E�gA�ofF /AAA+Ek4=,�)E%� a{as litt$�1a]��$eu�&as�9b*n!� $ , minimizO�4p-an�:" mforAVU�damm@ W�qby CO2�alM$t r7 da<,��-�, E��&pby biLral pneumothorax . E�5A�y;B)recommen�D�c%�ds�tN�A��]cE�al As�(m!N!�Z�Metho��dGped�#��!�)Y%�e fetu�Erem�?V W&S'm��r/� uter�8!�e%5 nZ�� e62dM#m*Q uRim t� a� wardA�M�b�5�iso!�xom E20� pup�Z described�l8-ie[, �3onE\4! viP@( DIV�e�"^ encotvaria%"�,��.7 !��`( Dharmacon ON-TARGETplus�� Dnajb. 36138|G(—SMARTpoo� � Lipo�an$ 2000 ( In�gen ) [2C� trac67F, Qa/,ofm� m%�^�5M77� 9�B*�Cas digit�)sub�AE*raw imag�nd� adjus! %�st�A g/)j6 FijvS21=,�X regiA�� alig��) �A�Hmultistackreg plugi c�)0*�� ustom-des ]code wr�I PythS ~Dme� &M��Adisrup��Ca`"ran��D ���roc *0or �<.@y:E &7!f��2ve�'�+e�7 `�ipopq7o��!]�|@sub� �Eps-g�6pr*�4�7�_�6!l\!��9a �per3� R W�y 0jackagV ImagayA��Z sAJQ�� TiE-B "<�b"�8e:' P#JctFocus�a5(-�! �#E�.20X o�$!Xl*!.a 16-C(Andor iXon �r�5A�pl* ultra-coo7chx$-coupdevic%eW camera!?P Lambda XL Xenon lamp�uu@ ) illu�G1�c s�a 5-mm l�:� ght gj)�x-�y-!�ge �5" ��9�-Zn ASI��st1�rot_ �>�# . An:| � 81 aia�37°CE5%!�� �ll2� ��m �,�&�i�6�01EuW!w by BeanSh1&e�� μManager�:c/H"-softw ruiKA�eJ . Rz�<���!C:�Ş�e���rty-e%�ho��/!Ye�N-�rin�twATin PBS& n fi�inl paraaaldehy� 10� ll2�-V���@�permea�Lnw�� 81% Triton X-100r�!�2 b%>I,e�li�1�M�� �H�tFMI n blo�inR�, 3% BSQ<��oa?ru>N�1%nR�&/ @� agt&,Abcam ab6940�ab�2�"uaOti-< , 1:!4))badZ"��%e �I>A$Y��cu�5d�& at 4ahi@�uN'quickA� nd 3�="�=!f%�!�-[pla��K!_%jS%��ac*��pr99se��2=0( Donke=2ti--Cy�" Jackson I�AResearchaB 11-175-15!Qwhole Ig�at����of 1:25!��~Ma�EJ �2 %�Hoescht �K( 3334�2� at !�nM1Di�m�1 Qbef���;ut� ��Eq�?am�� o����re�)a(y�Je��Ra�by WeD e)t6r�Pr%b 10{To<" *��/emi-dec/�D|2L AgardGel�pho�&��DD-AGE )��Na&Y )��`�!�ro��� ~[10n10�DA�N60 μq0cr8") �tLE�2%&�KiX bu�! ( 2Tri�200q��,�� ~IAAv<025% bromophenolf)��7e]N�a�F%,? IKs.�� horizon!�N%�{r!lgeFI� a�tris/� ine/�N �,рrA, PVDF&� �proy %!7/mQ}�  visu�Fmon�L-�e��=y�� Mat 95����5%in!��6�!�]8%�0dithiothreito�DTTENio�7F#Ms. BQBEfd�>o��IE ��:�l "P7 (ch Grou� Rosemon!ILa 1$y kind�?vid E (raig ( Madi�� , WI >up35C%I�$�( ��)laba��E�G��e (0X oil!�# )# �% FITC , ��E$(!R.QF(chroma 4901� 4900�" 8��il( cube�CeZ�0>:s> x!"9 3 . 7%?�Mo.���1��u��A���K�%1M^Cass�phosphat!pH 7 . 5MD� � a next��H8( http://openwe� X. org/wiki/McClean:_Fix�' _of_$ , Bis�_��))�DFi7 !aunC I�Y�9�_0 hape,�z1�9�c�LUq.wd�alwnIUC�&�I�!a?7 nel -f�1 expooI- exciuP>gmA�!�very bri<�2�e��+�/f��B!�.�)n�ta� . AsZ� ,�$��� by v�xA�8�NI7.�in LB2��[4�b -f'(.�KClo ~ MgClk 10%"} >�"z�΅��'c�� PMSF�An 5 �VB> .�a��C�! 0 mg�Tbin-i"�e�2 &p/��Ab�on ice;� E��mezF5��mag�=bea�'s immo�G�U ��0nyi Biotec InS6$, San Dieg�\CTP!� ��1 h_3n�NiFJ� bo�Z6���,f"@,e2A_!� step�dB ��d�$-W!o-�R�ShJ; :EP%>�An , 21]J:(;$-.��1~�b�5]�;MJ����YVel~"�hotM.q;( su<,a< 6 . ,5v.� 5%�82% β-mercaptoe �� E�&�#.A>[ EG��!� � ��>"�!��� � � .v�Chag7-G�0tg3a maj)��.lth issuņ�RL�=&��!r' .*hR curr�E P chal�?x*4(8"�::T�"os�cruzi <re>Uyp!)un0( DTU� !K�W�Wmanife�+^ m�c-�sj.&iKal���venBal �-cqu���,�>�( q&)��roach�0��A mole�1 �S$ sitbad a�9z&�q blood� me}65� ":�pat��:All�Arecrui��a! same1� �E>thA�!Ibirth Dwid� �T�V@&�=@@�e$ic��1 of BrazilA)|^65� , 35a�! 8%E�e�W�oD�9 b,\al)�%�e^A 23�|7J�OU%,6�?�;%�1�2�168ardiac��m�LYR,6��n/4 �5�� �Q 54 [��4�41 14]M�#val�>/mL��ar� q . #�� ran�E3!12�1%W66[.A(. Noteworth"!Har]���%v� h\7Qeover 70�>�Dl�Y-2�(05 [18 . 29�5�h6�.��Us!�4guanidine-EDTAQ�!�}Ypik��reEoe,$�,d2A |#Q six�3"�C"�%to �[�d!�5up�A�2�,)|!i�PttM�5!%�UM�i D.� fy��DTU!p28R ( 80A��/�`�w( cOA%&�D��PY l �"�1���1X"�l�6a�reE�s5� $cVI , TcIIe>� in� �� +e�to 40%� � 1%5 14 .]�q"I*�e, two؅� hTcV��F-E�co6(II� �mOlas�re�b�5 `0A��hc�9ic�&diomyopaa< ( CCR"5' born!~ATBahia S<# (�'th5� o!X� a W^+YQ�� "wEZ]U��,,ele�.2 Dob�9.�>.geJ.2Gq�ofwB])= ��B2�36hVI�]%�3Bo!H"�aw�K�(P�a!���50�Qfp�~I7o�b1��7%�Z4II evPtoh. Takaqto�",?� ltE�2upd�l�epidemi�3��L ledg�e9��inQI[�nlcJa 4 ��)ZAQbym�s J��Hs�le�e'I{ofiiP�mia�. Ce�( CD )F �1idC_�mO\|p LQl�%�.Q �Vse�KR�#f6� !��3�*cJ� [KI'Gca( 4*flagel � ozoanJr X��f� ) "#��Su!���&��D�^a�>s � estiJ%ar6rYl!�to� peophw�� orldp �7o590<*�2��-qe [�[@��p��`hS"�\���i"- ZliR` ,k6Q �[3 "�)�)9  s ��X�i)9kssO_�5�<lex.�@&E7���AO�� �!�*hA� 6�,.��Ls [�SN�Mth�Obio�%rI� prog�2!�Rno�$�!Z un&". "�[6*>y�is re3eI/y�e�@.�!���&{ qF���(�A, dO�tvgug�%d2� �[7–1>&Ie5[./�m!�T[1Ag1�� l 20038!�s%�Nc!�m� y achiev*i�nsu!cl�fy2oa�ayaix�n—9PI�VI—b��)"41&� 1�!�b���%br�Qc%^�Uh[1E0So fa $TcI&�E]�w�:q aQ�QP in Ain�Colombi !�0Venezuela [16U , 18]�x � V.� �2yAll& m69.C� TcIVE� comm�0�!�yl�9c wg�#Pre!�e�oy- outbreaks Amazo�>gq<.�A92k4q.>� MartFew^ . [22]�:� 5xhr� 6�%�,at Rio Grand�n Norte"� b� who)_��e�)!�I . Q.9(is��r!Şto�i�AUX� du&!xr�X� �'%�cffb� rtifly valu;?�!aSd�o`�@ apeu�>�6�(in>G2W����6�ass{ have��n s�)fG8ry2vA��A racy!u�M+A0f"h "� �b*�Mof9~ |!.P1����-qw[2F$2aM2�9l�]!![i0E.�J�F�6��B�:m �� p�[2jDI�J��y d��&�!|U�e/�irf�:� uO*.�9�G$ llite DNA�,k�R�*� :*`�ch#� WF, 2 symp�$i�[a.��/GZ�y ,I9 ��ba�5  ne\%n�UFn.� !��#gre4+)^M7% bx � ��Ig !bZ��9d1��!�!("� ��B��S3�S3" &P f � Ya. av���E'v�M#%1nd�T�V/qr.zL� :��fta & �no"3;exploTyet�Per'H�(5&�L���29 �_"� ass[/k2B�UN�2�G� ��,!�� !"Q�t)W!{R�P�I 16Vut s-�)2!XIn,1uto Nac%d de IJ �;a98dro�V ( IND$`, Fundação Oswaldo Cruz�#io[I�KnOij Janeir �d!�~A��)u�'idef�`�V�� �� !/�6!G�"S Z/nd*�u�a"�begin9m.=-up�"e��  0BlN#oyQ�]� aq�6:,�QAz�Waof-�MO&1-nA� forcU]>o �,. �j9�a:';eth{� �2{f�a'�js-s��I_\L% a._r"�Q52o#to4a�4:amb3V �&#��—^�, dJ��A���cP+i�39venge�{�Tas��� PRcal� e1��)*v�l[V>�his�a9h2�Tsn&)at��,:����!�.5%��2�s�+�x).*atesYT �� � b 퍵sp tw�):8Em��!?e�elo �!�L�<ór�kBi��M"ILe Doenças Endêmica� �2�Q'e/ �Щ��n�cri La%2: Tsz.)I :�(%� rectf!uno2$!P ELISD!, b�mg!�r�d�.(�t$c18*^A�� exclR�yk� �(:*7  benznidaz0,�X io�^R/�e��, �D���sch](xir�7heA`man�W�C� tiil�Pto<��esu��so%6�c:>�Z/@��&>*6w��migby| ���:6�u���<ɂ& *� . R�he_p�6!�& z��>��!bA�`�xty-f$:X1s5,�� 26�76)��%��f]ye&�4�$63�V 34 foA31 ma�� r�|(f�4��g�2�o">DHr:/>[32v\�%:&D by� ctro�@�.�1T"�3ir&�:���RacEg2  A�:r( T:eQ 4�A�!:� bQ � !�"cad�p aA*E�){% .�t< /" A , �tB\C�D�!�t&�b� �U\ [t"�A�ech9b��y�ach zdA-D��S� ��_&� &��z�cm$ mortaۃ&~ ajD��_3 �!:�systolic�S"ei%z�9A�fof 98%;{!: 9,5�mrens%�6:Y91"5:^;:Fno:=L"R�;.� m ( �Ln>g� 45%;%�fin>,~|�SN*'a�B��$GP]�( ����D�i: [3lVen�]62�- m�1I�"B � �'-���5^( in "!-K2 vacu +�9u�-(�1Icap�2S'w.|A�% an�W �u 6M G"�! HCl/ !2My"^( ( GE!�aat��a$�(wo� �ae<oŻ42. co ER .� m" t� A�e\/ F,FbE4�*l.r` ��9 unti}v�"�d )���&� !@�Q�/"L�e�I yG/0�K 0:�?)��i�WofwU�6��9��'�2-rol���per>H312=,\!k� l llel�!�C1��ll�"�EpimaBot%�90�#Dm28c��c�Y INPA 3663  4167 V��! CLV'%J"�"%~� Cole�de F*,ozoários danol�+�'T Bug 2149 y *]Qou%9doEe by DP$(Bianca Zing~�)�de Quí�  , Fd]T de S�Pauloe�P�z hE�P in b�h-��inf7 ( BH!Oum" uppl���16 mgl&hae�;�A.( v/v )�� t-in�Tk"fe�*bov�8s=,� 28�7.u�ogarithA�"�M�N�.%�y/!/�(�5:� -��)� "2- 5sa�G (�<)�+�$4 �`� .E�pur&|��sed �@QIAWAaxMini Ki�JQiapE, V�'c�-.d i�cedeT carro�/�+"�?by� ufa�} r’;_2Tmi�T6�\�v�s:�g�) �5L���<��q�.�%�A�M-�^�.e0^/L�%AE -b%�&/�<siQ�\�Dc�N%B�?��� n -�!fF Z2�2,Moreira*���Y&'(���.P(�7���i�2as s]y��jl:�Ae *G 2�i�6-TY{)�s kmb�VofKFe.x2(by Ramírez9 16]e6Burgos7� b@ �DZ - �V�PCRi�[��N&�&(Spliced LeawP( SL-I�|[TC� TC;d TC2 �I�s7q",�( 350 b��I�(*�(E�!��� IV��>mpP,ed ) !�D7 �k 24Sα rib�.l �\geێH�e�PCR: D7$0D7�W firsqB�1)x�D7�I�@  $�)f��('142�;'125 �% �140/14 t�&()or+GI�A10"s\"�ZB�Pr)�PV�r�V�f�+{!� ( 690/58 ��� ( 630/5��-�� re��e�y8� VeritiA�< Cycler� �<Bio! ems%�a�#�s: 5 Ή�Ke�lC?�" ,GoTaq G�q MasK/Mix 2X�|romeg��&�=U� �6 AfR>�Gj��f�5J-�8, 4��MA�9 dNTP%�32�5z- �1`achma (� c&�Cs:�@μM��Ai�"�1��iA_A; &-Fnd-of �Hp��!.a/.�A ��D;=D!aB�@J�@^%(**(5% w/v , 80n ,�4HńNancy-520 Sigma-Ald�R , S,Lou�>)��*�@at UV lp)!M �:�� � "� �@s^1&� F6H"eW�rJj�Y(ޏ��0MFJex}  jqPirón� 25� u�/TaqMa@foR)����$�`6�,( FAM/NFQ-MGh<� RNAse P g�A(( VIC/ TAMRX�Aw��2�q�ae�*�E�L F�-St-/ �3�.�( Rox )ABXR�@, Bas%xSwitzerl!���300nMi��h5’- AST CGG CTG ATC GTT TA- 3´��Fi2�2´- AAT ��AAG CG@5��|1x3a2b� ~(FAM CAC ACA�G C AA- -z-3’�9�!^9���1�!_.�;iK#a  G 5XQ%H-���P*�#re t) !�%�—Z����*�2�yL�<y�g�3l]E a�p� �A5o S R>"��V�k�9�A+15��%y at 5� v m�2{J`���C�_&h��.Ct �'q<r�QI�$x�A �%^�24–25�:2OeD&9 "04�tYa74�. Catego�Pdat:6*per��./ tinuZ0m�h±Y�a7�&`%2!:TGrqu�(le �, ""%�^t<I r��!^. Slnt�et-�a0Mann–WhitneD nk Sum  A*3� *5z#�#� !!&.7�!�- �� B5. A p-)�:EesZanE�05ma�P1dlyfAYA�J+SwA�Plo+[Windows �\on� .  yb S�P, ? ) . T(�iG\e-� � s&�mM��WCYdu#�� �� �� e "qi &vin"V'7:5*�A�emimx��Q.=;eq-s� y� �uA]�;�;iOS[4c=kto�` � ^g!wat�[(daub wa�E�P 6"�(� ctITxt�O�e Jep'73�� ~3A�CDE��q 3�_�R�}A�. FH he :<6�zeQnJ��29Z0e �!��C� �\�0�S!8AJ����� B 7Y��C (6����Slg�* 54 [�]�� t@ofb��5�Z�<( 4�w949�92XiZ!M+3�) �%6�!�n6��f��y�: &Z ���<,}J�>Z�b�>�C%6�IY6�MgZ �������n95^�>.R *� 8 2� � ~l>�~��!IJ ,2�!�49,?22�4�10BE>��na��'tm1!�zrT6�!(3-(6L"�78v��u1���e�/>�,�yH[߃�%#��/E-6e�&� % � pB[ .�9"1score$$"�m��c6�" CIv�2!?Mb�D %'3-�!'!��"!� 85 [3�=11BDq` �A=&2��ly6�=AS:%`��� he��^ 2�-� 39±A�9B�<"�/�JUh:�0H  ��c�!x6��)�N�@1Cm�.^�  ��&� M�B1Uup 6��� ��. E�p �a�N�^�@T��]�Q.�:� Y� rYk*2V o�|B�3(EagR*�a_��&}G�e&&30!49�\,H to 6A�≥&�BiI2i�ŝe>E�eG4u�:�m�V12"e&I-5�A%71C�����e@:J3+D NIA!Ss� �, (5H3��2E'��V�O�ot_>h��f�5%�5�.a3&\ :�5a21 �� !S56UB� �4���9��V�M&2i1 5��4}�1n � 6�knkAt�B,A�!a2�._.�3%$�1\E��6![%I�e![EH�[�[n�C ��DnDF0c�1b�>b+a� o 19%-76 ���2��'jIB 6m�d%c�>�� ��5' 18b� .�=2�k7�"}1A�5B|BA� b���� 07 [�s0�a���45 11An07��Z�f�/ %h� Ŭ8�0!\!T5� �A�p6H�eo2������6�JHIs �G*�ofT .&±%A7�2� �t"�}.6��U����!I� ��/|Der��Q�E�G<� ����A�^R�Re�?ab��regard"A!C )�: aF�i��s't�6_; &�tly����"&�9( �5���JIC��.B�30%4��)[%�26i�3BKA�H�:w)�JT�aY�� a^8F~ ���&J("+n[&�!9&p �V�8!i�G-Bw� "��� J6=T"xV_�O2S�Um�zseN� , *q#B�*�(��6p B�Z� �����3heu�("$�e$� !1E njun�>�̖�7ach�o;Cz�1e8 �a-r po(dl&�2"�*k cis�O.:��k2] <�* crep�r �U�f=V� y@!�g�Pri[���yE�ef��I/'k�$UM�G6e�*EaTF�Y)&/ �UtA�"�!r � ^#@$� r!ځ�.� �WrJAU�����t �M�An�"1�m6�"� �#. e�In��s!6l0w�K$B�i�gv*� ek]+|�+ �� .�vGyHv.�2A J300y$A�:L�/"s, =[rΚdR� /V/V0C:o-fou�uM�1�ly��*f�!�1<%F�u�_�I�I,Y E�0!Xr� e�C�u�e�.�i ��n:A9�)�[b6;�La��E���|ah2.R>�6Uri+#EJfsHP1e��>ru�Ezonacr:y�c�?a�B�J| du�Dpchildh�e8y d<A W1֥��~h8�e��#��&�/�!��:�>?1Oi�:t�N6'. S�9&��*a`�*P.!,N_RK.�AqM��A]E�� %�\���,��c��B����2g"�U{3 disp�}7:��"�B��(IE��G 1x�#%A&V$( Ceará ,�.íb4'P�c mbuc!PAlagoa�$Minas Gera�<nd>�)�9le-&8@~e�%�Q� �v�Q, Goiá��:W H+��6�S��e�I�O�*�z"!8:m '"�R(��!�I�7I�!��]}'�T�U)*�R".�]e߉�N��E@1M%]1�a�he` ��8e �n� ( 5/&– 7�W��Aco:�"t0Sergip�I���ǭ�))uGs � AX*E .%!��+�[�@�n�.���, T>zr %Qs�:�s%@lE�i�Im�A'�varia] 2�e�&JE.*� �s cir�?ng,hperU�r#�N�!�U�� -P� or%Y�0:oM%-&��!�s � �� 2�S:V6a��sQhJJE.� iy�}-in:�!o^��E? .5�.�a�5`>��@*��%c"Yi�.�;á�� [ Q��bJ��H"UU1�%0ixO�R��+ �=( 8���a�0a?��T� ��(� f.:�.>�M������/g xe|( � �s.�W)�2.d�;B��( 3@!�� Y.X%P��_�Q�( $�&:"!�{L>�'~D Y�A��UZ="�Z�}Fn30, �*\ 6NYreX}v�V6^ �D�Z�kor)�%A�A������va�Vs4E�O�$�B2� 2\'�7EcS2� �*)if�a#�ᆡ�O�{�hB�!�.�5�u�y#%�.�@��F(Y.&x 6EVI��a bro836���" A1@)1����I7J,&� �co�B���!(eom��T�6� n? � 9(�820v&�^qe /.".A U��y &u .�aT.&��^\�\!�too� to1��j�*� prof@ *��RT.| �zSf* 3���Y9p(/!|:1]6r=f.�hB� �64�ujyZ�VIIH��a2e��6`I :� ,�34�� 2� 2*���-�E�j :<FM�edV�ަ zrU]� 6�e" .�dN �*9X�&+BX? yYbig c2e�/a{�2�N!�sh��rAT�� !tX33 y eAc*�%Z61Y�FpK�e �he�&B('-��;�ew��8��bc�o�pׄ� prem�������5�. "�O�T��`fic.�8B�� &Wyfl-%f�val�Sed��=�m��+� �:� �! r"�\�+�Xof�vL�� ��Z3XM;��2 2 8~3en�ng]&�&DGz-�U�%�.7d�Ily�!� �ofFb"p��2F� �!ome>}=���i�Nm ��!8Mmo�;R�m�sub�#"9��"F a!��xW ї. A�$!�an urb��ohort�U>�_ ��[+&{�G&����.�m=�6 lexi�dynamZ!Y0y�%�e�^G*�L5CD%\"� ^�d2�(e�q 3>�R�.SKEB�m�Ao9b�$���\Z�!�ar�AS�Na��5�%�*�@54E��f�[m�,9adsS�K ��a� U��A, limiE:�zUly.@W3�XRj! g��.�><54J�V� ��dM�*Q&rn �",y"�J<� -a t=D�b�-igF�  6��_+`a��� JE zWw% !csU��atx1o 8 �� nonB,��;CC5Im"$OVyn> �.o ol!�t�1"�hYj ���r5�A~m8�.8�2�1�)6cu)!�I�I�(���74=�,��żE�.Lmy�Jn�far&�q�re�R�[�@th�o�� diabe�m�Yu�H��Qo!�EJ�.�:&s � � 49!.� !is4a[ewj�uc�&�� ��R2�:׆�{b�)�&n3comorbi8Ec=\�v� d��itself��a�yU e\�OoE��a2aCD��h��.m:"9�N��Las& A��>PD*���n� �4��&A�.A#%��0�r*�o�*ol9cap� "� ���B!��B�Ba%`�|))B�, by2/,-RFLPDY�e�dcHs0 reli��tW-�=0Ur��c��!�fQ5,� 0r�_&� b�Ban al�6thO�1]&�}���c6�C�R[ ��A��a�@ More%�%�vB� 6��!L&�9n� �'|�a�2�e�zj�Db5k}�%�I���>~տ� p*;by�B�E)w burd~�f�=K��&�!$!rd$yo�ş��s)-5�,qH52!��|ggh%�n���3n opt͐` ���y%]X%�6` ��Gy^ur..XO ���U.o :�.�"�@aS� ?A�A�e�9�-�%�2!82!,�"6H�.�:V�;'�;ur ot)��\.��5�� 1!5��05��*^_�h� �. E�!�!2��" I�A�2r( 580-bp&�D�K10B����=6�_g1�" [3cA�.i��b (�=Eu�� p:�%!�,W,Ki����"�^e2^MS1R]. ]i�q��,"[�atoIu.5n�t G|[VE5�gel�nf �� ��t��U� E2eE �$a�a�y�I�s�bE7is.��" (5��%+a��q�Z���, �7t��'��t>� B&�Y�����;DF�&� �3s$!EQ��}�.U -{#�j�r"$"�.��etj)�������8CF� ��r�rI�&^'A�A z��y& P-�sucD�I�=A_��%�CD"W -�+ �q�*�_ ����?�'s"�'H�!� �%�E�eA aA]&N;dom��c6W;�X [k1�����5 %�n�O��*|!( P��*�!UOeA) ( B53,6�!( Mp��R#&fiSul�E���, es [�- sox �9dZ��bR�batj�Q/]�$Yaz c46�!�a@%�e\m Z!�;H N�(�Gh%�( 2�2G���m"�E,��-����9�(�2.<�:�na�01ݕa E]ew?&xh"C �AE.198�32012 [3\N����!gN�9\beyia%;6�+�GG+M9"[+� C+ s CE�GFZP P MG%�GO �]rT8on��s� orig6�fvyv�`urm4I��� �z| � V!5�}�B�ur)We\�eR;~"O ���!o"�9_Q��F->of AL%R���]'8�Ni2�?5:m���� y�Pn�B� ��D �"� �9�aAs a.(�����ka%�.:he8~&a�R-%V+KOc ���b�xA4 ��–�W�fmz� B'}a*d%J&P'��N� � �+a"j�� i5&0*RGV>I�w)Q!o���V�UG!v�)� s) �*j�<"QEe$ pA&ՈhI�8�!&=& to S@r:�v%�,BX#S *�K!�%o��$ Midw��&.�,��uy��a�u���R%wf�ngW�"�=�D!�-�z%� �)M?;f!*>�di� sej�m׿n ȣ��~EDis6�>\��-Bn�!&���. s em� iz�b�w�&EF 6���4�#"{ %H�=E� �3�u���C48C��6N)5�r>�a m#��0en5�$.J �0@ :�| i��B�8 �� (Fr�Et< �2Gn!� F�S0�-�{oi&� ��:.[40�} A��JM�U��EA�!�fma��"�"~i |M��l�(a4�6*�C;1PVgdI j�&ueanY cw�d Boli��[3q*�q)�A&N)� �Q��p�V4Wz G�h"� �%1���I� e���.�o � �*��"��!Z��? %y -��&q�&Y� BD4aly|��� a2(�9�)>��r.�MN %�&��� �.! w.�" �n��'[�:�J�q�+��1)�)+�#2Ƀ�t� =L!�<ѿ%���*%am�61�2F>IO�!��7d6�$-8d!�* t�*i�� �*�c� ;%�9 CVI2� �)�;�>� 7E�0=�A"��}if8#be ��add�)v��)�aKn�W69B�/# ���%X!��'5^��%^P rvo�7(�E"�7:�5c�j,Epe"��7� c��eBOkno�o��9��6� � �MF5�)! UnTat)*6A �Es�?.�DAoTp2%~2�9|URen� )�6�/�/�se Z˹ѧ�8�8��jRab �^a�� ed enzoot��ʱ�New W�mP%I9��l&d~!�WK t!"� Asa�"!a���-&*�!aben.�bL� �s?Tille���&�sinl`tbk�3�Y~a P "�L672\$31"J� s��5�d �Q�8or��a�|&6 �vi��( RAB Z�LJ�all�`��� !���"(S+3%�`4��> tige�( L ��Y" sG� ��Nb�c�P cQ} vampire �({modus2�un ���Uid�F_} swab�Plun�kidneyn -�� eZvi�p�^W���l"�wti���#a��[h���^RT-W2���� X�n� . Sh"�/ �=o^�w���%�7�%�e�E 100%� ��\��6[U�a��xgsynonym�T��it+� 002T , �IZ!�=�)�-��"�E�phylog���r� to�?� a Te �� %� Mexi� El SalvaM�.>-Άs�c6ej398I demon��E_neutr��!J�|�)&��!��h"EXs4��g*/��U�icT����wv���\i2�)a�����}xa�perpetu . Ba�( O�H: Chirop���faveH�i�a� d!�*�B/r! �TѧAem26n5Ce��ah�švi g?nСh�~.,t���c�ql5�Zo"/�e���[�{Ga} malaO h�7+mD�'s �^���bio&�(?� �e.�t�][2]–[�&A®�+ ^? globZ� �' �(.F+Ua��We��qCo��!<Pa�f�Y&�]��s.Y.΄!�#�d!lp? �4�"te~!�E�p�fack@E�32U#5�novela�a��d b�����!/ZC�h S�21� zoon�� ޥR��e��� ]�"]%� WE�a�2^is Y�/�� T Lyssa docum!�V�&b[C NF�{ݵ�l�>JA �Dw� c�\7essa��9ph�pQ4V%�by�%eY�G�a��f� sy�|m[at� tu�KA���!5 towa6�c.�!w��in ��ly�3�F[4R.�epiq iqi�e��pӘ��%&A �.�l�w ory- 2�net?z.��b&�b&*��u�p�}ve6S�qA&A7%�%�*L>��/��alX� fe)&�:nsD �zpr��n���s&�&%�_�+[�N,�fy9"lle� $�*+`�A�v�/�,f ��  ��%��s�� �[11e�1�]G^^E+, �_��?%��wo ��lE:�trie|53>�carnivo�wˋaC�'�0����ebNe�, r�!#@skunk�#y�� >0�%�I �RncogN��^wo���UD�!]�6���or ‘�s?bL‘Y/ i�xdog� A�2! �b���WE�$&5i so-�edrB �sy\�z�Ad�ԡ wildlife -�% �r[��] *3�� appa~#eW�b�"���>!%�[�V.~ exisTG�E>�!��7". Tropica�Cb �� �'�.$pricor�FaXC0���2��\���� eE-� �e"8der��nut_io8Mfee$��� �L &Ȼ0!Aa� 6 ��iqurס�E� adap�ow 2��a*����mitI ���*� ,M�ily�Dstocks also��,��pVn� pr��re)^�Fv �[umR���fa� �&� a:v�sp�XE& frug��� AAѯ�,oE�.A1&^)&�x�� s negligi�5�  $�-�A��� D>�(F� [17��]Lr4��D�)nU�H��Organi �%"A��(4u, ongo�5�`'measu���Q��5�,J�e}��-*� $�c~n�,�B� 6ef�cven�a� W� !�X'n�!�ro#�m}�� <o"_�[2�6=s��� �>G t, where �samples from suspected human and animal cases are colle%, sent ,(tes9Tby the direct fluoresc'12>these >were due=an unAGifi�r unknown exposure [21] , [22] . InL$ U . S . ,!H erou�!GA�not been �e6� 4 is uncleaAkconside%E�GBC>�%�Eese� ed throug%�@North America [24!zVery few =Aߑ_e6 uponhexist!�0passive surve�$nce system-amonocl�?��@or genetic charac�za1{�,variants inf!�ngIe s , domes>�%s� wildlife!8est whether enhA6d6DHwould: ( 1 ) comple�Vq,�$ally regar5@ �c�%1q��@(( 2 ) extena�A3%� M�Hgeographic distribu2�circu)� among!q�assess%�publicEveA�n�Q,health risks.2He�2k. AllU��capA�.d handl)�accorda���n�Aw0uidelines ( G E~!�Ca�A�Us%," y An�s ) [25�( Protocols>i��Dus��ved�CDC O6q4Committee ( US�p d���� 1843\ 2096-�� �^N�Xhe Universidad del Vall�6]�!�Y)�4A�se} as9 ��E� aratA�New Worm3y loc%v2 part��qCenter)BDis� Contro!�d Pre�+'!�!9) Global0De��( GDD )!6 gramM�ten igU���= B�hKpr IiE�develop%�,strengthen g �capac $to rapidly��!� ccur id��fyndcmptly�\�� emerg����� threu. Ninet�9��it@ or%pl7F4e&5�mӡjs ��i��outbreak�,�empora�5D2�dat�k �"� .2depredI�Fh� 6&or neur��� illn�B"� 2�. Fig��1a*ust!f�p��� :�.?u i��)t��. B!w%Ac"{ us!h,mist nets se 0ar fruit tree�� confʼn.o �aw en�Y��cavx NQpope�� betw!�19:00A\0��checked * y 30 minuA.�rem�|ť�, plac�*dividu�6,in cloth bag�A��s < o a neark U-Mt)�,��re��y �s!���a 0 . 05� . 1 mga�ramus�D r in�7� Xketamine hydrochloride [ al/fe!�swabs oba?ed-termi��bloodies �9� by c�'ac pun e~��vy anesm i:Follow!�euthana,iq%�m�{ to! l�3af�e�Da key�;e�$of Costa R� 6�cS ard morphumea�   � also�( e . geL !g!6mas1� forearm l�ȥ�A��,lete necrops���&K on all �I��%� AX mmedly2dry iceAb��I3 > main-� eafter�−70°C5l�yG��$until ship!01���R��in Atlan�� GA .�Rc� � bandjfix� n 10% buf� d!Vmal�a��}ay!v1Gmanen��eZfer!/to 70% eAY ol ,J archivJ urpos�"Brain im��� s��paDe�frozeB  tissuQ�� acet�at!a2%a)� � gen �Ti�!q>� , �"f�,sothiocyanat�,FITC ) -labe� N ( mAb � njug 88ujirebio Diagno� !BInc�4Malvern , PA ,, ,e0described [27aC��!+e�i� neutraliza��bo� ( rVNx ���D����nt focu� hibi %( RFFIT�� mod�micro- )on sera}�%��i!��[28�9��ti< of i��i�e�cal�Q=�@Reed-Muench metho�- 0�:to 61 unit� IU/mL ) �7omparisO�� ��8immune ua( SRIG)�� coe�!�2 Y[30�-�%�*rŢhig1 ��BR �ɪA��)v . Fo�}:� is��, posi� .e( ≥��06 �))6de��b�� least 50%Yc�� E~chy Hnge virus dose ( 50MO !p 4at a 1∶5 dilz 2c10..� F� %Ps lP �h 2�Qged neg� ��!L.G%u���iav�@on . Ant�TN�aj�[b@�iABo�`a��seight�6s +�� gain�he)enucleo@ ��( N )e�� ( C1 , C49102589 �suppli� ,EMD Millipor� r e�( BillM, M:� prev�  ��31A�PUteaiH patt���%�analyzed- T����ge!l>Is [32�H3bVE}iso�!�smp!Q �� .g �� n growth ��$um ( MEM-1��M orga�"� �� DFA-ub�� moge�4�e�Pw/vqapr��4in MagnaNA lys�i�� h >izub��[�4-m� diamx��er� beadsRoche A-�SciEn$, Penzberg�e�y AI�[ 0 mLA� � as ae���� re soli�%A�%^� -0a� 5 ml"9w%�u� ��o�� cel~9Ɖ�Yrec�k100 u�test iDumYad�to� # �=G 5×106 mo�� blastoma �( M�9 in a T-25} �e flaskayor�� , NY��T)�2(}incub��at) % CO237 ��72 hour�AllH B sub-�ag�$ imum!� fourU9�oe{� s0 v Teflon-co�9well sli-e�see!Ew�31kFH%�)L)�perACi3�%Ghumid�.�j245�.�t r�d �$phosphate-"� s� ��PBS 455y�"4 coldR9 !�M !� .�{��-� visuk �=A@�&e� I�K optc work���� FITC"H b-�L< c�: q each[ag> Total RNAe$ extr�di�y�x��M���-IS�F�6(TRIZol reag�%( Invitr��parlsba� C�?. F*�Ipto� �4ofQm ? IWµ��y�t�n@ �mi� wA�PTRIzol%�!-�� Prim� �? co{reg1-�N� �R�initia% cX��& N�se}er 1066F��PARAGAAGATTCTTCAGRGA (� 8ons 1157–1173��which_(�IA�]rse� crip���Aase|,304B , TTGAC | CTTGCTCAT6{514{53{�hemi-Ied!���87 �GAARGAA�v� o glyc*�t gene)mpl� �wo' lappap frag��I��e�bi�(s umf2/994b%'760f/308���N�V����!�ggi��3S@(t Alabama DZineRwa{ enome seq� ��GenBankOe2M31046�j T-PCR% YkA8elsewh�[3�&� E��Zbym t� ��. nproduc�pur)�E�Wiz6 �(Preps DNA P#;SJ( PromegiMadz , WI.c�{-Lmanufa�r's mmen��� �� forw�aqc )�.h by)!��a� Big Dye T9L! Cycle S)��ReadyiKi �onT 1| $an ABI3770�r ("� Bioa�^5!��N�GN͞��mb���l��to yo acid6i �o Edit!�o[3�w��< ���t�ga�1�(s available�qU�nd alig� in C�alX [3�2S1" !� tailŕa�)�es���*�incluECac6J!jcount� origi��y��i� men sourc�E$he GTR+I+Geli=�3bSD(he BayesianD#`"�Akaike3� n eval�� MEG�&Q>5Q . No mole& r�ck7Ad!�iL�Y sis�=��sky=*��*"#�Vindepz,nt Markov Ch��MonteE�o3 CMru, xw� , 00��hs���2co��)LogQ binen� ���a�max clad!b edib�$ ( MC� treeE�U@ TAnnote�) 20%�< burl m*� in� ;,5�@ 4 . 0 [38�#E�aa� m�9 tJMPK9G. 2`SAS22|,AS Institute"GC�, N�)N95%��dval$ CI )I�*YFpro�"of�o��v)#s�*ea�nd ~-�# "� log%q6am���� a0ef"Gtro�guildaO seroal�. Spec� eA_a�28eti, �randomh�z10 �. A'@ly a single sanguG%1we�'�!al�_�he-outpu�Eaa�c{ex��*m� i��'=Ssex)�6rI_ χ2 ����h.�ignX"] as�_!9(t α = � 05 . �%.#", a tc of 672 of 319�&�;&�.�%d8&k ( n �220; �� 2010!135!2!��"F317%� �p1av !'d�rScum"v���~�#Q�by�. A>"�� !�56 . 3%)�mala0!�most f TtC ".[(D . rotundua�500; 30%�followe"�!Jamaic���ba�$Artibeus jen�.9128; 19Q(-k�#. F�*����#ngC398�28s�mon��!� %p"}'+F� of 7s)�� CI 5� �. S6A�R!Io|.�(1G ( 21��9)omnq�( 8 A32�( %z%!��-�Ʌ�d b*� %uf!� acroJ$.�j ?��)� x ( F3<*0m�h6�p e�4;� ( Diet ) a�3 . 4� −2!�ٝr���)2p( F>sA� 97 ,6s05Zt�t1u�*b�modelapairwi�*##asts � a� =/"'ce �� frug1��i2�%xs.�� 8 . �m��+ kely��b� ��� �to2rK.� o�N�in]r� ż�2� Y.��B� �m!?��6�F{>Naranj� NEl Jobi� El9�1e9.�2�F)iz�!!,u{Z���%�6b�.J: sexe� similaI A�8%a��P!3fY,es; P}-77DH!�e�()*-tdq�m����]R(o[)!�b���S common6s� E[E�c"�#in%�umpo ,�"TPa. c Co� �`t�!S�Rosha(Palo Sec2Iborder�  Mexic2cBN co�{�$� �g��on� �,vo�)��me1 -sth ��%V�Iant V3�2[)Desmo������U�,-�o#n)�!��d)zd.� clin�%a�sB�7e��� �. Add:�M.isXe�de�#�,!� poor physc�+;mwha %� � v4 b/wound�'�e*M�a�?8 ��W0~ M�he kidne�!%A2E�"�z���-5.� s&���bp�,"&R!spl&�/ne - �� lung�]e(� .��? hearO�&8 �.AT.�.D*%u�by2���� E�exc�%except� z$of Bat 321m,r�%N) "���^,ci+ A` �i(:=��)`-�I��In� ,E�o.:qaN*��� geneI� ~hem��6��"�^de�^E�to"�(F�,: KF656696-97g N���� oth �[ 100%�&cat$��>n/tAr$non-synonyA�[!s$( 302T , S�1�2u� щtoP!Wag)�*\ %�esG"n.n;(���|�rea�v��)�5�d:FSou* 2,�O!I���' lumb�H��� phyl��1����k1v&�$� �Chiapa�TabascoE Veracruz)f" �{[3"$op"<.FM�A�5� x$El-SalvadoFJ22849�derQ�-� �+� G ^x� u��ish�5 ) . &�2"2ec"�(ii,tXA� , e�3%RropE�^!/noveltegA+a�ne��` !�!p��(nd�A�$ i-a&�6zoono!�. To *knowledE)ta�.he firs32%���of)s%��i.52m Ks83���"� &�5S1�<&�Q��low (Y3� ,,n 3=��� he�� � �!�Q�B�tou�=4wi�_&!6��%vQ��I�M�!�El U{9,�isE3 unex:+their*�-M xim,#.�))4�4^/}� M�� e :�*��4% �St t� � space [40[#4�#�#1< �!�A� sugg�tz5.z��e"c g A�!� erriK8-J�If tru��,e5�may ha�6iA�duc]o*P!0.� via 1� h����aFA�1)2�e�1*�%se�9I�multipIE�:+A��"ara���a .Vf� ws2�7tu%�A "�5 Peruj5mIGrenad�;7 . 6a^!$ TrinD3( �:�, but*Z'!�37%=,� olimX -O [42]–[4":�)!m�!mH ran�"%r0� ,!%=� 5�2,M a[I�. Our�6�;conJ�9e�!n��%�!�i� 1��E�a � a�$�of5a�7l �5y �E�MP�%�� d�ng{U:t); �mJ++:�;+;ph m !C��"� dt46�An { ��Z*� ��B��f( �doe��pr��or`7ab�A-ti�)� tens���0�3�[4�FurA�m�(, �"�)`5�do�Tgu�b6a lack!�� ��-v�6BN"�,cutoff valueG�bQ�9}, a� ie\DGilbert et al . [42A�*&4��%|WA�m��&G h��v^*���4y>=mr{orjM#a����#nt�����aGty�ly  EGi������Y?eIsuccumbA�9�!�>!�-���a= J�E/Sobserv�si��m &9:�m-$in�&anѧpatie�<[47�C�akq q�onU�M�^>�xbMX to elucidN9 "�<�:]<�&8� excre�]Q+mea�(ful U,�8C tify�Tpo]�� =pathw�1%�Ui6;e� strut!��b ��V� ��of��� x�l�ZA�^*m,Bw�se5�� or� �Ase1$by QroM6� ��!a�#s��- !�ze (9��k �.C�%rraA.f�� in6).S�7� t�4�l��-�t�by.3 j Latin"�?�XrelGi�2 l�4�ireA�1a�ei�Rc��B>de)�-�ooo)��*gu<4s��z�attle(>�1. WW5!)6@�(te a�,q .Y , it �'4E�K��Lear�?Da ��@pread/ Ab �C9'AVogrooş. CullAA�.� ou�/,to benefit a"�De��>hA4�short-�7!v1vi!�F>�Hs�B�-<:�^�"�&7D!��li%�e-+is-�  %�� targ9� ���ap�A�2e"c1�3.�>;�!>!@J?�behavie�responu,���in�E�plrQ�sus7e�%�[� , [4Q!�r�Zm�!�atAI�Xbere�nomm,)�c��o�0e-�D vacc(AM���#eiq](5+[4�R�7� ":Cat�r(al� A,&�fa�.u�8!�jurisdioMjG�$P{@HIw!yS l Welf�[5z4 �_ol!�or�_|/f�5e�=�<i �\9:"�CdPG��D� to a*�bm d��as$ I�E��0aItec!��G&"EJBcuri ���achieve m �G eln !/c�el"G5�In(>�=�s��re$�u ) eb�v�?�3�!�eAD\IH72[ �Te)�of :� -tc g�r �� �A*� [5�GD9Gpo��5Cdu�(�H&pof.�� kwould[ 1Ti�q١����ci`Ac&�'&�;s!d~ bn.ra|��J6w("S?on�]ter�sqR�3-�rfa�Fh�be�)ed.M���!5�CzA!�KI��� by �:o�!AEX�Kmpaig�/ H�aI6�M!&t6 l&�;!��)�hylhc���f� %����aH ll bat-proof$d�1 ingsaDre fea�[5(5Routine�-�(E%2��"vto� erly" $ G%~-�- �k>d� AO�)IIsubu ��Tll-�"�D�)involv����acti�5f��brvoir h�. 3��, xc��2c�(t� E %� barri0YUa)�t#b����夡i��)o"4 & A(�A1ac urbana~syl� c c�,J6��.�,� !�� ng1l��$M� ��im�G�RDy h�D" -+�An!or� !���if�sFp2j!4��is es�H�.. U� tu5l�5L��i�Desy%.� V �, o "YMs manifeP6 �V�M fatal!�A�? roachesv�&anBKpAO!ec!�U&� aYNprW@!�t&�� xia�iB!�"�@"hing/flu %Ddis�`!�A;w,$prompt adm�O+'�< ��rn2-�6��2C� m,d "I schedul�urY�Fl-�ifa�>k<�  [5?Fo.��t !I uhrad�&,�$E�0I�E'.A~ ��+uthO��mp�p., .�gvICr pers2/?E�"SS r�ǁE��or��&�w�L����Ccar�&Q=�*!��� -i�.��LI C9 .. L�%�f ^� #I��`"zms fo|�H N�#A�!*broRde�sc�(Iy�EHN�+FL gage�6 !�of. &zRm a One �Xex+C�ص���2�p!��-X�'�%uro iE.lG&�)i!�new���jointJ�*BL"sE�ouch J�odQ�i��WdiaWB.��n!{�emote���A�!inupGR�MXMCZO� e,DM�ZJ|c1�[55S5$"(#EP!) e�:� � F�h G2�o�m"�&�P�/.>a�"LF9r�Sq�m Ve�,am�Ac�z(& '��&� ���scrat�& , sk�H�=c�),e/takenJ� #nd*� q-borne.���I��J ignoA�W o^$-�|+h�J-�h[o�K%�e %ure [57�5�&1���w�spS�(�N��Cope��v�l�5iEwx`TgFOE�|� �4� :,��be�v�!v �A����u�!xrobusH$ong�-F!S!�!��L� .�~PostY �!�@EW \���is%��r�+te chrof [ �pT�9al�" EWC la;J__� 2e= �t3P hete�Jrm�Hen�U9Stsi�*a�� ��,�R&!� J��lso�Ky�l��+ down-!`�M:��:9e �)�. Herpes< plexq�8�;�repQ�Dr*a>)s&h)inn��/!͉�%ua��5�A��1���l�%�!fE r�of Rar)��HSV2�%S"d&&� in1 -typ� d A %�–qBHt ( Lmna−/− ) m�embryogC fibrA�3MEF�%�.9S(,!`�<p5R2C!�i�siz � faila�� ]��E� ME��%WT {. CU��precipi�%� 2sE��m��#ac� !PE'F�S�dB!in2%-6*� argui_a fun!3o 9or2�|-Sg@9ex~�,�r=i��D:i.��*&_ sTec4\ s.]at�#� i R�I3a��eEc A/C�a� )݁m6viA-���2� s . R�(E�)gfh=�#��Y6~.�!�t]K_>�Zu#��[A�>oseQl.�bm-Gate-ea ( IE�3 !( hKes [2]!gsA5 � �V� �ede��-Q Is [�� Mh�iA�y�� !ԭ��C�:�� proc���s�a�>.a,��*}E.%iAi��o�s�%�i3HS*\C�Y.^L�%D�D%A�.,H!v:/�;6encapJW!( [�R�k�i#p�"}X�@!i' "�>��ar��m�!�y$"G )�![4[ # FUV�m/CU<^en�VekVi�,q� ICP8���ote='$ y [7� s*7X��M^.�!Mje��9a�/GU� �R�i$Lsru�J�����4pWP��[cO9�(�&���oali)?��oI "���1l�8bud�a�p;y�� Kw�0�2ot��|*n*+$� -=h1t2+6�.�;�B*�i &�Yo�R6�i a��{�3%�6�m ag �) A� a�tegA`�us [1�%.� W �s �?C , AD�MbC�,�����.�*Aˉ%/*ncoq �V he L�1e���O�I).."� s1 �5�crve�1i� [1�.6��fou�A)]�)@xO>�U?�>�oplasm:nW�L L-]&H  [1�M1��L� �b&!{�7o A��"��4��o�Mi��c��Ea�[aN7��gAU#�Fi=e���alB!���7�N ?*�5@[14a�[1%E ofIZ� .�g2��VM�%�# � � �muX � �9Yll{!p��  ag>��AOl�:J� [16 ҥf^""ng�qxe]y��%:m*�.:Fimmor��e�X�Ka�F� � .F knock�(m�Wex#Ui)�6%�5� �,�Zl�Mn5�b�n*Źw!6 �er�)>�[1��1�T�!Jofe�I�]@KT%�>�.�9&�x����[2.21]; h��in� &u�[���"]��$7}��u��_ F:��b��a1��Ri �$�f!Qv�&�� [H��!F�&� G��y. A�ii�be fu�%yZ/��&��)sL��.�J<��9��6u=� d��L�#pro^RqYa��7me�ism�3�kue;. q�Spl;(a�Ya^nt��B1y ���!�[�f� � viris%�Q� X !�A� e& ��%����T�^)2�in� k UI%>�o�6AU�`9 as� ��E�B� �� $! VP16 tegue9�O1a=V�!- �$E�ś&� !��Z=a0�.�.�P! Z� [1| Z!����[�YI��Z ICP0�ac�L  inZfw de�[yl�s8 OYIn _E��N���Y�"�N F'"ra"�.E:�`o��on�G./�s!�Z/rP {�K eyon�H�V� ��T�#�h���Eid��圅�-&�I�� s!�Q�o%5�2�>ga ŃEV!�:honM �I . Ba� ##!Fl��� IDZ) "�#F�A�%�.� !��KAI�%�� a�.lqVPhyp9"�!��{%Za!�yAH!�in[e� �>h�?recrui�#2��.\.� :5X �"u av% T�of"���' �rl �A,^� -�^�%Xf�WTmna+/+�Zd�"f >��� (�) . W�8uA�Jt� .�z�.9 �!��o�w�- mock&XU�B��mA�/]f� ( MO�K$of 10 PFU/��FiU at 8�Vs> la4( hpi �-C`�,f#A �WNT�B H1 . M2�%_ Hiff� i>f<���1oth%PN\�; �6A�.x  r��ed�]f6�"� �,Ity,%@�attach�:`G("/C�panG� cHQfew Vex--`AdbT+T�2 *mu:�_Sx2�"� e�%csm0�>k>.+Yi4d l �B+� �g�%� foci Wy# dens paEi��.( �t�.Ah .�)� ir{=��:G segY5A�*��fC()�M�`�a%�?E i di�,nl��.�5�%�,!�rGto �q�5x��9l%�V%�[31��! X> i6&*7s loo�[3IE!�4�QRm at 4�q���%2e�:pZ?nd�K�#�Ar*�p=� �2ha�FwP��!HJ�B%�� ��5V:p)OE��({a�hN�,"�&,{<��(�&�;EffA�RE,� &� /"Si2F} ��n��UV1#!y 2Q%E��@�{��36�d1ZA� %�of!��6eS q�h . Pl %>1�? .�)d�� �tt8-��Or~0�a6J>^ ]$( L . Silvɚ�0 Knip2 ung,sh�[)�a�}$@Z�H)�� �$emm(�#1 �}p% �,n� �e#! a:}�M.���eQe i[�&�+Wg�8����� �an�f��3����E���F2fJ�. IF�w>o�A{A�>� ICP4���( & � 9]as 3i�6�& o pein"2�!^�2���bbQ�Iu!��-g�#� quAIm}!�bT. �"- 4!� �J1 �28ssk[��Q%�u ymmetri:hvI�zH�!Bdisb�� 5���3>� 2ab�6�2"8Y>�#a!?� &>n8�na�+J1��{! %�:"�>�s!{.�Gb��r /q�,�#r6~X"�u���>  Z7� �qop�Z}V�� &�=E�JDE6� 2�s1{�U��i� �1��A�z�xer?�*d @�cA�-3��b�aorV�w�Frn�stdB�DV�!ICP27 #x%(#m�-(��� �2 "= u�3Fl�4� In aR-i�"� � iij8�q�]�#as� n�5�� O a 3i��j ao\.v�!f6x3B�a+�y"�bZ�e�)�]�I"I.>(�0T���e�$ BM"���^�W��)�%�5ea��6�^u �����$lvV���B�)/,I*�AE%/oB .ed]:*n co-\ qr��f`:��%\~V�m�BJ� rpy���>��&�"�!���\� }� �5g.d37e�%gI<�uam7a��os��� >&��h'[2�nH�zA�e���>A� <%R��.z��"m s>�%[�. M�r^X �,.�"ca��ma�{!�"V h9=�y$� T r�xifB7A�>)Eb�n�4 �ck-�JC'u�J|� ��t�Ftv;!�forOmU�3 lys=9�)3K9MeQV�$4$2�^H4K20 &,'* markH:JD"X-�I�",R6-��kb.�*4A�4�e|>[I,'[�0>� appe[coincxti�!��f�.!2�B�n���,�S� eU>�N]b)�,�\�.%���sjNNO.A�A$>��Q 1αAIP- }q recog�qc". Q� A|=&� &G<te�"��#���J�� i{&d-�� �ed�m!� e�&�N��i�&�)�( ChIP ��&�������� �m� \D|�Ti�� N� < H3�>A�>�q�:�,!�2_�e��h�=�ed��A�B �Gb�Aal- &k)b��B"Zstart�+r�Ve GAPDH .1�K-c��l�"O>)O��>�=X-sJt�!��6�eG� Ap�U��o�6j�B 1�n"q-�y n_Nli�%H fd) �@>as!�� "�\� & �B= e-A&� t� �dc"�2% &�x��!� ���Q����!� 20 � 5� "��$��;! 6� a�B�a 6� &�.W27� a 23:*���B!UE�J~R� > A�!6 �T.Kfir�L����(n�ppV�!:truD&��%gac.�%DN���"�72lJb:F�ht�&� Q��*ids�+��GFP�� GFP- ���Q1 Mm�5��{&� "� >� ( He�E�r^?(!��eE�GT ,Wa–e��.���p abov�>6fR6��.�Q���t� CP8m�b��j!8rErg��*�&FoW��F@Fi:  f–�T�Q��=�hKC����;Z��>�!��>�2�xA� $/by.k&�RrguAF��A��+ntEg phenoa8aE� %>�E�TԐia�2�O,[.(�Q�:(�NJSo�#��6 �$B !B��2j��IE��E��g:f7 ��qc���Hica�52��E%�be!DE3JWRl�:i��)��N�Lp��!b�eB4�/ !����.u�s]Qi�!�1 />�E��6�A�$ ;N�]C/tst:�%P X��2 aC�16'7��� ��� SI 2�I'& �I��h-�� �cizon�(B ( PA�A�2�,�9!�U$Bv !;� '�\A ��I�1qu&�q"Q �9A assa byVy�er ��6!�oRa&dit.m$��7�aXo$� n%|.�Fx�Mly�N  Z? �Q�$(� que-�!.��a|%0)�fUGto�E`AE��tŭure 7BS .�IGr:|�xFsm� �%O&�qatZ2�.�aow(�^01&�%� O�3)2/100� �r!; �%p!�2�b J�magnitud"�3�;�RAҭ�YY >!m#p4ty*{*�enuy&& 6CF+ -2቙�r=� 児�� A�r "�)�Ion)�m. A�}2�6t6M�aHA��Z�m�"� ��lyq%�k�Olg%>�a�&��Z�"*E� .  �� feI2�a0%Gv�Qq����O!�&� ��>�J� g–����.:0��A�Z�j&N� at�A�06a�'7)��� �,m�*<n�<,}� . We�&�<�!�L Ail\m��*��͗a����B�2?! ��0&8wp"_}G!�a';;"�|:V,2!@"��"��.� �H��cA R��� �&��92!�w9�Qm�Tnw�E�%��1�2T>jnYe� 0���5H#$EA`��v|!��y^F!�*�*' . fa4ot6h!.�/)!Ii�h&YA��`y�!a��[a)�e+U1�as yet%hS h!!6ud4�?@��&�#a!�%F�r}�&HD2�.d��ls�nu stag) ~r}at�(k)aO�"e6{�(a�9!%t�.w5�6�F � gw�J \cDS�I�"=��M"2, R].it�ZoE) ~!P.,�8�W)h�6!�tJ<of�7s%�aX���Zay�L\�V�.2b@��) e�!�+I��cyt%<�:?e'�Oo�L�JA"a�Mfa3tu,��8�%�=���ain �~�&TI�1�!'�� -�!*6�1".� plata!��.wwhile�ic2n�ic�vV . It%,:'S�su%$�c�caLi-d���Zatt�: .�.g.��]�'��@-(!C�F� � G�Avi�H.3^L3p W��-��` enzymB� keep�!�&�B��GD|!���_"�>JA���>; ��E.� V9 y͉��B:�*~ 6� U�j.� (22)Mg*�� J� �fwV� . D� Ŭ.A�4a-Ua4>�.��ZG!�r*T�A� �i!Fs;�V h<)�6�@ exerj$""c �6.�-A��N�=  , ho�BA&�<�H�km�V>�blocki� nceiv�OEr.�X%/&/�inputnU�s(��AsMR5f M.14%�V� ����� ��� . Al�o_��/.��&� ���ɂW%V�`�Bu�;�i�@5�m�bys"a!3������:?���,,�%�` a)3.�>�I�:lCd2s�:�:�,gžZ m�`@D"� �)6A|"8 �A�at�x�=: �"�&� �&1a&�I�erA�'�P�'�^spl� E�'(oc�<�� a��A� %fEam*�AJ�. M�lB�lB�{�a8 .~"�8�BBB- A� � ��%l J\D6B6�� �.� ��  sf�Alw ��* seemM��*"���� �Ef��an �@J! aD2Eof š��m,�P2���[�[8aI*xfB�r2j?&IonR �L����s��BWNB�*&�!z �k>�)g�U&s�!J shif�� bala�-towar*�N�<�9�f* A���=<�3 ��FH@T:= %tM-�ej�:� �9հ@%*-t4�Zb�2n%#atency.@-��pDng�ep2N͙)���x(u"SV]$Q's+2u9e willI�go. ���(orF�p�/����FMa���\�$u��"sX-�is�h�$!b2�s(exploS)by%�to� �P��=�!WlyA��-Z��!�[se>�#A����m�s*wXadely%m�i�0Ac . I.,H.��3UagB er-mZ&�;E�ol�; ��$B%� KennedU�tE�Wa�_ton��. C�&G'�$Dulbecco's���Ea���Qu@�0DMEM; Gibco )�6֍jse�Obov)ser8FB {+5%cal'�BC,, 2 mM L-glu�,� U/ml pϙr�O/100 µg��ptomyct�in�*�. W�A�AM-1 KOS6��c  )!�ti� d!� Vero3 ��Gb� ���ly�*7uMA9Ups A�.� a�""2� 2�V��3 day BUu�&.�N�ol��( �o�l=�\�& 1% glucosoWa&zmA��`1i<1deO EKwa�7��eq 53��� �cid/7�u35ANaC�@10 K 4 ci5:��G"H��� wA�9-cub� A-1%E�M��!�!�]Kc� / od�AB.ebA7alE3th�`v{+����*IiA\E�e�\�A6.$M8Y��1�or%�.�S1])���c:�Uq>D plusA5a�F9%.!oN�b��M� at 1w�5 �/�Xon glas��lip 24-b��05�p�@5z�� 9��� (2�Y.�+2�.�9)�Qi)+� �(M"�(p�SB ( Up|�3K�+Abcam6`'(.e6�]� :,� Sig.Techn�vRI�I�94040II�_bi�olyc��(�Xt�Fcox>6\*m&ݱ.�^8F(39S�oor.*ra>� 3-83�x ���Il=X"���qAlexa 59ڠ 48�ao 350 dya �SPf�u��E�3b^�]M"S�P M��!aVimh�_ Axi|n����,scope ( Zeis"]w��a 63× &���@Hamamatsu CCD cam<�(�$el C4742-9�(Iq }d! volv"���a5�Fr alg�fhm�  �vi�S�e�x�_softw�s>s��pGFP-L�%kin�.��=M h��x,!��ds� f � AZŨ�pEFGP-C1ar.vb�[4�SpExCɒClB�c��d&2(s�eZsVb�sY��at�*3'of*)��ӓd�IJ3,��B��E��О���� �6�)�B�. T�)i c�&0"�dayd^�)enejub( NovA��"nd�5 �!*%!=�!HLA� #�B*9O��e� *��)E�1%�=�6a��Ra8 biotp��}�a|or 48 hFH4 ���,��)H��0�5�n��of$32 �H!ѩ�6�F!� pi �P�P]1c*PAVidMos pCI-�7�~MpBS8� vin Bry�(�N�@%�Etto �J hybrid�L:IQ rm�)�9Gu2ȅo 1���r�la]��Q32P dCTP� eG�-ElŜ)�0~�-To-GoE=  � �sh�u.J  ���@�-��� a`� ka M��pin G-50>oum�h GE H�t�l=�#e�K6>� ğ�!1mLAb Trizol LS�/F��)e+100 mm/+h =�:�;1� UtdenM7�a&�of'��m9�,�1 M l���A1m� ethid� bro5suh����rophore������ agar� gel��!�1�moQ�× MOPSi b�45���m�r�)�A nۡ� ul}ETq� (in 20× SSCM�blo��&L (in QuickHyb9B(.{!�< �15��{at 68$�!#thzu+�" Sai%a4e�t salt�Q5s�C��~�Z�elu��V�!�c 5A�>�ndF $*� �fresh\O��?�>%Z �HCO:E(. Crosslink� �$r� 6�l ��raR8ofm2lC�A{e�u� �:?!�K;�aq"Ԭby �4l: ��o��y�,� anol��*r�9e�Co} �re.B -.�e��bye SYBR Gr� !�R���sm 770�?�M �sl�A*i�)�&DF�B5A-��u� %�0��%� #9EL, 6 �)�dup�2�Mo�,A2~����8�*>�2� NML008084� ��781–900: 5′-CAATGT-GTCCGTCGTGGATCT-3′%R%T TGAA 4CAGGAG-ACAACC-&;Ib gV#� x/��&N : 131105-6�,GCCGGGGCGCTGn��Z!���C*TC��AT> V:A�A�&�U�E�M6�D��arr�mP�z�cY�j�(A�"5�"unba"Z �Eje�{�0! or m)��N��,ec�����w subt�C.� �>� ��.�%V }.3D��JJ)YS2����DJX �s2�D�%�S}�`S�2atld enri\^/)Q�1�%!x6$�r*�2V�2>A��A>Y easy kiA�Qi� � A � <(i ng�I]��.6�o s ru�.$EQT�=�6ch� pJc1 ed 66;$�2�6�9 tA��ΔC8,?�2�vA> btU 1d�A�k&aR�rG"��a�� ge Cl�Y!BE��5er �\}�!.]�W6VFQ ��calib��MF(��2-�) A�F^ GADH� �i��Δ%I��-�ZP�3i?C-�. U�� ( Ct�J-CtredHc��z2H%*-C �]��Zy �is 2− ��6`: NC_001806; NP_044660; (�N$ID: 270339� ICP4R02F0�q�( UL2��N:31>:45?E$;5�SN;57B;2S�; 7 0072 �321��)�144��H�L�FA/C8018733822�4 ) lF869800100U�.�T16905 )�Mitochondri$7ig\���b ob"�$endosymbio8�#��gi�g�5rg>cfkA�tightly Q ��esis�cM�n�SuD�q1n� of ��o�6e���'a��R0se0`�r&( TOME�"�,�1��to�u��(f m./!.4�d��tu&subAby�eukary�! }���Ke�;di� .�@&#al�.w�is"S�*c.-s���� so f��it4�n unse��d"�*!tr�t-�\%��Bin &�k�NCne.[f of%0�����K�?;!U%NkZ�Z*s�Sx�metabo} ]*Calis anaerobK�Q2��5��excav�CT�omonas v�rM�(�1F��*�$4#1!��β-]�el T .C�( TvTo%$ 40-2% sU Aoe~+neB� .�b�I�Q�. VSi�7es��!/igh�na� aP1P���<ir!. ^ve��!��!�of!1r � -anc�d�Y �!(T��f<Q�Tom36EW Tom4PJw� heat�,ck;�� sp )��e�)ri�#p��rep6( TPR )��E�,x5L1F&e�Se�`T3re���A� r��e� ,�22�v N�5�  � c� o�f�n�0d <�M"Nse�� �:֜U �!�hJ�-.s]��1u^V�1�&Homp1���no�mologyd \e}{22 <k'�/TvA�J2�sor(2n�!H/&?( S� 50 Hc��$in}"u0+x�si�}�J��ron�3r�%�@U���Rs�*��hS�e����� skulqxhap ��v�2?!�!�R!%���}e��profi�!&?J Tom7�(free-living�YaCol�&",T 3s])3ay2]!���%m=ehre�1Qs�=Q%i�"=�Lse��V$2�� ( LECa��6l(:q�"�3bڂsub�e|�5�"�plK&�0tQ��. �J��Md�� ��JZ"v!�g"�f~�,q�A�us��%del��for��!�+_m�Z�d"w0& re2�CRar-�8d� �@ w%,!5"� [�QrFytou!ou�%�e.�ON+�\)I�aoug�~�d>��a��> ( TI�xA�.k>&7"a��Wmo� �k � �" dv1��anAM2�A�r��t74saI�m�}� �p�.G"cJ��0��v���.e�[��:���.�inV�eW�6,l six α-he�5�: �!@�)�PM��i&b l5� ( OM!��Mn N��ik%1��O( TMD;�2 �� !� �F�Z CYTMDHom29�Tom��Tom��GS #.f$[ carr�?���C�BG,r��PY�U�X. �QŨ�7�)T�on�B(6BITS�+G&�'[�ShAyX�e]!M�2a�e���C��t�z A�&v )g6� ��� fungpe?��(nt 6�zM.�%>2�I��1�w -! � �lA0@�yE.A��|amoebozo�=[�-�|o6�5"qI)6�fռ�<s��p E� a��;��EI�*� ypan4 a bruce!�z.� ( nazk��a��an� >5uf[ATOM] )n�^ort�� � 2% �!( >5!Ka>m $1I[11z(g-!��:, om7uu2�"�uni(iYn���]ifN�TE����69 �"Yq�6�5S&�s/>M�1�a�.]%�fU#+ɐonU�Sacӑomy1;ce�>siad Ne��� a cr�#�! "�(y�d.ri�?g%v��| !�mi��ro�4��A��mM 6G ?switc�Oa OEE� %�(!�As���6:�D���go�!O3�wA40��[P��"F -�IZ8urs�"^�3J��� A�k�#r�is��K�n���{ � 5I�%&� !s"35Ek Sam33 )�bP<Zbiw �",%�a.�%sa���U�9&� 1_��1�>5�A4"��:ciCE �[�9��st!��� �!��}p!9��U�^Qu�F �� {��$�harbo�g*EH�� .B !�w +!�n=<%QR��h Hi�H�e*� cas2�aOnd���"vAx� adap-�z:"�%�stylews;4��)\*m !���st͠6���ol5oD#(Parabasalia4:upa�F����� h~ para��^?6 .��venIG�!�xy��cig��Z�A,�)P"&.,Pa�e�0<�byA��-u ATP syn�C��w� �omiE��?XN���H*�B�%�el{�me �k��� �aE� /�llfA8&���)�i!cytosol� k2��" 4!�"0 }(�h!Is��4)Vz�9.#al B քoJA�TrixaAd xn to2Kn&� �� TS!�H� NTS-..��! E���e>c�8o X � � [2� ��"�G$�&��2�.�&��S�/�5@#.!^i�C�.Bl+ in 3�ufam�xw<de� !LB8EHve�6��� IWQ DB� ��kn�Q�lo� ma�yi8["4�un�[�T� k�gus-b�} !�vol�2*>YanaC�( VDA�g[1JO��.\V;�|9 e �{ ��1wʥ� �uT�"�,>e"� -� 35�mp3Y:� � [ tlNe�5e�ic8! ?]�i5�S&2 C�Z!f:T S�!aVsX(Ύ�HC�� �JfV��  6!.l�)�dFA*�"B*� �; :�N��Q^��rk@5[g�e�R682� jd)�^���Hal� Q��U�� * ! a�F��.�etrQ|n��>l �B�to�. M�B� tro�y0e����bio"���*2�\a��́g�*OMl ��6 ��aTB&���A�6GX ���Sa���6IMw!�N� �y�M 8aҵ"K] �I"i'Ux�g��4 ��9abl ��qF�w��!���!i!w�:4�jh}�01j9�A�F�inV� *�S�R �2 !�7� 40-1Mzo �-�s �N� ��&{u���w"� QtyI�al �$��!`�I%4%;av�qE]*��%All�!�L��"kβ-motif|�\xGxxHxH ( P = polar; G =�4; H = �ph�!; x =b��$��J,�QEβ-� nd�V%Z!X�A E�M*Bex��-�E\%� �.�R6 A�� 4� �=du�+I�S1�f%@BJJf9��w��#-]us�HHK tool-�E6QZSC TVAG_3329��closest&� 5)�1eA S2 T��. N3���built�1ک%^ hidden � �@ l u,&�24P-aa�e� 46�S1 Data����%emplo�f `Q!6B��aE�,HMMER jackhmL)% ,�J�zV##b}r-"b! � cand��Z� y ��Ac-2KA��&.��}30&0.�#P��t]� 19Q�&� `����J�2*�DxOB��N� "�d�;��B.:� 98 P#a�R loop��u�s� i�x�����5�c1N #�s� !� ,?E>T � �;!)  �TEiiVM[ j�!��!U(A��m�܍�!/0 he�=�D' &��0revealed thatd TvTom40-2 and N . crassa T share both positively+ nega �Icharged patches inside the barrel , whereas mouse VDAC is almost uniformly.eV�( Fig 1B ) . Hence , based on homology sear~�$modeling ,��was chosen for further experimental studies . To verify�\cellular localisation of_$, a strainS ress��C-terminally human influenza hemagglutinin ( HA ) -taggedZ�`prepared . Immunofluoresc%8microscopy visu�2Bas a r�, stain !�membrane�,hydrogenosom%(Malic enzym!ta2"al mark!A!ZedYorganel!3matrix-�2A%� Cell frac!H)M!�i�blott�reveal R!S�2vexclusI�in{.�af�IITreat!�O.2es carry�HA-F�ia Lroteinase K resulted�a shifU%_ olecE8\weight from 37 kDa to 28 , indica� that= e%�likaycleaved � �(loop betwee �foA�%O fifth β-A�nds \is orien�towar e cytosol)( s 2BD1)�Then ,�isola=:70were solubiliA�� va)Lconcentr%�s!vdigitoI� 1%–3% )aGnICsamples Xubjecvto blue A7,ve-PAGE ( BN �%��a:obser!59eMGt!� two high B�co{xe�570%��33 ��2C p hesea��Hs demon!ut�at�is.�av� embeddI\AQ.sal outery�.!���ikA�divergq4:;9%E��� orth�Oue�omp!qus!; test�ƥ4bi�)esAK.(is specific4he>w,machinery orO, despi%-eA2ia��M� sequ�L, it could be integrE� into%OMMIZ�u,:� fiss��1�s1e���E��$g 3�kF��, t.u�G.�) ��6_!'*�E�a ,olytic�g����Qresembl%e o��%��.'es�i�Ase慇� iAX s!Z�7t��dA�a� upon����$��Aldete�$t . Collece p�g �Hj �7Ne��;ain yeas]In addi�\o checku�9?iq!v4 an oligomeric �xU2�, we per9ed��.Zmiu� a 2�[)ExAhile Sc��6.48��.mD����uggest���a mZ�~�$, althoughA�(smaller siz%��a�]:H . Because�A3j�)�%Hwa��6��funJ f replac99. Firsa�!�H a `mu�+(, tet-TOM40�uchi8A� promo�o� dd by a;racyc��(via� (ous recombi�oAswhich w��deplet��Y��c� doxyc( Dox%�>�eY�of&��0growth medium�*� retardeZ=�9-'. W YN! overex�aoݦnotkcuAehdefec"# c0in� fer�� able�( synthe��drop-out�=leucin� (SD-Leu ) bu�2do so]nonR`Io�N`-peptone-glycerol [YPG] )qiE%To sub�mi��Y)HE��Y�m�煄sz u7 � �)s harbou� 8temperature-sen� a��K�A� —t�5 � 341�!�(n at 30 °Ca�9�A�M""partimcsto� 3I henotypE� q25 �Fon2��J�a1gF%gSa�an efE:AtA[)i��sam� AF�� elev% =6 (� �] gTY�9%=34or�eve[lower.Xs6� Thusi seemR� only2X��)���Q4�;$o identify�9�!� ners��}�:}co-`precipitEy�coIPs )�HJ� under b slin[ %�� �G�!�elu; �� analy�#I�{"�� ��iY�� 0 N��wild-E�( WT )?, u�a!t�4� �i�"�at 50]36:&enrich�R�u��re� C ( S2 Data%WAs��}��o E`xdE|9�� TMD� %ndw sets-�TMHMM%found 19 13D�fuA�,6�)oRrs8 on2�T�1�.��� �ome [10]%�ai�fA��A[� A�^TA 7ins na� Tom36l:h:�nin!( Homp19b VSam50a�alo�,QHmp35=�с�4 :� h1Ra�5N^cou�fMF(cV%#� moreV4)�38 �our�vi. �s)~Mi �%TA���r��s . P�syKP }�D�sz�inclu� th��is-�� ,-�,-�,�,A461�)�,d  i�NG�l!�Iy�7y�"EBi�l"tM �%MS)��e�ur!�candid�M�A��)F�r��6�nterProSq [30]!�di=�j> ���N"E heat�ck�a1sp ) 20-'9per�dom �!�TPR " ��2�TMD�His & W iteco �pG���ly or!8ATOM69Ap8T . brucei [11]4IIndeed!:HpG �E�E��!k38�_4queries agains"d%���"4 �a �f hi ��e-val�of  ,9 × 10−17{2 . 31Fn>�X)�� gnvare��� 'PR-a!�w(no signific�"�� "� a�!19%�I�-��did ") E �ei�Tom22� Tom7G� we����to-�q 1!�2���!�vagin|���be P�orH22�ied aN=%(a}6B�of aj4�,��ingN� It h�con �motif� �� >$tryptophanA� idue* �pse���fol  few��xy&re@%�Aya ser� �+4M!`a"A5AproU EaY�TMD; hw �mit �i�Mp4 ( TVAG_076160� S3�+In Barison!�^fungal L��2:T_� tsh�r;&T%_2�E/plant!api} lexae�Pkinetoplastids [4 , 3a|32] owevhun��dV� lack�&� I��(.Se��Y�75i .n�BmaA^ vincAGo"N�es�ly�3�  trans�` ssocQsiTOM� [17]�copurie;w�� � ��I� $pulled dow��~fa "���may sU a�s��ab�Tv�!�� � ref �&� B�� d \!S&�V) Fe a Q� rum�0ms��R p�} &�=�qup��s �- |.�Ju�s��� ~ elua"�5�-HAI�36 5Rf� %���_�i6`54"�,y�?#ttopy!E�\V.� )�adou�E��e�E�-�� \�"� �'����N� all F{y�ly�� KV5e�3cas��X�eP-�:� fm)55A�@2G"i.;q�-��"�6a trunc�fY%3B? �exterX a# �2�Nex�e. V5�R`6�Y�5��2%HR�i�Stimu�EmCD��,( STEa(*� . A ive�w hibib � �Vat!Z�:c�aty�E$�-:4  Pear�co�"icoeffic�� displayYO)�e?co2L:n 46 ( 77a��� �� ( 6 . Dec? ��ge!�� u3u46u� 19 ( 2 �g 38 ( 1���:�U�ateaaYs"�*�"�.#R� o obs"�#���ea�%AIof^�Ʃ�%y9ɚz�].�ei�+ek.�� !SR�2� probbr}�-�s�J�iT α-V�$polyclonal �"bo�$BUF9� � 5 2.E&�A19 �J�0leaN�weY���ong� ! 36~j!�a wea�$9 @eQ�6��K38%�;J !��#!�J� �t�=6. O�oY h�AM���iɁQ �ed�p �F�#erm& to val�wh/ �5�-q~'�)s�>�igh–"A -�$m���r�nt� �2�#�#!*o��Gsp^ � ntQ�. Bf(Im=JZ.N�#�.?4&j19=o !�"�# 8U�M-� �!!�6@$any��F�Q.�.*refer� �Jk$� !��]{� i� deco #wdαQ -^yQc���ˉ1^�55Wc 9���o#AWF�OM5!�tooon@ >��v �Q%X's�fir�!Q��I0J�]?�� �%u@ their a�&ty�incorp%RPB'&-�&)ToF�%���o� icip� in2ta&�imn A�.C! vitro�0*!b�!ayD �J�A R��.���)�H�redoxi|TvFdx�#IKn NTS f Qo Esch"hili dicf0( reduc�$DHFR )A��� u� k-"�A�sLi1� ��Z ([35S]-methiU(t���dar�))>-`}Ka����&+^�-"� :� /E��_,B� }�AY6u+�<!�,oQ�e!%�?  �!5��4autoradiograph� ,a time-depen; i�!�)ii7�,/ 9mI�.y%�&�J�!�otrex6�is kn{i$#!�folp�!AA��F&;.�#eFH @)��.x$BEsW([33>6.">i p� W.�F� ,��o��reg��!�� �%���.M�'�%�6� 7��*@'e�vN"a.T*��2 -B}��i'�$��H�*!�.eV�� ]/FB��E"�-: "��@�.n5�� ���&� 2�v �T��. A2��d�t &)�;5�.��i1�5�%�2�!��mK�a�b- tt"N:�( l�/�f�ma1.�(�">.))*tmo)�%.pro�q� 9 3*8l�%I0n/� �#2*附� �)45����QE`-t-�. N/$Ō� !9"�VX omit!�"� reA8on mix� f5ts!�AJ�-��}��Z��e n un��ed�Kte�!R7S>;N,&(�"�A�actJ�r5e�� ~� IB�akHspb8zoinvoli$��– �iou�5par&�w��C >�reco&r.�� 2u. they" bi"0o2T���EV�8�n����0ic���)�( cd� s 1�008m~)�)4J)402 ){&�� 2s�hi� ( Hi�$i.Ei.L BL2|-DE3.}#2�"ɓcoupl��8Ni-nitrilotriac?(acivNi-NT��,agarose bead%S49AA8n$d 8ɍB%preincub�wr u�1ns"ed�lysa2��' a�J)$A=�Mchr�b5eYrCR�U%��>ursor�1��.�B� A6frata� �a� α-subuni0 succinyh!�4A ( Co!D� � αSC�%,)Jl�&+ �h*� ( <�  3%9:kE�cd-A(-42�or mock-g)���1 h� e�+�His-�}bo�$"H �e�&Eimidazolw �����.�!_e; �6�"Q���p!�� %�.�,6�%~)B�8�) op p�6�V�4�.y�1.h#Օ84)to�.�:�bwFur� �he-'-P����%W�%� �'er)@.�N��bottom6:�#��`!so!%7�:��"!�>a �.:Eu�4snQ�.2A#�.�unu�8�oneD� 6�p6�4invwg��S stru�"�6>wŪr`� X9�i�F�4.�"��6F� �� �-� �F0)2"�.�Q:Bv7&\7to rel9�� �,t862�by IP "{.}*�oto Dyna�a!���ly3 '�xNX ��M�&�5#1�IPm6�e i}!}@!]�sil/ �: ( S5��S5B��!!�unF'e�/6�Ps K%�d5�p.!Rofc;-shap, Mh�H�,��,�1�&@%�,of � accu2� (Y%�4n�,ve(�!S5C.�s�-ain-fi�ope�s� P pre�Z as p<< , eac�2�re ns�channeg!�q���s�� A to:= of 1 (038=��"e 650��-�=-�!�(. Two-dimen�/a�:2G classi"%%$�'3 , 412y( 34%Z�)7 "2P average�,-�icR�)G!�ea��!21E�34 Å��9A–9�  ![orE Q%6!s� ��i��a�ccoun�aQ$35% ( n = ##175� 40.377M:- _5�I� � i or 2h8D$i�!�le-1=z�ova�?70A'25!in'5��0cA�rics$ce2^wofW!+":gu�8a�14 h00.h �y�x.��skullq�Mmeasu�(15 V72�*6a l=spo" a!;y�ua+1Ltr}7�_"^�3"42:��M2A-qy�Epq��!u�X diamO8�2 h�ner)p�6�BD25� !O)GdS;c& k>wo H!Ł��50–6 pher�arE1h' bynh3�9n�()� ��.��-�!�wo novel.yř�8́� Q*}*��/s6_"�%p�@iar evol��ar��4y��*�E-�$�+1&'� 9 �ca,cal�*�2�ed ��a� s dMF&�=ic# ergroup��%�a�cu�� Excav�1� stim *)z, a,-nlos�=K8(T�7!�S3&R2For�/2,schemem�1�)%ada]?a viewq �]!� major sisw9 �0: Metamonada �* mpriA�� erob�O roti:s86s:� � Discob:D� �-3{)5]0�:an�:w$e�5��of.��b�BMIed [36�Our phyldm �fi�E�!�urr�%9at � �*4M��,m-���"*�?!�mi~Chav��enX Aa�Q�lex�LEC��%�E�8ex�� ,is Monocerco�ide�@ .!�1)!A:l>l�?.��lu�llA�}Do�v��TILm([37O/S3]��Su�( B�-�oless r b�<n�!�&�-n�&�/�7��ssDR:}&�+ f6|our�s S oA�I�'- ������E�"�l96�B�ViridiLa: #�.7aR !G�"��FQ���f�a 2�oDf�79 Tom5�lnd 6a`m#iBx�ll� my�I7P &�C�G@�!db��6+. Conv16�-jsu�b( Stramenopi, Alve�aaRhizar�;SA�* re)to:t[34�oF�aV )2A�0e�re, E  B7/ocysti�)�-=3����ha�0yte�) lian�?$uxleyi [41nbIn6�,�n4comF�}�i�.U?!�Amoebozo=^�AMe puzz�;a�tA2��#a� of uniqu�� �W�-���h�����W&�3jsq=&W�q#(s -yTM� lB=1��! ,�%� 8D ismsA )�e�F: "5�I�P4�.�e$in Tr4c#na�et4 a cl*E� �-�?( Par�3 alia�/}in :�1I�? � n1r�2us Ne limastix zMforniaP ^� 2�l2&Nm )�or*-6Nh6N al Ce�7�[Biotechn XIn� ' ( NCBI )a�"nd2'-e&5regard�� heQJE��@�3� %i�aAJ<6299.�(, 810 bactemH)b5 �2ae�NeKIe at�W�ed-CLuo AN�>i� S7( CLAN�0algorithm [43�.1]4& )dA�_ !)e�5�M� 6j.10M�6Y@nfI�-��6)��)��#�P a�-n�(k )�m5 LC�'*�%MD��  inct�46�At8vՕ:�%�>$dixenic , J  �re" ���6���-QN-hby"�8� M�� ~d lon�Q�Bact����end�5� rCulum-a�-� ��"qERA��.)0E3 ubiquitin-6ligjF�lWRs9m!�ominan�&p=Y� S�Q�A!#! �ofB���rY��LA�@� "!:�s1mWE�/I�-M@5� � :� � &� �AF�is  is�by�` !�m�in�ch^�!"e se�te RTSE�/ ��le�P�&%�=��>1�B! In �M!Jhe��d; 7r3of2 l&�� 7�&nd%D�=��Seu:�S�&led&�  � is limc2to7ewGT�o,%�direct"K3UU�.R� �R �Ne)�%ee9i*.�&JN�*�U[1�15<To�3nd%��nw�OSin5�-we&>`ZU�$��>��:e�AKaE*:�v6�.) ^w5.udy ei*�#�Q"�Eg�"ly �g i-|��&�*X 2<o� I�!�1�a�w� k �=��A&� � ��&� .�2Eno2: � !�al%�TA`.:� ^"` be t�ly�"�9�S�,av9&}4β-bW*�Q. Ej#2�icZ���"- e�� 85it�{!l{ces� B<�!�.i�3ngi . M"� |iI*J5\��KE"�hr?m%f[S%�.�2r�a�0�.olo5���D ��"�WA2R*p!s� ^�,!T 0zE B�5��2�6� d2eXgMR�[1b20�N,M�R�` �>xc�M�|be!a��ul� udiJof .W es d�K&^;rocedur�244]� &Z<pB�HYed=. "Qevi������Zs������ BSm�-r Y^,$viC aI!$k p�xI�. �'�EcoI�A� �tS!e� >9�� mas�y ��"�SGG�m9G��xI�A2A�SAnle!��o�ab�5��.�a�@�1up���"$Q � 0!��%a�oHQzit @ser52�U�!�[�>.�A�Ys| �Cat �l �� thir�Ara� ��tI��[�t Cryo: "(-EM )�c�U�%)m� m�WSs�[4V��!=n�nt��e2��S�&ss�B���.*w5� �1&N! �yS� e�ljF*!� j�-�'۩-}G !�$��a� ll mmr�M.�Hj� a�K�8�[i6:3�3For&� An2�"�Ti�F�C)*^Gcy[i:*22i am37A� , 18�EInA>)d� $uAE�}�[28�ag~)a!�rtF}%\"Mi�-�?."�Z)e�)!MY a>%�,��t�$^�+�t'���8. �F�_Fm!o!Z.F A�\LEwX-����Sex� �300�.q�of ��Vs [27!�T 'Moo� to impl�@�ו��4?�I�%}��"�0aA�\+.[5�a�27Ds� �`'(Ry��QenK5��aT6� ��inher� ��6#pro�$4_an�>W1."Q—!}XtoA�4QSI��te�(s s@��/3 �re�!��07�E1�1�;4�:�� s� *�*�A��,Y�i�6�+�.\�1nv� ..3iniTs6���F�( 4�berXo�bu"� &�Omp85V�� [1�4H" GprD U�.��+%�� 40 b��]�*u"]�orf amily [%�4eS�*�E�A S6d��1�—��'�)o&Gin)."kQX���commoycestry {6{—.�2OJO�9�8!Z I�t r.exx��c` mE2�.V.�� 2[1:�HaJ��ts� �A�lo>$&"I%�I� �gc�� �Ihyŏbeyonp=WU#�� ��l�*!�'e��(-b� *L 3�%�J 6���6�Dpot�U��"�E�w#a��Z&P.uF�7!HY���x3eF�<�y�==�aQy 6��>I�%�ed� F_Lin�KG"hLd:�KQF"*�( c12�&�KA��5�.{28�O!&�K58%�.�K B��#2� }�,�p14I�*�K��n �2^fxte�)A�Y� �(E>����ac�$�-�� %�N1[`!S���Jas��F�is� surk#�,� �'n`L-+e �(  )�N��"`1� enha���P fnY o TiUM�TIM23Q� [19 J�4&ed lPMv[���@ refH%1"i :�� U292�!y�xw�7tr�]E�6 `(ofi�Z���> *!�"��h��� �Sor�p$#� N� in��� dipl iF��fu�,a���E���m���!��%$!����.�Naegl���LI�=e�72K���b� �.a>k56mY��S# .+raI#(.��4��6���in&@#("� �S��F  �� ��7��6 !��?�(�'-�O$��Qppe i>tcere��zh.*y failur�m`y�RTom�)�&2�!—nee}io��5�ca�� �BQ0s� v>g�`!W��b�20,A�tiCrlCaZc�CtFE�~�� �3ha�_�ir�}.>�d�)��g�c�!�2 � !�.k �' titu� �ta+2.in Fu.�tuda*��v� -2� a�76Bo�@system>�at>a*�4�4e\`!X��� �isy o'W"�:��C~ *v<ownos� 2�<rnfea)ML�ji=�6{hAOf��� ��&�!�"c)� �E6{[Żall;^�)1TC>�"Q8 P-2�a�7fP"�.pi�B9 �"*Kd� [.;a�aN�G�E0� h6XAcreA*�,� m�EJZA��t�`iHY3� [4,F�7�ce ask�*�I:  �-2�6�jA]a�"9��g. DSk= amino��LeQer�,�wc O2� hQ0E!��6o� <"ni��"� � ��m!r!J >h�tiHngAF�isG )wEr�Zf &�PtS �/@inF���i' � +IQsa?�nco�a��iz�KrRu�eisBh`"V �Qhairpa��X[4� Such�E>�y��2 &IJ!vre�6� �aa/e�&� 5,� j \��Es�}K���! �s�H�t*[TYE� F��2|�H � te��)P(t �s.wd���\M�i�a�`kAm�¹!#�i(=�E6HBi;2�th�Մ.�i��no�k[F?"�FN�� e[: ANqFm&���L�&e NTS [2�"�tau,_Z!DFM>��2b��:c ] un� ed ITS.wml5T�ݿl��y�Jkey qua�onr.Q���FI�;%~bc�s!Nr� y.^3� - 4E" ribu!�)��܍ȁ xpQ�/E� NTS-E�ITS*�I @��F�&�2^![24–)�&9a�&�}0sJ�-]���^ptWA� .]�g ��M01/ez^>�� Nl( d)%�!�I���� "7Oas hyp�r+L��-by�!M\1� y yet u�*�5I<-��B,���&�2iq!2"�= AQ}E���W* �c��F.["�z6H6q!;AW them� 2�5,W^�1"�(�& *"�a�H&&9 �1��6r`"�aw*�S��&%t�6��E3 :*&B !d2C�DC� �5Fi2R�8Fm�J j' �69� ͩK� 0$�!ec��>�")}��bproxiOsee� L:|Hsp90 [5�2Ae�35n? 1 "� l ~%� taB)D�"9e �[1E�&� �� 1��t�)a*0"��/j�� �.46" �l� *� ��it ,�{��Oq$�=�!"\Z��� oa�5F��IE��27f'�|[#! ]�� S͇55q.Yin�c&�'[14�Q�N] �,CT%Wiag�0�2I��5H e�5PfamAWpX&��,��QKalM>A�I1emp�o&uo2)���%?1nE�-�02%Q&6�!C�)��� h���qH"���2�*�ing!�6�-[s:TJ2:|p"�0d�52�s� E�U! basal *� n�,*�gruberi2�)�~2A�&��9 �&KA�� ��","*� 6�.�%�2��v�s als�M}!&� P.��'nd5�dO��0Ŵ��F-&�'a�J!��,origi�o�*� �d� ng �d;eg%���� N:I��chrng#e �"-) rof&�[3'�:A�:A5oge b��y! ;07�-ch%�)�s�","—?;d .�?�rJ-S"�;O.a"�!�; e��>1�z�-s"�-�;U,R2�2*� N#E�n.F6�ŷ3J�Z���ex�}�co7�+�LraCt�ga�7�*%2%�aI:p..l 0"� 22,D2%/>�6� "�e�der� .+���{�]A?6� .Qa�� Pr�YE�k}SE c*pa� &H6QV\l>toF}QlHan�->i�i� i�.�a vas�vQR��B� я�dg+n&��Y<�c��G�2�D00:B 50((o:��.D [5�O53]�ap� v{6:8��*�6[�F5��I{I*�-/�C,�!q� Dmphipathic α-heliH��&�� �*A ��C.r% #�B�!-� gro�U`)�r] Z+Yd%h�Qd[5e��� �U�&��=$�&�( Δψ��driv� step� o�)�[5M��:�% ?li�D-r–*R � irK$ch�n��g*%Q[��q� �possib�%riggeaKm5netRr2!e{cA���ense��d�n��.�al9ZIu � "lkly id�TR [57(�.ne�a��e0��Jnp$A���eCi"�[�ō a number!�U -�yQ���w!-�Iis,q�s � Az�Ehof poob�V stoo�[2�S2�%��sEvnK� >���.���mod���Rq ��%%��i^e�eiiC%44@3gf(ks�m1m�3��"�>��ji~E4�_o0q��E�� c\1�D���q&Ef-ed�|%t, Cf6�!����) . Anr=W�fP2'695d���t��d*�?C+  cur"� AA&77!�2�in2+<1m _2 !���?�+ea��%5�.�OM &� �o.i-8�WafatD7X�B �tN�. 6i)� T�UJ2A�a�5IniofC<�0!�S�)Q3, Taipe,Taiwan�K�r��BL5�{� �{�"O$ ne-Y�,0ct-Malt(2num5YM; pH>q�V515Lv/v�.eat-in�H>|hor`NeGm�T&;ą;,200 μg/mL G) in 41:hSV2il# ;�b@A4\Puromy\( D�I>X�}7�|. R=/� GW)�28$on Luria-B ni1'�TL �(of Ampicill�tD}��gJ_� in liquid_(��or SLac��9�f2YPGA"�~./ drop diA 0�9 �cul6[\\an OD7 �@ .  ?ed 5-q���by �L_5 μL9�4e.n ��, a�l*H�E21VDo6 ��5 z.)p���xc0G&U�r 3329nd/ 178!�)�~lo"��, pTagVag2 ve="�ba 2×H��1*�W[5�\ >�� z27793�) �h�s 1372�8rk 908 1�f�k28312 J���6 s"�s��R�V5V�V5�ZN����smZ_�da��e?&{.��)&� m��WTm5aiCR] ing*�29�.E��"qoc� -2 :� YX145�(( Novagen )=�n�F�Iy �no�e�Mr� �&3�a�ن�):or_%"�i�r-W303α� *��trj��34�y lith���[�=method �F q f��u(b>$��!�tet&�o��or �&�D9�, YMKA� , up[ ��� ORFe /+��T,�#%�on�qset�_�.fUL�1�pMK632descri{mp.�.60��/ �*�Ie�i�!�%r� a� ;�p�n�_l elseK [6�aG�2nucleotHLuh � l� �fS4�K�4�{� "�!s)6���-�-(�%e�DC�#�DwsdD�- �he*�v = Ov~�C Bank F DB )-�G�toQ�6/A��40&�+�A�built.< MMER3 hmmd ul!F3? �U(�,24 well-annoA� 40=& ( S1 �Icrsc�Vd_2c|vf�z�Ee��jackhm�7��� defa';A�ings [6vH���%j��z�non_Fu�;[0PSI–Basic LSG Alignm@S�x T!�(( BLAST ) i�$ti�aE�* &"&�H�aUOC:��.U �$MAFFT [65])0447!�6.�3497Z/ �]e5�uil%�22YWa�!`HMM W�"ږ�ANR0T"� xemey.( www . � db .!#uM�-�a���}of 14� 6� R� E[lq�G"!J1�"QHH H-��Hy.�!}D sour!Y�|gi� n S8)z)� bestJN tD\=����c�O)�m�$( https://a%kituebin�,. mpg . de/#! s/hh�q��R �:�NuI�I� ��xo ��eu)e ���%%r �on @B0 �://)�cb�dtu�k/3W/B/y  =?,laxed cutoffAV3�CiI]IA� *1vIp�L2` !�&]T��c��6� +E=i.<�eGasE&7+Fe2�o�}�Y�two.`��y�(an ���Rt!"1 �U�3x"EJ,K114.OA5�A�)Y� !%run s000.�I)��2Dinge� ��<�d!0color-( tax�p!I J9uV` � bMVA�!� b95���o�V#g5&�ba/>�ir2� �P&-K%J"? i�]�..�COG%+T(079� ��� . Multipl�7�����x[ h�8YBՂ0 trimQ 0BMGE [66-�U.�179*na�T�.Vt�P!L��7�IQ-TREX7]-!c(LG + I + G4�e�&dY]ultra-fR bootw pl $��B!�T2� b: *� � � u�b( � ID 5o8o�@^�  )�62!�d�140 O�[V��:i��d�B\�wic��a�P ( S9�>�1B�)�"g )�,=Ml�pa�saA�J ��*�L�r manumed%=�(U%�Ѓ�)��1m���� 5� made� $PSIPRED [6"�i -6�`��V��Hja �pe�(dAm)4�%.develo�f �Amersh agerx. SJ�EE�.ax !�aŜcޕ!�� m�"%�� A �)�I�*,.iJ&�vb�7IA�-��)� SDS-PAGE;.���=�HK)�F��α-Aco5�;�>Gan ECLq6)t��@I1E{J装.&u ��@8"�[7j. %Ji�v&0�)�I0 �!�M4v�E:� ��A��4 Fluor 488 don�/UxB.$594$ \M�V( rmo Fis�>t�qe2�VF��2#a�"� by�jqclo�< su� slw%Umbge��Ve�zhield��,:��4DAPI ( 4' , 6-�ML o-2-�Aind�R0�B�7ab oT  )�w %i'��$an Olympus,�-R IX-81:i�J��!]ia�M�Y)�I��bSo� , Ab�(�TAR 580:�2 635p F� g���5TDE)C!'r, �� . �.�acqui�!�C� merc�U� 775 QUAD S�%�"8�eZE�eru�u?equip���ta Nikon CFI Plan Apo Lambda obc�b ( 60× Oi�wNA �E..�AR580�1%I635P-l֗%0uf illu�VAXby_��561 nW�d 640 las1(!���Ja2!nm) !��6��A 2DaautGl*$�sigA�afil&5d (�]s�>�x$passes: 60�g625l�6�g72�; pinhA��mY ndyo�� phot�aPE o���%��| �o�(�/��a�8 �,A�M�s�>a pixel")M� × �k >s d s�in-� �e�VE�=�oodemA!TIms'a�softwul2���)w�Huygens�afe%fal� %pI15 04nC�l@c Maximum LikelihW#E�f�&�[.b� o �"N*; �9P+a.�6l���C��ve�&O Life Te ]��).(�vV�(*��u#"�or 1%*�p�lar�� M� pho�E�3Q�12%J4 6% �]ve�� b�tris geZnTu�Ru,� a�% ��&\ V���y�e6 by"mi����0�w$ �,Z�5�8�Y9�/y"��( $=�N���l9��,4 (4�2�A9�2� J�a 6%�3%QQ!��d3�� �~X �>M+& 7 �N-�%[�"�"2 �erm�"� :%}�"WT�qN�IUa�E/{Olu�F�8(!��j &U]� � DSP ( d obis�8�x�wyi:pi� ) ;q2� !=6t25w#, "issd�l��%M�qM� u1�p)�!�:I� wice H)x�M�-LoIP�h6& ��j�q��in MKGa((MOPS [3-? -morph��_;anw~f�o?f%�) �pot�rum"�,x%glg�) Q-�E cO�Pt�) "( cocktail [5x^��E rck MilliH[�%��!,y��X!r2Q:&�ur� v%� u�A690"�o� >�head r�Qt room�e~�av%�QhrAbBe�$|m�� 1��uasA4�;>MR(.�R� s٧!AqrHA pep� ,q4N� ��L {��*BW:7�(9�aX���Vrp" )�fa r’!��i.3�jFsta3�N �YbF$�=�SDS�E[ro�31k!g�-!<&�9>� =='7,6c�sp�P$in 8 M ure�i��w a F�  Ai3S7" e Pr�`�M( FASP ); toco� 2_,Wisniewski e� . [75C"FR�jdi�Fq>Q�siA��M+*A�\'�2K�0(ato�wy�I2MS/MS 2t�l6H�K�!!O6"&b�Q(�,lo��ŹT��Js�)�Res [DB;N�")�!�5$� 862 �� ^1�-H-/Y�el�K �"� > E:0g�an�X6�)�P�kus� ��4&{ 1H% �0qKde�/j# omeX�sg�U79 Å!l:� 0� *�6�def�v rang�e�2!�!�mQ�07ixE��0b�Con�zT��hR?M�TF�arNzs)z�Gpr�� m [7� >�}e@2�Aa pic. A6�7)7)�"��8.�ܣ!�E�(�e2box�lpy routg��  EMAN2�8]t2��9B�of. s1~!}in Rel?!�4 [79e A5�,J|� �c�2{&�#box���a%to 192��7�mmo���Aer-or��m?!�K�=�% *��$) ��~B< �& "%#� low-"�ui�3�{AU��<empzɲ�iyd5��"!0-��B+a� �BF!MEs Qch5��}>7>834�EQsMJ2�yNr)[s��#� �=��!�9��%�:!��!�,6��lFf I�yed�Y� e�)�� �X88�{�r�9�c"�fE0"��st SSNRR�ue ≥1p��`,(*�� sta�5l�U�eA�e&ft��� F?I�n"�89���@ng!.\:�a�@"Ho%F�1'~1&�/ FerrÔ�59100390z$Z �(to NEB PUREȳ �o��"2��j(&Y4V͔R"���,:z�5��H&x��!e HL-ܔ �ܔ( MGP�3 l sr}��(>��t� �)�Cy��p.("c(U!6i �T1�&�* /2��!_ cour2��< �:&��>%�� 0�L�8���~me�_4�A~�� 4tD: ^f)+ r�!�"� -�},36��S&V2 s:�!MOPS-KOH.H!, 3% BS�8�!�!7t!M.�!AT�, o��5&? 1�Ʉ2$L>M��gs�@" . Ats %�poi�x��`!~� fD���o i���!r:U�Mre-"` (�*�28�N -}�� " ^!&YBb2��0Mel"V( >�!�1!� NADP�9W�Ak�&�K�N�XiT�!5q�[+4�,�� �/*��{��qYi�� Enr�D!Y�Ah1�Na� ��L�2ha���R�e�w�8!4:� �ut��l�`7��"�v�� ��M��r.��+ �+ + )rV9=!�cl�g�8VE=fo&b S"u�&=�w # "{a"q��ja�8O-�C��f���>�!�%�d �Y&}L�"3��affin��� "=den6ba|�ip��I��9!&-�"S� Coom5e-�P(<�toa2e�K N�+in na. xIn�Mpr� ��`b@ad�at�Yp!+of CD4+ a�CD8+ T�AI�fe�ag!i^2�e�'JG�6j�3e'inflam!LrS2s�!!5S^dn".�# ?�m."��k�l�W4Jz��d�bifaH�±A�mV*Tqca-P�is�|"�e����!c��!�t� R-M � e!Z�a" uo3�,��!Hwe tv# typ*�k:^d cripэvel�r� �s2�|sS�]ut1�d1z�hR�sp�a�;-ADng�!�l?a�Mr12q1u;2%i�&!0rs1131017 SNPpRPS26��82ore�.�MI'xy&W�� ense1�LIL2Hva:�!9 1|be�3t���!e*���u"�f�va�"Qo;Q%����!�l5v�s�m IRF�� STATiSqJ�Nt *j�W�K �eQTL map�Rin�UOpr9{eMc vel �insa��}ol}7A�rQw[>:N$�KA�s� "n6el�HEz!�"S�M���> [1�!Eh�,:�� R��� cytopW enviroeA,�re�.a�wct���"eA���ם�E R/��defES9!V  clear�Bl}�NEinf=3)w���|�2�8lso ne�9�B1Gnd mac'dK�xec�`�j�����"1=:- �6 tartH.��-9��� sP�i ��a�1p�"�?&P��qA�%E7. S/E"�c�?>co uyRC�Xdu-@ �rapid�l\�j|Jala~a�p�4.���Ge���!femory-9 sub�s [�4Faulty1JA�����*Y�.�( T1DK rheu�Eid ar�'��( RF�,.�thyroi�!�Ɉ,ic lupus ery�`atosuK*SLź,��scleryQ, psoria�Q���bowel�~ l�|;Zrgy%�asthma�r�%6\�aBt�T0aFT2U��9��a�:ali����Y��ate����A-V�[zUGe�% -wid6F_����8� d!3+ s [7–1��"J �|>e?,��2 risk%�i�*& ly&�!=ex4%ukt���(X6|  tiss��nd�A�"�71�iT* i�\1�!���bp"�A?��iϕonN& 5B.4��!��3w�'U5s�K�ѥ, �]cy@ , neu�iesT.� Z!�2�[1�421�!+B�U�-m9�yf.��Syr"� 6'at>�8�neurodeg�X��V locii eanwȔ, !jF� l�M�5��geZ�6��-MXdeE9�2߅^XTst* dA ��!$-}ɻ��expanK+surve�@/AmvJ@�Lu�ED6 Ti�hnd2 "t%�)�*��!{pe"œI�of 313�lth!dividuaB;�N��� of� En%�a�zA�g*+ .~�Ou,n#%(_�zes  VtpK R����!�.xin��D2{ 'fi��,ewʹ��?PP*� d O�}�mep� �h�Yہ�} it�!* knowN�%��Ew�#Isen3[s>��|�&� >�M�.��A�8�W6s��"� . &:�s�igo�rB%n�.kb� 6! �4 �waA}I�D � 2"� 6� Ab�M�.���Z�e!�j"g��)ur:�ab�4R �]�%�-v sus�ki �a����m��  . We��B���Har�/( PBMC>:�Europey��,Es?�an BiobqP[2H�zC,��Q2�.>\"T.,�A�!�imm�oni!W1�g �,lDcċ=�. �)��n6"�)q�Xf�0f,3 E�o 6 milY(SNP0 *��I+%3j*839AEb�&ithin 2�704������. DNA� y���5�&00 CpG"IB*Hs �:vof!j���[2�add�la�*�&"I�"�  >��t!�͛�L2yr3M'M!��s�swes*?�,h6Z �%�!�~.�-�1Mb�Rrv��$ f�&�}�$i�x` tg�.b��Tb�)� SA) �E605{a�6��"05� "�ta�be-- false�)8/y�e ( FDۜ<M0��v��$ S1 T�� �0overlapA�)637 ���**rep Kaf2π1 =e99!�h�zF)r�I�"�j*� two.5�]O���& Dl�$��arbitr cut-�O%� "��c� More�^��hal�OA/,t�0ded�iPa� meta-u�$> e�5a�2^16]� bs )O \~Vg (=h5 % 4�F�U�VuS1%����a%>)�� "5 �"� [2mH$ �aa-U�b�e�)ev� �Jala�mADof5i +\2i�b/ GA| �g Zai�K%�"?y� c���,AV , CTLA�~�Y �&a:���DoA �c��J�[2� 2�Q \is * �G% ���R!;�] �s��byijU>e*A�m.�""��2K3 �ti�V0F�s%, >122b �AM��X�15RA.X"�rs231�H( +49A/�d8�D, rs3087243 ( CT60/0�=80�*MH30C.>!� 735 [8��1T-wi �2�s!S# 29779 9� Q��linkage� � libr�; ( LD�2 >78 )g�C�-P32�� .A0�j�:�ILD��l��)D��M�J� ) 'pes��3’UTR&-���K5� Br 91�A� -wer >m- ]'�>y��e�-��a�ten�>*��)(�ll�Mpop�v��V� ���2 R������U�A�BM�.�< �-)@ alto)i5^s` a�exo� Űis B��secre� -�U)�m ��*! �O P  )|ٰ� ��a> � 5�o�!9F�w>th �:wj��~�aBE�2s"מ�� g2� إws!"Bs2�v~ c2D�S<��,2F@�� nl!�W �] cg2609160v�!in�]� N7�eF=HYQ��۱�e)-C �yRl*z"aM�1���2�$����a�toS.K �f �f"�E"ZEg.ntB-v�!T 6�� B!m�al 73 �<8 �L� ^ �T �%�Q��y�@\ Za�*g Am�P!�74%�oVe��&M{�RU�� 5e�x����o�6|d��� 1M�}�(se�pJO�Q27��AG � plau�1��*�> ����cXgen2�m]���A"t5�%%"�n�8"�of��6�}3�3s^�� >5 Mb ad ���� toj.+Z"�<� * 638MomN��"� 5�  f�! cat� [��(� =(d 24/03/201 K/�wL�.�-nAY*=���&��a40 ���e�B�=> _of 20��378�t�/�%�^����(.�21 �nd 133 K;��33�h /h.A$�w }N�)�*ng�� *c)ir ���� ( I�u�Yf, P =�239!��{3^ � mTORE��gA = H(840{0j�20.V�iR.�n.b�a6�f��Y>�(bs�'broad- e impa��n hundr���� �EE8�/�K��� *Kki�kDin��}-�e i5 $by Fairfax&LI1Q_I&�e�]�A�l�7"�)Y�z�as*�)7`A��e 5´ Brib��������&�A&�) ( S5�)A�:*e� ��e�)52AvY��4� (vitiligo [3A5�}A`y*n Z�#3f 3J#3��2 va��4the nine SNPs �are shown in S4B Fig and their eQTL effects "C"4, illustrating-� strong LD ( r2 > 0 . 8 ) between%$top trans-Z0SNP rs1131017w$several of0 GWAS&ds . In addition to RPS26 ,' Sac�reg#contains!hCDK2 , RAB5B , SUOX , IKZF4w@ERBB3 genes ( S4A�)8associates withPexpresshlevels�18 �351 Kin CD4+GpCD8+ T cells , respectively , Z$an overlapO24 G(�(3B ) . Manythese !!�highly�eduhave i$ific roles��Lsuch as CTLA4 , GZMA !& GZMHNLYM CD8A6� {5Z �is�y� �%�%oE1�����o A-8k �>�fixedm�UJ �ed��ly��1maS: β^mu!� = -1 . 15 . 52 13 )a� �!�B62* f4�66�T� )�� !?AE� s� %C�� ,�}!j� A�MMB� i 0 a�-1s&&@ions . We here re��g�ur����2�� mAY I�P reg�U�F  auto�8dis��f��D I�=a�"� ��xdemon_;%�IQu � %�e>s�Ny acrossíD�� �"� rk k�L*c ir�� foldg er.i s [2425��Indeed�$observed m�ci)�sr a� NE w!�a d accor�T� joint.Jc 2eem� y�&L b� ,e tissue-by- IA�Uw�"n e pattern!���e"8knBa ��$inhibitory�ռ�d�VѝsEvo ��}%;organ�N\[29!�Aa ity-"� lN�2� $( rs231775�s308724�e806 )M����ousF�l!$atC^�2, splic#,�du A� solu�iG-� postPo�mod��!=A��43–4M�5<,���?� differ�al �methy ]!��4a�!� to b�xe* pot Hiso�9�fci�VA�is��likdueoneg�R. >�!�gen2� ,� �(tually lead��*= p HD r �be��o�2Q u� /sI � true>-&A0stead!�!o<���desig� proba0t capturA>A�%�!�>� �, a��low-up��yieRNA-seqis neede�aO�En*b�e�m� 2q13�b�� c��i��)�QF�at i� �!%F�ofC� undx!s�5g�� ter(ngl� gie� hejHUEmay!�stituteR; �&�Q. OurEp "is �7inD ,oligopyrimid� tracM �5´UTR�mRN���anL i[C]uI��lQ\F^[4r47�nV�zrol)���Jof��mammal�ribalA�t= !gs [48]A�n�-8@�� on �Bdistribu� has �� ed [4�% �� �� on�mjQU vol��� recruitMof�g ular)zdi���itm��in{ten�D��  %�molecu����exi��te [50!�H, o� ceiv�H�ged � �A�iS�sta+�A�)�2ffici�4a large number� cytosolic��!N�theles� �exA�*�>2�01D� ��l�8 2� W� Hr candid��IN%�� Žsu��,�[5Znd,[5eStrik� we.�aA;mon&; ��n�%1�{ �g"� %[ 5 ; {G �=t�.!&E}�-regar��aL ti-inflag�� ite� e 0 growth�surviv�ac hzs�_Z� ���E�L�) aof"� �l�h���mat)s�.`AS%��iFof-�. *�w]�� � T��� C)+ ts*� capa� tt GI%�/�w� �n�a &� 1Q�(D"�aa�sf= vY�=$iU a�{. F�m�x �s s.�10 of a�mouse-�%E���"��delayed6�t� trea��@a� bloca�0 antibody [53�LAl"t` "' I>I�!�11�1E�BE<�z%�erX'A�ag���througR!5 �&\!�6hFA��e�2�Id��p���^ $toward pan8y isleGia�up6��6��co1 � �""�*� mod7 �%!�profil�  te�phenot�K#�traa3Aunderly X�%�%so� � w iUu�� refU a�Bst�:ng��>2�>�"[� �s� wholeA}od��e�ylisI �&���!� !&� �Ed�o9 d %щ2bao�jfutur lo�$1!@ drug�iv� .  aim%��a�ygto�!���E�ֶoevalu� �� ogenic im"%��!Q�e.. B� �imi� �iJ 1J �nside��A�sam�4of 300��"@vsu�tens!>statist� p�#_cm�!�6 "�$y particip�"�� donoi&�"� R! Cea�Universa�(of Tartu [2�I)&�" 313 subje�[ elec�pAI �,�+�$n age 54 (�nd�+dev� 17H154 femae�nd 159 � [�approM �TEthics Review Committe H�Researk'N�,1# (A���a no 206/T-� of i� 2�08�011Zit� carrg � �oA�� w!+4Helsinki DeclaiI^ wr��a���I>5�V�4(uaQas obded�\+�! p8 to2| . AlS thod�r� 2�7�5}gui�=8�i O*tyI%us�%�OmniEɣ BeadChipUlluminaE z4� manuR urer’a��l impuA� atas�� z�6f#roA̡��ce by ,0IMPUTE v2 [54F��in �87�%386/so�SNP�b�$( MAF�'f�)05e=dow�eam��%WV�e{ex�1���p.6'� nuclear�N!c�X$|ecu?� sepQ�)6mic.�( �0#130-045-101;�20q HAutoMACS technology�$iltenyi Bi�a5>�.�'œ tococ!G:�!�en�_d �EdHT-12v4�`庁�� t PreprocesE���U��!}�don�A+R [55�(#Biocon�,or packages A� [56 (arrayQua� Metr��[5"-&,qereq�r!u-rMCis%�UM283 *h!(, 303 uniqu-�ũ~ɏ�m !&d� ��&"�%� n7����e!lcedur� re� crib 0d����S1 FilvV �Yex�"�% (NW )��T(.^�"eMh�ed�!�-aQ �6�)cookbook��elo��͞�mMed���}Gro en a eE�t!�Da�u !dA=GenomCo��JD( https://github .Y /mol s/systemsa(`/wiki/�- �-�-�)< prev�l�+. For%d5�)f�E*�.p�< midpm��mic��gA7up��3+�A� Vg3mo�+a��Mb qISY l%�on"4t &�+A�O�,EB�a��z/0��c'�^ 95�t%# #��rho )!S*^""�#��6“>>�!�normalize'”�Suppl�"ary M�')�qEw"�����"& appl� mAu� rvOE�- falsea cove�� ( FDR ))c���V.i�h� o est� %���U"0.two��Z!,B8w]�π1�� Az tore+,Tibshirani qM� ach [58]A?)pY�R qi�0 , default se�&s�'!�"� Aklisŀm\!fa�pro� �MA�& null"�+�2πm!is54n i . !�those�!CuUni� ( 0�/)!�&" . AnLxal�IAB]!H]1–�,x�!J�� ����"�rep�.�Me6?Q &E.!� groul or� ��h>}1)��"��d��a !4eHnt�]-e)�#  �E}f 8e�i&��-�6p � D� �)B�-framewor!2m�"-� � ew�}i�' Flut��+26]l%#a"2�"P�FY�eQtlBma!� gramm��+&G ��d3d[+/-��%)+�/l%a p/�.pr d,�V�V abov�!(6���� %i. Firs�-�raw)} � u���gu�(-z�e )a,F8+F� : ��)�T[� ass� AM!�� �%g-��pair bea�an � . Se� �i�ie$�mg�6Zc�'� hierl� 6X4n EM algorithm�,get maximum-� ih���� �6E�b�� ir �by)� zaS,g�ygF�weighA� ��drz)�F"�06�!l�ek9�a g�-6�%O" I��alA��",a6X-�^��{e�� pick��b�,N�y�aC �“the+��e�b�To �bQ!�H5>�� )�t!*�"�&no q�*r% (�(�}*P!� 9�)ڮ�����k*A by 1���5per� �hф(Ingenuity PO A ( IP�6 tool��2t�a�%� e�a��md6�'"�Yenrich|���RpeH.E$se/a�hi�c09jaq�� back�Sn�"R"�@4 74mӉr&�#wo�:��F5�/ is�$ �a�abau�)H ntE�s.D&4��A��o��A;�`,]�7fo�#� *�4i* :� R%0� Z�u�neR summ�s��8Onengut-Gumuscu&3359] " www . t1da� .�' (A,d 13/09/2016�� bpag&���<�!�]c)p:*3F F5*4Giambartolomei�410etXaPq�( pF1�/"� U�}1a10−c�:N2R���;��R?1@��EY���6�ao�%YU��9!l� we�ed p2 �12 � M S4��5$�)�=� ��rplaus�7of*����))%�H�aGob�"��E5�_hZ4( SEM�  �o � �����orL"F+� *�:.z chi-squ�?M. Nex ^�{Cgoodn#of fi��)�a��-���h.� mea�s::p�ve Fit�,x ( CFI�,Tucker-LewisTL!/Root M�;S � ErrocA�x��( RMSE�%�e_@J>����'"Ӂ�M`�)4 5A9 . g !B$or�al!&05Y�<o�8%G.4%B�!;L .M�$>fAkaik� E�C cri1 n ( AI�. L ���or�1�beD-se!��SobelI4tM��6�5����#u&~ٗ@,Hhe�c�>&�A�Aea&ur�i�^T�ou T�>m�"&�$ly*�- zero!�aGest)�� calc* "\)!�Xula [60]: ab/b2sa2+a2sb�J�0a�4���A�bV;$:�3sa b.w6� " eaT�� 2b)�� u� a si�ekst�5"�6^r�;o8.�b#��7���[ ,�2*�!e�ref1C&� ���AGa� Sn5� E�h�&F�i�=hjRZ@� !su7%�random�6���EZaom�.�"*B (A9�;37��$F�9�o_-��|( irf1 =E903 −tC4237 × snp + N*r) 9R�jZ��tz031z�534z�>{%�n �IZed�%�&� %_u�&h=�AicqM�Z�onM=F�6eZQItF7o�9Fby lin��. Graph�Yn ��� �� $ggplot2 [6�Dhe LD ZJLDhU&ap [62L �!�7' �-REE�LF> Zoom [63] �hg19/e118es Nov 2014 EUR��� A�LD2�� ��1icircos.� drawQ�C "vis�n� [64 '�1hi.�7-v��mD͉:�1.T2�J�~V�8 �m�*�>6 � {��v�s adjuw=ssex�g4batchM�achi��onA��A6R]*)e�I�� �*�r���'�$n_4.G�Socio-cul� b�o��� �0real b"r)uptak�scree�F&)ofy8 African Trypan!iai( HAT )s A<Democc Repub� 0of Congo ( DR B�6\'�addicu�J� �Bandundu�,Kasaï Oriend%provi�4,ţlag�behin"A�eli3#�.efforF�) �*] "cur�5� erJpat����l =P&c� �dA!��managm8�o���1f-q$ev93di9' voic|:/ edaa digi!$=&ci{� 1�e*D6ATLASUi softw�. H�< ��co�?� membquo��a*n!pro�83 K�:��#�Eixy#th�F!u&:� , sex� %coursno ho�Eo�noS&l_su*&VioZ1ngAXs!/�c �� elie''to�-�#r���nd �J>aaB� U�7I2!O-?-k�9:9La7f peo()to avoid%�GcampaigI!Bf�of!c�| ;v1tabooePcJ of diagno�c�!�:#) origin�"ai"5Ci B!:$0 e ad)�/� R $elarsoprol�men�H!!�evX2ce-d�became�6olete�N new safer.+!cC�ctmg� ��oa�;2C!�nt� U�y�should� xper,�!1�9�?��t��dialogue!(keep ab� unA�na�Ś�%/�!�. �%�,��IBas0sleepI sick��,�a�9p* tropb-i��4s �5ly po�")L s liEQ in r�a� [1–�/!ge-E_% clinist� Ia@early haemo-lymph�.#�charac�z�no*~<SE�[( A-�g%�insBMersM-doEoyet fe�he!�!�"aQHQ _T�who ;!Y u� ��lready8.�"padvansO( m��o-*ph�&i�' �;@6>�a�r��( centjG nerv=�$a��nL.�  neurD(%��\psychiaa���if�.a6�7 , 5} !еz op a��4!\[o^'E%� ˁX]2�p�=9�l)�5 7 �Q�� unti�8�ly �Ѧ.Z: arse�. deriZ"�ism$u�0�9b�  n�e$“Arsobal�f'AT a�� I�A�:at/,� l ��is quix oxic%Z� � e fa�p1�oS/&f!Aen�Y��re�4)>�E��0>���Ds̓�n,0!�!�I��O year"6^%�)=EA � , NEC�JNi�(@imox-Eflornithine�bi >T+py��9replaA�.� as f�-P q��s0 d-)�!d[Ah 8 , :� � �n![t.Z�Pfe�S:�.��How9 , log� �Pafi�9�� � ��SG�r�2deploy%7[1�9I� D� �Hl�Q�to��M�c�Fry���Nrem%46�� llen� A�.��ill��*�2�in �Q�Me��flso sEi��lPf��oryM�e[�  p��~&dE�%6 . Simarro"(PT"�#L12.E(-2E*ino�Ua;he WHO� �rNinp01�,� r�0&# �� by Robays2�0� G�G�2� by Mpanya2;%J;� i&� ,.;sA��a��whaD���/ra^I�p�2z��&O a%M%�&] [1�1�2Fc �4e� ,}W�R� �|� !� burda�mpoA2by�er�of��� ���1�?��'� e;Xr� "}e*�Wa� D.� A�i to f7 ( a!Sr. �e)@&;�6!7“hot�F) �� r spic�D-�!i� (�eng�_8M eavy� � walk�suH abs�.)�J 3&� �V� ly a� ��> �sai�$&q6b� VGbye�"�"x?�q3C���&@*� [IN��na�2j��6duIR� e��f� h]�on�'�1AnF�&�HYjad�jm�s#9�. Ib s un+2} �c-!_M��RU Ae� "Q-n�MorA>lth�K�OA�a<�d w�ir�9l8!�. "�Qi�,mN �B|A�+�A��{5T7oc�9!s���!�at��Cm�in�1th>f� �K2�$in East�1�;2��.i�ɋ=�s�A�&�!��j�JgA$.����^/6�ifSl� ""e3-�Y}�ndvZ[ho .�B�]+��A}X� {/�"��f�yir�� Z��ed.�!!DRC�N��>+na�6s nd"A\im!�� �-��Fngoingbs�. .��&Cde"�=nk\�z� �vec�M�.&t�-os!� }e��� vill�GG]"Cfac�XA;w� J ��wh� � seek�yief1u�Lymptonree-step 6/�*�X&�? ��L%ij�sm�@(Card Agglut: EVB�CAT��\Ehrapid.�<��Allv[a �ua��I�e;a�o�asi�$���� b]m A��u�$ pun�V(�G. D]Fa�g � iodBr�l�&6inv6� y.!a�#�3-��s&��pa6�ex�]��1VAa >�. C��+/y�-upB��a��Jo lon6_b"�L� ?� q ��on-6������.WY��9g���e�[a romi�0��3& a)al!�.���t* � o�=EJ[1�� lackI�u�6��9b�3lM by/�F�a ANa*U-e�t92� N bN�N�9*AT2�An�od^2p��]�)ne_ al�[`iabin "JX����Q�5in�;A�cj7I%�P}/ me NE�A`e lutAnD0la6�e� ( PNLTH%W;��� R~�!��z( FGD"6�m�=>98M���Cs%/9�A�X--y��iwo!�� S DRC: ï O�J"Q �b>)�� V+�* �*��cM�`e&ly"tq�d V=1�: 2�9 ask#]2� 2 [1�YRn"< �.t 1dof ��)lems *� E��a� , key��sonnel��,*t#heQC%�PuOLey� 9� &) FGDs�D B)�I�& k =LaN"�.�(&�col�1 �staff!d;aYN<G! i�4al�:� N[mob��s�ɿ�g� ��.( ����A�J �2F,!�e��w�' �A��A���;(3m�A�# ottom��8)ach  � C^ioa�Hstledge�'Y "46m�dthe"� ur qu�# +�A;re:J�p*, L��!�9�,���� 3�5NB\,B�!'a��.�i��� !r��-72�!�>w6�!d=�/fR�R�:@Sin FrenNn�I�an�N� ��>langun ofa�eM!!���� ( KikZ N Tshilub�/  -��Z�.~J]sr N�A6�>��A�U�U"� t�)���p>�a &l%�M� .?2�v����e=/��i"J �h� �O)��onI� ver�Zb�T��A�!]�-3!�S>92 i�]-���Osor �>>%O pre- 2" Kinshas!�YN)� IsiYSinb�(Q8!9V9� TA�J$-�clAverbatimO�Q�1�TA�fV3;+"v cv�"to1�$�- u#�?o-6�(��6�0 Pp;#/pe�=�4.��T7 y��Et- ;�cJ�iB�f� ��`-`E �#A!� !%�)�J)princip�V] oi5!b�� locd'�lsoap�91e� bBu&�s�Y:q&r�&VG d la* Ove55 minu��a��'. F%n!�c"`&PA�aa��aOcus 5�6�%Er2Xed�,R�. PA�8ep�|a� �?�iSAQU"e�J�9�?h!k� e,8helus2(3QicT�39 'S . P�GszMa�"e84 R �x�6 �b)aNIt+O>�LEHR�, nu*�.min��aF.� h�Mw]o*TAo6���&5�� *�e "\ ��.��e,prefer!^��=!0 ,��oro %#_ .bB u ��"a, ��%���+��40��K.`A{"-�ly�C.i�$�F�'�lucid%t�Ybl�]��coaB` ����M?r N~w= cr&d�a�x-���� y�=�ee��X �562�� sHenior�!Ak�s�'�:A�o����M�W����m^��q�A~.�W*n�t�[ate DR>B' ��. O�%1quSZJ%���a!8��\A r���C�on�0 f, physicia�-Rx �")��Q "��!����n �-�RM� ._��|��tea�d),%�A/!fn����!�A� on's�y��G�({-?2�3�cwF�I�u� qAw� c�tME��o�h#,nbZ�Kaof 70R��F\teBO M�p�� �� kq;3eS�i8 ��m]� Q��<2�YGmai�-�>arm� zfishe,UB3�B h&e di#d�q? K� *`&CU  U�R �%�rR", F��saT1$n MS Word u\ �!o �"r�'o� N�2E8%�* W�n�%coded�%A�t�����gs�Q�^>Y$�1@C^7}e�llC avail�J1pt��mearful seg %��(�\�h[15�+�`0)`1 labeland]�iq tre& �4�#a[80#re� � AJ!D"�5�,ur N�<�}G�Y��dx��SM3.���5%YA3>��� ��� gene�sj%�*)�|ad* �+ KAC*c -p�V�ne�#�z sub- �emergN �%m�.� >��0:mhim&�&u �B��" M.fe��� *"� !i"�y}I�$SX���MI. \0�)ug"� �s�Dop5I���i� � D �precis.8� GD��'O9n ( S aFA .:����"�XA����-�\C.�\�Schoo�nP\9�6��he�P�a of&��]" ial ,ESP/CE/023/1sI � ����m�a腢AUU :[ audiVy� . Anonym�3guarantq. O5 *�d�zd�'�pr�atDC]1�~ #X   ;�u�/�(�d����:>TmiWi�!�vt� A-bia �0u� s'��*�;� �X-�&l>a�cig]1 ��U��8� �jP5��N P2�2E�0]� -i5�iAc� easlH#2�W does�.&�_�nyaG�3!�“B�� re�8�…��( INT2g/.*1K*a� lth:�:h,1��&*7!:"� o�2nt&�3)0R"��*!X3�(�9%@�2^-*�{1�9��B!en&= 9u�A�aX s� ��m� !A…�r�ec�Z)+�R  4@Q& G J�)j . >j�u*z/ALs2�1B"�$*�4,� zR.�is6OaIhe\�#W�/�h�M�ReTe�NL �P �_adofe�uok���Ƃ!7a�F:e:d  )�!3Je�gE�rL' �%4� nickj5d�jodo~�� ;in�+cid �k(�s� “B�S�� �% w�Fo<��mto�2�,�J@�!�a����i%�you%,% �mou�k#x)*�&$�x��N&�#m a�nd sud1�E u?��mG^l/ &Z!&�9� � > high{pa�a��(a 2�rtoI�go}i��1KA�e7�le^[aH�Do?ihe�tinaJshape [_)y�began�Che],d�gnow%Nsea�s79�4� fr�(eD� =)o���N. W% somea�is� �*e��a�:T� x�WɅtnO c=�=A i7rpz��"�,.3:f��5oncern%�A����.�,on5�,�Pca"�%lso�ry �Q.M-c$l� �/H ŧe��rd�!�terlhM�A�"�ll % thal:��u"ql& {-!v�famil�P�%%�a?Eb Ah !L1!a ,�6 X wo�9 s; W�I!�  al -? A����hop!5at fu�t!Dwo^t.t b�?���A]g)/ɭ>�K���A�wpossiim�2��{���EiR mABI ��� c��*d�t2 1W� +re�4c8�q�, ali��q�?,�M2��l occu�!y�.f?C~i�gof D���p�*� �7n"�?7�' prehen�.expla��&@%2�t-ir�i�2 *H���2I#�:ai;� e5� �i�!�fay��1����2��2lp�:{? |�#ai�e&r,�S��� �*�4�2�W6�is P"�1]�di!,&� e� 8��t}/���C��� r�C�6!��7>�C alcoho!Zno smok3X coff�bpia��~�7I`s l�~ , p�Jp��7nB!��:��e�l� � e�A%��)�- :=of"o��Y>���oJI s2]]�pto� asAG!�newl!�A~ s'i�A�&& 5* Lsp]I{)�(*�yZ��i��e�R�C$r�vdilN\�j�� liquid&xad3/�u"� %=u;be milpor may�Zt�6|�]Mv!*� ��$ �+R�(cb �ii.�!%r&F>1 a,ly� )��'�)r)T)�r�? shif�omCto (Id\ 1�dAa libe.> DFMOL:ifluoro"y*�?Es*a%Dl�We� ݖ,P � at1Tiq   hlGufu� { FGD49Ala1d4 � �1�EQb�i�&\!� ���ll! a�*!�&�p$k��0 f�#�E*�Unt ex�L��e}BAH!��~Y> yb�H� u� �a�5&mo*�H�hE� �F)�top �J�;���Ag�{ !�d+ em if?2A�st��" FG� Uu tuna� ��]�k J�� .�3^�m�y�pI�� ���� �* rugg�Co R;1%� big-w92�±Kaa u5!�"0Ju� !kQt Ѯ�f9���a%�%B%-"&���O��$�5��/Ag� 3O�:! �� h:!��` k q1*}*��N�Ѷ6NJ��a���-aٵl%ex� dE�a el"{probabl�]U5J4�d��b" '&vab �o2 �o!t�w>��(Hd��� !=endh[a bOs���aur>X 1976�0�do : (�G]��Fad�iJ8 �:oo-6�4n`al�q�B �� a�iPbi��>U�I�&� �a a!��*� "%�;u��-&1NA� !wTe�5nd�9)a ��A��A�A�G� �e�A�2p}<�AM� , ��m!�W�X�au�{� atI�Wn 3,1�.N%r%<e���;�! ��k0s+�� onsump�.1�,&> � fati�K[I�?<�L�E��cutN}b "�>ER.��2l(� �%���fi�,,0u"$�9+cca -d #���V#,JQ�u�U��n)|� L9�R8t� �^�T"a&"equela�!@deE� SF��Tex'x!>’�?s sg�e saniuag5 m�)Bu��4�WeA�� N%as.dy��R� ��.�=l��r �Gx6e�6�%�r Belg�fcol�l lawexemp��� ,,(yiŷa�  (�6��4 buil�ro��!�I)j-/z��v�Cq35���erB��nutz*�R��!0*�!@ -&nEp �E��� a�s!P��6�� 3ɜL�;W �9&[��)S�4[�P�!mo eat]  ,�"g�9 ��I��aS/-Q��u�@Ng.y]t��u�iD�E!�A�FGDJ"C"� �Sa& �"��p��Fe��!]J)/a$Ae���k��� jhot�:}}3I�Ktra�L�arm/c��V�vZ�WGє�)� made� �y�i��al�osu�E�.at]nM+!�a�QSsaJ �k alq"��I�ơ�8Rm�W!�ed�m E3 �k!Q$s�xN1���a��i�t�4���� >F#nbe�;!��QYce�AOm"2�,&hf�ea�����A5�@�q�a�� JMll6 06�pA��Np {�Ox"�%[l��eE! \ EH� PC!M���s�%Qe� l mu���\_��iO#hill#v-��F=  V� o  _D�^5�se�#���fo�� !=��� ���A��/e2 �w�tr�-t"��2J�2F~9 �d�Ex!I�H2��Q�I1��2���_)��j {He�"��(N�W<:�T�%r ���,-^h-Wa5ʩ"��9lA���:�aWnF� b>o�!�ͧsSRex1A�s�E�a�b)p�mW�3�  %!�!"� !Yfo9B��J �2�*� �q�to�9G�a .�:�@2k�096�emuD�i�vXY� A�--IK �DA�i�sup-&�C ���e 2�6�. I�;���to�E�!�� I� ��% .u |��,c��v��ez �i.�> !;� 9��!b����blak!�c6 c�* Ap% �My-g “IisHDm � �K� �I^-��6y��me craz�2diP)T�W�kil�_���ݗ)! � �R ��������raA �orP��;�68&���OW Qat����v"|a?-=)&�  rYina��K�QsN�  /�5!X 9�<u;"s6 %j�9�s� E2w�Di�GZa�m!�| a"��/m�f"C as d� ){"@J/aX�V��7� 8�41(�6�W�l|UZ!��NA; � ignoI`0 >,(gY1ha���i�y%ɤQ[ ruleIV�t��5� V&�,ti�+A�acH$e������"e!Ca.' r�J ��w-�ZU�[y2h�5Ɖ#�Q�� �(JeI�6�AAGd� �*"�o� �nP�\a@nd��m-!�"�YJ�!�5Uy�e�Nc"���!��w^ CB���aq�wFo[� e=���f�k:M1�O)I sawi�� �^�&me�$. You s>[� %�r��sl_��%�. ARle l�c��sw2A4�C �85ީ�5$u�":����,1]s"z0�+ex-� b'o6 st��&� ���.c�`uL[�% �4!�!}���-�1� ǁ�a schedu l1�up� check� �L|ma�se�.m���!J��`6� �C�ul1�nfa�ya�I.����L���  ard&]a�aren'tmOn,o��x�!�m� �_vy�i�"QQ.�sit)� l"�c#.shadow�w*�I8maTs&� 4 � !�IUIVI�[�Zmk�El] ;�/t  �]�q“My g�^-me>Xoa?��t=&k% G� �~lA���n�A�i���{, a�va��?4=��W1 20*E*�'myE{1t�R,G)F�Dq�"y��o� �%In^/one�I ��N5 H17�househ�A3m.q�min�q Y�cZ3��[�� �(.5/�!d �q#en��* if i�3��"q)oa ond;� I am%�$1��ia/� �we�6 ?". I� :� � ?A��en�!�JleA me"rA�}.A_%"���9\� es��d:<J*��"u7�t� a2x�!�i�3<��&� i�5�a obli�3&?p�Q![y��"cy�� � {act1=l.in$w.^AH;z���|�W ΞsQY$�&�+div�a�� A�]/� to 8�eN1lo�i�o�-hu�S)��V{�llQa# , k�w)-T � �5�FGD5 ">L�-� b}��n*�!���� ��1m�Ks�y:W"; �h�an���eeI ce!( �pWfetamo�EG 8*N.���!��� +'IVAfw�,m:�L�1*-��1,Ev-s,�+ /\V�ma���Q�,A�uAI�a �BN@adbAw 4]Kin*�>�U4?Xin���)*#1wa}�!>*A�*�e~ �9 L� �B%la"f&o���"�]�59�H"�c1�.D)sA�� �)��\<��!":����79vbP e�(rec�ށ�a� “� � begin A^�e��.wW gracd,u� �y2��JBw��_Z�W�t�l� ��=e�Xr�q���gv,>qla�a�s .�f�f�eM�8P � 5  g,lis�/�Jg�9X-pu� n�'*} /m�M�iwl jE�s);F�X s�C�a.�#ce�ZdU"$8]��rA�rep��� �anxietyE�a�E�d�k!��9h2�%lso bK%�"4�)S(�A=Y/a62��k� agram�K28 � Fh ��* �;/�ih�q\ dc9��Yupa1�*�#,*�YQ'a���P�h�n Each�4� �� i��9QɌ)�is�d �kN�p} !/Aq$!;K in ��$rx%V>woP &Z"Y-2q� Ls��i0 “H� , ZRiE�B?waws �m�did�w�y*%�:&�3!V>�[ *&%.�'F$�F*�n�E� bir�2gai+"� *�h��ȃa�p�c�� �p!���%6�4&ik���AD>�X�t ELa��� tj �o&T&:�.>�hP3�tE5dAZ��9��h����-i�.u�\.�6%�$ A#�:� >6�f*� -3� ���.u��." ,recogni���$�-, *�-�)C!�i$PJ�n+!�!����.�"��>�.fj�X+mbL�nV�  >� "M-B1?�a�.e):�� lQ���& jig]IU�} "m��$��A�= �M� a2%Xo2���F�%v firm:�2��&?,� ��"��A&6)� %�N~�"�)! v@i}*[!Q!�d)Ypre*  A�ym�-c�F3!��!T�~f!m���nt!@3� B���ɵ�iv.^� ’=nF�M�67��p<�t">M@mI�ɪ�y*���&S��x �5&a��U��"pE�c��P a�j W>��s�m�2M&a�c!� ip�FF�h7"). S�)Y6"$r�(����)��ed|��$���y� �/ un�mOa1TbN �c� !�M�** ��-ykam�"<7AqCE�.�RemB�� Ay%J.�"^ iatr͠�at����:X*(am�M|�#�(>��Rs 8�c�=O\QR"6h��� �c�%ac�`M�6$�+i�?-igh� �Cr�|�a#�- �(9?1 ��&M�.�QD� S&�Z�L� A*�7o�1�;sku���JeJ^��ea�)��} Fail�~raB A"��!�t el"Xxdo�/y b���3ͦ!�gr�Ԇ 5% f c�!&no� n Eq� ur ,ׁ45"L�B]I�2H6:�o[1M�8�G� yt�6 1v$ge�-p��E������ emi'��^� n�w � geneA�. D limiIjHO �4�����z �R���u��!��r�#%;IZ�6 E!+>ma_v�vp*|vI0�aA��Hm�%IZ� a��;�XH�)�. N� t"�(kV�`,��:i=3�0congrumM�oX%2�Go-a*�Wc^q�=Km�D,� q @>[ya�O&�Tm� �%4� �52).��6�N(�-f�n7��hotE)1e��!FY�.i��}& enbE' 9�)Hir��� �.��C �u&Ci"�',E�lyq �)���lANO&ok%ɖHr�3<� {� op ~B1��� !� ?�;���� (f�zM:3)`�)},��no �*I)* s�,)�pS$�*��O�sde0�(��A����@�*� �Gach��*�A�q�! A�aAz retu�bal����%� u�aZ��U�+[by*!g8�-a��INK��� �&min As�.&w � bs"�+measl�)�2pox�chicken[19–2"N��&!�rapeumd ��5*��a�6�*���AT�iar��' Bs"Ƈ~��: ( i �=terd)!�J�Iye.#.I7 i��gtl>u�\S�1"�A��disrup6�����,c�b�>E�;��9 ���� l����� naز�A��aJe� a2< �GM�� 7i�@��EOnt� by LutumbXwHr0�wa�~�:�K�� mi�t�xA)A��� !�.��D6�: �n�!�cD�0!wmA K a�q!����5SR�. Ls�12c�s%c�AEa>���"l�=�Z��:k�A?" 9:�n*.n!@�&�vsub%U� &�GF��aQ�jo&E�9�� ref�K�H)%4��"�L!�.� !�.� .�*� ell z�aEA�E�.�Ӆ�"�5by� ��o]sd��2���2� � .�a be v�I-[8}tConvul��h�d �|�dis#un��ced�� �DveJ�~5–10%a1E��i;[� Simultane��7z6`oid � thiaJe�"�.Xna�tolerœ��.[t�2w�@!%X ���@��:_o4 seiz5��unc���+)� m4� �B cy [ڽ&�Q��t� k knR2�u :�> 7%�E{.�A�"0-`�� *��� ( SAb�GKn�nI:30�I��3Q� ��� � q� �;�wT3"�EaS/-�is"`+*Z2�����2!���J*��ea�mpha�E�!�xouteuMa�"h198�� �x�tomu&�!1n<.�+f_b in Yʘ ,as go Brazza���d�S .���� *uexZV �(V!�d!�raB[3�S�P��� rH�-C)���%~���:ek7�:_ ,;�5age 2%YwuP.�� "�9�!�m�%� ��:O��a�j}e(u;;�s��3��)i[�A��� .$��}"suc!P�#f�_� ]*��B��O �H.>'>� m)9���t�*�52J1?&in%�L&.YO"�e eF6k�*{[%i�Kth2��a7�� H.�M*#{y�U�i6Yr���&��'30% ZB�M낡(&�=Angola[Sud�$Ug~ EPXv�CsuEL�- .rep�� men8*���u�+A�� �oKk%h9�@2!>SA�:�Xe�ɥ&�/�~Uranw�w ��*� lZ ��$��v��P&�::B���[g�dac�n���N�jA�� visc-�leish�a! [3�I�i�aQ� �� Q!%G��ai��)�Bh Chagb*!, Manne9��%�?An� {C%��(aNlu):"��behal2sVbN��y"Z �`v'jor�6�9Z[3Nx:Q�& rk"�.e�GAG}!f0���ge T .��gambi A�.;H4h8#�bin� b��� H*!?2 94Mu�'ndI�tw,l9 �aEb ��8t* J"�}E9� b-optimal� tech�d� �|Va��>_A�3F;:in�W�L��K< > rho��5"�=I�"-+ �&H��D� A��D��q�!h� �]"%#c e� �7@w-2������H>),��Yy)��D�qj�Šs� "���}��n ��=�up'�sc��&�~U����  �b��if ���� i7 9�A���=&/_4I0�G#r=�|�ea���Em�iAZ�"� ��� 21�c�Mc���� spv� .� ��5�js�˅�L U0�: fash9/ �U g�w�AU9��AẺ�%�4o&jf.u� �&}�NM6GR�,� �%20h2�`؋1�. �<>��.3�9u+���Z�� o�&�A -4A�F� )U�s�@����m�=be8 cS!:n8�aIbly �_��'f�,)��kn^b!��g��"Dבke�Ent��ą4es6 Ru� l�vt57./}vt�gQ��8���E&ĎE��.�-�ޅ� i�s� � e benef�f�*� !�6i��f�#|.NYSXBDec/� 200 �Mé�& ns S'gFrontiè�z�&�+a��.��Z�( VL 6�TabarakM�ah Ho��a�)�]�W Gedaref S�UIr��5S fociVL!�� L4I2=R�A�s��[e 5c�c�G�xl�6�.��"��5tp Ma�5!r17 J#�J�,$*��)xhaus���m -to-�in 45� Pl-Gur �c�6. D�G�OXr���el�ops��o& �%�f�jat��Aw\ek�'( YVLZ���es�;�&&�u{��o�,st-kala-azar*�mYG�"� ( PKDA2V �b�o"�*t�L��3 a> ��eAAnew of�A�- ���)'ƍ�rk39 r�t�or � aggl:Q�( D �1A.�s��,�702&�5��e'��"� of 9i$369 inhabi��� crud�rtI��9B ��re�6�e409 d�0!8�13/10'��1)H!da#�VL&�HY�xruN� ��19�6��VL&��m6�~em�dA����ԅ��,)��J�u 551 2TݞU#�a his;�ij����4! , 16Ir��e0pr?�y! �b;�ld� IfM�^Ɇ�"�0/Ӡ�/�,!W!>�-R�#y,-�y� !�� x �HO�ol�V1��5%��:�943/9i�600ڭX*-a"?QBst]��eWepisod�!VL*res�K�gni��n"�f�nZ�. A�,��e�; cX #��y� ykM�py pe���%�adf��3������nQ� �'ior�!�(����"o��2��"exa{ VV�(!L��aw ed k���d!Tr �ic" .�(m��-�L�T,ov���UЪL .�infantumm�H�"8�� phlebotb�Md f^ {�" ra P&uSOld)lld ^Lutzomyi�New -m���Z��ad (�iu$Bangladesh�@Ne�i)���Q m A���� @# lr̕ ,O1 �chopp KenyJS��i���� \O���l�Nr!j��%�gm6fP�Lo2P���6���"." !�6�PaU�yf��es�* 1996A� 1999�� CIm���G� "�&U 6 . ����4ua�Eר��,m_.�.SKvil: ( �0�60^P�� ) [1[�VFe�higO=�[� cf�eb�'r�i ( AtT hE0Ra�>a�)Exof�Gal�7d�craa2lL\un n sk�k��ngA� �(��p�e^�"�P� ,% x)�C��J2tj6�/:�xmz�rea [�t.�"U�i.Rsub"w *��a7isu8j$v?�&� VL� deva��ill�$�uk�*ŝ left�C� �xInu=��!r gradu�2 wj to 1E���Ki�I��224J2�8TyH�fe�&�oAi��Ave� spl��ega� E��B�den�> �Po�� JIB rash$ea� �VL�O-M6�!nuQ?56� ��7u�[5�( 1�ap`r in 61 n appa%�F��lA�' m$[or%��uժ�V t�a mٜM�e.le�6 !I�a�m 2b&�; �#a��-F�ir�2%  ��sh6���nT xitl� If��, �E���"h!�[6!_�-v��-��;qA�in� �A��a�Ce�6*�0den�ns!+fly m��Ind�%a����a���$ ��hb)nti��x]�!g� � �:"�0EOi H���abednet��6�.�' �Ų��[u+ AlsoN} Ǖ'(y�v6�f@a-�~� � �i� zoon(c�  �1��' ( syANchagas�[ �Fu�*{Lv�7�*v�R �5Yt�#?�� I��%�%Y��meio rva!�66 �� �piz>K,��achH�7=�,s u�aW "�F�� &t��A�b��w /l50�T)��v��$��mhe Bihar���a|!a�HZϓ�=�"�Z� !In�\s�E�1k4�/^.dt!�"� .� 7U_ar!W'����9 ( MS-�uK[�r!L�� U1W ��^0!d��)N*M;!\VJ!.�� �D�@(A g -�Dom�Ntr�3 va%?S��f�M1VLҥ�a�]B5�tB&� of&+V!�^AI+s�"�=�? �W�[�eR�~ligjMySZZ�m� "��xe!�)���2VLaA�-yt(�(��:6. A�AE�B�:��$ etroF� �A*!�AUf{�,pr.k�VL%�jss�G%~ >��+!\�5a� .R?&�E�e�`V�!�82BEGP.����:R. � ��a�f|Gy�ee��N� al M�"��\�'s�qea*�W#\�Y��W��ͅ"9�-eOo���6�F�%�eac#t BM� . �=G&@%i�v^ n�A�s*����em&�2 y, *;:� � � fy`%�J )ĉ�cE�nv)��?* . A ��m%8�#� %& pE�7t�t$*�$� i�Ec&/���.�B�4 e‰)`EB��lu!z����ms�w��a�a��freb<%h�6!�.�%"U &��� k4 �E�b!A�%� F|F! ect�M�Y�!m��ghɰ�3>WW1- ����w lit��y� )m �!�un�P3ơPasi�dE$ !jQt ��EYF)���q��B�1��� Vth�W6 i�4 �Al�'re �2;�\N\!L� ͯ-�.��me%,hhistoryUVL treat! X\possible subsequent PKDL�0also recordedMM-i�!$causes[any)s occurE�Bj4were investiga!lin _,r to identif Hs�(y attributa�to�D. Verbal autopsies ]condu%�for%�reporkMexceptneonatalE.$livery-rel�,�acc�al?,!�these qunlike%� be ?�Matern?,not directly.-d � U2#rVL du%UDpregnancy is knownm be associ�A�$ increased=�toxic�Q!� mort�_\[12] , [13] . Individuali1 fevi]at lea8 two weeks���, i8diagno}jEued%u�AAy�)qclini�?suspectE\eie;E�orB!gpse (uependen!RofVtime el#d since �E�))dreferr!o4medyteams��examin ��cas!ocertainU. New2VL�(.)KE�FL%�� �Tfollowing: splenomegal�4lymphadenopathaor.�(weight loss�tes!� ma9kM) who&coGedQ7by��o�{�)�xa��,IedMa�I!� moderate  saeI� =��.QHTabarak Allah Hospi�D. Bec�31� self-heal��naturE�in Sudant!Vpot�!aly�M ��mmad SSG]�, mild Q��� offea61[6)�ar efor��1��To ��m!-�in�Bce !@sA�vi� leve��*�!�exhausA[ly scree�^ . We calc �n sam�isiz%<266��t�a pro� 7 �due'VL!K30%I� a 5%�icis/<( alpha 0 . 05 )!�e)o!� ex��ed to!��#ofd@around 1500 ( cor��d!�to %� nual��!,Br<5/10'000 persons day )ase plan!�Bn�[%RUlA�y fifth �$ through v.G�Rus�a systea�c)bprocedA�.A� K�zr)consecu-�!# tal!� heet�it�e ?�b: pre-highl��|As� data*� �A=first�eA���m� showE/B�much low�ha=�, we r�W20�p��)_6j1 analysi���%�E�Eꩥ�cm ingly-bBo�kvie�in.���wo� iansE�rienced�PVL�Mfl� in Arabic��!5disagre2 C fila r{$by a third ftx!:1� helpV$a translat� �Hhis� dict%fi) . D� AKid��� y}�i��mN� �ioa �h Fgdu��\Vmenlarged�g nod� vi7 mass!H!�8left upper part}abdome� �en �e�or-��,�af6) illnesE.dec� Z$asa�bab>'it� ede" A�VL��le\ 9FAQh� ivI��)�!�U fac� f� reli� �  is� ( . e . rk39.r,�4or microscopic2� of=� aspi�.Erqu� control� plac!p. If a}vu�to have9#i��o��Jڍu2L ,!c��]�!�_ .�.�evA�chose� <%\st]=recL riod!�!�&< �reA`nt'e�i�3"L, whic� ed��8 10the 11th!c April 201��$The averagA 6�" hereafter�T“�”�]409��s1n�70sesame harves9  Octo�� �us�}1F a 6-month:?.!�i2� !Pop)c%�&^by summq�*� s det0M�ur�y"\ �h��&�/prB�U��6, d� &� mid- &.�ocua����� ���back-2to Engl� � �u subj � to pilot � !w��*Cupd bA �2�-&. Data ]ent��3Epi$software (, Odensp Denmark )!�� (entry clerkAXI��ed ��St�11.j Corpo�), Cge , Texa USA Descripof6Oinf"�Abper2�$QuantumGIS�,� � 1 . 7 m) coordinat��Att h R� �ob�I-mad ��raw!�along%r2Lin Google Earth . A � of�% ty-f� � MW"� �:� 17 , 965 "�!18702 ( 98 . 5% )c��g����M�(AparticipAW�CN�!\94 , 369J �an�4 a7 e464 O5!�w lterqu�l� 0nge ( IQR ) 3�7-$ �6male/fe sex� i�!�0!'ed� age u15��'^7\30 [ 4}� by1� K2412  �692U113 )j. O��l� 12)�(a04, 943/95 , 609)�aQ���hab�x& m��$, varyA� betw-!$8%��34a% as�a�1@6t�,assessed 725# �2� �b2�.��L . Ou� ,m , 125 ( 24A��Sd a ras�KUw^aQiof 2 Ŋs �2w)�1!�4')�las�� .N3';10A9�DAMu ��260� A[1235� �%��%, 137#m " - !ago� B���3%!R��]i�preval� *��ra[d from 0! A 5N�Mos1� observe�!���( 8 G)en�requi E�!�) n addi!���alY`"�40 pati[!��2C . M�� as&Vin 382��p#v7 2�� �t9�!�Ax�?�XF=�ed 551����s!� ious�� !��( Fig1I�� �239� fi��Z'� l remainaS312 did�m?APA%� )�. Sixt�15���ult���z ed)primary!(��by *�!g4-k85E�0whom had actu�It c�=$. CompaE]c���s5�Bz: aco ,g t9�a� � 16����aM�alaW� uiuagI��disZ_��741! 3new2=@-�B�isenT� aoMa;re� enA454%H1�!l59�^ � �%�a�� 5� 4�}��) ��>� f�#pme�2� of&� aye /1>p��JA sA" ��A�Ѿ0�23� ZRu92e9Fa� hundA5!six6 % �� ed ,�A�ng!pa crude��� ( CM�of��13/10(>M. A �.�Fva:� . 02����[� a� .�+142�+. ABj.41A6E8!�d"A9wh�3"�!3J"� -2OMYA�8%)Q�iv�0i,�� E%�*f- 171 � &�J 299H ( 32W�a i��a9�m�<given - � $, plus 139ŀG�6G#TakI6|ccoun)��,a;a l !omo\��us�%A��e��ly A�� nd 26 . 1%�J"or S 4%�1+6% whe�trapo}W�� B�. O� �2F^q$acute febrA-T a�1�4nd ��(ab$to chronic*-commu�ble�8�A�wly��diovas�r!�diabe� ( M�!�Am~ %E&�/J5(-�,ed n = 8t , 4��q�_t hom89%Ťrecei i������53 +SS!^/ iVL-a& ific>mA1a�9Z�.^zs���!�Yn.<��΁��6�would r�!!���� I�!s� Gedaref�!S. j#of 1272S �affbV�E�p"N %As� 6E�*�fK Aevo ���a�reg�[1�Sti� a � *�4*� �{has� .�"�VLa�?��xach�&�! in sA}�@�Also ,${�l"7B �)�may0e �&�. HowhI�N �A�� %��1la�N$� ����%���=�! 5�"b[17�8.�VL3re s�im!� ant burde6 W"�jt],*� peak}tha� approx� !1yF� en%d�[[�!�I���, altho$gZr� us� �@sisk!� [19!&&�� �^tr�predoa!&a�� c:@ gener�".�Pro� fe Z})� 55%ws k"3 �&� ,Mis.�q� M.�>,c���GQ�aE[20![2e�Itdun����tdiF!ref�s�acc  issuŎchanga�,epidemiologyE�,�ZfV(HceEmisnpat�a�By�tr�,� ����%:t$VL: alm�60��a-)�eO� q��a�"� %uis, �( o�c.� ��RUpA���$^�� .�y�Q5�� skin)]e!sis�!:�,ayea^�2 EmaF%^�th� 9�@isA,���inaH�1 stud�>w� u% 5-����5d�!op9[2�23���vwe5�Q'!�6U!�i�^rRf. S�4-E$a�&[' � bK%�av�.le��Q< ʼng�e�"�5C&A�short-1��D�E�I��;�a/fs�U��%e�oi�*parasi �',L . donovanica��* E�lea�s [24!�NA�m�%tE^�)e'avail� apA�s ropr3(a.5 � �,b*�$A(( 4& moni'(� n�iow8amphotericin B > tera+n�((itefosine>d!�liposom�)>F."�asI&an�ite ev�)ceņA�rol� % �m�2� chai�i���wicult!advocw��SM�%_of�́`E8 implG"ae H(���*�A* �-�� �usza-*��Jper�b~A�n 16/72�$T�.5�� very�= y�,�s�"3 (bour-intens��cosT)pe��eqV �un+aA�.qe�� !4&� nr'"1$at:�h0'is"rlow�uu Vre�-nfirm l& of6� ��A May � Junea�nd?�a�* ri ��qorua�'th a�i�K.1��-�!ہs�o)�ed? K�ifAzU$da�Y Sept�- to N�.�, just���rainy �oA�%w9i� liet�,? �nd ,m�-"� �s �! yet s t"�:� �–2011^� ns# K ��(ren�n�-� �E-i" in�ayicsee� �Adequa�-����M�A0�!=���z*(of symptoms����by��"��&d/ to:�HQ�(!:rce: MSF�-&� ɘ�R��16e#iU/�#��t�A2"�H j')��e� "� but�i!�a-+iK$�#s._ �ult)%!rault� %Ezgood-�#u!� made-�v0�.�iiZ ll s��tiz�Vm �{/evQ . "�).),%�deQX�(�A�ly9$X)r�!�a-�a�F�t.1�+Z����$strategyA�{ area�@�� math�)ean"� �,l �-oxuth AsCecsugge�-%R2vL E9� no e�J��� t:22.� cheOmai� �1�amBati-$� host�&c , [25�TU1��an!T be e. Z.�o �� �VL6� _(y��e ��� regaD!!.�!��Li�a>0*in21a [26�Nu thel� tvbe�2fu�- adapuis-�� �"%�P1 "3guide!�orV�"&�&!fu@.�!� limim�_4ur�?� 3 leng�%6.(E E y ��MemK4inatacf ���a�n9IA�62�,�1��E�"�mFi�5��u�1"� as G!U� w�r �!2s� *)266ierrone:v��. Seas workers �0*\e��{I � �r elseI�"T ainclu�% ���q8%�se*-0bi%da�p5p>e iL (q��mi�5(their impac�#-�� �Or q. More�C se�be!�similarB�!< t  ���2>Z � -6!S�aN �m�-+y)}%$E���H0�&�/submit�to> &q6��{�0� �)��>��-dL�)-2W1�cM9 l�\nJ_!� or!�Y U6�Vh&�6 charAristic]; 2INGt�7E�1��Y� io�%6c�8nov phe�4non .�1��exE�}-T� 8)VLY�� 2a�+di= h �'���M  (s tuberculo�,, adv�d HIV�'�o^ � r . �G&� sign�v 2�Y�of J7er>jI����Q!Tmaj~u9%Q�X" ��*��1door-to�'A�� provS8n�sic�" way!�& 6� �-~v � ;�rq�l�� & $�w�mQ took� ce� �a�*� �+.>�Gyr?6c�9yze���6suGoiq�DNA!Jan ATP-"W1/eUť�0t�*bi;al,m���� ��5I rwo4$“nucleoiQ;-�#� Vr ( σf!�karyotic��&�aaF*�DiffuT VMD )=s fre!ua�4!\� �!10 kb doAa�� te��182�C )Ճ�ba�ng abundaprotein� at b� loop�unwind�at � ..�b�%��"e �4ly � ��)�5in vivo&b%F�$of WT cell!so σ_0σC+σD . Une�5l� Esch�hi!�li=UKa 15%z]!of!�E'�� � nella�,Q T�cip� critU  me�ism-R,g��jhr-��wa�aad� !�of ��;a 9A“92� o�/ inseg=O+en��s.jge��� ��( − )qa�7�= ups0mXde  down ofE6A�x�ksed!IbExD5�f�<�gx)?Topo I-g� replenish� sG�4# o �!��"(equilibrium�/t!�St�!2>TSb!*�?s�x.t�����iem`>(exhibi��.HB�v&,�h WTiT�ha,"�E,e 3-node syn�IF� R_ib "11U;�$��$Of�D J�Aa�p. hodi�r bon�B  lead de6$�ve�%3eg%Nwi�#u!y =�d<om E .�Di~#!JOw� N�� �G>l�JA'�� branG+�)#. S)dis�@s�o�ng��&�;axi�l� loop�sBi rearY7��eFucw �� 4c ���ebb��"EA����!nobstZ����.�i�s+ A��&I"�F��;,~1� m�5�(A�`tl�vitrolu�T�GY�p�g3bH�M,  modu1l�he^�y�a�.�)�qan���*�( lacIZYa �1a1Ject�gentamyc%�A��cee ( Gn )v<JuS�7A�eA��� ��F�Frt�Ca�7-F ��16�ct�s!\un�W2� locir!Py& 2 µ Flp&�s�seez8�Q.s��LacI-�'E�W �A� 50-f�Qm�=i tea� B-lacZ� m�& fu�'",&56h2 NAq"g/�Cin ��)6f top� in�o157��-!��S+�9C�2u���T!F}��3�I�eVd#lid s<+e#�(ntdiGrec* (�Y��)��AGpoint��# carr#7��wpl"�s �^e�9�4�( X`�P�, �&t half2Jala�Na�S� �)�lf u@.s��""−�206�6σD≥3!�scar(r�"-�$�{Z�Y�� . Ca�Li�m� appab�5!� bott�:) c�D"= /+X-ray7% Q l=5����"x e re����A{%l2> valu!8��4!6!<[29L R�B/at21�30!�)��,( b^arrow� WH6=j�o $1ac>100�7!%���`4�M�R� sum� "M~P4)�f�to�9 ����04� �-�3�aS e.gribAal rrnGhC!�>�ere�expon� al��t�r�#�>um �SR2�� R"� z!�!5�.����"�1%U^.�0c%�6(80&2" * sb�. rack bloc�U!*�i� dZY6�A0�EMn�,�"!4~):pLierq<{ h�Oy2I�Ar� =H7 oF5.�[3�32�bIn 198�FLiu� WangeLo�!Y�~��2�a'm�Q�)][3� �\*�a8er�'�an>qro�=�S �{ duplJF%e�-�����e cyto�X )�A�^in�4mR�Na&�Jas"HX6� z ��N �aE4eVunas�(!TR&*;[3Y&'6ic27.�en%!��ceeA]�Ru=",�> `OB3s.��&�_ We tyA."�'b=*c%� E /.ps��|e�p�>0*� $%K"���or�N*: c�) 75%am-.�_i28%�5!�y Je�,q��( twinM� el%C��#a5��6u�A��Δ����+��014 r. P :Tw��e�.�,�0B o2�2h�:t� O aLn(v (` A217 F� A205�gyrB1820 9�e� Each �!~6�.�in��2UEIL�  �[� ,Y�N�! ros� 97%2�38%.�. C�3rs "�gy)ln�]qto"�96f�7)U�(st�hiS%�O 5jŐ�&�Nw1(@)86� *� �h11%!|!K��� . L95�A��s�&c�nd �s t;L)0aN�-�C8T"]pb �ZH��Vld., *{ N��6>�g��u�W=m��"��b!M6 m�K)Ky" ^0 tOy x%j(�.���w{�He&. ���A�A?U aTi�VQV.U   1�"-w�FQ�=)��(!�n!�aN� ( 30°� T2� play1 aus� �6 5�n !8r@ E9Z� � �a 6s�*!G-�mo��#�|6- kine/*�2rm�7A opti� co'�& � -�=-�N�" �� teg�="��"6�!�e*�wor�n%Uempo �8�. D?Q synz?i� �MU>ollab R�Yr� ( +.�#:B fork&�[3�H.�@i�$rib���[ ynam�+6s@�E�X* ly un~Lbed5 <E !����7a.K"Awe�e�5�"F Af6�A��[y�eE*��.�R.g��_g�?\.f:���&R��CN�5d 6�2�A��.n�#_uNUpn� orig-/f� "n.B�$�l�]<� IV�$>)(9�.� ���D�Xd"� gidBE�atp��*�Atp�XS!�.?f 9ч&� f raneu *�))�te�*�!�!�g�o� g forc�5r; "q Fem g=h� �$�� id pJBs30′!��X���a� �'-D 30 m�S� -lif�&All 4�/uni@d=�qե�u< GyrA!�� ���tyr�<e�,aT���D�8va[M re-l�f�� r�aV6&S2 �. NH6016c;� 13TSMp��358-H\=)5�!aE�yl�&�1B DNA-� |����� [3�4Cul a�����7 doub��; &"�afF1� �!� log X%ɉ�as%�)Rd%R(P9 le 1tT� "MM� '*deriv ��A��t�Q(e/c�z�=Wq�el " nS��(1�_ !��2�WT�� 9±1E�)v{#N� f�8V81±3� WT�58±1�"t%�� �'��b� �c!!7 ���(c\aH M�*I�3FD% ( MIF )�b��N���he�m�bU����=�*� �n isog@E�nnSA�|Me�l � �2Bu)!�6{1K�I . {Ai@09.@G597-�i-�9.�#secIß-gl�?o�'H �����oebB!��$����chi�2[3Y"A�e�].Y &iE$YXto 45±3Ee�% ^.��a�M)Ab�r i5DrAE�toa��12I��;�_1\�MDKTh�?�TS-�s%�r�*V�n{i!Gj��7_�A~px s�@*�!����!�)su� �(>ATP��&� �coks-"a.�1 A!㉁ shif�9at!�=.v:Q�����2 B wo �me��_զ�28w٨gyr6521��( R436-S��"A� Mg++� �E�.M\�=�2o�1 ��2�[3�is�ɍ�+ kcat2�WT�� & 6�'E�"_u�(/�+36%!�53q)�]t~A�-B7�v�i�]��Aq�I2���������"F � in1�1� �)P?2SNE�O �W�$���0�[A���� ,!c\$TS ( C56-Y��$�ATY�. dimeri*5�StEhydrol>5a�ATP�m! aK&+ *[3��EɁ�*�%>k �c ur.�� v eX-N6ati�i. =3stto�H4�(�*37��a!�Jof 8±6f� c��.� 1� !]Gwo� �)HB �s� .�AQO �" :Fch� ]� a�1Vm���q�A9�"F4M�AsU�6t�%ug�Yvobioj"A0fluoroquinolo�2�E�C�;&�,[� "�+� |Y"�iLc*�+d unta�bng!�J�+>o�"�+:���!�+&9-*x�!oth5d5�uzd � ch?���!zd�{PJ�>B@�'rep"@4T�Kem� ��`i� ofAG� i4s�U.!.�{|.1�)�aӡ�=.age/reun� ��n^-� �e| ��;40ET�parC281�^P556-L )ن�A3 I�aw�Rw�.no�rU���nteK�C"Uc��.� �B{ Ƚ�*� ��6` 7 "l5N� �_�"�Q P�/�s �:�,�`��9!��p�uel�('-u�fR �>} �[4C4M.&" ��*ESR6� Mb��K5co�]iF!s�&ed.I|Ho� �o�0cr�A�7*c�,e��e�A�(itu hybridi-@( FIS�eP�Orie$TeHH��Cpd�^ inct*�&�tng��po~in�* born s [4�ABoccard ��+h3��U frame4!>jC7ee5��n*,%1��les> )! �4Je��iz!�V�=ny��air%� λ attach!��"s% �M?&vh>�E, [43]0-44� �u|�off�"b�- hows�(I�a*R0�'� *!<[452i2�U�� 5hA��may�DbJ (J��1I&genq$"ah��$�ec%GJw2� ll p"9u2�w)�I i5ndu� oi? to 7*�.�Ej �=��E!'y�M X%�iVZch.yQ".� .$=�map2� �n�!� minu�z (V! HFR�[�!��ge� �&a�4nda-�ng�eri�( 1–10v Ha]= ���ae���is�congruR*�U,6numerouAjY>� isla�,#��his 5%�!!o�ens�,BD6�!Rde�&in�,�O��"39�CIy�A� �l!/0.�+�[l�st�]���: sp�s93�Aof� F�Z:~�[��n=����0 Cs 8ehCs  j��k��sn arc%����s 4{$7�#aleu ��,h^�%.�6�"�" �[. 7�Vhee*�in"�/l!m� s!8�n*D� �sec&1#�.t! 8�i[�i��)l�sedge0�!2��!� h'.2;�:�re.-6vU LO 08O]N�T  ���F1���� 6�� a����@�'�2p*eQSTM4442Uye�;/�4sve�0.�ein�D)P9�a � matcS@0i� N�x�%2> .   ��.�r H�l�1r9��Rq-U�,6�!���L blh*2ycu*w�!� iC��s=a�:��� ( 56e��VitB{uz3!�}��|-�!�'1ed1N.%?7�� ampHJ� beta�0tam" -�� sbmA )�%�aA� nner&ABCi�IJ�G �Q�Z�73-��)�.1of91��60%5? ��?oCs 1dI� 06�f%2)�?I�t1��in� A{ �l$%"@w`verK3.�!�a�#�P �&STM0951J��^!.X� =NrYwZ3q � hy��I`*r�� 1�!�jU�c)�b�06E�� highe� I�9%Lwo9�=�y��9B�CadL�oZ� a 55E*2��� �6�F�h�&}2�am���B�q�run8Q�8q�6�jn�:�716\STM326N(gal col-1-�8�de/genU326Aa ��� �� �e�i^��e81��[� 5�=�!F��A�n 892-}o�S146^rCs 43�Q%��T�1s|A7��!E�!�i !�27���=�7jɌ58u� smpBu�mak.��J� � >E�SsrA *a/SsrB� hpol1!�/WA��-[46 �pseud!�eA268hAD_ � �����$���STM213ps����!�2��ID� ase-5!��� yegQ-245a��$e);"��2ofIc2�En3@ 80I��@&j�l.O �� s� �.4 �� $ ( purple a��o) A� 78�&M�.p.C� 24 N|eia� que|bbp&�tS �isWxnd ,��> Q��tSCsID MatP]uy"F!�mhom ie�^c� � [ a&N alO -GFPm8 . On�m.�'23�-+�sŰ�e�Ya� �hub!%�Ein [4�In.oh =�e(7& r�-z��14��5!g�5� li@.�Yq�A�"A/��:t33uE�2l 1553E�ST xI0ea9�S�oi�5. � aVN��l&>�J]iG.*� ��P�kkI>c4e )Vpl�}�^1. 7-|�" e�o=�)�� 7Pw 2R�7V 38± . 00���A�S�sti�[hg"�R�:1"S�va�� !<*uh A� 3�/%b�lis"�O�9�Q.�B)�7%� ae�")�.{&%�@?nly 470��difX)b>_ h��&�/�L �H�) aL��e��,[<wA��]eB?�.�,"Q!����c!�yh�_?!�_���19-2�6 #�2�2&%"�=�!�7:6`5&v &[ ��f=.�7?6�"� Cs�)��Ow�o=�tF7�WT se.���"� ,�"�X�ej�zZ���28±9� � dro��~�8hqan1(�&0[�!in�!���to�at2 r"�P5�.����"�!�-�eg.. 5 stopx\�0UBAS���1e�I�M , [5J95[S��op} ��qE�gyrB652*&s�8t�2 IO�F� 71 –E�29��s� 3� CEB�ho93"�� Cs 9)5 �G�Ej1�]Vp� JW9�"7�;r)��h�t!w>�#�<%L>RR�A0��e �1?#l`-)58��>2 )�)K96"��!u. AwIA%� a�iJ0�@*w��ma bf��!va��^4�Surpri��.6弍�e aa�atlG��T�hm6���,&cQ�< :&v&j)��[" e if� UD"� |74uC*�M)pa�&y**���(.N$JLz9-"� �Kq3�� *�#�&e��Rs57a66�;5�64� 4� 60� 20�,3 ak51 ?!�a:�63��v$�5��q�$�"�*�5@-Bh Ag)�>*I�33�2l� Vde���q} �Z&48U�� 27±2694� iCX. R�. !;����()�v*�%�Y$ 2�<�2�h�L1d"�,�2�o��Ne�9�%M~$D+�')#s �'�0��� �/.�u�;>�$�6K{). Like&u,a�*� �!-0gBb��������PMo,'e�xR�+.�5"E:T:31�%K�( an't��%+�,'!!I�?�37>�"^�I�"�"t7AB�6A\30Q 1fY 6-7�spr�� ����5�E(t*R)��bru'>w$�o� sto:5�E�",D�9D&`de�1!�ia�X�Z5H!�h�a�M�.[) orie��ue�&a�p"�',� suma�N�Oie��ec"���ple-RNAP�*�( s [5A>To��!9Z�28������ +3'#!�P+l L=m 7�a!#3e@� � 37 114��S&�)�pu�I�jf_2i.IuV/x�*>�( ≥Q2pl�:�s�\t� ���m ��lQ~� u �F�s�(6�u3( A �#*}�Q� !s < ��<he�m��54HdU$�[�liquoI$n -V im�GatPa�;Q1Y!%R_is�!��!o1bZ�;�ha8Giy�|D!.A=�iIBbnor�y;� Nd�*DE drug'i!  ��7of2 ub _I2Kwa]^�G��Rc �  -vd-��ub�� E% twic��oa�ow.�.�W.%7�"�/`+a�N�� Aqr|� 85 -mS�_a.!W.%I&�A2!�D)V&�.E� 7AN�.6��1E, F �( �4�'�� .5Dra�#$�3s)|�\"�] at 6m�.�Ixs ��`  � ] � �rp+��O1/H ��1}*11D , WM9%�N� ��"< � �2� )�� |9gpa�to 22� �stA% gE�!�5!109�Cs9 �kRh>60o)2q5# �a�cTS.���� QZ* ��� � �33�a!<&>>ow �yA�"�*, p * 2'.*^�biPfT6�A��3[5,J"1��=EJ�sup��e hyp� �?��<.q"j$�RE*I �w�� zm�)mBBuV�a�oh~FA-"�� �t�m a� E9� .�� a �`� *�$?��cIta�& A2�!�2�� �Gula��ctchr Dls�w�Lex�R�m"!3R9�? D4of 6 amino aci&�Xß�=+( RpoC�GΔ215v 20 )"x�K:���it:�E�6�!Bo'd E%q!�Ac^# [5+�� �Wa��)�Io.c )�o (��206- 21]y)'� s&" !�*�F� �O�] ���  �f������ M:�j��nt�YR5�I�X�;?��\0&�/ReT�� ��}�2t�!8J���!�!_AH&�',�.ept�+�`�W�!�A2+E�aCalxq%&23 � ��2��WTE}[-�(�" - 86±�1a,�09lWT��Vat� �[ 74±18%E!��� Rpoc.���&8%�&8^;A 13%AgA4> "�Pan&��chof Δ08F2EI:�!���cs!ra�!�u/g�|!sa.�/��2WT.-=Y_s; Fo��i/ adja]+A�?e$\*b�Z!6"��/"���E�j7s=� to 8�a�C}��-< E�36"|�.NCn ��{�4;Na�ūos-?̓�0eU��d!4benefi�}e��\2�'��P73 Pat��Bennetw�0von Meyenberg!*Y�x� G�`2^>X �+� K5lyi�!D�/�9��"J$[�OCŞ�M���!�[/1N-(?p "* ?�=�1cZ6L/Z �"�H at 8=�� !� KE��)�&`s� � d4e 5 ATM>Cz�#�gI� um�[ gluc %1vt� �Nsec��erval)%�<�3lN�bu } [5ZH��3tfV U s es��ka0z���n IPTG���.�ach"���S >a��RAo 5 mM�nd��wA��59inuJ /�#��L�;�T%��4BN�qe ONP:��0h3G' ePr�t 37°E( ��@ ��E>a�bti"�f�A( nt/�) c�Y!���)c&;yL6u D072 nt�S�� �lag��>0!Ua#arA���JV��;" 5A� �P!*in%w��I�tri�e up�0St!yonp,E��F� �s�d2devgt ln%mG�@K32B�#0�q3BFGqq�2�2���4!�t��� *1�m�fas!&6ewE���9Q�8R6 065ƛ�4"4D�"j�a�V#1=ʙ� f(a�"�o/��� �aV�az�9�����&wQT�C��!I;MPlNH6222� 2�E> 4W{�Z'� �of 32±6�"< s 40% .#��z~a �.B�N�Y�. T��q�JMIF ��Yk�� 6 �XmI�%\sr+ �"`N� eW&� �!ss�\��t afB"�)�L*�*� �v2%�d�$�t�~� u� �)Zq�e2t�65 2#,6hN@nd�4�,"E��eco�!�G TŨ��I�Ɓ�E7J"UC6�-I9@��_~!� is�lin,Y"V�&�E� eBp!,.>o�i�,"�?HB&�<bro!�T�rf�� ofJt9��F��� A{oE�|e��v�Up&Gorarily9!�6�E�A�_��~�$�$"�!�$��r�ab*z J� AH��"��LntN*cD.%�� [�A�\?�P%Ec{�&�=:�io6��Be�ae� �Ewof�?:.�JA�!���%�ca��ah�D�'� N��� )OP !�e&�_�ft0�s5%�er"F�I�u"�x""� TGG/nd�Q\� ��te�placexp�%�-���)�I!jA6�!%�: d7Wk!ny�!u� �I�"{Ih$,F�U!*� V�gel,b��A�" ���%vCK����� M�a� %��ta��l�� .�.ejANl�c&�Qor�r�i�Em-&��L�7s�AP)�e�J�[5�n58�s/x�*��)!vto�$]�6�g� %X1‰+ does�<l� !��b:@�a �5 � . ��weڧz%bz.A�)���W~)r 8o"*��b8at�KDa\ez>�CVmo���k��1�A �>T �Q%7of 8��&`.�n�Xv � `�)56_^en��"!��s� �xhi�O6Q��!te"ge�2re#*�>�]M ��_wo�g!���� �CM"��E�.�����^%NL���^!�Ed���io�� �o#� �1IR�e����)2�in�}A��s��Ud.+�i40B {�i�; o�x��T25-or�+ . Ye�V-[�$]���:� ( &�Terl6!�" V���� � �Ao a.!Q�6q"��5� 81%/$i+.@A��{=kr� �6%±2a#1ushr�tA���%/2_I��:@"�aqf�=2-�i*h��%�E_�oM(�I�vy i�y~.��$Aby H-N�Ri�h����� oW� e ai� &��"� � pars��_D*� P�>� y%�u�oe6�!� � ��+!6]��&B�ɷ ,c�wiis�&��Ad2–3�%PW"�p��&�Ųe6exe9�6�". ��dA�!�e�.�p�H"9��wpec:fx)��-vm�us�o��>�!H�z)��X�ar%�the�'Z '�I��ha+�"lH�*Q di"�� %�~�I.VQ )�vea�[5�RFx9�Qmai�U*�� of6�:��e ��ق;x ���*[65��>.� a2UR5/V&�"� s >I�!"�h�"��lre*�,lb���r��@Go1 ORFLg=2�e��iv��ve ��R�!�&=m�2T"�-� [61]ay/ �>�2006�1B7[6�( s�x)]��$ahI*� 1$=�.*�aB�c1�do���$o�'l���%e-�M�&�&��,� �8� �0�6 tu�@ �[6v*pԭ9=~ !!VorA!�2C-QorQ�by 10\jul�~in)$a��3%UR�~5�7 y [66~����qui��&!'~:5 95����� .1�5y�Z���#�*Q�A+!e�-�Sa�|!)=�WT&��D��k"3 (�L8�+co�*!�+a�.��WR@�"a�V!Dln&�Y�O�Wc1����C_E:WT �b��a��*t�Ead2=�dis(Hi^O#��e-R.perhap�vimk�,�*aG� e�e"re-�.Aep=poa�Ϳe��]Fg�3LexiD��X hpc,���( e [6"V�c���5 ROW"U��e�u F v83�>�us `�Yedɩ  !BE43 ^a smo�V��i!�*�{� �If%���a�2�&� part W ���5eA��Ud@"�oN� � 'L/&(�!!V^f��7�80%�ogI_20� G5B.K, �a\�L).� �"{j�!�Vys� ed �:\ in 5%22��l"ʔ �L�7gwGKy�-����i�rT:9z!�luxAB�r6�Egg+!"1!;��Y� s [6�6�A They @foa�un� ]>�=�e��*��%�)�ir �&�Gh��4�a?lN�s-e!p�-�%�"���2�s)��w"�p |lte-ha&5�a��="in��f"%9vf�5R3.�h2KSk �2��\b �m�#�CM�zDe�BS?��+�M9\io�t�LMu [6�?��(?n-(�r�m�y"| S�+�,ŭ!sl2M ��8& zYfs& ,�e�PoU�0�el�D�sќ�t*��񭅩�!"9b�)*�'on glob2� ����6�R5� "5^�}K��F�ł�F4��6.��i�7%�*@em�mH"�P�~;��5E�4–69(Gx�".� p���~C�{ QatG 5 sc�"m$( Rovinskik�Higgiz�*g&��! �lQ�v���/�����Fmolec�s�~h� �)�/V"��U �5��U6�"�%"�B&)#a %o9WU. NWe��s��FD�5hN.Rfh!Gre dQ�D, ppGp՛t�}�L , cAMPyclic G !�r��>�0w��Cozzar��F �(up�A�\s!�!��-�m� �M�Məi �Mi��o U�">0 ~uB6"*v )C�4g�"�4ԡ�caE�[,g%|/.l'st��� a-.�!NA.& !T7.�k)������� �K[7]b z#S��!w &}�iN��2m���6�G&p�[r;"�!�rR�ER�GrET-�$5� `��6�Dsal�s&B M�Vst�'� �r-s� matuܛ�=(h�6sf� &.JF6�(,( Chesnokova�&{ unpKs=�"�:qXk:�u�w�8olA�A;�_�!�%� 4%N:&�v�?u��r<9t�����anov.�i nalidixic 8 [7��E2�]da8�:�!�__a&j���pl��"�RD��]tq�a>! F,.�H5��Ga�raC'fes� ��": m!�_ol1!t*�SM�riU�a& �Hep�HK7�In ��, 300&����"֨��eq.�!��7a�?+*�by �?A�c>C�.V�'roblem� !� 57 �o� 2>a�of� igno� or�8��o6@+6FQ?>C9e�g!�m�f�C4IM+Js��62�pu�C5�����@.���?�85&A NubaQ�?�O)�u"�9��A�Z1J�' D&y� m �b��e>a�urjeq;�RS�+�� -0<��U24p#a NfA��c��� 2I z*�� �~��,al"��h&>�)�T�maximum.�s&U*^ �by�,]K�g!5��5E��"� *�2bot]^�!�� &���7uq�q9Lb�ӯ./ 1�e "~��s�\A]-f� ��p.��aun0 task�l?&�wض�1�t�jB1�I��� how �cM92�u�Op��v sa�2�im�8e fit���Ure�Z�"N[no�a�@�?n.\Ma phys�eT"~a�@.�&\���r�(on�msm�>�6s��tr�.f!�� auge� eH�v>�~|G�"�"�n!�mis��` . By�um�pUC19 � � � =]09�1tyaTWi��9AG< .�.6��k �fS�IsA�a.7)9HV61:a�N| ��Y"k�l�s�� 5%�WT�\? � l �&� mB�0�O�_��`n�[�s  ��/ yG����<����6 W�)� � pt �tvZ �8nf!<el.��'x 6{�~m���"�l���N�|Eg ��,�ve%AFEucel�:��!>uM2�ir"�71A= ar!�6�%��y2�Wefi �"IB��t�.F�* p��)6F s [75�l7El�XA�*�)�{ni?;!�ii�ap2����"   t!�� �0����<��ies&mma"GC\ s�Bu�*�+ orth=Ys�! -tun}�m�A�&7~)�"d O�? Rq �z6 ��!�u�m4=b�"^c?�5!eBe2�? %�68;aci� 9-��*D tail��S�1��s.%s,b%�oloo�}ͳpinwheeEY�&!=!.d�r�[o���?�� [7M&&��2)%o-ͥɕ�to M . 2v�( b�O� .`M�E��".5)yr�  s� trua#�^ toleS I?�`�jJy�u �%a%TW]x!�� !h]�,* .��.c&�=*e1z .xN*O �F&&�sV���r�xE0m-�C�)� �-�vmax !5�Y^a�qsuوi"*� ��� ��f�tngEqwab �ioY%Fe;vj*��1o �txu!�H EcK an ��I"����cY/U i�iOUA�oM b"�$�]reȼ�E work�gen6� n eu�� [�%�&X !Gv���as�s��� 報�tb ,?!�x` r(��@�2K.*l�!�-�er���edC�������(d;:&��� 6� a*��F��-cu:m�+�tPA��du@�2�,Q" �aUA be�,ޞ� .� �$�)H%r"I��(���� �7U!�� ��a�l"�%%�F�to 6�:�� �Vt"' o�U� U metabolP=�E p�v .Z"� r�"A1p&7littlKm�ly�.,� P��|.� &�*�&s g��>A�ult((a�e�osco�a%�M����\ t7 �4%X�TCAM��6)��" �kory_F�5w��c70n�D!B[7�8�EٱoyJ �)�ItS'e�eV�*� � ( a few E)!��� �( k� )�� ���e%w-a�3��=�7�S�-w)%at�%che�aF w�7 ��syn��O� �aceA��-ut�&.,d�3�u)ic`��%��.�[8B���l�)K]bebXor"�-� �x �)�:D1�! ��]��  sirtuin*��M`/deA.acyl-CoAǐa�[8�.A � #!�"�XpE�!�F&�Upuly��)>%TrULH"s+a�bi�hU��`pr�-�w t�:r����$ "� ��A�!��� shipu�op�u"ի� w��M e+}�� p�Iwere carried out as described previously [31] . Chromosomal recombinants wIselectedF�antibiotic-resistant colonies on LB medium or1 Lac+2!8minimal lactose.T. In each case the exp x�Pnt genotype was verif�4by PCR analysi!4 ing flank (primers . Ef.TKtes�nd shown!r contain a� sette-mod r@allele with no WTDpresent . Transduc!� crosse-Rperform)SdN�u�(P22 HT105/1!�d-201 , a high-efficiency t j� vari!)� , 11jiduQ�incor��A�tSDnatural C-terminus��`that makes an SsrA degrad)PHtag , which targetsWproteie�./byClpXP $��$e . At pos�J 9��011 amino acid } q4a L9D substitue� give6| a 30�� half-lifA{!�$onentiallyEwA�E .A�iExSazyphimur�!cells1j Log-iSculturesEi�VQ��� samp!�,at a density�050 Klett unit��AeL,1 ml aliquot'�h hE� placi�(a 42°C sha�;waA, bathA� 1 �ŏE�RU�]�. �bi"d ��(immediatelyu�w�C2�of LB+Cm%.incub�U�8m�i�C . On%�follo%kdayA�00 µ�Ev10−6 pion6��p��>�(on NCE glucŮ;�umefain!�8chloramphenicol�5-ban-4-Ho-3-indolyl β-D-ga�ide ( X ) plus 2�$M IPTG [13��P��C9 2–3!sA��,� dele���quenc��sco��by coun�Manumber!�whiteA�o��e�reveal)los%J lacZ�X�Z$data point�Penm��ZE��t leas�D>���Min�ch ≥!)���Ё�$or drug sea!ive%r6�6�o�� elong���#st,Salmonella ,%,β-Gal metho�b by Vogele\��[55!�A�skM�0M�QUABQX supplemen�e!Q� [90]Wino�v!qBa!�sh}6q�I�thC2" i[ or 37�S�ds (�C5�)!�2;havA�an��06�A���%�add� T500 ul ZS buffer ( chiū at 4�~).Z!�ug/mlBd�hA(�mtakenJ10 !�tervalse(A�$background1�!h-eo�Vfinal�centrI 1 .! M%>�2. A�he �%!�(drawn every�ece�mixed!2��9A�ab� 4 min .�$�U"� 6�)�!edA�%Il ONPGm@ init��d a� d enzym�a�  !L��aM.�%–4 hrs�a�� elop%\a�pproprm level% a�r)stopp �!�ad <-FNa2CO3%�e OD420%= OD550 val"�II�� � MAb r Un�%�*� 2 [9�Lag%�d�g crip�R�Jde�ed"V A�inJ� !3E2� ��rl "h at�2ޥ8SD!!"meaA ��ake a 6.���,( ΔKKLTKR )��;rpoC gen� 2�we��&N�DSharan et al . [92�� Four"a -sig!�a 20 bp��lap�N-%�C- );x egA.ER�a�e X paiŗPRpoc fwd ( CGCGAAGATGCG  )X@rev!P ( aaggcttccagcagtttga�cgcgggg.?f� l2��(caactccgaaa gcgt atc0tgctggaagcctt@c ( CCATCCA �  ) both  13%��ts��y�Y!�upstrea down reg0 �wAI ��in efra-X%Ps!R g%�9�nd ���O]!q  !XOtoEIa !�)��@V�( �]er �7���"����* of WT LT2"& had bGpree u� al�eer!Qfun��encodI pSIM6 � . Af�f !gL2��� to��a��,�a� 00.� "Y to 5c�V `!}�R2� . Smal��� %�observ� EE{ nd fis mu�at �  1/�Kto 1/100�T����� b pick� ubj�to%�s N!J&@out� Q:!�tem�� a neR vU ��AE%:s�y����A���czdI� ( ßU Δ11��A)�� Bart ��54]� gave�E� �e .�V� tra� ula��Dotozoan Leishmania��licat ,parasitophor�vacuol: PV ): 0share many fe�a�� end�s/lys ( . L . amazY�PVs� !_markedF ur!�infecA�s , but%4impac� PV size� ��.�survival<$still unkn . H we � hostM� ze�>�upreg:>� YST/Beigeu�a�*�"�E1 �. Mut� � Qcaw further!expansa�!@enhan�#>�rep%�)eco!(s! `a�*; �toM�!�. (did not sus&9{� #eat��:_-`ng-kE0I^in-�ver h, �d:���U�he op(s�InE-64d5�re�XQO� YST-)ō~a;�� hibiAvfEnl�d �ppear!N�ct�s�Hoxi&ve damaE= sincA�o!� of nitric.e synt��'no efa/a>�viabil*within ��iYU:their1E -!I�Մ��!��ua���u �:!VuU)Mѵs ai~inn�respon2o limi9/�,�%�!� PV volumeEi-3ng�q���. I�[��trypan��atiRJ%e�$ a broad s�ru�(human diseathrough� ! world . D��o���heL�� genetiP immunic� mE�-jd��� clin'H can r�� self-heal�c�^e��le�I� sa�,e visceraliz* �%�e]��(r mammalian�� %�a/A�sandfl�r��A��lyEmastigo���th!P macr��con��!majD�� V���(, fibroblas  lso harbo� ��[7 r�vte�layim7�role ͬ��ntM��[1] )�o�2���,:�.�9&A�i�r��%�al�v pert!{E�R��cluE�low lumi� pHe[!cNe��ofպ-a ,ific membran� ter�� ic hydrole [2] , [An=U ques!A�2o stud� =�pathoaAis how]�per� �f elyNm$evN dd�&�ej�.to re��ah[4T�#exclusiv \]� =(style suggeAe�:.�p9 s meHismex avoid kile�abundAo$microbicid)��s!���by �v_�h���iof! vivo1+%�A�of!Hti�rA� eres!J rel�!>_�EUat�&s2\g %���new�S�ral linsf evid��� )D>{,6��9dep��쁸u �1]=y�e�mpa�Ho oa ]r�[5]–[7A I�A�ngl�AJmorph��E��%�_�>�.(e+ {p��G9mexicana� plex���dirs dra��M y :}� � \J�, such�wh�Ea�donovani�����  .�/.� B�v$},�mu�]�e"�inu�$undergo fu����"I ophago>� WR ��V�.�EOe���� pG � �!�in cEA� � yonly o��_aw� e� 8ERt- s�7YaNPV� %m�F �a*M E/e�R�b��2Nmolecu� [9� direct�?vA�g�]� hypAOa�� exZA�� on�� tern%��2i��� AGY*3 a� � ��j 1�% in*r��Our-�sf IU>$��s&� e.� 6�ul%4��AUrol�2�A�} o�6|�  H, m>� �a� �as��ra!�8or��. iblr%�Ch�@k-Higashi syndrom�CHS )��n aut� l�es�� � chark!z�Le�e def�!,a#$ albi��% recurr b H�1� C+E�� pati !G� mousYuntera�i b]h�abnori y en�Yd16� Q8-��rganelE�10��1�]��]�i ��M*��m�I�is��cy!clici�@in ( ∼430 kDa )��invol�-� Knth�2�; l au����onj6, y�Pwo-hybrid screens [14� =of trun�dastruct*5*!�� a)�$of �%2 simi� BEACH dom�#[16L [17]1Ti�iX!y!C� ancho�Sscaff�"� kin_ ���r��m�\ "� �^/fi�"r". T�&�� sif��6��1�i�>{��,u� U!foc�minio�' =�&d�� yiVed2c 4. Oligonucleot����arr� -� demo!ϭ�at.I6 � incr�c$C57BL/6m�b��marrow2�( BMMA�e�^Waxf ��"� !�48 h (��|�&] Tef% ngs�confi�&�r��%�( q="!�� >�a*��!a �#ual:�:,4 messenger RNA:H�Uacha�a�3�!Q)[$ 72 h afte� �+(( Figure 1A�A� "�(&r'!5>�o .�r��i.� &�Eepm'd)Z visu ed attach�o�|amp1-�ve�[ui�3' &� �Be�1C�To&{Y eZy.�>�2�e|"�'�3A� �e-L� v�inEŪ wildVor͋mic�XbgJ/bgJ�I� )AZv�,��� rapiE(@(e>. more�(wly548%QEJ.f,�i)@2/"�  ���)�bHw[th)�ignanB %�r�"��ll�]#�!Q�B–1D] {���distribu�.�(�,T� as h�o�1�. e�m~"I���f -by- R$�( �� �M�pa� ��st sA�k!F:��arZ F�Q(is < 6�� #V?,�Qbabe�en ��+ynamic�(�tubB ��.�[1� WRw�aly�0=&�*�*I �&:2��_dN M!)�w u�)�:sRst]���I�&,&6|p� sA�.]>�Y]EE�2� %�9�eofEi�e_p"a%�"aton�se�&~ a��2�/favorB"- �o��%H\ F*�z �impH/&;b e*�0. C�2#is��E� imar�d immort͐&��I suscept toB���� , [1E"�r/ Aj!6�*ne �yonic��� MEF �"�ª�ŧfE�%�?!��ys���6��pM�>�rolife�%U�2A 52DE�We�A��{in2��ɧ fas�Ɂ%h2�œ� �t���%2C |!� �B��J� ie�$0in�$ai�)Rk*J �k� .� deri�  ����"�(( YAC-��)(� (ՠ)I�a�cop,��0� I��;��f� 6N.�!�� .�yGsŲ�6:-�6OI�2 -��t�A�a-�3)�3)�I\"Q�.�f.)�2+is41ա) �A0el�~,,�)(��inaY%Ce�6�be�&"�b!:w=� .h(E@aC1BI" m�eR�a{'ongU�n�M�,Sn�.�r ��6(t #%7e2!!Bs2�ng6�a�z �&,(.�,��3) AW��ud.wep&z et�S,�2:t:.��!��/pop�!! grewK �3haY ,�j� �ColV6�sv*?��p� aZ� Kric6 r6��a6` .�� next� d whe�I��.tE�s�!>PM0%b�� 1��!'by &�>asu . 5��E�f*]A~�ben�!y:q*win�v +* .�would�/�8a*�Vi^ lak�+xim�11'�e3�2z6AaYgl.$ cor-;�%&A�!�Y"��!�8Z�5C3 lef!nel ,�d�i� �� !�n :9ama"k��* "is��an*��Fy d�s.(r��� +">� B�trigg�8iH �x#F"� U�es =J�0�pro�I�blocksy�.ifEl ?U:��`]e�d2discus+ abov"�R� fac�#a'A�Z�!Dm�A "9w re�&+ism6a�wi:A��e$�,�BA�GZk�� n�%��=���&� ^G. P��%��,r*.&���fE�j thio} %�*8for�%�:�9"�&���"� ��i�&8 , [2A \E�*� pre-��\&a��a�f*E u�4 4 N xcoinci�yX�)�a&of24�^�.��^ � 24 hC :� un�*�)�C�Eua�I2DA�s'�)p�ntM��)#o �JA �)�bM�B ,2&��2 '��)�5�O�.�� �!�was��%pridD � ,���)�I0f�%�irb6r��cys# #6�-���Ho"��>nJ completa� rule�A��9��po�%y:reu��*�. F�X�qVS�a�6sh5"z)9 )N,m��Ey�.2|.' uh�c�0*��EE"� �)esL��(+�t�d�2�,JU[2gWS!�}�!.2.�n��>i�a�Y<6*�`f!�I��68Y-i�ai��. V�%*��K?m�.��e,��!Ue;& sr0i�#E� cm�^�.�y�D�4Frc Z��.(ngb�,.;E#� *� ��� 1EB{!�a��:1�- *��.F�xI��.4 ,2�Vico]"%�bef*d o ah&�/ad��m��BAn���F 28'�'��fo*7a(eyondI�. S�,*��*_ tr&�% doub��b7&� X >�Di1�EYu�.Dt^ i+�#�B# !m/'j �s��@,�&?B:�"� . A r$O�$l"5l� �'� \.B i�e IFN-gp+Ex$TNF-alpha-�=�G b5.( iNOSA-NOS2 �?J�r"� po�8|(ag��2�. ( NO ) [27 [2<Re 5 c�Cd�'�at �iW%cruR/' .4rD�&\D�)-*�p&so��*�"� ou"Cto�cri~ 296�� [2� 2�'pstY 1�NO ��tE� i1C� cld?prA�!�� �"in ordl��.ivf->_(>3� *besf2�IFNE*Y&<:� u(�� Gd!��^� F%([�![65&T� PV��� may 1�iL*du� ajconA&�of%ZI/recGntact�56�.?�`:��apa%�#8��ng_.g��.in"o>� i2*:���A�e ��/.q� >���twox �ys 3G4e�it�!Civ�%�:���#�Sa6�� comm�Io�*�/NOk� %��&�Z��m|*1 robup,.�6�)�=�m#&!�� wS:�#6�plahB�)�1�d9�!���a'.'�quNJf�If�n$� A,..jpx aI��"� s L-NMM\L-NAM�E/#%H:9?�/�1A�EeM_�6�l5q<>��/mC �ab"P3��"�9 . Fu5I"7��requi|#6A��(*!E K� �=!�.\,2 F).q A��3*C(���an&WB�8Y"��# �ȑyM ]*�9�-!r%I<,�0&�e+.+ae.*��� F\.*�!-L 9�� he f6M�y%��i E"U��"�D!d2� Q� 2B*��'�*d &al&d �'� idea ��Q 6��z�9�.HM�0�HrI ng! 9E.�/�q �a searc�K�H+B"� � f�#�]>[29I�le� nove rapeuN9�Dteg� agy,�e�9I2�+cp=�5cv6 . *.1<( IFLA/BR/67/PH8�g>ob�!e�NDav�Ma�( Lab Sor P�!ic DiJ:, N��al In�Mw%Health )E��Fa�1aE+*�at 27�Hin M199�Ia=l� G 5% p�+�6/�CptomycZA1% he�G$( 25 mg/mlUN NaOH� $10 mM aden#,>87 fHa�10% FBS�A.gC�,�Eacyclic�+&TB~��25%"\J,5% �;� se , 4�sod�L succfT�)pH 5 ._ 2 �,@^!^×106! �B1!ka�_ nim <6C�passaŔ�,_O;R l�dEC�3� PBS �&1�Rx����B&�--d�".+(�$) _iso�:M��Afemur2$8-10 week-f/C�-:�>+��.*�JI��Kd%)7),in RPMI 1640�a5a�30% L-��=A�ernat�VA[1�. M:2Cj�%s1pre�-xO1�I5[ s�%�9sC��ighUp glut�"8$!4@9�-fJ� � ��$- �!��@�.�$(� P2� � � �9,:GaX2�9&4�*�WadYAX  E"2�.� )[8CBI AAL40134 ac��( )I��� J . K . '�3�a�he/K��of Utahs%ACAx G%͒�<:�( 1�# G418a� k�:m�:A���#�.�%_�" remoz&J~E^ݑ,*�y � �@A�.1�e�pi��ġ���5�$10 cm dish�E�� expo�or�F! � "N $at MOI∶1�Vr ^T�� O&�HV!�C k�d>�!b*�HS�h!8�!�M=�To ~1l ��u�Trizol� nvit.}�$Affymetrix�Xto�R,�fd�a�,seYex��AQ*A�Jor),h-�:�6��024�%@ �Z,( GeneChip E&SWA�is Tech�AMan�2,.�Qc1h�5�7� 16 h��jcj�BGen68�6A!0 A<4(.3&;� 45�w00!> be s�p%��of 39 (&f48 d �Y���  34 ,8a�!�N�7iz# %G&�Z)��%<]m�9-:565GC-N-veY( RM�M ~ . Id.W� E�of.[ly�tur!� �!�d� �&���5of��r�5�A�fal�LoXve�ON�1%�Pl-a �4i>0a BioRad iQ in er De#a�s�m& %"� 7 , Ltd�y�� SYBR8'en fluo�Cr(_R:accor.%manufac�r'�a8� F�6�KP5′- AGCAGAAGGTGATAG�NA�!0CCCACACTTGGAT�NAATGC�mu���.(fy a 119 ba!^�O�'!2 �T TCAGTCAAC�OGACATA.s,CTGTACTGCTTA�:h42h[aC\<c�7 HPRT�R!��)& aW3CSat 95{ ��n45 %�� 2?T�/�Xor��^t 5F. F!�esc�AAA���at DnnGF stepJk�Fesh/ ( C@P?*�R�>�3%Vng�p]Wat��+EN�excee#�^H1 1!2 ru5&R&p�0�>�M�no&�M%w)Iio1r[ ach��W�Gata (�f��9!�GAPDH8xS5&�^Au���9����!�2�%�" s!'��4� 12-m�am!W glass c�9 slipaO 24-w�,��,="Q6= *7 (� �0511406��\ChemBridge San Diego , C� ( 23�as�T�6:���ZME�1 h��AA�.�( Sigm.=�S SImr �)@ r!���<. N-methyl-L-arg,[� r�/N- o.! 3 e81(.�� �,�9F�Kuor� �30.=E7"'W �a�6^.o?.a � BSVy� invai ofE�, pur��2�Z ��7�ha|h 9e(  )  �� l��hD+ >�.K,n�ni = � AjR� K.6�J� -,-o�-U:�a�6��<��e�Av2� emperQQ!�y�it�fi^Yin 2%+aldehyd�wh"K�>HE4�1A/� DAPI%�5�W,kpermea^l ��o05%N ton-X�Y%�0>�`lf@300�-9 rE"[, � �KE�v!&�. IO��ac lLa~ × o�S u� (a Zeiss Axi!KtO sc�cO�Y�a HamEG4su Orca II coo Q CCD camerG�Sby Metam�G Softw�( MQEaR vicz A�5�th cur�a:i5Ab,��&�,a��r el�S0es!� � ��6el�3to��ens!f!VY��e�[yA�'�=-1 Ko2�Q��gA�ZEK]QQ PBS/A� BSA/E'5% sapon�or�p�!� )� nti-�41 mAb 1D4B ( D&�Kal StuH,H� @oma Bank ) 1∶50!M2%~A�:}4Q�f"�$8y Alexa 488- go���rat se�h�7bo|( I69Hao�je`�H!~du�K)�V�Ms�"�>I�A"Y{�] �av=A>n!��cA��=iiK �/�s��\ngt"�PV�n/\s"� xoP c:.Z�[�7µm�t�of�cNEF�A e�!  .�4�V"� '&��!sycq8.retarQSo�1�$� s m#�cog\;�4BnUa�&=N�\he Allan-Herndon-Dudley *WGAHDXG�X-linpX^�B^Gdelayepav"b^,��#teA.dis���/muscle�Io�W� sp�c�mplegiaei� k] enD?� thyr~Nhorb ( T�A�T y��'�;assocI 'W�3��E�(monocarboxyg�P Der 8 ( mct8/slc16aO#gen��-�s a� 4a5&/%A n �Rthophysi~M/.-of �, MCT8-8ck�-J6E|intenIlypdA�*_G�k�Afaithfugr97� he"�H seTTH  �� they:�4to"L 6 neur�A�behavioA7sym�� %}"%I�X�6%9�an%U%�nt-cH−/− ) zebrafish�Dzinc-fi�D)F�( ZFN ) &3&�&edi e�`ng!e e� �5of)fde�D�9��a�-of!#re�= ors;*�Ait&�!f"%*Cof�GTH"�IA@A�S\Hto�55,%1larva)3�!edr��:�U. H�lxput.��ym*>VGA�b|�2d loc�jhnc�e,�"ed�"WexVM3Q�(A9 darki1�N�$d+)��sleepT %�E@�K�#Y�3VZi'>�W#B[mye},rK)��E�n&.T>{circuit�m��(. Time-laps|La90Xr7-axon �cr �syn*��l Ju�1aa�.T3� ilopodia �B ScbrqJA��:nsory � &Y��tic d�Qt,�s �A��%p�Z s en�'assess��M3��+O-�cTH2 og�zSn�W=' %  *g"�%�.A�?i.)�%�%out� >�Jb[seF�a��; ���9Kes%&2M !m�D, ��9�!�i!�A_����2Z�1;#7o�(!=�ad� �%��� !c�)�BV .� C �� �fundaA+ �,< h6�/!�W :E"zrv�F��Z�4kin �gen�QCsaBA� conn_vA� jN Ylie�rooE�D7 �-.� & -N��J.*.'�Os/iQ&� �% mostlaNA�nite d6�F� plex��2�q networkmu��  cEicU=ph5f* h �R�e�loodis�-��,�!�u�m� lo$d� !tX *P,A��@�ebt (in young mau�#-h:�Q�&) C0.�&, �uZ 2� R� �Ospeec|8Eq-@G� !�t�ExYIn^�� P2�;e%� -:� .? , �"�)�bcr�"��2�ir�"* �J��plasm!1:�.!�pro� 3 , 3�c,Ctriiod$�-#/ x�( T�-!#&�%�-AU!Kg*�Hrm2hNaW�>Zll vert! ��,�!Yn&� ��o�6.�,i ��,�� $metabolism/0ei*t�<�frr�Fdef��t9�.���&'2b)@T3�irN %�"�j by b~ngz� %�"� !Rr�0. A��� .�.M#0 te� zxg2J2��S5�e� �J ��e']M adequ���isQ avail E!h#W jroVF !;0 �!f tiss+m��%9h�glaF �n� vasc�L�s�2�[�.I*lelu�5/ (�l�2o( K&5�modMqA�� 9 KO�"aE}���oiWc"xi�_�*�!C�WW[9�1�>&�.�&/dis 1 8E����%"�*� ��Can  PxplaiU5)�+ onou�f-�.an e��!�polyp�K0de 1C1 ( OATP f a�:c`�9erA^t�"*od-��ba-|r�B /�0�Kh�81$A[ �^=*-AGt%�[7�W-Lś�4.��8niCv#|)�o�U!�2D-�P -lik� *=y -"3"%�e*��� powerfu=Alum��� kA�ts)�� � �W�w��C7)�arency�Ke"+TթAO*� "c �f9# 5I��76�!�x\al�P$-pituitary�BiAoHPTd(xis!�0"[l&�P ��6 emer�)���T�,ve-���Q� �,=YA�EN In l��Rsep;antag7Zwe l�$S"�$��b %�E(^0r .�2,��n�;,>Bisq��DIOiQ o.blood��FI�.� �E�� es7upt�q67ell��� A�knock-�o!?r$I��A)�x�[��inx-���"�0V&d6*"&��!q���?e�� *�q}[o-a �/e �)*�{86�Q:,Tf~&��� bi�xJC6��ct>�. Stri�E�com� CpharmacY�ssV�*��HN�<or.W 2����J�#B%1a63U��&H ���7,&-�� �db"�s"kyAA�� a}�I�v�"*�t��i$ra`e!#hct8!�us�0custom-engine�iZFN�A �%of !�o��82�a�(��Rmatch 15�uat�:�6e��HaeII�f site�8?�3irsLM�]0!�r�#6�x�". ma)coy !����!�in{r% one-�$-s� wild-t�(s) c! To�if��T� [&3 ,�V(dayFt-f�i�+( dpfQ 1�m&�:�*20���is234!dG&�uk���U"�rw%R"� "��c� �-e@,�(�= diai T�x)�a{JOo �y.ejntact����E-&18��20�8�{ngQ�R8 llel" �F�EfU4�.� u.&ZAkM01��t=$o��5� mosa�ou��( F0 ))araia2to adu�od �out���WT}� sc b��F0�uh=p-��6 fer.�q��@/k F1 offspr�� F1!�gen�sw6- ��E$^�4�!�6L09jtIUa?v�k!V -cli�(A�typ �O�M� F1 hI'ozygous-���+Nr���au2�! =&2 �/!�vct QO*jA[ 7aZ""vEeeZ.0  ame shift%�!�&��a�� �zcodAt a&<�97��<&A; &�PM@�dFi�, ^ �e9 F1 ҁWJm�A�E prIb� \9,F2Iύ�rQ�toP )�<}9�X�F�9sa�R3�C� !a�#E�� -el�%eRl"*a�)3�Q\.e�b)�Q5�^ed/ *Z ,i}�.s"#��_ ��%Aa��� -�@�0. �i�WT-�Lzc. B�{a�A�nd�Sc�[-�f$""|to EGFPY�Iof! C�e!�?M�9 -9mut ���'Nm���&3�&�6p�#)��&( h�.so��s�F&� �sigS !Ca?)um�b2!*� �dB{ ly-�p~�c�_BbqZ`M8�iY�[I#� Pds"����!srdi�-�K �]u�� Cf5~!�-��yo!�M�F–H �2��UrW��$O>F��E���$to HEK293T� ��Jy wz+n��-A�.2 &  pCS2-cmv:�)���he�,��%�a.t&y"W<%�*p75�ib!���c"'V!�Ke.%A�6�LI+a�is2^!��I I��mutYF�O�in &r� trssB�5 �!�6�M6H �D"�t�k4"&he�q� ��7*� T�I�� chieae�! ���lJ@� !�+ Ag� �2� iM !�z�B�Ton�*�* hy�u� !V��ep� �"� ��%q}��6TH-NC�*^G(as Kruppel-Vf��$r 9 ( klf91n#gra�)$( RC3/nrgn�K1k.U.��i� �xa� ���\Eg%�*$|hQG͟uEol��uCUsitu �6� ( IS�I@r 5e.�4( qRT-�i�:. WmUe*J=A�1�while �is wid�� �idA�CNSu�2!;�s"��=2:LXre��lu#0%�A���Xdorsa�L��3nd hindI` 2"� �4fM oa �Agre@���Ti/ r�P�y�MS:�T3! uces)�)�ti.�,4(, nl��~!I mb�=beginZ��:�.g� until 3�. ��zoE"u*�iQ,�/ K�:���&M&�$by 49% ( t�0−�364�df 8�<�,0�#2!!C46:B�@30� �B:L,�!x1g�!.���Q��otoU ,>ANT����zi.�No�"KT3� �iiHa:M�s A�n)�=*�$a"�al�7,u1�of.�nga)�5�:!j&� MBQz\6��F�Zm���F&�'T3>}u�!�t Fg��HW�P� �M�I6�s�H)�U�+do{%ot bp)keyF_.)�f*�\!�u�0influx%_ef �.%RG ��6�R� � �!ul�1eU%dqm|p���na�A;=N�:�� A� part"4�gus~g3R�&x %�N�, �i@ino*��nti�& e ol2�q? M;,U ^ B+ in 2��Q%2To�6Ue!�a�2�nV� HPT i:Q&u�SF�/! >k�m.�:��%hf�� �)�mM(E\yrotropi�ea8�# ( trRG;� -stimula�&β) shβ8 A1� dei�aB( dio1%�oԉdioz#9�V��6w�j "ju�Bi�"5-|>LTH)�i\lI0B�ac�%) aTnd bala�.B2|"~Q�g�t�'- uny l�pXI�.�, � mct1�oatp1c1�S'o y do� overlapA�yu= %� . Ne�heUE�& �!!6FuE;in��*|.:b�]���!W HPT-aF�� %s.���b�� h .�KcR0�-��t �, �c;�nd  q�x%ouWRalXF��_V:L.�$lP�M v_TH���2�Vbe).Z"9 A$!�at ol�W*�!�r��Rs�0B&ligand)�i0ż} ��l s)d�&n�/�4z< � �&.�jg8��F� el� �TRE�&�!�" 6g� [�Xre52x.��pl]yX:^)�r�1 yZ a�hra�=�;^-b -b�=�jF/bet Y+� j �� weakNE)��-%fTV>"�oiD�;�6!�Ay thrb��2]!hretinax i~ C&� 1k�d�&�E;ݵ!�)�,�N/ �d�\�\WG*u!K�.<!��!�bV �.ѐ23.� 6 . 6� "� 1�E� 01-�12� tK&4�: 45�Wi�.�ME�.6�>I��P+s�7R}E�  �h$� .���^V2I&�e��1�.�(rb2i� �jej�iJ%����Bi=��$ :vTHu�s�>���E:� ie$ aPB�/mag̊0�nHi�3 ( MR�� 7�w9;"�A~ glob�4�cel�t5��!�W�[28Y&6A)�� g.ecNs)�l��� �"�!e�Ar&8in��K�) . Gil�a� cruc�3>~TH/� de��gl�u�`� � � � [3U%[3M�O&���=e�af(� )s2E= w &Q .HO%�^��%e�THG#�nF+�Ti�a!���Ρ��$�� �I3Q�ng.cy�!ineage}�A��b Ֆ!OM:, �bG ;�wA[)O��**�by"!�*�$�*��..� c.� `2�28� F�2� � "� �2�� � ,�BZ1[by 27.XyY2vbY �p0r[3���30r[�:A ��3GJ�"ad*&�AA,�X����.~��^6�Q.3:�9�:)��s;t2ybK. 2-�i�f.�@��0  &2 ��cu�FbQ$yIu�,E�::�6�C�M�m- e�I+K3�y�W� &�al!�Qa S)�� 42��E\U22;��I�V��&s%.�6�.-��I�F�%m�U)[]�&��J��(mM2)1�r7re�R�����E�0.��FJK�- k�I0�Xc�eEC]V�R�1GH-,q� kV A*�Y���� qSc�'6V�ٸ\�"�� s� �$��*H 2� !�A^ �b" aaOllP3�C,reh � [4�m���)!0%H ]A<�0)O,9��v;_�%}ia4.4�Be.�aPB CW�}� s�7X8oj!5r.}7i} >(op!� 6 �lY��I.�exploi� e*Q�2�$ jZ8de���.r tesE0&�E.�&b����;@zn4%e N&a�qE;�&�4: p"�2z@ etra|@�&aceN5ac@9 TETRAC/TA~@,?;Q@N6RI5�!�x-digpvo&� j DITP9 In �]9k(vo[&At�9dBOI�e "H "j?l�'am�P+e�[4/4F21&� T4F-+�E�!nalog % � 1&F agonist �on��e�A�/X!H"ML�6�M,&�MY|-|[4�5�H"�l*7EC ��i[�suL"Pi��b5$oniB�9'"n drugG&b�)���=3.6R=���"^"q��ɷ��!CJ� ���`to&�&~AT�i dIAK�&I�C K|��'�a�&�r�s�D hose��E pre-calib�s�(�\/�4est d"�H:tpiggG���6���=rpV��"�2(�� M"iK��M��R. D%�40&�'M/qegg-w? i*SYafmegg:G/7$!�cu�dL9..� ��&� v� !�i9��Di1�M��s&wo � %I6��*C �"� z3 !7Ao-&�w�!>/S��t��c�^��<�PZj� 1��Yy 54%>�A�F� &�1(" 5�(53��"s �4* &� ,�w+E� mark@�,2�E5&:!#1Q� �'i^- ,iN (�<-�:�J�6�&��! N4�^rl:e� 46±�02; �:�\1 7; � 18 1; � 5 �)5 ;6:\6\2�in?))4r�%Z������y"� .4"y�Z�i�U�IRQ���9 ��� 雕> ]!�byk��pr�� v6� inN�QEe�D��9(�U| 9FMJ:( cELQ/5; T3:�_0M17; T46*8Yn�4IA2Ul ?09Ulc x,,0>l6�E&�.:� TH�"#�(�:�+�� "�jNesf– Altog]���^�2��$BL|&N q %�I � �;�: ���� F2Ba"�,�*N2 $d ppl�6B� *1O{N mo]t� t�n~D mov�#a.E�l��y ���2in�WtoMuta,mG walk�/�D�*%�as��:�?3N�Rin�T&�s4�mQVi"(D5�e(!f> "�w"i6��p��u�Y "�-Z� we8�W:k��Ba>wBRE7�d.Q JBof dozee( gs�)ta�ly [5S5S!rhyth�@!a QA{ݙ( n144 !ŝ8 h>&! ��Y�daIZns=. U�=/�U8i�,: 14 LO :�_�*���<�%" F�%?pea�? ���r_a�ę,� �gD� Zu..-�*�,18 . 82�286 ,�j<$21�6cr166724�:B�@}7ir�:Bl+4A�<2;�oj^�9�^��6!�AHB;!p9o_� 3V;�}t�7ac�x`r velohc^zDI`E:�K >GpeM`nutW ��2�%!�+ "5 Z�4.�9 . 5Y 6O��N�:�n�Qc�S".`we��db� day/M�{'e]��8. Typ6M�mJ�u��1�,2Q`.g � �J�:%2day-to- � ( zeitgeb%�Š, ZT1�h$-!� ( ZT�"��-���9h{ �` e6r?R1zF�Q� 5�a'��tj`6�-G& :@5�ŐRA�*�,>�A��c� 7a 1 cm/ibW"E/: − 1 15 ';�N−��6�6U�� 4Q�! �i7�a�mad�7�2�>� v!�)��8l8FwM� eP�ele AN5�6�qto!�V�s�[�#��X� �_k)x/ 3-R ,2y�i6fv!s2���VtAg"� �� �T.-l �B�!j0app�N��� � � a�]UQ�bOL �^�au adian2(��9��iQIA�!I D��Qe|� muliWQo~Jm~��*�m�#� CngAa4�od6` ness V�~3–ZT6�79.B* 3r�p���e"� 1!AE% ��:�`(.T B�m 5E���}�Ry[�� )%��;I�e�Z�"�eQY�9"�ba�DK��&�fs��b��n�Vq<z""'��*1 nQ�JIofH=�� Yr&>B�UxfB`( unp��`�K)>R.�`%ts�SR�K�.t�"`,�a�� .W\z�WR� u!; &/S��–[5:\9j �,�*o<��e��] �m"T` a:\ka� �!Ea���" w,A�!��+!�g"�5��oBhA�&`E�.t:on �� &� �arcJ��y�J|*� "NI"� &MQQ !iIU.:�IO ��p ep��re<� 8� B�� �O��2�J� �Yr�� ��9�ZR� s��6���8-Ȳ���F8:p 2hDa0 &� �(=4−�8(.4c ."�-GF2`[`r-;:'�ol���o;[,  e &�(.o��wCZA)����9-<�l�p-�>4I,��gi] !�wI/i.�Y X6� :�dayEB.;Rnotb.WAh�rG�!�4�dl6�:���.�B)R� =�� !�9�5�2-Y ,12�YtHF�]V =Z�V�!2*~F%�"��.[N)�F��2�'/KR�&�6� , ��+s!@(�b�u��f�(e�@1A ���0:�d�W�tt��Jg � cC*F� � s.pgb:, .�h>�6!�a �iahB� V�>� � �u�9�m&�%�h;�%A.��7 >5&p �%86 )5�*.,-�K myoD+F5�% 0f9)�.�[6�6��W���#.x�*� %.>EsU !XE)%a���E ���q.��:�Z� S�*I\�.gen�4�j y-"�WU-.��&VV"�0:� 2U-Q4):�a2=-M�uV&� �{A?�4�*ad_i0�uYk%p>�l.�#f�m\ ,�-e�� dysux�)l�:��x�&c TH depr��o��;.� IndeM�PAX&|* �E^e *�F�",N��w��t�@2�4� &"+oHdp�-eE}ory*�uYby!<.H%W#>W�S v�qaX)>�Xh63��I$tjlkp.�qo�d"��[�(l��A�ReeU�>jp-�e�wg�zf��t J�:�&?F�@&?LY�"e ��l�'Г��o�D���s3u"s As.�a��oti �J�{l�?re͖�2-�soC�i2}*�� labe&] V�v5]$.8�h���hu�{n-�1^��Y�Pl6�,�too T��an �nd6Q�nd.+ HUC F�*�%i.�# ���;!YrK�,V+A�E�.8?.��f�[6�>6�.}12L6�M�|!--d���%s.!0�M�%f/uc:GAL�/$d uas:tRFP[��bco&05~ tg�:�Y)z.�c���9��ŮE<�E6�O>�9�� A��4!�A�%Y-!{er%�"V=M~)�1%�6A–0 WKnf���!�>;4-E㡁��n��- 6r. �UgQ�)^1�X!�$memYFP ) /�Ta�Q�F%D�_�~Ru(9lem^`5>cK 5 �;^�I h�)zG !~� w�rb�!z�Q6F , G �K�D&�v4L �^Z�(�8:&A �2)�!W)em�B?a<:>���.�)�5iTu�EnU�ng8�A+�A�6�s�, �wBo,/�) i ju�zo)@A�a&2��dz� ��fih�*�� ��t� N$k25"�nœ"� !}  7GhE$�I�� |�?Eeu���4k:B [t~r�SYaDRann�����B�tB(4�^�_ۚG�B4 ��ni.%[15�!s� ly�d&�5"�RM����!;} ?[in/orex�z��7�.E���!� vu��!Z~r$6e�K!�m�hi8 &��;A���SY5;�wAu�)!��0of8� B(.�6�, sa���\����:���� a ������L "�Kd("y6�c!�o���A � ���I=93Are\07�i%�X'=��-U"�!!RA��X of�"hpf����"�0nFC/�:;ŀ�r�%�G)j7�Re�A(\gR�TJ� � �al�"�AQl,�x�6-�� "$�k�heAbW1&��+k��e,����(�DE��3i�-2����]ȡ&Fof�+!�� in�P�Q tQd&D2�(F�E�ol�c�Fa3�*'�30F"|. 5-I , J! nd !e^a��!"50%=&m/I& �Bp� aBE5[��1U��F� 17 )�[.[Zg3�.a6��9a*�Za��f�2� �!� �U�Is"v!�.-��i�w!�6�Uӭ�le "�Q�Fal�j*m?&�2�O x s��.ni��p��2TP���|�;>�h��Z��u@1!��L)���Ce:2�� �Adisru 2�� �*L1-X2,~"qQͯ6�, 2B!w��B4�) �e�&� o|#e7") ouch"�!!*i4��   scap**$� )�� !!vK$Rohon-Bear�� RB ):�-�A� Oc:NM�ds*J�� I�EZpro E towp�&�I1o [6 ?67]�R7"�?6�)5RBEj� �fu���F.e� PY�x� �5L��(�� �V�ns"&t�LM-��ganG �%�so5���� e&isA� m�6,�-6f� � p2rxt)!9 �=[6AQ�2CeU _��a�p ��D!^!@&4B� 7B–gK2,  ! v�"�^TNܡ&�g!6�u��pr*�0 3� <& (\ ���!o���J�5E"�(*�l*�c�: ��of.��|�c�7�y*�A"�&8A۽�j8b E�.�qD�A+ -�Ņ�:�#!�"|�-s���w5�u 1�.��Q&����!tructs"�%96 �% BA����^ 5�r �I�m�t om|��!k� �$y� ��Nc��u&��RB_(U G–wXEu��, t91�sor�:�Anam�!�"��/�4�$33�433h0�m�V�:��ޭс�ӥ�:OsJ:X"( χ2�82{*33�M"� XFv77��6z.�ŀ!"&� ��,%� �A� �� �(��<D.l1s.uS2 �."��x.� ��2�D"[.���u�toi������:�La$�)��8!� A�!&�A�9Mnz�<1D2 �=����C&86%�Z��Cn in single arborized RB neurons increased to 44% ( n = 52 , χ2 020 . 337 , df , p<�L001 , Fig . 7J ) , which is similar to the percentage of embryos observed in &�WT-sibling group . The MCT8-dependent�hation phenotype prompted usv�est whether TH analogs can also rescue this)Dlogical deficiency!I,mct8−/− ��. Two constructs , huc:GAL4 and uas:memYFP , were co-inject�0to one-cell-s%.fB= u)[Nthen rai!�in !�X5 nM TRIAC for two days�was sele�@because it exhibi!7!�dmost significant effect onexpress!xof p0}��.��(M$3H ) . SYpreviouQ %�s07ITDat 2 dpf , 27 . 5%]�109 )z42 . 8. 66 )��positive�showed m)��y=u3 thatAa-�towardX tail3.�!=1,Aspec�ly ( yh 4 . aLue3 ue5ydK%@0Importantly ,�number�%�-trea!�.��ˊ��:99 .:6�28r�naN$trast , no2�(differencesI�found!u=e� with)]%52%9These!� ults%)A �"�!recover(development!bax�CYsNk8. To elucidate !�aXC.hie�B we imagedE@ quantifieMg otal)� lengthB�branchKA��average �W <of�!U��2�E=aQ@. LaG�QMJEVJ��w4reduced by 32%!�.-(�|034 ) compared)�J�02ARtՖ. 030.�5a:ͪ ͩL–OMis de� �E�1$could b�"Q5!8a22!fy~5�per%� R,:6 (i , or!a�bin�k both�vcesse��Intrigu��a�wem )~he5�9�a1� t!��in cg�C�z!%NEP ) ; �-a>p Va�as.�2��r�78!��-j� �Q-�V�_�!fntial�B,he mechanism)b,controls RB-� �a�growth!�"ERs^��A��<. Fir�U�ud)_� f T3�@-��Dzebrafish larvae ,/(&p )o administe��to" /* "� �beginnA;at%# !�ge%�until�. U!q�prI!b Q�es�� xo��!,& by 2[ WT:��2�9WT+X12{6.z24N�S��e)��confirma��Pto mammals [70] , [71TH in�Ns��in�!]4in �xA�N�. A&� aY�UN=�in�sse�0�their.�QWZ` 88.�4�CB8A–C�/In ord o�yck�2&�YU�time-lapb ma'!cper��0ed ( Video S1jWe.P9LT, new%�l� 5aT�� . NV$3 � nW; they appejor disbetween�7m� fram8tervals: 15 min�re� � . Dura�13"u��i�� �Z�!)]95%�94B! 1�B] =��}�$ q�E52z � M01|.-45A7�z1;. 8D , E%�In addi��^ )�6���`>78Bb8 6'(�1/712�1��*��C J�experi% >Z �R��nge- �a�ǁh elim arv ��� Z� ltog�%]�Y suggest a��by��du2�r� of�l turn leadSaU�Y�5�� wilH9  i]F�~)�b.��f�� %aN�!\6 �might� associ�w� alte��ynaptic=i�, o al circui� :0ogenesis guid� ��of��� :5[15, herefor?��"*,(SYP-EGFP% n; tRFP�^��c>B.:�B� K9 ݫ�$se densitye[6��!���m�R&E� 8F )!J6p�lik> =�"�fmotor-~&} 6I–J�M–N�i�!��"/ @�;BN� =1����618G–I��nohoNO &� u}R!�!b]KA�ensory.e. E?Ao!3(pathophysio�"{ s� ly-in�� cogni���)|a��Ain[\ siHpsycho &retard��e�improv%�i&rapeu!�managea� . PZD AHDS �her�,, X-linked ,Mp-a~��.�N!affli�popg �%���e`mut�,�:�equM� huma�sI�edb l��s3 a diverse9 tell)��iatric+�D1�(symptoms [3� [463�Ba�Rse+, a�llon[earch * line �Ac-KO mic�VitI���2U los�q1Q�i\�YQN�] t� brai= ussigna�=,A�cIF4�in CNS.� [72�HowGno62&�a�f���r!�U� �EsofdiM2 rema� enig�icYE currKre-h� e��ish�6�a ZFN-b%�&Ag���"�%ag�k)��� mRNA!�w-�pharmacU>�.S havel�-��med���e� falnd��/��ed �fun$. Consider�9method�advan�EM2�pa%BvertebCy�49'�3�Ea6model20allows whole-I~�y�| in ltanidf �6L�|�����i�':� X� �'�o-track!(of behaviorI"I�%J)r͊*C,of myelin-red�{a-1�:H *� �� �� �i6�"< CAa��>Yass���&"��a ��WmS2�u�!lT�#)�N� n at!M�-�l�u�i!�pos�e�a�s!�81;U᥊J�in%wrala�heu�explag-h��of g�N� at d� �TH supp�I� crit9MA2�?]�)�Me*F}HPT-axisU/a�TH-�Y>eventu�"� 2�%Q�� bnLlit��ńOɘ74�� Inde�v���nreplic�@�HD thyroid parameter!����paH�Ml&gserum� valu��low T4�yR�Fur� m&H �!m6y1L%�as such�ntsh�dio��Jc. klf9$nrg� � e�ed [22��48)?2�th��9� M�.�Knota�2� 2�$impairmentW !�2�%& �:&=%#���,�a�1'Usk �re� �{3}��F�y ; n��theles!uap�2�!t]���5%�\. A�.��l�of�)���V�:�� v�eara�� �a"< � %Rm� �sample.K neg�pTH feedb� loop�st %�1 [18]% endb�TH�!�  � [7Hi� 1���tatus��љ� �nic2�<!�ca�nIb1�t �. ReceB,, multiphasi2��Mt!�"a%9)��--na!p2�,. While hypo Q~ exisy�]| dult6A[1��i�TH��EGoseDWTF on.-(ay 17 ( E17� Un� r yhyper�"< at aa�E18%Pmone�! prDto birt��o� e�6:��uaXw�"p�iatM�9�]�I ��3e�in��!�$approximata$6–7 week�ta  feAg,%jM=� a�A"�#� ular9����s6 Qfe�i>��#� . N6d sinc$� !�� orter ! aE�&�� 2R[76��a=involv�H.� )��^ 2�shAfɼ�edq�sΑq���.���*D� &�maya� a tissue-�$%�&h con�inM .,�)� Sup!A� � no� i�%�!1�j& ra�\thrab!��sg] e$y�i� bAQ�F)Bm��:!�3*bF�B�$bu� d�"� ^7N',.�%.�ofi+%�2T�MKglj�2Z�QkesNK .{A�F8 in�MKed]_1�;, p&�,�iniu)8, by an unknowny�B by facilimsӅinflux#ef !�H":�%. Clin>  (��C� delay�%S !A]a�0min�fe�in� [28]–[3=7a�[7� L O sheathsM� a&���cR�*@re ����2-en!e�e*�a al�)cursore��q�A9�uE� i��2X!�Schwanɯ!j"��, �I�)�*5"�E`���6 5" e�by eiR direc.�*R],":):in � ed>���%inBb�% ��pr�%A��Q�s%On"�)�Jly ��Q s [8�8�)�!*<- �m��re �ly��$ly 1F�'2�=TRs b�ng si!pIo0o. �-o!� l;ree q�W�!�(mp�Cr>p,��X Z���hTa��accounA��;� *�� ag !�%���t-L-�(-s%���'![85�{wᲥ ٙ�)pec�e]ow�ρL .�"�I.0 ,%�!�&�eP xons��nch�>$throughout�hf)�; +Madd ��!suc�v�A�yp��AMr-- 2+-rget z [86;�K. workage u!MO��ckdps�$egy�^R)��j� �i1�A�� iBorgani40of%k�ell%fKX�pi%�ord � e'��MO-B�% morp�:W-���� [20� /T+J�demg0i�� ed�E).h,eGaZ��~�&��vi�'� fert��i+iscrepa�i& bablt �!LunU�toxicOa:�qr0 O [8� �U�M( tect�! 2��e�n�S str-eK'f mu&/B��ac1$H�,IDg�!-en�W2label"� �6,�"areasur��.aj"53 ?$*�5SIl$es Ew6�+F .!D�1d�L!�9�n}�2�,A� BeB-�?� !as��tD3�B2"�AJB/*#eM*l plastIBq���6&T&!�"��@-e7��)O5W66he�+!� ѡ���.�' oc�� an iP"�:6)#��Y�(��� .�$&q *� F�1a�:l"�#-p.Z!���L2%�%�6A5r1�i�/de�Ni*�} R= .�a�CT8e�il~6r5�,2�͎ �1=&J N�$>�<�+yKA��%��AxonQ%  &�i��7*'$u� -�o�"��um��%,@d�� e!vQ�� 8,[8� %Giark� �[ H" �� ��X�� �^�Ataxi�� locuor�-"�� }";"[2� 9��6.pec�!a�a1\--\6�u� �.musCr j�,� ��/� %isF &a��t. 9!\�1marker "�%72���*F%A>seqcq>I)(reveaMe�Q�9�:�$A��1^6m. S�&����!� closAFe#toh .� 4 manyV^�"a!a q frag9X�dromemn mpani�SZ� conn7�=[9�96"�#%d2�%6edpaN16$� Q 7am� �z�,� �*=) � .� B�Y�%�}�^�B��"�!by�����ol� 1�ndy��A�U[99*� �3Atm4�rol�g�m� �K��Z:�6])cani�8 F%�m� 82�}��B���L)YE=edaF*g�g� E‘�tY� �"aH� �_��� yIB�"_6z;\ lon���� erma�� U!/nd-�ret"�',61 N4ina�t@ peak%&walk in"�ly:�High-�put>#=&system�r� �!")!\JHVi�q�c!]*da� d nihA�&� s���Q"e 24reach maximum !j� .��.J*� Ue(>w+0 onse�exter/l�!� dark muli�)= A�:�"iso��)!Mi~S� �n�!a ~5 �&8(N~>.�� %s [95��%i�mc�*r�s� da��'o�8����+�&HR&,, w���e?t6�.*�(it*d �� FmMauthne�[9=�]� y��N. !o���E!!�=���y F�'�*�i*U^C�a �lJ�FU�͆s^7NR�stI�vi� E�-��a� ���Ŷ&h/-p &.�J�J]f;:A�h�8Y)se��%�-G sleep�>a N%��e*! �) diue�&�IT H:!=�&o*� &` �2wakefulnm#[5, 55�5E 97a��6@2�*�%�hc!*ilg�P (episo1fg!��"�C��obu�2���lso b� es�"x m*\&rI�uyZ�Btb � e has b�5n��)u9PE� �pat��n6�.iW� occa��aMD�afamil`'��&( unpubM,6)%^& monito�routin� acr��lifesp�..[![em���r�/&-6���Y$ . Ap"� `9im��fO!�"!�^ j$ierq)pregn',aex�B� !�s>C8t���5�!</A*A�ea�)k" ttem�Eto� ize M("�#. I��@Acip9��TH��0 help"+� abso �, 8an(/@!�J9mpe%�& romi��fi� S�!�F�2 %vA�TH� eptors�!��"� Z��!��un#entry [4ō[4e�"u DITPAy `+A:>%o�!�^!�<w al:H[49�5�IJ@ro�G� h\1�%ph�hof� 2F%U2�H"(0 �Y�d�!�*A �@g�C# b�tQl*�*.�2aKi�,b�pl"!!��-!/ a�Hu��;*�=z �Anb 5ve>>%� !�%�. O��fu�^q�F��]`TETRAC%��=6�' .o�'KO)doublT% /PAX& ,*� ��fiW2 plac��TH�B -7+�$pilot stud�A�uD.vB� K)uncle[Jw�h �taqba]r�!l��&.'F�a,AJo&eG�e:is� !p drug�  s(<a�0ɾi�V�2�,�aa�oiM � 2�%��4�0?*�&� Z�1�@}1 A�ttB�� EuNB.� ><0eJ�D=!ba6asilyI�d=�9� !"� �Q/rpoi�,, ran1> from:).%Kto fu]�ed� >8!at�&^ !�x%8Lre�GM�Bg�E#X2g!A6�9nI2�Hod� ���res��!CF|��� 02�:�2D-��+�Ň� �.[eZ6�LŽ\$in%�� L��e/a�-y�`�� s efFt �!>O/BXm�& expan�Rto� lude�eEK�\tKed&�$2iw.so *J#�L�H<hout�Ei��8�T�t_Nof�"�, tz=E�.=6L cand�Ig�&��$%C bypass&Y1�:1 �9w�3,��3o�E�5ce our:c͉&, �j �� �*fu�E>���-��apyC,azJY-� =6.�. Our��y.S# f�G�  �N:�B� $=u�Jic.�,"] a�nɼ.��@E 4�ngiA�� �6�*/��Ea*M ! V4�4�Z^�41�A�F�E��Q!; �mg��d�D:&�+�Vypr�A<uniqu�])�*!,��,a�:v* *�@!H �!p!8&C�o��requi��V$M 1 �!��1 *�Ya:{ �J#�� "� �> %I&{ yVe�7I��eur�n��7�@�7%�J�!�)Eor� THA�utMD^1%A��n!�be ruV�#>v00��m�A�� � rP=a n)6��3r evalu� ��  2�*n���)��79.�&/:g�)�r�2m�e$7se�nga�r��i"�+ZFN�� crip�~ or-'��ec�nuf �e( TALENs�clu�I-��?igspa sh!�p/=ic� Heat ( CRISPR ) /CasjE#T me� traforbR echnAA 1z"� [98]��a��!� �t�Q%)��:��7A�F ��!�-M�9�&�Hl3a�6�Ea)* Q9- ��B�!�=���Guro�9omiyUk* �3ik�-m�b�G9!+��&I%.�!a*/OATP1C1� K"K?)�2� n�a�% � [99]!�B<��oL1un{%�a+�8�5de�A1��U*? . X>�6ngFse&��� �6lya2ge-scaleB�� ,%�M��nd �v ,opsXea{�W!Ya sui�%AGZ �Z�� AAn=��&sJmaint�i�0� auto�4.�0ho � I Aqua�($, Israel; Zer�, 28±OW°C�<H rV�.A3u�mittee�(ustom-desig�K���!mid�>CArcommerc�synf �( S�A -Ald�. , S�D Loui� MT� K  a HaeII���C���,C�fOPe)$H ���iP. Each�array��9'�EzeMLbp "[&up� !A*� �he^�<( 5′-CGGCCACGClTGgcgctcACCCTGGACAAGGCT-3′"�K1A �YA�"8$100 ng/µl�,!�)tasF�H�PhgeT9&�mosaic%�M�to �] hood� out-KWT ��Niiify F0 � er %. F1 h�> ozygZ;<"I!arrS7!v dele%�** -�I�ie�">[!�b��F26�4eny �,�toE3�'!�7 �APs=��.1A , B%�M�5on����M�'%j���-QkC:&�DNA�ex�}12:1�� clipl �Zf!�f)�1d�n� KAPA1�!Z Ki Kapaa���In�E, Bostol?MA�6$r$"M�manufac�r't� . Gen2�t�O�=iDYby PCR�f%!"p�%rs:iC gaggagttc ci3!Yef8 caccagcatcatgt$a $4 !234Abu���Gdi�MQ�Fsenzym�A+>D�run�2% agar<ge�B� le6pA of WT%�Zj� �%�O 10��130�,^��!H.�ms�S!f!i?W�E&AuzAiz�{>ent v0�1ed��E��C� zwA���6�. HB-�Lag�7&1ca�-L.\�"�!;\>ct�0lAy�aS HEK293T C�6e�e��%Q$Dulbecco's I�Eagle,edium ( DMEM7[ !j 10% �8-in� a�e� bovin6 ( FB��1% noN�8mino ac�o(a�m Indu�!� BethA�me�1O �MS_�t t 37P 5% CO2!v ��8$�  q 1f ] �5pCS-cmv:� 6O.mut or2-^O!�W6tr�a�� calc!Kphosph L o�E cul�r!umEi�A 6 h �A���harves�2% � .%� �ly��RIPA bu( ( 20 mM TrE� wW15NaCl , 1#EDT�41% Nonidet P-4� � % soE. deox�M�a�;Na3VO�RINaF�1c$β-glycero9) Gg1��r ]d�#$8ock�3( Rocheol*S�H�L,Penzberg , G�&y��LysDZeYRon J ,!$�nd bifuC_�BxzA�or�i�U at 4Q��sup�%ta�jobX �Protei�`'�1'0Bradf.4m�J�1 of 3I�%� �i� lane u sepad�a�8SDS polyacrylam�<��A��c%�r�R,`MWM�rdnitb8llu,�b1ea�IO-RA�UHercu� CAQUS��!�i!loc2%X h�a�skim miU( PBST�Ax�3!hblo]PL| 1�aIt room2� wHA�BX� � �-@S��a� $ntibody (  ( B-�a : sc-9996 �L Cruz��te"e, Dalla�� TX ,-, dilu�1∶100aWF"At^was 3,5Z-��N�-Cr��!Fse� :�gozD nti-�IgG-HRP�20�`��4 �SiP �visua�!eSaE D West Pico Chemilu)01Sub�tev� B��� (��rmo F�Kr�7c(c , Waltham�DY�. E26ish�a�!<tg�#as&uU)��e.ge+G�� n�"MC Tol2O [10� "� p-7rR pT2-2nՁ U*� Y�[� �( , kind gif� ProfYShi�  Moura�an��*^�^�- �� StuI��EcoRI� lig� to a$/ =� hcrt9Dv1[1�7q�!/*��< �# gene��)�h8iX!)m�g)B��YIjnd!�\ p �w,�P(%V�:�E�D�Bettina�>mi�TLudwig-M-,ili�%=aMun5@.�E:�%1j�� &-. N��IzE�V/F+�j��*�T�\|�BI�~\�^~, �a(l:�>�:k) /!�"B3)M���AJQB�fT;�:n%6�.B�M19T�4 EցD+x:� :~#)5�n�2abS���7)�� �ZG=*�$$UU&2:L ,�a�al4-VP16ma>�0Thomas Misgela]T�{�vT c!Vt[i�^e�$Gordon WanE SR ,%��f E:�`�!��"�U�%�&�#bysLroB>��G2�2 nVlF(nY�$i,Xa�[*� of ��,� micromanU�0nd PV830 Pneu�/c�DPump ( World Preci�* Ix�V��SarasotaQL� T�F� �beqr �U mvAISHAf*K!AQ&e*� a�coreg-+Y��Os:�P4( NM_001128729Tm�p�Q,a ( ENSDART057910[F ( AY86097��b, �D2 S178�m p0 94361 . b %� PCR-&w&g�� p�Qv atgacgtagatatWc:zttaaa~gac)g$; � OatKtg�aacgaag 'E�� ctac�" gcgtHmbpF ccac��cct:�tca\otI i ; p0G�cgsggR��Htac) $;)�Kgactc!-�gc�tgBPtt�jgg]}P� ll!��� � clo� G,a pCRII-TOPO�( InvC gUfCarlsba��C$ �Cnea"�iNot^ servXJi|tRenV�oxin-l_@0� �2e -Z�!�lb fue�"T a�WT%U 2K~m@X �Y�� ,I4 taacA�attccE!fagcga-g�VEh 48tta/A�t:F)�8sub.�pC.�"f 01]mX� k AgeI��"�m�@&.�2"1FN,�k0H �e��=-��Xba6A� �in EA�crQ�!XmMESSAGE mMACHINE SP6 k2Amb��)Au�> , TX�s6��<of.��-���z�!�C4:��yo!Y��ETQ�� �)>r Na� tinum taq��mer�T( Life#�tGr!�Isl , NY��!�JdE���gaIt:��Ea:�0act�bE�]��,!he�a��L�F�-TPQ83)� BamHI�SpeN9] &gQn'Eq�f,)z%�| �h^h,v�'s6�4Vsaw2 &��uLU�{!�I�A�V volum?1R�Ey�(.�)�gQ��ge+5 I�!d�0>�Ac$immunohist�misk1.�,I/�$�fixec 4%}0�<ldehyde,*n�#� �.rMi=�7+,�A 100%�ano�A}lrK!:}524( Perkin-Elmer>�_"%�]sub� tly.jb�?4 a!(�?�� �Fast R�!"DPV�?o5LvR��"�.+b�$i� �� � -MyHr} slow musc@!�-�F5� DSHBP;{"�Alon Day|GSjh Mia| i-RosenbaRHHebrew./(of JerusaleI�&�.r�oEq*B>7Alexa)�0 488 IgG ( H+��A-1102�z .�A�..�ńuU2�ime�s-�µ�,��%�:�N�6)p0�F] 2,*M b�0�<�hIʌP�]cA�E�',25Gd 55S I,>uw20%)�;1h:�^UA�Nrabbit)� ( SC-833j8,a�z�6:A6Y �����>�.Q -��>�. A:� �7 �" �V- �0Bn�Re�+ve�:JY"#:F ts�(trdiovs�ddio�smcte�oatp1c �]�b� r�,� !A� ak ter��P!� qRT-y$�;"�)e�� 32%&i DUW -zol:MiniPrep� Zymo Rxk Corp[, Irv�"MQ�u  ��<h F "�3 5 biUx.�c!q �)B$%�� poor 8� 7" .)�( 1 µgcas ?rse�/Q )2qS�0 c SJMix ( Q�,'*!�Ga�Xsbu/!MD�cUQt"�0  �A�-��@7900HT��al-Tim���A�4ed Bi"�' , Fo�0 C�+-�@ip�Ie@&%��)\i�NA-�H!9�!v+��gJt!m.*�g *�ga!��&!(N���!�r!�� )MJ!c.��.Nb�tA���!3 (VMM%S;�K��E�A��'Kt�4ctcqT6�! A5Q%ca uNr!�eA_a �; &��+%NA�!e ggg :��)�ga�".�!L1-Hc>��cj�E DA�β-�!n1x�E�a�FE� �WadQ7u%F �agen2A>�e�Y�against�ɔ*� �sub"܈�EΔΔCTooddH8>AB<ssays>l`w�B�gl�<Petri�:4% ( 50–804@�dy��"�**a��]@Lor 5×10−6 M NaOH * &363 ��roll+upLexpos�Y"]+25 ml.�!bex*6�3 Stock sol�b�5µM�n,�n,,C, �>��2!�E( *r Bi6�&T ,-n�6&05Jy 11"Wj&�h`6al6Bco*�!<.)�cho�;�pri�%�]V q� !�E��a� uApr2Mry dose*�`Ee%�&Ju� WTU8aur�f] :�t>��1mB e of%%5B�to%�nM)IE J�i &�~�YTUu� a��Q�51�>CestI�2c!I.+-�]7edY�D�I!tV�e�scX � or m%V 6�96�8&�@drz� shapZ pi70�de�-� A_mov$,;abi&9���Y6�O=�o�:� d(9��T T��Fqd�%�&iI'c�n�!;R�N�.d. S\e����-s 2 kb&�'-�� UTRA� [10�cp0 �U>� [104]��!Q%�_,�LI��*9#$of CaliforGT,..( UCSw0(3a�-< ?he!�1��H e,t2,5PD� BFA&o2B� e�j5i&d.#bzu\i�� M�- en.��m . At 6�U+���TW*^�%����divid�v 48-�z� �< n1;. Lo��:$ <.kM�0Noldus DanioV�$�6�na6�# %I +\on&Wy�~!�!Ne�D`�? accl#q�T%~h�g"�q� v!gre4d�� . Li�V�7i� �>�A<70 LUX�5ل!�o�<KsoftwQ)�Á�6�To -E rhyth�7�hAv<�I�< 6t*N=u�>��l�-�V�%ma��r�e"�C���esW6�lD/D�]V6�2� �om��930o� H O�4��rKe��#ve>�XA��BU|EL&?�x&kOq�z�lEthQe XT 99�(Q��c}**Ao=Dataly�B�)�5�, "�X�s�S�&+ B�� shol2�y{� �W*MISH-sa�ed� pla� �>4�4�ReaD^:dorsal��%��9>-lan epi2te�9roscope"$eica M165F��.�(�5�Ktaken Q +�dSu���2c큁�7d, WetzkQ.�- 2`Y�A8 ��B%%anesthet� w� Tric�@�01%�"9Plow-mel�-�K�9( �(A W70;5% �T"y> cham)� fill�.&O@&��2!�4�?���Kmag � �2�2��or6�H!.y�fo�Ur�Y�i{Da Zeiss LSM710 upr�Sa� <�$Q +, Oberk�!)%.T6AllnQ(NJ�I�Ja�� al�*it΋of Her2�<�)sda{2D-�4Adobe Photosho@+San J ,��.� ccAqy�rbo"��,�Wx*��ver!� !7l�W_e8"{eo�W.�J&KX\ neur&�nd._[N�N*J plugon1?�( �H*�bde�<{�9!.�"Fs�`�C5x7ma����%aZ�or.�� M��I�G�P-�V.�#y�r�w�=� �8}�f�5"tempe�D..�C. A3EiceAH!�xq�!|y�:[ i�!^ZEN 2011.&z�I�up�U40�T� se� ��2 µm��%"�9�A ��XryMC:,��$5 h .e�H�V8 cytomegaloviru�=HCMV )�H a ubiquit7B ��[majV<��) i�>wborn�Di)&;XedAL .;A�Pa�. win�FuvC<zPs-e� inct�W� P �ut*�n&%C!�gH/gL�o��e�/g�U $UL128-131 *iu@vi�$+��G , gB�"�W/�Rm��cors�Umachin!� ( su"2R!��uH e%�j+\� �� j� �.� )%�gB ,�!aC�H!�lex�Zy aF;� 8F-�i�* Z�H)-A{ eyS� UUi�gB�-P<%�� unh8o_B�. gB- Tom���cSd!�muc˂1�}50%a�!p :in)I�parti�"��H#,6R!�a��E-D^�e�wE' 2ł%��dherpes�!T;�%�%� moleq<tT�Jd�'��HM�s��)\ J1��f=i"�rea�no �L e8�A�sBVr ��pAE�#SV-12it&e[s ��B�XIjre�[ 8u �( gB�E�b4�A?inc�I`>�S�y, ��6s=]��im�ion�3*I�#de�R&G!v�VQsM+4;J�7A� inco�ed!,v��g%B ���b>-�. More" �5!�A�b+�WjOt `)��!�a�Lat-fF . E7]s,ll-�%�eutoe�� quir�PQa<f�. TG.~% �����F�ndZ%�"�TVIb4Eps�� Barr!UſEB���syNr 2��ves�ba~U'M itisCVSCG-�ۡ_�z�ń III1�%�stron�rM� �.�gB1sE!l-� I s [1�B]2Gu>��.�:[�OT.�T`A5� }�8_)s�}J\s:Im�U�+e α-.})�%��es2  gD i�Q�t�F�\believ�)gDB�ly�l�1t C&ac6�trigg�}:P����A�γ2�AD, `or /gp42B�!8�l�mi�G@to!�!k-b��"Slgw�cvq����2�hv� utVrsN�)$Lt�Ia���4�ntame&��bp?"m 9���� {9gB&��IL�8i�q��� tene�?a�F� EofAm ,�@nd:�esqpA���s a�sb�{:q(!�byAg!�I��8EP�ыv�U o do��cEY��? �5� �_,6>�RQ���S.M26y��eL I OyE�:i��E�N ed��wnu5s�YR3Bi bar�J� �HMM/_).2�f&�:vluy/�@��(YFP��(-s�% �w8 �'m&�ye�2t1L* X�[� gD�P# >�e!K�v�9� [E gH�gF�d|�!J agge�,:}���(��!��S!�!�-�R �a�r)?��. Surpr'm gB bound} �]n�.a*��a��?if_t�u�Ee_� eu on���ɑE�:�aR"�O0Oam�ꅼn���a�] Y� +poo& G �w�@�r 6�lf���[ (�%��ABL�aEr9��gB.{�I�=D s do;d-�h2��Bn^� �B���%A2 capa~w� ΜB�( �$$m�� b�!�� )s�*a�`~A�!!B�-cnecess�%i�npr��7!"�j� !? �x�!% pW ?"�a!lq�%kN�? �6."g�n&�e�!�ed�BA � m6viA\ en8 p�qŇJ�h1 �m�-�� !�NWuB9s . W"�,�* A��_e���"c&�>Pin TR�#ulab(AD169 along)dTR-��no�kn�KE1-�^denB ( Ad )�>� ARPE-19.B��3' ��l�E%�35S-m�^onine/c+;�4l�Uin >�U( N�U�HA9�ys&U2e[�$��( IP ) �gH٭ mono[E|�<��( MAba@ nn#`(by SDS-P�Du$Gg!64#�#.p��.qY14-4b!�AP-86aTd �andYM�U85-kDa g�f30 L6�,a weaker 116!GoP9vFgB�Xig �^!��m�co-IP’�MAb �� �Eoan AP86%perhaU��"ū�fac�K& gniz3!-a�8al*�,� a{ sqAb q2?�C-"O IP�"&�%�a2�9 gL peptid�Yai�Y3�he=|~E1�,9�6: 1��olD�^1B >A--?���IP&�=Eoed��H%�� ab�A0C�co-�a 5U �R� rn"5?K:Dradioq�e�8�l� -h�gB%�75��,n ��J�I=6��U�F�y&-Z�.v :�IP2f�N2��֍�H �;sA��%aP��?8g���bule0?�Ra5IP!w"� du�+�#ellUBi� aggrerT�N!�9���1%Ki�741% octyl gluco��c � e��gBi�+�6e�.�����)f2A–2)k�b.���re�i!��4-fY'"�0M�!YQp �|k .\�^�oCeE�m22���%��)EAv�GAL�4X ) Ξ"�0,un.�7�1-,!/ firmA&xZas y�%a ���}�p& ly�to2�"d �KF�We� ��7`� Fj�[In W֏�"ti-gHa�a�*asxx %e�!�m�e��� erea;I�\�s�!��$�R�e�no�9! Aͥ5��-gB�AG>�TR6 z1A��v�����oarl�{)us�)�/��r"`�&� �8�k�Ad�V`E5��� � !�Z%= cis-� ng*�/AP�yr�0�Yh�[R2�1tq�oJi�8"�heN<.��2A�~ RC-52e�d �co"ѻe�Ad-�e�s�AZndm( �Cev#I��6G!ɓI��. �^(�f"^&� ��l^z� � blotA�uBr�BRTa#eH�����*@ %�%C��eiC!��=IPI���SsPR� �F�co-q:ngP' Mi3 26Q �~�A#:� !�2��or ��2�e�2��?ip�A��y���d�1{�7�13>$$B�F2�� ��WU� �,���iv2�AlP#w�?1�IP Z eB���B &�  738 �j� {�p�(�meK"� &�q� �� 27��=��>�e*xs�vigcer��6e�Wr"�ka+�Ii� ��i��cu�a�E*�A�*�. a�Anew�!�A1!1sF izCmc%ma"T� ?gB [19z�s82�894�e�.`E�� (as�N� �"dA`-:eF!�5#9-wernN�]&q#/5�u.�!O��Qk�MnI�dkC)G�/I�IC3 TX|�t.0�E�[��,u E%&�Y c)w��6�  C-lEal FLAGE!E a�A���W-"�w��f���U(2 )@�ti-R!0e�N.��%3L��?��I�-> No ozz&DA��e��Af ���s�+k)o�'�a�AdA�B=_� s+uMOI� ( S *; �cu:yA�. �MDѱ�!&�8s��� ef�w�l1–6b1t%T]�ab����� nXq�66M�IV�%ٛ� �� b����a.d�W ��!p�8�F��d %�E%iAh)a�15H ;noa^ ;IC42��as�a)gD � e��EeGT{@����a!&���2�>t��F�6 � 4�AWp~atp/A�}a >m>*.�'6���2�i�&� R{V^ 5@�Xp B2wZ�!�turS$��n-z4\�4 hrsK q�%L, Y'*� U�٥�<5�fgl$f�,.��&�. *;A�A�is &5,&8 u1��@mad-)E\- >� B8$2��\.He�A�53SE|�">!�WM�I��9 SS10Z: -�mP��Q��@�:cv =��1 SD�Ot7�Mt �A�)�se��&H���|H� ` % B�y ~ �C52Br.�’BjAF�zgD%+DL6BU$ �Z:�.�� �b蹑�.�D���Pulse-ch�Z.�e���D,h&���kinetiڍ>n��#��� : a�a�E1��268a����~m2� %^�M�b!�AP �I 6�T120!�24�;./uj._�� � p!�$pl�*#orm >&�2ER��*�� �.\Ar5 /7�#le�9%�)!)~38"2 2+ {2e!��"%$� &�Si��#'#�'�02�i ir*����P{ ���e>�$,w.�$e�" %; BADrUL5�UA/�r�{�sbs�)��"�aR"�GR"�.-X!n ����  irreley�1 E�� (��&��M�H)!�n &�I.�0���Kbo6�2�A �\AZ�"n�D�LU ]�l�=%T5g!1A6 ԑe�B�*!,-i�!Y|��pur/uy)"�s2�q�+2�&!�2� YatDrdDp6�)-'%*""�z(�.VDUAL��M-02�M�.��E �Gk�aF*a�%!.'  M ( g8v%�a�E!g2)N:��(�j� � ���*�2*xEi*�I$,�Eto�96���6�"�A(r�M "$�6� &� yet Ƀ��aiJie��s8 ��6 >���.��hig8.�# �BXs`���� ( se<�xt�:� � &n+����!�6�.rws)*�0( �x$)Is�0&�$iM���nmg? mpetr 2B� �be<��ue� 2�:.�2� IP��W �2�um*�toiN�&/���� A>:M�}c.Ge�a����o��^<%��6{ 9.���5he��a3X*��B��M�<2'�yF/)V, doesx&�ly�I��@%���"� �C����Gu��N��L��a�ʱcU� �c Z�%@�!7!E>4@nex���62�ca �Aa�7/�Ղ} Wa�p;�>��,�<�(k;:�A2�A(% G��FNND�s:1Xq�6 � �4.4!Gf`�u&W�!}of�est�. /A ��^_�IA6e��" u:���>. Wk ;>f21�NHin~1�G��1&|3c �eW"�)ar%�pK2�,[���-e��� �YA9ta�=gBA154W�gBW240A ��EAE�I5e��LD%��B dom�SM�A_&L�6e �lo͂to�7�)F-�loops [2z6Ʀa*2�-.!xF�1o\J>nd� &�>,IF �4)� �W\UCI�gAD)A6 N�&oC2�] m*z* �X .�0B�0 1�*� 1-��t)��� ���&A!l��",$&� �&M\�ob��g* ͡ə.G k=��!q/1he�N�!-2n.sA�� K�2�>k2h�A^ l��d�5 vJ� mve�4e�*is �ap�� ��e=NA��4�)�}d=��makŸ_q) E�we�!�-�wH�gL��bcَ� y(2–5 a"�*�!�CMVdJ�e>�Hsurfac{6�y���6!aEBV��� �s�6u?'-��n�R� *�" ,"za#aΙ�: j!�| rI"���Ra�3X S� align�0s�qr&�Rr,(x . uchicagMo edu/DeepA7( :(�ydKVr��3D�� �)ka�(1&�,e@�.��&�7%�, �[d�&�.�L�!��6?C.��@�lm���:9�!]� a�0disrup� Kd� a'E�- gr�misY'A��S �few�>�s n� he N&hg H gia}%<� �PY<�{�!��I gH� sA�[2�U2A� ofs�x��� H2++P�����L2#%=�0S�H5&r! J�[� ���alad. (P�p S2 T�Q�-��>gH��&!.��@�"�<ar��nn:[%\w��ul�+g��yD� o�&�:�@݊nt���8V )A'Ajm &C�O;��jDz!�؃"?���<by�&dE)D 293T��la.�� y21g� 8 hr/�Iέs2K0 6�)5a�9+\.�d�&!� �_BheteroeMicm[��� �hc�mZ4In�.�6n�}.c��*Xe5Oethods�|m�O��gH!~gL�d2�ʭ�ٟ�assemb��L �-S��6�W&*I���FE%�:� gL c�1 -144 7"B;� nA�x. �3�w �KKT [273Xs:� �D�BE��w l0s��&ո�B:.�5(5eC�X�:�*,�a�6��{4E< we we� �)� 1C�s \&��͡�u�� %.1"� lsoBb�4F� �\H-rK�Mk inu�M���m�Lt�!a3�gl��n*.�0ch� 3;6V�� � M �s`I�� �)���fK6� %.�!� A�aOa6il��Y*F%�C"� %/713��!M\)U&�/3I=%Pulf:2bo�3���1@gO�n"/NF S� ABZI� ,agB� � �7 ,7-isc �e�.�s%�abkt��8�Y�.Vu�f"e~pMمa��L �& 1GUz�E�f� "� � �SY��mD{K larg�I1�EmAE � AMbj�D���h޾��tr(� .A2?!*�*A�#� 1%A�D��.��<�����%� �2���K�kn��I��?cJ��KAF1��TAڅ'%5�)�>o�;4e>:'Ae�#>Ln� ��U�B%V qin γ-X6�H�2.�=s�k��t� q)�.[\ .be�&�"�S�a2/��mXa�*�,?&�.��rb*B%AV�1=��\!A<�Z> S>,Q>e>'��(&���. A�Ag).f���� )ZWgD�k1�)�1#J�* �c� 3gM��� 0ѡ��� U1�>� &%aqhe ER N�!�&�A� ob^ � T�M&�NgB�Q��mN trun�����.V=8��1: "+)'es�@ͷ��toU�2if>  i��e�>9�AJ)1x�F>1��h�[l"�F�ng!L�0�(�U.T) �0 i�9{�������h�#!"�>�B>�B/ ���f:�n5@MO)#�7��7hx d 7H� v �!�;��X?�Al-�%u�&�of k �,��6 .� �.�$ �6���Z�var�����I�e��N^u�a�Er2�a�6�J�DAs6� �y�"� _Q�NA�d!x;# �4al-#5%�I6�."�H 1C�--A}� �a4a�( �5b���F61gB��h '%G)��2I -�)0:;�-�$h "S�/e��ή]5���o9�4!�B��vK, ��i<{6t�g]!=�"�. ��@�h � ��3 �mp+�I 3*� *( � C��uoI! !"�� ���Aj!� &R ņe ��A"V�7 ��Q�(��?���\of5�Y�)e�!2��aB��QDe�����S��E �Qa"q�P���zMA��i�_3�q���&8_�in"�/l�Pf?��W�7 -�Q^�EInRE( w%�m-> "�I%q�6�,�Oj�H�c�3�]ny�JeZ�-�_r�e��-f\ ,� I��$ )�=se> [G�'��W6�� ms!2�v�[��y�^%�Lvdub�;4�in]Y.,�&is�'A����A$�-co..A�n�aN;v �5 !�. B�Intr�W6o.Ie�gB:z�*mk\b�e!.w!\ f �� �t"�!�!�^�&o�to�Y�g"´0� � � "�!�"Ս��!�Q��Ya���!1J�. pref�B� R�re�eZ�a�=q\>� A� 57mZBG�>N�a�&/G�`Th�z`�~�rar[�:�'�Mx�>Foft�,�- �n equ2E]1��_�Ob/�3�!~2\(� re:_or pla.rolesA�.`�#orFl(( i . e . ,bu ) require�t��m,aboA��! m . W����u�762 mu���a3!substitu)� of 3�( amino acid-*q whicaQre deaA o alter p�Hve surface residuesE'n� �e�I��of-�w����C-termia�A�-E loop�:B�bound H. In or�� to defini��sm�E3fub�J� , ma;1G� �1�%�s����is will` -� large��1�i!j# or��,Eg . af��!��,than a singl%� tinu��equ�zgHGL!��gB bindI�e.�VV3r!�la-@%?� deterge� !�in se-chase2�6�extens](��a���oteins�� conta�E;na�r�%yt�˥Ocoval�2M. M5ZA�m* h Ys5�cq*M�B��! best d�E��xՕɁG�!h9. ��@has lagged behind�ZEBV-A�Eglycop) .`L, mapped MAb epitope�e)rea)�, s� �QeD-Q��M� .$ )>%�,d far beyond)copv E re� 0. A major adv�@ deri� fromF. r s ![ curr!� viewa�how!4� ��+-*���VM���result f�! G!�pos ev se� te  ���ͫenvel�,��a_AnA U� j��{orфmembranoD [E Blocka�hf # vity! gB (�A�s )��eE\%(x:It AJa.��iteby gD��$o receptor�� g   -~���)�na� �E!A�whea�j(ndeed occurE � c| . ConsistAmtiA� we d{��ct5� ���i��A�W ehN( . By�tr� , e�.�s�g� Jtrrespec�8�gB1�5̡�4 �id%q6g i�e2I� 8c�ly �eA~!pf�8=� Y�1�5�mI ,!�,!� reasmfhomolog��in �!�EBVAKa�lyKY,s [4 , 5 , 2E�Ta{k ��s betw� �Ybmo � �A"be�� greaa�k � coul�f�:m̉A�aW odelIVa�t!�r)p "� �m&n�Z-"Red]sE�g��/triggers� �9j �g��s nato]!�gi6� %surpris��!Y�/gOqmer%O (UL128-131 p�y(qP"�}�.���!�c� two��…Id &+�S��� I�F. Ve�]8at lack gO fail!e�a allH s tes��A-ء�necessa " into many= ty�;( 6eA#[5]D; n.� ,��tprecipit+*�gHi� с� ��1–2�2��%%=�9�� !Q��.�, 16%?21W2�E���pn tectable ~gO��>��%No�Z!�@ �T3m���NoF�;%2 . 5� B�Q1;{iITlex!�A(alyA!� �gO� ulQ� F tern�� rolle�!�g)'ue; o IPn blo��� per"�O ,Al30�r!�MAb!��aZ!�IP’d�PsA� � �e9��Tom�B4IP assays argu9a � �S��a�devoid  ) y %w�bn�!KEgB�De6_aAFJ� ��7%d h� od�X>�pe�osulfide� d!Il� [292In ad�!� X͉A.m@ �describG �! ���a{f D13?��G�� Q{[27�Wh�ci%`!� I�a4v�% is�to!uis��� iqa�we�1�ruA�out�viralYP�MKA}!�.��a!Ndʝs�� I" bondRei16G��� data rai !Rp�ilA�ixBm"�)ee锅�%^O�F . However�  geneA�of ��L"J w1L�%La�!�. Effor�� �e A s"�_�5�a ��inconcluZL�:V��'&� high�ar wea�� .��:����U �T�<C of�-re�s�or�m� . OnQuAp�B*t s�/ no�)�!�f%"B� %v;�!/pr|� e>0 .E�N�2 X �9JAIsi��4 6���"Can.0,!i:dbi�ic� relev�pop���Nm2��z�ll!�!Afnt����:$in[>�� ���i�l��)�e�E�%�X egB W >].sor� �uli�!�i�:AIZ adja�R���.�v��?� ou�!a!ssocii�EjZ�!or7I?!Ze��&��AWs"aG2(T �s secreA�?insectŴ�R �WPVap�n�q� ost--Ba+ s [1��I!�"�A[sF�, ii�G iliz$c:i!it 6be]T�/M%Q6�J�U�A�be�!�8q >���B��V�t&�B�Xdeb Cvaccin��#&�$e� ;� �%��to!5�A�� ��"�" . Pr�e.b�� unit� "ed5�)� ��E� tsuccessful [31] . Human MRC-5 �$yonic lung2� Fh+ret�pig!"edF� (( ARPE-19 ) {)�ed)A!(an Type Cul^C�� mc !,Dulbecco’s�b(ified Eagle ,edium ( DMEM�" uppl" ��10% fe�% bovi�$er2FBS )A�; /HamQ0F-12 ( 1:1 ) ^VU@,���r%. Neonamh%2der}"*( nHDF�%�6  Invitroge) gro��j�aseI�bacter>rt" chromo�B ( BA$clO0BADrUL131r-Y4I� u[T' �$ ����&�� ly [2� � clin��a��vTRA7L[14��iZ stock�pr��� �ng%V�#( 0 . 1 PFU/� EYa� s!�Mf!Vnc �harve�(t 10–15 d��L qo� E el6C'%�� � �`� 9�.vsr ultr��rifugC  thro $4a 20% ( wt/volA�,orbitol cush� at 8�000×g� 1� hrO%T��-Bt$re-suspendike-freeIoa�sto!iDat -80°C . For IPC volv!z%�2�X I�% see d 6-weui�d�$ �A�6�!� –3^�2�3R���ſ�\1% NP-4A)F��>�&� �m d^pur��%�10��)a�) abov�)i|`pellek)f�C.�� �R no� �Q ^ ]r"�by!�moN��ˁ�te�y�1e �$�%Y!Rco.+,i%A�e&eER� ,7et 8 �-��e~  �u[35���fic mono�Ial N�� kind�-E+�D~,HWilliam Britt ( UniECty�Alaba>(BiN ghamA�nd�9�:P,-gH�14-4be AP-8� -027�� 6 [3�-38]EDti-gM mo,�" [39]D<758(!�Ad�pScott Koenig , Medimmune Corp�.(Rabbit poly-"T pept\ sera9H� iAL�0)O�� [2� �dum6e(gO ( TBgO )��6��%�B Ryck( >�M�$n�)Missoula�i��k0EN�: Anti�!{DL!�[405� J)� 53S [41>$B SS10 [42!�!�D ( R45�43/GrV��� R137 [44G&�"Z4 368 [4e�a=�)��ti `!h���| �s�^OHSU u�va���l�&combin�sgB4M [1A� ccor�standar�ocoe19 , 46a�!_m�9C� 13H1+aW 15H7)��-��}�-�]"re�!��bmic j�.��.� FLAG M2%�! �"Si,,� ).DvB alnexi�.SPA-86!�H6= St02< ����i�or)�"d�+�lay����%�� pD cl��&@Tris-bu_3d sal^ a_X ( 50mM$$ , pH 7 . ��$150 mM NaC� �8�s�onidet �(�)5ransfer�  icrofu.ub�incubo on !��U10/� on-�lv#t" !C remo@b` �fug�lysate�5E� �0e i�)�� 8,L 8e��u"im� 5��4�   vern� at 4k foll�0bG �� Ee� -A agar2M 1 hr?. I��o=1�cl���a[ at 5 �,!#3 �/v TBS>�%�aLeluUin. loae�I!.-pH 6 .  �bero� 2% SDAA�or�1% 2-mer6oeM+ol.&�!-R (d�^�/ SDS-��acrylam��$electropho�, & iNY�?vinyl%3e^2H( PVDF ;$(� E:]�M!b���W�gelFn�A�3M ureaG ��]��. M|F�i~e�HCly� .�,A% T�%-20i�T ).5%g fa�lkY8, Z�inAGT%� p6!!E�hr!�FB�wa2�=i�hA�2�TB~hor�� !�oxida -onj���em7}�� .u�!�� N !��iM�2� �ש�E�"� s.L ]2� ; . C9!%�޹��Ne�m�!�_�"m)!˅�D1e��!\�)� U�CBio-Ra�ve�ssa3P� ��$�h-�!<+A chemilum_�-aGerkin El�&) 2��manufaU4r�i41��image�2 an I9( LAS 4000 s�>$GE Healthc�)� dens� ba� on wrnps%#S��iJ softwN0|�( o ( Licorf6�*f��c!9A$ ���%�M�in PBS�t�-bede2i.'st��a!��+!�:� ine/v:ion��&��(2% dialyzed�!_ahM HEPES�F3-:9a� �repla� E�fresh6�Nb,0μCi/ml 35S�;Qf&;mij&:02l;;-�q,�V:?IPq9=uT, digit!5Vr(octyl gluco,-pu&_1�!~�!�i�!�e10 cmU }%��5 A�p��trypsa�nd!o�tw��.�1F each G c���K�(�be $in 250 μl6���2�� : exchanu�Cof6FJmY r �%<%p-�1� .E�e5!Mradio��;�.3d�%by&�&of%E��!�10-fold�ess!n.b}i-q� ( h-.�����y�#�3)[b�0beAW&� a�'� nt� --�� E 1"I�%5 !��oprb  �a�)� byL PAGEV��3nt�8gL�A�� gene$by�?an�� lapp�(oligonucleo9-�<� ite-"�!>gy)�aAN,two-step PCR��( &TR�� �5s�temmj. Linear enco� 2Bz7�6�Ai same numb 5f ala�p!�An>�a��!%�5 dd aHY&�2,( DYKDDDDK )� ok�7u�W6pen�`�fr�m�oV}gH> �c18rAF mmalian"�on�T$smid pcDNA�1+� pSPORT6 (.�� 1�A, A(1�a�Z.�gLd!!"�a`pl �*� !�B �1O��ct 293TM��4 of 2 μg Q�1;1 H�!� 6V%.�g& Lipo�*a� 2�:a�48�K�B-!��j� !!�a��15b�-��{8��A*IP�_ ndcR�4.2PMitochond]! ( mt)=� aria[8segreg�#in9�=tissu}�m�A%�&�me�$ismH"m1un>�j\Eqatt� of path:��m"I8� �6det� ��� onset%Ms%%� dise9. U� aH,I�usa6�2,�!.�7Gimape?��u (m2D GTPj%=a crit.5�Dis���Vin leukW(�B j$"IA?I�2�!�surviva� �$�j�W%�'be a key��^!�5tic�!�ofMy�Q{Aod�#ng%6-xs . M�c6#AuY}-�Aa$inheria�&& copy��)�6py��r��8102a/105 depen;upo�  e*��typ!�2,�'e �A(l .plo.o�3 -!ai�(�5EPy�1]–[ GermOBo>c 4]�n-ilea�/a;co-�$rP<� �A�F�9 X,3s3 ijas.�� .#ab"&Bs!��0�>i�j� bm:�a!�dom w�.� ��9ma�s:)��?AI6f turn) [�H"�( !�ca�)�pre�.kA�a.�ɉ:>*�":,P?I)sY'1�,��!Vnd �ar� kgro�>. Mostmj�@h!I'ic SY���8 phos�y�=on"�5A�impai=w-A*pro�;)!�c@ �excee�`��th� � m��s{5 , [6gA�a�� w � t�of&!dis�?���>re�&*?�s͵i�aerobic�a!O[�T< mi I�!P��w< � fema85qT')��as�� [7];�,����nj(a�,-^A�h�Gsk�6J�<BHB>"pedigree!L��!For�a�)ecI�n�Y�?u�A��A3243Gh!�$RNAleu usu)l:�' MELA`6�,EncephalomyoA�1L' c Acid�.Stroke-�%� sode�#�eriph!�#&o�5���%�&�55`[15AB[1�y�t��J[!�I�0� S6(�5 Arsu�JA8344G~.2)$MERRF ( My�$ic EpilepsW Ra@,!&8)�0 ��-�1while#h>�i�>�A�m�,ely!�e"���1���;*�(d e��\ To#' esti� A$?��.E<>� A .|�E�D n 7ng�� neut5 Uh�a" )'��ab���� XB, BALQd NZB [1��& Ea� *��= xsE�a&}+t telyY�',��)D we���#E�� �7-kede �2�[��pr �"mC!i��E`3@rait loci ( QTL )!2ol�D[2,Fur��E�i8%Ia�5j)Z inZ�3b>0%eli&Ga���4 �*-s13� Žud��we�).& ���b�K a�1�&� V��;n�0. S��g+ rapi�&�a)>!�sta�?*�y leve� !�-K�A �onBKuH195 phen� 5ob�C,6"{1ab of Mu�I$sculus dom�Dc�NAFnsBA 29Sv ,e� , C3/&C57BL/6J�Ig�BR CAST/Ei��F� ,}n�r"�0En�3ed), >� p!eO3u :AEs%u}�MQm�q}.�pd!�fŽ=L b�ku�PlyA�E\�!ryJ�=�^Qe�outcros�+]/ic��/c��O 5tal�%o��q�F2�erO &,LAX6�MZ� �G".�hba�on�iA�"9 r��"E m�j�^ewe splVC ( Figure �-.�class� a�*noBO, i<e %E� nbT� simi�a0�(��i�thw in�ch&@ra� "�!s&� . A�3�a:#%K6��Gv�� ��wo. gard�Te" &�F2 cE'i� age-� M��Jiso�5���*� month[��,��=maei4&1U��HJ�6�%j"6g�A6%�W ţe� .�T"R9AB c@T�Ei�R 0 C�Gy ea�J*��� -5 ,j<w�%�:��= t 12:�, fully�7*nt�9s"8�&Fun�7eaf<encM)� 2We�o!a� ome-� link!�s�[on�� 1o8( n = 168 )�680 SNP+Bmap �12 hey�&YcF�4i��n 11 Mb�[�Wl�*�06 ( 3M%$–48 . 99/) �O�*a �!jNL�#sE�>R$( LOD 4 . (ge9p �.007��;'�per&� �X��2�&No� %�a�R! _�c��pi�����s a@=:o�� .*,B i)+u ED��v�� p<�63� <,�o� "211�*�310 )e%&L.�13:1557%W %!�4lyA�3��� x6!-uxSmdq- 8� �EQNŲ]KV:N]� *�D2 rkMconfirm>at.�6�ksi9 e ( �"��Q�on.�Y�bz6:candi <} with�+is!�.�� searES ��� anno�d=!Eve�S�6,�:��a�X&��Tf����ie"| � �I 2k)Gte�Op@$ ubiquitouA�,3H Gstk(+Ndufb2E�Mrps33� Z7�a�l�e�w�7lAumably���:���6s��P��+"�!�Di� spiratory]�Du �Z\\�"iv �-[2Y Litt�s!4e&=Ukin� Adck,II2� � l m'paralo�MA� 84%�tya�!N�U�& 3A=��e-INd"��( makeltA.a��att�Aa >�x?|).� &\ds�j�W�T���-length "of)3.� �RNA��~R!�/c0� - �-^�3�AV"en4^h�( VpIl� d Arg� Ser )Uig� � 3B��NMIse.�  evol�W arilN.nq_�E� � fam c[2c/&�4�3����Q�� exon!ic�3E]!�1. �%!� of fA;5H3!H/&: Sw[J AUG��rt �!�$ K)�`E�4� -��N$stop codon2�F�~):\��>nj3�splicAmo"�KJ[�@�!H.z)����")"� �CZ Q1L-�mA�,� 4aAs!\�U���rGp_!=2gmrep$�SI.reac�!U=�a �2�%�tra 58 �Is�\N�Yu]� �2�� !��n�Kob�^���discovSa G�A)o$>���Tac8�it�p1k�,�X%�!%�i0+mn� %�2T. S�Bz� � q�amc"ae4e�5~e ���BEfrc�s*<��i��!�3 ic&��. c��+of��/c>�T�EFed)5:ehe5a alle�Z�%P8�T�(M�q"$1�]:le+�m �.@K does��W�$�a+��]WdoI2�"�nch�VAi loca�AsqAMro![2iMz�� s 2= �iNun(�a� -*%>in youn�C�� S� �%n"�m -Bq-�e�!�lZ� 1�AE�AE� �lop ."�^�P6��d�TT"}a .� enrichA^`� a��J)���:2?� U,5�E�_I s�pl�>an &0#%�^�n&O�%gNM6-f!�^p I 2�^Ea�a �& � ���F�%�� d�jge�%n��B-@%Yast� �� d�� ��*�  ROSA26a��;9k6-k�;� �� n:0.l ,�U�.�Ap�$%L  higher� t?_�PMA�u5�E��L24 ��U- �u6to:9 A�p�By�pl���u- !�:-QY�!hZ*&a�Ie�3m�o2W6�>A>fSv&�ef7( �F)La�3!x!#q4%� 3�<� slo4&:FM6Q.j?.�[>x,2`�B�3:W�7ly�%n���Vli�'u��"�A�6 K/!f�� /cNx�CM>#Y1�!)X3�2Ci��'6VFdI6Zfx�.orAheBe��!w�� lAeF\ ��!Q�& &d��z,,Z�`���9"*1��a8�i)4"� ��)�wkRkins*}�EctopicA��::b1�?��ha�fq+on�1'�M� �or�U�, norO�Zm{oz'.N%ks!�9!8&�#ur2���{e b  , heR ,�H�skele`Gmus�lF��Nfi�(1tr�BH� �6�1B�te&n&muge P8yI.�GBf}wy��*\ !Oa s�a�J(��6�#ext!�M�APQrVgd��� 5�&� ,�%�,�1�S.�)I�! � �C���t�flP��]"}uI�h�HmA&F� c "nJ�e H:d6VQr��mea�l�`�&�*A�� of"�a�p Z!"� ���uC'1�� ���tN�!� per �j. F�-aSE��>u�)z.2&�i?- �3.MAnos Ni .�. J�!� ��?2�" �iQYsJ�A�,*� �� 6�"- "C.�i%A��Pa�M��nh�N�$.e�B�.wN!�3/V�����S��z�� "�geL(��b)�q2� V{.EQin1�a�2*�cc2F� r6�YEIu��?�|hco3b�,eK�czyg� J� � stoj exhi:EQ�ѯ�!1:�a��]� �0a�n� 1��a62%��B[ 9k.�q�%s�Tg p�!�!s��Ds &� 0de�s72 11�1"F l�a�6�q"P��M��SU#6�1gb�of dR���%ZaWb6�.Z�$,*g,1O6 & , up��70�7s fas�-�iP�  ����R�*In� carry#e',�+ѪIbNdeple67:oF�%�a��mi�t;2��#QRa|A�are&/ of wild�*mJ+,<9�Xism! t�.�a dNT�#.s�oT1�q�>rr�4s*�4$Rajasimha =4l . [!t�>**�2=(ag�*� A�-:�M-lycM� stem! :6WI'f)viE �:DUZ^>k do�&i 5;�;*�,f*ko�OMw= ]�fo.59�!Q��56�4�eXlymphc!� myel 3age �/InJ�ol� cryp_YI�noR�*� �+,�!+F�R �.�%1e�2h"�V%�l�0 9A��w� a&F�����:�wer$�6of � ity-*�/�)�a J[�"� 5$#Yerteb����w�Yth�Yu� angiosi!�7z –[j Both ���5 ([��d!�   a G1�� G5 switch&��coiled- motif�Aa hyd�E�19box����, �GIMAP5)X��zen�du4w"�5"(predi�&%/m�^�3�8� 39 . 5 kDL�/{3 &ear�y��pseud�e�V~w�.Oab�F1��M�P1+� A&��DM /!:"60��Pen&wJ�vw.ot�q�B� [a�Z@8�e& 8Z �o�$�bMg ti-apopto� Bcl-2>�M�����13*stC2[2��Ea5�origi�7 ")Mfac�`<+g���9e߉zpenia!k!diabe�/prBioBree�bra�.9�9lt�� � �5��� broa�t!��7�*� �?i_Q3a*�9*�Ya�9 �dyss)�l)IJ`(/@n��$of death a�61L&15 week�#"�d&6&��]�NU,�v$ ita�)��d8���ef!q��clu%x,u0[wd%�" *\r�!`� T"F�eJ�k� *�����s"�chaA�eri y926��"? ��n� u� e�Q.�� R� ? S2�ɝ�� %�be "]A�wo�,"��&�tself�  �s$A� in.O l,"�! 0R"&��i rect phys���d� �h �&%A.YP:s�� spanwVP� Kmatrix2�O �8Dfa P�>� �j�t� bL`2P�z� 3 ac"�nod��#0M|lt�^�\ rogr�~5 tOg�:c� as6�uSex\�;�/�� �ukaryo��[3�<%B[[?!:T-H��� circuit!,U� x�)6s nutr�t up9�e� sporB !J{UF# work!$-G�y"�q �hu�Ax� &��wh�:�{���)Z!' stkM apprEPAyMcG�*�UAn�CL Comm� ��2Regio�SENAd�h2Age�,Sou.n Finl�( ESAVI���NHɌA0���,, �� ŵ6� 7 %'�)A�5�*}1�Qd;�=Y>b1W(�%���h!F1�//6� =I!� 6 4 :)� ey�Ti�C �&H� %�at�nd"U/��a,�Kk\�!�on�#i/I�. H&�yїE/�N��t!mtes}�&�b7d� "mVB�*sby&��O)zae�G � i�'�6ofeG=qy� v�E% �� �E�"��n?&3itnUJP,rorW ��|� %&cal= !daGD"�.d"�]�$m�%� `to�%�W=}uX SYBR GA� ( Kapa; fOX o4U?PCFX96�#b�[er��R�(� }( �ward 5′- GAGCATCTTATCCACGCTTCC �Q[e &(GGTGGTACTCC" GTAA6+!!b��$o*�#6�beta-G4roglobul�Wfo �$-TGTCAGATA ��AGG.�-T�A�TGCAGGCG0��Sampl nd(�JmJruNh�(d%u�&� 1a��v-9W 2aG x�t� IluQa�[um De�PLTPan`yas r!�SNP�H$pN���eicE. F�+a�+,of 1449 mark!��pc, "@3EQin�3��b�4��!�_ �%Rr�9eF �byLu!�U_>UACG!�!� CCCATTTCT.�Iz!�(GGAGGGAAGTT!�0��di�,ed Hpy188III�&�Vag�W�U�c�Os>2�"�E2c# �a��S� -��Mhe1"17�!H-W��> CATACCA�CA! A�>  CTTT&A�!3TTT�?�� 320 bp�*g&A��a 170Z%�:8���mdI3frozee-l�0d n.Bfs"�c−�cTɌ�+A5�wTrizoj/m en`M�zA(DNaseI�"�= po�~rf�s�=��.1��m�1&A-�!�1��sA�RT-�N ( Qi�o ) �ps�s>� TC!� CTGACTGTT2�E�TG TG�GCAAA�&k� Fs%*H !D"|by�I�rUlG+"U�9|!n��cm�>�an�]A���AACy=r.�a�CAAAGAC��TT �!K��act6�′ -&�@%G TCTA>� -GA�HTG�H��A�)*Full-*�0-�� ��GGateway :�M�r�. pBABE-pur7n"�!=fv�d�2 �`aLPhoenixASho�Zic packa�\�U� 'l _9>.�]v!�E��l�k NIH3T3 *��n""9Qka� �`����b�t�#C�,N og)8H+�!���,dosm�x L> ϑe�8 �9 corr�(p-R ń"�=a N�8�~��1-d� ib�10 M�� ".(2[+h� FSChi-Squ"��o��'E��hzQ.{a�he��*i�G%�gR�$!�x�v� atas�g� a�no� �4,2�[ANOVA%� hoc �*,ing .�8Bur�p ulce4* BU );�ph�ly-restr{iEq�3�6�cMycobum N ans;aAj�w�LxndeA�rRja�e| risk��kN acquis�0. Glob1!,!M�test�=Q�U��Ho�}BU+often '��0�mC�taxs�ide8ma�Bl�_�b�aQ � .�L�s�-e n AuEF;E�Vi�i�6�-pr.�Kpeopl�uY6D�v!V/to�)I�Da�g[us��utbreakAnBUA[� BellR� ninsew��)A�Tme# "�`9Ec5>&�1en���eRd�de�!^PBU2��<�4�5va�;s�gu���U icia�#�$a as�i���ITE�[�C-��f.9. �<s4a!�soft-0 �Q toxin- ��environ� al�++. C&�Fb�+e World Ja Organ ( WHukanegp#�r�-nW,%��4re"#��+-Sa]n Africa�reXH!s"�t public�lk<onc%X:RC��.�+.�L �0 30 c� ��eK��!C�:� nd��u , � As�China%�ayWBbPac� [�.� ��o%<sm M . = A{�� ��i�#"��yu 1948 RVs� 2Q!4lso�0as ‘Bairnsd�u’a�‘Dai�+e[�i�<AT�wE�^t a� �F�b�Kw�A���'� !�. v�^(QHfN�!�W lK_ \ ���dMB)�"T �.i���umq comm�rboreal� supial�a.:�.nl��#oi Ubi��� &!a's [�o1%IOHn�dal�g� BU’">r (\)i �X_g*FF�+aœ [k13]�O�=mIr� �T&� Aa]  �\I"6 by �B��� #09 J �$�S�DI,�@a��9m��}}{�. x�"tim,�7c. 5��i�! unique opK�zy�"`6�M�Eh^ �.ifiD,h"gno� solymera�@�.�oL�: �'E0A� rali�!6Ms�bP.�6 y2!A�a.��HO�zabT ���< Melbour 1n D�xt�F��A�X{Servicea(DHH�k`_齥UJ���dUd( –"�.  2u �lEv �6Q� � �reK lɾN- )�eM�"� I�"� or "I�V�R�R�H|��@2���!��Z:I�.>9� ' a� &�g&U2[]WU incft cM�AX>��6r��U�1GBU ��'5 tren�!'v�/ �# x�pow�(���N&e�?ploe�r�onship!>�LIP%�� al*u#PJ�nd�0@q&u%y2��b!vS2"��z D�_p�m%�� &� ,I�0 ]{�en��'edQ-U^l2��%�+ . Mann-Wh�y ULQ,Kruskal-WallH"x���e%3�.���!I1�q IP (A3dK8)%La*� .B ��duJ� !i�A"� All�3�|ŕ*f�����-M�q�  Excela�06!aW  1fj�n Cuv,��ege!� , TX��S�B�  /%r�� TU%Q"UsE4legis�autho%bAQPIQ� Well�gAct�y5* ethics7"al% notL&d . Of\cp:"`to�Sw�BU5֥� �{;�a��M5���IP$�{d ( S1�H/d�gag�? 34 y�,(�Sge&�6�<, 1�e�m� !:s�7� � I ��~�R5wA�145�Hu35}�Nm685. T�,q!|-z1��J @0U�aJdn( .�M�ag( n = 1�:1M/� ��!sum�p��| ��y utum�Ha6)i��"�EWa&>W�A�� a5U;�. B9��"-io�da�cO�wo-third� ��Gr��s�ͮl� limb�\%���9 �sJR0)�bes@kne:-uE� qup: qM�I�Le(s2V� iM �6�A�112! �r L: 3�k251 xuIlvpr�WlA�a5r�(e*>�z48 bm�:8l244 xidp��)Pa��C��&l a隑7!� eachE5B*nd�. uG�eV"�2q�oZ>to�F"�( IQR 10��17-P(, 95% CI 1111�65mTz+<8T�est�ecm+�p 6 S( "3V�'�A� l7!l277 _( 9�!b"�ra�X =��"� UZ�ih|0~3�A�� .pr� dem"�^*�f�0aQ�� E�� � e6.(*WN !�y�es�-]� �6�AaU `�\���� C!]13M�!%!�y͢1361�I}�62 Y2��15H!�Uni�at�  ).! ��g�d�!ot"� )�a� ���f�( ≤30�Cv>A{��x ��(.�&KEJ� o%ZRh �M�I> )AU.u�P (�� 2�U )U 2!z RQ�S�A!wU9#?/chmnW du�in*��,na��ڬer�BU�Lld��(� �,q���epi[�6A#dAJprehenQZ m eill% ��_�t�rieB�]�a�a�un�� roup�+"���who�:o>�Z(6��@\)=�A�qvv��q��xԩoy�a��(�"F^"�Ռ�6�0IQR: 109–16(���: 1v 5C �Ou"��CvE^&��5�<r��s� � 2M����}7A�by� 6%. 9+�9aL2q�a��� 1�!�BU%�%5n� �&�7nu2 verag�&JT*a07�B o 50 U$ ��t�to 111B..4� ApHxa��1 ��e�a�nounc��r8*�RN�n0.W�A�ref�-gL4!�?} � 3/2�?Trubiano"[-h:6aVH� k sus 14/20n+j� D"9�Qh� #g&#�6–iO.�ompanA��.>E6�?st�����–�?2�&�"�4��_i� j �rE��+:�!llU�!E�r last�x� 2�IP2��e?fi��EFqu"���X}�2�U��*#���B�.x� �S hat QiG���a�$ w��ݼ��s�er ��g`nen�C �Ws*�v*( &&c� p &of�zBF6u&�v�S$s��"ffi|�S � e�B�M�3sm!��* sa�AZ�I�e�6��"�Gf�tru[I�0�-uVaa}n�&8!���%j��l.S7N help�cri�Flt�1��e�~dB� �2�'�!6B�DA���� dAg� �b+ ribu�%. P(�s%�Iw iO theiswK6�� 6�% � th�k @�Al�, pr�|�&GP[reA�7�kan� a�j�r"m&�&�3�'io^:s'toRq3 coas��)of�"� � .J 5privo6�"67is\  a}%v=!�AY y ( � Lm�E%� 7�<%ea� se[)�Iv�AYEH �#�|N�( 4R �on&q2rhw"&8#!�RZ�5��� ?D^9��Q�i�g!�^ rece � targ��p�:ian-ledA edu��^�3;.pca�sg�Iac��i:��8 have*Ve��r�� �newly2� �b�#Long da�� E>�uo� �>!��^�)�"/ly� se�+cCk�:� financA�ca�I!U�R�|�al�ted G irea�I&,�9-�!n�'o&G�_. Know�Y�"� � �r=�)�h+��;F� .���J��@����ach holiday�%`� U%�MXQ� millAsus�wm�"/EŜ])�j -!+/&� 1P vidu� ��at� �)b��! � �x�WT� n�k ropr�?�[tAg��t�.�:��+��#.," <Z E~o9gen)(by>$H�qmuQcV�avoid� �Iix![10[DqO p�*�.~–5�iv�v�p 15"�-�: �A"L�r* ^?%wE~���P e+a�_� �qkoa]�sP%�M%�*Y�s����1VIP�-�UHa0�mqva��"". F`��O� �( <5%��6Xs�"���lg� ur.\'�JHl*�� !; � ~ art�I i3g��Xl>�+�)�ss a���do$ �A �~+� I�t���&�."'.�E�g�(��.��L . Se� E�k3a�A���&� �� ,&`��#"_0-c�/Hv��11 \�>���/e�g]6�!o��~[�]�A!�a&!)Q+-��c�!h�d6�+=eqA �\�.a%�m�&� ��P5c=q!%�A�_K,IPup�"+#E ����1  �b�^�(z�".�B]� � рf�o6FsuB.��Aw^g4*�e *1� 22-"�.y >�2�I�2F�� a�c�5%�i2� 2 ��240 ���$2�AQ! 2�02 �2�09�1ve 21���b+U�2O'!AD%y��2����+ plan�x6d � "� &> �%:�7GGbB� .�9S�lm �Ne� play�UO�ch�]l syn�#���Hm�ra�f,zF�I�,�Rsh 7g%�.X+ �(�Q‘ r-�l!-M�( SSDm�tr&�� para' ToxoL���s�}?U�nizkk]!�+�O��7A9 cano��xin"E�E�%-!��-Q!�K*,2:%-on li�{-A�o�.����Ai���atdi/��*gMed Niem:)Pic���f C1-� �)� S�C�q�!�O��}�"�%CW N*��i %%"Pnd "�Q�� NPCU�%<naF&a=UB�, TgNCR��&�*e�hH��? -lysH!�nd!m�e��%ve�-IK�sphingo%�O��d%�[L� A��Lg�Cle��M�kE.�"�We&�cI�)�"x qin>�.���, 4�21d� jJA�!�3)���5fl�G� vesi��beneax�AC �aUCMof.&u��Y)A  m{]E'��X# f�-qpe= &5 �0nd.�5��<P�2QG GM1 qF���=J�To*pyrM->6,e;Ot" � srupA�A];�qg> v�0. Q-��4%�>E� h'!TΔN �0v�2>2�?H���)8c(��@hXl�afAyl�� ,Q�Xiacer��A� �סś6#No bund!�Dage � ��!�zm�] tubua 2�� q3�+ vacu�7� te!�� ��)�IM� n%�&�;daugh��&��� A��1"X!3,� �f��!b�W�D%my%sl�[la3re&_'O�Ft�!�pa��!� ��se m.e1� , YIa*� Pi2�M/]E�o!52*<�L��Ksti���,�l1�,1�e�w��!-� e di��/ B�)�����e a���ol1y� |homeosta7- ��.  gL'i� a#bl��6��'�ad�4My���h�cyt!��AKs8 inva�)�k>���V���S�!�� ho�`O��N�9innB�Zv�r&s#�eɫ9<l��t)��� cas�abAzWT/BG�OR-�n%sola�PVY��A�n��t��u�AKtE�t"�co-op�ltib?�%au�d2��9e�],�7� re*���) fuel�3row�.")�FFd���� v2��� �= �l�;of ��Ze:`�T .Q�a�GC#*!�.( E�ithRve�\E � low-N�lip$��+LD��af~T!��O�\cyt��!q6��I�i:&%w' N 3W7p)*� e?F �_*P r��s9`'BS � 2��},>� { 5�-fi�%:l�Wnv�G�]9 :����&u�0o2z&Wl�"!�l-ic net�,<. C= �EAoAKmUa9��%�&d�3:��� ���� �g9�!CaY� �8�.�B�nvn�� ABCG z���3�[a�nlQut).ede�r�9=�V$y�RF�]!bV� �Q.r�W\ .t((���-,�7.}2>sub]�2��C?�|�  G��� -��� !�!�4��erin.mo�Jric )fz!&� aquea��[7�^��&%E�-�� j�!�2jCR ).&: �NPC0�� 6���rt�����s [o�LvQ�A�>�%�c�����5 LDL-� .��2�i�6%��>�O�Uneurode� mvS �$.b%(�d �\i��Au �� a�*�)�U� 8 ��!U�js/���%��so�� "�N[d@,�?�oBd � s op�e�A.�.� �"��alQ��;2�lib]� ��is�3"K���t� �ӡoS5���G%g&expel6���x�}� [1ߓ]r( a .�d�T%+ !��cav�$TXmmo݄!7/�fc� 5�1figh{` �yv�E�2�� *�}, f�iy� D ( SB[6��%6��A|&ix!�nY�����j���%�+!�� Uf ��r Ŵ.�.n 6� -%l7ign��.&*&)s�� �$%�ac��[ A]%�a����%*�[ U ar&�An?._�a���.�88s�lla��j.@�*E��_!�G�!A�  �_ic� �P�-AnR"hM#cO1 oh"=9�giaorm�+#,Mmzl��� yv� W�EA��Q@Xs= �3����-E��TA""�*� ���� re~U��;� �!R �!��REB�*-cleava�S�#yMm]� O!6g*s�E� cripeV!\* bi�A�!� � 7-de%5.,��-)d)$ : 2HZ��5P��A=a tum�&upr�j Fƅ< �!�A`��$U]K�-"W� morp3KHedgeho�=, D��tc�-KIUf"[dA�1+�zof.F�� �BZ�k� V"se* #i*reHX�Stop.5toZ^�h�jaE�. ٧����A��J����Sa�7+ =�t�/�j� ls;lB��%��Xr+yox�Fr,,2� "4M>� �ɴ�;� e�h "P r�ae�����8UA;�var�YV"perturbMe7[m0X InY s�}a�+���%b�W�R`CRRca�!����/}ce�inZtX-�:nos��"6�UE>� �u6M�k=x�jAT%��a<m�!�<%jo7 ����y+M�@*�< �g�st�! b.��aTo _qar� s��j��;A�� "�%�gov NM/,"��6�)�w��*$} 6ua& q�ha/L!aAF2i�+m�E��&y3v%/B�webit��D B�"��~�%��ffi���:�Ez�%f��t�;I"!� �&�! >%�is&�� S<HE�qU2�irA�t/(lk��2g .��&_��.s/�����Y��ja��� |�&�6� a8p�� r>m� ��>�Ss6���2��F. �!&"av�E� w� onitqI zat=���-L6�.R* "�8?y &"�pr1�� ��ymAe�2�.��&�e��O@��cVcj/�*� ��?:r!�o!-�*� %�)D=oxoDB .� 6A%:g!�5��Mtj*1��.�V�� SВ‘��:Y ,-T-FD"�&re�R�@( TGME49_090870; W���!*��IX �n� ��)>D�a ���c�K a�aIY �$�*.p&v�(D�12050j����c������EA%��Q��CuIs E �B{ adz� :>�Hbe"C A}>�$1 ��>pi� an�&�@6K!2Neo!�vinu�jC3yiG�s3:AgP:#oa�n��~lo� v:;� A� heil[�� Babe�V9�2)��+�1Md� �5��u�T!�m�p in6v2�)WsA�[�%K�� y��eƔ �����@ ���1RNaEA]!jn�A�mp�- 180 �i! W i�&bn� ��$"α-he1�9F�SlI�Ai�.m�#� s 31.R�nd 51%.� .*Z �B�"n�F,1<͏v:'!�oN�0–��Om"�& �ys.s �-�T1^ �#>xeA"��_2� a=) �a,)n2�( 7YOW�>b�U1!��( Y-63zCG-6qC G-67�� P-69�D-i,86? R-78`��-��1AE�l� 1�-ya�a.�/"�.�| � �mp�Xx ��"u+n*��r�)��-y � ��AM1'=��U�ve�,:7w"�`F�i:�%� H� Dea#PH��2��>e�B�B��6�7 "Av�6NC so�c !d(&�a �x�\ -LeuX[�z��obsG6@!f)��aJ� -dUUa�e"��%��!&�*tI�M"�)N� B!,�+���2 oop-m8"Jt>�{c*�A*��`6�L~,E�S� aliga^�!�al! �6�k�b!�A�� .a35}�#dNq( 22%t!*9 � V}-q��0eF&I)p"�>���M@.�5e��i��y�Prhd G�}, ��6�e��bi!AUa�"�}�yS_'��4i"�w�all����|�$%�.*. ��&�  �5>f*Ck��37:�6J�Y;&N����&�� ( 59!�� !�-�� �@%61j� d 47 eg�j���6=.�L(�2��re'.9-,�(�NPC" gen�A s��a� "$� ���. �:@�8iZx�R2>Ri�IrupÁg:2�&��!H18a�quf�36z&� �=�-P-���3CHOJ8nJ����]y�a�*MU|q�[24*� 1 u��tA�" .,rl7\ abat"S(6>N/&�as.3Bj�d� � ����&!~Wn2�'�p��.�U_v3� ��.�Ba/ٝ� �"q8�7o*1�0WW�a� � �r&�2~.�(M�,when ectopic�ally expressed in mammalian cells . CHO �were transfected with pHA-TgNCR1 and immunolabele "�Uantibodies against HA ( Figure 2B ) . A fluorescence pattern corresponding to corticaln�perinuclear ER was discernible . Expe�0ly , no stainJ+�mobserved on endo-lysosomal compartments . We therefore decided to engineer a chimeric protein to correctly add!e -*;qes R|M5��`Thin layer chromatography��L�analysie�a neuta䁹d f�nM`ular ext1.�-�2 .F��-4of fre�ع�(have return�xo na�l�D�8No�,nge has been���A�f���. betw8>E,J�a�2��.�S5�ReB= didI,any decrease!�.�alF]���ordeuto%mis2� of �T!! ER . Nega/!�trols�OsY erim� �Ged6.-E�a trunc��&� con! a�rt seque�#m�C2 )T (i" 978�,1100 ) combiA'z�Ea [( �'!Qs� J- TrW z � )"� �-b��oth�]JWAB|ER�� �(2M�in#" �9 simia�%�#in-+.a�� A|sube�>! sphingoe�_� ic+0ly gangliosid��� (g . , GM1 )Ats ano� a�� eris� -�� ,syndrome [31W �v2tA� idic>t�:��vFNseF�-�ed high1Rof�, whea]!>� >!�-��is �%� undetecta< �q��28q�o��68ca( a��v; .�6�!q.�%X2�,E^�Gti�measurea�� v : r.�^2by�6�. Altoge%�,�s��� ugges� at)Vn$ vi�'u�� ectq*���jZ/l-Ouns"�%�auwayI.6o�$mote LDL-c�ca��rel�bEj�*� A*� ~ A[�activ�E% e twt�a~< � ����!&J� �parasite��� interch��Eu%[re toB���� :�IF"~How�, , Toxoplasmver sn es hs.BL!2*s 1,predict� �%�i unrel�F"[� ��is rais!waBtriguQ $issue abouA|e bio�i�t2�T . g�iA�sA�r ,step towardse�rstan/a�molec�ZY$5�, w6�x?eQin7 el���6i . Fo�rcurp��3re��9peptid�:��162!R501��pr(in E . coli* geneu  polyclo�4� Rin rabb ��S6� U� ,� 162-y ? , im�2�of:�y1Dsq.a use� phs&O long6}bod�Wsee�o b�e� om5apE,� basal�_ emitLm���7� Despa�attempt�purif�� &�!�يc2 back�n� ma�O�h���rOi�J}x �2!9 �6� Din-depth morpholog%stuL,. To circumv� �msnd� a= terA�olu% zm�2�e� Ʉs�< line �9n�4 ng ,i�Vtubuli�_�ԅ�� � a�fa *W.�a��!fgenO5T��resol= SDS-PAGEE!I� blot&�&-HA6���!����H"�1�miga�d����ngle b!rat�140-kDaY��I�hn.& �͢a�las&r onR��űaf1�e*���%�A ants��}�?0 E�pa�rn �l emin���[ �@!�inner"��Ulex ( IMR . EM-��s ��A(> A- tinu\atchworkA�fl�� ves�  ci�$naaIbeneat �"�'E��yQ� onse^irrI�.�oE �OYB�6z.�[�of�{YFEgInteres�e=Q4�Y�A�also vis�ony� adja%,8i�pFpQ�t>distrib��:m\���"D1 �m�than 80%��T5D�-;e�+!5� ��E�l=Q coun6�86aURd4(�4G�Fin�tWobo��xF�en�� wo oezu1s:1�.�NTP�pr"�taga at *�a�� HA epitop��MJ.VJ 6WusRW. P6 �Eie� �Q1� each��Ee orig!F6,&� m�!N!�y/"�l>� < ng"�E) z 5�S�. � second6� cla� MARrol�~ L �Y�� �&Qw"n*< four� �do nt nX�s6A9�--� �:�1D571N ,P913A.I957T%"� LV��<|���A� F�ba�����B�FqzpatA"� 4]–� hen)�ly M@)�9`a�16 0 24 h��sa,+ ,aA m� �!� IMC/��)�b�� viF�Q gave�"unusual*�, such� dab�2*&d5:2���ch��� &t�al"w (- hown��It�pos�� f�h� lowe��,���Ie]�� � rend� �i-U�ef!� sil�y. A �il couldw�H(time-course%�p6Jtakes �e� anIb$gi� a� =� . Wh�m����!�~A�nt�s ke�� �N�&�may�Q'#8!, i%�� plau=�2E#�a�m-�" a�A"� a*�Q29�xQe�be viem as e{ a%� ipl�"�� inct�s� *t�I(third appro��t�%ud�����&i�Dfoc�onq� � srup� �&Q�" PCR-iSmetho�"Y ace 0->5�"me��a sel�HXGPRT�#v'loE �tsPCR�Sou��n ��!%�b"y ��=af%eofy��MZ �cassett*N5D S9e� �AbA�j�ob?�!dem�$�#.��\A<ne#ary�in vitr�pa��=�. I�! brob�&�Δ��!�!o#� vacu� �>� �* ,*B$mitochondr�,A�"3(!q�h1�*8%S1�e knock()/z %$�o%z�D����&� �$J1�m� _��equ0 aD# ACJD"V � ;��vaga3 rrowE init�a�a� ior�� ext�N\!trough�u �sF#���# qpoOrend� necE�O� �!8�Z6Fas2z_on.E���incorpX ,ea5^AtiXiV#<)�*嚉4$appears afEsle�!�5�di onE�6H weYm�Gpr���-defic�U� aid �)ly!!3!��i!�=T�mmo�d&�%6K. S� i!@2"�E��_ appa("�! ight&J$�(agI�`m�ge�d =%i� y ob���d  inva�Qor egh+R�Agrowth < ��6<�?�_���fi)Duraci�'Q-��). C9,&� )@ r��!�$( ΔKu80Δ�vor8�1f>�kedd &�#�er amZ� �( v*�$in� se )aW� ,�A� 48 h p . u"� 6n%To ve� ��}A ->)�"u(�Pgen�EI��!he:�wF.-�-24�esI]�-��$6y�. Val�,-y�!�E�garg ��l�!:�a�c>�<2 , 392±504 cpm9693±13 ,A�)(�*,���-��R�dI�-w6"A�due�!ad?�of��-preeC'por)�at. mis dire�.depm nt up)/ ly suppl!�c*�[2�:�.�$$a primordi$u.!xS �*մ�t6C�<[36eI6R%�t� ex�� �+..>tto 6!-/e!g lose[���ni onA!�� \ J�)potent�6� rN�$.Oa��,A�si&.Z�- addi%8of�LDL!gA!0um  .�10-� �!�1� w +$( 10% FBS M#��ab Si2e ar d�(opa��j��jB �$A>50%a��"��O w��A�2� �6a�aj�A�My� % q�!all�)X�9�p6�R�in:>ey(eU1u���E�:��&� �+1}de6����a slowd�of�A2��0wer& e5@.*�Cv�ing�$letdA �3ay���"�E5 r� )�ITi"*�".m���Xe&�\$is�'�by/� eque\ �Yndo� �!H.g,&�enrich� un�rI .2�{�-Golgi*B�an)] ia�.J� o�#ffi4[9�Wen moni�-!�.sstatueH)>RD.�A�m.�In21/�ex&�*,,eD�R)Uv7p A6r!���a:w�� 's pellic� �rhoptr-="�M�!^Uu!�ins��n cultivq�qy�en.U�d�"�mK,nV�C�C,major �{of2�2,asA��c� ix6=�F�8� alidate "�0ic�E�a�w���( e����%.=m% �no�7!R olig AeUma�1� d*try=����'��ey"ish� &Ccon#Xo'fA� q , di�tr .�in1�I�� -�:�)o &wh !��!� mi� imp� metabolis�Hs�b.�J,!GFp �`w5 NTR��,dyey>M�tr��", �aa allo4� �E���olic <2E 2z0�A� }D�4E�<2q bund% % ~��B ��g�4�( sizo numb�'~1fo�% N>��_8�_m��;s  � uh( n�$2�,)u;Y:�df fiv:Up�1ellA/� J�!�=&�2e>� g�i+W$"K describq+*� can)����}%�. [37]Eq�)lycerI. [38]!T2��e n "�: ��Eon�8� investiF6byJ(.6�.�.A>�yl ��_9res� 2~3=�per+in� ai�2TEA�z�t! �4Mcyl-CoA:�ol ��fer��( ACAT~c �Y�v  ,F��u?>3. O@521��a9 �-�&8,6hol�7 C18:�142%�nd palmf 6:0 ( 26e�!m�e�sJ�>�� 6qu%,had uniquely�*�5R!�icosano��C20�7�"� Q e}io a l�?t�. ol �56:�; steau ! 0�in#8:�4 hido�<�4eNs��+unsa0L C22 fatty�=iP�2�!V*Uԡ^ U�reM�ed 3 . 5"U!to� pecAm!&6_j� f�(n�tQ�F�!jan�%!멾st��.�yl 9Q,6K,%M39Mvery-z-chA{>].Y�2�I���j,��3�Ai����Q�*��yR���poo3 6Mw�eiLuX:II:UdUqu2n� s�p1�e�t2�g�* �a�4��� � s.122��BCCW$)�)n� �~U/o��p :$Mn�Q*t!�S-/orq.ysreg*A>An.dcy i^NPC�S��8%/A��(*� -of 6u5[21�'2` !q+%�� u�b6=&t 9�. A$ �a�%s�r2� Pmyelin%  ceram嬕 ��4 .� ADž po�-J�2�6[4W?� �F� ato �"ya#&(;Q�9S�(��2�s11.-�(3 )�6z 9)�œ� � Fzy��� ��ic������44�h, eruc2Ń28a�e�18;13. S�7 ��coseno;��Rbeh/�C�;:0i�Au�Dthough!��)c8O�n1}U#���32B* hing �a�����c>�1%.zm��U��1p�w ��V( 8-'C6}2SE�ed7(w"L"�; 7�F��͛olez!7� �Op l�#�Qprofi�F?!�u ]���quy2y�-24�"�F( AN,�c6'�br2%�'.�I��%e�2�j �6U���4 YM���5smR�lignoH uH4:06 sela��.w ^!s�^1��n�� �C2a!>!�6��:T"� ={%��!+mU�AI��od>k. �*,�pra9[A��#AS�:�m+�\�L�E��hos 44EiT2�seha���z�.�&�**"+��u�.��)s5*�, & :=Aa$>ł , [4�<P�atidylA=��.��a�&%H ccA�61–7 � Si)� nex�� 2�siy2 � etha�K  –1 ,- (inositoR� 6�� )E�.Ts�KN5 .*P.&Tew@�Rc"� &�.O1(E���.�"Mp,� ���  SO�1�  f�] U� �2 V� �ed6�(�a 3�<"| ��j� ky�a�J=�;.� A�AX�kq�p��i�� �8homeosta�CmBU�E�AiWMhl�Khe�fa�og"�I z^� 4>�GET stonis���0nea� ��EMp- ��&���d3�� ��sR�%�=nt�Vly8w-�%"� &*i# capt�%�2=���be��2�7��)3 muchq+fr�nc�GA�EO1PVE7#O-�vi%j��� ,�#nel AAA�� 13oIN3"V%e %�@�� cyt&�&�/.C&���\&=E�1 2@ex�.� �S�A�&"d32��Zl3�.�A�.�a�"oK:r�t��7e�*]'ep%Ua )%horsesho"q4*@IR8b )I�o�same |*rod;�y��0.�7 �o(�m�JVj�%�se�1--ik�"� eX( l pi*A-{newefw��*mA'A*,*!n"%8 scaf�Ia�of2���As2O'/&e0�*�5�(�"�7���/�)]N.A*�Ru�G]\a$cQ!��'�E�tV]d0*�r4 ed d$0vo2�&RBd-&ndne2�Ja �(%�M lemma��vaZ3�Oar��1!zCoRitA emerg�,,u� 4RAY"�iqM�*�+*0:mo: h6C*R�6, bifurH! e/��QiV�s f;g�"Q>b;�j;�'6�(��1�a%��Á�ak9�R���3=�tr !&�?tX� N�,#*1lapseI�Mb26i�proD#ay�*vB�occur�(3 fasha�I�� N�Ixټ��ple9���!s�,r8�~"5�GK ygAly(�r�!of 0 . 5AG3% [4�<4�<>�8.�+�g""� �a�n��Em"v% 9�ū�0 + �/M��..�P"<9�c2�uA�O3T�u1�� #�},�iź!) ��Õ`10O�$Z.W& �M,"P5A B�� r.u.t�#e�;� ]CsynTNh/�p�A�!bFgMIB��elay2"YQu�4goa�E'bin�#u��4'�T�"mi5EM�L � &�8��c��C� via& TP ∼1A�1>�popC.*bL�y"��>-2�Q@��_&13U�#�  ?( �61% v- 418C}R>� �=^-3s�D�G1-k&��^o!24%�DE��w�5&/f 9/'�E�K PVv^��Y�� ��u�m2�IN6�K:�� fe6 ��4k0h(+$#n� tr&u. path5"!(:  * �e��I�r fibA<at�  away�(5� to f�3 iQJp".[44a>4�0� fila�*v*�!��\�-�F� A*S���z<"Z���`e!� �!;nk X�+ 2kBe granu!.� GRA7DSRA1�!4G[3 45]�S1�EPcz�PV��Pal em� is�1�ema�'ng �I�by ^� �&0:�yinfD�>A�M�� �6"!z 3@a��_IFAAM�GRA�!%6��.�&�5�'B�Ui<� rmT>)��6�=�Bv%��P2AI�S lti-����= *��co8!=i I (94!g���6���SWch bri�G��homayA�8�E� ��%6� >H�&s�E�(g�O�<W>&�@�S�(a�J robusm� �. M���vic� R2 �diame�9�length9���.� � y)g6�thick�7nd%�e[ F}�]*�(ni�t ��j] , al3�B�=�4"� =QK.5�[U!��b�B8InM�cca)�,Q�->�� A��dH ���s[joiG�PV�1Y#�%�i. a�1a physi"aPd:�d3���9lA���h"����!T �e�8s!wo>� ach���QNa .���8=}B��J5H e5&�A�JI wF CUC"�<sa�dg%I ��2be}�� "�0 spli�a��U?�Ye��3Q��u�ir2��� !r)!MPV seM te�*=:��7I�)�=|s�/�a�1VX/@ PV)Z�OA"�=u/&�]\~?��.�Z� �� a<&Z�� &}%���!e*0Ty�e, |mad� "���"���E\1n! ��z)�j]A���&� yO an"�F5��W gene����5rgT�4�a whyn�"Fp*~ � �Swo"� � ���Za^verthe�M f �:)s%Y�9j3���i�1��N�G !' �Aq&ɻ apidA4aź�&;B&� 'Cvo/heEt2�"�RB=dCmpA?u@� �/;%a_ �+A�"�( viruy �#iv%*.2@�J�(��19L>,leij �N �J� i�i �tonea�?j�.i��survival� & 6 dailll (6�>�d�<by da�'�{WB%� ၧ�hz�BS*�T^(er susceptic<z� 1�� syst�j���A���ie6�"7��bind"�= tria4J�B� ء�re sl" lyI�U'nE�p.� . A��start�`poi_d6�Won�$T0�8��� or9�5�*/i�aimA�7 UT�%G"�1%�Q�a�/ SSD-�M "�48 �J�&&�;���):��9� un60jNi� n-Pick��iC1-�9� *p *ty ( 30to6-I�- ��mM!�1178-{ ua3o�R( 131-�W�L&�> N-glycosy�js�>ipreg�K$ log�WPEVed Hom y Do�` ( PHo)�SSD%�a}0ol-�jA$d0SB0[>TH�jTy plo�n�<p c ����#hu"�n��a��ikk�r� 9�e�O�"! "1 �p-��K� atM(V1o12I�� �s w spa��; �p�64n�"a�-11f.#�(" \6fhmplexan.�!-hx -*)� cm�c� =B %��&MW . MuK"A in.Y� Mb��� K�HRp��-g�"w:�ad�o:C*e �.i��Ok4�V I!9)!�ITEGM1!�fG<.* +dH]3evoluAD!���f~�a�{*tozoa ,.!` ��$F&uC+ 6>aatDXst� Be=N�(? G � a�a�'Y� %�&a�]��YplIi�L�`giv2Q!�!c!?proble�P6�F,e6�n�'�36nd� �cer�`�!�foKS!�=)7]�R�_ doesJLeT_D��re�-or-�<�up�O)�:rAqx& grad%&nan�.5<��$uxotrophic%�.���@#�@AA��p�!oji�bŢ%_��#��ors��N6� !��t*�E@�C�7Le2*.  s� #�M�im�E� g���ed��2 , perhap`Z%Pp�&ve���-�@b�ecog�by*$Nach ����E8ix&�v.� NPC2B� J%��*d� ough 9 �� �LK"TerFl ��E�� ��ort�`�a*�o����2-� il�*tWL2c � Y��f4R"Ek5u!����� �-���tX� con�io�q&�,F���Q%<a( in*�GVh�ALl�9A5���>saYZ} q>�A�!{�  � �[# �%��iFU*z[at Fi��Lqu�;w r*�!o0jA!�viron�C%x}Xi!EE�e�6� v<9P>�q��eeE"{ i���e.�F� !�urb%�D�&2�^�.f�W�V pD&Za>�-#�/8s�BA�"!r�}�e �;zead"'D _�/�N�3��Q5h ;��eS�N�:.o-e�ola�.2.�-�N� �u�un]vs�U�aak�FC��i̭~ � %\PC1Qց�t/� %��i�E�V�8ADew!�2�J.>%m��"�b�^v"4d� rol�h+&"�g��A1 f�l�l/QTM*ye�d8�  (iX,J��lo�zx;2 ,5[a.���yc�!�0TYGw5�!� ��|&����b�K!|J@ �8.�� �_gb[|Z 1C�g �R� -NodVD' ( RN� s���bx+erm�*)0�acriflFbe%.�;[48 H�� ] �MwtE3Esche�:i�Qli!&� ��f*&Iw%�!�>�n��I!�:q Ŗ�%�-�2Yp"DP�W�5 ,-�A b-= dofvlnl V�� ��+��Z��cldi�NFoy so w�Aa0J �GNDby SL Sturley [16]�ein��* �yn&�N��>�y*� �P%&�� PAOar�.�a2W}Jor/UHer-�& "51�"9 of&� � �Dubအ�Xs��.��I!*�Q$ �D� ig�eukaryo�8�s�6�.�WFW arise"�e"� %�oV,lyq�.�of�Iep2 $w`Z�}M� .>M i��|>1[:�:�&� 1Er�a!br)�y of!7��#�2a�2onr�%�/ "]"5FM$7�G!�a G� �!�6�(Ŵ6��A9a�2�� &� leaZV&+�R�Se^IDsti. }'!��!,Bc�1" biosyng� b8 d[4�D9�it�e�E docu��(,F�!-'Qv-\ "�"�13�� myos�otY-achin��L;mmobi� d [5{DA( R2fcUgl�9�x%�A� attasSan "� � ?�2p]1�/��0l>�|u� f%M�Sact�Ja cat�[tQ/24))��e �2�I ynam�r��rL-�!n>�#.�c�"6�)�"�! -[i�&gnu8"yb"s�|y�. 6�^e� �6��;�&!5n$La�=5�le�VA3 |� cѱ��� q��0�-c�6���e�?epr[L�+ y(uy/"� > &Z �!"A6�Gg�]!��A��a' "!a*b|<2M�1�sh5.kx�ISP"���^e�\G9Y��I�zAO,.i* &Y�nL_ Q;!p� �:l�{ � �Oiz!q��=[5�A>�'*� �܅-�� t� Ny ingF5. OƌE�s " 8Ml�]� s&� n im!%�9��r*Go!�-�o-O�(� &P �t9Y ;Zo��Y . De&c �X ^s&C ��`�"w"cx�:�!�( ��esu� b "� fa� )\m�" ��!��a��{tneG �R' �vo�be*�_ir���r��s AN�z46 1Oy��)ss�u � ^hL�+-]�i>�q�p &�G� inj���� �1�d*� �~�*�Sons: iu>� cFi:.zeE)0yEz1y'�g.�.�.�-� indug%��y{P"e. t!w���:=wz|.8eRK%V� s; i � 6���ymors��aT��S��I| ion;e�ia�N-&)!6�`#c &���(rs��O9J�NIo�4.e5.n{Yn m�&mbBkn�^%R6�i2W=M�6M!W���"�,i)via* 1!:[5bb' M^1}2�| m�Rng7 iRw�Z�Z"��Ht.7elicit d׍u +6N�!(y�e�� . S"�kn� m29 �#u:/��!9�,.� inflN% 3� "parfAn+( pby!,�[��pro� R': crip`fMQ[5�<RD=�f��3; 6Ucytoki�eL@' !Qly IL-�BINF-γ-�T ��J�M���� �P����� 9d�z� apop" vi��Q4X LastQ�Oqi��~�:�s'd R1!i&� �n���s�zB, ӕ��ROP!��~ % _o �2�al]�.�ubv� ng>T�2STAT6e&a�[5i%T''*h,/spread�r2o�f�i�*}smjkɬ"��n6e�B��y"8�� ut[ �#1�!� 7� ��n&�$� 2� lZs*2d"�ZJ$��ngt#!����o�[B �Xe$���G�!��1kinjCp D teec�\ calc�c�l0r �#n�} [L#�`/f,e��ɡRab7 (2�C*y/�� � to"3#IeX �F Rab9:BB<EE� 9*f ����B#Y!�*� �]g/!� ���PJ�or �x =�p!&f"c^�>!�Z# umab'f�q�U�d�a&]:)\� .��u7�� &� �z .@0l]ub&�2tox���?an� �W,AY!>�efPn�]a�n}#�I sink� �o��.��iA�t�i�eZoA��u[PC1ɏvad*p)>�Q�a:Y�Z-# ~e bulk� Q3V,�f��T2�t8m ��$mechan��q��%�f �g,�Au��e��o%�!kec�BM!2�� �twe  know���|re�eFp2B�_�-.���u� ���, jNA-�[-��^*b$"� ��j.y"r�����B.+to�(6�'�lA�$.���oP]-�I2�"��g&2[5�;ql2Rw(��g"�yf�� .�w�?�/��4`m�="L !�_!����cto�d6�eM�>�t(!�F arge�tx j%d6�6���gG�E�a��1��{Y��ma�n +�!{:i,�I�Hy�gSm]%��)/.>� sG` enzy�JloY  E���z �U� N�Q�2� [37; Ligd!Copa�Jeata�pr]6ion I-'oTg.t�� �*<�al�&re�z� �U�yl W�ā��U(�?70@ as w)ۆ��:EXGu�pƄ6*r_%�!IlywvI� T *� 4{X2"� of�30�m2� ��=��Bd= q�6)�.��+Q�$� /m�"�5+&P]|C�& ] �B��Q2:��t! mpaR�ne�p1� ��>[ae.� %�E�**A�*!:f� &^%(TgME49_0382\�%��l:�%�"%"�B#�� eJmء� ChZ:�/��dAgFJ�MUK/#����X!t ͂a�KA~2FA�2m9enh�� B��b�  /l� X)B�7 �SI��6nAb!e[�=�n�W2� �5"R 2#�Jz�U�2�zZ)� �I� `Ke?Wq#uLv��6n%t. L��o��y�&��Ee}�!�E��8�entkHfj*A( �6$�"��ng of��&#d!^�iVŃ;6W-6��>::. E� (T�,Q.E*d by.�i*Y�pK rect� �drugs� Sablock6]2�"Js, ungi� ir��a���v"'"�&�>�[5.1_I7�u�I�e�e�Pv)�%�(�"�Da\�,] [58; Roma2�nd�9 Like��*:>yi7:PX.�� a!i�i RQ���=%a�� >��4�C&�Yv:he.?.�o��Ym�9� d v+-�B�I�b Aj��2��Pn MOnee �pl5Eo�J�#mJDvU�An"!')�[. B�5AIKAC� ursoL(Y), 4�:o&_)F[AK.2�- x 2& �9�-Z:l2@>r ��\2��^r*�!�o�Ws�! C!|9H�.�9m)�&� 9J21 �M/6'��nd6�)*�5���x*X9�!b6GiaF�5� 6,*� ,]���^"� "aF�qhepat�+W�&�E�exq2U!�!6G:� ,6W=� �8"�� !�c �*�#� Mas֍eZD�=Ai� ��der((L4-talk.F:i�HqcY%[6$"Am�!coope)&Z�`�w!]H t7.E�F?�'Ql�xro�". ImbalY !�e�2U�2k���*�E�.D$:��at6�2|e�.�V�BA�K!X� h�UP..Q,�a)ed-forX���la�w.Ni5a"�ͽ2�A*2�2b��n~ �'aIs�{��vek����>�an,j.��or�D.�a2�e>�-6,*Y]�a�p!kR)�� �zFF�'om{�p!|Ezڀh�he�au֬� { W*�G c�ha`st_es [6{!yhM�1 ""�B"E��� 3faW-a'>C&�)s2 Tip�� ell-�mun���a -eg8[tetyi.[6aX6l�-=8O� .�s� ���� orde� ��)�A^��-| cu�>�|� F� [6��6�e�t^�&�386�6�o&E)*��L UߩN�)��&2�re &�L� �1n�n�;r6�& �.�BU;�4�� � � �u��E���≡�6}�B,}�-;m�l�/'61�Azi�)8inta�'�.��R1>b�ere�'a�!RE=�*KK��+�IT�el  tubo��—�'ܜ)K�ery� �=P"�oj~�k1 p�A} aaDyso�G>_%#"� �-Bm%T� lari*k:I0 %qr>r V�a3�1�s��$"ecx1�M�BJ3)� [66WQ6� �����}��-%�I�6_ yT� A�:�)IIre�A�@(plo��u||�Xo=!recruie)O� 0P�P�!��%�X=�Y'u,ex���ma�;al&# woUIH�Z  b#6(um Chlamydi�|kN�(MST�E�u�%�!b5�fU �A�A�Cx,%I,D,FG lp�&�d/"�$!~A�g�P�e�]e+*�G:9�!wP fY=�#C �9p"�TM� �!�. S�Z�:"%%�M� PV"u� �WM7prelic�ryY7� "N�:�x�`ĩt��in^ nub�T ��!�>� (��O�H�SE� {ۅS�mea�S.:�'a� !T �ti��)<ke C .� chMy. Non�eL!�n�)b�](�(tB�u�*:)_assumpEN�P�>-�{�-�, p~li�p�4F ��cLB�Amimic�4��{A�� �e-2�:� A��;/+�alOA��"Vgare�� ag�@��a��"�.����m|"� ��}0:e�*d��8*��7�in>�[��,raaЁfn<=�#r,�u�G*"4/�ol2����+��& ,EIobea� 2 ,�ho� 2S ��.x6How�cisn�@�B exe�&�5�o6 � �8[U)�&��g�B   2r nϘ� c�� A)�b |�luc'�FBCch0yЅ.ALfu%  ou_&�ouri�.[�f95}�$L ��A�"e��*2.�w8rE��Z�AL"'�O�*N �z�"t�Fted�+A�Kd� �()�O m�mi}x擅1!7�et�xs� iT�e.-�� i/%��gl-�s�!%6� �yetsai� overc��� [7e.d!2 e-AzOi$�h#��2ba���#��)2�"bq"��y�"Q:��p'd|e� ~i�&�.R�0`��in"H S4�3��cy/�"�  g"lSi 6k�s��P4�ve�JP �� "�*in ApiM ]L�?pursuVdee�c]4s��I]B�5�,,TB� ���<H NY4Q�0!�col �&>Gpde�s �_908 a�!�b�:�'e؃s�PlJL�c%d��W�3� "InstitGLl A 5C� �UseE�mitteŹa 8Johns Hopkins U�D�! foll&ĄN%alc1$Health guih#o!�+hobJ|c�,lM8�(�"ٗ Sigm�St LouAAMO�'F��r ( Wta�M�\un���!E�wi�:�DntAq8'a�>�A�g*� �W\9 e�t�u|8�Ka�S�@e l 60AKn-r^�p@0dPMerck KgAG , DarmstadJ/Ger��) � purcAe��gSa�coGibbst/ , NJt Radio桡veagn $[5 , 6-3H]��,( 40 Ci/mmolmR,l%}Amers!ZCor��( A�7gton HezS�IL , US!{Z�oD�0�DND-99 ]6�InvV�(A�lba�.C GG&k�&�E?"�z5�%�>��6 i PoV/ţ!z Alab�3 , AL%3P G���'�}���c:� merc!mo�5a.v�R�� Ap�Ld5�$, Indianap��4f,9�( C2 S"�-Techn�� , Bott ,I�, ��( AbcE�CamR�g!2e !)LAݾ ( BD BiosI7vPalo �u�!u,.���y�޿( S�� CruzUt.�,)�,M.$`��$n��XTgGb�a�)X monor13�ou���K!)J�,�5$ubremetz (.�of Mont�oerE&E��i+sQA+�u/I�foresk:×( HFF�HCx;s��m� ov�\A�CHg)�y~�2&�'� &?��-m�.�La�iscum�uft2� ) [2��B��v2�%re� n !z�Ʃ(6��α-�mum*�&9vMEM )�l�(�10% fj�bov�ser1�$2 mM glut*DK�iCJ/pptomyci�U�units/ml�µg)��4rib��3.�jRH�?�B&3�I�dA�C?-$ 0� ���n� :��g�E [6���6��2��by RT-�( SuperSX;^-S޲ %�P@_num Taq~ &� ��Q�F �!) �a�R>ATni:-~.����by%U �t/m Fa[�� 1-1106�  p�q '�� ! � e��%���s2m Y3�CR� nMp1izXeX�Q�B�kughJ�.U�YQII%50�i���(�2Ι2�6a8%>�!}Jq��,�Va�� ���.%��,)|f�A�a�pA�A���*�%h�7.;�����d<t tegsFaus��'"�_938A20a(��(!Y�6Jnam[ �( &��) F-�,���P"��2�N��l��MDA��.��, R}���;�D��a�t J�,������"#A1�!w lipo-��� t��( 2L�[ �:A "o � ndii/ �:�ng-w*tP�J=8�Njټ,�8%u����1 n��M�LsagCATsag_Tub2358YFP:�S Roos@���o[�*� 4of Pennsylvani����*�ԉUM�� �'" �('{��"ڲMa"1&>a�cn[�* A�1j���U�u�R-YFP���� #!�u��z0wE>�X�/��am !L. S�+�ach�%��05) D�e��0 rborA p�J��A-"�>P)f'M�03e carr�+@�6$. Two flan�91�6F-&i��A=?I��8X>�C:"� D޴Ɇ � 2,5�;= �.= !_55I".�V 655P�.k 67 ���EAJE>J<�L . thn��%eN.R�or� Rab5N�m\�!��,��j^.l (� )�zv 6�HJLrr6I Yale.N�� J�IeCT v�haNTP-� i&#��K U6U SpeI@ PacIM��/EY  �Nh..U my5V�u�!t�u� ,.� \�m+[ۿup�ZHA��>$lhT*� ����I�7 u4p+!F$pS!�E�-���NCRO�d R N��:5�by BamH)� AvrI B�Bgl  %2�R9Ph"-ver�� m*K  � �of1�F, !��P���҂�>�H��C6(",.��V �a�)�:I(&΅*�i�q{h4I�"L�DH-5αe5"�~��Qi�� s� P� K�"V���)4`6ro;��:�8>��ϡEz6pFU*� "�cy�ALg(w!it�!�����* ,�9� s]�:e�1AV9Ahypoxanԅe- guan�O orib�m)[er�](3�)�,�2Q�FG�:�Ge�!�Q��)��rF�[E/a&�N�; a!�/�| �� ��ao�T�550-b��Z�*�p�n���=ic�L 1^�*�%�-�B��apden'fH'�W.Rq��=8>�AW|�pF g%di6o o�Q-�1��h���k��v���4�BfA�I�N��%nE� �%�U� reH&smΉ�s KOPCR- 4 , %� a� �J 6#e:x+t�a �.�-�z@ V\emR !�q�"a�A�a����2O/:�$F�%�DeV@S!�"T E��d1Bar݊S)NFP�d6_��II��}�  , gM�AS�_ER�coSQa�b ar7!I�!��BA� r�4�&�by�ym"�t��n�outS,�Eh%�m6��r��=�� �.yHi�( P��A%I� CBs P3-P�P5-P6)v�usn�*&`i]/�p*(-a|In��� | �6T�>AXn>F2������p:�`[7�:$A"F��h)�NPC-sbm�Re�% �!�.j t��� 9-kb� b*f1A,� �ay .�r����#80 µ s"� !� Ag. ��hV ]��7%!roA�.���eA���.�o�a Hyb��N+"�'"i�!�`randomly ��32P-labeD$l�q�B�t�{wa=�at�Z�5nr�gK�U.�autor�$y�� h"�}a���6k 6��!��P!15–21i*� e�UTROI�)�,1�"?A�� J.�1�o�D��j��W E�J� '�znA%t!t��M a�&s����^ 25AH� �*yco/;g���5% #a A0[ :�`6�to "®!�B۷� a +��-T"H  afQ̉�� �1�di�t��B )A�)k�`c�.��!� 96-�H�"�"�en_!Ba�^.���+q�`*�ɀZ�=�*Z "�>RS '�{� �n E�!�E��3�"� NCRU�%j�o.Z��g�N�� >�2e^�A�^% -�:7 �4M+��&�>.\>�� �0 6`ree� d.%a�! ^9)E��y&!Jl�i�Q<]#���Bb]6�A0�Fh@��>t&��a:�A�j;�%a~�su6D�%�; HEPEFg1%��l��%i�!TZ�#i���8.�2-�Jxy-6-U) apto2�nAE DrugA�iU#�o+�� �a�����~eEJ�6���iB�.��e��?��E :�����O51Zj9�3no��R-� ɔ6�IF��i�1-�Z��� ��� �Z� !�q� P1-P���� ��.iO>2 jN 8-P9a .�ne* a�+ ��.�"&b�r�e79ei�4bo����� c162-50�">�B�65�Q>k1?F-:5!H�~"��;�*�&%-"��bpQE-30�(�, Hilde� &�..8 ��al 6-H�4a�ύ��� Nb�&SM15Z e=�%I# de,�."d)Ni2+-NT~�g���7k!���%�! ^� i Q!�re�I��K(� ��|�"� 0%bu�: (� 8mM Tris/HCl pH �� , 1EDT�� 1 M L-argJ��-mk�>%mof4+thi�,3 8Dfqxi� N+�� 4°C��� 0$�9e�^e�IGaQqK� ate- ��XSCg Pÿ�;b��EXb�Q�%�5 pXsor�+��< ~vlysV(�, �)A�d<ish�M?�F&�b]3qV�( �� "k<t�F5��xar+;%,�sg�,>+lyM�gM-PER m"u:Axei�8"1$�1 ( Pi�*�*te*0Rockfor"I�0l Y.x$ susN�a� SDS gel-WyZ�–A�(A�c @�,M�2���J , 2%VIq 1% b�� bluE�0% glycj��(l%by boi@y� wr?A*+�iI��+ot-P��&�-G .�W� PtI�'�A�.Ikon , er MC� Mil� r�Bed-�e1���6�i 2-�$2ra*g 43% skim milk )a�H4m%�n�3�Ec���A���r( 1∶50�S�>z� 60Z. Unb�UB��0YC%��A��six���>a. Nک�/5Y&��98horseradish per��ase�Yj��goP nti- 2IgG�(&�4 Pharmaciaq';���;!15>�!TL�^alQ  , �y�.q)_lu�{s6�. VeroeyMy`e@#!AΔR @p:�a�$-O���1­!�edvz ry 2*7�toN�6��a z��eft�s l�^E�+ �e&����.ium ionoe: A23187�4 µM%41IDt�duc2=psf2�M�s�(na�=��9In aspiXL%� �!u��ifAafix��icA1ld ��( �X,2cMz?E{�1i�Eiod?� ( PIXm� (�@ 01 mHPI;6DNAse-�VR  A !1%��7X-100;�BsaFci)p�tɩX�ua�)�ed.1�.�r-�1�&t%�2�. FZ��a�&%��R FACSC.2�e�B% n Di�\�, M�� View�5.�6V�=t`I�=Xv|P�� �Jo softw:( T�Stf�,Inc . ) ; G1�2%�S pea� defi� OA�,Dean-Jet-FoxE%e�G5 week-A&fem`!BALB/CvN�:08�{ Jack�La*�%Bar H�$! �G����m�kE�5�iB perAeL)E�5×104*�4D�%H���&|�ksW�of uay, vE�as*�daVa�7O�!o.��ex�m;r�)4EA��Ws�a}epiflu��"��y �2] �� v seed7i�qasliF�24���q �*�Xs�G&B ]%w~�:��o8defhE d_I4G *� .$���Qe6_�Ŋ�86.+6HAM3"�9͌OL�9.!`Ej:�:V): �moy:d �9�'�co�QK�A1?488!I 594�7v/t�2�7��:�O�qC1;6'Z�6F�G%���A�� aldehydo !��6O�N8aSl%`N"�E)�$a Nikon EcAle E80�� cI�equipg�e�0a Spot RT CCDS;era�k?��IH� -Pro-Plus.�MeJCyber��A Silver Sp�(, M��i�m+ �Adk Photoshop�SԁMZ�� "�+�*^�n,�0%,u��M#�Q.�4�f36-� 7fix&' *4ing for GRA7 a��nd GRA3 , parasites were imaged with a fluorescent microscope ( Nikon 90i ) using a Plan-Apochromat 100x/1 . 4 NA . Serial optical z-section zacquir|�OHammatsu camera and Volocity software ( Improvision , Waltham , MA ) . Using theJ=, � �lprocessed by iterative resto 8on ( deconvolut,algorithm ) �glength(diameter ofHPV membranous exten�0s , as detect %�$staining ,)�measu!"0. To quantifyZdlevels of filipin accumula�6� coll ju%�8sequential scan s9�merA 1F�l. For ultrastructural observ �-0ΔNCR1 strain!ithin-seE transmis! e� ron Uzy ( EM )�nf � cell-�tfixed in 2 . 5% glutaraldehyde<RMiM� y Science!�,Hatfield , PA=�=!�,scribed [56]A]�� �%�N�%�!�,efore examin)mlPh!�s CM120�0( Eindhoven ,%�`Netherlands ) under 80 kV-�immunoN80, Toxoplasma-N�5<4%� form�:I�2*,previously d9538!5The9/�u�label�nti-HA v yos%� pups%us�qal losej�-1.a� vinc!� phenocopycA�8human disease .er-1�qone%E�k lians alogo@Drosophila Pentag6A@ inhibitoepdecap plegic�eR�0Xenopus laevi�� �,�6fun s�:a BoMorphoge�DZ�( BMP�u�ist!pearly-KaL��. L-;2a0mq'�. pO de�plausibl�pla�for�!eE��Cat%�E�Ax!)�$mice . Con�t��bsw !�an<( h� ��ed6�)!�a r��. fw� l� birtha�vale lessa�n 16(10 , 000 [1�I��a� lee�A=ordersP ount�∼25e�Zza�e�!� tic causea�Lclude compound heterń>"PAX6 , d��vo6)a -of-Q5��b8 SOX2 [2]–[4]�enheri�aor�QOTQ5K[6�Uz�TRA6 [7]E%posAPyaC �,��BMP4 [G Ina!Wof63noEUis !�on cl al2W but� nerv chiasm�op!�4tracts remnant� X magn%�resonancH��. AY�a0a'E�ips&�$ q��isq*tru� *] a� aken�p,suggest very�(failureocuq.. "� –�� 2� t * ,���� fr�ly�}edq/'B�, which�mE�associ� %^aa�ti�R ve patter�dis����oma? ( Fig!1a–1c� � i�� autos, reckv�P ( MIM #206920 ) firs���� ed 50 yea�Bgo� . inŀJ� [9��T origiw� illu@]AR�u� pect� 1O tIdi�͍� �B yK �bship!vn nd�bsisJ!�wo rs)hunY�.�,1�whom haH6�erXtr5+a. B] -�Xsynosto��� he 4^,5th metacarp��8 a� four-toe� � E&G tissuei. A brom� simia$E5i�ve5 �<In/�A0d%� @��ing�)���s4.���N -�� prob�� a girl p.\ lear�disabil_9 :�sh� fing!�'ly i97, 1�!I toe�  feetE er youRM�-. 32 fur%O��e](n 23 differ��0ies have been91[10��2eOQ5OdB� `,; 32/35 ( 91�% )%�2 ( 4O8��Y�:5�29 ( 8Q9F/rI Z.0, 20 ( 57 . 17fu�of2�4–5%z13 ( 323N�. O%Irecur)6eatur&[ d or� � � 4!)iper^�r��nadeathk0 1��he 259� . AtE�point�sub.� �lpaper , �tlittleEkm� mole�~bam�Aa&T0p1!�23I�a9�LOD scO>3%�E2��!n�\linkag�-��reeN�wev�no�B� &could be.�{n"� � š!E�intl [17��� m� I(!�BMP�ac&� 101B33Ra�-Ts,~$growth fac� Lbeta ( TGFβ ) superes�peptide64�*� � encod�� �BMP2-7 , 8A B 10Ex BMP1a� d�Gnot N��6�u��id-like)ase[30]�%� secr� into%kex� ell�space w` hey V  � Iine-thre7e kin7E surfC��ptors �+BMPR1�d B�`� iDappsuffi�^ ,�!�,�ca �IA (>� 2 , ACVR2 � B> b ^� phosphory3o A�BMP ed�endocy��# acti6���alI{du���cade [3b �i��!P%�6 Ue%DF�a�urn2��k Ser-X}SX�motif a��C-UC enda)"� a�� lo�mw�!eM� SMAD��� 9�=Wed 1/5/9 ( p$ k�aN g� ory-� R-$a�t�AA�co.�,k!X / BZlex:R loca!/mnucleusmit Ez�C crip�f�=med` L-�Q=!- [32]�t h� cent�ecome��ar�tEoI:Vcan"�in7�>ohe MAPK��w�33s! �� of:bgradie� is u��vel��roughou( tebrateP~6 6kama��� of=u68�q�to�L multiple mechanismsbalQis�n"� t ef � a�9R�hlex �"system!demonK ��J� dors�nd vea�lf!�}%�glam:��[341� Z� Nh ( DSC; Spemann's organizer� ��; %q1zAQA&Bmp5� from^�-2DSC�R� gg��d chordi�~( toge� w~tw' -1e[35] )u�bmp��hRF�!c;E�����;��� �/! JGVSC��� sD4e bmp7�[lsoe�= bmp-v�� thel�r�� ) [36� sizz��A�ll���*a zinc� llo�d�\e��ly��1k[3! an��pr���ambi (�ԅ�in rane-b` �o�, a/� � lackISc yaeR�!� thusk s do�Tnt-neg+ �Foph9��SMO�:F �b$@ �n�"ini�!Iha�eri���bas�� Q i*���y�� BM-4� %|ռ �xosteon�nE� !��� lA�-o Dclosez %2 [40mis evt!ari��rv�41I� istsi�N-����f a�tinT �,�t2�ml(2��an EF-h��u7 Q�|o��� �in>, X ,�2� how��)ġ��szUniquAyamo�)�1_62� mA0ţtoSze 0� �1i��.� rstitu#5- 8uV �JJ�ń yete�r��may�by sti�"ng��-�ed2 �heh �� i . �� non- reg*2 �� s [4�W�#�E��c��EI�L �2�� *>F?a_tu!�predi�#vH�!�1g !� ��# ourt1JL��. Whob�inSu hybri<%D( WISH )9biW ?�al!+ja�\8omography ( OPT�iv�6 e&��q0!m�!]* inF� �bu,d6��tKe"#eB1� !�*� “p6�”�����1�+1 g�Vov�#p)P!ϩ�d>��W!�-2' a�b �ve"� p�$�RD&�M�*��n:� en�Fk� "_ of D:�( Dpp!� igna� in vivo � W"cuw e po�"MA�!j����taၰTd&�!%�]E . A:�at*�!��qed #�a~%�m�!E�10K SNP�p data�K"� ,!�atly}h�yanguineA�pedigreE|A� �&dividu�� m��u��A>ed� ck�>20U�us��a row��Z��(( Dataset S�!��is !confire� ���"�"R$9 ��se�giv!���5&� of 5*dd�% crit,%��� narr�%t+! Mb �%atellit$rk�in%B�&�e joQ� e\� e�!�ll con exonsE� each !�B��%$cedvfvPQ�'l�'�1]�in �$�gene:e$C n�(depen�2 H$�� Ufou2Qh�f�%Uh5*2�!TI5b3$6^ٯYteŸ!�r�; 4�"}$��2m�  d!%i!oC"ser #Aa� �$�$. Two*A��$Bge- =b,�5-�# a�.se�#V � �"� 9Hb%�No�E(��y�c*�� P1Q�m in 190 he�,(y blood don�.6kinBR�6h14Y�"A��no ob�)�6ic5cx etw�9�qo�H!ԁQAl �5�; aa�classe���p::��sdwo�six�i4-E�n�=l�-DE�2��͜�'-m\)w- �! is sE(at we �Eqd a~�M[6H unitA��6��y��� IimpairA� �6N"6�<� �u��"�#�N���2�. A$' step��!qo*�A���veJ'aIol�& �w`dertook.�a�!\ 9�tm . � \ �h_} T.� EA � ?,�rib{be %��� nd�� e#<to cre$ a 3D�res&���!!#7%om_;'rimetr�Qi|(����(�w)ateY)P0a,��3� ,3b; Video S1 2��S�M�` R ��,i�l�#te 1!�%\*� s� I& Hv&i"Sanlage�-5 dpc.��A72�/!>An�!in�-�l�to9oT!�"��T�/X_�re�A�� �"h)!9]\*6"i S�0g.�[% K� !GpharyngeZrch�9 frontonau��wa low-�1.b Yectodermf ya�p� ves�.� �'3� �� no�=~U{ف � �6bitself�?�]asFO 9��+sA�EI'�E1I9}�3�lAt+�Vj�u` g!�bx2.H)bates)�>>Mne�2tub=E �In .(A�!�)e i� � ,nd+ �F"B1n�we oba�,.V)Ea&�,Pre-C*�,�!�6��a LacZ��or�4allele��40�!�AMEUCOMM�  [4"v�g1d a��!�6detai�4,A�8 ,4� � �uSdI< ��,�,�L�fH-U�t-G=tYS� ,� sumab���u IsplO1g.3��i� 4� �6WA�� |-�5�O�to"## asse��6.�Y�c , 3d� nd 3g�OSpattempo'}�g ���$� E++)r>9�gen�+��E�d+A j0.?= M%�( z�)�y.X-g^A�A#}�of����nt���cC.�s�A_�nt �A}p/����. C.:t.@maxilliary-mandib�h:%���1st.�( �F*E$��.��ed�gik���p�0{of!d2�9�)�!0=́���AuhN� hym�.��c��d�� ont ����!�is�)1� [sub-epi&mjA %2/. Sharp �ar��3* 7v, fVeN?maj�,W&cJ&&� & �� $AD!0:�!V����3�m�!�ey�6e��Cl�*%QA�����3y*�)u�2� �}��aAN%�i��a,=C�F�'*S*"S �&ut����M�� O .�/|Q���2�?�nB!�mba%p�1(�� O�5�( ( +/− fm�a��8&)X oss�k,�5�4�����11/12'�����Ycj–3k�-�9 ::.� neonx!�b�m�cxn 'erm#agdidE ���O&�M�6f�� To���4l>�����to � hd$a�soon afM1�'p2�3q&K(le8��likb�'4"�"){c�(74E�� Adm( 4!�1A��:u�5 3i�RH�'it�aucS) w�Q'�a$morta ��� ��t" l�9une3'Z "�*in��"�( Int�e� Ey.�8IDp�Ma^0-$�j>meoridpo�=�rii� reti����5 in 5�6%JU1ue�"[a6�y�E.3E�>X{pig ed �� um ( RPE 9 !6�f�/3��5�i )NT�1n0"�?Z)q�AY�ee�9EK9g . &�0�� Ŭc�at j�3�4:�.t! AQmNoE�/ny�6�0a9n71.� j�_)A�I rola%"�%�Edfu��d��w2�*�� A��in�U�P����t�@]�. Six�th%j`;!��";�:�:)`l�qN%09�s�+�!� abro�!oEx>�o g�� .�p�$rg278Cys &(Thr283Asn )!%��*!c  alEUf\-+��@;� d.� {s[c�%�*r3�("�re� � ~Z�.�;�$ى�� [ �#"[# p��A?of�`#hepsink�6[45 &NeG r )`��)Zd �ty��A�2'�7g3sidue. � !>�s5B�r >3Y(; �-A�Zv Y%�a��d"�! trop�isť-1E� �is[B  V*�&t:�$��3�!� Q�!c-9to A�$may disrup� h;< �:!� :disulph�-b8ng�M,�j# . Gi�Be��e�*5q�:w BR��e�hos)� null�AV�reaY7R)toEj:+�vMlm�a� �HE�� ��.A�,�0�3y�mGY� ,%Cu�QN�u.�I:'CaM� H�6�#@0 nvol!�in�(4 dOdI�� lung.� [4�DI�ż^9-*��!�inE�#�&:�-�}��� ^=aM1=�!�(� 6�%��� +ena8$ ��'K!�� ly�0, ���i,Wn�.-1 ����x!��'"� WM�is E2�2*�&y tima$a�e )*t�?��&Y ��Ww����.d4�>O �.&{:1CJ �2�5-�e.v, �!,digit number.O ��*� ly �e� Na!2M!\-�r"��;or�E dosag- so�#hedghog�/hh ) [47([48(<&7�a����s9/50�sA#Ųnt%Aj�E�ez��� �@,a(�5!�m�o=�!���>� highB!$�� ��)�A+U.r*���:Uq�BN .�i|� �9 tha���.>~ , be�U6=ibP �*Lay �*Q��5�  �b*� �!I �+ : E< <! 0 ly�Z�,e�M%� Nl�:t:�C�8-z�J 1)�s���"�Fz �ŚV+�? ���0mo!�C�iar� =scu��WCu�:2 A��E. A�� (a= <a) �lF(B��wee�W8ly ma�wilYGsw�is quese*H lso scr�$d:of-��_toE�"hypom�6ic=��7, A)0 "�ACe8�<of!�cis�6ad gofER�Blig2K��: ���T�q� G� �& A�-%g�pO x"8<��9�%]t��*us pop��"fu%'b6s �FVo l�7�+chiev�U�f�1�/; ap4 riat�<md�7a��.�"�4� an��or��!ZCw��_}&%0=,a��of.�[51�z_+Mu�?f�w(C ab9"A�9m� taO _u,o�3&R3 deriB %�stu3L�(&)^�([5�Bi9�ϥ�deA(Yi�&,Epa*$Fpa�A�� it��5!�lo"�.&L vQ�.  ��5;31 �5��)"_-Q�bya$A�"�-�1cy�7~/�0ts sour��0M79j�oj w!)D t!�" !�7PRE� disc�+ Lack!��� EMa  tee�1na(x4�l�ء��� 8�*sN#�8�AeX9ce >�>E&� ��.} ]��8# life Ra zhang6��l2�|�[5�I�`eo*ck� �+. S`�1v�"� mustAfpr�H Z��F!�)�*�:a� o->eri%>xpa�R3%��"� .# � . In1� "�6 ex�1+,e�,�n!��eateS1/�".k �"%� 2� by al�1G,Q�.�5$�M�37 �N� . AlthougR�0�(v*%pa�LyB� remain(5�elucid�C,� !d%-1x9;u�m��imp�Aqpro��< ����tica��XN:%�im���!=s�-@ �S�C%<�R , [5�G[ [8�� 9]� �A AP3n� ,6�G� &� W ea:�"(&BP, corne "co_D,"MdyI�0til!I���e�ad�M�>4���>�E��#*EF poly}X"" lip/& [6~ � � 0b*� A)*� $���F� %H�faNreflect� ]Lm"�on�Et��J . Fo��s^�At�)��%�*qV.�Z!m�f��CAP6&>One K��d f��abG/&&�2!6"� TT�?���)"�3-_G.n�=�QY���*>�oG-JnAG.�V (sam*0/�(m q/to *�B� ep&FU"G�PgroupFBAR>p���0��nd *y��Q  (~.By 5′ #e�(=�� �e-��U���{ �H Slee4beauty/ nsposon->d��&tQ��" *;a �$ ~a�x�G��Q��SJ`irB��u* uni�'�O&J%ir � had �Ssv�Bd��������p���*&}4P � an!�-=��!/w.�'?6!��"kC�O� �4pFI s2�'Ukq�.[7bjA>I��:0�2�@e�yIQ� �[!(QSe*��<��6\%U�(,�<oi��s�[%:�E40“Knock-down�6exl��@�a�pholino�� �� t:G!� �ab�it�#��a��'�m�!. TWNge����%�seo��su��_!�-1�f�?�#2�� ino�Y �m've'!n*�����NKe�=���� ��1i:V0u�ECwuI1< M�y�.�, i�Q!�!�"�MM�deC7\by>�M1935 �MI NIvs�g�,Va�6M��of�0�Xs�0 �*�0�*!2i�X� VX:�y)CBgPY5I�%AP�%� D76�7ar�4A(aY2��;Q"? SGya�`�[5if�,AS&�5O, 0,&�"�elp&� %;I�*� L5$!/(�B!fu� work�8ll� ��d � carr� H��l writte��'I9;. D6C+��i�= ��" �Y1=Kin��ZQaF��P�ie!��Jaff" 4�by  V�9the/ comm�}`DE=aUKU N�3�^. S��L - �B >�publishS[1�T[1�22? 2�T26] Pa)~�b�1� d un"F sib��omic DNAL pl�Aru�7 AffyC0ix GeneChip H�V M3: 10K Array� Xba1397%@utm e�m /ApKoz9usa�Ex V AR 1I�*sub�ttE6Fn�9ALOHOMOR�I$llegro ( V!�2P(� ]��c�*u _ rval+ r�2e%�-EEnsembl ��m8(GRCh37 0y; http://wwwu? 5. org/d]L_sapiens/index . htm+.�a3$�9"�+triIt�Z�Ho�Lrepeat!xI�� ��ad� UCSC�Qwse�D � �. ucs�Yedu>�!�PCR p�3�R de�,eM<P3�X)8frodo . wi . mi�p[ D3/- FAM .Zelab�c`plaL:�J -en�JaAforward ��l��=AHte�S�i��nes�&�:����GeZ /@e Ampl�* ( WG'`I��I�T ,iPhi V2e] 6� Ki{/ GE H�8c� )5&[GgA�O manuxJ8urer's guidelin For%�, 50 ng� tempi(raja��h>2 2 µ�0im!�!�D2x Custom Reddymixv#hermodt y& H2O�25 µl5.yc)11!o@: 95°C×3 minute�8nd 35×c,� $1 $�66456 � 872*;���"� �7of.0 Y� AAJ &�=b��%��)�U!�ei�%@iXBre��_lS�:J!~>� Appla�Bio}J(s 3130/3170A2��!�.bank ��� loa}Pe�$NCBI build9S2%;�&�6��M-( Surveyor S&Sh �4tics LLCf, Uc, ��V�M8 (�eCo7]CorMI2�g gene) aE�A��a��HAH!��&�.,E�6��"���m!!�aF3′ u�Knsad ( UTR )m( q�M��� T3 A�T7 �`��i� TN��RE�U��<r��sqHi}re��l)a40 �-Y��� M1�1chA)� q��&� ede�08 of RT Enz�>Mix; �E�i��)�x��9a� l sd�,9�}-ei�%�!�œN.y�MA|a�X+ TCZCGA2,���Z Hpr�#c �TGA�AɗG ɋ!>6e� CATAjAC ,e��ch9W��&��ri�,�"&pti2��/s384-w�t,VMl#9t�Eal[quP5 2�!_ HY%�ro�wa~A� .M��.� :^ ; �wwd"�A&a�lcohol� �!Txylene; embed(� araffi"8:xt� ���ee�c�bt 6 µ9lrux6yN.rsM��$haematoxyl�nd eosu�skele�pr|v�;'"���in 95%v��24� s6O7� iN 00% aceto! 3 $(���( 1�$e�3% �tF luS 70x;.*1*azari�g�P.�)y Y��va 17rs.] ) 6� ��=���% KOH;/30wycero {�$-#aiod�P�KOH/520H�g HE;%�F �%U#.dBL( 5-bromo-4-chloro-3�"4olyl-β-D- gal~apy3|�rU!��6�a�llows:"� �2��x2lKApr�F%��T iSA>l "�� 4o� 9ago in?Q��IB3x.�in3rg��& (� MgCl� } 1% Sod5 Deoxycho� ,02% NP�\,[Igepal CA 6 fE3�) Ff!��in βrF!esidb%_�085% NaC�y5I K3 [FFCN ) � 4B200���Xc (V meg�L�/��|.Ba bF�/ �fixe��4%@)W��� * GM�iY^ n�"<}as �-�i� Li"/�0% suC}e/!daB,�G"$OCT�6i roze�Y�_on dry �5k�aick�eW�h −2�, air dr__M�%;�6I�qs%Fq� BABB9]��Benzyl A��: 2�8 o��a2� j�/"� a�pt}7s 3IS �er 300�`Bi,�� br�M5�3c"ro(&c�3 cap�� 9Qi�! yal %( wavek�s: excJ�Dt 425�}, ev<ion: 47� !%A NEZr�U* �us�]3 etar2~�",�Techn�1 D Edin�|h1mX��c�<VYshold�o remz back�&n�\�3ly��e]"3D)�Z"putF�V�!r�p7�.��T3 o�5b0��:�[terferon24s�Rts HIV�l�. Hw�Ep`p�%�)i�,�Y�i� TRIM22�# a ke�ahor��! "~7io!�pro߂(�fy�7ge"z%�;*bm�� �AU F�? �aKgE�y �7G.�&up- e�*� W� S[,@3  s�4!�ate�O-*�*�>edJZTog!s� ~5!� � Da�F�#�P�!*"7�w�m�% e ;g�o "%��Ide8CU qi RNAi%@5%tA%�rel�m�qa�Ja jinc�9�!c'��mpl�%R saAra�3n��# tivi �E6Fur� 1rs&.J9gbuHof virusd�s!7h GagXL�ځ�9W� �Q �. �Iblock,1of MLVrIAVO�-,hh|��fa:�/6;߂cytoplas��v!�of%��r@(a�&*��<a&f�2g2xH �Z0-ht �. N%�QM� <.�!* catafgYo��s Cys15ET 8�- RING�D�&"�9P a�I� �d>se���1�7a�'3lby�J�ob�%Arep�� �=}*s�&��I|d P�inL �� ' �e4 �yA��PIn�k!�A�"(5m�b�;nyI�e%�vokes�L�+�(d�TI=�� IFNsn �Ne�2wan�V9]st7E�1#s"R7)�spread!~�>I l ( α%�wr�#��m΁pz+QRwhile)�IC ( g� )!k.=-S?��IFNB uC%�vg1� s be�klIFN.ak rece�qmV"�qAQB<`H aa ns.p!mvi_5 e Jak/Sta�LIp�8 lead�5E�� of=�-�ons�2����sy1�4OfA!�K-���PKR ,��seL�x��c!h+A���)in ,/~34], y��U^I��w��ed!B%��9461�  �oa�$HIV-1 life [�)W 1~,�5,-,�/InJ2N��!�ofor %�!i�h �agr)�seetoe��po�=(6.2)285�"�8%lb��*E.�*fu� clarP'-{K�,�M�U��~-� ISG15��h,.e�|.��,way�by-toW-t 293TE�s5�!9!$rA��NTSG10�*)�Gag [11VCMAfK�@"� (�� )�s�6"�/it�#�I n �[r.�P5α %rhesuT caqu�Rh� ) �sM�.E='E� �A�e+o��:�1%�;�*48�cc2�0+ o��+��E�0a[.�a,lx�>�miA&\N�>< apsi}dCA9`�o�8 Q6shbot-��cor~AN - �%!���E�I� ),!hI*Yn�'1=8n!� ��CA��^n �"�-�2  ,\22]�a0o%1%Y68!��9 3Eh|NF.=�q -HFD�3R�t �8� 5reuAs\*�%�'btEyhkmo�S�x�Jto~ ��.[1G>�)3"�  aXF2+o RBCC&N �Br;_G"2e ��orB-box �g!Ga!�d�lcoiled- q2>1-A�.� ^?=aFalized*rfj# [�/rA�6Ip�H4ss E3 ubiquitiPUg�U�_{�98��20Sp[21@0. L�|is� ��"�B.uVis�7�kto:'e 9�O4bel]/)�!�1��>mer�'[2�S�(al:ee�-A a C&�x SPRYr�~i" ��q>.lLM�- .��2dG"' [2�Ol1.��E{G.q�� ~�Mby��A;�2A�&~0| �fof(.�.��ffQ*�iw �s EY� -�0m%U m]"�ut6ioZ �"�%I?�r sarc�� ( HO�' )&*�22e��?26!BG�o�%�7aL2�.b$-CD4/CXCR4 j� u~�4�&"'M rob�ABW h(l�%)�Hn eA�IFNβ}�2� 22 (InVras4df-5���k5J��seB\� �>:in Daudi �. Ove2of�k�}t#bF!v��LTRda�i�,� � n COS-1 �>4Iv�? udyA�an����,B�f�� �.�)%imYNpha�j!�2&� �+;H��ct��GA�6�%{6[27� -СL�@�Q*� in :�poi/g��|on [2�P�����pshA&)b4ic lupus eryth�� �:Wil� umor.(~�l9Y��C8.�a vK^t�E-ti�"� toA�*# T-a�8} /� by CDC0CD28 [�|,$ �[ge��(� �%[,�p�!35�N infl� tory�k�2%@&1invCg\e&B ��-�ML~ŕ��Kg6A"kqrim�� �s Y � ,&m�bna� he �** �>���rS�K hairu��s"��Xt!>�� ~ ��� � �?���=*�,U�A�-L �8f!�o�[i�=�t b��wUG� F%. �*��KGag-oj�� �� !46.#��2H.. Y�7Rq�E.�5jA���Q�arat�rup%S:�� ]* ��2�a �ad��^CD�)CŅ(:�)"�=�w��p!���K�ND)�prGeea��цW}%p/.�HFri�f��%�I/β-�so��HOFp��a&a _ ��-@!m�?c��Qsn.S�c� r_:252 to�!�a false!�cagy��7%; T�;k`~;�A�AIp-�"gOAS��� 35-f��) X1/��4 ISG2�{∼372F3G (12RF7 3!$aH 19zed�∼18��f%�ed3=�?y�42���a1q�O]east 86 H=�� -�O�J �� - not�g2� *ed319�=a�} . 8Ao�� !O� �!Nr34? "5Y1 5del%@,� 2 TK %�$��V �}h}�-@L�vo&Vae�!T>i-No*n��tg͘"?a1K.� s��s�AB��O%��J"��ro6K�jO[���er�~:eT��-�22aTїt�s�?� d ����|alyze%�22:\��r6��u�%NEHsIB�F �gglut��� A ) -tagg�� =O��%OrnE�g"a :3[do�>�im�a�empty v�m�3�_!z�~�4&eEn 4) A�> ) �\A�� 2�a5;!)8;$( P = �#�3,-Whitney Tess0��" UgonE���"c)S toxiz==�A�e�3ngEe�t�����G*aV!�=�-�e�)�. Vd��$�GeA�e�1a�`��W al r�B>Z� �x� p24C�?t�3a��' W�=qhy_�1. �F�Pd:; �W�A�9YNa��� �z"0n �� )cl� LAI ^�k.�par�/U BG�  ��nex�U�Avj! w*` "�AbyBf 2 o tAjM68 "caent�[�k�����b� Cell� �1 pseud#.��VSV-G en�Ol)�{�A{GFP �Wtwo is�&E8EF^I�s��Y�a�On�X� fr�� �po�2v�r�YfD�Q }?�H. m��"� )�! / �Q�)X�<%�whe�� G!a~-J kT"w� !��,!�co5�UT �CF�3 �W � kbH A��#!�4ed U2OS , 143B%�HeL~� he�! �% s�4d�E� a �. A��c:YA[e�a�/�!�Q ( pea܁5�-����jA�} %M��A��!Iu a��HM�$ lef=i�ŝ�+ ? to n8�wi:0�in:�x=BWlE��}�Y=�0'!%n�I��l~-S, h"�I�!3�2ˊ!0v abo�Gb�:.�%�- -�Wata����� ��!u����|�=� Qc1�� k��r�G�^u�t .� ��|duncer���v�hysBWw6L �Ł'q��[��Gm%o�we�f�`�h�%A� ���ŗw riboGi�� ( sh��Da6A���M��%"I�YEx�%6-6�!Q& j�e^Kl�Qm���k/�;n3 pLKO�7/ ��#1��&N� (5Q��& � 2�q�A5E �%(.� !|con��)�8� .�i�Q�� �-�2��Y� G"&'r�Ou�3V d B��}�,pI���U� 34e�ἡ-�-� �Rb�}���A2�.�;+&�' �S9� �t� z!�th�R����eAN-1���T��E7A+܅.a"�:�!d}�6�pR9�A.�*' g �6� ;on�)2� i�B� 9,� IIQ*ڟI3*!�_ �����+!T�Yk��, ddisplayAa�ga߮:d N !* ��YY�`ng�>S1�M�O200ts�0JRUII��rle�#o��r6wqOond2f� )UZ!-#�Z �.�/o�!ItB:� E�� A�m�Q�� IFN%S>� mW! �5�!�2��q<&_"� .V�JJ�1Vha�&l3�ar_]�$d���j� ��1�"/ e.�Ziu;u�1A�R�/ irAMvg "( eg 1��/��� a_dambq J3scram �2�-�!s �A�aO Qn.Jq 2WH4I.��j �)��)A%�"W f+aLA�!3���f: �-7ЅE�iI� �n- �aNvaluesE�6�iNran�T 3 . 0�to ���� 82o��nt�l s la�"�,.y�v[ .|0 �,�:4mea�!VZ�&U )B93.�M7GooAl-V\�K"O!��i^a*�6. 00026/)}��t��� � �"A��-/K &H "O �R� �"� ���rE�.�Q&� a�*.��8w#[it�kf�"(,!�bud����V�iUc | �6�no:I�5sonAu��&� �h`��&+:�$4G���s��t m`a��!G:�by ��>}YqzY0by46�>b0,: �X don-s6m%i |� %�i��! Tr.��+ easu�!2 of]5"QL" ��ul�5*�#*2 ը4��" =� �,.qeE"I}�E9eGB �y�M��w9"B" xa��.C�nx�!36d�^i~�F�R�B9��N�9I� �&�pE�).�wْ� ��4 m>�$e leukemiaI� (s2��eq����an2+�2)� *��G���� �2�Pol� B&1�%a-�Q*�sϊp�D"C .�� �Q_W)9m� -1_=c� T6�\f�f s_�i4�ona� We��*�!d:U-�&E���A�>�3�"a�.�*�1� �{I�ba�u ngxlC( �B'4� m ( p!f Cq)4HY4�/gjWe{n� �6m�yf2ypu�3�r=����fE;ohexim�vu 7&R�]5NycC&�>.ˍ�%� visu!>� fl��ce�'sc\���o���: slicg r�_-�� �u�5A� A�.�65i}GFP}iiAf Ab punc�32��z�.�n�VW ��� ifA .@62\����� Aю&� , 12:f�88:Ny��Z�2�AQ�)��)7=��YVq�! N �9o Ya�V� <0 .� �^ Chi-squar�%��V\ .�2�9:���1d�<�;V�9"I#!�)�Mm n>�f+BI�� 2lGag�A<�*I�EAE�� � , 64%���B�6Wu �޺2Y��:g�7��^�s�/!�]�6�!&n$)#ex�Y�6�22j(."�6V�$)&h#�Siap1��E��]�&MI�s� -tqF6dimin&N� �> is�uaccele�!.i{ eh&Bpulse-ch�"�@R�z�r� 5whD�lf|!gg�!� �'u�S"�5Zc2)�M5�w��i:} e�"5+&,����1i ��8:��^>1AԝE �j� J� 6v ( "byWJB9=�A�is �wA�M�%_d turnXGag!N� myristo*��3� i�ot�<m� @a�. >��-�c F�+��,L~&Q{ͣB �)�&�  >��mG.� �=*��q!�:J c"1ed%E��+i�q&>f 3H- R!*<o&vV V��agD �t pp-�� Y5�aGBQ�: �Q��&1 *��!��)Y& �� �:{-g&[ �!��.%"8J�q��2pd2�u��= �(�B ��4{?rx%arL1GA�!%$!�O�m�,�"� 5tE3�y�>"�5"���h  ;cyA .�: 56�xDSi�-�Is�.B!�!]J�-=^m�A�.��`=�hO#K�i�s�!{=hMR.rN�2AI!�m" Uqe\"a��wo� �)"�"�$( C15A/C18� J�E��<N2� n!�"߁�ej�7jP"P$s"�7(zet7W�Gna�s�B�!��! R!�8A�-��!n�)`lt}z*k�KW ough�!UTQ.e�ed �8�0mu�6EaGaM�&I"i��!E,�Aon��nel���*Q ��6".�!%-B����noź"�lec�2c"�CFP.!o� on 1�CZ�Cs �����"� ���6�wt�mS ct"$�!on"uM!"Pr55Ga�W�C6>a!�Ffu�4��1���.� FLAG:0,� �M ���D&� :S*;FlAT�&*< �Lo-���of � �5�7E�Ru:sF�:� � � -U*3m #e�l2�. 2�J!�� �R2WA p�z2&�6��("�( ;L� ��ZGag�;n"�,�Zan!"eag�1��SfM2�@22�co->� ���\c�GZ� u"���s"�@5tor�. sKI`t& �-�w �n"�J06G40�DwDu"|1 a�V%�A�� �:�3�du�,�5�$���(t! .y%9�"� fFeNKWe�p6�&�E�2LN{ ���5ah(al��!�&r3��-�p��� �.�"AS�  -��6�QJ�J "��a$9 �.J�{�aeeaŊ>U&�>n!���6� ��B^Eo����*A��l)!�G:n ��(U>�uL= x � .�–n&!���΍�u1�I��Z�+0��w � %b�H&7 � ���9"�AQr-� �V13�orA|βE�+5r8��K"�K5-���+��,M�E3��"� ��unQ`r_E)�QiF*jA�B�8�v�ttFD:v* J*��� FV��D #�{Qq>*�J.�~� ecn�>&�: . Coq�-)A�kNm&p�}!�r]�(V��prono*d� "+��� "!�)i:!�eEe �Eg��eI�i24aa"�=œ�)� E P�1� �}�1��at]K�s0+�ma�B8Q� ��.1T�#�Q0[�s1G�sa�6%��65 *6m �}, 0j��A  ,eN�AO��"�+"�3A+�T�z!_$AE��4 UG)��LTR-dri"�L";�!wnZ uq ��OP�W1>��a*@/..XG�I}�I(%��X��hTA�8~ �lAX�ca�La� rapi'^�+a�!!�X&�A[66�X��{c Y�dra���6ѻg@8il�_�D� AN2|<or.�/&v/�.�F� �iXq�IZ�fas�.�1e:_q&U�2�*2�A�[s�is ba"�V�[J��� a�ecx�is�3:ur�-$����sGFF��t x�6U��� of 5J|*�[29��� aA�&����pk ��Hwo�&��as�[/a5@!b -b 8�H� 7�em=15��5Oq=a%[6O6 O��>�1!fAJ6�*β�6��.�O>�!�(e wb�' 3�=E�^01a�2 m7V�;��3 .�.�I�i|&}NAu�N(ac+zm�N ��ple�hm}Z5`&YK X."/V./)̎be neel�4&}#\/>h"ˍ�!X&n��fiA=FrLM�.qL0��!�c��� -/x]G�t7I�A������/�ventu�: e-up��V�[6C="�CVpu��A.1� ��te�� bc�a����)�l�+!� mis-���"*H(V� �B(�6.�%y>Em|U3 a��ao�Zg�B�..�A7�d��ngan�Jj�s 09�=A0E�bL !BC !� modejAe�� 6�%W ),A��(At->� J(!�$noticeg=�1�����.h%.!�quseful!q�IV��!���yU�]"��}=W ��!W�Ve d�bI �AGHow�ҍe����t:l. Z��M2C��zCsc �!��9lem�&��g��*�L%��5�����*o\Y� A>1�uM�s"1Vlin�� � . M -A-��Iw.�t�M�I��lA�ZN-&� m0oyl switch [6� 6� 7� 7�SWaS"�ЁC��u,lo]!�]�"�"k!�-;i0M�_m6���!V expo�*! aT �69�aY�4�g e�� �7�i>,zZBG�(��g&& A\ex2�.�V&0 ferE5"? (aOan*+�i�J)AQ or|0t"r�oaH"�V-n7E�U��+��&�a�,"d�z=+"� M� �"�r�1 ize-e�!E>�!�J, rai�7!��N1%�(<u�( �|)"J�U.eee- Hla�!�9�a�Y �R�� ) A�at�>$?����a newA��1�out �K*�i��s . 2� ,:,� $= �e<�m#����t��O�D8 ( Dulbecco's Maed Eaglee`g( DME�W^ pple��o"�heat-&�d F�jBD�SQ�( F�x,�  U6P��iL�e�1g�yStrep�c=�at 37�xr5% CO�DFn/Da>�S_\mWc1nŨs:f*,W�D�2 m�A�y�e�.:BoPC-�qlc2��*~Bt Acce1�X82/h�; �#� 1HA MfeI  XhoI��o� �}to ���. pH;v�V �6�w-p3xK-CMV-1+J Sigm�]HindII �baN�!222-&r69 Ha�QuikCh�4Fge D��ed c`��^kiF� Stra�{nkΩ��C�:?�dDB ���u�a�/"t!g�`�s $ei�o ggaggt�( gcc ccc at t ctc c <6( �% LTga gct cca ggg cga tgg g tca c t tLFO � �-/��aI�Egif�>M>s^kSloan-K+v��I�� K C$�C�= (��( . #RHS4078 /&�72(45};,()v8#6T03979-9574742;�J: NM_006074��x�e:)Acgg ag�>t�( cta caa gt c%� aac ttg t!�!�gt-ug)O)��.�22��4��gt� c aa�!�A*��aE&AVt��gc A�ttt g�a-�)I�"�GP Open�hqS��� 909%v�sddga.-� 186%{-T-Sct!Ag�agtcgA�!KcA�agA� gggcA�$cctt ag5MA�6� [72]�hx �. p (ߎpEV53Bێ�>@�p6 /Cgpf-�0]�&0>co6\5 (( p96ZM651g�Qp�-()[Dr!O Ying',Li , Feng GaoLd Bea�Pe HAahn [75`�CZF mono�!e$J��183-H12- v��,ruce Chesebr m Kathy Weh��[7a7�'78v��5;I��(NIH AIDS Re�W�R�|4R�~Pr��m , Di?/2:, NIAID�$Poly/MonoU� ( FK�O#PW881"Xf)6$1 , $05e}%� 6�E�Biomol 6X}. Unl�[Qw���llU���t^&J!�s Lipo�a:��o��2ox:&l$NJat�∶10�Qi~��$�cAc GFP: ���h 2�9�b4��naVhar: _��N ] og-p�, "fC�9  fe^��PBL%n�]al Labor�V!�Ca�11420-eC�> -G a Qi� RNeasy�x.D�����d� )|"� t3mO]m�Hcr�yby.��,( Santa Clar��`. �T�p�i"G"qOh��3� *ڍHG-U133ACQU du� xS"�;ce��i�v�[A�Qm �a�p-of���)�� tl�ͥds: p156RRLsinPPTCMVGFPWPRE<@n� ����segE� ) [8� pCMV�S R9 (0packag� co�o�!�pMD�+>cM N]R&[H*�D? ( RsbdO�e}ia��010�la16"�Pi*��m? %���0b>AXI�u�Zocols [8݇P"�%KO�&&[�EliquoyPdiEle,C}�2'D�{) ]v"�Ce� jJvar�*^,)lQ98I�Qmin�� F� ���di�GiF�VAG��TA [!Hre���HfrT /A4=MƁw�'&@u�"@�r�i9���R{p�?� d ly�#2�t(K)�{�, 1ml�Y�B�N_Z�K5Qifu�!: 50 g�10!<s4��p�[� a  74�}m�t. ������""Hvbet�ua@vIzN5×-��rPEG.�t�y800���A 4�C +(�ecr9�5ER�80�45�ď��/:��{�"ec kˬaUC�[V;� 9�kA��O&{T=$�<8>nelIR�2% �9:�!w a$y cusha�o�&�w!:EG-2�)>!�s�w -pur*\.�-\� I�e&7A{3ytoX�2�i����# S)sEW�(aW.�0ta�. L�� a��t�F�?�e�x�B�� Ay ��=�1� 2�� (AZ!� ed 1�5�J�T� ( pH4E5�D2%A�)ۄ) 8 . 6 ,6)z Triton X-=,b�P�Gl�|{77 n DTT�F72 KC<恇�be�t u��Bm %d�.�B�a%�B�!�� 63 g�pF-�l �R!�%��J�a��a�t ��e��S|��ٍE�&�I�I$pe�E��Il1��W�IPAQR(mM!� s-HC�{-�4C150:|1 %�, 1×�&eteo tHHI�o�RX�,!z:�E4% ՃA�� �;g�H�!� �%8u/��n0�Y' ?�c9^�deyua\2�a~��WB =5,>%-�5% "�}-63� a:25 -fre[�j��2>���lea!�R61�000×��M<W 6\Wce/yA_ ���%a>��%9AP%G�01%6�Ahv� 1�'�Q h�u �� A-se�q��&!v1�9 `8 le r��.�d��m3����P 2�.&K�a�BSAF:aL���rE�6�–1 m��.�E�liW��� /"� a ������%�2���!&��oBHe�{�a�<P sepa� �?%1$SDS-PAGE g��� q �)JPVDF  A� or semi-d�ZR/�%�_��P.�j(n�!��X�M/$in 5% skim�[ milk followed by a ∼16 hour incubation with 1∶1000 dilution of primary antibody . Detec 7�as carried out using HRP-labeled secondarA( i�<5000 for 30 mins ) and the Amersham ECL Plus Western Blotting��ISystem . Membranes were exposed to Super RX film ( Fujifilm ) or scanned u��La Storm 860 Phosphorimager ( Molecular Dynamics ) . Densitometric analysis in�8linear range oftZ !Fperforme�lIQMac ( v1 . 2 ) software . 1,blots requir!xquantita)�!verif!�)�an IRDye��20 , f�POdyssey Infrared Imag�-�H( LI-COR Bioscience%�ccord(Xto manufacturer's direc��Is . Nearly confluent HOS-CD4/CXCR4 cells in 12-well plates ( 1 ml volume )I (transfectedM� . 6 µg!�$pLKO . 1 , $/eGFPshRNAA!/TRIM22  . Ce�%ecul�dE�m\8s , after which!�y .washedI�rea�increaE�concentr%�s�hum!�$FNβ ( PBL!Y�medical Laboratories Cat . #11420-1 )�20e�!Z The )?� then6�:-0!9. R9 ( enco%�8full-length HIVp. A�= viruA�leaa� intoyT supernatant ( 800 µli�contain-� in 21��!� lysate �puM�Canalyz��.+( as describ!�bovaMDe%xed�2 ress��)� mAa�uKby North��a�H . Briefly , total 4isoA�q��RNeasy" oki!Qiagen�R�nda�suce�%L�# dmori. C���E� �Vglass sle�E�� 5�X subji�to!` unoprecip )jp24CA , bod52~�S��b!�resolvEg�s(0% SDS-PAGE�d , impregnŗw�u@EN3HANCE scintill��:�, d= �*� a ph2| screen !tT3 days at room tempera� m� ,�d�n�nt 8 (pulse-chasea bility�ay�Gagv. 0as previously*%$0some modifica s [13]N ,10 cm dishesA�a���N %�B�3_ � R�!3eA�Gag-optf� 34� 7�[M��Q�E��n�'@ethionine- , cyst q e free DMEMg P���cal8 !�1ej6 qd 45G�5�uo<[35S] EasyTag Ex� Pro{�el!KMix] 6�2�2�sta�d �growtѓ�a%heat-in.veFBS�_ t 2�RREp� w�imF�f$monoclonala� ^�P ie!?P�ede!-�>Y ��R�u�by>�<.mQMutualisms �inter�a$ !Non] both(yers benefiA�Explaie&their maNnance ia�oblema��, beca c!�Ishoul�(compete coo�kiv n�ale9 �� inst�&. Monoec� fig� FicuA��polli�?by host-`afp0Agaonida� , wh� 8larvae gall ovu��� \ir “fruits” ( syconiz . FemalevA�waf oviposit �ly!to � a� ins� $ recep% cu�A�s 9�e!)8 %~a widZ documenA�segreg� ��-or�%�inner��B seedou�� �� !�att� 0suggests that �avoid ,a�%�rev ��1!�,6a,}teresult�9�.�However he mechanE� td)~{exploi2�4remain unknown report �in-n$rubiginosa� ffspin6P�$vulnerableA�attackA�bsia �%81 �outU=�Par:$sm risk de`s toward!��ntr&E�umE�o2� provAkenemy�)space�]$�. W^%� �!y)�!mgradiW!5 viq�is likA�to�mribut%#sel ono }�MR2�I'b c{-O o foa��subsetA�M�, redu4��a�=��A�&WunidentJU` mayArefD � �Y�persisto indepenM� addi�al facto�aAinvoke�snt def<su��=U2!0ej physiolog���str��s! 2Oh�!�QyGin ��availE�-4. I� bi8 ADdriven!|9�aAe leve�APindividual gene [1] ,e��= ex1#of� on ,� h� 9R,AAa majo_Ajž chal.� r�ec5#����cha eri�by�zi)al��E�� artn��[2]iusuall��v� cos�� vest��sTeac� W!�9�u�0�" one� ]� im�3ng unsu$%�_!��o��aQe 90�,,[3–7] ? In �N�=���,�i�� �anipuw�j wby���#%+.�Y s�� ��[4 �.��aE7raI�e!A��2ahal%�en!~b� m������Ycl� y�w� at a high� -to-��io2�ngA�!�!�rd)� [8 , 9f Fig�e]"�n�ir:�a}}����Ga czic�pl��an oblig�9[1� 1�U �q�ee�tr�� � � pon emerg���=7=edis�6!��Rree's�e�T%�ne}pro�ˉ�)Acys%��Ytoq0 �n�al��� fav� S�/9 Raximu�mb1 fu 1 " I< ery&�b�� flic���est betwa�t��2 6�a�!)�<at+ st 6&ll�C year�q0�+Ew�than 750I�es pair+2qE������s��5-A�>P ,� pitezens� study= f!m deca�. Wit�F,%��th�flo%�tyl%re��ly vari�)[13 , 14�xA��ngEV |(�nd�OMf�r  shor o�"i2&� [15–18!=S�upNel:�wY�n�  corre�ad�p-ndQ_d_op!HoM�"� ( wa�a%�����) 'AA"  cavh� � most long�vR� w9 ([19 , 20] (�ure 1thes��2 s haveɝsho to ref� �5�on�"Eaio9���!Aun&S b�:� 9 3g r e�&)�2���durA)( al m�$ &�inR��j ors' N�Z ly�%�in�r5�)�j [16A;)0�0spread observ�.?t�� u�not nearily��ly excluev,.���9�pro"� 8 �� g-� X ism:� ) Unbeateq�}—I �. b�kf dJ chem� lyA�� c��ag� .or� valqR  [2��&noޅ�ye�Yen *� . (� e^for��s'.�too)�%uu� peneOIwAd� ofm-[14�� � many]9i��%�1 ��%�AUien\e?Z e�or� u� i���( �Insuffi@ E�—�=��pasA@!�odi�- �o few2F!��#v� fill.�i� they 2 firs!�8t�?�";be � e�>6 [)cAl�a<?�� limi�mn�ŝ\%he  its� [��.� ��� �Iof 1�,<��! -�2no"`mO-�t�in\ a���y,��v��aage ��4ofe�du�" un�� [2�2onsequ/ �_e�1hyp� �E�fai� �.&Z �.tF" 9  �)s>@keyZ!�puzzle l�in%-why*�) ��6?: . Re , a!|rth�ib@"onk optim�ora{$�b��|.�,�lm �C . Siw O%A��� jT canA�-T/ ifI_fi"�i��"0����o�ndD.�die b�lay�!�H&ir� [I)O pr.~of� vu�ZS end� �ex��"fitnes�`?(* hand��� � la�'�`}��t� d� r4!p�f)�2))!2v�Gsuc�Mfu-�Vre  � /o�(*9yK "�e�2R Ie�"�! �8B~2� 9�>Eb.��.9�)[s!�ji-20 lives searchAaMthe� ��2{becl�' . Ind� R U� �hy!�ri����>ol�^� �&ed 5Ak.�� enmR> � ^ -ze�ra?��oi�2�a45� &raM�}!�z%�*E�s  s�� u�H0pr^ nc�`c�.%6xal� y�&j�i[ �dUQ,�B�.�be!�p����B6.�#-DG�'nonii�%2k�3 Alth� crucK in de95� beha�� !@q,diB%t>A������ �iA4a��$us6�is2g&�&� !�5e��%���2' ku la%8 s du%�a)�,>" UXi (p C*n�&possibmc�fecund/�D[15, A"I"�fZ� ! ubiquito4 -ө� a su�of%�!!`!w^� 5P"c�also as ╶value�m5� "j��is�Q� A]�fig �A�pa[ oi�o��qui-�-�se�h��.K An5�"�8i~��`k� �� eu��inM2�%F�=It!� *erc+ ��atf <����2�[22k7]��u ef�,��!k�duU!h�L�]�T 1�1kE�2fYpg")�iU+!pun.l�p same9� �� �d�-l3 ecis!Wmeasu�� . If5�ɒmw �$��� ���l �  �i�ll�%H��e12�.w�" i.�wa���$urvivorshi��w “e:�� _2/a9Sa���1 cE� i� make�on� t}-mw !N >RBUy͝R /�SaA!��at �6e��Fes ��2Y . If6reW>�gYv���m, we w����i�exe�{�\96)2��:cZ8>�Q %ʼn�a!!F .6�-�օ�six si� $in Queensla[ , Auli�� ,�E�&��#pa�-� me�ord�#I�m)& sign�a�:A:G.q #< qN �or�A�ek< ex� by mal�(E�mb�AP�s�ZQ�a�P) ��$&_�-�0�t#sy(�%�:W^'n"%�.. W�! R� vari�� <!a!��)�<( Wald = 112 . 0�`p <�*00�E�y I��K!! �]�/Н�s!d:�,I{80%�esa!e�to 0% �!v�J�!( β ±�'error [�_ ] = −�21)]+1Y �246 ,.�;��. OA[��*N.e �0X��2av !� s�Dtrong��)!h#�"���Lm�� h �c/0A)�!d re�5��A&6��m! �u� "� =�1�s��uget� 5� .%�%�!s0021�0) -�3�,4>�sup�ng �pi�� ��p���� P#� ��/far/I$!x �um)�-'re�, aI& "�0 mean<ye-occupq j�6���t>G�D�(o�'��( F!#$45 = 4 . 8i�=E�03A�,D .B#�"� f�H:H17�7� 6z�� �um siz61 , 66�6i> ~1~(���!�fF��3�VE�)��is���2a� �." ��.��*���i}� Y8}i~$ �A-�&:$O= 90%!��:� ��w� bLiytwo�!0 , PhilotrypeA��Sycoscap��[2I"[ A�N5,'"j� )nse�aV� , ei�AQ�umaP�Y_a�va " (1$�()�Yby�;�)�6S'� tissuA?iw -�eE�rrP}DX �: ���3mo�%a��ri��r5c%��Fi`A�5���'� �/��.Nu r data-'canJb�+ +FS “u"�X �.^�o%��( a�!��2er��.w.HItA�L,be no�", h**MI� �*Ey.zF )*= dob e��N,���0eF"s(.�might6 be un&g':{!A� *.>�we�7kn9!�IF���O1�M� Q(#lo�3!�f�H ency!���M�:t catego;:-,:>a�y.&�Ba &f � r1�**+@.�( TV� a��%�="�pon�  k� Uh� se�)a[ r!�� ihood!A q��8s�!"� 4�s��.E�u�� �*vz�!�P& (�s��^2g�(OE#\�e��E�$T"\ /a�� leistodon��i 4�%�s2t �I�tETB&,�:� . Tw�+&�3y,� (R t@� �"v � = 23�;58 5�N =g3)���oit�m86� j l��� "� 37� 25884k6A� N &;� 6 m2Y� �Y Q�20��J�(!rW;A��)'Ew�an>t� exce�/F� �( D� �Aun@ Se�-beid[C\��,T . SegaAB;Yu , J* idle�=�0Mu4ook ,�ub�8ed���KU^�mEi�1ma�kUyq@*�%%E2!�Y�Y��6�(U�\ly��veC- u�,8ci&2ˁʅ� genu*v p A � rehe�%taxonomiq3,�)�xbeyon&�9is3&.�aM�ir"�'ge�> phic�#g� !��BK �B�)� �%b�/9!Fa"�0�(e��, ['"" M&� �I�a�)�A��.�&O$� � sm.r1 reE& be"k#AX! i�>o� 'b-3< a1 . To test{&��ž ���.� �.�,ri�MalvanNa�EE-�)�/if--� 2Y� t�/��$�(� � >&o"i5 �1�. �,qua��a!�vEy:� [29]!�%� �,m� diam4 ��"F+23�57�3 34 m[�616EhIn!tr!*, � acem�3}��}2~1~75~� �#!9 �� ?$� %"ed�-d%'D*E� v�.`#va di�- [30]au�"��"J or�4�S)�yAv]r�4eP�0�~#]1�E,�� simi�GuD-&} &^>Ga :"O 5; Text S >X t�3P.�^ ae�2�mf�*2j ; ��]!�V� is n�wag~ ec� , nf B .�q�a9nA=Lų9/,y�did� ")+��� (M5Ma4p�5)Ea��g,a� eD -Y���( _Z1�Y'6_. L"��t�(�1zFimr����aaU75 ��2Y F%�,e7� �>c�%�~�%J-e�st� ���56�]K-��:=V�6�+1V0�� 6w*no:Xe,� eU)�6�y "H3assoc�bI� � � &�,>� b!��;ec =*oo�edhIh . OuH%�.�a�(w-how)Y13R9�� ��*�!�$ � by �22�� &m,!� �b9o�y]!��ovi C&�w�GY�ii-j  d6�]%�Ar�>75�Bsym@7is [7= A�!3�  ,E�rol� *so�32$3Q�!mob�.p�5{  !A�1ym�0)!�u���SIt31\�&�Hs�Vvi�h; tough�&��thick�y=l��5&4 ��.*�0A� nd h� ,�݅#���!�b��.* Kmorph�7y P%>�� "�*�of�� !�I�^> ���e�� -�N!upծA�1Z� �'��. AU%scH1$!�-!environm2; g� a"�ad� ag�!,�,.�t�a�+:�>by$b6ing#an abund%�A"af|�$m�in�to"�"��� . Lav.�x'o C��e�a�(~ a {#8.Ow"c e�-)�� `�-r5 ,eLq �&“pen7!!��A2���� H�t!�m�I .�^Na۱5b�7�2 s�J�?�8�#��U �irdA�BMa��ʅ� �c� b"�&^�n=BL+urod:E"+>f< help!��8lS/he evolNS�:dox� Ka�!�22!bge�ta+s s5#al�magnitud�*n�)�> ir%��[*�P�!m�g-co2�arms u !�� ��!u7 fd� u%t� a6b?�*�i�� W��!�H�4�(�ua6R9�^� B.9"F6�$2�u!� �%2��<�� untapped%��ES!�� s�!#�"cNlE ��aS�1�!���I�� ECBIofI�$D�*�@BW~ �r"�p�7C(��n:!-a%4A|�]V�%r �  P"Qva�l�5w!&�d&�!red)�gW�[31��U)eE >�outwe�=!<��tAOtnet]<%9�I�#�a^ very>aV �Y`� de�9{$-f �j6aI�U tD&�?tOP 2 6"�3!A�$� ɝG! w&H�bbm� >�as!.y� P . * 2M w��F,*� o��I"F*2��u!$�6 *i -�>�}�b,1!my%!lx�@FH>�"�-�� �Y�i8�m� @%�� ���� "� :^G�=6iQ b <�ϥցSrecF:Dl��>SM��LG��D���4r.a@� 6��3shift<m� �$� IT_X&�Iout"1[�33�MF@!stu+Oof di�.lg"d�>�Xirm�!�ɨ0N&��� p��A���';g !.R[175,2]!pA1�'G:b_. UnlessIT�Ystu>�;N�Z�7e%� �'�? logarithm o�V��|&@ ��.��f/Z"m;�f�E�-m>&��F��P&vCLmi�Smodeli�inclu�4:Nq,� um � mV��ic�. Sd/�EaA?]V� &Xf%A�o^<pc�4a♳��middli2\)�,%�r� QLb��:b=BG#%��*+ : 3�=a� �BC#n=QB<n.�coE�;`IolE�?'� %�5�>tIAM5� n�ta%_n��!E�%#a q*�/g�Sr�LZt�<�.%I :�2��!u["�-$� �(�q��sx"� � had #/vaaq a&.+�*->A�"�%XO�� �&�&%obl��w�Mm v�s VL-��{e�$a�� O>�<]� ( 0�e;! 5�mdm,2�"3Ye�1�%�es�9��h� arei-�DQʁ��(B×�th�> 8 �.<noni�ly �( 2�^�E�e�M_��u���w��aNR�W !aa�do�y���:�(�!���-��aq}(s .��Vert�?�R���U�3a � gJ�3E�4� E��2 o*�a&9L�aJ noun� i�i�CIlTL�8ebur� biom�X�Bo�NojFWe� &=aW/��8�StriIT} � �Q@Setaria italica xvirid�7c�.nb�+�s pogJ� %\�A�5�9�1Z h� � 6F�'�ial que�5�TB2� !N%�A�d�ty��heA�-destruc��� 1}2�!�� �^� moni �t#I�c�{ life p[�SI�fY;�=�]�fin�m Akf%n:9un�0w��\ Z�@!a'5M��U|@F�v� cha!H�!>� �,�zi��; n�a her�=�[ polygenicB �#�!3U locimKqH6]funU:�O �.�� e>C�Xn�I*�3ofRo-��sq��=�]�%c��E�of��D�=�HK"��S��@4*deYp�`e�IpoqL amte YE�inu� KM}��lel�*%��;-weedy @$q�par~acU"i�'2s�+e )�_&�$��"Z�dom������� �G4�r��Hm92�. Orga~T�Pi#i��Ylex!e��H���ma6. Ua�s8Ya�AK�^� D�3"�W�riɡste07�GF"D rw�i5. H�i�] �,mwI�one���2�. DD<�d$�=u�EKa7a�agrE%mD1 .��x� an att�7op~6>R�-rJT\�"entury�R. PZinv�Q!�v:�qada�eYiaBlp!r �mut-Aet�A ighb( �&� �dr�L� .�%>�+iroconcomi�P�g@llo�!f�*��� fAm�.� expe/=toiY�!�?�  GyJ� m��^H7(s hydraulicPS� �� �5lodD[A�U�� `c��'!���is@ �Rlm,�`. by�.�[%FAEMt�K��to =Rnd ric,!et�,�1a�Gb_R"ɟF ��-(:�,d LC`ErAz�V<��`o� carb+LartSV�� nutr!U �9�[e�Hc�In& rop �A�e@{ ='! �"�"� �`gr�+T[�!�=6Q� �8v� bree g(a�& Q d �5!���L��pq� �Poacea�%a famL�a\ )�@ EYreP$%!MbioeKA( 5�V"NH!no>�:ͩ'�.�%^!ermP�/t�%�%�3!�:�� �g ��ѡ0ly�2R; [7–P.Jh�*�97maX), sorgh�7sugarcan!Gw�U�ar�+s� �e h�N*yL,d��cQTL �6!6& a2x_E&f multipI"�  9/�A�ec+�#�P3EvForward"�sca��mu� &�'s��E�an WA�approanlo�y causY`286�#-L[2�7�"I� "exhib�f�3?9d/E&gaMic&;D�!iJ� ��*�s��� %��D��Ub� [�38–4pM��w!� �� 2s:1a�atY signl impi��Breg�W��2I� �.m ,. Surprising5D����MqE�e��� "et��-�2� i"� ? " �.�al� �44��A� ch� �f�a%��FH� ��)i�j��a:��=@ 2�i+�\�9ebaNdg.�al"�s��l�pt4R�|�cr%*� eqphenot8`eQp�=�t�Ql<R�Lũa�odd`Z--<putK�( 2rtechn�#iKgin�HG llev�& +�obstac6 [,)45a�Utilizc1��l -m�6� desi��J�ds ���$Act' Ms [46a&8`Eơ��� �m�PFur.<obVa�h+j�3� view!NA�;e�N�a��WfaB��U�. A� .� ' !e�us"356��(nyi)5Y�a;h�4ry.L%u{CF��p�G^*[x!w�W!�iba)-� disse"pMr4mEfdQ9tKe=r&aiT�@�-rop��m �D!V�F[4]<4� I!&"�1w6^n�P� �%?�-.5.�2���x�#i�#�"n�u>2<md>1A�~�rF��I ( RIL ). [49–51]2'twe�#��%pt]=�O� ��. A=�Bra0!� s 6R��|�q�s&�3 �un�$la fN8 AO�-s&7���Wy]Awcu�U^C� ��X�%�=�x� A ��h/eg��finQ:"�_ �2�m��. A5�F7%�=��r�Qof 217<�Pu����Xq[map��) AO2)�C���BBr5b\�wild-�E�I2�, A�!$0b�.3BDnY�:k >�s�b�,%Hu%&��O(=Y�5Our!R�`  @� ed�/^�sAn�at Un1! of IQA,ois-Champaig�Z9� ]��g����M�icA�p�O$E5a !\J��j�zu�4i�2FA8201�A coL]��N&}�~��X(at Carnegie�WtitIfA�S�W3%,Stanford , C�o��!qBellwe�PP�Fac�! at D�kd DFth `Ce� [5� F%fexp"� �9� South F(jV� Urbana=�&um�q!J3>S)�A&��5-f�btile-d�mAe{o���r�\n aw� A��she�Q� 5�q�RAto�v6�s�Y� p~��re-appl����,dr|Nrr1��yPt-e��dr�fp�!EaV< ��feYT���lo :��gI 9��wՏe� M�!��41�������M�{=gYF~ Y��%U(W E!(2  spar1t �ARFq�L��X d��po.$Stuewe & SC, Oreg0jD25x A��E�: (:�AQ��edu!-d\'6�14�h Dee��]u�� mixe靮75% P�,( PRO-MIX ( �vPGX 8, Prem�]Tec��Canad ?)K% {kr sbir}in�j$ot capac. P.,Sl�!.7@ ` �⥣ LnSd$�LpuvD��KJs e&L"o�2��l�@-U5��.,�ѡ��t> .Eat 31°C�1 dark23%��F � �humid!at 54| 5%%�Well-�]�s� back!H��5J9��ht1�h�asu@%`ci6� ,�$� s�c���Gi-�>�!�no"�I [A�ad�$'D los��bottom� e�!�;�{Y�p�S bag@ ��a� week�a�P2kvoie fi�g�gm| ( LuJ� LeafA� 0s Inc . , USAG~t 4 C+B.*%%�ŀ�( inch&>(�w)wt�t�0e-.}~47�w3�6�%n( H�� �nd#;5 �w$Osmocote Csk14-�mliz��Everr6_ F��¡V2�P5n 7A0�!�L!U a Co�ethu E�l a�utR+iod! 6 hP/8 h na+; l �nsA�a| μmol/m2/XuMday/2eW; iO~I�jAM^% ��uN "F%ňb R�o�i?sZ�� 25����5006�?#!��te�F�f� mat�5h.Y�n>!)e�m+Bz :Fk�40–80%�igh�Aje� ��z�z"��A2–3f]A6) �I�w&*�"aN(���a(WI>"(@)a�]-" w# : 16��(F� , 715348!�, 473 cm� PöppelmayGVCC� F US?95Q> MT38 �6�)M59���25 �6f[n�nPanicle*�u6}l e�#��MaoE\�~%=��p Om0Jsfop�I�[r5�[ flag�xYt s�_lfo5.X$ji�A"�ne�^�kj���tiv �(�48^��Fd&�mƅ�%s ͎r&e� ntCV&s� pack�HENBH ��/ C5 s%d�_�A^� "�[�(GJ�y�hr�%�1-�)%�& a� !/y-axi� �Nnt_���DR;5�to9io5MwalXpoi 1&~!)��2�(-_t'_bs'y�F Vy y-co2�,6�o�*D?f 2N(% roid-�}F�Uelq�-6atETm�q�': ,����+& 5Q��g"Uml5>� :AX2>" �wi5�;���e(�8 opy_M�A�C1 Ral�!�Y}vi)� %2�mx�o��y�eq�~� dHRy wind�|(j;��XM�h5%�#B�,I]#2p�z;Jn �w�xr��t �7�x 6.0.< �� 5�I���� of2�at�.%� �)� z�s6+)�-)( �)!�Gst9� R%��|oe#A6Q�I�_��C9/#ɓ� �2)3�Z�).I ��"�&( S2a��HS2;Y��/2:$���'�e �"sss]/Wof�%b "�$QU�. �b�3� SummarizaT �2�de�d�8P�|A��$��|*@�)i@Yea�V-�,�pumD�m fI�a��%�$(.�i�od does%B�Dat�&�(!�2�0�8�+h@QY$ ( S3% !�All9��iI湐Q��e��-%H>&=./-%�7`I<B2�h. L�,EZI�s1�g@ixe� �cont0)�A�i�S� cm )� !calib?o(zAD86����4"" K*���&�MW�D!�E������j-oi� ,� ��l>*�tap�b`@��  rec�>�*0 worku�a pD�. A d}8v��-ma"M�"x���.�"�:�Vu�!�% �a+�O w ( GBf �!I��`s�in [5�,5.)&��]a zl� %x%hNX��F�g�� ]�". H$4mo@��Et DNAex�3~9dv CTAB � [56nqu��% �a Nanod�'1��S�lro�E� [ThR"� c;�eta� , MA~�trF doub�!i3�2�Xa4 enzy1 Pst1�� MspI a2que� ch0�� comm�u�2D4E��d o�irc�� fragA�\� s [5�(1*Galeanup-Ag� urt AMP� XP beaH BeckN�Coug; BJ> , Ca�/ba�dbpn+�poo=h subm��a �8!��0-bp !�� n3s�wwo�$�c(a Hi-Seq la��[Il (; San Diego�%��$�'g reva��4.9$T7%l U0e* pipe�<[5�dRawRMfi!�Brem&�+taX�%�H�Dt� �h� Ѱ�z���� ��!Mancho lA��8�a�me#�! 2_1�hytoz1W,bowtie2 [59]x�aul�Ge�Al SNP �;m~Qii�[ � i�=�3coe�4�fs� an �V9))!ϝ# ��taxߎtQ�� �rrg�я2.!#%_! as h�ozygous\M!'ŷV4.A��n�and�R6��� Ft�8��ll:%�'ac& >�:� miss!M y��H�"te&,,F64�F612!�!�A�g�0�Q�ra6�R/qtl&�[60��Ge#$!Q"|"��.edś)�Am��7 '.��z�G��!�!�1 $non-congruS<6�~QO)0!.'��J�SNP� q�in > **iu�o�A��7U"+RIL�/p295 mark�elN��#158f�:vP' !��[. Dub�J!4�'-�!ni3��by�Iwx!zd&p&fqM adja� �B*� anҍin�O-h�/P�YCofBkx.>BK�>sm�>���e~ 36%  �6Gs /%�&@ �(ono �Cirrone�,AqQP�!UaB. N�\ impu�)Q�1��5��9��`lM���[ �6�5<X1� ��i�� .x (��@�!�if�&28‘no_dbl_XO’ �du�&5�EcB!�&)) �`5aZ ce�m�~*��KosambiV� �s�k*,!�3=�x�O005u Pkto1�.l;�s9P�1E4���Pir�.eY'1u��5*�%2082dQ � �5M�� 99�np�h.m��;iYLs_�!q�i��).�|:� !�A��=E;r,,b5�Mn3n �V1�map*7*` d. !�o+m![49 , 6�QVF!�com@G<m.�87&roaܨy>2MA��~sIH�SՃE��� a�'edTFar�4YXR"}lme4 [6�-B^�V�wom+�Q��a�QX�./;^^� �-��Gy� ��!ef#���Hula: H2&� =σ2Qf / (   +6 X h� / C�a  ) -res̓r&�*) �Y8���Fc���=a\&@u<$h� �2!"EA.^gc�o�1���97P}0a�y>��=���i .%�UpApiH4E�nat�6facH-� :s�6؁u 6��E�}:;nj�,��V^� D��(���p*�0�E )s�,k�-��7Q�$so6/ �+ic> � llVa� Ze��K corp�&�T�R%�Bօ:zANh���:p:09D . Be�)�� unbi� p[Po BLUP�Xc&hReR5.�3 <"KU�i�9)E�9i&��&�M!?�j�\�). k&a�F�e��  ��.�!���0A� I.%�e�mRJ,: Yijk=μ+ �i+�� j+ R/(9� ) k ( j ��8 x9��j+εijk���m!�!�= ��"�2� , μ3��ll� ,yi -��,�Jt�N}jV/j�;um5V��I6okt��X�sA&q�heB[!�(�2�) i�a%�0a�IiE5: .�^6�)� �PP A$j �Y�A6e� 5KEn6�!�E`�� @rm��EQ6�2>&i�ewG� s�`M��LJ3S�><�� ��>��F�b:n ɂ.(%�?�LF�S�sR id+ �ree-par �VT,�N!;G �rtzs  s*a a�E����st Akaik�� in�Jer~ ( AIW)�e){%G�Zd�g%[&B�{R"d >�6�6�DD !�@k�� ���UM%-�%e�er� �c�6"+(!+I �.�Bj �7 R�!1]fun��![�66 IA�FE�q`aFA(cus0 pyth� nd RxEip�3.=.![6oQT] ?~6u4e���[D#�)��   20cMu!arT$�)� c3MdjoV�< &�!�p p�p.���Ak��>i�va�\�o ge����] . Eh-2\�6'� �a�blog10NSZ�P�Vm�1�v[��u���E� * {JNF��mR'�*�1�.g(VJ�I.�-!#a��J �e}XKwak �:�ܚ16 [64]�BU�>��( S�2)�i�Vum ( M scyqu locu�+�;I&� �)%m8dV"!�.�wX&$2��.Yl��n�(&=:�:��-=�- l�uIdh`b˚QU empi��%or) �`8` �. �(  !Tas�%���-[O�linT)��+yj1f��}�U�r��7of% lo8s���c�9?QQ�E)��!a%����#A��x*M �mM�FFKco�2!1�4re�:_ ĥ� Q !G!�2��ni�E�N$A �E��ype II���o*<%( ANOV 9I��"s$o�q�_TFJa� -one�e,�Aq Z XZ�&Kb�1)!���icsizZ8i����zBW!7�)6q �1 sub- a��= *� AUd!� 0 vAI� ��s�JB:r�)s nXA���5-"^c�oddT�� confa ˮ��val �"�%��ache�#.�ort~H(ge� >2 ( �cOPl 5)%�y�!3��he 37v"���s.�:(�!me$u�l�;� .% �clo��m:Ra�r�TA�/ N p.�C�ei))��MOGDB� -��&“��&or“dwarfI�M � �]m��OV�,�%�Inn�� down�:�o`pecies&'�!���r[C�, R!  me Ann�8�<j�l�&T!�����sy�9&�>�!>�e ye�A�|$��A$synmap���#'�oCoGbm�l,eB�! ) [6DS-�&3.�:�E���&~%1_ |t'out�O�9a:9h&pU+�2F:_-:_�*2�7 R��roBLASTMwA� B�!@��A4F��#xq� )�ic�I�.A�)Q�Iyo��� t%e�7عiA�w2v1:��E2�w�4F��^�. )2�D�a�" )�� &m x2 < �E�Z�M&t.����"� a�S , la��ex�]��>6V3:�8_l3��ns��^!�[s�}�!��2.!i94����FJ8% "�!w�#ݥmp .�2��������Xf�)�(�2?�aAD YZ� ��7 y/�!�A�� or6vwe)�im&��6�I>sea��įg�()��+i^�{X�QmcR`2 or m�J� :�:�4 autowHd.�m�+�%Y1�R\3,��e�3, #�/,F�/, c�1�1—se:_ finia�q;)�2-D�-cNU !\����&�% �4Am?B�~ �%.� I�20�B�dhig" rread�Q2 >d!97U@*u0CA�i}.BMzlea�q( hL8�J?y\USOo� �bRs0�,[/;S4I� �/y&n &�/#$� ^!/�iof-.k 2I2�/�)mo0 82f W>�0�/a!����ŧa��&"�'i�as"Ztui�+ly sio+��&�aU^)�9�,�EoY�!)�y "I5 �AF��f]&w�!�p on�valid} Pls_&J&2S[�7"_b2 2�S ."� (j() XB�AJ/y2% vA~pb��Om�.�"a�1,��d����472�L%��O�5)�Z�� ,r9 *;^.�DT��V-����ifl)�  R��4G, DDPSC�*jF�-GQ��6�y��LY �8 �eRy�( �A�ma%!�Yp�3Mc-U.'tl&$ �> ��1!K�$.W,{-��A�?"w7J� ��"."���#�=�&���S5�o�i�pr�;5&�*�]*B s"9 �&)�^!C]Bb)n"dU:ima�C�Fig 1c ֭E�*�0� (p�'*&:��d ~�D� .7U"in�5co`Wof 146=Z�D(Q�dd�EKend9E���.��38�4G{�3%��s~7 0M� qwA�5th% 9 p��n`S:�Mo�A�nsPvX1g"����app�+]�� roF��=� �A�hHtm�5i�V if5}t�!GaA�.��W! ���i�" �)�jn@y �����KC��U;�e�K84�1:���>K2E% 6�W=�eWX7� �082 �"�b��>j�5d60(Q� H2 86�`.9!I5V,J23�� at��aVG�da&�+6����Z��Z\&� "`7),1 acǏ"�d-ԍW6:y/ofF� �X�re�LUk%�dra����ge%���[> &3 ��� uO��az)X2�XY�"r�.OZFAa'8�s� &.�"� ng s!Me˓d���{T <ziR&&�=:7"-�� I�'� ��7Q�.9.!]E5�p66�!�5�5���!V!��b.v#�%@!��8"t "�F= �2_ &� O <�.�RZ.F�L��c%6](�>"� ;��A�ND�dm@�[�Y""|V�)F���-A"$ad�V�Q'"] to� � nt)�blZ��nh��th�m�a��)�i���<)��"at"ke^�ED!�re���H�[ e�Au6v �"Q� �[6�8z-d.�v�t,5S�w%63���nq�$&���o1�% 9f <6/&, ( S7�GS!(*"\ +Y�auF+���vS2���!" �} � R�)Mm� ]o�E&H�!�"�7&ach��A��&� gD}`���M��"�  �!!xir&�O� X &�QL&����A�p'!�9f�krB9�+�F�1#Y��iD/�eZep��=Be�com��]A�zJ�L��"� !}���!Xth -a �ȅC�I�X�se|�U�6�� �Ha�i�Z c�o�)P0ithEMOL�.��H!�hE{�t!FF�ii�AMh )S����Zt-�Fu�kl�Vg��;Aq�,�75�E,�TO���aK8 ��o�YI�tro� ��5<�te�� ev3Fv���x:���J��"���V2�es=ub�d qw� �2~�in 3 ]@,S8���~f,�&!� �/#letBo�'%��V�l �U�=mmad顕Z�� r!�Z$p�s�zoR�`o� ;(a�� ��Cs_;O��4�s�B�"0 � �l�������b�(�V6��R�nd�6��j�.���ZR1nd �Y�8� :CNoneth�<��VVc�-�@ng��~V:n1�J�=�. U���s��Br!.D �Ƒ1N} prox�fhowzi:C@W�D%�jc6� Mo����+ ����a2e�TpT3}��_*����#.� 2S4Uja!a"W9�at26 �q�2'u!�!. z1�9V8&E��g�X��+u� �� ?�7@ y�a,6+�A��8�p��� ��o6�&�7?����^�I��"�.N~.h|d n>�D!"mk YU]d�>[,��j*�{�^�> stocks [6�A|Csa�s�[pr1%��18���.� 34�d @ �(�.S � 8�?z�u9@� ��� �D&NE�$ alig��; ro�9�!�.|m�P"u ��*�ue�2�A�>�4�%3��>� m"'[� �5WE;a��"*<��!� 1�� A i؊JJj,�F�?;088 cM T"& �5*T? ( S9��)@*�=i�e(C�(^&Gq�7uaZ�#es���{J�<:]�h4;:��H�,�_ag�"�!t� ."qAA{*Xu<�K��'��p buil�E*w;We! lyaYT]��H..?.!�opt'�,m�J.N:.OBMFl &�$xl�7C-,�y�6&�%�!/"�Z  nu�`1Q#��&=8�:>t� �?/-�f~ a �7of 15�"ieBasR=vZaaw~212�P��O  D 5jS10}/No*�(t ��-a3� �'ManE�AY�U��F��e grouq~to cl8b�liӨ�(��E�i0�:�X. .�1"%.oiu�>�lyX#q�THa�radiu����apHj*�5sN��Z�+ed� Na�E� � f����Y� .�'!�S1~!�S6%��A .� 6�d���"NV�da s( 17/3��!�`e U;)���>�!̱�>�v� is"� ]�&��+q"4� �0�Hj��1!C�${g� �� 0Mauro-Herrera�.� �s(�~ m&- � e�  .;A (�=: S5_419�1�\]V1��2��� ��:he�S�i�+d N{����9%ev�3 5w�His�"?/n~:�!IXmI) �� 2�.�11co:�=�R2,��-�'t�7�y�,�Cu�_v�2M� �ccr #I:733�eJ1n�B)��X�v1=>?&P:A}���e&& � &�BA_sh�q���. ���� 2�!�6Sunv.�y>RM�gth T�p8B~w���6m� ^S7�N�erl� #��0����in6�oNp-U&o&�|���Za�)�AY"���5a�+�%���F��o� �:}� 9_5225484J�)r&oA!��%Fj:b!%z)� �b>�i~� ( 13/-� �2]#~���;2��ׅ5�"�2) �c�ezQs)o�7.�+ڿ ��9:�0*�V1�:7���ns�R��I~�A�%�2�y�"�y�on&S valuIE/�)S ��' 8E��S12*� bjE , 18�{29M0 �:���& W(v �I2�b(9�ݬd �l 2:�� j��as��KR �2�, 8�]�"�/"�<&D� M�11.`;� do�_-�(hV� [�eVn��l�eLc &���f��K��1��U*���� majoe� �}|�!*%m[ h-�+aq-!~tim�� U:��:}F#�(�& d��� %U�aV���;0�o$)���m�4To�j ��ch�s�7]��&�+,ia1'�.� i&j�-Ar� pr�p � r9�"���.e�y�f?8���o6R; "9)"�3>�;V�)3�;[6C6c�*6!��A�bag&�'��6�G/2�=]�*:��=�1) # *���E�a�%���)P%�I�s�[thods� >*lq�P� � ll ca=bB�\E��5!�a��J�pl�?di�EO;��Ta��jE�w� �"6ng=s0a�rB3z��3 �J@�acrromos�c�t on c5!�1MNP1��K�� 1Q2 …p&�K5@�ea/pl *� �0&� -�����u�*��6�}��+.6�S9�0-l.�$2��TE�˵�EI.e�x�.>/"� Yzԉ )"B��w�?AG� e��,��l��0p*y~P!2&�f�+ib 0E d������i�w9�E>8X 5� �2@9V\ 9@35"v -p7J-m�V�,h �)��Ї��2mnY � ���05�H"��?�mB� star��$%�in�@�g� �>J��/ *� ��Mvr�e�!L���E!� 3�s40�""�k�Q, ku��V c\�_N���t�(%2/�:?!N�K�H�3~�3?l) �!*Fl*&�0T8�z�%� )/��6� E?,e��1 �6�A�dQ�g!�.2�c��,)lya�eh?% h#�p#6?��&©�lle&�>z}!�)*"�&g"+�1kijM�-p*a � ]7b 11)� Ņ!��c"e*>�}(4�:51ɍ*I���E�&�3 mA%.iQ�"S�E�"1un* h� W yJ���@.�**� s��*�!�!d���])"��s�/ ��&�G ��MDalD [| `u��,~!D�&"�mC :�>!+"o�4is significant�ly delayed in water-limited plants ( Fig 8 ) . QTLs associa#��with maximal and daily growth rate are essentially identical to those detected for height , although the time at which these QTL exhibit the greatest influence appears shifted toward earlier time points�Pthe experiment ( S12 ��\No significant QTL were �fie �eitherK day �1%.occurs o /iffer�hof this trait between treat��inAwetdry9I block%!e!� outs!�Bellwea%�. EarlyLe develop!�d , individuals that inheriI�B�lleleW posi%{)0will be shortE8a�oseFJ A10 Ii�9E�A effect �is! us a{Xthen counterbalanced by y(Eqe%Eat�%�a�l�7%�whA�!2.� increases-$m�8at maturity . IA�0e RIL genotyp!�re %B�� to fA� ic clasXI�o!!e%!ree�i:!% ( AAA )A�ll �( BBB )�combina!�s�)�E?$is discorda�( ABA:BAD,�)n-5s �9clearm�0�!+t!�sI�Y2!IsAQ throughouICA�th cycle _�!��F es ,mUincludAAe par��-L%@however , have anEe�?� �r�E� �c!�is init���r�5I0stage.h� bec�-�remainsDf� der-i6���iIE well-��ed>�Bi�e��a�N�%m�Mhe�E e�q larg!�-T��ofE�9ybute�o!|takenaP both%2!! BAB�Vin 13�C s af��yingq�ce�Ir{BB��z]� !nta���of ver�!!tha�!endŖ�# Er|�� ���in��is foun|a���as% ���contribu%�Aw:�������re pre���WE.i,%��also sa*�� onal S�%�� %���R�a�.A�mos�?:�a fai�k��to�9; drivA2����% %tak/E~i� explix�syntenic�,in S . virid5 r 16�20��:�~ �exami�4. BLAST search� �"utiafdA� �!1�j�g4a�� d(. Compariso0� w�stsY(�&ca� ofB%corlizE : 1QS14=^S� promi%acandid� �� �sU wom!w��e=�*m�� stud�A�'���oe�29(� )�!j+|.�Q~ZTrice SD-1 ( semi-dwarfA>� p�Xve gibberellin 20-oxida��$nzyme [36]є!  li ~ in 3�� kBp� peakeP�ee� Ps non-synonymous sequ�,polymorphismɧd�pecmcoe�2[1�An alter�v�.�BV%�!uwa ca� 156� awayi�J�(� iv3)��DN�u�ma��Na��a 3-oxo-5-alpha-steroid 4-dehydrogena9�requi��A�b�.ino4bioa�he�[19%�wo���k>�& u,eQ !+on� �eR��� �KnAj15!Q��U "�5 /D8 ( 83%�f/r%�A��v����[238 4% �y>e�� }�in an� i��w!�(i�$E�fic~*O M�Non5�NE��t��� B2vl lap% ��N�on !�J 6approachB�*� 5%Qr ��x er� |�]aFp7� 5@48yV0iMflibas�R(eucine zipprotei� volJin� � ng flowe  ��5ste [29]a��S V 2)xi ly 25��E�!�U�of k(��a|&!��!mon)5xe�103y�R^)9��27)5��$c acid ( G��N2�dich! �first�mit!� step�GA:?20m5Y��A�$italic D2 �^!nu�� i�iju�ut�HN�Y/ ngle.k 1h�dis�arm�Ch a�F A� ��lo�8has only a mino�if  , rol� �t� @mu�lis.�. AltEt�%u0%"s�U�wit��J��@MG$1@49 , 3@67@59@1E� 9@54�m h�i� icul`c��x}y� !>vya�Mĥ%5 ơ  :�"S ) . B� $e�i�-fb�pe*+ [7–14]A�e lackaunderst��n��tempo]��pla�g9 *��N2V . A �imped�5he chkng�� �{repliɟ� sI�impx� 2�; �V�!�t� repe�Oly meas� A�t�nu�if�>Dsystem0 robaj �det �tegJ �'�-put ph9� plat�s[v� �hs� tacl`� propor��energ� a&� inv� toB�"� Nge�ve��mas)(grZy��!]$rtant feed�biofuel)0 s [2 , 701��As dem����,���a�%$ fl ency^� destruc!)�e!�F�"�U�*%ofe�ed)�*K12 coordYe. "i�*u���AUe�&��� ions�*I�2�is �!R�Ey�inu� 6procesQ�si�Awong%'A�"v!�3�d�6���"�Oua1 Am�Ik!�Y ���mponePE�st�7&"ce:yre�depend�upo"�.�. R(��$pro��* $“core”�,am �establis� :��key el�!�G x E!�pon�. Twelq��"d each;!&� 1�t�� reg�� ?m=iAqD >)G�y�hin �ye��$,B� ��J� �)��acrosA�b!u:�� ulti�#in9�r&) M~. OverA�� ct g.! |����H��KongruA �a��} /ofq~� ed� %-�#�M�����E���F�5�Ż"�N, �j O��s#��+*�&2 "��!r�2eA]]!D�* !)reed , as�:` �gtsɷum �% . L=!���-� numbU!E�%)+rYB�Y1}1D�OA vas�Ijo�#f H-6q��>��J1BC)*-#dynamic-$eM-��2{U�#l�(2p�ia�s!U they9m~�ble"#�i}!!�F%�}I$s favo�+ com�U wild�� !r>>.d # t�Lc�r� A��w%/�,�aha�+]�.�� rapi� ّͩwhi[heced ;0 ngerQ��$��e/".*�Y�!���&Wfo =1N�Le Poacea&�M*; =&ind"�"|"����d n�%���e� �linkaH!�!"*_marker�5A#���ly� �e�!��N� �@$�r5on!�l_ fur� 6�(b J.��!s *��!8%��+posɿ5`�I+C}(wL1Ddiilibrium afa �Z�SNP .���no known�5w5$I0JB+�F�ey!�ulti�novelQ~�a�M!D�!stark��c�� n rank or�&amT 9 iAHr� �F�,�Jpe�s&h -B �5��oF���det[ e�ly:lapM�"�,�&���$�onE�ew flic  ! s_.xcon� � * v#window�KP�e��n |�' P*�Fac�"��l �4 30F0p �e t" 1". �e@�W)a-AQ� c!e����.J si�an��be!�iab�ll 9!2 �E �]AJ� �nto&�  seed��'trans;��stA�2(���#ng9�"�#to�U!�A� mAe�a�toMOE|�re�e >lyOomplex���� �$ map ',!��p�� �bAj�+� divers�rmplasm-���Yp.� � a)��y tigh���ed �(�in bree�C A�}tools��!$o�:�t>=)8��+%�2� �!a��$��recip�< �=!f�y %_se. sh�b�� 1K3��a0) -�  of foo6�$crops . By�biX&ir-!)pL��Ris�.} "1a�� deg�. �c!� �Ya�%0w �m�*O.!x(/F�$. T%�1�'�/�"� �"�. act� �v*�0��B>&u A�żF� !uh�m�qG1�S ��8� .�#,?qQ manne�0emerga4  hto� &&�-� adap^ .%G� wetl� �Brazil�$ Pant!� h�+�a!��)�%�}qj!] life2s$hematophag���d��92 � %�cir*Q(zoono_(arboviru� A re��$*!!@Nhecolândia sub-��#�ree: r%�(e�3�.ar% flavit�2m0!mWN- E�Ilheus ( ILHVz Acb16t�%ac se! sv4hor�,ley�#b�_,5-I5A�J�U5200�4 2009A�o ext ݛ, w!����234 ad- mosquit�'of�%�aJ$Ya� 2010a[��=�. M G pooA`mI"te��#ss�7fo��3%�)kon C6/36g$Vero cell �&H� nd@ �$� or5Hal RNA�8 up-�*!�-� RT-PCRn�+o 6F0!�50oengorg^ emalM�meiAe�5sca�+r�es�p1��%�by cultu�nV7 �B�A�d��4i i-&� t�2 ?(� 100�,Full-�� �'� E���ed 95%�1Ninth R��axaUI�� al�(3!�'Taxonom�V�1,-j ��)0INtayam\group [3�%�ca�omai� sympto�cYsS humag6�'r� �d�#Abphalita �" )Drn South America [R[5�HWk� �9!� i �$Trinidad ,��am!kColf  Fr:h Guyan-|, Ecuado�5$Bolivia [6%�78910 )�1%�%-i�5lie$�%8~4 ���;�� bird�C]�A��U�in Cent��!69primar�<�M[13 �)[15 �(�j*�%uNeZ T� er!D��&&s�'ne��keyA�ma�&d ��ntibod#rv &neu�iz�� � for�}�!�{ocd)B,F!%�[17AOI� 19907��K6�w� Sin sout:�8L Litt�#s�abA�S��e9  an;>q :�a O16d( u�_c)1%oa�*�g�Uwest- A(M�)6^gto �s�/!��.� ��O �)I�+09��cus�s%�� A area^�j� 2�� %e*� p; 5��0�4���of�A�al�� , Cacipam�( CPC� ,B� ( WN  Saint Lou�0nc���( SLE*A�E [2"�&)�2o G �.�3.1 floo��surfac�Gag x (14I"��km��� %ais� i=i�"11*� s�(g$characteri���se � ~a-(physiographu"h og3.2���#A�7 _'�#& �:� 27 ,�!1!�world'sM�} �!�ubtrop� lakes�|�/s%�:716 *[2��2�!ca��.@N"n 2�50� � [2�:!��W �W �W In s}7!Ncarce"� cer "� vec(4m�%��� �v"dю"2 ay� l�� �#� ^՜.�A@%����� [W- , [2GS*� ��s6� �� tv0���"� ���>�n�bunya�$es Tacaiumt AjMaguari�1)Cr/4h* ��A�>fG���&�2W��,��,��M��1���!N 2�MPr���͆jlR`in1���2Y�: &� l�.�E��K�j��n� � g%^��I� r�7�5 ffort�! �6;cur�&lv9%��� �W�2:X!c[Hq(dN�89�, �� In Octo��, Apri�F��atk�o ��f!M�?at8�random�e �!- beef ca' ran�5��r�4a�Љ7?(6� ,�\��%�ebofy�!fF�(( 18°18′�+ 9°15′Sd 7°0 <–55°24′W ) >,�:8��'�(!�%��%$authori� vDown�o�$��^a3sa@d�p�@�L >A1  Ethics.� xf Fundação Oswaldo Cruz ( Lic}&$ CEUA-FiocLW-1/]6�00ocol P-74/10- /AU�&�InstitutoE&Z;+N]%Jeso�&U/l wre�&[L��_l!�J+� labo�y4rQey)$ immom�c!@ anes�jia�%Le�i&by"�"�Gm=8�  ea� e a2��ic�'.n2#7�)vt��b��of up�5� �&s_5 sortj�!o���:metho<s~Ao��p�,�!�g�(,t�?sto�70in liquid nit8=���J�vi�Jcytopa��(z E )!�&�plaH=0�n*IsMN+ar�bt�� s [3y Briefl>olsI�75C�: ��%E plac%y:propylen�4p!�2 mL tub� (copper-clad�4e�Ja�1,$of BA-1 diq>$ ( 1× Med4"199-H < . 05 M TRIS-HCI�% Bov�6,serum albumi ,4 mM L-Gluta�, A 35 g/L So[bic- n-�D0 U/mL P�=im; µg Stre�ycc2Amphot� in BE50Genta 3����aA)o�U* trit�?�2� ino)wdu���A�Y *pre�� 6-�G �; styr%�uup�ah %���at 28°C�37 ,qCi�,,A� 1 h �crete moeYz y��!�to optimf;� adsorp* . AtaV�44�5erie�3M3�en�..@M8 DMEM� !�leS0, 2% Fe�k@n�A2, 7#%V1 M HEPE# Non-"�Ps AVo�7��MQpyruv!�I8�NzN%�ad��I -�M1.Aw5% agar�4in%$�4%e�$2× Ye-Lah2um![ 0× Oe's BB! +!}�%Vc�.1�8i�$�1�>n�2����FFeE5E:�.�$� %1)q}qNincub�"u5in!~ CO2 3 10�$,%^%eKS!�CPE:p�>o��i�<�)�Ś2�i�at�� E9�n��Uda�L�0&� 0"6 #%bs�;%+  �&Z�-wETa�Both i�6 kept� ��W�@��A Syb�*! Bf ��un�$al*gof*���a.QGa��a��"W�al nucle)<. F<,�Uext��J,q-�n x-*�us genus&�If^e� �QiaAmp/ki�Qiage�mV;]CA , US�b�a�eT�:2:�6duc10�?!�� �X��pr0 (��!O% 2�.�G�)A��!hfi�+E�aluN�� .�xQ���).�-�� @ Sp homrs(��$��MAFFT v� 017 [3%!�treE aly��| E|aA�l!Me�v[e�KE4���A)��=$um-likelih�,�q1A(a PhyML alg�6hma� SeaView 4 [34] �3��ootXAp r�8�+ Geno*�%@� 9$e��`)(���His�3i���u�B�fo%!�NCBI Re�?�KL:x%j�(D12932 ) ; Kamiti Ri o u#05064#C!if)9 t6(15(u�/Bl 0860 IW�lsbron2C127�]; 2�%���203�M; den�F 464DV:2147 �2>�J�6 1477�23>�$; Kedougou ~ �12533>Zik])gAro6��66>�* ; 0994 ;Jap�B} ,143 �Murray lw Ec. *�,m� �:t�,16� ��C7� r!%��;wh3Z<�"U�n~( zRA2�B �16�: ��hX(X ��,$$equ v%F;ff9A.��c6oJ&1597 �lcaud{o" �"commo�!�P� @Mansonia pseudotir�)4( n = 177;m] , 6%�H*es �� \ �%��-(q2o..�,%: d fluctua!Y!�/ ���  wQ9 h�:,!&�&Z7�Žc�use�UrOae!,lowii , Cx .,B�ordecla�ch�c8�M�hum@i��re)g)!&Y-E@( 9Q�*9d)E�tV: Ae ..).!� ;t�vat��460���2!�%K%�A�*jes1di#t)�MWUma�� c�Q bm&I�e$�Q<294; 64{!��Y\8A[aO7# fE85� 11 . !O-�^ q) , 26d@)�*D>�{nyJ�i]|na,pophi�MbehavXN no&,(fore)�&r�abont)s6�N#6�&�9E��W(quefasciatu[J�%�� EP]LMoI�q�x10A:Rt�{0�{0}~0��33��Q�VR�� , 215 ( 6a 9EkAQ remoK�{!Owa+a�&'��C3CI�Cob�e >|AzE�A~(X3%�mene�2deN-Lag7e6�$on1j+enI�icY�. ��292U73����jI2! G�B��g�2w!9L>�2>A2�LB.ys�a�6�3��P%�3r16�<ay.t-���,!��N�E:34-bp2�c 2>-�,�\as�@lU(�d���B� ��A(h+j Gty%�2. #. PE1636E>� : EF39695a~�!{ha� e-�DofE/r*a � QAH588EuF695% �0�of 98% �R%lm��"g759!=)�,�d���wh�E�f>&4 Ka�L�.&� �axa�simila(E�ec rigi�2�tf)�,1J�q$A8�3� RC:2� "�% .#lA6&\{�AS!�En�9&�H� 1�%R�FSE80�:�4@!��� P�KJ,\�Ep2[E2A�Kof 44a�*�Z&n�-ndh��I QH2.��� ��%f �E@�;*Iinser}c� capsid� �>����T shif&Wi��ue E24�37C�s 166�5T4; � )��M�Q�!>.Qq��(s BrMS-MQ10ede�I�!/publicly�#e�C�6 1L� "on�KC48167Y9�M�� -rM��*� V6%o�%18th ���� 5:35am7:00 pa n��r�@�.�E!�r�$cia�goi� S� alO�;\@56Ei"� by���.k/�(a6@9t�=d$�f�i_kn�D1��'1[��se�R3n&�7� �*%�!<& ork�:�\�q,v��M�^T,6F*F u�q)�!�QT%�a�>2� �X!��� �.� Q96N ��a%>�.�&T,��$efficientl�ol�y3/�etw �*c[3 /a8^# �laply��c��Rsusi'�Wi"y:(�"R�:oi�25(��0qeBE�q�of�'dUc*{:-��U2T3AX�Mp-"�5fc-�Ed>:ic�!�=a[, a!��pat�f!P5��v1 "�`�H}:� ,��"B�m�`��}��2j�^�9,E�B&�;���7te.���B�)O ����>��|codm\���61!�,'�ED]A7�Dorm se�*a?+�Vur�'A�k�)G�a9�itself�+ � �4 y [3�0S�� #awl8Q���XmE� $ular pathw&"� pl&�[is-��ng�5e�%KU)� ��5� ��[3*3*BeHE*���E TaVreA�H]�)��HhemL- �  as yet�fiP . Fu!��l�Estro+c"`6z)��ce3;�u�vw�J �[ ���D%8Z�a�of2�q a�R�A1 �. Much( nun�rv� rega�Xg��&sQp,I"^4-. FrB�e=!�K>�, Wphe argyritar� B��vU��!�5;75���f;#�@% f31i��cE;�LB�-�3Oea�t��Mi�d^�9-*�e07�5 V%�-�.��O probzJI �[a�o%�an�\ �[f!>�V"^F��nsmissA*"yQ-8 �.Z�; heal�ton: �!�J�[4z,� �l��.�")�6&f=i"�5�r�-A�iD���-o�>1`*o- ���, 6a�2*�oHo�e�(E�?>7�N�C�!.�+6�; ; A warra�JP6-=��i�EF39��,� 8ill�D KE.)�:ci; .�?Scab��� e.!.�es�Jr�F�=] glob�;;"�v�o�4ly��er�NF/A� truly negU5d u�;�;� Fo�s�T.�J-�manag"|9y� Q� burd�&Q`�GvVCu�6{e�toU;x��� �` vermMr�jIVM )�� insu� � drug� $cA�is&�H�xidFMOX +{m�Tadv�Hge!pharmac5opro�se�Lme6*�i. UF!� r�es-�P�3pig��re��6><&o rece!+�ly}� mg/kg o��+! 2 tw�j)6no9j . We �ua�"^� anjs]sse�<�~ �\ , cline�le��pruria!ELISA-�J ti-'e)i IgG �AA�"d^< Plasm�2sk�c-�kiv5�"3�d�t + 14���Yl/MOX �9ut�wo!>9�� -freA�!{ ac� 100%��m["n�d untilɰ-�H ( D4�,a�/0to 62% (!� ge 2�S)�g!�aV� IV2� t��i�th. C1�)t�_R�Cn�< ���Wis�2!  ell!595R75%�#:�!�!Fpe��~9E>Vn�Vt^_�!�: �reL ��!�’�?tiA"feR)%�e�t,long-la�9�.�]y.~�tez�e-d�/��)eZa��AD�*ecu�5asup�~�C�,�� apeu�)�:achE1�. �a Q �deV A��J �eR��/ [�(Itjw�C"�A�!e WHO �#!��/�� �Vvp^�7�$urg.�Sof��e�7S!� BN��OolHW�Aw�,��"3 est�BdÉ100v;30 mill�s/y�X[�I�F!�H�T!�[�F1i�Hnot6Qmorbid�4paOtula� �` �~vul�F�, �8 g . young�ldr�-�Gn� �B�q�!IՁd2� qqB ��te A >mAb( NJrn AulD.Fiji iss ) [5�3mFScratch�!���disru�=�0��barrier}��Tid7an 9H~�D3 b�C�Gw��P�~X a�d,��%{����%�J-��(�post-s26coc* glomeruTt phriJ, rheu�7�rt�A��8A01 I:�=�"�w�� ris�~Q�outbreak�?6a��i�<:�chHA� eldeANcu a�er�9��os�Tl%�1a�17Du'p�|leN.� �IY immuTu�Vmi� &t.4 HIV-oHTLV1-{A�at� }a@�I.u few*��m�T� 1!fai��q�i�T\� a7l�k�Ma�4s��*�!r 8b�s�8nzo�/,9Ut�'o���x lathA3[sJF3 E��&�h ; �I,��!�o�>�~9��K,�� mass Badminian/>�:x;%B s [1ec�e�u�1:C�]ooE!e ! F/�T�1�}8as"E p1 t%?kDna��2o  an ovicid��i��\sh]Z a re"��a half-�SEre�z,&�\���G�<e%$s! u�"�"dcO<u-Bs"� )l^x "�u�T��iC6 �;YC=�Ga$�[2cGVGa��e�>� sprea�4]� in�B�X��M�orIQ\5�hD�@�c�D�os�_ [�DF�nunmet �>DQ,p�� A�J� �$Oim�X Nars{nAm� �0���[>sx� �1OXj6\hb'by��w�� -%NtoxicoB� e>,Q:%�AJng��� er mea�Y�3� .`�M�2�[li"�#��4�1&�~1C� %��\�R! ŊՇ1s,�R;dBex3;A�a�;N� dev�xby Mouns�*t a�3�i�%APe"` s�e2�\Au"� ,)la�A�1�-{�aB� a?� ARh?]��d� � E�. B�%�5p 2,#h'5ini�-�> ( BD Vacu6!BD"Q�xuVUK�P����_U2�% on D��Da�a'�K�MVDņ228'r6 , 43 347�w��T rifuPS�10Hu�%at R)g ,Ssma� "�#._4al biops�%4*�k>pig� neck� �i��S��!�F��[ane@ 5-mm |y pr( ( KAI Euro�bGmb�?G ny3A�a-ҁ�uTrmil}Q i�R Hypo �h ssue,t"�a( %b� R\�v�;!;M) �9 �c�SR,�*'b -�5��?i� ro�N%fluoresc�*G�7Q%eI�d"�U�val�|d� cedu�6 C6�.li�di&n�"���99�= ay#1Q 0 ng/m�WEz����sae�&�]L�#05DL�1M P>arame��$-Z calc'x��a�!-��a�I2i Kaa�"uN�,`��&A�InnaPh�6(, PhiladelpnVPA�+��� ��2��X:( AUCC�%!v��mJ ( MRTj$6�ev5�21<�-:� ��$ fsur� 2��-!!�)@`y$hm�#�Fez�ol rul} ��f>K CmaxJ�ime}( T �e�6Fva�< plotg �i�� T1/2*� a�a"!��'M1@ric Kruskal–Wal�,H �)<u/ �E�%�$���� u�՘x=�6�FhF�3�ula: E�X<( % ) = [ ( C–!�/C] ×��7 C�LE&�#3Q�� ��"u �%�T�=�Ie��XS%s)���![1 "����-|>�#5 R"qs. Mpre–M� ) /B���e;% OfGr�P>��ɺ����urA�4�6N!�/XV�G�"E!�#Ӎa-!&�Mpig-�e2A��$or6�( p <�7063��u" bira�Sbss��mCx�q� Gx�� q ( zero'�)nejZM Vuon�za�YSTATA�f12.�8EL� a�ex�a��G ^fpt�ev( %OD ) �J�riy'inOD� −ODNCAf ( ODPCUsi�3E?UOD!���`umocXof9/q�ZHndp#.'iva7�| #.��A A�Mn�tup���d)��� Mann� hitneyȁt�!]Pd� L sig&! . k &�K�C nU7E�vi�kNeaV`1;v͸�1re .�O�� et 4 week�}�,*bz"qumh�(�(,B� g*� N/-� )�ti� ;7r<stead2\�Q9$."v�lK �m� d� D��n�I �Gs�risen.B�p�iD sc{ong�_��6+A_����w5 ig#E=�a:���#�wi$.GI�)���� A�3��2y�!�erm� o ԁ��70)s�*Z� p "14z7N�"87?)�*qy lz2L6L.��q1�YleF7�r� �� E�"u'*�P47-/ � (o�Dex� h�Y�d�-)m( enh�tdE�AS%� hair�=��>� _=. &�r�P rE2ut"��Yd),!�2HO-G�@!���an im� �a*v���o�E/�D��.s1B�,!01,"!c�*led��]ʹ,B�yJ(�+�/��)acki�Mg��a?! Be���w-&�p#' flam^o�${N doX+ ��e���M� leAJ>� �s �a�G&a�� acar�E;i9 �0N9�0N p$��y�9)�uv D14 onFm <$� 7! c� �`�FF���-p ;cu��: 1�mFx( �endM ��K�<^#b�I�,�>at%c2�.�dݬmdiffeQXh j yWm�Ka� �u���!Onh_d^�s�I�4nd�.} ��E<g.��mr�so�PBFre� aZ9�h�5�i4��A�>t � [0arply%�3H1�%�a�S c�(��Ol��/e�%6Vep�& QB�� beitE/�e_1�. Pg!&AA�A�X/L�_��KZ����"de!��s �!=so-�ed|W syndrome(|iS"hdͰr��"�*�ZUI��h Vat*y�!to �r� Y9[4uJ�:5��"�e�Ra��&f�rs �� "�'�A�’��*�k �A�)4���:oonu� M���, �ZeM ,!\B[��. VideoE� *�`%%%monit�x^K&�=0�!�k&sUk}[0��3���H%�U%��-�!}tGL "�)by Kessl����/.�]3}md1z�0�am�5%�of �� }m��E�6(dfb&�-out6sl�%�2/�w) conv�J�7*V8�taE.e�:�!�natHS����� ����$ rele:&%`A�n(�h1�co��@u(ln_)C�re�treI�!48'!�ex.� ��"xI�be direc��rڕ�6be2�+ &7-�c:�uab"/T,C]r<i�QL�$rk*+���- �#�M�)���soqO/.�S�-�c�&$ I!c3�U 47a�\ i�ImE�:E�l�&%�S�w��r�ua/12 TJE�POurB$�caC� �\AM-on�n aթ� �G w�B[43�Ii�/��"�3[3 4{=&4U���[J�5�&Her�-A1 &�mg�m 5V� �$xO%�qe�\�oe�5���s��6$Lifschitz �;�  �%,l xP%�U���R�y5rvI6!��Zag!:pe�Ebe�![A��*#it�M3��3:a4efflux �kABC�n�[rs� , 5Ձde.� ��nda�ah:� W�A��0���MACIt# ’ta�Od��36m�r� �! i��Ba .��b P-glyco3sub� !MA@*,o o�,D`���.Z �Jl�is si�| 35R5"�fm�%a+y�1ㅡ_A��nes��t2!w�$�e.�)�. P� ��!8 g�1prQJa 1����oeI�d-�c���.t.��&[5e��!�p#yJz4!�ve�4��!=F s [5"�&� � s@Nsh�yb !` =�l[56"In&�'�� u&�-948& ��n��Obe ����)t"�"YG��n&�fB�I?9x.�[5mIgis-�, ���.�manifeM �6c �z s�R�r�"[5�4���9 s su�a>p�&! ��R'� �)�]��60]��2 ��*_ ; sca�rryt�vE�cr�)�_*�)51�n ��^ad02_ I�aO�\d������� ae��I?V%�s E&b�`ig6(n !"wAng"y.3#!A�ew* #E�A��� Jc �" . W�n]5sF �lg�d[vU�%A�S1��9&; a.0:' �K�kl�-R���#A�)MoX "�+B �e���zk�DPam � �5e��6�6�l docuA� �3VM�'ur"�oorer�H"U i ed %b��&���h &eLI& ��ip�QM hyperkeI�,�+���(% w!�l��fa1� ch{1lI%to� ubE�lLbexpp"��1��:31-�9$a�oNE;�}�� "��x �ini�<"+ti7!��Fura\m�me'0�of>��W�LS&k,A��umkJne^. 2��� [6�NSeX$Ep�� �.�$E �!m%� #�t!`A#y.&$'. E��4�A�;�ea�>_ �tsG�)ss2Is�cer/$] oH <"�3�&��S9%E�qo�in���n|yw&����=CIN� g�9t��t!�a�d s [6E�ir)\�`dR3ō �-996 �9M�9^"I�6��+!�ng �^8beid'n�"� '� m�&� ��6� A� ?[2� 6�C�1a%fr safety]gm��e� to�vli��g� �-aQ�:0k a*aQ5RΎٚ-1 gen:MDR�-]t@�0@�,)em�Cs��i e:��#��aB" se I� y 5a!:)� �9y4 volu�h _ ,6�Y�+-t2aT!xa �#(of 3–36 m�!`*9�K� -Brad�Rs67� Las�Cwݰ�!h�X�k�gk+�� deQ�!��net%m[po a� �E"R2*�0!�r+>A��s\] ����<kewis!D��/��.ؙ!�#W�r�!�!(Q�1, � lly-�{t6y^p�0~ &�/�r��a ��4"� !F1�i�)�iw [5����9}�F%x/� �/� ���xt~��w*6NZ�alsG� aD �=I�!�n��+z �jWf�1!�� k  1 ny yQ ,�&85�%�@:hocercia (, d�R� ree-of-� geq��P�E ic Mv)zan D5�P\�am [6O R��5 )�y`AkIII�U� 1 s ["��*���i$2' r �v��aK ?"� on:��N6a'*�7oI4cTo�J�-��I� y ��obj ��i[/eseE���n64UVaR� E� �!�=0eg�)o,rty-subr@$hI!� [�i �!�yIss��J"�MG$ �re�1 uo pur&,� patc@ompB�C �ka��C.\!�� !�= �cAVof�.i"�? d��a piv�q�*III@���.�1�S!�now f��<Ull soo��" [7R N�MaUib�t� �u�E�����,�j mole�+l�X79 &o�%�2*� � a(ys��d�0 o ex� �&"lfu���ZAn��pDOIe"|7l ph�do�ah PG )��3a �n � 6J�y(�+p����!S%�(tϵ m!=�%e!A�:$i���2ac;?�Hc� gT]n`�~@a}%��inv6�) ��%��E�i�t-| Ssi# . Staphyl]8us aureu�7a Gram-p+�f atho�grenow >AycR ��-�;lya�Avti1A��"�:A�"8.�;�Genc� ag*� ��PG=���5( 9(�,� !N2� 0 orga�,�IX�5a gL` *�!�^�7�al6�1�� de\>"�SM]n[gea-�< 2� 8dae `@-�-"wi�t�;BnooggH�orE1 p9s�qt�ng,ɍ�p��PGz1y catal�g�yy��p"�p-b� ng9o, PBPͤ!+bi-q�!&BP�LHoL��PBP��}��&.7*ɍ�a~cpZ� ���2���-�ry@ me�s�M���Owall-i��.�,�  ly�1�A�dii�@Vimpai��!E�8 Dros%Ya*e IY\i�p n�%@�FtM`�6�r�u<, namely PGRP-SA�' ��]M�+A1 ��EZ?:� eWe.N�c�j(��aԄ� �q� Z�)�r%n���hp���‘�2 9�of.�&���1�bB�!T2R2>�d�! AF� ende2���L����3k�A��6i"�YK.7:� ��j��q@)J~|� � ��f�9n9R�,�<�Gfzx2� �W %Nec ��ac �N��_l�9��p�>> A�s���.dE c��:b ��c�sU��A�M'�*�; crui� hierarchyS�J � � ���HA� im���Os �s"A� A�r` e(_��A$�� -o��c+J�� �� �-�i��� inq)Flso� �֩(��bx y�  /(�V��a��wArlex�!>� KJ�%�Up��*l,?�v deca�agoӋK'Qyet�Oy*��9"�>.!�2$f� 6Q(a��)PG�& "?����*| a��8 �c�� Iq�V � ch�%!^+Dng N-acetylglucosa|x�dmurݞ%X�� ��-�� by f!��� �e brid�X i6nmes� �ess-bea�saccul ��e�Y��Bl ��� $lyr m� turg�?Z&�a�g�0VG!�Gc?�#lu�=y!A�u~�iv2n��ny��g!��s β->a�nd%�o-'��r�(�S A�� ?f�[�� �ia!. DZ 1�g"^q—$A#osy�%_ �e�—� &dR@a3�]�jL�E'A&ym" R%a*�X ��Q u�toW.k�6� -) �E!ayeI)^ ��laRnd�2cm�MBK@^��gesF�f�(!�.U����=�t�wenE�E�m�PGi%����IaEz2��qA&�,�H��of)MšsDZ"�+�4hyp�5-�Q#`' W!N,�o��Gin:� qEte* y�v� e � av�bex�l�`-",� ���-!�"TT d'*� � 6a��M* cyq1-�n vor�awaFb����o�&S&, Esc�c�;col�fBAC����i':,I�12%Q16 ��� ��#3��m$�ixG"�o unrav��&.Y� 27 )Bs,$V��6��e �yj 5�*��%�/٫9�l2iOɒ� �/%�� -4!��FicS1-.> *U ( MS�wb�^ExJO@�e�� F*B6ER2Eɹlp*�n�} "a �2AA��IM|m�� �A����gͷA���affin�E1� .`[1e5�!�a�r)A� A1�2*p �e!�0eb#a��blm"�tuEƥ�1�zJsp�9M5 e?���snTP)�"�.�E divi#:�;^A[y)`%�-GEB�!�=�/2�% �\����� �G��D!�ZT �R�inIYYW �A.���!� �doE�BP2? ��p���1 A [�&�6��2�d��"ofYZA������,�2Ad) �%(heR�A! ��A�" [;& PBP3B PBP4?�M3�hg-� �t e`�!$s��lWU���bV/m�� %Ma z%e�f��igʫr,!�ed�*[1�+��� t*�Bs*� �R�6o�y-�kd E( CA- )U([1�*Bers�!��]�q�N�ur.u&4*؁�I�+!w�r��Y�d�/g&2*A������1�alI-�MGT%� SgtA�K�C�)�f wo auxili��, Fmt�� FmtBa��"� �uy�).-mT�K�O��>a�%~��w;'�_[%��:�Az���2���"P9�.p� 2�"�0�� .'��%��&h�*�6l�;ng _-� h��IJR�c�(! 8@m�death%�AG|bBHrculo !Q AIDSZb 03M%����9.�emphaAL� �%ewZ&W��q �  �/�&:�t�0�'� "��"+�s ��O� "�.�/�!q���,�`S.f�i\Q ���&�(22w �%�t�,��ch v��T�YU4IooD� .�c&(M�!�5z� We�"At.�a+�[2�&d sol��Ţ�.��s� {�� l��" � A�deI+d��,E�L*1>6=e!U6�1��5�inMal�&��,"�aa� t . |'4I�exact]Y�&c�#^�a o4��2�>sw16;rJ[ Hid\Markov M�C�>HMM�=Qa &�%bio"�a`4W��m�y_ �-)�� �re�C��u�)A�x�,bP ��?d&#��� &� !�.� 1�,( SCOP-56601*15983qj}�I �� �3F�(ly �\��6} ) 2�Xdn s���i!�2�(�;�u�}��)��&T�"Jla� � ��7)5!��7!�!"3 !=$#� #?B(. Nex7/wpE�%�.&to 1295*�-!�& ��doc.6�M~N� "�!!3a`um wh�& � � 0g���|Ad�1�[ɘj�b� ��%m �.�V�K!Co"�)i�ų `�F�)/'�+Q7�1!V�$. 2�.Aco!�-��-�td 2��%�ap<ny6�34 gQS�W�,ang!Rros�,to��E�intra����Q�1hVM�4:\p!-�x[� �o��kE# ���rPG ��.s.10in~e-�YQb� "7A|���os��-,Sphaerochaet ccoxTq)OEol A � PGe�| on` � EpPAj uQK ��:B, Helico � pyloriE���:! ��� .T 1�F� !a�A%twoB� ��B%� )VI:�M�2� &� ��via*�UHde�^!)�|or>3eKes.A�  z#�Gect�7_%�sn�? Y�3� v�A���6��!��9�[)B�-bs�V.6� *j6� A�&��> pens�&� ����Z=n� F�[�S�� In �t2A1\/ A�6ult�7ej *.��!B58,����3"�RA�*�� �.� COL< gR"pbp!� pbpdn5��e��mg�ns9, f�mec2 In-fr)!�V�2�2�iT4�tO;J6iɑ��� R|kvutDH%S1�&ww�� ���vOL MIN���0�hR�1; 2�&) � it�}�O[w"��f�*"� �>2P��ity—eW!A��#�Cn[gt� �heȡ��T�z&�V <%�ab"-( S8�k %\9s��o ē%��<fir�'PCR>V��IoG be��:�B*Q�ebto�p$$b�.�H��H�m��&�u�-h �5�n6��[�5S2�2BE�A��6�6*�(r l&�q84i)4z\7a�u��verify�@�%ls DG]�e�. :��i�n��!��vOp&%�u��:|� �,�(eb�,IPTG-i^�PspacA�mq��4qt back}n�aGJ&"� 0G $��2}GmP (��E&thc]��%�a0s��� BfE�!�SՏ�ɋ1S�J 2�O&1�at) i�`8)j �Q_po�*��A��hul> uti� odue&9";!�� id�7��%�8�_!7$%8� M(:6pSKN bl�1%� >J ( S3e%a���GQF43)�or�~�_v�as9���v��"R.{��]�of5!��GQ�RS"1�Z95e>��bRR.&��"6w�.SnYN.�4-vUm recUa�s� U� _�. 2�i��6_gAg�0"�tELaiVN ur ! v] jX��� �t"dh�&!�AX S1 T�AcP$"�.�eկ!�.�,�x�:..�fif��9��*?:% % �!�pcRCOL��#�3��v'*Y�%exc$siE:co.g��gle�RPZ g fiA�W  � &Mun&pJn}%ect�cYT�F�Aa�%|�Lc*�L�< j^�%SNP��� c{��5� ;Mm���` "���Bunx;2�/sy]/< lyH SNPſ+2�a( @c���$molybdenum>|,^� ,"�VT /a��a�. ]upt���Uutrf�"���7l&���b�`9��p9���c ModA�"J1�i�oA^new6 � #��vs% autom%2�-�m��d>|eluec�n��cha�.�adaո�pM�"�L-@:v^��e�"{/Ѐv��ll������4 }A�1�3$��( -Seq��EL]:xBkl4�ܗ� s"�V0a|'e- p<�^0ܷ�two-fold}m ,BBA�.�K59e������lysJ1i� ѹe L54a��2%�@e++ a�"&�hL1<  �aI� 1?H�y _pD5!f %vraSRF٠@: a*e6!Om�t�� �l�j%O,N j m �R&j,Ddamag'f` �%� vraRE� u}�6�;aO3)���Yeo%#���hal"�R46 \!&�`Ah he V!�* [�� 4�i�& �`:c��"_q1�*�d-���*� �+7�J2 �.�x�` "��BR � �dowK"� �a*���)J�/* '( sleG��3�� lytD�. 7SACOL229����1sce1,�61isaA (]8a�lytM (.D��um#tPP:��� �[�B}6�nd2%>���m��>��� G� curstQ ( Mur A-G^emABX9raYe 5�.:�q�E.����nt F !�����2�1}i E�i~mF���e�a�mn�-�wL3E�m�y��: mi�!c�!^*@=�%oluEx2�d2�=�LDNA dye Hoechst 3334o'��dxiA�^f vanco �( Van-FLE*��label�by_�m./ al D-Ala-!idMmbfp,�l �h-�n�.?�;g�y@bdA�l��n:g ,$i�"uc�}d Illt�i�M9_ ( SIxndR�33�Mf�L�`e��)�ept��3_�1�2 3�̐o�aF�C di�Zef2a� 06 μm ±�Y08u}�7:)͛��"Jvu*������]��=Ema�0}s"-� �@� !�0tX�$7}-���2w�[��*�,o�%  � �A$�O�z�-"^'!} um [ZmE62%:0#� ��c�$!X2n>�[��eve �"�T�!W;%���e!F����JP!��N�.�p�>ur�3^,Gq"Q�"�NB!˱ di���R�3U!a��/&�2. W�H2�����4bTC�I-&e-E`: �0Vcl( HPL�1�UKD*� L !�2= �9duBA6o�5.�)2�,�a3�V%� , S4v"Pp��e%_ex�2/ �)0!@���/I�!��E��1v�"M&v嵬�*z @N��4n.[14h5�*� l*� " ���Rb.Y�g"s%!y%rD+ax��a�!�5 !DFmt� .��;�=2glyi$!�sE�!O=.!W*��$"�M�~ �a3ith�s/�le��$p4 z?��E҆Q�t>�K~by Ly�*miQ(`Dzv �����+R�wr��)�g]%*��W�-e�ta�.�eR!$AaG�ΏVZ�^�;��U�?�� ( S5uWe ^���A���i�� �`/>�2"�� si�+Qh��%3a��2d,,, the other ��enzymes with transglycosylase activity , has no major effect upon glycan chain length or composition . Thus our results show that S . aureus can form a functional cell wall using only PBP1 and PBP2 . Importantly , the minimal strain described above was constructed in the background of MRSA strain COL . MRSA strains are adapted to live in the presence of β-lactam antibiotics , i . e . , in conditions where their native transpeptidases are inactivated . We therefore questioned if the genes pbp3 , pbpd , mgt , sgtA , fmtA and fmtB could also be deleted in an MSSA strain , which is susceptible to β -lactams . S6 Fig shows that strain Newman MIN , which encodes only PBP1 and PBP2 as PG synthesis enzymes , was also viable in rich and minimal medium . We have described above that deletion of genes encoding seven of the nine identified PG synthesizing enzymes from the genome of S . aureus has little effect upon viability , growth , morphology or PG composition in rich medium . However , in vitro growth assays are not sufficient to study the fitness of a pathogen such as S . aureus , best known for its ability to resist various antibiotics , in particular βU5@, which target ce��synthesis . Therefore we measuredE��minimum inhibitory concentration ( MIC ) of an array  tibiota�for COL �h,MIN , Newman  . Inyabsence�� ���)0 TPases decre ramaticalŊeveA ough��;-ls�2A�PBP2 ,$two5�cap%Rof�a!�!w2�iae preUy=�[7 , 8]!���� been/0viously descr�4to have a roleZJ.[17] ,��interrup1<)�rrespond� gene<ult�fan 8-%�15hR. HerA���wh~+(.E� u *� q� ( i . e .$=�2t A�AqA� curv�iDa�U�statisV se�Ch ]� (is could be1ieBT growth rA_ s��?suggest=exist��a|( second fac�� , be�N�h* d^�� $contributeŨ�� �B�. W�� :sus�wi&171C�yso�AI: hydro�,'found"d [to!Bin� d!�X-r9, possibB �vΙdegre(PG crosslin� [36 , 3E -lA��ris1�amq�ton to�Vist�wdefens9ch� s! h�.��o� bac olytic"� . O, ayX5�;~Dqu�:� $lex multi-  machines�through uscree,�A� � �in va` ��pecs � clu�s.8[38� to id�fy all &�� . Howe? � ose�7 )%��dispense��]dis% 8ed one at a timA�y� B !�nd��s [can+be si!9 aneo� le] from%genom�1!Eletha> .R �suc)j� "� of)�� �=f�L%�r1�, a�g ��%�� .qAhkey2 Hh %�fic��a�effort�Fbu�aUv2 |on4�4e smallest set�F�IKis work� Ee-&iv Q�A�onent� � molecularQ�ry6�>�*� . |e l��1990´�JAöltjpo\ aaee-for-AQ� !)�(of Gram-neg�PG���O�at;5s�%ry�AmEPE�:�$polymerize%��fyz�}�� llow� er5 new � ra�aout%] romi��igr��� � ess-bear�ata} d�Wan un)s%��!ΡCe& [47!zWh�>c��!ı�=0minor��ce&� aE���A!�noc�plLH }hromosom9�! ngemb. Fift��SNP� re.��msca��gS�Y"� e ed��in� r ;�ͺ{ i%! �(molybdenum-�M� Mod< I = arkan ABC)�& er system��Uuptake!jnutri� [25] ��'.T�q#NM,��-3t�i� ��ct�sup% sors�aJQL [ 5E�B!-A�Z�..Ln($criptome-w�a���ntUtM a�-� >�,A�to�� ]��!vea$a down-reg��a�}PG���� EIs��a+ ) �[ ���i^!�I�pp���A�atN�� *�ca@�ncɺ)�A�5N&gAXm�) auto� ns At~Sle1 [48y E��t�"�~�Tione�50be�  w��I��N�1J! &�% t. surpr� e�"J�V -u�6�6c!h2�)�Z�,RNA-Seq data��&� ��2)m�PB.�  un[ga�a�nt�U��.V"� 1]:"�� suff�'�� ��CCW-�F �)C1�.2A��6�)�N-�PGA�\cursor Lipid-II had altee�UH�,!,,e5 ���� at:P��� �ly�� aNai9Z�summa� is study�����"d�n� f� in.� . W!ur goal7 A�to r ce&P )|�9^��! ,� reB%i&m�,&Opla"�tr} . Ap�"� *0!Lize�PG�8$ju�wo$�J� ��Mus�!�ɡ�~�g].�R re� ��%�a0���!Ke�Rre�) re�>.�&A*!� aulo� cres.u��a�"o�$,��-f�i2� ���K OCis6 �th�m��eEis [49f T!�M�Zdiw)t�� esti�!�M%moC��:� 6fse MtgA�S**�si�)��Q�� is f�oby%�A�reh� search.N� *�!HNX ��Among� 1295�e�  �!�f�livvOI6�fe ~�e.A-OL���U &$te hindgut^8um Sphaerochaet� ccoi9 �I'7 ��� 6��e ^`A�-��`'+Q��cm�eda�%M6cha_�d!�N��+A�ic>um Helicq\pylori��#alj >�a��&aly~soljF*!|�<�of:,�2�e>E0*v j�.)|� � �a>*6�habitat!��"� aj ~#���,� ��p �*�.�f� ,&( s�/��-�E�Es}1DA;� � ��!p.�)�*j!�Z+Tk/*$)"��^%�!��*)�y *#co�5�a��/y%�A#��0!mGby nafcv/Z/sYof MR�(�m�)e(cic B�[5e�rez��U*�+* �e1�����A�Ub!�M"$)�.H��]�!H^�&&-lyZ�Afs)id-rA d ��\��re&w,�i"&�*� %�u",&%�'�d`$P ; !��� C-NI� �.�-�6�. S���%A5�!?+�maA3meI�&%s6�%����o1$(-� f�%� y many ���%BP!mo��a�e!�n�2�Qf�]Y 2jell��Q;�(ly2!�sdu�#cyA�� V  �nd��"��nm�hZ=q#a5� �/�-e4��a$.orB. a�-t�$t ss#eD"� 9l �&�3D$3�d 4"xirA strmC outl�3^�.ppl� g �!��method�+dc*Plasmid # prim /�Sn�s E�F+T���1J*� 1:��n�% 37°X1 Tryp�soy brJ/-�4( TSB; Difco )!zon2. agar&A&B) m*� pri� .�&�_( eryK"�*L10 μg/ml , chloramp-col(or tetracyc!� 5 5(; Sigma-AldE���R0 0 . 5 mM isoe,8yl-β-D-thiogal�)pyrano�), ( IPTG; VWR%�For%Ath�z�8i6n6 !7aE�p)l*SM9PR21C �%A�$1 x M9 salC2� MgSOv�1 CaCl�1% gluc�', casa�acAP, -Thi e-HC�G0� nicotinamstM .�#Z00A0or 0;LB Y,A?LBQ6QW� q>Q3105�ampic�(N�5* kanaI=F), 4(5-bi-4-EY o-3-indolQ NXQ�$!O%NA!:�. A:�dis�a�G����A PBP-�� dom1 �&� u6 SCOP-5660W159832!��S� fami ata"�$N 1 . 75 [5�a�xA��L�0�"��e�wA maxz:�lihood t��k1�Ied ��softw�W,AMPHORA2 [52�$PhyML [53]9lo� �ocedur�Fb�9,Wu et al [548 Gbic�#�ex�.H �vid�4culture��;a��@%e����q)I-l2�(Illumina HiU�at Beija� �$s Institut� �;M:;*Xo Gulbenkian de Ciênci�&Oeira��DPortugal . 300-bp 4en�.ad�5 overavx averag'! �6"�#. S-3c'@�assemb\w�4SeqMan NGen 119�I�� COL � ( NCBI�(esE�NC_00295A�2 )A�� � cN���, tF ��-%��Ee9�o)� )fi�*�,�� s oci!� M�. Low �6��%�9�j4�-be *50% �<#o�,a�N�6n� Y�I�so0+d��ona�)iluA�1/200�oxsh A�P incub�)��aeb � exP"T phN(( OD600 ≈�6�CO {ha�1}i�6xYQiagen#Easy Kit�t&�*?sB=�evalu� Ga 2�+Bio;ze� Agil�TechnR !t T& T(� ) �� � GATCV0tech AG , Ger� � libr� pr�2A/�2"d/r�deple�2DN!?treat?A�nu1I ng� W�!2>�an��M$platform (.�(, 2 x 125bpIs�th)he �A�� alig�(� COL run}�q�)-~$Bowtie [55E�#� 4/�-� f�� Cuff.&)�� ���sWrawe ,�!7quG a�h +!� Oed���-���&�F%%w����KB`!"�:4�"=;2O�%a;� \�>+twoU�. G�4of��i��n67 liquid� A2m� �!���:;1Z� E(C� e�^+sha�3���monito�.��|�m pbp1I pbp2A,%  roX!Y � uci^#/o9 Pspac:kby firsz���s9��in� ��� �6� .V��fo�da' wash` �2-fr��TSBT��lQ�inoY1t�4dia��nd �%2.��ag�A�C�9�2r�. DM҉�?@t�C arJ2DA��-g�F;-I��)n 96-�9���=:�zE�ad�at a fi�@ de2D�D 5x103 CFULto vW*"| 2�@�5�of��e E . P�i�0J�24A�48>1]!3!5[a���9s�)n��ve8"��a�V9�'�,��� 0Cix� �(����)� expez�3. P2�=��Cp"m*ly�A�!os�*�!&QC[5�& MuroI 1C[by din9A����!%Dgly���Ѳ"��purif�& d��,�a��:f!�HE�W� stapp( 1D�FE��e neumococc�>mi  ( Ly7E50–��)&g5lyf(3� {�a���q�Ya�)�� ��8e2 labeb%m1@dye Hoechst 333426In>I� )%��!��>Van-FL.>, visuM,A�y fluo� ce S u�*� EM�,�.( SIMŒImmuno�1<�'Δspa�� ��]eMo�i�a��"�+2@ FtsZI�?"ed��,EJ?/��~�ut &#%.H�(All.�/��><S"W�<*4)D(�>!+ &� by ��iful7o'!���Iiphosph��sa�"�0( PBS�0�$Na2PO4/ 15 Ca� pH 6�9>A�ad�!�Oō��of�4�y?K]���:��e spl�n� W��el�b�$zyma��h�"NK3"�{ )Eh6 h Ks- t I. B���& &> a/"Bas ��per!uage��Kcal5 0 :V= ula:� T/ODTE× ��(ca�ODpHQaO� zer!�d3�%F/af� -iA- with�)_��cS!�%<points��i�K25174FU,( Bloomingto2�C Stock Cen{))�\ �2 ild-C2backg59%f�@�@� [58 , 59]6Ba loss!"�%��in)he.� V��e1E.e� aE� kept*ma�$ maltr+� \!o�bottla���Dat 25�beN&s�<�F h2qM�;H� ��-�u� !�16�;�%�nf00 rp�+7A�P�,i�-erile�-bufI d�6�-�WO Y����GF��e)�re-su�2 in��?� ��*7 �xgE� 330# hermo Sc�,�ONanoDropa60�ftropho�+Ip31/� m � ��s!�b��$� ed 45�K �dDirty CO2-anaesthete.femalem5o*2�G]�( a!%2–4� sq%I6"�3 . 2 n�X>y)[�]�6�%c�� ��"�O"rIinvhaeY.mp�G�@a;dor�r�+�2� thorax"�K? cro- [o Drumm�C:� # IIEJ&+#�7�MW 2ed�x flyA�:$12�5as.y� Mng�1gen�G"� 'K�, �N��E �. FFK���*�Qpost-)�!%AJ3 �2� "vials(& ry 2)��P scor�"� m$9 dead ��C , y 12�3 a 4-�b o�%!f&q Ap�N�]"� lk4&". Este�d�.F% plot!�%jA1"8set^hLog-rank ( Mantel-Cox ) tes ��2�s"VGc�&�-L )5cla�%in�pl�95%A�f_+ca� terv!v�$�&omi6�graph!)�%#G ����G%Pad Pr�N5 (SF , In�) ; P<��05��k_)G JOA�on�A0�8t .Y�Burkhold�@ pseu� llei��!Os!�saVh�.mD�: � I� huma�dcit �/<i�x$-to-manage![_R melioidoY .�=w?te�3ag�)�2p�/erapeu��v�Dv+ mortDre��>rw3IP >20%!�NoJ n Au�liaA+Y 4 "Thailas. S"�/�7ittJRsk5�#abQ �6B .:J�� inva.Ts�O� in�%�#( virtu�#no�@g!�.lE�zH�of crit��&p3sE�! <��5�'s")�$.J�1 assu; �B�ec\-ac�U�sqm7*�*�/�7�}eQUE��g�. & )our�FA8c!� a % �@ carrW<*�5�3��%!GA<re� le*L4 clu.R+�G..>�)k#-affin$�J.leM�beBfu4vZQ�ag�&. S(s=7 )=bnmNms5.p; qj�TwgeG� �.�[F1 ( mb A�py�Blipc�(1.�aSin 1710b4q&�4�Wd�.m"�)}/�� unre�dA� �i2�E&�I cepa!��'ndci�C��f,�&*�%�VE aNhorWi��D!:AH�wo Dn �6loc}Dhmu�he�?�'�!�Hmua�",#a u�:&9 Q�hemoglob � Aem�~���# aY defi� $cy . Prolo�3Jof&a��Sin i-AD� -� yielp � Ato �eF� I�a�'5 �gYJ�o,%Z8(A� sourc\L�# ferr!t=8A:"zt }��A!4Y�syj;�b/or1�4;A�A�!�!*quadru>J-4�@ use �ErI.�%�,i]nasn,@T!���J!�an ac3 b �@Q-VIB>|�(employ 8 ovel�-%P.�*/�L�y\�:su�Y� vivo� +%. 2�F<6�0a�e�S3 �T2ly�~"ri soi�$w�X)�!�ls�="3=�jAai* mamm� aA�s�Uu��-~�2o�he�4�W�ydiF�[1]–[�kF�rapid dN��aggsG�3&3of�<�9�e. pat��5u-�1����BU=& an emer0A %��-W^ &� �4�S�4� Rc V�!Trop�M�?�<�Dworld [8%]1�GI�.�,% QM ,� ��Eny�.�^�*�0;]9ron�%��� olu�e$too���q �[1�G� ��m����teg� byZ Pere�o��Eof-���.I!O)heme [14"%BeA�FAbne�#ty%>e 8,.?�7 m&EQ�]-&P�0�$�6�>�"��,{0ttenu�!!�e)�[nUl [15E ,3In:�p"QA#%Hsi�O�Y��4604�)em�Z!(2�Cy%�\x�cc ) [2�L.�[�Ue��ea�u� ��ide"� ( orniA�iZٌ,x %Sep��in�I&�_ , �/�]/sl!=�X%r��!-WE/aշ� , [2ezVK&� y � ETFrinFgŰ�um1,f4S=xa��=& ,6� �aVe9�C���+�rt�9 ,�Ce(�F�uma�a�� N -lim��gA�Jas [23I��'�?5*"!VwJvB alys}<��ge�F"b a*�� �2o^ � a]@(�)V� !)�m� locu�.��s;m�� mbrafA(%E&9r!6)�9&NN2(2�im/5W��R�,/C�y�pu�_�Ka�� "�1F�  oFj��EtQC!nc�Nat-Nv�Ginflue�Cc) yDvK[NM�J(�un��<aV � IPst��s�<�B�� �2.�4AF�Ed�\s6�2.�.SX.fi$m �/��WtoM[Kc9tr�,%wli6R708"�.a�tK ( >130 kbIoo�+"_[�!��W, GY�T'$amrAB-oprA�T,lux pump opeA�  expl�gentamicQ e""08�se >90)A�s) "saaer i`i�%�/ be�tiU�>>�5hys�Q�M. DOfA Ac69g!�r6�bio� ��u��#�Q�5A>�32$A(dsum�N2�,)d�2a @� �&� A z� .�fOngK some�Q*Ch& �hon� eruginosa qnalog!�. py�d5a��6%�&1�ŝD�aNl�%!� ceno�X"�!a����*5l�5d�g�k[:f. A^� l�>6vK*�L �� )�E|Aens l �!��2�I46 ; soug�Do elucid�? �ZyH6�Y!CI� ~���Bi�e�>Ia". >.� }>��\  �s�CV >�6"/All�c "%IA�B]1"m"� S�Q A�,�ved�, safety Le 3� SL3� a�Wy�2@A�liS%.�"ndtocol�Un>Rno��EM�Qm a �rou�Yk&6�6LennoxL4�6[�f~E�6ye�8MO BIO Laboratom , Carlsba3UCfe�5EscBX"�'�d ��a�(�la�re)�;Hh�*J2"s:6�4Amp;&µg/ml;2�4Km40zeo�� ( Ze�7 , 25!���( G ;1;�5>�fI�6 urone6(@5lu �5�Ad�6opi�c �6 ( DAPl20�40�vA O R ngF�qS9Ɓ�=#t)(:e5o1� �!x� –2!wBiΔSmrR�)�� ��o.�$35–5�Km; 26 Zeo; � –3+G�jA]�\ purc�1Q2EMD Bios��B San Diegoa AQ(�$, Su#Lou,Q MO (E�! E� �*�'>QQ�.%�,( LL− , DD Jmeso-irt as*qY3S�).A@�(X-EJN�G(oBi�1�1��>�. ArabGj5rhamnosAqq�4n�F�Qhon�]s�;tR��k|U!5%��F oli DH5α ���1X idten !$J+)v�,x �)!0"J+"�yGeneJETRini' kitFer1as Life!A( Gle?niUMDG�i&F7M t Puregene �1 ,4+�Kon}G7' S�( 4 , VaCl����2F�-YE�2c!��)gel�7�E$�eu6� GenE#5:2�Iw.!zCRg�Ra�w=tri�"�9!��mod#$� �:�New EngBBi�*�� Ipswl?, M��VE."� R,cc3_gA�!� manuh8urer's recommen�J��A9tyjl�@A���eiyTaq��_�PinGiFi> .� blun &�J�9�cT4.[,;de$*ory1#k_E��N&�)>�B�W ��_$ard capill,�fer& blot%�*� [3�QuikCh!xY-�%edp a�!�US�Q�- anta�Ur{e�AuE�ƴCompet�B*�'��� �o�;P!- rubi5]�=�me�A6I]N�6J<1YA@>�yEdrop-diA0�f� mm�(r:s ( MF7�_VS  ,E p6C�]�30� mIM? ( Bill�b![��@20|LBAo!k� 5��l�B� go���%N)by ^p> a�l!�y�2�I>"�&d5W[5o BrieD',C#n� �#=e�w�) �`i�Ging-mM�r�!�&�- ed 1)U+ iquoroS � \� r �"�=atAm gap�po�h.+�cuv�d� 2�.kV�Aa�S ePulser XA�)�Bio-Ra� Hercu�+,i �.-�re�"�->x�out�n%�1 h!LB9艹g��*qCsLJ��quB RHO3!jA*�J conj�/ofSk}N[3�3C5 Ϲ)�G�! 2�5�5. E{=99lG�I�R�Imix!jnd!)l84to �#ile�WulE]ce�m��[�O�0 UNgon�*�y%��"s aug^ 7+B� � . A%��i*/��GE�Y����r|j{1�"�d~� �,Oligonucleot�O�:��dg�� 2l=, Coralv�� , IZ%oreB�S�:&SQ�2��76�Sr�� TX"Sa�In{`6$T M�"J !�u��To5S(ate pEXGm5B� ��9-kb fra%��PS856 [�n�rel�(�n XbaIj6+un�i�-'ժ%�u�JM110 �m!(�Q>!�SpeI+\m ackb�pEXKm5q�pFKm4�.�b�67DwGEM-TA(�%meg!0Madis_5W&�. }� Q�-0.�:�8."reV� joi�by E��pr_ EcoRQ�1 ��yKa GmR 9,J`v�%gu�Cu--ͩ�~llsS exM���diplo�I��)E��n�-b��s=m �suB }#e.~, I-SceIRor �p��"tTs��B;� �c"�-=�+(AIs YT-�ſ5rc�D� Ab�,en�0at ro;EemperaN !Ere-Ek3 sAk��white b�0���#o��?F�.! %�arkqwaml �HFlp�g<se� Mu�v��%�Y$ ky��F��3CRA��">D �U��$� !��^c}m�6��Low�' �"�l�=D1 Che�U] �+,dex��!}st Bi0 tic-�I�C�X�ZqK�ron��N!:&�Nfi�etW�"ex-!')� TSBF�v ��'6�of#DC [28�D�o.FC%<P(� L )130 �EtN�, 7XI5 g�q�, 3hN+58w~w/v� lyce5*�|pH2 �:0)e NaOH�/�.� haloa� � CASu7as� +t$i�&Ag?@�Y;0-5IH!Aum%�9acla!�a2 ) o�ql!�Bt�881�%FKR<&�Ba� 24 hR�.>%�h rait�]pH "�y*!A9e�e�+�KC!2A��9neA* What�541 > paf2)%QrA�^�dC �"& a@ 2�#n vacuum8a�un�HL�EChr`TAzuAS (%�)2��o&;={yo^u4�V5-sufo}=-QM�elshu�2�(�2X*�EqC"�.���G��ve���%�$).�&in ��@e�-3,9)� B�&n&7 77�:)te��, pel@!�9��µ>q� � to 9cl%t:f. Mix�O �}� �rA��.N�5/��$ �$in A630 nm Vtoa+un"�EdM�o��!`�?a>�de�"ya�wA�J>nm!� a 1∶10 Y:�F-�aD�P#.p&u [41>!�� L��;�ufn �Qg �Q�W�p1뭐/Qa�)�mg 73# i35 mg{�dis�? � deioK>'.&�e�"EQ��2 61|$FeCl3·H2OR1�@dS. � B6�47�$hexadecyltoEthy-am�?um��S( HDTM�in��)B>� eWla�B ���z���31f 1>���i�S1w2��( . 62 g sod�succi�1ZT. 68 gi ^To���6� 43 g�A�T�45 . 44 g PIPES �2�54^�?A5�E.l9�Ex�e�ut��coo�* to 5�T,1 @�� slowy�|8mixA�)K:�ap3��!m�RW een��8 a��mm Petrih�s� LE� much�sjS f oxid6@du�d.�t�t'w "� !ioriginc=cip�-* Schwy� Ne�8!�[4�+�0���:�1�A�) �&$@/ ��:DWi�[ullU?�1bc!��tna�O�]>�A���sy!&e�er�q�FJ� �� H�2�$2�� �e�&oT� �E7neg volu��thyl �. E2 U.C c ��dr��r N2 �z �@�?in��Z�Fano�l�pE/t�tryE�&��"Co�Y do S7UniversJ%Bio&~ASC�% n�Q1�Ry3es"�N ato!=a#e1��L!g = 6520�drupole/!n-of-fli�&�,;(y�� m6�erf�a!8Chip-cube nanof�SM<�3TLa G4240-65001 chip c.�ilum 940 nL en�Z��u%80 Å] �#m×43�C18 pߍ)�*~'atE�6�/� �:� grad%4� � �va1%!%�A�E�3�A��O!)3!Zrospra� m7%/�+�� o�/ve � �1�F#:590ers�dr�;gasA�� �D�D)��[9yxe X ell-g��.��������I") FN2 abovS}4Zh:� Jj�:^" ��d� lj%Bb��30+�oa Mill U �−15�?l��devic/ biomax-5K)�a 5 kD"l��weia&cutoff .a�n�D^- ��-<.��AR�e1; Assa�Uz BioV0xIncorS�M�5 ViewC �* �!0L sI�u*�9, ���c9�um�!��`e�6�5�I5 g/LE 2e i.�)z!>�>�:-*)͖� 9- f�)�E�=�%�"J)s� d��a[J5 �y T �ub--�d�1�-7aa�!�!oa(M�c-�+(&nswY-=A s�I�� M�'1 �2Ts<�Y� Xd� T1 µM�.Z�:~:}#�o 4��Jbv"eB�H,� *4��g[](4�n*<6t! g/mld)8e IimEr����3�K�� 42′-dipyridyl�O�M���+e*R):�NMM �"Y in eV o[?ns~in�dci�" � �+ngU�l[5th �&$nergy HT M"� ModeP Rea�{ !4oTek , WinooskH?VT%� �l"]W�-U:Mҭ�: wzB4"�Tflat-sKom� ��/ng��603 �e , NY@'z=Te��A�s&*N�rp"|B�Jatnn��Y�G��%�up!���G ics� v : An�b.��Q&�<3�&���(���eB*^&� e Gue#p  C���Us)f&�-y �,)ON� al"�^eHe/l���$K.���v��Af� 5_�u �2�Com�G!�Pjt N��:W" 1736��.+c�'-�3qBALB/c� L*:1 Jack�2�.(( Bar Harbo$MEE/�/m��B��K!U$4–6 week%,agc ! � A�&�2�b!�M�hoa96iiKor cagesC � �2"�8c#o)p"CV&z0�; f>���atj��� rY�2� *.u�&�?5"�h�E+u, "���b?�atz 8/e9tha !���Z�4BS���A2���s / ,!�MManest�Mb�itr�itonea��iK2 .DULBw� ke�nAס� mg/k�^( Vedc�-SaaQJosephl*O�@xylaz98 Ben VenueÁ�BedforH1OHE�MA�%I|m .���>?#�A�2� 16!�! umŭ� !� no���r� LD50�jB!.6Ai�WF� Cݐ�~Ah F] "�@��bZ 026b�/��"+PICFU )Qeu�%U[d- n}��I"� d LD!�d�$��2h3×�Z ( ∼4) QI1:ti[ �EؙH �&��yſ��!Q um#LB}:�_~u!�TjBD� a0= parkAE.Eu- asia}d�S{&�6"�j�9�8nc�;�Nu�A�&`�k����fƗ!�stimu΋d�4op %f%i4tZstcC�(r"47>15% bod  .�UburdenEJ=� in lung l�e�spl�tissu &.X*]cB��E7-h!�AF1� n�n�,f�I}ol�X�;�b�". T �$pla�; in 4# s ��,j� �j]�ge �"� toIwer��F�( Sew�, , Bo �" HomGa���i �]�?n�� �&TSA �!?&� "� a�"�],po�o!�m4�1sa�/�!-���?a�A ��L rgan1 �as�CF?S!k�2.,-Lٶ)J�O. 0&Ag�O P�6FL%S+N"3+��s?,by Kaplan-Me��-,�&I l0QL�/�B%2빬i �8� �aq#-t Stu�@'s T-J[!��Na6\�# IA�9Gly *w;Cp-(fes≤�013wX-daa��Bon� oni �D)���|�I �w%Ae^A> ,�"ere%,���Q. To ex>;�@� &���e�;ory*7# cJperhap�*��!?<oKu� 2�O!`�$ts�uI"%@ �^�M&�;0"�>,1Nr M=!k141I)s'V��pfn& ���T�>�(U���*�@��IG�2�i��>�� t �!6a��%�dqQʌe�* �.� � 708aP(�e"A is�Dn�Ino s^�g2��!� "C*!c�manipu 3.:�Ewo�ia�� �v��(to� 3�o��u)�!l��I of6��Eq#�t���*.=-Cje��Q:�EM&!?.I/� ��庡E%��7t�0.fn94BURPS1710b_205 .155�FigJ1� �-�Bp7kqa L6�9::i(bleg((x;�$_3�ider*�(��%5d�T�efMLIt_d�'!iA�e��-Y�%l|L-�!;�L��Ua�.Δ-��:� p338Z ��3e�] mbaS-mbaFB]!�i1��-to-toP ΔMBw:Bp327 ^o{!�HZ/7��&e�, S,�aK Y�z�$�N�*-&�%*Y&($�]w�At"9m. S��M�Lw!uFp.��]�T�20#�e a>�#ʇ.�"�]�  qQ�B �9W��FH��!����D�� B FI�B�)r�U?beh6&i l� ]��ti�$eI�6(�A-2_)>�&cappear��1*U�Ca�-��N al��Xi�sQEJ�)� bar& n)Nee0J{4{G al�I�?+v�U >Np��� minu\ Fex��e)P��ct�.�)�a�`�l�Wby-�i}X A��{��ct�*)"Ȏh+�lo%�1,de�� MbF)�s(��+�`+ s Va x�� 8%�A5![no�*1 zzeό��)dI!Pft t.,sB��H�G�IE�m��38�a[mV�To v39 narrow�^Q�wpE)8��0$t !��H��ll1/-d"�iw�}AntLQ3REi&1]rG�e�ȢK��2��.RbyiA�i�2/Y �-/ JD�  -!? u�"6^ ���5N�.�&=F�XbMpTi� ��z�K��� ��ea.�a��8���)=�tKN�L�& 5�x2xř[�A�� �7(��m*� by�^61)��*( s�ui�a�*u'�U:kΔfpt�41�s,.pchAB�48���ΔPCHX��[*-K=��5N��j�Q-12E2�(b� 9_.R� �)!k9xA� �0N@A/65�<P"�Z�a� aWk9 ҵ�>IQ1 .N"p>m�%c&nZ9� �roun J&�#-�#�uel[2u �.FC-�&�W�2�  (5���s-6�1A �&� �Zr��\LVa��� .Q beit"0,!U#N��<6e32(078 M+H"�o-9� [44]}/B� �0DA�@��B�X`)Rcr78�l�fp*GPch) PchSA2�!�n�UngY` etec �&E,>�Di-T.�6in9� o9a�2�A�9 Y�\ )� ����n.�2+j b%�.��'�`*K2@1."V � ��ilkJduc""2w#y�2%� �F�">�2��=m2Vu�A�AJABga&Ӵ2P�^�5Aby- B.�b��~&,Īg�En!^ U4�VP���un]6s6f&ro].['^,6IG!u�A4 6�V�,ib�e�Dv, aki�SpqU139o39u�2D!�=0��ˍa82u-a��j-q.?��a&�P6�&I�utwo"cho=e�1ȇ��nP.B��e2��� !! ..P[U�s&��:�&"�&an{2� B}�AR'��]�8!|>��� �&�%)�L �a� �A%:�K_.�0T~5A���-�&F� &_ �:�. =&�tW� �es��� J,i����7>.ڰ>0doe�3�a^���\���up0 s%jd��!z� S�&j.��K&�w!�`�b1�!��GA�2�mao(��*5�1�.A��+�qi'c��Gv�+A��>b�ie)sa���kaDxstu�sE A=sw�l6�8!6�p��6��B�c"bc�Ai*[tonM>{[28J�>�Y�Vwԛ�c&S�:��-&��Rof �"( 3� [?YIf�z2��YHMkiseQo����sN6II%�3�T�E\e-, � M$of YersiniTL |a�RS9 TonB�:�m #5I�� mor v��*�� th�,rIG8� .l"�D9� ��Њ~�-e HEM%f&���-�(sFMK96243�log�ay��re-9�a�.$�� ��# 6�-�Altz� ki����e/�`�K 9�!�BPSL272���+Cedie�sa��AA��?t"�-�,h@�FexaЄ�,�;�g�O�27 �p�1s9 star�-7*� 3208��p�W$�Cc"��P��m on logy�=-�g']�! 8��^a�>}��Y !3515��37%Bto 689B)T shortens  �ope.Ba� fr���edh�L�$�OdN0�99%*[3�P�G1�]���742��171, .4* adjar3X!.2�>$���(��=�R1*(�a.xI�se�/Wu�alBAi�"> I����h��� l K"4th��aVAt5B�iA �\Xro�NM9fRy#"�"]3B–G,�:� grew�!du�B]Ra\2 ��"TXw�a�6 a�u-%�c3�� H"6�n{!�:�Δ��âbΔ�rC cm*�X/�i ��� 6�h�D%��(��2���r��5mR�{, N�;@l�w � L��� ��.��/ b:voj�@ ����]� Ir�P2ŎleQ]e�)�� l� L�.si>�)�)lP�B@'��f���Ra5R.�s adapa@tR�k' ��&a#aF%dY�V�9!j��<.�l�)$1 ��`lU�y�!ab 60 h!� ���٤eay�y�~;�q�I�R�1���o�!jy�r��� �..#����9}5�����H,*�>�}end�[uf5f.o�R�)�` �dre�E�8����� 1�AHs�i, lony�,if�J=Ié qf"s�l��c!�e lag{�!Jm��;er�6W(a�+ s*�3�. A"�_J�j2.%8s.XG_@N�4�c%@i�.af%!:!��9��a*� DSi��6��A@I�tr�or< su�0.wAvri��� IE A�s�j� er��*f�M�%AE. 2�y*Po �:����MB�?�� �c �PI��F"6Amc"�3uso�8]S�3�.m�2�2[hra,m-c���%olu�,�er09Fvw*�4.b�Nora��of-nUH>�)!CZ�b rast�.Ff�=^ )V T2|.i���� .�2�Q6� C–i�Thˢun�3A����AL"�0�p�B.l)�i@E�3&&�on6 J�G� s-[~�y唑>) !�i�kF ��6!��.655�)�F�rtin�I�-�kinE'�� y!�c-��7�uinJ���`A� iwFx.e ��de���m�d�[ q.* �k��;F�/AY��)�"7J?79*� zj�n �zz�th:��.ih�"�F"u���(U�!-e*hR2 �+M u5�z��e2�p�Q�b r�aE��Me�B* "�n ne��B. , nam�#B�n"�g�nk l�8�e2�O (%r-���"�o��.S"�܋e�m?f 'J�3" 2n�u.X6recei�a ��3�.K.2LB∼*+2]B� m�6!��Aɓ(�A"Y"�1�!� Δftpᭂ.y6�g�s� ],s��*a�P*%r�9��j[*�Mq"�wf�)��Ha�*v}��%=+��"�.c�Ɖy�/ .��)���n8A�typI2nd*8'"ymsymB�f2ve�2A�q�&"�5���n�v�;I Jaz8�2�F�2s��]d8 �=/�N � "�) -to-death�� s"d�t� 2�s!�na��"0 �"���� . Or�1b�3s �G9��^.�j-��6���_ B_3!��3Xxn;�Mm49���)Z��<�8�`�&���V��&�l5��&%E�!�;'��f� treO�c=ply��� 2�� ���) ���%I�Q age . For"�� *�i�iI�Vq�$��.Y(u�A���ce�m–vMa�(����F'*�b�"zEH � Ũn��.Y a�# v�en $�K}0anvo%�t�5'�fm E`�hoՂ[2}a=A}*'2&A �%%/$��;e�'Z�x ���#" IR���#wIy�{V��oE�� ^ ��!���m�* nell�x mr��r�b'F�9g �-e�[�,�L�2*� �j"[� tD�enefie�Q�ic.m ):~*]*-z� uDzK�k�2f�{lw�. s�)6CA�t+(.�al �X:�ad]Ib"� _A�2pl: ceftazidD�4DN1s%c3~B��s@���{ &�0MU�b�*2�;3a�m��A?penˡ>9�쥥�9 ® �>1N"NŅQ.E.`" "�6i""\ .vP .��`r� f� eślo�$�*Zq|zB*vewr{M!�AKcy�7 fibr��=f[8� ����B�e&args:F�2S���]��� �6uᅹL�JX�I>�m�.*g gi"�B:�='��L�ou��J�witA !u� )�may� endo� � )�vsͩ� �=_2�8���3�y u"W ngz�G"�4]a� � 2I7m& }}.A� %dec+r�4:�|�a�n&<6.( 2&x�9,vɮcKon�:JX{'sa )��2�a��#a Fp7oI(en we ga=����:]&�%uF6 ��+"�$Ji�h%ȁ�+ ��tr"V�SWr !�3# ֑7+�"� M .�de��L�NR�8!JeT����eerA$!�F 5.ա(A�2�=s%w�*&�-� �_�3]v{4m"a1Th8�.�,e�W!i2w4'%Q4!7�x�^ �2�}"� 1Vv��p"T�( 4 d �B�]!k!� n ��s�5Aba%. [�$d2pheno4 �3.�g nd1l�?re �m�=� �)!pI�C%V�32t ������ �r�]� h F��dM�*=&�.4 I�oo�z��6L&$&�is �! ajorB�� q��H.��mN"�Rs'Ea��n\a�-r�eQBb\���� E&8�u�/��5�� u]mW nge-.>�Aa6��'�Vadd�"+ �� �N)� ��y"= �6~a��B:�JCzAi-��(!�erpre�s�9v mea�)atIl����a;_ �o9� \up׿�<D%� .<}��ra��1^*!�V�as��an�1 shif��.��3 AFap ωZeV�2~J�'N� &�D�U�)A E&B"�1[���,(� */,��ase�2$"3is.$(pyruvate-ly *c��y��%�, step"� �e�-!� conv3�m�&�,wali�0�,2�,�- pchBE<�5:K0a6�0�� �7 | c�e0D abro���2}�ru,�t�� �o�E?d2E�� �b@p1 c� @nr2a�yl�a�iA�N�.� {酏��2�xX)>A<9�"W / 1��}CEF�oc2 2�~nd>0�MM�q�3��?6}s&��lyG:or|�&�4� ZAH��of��.�.)��"!�}���d:��?�+�Ob,� ��Co�]n� ҃o\��X�2�*���ng%a���:��! seem�9 playA�yP P J OE��*3�Y��&�;no8; cernOc�"nհwV2�F��!c1�('P�A&"�)�1i,)����"�BF�$e�>)A\Ï�ntact>�+F18j�Ĝ%�Z8-@9:a5 .��*�$( p = �:000D�i��!P:]`�<�o���…1&Qe�f0F �*��7kv�1 .b5+�u; [��a�k #ce�"�I? -�\� by�]�"�day���GA��>U�usp7&V q0 27AB9�F,0:N.��06�5Ud3i(W��"� �!�V)haɁv�)!�`h a*�7�0��3A��*� ��f��RA��*r%�s93A6�#�i66�5_ ��5j�5B2 ` � &m� a�f*��� .��il*-2��)I"�"��+F\�6.[5�c&R*!��c�A&�B� �s!�t�rs�$77 . WiG#t.�*�!�- ��el8B�5~��iSAsRV� ������I=` !*�C�<Q{��+�by� -rib���/�$tase/9|keTs ;! $( NRPS/PKSjen"�{B��.e��12>6<��!(�2��s-� �n)[26�e*S�se^sC�+ c� ir��"X� pTa�3"�Lof 8���&?u*A?� FA�R�a�3I��I�B�#y��rAi� �@(is hierarchC �.!:!T}1/~R�.a��a΁�be6�:FI6�ar�;�KqMqiBPSS03��a LuxR���4�*Z,��Pa�g�?299– 311 NPRIqM��s�!;.�)}�&%jPO [CV��(BR�0in�2E>�-P�i��WIA�űiQt)�� 6��RvU|ir=&8 �&� ? e�e{�'aE�2RC"���5�eL�&��(�(n�C@t� i=,�9���^�" ѭ�2;��IX6���6 ����=0.�i�ssociP.� F� �E"H��is5����#s�7%�&�k!2 �6oA?5��.�aGu*�:�h� �=����o��.�wfirE��Jȃ*0�&�/-�* uf 3�q�Q &�0D.� �n*��Fn"U0ba�4  fail�1��0*�*a2�"DEJ�6�`�"� )2�s�hasј �hemm��A�*�7��f\q9:��.�Wa�:6�&�.�/ ��2e"-F�%-MU��-5i�d&z΅8(>I.I2p�I"!�3EP�*We����� u iZ� ��G �&�&>K��=e!���/ ( � ��]G�|E9���s>4,�E��� ew.}v!&�dap i9!�)�- �" oco)mly;1E ���J7AU��1B �*�.�2B�I�� i�!=�6�8[ )*>�+*"";(�6R%m"~���"�/a%&� or ��� �I�\!, �g*/��./+ �7fr)A��n+��l6Y,.ax*J#�2 ͽ.A �%�^"�-�teo5��a��f a Xn -C �)��o:YA�P4-iron acquisit�Rion pathway has not yet been characterized in more detail and its role in virulence6D�assessed . The quadruple Δ141-kb ΔPCH ΔHMU�^EM mutant strain is unable to produce malleobactin , pyochelin and hemin acquisition systems , �Pdisplayed no significrreduc18in lethality ba�(on survivalab�ute murine melioidosis model ( Figure 6B ) !�is indicates that each of these s �is�ens�for.�othGvidually)� n combina� . Wh!�ompared!; 1710b , b)�Tal loads were slightly ut.ly decre%in� lungvsplA), 5A<@the liver . Ready�s!� � from% site� infe)s!� lacka� differeAUz\pargues against any general deP/E�vo repl!sA�!�F�!9�s may beA�4ociated with a-&Z$iron uptakax)�]�6�%�is A�v [by HstoreA % � �-(B . pseudom@i]phenotyp!s6�sideroph^Z�ityLtracellular lifestyl! m!a �bU>�7ogens)strong.o-i8�)�s are ex.oL. For !�a!�, a Bru�(a abortus b�inT icie�/4grew similarlyA�a wild-!��T0n a mouse mac!agem�[60] . I2n� betw�F�!��-6Lresa�� em ,! rebyAtribut!�to@solidate knowledg 9�5�. Tes��f�!f� orga�� show� at 6�g A�!~)-I� predictAC��they subA�ti)'n coaH�of�6=�ought�be=�l�Zefu)�� lex scenA���manual E�� doe� Q�s�v$or eukaryo��9,�yb� communit!�,��v-u� inte� ions . 25!@� �3��ed�-�9� repositor�[1�!T!|�ge�| Pdistinct ( bio ) chemA� ent �%�yp��ccountE*thousanda�Ua� , reA �?A*a^: assumE�ASQ�sma�> st� stA�,�,also e� 3c� ule}s+ ap"� %�ge�� anno�� [2 , 3]%�ف@omics data [4–6!p� U��[7–9 Q!�8parison [9–12 drug!`4covery [7 , 134!�engineer![8%5!��(��a�qua!�aaRly reI7uct#%� rnalVd��wi_�F� ]E -h��m��9�H u2M:���%4�ist{%I'c]1(�.luůboundar�.PaA�mas�1  )��d a�art� i�I�[1![6![4]�re-��A�r�to%\VZi�J��C�Lve . Enzyme-driven (� oppo� (to spontane` ):�a:f Gene- in-� rule�IPR�� � on�U �� multi# �G C&<wheAp altANAl iso�s� e�%b4lexes catalyze!� [17!eA’s eque�Q�9���sE��tm���corre!5%�(stoichiomet��.>g$ rsi2describe� � 5Jope }forwardxack or bi-dir� ű A fluxI�s� y2b�ca� t��i��absol�upper a�lowerRm�6n. T"� si�feruVad"jZas o6jdefnu!gnt��s� �5) bi:� , fi).� fle!�� mole� a���F of aee!q�Xj��sF growth�og)�E�se:�C encoE?�dGSM aima�b� �J-��%ϑ� Howe�, ea�.$well-studi�b&�Sacomy�ce� siae�Bacillu-b=A)�uncer�c� du��ϡet�!Q%�se:5���� ��ddrKXon�ert=!�sific li�tur� �}rscP '�� E�b�s!:al year�!= exam��, y es&� mDofF�:�G )�oMtd erro�winfor� on�heter7 ���pot e�co�� ory)& insuf3lyAI J*� t�|*��8�rna" <spell� a�o6m ("�t8 espaAV$) [18–21]nd�fl� ng�62,+  22];!A!B subj��v��5� pretG]- 89)j !bof�li��.�)Q( �:g .]&� tq�� ) ;? ( iv5�ati���Tn���amE ( re�)RA�s;IkUyk��"q�c � ways nld<5a�5by� ingl#mpe,2 -�nd��yq> vary!ci�ua%��i!Qs��te clU�lipid�Q olym[2�23�a��2equr ,� nu�y a���sa��EdVo�*�" ix� �V�o � iSoverlapp�[24 , 2� � exa{A7E��5�cV��Ybe draa�c�9�ϥ�es-ihumtnd��st �agree �on 3%aO]�35% [20]��\����� ��%w- igno��e� �,�to54nd water imbal�, Di�s�%��!6Z�t) |I%1�hor� nɨb �&���n��log� ]�QJQ s [2J Any�� aX AS! need�( somew� 8arbitrarily ) s%� ��%4���&���u�)EM"� ov�eE5!�4.�. T��uBsm- A�r�%�!�5 � im� 6 � targ�q),2E %�R(M��0�H� so-Je��.aH� ��:��ne L � . Co2@smn���scopeU�AJuniqu]�Xi�al �)1y%�mAM�S�d M��h3�FO!�lik!|toA� reli��@discrepa�exYQ�%eA$� mustCcarly��oQt!Gmappropr;i2!.�.*� whw�2� have�g"suc�fu���Q�( g )5���bud� ye��A����i�'�(�� v�W)�"�of �i� v0�s�}� To&GR$bottleneck�r�r)n trul2r!RB" "~�ev� �,a{m@y#�jG,:+>�1�b%� acheM�� !�� . It� �a eɆof�pl��Es$ 6)�esI�ANgap�n"c*,ed N[28!�9�TE��foc� ly��BciE�na" ( aej�ly��ort� ch�ngeE�match�&P�or]l5�le�&" [1�c�*,�metho�e ��a sj:�problem%$:\.�d�d�v4 �2�y do 6 �~Eo� e ca��etwo6�&� �%�1c�a� at�t*u gran]) [3�Hm,=�rCOaa�_� 1� wo!�m�w"�f�beyond aA�monY*� �6�-< �,o:a��=i��!A9<nets&c�� ��� ZufU �&�ie.��8e�ndA�8novel algorithm}B�s�Ek xp AD��2 �@owe� �J��Fa�Y�%�l� dard[u� [31]���a� %�G�Gth� chiev� N co:�al���3)3�re2A(�"���3iv�’A����A!�. Beca� !������Y.k � �$*6��ec2i yx~ bestFDa5��J^ . To�"�1�*T&5t}II= ( I�)�Qje%w�#Nh+ �� ( co�&d |�y(eA�es:��2  AhA�aHa�. W�""6!s��J/!.�yU�E1�u��&s)��sei� �E;���m-��"nd negb�#�T ��& 1a� �]�$ softw� [m�&e,'fo �(�ab��� �&2� ., lea6 F:��9i�a.�%�� a g�Qhn term���architec�.� Tin SBML\mat [3�a��m�blangu.$�xbi� y-S2)S#)�!Kfirst!�verA�i> �""�T YM�MnXRef;��. Next ,� ��!Q�� � zBasic*t M*( BCME� �)�l���2���q�A� with�' ~, �mat> yielE a R�dJ�R�:���w.[�!r� rconnec!q , it��n tA��!��1��to�L` uishco&��c�Lɞ�#�2t�! � F�2� &� �f@�#?(+mbigu�ca�6A�dit gu"�" user�decid7]�A� H{!�r ll� ng�&�A�R6} repe� Rd�A , minimal eff�$,!lG � �e�*c% made choi� $9�5 � ��!�>*�)�z"�y>� yF"w�!t��aI*L m7 �K2be9Al�P 2���(���!.�5."�"u, ��cAe� �I| merg!�ŝ& a>y A��h���%���!\t ��A� ound&7 �O a*t��Kia" ighbw.s!�.�eS )���issue�9�.� inmġ�._( see!P%�R . Perw�"t}#"P+utida���&ed = �% �Dit��!�3 p ��"� � �� ,aa! y-1D.�n@Q�)�M�cE�M %.4allows�4� a���$;!ca&�5�6 �lAlq through|chMj"�! bran�poi)�>b�mB%��V�&bi�/#� become�a/&. S�*y�%:��T Cͪfo!"Ae�/ J4!*�5�AF�\��ihc*"aa>/Y�::� ) nes��R i` KIQi=dox pair 3���� .�H�+l6 �Fura�m�w�Wdeals � }�"sub"V�'a3 alp,b6 �fS|ng-[mom1a6Ie �1i$J-r� n �5�D6:�!ͥ8ofJk%p!)�-Ft��9G�8Y�/}�t.A.hemae.x.f A7.�con^*i�$in�co�$Z#�� ’s��� �7�� &)�,ٍ�m�)H�2��|� �a�}Fe&7choos�36H handX46}m"� i,e\ �UzQ� d&"��hdi��yu�.O &1�!��-͙B +oa/�not: if� ��&f�3Ou�2 8e��B� ����%��q��ń exac��5@i��5M�)] vako�0lh�.e& . d.\AQ�?to+�x�d�3s��1�!pe�a� heur)ce`�ou* �D ls�viM5��"e R �� &�impac��"�%Y�a �M�rre5�"+ �y�:*t&I sum�0)E.����n�cor%�u%ctnesL ��4 "�. Ha!� ltho�AQ=m� uj-Sd=..9-�- trem !�q�rG8 mmend � + i\!�of�g!(�To"� ��5��&lE to evalu|*�"�/�� �� �f�s�N))a!QP^5onas � �r�j!�4JP962*0t(iJN746 [33])��&{ *; l��Fi"�n��Y>^z�sA�surpriEwy�&:�il�9ve 58%!jg �333.�u 2q�����9�q�u)V��S�*�A� �!�44%%t>�11 �� .�"n3��&!�oc&a�1:6�)Ŷu%�E\ if2�*s]&�( xE a�1v f) �z�%�)2�*�)�unrel�0ny!U*�.�&�,YF"`*>(���app5 l���yn l6I�7�mut�:exclus� H>w�rh &�!d �'>9*I�6a�&�6(�-�#ed( �aA�w�9nD'�h#*�(J`� �sa�!�r� � bias~m�0�, . AfZ"���s{� ��i #) 1��0fr��!��&was�5 (eoI��x� half>NB�92* afA#=.���43a; S1 ProtocoS)2,exempl�3~ �%e < W"A`isoI��;�y!��)�, m�pL����Q�s&Rwe �o'>a�-step"o5�)�3.��./9�4 verg� nW� ���(�U 3VFH&��ed�V���Prex>�2.�(!o!Iat!��;)on�� y"���q)�U "`I�R�EV!��estE��A';?a!c A�%lap!K53�3BK6 Y�. (v !�d�2p=L&� $&P ��N�EM+*�)�[In��tarA���e�S%5immed�"ly �+up2�1{6I=W*�� cytoplasm)]split=��z%� *��sUh�S periTic* ��v7.? s |add@ :�]�ߩ�� 9��cp��i#(&�'x1� A�') X�ne5T EJ���1e%zh> 1�t GPR�1or5 2^a��oJdidE�R �:�s pri� L %��!OJ'+h" j� M�isQ�wN!�V�Y� .�1���4pr"�<pub�)��Co jS on5V patterZ-n%�b�genq=�@� ;%bi�!9�E,(a ‘strict�&4�S26�Fi�Y&��ye&;� aZE��:��&��Cj�;6Hb�>P�%dM}�"��Eed�# !� �A3a��has� !.�6 �;J�E�@�!FV?! ��:�!f v!>�Lf�R<b�m�E!��m^>A� �? ]��number;=�AY��q Z� �vte�%.g� Tq�-�� aE>Z orig�Eng�<�E���L� =7%�� � 39%��*7�(��D&��&b!���>� =�ɠR� ME�%����8JH!0a�re-runu��=e�out�e,lea�F23%RC �DIn ad�Fe� �-��SlF!�!>a!��CL>ngko�"!d�C_%��I#?�5d u:� �*-�3i>i�:to�B�%z p50%C� h3M�� summ�/�>m,a1H tudyK*�l1 -�e!�v!�Ic"h�"K��6�?�%ts�1*� =J>&!�z[ nask�to s.�-��52B� �'r�or:%>h�*�2�i���i�!�k%=FnAOur� � i��I�[ �%sy>Q?�Dfu�6��_��n q�BC�m=!}simply���9iq!}f@4B�p��3q�would t�A�ve"~ E,f#\�c>|&It h e&�' �, E��+qbdAA�1�2�=O1|�Ino%mto� *1)�;�wA<�?��5"�p:�Kc%; /t� !鉭����� J.nefa� ��.a Hrst2��0PF"F��4� ��]��'� ain4�+�0Ya��s!e9�e�non-phys�$�/ CO2 fix�k<^ �2cycle0m�Al1moazO��t9�a|A�O1Q�!��E�X���9�eBby/f�Gmaja�rr#JE4�� . No�5�:�C*a�as��&�K@�i���%/ %�A���dr��a 巡�1�,�O" b�F6YgR1�MAnD �CK?�al%�>?A��"Y�edn� ZG t as�2!� $a/�*��iARA��5������ v � �(57� #%K� carr� c�=�brinciO:)Z ȥ� . As:� ��n�šj>�a�e�e1��!��; �5|!�AF��Q�!�re%s�V9=�I �/ Y��<pR�B�ez occa��dis�6uNll-[, suggng� new� �����{&�I neiaV1)�cap)��at.t!��� L-qu� � sol�*rbQo�L2pjE=2�M"!e�!��6Lq`I�behav� g1E�� P>�1�!11 ����6�g"�3A�� {��5"�of�ai:the�, 0�"1�s*E&/&b .sS!��=tyae��l����QKdI�;tM!�thYZJrS &� #co�s [34�2W�_ 2�Ai'!� �64r�):2�a 6 ��t�8�-����)ŗu.m�� 9#r I:�#wTpu�L!�v%,2t%,a urac�A�Matthe<�r��co hGMCC; un�6Ait���t��u�tru)�fal� ��cr+�G) [35]%-�V �GS3&��  b$.�^5� �.�m!�8��i�xBC�]��J)��8��nelQa{�Cc��W rout ��he}H> xcep� *��!��2?by�L([BB . s�A�8For6��k aw*���A�&�T�s[) i.f�'i�b�&�/J�y��,BSu1103 ) bezl:l*TVa��de�or2YO844B?�2&�K�optim�2!��5UP���GrowMj�[I<I>^A |��dHpPr Ac� de?Q* ��!�itLY�+C,�+-�M�-Յ�%`�^ profic5�DRA�1_:<m� Q�/, *�<verage]a��4&�1m.mT!ȑ,&AmC�T� �Rg�l�e� � q� !���H9���H � a�R,&�-B�E^7nfl?@�.q6V�k5� Sin�3 obus"c"E�a�l^ &@w/ pQ.�!how1"<f"c�&�do�V(5�)�  N�LerJ J��E � �:"� �L@ a3>�/@"��a�,s iMM904 [37�!$LL672 [38]"�R�1)�#�9I��. is e�|)�5 docu501 5b� mp�+-� �>2�2� &�f6"� �"5*�9Ei!(2�I�&� 6;(Y�:�I�!Ttr�x 7�O�!Qs�B�x ��aObBa� O)e�$>>���e��mmeda�%I�Tood2��f\f}n"R= 0 . 98:[ <a�"d 87�MCC 42; Q�Q!{pUA���:�m"* b2�7�=M\oaim�U�!`�X�sui�CZ'FBA�+6d��d1�< � :�"��1�Q� � CG%&� �,&� *F ��*�I� �bZE�"s2�� :Q?�/����-^-1�eU���`believ-�A�g5i���!ed�fc�2�lose-to- Xqu� �of supA��tD +�s ��t�"'enh�4fu� ���I ʽR�yHed*ZJr.�R�Ѧv`!F  ��&�K"G2)=�[>�sh��D�> C"�Gndu� �d�� mo4)*�:)�"�@)�-i�t(:��&9E�in�k\ N�N�.Q,��v(a� opaghX M��'eHs�J�igy!l�)lA��-!A�6Hd2�r�Ff�| �} �!��T5ŰIFK%�AM&��0,NJ&{���/!)(�!"�so�[pV g�velop�H!�ɒ�y��a�2��#0#G,�: B a omin�A"h appl5&odaq7;i�-ultEic0/.���>��^j(E* �<�alr�Uru���+s�U.�9!�}U:r=�(7- >x& -=�`U -Jf?1.2U�e0�asw:.�=E<��>�c� theo�L"b�'JiA��E6�/ �"�'� VR �28ceC Yx�KH a� �L�M�99d�X��&(!�pI����ina�%�!����"�0�!&�yG� U�"�A�%�Z6N5"{3 ��4x&� in or�d�k=B*�/ surr8n� B ��Uf\�%;67a e�5k11��E el�H��1 �zW�G!R kl�5!b�)os�:�Ae����-�up�[se�Dn��4)�s79�MbM�fetchE!�W.pA � � >u<6 � 1P��^*�;�E! trade-offuq�� !�Al�v !q�&�C}�.=!8lim�<deg?�K�h| 8:( aYA�.� AlsoIJ�M� �a%1'gU_&�6c v3�o� 9�o (�#72 xten� -�z.t}��� prog�SaHP !#B�$.! y��aI�'' "E&8e*a� � �a�A&Y�bri�^���I5�:nd�:-� m(��AB���"��U.shgeEaGa�T�J�RRK y>�'e? �? #It@H� �[]��wI.� � h�'_3 effeW�1�qR3 � l)�R%�큭adKY$���J�QYv�i!h y.�F�3 �B=?-yTg�� ll'�m .� �N�jb�OM=%�\(e�Dj)�mT���F픥lE��J�e a6Q.�8!�U��s o _A���b o��%� $ �"2rU ܹ��%�M� N�Jj� itB�GcX" [ex4+� ;l.�H"�X��QuF ���As5*^f�D�4��� F}@�$�7E��>�f( ve p�Z"C i��ed)�%�}�4%q"���H!�h%Bidu�C �$!�9�M�B�F"ta��P� � 5 ~ ac_2�F� �m�da*B�� &�8a�Xt%'�\c#A�&�d� r qgo^luc�c "�M���d.�ba� 4^�%�4a�l)z(r (u��l.'Be&�ba�g!n>A�2SA�s$�!�rjSd8!��.v�\ m`ap-fi Yq�X39]*�jb�oqOEW�9ppa ��h�G�hznecSRz2e40]!�re-N" ���6 ,.�!&9��n$.�C�|@"!;�41]�^+�A��!Pa�"� �Bi]�o6�[3�42)?� �eD�+0]�Q�*] �  :%a�Ili� und �!new jEYIL�a]L� �wm*��via�Z����6�hwhole-e>�i�C���M����A� Mz�.`of:-\.e �%n2E"u�gv�@"vQi)L postan�dic�qy!T�m�s�C9T%Aͥ�l�meaUA !H���yi%�m�widf ~c�^��n1,�v"�S,a�"�H��"Ahelf6)�e��2:+ofuD� �!���L�4�%bcr�Yt�^*{.* d�ng ͚�r�Fet�MrXE�,.pa �3C�/� map%�<( �"}�s"��s�a�va/ . `�� orth� y��e�f�Jk)���"F�� top�pf��arc7dR�2AT��y�1nd{Za� hierNi�jhi�1p�T!�b to"�=advk>~7 � cont�!�3! �O� c"jYb�*� aie�:�&=��sc�,U greaC�tle=:�* -buidO_+iLw�_ ���-�XpuCp6C^�AA[Bm� ru �*�K!�&mA/SX��*"a*� Llay^��w ,A�o"�pi��k*�cc*9���P!��Gg�!zh$*_D!�o"�"'[,__��)}vZ�nB�[Q[ 2�]>�d ,�nC�T�e8��9�N:�?re�Ɍ�ei�by � l !M� au�`A�hb.)(pap�b.��N-TB �$ downLy.�yLhttp://sysbio3 . fhm�*+eC a�a,uk/ . iNJ661G#E|'2 !\2�#6j���&�2�"re�'LfZ�hory9www .eh netx . or�dSee�>DaIu���� ]j�'.��[I� r �-- �COBRA box [4�) 0bm�'! &� %�ad%�&&=o�H<u�n���A�!&,[ I flex�k!�� ��["�%@!m��ck�5G1 �U*��m� ��A��nej�kwi�FR`iqte�&Egnoora�d{�5�y� defa�cut�6aU10−6 )��T�I�A�O�R *vs�Z( 30%�7�wit!+I�b"1 .ICZ�)�aEw�u���(i� no�v��.&�T��=�n�w 4�9"�4[6@1��� l��tFXSF�G �.*�:@�'"/ v&x��t�-�55.�W2��!�� "� a�� on-�4�f) ijv+V:�L ���lWYz.u"~ �eq�X-5�B��aXW�B5%a�oL"�Dy_ ae� u>Z&� m�!s.!i"�I��7 ��I!� +=tD !S'dM{ ��R��n,�.���1�2� �:�PRVq �� ��h�.�x<q �de n�2� equԁ~B1=�aa�r"BF perc' l� >s �E�a� esho�$oM�f�}F�Ej�hod &�VI�&�R: AhQ/1JDr�Fb(%�u%� A�!"� *�Y!T�-,�NG�$k�j*�f� �3qR_s�H ,� adya �in�)2��] ncel}.]  k qb�DerH1�=fy>%e�li�(0 gram��z*n�)�%9.�!'"*&!ݥ�t8���iP��a}�!�` ��.� 8z��.5�a timbbI�qi�B�X�*�!2���7/���#!ޕ!| �P��+�%=,i�!�Ԃ�!`d�.���sy�9s�3Vz�}A:����~f��vaPN BPe�'��VY#uM#͢2�q5� �b>E�a l��!�2:z�i�� c� ������ask!�!Fw!��ꆁ/7*5�pi-JQ�����-w"�N 5�X+�I.B# E6S0J2".�9��%e�  sepa :�C(matrix Scmp;j x r.�4��rs>)r�\H �yof�O<X\�>s �%tE�6]ColumO@K)9�I/}.���+J�jZ;t�"t� ���e�B(P,2�Qun�RM!� plac&�' UNK_COML4F3%ach� �M  Y#A�;,Z_EFA��|A��1RV eaZ^��9a �I.)�.�'.i2my-9�!"� fi!�Eo�)2'�<���)�un� R�. BP ��5�3 B%{rB���a�#� kex A:> E!��yi(�a�P�,���no�AP)��Fs.En�W� B(�$"l? �J�I��S2�UO6�K=l,P�B<&�Y B�stPE J4)'I2us eas�qQ�idCO kX����ASJP% 6�9�H +"b�S5�Ih\�JR|im�0p]ght|�4ce5#`T 1=RCL"%{|$E&�@�yDiS*| �/2� ‘TM�UR�:�<1^>=RC�_E?���B�(l��en(5Y�dH^R6��,q.b�RC%�A�TC�\�@M5S-.i�a�Y�R� [ nd T b)kd ^~_ �AAEs %�؂]�!,kepD2OK>.�� ��]n� z�2��'# � �!���d*�l.� ��:~ �� ���A:} :f�,<;�bL�j"} n��r�t�3�T2�E�~ ou�!2bc"�db�Y�2�%��_��n�{l^?* ,Y+ 7ase�"�j-.'ek�ۍ��lN�)h��A= 0!DI[tL .a� e�Boolea 0/1��Ͱ� Slog�WV��-F��T�"X{YI !�!N%�.�)�20-2��m�bow-1� _�#A`r&$b$� �"+a&@I. F,)_z| >�"(BAZ� � .z&�%�c? a+�8l�tf("�b�bB(��p� expa'J�<� }aHglC +�+*�K�)z!�9��%�co-�Z f�e�!( ≥ 80�K9��+Wf� 6�*9?)�.D���!2y�]�to Srdx+1� �B�v�r"� �‘y�[�L�!J Mt 9�en]N�*�A"� ;�%��to�0�)�adKs ‘1�8B�rowf-�Ny�V�cj"���!XM��)E�s 8v}6���F���y�2�!-n6����N�"5 co�X �8 "Ŕn�y� +& a# �nonzero�jw Iow*�*;g G�wa>?IW�eK�w�D.@a#. �t6#%8���X Wb��0ng�ts�*�.se�s�Q&RQ A/s�A� 3� ��b8Z�>. �>H IO��-��qB�! of��4���"�%?U����0@Muc�os1�~hg�s� )T@S��omB�,"Ci :7 �!0�ki��^��%( hI� �rRgedq.�m�%�A3�inI�"�=A�d#�FTapuzQ *�G�"j �A�RA� MATLAB [4��,Gurobi [46] "��4F�'rE��� b$no#go� &:<���i� ,�>ed “mE�e� , ”Aȥ���!�s ihhA�in��b��qm�&�,�a�ic��!. &�|aska�PGCgA��);� � D-a!m2 Y,�)zebraf�t� (D=��� latinhib�G�^!C2A>"!VN�u�5P�A��HngAL�al)=r 4�g�T�cru�,��aa�<Q,�Sw��&�I�-�! /�C-�. P#_�lo�+� �le��A����6am20b^xylosylE4 ferase1 (t4,v"��"A�syn)  F$)�MM�D s fa�<V]��]"��lA�%-�ie� sulf�!�1��Z�z'b)�zF&�x-��F�&�.�Eie}0{�: �" �.�ing�Pri�X �a�%^7m�q&A*e*&�E�as�,"( )�.Q�coc��].i�fy`.�]4A�YA�u�A��0V mark�&asO?x2b�AolanT$10a��Fa�� �*A a�e(�&:ed vF`inA �!>UAQr.P���294aberr{@M�o�Mu�� �T1u�fe!f.L hy8 roph`h�R' !AnA!k� vitr�x���2��Q6*t1��*PG} �ZO��.�a6em��Q2B�� !�! ��r�LA|��skele�2� V�{b I���e�3\� �V7a�ml-P yam�qZ/X�"5(e^!a derm��V� endoiCal^7 aG9��9�+X �X�9 at&y�oF�e��D���f�qfyEKE!?m chy�gRen�oj5��daN �� Y2s��� 9�6 Mܡ��.�� ��/Pe��kɬBY�,p[��+��a�a��y��9�*�!1��vcD!��. L�Y5g �Y ���Š derg Ba:'�9meH_��:�2��d.h an hD�h���)%�J��� l10; [3] w Mean!V,-� :e��i  ��2�"y1�A�-�D+osteobIl��Ti�5�.r| "�"�a 6�C:AAƉ��X1�0f;�v�[4]–[q6CM�b;� �S$factor IhhA�� �%��2 s�m�A65{oth��Q&� ih�O��deA�:�2V[k [8]A��/)2��Za� T.�ssE� crip�6 �[��[9%1��a1)@�0�)g� I+Zif�� �z�� I����\2G��0��. Y ��A srup�2y"Wa@� � P ��~:� di�.�5Exosto�9T� by�o �in$|8Ext )-T� F 9 eP ze he�"�& [1ag[1T�Mo�!�Ye;Y sloss-of"�Z �d㨥�f�a�g�ZE�4}!�>J �at(�� ߌtaY�[1i�!�9�)�a~���k�onQ�of6�,' suga(ecurso a�!�9bob ��1w, n ÒJ*Asha�Y~��a bQVz � A]%)jY���17e�ڒ. I\�-"�3�o�� f>~L/ge`�=&Q ���5 PG+�Bdqh�u�m�� f%�HS2_~�E�lH��DM-:� ( C])U�s�����?on�t . Aggre!l�� ~kІՍ)�I( AP)%�wick/X%w���@d*� C�~��[���%c�@s|F��Ɨ�s&�ee�f�ha^ i�x � ��VR �'�PAC0�|C6� M(@rJ�ZA�hyp����;A3!��\ce�6sj�A�bqٝ gene#VsN:�&� ��larva�Vw�Ar^:&I�nVt 6 dS�>fer��x ( dpfU v[2/6' rQp c�%)�2o%��>�h@�dis�����L�B*Q�!histo"�!:� ��{ ��in�!�l v, �inE a�Z�Hscu�J� :A� =.st��u:i�}�ra�=#��ll.F<PG&e�*9j7gK�@6�$I� �LZ �6'. h{% vivo�M�q.�-�or)U_ja[ �� nX� F�S*�t r�ax 2!`�Z��F. 9�acl#}ba 5� In�Cz��5uɀ&�b1&!�nt}�����sx����9S~n Rݭ�� dromYt�AwRmcA ݁� l�>� FAM20C�!G7] . S�^�of�8l&� �Tagen�A�l edF` �~0 sA atom]86�#� % "� *_ �deۚf*na�%(D=/W 1A<�B��&Q ��&6�|der:Q b112a� ��Xx 1189o"Q�homozy0@!%� q���2� �$["�!�as judWq by A�r����G�C��H�4&_I������Alcblu� T2Tm>�minA =�!Fi)_��r8��'��!�*� or�A�2~R� . C ��!/.�+ 6\�in 10T"1LJ���"�r�]s# e7;�Mo"�gV��5.GlA$ I�d%��5IF+�"� }Z,} c#�"� �jwoe� loci�)�E�/Am�A�5Q�27!i"LaO� .��,-�� (51/212 ( 24�9 i� e�g��A��%� �d!<�ahi . Likewis��8�89*��2�60/208�9Ɗ8� rz-�j% �Io�@ ��*�� ��={7; �/()3s� VG?��0=ach"�- :��NR��SAJD�O�;F ,.9� below��*Ri�eU sqci �M#AW�&��1. س,*I�-f5B����I�p � cran�� morpBC|�t�_u�z pfؽ�>ezY�� sUhorSQ �#U��&(�ib#��AllN�� !�v��ad���qlox5sina eE��i�)�eS%�"LZ~f��|�9��F�,� �&��8 �]8>Ωjaw!�� �z��midfaca��ul�vey�0�I�tJɛma".�-s�ze��adMonsiiop�MAb �"tom�8�( OPT�*i�E�6=�x�� head�?|h mpanE�yT2�JAwo0H.�^y]kK�Le5bL�Z^n9�� �c�zneurofa �j����ma:!�%�CX ���>�group_uQI�� pp?�@"��>/ �D���9�$l��Ws "� &��*�� !�xy��F  �U�� AD�=ȥt�� ��"/� ( SS)�1*�����b 2 cM�& LG20!JAk��!F���9� 2A; [29];�7kۺl� d�#!�y") �) T�( 991T>C��_ ?FM8s�ocھin�si�_( C331R;qD2BM�C�0��(�5o/ela� cDNA1:�5� a 1162C>TEeI�!�nt�s1ex��� �wf\�) amin��id 3881Gl�> STOPAG trun�Hng�� 22A�V�$�T2 CyA�)!d a389=�B.�&�m�"%-�dP55 hoursV�h�� d� )�B[q  j�x� (�D�A n�-)W��M"! _Le-�5}RNA� a~P&� "�0qePeM�]�ʁ�D�t'#w�G � cv]X�18 u����.�. m��#R,�!, j�a��:4f�7u�3N�8�]-Di�e�S)%Avof �!*�8iM!gaV}Ks��e don�P� � 103G>7f} on 9�i9� ��^ shif!�bm$ed C-7Ki�C ii�!�&_X�j�i�G`�}�70� rFof 919 ,�PE%�E89�E600T>;�i�%^E%�eA�;��-A���534)�SP#o Ala=�E� F�`28F�V�pf �le=89F=��+� a_�-+P���atB�!�I�A-)Q}� m�byU�e�%#�,ui#rF`to� eY�Zlu�#�+��JF%F���.tgnt�(ryo��in�   Tol2.�b m��b a� i�_ ��t"8% assa���N�. W�� C�<)d �7�( = 10/1�p!� 6"5"3/8�.���en!�!�ubiquitMbeta-�n2a�mo� "� 3A–3D��A�E2���D 7�2�>�{entVQ �o�)>��U.al�a:�%EB�lɿ���qM��Dmosaici�unE�g�=�8�M!ԁ�o��J/ob��_�;3c�,�P!6��� S"slcv f.EV!�klųH( 5�1-9B$a*�z~ULa�F. ��o2<&�l�'er� r.�_!V��q"�(.) Ba �Le< d�' ed^\E02heavyZ^YvIq`�P$a�� �!P�Q"-�ceG. N��$c3It &�ys���e�.��rolhL).&�F �6KB�;�o�V*�S1�sKc��� B�%�!Oqe֙ P ���� �.YY�0/2��or .� 0/12��9��76>�C)�d<��~a-=5&�A�{zng��&�R*IA�w)S���| ����&� �BoJ�x!v&����)�YP*�z�� � q� 0/11"[ SE*qIP�JH��Yd"Zctpم �C�un% �#�<ue���fa6�at� �%�]�MS� �wl)� m FiE��?��zmis. w[2�ʕ�_measu���JU, p�(���v"1(.���&%pharyng�/�V�:M�ot2�oat 48�� "?>�_60� u(Sa;U��sv�anQ�pl�aP��.�,]M�}L?�4�(%�!����;(heat-shock-*��pr"hsp70l��A/%aX/>�at�pa�o�TvNU�� �aR5m�!D���6/7}`S1r �m���^s�_%N2�B t�3����e�M!&2�#}5�e ��a`��� gen]2B� s 5 �Wa&�b>"�<� ��_)6go*vr\SA��1*�>��"�/�c". Q��(� ���2��!��j1 RT-PCR�3e�J54u+4b4� , de.y.Nkm ��� mid-�*ul��iE�<d )��ic!\�e!�!#,situ hybridin""�B �-�2}&&!� t. aC), 6 �72%���&n by 4m)4B–4�4G J!I2� �)�e-�%JC`�F" �$*C,�_ly"`,*F/�3:��4�� ^w&C'aq�Zi�$��WP�'%�f>�kQD1� -{? c��s���WH"�g��-�qZU�6%&�"�.at �,-�s^��V � span�2A��/Ck0&�-Xa�]1�1 )��%�AJ� Aparmoi=ir up*�6�U�&"-JaJiff�**P6Bb�W�2n"�0;�Z[ M� /c��G1*7QE�%")!��-VA��F Paus!� elev��9(" . Q����#t}$�O�+ lysa��D "��=*�"�clu6�-�"�%��*� e� $;I�:T(f�, 5'�% founMti��&��Xa̭in.���btR��ftX�,!.�� 5�5�,5F; ANOVA p<�0009. LA�e>=u �]�)�7 50±.^0%"57±2 .W i�[:w8߃�iv' ��"�VP��0b� .���to 39 �6�E�<&z ")u�5/�(6�-2.�� nu�QVin UDP-N:�&thK:uxs!J�Q�x"�K�!aE!>�v�4�.ep*�6a��B�`�6A�� F�%q|�� "�:�GdW0�(-W�ZI�e ��_,&<�z�v%��l�R K�ym*~;t1qD�?:.,&�!si�%O �"�"O less2���+�� E+Y 22±5M fL!MI#��6"�"�m��a�b& 6��H%l1%�%� z��@85I�\lL l0an��,age!�Y^;) ^VE� %Ag�5n6�la | L&��gI� g%��5��'��PG"E�����+�qGAG���� �-��.b�AWiZo6- �)B�5hJv3(1QE��:�0�+/)�?�-9,�|e���0Ll>��, ~�2�bF. HPLC)�'on��Mm 52 lI/&� Qkb\!�& -PJBS!�i9lB� 0*K"�9�[�mH7a"0AhBts7@i:|utSQ.%�R�TM 5Lco�l��a��� �C;.6���1 ��6�q�>�C{y x2�o ,M� � I -$-/ήthMkA��3��%�#�:.� M� ��d��6 6��Nous!�V.�Q[%n �U�!~!;,��me��T �`bod��recog�- epitopױF8�in2�a�B�Ύ��"sY�A�&�+-$!d.�vF ��&I�.Ԩ��^�"��ȇ% u��F���t6Si :��*k��iumv�I�+ir5�"�0� Discuse��SiAhFI)!L�% upo2�i�he9e@bz"o4��R� �A�Ax6JM�mTEAB"j"0 5)C�)��l(�i�B+ٍ�s�Um�,vn;�!&s �{x���D$)to �B6 &Y$�1 .� "�p�Z8c��F �S��ici�� 7a�7� Desp�`%^7�g ��&9h�p��of �h3-cop?<%�R it�:&")�o�Ki�-�"[ . +-h"�-us1\&*�1 V6�I�noi�� � *�0 x!U%�B�s "�{1�lso� 2�my) !E%/J]%%G�pista!e*�"�igQ7l�e�B�u{���yk)>�4�� M�)v3m!meOj�&N ��#'f�8l��i"G2d6B�!!=V��"|����6�"� �'w����fINe��� %V�"&!���-m8*1H%��1pl�\ r#+:1��*Mas.my�q$c����d���V��"l8A , 8B���}d �amo=�{9��#t6 .r� ceratohya�! E�9*��b��_8��E�MEgr7)��inn� ur�-m���2�9H , 9I%td;xD#|��al]��at��E�IP.� b�!��/�s�A1$ �9w�Qs ��G�at~�E�J�*�Tuc@Ca1�ru�Oah�Ci�he��X7��pW6%Sb5��J��L�)��,N�I>2j d  -:X!:�of>&?��%.x sa��cG.�-o�$��1m�VN�}������6D}6&5�� �` a�: BY373Dl,�)� �kK.�m��bZ�226/�"Pk!di6NM~H);an)/�$��5>!I�^"Xr�c�� ��G�}%=yU�ټ&�K, q� "3w�Q�;گ� �a������" �%A� o�s�a/Fne��I�!AW�' or Ra�j n���4s..~8!ŘO�C!c �� a��� .�N[3�Lz�4�$�9�i�!L�Q;&� ��g� dn!L�*� h�IbKp��,��u��Nb�Zk��25%� ,�"��!�o���2Vu$10� 10� �1,!tz ihhb.��/��mA t� e y3� � �F10� 10o#i �-!�ox9b}col2a1a�03fDx4-)�l2�"q R!O�'m hG� t�pEmu!�*�"� i�2nby� Jn���@E �>�D*% KEg2�� ">VI6�l�y�6� .^>�!�]"�Idc'��p?�aZ� &�*";�ab�B��8%&!i!�%��*%��'| )6�U��*� $�&u(~�2�6faPm ��e�Hd begu� s�r��2T\PG@\Z�C#;�(���xe=�c"�E��*&�)�ͽ �"� 7��*2�S�. G3�E�9%�.E�L!���R� e��p�FE�w����+:�I"� �O�4� Z�� �|y%�z��X�gal �S�Pmi�u�g��R�F��G8�).�,]W"��!ᜡ��-!�*��,�2"z-�ER� olgi����midK���0uAH| ir�bio��!a2&� �$�{u711�=-� %k� �,6V��at16&H>�C����%h"]ZicB��d��4&�  �y.��&�c2o�Zellj!"cyt�A��Pt`=$�"U2 =�g a6�!�,6=�M�u�%i]�P@�pprono�d"D�QelI�m&�C� �Aya�� �!�-� 6�r��! lo�>o($y� changes i�n gene expression ( see Figure 10 ) . Near the end of the xytl1 mutant ceratohyal , we observed chondrocytes that appeared like those in the center ofa$wild-type ^<( data not shown�0Furthermore ,2Hdifferences betweenX Xand �ts in cartilage ECM ultrastruct! . W�2)� Xprecipitates 20–50 nmA�diame!��sA�iI�i �( *q�1C , 1-EIn addi%� to verifyAe <0defects , our6�\al analyses demonstrated�tjA�layed U�`hallmarks of hypertrophicu�tiIl prio%�th�ofe� �8siblings . Give%� se accele �molecE�a��feaa�=�!ur yin PGM�! we ue�2R0genetic means!Q=)._Ihh.Vsignaled!�m�lyDinducei�EI(al bone . E��of ptch2a@ dow!� eam !X�1Hh c!�,e�increaȁ�er���$lium[fam20b !6.�$s at 3 dpf}.L0M–10O ) , suggestsm� � .[ . No5���in�al�1 , gli�nd 3.Je�ob�`�� �or�mŘs��I��s.�P�R ,FR,�haps ref�����noiM�� poteA�(l transcripargetEq2�areB emploa$in everyE��L [43] . Because ihha �D zebrafish have deii9�$al ossificI�[7]A ,e could test� func �!�1nceA ea��v*by AK%I-;#!�%y double �a�P��EjQ��$supmed!�P��2A!�2HI�how)�at �i!�$quired for �2(ec�^�4. While epistaa�to%=:phenoC�.A%At!X did%�al��&.�x redu%�!rb�,�MsisAf ; i��pre�o��a�ʝ� B}���� summary ,\sei argu��"�PG:n7 primarily2�!"ti�of2&� )5AM%G]y, whic�n second ^trigge!�I�F�� Y. Inv��g -v b�;H skeletal system haABve��substai�ins�T I �0d.Zrol�t� oglyc�7@( PGs; [14]–[16a�[1820]�H�� provid� erimen� linkA�qͅo0on tissue culKE� biochemic!� ssay� !qsɢ��nr1� ia�e=X of b� 8heparan sulfate� ( HS�)��E oiti>&C&�8 �5EI47 ��1.Qi"dur!!�cours�� h geniF� (in vitro [4ma�� f!Yum��ivityeC%�A�8 Lo osteoarthritis [49��Our.�,2Y/ �X!j� ��sl gK or a\ dominante�!b)in%*A.�|, spec��lly"��us5vid!.a%�E�� extE�decadI~5%i��.A to�A,e{� eM6 onlyu� }�) � Yr�� qvoUge�\b [30!cKnock-�%�over-�eQ& ll!�e1 dH!��dmo�XcA1l� omote oda�blast"� a���4from mesenchym�b�`� s [50A�althoug��1,ar mechanism%bth��ol%� �,remains uncl�. Rene�focusa�*Ues ar��A�!Cl��hum���ma��isH cal� R�a�drome��Q�!8$ FAM20C [2��27!�Subsequ��EYe a� logoIc���b' �UP��hosphory� xy��on a nas��v9"@ 5G9 �[���� s��e�lihoo� disacchar��repea��ill beg0ed by Exostos!��C� ���P�[2� :�0.U��!)�( �Ns simiA)to! t1!+y�P2�%Fvo}F�Iof ?,cik uxs1*s !�nts��lAAimporta= %�!�A���W.-.:jall��ke�! X w; homozyE/viaj ,����>current.� mode)��tudy howIss�+.-fYvariety�e$Aa-ra@�hysiolog�proces���� the�ve� impl�`[2 a(,�Inati� n�mB�:��Ufac dysmorphi�ndɌsclero�as"bMh)�],"� t� -�� af inr v��dela �o underG aN e et%-%Q:� . ThD AG�P ��IreAw ed h) help�+yu!al do�!� enzym�� ge��encodm� �9 previousl-�v��probed�"� l��con��{�  acid&v among n�0 � Ts.�si ���)b1125%7Arupt c� 2� E=eK� �ed �& !��y ���|in �bq&ar�u"Fu �n) )r  �-(confirm whe� suchEm)� abolATF� kin��acV �="�.�a�15�[ 33�a [51]"��=�e��^I��s�X!e8%eE}b1189 �� new A��15�M�replace3 of1 !� with alan in.emayer minim� N in2*proVa�. AJ �8� ia�ire� cI� �%; 's across22�E= it m��A�!� a1S��.��4ultimat� impa�Mper�5�@i�1c28%�EFs smyMI�th  runcCa� yisA{oci�%i-?- �erA_on88645� erfaa�; www . �mbl . ) ; t -b� �)� ge;brecog� on�inhib!L"a���� :SJ !�oGm!c-Tcomplex"� 52]e7e�ex���sig� to i"!ey����X P.q+U mer!�\ qu0�vkr gl:s!ra� also3l2.�!@ZN�Vq�uniqueq�!U�6 al �a�� .� .~ �]B�i�A�B�|�"a�or�Tşdo�8��2�  d)�e% . Mu!��.�ly�s� an ei%�� nt alone;�* �8��re�� a� l�aof � S1 e-depen�A`pr"�4xi-��Zdra�c*M� .�9]C)CV�}refA!�� 2 6ki� nul�and/or�nd!Zp��� maskTir). Fato�&�� =�j�( !a.� 3c0 3 3;3�< k_tw�� s(!�tL orth� � to� XYLTIACkb)<2; http://uswest>A8/Danio_rerio/ )6�b}�u�� full set��;� �wo����w)��hvi�1Ţ)�a�ens�/AQ�_.� . WeqڡUc2!1:HaF�*�ũr~�, bmic� ficiaR��2 q poly� ic kidney � Eut�%� f ��[5"�fin�).�I�/ � w}ae[ &� endoO>�vals eIs can ne�v�| regu� �!icBa�is�s��u2U)�"���apeutics%C ]= �u���oc .��� ch crA�syn�e�4��[55�Si�FaU!YL| !O�=Od�3%�i�d. i5R�6FA�g"�4FzAB�beɘ must�%�-  e  .?�quN�"��� )�,����� b�te�edNnt��ly1*!5�.. H&2s.�q�@Alcian blue stainR2!D ab�e�NygŖ�a92i%�w,��]Y��!%�� % [1���A��I�C�ermed� 14of ��re*�!��X��h $n�facg"degrad �z-�a nor�,� stag%:f��# l3 erZ�F� ��u�$�2�%5; [5g57�An: explan Ρ2!2 lack�5(�n 9�in6�i�Tt%��fai#�e � I6��i%�u�:e�jQ� : r� �fS!�2  upono�1w)RerEis �u� by�E�,� �s�瑠�^n�w&sug&ad�!-! �n]cy�. Tog#��%ɞ) Z� u s!��'".� E�o��dea`fA �  �R�Ab#� us� �4���"B_YA. I��*f of runx2bAbBP)s.�s�y drives�6QZ�#s [391��j$as ihh co-� &� �#^QN![�[38��As V"; �sE�� & ly+"�a�6�:-�X .�XPli� �S�N#( i~  .Ag�&�)e��g.#.;i��s:�P�Y��{%2�%.�&�%y ,aSluJ ,cytoplasmic �An�GqJroE�#Golgi` ��mith i ac an� &.&)�.��h�'5ȁ�i�% iC4 ia�J ;s��_7# hangN}��)� G�<*�),�}�:A)c3*fF*A�!-e�� .� ���*of GAG$ 5e�#ncorpo� &)�d�e� � hyp�S) emer� 1�*��N� ^os�2�"�)�,��ailed�*��(chick Aggre5 iq [21a���aim� df)h#*["Yby��2� Zs !��c�e�.�>��w�exa����&ive��")Win� a !�or �aliy+�!�% , [5��&_".; %�!P����!.~*� 1!|&E� �. $ expaV e +lo�g�� �qE�� Ey. Allli�( maina?�4nd embryos raia�r�e, stab\�'rotoco�9]oIACUC rova�We ob ]�5a� 1127 8��!=l;th���i., N-ethyl-N-n'4sourea ( ENU )!�Dan AB background [�.��ahu2131) %�e�P� ghamV-(fix�2% PFAhPBSEc 1 hr�"was! ,in 100 mM Tr�� H 7 . 5/1MgCl2 80�:e `0 . 04%.� .:$/70% EtOH X� nE�, tak�-<� ed /�#�#8 A/~�; 5n+ ; 25 �RJ9bleac-3% H2O2/�5% KOH6w�lids ope�/-Otw�ino� erolF1JFpZM{in)Q1!Qizarin�/�NL5U^39�a de-W�� !,NR. LarvaeIG�incubV�036�I Medi,�.is@ ze l� � raliz� . a�,oligonucleotm 7!c�pp�!��2S4 . SW!ce align��s �mad�-�Z(MultAlin [6#RAD map�'loc�1a�$to LG20 [2�$&�!Uple� ! ( SSRD' Q*�#a a����Zof%� 2 cM"8SSRc�1byG)�'A+B%�C+D�!0scaffold 2914IZv7 (�l,Info/Index )�|Ad!��7���&."2A�IUi�te�" e�p  z20582{ed zero S-ov�Ir��-&D+!�862 meio; . RNA iso�(TRI Re�Dt; Amb�Inc . )��EN5�.A}$U�&clI���scree��a/r� kERi� cDNA2First Sx d S�"ůkit; Inv��gen Corp��� $x Ra��e 4ay�lMYPCR fragI�,E\�0d)p"*rs I+J a�K+Lp� A��angptl�ralgps�blact��)��z-��q��`p,E7nt&Eco�x2  Hid8 �*�"u sixt� :ex*f�"�$2B F6PCR-b�)g�-A�yE$��er� correspos�6A�)����0�-�A�m&0.� /614Q�;�32a4�!�,]� u� !� [��phx also���'�-ly�� >� map �q�, hree m�� ;�E!-��!60y�(��5���27E�-lI�di 2A�t6�V+W�HaeII" Ecu9�U8.m5:m�K,arker z10805�9b�8!,LG3J������ f�7!1B^�E+FE-G+H2�380a6��� A�Az�MR��2D%mW cu� �'predic�a�, ( LOC560951^�!.ec.�R&� D':�-1"!�Comparisi��Ens -�X �!t�*1�:r2V!s�E�aF anno7d)�:of �1����@2�!7about 506! QN-�Da�o ���e1"��55′RACE)l3�S�� libr*1uQ!nesƱwM%�N long)cuni�����4( Clontech Lab�or� ,��,!A& un9xy��in=�c! kb upst6 �=��<.e���mh%NZ-�$%�*�$�51 �*��K 1u.�, �:J��EE_F> ]%| geneJ�O+!l P+Q , R+S!xnd T+UE&submit!� to GenBanC; Acce�<$: HQ692884�S�! "*Q ��8 �_gDNA )�u spl� donor.�G2103: �5��9B�B�P$I0��%& �J� �?'.�6�738F�)�=% c t���= �\ �pe *^a1w"B= �)7�, cryp* � ��( 6/6�;neF2% 22.s��mm��s�5.3� a te� &` i�(:|E , 2F�+2�W��e a� meshifbA$�%d Cb�yF��;%hat least�� 702 (�2A�919E�bT%�nS89a0Shad a��:$�% i�' .I��*]�T1600:;6!�7#nF� �+�5��*y-&�'a�36*534)S� o Al-�&5���6 �Qis9%�hh/t �yc *� /63". &� iEi����. X+Y�EDdeN- }O���)`�o Z+AA pHhaNpAntQ m��-lengthN z�� E� 8!Q��4��BB+CC'i�e��0DONR211BPL(mbi�(Zg LR:)re�"��^ff+ME�� ro�/beta-2n2�'hsp70la��2r�GFP f��in-fram"� dq8 �vec�(pDestTol2CGw (&e�wU2d cmlc2-W[3�(m %FpCS2FA-�� spos,"� chie� neur�7 utah��,r�upd&��ere�"0V Ktc1ZwL2 � ptc2.A ?,zfiA�or<,.��M>?� ��a�Blo%�T�X�$mR �A �e1/pj�BCR4-TOPOJ/(&�w�Not�TE� cribA\T3 Polym�:�i� DD+L3 P+EE DžR�RT-�u V"�$�ly�mmuno�za%&24*�1"%)c#o%.$ bind�a:TAyco.a;"; [63H"�.�A�tG6W5shb(b EF .y�$�/ap.V8i"� !of�:R�inc%`�;ly�(wr3�q�L oc��Bjorns�et �( 1998�'llows:� wea�llL�#f!cep[.b\%m .�,6+5 durea��d�v�Eiail� remov�ora�i@A. Sa �EDNeasyrQIAGEN �:un brief�3i read�:trometri�8y��62}Fa !j�E�x<o�%!�tri� �% . Error b�=&�,�4ard e-9E. G>~ (A} )"�. stryŬ.(by%� UCSD CDn�C�,ReKc%Rcc&�Qs� (006 , Mis00�*Mod004�'ro !$ 7�`g�o . ucsd�\des� html� Somez*&)9a��"B"�A�major.=A�-�, d~A�/ir�A�lowq+��%��$inK!, &-,. Digi�ima� Klatɪ� vent� view�&#Fe�U.�"O6K�"�eA �'valaHmi' cop7tt�G �XA� �� �cI�J softw�'( O-(rsbweb . ni!�gov/ijB-StaB`7 resh&val�?� appl�q ach)� .�2:a�*iaX�<e� 1�Z}�L�*� typ��.qa� A�.���"�%f;&Aa�ze Pa&9les.'ʕFw6%+)R� in 43XH �an hour�,�.4: %�J.}% ],�H ined6�5 Rp7a�*�R . Af�)ey�F�l, d�� CdqSg�3�"�me�*o:�$i�@benzyl alcohol∶ o�7( 2∶1�5E� ycapO%de�Bioptonics OPT Scanner 3001 M ( MRC Tec��2#�ss;a�$�9��ri�9[4�B%�AVf��nmo�RJH . Ze}He!],�! 8% glutaraldehyd !��socacod$=e�r(room temper&� � !� then&4°v "24 � TU<�,r� ţjvnd post-I��1% osm�et� ~�a�. F52-.e5)FngA�dBmen-�%�step-wis%&QK���%ylene ox�� filN7d ��8nG�W>.� '�48!6at 60!R. UP-txNs9 #%Tl&� zLeica 4cut M��t�����+ZregE�a��spindl��M n �RNAi-� ng o�,!^S�G=�A�chNH ofteu-�(�8 �eZ�Ime6�6��e�stret�$to c , ab�0pro5% ��p(ACa l�"�nB#!�ta�� .=�Ta�1. Despitl,sQnomal� E�"+, bipo?)�%�m� Top2j{2Fobl�K=s4La�m��/B ��+letACi�*to D tow� � �,6�Rg0Be^@{!�V�jBedM�� bior�6I�&�Rat eu�LN1�U" much�,ieR ��e� , noaEex� r9}m( abilP NoJ�a�nQ1>�2�3mid5> ��9n�9,�kt)� R��3f�3e� �,az=�K�-� divi�:IT^"�!5l2��By�v��-��uaA�>��6M��I%�n�k6.B6f�@�Lrd�U�M. I�+ st oaWsm�y Qp uw M> D��ir!F thfu:��f�$8.U�Fo�2in��a:>�4alw�L}*�0X2^���K74�� in 6�Q0%!��q[�-NonethI+!'��QO�,����V��c�7icienc�0&�,��expQ��aP( �#d�ibu�!)iZ)�e1��8e�EH1 reco�e [�>��"}NIV�!�~5ne�� �� suff��LA�Q� �F Us)� �>7�1ah�YqS�+�t��ofF�E�o [3�35�/Y�m�:�,.q.\�� dyna�Oly18��b�>��0b��!�!26 congL5wa�>sI�&� w S7pl/E�AaY�mF�06Jn mq9s=NuVA% �80o�K���Mk�Q�2�IzV"+Whr� �.stf@d8 Jp'+�[�+ESa�� s�*-��%U�ngE\��.#G�"�Vrane �]mat [1(,Cu��*Q �!barBYa2~*> � l��re-as�E�� s�8�H�ilLom� Q� oppo!d5f-Q��=p�n � idea�l}s%�4L 61 �K�R.Pmz�;a�B.,��g�#%force��to~ng�� �1�>1mA�\Z�al�)�F%� 5� �=u�� .6� %��AH�one�>-�^VensAompb6[1ŋ��3#@c���Ai -lik*+%sP� 2�ese�3O �?d}��~�;:�`&7!�A�� `AcO+ ��q*MX s neI�b��*=Op:� �́capEY�WreM Z-5^nd break�Vr to1 6S -�rep�B�pA [1�3T�!*C mak�L>�Q^6�)��"*c�4��D!!�63c�)�&Tb5S �q>. UNtunJ5/AK�6:���XElimit�T& �>�Y!��k�:ico%J� N�boT9m�i�Qu a� s"VLGPOM%��� ,:�!�u��\t-s ,5�ul*sgE� -of-9�"�Ca�^4A�lI�5ExB$!�a�JN@:�\Cur���e�"wm=ŌJwo b�!J�:&� . VarCAAhQt to@~)�irXsvH nXl�VH�^��<n m�([1j tZ�Jdu� a�on.bal�*am6e�&t�: `ye�&�A�Z�S'�r'"�-s�c= D!�nE�S6omy�3ceu sia�!�5� ;Q>��ga�/t just "��4as[ګchizo� � pomb��M�E�V� !a n� %va=�<9�of�,pe�^�Ba�ONHs^9�:� blocv-6� ;A)�E1� �of �!�ul����A" ro{ pAIth�\l1��D��stvVun�v�u�+Iyi� �.II��:1� &�[� q�,�O$ �(lu��N����0�i!c:p6�4+ ��5Int�?O iy %�,�!B�6&�XX Gl�-"�Haag6��  , �� �K!�i�in J & �a[2 �9F,Bo� B�eeakn�Ov�Vtca6@ o/Han.\<���Ms�]vtOdi�S�# �� v6 �o!/ mild]Be�se ��'�L9 �0�"F=80�Wc\C��S'i�Z�VtA I��ls�e�5I E=plBmBDr�sa�y�=�U� � A so ^t�N�aif ���A�! !Eww!3�g ^:!c�RIPB#t HQ7rd�9J School)availe�a �F.�#)� duci�X- � germ)&y1� ��@alpha-tubulin GAL�( atα ) ;Dr R%�:  � Astart^���robus�at(yly+ ge 3A�!(=A�y�ZBy.O%�!&S� �m�Mo] b\?!���r�HD�ya.�  &Gw�' ~is FD�#d2@�ma!֕�B�� �*wNyA 0)��yl��!lea7o� c*� �*�>� &km�"r� ��A6�&� E��W Mw7Vi�Tp�c{Lu&�,n?:�<�$mb�M�$W\A}e%T&�m5�d�'x��!j5=-in=+o!YvB�llu� � ��P-Mh�kZ�2v1s!�er:�. B�O^ 9l�>Ea�L� ś��im��o t�ia��}�BA�M�"�!-a��qα2nm�( {mat��44-GAL-VP16}V37�}u��short )��8Flo�:�Oo e� !�e�ec Ѩd ��"���~��ya m.��_ By W�6r4No M�g!�%"��!�b%��/�QW�RrRc�.<8��c/��� �&�fUIFS!3��c-v����`-�"c6Si#-3&��?'�1 ,� a �b��2*typ�߁�re���e�&�.�1 ɹi�+fluorescDw�a�'tibod�'Yz!]k�rEUe$��<nd"/��gn ; hist6/32�Z_�1rin�s( H3S10p� H rks 5ii��e�? 2*a��I!!q��fortuito0^�3�&k�Ang^��B� u�g:wi.,q1�b?"nC(�E���e"�� !he>�%v-�iva�"��*$"�em�Ongw���ul =KZs6�"u1�8)/a���6%�Hin� FAz�� .0by2�1:#B� $# lemon-sha)i�--Pr-!�of5�)two-day!3t-e�s�s��dM�enric�(:Q oA�"�( u�D��he��s )}5�� ��*9^:)D)�&0%�.0/2^F�+�6�-��[m�#rF ��{A)W� ��/+� n'�7�1/27 )��f�t(!vB X�T*O�;p:����vb��raU]5u��� I0.z9�.�( 3 .�]V, -�Py%ue' 4TF4%%25%r��k�;� ��.N#��49 �\_�7A4�͉:,��0_T�12�Au0�.my�B–D*�.&U2��N���f��e�:�.tos�:W�9lSt].n%�i5�an�f�5y�M��� U� N = 2�B�K24"+Tqv�2��"�Q|i�!�R�Risr�. R`� o��-*&�%>U:EWmaf� �AK�n\+ɑs� ��kis?cu&,beg0*3&#7.K&J5k shipA!>�_ � X ^�C�0o@a IFr ( CIA���.� CENP-A1� >hi�_/-x6QUf, aUfPC�&� -sd0 �k�/�(��V)s�dr�!V!#sixi!VV� %��+��!��>%�M��5O��&�"�6u�<&�Iu|N� ,�b4 �a�$�'�tip�>( in 9]N�q 39/4q~bV]�"f ��@6�at]�-lIov �z53�e��se')(/ >�9"B��M�tb�A�I]5s�%� �.�FR��f��ci be �H$ximum numb�y1l ]"a��ji)P4Nf�1 �614� �i�pix*$[ɖcM �.maac�[�a�ccNXe averag1b �f^wi~.r�s�,.c�r2BHwU3/�M��L����b��� u>B��� ng s�FA4X'.�a���s�l�66'� co�v�/�aut&� �+vape�7�LA�.f��>!Dž.��R�,�q>movii� QQ�u�F� !"�E�-B�V�_�6y�_u��!o)w�Ý�=�y����$*�-�)!gm�tru6 i�e�"�.j��-i�puror pu5)W%ői-`� � !eR�!��anchoyM}�a�fٱ�. SF 1Ms�D)�!�$" 99CA�A M}U,uahinIr��+�, )B�l������� !�%q�"�.^–��-�f� �:�/m�oo�1V� AO' h��� Y�+, 8Ձ 21/2H� m!r&�Z7jL� 8 / �ape-�5er=-r M �� 2�10R27"s 4N�� /0 /��R�2�/9�>o&6 abov#.+Vl1`�e���wi�#G:0K8826( 23/266�� o�[����r)_zu?-, �e1�U!\mo�#I�h�vs�02���*� H"�%Ua)�N�� ��� in 5AXo5B���} �0�na�.Nn�)u��uW>�rb �directr�e���6v�AEik0yVQ�Uz�:k#"a z}<ima6. Video�XL>Qquickd.o:Sg�;�0 vesicle�&�4i7wb�"):��(��!�1���A���-�3�2F*L U�eC;edP�(V"�FdR �of=InrMtime-lapC�B��=goA�j#,�<u*`!!a�B�.>2"� n�)�"�nJl�&�!��5U�?��2!2=f-��'f) � �c� av�� `|Do/e-���� u�.5 vFi\�8/NA)9�M+ghtes� DAPI�&��OEg2o4&&b�" 6�U d�k-:�X>� . At2i �-br����!@:�+[�yB� a70 . �� [v/.�7F�,2��"� "U � berr�#Qgmy For�x �*� c= leJis �mid�8'>��&�Z2C&� .e �._�׍*%�>\�+2�r�V�(y !*� N�&dtGth�=��Dine�PH3K9me3ca �D6^>/��6�n [25�%P}��2G&� A�ta@ 5�B�� �@M}%�JF^��1�o#[eE�*� .�"f!.��))�;.ul'Xso��P��v�>�:^6�B .�aj��o�J��<sa�wenl�6��&_с� �<u�Ff:�c��Iro�3)��bH �2�IE�!#f��_as Z-�Q"U�E�nρwanA�tN� �.�� ��7 !����>E�m � �46�&�6c(adA5�lY"^W>�� ��3`>>jQ�S�0,o �^- F� lp7A6j_.�� eM �Rxu��! .�> util]`&usF�M( FISP��|� &�^of&��=ok�!�(�R�$^QaZ� ss2(b�6 �a74j �ubr9 X�Tn�O3r_>}%(n,"ga)2R �359-bp vKll>"N?g#dr���)vj(2�63� �Fe1�?q��=M[��:��.9?�U /+ $!� ,��A�ll--�� nd5vXl�!t�Ə>S�6 .5 80/8��M3� 79/8A2�2���4A , 3^F YŔD"E��,\=�E�an.E"��qN"�d� 6�8��:��q�&&G� �� X{G� 16/1�.� �S�H"}�*w])%��al:Rn^25Q�k?pE0 �0/8A$&�?5q�edQf�A�stbM)Rm4V��%%R��Q��]<8 ��SV� ��O�#?4F�(�2�(�egg�am^\,9�E� C–�VY�n.�e"X}�.w)�]� �!�v"F� e{on-2�:w�#YfB�. Two^�E�� "3  n�5he 16U�3� O),�M/ ��;)�- A�r�}%�!2v�. A���0r���AATAT�8*V� *�>$B��GId�j m ��GE�.�9`K8�J7�`2+���-e��O�����6J��͔q"�*5�4<&.�MaE�, �6 �!"b8oi� ~��&O-aBRGP%�#36�!.�, � In 3$�27�G�����(y*�,�!�#o"�X��0$.N 6� D , �oe�&|\� }�)��j-��&M s� b��<JH�IW�Rc2�7� Q.�>06mB�� �Ex9gQ�� E���hCinguiS4au&e $)�S�$s�[!�>2!F �!�a�4�7AO2dH�~ .�1A1�11U1�<%)'m,J] .2��25z6���C�:�-22�z%��Wv�rG��Ք�;�|:�)MAq!���BM>M�.s6E�J&'�&��8*+p�|Xj^6�61� C��%F���>:�&�iL:�+� .;bLT>�aZn m*d$%:6)���2 &�Fx��FKCAC1���B):�!�z� 5�&:� Atee�,)�e9� ��RY &LA,�.2/+f];FX��5&� IM-9�jw�1=!!Bf�&� �)c in 7�c��60�1�Lk� le��S &� j� F�,QZp�:a X%;ao.m�9isZ<!W2RJE�d�4ivE  E�4.� 6t���3 In 23 ��9B!�rmal�?._Y8�Lq�ob&4&2!�T%�Y$j�AX:CJq� A�n3B��s�Z=�y��Z 4RF#=2(6m�)6}�� ����:� A>c�1M �;�R2as. FS6�&�$6,����IE= We& a.� �>�Doҗ*���>u� ��ed99�.x � y Rz� A(5Y���q�-oz<6: . UL�U��;o@!�->+�V� 6�0!51B�6�"� _ 1� _ �#�F��We�.�� y�Z� �x$:��V� ��*$ aR�.* � b�9]YŹ:X ~���m_j�1 �'} ]����%�14B��le��Y�.%i� �>B@��=,:167B�9so��RMe& ���%)�� !y in 3ݥ�3�2bq7u-Aׁ�ai6�5��Od away�/.�'Y�� B�2�E�2�q�,oe�'^~�՛,� �#a�!n.�o� ag�O9� �e?!�:S^�N�"- .�� ,�D]V�Von"q,Y�s��6AU�C��& y' 5\z�~\:�D� .�&� &!.�qR5�/ a�P*�MNzre]�A�bo((E=�`Fa#�>/����9:QEif\Xc�W6Tdv*�KvA�pI��&�0ha'a�:�+��>!V��h<�'YzaS��W I\m�Av�!, [��d*p�h$U�� rawn�߈1�.�E"C^�^�&\!�� �Pe,���~'#>m ��a�$s��on�$ >/ent*�[EX�y�>3d s X$e�dTojV @�d� d B?����8%X�����/ _��#�%21-�<o2�}*�?U�"�?A��Fed>pAK �L e�� B +6x�parI�(�! Ma�0Ï/Methods2��:�s�^sxy)5RsK3u�iCG3329%at 18aY!C21�=%� 26�)randomly��E<>� cram4�Eorigi3E52m�N�8 H�]uzt����/ (�umq(_1"FG 5j�!�u�FdE��GIst�2i�.e��. �� �@�D* ( Fly�I%~W{W]��r�-*k�� unti%0.0!��Rwe���A��aJE%ck.���evZ 6dm� �!�)?��$J�)ﳩi*‹�7"�m. F)��mi!Y"vj�!SNn[ 5�v�Z-"9 G �A�.sh�Dlc1m 5. 36/6�;�F��7�>�&sE�u�)9nS�cw�t�;&$c�a BAC�c!<�� teneLF3C��*�"�5�/3/4a��:i�.Z4I9� 22/4IB�j SO. U} n�s 7DE��x*� ,�2[3 ��Bi��: ~�T1N2�� �3/4�q2������rg��)��N��n���� M{^,f�$� � ar env �.^2�M�Jie8�'zq.���� 2�,� !�5gA doesi�+ �(6�IenoY5� :rN�.���1_doqrul�rQYi4e[!e�k���T.eeJ� reRh2-r*�X��_3Q"�U%ۥ~&! ۠�[� �at� =q �+J�ӻisA id-to-� a�i��A"}by �%�r4,}@ !�!�6g�cAl ��"* "�M�>L�"�2+!9�ˡ(ejT�`-),Va�M" Ye#J��6S*F�Pa-$f����em Vn3 5�}�� ���L�* >%�A�V<k sG 0% ) (�.�=�nn *vU� 2H�ku� 6#����90/2�@ �s>�u��|Q�E� 9>�@8&:7 k� FL �Y��i:e9� u�ba�3i.�iI���ua}-A�p�>pr��u2(4r ,��ndg"6&�%>А��y�ur�.�L!�"�=organ�-C#*�6PJ*/Y`�!>�?m[T�,5 rosety4P"O m�h"XJ�e�m&exݦu_5 !a:AeJx�<��&s;� leg�3Qn?%&��qY#?y"�ZU��:�6Y.�CQ���(Q� [0/4K��ha�>zQ� �Ta��ngZ> ��*� ma!�-*� 4 ">X��oCB [3L�Mengoli"e ( co&�)�"+%s" ����L3 by u�)� ]�lo�*�^���Rhfpd�:*�M9� ��I�B[pLpd&bm��"�UB�*scIto.WJ�t &��%i:�o�~x���Sa9?1 cn�5Hi-X%M>G&%$X"�K:f6� ��aat��6�ZM#�����#�@ ��c��9 �Ia�7��9,��A�fY fash!t�3al;!�u�4�"�Y �1��3�. I�Zworth��u.r��9��d&�.@ + ]�6T&�5�*�6�) *),�Y^YElO @��`Ze{�&Y%~s!7 fa3~&�"b l!P+� sA�!�"5��c�2�"�GE�!�5��X�:.�in����+6V!� M:I.tq�u-�I~�Z6!�"Tp�{ &�=%bxS22F;� [ farm5 .�.�Mׁ�.� ���,s�%D lag�A,.�HA�M}�a�?>�36AO��ngi:e�see�caN*�2�hc�x!manifes�(I':��dl� 1αRr Z3y ���&� �in Kcu�*j"  .�paiXDA�ᣙ�!�bZZ[3\�3�bH"55 �ce&..��貥9+�Ġ �q��ach�p� �Cf�<as"�Bat�er� en2�ѴM2mi 6XCq�J2s"��Ee��anB�-A"8 �&�Ru̿d-�6H��d*@!�V��)eTq3*B%�r(dA �e6��%�Kr;no9���_Zt:�=6� l.X1�Zv!22-7�N F�byBM>� 6Yy��u�6-lablڊbd�.�0��)�'�| dualIq�%iB�Dx�t��!<e�AI ,�Lm�1R�-�$e��B ���<�<;k0�=�c,�� 22%.&lDu6+R��ERu���S�l8e� ��6.:�B�|u cܥ�& u"�(nanos-Gal4:�^�e�ch�P�%� egin�kin'6�]�~m%� ��lao<���.�"VS��De�)�w1��� ���.�n"0ur�� �?r*�m�g�dst �� �xBf!K��I� -i�(A�3�� gm %�� �Mց8�2�E�*�gF�n e�m�l o��e�. +�!P�t^]lI Eor V�lk!two iso e���^ huma҉AD �+�Rf"� (�i�Q�d�����.$5 ,El cyJd:�5\ !V%bL� &s[41k4%�M�y2�#!��TR�m>�zαpHeL���#!!"Ë{Q dfm�;�.�I PICHM� lk1-�ȎhseckpoiUje�ns!&bD��h� / ~ �*y ���"� 6" p&�ato non-"� vuA�� &o .�.>4�jA�� �Q�ۄiZo��Nt�2 " �����A�A��u[��!uNK1Gh��u���{23� ,4� 2�]a�0� a { _w��. >3A61�uE&&�'RG��6_f3FdeB��3 !GFD�|K7a��'Qs�� �b p{h��er �/2 �al:�K M����Dj ��mFEyB���)��~5Q6 ����ighu a�A�o.as�p�UXc%BDby Hugh��' .�6In.n�y]mea� cohe�LG��ec�i6�t���I) A�۫ _isn� !i&s9Yi�Dlie!�j+t>��"at"�t�r�ezz�!�IqU%5o��"�A�&k[4�{�.rp; t�*Rr�X�6� q�F���:P�6�c%/N�  ;.Flb�w�OWm�)��imn{7#�.���6awoU&E !��!o�a�"N�5pe��N6\a �YEE&�o ��$'r�M�rz F���4�Y�96hL���E�i�M��&lr��e��6�i mka�Vre��P>�r6ene�i�� �� ��jeo��n�a�=enU� ��)(�2b5�n�s[���O;8%%� 5�i.�#.IQ�,a&� �"Q�Z?�-fk�7�#6�&�Q#+T*�#�rA ��6�E/��4toMn"a>k!u�Įf BU^3 h?� i&�ű��eH*/y�* �� �VIfS�WyF2�P~c&~ � AC�^ic:n&��Q ()E�����-EJ�.*�E:�1*BJWM�6j>�aXg�.���Fng�O^^��� �Q� ��A�v��D��*� :)mN!��x�nOOB�)%.de`!�o2Jh-n�~-L",����J�. Globalb~�loo�9� !&qcy�ir �:"o 6��Zobscu�0�i[#x�|%;H�:Ma&&S2!R25-�.H.�e�6�.' E�7W?v"��2h,���in:H��3en)�M�k&�+"`�.w)�!r�����6�U�!d& c*�6!5:�-E9+-�8EY; �V5:�:-&M�n12��jw��Yma(oo�o�Acc^���6�� �>>V�i�e:a�adZ�!��r�Telf�Q0d&{e�>�Q�3N�O6���" !�A�lppў5�*�>���6bI hb.� b�v�`�k�an�!�_�:^��]Us�w�M3 �˜h&�A���:>�. E2�A� �^��Z s�*�  ��%5r�\s��.<5 �^�r�7��Qv.�t� ly&�-��%�v���2?�sAA#6�8[Aʍ�:G#Cy���3F]a��O���IB)R�&5J*R ��a�2��{D5�b_1%��9.�a�.��f�/��Jn e�@��*:  attach6��]�E �2]F�?�0:zI*���u2E%�!��.j� L6�� o�� %n�  �aci/�$b-Q �ofV99����3"^)�t��l"� fE:��vby*k���a�ݽ���,.bS6- �m� �d1(���$>:��o*�*6�^.���� �f�#=at�g�%� �!�!&6��:.g"���[t p �Z)30:� ^�i�2^�K�Q�]Fu�<>��.� ap�6~z�'�S.�J.�&2G�>�6 .��n�I�KbF�K�.E�R�� �Q0X�$.� 0Dbe*�!J Z&m�#A'�'{��t��u ������a5c�lp!:2A yA " |J��w!�6Z6, ���s'{�2s�ᨕMsu6\(� what��*�)��]a� erisrM�!�� . F�y�# main�,A�ٚџf��at 25��Fl�ock��o� ����7 y w; spap��w;�{α:�{( Blo�kton 706�2H, y1 sc1 v1; P{y[+t�27] v[+t�3���nrTRiv�,GL00338}attP#�.U354�Vaz�|��( CG1022�geni;and y v;2 9 (aucɝ�q�ro��p iY{* .&.�$cop"] F2or)M&� kXE��s)}%�͓��y!b-n s.C���{D�'��mei-W68�775�UO�>I��W�� y : y/BS Y;@a�0 µg/mL��6-s�id�� o-2-:ylindol Ypc� labe��uQ��� ProL��G��2��a�Fp0v 5n�A�s,�:WO]�L5�,Hoechst 3458�2*��)��P�]� �~!O%�ua�Dfu��|�8s:;<%�-*�1( AbD Se�, , NC 1∶2523,!Hs# t25DM1� Sigma-Ald�{710 7r�ti-�) [51]bl�A-2�d-hO:-3� lysi�dAbCamE �!�rF.��eG Gss`M��3����� A� Alexa-488-� 55�o,�647!YjugE��bo%�( Mol�rAub&�|1� a di3 of�40�4�ADf{5�,i(af9��=95~/�$exa Fluor �Won�t� ��L"[pZY�2;xe?w) @6JqCy3�^%e7ӝ�E�dGoat 91V!�hyb.���.r�t 3+��%��-q�EOr�2�R&J 9�>M555M&@�N3����J�2f��7>eUc ~U �by Integ�>��T���'*��ith&=��.�I�!2��>� �"�=��=(R03D1p!�7DE  39F1t<{l��c ARES>�a�a��-�rk�B��'AVm�Ylu�� Mse pRsag Mbo6 F"���pr��i;���us#)ɓw�7� ht�(210���1�'u�c˥I*E on i�2�Bg5X �V�eoy�7�Fy �fer�$b*��d;25j�C���I�gch�Sd� ��g2+ amio%� dUTP&) %�!f.��> ��1>uned�$�-deoxythy��ne ��&��痉�1D( �Cuni��T�� �x2�:� �( Roch�%%�aY�to�?�A�Q%��o:�� ���E!�a { O � �q!/N,� w: elle��J8AmiA�e�Au!%GM�1�A�dy��)ad�dis#��di>�yl��ᨑ3�&t��d�dE�–�%g���,1 M hydroxyl�8�d�vpurE�,a Qia-Yr �umRQieI� L�1)EedA19�d@ �R� -���L�} ԯ%��G�w� DeltaV�*�d�y�/A " ( Ap�P�F , Issaqua��W�<�7�(1 quipdI)$4n Olympus 1X70Pnr!tx� d�-��CCD caC�M��s�ad vC%zAaa,SoftWoRx v .�3*�F�l ~�͵`O8an LSM-510 METAa f!�.� ( Zeiss ) �< Plan-APO 40X ob+Tv I 3 N!-) za����a 63X Bap�"�>5hR;��.�acY}�!AIM9vE2�t�} Zm�nd���e~to]�.�u%gNR�x�VK1���$is CACGAAG8c$CCAACTACAA<�ob�� TTGTAGTTG %TTCGTGLottom%�E/21hj��Be�a�@~*Ma(M/B!MOB�-�K+A�,by Operon BiZh:�a6.��h' !]�e00�����Ls�m2=�). �80I�� ��.@1S �CT:> TTAA-6AA:6AG����!g���g $Valium22 v��4that was diges�Lted with NheI and EcoRI according to the instructions provided by TRiP . LigaM�^product was transformed into competent cells . Genetic Services , Inc injected purified vector GHy sc v; attP2 flies�y+ v+  were seleG�0sequence-veriT<. Numerous femal G Aallowed! acclimate ,grape plates)@8yeast paste . F�C)err Gfreshz@��D�Xlay eggs for 1–3 hour!LE!�0in a grid on !��%co�?hatch!�approx� ly 48 hr �r !�ve imag)!�per-�on!�ethalF [1� , 3���AmericE�A�VL��is ca by L"� 0 infantum [4]hit,vmita�to huma 0nd other mamm��bit�Qs"�[5�PLutzomyia longipalpisa: �pec�L�hleboto� involm�VL�sejinQV[6 , 7jBe���conside��m urba�a�oiruL .9A�ey ?rucial�G� txVL epi4 �J�@�!# 5�� ratarge�� turn��of^n��a�X  � 6X�y alI�1��Ash�et al .�99x0[14] , Dietze67 ) [15��Souza 200 ?6] have%� a�N��6 insuMi%��I i�� VL emphasize%�Vn2� }�Etcan m]U/� ��VLQ1!�� �s�u l  �1f�� expe��ntah� 4 -8\� s�1�wd4%2���{ia� �y��A� v���Di� 2 �] s [1��(Killick-Ken4k=�19M8IDavid 2001E29]�or�Q �ed6��verag%,96%!3�y ��re� 5�%eight5*� !,�&!� of v6)ES ruptq e �����)cycleE� L�mN on [20aZ few field� Ive� E�ia� e>�P�Ayex�- 2�, �fere j >� �[2��23�4��Ribas2�13!�2� evá6 6 ��mathematmodel� * i�5����B�sim�難 oc�cEVL�6 . B� !ip _>x� RHa�a�8� z impa�)�!��of�Hn:e��`se�1Ku:.2�%��� sepa ly� }�>H;AB�� q�E+ j1ly�2� carr�u in:t$in Italy [MS�Iraa4RN�R�j �$� e��&z�=�l duc-h�!��*d .k . HowH 58�d�� �$�KlPv usnicio,d2 kandelaki��|)��inc� a��  (h #  RA12�of.�"/ eYD-roun3�x o5$dynamics a.ng ��JisAhs��w��c�� ����2 2�S ontinu� [2ŠI"� , Reit�er2�04��8]a *!����& ���'ya�t l�dB_!:u�aJ�� ��"ac'�!�Qd>�P  d!�.�RwN� jofi ���it&W6 �E�&Aof�\iz!�a� �4. Camargo-Neve�201���:� �_ "��6Fssoci? w�!>��>� �Hr6*H&< �a7d�of�\�<mua�p�0of São Paulo2� �� s’M@de|�G �re{tA-�� �"tV� e,%�tz comp2 = � s obUediY thei� �o%C+a?rol�Our �"Binitial #emp�� E�$real-worldmC�� a��� A)��!D��to�P k. We fur�2 f��ng�O6�" ,9]��M]bo� �san& ? !J�m��)a�~�,�1���^y.�u"�no�")"8�s�t��j�)�sh:� !�/ari�d�� �� !�A2��A���ll�<focus�#:B(!hgen��u!<d� e��� *��� i . �yea�q 2+,�Ji"%�7l numbn�- tray%msemi-�^ � O���E[5�ly{ q�%pl�iB%�2�� !h.�J� A/(l�26�ai(�:"{�:BJ�A�x>��( toge���S�4���A@�')���� se� ?tho� ��El��ip:�!6�F�e!&a'. �6K"�'�H( Protocol n° 29/2� dIns�8al Review BoardE�A� E&�%m�School* medid' %Fed�Uni� g�� ( UFB�&.�!���{�R� forwar� q*ZEC* Ce� ( CCZ )!k�çariFe� $p haK -��llT aZ. ����e�(.��(ir�"-`i�ZA8Decree no 51838i� a�I �#Bo+YGood P|ce Gu��E26)�� 1�Counci%�V&�M1�,� 2>%All��who agr"y&i� t_EĉY! � ter"f�� in{'3��. A� ^ A�u� tr� RA�-wg%  Janu 2014_ Nove�5AaX^~!- m: j:( Fig  a�"P %x�E'����M*�!, �6 � coasAreg�a��amM�,�n" d*�+29c'73'abi!�th62,(seholds [29�F�(2�%to, a to�of 69 ��VLI�r[�%Y>:6�eR6�A�6 Xpe�F�l D�"2!�Mb�*a cross- �I<*' ����� –2012 8&a,A� asit!�molecu� � is"� ng a�'of 40I�wM'�.� A��Zd�&57 . 5B .N$( S1 Tablee�TwoEu� G(�.MRZ� : ( �r�>D ��Rc$"#a�i�caliborŅjB!A , MSD ) (� �)%_( B !�&� �'R�< �  I ( un�di���TNY )���i�O �(!�A�6�'��prmm!�%������#�er%�լJ��#R�#F2&!�ԁ�Qe�#e�reg(� nviron�k ��eri���"o"*�$�;, � ve vege� a�E�"� ("i� ockM&atchickeR hors.2a�!��o/6a��D&�#V{A��.s�$-..�. #�1��� �t6�v�.�n� �na��2U ��; i��!|�ey�pleL��m+ail!$, %�� data� �2�tif��!Yq70 ��'���)�&�2H�' resi%���6_ %E"�i%all_ �%�od usub&�*5Ro�)r%��-ff!�� sign�gg�"v�~�Ollergic��aAT�� (`.skin le�y der�tisKery���rurit�&d haira%I/#�� !H2(e� disp94 �E��" Ezm8 advi�toA ov�� +(�(x hyperseno*D � da��"d; ��at)�l�%�`-�d untiIhn`=�]H , bq&N�m��"�!�ids keep�v��^|�N.� ,V�.<+��J s�3!f-�!*g��� " v{�&� 51el>��I�pera�"*'� "�*Z/E�ll.� in���k�reE��ca^E��f��ho+ �ha@b]*��0Y ��k�!nrG�8 �(�'![ hort Naa�<%'I" p%E�to*�(,"U!�� �0 g/Q I�S �cou !t-E� ’s���K!�[)�C��,N2{n�*�-T)��s��i��!2�A�re��K� K|8)"�N�f�"}ccd0I�6e#n�a.E �E � Q�aZ��%c1� FB<% �E�f82C-�dm��)ng�a�.�#underw?\6d�!&fac�t�#-4)2n2}, sŀ�ue�� �)ru�udbegin�5-PeD�A(or leaDat��!G�VHRu1B }}��Vo�6*= M�:Be�'2��0�/q e illa�B� =�2�! �)EGfirst s%a�&DPP LVC* ,io-Manguinho�Rio deeiro ,) ) rapi�-s( adm�/�)���� f manuAIurer'� ends!��A��=$a� ���E.')ʥ�e�����eI��%t22�venbl��W�!;i�o!�&�by EIE�6� >. om=i�CCZ6��>�oD,*.�. Datav3s, a\I'� �5nd�.D� %Q�Ntru�INdoForms �;�01&�;($Inc . , US:a�:R"T8 O EPI-INFO ��9�9 (a��3D�-��P"�—CDCr$STATA 12 (�:taCorp L:7 ��<�Z�chi-squ�#A�0 ui mvk �:e!�� B�7An1:�FUe6:���a$���s: sex; ge group�O[ phys^ build ( ),�y.E݁I~�$�cal�aYaa� }|����i����� $<�&�%��AH�J,of.��#>w ��t��EMF�!B&V ,dw�new W��.��1#a1 �&. Each=) �C&G �!Bfr2a��2�4 �ird-N���!�tz9IFw$6>%6.� s cloA�c> X1KA%P��%w"�!� logy>��k� u�}I�*� &� mE!G� w J�3. C� is�.��2Z& �.� ( Χ�~)�>�m�^� m�sE��=>msAJ�5)%�II Ee�D:6>G�;� � �N��.u \ ( 4�)�%�-�;y2(of: 1 –RR!�u�)�C5�:�a�4pE� by MorgenR>R l.80�%30q� *&�e� .�S���i�:e���*nA2.�� , siA=we"� eq��=�!B�,M3halxU�eɹ �sR� d&�A�P#�A��Ao�2waf!e�&e %-efir5>�2� . Survi0�_!�����h!!*5V � ��2�v�V.�"iD:�� Tс)6�T� ���&� 11;(�,er.�)N�ݔ� s�� T �wo) m#0Z�+.aɇ6Ra���Va#i[%%��E=�I� �%� 0*�*. Censo� l-2KdeathEw'�Q��-ab�J2� �A�,. Kaplan-MeiT nonpar�? ric �?�a�?d��k�JE�fu�% , depi� a~ ct!�aD�;Y�a&ilcoxonE�f q%����^Q�aFi+�E}iw|� �]�s�� �%�e.%Qp ≤4 05 �!�F� (&�?)q.L;?GBApril�4�7)�.C(a|�May .Jul �s. �& 404 &{$=N�%� �:*F�;"us 119�*V�� F� B<�0ok�+JFs1 August8#4A�MD5�%X to Sept| ,A p���$ �[Lto!s 7!6:Jto"� $VDTKp������E�e�"�S *�A��+��"m . No2�.%�w?�f(ac&ofi�B� �0�QBno�*�arey�-�\(�0�!3 sum�(z%.Z��(to .!p�]$e�u�A&0 *�'�'2�"z@"FN(vW�&� �����-F: BQlf&]� �!5@, 65 . 6% ( 265/4(/~}CMIF��ed&? �P��x"�!<&!�z�� d� E-"^.byC, 2mA ( 10�/��&�sjc�,d��"Y.ysA�.��� �Ej" 6"�� �InAl�96�F@?.� J�( upo� m# !�-�-����|!&!, 6�3!�73/� )�f�@ �8� Nt�le �&7d46 d%55�2!3�9.38 . ]>i%tR��9ulU in%�)�o<. A�8A�6� R�Ah1���inuYbe 8:L�.Q )q�p.J�*ͻe*�A���#N�bqA�J< 0�8v��2..� �� �, 167Q i�%��'�x!&K F�QT 4'5!� 133/a)-ۙ'�r �2��.-, �.!�&�'F�C�!"S2���V96:���!�ng%� repe1in 43�P� 35/8jI��Ei!�r/"� �Z��Th�Gab6��lb*q'300f-;F�!131!: �-6x,.�1�pyaQN8��M 247/�5�eif�s9 )d =3v��c�T)��!�., 1I�z53 ���&."u�GF!�6� ���a� 1I��( �5 d;�in�.28)Ise 535�EՍ��&e��AAl"P., 275 IbI5%!#z8s2re�(q�^? 8�i�16/AL6��U�,� �H 75 6i ��!vq , !�y10 4of^(g9���.A650}-121�.�2 b�e�&���*a5Ct�a|J�D1o,.�37M.� RIjvF�, 155:�*� u�a_, 8��e 320/y1�>l5��thu04Ulaoq���R+� i+4 o=�:�34"�'aA.�UA#i��#b�35Hg~V6:�z,N�)��.5�A7�i2�193In:�bF6F�2��88�a 156/P=�EɁ�.� . W�*h CVL-ux4,i�4X22 W�6c LISA �I>!XY�}f726 `b�AL32V���A�4!$�F�:c ���8;\ ��3!H0"-�FS�2� %2���:�+V� 29�ez�R%y(_[�-u��Ay: C !-c2. �/ 6��a" :�D&�7f" "6Q��ջ�6-6Z8f1#,m�!��B�%%� , upn6��&��. F��s>� L�#han 4�0DAb%g"� -gMіreC G;��� H}m� �|(Z :�on1VE�"�Nto/ nawen�)�%�Q!ov � �Q!"i"��6 ,�*%d�! same Y also��1FU*A %�!Ydrawnq2tZ ven r� 8'4'*. -TeU*i�;4 ^" �brL�-�:`,i+�:B�*�&h %4s-=!'Uc!�I�.it"UPe�G-of��"�.RAW�w�3VLq�F���nuDNt a�[ahR2���no�H*�lde=2 btw4�W�B- BM�QC*Jm��!��2l?0=�2�)?1"a�:Ddespit7*(.�K@n.�i �R*:�a��uӭtF� �I{�0pri���Q*��:95� a2 2�e�"��0=&�! 72K�i�2O!�f�<to=�lyN�M0N �>�Nve*�T) s�.!,ha�B�@e�>�nQI�\4�R]�D��Ja�JL2���i>2`!%@!�m.�-�f&&��.�>�Er Ai>��%�r: -�-s��.�H]]K�*�q6@ �J*sF� k/ �oM?-VX*al$� �V>9��E�� �e � >E�2���"�.299681r5/*�"n �e: RS-�-Q 8F� ro�-��2%U"��A�5� Bd� orig$;ly�. O�Vse�R"�124/13�>V !Nre�ZR� � � 9 C�"x :� �2�qZI �a.��87 �:u9a� 85/8�P�Rf �'n, � &���4��6�AH-�"?V�:� V| v�5�:sb�7dt:=# <A+ s**:p22 U%�" &�>90 5Az 21/2jA7�[-X��Y� )[!,M'!�!VVL:U���6m6�{ anin� 1jn<2A�.��wh�.tv["E$2��F�%F]%M.U �=h*&at 49 .� .a)�� အ^*��Cg"w . Fur�BYS�ROF�!DV^�,!��/�[Ł"�$ �&�'�*) A�٩� vPb� V CLX��o2!�-F(���e)E��_K�i�QI�-��2�/ cN�&6�:;Qj6YB�((�!002�d� /dayw� !,S"7"i$A�';�O�%��mj�� or�$]�$ MY�n�� La�.gm�2� p* $6�9, pluY e 15�r�>Zm�!Z"�3�b� �Jcl�dItal�:45S?�^A;5D&�)\%`$�.LC al$Xq9�T�a9�)��2�x�onv f&��|Bg �I��M�%��=��:�5�$2�,�@cri�!L8-�2�,0 E(xt .B86&6�.��Z�9� \N[��e�&A� .6j!�&�C.!�� !�� E:�11 �Rq:U�*22�R>F��1^AE6�&F�& illu��ng�proba�it�c���u[��:tEH%���e�.2�'Y`i6�X 2F����#�)�h#-�F"v� 0"�2�af�?284 da�\�.�a�#�Ba�;�&a.�+ �% ]�aZA(sBM+. Au502Ru�';i��&�+VfŃreIq101%!5�1�RF$.� �5�!Kbt*6.+�!K65KFPa>9$2o 5�S�qmo�>?a�Ger&�� ~�{�) ��Ufs:!�" *�){A�&χ2 = � 78; p =e0� . �_!( be �Sjor:]PPX+m* �Q,"�ext�>% m_;!��N3(�cX��5o�oNs [31]!��[͂, ^l *�\�. �� b^!?\!U&'JJ�g��^6�'tx ��4%�By X6�Z�v�Kl� e$/�aceT#order� ��56�S ]NJZ �k"��eQ��Me= %�*A�& ��. �G�.Ji^aVG 9�d��"�(as@ m(6;2$%7%�o��byg&rN�HY+by�+ ião*g1200� [32]!�aJh)e2�P�6N��d�Lkr6�60possib6uRcu� �2Ov14�sr6!>����B]��Gg�j���!�at�_Ze�2Mc >2�<(normal rout��Px'cH 2@m.�J, ai�b)N�" rompMɾ6�0�;f.be&,s:� . Ch>" Q�kis��$!�Ŗ B�Y -fYr.�,� U;:�Yw�t liev��`�+�i}!*!<��RQ2��U�2] ,-#8]��o���f��^R�bdA6��y�,�a�6a���[���� #"�k �:- �2��~� @)�>t�"w2<`woqb(e bias: i )=�&n� Q�inc,�*I(7'%J>� 2��>D �FJZ"0%�s��tal ��re�� d�@f�1�CF�""perTuag�:2 :�2�wB^�U1; +! 10 )6;�48��$8�`"� �b�jh. 6#ate�u�v�9|5^(I? *gi!�1��MT ��}(lo�H�.�may�ex"�7Adq�a�z] whol"e6Q��/. E#*��D�#*/ as4�:V�;� >�d�. �e&b%w` �1.b�Vitu�+-�2�no�e�n ���$V47`F�, �5w6D.��RYY8 ��"-BwR��N�5 +Ne�4 -a�%�-2Q3dMtLI?�4�"eb��1��rewLc  ��i)m �2 c�y4*"��&6_B1hav?e�x |�p � b.�`#TI��_by�S^�^�H:�Sin.�]",C, !&� �R� J� UU~�6w�%"EX~K � � a!"[Sa.��J�/Q9iA��S��9%���2�b�n�J�]no� %se�BsU�mV � � �)pur�k��8@)š�iyBy 5r� � m�65fE ntras�!��x��r�Fuz H�C`^Nu ���ofmgd&�z�A�ajP4q0%� !Rf��^n%AQw��5�G=aroli6� �'[33� nQ��U�"�eX aY"iK/transm�co�aa�z� �Ra;J�5��0%.�2 9;iMF�I!\&�k!{A&Oe��"hd>�h)�sU�xaWR*�o6� �cA�w� secu7J�S)�ly!���rjba���A�%3Y�.� �h�*�:� �KJ���lA��5N'% 9'YME�kto�z�;=��gx �;��,��Ý�T|6�+�8 lead�;sW�im�!R��-�AO>na<at+9aZ(S�y�D!��9��: l2R&�r�s'�H �Jye� LaJal �Ee��VL"g.�Y�hCg �2z�;�e� �e6!\ IPop([3��3 tTak�9�^Q�t��!tsua�veł!��. Q5s":x.%s will�vr~�{�8�ffzQ*IWA�lS!k"�$�e�Pl�5:~'in�=Oa�i�!遉)6%�mZpNro$U�CQ�"F�?,� "} �+�gra^slKj�2"I � , es7�c%��A�suscepti�Y�&fjA�noAZm���%an�/0pm�m�Yީ���2X�^HEkennel�.�,6�[2�sIn�k, Gavgan:�?[�kE* ��.�F���c�.�-~�:  6of�(A-*��ѫ)I�e�!�U .��� -�T���v��!��@, �*E disappearMm�g apq{� A��&lyR�6�eu &� ���( n = 9[+<.EH 3 J\#T� �;H influa�d�s) Y)i6?/I�"O*C Moree� %�e*3Rs�oE��!ic�9+ Zk�z�u]�T�b �-XB�b&��ss:�mê : Va�[cn 2�rd�ty��ɜ��!M�NR6�i@:�� 5ou�nt \&� bH�.eY'( pow�PF� 4^���f�� ��c�N�U���<k�z�.e!߭��k��A�)��V����M{ c,JB .�=80% �; u"ctu�8BOy'�L[�i+l�#�J� ]L�>�Pu�!> �)Jm� ]to:j60%�aQ�ImPQkm�� ����, mai�"� �lemUtejbresounA� ��ur^ �j"܅*~ �!Ss �/io�1abLZ�lv �2�>/&ch}_���-h�o�66� �n6�B�:�J�J$@aq2��!ran��"� � ����y��m��",U�� J]c��� such� �!�v�Rh�1n����.>~x2��sb "r� �yM*ae�&�jM�FF ��.T elev� ��tv k6� we mustA^"�z%! GXERi�S2kh tegy�!end%o�"X�A�%�itself��u�Ws�%� adopA�0�q:��HIlle� dd�la� 4� blm�,� �i� �m�!��'*� L��5!�:I6>g w�A��+�a���H[ ^�u�M 2@1 sd2����$Ic�age ,%��Aain6in "�e�6� i�!�*�u2� �M��{il=�aiqWr5 �!Ob/ �� 5� - !� u crui�cB i'�^F�. E 1!�b�deI� on m�\� ors:J%en� %H �e�vTE����^ � with6aKj� " ���~F!����n�6�A��A"a�a��Sz!��7;f*} 6hipd)j2�!��0Z=��uD~!ac�pq ����o� y:VyN��/�:�2U!u�*� � p���"%*�� @baPo�S eno��� su�F� f4n&�: a�e:t��.S:�":�ɂ%�� ay7ghM�#,�]�j�g�e&�M��2�a���6I A�!+�.�!�as��toRn�Z�?B�-SA�"Dx���H=�A��c�� m:�%_It�o.�%��U>4323*umun��&mA�ۅ�;� q  d�7��!�1���\T)Q��w9� ��Rdn�%*��-r��gu�cOe�2�'A�!xAE�:!e�-\��A�}) ;�@ 3�;�)D (�e(ra�gbetbuckle�Q8adaMB V�+com̂rt� ���!kc� &��Q�x!�.��X Ĉmosom�Vr�\us��I��M!a�l�"Ciir�1 random ge1nt6_����u� �w�ia�r��mmcdiscusA-\��d(x� antagonis��A avoi�]�#T� BmalE�rm�M. HW �#exa�C�3�a_^t �&!\taxr,�' ;�ed6���mANpro��!�ap�t k"o=on @exA�$wa`� aplo��E".��Ntabh i Ri���1!�!�O��Y*N��[ u! �J��l��(a)�moA��K:�2�qe��b�7X{A3j,le k*sk6%S v����max�e ne!�v��099, 5.�k ;+ra� jam W�, hypU �0�k(Enj�opediag �Elm�( ENCODE�bd7"Fu,al Anno.� e Ma�BsGenAK( FANTOM�pr���:�X�r* ���ofmX-lin �ae<�m� + !za� !^_uti�:v���)egA+�j""!w�%Te6�t>.\�V"�,�dt-to-X{] o �re.K}� �V�Й����=@Xn�:0� Alsoexp�#,>WY l�5t!��%ab!`Crei�� gS �(p&"!��� Ps abundj�n4a�t��)9�3"]]!�.�9*e"�6�&��� %����!�fu*`8_jFzIerm%#] �q+��`i[,=W� ; o�!� ��"ha�z�unThe� X!�bL2[��,!�3& ��.k � �BQ�W � ��$un Ev"<G.za��c �1�7 &�L� �1exaggesxstr��s� &�7[3��2S�fo�`��6n5�.���a� A��y.(� �$�� e� [9]�& es�3?*. non-Q9��Y.5"�zAT-� n�38(o A25!���Aise8�05�� 7H=�-af�!j�egW �A�fav�^(AT→GC SNP���U$a GC→AT U2O [1�bT�w eC.�GC�I!wVve&� h� paro u��pseudo �K |�� X [1a�x�I@d$��sF6�. �z�� hemizygXkn��� ��c3L,!�&Dm;���"� �-��� “c0 X”*< —��Bq.D:Km�be�0��[����S%������4fX�!b2�[�QE\.`{I�c re-e�no Fu[, RtD)4M]&�J���o6�����6� �h�fR ��a�>�# e 5z�-�$�&q�`�� uGs " �$\mA�i enab}=�&_�ladvVe/ rdisA�� �*�F�Ede9r�.5#� hidde^(p�cA� invae���/%?��l c EeM^t.��`u�-�t11� ous/�.�..1u�!�t�!ɴimw� s� he k gY��us!�oeh$.�5#moft�{�9K2 1�E*� !�!3-��^� �] �T okesA�ifiX���l>:�y�K �/"b �%�!�.H���C�v� Eu(E[�!�e�&�C��2��n� �!�6p!���3�YۚU**�ĝmpa�%eir�j#!�;Ye�� pe�phi�:[}!16�s�&=�I�"+Z��:F fof���B"�5� ��Ce�roI)�U�>�  SAXI�� [18��a f�0*�!A ���5�m d�%~Q}>�A�ereby�fu6�1�A�(�y v��!�u1!�2C)1F�Ay� �a�`��=Jru�f|�fr E�  claim � � (e�� E[3 , 4"� a*~2r*� e� �V��vVU m"#2�,���R%2��.� ed copE��BR?[1G�e�is po�6*S*� !5�.�/Eh%2"�-� a ]NEe��s�A"����%�"���.%1unqNly �M��e�:�T#J|=d-^��)*XJ5 X2" (" N�"��tM�e�fm)�GOI�5� ��d��es�$�Pl�x!;��}PAbest d�T�@�0a�so�c"_. WsG(%853%��mon�en��-seդI�aqsu��a�<eio� �h��.\��/}� ome�:� radictU.: ��1i��  ex�!#�M_�.N� J*r s��Z�. e& �#�g�qc�8�C-:!�6� v&�+ Drosophil� m<6>+{ory-gl�iU!�A5� Aex^$* ( X [2�C�"-f"�F�pos�f Vicoso%1 Charleswo!5[a�, wish!��gU@IW��K,Y�J|�!ar�H*��&fu(# drivA�YM.v�GE+� �`]tC i�Aci{�&"�f! �"I A�E�� -9� J� �.J�� ny6#  . Put ��e�2��!���S>�Lre� par�  si�A�{6O ( diFan"p����������B� 6�np.>�-�1GX%?�@%=��&J� l�2n8JA#!�� �=��2pZa�%�.G !CixD "�5���`M!&�pch�V!c"|��ach�+���� �.ru�}N���n �oI8��t< �1I"]�� alj�:�in�^� acerb�AOA*�el�GB�!“weakpJs&�n!��CcE$)�E1s �/%Qdmecha0� sag�mpens46f�%��>� �2+�is�fer-Qb�27��a ,�"� arg�h,� make rdA�"|u]HE]rBI��G n up-E�F=q��e�)���Uyv���[�-�(� !��=Qi�2 58� �wal�[v�$�����r&.�>��R�'����.� Bachչ"�9Q��&h�IM A�^A�s��a�"�u�� up-r_#te6�aA�1ent�Hk1�Na�  -w��:�in���* y��E^*+ . If ,*�.Avfly��u����2e  �"x��^@m�Nc:�hip&B�, j�+�AH�Fcap�!A6|5� i�171�. Ind �,v E"n��� E%N�I�&�t�/2_��6!i�&�%M� � "� w|/2LAI�a�esth���Wist���I�!�i4[��a62�^@$!���e�|!V 6��D<�h&� o f.Y-3 deca�2A�z&~<�re��4�2�>V@p 5).�eve�*�&i�Q�"*�#[�$e 2(!_.?h�YT26-}�B�0N Eex1->*GA�[cH��L�8A1->eo�-�Jݺ�[��q��!Mng�>. R�E��)*E�a���l%�–ji�>ter�X%�"�er?��e/��|Zbo ��EvY'R�]-�E�e2�a1u �a&S���pl�%jjf[3��3��Assum!/�Dr�$���s##)���GQ5 ��s&75� � a�PfortunŒ >v� �o-�{%Xs�� <�z Un���q()6�p� E�� sI#8^�m�!`o-�� ��3A�sus�/��Pa)�o� � +ͭ-�f!*en!r���it+�DOIf>Qa���\�B`�r* X�S�1ety� E+�ree���� iŪean d��F�"Z?�&"b �M���h;L2^ w.� nga�al�+D �������� $!,O !TWA���6olA�ect e�,� awayɯ(fa.�*)E�22A�A<�(^9-BI' pF�le�= wh�b2""� gm�,�! ���f.G no?�ၺv)�&nIir�!��A,,A+�D /�.ա�*}"��E��%!\"?'s4� coup�=��^,O Il��G)�&%') \ [�M$&Qm�2��\�D���@&F, seekVX!\s#D�. T��� �9e�5loS1 exW?㙽�F8 ,�W*!��U* "a meroL�*%X�"��*.;[36R�"5Ttla����pa��?aF� $le-nucleot���/$�"[37n"#a�libra�7! 179H)-�� 513 iso`��?�#���)260u cer ��J+�n� fash��.�,[3�"�taiaO5�� @eln� "�N�,^!��N&R�G�Ete6K�6����laborag� col��Hu`� tic�'ipe�/ [40]�ow� toM� ��L�1MM��a-Z�[4 4 � work!s !�!Rq (�m�-P"�-D��downloAF'h  to�)�co 6ߦ���/����"�}d�/http://����gs��ri*E(. jp/5/ . A�e�!�� 29�l�� �.$���We) t�1i~sj$}�4:� Z<%+XX?>�.Fa2nis��I6,Q���hL-6�B�.�2�H aTL�Vay�e�$us 261 tag�� m`�o�TPM"�BA`�lSD�e*�5�!]�$*c( a:*Z , p-�Pe <�e2e-16; E3iz�Q�] ’s, Z� on��ll� 6p�9M;?M4�uA4%b�a�of���p&%sk�)&��, devi�+��nul�!�� 1�-�X� ce;�0 Metho?..��aMB�>.ls`�Qd.�:�-�39%��M����aba�t�fp* (%�es�"� !Vn�, )� 5604| ( brżM��/u71 [BEX1��NM_01847&,��2l �o&gyrus�"�cE�^�ms%s-6 Q��Bat �g48e+05�emoglob��beta;�005186�Ò;m�6i�.K1� �A�e�0��|st�>���J�ȉ(|zin%Gz�a*� aaZ��+e�%�V&�� , u� !�E�� dAr).�,N�"l�g�a�(�E��a>BB, 0o cutoff�7+� � poA)7�'�0�f*�3��.�-����%Qof���*-fed�(��A�� 2�@X%5Y'��22321%��<"�n�=�� 96e-|��� ��a� imum)mum�O �w10t�Qs;! �-.�Jr|��# m�CC t"�s)�7+�amalga�h�\�2!�ICum�^x ��of^��8F.�A4���behav� �=V^+/�AR� ,)q*24�A�-�3b>&=�".JS!rt��%�"�"6R2a :L 2�� Defi�Qvyat� R.W�b��d "�)A�H ���.���if��a�h !M�"e�7ask�"�(� A��^iDS!��^J/tP\ ��s:!�e, �.�5x �sdZ�e+>ŋ�&(.Xh#il���a \���:]? llٟa�unambiguW-a�(Dave� �ige!�mthu<."X,!�^�E�m͎�E��8"� '!'A��0-Qed�9�ca�9486�K,&=c5l�>� H"-�5�)�!!-�%3�U' ����/eZ�5 ( Bo2of:re� 2�XV%6i���yorňe�6J��'e4�������5e�ow��we�{aa�a�F? 2��o3a!��V�M_A�o�r`���1r{9>ZW"8b��Vk�A�ISMF:�E�ued|6n�en��T��̝ua��Axi:3 n5�(5����� E:G�&�-u�lV��� B� �� źR�:�!�e� of 5@vdnstu{&e<X� 6]���>T-X 2�c!߉&se>&��6y�6_(y�07 N��j�m,B*!y��B���)TM+5!hyBL�X �?'=�is xl��& �|kHp.0�Ax� n51A�� &� �a�Kk er [��* "� ittl�%�u� arti�%�!.�ofJ��*Qeena�|� !3t�v�� ed>H 1�hb��oam��Ŵi9,9am�!J$��2]/0�e-10 î� )e&u tt&U#�j0dd���O�on��r6L wand�RNAseq~f����ng! F�Mrth�G)�� f�:w*""�/ea�;�A."���_od�� �-Br�"�!AW��>� s�I��.�a�  P"NS%x*.� ��� w�(�ezw�im�tPa"ZJX)�X�*/"d �ng�>b�X.r��f�L}}&�:,-�o�  �D lQ�"� .�S"!*we}H�Bayes_%hac�)�s�)&oG�Z���n@��ta~�{�Xnc.1 KtE�f�S+�t� <#�&U��.2ɾ,�� �E Z-x߭�fa�,�8no�&=gy�]m*$ f % �s$ '*�� eMEl�G�Fn�iL�% So�WW�>,U�g� ���"��II��i�>��KE �#fly�/�%>F�<6�1&�'squ��ɡ�eQJ� WG(�E� ��'` %�e9?�Z:��|5_ >8 �1>�(eaA�)(�WEA��:�%E4s �EFé\A ��7Όe�oesJN"��m�U0=�q !Q�["�?fold- %�&eo����cer!�G�H�1� !Qa�KW�lo6gEO(��s easi�o doublA�Em� F?����aFeE�M",���"�"�����  +k�� "&-�����e��K��J8'an!�!FeE!�`Ae#A�O' 0#e�(�=Å�f�ZJ�A:�m�j>�Ft' � J!R�'me��? �$� U-�< 1 ea�sYy58%��ފ�A y�՛*K�5&��A���qq�H)"5MlF/m��� b ;��iNkW�i�!��� !��j�*� �F"��d =oY.��аf . =�}<�k�ٿ spli3 (c(HaڳB���wo�es:N�u(�16��=RI:M �Wo�%!��*� clas0�F� m�\���@acg�!:%M>� �B� M%"�f ��)rMK5�M�JD:5�}sh6Oꩁi�S{!�6���,b�. B���f7.!>�%2Mjg�)X.��Z�- es)!�ea�(5�F<(3)6�;R5*�N�_<wC�:�qc��P{/e 3:�BAer:he>Aa�I��(e��(.a@E2 :&Y��n�'J6f yZ%asFV �U����{�KN:A_>�)�*Z�o ���.�*� 'o�C�9V=N��zF%�I� 6�2$g�Z�ATaatU+� BiII&_ &Zs.W &�d $es!��6c&Q]����!U,@!"� mHtopZ�or�\1�zf >�)�I��C�"1y (x�$/ ��� � �JH$or TSME-1%e� zi1%E�cI[ ,*gPref�~NY���(N^ �arr�`t�>���zU"`(�. ?<�H&�j �" ~�. l��>�]-)�A2+� � 1>�)�!�� 9!Fy�(]Mla�[pe�ZV#epithel B��Kw3fic laz["U|.��E�� e7-%�=->) U�m d&z)�A��Ir ?+; *A�A�q) z */ld2:qC Wa,!gec �"! X-to� F��d��zeW(� � s�on��� ��8�6d`%%i" L]�;��AM �cJ"� e�ofR��� �2�. N� [�Z ��gK �@���F�A���B�f��{� g�uniqu{�Z'���C���]cn!k��rM|�$u� 6��!�If -]a�-��NH.>j).�; � , �A�*#>y=�v ����,U�v�1;GnX-]�!2%�� A�"w!rD��UpO(&��I�#w�*� QKA:�Po�� �%�pv��rho = ɕ328�"I788k� -1%;2 23762014994 �!�T� �cqi�1(*A1UoWF�Q�)%�Ke!�e�px9�)9Ј8S�? @�Z0Zs�Z�:y �r='87���162:(/284K�d/002253Z%p �1b�&�!K�. sBAC�+�Y26A*�A� a.�a�]�bvN�a�>h2e}�i�,� .��3�)l>�2"-�.�!obS/6�Rby"ci��M�o �(,U.v��.*5/s�m�+or �ȁ�N�S� ��6�Oexocr���? gaA��^���&=52D!�sub�D�ay B�=arK.:T�n,e ~�aWor��ly kenX qZ��? tongu��;!\ or e�Bagua�3 og.�in �pj;J��w4–S6K'u.>� 71�J�s"�$�GL�1��AJM$G BM�"��4"E�),�Y2Fy� �׊reE��t!��|� )JBo6 �YMpro�D���G� %�A401*��s/ ��bsi�A���Z��u�͡v�(VB N#chaN�O"�)��rcr�-n2�2 �al�,�1S7)��2se�� -in--7�pa� der����159+_tin(�U !�It* �"!�at �g�r 0�k<5>-% alQ#!aY%��!FD4�ZE�Vm�5V>3-KNM\—+F��R�ls �S.U4�&�� I� al/X% "� 's"# �2,.���A �M .�� G'6a!m��c�N!�:��14 +!�.i�m%-���� ���'�Wi%�c �,a/<�Aqp�sd��"J��� musc+�:�� enzya�,���b�>"� , lid�AXMdi��EW? horm �0i�cI�%oPm;/!5$ �d�s5 S8}If"T%GopR�"��q��r�/�7�s6_^)Vory��{ ( S92�s>z~i�n #�@n�9��Z�melanoma�Ki1�E ( Mj) tumor&� ��n�!;ctp<� �!1e�a!mitocho��Tembran��endoplasY�retI��x4�9,�ro��"�t��,=Uopoie�, �59�xmG7, a pack"�, neuron elop� 7 �rib Hnd4OJthz&f2�f*`B�c�_k ] m��ry ��!4�`�is%le+�@, but not exactly�opposite.b , as'@former focuses onR�in>�%Fl �latter)Q only1V% -specific5� When!�Danalyze histograms.�5�(( S1A Fig ,%ELalso S10–S12 Table!+, |7- s are mor�Xan 1 . 96 standard devi!�ns over% $mean degre%7.�A�=J<48 , SD = 0 . 24%�These26dfingernail , cruciate liga!�s ,&0adult pancreaskiC palm (Achil�tendon 4inferior rectu%H8eye!�nd tongue epidermis—suggesting preferential�%�a secretory� , or $extremely A�A-highlaue�ped structural proteins . More%} , itA�strik� thatE�IEs�epi�sub!� tia nigra� tiny br�Mle loca�xmid ",E%�de! som��ta~. T�W- a'a ylower�of%_breadthe �aс� he X� a univers�henomenacffa�ng2�,�uhE�an hav!$its origin!X�fXfrom any particular typE�14su�� sexy�,or mammalian3�ei�siEHretropo!ũ�,provides fur �es�) trafa�(jam hypotheI. Just�u E(ancestrallyF--BA)��can�ݥ�-�� ust!�themselv��!z0new haploid-X*oa&o� copi�!BB�� ���h!�chrom��i=event� asso d �b�of)D)�5B(EQ� is 32±61�#%�8“±” signif���26�eOt!Q seenE�X�M4�p wn(of 129±293�OL-value = 6 . 347e-12a�a Wilcox�est%V�WcontrolsvAmodŻduplic� Eso�p-�*clearRind*�|im�E�[be!��Es��a��gards��a!|f. Both)��=��6PX._pa��d��gaksym� ��af�$!Z.�a5w�*u� M �b*.few@J� E� a/Q�� ��A�)4��! a two wa�hfJ�facilitp re!�l%�f�!�\ tow)x:�m�ion: EuWian ()appro��td 50%5�eW� �he.6� 9J,. Howe� , oldera� -exi !�!� deri�?(�round�{whole)6 .�( 2R-WGDe\chord� �bil��1s� (experienced�ssu� o� ,de housekeep!R �T E4��N� �e.� ohno[�O!:.�)��numerous%�aM2���human�! [51]�D2AEn�e�$-� 572 }�Q , 078Y�o nom map�to�!c,��6� ssum!#�J)��to� # key E�A ne mighv s�pec� et!`2� u�)�toa�e evolA5P oA� adapt�҅oen�QB�T a�l/  �fac%�� A4reE.>�c� ha�lo� half-lim�t�J mRNAe �� Alt�tivas,$B� jbicap�of rib* b��ng�jequ�m�:�,)!2%y einS p>8��Z . SA��se)�s) $recently b��|dE� inde��:�%A-9!%.>a�a1�densit �s [52]P is��> :lɮE,�o mak!!�e� �i�A%�low1K; E�XTwo"� possible \EY�at�can5 minea9�6� alBrt�?SSv!Sem.���7 �se!�6�mimice�di� _u� by doubE "numberQF s availEr�e;:� U."� ���ncea�sup6d��r ���y%�e T �)A��gM�a��?if�th!�,Q)to N� ( 4 . 41 [ Z � F  one-siQ @ py 0263[ e�)2� NEa �eA2 . 72 LfE \ �BF5F6F-Fp <` 2e-1�� , h" doesLadd�`EcFi�  , na�whe��2�su�pA A�A[9��*� . CJ/� 5w*Z_  ,nM�siE�B n(�/~e0h3F A5�w O)��twice2 �Y�in:�-�[ k1U�C5A�, .�Y)�a� �*� X haA�(ly 22% ( 16!�singleto�esu<9# 7 , 411 )��.� w^�sel�o -t %�"Estr�[sth�ŷ!.20ii_w�.�!�4ero-��JU�%� . In(A��a;ovej neg��A�r�Fon betw� � w��JB ( rho!�22;R����es;J534b5 �}�aA simp � lain�s a�t�i�] � estial/l:�)�[53��=!0 taxaEimilarly���di�4d X’�!n->~in �!=�-A ��M ed u7�med %.�na31 TPM )a�!cutof�Y�en cal�3ѣ6�]��AL low-s) � a�67�%�&H !� 57 (�z�� 028eZ�O"O �[ar�4�d22I had��!�r� to i$eYto net dosag��t!tho�!HKA-O�� !X�a�� AR��=~�<�N6i� �er�'w�ad�tog�J�( ribuE�� each~QrguUagains�p1h,���&y t%�m� gene�n��(�g �MAGE )ks�� �ali�A"�in diffe�"H,��!�6-�n �6�62�h�Nst%�24pk�%� T!�is���:�, }Aad�` 1�ia�tre��be�ex2�2�2re�-0���lik] �Kdelet�us im��a"��( . While by�FsB ful�Nlan��"  ral� �upA� limi��=�)*�e����to quKon "[ in"[ of �s . Forx pla�it��noa�68� X inactiv �E)�E�28s spaw�#Ƀal!�r�w`a�B�� mal�rml [19� H" as�� �%)b �mak< A���n5�M�fac�as ���g�-�"!A9�2���W)3=�i��t9Eed . Our � placa mpha�-�Bji m � i�s�s>�A 3a��T �| ma�a*�B�a��nviron=� ompat�5�-I�-@G��ny�(!� j�!-�z I ��[hPgical ɋof�m�requirz �gmov�! p�� �"vol��O9��(AIYb�! SAXI-� [18] �f�ARder�Xac�V��dir� t�r���appear�#parsimon�;�+w shu!�w�"X :-�Xj�R�d awaD |KdJE�Sswell leafs���A9uL�ia� sal�y� wE5 ��� 2F� favoreButfIEbo K( 5�:��n> }!ncaua�N_. I� is lA\@s.evoiced)���cor!�r6�atY�:�i/ fol� o� nsequix�H���!��.�WhE�n-�65 be e-ly in?#I�E�* � s� $ual antagoa���e heart��i��A$e .�sI ��y8�  .�ans6 . ByC&,�N��#�C�mitu��O��%�6)is�n� feb*%�=%3c�AnJA!6@) �Q�to�)al �(�n���$�a,IitM8�.�:Ix� !�B�- Bc ����, �"% 9%��&�@ willA�j��� �  - a*�L[&2Q쁛(��RNA*Z2�uC�(�u҅���aP��advE�e� )f� )c[�'a��g�W�B�>f!86B)%8princig �����s�qes=|-#oQVi>"��&�2�����vok>�i�l�a�*I%f��� ~h��A�f��)' :�^��an"�"���;B�%!pv)Y w!聪&� t s9�\J ��Es�z��j�a! broa��z'p}&Ji_s%Le �/tic),��hougha��^ar�[discount>�-�onA�2 llel��n65�.�6���facq � ^!�.dn�act be.�lyL, stoo"E,*ex�a&� 2�!@w� s ? Sr"A�interpreb!defa�8$f'. Vicoso��@Charlesworth [26]��r| cb%�f�+!� p�z�'>e2��`]'�� ���)ybe)�T��!� yper}ܭ��'heyQ�]W��x�'ris���Rimprob��&�|J�##ominan�occurs �[up-regu��*aFo�%�A_� �t��e& �d"�)i�-X���(bߡ6cid[$l� �*�����&�t8% %SX"�2x�w�a"z) X} �&ly didb��� �:�". �!�]*<%�9i��)� d bi�"AHs'em��*c��fng�fAWo r{.���/is M a'1� . It��c�# w!4esNw�M��-F��z X [54������ )�7*. +!%u� �I�.��0 �x a��*ult� .�ng g-�X12an� (�v" abov�{�).x�,���/��A�%.!K*Z comm�� �*�,5�raA�N���I:*:*�xly=B�(��.� ��n"� al�?ceAeyo�N�n? E� � look��A��irst gl�%&��Og'2kEv>�e ny�y�ѵsh9n�.�{5�z&/ idymX!_!� uter�U�0�Al�sJ���q .#0’ �� סeow  +�-j+untAw�$over-abund%)e���~be �+t� < �o�2aYd�/a��r� ��a�� V&9iv>��is�j^��1 unknO, amongA�j���)i�"���)nta�� 7[ ePol���/D !�TSMA��VO�4�r�"�:ya9�\&�� �%�"\is"ns�����!bG"J�i�$��a�*�!�M,v�1/ R!c�~��- a��"�2�BI;[55–574&hemizyg�4 cXO�s� *5-��#�.A…e��y �&�263 *oe�.������ cI �o� er�4GC��xA]j[58QN�#\w���6v�1�rs enZ�bi��M��:IΉ�Q,pY]6�-Brbya0 a�Z =�)#neiE��$(t necessari�!1Ysex����s�3U_!N %p%6n�I6�cer 2funw0�las�6�*? OXmpt^!�iax&�A�we� {fix~�+� lem> .���ven tS �&a5i�>���J. A 3caveaB nce!�"a�f(�.K!��/� ll�@e& � �*�%&62{�.�ta��9- c32DJ$�!�b�5 (o2�8 in�F4eBS3�)� �9n��1S486 ,I. Bj � ����)� 3t depyW}I�.�bS:.�8S>�8,&�"^�% 5994!�n- .����� )G'�� l� � holds�Z6C�� �:�(%�:�!�=}of EU�Q-nd links� �ual~3a-� disC}�L2* 5��[59 , 6+5FANTOM�� colS��e� brar+E�new rai�7�e�7�T�A�!(R �"%0>��)M8�1d� hin"q8!<*�8R��9asa�l�Ja:,� born�,nd embryonicJamp�. U�d>e��a��to�<m1.BeF.K:>z UOy�m�n� }e�t&�#!"�a� RzXa?W&Amniota%qv2 , S1ͳE�.w&A �-"�1exm�7� :�)���2!�& !synte�0reg��)hickek3�S9��� �mapno-*�D2y�&ndK �-6iL/��S17m\f�:�a�"r�#par�t�>unres\1�0y i��i�2Dref�)� I��y@ry@.T&�#��3*� r�A� peci U�e� ��)voT$�l� �� Ms%D-� umor-mY�antigen]� derg?%�.$��-�9��S)0�- d fr� in*� v&�@, � m#�?�,I518-�!�Rh1&�� � , un�%�2�!(�)��:� . Raa#!fe�t�s�*76!�val�6�&�>q,e�( 0 romo�7�Aͽ, migh����X�Sa toler��.�"A�i���ver� �bż�� Ё�"�g,!�!�s� � , m�"ru�ro�,-� �*f-we>�O V-��]0b[,n� �+ ir a�y!.�i&"H ��!�alDe#$� N<7l T��i� a& tr&�@��#i3eg fac�!blhf)��ViK9o ZK s '%������D"�+�� /�U6)Z� �mf� in|ch �T ��U�2m .*st�(W, ��% /B�C)d%w=��.�iSQr�5f�i� s��be�(y��J�.�Ee^>]s�3a�gE�Kaa�ce!� subt�Fan�ed�76�o�C�4����)ndFal*{*IH�^��.F . �:B(re 44 , 218� RefSeqA+�?i� .-9&s�8of 36 , 382 matw:m�n4R8( NM-acd i� * nd_1836�co~#�5 NR67%�^/ incl�E�Eal kX�pseud�#�' fi�G �%er� ed!|!M�1se>A!�x4gin� -b��l,N:( pRto FebruuI 2009-og�E� ,embly—hg19� �&l��qom�UCSC G 7@Browser ( http:// O. ucscfJ du/ `J�/E��7Da�BED )!� rmaC &�tŎb m toolvr$cgi-bin/hg>T�Vb1?eJJk/p�st� �#4�;K]/)v�44lo@of h7@. ENCODE ChIP-seq%� 5B4Z�@��o& 8?AX� pr7)�(2y'deA�As[46�T%,��'multi-� e hLte�A}G&1�JanM<1�<-freezeG,e#sey2 , 750�490 peaks�� 148R��d.�>71�-H�24 R%� eri? 8�)�� condi!Fs [ -A�)=��r' by e & 0lab�ad�?ng��a��!�Biz J�� co� n�&B[1K;e V"W(%�a!�s:E My+Lab APLHudsonAlpha Institute% Biotec?y;-�4of Michael Sny�#(, Mark Gers�<� Sher?WeismannpY$ U�IitTS0Peggy Farnham-UC Davis6z,Kevin Struhl&Harvar� White!�kbChicag�H�Vishy Iy�MtJ.Texas Au�@� .f!�xlG !�weI��&!]� est �=��},�> reli sc�%(f� hundaHpoi7E�Aas�KS3A�3D�L �<�1�$usa� *E/�=p�#n� �*rob9 t!;�varN�� �� �verifIui5i alog��-� � Ij+3�obXCaEa��aA�Septe=201�$a��O(�0-�HV3 #� A30..2161R�� d 91���'�Ru�%2�J�LW�=20]��o�2�B�N!n�ي7%��� I sym�(al window a�C%qTSS!�v�Un�"�� \wis�!�siz - an�,kb ( ±500 b�%FJ)e�u$�I�le��(*gR�*" -32��Rve �M;ta��8�az�R�M� �S:igA�2� ��A;I workM�'.Cloa�a7Away��e!�A�-�&%�0� ,)�,unique��i�%� H Ov PolII-q�!Zhemay�.:� qu�Sa gS(> &�V� % . S1�ps �is�Fo�L,a�p�JQFAY!ld r�HE�of"�4���]$A�N(�`A'ePe�d��'&�*���Ydi�Q�8A "� bl J*e4�/l�6n-n� R$d$.e�L�*la�"9jA�C.tag*rU$� toN� +/-�}� ( bp� � ir�-~ ����d� mill�(�;,�x=9-[3p>* �"igZ !!en>�1c� nE!�c�;E)!?��Uas�Kon�Ka;�U 6O� p���<u�A*S��� t �-'!�PuyNX5A���urehens�*(�7� e?I!�� �� a�952 }af396 m�H",�"mD �DI�c�$rE s���!�daNcap��i�`�.�(I%)yS�Et"� �cha�rizes ^ * �?r8�H�^ n un0 fashA�Q �le-���o�"� [21��CA���A29�*m�T>��)yR�2�p_X2sa � �areeFam�l�%� [N62]E6� A"!�!U%E�03e=f`;+jA�3��]-M 9'% �0�s6� A|sam%|�a�I�� o sh$"�#AG�6.e N4"!]p*2�*eG%�!��LiF ��5 !6aa� pre-&Ato@o�4��65st�$za?n�=�=%�a�&8tax�)6e youn�.Dn3O���ԍD��� �3W�Cte�P.<�'ts>"(lgorithm aiBK�recon�M�" �� tree�%�pecA>[64A��.~!;as�#"� Dp�2e� phyl��0t �!�-#o say!��s.] ��{baA� �2S2�iAta1 �vNLa&�!^=FA�eX^&aV:0��`�s�9�� aled zero�J� �M. Fu�A�of��2{,!���Daa���[4a�5�a�iso(��l�i� I�w���2t I��2AY�HWN@, Homo/Pan/GorillJ,Catarrhini ,"'PKrAmria��nd? re both� ldre#F�`�Ex2,�is�e�� iA112.9Qh grou�inJ�F G�@achaW���FuVg2�AE f�-exp�I![ ��*�*� D(��!t���a"";d��m<"�#y-Xq�O>A06eA�In &�%� �v� ��rth�*"��~�_:@m_Gt|-���g���&i�s*�B��D2=3傅G�N.vA!"�Ystopp�of!v�(!�e�),�� �!36�*�Ef�Ow1 ucleotide&�*�Dne kilo>7 ( kbpA�6�"`� ��c� 1�(� �R"k" a� betF�cy�7�package � n] gA�%��/GC>iso�R* a 20ҡve� k �8:�m�1�0J�.j�a mas.b�O"�+��R�S-"$. Hsapiens\�.)H�w�!"G BioC-Bi56�#�!�5}g7XwRepeatM%rEvTa�m s F�reV��overl�R� ly � ��!��om<:�GC�W�21��%*�1?!�,r� :i�c�&%Y^GenBankq�EK thir�don"�%`x�n R&� vec~a�c5k�5�to:�� c�GC ym!�Mai��Vh1st`#�l �Xatq}1~I!⅃�Ha�`2X�'a| Each�&! seF �E:?�W�,sͲ"& donor�:�P� �� �E�,!.��]#bp��D�-!sag��[yAMh�2� um*O* � �0dNTV:�;�Lg2� u�-�& .�����!W��>Me�)�K,F.=it���Ib� �)JjoA�E���9! ���� ��y&�)J�:� : �hJr|!w&J�A�pr�Nw���E��rho���K71�" .�O�698J�V�:�I}8D�fra�!�1%" !5Sde� aB(�b&FX0e�a ri�6� AEv���!z.� i 1��wGVt�~.~� Zf&EN�.�F�c(�xrhoErAN85JM��4J,Zg%". P*�0�:/ le ( PE3O,�OG&RW�iq.��a�8�%"fA�a���+�$�� ? �f6All C'z��e.�A�purf^�Ky>ŃP�o�'4#��o�7 g5ftW#1Ami gg�#�&| e�3n���'6�F�I� c �/���<es�9of 75��&7�(�geH"�*19"b(UG-HZ�-F ! %�e JA ��)r�,,��c��R��8 pbe&�o<Wa%� �5��$"�Q%b:�&�1 4!�( S10t!IWga ran9?z�Md�VCst&9 �4J�!skeV2�ofNJAAh��D by� �;��2Q3095��5^sMiZ(GV�* pick�-��y3s%�N�mo&�Y./�Y��43�2 D%��l6E/ N�-e��I!�!*GI� ." Ua�1�YI"�8��dmxl��uS6>`VV�%�2�f50 � (�as ne�,e;�4/GZApѰ�-Y�.i-&25.�A��% ing:<a]c smo�musclQahepat"_1m�hy� �0�g budm � em�2�- nic�� ( day �T 15"�&�abod�Ivelop�alE�!�rs@��5 h 30 m�o�d%�<9�&� �� h?l)3 %po T�>I!�Oc ed5Ab .�.�U� J six�s �[E ��, n = (426a$�so�GX241*](�*�Z"".i-m aor��ad�,�#�E o 6� .�9"2 of 2�b,&9d&1� �qd x� ] �c"�� |8 . Gi?&�.Q��2, ��9iBL>EAr�6.�C�a��verteb�"�K2m�h�O�fka"o�on�>�c�Re�W&8s'e�AlI,y]���[���e�)5�', -.ng�#!�-+neDR�<id)q'edq+. �lA"Us �FTNR*n�oX%���so� �d���y"�8pu"'ia�9yi?��o2<� G3 ]X5e3i�e�� $2K =�F8��)uX(eL)E�5�: e�?of=&!�2fCL&f@�Zes�i�IM GH�ofB-� uiA�2��!�II��IB]~��Q !In-��+� ld be naAX�P9��?ng�)8"-]. S�"�Lŋ"k͇ top�i�n"""a*��o:  fold.�-EXE�t�.t�C��!%ec� �e�KD-t� I�Ut<�; e �"�& � by F�r��3~ t<�4E �4�!)�>�@>}E!B!;�e�<2KF!^)����J�![-]8E,4[wH� � �W� �&�Q.7Nb>Ca6�,9d<]f�{&�s�8gtrR.�2%)F�zg� �nBE�=��&�~������ *I`E� iZ9O XI� lIy�:�asr �q*or ffo2� cut-]&uve&:}�� o The"H X)u�*NexE i o����H�y:>�,�)`z`�Be2�=�b$j�naZ����t��;a��)��Z�ndR�out�bd�-I�nste_of����ali6)?�a���M�"�.por�a6!��f!�i?nZa�V^�xT��D �m S11:>�! "�BB��% Braw0e�s . [67]p:eq�.�� )��!,eA�4�0F/ employ �E�fH5=9 ��g!re-x�G&�m($-Chimpanze!gmI7Ho�D"meffN"�RPKM_C�?�6@iveAlignedExons_PA te1to1Ort�Cu��tx�e�aǁ�!<./��� _En;(57_TopHat_U�1 Read(SRy�s > ��(le�ry�<�'- fV�m>�2���[so&W%er"�/w: &( !� igu�c. 14#027%��WZ`)�BayesTraQ [68]!�2��^g> %�=�. cur%iW ED%� �Uav�.�3@-�*ye bran�e��s��&in^UR*�%9�( p�$�).$t ach)Hmea �ZT nym �%eg��&R#%�C��DD%�.\G>�circum�% t!�&�QPor6O�& �� �%�Z ��%%ir)�2��u�*^+x �"D� =is %zu�a��.��AM inpֈo:�To6�]�E�%D9|g�*m��Q*ER L,|��,2spr؇��Do buil�7q=d i�a-a��S)�w-!>d!,(aQf�  )�A�-in�� converg�� o�W�2A�AA%�Si�10%!�.��f *VA�> -7�U�Kw���ъ }p L�maB( E�,s7�( VM�Jdi9.H.sl� t!%W"�7a x)�� �ic|�$xo! A �A%=U�%�8h8l�_�.d��3f�� &�!��q�UJ�enQz� If E�pfb*g f" gA�f: 20'(�EcAian abb19��"u!5� is V2@*T0it�@�8��$ZC*^7Y�&9�"�?QEJLV�.t�r� AI���!�EShA� a Z-�E�aE�a�au _K�� X%- a�)aM�lhi� @HHZ%,Zmod = Z–M�a"� *�.�hav:N-4Z!1l ;��22�Fn6}Z[D{ ��n>���@/iW,g=7/� �o�, na�,e!�"�gIz2-+�@ lase�~A�!�nyB �P>m�i�.RJ"Z*O0) :*�-��l1a�T;$O e�e�*�a�h���F��+�VDE����sl%j J7�M�� %3q�g assaby%�lv��t}��)J�� A�meU�7� A�a�m,�,,�:.d,5!� �in/(R<�+2��.\9qQ)!���@Dguish��%I� X��R^om!�lyaern �� og}Uic path�7$ Helicobac�Opylori ��oin Af�/!nd�4� �$eh�ga&�Sa-"�410m2yBT0 "ge� pHE�hinct HS �pop/\�;is�.�?$ap!Du�& � : hp 1ar 6!� hpNE Mrold����t�:H;�A�FFJ�u�h-g\z V�:EnŬA/ deeps7*.I0�5 : Antici�sng) T3 anci`H9<�ageM��ll�E��f invg%���-�Q�~nd1��N�x- Baka PygmA%$in Cameroo�FGM�biops��"E�HsophagoE�,oduodenoscopP577 `e"":L�.���41016�A? vidunaIboNCagr��t�XA�9�Q�(�q, �I*1=�1 d�z1 �7S���M�(F}�Y Z�2 8% )�B�%n �( 82����4�8l���mlo-p.nk:!� DNA � A~`%�m U to�9fy�&�U��e` \|�V�N:"�<by�or}��(9�.�,"ark6�� �9�Y=$Nilo-SaharZPanguag�8B z to E`9�2� &" al Wa�sub��. a n/���16- dT*�Hmai�;B_q:iaEs� rts �9��A�we]#��a�0Bantu ��An�4-�O�!mi߈�QE��ST ]. f%�U�F0 Ewi���I�&frv@ f! uJ��6�Vdem�"[N.R�;s �).�,D unus�ndlifd��6e .�.era.܎� �B�!O�*e�E�#m�/I-xNA�l�@�"��udu�m[6�l�d� pUsa~co�]|�G�!�p.�?�.r� ��e�'t �� �c�STy$0V�?��zo�Vs�:�;�U!��:0�L s . NhA1 majorF�� �cts*0Z�n-& ld'sB�� n>� a� al�!A-_�,�a�-�ear2hildh�H!^gin� inflgk���rea� ympt�D5��n�Y�n. �b15� �r#dI-qor �al ulce� >�%�=�%Sq"^s��Yicac3;mucosa-*� lymphoid� ( MALT )  ma [xET.C}i�[�pl�JaW nt rя�[j/+ z sani�`"�c�i��a-�> al horizo��2�is(M� ar� цI1-MaEworld [2�n[SEAF*�D$)x+U08� 9i�Q�)� (\h�at*A global"�"d5�!ng >90%�[)[4]–[7�C1�!�of.�!gI���Q,E]ba�1�[��>� (ky�[BD��%Be$���h�=�C ]Zaa\��� "� Qn��pve, �����l� !�_ [�ii�" na^� carr�*�[!�m I4�s left ��ut/, ?͈ go (ky�� � 4TݗayP(iv�@es���b/  �7e� �_�%!�a>c6� .�.K in Eurasi� Sahu��� Ame� s�A>1Pz=ene�E �3R6E"�_�Ge9 .�� �,"�2!J peop�3m\Pa�*�FcolonP5 '�9�lmY�! I� [11a�na� Indi�me�Ma�R3 BSoǔA�A �r[15aG Unti���/� &��lit]Z,`n�� pa��o2m^�t���)+)<�QW� i]�.��ځ4�>��gTdgd6� &F I�2A ,CV:dT1A�$1�_sub�jE�C wo�: hspSi��em� �!{� �spW0�*i` 9in=5 a<2@..�� % .GN.� s�W��athiopi�( udaV Nig�nAl i ����m/��� ll^�,6�W:9 E�2�, Namibi �s!CA�Angola��)� , [1<.a�ed� iIs�lt�K=�]tu��FE�&�&�Fi��� H1byI�s6��E�re @,.vma!_1IU!y"� �_m- bec Q�!�Aag MC��� ^s) a!��@(c..�:�!�click��<��CpH!PB�6�9�%w���[17��2�Y�\ -widwaly�of..e?���.�� reve�J�r)&:�25s` �,!daTnd Hadza�W�d� UP�T�,� �2�Z�q��:�s �V, [23��2��A�2�sIAse~!�*e� e��� >� )�A���56–70E�[25 |e�Po� spl�"b�ac� 2�M@.zx��mzY/. M�jar� a1.)��A�kI�aKE�NJ$ly 32–47 ���27]�] !,`&i0"� ���{!�� .C ∼2= (6#�-�VS��Lap E$M�  a�l�Le}�s. ٌf�"� 46��Bkfa�%�.�*2בX1Y!pr�!Y-�on;�W�vH&I6�,!Q:�. or 3A:525��":�} �r��2 i�Ju uW�i�.�).b[mic/ !�b/W / ��� � y Ef�tހD�Qi� ��rth.L�NFM!!���S!x0humid HolocenE riodp –9%9)A�4� � �%��znun�Na� r�� wetlai" [28]& M�S!3��&b�!i6� � else�9�,�Ҁ�gQn}eL.�a��N�"'Zva&5H2�.�T��r+��.1Y��Wa"�zY�F!�.�/9)v2Q �l[U�dfulM-6�ose*�D�A�a:�x�GU|�ya�m%��1�o�-0�il�a$Benue-Cong� Em�%l >h..�5c�7 k"l %��AdA -y�/mia sp) 1vI�9)�W� of2|m� !Hst 3–6�[2)b:��e>�d � �D]� skirA]�e �; Mr����,v2&A��s�a�sB �yO p$�zn �2 ��8n%y ��I Q �:[3�t[31>�*|�i��i���r4s� ? , [3M �3��v �I�.� �Zi] �1�h=�r��yse��6(��?�[� �qЩCEa�y mit�Ond��Y-*$@*7 �3nT?y� [�1)"� �26JBG"VzdE�8"�"��-a .$l_&?v,5yJ po", 6u�DeM*�2k�@QM��b�o�at��a��� �:�%wH���i�y�a�&�GcwhVh ^C<%�c�@}�3� 3� !�kD�Aiő%���>=��JAn�=�(5jg� stud�O[H�)�Q��� sub��. Q�!�.G6�Linhabp'he2=of� , ��!Gabšn�P"-f]�!�f� �y�m��2�ik0 v [3 a�.�j��v6>M �At�_�a}X N%�ah,jma�*KJ�o��[36� !�3�9�nu ��NLa�um�!Yme\scree�=EqAEx-%��H�eth.FEQ��za�qua�f �(e��25 f���6T >=e��(W*5Jf?�Ye2#�s: � !�!�� 6�m#A�R���t� &R:PA�2 )BR�%F��'a0=�,&|+.<ir =��s-� ���;C�6%*iA���post-w ����B1�La5�, 8HC2XTN�[)Ei�<�y.�G='�loA�2V f4�. �-G��t]in 178��~&�"�r2W"J�by]�+")���l&#"#[b j#��A�. Amo*$%9, 4�C8%� male kH,a&�T.p�ipa�A38ز$]=�2ٞ.]�5a2a�0G��e�-"�&�,�/pB%*�� ~2�B� 0~� ( 81/101;*-#w&� �.W�-ncordq6yz.!�&�%��[V��A7a*(~i�� �-[37�H"%�a *��� h%�Q�!��+����ۣ /77;|K. 8%;�) -squA est: p�?00AP��"$: �5"�!,���x�0�Ln�,&�.K%��EG��AbA�Mbang�0/42; 2�H�$!,Yokadoum>�6/35; 17H�$6 y &�8 ��T ^r km (�1B-%CwE�m/���tl�` � an me�{2Y�% vA�1am7 �ǰU,/"vS5\ �( 9�%9 ^7��%2�i#�cq;�%]�sL&�> : p>`0��B.��-�sEr�+'$(!�V�%�a��-�aga}6�#�A�#,��Hy'%�16.$s)"c�rI�1w%P(( OR = %t�)95% CI !%��3��Ka.�. EndU(ic �,u�S.38�4� V 2T#9$)��(�(X��9y�G�N*� uX�+!sD��i.�c*�,witZ statVZh!K-00p!��#R� [�Mo"7��n��p ��a�:hn�I�y�%�A*U���despiV0ir�2,I��al2.:/&&&RG.qI�����o;om z�-�reM. soli� �En8�%�`&%lYv4o mbP� n�ocom�A�j!�wYi< te� i�j �%(-�P)l6�Dd 5r�Ɓ��]�.�:I��  ng u^� �(“no admix�wmodel�C� !�Nag5 8of STRUCTURE [34#�iE4��0thCos.{( 67; 59S�2N-( 44;� " 2;"�)=n&�hAxJi���-Europ�A&�a��6�]������0�i24novF�a�Vmq ���*�& 1�xsur!�� )� 9D�� �A�mde�/%�&%�ٓ 8ch&j. !u"0�it|�sTe����Afro-�$� AHNR%#��&�e��8=��/Be ���u�2HQ$36Jim�"�K ,��#A��6*&Zd �!t��"�3�9�} %��:� u�"ō�D�W tra-D}=��I-�vU�V �reject�u��i%Zpanmixi� p ( KE� f 1f��i�-a�p��e- i�,ppr�j.�\@2�param�>JcM�on��(��$ ( Jaatha +�0 ) [4�w"H>� e� �{� :Z Fw�,OicG&�/�%T��:�#&�ex��"�� }�� (�Jco-Xj )X)x �cdX9M 4695;f��C�4)e��4KP�/�2 (S5009;�� �growthME�9SACz3��kX'�6<o*-}a!��i�*�)5��]e�2�.s$�i(he)�H�� �b+�&�*�/�<�DĆB* confVc!�mf#!>% ��%Љ*�i. All�:6ge�>�O�BH��[��<�;�I�Q��!X�1H&_of �&110# � yy�U�%GY�Eo~>#�*w� ��\B of 8�$i 973 m�s*+&z ���prn%S6eb�by.�begZ6�%iQ��\@l �4-��� �=Hc�'E<"�5:B!a���}-��"�-6j�  toر`����"�6�K6� ,1���_�/=�%Su !��IE�"�!�a K�2y����s� er�X43�n� �^2�&e+AF� i &�+&� �I�&aD�Q,�)�A?Q t� ���hWq� 2�6�&spC �� 2�S .K(F�*%U.�%�hJ&ڌ!Pa��"�69M=�*u,.�������FJ A�Y&�"S,( 5�Z,(@!u�3� �D�"( 8w>s�1V�21f�vE�#'‘9/1f�)��G�A+<9�Y�C�ClonalF�%�uhTt&d�eluci����{;tru"��%& !�*� ٓ\ i�� AbX!- F�LS@!�'���e8 sӓed�r*�}��5p;�� 7 EIq�!�i�#�7<Z!Z@r�M�7���(d�='cla���ala!7y�����'r�Xmssp��ng�k�$�92�sy�I�1>��օ�i�Pgu$J>c� M>%S 8� 7=d�MS.�FW$�obo+G� �f(2..�"�*?KL76S�s�t�CbmjOa;B~;Sr�!kilR�E�;wng�X����) Rupno�lQ4�7I %�c�6&ttQ�3l�fu�d� h*if89�)2���>�M��!��$al Q%2 1�"y22A�artQ vE��s!��r or*B�C lyޅ=>H�&ree�eAsFg�x,)yt�Ond �N�wiUiP��d$�R&NoW �84�a�suscep.��JT�a�-M6W� �� n0`�4�100W� 1!k���"�X�� s [4*5�*�z!�U��aa2YqM=B�I%hh! f � p4^!�Te�=��7VM#_� d 5�/A�d,��t�D"3 �1�in�ag�as�R�"W  D�: #birth%,ag*:Xdea��rTIc�!3a�blg�E 5 w� � ^�=�� �E� � �f�ui� %�N?&^%�� �N9&w ..�m9�&���Y\-c& mortٺ!i�l�.��a-�:"M[4g;�H� -a5�> g� n��!�&K���ą-<�artne0"Ls%eralv|-%"e-D A�-1��.�<�g:W%ni �qEeA�f j�negligH�.�#a2=��loTw(no*��B�,Nr�s sour�-�i����)�U9�,�K�kr xl5(:� ��mE;*?9RDe��qu�&τ��A���A"�L��if)K%B�G�dΊ�,>i'e+�$l[.6c� ��F�$wa�:��.�)��q�-Fhz^tru�r �9��$��n�>�. T Surv�"���a�)r4y88�$� �librium.���e"&b����2%*W%�E���^&6y�i��ZoN� S���6z!zE�.�Oe�ish��.�AKA�pr!�{AN!fa�ab�hor�A5cQd�C�yei�a�2C[6>}%-�I  -=.6j� qu5��"164�� �$� �^O[ )B)^ odelAvar��iU�s�*f �:"ij�kbV'IX�n� ssh plauW�rat�!�CqV�$ n��literG� �we"�҅S(%?"e�|. E=l ���� K1�"�<40�\���A�& 9<x*W"�!�nZ?or`s�OliX!���qe�-cw"�'b�)W�E�5�!�m*!�� !U%-����x��@vi� �>� H #"� �H& �a�6e�(! �/ey� st ��=5%o 9��2�ʙ�!��6LF�Ia���i��-ki!V�.��.�ipUN�4L"A "�/��� %p6�. MvQgE�ct�I��p"~���~  �� �'$3r�C�F .��fa�&toJQE�Ō;TteQ[9n�T��:l1d rapi"�cno��j, I�e<+ingful&jL'�  ��� �NMa��!�aqH"5*!�-�e A"U�t�LNE1c$)�x a6��.;Ea*h0�8�Ma^f_TZ{�? ceedc-~��� �e��� 10>$\v 2�T appl��I۝�a�ty7.�2.��9g��G�4*��A����?&�Ub �%o�.!��!G*�'�H��eAյ5;id�Ձ[��!c o6�[ideÐa�U��qp&fai� �3.�;>eH% ��A�g ?�m��]$%���� �s5�Ze�b�� c!�. F"�:� � ,AXipm)1�y-dn��,2q U2 6 �ZH.9,n�� �Y� e;�sly�t�dis`���!�&����i:* *�7a����a,I܍"��I;q2�Tz�E.�tAD*����)!co��qE6�>D�e?�/�!TzB_��m�Bx(� 91� �v��d*�2;.WJ:rJI�=6k�K!5*V "�2;  f sugg@��5)&?&!b'tW1�to1�� ot X l�ros�5e � D1s�U��ogZOM �E�?�u -day6� �0�%�*��!� ��I��{B�Ned6W%?�� A *Q!�,%Nn5"to6X���aa��4�aG,�as��roJ�6�@WU & *>N����]*":�a�ig.�Iw}i�6�Qs %\�s"5 !��B1%�-k� X�po�`�->y�*l�.�Q enig��c-�5s�j�9��?;d�/2xC * ,!U!-m�� �}�pN���Y�Sahel�~g!%��� . "�|i26bB�eV)L� �O�Z"�@M��%����'0&AG+9^spo��� �V" �:3!��e�U�2b'Y-s.1.�,,5!Y #t�O !,�"H"�� ~�a�SN.�,$A�"B�H�W�F�ycP5��e��e�<�;�N�A�͹t"g$��9"F�B!yum$=�inQAQ���sitq6:N�?�3L^1"f!i>/!Nya&�QTE�p�B� 2s)�k��Ja�hsp=�-~U�.��!H) �"�1.T6�%?��?� b-  Q�T-����p�T�1�Tq��.%��"&=�s $i�H�al9*��S�%)FNb!"�4��2,�8��|� tm���l��%a�!����?ilgra5�  ��- i�)J�'u/c�#!<ao ��M&L���6�H*�= &Uft ca�LAk�xr*�2&D g*iD���2e"� a��'ins���N �;l6#V�lK�Y~I<� ���D6lJN�!s#�0 Rm�A� ~ :a �aab"_�s�� cant�p]t�*7,m ��:s�c"Ÿse.��'�gle�{a=�AD=+�%�A"@ ��jn dai�n� X�F��:�*B[[�5�^�=�ex�f�\5!�I6�.2@tA$N GQ*nwe% �D$�16�C �.>=.�[47E2 [� �Va�A'a�冥�!6���9���$��a.5 Avcqub6Ca�]$ Wq�gG e��a&�7�`.��� =�4pyGJUp2��eEA�X� �1!E�8� ��) :*�M��pYa &M9r b��s� �}xrecip��.�Q� ecisl��w"���:��h��1�k��s��(��-)y)� 5��!����N��tok7"W!7R^!a l/'|ly�.�*k6' �E�5R��ni!:: &� i ct.�5f�-� � Aje�a ��050�C�/�Q��pa�bo�Yof �&�05�V fa���q���,H٣me2�� �le��6�>>�wF�*e*p &�],L�ar���?yAb"5xO�KAzb�V�M}���tic�9∼�0r  L�>�<�e�Ab =� 3<n�un"7�*�,ound among t�he Baka is also suggestive of several independent agriculturalist to hunter-gatherer transmission events . According to our H . pylori-specific t.;Dmodel , the levels�Pinfection observed in �,can be achie xa short timeframe after introdu ILinto a naïve populab0, and are rep0(ible within� rang%,(uncertainty�pamj!O(mates . The�rat;L10 . 2% predicted by])undertbase scenario was slightly low%a �5d@, possibly implyi!�hatUlat�is�luenc �$continuous7-/%m1� from non-ECa6�Regular%E ongoxW@act or cross-migr)nbetwee-�%y>SwouldI��, a higher ef�6�,size , which <incre!GAU5&YT%0reAveA�%(mi)8closed-�,. Converselyme note 8�a�ow�S\0ren make up a��propor�of%%}�. Our2���c� 5Tex!IA��� drop��z!�>�$- though i!�� 6age clas�a�&6, o!�u_ , re!�,. IntriguingE���)aGcei whenB�8exceeds 40 year�de��eq / � t.�in adul T�^!� roba� becausAnger-li� /��(potentiallyV!MVs���lA periodaHoweW2 s��s9 �kob���*var !�leA�am� s��le hold!�ot\ vari�=sas��a��se-"� � ;I#taneous.�!O & valu!�&�a �"] a�D dur=� E. Apart��vio� on%�H assumpA�!� ����*��.�account%y�die)Ld��fo��a�� se�tm inal A;of rain-.lat 8with antibioticE pert. $[53]–[55�PAv�Din Java , Malaysia�(Tanzania ha-b� at� d� lo� � [56]�(ose epidemi"� datKv��t K�� e  lA��a2~ 2i1�!� ed �[57�F!2e� gene!o�n��immunit��isvci�o%s��E�� play�V$ role . We�8took field coll�f"� biops!�n $wo settlem+ ��he%�)�E��^ Provi��Tof Cameroon . Yokadoum)�Ab� Mbangf towQ�r~ an 2� inhabia�� t lie ab�250 km aeHMBantu� s`engagain prim�.x (%�prefer!�js'aF1 n �%|w>.co)�!L�y�?1C1? surr��� both2o. Study � icipi;�6se!�6� ����W=�pai!�Esophago�4oduodenoscopy zperform�a ,if/ 0e( e4st ( A . M . )i�writte�D Da*�atj H�sI� ethics{�80002/ERCC/CBNO2��!05�e} Bayesia2�assignɫo� 113. .�h&>aS i]an�r 792A pJs� global� erH[810I�e “no �x��m~# ” A� “linkag.de-�pr0m STRUCTURE 2e� [39]�����%�`!s#x XR� da]�.���a�xpl�9�Qrecipr��� �iv� � oroe{ rmin?e]���.�( KC8 �� set ��. 9&ru�5Q�ite��� a burn-inAPiod�25422riTK �e)z�!�a�a����p .� reveal� ؝ksub��t UJ�s0 J,or hpAfrica1} hpNE 9�!/~!J�,�i�R@I`�~,( n = 44!�� fur��5 tog���93 hspS �!<7W �eQU���5�64��126.Ib��%n{ e 65V6 , [9]e well61 un�N/6��%in Sud�! 2004%>20�Cul�Z!QIMce)��e��>� �G"@as� crib� boveE%<�es� Q#-�:yy��Y8�5�� log-CihX%��c� dis ɜB�DI h [6�Ysoftw\Cl. Fl [61]q�$��wd' ���hip_$A��sY�!a}qy�� .�re��#s phyl�^ ge ogi�!4a��on�,�feR" d itlu�c�kdrJ.� rc�deml$�*�[4E�پ1�� run% 10�\ MCMC./!7 a thin�i�va�,6�E�i���hN�. T ��2m��ENY�. U� Tree'�$62�$ 80%%;( s tr�|.�Faas��u���9Q2.��Ex�n�#g�Gro�oth;B��AP�aU�Jaatha 40]U_�+to]� spli�_���E_fv� �� !i!ale�ce-ba��u���"7joi�� llel�)� y�sU,umm�&� |s��)>mposi*!��LI o3$io�v in�r-dA�&mU o'��!i9 flexibil� a �e>�^+role�-.-y�2� ine^�� ry� D icia� ng�a�=�expan�Fd�F�_[%,Q c.�K$H �&� a���c1�� ame ,��%r��%u2^ robuslQ��!�b�i�res%� �g E�,aLmay be %�U%d stud�@!-W�n� %s:-f&�! �y" 'N� >wi expon8al��e;($e��"in�(;$��d%��.�evolv�u�.Jkay��{ � ings� x�di�.eJ��  HN�s i�o� 9 led�/hx,�F>�. Aa�)gste%weI�d -a�M Dsee}S8a�&k Aei���bam� spac&�bc star! p�gA�a� i!��A �R,%[Jg���p�0"equal�ckE&��ch.dq�o" !��'ms [63]�4.��weA2e�!6EM79�%E��FA��G{m��.&��)FB�3 `37�:� ,%]< of �200����&� "z%pE !&Q)�r+a ^2�232�Poisson-�e)da!f��a�I��ar)0A� sc�&�(alA�!ą��!D* A}% ��{t�$��Da% j� ���22�Eb{fi�� %3��� .�� repe� !���I=V�JLs �f;&� s�(~�:�*) b%i�s12�=t*)ma"Q-�T��.�_/-��N-�R�%%=� �UI�RA!_%���� confA0 ���4)~N� in*%�iIava��  ( μ�# 9×10−6�)i�avera��! t� �.�&8in Morelli et aa [64]!&`1D lengy/�nee�*/ach�"ilibr�*� iy*!��"-,��+a!�� age-T unJ�',a�if E RupB0�4�/mz�?�. d Suscept�6-I�ed9I )!�}�!E�]��!��'! !l� �}nam�,&--( 0–5-�old%�youth� 5–15 yo��+( 15+ . For�(��*a �,7sa��f4F�)����&7If�e�avail^ Y)��!.��.�,�:B- ( Le�& *  ( �%survivor��!J�57N1 1 !�fra"�4.Mbor5�(*n-s9� . ( NS��.�&�,!Wey &�0�3ly�8ha�er�_[6�2 9!I�ae2� adja ESei((%|Aka ) N0�%9�;�/� itiv� nalw>�� r- � plau�8.~ �r,U�6Al��< �"~ �> ast�I�byR�i�� bY+�4A)�2dd7�2r ` @�;a�n{.�e �) ( βE^wei�%"f, b �Q� �- i . ~! intra^�-��xK � i� .�iE��E�dg, ��:Yc:Q ��4-Pve D)2�&validA� β--;t5��Q)��hem!ͥ�4��7a.�ofh,* (*N�%.i. or.zB�0�)�s� � w�")�~E�%�Dp�-��9(�"FigA���r�5%��-�x" �5E�5W.yV/�"�ch�<� input.�uak�0�=5�(r"+�,P1�ozs�+6� �. W` v�1Yon}�6�D.)ve���.��(gMes # . S.�:� Puntil%O� r�!q&8w!�a1 � ( dt )!Z2�A, I��0Runge-Kutta 4a�eg &�'iThink 7X. 3 ( H�Pe�(* S , IncS*Hal' , NH�"A�� mad����H.�"py�? M�' Locus&u Typ��web�(��"/ ) d�?op?!y K" Jolley�JdA�Un"�0of Oxford [66� h-velopm���0m":f�d�|(Wellcome Tr�uEurop�UnA\. EA�new���"G4���"lan ID ( 1663 83� P.Y�Dengue virus NS5� =V l�8�@E���h3al�P �*rotein�$iA� spon� a�cap%�,EAy;� repl1�%5e flavi �RNAc!%� �����E�P�lso�]�[,t X20A�"Al�6r.� ccur�_�cytoplas{"5:usual����3�DENV2�* at47localizCOnucleu"�;&� �no cl?�2K9p9�th �.�exa dyof�W)� exhibi|<)�pro5nt*wn�ar���� mplo�6aX&ofu�>an#~# uA - %fE�%�@ 'swM�!:�!�� �1J2!8C-t~(al 18 resid�6( Cter18��l���_=�(/ %EM�xT9�Q@-�:����*mo6Bb ng�<�&T B� �a�eXar imp�Cre � �lex�be&G&, crys��iAyviA�1 at� 2 Å!7olu*kx-ray?�y �3)� e-gu�mu/%�a e�e�g��in GFP-!c!�e�)� or 2�(2U�us / �5�)!afor%Zsubcellu!�mYI�. Not�9�+�Y�/ # adop� $by Pro-884)g��7��3 .r1�)�!V)�D7:�!�Thr� LE� �!ERt:in mis�!5�?S5DA,Y���5!�a���fitnesIxt ,J n4: ��#o ala� at�� R8884-o!-��!��Ba���+� V$=,�le{/�v�: �,%,�eK�l o� ;e�31phentoyp,,B+��!a�!5 [eVu!e!�m4hyd�/bo# Y838�G�� "�GB�P=%# ssH��Ye:ari2����e/�Fn���Ѻ���cri�(Atr��A��E��&4of �� f ��BDn"H ��� t%�yh mosquito-�e!��+is�FaU?A��t�8�tro�2&sub�;/ . NeP?alf�!� world’s.� ii ough��6It>�/d��7�~� millA� symp�2�( .[(s%mre�� ach4 [1 , 2� 11�Kin hum4, c>� i6=R four��ECut��tG� edZi�ser ((�%-. is !�a.�P�h�@ nife� 1����=-� of _D"1EB��� self-limi�-1fa��F )��@-rate� i�/&?by vas5*nCkaga�thrombocN e��%�E ts N&B I7m�*^ carŷ� RNA-���A%m� RdRp!��Y� HF-associ� =@oLC�2��IL-GIL-8 [19��(VW�(+ eJ�h"�5i�%o�� �1 2 [2�G���"OUBR4- �ed 'd�d � %�!ine �%�I� erfero�g�3��2A!2�S!� N570�!{ K330��keyd�invol�y�$*L "GK�F�aca[� @ly!�Q&)���A>a�i7$s!�� p"z� xn"RC�[1a�25HD e me�d� ls s�Ma� e�.i�!!3��.es�;{{#3 st#Kin�r��NA�/�Eodu+A !ZA&� ��b� doesO1�+� 2� z*�!�W, 'Ao4I& � &� ( 5%�WTG(>6� M accue neg%�-R+nd%��he6ofZ.*xH�H�e impai.IAE>,�%�ա� �synth~"� � �)[17a���Eve�o!A�l �:m�E�q simi��%�?�]rtJ�be� � �* utilG���a� an8 m�Uner�%)�Gf " "�!�beta-1aP� ees [2%�z��� ic*m�6b� ��e a�K.5dap� ae�Qc�Ndq-\ �&�7 ��aX�J���:p.KqAm /a�mE6�recogy,m9basic-D-r�%1U�li�R4 NLonIacilitay<�passag&Wro�P�2r r po��!c –2�6P\'Af6t�(�=w�� � Aa/b�(�e 369–389n2�q3�QB*2v 36x [31] D"W�-terdo� �4e�Bg!7spa�--7s N405*�at�<re"�y q5y%��)q!-3 �[32�A3�s���Zmape��YpalBthumbA� �sI� %<�!��It�R t��e�b(Bc!~QX}s��e�, "�.%O-S= gqF!�!�v body [33w/��P6"��72/�X��e~ "� b*� 1Si�d=a40cyic��z3%�47app�g-be!tC:{[�6In�-%*�)���der*Y!�[%}�k�&�%�#"� A(]!per(E �"U8zQ)a&� w?6�) pL6#- �Winf�Y�!�s!�mr�&�(�=� �full-/%!�u in�'/y�s"� vune Qly!8co�Xd a. mono� te��in���?e�j()�88bD �=&� is v�\*/l��A��9hź�Y���c��"Y%[1(134]\JE 3� I�%%!��+&Mi��oligo�=�����Wly��9��[3��I��is�  , a>bioch�S��� k4E��rsi� ticsv�Hlp@'e<ic#%!�F� �A zu�BL&�4C2.�!cZI�A�*�*^�Tn�p/JyH�Zv�bG�is��E�*.� a�2�Ax� � E-t!�diI�y��2:��#us� . ToJi!,!Ub�-z�yVQ�Huh-7���+"��qu��i(r �)�� lajYsc�&w�M,( CLSM ) ima'�(w" 1 >90%���>��AW��UW����4=Vd somew�.l&�������!�Fn/��K!84 ± 22J9 = 5F9CI�BrsTɑ(.x$2 j=,P . 75c�A0� c47;\3)1�@01)�6� )51J1�4-�(9�3�,4 v"i� ��a�-�ilR�$A�� A549%8 VeroM ( S1AS1B%�&��Ev. F�3DSwe�f�$��R�  shuff{��n Zp<��'�]� �8"�>be�a�"rq5)��al elh%�.�f% _ qv�>LM 4b^��gegs encod�!&z ��atifJ5,+MLA7< /* �7� 274s00��Y�,E�1B�VnewO"7�Z� ` 6 m2�#27�3�O"O& �!�)t!?# hot spot�&9�*$#l=!-�� !� �V �&�!J lap �F�&�'to%���cor>Q6HngYf`#id�-Fig 2E. �[��ed.CtaSY�!2IGFPAd�sa�in]-�� fixe�% 24 h� t�)l� !s�eq5thg -]] ń�s2AI�q1fu�d| � �<J55�406M^�@a ,Q�0D11-273D2274-A�,319D2320�(405D2406(:fto� �48�;!��+��9�%��e� l�eѥ�>��2I�� !�chi` cF5�%Ȏ�92)1=21%1221%1�6 , 7%8>��&)2TUTto�A��"BP �!�.G'!S�;MYѩ� is ��aTw� O*N en�C�  ,�J�-��Bde#�\"� >��� �J}�f��ex�Y6.EjsJfy3:<=i,�ui @e"Ce��Y�E( i**lei��&m�o4 ( PDB: 4V0Q [� a� 4K6Myc)M�=�9�iuy0�u5�Zu9-�2 �JB3�W394�9 49�50�53 4�576O�K6�281/61IN12!�r=oN6C:9E@��$A0�d ��%�0:L62�%!@7�-+z�1��1!0A�n � �y��oe5f2�*� u"qsF� �8U�V �>� �S ���>I�!} .��C708D1709�[���� 99�R%!��.%2�3:�e��!�!��)q�d�x�m2����"iN6r5�ic�hHto�A#R � �!�2inI��ڽ.19NE � A�i,)��a�V=�,�um5�!Vere  ( 67%�5��l�V� last 18 a�Y2� !f!��zq/�`~ls�BoK ��� i"��(l>PA3F2UA!" �2R�F� �2e�Qmodel!9�@ �*ic��es> ,p �X.Aai sefO#&��}%me�l�`�5 x pack�a�in�f��"� To t� Z*� rele�W"�']S-��� trun^d�b!�!p�}op codon�' 882�883�a[!�Q�I�E�i3B!��  83�2!�Surpr���m��� 21-�� �z .�5 I@7ABAconH%I�&���"l.�  � �� BOFR�!.�� �a� 88i� �W21 mR_aE�#=y ) m�&�i?3C�2l"� �atA�g"se�3)�&���E� �7� b��B�RA�re&B!��plaE�J���� � �6�!mI�� sh�fdr0eUor�V,:�� �6u��>� 3�l1E� 2883%�"��l" 6c:k:% kR� �j19VZ�.d�M�a�E� �U_N:�N�7ens�7e�!\ph�'non�D���-�"�]�a)s_.�V��qW u� to BHK-21��HEK293TQ!�S3Ae�S3Z6�77�% � sS6.F� �+�J FJ��V�A.RU�� m�Led!6�� u ��I . Du"5&��)�V�E���*a�M%-A%�Q�Ň"��;�%%*�Y "�i ^S2���:> UA? �at��&88� �0!89p891d �ji�!Pl�D��%�to �F�3SCE���M.��[3�h.�6� #e>�!B^v�#= .JA>%]i����1�Rtit�!�: j�#G, �Has>*�r"�$s�'"a1N>B�!)Ja�a.26�of K887/j1!�R890/R2��'e�A*9�bic6m��W6xs 1>i2O�&$}r!eimJ�KIInclun@�(�In!K��3�t6� 2ៅ���. Remark*�4�IA9)�!MY�-A��5��lo�%oa.��]MiR >K6 9�> 9]j ) �$�J6XY7"d f*!5 .�D�" 88*88 1�c�31�isf9/N8902� �� �EGi�&eA�tleO%rge����-)h� 2�#1�>two�qs:!�un�$why%�B � .!(!b�sc��.rE�Wt1c�7:"�^�aKk a�! U �AC�Bv%f,8_/�C�+g��9h$�W��Q� �|�vN�BXF5a &T::(~ F�"�!��� a� pV1�7 will�y�r�39"Rb ��1�"� is.� ly�omx�cf5:of!��+86�9 ��-i�@d}�>M���i � ee uto-�,ory-i-,a5%�( A�4��4 [3�(A solid-cT1c�'yE�es""� &�^�E4Q(R<P%&��R}j GST-\M�E�capA��5 gla"hi38 tit;|aA . S{�ilu��)8Pa�ad�2. 8,PA,r8  �e�c+U4 ^rob!�eh(HRP-conjugam� -H !E�#!�His6 tag!� �F�1!E 865-A.a�3( Kd =�53" 1 μM1 616B�b3!str�tto �t�7t1t89�49�a�5� 9q�a59q�1a5z �^13B�~ _irm��4��a��tM�C;GST p3_do��sM�&~&}"]9-�i� beadJ�%�68,)�vl=`�nd�"tU of-J)�z(by SDS-PAGE% I�"Ja8��.��34 f�zs=at� �3.:u�As �a�i�eA~A������6�A{4� s�v�& weaka\� M��=Ee�"H-;I]4mQD��A�27U�6�3>BWV.DA4 �tob�aka�$&?O Nl�&!G� B�>35GɃ��� v�lM��($NQ1%��2-z} T��mea�5! 3&� ):�K��!�W &�"t% t&�1 SV40 T-agA ��San�K(1� 1q~nMpEc|�5odolgki�bk38��6T&'w.L(Q���(!�bg�[i�!Gb�i�"�"�+�A�� 2%n3h re a�0F�!��;�O%NJ!� ;� DG���>2)�dev5J&5��1i$�et.inq�iL*!岉�ybe�E�����"�%� In"e�}�  �a {1Ѓ���"!�i�Ac:DT*c�l|�"8*mmm�-�V�*@porhFe�!Ser894 �J&a �N� BY�JDi� ���6�-aWE%�;:^f�~��""$58o^�!-α , V�C�y%�r�[-�d l�5 D}��vbo�(-�Ab.C�&� �q�� a 1:1U|D.� EF[e9A\=�� E�&� �aV&:!�tag�x>�6 �~ immo�0�.on.����wa*� )&2� columng'"�l� ;eO nd ep3�� 8 ��B: c!�!G!��]<��N(?�j<aCGm���!�46@s) �4ena�G]M J)m� �Me�z<�Q..�FN� =:M� ���@0 ��m)�7& ��@ug�E)2�* �_8l�d�Džngr�4��oCa_:!+�F�RA;o  H!� 1:H:# .� wAe!�P21�4c�*ou�\[1ces=A0byra 5�� 25!h.X#3UL~{2�1s �T��T! �Y R/RfDV} - 177/21[ 183 07!��%[E�f[YzlyM�T1G��c� r(*� "�aS; �^T �&�e!.*� �Dsuper-�q6�3A�n AUc5(en armadillr��ZAeARZ/� E�Zh .C�Wα l CS'�v_6al c�Cs� d ��d13p+89"�1o�9�� l<�0e�S;majJLS"gs�3of��.�(of-?�".! [ �6Y ��a�nZWIs[ inxR d�$b-l;ct5�2.*Mb�!��-d+ *+z .q�Z !a�IA� "d�%inM�� I NLS�\.MNS5 val� �AAd�dp�-� 2�V�s R}K >�i�Z4 e�!z'n���SG�z�=%f�~1a��~�s�we�"�=�ct-!�"[2�th>.j%3JA��ed-4nˆ�Ma��M�=� of Y!)uA�2�JIq�6: E354B)�� �0Gwi%�msRP 6D!#R3�Y���-MA�ch atom]�PEM, S88K,M�%�!M��?- s R2� W23n � N235�:_��l�� �� Ye��/2�� on )S��4alt bri�c�A0carboxy�$XR)TD19��N� T155�\ckb}1~�.�|G15���9�sm�- � ( P3.�yx2u�qrM0�;�&Eidinium � ?2�JC N228 �ls9Db>�.m.� �s N18 DW18h4�A> !��5>�N-�Z�]Q>!��C�d?*1%s%9UE�%'�s W14)�N14�A:E, E892A �!Db�oS1^n�ݥC rmin{#, P1-PaB�I ai¡�l��!�iB *����he �c �&2R*   !'s�'ixM|D5tng99-�)� b`�asju�C�altu)="n�@��fez2�B*�<al�t �is.�6� Bx)s�W)�5ŁcE%ȡ��W2��!`:�0P !!%�!��5B� B� �=��&� F�q#�i�Ay�:� F�ː!�4*1\��#.!)&|�a%�=E���!�%[F�R+Mb1�A��. C�'r%Oa?T88?Z�{og�B� ��%����Nc�U�f$C opt �V�-uc�"to�2�5z�'w�Da)� �P"� �!Z1"7!A��T2I6ɸStrd�a$e>Y�I@�i�a v ly"A &�Q ��! � L��3VNcy&�@H,٥)�a!P“(#rw�"�*!�urI � �B )��>/.��R�rrB^R���n�Ibaf��$r�Uq\��Pm6�?s ���.oa��- }�deE�)�%DB1�19� ~m��^�Vs )impEEP .��[�2t���7�� ��tWY�Z�xb|*��=�s�n@�'<�;a?Ox�=��a8�a��i��AN�e��r:we embar!P�W|m4,<Ag�x��s� �>�\1��< ex�l`G.�W'�)�"A/� A�(~"91A�I�fe%2 cs�c"YRD�A��f�G[1|&I�tro�Ie� cripZ(�y��<�%^�<��H!�f)�It�vPharn�>!C9����ms@@Lr*�Kb�Lal-�h qRT-:�$A���I�by IFV5N�i��)ia| �C��naZ��Y.��S�^za ~ 2=wn1 � plaq�zac�!Dor-�U.�V ;2WTCuC(day",�j6K:.:1a 6�y� pD+2+B�!{l�>�F7A�7�]�a�at�TQ�us �T��U�&-CdP*2v �morphv��Yw6b>rB�tom ab�Hyp��mb2�of�>raAwu)�{Nz&��L � ����exVH leve/C�jt$b mirrI'j&k0�b non-U�v�a�l.]330)�AKIment��M.o5-A6ex!� �u� dsnJpR�2�l���Tm-."�37ɃN��z ��!  �\$ b����UE|��Ui�;5�!�a&n��a�8bͯtz�6;Y >�!09�.�.�E�2�e50-f l]5t�" CW� days�?4�:��7D� � ��!~ d�:bv!�^\=EVURun�:e���"� a��V!�%~U�lk!'�/ leth�q�e{"�;de"�z!6�F�'���?)�.dis{ �Hn&ZTdH�"� .=E�Amb��o�>T�0&�*%�+ed=y� e��4!-"�m8��*�B!w;G ��d:�6.�orB�%aAdK!va�i��on/B� "!���d .ssA�0< ( S5��A~ ���5/to >95%ap�!E*T$JA Kx�4�/o�r"�Dl�"j(  Tm�#�~+ m' moflu=o�p, �6 panen��o! S5�XS5C�,�f._�F��*� 9�.�&AE�>aaw�to�.2N��[5sO5�1UD&N5M�doe�La: �#6��6Xa4� [5!�Kn � t"� ��KF��E� RCa�Cf ��m9 �6�1^} ��bof ds��A��WT F�{"{ ed6} byNC�"f !21 "� WT2��GarlierR � "�I� :!�J�me�#]*��Vm�#-V"@� +y ,�p���:�'}pap� �� �w2�.9!��jDGe��p� T:iB�( �za�rowh8d#co"f0�illE@V�ic-�E�X$F��middle Qon�_ �RZO6�\� UNZ%�Ssc� ~nd�� �!�� J�.7d��!�e�` mS"$ T���8 ����/=�#6�_<a�^�Fe�=�6v�2�ua=A'i�RNA2 �membran V",[.D� P"&�'�!?��g,� Q�is�@R!6�or�>aS�%:�K\c"�Z�"�� �%2�R�V:�CinFt� � tail� �2a�g(���1) � on��n. .�D�yiYie:]LS� *�)< jnq��M �NV��� ad Q�le ��"�+Ahu�>6, �i�er�#ڂ3(2�`�"�g� fgest�8�9. Lik��y�.�� e�' �E��� � e[� 2=7C%*� BK hP�� Nf[![no�<qg "J �d"�[�r" "re2\in:ia�J�x �M "��9A�Tu�ed �|��#�4i-Do/ �spicu��c[!�>�"C%;s"�H).�� ���'�8A6"� arA�1s��eei|8`�B�6M�ai�B� �*F�� aB gtob�)A�E�u�>*�"*�9^,%`�*�4.D�t 4��WT;.F5 A>Al(F�t ha/���m��h y�jJ�a.�&��Ma<iHC2t*�Q| eluciaa.w! H � e�r�ZllB}�I����)'�r&YO�wa� �t�Cr�t$5L(z 5O�'�wα2-α7 |%e�D�c� 4(�F:�34�&��!!5t6�[ ; αk .m� | s 34�I35 %39C=405n&}#)���fi� tie}.L# | :� α6�x2�6z38�@�s2�c\ה]� �C(Q%L@By.q^�6T��Nju�rGh."�XALA!�g��;��(g-�9b�+ �b6b=*�to αv&"Beunambig���G&*�d2nNS3"��V![faF2yG]�of�(llxA�^��Ht �R35�� ��S{6jR.��I,e!&mT"1 �&aa"� MS-�� ��@  U �_nowy�K�&P @.JoLen�f���! �usJ�f!&� %3B��g"H<� ��%M��J��+ s"0G)|�=["j`��G%C[�[42]�-�s��dR$i>�.�� U ��(conceivy>�5Wa pleio�om� L!<,�>v�>e�o-7P�Hru�[�_*w^�J�2��q.7��u.�!�"��c o!C!|�/'n� ���oO�|B�![t�j����<368‥gfl2x-T( Sf,S7��+�/ <is�1!nAVi�[ed.�.�vA!he5Q:v�"�C� �.�* �A5�F&`g�"tfH-�&�/v�-g2>AU7�on�s|]�jEi*�.��Bl� Z�]� 1�7o* N"i"*2G6ne<1F���0trou`!��Q�9se���_#ss��aPu�{�f[.�_�6�m96w!* �g^�% p \by:�R ) �V!�L=ven)4A�)��mܬ!�e�MVUN,Satl�MI1�88��}M! D ~Kd���]i� act�N�(,��z aE0m��uU�{řm�$ |�%-] +) 1ul�5� �_��6�Wi�!|!iU�q�8u`(a� [.�U�em%^&�J)!�X6�=���2"72Ma�6VF:5 a:��6�W1���a, ( iva7&_K1Y"��!�2�mC2�( D"�K))�a t�rm���( 2×��)�I�)�c9PS8m�� e��\>-A��.m*0$;.�2x��b)�] 66.9.*�ko�ɞ puzz�Tat � �o�"X*��}51!{N � bo8�$�k*6=I��o"f< �l��35W2�Sfactor%�<�����om�{W�o&�',_�Thr^%(sba�a`� 3 &[�� IZ�.��j&�5 � ����"�@as+)��"�de���b�%�!As��:A�A yi(���um� aBA�e�� ��me en�k֭2�Q�1e�]2�� b ��Lc��+I7�ark��W6!7�,�� ��u%e*�"A� �fI:.�q� �e,I�-{��U�Bb!#�� �� �'��g).�u�* ��E�a!V�aB�v j�a���"�#*Pf*y�gat1��!x?D,ovvL�>t P*�1�fb�4�{>s ��!�]�sa�a�"� )u칍.opA�*�>R>a�&�-�4%8��6�>">shutt�c:�es } S0(� is�D`=a|�13q}�!"���1GIU0�B;)�:�at�s*it�6�"qin�j ( S9�i!�(k�ps"� U�Y6C'Am�UCVN��>� 2t aWu:� j�@6�tSc? � i"Ee�|v2�u(w of i*Ҹ /o s�I,}957�`ay�� A' }2�i[�pOvZc`v �+J�#��^a0!bf M�;m5�&� !�e+ *�,�lig_�schޜ�ra�O&�to+:I\Y�K:��Mb�h2�0.hoEe�.x�&Q�%��t� �w�l���De�lW "f I��2�G6 } U\mW>";6s*����>�)uZr2g�@%1�fn�� XXKR ( ^D�|( R/Kq\��6 LS!�B�^R�% �o[4���4E#A�� s�o kC &��X�/�A a1bui�!�A25f���M�mp&�B)Zc:���D�he g�Ns "(�<_ eats 2-z�I!��"�Cc4principa$��ca�|�Q���!�&�6!�`=P2[6�P 5� 50.��l2Ȋj'�D� �e crucAe}��JI�m� < ��.�UP2 [4e1�P21���b�9�!�U��v α Asp192.L(�:�-"ދ�&e�*��p&��A$l��adc� -�}U��J�� � �9, P�P�<,!�s > ��$U�2l� s��W�!5e�P�.m /!RJ�groD� ��( 2B�+7�ɖEO�z%2�& PD�2+<=!."�2I<.�re&2xe%�DeV�aYO.d�HVN ig6�� �a�s�;2m �" E�Yݒ6"Mhest2�i��=# j��6� ����Z�\"1i��O#�RC�*�0DEN�=. C�!xu�.��.6�!��|��!x�{� M��a�I�{���B KRFRgMgii]� )��6?R��X��*�K� �:Wwba��(:'�:r�1.�z�iBK *'Z �!'!T)�G�!:b�/��DŖ��88)Ov+m2e 5A��!��G �"�s .'-l"  ,�� 9J�!��)"�3&D:Z�Tp0-U I)�S>/\�|�"rU�0fas�S�� �.~ A��&QmA&� to l��%'"T(!�Ki/p viro԰�D"b@ V~:;�$^� �& C����Kg�a�}#�[���96��-�s%v0Bs�Is awa&��2i�3��.y"� a�2&���&�'oft"*��$)�E�s&k 1&�/�@�,.�vr%�e)R*;"V���.I�i�irT;q_n"�ees 8.&S10I��>&!��QmE� FB� �I�^�lsQom�FL.:�&~q Zika�us [45��`Tick-Borne Encephalitis V�6A�� 9�<o �v�yhq+l�9��howo{Emp<Vf ? Onfs��R)�E�b!h&�a��$i+S��vT)���!�Vv�Ar("� n�Y.1. M&���on� -�") e�*� di��*R`:ha[2�~ ,dqK840/R84!lAN�/� �#x�#�*TchE�iBa�OwEMP=�&E_,"�a��*8�a�0%,@�9:�y�Go [46]�K.I@d a.�y)�:A�i)?A��Re�>A4s�JEh��:Qt�:��*�&>*�&II.`Ze�=N U�%��*�&��e�<=�*� ��O�-w�T\^�!Lol6}�"�-2�>�3>���%z*�gr�&>���, ��Fr�5mx-m'm� loop delec0( 795WSIHAH80� ��M-"dA\d�ss�}A!F� F�-A�6�n#�bo�ԁ����ne�?ޓ2 zk�!Fl"i+�u���/An G897* � uA�kan�Lx)��se�xM:�$�� �c��u�\E6MW“.��mHCq!��VstGxy��ulH���ba�a!�*�s�SI� α2( α26 !q" mon!��dB�2tO���vX%���6�6A��W��5�]d!�n):��-���>!oyrrIK�W�����Ss�a � ��& ��M ~�uc�!fulU3zF[&n�a��� L:"-X?zngd!�!{s�:of* ;�34���. O��*�"&O;/��S!1t-4(�sarrT�"y��o}rС��nau. 1��`� �!�:ɊSS3! m�>N�um>�9��!,�eP NS3,��!Q�=z����e�Vi�)1f�ic%�2��v�?k���Ea� �0�sE��� �H�-e�1<KF$� be "��0A0 BvZ&�a,�10S�m"�P7�b o"� ��z�/ (�b��S11"xi�A�����s. � ����!1Z�-�WSv12����s�N)o��A�y�%jv eC erH  2�CA�!H�"XJZ i$ �RC�Mi�! )����AC�) Xs&����P� 3s���&�>]is;'sRfe$Ł��� po�nCBZ �e s�� ��T X�c�&::RC6��݅hnusRDE�� iew*w�e"�@] � AX z&� A(��:��*� A�&fAűsby Ho�O!��;ag�3[W�{(ye�?�Thy�Oe�*� ��'s�s �!a genȎ{K�=z�ay2$!i��UTR8handl*�U�e�"J} x2�q>���s�4-+��h�_*5x!#)&am&�%�XG�C�Ote%c]or�`:� RN�Fe"�-"�|e��� X�A�o6�%aV1_���G`�a8�kstYu.�<1 Q3S3TP��>e���j�N)�e�.�B�-�F}= i&5}%9�O6@ �%g)� � ( ema��W�*:W2O.�L��J!IV�iO@�8 n`@��w$�U�<weBFLtif� u&���a�!�y�k2� %�. i�5uZ��^"��6�b�OJv�to<4�1�2�� "� �!��f"r�!9.�4K Y sI��yE� k"%�i%N-Yɐb:.y�a�d.�y�*e"a��{.�Echild#��#e��e�birth de�0�Y�hPyi)� [*���EaX)�RGu��iG� rréAldr���)0/&�.y%�2�%de�Ya�--9.�or . .)�( ATC�F:u��\ DMEM@au�= GibcԱ��leDGf u]J FBS T�0�ys/ml u�c#��!�100 μgstrl")� % P/��.w��7�t cell!_y8>�%� glucW �a��.<� [jB0Ham’s F-12K�`� �.6�AfmRPMI1640�hAn9-�@�_���~\5% CO�ZC6/36�>�F$25 mM HEPEI%E"=at 28��`>�;*� �l&�$ & (� Bank�[e�iRs���av�� s�":K{EU08123�S2 ( 17�p S*19*��4�Q39825��DE+i����mgro'&.]Lt��il�w)�b�I��av� t -8HՅse��u�"���+\\outbreJi�� t��O*�9E1�B���out6�( EDE� ��� inga0�1�.4H!1�*bkH� r-����s)� ++ � aA 2Pby��52�Of:-�%�Q$��A^)Of&�oc���$ET28b ( Nodn�1!CM re-cu͎ NdeI%" SacI��bo�kw�$��eEZre�ki��Gen )A���a manuf urer�u�oco���kt&�eAR#�j5%l1�#�T(�H�d&�f�)�E��J ��A5�-� PGEX4T-1 f�.+-.!� �mammalm��J >�.1!!�pB��A�UGeV�M��o!1:�sA!^Aa���)]��&f<9S9�JTXho)IXma NRpEm.C5R(E�tecP�.�1#)A}H:-�t���!H sQ�����JoveЌ�1%�a�.m)8q9��@deaI�S) ^��*��^g�Z�!�2*:"�K�)�.32�-4e���To �� te a GQ�,!%;��V���iQ�hforward2 er 5�PGTACAAGTCCGGAATGGTGAGGGCGAG -�%E��=w ECGCT2 CCTTUGTCCATAG GY�-n�:�spEI�U�2�m��u�A&1gg99y��f�"M�F�Vfk&bVA�^�I�)?��t^�����3:��A��:� [49]�z"w��5�r_65��5%2� (��� : PKKKRKVa��hls��o�&B#i�6c�erdC�(��Ct#�� it�^I��!`AI�Z���Ol�B�U�' ~qu���(�v��up�es## �T"�0n>X��,|�6$�5# * �Esee�o�12- 2p��mg� ~�&wB!�&9ޡn.�  %�5 !��,Q�,B��"��LipofU��o2�r ( In�sL=D82%d��M5$#P,6$ aLn( De��pf�*l��:� *O WJ#Sa22� N��t� G �(dus!(QuikCha�*II XL-2A��' Stra�Nne.c* ~�%�u�E<��0y=Cs*�:{M�E�EO�&�byAo�Jd��m��(. pWSK29 D2�`���+!G�V,A��-a�2-�2*V .ǔ:��� 8�+88a���, �~!� 891 &�"!�� 3�I�2��C�exUr*7���by XbA � 12�F1+2Q(Ɋa��"Q 6Y%H.2�I�AwzT )�i���� $Escherichi(li�  .�<,BL21 CodonPl�<DEs, -RIL�w(6�� � e�K"� !">UhN�Y�CH���oi�N/B�/ermo-�TT"ce �&�y��ur' �7& {to check*���6��[11$�i �F1l%j(1`pLysS5b&v��J/ve�� star� , 5^lET� 6,�e2�����(le 2 L baff� flask:��Pm2�O7�1mM MgSOazamp�(.�/� 5% 20x NP 2% 50x 50�F1% Trypt�',p5%jk\t"q� �a2ٳ�KT!�UEatA� or��l90 rpmE�x����:tI&&_va�ifB~�yaݏ�A6��R&�.M 3�et��usp��agA; bH��졛�:":sI!run �H4–12% Bis-Tris ge�&%4��_y`ofdх��.6��F.$ ,peptide cons�Ctructs in complex with mouse importin-α lacking the auto-inhibitory(� bind(�domain ( Impα ) [50] were performed us+ton-column methods . Firstly , q�� then5�.�2�$before elu% of !?20 B contain!C<10 mM glutathionA�E Hf-�m�analysIqSDS-PAGEM�$pooled . RA�al�vaffina+tag/L necessary proceduree(crystallisa�,�jbye� ng 5i�A�mb��ITunits/a�)%�incubE� overnightA�4ad. Separ k-2�� from%C NLS-)�5M as achiev) geleF I-�cone� ^to 7 .A�a(for DENV2 C%�A}16��3 . AllPed�l1� sses!�9A�tyM�5��� r4RNA template u8(in de novo !�i�/elong �[y%ri1-, P\5′-UTR sequence , 72nt& capsid-co�Q%fe�)DA�3I([34] . Bothb-cA�!,+O- obA� SPCR)� �c��clA�(!@,e GenBank acA��Cnumber !�b�{() [17 , 48]wAClap[A�to join�T7A�moter-6��product22��-�final21(�6 -5 )�A�A�!)�Hin vitro transcribe��T7 mMESSa�DmMACHINE kit ( Amb!)!#or%��Hhe manufacturer’s� toco�f��slekmodificIG. Brief" reace�mixA�-�5 . 6�0of linearized�( ≤3� ) , 2'(rGTP , rCTP�rU�(4 μ1 of rA344m7G ( 5' ) ppp Ae!Cap SV �� mMJ s-HC��pH� �K1 MgCl� . 3n 001%Iton X-!JA�YM cys!4e )-�BT ��51]���� pre-annea� )�w -U30%�(QR� a�  le-sw�d"�of 8. $a 10-nt du�hairpin3� 6|;f�P-AACAGGUUCUAGAACCUGUU � ):A �G~Gat^HA;5B;>:�^<6��%zABhe� at 95"�4 Sc� to�L�S9�!�a љK ��� ed:upG3 hnRT<ɑ1c�$time-point��e�7 × STOPy���mM Naeq2)&mr�5 ��A ,!\(10; Promega� G25�� calf�jst9 alka; phosphatx 8( CIP; New Engla�Biolab�=!H�� well'b� �As stop��91��R Hshaken� �b� ��rpm ,2*.at!_!�66Rre�d� Phossmonito��rea� o�Tecan In�e Fz PRO micro �0� t exc�ionmax� emis $wavelength%422 nm&566 ,�1�KivelyAll data M: coll�ine�E9� 384-!y b� opaque)Zs!�or��PAt� ppropri� Ay post� nsfe^ ,�s that �ei@��& 8mammalian expre�}smids� R�virale�,$ mock�[.fix A�ice*d(g : acet�1:1 )%�� at -2] &�fixT �eo�by PBS%��B @by immunofluoresc�E� ,4 prim�antibod�ZLagainst GFP ( ab6556�),:1000; Abcam or? ( 5R� 3W [33]apsecond:`co��da]Alexa-F� 488R.594�n�genE Cn slip�� moun!x�(ProLong Gol tif�reagent: DAPIFWDigity imagbcap d!L@Zeiss LSM 710 upr�confocaliascopeA�arl 1 , GermanyY4t 40/64× magn.,Iv�|ss���Z&rEK$4J software [52:0For grey-scalag� � $8-bit fullA�our �]conver!;to 16*BG. uIUsi�~� on dB9A�R� to dn mine� rcyt��smic 2�rA� ( Fn/c )J eache�-��Z!4� ula: 1=:-Fb ) / c , wha� Fn i�(�2} , Fc!b�A�Fb'backgro�2K[28–30])�� valu� > 1�Qs5lAWiz!� <2%.�2)�=2+0equal distrib0betwee�*us9V�� mean)L± SEMI8 alcuO#≥a�y���3!�.jco3ɇ(,rmo Sciea�ic PiercA ��rin�three��si���of�h&^�*�� 05% T�-20��I.i�.9� UEe��� lys�s�rip��-$ �a�c�����-$1"A !�t���a"`B�"�..�ser diluc�( 2-f�� iyin%, staga 1� � P" %re��-�^ ����.!�=.�r�!=~A5pr�%Lti-6x Ha�ag HR�Ŭy ( 1/5�% �):�A�B� �n dark:� �!���Z�/_:�)R6 KoI|yZ��N′ , 5*tetrakylbenzid�D(( TMB ) subx t���(in�!$��� � (( 1 M H2SO4>)��)#"l�aM&d 450, )KD% �C 7Y one-site Aw�5E��}�[PPrism Graphpad 6 . 0f6"&+N�a�YT`of.�-�beadsE!u��z .� R)b� 6��JHi&���AN �T pH 8�i#. ; �] unb�r�fu� K�-y #�.�in!mlC�toa�v j n�of UbxSʨ2 >�8���-pg Z�.���B���=1�y t 500 x g8���1o�uAL)�d�%� ,V�� �� �� �A�=BE"�Y!, .|1EG� d L-.�s j{i�  9 ndE� � �i� �*�Densi\�ndy� 9 G&R �? :V�B{In:�pm��e� ropoQ N plk real-QRT-�( reverV"GP)�b[ ( IFA )EZYexperim� a.� *�*�[17� L� �-� � -hum��� +!?ds!J�J )$ body J2 (� c,i]9�.�R o�WC 2� l @Olympus IX71 , Ce�! Valle�US!,�Q0x: �yM-B~ e'M+> Cr\ � i�>/%b3%T C-te� al ��"\e�A �a��,sodHi��dmyDTT�j�*pq�pam�um sulf��!%� �HEPES}(. X-ray dif�!�e�&�a�AuJ Synchrotr�%- 0MX1 macromole r�!�;m� [53A�D eR� i�(iMosFlm [54�� �3.�%�� indeQ�aH cn �d3ha��& refi qi[=."-� odelY6� z COOT�Jen�g -;� correctly�Ed��m h�#��!�T$y map gene)+(9�-�!. O best fit2� s�� !<��8G�"#(&� by R�, R-workc Eot% valid�E $saJfiR(�� /n� ood �M%� _�dep�'� ��#$b�!( PDB��k!�51eG!at�(factor$e i�:���#2`c�)es��i�) alpha �availa�'5�P�eV�"�b�>�"s: 5HHG�5FC8 :/QStudent�!t-tA!y#$2�statisti�sig�AV. P!Hues�!��05i��Kide� s6$t .DjVer P�roMwliminU' gram!^c�on& nega� rop�dis�5NTD�M� not%Msu�#A� ��Aw�valn�'eikoffY. How ,#yj-ende�c�r?havr bbx�*aunch���-upAr � beca�+they  �&5'!��!�� planŃ�advocac� Each�\, has its own�8p� guidP��7 �ng d. W��ge� phic� lap am_%e exis�a tA+!�ma h��couldq lt�OYEt,ource savingB We develoX�fie�est� l novau � NTD{a��$( I�Thresh"M � ( ITM ) M�,[�( lymH�ix+a~ ( LF���+ homa� chistosom $� soilmit�helminH( STHe�y �is ig��to be5-effi!͡!�"" purp� .]whe��a � ��0rigger publicIlth%Erv� �n��le� i��$EMI�t � 2�rela(on World He`Organ�4( WHO ) recomma?aqdor#E�m�-� age ZpA"�� '��-A� fram�aI�c!@but%�>��^ sub--ra%A#FecA�mz��,.A�M�o5�bD)ay- i( curr !q'�oE|!6.�A pr�(�!,-2l demonQ ran "a�+st��9�w�!sta6� non-�g� ,J*�iAB� tool�~fac!�2 bi�0y�4of much-neededA�ɚin a�6�. N���o-� c%� bactA��� af�c!�m%,�7 billQm w�V's}.r�peopla��@a��B:1 phys%�deE�%� , lo� da�no��+ivh ��ci�.!�cna�affli�2� $viduals [1� Five��s)�&� [�Zve chem apy:�a,�hocerc�r!ԡ�e�|;���U��� or .� u9�� tra�!R! impYLeslwarJ;'o%< In or� 2i/�rapid / ing1 of!�I�& to�b2�!�� ��" some��as early 202�!Aglobal�����y�]f� Ab� �!te��E�ca.* lize)synerpA�'�pa]ntb�pr �!�th!9�. Trad0 al effort!e treaaMa�eA|I�;1 ugh �e]a� ofte��5!?!�zm� 3! pone�#a *potA�al!�cuL�%�g� = s [3[�/N$c��!�2��flifaK ���2dfisx4�g�58mass drug admin� ( MDv4of at-risk pop� ��saf��e��vK�!+don���5harmaceu)X�hn��[5�Bef�anu� be  �a��n( must.2IT�-�!�� A6.!�տ,A�es� i5byI�� ,%Ӆsurg6ed [6%��� f�7 step�t��ss!�e� views� � 6%~ aL2� < n:1a7� survey CL _0 ]e�) � "X y [8!�C[multi�EY &�)�-�Aρ5�urden�Pto �-�! ��. AA�u ,N�enl- ��!fu�9ab)�ecu� N%Mto[ !�t�7io�partner�mw managE�VA Za2E�a� @��pro$8e,�un9�V �"�a,U 4Saharan Africa-�� E: reas�q eAAa �E�� li�&g e �!at1�"��Mi�a�of� !�wh4 )�s�Ap 7� &�F. B���ten�$�  in.6a� ,� is �,% �,e &� "-to" `m�� �]m�M&i��!��.�!GaA��0 [9aTe�ape&|A�novel2�  �eO� D.ga�r:�0ii%�LFara^LI�� . Our2cdo+#otA v�1�%figure)x �,�-q�at"���zyit�2���al-epi*E rig%!d�Y�� � e\ Q��� oi�0e�tr�in� / w�:��A��Om��>� to"y - &�a1�9�\:g�b?+6"p ����a��dF � �&���a�� � >� II�$research sg - ed nK!.���xBanamba�)b$( Koulikorv g�!�6~rea�\P*st� y�!�88 132`sm�>08In �� �^}uy B11urbanF�Diourbef �rƵ15! 8892�1N%.�%�&)k majo3ethnic�, B!Qra%�Wolof �&F,,�5� sist� farm��livingAA.� sett� s; a/ yPeuhl x3� emi-nomad�eng�)aK heyi�� retR �.A�5\� �'�Q�oA� he Soudanp,c�alM[10��.�QvitabI��Fprovi=AQ���v6_��-&. � �C ongoMinF�� �WinF�-�&ca�! i .��lP ��� HO� ;ed!�employA'5y��l=6f, mo� � min�cdap� Wm,���xT�}0�ɔhG+;-mat� phy�5�~��CTA� inaxNOW F&(,�,re Inc .�!which�� s bl� draw�fin�ak�*as"�me�6%��.eof Wuc�ria�croft�ti$-inu�aB ≥15 yea re�nM�villaB!.t n0t� 3[1�2K�% a�8 minu%�r�U� !d�lab{!ory t�5ica>%2�!phthal�*exa4,dIey�Achildrz1�1–9 �� clinn ��eSe�q( tou(fl0I folli�[TF�.Avof fema�t.\Vt��h�:o[TTb2a,#o { loup� natu�l ac:�=aS�  >G ng S�6 m [1iA�S"�a haeA�bO ��.e uAein ur�%amp���66=A��-Ŵby =re�/���R6'diO8�26v!�]{I{dwk them�Y�;me!kI*���r�@s"�@O � � ( Mo�,:��also by.�3i��$ard!ș� y [1K!>�mansona�d 5�'!+$egg load ( w$ �I�cD9�R�) Kato-Katz � [1��s�pr@receivSther� valI(�eEs Com�.Facul�\MedicAe,�!Ry�Od�Flogy-St��  , Uni�%2 ofXako��a ��;�Ne�alF�a�-�R" ( CNERS��Dakar ,� ;�eCDC'scrZR�Bo�, Atlant%G�6�$l e� 4%��of eight6��%�as�?to!o� wrT�ns���-cip�m:s%��sch director� a me�B+ he team�!l�� Bt C-��u�( N#14 �) ��verI�Dnt �<p� b��_� Vwho> �! �6g�their:t. W�'��e�"�%%�/�(or custodia�I���E �J–18-. Cѥ��fo 2� ave >�uM� tub���-Ka!l9�,Fbeapl<>$twice dail a iod�six week;F��6��&ͫ�refer� M�C�h��8eA�;� dQ riDsurger� PM�!��#!�a|W .J���5i;��b�809UIɴ���*or�)D>�� :� s��A% ;eU�=. T.�6�we�kJ�n� �v*�resas��"+� �E, 1�?M!�AllI?p&�{9ii�E.xpendit%-Q"�� d�\i>ic%fG6�;go]:F [J,Ap diem�#"�5'l>m Jlodgin�Etrs:Qq��+nNof vehi#N , dr��^fue Nisupa �m�Ra]$*� �$Anp�"�#pu<A��r$A�"=z" �b~3e#� cM� ��t� LFE��AK:�[/ ,%ym�/Ta8 ~. &4 v��4ofQ��ynelYdiagnox ?1 sala!�%LE�/��-i�'A�e9CDC �a�͇EI8*+6� �!�LF K2�:�*)oc� �>6�� :� )>�%B*� c.I�>!|tj- �>�E�9>� � �.S� �� %�� � 2� �MHM!WheByl! ool:$fLs6��"s-t�-��6�J�. FnQ",���.���:��M�Ng��D�A=, +1 , 898mA�I�a-900�w(2V��389��� ��>1�}4�97&F,vqD738fzin 35~x!�.VMp&aa FalO �['!M�*� N �" )�,s�� s shs in F� �6(]�J�I�o%�����k�':�9%2#: 4 . 795% CI:� 9–'65: 0#0%�0 Jb \ed�oi)w �]%�% 5ordm"b7�&AD*�TTAge�T6���6�!D�3N�4�. eK����LF"��M"�9�,3.�� .�)�8��to6>1�&�!�Y� had�gZ�y/,>zr���)Zs�/-,aQ:J>N"�:m!E O!�6M%�ed.�QR>L��R� M!�re�aM9>vtN+ .��}inI�ofz�R���T fI �fe_he` lMC!�H"!�R -:v��A�y��J~"Ew:%,n ly 3�A�7+;� �!X be��6 hZf)&R@ �se"�)-�F(E�UD �Ae�a�I*&�h&���4Rk���7"� Ro22���|��1�>�I�o61Vz�914fz�o4xj!.eBa���^s~7�4�E'�LrXTx��9�A���q��3)�94"J 6�1�8�M��1��4���N9=Q��U�>r�e�� a.�a"�#!cSTݛ. �!-e6{!E %=݉67+5j���2b��.1�%���7E�AsB�%������&�h"�1An� e6�m��-1:'>� i*�1%�I��X!q J>=*AQ�f�ʽEil��.�>�36���ŸJ�Xa !�wh:�a�w.�pdid��&="� O�2%�.�R t��(� !���I�a�.�"�ͺ45I�B^"i(��<,��N/F�,?"� !f� decFB6�2k��X_randomly/ �б�x�,O %�_+h�Mz .��5/1�F �+; 5/9;�j bas���ea)����1!�2��,x6highly"�.!l>) �� �q5mq%k]!&� ZI,on:�5OB:��,%K�!Zcw|3!%-g41.E�1/92%:�M,LJ z Q��w*�#��2oka�\$~��R�;Yb[of days!��46-Z- i�#a�5s <*4 . ItOixk#ly� hour��� �-A;DY+� :�d0�&ur K�f�H">F��D�b~-.� �ve O�*da _�FA�@� !&zslUI&%�t�-.$ �si�?6�J~ v�d6E�7y I6Y�N�+L�]�. � �5�IA�E�!5��. .�8"� %|tA�6��5�Z-]v�EK�&e1q a%�C6sa^U��,%���h)n�N.!� 4�H%A=50]B6� ն*��>�� 2 � q�Q"� P�F�7� �Q�_t͍A�>c T��a 31%yP5�(ED( $�968 v $1�&039�`!E a 19fEQm( $�'442.H372 In >'>�U�s�W"�+����>O-�a()O�,&��i�3�H0"�1j. \;�A`� gZ6|&�.�zB;))�"/�a= ope�a�olCB!� &�-in|JI=2�:i�d�K,��&[=$*&�*V% �.�+��J�1. WD!re���-Emte� ��2� i4-:F���{&�-1P�!a& !,1�3re!���l�A nner�-, [18�11�-I� "�4J/>s9 souer�,ur���"g/[!�*%1nz)�*�U2�be)�, ���#QE5�hV�#�/-�=�excep!A,*�'.db� ��� �ny�:%�i=' infl}fP+4�-�)�changFgi�B1�� �&� �V�43 " 4�6�3�4]#u�%date; aYe�MCv � de�("is"G&si�Vl]G ri%��E!2w E4f�An� "� .�+ Az� �4�<moduleA%{&� �-i2=/uL% ,(��bG b�)� F Ew2a�o�*57To undero,%�1UA� limi�+%�!>�&o3cri�7t:J�.2is(cla�Dg1��2�1al�5�G.wEQ%Ag"� �����"(,F%Po%��=�\c#�� an8Y- �feIC��.���J$��e,a�impac0k�U;�.54���({possi�5G3�.�edU�1���>l ,> !$|-�AitiS"  ��i.�. A�m�%0cI��6bA�%�".�&Y ,����7)^>P;���M1�Z�j ssu�l�,3K%y%��>�B�4ep&E4a�?B��4!�rjJe bwd�Y}��Jofa��0�mqn��*��Iif��A�Ebsb1M�3e.�R2b7��in24I�8�b��G.�!gw� Fh��I9!F5�aeoG�)g���se�jabo;�D�%+!BzUksa�$c�0a,few�@^��go&�$!Tj d/�s;)���%T�lofeN v�Х�>k!^S"uEw! ac:E!�GAEx"z -'��*�D�imᛡ� e re�0a�ven�>L!TF�I�"~a�-� 6!�+^�+5��0��R��d:�-wAbi�P� ���� B yearA؉,�4sesoA7a��!5�vd �Qi}} �]  es��$4 ol A�(�5A.�  73"�+�^duZHQ�se�N]� /�so!li�uq*E�Aoat�1O9 s� �e\2 TT.�[2023i[2�2�Z� ulAon��10+re�woLciA���womU4br!����-5 yrsbB>!aSy�&1Dɤ6�V � :��/lyJS�/b: �DE�� e�. BE~onmK�,:��qn odif)B?[Jw make:�a��{�b`%��N�� 1Q"�-���"r%!MJNa�:��v!o����6 lDKc��al� 3> ��!r"� aA��A)e:r5���h� .EbyeR��JU�F�>�. 6;.cPI�a��! ,� Y��8, luE�a�nvt5��&\G(qcon"�S�vliat=of� dk%A&�,e!���{v)=*|&F !I/IEi��-�J� L�&.A�mofB�,���%is?241U ����^�9�1[.H-8G!�in"w �.�4we feel lt be��E��hoU�.0EYmB�Oe������&�>-�v�ma�;�'��>!_or   subp"#&Dm�u.[2�6�A�* � 8�!�>�I . U .��~�1'ta�� �be�K at r�G%�4 #4A��d>�ec� �66�Om�JeG6J(.~of >5I*or[L"p>&<1&�&�he9:" �C �&�g��d2D  a-~�85r� "� ��me�*e te� �0sankf� &?: � Q8Ur8E>e5iOhMY4auun��uf SO %asF�92*� =)U�D �EQa&� �3�O,�ansO� im E���a�v�3d1�]&�&�C^G�28{E)3��kat kan�inK�^���ORſ !� smtea�9���>c�A�6�-�v���:QoteaD6IK"3�D&svg f"S �%)&�*�8���DAM��%mir.��ti�n�7_P*�27>q�XmasAd.JR N %! !��4TJ9&_� task �1�dD%��[gyUVc�|!�>�@I6�IRo.*U)1ehWL)s 6�l)H=�W�BeaA{��staffe%b�~�s capac� builq b�,!����"i�IU X*�4A�2�v����MM|�SLrelucqvto�Qk�A�U"�Qe1'w�epe�� hesitancy��ax v�e1urs���d)�s)�notic!�a�yʥ�� ��* 68&�d& ie7J%#M��6��&��,�sus 3 2�nBe ,&/C a 5- � Dinu�a 72)�7!b��%as��to��F�#AcA��\�So$*��cerm �YE2����"b�xsa`>b�ly�a8 l4Bn�+ �$d� s�[�MQ���mee�A�K7{!���pricelWAT�Med>I&�!�,S/ork?@ ��F �# aa�.� DbeOtv;�)�*no� co�^�1ywor"R%A��-1h�hjbPa�w�v)�>B"�7G=�i;s:5�i� D�H���U�f`QBe � Q}a���� ���>de*:W� ep]��F�Rll��>��!p�2 ��!x helpI5�~+�D�!�" x�/W2�R& :,>*$ e  <�6�U�t�*6�b ) se?�;"j'�qx ��& � i�-�>�&r�Q�a��"�s�T! >�6L ! er0�>�aO>�.k_%� ).�a��t / N� �@or�� "�!�ed�R"md�S(praziquante�T �w'b���AfЁZ��4�"g>�!�Ja� alw%)Tn-in�r���x>t!�!��)��� sj r9 #�*�3 N�5ly-"(��+J-sQFaWl.9�g� ��I2g�JfI]en4��!%��1� {,]EѪ�W��4� � ��A"��!"���%�BZO)�ņ=G*� %y>,Jus�*ai� nag*@Q ": bJM. Fur��#se�raghaB���Moz��  ���l~ �:�._A��1(�"]�! � lear��� :<m�~ 6^ feedAz0r>�E�ag��d�T cogn� �5) Iӱ�U �LiW�T�����'�l F�st!�ful��O�sI|o� �%"�[ ��BM0u\w�[ll�i�u� ���Q�'s .�4U$accharomyc� e8�sia� !�� d p*�Cdc14a|-Mh �it)� mito�.c ancho��on4{ol�nhro �QA Cfi1/Net1�C�until e5ana�n�T�6�8lc]H� �{}aKwo�bly �st�3�+dun�@ pathG p�ote �F�� e FEAR (7tsL �() net� E��MEN�mit#)t# =Tu�+a7�i| geneFia{rama)E�re� <%M�-�� a�Nubiqui�E�iqine H2B��% Bre1*&Qa6� S�=K e–&o �of! 14)�)q6�&g!K n�vt�is�]���:�� ed��5GE" Da�.�3�yl �n||ines 4%�79!� eH3K  7�0��0r� ingl�(�� 1Dde��yl!/0( HDAC ) Sir2!�; asse�Se�iZ�"��un�aec)�p+q�l�T]^*)X�nd/�I2ZKofi�q�F uc�ZC.i�rol��'d6�e�ntext�tra�+%�A���sf a �b�oon~ cod>SI5% arksA���b�\fn�es . Tosq��Fnd�crecAher' c��'r �bn l�geBcytoka(�eukary��I7y evol8sop���e�ng�c ory -\� P*�Sr"!vt fnO�d%兪�8aO(ZQ}� ��eing mu�Vte-t�Q!eh�@-�zQEon �Yn!> A��UA me�is�%Vbud�yeast O��-� �}it� �(!�& �2>� tg;��� N is k�a�0 ��1"�~�q�C- �j�N��fT.}�AS0���. Upo�jie�N�.<@���$i�r"ssIHviaiKor��fj��*r&H!����1�%  �uQj–%g. Libe� /de.{J �Clb��i4�� kinaa{( -CDKs!�2S=�J0eB [3�6�\W�u�Oe lAcdecQ[Q5��u�o&�, dub���*{Fou{E A R b�M �E�N�)��oge ��vBx�f,�d� ���!�rsl bet�R^ �l�NT tw�J"  ����gy"%�,�y roll���GTP�s Tem1%�A�upsBm��\.A�va��� Bub2-Bfa F ,�,h�2�O Lte�\"�hd� } �q��J2ye GDP�t� q��7�G�6 pindWHyYj|( SPB0 A�Geao da�6��<��mi�r�N�ur��$hߠ�by,osї�6 ud l%�%a ��am/5���ngZa��)!d Dbf2/Mob15�[9e%$YFin�AR��n va]J��,P()B�,�0�' Y 0Z�� �A�ޓAW��stB4display%�~��F�I/�)q�[15 �Yido� � A�� �"�-mI���nh��a�'C !1 enāe� �P kE��!��!���un`!�1V!�� ).���G� epistage"�s s�L �a�� �d�'"� �9On�hd��qŶoly0 fuP of Esp+J�co�n��AP knuOiy�seՆace�A�})%Ikineto�u�%fzSlk19!.�d4�qlogs Zds�pZds2 [!0&�:2�bTL l gr � app�,Ui�Aoy�2A%M�Ñ,ed PP2ACdc55k w"j-r���.��e"�by�1,C U�"� 9r��p sugg(Qt<#M� accuv�<.��$ ]e%m��|�ab^y���, ��4br�"�27�a$eQ�a5v Spo����hom� BnsAS�F������2�Olie $EF�\7 *�IR9hU 9�-2 (�i�! bu�g!�d{q���B�!sIroA��Wee�qu��mo�'� inu� )gu�`en�$G a�o_A��n�� , [2��[2�orid�X?2�_ Polo-�ada�A�5aca\v� �bF%^M\�O/�ځVA�jC*d[ 2"g6Zdow�ve&ori�l�*o��s��potf\��t=,-�):27] (�9�I�biou�)� + 2���M�譿-=Ɍu�QB]Sm!a m�rY��< SPI�W��)8��,!t&;�` r��"� i!�f�.VM�3A��%�na�$�Z�B<f}�si�~�a�t}�� � )�IN/��hq��fi�P�]n,repeamRNAA�ǠI&Q��?�r,r283��11��1NTS1 (��lcri spacer |Yk�� "� on6�e ��"�'1�s ,��j�'!Kblo� repl� fork!�g�v! �[���ZK�rT�!e&�s -Curio��,MR}j�(�on)uYGb=< D is RFBE:���l(�A��"�&d %|aN�E!ڭ���!to{�,3hD orZ�!�V'j a&�\�-!oveq�?}���4.,19R�C���!���a&�qlB�kng)aY.�%-cu�"�/e2M6� on Lysine&||-~y�ensferfS�!^ Dot1v&�l� 2�rob�%%+y�[31iF�iB 6� E%��+ mono:q�1232�2AQubH2B-K;�5 �E2&�A�ju�ng en�� Rad6�AuE3-li{�[36 � DeleE@M��de.�`Ubp10!Ef6�^ d�P.}Qt!|*�+��9awf!>e(*�Z��[3Žs� ��Vb��* �!|i��@%�.yB�5�nt� � e�e!� .�4synth$l���] reens lin��.F on mH{n���)mbh$-w [447447wrv�8gY Y�?�{ j6�>2���&�ť�a .�,veri(�Agg *T s c�a�7!�* (� n|���:�(� arF)g ("P >ab"vm!9��M�.�>�!G0I�[�> 3y�� .|ofI�BW�-ho�%k �zs�lN&du/ aberr�+��2^o !sA�bh�v!�o�]1n6 [J-A2new}!���u� r�5��;*=,w�ellu#�c!fF[n$��yRgrowth}s��+|bre1ΔH. High-~pu0�croarrayR5stuű�ex\J�V��a!kde6�exJ��-�( �A�.�. S�)aR~�"�u"%n/.�R2a�<=mj�&~m�J���?� ɰ&TB� �#zm��� JG:[ Spe�F�,5�m��r�=r6� ` �A}v"�8!�r S%2:>o�1B�� r�}�iV^l6G{e" �B'i�w����O>�9W�H�@�[��eD����"M�ltedo�iRe"r8�bina�+o l�)a URA3-Vlܝd�)r LTE1K� H��m�on 5-FOA�9�2�%a�phenoER� �>2��.wBUB��p�E�t5Rr�%�DW�E�oj�v�9n��%eEh �2!�U�SLS5�f� 5�7 .��n�1�l�w%�e�e-�RADlg 1� b(,.��Ip;54ciF�arg��e ( htb1� R 2 � ��!p.U&be.� MW &�+�'.l�Y ipleuc�%�5i�V� #I�=���7v� �3Cw��Y�E4& s�� !=�a)�*3 �J%�Y;2�.*��! ��4p�5��albeit �踁+ lony���D6���3%inz�����:�m'di���suJx�qm:f aF:�Y�m;*� ~-d( =^�4=w ho&#�e�|6d*RI!�‰O�s� -n���a*"�(��ar�SG1���'g�0�n�&O"�m�&!�5&g�0�'(d:n)( i�!6}�)Zn 2b&��4aa�Ͱcdc15-2%�!����MB*zJn>��!�M�"� "�d%W/�5"����u%4Ӛ���ad6 s>*> ( MAD1A��t�wo�+owM�i��:9} ex Rcs�ps� e� [42]!_��HaSlet�E$A�)�1�� "O oleB�Δ bns�)is2�v=p"AIrama9N�A,*K z 6�6� �{�q3�� + &8 �)2B%�2�'���"�2��.%��e�e��-�W�:�/ *�0� � yq/%�dv�:�re��FA�:xZ�. {�}):4V�quadru���<N �&a�46��R-h*�&�>�+=cwe��tg3��{ �asy���|Q�+ �� +��M Kb�=~&�'��x1��F6w��!nd�R�m+a!Jwq�(�J�-=��arker2�}/ep�� ��e%c�z=�2p�n�/K��v��% shor�.nb2�nµm w�:?:�I �N� WA6�)9šMT*E#����}�" �>�(c�>)��MJS"W\"�%�-$� V���:V�q� �e�∼40f/u�3la�2��met�.nUW�dy�:�:_��"�DA�l=iy�wd�of�30–�� at occ�apr9 to G� J�*;<�=.�.����2�m�W�refD4( �>" nF(�kS3�$nW R�v, 1�� �-y��0E��.5��-*d�!Gq歰T�~`��:�ML-�Eti�Et6c  �=�mIy����m�0� x,)w 6�N�+  21,,%�6;�)E�1U�a�a{��50� 1� �y(A���ia�9�Ma�1w�P::{` ∼6�� & �y�N�)Uh2DEhS�@sq��K���] $Əv6�T� cr���� � , [4�!IMQtjI�Mi�l ;� r�V��Y3�EQ�� J�5�R�!!�"��u�^� add��i ��F m7L `� �M6 q�ub;��JQ.H*�c>�Zve •�(��Q��m3W52d�M*/H .�g�b�� wild2�-_1�Un3j6�Bwe' tope-taggg�al e_2�aM_gi\h�Gi&*z�-Ri= ld ��\am>�@ c*>%��\& �]-�+ �s��t�s3�* Leve)ӡY��Q��v�U ,S ��-5�:6��8~��:lif.1� �c� �6���sq8� 2�6551�.m E;�=e�I�1i�0i�Pm�-��� e��i�6�)�YW)lC�;rs�s��� �D"� 1ys�s� Cfi/~$)x!'�'1��&sub�By%�+TpdHtM<ISK�]� 9x�Z!�4�1u��bW1�F+���)�l�Ŗ�Z�*(�ch��F5g`�>d��,&%-�M�T���4lnUG���2/1��M}:� �o�-!X*"cE.-bB��2`9B_d0�*���"�i�1;.&"{4-l.�!��$3$) *f#C�(6�"IdF.k�j�-qc�]spoZO��6�/� p�Ja��S+o:dX$6>"�E�� �J��5� �qh1�"[=� ,ހ�?ugh �%j ���.bcF�, .�4�[h�4 �rincH2�bv los�cu"�",.�$d� ��2�siqN@�+Eio�%a�Hi�PverqIng �%����3u��!lyq�erA�i� else H�=%3&� -Wce�ꁁ�' �)2� E�� a�tI�w/A�6~no .� alp7E�� L$alM�aand� si�6oR)SM �{gm��&�h�e�J� �o!���E*..�#�l�=H3=��wP�R�AZ*� �>{.Y a�V�q�1  �b&�$>)>q<7�zW� 8"��::[Rt ���?� 2�(�)-�  )O��8a�|�� 79 �@*7)%T/set&} 7 6)'��� �do.F..�4� �[a#>�D&���4* o |� �isGH��T��D/*,9 2 � �6*�"ls�["leV� �/I�(� � .�&�N:� ���Pp#!"}&�Q�V�?a|��pr��A@&RfQ��! :66�56q��U6�ET�4DOT�.q4� �2>Q2t�&q� �F�1�� � \aN-� Q�YN.!��4V� .�!3�=�;�9�sVJ��}:M�f E�9!N/�J �+'qk"Cil� s�K8c -2s� iscUS�+�*� ikAS�/:�I"��7P E�c �/��e5" HIX@��32�!�es���=,$-X2�PEe_t՛E)a?�<�-!0&�#M;8i"�$�o"�;6�:��inM�Q�톩�41t!pX*�a.L� >̅�un�9�"��"gF_(�g4R%U�qR��5:v"},f�4�Weq��r[.�s2 -�i�1'-?&��SR �Q� 0!�|diM�!��  >�,! "�f-&31K�S-�.�9 Dam1]�un�L s [4ӕ��"9?a��$�@A�:�ata�R0+ �A�et.�F!E%��)�{�5�5WmP4A��*�i8��a�m@��rx��C�.� �*U�o&��� !�r�D�Br2-aq4 J����',&x4h:�GA4�-2�VA:� QR��J� &� ��*�E %�2So�N�[6(V� SetXArS7!xF�oIxDycatalyz/h3=�Y�3l�S6�H/�set|!2�6� li�v&�* sick�Ig�;�����" �36Aps,*2|R� &|+p@a�.}�6:X�a>Q�a�ry�6�)%�3HH@qbnG�I�?36�5�7M �l�@O ��B��:� 0��6 :& �e�.9Z�"��� m/u�1�aՙ66b�"z�gu!D&�S]��18%*Y2eBr$JE�R5Q�.�9i�x�ELQZh��3d%�%PY��+R M��m rpd3*<%�/J+w�%Ytu� �b-shuffl Q7Fgy9`5� rai3a`����XWM�ED�! v &3;�$�k!�6��:m �6=R> 2%)UrVR;��&��T2E�V�*Me�`F�U�5/ How��.:ya�@����V[ � �Hda>- !�DdF�F!�m�sq9pA��  #%�[45�?�>4�6��*� 3]�b�Sa �+�t6�� 9)A%�-0S��%a�~���M /=�B�sA�>&wv8&C9inՃ ��y�6���x�#���E�k�2� �: ]u�"Z ��D �6c%&��a�J % "�"@!~,%e�Ԛ�. r6g;q> l�^I��9 �oA5 �,:�c�#�%�+ �s?P�QQ���[4oE6� �2A�:���.b::�dla?�!�l�BQ� N�K-�s�!:�:a�ais�-h-J�C ;�~i' &��Q�2 �;&)�&�l?>2��ir2�e�~BiVOsir� �Ap���<�2\$e�!���}3b".:cV�I . No�ng�6u�e�!�� �u"���Xu�6��6��F91|%lU��9o� 6�r6�2� V��>�BU��zW>:)+orJ9%& a �\wV��W�  6�Q�5�inKaI�R�. "�tty��{0oS�&�[ �m�!E�em 0Wa����r�#� �^d ribrQ�embŮ�&T�[s�&a~K TA�u�~a�8�LmIj� �QU*�R� �2��;~��h�.��d� !�R� a9� "�0Lld=I�oi&_�w�#� *9?�%�I2["#]<"�2N3Af��H2B1z�vE�.���H�!�sմ�- o,�uN�ueh.�BRE��E=U-d�R�5]�F066�I��B6�2U4r�2 e6�P<��I0h�NF5�*t4��4&l�mWa2:�3!�T� a� (խ�A �^/%�e*���>��Bso.�F!J*l�6%dF�Y.�FPs s�G 48Dmn:~2��1z�(a:>��1b�fU�6! L+" &;b�0S� nJ3&�:� "F�cm:.Z"O -�.:[47�TNon��_��se� �$�at�4V�_1C���0��� H3!�:�W�U� )S��2� F3 �%L�j:�&)`�8Eq a haploid!,4��, 79R-��imal�:� �d"�4*� *�4��� �-2C2i/[4F� -{"�161H.l�<�`sVa�S&�!e:{2E�N�"n˘WT*30%<SV�*� �i���%����� W$�]"`*I(6_jE"e�~&���Fd5�&�%or=��6#�sAme"e�� @&�*j&!$"���.� aYz �6U.��� y�)@%N�or<%�A5}<&|�  l��`.V%�"A�.II�D�!� .��6��"z�"Fa�2�!5*��+ �"� [)�(K�[4�H[5tMDF !�i � T��66��� �"�m0u�O"����;�i�2 sp��q�<i [�� . La{,2�"�b��Q��[ I�E�A�-%�Q!�-�.�F� ^M L!1 @��=N��7�32I�-t��.t�isM�"QF�����˙ �F �&O�N��&�OI��ol II�6"��]�"l Y�duc�  �a ��a�AU.R! `AZEU�ѿ�ekE�, [��2&QA�`A`���� "� )[�6/c��_� ^)� ve*�J5? :!u�}#�*d"�B� �6�g c ^ ��.�AUn�6�.a,*�Y!� �BV6tB�r.�#6/A^����sh�1�uP61ds"�/�+!�g��M!��gre ���� �nSI�Q:/(�+lap&J#�x2`.[z�A9eE.>�K�څ�i��y$�� bE��w L0hda&�&a�OH����� vA|.h^ !b�a�tU��� Zm"b�KN%�B �+V�tc7n�4MH&sN9m�,ј� �� ����+�6H���[5%"�xs�6�?" N�q�B*�$���#:� � "F,7ia\�!IiltZ�V�c�bb��"�0��c��%)�\ *66��� �m��!�`sse 8state for mitot�ic exit regulators to access the chromatin associated fac+PCfi1/Net1 and Fob1 at7@onset of anaphase"to enac # rele�of Cdc14 ( Figure 7 ) . Surprisingly , our geneti�Pperiments indicate th|$is require  i"ependen��action{-��at 25°CA2Q�um+ thenU�<a&� al �$until satu� . Cultu���22 25 m� q4at room temperB: �!�at 8t ���e�sOD 0 . 2% � . Alpha-f� (nµo$10 mg/ml )� addD wiceA�each c � x tot�2 . 5 h,rreU� in G�)To��i�e�aW� 3 � %firFol�ton nitro#ulfi��washedɻ5×2Celim�e�idual a!"� zt!�resusp%d�QLE���re-warzto 37A � e 0�W time"7 i�iv�eU�gen�ducY fcub6)�Ers+�� . 1Asa��9&at)�= �A�p!7s as*q be�U. Timcjs)CCDC156<per�- , above excep��%;.6!5)inM�!F��i�uodurA�A!E1. S ��>Í�2�%3$Buffer KP+���%��5 �ac;z!�MNly byk 9 3 6 EEF] ( #6PBio  ) ���Jub� " �riefl-%.�at1a B2� �nH xt 14K�2��. �*$of superna�#I load8nd run��� 15%фIA�-PAGE ge� #345002�Bio-Rada�nd>� >�or 16��PV�9� at�  b�(�2�  b�, u : � a%3�B, 20%&`�Blo� cu%�a 28 kDaAgorderAsimultan� lybI�diz�&ari!�nd��E���or�ETBSc!�F�0�*D0!zF 2c+5% milb(�}\B�� ede�1e )ŒDti-myc 9E10 ( sc-4y$Santa Cruz�  ::o�ti-di�#j*#07-03? Upstj :"���!� ,���i��22� .��or rabi&HRP*�( 170-65�� K Q�6�5f�[��.T^�.]d0a�y enh<�emiluVsc�n&��� #3408!VThermo6�Qcs� pq� epro%b�1ti-Pgk��tV: aま( A645� Mole�r PH�.!�A}2U��) mid--(� (�����3 ��N�%�1: N�A� . Glye�" � t� i<c" �1�M%72 y>^qI�2�-�*nTj� ��� ��Ao��e�aF&�F�!�V0� :caҭ��s�&�HEPES.c1��,� "� 1��ton X-�0,�F1% sod�deoxycho� � &���A7b��}2i��aJU by f5 V��1�lZ��R�!l�!�=�''�*�!&�'A� sepaBV�:�3�2�. Son�A�U&S a�bath s +o�Bio�Y F0��*A�3�o�*d-offeg��)� deb�y�/��"��dA5F�yM�N�Uu�x i�eBmix� )3��^�U� (in G Sephar��7-0618-0�,$GE Healthc�Zm�Oin)a�}in>�& 6Bq< �. A��!%��= OveW2� hig lt6"O B��mM��m����ff�2��Li&� % NPi� 5VZ.��5��)TE��8 .A��MWeL"$ }.� 6�e 1e I I�!�!�)�� 2(6�A|Վ�$eluatI�n��6F�%�TE+!67�+Oe?2 K�*� 2>� �� �(�1 stepCJ�&4.ZV:vQiax' ci�cop.Xse �)J� 0ed[�^#%^ :� subjJ)to qu�G9&�"�(� "��:% [62] y$ml.�9�c��*v�1��#-f%�$2#�"�:M>�#��P 6`"�%70&Cto =���9 ��a�"h%�8ofR�Ea&b�J>�̈́of RNb A somb(��% [R550�/}{�,xQ�ly boil mJ!!M�oFt�.he bench�Y�A34 h�$!1IH.�5�B�0epsin.�5 � [P7��,� in 5%V�� �6� tt�-Dž�~�Q 5>�qf�!1sam7/f�$� �7� u�1 �&Sytox.1 µM Gr�[S702� >5 :!pH �.��A}�)�break up� clump�Bon 450 fiere�.I9u��q:!$�� !nj0day� f� cytometry)_$|BD FACSCalibur system .0�An im�3ant!}earchlem!��7�"al biJ5y[Yj7�Eof ex+}�4�%,� � co- !ed gen� rche-� no\& pathl icalKR2� !|chaS&er*H6�1� read~+ thesm(11b��$ �/�4.�dat�1�(ia a� disc!��/su)$ L�w:severl5hallengeg.S9�A�u�1in�0�it)�a��',%�.�environ�al variɭa sapl%uncerQ0tu!! numb�8of!> �T j*�/_+o�behavio� W�: velo�51P�6am@ new un��vi!�6+ framework�d�� HierA`%�DirichG$P�)W3ata�7es G I-ɏ=[�1�u0Y}%�to>�organ�$tissu%��$ roup�!�!�toe}lap�49C�}q5�7F6,w(produce mapE��}�4�<� by�Tty sc�1%ex:2 9 e automat!Fly�,r�0�in?Ug &�0!� real^L!a� %' , we/��!�.�out&� Q��1r.J��u2%odacWe" &.R�A,en�of 62�rt�*-se!�.b�se4! "+�2�:%hhe�al�>in=i�� +��#e-mod 2a�m2e�.�-�d Mp�104.�=�a� s�H�5i2)�� *�&a>ena8�Axvol�in key1�7�wayE�/or�5 by NF-κB^cr:7� PYome-w4e*$?. Fur&,2���ed/Q(�E appeaPim�s"�?N��e+-�1yp녧1�A1�n*lu�9WntR!�neuroOmit:+[!�WW lievr4�m)�N�i=x�=V�will be�lfu(gui�fu��a�g�@;!��<5J�J�!�6��<b;� �i{3t�6�'�<�4“�-taQ”%._s5 w o�~8 main�C, common phys���1 }go awr�mdisA3!�FUXD:�1zipurp�� can �@2*�il�8novel��&aaI=]�  . ��g� )l�B�!É �B" �'_�`de\"k �, ari�Tn QcoordB12of%R�A|da��իá�F ��U+o-� v�(!�e�a g�<=� a�� �t. Under��E�oc<e�c��BM? � :has)dp� E4 �or�al util��� ӉT re vA spec�%�a:ti���'9or6��)i�E�y��iagnosR h6rs>2Nc?!Ar�@, � �M��%�e| dive�2el �X��>JA�!� u!�si�@i`un���C*� �;it���AV�AOe�at��|<�=Cwpe �8r?oiIumDsh�l%)�$AW�"7 !Zl or ijk) ���?FY��-erpret�!N�EeoanAx e2P�OheUVA�� a&� A�� l%*ge�0hNv�x1L�>�7" ��u�M;d%>ne� ar�߅Z wd56 z!_[�ms�Uer � s� F 6,� � sE�.e� �iIFof2�-�u.3 toge��i�7M�o>. E,Aif!�� a!� f a�6�8l�=!5uYB H��5�.a:` ��ynbno�E�a� ,� � ��?often)"a*��Gv�6, sY%v5wY�5#s�Rtch� / ��&g >A]6� backj n� Thir�p&� ]1�bJdi�Ec/6=(sC!�&yum�ef� v!kun�@Az iori� o�n��U�umE��ai��.�e�a�'�G��ver=d�9��uQ �+1!5A�r�*.t * AFa����� ��.T ,7ig� Yyi�1���V�Echa).� :� �52`�n^�+Ip��&.�"ōfe�-!&f� algorithm�I��0�icrea,ng���.& �ݩ��Ax.��. q�.G hand� �:V9lW7� A�l*m5*re�y �G� Fto]>�U�1�6 be shaM� J � v>*� 6�ref�D%5�Do its.!.>�5Rheau� origiT= ��\s�Sicitly�'eE�.�,! babiCCic >����of �d i! RARssuN:to! A�i!^�� #TH�PE�precise=q!�/ �t %}Y-�%�v"3�;aafa�|.A�H!F��)�����A2�� prov�a na]al��ns�*� e;K?en*z N&���Nv%M�� Nbby� ��n-AZlic Bayes�Htechniqu�=N�q> ���m�ribK2s|-�%^���2��.�>�s� terGf&��BIg! 1[n n�A�Qusagea�A�A:��aA2i� � i;.� )]�ya�G�Is how ��!�1!�&� c!d>�i~�Ne9�#lirEo�. indu� � )�)!=4A\�6�A�s�^O�eN�(pk. mannAGn t=Ha _ed�/ . g .�WN�i us �"2�Cc PNL��e��influ�%��| Ao�YH)�!�FA^ er ,-U�#y�;in_ *������.� XU�f=E��r&Y�� 3 . To u"��E���.��L�us�to view�&|1 n ~R lineA�of6� lear�G��� �:.�:�/enN�TtM!�9�A�be94ssacdhSh/q Y "~,�aR� EM�matrix!gto"� s [1� heur� c[a�y s [2"�r� aqYS�els [3&$H$al tests [2#5a7oMA"�I����N&�N&� st� K-me� clus� ng!:�9�l�K�� = (%k2nQ�llM��>a%�� f n"�fFngyaNbEQisUE!�bi w�=�[2+, 8–1 Nj�LZR�iet a��4N�.;P manyM4Y�fsE~�{�el�Iultiple��.|�a���wo�erZNu�!ra�top�Kodel [1�$12]-�ez%�k?3�1AE.V7alismAows2�� ���~T�sumwNI�yp�5�!�Q�, �Q��>&A#)�@ A�a� � �y��7a�!�S ly )*� �ce��be�2�Q ��iq ��e h.mstruc%8� )?�en�N��. AZt `A�m� lik�:� �d&� �e��wp*p, also s ad�PagŖ26� s te�/o�<�robus�Tno , beca�sW#*PrengthA�(“borrowed*�ite �A�l  AO �Uu��he��� Pf.%:& 2� ����bA�ed � easily—�jyѻy��xA�Jf�KNy�=6� 2���S�Up@QRo�G�onq�Fi q�B� :�y�6�6) TI�Q&�eSN���ia)��BM a�8acEfu�"� )Ef�)Xon�!�-�g�d� �G%�&FF�6� /�V�p�aNpe��!a��Ze7���X '����e�Ar�Z%�us�1* �a�͵s  ly!��c�<%r e��7"wB-ece�a*i.��1�O aSa globEZm1'% t�Q We n�RDat Medvedovic et ac8� �Beed~~�g:� "�,V[WJ�ټ��of6�B�g�o��[14��A� e� ���e d"~!6=ze2%} Z� `�5 ledg� n�D`I��l� !�3a�+ofN�3r. A+Q�@�S!��J��r2bEá�&�zBakXf�Uon �im]�a few!R�[1y 17� ra&? o�[r�| Ki��v e� . Je� �pYoung*�.a!a-%��;2mT�� D#� �e����c (a ��)I�z����pa'>[1{YHow�$Ah�[�+Aڭg��r.$6inc� � rely�� tens�0p��;2b! �/4� ess"�� e� manu�sAze�"�of ! .� �1Q8��0Results/Discu��U,e5a�<�!'r� �e ���!���~"a���-����� x< a9�de�!�� Qmai�Ŵp%�,��*.� �=K n7=�ixs �Sa���,B� �+i��P"p�Ltui�Rverm V���54tZ \t�a�&�$!!Fex�F! kih�� � at6qnd"��[cmJ)p5� �� + y x.� %e�+-2f� J�m_��[1<: 20] (3 ompai�ur�'C ,�=�lyay\ŧE-�.=!!vwo�8mUa�)��WE'n%�y2��L��pނ%,�s&�PqEH���B�%�j[21–2�a!�"�n�#-6 L5uN� |-eva�0Af})�av�8%d?.�k"� ��AhR cate"eZ7��� [28]E,CF�Yl�*!�"�%EOprofi�b�n:D�%famP %B�%[2�^&� w�a ed;*�r� �f�& ��[�d!�!)Q1�ue��5 �a�-l�!�|$� �$oLb\%rWK�,di�s . W�e�'E>Q�N��47(eRY2�n>T�N-J nZ�.jo�ermץm2lOur o2�N !C>�a� �%�=$EaUl�G : capa�PAp��"�;l �or�mpa"U#�Y� ��iCal p� on" ans�(d emp�+��� d�+E.��.4D�a~In 'S�:��sou##��)e &�." e2L arra��y/��xT�w� x=�.�re�)�i�po�c��=Cc� *� E2����In.�|:�� ai�a)jO�40�d!!�qb m�I �2�(�e�Z4RP. Each�z�40sI�+��Zl� �(6�dHaN{oveS-M!e� . SeI�Met>,� K de�C!62  schem�@-?�e' doesE��RcapitISA���]�. �&Rit[CeA# cretaA�4S��“unitsco21� al%;W2.'crI�-`E�2��is�Zm�cee,E!M:}<g: %Ay }k4B3&w!�?Z��&.cY,m Pear�2core-�G!�� eeV� aC1ge_k � [3y� �tsor%��)r�(�s�3�7(M�-$:vi��� �,b� �k�Wonag��3�iZu!R& U VealGXgh!�M� Y=3R7%@.e . BuYhE�)'s failu��'_si�C �%Wis!uu*�Cis� �@)3k�4“a�ha�eA�D�� [, makam� &���)t*��XI��demon�3� ��1) ��w�%� ,�,t�����:UI$broken�hontŸ(�GE>in�s�p4B�5\in�_?!^���#.�in9=�mnec���M�mo']�'a��� f6���@takIGI�1�%acam>"�. T�lv�1U�.32}幅kSamba ����a�)o*f2� 2jI�Xj�Z; h d 232�'!<:�$( unpublisw1%�EGE� d#�afi m1��(A]s6��5�1n,~q�r ��BA�s� up���P m�cs"� ���at�'xincorpo m�"Teii3on6kSin�q r Va�JD�gpos�( SVD ]} b`)�CEb�AP>ue�a %Xe�"A�f�<s� 5q" �-.� %�!(e1�Ak]`Ev�d �e 8e“eig�7ne�a��-9N!>�n@ �N6�!�ix63 � �)[�35�&�� �$�og�6-Z!�1M�A�m1$m� �z" X [8a66–3��A�x1��� 4C TDY m="���,c-!3r�oῡ� / !I�i��2u ]:�B�#e9�,U�� ave�t��M�Q&4 n� t� � e�q$ V�D/d�f subtR.%Ve"-��"����v/9��non-neZDv 8JB( NMF )M�s�part dr�1�$a)Yio Zl�w!�.K��Y�u�E��)��%F�1Q[I.B�"�%n C&9� I�ugar��6d�b��% AtlayN2fy�*!o= Affy�Nx.��6���.79R��61ias���-S� ��&�G by Shyams�tr"� p X5 �-Y=AB�115 �Qc[1� W*$%fd.�:h��wo& wu�^ [i �F!>h*�N 4�,A�!5wo.u���7� "�#ey� w�-@Bd"<my�Gyip,#�".�@Ib"w B �Z�s�}Z�Ci-�A�B �=ԍ3s�'b �8�a@C 1�&Z!�t OntY5( GO )Rl"[deE a0broad�h*�=��) q.L�s�%wY&'2�.�GO.@!B��B�Fk�.1h limi��b"�&��"DP)���#} e0j)�!�m�enc�!c�:���� each�P+AA�J�Bb� . *^ plat�O)� soura A�) ay)�;�9"�g�, b�b�%'ly!�b�+A��IEW/e*zmB���|%�:Y|��=9�� ��a�u�x�.�I!t 4�I d  %�gW�Dt� inf&�� Al;4&�.'o�Ec"�1 p;Y.�zaylF�2P��Ty*!�e�)��%KzXn� � "wo����"pzSly ( T� 1"�Km term�]>�Q9�-��J% 5��{�s��"Z!F�G+d2.�d"�%=� �'$'�%y"�w~I6Cɖ-s"3y�a�^aZ!5 ��at��.�J��` *)�a�<' ��y;6A�k��3%Q-%��.6���'s do�s�E �A�� ��Wt 6%�to.}'s6� �. _p6Q�x!0h�m/�*igXJ �#K"��gui��))monshi*7YCe�!�I�� A5 m*(dq t�P�r�h́8%nst%aA�(z� �N)!Ofas  (�*�d3 vO6x,nnbf5 ^q!�1 slow�>a6 ,��� s�jrun)�V QsP2 GHz Intel Xenon CPUa+*Hse8 (E��`�A�;2.;mp.�F75worth!�A�%�.�,I)6!-ID�� MCMC&�)�<�!r�Y, ran)G�yai�!3U�[��7a�“traX.als&$!maximi1�Ga<2^!�yO-*c]�"U ��  �] .[�n�=7o#�f!U� � g!e�"�0a�s6(&��&2���M �Ew��!�t��" t&9dynamic=a*bi� )�e—a� �&� �=`=�j�We!�l��A���&��&OA�!�usLz�&�rS1E�a summ =�hF� %~Q� `'A� F2Fi*^ab /-�&�,���&. B�Oas4g �� �%m-C�m�Kd!{� of sixw %Bp�A�-�� �zHP�%F.`� n1��� n��6W�@-'o�?�+x�a|V5i%dW}^� R�S!}�[ Pp9%�;im:��i��&S;�L�� ^9K[2�2�e2�8$�1 )(}N5:a� �*� �'mQ�ur"q Am=�1�_) � A �i�&I/,i��~%Nnd� s�?!�By�"ngz +#ED��!ex-��>e� �lY9Y�=  '� ����. EJ�9a� by 2�-72\�xd�.=��kc_#�(10A&412(-20���lZ�z:tho7%^}�oA��8�* ',+& *l*!wa�)�4]U!�`'RFs��M"�c�G�͎m J4a�0,\Au�A'a �l�-A� puni6M�Bv�F�ve.u��%L %�� U���by2�.�=GE;E�%$ ?V��3 ��*fI��ũN�6�B-[ !4�k��/Nx��%J�6s r���4!�0� �{"`A:* n'0Kyoto En�dyY!J> �d o&( KEGG )!�PY0H�ezL+A]�N�%���l�i*�V6�( 50%;Er �"-0 ( 59���PC(�@ig�H6Pa��I �p]Fi "�0E�"e�&;Mo�naM�� N�W.�*�1rR�W*Hd�43�Wcasca�~.�6a2�ra=r;B.YF)ar9aY�.nno�ld�&@�s-��u>Z 65&���Au�J"** *ʒb�i� � 쁂.�R�^YI�  s S4%�S5�!��,�_YUVAhRuVKWa�=Y�SvD! �2*2Ne�EQ�(ChIP–chip�&�0�4in0!�-H|–� jZmEphlA34^4VW4!4��ϕ�?:�"7�5%S�HtoriP[39�;sof� b E6�:� (n� -8�mY���+ ��w�3 ���1[��.�(!ft$.� ��d��=�:} ����.�� �%I�"&v�-�fa�5mem=��*lap� �Q,A�qd~V|A �Ba@�ly 348-���Nz�0j^2MSO�!l �-Y�V5E�BaU�C� ����DI�3�0:� exeZ��a�g a��T�G=A0"l*%E�W�;N�qw �}�6:�`re"o��q= 8�;BY�viaRj <�aK�X=1� ���V5B|A�uh 2�aa9E|65VB96�2j�6�/ts"�YA�o>�*�I{�Wtr�X�A��o—� �i'��9�[�a"�@5�#a;6&���*Q;-� -�2�A8����[S:�*he �v��l\�:B6�O!E�N�?V?"9 �6a,�eb� � �0� 2aemplo��!ycal>[����,2[M���"V�2Xt��jF�)little �V��!JNOaB�^ �ß �V�i�O�(eve����sYny6�;[owJb&y St+iN0�n�F!��&���qSU!6AB�)�b>_�7uGMi m=2 Nn u�d,��ignn+. 6�����DaeLst*tI/]��md iF�T������M9�ab� v_ 2 �6i\, EP 22 �8-�=/r03O0v.� )� z� E� aw cɥ cytoskele7wY : hsa0481,y��Z�e\a[�Tmo)V � �@i��]h!�^�t�i�V�i��*�mt}F!�lsha4�hakk�?L6ccu.(9k���n;��%�!�-% flec� �)me"�_�I�A��-�1e�se�; ��r͸%e�9i|]� ngg*MQPerz�( PBMC�:who�Ql.e� %�Z���!�Jy��"yzyA�d2x� �$5M��inn�r�֡� ity-*s ��`Ig�9Fe� a�>�i�2�&zF��6 7 �Ou/wMC�.M,��DRO �s�a<ma��$0�a�'trigger �m�uW� D1FCe�33R�2�|nioV"�i�%��}}j���V���) � Gram&�4Q� N��eri�J�i���7BZ�tella�twI�O!�-J�e��#-apop���� �* : 0006916�&We hyp!�|�%j+ �*� 4��I�68N�2E�14AT��E�l}�y2��,�!)Oe{leukins/ fera�,��,�^�-?E4J�M �%-a�]��� 30󒉹6��a^�? E~aN�>A�bSam�!�77Rd98��0Ze��na�el~%��U� �orM�.Io�C� =N�k)MHC IE�  tM�ta*A�V�2�612(/!�� ��-�au��DVQI$lvP� z:2���r�� mit`� hagoce�!�x 2�I%&"�a�a �1=A v9�Wu�9ed�"��S�pN� revea� Q{(A�e$"ha%��^��� �RM*�M�ic�hF!.8R}38�913g:z�ribosom� �+A�Z� �< �HBg@>%��n!�P�"�.��}F;A9def� �vi� �a-2emoki,H .* 88E�o d�q.�or &F IJ=��7-'eHJZ,S(mA |?h#M.��ۥBt_n@l�Fi�!^9<�!f2 402>���~��H���"� 0398` oxt���&��.n019( .F�1'�&%�1"�!B!5or vir.+)} Z7-28-�a�` !�u�֡@jql�fungis �W, ;")>NA.��X^�]wAo�)������`J e��)��ob6s�%qsc88e;91q�du3�l�#r � t)46�or1�����[2F���5i 2� 8� //� �-H�9>V(� atq�=&�2!?>�.���t�n<��P>��ag��!ya� "U�� N8! LCqti�9��� �jv�Uz�"-r6�vw0���1� 5W�!j2r13�bBr�� EP 8N�B433Y*12A�u�)��Hv"x!�6wMl2�43Ŭ�t"Jw NT7A�FZD2�EP�� WNT�WNT5A  MMP7!��s*�(� -^"G� ��Ym*&.� �?W!e�d&,C2�}[4+c!NH�!��LWDH�� SmcB�[4�&-bS=�Lobov"�;2�e�.C�F�e!)7B�eE�,��6in vas}r end� <ii���!� cano�lZ�[4lS5k9)�! ptor)�� %&6o�N� W ro-2�&{( qN�hE, T�'� , IL-X in2,��y����!�E<U+[4Av)�C�6*e"}r5�RAou�>:�I�wab6G�ua�wO�d�1$f9� te.?$!���q��:��?�A2lI3e �bsW7QR+��l ��f��v�^.O �����o&� 6!o5�!��`�8�i!v)lyh :}!\jw��� crobg*s� :L()<��| )tA�k "l*��'-2n,njS5Qt.���DAR4�2t1��sf&�"B �F"�wID�o!\ �=q"��C��ޖ84��4^�"6����v'k��i_?6eT�="a�ayW&Ia�3_<y>6k{ 5.��6"6a�B�CA/�8i|`��J� ��B�}��rmo�)���/&�v�8lad*N5!mMM .}�9As6�2� Z��Yb��N5>>��e�,U=&2�9&>II#!Q��yl�$ine ( CHRM�/,���Pn��( CNRG dopa� ( DRD a�9�HRH�-�-�r6h *ail[� ܮ���l��! E�|�o6��T�>1mϏ{a�# R�V&PX�F�6��her [46�4XJRy�!!e�i 3)�:�=��M,� ��.t2) HuA]�"G�. � (Qh��)�Obi5oward�-a=F��#xr��%��&5�a���%M�mMz2h"�!� J�zq&!�.� *�%R�:� EP 99N\58�D:�0)Zba�:&,$\"��:-2��:��$6�"�al�S alIl��isϙ203%h�15%A=��ke�&7ytD5�8!_�2ls>�"�->�(.GRxOf�>B?�EA � ��qe��n�b.��� TollYfr .�462ʋ.� 7�Asa?2t.eXe-.�o�Z"-AI+!�M�NM���A�Ud�_�mf s��m=+&_ �%p�!%"� TRAF�AP-�S� �Bi510���IκBα�u�,� 99%�!�rizrREL� p6a!p5!dp5sAD -REL!A^*J7 10R� 6U5%�r+)�%q>1�de !n� &�A��.A���AO6$ . @f� �XQtjLm+On"��B�2y�a�+*a&N���?�22 �e��s�S>�m�I sens�e o( ISG�#ᥥ�� '��Bfb��&M�)06��*._�>� �Ha)M*�!� nee�%�asta�W "{c* crin{.2E !�ɦ loop5WR �:e>bnewp &���L� 6+B, 2�2decVg�Q�5a�e-� >aAhRP� Fx*0&�M��s*j�wA;F�e:*sb�&on v!� ask� iU&�4j�E�U�y%.�a+6"�Mrr�\rYAg�'9I@�K�!=)}�EJcay"=w!�!g�woNjmw0l�8p*��%�u� en�v� {�ti�(�7�O�_v�2H �2W(��g�,f2�&42t �0�?'>�app�� %�took �?B�XE:&� "��$B�{AX� E��6�NA;> B����ea����Bi�7 �� &B!�K.���.b�AR+6%1�A_MX�*a=]�1 Es &G�� /�sr�.N �31���%�K�>�inj�W �bdB#F�E�1 �%�<0!�.2ؐ��c9�7�Z�v:d3����f%� e*y0�h&" F�0F���0T!�%u���0E��� �q��#A�&a &W5�6�6]}��J�B!Y381 �5&ZA�un�1�/z��Jm=/by�.� .>� 1��Tal&�1 nergަye4 �x�v�"�[o4���H��:�>,gan16i���\�j�Bi"�@�o} ~W��* �ode6��5�?T�x=聖�4a(9��-��� �"��0}7"?=yF�rBer����r�pn�� umAa��1�SrAkDR�a����l)N �Vja�Í�1�v�}�}�-|A�=/5�,"y" them)�*�,Y��C�uR�ka��1�O��yo�; B %�.Q ��R�F!U!�M ��.� " .��: M�B"m E�^�p~W�vs*�ewq9J�.��52�-d�5%�"rW*: �� m2��B?.V{߀?!�BN13)*�J�5���q~6a�@A�kno�T,����e�Ft2���P� � ���-�AO^ p G I�� har�#[Ge��*nAb�JQ Fb.�2��>u"�K!Nh om��>x2ΕٍA���{ above-+'aN�a�tit�TY�9?t�H� *[��  �}�="+6�U'�?lp��� i��.,�lq)��#�!�%#so �����a�l-�@*� <4>C�I semi-2i�f���q�}0 ]r|G�m�j&%&�@A)9l�6�~� .�*�#� b"��r0a&f�O�E"�oP����mUlq�E��t� >��z��hf1E5�;�V�>$WA'�)��4ZM/�` shold phe�Cna [4߃ 50];%��e��Wa�xa:V=;�LA3!XaG_��� ��inua8�-�. S.�%�� at9��6�n%��qx�b!�^�!jx�V�$� capT�A��%1EF\�sc���Ձ��%]�i�ip*2 'M1t.&.V=*�2Oa> &\f��nmwA�\��a�s realEbc)"e��( E�x�e �A��*� e�&�c���R����4'� ��c~� !��deb2X~��d�+&bC.�v\!~�+�1vxlla��g8iېpre��,Y"�.*�?we}��}!�8v��x�%2ach% bE�|`g:J]I)�3ly�� F�.4 �$-��9A�a"<\&H�YI�inN52�&:E ? a wQ"i �1VO *� � �){ ,���� #Y���OI��IwY7�n2�E)]|isE�JQ"�F%� l� �:�@��*�[>KQ&�jF\+Pb�:�^I#�<� aT��(�X�u� A�-�"��!��Fp�b.��9q_ng.�;[W�51]!�*3<-�*6 .�IcM(�PK�n�p�%�*–" NZ� �-�?�mis�c"vQ�D�,a��tt"ҵKF2`T�6� � D9� *]^r�1AQ< �z� 6�.dis�[a�I�d�EF-���-t�1�fF5Ft.�I ?}&�t���M+ !�D!��6vl "@  �or��Nd�rf�k� ���a��F<>��YM��*�?�5"@�[M+@���e+>�$rU�fa��a O�ⵋq>�4�; �1  s� 4A]lot`�e�6r�5o-� �J�@$!��"�� A��B�)�i��*�� {e��p0�P 9��t�&P!�!ti�*�N!&%�ZU�p&C!m!�&�"w>�Ym"E -B.c.�>B*�9a�iK"N�� &d��]�f |� s�o. �Gct�١�mai�!!�.h��ځ�~ qgbq�i� &��H*al.-�e.>���\"��a#f�'� I.�2wmmor�� .�M*�Q�E~in<) *�DNA� �"���{ x��QE�!�&�k��b�,ed9 surg��r7 psii#X.=�2lp�custom UlZ*R!3l�(reD\c1���l� �.02�Upoo:�11��!��� �. \*��W!j"�f���� f�x�o9 ԧW"�L��Non�m2�n�m5d,q Z?*n.[204;W-�ƚ�<��s)moa,and s�=s� Hom�! ( bu��4�&�_�[5�1A a�r� "� ed H!�G���-ad�;ed mҕ-%���( GC-RM��[53T"�pe�� �M? �3BCa)���}&Na_�bt*lLiXv5�by%�ge��� �n 3�7tcAR� AIa�g%"�!e�xm*�\ �}���xim`N��aPq�aE�EPdeM"Y�@�1R��� wv�A%N1�b�A" ���n�i�SmIDCon.kr&�f[54}SkrQ�R2^D404%�,e#!����p� l� �u� �.o�� ��2-J��Pi$�@yc"�-& ���`>�0�yxnd�,��duOj��K}�%�=hE��%y�12�i!��]:7 !I�9-z}a&� %6�>"R� �u&A L st �jtaN!�'{, ���c�(a 2��i%�(�{yI���t�"��9yb, a���imte�^!Oer�DU.��� ��iF�3bW���O���7ini a�(��F��@ �!�&`�+!�mA�I��F�J�z0me �?*�ri�� ii%2ny�$�@venty-"TxM�n6!�_R&�dA���J�Ma# P�' ab��A:#a�( AAarl:�f:�1!Ha�i�!�tr��2 H!�magnitud���oAgQ�`V �27-%� �Te�e��a���R*�v}4greedy agglome ���&r &#,in Hartemink"�;[5�gIn m� ntb8%��e&W8B�Z&- �-�d�!S2p�9"�4!ib�( adja�4 Ci�e��14��+4���W�-a wٜmu>J"�0��1����� �*hB��+topiZA6d���5[ choo&�1<�q�. cur�b� by_s�7�g�B�A�F-)e i�E���,R�.� :[iE�et5�s hb ��U ��e .t���s.�pv� )� ' �n�yV�6��DBa� �9,!�5isi�2�AG�e6�2�,�oIV�, �luctu\s�&"�h�-k V�ez der�EX� ��c�B�v* �m�u�$ To�g�E2X"R�> �EJ� ��E�>.�B�%ɏ�%of�S�p�f�� �% 2i�#4A|�jipo��sacz"�2( LPS )"�>YV�K�.�:�]� &F. ur�b}�!^a��h�y?a�I�4 "�&� 8� �/veC �sl ��I,9��9K �%�!�7 ��a���.{��[�-g2`n� a p-� a��!ofc00�:�1.nN�SG�(�T���>��Teh��̤In6�Dg�:(�,�����#e �ua��N@�Ur�!;�(��<Q�v�kL�!$!�t��4 aQ&�\!�%Bv%?!��N 'paZ�F.�%�!2��*5 mؽ���M)�c����2I�Fz)�kqcA�� is6|w,J�H(s!gllFd�{ YC�JL�!��nomA&P^��gi�5� B�Wva��'?!�6 �r D�@2:%� ؑ��xo��l�Tword wW�� docu�'-2�"a\�]�'��c�DJ zچ�5)RZ�m�]�6"͐d �H�!= )��e!_�EF@�2-� �!�"T t��.EE� &'�.S�&:�achB�%2-�2�%/g9>��"���#"%v3�A�Jx�^m . One usage modifier variable is associated with each tissue for each program , and thus specN(s the possiR(pattern typ @$genes from )r Jused bytisn. U��ps are sampled hierarchically �influenc Qother Ss . Ind$original HH� Dirichlet Process formulation [13] ,?\entire tree structure wa%@�d o%K techniqu�scribedp efficient:\inz esQRwai addi! al ste!�dd cE���)�)�( assignmentIi�y2�Ufe}1�GenePm�Dalgorithm summarizm�2d)zpo1�(probability6�� consensus2� �recurr!Xexpressa��/ve F�mixe���MPparticularly challeng%io� because%~y�OA�on%�ma� fferIach)�,e . Previous)0achaAorhwz�.lhav��Ded pairwise co-clu%zng!+-zia�(s a similar!� meas���Linput into an agglom� ive QY[14a7T��y.fea��if!+re�� a re�@$vely small=Ditems��bjed��,we employ it�produc�^7. C^Qr!n���first%RutUa\emp�alm->�� at a%hei��s will�i���E same2��}� ]co-��wy!%��Uhen�hd�,5�F���La standard bottom-up:�.*V�us�Aɥk(linkage [56!皗However�!is]notYAp�@uN�@in large datasetsu�oEZ]A56Gt!�would ne)�Abala�A�6�W��velop!y novel�.�  ��K��2��3 discoversz�by!�bin!inz m- MR1�Xreoccur across multipleɖ>��R E��F�!�.!is�paa�againstϵ�deriv��� p��nI)�Hel��er! tanc�etweenah�q's" � ene �r��(�of�i�2 C�su񠕀,e� $� merged;. �M, a newF�U� antiEL(. Statistic Mtrack!o/ n� , includ!��?�b�F1Ait �e�, i��vera���B i�� =�lA��$!PKx- . After� r�sɃb!�collecaY�frequen!q)�� _)"filteAKout!@�� We�� 4four synthetic �,J 40��1> diviS equ4 among I)5 pop� be!$Y�utai��40�thm y� mRNA-\; 6� $ � �� lap�e� en+nB� > J� an]"�� e�w5 P1s> � . FQ�2,m%Y�[s Xe�6p� ed :gm�I��� Nw%pii-�2:U!_aA:��weighAhA�hI 's underl:��� -9���m�pertur�  � ve%��Jica nol ! i,e microarray �v We manI�clIfi��ii�%Nov� s�  Atlas �N 2�Shyamsu et a��;� AhA�%> high-�, , physiologI� cate� e��A��$ly ( see T- s S6U S7 )�mI�)�to GO b\!�S\ [27]D KEGG,$hways [28]�!�IDConver��softw& [5� A���a�en�  score�w� id�shuman��or:�coe�Rb͙fQ20�i=determ�.ignific��of:r,:q,�0NF-κB family�Gnscrip( factor bin�*,�u� !"hyp��ometric68to�$ute p-valu�nW!rr����M�eL4sis testa�!gpd7 of Benja�%�,Hochberg [575 We �a false- y �� cutoffG0 . 05� rrespond�� plot�cHly�n��<iA��ap �ariso biR� perb |[5�Th0 x$depict log95ohorizA l axc� frac%�oft�$5y4below a given %�XA�a� V. D�� 1�A��!�most aba�nt�=%��� ( i . �,* �UAc stB�o.�.ͳ )%�qm ed uUn�. Not=at�-�9�. y;DiT�Yor any ��Nsre *��6$Java sourcA�d� vail�� upon �4st .��Memory� 1 T helpe!F TH1 ) cel:cha!�e"�stW*l of��Herferon ( IFN ) -γ� wellbce epi�:�imprin��o2 IFNG locu+A�innate � , NK @play a crucial ro�I�defense"� Pcytomegalovirus ( CMV-�9VA. main1Iof��. Rec� � �I shownat�ory-like~s can� obser+ in� sub� a� � infeiV.2a�le� (r mechanism2- adap�#pro����<Ai� I-ly! � .'QY studew&mI� } (nly NKG2ChixsAano in�t�( H) seropo����vidual �wA�]re� ��. %Fnon-co�s~ ce!�NS ) 1 ,"?to-� CD8+ TM4orE�I�, e ac�i� v CNS1%�a6i� to enh�GIFEtrݸ�&=tiam��Lo)2�T$2B4 engage�9�žnsist! b �mE>:z��#   id�fy.Srdas se� �� mark�qWUv driv!�strP �� ��CMVcQ/$an� �provi%�a mU�baᔡa�reg� !�U�femgin6!. In ord  o su%�fu fighmka��cby in�ell$� oge�inR�iE��ed du� (an immune r1�priC��yM�weag�n�al kill��NK��. While�s���a titu%�I�2promo8 U�!�-�#�� at emuEXst� [1] �9��v bm=KCD4yFi. � t� o d A|�.ef!cor/me� ��m&� , naïve6\ must� go a2Z�� sLwardsB�))(e�)��] acqa�EW�A$��y>-[2![32 A key} 2ili�TH1-li%�� mite�A ���a�o heri�e DNA%~histon� �� � cis-el�OaQ sucha�a9Y nd s�a4 n͏JI��J�ZeA7G6b���b� Ang��! C  * � ��)}2��E�E�-indu��(l upstream 詜15is.Ev 6 kb��46��mo� Ifng)Q 6;,e���%sa̅�ory��%ydii�� sit��],-bet , STAT4�� � NFAT���in�/ opena�figur%&othkfun�as��͈r��n�� i, �i:�TCR st�ah, duea!��� � � ��=�-�_���-�mbut� � ki�;cepto��[3]–[8a� More� �:hT�X���A�n�1�anN�F �wo)are)�[9�1OAlthough.nanaly�� �%�� V otal��revea��b�somE�Ew\zed���1%&�suc3 goes�{al de�y�onѼG .�"i�r �!��Lo ���.8�E�" iE�(great impor&. T)[bes�61R �jsyste]def� \ of��8F>[1 �� ɶ� >N J d"���^A�6f M &� [16AAihapte���ctF;[175s"J @pe4( IL-15+28 )|!=[18E"2E�P�y ��$of C57BL/6����cl%�ex� -Ly49H+99�� directlV e>&� m157!Tte�f �[21a� S.~5�per  ��month,�c� eng*M� secondar��a} ���Od"��u� �!" � �� gene��of2�.� ��a field0a * rese�# [22)�a��c�it ha)en���prolif�Az��-[�rel onE92R $ɴ�a� PLZP-med� $antagonism�Blimp-1� , [2�&ita�c�# whe�$7,phenomenon m� beao.�%r� �� �� H1�tRH��a�"�y alsoVAU~��t"Zsha�!�A-QD erto+%� � 6� o+ )2, CD94/T+ , fur%#refervasB psED�t� ��!�encap�to�neg� �− ) o�&�!1a�b "�vitro��� tceA�-)>�ibroblaJ[29a�I urs2 re!�_�� solid org�,r hematopoie$��plA�8G2C��1cer� donB��&s�6(in vivo %`3�  -���)tBbrE�j ��yG2C ( Dhiip C� .k�atypa��ugges7pEe�G| pCD57 [3� [3e���"� ��how%�mvm� “�ing”E ��.�is. �"o2"Yi�. B� %CM�inhibicouV��uAvrecognizF � M�"HLA1ILe-E [35)��G,whose surfacE�1I�a� �peptides6�aleaa"�ofRqB�zaM�o�as6�dgenA��ng�APD depe,t fash!�[38�q3mfcsEa�F�gpUL40f�a�� � %� clin%Pisola� ��**�1Y� TAP� � mannWnd en:-%�e�by � A� C [40�4 �exploA;��st�g��t��� down-m !VHCV����U1� �^� lock!!}[42��Q*w�YqVe��.��%-x�sN|ofA;-E�:�%. A� }Fr* %AA�l�i�+���affin��HLico�"1��A4�+ �!��up:d F6�,an escape ro�n�mJ#���wd elimin��D9ed-�. ) �5 �co-�z�-!AA�x���s�6hiA[ e�,+2*typaly lack V� l�4ng�AO� oglobulin? 5�( KIR%-c%self-AH( s 2�KIR2DL1� 2/3KLIRz � %��� , [4�IM � R�S Ltim�xreE3&* ompeF�ve�x�� e�Fy!^6��pe`� all�Yoa�hh"� �� !�!�QPխundQyL.q � &� Kv/, �k�W�!�aim��ze"� *6�4I� c�'r,.~t)�.�1�c�!�tq �&���2� *�fh�""�U �!�&I 1y=qAcyt�-Eed� xed�J�at9ted�[as t� r�)%7n�"�2�z ngu��acta�*�. |!�9I-�.���b@!3 !mox FNG/})�( F� e 1A�w!�al�@.�statu&�ed CpG�id� �_he�mm  "�6dre F_k�f`Ny:]�~BDx .� �P���X����$,��"�ee�u�~\�u!�1KB%K�Ha%letK1O:I� emblA�co.�of&I*�,�!n th� fR�C+$" /re� s�YPef ag��!(or"�� �6���-� mi^�!4�� �-oAXbly!|���*(uc1&� �r*Y[1S2� .�.x$1Jpare0l� �5(���+�x�0d�1�!Y��%�infl�x. C^��I(b�F�-~� Y���%.�&A�,�f ��B*es��3!TyS ��,be2_ !&��� ,8A_ alW. SubRng8 $ al��A6[1�ult.DE�Nex����j%�!�j� u�� y)a1�K2�Kor+B 6ta&Gr e.�,�pi&�+ "me h.X�i��I~�!z)$gn�Cleast�G >�As"-%_��M�e�e�3B*��iS"$-y� n�.46 � � fai�6�&n 1��,��.�5h���&frsor� 6dim��0.N-HRm�E�մin&�5-� e�I���1�sA� , 2B%�M2F�2i0A�+Q�A�.~]�G!� �=>4�s"�q&� �S Ba�e�r�6| .6d ,Z -fgiw)x�(i�i"� ���+ �#� a�1�hie=�1}C}+��if no!� GEg�n��ba6� �AP�R2�!he!�q���.�ogTe�se$� \A'mNs�k!��� � O&�a 5�!�r1 F4,O6.��F &E &� �=maj0 @i,�8�� CD6�K%C 9�J*+)syH+b=,h= 6�.fJ�1I�s edu� 5<."ze n�Wasn3G%d"% �kA��culiar~a_+JdB� Euhi �.�)�, qb%? 5in!G7+ x!gn�w2 A� "U�3���rprisin�M��� 2V�� d^� 4fiGWe<ly�� o*x1o!�� j!���*I :>A�V%y��z��es� a�+��� � yearEe s Q�%�E>spoo�m�3���5*�9��4�&iq�.�_��6���\iX!�A !�U?still 28 lyNfS-� �6~�e �s 3tS2�#1%ng�C�r%� r�� en+ &f*.�.�(��!mdUJ��F� a�a brod*^.9n � 6���.EAowe*. RRBS- 3�a�t"""c  Da�QV�!�%�D5em%5�� n�0IR�+m�2 =b"�a&� ��/or��#Tm�6 !�RB�Gfv�8` 8:h�*�eDit�t�6"� �t) 6�%. J;i��9h��-=� profy�I  seE( �%9( �1/9V.6�f���m�#]�-%D\-�,2Um�a�a2� �!r�to%�|%�3�gF 4�'� l$ a decr�?ng grad�Bof�i&/to2�I�A�v��B-eC��A�to. hi ,A�judge";1 Euclidian!�$IYa�� �"����%�-��uK� 4B��@�0w��� � !���@!;,an unsupervi �i�} (principh*mp-B�F ( PC!���j. M�3� �C���a yX lymphocyt�bB1�capr1�1�@N���8+9.M�1�E�at�nextre�.n"~ e|9s@�I�F � PC1-T5, �!>PC1 dL%� of.5i)0O %>�3a��VM9�I#>L���d1�Je�}�a�� i }�! high�4��8�Oy�1��l.�T:8pla[ [low6Z. H%���--s !r=m2Z-%��3"�'�!P&baw. A�e�2�*J"4 u1���re& d"� �� As��8+�9?s .TBX21O -�,/8EOMES ( Eomesod�9�?PRF.i�i w*hE�all��r-�ed�^�� �Jpronou�J6�1at"���&�&�j�Y�� TNF a � %�1�� N ��h�9A�-m�2�j�z/6 PRDM!dBA')%yZBTB32 (" kn^6as�'0 , ROG , FAZF-TZF".)p u �:�� AQ&� '.JedUA[45#45#�eE�*E%ve bur}f e(͋-<s#+�(*�.(I: �,CpGea:),A�- i.e�� &�:���.2D-� ���y1� �xo�� �Uor>Uj��i0J� �� i�-�4~ Q 3i"X �4H1% N.J5�-sLas poV .�!�F�/�their6�ikf'�C�y1O7d l�3"�Lly�8��,6�0.�o}� *�0�@2sFL12RB2%.d8R�eS3�$SC� �] �:.�'M&�0a70f��+�_ - !�A�Zy�Uf�Mi>&9J�!:�1J� triggeJ�/�jEl.R�GNKp46% NKp30�iL�b*�%�YB�^(f�ngA4.AI7*��d poor�*)9� S3E� AH+.�&`"�;"U&Z2* .q�=�*fr*[*�)�hyf@T(�<%.��o�OA�b%e:3:c"!- �-�E�F"��( in�+l. . Si Y�9b�QC]I�6',1ih�^k )� ;e,ng�&I�lAa|�=>,�wnQ��� �� jM"N+%��"to|&"�0]Y�-x��(�K�'� �]ZQ�GR�6�A�y&�!!��� /Iv�R9 w2MAe�A� i"&!coYA.6� very���-bA4Ubp$z#��]�.�E�or�H�6���I�!��1�s 5�a5Be�&V�C�'he�!a"m -<�� +*%%0�'ed�A~2F ��A/ �ligE CD48%��)�T&4B/A�$LCL . 22 )!/221-AEH �+��-�Vgh �F hon�i&��`@&toV5S 5o�/is&95e�J��BN�R��5q2 @�lyp� %*hi� � C]K�G*o!�*�-@ /h)]E!�?ob��e- bodyB�e��6���T&(#dq>:\1�Q� 5DE$5�}C.\Qaz�AreQ!i��AEF��l&� %��{.-t�E����ti`Q��m~EE �B4�$�MS^s6T6jy�aiAtoN Q� �&�d~� ,�P��.�5!<Gf�&��4r�F� . ToQ� luci}5�*�%/ss�-took adv�2g*�eI�NK�y�!�� E#� %xYv6bQ6!-&qB��nd^,`$,�PU�1-R��U�6��I:��Hr�O,HM�UdS�).u3a�Nwve?J pGL3� a�J/x� )A�FG�G( −571A�+7 ,���%N�BT!�!R>��qy:�E�A���n���*uW2�[!EA�Lb�0q4SK@��ea�TS�%j5@2!��A�^a"qGBI�Y�@� 1�MfGr�K2{4:Q�Cul[4�7�C2��7&R0�Mas>*�8�in2~w�oUV� =� j����4�E�12�E2qIe0a��s*yni[U tane�^]�@�Zf[4./A�s�N6, w&�Yas� A��36j U�=h�%E�le��%���,7 �chC|7� �f� o.zw ��6G7�^!�2[� �&�D*�5�)=dA�,HNg�A wid��&�F�<q.�:�s'��arka%j9�]a! to�! ���I* �)�m�"�2is  �� RJ ngth�MJ ideaicommonom�9jNIQbeuXal�v\ �:+� �. IC'a 7?to@ �@t �F�F��o'U]�>.>6low�Xvi�K2xA_ts_-���Qe�yEi67&[5�=2�# N pret)_�9��h��V"G�g�ic:�A�GA�ɧ*�A"��! a+�4ip�#5Ms>%!�ab"�J�>�tec�'�1!&emia �(DdS?6sil�2M�=CMV. "�herpesnT�Olsq5_Kes�&�-U�nd" �p�zhe $�iD[5�N5�BWH�Es��Q��6� :M/).j.�? Co-cul`#{�!�E� �%n� >� �"�>f*4DSA�e��*Q�r qZD"|&J�g5m���A?�X%l M�.0> doe�� eM_nc�ME�w.5��h!�8A� #22�I58a�H]��i@�a�!�e �6�v �\g/?g pro!Ilam-Ery"� 9�R�=n��k-�'Wd\,-2���N-�E�6X�)��H=6+ and/ h rviv�"&, [55Z im=B!�A��>!�!�aY�+I��u_g$-�`ZM 2�!��"5'. F�G�d�a X�K� of�^��;�K\s!�idA#A=at�ke&8J!!�2M!:SA>�U�ơ���"�I/>�IQJ A�E�%�E�of^"8Hi�  %p&PJJ�!�m,�ac�&;E�p 8E4AUby �.�"AN �lL�/sQ+:� �nJ��E���Sl�YwhY�P�d.����Fc"�HxiC���O&� qH��Y,$hikungunya� (Hepatitis CHus:�h�)u�m�;��.���f?+&c�8�R"�#.�clo�4�mbl�cA�aK�"CA��Y�ɳ:pRT]-IB�AI�.V=A6ar/UA �u�Xols!�[.-J��<%�a\eeout�of un�k�I %��_�f(1vL"a%h�`b� i�WR[5�H���� )!�*US%%E�EB=.odK,�fre4f2�!,set�i"E2]���]\a�YOIpŸ%�r�d1[54HEY= d R!�r�0.on �u �S?-�!,�ac foS�hg�P��by�,;I"� !Bs3 c�=�"dcular�J5� �&7@@S*� f z=PprorD(%�e\2�.}ychZ* C�! � :�&weI�� ,-�CD�6[ 6|�:3s%��-�P/�iDe@5�9ūe Tn8�is�l�%�9Eu�#�J.�9�[�# , [6sKI�\A��I�(64'.P2*�ra�~A!$*+��!SA5"�&�B���IprAks"N replenish��nd�5 main�a�periph{%x$la�B�I?my���]�f*�h4v1y�� *��p^C%`�yt+2u�patl] c�D�e.*6� �^?&2ca��] tend%� view1Lm"_^�b c*�]G � bqb� xb[6�62K J�,�ln5=��.il2��AR� bran s-� r�V. Leuk�0�n�Ls�j"� �adult �.�0( DRK , Berli_Z Germ�)X writLK�o�B�tt%�aXv� �.lolOethic)om<e��F�A ( Ch�séNz. PyQ,blood mononu ]( PBMD�#"�5by Fi�m HypaqukCns��"�3� ifu}"on)"lVL6G�A1+ �<64S2>wZ<2magne"�R�@/$�� J% CD3�Wrob^�`"�\( M[n(nyi Biotec ~fo^y hf@"��,ij( FACS ) s ,Aria II ( BDPses|% ��M~7S�� �CD3�B�*�CR�f�B "�A/2( CD62L ))(�e ,Teby���Upu)(�L95% .8 c"`iO:M1�8%C2�7 31f|2k. NJ�`E�: CD3+�% 5RA+ CCR7I&\)$5R)+! CCR5+�8Ra+ [6�M63I�>bV�8a�iY�w� � %�27O�"N3J3/u!�-�5l>�( Fa��u&,i�%Os�r�'� mAbs"8P�1I�!���es:Ek< PE-Cy7 ( NCAM16^'eaAAPC-HSK2�ma�03 V500 ( UCHTA�4 V45RPA-T4 ACR5B _ 2D7/)N*E56 BV605bWa�Eہ�CP-Cyl Dreg56 !57 Pa9aBlu{H� A#�HI100 CR7BXG043H : KIR3@PPE�X95<(3D1!)(a�leg�7�i1� ( 14321)% 3 FIT 8070 e� U13459 �Ra 70625` -(*2�in-ho'Mcou�~T~0iotin ( R&D S�]��1E4mo C1 . �( eBi���� �1/S) 11PB!lA� 2/L3/So3GL183� kind�'�&Dūn  d A �8retta ,�pov Ita'I��Q conj�~� o !�@or Alexa Fluor 70nCD8(( GN11/134D��C!�O1k UCHL!TRb�848�DO20!P�J�r��']e�aivJ%�-`edi�^&�)e�Strepta�g -BV4�*Bi.U��=IgM Sa�aE�RMM-1�B. V�d��% "�,�>0Live/Dead ( L�"fixŗd8 �s�%n�KtW�qF:->�6�at�(�sF�Wssa*-;Diva S�qRWO�*& a��)%�Jo&r( T0% Star ����R��   RPMI-164�� Gibco BRL�ɁN(U/mL penici�x%�A�1 mg/m!8!� omyc�*�)l�$��10% AB serumA�FCq8Lonza�ToG link inctAt2Fu27Up'(q�,:�, �2( AF29-4��46 ( 9Ea#N@ A���� :�,:�(n�)I�]�r~ti- � MACSiBA�p�{�7lJ� �G5�D� ,  e �j�}∶E�^ax 5∶�5c�cub�&Ej \;Ur 16 h�^er�WM&o�1� 50 nE*���28D]10 µ2B�\0ldin A ( SigmA#eEi}�V�?=. tE}ti�t6&c/or"�[/W%+V.J%; �∶.S5E10%F;1&, add�+V�AS Golg�i/)B_ a�L1%t�2)�f%l6�6�'e�IYumZ�au�72�'Tpp�xof hygrm�B>at 255�5{.;,%z fixQu6%A�a�tldehyd�Ern)rMRxscopy S]@t �ń��traA�u��J���5% sapon3ED -Ald#w�oI.F 8e �k�FAk*k Abs:AAP�BH J�&�6"� ,2�To  �\�-�d� �M�� .�! CFSE-labe7( � nM`-.�@EHi6�2.� β ,A�.�,6#� MBu�2M�� �� a35 d�)i� �i��)( ATC a�r{��J ��l��� F��,es�*�$ac�*5-AJ*�LL.���J�5 µM @*��. N}�"��.�1,} I�N,oSpinC�Mm� rey Nagel� nd r�$�j�rb"�vR T p�VR�p". &H|m*"�by qPCR �,a StepOnePlu;'al-��"IA' TaqManE�S�%)1Ur�Kto -|fam�r'�+�-��) ApplT� " <: Hs00155486_m1 �;<, 4333764F GAPDH� !�normal�9o '� �m!Km�}_g��"E� #{5d�NΔΔCT�,o�Gb%icR%of ex"&:�qd5�bJD[IaQIAampPMini Kit?bisulfi�V�r,6�S,�A�p|)�s)O d�f!���(.�Librar|���K)uprepa�2bA8pr��*�=�y Boy�`tk[65u�U<MspI di�fAV16�NE��c , end-�i�z d A-=n4 ,�K��"� @�,� a�1� barc�z�|sAU\2Eb�9� !n"� Tby Agencourt AMPure XP)   Beck+CouRTxRyorTnd��pI�by��( 12 cy� �C2z p� U l�d%/ ��apoo��̀�"l%�ya�I 12�72I�a�,� FA%$z�,f�!1�f(∼2 . 5 la�B| ly YjE) Illu�c HiSeqL 0�1t �(a� bp s�QeZ'd��*s�'� E� a��b�?Pxb�3ouzo!YA��>�M$!�*B:�allK_g�3Pr4“CGG&i)�g ailoa]-A�recip/' o|e$2 darkQ*(akig�+� ��,214)EreNA�$.iun . Raa+adMCtrimm; !0-P{=E�enYnta!�e�!�**+�!>�!Ph�<2j�CutF wr� r Trim Ga!L ! ( http://www . bic�W2� . babraha�-@ac . uk/projects/�_�}$re/ ) [66]���t��$GSNAP [67]-!h�m�,( hs37d5e��$1�alK�c s-SNL8]%laXtoA�*<r%a�Ն!�@"iOw!Is/dele �L.!�by dba v138�.AaE�te 1vK @��ly�*7A��9a�U�as�Mj defaparam�"6 ex�!uOax�7�+w��.�:10���m�6m~MTf� Aw�Rn� s [6�0reVy!a 8 um c_5-=�Ba.)��h�$l.a�\�2�pXNlLnbXNo{qan2�-1��daL�Y-ttma�8!]�LA : �u�-s�Ii7*5�TH�����W!��*a &[sA*A���ẅ́COJ%yk�C�/�\z7O�"(of 48 . 15%� 3��1 1�03  78 �64%�4 . 90%%�Mto PC+*�F�A,` tt2o!A 30 ,+random�*vmn ",Hm �/ gR bo@!�#om`c �;2�yTS��ϵwSE��0G visu� 5�!h.��?� Beta��EQtu} ���2�b�e!�� aJ�QZ�)ategyE�-$co%�P�$ en]/v�3�l���e;.��J void'+o� �|bi�26}out�%!,(ceWt���uz%�a#sm=g6�!�%\ WARD�age cri>�oUJ�p�%���.�=9�;l "�#�Lory� Iu!��*x ("%!IOer�V�hAo!�d�EF) High Fide����ochaQc+?d >k|Firefly *�< ( Lu�s� ��c�>r�'r �> ( PrLxE4u "�<2�se@=*� �I kCJp= kg=(N2�< Rehl�r�=. . ;��uX��==A�^�r�* mende�yNew Engl!a7abA,�� ` c49�*Ex6t II kit�>.�#*aR�� deprݑ� L-2 �/24 )�as:by �"oU�!Amaxa}v�� �,���L" 3×106gA��.Q�OgE>/)�)�E�2 !0RL-TK Renilla.�nt,a���4(roo�N 2�a�,.�-E!21%12�.6@Wc�0�6vJ�"Z;^b tu-�!#$�H�m��� !�}�y+�m"�)�Ne(�a�� !� Duala�i*>Rq�Aax"�ccb�\rruo/A�y�A�Ŧ"� an O� L 2 �#e���AtekI%thold�Rn�.�un�;( RLU��6�J�@. mptyMCsEV�IY(k&|$. A li�Q' ����^�*r� ( TIB Mol%��lXT1kin Sup� ng I*� . Wilcoxo=/ rank� H�$GA�� mani�e-�"ˊ�6�z��.>E:�s�2�މUlm� "�M"Y cytos/I:�E��c�6'�D�ed-�YlU�Uvs��N:�!�!dt�IIIɹhe o> . InE=ca!,B�0=lA�� {���e�umT3opVng5��,�PngS�>q_�!exo��.�Drr� dM] LepB%�F�aO� �! ~Rab1 GTP�8EbQ��M0 guan�W� �| exa�ge��( GEF �J/di͛���}-q@cy �o�GDJ,%��hae~ �-� a,01@(�~�kity��&��<�.4!S�p�je2ica�$^�A,himur!�)>�h SopE� SptP�e�X GAP ����%dRho��of �s^��2�:2�*�<=!U Ty?�Go�n�7(%�aP0i?�h2"y�,2�of O�/C%Q�)37�Dbal3�19� �Dng� �9 �!*�)�} ���@1��A[�5"(�k��T'�z�J%��-wB�fo:��ha˚ls��e" �s��IR!��@a�!gs�F,y��on3�)#�M�Y � Fh��ly ung��"B}ng&�3sVbC�ex[ .F��gram-"ǃ�>um3ou�Hfo{freshwaF enviroA�[1�5WNV phagc2o�byF=,B��3IG���*�-�V���_t; ɴ�tN��Ѵ�5�!A[1x31�@� A�J�!* RJu a.varieI��cy }�R+amoebaeA�mg�(es;^u|A��x)�`e��niaEed-&naires'�9e��q[�+ e Dot/Icm��e J�� n es� �9l� t �: i/oNnsB�q-Av� %|o�))B(&F,���seJGmJ�s�1}a�r��e��4>� vacub?,��QU">,K !�h >5�{�4!Ρ��q.al eg|" [W���� B�F4�ia;*�7bMe� chem>�!US �!CFX�H�@ �!z�<U" A� d�wBlla|�|��!\76 �o acid!PE�llu�e! <c n)x&!HQ1voQ�X cadm<�. Aa�e  ��E"g�ca /� � re+ iz� >q%FE�f,"" EW��2i� n E2A��/��enzyme ��v�r ֡�sub��/�79���A|stf;��D�a]�&L [،E3 �0�3\s s�%���r�i�m HECT�, RING U-box A�NEL �A , [214��� each Xy�?rIin-\u}f�HAO�q_n dom"�_�"6@���$� БAY> ��� OZ -sub��lex%�KSCF.&�SkpZCu"�.F! )~�. �By Da .��1e:"�2-.ד5>�>� $car� �.ia~�!of�?�� U�6}"�Q1A.# ee bY�I5�i銅Sr���,�?to!�u4M�I M'NEL yN�paH/SspH E�!oem�� �s Shig�flexner[gN� [2�E[24 [�A�m&t^ 30 homolo�A{�J �Vlnoi�5+]� seem!��va�I�;JVEPn�.>�eY�e&k��:I�K& docu �g�No�oi�G� 5�-%�ne8wah]8��f � _QjAiEF^s�jc� �6sI#�X�W�IF� �A�I���-e) [0�!ޑ�e�-m�� 3��xAnkB/LegAU13/Lpg2144/Lpp2082 [3 FS����oe�&�P��l�@a1w�1i� ��A5q7"��2; �. U� -glyE�Sa)�kin Clk�ס?���(c %�v.�.eco�t��*�*��*� ? �i!Vdʉo�>A$"4�".�%j6�bE�+ximumv�B[� !mNi^Bs sNr &jQ.Ž geneI^A#���s�xim�tU/� NVn&(Ql�;V��a�&��VipD [36�?�[2����\S:�xNaG�VR  u�/ y `���1�MDactM�"� x:o�U�F�!>!)!�x�k� ��x�2�1 �7��F� vA>����� d��G d*j:��XwXlas! �� s . �..�pu!&�FID0vic� ��l�EZ�assX N,5Ak cAMPMd�a�; ��C ;� �za� an� -t.a �-�!n adenyI (� ( Cy�t )��R�n�� ��5:r6#�+C ����Hz�hm!����.b� Cya-Ehf ���0 wild�1>�![_�a��k��řan�0gy8)�mu�z�V!�s{:{a�sC�(&�}� C—Da�wisk [*�Lp01 v�ΔER - �c�;Y I#w%�7�"���JNleA�did}e..^`t�b�j�.� .���!� taggP\MyWPc� RalF;�,�d �as�a0I��%!|ə��3s�n)�A"�-aA0">Jamlm�C�z&�.w-�E��tL�*�oE����estig�-�`��E�6�th�JATc�&�(e�E�O pb��e �ׁ�%,1"� MG13 -Re"�V~ld �>�u1HoEpa��1�e%��ϱ af�^v�.�E�1D�>%FC#ngi� �A��!> mim�E"alEnt}*;Ya�)���� r�A�g,0�AE!�&X�5S:A�[C�((���A�)���h: �&�a-%F5��Wshoul3Oa�o�L�I���zl%��(M�� deal��H�^Q7 dyna%,�!.�q��2/ �,�'l�i$T�s��R3�#%+non-auth%�cԉ>(J$3 �El>�bbl"�)�or2|e�n�- &�~6�.p��^��/{yS�A��^eSJ. Pur�1EX�& "�estr �.S&)Ka�]"� uM2A�3H@.�<� me b�ehe�&ed GST-HΔ�\x +. އ��h�i�e C&-dz!'A�=haY&b}RebD�%A�o���)��e� .-aMPn�"aq-MAW���� 2 �L(�- )��R1JRC. Aw!&yZ��2� neitߊ�7=�n�.o.�9�� 2T�.�a#&�41<-�. Col�&E?!1--,� 8sO�!!�I�l0=�?p%�!Y��H�Ή�!�ua�2݄if �~A9to Qc�m�ca�:Y}i2 ts eip"�, E�UbcH5c (�A!Na�rA�v�Krim #I39%E�EHquVJM BE� ATP !C&���DuE�#;&7�{e ����+*F/��,� shif�S o a I#hW,�Har�)��4Figure 3�IB: α%{� Q�V�!�Ŗ� U�L%!w2� e ��& 1#�'�a��t )Etar�5��$��Y-.�6�< M!� ��� 1pull-L$�6n?��sjn�V1�by �}~�iblHg 9�T-p.�h06*PD:�)�"/%�# �A 6  _VEl2�� ��7nEs O�Y"�$�z5hW#.�GbyE�aMի�>���<5�ESnEB!�c��.�r�} ,.:"��$�K�min*�0triple-FLAG (�,  )-Qtop�Cg)( nA^�Is�bmL heBP ch�q%R��Y�53� r �A& %�~�0� Al? A��� <A�V���. Chin!�ham� �"y�HO�FcγRII-]c� .���>N ���&66�E|&T<D a bu%����1%�;itonia�>g-2seov6� \"�1+] �m -�2G�_ U&Eq���#1]-�6� ?5�A���"/ 5U%f���]�7�� Q ZSA&.� �\B: DMSO["vs.|IF+��#w=&%�2� q�hW�)�&X .i ,J~6B&� �1 �A���%�:EJ#�|7 6,1�,%�o�un�#edi}aE�u!gisJ62p)!�<��def�@�*.���rescu6yl A�:�<��us #s*�!O :��F* =��:/149&t �!;%oES���0�3.+!�6in*�ly@:-gr�ei�el� ly��laborat�5&)1� ��&�-H�e�$d0��k�kM�!-Iia4 at�FKts� !�%�7(��_ ��I� r�/,.5�9��E0on��p C+! thAB��Hchx�� �A.+""�-�]h# e�����i��46�A}2�8eJq~.zd�ɩ�2]I�R+�/]2�2I� �B;$�?dH����do#(Fl|HO^��>�IN��3xF���_e�G�\z�FN l�i:�aؕtl-�Urs%r��>{)�p4� 15 m�pA�eE�>���2�v =�1Hof2�de�h2Ri`by2<:$,J no lon��ei�!BO��sn'�M�V/im�.�.+� �sEi��2�A�6nuM�+i�� q�!2eNa�f�R>E�Z�ؗ:� !i25 E�56 a'ElI�poiCI�˥�i&�F�9 B:�!*f A�&�EF�q��Bu�V5W *����Jk�j]� ����1�F�32A.dD )/ !%:�Ek9#C:��Lasa�,��[!!�>�Uir�?r������f, orv .Ccubro~!�B�2�0J5�6����ұ0a�ne��T��.��D: GmES�bW �AM7>W�6mF. ccum�5� �4��A�n,���ّ�^E�! Ln*9dis� a�^3w6&�S !�&� e&�a��&G'9E�`� U����(�DlAdi=�p!�X� �6���b�=bX�rupQad��YFN+fq88{&.��uadda*!pr��eButA�ݏDro�4�4��' �[4\�Itk*�a�atB�)�E�� hJ6�oi�1�/+-�d�8"Y2��,[3�����"QpoQDfs& �MD @&"7d �wel@ �� �"� tem��& &h�v�[QJ�e2V�mb�6� oxicA�*�t8of |C��( �g��2�C6�^��� �.� %R��e/ illua��a"��~7ism��w�s1K!�)6� .�A&�A��\dR%-�*nV�fe ruff�Oby2�+fA�x�6�S�5N�u$5two"��X?ct sus�Jl��F"� � Q66-�� �aw �:n!9�6�t&'�.:� _>�6�+ trins�1�f!%�� >[ ;Ox(E>:�n ^nL�m�EM�b��rh�����w~Q 45a- 4 �""k�0bon��de�E"/?—��% @X M�n%�d7q(�!�B�-!Y�a�y>i@��'.`+:�5d^r!4UH %�pT���8q!����> Ba�mqv�atV!li8 &��� �E*/68AX.��n8 a�=.�K3! ��ers"� Q�6� }��a��Il�k 4�].�4i�!Wui �� ��s*� U���-'2N�+10–12�Ba�is far2'�����n Ja(� windowA܉�I�`25-�CI� LE�J) ź� -��Wa���ami5 �7%!��(+�d%RS�K&�wa !�:��`!V.� �H��4&frai�hP�&�~��I���DG7� � �0.r�.ek.u.�� "y2�E Ef� ge5!!�u�f\��,�/ aso�3la�(��]%� ^�'4�O)�scC � �0�E!!T�8/.����_%e�C� �F�q�=�-�6�.���9r6$2Cm�t�a��&3. S�PF}I�4)� �IS�X�YE3��<y�z�N �6�E8mC�� . AvrPtoB!�a ��$ Pseudomon�My -aensx u�[�&% z�"u�.3the�!J:��3y r��e`�$m�A��QMMm 9j�� r� simAiec�.�f�"�/d&u�at f�4F�4,fQ�� 3EN�4O52%Sq6J*�-�A�2� new ",/)NQ5-RJ-,�<�5���⡷r����fa��h"�tE1m%�i%�%�Z�5A"&5�}ȤYQ�y4"�{\��r�S � 30@W4�#i��I xex�J!�@ �E��$�{8��8[�4.*�ġ�tud�n� �D+�3 l"@y+9�Xi�Istu�R�"1�"02�� t�_^�1� 9����!rt�$��˕prejudi/il�#��!�t z!2 ��s a�rw "�F��� ܹv�E�� � ��32�I�a:�G*�of�Es2�J� All.F� AF:'� ��$�{2�fB' ?m0P�e�9�n� �4coal-yijS�PCY�p���7 g CES-�!ed >1A1 brot0dN�&4"�� �G� (��lq#� ŠQ��$('.�!�C*�Ra�aj- f*�JDV;��9.�"�EW%b{O� ]<lic exfge[ �E .7Pi � BL�l � B ompT *�[)]^E� � �z�,]/oI#P)K�?JG%nO�e�TKi] �B��� �4�T�"s"2BS|0�b$)$uڃdV 37°CAf5% CO2 α-MEUf�leY�heat-i�)H �kBS��AUM5TCustom m+@�'la`�� �@���.5��,A�]�.���I�@�(r +�F6 Bri�W,J�E\5E�in 24-���,%�"��#8J��Gng! l2� a( icf "�)� ( mo�W�0}!��C�opson��A���( 1∶3�[di4O %E ��r��ed� �ly�inmjµR��r4h 1B!�| 9NaG9�xrak EIA&JY GE Hr�c��, RPN225A�; 6����!��"� n)h�.)�!,aZ$+,ikedST-u�����vFz�.� ��.,�P� pell\��a 2-l�U��R� as��na`) f3�)m&�na��MK5ic(�al 40]n(E�)E8-A�orNZ��Lm��� ipit)6�6���1�Z� �2�E��Ol����M��9\ o��!�di�/�!A�9Are��K>�Z�;ini�Mia�*6a�( '2}TmaTHIS-SJ� R�0�m*�paw�7����wa��56,% /f�05 mM imidazol~kA��6�RPeluA�e��!VM/o2O!�e7a�7�!� repe��ՙ���y�!��luaQqz��p�h _ #b}� half C-qof� M�fO���H 7�b)��* salcHn�Wi�q��Y1 M NaC+o ��A ��apmnt�3 Q 5/50GL>4 colum[ GE L��ݹN!}!Fҙy�"�# (�to 5 Mq\>��z. �fm�eak5:-]q�2�Jae[er_ 6 10/30�^��e�f�~a��5r, 150A6�)LN�-�A�*҂b�atc��evi�wlip�!E�na�7B4�.�K,(*}98�W� 2�l�t� ax]~J_.�orC* >G!EDT! DTTm!$1% ( w/v )A�ton X-av)8F�-��2�� a 5��%�2�TlC+�e-Sepha%�!u6�j� ���l��UC]�� . UnNK�|� eb��� J�f���+�ʁ-s:;�2 9a� �"�2omi�Tr!312� �<n�� %�asQ�5!�%8SDSx z�r�>J�pt-�"Y5&�Q m�[v �1p"M`ZDn�Qu'.� � %vZE�~!�1 s; 300�uE3�I (� .x) �D���w{�Hed , 24G��� ed&e Q�� G�+WBEH� .}%b�7�0�H+� EZ ��X�Ges�R�܅�2��\up� s�>o8fic�B>r��eaction component proteins and the resin . Pulled-down materials were eluted with 250 mM imidazole . Samples were subjected to 10% SDS-PAGE qpanalyzed by immunoblotting us�Cantibodies against SidH , RalF or polyubiquitin . CHO-FcγRII cells ��replated in a 6-well culture dish ,%challeng �4Legionella str�8 at a moi of 30O!6presenceopsoniz�@y ( 1∶3000 dilu%�X) . One hour after infe)�,Wc�washe!�ree tim!a ith PBS (�-warm"�o 37°C ) to remove non-internali%qac%� in furth�cub1)5%Hmedium . When indic(, 10 µM�LMG132 ( Calbiochem )!�equivalAqamount-!8 solv DMSO� add �� x,30 min prior�9+aA�llto8%�c!� = . At�!C points)nKre�Rm cold%rA�lysIP15!l�!�contain1% ( w/v!(f digitonin>"%Cm%B(N-ethylmaleaT e ( Sigma)�pre%/deuQ�aEL,�e�Tase inhibitor cocktailM�1.�, [-AldrichE�Th2 0scraped off ,�li�Dinto microfuge tuba� nd centrida+<16 , 000× g forA,!� at 4A�(to separate%�5#(-soluble fr��5WtransloI���� from:EinnGV.%f�M# filt�e�@ough a 0 . 45 µmPer unit ( Millex-HV , ipore%pI��$precipitatqׁ�-FLAGa? LubX �, ext!ed�-nP��A S!TosA>(GE Healthcas, �.z SDS-��follow��b�~� resp��(vely . Five)�@ven days olds yw A�P Drosophila melanogas!:fl���uahA=y�experimea�. Bef!Pinjyonmё�-}��wa�kjus!>to%� 1 OD-JGene Qua�!$ ( Amersha�ϥv dist!� d wa�. F�anesthet�i/CO2e� �6�� each�X�<��T 65 n�Q _ ( approxi�ly 500a�ony-form�kAjsIS5�carria�ut�f�W� 4vidually calibI�pu��H glass needle attac�o IM-30��cro �0or ( NarishigI�. lw!� +�0��abdome!�clA��� junc��%!thorax%:!� ��ralB-betweenY$��dorsa��ticles��gY)]h�W ferra�$o fresh vi�o��a week!�Y2assay��E���1�l-A�qhomogenE(in�M MgSO4�&�!17ed seraof.B samp�e4�on CYEE�a2�0�� g/mlA�eptomyc@ T��pat.hvi!tdiversif���in newlym�%�dMRs��videsormɥabA��,host environa��r� ,ponses typicE�i�a + C }%�mit� viru!�!�ex%  , si�Tthat te� o evvx rapidly across multiple early-�l pati�icould b�_BM enabla�escap��om` mon JF��IJre7 t adapt)%��� growth!ia � �ed)@,� �J!rs!��less fitWms!�!<)*%E-se��}-� �s eviousv!aH# %estig X>$of HIV-1!� cod!' sequ!�A 81 very-)B subtypZ AJ ~ly sh� to havE(ul! �M s�orA2an f K le �8es ( n = 78� r two��ly re) %%2.3 � I�hse ca� ��! )��G canA9!/��d accu�ql�5UD7r!H bothMdir���ubstit�s� � asɓ�>�insere��G dele �%�Ba�tegra�in}�: acut��c!wa�; we find ea�'ofI���ak�Y �$identify a!�se codon.�US ed m��elyA�n5Wxplain�� de�=neu�0�,. Of 24 suchKdy!��0 , 14iei  ) cl0�� embe� 0in CTL epitop���leXverif������� redi%Hba�oEV��'s HLA+i|�$nucleotide��ext1ca%l$of APOBEC-�a!�G-to-A%`Y4 , despiteaH�exclud�W4eavily hypermu� �qq�p| A�A si�In seve�&qa5]!|f!Y�59E��n � motif%^.W��uggaAng!�t4ay facil? �K6�. Ten�J��Fnote�.N%ک�ors9 �i , in!A �e m��fr%7 tly 5I!s-%@fu��pep%�of gp41_e also��E�!np ribiK� 6� �|� Aofy��q�a�A�we pr�y�E�l�th variɓs\ in �� loop r!�Y4envelope glyco� is }����s!?�!zof)*,ional hotspo��OurU ult� � a de�ed view=� proc��m6�Ռ� %�Gm�4$, highligh� Nr�of.�6�in shapP) A�)�durKest'sh�Tnew�Kions . A&�to(�j�articulaZinitia I�> Ais lik��toll�x56��progresE� �3�w. M� �E'űe$�he�'sq} � wim ome underp�  sur�n an or!eref�s�ti� � :�A�Zl��eqIG�c����y fitnA* costE�5�� addiDami�!�o��� ii��!�!� , 9�Ů� reA�$� redu� ofM=�[1]��8� vert wild-A �% �� � [2] . If69 itselfi�m�v�+eV,�7�,, &g I��[$are P �Ŭo~ muco� ��s1w!6i�� h N ��eq 3�C o acquire�mA;�r�o��%�tissu(Si�A2 �V�( Env )m y��vital�7A �iT,%U targ�J�A�a key��e��A� 6)1ropism-� �z-he&q ��ene�of]�est .Υ�trimeric6�6�}�gp120�Žheterod<={exp 6I�)Qsurface<%� nchoaO2&iD le b� eM�(embrane dom��e �sub  . V�%-�yک-A� QbngC ��CD4 recrE�& CCR5 CXCR4 co'L[3e�hSt, uces�"` �hange |A�trigger: �v� [4]–[6a�Acted �leads�[CeQn% 1=�iQ)![5�[7\deE9ѳvaccin�apof elici�����Env� � lockoal oi!mp�� A� vast&��Qb� y"� ����%�v�!�th�P�ֵ�Eorecombi:�" coupM%4m��W,` h M:la� number! N-link!�lycan>�o �� kat�gv� at1�8!�In.�I%consiʹ five�ly)� (( V1–V5 )"� � spera�amongM M erved ( C6C.6 [9];�th� , V124%JV5e�no��se  shift%�Q ,1.���lizY�1 syl s�[10E�11! A�%��} sgel�B�� [12Ponly wa�� CD4-)^q�takes��c�do& uctuA�q����� asA" j�� s [1�[14�2!u �soc� w'a^ �pu-!$bottleneck:�in� � :h �� .�>3a25 [15�W4f �&���hey���I�is��υe$*q��Va� Xunclo� DNA �i!� deriA�� � le geny %"�( SGA�f!�sma�al RNAGd� �%��eM m% , [1��v� stud�ach� 102 ��BJma��&��u2aon six clin  sta�5accorso �� $laboratory�r�vitPfRLby Fiebig et al . [1��Ou� �"�y &-cf��onOoq�out�1�I(' <ca��possiblyr�)� -)��� U�I_R )�wM�.*<"� Y-�&� a�/ge & �EeA� ance �%ng�/ai� �=81 �eJ=�.aU� r ��Z8becau% c5��ob��"t�sAis���to� due K �� ntir� ()���24f2'al �� nt )A6o�w have "8 Z�ata)�� E4is-a�i�H� �10%�67�s per1 ,�e��dA+��e��%܍A) -) � %%'9�L . Phylogenetic treee�!�1�s Zu |� s ha�7 ort � ch�6�f.�al  #Arg@��c0 � A�>!�%Ze�& . It���m��app�� tandard p.�mp�y:I�se %�� sspwhep M���6[o �.pi�9��#ochas!m�d�����l&� �#uqF��"� oo li�!�"��% ��tcal�cr��Q�al%��2�-J. How� ,�]E���ng al]4si�a�Te�i)�.�d� I5{ simiA.61B�� repe6  �.�wor�MR same . Sha� .sI�>�I? F >l>�al+ �zH&4i*�t*fI�Y� whi �fA���aq��wh���� {a:� !A�iZU &�X� ed lw�na�&:�z%>z exer? G+ U�o�52� �����1!6�Y�a�Q�!�Iy� �s)�&<>WU?�b�� �ev���cexͻT� , s�%at5$)�F 6��� waem>L6y, m%�be �^ an un�Iigh�9po�p aN. U�b$ HyPhy [18� � preScompu`"�am.8�fi2)NJ�#�x�{ metho�$ateK"�)0ind)�4q�yIee�&<s �i/�\��To�!� reas��I^i�s������,�O foM�at��ne&ime� 1���xb��!e'iou�R,�g%�9�R]�  �int �I3aHto� A^um*� "���&�. A&�&)�^R- v &of%�ha�/"��reA�At6Ai��$to chronic-��[19A� [20] �� � hough{b$  im` charc*�+ 9  AICe s [2�Indels��XafU `�cog�on [2"�Y�*x��SI���e��.{ � i�$ -|2�!��!. b�a\:9 =in:K!ex� �k �hM&�eneɟ%�> �ai�C��e*� posi�- � ��i�,m3appea�= o anK&�"by��L PPcytotoxic T lymphocyt�(e��s;"�6W'�"F via}j-���1�gDa��� 0inu��a�pathway%�a �;)��frame�6b�#y!G prea!��%env but% pref"�ly fix�]�u���s�[a�!-6(yv4 �gF,".zB p&�Z� . W"��� of� 9�ժ�oP207%B$$]>� e]>��"ei b9)M��s s�. ]%cumL*��* on x] &��! � imple (!S"�s gi�*�Q6 valuŅ ω (t#ov$nonsynonym-.u2e�)+ont�i��7 �.& A#��&��;"� ��is echniq <��� �Hn>��mean .�� 5G� sign a8gra Wns*� u$!H ` alig7((� 5��%A~���� r  majorY�eA�v�gin3� uri!$U%(Z ω<1 )!w��1��JmZ!� }>�!"N.67%�loverlapj groupe 9T!�A*e� s�&t5H�� >](mtI�II�6�� s$2FB.IG!��JfDV%�reb�)�>�%��soXaeZ� )�&*0Jdid�d�.�be4+� Nv�A� �in�GJb!�z��D( p�(A52; T� Ar.5��(rs, h"D}Y� � ( M2V2 �d��`�"S& ( M1g.re}-q�5�� p-�5sE�006E&� 0001!8�7A� �N�–AlAjQ ,� D�0(JQ��6�&A�y<��s �.K F&}'6($e��5djHg' 2 . 0�O4ww . hiv . lan�goa )� fift� � u� �:�( ��[ ologo:�sup�0�!��e ;��Fig $SA�+ 0Z3n�$�F�.�6uH3 *]& �'c�r falsZ ig�]��:�#i !e�x"� � "3��FLŜ we w .ɥ� "�QR�:�. T�mi�6 mpac�6onb R�UL2�eW!�!��.,e v� 66�Ba�1%te����e� _r�E s6� ��} plac&� v� �R ω>1�F�% D )%�en�6ed%W�I�-g*(Et�O2�RB�se.pof)]'biA��reJ� �1�s�per��} ond��Li"(*�V:5�, bear!eT in) �ve�!(����$&E!hig�9V�WB) y�i at s0oM�%x i!J�0gQ��5 .�)ra1 a �on �"ngA�� amin� i&o,�� �- ��wpos�:L-ob%">�05�belonge�v2�d�.�discus9!bK;�1I3 Thir��A=*(U !ZA67;�#����� & ree-=%�0�tt ��1�%Gt 1 i#$1in�L2A _��.J=!�C3 S N.�Ew��bJLiyh �~3[ !�b[ S!�It�gs�2/(<t!�"�,2�. Six"+#!:%�O]�b��-m��>" ����pB ) ; 4 ]!�'�T1��}w%�� !s�*� carefu��2+BX.�N��Xb!>�)e͉&���or�errorF�"i6�16S+$[ )"�lisŖ�"�sa+ thei$,:�� � !^9t �on 509q� HXB29^�&2�� ro�'O6a�*b.�� �a�-�a.�a�a�it�s �beginW  ����1den]'ej)���B�[23�=:��| @6C�\�%parsimon��Naa �I�7��24.��K5 �=in�M�EAA�3@��� �SI�3GAw F:��N+2is GRD���R IUPA��d�& Um�D G ,  or TE\A�lit#1� 3%��!]�'D� q��(r�T3a� G&�2��23 �Y le 26 . 84@ 25/9o6Ql�c�as�-<�!d�!f�a�#olva�bx-�� GMB��A��81����Mlb/�:!��G*03-�> 8 . 6! 32/11�o-�8�'�1>�r�I ntr�i,�z"�4.� ��%X K)i bd"t0�.v�5de%IA�pr.1!(R�11U� &N� �P:�re�#t1-] �inc(8661��.� �sher'J$g te�*�004�yU e ��]A� 2.0!ߥR`�Gu�>$�R.� �2��� ��! Q� U�ed�)��g@s%!Twai�S\!MJP(P�. be�:r�5��m& it�����#� E���2@ s.n b$a hallmark��"�<e�2!f�5E�10k lyJ2t '�� 5* �9. A&�,� !�� on 965A`!��)! �"`9a&� i�;�;*g(� 3F��lsUDeE w )e 2A 6th� �)t%e"^ %2�Y"2�QV�)a�6x!>Gl � "9�in�M��"� �uc.#/�"�fA���= Y>XNfe�"s��vio*corroc*iv*>a ongo�n)�v,l2A��)( �!y�*?# �<-�AIao, T4cap-#�;�M�tie& �B�,)zA����otdif~q'opK�:�� �;��%{avail�B nC<^9�/�to�k%A"�� know2i<� Uliter%�'4S3ɼs!6rop�9 9�z5%6hqSe�"n(��Y�m.s�~>n3 ��summar�Ba3� ��k)tmNxA�usf0!"Ab"�F�&���'*4iy�&�Afsus�4i� _��oD��I�| a T-�3� seA]�p�9a���, 18 *�� �<s�a��m�<co�B%�e�.� ։�&!, s ens"s2#R���N �Khg11?�F~�$re syn�E���"ve�?ELISpot ICS 6l&!�� �( 79 ,�]83�g.�,�!/e*n!�(%xvol"2 w��e��X MEMI!��3 �+�^q�< �$d"~B*580118![nd T�"� &�^Z Upon%A�, 7inr?t makebkb m-�4 ( KAHDPEVHNVW�6 d:+i d>�I.nt7Y7|��#%$ET~%eg5V�4 M�6���8 �� �u��A �4lac_ A�:f� 2JR�< yq .,a �.S�4 .�v�@ g . v7"n#�19,�=�&�)P  6U � -"Z a�ť����< e�e���eF��&demBA9Acy!�^exf� it doese ����nrK��er�K� m�. Furm������ a� �GB#�$A��( z �Ql�#�8��!ub�D1,!.&$� �'N t�-#&�l��vi� "պretro� 1uS�>%!�a"p X�!&id0-AI:�3>�4 valid �=-I�W2@��i"�GA�3F�� &eR=RA�%]"v&�enhed�*�� f>�C� 6x�� 6C�EEޥl�)�co-�@a�~t��anu��DS36����6V*A��:�9�4��.�u}.&/1wI_�leL(* [2a8A^ �tE��D&�n���"u�5Hpen� :�$A�&MF0�56�Q< {*G���V�&A�Yg�hAa.� ���U�L���1 �( B*0��A�Co�R�A��>)ځ�.str�:���k�g:{'E r�!#6�G � a��PJ�–�*A A�-ֵFŪ S.�" VMȥ �� 6���12�u!��$QS*y can!�be��by�(NaE�do%�%1q2&� A�f%d�QbF2�7e)w . Two � ( 41'Q838 �e2T x ��=l���6*���aGA�s Z31�TT31P$ �=}2a�h�6I;�"2c�Plz,ydAD.x@B,��ut�$ .{�'� ��a fE�AQm7V)�u e�5z%�G�5gM "6TI�-q:2�5�6%Z�m tly2=Q.O7D��(E=�asf+a�� �6�� 5~ ��TU , un�F :u&M*X5%�W"� esQsde�"�%g�(no��enag"���E�-b .x��+�2e�Aftra5�I&F+�A Iz �5OA�`2�F"", albeit�Z�<meBis� 6"inV+ . No�W�w[wit��dKdoRh3n�$!���!�nq)i�bi��\�0 2568� e��� ")�}]emJ6�(4QB�4��Vacq]�T �%}M&I ( 64&Y@ �51�!��] )��^$i@6c,&�C5�J���� E �*aDc��C�@>�_3a�.!� �c�11�wo-�;2*00"�uP a ">[2��'A�y%`Z ISi�e �I1�9Gl �Tmp�to�rB>,�4� �3���aa.a)��_"}#maximumIPiho�6A�} a�� Q��86i?5�(> qA�qN=�27is il3 !�U "� . Ch�G��-m~r,��J�e�\ ��m,T�$a*dv�YH+�}-�t� %��oftm$��r� !�ier2` ��� �S� . Ei�5a� ��� �S�!in ^.� s (�-p+5.t��2%*"P.mbyD "�:�*!�ag, cu :� �$�B}II �@M .6"4544A:�uW I�a�O_#A/�(282`@.�49"U�la�'��� os���q Var . +�chAx <e&��ngM%ZLvFWr��/&�3��2}+;&�ma��d��me�&Mto��%�OX�6\!IE*a���to����6E�� ^�yh @Cd"�!(�D2�5� &� %!k�A� �-Eon;2'/!�7%'>% m�@:a�wo&� toge �;*dJ"9U�@so���\,6T�e 8�s�la�"�%ǭܩ ed 4!3�=!��s.��Jn< Daa�ca\�Pk�S � 2�=9R ~5i>#)�$3FeM�Ts�Ap% visu.E�oA)6 half ( 38!�8`+a��B �kE="B �C�->�-�r9@I9���>a!&�]2�7�p%>� { ��)`�%5J� isI=� &� � 0ZXS�8�1.T)�a�q�T ��[&�#M si�Aof��(uF&*� l=v"uB�F2�L� jٌnnE9X:�CJ/-_��7Ak A�[ araP=+8j�� -���%�&/� ATG� V@c_]�4�X��9��(��promon��� s��gA�f�%�.�eQMa�V�A("nkc"YUyE�LLM�����itI��#�0usB��ow2��3 .*�n��m~1s6a �+s�)e��%G/F6�� N�G�2��c�.:!=*�"I$2AR> Q( PNGS�2!�nv��1Q8X- I�b��'��it` orb�X�%!�)_2�lfdP^��nQ3�9r!Vin �A�*��Z0$( NX[S|T]X�� re XA��ܙS� Pro �%l6�&�#/!pex�7o�)1$�-��andom�<� c~un�92�a| �!�nisrupt-!�:W.:(736; F�:V)<@ ppl� a��I"HoB�I&J .8v�#-de-"��*z  �0=L"U=�s�Q ] AA\ ( co�P�j2best d�PCTL/CD8+Fky [25]<(�GA��YN���out����^E�} .�Z7�e]m2�`2G& opZ 9 M6g67938^&�F�9~c�� ��� &�� �@"m � ��#!)M, l X! noi"uP� &O .:qa&l?"f ����ly!b�K�co>m�,N{?6nW��edi8F E�y3G�f/ ��A weak 6�27Eu+ ]MU\�Qa ( odY ��: � 6��.nC��� V-�)!� G g!� x\f� �"�ed�k;���}"�<9 "9for �H��!�cl��ascer�ped�n1BGl�At �r�I�uep�Y�Ek�U� ɼ, theyE"Y&o�6oE !� leth�2en]&�cs�v�"is�:!_Q� kA�i �%�<�E*. M'6�E�8�� 9 Ai�8�ex�'�;"�h� fMF�`�ja�ruzHaL-=D.=7!t���A'al�I%�\AU� .!� 6 T'�I�_�b�@re�7�"�c��a"� �.bin viv.+T�cuY00)al arti�ZAX"�5�NcX�'�A�Z!X: "� ��!��31���(le>~ ; 11EuI�Iv20�jr��kn�L!:buav�a�S-`5b'Ta� J532�qy4�17vG"�Z})tnu�! , 4�82�13 c� in�atN=�l!&��6%-mc�6�(�+R3A��y e 21`ge�RAVE�(H#e �hF�don�_=�4424= �D3-�p*ensYnT(n�4+Nby��� keepi�Nw�<8U "0EB22�9�I)17)<2��iE���ma:�. HL� 6�92�2`)��Cs�!I�a�a1��� � @�N�&%�&l*$!�� %��JFZcU&�MKJ�� �7rmWLF.9KAn a bi(�a�n���e�m�6+J�z\ wsur2F" �.`aZ� 5Y2vAx9� c� �+%9e�var� r_7V4�^"�+�@&�B�]n�2:Ci+��2�byQ ��R��c. MV�}� �-eLe�^raL"��,se;�s. �bI�lE�Bse:K !�ofM10&E" �o�#f� i!�%��3�r"F�,&1�r�;ircIA��+�4&~L w&n-�;k�u�l$or�%IN��N�:�1��� a�ea��2stretV��A�u adja�_9:f&dYwml=tn� !� bold� .^ �����.+ brackets:W1�!Wnf���19�5�$�1�491�\ /�!j�c�F��P' -M"� CQ�*kmM r� O�8�Z, 4�U�l+.�445�U+or� �2~�ma^�E�ه��}1 ��5i��,�eem2533� y|'a( "217 }pairs; r 40–601A %ew�uma`�.1N82 sm *&� a�2�S5N( 33%;05�r.�Q�56~A�be]�289�� U821%-Q/1y!�Y~.&� shN/ + s 56) ҁ.5�-s" in>o9�7N%WU<�� EC6nout-of��6L 5W.�vy e8�%�7!=D�-ٰPB; Kolmogorov-Smirnov:�"�"O.�^~��EBS!�_,.W�A �o�h�2�R�of!2Z�M�`6L,E� �2<+aG�$*�8�Z�4V3 �F�We�*�$�`�$E�K���e&�B%)�|.I�PO���ed ω9x�6�!�roY,#%� >-.�YM�c�+&E( Z��� TAeY�%\5*2�+�Ofy�ly�1verag"�%w� v�s� QJ &� �p n.CH�.�.a � �)�_�$N:"0 ;r�_. 'M��Z���2��VE`>H�Rs .�a��r+N�q&�1�%Vr-��"'-�R.g7)��ino8�fV3wk/��f ��?  " b{�h-� �#A�!B!�� F�{ `A;M-@ Fw2@ocoinc~��ri�%confi�YK� �y �9* �a0*�'qw2z&�%4\ E�q=_r"0�xa�A�Ũ� a��FYfJ�����;&�@ctr"O<.F�)� �/9�(�L. Mr �mOrd �A0�dT4./m�F�w`� Al*[ po�&��E� ��9sJ!9�!!=. 9. A�z%�,� c�0r��9'| %X� ���r�!~KC�Tdu�Cambigu� 5X��~�$%�Ace�}iY^~lo��A`>�>�"9�o�\ooAs|�*�}�!srw�b�J:I� � a��(�ec��!&�#-tM�MH%-�9��'&� < vy;>�`�@�1s�*eal���4 o%afA�c�%p} �:"�'F~f'�*�53D*!]>�1h�a�b L �"�\n�9��Y G��&J]���W-;.NZF�]>RE(K� l�� �16$�Qr }�n�Q��6�0I*<\FC\)A�1��%yv�-�u�2�l6�s.�&)�a��Q�rs�a�`�! 0Z�� �!T o}�$�^%N2� lH;��B2&S1*G]II&�'aPa�at!�n6is� shajbyN��A�dA$.� S�W� e{$s-�I*h��y2!�,0D*+�fSA rnL E�.  each��oA!��A8FB�*�.� � 2Gl�air/� i!�!5EZ� � b yم9��e�iNU�z�Issump��s ���fyA�jv�` "�mm1�.O��|�:X]3�i7=�)d uC9�6e �!Dh4�3"^, 4u*ha�!B*pZa1sve[E�[�ttemp�l�jRol�#efM%{�� �W�!=3ndQs��e=�G">�_Q�P)3Ta��_"B7/A�e.v$*�2eI� ��s��0�6!�J&'!Q��� 6���yn-*� XE�.�1���p.;tI� 2!�p�(L+&Fc餡�r2�}pis�e9N9816989%�"S�26Ba�als�.]�!� �|@(b &�� �(*�L,�i90C�� � �V6#jWe m?!v.�"7"��A�tJt s�0y,��du�+'Y% �ze�;Z�� �)� ���0�*.�, [31]M Eo��a�v�>�C.�4�� �sXM n�� �����6{"�t3 1 K�!uZ2����!C�eme.��Xn-�0A�iH��%�!�I/E�m"2�� �+�* n9�bcs!*:� Hr*�+��! I�xrrm] � ^o2�N-�62tFD62�pe�� ���#%3,"lL�| h.�t�A��"� j%�Ez�stM.�*"�6n ��I���Y &G �t�-achɼ{!un!$V�._�B��(soy� �M "�<���A:�a�o=%�&� V�AnjC���+lyo�i�~�6z9�X 5J�\�*�>s0%�B��* X�� . Di�! ��E�"S9(5d �56� ���ՎUI *_6�J. A� on�;,b�;�7e*f�;�!�b��e�*D8&j?6�;.� "o�;e#L6�dnt&% E��&8;"� "2!�EeiZ ' �$4 eemaF�� &� )�Aom!�]�Abi"X�mcO,y��""R.%$V1�� NNof.b(E? �a5�Y 2q(m x!)n>RL(�W��*�=or�="�+HU��@:.;m�ve���*.� �z��+A2t-2�$%�gn��Cnta��C!*:u@C:Q IIM�+Ad#�i͏B�te�^Q�X�J �T��s E� �I����)B�j#0A.��wo���m� n�AeqXm��.or.B2i. N52�9�9� e\{ �:�al ����� &�{pl�.�{��˔a�]�2us->&E>�z&�F["�)�&�&B�Y"R&A��J�a�Z�"f�en�J� a&($)�AF, �*"{�N�; "7+:%�AWG2a��1�N^M[3R��$%Mof r�;M< g���%��surviv�U;� w�u'|�@V�ed' rbohyd�HhfacϕT�:G�"meΎo�yn�0S!�r !� )o�,B!� y)��0�P!�� heno��1�"2%in� e9 Y Ev�^%^�to��6�x�6F��A�1&5regard�9�'h�ZE�#l2�� �* ,�y!�^ntWe"��" cceleLu4��"=#�H�>ial��AK�1Q>O6if��8"�5:��A�for�5�a���E�%�"�PQ&�r~p"YN ͜�,6�DB����"�Vm�� �~!{E�n���f�c"�!:�:E@l��� yXr�'d-$Y�v'b� �Npa:��m�N .��_u�:8�nbqI"�; �  �YBF9 �B��>lso�a%�K&y2�w`:NY217"!A9);!otifF!� ,{$�'nying�.rt%Stak��0\a�15��K��a#:d2�f-9#� M32��� ^0E%�3!�im,t$ect Vif fu���WF�.�t�� �p�rM ��ȁD:u@y  ��iB�b!l!��M?M[^!��Uem_%"�H �makX�!�K�v�6rR&hA�n ��T�Y!��ě[3o�]y�\�c��[�" c&�hA'� O� ��1l%0oll�3:� ɨa�[35��38(  anim�a�hfa4-e�#-s�!o�"�(!g eek��.z9z4N�E�K�!.��-eny��3um����I>A����A��4z�[4-{ �hsuc0�? Bo�.y bh� dis����e$�15o"��l�3�Ov!��/� >� �X%2Q�m�7i�Z��pn��)�g��e1my2�%"��S�y� �"a--�.�'. G@�a��)�iT9� �.N!�6�-w�A��:���&&A�7 �֙�=*�)E@ ��-<%kNaZ o��Q  ��J�86"8. Sͧ�ha��rm����2? %z. �9g�["�"xLAn "�re-""��A�.�effic�yq��"�/_� , [4��4"��e�G��#U�D�%�rw .q1oA��d���f�V CD8 �B=�no�ger �c�{ri�mXorigi�� ���*44 2�4�E� a���;!w"��U~�$e+�2��%&�5Gab"i�N� E�"�o�sf(E,[��!�S�]Yw�M�iO@�d&v'BG�I�} onEa �f_9t{�ag!\&F@tI��W9&-�� a9(;)y��(���N* e$e4ex���+�n25�a�# 8��&� �a�͇�! of 4>w*&�a�| ҁko�B 72 "�]#^dR �vW��M1 c:�-+���  �sK[�}�*�29�j$�.�2.C"y�&E�*�0a T`��r#&��Jr*�+an�!sz�%G ME^4!�A�#�c:� j� % ���%��,ina(4�<@W"}�=)roy�env!j�DN� �F ,�Eu!Ne�aE��8!9t5� U@1�V3�� �Eglimp��^6����/ n���.=*�of�RBk&d�fV i���.c�7cN ac�'n ��2.1+�&�L ��/M}f;UΥ;e.�'1 : G%�1y�M� t�G���)�+of�*( . .�CG�3%���.�dynami���" �,�RT��%�L!�"���!�)�"#A%�'�&knomaloH�b5�i�givM7�ar�k;y*"� � �BC�6Yer:["U^a�~1�rou�qEk);���0�mut���8 �S6m �ibA�chI\!��$ .:mk��Yh5�!�m=Xٿ��he�ab�3qA� ��l�*t �Q F 2)� �� s�,�J�7u=��.>�)ID��fg9 Ei3%n.��D[$ve Darwini�dO>�)50]R ��. E*5 is�3works�D��$ard ��*s [51]!p� �� 3x  X.V? � U *�+ critW�parame�| ))( �is ��8�8#Z�8�[�b"�.ly��!<eL,!�� ω�*�ly"me� � As!�6 �!E=�z�x5D�"�"�.)hA1V%��%?�#� �3N[p7X"R �,�d �U .�n�N��y�W, �G;E4���3 �:n&z~�see�"u��)9;��%3,s� "ea �ach [54r�q� -to-Vuinueq"�� to Mť��E�Wm"%�55�*A���U�,N,� %x�:��afscret��Kȴ���et.es:��Jj��2s�f>��Usceeed �!EG;aGiTF]���)aY��F4am6l� �>%y`���+\B™!Z�4���%��"p�5��� )��<tes�1�,>�1l9omJ�L m�[)|o"��A5 ��= ateg�H�#i��at zero� ú���mix�}�LI Y�ywwaI�= 1�� %��?2�1�,C� � =����\X/)CdQ�ω)��,nd Di5 nd θ�,a��ta iab>b21�,G*uN��e���lW�W�q�)A*O{e��*�/ by w�j3(=Aas),Dik�!�wN�a�Wͻ s� �*tW&�e(W��ωU M-ܓAc>AYK;�"�i&�p�m5>A/FX��56q��,a�B"��!ofLEo"�e�8M �e�e%�ω?q��m2+y�,naïve empir��Bay�;l�[5�W� n%��a�e� r�!�WD~y6?� �u)�he Goldm� d Yang )= [57]�� ��*�3bi�y�usa�@o� �2�@�� �lp*�F�5���E"� �je us�.�2!w�qdE���A�� A N�ke\�! l~��!l.��e'!681 .r2m:A�e� �ext�-� ��1Q���Elefy0Y15M�-?���� ��A*�Q]��a�y��"6.N��%�C�_�4,=K"� I�PhyML [5D5w,a GTR]�6[I|�\a gamma�ua["��"*�[5�5e ����imS -�b!�%�, � � !j!�#��Yq�+L���3����&�6c9&spa"{"c�[664S.*� B�M�zP&�.I%�:La>(�(a$yz�:)�;R.|E(V!�}/"m �i"Ou�%ly1�MF�o1R�]��rP�a�7� stW�MRC%Y�!e�,a%�m^) geE;�5Aa�%$E�$B!�Ab�5s ��&JLA���XM!0�T-� e tipU$ I�*3< . Su.4W�l�8't)!�tax�+8tV���it back�6�?elBtila�B=��,�TP_,�5chi�"e ��%�!�A�e>:C�D �) rb�Ypnr��exadq.P$7 tab,D :er�vyRi�)�2Ms�+3�!n%?!,eK,U�L un!r��W�#j\Y HN1tal~c=��Mvz!�N�a�Ew�8 .�Jda�=�>o�6X`�=�5�Y��a�r:�a�} 2�c� �:J�"�F69�l.� �)��m�2!�Pi�,{$��)% BO*6ue�5 �@ed:I ��I�AV;. IV�r, 2VJ!�=v��^a�L"\ o Iadd�"i��Fira�aZ7? ��It�0 or q꞉�<�w 2 [6�#To"yI.p*�xof*_���l�)�U�� Ų1�*I"E*c���(�G*ص�<�!/r�sg �� s Yrs�a >�A&�� ���x�"!< whel� la4��h" sta.�<gi� :��*EW_E�"erl7=A�:use�y PC�W�!`leF����\(J�gѝ�e�`6�i�Q� !���r{�}g���s��� ( 2��[62/gA�O�"<. 16×10−5 [63*ArI��9?.��in Keele&"'��VBN !�t-4�M2U�i' fB!eEX�O5o!}^L Kf!��a<.��)`X��PNx~ bp*�O!�%�A�O&ICa`f � ZK- #A�R� need4Z$���D@!�cu&m���]{73�?�Lng>���+�$�usplit!�nn2A�(je�*�}(��a�A?I+��ʰc"toM�{"F�U�% Wsn�n MrB"�Pt�L�M!y!s!�J,Ra��" �E�"� h*йZ�2Vxd �����4":2� ��j&��syste��� trac�J�'.��\0!���#A���n�� 4��,�'X0�5[�Zag�`!!sur�g���"a�rV��#%�B�V* �eE� to 45A,!g"� �i)eez�}�F{~- L !C"�| U�Y-� �e:���.x�� "�9a�7� l��.�h>��)�aW�i��uw$ERt� -�*� E\%�NdAN˝�n-���s�Ql!�i+�p��_!�#%��gP#�`Aq21$.t s�/%��!-.�#cz��I ]9Es�D+Bf0TF xces& f�%i.�#��9�y-*"�[Aso��>#�7#Y.�v3S U�r��`0. Cry����d�iphlbl�k mono�ar�1+ tha� C!��nCC�� a� or 6�� 3��, 5% M�!� 2 ����#e�Xy�!pY��@A�y�&c(se�&y<��'ic��e#AU��&ƌA���u�!L ��{QZ7�-CD28 mAb ( 1 mg/ml; L293; BD BioscC+ծ��t249dF35n2107��exa 68H�H4AVc��� Bd�ld�� �b�!11U$Golgi Stop~sha'gen�A�{1�� �A PBMC-�s�]%�0LIVE/DEAD FixCViolet D�]CZAS0 ( InVit>f , Eugen< OR$<)#14-Cascv BW�( M5E\�5E19>"HIB 1�D(a"� d�m+74�aD 4-Cy�&05-phycoerythr�� PE )u -T47 o388-QD705 ( RPA-T^�27P-PE :27�y57-QD605YNK-2845RO-PE-Texas R����-p:Q�#C;اkmanCo1�rO�2��nuoat room  LeJ�.%͍' ��K ermek:�%�Cytofix/F3A N2-� 3-Cy7-APCA�K=T8IFN-g-fluoresce�1sothiocyؐ� FIT��( B�p-S$IL-2- Allo%�/%�d%�Q1-17HX� 3TNF-a�)�Ab1!���MIP-1b D21-135 "�:���452��.m9 wash��Zfix�-�run�@ custom built LSRӁBlt:min7���0 w� t��0�c���a�LSR�> flow cyto�!(6p7� an J , �. D}0 &"�"�\FlowJo ՠ2 softwn ( TreeS� ~Pestlr�-)s\)W!�d Spi=b���_v I!e ,p�(��D-�M . Roe%t.@��, Research Ce4L , NIq�Be}dͯ,‘Memory’l0$$s? �ua� ve /*�s / CD38 /��A �`CD27hii� -neg�?.9(v ���)�cytok0i+ t�� � 2 !��VA98�� M D�m��+!�(!�2��05%�0Z�.�n��p�%�z,E�6�epi�� tic silen����ud�yr,mu^b�>bio&�+���-o�+ z A���so� "JZ ~�3s eC% �!�b�W&o?2�1� �.B�S4u corp��,wog7�*m�. o, nam� $H4K16 acet�!�H3K79�ig�(At(�.�"x ��-�abEoly*_)-�hav�B�'�=� ng07mo&<��&�U15robus�8�$N�]A��,!��d� �,4!�vŰ#9G,17)}�Wa novel)�ɸb`@� &�w, � [!oY�)-9�'�0� turb��Mknock- &/ �2- `O�%�% nzyAc xx7�$AB�EX�}� �s�al:��� �&�1� atch�!W!�%�a�-.)�A6ti��m%!R���U�u��R����1v|�r-intu�9��] deF'�>nci�m��^I��e�a?(eX"���@spY��,}2f-���a&�>"�Etheor��al.) . Spew5E�,V�usI�bq*of Sir1; ruit%�,*�!�st�J ��4y i?&ly-�>AY�0(ȅ �, sasL�dot�illum��nx� tro s�D- of D.2s�C��of�g �I. TL.!!e�h_7M-�urA�r�'E0w�� aud� )5briefV��JAu���=�9���)�%8�,l puzz-�.o>&]SA�:Gting-tg�I&�� RegzvSIo U�i#=i��?&(=pivf %Sin>3��$Ep0S�O7�<3�a�A)"lexI5-JU?aNof�& Sir1�Zj9~A�m�It2–4� �Hidden M� ( HML/HM�C7t����!��ѩ� fact��] Orcz�p Abf�� �%+�% ific"N��0)���f�%�telomer��playe�Ҡ ligh�?�et;){3tM5;y��)5^�>!�9&*(yKu DNA-end�-��s��iS`b5!��.�X�ra�� NAD-"a de��se [40P* � Hist���O� tago'����/�, �>–�:�F Ns_&t��)2�"t-���#)�a��\���pi�40Sir3-Sir4 affCOyH%ro}<s [;B( ��� by S��( Sn hbAb�;e��)���� �$N��,��!6�;7!hRe!�C��&�{�GRa�7&}*> !!�5��6�8l46 /!2:themse$_5kruc�����2R_0�n<�7��.!5?u@6�1unh���vEA er bp7%.ep*�Rs argu�rs&`�bB,i��-�uheu� lociBWFo+ ��!mi1��.�r '��Bsk� aL|mut.�M��a�(/ .�~reover ,&WG� k���nXL@�Ao�%�ar�1phaLpe�o&� in � F2� [�/�2&.%�9�te� �>u�!O�  � H3K9%�H3K14�� H-} dera<) >rH4K56�'e�9�Sy!�2 �.H6=�Uh�H!��.&�Hee�Ac &�?*M $ojA�tB&9 ��ur��;�-�\&�/� a.� AYu�7�2a1ubtle— 0!��Bela p(5su�@���:N�!Mr9�is broa�%A c �E���oT-�4r� "c ��eZ-,=�bI�&V-��polymer��IIhre��a��&A �l [7��.��=$�x9 "ys7 �Lmen�aNot[pri�.P W-�%'s  #�4B(�!|1���E-c�%l'0a�C56I�6�D�!( ChIP )��%�,�,u ash�/I��*��imYA{!�� �!V[ ,�6 �T��steښ!�& ofBN[Eo1���3�AN� th� .K.����eEn A}���a & heri�(e,�)c$�ϙ�AH0 %�. t��8 B�y"1ͥ��+-e�p&*h*�, a����/�K F�-� F� i��H�,f[��)J3�7�6A�>x���he DOT (u4rup� Of T��.�M�!�6 �Nt �s��79��%9a�e1&c8ng�$B AEsFm basiX\Q�,1�i�8� �)b �–:%�s{- di-i tri-"+��hF sidu�x,�0# . St� ! 4/a�4���disLcs ���ua-��&Ԧ1�mq �,} o����5� � +�� *anR�e!�S ��v�#��@dBr"���4e3��6�>!&$7 Paf1y(��P��A�t ng F[ Ǎ/i*�c�e2&J +a�.� �S . J�P �!�1z. [6�G6�1IҬq?c�s� feed��s2}al.)?2r:-ly-�o�>rk ��u��,>H H3K4�-�66�.54�+� X!#1b�s)�類b�&Q�)�Set1 [7"� p�S��J,@yI Ai((s �p"�poo�n� stA�o �H�6*@ "�A>�Ue"q ! � [!  1�7 ��uD��d6�etc .1^act���,| inu4,A�!�M`dB�Rad6 &������2B-K12C��<�<#byI���)�)�[7�NUbi|�.e�.?< implicated in tPranscriptional initia $ and elong [75] ,such a t<�I-histone regulatory pathway acts as a feedback into the establishment of tN�Dactivity . Another xfKFE5$e marks isjinter4on of Dot1 wit��acetyl�Lferase [76] . Sumoyl)4is a silencing<l-might pl�Hn important role in�Ahof subtelomeric regions [77!i[78�Variants/thew'9'80Tparticularly H2A . Z ,��complex�^m)�Xhas been shown to deter�4ectopic spread��[6� The %of� v�,invite a hos%�connecAtvtwyDchromatin assemblyEzb�.us!fLfluences are perhapsipheral�!H cent^�%�h�� ( H4K16Ac.MultiplՏ )�1�ame.�can getW—we!<el�a!uge level��A1 ��� meth�ed- (( H3K79Me );we tre��m�[�GC)�ae�l unmo!�h— it�neiE��ed���or!^-�N)� X%�D!�:����1�!����1�qs��.��b�!5?� 6 �i�Qw& followA8biochem�1 proc��psee�e2 for a�3oa�y+ me h��dexE�8ysE���mo(neighborhooZ+ :�� m.��?2naQ6L�>6X�LThe�A:e� i�!���param���r�K�=as2Ɂ� ,cooper�>r %�V Sir@!�_.Ba��_ first�ul��)�ph� spacA�a f"d����� %%�< each point , beAa�G choic�}=Ap�s soluAms%�� dens�ofM� Q�di��Hpertiee�s��R, likeb�T B_,��U!��or exam��,"m of bi!� U re wA a���%�e ( )%�ute�s��coexist�t��isafQ> gains2 los�*: i�through�`!urbeX �4turnover , DNAa�l͆ tochastic!}�nzyma� re���!,�"se/de�>se "E�etc .�maintainAherit%5f�2 a�A& loci . B� � !)q.!�le5�, exhibits si�aneouslyS Qal.�e�%�z )U.Ei rangI\ valu v]�wB �aboOre un~ .� ���%�a:,ld type cell� responds�differ7M in)�Ayxm�ref� � u ua�e E�m��s �-� ( should li�-is-g2P�.unaZlyraffecI�B��g�,—a requirea 8robust engineerA)design .2 } tud�R aspeSis < ness elseI[2q[86� a�i��K&� !��s�J�A�faithfu������m�� re!�rib��%�di���"%m� s du�mitosi�yA quant  measure=)3� of aJ���volumM�hap=U>M%!% �;sup�ed [87� �9 outl" BS�el}�6A[E�4uniform steady� u�s (a: �6� 2z.:p2��ҁ e�-��.�b)k:0@J��Z42. �:�3ono��lis0to be��fu`%k� �l"�y . A ��lA�c) of�U2E�at onlyI�!4� !�M}��rBN lC 6�Visualiz���E�2 )mL�hE��g� � ��two2B�e+c.R�~$urpose . Ek 3q�d by fix�٪lr�4e ���hL Po-� 3 ,�iJ!� wereh� �Bre�šal.�� 's2�. O!�M &� �1 �I@���6:{is de~ �diamo�@i� 8M�EYgr& star� !U�#0magenta circl� � +2/$blue cross�0 )� plot!a�d��A�t��conven� � �%� aper-���g��f� limi�in&5preT "h� A��"k1\!on� �)�basal^H �2v��,%�pro�0 �conNrE!� ambi�� �!5�ekno obv/ ary el1zMqk% %:A/�hI��$self-adjusA N �!� d!T2gis &: ��6!ry;9R a%iZf4| s achiev�%s�a� zero veQ ty ��. A>Eg(, but stillE���>\ , e��A"Oo�)T�[) !�Denot!by=A,total number!*2��K*� :"EequI<%~Hminad21 )���e���Q u�A ��lreaa� �de"?] � mtiQ�e� on� [).:nee� happenɡ%�few��}�y |u�A-%� r�6obserA$a�be &<06� i�A=-6==\j��!�recruit� � ees un�6c,A�ellabo,`O.h!��s��q2៵�a� a6�!,�c�Zqnd~ � nim"��T ��nc� ��in&��d2 d&�iab, ��|,!� redu�X�. Becaus�^B$,A�n' ngle��AZQg�h.]�Resystem�5J�.�aM3�i�A� fron og}sa�rejbef� � _B4�(��"Ym��^E�fiJ6�46Y�:� te�!Eu���J��a5/OinZ] �is���i` !cm&� �diagram�}sE��Da=ZP�,�nUJ�driS-���ue-.-R:& �l�|";&Q *� :qs 1�)q>P���z%Xc fol�e�0�� &�� non-t�J$2fi�vo�/e� Urefe�depŦ��",[4�[488 [89]!�`�"CndIm>�!}Zu� x;�Ct�� made�ci� ��second28%Ye��atm�ӡw&~ ��A2inѝ��� rѳa�R�:��U��va � spat!�feG�B�wvestix!T latt�n%���W�?ud�!n2 �pancy�9��c a���g�e�/"�� e�end@I���:�F� "�ed%��A�e�Uris ill-� as� iI 5� UchaY" eriz%.�Altyp>siz1�s� tch�%corre)f length?A4��g*0��i� %�G�`?( z�� \Aco� .#6)elYV�)�as$����tua2$J5N4-�Jkis��x� ��0>.�Yudo�_f .. How��E:E�9�& u$� J�sA \ng�e��$%�2V �;"�iy � �.\ -:�� ruly� %l sensmnearby] � rry opposz#)� 2selec!_�Y��!�p:"i7pr��$P%�he yeast=�N!ink� a�deb\[13��3��5�[6�$�%��a:m Z assa��I��icmi . �Z !k( TPEV )���bn�qu� onE�d&&$strain [90=E.P#2 �� �5 �91l#f�#eda��U�8�ex�E1F� �}ݐ.� ��,��"�#�beaa�%�&� on� 6)�� �isyQ� ur�� �!�iq%i�2C�i\� s�u�7M SIn�!lap D]ble (� � " e�)2�� .�&�i5absJ 1E���$cA� doub��ne  11,B#�Wtru �*-&" $plays crit�&eI��i&)&h1�LBX����2AaAsi�� o� 2�)��&�e piv�����A>�'�'( t^L(doe y a@quNKof�5:!?*J#ho= hyper-�e�Al �� ssoc�dpR� .�"nome-{& �s [92��:Xa�bd�!�VbA#[� ��98(A�)let" .f�a potMalM�(,�+�����n)��!M, viz .��s$A�w><.�� �)2too�in=20we� alwE��$U���1OM� e� .� r�a �al ��n�is given�(�V*6, �� �\�A�s-uB�lMbelow76;.�JA�� �I ��A%��e<�A� !�a��!� harpIY)�.�� ©Ae�E!?ossoverB#aO_ , if!��1�paDal��-�W�1 !�l a�"� � A=�i% ( β )�m nullU mak�fMw!Qs C�nd� �&�+ �Ɇ?� now._ a clearer�$f0u�!s"a F�E���XQHn��. �!%��ed-%�e- �Ź��)a2.2[4)�A�!�� reby�; K�Y\22�lsoF�T� ���^(� �� -*� �7 ��A�* . Key�$��s�IvY2�,! sub a a�. Wnv��!�aly/-a R�1capA,�e�hm.%d6��molect/M�Xbud<> IM; ( a ):R ;N � O ( b29��0�!A�"1�"�#+*9*��.�s*].�@e" ?by*�group��*ti�*as mu�-exclusk[?/4 1�1�51\ d��� wo.��*��&2ine"�~�)K �'. O"� �� Zl{*e�a�%�.A/re �(i�6� ��in� �� t� ���{Mq7 uaIYr�& upon.y)2�Bo wec.l$$\#princip�)�Mf��/ao-yp/knock-��(�/si'AF,O�څ� �+b� tend] -=-��!�@!a�/!}ndB"1m�'it dib eth�+�p�=�6�i�$Z�1!_Is���O|�.!��� anI[.9͵h�'+p"��2� � on direct2J�݆,My4�2AU-�� |$  a fu*�-u-�jir2's &�'%zw?pu�te��&��J�w—��IM��alt1cr� behavio7Y  tAc&^�zh��0 d� f�a "�2A�8alE�%��(on �s6�!6�&ESu4� -��ie�m%�N3 �op$��a%^� e.�al"]��� y olog ^8. F�ak bre)���Jen���A��er&B*;}%ف�e�'i�54vA�r&x.2@ _ &I+#le���6%a��3tl�%eas�6S9[� . Af!WpG!w� ubmi�24 � y��Gruns^! lab [94�s"uI"E[e��3>02 �Y�T ,fP, Spec���2� -:&d�!W�8Rw��a��5��$%:x�aK*� nd12�c�,�#provi����\A�"oJeSa�to:��J� !��). !genB3Me&� %X�%�� A��P�D�4&�2 \�&�'u �2`2 *�n)���!q� &�%�A��"#�bA��A�masA�� m"R5�>�� �6�("�)�2)�� ���*�!�ex!n a sue-�12X*��2( 2 )S �U'z���%�� "�)#!�x at� Xdep��nS0i�1n�!s_�s"z ��8fN/"a"0�1 igno�%R&�.A�r� a well-miim& �inf�<e �-V=#Vt!V@�i�mi9� tiuW8ob� !205�*�Ss�%F(6A (c/� guid%c)��R�I9^ o$ar=e��39Bto-E1Rm3. C�!���� ed/aA��!�.�5 )��1~� �uu !�%J6�(1x in9�u+ i�N��Tn"U�r)�&�B�* two. thre�-c5�6D� .�H�!7."� ��� B#aAJ.�ţ�n��a�Q_%B !fC�� �c.n-&�, � �n�5w"�$�!2o�*�|�� �qb.ompromi� �L)r�.�A�Ktu�4�+/tui"l��G.3a?6*���~fto�>b��&�e  fragil�,x6 �!�M(��mfɶQ�2�Adisrupa easi�y.�%_!E��I�� �2�]ܡoe}&� a � fic%#l%-#, rete]3,�@aqua�> '# ���&�*3 A(9���-or�Q8m,un�'��cerFFu>add��mE�B:he�na(,h5�@|9 dyna�;)��g@M�Mc^u1!��=9!$cusp bifur�Ao�5]a2Hi�r ��&@>A�G�b� sA[sme6� !�&8tx � �� V; nam�: ex}ot��e��Eye)I��Ig �%�Ջ0�?"�4)?*�2�c'3 ) ; be�8)� �7OI�)�-�!A�i�a��@GE�verif] *..�,�be W�.r�7 �)�#` %�.���7a>�wdrawn�!�? ���� ap�+!$tog $arger clas�E/����.d&wper]6ed �Gillespi� gorith +at-e-.�3l�7%� �"e��5a �*a�J�1a�#k7of� )&�a0�O/�%2>quo�Ya -��E�7� un�,�˅��,��a@���� 8<&-N"b���#�:s!�On�, alter�:2�iX-��@` � h divi�"hal1 ��* � �9F�a5�)��r�?�=tGt�E�Za8��� � � O (E0– 0"�!j8x&5isiseL��ut2�%R> T!�.k2r� �Mpolymer*�* )-\<��.�D �Vin phys�1!�acw;tenY& g e�!6MJ4a�� ]�or�&�5��baN*� @,aTE ��5�ten=9a3“�icN+”� re��u�o��is.�!� Xl%W'a� d%, B�y sQ�27aQJRɓ�I� {!�e !msj left�%m  (�r|M/,�Tl�!�g %G�6�-��mimici�2#�� �er  �ML/HMRE-A�!K‘E�iU07ers’0S "[ŎR*��%� (*�2+)h"�A�a,���h�-� �tB��fluctu�rgJ6�"�a�Ong��nt=�a �*X4!�":z4. P�:� �i� / im�$epd�is execH� a�f�!c��6h�or("�Mi!�a <ra�MM _E� mill� ��r �M�MEtu�Ep��!Ql <=�approacha(/-�a�wo hund�ithous�3 step�Sam�AHg� �� very d ($ V!�!� 5000adls L s{ !N9��3s<:�( gra�8�%�7eu� 4U�F!4��p,*Q!. / mU&�(s �*_�62g� ��q>m�7 A Four�KTf$U �G6<'s&C.s. E�!�heGsEG�HeFBib7.~.�). tq !�H1a����,�&E�as��5standar�J O �J��!��A�{'[ fit� � A��1dby� a -t�(( Slepian )(!im6mC powe�Bectru� sChronuxr(lbox [9sS : ���- J� ��ris  �*he �-liAh& 4 R�K�6�Sta]-u](iy)� g�� wentyNbi�dArA{�%"" !��'cs'e.%� utilL2a���1�too� MATLAB ®�f��")��w.�l).r>�2.�LS��@9 malnut�,o��SAM��mo�3hildre�!pT,major health�� blem!�2Rd�Mop��countrL.Smanife�=in�*n oed�P� �%-ed,�\2��R ts msT� ' m ��G0as kwashiorko��A��Vo!��-J1%">cB E`ly"AHQ/g�O0icrobiota ( G!Mdysbi4F�6r�SJA/ link��^�.@p�A�yai� JUs� e�'uA��"�Hd"� Ug�Yn�su"!�E�ej>�orA�.�2!.�=par� �&s"a�:Rhospit�C�-Aya^;,6–24 monthc � , fe�� ]col2�%t admiy1. T�.genomicJK�ext&�6Q,E� PCR bx�q9f9� !O y De�r!: Grad?AGel E�rophorE`( DGGEaX�ag-enco�16S rRNA�e-tX� ��#�con seqWq�pha� beta�er�0�+�:r4Ti��� ANOVA*a��Kbu�+c�G-H$of� "!D:lo-Ag arisO6 A( . Of�87%�uB�\Q62%M|!X�]t2b, 66%)�bo�X!H\e1/ge%�1�61Q9.>!�f- �H�E�L� ����<5B!�!�4( p = 0 . 0317-�b�L-=�=���� �hW%ng !\e�a%�di1�.r6� H"�6:���u'�$���r �Y+�Y!GM2�wl �!t:�a�(AKSIMv,�Ded UniFrac , R = -%0085 ,5?584; un�B21719101[Brbte_J�.f2�3GM=^I�B��<&�no�.7�h�N�j�Z��id*�. M.iu�R� �KRF%�� !���aj�c�AV�12 . 6%!�Ddea�b.� youn�than 5�,r�age�+F�t#:a$a> clin���M,��J�e\Xt�W��A�F]-E unL) . O&T2Bs lifea� eateY&4!S� ^Q,2E,�K�[b0[r��bieW)��En4�V eato�Q� r , ski��P�a� y [2!rAl[gh2�JA�si��!' 1930�X�4rH�GhyplIEab6)�}4cie�=x oxidDstsB expla93[3–� �\/& s suggest*� �R x2�[G.w�~E�CL �A�+Nw!1� ic��/a[c�=a!��gu| pKsC>u�.� y�,trols [8–1�.Concor�2�it9� ��H�1 load lead�Cp�stsIen�� flam>o?�3� 9!2� ;mal�rp, [1I3�,� ship5��"� MGM�demon::�.Hfpl�PG2} �Malawtw�airs `)�uI�� 2w>Ninto ger� ee m�@I Iwhile!i seem%=be7&" 1s��"p a�:;8:�ilWm�U"� wh"G ��6&����&l9K,.�!XJ�P��lcI<6� �Bu�`EOGME��qb��*���W`ga�!��8�\.uq�G��B͎�!��.*a�yEG�!uw>�2�3� ul" �N3 Feed��!� f=120S"= 59  [,�&��/AM!�fA[c�QU87JT2� �K�=C� T�k cei! OctocK 2012v March3� li/r�I� 0Mwanamugimu Nu�Uni�XMNU{*Mulago HN , Kampal�q7 )>5y rece,_B8r�b Jn_4Ml�(�s Integ�d Manag�3 of A�2� ( IM_,&�!LWorld HUOrganxC( WHO )Ű ocolZ@:�%<D: apeu�^di�F75e�F100 ()Jse� Fr�). emk`c ���ickampic['VA;�!in� InT>E�dehyd�%���Fxo��r)�2A�2�( ReSoMa!�E:�. Whe�@h% �l(l?had�ag�]�Lt6B��l?[�the=@isE��out�F�|Y:�7fy-to-�:�e-�fp( RUTF ,Z� HIV p��� o���o�m��]`4hi��dra�C comm�,lSA9[14B Iu��?erit,re�2:n,��U�%S R� -for-h�a�$WHZ ) < -3yQ devi:p/s1id-up�>rm-�Rum%d t nim�sto~ at 5Z unti�hr.�t�� �. A�en d��le�4.�:�-8�Iaft�&m%imXi�� pb dry O to.Q of CopenhMXlaeA�� F��qP,�� ,Ap&�f�aa�r^us!:aXQIAamp6S�Mini K� Qi �Hilde�Ger])F� Afa�i r’-"M.l6]> Ke=i/# bead-b� ng � �$a FastPrep�aratu�QBiA{W)MP}�  Ilki� ,&N toK �U b�l 0^. Q�+�*�(�m1�9@%R�confiH�$NanoDrop 1&�7j�e Jhermo)�t� , USA� �:ea�U�mI��a� .AzO!1��Xe��'sc�>%��.��*;. UU,V3-�"A�A=22^�9A�GGE| carr]*���X:occd"^SI�a'�g�of 30�5% �(��n INGENY�U-2�($ [17 , 18]%dV3e�V4 �DF�%�a�# �p�;r�}mh P$E�?Nexy" I�6i2 Illu'` , CA5��( NXt_V3-V4_F 5’-TCGTCGGCAGC GTCAGATGTGTATAAG AGATCTAYGGGRB GCASCAG-3’�PR PGTCSGGGGA.PAOLGGACTACNNGGGTATCTAATQ; adapL$�Z boldE�!�#!nb.A6,12 μl AccuP!LTM SuperMix II ( Lif8G���2,I5Eof�)he) 0 μ�,".8 ( ~10 ng/��8��% se-f�w�ma�a tx&m+2^l)�runEB SureC�3 r 88� A�0�h=�. %!Ti�'s��lA�A=:q��C at 9ŀaa2o; 35 �3E�15 ��5/15�68��A40 s;5 � final *;uat05q��orpcY-hsI�5�!DiA��,R�ed1�Phu�+$High-Fidels15M�:A(az��F�rF, M�, IM�""6P&P7 �aABm!� =|jt�N!DJI���95�1!Z;!=�0:�2!a721�;:�5�8$;� fragN�tag� pu�/��AMP�7XP�f�?Beckman� �- G�2� . PrUAto libr$pooI�l��#}N wzf� ya Qubit[#o�  ( I�ur�parlsbaz}e!) thenq�% x�#ly~ �L./`�en�fe�K"Cqi�of��d�uN 2I250 bp 2-�MiSeq���).;&~B�yk!�0 . a�.3aw dataBe-�j��-�66-y sco!@��tr� -{CLC5�(Workbench ($bio , Arhu�oDeH �)D��se�%-��Aowyli�<of��01� no �agu@#e�ot|<�(,)�hof����e� Meri3�-!��9}Ij�“4ZE2�!Ms�,� - defa�n�� QubA.ve InsJ IM?#al Ec� QIIM>!X("�w8 . 0; O�Csourc�hftww))�� ���U"  . Pu ��Q �chi�;QE e6�2USEARCH!��Du 61 �Fod6�O;po�G Taxo�"��*OTUE:�U;),�(g�6�1� 116 �b�m��m.�"fPrcH�Pj orm�! norm��%0zu� Bio=s 7%� ( Ap�MS4NV , Belgium ) 7�mi.�3�0A8,���H�m�/ A�=� ( PCɹ!�N� zJ�<at�a!e�j' # �Stata�+sQ.j!on�2�(,ataCorp LP ,`5aa�M ;-� t+#( }ent� I��A�-:%�%], c!�of2)}l�Ks�led /, !�log2�. Sign� � .N on PC1-�(�do�%�*�!twoN�"("�!0�"(�w5,���m!�reg8!FE5!��C1 �e�#��JVrrheaM &�-�"�o�QA�:c"O`!n=.�2��vl�4fm!s�&$"�#018�PC2wPC3 c� �$Efj#Vo896 8Q139r-We��{G�:��^3&> &hig�t roug3&��!��G*�:E&;at���3 U�$as 7054452� n"rAof 81085de���Mum = 136  maxi 342628vLD = 52632%Him@%a�&�*>]402 ± 87igy e� �PRJEB6"�B%,s ERS799842- 92)�A2�yCa�u2�_ ! *�#.I]�U��% �]78�16�cA��=:�F505543F�(B1&t = 856}03! a�OF. PCoA�qpatB8�Ř,2�y��MimilaZE AN&hv2�() �&�A0or^r��d��un�&fK&�X(T&b"&(�3�:�no.�!�(o~mZ�& )nB�&D�PbTT ng�1���c�sb 7��(,facto$!-R�SQed6�&� p�b@`+in4hou�%"++I}+0�(r~2�'4AQ�� 517;jJ 9%�025840!I. T@ZL�'a���Anaw n�&, w�$v�JaAupO")��T,12��122g,. AM��-.��ac~J:��89.�(02�� S1 T2_��2�47.9)83�ln.  0Lof����#y W�� H  Z- �Z!2�U-3 SD�"� arm�oB��� 1� �)%� bm -AgejHAFj�*� A�ɬ:AB�+=�An�p>E�5a�0�  2LNei��{ �%��*v�(�b�eV1� �&� �:�v!�� 6*�pvS�34�er�SD-)&2.M6�l D�:�� D 2 :�( n = 33-�a��+ 5�u�(mɧ�� �.t �Q2m�ofA� P�To� (b�36%� :�A 50.:��a�B�oiaE 35%B24% "�NI�Firmicu�8($nJ,J �3m��:�a��lo Entegw)ceal+m�E ( 28 �46%>�& , S2-�� G5�8l�(db &/$-�c��y �evotella�a�6� genu~ ]5^f�2��w".�*� -^�fi17!!i. A�,a�>meUq�ft�g�4� �Q�:�I�N, v�41%&^�,�g�Bon7oni/FDR��`;� �U.� . NoZU�� ��01 �GgI9e�"O ��c�~p�f�(6}.vZ�2u ������mdGa:-*��=wF 5E"6� Our y&�/ׂed look�:�_&�1 cohoP5}�:�~u �<*�M 9Ah.T4�@t.9.X[Hg G?�o2�52w�Fb�2I>�%o&�2B.�i"\16z_1��A�tV�SndP���&e3�e��=w+n*&r;Be>�GMm��w>DJ:�otݔ� ���.>�5��=J!�Je�JsV s��nt ;C l�?�[) 1i�D�(ar� �DEH2�J�� AZ (#Bv J�.NAA6ri�0g>*L/�E� a*�/�,P�s Salmon�k , YersiniVibrio%/ Shig !_ ��U,s n!K(kyg��!���!B!%� �Obe%j�.�h6��1.Ka!�U Ua�#U$in Burkino�!g= it�$�,�i%�age-m�nd Europ]hiQ)�j�,E�s�&w r�:�1v �!t Y!�VDiRfcgA�K�PA�%��(HIV-in@ro�%m��Gl�Wo�Min>�V[2 1I$Vpla�Mb:�2"�iR�I�a�q�� s5 c�4}�/y�A�ut"E0_)uAGa onship V�B �OPUst;�ed� h��GonK�(gyEEi&*�/66�5�@���e5�/>W,A�� E�2y�S�0Sm| �fK:3Bilophi dsworthi�(ׄplay a�[�:~0kw&�=(.�| c!�ng�"�P� sul`$metabolism[2.u op2c=,2��j� "�0n�AA)6s�5v0 @ &�9.e�2� ider.�o'()fndvs �huGG�0a0OZu --+� � z)J��s�[M>r�,sI#6xGm�64�ER1 SA/�>�W"�2?3�vte��#l surfE1B�;atB$ ibhR�.���4�M!`="u\zY�a���r�%lyQ�)%5�F�&m{fpdon� ��?&f &��� �bnd"_6�viduaN'��Ugr�8%�.N3indosc��V�ake 4rec��A�col�%d ileum��n!�es �YY�i\�y%����,�6�p�8�+ly&�*;^2�)�biopsE�is��!�u�.��oy��G "lR��F9 f����stM-1e �+ed�?t�:12y >�G z\�/��!�ic*�0!�a�"�0�.�iy2M[� /T�")! ��wz�m4} �ff� |I�circum�3!�I��PM%"�. Fur�^"�down-Z;a�1�(�~�Z V<@)uQI"it can y ruR�)��)Eqa%� �qegsom���[rO?5�""qBdepthA#Ig limi_i��Q�+,�-��X�~%�6�u E�| V��Ym$dee3�� ���Gn nx(!�@2�*#"!�df!9�-!.o%�]!�cahaa� erisi��$E�6�!��O,!�is�\�:g�!h�%apaci�Xqr" �*e Aw&� "� ��6�*�. Fin[N,� "�JjmalJI=w �aJա_ $ w %� ��� �1R u�1�[�0,�meni6 �.qYEea&]ϭE�,HSQ�m�g� liz� to9.�un!��edEH7(!�<V J� �sage� � %1�Qvironz!�w!A 7�y����et��"@ pre-7pyHic�mpr��EXneficZ%A��*W+)<* y u�=�![2�y� few ��9�I�;�7th, unQa�[oK6mp�Si ��e�a�:!Hi�@veBOJ[27�7W"lie�q�ifN ng�R/�#tH#�� j justifyu�� �4��� r��?^-$)MY �#t��mr�u} 7eU0E���**w�v���Dav"�A�y>N���.�6 �_.v�)�albex ��Md A� in�#fu�5�ofAauN�k�In �q�in[ a�/T"{"�O� mon~#Y� a�� oB!�by&2l� In a!l�J:��2ofa�3B~,� <2 .1�#;�Sac�vomy�p_uA�ic�3so `$S s�qN��S .�7adoxu�Ip�^V@�ed��th�SDgeographic origin:&ea>i��$"to�F�3e ^s� �A<1/,)!� as A�)�4����&0r&�,$cT��2P ( >40P$�Ins���7�h URA3� w.Y�Ja��;�p)K� 2 �sE2����0&� TP�*. C�w���J�Ao"�1JiE�xF1 sp�,�<SF�u#S���s|D0w�J�bhdi�ߙny o.� �q raitI�( QTLs 3Q.? ��Ate0;� ��� in�pl=$l:e�}�qweaklyFq6�+�y�,!�(ga�*�c�DW<al �>�>R!t�T!�� �� ���6[s�andCGeE<s�� mapA�5E�!��>re�g�G|�&� ���r� . W�M%��+y)ve �%g��xu��val�+?��proX �zyg���at YKU80% TLC1� �e--�- Х�6EsubpopdyF�� wApo<��� �v;�nA�� e Ku��J,r%0a�s n �ve�ustaz* 7� ���!el= comb"��(uh-YKU7 �qn8h-inA in v�S>�. TM�tU�ve�/-sIsi"|a� titu�$"�] hrom\mA eukary6JR��H s�Pis G-r�A�� ly19��&= a�X!-�FV[��a])ofP �q��[og)Ga t�/�:T%�di�`h�0� ���repair�tE���)XQ��rreple�>I� �L-� �� �0 ei+��&a�y r �Apensa!�a:���`of��>�� � s.��u!�e���nd.M!��1{Mf^v�-."A����a� a�ce�sia��m�-/ic��is ∼3�n�ls  iL�E kiloj<� "� X.�����A�&� main�(�(quite rigor� ` �.� ��  ..�di�Jy&)O��LM, �z���* e:(�`2�  � docu� A]R%�Kv 4'5�[ކmo�D[7�4K [6S��a�%�E�InF�.I�� mple��eWUdel�>mu�Y"�o�# g$2ewak6D��1�-C m_a�֩NW�T temp� ��| $Rap1 , yKua_�� re11e6le�8if1_DCdc13p ��> sp�zao.W�>�E�Q sw�"*d=��:�s 2 6( ". ,�W�W a8$:S�pa 1�,yZD��&�0 2 ��VTyA� [a�yD�hwom|x&�ny.�j dhʧlYi%�rz.�}�U�u�o�^%�y�t�Tk�Se�V���dE iss�&�e> k��.�Z �GrgyE�=!S�*~a g*�R5J#!��>C�r� ofQ~��A�E8�6�b,h9�!( no�f�h8 ����Af�-1�shor�.�$m �'. 6 * , Far Ea�vaJ"� A , [1f�HSu*[�UR�k ����>?��!s9 6� �llu[ ��� e.paut�I Y′ቡ !.�ue��c'8:+�� �EG�i��( u2 4 . 5% )��m�t�3%ny�]N�Je;�∼�+7B-A�� 4J!ĥ� $AaY"3 ��_icmb�5�(6a!A�a/aġ�5me�ismhP derlE�EQ%�% . Tw&�0t="�Z4digests hybrid�pE� a TG1–3� Qפ�to<B]�12Z�g�I�� SouMn b/�����Gc1� 1�ne ��^Xho�ucyS�eFeA~9T2L6|<9�y !OjuPA�2[ 1tW��i�9 peat�5����AY �62/3]m �� Q�d-� S288-NdE>x�"b�Ɏ���:!N o� ���&�>( TRF|of%CJ=��d"�=!�2 Kbp�sn`3%�3L�:E7�3x� of 5�4�=recogHF��e�8�"� [ 3D �uE��!�i�;C Ip.�16g�w)Ble�)&U�)�@ ct [�F�^� o�D"�$���9�q�6 y�M����M��4�BP��a�ձ�oM �"� � ed��B ��Ý�@�88�+#�C!B�ced>1=�,M� , Y5�2a>SK1�A,e�� ittl.�N�t.�l�Xaր� {�FBVPG669���1s.[,� �N^L: W�Inf�&!�1ll�r!�iriMY�7E���is9��cXcz��(c'~� p"N 5� �5�c�=�A�aA)� .u!�"8�a.h{r�� �As}b��*���F�* of)$by6Uo(,e�q� ��!�\v�6d��r back!�2,aN2'Tr��"w]v etho(� ZX�-��rte�s.!C!W��� pre��a".] "�Ce�."l=,� -olyr/Cd9ڍ^fB7s!gi�ng�Kden| �>duIr�"� dja�$MmR��%́Q�.�Cv�6!d� S2:* , CBS43 ?U�YPS138*Mref�N���k CBS A�YPS!]&3�N44a�* a9tag�T�Fs VII-LPXV-R /��M6��I5*�V�OE.S���N b WwegK!�he ERR1���Zno&l+ �l#p�_6N , �e �fla f by 6�of c! X-�!7211�%a�� r���RTi�)en�B-A)%�Z� ADH4m8l-US�FiH n Cell�6pro�n �E��'�# S� ��meq)o cF2�0�AS�%G}^�W�A�Co6/:N�-�):u"r!�gJmA�m�u N1(ns: 201±15!�inu438±29a9�L9)�. ��IW4�9�a� �in-�.m(�cwn6!s%!"4 #.c"�no�A q p� �Jp�A�U�RID�.� S.)2��(�'*.D{3�der�Z-diploi"� (�2�� ��>l�!B�ti�.AEh����eÝ7 ce2�two1�$s: 189±53>�16±4!�%�s�b�U�k*J� ��B !¡�ǻ/O�#-d�Ms1hC5�:h"�6 ��0�a s 984dħz� A$�",���it�&Oa)! �,"{%��yˍRQ�� M�eN��&I &X�� a C-Ӻ ?Ud'Y�%6e��D ach]Fɐ � N�%l�fro`+�_fa�ll0U�3a+�9W��. �rL6���2E�A��A�as �d �e�p{r�� � � �2`�a�a2!İ�F&�a� )Z���:waNn-F[16�-k%��� 7�~�$a�+, �ԉ: !']��'v\A) �� �"s � g"u�, �8��ho{�4( 25/2�DJ�b se��z-68�2�("�148�D,?%��at͑A� 93�V92� , 1429 . Gi@)�O# �!�add!:g* S6Q e�1p��%)6B �)be %�b>xe\ mpar5lA(E�B�*\I�� u�����K# ��+�ppUO�!�a� otA$ 5���.<re"�_� AJ�3�����s!�%h�&1�14!� to 7%�D*�� M%Sheh*#"� � nal"�1�&�� 6 ")I�ń!z26C)��D[s��Q�B�r8- OE�9? -add��}�S\�urE� 'c""�3 T���z!O��N� �1�� I�w!����R� � &�lr^��R�.�at��%e_�/��� �� !U9 e�rj�^au>�7�-U2Gi�f&��<lw"�wzR!�� 7 @7�5Q Iy h3m3yj-=�3�")f*)�� AU"JU�� �E" "E W�'lack b�3s���YinCF�b"4ibPIv:������"!fg�ޱuf+B��?��"��� )GA�MRE11 c"�o&��8 L_*�ɣ�L9$as RIF OP h(K' �a� ��3l�S)&�����#u�cko���.�or�� H6s�2��!ez�� � �,�"Growth+)e��"� 1fyku70Δ%Nm�Δ�!}�P� in=�6�m�2�;)���~&p�� / toleI!m)�m�1�a��Y#&! a�Z�c�or�%cin��.��1 �&��;�JQ28 *?�e�"�E@ r eE�797�g�Ƙy� e� of �e!H"#Feeme7� 9m�u��F�����E� yku8A(�0ult�9� � .to/E/,5T�� A6dra���&Ue �!e}6& o�á��/qA�^��i}R�����"Q�Q0nEh�� s?m�!&A9:�(� ��zns��d" ��4nd��t��� �m�żD1a�i�[we*� mounE$Cn� ( s1 � �oc(A�6 ��e);,al G-overhan�.� �1:y��d5� $'Ku"�&�!{�.�an �Ast 7-f_1�9�1 t2uwe���) 3rH9j-�BQ�-�)!�:�97�a �#%�%R*F��k �!�M ��of%.A5~qTg.�C. !�CB�ΔkA�%e�creIZ�g�(�IV?����ykM5� ����s�v>2r F�+��t Ey �OI Aj/4sŗB� } .�S��*�RQAbsv��f.H�b5=-�m &�A�Q �� N&�!cesQ "� =�:�Dca(!� 1�t�p����i�%y�߉ l% AMrif�!:p Q��|w�#.� 1�IfG oe�N ��Uu�9�le�"A�:AN� �6 aso8@//�.�.5 . F1 h�"�!���� lf��ŀ:�$at (f ��th�R]a�!*A 4Zl>�rep>�$n4=5k [Ol1� t��{�&)�!�n�W�� d 84!  $21 tetrads a!/!+5=�K�"V� �3�"&�*�( �r71%�!*;!��o1� �c D !)�.5u %^m *O-g�����v�W�.�Ce�=�q���  �B ++� uinf�:p-��%Z& �� mei/�<a�841�E�6e5d�113,�h�d 6�: = �16�E�+/22�`�u9tm>QEQc!�&�2.�O�y[&<>: i�:atit [21]���lm�&!�x:�."%�"� 6�($��3*� e�.h 2lo dg ����&?1� � ��e�p!��7��gr*4�v<��#1�X�:\�Vf 3a5i�A�EdE%a�C�terE?��V� w}*yJm&Us�ng)�?U�CO��is c ��{�2thirdVCOm?A��2� i���5�!�*7�T2]–[j��&v3b@..��4�cuJ j!wCO*� ��[?��< w84�!X genMn$�*K�00!�e��7"�d u:�"�& �A�RA &�� =Z r!7"�~ ��!�( Vuu �Sw�,)!� lso 2t7FW�!*��(in�7va ��.��M����y ( 32��[XM.Ot$�c"� E�A47��W��g`v@ev��*.�e��1:s �/er� _�� ��*�� �� morp�:�?)~5ao �2F*�p�`2M#�;������#$� m�doAE :�9�1DEF|EVmC9 A��2�!��"�?�!1- �!@n&�F,a�.�0��̍� val��2�I<,IXIIZX�h*� QG:�S>�b��kaF4i��-z4C\�#2� !�te��\���sp�t�S"��(k.300 K˯,:>B�m*>�69(I �!CT:� e6�3A)y,�3z�I�0a�ntagon"e1�w�xA=��lle�$��ng�a9Y�6a��rm1�e�N,��i�&s%5x3�؜( 140�] 00 k!S��q�� ��q��c�;PA%��)A��,7�5B� B �d a new��m"[�iV;A��  4E(a"�SG �!��+C ESTRq ]�ek peak��Y�;.CraQ3�5 � "�(!U�!%"�'� t|-st�"M�:�y"g a)1$�56"/" p �5q�H#.2]�i�!�? ���ovefj2B�;unSM�n8L�!]" .��a."�wo>��A' �fedv% wo-l Na��h�""*)`ɑ����Nu@�&� %h��S7]i��  �Cd�2 d ab���!.&���m�s�a�5%�1lC be�v'��k � �� ȥ�A3&s��*�"�(. �=e�E�>"�Lm�E�r/� &v':K5A�Z6���A�.�Aed)Lwitis�%�{%��4:S��epw>E �t��, 1w�ԅ�|ve 10%=S$!u%�!��cnkq�6�.�i� � �strongl��*�.Br��( LOD �,bu���D2�!'��H � 37�*A�276 ' Ai��v�4� �Q�.~3>�^! T�(�@V!�a.��ya [nd�& w���@�H�3N3�DW� *`)���)� ( 7�#)�]�h� �/�\]!�t�&t!!����2 @�5�.M� ct,e� )�v�.� �h� noB%��,&a3vh.2��l)w52)���2� -DJ� �,qBI�82�2�a#Y�9 . 74A�bXci�?al5�s9:�!�51#5��.=�%�.n�.��9!7��  [$:a=�4��"l=y���>bO!� 6�NmB?en%[K)J�-k���vi�~U� ef$&Q ( 42���w�)���A�96e�.91%���v�7 F��>P�-orxm�qN�{&��� ).�)�&�s)٪��10!/ ( 29A��k3�( 1+9:��>�T"N"� �(�h�  A@�T� V|T���E�, a� �]� �J�6[>h����Ŗa-� s�'t"��"w�~ =wen�4Q��qY�� ��PS7 #Í{A0^@H6����#&�!"-����/ �� �8.#)�Hq��%U�of Q�íX^�#2d�A�n�"�u� ��@"�j|M46�Kso�_aJ!JMb��Rdi vs��ykɣ�y [sy2e:ic![b�I�6-�=�8-�$5�3L�J���U{"+�MdNN�" / �!��lKYI��A> =x c"531"e�!e���%�� �9k n]�aby��Yj' ?Yt%��2"Ku'"$5�!�ji�m2% ��CD$ � 2&�+��}PS!�2�1oL>!@2h�C�8�Jto% [29]yfSll�R<]96c ���T��!�r(�RJLt�u\J8or�.�(hxty!Wc*�F�h͕�%�&0z,xpla��&Na-݁�vBJ���bY>E"2 g�ay@a533�%W�M"�2g[0:P �]�}a�>��46>�B8!��R��"��"!�dN/dS�l�2b��Ӥ!L j2�t�3B�wh���E�� vJG�$( N}\iaM��/be�t�� , �;A\ DNA- �"-barreIcCJrm�F� 5" �M� �H9� ��� �">�the1�Phe��"�.�"f/E�K&�#)x�t�u�a �A�=fa�onyAK"�b�eb)�b��wS2���3�* �o � c�B�� olym(sȢY�,+p"�?��2� �Rh�>�ty�% I>�H&+�.i�Q��<sI�!v:�v=, ; �D�@�/>%-��@" �*97St���I�ed& �s� R*�!JsP,elomere leng��th . Our results indicate only a very weak correlation between TPE and telomere length ( r = 0 . 36 ) with many of the spores exhibiting no TPE ( Figure 4B and Figure 6B ) . Spores with long |s -no �Twere found . However ,spow��short 6F8a high level of>S-%`ing that a certain number3 Q�ic repeats are required to establish silencO$. The fact Z halfNhe F1�had��Pcould be explained by%`presence?done allele in CBS defectiv!&r .�Accord�Dto this model we wm@expect at least 2�!T0in each tetra� lack�.� in 5��21 .s thre� four[M&edJ$, thus rul�ou!-�is simple hypothesis . Linkage analysis1� es sADal markers associae with�!c,phenotype ( Q�0C ) . Because*$measuremen-�Pstrongly non-normal ,!Jused aparametA)$method for�ess�! strenaXLof a QTL ( Table S2B�6�does not17A(ong genetic^�$ions compaM�M�e m�E�reE�8two significant�sA�5%hce cutoff on chromosomes IVe�IX X� QTLs� u>6I6XI �lso�ed)�y�s!%!, but�! .�aA0e�i�. WasoAsndUa(Q0( RVB1 , SIR4TEPCL7 )i� show%�a�is^�esupport�Be ideaa$widespreadj/A- nega��epista�$Iu �%�s ,A���Z,%�� dilua�i> $. In order� diss�0]��interva)B��e�w�*f��7ge��Iis%�xis reg�yƁ�r��an addi!�al set!92 }\E�e CBS-!#$F1 hybrid Ev66B6an�hr] PM� I>BU( 86% )&� sequ�� e(Z&�9�1!dz188 new.��B%0e^M)FE selec!�128!2 them , ob�ed)432��at�� recombin' v.� ,ہi5��valid%�W n�YFcon�O%u�8xWilcoxon-Mann-Whitney rank sum �,( p<0 . 0001�KCղA��was mapp�m�� 31 Kb-5 (5� CDC1%�MSC2 )%A�LOD� ue pL at�O"Q6QTh�n20!�eR�!W��bea�possi cand%D�SA��( HST��ATC��REF2 , �� yis�N evidE�p0second linkedN%�map��a�A�quantit�8 variI�, ��X %�AcanqbeE`$ed easily Y�Xreciprocal hemizygosity� ay bU V� C reguleLby ploidy [33] . Tel2 �s6�differ!���ntroll, a large*� (loci fulfila !�d��i�II�� lex �t . E%�reɆ have�nBVto!D y am� S .< evisia ,ains [2] , [���y8 a broad pictur"( extAwofY-�of� �a1EB natu� pop!L�7!�toAestig��me! isms behiJ�-�Dwe scree�8112 Saccharomych �n� � i!F��1a�NA*xt> B4Yu�a@wo geographic sub� !Y[ doxu{We��=�, CBS432%YPS138 a�TI�%Oe Europe�Und Amer >}res iv ,X accu�ly# dB�a�dividual �detɑa mass�3-folFGJ+hUX(: ∼150 bpa�C� ∼4-w e���divergaGEUE+i?majora�of SNP� shZ 1�:�makes�� ome-� �� ( studies im���%loo���rpec� �s��w�Bmu!�� A�5Nb � s&pa~ously racterih � Est2pqe cataly� subuniN �6ase , stit&= ev�^on� dom� ( glutam�cidA:i# 76a�lysin� S288c ) � ax�incre�of 10%� [34])4. u�� xact� A'ame�K��0 U�6SlineagV�to glyc�)ɜ� partiallyH�ED��a>�"'Sm.a� furt�h9��-�*y �n n q�byQܑ�B�, dele �H� �9 me !� tena�aAZllproa��%� #m�G-over� �WT�.A�nt�,. One surpri� f�1n2D� �� ina�驍�@Ku heterodimer diDt a���per seCQZ] of G-tail�'s� Q�B�!�@�|����%&ins which��<,its func!M�T  se��&"-Fs�b��Fed!k!9 laboratorH5a*To %�R� �e%��� d 84.\ B a!�c3 Aiperforme< a-6� I �^t�a robust*o data� e "� )�.� Z22� Mic7,� m�lsoPse�eme)�%|}e(�&� (�P)M�!�A�edim �"o2�,  ���!h* EV� seem!3be &� multi!& �T4 SomEfA ,. H ,H:�+K�se/many sI�mb�M�2�a�Pw coFjmL t!;Indeed�t� �2�in RAP� SIR3��YKU70)6EL1}4 n!8 �eia�%\orBw$independen�<[31a?O2po� � %H.g �M�9�1��Ef"�&�%�It � �b%pFe�g�5:��� sugg� �%�O-mightz k\irA$ . Althoug Bx redu� A�in mos,�N%"nit&�_ t2 elimQeN("e )��WE�fi�o%�iQq9na�:. � �U��s!f�to��" J��witAe �%�LC1��� �%lA*B �he>�&�!6�| .��on�9du�8em!0>�ine{I"!Yb!N>. A4�&._ha� en�I� docu��MTq a�mismatchair�2s [36� 7a%Weiued%�:�s�^"�i����U�!bly1[d!�sEr!�_6rir low fss? n"o top �6tud�  s ( Wa1 er J]0Liti G , unpu�e� � A��� �&� rev�iz��= A+V� &� A�6� in.(��r�!�@exist��do aeEbr�n[12%�9� I�a�atibil �>�C . el�s5�iso�in Engl!�HawaiiY�! io� ]�[38�\��JR�i���:� caA� F>[2�9a�� iA6n ��&f��}�M�I0te=7!��Z�soEa dram @mpact,g?e viaM{ v!��!ɐd*�CO� ?duU �CO�NQresol��B-�w� wlDen9� �6 toAgE6Nbreakpoi�~.�HN e�"+�� meio!n�Xt n��tA�)=� genu�5pr�]t� no aneu{�� pro�� �rt� in� ����"� inherit$. Why.�:�-h��e� e}U .�aR��ic� pert:remX,unclear . Wi=�a�},S ;�� 1 nsuA� icto T!�� !P ~"� &�� }c(described [��S� �rig��b�! work� lisin�rSingl*5tag��-CVII-L� XV-R���K(by homologoY!2�uv6S of unique/y ADH4fERR�a�plasmi� URA3&-)��Y�V40]a�)�e clo- !��sce-\"naV �+9i1%j L{ix#�pla�@ser� �iN of c�suspens nU (plete synet�8( COM ) , 5-FOA�,uracil drop-�"' aincub�at 30°Cf�3�Hae��Δ , ver ��"�)ztrufas ���di U��  Geno�DNAe ���Sou� n:�e 1�� ��� y��4R AI1probe%�.� labe&� pLEM� a!�Eq��a�:�E���.^ �A �ed I� ImageGaug�FUJIFIL!�.QOu� valu&vtex�averagK "?%3{ M: li�'8s±standard dev�. Yt%�31��� � subj0todaea%6#���4E^FZg)v&fiiEz!W n�of�%a�M ic bNnon. F��Fsx at ∼3 K�!=P4.� [ >i ^��!.��as` o�%i�v'o&(A�erv�*loa'AVrolE��& lane� al�a2%A|n(a/I!�Œ ��!uand��ra r�e!|-woM�'o$9pM�~&� a�aly`�fold-)��=�i��ariso"�]�WT%h:�)� �*��#�!�]Xif Phosphorianr%�eyQ�Iy�E��/� �*��!Z�&&I�� [14� �)cw.�a � map!n 113 $�]!� d 83:� ��� 21`&r-� �")4 �[%dac afte�+-�'akA�@!hdM#�����h��+A�x��ig�"� melt(PCR RM- )-�d(Corbet Roto�<)d %�ace8,HRM mix . PrM1�I avail�(upoR qu'&. S ncea+lig�)�(ClustalX [4�y(Non-synonym�a�' e6 U At�#?# ei�&aE+maximum� ihoodx)= hea_(gram CODEML9{@PAML package [44] �t�*top= l Nm�� r,neighbor joiŎ�)�*men�yi) 5B�*!�dG)1�r�!softw�[4�S�v(al�i�- madeAS�nt t T!�� un�ed[�  uneq��cIV^#tG��kKaleidaG�, ( Synergy S�,) .��Under��A��cog,v nne�rocess� at u64lie human deci [Gr� -Cc;�puaGof�!_.*ls�P$when , peo0choosakSE[� samp!-s�SMs )�great@/dvA����sciib�!um�s��emfI| a bo�d&3Pm� - s�-aBsp� ti�� ( RT�b� A�oe�. Ha�,��demonaAtegifficult�/��o�?n1Ax& forc�o.p1$a�cD&all!+< !><&*�C!\ly:> 1!�er�dF) delai� choiM�ter-ABR(temporar�#(, a scenari�accoue�a m�E�� (SSM approac81We� elo&�%-=Qdng%���wj"&� )@an ctroA phal�� phy ( EEGLa ��ag�-�{�9r( fMRIl\�/ W ,�ticipaQbou�o�y< fict�u�ocks ba on2��s��c� ����f��Q�A�� � !U� �ns"�d�  RT��"�+ s ad��!.X0aRd�Ba&�#)� ostp<AD�&ekA(e�a�9anA �"A�)m�ime-f�] ency&�of%�&�ac%alter)ngAJz0of de-%*i� oscill�z�beta- !O���d,( 14–30 Hzf�c�e��#�s)��2edl%�^-) inhibi��!�U1len%@a Z,%D!A��a5L�tod!�Fin� ?�2t.d-k6gW�q adap��k 2�igm!� �U�3toE�� button�eh!dmor6w6�4�how�7Paiode?%��cw�\1"! e8 u���5s�$hidden dyn�") ��on . MaY��0�Vtrigge�A� A(le���u���� sourb of�� ��p��urchaG� e�e� ��in�c� we[+lyu$��!�pr�n_1�wit1��KQAa�tsq � AoR+ar�  . UsuY/se �-ati�i1w6�Ae> % as?#a�col�,"r]nsu��i�o motiv��IS ular�Ywn arch�BC��L*E�un 6ty�x�mta� %ch “9�!Au7”5� dire�$$�!��pT3oB�0EXbehavior�1��!�a sales, or�5�!� shop� �{�$l�Ao��1��ll captuM���.ode. �pmaO.�alA�N��"l-� � |s�s� t+E=� � !N de [1]–5*�&a��.*an�nis�mUV/AYd eds untilHQr�cri1' on (�)# �6shH)!.met�a�fi8�s�, elic��.��G�rat���7E�Yercept� !��+ !�[4% xA5 they���raŽ��.�� ��)!�pre7,� m s [7^1�[rT � �-$ rapid [11Z7*!ss�a���may lR8upaR �.s [13 M�'H"�9� ��� assump���.q-!�i R���Y%���h )�=�*ac�>%�G6�Atypic��a��id��@ �!Ⱥ� �V�1fE �w� �"d*[15)[E2w�#"-� � � �-�|9-[1+� b+ �*to>o * s] -buy�paA�gm "�$1A�M&E����rob���2��( X$ng abvn o/�-a.� mannx2�  $buy�7r" �H &nyEj�j�� �t:5�+"�� &i� x;�a�a���#��A�1. CritMU, bey� !�m��&�>R�Gem� )�ifi ,+�!� NY>a�$,��/�!u �, �e�A�le �$� �%.�argF7jQ�F� fail� i �/RT pat� I�is task]nP;aH umably*%y./-�Q���*~it&�$��x �� 4 �2� " ����� �R������ ��!&� e by���N� �xM��  !�51�:�I4c|an�� !qT!PR� �� KF� a well-"7?��APC�vf� M�mo�Q[�M��2��&� wIeq ���>�f;Ig �A�T*R� E]i��92&m�.6q��$ . I���?E!��con�� �he-�et-�he%�s� ��,asons: First�-aSo!�r t�� �e)st �>o ��G /�A-qi�� hig.�"��*( 320 v120T){ viI %',6?ero�a�%g6�ntrPlow����!Ebloxygen\#-*�ig� of ���2mslAP*"�a!�.� !vr1mQZ7on2E�ityb in:+��A��!6& w�.�� �I$lI��� &I%�i�e�>see TA�S\7. A��%���I� s il�A��,A1A?��begin- L:��{i���o� !OŹ�y �<�gatAWt�arc�^\e�+A���� . Awai� -�3�%B-}eda� secu�4�� 5 s �. P�1g=n���A%dese�9six��@;'s�+PF8����"�&�U,� "9 t�� Kcur9) �oof3ve!*V �  goal-X9uy1�Q<%OEi� Z�IE�r o��a�"a>��{�#%�;� eend� xp��<X%%�t*conver!�in�e@@<�)� hist�mn;��! !�� sn!y c"b< addr"�G!�F �i�����Ca&.a�de��0T� %-�����,z�18 >�)�,x  windowa�� ng��Q.cG�Y�G ��� Z !�� Ml��eded piev e�(� � � A Rb jr4j �E� ��%� P,�#c ^O 6#�  91r�l�6*� ����inc1^>�Q�( ie- .�3a�%��of- A�a�4�8IGB ����lj� ( DV   R4% log-�( LE )i�al�Dy �]C2� �?�tiq?%a Q|�{ 2�aEi-��n��i���!��MrI -yJ}(�piJ>Ei�f[E)�x,%'m�u5�(�7�M)�)rJ������ 6f�s ��Bap�&�EBU���f.p,�sF{� 1)( us�<8CZ er^��wf� � ludq�!0i-i!=e�by&��u'ed��E unE�6�m "W. EeK����am2�� MuP) C �!!��DV���*-N0 Ecs�� be achie�+�a��� \"�K�^An���a�Ei �iQut!8tinuo;1.ati9��stepsJ a�9 X�  M!��"{w�>u�-.DV �s6�k �.�Jed�+��aMw op�c�e�5]!LE�cal�=jupd �oniw�k) :e )�� re rE!o�� -(��1AZ6! �I )w��L elap"� e>P�Dc�>"Eq � 5� _1�l(� r$n arbitrar�?!�#!ca .�e�6��,D"150ts/%o!dqk? .� �-"�(frame�.ASM , EquI?1!�M5stU�>0Lb �8=��De�9Vdrift��6� K�f�%6 DVA�*P=a�cf#or&t "�I�/�p: a%�5��R eas�?ten �!+�~A�in� )�third h2�3շ69)A��;5J�7s��be�Fur��ma�u�M eA!�s9noisy��n!bLE� erro1rm�1wni2a�*2� ���!a% zerf2Q"� &�,σ� aAp". D� �@! fC"�)&sw���7�O)��(�%UEq !�a*N2DVI�`�Eod�E��!&[+n�!omA�!�cF 06' yaB� mT)@��e LATERME[1t!�$Random Ray�5!�6BAs)T�!riv)?M�5> ty P ���"%)j��!; �r�dz{�0p��jDV���D)A��&.9hr� θ��=�DΦ ( x*Dͬ)�V- daty"av$x ( cf . [!i�1'bty �5f I �u��� givena�p�akr[ !G of PI��e�Uo t�3ՆφV�r�.*��c3?���(.���( �1z �!y��t � ԥ�noM� �.4�)� e�i*5�T�Ua 6S�Va)-�"u!wiLG"� l )c=�+>�V�is!s�@So far�vha�W &� !ȩ�Q�: . A6�' =i!{ds GVi a�.�.� at e� ��5U* tmax!�*�i�)�i�C Ca��T�ia!~E9r t0 �8m>�^on-�oaJZ�"!�:�8 = 150−t0eRA� �6|,�~I�iza�:'y5�+�A�ixt"�(.�U�!���De�bo )�pBmMe��k%� l� puniss�Ta�o+'�l F&�'��>i /�e{ c�,m��h B��%M&I  !d .�%@e-=9��.]%I(�M�e��� �M/�d9vT @=� �D���E�6U�θ ( !�d�T�:�K� , λuP3���0�X4,d�;V�I��!3α6V infl�)�W�E��!A<p( CQ�%��8;01Take%3geX ��CA�6:�s:�V��O �on� DV^Q,i�r� 5�� �é�F��!_%�w��mod�.( α$λ>� 6)ّ�H��+a:fy� ,I�A�*UFE"B(��e��ViI�%�{uiJ�,, i0KBQOe�v �i*% :� "|o�s2� �&!8up- pan'&�2*@D).ٍsɭ(%"ee2�J2#`e.l,?&�->R� !}E& Mmiddle �+M7... A�< �,")�)X MDV` �E-�.eg- � 4"2U2�� ly)�s�/s� �/LE2��;f� ��Ain favoI �$I;,!�DV!movN owar+ R� ? }��� ~o . Of�Z|+w)��i��n9�B,��Q� \�a?���_Z?wa�2 o-Fur:�.2',���a"�oej.�!:� � \ �,y�`� � �� "�2�e�� n)$.�.G if�"3��xplBU�F0? Ak>ser"�,�2� clar%ist:Q�2`,e*}��,^EU* s� ��yJB���a!�i<"grT)i�7bo� x-axiͮ�i� e]ear� b>notonir*��͆2�Cg�nP�$t)�Aw����:��800–10m& (�%.*�HQon�(i'rqA&m�B*řSi!7 ���B�y2B8 m1�)+ ���"� & �  o^#� m9� �Dev!�P16 Os.� !7�#�Hs/��M#S embl���h*Bf��o 12��R2^ �&b isy�� Y � enti�A ours"� � .�0"�0)�I�A y!�a{*is ver�0&.s a sm� &2F�ac9-J�f��] ) A�n"T~ !>A��G*A�t?6n-*���2�%.�.� Z stimulu�B�0%�cl�8 to 1r\a-EmmB3����C͓u�!�s���,mS�(A"I'N'*�(N:��6�-c�E/ ( ex�.��>�te��W��o 0j 2��8�aI�c�E:�6�%A&%�a�5yu�of>0�X<23� [2�BI'?��A��R�0A�F��k��)�e`; s�M2L( 1� v)�Y�VavM&!�U8Z"exWZe;�egard\ofF� �|e�9ed��(r"M'j3wŝ,M �2E!c�j��.:����:a�r6� DV&� Z �Aa[e1A!.��ZA0;%I�B- 3��&����� ���0ut�Poi E%��nd�k3 �m>n� sE����8���2 γa�B����WY���e>� �|�r*��B #*�#(R���LBHiz��'�R ��I'a"�"6gNi8� � 6N�cAval a+i��A�O#�r{m�itself&x� / 9�| "x ��&�/!O}KIE�55!'&uC.%7�$or= %t":  h�.oNGNqu�|� buy|&� )_9�no�E�#� � ��Q� g����E� mean�:�c^�� 9U�LE]?^st6�%"+�'3��65�53-I “+ +��or − −&keI"H�Ad|$�o≥�eW]?�0-(OZ&�2��s E����[�hi� ɷ�� S�$�-!(!��)��h*.lI�qr6�!)� rea��.4l1�.�� ��EhAk��'�EJ�Q�6ps� roug�V*V92�� $ �#�:n� &�Cm�et)r'1C�aDra|@As�+A�ng�!=:��} �  �A� 6$Bayesian I*D�6er� ( BIi!1��rB2�1u(A�M0I�out$� !Q ��ll,1 ,( T����.O�8da�A�aA!ţgD2job�BMw"!(�L90�k��>�)65)�UwLpEa�"s Ma2MJ["kSl�0LIre vir�ly��c�]e�u�*%j%�"!�tJ3 (q�M1*)/A�O%Oe}� �#��D)�1<�, 95h;��3�9.Baw)�fLm�!sn�&q#� at�2Z)��% RT (:=����0��S�6�)a���t4 t�4�M #RE��]I9%LM1*��. W�.:�2�A�"�?%�fA�ar�pl�3��]{( y.N �ł(E/Al �A���a &�I0lF �.����� �v"�"(�D�%� %SbaN c)$��A�u5�. R�=��.H"?.��." ! ac�W�`o)fi�%�"x>�alQ leaMope%8&�(pA?�b��'�y nJta�r0 riba0�lDv�KW*�� B�=u�4�TB�plxIB��buGT@�3qM!�wA��f� of1�j� 7��lya�k6�E%N4G�_!�-'�6.�6I�#ob,VI���<poofŻ� ,2�re/Yzeo��2:H �b� �`����i�!+&9 b��-be�<�n.���m�e t��4�;- ei�M1*z\st�2�6a-j�&!�)Au�e�1!H�#� ��ir]!���t�*1AIV!��4!eIY*E�b-�Ly]���| r5q04;W�Z F��U.�" �E���.@�?�JG"�� $^e �1�:ook�(��| �$�V� ^�L?��(��!{: W�7N/� . nica#!*lap%�EteD,�s�I}�A���UA.�2��+ū>,�%0�h�EE@u=Pf� s&{0} *i|�i#^�zb�sh�jA��&���!��Qa�l �.� RvL��Y&4=H4h��%�qz.g"{�6� �“push� �.C-( �j� ,��[9��'�4clu�ofe�q�MS%e�O:6.o" ��te��}M 9=&� Ѽ� 1 @�G:�i�^&� )"�he���m�%�,2.( 1� . 62; p<�v��-�t":+&�!����'"�#tZ�tzpA0er�)"��B[R� =<Q1�fr b�R��8"z5e ur�?a1a�f-4�%�a�Eo�� a+�E1.J" ����*�R�5su <o"�q�SJ� i 6�Nn!��^c.3��Mmfa�+@,.�"d�i���Z�"�!ma fix�"*A#�"?n<���9�� 1J�"&GQ'if�6c�Br�m)�m�1y !�&���2��O� , o%�P�^EAq����A& < o�7A dXAwarra�S�}A�wX ��� 0A+"��i�ul�9� ��E"�QcDmp.[ �-�| –��0��5b �ZL"3��� ��=� are:�&�JD��P%K,new� u}":replac� 46 DV;!'g�pE�DV �u|�G�5q�ZlDA1Ely�LE�i Ms2��sI�1� ����aha"�1 R)F1�5 ; ivR�fA4�y�r��OY5Qe��"!�D�mW*�a�q�.�U'2 walk�?�(r ��F|!� &G��\ala9��5)� "y7�fr* 6SQ^r�(�D 5��xal&)E�nd"� & 2VP6�� & �RA?�losed-�u^W�3 �P��N�2ADf�Iq/�4nq�3fu� know0MIns�6,�s "�tE:���v�� �!(H,to�,�~?v 3($ D>� 6hxZ�ic+ c�qc�E$:Q� i�_m ��xi� |iit]!�� UH ���*� 5.=!�fUe�}ng�H)&c|с�*X&�2� �&)���2a" # v0R2� 3�] to.�"�LGDVZa.�i�u����lH:�#r���,��!M�la�e.C���͂ �� l��( �@i@6 L�6��,�' U 2lea-`�L'�#� ��Fp�&*g) �DV46Zi�R w0CA+X“�� �a�!�m ism��Ora�,in-Uhlenbeck�R\�T,(S82�R!!2�!Ug.?E�U����,�0)�DV��-4b.mIe�Ma7a&��M�iod!؁��,=p!Clu/'� �nyM<u�5<x{;a��W�>�� ��h2'r�,!w�'� � &&�&�5�.�q*M�ofA�p�$)J�"�'S7�.&�� �Xh �3mmog>�=��occ�2 l�n e*�ed�:v� !Q�eth6+jumM+" DV u:Yr�!8yRe#�*!�lsoQ|cc&��.r DV {s�U or d��i�Fwc"?=�. M��|�z&lau�A. m�iM0i�� �"16�.`&< =2A.��I60o�"�6�ea��2^B*%H �!��Yu=� �!��āB�%l�)j��� l'�F.�of �A�.J��*�=: Ba� ��n�e>( � I���F?.1��Dbv8A �aaj&icA�^f�A�a��,� & RT9�) A��!�odvC narr,g�Ia��PeabruptM׭��F� z:in` 9�"N B� ly M���"j W`ept;G �TE4fW&4%B�!�I"!�+��en�L.�)3 �-�*]�N(7�� >W'P.;b��n�o(��r� d )� T�(:Z�M�;�lhzl��A2CRwor�?�&mA\E�(t�aHm -��E!"�o%�.] BA.� �kYAn�".� sF�P. �C"P *�(.�,1K eD)&�� +�*` d�&� v0��B:� "qu*���%-Nh�]\ ��� clas8V1"�F!f �y.{�tm� �|Gion fy�i�1."itaDs(� A�5�.&switcw� 6�� eE�GN�D$�Trs i*R2uor1(*~ M� �&L.H��gJ!s 5N�3U?�w�� E��� "u&*)'I3�lyQ9+GLE��3 �"�$�&4-�2�a�2����E� ��q�a� ribH�D�AL)u� .xDV7%�!�& �7�� �^y, �Cly 95%a�'-�:E"P#%i��  A�E+!�LE�Z�2RC9�eK,���J |�6Xse��5�ceK.{�k,�~E�t2���!�?v�m��4y!B�F� at2"-�s�n�K�5� V� be�T ~���?��h+eV[=b�\�%.oI�Za�EE�a�� ��:/"��Dw�P� �@&Z1 , nad!JFL� -.I.f�.ƙ� 6 Gi!6��!ts��?"�Z ) un�1u�0�6E�žs+L�e!O3Mm8[�� ref,e$,�pa �!��\��,"qP. O�hkP���h���m:�%�via%-zai,:��Qs._�M�-�%�M.E�ei7�a:�Npr��"���[25c27]%:�\b���pM�p�] mainta�JEV�W�e�p tatu>�\*�m��aB�!�ng�7c�.�*qY��eVrZ �-~jmv5D*-1F�15�9E��S�=E^.�Uc)� t�   agai�JM�2<]�. gure 7A (:c?Z>h� 9>�ODSF�^�^5��5dkB�� 1g�9I�w��(]�a<�-is RA�vBlibeSE�5),d,�~ phase-loc�[{�*g�}��I�!`E� �:�oZ9�8=N3b*�0I�63S4y.�W/�X0M') �f�)�.a�p ter-&b)['m�� &�1%�r�%"� .JA a�4�#� Fn�!Z�%�e2� +%����*� u;!/&�# �^ "� ..R 8cA�ate%.'W�S��I"� �TMQ(:i �L2� �["� j���&� !q��R1���!��I��>ela�j. For2M=>3Ko�Z!)�Q$dian-split6�Rd.�U�%#�=�>)�����-37�'�Y���m�D����n."3��E��i J8AM��zof�e�i��1Dg�A_a�V&k��B{( �29;M 3 . 15; p�J&�N�/>�xa(/&L ��cɊ44ZKC b"g�.���p&r�7M�Zni�% 9^ !�= 2�=n� a"��D0�R �<� piR�3�pea�/=Yd:�m�d � ��cok�hH��&�'4�'1�2':��8��!z)Ru�d.�L&�/�ޡ��acha�� �yvcv3:Pe�c�6�C�"��� >5�Eŷi9ppl8nd����|�=^�ZB�h&n.�} !@.�) �-��Xi"i�we )�p#W*.=v�IecJ[6"=%��or��R� %g.# 8wT�C��o'y&{IV�6� b=!��{�! �� a;.f-:f-�5���5�i�j 5 to�Af m�.;� �%�>��)#-&P�."� ��}4 I��EJor�`O Z �e vie�1�=E �-��1�� 61B2��.�_2�zM)A�k2�'A�"~#c ��ng*:� M%�(�N*�ctN��9}en�vt��m'� i�wor"�$>����D-MIu*cRi un 8�T}1A0�h�I�^�$Y�2 &A2�G)>>lnmea*:"�9(J���&�d��U.��My�)AN$a who|FAn.o&�*8� o�'as[ es!��@�3oC;:�.F"r1� )Apr!J%p�#5$�� %c;j+6~���� *�7.� s4Q���a_p�Ppsych�� �%au-�2Qt�/�*�N��=Ep_�lji"�\:�t�f�. Bi�dH�*.+b"�G����#g100f%2H;_�y*�F�z �s�`�2ai�)[�c,%�e���igis �j�1��1"�3-�c}0�\i7.�A�J�$*x3��A&�g�ݩa^�d�a�oN� , !�&�H I�hos!!>�#noa� 1� eI%M4esG-!�*b � ��u� ) circum�Ace-��)a�&x,&n�aX+%�W��"($@�)$0"- .� u��haU��O �.&."&�Ae�5or�M!��n!����S'�n�)O6"�(A�"��ivfly.��Q$rPde�MmbMl��!-to@�&�$nd�w���`ɯv|I2�#�(iffE� �m�O"�N.� .#-�"�5ansc e&�4of wh�T.��gesg� ��a�2�Yis2E+5����� :+*�O'�i` !@�a�fal.�� 6/>�M��a"�#m�N!�y�"J�" ��L.n>&�%r vc� �9��� �5����]t *�;AnuWxW&or�7E("&�#c 12�}1�.w%p�G" u+�.3�>9./�fL��Hur"� "*�7��2orm��Ae�� :K %�F�pA �#!���*&nB. U��|6���u�D`�H�h��}b�a"�bg ? Cb�l? !�.(%q�2}U)5�F,t� t �4X4np��.,s.�%9� �F� �_.��#/�"8l�*fc7�� day lif��yu�v.� auto w�0 "+ a\}�se%��,.A !���� w�>��g!j.Bac��^`2I�r��=�orM�N.T��P��"[e�.1��H%Ze"�ws (]���!_a%.kizJlAy�[ A fiel� 5��� �B(� –[�q , [2-�["9s�(�hod&�i^{!�zlso"o �~l9'P˝V�W�ym�%B/�>m&ð)B�E"��nCsi�# 1���;��YC�*�od%fw Et��defer�"[^�ϱ6]A r�+����r�"W�G*� (A�refus�b f(.9���&!�~!<*�)9�o�Id(<relevJ�F�kb�\As��i��!;Fm@�p� !�}"6�"�AGT�"�D tEQuset��A� $Al#��9S1#.�� "s �2����t2–4 �E�8*p+� ���a!!�proc24*�s:-�1nr �`��A ��m�ti� �v��� ��b�KEs ��NU?4un��g.�.)(�Se69%5��u�_�ts2�"`F��:&� �:�!��#.�i*�v1�A�� OIpag:%�]b=�AL82��Vw*:�ډt-Q�"Y�AnERPJ%M�ރ syst��El�7gxin�@����"�����J�lu>KmB��P��x� &�6@B�v�:�� so�lj�MldN 7%�Wm�2���!!��6.�!rec�Ha�6� &�!��!*.�T�%"K)"Rl5�e�K��R[6��ur��m��L�U�*7>+ �v��"�~+�fi~ ��onship:w�n�jNCe{-�E#^#>�6� �`l�%a�3a~%���cŠeKiE"�eA6�:d2��alsR � be6�$���*�"�e~s� y���%�!�6���]�!!;��^9ndo4�us%�� _q["�I6�k^L";ng�!9���!c.%�'2�%��-*� ��%.� i׾�fbeUa��h&��/���""� %��a1�ت�[�N�A�!��5�ni�D-{n-�8.E�Qat���w*�W��)W2e e�A�a:o "i |2�/->(�(dT:��� � �+1a��#2��8�|.ur1�v:�VDo-W� ! �#aCo% # c��E�h~0yN��%�wE�b/if%Ig i �sIA�� cor7V $9R���,s� o coarsaj�*Z,[��Gie 8�a�'EW�Da�k��"���F � a���LA�2�n�a���?!Jj�A�AD��B )+v�!*vw�(%N�&� 2o>@x�9de��bfjw�%���m9�'��ch #'� *�X2�e=�� � i YwM�l [v��(o��%�b�/!& )E��:�ima� techq�� [u�;)��qt�fA/�1��6 “b~�box^@͉�m�� �j��?�Qep���ܚ�Odov%b.� ��-g��,!����odis�-.>%�iX�7.��Ŷ�1}Z. �(Ab� )o&@ �"e�se8mey28� �@ I! ;F�� d"�--i b5�1yBfAT"��pS_;�.�Z�F�r�:-q7$ed healthy( �DE u�7�L(W -to- v)�. Data�2'*G  %�Ja�a|e(4#�Y#1l�.#"�group?,>e�O�\&�$/f��VE��^d�(�!�9"age1'  2k-8 y�l , ±���20–32 ; 14 femϘ%R� )����#q:lm���e�mittee�D Ethik-Komjdo� Tr Ärztekammer HamburgaC^ ~9�$�princD��P'�$MDe(nk$of Helsink�ZAll6 gave wr��)��n;"NI�rei�o�5W��an���ear&�#�=NJby�3�p�? �^�A"k�%%\re Dq��\01 ��%�I� *p����ro"�m�a�J{o%�J&�%��P!\�4(!_f:�� E~��A*�ku��aR�K"A�3 !�s��s' �P(,gsEn�/sta2�e�:rqv  ( 2 � _"5�n)\�J����Oa� �)�"�O� �. R0+�teɽ},q^�21�)!ih)A5I�u�/�)�S(8A�� �"MI/t�Jɋdi@Z�� ز&!!"�3=(� ite����a��1?/A�� !QYm�1!�m�La�5�s2X -N("�6aR� ��EnUa=a�L3�f�7 *{ ed =%�te ��n6-a�� )��)�*��� �fo)A��P >m[&=BP(!�w%c偙I��I!onl#]Cb^R� �$+a%n���ey�v�� ,size: 19k hes;A,�I� c`���,95 cm; horiz��l���a�#�* 6°;�3DQvi:#2 . 4° �AE%�}�'���9a!�tt��M�s.�qInH J*g&0C2�6 �LSN�%}�RU�e� he Ppn�!SK���( Neu4�"� S��NHt�����Ib�,�b( ��: +80�=gaA� −.A��L Z� l��� paymA���lu F BuIJ� !��l��!�y w�S*�9:5W �4a��!Rs.��+y �&� �024 ����d�ݒpay1�y�,���-)�E�e�&�5��2"�# : ya@N!4,�"*�g� �g,!�“�g��� & �2.�I�I �sP!�)%)e�]l�� QOj@u{�?*h priowx2�]EzEE1XseJ"�$G2� nP=�NZ�E�-F�2y)�.i^Lte�bE/j!� � P`g5J$� +�57%�za%!��S=6.432.`i�a�5�GO=�)5�� *�$anwo&�#C�A =+G�A�e0c � a���lerbalancA������~O�>laV��E�m�Q�Uv&��8���� R'x�S ly 5mu�<a�i160bp"� nf�?um(*.�gE�AUU+�%r��)�AvbL(�EЉ�P-f�ZW#2G1&�*,ex�#alg�^hm [40]��R�2I�Matlab�.�: uj�T^p"T�ΘI$ mini� ���� � ɔ��.�log.�W-�*<�c� �m� If cRu-�sK&)��" = �v�B��E�i�_� �B50!��B� 1�[ i�.�x��"n��I�T"�iI@���Pst1��tN�1�"�TJ� �S35.�(��|��su&x�G!a��� �q0t B�a��%mhE��2u.'8�)h.�10f "h��u ut15 bi�/1��NV �� IzA��f(J�0�%�� rmc.*�B�SA��*t`r��)�:I� 9�G �*us :�� �i^{-�Fx����korjj��dQjPI,%�{a�5A �yq![*\����q���lex" V,9f6�]s �[&#&enOs� M�eU�C�p�4��?r�-�57 �n$ve Ag/AgCl.LG�v�oan���cap�$ctiCAP , B� P��)�Y��p�GJM��FpC�Fpz , Fp�AF7 , AF��AFAFv�F8$F5 !F>%��)F6-T.C/C0C1CiFCWFC/T0)('CX+*)TPSCPSCPSC"�CP-PYCPYCPY/.-,+*) (�PO]POWPOQPOKPOO�O(Pee)aj�rof�:Hz . 7"y(a2�� u�*&��P*e:e�ocuY��EOG!��usc}�"A�(/myߡ��M-��w�lc��5A �ug�� sLfcilii , �ۡ0cu�gWCU��+~�We.�!b*�a�!!,Ai�E�$�d&��;8e�a�� �a %* v=�M�r��"�& *:�a}+�6b: �h# Rl� EMG:[-��J�;o�oz�& -�, T!}uYAY��C!(.Zat FC.���n�{I necklE5krM�� kept )v10 kOhm3EG��9NGPA�o"]"!1T u3E� Fv,trip ��I��� >�1 seg"� t��_�� epochsU��P1 �v�!h�,Z�s� :=��[e���6e�� M�a$he��s>�L%�thR�-[�c J��_le2� Y-|݋2Әab�. E�)�!n� �:e�4��! �N�ed!(=��fi�~"�#gh pasW �1!3ag:8ON� e]) "S�-Xnumer#%a�bF's%�o B�uw�(u�SYo�tt 3":)��O��A8 �ofa��I��Gra6�-CoE�._ 2]���a��m"�"��0 �E{ �. Artf1��q��6d&�0�o��d ��AX �a  �"Ҧa9Q,or"`5!?h�ޫ.�%"]ino"4man�V���#A)9B!c�i%�*�0�v7)�Q���)�`"4K, �e�7 H>z!:�gA��@ �E�&F��A�-J',&(�B�:� i�&� �c &s�S� a�e�� (a� avoi�nv7wv�+-ev ,)��BS"�%y*�� #%*�Q�0Ҡof�5a�%�t��c&2�J.�"J+%�}!���,ing�= Dtrans) % .W�����a�iHa�P�����4� .�4�9ʥ�B�N��wav��q}�+w5�-�%�YM@�5d e9sEG()�])Fo}*A���1M�{�)��!+�,�"W7.qM�+ML �6� IaB�Li�} ^ a��&�% C� �1!�v)�=j=ayI�mA�ngWiM!�*J��&�[eP)�I"b"RK>�E�Raw9���`Ur�Hob� 6�#$�3<�ed.�� ��)�es���l!��D�=��.�O-f��>BÍ(7!7G.��9ecB�5�E�b+aU���Q��1��g ��o����Y"�I .�P ?*X�=!ѡ "�*�a� 6�Ci.�.e �"�;2!Q,ᯝraq(��EaN@fA�' hA��75�N-a&IT�=�I@�ʹ.�72m Q�Za�a$e � ~"(A�p�S!AO!��_�SS surv{�Y(" �%��� ]*oM8|���4��" eak �/P�6/Nl�=P6(sdeӠ�! meas�F�"x 25�-a^�a.-9!&@Vs!�a :IA!�1Rm� :J%ps��"� 6?1ƮZa/�sun �!�� � 9)2E�Mk� �$ф5X}? .�\97ditU nasa�&ake8��( HNPK�a����� noge=��:somEC,ve skin�!�r���ucru�� fiss~y�U ~ lanu�e$Labrador R=���W�j����o^\�y ( GWASL]� Y���� 23!ntro�L�][3le" =s�� ���/�� 2�raw�(4~"×1�1�Q!��}iŶn�h��ims%�G13 �Ż�ahX�2va��# Mbt25� ȯe�O-2reG� O�mh&!a 38× �+age%�T���3LG&��".m�F�w� � y4U"-��GW ! �sz!r�.�C�� r co��%@do� nd/z X�1�e&�E.��)>S�lm�b9DM`� }^a�� ��4�-�aƎe�pSUV39H2�e encoE a �gne 3 �9ak3K�n yl��er6���R�hEyat2 "���54( c . 972T>G��!Z�Q9�ank���a��xeI� spar�.( � �c(��QUe��7h�zym)p� 324K��We"�+_R.%pat"�G 4� vep�m�! vivo�/- s�M!�eB�d����*hyperpro�? i� u�"�!�%!0&֨ �>-�'inocy!�!�g{o��* & ��Q�vW�� ! epig��*~�of2j"O��H�^:er��atU3%@ a#t|. sҊngQnm�]l 9[. ��ou���1X�1��t 2�o�% u�>qu�s% thel,�I���sH Z��� 3E2viron| .�� rene�[�3)!��byA�t�x6�:2">8��r ԅCxp�juxta��E�%sImembr��k%�hʳll.�)  cyf%"yw r�)�!S�*!�go�>-]Ue!%lO�il�&u��ł%��rc�)6�ue#(al renewal ��is a tightly controlled process that relies on well-orchestrated and finely tuned changes in the expression of genes encoding cell cycle regulators and structural components such as keratins or adhesion molecules . In their�@al stage of termi@differentiation ,�k X(ocytes lose$ir nuclei �Hcytoplasmic organelt8to become corne C,, which formK ou�ost5u seal! layer�he epid�s . CPfro Hsurfac �20|will eventually be sloughed into�xenvironment . A complete turnov�(nonglabrous�\takes about 40–56 days!�Xhealthy humans , 8–10 mice%H ?22Pdogs [1] , [2] . MuchA�grA�0has been madej�$understand!CofEa eYtin:�dur+alMs6>!�a numb) 0involved sign)�pathw�Tare now known [3]–[5� The !Ml>bprogram}6ufollowa� clin%�lvery active global transcripE�iE� basa/ a�ilenc�-�._2�a�[6!�SpontaneA� animal mur\s with hereditary defect�E�nor.>��j2�pro!#�op�unity�5!9 tify5wa�onentE�Glex reg�#Dy network requiredJ4establish spec!IA� ternJ!�.. Due8th��4al pope!8structure purebge�A�0particularly � suiA'fork!�(analysis [7%gucA ful exampAp/�utiliz%�!>dogF%l skinA�,earch includAne1@M6<�5m�mde�yincXhair characteristics [8� ecto�$al develop�*[9A���$of ichthyo�10$congenitalIyoconjuna�$itis siccaE�<Mot J�a!ex!5a�%fol��Hin Chinese Shar Pei!6�B�=HY�n� parae e( HNPK )�LLabrador Retrievers �nreA�Ibconsist4am ��ZMV ized��iE�4 � lanum [13!@[14A+�afaled �-� crusts% fiss��mq2RDat a young age butE�o�� wiseի��a,$hognomonic����ologic�Xhan�2 mark�iffusD1dA�hyper9sYl!by%ret�oE�fM�b umPum�an accumq�of�[teinac��Dfluid ( “serum l�” )��Z\4( Fig . S1 ) .)��here�a�� monoA�c autosoa!reQ�trait�A=,so far excluA��en de��b�%F~ breedI. I'a:tud�k used aa�4ome-wide assoc� (( GWAS )�wh�9ge1 re-sequ�%0approach ( WG0of%eQ{J�to�u)�g��les!� respa(ble�()L. W lle�}s��� 13 $jtI�23A} trol �typa�hem%�%R4173 k SNP chip� $fter remov�66 , 981I�r� � had low c�� $s ( <90% )� ��non-in��a�,( MAF<0 . 05&or show%�stronga�-��8Hardy-Weinberg ��libriumQ�� ~p<10− \w!� tained 10�6��Kf� !U llelA�B'a� ree best-ed!=�C%OEI!髁 $raw p-valu@ 4 . 4×�14iN�81AeO corr)� 9 a%�0100 , 000 perv�{s was �� e 92V�w�>�le� n 5 �7 %�!� loca�on chroma�0e 2 ( CFA 2 ,� �B�%Oic inf� factor)�F���,1 . 28 . SubimtlyECaqliE homozygos mappA�u�to!�e-map%�rega^Aain+�C�(16 . We�v��s�f�)u]�� lik��%in�to��� e�_  ��cenario6\(individuals Wexp)�]AbJ G t ( IBD )U� causi\� flank�5�� eg�&W] aly�\�cav aextended-C�2|EBsimul" a1e shars. TwoIa�!��5of�8p larg- n�� incirZ}[intervalAQpfulfilx our � c�zria=yN<A�139�%�%��u�/��wd�qa� �s� 110A] secu�١?m��r-^cov dYUJ�shouldvqf�r∼a 6 Mb��� betw�!,cx st h� e"us�on ei� s����Mi�2:2�^818 , 25�22 , 414�4,CanFam 3 . 1!�embly;�C� A to� of 15A n�.ciV annot�V �!�6�on-�( NCBI:y @a��I�{�5�O� hS94E]4its presumably�0 te�U2R��Ne2 Fi��a�e�ordera�ob�s aYrehen�E7 view!A�varia� bwe �cEFe6�of�}�NJ{��c"G502 mill��0 bp pa-ena�ads�vaA�tgun fra�6 �v�6f@to roughly 38× c�?he!�� �aC�.Aindel9 wśe tX?rexcIq .�b5Boxer�cro��e a�r>,!U� X ∼35}5� ( Ta� � Wit F�aee�I1 , 533G,�4 4 #p"����synonyma�x2E�O�th� �|ed"DreA��an m�p d�an err�~��:Uasi�)��t)  t�rem�H:��in��cohor��^�3 �lyE� :P , SUV39H2:c . 972T>G pZer� ly�� ��a_v��H r!f�th�00  . As�[��AY��l�w� und it .� inJ[��"no�139 l� die;� �� J�15�; issense�Ս& A!�e , e�� upAso[eg# 3-9E�log� 0Drosophila ) � , a Z3 � ne 9�3K9 )�ferase��heen esul&�!�A�sOgR resiA� �cataly��!��e SET doAqA�a�( � N324KEJ~+ha�nam2 ccor� �first!�inm�it=��ft , Suvar (E�9%o hanc�f zest!��� s� isupra:T last�%m2�8[17��8�BaAza�Fz"A�sNW�!�similar5�%nu5AiM�R9 sugg�ng)�a!�� �g�primari� ���>v"M{&� ^�J C–FA� I�.�*� a " 2 of"� as c� date� a0% �gd���%)Z� . I � cau�A�g ,("N physi[qi!e vivo�m�% cleaYdd^':is quHonYC�#t�m� l�� !��&� �ly�xeWq�eyhenzym��#�*�s&�ecB�sQeSuv39h2ici1"c( de��>� A 1 do��disz& y ob� �oB [2^#�=� %�"�2 ����i��%7eA%% �)�� r� �*dou�knockw))2� both�AD �(2 exhibit s��e5ci%�!wŦta�<�A R elomA�length�*n�e�j��,a greatly im�_ # ndeV d��wth)d*3�ET&data ~i�SV�B�� t=�a�� @u(�Ub�pla2b&2d�^���)e{symptom8 ��Z� � Pe4� � �+"�!�he6\� is cur�,ly uni�why2�% a broadly, �v)}� l6 �tissue-Q��y�!�$�i��,! �>N*� "�* �p�e+r��,��œv5be�s!Lo� ��r�e� �] � i��ense��� c9 �la�A�is point%�Qiy�i�:o".V�hitjA� arguA")d:$ �DɃra2� s� ep;subtl+te��A����A ssesy Our�pdE�? es�Ol� mon�&!M% ei��DT� ��ems  prob.�Nlca� b���!=]/� .��.{. S�.��E$AF!,.5� er�in�!���olX ,m-ey %���CBb�/b4�� f)�K�er�"0�y&o )&d >�f��)"� ziN" / ~6?�B�$. Although\ m ye�vik]���, roofu. r�,^ 6�Dtog~) )�S&|"in) �2�U��&ly:��&� A|�>�. Fg/�(���z,:�2IX� d RNA�(A�e� v �1 helpa�clarifydowa�eamQoa� lecu�a��eda&A�lac�hrol nIe-in���!�s� ult�b� �/� v�n�4*�3weDv:Mw%���� -)���i �%9�A�n��ڡ�re�avind1-f vl �%e����r� �ep""16+r� . Al���0[&5���� B)�j��D$%<*�r+Y e�Al[ �ir own%HA�y ��'��,“CantoA�8Committee For A �ExU��($t-Bern;�ma�22/07�H23/10` & #,EDTA blood s._+FG#�We�B��$26��164��&�cB,be unambiguohen d�o phot�3ph�6dih i�Y by v�%i�,5�2)p+,a)s LUPA atTra�P0�! [27/k�rp31�\E-97a�"re{'proje�2��Instit� of G�,�SUn!#of%���'� ��a �� "19 E>ssu��.*�2�:E")a�i�a��/n}Ur���..!iso� #�*�4�!J5��!�N�7(on Bacc2 kiT' GE H�6cc�G)����d�� llu5$ canine_HD�-s�y# 173 , 6622m(�'-zCentre Nb�e GéEmag�EvrZ+Fr�or9 NCCR� mics Plat�!��6�!�vh) �eNsto��� BC/'� b�[#A�9(5 (!fs%WeI�PLINK v�(07 [25]����)�J�/�s"�/2l�)�*!�./E�A�� >i�2d.�. >90%I/ ed 1�165�`w^��es/E-2YEY J6k)0646J�rf�5ency 8/ ) <5%�1 6&bde6/ng }j6/(.&/��e;-A-atase��3�� f 36��!@1"E/SNP�-�q#0 ^:/?fP; ,empir &�8resho+y]�Z�.���%�arbitr� as^.; �%�EIqto ��A��,s+��#(��k%,�s�ld"�2pr"�[2�#Brief�.loo 4nXus&�)ea�Mb%BT"!m�9t00�%"�,� �-��*[+age, ����Dnd }-1L31�r3&�-a-[7)�-q�;CX,l�+37!�e,� !-a�� eW%�BLASTN i om nYe"�$!c Y� �0a�ion�mrno@,�a2- >�..��&� @ .�w��& |���;� K N�,( build�. h� 2!�Ax-��-"] y&�+�;uaH9�(XM_535179 .�mRN�"!tXP�1U$���#�"�*g sofa\ "ilico�R'6�&W�ep|!a�6r,� 3�,insert �1�&��* lanee��SHiSeq233\ *�,( &-�We�-��$!of9- , 73�347F3-orZ-E��2Ez+b-MZA�B2us!�,TBurrows-Wheeler Aligne�(BW!��R*"5:+ -r16 [27])1defaul�tb  �.ed 43�/76(18 uniquely����,6sorE� � !� co;�����? mergV�39��� � Picard to�6% labeh3PCR duplE �h�E27H( http://sourceforg( net/� /6rd/1�u b� me A�Z is Tool K� ATK5nv2a;–P6[28] )!��"< a!�� a\t_&odu! �!�BAM�'�Va 0HM then�@��u�$eda�> �dL f �.I%X�. eachN � U�w.ma� QX�69 as ra�7&��"� n�@!�flagged]�_fi"� m^�B iat fa_!4a�/�@A@LJ� Q""�l!,P( set: ( i ) SVal&"(MQ0≥4 & (^ Q0/ (��,0 * DP ) ) >a[8$;FG�nd bia%�8Qua�!score� QUAL<3:0 ∥ (#�5 pth ) QD5 B.w ) SB�00 ��4�9window�"1�t(npEFF softw� [29X >����3n�3� � i+A�edi�19 �,al. � �0M�GW�n�4$ <�B!� �g8gor��.Nv'n*d#�: NON_SYNONYMOUS_CODING , CODON_DELETION INSERT. CHANGE_PL >N5F#.GFRAME_SH�- , EXBED7. TART_GAIN LOSTOP.OPHPLICE_SITE_ACCEPTOR1DONOR� heL ? "� �$"�29��69�3A��5 335 N$?>otil#,�}8.�*!#6�<�V���:a?x� a�w8�R388\4� � 6�( 9�5%] �S-�$5A8A�,w|L ed��auB�1A�a� dele ,3  ��aew�NO��u6P�4[3X!T�1*s59�!{��Y)�687!(1 z6 eF0. MH)#s"u1�, �mi�+atell�!repea !ndF�%�="O4x>a�m��b�N�A visPE*� �> I5� A�g?�Fenm view�IGV�31�T��di�?� yR�S�Man��� ��S�A2:"�?toa7�*�"5 �Qr�2!H��ert�:--�+�rse�?��&�6� z%�p$tsM{@AmpliTaqGold360Ma��mix ( Ap=Biosyst�� 2E�#Hly��!!< ABI 3730 capill�7 �%�Ra�>treat�Ax%c��I%%$shrimp alk�He�sph])�e4L 6�2 ZS)�]H�-|TCo���Biops�/A�n�D"Dn%NPKY�( n�,6�v2\�>p6'N%Ycsed , fix 4%Am�% embedG�/ . Pa sl�~Q geneEA$MHE�+�J �o� �J@,".,of�- ( of�"alb0 symbol MKI67- DSG1�� carra 2"asZ�3�"B"�!y50R?,� � heat-medi�0gen�DHFal�'sod�*c�t�EyM�1H 6�5×5%�720 W4, crow AS=W�&v�'a moist�@cha�K, ck� 4% b�B;Ealb� �5%�Igoa\ !inU���KA�ᖁMgCl2GCa � PBS+��?90�room tem*a�incub%=e|�-�tibod($Ki-67 Cell $que 275 R-�dil�, 1∶9oy0/2 ProGen DG � 10 ,6.5 overnNat 4°C�aEpr!��1ond�O!��Aa���"12f�.Hiicous-E�1�0Hoechst 33258%.Gm3�6�2!�A�um0AKOm��� flEl2�until"���* . Each IFy}��(�wc!%�a-fuMNe� ��t 12 )�"��Nto ensA�':J4.. U$� IgG�t�,�G�]�� T :=��-YM�feEw�&*2d�)�nbi����&�&�c�� by�;%au09� �5KA�comparis��24 !>t[B�2�� us6���F7H:4�b�6� � otal!%�L&2x-�L%I��5f!m= field��. HJ6%3( � �:v� %�n3lj4 B עB!�5< Y: � Irn �al��R+ M�D.Q A�%� n NCSS&o $( www . ncQ$comm��N�&�Dii  1L}( MANOV1�RNG�H��0s��ME�:aW�9.x�~"�P Q�{8uenza ru�$( IAVi fac�(ate e �#a�and�+� ai� Z).30,, tinc�,3 �=5!bVM<r6�lo% �V��ai8s c��@n,� thos�*2Q turb�:-I=`f!N^ed,. ReaeEf%�Z�;0 +7u �2r�+kiTE.F�ep�Fl� 7$�^ ld2& Ke> � 0see��le��-A�� v-}s`�%�.�C.+in c2��Qs�O�d�DfW in uppe� midd�4AFZ;U� �it]fg9CXA�ns)#d�i�.lF+#H �SOf�$ng_Ug8�,K"m� A��2@)W��,�r> s��4%Kccu�K(+N�k �A t>sm'an &�Uf=L[���n}M8ff��Zq�-]RN���� &g0&��G�.�#ran�e�X890!- 3412k.!CO+y��0MtE�"�Yglyco� �#�@gg� n�@��I&$neuraminid�( ����of 18 HA�41–H18�S11,( NN1��+��/�0]�[R  E%32 ]6E� S9G:�a�ety� birdm%e!]�U!�atk.st 105�(�+of�%&8 fami5[0Am\Pw[b[� liv^�Aetland) aquaA�e&�Z�+s3 A��U�&�'�,uckdge�)�swans;%CharadriZ>gulF&�W >wa�Z )�_%��maj&:� al!��Aervoir [�%:�@�%�cNc�,� !C�)�M?89�!-��Ka�,( �T,�r,� 3��hor��� MW9�mai'"*5IAV�ep�]�ibu��Iappear� of new>�L k,�d�)Rdom�4c poultr�HBe)�6I�(3-��A�eptorA αi�-link�ia8RciSAe�GaB!�bF6nF6 Fo BV i�S* i�1!� they �6N"T �rvU�pl� hp�p "� !��K��thL5��821 %UE�Zor)"J TyJ�-ur docu?�#>5 �Dc�� rc:! 1957�� H2N26�30y� d��H2 [�A�# %� [5]; ^68^( �;Z^3:^a��:bz 2009f� 2f PByPA%�s �) � , PB1  k��i2o�Dn A)�A]H"�62� �)��� t#���� �&�M� plawq A�H��k( A�mu� o��Hyeag:�u� b att�[, �thQS!pco-cir��;)F!�)6�i/�� whP0a��]���b�%e"� ��$a stud���e��ko"� �mp�of)��%���S/ )�&Q> �H9N2 i 'Ek[�B #5N1:#A�[JR�\lb,A�[1 <The�d&&4NSA�Z�%�I[�-u�� -dep�$nt [7 , 10ob2];�e�b,R �AleP�d�A��eri*� �*1�A��L� ��)4%[SJeU�, given�$'9ti�(@d� �HoI{ona�'���/� A���AE dyna�+ofi2�hA�̥Ni �I�[14!6�Dj5>� %��#� "^�1�X�L*LEff}P~*��Rebi�6Et��I% s by a'oi�%�in*6= witha�7preexCng �z,P��uns&�`)@ !du}tZa�y�tes)�hy�E����"6 plad.9 >&: N����� 2!�)���co�[+�]�=/z��a����A�"�/�2uB% ��A��(� � ��B��t�%6�_a �op $s�c@-i�;bc�*2� . Fe6)#I �,MdoU�Yi(WD simp��"Bbe |Al Vas)Z] I�A*fA�"O&� vA�"�Q� ?sm �<YB ���3�(��ny4A��� mustTEw optim�]|��T"����-origiZ � Ze& 4 eJ�re� ��.3<\ �%��9�" 0��>� .�KN ferome\ ����>ea� M�1fA/y;�(Wis�,n/A00751454/��(��)� a_ct�:"��Mit!wto 3ʹ-� ,yl-N-acetyllPs(eT ʹSL.%� OA&%6�F� to 6~_6R_J? _� .A �:�"&@ %��pf(/��ra� "/ �(a' .'-�we"Of�A � 50% S� sugar loa�( RSL�c�3��'�-a�:lfaka�f�i�6s�  ( f =�+)+�!�� agg t�A �� ���DB0e� �U�= :4R�"�2+P^���E1I�2 v RVg��3IU!�==) 35 n%��5�B-06 -lL1Aeft��e��X$!Y M�qB�96-MB.2�-��Q�&!�J�z��I�3B�ombg� hedM� S1 T�A�viA�0 B�S1�U$9�� ( S2K�\�c%<��& (� ed 6A�8*f$��rf1B;� Text�!:� ��)�e)��<��"���u�g�J̀��y�zB ~�A.�–ݿ , A/�WL/Texas/A01104013/201v10 )�FBi�MA�#cA�-���$aq ��B�a�A�W2M�� ��x}ir:!p�p%�A.�YgW"�JxFs�7�XI"� ��6� �n*[ �=mi�ams�c!��"� 6_*q('eA| iW U"�L�9piNF%\zd D!;wo�6� actde� eachaBn &# a"M . Te#oal%G"� *�a� O!pge�"� �i�j � :. o�E~� ?im .t��D%8! s�ed B!�i�,�� tim �xe)6� �2Lk�> �e))�9� �� v TsE�y� 3�#post-Z� ( dp�/w�in�Eo6J on 7)b�2�E �%zeu��x' ( S3���$�:�>��Lo5�L�iAՉ9JA,�-by �, level�re� �Ta�!�A�� ��_e�dt . 032–6 . 699 log10TCID50/m{ �7�vXg)�,�us�w@ �77& dely� JpZv.S)�A�� � �i+�s�!!Z�=- "R$ ItitC 0#!F�"D� �E�-"$W)�5�3:wG^6�-. N6�X&�Jig���� & %e�(Oughᜉ�(dch�-�E�ob�5%�^%'->�|��A�2�)T2nAKbottlene�!A)��ŕgia�i��Vluc94��6|(�I92^X_a V�e:$he%-FR���>cs�BF�. S.AN#��vir��� F#�.�2uB�%�pur �%plal*ass��nim�07e gA@5��"I-a max�0 T���}�F�!i� gA�I��, 571P�!O�f:�1%Ie�R��:.)�z�A>212 2���� . Of%�.� , 15zm:�1�9.on�Lpi , 264 bR&5�1iv150j*�[���%ҍ*N"�� RAzF�( n = 159d!&u�"�7.�%"u$ )08� ,#+rache�d Y3�. �ɐ,broncL� cranl�s,� R�#2)<=R&, Oaud3a N�� .�8�B�$"��4 2;2� TheEE�1�subfE9o j-D3�1a[)�1-�"�9�546Y��>K:O�5�stocka�!�e �ft�eb ��Dee\ YFO��"&�!|59 orph6$�UJ�*Z6�I� �Ege9�F�32!nY'�u� �n���same #"�:���sQBc�"r 10�:837��Q . Ano�5�w>�6w47�X8V fyA {30~M`~l��AOa�#!�g)ԥ� �� p)�I�5 6�1kB54b �B63�r�+R6Ct9HA�N2>es;���1f7E�>$;�2/(>Y� NA >E� chQ�!�"�D)SA��vA�)C-v �("Iisz/ea_, R!EKt�qZ�b<� ��.,� "Z&six_( #39 , #47B��E(��hYqI�6� ��J�H*C. A�5[��>U� �5+onQ� � -xN�B 41C!AA�= .�"�5 Yes9n xb11 �r6�,kű%|B� :{@ 6a�e�a.�Bf� !*�5/� ;x%Y Cj�t!�48�5� | ��:�%q�B��ke�:=. ( 19�ͅ� *JdK Fe(�*ѼH�X.�&�.&� e��8] � F�in2j*� .C� F�$. A������ 2�%�}*�0%��AS�nat�A o��:.�sor �" ,^�� ��Ofa�.A��a(2�(R�qA�6�=8 �A��llF�~�� n�E���� hz� ��&�� gJ���VD&� �eT�&;%�0"�� �).���V,-A � O4+E52&_�U=�.A=��)�e�0u�8SN�n�0a�8�9, �t" l:3T637 3�� alveoIh7pald>54� q9>. $+0 �U �OI @, qU e9� to�~FeQ %VokaH`,.j�%* �AH%� II pulmon�::��Fel�oq&��_t  -Rnd �_ neumqne aed α-,�& R,r� s [2F �S w�tW3T.�- 5–J�h��B<s*�� X7 w�{ ,�32*!� irwalG�:8roxim|By 3E� I�, I| M� �IY . Peaki � superna��ECa da 72 hr6^�+J(Madin-Darby$ $ine kidney08DCK )M���s 4e45;V l~ 52 �́�}�51�".�3�'!�i6�t- �^��be !�7>� �;"� 282�y #4�A�e�1=�p�A/Ce�E�����7A!VPk�Y�A6�S±a9>d�Ron; ±� 4r2:�� �tiE�IB|laybE)�3E@ r5�:rE'6� '7.B:'B/G&�,!J�8!ly�7���m��%D[TEM�A+��( R)E%��6–A5>��S3%�A�, a-e%Z LRj���±�1A[B6!_n��%�A\5)�v7�@:vt!�2'0J'B�All)F�:!�V t!���repe�T�+!�N.��%(5.}[±"�C�UonAp�89 e39]>��!a N.��%/��!�9j��uB��u �B� s�Y=�3JB�(cB�V-.\7 (M�2 :Y�non AJ�c06Ce92(�:u �R��?di��&%�iU� �)� J��$"w  %)��ly) �� g/orbe 2ly���:5/B�!!",&v�(we 6%&_�H�g:�;�S>� N~E�".��s�Fa�Ffj4*\�!ri� qwo�g:�7j�%� .P��� IA:�!?�. �ur".0alF�J �Con->�L�H� }?� *��@(I�0!u��v_1S�hg&Fx!�,tV�7�5s� 3�V��S67–A�67>��� ~A�=a\uf\�T�JRK�I%�"�!;!gV�!QF w��e�&'!a Xes 09-S6.0A��R�B�� e&7"U!% ��?�c0Q#&�1�6�heb��5A�>{�e�a"��`�={(� J��,��3��@�*U.Z��)&F�(��S� �  .E>��J� ( S7.�)Xm�_��e� >�5\r9�verAuon 21%J ( HI:�1:6��1:198 ( S5 !S8�NoI:��V�"�i*�M6Aņ�uy%�r%Y;.�C��~� 21d� af!���Ow#ZMt .�(>�!#�co!oU[���,�~�Bbec1I�� on�ie.e�a!�A%���wArAف`U�NI�NB N�6 summ� v$.�!����B�9b�4 tA�"�P�'E�^ an e�N�`�!oa Swin�g�8rG , G0%ng.�!.�7�#%�d6�9��ch.?)��l?�4�1"26 outbreaksvs ;a�i3!�8y�"�isE �oomm�7Cub@ H2N3gZ, H4N6�W,��T�]�H1N2 [�O,�3 [333 H5N)4 6A3P�eH9437] �hav���O˕.�6)8uL� laboqG�M� 8G� �sB3oM��r( g ^at*�'(of sus�3i �4.�'� j<=i,ɛ�N1z ��� enzo���"@���[W.%�D� Pt.�.6FJ'vep`a&>Gi YA�6Gve�f�Ee}5&S ��y� A��0���Dig6�l�IAV6A F e�,F�;r h]�6� b�m%![�EU’^| �Ua f6�9�v \" UC;ÓIFHP�rp�a�W u�� "um*l3�,okey/\!za.��1 |lI )�2r(L ECof]��H�<�<0M�Nd&A[� 9;&���;3�;P�d�6es��ac�>&1Ŵ #s�9"� :t>M^�mE��$In[ 4 � '5N12'Y$[8���4��]�>/a�[4�F�M:�х�&�zhow.(%��|�<-"�8�*>�*>�D"�MI�AAg@ � �2:O830AL254AF�M��8%:��%]�d%~6� � #oM �AZU ?A|*� � ;i�a�>K& �J�R�"R8��a�)(�b � fd�� ��" �Bind/��VQ�i�&�7�. n�K��6=��.!g� �C  Y�$w random-, :� y o�K%�tj��!/^���;Hb0|� troE��n�:�!���@�@�TiH U6M .;u�F�[1�1�-��4-M��D4�GaBG4]�!�!�e� on b~�� )�qf�&H"�)�q�B#�a��.'E�U�.�2 q�rA";.I�dB"$m�!�&| uu� E�� (6� A4f1 �'6�a$�`"� .�N[F/�|�f��I�k,� �!��p&bFX"if �u[i%W�e�to�:er02th . F �7W S:QQAE"_*A&]A x�:e"K~i��A�qe�=�s � j�K^P�J�i�M\[ "P&2h'$� �B�:-!�a��r� YC��Bn v�-I#!�@� � ��3  li�`m������e - !I�)� )6�=ů ���5�[!�2�u,�� bzPME �6&-`er�?F� !��2�Gv E].�� .5K&�/iA/ :hl�]!]k|�TE 6/be^�2�Md� Ag"I�4e unbala�r8qL)�2�!f j"RN!�:AE=^Ůe .Ǥb�D%!Rkey'N!Qz G��4M%Hi= � s [4�P&&e�(�, �%Z%�02U� �K06&�,��m)�Q� u= �`U R"J��foN����{WU!�p{�%qFlj�� 2�Nh7r.�[*� fv�\,Uis"yT� #/*�S&�J" ribo�bXS) 7� [44]%�NS%Y [41�L}*��e)�)�!�foro�e > �#&surve|c�Z�FN[��J6��  H�)� >�L �b�!u!Un��S�ZA�4��P"rw"'s�(>i��i�=eL:�o:�<�HiMk�;uR[4=L5qg]��*�Mj�) %?�9g�^A/��=�m�2�&+ ��e�u�. Adap! &zNr A .D�K�7���!U `WE�6�M`or2�2� "39�N��A9&�V(2a4OfI�G-"�8(�q�� ) "03,� Q197R<HA�Etl�=�s:�*� .��Q��s�E6� �!�ove"LV�upbYB� !�� �:r�h�[.!�JA ( S4*��uQ�Z "0���]>��1�b9T5baR�b9>11%_ J%���T9�#95 >`{9��glutami�GGlNQ�W�&�197`=��=j�IP86aN��"6 �^�a�q Argo2 �}œs�j�gYL�=pWe"~ �A?iT+ "H\�E<�9 or���M�+P? #e:1Q��ntqS�"]c��e%[.��c2�"6A �,��� ��wi� mple����+Q�l vacc�^f .�c�)=� �E.t� ]!!�>� m� *�bJXJ�:A��vIo�9�2.}2��B6="^��.9" �� exEb�.ruL oEP(, pseudorab� �M9g]�E �y5�#t �d Ǧen.l� �ge�b*� paraa�AVݏ�pri�N�T:p*�[AYe�qF�%�-�9�s�����"z� !�6qd����:�N���Q]k�m clos)���d�w�? s [5�TN� thec��(IŒ�.�.����e"?��� 2^ � a' &�� &�*~ l:�y �R*RC����6�,2�W N�Y�ecologyuoG i�E�/� p&��!�ae Toam%�lyA� , 5:In�%A��7�49�:372�ah�c  6��[532eV.�EB�C&��a�a��2 E�f\Tw �d��m� �p�f~��a!�m��UyS-kb_ 1�> E dz J^�s.QBg̍k:�R poc_2H 2l\a���sorv !�Y�j�9��mW.=eAi�Ld�V�LNk ey}{ c\*:i.��p. ߎ P�/IPYXU * sI�:�a�$� %Jaz�&E#D.�e�12#& � e.���!!Y) .H�rG!��X�n�*5zq�.��f�PeP> ��IX`s!�UJ)�!, /�h4,%u�In*�$�>��9�llu�t�w�F$�f�1t>�E�1>!R�4| �"bJM�2�s-�� 靡�)�NV"�-�!i�� � D*��ڭ9>m���aH!�'N@pv�!�)�% �B��>.2VE���ct lth ql s . '%� ]��&�9� +�o)�ls"s QA2296�(0�P�eof�>Yc� � s2 �QA2494FM!2.8,)��c�u/&�H6QiA.C,i"BDHs�Jh�H�#V�C��}UseM m���N� alXe��Ue�Cen��( NWR��C�(|%�A> USDAh WelfkRG�-J�Xsaf�g�hoco9�. &�F�:�u.�+(EJ =�.�):�Qw�*���Iy �LUN 2"���2li�UTԾ0e�!�Agr��nu–5������60�C"ߎ.��8F;a�;4adenocarcinoma>�;�hchick� mbry'� brob��� DF-�%mr&,H�7Ame�� n Type Cu% C�K�\( Man�K VA , US�j.�v T�,�E4in Dulbecco’�dift:Eagle ex,( DMEM; Gibc<�New Yor3l c����*� 10% fe� 2�w( FBS; A�ita!� ��, Lawr vR� , G���Ig5% COe0nd �(td٩��ʇD,�DStacy Schultz-Cher{�S:!0Jude Children�RM� Hosp�, Mem�H , T�[ �i)�d�% �!dMEM/F12}�h� Fis�AS!n�, Ash�NC5�FYRU!nD8I"f��Vi�W|ag�3�_3�ags M�;I�5�w!�5)�6PAn�lnlHem�p��V*q inhib���2) ��ỳ.fby�"!@5%� �eryE ��Dc9+ggc d [5(&�uE��I�s{�1U�  �b:%�elsew�[51� In b\ ,!�h.b3,.Auro��iq� &� - 10-�� -d~eC ~to ��6I��c � '��sa�kenicilli��str"omyc�rb"A|� E�Don1'of9?a 6-�,p�B5U��10��)} ��(��,��N�GbB /݉o2#�>l�n�ќ��!�2a���f���_:RG@>�*�DI��al�t�Mex�"I�f%� King��PA~V�7NA Ki=W� 9 �d rnufũrer�i?�uc !� rcF�-֨ ��a�iiG��N��ra XTv�R�!.�~n 2a M��xg��v2I� 7�s�o��� I��,�� Diegx C* 4 ?^�&�6  [6� Vd� a3air*��6v ���che�*by FastQo%B��ham� "i�c3 https://wC}bi2. b9. a��uk&$�fastqc$�!q trim\n by T �c  n �G3VCUsa.GLab� �� }uTlab . org/cms/ ? page=^ S)5�q.V����uq��&D!�a&2Gl��=i%Ja��4o B��of*D�Ue��IhBowti�0Johns Hopkins�%ty9b-,-bio . sourc�"�� 2/W�<� shtm0aP��T��f�kE��s!�jUA�a 20%&��cutoff�NEA�T�(,��խ pseeai>z,V9�]� %T��J�Oc(!j&�PBS�t[k�� a �29u���Ric!Z�I A 001�/y �[um�J:Y:1 #a* I"` K G- �� �),� 3 mL��"F8 b: A�a�.V q �� j)>IN.I�9!�du�) ��.�N��2��4D3A)7R"I�?�nI%�*� M2z�f 64[59��O6Ob0 su��� ad<7 9iifu��)�"b e�1(dis��in%��dia��"i!�a��p�� X߭nf_�a�tic >���dodecy�� lfat2�X acrylamidf.l eo~ roph�if� 6!*�?biotinly� �{a� alog��je��e�0rC$rchY��GlycoTec��Ga? rsbu{#MD"��&fA�� hat 5 nM/��A\ ���ed>�Aйzb@ 64�4an Octet RED96Y f4mer��p;�e~X avidin3!�+7i&b PALL téBIO=nlok�1��)�-Y:�? �Z7� �?.|m���GE�Eest valu�/> [���!R}��Xag��c* Yf�*�9 (-*7l�a (GraphPad Pr[ŕo�1 �&g)paAecom/s"-so(�/�Dm )7�"{ ��(�f"+���l"�l-���9� ��a�mM��[65ޭRS�l("=Ks *�m,2>mA�i to.n��Qe1C"�D|~tw}p*8X�KM7am�)%�*&�im�F+A &UY4323(29c16�O2 k�k��tr }E a ru areaa�Stark�MS�,A���;�JraTB>HV��#�ns;>' ��, M�,ssippi Field�AF�.�,3�D!� quar!�aq�, Xek��� I){mf"z\��y�!�wI:�r%�r%)�ELISAafy��$all�Cx'5%">!��l��r���3Zyh�S&ues [i�aeCal�nia/0>�r Switzeru�/9715293'm3�<�3!A/H܁ Kong/4801%4%�8��%� IBfn .� "M"� ,!�d��e&�a)�jE@�I_2I�Vɍ%���"�N�<�z�cM) ���nm'a�uK� �@ �:SK�'=x?�maq= �� ��6�#�'m�-���.")^122�%�"�"�^G"�+.&{��p�. = S;�=I�J. �P��>@.M in�Sdjo� �� ( 2)/pen ) n+�hNB2 ~B��Hj�:�!� �jb-�Ӈ.�� �G �CZ�h "-���canesthet���aUY���E�.��2D�?[�M1�)�~_9Hy��  � 106��� Ja volume1� (� (5 mL/nostriKi�A four2�1g��eofT � 6_���g�# /��c)nV n �s a�l�NS� ��"*�eja�by-I�.Qk;e&;��ac�` �measu�)FQ�����A KY^�*&$�,E�>��4�1a�KZ*�K$necropsy!6.> .�& 2�@~durc�L+T&Ì�0h�hlun�L9�x� �P�!s'RcSW\ 9KGZlsC�eS!��,"�K!- y� mUn��E�i &�%����:x.��.l�9!k�:�P5>���16 1a�)k)%15�i�%�(Tpch>U��3�)4 4��odA�AA^�on!q 0)a�df��b!eBG.avp� jvAj����s~B�G�� :R,( �A\�ɽ%�RrI�&� a�s5n�e�IAN|e�!�oC��j�3����K)�"�RE�x� c�N+*�+>k�(zxday )!X� p��E avoid*�&�k�,i�te�1�;ɓ1@M�H!^e��Q:�out-�A����1#4�TE in�/steel t�y�'�;dis� ��L� V�*ji�8j� q�" %|!�fN �sterile �l. Nasa��ծon �G 3 , �+!��& �A�yu�n.`.^YE��Sw��!PfW}:T���<"Om5OB�a�)m�:_I�6^ ���2� )�!�6/F�f"s��ejلE�%�Q pig:ln6�n�n2�n�8��!ight :; 2< N=| or�P9Z�o";S�96 "*�oG pa� >�thma�&f@, r� ?������Be�q��f�0� ��d���%I)j= (a 10% ( w/v]�i)2�A|A��<� ����Fw��o����� �#zthF�yY") 4�\��i<Cdp�D�9�*$1� tIY��� 6�L(n�k[��PR3����\�(x������76L��\H>6ge�Co��)G.!(JT?,"n  �X� �=a� .^��,��A3"� �rf �I 2}>" 1>bڐB9W�6�a [ �=�9"�� � �@�ub�6he20:���SN!�14�f;�ump"N�SKz�G21, �X�4 �X�Qe)�:)U%!�={�O�;) E�2n-:� � imensJ�c�.�bi{f�R��� .V� mMy"� &!ap&ex�h��as� nsV-c=one-way ڜ4����οin&.�� gm�#ka TGw jor`"{ez 9"&atI;S}p�� . Di��K+��a P��A� t�?� •�e��j|� _�Offsp�H��ch��s�,8�oni*�6ome��s&iasis ��668�it�]in-o��TL���c�QW8���1���_?!�m"�( �6 �a&Q�morbid� . Ef�E��prazi��6 "o�� .���7pregna%�onS1>(d ��wo5Ji/U�b�w�Y�8* 7.�,!X un��>R�8cr�**���a��EU.�!kV�>�V gel ye& �H"l  Ug�f��$SRCTN32849*,V#"U#��led-tN'a�I66/es�t�� �]�I�%�!2�ClaceboF�e?5\� . =�n�& cytoA%(0�<SW#uSE�$*Y�^T�/��ANof FoxP� NRi 1343�,�.�,Uw(�_�uG;Z�t :�#CdA�"�'s7�͗z-""]/HA��"�5ch �:R�HZ�:�F�E!�" H�qn^��(j�v �'�HE"o��@M��(��aph��:� �v�%/�C6s��2�a�he�|�. I��] ���:�a��BR' uJ,�0U�U�borX��E�>�B�[�X[�$T�=E����G�"%'"EA+y�C�0�drelevP; �*����� n�b�rc!r%�FN!��2ole5�AyE� �';=!�be&�E�7E�2��mẽisz[�����!\9?��t!�� fic�`AWq�*y�K1��� ,�f��(!"Mne�'s4�� ��' :L��U , ��)N!8�E�[,6��s%�n�f� nt�o\Nrdd�odV:�wor�,���1(�)Ġ��>�s�VIk�> m��&Frre hz��vc�1�ibm�y:s��:�iJs!�$�Mo?�.�>EJ�A�"��.2Kq�j>! �5� m�0�4C"2� A�� / �-" \v�@A�K}�!:c�L @ oZ�0e�&f��,F����;(�Ki�D�$�:. Oe�,FuR2�j��AYy9��6resis��tance to infection . On the other hand , children who are exposed in-utero , but do not become sensitised , may have acquired tolerance��schistosome antigens , which might render�@m more susceptibl:��, as has been observed among offsprin wom�Xith filariasis [6] . In ��a%"toV� �als%Olue!\� Z`morbidity . For example ,�$ low incid<ofacuteBIsyndr!-�, Katayama fever [7] , in endemic popul�8s is attributed�early or9�6� such that�y%�a-pmodXe8 immune respons!�td subsequent pathology associa%w(S . mansoni2�BalA�(d type one/ two>ls� need.o limit=j[8![910 1 2A��(s establish.�could�-�this b �$ . Studies!vmicA� ppor%4 hypaLAX%HiQWA�$-idiotypiciS0ure induces B�T cell�iveness!�Y[!nm2recogniasby)� ae [13���ea�.uim!� oreg!�ory ef��=�~IٙB[14a>Rec!�E oepiA�Aical s90,Kenya involva�(school age �v<( 4–17 years )!h.8Q�$areas showA A��cytokinM/im!�antL>�y�[1525dys S�-8of pro-inflamma%/gI44be a mechanism �E[ �Phood hepatosplenomegaa���inB� . Ita�estimeK�,in Africa upA"10 mill���per%C havFSdur!�0pregnancy [16�40:Kof � -bea7!�RW[17AHere w�"!yA�@ults on follow-upU��at five� s ol��exploo��>Z>�a�$its treatmA�B�)�!���WE����s�U�whe�$eamselvMUeNA{o2�y . Ba!o@ jb%� ����8!��various]sw��S�PB�[1� 1� we meaa�,d IFN , IL-5 13%?IL-10!���Bx,worm ( SWA )0eggE ��!�m6�QT-��(s . Written!!ormed c�<�nt was obtained from each participant [20AWFor all2�'s*%0, w�jtheirA�$or guardia Eth��approvalJ�A)Sci���3s Comm�YNlUganda Virus Research Instit��,– Ministry!�Health) =N�4al Council for2~Techn�vy��London S�g of Hygien�Dd Trop�Medicin��T�롱y�a6�y ithiI�,‘Entebbe M��r} Baby�)xy’ ( EMaBS; ISRCTN 32849447 )1� srandom��x, double-blind placebo-controlla~ rial�`praziquantel versus match�� 9�(albendazoleb(B;usG,a 2×2 factoxdesigA-II�co���in 1munE�l A+!� adja�8� bi�r-county��-�. Preve�policY d exclu ��tUlactat��eMj-1!(>8 �2>�C[2; �A�oug is�a�rescin� [22]ore had� � �a�Eñl�Y=�ofB�B�rega�ngc �0obenef�(noutcomes� $as anaemia� birth weiw )� possh adAIe�I�developt fetus . H�F e%��ide��to!�requi pois� justifyb�s [23��P�t-�w!hrecrui �tw April 200��November5 . At4�$� I.��i!�st� s� sɚm� ��C t���helminth7 A�!.� �Im! Kato(z method [2J Ch}�.ed�annuall�� �A�blT �6c�e�at�Lvisit� ~cur���,�focus��&��} ()'at age.�. The �2�211&9^0� B#!w����. B2�(ɭx( ly 6 mL ))proce�GB�,A�smaE�separeH!bstoA�(at −80°Ct�� eripheral-�(mononuclear� s ( PBMC� %� isol>X@in liquid nitroge�P�Ꙫ= T!� 0��I cult� �&� ^�,�� .fbod�ay�A�per���� a��gro� 4369�, compri�,190A se m��dZB�!^,�Rarison��X ecut, ser!of 24�wh.udid�. W=.K � ` !2� 6;� �� ��9as�yŖly�cribed [v[25K [2R [2 .M!h�%_suppliedA��Professor David Dunne ( Cambridge Uni���H, UK )mlevel� endotoxik e� o�E� ions {00 . 086 EU/mg% �175.EA1 diluD!z�M_to# k��con��r��f� µg/ml�r� �inU�%negligņ( <� nA| unlika�t.�J�inAle:((. Briefly ,�r~ !��Q!�� ed 1C4n serum-freM diu RPMI)�e�Sed +gluta�/�[e� llinEP,streptomycin �Q�>!�,Ey4or phytohaemagV inin�Y HA- SigmaQ E��2E101�in 96-wg$ound-bottoa�� 5�p����TC Micro2L, NUNC A/S , Roskeld�(Denmark ) ,�left u� maf ed .e a (� µlaM T) !nad�ztoER }a|incub�3 t 37�}<5% CO2 . Superna�M�harvesu(after six d��8�to st8at room tempera�Aone hour)�vi��inactivI�buffer (e' 03% f0yl phosphate a 1% T�80*%�) ) bef�tor�L.[until���analyQ�gB�ass��(nterferon g� (�γ%� leukEAI��A�̉IFM=52rAd�6�as&� 4OptEIA ELISA K� $BD Pharmin� , US^whilek3E."� I��Ÿ pairA�VF,)�%� ards& "\&�!{B&�SA15�C� k NIBS��Uv��of� assa�l>cut-offcdetec�.|,�!Clowest:_� �� v�%9 p�"�1�8.��)� 166 13�QC?��2�nmrgen ly�, ( Figure S1LTo�%�,gen-specific�n,��2K# 6{�4 xsubtra� "� UFGA&t�� M . Pl� ͌of IgG1A�gG4%(IgE�7. ŧo in duplica�byM�� w� a hi=Hrough-put semi-auto�system2�flat ��384��m���$ ( GreinerA�-One Lt= Stonehous��E��co�L��( 8�� a�( �Y4in 25��bicarbon�K�� AN��overnR at 4��. AY� posi� pj ;myeloma� oglobu�/is1Lre�$aD� m�mA�A]��of%�bo3 �I��!. S� %Ʉat�BA"9 � /200oE(�E*or  EvBiotiny�md m%�A�-human P clo�� �(:� San Diego�-!,u�!�a� � Poly-HRP-�d z onjug!�(Nquin Ne� land� 7� 1/40005iDt�"�OPDa�s � stopD2 M sulphuric acid��Ab� col�Zg�Opt�denAK�OD��rd9� ,Gen5 softwar>C.� �N calc��NNb� terp� !D6w�8Normal European( ��ied3 a� aE��to%���[�s%�u'��#�set!�three� devies abov \m��nF�H �!�s �AIE�to�7,1�#L6EA 54>@46@042:B !B166 2��0 b� !� x)#\Lor surface CD4 , CD2CD127e in�R0ellular FoxP3�aE)�.�2 $( Treg ) f�encA�. Antq�.x mark� �A�� fluoGe��hiocya�f4( FITC ) label�B&�( Invit>-Caltag�amarillo"H ,L coerythr PEV\��% �\�_J�0127-Alexa647 ~�� F�A�!���i�r��nt�)%�8-PE-cy5 ( eBios�,��2 . ]tha`r �A numbersy%�� Be1(2"'2�G%�+V\ "q ��m�el>4A)20 minu�KbdZ a�Gin 10B Q�mix'y!�2 CD4-EGI�-PE�E�9�at ��1∶40 , 200!A#vB�wa%H,�>meabiliz��#!A��oq[accor0to.�'s��mm�$d protocolFnacSI FACS Diva��o�17-�Afw"'me( LSR II�SY5�G�12 E�a� �|dat8� �vFlowJo�. R&j �>B �?r�� defi!$as!�+)��)�+%�E�+�edU#���`ngcate \$can be vieA�in"� � ����I�expres�Ar!�!�s a!��age� CD4+ =!��Eon��' N i, term%ege!� ů�����y� MFI_ hR#wf(mai %jI��( � Iw coh�"�"�wh�����as6�#�� V�%!&i��FVisad�I�logist< g%� o&� odds�io%O&| vnr,�G g,val� 9�rb&"I&ho%qV�B�w .Ft�F&���#� �almY!eu&ad7�Lf��Aa potent1�!)�n rUV�inr h�E�� ,">Bre��&!;ntact dlak�b (t qedu� ,�Useh�!A<oecono�&staR6 hook{ aRM=&ellF$�$� ,Mmul�ri�&N+. � )�A��a�Z ofZFB�onZ*I^nn��r!�asi blF .ng)�2�b"�dae!�E%�Z+not/�e� si��t�* a di Mnef!�!U%Z;by#.�M�a�u�by2 ducr*��r�(nd�!!Qp-valueW�@0a . SiA�prjE�b�)�5+F��ver!�w�SfurA��lBlstes%ͳi�ed1=o��l ��l2�an ��� a��nT%`�yZ'q6 repe%f�s combog availeW�R� kll timAint�oJ�osu2sel� �.z�o>�eٗa�de�b� !QF&YO.R1k",F�ABU�.��>5'HN���in&I�&!|� R!B.�#A{�#e'm��� k�#� y��&�%21T9#��R�܅s��(|�i�"��# Q?>�uo�-�2T2�#HU re2l)��.) .&�@J �Isk/ d�%G-E~!veI��Oher�(log10 trans1 \aN\y linr&�w bootpU" �� bias-corri8accele� d.Ecoeffi� tIB95%�kfi^.��val$�back-.� to gX:� �a�Lb=�.�n�m�5f�un5ȉ�Wilcoxon�%k sum K"�4 ) W}�a�JTy]�,p���F(kFz _Y�!�:e ��Qro�*�@of.� E�&� � ���of  *H,j�ER�: ithout h%�1�5qof9�I��%�%1ed����m1these�so%�g����]Ȫ� Of1 2507-enI(M9 c"�2345 la%&�re�nd 1343!f-02�$"T ��.RF}, 703�2�E�640.��E�e base!�$rr)  A��"a\ %!e7in�� �Bn���(bnt�!i� Uzj2�!%�a�( TH�. A�36�) �$( n = !�571�1 . 2%6/�e, 8�1�1!��l�,, 24 ( 3 . 4 mode�D �23 3 heav�� a�2�F{�!��19��J� �5rad��62�18� . 8F�Thu5�E�U� , 25X1325�, 1216�) ��k�)�.�B!B109�!�1�, !21`=���. W�Rs2�%Nl3&�"e�*l+towlPre(�0�r�R�6�Ov� , 32!A�6]OMV>,��AEF�a��a `leol?(h$��se 119�A�1bi'!86h 9n)c=[F�5B�p 2aq10:s,�2�>rJ�Despi>6few�)%�8!E, !@���� a>�N*�06�0s� gra�$ep�of-p(m imuma�, max 3384- Fift^+( 4F+9e�u�( <�@�tw&2!�7 .y�u�(�–399 4!�3( 1`e�`i�( >400 ,�,1,�Du�%(&2��6<��� , 5s�36��2 �M%�gn(19%$10nm3 m.{y. Soil��i1T5�, s!��� O,m�5��H"Z6�$�(, Ascaris 1�6 . 0!�� Tric�s 7!���!#UA�,��6�nf.4No:,9�E oor�v�e*c�6�o�(H0�.k *�as�va$Y� � =N�,^tr5 , lo�of� � �+W�!f/(�Hc��Y��6 buil�i ,��oom5 ite�w�a�eEHvM�5�. A+� f��V'EM1��(�dha V$��2��Cq6,|��: KigunguAa�2villag���!��"�m!w���fV�tha�,63��-�=is� di�ly� ��hk9w}lso,4�9'p2� 5+ r�8�-)90>‘"Rtl�4ugA�er� 10 ( 38��!�B=24� %2�( 1�E�=bi)( 6 .�k$or Manyago0��0( P,00M lgh crud� yi�2gg*% u�V��>yV*J��+:�9���B !�/�b( Vf:�JX!�e�f-)b�%�los�T�"&X.`<2����h BK ��a t���-c�<�"�#c")8i���@be!0��edu�X,:�5��=� )3*� $&KZ�appea�� waVstrong�7��uSof"Rw��."�ag�i7�igB>�|�9aFz*b �(& �!�p=%#24s. Beca(A~p��!Uz6�.�{"�;A� �� u_ZdB#on��)���5�]a���ll���a@.��%�(\!aSB.ix�� youn�a!�n� �6.l!#* olde�+ѐ, depen�o�� 'sl�B �mg"�� AE^,V >�"VOR+%vCI57�  .� 2.�KFF hunda �thirtyN/��2�I..&.1<"s,3�mp�<\=.~. "� , 2��%2�"��cei5�e(6*� �229 �2b�r j�y�(:M !�R*t!?ini�шm�6� eQ5E "�2�5!3�<EA}5��*�R�U w!� of.[ J S 3 Text �Mс.�����1A�C anA<��.�s�AJ�y���/AexcG� A`:�? SWA;95���.�B�!lowerZZ (>�(�con�":n +aR��1p/z1 �Vzg6 #^cb�5 b,>>�i�8 ,� � 39�)90�2 a�4d���]hHj;N�vQY &�Bh2f�4��� �l� (���?h�A~W�B.#�d݇Z: B�onR���Av5�,2�y��o��V�a�r�Vy�>)0Rpi����KY�.L3 "� uJ��!��� �j&0U�BYI���9��95A��+�2 AM! i*k?B�&|S2����}9ܵ�!�J���.�,.MY�v�yu By�GZ� ,w>g �B�� "}3�ta\E�d profI5J�� aK*N�J�2 2�:�DQ��u*� �,^�Bw�-&�F�n"5��%�ic, wG�B9E�still�eae�F!�)���q i�>�s��"�4U���Y+:Fy3 � a0!� ��;�)�Th�w*�I�FQX�Bs�&�""�Y0F>. N�Mthe�, 6z;�(�2�,�/2�� FkFN��*�% pic�9LG^�N�u>3;1� Ae\ BE\� C D H�DR�"� I B���J2!r)(e>L a�A�jF , �P��)3FF.� ��622*m?F��My6142�3"� �79V�e�!�off-s:�P�em.nBTd8�542x30Vxe�` .�2�,A&i%3=#�1��0�in�( 3)Guw� SW6O&p8W R�1!SO�O.�$:�,�RQJ�5&�, 5i2�`�!W3���}2�Q2O �.�% , 28BFN[6UJ`"qM&�[ AU�'S:0u�#~�(�^tB�I't %\�{�7!*$:J_M7�,  32 913"��1�2\�Ev�9��5EA�z�6r �17 5!�6�,6{�8�% mini7�Nr�+*� lD*�Tt "�< G!�.)�.����""� =9Q���#@ n� # �\Q`��>�J� �'' �no.�"< f JB�Sa6yQ�9&35 X&.�8��%atJHA�hMV>��9�a "k*"DS!`�oU enc�Ke63#h}!&,parasite [28EE� �Jbor� �#B.ma�"�Plong-p2z3�I1 �9@. Two2nR*u�F�E�2�3�3.l" '�/�128 CA��"s U�1;}y�ލ�O�� , 68�b�+!�6�;�Y.�(ad :j lA`B2� 1 V�onF4(I�J�%�a�VedF.~�^��(*�(M1jZ ��F ~UC)A3��i�-�209"2�B�,�17)P)���.F�Y8;�!Q2��.F`��e.���S��� �n7.�A�JkR�� -J�.:�.�oo�;/0aE)llfL.!.9!�F%aB� *�R"�@���pV�!(��iv�YY�y��aGf6��2by*�5�?ex%�om�Tfirst!o�U IX!3w�.�t�C# y���M&�5ETU�lu� e$P:3[B-i Ֆ>�,I�,v�War s�]i*S� R3\>y d� DV�M* 6�,no�R��N�^a�"g>�apart ��"�.�5�!(� e�(4 sd�how�O' .A��8 .%.�-�+/h)!ig�jk�BA�>3s�a�fty+**8�!k" 4%.a"�#VF), implE��arZ�""$misclassif�NdueP�:�HV�&�Q�0[2�Y�2�3.h?� re� a�G der " 2 actual.L W[30 (�U�=r!A�E.�"� "#E�B�]urvey6 volv�*�RX5�ns*�T=�"�. F�7��#^^��3y!G carrAp,��r�� urba�_!�*0 rapidZ1!{wi�#W7��!�_$ d piF� aL^t�-B�}A�./1misi2. How��e! �S eveQnbG2;�Xi�E[8���Ychave qu� �= .��!�.2�&b �&�_A<peri-%O%�EFq%!CAL roadat<% m &�&bia�N� e.� z�I�Q�&� o�Z�=��&!4n���oRL&a@Z.=> ua��(�5� ncerM�$`itusre)�er�*�eto*> sourq$)��E�y w�A�"� n�a�H�Aɡe�K oF�`�ro��o�-�Z�G%���RectN\[3Xpi�"�"�E�"�.��Jse+).0 � ��predis!A9U�%AG!4w>Q . O�si�U�U_bo!�*TR�f35�A_Pafo� !Z(ntal malari�HbU!�V��eie�QA���A�ve"ja�!�j �!��6?fA�d%��o�8 �&� VgCo:q.�+Zed 5=5$~�h9�A~g2tYE�r/H�^��f!� i� �|T!+a���.'2�.,j=�x��=t�ze�*�>�% ��&T.(%ga�Z�2�:eR� &X*"m A�� 9�. "QA6�s %A 5� 6:/tA2/*2z��e�2e "u�\i� �� Ai��El"Z -][fX��� bicŢ�'!�Gmi��wa��( ��hen�O[3i[38{ `\noa�e�*o:�proa"�_"D.�I�A`�. Our fi/'�f cj.<�WNC�a�!@1gof�c��hala<�xin2PchronpNl| ��ad�e�-be� *Ji�zyI% Fr�� e$ai+��l w���>���*� 5;& PedwaLd &\+E1D\.i OJ!pEBH~� �diagnos-,.@ &1F�as.�*F weake�0!� �-heM{>M reig�probab]�m{O>R e��` �� oniGv/PV�B�F�m�m�VA�yB "toOT�isqo �{e��_���!�!we�aC��V�R+y�ae�ei4�%d�[�fc`"�C[! Of �-J �@FG"� aX e:l1A-:%��"9(eat�-� �J�.n�-Y1a�_i�.�]2�� _ B . �A Ns, capQ�7wi�e both��eS"�|F����cy��l�.whyA saw]Sl��� )�) �9.<Z+&rI+bYB"a#to�& ��TqZ" 3 B&/Q-� ���>� .0a3eu�p ց~ѩ�;]�5w =�A-��P^?�g e�hF"m &�Myc�A�msad� ���6"�q��5h)��.ly er: �6f��: riskt�1Bal fibr���N2��k39]%F!�jap�vum [4�In:Is��pf�n&�7�8L-6eTNFj�&Ql"@g[4q:N6tv �aNv.:ɏesug_to�How��2�A; prol�ssiv�iA��K� +Y'�S4e�%nR!w2"G�<+x �0�izf ,m(��P�*H .� !�.�-��m` in v\eX^^F�WA:\Pb�a"�\�1i{^�,"AŹt}�s� �-G�ILB>ro�Ktv2�e~p6�W ej>�:�-�=Y� ��S I�N� At4!��In��o�I&id*: AA�a�Q?*Z !��Ty�a majorn(E:�B� �b%o"�.jy�or~�p�an3 oiH�:E^N�*�.�2� do s{8j�!_zc   ���e �F$2�N�A�magnit39_w& I��0C �^���ilV�Evp]eluciL5dU��K*�Nlar� studa im:$"�ed*� ��Fo^��)��.rhalle3\09crophage� ��c]'F-NPa�VJ �i��a�w�g})�mi]aIis�p t�f9dZremains)ly unkn�0��desjhIO��c tory��WxQwde�PtOc�a���gcyNT machF`yjre[3or-med�x!8,��to1?qn�8lo%�f�V*e%5�:XcargoH lyso� ���? yin7 man�`?Wp.�c�l�Ua�?0tein kinase C.�osphori_!��|= cX<co�n�.!tby5�ng�eoi�tol�<�V-3- uENRneola!Ror j)/ic upt. EcW�4a` mime(FM��d su�L!B� e PI6��ca� � |%�9a�!�ab"�?RO. TogWt���v��� !)toU�&xto ��A�� naliz�degrad E'u����U �!/. Mugsb �aA scava�r�I� �p!�2�solh[!%�i`x*�!� c�6�YenL�[�;sgvaB �cbes [+ �_in9s via� �}��2%) e�� S! 5E��I�z� o� �k<of"]t�Y~ f#_U1&D F�ei�� l�j20-�a3G=Os�al  n$ , en�!�#i'�" w� =��K���Bf�{deINvKJq)�Uk cer�\�A s Ycyi3�A}zAN�&� :� I!��#>>ic mycob�LxA)vi;�=�ag���ubercule�#�[]DdEk%"�%=O6� o!�J��6iX!rU=�B�KA�!�nn�B:E�(DC-SIGN [2]-�ON�+>�,b7/ e=�oL�c�fal2nb�}� bloce%1AS-ў fuE���� ! w'^y�>��stead!��@��k\Kpio� s�v escape�–[1�Als�a� an-�&�  ���5c����kP bev� ��ZqAg�5�%��>roy.*� bacil&D curb!3�[1�F�m� �q�rY"(�ay�Ii�a�� kw�Yap �bi<�Xm�1&�.�irK buG&[12�A'oB��A*!Q�.ba& 6l ��}���� ���,�# on-s�n%�=K!ǭ � i^[�IT  uU�~t .Y �&�1c�pr usa!�, C�E}5!I�fN�%�B��be� ie;Fsuc��growth"�D�=1���Ech"Salmo�\$, Shigella� vO|�j|In �h� ��i� ndriZ �uG�B�%��e��|�',N.lo!�H'1 ly�oq�us9��2 jB�.� ]�M���)�" o*� "� >$&� !^wa�� en�ng-)e:/Z{�3d�HI Ä" � E�upo.�1+� , �un���� ii5ke�WleXr W y5J )I� � i�&� e�N VT (IY� as P57A�TACO )Trypt� n as�ASa�\Coa%"� �K$rigin�Fi2 �'#Jͪ�%a%�i2dgy$%�.�by��r.P AE�>�2���9M�!��he Ca2+/nkineQ\PA�–�{I sŜ�Dn- J�}!���& @:Kqa�&tex�#t",G(�M�Sn )���)smڄmbran#olQJ�#�oR�t kine�&]I �!�IQ"!�Dt��n*�'��$idues!����r�1.`J92X(%$o%� plas@puncta/, x.���V2�*! ���65J-"X "��>�ec�rͲ9ZA� V�Z�"�Aproz��J#�k큿�}(�l&�%2e 5��y�A��;��G��V:���&��.9�>��*rQ+:�� &� d�*.b�onAt�%�mv -γ jv Jrtumor��-α�pA#e)._!dZ)ed.qa��1f*� =�al" (�C?�H�nFi S B� [�{�7I��s�*cl� in�tE��6j�{ fq%2xÝ�b_m�#scopy��e�at2_ e�d!�"��0rge s� !� vacu���arr��&P� ���!Ev!p� o�3� �2� raa�=n6x�,�|��9: U��"�-C�bole�zo12-my�[��13-ace PMA��is�@�aB�[ .,h-"�@B/-��DI1n�q�/-ze!r�e.!�V�B;�� i . 1C>��1V?�> �+2x, f�%��-a/�r،&�of GFP-d� �uIF��Z���� aT �i:,ic inhibitorF(iڋdY3-�ylade^:.0ř2  V6�S1FH~s judg��& �a oreEn�%�O�W�u�U>lQh � ras�#�Rn�NolymerY����asin D�v�ed�ste�enaV��"��� � _# 61� �rs9d�cla�r&%�;$, ^w,dansyl cadav�( MDC; u-),�hA�R"I�%�NL>=��$R>��U<-"s.�"eF�ɤ.�icM�A aP��.�;a,'b iU�Ea keleW$�Rh.�l sBlnd�e q:vT^| !�U�f�@s�#�G2����J(�t)a�G� ]��iinguish6�/ .w-� aa�ntm� "dT�3tb!o :I`eC&�| %� IgG-~ed �w Fluor568-"Z|�ad� Js�W514 rhodvP.8dex�0 70q|(@ �]�)~. .�ur��� X �2�b��yHX�� peaka�%a_S1est� RoV'�!�w �X���Ec~�� a �8de) A�gtyLZ"�7M5Gz 6� pB�Q�S1G=(… panea�>�s5E.�� 1�.Na b�6!<�!36 6�.�&� �HF� Whil`1��M�B�*���sh!lr� %^�/a>:���2ZJ;hI0&1 t���¡�#!�!�JzB�>�middl�4n ��UAq&|.q� al@ i ��: �� R�D�-c؇P of n�FR e�#X labeF#2�6gz�1re�(s�8lQ�� 1k�� �%k?^� a�:�vea�>��c)T�� .�R over2�!*n A�o` Ri Q��2iu��~�s6�I�r9 :��& Q�E5� Z�2Jj:%�2�6��+engulf�.*�yih "�!#2�~�3%eZ�22N�j��5p;��.z"� oA�  q �l&�"AK}��ofi�E .^ui.M�BrinumX sn� �IaSa��,io�3a�-�@�y%3�eo�kq�%�NyD(t dye PKH-2UYe#%y!�r�Qof2��.�:{ S2n vb�!�E9�� a�F� iJ*�B�a&�>�\21.�g �<h�&� Z �Ev} qWS'T*� � �"R'X щ>H �?}� (��%����=�ly-1��T Ep *�"3�2 �B �IgGJD^ � a:�2 E , 9��4&q � �e�"-Ot%�  mNFcv��'6�"-  �*N�����`rQV/>,.�Qa���,n?Bl% �xT h=�B�a��a� -S!�!r��6s�0��lq �r%�b*� M�z�v� �)�!�n� ^�,"Q4x !�r� �(Fvie��a5�  ��'�M��x�8s422��z�&���"5.�+)Gm6�+!3UAN�� � courA@T�, � "(, �I;&� e�noticeA>�] 9!�!4:�+ğ��!�N9Z p �V���3A� 9Mov�0S�Y� .]��R�_MN�;α�&�K�^�,2,�ao�[o� ))?� .�%�8�-d�"N+^�a[�9C� i�S3Aa�q%]M�^"Y�� Tx�u*�$po��ve�}*/��A:��filip�9B�4� ic vesicla�:�FM4-6�W�S3B�� �~!](R^B+ ( PK>�>. mR�>ni��0rom% 6�Z-�a�%?nde�qp��. mDa*�VE&Lce[r��a'7(f�3�r6&u�"�Gm�'i�ER��=�!nsO��56�of�~�#�% 5� M9 �trigg�g }aJ .}�=D"l�%� Cr9 –j�2|e fai� ��ul�>��a�>:(�5u-^�e�� �,o!readi�>"u zE{9=d�n�at: .!�p�de�Z+y fGD�er��6C-�U�G}K+&c-����? ('M�g'� ]2�=�&�,�8periody �"�0r�s�6�� C�f.7 �)f:Bby1�!�6�"M���&>Bran�&H.7fe�l�� c���aF�rie�..P�,-{2s%Q&S4�. 1,s'$�t%�bye�Qw ��"�!�V!�ob �� (Q�26��� �u y �7 9{���� n turn�)U�H��~��8u�!/G �A�=�� �4;  s#�l +��)�+9A�*.m�"��l�%��o1FeZR!=&nYi" �~-�>�#of�!�Y 9��aB�T&� 9�%%�A��C !��rm�4s�I�Z�@�6"#o��!���1s| 3P�=��Wpur�(� gQ6a3�s�+"~&"�5�%Zty�$J!2]� iAY� n�|᫁�.�I(< V�!n&4 S4�. S&@� two-diment0(al IEF-PAGE�!�6�4"c#r�poĮ �q��mݘ܊#s�R���H!�G�0Fx+4-s>9�y�r6�_�B� F��ğc� �ion)8].Z��T��3GE@B .5�InW��4��*�i_"N6L2Vn�Dg:ack�dnd*YAd.Z�a�"�S-IBio"�hcy>/[b GdQ� ls �k311�}5A412">�bye�( See=[�a�M�� S���"�4�1a]H8se���9 �����y�,ue& re mu&�Lala4# I�;9*�a���#i�p=�.�|�!^iaM EGFP4M�y�3:� wildfB&�$I �%�inA+Zf,�U!��� tagg.�>$2C�Q�a���) a~=u.� �zR �N��9V�u)�_1�!�CN�� �� S-A.� !\b:o� �&�EIQ�Fbw(!��� 1S-E w)" s="[C.��ji%(�3?yt>�q�-N.�%Fsub_��f�u��bn�8�QcM��recov^> ��O��Y�Mo�A�9�"A$aP/ "a�I/�e�K.�� (\zs&�� �) �V.�+S4�.]Alj/�F��-w9>�vN!q� ��!��&�&:nMF!w9�m�g<� 1j� Sa�!}� d rQ .:�H^�+�aat%�~�. F��tPK*?���"- �T��Z-�p pre-�j��VI3ED� !�e�*S1V�x Ü��6� |VK +����] omit��'�%O�� ��*�.�� �.o�V�;!�� � �_Bed uncl6�( Vn�in_v�a�Ox f��er= L�F�&�B�M�5�A�*��o� ,U�,"�fZ�. F�_,!�.*$ E�b . B��6� � �Ij!�2�*a�U�Z�(����j�l( Cor͝r*i& -to-��2@ͷ)�)�;��6��F2:�z�6e� 5�y ���.%"1 Ǩ[6�8 a 3-ch'C��-��Nconfo8*�) � * F�=a���#�7m Zq�"�[�eK,6��TDly"=8B^�<2�[Aout.�`4�"�d71��9�Y5E��.Ya8� ��;U-!.�Ae�B*]2��A4t$ D–:~n� .Rz|�Fe>Z2�U�%�jv,�.��Oi��!a2� Mife��"< 9z&� *)"[.i�B=2Zi�u`� ���hB*l�es���A..�Y�)�G,5XIH�:�5�n�)2�52��?sMu�f}�e�5��27�a�39].�,�,4�D !�M�qC�se�T!�e�q �R�<*� 11Ֆ�"2�F�rv7a��icER} 2�����9�-�|" �&cs�8���NE,�Po�T[ Z}�5J��@_$� D��|��SVpB'as���B"�m��m�h!�+*�!�!N�'Sk�BAB��R?Mx*W in��2�/Y�s�uunalt� ��"� >��qHo"5V�!"�&�m.Ŗ ��w1Q����*B &�u1L�"�N�3F|ᾡ� BB|�(i�H"��<5A–b}^Ztal���e� o)�2� �e��2 No�.W*!;%Q]�Y��. .�eb��Q~ � +�!ure 5��.6j):z2 ��F� i�cidup*�6J� 8 B�+mk*b�#%N]��;U qff :K �HB�.�:A cruc�/.2Az -�>>�=j��oc6\N NW!�-�����r�*_��8�M-b/�M9A>�8( SNX5 )2�T. IG9Nip)1��&�2LT�m�n� �3Y��a�s �9 blot}Z �7"��"*� �/w� 2� �x���62%&Q S6'#*.C����@x��2E 5A���b�Q�i M2iS6���u�b~��&>�61; �f� W1�A.Z l��BCCA -)�6� � cx�2�2@0:�� 2�#� �k>!��}kGX:�:c&�;I�i��I"i.�:or 3-M2$=q="iB=:�&ƹ5,B )�~�D��62������a[:�BEP"�=��m�At,B`!x:n� < ejU�*��a���ng�ia;T11�:B,=�����9�kZpZ.�&*�5�2*&6E7+� RM�L*)D� �&\-.Yb&%�I�>�$7!--"� a��+�99�to na2 R�1)��&�+x)�>�J�h5� ؋e��=Yr �&dqO ��it>"�S( PI-3(�J�@3]��GpsEr�%m�Wz .� �*�E�>���E�o�leU�!�2*?2�L\ *as�29�a.#f=L�1onX?AZ�U%� � Akt/:�B� $Ser-473 [4�<"@�.��#$��>Y�A�}�L*UNA�8�o�+r�BN!@7� *B/K* �.���Ih�Am*. &"�>�� !%>^+<W�T �6y�)L��!tEJ)�ofHbu&�d7�. Stri�S">��Z�"1O>�!�"6�E�6+ �2+N ,�R��FFBj. ]q�+��%�"��)L��a�ax\*C�( ∼90�a^!�e;N���*�2aI��V�R�z{1�.~��.� Zơ�.0~�*�Z�2 N � W>KTBz!2�Y�.�N�#5��^w t K��j�ne !�F�. il_ &E2�H�� �X;��, J774 �i�or �!>���*^aEkns%�6!� RNAi ( [2\�see�P� ���� G q� ?-�#�U*("� *CV�F� fJDto�M(!Si5 ��:�2���w6��U)8e�%>�]N�se)m-%k ���o�N&� �a�x -mJ�6gq8�LiI,֥�"]� s^ pf&�#>N�z� ��"��' �n�. o Y� �,�A�.�ed<k))� 2�����.}:�!Ik&R\"Vr�ȁ0-7:���p !��/*� r9�(mԉVc ��la�.�. 6�a�. demo F �[>&B.' UZ�9jo.�m:5X.wX��po�e;��Irp<��- ? b3O��NOH*%atn�� Ai!�n�nF N� Al�V"%� R �?5>kdM�)�)� s opMw4% pseudopod&w=s-a*�I�UMOSe�z� e>�a-*? �"M8RS� O���MSNX#7NXy� Thir�wA�de�IA�-0H�L�92[E���Fc���2X8�;!U\"eHEsVF�m-A� Na+/H+ ex]�X RMiM ade�cn�Z[w!�a&y�a�"�cn_K"CI:ZV�6�nonmus�6yo(MII�I, [47]��jx1�^a"��\"�")�%b.ěF�.H:G��A�z7.T"� B����� ulk]�W#leQ�y�&6'I�A��I��1� ��g'^'Nn exq�&� g[!�^m� ��cpյ -of->��.�1era�5bEt"Ya�N��L^�i��t�XjV�2�X�| ws �'�%�{amo�]I�**l\_A28]; s�)s(7omu;�]9&!g��<�Yw-���!�s"M_b*��u2e�16n avoiKZXE�altCfa(+t�dp���B�12�~��!ENYc%�I���'!� litt+��/co�57�VEp! U^;n�Piv��: [4�2�n0(eiv�_e>�l rictۇzk!�1*ic/m�c-� mayi���) #iJ��U�= � B�[5�@"=6\Ji��m24��%Jb�^e��&�N�\p)��5���o2%.�,org�H�Pza� by"24i2�\�&�dL6G�}sp��, Brua ��!�M&�um )Ar+A:u�wp \"yl!.�-I��a��>%�f�<ioX�a�4 .!�E�! >� "� .:]i,�4!� $݁m�Z!b��M:+"{'��a ��0$2��>2�a� MI �)& r�Ja�1R1���?!�7e�)��rk&� aɲ�9 t rom �gF ^�a/'u �.��i�oA�Zh��M�7�"e�Tz��( , [5�[5�dAZ� [  -%�cfam�;rʷ�9 ��!MsA�� �mdZ�a�nUaQ*�`�RV Au�G�3� -^�nd�,Q�|�&�!Q�Zq)?��K Z� 3y54u3b�1�"Q:>�eMh�2�%�lie�e�"�&/W��V��2��:�9tA9?�F�vj/ ��.PD�����.� �.l stru�( SBDz6JP� npu|�mA9�BA&D5!�$ |*�d%�,a� BJ��2 ".�A�`agC*�AC "�compongm .��3�-�*c: ./�_JotL  [4�Y5|�Q�E���-"��M^BB� U�� �!H�0���a� �Ke!�d%�Q "�o.�Bf�[=] s A�&� 6�j �rT20a�:��a�.�> �!���.C�&&�V�?� �VN is�xvol1]�Ӊi�U��� begiX9erj*t[1fxchqhN��>IeinI�ac�X� U�*�p���n�:�Q�3"� �%�crq�Zsl6�e�awm�)ide�XPX��&do?63 eIPI�� ,J�P2 [5{TaO�N-XuIorJ ` � .�]/�9�&�="�/"�Y ����>�de m=k2;2 !� �>�A� ib:to> -7�h>t )PL �{i�BaeM�%��4b�[55w :~9B�A5G9Zre� i&)F� *�5�l-]5�=�of_"�on [5�lg aWa�u�iK�3.M>O0a 6�b�A`64/� h���>�CZ�/b��78duVo��)�M� ���nzreV�6E ��3�]!"�6Q FnalsQd�o:�^�fx��~e&C Y&��#n�c�-�)+d%�GG;G�F�� v��mu�i�C�&�up�1�-&g� ���un%aulgy9� &V-32�9ʡ9/9�Sj� LC3bE r�(at ?o.))(i"=�" !�- �#n r3i� anyU �n�)bUS.D*�f�@��n )��l�OoA3�^J�iI]����"1#yJŽ>rA��5{ )~& +04meruQ� ocyt*���x�M6��^nS,�n�~�! ��Se�!�vi*.T6X2� ��T lymph��FI6��m-���jO.Bx a� :��mu���b���)u=� �ce� d:�q[6$ 64!�Ŗ�"�&E�&y)U!��"G�� �P2~B���nJ+G � �}���A�.�>�E/mas�h:}A�.y&& � �H�� �.���vcoL��X�S ��R� %4H��i�M�Y�%�$.� �8��Z�*) !yp`q�&�!c lA,i�� A",a�v��<Pmanip�`��&b�fu 2���Qap:=&B ��H�7��Oshuttſ.**�6Basd .�7.kms�>der�lb�m�knw"�4� Mr*�m�Ρ�ep��A�*�Nuw�un� � d�w/ � ��ϥ�$c>�"ja&�") Lven.Jo*� Cant4�l-StadtsAlic`}�`189�(a�*��.0��+ guiR�IP( Tierschutz-Verordnu5P.s)T� Swis��ui:la��LGesetz��g�;-�imm� ��e[J2�v ob+ �-(e�6"�$of NIH-J2-�R� + (�d gif�Com &�< . U . Rapp; [65,�H�=irk�b5y�a�Vagez���w% F4/8��CD11b7nQN$Yz�.M{�"'$��h�"b- 7$�IW�-L&x�\ DMEM89�;.�5 g/lt5 coses�ls*]10%@����ed FBS�*AA;��� t%�I2 mM L-�5t�v%�"0\( DH5α ���LBnr2��t& -,M . bovis BC�ZP�ur�in�2#-uH( My e�Ktr (c [66]!5���](NZF214Cx kin.: Wilbert B��r , Am��da^A�F��%�� %�A�o9in 7H9�!x OADCU�ich�ea��4 kana��5��g/m!& c�@�]5&%�~.�#Ot^Zr�e` R & P3,stocks of 10�>0 µg/ml were prepared in sterile PBS and for activation 1000 U:xas used . Phorbol myristate ace( PMA ) -hfrom Sigma , stocks of 1 mMF� DMSO�100 nMAnf6�p. Monodansyl cadaverine ( MDCFyandRmM�Bzoat 20!.LM , Cytochalasin D ( �)2L5 m%Z#�5p16@as final concentr)`�. 5- ( N-Ethyl-N-isopropyl ) amilorid�EIPA;R�!2mM�water�5�=Fb~ 3-Mez aden)H)�6�1 F`!Ƃ�BlebbE$inZ@10K2>��$Chelerythrj�`I  Š , wha`Herbimycin A ( Calbiochem> 00 uE.X] 0 n�/AmikaqVkjIm.j9�Q�(m�VtFilip%�Fluka:�Q�.emethanol%I%���, FM4-64a�8olecular Probesu of 2 �f�5҆FLCoronin 1 antibodies Z4either polycloa�rabbit) seraa)pdescribed before [40] or mono 7mouse6-cn( AbcaA. Oi�%��: =N'-aci$Millipx) ; goat.�( R&DZDSanta Cruz Biotech�D$nti-SNX1 , h SNX2 3 4%�25! well-(=:'�af*)c)rab5aA�N�; ratBLAMP-1 !rXe 1D4B ( IgG2a; develop!�(y T . Augus!�$d obtainedɀthe D .$mental StuE4Hybridoma Bank��,$UniversityA�Iowa�E'>�GFP�:w,Z� phosɶ-�phothreA�AYd)7 yros��C!�$Signalling%�d.u!0aa�$ti-Mycobac��8um tuberculosis� eroTI%b�panAKT� bodyf� v �4( Ser473�e�?F�8. All secondaryla�( SouaIn]�we�n blott!aYH horse radish perox�;@HRP ) -conjugatediVA�donke tA�� ,ti-i�or2(e�j��@immunofluorescenc��J�AlexaF, 488 , 568t647.�qG � �MEaC, ��rai� in ��,. PKH26 labeED�S gene�7.�tote�(ines 9 , 31� 356ah12&�G �,glutamic aciQ�0primers given�@Table S1 . RNAi-r��]$constructsi>�rEby �![�regA�targe�byVV @CTGGACGAGTAGACAAG�TGw�L!D�du�&italicZ$to nucleot� pres�M/ same�of human�by%| R|�1)iu+in.-�!1�ntAA1-A1B. deno��a%*�Ct�enoT ci�as2� initially �Amaxa N�fIW4kit V ( Lonza;� (gram T-20 )�!PNe�[.jsystem ,OlH4( Invitrogen ) t@prV0: 1720 V , 25a� Al1 puls���  t��rsor!)]Ha FACS Aria III ( B� n Dickins>�[)�lyeol�Giz�s�or expa ��� precipit ,, "Y �4flow cytometryP. *_al in!pA�>�as*U8previously [19]�f m&�KoculumJ�by : ifugqS-� cul�6in 7H9�x445×g��et"u � clumE.} ���2%� pelle���650dat 306in a sw�bucke�p��(*� 5417R ):�B� %}5l*� iY . Da�Y prior�[ %�� H . BothF differenmD& .� e�or�$5!�-treat]�&� 10-@glassB (aP00 �Y�2-e�48� plat� -colonE�m!c$unit enumeQ, CFU�Bn�; �2�at OD-<X 1 hr� �ed 1a>�� �)!�� ,A�g.� a chase!��*��:.�qu^ m�0of lysosomal ( sfe�he*X0LAMP1 positiv6C�g� IE�divid^ K�&� *� !Cmultipl by!�AWcCpera�ag� �Aa�6 2w �!�g���sampleMA�( �E�exhibi8Z8( �or5 ) tha�zQ�2}��z��ed> a#a �!]#�~�lsult s6(� some�2� . Reorgan��of*�ia� M9 ��N��[A2iimqof:� NedcuFiji [67�� In b -͡Mre%AR lq !zmar5iyaou2�+iaed ( F- -�]�,>-inter�fL"�by ��! i�9� apart&<!vtex�q��]TF"]�;a�to dete��e�6r1�A�"z  `subtr���!� then6�)FI6��c�U�<l!�R�corti�C�. B�grown���* '2:�24%ls! !b/s��&� �IFN-γ�TNFαe�20 hr�or�a�4,&  He$��*z pecific� { pre- 7�Xb.�,�*�,* *6f�CR3AH��r"� `�b!� . "8t< smegmatisd"=atG MOIa�4�2Y�0� z� t 37� �90�.2�$mmediatelya����e�s)�ic�ld PBS2p"�%w2,%�r"�( EM grd!�A�fixa��+a�5�o=aor "/electron&8��n�criI�ɼdryf7$nique [68]2�:Da Phi� s XL_ESE�In Fig�D�m._� fals�lo �AdobeX",toshop CS ( @A5L% Bone�Hrow-derix.�`� in 6 =1_6)C/� )�.Bmd��abs�ora f* in��oe���co�, #}�IgGOmannan��&�*�$1 µm beadE�r*�9D"_k �&�ed6RmN�oryL�A�� p&CF7��2iI���ycA�60eZun,. SubsequentM 9%�`Bfe +2%facolA���flushA� in 390.mW �Ab�NmW��腻$F4/80-FITCm$1-A/1-E-Pa�/ Blue�2 �on� f*���n�. J�bz ur� W 7AAD-PerCy Lifei� olog� z%J�x A�ens�� , un�@ingle�=� take As� �!�apopto� . -`1J staurospo�?3ś%�c����"a-&&Ca II� {ex�� �yfu�M>�zՈ0&� %�4m��(channel dur!���\A��E� �) &$-$� MeanA�&$^ n} a�!�b� up!'AG&! c� ��he� ^Z( x)�/tC i!lcargoe�5 >� k ha`~ ;(h � fix�ime��>R.@ ,��w"J,v ! 1-defici� or �feron receptor$,I_^��ځ�:O(a�P �g 2�XM&e .!U�"AA��/f c:�&��M��]�ly���bu� a�XPM HEPES-NaOH pH 7 . 4kmM KCl� MgCl�#1% NP-4�'25% sod " deox�!\.;HProte���"at�� (�� mo S%�3 )�r H�:�lys�e�<�~ 16128× .�,�)��!]supA���u20:8!F��p g"�3��"PK��aleʑtssay E:(.�� equalteA�mnac�6��in 96i ��me#��"o�,e [α32P]ATP&! �l)�ory!� C s`*8e RFARKGSLRQKNV��a���!&�k :[suW!usC,l�+��al.�)IP81N!�$e pap�*"��� 4$a scintillɯ�r���"��QA(.�αj ng.�)�)d��E@! }nsee�# E1 0I& � &�#A�c���!�_ �!, MotifScan2�0( http://myhi'isb-sib#(h/cgi-bin/m9_� �7 In p@ le� 6xls9#2ya�Scaleqwed sy . org/�s&)�e� �!st hyd� obic0' ( Ky .(nd Doolittl� high2ac� ibil1%Bj!f�.confi�$)7NetPhosK�16�s�Gi�if�as2pulv� :�by!�%�kin�� .��O? �&�QA@ .C2�I55 cm �&� 4�2a��CE*r !Was� wa�w��cic� �,��P15.�,5�#T-X��+m5a�� ( 5r-Tris-Hœͪ5��37��Na2 EDTA PMSF 0yceroa�1%Nton X-y,��05% dig�r&u" HALT)�!�%eZ�,GE healthcar!;tL.�poo0 D>�80"�)*.թE�!at�pas!Wth$ a�4� m fil�%cloa��anh �[colum�0�z�*!slink� ti/"� ser�)$o NHS-coup� sepharosei s (B � w�6M>E !�mM gl!/e!�82� e5'on�A�bound�(ZD3a�r��oN%&� (%7 5 mL��.�neutra� �01/10 v!5�1 MAF]�8(�i�.�1�2B" BCA ��� lasma gamlobulS/BioRad���. dar�+d% 5�-��ai�f>��e�7byqmex� ge �an:0con]�!8A/55eI,0 kDa cutoffE��f}��()��(%�two-dimeH(al PAGE�F<A��e�3Bromop=b)�U&Don 18��pH 4–7!�o�(�7pH� ( IPG strY$>�r�**�*�'ph 5�a MO h IIa� step� r� s up�3�)V��C .�a runa7L :� ʥ� 6),50% SDS-%lgel%M20!)lengthR�. I,"�A�.0#(by semi-dry!�n^3"� �.� membra]5Bi.�b�� , [6� �6^ >� upon�'��w{% �.)F�^:�b� �p�S�G"� 5EG�` 5�d84% Igepal CA630V�6�  @3% Na-β-D maltosQ.6%2.�&G,ɥ"� inclue%��cocktail^ ��6k ��$)E<2V 2�� )Din:w ��h a�(01�at:�)� . A�/s~�Uto Dyna�sk �\G���>,thyl pimelid� ( DM�/��&l2�y�� w�.s�>��(ni�+�%W.� S����5e� 2I� �a%Mag��.0$�!� �ge��P �3.�_m. 6j3m!eda���)���th^� pH 8�;%,/�k�doi0-�� ] �and��2�6Z(c$��26+)C�#r���.d�:� cShomy% ��� ,� �M�a҅r �9:uG eA���#� zF u�( A/�� , Be;emE7, Leupep S���T, orthovanaepyj spha5 , b-y e6F&)�-o�r%. �n9R^!%j Dou�5qe�10–15��ok�7:�,1V�6S�t 4I e{_%alN card �B���$t � "� � a�� ^AXlW!�% &��w� �� G:%.~��es non-bB[70+ o {� .ze 1��u-m�ui=�i�M�-�-#n�1di9��) -,2again)�� �w�V5\ na�0!_�aZA*5`J i.�"! � �2J1k�/& by&�� % �& �`.��]sJ1to�L1.!X*&mR�4.21�%�4%��$"�G-�e-�ed sa4"(B)%/permea���の2% sap��0; v5%�2 /BSAvmf��+:�72�(DIu$Dulbecco's�*� �>�&��&�! /2dJ+N 8� w-qNn��0��0��0u:>F,*� "JJre�.pa��2�&!�mb$+/− SD i�T play"�3%`+i�ofyq��s .�!���2�.����v-""�%�IF�"�t,�$.&s*"��jM@9 � �e8-"�v�).��)!4od�#B�� il�i|aKto��_������2ddE,of�$ equivaltoA � !b  I6%�disru�g2A1�li1Rlr mill (!MM�D; Retsch , Germany�N�71�dJ debri� A�)�=�8@ :��h�R9��i=.!2>i�6 ��� ��X % to s�%�0 moniD.2�.�Y ne-ma# N#aR J7742�dep�.!�"��x$siRNA [20]�6.�e�RNA�1�$Co�1, namY*�or1S-A2*� E 圶4�2b�&.��/�*�Q�2$F �.�#_9I�(��As��Ak�`"T\8.7,)�TrFBݿL v{ �"v "e qW)P#& 4�6�A*E &A��>�?,E�@ Y;R>��n .�[� e� rene` vigou� effortsA�elimi: neg�9 ropn)dis! aiHsleep�sicknF<(�4 Afri[trypane,iaa�or HAT�� >atv9 �XB mCcost-ef�2_/ ethoo%f tsetsb�6�JWest Nil.]5UgandInew�1 esig^$ins�4cid./e�6s �be�a�o��� area��∼�rkmH(V o9:i�D%t* vAT<wN>>�(has not beedu�"*�39 5%h!he�w��1/A4�t ,� their�ept;�Z; /�$m�1vWeXe(knowledg�,p٩�C L�)�ba2(��pB 1I�>hey�"or��2�W%�- sixt!&focus�upA�cusX$ mYafe M- icip�8 in en��=$ss Arua Di cE0DiW  audi�4�Ae!e���n�F.��^>a�%6 ato!tpA`!� view�� both �)e4y� ��heWA. Despit�-�I�la�&HkmJ.�#1�Y�0%��)U�)�ver�4�" (. VI�� ho)� ever� n�ps ��%ed fear�� xiet�Cd pan�,.Efi�;enV �khemE�is�� re)`toA�oci" -� witchcraf"& “ghosts���* r”�.cha��V ���� phys��fH�Fillel, dea�mis�.unJ8By�.rasal-�rs liv�:� reasq�r!*�%e�E ]�pI4attitu�oward��CE�fu�6awAGa�e� purpMA�benefa��=l�crI` rep�8F&%�} simi 1 nega�4E$m�)�i��" vl1*)� star�6a decD-ago�Iur�s sugg��~dY�ir�qxim� ,>f%=var�m�1ly betw�-{i:tA?i2>ajdu&a ^(&.:�I:�ݡ�su4!!icqI-baA�6�stO���newadsuc�'5� . SlF�Hu�<��� ��6)�%��da��FHAWin��I�p5cae.by%-�T"_a bruceia�nsmitbby1�fl2( Glo�*SJ.�Jx#gambienPi4ch�(cm m!�F�foFins!�CTPl ��) A�� aHr! i�@ud�0���. Tida�<$vx<rE}oAL� F� path�c!� live�Q�estim�o)Ls econo|?! O US$4bna� y��[� In`4uak �2� ,.G a raof�J!�Ksymptomwh��r"�6�\i�5t�Be%�Qth@��/" impactR�AZan���$!��4%7burde!QR٧�is�ty-adjus life%�! DALYM+[2�In��to�!�_� %� haveA�� tU=��o5z h�N hold�s.�exist��of " MA8��`61 remains�?e!�in 36 nt�?��  [3 ��%!�� ylac� vacc�A�Jrugk0 onlyn%j���ng &� iZ a��45I��G�)�Af� %;a�:� a inA-en �ag�mo[Domm��DA�feasiVBran�RPof (R! yZ,�k� &� �tt�!kk� �_�6n�Nl foci�G�~a��:7qd����re(bhER� � availa�!�h�"iL�H!��9�a�8earch [4]–[6]� i���)Ɍ%� Cm�o3 �pd0ec|+V� M0reducA.���nd � riska�. Combi� ����$�@tera� �xofJ�(by 2020 [7]9!8]1�Q�is emer�@N$na�or�,�1oŲ;sea�M[9P1sAs>V tech22ya becoK?N.�d A�erA^� %�a�, under field���s [11� mak�A�^ A�So� E�lE�Gle%k1"��� cur �B�a  2f'ss���is� !|a bigg�r� , evalua !�6�y Asu!3ayRa>M���squa'kil5C�n n�-wAdBoffaa�u� Guinea#smQ &N�M�i ! D�/�����likK"���ne� � ala~9,�oft #- X‘public goods’ [12]I��E" ofA�ln aq�S�extenmUyo�A��to"M=� ��nd ge5-ph�8� �.E���5���dec5)�!����re%&ly��,e2  ��!��Avi�� �#e��:���v�~pot��alU��� =e%��� re�(� 0is may be due%��� lac��M�eS verne)fun!�co�Q� !f.Pi�2Gbutk1��ha�Er� �� ��x�6exa9 &$!����stroyNr vKlis&{�a*O4!�,��I�b� qv)& ad�1�;6�=, � i ,�involq:%�e� %D�8�X. A"�8(��olvA/%��o�;� �:&.� ZQ� toolh-Ie$h\9���Xq!�"�%�in> v��hrol�UBC�*�� E3 ]-� ]s�e�Dn��~'origi�2S,WHO Alma Ataa�l��D(in 1978 [13�Z[14*= � de.,Mne\Lu!Hal ap] r�=��K.-de�r�/�1emphas�*as �O U9�a@ip)`to occug ��HhO u<aɨn�rah th2ass�'�kci�!5E�pU+ 1jof1|borne��%-!�principv� assuA sha��respons�1�<[z"�.�to� or�oA#resour,A� deci7A�power� �{h�Jo��>"�Di(�*[15MpSce how� �Sllaboxb�M���K=�Aac`1�s{4V?rc��:�i nife� 8.lR1���cU2����)G�p�Ii�% ispa ���9 �8�L]"D�it1�5� �H�4A��s!;h �K�0T�D�l�s6<reinforc�')4C�mut�5�/Roa����Aȭ�M�ay� blurT;a-40I�1�OnX1�achiev��Vpru spacj<)P �%z�7%}n�/��� � �� G��EhA�al1�IK*B�6k���q�KaZE#�rapeoa�JaZem�3� 9q�UQ�v�7.�ver��5Qi�deplo�!' enš��( E�, Kenyam, Democa� c Re (of Congo [2V 8Ivory Coast [22�EthiopiG3]{$Sudan [24]E�=l&7s�>^,UyR��'a cruc� el� eJA���� 6�� %��L 1�)�DRC s��A=at "f&���""�%EPd���)�� genou lief� �3vGa�H��T i Y!�')�ly&� al failua25�?2IHe,*~K�v�R2H&Y:��] took:��na:&sa�t*Ni i �caq �h �Du� "] -supced�H[Wl%�D��*�%��he�6 in or,��8 y: i'ac-D��� 3 � Nj!�i@proba&�4!*��6B�& ��Q�Q. Wj�.Q( � � 6�2' �I"�  F�F���*���New*� � � !�� b�?ommend~ se�policy`W �$���laXim.�6��HE�ex`%�i�rC�|ine$B.�� #}yAc�2ol.F!che fu�R�? p lear� ��;*� ul�{� �O� d ") �nw!. ; i��"`5p�Hdu���L�yէ nts'��V-#k L M�Re���csgE� 0Liverpool Sch of T" Medi ( ref: 1�W7ubdq�NE�3ounciIE�@c�&T&� ( UNCST )F� bSS-256�HLhUw tric� sub�2n�P dmin��autho� !:�� %f-h �ab�@!�)t1i8Mt  soh^Q !�daF[ G��b.��bf�S.��� k qu� ons; �volunt,^r�riR3toŏ draw���EW ��5 �wr;�"A.�~IR� In c�;Qllite�*��Qe[ger� @� �E�.ron~ a @wit .�5io�E-F� �� �#sto secur��a�X offi� a�he LSTM���%�proP  , �!,Q�4EBT���,&fZu"( FGD �.�7�j2V"( 03°�1�N-�A52′E- N-31°009#�A�$�(�Ki��[� iY?se-z~it�# n hi!F� A�lys ��V&$sB[28�Lugba�i��ved��Zeth"gr�#�O�K�J��mina�y Kakwa ,*X!��ernEw!�.&cl�ͺ�f � b���� popu�B�n�ni�Kly�mi'Gcrop-�Nfa�<ge�X �ms�-I�c�Bv� maiz� b�!e sweeQjtatoe4T!hco�l@hChR5�)a/pome%8<Goa�&�a�A breesS�P ��6�%wPpig;)n-Isl�]�&oS�Bfi"�K!�!�lt# s�1r.AMdom��cŔump���x%�er� I��A.g=�m�i�>201�M6��a.6of ��80�^400� ( un� �A6GRA#� A�`  religU[K@$ �!�Ch�q��Fth �{ngl$)A*+S!�Musli %W]0m�twoAup�5��fd����dU�C/��o^���&m���� expoeeWb� i�r�Xfd*.�] af�)eOE�IA�*Nb!�< i . n%A�in 12�-th%Ay��) Mé� ns sans F�hiè ( �B)2�a��2cre|qg � *V u �4se�!�co( HAT+Ep�M�!m �!H�@�)< ve�X2�/c5O45%��� ��(.$�)3%Z 8% !�,��*age=6 :89%U�� >�5�w��n�(9�)�9 s si�2�P(��NyA0 ; Omugo T5c4#e �SZ � �&�%K�(i+#t�(v$���,v�B��q �%ex�#�u!�B5�o<A�)�w�7r 5asA�3. TP 1S� char>NstX ���G&-a$K!M�Ps"  !f:�*� A�W��1EA�0!2\� "{, �5ZanI �� �Ter �@ maj"i��Q�a ��!jD�%$�(.:�� �RBe�EA{l�d�(by NGO�!�Fr ; 1990� a�r!T(y %> gP��dc�. A �5 year��rE�I*70A���n" P�0{ �s sar/o(͋1>#ysN!X�* )�ersm.�*une�6�Entom�Rs�d. H"�ML8 A@regul�(�2��n�[ir -"z"�0did B��.j n$%��� Trap-���<LABfr�T enoughA�e�-V$+ 5:to famil�z  mselJ%) �'HAe�:noe���:��s�?F���s �j �i�%duc!x�(b �<":(�R�Q� �%ɉR�A:I�,镅�y@!��.��-�k���n9K�e`�m��bn!�Fi� �>q�3pyramiduap�[ i �u;E=oTD]lCY>��A�\s /&bqt -iRru�j"}h����_%^�A ���ek��y%�co�)!/�'� j� 6wh� pre-)�#9�/6&�E]�r|' ��/ begi � *�0. N]�{�>� i`R�"��)e��w �AI�&}�noZ& �6]Ѽ�,� b)b we obE@��six L�L!RV���Mc�ł5� �.Lᜅ�����i�k]CSz�2&@:�Declr WI=.chs�exwhe�2 id,$��a�">�le]iif�y)z.T0"� ��arVd" �ho:�d0)�UtD6 guiC��uu pret"��al�!�f*l@ref�CRXS��P5��:!4��,p�g rJ.j_�3a�"z�s"94Qalk!��** free,[ q�:A ��cmal����4e&�/Mvaٞ9 3sw @]�kom:2&�M�. O&�, A&�H�}FGAJr07 crui  j&W);!�ge ( olO-!18�7�be P��i! t.�,wit� aP8"n.�%. �%�&A�re0mee& 2usu�*�m"/2�{piP�RR�.26V Ꮕda DuUi�Uin&ndW3ultaneoqkeA�4i�BEsh�a�*%ora>lm hG �x�FVK5�aL1&as��:�Yacator/g��G r/no_6ak�UF12& �6fluin�N" nd����s�X�' ��,a��.��a67xg�vou"9eA�AZAۑ���2��|d"�7inQ@%�7%� Word docu��sxAB>Y��s��+ crip��(! ��M�Is-che&�tdYvGby!����A�$ac2)��U Yu�A2�,"�8�,` read ��saxleP �T*8I�"��nd/YB nd u2X���8%�yo;o,HS1�aZnd���B�� )�c3 nex},ep ���\(:@��odj[~"��is5��man�jMAXQDA� Softz7[2hO#dPcoAL2E���?forNi� 0egI^� . Ezt��!CD:ma��I, ��c)A�*�MVK� es�h6Cx! -�y94C^ŕ��k1�$��&:�UU' �ew� �7meaiTd���ty�>quo�nA�llu{[lE��IG2Kr�sEe�w��>fR�g!Bez:c z . In�E�all6u�BY>&j S�6� [j�3�#]d"���[A�9S �2i��2A~� ~+3' sifyc% jwgor�K �(��, wiijofi� �sub 6m �;!8�3u�0�;a� D“R $�f� <,ly��gn��ai� � nuiss�8|  ��Zq�� e9Xas�0A�r*�avAB�)�@uth%�!�lveFAcola��)"�)�,��2�!�o&�=m[zaro�96FBA�Y}roud]��A"�+l�(� hnJ9Kh�� �%�Xy�Bxe�1{�4M�o�0�>!io. PUs V6�^%@#)Z attaz\ )?-so :�(e[5 a1j)5 /m 25 ja��+��z)�I�w"$#=7!�ondA"�O � 2�" -�regard�#a$i7E�stimuli��2A��J~0&�oWensuse* � peak��ie!�2�:.He/e�r>�� P��.P+E� � �DyfvE;YDiY� v% quic<��& PI��b, E �2[e�TX��retur�n.�am.sQC.�a���U�%DM�painfu0[�&aMbl���1�pr)f ergic� ��,"*ha3��Gs9Sa� itch�:>;agJI�naZrv��ù(to8֏Y rrif�i)��� E�k@�$3|�,�M,)�!r5̅V.c%/�.;e9g f�Ip��v�~fZ�$-E�ly���Ra0H2�UN%-se�unK$U^A\b�6�/)~� -��6si�? /-3!-4E�f�A!�NF�oaK$.�����suspic�a�)��_ U un�B�few6� �t& urio l��Wro;X( J�Ao angr 1o�MQE-C�p'{ @ta>"�wA��'WW � HDE1B���'�hEZmR0oN:nl~nFM�%|!a-~.��� �w& ��wq�E�� l&�1���: aps:I1�� o��A�9ڡW��wa E�kappea��G_t utW$�6p!�%B :} �cF�W��H.�a'i��%q > "Ռ:8.� �&:6uofa�+�� saiS�GyN%1u���iF�-� e�E: � �L�7�G:**�G�a� !5�0��.�sm~%"yO, �?.6�Y�� n�Hmm�%�AE�� �� tr%+,F�]Ive >xIYe*GdX���/�'"�/@ %}a32j:)89�� #A on �6>%SAif��~.�K��I?cQ5d ?I�i� ll�.��G79)p���IM0wv "��< P&K 5�i}��7%X ���ed� �n���w�J�9�[2 (A�2J,!A/, of\.2L�acth;l ALEKt�"%wzW >,HGa�9L��d*;L��.\Wwhh -�Prs�oP>E�8�y! � V6� yG�� k q�ed }id�3!�-��[!� ouchps&� Ars �g. W�]6� z C!��D ���!�d� *3 v�;a�n!�a�8Iұ5n2�!�AQgalway < QU$s� ic��(�o��sk$4 punish�޵OB "E0S0�� t�7im�(o;$s 2+dem��ate: R2��)>,6����2ing-/���ot�YI57 �!U!2�2�"; althoK#� 1ep�.u�^f�#l6R2" � ����4s*� �Iw2��2:XU"rib#�|E�)*U�� � � al�y �>ng!: by"H1�-�� -rA�, s_<*�4a'ng|"q�� Mr  t(�RsH�^3 .^ L9�%�"g?em�=E�(c  a E�� � 9�>�NF! ^o�a6P>, �n�M�{ !"*Z'-���HV�� ��es.�^�s�>A A*� I,�Lr?@d.�<9'!� !���J.�$3*� s7Jx8E�=H� {I�� �gny?oʄ g,' _GE&�x6lp7�6� . P"  '�.@)eGw N��&V:�y-*��>.l��bb=�XM�i� aN��. Fm9��}��i%� �%"�I� !�re�i�~3�NV�"G�&R�~���c `-5�e. *Wre��z"�'52 %&�?%��$��)� !� R? �"r���a��ɏVCd �)���'s��HrF!:�S� ���~app�0�a�hk�o!���%OX� �\tT��rea}1)� Bݗ!�0 so �biae�AA62=dI�" M�3:'I���JÌ�BAng&@E(_&!�im�A c>$4 Bty-�6})g� ��li�P[ 6� K.��R�:b~[�'+ funda�al bi�+%/�EEpro�Re8<� K;�W�}�pr�9[Baa�cKME!��� �LpAj-<�2�n &� F5��Ye� �G� %Q y?&�=!��2��o2w7tre�*  ��e�"W/�(of)9Bb 1V ��P�?Ac!�!@�"/�_�G�8m8o͜2'V�kA�k>5_e0Qa!esw � d!�M�`!|�m� 2d:�. �]*aDor�eM,/g�d���o�s���^�rEp�va�G!�i�4.��� ingu5�&��utc%Xof meil6�:�"a�b ��>�%@"�C��M��5z!�pervao?Hr2F!�sex?Z–V�* E64�4bv� I�JF� �h��E�ic6�q��a�{U�o]G� yA�"�2E � [# B�� e*<T(� �graT�V nvira�HclG;F-&'e�� Rl m| �.if5r�_h5warra ?�coMc�[y1�=5\� uJ"� :� &��%�"a �<� F= �/8Lv2F� ,B&p��Iq�ل, l'}�+m�@ L*r�m?�� )b�H8I=�>dap�o�� ���߉}.** Cabidop�dhalian�@Sac� omyA ce?�sia�nemato�b�XA�25] . �s�K%]�h���,�C`,�&a�f��% � �F�� � 9dB� :!Ow�010�d,]f!�B_UM�]no�[��&[+6� � ���A �&orA��Ycd$��2"�[��F.6i�e%�,���iz6.�e�];m�6%H �M, [26%�3`S�^d �% '� � q@� me���r2xh�8ed ei�%mw&nm��1 d~H GIJr�^(@g .�laenorhab�Zs�Lg@[33�S��Y�[32�N,!h�<iN��/ek�t4��R ory/QI��J� !���in 1�0.oi�3U26+O["3Es:�!%customa��Td��"B a�; omor�b:� 6u�i7�-�Tven�A!�ec`*ev���@�(** 1yJ��UD&A .���:D .6� , C�Al)�, mEm�1X@�+,e"P"4ӡ&Čr2q��0&�oaie(2�%�,I+3I�5l�f�a|"�a^v c[3i%44!�a�aE�.�vq�� g-9D�Ne6e�uO74i(R �.ils������ra���k^�AL3 ��5̄ir4x gndx ( DSB )%�a�p@e"�Je�se6�.Aj� e}�or��C;M BA�CO5�* ���!P:c�we��GCiR֝t�B*� MAa�& mw$e�rr! ?v{5�<S�IUR)CO2sCul�!�"<�ofS)e^t� �7u[X�� terr�s� Z^quilibrM�F ��� �˔�Wle�~�no� �*ZL�~K�� �t� GCC_A( %�Zt��t� rt&��Bs [45ea4/JCor<-���.7Kndp6�e�rimN�Wte�)B� -��S!�!��G�-!�AAel�y�b��D��e�7 ism�aCO �r'�!rox8�x6���.8�GCGoverlo>&,��p4 �$ .ك� �>ee icu�A �3 ��e� ed� . To� ev�[ �s%fi�7� w����F�Rf���oe^*h>ofF[�M�A�A?M2r����C%�>�"yen�a3��;"d�# ��dterozy�B� :�m < �s�.��vty �A 3 hy ���gen^�2Pe6put Illu�s���e��c2p�h .��mRio�=t� EPuB?�y.�WT( eIa6��2�%�!UT d ^.g�ap���OsP*��&]&ŴaQalFq�S!$J%x�D!���#Os�asa!ora��p,��EgW �c t>�X0j . O0Jl�#m>hSH��!�)Q�S4�49z�00�?0^ve�pWf�+aBZ0S$o!��"�O0�/[6�-'(!9�GC� �g)R�d5M�@!�aN3es�2�aW� Ŋ�u0o( 8A83 >|re"�ilG �NvtIާjEh,�ab` lin�N , 15-fol�!g!,:�ma�)6N �" 5Pn! bM�gs [Z�Lm5�50 p� S w�QB�2h��in'g8� .� r � $briggsae [�[m A�,pseudoobscur&\?; �i!X!�w�A�e��BM�A(of 32 , 511�MV� e�u-toA�e��B���2�":@� DuU���*�f�rfFn�,� &� &� aT�j 1y�im�COA�& [�n�$iguQutO�CSit>�+ a1 .Oll CO��7D H錁B&"�7'ur5�is 28� 3 cM�"_*l5>p3g�:-"1( 282/%a�A`.�a"bx �QfJ�^_( ce�B2s�2uJ��<9�S,Baa{ E�s�4!�*,ce�2}� ]�a�sfvisn�trd1 Ie495�oAs-��|c!S�:l�.J�  te�j�PAL�Orom�w1�� Y���I��It:�do"L]�eNZed��seg� %uwi�!t,Dasm�>[5�d�u�p� de�%VrtM%�ec�Aex�al6/5�6��?, [55��[56�`ou��h� !��~Ifin#c�lAY�!���� >in�Ice��U#A��o>jxo�.�j �JkbA���b�a���i�,5�iEeM�6� !�MwY1��5P<9R 0001���Q;0(VD e�ll.�eI(�ep�MH=)w�� to-2͈&��*� tr2�yabe��6� �'��a�8I� �u�lo2<E2s: .�ig:�,�A�e'vshortn=t��a�sj&_dja!�!�(-kb windows]!���5.( e��B�. 9—16��Mb�A�X6c��fng�-�&aW�QE�:�. M�,�10� �qbe��in���y)�!��V��)w2st�cD} l>K�k�VYi low�)�.�k!� �+�1on1��8!.i�]�arm 2��0�7DFN�6ic/yK.� �"��A��B\ Y/:�!A+cRre��i�Z'rob�!�y3a: 2�b��@Z'�a9"�}f��@&�Q G�]ood [57Ś60�T*Kd��T��1!�f��Ic��x"1=> 25Et>��1% reveae�  d���'�<"�96m�&���.Q�w�8�H[ly bQ~>4��)�w�G�u�M3o(�(-g.>�Xes��a��"8IS��!�*�E��� @�.D:@s��F��� magn�4A�,�on"��`P5 beit2�,�>r@mX( S�78man's R = +�|45X � {J���j{ ��p�R)�$olyge:aF basise0CO:� : EWx(nt EY*.I�!6we �!� ?8�i��! ��dex!XDis�Uion; RC�&t(1�Oj&~y�&� F �Iee�bgA8�Xa Pois�8� �>�0!�a �Bc on ��  2� .Q FE!�C�4!*hi.7#��_ � ��>6 ��_ s�aof%UF��)� n �0 107a�22%;a�!lf2��)e�/aZ�� m���+a)@!�I.)e�r�vf� O�ddU � nAC�"a�IaEiV/����mde��'2���U��9!uP�L�/lu;ab*0 ,!�:03L �Zg"� :�242�p" �5�ww3(�O1}�&6; f1���r half�%�* &n(ca5�#���2�}%�-0�W��'"�X*< B�DbeEim;�[I�)"׏ �)m��� "�#%��,b�&= �� � 91�z�q6#9R>�=hr*s�c��� �edne$ N".~&.E��El-1M��+P 5�Iple�=A�Al�_>�*mot� .S3M�a��% “ esMr2�Y�. A �)�:A�9a�!+�E:J*&�B��\arithm]) �ll� �Cg�a)aiV+%�"*� Mhar�^cnaMJba��ou�(S��rVp i �*�!m 9CO �~fQ . No���<&gZ%�.E�� Kur As�qly���-�A�me7*� inC)�"X��"C_t >� a maximumw$lih� algoE] [62]A3�lh,oơO�<Z4ţof=) ( LG�2�ia�"�W =e!A6C!� A C% ( γ�0'be *B7S."� : arbi�B1.�Aj� )v�d��γX�!�-2 �−7/bp/�me G�d 518 bpn-�a)3l >2#>� z[ly&4"��� �eR.�&COL��RX� 3R�X�$ve�E>�139� . 49��Z�)S! (( 456–632��R �GCq�D ;�j&�#'�C����+Z��5M& >�A�A�A~ K]!�b6j�G106�7/B�ros eu)B i2|BbX 6�+t�r�Yazoa�Q$�h�6�[6R~67T�  � ��A 9h��ͩ�aG�!� � � .II�ach!��–[6�,In t;e0ab3��t+!{¥�18�/�C&�&z�sw�s c∼`�0-�8Ja[66��u�X�9��γ∼A�2 :R�!(��:Z f$he��"� �^m�~�=� Q��γ!��17j�� C"�(a,Ss��Vi�r~i�m� tio GC∶�∼83��} A���~!�"�M�W&�sc%LFٯ"9! f�[��!hA)�}&}����wge6�8(M�f��.��(��).�Lc��.735e�Q��'. A�ia]a�Eo61e�@�"� �WL"n^�,to γ-His2Ave molt��ہ�S*�!on�Á�� to�!)&4Tf6�� SBV air-de�<1�+7�<D1d~C>� ��m8&�4�yu�F 2T@2�e?��2� ��7�&Y���J"�asA��r<�"���J5 :�EkA eJ �"6���#U*!f�e��cS �6�4� Y�s����H, ��� DSB�or -X,���G)%E�9��ing)��%�d.FF�VAO��~reAr makTC+���(�#N � f)�99l �PC"�`�L�tr�to �r+!?L w�x��th2�ndEN��sAr�;p  \.GC �� p }2�)52: of�XF�*� ��(a�re+a�6P�.E��`!Aqj � &pΒAt:� �h.�5_ a ] n 80���8�g%2�$g��aa%`agH����w�A�>CO-n,2a��H:}FD�cZF�-�.� ��9=�"\0E+6s&�H)i����!��V` %�e�GC!s�c*%� A~�_("fs,�E�)����]/eff�+��%� ( CVa����f -�^par�9r !a�e�)-��]�_.K# �+�v� �U_2�61�! CV�3t �!g�r�/%\E�M[) %T�i2X%�(+c�,Be"a��[maE�%�rk]GC:e:z�Q?CVA�>��l0!�y 9A� . 37 8F� :7h*���ru��gVg�&�=��>W&] ��*� �=o}jwa�.&#:�#EIE9=�( P&�"5�W#n�"!O�$..Not�R�7y���iU !�m�,!��Iibe��:di;5C��%�9�,e &�" ZFXEL"�> c�p��rQ�3:o�96�a0ndQ�CO����!he��C ��lt�oB�F�K  �FL�.>s%duplex*�!(�K �.{-;"�_ZGA�h!aFyP�( ) :C ( G )�m�(�Ae�>aNS ando�A!!�@lp��.�׉�=�&�1g:� mi r� t50;"���H0&zGe�C2y����!� ?�{s��UhipA�P�6t��( �^nyh2X0�� A�G+�-n�2Atnon$gDNA [77�[7�(In6�<�D'nou/A�"` & #+�o->] ! 2�=A ee>d���_^<i��_� ( ulL#!��3Z(�%�5]� ��)76�:ph��^�JA�ŢB��a�&�x���=K!N*�4[;*�-)7��78�-�Ga�I&�B�"�B�. %-in��iS�n�"B8�"��_)m�-�K� q n��8a � �D!�yx�lE��w te}�ic2F2�"03�GP>�"���c?(+−!041~ -16��An.D0�>a� �r%j��z�@s o c�� �5aj�iN�A���mW n� -�8*�;>+aB�E!�N\Ak>?"Z��c^� �  p6-SE�(hX`R���^�y Дb �� /:����?pa�:c&2B���annA_."����N$�!j"�E�~"B)CO�H���A2-# AwGb���"AA[r�ZexA�[�?, [80-81]%[�de�t]�,��տ}6�V&C8&B�� :�� vhN�TVHm&"86���m �qp ,"�$a�909!=���701, >\�m�r��bpM44Z:GC :aH�B���<)� �*� �n!��#��sur}hafZ�1%�10X� �F�(�6#7�&ơ�EU���I�.M�&���QA�$8�4��C%>� J`��( M%�:`52`2 6 )�`�*�%9'7'� >�� ��;R)��%&80,t>i>5��~� =5nS�. PmD&U��4d�4�7fJ>a:)ɴv��"� j� �s�Q�Cpe �,a���=�CACAC 1CCTCCCT@CCCCAC1.�#�erst*e)u���qġ�4���CCNCCNTNC5�-KEd� I� B:"[ s [8��A�� �".B{)���AA f;!�Y� �2 6[8� �)#H� }� i�mu�Q�*���"�(-�a�1�4 �sL�\qJ� �@no� � 5� TGG�as �F7G�js.N�� mammN=�h���F��{fer�PRDM9S�)13-mer:�)�dYPd �_via�>zinc-f�� array [8[C[8� !0���!>+*���3in 41�IH"�#[86�.N�)� ��S�'��b)��{eZCш� w{nD �"*-) ��!d�#�|"m$er q6�� Dw�H�<&$S� MCO4%"MCO16���� ��4A��7-*� SU�ӫa:�-@E��� ��E[8M �" Q ��L[a10EqaCNTCGCC���o�@�&�a�(6QA.&a�� r=��?f a.��%�$�3 � [CA]�p[CAG]�t [CCN* ' ( j�stret��i�I8�\ɍA�>YE Y���" i"IH`2on-LTRnspos�el3]�i� i>�1 3′ UTR)>��ly-A ?W�a�'l l�E�e�[A]n-�-TVa"� �� >)�� 8erR500-bp%�5�?tH2 ��.� uM �"� -�N�z�!F�ly.�.� CA di]�(E�%�MGC�1a�i>���[y���K[( T��E&u yu["�H.�'�nHEl �$:gh/� �� �2�&A7s�Gi@� Ɋg-Sl �+�]E�Xue��r� &���K�)�U�!�I Q��*�e��)B�($events . T�he detection of a number ( or populat)�emotifs significantly enriched in sequences surrounding CO and GC events indicates a fundamental differAD between mammalianClDrosophila DSB hotspots . In.,, our result�ggest3s occurr�pwithin larger genomic regions� high chromatin accessibility containK%.�stron� link�0than other eu�:!f�?able� . No y ,!�A�CO-$a�notAvependA D. At a 100-kb scala�$we observea\4egative correli/�γdc�tAnea�nt whe�3 alyz��whole��e��s ( Spearman R = −0 . 1246 , P� 81 . 6×10−5 ,��nd afalremov`8telomeric/centr U�(Bc191:c2 c44 ) ( Figure 8EA!�(is physical-(!� γ/c!_Tio reaches values >100) c≤� cM/Mb��nsist%(a���A���:�/c at�ڍ�X=[B�[94��SA�al hypA[� can be pu�L warda�explain�di�,t landscapes�;�X��!B{��a�Diverg��<repairahways�~b�spropoa�i2T�R$yeast [100e�10e�%F,a synthesis-Y�strE0nnealA+( SDSA ){U�}� only UG"5, while�res�(!n�doua�,Holliday jun�( DHJ )%h!݁� eie�CO��GCYqS1ErT> �-�FJ�B ly so��e a �of �,AGl%D�:�Ze�.� lack!,�e!?in2 Ū%BmayA:bng.i�5�͉O�<B�R creaA��-c�?���:�heJ��~�see.�arga�againsa� e op��!# very6 5al dom.IDSB!Zat�PI�s a}*paE��same �I�F shipFJ, togeE E��)?��verlapA a:�y�!Ht�i! above ) ,Ya sha�originAnd thu� 2��disparx of> GC%��j�7^M=" � 9Bce�A)-ve��of!�-x1g�e^amversusI�)ab by a vari�':mG)� decislE�DintermedO s-�sol!�toa<mB�produc ����e� of mismat�*d fereM[�for� o�=$d/or exten�of hetef plex ?�dura� mito�@!�mei �o[10 -  d��%u�sHCOs�a grea�s�a9an GCsR3�[A� ��i�-wide{ iH �6x %�in58&r s��at5@1�i�F!?r�c CO∶GC���In agree< E� �S(he rosy locE�F� showa- mallo�<2qMV.�5f,polymorphismA�27a1!�5aA)I| e�� < wm 6?� virtual&8 ( 23T8T�) [66!�I� is t� cy�rconfi!�.�*�)��i?A/gin9��}�>f *� magnitude�lEZ� DHJ/�`}�U%oa�� am�!�a�GCipJ�f � iEzygos��c� favJ},aTGC �x![-R[10� = ��- �� $ , nucleota"@ iA,n [!�nw�inA rangr_ 7 005%~ 7�" to8A wis6�per bp )E�s3�"�U% �A�� , c!<γ ( P>e4!� �s�o t�!�po�la*� ��nw4v� ga5NNU %D�4 �=L. ( π K�i�b� adja��� �"� 9;�M�� ials%kMethod �Congru��%<i> aJ��choicE��SDBS��o�'AEECis:�*� _��s&9N-)#π�%}E�q�B 5g <1� 12-M>| �\ 499[ 6Wa��v :� [>&97A�;8>�>.75.S� � ^2��� �L0ly�s� v�5���s&� �r[ ng�haK}"{ 0[semi-partial21r-+f63Z10A&� 2E!>J09J9-�5E:� nI!-ItaE'i� �+ng�"notz ��MDd �of!�GC� trib�'along&� es� ini  us ut modd"{a�chiasma �� ( �$e “count�B”� ug�-��nd breakS �l�!4a fixedorganism&�" m� f%����C&*)l�Mneighbo��3[10�107!�A l� � y Aq� lude) e� ��fr�� lыed�Na secon%�)i��t subje^o6| [108�a[extreme� ��� �2��U=FFy v�CO%�GCoaerefore�TmAEba�c:�!MR;a�AUa mN dynaonOvol�*� *�zor *1 m�����*�h� �at�,�� $much lesse7 V !,� ^n omlyy�A�E2� . To !di}�N�q)lo&�(=16s����we� f� ?�e G610�avy3delimi�by 500J or� ( CO 2500:Y��fsIŒ�M�)4E�erm��genic/"H s%� a2("� toAu!$�*i i.C ( P<� 0000 �10A �V 2detail ��ss� most!�u G!#�����pre�OZ �&� .� |)�A�� A� voida��"� �ɩ�*� lBl&��loo�at �!�9�=�is�2�!�6a *� GC∶����uIK, giveA�R�)I+!QeA�"� t�>:. Ove� �data ` aTproba���MIannotEZW scri=al uni>��>do�equireB<�4v� bu���!Lbzng!,2r factora��+� ccum;of:t� near�mo~Qy. A�v8,:x��adl���struct7,�&����ihood���ɱɇ&�%N (��9]E�u,}er��W e�ui>] >U��us��5��� AA�e �n��i�bofm�,is +910 from:��S%Z���p#�hifE]���ev��!��() +556��sh�.�to +3588�4; Mann-WhitneyuU� 5�192N^ More A����5�M�Mramŝ_isAA�&'10B%�a�cA�gI e������r� �����is} i�C "�B�M�*��� :y�i�� rough �� [6�l" �4�!� del�:r� e�ed�F�!� a�i defi�6 �a4�.�,��babN_5�io��pro("� N29 p� nder�(E M� any �ina3!�D'�� f 1j  ,�4Y 9�try�o A1rol�}Af:=on%A� mnn �lic6���u�����>��. &�!"p"�(first coord*"ed�$-*V eukaryhpi��� �!�*��%'in:����"is�luisP >m [ two outcos_F���!�r� �GC mapoe��b.E � !%Y%�B�mk; ofK pe�ob�$ n� ed �! ol"6CO�-� insigh� ra&9I =�of 250� �Q e ty�B'Ade�&�"F�re a -folb&na��&>X,�)�v?#6+Z-�%ET ly p4u^ m�rv f&-%� coldp&� � trad�:~&"r�#r2�$(�)�[2 #� s�$� >�$%� reve, clE � �� �Qg%Ghuman�#m7[11�11�H�hh'!�>� ly*� E�*+#E}A# tric!�C�NAH[4[8 8-$112���=, 9(so�,�"4 s~$�� cret�"=!%�� ; B���-� (1�( i .O%�F� )) �@ � geneous.��8[)�&�^�i��e�b��&hasIY&edZto5��ens* !�}� V�inaP56sm�"f�'Sc�ifier�mmc=��-#"�&r:[1.&�Rr � litt�s known� u* ir ac� f� encyJQ�������in�Lal=��Al coll&+�� #>�mS�I��e�&a*��Znu s%&��KndI�$C�se��ct�oYB�6Omo1�A�d8 k5�F��BF�.� ��m>��6~am��O)N s �>ACO�at�"9�in(sampl�$!� �!�emphasiz6 �!ed%8�!��T*�6�"�s�%�raah n!q�ng! r��',�0�� ��h� . Ad�&)E.N�f>���j�!��!�apg%��E�G4 fu�cap�W2relevant}sME� neutra -��( e�AZPCb*{Y�a�s)1�]Hf>b��2'�"mut� -ibalE��Bi�-@._ ��'ec Ds� �osri�"a��Ki-ysca� A:sat��fic���`�ex� OB(M:t�'a let�.o�E���| 6C�For cis-�W ��E�ir}�m b�H )f!�� d!��+x�*![ L g< U!1onver./. alleac� : @homolog� � 7'y#� � [114], 119]�SN(�(ste� c&` & zYed)�e�xll�ow�Zas&6 �? Yu,U)E�drift���� s0��iex�*ceB&t t6$2 nom�"O co�$���+,&1dir� implZAF�t9AK+��D�� �W2$ LQ�4Z �tena+Yi�Bv v9��F � weep�ARhitchhiRB , HH�.0124�.Se/J�"�/%Vvost�/��Udeb1riA��;� o�backgr� �on�BGS [48}+25 6�i.�#E�"0�s w��ope�n�'�u�#f�e��.[( c ){*���oonq��c���inkaLiu( HH a\'�).kBb ��m+%%12�g prev%UU�[1� t09%"t02c 127�30�~ a�vbWo6!*�2dQ�A�&b$2�#t��co�3Q"�"11;"!!56�B�!&K011��  Ir�0��}2A-� �πaW9�\� *�"�497NV� � �!��1b%� side+*m ��^b� inv#p�  6t�regc/,- 8l�ᰙo.� CO��embed�� ,6E o^�( wT�2llxG effect� ) w'mQ !�.�e*Sw�2v�*H*��.�3��ed"�BAa�x��ami�4cid stit�!{� �EZ� pkd�e�2�� adap�#*� [13hW&�2T"�im>un a� ]�a�S�1�Oa!'!�a�)11� �6CO{4e%�}e2T4eo pla�,�iml5 ��in.e)ˉ<c*�6� ��� ��aZ[4�����(} &z7is�k9� "� � stud�of� e�.5Uat">3ly� �. Nes�w*9-Vr2�environ�+� #&6#!�&�inf) ticu�6e/o"nN�"& ��� �ex�2Űe�9.r �&��"� � 3}T�$�K �-synonym�ɻ� ; be> adeq7Y�)"�>� flan�1|� �0ge8!�v�J/a .� 01AB�f�P�pF,�r� �� �bw9i.ex� )%�B�.)5 reg�ory=��0�K"�!�I�a�^%)S�a�Y��0owe�<hsAd2��&D/)�no�|B�:roAorF�. Cur�9&� �c�.A coales�*si��/E� v�o�7;��pru�� ��&F [132�|%s�CRwS6 �ns��2"!e��A�γ�&$r add flex�<by��lu��!� ?c.�,]as�'!�E3���6�&��a>% "� ���t eagY r�QA �: R�APalogy!= 140ur�RN� af1N-"U �tak!�cx(����ly:�6�28 ongSe4�ls ��es)Ml�<corpo!y:Y%���aji$���rde�.2��&s!�3 (N�&� . AnA#�%}intriguN �.�(!�l :�!� age���m'I#� ��La-^]#��#�&+@.g>���2��&q�.$CO�t n:��`. U�e � ariog "�� �bS/A.. �%: or HHE� v,7�6 chan!Q#"�(z w# turf6`#�d@(of fu|!���s!"Ek�"E%Ayg?. Fur�"�� nee( to/����aer�spa�A teh &&u)u�iead Z)Eqm  V��� stocha(�-�v���a�:��q����SBA�YonF�clu�+R0>�)!+e%$� lay8>� 6D�H> :>8�v- (=���E5&�a �8� � 6�!�a�&�'. Each��;A@ '�B&�A 2 shapasV! ��'� [Y#lap:,�Y-in"�-�M,&��y6A��,C-�(newQQ!�a"�Dge�E]UM,!8:c. W.�6�12�1inb��.i�fB�e_)+�reoly�A�9a%lab�,� of Tr�BMackayra�� *���Ral� ( N�5U�=ao20qX �;ll sib ang.AL�oIa��lh/6�e main� sub�)�-}/phen�ici�{"�li4 [14�>[1GH.�u� _ pro�. are:& -208 , -3�+-30�3-37�,-38�- 3�@ -514+71&-786 a-82W$n"US5 mEY)g MadagascaoGMDGm�D1f%:2carri�i?1-r��@*�arm 3R%9� �/A�"q B�A� H%�:Mexm�I\!z�I �8e�h.E��@�d [The.�%P�G'Hs PME( DPGP [�DYA:?G�E"� Panel;GR;A�!�N�th5 ,K�u8q�i�Z� RAL��,Dm=Illumina�Cd��aM!Fd %�5dE�> ur.M�1Wto ge�|�uX&. )pe��@NP ��Aq�3P�pQG�Ctr� �!сN!�[ l�e"�=M! us��&\"�, "�>�7*�( >�9bfem�Eagt�!A`,g��K#f`,[5]6k T�D��ef�1pse�,% 1]AC1 �� Z!� .�|<C )m�a�h�Ala� /dark cyc^F! &�� fl�#n� in half p ,bog!�G* dard�!n-meal P . R2[\9ig�!�you�1–2 dfD��%�)j s [5�T0*�A 1% �d�!�fl� ofF ival*:a%�w�6 hA�rvirgA 1(#to!��#�egg�ha�;i1.36–48Kat� which%�I�adi��� !�A�offsprA��{em�@ ll�, T}<) �%both ����u�'<� r�*U~.a�jSta)�approNGV� &of ��over �%n �y:�!�~typa� ogen�F2� �T!�xim yd6� �%i=A�^dl ��6&dv<!9tert:( RAIL�T��Z ssib�Fi��min ����e=� Z�ve �pe�forty F1M} , twenty �`� q , �4�"3��"� �� EH"|�$ewA'tl)`he�EN^]�A+� �;5y�:�y >6�F2 ��.canex�3eN�i��a���5mbto �-��#Kro-s-QbbUc)�a��Qof{�Hj!� progM�2f1a�of!�up��LF�]i�] �%�N (X-�eUdu�4"0O��U�Em�� )$�6*i�l(�2e "7 sib-M� ��iE�2'A1c>=)a`)"�(�dFEa9usF� q�+16p �8 ��T9� 9 iaV:�L �4 � �8ur !&de) �.� mimi�I!�@spo�R-!�/B��m vidu�+(]� �W�,Q���9u!`ee"� �]�]�#�6�F=ac�b �x ‘eq�7 E’5cB"u ��� A�map lDP�BV . 87 . 3 cM!�� v�M�l� �Gclass�Mmeasu�G( 2829���*[� E�!a.3!��! XRN;�$'s 4przHl=�.pta�=e�9{g�3e!�!�eU]R.-�2��48J:=�N:� . Fif.,M9Fk��A�re ��!�I�nsM~�;  hybrid R�\�W���J� JP���  w5Mn' we f ��I s �:�D!C H Florida C�8=l N��9�sa�w d .�."T×2�%�e11onDJZ%�2*�Lg�� or 3 � � U !3 theme E��'�-. AM ,Ng��6c�.�5�,A�v�`i�1A=*8 in v`Eto&� �]r�B� *� � froz� −20°s !�)w*�-k:�350�edF�A�ȩ�na��'�&a�ni�!^if]�6F��[EU�BC�Y�a_yRS5m�a sch6(re�!*��E@�me�F�(,&�5)�Le;A=}_5�N���"�L��.I�/!�� �%-+ed �829 ;5(���le-N "Clibrar\ ,�2be��Bd(860�aJ�0Ba�1�1� g>�ii Tissue Ly�@$LT ( Qiage V� cia�38Rfo=W��@�d0DNeasyd &XKi�:bS�V$ocol . 90%1�eluE�NA  5��7a� a-'y%�Eby�� �� V�.ReM*kepT�or�id� aNark&,Yq� A��Q�5 �(�) y4 ��6ach� �ag�!��Xa Bioruptor UCD-200 ( D%�odD�lXNJ�$u 5 ml tubm�set� dEN.� con� �Lhe�M� at 3B. M�-�-�f�.�5�I�y-�)I�Caire�a�( 15%!Cu,=�Kej%�6sa�%E:�by�c ql�Wam�FK a se%q $ gene rp49m,Real-time PC1s i�Roche L�C�r 480; , IN ,�!�isI9quant��)!l�0a�!AuXd�%�N su�\ful!m�A`�.5$J:�aF"QF�x!��per_:\ �#l�Lnofb a ����!p�&&� uޡe� to n�Q�+%y9�Q6���%�! !�multip�Q�dn. S9FJ!g]�安Dui NEBN�r� k��!�Eng�3a�labl MA5�s=7b?�ީ�u|[e A�zer IIx%G!$HiSeq 2000 +ru��s# Howa�te.�!�Fac�7e�a��"`�dKHigh Tp5T�L. *T@of North CarolinaOChapel H@6��? mapp�c &R-��o�*w B� haplzGaq�wP�����(�6�!!�w bPlljg:aAK"�al�,A�� i�A$i�L�Y1A�4 (�:!�Z9�4�l' � ��)*�'. DM=�:�de�=�Zs)BCGg�(�Cnumer�( hundre�n��thous�aW`ontigu,Uat';�2 8��w�:r7to| �0!hll  E=�-���hK��2�m�A few&sW�e�L>\d:�*gew�$NA!u"�@��"��2�Irprinc  ,iS%L��A: iU.�%�in*� .) be�� -�Ug� �)c�J� )..G!5�,� ���1,� �ePbp%�X<ce� ŋaia�_10–1%[6�B�#a,�)}a�� �+t%!�y�J-�u1��. a cut-off%8um�0ct.pG�bLG� F���i0$%of&�3s�]IPa�f��� &�Ff�+ e.j~K�G,ů�{>� P���]� appl�H�?�"@a�ZE�at �nR�?f As!�jot�mr� =�n�Ha�^�A�or�3&,�.A��Z�!9�!�����A��&�" �!�{��)vhT�?ge'���/Y -a&�COP .�SujBo�9��$q�I�,���CO�&UCI�9��)�I%�"n1 L$�w,��U�U�� ig�`eK!�6k 0e�6n�^��R!3�@qL� �E*� of�16%f 4%!uo'��5"QDs �d�id: Y, ��=���� of 3�511!`mpA�:aA��{9s^'eUM0��"82�&:A����*T"C htab�3Ů�C �!o�?NCUc [S imoEY cM )E� mega�B ( MPF��1� �l�Hv � of 7�)453}�.BB'!cA�2}�r���!�9GC�d��/kg7`"�^��;Mo*�O�O�:o�O.W8�Kbl!ha�E�m"�c� SNP%� v"��  7ais�a0d `..u9U�!W �st.�AnB� ��%�P.K&fi5 b�X�bt�I?ac��#Mwd)`S,(� �2AŢ�� �s 8D>*�,A�DA<��N� "�k,/,5]� welle2�E�lA��'!C�2o&6%FjA4uru�> ce/a~:;1@s��aC��-]=)�%N�0f&YYagEI"�8��MK%b� G=Rgi�O�j,)�2����Dal�4� �ab�&��!�� ni�Qa (�6��D �3tB�9��0&K expanNa!ZI��*� algorithm)8 i�e��ta��ly��m��ice��}n��B9�arbitr�9|H_H#.o SNP/)�E�II� �1SL6�'�>Y� @sj��1�~ , un�0'G�� w�bXOh�=.�ES�8!�outC � ( le�D nd r�*� �%� �zWG'u� �t!�1�( Lmin;≥R%�EY�K Na [�L �ec4a �2U\�yX��/ �"%:�> 8 ��mgc�Y&r"e"lIy�&s&\.% S!J� Z��Q� Wq�s3�noi��Mca�/�>_er�/teYe wo 2U��e<.JEMs� f� 2�m2BA�w�+e�i�.�%�m6�A{,. Let 1- φn�WI9�Y�� r"�6��n?a� ��W%�kI%9�%  �!|beAa^�A` L�w"1\~ isaKts lo f�JniE�&( �Cn��er,� he M�um.dEђ( MLE���u��u!� log-]�fun� � |�! ( ���5�2����L�.  om>vT��ETqP&, oa�A>� �  H��-ea�4E� E1�� or!�)ZKFS4stɺ�: i�!�equalU:ocoeff�y2l9 ( CVx�P�5Y!q8�AE{����%"f sgedC �c ,T1�*) -h(�* in5�<�. Pu'� w�'"-� o9 ,Lb�$��S window �!��^4��!-a�dom6����F�B�A I)ei�a�"*x�ri�@&@t5je�viy/m �'"�E(2�$E�� �r�T| �/AD� niT� � �� [r;7ex!Dispe�620%!R�Ah�@�<*SXJU-JIf* �4e*�L a PoissonA�BA|.�%�h !zB� &sAx&�iY �2��n .?�"�� *�G�.�bs0I�\"��.6��(/{89<�is R∼yT�sr��!�yA�g> tq*�p)��p fPo e�e'sR��&� 1 >_�9N""�,���wA;�f)c( wFMc6�D�pTF�QpRlGG��‘�ageY0�-A-eB�! 9iV2e�i&A w� mi�S��ek! J�YJa}��s�oI��'�\�!��nya8�.F"� Gq& spie�?989 )�8Z6z�A�e�Awm�a3&� ( RCC'�� r�\!t �cj \�.�rN�a�H rM�1��W�D% i ulun8w�],o%�e ��6kr* o� ��_u��i2-�,%�/s oW��Nt+15y%BL�( �O=~K��6!��-�uJm��� ��e�t�[�!"�hZ!� �� 2��l"�%�.! � BA!/r��-5-{�sN�e�o � :"6�( �(e:�j�=y��n�Ym.Z.*a,!05oA bi�;!e%!�is6�s �E��!:�#N.����<ema�Ja�"` �e#V) � :26(�  a�pcwa|" .E>� sV�^ w��� !Y4250�f to 1� . VN�0��l4�M!�Ds6�zAes�pk 2->5ge"R !�mof2� ��*��biŃump�+nulGE5����* dp[�=&�yre=m�� y!'�#o�J� � ;�Ki�e��5�H*i � tW�k“ t-1 �edaQU�&#! �2H>vR�A �B"!��,607�"ea4 37&� q jNf5D�5We �MEME (��-4 . 6�� �4aaaw!za�C2alA�e`��(���8 sear.���"b$9�#0oun^�IYWE:c%��  , 909��)3 , 701�U*!�F � �6U"ZI i�e`��A�bpa�!���Z ��v? 5′ � ends� *� PE�)K��-}A8*Y�L�.�K�3rz20)M %Ua�2&X)��8*��� Ne&��di���:���.ubah-r ( E-F ) F.�au��x.""!5%r�]9P�A�*tatq� S�dI�z(-X-�a&�!�[ do%|To�o%�ar����&�"��A"ppl(1�"U� i9U�n�.�2��commonn�� � Ӆ-p<q�10B�ZA�>j(QS���s�P[^ �}>�6�2Bo xth��M���D� ��!��ignt'���M���&y.u/|{��r�\�R(��,:, F�3jv%$ �,�%lB&B,, etc .�T7 "��>�*J !0z:'!��+6��(�4ch�n�g;kE��-��M0 , broa�0d���ph�t g )hTEZ0ŹB�5��3:]ND5^orW)�Zd��B�*�b/�!*�A�"L� dup�3beNAT/GC r@�vkLiρ��o��s G�C�� ak�g�5�� H � OurY6%^�)�Z�^�E>"��B*&LJ�s (!�щ 5h?, Janu�201aB%�&pY�#� A�"1�%ei�;�I&��uposE/el�H��+v&"."$2�W5}-1!VJD'�ac v��! 1eI� kQ NCBIn rPad !a_ ( SR�>)lSRP00069�AR� � �UF��%�� 2�p�VduN<#dO%vA��h$BWA-SWAX8]�.�EK!A�al!1 �%�c*[d! s�1�%��BgM���!H^�� 2ZQ40E �U d��s�As1�' iF1ta��ing����-i��&�*G2��g<^i��(! ����e� X-�Xed/ adjua.� �F �E]aut�*"q� To ų!�>��6L-��8"XY�SX: 6jXb�B� R� 6>ni��ƈ� F��π�i�kc�#f&#6�t}�KI�d��7��\?�#�#�9�of�Am�u�,� mJ��"} ����" _!��!/: *���)-�dpublicQz"u=,��ŧez"��aQZ��www .:~ . bi�Dui"7. edu%E60z,.A�< .�IDN2/RDM12m !Upni� A�%2B(!|onA��RNA–+�E�u ethy�poDdD.machin�\(in Arabidop�/ thal�VV`6it"�"AC�A3}(x2By af��wr�e�C@DN\/w -p��wo a� logs IDP1%%IDPE'PARALOG �=lcoD?- ��"� aXSJXH E%Q-[ss��� VPd=iz �,�ve>O$C-t�%lXmI� u�e6�Yf�=miaYaE$e'6�.!Nendu�$\wild-�Q��B� %�lL/-q�`!��c idn2"nt�A:H ��9��,!�dem�b�G? �]� unch&M^d �5jB�>�-�/%� �x�"o V �5'fi%.)!>Ld�voy.�23RNAv ud� �B)pA�a�8 silen%i9���* �6� "\]�b*1!Ung� D2��xincap� �P�ng�7-�U-�Fm5!A qeM.%ZI!t����*N2a�?Z���%�F�6$D1���q1�in�. >t�"n�S�\ epi�S*0mEHEEiU~E��Xpla�Canimal��Ib�>mai�:B6a��-��N&b�g� � Od+[1 f��.rhw&O]by!@METHYLTRANSFERASE�QMETc�G�j!� by CHROMO 6.��CMT .HG�ok�DT+%|8�[~s�L+ SWI2/SNF2�(� 6-&�-ng� r0DIFFICIENT IN�ATION�DDM�@�v"�0A�en !�:.[_�� hist&C H3K9 #e�fer�u KYP/SUVH4y��Yqa%!$`s��i�;Jv.2p��� [�q�XEs�ish�JL:#< f� RNA-�p��[/_&q sv5I�# past"{8yea�X!fai�����Yo*/.$n6�c�O!�@DOMAIN REARRANGEDA�:��DRM�ocat)$7 nNp}2���–[1U�O�� 3AN�8|iD��� y>o?�]. S��tea8Aʡ9( s��)%��&�j!�-Bl:��r-�I&1E'Two atypS,��&���A -sub�a?*a xj E�s Pol IV� VF�bih � ~?�!�J�:V[1 �19%{du�K"'7qII����P�ZV��t . NUCLEAR�POLYM��D�V NRPD�!�eA�) E�uV�ZZPE PEfP!OV Ut. S@ m!�p7'Ёl�9� �9�� ��4Ye)eA�byf� o��5IIA�)bS�C6���)�*SY��� #)25�ed�8+�bDEPEND��AO=�a�RDRa�A#��h*Q24-��A@I$DICER-LIKE�ZDCL�Z�u. \"� %� 9���x f,2′hydroxylr[�-�Oi�K�2,HUA ENHANCER�IHEN!�AV�KRNA)}loa�� ARGONAUTEѢs AGO{:AGO(dor s���$mb�:>!2iRTe �op�*�%"� ( RIT���[lex�X&O��b] [2k`LsNRA��8KOW-CONTAINING �� CRIP�CFACTO)KTF!, a SPT5���dnXbA�%ed WG/GW"��lir.� � �>__ \ JM� help�qm)9[�n3F�A�V:�9U)�b�"by!�4]��Tvoact.scaffol"!lrecruit>�p p��'���i� ��W& <�r�E)to9��zleCm��<O14Q/6TonTseeyo ]a�tP f�F0 ���)F� tan ��3�� DEFECTIVE� A�DIRECTED�g��*� R��A\58N� ,6X8MERISTEM SILENCA�| DMS�"NQ�yEa~�a hing� �� ��b & ��e�M� RA�!���#a.� DNA-L R�m$'9M� DDRNS!*, ��aE�>iVing�[36��p. T lsp>� E��%�F� �5�@k&x :RG-=��� ���o `[�rrkHRDM� /2|J$,DM!�aEf�/-P� ac�cith%E II , . [4 4 Disru��A_�*f*�f�O�n*�ofXr�nd$II��M)�s��=�j�)�.log IWR�i� s��.�6�;IIў@!e� cytoplasm%�= � �X�x%Bd yFe���oPuus �B1aolis�,�i}c�E��A\��O�MŇ\ar r"� .�i=�V�RLASSY�� CLSYq����V�!�0SAWADEE HOMEO� HOMO�( SHHN/a� BIND��bdD�d�2� Fw)j��"-of6? A�–[4�A^�! IV c*�� ,-)-�/��+*�<�%6�&" �� upstrea�Q�H2� 6�.�A�`eC �]�� � . H"�:�ih .6)�/� �%�tܳta<>w!52�:^M8e!te�'� ���2AA ��*{ 3�$. INVOLVED�(DE NOVO � ) /r�1H x)\6g.Tx! �a���foJ�!t�sc�P�6sfP"~|���WN"�  C2H2� zinc�_'�� EG�NzIman*��� 2�, ���mj�2> fami?.A��j5&�2� �A"�O�p$cs�Pto SUPPRESSOR OF GENE:�SG�.B9x! ost-�8m  �!�*�%A��-�}. B�i�a9l �2t,!j)LF��SXS-�se�rB�c�B ind �,overh��J)� , [4��� & >�vi m�, ta- �nat% , [5��5��d2|%'�"p7�ɺ>�p��c�2aV0a�{5s%Ma7Er{Ũuw=�tsY� s�@�-��-�9?eo!�F�!Q*���,"0n�\e .m�I��"�'����Jg�hs !N�aJq��itself�y�m��qm�:��2�hig8{=*�~�Y� F?d�inIs[i7���;\�b*pX!I�1�|� � -�wy ��;��we "{-at 8")%��� QarQ.�:f�ichyna�\6( RN�/>* en6,bw�Vz���“A��J�isJ�� EpF� M�AiGJ��& 5%&�{�I�>@YFp>WzW�A�Au�B�BN2�1aa�(�)@� DJ� �E�gJX��.�n6[h. inct��aI�J�)�Za�: :vJ�-�A�$e� �!�1��& ���. T2�|� ƕl�2��4 �BucyMrb#�a�#f&Qpr(�-i�M6xMyc fu 6e�U !�`7��Cia*�-*os1�-4��v9UK�� 2had��� �v&��GRD29AB� luci]��( --LU�=os1� p���F5S\k!�"�Z=��[�kO*�4a�2#-F��t%��&t�ost�8A���!�I~|O>�deB� AtSN��-p& !A�N�M �_�c�auw v".21�(}yIMex��EQ-Y1�ic �<s% dZwe�fn blo�e�o�A�rd bodyz̠BzBh �&n"!E=&7�!ru+�yr�# �:� �c*/-Gs+ �M���y�w�tj�I.Zņ at �B10 KDa�anR 8 9�a!. MassptAElKassay)�}{jOo)yV� � �-��G!�a]-&>Sj7� e8dx eC9��N�1���D ��i) AT1G15��AEO�9�Lx�bb2=W�g= 4G00�}=&P&��%�Ry�a��)�!�V"�  l(t3@6T�o*|�\R� i� >�L"��I[|%t%* �P|#e�2�Q��deH4�*��eA-�f!"R��N:��nt.�2����)u�'N2q�QRx�.�u�^�M��qk����� g1d� !e!�Zi�(fF9P ��,fur�"h!V�y�<����B.���bfi�"� f2E��i�el� peak M�|.[ A�s5!}��40��yLno/O*��byF:��DP58 i �I�:0�12��i�\:����1Q��*����!_tetra�f|:.�aM/2Am'|MF=�"@ � ���50 �2\!�z*�(��ed�3NoOho�� >�rro��M:>SBe(3��h 1%zTt1^�V( (� 'At3g1255�CAt4g0175� At1g��, �u 1g1379 0 1g80 5g593�� L18RA��g9*�|2 ~�l'�sf3 clad�NTJ]�g!�&�*lig�iW phyl��eL"�25YS,�:�O� PG"Aժ $ń( AՄ)� �>2�U�* �M�-�.�,�Sl6�&^A�����9W� 5�/c*% ~e�Qon; 2�$microarray�4by'A��� l�N�AlE�%� �_�Y� �DN5�� � �e�6c6Bat�T� I@&�* vP-�ge����. Y��two-h�vf� �.�,�.��LA!��Z��թGs%e�!f%��*,*o 2no  -vz.�o52On�b�u!Å�baQ��e*6 2� I�e���.�,E�unP �{SzeA��w selv�1�� �}puGs�.6%6���%cril9�a�Q�re �[�:o!�%�%r.�2�;��z�xA��|:Q�E-]�A�Bzser�A�run�GZ"e~%�vec���_�B�9;� Acc�^�2� �8�}h�tAp �i>�0%�]��4B�A&�TnA�- $�Zf2*/vh�� �|sBMj�Jo��&"�!b.B=��4 �:*��8"{C�/5)jJ�6eX2^��2 2�z6 Athoug�Y *�Gxs:!��J��.�3Z�v6�S��te.Li*� >�&R!2 Z:4�m�U3e_by��3 iJ.jNK��I��%��Z,��u@2h}�&E'A dund� a@ K�no C�� �j�r�+t0�c&\}9Etoc7�x��mQ�*�Z� .���Y� glut��œ60�:tryptop>=61 �!e!k��"oEnTB� �N2E600Q��� W616��BW2Z6,�G U�����r�� � %�j�� dide�'l2\>LAtYQ� �k��>�9?dNF�3.��(�-CPa ���]n��&NA6�!0^)�=Q2 "2�B���vo3�V>�D=h�j:7-�+)���6��kj fal*�2q�A��R��� pҼ O*�-%�5"�e�"�7�:��t]6 %%l�7 �"5a`�J=�a�&��5�3a\i�a:b'**X#�he`)�6,���i.i�8e`�-^(? �W�6R�%���� :v!b%=."&�O?D�D=�!c>G>!:E`M%AEf X&���&3 �v�:�9�� M&�1�,�!V�D:Jq>Q-��o failA!)�!<Pf7!��a� on3wt&W>�Th0I�,*~:0}�N�q�A|!sAA}!���r�R$�6I�A%�) ��A��f^U��*�re\]!�N�2>%�V�.�2MZ/22�2H2? �%35#� ��tr�*�%E�9u�A!;�q�6��it�-R?N^"�j� �)*�Apo��=.� �=i�Zz%��P:�mE;�i-x&}~��,zOa*p.�E� fA�u%� E�� T ٝ�*��h"�?��!rumGSDS-PAGEo���oF;�mJ"Bi'W~�� �6��gq�,6[*FA�9s���� `F/Y�A6�@���! visuĀvb5 threS�r�A�~�pl�Irsilver-s�g 8Ve1C_!���:��6��Z�ri�'�%! B&�j��% �6�+&v,9�=�!J�vt2�e*0!#a�>I�F^q.6�F>- VN hii4���T �,�� 6J�JNo 1���m�= ��ein�K�A�: �n]r� � . A�J'����.�N �-:� 6y�(B&>�VzA�o}HT-ii�6%j!��?idp1-�$SALK_07537�`a� idp2667��b uBUS3;?S�U��@�&:�s "�l>�k?� aU�e���9�c�,V�S X � � by RT-r� �6;>[ �n }.Z-+=Jl=Ics����e8ͻrup �.�iw!@��T� NA"�5a(l��eT2s!0M�5 -���� r-sU �w�$-&��yEId D6&��#, IGNb AtMU��MEA-ISR�t(nd Solo LTR.4s���e�A��:io϶�|&(enzyme HaeI3f*�!�E�h5G>of ����#�l�]dn!%9 � ��dpS!�S4&� @�Ev>t;6VEAa�� &�[�Ӗrpd�DSou:*u$>�)o=>F�p1�!�^j�� BisulfY�1A�>�>�E�%I!VQ �%9)y �,Q�+i��tf�t �CCHH�uR4�b4B)�s؎ , S6"\)A >��o>�24�as>�of ʼnC>G% %U�D NeB �.(� YMI4�&�%694z)  S7)od �Ie���o r�9�Z6� e�ec�9edvJ�)a�.uP1N2�k )�f~ i�a 3xFlag`pMj�:�- V����)��}e].dI�)�B�' B�.uo%!���eA�  ����[5�S8�,>�( �:q V��; �� eVlyv*c��ca�%S8i�@�N&�&��4T;2�>�)k�4!�N+no +[���q�nBA� dI�r loci9]�>Q�<;.L7��p1�6 F >�e�:��,8� q�!��B�e�1ހ�B Y 9F=>�!�e� t,�4XI' vvG��k�+E��%V_GE!I}fe �EE�M )!��.�b�miq�*t�L6I Y>+]:i�!menh�H��"�J�(�!�5v5i~A-%pe���hp2%kno]�a�:�B�>\� �� �[>r����le��ML .!��RM86�a.m5UR�����E%m��<s:� -ն�q�.F� �"J/Ο2�N� �"2Y��Un��%z�S6� *F;!�–*5: �:s82<Lik��u�X � �;<[4.�7��2�!�2/5[�'>�F�Nf0*�$�� ROS1>}��%aEU)$��G of�Bw 8L! "%Jm"|R%n"Hz*{S:� @�8�I5%P.a0a� Ld�Y� �%�*�p�i �5i�>� <s�l _ideM|�2��B< � 5es\�B�W�q��!s�J� �/��frmwh�Ye#��%v5K�>�2H�%�.I�0�D6�1jF Nji  7, 100�hAU�!�o���3(: �'�5�$&)� �(GP��!C)�0.zB , 5� �2(I��8;25hmS17)3��5l�6�IDs�!��i��5�2 *�X 15RS2�at.�*/>�1�2��T -"> P�t���;>�a0N @>�%�� J5V�2�"0 �f�!&H�hP>�M)�9�2^0�+AA]�Y G�/�eV2�[3��4�=�g��n�e.1�:� a�e�Us� Bg�X ��9i��u��"�}>Z�]i��m��L�kbha{*+)î�a�gψ��!bmO�6� s�,騩�%�%�x�|*k>k �3 �Bu,"�B�F: .8�> x6n!LjS&"`>� A��GNI�A- !� R6+X$��J5IŴ2��@s��@)�:�(.�A"/A%nJf&A�J}%.�afNt���" $-B��� w`A2��@B�j�#� ��Zo"�*f�)DE��I A�b��"B4!\�v -2�W.�`e�rophore/mo �shi��6 ( EM&�E�'-�o%A �5���^�� �8jnd&�@bi�ri*��%z �b��e�� x*�-]Hi^��@- t \{jrob�da> 1N labei:2�US1�; ��kJ<BJ�x �N��C��� 4A�N�wKblunt�5���Z��T��\FO>::PQ�� 2���J�e� �.�F!q"[�(!2B� N�5�6"� p�oȁ &0Ext�ddeO��FX 7=kK�2eْEb�������JB��z�q"�"�6!�2�,�^!h�Dɗ!���.G.?!heT&"����E�R�� 07� wh>�����`�/.?�t�gMq. F��)I �Lq�� �%�aZ!�FK *?R%{!Si"��!fe�-Ȉ��6�Y�v4$gA�4;6��4have roles oth�er than the nucleic acid-binding ability in$TIDN2-IDP1/2 complex . �O has been previously identified by two independent forward genetic screens and hNxdemonstrated to be an important�onOdthat may function at a dow@ eam step ʸRdDM pathway [45] , [46] . Our results suggest ]�Hand its paralogs , ! or2 form a�!required u . The DDR$$is anotherf� acts��39B�8how , however ,)0�tdoes not associate with DMS3 , �)eofE.� , su%%E0 differ!� role�ea!Ee.�of5o fur%,characterizek=IsIDPYv, we A:I!�X-3xFlag transgenic plan!8nd carrA� out affinA�purificaE/of2GD. Mass-spectrometranalysis !OA�Aua>.�co- YLed proteins included� as well�0( Figure S11 �$Table S2 )6aqm&< can existQ� sameg-contain!�u� F)k0more , becaus)l4idp2 single mue`a�Hno clear DNA methyl)2defeci�aA�toC1�4��4�we!potEat��N2e� alsoA>aMq�al�A�!�%.�eH member!�ah!} family)<-s nin�"s . A!�dA ��phyloAb��5�5�1E�A���i�5�(, AT4G01780#lAT3G12550 are highly similar!class�0 intoEY%�clade�:_AT1G1591]<4G00380 have low[A�!/�belong!��xaI� A� tudyieA�);Ew(x)�%��)�ea�:x�%PA� , homodimer�BitselfA�ut it!�une)to>��� most1J��b�:V&. ��s1 N2���-vU�P2�lrely o!o$e sequence�!� betw�O%�%~�f(. It follow }in)sxN2 ev�lyщs som.rpec� itie JA� pres��in x �2 !z!ab ��N2�a��coiled- domain�e<J�r.AE iz�~of manyy[52��yeasta�-hybrid����EN2 �s!�A1�:�in ord) ��Y�, wherea!: e XH�!&�Q!NTs6�'�|!�ŊN2I@�pmE5��� 2B , 2C )-d�reveal�fes]aRR2hthrough�J�0��,t�+ivA�. Both2�)�s seema�beFa�5�a.�a&inAin vivo�� ccor� $to gel fil< !U�� fus�JN&\is ∼400 KDa , correspo �n tetra��1�!2EZ�1D%�W�~�� �ͥ�g,A��s%0 a]�=�irJ���INlel.�w[>j/�sset!�UFIEA AC-termi�Us!!�i�A*uB�(assay detec�n6 �ܱ T� -�� �!{/=)-]5M��unlik�to direc�'�G � each�։���r�suffici�Ff%D^/2��Zb��E600Q� E�in�reduc� I�q=�ain^w*� -;p,-6xMyc pull-X -��De� 3��,��E�he &� # T a�.w-�.�. H*� �W616A9hadA=ef� �kfNPN ��itBP�- !I��/E�i�0Ig��Z ��%;b N.=��/-9u!i�:�(2x�>� = �jI~ possi� �R!�'Ey(>�proper!Cemb WZv9�!A�Qa sit� atF�s9�*4 � EMSA-`� �� N2x � b��05′ overhangA�double-�n� RNA%j blunt-endR"u6�67 which� inconsist�(EG� B re�9]����% � type��.�sIz2�Q�Vbe due�,!�&�N(probes usedA %s _ a "v?%,21-base pair �A!D �too!�r �N2%�!� . Alterna� J�-!�2���d* �G RNA-&� 2@ . $)�EP!8f�;lengt*� trunc�A���XSEiF� s��cap of��5�J�s]�A–6���q x�e6lE>JP�� 2� �1VbyQ 6�aGsubaW� �K� boun9F�{ `"1investig�. U�� 4)�?�� ��%M���$N��Q  ur �experima�y�D ,q�altho@ Q,%;6��Qv.r# I* �a�5� ��y�N�=waP� j� pl� 2�;�X�,&a E��9o�-�>R5N4 ,HS6F9xN�!�>%>�QL8�.��:e��J�� 6regul(a�2S toge��~I �\ar�5toAVl�Mexact" Uu�h� A�"���lB .;q�newly2g�J9es�ialEH�. Dur�is4uscript was un(��ek(Xie et al .��� �Vn -� �.�(, FACTOR OFE,METHYLATION UDM1t FDM2EN&� dund�6A!��[55D!FB synonymou.4"�!B��T6�u�sw�"o a�P1/tR= %��& �^���J;�>�QR%zlA<Qce�E/J�M�% . MA�A ,)��t.�d��IA�u#U݁��:m�9k*�*`sub� fromj3��cl�051(.bnd*�)�Y�m�N -�i_via�Fn2%>>6�E& ��2B–2!oc  ,� �I9�%Q�8inJ�N�iْ} sqn�±F�� biochemic�uaM %*Z�.Oe c� ��.6�*1(a�3a��$q e�, "is �@�o ���V��. Disrup� m��J�a�dn2&\ b� r� �{scu9.po� �; FDM3JV.� when�.NI�2�,were knocked�m�)���, �idpI9 2�!0 )�z���8oubtedly much m�A icult���.�i*aEnref6,<�aso�� P J�/�fdm6� �strong%��in�7.��sib accum��t��f6�s��� by2�E. Taken��,� .s a�>� ��rs�2_9� IP.H��pro��insighta�I )�� mechanism!�A�D�CZ $. Arabidop�G ma�al�re grown MS!� Ň \ -day�di!ps�22°C� A�adAIXs�sflower Znee_�e$e�5? �|1 soil� � in a th roomj�E�m�ee"Y "�!�wild-^ t Col-0 , nrpd1-3 ( SALK_128428� A�$-5/rdm12-2��$LAG_550B05 !p1-�:07537:p2 6671a�-1�-1�nd>�2? rosY,% �1/ �4a �n*��RD29AAaLmoter-driven lucifer��M�r)�gen�B�genomic" �_ ampl�� clon'M�`binary pCAMBIA1300 vector��A�*h taggi&k��S12A ,�)�6�P1V�>� ~��"Ex�5��n�A35SB=GUS96%1�hrepla�by � .�/S1)Site-�ed�3Ga�J.� �ne� ��4e�&�)R S:�� - �H\y 2^ ]��tru��y�k1�?� A A�M�by agrob " a in��� �T1U|&�!di�on�0medium supple�ed �H20 µg/ml hygromyci� ��r!X� posi6�dling�� f� � "! �re�am���orFEE!4-Qt 1-M��6�"x/":99�har� d�94in liquid nitr� �� :�F tz%� 15 ml�.�"bu�#X ( 50 mM Tris [pH 7 . 6<%1 NaCW5% MgCl~(10% glycero(0 . 1% NP-4�:/DTT , 1: PMSF��1aLte�winhibi� $cocktail t�t/| l [R� ]]F��centrifu!,��sup,�cube'E�10A"%Anti-c%� Agarq ( SigmA 7470 )!�)�$M1R+4596 )� 4°CE>2 . 5 h-�Axn!�re�h/wicE%5 m�g�%10N�M�(n five time 29N8A�e A�beads-w"�EaeluA^~!� 1 M ammona` hydroxide�pH 11�&QaT%�am peptU9nF 479� � �fi"�!�runa�4a 12% SDS-PAGE ,/!�.sil's��A&��P�%oS & Kit�PROT-SIL� . Ei� whol*�orJ (vidual band-�cuti�r�!�"3& �- ; ��(� alyt� capill�:columni�8µm×10 cm ) paA �(5-µm spher? C18 � d-phao� T ( YMC , Kyoyo , Japanef  �6�spray�I+ LTQ mass .M'e�M$Thermo Fis�(S-W ) �pp��(a nano-ESI !�sourc�f DatasQ1%per�g�$Mascot ser!�( Matrix r#Fi*) � ` m�synth' drop�)� $SD-trp-leu%�se!ف )r&� �Mi��in.B, [at 28� �ser�,decimal dilui S/AspY .]-Hp)R.>� �to� mM 3-AT �ad?AW# �inc{&�'e!�ingency/> �!B#GAL4-AD:%�.d BJA�A�ex((L%Dr�e��ne HIS�prP�!�th5)�!�9�v3% . To��+<h&�y*�2@(C.m�&�a� muta��eLiZi��*2 .:� themI�I�-F,P�or���P�ndiؖ�MHF -_Chop-PCR�.ou���ibisulf�!ZM � condu�%A�estB�.��ce.�(dig�c�&*� -sen� res�/E�0enzyme HaeIII:� }*� arge � ���N�v�s!�fQ�����Wa / 0% a^  t 40 V~"n�6� B�)KR�, 2��>�treE㥤so-D� a�convert�1{$ed cytosina�o uracil A� 1e�3��"� raJ EpiTect BUHg Qi�!f� � 6�!fa�Au��ed=�E��4�onl�/�by CyMATE ( http://www . gmi . oeaw . ac . at/res^ $-groups/cy  ) [504 At lo,15.� ��"&u�'�-��s�� A summ� �S9�8(�h�in323- p� rs� !�1��h)< de�b z24MU(semiquantitA# RT�VA�iso��d� 2-week-ol!�5��asq$ly [57�ACSd2�DN� to remove�2+|* �nd� �i$ !\'4posC e!�-fe�3� 1JEL�[ag!v�>wfirst-��,&�B>�' -encoz$geaS$, oligo-dT%asa � u-�> itu� �ie ACT7�j TUB4Na&.X3 ntroe�A !�#!�I�)� �%F AS ( No RT )j:��whe�Ie�2X�4t)ű�A�)5small3p ̓mhext� neA�45% polyacrylams��� Ve�3–4"�v)a ethi�?roB-Yama?(ve� ro%6fer55 Hybond-N+�4raA ( Amersha�Gvh�01. S5y'%MH[γ-32P]ATP-labeled%OE[(o`[α,dC-��pro�ơ�f6�!.�in Per�Hyb&93)�� at 3d ��!�B�,�ire�<�􁭁8�+�Y4����LET28aa pET3Y:2E � a�;* s -�-b  c;%�.� �!��W!K Eachi�%BIor"E .�7i BL21Em�ahof HisB� .R% �{ by Ni-NTA, Bind Resi1Nov�v�n�@M� phor� mobil�4shift�G('�2�)�]m�&�as.��w[33��u !��&E ,e��R#�$s�* end Q�mT4e�Y� kin�G.}+ I�X-rL>il�C w0.�sNeutroph� ��A��� ` of ;nse� E inva��k%ih= rapik!recrui�����.sMLeishman o1A"�' brazilieT.*7�1ple7ofLlammatory cells sign�a�%6\C����x�i� of n=plus L .6�p+an op�e �1x& %!Mco-k"ur���ac!wage)?.q1<iuw=ar �kil�� %us!^ask ?:@on"%�5%nF�E!�. Her�wA�ce�ona �A��i4m�z2�ndFg,iloE�!� Av&� apopto:"f~*i%Y�"$erum-opson�B��a7-o�! in mh1>�67#8+, peak� at 2 In vh �o%%f hyoa�ol$ -elicE�in]� or b!}marro6�toF�mod4!ae2�:�duc�B�r�C�!H -!X%�(sA5o# �j�/E�tr[� ;:�=82�S�V!�T� outcq=1(impact�'peli"�,tc') �3e-st�����on . Ys�J&�-com�C�@A�)^2��o��,�nga',��( rev .!?[1��2�-q����XoccurAM�to vari�-stimuli%�� *�ro��!� adhe# ivas�0��,��c!%s-�U���Fx?B��#gr[d>Pat�� phagoc �kb>a(���G ��2eis quick�/is|i� _gYGegnd�5seg-ReE�e Oxy-S�4e� ROS� s6qhzBtoxic1(B� [� P2�%�"�sec o��a�'timicrob5F�y��_g.-�%S�@]#�� ribu��KF ��[4A Reso�!hU���.s���;?a�!�v�Q�s�%profe�al �cy�3��s0 .�[k02;ofZde�+ay�W"B,ly-�9IA!1�1a�=�2Iq�� u�[��1&�4al.B y�,2 p�3stinc� �\7�:�com�'%rof mo�+%�p�  A����donovani�infantum:�U � R� [7 , 8AOI�t.��mon%�� ,enhanced dist$!>i�t$ [9–12]" %� susc�" ;K �&C�1.X�$ed Th2��developź[_..Bd"� ��Ba| l��.=&� �(.� amaz�I�\6 [13�a* ��r'ceA���a�cidala hinery [1e�&�%eڱ-,�D*� spp�:S u�ithin� -�"A_par�� s [1eg�geva��ptegy  6aat.eQ0�4ya loit�.�E�c�/.��C�1lti l�y7is es�&�"d [167�In�.�Kad�H�JvF%!`�f]�[1O'8]E�A�q# -chagasi .� [19]�.Enu��. Employa�U#tur D mi��^ BPet� �5� ar!O9�sy$�]�ii9b��s�fly b1, �1re" =3aI[20a�I�is�3ZYw�6favourC�Je �f�e�,, Ribeiro-Go.'N�i\K�9al!r i� rout? .z(�rader. , subcOKe� ntraUton�E)�  �F�ca)Z29,by2�!\��U~�N24 [21!SP�7ouv� .�L:�-)A:~&��lA�.�<�� d�G[2J e�& !��T[; �| r�on"B.��.yI"�D �!T6� TNF� *� .w �NQ�S9�!N.liF$=0T�je�?o&zenviron%�,��a���91�.x inve���H"�N6!%Knal<ors��45Q�!2��0 8. Female BALB/c�e�<–8 �v ag�obC)�1`2� -fh- e2k;��P workE!� a.H�Guide�*+A :Ey��7-$Colégio B!&l�8 de..çãoFand:$nselho Nac;(d:2q~bD"lou7*(�nDin MHOM/BR/01/BA78�2 [23]A^�ZW.cJN �res.m [24W.kin�id� Ph�p Scot�+Uni�A;$of PennsylI a� Np$k0 Schneider’ps} �um ( LG-2F#�'FB�$2�glu�A�*.UJ0pqR�i!�me0streptog0. P � �s�4t)05u� s/mLO� closoz-to>ascera"�9Wm_I.#&E�/�+ ( 7 days �B�7�فO�@�� )O2,z�&w�.$5% heat-in��E&2 esh naïvd1rum�]�'@. Metacyclic enriӡZa��_ s�h2� else�V[23 In| & � we e e��( WA� IL/80/Fri�  )A�dea��Bpr$Kak.~[2w .,�2!�dS5i-p106���9�6�~ 10μ�ueC a 27 1/2GI7lU"C�m�� }jw%�0�P DMEMq . Af�'� 24E�48h�&!�&r,Y sacrH!n�6 dorsd �r � shee&E!4���forcep@eO?leafl*��R&; RPMI^�C6E�"bi�V �16h%r@s emigra�x� ���expCV|�)6�un!��.��3%2V��� �lJ�(, mAb 24G2 �J�Xlock FcR�=�)a�e���@ti-Ly6G-APC/Cy7 (�'ne 1A��( BioLeg)�!@-CD11b-eFluor 4506M1/�2( eBios�/c�$�]�$-�%ac_)�0LSRII2�/BD� M�o!6a�,�%I�$FlowJo ( T�� Star?n�%��Per/ &����Di�Ma��*e ..) ��'by �%p�ad of��thi*� ( SIGM�Q,c*�2mCF%Y'18 h 1�by � washQ6YKS)Clefh=�r r 1h�37� Non- nt%�Mrecove��,cm�exa���ty��EFAm)H&EI�AXofE� spin�؅�aCNe&�ofO >90% �E�29 6BA�J��5�! � tibiaE(femuriP ;"��.9�&�%mAba4mU�0NIMP-R14-FITC��"-1A8-P�K(A�PharMH-m-!,f�Yby MACS-�� !o��I� e_d PE magn=!5�2iltenyia techE�>�J�-�l�#�\a��a�AOnj�6� o`�Jra���B�.n>� . Pu�V:��A4e51j!e�53!A=8�� >95%A�ws��IE�.շ��e-���� Ly6CIA&d"�5u�c!��.W��-.��1:�Ds �+1A8+�int:Gr1\�,�@S2 Fi$^�9U��I.w.�j e+6 de�2h�� Z� C� � � a�&� �μ� �.� ( alli�In�c�\�"� �Xor *�W& >[Yt�:1"= :�c�m%(�%i"�)�2�j2&� >�.��E�*�by2�r3 Data)�2��tessa�@ �2� .�I"0!� 2):� 9r�"Fod"�qk:�e&�#e�FcB�(a6/CD3�@�Gm�Gi�iم���"� M18/=A?����8! EL-1@^]�E-b&� )%��isotype��* Rat IgG2p�a!�00�`Z?,.\.e%>Mi� heP%3��%UQ�Di�"3* ( DHɀ:\aa���DoI9) μMo, �Asgo1*t=.`�:��'$bol 12-myr� te 13-ace3 ( P�(�&nM PI R2�J%.a��Arie���]E0&j B ;J � ?B�e� �! abov��4�=E� K2a�7 ��mea�"d: 1� Brie�I<��)�nas>��6�?ad�(72� E_ tripl�-vELISA��&Xa*)6����b"�?5 Y(�'1 M (,5 M�?�+5 thyl�3��?�D�2�'t"PP /;PMeOSuc-AAPV-pna; CalbHJEB150 �,&`.� Y�A�� !�3�.p2�aсv�jrU� bsorb�at 410 nR��7ilu!+�human&�(6�E:�9� �BBOTL#6�ۚDE�S j?co�:!� slHM`6I>, ��f merc�k�>$R&D Systema�T&* BB��oreyG��5b�!�/ .� �P<2E Annexin V�H!PAs� D Bs�^ne ^� B�-V=&.= �A"�'B7"� by u�^0violet irradic ��@'( 245na-%0�*��jA!-#nl.DA%.��!?!w:� :�.����A��b- �T�=bfix��2�Dut+_dehyde ��Tcacod"ge�z,�9�I!lpost- Pin E OsO4E8�2t ferricyan�2<{-7@ch%* ���s�R��..��= t(Kh?�c,��acBgō�1$oly/Bed 81�J"�,��rB0. UA��Yio"=2�urany�(e� eslKci�a "�X Zeiss109���0�* roscope o$.��t 80 KVF&�,�!!/rQA�!SV*�non-para�$C�st �4@s [Mann Whitney (�-$ d t-"',Kruskal-Wall:�& Dunn�p�f3�A�=M�n� �TPrism ( GraphPad softw� p-valu( �=�a:!r|6eV�A1!L courI*V�".�*�V� c-��kia%e�1xkiY廹nM/[� )mo� =gA)B�&o. M�%���!.�BIA?� sE�r�*ed.T F�a�*on �20granulas;%(wis popA��%def�  +=`FigpI�. Six h!�� ���W;Jot��Q�mce^%ynumikFx*ar_�[�@B)�v� 2� `4sa�!M�B wenty-fou�RD*r �!>�[s=�q(1��!�.l�phA�;&3�$A�yiszd")%�( pq���$aao%KC/�I-poL Th2�U�:|#�A� �/:"e$  a�Bg.� qaH�.�:is"�2"ESR�$2u.l�N!�4wA*� ~\/o�)&�("�X !�"�+s^/�62L�-iLin� d��!�8�af>18 ( β*Zt�+%We�#"s�R�eR'sij*�&i#!��+�h��CG�:od po��6��V<uE2 � �UW�s%�s� 2 �� >�� ]9 �!@�\r ����nzB�6�$&-,� 6��=U!2��In���*w-��gp��ed2�(J+ �+Mb"J1.�6,-E�!Slat��Pas26e�&~n�in spi&r�#q �&�&} �%&$$.�V-��per�&agCe}C(1�!2L� "x�(36�7�12�_E�as 49%�a~�>�#6e!K�"6��+ Aam�W5=I6��%���.()Ef�!Hv�*low6s� F Z.WN��1'X�T�"a��Yebul�Jom%^�QfW.�)��u~�qV!Na!.A$�KfC�S4 &0��sia.6�C1��,6ly{\3=.�]c+!+e�3&Bd [29�  -^��5B],. E�9�LQ�3�D�x� �_w�#BN�-�6Q A�6648�6{�63�6B R-L -l2�.m�N�.R�lsoy�}�� q�u�!6bak.j����3��L!soh �!�� U�%��62BGex.No�m� .�8: .���3se.Q a�c��p.�I% B�up3E��n* �cgardles5th�^a�L���5%.e8, e Re)�g5�Ade�-^E�7� ��>m"�]nR6_ign"�*s dre ���ZZ"y�dZ&�-�.t�=� �� �wq�4�a�6e|t�5ed �d�42� harb�<>�-�v-��f|*�-�aLR���#�p. }"7I � ~�4m��� "�:��iupo�:�>j� Y!A�A, ]h�;or�I)>]5�5Ae �CxeH:�(%N�6`g�Bu% |t6��id aU?Q:5.�S�z"��"re��a/n�� 5C�D��.�M��?m,@*�oN�8�P&,|a�="=[3�: �4�srea :�1A-�>T2�� z&�0�dendri�A�"�ha�a:&*r>o�adapt�$ immu"�@ se [�&"e�<)BO,�gg�!�*�85 by��"bBQ6�:�\^�)I��3e� mannG'z&p"f1:wasful�4��V�� ��Aa9)^eD2qE�ct IL-}or 2p40aB� ���".XN���c,!�s d�5by*� � sphatidylM�( P<�PS)^~�qeiwby&W�k8�6N'B���)E�Ba�0>(&;L�t&x�B��&��&!_s "�k!CtE06*�}�!�6�K la�(9: +/PI~.�Q�7�E FqM�<�ipEF�s�/necrN�NZыJ�. O%9d>hA,B�5��U UKaj66�);J1g���M�2�R�i�..�3Cranj�ffir�KI G>�6�.a���i�5i� pyknM, chro�"Bndens�*#bremna�-v�OFdep�2&&..#9B,�<>�A �a�Z�,� plas fdisorgan�6!�vacuo*�4�� �I�y�&�5�Q�.݆e2["�4�'ll �r� �� �i<:1"�* Fi�)DM�9 �&��o in�0�� � !W �delay.r]C[315B�>2���B2GY�i*5Z� e��!"�2� woul��so �C)p^��� deedn_2���*� 2� e32�NDAPB!�9��_U-�B#I�M�!sis��a�.$�zto UV�heA�.a���"�'�8"�"+ �. I��>�2��l:�S� ��)�F�2��n"�wz ~& 9] �t�� �N�� Fw~2*j9� . Numeez�r� havR9>�t.fp�Ba cru�$�~� ��}h�ffungal�F���=!��*�[3�<Ea�sr� e06քTJ���",*`of2A/!�@A�.�AgD_dal>ulc4 w�Yhe�msp�k l*ten&�;&u �9.B� �<��>2�!%.t& �*&�B:Z0G�Cs�8"N.e Gi�l%�.�� !df�Wm��wnc�gi � �6�@�@�A�u� wil�BW*H^.Rpur�Jacur ey���@"`�2��0ond'B�)ur +f!!G9 �q�~"]�e�7s"� w +fla��R�hg)hto�/��0pr�I , -m�a�fRj�2QeCI�.J9 "1:!��ed::�C�%��J`�Q&a�:�5�it�yԈ��M}>�\ aliv�&�� �N.{vu-U , 34J"�w� | =� infi�%�o Q�B�1,�y�!~��ax^?" +�;7-OZRte�_a� ?.V�-.�F,s�b�Fm h�FA&��Ico�j t� �6Gr�#2�y New World...�H)!�iR6 h�in�ovp�*Z &� a{e� "�N.����{1�3QM �um"E.���s� �* >n� i�%T�S��AA���My .2�!se� leukBHe&�7�B�M�K5=�\�� g�\(:(&He��ed>Xothelc)[35pGr�!Mi26" !�LFA�s�6a7+5 Mac-1/ CR&tb �,p150/94/CR4 P31c $ t `B�w��a� n�9� 2�b*�)5�ng�VEM�hJ:�DB�!"� !�ZeHJ�r�G�!��D��uk9 )WFV� 3] � !�p.�Nof!� r:�# ;66�&� s [3�D3�I��.d��L&�$!���m�Qip�1�Je\;���m�0nd��V [40]:I�F��.�u""�5*el� :����P}�s�) i [4�f4� U:� B�e�"[ V2z� /U"9 ����obp �(L��$"S�.�6c��28կ�z� �q�,a>k!�b.s[4[Q��� *H  >j.-is �!26}�M5n>�,zB�7�f�@�)lZ3v�i�l[# �ava�rHD_.�.�M6XMlɕ. S�c�1y(z|�� A�\!�"2Qa�.�9�s v� 2K,;�xW fMLP2�a|%��+8OS�!A�E�canD$���">-�!��� >(M�&}v��B.�( ~�!) �}�( ~�%)2�y ���2o�$ know- �}may!k�)ngY�2R�}h��)G��.� LPGN� � .�in�4�%*�or �[6�[4 *)�Z$,)?2�!�.P.�:�vu$c!�\ &�� hall�X]1 4�AAV�/)�gnIE�]�"� =ed6�\A�v\:�A��r6� C[1�244e�F.[�7i��:up-"p!i�o�0�&�!vMIP-2 [4�S4�;Ta��Q� . �&Q%M�an Ezi�^ncomi`2 ���b&=� CR3-u.�o/@U�-a"�e [4�%S�+ ��� *� � d89�-&= �V:�N �!aIir+U���"�!%� �s�.%~�( a5 14 �"T�2�>%�"� �QwA*� elev�12�s&��B��, "��h]:T !�ki �r&�*�i�Bc"(`"P�9�AT0Va�c$ depeS�[ TLR4e�y0 g [5��=,��iB.��m"�^?�.� �z�dE7��� i{5�Q�6�!t[>ok;Hlt  "�Py�.�a��HmaiTO��homeo�]iw,�bamHz�!!�?rebgY�2csi��. 5T+ago.� ��[̙@T.~�recog\/0a-de!C�]sA as T�TAnFasL [5} >#B���2� �,�:ati�6]_~*�H�� u�.�ه�Pen�r&h�deg�7>��P!}� :yw�7A9w�~�!�f���t�/j� �A�6�R 6�asN� Z�,.�1Bk2� �2�_ in]����0�.<�iA�, h�2�� Z�);A.�� [54�TI��lso tr�#]A�B�y#�.ů��Ѯ�2�1B.*]w�"� �&u{#!H.���[.# 0Z2b}V^�+�-A�!G lifes�|�q�Q�rv%�.^ .�[39 , �p!�:�ve���~KbXg sor= !�u�M�/�A f��w� -^��(y��2�{0�})Q7 tras`L.�-��,�^�'!-%�2a ofN I[�D�9�/~>�j�Af�*�;.L!!"� .� A)2�qrs�l�*� �a� tact.%bfo*l\R1*R  �7h(C�[B�Ū!�.Uby2+� �R�&.o�Dg[58�N� �� �D6�\M1�Va�ban3 &!T�Ak2�!%`:V�i�����L&� �[5( �RTpH9Y,"�li�%�'� �Q.C�|�ndJ�HKr�� �l!�2 &�L%+y��5�@ D �>E)r�:�,"%�|^in$�Ev&�1� s�}?.�G!thutWvide a�P� safeo3priora�[ u.�:to2|U�6Ն}�2�e� 60]E�I�B6V!�2u.L-*� � mD./�=UV-�u.�4)8 !����5# !�E7&1`2�[&)���2�TDl" . L�a1e���=,!�&�h.�A[!H"��o�a� �predo in92��cenh%� ensu�=F�i� �r�b���� )�,/�.ism�sa!�s#tg"y��!�B��vng�!d.}!��6�@mE�]2> B>�!�deX:���:��!9d&@&j�>o�a� s ".x �Y�AI��jPf8��@�j. sB�%pd#v�hro��%��%M��p�co�ConV/&:).SJJg�`�"3�!.�h"� ,to  -talk {6q/ s [2� 62� se8 8�Z� F�-�~aXb�/N,&1�E��(��b�>"�!� T�9!UV%��_yB�on}�@.en?O�"u "Dh3 5Z��>�!�k1��^r9�eAHQj�BjaaW�9i��;^pla�.:�%&G_$.��Vacci��e�o�? O �ov�1tubercul�� ( bTq0 att7 s�\#ly�V�� n�]��K �5 (progra_L!<�.lle9& :�EU�G$andidate v��#D��Myc��um �s�&ilUs8Calmette-Guéri�wBCGl�dt}yB��'r��)��>k�,es�tw"&is ��etNM if""`�rd(%�#!�ofVk5bTBK\�w diagno8G l; at DE�o�I�#�j1�ed �`ADIV>2o���&��ti1Q%�1w�AaedK�|-���We� .-herdl hH�=�g+?�^om histoH� �GS�PV�GAX1&x�s�feasibCy1ch��al�ofM �"9 �mQ�y�A ne T.��� farm�g�B�Z!NY.cos���X!�!%�*}�#ri�bDM {��!BF n’�& ingnPto adopt2��&7\2mo{w3f%�burdeDy�Z nR "�!~1in GB �iA�eG A�tk�CE�2�-a�g�!��/��atIgA-ab�iP�omGa�ed benefi�I�,.yne�vRw�a.0c�-be mit-�4 �trelax V��e�m�E&S�r Brl�f"!hid!�N��� in O�# TB F�]alA@iu^%mlU.5ra�8�=�� ��8r%��a>/�5Ld��;eo~WWe@ie�!�t a)�= 9�at�+(st 99 . 85%��.�of >40%!��i�3se� �Z�!5��JA��Q쁝c&] ���O�B.� %�%��f��� �%�t�.�)�q� chie���Ű�"ud+a "��%�!�%�antigeNh�ma&sa>)7��3I@95%CI: 6�u8o| 9% )E��8to� t-mortem*6. HW �e�F >i>�����*�IQeq1��L��l!_J�v&dhl"�5 fiel�ia!�� 191{O�ke`in�.�BM~"r� ^or�@ uC� 2~..�r�dA;"�K.� �t t) ��i"e"H gJch�a�E�M�ov!�0$R �2�]9[���L">�n�i �ϥ�"� �� �-�t�  var�3U�\rs_T�t��]�a�1e@no VAmup�vʓ@�nica�rof 68%�s�<.OVW �ar��a!�=l��B!� ��Ty����1���*��U�8�s�&� :�!�rYF@!T %B.e�e RI [ �"M ;corners�#;surve�-gE*� Cteg�8eA new gКaX[&Q �i� �Ɯan:Z *L %�"j Z [j[9];Rns%�hHRportun�P -C1/ }/a -���For2f�e� l&� 2 !useful%r� �K ntexEEu1�a##gis%%Mx ��.� must��e eno��o� weigI��s��*� 5�e�en]�5va0��C�3�m� rigo�3ly�O*ijb !�*- ��PI�&�`&' !�.�� Y "� � ��s%�����@2@5e!� �i�;��< =G� wisf`� a;�A�ewGM��.�A2tru � �eQ��1��"H �̗mere�� �V:h۹s؈� l��` -pFP�W���4a&�j,a!a fals�S�a!����( E��UK1�{�I�-ZVal CervEGC5T)��� SICCs�d�4�n�‘AI��-`�� ��!e�6�,!�)�1"�tR&�aa�Z a%*���!M",�#~o��1!&�a�a hyp`����5!��J�Abavi7Neri� ��excee��[thmpab�� a� % djus����z��)��*�!h� =��� &���pr�c��P�sx�O��2����%)%AdyP*u�d>>�99%k^%i2�.�>1��&x �e�b^�55V%–9 5h�>[�|O�M���e�2^T BGshŚ ,"�A�&�A� appl�k�ll[ ""!u�3 u!�go�ta�i'�� ( 60dW):r�3 terv� ���D"O# ]‘break�L(,�>��no���� ٬>b)���'&7�as6g-�qS"��( OTF-F20v� $nta�h6Ν>�1��e���0^�� &���eMr �!� ��at�C"��F&i!uh$����%�1 draw�!%WR nd a]s𓁜te}�� �='Iaag�2Z@4yAes6�%AL�9&��8��h100>2�,la"�(a�=�@,�s�i�in���!��`�u�[� �ng�b9 Crably�$�Y��, �((qe�m� non-6��$�*,�!)e�+�)In{naqbR ��}����B�'� �o optim�X* ��u� ��fI�#1!,�&�/ly =c�&����^,*�+��s!� ����c� w�t� A6�I�mi��"`�O � �mJ�C7en�)`i�*��50%!��'e-ed��du�J�of b&L<�AX XC���%lif!�� �2� G3�rep c�EN0ar`�ʬ1�re-8+.�0�iE#!��ی%�T inE��c%g�b.�<�B�� V:&:�� ,2eP�a��5�'��Azwa�Q �D#Y,%� �jA6��r�*8C2R �mfac� a>Eױu� L 2b�).F>��08*��:� �%z�� :��i@"���im8u!�( �&)�x/I4Auҹor�6gD. .�s�V���E.�.%�d�+&�-�~ �a��A�pfinan�D����c��O"W6nv�/v�,',ah�<� x�e 1��(!� b�Na���h nʾof6{,A�5-��A�9*N�haK%%Y؅b��# ight2�to>��� overP����xn"�bZ7o��v��i9),��Q*9�I� ompevKeօ�# ndem< e�m"�g ������~!2�"al!.oNA��7�)�n�@decade�6];M � �x 9be��£ f5 bA3 on p�s>Wenإc���D&��!�N� � EaffordI�.�Ha{ iYG[1k.)i��v!��A�-"��ThoI���o���usQa1CF�� �Cp:�0� *GrydP���.��K�e�� u' 6�A;YdQ_V�ur!�.(�T���E�> ��llaAo*� UJG}T� R�F� !$�n�.�w��pro�� /��"*�� O""�IAg�� towaO"�2�!!O��D�a�)e.|#h�����ZG�*� %�*2� 19e�je"|�Y| K1��.~}#)U^(E��0H MԆ� EUN,��h��le&�\!�D��R�vout7g�s��� eA��6&b��W�acp^f5.� advi��#!�"�F�d,Safety Autho�h ���Q�io�;9 , em�X�PN�Y% 9��%���ac (%R���H���G;��a� nQ�.� a ke� �Q lookq8H� � ��olyN2���:� gIW� (r��la� i&�Vism��[4.5 t� L ��A��aim ��+rf \ ��of%`.gA���A� <M F�,)�L�Ved�c�ly &��escaph * ���)�i�e�e! e.3I" ��tenR�r�wE1)� X- corpTAb reall"� A�g�m��|n�F�1��s�%&�%�a�e�r�~1x �0��2`8 .#F6�WJ���*���9�����"�#&�&�"L-�z�?=]i[��^Q��w�*�ABj�|"�&n")&�lD*�EJ � ly pmS]� �:� > �Śe  + e��St�!� j� >@ �f2� ���,q�P"�0�4=in�t�F� ���5�oa!�tt���ea"$ey#9!qbTF�����- aver��r�Q� � F� :�s&�J� �)iĶ6� *�=!�  a �! manag�>�U: `l`4%Wnozzpogu&a�(epidemiolog�m�� �$}fi�par,2qcho�Btoe�A7O x� Qze�� �+� � :r2+� � ��&� A���&^� A6�4A�� �Y��zd"!#�gpr2�\)]>O6��&�>l�aօ��nO%��"5I�%� ofE.�at?�L \�**�*p�&F^ , BennetIkBal�Ou�aiW�+v�s��dux$� !W��ovX�v�Ba�m�Q er`"|��_=st�:A[chA�d6W ��]&!I��ne� -���;�q9�m i�ZJi n�p!�9,[a�!F�.�r��=/�����,��g��{�d��. �� �0-�ct��m_whe[k .�y$���#!&co�-ͻ�!^!8 ���:�!"�.!����*P.��o dero ,~w�7=��c�!��#�b.8i,�NR,%l=!��� �-4S �2Y#.��5 >_S12� �� . ��ar�Q��4kq@�w � assu�JE$!r"� �,m  ff��2�+N&AiA =� turne�E��d&��TraeHO} ( CTt&8Z2� a"�o Q�sA���9�E� �8Z:��on��Nq!�� ! 8j�l�:%$�) F! �y"�&=6sa�f$n)7rOM�!7%�}�",&�� 7�m�!SI=-��  �10< fr�!'�$E�A/V&� ��-zP=A,ms+�T�J����e%WA�.*&��A&�Aa2�/IU   �ԅ�yDe�� ��� 5Iw e^.�uV"s�v9p!I a�UBe�q5��!�H�(_r���[x�.�[�k!I�5ngS[�9`��Qyou�Lee�4d dair���R,�aa iX����-w\�6`Zth!�yk�#��%�feau���ol�!a� ve1��T@`1�-A�,!�:�i�w: � aF12�� � (�rEc;4"�5M=�- i|%7�>��v+ pe �at&��3 ��o�!����q�v6W2�(� &�-Oc�-RA] ive-�+�: SORI ,n/$ )i�%�6a{ !t� i.�B�8us�� �itej� 7ra�. al v��Q8TB!���Q9�[22��4[�2$�1�( ��+<,a>q#`7�aP�Z%� e5��\A:�E}(���lt O oU�cP%ve !HbM�i<*�=A�Q�uaIE��SOR-T�ulda#Br&�‘�e�"2-C[���`)�s�� ~*�A�Tl�,�A56stP]ɛ!��R�_.*yw*�($a SF �` M~- Carlo��l� �� of A��e Bayes��'6�A( ABC-SM�`�% sti&�!`Ed��~"A� me�t� n*�0�� :� � s3 f goodA� -of-<6À!$Jt�iECbyd&�?��ng��$ ( PT!�!� A��e m"��a�B(m$orQ#R%]�U_$r�-��2G>�&!A�=J!�� ra�V'�'-�  M�a!>�� w�D!�p.`[��sT)caV!.x A�soa.��Ebackg�,ŊeI���q|h56�!�#A��ub_�Es���[I-�6-prolon��n�5O#� �&A �~rH.� �)C";�� �A���5�*I�g�]=%e��8)mi�x ˁ��a+� 6��%�F�!I��!�� A�ɵP�N[�Tow]2 Fv� F.�e� disc�1�qar ���fU�r!G�fq7s l�>)��E� A';95%Ad�;vsva�;Likew�-�I-G� FMmH2&��+�P�Zu9 ap=e�2��J6q�)%qA��(�J)�fm�Y�7Hw=>��AM�H ! B��NT  ��a� ,!�j$rB_#,R^An����II�2� �D-�.O #   ,E�new6�Ng.$"D e/� �s�F[!���cA -�QI�A������A� ���9G*��h�]� Alow a�4 ]�q�uP� S.�!ti"�?�A\ nger�Ji�~ "`>. C(��� �pur� ;:�!9BdMM��a��gi"�egmrvoZ��� u� wild;NH&�B�6:)h'oa�m�%�V��14n�x!{!w�M�"}U2S7�q E[a�XTe�A�&$���e�icI�% ��3 V2 4!B�2houw [͜� >�[Qt� a�90��(w2�:lac�?AvE� ��e;� ToadBJ�<93ge2{�̕,&� � c�u� y�e��I�� 3� H"�HtTp%@H� �im�(tA�r��o�%mo�*�dp�t(���5 bie�j4�ant�i�-.g�A1���R,�o'A�of 9( < 2��� �!-;��3��B%��,"�noI.��(!' empi� a��p� �p*�w�;�,&�"�E۵r�5�lC�� ��� �*Wn� age-&�:� �i#�=@R��->U(2.L��-E]"�%�-�A�o �ld93�)J* 2�:i�n �sI�����U4L� @�.C,���"v"as , u6�j%�ih*(��ztpu4C+A�:es��*[ nI�eq%-�i�rY.� IV  IEq rMHӍ< ?�un*B�L� �. � m�ed��AN>Q�U� %�m�E�BA re>`?�%_ ?� ( S1��?S��y� poorA�� ^ � H&!a%�!��Oo$%6�i � p��X��qLc�r��4 +�&:B�de-offv 6y �Kr*mu� 2��A�-�� TY"%�inT0of Gutenkunst"����,�slopp��?�ps���i�"�/iT�a�A�Yeec.�(e�a��"o�P ���w�g8 e����,e�8 S51�,wo2�E�!#��*v shall�D�=[n�bA�4�?�J.�i�F"B�u�a(rimo)3�!�E�a��r�p&���%6m(�*��(AA�1�,e ZHC+��)���*� p�1SLn��( S�S��S10a~!EaR@�Y��V rac�e1#*Wv"��� :Y Dac��S7u .2tne��+�Q�� �h<U��4vaccinated ani�qmals , but differ only in their reaction to diagnostic tests and in having a reduced rate of infection by a factor�Lε = ( 1—individual animal vaccine efficacy ) . We consider a set of three 0ah,scenarios us� � ent combi &s�(tuberculin �DIVA �6 motivated�hdiscussions with UK governmXDpolicy teams . All�0are based upoi ann�re-.�of herds!xconcert l /�cThe �Neg!i�\ adheres most closely to!� cur%$regulatory ime w5 al1�s�=! ed , �positive-�,ates subjectwan addi!�al �Kttemp n �falseREwor�For�%�Replace%z��a!�isI�u!|for un1pedMiA�%�s@ed<Ja yY$ . Finally! 6�trategy-Nrestrie9)OlifXI oe] numbapf��Tconfirmed M . bovis leI�rathe!an �-� ity . Unde VLend=!es1carri�ut as u3B[ . However%< N<, short interval%!"4can be suspend!_ft�wo clear)s !�$wo successA7�s-2�5�a8foundA-have no=1.�mp0 eachaIthese�!�(by challeng�newly9�de^m�a !�le��͉�onmIe�. Benefi�fKion willI?$be manifesGif�+l proteE!A�suffici�P,to offset an��creas�@>4-D,��^D, geneA���eiEEsena�z�9޹!�hu4complete speci�ty!e%�!�!Q%�use!�(r key measu����8e epidemiologic��0d economic co�Lssoci�ue bTB ��e to assess%b)`q�!~at%�level:>6sAL demn!�sYw( R ) ;:4� s ( = �%) neeA�tQ�2�( TJQin�|E\a�ft���s i?2HA��C( burden� I�mis��b��i�, B )�f��!�9 ldthat experience a breakdowa� fore7-i�)i%tonuYe ( N�AlthoughA�of-of-��ph��si� been2����qsk�est [9]1���t����viabl�2GA�i^tta�s6|γ-��$feron bloo�`H platform [8] . Thi�e� imil�Ё��uwroe��d$ $e human TB�8uch�m�Quanti w Goldak TSpo��sayT ea{a cor bet�Uper�a!�Hcharacteristics [30�In;m��thuSICCT , � preti�m�6E�ر� adju�ǁ' rade���B�~a:$�E!G&�candid�^ude�I�� a�� �response�hree !PPgens: ESAT-6 , CFP-10�4Rv3615c . Data6=7I�S) sS.�olleca� fromm3A���i�}�( 107E� �/ �, 109�) , non-Ccontrol�|874,6D!u481F a sm��r d��Oof BCG�/ed/i��x�� ( 75�D6:b�214�W�<iti%se-:cut-of�0 lues�E$2���maximiz)�E�.]�he larg:�R� . Apply��:�A�he�2s�� videa� �hmŰ ��Oe tof 64 . 4% ( 95%CI: 48 . 8 , 7 1%-Y99 (.�4<96 . 9–100% CI%\B&P �ei]ۅwe sim� � r�model � F ranga� *� �v"� ies ε~[0A�] ( Fig�Is ltera  er� ��lin scale S9 5)!�cro��� �s� s .�pr1}ɋD ve&�erm� hea�aI��0remainAon��Mx� movc 2��C�� marg�_�comAt�� ��&�E�.���!� s ne ar� �2��a��Aq�coN�*� j��A+. Even� wek uma~at2� has E�"�,/ failaGs��%P 5B& thI}a e�-f� iz� EJ� �a mediay�was663&� ) !>e9�"� ( Az)!�W ��2 , 392; baseAإ�2"Q�*� is sam0Sison , }r�] by f\he�in%c � a 32~0!��8J451 , 554 , 0102�8�048��144~m"� (Np345��752ke!S��despitAnMype�of:kHis"�c%8driA�al�� ly!Qa high6E ^ duOe lower)�.�z!Wa=a�� miti�dA�� !�25�, a F�re�sd% 5MA6tN�P���abs� :WR�1��277Z� rela�impacBX Ax {2[!�j�-F! � >�s )q!,�particul � �� �ly!� = hc�Aaa�to� [!��� when d� n"�+reu� P GB���A�ch�we �E resultsyb�MEh�{choic3r �-e trans� ��� inde�e�_quali� v[ ��bpUrn&X .�SOR x(FSuppl���nInU ev���:�(study demonI��.e�import� of)�!m2� ,a�]�"���"_Win de�%�!�am-ef4��� :� �&� . To!�l�is qu� on%mdet��we!O� yj�-e�Ppoint)LseeAa.p%�b^�as a fun�2>�q �� m >�E�Ÿ%f>Jwe1y�M broadaNam!T sweep�as��d v� �Q�aEc.U�7ou0 w *� �!#��a%FDisM���we fix&<at* �0 . 61�cor� dW�!�U8)y� ac�61%� focu:W�� prox*��AngZA^* A$ng>2%��O�,��4@qui�pJ� !PN�&� ( �Mcal���probabil!�owF��fngE�di�bue$of&2!ag"�23��*��[aloneA���.2�apd by�� pos�or drawsI!�!yJ �!+Io��%��Qa z�.1Au1A�TGpro���o� ersa��,e � �:��� a� G65P2�iE �� + capt3ruainty% variQin bo�!i�1DE�!U9K���4graphic stocha�ATIs� �E�� A$b+ �.�(1[)!]1�ig���5��u"QT� s �5��� !�[Y6*y��&.�tak͹1-��� abov��)�G� +%�� "m�e�ly�a��� ca w�=�q� b� �P  .�lrai��*<ly, M�� �6k!�*�!����e.�neu�Aoverwhelmy�B��yBH n�A� .mofI���*�8, 币�Bp2�� . It�uld h�b^"a ~�.A!A��i�!Q���6xoccur�piN.waA�ng�b zeroEqn�_0 ^1.�t�cextrem&��� ffor�by5�t 2��?N�E��q� lt�J�5�?Q V.�dur�e(�frequen .�s� entir <2@�Q �.)�.�2.,ZF�%�90%A.*Y ��bsolu7eeR �(t least 40%e�m�6] Q<:92OF?�5f$ D , E , F&� !Q�E�. �38%� b�Z z�A�.=A�@1K Fa�A�e�٢A���4 O�again ir^ Łno���n)onshipwL>/*U"W � E�) =�is��ar� ��ly (e�s potA��M�a�� c>�!"B�9�D%��b: Cha�Send� !q墡!8�&�#�!�e�!mAcisible"Uini3or&Ua� "� V�a�I"| !�= �X$5 G , H , ���Uy�er���)�p��(�_ver�� at >e�85]1����k�0V�ށ�o�.�*m!y ,veA�ac/ E.�& j��'�Tj ����6~�U�;�� ., of ~�Ie��i��isk# leavAs&�A���he��4!�.�"i�,6$:magnitu qi�B�")��o.�qw�b'"8yA�s�u��iM end-i defimo i . � �f� VLs )ExJD6he^_. T,%Frecenr �a shi�@&t� landscape }�.�A%o�8EUa�i�du"9.|-e4���� �c�6eN&legis�u$oa�owl*Gb�$st�%r#�)e�'a �$ EFSA opinU[19vOf !ralU���{ E���/.�� suit�e[A!��-= field tri�(IhEuropean��14w&�.'�� a$�outst�ng!2 $e:�"achieeDe�go�"re�igh< E:? +.�.�toA�ten�it must��� be3 $n6.#o&�)3e!s.A*�farmers� well� �!�V�� -γ.}s�ibr�toI�x�4.�Bmp Ap.'��B>�edi�d!n abl* %��Z�62$A2!�!ن�~s��{� ed"� %�%&!AF�v �h&���d I5pop�aUL%n a&;/ a36�E�b� to 3 , 67�|ei���58 , 97)457#.,,��E at �9�710?!��5�� �&c5�traR, +.sna�t s � practBcx of:�s6�&*%�J�a7+de���cŎlea:de=�of whol�AG)l�&a+� ',A�A��.� E+�Saxed�eggew#��:J���{J� J h� �( ��a�[EA��kof��%��r��F� ���5I ��A&u�rA�o)>��iV�FVitself!en$!M%�y�;h� e� !L%�2" est-�x a�> � e me�Gism!�der"A" age-L D dor��n��s��a' �!�� poo4��st�&,A�u&:�.Mmay��%١8ic= . OurA��velihs� �o�-���)1<%�(Q!(A�th&�Nlef��t�2� �l�, �e�U�I���N^y bA�dX0in5"�+�*�6L �� &�ing—{i� �E�Q*2is gre-)no�(. Analyz!$ ly ob�ed�*~%( Jon^Vzrmeie^personalagmunicE� )H.� �nd:>�%J�&+ ��k/�a�A��AxU%t� ��+6|S ;a��!h�"iyv�2�Aәc of 73 . 3*%%61�$ , 82 % ) ( �1�&&�',"�&�(�!�.� !1Aae-@ *M)� of >�8v��ƅ���" end3��N��sliterae�[11) 6� misclass!f)�� u d3s�is im9 E gold� ndardqΥݡ�lAK�U  mpir� 6�N�toi�&�U I �*� a true�-��R! I:�"')>�A� 7v��R.cannot��J!� prior� C�o' p�,be�� %ara�be&26�.B�Y2�&�-.+9O�M<pre&�!i6q( whichAua��eviouslyWcu�-� 5�c,�5�!��a��s�!&��ich"� in�nb j/k*�Ire�,no%�Ye>{or cli��l �0U�dis�0� ci�,!&�b�o�lA��!�&�at9Rof!Eval�t�r�  J�. A>l,�,ip3aGro�#>�w� vaile�i96-,� �m�3e ,E doxaUly�an5.� i6�v11��8� ��d r?&e�&� *� �is)�3]���a�.�P !|a��2�a��!��Y�y)�4��6�|Y� \w.��!��dftE  �a���tdI� ��monitoe�At^! u!"s4(s�2' & �3pr&& *�E�m!1�"weiD=�.� %zm�N�wit���thui��"38mo�)6e&�6 f� U� %�"U1 and-slau��9%��out�*zae�"��%� �a=�t4�5�is;y�l� Systema��h�"o�4i�t��^&� ] tr� � is W� a�s doe� V9See� � stor� )C . FundaaY�!X�!�a�&� �ins�s"b dynam�1A$6�%�$I��%�a� �=�T�6=Q�+im�jD %�ex� t>�� mDa6�!�larZ s� "�%r 9�Bgap"�M5�+.��š�e� l6�.T0���cho�1o�a�{�� s) E� �a�.�y�3 *�' "%�iItA"�!}$acknowledgt GU]�TB� �'limQ8=@�kQpofqAa mean� atf*��?��id�&|  � �B��8V guarante 8&Z/�yxg �5lu�/�(�9��Y6�'��e �rrelevan�䁯 "v'���  6�).8r&:!,"Wof)*�;ppl�*o��g�� !�6�(.#,�nbi� b[;rA �"k.m�i�) " feasi�b�.�-?.J. Derog��sR .���F`P�k,� E������( at��s pa%R9�elp�$XseFT/ $.e�� % ��- libet��Oo��y����e (I)-$Z�"b(&mhf �< G�5�`l�6�P�Q*BEf!Gs b��deploy;�))�. � A�i!,�F! framework����k2hApBZ����V2v i$f9yvo����8 stru}A_��A- in G9Bri�� >Q�` llow:rAlosurEo�\s� sxict� �)e2�$:a� 0�� �AN|�)`- p �c t"�3ily��:E�}z!!raN e�<,A�tiguo� �4ng�6n�0v�a�?f%-upM 5�+e�;-, ����#a souri��D�MO! -to-&rw~-��B�,to “new”.���w(9Bby rout�Csurveill.����es VE-WH�: 1 VE-RSLH�eTo� AW0ofvrup�i/c!%du� ,FoP;$nd Mouth EPc= 2001e" e�)n !~i�4ouWS.� �1�\ A ���ur� �^W>A{`rt�9�N=A1/1/2002�s1;�.1/9;8I$;deparee�wpG-�"�#no upperi9A&8zel� �do��)� hadh5inimum��3u��e� !���" %030 CTS record�� *�CPH� i*zCexclu�&� Y��>�� iscreA+�0�of:w��&i.a�aR�� �:�match:�W2�Khe obser)ata1nQ=goodness�@f�e^  For^�M�-�s� Y.�#ist%i"� a!J""� ��:�r��?6�mtif����$ �!� ish qp�a� i�( T(��Gpur/o)Xcheck!g26G2 H�>\�-$�1.�`>%]�*!cr 'fK"!ho�Tcae!�6�1>�w*$a.B ,-Q2�AFT9Q repr� & \8lT1/�anonym(.E�a�>T��!�T,���s26?e���S1KA!�sAg$�=we�b\@ABC-SMC algorithm!�[26�bWe +1�IF�@ , 500� �d ��icl~TEo3&4��u3uni�6 %tU��@!V% ~ne72?�I�!;a�D!�\H� 6in�)g�>A("�2eɦpa�,� ��2�� �@5�q��� ��:!�,�����@multipo!�)�%�!�)>�" �AF-�!u& to�\y�6��#"new����� m�7� -  utpu � �!r%�[��v�r� =25�|���!T>q �E�!ltn�.�Jr�s� ccep~ reMs4!Y�ac�� � fv oler0 s M:umm�� (���.a�N�JNkryie*�" �%pe; KI%Ct1(rmal kernel��twx#i�)o�'���Jr . Convergѐ$�A��I����c&M"!)�\!�. s5�,I�SKur)[fF?Fig�� �Xa� 30)#e��,�%��1�a� ste� 90th!]�#ilU�Y � :�&!:( �s&i�6*� a�d'�&� �Oweck� !ρW� �X%��o"�&�]6�q.N�&�&&7 in giH;>�)�t�A�S , O�.…E�� ".L�!�'rA�%�9 tin_-� Markova cess [32]��li Snd�h'x SORIe"2=I.<)oŀs 7$�E��X[7 Zj irt%>death0�?�>I(C֙�� non-:�� e�Z%� em>xism�m�x} 1!n �����9�Qada ` iI. De�E�aQ-%!�Ah�k%�1Z next1�%%SMMARKOV�5I��`==� �) QAQtNON V . If2< s,��5���UeF� firs����aŷI. O�wisB-�(B� �%��|A��)?%/up��*"�+�^8l lize�S8Fc off-UgQS%�J��$��nLct�522�9e�oQarur pi�FA!i*_@A��wal��.!-!7�6B"�G�%w-v>o : HerdId�Hk2I7 or�)a< qu�)vM Occu� T%/%h.�Sd�M �l�1#��a�I_on5�; AgeORFg5 Qiit� !��m�\( 0%E%; Life.�total��>�!��*'8ny WIPB�AgwEV� �� lo�te�09�*�w_59�̓>��I��a0���gtim�T0llJ+�9�� 2G�:%� lifeaF:V%�%ZA�v��%�,,��.&q -Ƶ[���st��G�� a��h( ow ("�2a�v"�A6�,MO,Y�r5�f(�� 9��!6� �<�M�a���'eP: B��_�Yt-h+acfE�,�=�) D�3@+�Z:OffR86Z=W�$ ���� %��KB�� orm�%aeC ndomqTM��=,M�> 001]9�en�E����_4j��agdJ6�a�G�.��� e"ixO�%�&� )�e&�"q�E�M�begin�.o.l=f�. A���'t.�g � t!"�6im@t�re�a��%����!��("�e�V.�pr� �sXY)�`� f�Ke��%� �)m >�u%5TwawJe�~a a�} mdJ&��)^��#�#I��is�wx xB�c[,Q��Ms%�,)}!����p2�CF`��h�"� erm.�8��`EF�a��!A�)mN >7�.6�6B�e_z%Z( (>'2~.�n�-F,�EEnd3 a TB�Ea\w I!�Q`!�� �k��S "� by�w�r"� � ��Fu7�2�%2)�at)_�D�ahe[ c7 nk$&�Nm� �)� �%ͩ,q F&�dALward ,� � ,"�s.�schedu!� lN�A�5 year�@�!8J� � 9��!until�Q�t!� r�"+ �.� deci�#>s=0A� �!�y�Bin S8" . SI�b�&y�@�!go�V m�:>inp#W%�whW5 �(:='or A)��<24%YE��^s:? t,�� ( PT =!��Nn#�D�f%��Ud)��9�)�%!t�9e�#.�L,"dIA ( SI?\�B&`ZsE4M 1 n�^�"@!AY��/^&25 �RZ�# LwS# s—�Iat V�AmA s�$d(^;aA:{. Twoq&� , _six�+t�b��m.!( VE-6MAn e 129la+["12#��n}�)�A s�!:FZ:6y!�, e���:�9&g16�B��"��[ �qK �� lso6i�"�1.l[0_ s �.�rE�iB!H  ccoun�$!�*%Ha� �]Bqe1�A\.�del 9)ngta�$�= "�,1&�e�1J��:��d2�direc�/%������iɿ&!c&r&�2!ypŔ:���ɟd^�in%��!4�9�i%}"�� K!6:J�hMAmB2i�g� eligDcr�4ia��H aZgir� A#��'ur ori�X�S�;&T �$.�%xV��W���� �`� �%B%rpoE�xSR� explTly �ZaS��a��%��th���exi�#� L��*�3 pre-* 2� &�A�]TqA���*�gol�e an 6 week �l�>aI��e*d%Ñ4�#a�8)���be.e2�@N�@lA l�/��&�J��&U&T&%C�,"� &`W��&B�.�� era �p\:�W�Mul�gNom.%$� Ifu�i} ;0W N�{�!�s!�D6� �K<d8)%!6� "� � e���i,Mt-6%-'ep"_1+0toa!� �sp%VR*� ���89:�by.#Q�AN�:� �k2bK"�)'� ��Odo"eE:n��)uB�)`.��5"> � �e swi�#� V�)�*s ���OTF-W�le�!�� JI2,Nw��Q�F.� earl�;��ńu�$d:\�Fb�S ��W@3�@�' s—� � !$>/�pX�/#�Il*�I�:!�dA ɱofoG� �0�#�,%�!Q�is��{�1��٣�i�-�}me�"�a look ����� 7 ’s�"�,#F a� tVf��N-G�.� � BernoullieF�  5�#2�*� )b��)�>�#� cul�)y ){��%�k%!��� carc^/*, e&Zf,� 1"2!{�0c�4:y 2�sh�8�5u�2O)�"!�3I �o�A"�GFAQ-Ing�]6Zg the Asig�o:uPSL ( ɑ�W�f�,�����PRI�;=�^2.�@c�: at: �$a ) =PRIPV�MK-�&�,�1AJY0s.� )up()a�at"} M& �4V^�ye2pha�7"Ph��S=}10%R��*�chh<*W5��a*y�w� a. .L�"�2��� 6� �N"_q� �+00a�qcycle=ny*� :� �u?pder�A��a!� �F�4��=i3� OB���-�_� �th ib!� ,))eI�G5�9bnZ@�o.V8��[4] , [5t'�e�_tu U�0��=�K"zob� e�d�=su�4!e��YliCi�Bty!�pos�>.q��3�!aW1�6aOimeo2!T� �K R��X~!p!L#y%��Zo svJaQ��Oprogrwp�Jo�]�a�. CU��,rijh�Led�ut�^^�Mǁ�� �6�;ein�holog�J ino�[d9��;but% RU[2!�H�V,5MT �cd9�V!�5�`�bt_ -ua fici�D5 )�0"0$8ru�$3!)�i'5�%��%e sus'o�B"�$E. G1$F23 }� {F}P��=!��E�onEeJ.�,ho!*toe�lY�W�4m�!X)b�q>EN����� (�^FZ�����_-capit;FduU%E��>V|ac�OA� "Obi6�is\%�U^adn9a��6^!��\ *WQ���as��k$r�9��)�Dve paue9� �:&@}EF%h" � �d�aB)1�eG�)�`Er�P!�6)G6��4un��#L�j =�5Y*�ba�t�-��w&h3tu�( VtOVy(OV� �c�uO!�s�R basi~y�f2��<�SP)1�y-oQZ �A� ( S7> y.&�&]*P2�t��@%t �t��Gw���averag6�7qOon bW6NyjW��, [33���o����h:6y!*laY0#.*�Ft� &�=.�$)�IS�&� exa-T%{�as�%lyYoD+�� ) g,'EyW"est��M^btTV� �;3t�La�F�;(�yXbe�!�"�:A�6�an5�&.fpD~.�1-pDFP�3!Qr��'HYv>q��vT� 1�:e A�Eohf�a gap� b�Aghl�SAhiI[� m?�� &�1��"�*w� ;Ap/d&> �&�r.�:� � &�T�J�J�J�JE!^B�A%UH"�4j�I1c!���ak X*A��A�"�I2��|�As�"(4i�j� >ErwD=si�6&>  7 :qZmnV ���.8� F��!�U�B�A�F�veL o�4 W@| m�!I"� o&�& K y!r"�$by AHVLA [�3.�er.��:t 9*91826945K:d 720�(p�g.�. S"xM % ad"p e!����!�Ekt.�^+:����6�<� �c&qf��=WeAGZse�x� wP4I[� "�.cof�1 �f{� samp^&C��y!;� D Q��7�c �!)� 9=�-� ��w"ua�e�yH[$2=%��a�peWm�qaY�!�� &�}�3�i��T� t5Js�,�S�e�I}U�y� :n(V9f� �"%Tt� u!}6��H �8&re� �BgG%�AS�p's>��;yJ�&���C-���MZE N�6�W#&%e�Q-��`0!m2^�a�.26G9��z�Q�d"6�.j:�B:wv�A�h �[U?E�coarse-g�Xed 90-da eJ;���)5A6@I� ] �s.�U�,.f�Trichur� iura��|��!�c�pworm� ng a 6500 millAopeo8 glob�%, dama" Fphy�J grow�2�e��e�=6E�g� Q C��drug t� ��M�.{a�� �i�ads1e �,z v�M�n erad�R�� amm^�IZ�~& �uvelop� �M%R uriaTQ. U�.9qm%w�A|ablished��!�T . D%�,�screeAa l`]�2(f 480 novel%-a� �{ molecu'Q�|8cai=!�l�Q%o�r viv�sau��Q�=IyWL0hydrobenz[e][�<4]oxazepin-2 ( 3�C-�#�E�antjin�M YY-��)$UMC)!��AFEj�edcA resye!� ��GF =|#�^A�a5�xis�%���_ child>e��." m�N���NhA)�Tiu0 M��D6 A6� ( MD/q�sO*�y�G[2�R[*ty%F ���imidaz�=.Ai!aip 9E,s alben6�\EJeoE�% i�2�cu�Aa !1*X��r��az;�%i|� lerrrm��g�b-���%uA%�>yRt�8E�� es [��en9��hib�Gicrotub&���*AlY�]�J im �C�un� lu�& d�!�q�F as Asca� �'��3e�.� or m=�i��n.zof�Lo����,=isY#al�`E�j ,8�ydv�w burr�O� u�i4��alNT5����Tsom�U{�A��&>!s��aO�>�A�%2�s�u�i�fACɪ.Nof�� � A���E ����s`�)!Ʌ� in m] et�sʊ��-:�!)wo%��D6�Vo$plus iverm�&n [10]A.�$ox�U�Imo�[��`A�&� Ir�83�=ro%��!+͑ le-p}����B%�yT !�>��rgav�:RT!!60%T0Ab�!al�[12 %3� �d.�� m�#*�t�-��3 o!�.�y�AM� e�!# �yiin6Mu c>$�Xer/ X:30��A��ab�em*TE�4 [8��TN�"��l*i�R�wE�&�E��zA�D �v'�����!��q-(pproa��new ,9e��A�� rug� !��I@��l�e���|ygien;san��>d&�2s������ anti-��u� �A�]e&a*6as���"o�C!T~ / E3�is�� A���ma�sc�^_>t^!;'r$G%+�"|b.�.xCELLece[];:9metab���vi�lo�"A2�1g()�sazD , MT�Se,cid phosphat���; s���mo_pj!riseoa��[ca�y [14���PM0et�plq%%p��%�n��j1�9�. Koné�ߍagu� e�8a�g pa�H�rh:m�a�[� 4Côte d’Ivoiv4o�1�icqD]f0F� .} s [1��Notoa�� ��sI� Combretum��r�um� blockA��EIU�k � vitxz�,�a�am/du�=|�`w %�m#J� �  j. Papay!ctex")�Y en c~R|1 `O)���pur�P�$?8 papa�, apid���AveF6�� �!`�;�(�-2���F�K��NsI�[��M3ߥ�VP�.Ta�vD|�J*# �ils�e2�w/���)���a�b!92�t.&.c���� !�su!:n pTK[20q H�&��]�9W�9��* �me\P0-40g 1� >)be2��q�0pat�], R���{oli 7��m��:8:�Bhutan�� dais�Ajani� b�\�+$, bergapteI�isomyr�ca �2%� Pleu\rDWam0e )1���.h��$j#� e�n�R��2�c[u7 M�[2�22!��&�B� comm�%J!un.��!��fa�)Lu�&�"!�I�>O> soil�u�Xc�3.��i��w� t�_�v�I)�[ �nsu�A�a� !��V, w+:or x� �hV�I��� A�� ��larva�v�A:mucos*� um��:�E9o19�6�,����? k&a�Z%5G elum� caecfS�}al%��,N��9&ha��5'ɣ6�{ �a��m( or k�ne��ѡ^�m%�f"�>-Con;b�ng�Y� MZ�dr9&}d'(;� U`:�%@.lA4in_sa�2�TA{�NdEx*prw Xo6cbD ~"@ -H'A9U�L�L5�ѓ%�-#3� b����9���vE�rol.Pr avoiTs��O �R��K�U Iw� (K{�?X9ual�I(��in. al hotspo�t as�=riq "�Lc��Vb�9orU��� �jt� �"5� �!�!c�����.f )e3( SCIk�ee > ��[t�#� � �l8 ! Ϳ capaM�8�l"� �$�=c@b9�M�*�( adap�k�: [2� 5-e�+#"�$9g!�%2�BaM�geL&�j��- [24]�embarG n &g_<��Kov� sear[[!%w 6Is���YaU. a viewa}����-Iu!�He��'t!�-�^Ae*?�j��'s �a�ly�9H uI�� ��� ��!��A ediCx`GF�?"5 A".<2�0�,�CIUn.s tManch� r AW! Welf�X!�Eth�Re%� Boar�*d��/Ф3��  d���hek� KingKH�Off� Sg�\,ced�Ac R198gT�F.7proRWlic� 70/8127 &��~&���%b,meB&hTServi�0Fac/ � �Ҙt��.<. Ba>maM4nd fe �[m�oi� a� !1200 !J�FU+3gavag� A + y 35>�,�!up� 5�ᚡ]� eir5aJ�l[yK . GuT'op� long�&d=a� w� pr�rARos��_k Memo� Institut�9RPM^E 1640OZ*q\1'penicJ (� U/ml�>d��eptomyb 500μgi��Oorms ��Jd 9!j'forcep� W*1� :�m&�Lin�-��N�ti�x*.ly 37°Ce�d��A�6$V$�"2� "h3�Q� E�|Ma1�9a@ll�* ��75μlA�!���c"�J���1%�z4on6���. DMSOV ���sol��in �%pri2[s`#�<6^�1A=6yP� ��Gincub� at-�, 5% CO!aD'���Iwua^� 24 ho�.EV"$M,�+f�;I��&uto�;$�f�n�m�5|a E!�A�b� ach e���reshol� � A!pixelS e�'yca5���'� n"�>�)� �"L*)#&r0[2��_OneR�%u!A�>�%s$U�rep�_�~:�>!� repe%�--ek� ܈ erio�yf�+zCgiv�in�=Bb�?r�s�;"vG bUor v�. Dose-bonsWr�e�*[,�ka��f{, log-Y�s^G,IV)R packag� c [2J�{�&u!|�AnDŽ( ChemN# y Re�  L&� ,��E�Oxford =�n�@ŁEI5�-000� V�&��UK9mb����a��6" A��(' prie2) sk��A pilot�!�u�})�La'5 subsd�o8in5(�%n�RAae1�W%8 sca�lC�)�!d�M-*pq9��:me"� "*Sc�n Z stry�mA�O����r�m��twentWzEA�mono-%E polynic ~uar��+��,I������b��dI�=�ha)*��m�i�� 10mM 7�� ��!� froz_t -20� O?�7A�:��.�+j6���: �5say�%��}gU un�UID�z�aten�n{o�*- ��1tJ�os�(�#i�RA�ip��h�Yh'� 1f�1,� /��$�+� 'map�!�VkZ7W�ror [2]%j-"� �F5�re�R8CKli!�M��y( n = ��-r�f�aa=A�e*U%��e���Q�p+�t�&"*��`"_C?�eB�"�!�M�rcӏ&|�YB�� �E�u�!*;A�$ Infr��( IR ) S�0ro�%G�# �c y ( ESI-MaHRMS-E! aNuMag�Re1�� ( 1H� C NMBa HSQC]�M�kp+l.��`I�E�w)}1ar!�)� S1 S4(�.$�.!�Z�  %�&A w" ks� %�vehBE!�!�Q�tyH�> M[!�14 sa�room ]�ew�. Ex�E+� �%-&��in �!t30 ��@�4�)b� 1J� &cuB![A�&~1� �I��mwcae2� �p&��A %�p�'o:HCa�P�  &z �dO-ech�=<����%��.srA p Rrg�ng�#� &� E.�/�'�;mG?;f�!$2� �E��-�.�%�%�B' &�4E��A- �e�� occa�H+�A�refQ�!�-�t � ata)*"܅�)� "� (I��2��'� [Aj� , C]�wo("o,'C�C$OX03153 [B55�>�_El� , �a�`Vs:�:a$m|: 1�jO�,:�E,l:GSWe)]e7)��2�!ANOVA�1~v3+ � +* ��"Ano2-C� ��`f(" ( P ==]W�5 �\!�"47_W^r�%"�AE,-�%�DE" on�yj�)[ �2�QZce"rgr�( F81 , N�=0fP<�000�k �� Bcsho�?I�(Tukey’s h�0�g"nD��FZ-� gwh"c-Z !-�u���� ��"�!�,�{ un-�E.�E�MeeQ�*� or 56���� dark"B�e�� ��� 94Olympus SD-ILKa �hU-�� ��. CMT-93�n�c�/ep:�0�6�4Dulbecco's Mod� Eagleed� ExV%10% fe_cal��rumACS�1%*�-st*�"�(i�00. C&  �96-7  tissuGlL!� a d�3x102 �1];� vo]$�g��� �96�(>)"� �&ng 30%��flЛR� >6� u���kNa�%EEU�a/a1c,!=!J &3ZFE��Z �)J~��(!�SOke[^ �pchlorp/ zAKQp� vaU-+�c.b3(N� 80��%wAD. M �um�6 aD$8��]rb5%��6+5�)W� e�K"� P72-��Q2�*t=�dhe WST-8-T}& ��fA� CVXAKit– 8�igma Ald� # 9699 Ed !�LCCK-8yg"FeAfI�,Q�e�&� �a"X��! 8 @rbT Y ��Z450nm �a�]eM=�U�, = 9&e.�"k'�6��Ae�tfy�$a:-a��iazan dya2F��!=!O.s�e:G,m�% � %�E]l PBSek of neuȗ%an��D��efF 633v.0�( :� N288/j�R� b-���V�!sBLB�!��C�*���d�5inYbu% e9o��49%{�M�f ��1% gla1 ac�3)).�. E�I%I?� shak�Na�&�10 minu�m|j�54�M�l�U�I��~ake0:m!�.��")��sA�Gf� Pad Prism%&f�# aN�.Q��+��"�4!n-:e-�x3:hipWe"��� 2�Krcdk [2��؛��T���;@89�ly�2lS?stE$~&��J@l $I&*(�N��]a>���)�@m� "]( Caenorhab�"s eleg��� , so�� �-G.�Hon*("�! r�&W �1b=1o&'���a-orga� phenE:$�<�6��<>��"lys�'m/]c* ���?!:6;=sia$,r� �< 2Sc/-�MCv"�I��_^T�=� �A ou��G "���A���O .�d4MriG�U<s96L-E,� M�� �J�v"_4��1(�ā�ts�8� �a�raw!_i� �$2?6�8� (swim vigoro��\ol ��5P.�<1�)��5�toΦ���4s{od�@e: volcano p� �B� &CEEI/1�maׅ�!��,{le��&�ly � H.) �1A�topݖ-hVcorneg_��a :����fu�WUawe�p��� a9"�E���eA�I\��P �85 ( Mann-WhitneS�%�20Mi%i �A^or"` =%��"[ 23%�-� !r�i�y�X M��. 14/F���))�7��F�e� HolmTcu�)��"{�arК\��te.C>13!�v8 �3)&uv �%s m�c�*�$[~�A�1D ,We{:�Z2/>pDHB �Na�*]%��_�vWly%'reJ>-�e�al fam-�A�)!�tF=Td'i2BA"7invertek�%#��aE4. If��!� DHB�>�3�m-��[30H��tc�*%���D-� �b�^�A�f� reiX4�cri@as�����m��o�t�i.\ hks:ty�6i���(iߐX�9���Eo"x�)N>K cm�-7�ix���h;M``�8�d.�52�:��.���qbE9g��̀tާ~ ,&h,�m� da��YM l̟��m% hypeAk[z��0� fR�6�)is�(��#&�#1aA333.����. CQF��.�+ E��"�(E�E�A� rF+ T i:k�Q��%u�!��+ i��Zd9, !-A[6,]��*�r���]c�s���*m1,�,c&~Di(DQ��W�7�� �pre� ߇�k�b'�!�-zQ�)�A�4l292)@ei$VhC�6W��9Y"?� 2D .��20a&��c%kM�&-Rr��@R �is�dy*%<���1��E'��.3��5���$$1 �+�� 1D all !0^a�A]��3g �W�Ag! inus�k� & aV�J��6k�t��%��M���q�%=���a�is li<�CW*�7�&, ar weight%yD� 3B ,�armanbρ.��?�^on��R�p�ed E� phob�hD>p�SpNp3ـ�r�e�!h�E��9t� LogPE�m��;%9 cumu%Q0%��maIC���,�"b�8ref�Ga�aY�d&ItyV�A�permea�Nh�4lA��4/ �:E�%Heb�ma�A��1%�raF)A�ձ����GZ(�" nO"rB��$E��j���.` � e��se�&/` ycampaiga�ad�{ riag���E���!�2""TSv �/���1–2'�*�K!72m�5 '2�N)#2�,_R2�NRAp� )!�e9 �IS|�T@9S�% tsm�Bmi�Lengag ���e�:!C1�&�&� s6��u��w�� xc�t\DaD"%8majaU&m� ��6�1�6 ��I&�E@ %�a���um!T*H/M9%�g*1or 229μb"A"�5L4�:[16WFg�5L1(vk�Pj57 i[14t<M*�H6�f��p16 �qg n-#at=( 678 �x�� ( 33 L�L3/L4Ek>��7L&�Qi"R)>�>%�Ao&�I�u0��&��--RJ" �.:oeff��teU�a�?6*m�}B�G�%G2� we��ha�fD%�ny-i�/wA���:(��*���"}T�k��I("��nsnM� ���)�@� ���5)Q�ˁ�sitAas op����� �(KTrF%�examplITc.![ JA�a"��a{R windI|�Vd�i �,�a^F�Yf�+,^�!�2�ed��vJ�T<�e2$.�"�'�inc"��n W*!�0�sՙ*�� 8 &�aZ !�I�BM� P@���C6�"�"�al��"%4 �H�^"U^sN�֭M�T 1b�f�nM weak6�(�>���N�U�cQoU�� �(4 )a�9!P7-pyridy�0��a ���Ppophi417-bromoa�14'"`i�>9 Kd�ed po? surfa~�re�$tPS Ij|d� ranDj&[3�m�m�m�kq���$ iscu�J�!,ng�:��= ei�@ry@��V4Lpl8a�QiM1m� . T� t�Uesv�D���F�a\�E,��V����+Vadequae���a���� ��4 a��Je/h�T `=oD!�.RxF�6M�go0G Sinu<<#>�3� !p  �Fp��� Ab:�&P�.NZY>�A!a*KUt>EU�6(�&����x�9h�q�2� �Cr� ���*+��Ty f*be�v��"2Y!Do���zuti?��ۨ�1fa-o2/ �R"FEs&�� 1I�aC�4�(m*� n�Y%(Ainvt:�I�� 6G�i �ƻw0��E�*KCa�A6G�W�H="�*SbG�%��a#�8��vz�N�%G�a�t��E!qv)G���$�"Z�-r��!��&NH{:oUa E�l2!V�` R.�oass>�&*:�"!�E�6��IAp�A!r�f�1a>�Dk&!�AX Mwes:&4m� 2�!�5�A��� !@�p?s�q!Ka�kay��Kmb�\Asoa�C-xi�>!'�kE3=U0F�2IM��a7+f�6uI?y�:e Aon�-"3 fc*�� !#r"� ( �ItL��!!�1�$� o�Im"� 6�BE�"�%ۆ��in�6B�DR��.^����%R (��/, "� 00,!?Axs�=d 5A��H���,�=�10-75!z��ҽ <�/E�ed{-up�7. 5 D�1�/�  �Ɂ� ! �����US�<-�yP%���}m*!�U� ��V���-�l�@�(u ����SiA]a�h�@A�n*��Z2^���_H�V[d���Uct�He�i�tem�eɺL�E�!�*U��M��"2M4� O� �G�dR��P� p�_���E�ewI�] !��E��HAs%T΍Q.�oBk ���bJ. S�S��B�Q��reP&� �cy�beGWd�\��!2��)�r��ve�""� j)E�A��@�o.�FE��` e>GZ> 2Q% *��p4=A.bhK\!��TBN\\,*Ym{<X0[�#e�n:F<yP�[35�"prazi��e�, <hoܳ!K��!�E�.r?c0�s�Gaw"� G calc!.o 1���[36�ia������sA'Jn Q�Of�p3ly�y)�s�DL-gluta~q�y1#\�u4nels [37–40]�g*e%Kn! !�py�l� nicotinic�WFr agonY[4�`"!lG�E>N4yXsb&,@, rono�� R���@~o�s� !�yy2ss��_e�a�i� ��-� ��d�P--�) hebK:e! �=�$ed�Q"�,��� .1_e�$`+ ,��� �rrea��vul���5!k�����!A��%�`B[4�Fur���,�eI%�2��^��:�`) Y�w���& ��ly 28%%Q36%4n��CA�v>.[p?B�!!=:�.[de[\t�}`���%���^J�^����B�\N�^Atj=%}�m�.�Bo�!�݁^B]%�":�E �KI0e�/�!�MU. S-B�u <�,�{ l-ag�hildr Sn P�N Is�� �xnz�U� 8L.�%�a"Ɏzoz���g, t\P)n���� g<�#a���anaer�! 3gp�}[sm [4�OP ��_�F�!I*g_�6�[4dS���V���n9/T17 }Kq�%�.�?���w*�'t �e��Yp�c��#.U:�bs7"_.OD���:! ( 2N��Au&}d�.�� 8��sa#�Y^ ]*�X�a�8 .��a�es�Oticipa�� �dba���H,-.�>�5�fE�1�I�o:�a�.D�! �Z�"��1�ԡ� ��6�5U�) egg-�8� )��6k�*L5�e?�epua�ap�'� m gad�`7 %�"],["�b� A �--2 -X�FLAa M�d) �tob�a�e� mU��� .l�D.�.�Z}un �DdE� �,pr0�%P��K5ce�,c�J��)�8�\Uiveu��o: �Va��A�,� ��um�49:ic%�a �� ��� profL��c��%�is�+oa7r�A�"= * ":."� itU%M panace\�th� 6�[4 3�1U��&�� hooky-�M�wE�� ��ϦNW%�-�B��!܁��d&dD*'�0-"�b.BB� ��n \r ide�:er&1so_nV�s"� �&`W!�pip��:�  !�,dr�aG A�ly!Ko�}Ŏ�v��9xnIng V(�a� � ��� �aP�07a�T heal� �� , �5"f �!grEuApe/e�$as Haemonc7 7or�~.*� c<�Xrde28s e�>�a���442e,�k��bI�W%�&'��so% = y:�} u0�jA�]� �vDf�"�B�*8����a��W�!��/� �r���o=��v(X tart� �#!-!�lu�"�"�%"�"=!. F"=ae7��.�7 W��MQ�t? g���T��&Lb�[*�J�rfn.OX!?83, �vCo��/�s1�� �.�v"�aB,t!9M0J�!, ��,~"A �� w�P�uy2T*X.I 022%,&��: !�on|CJq�A8a�e �� t�"F_+�Agc.�, �1#-5>49#�r,%>KR&�0��o��-e voS �a�"�![��' e��+{ �.��)�%��~vifKR��BH*5E�.�for the� parasite , and are encouraging in the context of optimis�Rthis series further for post-infection treatment , which will require strict safety��Uhost tolerance criteria . Importantly , the DHB chemical class is both drug-like [30] ��key%ˆmeters such as solubility , permeab !��� M^M$fa�.cAT2e, includ�$lipophilicA� needA adheo�unormalA@Lipinski type vala\ [46]Afn addie�, a�U�c lQ�may68,i E�any5E(absorbed5�9z,rapidly cleaAI . Thi�)�;p�! dA�ibu6�an anti-9�i?AA5l��ed by%burrow!F�(whipworm in�]Y=epithela� cellA<)�!,provide some t��from a�s �iQ limi� understan%��is aspec��biolog�k@but a study has d��mi� , aftere� �of pigs �.edI��T . sue a5coni�%\of��0benzimidazole �in�Iplasma%�%�!�%@RA�s��[47Aa!�tightM[4onship between.L%�2�s�oxfen �l��h)lus�`E��;!| reache�V T%��circua�on via��-9� erea =1��¹feb�indM��W)9I��] lume�!>r!�E/e bacill��baa�A@ialisedA�dea��e�in)uptak��als!Fou!�to be i�"  [48!�QuaZfya.!=%� �routeEkinetic%�%D=�Fll\r��K genera? pharmaco E�el عO���� :G%�9 asb . No�1helmin�n ctiv�Ia^ prev�l��en re�}ed��*�family�ind��itInot bBim��i��$y inverteb% Drol approach . Alt%� weɕL as yet id�Vfi!Jhe*�� �is�of#e��3dihydroa�,oxazepinones�0a novel��n9*sIi� �G their 5Mon�α�"�al�5cess lea�-�V&9  e� is long ,�}ensivA�A/proneD fail� shi6 d stage�E*pr as=%�= � D-throughput screenA^d 3 i� �5.axPisease-relevant assay�� well!� buil%in�� y�!`%!_on� arti��rly��Ao &&� )6e8s ( DMPK ) . Re��%Orie �rug>_ negl �sE罏es� ish� a�d �A{hit-to-%�1�[49 , 50�p��6?meet O B2S!�se�!e��a���7�.��world�asa�firmed%_� w� syA�siz.�X, sigmoidal dose-depend%=,* chemotp Şpasses%�-lA fila ? a� � ndow�cytotox� �B$ mammalianų line!G-Bs} � ��%E�(N�O ll )12V%�cB� asF�a��!�14a a� amene � E�dC se��expan��)suiAOy%1n�.i�i�tro9�-��in[� mr,( 26–57μM�Cquivalk 8to 10–20μg/m!%:.H213on ( 16!�winhibX again�heu�$microfilarc 4nematode Brugi!�layi [yl& st gap� JP e:Bisqtoi�. Ae cus2��� s� ,:_thA\m��1A:I��mf�0��ve smAv�e! I��6� !)6 " �� ��w�  ne�K ��a�iE}possi�e���y�4achiePf7milest�Q!�2�s5�Ah�j , nam*a sub� � redu�in � burdenE�vo � !An exci��A�le!N�usͿe��6�aro%the�  environD!�dec� � riska:�7n% Ag�!�egg.9e> ]��2�c�all� w} de�sin �!a�mS%LadXstru�challen* . CoE� A���al %��Ib��E�e�g. A";� �nb�w��aIN�� both�i-�Ӂ�a�a�I��A�v�m�&nto0killing/expul ��A�g@. W� e fa  ,�� �a�E:f�sW��initi��ba oIuur�d�)���!����&human" �(uriasia�Howeve 3econo;reali2��ofI!.R �Dmea�� n��mpetu��hi�N"pO�At �6�comp�:a�health�ustryel�GT"V��at-� agr��A � an3 _!�\LpecEW�; vulpE�!dog�Cb �E��G 2~ caus��1��A-!ty Ql� ig weA�-� [52? 4 Inter�Lngl��BVoutdoor!֥6�du� ��f�}�Rresul!� ccum�of�-|d��#,!�soil ,��%�!W%-�an=[52�T��Ŷa2�ale- ,q���,�IeNmA�b&�usefu�]� �� �i���� r2��fe"� ! &=u�YF.� �� 20C ^ memb�, e a to!of 192b�� { ����soeO!�_i iI�M� s�� star &�^Far fe�!}atE ����.�5y eZ�e��� \�.�r*�e� idea��"(���a���L�� !d!?��2�j. One-�-V� �� ,���er� �duca�ya��m%�"�}4� , pr>way!�a&�.�u=!�: �successe�c)2� ���Q)��� our autom��"� phen��platf�supporm�8 tyae�"���:� u�%�Ta2h!�%!�� �4o� !�!s .���A7@$“date”D“Ayhubi"W nflu a�E�!$�q rotein– ��a $on networkauD�Xdisplay � co-expres����n�whilsty B�Om :@� b�o!6� L :aElo�!(coordinator+ ��) glob� onnec(. HT ,a�shoK!"��cPQQ!)�QV � fac��}��� inB bseq�m� ru��|,fewh��!,)2d�!5{!���!�=�cor'!��8 ngjU=a k"�E�q�t�hub fun��� ate/{�!7! !� origlyeMveWbJi"xiaj� imo� !)�ofo2M;>�is��r �wrobus��method� �. A� �� p%Ak&$I�)minl5TeI�2�AU� ,�fT *�=5q mf-�1z�Z1zE"imi��u/te<ng�a�a�We i7 thin�� erm� aE�5�chotomy�a�� �2�M��%!{[ ing�z��it� bjre��t�nce�?of �U f- .n s ra�� than� vidu  � Pn�,a� �� data obta�techniq�"s�%yeDtwo-hybrid ( Y2H )�!t,q�cap%%����act�=�occur!fv�A �aim phys�!I�&�5a��,fTm�ed1Ws�iy amongahe tiss�, n orga7���i. ou im�u)>/ ��{EJ��"��wA�v}a{�� u��m ,M8- a g��  on��when �6�M� [1] , [� �w]incorpo?%�in����Gt mRNA1E��E*E4zar3ex�&� anH� q .} �s extd�hq)q[�Ia.:!5�S�#)3(��{�T��y defE�^as9��degre��� st 5��� * +ref��nu� a� links ema�ng)�dAB.�$averaged PoJك coef!( avPCC NM��Et���)eya��&%Vat �f)A$w�ɉ� es: thos��a� t(�ch!Wy ��ate U)Ec2;�<so- 4��T�1r�&e����e,%�p5 her! � ���!d�*."!�M�: Par{A3�!t!�" e ZW+��s�A��&a_oup[�y��Q!Y-�ed~O�M)�$987descri�%as%6 er-lP!�) �  g tpe���Ec�a�[�Ka��t�_*� =Q2*) valid�8�/5�M ti�?si�V2 deb��, sequ�%5apa.[3]–[6�t���e�a!�be9 consensus��!M��a�wo "* �� E*�ne� are:3 ) I!2|st:5 s truly X (!�op> o exYng � ntin��vJf�,oua@ear-cut)� ingsm( 2 )�-�V E�wa!�" observAJ"H m ? &��@�n arte�KGe "�,��F ? DU stat� R� >)eemxyy answ!�."d,A�pite (�in!ca��)P !�go!MI"�� hyp� �AIEC�?ly���n�E*?-�� , [7EL15X� fo'ha� 9� !Batada �|3A�[5w2 vis�$%^iG);A�- �+O blem'6.T&Q �at%�5�.6accord�AKCi��=we E"`)��beh�urY+ � deleE�����u�s�q����!��!o�k7�x�m� &\/to:� �>!�.� very� �!�/`.� �M�ic!�^ U�a�r�"�. M�g�(F K �a�m*���,c to>�%"al�jD��s�jx�!�mZ��' .�͒ Ou9�� �/)��isA�tl"&��n�j!�� �1�$Ehl]A� )�r�d z gori_ *%_,M8� ‘��.%QG��&��fA�unقceD��M�<�/j!� �[8a�c ap�!in7prF��0nt� by Taylory� 2] argued%�!� exis�ś‘%�-��!N ra� —a>3 gY��-&|(%HLy�—MGh�zac��22^iq��s� bin�"g|] �s�1�#o� %w�al!�thma!��0ise:� ��=ox A kern�*pGsmo�#histograX)�2�� \ doesin %-"�Rly2dev�"m un�� �DIP�� [1r[17ES��s alread�,�tby>�)� � %%��,� N���bee�a,a�A!�!" p% ��A7Ta�.H made�iqDJ��hEj �&sN�%��t�4k�~�umbe9 ev[%� absea�M�moB��A�~iry��i�ttemp� S�sg��9Gof��%�K�� �t��  �!��/aR&2�?Z "�q�ar8MA�F�ld�'p� s� sor%֍46� ,A�t� ��i� cohep-� of nodw��[1/5+ �Fio+��� te c��� �. S� sub--Gqknown�c� /, ofte�spo�*=� ala�ta8� 2m,S��tudyi�/�aGra�vEbQ#eIcQS�y��� !��N9�[21 ��+A myriad!*� �x �*4cr� �51[19�M �C7A�.�$n��pgraph�QMim�Q�toF%> ak&C dfae? inQ5exceeOe2� "�!ex Et�.Rrandom� ( �eg .An%z� eachE�� ���>�a�z-6! E�es$w5 Qe�}� laced )�:�� �( dard.�A�e66�Oa�ec���2�sa%%)�9���max9<ed:�W��ZQ,.��x4Z%n!>�rG ��:� �$� s!��P9�purv o� b"�; �t�y�*�<>-*� �)� Yale!%!�b&eh Zm !�": ly�u in nT��sh�$L*%5�{(��w�n q.?  � d5nfV;Y ����O��rU+�,a<-?E/�e�mea��1�,BN�mp�5"�E�mea�:c��� A� �$mסV��o� :�;mu��i+|��I/!"3)���Zz 2aY=c5dwam"Guimerà%�Ama��[3=��|�S[>�>Qd,4��E�inI��!c�6:We]�-a ?Jse �m�)�!:.� /!�y.k,Y!lib eg:A  �!�-O@ �wo\: ab��>�"F ��� p&.?a�� m����$&! ��Q�# naly��.�^p7 ��dis0a�ngt, ncerR5�� lete�1!�r�;� �lac�& reofx2&; ���5se��5[32�3�8s'��tg��"Ymulti�BI��!fm�&pr �!Nc�aff^'y� & I�I�|( romek&( AP/MS� ( SeIb-B�in Ma_5l[ M(�)�p!� , Yu"z e�]of .8-��&e deri����A. sourC-4g�-!2����r`al biasp� o a���)��z�!P]��i� %�B[1�/In.�RirqT�A� �!�teS@��=&��I�xe.B;atI�s� �v0a �orE�ѐ�l( i .E� ��ayn�C.�!) —�asM!>�2�Oi! � x:��in F-1�5�!p predA��0� � �6� �]8�6Uo3112t�($=MsF$�3�2o8IIbe��N�Co !�A�==�� .F0�i combe+E������6M��"w/ m�1 s\ �Vt�W U9-��*1A>� 5a surpri��l�#�ofulapV�!� �T0��4o% -b�ݍ:s�d"~ ��� 5 a�S 5�b��Zk! ." �[��<woqD,�l a���7��B�s2d!�m�A^emselv�%����;-j �!S link*�ce&��ũ:r�, y [1 [39]%��o. ����2�&9� � ye+!�*�Y)�Y��indB8�� �{n� &��!��T�I�U�or�T&�� A�`� �kaso�9] �=�-$)G %1:��#,��!�-%vicE~;R �f��s��'Eb summ�E�$-�)apo��dixox�0]H5##M�i^aS�p�Q�*#�"�#i��E angl�� demo�"a�GpriKrgBtehfavfAHl/ hd"�#�-�s6}� ki��of>���!���". O����0 � vul�A� toa�acke�!:AE E�%r�%onNAB��� n."�B%��i �str\ I7���"J . ,5` ��o͜"=6�nCdetaij � @f5���&Sz�YA.�!v�e7uKI31�Q|��*�2"n ���(pi Fis���A��aj� Y). u%EX|Ѳa:�2�* ��chaL er� c �Yzlie*�um�'y &e%��.`'�6�ir**er� -in V�&�*��i� �3%�}#O`�}hJ�3v�0/8ng�q (5a�)��҅��a� reve� 2In�F"��&�؁�aw9�e �{<�a frame9& %a)�nusJh2�'k�k�r�+�Ha�X:g&/kA$N�".8�06�Zbk �!e�Ր*�*J!e�w�56J%��e�Ii-vl"^��. Spe�&� M."�a2uY�"�!/�2,! � � >?&�x�ŋca� �6��4threshold valuy�(�a � ]ѥ�� )�"�MorOtop0� sepa0'!`two���^&  � re-2jh��� ��ro�9ee��Y!;�mQverD#2jIm�o":aLonJ �� , [4���P�#�"su�&ly� 5O&� =l��abo A�&#9�)�2mN�A �s� ���.B�5]\���i�K)A���Oe���4�(!ob�)� n�#�N���, hub'oQa7is un{D���nge@ � �!!�*�>�< �#� �O�A5�>1tE"qu�#B�+�Jfewan 10�� i�)gen�5�!a�$! �H%/&�0�‘%{0�3as�dhigy.Y�S3�a�j.F�c&�+�� e:���/��'� 6� n1J{-exw�P��#.saK&R� �*=,.��5108���%i�iH$�� �$"�.cal]H�X�)acros!}=�"=�6endium (2x �zl�.a`f�G'tit�2.>e�E8)��36R�4K�O auth� !��� �2�y�>s)�59.). U!�� �“Z s�msj+� [4U�u� s�  halfA�G1(5�0->!�-!"BD��C\�:�4)),�746�T&�- . pp��%� �N� s>+ ;v�Lo�T���%��~�xT�(is  l�9t  in� er.�6�R��5-�&�2A%.a�M�y �a��An�> ,��� �!�� *�;YNundFE �I\�� e�( �ln # $��La6�1j� �RJQ!(9up!d�a�J��n!< p�d� ! On&$ Pr)V��H�!�;Q Data�  ( OPHID 41];� Z�)= n�!L%�m��2��-Y/y� s�:�)4:$ raw !�ns #%\{*0��L� ,.I�"�$%N&o �2e�a�T�!M��U ��[4�0�,+�EV5&( �n �!DI�4GeneAtlas [43] ��K Affygix MAS5&t  [44];�"nPrep�Ee� D�Y�g��GCRMA2Z5]"�/�� �0a���o�D!)%�&?)��e(!by �,�)z,ig�"N\�.G�1��icO .c<("\ Ttop 15%A�L ��1a�,� �$da����awIo�115�&3er�%T� *��We�"#y ploxAvar� �&j'width@AX%��"U;��"�&�1A��J� � *�..� .p!��-$AX>v mj�  a�!��:D$na�W�! �a��;� s eas��b+-gar\2�r���Y&eVHarHn's^�'Y' hecka� eXH3A�!�� 8�e>�� 2=�S �a!�]�&�of.'��wH �!ry �-frags� l�@u WQ ( PCA )`�Y�5��e� a5-2�A�ub�*D���[�1 a5nEc �W��*� �]�� #7!be ya{�$ "4r .�2*9\�o63�; �re bel\Pa b�5՟%"?_ aticAC N_��che-� ��<|Oj mW@9 (�[: ��ngi E�"�:� B�� aC%�& s �Z norpe�w.N24100% ( 259/259a�cC/2`A�6 er�' �<C"3@56/186^?lN^`Azt0E�v,k1LeaC�x.9JyUH"EV " t�NIj smea�` mU��0ityA3!�K0t �A��aiAb%x$�Q� piJ�qj����g0 �%Ka�p�&�#:7�NI?C�ap�� ȉ ��m \D s up5iL�3��G&� Remo��%�? i5�v�3r5`�2!ig o) oi��a��oneA2�8rba�c2�� ch less ��6bB'&t.a6�[6�EraV��top 24 �&3 5�ari� !O121NobW0+-nc�p~p.�A[�> 5�a)&`S9��"� s[D2�+ !� � =asola���B �� E�1 b�_65y1(!�nC�h+� c!-aX'&,ecrQd2�(( �"{��t�H�"R=�gW�f"�� �di"Cqf�Yed�A�� om�e( FYI2&�(9tonx=/wc���.a64!91L� uO :�,� -s�R-��& .�� A-pf]!�lned�&PC24/Uni= KB:Q04477A �%N*< ;� invol-�hromos= fon{`�9>�d)�.Ke�.(= "�W��aPA�e{min\J/���c���u}E�h :YJ y� �):]is� ^MedA i�2� )EaI�9;X�1�{AC⡏��"sparse;���)bec:Va�B���$U�Ae-�Kd� ( FH�?E!Boe���=a�Ey��so look �� Y2H-�nd  ��1A-S&=.� of� � : di/ �PdowSB��9��/n�%the���5�%y�bim �i�N#1a�� pat�<�*( CPLI�n���&p�cYQ�C!]too�� �V�H�.� ��Mp:ou*�f|2 s "tlene�%[7�(.� V � �I�� 9AU���L%�e�#c2rrpy:g�B�8�Jo �*�.Ջ�60�% i#��b!v�T0 . 5%vs�8):]�oC5�A2�( ~6yA>�0ɒ10E�� # ��QEa� a�e&�2 (]�:%^2�"�n� sit�>/. E. SXLla�W� 6� *���M8] />[boQ%�!���^Esn"11�A�T,b*� &�r weak�'claimA�"?9;& er�'��`� N/� �Am�#Q}1'1v1r>princ�_e!��[1viur&"�%�-@�PgA�A\2nMd-ql W%��-� ��Kwo&5 cre\%n;7|:ѯt n�WbourhooaN�#�6le3g0!>� $�^A��m�!Cfoc�Fn ��6�6Ta9%`s�2���t �y .f�5�p!$d=ch�a���j�(' Vg(!� �&d��}>�i`S�&�+i�`m3��6O q�onM�ir�2)Azu�C!�"�����1i/-&�)6!]�� icipIQ:7K.f.��. sp�?GY&�li�KA$a�M qA �(UKa-2��,��!�pla(k���/a7to reg% en�s���,nA�Fe)�n�!�#+lH.9dek�e� f&�3g 65�!� e%\ mQI1� �%)%^� ( Ce!�)C�(r S�ts B:y:�ome !�1@CSB-HI#[49;��F�5359d&J$.�de�;yy'�1.�;�P he Potts �[�g)PT�ES1�1BO 4�� )�E%�q�raJo*c*�?�c+.�,&=} MA� !A6hAd�q� P ԩg�Kad& /reBwA��get�o�Y&.����2����U��&v!u)�ib"�A5a�C%1 - �paM+�se�i�H3-�S� �@� � ultsE�n m-�&�r�2�r{uihlM%�?�s&�0. SA� �F�)u�-8���l�RoT�� �aUOas�M�&�(ŗ�*`&�I�*SA�o*Or�'&unWP�'ANaPh��wg�ީF!:��"/�fewA'fut��. D�� �b571QGas��c�or�orD �-"�9� �!<8al���Fs�~PT���i�RA‘kinoe�@(v���Li"��& s� a�z< us s5l�+n>:�t�=�Y�G�#eI>_>)e#m���!rl�2�  9L�"�. q�.<4A�!{�G�uV)m8Ka�ac�%RT�4� �'7%�R�!20l)Wran�&t�C� �'����im!Wem6jZ%�%@�r!horizon�:��."AIx%of� !ed!�&u,rx guis� t}w ��&́9�)im�{a4*� � � ##  ���EIcarry�()��%�%�0,a��%� ��ek. b�6�  . �f��5sfH&$ � [-�!d.f�&�LH�k �!yr�Z_%�B� "�3E�!Ano� �/�A.�at.�L�(be8I(���¡�%L�a� -���ů��8 �6re�)�f�A�-��x2>.>�!-< T�tewY"]Y�YENu�'*y-ver�+�.�I���x �s? I�9�ak�3"P=})�$A�b� ���&�U�nV%�B��8��������-OV�a���h4�p15b�0v��' AGiC7�6~%��.pkjl"�G"sx!�A�j@erp 6��us#|dn�n�{9�q!iI��D�T3-&�Wa%� 9x!�7x� I��1Ak/a5Q7[2�^"��k6�.d�"3'*�"U -#"�d� yP<4n�M +��=t)T�o) !!=�3�^!�r�[%]�8K ^m�F�%1we�V�_� ��d�0�� o�:� m��ut�... expl�] 1 �&�3b�-�e��%�:�p BQ{t-��Uec;!B� ar"� � �!����]�t����B p��%i -� �mask!p�ZE }��N�aI� �Q� �Ms�2In&m&�p� p*f:>!5!��r&�!*4`:VQt(W "n.%>e"��:a^9�%$Q&�*�$�G ) A�{�W 7v[fK `i��5�r: ,], ab]+of "�.ng&�:cA�((cu~PCA�eeO2�VSE����s;�Jhf-z(M choicH%f%���� �8��7e|O��e}J/d�*�=�WeɊ9 c!�"�A"first�-scJK�|ihL5� �re� �uY Oir �(�[el�*�o(��g���� coun���"�^A~I(� 7 ommo�S!�pairw , <#� �s�@� %$-�  �{mY*[ �EM�tB��,y� 6����a��&K|':� �33�� he Jaccar�$b[�v3r�7s)�0Em�t!�'��!D�������A�A�V�c Inm� �]�]6|a��U!1~i m�1�A��3 ��"���x �*a�s"�w�-�A!��1#*�[.2!� DIPcfabr*#.eOqu�=y�,l�e��0a�( umer3A��L;:|ao��[Z QŹ^�!�(^�7$*)7"~A�!i��'2a Y c�d4�.2o)i�!��J"�":6NF_1�-2�N%�b�Y�My�&�2�N��e�J�2�49�r�8f o� !�%��|*UA� t$`e�c!��*hB1*a fifth;5un�m(=Y����.�A�&�]Flet�din �� ��S%P�Qpru5+�E{� $ �-s�x� Y�Q me�B�W�~�O. K��5�<�F�.� Y.I�|( ��F!��-� ad��!�!A�G�KC� iA��$� m�Rny��_����1a%� �2�@��doK&�BZ(N-=�dd؁|?�("�f�� oa�Q���2�>|��1RqE��O�+r%?�x&�$ no��. MuNresearch�.F\ S ���e�h!�"2G=)A�} drawa�:�Dd>�i.�U� ,]Ls, [53H.�Hw|R�z�Ja+~��ns�5s��B�=�@� ��8!�.�=o2�/"-�I�eaki�+� n&� qDmf/a&&�cj �A�H=,a.E,���-�8�#� .=Jf�W��D� 42b�BpAj!6*+J <���Q[�.��N� genuineaa2: �;c��I �!&��hE�v4v-6!͙lo:V�8 vic��Ts���5I�&�c�0u;f"`a�  a��, �#�mod� a>os�X-�A�\�A+ Qa�&�a�?*X Y2E�!�n�ClEg��h2�woB� ^ �o.}�Sa�ne&�A02H�GM.�AYu�`&.>PCC�X@"WSV>f2�T�$�w� A6p#��~�CS?6�\"O=�M�an �+��A��%e5 i��ve�� n GO>� C�n+ �no��q � o ���^T���!�GO ont�1�����QS3 �6he05^���,!$&p@ *x#:�!�Nlogar�a�y> (�w�&NAl, -sc�,2o)�YI.��X& Cr�(DJMC$v,h��:en*�lus�Z(top left>Y��ve�QB��� nd�=3�ZE,0e�i���$2�T" rib"/S"�S����*e�)2>�!�=�m �xy,@!��� �+�ZXq1�a��(A�)!�"�t! . (�*��px�� i�1�%aL ��@A'�)R�K�a���.�&���J�s1�a�dq��"sq�!�i�a2�i~�{�0�sl>� -l�vi[&) �ne%<�UA(J�a)cF� H�]n �>V�X!Pm`S�f�2�*�$C;z;f��JdW.2�6a  & ��al �!-�U'>��V��3;^=5Ie-�� .5 . )+o-omJ3r�CisQya!�(/M1tie�*���Do� � �vJ[5�k�'‘G(i�.�����Ia���!�transm�*^ E�&�,mr:�E��6�Wof� � �� [%s:� � I%�5F*� ��3�/ kina��I�l)=!�*(:�GO �e���a0�q{�))+� , GTP���Rnucleot�(b� ngJenric�o*d?�X v"�4�2+/2^. I1i���J�Y�ed)��9�u�)�� V�Hg!..fYsA'�-*Q.Y��o:�S�"&Y A])� 4%�$��P i ar ,�!iQx&�:�T� Is�i�� �A�y�&x4=B��@ѥm n?c��q� �&Q�!��**`r}���X�J ]H* �*� Alin&�"��0Yz��HPzE�)!�*y��(�t�AB!��.�V2 " �Yy[�O�b�sa1�m@I��eP�r�;&�$�6A6� �z6@�2����,>cerA;]�,#�,!ot x�dAM~�U(6ly !�V8 �M[~:�� i��n5* �G.� =xbey�o���d � sud@�drosV�%zE�2ez� a�". a�� O ����N�E�&H !�oaq� �  �!>�)�a� ���"�u���AEm >8�W�$P9o�j�:�6��QJ�ǁ�*���.�9��\� ���,"}l$y*�\�FQJr�|�� �gMa �]&2��A��, Gb�%�!&!X2L!�}e�'i�?��mop�e�.4 �fenh06']m&o*�%1p� !%�. �r24"�e�zaaiR'��@* ��Р r�[56*k 59];&�Qpur2~Y tagg& %7�|� mass��J�j�=ql^asp-� s [6WW[6Bcu�Ge�6�~ - l�hrf"[62� 8 silicKdi�ba�on%ey�7)W [63])\r#A�h�8r���&�  ,�>/ �-�WM�K��!*eo6N VUK��*�%.� �a !� 2�1 �v� �TI~"� �+|P� . Ea�!\�y�4sx�Da`� �'a�} ;��*��W%^agg�#� 3'�E�\ ��Sac�bomy�'ceOae�+Q�k3m�m�'es"+��"�)!4 j2� whol�$%J���� -*9IEL�^π�p�[r&N.-!�N+s��� !{ ikz G"�u�1`E"��f�`6>a(.l �/e�2hs step6�V�n)�$A� ��LX�AbeI7� I�X�� �'[�2�� �>�11\cEJx)��9 5#� &�A;�$&;7en�Js� aR baitJptot% ��Q���7āoA�m�#�sao!�Y%�a: �e6d�'fA�� upFk�,-�;g"�V2 FC&A� spok/ m$�x�el [6 ��% %mo�;�)A$iEk� I!REjD �&�-Z�&i�0�2� h�lf�*]�>-N�]6�&� 61/> t6�I;���e�-4 �t�E�ܫd�.%]. T&݌a A4a|:40�{�R�kui2F�Lr.�Ho"%�A�,���^A�!!@A�}1+�Q���me�*. supeK'�*!2�,2����x)��iE�-s�d)6"f���&��&ni��p�0 /�+Q��O�k�-8]����L q�ly� fals(�L�.�n u!��"'s؛c�:�hoo%� ����bH�!� y2�g!�itsel7� � *V�(,04us"?%m+t�>m, f��!95לk�*@rp��n1AIʘ]uy&61�E��� (�0�!�",6"Z""rA8e-1�g~9G\2e�9E�z(>��i<�O6)n5�.�smiRA2�!L"q-�>u�n�'%�ata�ea�fasp�"|�Raiv�*!'ـr�*�l: BTES ��)�W �C�A�&`(no-,or�/�$�&�Q��R�l /no!�).f�M�?�u ( gexi�1m�>� v ode/�8S�ed� &k0"�, shorQ�M�9|%�˫ F obj�&.�'�!� eE\M��@.` �p%aS�f-N,��C8 n e� ���H����vir E6{0l�F >[�r1:A|I1:��a��(9T�s�U�>�S��p�PƖ�-^�sLAo��w3ט�&C "���Q)a���%�-i>���AT29a �N�`���(�e�R_�$ sp���� V �7�,5m���c�Z� �b/f�M��>E�v?5�0-"\�^� ]�na�v�F1�Pe)E�,y_ � �-� �Jpw N%�dli�J:�.� �c�A� �oa����it � c�� ':i *��Z�� �J��ZU2Hm�\F&!�recis� v/inFSH�a9^-��--�K A� o�w m�I�I�i�%�N&c$j��%_��b -� ulaҐI deno�X�p s labe�YH,JV"�5!P� !�J=�M9s�T`�LCɧ<12of�ESeH.<E�ȁcSX&R`c0)��N�I��a��%s�y!z ��U���In �6)+�!ݮЀ��)g �9A�A�`~i�m_�~*| i�-@!uniA8D I>=a�.�rs���!PA��'&d09n��O&� ,�]�b:5ACm�Awa@ -dim0ho�space*&���o�$&, �F�AvfF� �-\ V�Wp��K�2aQ"��B)�boundaR�I!��(urs�bit$�Ce>si��a_�*�p.marEFU����b��gt:�3R Qaing�D�‘Q {/o!C‘�G�G�`�}9.95!�N].� ň� � xe�hub~ppl�T�� X� N]e�%V6�_>%YA�A�mx&q jE=�� Q8�"�A�"�� KR�a�s�:�.2�M�A/Ied Q���a]�w��.If� ş� �Υ�_ <�2�o!�aI�v'r� b�-��=y�sC 04n�$Hq\ > ��l�)��1V�;�ei*#:�6n ( �Ve symbo� n2�K:M��!/�84�8�*.l� U%{C� B�H&�V�� 1Q�M�r�a����p<A#��.C . By홡�A�Fv����!Nan"��A��!��� :v.a�"�&��8he"p�'UFwo)fa.T�&?�Q �ei ����.nA�SI4] [66]���=A��n�1 sQ�� ߇$l9 �$n" �#�ia I1M��.  }21��1?��Ln � ( 4 ) Now��:�u�b4�hBn&Lјn'�Ci�k,M���M�� %]s442+� d leaf�sW1��? �L�D)�!-5�%i��Fs+=<6,by ( 5 )��ry)���+�9��_f��F>��?1���A�3o�,e� �:��$X��*�^@�2�a!Ud�gen��ceIv.�a!d���L!���f?poo(add�(ec�m{X�1E� IM %��:tic*�n ��;pidem& ���B�SF�{6��)�&7 ux}HNBE�[E?� s�-b\<�nif muQ�h�#� f�!�1f,oge]�K� . To� f�:��E7I!F"'� � 0spou1���M8 oduc�G��&ep��‘2!g�,�a�|����Q9�@A��:Zs5�2oe!�USp"{S�"�bߕ:�eH� i)�� scenU��ong�-Y� evolrT�����s�R*@B^ 6�90A�{��1�-c[�1��W.xN7�$n�v�"*�sqZ%�J�ideu>� irb��"��F,� ��s.��5.H��Kt21�!!R�W 1:"(m�Q���2R.Hn�x���9���F�S��UU % R packag40m!eqd���.�:&k�a�am�9�s��� H_~͙,1Ype�q��jlyE�,9�s���vir�>��MdeE�!.�j��6z�L�0Con6]N6�?at��8=m�^��)wStr��c�(s pneumonia�$Shigella sgGi�:Clo� | ici��d-> 2��*Y2��.04 l�Ep&� al&+-�ofZ��75)Q+�U` 6&�e���0toolki�fGrY���#f nt�l�{"�->EP. UڑB2dynamic� !e=���e�a'f^3�)�xntF��)A��I7iv��wpolicNValQ�s!{"�&&��E�:���2. tͨ�s��h��r����bQ�/U ���u#`D[1–� Z� �wA�g�A�:� sAIs�E�c \E]ղ�|-Aerr!Ae��78– �����1demphaIPV���QtG6i%�Re ( WG�E!, now���Acol� 6�]�[v�6 .� %*!qaE!WB�s���h emer�'� begi�gan)p~.��a_tt�ng |] Z A#ce�I����=A�6ͣ hip"��~to un6>oW>&�2��"��%,�$����A�Q@�LE,/t s r.gg�- :b6g�� .]� iims(t�Q�Hx��"J�!B�?it%<bk7A�t��6 sG�E�O� r�0f�%�E�J�;P=e<a �1&i�b,a��� e�"V��a�b� manner [aF-���Ko#aHF9# s!W��:�� w�yl� �2�+��q�]*���6%1��`� ���$)��0lexY�� ��.eNe�a}!�o.����V��e�z[�|"L�s &2� �ep\overlaiB�0A2X�or)�� %W"a ��2R��elf [13G��"�" un�e? AJ�of�  �O%|a>�i�mia�N�c�3l-��.�2��2J�Qk�Z�9�U�#�Mensz ��A�bEv8so+G ly�3Z8����o� .�>�V7�E>I2[aFsc�.of|&V ��IC���/ I>me)����k ledg lo�*��:�"�#�j�� �uv~%5f� .&�H�2������ ���yn�4s� da�H "?R!x"�" �.�e"�&1�Ea*o� �/�:�[a� �a &b!�e+�%���L�! �xr-ay�%~T\�&ǣmd8&� ��Иh^��Bc.;Ec 0GC�F��� A� �2"��"52 ff"$ � ,W�P7�T�Q�n9�lQ�ic!C) .N��C��ata�&�-p.!��I�N�[11 , 1h aN&��ed���u�:��B�r���Q!�n"�KaJWhZ � wundoubte�;�� � t5,3�\!*�v|�*4 EoA�A��*A�Ag�2)V2!>�b� 1 ! oJ!��a�!�g6Nch?��en�F�ic�6>�f=)6�%.9�,X!7Ԫ2��;aBN:2�B8� ��ed�2N���'.b��5is�0 empi��\"$��eD�%�ci�`b�p !�� � ���^�H"P��mo]��.8��&�x�"� E��0y& >��dI�!?We.M;�"a� _ĉt"L A-P�!�2�=~e�>�B0p�s��1*t"=�i��"�T���( jvC_���7!e ( MDV/!)!���<�r�b( W )�}2!�el��U�ri<��+�)% �s [24�Q �q� pea�mR0:z�# � �F�ae� � ex���fuA�s*�pop1�[25�B�w� �02�I���V Y}&W��|a�^"�$1�s.?&�6jq0Intuit�vT�v.#]w��e�=R3}^�xT.E �,�S �o���.+:y%. ���> ^N� x6�,�DcaS�)[*��+��1A , S5-cJ4A*I8%J!�`m�de�^��&( },*�C��!�r Pois��2(-��ix�Q2a�h u ;�  <�� �� . g���-J)�" ing-%�� � �Z�-�(6X�. � Tg7�`�1u�*���`��erQ t�=k(6��j7 repav��c�156 � W�ve���/:�� . 8465� M>�-�*lK�ng��ߢ.�s \��JQ:��L"l  %W��l=.5Jm�OA_�Wm�4^o"� "�,+�P��2�E �E�:V!��d5 YUR_�5as]�9��)v_wrar�2*���,� l*}4(AI6�%5-�u���������C�j�#��Ba�.��=sa:clo@6�@cwI �Q�^q.�*4L�^�@4�}�$ ati�9nw�in��s&$:�y�%t]X&F\^� !��30%�[5J�a��3/bH�C����V�. Few1����>.��p� !AR�:��"�J�P&<�ME2j��P  *K ����| 2 � aUe� E\�IA�*�aZ-I\&l  tSG�?�"!U�i�1��..�6*� Tz.^J�In&�,6 5�1A-��; ���or��eX*$E!��� �z�I�R�F1�~�WB��A�GB����;}"�|f��7}! ��o�&rϊf4 + A*,�������.c�urRsŢx1�l�0r-\�q1Hm����e ?r>��lsg( g=�n m( E�A� ��� sl�&ly"� ����5(. 9&�y0D5) e � �`t) e#, a0eH�l4 9&B� A��ffP1�%QJ�{Kd��8�ax�|N"�0Q��R�c�Fu6�ougAN�U1-�333� of 6� F)in Oxf �h� , UK(�E�Z�! M�J�]F�@?E�u�)%=N�q�0��[ eqrgNJ�%��0)��s�%sJ��I5/�a^&"� 4Snitk��:��0Z�C�7A!!18��:{T l�NV e �T�`*r��� ��%I�9E�.!�����t���G%�Qi%��12~8 d�( ��ch*&t��?P xK.yE�!62 . 7 VehA**��. K�Z�a�'.4&��M?>�j5�gez&�*��Ft�u�� �&2B�.c2�EzJ8hU�EaS���.���%!1uWh*��,;# Z�?�R��]=Ya��:�} n�amP ��ņ��v2� *� �C ra��*�`�),U %�� .,2�w an�Ocestry assignments using the posterior entropy ( S1 Fig , S2 Fig ) . To describe8Dinformativeness of�mgenetic data alone , and minimise confounding epidemiological differences between pathogens ( e . g . temporal g,will be more.�4 with lower R0�s�Tre exist longer chains -$a greater c!5Lal ) , we calculatedK absoluteEng~ accuracy!�outbreak reconstruction upon incorporat!�WGS �!-recis tok4mean transmissFdiverg!.l!�p. A�2�:�in4absC�was very!= U!th!@ similar ,!�hsiderable scope for improveIqi=all p5�$. UnsurpriA�Hly , higher averageb� across an�l!�o5�>�!(��of bothX�nd phy)�simA ioE�a'2A a*Howeve!knatur-�is)�4hipQ�d Q�1$two models!!.� , a sharp!vtrast%�observJQ M�lowvA( C .� icila�4S . pneumoniae%�!�whichE*!�\ided essentially no addi�aly�on�nd�exhibitA��largest~�K6�$, SARS-CoVJ�-� d nearly !�yiwrect anB$ . The eff!ofv�omB��e2 tronA�nonli��T��!�yst� ment27obtain=�0�,1 muta!qs�q1US.2 pairEWnd���Q�Es tB��l��$pronounced� increases�r�resul%�$in markedl�]ej'(.UT��most eAy)UA^:y,]�M!`�5�w���/tha��%�Fer2�eve ough'1y2q���!�lye�times��,�~�m4ificant numberA�M�ie�@ maina5�?A�l��ed.� . At` values ,v��also poo�predic���2�52,�%:id�ca�t�n�in spit]�ly��er!�~S( 4 . 83%�3 . 4��respe�ly��A!�Ŭtrend�1 when�L��!XasaQst� conf�c��F4sQ�Bny\]9i^���* reduarF� ,�yU.�ya�6usteep����e!��erU�-exta�t�f6-9j � per�V�Yo��CJK 5|)=qJs2� Qly.ed if_ ���� �da�nc��is�not�cas: �U�>|��V v� r7�$��Y�� :�--.:2 RR� �st� a goodNL锡`��of5B:�-` successfu� ��tified>P�c��s hav�2 l\ uF%�!%!|mn� Has a metric had pla��0them far apar)�.g FEk��i\ly coreaed��SV^=�v3���*\ ofVH)�suf? a a�Q�k o�C� � ���2���J� re redP��v JRb�E�� )�.�P� . { pa�ha2 troɖa!concept!‘2���’1�as" A�U0Eu�!B.u�.� �du�� �_ iousa�� ơ�estim�.I�tte� j���ca0&����S� 8ased approach ,bwo�t�m*�  ev?�S�(comparison �t�dem;�howzQFa� $s our abil�to�zA�.histo�� � ~� var�-6Qamongs�Sdi%�s stud+, i�gener��voqv!/al � A^ zero%& 9�u� �85Nary?DOurA�ults sugfſ1fra�oria mA!%ofm�e� ���Iguishe�� ny�$c scenario inclu QZE rapi ��PRNA viruZ sucha; EBOV��MER� Thes� ���)L well� A�y empir� � � ~ �i� .%2.��ItP ��ed >0(Influenza A �8 . tuberculosis-Hto� v%��p8 6x�^&  ,6���qte^ play?r�yet�-be fr� -p]��TbeK ly2�)�6e�R�q�s-p�i�333:; w�� unex� ~ is� assu6E� each< � �ano�  di�2���Uis��(ears unreal cw � �}� 120a{�� 36% )�no��r:�contact�5their2W�! [17]�*� tE�*� 0probably sepa�by unI�!.��a�bexa 0asympto� c carrier'� �e9�g�ve)cg ��2x ��Et uZzY)likAq agre���h���� . It![tA to6�5hfrom BA2 &C lend����rt[N" %�i6reb� dicz*� lev5 of�z�F�� bse� . Wh=FexplanE��feasibZ�.u@ (�GDQ�s�fAg �* A�$e sensitiv� saa$individualm�kW}d��VI���! �r�u=of�-eIy oY�sEZoI ak���edM� limiJ`s��� �.� (al&imp�eo��2� *E =<� d clI�f� 2��X� � a �A���a�!�utS of6� m &� a��\ setLe�s*o��%-�� f���I�K)�"f���]o�t�!V* V)@ mn�� � ���m �!��� $s [11 , 10� Comb���*� ]���"� of�b!9*zto��!}*46)�revea� e ne��p�e H sourc� f/��.[in�cm ameworkaP Prom�Hn� e5analy of deepq�AceZn alter�L�o%1�ma��*y!vQ._ �ve�r 2�!�. as���� hod�s"�C! .  routw ���act �^ �0dox�;at�i�no�=�v%[be�whole �� @, Didelot et al .Q>� AT��f�2�M8cau� b&|  i�U�V�same war,vasuu!� &�pl]�2plinks g^"�C>U E[23. H"rsa�sMk2W DžPg� M ��nd&d a*.!]o�. L�.�?� z r$ �h!$��!�!e�� ofE����a~meA�s� !��2im�i�>"Z�regard�� <ly!�-)��xay N��cQ�e� >on��x�"e0!l 5���2��4]u�� known! skew��bime*� -�g c�mpl^� &K,!&describ�>H�q [15](E show�a�^�!<z\$e�E2<&e,�� I�to�d. Beyon Mfirst� criminato�� ,Ik2�2r� seem�� oDI{�b�!s.�da�A�ɔ6!#B7 , raa =i�~_, b!� �z:A�o�� hip�wea�QIh�#" ��it�>e�%Xk ���s�P>Aj� A�.$"Xis��ea�l�� held ���`T im� 7 t�S1��><!�� bI_ ��_m�!na��", asl'hetere�it iP!i�us��i�r��! rib�����ׁ�� 2# . To�� �,/� ,� xy focž�UAC&�&�.��rAt.��F�&� o a |�~ou���w keep��)�1�j%�. I1�'.(!%��.�!s!,!�^M�T:1,%�robust%��c3a1as���# s 2 g3�v aV r ���*"+hav<)p 'cm*�)A&��nB�NL in.�!D&a��tudy madv��/p ��&might2 tx �W � @ �h%zw� q��a��en�$is equival�  ~�2/����"`r Y! lack!�avail%�E_on�de.#�� coul�4!Sbia��. 4 inA�cn �w5)N6Z%�#�S�systedA:subg-( lags"D2`a�� !� ( S3A�c#IGworth?  �H�Wat.� �&Lcu�3� �lge afoon� 2��cNd- �E�oEkl]�� om)w�c�$llm�iso�+E4� ��6X)�Z�ab'A_%�� >�A�E�hip9g�#�5.i%Nun � �}%��I% �!D terme��P�q�2�� Awe belie� iQj��ECu�shE~c�9��"� � L�-netm�S8#�,�� reT��� �b�-ed)] ed:��U l��S ",� y�@1��- �m� �� ed3&�%?&V . M%��>�error-f�% !�W �th-_%��Y � 2I%sm�sE�� �H��#4le}o,.}�� n heavily��% toph?/!��c.�] K��E� 2�v2U �G*2Xw� � � '�opt�0��. Finm�� }Q�/n�9e>���Aq��'$bottleneck�'2���n!]str�%be%�)tA�. AllowEho P >a� �)$� )xAdlemA�sC y�a��M���M&d s�!�uQ4�� ag� d pasA� thro� "� = toge!��� issu�'opnup2�quA �/�#%�alaap�F!�]��teg� �6��magnitud]!F��)��1y�mhfunda 0al mechanisms�&mi�bco�2-5 �i�2Ű%t"��k�& be d�+)"t�!v!g�f� )�q!P6.us�MABQ�>� [107�08{./adv�.��5initi�a r� � #! oderA�fQ!"".��� shed� new l� ix/dynamic,c�� et�Hscalex09�10�At�ocA  IseS E�Ae� p exci5per-U.�r�4�)i4on-to->o:�3pro|' [5 , 6�3 , 2�{%���"�$a�R ]I�.L!�~5� ��g�?t��6k�T# Tl0 r!#�1.�"�3����ti5r bacK6inefInteg� ng�typAq*�(� &<!��(of:j j mun���cH ��] tra�� P�7��2op&�*Safteg �^�. W�6duc�p; "�review�OvidEm !oat�,��aYalg�$�� A�&�,Jic�j''p,�_HDdMomeg�4�79�u!%�� u5 ) arc��O+or��� 01st June 2015�=3rd M57�$ o publV��,in English .�mon n�e! each� �dB!,s�aar��s:� gvIwea$� H� ‘>;OR >� OR.ai� �(. EN("x>=%U� � proxIbN��' summ( �mpų9/)dev*)恮iY: s by"�8aujarithm�Qwe�H&�sc  z��3sL�t�(-*edA�4cretized gammaU�5 1� � 2%&)he�I�DiscrSI�R pack8 Epi%l51��StF(s��� i%~�f� !U�Y68A�itɯ� p�ine�2I �>ea� l�!7�-� f} ng6�. A!&"d#!�wo\ %W&�q�� ����*a$r Clo!� dium� �7�_%%A+hoo� %q�#-�  mole�r clock\ge�d)�M�\ ��pi��R�,4�@ong p�-�h�*�ph*>�� [112A Mu!%� conver-u�2)> *y sit� day��["�E� Ur�.e!6�mX ge5� mblH �e GenBan< posit� [113�a�A��2 :;�2�y  .U� �A�R0��:��ba^WORBtv��I�O� ��explicitH fT �fb, def�Q l �(��T3 cond�< naGu��(3 dexr!ja�Y!s�.Gpop�;= �ele���>qac��>uWV ��2� � �K=���::Us�(!��� �zmL2ZiR��-��.�eEi�K!#,�&.� � g� .�%(�v&�$� f����>)�!*"4d"Zin� � Jomb�1"e5] Brief�J1�of�"�3� �Fsi!k/V$s"rzW "�f�R0M-yA��&!Wis drawn� �,2��-��[ ~E�;2���%p��0su%,)da:š)&-p6 Ge���( th LQQ� Bn&W*�U�E���(or$U= gliges� :�b� U ts-h[lyQ���!ZU<?j]�,�c��i�:�!�U� by K�enbergY�26��I�s9�B�)�!q�tsi!dsZ.2Kdstead eDE<1rs�.indepenw!q�Y "�&2��,�+�pa3,� #@�?"_2!\w=�9��!�2A�2q‘�C-� B� M�Y2c�$�r2�M-�co� 1 aW:T ��� v l�/�U���s� �sum֖l.V��5I�ran0 �* Pois����0� ��!�A�1�yiA�".fM�e*Q(:~z�!�2E>�H<�iv�iM���$�*���@!%�'f�8Q�!nga+2�i�hQA�@p@ou;"un��6*�`}��u�,� Y*'-d100 s* B)],Ui��B�n� B��M� ,�IR0*�Ay.�.�ew-Qj���dA4�Ku8"r<)� )O�  �:��.2��/����5l%�an`% b�(A��ݯ of 1� �x� �run%d500� s�5until 'O�u��&�$mC , ex ��24M! m*Bsweeks�/!�� e�29a��f'a.�E�g�edEvQ�:9BA�A�5T2�mP.Ium��of 30 �%��i�u��;.� ��g� ��� ex3Qby �!�����s.� �2e��AN�1A`E=�R�&�2S�)!�D% algo+ !��\26]:�2 B4*o)e�G�E�Vu&H abov!� -�aYE�f�RZ-�o&� �_�i�!��� :�/��growth�u5gfi� �� iol3 .=B MCMC�"2A�, 000 �EdM�'%E4_7�J 1/20�C!�.`�1"�VM�burn-in�io%�!!A�as a-:`,$ ssesHeA�J!6F~rY�!��3!�k8 "���&Y�e<9�Ese�!�c 6Mi>02WA�!Y. /%:/-WG]L"L5�uW "9 ires.ɏ!$i�,*�&�aRN��� �m ,�0a�&6N1e *"��<�Q-�Squa�@�.�%�>�a6�(�$c&�z�E����ensusJ ,>���e �mo�<&�?a� ctor=�� �vyclA�A""�)�$Edmond’s=�[12+��G:nNw�)�d1"�N� ��| �N�N/5.�e*-{�.e�G8 �-[9.�)�:UO&�P"�P=�uF%J[1�+. G��%��(of��fK ( k =�… , K"'r61Dd: −∑k=1Kfklog ( fk ) (B'An7�Wo0A x��s /� 4�O �r�EVN2e"" O��>r��ZF/\ ~>4.��X chromos�in�>5, ( XCI ) silA'�sta��n�b:= fema�!l�� but Za��E capeXEN�$fQ. &in viv toY�&�m&4`reg��i�(=we�t�a��9le-� �9ex�&8�%�Nof X-&R�:moti);ellZ �.ed�A�i* @ �sfe��  lVcleotid}Slymorph . U#J* inomI�!ͶTic.��&.*4�ntinuum"R"-)�EFnd.G�!;Me XAiq'�valid�` he�@ -seq"0��ver.oRT-PCRI�%�es9�Re�r S=SrJ�. B}Qco8e.3�I=e'*�5��% A��Ku&'1˥wM�. S-8 X�0b�*ndida�3or ;�sex2q. O (, few L( 3–7(? ����n� !K6f�3�:Wg�B!�ngh!:�)�pro�I2�Ka5 vitro�)X�+3@embryonic-kidney-�Patski A� �('A�a��des9� �)D ( 21�,o�� dEfA� � 9!�oa�eI6B$�$2�4CpaNer;II c�>RDN hy�!�':  o*�G"#Xi;�(d ZCEw&*; �� nsis�<#p^N�u:nat8 �F�CTCF b��ng he�=��:C�nse�9b,&a�a1�B�,���;yIG~/Bo��� Ct3 al�� *�GXi�fe�Q- �inZ�!�IUw�? j" r do�� He�"\). Dosag�!m&a- W$͋%ch�Bp�4T ��>�E�sexd *andom� a�"n��!�� .E�p�s [�IV"�fu%0F`X(m�w%T-coGA�X�X( X@u?� cript�aA�S$"Ph�onl ���!�[KIbKroI�ma�9D=R ri-v6y�2D�9"7A��Dne H3 ( H3K27me3 )�pu` �K1 gi!DNA�6T0at CpG islandSm5EH2A��)�a��\r"� �"�# #!�poM�2 bT�i15�& %cE��$De�*Vic�$��J rjy �thu� bi-��b*�k z s [)&4 SurveyE�culAgd human/�[�4id �kin e~s���jv(?F�'7y��.8–15%!-mm�E �tW�����<23%+ p�0 $bl�$x@ 1)�1120%)y&�el� �d�[5�m!E y�~r;!�ig"eUsex@dim"� in�݁�1~�@ �9�.� t le�YE �DA�an� n�,l pheno<{)J�JId�=�'� � kP 2]( 4H(X ).� Turn` yndr� cha�Jer��by�U vi ? in u�5 �r�?,ArVI�E) an arra�4ab ��5[8 , 9!�G�-is-!�u7Fl�2�����co�7gt*A:2]%�i�s}�vmo� ^soc{*wPy�[1� 1�*Fu.?G �)�I�pec�uB�A@%��R*�)Wh�,)>��eu@E�E��m �0d��Q�1[2�2��Li,.$1;i���� �� f�uin"� t� �2"� K>u ^ 6&� &Y�!�i��2�Ea a1a��ׅ��]�V/��:� cI "b��%(N*�F�&1[y- -clo��low-sor� , % ."!Db�Oon)Q �& r �� (` )I|; le1/5�G 00bp* nd!f�M-h�A�[�/M rophoblaA�-�i�;fDup>bnal� �wa�%�%�oftQ!�*�,wayz�h.i�J�7!j[&A*� �N��t �JU�Uvo'uj !!�B addr8po� �.�� ti*�(re�4&y&� mid-� a nta�b-{��J�vo;k�8_8' @��mp6,��-"� ��X���YF �s ���-z!, Ij U[2� A{OV�.� JI�� Y��a���Y&�F�$to >98% pu�R[25�jTo}o�q "�3 �p\-�Qw�&veCZ�; ��U�F1 anim��1V�r �XFa���a('�i��WX �#��y�;%� ���(oHIfW�=6N�Q� ��.�'�p2F��'^"50 ,d"� �a+2CRN.nd��.'!�F�_��L��@�a� %���MU�B�ZI�0"�by�Feprofi��wo�K? 凅��?\� �c, 2�ɷ& *O a:�E�:o l69�ofM &�%"[aW �%2+ r�M %6 )O. [@/>z� !�R9U ��-dE�� Azyg� !ya dele1�A -0aZ A-reped?f  ( Δ/+�}7]�q]mP%)6F� �F17(rea�<_ed ) �|gen����i�%��fai�g6%��,� dpm�F��lI sq�T>a��?Y�"� !�,&�p %� �subjecOG�( Ubqln2��s�*Fy�$�G):S1A"}>WiI���aspleen�*twgult!S1�( b&�Qrep� s� � o es� !���O�>seLE�". �W, f3 �A�.�"�_�_w pip�B(F be�w))EI( v=%z�s read*��+TZS� Q@�a�Z��?���ls�6-��wAJ&)�"C:e�A�*��A\�!�)� �Lr@, i . �&I�� E�G.4E X� To&0 ) Cmap!;�nn�0 �F1 mi]A$a "pseudo- b"'a�nmbA�)"�2ngM�%`���![ I�4+lmm9 re�M �[2a82�KEN�&Ev!mIns3� SNP%�a� Nov/2011a��U @ in h+ %��M-:1�)6z alig@ "/�(�� 63 �a�se�t�� in M~ � <M%K�kW�.gKAC��A�-quI��HlAD pped �$( MAPQ ≥�%)1aQ?��$es: BL6-!% �� !��� �'( � ; ( ��-�jA"ZEk zE�� �i}w��%� �0e�� @!:ms "R " 7�[i݉�6b����BEo4���f2���r@ � ��mfi�8A�*�M � ��#�!�"Ba�P AJS1B���"�5diploi.Wa d�AOm.9�h8cufflinks/v2 . �$<2 [29] ( http://# . cbcb�Omd��du/��&7RPKM ( �w kb![exo��9 mill�2�aN'X� � SNP- �haV�e�)�.�a�-SRPMXa �G 92�-M�!��i�:�Q�10�V�. H0#Y �#s���^�V� \ :~ A�2� # �a�Z"�i&N.� ���gene iA *# X e(&Q))M96-���,/͝]� ni9!ni :�(�le�] ni =,+*W*sdelW5&� 2 ni0~B� (F , pi��pi3� 4eg5%�r� �VEHE3�P 5x�2"o ?�!Hi^=ni0/ni Let zα/2 L�(�#-  ) thAGwil% N ( i(�J�55�Or�\!�a�+i^s�^±k( 1− ) �n�s !�A�bSItoHHhe�]Avorp2�@g*�E�:7.i*io rmE �QMexperi�AK4be rm=NA0/NA1 )�NA?pj1yf�aut� al-��%"Q�� ;�n"�A�X"M�Xёin% A:�0CGZ�he2�Mkc�L�,.FA�s: pi¯E3E� 0+rma ) =pi^pi^+rm2�)E�up���p�]�8c'Q�1|"�2lF:"�(J�%�k � "k"1A�A�e 99%Z} ( α =�F0A�m7 Ga5"�I �E�e�p;e�R�[!�"8.�,�!�^measu] f��}≥��R�%�h!g�)$� "�5(�kX�P&≥,T"�L*�XN\Noe��m| �de�2r",0�zlnc� Firr� \  . BR� /�yt�-�X� *� . - psdo�� c�!ag��XaE�Xi viTiLmz UCSCd_w�!a���a}�!o�&Fd�ei CQ<or�"B8Fig� 1–iS!�S2�S4QFL%��l�\ord�("� �s�RmS&wi>.:�)�CW�~M�E�� " �1u%de e� �bM��s dKA��� �uies���&�,bApe�R!�M�^ �Xil � cA��j q�� eg?�%�M@Ox', , Cfp%m Plp1�]5%H 3%!E-\&$N��� .= Xi (� usA\).�-/2�;�V%2p7mE/C sD , S S1DE0W6�a��5C "�RefX(As �#sfy�Pcr�0it a��')M, 3p$� Vtof F1���>�( SA�S33S? In *�36� {��f �*&r,i�ly�N��F1y 7Nm.d��S4�*�% A�u1� Qr��A` o ��u��wo��!m!)�"J ?ll�#�z2� A�rar�&�&] H�OypICu  v� er ) did�� ar��in�j�ř\&EX� � l�0*e.� wY|ouSQ��h��> us!�x�k-aKa� *A�NW:�3 up 1E7ludes 12 Le7 �uRv"�t�)��alŋ!kg� �X2� U a"{U =� manF"(Mb�.� p*V@rA#&!!+ �!.pwAkulat&JBH�Kl [30�= "�m( o& f 38��71c*��i21ss�A�A �!�  �$ro�$:�+ ( S5 �A�O�:!��-� m]<a� �'!�~)�,�a o05530601H04Rik�9�.I�U"�is�%�*�"8%+Ѻ4cur�pri�(no]]MUiW �L&�Mid��� Em�?dd! �b!�B'Mi� .! g� ( PAR4�9"_ !{)4sQjF��>!6P�y�!.�.��dQ�m~Xi��& ��xT6}S .;; 1U�LutA�%�[3�)"�F �in��:�SB�.M ?2|E� E~�Au�7hof9N�%!_15M�).Ɇ�"�=.�,�<���22�:"�H/)��|�D)n�dreftEA3�.�p�@K[i@�PJal9�� � �*e� 1R~oe�f Glevs'to��y ���%�as T�`@ ͙�P:In�[��ll jO)�] -w��6�, Gpm6b%� ��a��!ymy���[3&M= a�z� Y�bZ�� $.� �6 Gdi��Syp �een�!��%"� �lA*�)sQE�*�*} 3-bA�Gprasp.��� a>�'triatum-&Rbe�xo/y�on [35.!Inq}R17m@M��yP�G��5 @Y1m!I��)5�;)$� , Vsig4A<nd Bg� i�TT%(immOY#[36� CT:+�:SS5%�9 �\H��� �5�]5��vv��2CQ>2 zG&�A . 1B�)� �f^ ���&�y �!,��+m^i� q�%so� �,� �J�Xs:�2v3�t)Ld�.�E� i�$] mAe� F%S1G%m6)u]s33lI8ns15 @s�� ;-�A!��&six"� al 5pIA�I�Eg 1��c��DE��^J� ! �4( Idh3g , Mmgta(Usp9x , Uba Huwe$1810030O07 !)AIx�& KZ� , AU02275�}Bmp155n�le�V�"fE����-kY:S1H)p1I5�S�J�J���k02�ocyz6ť�XiA�reM�[40] �a�!pV�$Qe�ad!�&n� . XVA�(`�u�.d�3&$2p�Lia ��I�eI�} �-^�(A�IyA9� �"� t.C � .�W"B �2k � :"�+�dAI�ur +�aD!�-(, n AB Soli�~tDU d�O��0or ENCODE [41� we.G666I�.oS6=Fifty-&� sі�-�i��/�F1��2–S4Jb*e, Rli�`"D in6AAM:>�U . �|w �%FM� 8�l2���v!U]a18�dpc�)K @iR�'uuI~!>!��z�, Shroom)(Car5bN-Een �AinI�%�[�<�'2Zin�7"�e. )�)n�[eXe*�9%Xi2B'Zn��I���  Q`�b�A�Hdac62p  !62���>!-�FDH�M�R�-�it does�0���i��iA�p2q2E��:�kbi��!�2f�2�� S�� N�p$�mFC!UI �(%�aOJB��[.@!�s:@&s`�MIir2��%Iҡ *�K>�18]� mai�atO<i"��!M� �}/�4*SNP�e�&d*�#.�#Ti.�k.u� a7)/XaW�2M1�0%�a*� �#a��Air�p bod�/�$M8,�s:�)��N� to t�in��Ar��%&�*:��#U!D zYKI��  bR�?)�m. T�X� Ig]6�UrE$,� !�BC02296���A >�1Jl%.becV!�i $�b������1��� sholH#}��$6720401G13c CN�&� !M�u)"�L��it� �b��!�'#cutoff!�q�!� n��dJGr"�of6�.1�w�[�s���%R*�,TG��o�1� vey)�)! re-6�Fx*S ��/�FO��G ,��"� 6�� <�"lso+E�݀s 0[42Q �b# �enrich!^j6�. phosphory6at �Z ne 5�olII-S5)4a5�3A��H(&~2�.�3*�= star,<� :( Yang"�T,�us�=�l view-e "�A�!�6] ChIP�CMa�,!��!<>�<onj��Ai)�L bSAfr  �k�3c?i2�A"�/�ɂicS!�eJ<�P:�r��&}y*+* "�A69D!��g s�d ��` & � Ddx3� Kdm6R6�e� �S2%�6� HJP ���2�sJ:Igbp1 B;�v`pfe�1���, -*.�" t� �� �eDB�a ��&� �)r9o�d R�I89c���noe�2�� ���),5g)I�%� .-wSi���1�!r�,en��� 19g7 J-��c<<� 2ڐ;%s�7vB meta!�ͽ&� �&63�#u%r�E E�% �2�T`J/�}.7*5�B�1$4=�4Fe!�� KJ!0!�a�ong"�!UI��Yz=�yver!3Xa�l �Y�* M��B�4G�W�A� 'G� � "�� P6�f��R`�>�"�as%'�.4H�Al6}sc� plotsR 8om.gRZ>E�3Xm\A"�>1�hno���h�usHai�*� 4� 4E , 4I)�J�~h�rt�|! ut5�to�ae2W �F�5Ih i�"id|prcf��: 2��ur�-�"�h,Ê�z9jYY��!T<�JgEaP&��>5-�iry�+,. 5kb ± TSS� �f( Snx1��J�PhfD2Trappc&�O&3 Dat�R� �Xi�atFrbe�" 'lapa�7:� �%_of Of�n.U!T2)(6P& TRAPPC � SP9XI�r_����� [6>A\!�]�P_O�"b >8-�D�.��;25a�]a*:w`"Xi.E�s�v, 5%�&v*�$ (< "�'r�c�Nb�A!�T�"� >�L!&i�Y��A�EE0TG,JuvNak0&�#b���2�none"�řq|�L�\& o:2��6Y �Ee6�F1m'e�few%al���gvos�a>[#2�Gm�numer:!V��Do%�:l#+ � �=�)"� !q:q.�13aMp�Mb�M� ��2& �:� �Q{a 440kbp��B1:�}�! S12QFurA�%5, 22/>EA�&�Nd  a+in�#8( dark gray-sha!naО )!3�16 �#-r� cis-I�v.&�'4C �L)"Zlye�π_-FC2��1mhys�l�#Nn&�Cdk16&/orS 5c�neu5{pX}Vh�*-[4�2@w�FqFTN {�M�nz c�!-��>y2��,u 22�>U "� �=�eAO�by&�.*l�.� ]s� Ƥ�'�|Ao -&� 2���:"EB>�$s&�610� l�vnd MEhe DMRAh� &GMh8-%�&A�T"�*2? d [4� H19EWed&�=2�� Peg13��* !ANPR�w"�D) A_� B��{A?�� 89D peak-a�1��5%��Z�t*G;�A,�Cqcr*y0D3�.�5�xaramm�applib0CisGeA( FDR�10-3![4;%46_JMACS/v4-4 ( p-�W�27��� K7�@�9ad�V��A�*G"by)x�U.0,2�%� l6� "�;Q�*�5tes�5!�41J28-o kh^��A�i�� 6%:6b�A,\'-S"� "s:A��>.�2Z.1-n�'bln�6�6 "l +�&��su�E6�V�R^��e�R)W4Lb7par�{.�k2�,o$�pq�Qu��N<��:� �F�&x"���*8i�icyuk'nd �9�mJ]uQ %�qq�X�'Vat!F�&+&�.�/7=pX=N�8bl +sp~�$Nb�'d sp�q%;Io�1�!�F\ in X �B>6&�{Dp?�2�� q�u�E���6�mS9X(26-~>Yew,�8<0�;�f���v�=�)�!��6Np��.p!>��zk��)�%��d =!u�� �|�"≥�2�>�Ew�q_` M�e-�aR  )a-�alU�*5fn$> � (5��1g9�)�3 *d<mD d=* �- \��=-� �u-&�;!"b>1639/226�'374/53�//th�+)!(=�212�3�.Xi-�366/2:�218 2416�4B42� ( S7���>mqB`!: <-"�z6�0*k]AKr1&A+�62a� 5smE�8r bu6�aD}�vspa� 6~2N{| local5�:N�"? � *�`i�a sli window�8�(�l:ikb��tep 1kb%�A�le�yX�"FaF�k6 1i�o!k�� "M;�k�����a��p � . En�����iK%�]�`VNw of�0% adja�3.Am ��2�4� >vc4s co-%�iX9q�i3��!Xa!~&�]-�‘at�G"��6�6B%�8 c6�+AO*.!���ro�6|t��[�P��E42�2"f��s"_�]2=�=a�aO ]�k�p�gek6Rf�:�=i$5'^9 � E ��displayI"/&�� +j�5\C%UTos 8%b1��e'��1� in n�a�x;N:^<tG=&�.�� '{g3EOu^x�gK�(e�)sAx� ��-d ( ±a�' !�T�8ch� ��U�eBs����2 W2�!bV( 8/14)�;uz"k>�UOd�$Y#]s�:of��6� s; F�5;x�a�Kes�\H&hE.A<t��>�&��!a�/!� ( 16Ie)�rE�*�Y,A�b�9u FN *u %U)�3 ~Qw'�te.Oz!,ic ;Qs��aA JontEofn7�s��, JXi*� �%�� �J�4C"er&,ng"�E��XaB\U �/2� ( S8*6y!D*�a^ ��M! inb�+r�=�&� V�B��)h'�b1�$t��#a �  u:�X�U�Z�1� �v!�^v���7���"�#�sB ���>�*�kW��xtUN��A��QMt$@�br+@t �m!13"L)4�%ransiaS�8���ii]< a� �!f@B� Tfw�6k$� ͈tNO�� �B`:�d��a8t�b=F<�H.c2� ( S9]����no� :.K2B5!f�4I��nO abun-Ac�bA�}���"uU18&.��"'|W� *KGZ�!s1�"�.��:#1��F��U�s ��V7, f�us�@5,A�8%3%=>� .�W� n.퓁(�=4q�:�!q,Kdm5c-Iqsec2 6��6$%w8 1 A�R���Ua>m�!v"G&Kantr5/ downstrea� E5e") Ios%���s . 7� R.>n R M�agrt�Ef�&�4 po,� � up�!tr�Jj�v-o"1w�-�(#ggZiq!?^`� *y�<1�%�1�� >�&"xm�N)�;2�%�)���A"�si[[�u�{����$! Slc16a/�*�  �>�2��0� �ɑ�P A� 6�s�$!�1-Siah1b I:J��r�OL{ IEM � Qa%6�= le � W flan�& C&U n Z� �2 } x)iI%s �F-&%�efD ) GFo%�AC:m !7eU�<5� QFY. Takm�o�,�+A&C�W>g.�~ helpA� figu��� I�s�c�xl�lc loo�LM~facili"�sorgani&| S��s�M|Lphѯ�v�iS(r�y . B;C)�&D6 K!w2� ]�$�3E5.�e(�*m�T&N(��Xo'] �"F5 ��.�(%� �e�"�(>F@AA> P� re tightckola�m]lm"�K6Q\�'mono-%36Y�Kc&�Rdv1a5y�)Jc.!t?P�`�!�/ ��f-"}K� comprehen�7-�i�B��Nn^ g!7f��!�*5��a4gWe�I2#>v�dbiquit"U!Z"�ao trin�- er�nC+Ix[2�zV"�:��~, , Eif2s3x�ɥ~ ^��0�q�� Y-li���t��A*> [4�f52��X/Y _�&xh"�D!�:m� ��V%� A�+'���m-Ioe����od��_Cwh��ey��Rjanl&\�Ⱦ�,8�@>�'wAso.5i�y�M )��7ch ��N�W�!)vu"xBm&rtlea!�e6�q��#iss֦>�,6�p= �)񩉁"� wL */ N$��A�G(B0BA,|A, �A, �A��$ Tmem47 [5�D.��֗>/Qlr.�cof�b���b-�b�1��,N "L ;� labe���ZAL�fca!�eus:��b�h޿EOq�R<-9�saLor~%��12, f�_A�.U4A�='�N )(:�/,"�/q�,m�)?K�/�  �� �pItm2a %� toRaw��gYt&cJ� �%�GweI�t|�: j�F>�F�_�f�:r+i�&�in%��<)�[3�?5^D6��۫�G6�6�E�*��gIJ�فw2I ��-QPc�+*�I[�3K65MN�!� "JO  ��Z)6���H, GPM6BaYYPM PLP1�M�m�h�D�*�c�66a,&�Z`ma�0eD[_+5�]Rl�epc�A�"�*�I�v�aE;gl�Uh�*�nDome@+Tu:no� b��,Gilw �aM;��Hn�m��I�d&�P[5�m>�-xe�novelGC��z3El�t8&7ECfp!"=EEmJ3s!KEdisy��5�E)�[3!�38 , hE.n��eestabӔ �qRZ� 6m�)�5}jW3inc�Y�����3Tu6��D"���Pmݪt��A0�F[6��� �*^&� r�z of�3I)��"qV E�z.]Շf CFP�BGN .O�Ur8� ��#M�F��I�rsh- �l[� R5)A���B%�M�Rq_9� . Do%@2�|R���t�!Y�+a� :ai� ? n*,o�E�:.��� 8� v�0 \� "�>� �Pb e sole �!:forl��AR.:��˫A��2��v�G ( 42=;�Xa 2,( 8 A�[� q�:1@23�1�MxA�?Ia � 1:hIu�"l^k6Ma"�B�f�`o �-���ur �* �;�8Bl�dergo��Ol"5)��V ɚ�A**l[6f A�*, : a�8&�UA"ݥ�~Is m�%p� �)�?l�P W2}Q @�"� �@K~�Y��R  {&a�.�!x� �� �\a� O�Y��5ict*��=ccan��Ja � *�bu � XaGF< �!ci#6.�<.�( xat�iE ,".nK�<105% ( median 18�#�Xa.9u0�0S.�NX �ta�ŃWu:,"pt^��ɥle�&3 ��, y|uge;v@r$`&1)-�!G �W�` �.HF��<onBQu" ."Z3Q���9%� � �*{�5��t"KzaP>�M[6� � ie\!�7%$ j��AMb�3a�i��i�o m�|rAs �A^o����b � -�y6�/��.�>"�fB2�.� �.��Q"u�' cqui�a�pi!t{�s.r�Jar%�4�2 u^Tul?FuA6`�UN�I�k��E���-� nd�G3BAl6��+~?�1e�>o wf�E.%���<�U��})g!�U����J!Z� �>��]�- ��� /G�� O��� �a�!QUHa��v=ts���"6|N.tCalab2�"�@�S2���( �Z� ( 35�u262fLe�}q(�t�W݇tw��~ C��T�p��eTa�oi�apF��1���}3%d�\op�' a�������@.!CI�j�9>6���y"B>��"��c@&�9&�'Tf:����&"�C&$8�!�� ��U��ie�:?��Kg���jaZ9�)^�� RA��"j>�hd�n]f�&�y_>�t:~���;>�S+o�1�2��2��q.E+!L, AE%�h?iڥf�r%,�*]t� 1g�e�*E,�}��ak�Xa-�Xi�Q[6E6�Wa6 in�ta|YES.�d��s�@�%��a�%� loc�b*}b*%8� ary`s�;�"!������e-_��(>aLIMG ) [6���"� ���K�t{$��Q&R8a�a !�chD �a �OU3���T�vcal�.a�_1U�I]�G�����6�.:�E0�� lo�Xf�  ��:.�6�>V-�5�a�� [6e a��A�cUE/5=��1�6�,eaF+��-4�<�)!8,<ؑ%��:2,� !<C}W:-Qu�ylA�&Gby Hi-CEM*�>� !E�`�"!��[7��(h��:!K�O2h*2?2*� T':Zm*-+d��Upl�&۸I�*}-&+E�J..�RMdb�_�u�,�e� [71�7 F2� �aa��l6�a�$�dw� ngag� >a.x�is-2�� P�;e�� ������ �"� > volv��%;A{ha�e�a�tM���<�e�M�[2*7�~��(Z�+N�>� �w"��r�$laf�9�y ��� 2#z�) xpan�&e �AG6t-disru%�>�U$rdB;P�- "�;in&��,in Drosophil���� �!Z.1�"� ��b[75�NlosA�)�q��uper-enh�frs-FP(���{�d2�*[7w�9yI2�aA�j�5CE��yA27g"PE_�M#5C�*�!�yd�A��( TAD6Aa���in J g2�'ti�U��f�!m�^+F.k$[7�m��ac&V ��uXexA�z tru<�~���_���bu"o�%u��!���T P��_Ó(֗<��ti) &f m��je���J�4�:��pD�j�!�%r1�!&i!%5iE�a2H��C ż�ite)9A�% . O�jz# , �_.w&)}9c�$'4���%�jb��ɥsgr�/6J %����3>.�F3+�HB6�g-, �Z IKEN� KA��f=:��: Jack�PLabA�. F��p@, <%)&(3v �� heri�j1;istΔ�&�%��n�.!8|E�i L0!'�2� �a�,c�ZE�#I��!XE %Ex"��>a}�CI!�"�1X�ll� cedu4�iշ�%�e�>A�a��[b�e Uni�&�Gj|VAV� CE����&��*�E{ Oy�AυsEaF�A�#os�n%synth�pep���� �ab1848�'A�m����:NssZ��&�S�u()WSPK�qTq&{�6�GB�6NCBIv37/R΂. R\H%�.:���,)zXQ�.��<&{Q|n!K"pa{JW/&R�KD�`���)E! *pR�{I0BWA/v$C$5 . 9 [78])� defa4�wm �r�.t0H=(D �u'�� n�v�M"҂(!scA�(:ʂ(N1~%@�V�E�kep�-:�"�2^*�_0& �:<)q�B~��61pi Exox>>)��e�Fbowtie)g1w�7 [79&�b�4� �!;&hK g�$�CaM&�)�TophatBׁeP������6��H"m"x��!A icH I�y��� n.+nhX (d $X: 3168078�� 4279�w�0=P"�E' "V�|�!a���I�%� %�. P͙fir�al&l�!�Xi��Q]A�%ihm��O t?Ean.3l��edZS" K�.�*�KL�� &$Xi@�[&b� +����l�j!��ach�E����$g1]�H~d�-&GaX2c�<+Ma�C�v-�!O"˧ve!?�MGwއ�mach.d�am�#a�*6�  edUk*Go��E9Az59��315 iP� �_���,062#I9.�l2����VZ����.���$!��*0 ��d"j!�he��B�Omnibu�GEO; +�wwM�ncbYnlm2�geo�)p e�nC�GSM97086`�&K&�"�0a�3� q�aB��uE4425�뱴s+y dF�2�f���v x�GEOl> �N�59779�&+T)�$F-��2rrM101417KP � sacr� �Peu�% asiae�) � y�jC+0RodAcarboyox?�asphyx�.� cervis!�)�\r�KF��8ashington's Offw!of WelfA�. Hus� �nd�wp��eD;�*��j��M��c�"5$tea�, mala~< sit�8�nLa�a�ten{|*!YaboN7homeosta�6�_s AR5� ery���o�� Plasz�,um falciparu�r�T a�|(�6%e�n�ohemoglob�!Rs�$ic!Q �(Fsmepsin���acidic f � vacu,B� ydro���.�$a�teSat� tHy woNr, vivap�5( Vh�-=[ VX-3�&SEP .;Put��&B8K�d)J�r}0 el@p!6kaoB=6\,��""�u orth�&�[(�A�. �g!�pM ?`���B�ic��chy "�o1/ro�.J�`K��xVX-4 *�/d d+ws�� ":e dQ�ES�)�Brg�,micro-enviro`�!�!� Its M+z)�vOm>,st benzyloxy�,yl-Leu-Arg-4� -cou{�l-7-am��( Z&MCEA�Z-Phe:` �.estA~M�pH�5\ �a�#� �ZD�Hmax0�6�( ��� Q.)R���;�&AH� aminT�i��nd Gl�caSP1 1o��  $st�,�%>t P�OP��P2 uB����d�!�Leu�pH5%/Arg �T3.�%d zeA��4S2 pocket were| substituted in VX-4 compared to2 and D3 ( Ala90 , Gly157`Glu180 ) . Replacement of|abolished activity against Z-Arg�MCA at neutral pH , indicating the importance]4this amino aci�% pH-depend��@rate preference .�04 was localiz �>0food vacuoles� cytoplasm tLe erythrocytic stage P . vivax_4showed maximalF�! nB�!j that5!X�epsin 4($hemoglobin�detec!�9F/!ic. %Xrespe!�ely�demons%-s^Eswitch!�,, which migh!�0fer an effici!z0mechanism for%[s$ific cleav-7di;15�sA�Pintracellular environAas� �0function as a=aseQ!�1arasite2�$ , a matur1ofbyY�orRA�!�aE/8skeleton-degrad!0proteZin�Q�YMe ;ol . PApodiumMT , onEg� mostA�Tdominant human malaria)h(es worldwid�8causes hundreds�million illnes" each year!nd canA.ult�0severe morbide�ndtal, EXially/dchildren [1] , [2] . Emerge�=spread�ultidrugpist�iQ�a� n increas-U blemU�!ssociaa4with fatal dis%}[3]–[5�Cystein�)�% lQ$ s arA@timata.involv�1 a variety�(physiologic��roc-Rssentialu \'s sur�(l . The pot ,r��of%�cR��8falciparum suchA� 8in-2 ( FP-2 ) , $B ( synony��′ )%� FP-3!��VI�aeVM�rC[6%�7-!�of6j��s�b� v.�[8AA.(rupture via2Bcytmq)w!�s foll�� by merozoa�relIl9] have been well characteri�,. Genes encoe�0three closelyHEclFPs cluster on chromosome 11E���P 12-kb stretch , call�]ha�:� isl�[10A�!�%  B shA� simi� primaryZuc%:enzyma��propert� [11OKnockou��EYV$ gene lead)� trans��block!�](4��beqin ear�Ivasa"U��in oo�.Yin�(quitoes [13aK[14!��V7:� �a�Ldisplay non-overlappa�!2!~th���kbiochem��QvE�xpress�patternA9!�av0as redundancy0| lA �x[1��TwoN�,�#!� ( VX ) .� �a5e�ed:9 ,I� i4 ifi�ޡ`�� x [1��17!GVX.di�a numb�f^ ŏeq!�n� clu�a�Y H op�m , requir% eQ!*c!�condi����r"c e�M@�j*� (toward pept*r �positi �ged�duAqte�P1 &h nd Leua�P2 -St��al model�of:4h� lso revea� a top�=y��to thos�27; Z ver , �l�a�d8 c�re& ��predi& siza�� bj ng pocketi`res �.�l��3[18AAi�<( XM_001612308 )Ix[aa�au)m sign ���!�to�1%#,recently bec�Tavailabl�%�nucleo)�equU 2� $( PVX_1952�  239 !�40) ; its^�.b&��� remain un� r��terest� "� 8inhibitors impe%od J���focusi�their �f�� apeu�� applicabi� ;� � :rair norm#� growthA vitro [19!�In adi_a�vM(.�membranec9 .�i!�ed!broad-!t� =of ser� !dJ [20��21���m�furŕa���<2 JZ will�rhelpfulA}investig��)s=���to.ne targa8��a�G l � � Howm���rehen�� stud�~�E��hinde�b�1 in-��ul ��B��g tudy��scribe Z�of�� ovelFAj , dea� �8��-4 ��-4� 3�_s unusuA�V�A-�"ag. Molec�X!���e� t mu�3ana� *�dV�E�&� % ����4� 7 ytly C *4 �ci�)ct &I nd�"�!B@sup �X��A�a�Ɂ�ten&met$c homeosta� Q rchi3u��re5Xm�)duri�0;develop� . All anA�s ���lisE�y w3hoaccor�e� gui�(es from�A�a�aS�A�ss�Acc��-�8of Laboratory A� C�( AAALAC��!�ocols �appro�bygInDional Review Boardw{u�@�eJw Rese!\ Ce� �LSungkyunkwan UniversI�g pE�zp �N�!L*� %2 te�ro� .� ide�� cDhttp://͐b . org GenBank (&$www . ncbilm(ih . gov/ )"� BLAST ) e� The *�!� )�ofN����;(!� BE nd3�j���DVXyoelii ( �� [YP]-1%GY7VMberghe0 2B2B 2%�Q�� e quer��,I�a!&eshold�`0 . 001 ( E-value cut-offI�fter ex)  0 QeA=H�aligned oC�alX�^ �� A�Doc��7ec�� �fpuoc(&�0neighbor join�*!5�um #lihW tree�"# PHYLIP ( � . 3 . 6bMt(TREE_PUZZLE! 5 . �(da�errora� eachA- �n ng nodes�����oot�� (of 1000 repL �.q Z�s isoe�A ��x-| nnot�asB� !�VX-1; XP4 5807-�927!,�B�$  !�F g&f��)v)8ope��frU( ORF )!�!� amplE$for8 L( 5′- ATGGAATATCAC ,GTACTCGAAC-3&Q� rse7,CTAGTCAAGCAGAC7 GCCT6��erQ#DEx Taq DNA polymer@( Takara-'9|genomic0(!� n��6�a Korean!&�( a:$erous gift)�D� JS Yeome���pr�%#gel-pur)&, l2 �)�P pCR2 . 1 vector ( Ing gen �h form8 e< E . coli Top10 �s>C)�N !� rmi�CTIq(��tR a2 Sac I �)�E�C ?TAATCCACWGCA ^HPstH)sPCR�ucI 1��.�as b d ve ,%1iU-QE-30 *+U6QiaI2 |�id%�.lKJ@$M15 ( pREP� QHU,� $n overnigh��LB me|�induc�J 1 mMaRZpyl-1-thio-β-D-galactopyranos_�3 h��37°C �b� al �Ű susp�aB � bu�then   rifu�. r��u���Arsuperna� Xnickel-nitrilotriaceticQ ( ( Ni-NTA ,9�atograph, Mi�manufaqr'�s�A�. O�l refol��2 i� �� >�100"�t1combin�l a micr��rmat [2�For l�-scale�,9& ��!m�!�.il 100-��<&)�-�( 250A L-arg��A�E$ethylenedi� etetra.p[EDTA�5@�A]gl hi� [GSH!O oxid�:"SG#A�!5(mM Tris-HCl�H 8R  #incub�Y� at 4M�o a,a��%�|JeX,E]pH%2adj�# �5!3A}h�1%%di�A$itol ( DTT�/s��eS�atm2aC2 4�0 ta:�6 .�ͪja�ne;%w�a� riprepA� Ŧcz :�kD� Millipore�fully1/%u�se5b 4by 12% SDS-PAG��>���er�to�8lyvinyl� ea luor�J�D�"s(2�!s����(Coomassie bO �<b'! exci� subj6 to�%7�A c �; 477A>(�(120A PTH�zfcY� Basic SB ce"�C Daejeo� *m"$Six-wk-old pe.�hff� ( SP!:$BALB/c fem�mi~��,subcutaneousl mmuneq3 tim< A2Ez�)�$( 30 µg p� a !�? )aFreund'se5 vant�$Sigma-AldrG!)!2-wnterval3$One week a � final ino �V ,A��� "�in-�/tail v.T� rm�bl� A collI,by heart pun�������se�!X2f t roFemper�J� . A�&i!�1= ��asI�q0^�� �1P��KiVma*� � w( GR Pad Softw�a n  �aq�inn(� 5–�"� t �Qphosph�SpH%� 0–+ M�"@ ()!�)H 5��<��5N�%�m�n�A�� -phe���}F�}, ZF���(��$or `��Rj)�N�E9� ly employ�Ww trolsa%pH�&���E� easuA�R�Aef���2 a�t�exm d ua�i�F�GS�(pH�;7�Dy�0%�A0�N�}�=��jF#qhe� titr�%rd� i a"�&���$$-epoxysucc ��ilo�0o- ( 4-guanid ,)�$�L6��synth�Por�libra�%��toy��d�e�i�8(S1–S4'e&of- . T.KP1@yN d e �y!��(!fof 20W�asYf�E\su $W� .�!> a !q� ve A�a�.HP�%P4"�!M`ranl*���"mo�&mixqE�AA�6859 �J'[ e�"r.�(AF�c�,&0� omit��� ion2rs.�nor� �Y A to()Ialiquo} $5×10−9 � of y=FE�en� _�$�a 96-H ro�(-1 U-bottom�� ynex�gt a� 2�y�j3�>->�� 7�,��let(NYA!E�N �-6�or.�/spa�*o'dd�%�20%�(.Y`e50�"��Tq"A�3jO. A9�11�8%� E>�"B 60��. E� %�y8!U ound� j B�3��. H )\ re�� E9ini'UaQ"��!�)1&�EM< rM'!�FF. aym�perE.���&Y *] �-��,A2 OF& "in)�e��# 1Na�&� ,� ,b (01% Brij-35e�1% dia�ylsulfe5MSOe�To obser3, ossi% e��͏6�,:[ ( Pa�, w�+6&G6(v*�X�% 6821�%��A�;.�6�a�n�yas0v�ly*) [23]I3ͩnt �4 eI)#Q!�a�"�by�:�(&��H"` Rc��(2� � PvPM!�g�-�^xU ڭ v�Y�LA�n~ ��3 h�ohe!Teri�mM�(yRUJes< of EW( 1�e��, pepsEn A�Ac. H"�3�ց&���Q,!���a3-�(!�2)��YbA�*, A"F f h'2*�#(B�inx)5� �!�.^J�\ �� . Er&5e gho(U���f ��rypotonic�O��[! Iw�B��J0��I�1�,F����&�Q%�by&b.Hoblot� F.�t��res"2� [� &�P��!hM*hq��/�i��05% Tw�020!�&�  ed sal ( PBST6;2% bov� albu:� �E@:�.� �bo�'i&�, nti-If�tri�-6�, 1∶5�lut�5� <�3B� :3��;�5zad^w� .= . Bl Eh�L' 6uhorse�5sh per�� ase-conju-)d A���'�- )YI?Iwy2afwvi(^ i�@4-chloro-1-naphth64C1N;:M)J�3%�7 ��8Comf%�%E��5��&��E Silicon�ics OcW 2V6k��� ppei#two6'llel R12!���+( SGI��Hom�-UE�as orchej Q�kSYBYL�$9 COMPOSER:ulTripos �5VM+Energy�imi+��m"L) dyna5!*P$%�es�DISCOVwof�2II�(0 ( Accelry&8 ge"� w2l.�8o� e�0P%e����- PROSTATQIn2�(Profiles-3DEul% toge,E�.P$Matchmaker 3 . >�/Z �/u&(VX-� œ!Rx  !� ��"o�.b) �ir"�)I�h8!�!���KaA�i#anE�og���� �/M�than 35%cWt? ElC d bet�K!�fin�0�, *h&m�hI��%��8�Fg*���{ cath� s K'ATK��V FH�!MSMS6�/ cruz( 1AIT� >�S(Ginger rhiz00( 1CQD��%AE* TermV�"!b)=�PU Data )ac%on �2�+corX<�2ng crysA� ur)Site-dirb�,gg7i�&yx-�8 QuickChange II ?D?Mu|=ne?Kit�_�S�fA p�/Y)��a07g%Ek39A�� 8(!�a��g! g? to I�~A90��?4S�G154SX&ru-to= ( E180�)r/?dI:e middle�!Q� . Pa#=al�$inser� in :#Ja��f�$)>,Pfu Ultra HF8�� � thesw9it&' 16 cyc�7��$�:�rQ(erkin-Elmer)fdiges%,i�MR �pDpn I8 �e.�%ub"�,�incorp�,]ndM *<&" XL1-�(��a]� As���ve�&by���`. Dou\ oipl�;ih/Q�ofI,-��$)��LQ �I_2%��o �,i��$"�$ ]r*I��A/�4viduae&V **#�v$T��� smj9( 2 µ���� �2 ��# veni"] Gim{%j=m�.C�e�in(*�(n�(�r"�:si!M 2G3% Giems�!ran� d �Ldraa� un6t! film Ntre"E�3% H2O2 aa5�%Y:_ 1r� [:8a�   body��Bh in e�a � "�*� ��dv�2 -bio�1�Fx�AKb A""8|a�'ht scop� Axi��; Carl Zeis' By data-8ngaO��:SC TIGR , Re�=+�/,��م�� e� � >S0b�,�9&�%pr"�d `P:� (r0DB codeY709141�!'* �#X �. W�4ig54�� _as31 319�7o�P K0cI�o�� �7��0�(��>),"/@!l*^0,$reichenowi�$knowlesi��lso+ed fourB?F� �. Conv-l�aviAfnd�186�>�C��/�$gallinaceu�A�0�y�0u� onlyE para4 �( Figur�.0aded�'.� �44( TC5625 , 484) �-�:� dera�6;Ae�I;tyIVa��M5OI 59%9�3 i18i�<l�@A@1� 583 ��� high*�@M��>�>�N F_2I=�!Tov6%!� -�$( 37–77%�1Gg�r B"h�/�E�>ttribut%-to�mN-t�-$ xten4>[2�>2]Ci�c���nw| �B ) /iZ!�( )�1� ,*�lu�8iEe?r.VA 74 t� l��T7J�"d&=l�#��cyD ( Gl�%Cy�H�"As� Trp94(re �#n��3Lst�z��A3i�1 -imidazol,F� � an�<w�+Gt"] B�*�.sIB�� F(in Sup�!!"m<S)<regul�6motif:��b�;s�Da b�DtFtraffi�#-֡�S;orũERFNIN 9�A&�-�=FP2 arm����<�56�B�� 6� �/�f  [25]�F6]-e!I%�U)e��Er�8v0?e>�8A alQ�:_ .�wI� @� o�)Ajwhe.G%�lCA��$� 7A��K!<KP�barrowheDz� Give�fac*@A�@ulf7'bridge2l�nthp%!h�5"�:t�4a�nga�. �A�� yAdS(��euE~�[2�F&m flex9Q�?!��%�-�=�*�xt�G!fom�� c,�)I*J,�!��Q&7iu fj�cri<M���sugV %Kti�J�2 ��)iSogJ(j�e�seAu'T� ./<?t ��!��J�t!�Cse� ific� iTtyi�,Fqp�A�:*f *�>ed�lX6BO!gA"y7-y7�5-��8%G"�qve=retrie�:Z . D�F8�Gab�0ed}!� AM!�2cIm:J_ g� E@a{ereՎP$A�wo=~�6^$&"�>��?&�B>�?:a1 clad�+"�F�r6���Vz �^@a�NF� oo!��;�vbF� eqi!% majo�Bvp^Fv/lE�� ��> ayJUJ1CLmCn�'al�@N8D& ~�96$�"�quartet Z�9� *�9pr3m;i9not�On� x� !B1O�9!��o�b�Dgu3:�9r�;A�� � &�� �G�� ve dup�9dI�a comm�/ces�Fbef��$gA��"q!�&� mammal� G �dag�a  fami1Ƀ seem.��"��along.�*� nor�=a?Ps$�Janu1vo� ve�}!eva. Meanwh� ,U�ohJM���h!�cI a�vo��pathwb!s� ei_ �<7A�Z ��Kt��O�ele6%�>� ����th�BxSmay �CXi�Ak U1������ !�#�t:re�,onship?S!�"� �ma�" Ylo.���c" /9�� � �la1I�i�N��!Bis �D2�&O�M�A0�*���!� riseO asF��KUý�U�[29� 3oE$ �4�!!�ge�A��&d2- occup�%di�8*M� linkedH%�loci (F� N)9�cg�'a�,7QcPgaU�i�UT)-� ze�Ad�toX( �ic dosag�+!�deg��FgHm��3�Lpr�R�aURq��o(�812±�7*I,%��-tJ�2"�-i{ 2271 ;34 t^of| i266.-A�M6U�]Bi&�Ms�G�-FHFA1�QW5�be�܁�he%-Qex� �iA*T.:�P.�K"L�vinck�BVnB!��( �B2�Oe!�1�fe0�)partiL5n �� R � � \ #cev"�Iո� [3�3�:The@rqG)�}:Z,5I�^lBp��F(:XM 7A�xggestB7 A�C E�% ��5 )�*� dSIr;� �[2FO� ull-"g�\*d"�@!�ɢ's6y�.E��� �UE�& ���Sal�>trV (RF"  >�M"F��A7.#o�)Y58406��. A�$-���riu;j:@A |WE�+�|&�in&"| 2k. P6�8��A�l�.o$`a� �&r0�W{S�I*2&�T*�=�!�� /ed 28P;�( lef=Tne�6K2B[)�##.��#8' by g�in-�5.%( r�pJW�#=-l�X�� ��� 2t }��'E .� �*�U}~7uc#��E�� NSPY�6"- �# .�8&�0dia/yl��/ 0phobic�"Vn;ir P2#"{"�8!� Z-FRK3I-�2�?5<2��?�'I)pH-�4um�O�v5śa �n~ �Da� �at��3R ��9-/2� H� 2r] (�4�UPsF'ab�B7?Tresult"� � �Mu%c��@n7[ACS-]�1!�+�A_T !yrr��S�;)�&�]c6K�[be&�:.�Mmanne|3I�Uin�2�0墅�� ��-�at%��XH�^ s aw &*��N�&yyA�expla,4on%j3�e�*XV9�E� Steady-a"e� �%'Znfi�Gv{5�;�{te util�de2!�onA��HApnI�da O y+e>iX'1�� eB�V�!��H"�R P,kcat/KmMZ��9��6@D&wA)g�Gt�dY�t 32_a��aQ�edQ:, 3P ibEa�er�� �a�u�8�$�J���e!h��s��ed�6lthougA(���HER2��dr�&��n ��6Ving� 6�could6�yo�9��. Phe DXS aroa=c R�Gup�nd��i�!Jfi�G e��&�>������-A�&di"�on6?(~�(r�SJZP"� e!�Z"�%�G�82u758 "�"P..fp�[of] �O�:�P13%�F8E a�%W�0:�15pH�� s di)�r^9�4�f��*�qpa���� excepA�atE�. Arg8P3;t ak��e" 5�P���u�s�%pH}����cstrik���dչ�X�H �& G9� V� )�)���"� �c�a�[nd Val���(�)�~ ,�a��nd��)� /> �;g=&� 2�X?y�)P2 MetED�/ �2Z�x�)�!A�C)�6�� i!g�w �7e�B!OA �����!���6m "�5i�&� Jc6�F/Q�2�a~�.s,az "�"vEna�averag�irw RMSDxP98i/(he Cα atom�> �>�in��9�.�^E�"��:recogn�0bc-Ez!YgoMVXa�'-a5��"NA=�&W�CjS2��(Y+9"�j�X;L]O|�"D1{*M 4A; I�boxZ�FXS2� � �%a�m�f� %�m> �.�&D� ):u!1�diagnos��>-���bMleqHg 4�5�>b�str������)g ER. Ss�*� �10 c*s#.����Zl(du+�7�Kl;@-R5.(>}+y+,/�- !SA90 , �4�VYB� o ��"F2"l'�<l!G!�"ta ��+�-ag.0&Z< V�O�Aow� 6�4B@as$<��J�,� ��,s�'a/!%"%4{-�sb ulti%�]xs�"l@�2�*e.ild-t�eE�.6#(I�*)�lkB"� �˩�"� 4#�UsaP�q �8��Jkey�� ��,d*m! N� ցimpacg"a1M>�0 &"�Z� � �A#�X, a Leishmani�ljor� `2 B*��/}�a�o���4o��PU�U\in�Bct E�6�Y�%�AMC�n�]�Af;ɎGlu��G5�[3�<A"��g ��p"A �p hch*�gc"�*Phe- ��� P�;s'�"&�"�31E.�wxP!1�ubw �� d [3�(AFFFW of Giardi� mbli�'��LrA|-).�9�%c%�q� both&4 ��"� [3� A��3l� phi�p�Zur;#p4��*�(R�$TrypanosomA�uz,}P )-q� �hf�20 /*.vq-�s5i+a)w�& !recsdor3o� ��il2 �an6�ua*�Jpartne@[-�[3�'��"�=�Yb�"�&.(fPJ� ��Vnd2Q�Z? "�f�e �) ,A��E =� u-� � 's hm e&nFgB�s [37]*� ��b�*2 Q�Y� �sRTs-Fre�4P egaE�&g��*�&!�ųo"�V capa-�to�'%y)HaHgr�3� !�.�s�t }�is ��-8�%�*�=O*n� !� \*,5��i*�*H�g� &�#� u�!"�)vr5b}�q9U���cA�Ra &2�,KEA �����RW)�< Wi��W �`+� ���m ��H9 [2+�8�!�gW�"J s�8�cbQ!!~%��%9��ms�19�Ser19* Ala198�mb[f>* .�[)�ed�t%! i�ath,.AY� SWA.of*� � F,�t 4 o� $d a unique Z��#morphis 1�@aέ�.�k@ rp/ed ��r����he%D?�&J 錅�~>��%!�$ac$(in�ron.�t�].!�a�1whe'-4"� �*�4MA�_A�si�X ��� 3%>��q� � �),Mi:-. x!��*�$[4�q*tspe�b�6�ms$W _#�eo�<5-s�F4-PM14,j)�PM4 or& 4�!�2�9F:��3�4AIMka]0&�x-rr� , PM�Ma-��histo-as�5ic!{j,HAP5 "$g#%�%E����8s $��a�,Wf�"=g1U. � , [4f!4f!*� 2�P�Fi��# , ifq<*,ATsH�=Q �6_*3��yW~#vO:�H!�e8hIc� ]ec"� �( r )"� � V~�I�| y5LIaut)a�oA�u aT@e �nd���Zless }3�7a&�ipH�W . nRW A�K it.q��B\�D�A�F<&F#.AG X-.'zV6��/lem u �ce�%~�+dose- ��S*|$(N�I�U.R.�ju9r.,I4y}el��)��wQG��=I ��JJ/�9"6-9)\!5b )S ��B�Z�3A% �]�.�?1ء�E=Q�.�3��s�<end�_s\Creb%um�> R ) -deri!�4 - vesiy>o6�8� r�@va�}an%ac��PV�:�R-�s"�=��M�2*(0!�4*;U[43w4� D/�� ���ip� _}g 2j%�  .���o�P��� z�x~�ER5D5:�it���q�@a~4,���-TZJfus�l�.)J�1�9 �yob*)�csy �x t�2/5�54The*6a]�mpoI#�Ay�ic��0T*�qa6 lume�� "d �Ea�aeu�&:�6�N&t y%�>� �an!�ex'r  AEzAQA#>Ä��� 6waK��4R� MT! ~� "@&� � !�!wg�i�m9Ka��W*P�%��q{ >�/gI/ me-��I"!�%4>*�k�:�5G�  �nOCi�a 6&�H6�?}y��0 iR� ,�:0��)c fila�turCaq*��be*!ta%Ot�� �!�>��L� T ��e(*Z (�{�]A>;�%v�]�m�saJ�^i�d�>e"�8t6y�ic�򈁃�7A�v� EA�TQ�i��1�!!G Sf(�Ar&VV, �Ps# � � 5�W��k�*-I�T�i��_,v ��5�bcross-*2Iac5g  3�~�A�_���6�1We&��sao3 A����g�'A��R6B � 4> �nۡ�"�B;%!%g�=* .��"�0I�q�lasma<#� �6* E9le�Cp :��.�of.� kN^�� ���& &�G�J�Q�invag�twQ� �to4m Q� >!�^A]m���0%-O�facil�m"me  i C�A��4t�(AC�K)�1�alQ�,�U� �'~en�h�"�~�lex lif�cU��ɒ.��EHba"n�.t%�fre&`%1t�:KV6��15�� m�)�!t\ Q%� i.:�of new�QD=lBᆁ�Work �� 0�:!�vKe2 8�h��:H)�a01's� cf��wa>]8 !3omp&��,�~!�-}�D ���-).=z�^�*�!�#ce�ZI'fer�a�I�hn��m��j�m!!Eandid�~1��R echn���{u�HEҒb���!yIn!��a�*n" grow�H2:CO2�hsynga9-�xi]H2/CO/#)� �.�� orga�Did�hasa��subT�bivz�.*� adv!gd}=ign� ategA�E9QE�5�ha"o�Fin!�le�5�Q�KabvE��c!<t�d �Q2y� accuv�;b� pAR�)!JH�w�Rc"s�re0� iKa�S��y�!Hq�smE�maco�l�/!;( ME- 6)�%�eji0]��� I��,�s 512 Cf*rid\Oljungdah5�� -re� �VBfirst�A�E_m-�&�_f�u ��r[� � e� l��j�,.�>zpiG <o2E>(,%$vit;=�"�F*��� y\is RNAD�6"7i8�'��:z>+�� I�us� �NMa�; V���Jq_. U��&1h+�hY!5oH�Hdy$�8O(�!l�Q=!x) nd e#`A�er�"��Q�RJ��+[2Q�ŀple�����daPi�. verf�sm� �D�u�m�G��" it e�!}wJ�, �9!3&�of glyce?w"(�l�( �~.�-�-��R�cA�1��_��)���b�Fur�#m�9m�1�2�val����han9D9]�Vs>ed\ � e4>�l:�)�m�window!Fo6��8c:A�&)XJ�!t�a277:Cx�kx63. A��&N&g� 7!mi�!�6eQ�G�,[QB1� �A-eby�AqwAuP!�n( -fix���p�toR�[O.d� ��!ex���ipoo�E��A�a �F*�no ATP0�Q!�i8.�8�GagQ7ot��=5-�� �k e-en�2%!��*!��o�yJ for��IE�>� disc�T� 6ex*���b�?54�hox�-xq�� NAD+=�eRnfAB� [$!Models��Jint-baa�F�%�a� � "Y�M��Wy1use��!�!q!���!)*u%u�����flux [,PWNb`I�d 4=�O�$`luc% �b�LQ^:oA�&= 4 o�J�!�0Q(e���,\� of2�� "'�w.�;.et� ��� !��!.� u?hb��_ )���ee^��i��pthQ�/ n~]�ŀu . So-7/!+"H��A�Ab!8�� l&z �Q�a e�D��"F e4�e��p"L�M�2F$"��`fc  crip�gJ�$o�% � *�!!�b�!�y�b;7"�? [9�j0nIn"� ��1>J abuŒA�Yxplici� e� [mea. at5�.BsDnowa�Io�.�/DA�ut� �_ ": �"<8� !{��a"-!�A�!h*���arJTE�7`gt ��&f"� e��e��6�$ Tr�%A%%;f!%mena�" liv!�&5 ,e.C�#c� �Y9&T[Z.3R)�M-r �I2�enj  . Yet��$&�-ch�j��"art-.~km.�o:$ne^R3 e#?r%�u>Sb�9a��HE�F�AE!�h"~bB� lump� um�L� o � &�(�K� #r"R % %�y�#�| s! ! " A"digm be���gI�e�R��"�ed2��(N;ccoun� aʁ�w;A�MTin����$�Acm�i� �/؈O��oura�� spon�:o�m�8:� ?�;9+� � obus~+�Bw@[a�4aT;�7 fine �6 �� q#’`S�( iHN630�[5z By�Cr8� li�^l�P ����4Oce=p–J�,�P���#p|��f��5 �)���(aq6)�Ais�of 43^���a 42"l�%e–iJ@ . xmck�d edo  stoichi�r�)$���2 edox�� onK &{#6�  1�� S1 F7)�;=`#�6��>). Nex��}X2: ѐ( & E-matrix .�}�c=23!�"-�9!O"Gm��k.X196�f9-cd�/����ORF� , 89� g%�, 576�qX �N��i�@&�%rho*l2!�29IHRNAM ble �)19ɦAr' %e�@ 17!tN!735�� le�uQ�6 , 219 h&�5<�o134 �b)!#�Xs 1–1��S2Q. B� ��&g(� ��c�B�do:�� !�( xd�d keff���dJ� p��!��set�� 25 s��� G")l l����]w�e�(in Schiel-B� lsd nd Dürr�Y]E�>lea`Brend r�4ss�Oct��.2011V�d. C��I�hAIr linkfc{{E���H aln!��H!<�� COBRAm�K/26A@�U�2#eC] 1*y�!|�g!\�w�J4j;1���;.('.965_Mr pickeY.V� �!�x "8cB�"� !�bi- &e�9��si(�, g_ �&&�<�.� il� eh!u9��sJ?qW5 ���7�j�JF=,.F��p�Vh� �NGx1"�`oJ��E��%�4 �uD^�o-E !Va��I�� &9Zi(2��H\m�Un�!�M)�Qˁ mb�xA8"Vum nu�ent uptak���-l�*2�LD�*A�r�.�2�-!V[c�LͩqA��V�~w%zs�T� �a/e=a;iUar&�M�"�7�n�0 -$�1&.s"8si�a'�M>��0-��R5|or"��`m<2%�V �A�8�E�� � �?.��yield5 i� $�� CO , CO2+3 or f�D�?i_T�. OJ�9<(�R wast�YA�M�=}�8ot[[MArH��in+er. �ip�%_�$��5(��:�dBH?��)wh!&X�men!�� iU��w&-zE�v� ��V}�+.]�,Y��M= .�VT!�� �:y� ��xy�~M�~8�6N��7��gB*/�X��� ]�in�,s�� garyR�a�6Ny��%y�A�!�U�M�. WHNm ����1.X( exe�ifaIbCs�R�}ing%,o mid-log ph<$� 9"oc6�! stagw�s"�a.z� �/trade��e\��+y��Im�� 2C;? 2�S"� ���.�recapit�J>�Y�MA�� Ig balaz!!2M# �>t*�G3-bh� diol&_)��oio���o�kk5;-`��"MUqT $!*ofFx}i�mo963 [so <�F�4.� 1�!1��Fu. B��%�q�X�5Z�ryMs62frl@ �de�3|��ZOeqA!�|�Wc�619!1A7&�Iw�J�&[exp�!�i �eas�2!V!,�!�D best*� ol#.��WCF5�& ^*-�G�Nh�G��xs�O �3 urac����+i@�th1Zi�4�= �!&� �Eby��� �( P|on�r:oT 68 > 29;�ar��ρ 0 091i�301� ��(}� m�()�Eu  beaɅNa�o8) �M1� ^&d"5R��bGb;�x&\}.B�be&6V�19X.N� *7*�Ų�/ glucA�AB�4wO[h�lD (<�II,zN�saR 4onh%�aLm>c�Ao�r'M�ET� p<o � �F���e1Q���!�&?eQ�s�!;�?3B;���*�˛ˀ�\� ��d"|un�"�.r%( <^D5e-3 mmol*gDW-1*h-B;f�MA����ݩ!)�9�xyl!�or5��u  '�oinApyruv�h  � �-�uw��e59`e�0��qc"�s�Jat&�2�h�by ���7�(��Q�)�by �rse60V�?C�~. L��1:,=�&=��  �Ji�.5 � !�##J ,᪡�m $0$O;ve���.re`�oeH�8ZAr > =E�7Mp< 003I�1�}ibo�~6�rr(r6 r6!r�r. Ama�!�1 �?,c-��ell- �4-�,va�A�r:4"mDA–4XFig 76�,Y��+o� st�}&� �:X-�u�ge��vDl396sa3l�c 1)�$AYo%�� ( r>��9 , p ]ce< 05*B"7onn�VJ�.�1.M���7���fxo�#AZth�[M8 �E��275 �A;224"y i G�*-�"dP ���{!�*�"�V ��G)(e���$�(���B7 �sIz7���a�U�. U�32}+�,:�n! ���r =;2<� -^r�( rCOU 983)�5a7ri� 96884 �4D�4�hI&HŖ�0����n����'rb�+n�2�7ge�B ( CODH�t!P�10x�e9�/f��uct�( MTHFR�E%"i�65DCO" . -o� H ��*oQ �& vq �r1�RNF2 ��N%� a-wa28>S���g qbR�y�.�i�e 2<�<F�M2��%��in:NADPH95�HYDFDN2Ќto�.1!N��9�.  In hetero�.2��!�5E�!ve@%"�2� E�E>� � �E��]}�{ &* ( r��99:Jp�10!�4A����>$+ !���9*� &c0.p�`g2`0�)����Q��57%!�!1�.M0͈��'"��LJf&�� /�<e4}���e2A �e��>so�0 he Nf"P�RNDPRE^a�%rld� e:X��+u�AOR_CL�dD�:WEx��e Q:R�%�/# r |-3-&9��ryGAPBCA��"b�sd��l ( alco��2B; ALCD2�!)�1��. HXf+n[|2 orroż �az re�'!�tR� s mixqV�`�\�2u ����sugar!�a� ��s�) [�wc~�,2t!�.�ɕ�ҭ%in&�,�{�b�Q��eC�#r�.�  eA��$Vx^)�Ln6,tle en�)� Ca2+�uMg n oNiZ+ C FeNa+ )F �/�>�)� r�or � #CoE., Dp�6T?!� �4V��(&����b$ JR[�%Th��N�Al��Ps"�'�9.ze�lp� al�8m!7� �  in* ,I'��%�s.+7rro�^p�RHec  �2E.�&�**�6µA 6��i"$FA��mRp:�6yl-CoA� K>_AC�,E�!�EPhe��� �birdf�� 2X,�X^d��!�carryE��H/e�,�gICO-�=%hch4.0U&�! �T�K���$ragsdalei �)A"�Iru*�M �!�b�R�d� �-Ir!�@<)P�Uamt/&%� al=(��'s�8p�of.1��):�3in�;�Yviv6� � �d2c fashE(�-�o50!�*V2�TN  .F4E"rL/6&q�G��-(2��/�8pe( "� A� � x�/2=  )5�c*�d&�)�� �p.d �.�� �a�(�^O.�0��&�~U�+!Y ��f� i.;� &�t!��9 -�B�Inz' �� ��iiq �&z �383���?ke# �m̳t��%rfQ Ginoid/Q�-sulfus�#*5�fy�MET�ZM� �1:+. Finf9��<Ty-�V@�!L��acC��}���� P"-J :*� Y(� �3�}n�&Ʃ/�ntAG 1 . �&* �R'��:3 12A!�.� Indj2 Se�b�� OͿbyw��un �� a�L�8q3/� �E6�e gard�^��V�use-�0x�7!p5x!x ���C�Dm�dep�Y\ �D6�.f  �2�&�9y"�n" �S1�l�D Remo� U� !�]�o��2u.yW 6=9( Δg/98% , Δ"� = 99��N&d#� �y�oribU�u7 �5M!�j-� �g� 8"ls�"�!�e!Qo�m*�.?44 �\�=&a�� qNs"�!)�g�6L�6$ޭtes� -Ű��,�c.�A!a�n�`V�0-(A�6�B�10� . B )")K%^8Ũame��5�( p21�!C�B��X��199��^+0a*�r���1o06; pf�M�c�Zr�; jh2eiͩ�6D–6G�]\,a�59���01�,A�1:o�E:ii��x1�Ŭ�!b)�-stK)t-A�)���?,3.e>&9A5��"(1&9K„n�?6�]8^<e&:,�Gapp"��P�m �N!'�exR.~�*8-J -s(��H. S�7"J�� *&@�l��9E�� .n� �)>��>$e�!X.�2�G�%�78r}"� �71;ng6��QR6�!/��{ % �⊉Cng5A than�until >~� Figs 2�'|F2�%&, �� ene/"�!�.E�o� "4��� ] ��:#x�A�5% ol�^�)d,5 :J�_�;�6�>9�ra�4A�PC1� %&smIR2.� !�*s��!��s��PGdpA� a�&�' o&����L!i)�"� ep�?��s�d��*z(k�f"# _( a�2aR{!m�g��4A ~�LyE�cGN2�re�iD�y'opU��3�6(�n�!) !�2x�p*)~!�� M�Psm�%.-eP�b(�!�)2�� c"X��� Y�!���ը�OW��" o &6�B1V�at%5!�ESU �q[zbw?c T��ZrE���� � *��- �A�try2�eb���ha�@ HA ��"� �o ���.�B����&QP; &�9�Hstems�lowN�,A!z}� ��1.����� c�kE�of:�,�-��.�i�"i9�&(��"*)tin 9�m��t 1!�a�s�:c�gչl/k- �*s�X"�IEM!�ńtrace0�A2uJ�%,*s i�����5o�f.G"�Q<���,�l2� A���Certurb%a�"�!�M"�E�4k4�4�o�f�?�>�f%M&�B!)�z�:types . ^?(( ATCC 5538��a�a_ � naer6�*���x PETC�u�HK�um 1754E�� u���3��F_�'"� �% �= 25 mL��L�1}\�L��� plus�<mMr�2�M l!@��%�s���u�#��X:��8b��Py"e(�$�'�*i)"�'&�$$&�\ ub�!n1r10! �5Qequ��:� A�\€3�n^$ �, B as 5.=A� 10mM&:)�R-�ed*�$of NiCl2*6�Mn�CdX1s ����h:m�,b� #� +�u�(x{=!� '1� ՘)�2�)��� clav�.C"eroutin��6v�.m�"f OD60+#CA�H�Da U�"����o.!c�o �6h3 -Ml^~(WapH)!m2�T b)>Q|De�'� a� Z UV absorpat 41�� ac � lDQA�nCelly��'a2r�^(. An A8�(nt 7890B GC !a 7�A�*= (Mass QTOF M �5$, Santa Cl��, C�b an Eʟron Ion"L o�F ( E���rm?N�.�n 1"����O, HP-5�5%-Pheny|@�"�vsiloxt�GCS�um ��I"}����v 30 m1�A'A`25 μmA�ick��0ri�j��4 ml-� ��%�lyophΉR(�nd� �J��natμ�u�*-!iţf %5 son��204|�p9:� A&t�5carN8��h�,�a 2��vq2da*�a���r�Gd�I eptum��>�mi; a 1B�amB�",�b@e�- q��>�GC inle)Os ����t 250°$kse�I10:��li?:ma� llows:�3�t 4Jho�9or :�nE� °C/��oAj� ��!�t�6 ?scʑd m/z rLKof �E�X�Q3�8400 amuM cqui�2�\60� tra/s�dM0��xH�65�jnAL%�� ctor{/A ffcɦ {�MA6� a��blank� P�tyI� ~S rsp 0�yE�es;a j5�!�p�à /!jo^"Q#v!�y� i;� *�G�JbiaaP� �*"�)�*v.à2'%DJ� %�"Y��Hus1 s�v� . 08��lN�ana�h�caB�.�at ~1# 2, � �Y�� �e.T �n�(�L*�g2(r���BXr�unde3%AF*] �ueg�"� #e��g�o[�d�&?5M+��3�d%  �����*� Wiley Reg�Lof%��6al��1th E�U�[�mk@�$a�&Z)��Nn� MS Search6����A_D.wA,BMw߀ pr�P�  C� pell��>co٧�6if��!�N���e�s5000 �+Y,8 �� &!� 2w snap6ze�o tI �>iqC2ni��=�n kepR-8�[ �lys�_�p���1r/&%\{J^i�2G�mR( 1T����}�K�A�.,0 ,! μ�.TrizoAy �`Thermo FD�r��Q�c '"� 505G0J�%N�, vortex��^nd�G�at9,�[�㍅by5�FF�nd 14wa��AE���8� N�UJ��xiWCsp�1;AL� i"�aqu�(fryonris��ICW'3aIe�( ~yIRNeasʽ k�*��aj��m$C=9-i IRLT"��� of 95% � �)!2mi!��5rQin�IIh ��X�C���7��([�b~!�.H�[-'�._ribb�l%!(�/IV"| �UZ2 Zero (�)4Ill��<�.�n���/�Jeq��6�dg� nded3K%� KapaD��/kI) �.Qaired-�W����HiSeq 4�� C )�k��M�mVlA>�>��M NC_014328 Bowtie�|FeNC�$s%�u�f�� l>�& ESeq�- � &�ޜ�eꥥ�1bi2 �FPKM-��'DC�a�d"��to!ZS� 4as SAMN0739109A�'*+�c ���M&.G+O��L�R��<so� �lc��� ad#�w=fv  *qO[��1Y32-\��Z�as��n6�Ii06a�PROKK��^!��cA��)�Oi*B�6t od@�Va-We�[2�J_If�h��� � �ti�a�N��Ao� ori�i.Y'�ws"�?�� new���zu� r� &�No �MπF F�\B�Be A� �G< s��e�� �2��*C)��Kpy:��QP.[�A��4"�!�+N�Ec�Bi*�P hi &�Gj6��� �M9�)"�EscheQ�i� l�5B�jl)sub_�� !�>�j$wL �(an��&AA.!~�y[a�9ne��1bY�8(M�%��D� fy &"��W�+[2;I�Us� �L�\�F5lN9 ��ń�R$and the me�thod established by Thiele et al . to fill in missing knowledge , template reactions [25] for the following functions were reconstructed: essential rRNA and tRNA modificat[8, transcriptionla2oca �Ple bilayer membrane c}Xaint , and Fe-S cluster�m D. T2runits ¸downloaded from MetaCyc on March 23 , 2015 [37]fDrho independent TU M(predicted u�, ARNold [38]�Dhe gene-protein-re1n in iHN673 �converHinto 0$ complexes� upda# kUni' PDB annot�s a�llfu)�`al similarity to E . coliA,B . subtilis~s �modeled�contain� �0stoichiometryZmod] D. COBRAme was used��4rise this info1�%$a cohesiveNel [26!_4All parameters)�_Xere carried over exceptA$ t.�: !�P( non ) growth associ%nmAnLenance ( instead set�!�$37’s ) ;Yun>1proporE�of teomM E 0 . 35 ba!on reave + in weight=B]!E$can-SE [39a Each%�4manually check�see iEy!��m9 ment)�mo�J . If ye��t-Cir #��j=�to-&@el ( Tables 7–9A�S2 File�V Selenocys�3ɮaincluA5. S�N4ly , ribosome-���p Thes��-b�1-in ara%��>=;��ntiale��or6�.l� arA{sequenceJlW]2:vex��FIf both6�2E�޷4–6!.� NifUEf�V�r1�%$iron-sulfu.7 , whA �e�$s IscSU #\�JSufBC �R[40erpi�for fi� tepaS.���f��Hyp�6nickel# _USoPlex�cobrapA���R�optimiz� 5 binary_se� ( )��s�[cribed!d��[26 ,� , 41�A��nalysis^)d �� `python Npt� in Jupy��Notebooka�!Lvisualiz� Yprovia{@by matplotlib [42�3�n e�~>X�� tain� cod�2at can cre�Fig 5 � m�i�� suppl��. Scip� stats� m�5�istical 5[44�#!7 error bar >17�md devi �.�� ar�in vivo� t�  silic ,"�!D Ribo rea�!� >�AnT "�,�a CO5 correspon� �0965�Ked ORF � summ[(d logged [5A3eT� lcul!pDp-valu����* 1ld4randomly shuff��PPearsC @recq(d 1000 time2� )�%�is paperAUp(as a pickleT� � _M�^ )� O� -%�tible�s a vail�uTj�fi��. A).�K -���.! I JL69 is 2d�_rZ . x)� a fu��Ab�� a be i!g:'ZCW�runI*_ ',me .��Curr@k -wid! k !��!&  ymph Zoid.�( LCLg���tinct n:of �!)is refle�byeNprefe!�Ngroup!�of h(type–spec�%!� i.Jl�-Qd� -]$t pathways�que�ea. iss,ype . We pered cis-a]4�`+ SNP�o:%�-�` )�var�\E2�k%v isocтour\indica� B dif95A�a�"xQin)ma� part ontrol��by�reg�or:� %�seV�R 1i�g.�3!�} a )P-5�!� .� fashȉt� =lsbee��fir!�(by RT–PCR�vidѺOurE�y suggeA�%>multipleR}�oftenA~]� �AH�-H$ may affecA G6�on5DAoanl � au [n�A�an��-or-n7e ] . Exw �!�hA�pA}�a��o� 8ne mineral dens show�lapI�probe2oobserv� �a�yI  top hit�����FAM118A%$? te�y cQ�Ltwo�i��al clin� t#, revea�a �� 2?i` nt .Eapproaa�o� � y%ru�!�Yi�sa:usefu� det�ngA�!;�A�of�Ucommon!u���IO!!ō-a� O�Jy7�# ]abE�AxbeZ�aK �llow-up � y��. H�*g.��pl� a key rolzsha�� phen��ic di� ty amongsa8dividu��� ���underl�$mechanisms��$ polymorph�al� �B !~&4or Jg!�S ��# GiB��!�a�F�ed network� se �%s� O heri e quantiv�_�* sus ibil!*�I� : #s� . Many ea��� link!!�.{to6�ur� ����co�  ly dem!1!SP sp� Arac3 stan%�yin gover� ->�gpop��a6-0o` "tr%_[2] , [34� ��7benefit�� ��ezE�ng2�E)� ublic?"7 a/@HapMap� sampD {R" �}a sub�X(5CEU )Au�� sameI��we>Tat6�a� �Fed���fq aɉexonicx%_lBtoI��Gv!�spliced)ri[�In a br�rAtex�!sof�޹_��"� ��!d����P. SuchC`ces ena2"�4Eo�cl f cassetta?hich �,=d��u"�domai� ?val motif!�o�6 Vb��xin�  1�� e 5′H3un%0�d regi�!�A�to2�@� Zo��itM lq�i�],a�"� . Al�gh%�� � has%�� d trs dous��uAof0�.$aaŁZQ��:���icsu�~is���  does p�cer- lim�M!. �� immort�� &l rD efore%�Ed�Rt�arKcR ݾ:epi��n��in byx6prolonh�cul[7��8� ven o%m� deri^ ��a��Q!ni'[10Jth�ay b�buly re�en�w � � l�cap�a�ɸ!�i�ofk��R2cavea��!�ey�  �to�a� ue� s�� "2 w teracf�=!~.T..O� focu s&an�"� �A��2E�in�� Ef�atEb�ra�kQg�a@Q# e bea��UdV qFB&7seI !�no !r�'i2^>�!ѱof���in��vsc��b� �ѪA�periph 4blood mononucl��( PBMC )9 [11]� so far no-s�"�i E!�v!=P eC.�U*P ,����<h� R�K ��!O� � � he b� reE|! proces�U "sor"%roducto !$matrix [12SO*Ay"A� Ay!�� poro�,��kelet| isord�Dharactery �W bala�� �J�,.�� romiior weake��strength �7ext~~"2fragm�.]F���� ituaasAH�!W(routine hip��lac�@t surger� ma� them��E�!�` resourc� stud) �-� �& � 14�[15!��a"�st�� gy employ��Å��U�AB Affy@"ix  Exon Arra� a.� ��m��w��>�* v . Ge� ��!E =��HOb�4b�"3�IlluminaX 550K c!z-J5� � :�2it$ �V ��!�|y� 2�IQA��.to�����&L��b|$�l�qZ�bi&op m*AN/�is �!A�a7ar1 !fprevi�resul�!^E�@e�� e�C�� 6x�� *� �b&�՞VAU�"��rF ua�A�$m�����!���a �"�fe ng��� eG w�'be��cue"-D�`� of%1 . Fi/,2�5K�t.�2��;al�����Z � [16i�< � s2�a�gn�A6�$hl baQv�"e6� � a�ve�M"�!�We se���X)("�) �!g�lap }!�f"`fine-m !�� ��edn�e�u��al � �nii y . W�estig�gB�Gu��%!"�vof 58 un�uB�(��&@of Swedish origin!+VS$1 . 0 ST a�\(��!A� yearSbirthqai!/in6! S1�E��*�I��E��d�Robust M�GA_&( RMA(lgorithm [1� 1� Princip�ompon" ( PC=a�&� h� o>�.�sco�%nd"%��outli�Aue"�eg_�Fig7#-2GM�eJ���4S @by EIGENSTRAT [20'n���"of major.&�#�s� �d b�"O $( P = �(17244�,Tracy-Widom 5�first E� axiX A meC&Y%60 across 17793%�% *�!W�\\n arbitr�utoffsa�"/ab@w�iGr&� �0ora�L�, �AE>��6 . 193� 6I��,� ��d(to 9227 ( 5aB9%A�nd 9292�)A�+ ��� F��-�wɥ�*is ��ed -%�on!a�&���misHk 0 D��$t very lowq� or jaabo�'� back�nl + vAYchosen� �w3�&a�naQ)�fe7K*of�)u0!��. F� �li?<, 7733 ( 43 . 5%Santo� ) U�g�i�6 betwa3wo q� �}�`R � a�Ky � �T-�sa��� eBxs 0me U133 Plus A-0� [2S#2�a�� {_Ingenu�PHAZ ( IP�����seD))9$uniqu�in�%�!) most���ntA5�r�ed�s}0�o�j < ^, ) n�-j a� EY}�i"�' S4��-Wnt/β-�ni#gn�, BMP (�m��,��)� /a?IGF-1"�ESY%yB. �.�ret1{ "M m�� Jk[2S2] 2UC"0s!��s!�LCL&� )�, cano��� d B-%�re f=4NF-kB=6 6 al killC�6T �i*� �immun! :$seQ�!l/typAlyU�0"Q cy�xA��+Wso��J-1,of�?sh� !��LCL} )H* S3'nd��-$!� ular��*dy �viv1Ma"_1 ubiquiti 3gluco<�!R�PI3/AKT=} , oxt hosphory�)�4purine/pyrimid��A$sm^!@+i�/�Wfur�;C� �)K�9!�`up�+ ei@�"or!b�">3×f3�B�)9w2%wwe aga enrich+!�t AAu|�8A[int!]�j&�,��&�Qc>m%�Ag�l0� d:��( nV 23A=�.H#A�o�W�%ntegr:�"4n cyto"�yj)�b�..',!x-.�)��49� ���i t� ��E�V� rfer�)�G�s>W��)s�A���r  a�!�e�%٬�>:�,a[w� �+�R�ua04tq$. Howe4,p Ye t� �.ma�sma��I�AxUV~���: P1s]��nd�Y5PE�AS�E��#&� wd�5� �+B�co&�R1�h!�z s�f��6�"-P%��" ;�weX-�a�e"� a de>(l eE�Dc"" o ar reg3 �"J+�Q�S��g al�h2R: !� A��+s dW&0fa*$a�m' a siz� E!m�57 o!us�)� E�Q��� s� Ere*x�mH �re�. #+ �s�reaW A'9! r,i 6ed��)wd9BA�owe��5y�� ripli�{�&( HK!�bX �&d!3$accordingl�(a� !ZgMt P,%$tru��xT!��a.N# ide+!&� �ng�F�!n�: �m1ook5t�{Xorqj���a.�D3, aX;batch(&a!s@e�Wvecu ()~E m�]p EQE�%j~(mE}!i�i�(!jue$�(y�s�,`ev!��e��&a?�&1006��! ��e�!8VA��AKO 6B6ini ,�q9cri�a��K: m�2�4p4i9᥁�Ou��9� ŭ"H)���9�Ewu*+I�sg.ge)�(7 . 298e-11�t�327e-0� �*���a21%5�^{"� ���:Ulq<�0~�/c%��\B�%w a{O��! �"��a�&K,s; 18%%�13e2�E���ERntA# �A 1 FDRI0a2�.����cu�!��ck%(�Ia�o��F�E�MWauul�<numbe�=t6�at �U!'�5Z�:6��2{�u�E�:� ~&A�2b���!T�;c1p3' non-1� * F=op9�: !�%1fE2�q�(Irau}347e-22a$5 . 48e-06�  +2 �t a PQ�K , 47^^� 1�6� 37I�23%�E�, aJ"���e�M<�S:2+b $A��## Y`I�%�("2B�*��6��!]Q�!%�B� oMf�Bq�( ^1� ��� �|�Eol�!.�*�/l$�5�v o*���6�*�(6h  )"g�.bAb녱��!�=�)�&� e} pE�� B�[.S!����(>�53 �a�y>���;!�A"ug!� "� ����&onфc)� A~-�4!2Ba��! H.LQ6�b� �0 [�UC , S2D�[Cl�,,�!�2�a�eQ�rI�w%����2A��!G;!-� l3Q�� �?7 F����� � *�E5a�yp�)x�1��A�In6) � va�2ed 25.�r!s%��strong�=TAgSNP2@m3a$81e-37%�E53e-08 )#!kwe sou�C� r�!=)Z�r� !:} ��V �(�U��b�?o:x2:/ real)9 RT-�3,&��E,w�"A��#I�3l�5ed!�qu!o� ���-�AJ TAPjCC17orf5�X%�~ un�(-#cA�y �I&dE�. OX@h�;2���18 ( 78�a���.� �&�UE���"ly&� D m�Odir�  f�4,%P�H�2��AS ev�a1lso�K�#p.S*�6 d a �i*[�Z��:9)v))a,.n�� llel�F�s occurE�"h6.�mannee?E�!Qi��N%E5�p�=!&�p�$��?�io��r+"�22&��EA���. N}#E\23I����O 5kA���)uL�0!ci�YBT���8�2 i . !�>v }a0ofQ���E�*Qy,a my � 99M 0&�"^�%J%H.�. O�Kr�on�oEraJ� itself���� ed>�)�^Ce>A��Ձa>to� 1&� + �m��a�Afjp�c� dlt�G�.j� lexmNpre���-#L�8*M �t� ranJ-��& RV &\ �� o 84=2�To]a�X3MW�K�s & ��2Utoi// 1�!�"+ �]%��ei!�Q���&�a�A�/5� nV .Hdiscar!l�i�48V�947Z"u]��y��!P2? ���"�&A�1�R� "- �9�A�!�2J�V]M/18e��ЩK�fiG1I�$u3��%�# �%n�5 40['34>�e�!;ed{9.a]:�%��h)��ə Fn� half��.B��� R F:Fn<1d5 f�e�Lis"�a�nC�"2�he19s$)�%#�"�+:�dh;J .4�*��%�umicroa�#%,�U|20ry Y&� >1�"�� ��U{� O + �.K R0 a�e�)ro�e�, r we o�"%]{��Ypa�26��+I?!t3ckE7i2g���IA�%�K � l�4ve-�Kde[,qme[S ~�m�2se�=dv) &� po}Z �J�._v 5��P�>�c�9R��We*G'MUl < A�y�;a%�!�i ur �\( TIPARP , ESPNL , P4HA2mCEPN;!���6+ Z�:� *�.� , ug+FP�>�� &e �B��!��:�H!�Ma}lME!a �E6@prolyl 4-hydroxyl��"  3CQ�llaQsyn�i��)L !B���$A��5n�? fam�4�Q'>Z#� A�a �*Z2el�"@3�e�� 1Fh�mA!�nefm|� ���6:�fors�pla"i�Ao�9� ��he7"�C���Cj�I#;fU�r��-.�>2�A�)��8�cѯ��� cis9/��4]��6�yy�)��;ibu=o��rg2 �41 Q - K ua:)ۍ�sFEly�!5���)!*2�4� �6�xy.���"2.� & . W1 ( LOC5500^%Psq@un)Y"� �X�i9��083 , 52aY �187yre�Tq �.;9!900� ;0!�18��&��K�yex�B F��a?"� ar"j 6�)sA�V ! a8! (2�n�9t�!!�JQas�X�l� co;5Q�) *?65maiW�Jpu�Dlr^�A&6�!ex�BU/�3ver�,d RefSeq 1. �?�2}F�5�-Qt�6Xa#eR6, *�?bY* ��%6:�b| ��<r0( NM_00110459 : 1791���%1bC&�a�&� new�c61n�I*�un�or��9STDW7+Q�B9O �49 A|*I�HRACE ^6)�&3B9c %�/b��viN(�/r��� &ach�_zyg�?� tqS�7�Z����A�*� }K�)�p@>���UTR on-� �I 27(6��{"}� �"(2 ?.��PE{2J]TœS10J �Vz8�8SNP"&"._�6Uqgen/th:�Y١V 546;1F%^No�"�Li�_ �6rGd��c>�N|�\49�Y�f8�YF��n�W�23F&'aNX�� k cMa-s�ext9gd���by�k�C�M%�-��o* I("'±2Ja 1�]�J%�2�,z6v��& Q&U9� �=��EUoT6.2!�Q"LD*� *V1v�4}���Q7agR deR1���5causalu�( A�eM�r�U(yKce�2� "�w5��ahe��� 3i!)�by6t u"-�[��IU��V��H�_airx��. A� 4 S6�@i*9$.�}Q.Ns.<BU�was"� 93� s.c�.�?�4Yoruba ( YRI ). �P, [k2�4| or� pD �q[!J�pIJ >TJ�BMC!��!SNP�A Datab�iJ.6!�WBYb�[n(CG�[.�R6��%q lDLa%5�\au&� -*)*� eP.��%of� !��top4s� 046� ��M&%�coK\I[-�S�ed el7U eCmen9F MrOseSWh&�>, 2880A|��qe5�A%���Dof: CCk! CT26�T. 72 (� .;1��H-W"� P3�:,A�1c�u lumbar sp�K&�L006c #285��� femo� neckJB 61 ,@77'. L>w6)ed�67 g/cm2!�A�ir C��&�h��\�Xp<�TT��pursu R��ߍ�1rsMQA`�! in 2^Q42,&]U�Ro�damM�G�0�Fnd:�&MA:AL>0�LWeI��  �")� a 6 u�>���2J6F3:-e.+6#2A!h. � u���C_ � �2��%��hifB� 7G:-6'N*~�=g���%LjD)!���D�'�{�� GbREo�DRQo* .M�";4G)la2�� N on6�&�uJ�@ABr%.-�icH�-O�dZOs s1;�85}�r�:"b�R�DgQ�i��5��)>�&d"�-1�!�c�a\ at�NMw�vL4 >�NrH:3&�6� ji�*.� !�.��0(�!y&� !r� �@�Q"�� �� zt6)3�8q!t�M!=al�;�top��p&j"p�$"rcV"P-Vr�?u�:�:D? � 5m�$�6aAA�sE�2�?s4 m6&-;I @��"�>�ge�_hg�qnd&�A.�fac�-�2 �!o�a�E��"�thA �� '�/ ��%?2W�u[B���rqj inositol �A5<�'�n$sm , N-gly�$.� B6)�^"BFu�Y��>%i\&a�!!as�9CJ5�MN9�y �A8�R�As.n3�<sheH z &*6"�+)um�esV\0e?�N=�[;* i2>$�J�nee�fmWte�E7�spa+e�Hv�c V mK$�l^��A�nd�#� a��O��&�)BZ:��Nr2~Gu�.k%�x)}j elop+"�Utight jM !�<keratanmA�bioYrU�s&hN aVk s&Oa�4A�&2� i�1"iRJc,$duQa vast :'fB]�"�Yq�%%I�by&�.=� ! )F2�'fWe.��G2�!�� F�$ ific�m�q!�M��0a���*�Kor ha(m�>"!ll �,.��� #}K#cwB�9@!��+�#,�QcH�& Brt��!���nE1��f�E.z&$ly1{c 5��>�Y2;m�ai neur9eU��?ova��XiTAA(��Gw%1M[�MC�^ a�+B I)��a�� rvT�� ��knock�3 mice�ogWD-&&� U�cal1"S�a.�A�:�;thsAd-E=6�,�)��2^)p!�recognfY�~C��kr<{-�!��)>�,A�A�re#!um+p9�mP�6."�:&0�d ,�jRY_]�Q�!Aa2C a2 P I(lyI*.�a%w&x'c� �G&6w��vy b1�� and/2'RA{� "* 2{%RN ɍfu]_' ��Z+J+s�I�fy"KG�UbtIL���I�']�#�%>�*&( ��c6�[4 scad�dowhCeam"% 7TnY��" plau# expla!��a-�A� comb('*`� � A���� ����� ably�ess!�: "�q� ^O�E@~&� i>g �3�u�pfJ��,�5�"OG��NB�UL�1�2:i�iUi�>-:G� ("�o:G7 Ii*�F> �w))Q�u!).�B,l_%�HOB-�OZ �a2wHe�oisieWT)��Fs#A�lG21in!<s%�K*�E5� �� ��/!A�aG.� ��u,ls�4!�� �G&�.� laW*�/U�,f �#�&�fa&��3��{Bc�be�mށ�a*&�[QJ� .� :X�,h6rea5d cyRa+>2 r�a��m�U�n`"!�t%ly@ytle&�Esі�v� U���Ql�W� ,e>`6� 6<W�2%$Eb�. bEab�_g�)byQU=�v>�!F�c�.{ j{.x!��Zs�LI�!�2 � #s�`is q!A#�|Xq�{> �:V�s� 9w�1AAp �q?�he�T% !!!�@bur��͉��sA���Y anceHE�+���o��%"g �&s �� %�a�>_ 3-�P 2a�;2Eu$woUMzX'Mx:(��&5two fA?�vb��oM� ���(���xn��&��i�[2!XUr�C�u �i4-1*;/XU�!�� �L+�L.ne��-&>m��\G�!z2e�hB�� ��31�40�Х?!Bly��wiK�L �"�W4��&�54� ����gilh&1P~!��G��� 6-j!���)Ai�]�"[�>se2d$in dynamicag�e&�X� u4�0-��1r �@a0vg5�����N�!���I�e� d� 99sRTb@�4�9 repa�7Qsa.�b.(U���Fa1�W s�- j 7fal�+si�+? F�V).��E���� assuxza lib�7N`!�50%I�6M��,!�b@s�&�iAXt*�=�(m�a 2AM���n ��R�D=ook)�:& �9� ,!2zA maximum� 25% �Op-8� vq�4 A�� ��j%��2am �:�aHa�E�o��.p -4 � �tringl[6,BA-80�_�\� .q�`-�,9 e�!��& �QH"zTfe�Qthsvl�2t=m�>��;�y���he$�a�d�K� s�LF�!�3a�bBorroboiA��աV�@6g�,>��g��+Y%�U+W!��Y� %����\ � �qW���U#)(�SB�>�as't��y �!�Seh�� �2\"uyy?>:pliq( ULK�"SLC12A�*KLHL2�2E�&C;y���* &�ހd-:%q%��&n�jINn�%&�hp{C�Kn.>!Qa�W��rigor5(=b���:y�i:����2,!hst�can��5�ZalE��:�-yal� J�� More�R�� a�F�RC�Yam"22pQ~&�!re*qwA byX'hD � �ceS- �"l� ."��^7%"�I� . I��robrA�`\!�4)9 ;:�V2&=iR�>kx)!wtr�� Q9�Q�&�!l"�&I. C2�a��+-�K eQTL�J�+.S�2ELa|$^�h�*�∼20%.A^ �w��7J 4A�z�y� �$^F����'P+��!9 �{�&�{�h!��UH��ve[��Fz%�"�aa,K%�*+�#t��%K)��^I"(+�Vege�_u�^"p iM�}&�"�.~R��2��h!�%�*� -/b5-��e*� don��as�or +� �MD�Ya%��5��(l�9�V".��.n�!C���2!��Cy-�u:h$>�?ral2� :�� V6;"�}�&�so�� "r'�� NBny*-^,E�l�&�X=AeUAngJ�. IG��!vaMyAq��)&~��' � of >3څf%w�vw6e_T�; �!� yeG$5���*:&A;Mmi�:"\&,|!�Vh9k"P 2�q�, had!Cer���!G�geE BF.Ao 5#�� /%failur�r��%.�"T�1j$rob��!laCI !�o�1���a ���B*�(6+)M!�I t-hoc ^�wα@0�1� f��P �(519Ove �e�(G�. O���Qlik�9"}��u� dT^��� LD ,>5�!mes�,�E�o�%Y�� (Ae6�*LpTA�7�(H rule.9�;svhM0.Y!c&� "h!��ib n�p �aB:�qA�� @��!�M��~.: �ty +M�r�D!�m>�}d"/s�Ks���\�m�y"j@��'���l� B&-"��!�uq�.(2�(f!�*� IInLIfi^1�ih ſg����x.�Q|F_�)�� � %�@� os���cg�cEb!���<*� i`� �Is� &�z!W&�  i��1L)2lE�I�)M y doa�a7advantag� ̓ila]!lwe�y!fp� 2� >�u; ��I �nd�9N*u)�R��m��o�s�2��5�� �(�#�_�"�}<^bI  y�&3 &gY��p2Dz�!�VN #L<@�EKx. S�w�+ar�%I?�E�}�o!H�E �U� �2T��loTK�])Iu�:L&V;6 `�S�l��2�.� - a�2*m�)B�� b5j��M !�J-�� MQ/9�BO��b&%d&&� � � ��6I�"��ny��a��C�ta��B� FV *�t6-`i�I�*�ar.=a�%^�2n"Q&w�!1�;!�|7.�GZa?!0airvD2��J 5 moleI�baIbehindEJ����d���gk:zs �� trabM� K �proxim53�. shafz���� y 60_ �Fgo!B2hi6�{�7� ��C'�  th�Dwa*�,� w"!"�}in �um^. α-MEM (�Dma-Ald}k , Oakvn+�anada�["$�] 82 mmol/l L-Glut�2}(U/mL penici�))@00 mgaptomyci%pInvitroLK, Bur�)'~, {��18�}b0�����at 37°CI�5%��il!H0���+. At 7�>8�\%��e�P harx�nd!�6+in −70tunh=�!F$~�..ziso�W�l�M erci��5 le TRIZOL��(�E�?oco��t�@hXDNaseI3`mb�In� , Au"$ , TX , USZ@��40Ac9S�*� r{ [ l/chloro���I�!1!\�,#I9 (RNeasyMinElcK]nup ki-RQi!�D ississaug�'UW. Highg��o&�7���q�x Agilb2A�Bio�szer!E techn�/ Palo�uoA���)P!<�E*�los� �X),Nanodrop ND-JI(DT6sWilminmMDY� t.E��M���`�� lysax)�Ge-cA�$Miniprep K%hSi�>�h#jAhU�"���>��!ur��8A�profi��&98!��)�i�dB�u1{aA),(.', S�  ClarE,A��eC graQ��r�e�b��A!(��җtr.Ac�!��<���&tin-lab��cm�t MCt hybrid=�. H �N t 6dt�=s��q���av*r0-phycoerythria,Q�%���>aA eA�TS�er� �c�@oZv_�gt� 488 n�O�*� (~XdeT%C�i.Omnibus=�0EO; www . ncbV[nlani��gov/geajac on[{ . GSE15257AllAS"�6�*�v˜�AXh<�qI{-0g|2�yAr}m�}`�F}h]�P�&(Tools softwpackag�ToL���i�0o��<*�l\4 .&� %* 7%�� ��rawB���z- L`-mle�1, toge�.=� ha�zn"�%>7�ldb  ��<12�{mas�E-'���#��arq0��d""�$/"iL!46� o�R�%mj� �-�V m�[ˤ.lT*LFU��Y1F�3sum�� a�CB a�JYs.��M�5LA DuoɄ(!��� Diega9��2����v���!f:�a�� 6*!M�i2z8e is 5<303��w�,w3 (*!�%%8�Z[H�� c� <98%bv�re 90401 �TvsN�:�y<5 FF$X��}!y��(U.y0 3�I�).�",)�4Hardy-Weinberg�!ilibr� ^�0;��vM58mcs�!J]�>Pd�(c,:nd:���]Y�m�gdpsP�H%7"�M%��r�|{27��Ic*q�c 1�7496�Owe $>v XF����a +DKb QD��<FrMaor u��_� o��.�, iSa:F,m�:#MepٻPLINKF�[27�G-E�abTre6r�z�O he 1�4���'E'�q�/$A�uB8#�V*�, �. Raw~)M62|7){�ar1Pympto�t-&�)cB�e who{l�=�eI ��J�c��"L= "�6,A,�t!m6�Ls��c` $F711� @)[op4*SN>t�N�,C��1 t�h,2R%�x m� w��!2��� �S�e+��$��m�)Dat�!Cэh:&�$.�IDi�th���#e�T�=? ain�P- �up �Y�appdv�6!s%&�86le���QJ(K"߰D>'s�nQ�B id o� a glob[�l�MI��9���!(rsBm.�WA� a��q*�5*�&I�-!�! > �� �e�M�E1e�A1default�+"8N2��6�ItJ�#6lh��!"a"n*1�nn:�*%S d=.ݤ�c h� I�.� )�>�$ he �e�/O�!� 8me�i� !0Kф� b�zinv�J�<Mx!���`). Ff�r'da3zes�%�� c��rI�"��ہHa�t�J����zIe5#j�q0 !$.�o:��:�M�-T����*�?:�M�1nU:e>��5:�H�hR:���I�!F��/m��|.� 5dAXLcB�H measuA!�wo I�: �4a ioh&� IÕFiEmapA@q�6�&> >+ O>=V�disz���R��1�>X �!..�fe�=lU��h%��u�F���nd E!�i>�J}�I h� ���,�HTSuperY�II >�p�C�Ne�)e�is"� ae��"!3E�K)�)M^C epe�uo��ir bY9it� !^ge)#��*�s -�s��J��des� & 9 llv'�Q���Peafe�"cus���>�!y� adjac�>e. A$�%tb20 ngeHՉ5�ɾoXf�f 5CR-�PHot Start Taq Polymer�(���%�#d���at 95�(9Kmin�'�'i�35 cycbB*30OO , 58 ; !g72 4 $a�ax�ten�{-5 z. A���M-6 h�L*kg�e �n�" WZ,$@ h lPe�U�{�es:� ��U��!�Q@T�,aEa8aR_!��+SNP��e ߁͖cMc��utm"&]Qa6!�5SYBR Gr�PMas�Mix (a�lalB�Cstee�Fr C, ,9i�.�'�< stru�"A�,n ABI 7900HT�j�ru�!�_X� �etp+in�^µlmevolume~ �!V��&�� s: 8F�!�m32 µMA�A�&�M�;� ing:F=C�R2�B(,u�45�J� 40V�Rt�4.U P eccs e�  4bNA�&�8\[AY?$c2�xD|ac�!(-,�)O�n*ceKiXB��Qhu�18SE �nd�z��3�""Dc�%�es(W� �a dilu�s�! mix �C"�: H.�acon��_B�c��(|"7;�5yQz�f�HieeKef"K�2�"�)O� �A! �9�u�!���)C��z%�shQ�)� hod�*)�c�  r�)�]�d.u"R7��2� "� ��1Nj I�!.a� �D4� �!��N��*� / ƖO *gn O[ ?"�Yc] )3a�% )"ofe� 05/N-%Nm �&� �)gt�� Ud�(@9 �*��(�+, ��d"�wa�tR� . Qu*���&A(h�a�H?��="5[!V4K**be�G93���A1)()�RapidxU��D�Endi�\)� U2ݜhe"]`&�C^/�e"}b 0.� �2�:�gui$s���nG E� 1 µ*� �BQaA >�e�SA S��@ ��U(I�oL� %E�Qv� R�! HA�at��S!Ul .��C"3!oA=lumR�6UHO�Sm"� unincorpo8dNT�F�� !M&& ��*� F �&&y,MALDI TOF MSF6x|!0�-���a�.�Lcg � !R�c�%�*�,� r&A6tl6 "��:�nfh:,v!&2�h��"� S$� ��%�= !��Ibzta�@FfEEu(A"98e8( f�:�  � ��\]-�V�:!�a�C)E��pY)�ML�4A��kqWI�s��e8��on-.�352:{����)�%�"L.��let�$A[�D)�F�.ͬ �"4 0!��3 vq(.C�0& D( http://frodo . w�&mi� edu/-L�)51�70�.�y4%)P 7m*t %) ���u�+t�A�tZ aw�3 7�:h"�]V�Caucas_�male suO�&#Europ������GaC6 , �9ea�A�&[^�2&'.�,h%=� ��<�y� f�� o�Rf�,�%epidemG��-ig�ebt:e��t s�ȭ�!� worlAMclu"US , HD�K� � � ˥Y3�s�of 3014va. �69–81��.� �B����*� �6Bpro����� ticŝ��x]�$!�"62]+",,��)�Z����:�&5+�,F9ip�p�hJ'w=9er{�2. &QU644�t:�@!�+�A�ty3��:� 0!r�rio.�Mk_&���+P11�zA no-}+&i�15�t&<$o"ustom�ebcl��ilY#:�F1^�&z,20(�\&� Lts�.~�N CEPHQ��I� �6e, 2308�C�/#��s�+90)��&`h��2wo(O,��+(�re- ��r zero.bѓPoo�Rmla�%����!Q _106Ner !W:� �"B-prie*�ɥ-m�OAny6n�#ll lbe|9A�5%]�20A�~�1 autB� al h��U ��>v36�GFDR%H12H~#�8sm�0 �!&nd"� i�a��y"36Y or���"�*$ !�he IB"r�!he(3'�- ng>3�� ( away�F���)� 8k1�i?�%�p�>&ies>97.12!J�5�g�;�} 597&�9'�.0�$.����F�?69� ( SD  !�y��`r54�4�.hwo1 ��",�G�"� a&���Mnm�> VM�"E SAS �s 3(9<�e��� A ���d�)ar�, ���kz&@ q�;�8' (6�A2�) ��&�!M,��, h�: xce���R1ge-$�-ad Rp res�0-cC2�dB�%�A ue+!�X�v�s1)!�2-1��.�� 05.�SacIk�;(es eubayanu�@!Pb)ce�isiae�q�� lager-breY _3 2pastoriM��� tP!��(&X� FrohI1�`!.G'i�Z��6ot���α-tri-��5*�totrios�S��carbo2��V�Dr�Q ’s�In 6#yGXaA�x�Maa&'nco� ����elomMAL%� D�� r� Բ2[ �w�-[uptakk'ͅ6 )!( CBS 12357T�<bGSeMALT{s�"e�� V-� α-dB<%8it MH�@�� \%��=�EGv�t�d�.�A�91lik�&evolva�/a�?�~�(!�a����$4����`M.�� .]a=Q,.6S���- mut b�/��f�#UV�����giQ la�Sory�'! (A�n-�Eed chea7�uD�LP2�"�jwoE�o�-'!'QH d imAe� lt!b5n-ferDI�in 7 L��p�]���UalyW)2 )2-��)a���mosaicM�41��8U�%�rep�dE_9� ~�� reci� �'�R _ �[� e oM �*�l ertio%q�N eMal��x a�[*" ).�,C_�* UALUsu�"Im�Xlo2� Ge4!Ogene neo&�-i��� ��a-k>� �resemn١�6% .2�}6-%ji� �SpMTY%tA'2�}7M!d�J3dE|�i�1 MALxJ!ndoxus A����� EI&1���.�6��Z�6�iF�y_��to\)�a\&�ˉ%�ap5|u�|$�;Q. 6s�A}LEL> Patagonia%)]f� ��a!*=Yp����pe�vv�: �=r � Az�[!��َi�ska6A�wbio"k%a��qa/ido'U leav=�g �e�Aw�v2����9:A��1�>"�C�_A%wi��� .fiBL�a�&� �Q�?�&$�5a��Csug� ix�T15%�~^�s� s��a���z�!�['f�[7�)�6K!%=�LNv �"e_ �H�!�39k-]sCL.� .�[8–1t�Bb �>�toz.A". ���!O�7�!�vtAdro�(1d[1A���MZ ���?*� ��sli��MALU8ca�Ou�on+{�� &��mie�X�K&��h�r*Ou�2�Z�[ ��~� : aMT�]n�n-:or��AA� MALS ),id�/��-Ses%oligo+���7 ;A�!��R "k Ns�? ���%����A��"l�;m5p�����3�[�iLw E[�n  I�v)Wye��s.QZ��M��hl*Qq5a�A�:&^ ,�trI@-�$an ScMalx1.r=�Qh��� �ow�;�ea�s;p uran+su���zP��f iRs �& [1�I*� 581�u&�0on]� VII��:_,� ScAGTa�~�.��F�� 57% ��ot�=�ty "ScH5eIu� _i����-�5��"A(N���"y,E�IX-rM:���_;?1=>n �0�_ri2� �\�8>eM=���>�s�P�D�i"�n�&3 E�a�A�a>n.;,zno6�.!�� Inde��h�WrY�6�Q� ���wo-Sep�<�u�mgW 0 logy!%-�: A7 A� H� 4}=��@Sle�r,Oa�j��� � A:��:� s�l��6_�" 2%��[� 1��E �,p`a ىN�� At�opW�d��CVA*x0th-�'!�Ջ�ɇ�R&5cno1��i�� ��=of6_A�ne��*x�Y!QTTj/s2R ng-(-�gR@m�)\a�EZ.�9��.� ]G!i&��ons.a҇i , 2�NE�)JTv-!�%�-�O�= "�4w t-2/2��� .� Lk� I make~J��Մly3�t%Eb�� �recq s�/GA�F"nX2�W�?��hotspoD&��=�p[2# O.�Za�2'j]�@iWxVan j72�ea�a�kc�RaM dP��!�DAXG"�~g]�=c: albican%rml��gng termV�Ds!�rto)��#Tx.�TLO)[CGh ��{�sed�>޶k2�s"�2YQ�[�iI,�.� !4��opy�1&T7� �dis]&ar�E�NlormIKofэch�-A�M!&PwiAsPlx L.�4nMk)�8��� ��!R�sm���nf���!a�9 Id���D @y]��eM�� *�q,S, MALR) a �KIa�pJ"�1t^VE#]�U��Q�@2%` �i.m�6"Cnew b�!'H3� ��.v�* =cop� faci��emergemaagZg6�Y iKAby !�e� &c:�:)V�k.կ�=6y�孙��*�#��"�D%x%� y [3�� ( iinUbI�()�Z� &M/11!�w !�W"��"���q�A�M�0dosage6���,ng&i�\�}�@�I�N^ofA�� �s�4! o�i�2�O� lB��,� �rt}.��3Z�� ��>� a�C\( 16y%0. T1�a-�K"�� ��q�I����:�lp8�!Q1$sE���jC�R[1��28� 3�(4�&� c�e�!a�A�ROw�@20EUea�i*�I)be� ��㄁�nd� �=�y�xmg�T*��@ ��!�}�JJ6dA�toV�co����?t�<ed &&}Z:���;I�n:� t�new5�1&a^(y%�nw�"-[gp�spNQTGa�{�!b�FA�urelB�.8]&1&` d6� Ś}#�g*�A��N�)T���:(e[J�bz{J�[sMT7ff�N,V- _\b� Ib��2t.��B��s6�. LR�� c�^ly-� z:a/ wA{\.{  &�J ɺ�r��n�������*�( favo�"��d߀op%�g�\ [4a�4�S�~$a�Darwin�-nl��B"3��| �� V�s/u~oshE�Aq� s acb� Cv�prL>0��+!+5��zou�����ttA�[4�9N� ,01� =vR�Vmp�!ri 2E/]�9er!#e tole� ,�.iIc nutrEl.V[inhibi��9[4� 5+RUlsu�V�_y.�&��ar2oAq�49e alac�,"}�xyl��[]�5��5��!J:�,o6 �B�&�.�%n��&��2�i�^ n�^&�.[5_ Theo��/&qR�I�f]��� �C&v] f;�.Nzz.!3�=sw$$8 submitted S . �Ueubayanus strain CBS 12357T to UV-mutagenesis and laboratory evolution in order to obtI|maltotriose utilization under be,rewing condi$s . While E a non-GMO.R-consum S . B��was a goal in itself for industrial6��, we were particularly interestedH�the possible genetic mechanisms leading!9+,emergence of.�2. Indeed �@hypothesized thatIk$plasticity%� func!60al redundancyl}\four subtelomeric SeMALTMs&=��,( 46% surviv�IA2)rgof��gen��popr�ߥDF�SARcoF�.�QZ two weeksYY,Q@!sU$a%aE�3 3, ��~concentr)uhad de)�d!10 . 5m�.�$subsequent�xf�uin fresh � , 96 singa&y�sor!sinto a# well��te�q�YPD1�(by fluoresc�2-activ%�WQA)( FACS )AhA�Q� �--culture��� ferr �j�%�,�which.rmonitoC,by OD660 meaa�me����seven2�isoA�s��a$highest fi�� KE4selec!6!�4named IMS0637-43f4o characterize�o2�MF�I.+�ck��]H��tpastoriB< 48A�r �n!N,shake flasks�%h( Fig 2AjS1!ש\187 h ,i&�}�8did not show an�"ɟAc sumpe�. Con��ly!�1�>�, allO(ed over 50%.�2Vis91 h (�'compaAto 43 h� �!�$Upon reachA�J�b�a�� (ed 93 ± 2%�� init� =�-}�,M΁9similar�!�92%-!���edA�>��� � q�sV ice�"� Ifi�b���ed2�iJ4E�y5�->7 pres�>!RA�%se-�145 h#i��M�B)�� !!sam%O� I�.�5 �dE7�#��a�� |2n0Nutrient-limi�: thQ�qa�,ive advantag�sp�Oneousō��w��a�er n [ affA)(y [45 , 55]�Lh��1 mprov6T)��8� &@ ly-rele��9#!9 pool4 ^n��ubj��tobW a chemoa1�فDmodifwD er’s w� 3 avoi@ e2residualUu� pr��t1oone�.�.,Bzaa dilu!�6-fol� To��engthe� ��6�� i�j��F !U]�ncomplłed)�10��N , yiel� 2  2 1q0, 1 Da7nd:�hg z f� %1JM�E�IEh �availabr � &�|4xygen or nitro e�g�supF�mK i / Ns,d4 *��?!�{-7% auaT �ed-7Ill*H �c�U. S data�� mapp��\chromosome-level assemblŭ �.�[9]!�,identify SNPa`INDEL�(copy numbera�nge��ge2d-;� �637�640 � 642c ~ �t!O116�5.�12� vari�#(� D!FaC� In ad� �� shh��(:�8�39u�� carr� )'cal � . Ovq�97� %@�)Bof1 %�S��he��zyg�{�� !��A� hapl I�� I�diE�bG<� �|sisN"O& ) � nM5 , 34�9�ff jPc regioń30 7�synonym �48 �k ,n amino acide4tite"I~ �20�maż$stop codonN�Nm�52��)��%1Zviously��kiU.�.L �� [y%Y��Arqa duplm� �r�2�)D!0CHRVIII . Reajte-�A#iI.�(A-_edDq attact�$e left arm a II ,�UFreplac� #/f�IIA{a%X reci/al�locE^-%recombin .�losc =��1Arel �is;exA�/6��� . Si��� to-�6$in� \d�i@lN+d[ ��? � ,et!�ECs|f 1-��ᷩ�V�i2tud�t in m�detail��'�excepo!�!:6���� ��MS�c]���10m� , 3 ��52x1geRT��F+A[ �  u 63m�nd{w� �6X�I98% �homRHaAu!�Qb�ss�6�it�ti�ء�>*!�&! -� �V�, �5�4RW%�abQ=!.rE�1 � expl�A��� 3A�/!� �� is�B��w�t ic��!�6s �D%�no�Aa~=2 . Howe�,�QS� �C5����s h���% s:F`550 bp�CH��incluL 9 1 ( coord��es 950� 9 , 500 )!s�Y��l6FX��>`3:`1–1 275ZQ�!�>QVIN>35 ���:5 . 5 kb �>>�4>P(6 , 850–2+ 3�. Analy7ofW�w� A�Jw.������ a� lex s� r. s bet�&� s Ś%Y���m� deg��  e���!RUAMAL lociHtheira"���J�,s made exact�nstru�{fi As diff~ t �m� �aѡ�e��d� �-r�� !qon ONT%MinION� formA�ndA�e novoaome&� ���c���. C�iso�)�r- 639�JP *� >wo%5��a�d occu�. Both!!>#��"� alIg��he termi11]�P a�� H ��c6H4mA�Miw?p! .�`Ia�3B�Tis6�%��`nt�#�.@� mUÑ�i�B6!>AUA c)�a i�-�u fm u!�rb.[!^.M ���M(U w02d2K b!�c2Nfirst 2�3-~CH��b�m�3ly��rrwdqes�Y��,X%�! C�/�j& �ri> !Y��(3 nucleotidr %.�s6 follotby 6968��*��682Y!���237V �Z��Q[!Z*L .n�"� 3�Q<3 Ayo�.]��E2f��c\age~ ley roun�Qd�� unal|%d%�B^��canon]f�4��!B>T=� � ��iZ%ope��fr5 � m! 5’]&<42�i midd'f $1$II%��3FL3(.�C�3�T�To ver�U"��| �ORF�e$PCR amplifB u� pr�s b��ng!C�p)tor.�A�m23.�a!1gF �b2� aLbut� ��&`�0��. Sa�r1��r fr \�e4:gconfir��c5� rgan�& R! ,A�ch3(�-� U/5�m 100%&hto >�.7� 434� 1113� A,^C1BC43� 112��Z{3B8114~ 1842�8SN��112 �!�N �� 72�w� ��61VA�f�! re�va2�in ��:E*!��!G.[B&0be unequivoca�attrib�t9��a@� erk� s.i.$ar` ��%�))� �2����*AJ\VZmhav��meI� R2a�RE� ���& 131�at� %�85!*87%)�origiV I��i%(!&a�prote� � exhibi�9� �88%�!�.�&�V:+��ed�ale�%p�%r.:A]�ss0&e specif&t+qby�'6 ��L6terti�)�� ,���k).!w���predi%%,aXacomy� , ��.Eo2�be1 A�� majL -oE-perfamil-3a �,membrane dom: o%o0f 12 α-helix�4��� he s#9d 9���SeQ�,)�1P ��exclub� �!� @3 9o�;��5�=���D�re!$%hwo.V��.;�"�`� thanq ..���}a"� %'�OE6E���'�/&��i yY� K� 9�-���5$est�-/+�g  ���3 -dimensio�H� " �6][A13EHal-$���ht��alTA I3S A$� f�0i�� !2���:�of� u"�0e�6�H5EU�m�Eal�Gs �m �� �1 ��wild-typ�&� *.s�$)��a�to1�M�2C�"�0�{"��2��v!�g;#�r//6�� ,�AL��� ^ �s���2i) 2�6����2�2*" � 4a*65�Co� ent���$�%� e�ng�NI� �A�c�t�e� inse�,�2 SeSGA1 lo, enco��a�!tra�%u�)�@.-s�q� amylQ/] B�L vegea%vu+th [5}60�7Grom<9�)As:�IMX194� �,Δ::ScTEF1p--�-ScCYC1"1n�,2( ^24134%�.�!Y� �.xa!��T� ��;t�4#J&S� t�&�17UOn)rf2 ���� )2� ����5�)k.R%25�+\%1\%>�3w�5� �grew fa�&��a�#th6U8:U. GB3!�Ol:Q&�3�"m Oni��!jN�Y}�) � �g���17%� 9) nd"�+)� signn ae�. M$s f�q- �� Ս�9�QHrnt���)(rse engineeP!I5�( 6 6�� M.\%�� aR]a�-± Q*nd�.w$55!.�Tin 172 he�E�perio43Q��at aF.u005�W�$4 kK.oIB n-n�, dem�;!7 capa�7�\��b\. A�F.}Օer�&213� *�UrIP�}���4~lR��ed)at9V�7B"��-�2�.�: ::f�7RL8��playe��grs.3g�:��6 yeas�7 we a��/U�e� exis�2.�V^, . cerevisiaSd�^p*+2��$In0io7%Rj��E�0�ScAGT1U e [1� 1-%10 &" 'is trun�0a^ non-*� O.�[61�D InstT6�'.� � 6F� !T��!� : Lg��SpMTY1& Rer � 5���; �2 2�e� ..�vH s 85%5� Ut� -A[6�63!Although. \I �$�([20+�"�e�76AUS!�!�north-AeaI.&�  (yHRVM108 [1�r�P-L!et lso � ���' s MT !D �� MAL� ��:2[2Ah22!.�to%�]�=}V� �q� vn�8J�*�!!)*���� ��� "�[6� ��� s 90j MALxiws=,��dis�� s se�alb[%� s [6� 6�2 rela,1ly �.�"�!i�a6M`!��(�� theyzl�=P� oi^:� BsV=S �c ��-'. Moreo�v i"�}>Vix!�Š^2y31aWracly��;us ;ir�'� 9I�2�A no e >�X�% 9.er.D&H �?r �).A���as� ��}-+1��:-*%v� to)U31 deviE�stronglyI�Sa *g=Eof 89%Aiit0@ѥ�we!�316:�$S288C [66]!ab�4�$r2�–43�N627–77�!796–8B586X968E�64 84A�� iŵ,79%Bi4562_65F 779�"50F 84�5k+82F"9697 , �+ ( S8"� Align.W1P)�2G��m Ito1�9ed \"M>�e�3 acrv#s�$w=�*E� G* �>LBE�A'6I1�x s: 9.b>�478–53o94*�>)5%�!��r+7T79&$=iTh�0�=�p�6qBxe ��� �+E� *� invo�(6��'s"�h h���2�C�b)�= Rn describ�0{L)[&U 2��� ^Mcan.Z'/reQ0AD�uct. Its=�B��}@ 5m�4pl�B*; �lyj� ���:"Qs�4�]��t��!� @�<tooA�rt& 2fy�ir] vena�j�U�:�%�ea�th m�B"^] be b�Db+ NCB�,I)����m�q g!�c�st hit �) �t6�w�8g�W= ��� radox&�GYPS138A<&!Uan�4�to2�6]im, SparMA�A�$anCofe�AT9�s 544�J75E.%3F���2�2O�aE�j�v�1�8%�!ax�B�s���� 5q>�J� � beE AR+� 2c� iA&E$-�probai3accumed.�&�>"�z�:.E�&) V5']!�&�< lag�I.�I���:e�i&~."��*\-scale bF�I,�Torm�.a �\3���of *a�A B�Jin 7 LB/�B|*�-grava�D( 16 . 6° Plato )�/( F+�93 ,�a�BMll".A%�BE!2tD::Wdrol5��19�6=A . 7�6.�In.y *� B�t�3&|7� .�4A-�>�+* BEZ=� �67�8�8pA�:51�>5!�in 200�B! 1^>S�F� took�:33J.&C"�n6�su�:6�!�f� ethano"*n�/�o�Y]',I���1�|5%Ere� �2!�e;�v�1E�D=�.�Bi0[@aa���D�K� ~�;�:eo�by�xprodu"j,aroma-de Ang 6r��� $er alcoholdiacetyV F% 2�� @A�>B��*� l�Bf�!"�F�*)`�A-%�2�2isc���M�a 2405�2�q ]5? ( Ta�M1�.>�%l� �. �off-flavcM5)���X agt��0 sholJ25 μ�?P 333h��]�"�!� w�:8��Q2� 99W |/!��"�Tt����g A� �L)Q%�%tb�4B�Loin ��6�BI� ��Az�`Q4>�3& *�s�,@Re/��f�(. Allbr�\"aE-:-=��0~6l9�$.NO[*i:���=.� �I�%. f 3��)!H �%. VI [�2�-XZ�, Zm�,Z~��2� :A"�;ND1"� at�A J1(;1 . Lon��$ad nanopor" !�e��t���$��mr? ed2F-��+, �aSM2��&��ORF���)n� q ��:R"�0��9J ,� %��)�newly-��m*@ *13"�aM  lBE��.'sN%';�Garq�> N!"�� 6l2&$R,k*���odt �Qig"s�!�� �:acqui��! �!M!g&2G�Q#�/� ����A;�J�Sb24oQ. �)v�% [67]e�-42W �MBalYB�": noth!is knoxBbouV &�$�(id%>����6�(�.&6��O$ onin �0r "�$�!505th�557th�T�U)pe�N�!q�'>jpAritn$�� M�s [6���A �6�9 sQ�t2�*sE&�s�;i93�v�Uis@0��Z� yQ|��!�R$l�Qy depen����>�O55\� AV&�p� `� raI�; 7Iof�&� 2;a�$1��Mݿare� ��j~SB?A�I/tud.N��n�O��)oU-�<��.uptO[19�0fa 230-bp!L�F)N h3x>�%)�T�D��9!v>�5O.�sh,BP']3];��WA broa�Xu�"�eb-X�2a�al flexi�IIw��)�se '*!�5 "�5i��Z0A�X)�� e.�,�d��^2�*�Y doeshI��U�5n&�!5.�M�V�t0U���V�8or*l propX-�, ��6��=��UMt�Qh*� �2�� 34�b��/�9ar ���>S4�P�#�"�@� �,�G �� a A��i�0A�!-.|A� B6] r�#� t dr%W��<- ,��illB[�b�6�!eI�ciɶ�'R�"ofF�.[6�/dZM� tandem2ea"1 _/succ�= anti�. citT8"�G�!c Dve rn.mo ��f�>�:�� ���-=d&"! edAdy)ly"�TLO g!!$C . albicaa*v �0 ssocMO �B"#\ [3<�t*�2�#IbAW� n�<� �OR3/ch& B�� V[��2y ��. NNS\b�` vivodm� �ՔyC-8minis��%qm�]�M� pathY Trypan�Ha bruceiaDev�=�4host’s immun.stem [7� T .60 �L�X�>ZQ,urface glyco2 ( VS�[%ae�a6� �~tU%�� mVEpseud�es [7%�D�Z7�@repeti�elR.k!�� �dQ��3by WV��.}� �Xi2:�V[72Z4�5a��P swit&V��� qualgas^�it*�'� e.� :� toQsU�%s���� U\2�7a���$�$��Tc iA�trp.� T)��� gy %�e shuff�o�$fu%b[77�QGe2*i�esu*dom��-�K�\+]}$�Z�!A .�<scree�1�novel�"93�Ao�J� �V����AQ�reE1!c�]WC��A!bXB*�apo�.�dR� [77]%�e];A�ofV1�0sE.� 2, ��:�Sorta)nAn(-�Ac n esg=�XN��ccele��1:�new enzy�(c=�[7� *�#�(.� �.9.��f�YC� e�A �&� 1m albe��T�ngU��&z'�,͝ �F�Yڅ�!�*�%42��al)C.b2jII�r&�[I� 54:� 1�is{u� an*� y62�co�U$ounyda w�b arra*A5߁Nin��1 �UTJWqzg6e�. ��7.�,2>"�mR` �*�)Zw �� b)p�1M�2@.�2� �,�&� J�~� .`. a�Z^� *�# � disAa?�s8tivEM�a+�Z?Bf�T:�~�f:*x ;n. !�����V�N*5'�G"B��&W9 AL&��U�!�yb���(� �[g2b# via�,� erJ$� .c A]S�29s��� r�cof dou'aBnd�ak  inva健�)�(q�1�ŷ?*�V�^�[8,R��[|>��� �^:mEh"�QrL��92\�:to�!6b^JaNwo"�"�����!:hx0uvarum hybrid�U�a�� a���!�2�I6A�th�)%�*P2����lo B��&� !(�f saic9� comp!H�U%��#��ge%0��R5rE@a�"�%�e�Y6��&. .�!�#'!{B�� !: �4%eRlos&J�i�Ka&�3�L�+2}H ES9n�H�R���  R=)2����expens)Ja�b�As"�al-*�j�" ^DP9lom"�&� [28 , 3��3�/81�/!G�����"�=i�.�{��b0B�t�!:L- a2B#�S�h�IN:���,+�-at E"h�.��'MWA@�d�f7W.wi%d�bu AA*:}� �6pORF�``F5� un-9to\benefic� ,�c��A�sO� &bNwSTc &iI�3��H apid��2Q s{dap:�o enviro�+ Lh7F�5�24@"42V h�[a large=�x���3�VQ7s&���:?a�`E�v�!U���bX mF�"inJCo� * !��Ufl� X0onm)8�8" K:�s�>�/�A�7��,"�ny&� "=u)�"reedom �6�.F����&�&.�c� !z�#tI}%�i�2�6�!LUnAh� �S�< :�p � F"�m�6n8 �2�Q[��Kd+�1P}�ir��n�X� �Dcod�l�gD��Y \ *� �\[8X 9�Aaiori�7.)"7YY*elucid�%Q2� hiL t+For"^���cid�=Zs� -�S iyDr �D)A�a�ce� l��-.�PE�1�-hydro^>�!%��>�"-�N([1"�3�� MALS;B����5uby?i�':%%�g�92q��KOcul�P����3�=�"�{ dO&nctu�s:���E�aC4e!�b ` �X)s�t  �� � ��I.�i>"is[ M ��it"!�@s�J��������A@"$��EJ enge�ha�aWb_ dis&th>U36dp9_���]toa��-� ,VC � if m�2' "jC1�r1#�/"{8�:�[4eԉs 2[�B!mk��ajM�t���as"1^�eFoV�e�:*c�FoAz�("�Ha.~.u\Q�F+�E� �Sm���U� �Nn��.� [ W** +44 8Ex-k.�-�2���*A=�EaCE*�V@!z���ѡ?!�i�d-�[3�&� �R� n:Fky� nz4-�2ret]�. H!�w� cleaa�p9Je�T^0�R!9��3X�� 13Ac"� ��X"p�k atn V%��&H �k���>1biz1��Gi�pI0�G�2����&Pw#9�Iyaa bodY .'2 sub-e#R��Uir6��8*is� � 2���lofrs*� !2J+�� .� ��0l� � besmotspon�!<Ŵ2n��D��QH�0La��x!�!UbirM�w=Q a� 2���YE�/#,3a2L.3%b"�+unI�eq�&a+��Fs&q!"Q�Zx$�wh6s�  �J insu�YoAz�y` K�i$�eg�((0 aris� �"0p�<,��~�� �Rd�Y=�Q|AusH"�$d�ep�(*� B��*�.9�6E����sXW�+)2��&su�eW)(&fk��^`!-.Gphenot�J�e�F{$ wholYh` x +.�Y*j6�,5e&5$g: 6�"� li��dfaP)iH M 6%+�be 68V�a!i�Ui���j�� ?�R" ��a6�.ca�1MIaZ~tNfZ!� "3�k*�;&3] i����� �a�^&]"�NPLqv)� �9��%!�&g, �0eJ*@"� C�`��Sf.)�.�!r� �[�. ) �fmC�d dele�t",&��*�56�Ai�sU�)�10�d}����VN'י���z i�2r5�al�#M Ha��y��'�82a���� i�yon� e scop��Us5)2��4ovebF-f��A~�!�_� ) ei�m�2�"I 2CHTMne\ ar�Rsuboptim%�&��;.�ng.Ss.7�%� �y �&nd*L 2sWimbal� U�.�6�!�&�{metabol�teps [9��9� J�7�" gard!Z m��>�U(�2CJJ)k� K�.X.� gene��� �"pa�8� do��JzN.v � atBV[ "$ qr��Y����n!L!2� jR� )"�of GMO-I��n"�t� "��y' custłepZ)issue!��G& �n1�q6~4u*�|be�:_> }�Iuvatp:�:�a*#nnear-�2�*,%) E"�{,�a�P�6*�7a5"j6�dad�W4a�Gs�Vi� ��6��$S�M��4|5""3pb#�>�I>N �}VN if�wA��� u�)la" m�&�9�e"( �s�d J��*.rQ8omi��lX(1:=z,�[t orsLk@da��4 omic<fit of5rUG&�[9�&6y8��,�<��e�)Ł,#2��UA*�F$:>9kesi-3i �8�Af� �[�E9�&6Oq�typ2l( ,^�44-vinyl guaiac�TaAve-!&_9 r [9_98�akt6'�0ynh% B�%��" 1�de�[9�s"� p&U� $ic landsca��6m�] �%ed ~db��dm*3 ��HAM%�O��Wo-AZR?�ac;:�`er��em.. �'6�����{!Eap؅s%�lTZ:pewA�)L >< mA �F: @. , 9�"q6to ferm�.�!b�t�<� to�'��t}of:�, &t0lNQe0�Ga���DQ��6L� ��. B�[�< direct!�"�qai�U2OO*�6]{a1]valueG!�genamA/of�-�i�!6�P.��7 9�.�s [R100OI0X All)RUBK �%�M �linin�=2 .:�9 �.�[1�7!.eE.*483 [5-+ 103]�|��4�K!5W/߅,a�-AQ�~ −1-8exn] � pept !H�>an�&�)@Oon^H�,��aF0�|lyc"~PA20AL(30% ( v/v )��� t -80-{ �&� .aC smid- propa[S�n�&inF�1XL1-BA�S�U0 mL LB�~� 6�)G-15*, �~Bacto Y�S=]NaC�dA� /ampicill, t 37�.%��hpre� dm�' i)��9�*� . Sy:�s� )�ed �8�}KH2PO4�.�}NH4 ) 2S�V�Mg . , 7 H2O0f%L-1�sce�/�5"�3!&vitam�o ��!�,@0QY�Q���0��saKSM�:�8)m��,d|\4autocla2�M w/v  �� Y��( 9�p8% pur�)�6�8Glentham Life Skc� Cors , Un�/ King� �"3� !iM $HEINEKEN S�� y Ch"B . V%�$Zoeterwouda�>F0YF[�5Q�of Zn2+>-ZnSO4·7)�=;��30 !�at�� ᵒCE�fi�d�iNal��EH$2 μm SFCAnmt Cop 1ssB herm$L��6, W�4am , Mtp� �Wk��Z�e�Y�"q�P��d�3|`�wa�. Solide�a��F6U�of���8( Becton Dickin�p,tE da ,�B�26.�jsaGns�?�����pUDP05 ^gRNAS_) �e������l�(.�Abr�nF q�Ke�e�0 mM )m.aFAcear[10Y �{The|4s! hum�F(fluenza vir�o7h|1i�l inue� s0 �amorbidad�mortal. Tim�nd�u �2ss���dimpact! �dea�qA$��=A�i� plan�E0� ;� chal];�#"rn~ r, eMqM�os� o�tenDe� unbivsurveil�� .�,a�proN*ngw7o%3*6-)[.�%"�+e� est��sV{��5 ?�%�#�4ss5mc %�E!vi� Q��,�!U52�hir� ts��O1Q!��s(!o )�  easoq92�U'B%L��� ship�,���d^� op a�ho��'� ss�!Yg burd"�fwA ( H1N�G�!�@*A�l�1Li!�L5�5lI1P. Ro(st�e͡�B�!0�5JshC)elp%�M�ost-eB~v"�A� ha�ׇa^�c� on . Sf���6wil�Ju�� *�I�-[;+eubOhe��| ū(<���E� �Z��– A�^z�:Amo4he�')%�� H3N2AVV �d B7 m��C ircuANng��Ղ�e�Q*��.Έ��"va����I@��FGe�>%\�d*[� o�'�;rtm��s�h" (A�i�co��18hemagg�ni��H�V[w ���t:ic���^�� vary!=magnit�[3b[�9 I4(B�1.�)+�m# �w��!�!�W"��D ledg�'llA� e�9���] aLM�� n���mpe>tepi.c/p%>ic�*Z ,!hM�autho�D�o��:�.n��qpa�teg> yK"�h'usu7r��� S0�Us���'B�onM��3�n��ng �cy(fa�r�u ( CFRn! M�&D.Q-3� =)��,GdiagnoHs� 2in؃��[5A[A:�y�'E��\)[�H"�}QL!��� Ly�B��0śs2�2/����E>!I , be�i^M%�A] h�27�/ver �m[ ! d� i*o0ll%,a�is�,�4�n u�)nAp��7�Za�e �Eme�M/�Nwam�q�=NBD21)��X!2��SyA�4e4!�ex*V��w E���; !�`I pre-"h,u?(�LN�dd mB�aa�n{$ ��5M�ۈ[a��huM:4� s. Despi�Z��X!E��.��o�.� �yq�e.Y0%^�$! >�*%�ur3>�@�!) �Y�)�'6X �ndW)rc m!�>� &� e�a@�e)dU -�US��byb!�m� all-i^It�o(,�9(��G�.: [�<w�=� !* work�1ow`5�p J�� u�%�M60 d* ��i{ku!�d�:�K)oHJfE�"�� ���u|]\!�v��� i�!V� 6/�'���!M��n1�* ���:�M .Rir�K9s . T�8%PA9a:SJ�vO>��bI���� ��>�zr� �U}Ou by�GidhMgd-�"fJM �ѥ9 �.� �Gݫa�R� N1dni� j % �~�� deno� s “9E $”� ee Text��4#USYz?���)�� !� OAQ� FQ�;>.������2�. �,�Yo �� �<1ttwo�JlO�,� �gd�l� �F<&$�H")�E�w!$%->"s�"1����I��D\BG.\oba*5Csi�3,��ه^���� EX�4� �a��tb{may�a��,wloo��?� �*��ebV�I�$J� �2G�QNy��j �.�k1$w �(�.*2q �^Bu�9IU�� Spea}^& Pear .e�@sN]aa ee M~ia�- nd M�as` .���5+�)uA,]!τm�.��� 3a.�x�refTin�'s��; Co&-# ( PC"r�1r/S/).�^j���EPF�u� J�`I� M� = �79-,e03�SC.,6�fF,1; %�8;!P58�g71vFg002hIN!%s5$� :�>�65B�12��6�3V�29Jg2V, 46 )9X�� �A��pk�^>�� py&��f!4I$ ,��dug> ��+D�2ag �m">A�E �&r �6mUA@�' Y.p' ���Z��Q !.9`�Nb'besŠ�5is* thir��8Vj00A?;:�7Z-4�cY!To"� i"Q���=�F�;/x 5 B��J��$Eg��-e�M&�!(JMAMj� a�d�q� @�t~-���t� 6��N��B�ō�(�$.mծ�D�����2a}BHBi!juno2� YNE �!72�� T'� :8!8�"\ � 1 6 �@>�u ����EJhighl�"�$ boldE�f6��D�h¾n*ly1L�� ���9�{ �by�co"!+S �fn:to#7V�06�00t��p��F�u�|�m`InF�017Sa`\^�b*7�,[&2 �" �ܭs9"n�-"9V'00�� �w&Rqj! kC�og�&���",.[L.J.�2� &? I�Ba�6� "� $uta"� �+i�:Ra)!�)�.�� i � fp0�o��cKmetԲ7lbyo)T~�j?��gW&�^]���(p�� �, X!Y��eSG~��S� ߒR�a�s��F��u�B��FB�4�&�~/!T�����hae�2A� �y3�6�S�= "� %��*�TF}������9��t+_�PC gr�2bʇiD��!'B��;rk~".IQ8�5 �BMd�"PaveJ# ��� F�afUg�~C!!1�T�1" Y�� }" &�?sou�*�TP�ac�q�..���$q|� �R �2o(�� )����'T&�B�*� 4�is�qu!=V=P*51�NNani�i�FI�1�!�6 Qm Յ:�� <� &�a�=����u!�QctFfS9 i�"� BZ!Q�� a�)��%eWaf6�u�w�P��h�tT H��XV�%*#|C5k�;E) i+�7�* g�&> ��b�6%4��c�#7zx.Np2A��e fitu$��a�n-paraͽ�@ l polynomYI�a�)i[6 r��s�R )7r�  ( ��T�B�( �+�gW�4��dLon�ic" a�RN�0iP g v��9infor?�3�ixH�uaa�)I,a:i�j squa��jJ4�irj!"J2�#,��B"fܗA�eque):�r )�x' dard�*D%�t��erm�L�rh�d�+&[�]�� �fit�m����r� �"��H�4 Z�(!��A���xI<�c�v��#wh� 6aNo ��E(�!obu�o��liOg�um��I $}=�N?6�[�><u I"� �)ZFK�!`�!ňeR���Ba�v(: /3 51e-C ]~ �� !��g�FUtrze��&}-�!��_t�FEM� 1�Mc e�.�$leave-one-!�val&N0uPSa)j63��)k� qz'6r��y"� j&kz�!w8#�UaB reli�6of yM�)E>� .�5L>!p��$� )r�i&X)B]DA/Brisbane/59/2007!yL.sta��ܯi+)�y] 2k6��008 j ,^ �BdF�of 50�  mill!�a�� MR~2�*9�2l��:Bj�p�>a9��Ca�E�;" s �May�v[1 )�BJ � ԢU��kru�nk2roR�G| "�7��]�� ,e�:�y-I12 a �d E�6 n�"% �Ziaomp���V *J��tnO�V^ \, A/New Caledonia/20/199��,A/Solomon Is%7/3A�6�Ma�I  �ZN�ZE6�gJ�iA1Id^Di�|2�,�<�Wllact�=�!�!)�#dB�:*��2%�3..�w6��_i?alF�E$&F � ylA��%9BWk(��%r��0�Y&L � n5wMB%E��>I�-�  �C.*�)�! !�FV�;E�es �qe"�NyD�!*4-m W�� ( HIz ssay!��,*q;�<-�2[1[BE3�}lem9m�$vl�Hen����� ve��h�&b*i�Hy "oup!�<� �65 sera2�)�� A*�"Ҍ����M:!na~�V�` f�.|sz}",�w/s��)�ӻttemp�;fde&�Y M��k"� l*�4�.�(�8 �>Bonl&[14e,�U�ީHE0�i�>��Or}2�j�l;46���( veloo�Q6�*�Epitope- �A"Di$ ce P7I�EAD� 7o� Z�u`� IQs� L �, �(cy��3�1�D6�l%�A?Mo�V0)a�D&0 �&Vb!"Y3C" X&�^ t�6�9����&*�H|%oӊ&e�a-� :�)Q is� �S��D��1��0\K�Do#kl���ng�}x���T0�=%�F�1J�ofF,e&)R " ۡ*� �r�IHa �EUUK|Os�>oA.g8�B#0�����A�2�B� �"'+-"uC ,%u!�n-�4��ed�Q'yf.\Š&s m>fUmB��.+ /�'c]����'0TN: ,[F�}_Dby -9�@AUz@�1��iFi�4.&&LU>/�eS8on�v"*BB�gYN�s�[z.6D1l��Veak�!��5 L��JI�vEi>�9�J���(m�ݍ�� qg?�ff6Vf1a�*��&�t��4u . Nowad�!!�3 �of�� *<���*�P� routEz\/\�"6.2�2� t�i#<Nh�. je6d����- fpu��7techna5T:Z��"6I�sa3�6�.J:'9e�|�sas�3��os�kof>��p8ale�\. C- myb�:&M<�ˀ�[-�.,oz�R<2���1*�+�Y�*#Br %�!�Z� � � � N�1:�6�0�:IS�FaD�2�!7!h&�ny"�KD�%JW"�*�(]�B5!�� fPD�Pc �3tx"�� mole�& mark�[1�2re�N[Hng [17�FZmdyV%�:-�l��I �-r� >�agz0X��r: p&��,K%$S92_vaNw��� ercbe�um�?[18]–[��*5�X!���5�!���f2�.��!�n�%Z;Z��Q~�R�37S.5is�e�� � )J:�9$al�%:.J�~ye�<, Park eI!�u1R�+.�*� be!a(uy�&�* :1c�K9Usi��u !8h��r��� n�: %Mx1������J�y��g�!���� ���.f>�O Y���t.�0.&G some�Psur�!P{�*@B�@� *�2I-�>��0&�e�e�uM y��� de�O"hr�H�  x#�� 2�e��t�Mf��� �c].mj i"� v=n6&BD�RX!�o&3Rm�:!"�]J�*�*U+>j>�Ra�:�!�a  w7��>a2r�w)hig���ro���0�3A�d8�<,"s �V� ��r� �uq�@���B8>��ZWwJ8��*Bq �NF�!�)�iWO�+e2ч4�liw� sampI)��e��F)2�! ]� R�( +ViԾ~� P6�%� �a�31�.e /'s"���>UԱ]M= di�"�H�peopl�$r�#e��4 o goK%+%i��$��A�1.�!-.;'!v �2�_6�4,2JF�vk� S2>�"E)�.�-as"�~B]!OeZUT �:���#&�&� a��u�rocal� a/%�reMq:���"zE�g)�B��n�6.I�6A-z-QButa���"e@� ?n ��::��@a�V��w�Z$i>�boxed dogn�S.�'�l&b1p�9� ��noDb���"�.Qb2�.%.)6&IW@ Lh��:%�/hBQ�[ �:� .#�ly)_ �M,}Q�� ��ua�6| �X*� = B���5��EU�6vNMuA:wa�.��A&�E=\� B�, �Z+2Nqw!+������/es��~zv!"}H���a)(-r.�2�.� i:�V���v�7I��6E� 7.,%�� �� &�t2�#�"1/�z!(*V"� }*�)�,b�`�!��J�( [C}�Mon 95��1�B� {aaya�m��:�%������]�wAyinki�!��9�)���K���o< Y��a�Q�ZeG s2qH:�NAU��B�NE6'neg)� &� 6H�Gndi� A����NBi�aF�N�:�Km:���o2�K��A nH (�X+(ic����22���xv&}AWq��*�*�GV� BY� alcg}B"l%��+�'.]to6@A��+A�i��B%CB�ab9q$B�/m� �f�L8B8� ,� ,9,�!�5"ed ա>�,�a�u"sOɹ�Mp�"a�? ny"� ��9�S R*@, i{D�x�c�ckno2k���"d�%�t("�i- ���� R#� � *�7%�c�Jof�#Swi*&ȧ I"K%j�-Vu( S-OIV�Ńire:-)Q�.o25�/p�G� A�2�.�B.A]ps�a���&.'"� [Wme3 ag�-u 65 [Y��A�9�&�\�P�n&\='9I�->O���>%)N�m%� rr��.F� |[Rr&e�%!}1�&8�wv6"�6�&j��.� k�Pim.�!O͆.�EH%�ac^���A!�iAAj��=] �=Yz'4s @Jo�$K_!&� z�vY%�n�O�&%3� �75i>HA"�nA ��1�.>3�FQXo�:�*���u�qo$**&����N�� b郙0�fEgV INa�;t�% ��2�Bi{Sg�Rr�SF a !�n%���2oP�ammm6"�h!GI>Fr8Keco�/clPm�believ X\ -�Cbe �usefuΚr1U.Z!9�B��(w; fu�^.oMe��B5�k�F�`�B��%� PB>eBa��Ed��� . HII�,.��mUS�B �US.@� �F�r�i�Z9͏US*�&FU/ir��y�/�s�e O"k � a��"�) /q��� .A1 & 197�+ 1978}ot��+�+9L# coll�n;E�[Xrecord!Y docuA1s6!<��6 �I"���R�WR� �d�.�%RY�mmwyGWorld HoVOrg&z�( WHO )�A&�oJ�(US Ce�&r'D�C? !�Pr�v�0 ( CD Ef�%�h�$"�[%i�wDC�%^fV 5s�YC"1��)��n��V9riu>�^EI��66_F�.� D7"�i%CfluQH2�Y�27b�Ie�%.Z +M.�m�|��V.�">bSrL�ifL!RQGf]�4y�#��1���&�LA�RG"t�s�/so��+a����8.*n'�""-}�j�i�sA�q ��by*4�4Archetti-Horsf����!x[2�W24]: (J;w� Hiji�+RHI ti1_�I�d 0 tL*ra�� Ej� �!H& �*L�9�1&�1of�(*��� HA�c�^� ����331���)*+eC- �f�+Yg%�se�>�ŧ14� ��F���q� 2Q �5�p$�!�m�dU���s/eK�C!WAgB�7�=��t� %BB�200\��/&�'1�2 �e�F�S` aCɄs��gv�&}2�SiP8ekJM��S� ��!y��6c �&�UHY�9�aVI�sq�A�I�)5a[��)xa""!2[N�R�)�R�P:*�)��=y�^�h�of Y`r�Z(2?di"�d J��� US ��0ixF�tBP>u�:�� al�4;Yl i�:fig �B.w UNIT9:�%{"�m�6�) \F)B�pq�M���*ށf":M�t : Step 1:F-i1�� of Y%"�p2�%k"� � +NM9K.�eaAC�"�d2d�� Z�]'۫(/"O\.� e6N!Ge� 9H6#�w)i)�� �� � �ub�Kjv�}L� �n����&9�mula�Z}C�ZXi_)�ssRmBf , Ri? o.ŕqFv�We��m�Bh.I> 2: C-��? B��R���g:7a�Eu-�� ��n eSr���� H�:�2�/y7��` by Y��--� h-3RInB��N��%N��}2Eu� � js6���suf�!� ;.[-�F���-& `xen�!���%:A2 ��0�IeOM >�E��F� :W� �F��TNt�s�"2�pe�Dag20$1=BWB9W&j�bM6� -D�M^"1�.Ftw:�2"O%���%� de� .FR\��i�#5�.�(i�G begii�#=��en�$.) >a���oV9>��.��A=.� �A\e `KeAll^ee2�E8R?*� J� �.���!�e�.CM�b���f3X��Fv�I�9�F\ N��A�pm;A3H�&�'�MTa� }�&� !!z�ies c�aused by antigenic strains and their ,distances to4 previous i-thBEL were analyzed using7PCC`SCC indR package [10] . Finally ,��two(��combined�hobtain a better correlationwee �s vari of an e�xthe total excess mortality it c!j0s ( The calcu r0of integratedZ1k8 sees Text S1 )!o�mparison- N�geneticK( numberuDamino acid differe%�m� �vA�fur%I}{ blim est!K ys2 e-� A`resultsI�sh in"� D%�N a3�.�of%�metho��ng]Ke�nts!V"� a�|�� �b�5�site-" d `� se&� A��� I�is stud� ��statist� ;s�� !us�CSpearm� d Pear c}$ �-,carriAuq�K.n�R�!=.P �is%�d��eSHcor .%���Wcl�o , robust%nonM/ri �is:[la>lmRob9lo]�vrespec ly .���8Asian soybean ru fungO $Phakopsora�hyrhiziihan obligate biotrophic path��ca�( e` dise epid[ �^ Mole� r me� ismsi2 P ..}A�-�i�L 5e$ir host plE���poorly� stood-ugenome�ATV4encode many sm, secre�Y$cysteine-r� proA�SSCRPE�While!�� !�thoughta"5�Ac ��ir ro�E6P let!�un� . H� � .n cha[��of>H� andid!�23� pEC23K a ��oe�C�� ��)^ immun3 . F��m�"31 X��s�U� crip�6fac�GmSPL12`at/-�inM$*�!il�dP� tituM�pve�%freby id��O�&C reg�oq1defen�x. Collu`,�=��5�eve ce f- � u�Y4I�IFA� sugg�<2Fs ] 2��%�;spo�E� %1���, =a1. R�6iE�r�a7�-pec� M�8order Puccinial" a��a�ong)�8s [1–3� Theyenot%!W�B��"4mplex life cycv7efDtinct spore-produc�sta=!Ke��al% . As)��;!lonize���t� @A�yph� ;e*!�austori��! R- cell3�th�l�� re crit�U! nutri�uptak� metabol��|� !��eliver: �/��E�manipae)Ms� ms [4 , 5!�MA�\�pFTbVJ �0hrough whole-�� sequen%��in) a���| studAq$[3 , 6–8���m�well- $dJ�!: froma r* �%�$es: AvrM , L567 P12r�AvrP4 GMelam�K(lini ( flax O�eC�er? P�2 ( RTP��Uromy4fabae ( broad ��L,PGTAUSPE10-1 7qh gr� is f . sp�E�whe�dtem��%/recente PEC6:WstriiA�vZ ripe\.!^=)9}2�h#E 1���ns�A�i�a�Z*�def�by'bil��rigger Ra��� mediiM�> �Q[9–12AN%�� � first �m&v�$o be direc!C��-�%�y�toI�m�dur�in5A� [11]m�moreo� ,6�� to! m fibr�!Fb� �} inhibi��[9Nl� i(t�� "� still rem uncl�.I� asal!u!�==in� -�F� ��!�*!a@ sine kinaY[1��Pi -free% ays"4 demonqt�� autonom~ent��Ice�MzAvi�_�-�[14–16!� Addi!��K=P��My�e!0 �E�: [1�@14psB� ( ASRe�d n�  seri�thra�to",��� rapid� �%A�) of lA#�9 Q� us uredio�@sm  optim�nvironHal� )Ks3oHhigh inoculum levelI�pot� %u%yield loŮ[17!+Too ��g:7 R� es�B� td [18abut mon� h N�to%sis) ly ax come�N�nt>sisola�[19�he.%pin>0 Hcr kesa4earch8� er�5s% ly ��nt , beE!�y may!�w  new qۡ+�8�� trummi��� �t��is"�  a1llprhinsQeKN� �F spnG. R�~�,F� �pur)ׁOA�2l�zh !��4J+H�R �bre�%?���":s1�&� s ) [�Amo�pEC!N,[SJ, i . � #���in$ at hen hyps.�wstre"x r)�� us� s [2QSup"G of�/� � � nl ec� "�AYs!Z �# promote>M^c�TAUis nearyUǩ�x�E cogn�"b � ��"� in!��!y:featu orE�a5����s duAby]�[21 , 2���{assoc%m"�pa+   PAMP!��N�f-/-�c!Vl� a typ�6J�as]-�.�( PTI�3$ perceZ �ter!(9Q� �E�R�`o?-�f < surface [23–2� Bb���� de�onAN� oswe�Zwa�  re%�e oxy��� $( ROS ) bue ,i�.e� ional up-� k%��d�,�of<re� ct5�A"r��[2��Howa�2s�>�!�" *#sucA�fuX9�� "� meano!0�P •Eu�[I�I!�tur�!.D # evol�-��m�%FfiI much�erb>L] EEJ&� ,�hA~Zhypersen�va�mv( HA@�C�-��pro� med)�death�R( ofte*z by nucleoa"bin) ite le�~rep�( NBS-LE�5/��rI����s#A9��(�= )P[2mE� �:��GHRe�be %�lyZ crim�Aa� ma1_!�engFnd��o� y shAc���alA.one�[2�TWeE�I e�����Q�i*l|*?c!�N��g$�6+3g ��i����t�� workA&e��=ed�KcreenA"��R��5Qs �L!qy�ac�!m�d , Pseudomonas syringae pvomato�Pst�One���we na�!S�Suniqu��P gy��5nHR%h6�Q, majorѶA� eePt�#� E�8 ten-� motit#at ap��b!�A��d$��7*i [���  Aiuj��$( SQUAMOSAaHr-m� -lik��} 12 � RNA �A�of&��cZ e�EL2 A��%*��%R�2��prior E� docu�  �1h a fewI)J� �det#@(��_ɩ� �" M�Oa� curr� y es�ishD8 M.hax s��!n�2�v%T-"1 ,*� �$. We wan!to�rm� if ay couldY�A6bTo %��clo�" 82 of 156Psq��8by Link et al .K minuE � A��(� pECn� � !M�q III� !���)3S~A#$, pEDV6 [2"� :: `�  (% � empty (� inta� nto��� in DC3000�� �����8�gs ur� riA���4N . benthamianctobacc�� tabacum c� Xanth�"z m( Glyc!�max *Williams!�$) [30 , 31As�3 �( filte ofs6�.�6wleave����-���!�)o-� ( EV�(t�bde�E$OD ) 600 n�0 . 2�� 02hI (macroscopic!b�( 1A121A�2S1AS1Bp ,� �$� ���O��e!,M:��� � 6� �-in� HRQ�I| 23nsv� delareD%-HR��r�N�I1ϡ reasA{Q' ��} NP-�,��) on NicotE� 7)�m� force�requi :uH�"@, sVR�3��.w3#�&i�e�[ �"�"(we only kep&� �"�Apx�lyA���y�( )]�r�\ phot ph!hemC(d�� 3 T;-nfirm�/HR�a�phk&50, trypan blue�in�O��!d��ct� i��1�� �5FiA�i1AS*. [. both�5.9j�IuP" leafAa��o�]�!C�nge#E�at eaN)7umm�y }"y.�����n�)c)T!hf)1F" eakea�HRA o ex� IipossiD��MOex ��xf�A*�� A�sgenK*vi, ;st���b"� grow$ ssay:�E�!cur�$�GL�#�o)L#m!�)/�D]simila� !�30�\�nd5�HR�not du�*Q�in Hrp��Umin6�u�S2E��6To"�inv%�"whe3%.a a~5{f5�UY�= �tB fI5:��%8:�9 �ed{he(A�I�� ��d'� ic%$fluorescen�$�* EtHAn [3� 5�5�a�dilZ1�'n��N�t�co-i>yu(cF�A��.�(( S1C–S1F5�At 42 hp%$ �q5fn�d�"��)0�<|� ���02!�e��ina�tr}-o }5%I�i�E�didE�!!��E��.�TX�!1or�<co��}U!�.�K#p��b�} q���6���if\#qx��atQ]�t]�r�'�H�’& !, a�2omlyE�� 4Ye�&d,�Sb0��>a� A�!�a FLAG- ]n���,\.ol��(Cauliflower�aic9s 35S:L��)Ite�%accumu&;56}v!1�in  -!e epen$i��0\*�&W�r�ao#(](ti-h )�3 ( S3uW� rbd�6}�-B!T-inj��7!3 estuyɊ�-5{5i��.�-��Om^ol�:բm�! �s�c�.�*f 0Tg 2� B� .*pon:���',pasNR: }Yf�� B2�je�iO�m*XatJ*d�F�"A&�)GyR62�^.�of�W�c�and�Um8>�EK emarkere0!�:�4Y+�v�)riase-PC. qRT )eDNX �Iw n��!�A��I�E�aɡ�ati�5,��,to�]4 �&=i.B ��#�d��/"PR1�6R2 [34 WRKY12��f![35�6(a��K6W!1�IA�[3 3$3�Z(U�edi�6�or6�� }`e�Y{j�� samp�&Fc�(ed 16���V�� eI of m*) G ��6� !=�a���o�)6�E� 5���,�AH- #;duc%��pl-�.2� _eIK%E B�e2*�(C�' ɦ���y�� : , �-� 2�, ��23%�7�:� � fold��8,%#[v % �ata$�m��Xe��BEA&it dampe?�n]dow\#eam)&����7.m|�con�2 !�?<( S6-,��F��CM�deAA�CM|CM2 se+/b�lin��rega�( L)� a C-�1i� low Alex��( CTL!�do�$)�2�: Alig�"AmAa&=M �2�howa'�6x19%�tyjBEU-�be�sA�a{# fami�" f pu�������in.�<=1�-usO4112!*BP,%�+d�uS� � varT$�a$�!R i�' ll memberu!��4ingle C�'en!@3>pAAE �M0sE-�)�dgsh|<6� %�j|�&�&F*�e:p&�;A.&��ex!�� �#�"�' PCR-�o�",�,WQ0d� !�*ic DN�=11pa"~1"W$c��# :geC�u�,��uA "� m%�P�$�:�!a�&� �7 LA04-1 [3S)�*� polymorph�1 ( SN!���6 t 10Z�!a�| 2C ,4�T. E�?=ei�i� �"9h]@�*&.row�6Tynonym�&( solid:$, n Pa alte�"!�co�5. Two �,60�9SNP180+��{—��N5�Bg)j. ( black a�I125V !�A289P B�)-�a��.`-�,A h�8 ozyg!�� ��F�� H"� \BZ01-PG01-��HW9!�� m�%�&s 8!M!?10ZWe "�3����7ll9"�of�93s/kbp�n�%6R .5@1 5v0� qe�*� draD@�"y��8ha:SN6b��42c housekeep!z!���D��[4j%���~v�!9V��Y- ��>��6�'�ǡ�t!e.��;a.� �q=F����af�,"X�l� "!" �SNB%e#"���l+C��:&�u�1� origd!�heQ�M����=>>")1� !�*� ����77 ( S4���B-�mut�=� �3E*&�,��>�J2�-�Qѷ��� -%�"P!F-O zB�'bG)�(��w�;i& #!�" XA��*( prof*7.#v9�Kal*�,� .���1abund� �l/��,n��g�J�w u�"���P � vitr�@+(g�;tube�d) ��3"�?!�"�m�*9 Ms')` �ed�at�8.�2tiEGoi$����~�14Qp�>a� ( dp�] �:�* RPS1��PDK> re�#�)��[4�OuDaly�:��M ' *� -��-le�)d�0ap9G!Y �i< ntinS� .�!g)-�%cours�&R�APi&�o�'E�� �is�sd M�IuV�`�q��IA-�""�#2� ��Z(� Yf� a��6toA%� �kfu�S r���Sac� 44ce�Ksia�E&����f2�����-2a�Ov�l�2!-��R� yM��U&G%!>�� ?"� a�: ,�2 trun$'d!%�qe��%!rof"� t a� cJsI�y|�v-���&%-yFS5�[ *b =��� ˝|e+їi-.�$�p �! �x&nybeZ\ �.D0nd middle panj4:S �O�!S �]�? CM ���rVN��:�1�!�E:�d>X�b�tog��,n"$1!���r � :T lby.�. B,4 6A���� deci�**�sstp� �) ng!�i�'so.U^�**F1���0$. ArabidopK thal$eco�" Columbia-' Col-0 ) na�� ex�8��t�%vehl_$*�0�8]n|!P]�ΔCEL��w'CUCPB511R �Fas littlR_is obs�5inQ�>pwild-�v[4� 48CaF�as.� in A�,1$m>j`EY�"� �i�or }�I'��r%�f7y��KkM}d  PJjJH}X,| !yYQ�sigNly �cF!�Jw.�g!��,�V�yW0 fU�9}DJ�%yM���9+�i��"�+Ou�G#6&.�ce-U�d:�e�"C�it-'ld enhY }$of=`.�&� i�!a��&�$Q s�Gd��N,�$͇]�o:���36a*R\��~100-?�U^2�I6r.�u9I�n� ]�or Y��ւor�I�Y��ioa�v&^��aB�.3J�A�&�6�+MAFW1MA�E?��egi��2�� �:�E4 E7e�be -as:� P�B�6T� �Lq.�$^6J��%atN�%� �+���&�!����� m�dZ�( �m"�NRI.H�dto�er^72�N�A�7E  5�l�l�:t )�I��-Y�z�,F$}�b7,2),���T1%���'e � is�da:AE0�z6��32 J�!��id�S 6EFSJ�re� � b-P7a&�:disulf�YbrBQ��a�( help%Nt%g7i|O nary��u�Xr)phomodim�o\Kmo�[4!9Ugaz0hy�m�( Y2H~we�nd�$�2�5o�M_4�citsel�VO4S/6� �&,%V�4�"�Tng� J-��U [w!�a�2�0 }�Hbe�[���6� J�4*Ten��s>�%.\m�siA�aneou�"cul�d��#q [4;0A�? =�: N&o! half��YFPi^)%u9*�!6(c (&��hZ��8en� )n�Recipro�3GWLS��?@`�!��)�^�"F2Q�AgrQ1p: um tumefaA d d!A'}I�B��)��onf�miy4 y im�A�� �6n�7 H ��EB�"��)![] alo%!V cyto#Rug�Nk}X14&r �+�Yle �NE�$&sila]ic sub@&uW0l�q0m�B;�i�OE%&�[�Zol�BYpsF�S7��5F"^/E�� ��be9!E���E|$��6� �uER)� �[Y�Zur"Y4"Ic$%(rCJ.! notiL0sVC9�e�!*:� Ky!uA�&�"y>klaUIe�s�'aYbx_ rrouu?6Q�;22��B�.Ub%M) taggq&�-�GFMa�J�!e� �<�DaE�T' amou baggre�]K*� %\ cU� ( S8UZM22m�J�E �%�te�>M�I�� &�*V&+an �7 ag~t�o�Uc�# libr� .%i3%�"Q.="�E%X*�))��899*7� aa )��"�R(�9m�10g00920Xŷm5��!016<.������6��W"VM�!�*  %-g�c��a�9QV 1G35�'6 &"� +&}�+ 8 GAL4M"�;�05� All�*!��&61 "� .2/6ZN �w�[�="��F �� � �"1,���/-�NM�5W]"QNN� �@ J� F�gs6�TBF% !.6{ �`E�VWI.9s �8� !$v�Mt�0�s�2a1�:S =y.hI a �\e�a 64N:,or.�endE���-�l )�5�� � R�r�by:�"�a� ( S9E��,R��.�6<�1@I�n(���5BrCo- ��"�>I^�b�<2� ��6�81 R�of��-5fa�@6�2< :����!�6��N R72x)?d���m �O 4iE�UC] 5���d".� 2�->"&��>We�-w�e C*i,�,,�%:j"C112-�"�q� �y a 10"�D-�*{$c]SPLNd2, AtSPL&�;��"����X[4�D%�i�7e�!-f�K)W1AA�(.} NY*P�!IUr,��u�.��ct 2�:)�).�6X>T��peM��q8��i!�"9��m`a�"wrJ>>:extA� A�a pull-`0:.a��0GF}�azb� �m>r�7�cng:��"C solu� uH%� ��X jat 48 �:!�6���$ own ��c-)�Wd� 2Q8a.D%�atF.W6+Z-U=�3a � >C $asm 2Vu�lE�s�!co"�S���o10�3&c#b:.76�*�\"� Q5.��w1�!/�a�E ^&apf�5�ist wid�in �0�i��')&h ��f�M>]!�>T� *M"�7�"&*8;q$� �`logaa!qse�byM5�Z*�. B-Nb1_-~6PNiben101Scf01773g0400�A/o�f)AT2G4707� *h n&7sulA�8o�`2q�e�)v�l1!��=12P.��-36�%�!22Me�,&�Hse���eo>�ہ�sA�QeofF,2ANME=�anM`4*? )r5���`�z�� �s�U�d r&�F4Q��[J�c4SE�5/A�.8.ٮ*�4!3XB�K�O�K�5�5N�� �jvo�Pq�bia"�/��YQe�l2Ie6"$�/O)5OK�dralogul*�02g0082ANI�/�=� 57�. Bq�f�*z�c&U*� seNs�1�B�[�u�kEv%Ha� �t�K�%%�+r98As18 7�Agj wardE ir g�rsR$e�Y�ar�] 0� c�, b\�� RW m� �����", o�be?{��" �h ,*2 (2� 9781g00I.�*�m.� 0687� 18 *A� �>U 2558U3OG� E���I�T�co ra2 TRz mK5LTi W�v�Xqd�Aed: �-1/ �-2ii��m;e� 1�-n 3/E+n;� 0:9#s>7+#' .KAs>7E�! -���* star�&howV �Zympto!wC() no oiR> (7a=ph"� or�=" &��)+��A�*E�8�;W!�] �*] a�omes� `!��U> %d�y����v @r S1&K��N H-1%�-2z�~�G�!i6�-by 64%18%>h(>IV�U ?"SnL�4"� �� �M�b� b�49 �67B��&�AI32�A�B,'impac�D2 ��N>MF�i.>��*Cer�  *~J�� }O\ !N;$�R4[n M��Q�� vV�u�*ZJ inc�6&!) -.�D NbPI1� )]�M?2�:] 4a\!(R�A�B�Yŵ!��� �K��N�Oto��j � . K�d/$dic!j�P�� fila&3B��!�dxU!��=I�os:|vBo�aSBF� HbrA�^��`m��8�"[5CK5�- A9"�3�mas��%(= ��an 300�)i� high&�+�P1(%���&wz�+��+2�=m�BA05%�mjf���/��eaQ-4JXa ��f�D!VA'*�\�9�8=<�*�$[2-%�>�p�#v�qPt�  eci�<��] �u� � ��du�-�e�~�#"��%aa / #�kun�*Eu r enzy�w.�r&qt, hundreFM!e)p99-Lfew�bY&%=�0�sp W3~win��Spa 8 , �m5�,� *�(25Ak"����to[x�q)7+>�&VA�3a�h�� al�a:#?�9j ;E�XQK+-�,Q���2�be 26�U�c a6�21J�( 7 .�JA�quali}d8))��H�TeG�Tuqba���la�11%e��G�pwo0Lf� a4a�lyFs�7.PLA-(�#!�5�\�/>�!,i��2�] o!�&ZaAHdb�/m�m��i�%H 6�JD i.A7-�P-�?���b�-�bJ9LiYewi(cHL,2���,9m�K�9!�9 �n"�g};qa��-!b a��aN�. S~m aliVMa �o��Ar��410Y-re���� )���2{ �zw�-E_ve�@a&�IW@�Aly�L�FHK f-�=�hBs�+�O��=C;^�U��\ 2�D x5�ina#�&� ���mpl��i&M"A�T$n�MNXy[/A�:kQ�!cop"!F�!@ lM�An  Is �*�(59:R���Q�%"T�n-T�Dua��a7P���/++: h !�J&!�to�DFfDP_7.J�0*$S�*90*�C)%��YE��on��2� K )69s _3F&�!gtdje�>�=he)'.�mo2/3�a%��Zd.�%,&�"4 z',�%ac�ae�maiHD�`O59�S� I"$ . It�&5� ���a�ER�Q�K ( LC�lte!n) m�~R� t���xA"LCR�B�-an [51O�, B�. rans�Z!��%p�,� LCR-m ����$also enric%b� t�6-ɇ� "� iA alWa� XopD �eom�jc�Sos�jvesr&oy|A5*�@dA��9 b3 al* on21bya�� a coiled-q8I!2-3[5/Wm~zj� n��D e�!keI�&u ENa�M"A�&���+beL�4!v%� -�,� �M�#�?��!at�&�n!�aa�?G���i�%�mmudi}sBsKi�Q�2>Ql+&.:RAs>~Af�(, South Ame �!U��� .0�8xJ3�Ioxima~�32u r!M�����VV�����Z7P:=�� alle�Xazws�ə!msi@>!�e� _a2�PI�ZN��A�C3a2�N�P��u!�A�5 �@!��Qi;�pA�v�oe�� 12$B�إ� V�c�SIK�y\8M �.!7@N, onl��qa�T`iA�oN�9t�^o"i�w9OT 15j+ vBi� ic n���:��FYnO�ink� sexu!{ros/!s�e�mly lim�E@e�Y~"W ]1, 7�a�Toe��z� X�� e util ���s"� � /D,.#2K*pD,EIX$�]iz�d��l^�/�n!Y�F[�+� 29 ,% , 6�!In�*e;! � CI{��R�q)s � ��:u}in;��7b�J �;!9L�;th!�C���_ )5!�=��H&Ug%�m� A0le"u;-�a&��oi8=�m�HR��na�(&Q�rOu%Q2IJh!a HopQ�(E AvrD>�.nz.s ��`&�&Y��a_$of� vergi�$ a�mAvr-R2��DGE"G( legua��x naceb;e7�4a�mz�!{�t �w rect-!S=k.*�7!��M��G4 �*�g��C�qPBio!q��Gk:/VBc�d �.EFWf&�///aQdu�&�a%2r���~&tUeJ 1�$S&�)Sub����t 6x �-& !<� �32�zF�it{#�Q)A��mmo��d '6GAHR���g��rn!hev�$P�RC�� ntir�,�#h�&� [�w�,�f��;*I���2�C!�b,�b�N��#�cR�c�B%�Q)���� v^m�%�upy��G �7�B�s�CacBT}��.q�I 1kEd� >CeC|62m� 'e0�L|in2�SH"�Z!kf��ng h} hig B� egin� _7�L�5 essF �/�!t�x��"�apy=�8earli�@*^$^3-Sp@�iaʇh*:ziygCA� ,�xaA e� a"�(� 2instead!"ip0��Ssʏrm�2�s.�die [6%VIi�b����%@y���!="� o&�:s%�7sB[~�d�Dm[>t� spr�Tto�]ghborQ:A}g܆bw*�]s�I-&en&�2masPv.���%F"^ �C4�*�&��a*i&:����.�.�7��ߎ���c&}�A#�RB"1m�Hr�}! ���N6\al {�iga"t-�S&r5��2c���cB.-�y��Bd-7� Ο!��zbipartitn^s l.,@�a�-NL�w!3S5n�E''(d Zn-finger:� s [6%V�8 �� ��he ���o"��� .�Fc��e��*� XE�)/�!�>�6SPL�)��<6�!��!�i*Q/6N*' adapcA�R&1�Zm�a�Ei[63i#Btochro&�[�[6Ki vege[ ve ph'iE�= [65D�m!�[6WiF�gynoecEC� [67]coppe�HeostaP[6:A�7r>�&Bo=.g�%6 �T�e5�&��GaoAa����8ar-!�8 R!Ii�[C8|K0�AD��of!�.E%�"�5�%I�a�_��e~�)JUad�_an.gS�S[6= 78 �$A.�j,of�6a�P���P}1.��6ɚy=">B eb��u�o clad�g)ll16)� s [7�V"�A4!�pJ�1� ecTly" lto Q1/12/14/�@ ccor6o�6lE�,�.� IEv�8��<l"J.���Qt++"�\2� �1�'ڋ��"5aA� ays:,76 Co-IvG,��O ��a�nr�ly "�<e�� tagO#:�>=+u�b�+�^:� en�M�)�%-,&�%eh�"�8f�� "&�7 Ivit.�6^ eX�� rI�m�R��n� s�2 let� 2E!��W 7� b*�c���`oloxh�.;&! 5’�P� -UTR��a�%fB14o"d�/ :GmP7�if�']� �, � ���"|H)2lEH)ed6V� �U& )w �O7Ce,9��"�'9!rHBe�!!� ��Kv3�/U�܏+J{nd�TAu=s !Lu&7�Kis�"�/e��U%�m\7.\�5V�!K>�6ri����Y�m!>� o��"2�3)�Oia&�4"F5:7���a�H �1L�l� &�6�3� �=�Ph"hip"dV�fC�o*�H�~`��%�e�dr�Dv�����A�&x P�)�2!Q-ed>.�.AX�h�+AVI�2*�2�)�&�2 n��pverD X ng��2�s?45�s%c5 ��da /&�*[>!?P�nG�Q�ag�dE�c�6PnaAj %p1�9�+?2�Q�+g�/61 acv�� AeQt�vens�% 6h� ab"h�9�.4 ��ost�z} a#  .!E��!�by��$6ve�or�sN �L-Le�q.���� �.��9B.&�/a��:�[ab�w��l�bU18E�7�<c*�K<0�<Ab +pi"�X�< �%����D ���^'&� !O.���C "�h�*W�Q6��&ea�Gu.b��my)��N� ) }F�S�Q8@� �Z9��0%ҡ����y�gl��}^��+��M�s�>� �c2� ��qUc-��5 #mm&n�a7-�^#al��%~dif}.��eE-c�w[9"z l6�MZj��RNA��{n>�2dN�{"@hO��A�a�k�Are�4A��ǔ*}�+@�"E�+� ��ҡ�h��.M DZtVa疰bm�:+A1qz(�y�_A[i$+!�b� K &g�����F�q��.^�N��Ec� *�yfu!g��wL �%�.�to�T��{��-� ��i&�>�!64 �1�%�`�9.�AL�'ZEB-��!Q �$2�m�f .�VW1�R0,� s�-2��� � �: do� 6d�or-Y�"���E)6i�2 s��A��}�m �'�Q�|{ h�+�z1a_�/wyet����:e�#Q�aegb�Rbl�1�,%�knock �<5u!UM��3���P�e�)^/ ���Lo�loprY�ojup�Je{RNA-seqm%_R,nj�e�a�R]cl&ZzQ|;6�~*s;2ek.�/�+]$�I*��+*�,��g �"��9 vail%_Z1i� Uc�%�@,�!MmR"\ �� 9!�v=KQ� �N A�t�)��i��+��e+ūe!��G +V��MexZ7#�-�w�5as*�)?K:�d3�#-e�.�s . B"*� uͶk��a>e��>E .�(06w(t*&[+f �Luria-B�pni ( LB �r� at 37°C ޶ Q)�"28 >Z)�e4zliquid1 z��#.��$�� ALB=4King’s B ( K�Ium� �. P2qpmoG"��55AAJ|�ndard H�a&al�3a��E HB10�KpRK201�$� �aev-ai��Fe8qm���E>�,r\ #h"ޡa��}�Qnj� temperi�of 24)��H$20°C—2664��$45% - 65% �ve humid� �N-da� *�N͂ li�L�TE#k��J�2�( �1A{���shortJ�0 .�c_:n .�&,�5d9�f :�(Zb(ivar Thorne9� pra��%ua w�8y�C���!�I�a@02% T�2�2%NEk powܫ��*:�(D+ ThaiTZlaboratoR"�on Un-8ität Hohenheima��1�E� P# ���� dark�( nE at 95%YA�Ex tXT fe�$ �Yenh�{Q�embra8-P6�6 �!$.�t~� Geno�D� :�S:�2��>�0QIAGEN DNeasyIX M��Kiw7��ic&p�P2�w� Q5 High-F����Polymer$( New Engl! Biolab�ep��rs KP680%� KP71$DS1�An������˸�,E '{�]Ae hangUTaq%� ����]�pCR�1-TOPOUloS�I��7���~)YBioEditG�om Ha9u Ibissci�)�$ Lfy_.� ��y%e�m� "�o�TSN� B�.*[��J��� 5%u6 weeks �P,fK5+{��5!�:�i�{[# I�$� ��2f7�9�*O,su��)���)|%�;edq1� z�*{ 2�re- Yd�2-\bu� (a�$ μM acetoF��,�9(mM MES , pHʁ�-!10gCl�L��N��� 3 h JP2�)5o!r�.p_t�sof=A2W%y7�ght�a�a Sharpi��maz� (&LM^b" �umUlexY3� s noAʭ�fG�A�&\ �=?a �*' by cut �# disk)� rk bore!�inner di��5 c�R!��,��gl 5ū�K�! �ML �A�I1>5=1e�f�z^j��KB �6ap.8X�(6 tibi�M!$T��a�X�J� [76]i Pe�;3�6r. B$��:. �q�K&s)�hag�!�"��x<�Ucoh]�.��l�Xp�l kZz ( - .+Mmix#�8$:glycerol:Mic��:��:e�o�1: 8 ( v/ ) � a\5!  ,��o�6 �� ^�24 ��LǙ2S�dd�x��65 g/mlJOal�� . PinnestGL 7@֞ af e��r=�� e-da~d��ef%��!d"}�. V��hrig 9g #/,�dev&`�mKA� 622"֊M !�ib~t�q ul"Sf�"(}JBu�2 �:^�h��f�l& trap�� �����irly7ecc)�thod [78��4a"��x9I.� .���칇 CMD/&����17% �n�����4 w/ok7,��13% drop{mixE� ��top6!,�. 8 ( NHQ�2SO�G2% glucB ) [7�Yt �8v�lon�.��C� � djdL OD �Y nm =�hB�qA��YPRAA�s��O � %�Jo�� 2% raffin�, 2 ppm6� a-�P�m�2������( ���RS!�he Match>Dr LexA0"-hlss�D m ( � tech�a� �`or�!sY��Z-"�i;�C�:�j� �pA��Vk A�p�8to RK� f���)A}BD����xU<�$6 × 106Mf��L!%� �*2%�rGal/Raf�r�-( -Urani Trp/:s )����manufa�zr��0ru?:!�=@. D�5n�%"I�� o��%ƭR��H-�O�1w1�Cp AH109}�=��jTw5�SJ�6�Ăa06Zon)L!;L&ftZ���3Ra2&�1 H$�o C!�rbt%�.i-�et�l�tjth!8"fng��� A��r\#nT3�7u�!E-&uSuppl�rl8 �[�Kc&�`"lJʆ!�uaMEf�;!.*AdGateway[3r"�Q,pCR8⁄GW⁄H ( InO��P"s<�i`x MR��ryh �!�mz$pSITEII-3C�T�` �4LR�wII>z#�(ie$5 ���O � s pSPYNE-��, C hygII- � ) 15}$pkanII-VYC(�. Eachq�%�*]ly�,g� ��q or nPqat!�NPiD"kj&NeC+ka�nt*+ elCx Rese�� Faci��T51�*��: .��6�Kl �2�� pre-� G6] Q�k>�Kh(( Sigma-Ald(F�Rt ���F�ro�ngU�y!�wasXF3:"*�2�be�h%�b�E��5�loa% 1 ( 25�Tris-C�_ pH 6� ��30� �@ , 5% β-mercapto��!bS�p� �72�& ��(n SDS-PAGE ( ҽ5%"�w�wס�id colo���alk<�4 osph�����6}rserada+pe6Ed�o( H�i~ſ2�mg� �kE*��R�,&G��:�))��!��$�DI� ǁ�RR�( Qià.�22v* ���ofu!�SuperSC(P�F�Sa�d k 2�EN�v sy6�5 . QuA�A�v al-�$�}("V>���P�a�&9\*&T�U9����by�Pnt�� j iQ SYBR G��)� (� -RadM�iCw��.�I2-/nt ACTIN4;���%,t1#y;�.%���<i�4a�$�!�"Y*=#A�����I��g�Q�Gck W] �IJ�)5GCt��(( 2-∆∆CI��7+if��V6D)!�A�6|�[4-81]]4 �O%x`x , Ukn2,2]93ay��� �� }.O0���T AM.*)sbiUvio}oA_i�4rticle bombard�u%9aA# '$PDS-1000/H" �YBL$,��cu=I , CA�S�R have�/�`de"5oA 287 bp��g�� b1%�#�t�!�%1 ( GlF#xZ# 28y+Qi~k�N�)�c*dp�1-V'Do*�c�q&+bk8�5�k��&�#A�ma"�cajm&�KrW\� �ga�"I3FJ 1��-Q@��!Nangia.C^4 / ml6 ����1m�L.�G��36t�mo7�@� ch�!e=7. S�^m8top} �"+a,rec��+aB�"���"NIY a�6u~b�0um Chlamydia 9rh�&!�va$:� 7%;�lri��a�:z0-bound vacuolÍe �&AO. M���4t ^� �r�6r!��1B�z�'a,mod�/��0or0# ��@.FgI�Qd́�9 0d�)�-la�@�'&�-�PI3 kD��H��h(bO�Q��e"˂1G)We2m|E�.@��tyr.�� EphrinA2!+c��%phA��$c�ad-�'!= inva%J�=�� �*�s.�( K�dZ,�,!��'5c6���u,%e 8 �craUh sero9#LzcCt�to�Avb*0�*!'u��.d�!�4� "� ;&dXre[j��. G/� !-F� Vh2�&�inH95]fn&:. D�2Z>, jr �s �e_:umA�!GaB�E�6ml3%wAF p85 -Bo�"bX�!J PI3K!lq0. �-J&/Ak�7g�,Datf� .�.J+. �.�fr|!)f�/�+��5�*m�k�6�c*t;�A�}b�d�.�!�>Despi34A6%�- ���x2�,:GqGup-u2D�/GFkERK�<�-���!I�|��i_�F tosi�T�.� ���T�ngM��+ ʁ nA! 6Ia0� gY��-:ՁU_uk�F:�-q��Our�Gt]�7!Mf� e�L a���uO�T�+i!3��*�17-8*�^���saZ��.��engagaT3�׀u���y�"�%E-H�J�ّsubveš!4��-���sY ��i�� D.v,^hu��a�oge�8�N��K � acu�n.�royP�8; GX��]�`V�s A-C��� ko��^6i)N��nesnlM��:�<s D-K =�\�(aE�1tm?i0�;L1-L2�a�DS lymph��nuloma v�eum ( LG�i.E� pneumonia ��nmsulz� m�wy-�Yd7�k#�i�)i�� h�� Obi�Eic.bܡ��:Fus32��ngG3m��od� ( Ed-a�=2 p�!�Es!8oaJ, H �uAztW_aCTRTe��<d{�!4C j4 A\9en"; I�,]"H a�� ka�EB t��a�b|υ\��j�%wV� a5{Jz�� EB4a�@f1!�1Z�r� ��"��%�%wM"�&ou�d�$" ( O��e���DAT/.f!�bf,"�3 TARP���FR!co-��̌ es [� o"� ���-�������,��!~bel��� �Te�_A0���th�:B��J"�;�,h%�![E��"%.�#�5b.�d�  Pc *���!�8�J\!a&A�8�o36T)�Xle �5�<�'eb�@n��6�[՚h� �S�4�)� ! a�z > v�\!�-n�� ruit��Rab���W-I�%} “sn>”[ulret��da� tra-Golgi2�� .%�orgC��Y��end�#s),r�rum [5�hHos�U�5L%�� Es� h��[6KT9su/ 2 I��u �i�&r�PD �=WFK�R*L>�.c��*w%b�% E�u�: [RTK�+M0ir.�^� casc�J�pl�< piv|iIt "$ �B6X� ng%..�� �!let-d�� f�'�-�( PDGF��o�|!Cmurida[�uj�ex 9phagocy!,s*�6��ob�ftFs� �zpY��v�!i�e9��A%}U{*REB��)��ef�E ��9�s�5>�� �*�[1�wwr(a&� � w�2b�n "Se)�d]�.� [1� 1� S"�U*%&*!.HJ[��!eto %])Z _� ���[1����o� "k �'�B6�Y��X&�!�s��];+�u��B��}�1���k�rig h!�Ds;�st ]sub&b8e�,;Bzng!@16:y9f`�֥*�Kun�#�>.�!zadu]Oos|ie�in [15] �5�Q�y $axon guida rgiJ �� �� , mi�>��o.� i�P&�[+���fe"�6 Ir�B� Ca 8t�T�6go> Ibi�<y`!�9op�|op�'eX I�V(xEY a�2�J*xmglycosy� dvelD ��"w��.��.f!��Dibron�%n� �"glf �i�!?�?6� ]"is����/ a juxtaq�.������alpha�<( SAMnd PDZ"�f��%=���=y<��:N�<-��s1pp  idyl)ito�en�)y-�-A1��d�` talk"N � , MAPSrc�<)a�Rh��$d Rac1 GTP�c�5�lh�� �-�a;c�tJ� apeu��?"�psA���cm�lan��"�I)�6��,"(Bid�[f& ��u�ũ6�� J^."�a~��2�-2���A2�d�C�"�͗��",��N�. �rA6E:4ݐ�3�dr.HVI�h "<� NZ����)D���\���mavA�r��rs&' >&���9po�Fa��WaC4�#:�BD �� �A�dop!n��*�ő��(��c �p���. HE�ep�>lSbcarcin��yV HeLf,(�g rce: ATCC�l. CCL-81%!�'"0-in RPM (GIBCO �410% Fe�C��Se� ( FC[Y���i�e�0.��Z�Im��uCS��h�"co��� �)��!l �0d th- yHUVEC )=Fq".��um-�!�lp"^ow� um1�#aSG�$Gibco BR߈. C��= �x�@!�5% CO!�n ropa&��Ctr��� Ec! A 8!&�`A�r?*h#���L2�E�! [OpGFP::SW�$IncA-flag]A#E[)Z�m!a���Me"a 2�W Stoc�6e��to��froze% -8X,/Gu�e-�Be-gluta�$ F&[�% 22 M'r`/1W&Na2HP70ٌ8O0K5GL~8�t41 fresG�)�+`vach�e�%n+2=ʼnbQ�a�e@I?!{�#��of!�A�!�Y 5y5ejU Anti�� �m#��( W3c^��t� � �N Hsp6�?GP9o9PXH-�', Pan C�}iGAPDH)� purc�[��8Santa Cruz biot�Iechnology . Antibodies against N-terminal EphA2 ( D4A2 ) for WB and IF stu8 , pE (phospho 8Ser897 )"RKAktPI385- total and 4dwere from Cell Signaling t��FACS , ��8EphB4 , PDGFRβ8IgG ( control )�(R&D systems9=y5;4PDI was bought �@Thermo Scientific 9 -β-Actins anti-Flag -�� purchased OdSigma-Aldrich . PhalloidinBzDInvitrogen . Draq5#%NTBioStatus Limited , UKP8olyclonal serum�IncA (�-rabbit!8as obtained thr�D Gramsch laboratorA^0. Inhibitors AILPI3 kinase ( LY29400AeD, MEK1/2 ( UO126 )%!Qc dasatinib~A.l:$H. Recombinant humanHrh R ^rN(Drin-A1 homodimer ( 6 fu!� withA1 1-Fc�:�65F�pro%in-HisfPHB�4lso possess a tE"d iQ�!O�. AR �,2�Ig �!�.HLife Tqb)�`Chlamydia adherence assay>Hperformed by pretre!�(g the cells)*� � ( 5 μg/mador !.�H1 h at 37°C follow a infection 4(purified EB% 847$in HBSS me�(J�) .9!�ed V�A2B�A)�a�m& free d�ain��$0 . 1% BSA.� Ѕ�$he mixture�addaHo=6'incuba�!�.�.I�surfaceM��$blocked us����(!� )Ӂq�g ( 109�a� spec��proteini�.}j�J�. Befo��ix��I�immunos19, e� wash!h!d timeMLPBS!$o-localizaEof~e�i�!de��(ed manually)� blin!t��yA�qu!fy��*8 diffA�t fieldsc(higher magn!% {in 3 PDpendent experiment�/To!Lve�0direct interaI���I�LCtr-EB , a pull-downRq.+( L�A%4u$as describa;)� [22]��q7 k!)Yk�q6#q�u�.E> RPMI� 45 m9q� 4 rotary shaker��ddi!�%�,.� -pre��A2N�EB!ab!�a_A�.�(centrifuged�5000 x gE�4��],. The pelletjgently A�3.� ice cold-A�byfI<atni�subjec�$to westerna�t (� ) analysiAk��invas�*Z�trans�NF�siRNA�lucifer�gen�uci�NI�a�40.�or�YJb>j or α- Na� bodyR.xas aSioa�in%�>�)�bacteriaa[,required MOIi$Y-E왍4–6 �5�E N !e_fix�'4%5� PFA�30J' 4Etaken0:�after�Smeabili�o� I6�i�$overexpres� casC� S%��g-pcDNA3]o �4flow cytometryYWto�H%urelativeYe rateaY�compar%�oՈempty �-U�ed �und6oni�!�U�o> &��eLa I%�&�2 �$. Supernat# �� prim�w Y�as remov�n� "�� ͩENa��s Wone set!� �ly�7(glass beadse��lys!W}pa%�j a pipettZveral�qI�suspena�s h-jrato =),( 1:200 diluaY � se!w9 !p \next day6�I��4% i*� 6�� ( DNA; as S �Bcou�" of nuclei%Hsp60�!:to 2%7Y�inclu! . NumberP![D u� �LzA�aA�random I�C$microscope�size6^*�@by ImageJ softwar�Nhttp://ij . ni� gov/ij/ � Full lengs � �*�  sequ� H HA�W)u�(lap PCRinserA�Pinto pGFP::SW2 replac�CAT-�IAormɴof;�2e$previously*|[23u�1lasmid%�( 6| ſdO 1x107 IFUI�mi�k(in CaCl2 bu�  ( � ��d!x*0 ��,room temperat ( RT%Z� �:Q!b"� McCo�� a��AA� anot 2��. cultu�� T75 flaski+fresh# supple���_10% FC� A� 48 h6u�>by ileRDs���eito��E� ���h^�� �e!V'�fAa!�2 U� ,penicillin G%2!�CHX��aP ��y �. When duc�Gq�z visible ,.��!ti" !�atcon� U���increOup!50–70 �arepa�Lstockt n���^�pM���( acces,NP_004422 . � as ��Ze|mpl&7 � �(of pDONR223 ( AddY ID:239[24qLresulA.Tcas:�����( *�\Mu� ѡ�out 2$c domain ( # ΔIC��!P�bS �P�8sreg!0of2{encod#Hamino acids 1–560��! 3� %dead m � �K645R- �d �"�bybk�ްers 5‘-ccggtggccatcaggacgctgaaagcc-3’ and *ggctt% cgtc% 7A-*i6�= es LysineAUArge��1�!�E�a.�. "� !G�4:aQ"(A$,11499 ) [25]��., <e u!{1 .&�iper wuin 12 pl� 9* ethylenim� ( PEI��OptiMEM:V0edium ( GibcoEx2� � chan�1a��5 � Iu�"�at*�! poit =2� of6�.� �AFG , si�( C"�: aacuua�ugagu cga5W� pre-2  DMSO!kE�&�( D� ���.٪�]� . Or 14 h &g !)2��Oindic�j2��Dx1A�.*2ZA�[�,�s�:ate 2_$Nor>� . Un Pede�ed HUVEC.�2�%For�K i&�or MAP.%X �i���2:*� %?left uV�5�Z%'.��� (� �. Fore ��!�} expo� B@,.gr�in 6-�]�R�� Qre| .of2�}Txoin*�BSe�detac�� 5 mM EDTA�HRT% 1 1�� c coll}u(pendorf tub:nd~��*5(�ck!J� � � �� 5*�,:`�M�6� para� ldehydŤFq�� at�.� ��E.2� A1[�. v�}un!��  ba�ng!�!�"�*�U3"["�y�I���ed�i�)5so�!�"� )�����) dark2�adh� step'�-�. S"�$ mouse-Cy5�,( GE healthc? , �)^1N�or�.ltwo&�0 Q�t$ &*^�$. Via FSC-�S , popu�on!�intact-!%[&!C10 , �%�@ sample�U"W“T$AriaIII”F!�“BDr Diva"�!all�1*M CSalyzer 99 . 329���Kael�y histog}��22�notA a��a�!���AI�2Epe.A�Z�42% Triton-X-10� %ϩ<)DAp!("� !�&(�)A� �� ng-�,�V -GFP9).�exc�a�88 nm%�E�t 647aȡ{l!2� �K&��`�i �!�*� .|p�;As�-�Fi�(�-1aJ5–1�)I�induco apopto�� 50 ny"u r*�(TNF-α ( BD8 �!gen ,`  Diego!D alifornia� "� of c heximi�L�)�� E����!6F�s��o�%sz b d%�4�)�֩�aA:MI}TUNEL kiRoche�b�B� PARPA�lea� ( C- /"zd �!..yB~ E��r�� auAGCt�MO!�xB�reM!- �EBQ#w !� B�to�%iunboun0A�bV� �ve'oep (-, greenM5) filaJ �*�", blu!� ��`n"��1�( both�t� newluvad�V"MOneighbo�un=�-[6  sat�!d� !�. P$a membrane��E�isoI�)�A�� F1 ext I�Abcam )6� "? ,150 cm2 dish� �A�^L �}Qharves�, Q+w�E� cold���S!nin #geny.AQ�C3V 50 stroke���a douB"D�5%�e!& nwas� �putM<>(*�to Ma� ularJ� �.�j5%�2[fur} 2by�� ocol��ier�10 �>μM Z8- !2�S&�* ( UNm�^ cours*��M &� .� K , 257"�7��C{ 1��5[425% Na-deoxyche%�"� X(final volum  1 mlEM� k� A��.G 5�6 &atg� �in�n��6�m E�40� ice-e acet�.�J�10� n5 n dr�$� �$r� �'zas!n�8usb!a@�� �5�.�.�I��iNA�-�� r-u�$ ��* r RT wj9�%U*�e] �$o2�L!��A" 2� &���y(� )N�Cy2 lin��-m� �ianov 2]ؙI%Ѫ�l2� �B>� s`@ohb� ,A �B�N��1!J�\el�j!G�]i<. S� M$!w�Es� _m�+'MowiolO���aNure�hA� same�� ��� eachF� � precipit �,��orf> �� �o�i�E3�ɠin�' NP-4� �QmM NaC���%/EGTA��04HEPES pH 7 . 4M��-0? 2R�#2md���*� @:*"##"A�}!�h&R9,"�magnetic[ . AllET�k ��� ed d��P�%[ carr��A?a@%c.at'$ �otp*�("� ��_� oox1K2`��d �resol� 0by 8–12% so_dodecyflfAH( SDS ) -polyacryla� gel eWrophoreF . P�iZ3!B$vinylidenee luor  � { Diag�(ics GmbH�u2�Tris-)y�.&&n.,1% TwZ 2� d% bovZ�-lbu�:��"M�+%�YP8ni�.1�6M|�q� peroxidas��up�e"g&� ECL"/ ierc� A Xan Intas Chem HR 16–3w"rea�#Is�/ band �u  F:!Ws�(stical calcHionI�h&, Exce��Mi�!of�.Z. /I��a�B� ZuXthe Stu�)(’s T test�wo-tai!2 @&�MF P-va . EPHAn 196�,"( 515 EFNA1�#94f,5 B4 ( 2050�U(�14$GP96 ( 718 �,( 5245T712 !�h&9 UAKTd�1( 1�!��1( 559B. �broadly"p!8�p%!=&$#qB2 a%{ag� t�0 that orchest� AJ�.-hP���"R+ promuus!qloo�r .� e�associ_��Z�I�6om�#%I�rol� thes* p �l  w�TDU? by x),y,c�RNAm)to �| tify ����%|"�(�Zy!�develop�KRAFGAo&3TTFM ,�!�|��Un�&cte!�,  rinA9$cepto44�'"�RTK �moa.+�!1 in�ig%�duNits potO3al��"� Ctr]U%)�d9kn�%�!|I4g r�. We f��if � can KDZ@!z� '1(%to)�A��Adh !���#��.hp Q ^t�)Ns%,( [10]; see L2Ma+l�Methodsz:�v�6ils%�5��� he� EB c"�/ei=)�!�)1$.�.)�lig�* ma�teE� DB#^I��1�Ftthi260AUre8$by 35% upo$�X a�)�S.@h �rA4 �2Ep )pbkR*�E�insFp( Fig 1R 4�bse� ults sugg�e��EB�;A�L Q��)z 5 �-sensi�$1n�Tou�ver�t!��0�0w� �'FG �-:A��%t"2�oabi�6�EAE%�A26� A ell-�3ed1� wtWA9p���!�-Jpri�._'57 E��%�C�1De\DF 2w�confi]5?(&2��`2 showI�at��Gac\ ��ed�S�^M�E�T��y�mon�d�F�u��EBu �5�&�2EB (��]i�!{��c� �oEB�*!�U�a�6)#�.5EB%���?an un�.edj7 -tag�$�m�1 F= �'F�B ��epithel���s vI7"�l�Ve�:�Eg �s)y<�Iz-r�'5ns9de�9u Ie~7%���<y )�!��$|� ud ��`2�)�*�!!�3!�E���3"9 Z�e�e �1$a[M�G%�I�3�a�Jat9!�U#+ �  �d(af��]attach6 [26d'���6,�a ��Q;,� %�ed bd f�n��,tr=>2�F]=�2��<"�[27] ha� e �-1"s�2cW� n 2u !�/ UX&��by.�( refej0'�' !+)��2��" b!oA!���!S1��Z0:�EBB����1A�u� A!�is��o�i9i�6�8��!i�~ clin#�ppr�6sm�moleculD>:�*�,F�*;@[29 , 30�Igv is!��>�+} �E(c)*9@A�k3e|�'μM�*&�)\)�! ����73%997%� p�Qv�A�EM�though�can!%exclude�W�3DA*, )�@s like Src family4, BCR-ABL , KI?aX1ka>5��4PDGFR [3�# 32] �dra��UE,*u)y�M]QVolev�of|A�rE? . SiK 'fJ&@aSA�8B;amv�!��1yA��� h$, but)accumC�Q8/"<��,h�0 �!� ( p . i .i�2+5�2�)\is@ �=�nd� tinua�5�)".�>�$9��-�5�t&� subs�5i&Vu��"or �Ki�tsI*쥛6de�9��.va� .� � 1E. �i"�) A��(�g+un>QI"�7)W ���or�8"�'2I0�t��6�J*$( S2A–S2�  -� &u8ab22-fV%�B= edV� .XConsis�)zour�4m; observ�km�Ax�I�rFW% 18�A�!� �@y2by arrowT �-^. �yin�)e�Ab6_O&la�A�A�u�y' �ѥ�tso far.�_#a� e:oN � �:zA�E,,F���display!�)D 5s�T��Ate.�bD]*s ear� s y#q>��retura to basD�s!�3�����abS non-*"��onA meas ��!�O�_Io3�3�!sai+AWqu���:9rapid �ireg�p!ofl)Y� f� < initK1.U�AjC�Hm�XzQ,ct��I/�E�V"j��*E�/� �� al�86�N<� w ���!�ct L�A*:"!5a�sa� �'-p9a�3E��� m. �A#yu�&���M��i�is�bably8��by.3X� `>��7�"F 1-� aggre�'"�W �/5�h6b:!!�*��QI1� �-�[3�@���0 -���� uto-#&� I���M�egrad G!YL�NU�jby�N&d%Ʃ�Vn>��nach�da 9�M�t�kV(�=M��I.�->�d�Jd!�via�?"$ s%�heat-kil !"�0 f!$% !�A2B� ( S3�!)6GYPastJ:�I�.k()�a�� 3~��ii!�E���E�%��9�+G�wYa� star@ �  ar�42�=d, impl}L�� �I�!�qby��m &� �- W@AA�8K ,>�aBI�Ynd de-� )V�-I?9�}s�'>38+7[ �=�%B �!��e !om (he Raf/MEK/i"�>T/6Tpathwaya�a��p�  n�Dl.!.� A keep% �����!1n*]3&+ !�te [1"�A z)�l�Gto���ԁ�A^���!��� �0t7�Gstu�%i ,Z,( years have��o �"=of{��%P!. [3�T3@ve��1s"� e��B!�)*h�.&[_,� genous-� he. p85 ��o�Mubuni��D(!V@8:�(e UWz)ofJ�.�F! �2� d qco-Jc%4I�A+>j5";%��-�QJ� N!Gof "E�q�Tn J��A�aJa9!or 8-�T"�5�q��\�A�by&�Hi.O�6K!��%! �1Ka�6( �R4 tron�� iG-u�kl'�!6Trecru�g *s)�Z��� p ,�, data��!�6� GR %�"lD *C� "Fy-�" EB-RB���%��x � �T>aN�2@6� �L. T: simi37 cS�=����)-�6��'-�2.�)- gGb&d:>��(N=Z �L-u A|i�5A�s%I+-"Ii4�.*-"3�n�Q2d;U�}x� �}aeaA!�+1=3!)%��3t'aWi� blot&{ ��I!a�nB �B���;.H "c 6 q)am�/�> J�M�6�EO,�A%1ls�" Ft �|�"S3�<"<��- di crip!u&��J� �accord!�to [36Rcor�!*a_-�q�Jo �9 IF"�w^''S}cG\\�  "� bb{(��$C . murida�[[8]%�JIFC r-�n� � ))�\$��B& IzK!�ans_ ik,�βN*�&506MA=k�gQ)�E� ��orjB4.E!{�Fy �E�Vupc�H�%"�06��~�2�?]'6N~r�miA mid-�!>�P^P:"'��H�;M��=o�im�� �]c�%!~�,�>} N�Fdq2fI]A2R@��(.�%�un)�d $�"] I4oFBb2*2�*Ţ:|ep=>RA,�4�PI�N�um1� O��a�i�P*�&a�]/,Karunakaran �l .%K bmitA��8I/�$����ct7���1�i��� ���E9� kN��F/ic�!'�ytr�Y spac�"** defi�LB,A�2�[�2�7M-"�"e:6*��)s�:�p v�,�-a;. O2�VP%^)Z&�vic7y1jRA� �� *H (�?!?8W+~)cYT ( S4�S4&�T"�<o proofE3@28i�Ary`��;7J41*F-��h""I>Tp %.FTV%26TRTM��<id*&T�SY-T�GFP1T!AA��!�'*i�>NQng� "�a�-HAc(1-pfla"Ta5M��6�1q�J�Y* %�Ct2S�rem�%%��1�� 9 e6 1�"�2��E%�4� ,*��.�I9.�I�r �a� e�he�A&5 �; U-s89�iMAN7!�Q5%Y<ݫ�&\ճHdk<2a�&� !/�� υj*�"�D ,A�K'�e'+�&is im���t�'�a6j_�u�����R� �2�� ���&�1%6a -[S\ofKQ�5:� jT�?�1&r !� "20R0!"�.k-)�enU;� �� � ir&�<��)�%7u� JQ�'/-� 59 I6, 5*�A6��X�wd �g�ziK-I{�v� ,� �:J� iI5� e�i&-o6�inIe)i � ���,thah ?�d�(�J !�F�%D�� feg"�%!&�nod�ng-i-?�i�QcW�'A-p�g"(+*z05i:. S:�[ A2R){� A%FZ�(&ximE48]*1��+:g�M37+de� +9O�#Y�l��D�5�&�[��Mh>1 ( 18�%a�! &�:I� ( 43.*, r��*7 ! V�[i04d;2U0JU!��2!�� ��-��*!�il*8.* 'NB�-�(]�A-�u.�%b�Y�>�a&�eBj6L�!��4iYesignqere���s.g.%w.@�HQqd H V!�ZI"Z��R�I F?% *e�)�� �>H3����>�U�r 2\ H:[��e�*:�. CF���0� f84A�s � IRi�d.���2>ET%C�2� �$2�mE8%f�J6 ��en�ha�*�RT.c��e��6ɍ�.����Ev�6� h��z�6B���a��%'-�!�� ��"E%%|.g I �R]b�EP"X'U!26J.b T!h*z mr�a�.ma>�e�r"�2kd dele�m�[la�R��'' "/\���h"�, �vSAM�[.Z\�r� 6�^�)B t �V �+rwildtyp�Hr�OAAa$! 59� �.n-nm v�Hj&ZuB�r� c+%!mto�6�%Q%ng=s-m�$�>� ��.�Pi�:kof eiE%��%�"a��m4�/>%�� ��i � B�f*xb go9H1| appe;'bigger%:E 2|M2�M  ��]6FAeb\E65l5&l.� �:���.ean �%,.� �!��6� >��� �$�r] ѺZ~ ^�6>m%�7�#@�$kIGAnd6�2� U�ma�;, ig .� >7`?ngu al q.�:(l�)d&e�� �9��*mJ:u�/ ����� madey0�A�\@&ZZda�H,r�[*�*^F�/i� 5NMN�Pr�pme�fM(a��02K.$�#�"� ["}�0"� 7�a.S 6&IB7 7�9DA k?a j~�0�0RTK�0�0β��%d��A/io�eB�6m2�)[�2How� 6_J#�f�"�t6�6Z1 � >�)>5a�]�ޅ� � 92s8Uco-vI�to�6E19���b�#ve��TF~!�doe5emploq"eT� m"Z.-*�2�-A�6� >�A�*"� J:#$v"AD2� ~��J�^.��]�i2%&DA��<��os��s�#9����o(RZ<&�"�M��"� �-C%ep�9!�"��.4  G�Fg&=l;t+ hN.fIV��e��v)N���se-w'nt��I?7�76%:W3��+mil�E"��@DA!�Q� 6�&despi�: ��6����*DA =�,y9 �^:n6?8we&� ! 6D)L-�%S��Ai6��"� ���yN.$'E � gene�0�.6hdZ�f"�1�  *#� [377� Np !�A�6�H�^5�g]6Jg2�F� .�r!N A�� ominActU��>l�(��ire6�* pQxR�|)�Jbe�"�'"< 5��x�D�z/| !?>�e�2%`long-laR4&*ad��on�'!^d 34R�i�i� �u��m&� "� �;inv�NJ�*�E��!A7c( Ras/.") ��hinZ��!:�fEbE�nScaw�-.�:�MEK-1�or U0�{����~�7o*d��;R�"P%ap��� chem�:Q +"e|��&�"�3� d��ip .�q�r65E�>�\.�_ �� �"� ��b� a�K8� 6�(�I !�aa)�&di8#�teg4��]i�/=+*C�_so =tnK!�i�'�}��$&�},� =�L*���5!�� �]!vMV� mote8L�kHdM�3��a�R"%f!��x�7)�V y��2?-W�J)["b&�o#st�]�1��-6��*�Y�!�ij"&2�>L �m#�- by�f�E;-�"J !��)��%��*�F�lanes �F4�5*E�)^� d)�1 dionn�necessX6n �]t!O; (A, �1&� ��z��his&�"`i�&ma��@ by var �`i�staurospx^�/etopo�� ,tQ, FAS&�;�gra�C e B/qint.[?. W ��6?n� " K�N�[3�?40N&!'A���6� t!��1d�]/� �=sM�� E �#:� ;�"�bb"u!.! 2�& o� -�m" (�!to�)k a�|�%>\hs�9�� 9*� �s �!lrBU .>�*&@a�E��M�� RCiI�.#�"�0=L)�byMl/�c#^,%qARP\ vag� @-Xs@>n�$9N9NT*�Cy�ye�ws Wx7N1Ii�v5�,*Cx !l cruc�.91�6�@ >2�A�(a"P7�f3("l 5rw�+� pneumonia)>� �serov�1BAo�Vr i!u��E 6 D�"6 #S6���]10A�� m]"S<>�&tE�M"f �tr-}t2 z�"p6�f*L�C>�HI����H^R�e  by 28!H�HJ)10Bc>(�*r ^��wC�xA$�j ;P-3�.�9�B�:an�;�+��;�V10s-10�I�-�R )A�oa-s�" &� �2*�6��>�by�5;^�H�:Kdata']�0uti�A=4s �>&�G� Wei�3��aM�6A�) !*)��m�$i�3i�2. L�E:��ZZ1"� W* �!n�#�"r1 J�:{1�s�=�{1*c1Y��6])/-?1��!-N%�2g!�����a;"� !D�c: *K �R� ��/�5�#�1 �Q�BzT�Z�"��]IB�-"�E��N�is:P A�nA�rF �YD=. F�XB9�4 �Hcb�8%%�.�ry#�poi�-produf"hepato0u�3[411numer�7*�)?ubS~t�,�2 , ex��g divers&�Js�vas��.�,�and viru+��A�Kkr w�?:� AM��G�%x�� a key fac5������:&��Q3Qbi�?",�.�<o�i2S� u/hyp�� sis-SVA+om�_�B�[a�s��curX5 work*��9 )$ ��%� 8 ��."�L�� ��h?= �u`u �?>> �" !��*� a.X"ٔ <�t%�u�wa��ver ,� �!�( �A���$get�8.x &"�+��(=4��2L *��Vz �� сM*.�!)f�&A"� }�F�g1 >.a !�"!in�d]m]o*e���)r!�>E�7toizf!/d�=sqmUK�"� �surviviWI!a�y lG��1out�!PM�� A�I�)P� ���Iubvert KY�~extl�dxs$i to++&� >�e��> h*fi�9�Ş-L-�engag��>2�r" "*l �p)���b2�-*^1��o��E\!-a�0ed) �i� *�#�propa&0C!Jq�I�!�g>nY)�Yé�wYDa��E R�[�@dPYH}  e �߅��M>�Q�� �"�т ���L&s`A��itis CI� [�P�Ka!S�csarcoma2N erpe�Y��[Ra���tl�,�4e#il:G2 an�*--7 E��B!� ��� �� "%oBA�re�/!o9has-�!�6|D:< A^P��>�am�RD+�h�*>��'�� !�*R�~�a"�2sX6un!W�end6 �!�#Our�n؉ta��[� 5��d/�]� �bo' h.�ni�u(�(70 I�*D!� ��a��� �^�y new�p.��Z Ё�1�s��sؔqd}T5GofK�%>�� ���RG& eV'S5UN5.D5s -v! . lo> M&UN�#�-cf��J ���})�6a��7�3X �`tzb*e�`��GS��(Q�%Z&�u�!  w Kr+ s� �! ��2z���Jf�E�p�'a�u�2� ���RU �!ik�'&�8- e6"|�E$d$5�u Mlya�o���:!GI�� &�Hlysoso�[4��T�so-9nd*:"9@X sf2@at Tyr�i[43A*}(�W6~���G��way [4"CG&��)�a�"��v.| �.WH�%y�s!7�<&0�H+DK�iA�6� a�le5x^ �'B �"  R]I��V� hTb&��O�! �-_m o>1i� }!Y�� u6�!"4 �!�d6" %9�� �sur�Ja�4*Q�"�B�MR &aFFu��"�T ���e)s �ii�a�: �ա�.I8)� uK'%[$t��e�%*�G�sl �2/ mainj?��Lvor�=���wY.O �z3 !�mE1�I���J�=�m"�2!���MR�e*%N�occurPPI#solic � ]� Y7�"*z!�&h�Qly�&MV�!%A: soma*au �>�lU�:�a�MUS�^)]�\9Kat MB!.� p)HW �3| o sf6reR}ĉ�a�>�2��Tf!�ng�B�M�-a�bQ�� 6�I�1 �T ( 2��R�M��6�8ed�+-E}\>0([4*L&�A�*FKVF-�n!M&peripher#U9o V 560+! m:s� ��e�O��A *RTK� q A��&.} 5�!'�nU��r&beD����a�:!��`ho;c6�S�CFi!@.�^�6WJ�:M�]b5�V� 9>�$A"�>#)&�^��P�q ^8�%[13x�4]� �:xif%�� o��n "�%�multaneo$.��L�s -br�;lt>h �%�nL!�N�+.��)��*E�0A�&0J4~Nqy!�&�5or.�.S. D,W�%J.q@� ��7 larg;&E�� ng���|Z4 �ode%�u�:�+���m�e�;ism!���!rddl�!V�!!E#1V3LI be l��9+T� �>�a_0- eA?�(�&Figs 7E� 8A ,�"*e d6-*60m�Bh�v�##(�by*22�8�0~M���i,u_,B1�ab=z�aaO�/2�ac�X�lli![F�%1q!a�.�+aq�in�4�7� "�%P'I>�%�5 ,�=A�&Yg�e"qH!pNW. C4$&� L�E,�b�er���Kn 7("85���q1uo�>�AaR�9)s6 2. Aparۧu%L�r�U&��� !��7ta��H)A� Ras-GTPub%J6��n�RasGAPV)]d, Accd2on-Օtry6|f!�Rac|��R��_-FYN%G� n@Cbss*$*$sphingomye��tra�g.!IU# [11�. More� , ��ona��o�2��L�\*X[4�mIn.�)d� :Ereab5i��$� KSHVA7l�+macropin� �(Y(2.�of >[fUF"�JEph"�tmpl�|�-.c.R(�2� A�:!���.�* s [4l09�@V�BtUk�/3f"�]ein�>�.j�A xplo^��Z�#&u;< .H���v"D4��d*� i�F�to"u *�*]8 >� as�$�2i5H  v� a�^ ? "(BC]�N� �QB�)t_0st�*�)�'&� 5� f�J�*:%���� �pro*[ BH3-��kBad� �A,?�#2E:�Bcl-2��:er Mcl-1�.{n��r-��"+N$ ha�gr�a �u�1�'.`!�tA�:O���U�i��OuT"�Kis&��Zmis�A0e�!>�b�2�c���au�Yo�&p 1?nl�Mi3�k*�& Y majo1U�(gn�~rAkj>�Ndic o� l;l�cR{ conn"F? shor�/n�(al [4�,O��an ds�� hete�( 5�-��!��lar1 ,�\  , 90".�6�[e&su��V�rbeliev ari�"e��<��$=( !� e:�o�{9��>|6].!��da��evhdz:�o[55�51i�&� cG � 6 [52 , 5�`�"iZL M&:�� ��:�Bs�za���!I|!npr�K Ep.c$B3co"�sA�l�fer a t��&;���"�:���� D t$use�7`+��Iaa�5L s [5`/55%0 "� �7 �(�AL�0�݆A��Tq&"�'toB�Lg� lbe cap��E�ng��a�6fzt1s����5$�eq��Qhow9� ��$���!}��.9!�2!ssu�jr~l�o*r3oi�� a�suJ�$?N!�6 DK� &�sӳ�k>��r؏A�e!�u��� artmݭ�<hF���r�5M�j�"�'�/���<&Tu< .6 �6)H���r�)�l6�in!o��aa��!6)���s �e /.� =���.�A�e^�l�(&�9n&  ��"o�$a��feP�E�t��ni��dbts)E%by imL'ggaga ��1)�5&t��B#a#��c�"�.: E���\, m�] �! � ,E��!��A<ې&��9;rig��Abegin��!&.�F� stmbaE�����K=�x)U6W*Pto^}aveu�n�I�A benef!�%h will be])thys un{a�lexP "�. $Z %�} ośQ r\st"�A fu\�* =,`>ap�.s�5!PI$}#�al"'%��m[a�uctancA�n dendriA�MJ neur�w 6��+4ic �rptJB���*+ E*� et�vol�z-���Vne�'H"�C%@2��,theor���ffortsu1Ԅ�." p decad�(�k V2�!ps� knnof�!�u�on�"#ezUVUH�we� -a�T�boi�g @l�tert!���L��T�K@a�e|ut��%> mode�#Nf)-�ic�<e�}N�ly|22ar&���At�@�tB ܏em��G dynamic��g�`y� 50 d03*�!] �yڴ4double-sigmoidMpon u�x�2�ly&� �fti�gangl!zaL We claipei%�<�2�!��Q{*BJ2Fpr� i�qw�(%&4pe?-�sAw e=#.JM�.D�!�)�2�shJ h��aA� c]:�. OneH�di�@ Qfe��� many��.�O+C�6[!w Much2��}�g�.��4 devo: ��<�p��of morphJ +~�-#az_���!si8�,[j0Z�_ oZ �co�02�N\[2]–[:"d�$%��Jls"|6�QWA��t )�-K��s!E�?�.�A�"bi)�o!�;coinc�<c�'��[b [�b���� ~mpi6�[7]� �.)�B� c��K!�onB^IitADRPD"v�m(� robu>_n��U� noisI�spa0@istribu!Echa� e�incFDg synap�in�,!Qn&!Yet�nі�Qo p=izE��I_vie��!r.���:dev�,!\exquisi�#!�ed�!Kr1� chip��!�woaQJ�bzi����T�A_�)ՙ]=param�Y%��7bt��Z�arÜ�!�3t{�t}n�9��$ +ջ� [9] �-���"!V���y_)X�H}exae� e]�� �f�A.�3 n�V���(.� p�O"C"::QA&Gb e�;%I�"[ �ye�͆� �o�E�? y �ela$�z9?��s�-��Y�top�y�faith�G�";#meaǩav.�@t 8ůam&���chlU. MN " �h � ��� stochaU~*e(dG ^�Cs �h&��Yon�!�a�B�aϏ���@�f��ed._� `g���5>;chA�Zf� boos_p �� ou"..L a�ٌ� k��u��{W. 9f!�s n�%.M ��Mo —�xveq 8.Mc worda��Ro�2hanyf�order��gniZ�%�ue"te��}u�&Q*$�ad�iv�d� ism  *m�D A��� hund�X�bM�r6 n wAw Je�O"�*i�netAM�" [10D�S)�1�2�seems�4��3 c�I�ed�e2�pEur��We��� A""�v2u clL}a�I":R%{e)���A�SI WAAa!u"� backg�( �ch�oi�!�behav�N� n&� �m�We1`!_C�  �'�zofFfE<� has05�.� 4Rn� ���!� ��ItiQ}"�9&�*Ťm�_j,�evi ����>yXm:+ w/��)�EܙMi��� 9��(phenomena (U t% �T!<lriz�|� N�B��!�p (M_n� ��-��Lr�t��r��cBs1 �,!(�*�( bombarda,= -r�^� *�a��d7 � -�IY , na: iF- [0�q  need5+�OeAspAI Hill-� s�$+curve;�P�{�:[uZ�(�^�f^ [12]"$ �� ��: S�SwhyNj./B�? G�� answ�:>�DA�A&Q���A��(�Mbe�.1� ix�D/���UKw�ze�MuormA0&"#EC!\4E�2\ ��� ������!�^ Z'2m.�*��q� �- �-f��t�oun) A��&as�cR%� biophys�M)j)�s))few� "��3�5Ea�[1�E��"0hs��� +9� p ,m`&� �"r.� m��Tlexu&� �q� .��i�(�acic�]m jJ�j�a�du� At\e�%� nnih*�>$� pulAa��` put-�F��5!!u*n�KوM+[,)� <:~� �&�-̛f�\-�lum . I m�al)�sci9: ��>C���fI%� ��traCV� isIv cў"S�equ%NsE rek���%��>�!�o��A!�w;ngmqle�)A?�a!�ionicA &��<"WV� t�,��U�(ec�0W�c�uf���m&al�mr�T�K9 t+)Habundbie� �� _e_�3�Ug (� s!.%sum(-�A\ *� V!�is]� research�S��i��!amX�%+�p3il A_�%0�aE-shaps7-a����=b��ˑ��:[“-%�U�4� �15�M�����u� rame��]2�䅶!͙v*�unvei!�r�XCM�re�e���28 -�5��b�;len�x�Wi"� � �q("!<�,h� ngle�n.}6����oJ synchronp'a9l�cl��z+F]bra� [17��N�2GA�q9 help��v��9�� V!F�"�`�� ��=A+;�X �}!�)��-&�C.Ka given1��J4qa/���4�f s [1W#D�a�>Ho ""+�" � �"i$w[!�r'F��:� �Ze��7%�2i�F[19e 20] ��st/Y�Nm�r[@5��ru�c –�/�D$e�6��)�&rM"��st�T� ar� �s�0E��B7�a �.���E best su�(!�add��m�>"�^i�s "�of\h� �j en m�/Bv,�81?�re� scen}RA��y w�]"Zly.� t�e�R� ��A|��1!]�s"45 ��tan;net��ec%tr�jN`��m!so-�@�&\J�� ��^"�#GEw\led��22Haa��*c`�A�fYi�3�\(�h2ea�sc�pY˞6 ���M-!#A:aI�Dv�1����\bo���2�!mfac� =[����(DQ�)E�X�?�AtM<:NQ�C�wa:tI��mor!� )%Y�+�q*�=2>�w"� e>G"� refr�IG5U Tv,�'F!6aa�P��A%�j2�Ne� each?�u�lpm��� % =>e�T� YEdoc���i���2���&as� 6; !�Y�t� \$Y,e�F��� !a�o�K& u*f��� success�I5[9Y1� 212?.Con�A�wis��1& >� ��� �eH�2! &�J-z�e-�w��� �:�� . BuE�Jsamg� R��%� Wi��reO&�x�p arguIt]u�a�&B�"Bb�`y weak. !�� �� A���basic (.a���M�0m�t r1r.+I!)=  ��B3�n �gn�a5 ,��� t�, sym�f,�b�"��domnes!Qdis���+eaq�>�*� et �&;�55�%�'r."irsA"r�ci� ~: "h�y:"p�!�ele!��!dw�!��dOE�"s� ��*�Iapi< -Y� ��ax�tr�lz6l&a�orU|�4eB ��-"�*��RF� [�J�r�b0�2�&��gDrosop� olf�7y"�3{5~�qLcg(iaw�A>e�q;�3 ���9���|�(_� al ,� 5dڞ�>e��*"�A}t���.| Po�$f-equilibr&�W�absorb!� J[>�T^b �d�5 � (ey.��tu@�&B� globI�#g ( quie� Y� �G� it�_ escap �����5i�b&j"k*a�H ����F�;?*aAE�wl6 3t�=)+ !V���^ !�� ��M�h=4di�bA5u��zero . D":s"e�&�-O!�B�-QmpingoD��!�U � butt� spa�M�+'�<�yAmi17�!���e3�1˵c� a���cerebel*.Purkinj�>/����C�<Of�r�����IsRy�0bet�)> vidu�}�M t�r.�|"rs��rm�ź"�nt&�c%$y �9-: ���"II�+ �AW*uk�"A�E�th�UHhat�$Uk�(\s��?7�Ԇob�!�c��ey� Ka huge|��3 lute-]!95�A�*� wAb""(A]prejud=$et � um�R��easM� "�1d�im��' home��m���roz�g�irba-% AKGM)�aL���"�d|'�� ing:\�~&� Rh�<:�&���%�!I�!W=J,"Y"�ng"� $#��e7�~4t!a� ?` �!T ee<3. 1�`I !#��DZT��)oa  2T: cost�+"�� ��H"�,C!M%uA-.M�x�7� s)/ �qit� wR�$b-logarith�h\��%N!J.��, � ��!5�_I a�'& =g�R!�-�ref�a�v0 n al�0j&r5"� �0y.S%�Iois!P%A(�mJi=H%v� � o]F�#�/�} ai[��Y)� Xeak�9ix u�I!���� ��-�(��p #imbal��bmo�zD�Us,5)��IF�6dd�i�!/"�%), >Ctha��%v . No�J% is�!�*>a�9ce�| i��nI� erPz �ecpYb [�y2g;��r�3�+R$sub]�M�4ofX*} 1"; �Ul4��"+A��)a �Kec�D^Y*S4�ve�A�a�*�� YY���a�4�5a �� �Ɓ�. G���+� qRi3G o3 now�Q ��at?a$�w5S Y�E6.agod�AgL &�-� !�6�*l^�F��2�� Na .�+����% �@,u���#wi��i��.�D� iv?e�� es&R may�A�a��9�MJ*N ���=vs�¡�� � %�wh��R%�Cs � Zz]�2�&� �!����harR-�1suSGAF| >in))Y-��=p_/*Cf�M`�A�*�-6A�j�2\I�i�n�sus)���="� A�a.$��% �:. 2veD��!��K"��E. 2�2*�?{co> &�.�I8 �$u� us� P� o fi:k`A2d�#,���v���ax���@[�λ %w'u&bY^ %()�(ow� AsETieB�+�. �K��)��R!�z�A�qA5���B Ace a<%?�? ��D�n�*sbA��H�v�5Q^&e�"x is}��,�~�'}�i ���!�/!�6�Y&� glomeruE� it�0�4� byRI *5�� teb��Z�G -principu-`se�ŗ)��mge [40��U]5oLņy/ situ� =�a�0leLf�moL=. �q��-w-  g��umV!��>?�FI\K�d�,�86a feedJ+M���byR�!��3��;ur.<0,>�re�jpask6%z� ��B.j� �3��VP/-�[1& -, [*Z��� � e�%s"/#�Np4rp'&� abN t&�&�+<��=qSurpri�ls.F�Ie%:S.E��!���,�Q6 ms$I� |1�Y��5�z(@pS urś�O E�A��>����=!9�e��b�;�l6b��a��+ciKeuuss� �c�K�r6M�"��\��r",� ��-�w!#��x ��m*� melanogast5a�+�lo�6�>�g� ' -`usW�a�Mid:�.�'aj�rQ@�( ORN���To�)�� �+=P��fr�  wr�'�7a.�6>�*~a.� �})%A1�uA�Al�!Y&+ �!{�ORN �0:v��!>FE���NB*ndJ�fi�r�� Root"J��v=��W)t�-a!s8�M�5�s�Tc-�Ay=.e�P] a2�IԅKse auth� ��ixa maif`%&� �e�*�pr:���"�} ��^%�E"Yh���!L*�� A/��su�N�HA��E�7���Ayul V�G.*�?YEs�[.��kIlmam^an*c bulbP"��N�����pyramid"*P��MZ%g!�ro��Eu68�&�=!�i{�tusefuO!6 ��L6��/.�Calcium 5�#c�3� �~M�Q!��:�l.PL& e"�L!hG6y2?��e�%nm&*�� M}loV�u2�er�#,�&e*��Kg�j"� �|woR�A�F�5(��2�?)�5m"�1�t�S-&�� �+ND�x̊: al��"�Oan����!&~�in!��W1S 6� *� �YA�29��(Y�u�'g9� �&"� ���� %R�aʕ-)�a��1<O*� �,�Y�� �t��l�7,m!XISm�"�/ `ez.�rR�!�a�� # �GFE�#�ydesir��;�!5�".� /�E�*� :p%Fp dek8a m�.U�-a+!1/�#��� "� w��9s�u �;"b  it mZ6beMul��lerA�4!�,ros"�#"�@� 9�)���E1��! v� ay�ex����va�%1&BH2Stl hippocam� )s�!E��.��us�_[�TDu"�1~c4al�;e MeLR�?E K0ion ) , our m�Rodel demonstrates that such gross independence from branchlet number , detailed bra dynamicsTndritic axial conductaR�and tree morphology is possible , "�enh3ment ofa range4onethMst vi C$properties  se excitaa}�s . Double-sigmoid response functions have been reporte&|cently for retinal ganglion cellt| mouse [12] . This unusual shape!(trasts with�Pstandard Hill fitting�T . One wonders whether9 habi%$4 A�0to data could �preven�furId6curves Ehav�6 in|8literature . It!�,very interes�%�Ed e 1vbe[or6 a di/ctive fe Tof our mE�,in a certainM@of parameter spac�Can we � pret�(findings onB�ar-��erm%�x$simplified �A�U�U5? GMJhA>+ arbors bu�ir sizE� smala#mpared!�,, say , mitra>IVr�typical �E:i�!�\order around . However ,� a structuSanaeybetwee)�viE�a� . We show!�Fig . 2Di6an ap��(riate choic����us�leaEGaY��  which�&)!experi�aal�" . Of�'rs���quantitai�it��,lthough goodA_ s no)�F) [45�A�be�@9�,4 "; e�e=p ��l��m69 ��8�hig probam�of| transmi)I fall�[below.Blower�R}mor�ici�siD�� Il!�ef.on�]!I,same level ?��qu onibe answe� by lo��t-14A�> E�,on-monotonic!�n !+ a kiatf�onE thro�N �w�� primkm�a� ized�an optim� oup%�am���s  o� !A!|k(��so ? NA�E�,� +a;h. ,g!�en�, �aos cre_inaf� xmayaA ar�� j �$�� agO fail� !{tooj ���i ��"� i� �� { a"�screen!� )�1e: backwa� �ac ��(#ͬ) "~ lyI� lock!8NEincom��, � }�49Ao refaKYmA��LQ�E��53 call����8phenomenon “s5reM�”� a�J#� ed d� !6-��nfi�a�z symme .��s!lj���.�r.Kgo�o zer2Oc�!n�e�sA��(� ��4C 5C � 2�.accouf�/hjointM �membrane�<5 .�de� �yregene� ve i�75 nel�� Na+ , Ca2NMDA etc�A��� &} � �&�isn�exq ��� l? e manipuli�m*�(� �� cy ) !o�ha ���mUic tuft� �kredic�AhmAۉY&Z�E�*�Wu� than�-"��-p M��� nihi��M�EJ"ed abovja.8 UcolliGBIi� ��l*c � "xbeh�bo�� �.�(a:\A�Ag����to��aor��al(% ) ��N��j��hfo��-X��ngF�� a���2+%�S W� r�excep�,s [19] , [20� !�t nonlin�ummQzt�Res)�6�haA en wAKu�!d!zc2XRxaM�h bio"x� art�s��G5on%Zv.�. Tg lly e��A idea�nsh�examin-t�>�i�%vitro1�����ut%8alA&� ��follow!����A<ests:c�� �Le+6xE�at)n��!s sti1XE:!b�aiE�reachi��� e% �to9^>th�� and/O"�[1�47V "� we_"| Jr!�ɘ��6� ���&� �at.a st�ly attenA U���-r4�7inp� �� l su!��l�08principal neuroab48�4A�;ofaaPa�-�U�ng�1�assf:�see�beable \� f� up nLai�6D� lays na)�oE�ol� �o6sFo�4be epi��a��perhapAai�y)�a"�a2min5 r! pr�,N� �� evolu��� exapix���ious r�ds lik�oa��f)�Qbyq�icip���be a�ed:]�6C��2qu be f���Q(����plastic� or=) a���A%Ga���bsmiq copic (kal ) ba, St�s lawA�psych�x s [4�5� sta�%A�per�M@�ou�teR growsI�p�k. I�5� work%���ed net���by assu� a ͛Pionship"U .�al.�� \)�!h,�z)�a1-E$ex�nt%5�� -out�fm"!& �" ��e� G plaO �sx s[26�*0 !�p&�tarchit>}1��"� ( ven 0 . 1\�T���)�mea�5�"��� b �ed �(a logarithmEy8Weber-Fechner )EE].2�fmaY�:�A9"�nq�!xZthese�-M1 f-��&� ��yU fi��qac( �log )a g!�*ٓ�`s!ye#a�6um�{�ce�&n 2[5vw�u5��atg,-�6� *lm��“FTs_5�a�early.� �%5o. A�pr�ia���!�1\M�!"�a.rs�ʼn!�&q e~P� alread�i�ter� hemotax � z�eaF� ple [51� [5�I.�,�� �let di��<�describ'!yj �e5.di���pλ�5do�$c re ����-� � h !qu"mlyI% typ g�liz{ $ e�5 ��t! ^��~*�t����continu�V �al5>)m��or&�!�equ�|� ly rak�!&)�� *�"� multiw�a��:!u9u�aut�a�yf"v6�P!-���al}�el�"s [22EJ27 � We now!�l��lyA�� 1�!ntGm�!]�A.�� addr�=�i)M#.�. S" �et�#*R iw6Ys� .���)~�*� ,+ weL *awV � oy!�<en�r� &6�aPi.: inc"j!� wE��" ne� ��s1 ��rpo �extribu�&\fula�� +��R�� �E��P ar by)�%hmagnitud�3P*2�A�-<���aU�e n�%of�aXsee8toaU� (� e�w#r�u�Rmi% welc�� �iceE�pey-�$to2�-��# ost-"� potenag�PSP��p��"�^inhibi)� anag&��te"d –E|AuY�O desp.�I�� %�o!R��a.� i�rt& ɲ adapA;to*ia� ;2�)�a$bRA# pped�Als*modory=YE��hreshold)P!>�p"&+ kse��E.�s"#� O��tas� .MID'!W9x"��wPoisso� $ [ej� Q % nois�, cor� �1oɈe�A� ime-�� m����a�s��2�! new �a �-���&s��-��:h��!{��H .��� @c l&�!!8-�I �s� inl7w� -�9�e �TK � help� expl;)v@ �{provi�"anal?%�S ury �a&\)f � ,� �t[�� ,, [53] .J in�$��reg��ina** I]2�&�,of��8!�}!�ser�� cripto�,+"�u0� �!� appl���)�mM| drug��c�?#c& ,se�and�Nt�yE�_$ of�+g metho.&!�mm�!ba� �+�cit��� bi_}�ey,*�xF&��suri � RNA abund� obC"I =>� <(s�?takJ*�"�#6(��roteinA�A89A�� f ��L"h� %^��m� !ׅ��i�c!6(�.�x+!��� spec�Q+a�il��g wA�Au��I >�machin�,_ globN(5��)(negf*� W vonveni!i�(wc�1��-��o^�valid|bia�a�1$e engineer��M �!�*we�'[S�' stig��, u��; mbinU�mi�.�IH�+i�r �."�/�mȅ�meE~�re�Cin viv��!1�!�Av��!� FliA-FlgM�ule�E .�i moti�&g. From%se��!m!Z��r�by�neK kine -8��exU�.�c �[�*� 1,0o�/%Qo�+�-made2im��Ohn+"� ��e8�h �. More��) ��&� �I� h� I�AZ-�>���sH.i�,Zb��'er half-0���. A}�y�] s� ��6�Rn�a3a{ MBG���r71 Qw�tud�#broad`�� whenmJA�N�-{to� ab���/�d�EU�M�a�I �casU�B�,| Qm*/r6�r�a�%��q婡l��liA"Fa�=�A6��-*� promot�2. DNA�arra, ��s�ai���&-�% �f��yie�2ugec%�!�13o)7s��2>��rogramA�ba"G�1>%�-�th��Q[!(A��Zg�1\ a/9Ep�"���ja]M�infor��on��,!v !��A�us�� a en���%�k ���e�fuey$ velop�of"�!ЉL!�]�6� �&!M�p/�%�6s��trya � �" a�Ɇ�a�� ��`�3%v6�8�An &+��� %j6e.�!�)sucO fu�a�e���)a6!taP1a�{Xtr� 0m� (� [1–7]%�re�2�u majo,6$ !�Y��e !�"�o�(e�� 2�D �7%�� �5�M %� . A�!3(�7)�����'&��&t�i�[8 , �wis%�r������O1`0!id{*��5�a�%8�6J � �ɗ�!�e�1��E�ia2n.� 'v�,6t-1.in8 h.X� 6 +���( few minu�*� S+a�!sEa� ��qui�t��[11 , �8,�Aap*69��gen2��,�7S le"�  ,Dt��g��r�� � pers %�s� n9�I&, end}"h�%llI�a�'A�{ as�`0[9�v�(� n�Up �9 ZWeiQ%�'y&�ly��d� spurj ^}2�Ei�t:i;-�bm�adv� d�"ly [14�5kita ayet&� �4l� s�+iF� � a�q9"� �f}0  de4,3!�y0ma��!¡�� A���3rol�by����S� ��wRNA�J�-��V� ��� �7n� infl3�������?�p��fc�� 6–19�L�7i�u�cV7o�- �3B� ,#�Y,!8 just-�M�.aV&V��%ref�� *��u#"��no�!�2:� of (N4�polymer� !/ ribo-,%' copy��� !pC!Nmino ac�nucleot�5 pool� Igno���Gś+!�.{&1 3/��"� �th $ t�ʍ�> ro� A&���.alv2X}�V�[20 , 21A7U� tunat�2F%k�maE"llmq i'RpQ=eS-4i�1ul�,��f�=�/�L wa[T[!��F�=�Hwo�u1?ly!h2�o��~�: ( i )�." �a�: prox  �i>�A�( iE!�f1is�2-�m�!-u2��!A�" e��[`~�"�yrecogn`2,�liG7*d) p8�u�}��Y��9� aimAi^ pape�?� >�F*edaZ0nd!�*�*a�<ach>b�sAWe 8�Ofoc� I�� J87� *� .|fluoresq �orW� �s�(ch�%ch[bee�wic!ArB)yea��,�!v�b!e�3b00n�/�%{A�[23��@ExploiE�I%�maX:6�If�|qmc-�* mZ�� R��� shor7 �*.� �� e< avail9 � Q�u6A% asA�-:!�-�> 9�ce)M*� g�d�Z��� ��k!�k �"�8eR�I ���q]dmQ:}@ titu�<(/�edE [17� 8� h!i�Q w{2 2< ]:ot�* ��*b 2��8or�> ��4>�2?��� E!"�i)To� t d�4ha�t%��-;�2.�in���e��;6��X��!.{��A�i� ly ?� �Q9��2 ��xed ��{XE[DEm*d r5�Q�syna�iE�flagellI%!(*t' 5�gb$EscherichiAL$li [27–24 H-� & mp#�e:%g%��!��M% !'th{t| t�orV σ28Apa sigmQ:cAI�!�sS .� �!pewcoa���r fila��}j�� !6Emo�����A`�uW(<�C-2�%�&"� V O*|��a <%encod-{asa�%%��p��{Taa�)J�!"�9ex:&�J.� A�-um!�C�2 � phosphoryi��dow�Jeam w/>b ��GZ9�)kG%on0"[3{ 3{ �.!u2Z�3/check��te�Da�-��;�� casc�.%I!G�D+well-sui!��( gV�JAj=,purs ,Q�D��on�� q�&� b*�1��"W �-A�pla�, &� o1�8/-A��&3 ! �%��m�2Jp �wild-t�*a�muDF*3 �H��t q A%a7 d%�2)D"�A؁� m�>�( " ��1X.�r�%�!�� reli������F2��:� 2&� �E���a�Atep��-��-��f� flgM!�g *�!]U �ib , did� �o ^� !�*ea2� �[7n�.q%��6Z �;5s"&.a��� Am�(]P*�^@�pi|�;!e!�#� -f� 9�3 ,Y�.� �4� )�6Gn#��n"B ���-�a[b E��2W ��IM�.d-l�%_,� ��> arginE�� JDWe!^}& e�third)(!�2��OE�ş� hf"XEe[LB�a"2Hr0"�F*i ��m� �.�ly �INUDm4aa"�>͙z]D��)��9"F�!yBag#,wL*xp)�=ƥ_of)* . Ad2C8"�)�#6 E��jF�!�[� j%����!M�2w]���e2Q> )�m>V�$p�ͤ� ���>�U2�"� %A�/ t�!X(�y�cLE神"�'�2�7x'H�i`e&A&��zal�"�fQpo�A  �?� F�"�YAprokaryo� !�euI s . Q ��60 �% Cat"�%]s!#i{uJ�o:~ hiero)��h�l�  clas)e�"� m�-��2~B��Salmon�A�!R"� , 3$6���p 1flhDC2E ե FlhDc FlhC� �4A� a h�To�1muA plexɨa- σ70*� 2����2 �A��lS5� E�mak�up>/ 5�a��av uk6}3}s.w( ��B<%b]e>�, 4��j�} [33]I�!h<�!y�Q"���TQl�um%� X8:�� *��8"5�a��8Q/� s�I� 3�J@)�%6��bi�DA��i=&� assoc���f$*�.�93H! � j o2"m� 9�ƅ7�2�� nd�  n�1b xcreZKu�& &!($basal-body=�CH��eO�&0H�8M��id2�%M�ar mas�Dy�����1 s [3] 3L�>*�"�*� ������T���� 52���&minim�ed� gluc�H[3?�%is�l6environ�.� w �}molec�4cyclic AMP ( c)ouE�;Ek{ du �6m.��SKin8-^�� Crp [37�I)�!/�&� �F)�>�8u� a�s�ڑ� hook.( HBB�>ru�S*� ,�~A�v= �a�m�s�)ANs ; ��Om��� �.�;�!k��~�"�'�)�.���+iFTlea� ��l�em >/!r�1��r82| v�!0N�5 �[e�Q� U �.�6�� varyEMpW�,�K� ar (A�61�G3E� )�"�/� is wVcE8is�.�R0 � u!"�&fu�al fuA0�a gfp^oq �h h&�(�$� ctQ%��;ow-#�EmixAqw iAb!*�JCPrb 4�!re�Sin 96-� m�Ep�Twf"\Jw eG ly-e-)A� ocol�3��40��Af�A�Rv�@dY�Aul� A�he��^ dilua�~ fresh�u /�)�qbsorb�&u� b� # emitW9�c�r��at 37°C! a6rru� D or 7!� 16 h3 ntil%Lth arr�| occuJ1Ab�1&� -�5�J&K��t)a (��M912�, ) LB)%$6�.eu2.q.(:\ deleedeU�-E^"Nm�Q RpoS�PsgD��CpxR ) [IA�ti@ e�PBtrength1�i�5|aIhe*�\.�3�s�s D.*v,\%�3o�$2K/�O}�d l��T�]�5�i�av2v�"�&ly�E�i�E���!A)�� j��"��< >�PE\6���R? Ţ*C .���7�s�i=inguish�J Y6Z P3G=~ ( Text S7HFs�?I��O){rai��C d>1*%�I�5[2�s�I A"�Z`�Ł�w��&i7%�6���B?6 illu�o�Vi"�Y!�n�$F;���A �M�0,O6{F��);�"{�V��32�)�"NZŭ��E5&viN"�7��:E*� �5��is� ] �Ja��x �"@,ea�6,& �"o"�t"U{:�e]H ll�{^*SmqJ�N�q ��*!a%.���!*92 �Q�2F�. i.%�*w�%re5J��"�^as� �P,� EE�@� �!q] �eac�N�iIZ"z4i d acqu�5�8!�l�y3�- e9xRo%e|�!2un-�t�)i�V�.�W . 3�w� x(# @f�]�Sd�1��)Δr��a�in�:* M9 ( -M9���)Δc��Z1.1�)Δc��^2sgD2v )^1LB�1Le I�( 4&�>h7WT 3��!���i2R�yf\QZ[� ��+V!�� 2���&�.� Q�Ń�4gj=�E��*.(5 �} ub.� 2�p &L� RT-qPCRu�6e��SNU��I�TF�$mon& D,�"�o�= �y pC�ge�e+PXJ �.W)K� ili�Kat � az 8� +Bb !��B�J�_L�" � � � p!�Ic�=2mLM|��l&�[39]:e ,�,� ��:lso clQN�m) (1 \A�profil &�UB�eo�_E]Z�F:n � m�#��Jf"=sta*N5ina�=�$ P)�a�0���)!tf�� ?&4P�WN)�*I!�.h ~m�As� M�6��z*6�-�YB�6x�^>Ya�qC 10-f�$.�W����o��=�I�circu({ 1&��-stWko,36dea%j �"� .� m%known6af6�&� m� !� $"� &9Aa(�E."$��+ !4rs &O7�&�Xn�D ){� I�K�D*� @e F-$�� �f�Q"u�T�[W q�QE�wF i�3�[�1�� !�" >� ���2CU�M��?.�&�+TI��V� A[0��Q$kz2�uhCm�'�"m �{��"=;��� a7Ln ��L�FlgM n@�LP�*�hXa?�� �Kn4A��.�i �.Eu�(y pb vS�z:� 2@I/? � 6� I5[4���1�=oa}E6M�E�G�DM �}M��92J,�!�&3� ( ]X.�Q!�e�(!n�m�G�Prg=��in �A�&so-(r�.&�:o�,+4q�W���q-�E�X��)mM�0�a�mo�� A��M<>"P&E�U c"TYe�adeiZ�� e�%ICeD�>~�5�/�%_!�Uj� ZWY}5E�elEh�43��&h+Iڙ�!"i�C;-+}3�~4AAV!2er�}re*��H:�o�%a�e��#�UNH�J�!�XE�D2&X"Q�gret �>�%%� 8N�>,�Y��e�val�a�!a{�� � �re*�->�e�"pI��1gM co&#d|�� 6;%+�4�FC a)�T .�iG>� U"~�m�E re�n�?Iĵ. D"SR�`KDb�N U� M�t:c2�s2�=:�(#,%�>�8�ᡉi�9M��T� ��$w"�CPe" e�h E� � W��EA��E�E�Ag�;fn&���co&�t�vO>by =Q��#���by&l<=eD�a,si-� librf�C� 2�.� xd�R� ,b=if��m� faste�=o�H 3!%� A=� ari�R� 6�t�0%4�$[4M4%7*� w8 a 2�yAM"�X5��-Cjin�(j!?6�-����I is: �=Dt ) = k 0 + k 1 p �m f r e e ( n θ n +Z, ( 1 )R8= 1 2 ( − ( KDM Wo e) +�"2 + 4 K26~�� ��"he)�v�6A�\, p�^& � 82a#Ab ,! ��&�U���0A�6gI� , k0%�k0+k1���)�!�| 6���!hM�| M+{i�j�. �;.�/20s!)�p1��o�%��)�0l�n�,'i�2z�K��l.<\:p&�>�� n-ne�n�$nd n ≥ 1R��� !1*z θZKFavA�arb��r2kunC RFUK% !�6�A&}�wvDxDmin−�H)�!>�8�et ���[ N) Nz) 2:))v.��xhF X[ q"� :�&%t How�9is�m0\_! I:3B in Eq . �p�?pMA�r�Kg R"B ���of&T�:hgy�Iqlc~ U,]Qc = (a�, kG�Fθ , K a 7-4���#�}%"�+!�KiA�"7 Ay�a�^M�o r"�lgo(c_t1.t A~��error Q�$ ) ( V� g �UM;n-squ!} R�l�Z�Q���9=) of Eq|�J!�mEp*�.�!@bso< Nm=Y}��� ��YDcr^d � av4p6qc�)9#hys"�S2�2a��0@6u�"�[ θ l� +b j(!B5��5�.�.t)1K� ��+e* f c=C�z*�: &�Q��E=ndՓm�D6P:| ɉ��"�i�|w�eF,i(["�) aa� 3*� J�A � }�"=�!:Z�TU�Za?)3� : 5)� R�j1$Qkes} mog�; bootstrap}h3 X>resM,!;J�2>�AaatSe$p�P���&�Cly-�[r�nd�"�]�Ɍ10�ɣ�N�I,%��㭎��/�$�&geC� R1%i�h< 2r��A{nd���_'n5�4yiss�5l6g!@B�(nambiguousl�5fe$6[���4&�*,z1�jD�i&�&coR+ZYk�nealy0aeR�. a�w KQ�Plue�1m�O�byi�eTdu��J1�2"f�b� cBud�*agU��s'4Ja 2�i&SZ !�#���� ��datac�N͂A�5&�!L��A$�i4M ���J��Q8t�!A.fM9.U� �*eiQ��b IL \� > t�6 an h(>bLIMAd� l�(& ] A�Z�byB� �R�=� p��! e"��"~ 5�-���, "0&?A�nd> �N"`Z|a�Zy�Gf?t�B��y2GN�.�j6B &�O�ba-Fn=E��"5A�M�R'�_ �C.Id-9�2M�x:5/"�DeNIS!#vO[16 , 4oC�o . CoD�U[�� � K�g�,���� �c /&� >�*.��nd- 2\ �7_"6�j��e �6Q:3 !9�c�'� m3re����*�i���t �&9�.E�$*f3*1O*�N6)etabo�0}+rsAZ�i�'u A�QZ�Mi�� t51 L@!Jx ��\.��dH%�� N�G4 "�8#"EI3�V� !�dirwK�+-]+�BR�F�H[�Q��r&�"]�X(��[1�kw B&_u�pR*[AvThage λ��]% .�?�con-�#"�.c^Z*a-��*v� �S �.u�vP"�@6N)�EB�&%�7;! >z.�?."J� �hw�0ge��w��2T�FSi2O�l�{3�*F B�a�e-'.��l�#埡ko5"�U��z� M�-- g��� Gi�Mscu�:)� "I�M�Ks }%ext�c�Xl��+ac5\I wi�ki fVXf���La�5� D��J� *�>EV)�� I�iiLE�� �?��%5�`"| M�f����De�� !� ) wa� d`��r.a~>�x � �3�g4BE�WW��  @,A��M%|�D�Rcap� )(��e�|��t1 A�>� A5R�a�-ݕ5-\p�,e=�=I��1a�h f! 6I"�%�� �B)�7j.r$f c o n s P�. ( 3 )EFf���V-�8hw��p>�A� a�,ut� �I^S4}O �\�E��v �Ts=�&�`5}�C! /!� r�e�7|sqL'�m�y�op p��deZ��do&Vqz)K�"�#ss.���m��? �* ]N+! .Lg:�U��27�� 5.*��i��!*�2R�E�t�ounsatisfGpXA�.k,� a>6�l:�ia-sI6�J��\b�)~�� �D1�D�0x aZ�.��� G&�9d)JJ2:�'��T��� `c�s�)��C.�h:�1�.FOz8�$i("��0MXGFP6�hy d"-�]�2�.��~� �rb�8~a�E� "Q$9)�-"s ���`(K� puls|"e*phL���:7F�.�>��-`,a�u�� &tpro�G�e"�>�.7%�, [18"E.de}�u!V>�WP�R� .B�\"K :g!_=alw*hF{n:4� �H�A!��9!��!&�� - . P�v%y=��&�sc8Tp[a�caa�d�rg],>��Cm" 4.�7�Y��j�He�d�j�awt. K�95��ad' �{.�AA"�X� ��*�yM*�*�K�ErW!�CMrJe4a 19 h0�a�5�-eʜ"#lB^inR�G>$3s�A�T� .� 30� �18 :^[+~�s2!Z^���c�m j��nJ,u����9�a�2hbe���*��g u@%q�VA�M�#8oZ/hG8ub�&�2�k]I&by Lon.$ �w�,ɪ.NtJ��B%�M�6�&OFB ? AsA<� [A�I�eZ�&� �k=�A?Am���n���-0�eA "�(t +&� �R���2c"�F� { e"�  ��H!�H��̝@!.�*9��?�O�T9%Z] �ʉ_i�tC<� 2c4?s�[-\ io��fi&AjH���?"q ](Ew�!isF��k fan��12�� yI�2( via9g&���Ll �y smo��Cu!e riZ$��\� 3v !��d2~�4��>��ta6�u�6C:�1�2��*ZM�K-�Cr-! N� E�ܝ�1j���~�ru�9^CR6g s"oO appa>NkB��e-(�2�-l��!��� DgM%�e�e'y*�\:{F. D,"�r�fawFd]Hs�%��4extra��Q� ���7�&�5�[5Q8y Oa)'I po"�� stop�؅���JA�new"FE�Q92%qg~-m` aA$�e&-�i�/��to 2 hw3dC2�(.��Q��%�nG<c�2o:.( ��/ �"��Gimt[[a� frv"�tfl�rZ&Ap& b��i ,�<Nf#� u[��-H� A�a��5v&�*� ��,�m&<"1J�[��7`<�kmc!��u, � %I&� z�6�m��.'W��ver)C���u�F*Ued�s�eg:a�2"�.!<�^iQW!�E :,�-��&75 �C��:M�P . M�'�WN�ac�VXA̞�*.{we" I�=e)�"r'2–3���,:�Ml~Z��.�)2��:�1Q_! �Zcap$H�/2v1F"? �&�i&��-ZM�`�j����y������ >��2�%5��zd�! ?�"� !#˨�F��0��*pI�r_���n�/�/�xbur�A� g��)���$6� we sl�ZlaxM%I d r%���]� ��E�"�!6"* 0%#W�O0 �Q�roxL{e)rr�5E~&Jh)�"5 �^pґ! b"��"] ���:�o*c!�� 2 , nam�)�.� �:��å�wi�raf^e"2'�uy��U�*͛] . G�r�ZsNA�� *�P6�Cfav�n�Wr*+�MU�u� m6O:�"sV'  `�A�&�a:� fe�r�0>Po,* � ��w"�a�� L"�J �>b�&�gM���[�r6]EK�{6J �1!r*�@=�u0�7�e�my d [5�3A| 0fT i6\s.�V�CN# NAQiQ6�aYe�  ��(B3�"8WF!$u�e�2�>� 2a f�pת�P 2Z!��Fpf[(�!� iU�-*Y a�EN���6�m%�M0})* 3 s�����G����!naݤ~<W��]�v����+6��to!�y��\�>: "�&%�c+ ��aQ�y!�j�"8E���&@ IET$��!�Cl�I$�&q�lO����7cI,,�H�LoAb@�m����66 ( 27,51iV�4 h�G ws�-k�!3*_&� r)Z �f^�"I��� =����c�geI�X\ ���IS�s�}311��24 �<"; ]}Aa:�9A"�K�^'�GA�!���E �aWaF!=.��� i� j�� �5 R� *2�j< EgM%F4W �@Sretur���"#U�@k�&I"�0�,H esir�+ ert3r"�'y�5�2*�Ma "�2o JU1+%=;�� � �Q ll�(��n��itu%�]22�5< �1l��u� � !�Fx�r�!��"P ubs�8� f��]M!���Ark%�5��4ғ�dre "�$!1>n aH��՜�9a��-m�iz%�� oN��d%���&y.�&�gMp�>h"�*-*2��4�1ro�A�SiA!F�}�\Fd�ˁ B�4, e���VO�]#4Y�jH�NP/��� intuS�� | H9(�'� or~M��F'h, ���X�e*�u��E ��{*�>� u[nP*�1ae�� b!�jgai70(,A��!g��B=`N�� �T�w�D�u<ݦ%"S � n)�hQ !�����l.v�'�!T*�S�ŀ� �g� ���2���n� ~m�#e �Av�eXd��"��� M2�� ��r�$� q��>far�se�36=R,_6tVi�1 �2�ruA�q�U: \*�S�A��*(J �&�,�� �*$ kL�!U-/FM["�. R� x�Af77!��duC!s2 \�I@)^.�����A�I5"db�4����.RX)Ya�o$no7T:���-˼"��a�3��� %u �  h�g�O�Ia���eI2%u"95X I�O� e�H&%!�6�Q4�*�+�A�!ru�.��}s���.�� a��D,��Egth��W iew�9� n*�?f�� �s��(M�E����r�~! g 4�i���t�S�&�� q�ra���r^.l zx:�c��t!��E�s&�l1e}�!�r�?�FR�xRer� A}_-silico�3&F}���!/�>:!�om�&�Z�v�.�Q!�R�f,c��Q,.�fw , p%�,%l2M��7S.)Fi�3/�0I6�/ee� t�%���z��;���%s��Z�>�">_0s �doM}�}relevP'M�"���F� A��:ri�l&��~ ario PA���.��rC$-H�bqll�H�To&�!�6~J e�Y/� %�� 2B>)��]��l?5Ήa�`��uo�1Kt&O}�%�f�B A���+�%�@ best�I� �[GA�of7%'�� g�CF.� !�c6�\P(ve�4�4M/B;�M;� �L�- ��a9%T�F�2�AhasA]l�w zVGB,�b HNF5.&@���,  �ta��ba�!� ccor���2�ba�(o��%��.�Ma� g�=�@yiM�JY�*�QBI�*4 A5>)��$C ��N� �f�aN�� ѥ` :#�k�/Bs�J��|s)k%+2b" � ����L�Q�!M_m.<O��k��j�ZQ-�:1iAe=�  ]�zB�s�y��*� ���zC Nt�'j�af� .�\:a�v�/M-�� /����2�mNB�(VI6x_�S ,�y�O�α��7�0�l�9��x?t �$�B/�!O �V��H ��i5�KtoI�-��-Z&� B�A3( r�Eid&_��.� set-u|J~od��"�&�B �� � Long6�z�h0:�e����a�F:/i(�0O�A��* ompeB1� ���ui]�by��A{8Z�B�ac. ^�>��s,j܁aloÙ� ~up/�lefׄrne�W�613.� � res\�� !a�k(h�--^"a?�a\�5(�F�t-)�"�u�w.��� �ny#%�it����?<"5*� !m�{�����"4D%c7"x�(���zC6� ?. .���:� rnof* "� � 2�(w����0;�A��fa��7a-�m� o@TmeTZ�|A*I, f ¯s��y�[|4 α"K  0��"�F�4 U8y� )!�1�j, ���deh#N;A+�25;=:6d:B�N@A��1^�T� =��qi.�5ѿ�A^�e��.- Amb8&�Rα ·Jm9--d"�9+>· �9, (8e�>gR�%��6�2Z!� �to �:2%\e���!F-�a�α� �0��� a�v(�"aQ�i� Ba1R.>|� � j������^���EvR�1�j����N* ߿I0�b���-misU- � F# &�%�ҕ0 >�{5.NNm�1 I�r:���)/:���2�(!�bU)��pa�zk��!O � m(�s5 �? ntEU3 � FB1��06<�7*�;�� � t,� %%A�r�,ɛ#i?3э21�>� \7~& poor9!���jl^�L�)���R�vC%� ≪ �#ze � �&Sj lyT(sRN< P>N�5+�)c���\�"�]F~��(UM%�����A" �>E!�"� "�06���*"1�"� A�r�6n�:T�S��.�'2� ��0itself%�\#p� �],�. n� �f �� m�a?"Ynv�V * �CA���l r�x,y .�fl�wY��>?u�ED2��(:!w1�*� /�u�ly�i���%]0�8Bhe;FdAKg5in��"� F�a#'� AArov�=\X(��A ]A�7%���"N�G"�7No>:9; ��m���!}ly�pXB�ica:�!�l�+\ "��2VD2<��a�cΓs� fund����n<I�a!bea�w�ia�v�\\��Q�.- �tu��pt0">���m0%�e�!eҨ� � "�cfua E"q+6 �d��i&��VaFY��emsel� W��Z=Iva��,u�r�|J e�TA!�c%�!>7��iA��(e.�E I-�%����#t(A6 �����3a'V6F�B������TNMfo*�J #� ����4p � ���rU�ˆyo�>e�.�Ps& 'A�Mt3�� �'g:(�paA��Ed*��! B5F^�b6.Kp2���R�WA�A�,��� �B��\3�cF��"�=�A��!�?�mzBi�-���� .���� '�#E8I`�89�!�%�&�@�72�R�su��LB���3%{gv"� �n... O��3��J,ppIg�&efF�:�;��Md�Xϐyg ~� !<�N�C!�����#wo M"�3%%�Oim � �&^f* M�m� hamA�4pW%����C?e~!6%.J?��&|K$�%J�A �+]aI[BwhK��n rehe5�{A`of"))F�:�|�$DREAM init�F�oJ"�"��- J���w""2aJ�q��mz 5?�&e�� =$E�[5�B�0��R�DB@�* "3p!��(Inan un��5�!,lisA�*�5J᳑22 "XVu��aQn �#fr0da�za7,!�K!�;i�[�6ficTa�MM��+9!es(�&�12eaI�,o.o9*� �>� ��� su a�V<�7KA9N���coi��,evdrA�e��6i�5*�P ��;� �"L�}$-docu7�W�o����[5�5�(As Lovén e�/ ..|&d �1hU~�%7*iF!�v� FS�`��28ne� "� )��y�� &��N;&*�r[��a:ma{5&^%��&���,A�5��,�a����u��7��" "9��~~}��!� ����. &JD+�$m� � ��@?orol�12�&�� /&���Gϳ&�2 qr��E/Y;��A.�UC��>�� �#-!�&�#Q�� .�� ='�2 .� mSV�.Y��.� v� eV�d `][1>[18Ƣ5 , 59�Ur*�Gerosau�w&� ����W�ji�� �!�>�-L"8HI/i ���i��ioD�*[1��T���Fled��h"0�!AV��~_�+� �_�?3-��ofC=UF)���n�] �V��Z&��� k��n � F�%jH !]aё/8R�-"�2�G2�#"� is orthog��to&��yE: ��SM"" eni�j` )П!3b��=�4G62:=��/�Qetx�2rj*�D[i3}��Q�DN�� u%Y�xp� �x�� �����,�lQ0le5B����Matlab H ��2= VeX�v�2 )���6e,�����$�`����j� sui=��D��-r�nB��AR� �:�P6�.s"iVE�-x"�!�&Cfim3�@" %�nsx?�#�~ �4 :( w" "���?W�-vR:i(x��u8.�B��Q�F�٘�%)>t2P4"� �$� a:[C! cha�2erECat� ?ad�E%���!f��&a�x?5 �+�y�#a�ge���o�<"HJP����� to�qa:�?�I0r*�i��A�Ma.�rs��j�i:�3 ˡ�!7.#%ij F� ,0zo 'e@�2 Ia��? ��1�!�isij69��chS��gi�s-U�uy��:�lN�!�iEH�"�"*�E�x-3��W�)�:��M�����B Wava�~�9"*�Z�)�= *� �Ge�UuO���2� *!���[�t&G9�EF"tPaO6 0 �Sy�!&& b�"Z �*Y�rsol�$�"� ��IN �H"qnB�4=" -j��&y!auE!x��4 1�:�e�V:5}&i`�VY=u ��W��D�+��s"a�lj/We>}�"��.??S!H�f���*�7ch��d�N�!p�n�"\�&*�A �&�^�$.I.83$_�Ke)�M(mZ).� , a-N�eriori&�-IR7l �=� )�F=���0)"n�Al1r]�!�*Km9�Z 9 �~X]~ ;t �s�ic�R !�e �ze�a�C%RT�hap5���U6� Q�u�r�E :d: M#>a]�/���6͏&�$F�:@$sharp drop��2�"�b6M �}�-�a"!Q�5��wor�u��J1�NxeIaz�YB�n&��o V� eo* tG� ���,IR�rR1s�u�r$l-�j��O�=��IP ����"ed�u*�5a�h4A�l Z ��@6�P#���U2lrd�9)�a �T %9A ����t E�$]�-M0n w� i�#�atJ�+ @e�u;"@!)nz))eBXm�^r��� m�"m! � �n�G%�u�mq� �oU����p���:YQ<�Ba�a�,��urү�[dB��m B�ym ��E2A���rF?vM "�1"� N�,f J� �H��j/� m��;1��#��)[� 5%�*w;2%���]T�r��}!a��,��V�9=(�-��%E�!��"< u �oi�.��RJ)��_��an*y� !9A ��en�%:��:�aA@ngeh�&�cn*�_��?F)A�Z� )!��J�5���refS<i tN�xel{^Ub*T�m2i��X��JXEx�-�S6)�!oU � lete�Z , 60–6��ah �A��!P"m�E.8��"�Jisn3‹!��M"{ �- �Q�6���!�&(3���%Z�."*�1�� "� _ "�Bex� *H�u}���g��-w\b���m�$]_&r�i�exi�/8w6,%�yeS%[63!�2�.�-B�d�4ݛo"s]l- -l��=V+� ��-�"Y %��4T= >10 h B9�Ucen�;��lab\�o;*�2�M�ms�}��{PD?, i .%C(, μ ≫ γ�4I"�"��eZ�LDrrLelc�0of- J<regard��1���(�(ly-6)I='� . Tu�Jan ��pp���&| Q�8aQL= oo_=d�)�5��5 �N v�>=��m,cell doublin�Lg times well below 10 h . In conclusion , the applicability of our principled Hroach to account fo#�otein degradation and global effects in network reconstruct-dfrom reporter gene data go� yond�simplea��-understood biological system on which it was illustratedB,the specific�analysis"ident �6y f �by mea&� &��ulas:N=��,�J )N= d d t20+ ( γ r + μ r).1-V+ 4>m6��m < γr [min−1] ie2f� =�t5+!_�C!(�Nr�� 7"� �mB�Q�is defie<0s t1/2 = ln2/� <�6�is� res� ,in units RFU��F�2'-[ sNusual!�� kind�measure�sM�h ! 3E�. � asily est�$ �� J�,���dard rel�f5Aln1�/dt-+��equ0� ly� Fa�� mode�1�Fm5wg=,�expla%�in �tWe]4d cubic smootha�spline!5 csaps fun� i�)��fi� 2�!_}ݍOd�.5T�1 ,U�, d!,OdqI\B�GFP6� is 19 he�r =i 0006±s 0001 )U matue!�A?Q] o shor 4A~ ,n )0ity saf!�ign�. A�i^]�-�� � ��V�actA�%�of�es� enco�� aa.sN 6kp�� [RFU��=:��= � γ p����(, 0 ) = p 0��7��p�]���I. Notic|� e�%�F8,,d*Vi�des���.#��jA� secr� thro�!zcmembran0 WJ .N�ait;t k�3n6�by numer�int��/ tar�T� i% 6CpA�T� V ismd.�6 e�,�reali�M���l%s  egin[ -O*� �re( !Fs �A�e� �]n1�]..{p�c� ��sum���E���Mp[��eady-x,a��� �Eq . 7 SA�Q�( TE�E� �6p��� 8 ) �a"M�.C�e��|�(ime>iVHA�� >a? spone�2�A$Qq.!LeOe&�,[p}v��. U�9lHQJg�in��A��phase �5 �d%n8��sol�b�& quadNgE"�co-Lmoqty!re�tw; ��' A!l��dif�isE^r chema�Fir�\p�`vɨ FliA%T��!� able=2!�-cour��Ee& . D% exponGalQ3,AR� �A�sjm ed ,:� have͙�, dEo&���B  �aAio2�r�,q (is no longe) %�A�68� '�( 2 h�/3,gM [52 , 53]�Asgequ->���;�B%i�J'�:[�i���need Xak�o�pN s γ′p 6�;!F�. S!�abome!�>��a�!��notably*.v like�!�e5*yq/fA�,�,%��d B negligiAЭdfe few hA�L]�[2�J�A�2 ��nsa� ^6���idis!� uishei�ba6f.� a�AL%��;5i\to+0 �i��`-extrapo��obser��18V�t"A6 s towardst Ir 8�i"uWof�R}aD��N�o�?i��SuP��:��WT-u��� LB .o"� deri�quant���t, ? I]�b  conflca�\(.7±2�u. errorUj��l�� ��6–7]�alAB��e+W*V�U_!�X&.�M�WT-LB�de~�"��0viously validE�mocol [6eD�y<al,c�@ F�6I�� ��aIc642]A�#� tpat{A regulator�2te& A��6#& g eOpQz.��Zae ( �Fg .A ��A�faG, but�M%���& machy )!not o�te� ��=7ndni���a��geO�� hile . ���Z:U� one �Nb!an�� !+�A"� �);ɐ�N:�a `��ots nond� a4"v�cti�64 incrJ4re-(aAny such9�yU*� beS� terme�a�*, i .%�,�����gy perk��ak!value +1)E�, ���Q0IAMvdo�  aN"EJ]EmoE\"� side���ve�a.)!�mjsc% �1�6P��nd^.\au��v_m�%�^La"!i"�}��urA�ijQifM����in�istk�e�.�if6 vi��moE�ic��"er�Y�!��[ igY )[ic�ɘn�#modul�)�Mma=pR!��ĉu�!��!o��I;c rQ�r=any .v��S )1ea,EbhigheE-:�6{ �>�]Fsc er�8e algorithm mak��K$�� ��a� ev#i%�ay�retur ��N�a setA��.�A��V� ]x�IsA�^RhavE o Q*%U�!a�!� ́�ult �t]� u��e���邡� ( M�$�m�� )m� �.MnacyP&ehec> robustnO%�?1# �Ku*a )��Na no:l�dismi� beca��ȡ�le paių]�%!QA��.�hev!cal>��.��ɭ�I�"�5ENA��N- fZId, m�� t] � �?" Sx~, c )!2!� c��aX"of un�&paramete��x>(reg��Q���' |of6u�ia'in�1�3 �S� &h�%�A� ecut��s<"�#"&"e"a ei'�!E�0 fBfM� ��flg&�#vx = (1,/�� r+��o2�p apa�&nd��( Sp�$pMS[all�!�yk�k`a�θ , K%�a&�M - I6)of��N� �~ >@�MI�super' symbol !�d�+m�2J "!Ubds ∈ S = { Δ r p o S -M9�& c p x R.s g DJ LB , } . GEL2�![ ‾ !�� f2)! %( )��veragdv� v#�s t�T s aO��Zl f ¯�± ϵ�6Y A��2`rep\ Pεs��!tw�]$.� �O mean��e" c #a7-optimiz�A!+ů�)aϕ��&D mult9(rtn,searchU{ gs �"�](!(ɠ ior-point�> , fmS � lo�}�n �s�We tr�s���g�,2�q avail�mK � 5 �toolbox8 !%g*�B)tor �� besV�ROspW%C!H�b ��5*ts%q�"��'la�� 5�a��.J��  ����. How!&![��g�OB� y���t=Vrh!exclu� "BI�Ihof Q (Ţ|'&, � lN��is fix�or *d.�'e-&� �� ~fitAuz!> ��&��9�f$sh�' ����pe%�#* -post)ori"�-a�/"�!to en � �t�/uE�5a�,��-Cissue| s 0r&eX1b. Over�5N�lso9�ba��JEW�#!�vi�_ �&�"%,.wMHotspot! �9cha�erm��- play!.� j ��ro*� I0axaxm�&en)%�Y,� �zo7 ic1 h?-���"E��environm$� �Bii� r> e�b_ infl��. LISA6A 90 nod!id� builf"ras�)?g"oa ja�0 map/ area�ARsN0 09 km2yto�p)q:Cl43(�. 39 x�,6>�6UH�1ss��ZqH divi�h�/f��aa�-O year ied:�dry�sz6�2!m�months-A5�x�1)聈� (R .APIF5��(T��heter��eou�3;o J�pde���nd�e� dis� ��of><�Y+�icross�Gamong%�F�!a�I+ly%Yx lyW% o+!���2%s/%,� )I4re-establishedVwubPt.��2�ry-occu�m�. EH�f;three N�cly>�fur1 south\f�E1eE8 S��a�uor�(!�e�a�i. �=�s�mpA�d� rw6!300–-mm\b*]hui!?ɱunhabP.�4sharply demarc over�y��!�^�� �0-�4d�n͌I]evd!b��5�9�9.of�<ng aggreg��uu��ho�с��"T�P��shiftF2�{�)h(E{�mit�$ ��si�!18! %��a; ��`associ%Q�I��7,�@1an�%pa�ic� �at U�Dagr}$� � �!a� �.�&S ��up ]n��ngL t�?�dj(of syn ��}m�)human2��=v!aS, poss�c"�I"�=JD��$. Outbreak�"� � � �yd�:� aq�often))`littl�5r!a�e spillE�E�5/.Q1�&;t�B�;u��q �ag)K chanpin-6� "Va�� examb<$, Tucker e��(G2 ) ��n:Qᴁ�:�histo (o.z$Ebola viru%twe n Af,�41994–1996 [147&Odespi�esu.Dh s�5�4s-���=)$la�ly1�isZ � e3ss�3dic NrEY"� &� .��u!� �� ship� siz�w conn�^F�ps��X 2V"5 E .���. .:Glass>+K�>�mn� lsm�orŭ��.di� s!�-��Q Uni�Sc9� "ztl�͢!m�b��e% ce po��ic�, �$Sin NombreM�[2AdSV Rs�3l�� j< ��r� ɐ��5�2u� ep�'�fa�d ew �� sm!8B�a pl#eqb 1�!�Ła:�ٌsas hantai�. R� -bornei4]�Y� �  8>oR�I�,  phic����EA�ApY�5 %R nce;�seՆ�&j�/%�5#��:"��*<4!W� d mi����1�+ � �)����� { �in>}�K��9plR;a2�& �m%��( �e�cyc�q9G �es [3A�P� E��h�{����|QA����North"�=d� ��a���D%^sEhn emerg!� [4 , 5�Si7��-�of HPS!�1993 ,�h)Wh�- or��e�-�6�. W#qtgeU��>x65at_BstiSi� ll�B��%�ECE1��l-J %�� poor�,nticip� . S*alF/!�� d jR��-<�sub=!A exti�2A��e�� ppea�����!J —oIbe� ab� [6 , �%Al�Bit!� � �,�e"&�!���"�s��,mSe��U2~�"�Q�"�7}& ~$&m�+��>rarely�V�. C� �` , 17uu!-%p�& pulm@,1�� .cqi�A , 8A�On�1�!�Choclo)��hi> b��Żin� 0 [9IIn& OlV��ZhA��!I��8(1eBS�e�� �< prim /�$ � �#-We.(B!y���- � "u�;-�eco�F� 6 �WeR� �/aal &" Zi"�%T&�$ ecip�I) [!�R peo ��is�aOa� l [4-�!cAzuer�ninsul�preval�`���IgG!nibo�Cin>�Kr$  b]18�29%��&X"y-�O2B’ h�- X��D�W�.A�w�]*o� la� a�!_�1CI!�J2of>4�G)b� ue3. H�:��inA��" ,A�sek� ![� }eG�&`Fk d�# upl�BS�eco�I}s�bd�, . ��&��&1 #'g! G�7�Fao�C�v@,e r�^_(��i&�ltC�Jy ( Fig P8.>i&*� �Hcoast!.B�of�%NP�ria�of 128�5� [12]ly floo��K*�un�s separ]+!���ex  � B�. L �:' 94 MASL (B�#b�Bsea leveYB%!L*��OA&�9�*�1F xima��5%�@ . 0� �:�L e 2010 c��� �2oof><$as 9787 in� �,{��*�98!�@�&���/..� �( 97362`)}��� �� ��-� ’s�o�)is me �Lr� �e�. B�� 3500e�$5000 hectaA�+� �B�>`!v� m=lA�f + s [1r O� &c 9rs� &HKe� mG� cor�~s� typ� veget/! �|cro�<or��;+g . melvNw M a�Bq%�P%om� �,m . Grass-fC6G�'40"OEeOAǁҥ�i�%�ex�:  inea�G r ne�st�+>!7�I'F�$ ) fa� g`���! �&�su�sBcq� Janu�!JM%#��:��May5 NovBM�"lJj)�"�+%@"� :[1��] % annu�2v!�eHAq12 Io��@1551±1199 mm ( D��t�\5 �FT(eolog%�  $A mark-rec�b:�e�8M���of.�`)o֏. Six��pp�Zgr�L��&�(��"peAL �u6�6��.� Sherg�42 rLced ( 3x1)5x9 h ,-HB IncTallahX� FL $I adRx�ia\�10�*Q� �/ I =�:se^�� >I*�K� �~A�n��O� � >d�,�_d�� 7A�a�,v �Neda���ed�m30!�e=10�200 cm!�he�:�'nd� at�Gs��da�[Qs �GtlU 30 m�.E�} 6&Ha:�<��(�.*�nd�.- ompoYeaneR�u6�Fh� '! 07nv!s�Ipra� �,� !%8arvesr agro�;il'f|0l�#)p&s2�L��field buca�Var8��:� �,�*� ]�2��x+rG ��s�aqo"Ins . Tr2��u ��"nimum2�LMa max of�u-.�Al1M.9jgeoe u|G�(P-��S U( GPS )�eiv�JG�y 60CSx ) &!�4WGS 84 / UTM z�317NiU)�th� $" V)A o��) ���. D�Uc*"� bega!��_200�!en!�in&� 2009.p��&o$ �sly@!�'or� na�K#�Cf~!anesthet'Ae�?�ca�a�bb I e�9 draw*�Rrc retro-or+l0u�*aMtub�)� !�ha1 in[1"x d�of x%�-3� fil�pQ3( What��3 MM CHR�w numb�/�!tag)4la���'/s ( Ne� al Ba(Tag Co �7New� , KentuckxU�" Morp� tric��1(uWt&Z&A8 ge!fL �vidual�T!0taxonomic keyfig�K [16]A >H#ARAvi!-�; shee�Xmat�yI�m���"��-�rel 'd� �'P�s [�W�Wl�z L��+�(s D!st#.."�@w%!e� �@�Z(�tR aZZO_$"�2inu�"i=( r:k$"�)�+cba(s�J!L*!F�by!��!;Psurfac��Jc�dinver�M�-nce w�8Q( IDW �7]2 In wo�=Qw A �� 7�ac"hi aT��%|' ��Jw<� Oh@�)].�B-I�>� eq@jI-fD1fW%f� )e9a;."Ol  SmAi&201UKa,9*�rpo�$�Q.��m,re^ a!g��I,Ax�5so�Y!�336�d!de)o"E heV ' ( 2637 x 338F�&�m5"'!Xe ��4&%'3v3''694 . 1E. "�A�0xa� AAs�"��M0s &aZl*#e�6Lm�9�-isapu'�(c�Ku( �"��-�L*$! �!]$"C!���&� !I�toy���d!�ndY,!}��$( clu!�.�9 )*s&,��c�U.���N)[18�-T�� ��2��[ a���&d�(��V]+�'!�na�borL,"9!�q� /�� =s a69of Ht�I[262��XR�*�EU�)e��?yѥs.�cal�I��(Moran's I , � f�>+!�ql I�)B�AaU(b+ �� ay�u�YX�| 3S[ Gl A�$C�.Use Com�&��!�,Gorgas Memor�(C�Health"LT( # 001/05 CIUCAL/ICGEU]July 2005 ) ;-Uccri�0a�5��."In�A%�al Gui�/Princip��� BioxKeRe`4In@(�S ��7velopi�y�ci`Q6hO�^�5e�Med_S�<��CIOMIV ��9��" ccor�0�Law NR 23A��15�7 ( � Welf!�A�'a�Repúb�6 de�á . S� NO �*no>fV � d unt�XheB6 M2,ŴaC+E,d�I#�)few#I an 3��6m� 2��Ag� �MD*�.o~�iC they:`�i[2aa�VN200�V�e.�-.>%���KOal�=Ga,r(Ceak���8 bCb���� b��:t">�%e�1)re �X�%�CA�!�.+:�,>�dec�RKt�9�F�%�.�.�9��*�#�;-x>me>�.��%�L"� {:���!G�����M3��asr�_1by����-,rdlese�cl�ic!#�/(.',6A���L"c<m�`��by�'/�v*J 6(�t lag�6 m"�-)^3a–3kxAt0 lD�La�g,9rs tyjCunc|."I^�9 *w3� &� ��A�n��"ap-A� ��Q�d�-�:�A�r%.8E�J A&wN�r�+&� /up�iqi)b4�2� re"O#���� ��022A6�_y�g 2008�U�omplgwid�"arib`Z �-. B�n2�,; Mm8�$�I�lo�� left/Kdr�(2"\ En-�!nMA!�;$;iup$�$ orig1Q a�u=�] �e�&�Qw19�. . &�EW-a�E���)�.O2� ����a�duϡ����d�ly:�4<vE}is)�� .\%!b&�in�)��r"�#.��E"Y(-" (qu challe;1>� �4l-�: (��K�'� >*"$atY�ss%�g&�'ex"�1�~�.�!AHq-n08)I�_' ��L���F pr�t�X�1�4�"�RAh�5A��Ii�1yM�9�m:/.�flu�X�Mm�E a#5}I:� � �. N�4yF�e  #"� *`����)8�.�:Z5�&seS9o �*�� be:O �A�e� �;�^9PN�"ai&07pro!E"Tt��%�[ ;f&# �Y 6�t`g�=��#I�5�_,�0��E1�GE2���HK" )s��-;5Y$�Q�Y  a&�&N�6O 6"�  �� 9�.24B`liwb- kte�2�9�of/m��B?of�ilF 3 �' know!o��emOɶs��r: rked6�,�! day ��r7 mpacg(s [23–�b&c2sN�'�E6�'trodh�b �v 6<'b�Z)�%� �A��&�5a�j[2XE2c*N repod�+�:�Ab�' �+2-0� " iYF y �..� sugg%< A�] �\, I��lonv �5Vw$of.7�%�iA/&� ��:alt-�un�bAG�g ^#.�2� � N+-[:���I�9.� I"A&� &�� $��6<� a�X*�* ��'[ �?��e&G%� �=�[�#Y��W_�Wm�Y �apH!�&n� mid-E %U !�B�"�;�:��s�"L(�v ȩ��o"= G>� n�0i4�ane� !�a=g&�:!a��!an�c{r�SD o2�9�. S+J U�.��/j3a.�;A):.:ugh�)�^ R�ksA�� u�["r m,9!F)m�$is��eo%�5�AQ�RN+W�e�Dsig�08;14 B�t�\s|�-SGI-i��&wda7{"�k%>s�5iAsO" �>��P� Y��U-�/N�LZd#A�,q��XW1aj�AJ �lB:� �Y!��as�^e�@nt.�U !�2�� L �tN82] I�!H–��̥[f�EcAo.p"�Z&�EA��  Qr/2� e+�,�6N �P� ! Q<%�l"'%A�}��$!� }�g e�* �$:!m&|N"�� :���'-!DF �)Z��)Q>C�6�)�I�Pa9.  �%�V�( < 1k+Yx*vs �O�b��Q�g r ha�gac�!J)Y!�uB.@E� L�?�SA�9[0�:�-)n�@w-��9QU_s$�ly!?� !xr*y>,ay ���X�L��s vAWrapid 9aC?~<>�+ �&|p�n� �X ar�j)��T�aEgraA9recs�y��&U9Sa"?U,( “good”�$�3<_"+8!Dk�F/"#� sudde�;�� �e7ofW "f0T? ‘�-o$ y� 2 . Ou1H6>n!wo�9�g`AO�� � p��K���"�=�5ou �"��/_25.�A a.� $�2� j�\7GthUend�� �-�.\.:r�"1���2,�n_l&`3.B�<��/&a�"��"JI)�-o�8GZs�>. Dh?m*�7eN� "�C��bAal-����gg���6 7}w!�aa!Fu� �A�sh)"cl� de�a�wa�6� ѳ!�A�o�� cues��"r"�K�o� l UX87s .߈A"in�aA��y��a�M* a�.,nism's pheno�� (B - ) neu9(4‘hitchhikersa7� 79da) � ��.w$P ��k�M elevX - �i %!biotechn+.�-O �Vr""*�Mza�8 � gn-(Im"}*�:Q{�qa��{'�^a �Ovad�W e-ex��ng%j iK"c|5t�eI�,�aљ� vacc�m.s h�9dev�a� !@r�H‘�t�,!{$jmajor��(�%�`ke�Xgg�#ni�}Ii]6N%�t-�%�as D t { �kch%f� �_ #!-reET<f�! �a! �min��id5���%�iqu%yd�gP� l�"� �%accurac!10 cart���HA�1���j*;��Ano(5��,J�wx%n �� HN088Pza YoH3N2 )!��;eu 1968!I200�/� 9 @Z�beie�AE+po�V�Y�!�E.�gm�–"� o�C�oU ��$[wi�J� 9�. IB��.GA�∼J-,�o death�T� ���R��"�r)om�h�!kEBe:#77a�0!eps �[�D.L>,5i1pandem;�A�C5100�ha�P�� mill� �world&�C–;!�w�c�D]|�M��S�)M! , B , C�ll)��8Orthomyxovirida�Bmi�1iA��8s�, gle-=V�-,&� se� RNA�GY�!�BA�1aO &~)!� ccum�QeNM�abody-bg&ng�dpitop &iQ[ � U ���)v6n h<��U���% .Ki�6&�6�&r�a���!0aepredoX;n$JA8t9�epiM%�G���Ő�X6s [5]�r�,y9vA aM�:�`�E��&�+A!�o�1)1ir"�+=36�( H H�P!� neur��id&T( NNA ii,*  � H1N1L���c"�@cir"E&[7���T"�(Jg"S  migr-M�Ƀ��tT�E��reE��U�. Russ�+(ed East–S�N4 AsiaUX ~ �&z ,i�ie"� YA�"�v1 �see1[�}9x A�rDs China!��/,�ht�CA�8too�~9'��!�"kE"�9t;!�-:��ouv�^��6�G&#� -"� �A,@�,� �cw�u���IRW�2�'.�&"1HOu!�usurveille�camQkf$�ki |յ]md��a\}4I|inhib�aBI�*ssaB1ImM6��"��hntiserum!S He� b� d12�sby�a.�=>. A"� .��*( d�}u ca5�Kg-nor V�d HI t�(I�dRl"0A��<A t %w-.Y"�8�%�& – )L�'�<IⅩ�(��})�:ap;�E�,���T+&)7,���;>�=wo��� M�z*� A���) A.�P/0�|Mpml���\Q �a clos�KY8^�^ �si�2 revea� �6:s���J 3�,a��;AKR�(�re�"E�succes�k��Wy��ari7V�.U!Mge�m�zUO �� -6 �b-"���eA�depen���%[o"A��M �R >�.��z�(�PA�epp1szR�V�' ��q8"��>�`r�I�oC �b1~-f6*E/i It�>4T A5:� m�g��p�Ein�9ig�!M�b�RsNO� d!gm�n al�g,&�&�E�e�I�! \p&-g� %�!5: .Z �-�!�6�/3iQdirec���9�!�6qY�� 1]W eMVs �lye^�i�aSOL݂a�" requM3�� cost-AknsD)0@&@A�&_�u[�iwO� I�en&�+�_��,=J.?��^%9�5�c� b֊aR �Ums !@� h-�Pe<&�e������g9� sC�z^2 !�� .�B"�">>*C �Dast-squa�2d ( LSpp��!&a���j��n�"nY�~:�e��f<&�Ofm��| . It�O�7*ulM�!d���9<;re.7e-g��%?es*�5}wR���.&���im~�!�App��HA�X�fr"��a�h�>2 (�  !�N1P�PeR�A��-vt!YB'�5 C>. &}q1ed� 9e� ��%}F�!Y'5*!F�Vsu*ls*Od ��c5�R���"�8-vf�8eQ]�mEUo��s �Ɍ�!!�i" y�b�4� . &� � " CJx�y4|i"~( ≥1 MHct`�@z 2�exL�MeFi�< & Me�52. Exf# a|IesoOq)��eeR�or�+Q��{�X� ng#:zBo�,.(nin*1)6ng%2�( T�#�J!yQ�)E. Abbrev���#,( HK68 , EN7�{ VI75%YX7A2SI8BE8JOBE9#WU9# SY97qFU>Y�u�(̅n:Q:dYK.ɀ<R�.�Cdc!�Q��&.m�:�� Q[F�F�d ��u�,�]����.s =��hH$Ix ct enough�war�4a"�@! 5"�2W�us�\Ja�(��ofZ�8.�~7��^ng5?�l���4S�. ��2cho�P��w���� quiv�U�"i��qb'5�3:�m@.Fe�A�9�i�$�.6"� �>�s}��qu�Dy�e�wot$[:J����s6PoK`Z�tas�#r�*�:���&�.� � j�r�;dL f��!�]���Vn�Kee�%�Z~La�:�n��� &u)~-9 A/N%u# /938� 2!����in> \@52P!�Wd receezxby�&K . IS ��-� �X���D–� �9�G lyAL,#�y��0�]�of N145K.3 ,6+6HE2� ���i� �Z�!| a >��0�6on�y�kF� �/It �al��y�N �6�e�-�s.}b�-�%eA�-��e vic]�Q�p,��f"RBag.F ��i� )\ B�W-� �!�e0�g��a�D!ש�dis^���A7a')�is� �  (���Y�eg�4&!> ��/of �K!�< �2F��� s�Jverage*� � ��,�E�0�>�1�>�  ��yCEwat-Ic6=�Mc!^)JUA�teːingY  XvS�vc/��"}3a�?'A�iSup�*� r N">�� @s u��"��9����5n Љ��D i�M9�OA&�)!)�!f!g ) /�4??�5%�GVm��E�56�Tra(��%C�* ra�.T�Ast �t�v�OXK�qr op�� a�:/�–�� � j6�-&$ !- ��� . 8�2r�r�����t�]!sJ� �B� -���7a�iv" s pu!o�2 [30� [3GA� &FU�V!��` q�*�K�,a�2 derl-M 4 ����e�� 7 |�-Q�Uf -: ��"� ���J�<.{ .�yt4�|e/b�m]�/�e{fe2!*+')��c4terpre�>�U�!j�:�A�q%5��h(�O%�!� phyl�a� W)e��B3M�X9pZ"F1u-E� sole-p?v�N=�Pa 1� ) k-�, Q��Hac�RInE�se�60@ �9� .v!YN�ND# �in8��I�` &�"!.��s Zn8!��V�b L&S �} �(�26�jy(oeJlup/��-!"�� )_%e�=i��� e�a a�$s5 P:�.�!�o9���1�!!�6�d��6� 2P .�.:)Z �&~o�5FPX3'o��HK��dK.�� H�� g�N!@A�A��]�2T n−1�Aס�I!�4gn� ��^ٺ� � zfPap\N( ;��� "�A ,] *Y� �Ub ��6?(�–^–�E2–i>A'6"�- l��a~�QTt=�����!5�= N��) e 12:� ��9� �"_� Εn"� ��&#��%"�8Yg� � G ?,S145N , Q189� I217VPI278S� e�� O� �L� � �on�)f ��\�'x y^. ^ !�.��.�92!�2z�bG6Aj8HU�MA�.� aFIR�%�j.�f̂.a�6o* %&e����K-�IR�fUɛA 4Tň� ���{M� �}qm�N�I2p3 �tc� io�2lO'l7�NT7A#�2� ��own�U 3�K�-!�h�#uo>�%,�,9!�(�s  �b,* nois�o0 cty,a�t j ��u\m zJn*&%)�7� !V� �9h)�� tW* D_V%p�F�<lG�D&�% .i�� ng:��bVs��ed� �,�#HI65�wo��( A/H�LKong/34�d^"�걌�h�^6 -�1vDyCA].Io #z &J,��1=s labe� By:4~aB���(2pr (W���G�)�&�!��)N.^��toR;vX2i��7=E����ur-Nq��?2�6,%(��vb.�)�4;o2!��r:�9�0 G135E!)T �u��. *�0s��� .N=P��>}�6!��;ay0�\atlDT4I<.;mv I8$ �o �A�9X�s K135T� N262S�$�n� b1�j>�n�h Z� ��K��� �i=_oݸ�Q?�"� &:,ii$"�a�s�&[�����wR Z<�a��%vs1"�� W{��JJ OstU�9�2r( i�$�#�KA/�=Ma&�a}E ( iJ8) ?��]�u�! ,PF}�n9��@!��� NM�?6,a-!(� d �=a��p� )�A��or.� )� !��� 95p . Mis� O,"�J �A �"*�Id�� n"3�rasa��� �B �R!/r!��d&�"]0G`�.9I , 11E'13Y'14�#2���20��satis�aX"%/q�S�S� ��ex�%pm�1parED��]9:��A1�."Whs�5�!d 156Q�.V�p×.Q [3Ip�hs��89�@F*i9& ?,; ll6g�q��d+'O2� �.\-Z��H15iQ156H%��" �QF�(O [3�0B9�.��!',� $q).����Gix &E"�`iTa��)J*�/kF��� O �"� �b. C͋��1E#�_�4aO�}a"�1�� \�5%�Ё)[m��-�y�d'yB�( a�Xb� p�mbi�C�BY. Nv"a�.�LOt2��-"�%�]:06�܉g�p-F�k1�����u��*."^ing S��Jߒa_a�LF�X�:oߢXF� E.�6( K62E , , L226QE� T248�8%&.%�J(# . N�0.�2G�er�"o�FSM&.)����WU9!^.{aZh�-�"�� wo"�M�FjY�)� A�2j),e�n� "�19����m";�T� P� Lv�*�h��I�?"�*� � &B�C 6Yg�7rseM� 226Ltʮ@�A�5�F�p� �Y adap�!& bird�ZBheo1'F [35�53� V112�d> �� �KnIAO��sj� �F��oru�3JnM�(p�J�B>3 �*E $ � ߕH2k &}5.hݰ(> �yE156Ke�Q5 ��FSS��int���cg�K���*)�y���R� im; #zobuy,���$ m�d)��l! ex�=�δ( Q80K�yQs Vb( S186A�S199PEr V226�ur=v)d.�R��.� ��G6s:G+Y �A138TE&I*hh �A�����N�Wr��a�yx&Ii�Ia�i��_ )* H��f �m. C8Bi1�� ���m�>�"w:*�s:JlsoA�m'yA o!\.�" �%PB �Implɱ�a -s!J� .�­csB��5�Cl � )5 . Ofs 1,m�E�!�� /�p� 4����qq�s�im2'&'t��ـ)�ÀL �"�� .��^F5%�� r��(��,M��, iA�q� ��GditeW����'bM� ,;y�A<�>�����������y-R}N1���J�e�&�>F(i*�� =��Y_c�"��A��4he 35�@� 4G(O�,b+d hhe�6IgAI �eUV defa# %.hBf `F� <&�ёD��sls"(u9�&މ|!p� ��a+)��1^�R�B�g���,LS159Y�6W.�l�Ql�}f=�11c3Cs��Bu�&�>is�2�-c�Q�O�>�_t�#2"��a��-y parsimony�Supzu��T�r��?'�!S& �XsrA�by6{d#��εo�1�a!��x/^�"t�>10.io7�jh(4et�$.6qE)e(CQv9�e"P:6+KH! nsus�� BA�%&���! U<"�#1F��E:!hmE��i`�eLCAZ���cI�>75-�g�+ � A�&� 6*!��24&�Z�Ac��l���b?�Q�.�,noA%�A�.I*7�y�v� w�PT.>�?t�Ri�Pf;M)c 6�R�q�b>-��!�18 �(ja.�CopW?ya��@1�&��@�Pe�A��U*a!�%� l(ate-of-the-� �!�beG<:F}�h v�,�/A�Os-13%__0�8���:M�9��δ(?ve-one-t!bm(%�w+:� 8�� 8)d 1����>�ly;m�(� �� Qa�a*Pearson'�r�Q co&2TN �6Ill�)q�*P Vo!�IE.�)}�Q�452@r���>hR1y�IECJ�[40];�s8E�V]Yor Bayes~.����@��Qo[4�9J�A  Far�Hj{%�B|a��.��}�?&�!%r"c�!Qw} :�* a'O�accele�_�"�[H�&x �W� ��FI2�9k:w.l.we di3��Eitm'�I^��M�Z"�QbV���ŧch�bN{�AHx..sMq�MZhoX�DW\@ud� E��2Z N�[,1.�U%BM���*�0��,a�Q �&d 3� tif$��n*D�*y�m"�to �C1J�Rd]�"��I� $/� �B5_&�8��a �xdom��I(Er�f:Ts"�0%G:� �..>�J*���^�:Z�@ � C6&A�%X!�eg !}:�9 6o1F/k&&� ��jl�Y�q4a]�(&_.�M�{a��:�� vhؤ���5�� R ZN� ��"��"��"?�!N�Q.E�=�,A����u��r!� !D���9�Iv*c� ��P6m��1 i��� 6� � ��� Aq[ ��/>2V�s�Gr�t^  >� A�(#F�@\�A�A�F� %�A�.�VT &>��A'e���sQ�x)9�v&� "dkh�^ɨ� u�!;� 695��+&>��*�M�tIAȩ)��w �eA|GjR�"!��bŇB�3a�g$�� prec�[dec�ʍ>�3�S4k� �3�)%�e2un�~�?���h!��?!��8�n=C:P&���v�b"�19h!KH& 1q&�a��r�j!>�+>��\��7�d| $>)un�l "S�-f&�%�KMQ�"�5� �6� , 19"ِ.I~V[ */fT or� aeeF �x!}�)>�(�F���37Fy2�E?Mxa��Q.�'a'2X^���*"sOGi�']J&�ye��"��2taxZ;WP*�z�useful��E�! 2���V[ .|�L �3ofu.�i �"1Okr&W7�$i� &�:Q6 Y"�1����K�V�yY�U=n�EZ>��bED� nu�b2�!A3xW �D�i�=ם�j 23[4]$H"��= -G�>riI�%���s5"% I�� "Y.i*i�y/�a�P��A�+� y&B���<�!r�veҥ�tX���d��e Q�����V softw+ "��upo���D{ � auth��K�r�a6!�# #(vSy˚0avalli-SforzaEJEd�2 [44]E 2�; �"-�p��!�M��B�}�Mw!�6��Q�_!e,yc)"RqA~� �!©e"� "�<�1�QJsvorJ( �6M�'on%&C"�� Uv6xa����9��� s�94&I/�!:&9���kf>fR�e:&�N�a 35-�*��ЋAE�;XC/&�5:�99��%HI��ay� %,hBT�!sHH�*/!�! 6�6*/. R*�o##4Jf�"�' �]� w� �B�,9�Y�Dz��"T)2�*a=� u#EC"%-�,.Xr���5stiě1C^�j&\T�$-S\e�2�[2�P�wW�! gi�YD�O&#d:�ZW!;� �J��0 t�2����� eIF�) �6Rti , j��\s � )N �I �n�leaf i� j��� x ` , k M Ied _k�oV\�O ^j� �2uea,z��� �X�$?8wy���hKst� �Si�)ns vS����g�A9���u�ly� A�pb�,)x�%D+YjFEۍ�--�e�K�ob%:�?'yve ��� iu�.Lawso�`Han�^a"�!x�rE�[4�BeZJrN�%�!asymmb��$.�IVdj,'�%�4�.!� Q%� y7�.9F)s�y$ q �\ne�_arha1a�.) oM C`� %t&13OEw�TH�(VtpP$up–�/Eb� I� 6,2��Em�"��leE��%��6�/ � *,�=)�dspry1�Aj t�9n,`~vQ9,G�+a"S�]0#XvQ2�KE :uehB oH|�m�eF�3�Z � iA�|4���a�y/ ( LCyV% �A1�NPjP8. Now �2�!<ge~L)J�FJd��*�J��Rt�tQ<=Qb>2�"L)To"�!�ij�:B� s-�l-}%��g b*.}V7=�!�*�C�a1&-s:8n "2R ( MAE�'roo��an��d"RMS #� ��d�Y\(D��( Cl�veJ"�B�a"%�i�%�!] "� � �N^!�t��a]&' �4X�J���"�>� }� asE���I"a~&[&��\� 6+���zu���?�BF�*��s D�! ��cR)�R`� �4�zs:*:i� ��1 �3�;oy �d6�z �>��jJ�>�b'�J�#~O� 9�%. UUXs!= k�S2�1� "?�Xxa��)t�*A+m" �*>u]a��?p�&�X.�y `zouQu bE� 'F�A* � ��)�|_g*[ *}�-B�. Ld'Ngo!�up%�"�:G��B���}��&hom�JO\^% YL١X�ֽ�2�~�J�����.:Y R!���<�)�6':N! �c�&�����J7ge�| �5a9rv�R`: l6�Q]A��2� d"��#��iN�&�7^� �?��8Xn�En�!)�?I�)iwo �o� e\ Nsur�e�Kyd���"� `tipm,T %�wo��� |�Abehav �J}�X ~�w\�[ �&�\rgI� 7iP�"�� am����.ZK)KGc �:sN� j�C2�:A�F:�/,.�����a��!� p(�5��ambigu��&�(R�8` >"n7e�=ic,6g�#� wslea�t7 !&�<�����,.E1�n�*�JAi- ����&p� ���6�c�*&childn��9�Ir�l>O"%�I��Wa&N tom-�Nr]C��i��r0� behi^!a�a�N?ifE d?�f*~]Ae�I}sN$�+ra�EUO�,fejH�+!t�� 1�4^�,A&�� su MOm�pi� @t&��258K5vwF�(*�gu�BDN��a�w"�~"]�91363�  #�  :Z ����5{%�8&��p <�%t-�Muscl��7�Dm5�o�qdA�);"� � PhyML v�U0 [48]�q���w/+ �8,al GTR+I+Γ47l�MJAf�le����achA@""lł�ro�IJ �nK,nt� ( B5Ie GammaŃrib"Aq�-!\A��K��� �"�3+5�!G�*�?%�sJ�oW:AE�tQ+��o"� ��^�Nt%�sl�or�{ {g�0! &.Garli v�)96b8 [4�7,]4A/duck/33/1980�e5�St�C���� $6� ���he"�8"V��%хJ'��%6))F@�h6�H}r1( !�0!�s �?�7e�CU5�"�Z%�}ste�Y%��XB�-�I9""nucleoth�)@�f. A�"GX���h*L)�'WX�(maximum lik��elihood criterion using PAML v4 . 5 [50] under the JTT+Γ4+F model [51] , with the frequency of each amino acid and the Gamma distributy`of among-site rate variat, ` four �categories ( Γ4 ) , estimated from the data . Based on$reconstruc+,ancestral se�es fo �Xinternal nodes and leaf/, a�\changes were assigned to{pindividual tree branches . HI.ay ��HSmith et al . ( 200�was u��@normalized accord!� n�se researchers' methods [5] . For-�ntigen i�$ntiserum j^!� correspon[ HI tA, h0j ,$!�!I�s�s d!d = log2 ( max ( hj ) / A!�wh!-isW0maximum entry%�.�. T-�r�comprises 4 , 215 measured values between 273Hgen)�(79 referenc!�rA2As no!zl Ain1�(vailable in�IVR , 186SBRcouldSbe mappI a geneticUO%xE=exclud.�analysiA/ Addia ally%�reshol�8( e . g . <10 ,EzcatE4he lower bound�U�-%#at�Zst twi!�s highM@B2�,llA��n . Toq8L undersampled groupsA�ll0lea��to sub!�s�j!3Lhuman papillomavirusE@ 16 ( HPV16 ) infA7onE��1ofA�id�h!� impl��9 cluster' mito����i�reveal($previously%^termi��me��ism��importM�ki?DNA ( v�m`nucleu��In)�pha�!!��5xndocytoa�, rou� I periMarAPa!�nd unco�, but ��fai�toay �e� NJ� Upon (ar envelopenfor��a�'.�)�9�occʼn. D)�!e���>�and L2oci�w��Ychrom�� � meta vpA�D��,�; propamta� �MPsF�breaka�Qk� acca���.'oplasmazhp ults4ntu� E��Bgen_ �wbyme�{inv� g)[A��|5JA*hlisE`A( funcɤ �d� �> will�� oreover ,!'vid�Presource�futur��us-9�%�am stud�`. P2�a5��m�i, nonQ7deQ�%�Hcause mostly benign�rions [1� Se��lV�e� )�sA���ow3 8tiological agen��no�}tal�zceraiand tum�w-�hea� neck �A� !�m ,1]��Åalentm~!� best-, d [2�-^[3�A}spher%Vd0particles havI icosahed6( T 7 ) � itecE],%ua diam�Jw 50–55 nqQcapsid form472 homo-pentam!� �major� ubalA�te�L1 p cont!d��aD , 12–72 copA�OinbO 2 [418kBE�genome�circul��$nd double-@ n� �ini� y�EUs� � as� teme�s�transiena/��ify���Dsquamous epitheliaM�Re����assembly�newu���!A�,� � � s dif4 t���A�in~b gran%ke�*n��eu�iAm auth��c�:X icul� be!�pag� in suffic!/ unt mpurit �K�w��Lis known about early�e��& A�H�hU � lear����-aK]�( VLPsA� nd pseudo(�Ps��� se surro�?e9!qprI�� osi9�rcy8M�9=���do� carryQ�?I�� , [6A� Inst����mY � 4��Mdelive� toMs, expres� a re�er�m , [7sB�ng�%-!+yof�sTtissue !��~I�depends��heparaAlf�[%/oglycan� 8HSPG ) [8]–[1�@Highly s 3a�me�-FHS in�fir�Xs�C�!on�x���incom�vi<[12 z� nextA���� 0cyclophilin B��8 peptidylprolyls mer [15]!F 16]:��N-x ��5[L2 burif ith ��?ex d s�at it�Ya`cleav �f�  [�,x7 8!��alaBA��tA� hO !�a loss!daff��y!�R ��fera s� dary�eptor!��4 -920o $as alpha6-�gr��,annexin A2 h�Xotetr�( , wthb o�UA��-�.�Af�znz[36Al�moves�le"�RL2��&�and ev�A�locs%� ND10 ) ar d�^[3m�4"m)bisF�� r�Iv. Otte�ڡI516Y* prog��<���we|o �[3����iE�un�r ��I��fluq������ �nt�tud� we��a: rge-scale !werS ce (i ) sA�i�pV+!�pro�ga��� �. S� P� emerg�s� ful toooz� thogen �k"A [40��B�c" � follow-up�� 2g�G;at sup�Nes�16 v� !1ncoz a cruc�<rol�1�i�16Uk)�. MitmwasMO, s� E�ar AZA�:e&�ԕ�* <� ( NE ) meabil�fac � byF4&}>B )", ja!M%��áW��B4e�"F*5al�^= T*�A�u�f�a� ^a16-l,!�pem�n� o�h �7 m�&,I�in �e�l�� (eLa ) ( Fig�1A%3�&T,\ �u0ŭ|ai� a6� enco he g�fluoresc��G( GFP )�E'Rr����megal�  ( CM� zpromo���16- N. ED -�1�m��!�qu�of-in���2� had �su�fu��2� 4��,��6���K��E�u3 � criba ��dI� numbWAR� %4 on�GFP-e-ng )%�@ a367 ' �hauQ[$microscopyYS1Ew �ica��:� keptK �.10%-� �in5� well��v~T��1���T-�y�Nes�Md�2��al�"�c a ha� C,2 xM��Ni6 :iied � when� le. M&-a%Pn�siR� 5 nM�we aia�$to minimiz�f-t�� t ef�)�*nYfalse-5C���i�I�^fur� e�a I�Y  ut� ipelq��a�a� imag�[4� m�D�superv machPA�E� applyt�B� )sA�,ը, apopɓ� echnY  phenot,1�A��k��wo�M non-�, lapp�%�s"Y eachEA �%Fi�rim� l �S'�A�? eco���e BV7 , 000��gea s!�A�&��nhibiA��) !�F�d3Hg� �� libr� , Qi�� ���'�mp a�-� !k�� anno�ǁos-sgofue!�M�� �h� &')^man��yi�re�a:raadily &z!!(=t���Br� A<��)�tiJ, l�,e���pof 315 �2a � PMrep� i i�d� e��g�aby&�03 robust z-sc�{<%�S�ll��o��vf�1��� ��.� ,�= of���"f"re�is=}0at http://www���� . orq"�t=�i!� diret%�A�I'� Ep�tee :�� madea��)|F�pe�*�nIZv6r ( Amb!� ) ex�ETa few ��I?noJb��"$( T9��� *�= �� repe �I��yiE 169%56% ) �e tes� 291�3-&J,��"� eria�N:[ Э�iNfi��hitrA� esen~a broa;ng%�Eey�=! ";se%,"j�(� *d *� "� Ip ion:��Aq phosphoin4de 3-kin<( PI3KFignal�(2�by "sub#PIK3CA@  � , sodium/honA1 ( SLC9A~ 8 , SCNN1 6minus-eQ�� tub[ - �'o����dyn�( DYNC1Ha� L1I2 ) ;He-regu;%ng ��9 MARK7MASTL )�tyros� ' .$LMTK2 , LC!-, )Try\on�ata�( INPP5� PtPNs'4PPP2R5C , ACP5 ueb�ɿG-!M�Ra�(HRAS , RASA�(� A�matrix� l{!$ � MMP1!��14�4�O, X ,� R$8!bolic�rcat  �� o��biosynth�'�ryi,exp�������.:%�| �� n��iora�n�ItoxU�a��$tr i&� rega�)a�ic� *�I"��2!�� subj �to rigor�bio^! �& alj+thmFmbEq�-%H*-ba� Qonzm [4 W} .+M� h7�$1 #-ng��� 5��sh. comm�Dsin pub!�d!�EC,[DAVID; [46]A;!'%�� enric�'wO32��#W ly1� V�networkA��)A��hu�"Z:c1sP���-.s� ng�m,�[STRING�7]�����bq" �hLA�1176Sin"�B (?�S�[2? 9gsub�Ftheir8 *� F !��,G  y&u�% knoc�$�piA�� AOaE�to visu�u.?.�gra�black K � both%�: n]tY,1�Z� ( da�)oxH. AE?*�E��� ppe� %<, rang!��ro molecu�",����k-"�]!��nel� � a y � ��a�}H��^a K6 ^,��el �trck=a�qcha��erE��b�D; nsdu~%Z�i��� flux<�o� tsv� l%�ope!�wc*nu<�;`��D%rM/a�o�p� ���&ngEd2��-Y!�� AURK�CANAPCtINCENP aped' terco�+��� outs���1&��e�� abundH!1| D$m .ia&�%A ligh��mM��te-�.%)IRse zi�2 :�"�S2�I�,,, Ga�zl�� �cl�(2J"1�HDAC1/ CCNE��! POLI�yF�de6A_"� ��o�  up��%&��&A���9 �A""� q_we�!6+Ntep+al-�hip"�0lq�m�6.4%�[� he��S�f�i� m!kNme� dens��ega�%,�yd7#��am�st[�4histone 2B tag��$ mChe�#( H2B- [48]�Ite������7o k!���� if5@� K nn+�.monito(by..�U�2A-�(row , Video���In��������# <�*ge �5 h afV=�Fd!� newl�W�i�� . Giv�&at.a�� j phor�$m��in vitro� 0 J6G3–3h��e *tiv��[4�"� 33r2&gg�%�eE#ishqU6�c�4�wD-X E�o9ѡat5�_1M�on%1",�'.%���or�� observI��Q!�]n�2�r1��&#.�s*�.#i5Yc)�Nu%e�"�r%�� ����t� 0a�S%nd9-D0%�4 ���.�� �.���To%�obx/� RmI.d�aA}HaCaT8 Y� "��=block��A�t���7. P*p�he (�l( S- ) �/A.O� aphidic�#�� ap2- (E( G2/d� )by�) valanol A CGP74514��i�!#.�/cytok-is/1kby��ast�YHC��AsA��v))����'��!RI�"�f� �S*�G1g$S�� �~S3 ~v8tR !�VS +7=F1]Y4e$+l*2D�*�2rs�u2��� �7�}��K6 �,>�2�7��iTve 5a�S��A middle6%\_SET�8lim�-�)"�,�9of"�\6�,( PHK&as5R:i�F%�1� �>.�F��6%�Q8�of�& deri�! 6wG".{ Toge�A��6%!�Jmn��;>���ari�]�in&'ofB�PsVa�E'�+%�g6� =�o5,��� mi� to�-i�9��m^�}aJn/anCPG�0d�Y 9�a)e .j * !6� rupA�aY5sta �4B�Amo�ltr�1BF�� B�S)O :I1� 6ng,~�A lJ 2� ��M�--sAopo!� spina�ap��� NEB�(��!��}n KIF11P? , [5se�!Re/ob_7�9p. * ��; featQ6�"K , erraX �"�ziX: ��5�' nsisw��FB��!t6/ � ��i��c.�E�.�� O!�o��r��1@� �0|&%�������58 Q  3�)� 1�.� a$.�]�g�e�E���c xC'�-�ed ?��&.(nskele�5organizIP, + �)f  ,�m"[%�Ehe� .�8i�/�'A�IF crip�7.��D[5�+As hyp)s�A��ly� H23th���may�.ect2|. Earli%z+7.! a-.*i@5bi�6oC"��pop�[1" Z,5*9-"i�Z��m)irI� [:)�key qu�&ref� a��Aj�!`ILeam [��u�)m��ӥ i��T� �(}u� 2s�1 ��S�&�-��,�-���A�� B� ac%��.��F^���_<�(Ja;=,�(�:gEdU�i�Jr;. F]2��?�/&�/of��r&$ly labeled]* )U!��i&I : by f)-afmetry��x.ihK unafA�ed �S4p���cloa8& body"#L1 ( L1-�7� � s �2,)%2����\m��!Mi�9=/54] �� to lt,%�%�!p6� ccumq+�� I����olE*� >E53)Š:�ib8A�e�al ��M�U}�AM^���%A��6�!��unperturb')� . Ne�7('vA�a}nsj.�(spo::�8tc3D "%A�Hbor�F*� �0�7�! �Un]�9? B–I A�� �x�7[ ri�9_m�&EH �&d5�2�#�eSG-&� ��!2�a� llE���exa�}�A�� � 24 h�}��-� ab f2�Ah��by NH4C�� S�2Q h1N�)�V�F�Z��Q�5jS4�� ������-E���=Un3E2&ft%��%GN :� �#$� s�  ex{ ���� X6xr} , 3��a%���a�, iblemnt���>� ��aleqA6!m��"%.�=rea i5;of%- '#B� –G%#To�� thj �:AX1�v�"g!�Z )*�.M�! 5-ethynyl]�Y�EE�-Q�%9(9@HEe0���I.A�� E��/ �s�{| )�+. I:� wh3 �cN;or]B!�-7� �%M<to LAMP\ and TGN46&X,�Lur$603I , J%��9A>� mark3!E ��g!���,� z �� &!E��7� �� "�'a�.�� Ehar1 ��EdU6�?�l� �<�.�^dK��s&: �΅2-��.E>qEr%��r� ��� 1�=�!Ef�,A}�$.de���a Ayy)��8�m } E�m�ref�Ic �5VB\3Mzc�8��*r7r��:U&��$� m�PV�: :U*anO;�1a�. Our-�8 tPs%dNf J{ �)� traa�Q�n{ acid.J,:�e��i� t6� }Κ�H"� 1s. Tak�.���$1 ��aZ�, bec�Fit��ElB6��[.. VA�AZr[C< %JCus/er� explo�9*e  &S'�!{%YG ar p�`&^"{6[55�>5nA� �]�#'� oIot�airH �({exn) 1n:�e�q�[58d [5:k9� ul�t�5:{o-AjI+P hutt�*Eɛ��J.!O." Her�NSV+ex)�!e � HSV-44-�{Ls.��F��"-=U ts�M+a�*i= ��[689A�$�&A ��$es��=E\���M-��X6C Ae� �"�C"�Sse���CD�Iy�4�t�9gen� !�EG�4j"2= ӥx. W,�J�-�RN)� 2�k�e! ;�.�>:�&"W+J"2�>F8�IVi�Cta��c= f%�toE ( IBB�")&� Ne in2Zand:*" =<�,��Q�%�karyo Jn-mR>� �>�z*Z.h ��^�5D���'im��e����b&�:�UaX��iun6�e&�iE�)dv%:4��H2�m~�F�6a�tx �F}���< �bSBle%^NUP153@Q.R(9���*�G�Il��\#baske�,6 �Z anchor!�a�(S%�a�XetFZVEi�M6:While�&�*eG*� i�i��J�!ul>8lbQu@]��NM�#"e�   �6�Y�vi:f-#�o>)>EF . SoC �^A�"kk��%A�� ? OnsCssi+>�"�it�"�on��re�Ac K2 barrq1S ���>!is�6 mble"'P><,E\N%Lx#Hg t�QF� .=m&�so�o �~YE2� though@Epr;=�er} ga-[ret es��^ !0im� ndow�-�= 4 [6�NIlJ16@�V�M tegy�A!ZJq, 'w�X�{c �damag� 9zg�0NE 4-Erent��(!! �to 6�~%��S�?���"�S-}'ar memVe�,:Q ��.?6 parv-si3a �2p "$:�uuX��6hoA)NE [6�2T� Re� en!��)sudde��an"��!#�u�7,tle�;G}7,I�� k!�B9e��c6��H1 �ed�*9Q a�p`w�Q�(�&h=[g5��'2tI!��f �U� �arq�AX�7DJerG-o��?m�1��C�� *�$�W4* 5 5C*1� �{/V!�u�f� k h �U �"J�x'*�W%J !��>incubww�E�20±13"�?ab ex��)�"ŕmL:�m�1jN !nt {!�ed� of>L� D , J �=e1� -{z�>�66 ��X����{as!��&�s�>�� 9� �,�Amr2I�w��l�C1±�*�9v c��$�!��H1"B.e-t �*�Q�qO<[�r��u�Q�%` 4FU#&� 8�Wi�mtA%�$�_no�� ��I]D4H�&pF*Yr4Bide�\at��/L^T�[Gca�3�.��s^a�-�iHt�6��"� �H.� qR}Me H�>!@�, q��OPa�x"�O|L�,!�w= !NE ��1Y p"J +2ehiNE2�:� al!�gh. ,B4"Jm""<a��UE&�!?!Ms15du��sh�[,J0ry�"t#2:��*�r>ci�.#uF/Fs>�Kly�x't"rkS�4a9Q0[6�S:VDN.X8{Zs�K�%[)��m�"�!rem�of� 9&� ent�Rrp~,a!y{"U/a�da� eWi!uGJsma t� ���l�#ofF�inE�6!�E �Io��_B2��%�!. *�\K�"es%���Z1�f6�rY��IQ �en�n8�*��R���]a F�&��Rm o�[�}&A� ,- # no"$EPana�:&� ��"'!V�F^*5'�1:��)�A|| -�1pQcS&Q!^D%�vm: �?ib�caL�4w"�e�^2[an+l0dE�i�G."2�~)�(H2&�3A�*6T.L2� Ca6� �*� 9�* 9 �b�L����z�[61UC:�..I'&�L,ZA.&} _ !� b�. eY�pT&D*,1QQX:T� )Օ�>3n�b���j�� ��&���ii.eKs��!U"?byA�,a�;�M*.seNQu�aly8�csh4i�n���S(;&�R5"V5�A�JtjB9c8E;�x A1B�R ecru�/N�h�����. ��2� ����yY�x!7�"h�VR "� pa�T)*3>[ ��U�wh�a&/s"eN �x*9z�=i0!Q"e2Y-�Ap�_�Z��hJ�*"06IT f� gF<we�9� q��R�%�E�Iora��,�h�4D�a�du���5exage%�1&29)}H�pRFP��� �'� JN1de���M-�2bey>by�.%��DgN�>1A2W u�iT%�.w��F mNh %l.h � *�4uq6�( ^, � ������ U�@–�[�A 0�U5�_�j::a��3�W!bA?e�[:2��9�a�Bdu{Mc.�m��-3�'t�6Yk��: lwayAur 8d {U��9 2�:s S10��E" �.-*<�gB�:V0pr�1�,�o?L68��EKn�?rag��ig*!� daA��3x ( ≥�j5&[K)T t&ePcB2�5 S~ +wa�Wp�^�alM�Es:"�,carefu�TEof}TRo� vp"'3:�"@%(!�%�r�A��2e�[01 :(3Y  9au��'� ,�)a�!���R\1�9"7aw . Se� $���E�*�Ch �e�w�adDq �;�,&>��,�&���e 0 �:Q58per~.a�4F�Zc,9 versus 27%.�+�hir!���)=�4�dE4A�i#F�S7FeLPE.e15"D .1B�m�')_m3dEp �aDal.��7Iff4���7 ap00%\$above back�mnd� C2:e*#m����&$#A8d�Z��Y�s� �meQRa��#�U^#�y� .Y I�?!�*V ��!sQP�5DE:E)6QEbl% Z ��5�$Al��Kt�J ��2��3�Mand�.�A=.)�����A �m�ed���E%/��of# 1A' Brea�Ju�4. Stri4)�fv � !�stron��a:+-u��D�ZZA:w0 e l�sR�/}-�0j�6� %_s�&>a�hpr2;eew1EE��i �)Xa�a�t9# %�r�o verI^�"�6��.�tw2�Q� USa��"%7AL2�soL�I�Khd.H]q*LO 8O2AEb$��r�fE�%OH.[6B&69�6N)��k.V ?la��Ae)Smk�5�S8-$� 3o6.$� WG X�2lDYI�%�I��~���� A�٧��1Ax�:&�!no�%~��NE�x�8b�o�A�bottle�n��"�!CEhW !�!  ^�h2�� �@}&xJg and�y y+�6&a�em�n "Ft"�A��o�#of six dV�A� reY EV,�U-�N.�assay�G �Ycl�O.�V*� �aJm� � 2(P"`Z[@Z,�O�voimimE!hpitfa.in�Q&��#approachQa%foc�%a�va�tE�n �jJs�c�th�n,`{'M��!m��:�Id 7>�Ytz#A�-�so-call*" rugg�X2Y%�RNA� QcY.�c�7X&�Y�,�Ue"15ud:aJ#V��*\ -���V"� �g<Ou6nfNW'�@ sepstre��'N�Xs�kf�`*�deD<�7�volA��i�!�)~�d �-up"�Xdem�}�e^�&�Ige�!g[1:� v�7�&IOy�N� nove�Xs93s�h?� %�]Z �0.��*A��*-w� A�-MN� �o*;!eLa-S3�? /GwA ��;M�#gr�X�"-"�.?Go.�he�&dVHm� ("et� f+�%���!��7�"Ou"� 262Ar%.AZti�Y�ipovsky"�~�by@+B2�E��S���A,$o+g5ah �]I �unu�QL !���s ��38i/! J�,ia��?�es� �S �yen�_"�2Z�e��78[7�,""Mdeh|A"�twoA*� � }"uTvZKR1H �>J d{�|, �;s�?Dgh[�6�&EOaq e?,6~�:aKg-vis�Ua�p�'l� � �vJ:UFmR!ie���&M . B<&� �l�z�6�j��of�J dH�z&� H�"QE�>& path[�W!q� A�'%sw"q�@�a XLg��Չ�o� �;*� aT!6a�<ais��s!o?[��� �#�$�Xnm�e��F!W� by $��U�5�07E�un-dat�fil| uniq_ p>yicer�1  -�I�WAor�i .� they��f$x�t> >~#?q[�V�A�re�-B I-sq �*�"]&��Y+&u!�A�7.U/��ztA�R_a"nus�$U9E�'�&�b6� �>����r^�3.�MM-,% �g^#�se:m�,%�Iw 1e!.���&B�"9�1e�r�M�* �-Au"�LS&�ɲ�5�E��.E�en"#��_6� y�8cynM,:fnB�:Iۙ�"�AN�5>v�|�%Y.��%/uT �Dno),�E� ��9v�"�6�k.�D@%�$�f&m\�W9 �!��^"s$ ��B�mc!X�P7 ;x9��m1s6 �R%'4"�R 8%�aF2��(�{72)pa=and2��3A�/�!(>?]&Z narro!5to-� � �aA�-M�cdis+K-Z�� c� � wo���A3Eco-��g)9B%*!�"s6�)Nr&NP2�,Q!6��5&,�Be�%��6���B���[^)am�r�Ut�y>F&�(��)� do�jNE%|.�jAO�B�2�.\-ѥfU�o �?=�eKQ�i�a^i!�e�a.61�O !�a|�U�:�' K�{EMa�s[ ut 4� 60�!ww M . s2"*&��Gi�O0-te�}�U5� d���7�}o�\�u2W :ck� �wop ��j_al& �)� etm'>VEc�2��2I�)� � >�'�&�#�We� no!p%�w�3b�ABQ itselfX�iA��s��!*9a�.�J"�n5aA&��~�=fBVS��$laJ�*��,��)��aQ^$)>F;]�L&��!֥����r�$�!� a m2 �T5�1�My a�oi#i�B*�~�A�D�ry@g�Bsj�h%�>T �Gof Pye�o��@� o2-%��p*�"!��q��#";'r-�6�V�" �a\:qW%!��-�*t&��NEU�%2kRI}|?�kHHPbS1_S�/A�suD�H�6'� _A$� "h:l� �\%`aO: 2W�*��� I7���gz",!�a�%�+*�}��.�@%�A�� o �L2/E��/l� wa! � ���� spacS�%C"z ��V*L� �r�;�� 1s:-0 xir&ReW+yv �^��i�`�[a���%��iA@w.�聁�~ i9M�6a EbQ *Fk�6�%���sp0pen�rqN �MQO nteg� �?2�6\n�N Zm�}Zm.��q&��{�+� A{ ?�*l:)�cm� gE�U��ue�z�1I�1nR8s�ߒ�2o��a�2NLS�d*+�:�A�n2m1K���%�Dy9��>har1" /�AE7&%�2HR .m$!�*�NLS��;A�off� %a  (1V convw(#dN)aIan��?#� of t[1�[-`1�J� C&�� }.��Ra��to�-�jl��J<an��%�[4�R[72xe2����2�-N�oAEeB�*� k��� !5M�j�*��m>�1�q�f61 encl�L ;�E�RD.;empzV��f�2��L2@�{s6+)j$-�(�QM*IH&�z#20|c�'F#!�p1��AF e leukemi�,r�4!� he E2,m [7�7k<�X3A4! F �1� �sdee��'sep� %l2�A|:�2mZ%7"� .��x � link����=episomw���!"�);Rek adap� &�hty&�^� upra��� r�L2E� fulf��a&��| H�a��Bm���ENa�?taxcM�f�is&WGt0!�mx���7!xa�on u= �&+�i�E�A2f!4.#��"�? ��&�R&u�*o" G&�0s�8�q�0f 2�qb��on phys"S��5א3A!�U> � ��9��lan���!4a =�.-C HPV;�.�/s�A�wt��h<� skin!mu���O���ρ�t$�.*�@,� dvan��2b� a6 w"�!�q:Y� E����Bnu��� ��_�6p� X6�_[7ւit� bene$�e�o�Kv�M�G1 w5f &&��Q���"�-fW&&Dc�kv� ��AA {U�"_��eReoi�q~=�IeEiIwe 6�outh�!� 2����&+)iT+s0trigge�4n��-�f�e���-m!�"x P��e1[ a. *��x ATCC>*�d��origi}ל8Norbert Fusenig�%aM DKFZ� eidelberg<ereyP!�� gift n3Schiller�S ( NIHg:CPBeadH�US�+�d0/`0and�i� n of DYherleJ. enna�i. <ME9I?ob� #� E���11Kyo�xE*��pJ[G>��Ye{A�)8500 µg/ml G418�bA �*Umai0 ln DMEM�e ibcoRv uppl�} 2f�]calf H�( Bio�� �8MeKv��hd�cN].6W>�.�% H2B-�15�) �>�puromyc�5 �JVu-.�c :%zE�P}1! �M_t"]>� R"���{��!�6 )�C ids pCIne�� pRwB'8p16SheLL , p18s [7� 7�&Mp6^a��Gj�..��8ai�.&�Qle��(  �) + jAH;l�\@?��C$k2 (([8]�*reU=� !H�ngN�L�*�LY�R)c9b') [�L��`p2�fA. Raft"�d �A�A��)g7{ ypicq"��'=�P��T6��� harb�Z& e( 114/�'SVC[8�Mn brief�aft$�`4gr�t� coll5~P]2x� 20 d�2) 29.2wdou/%U��lo e��!!benzo[z"�16~<�W H3�d+ae debri" ���`ntrifu�)[8'H0Hoechst 33258�e�In`mgeDjRedDot2Biotiu��a,all�rWy� Sigm�; �^monB�^���M . Sapp*hH!��^)3�T=Y�iAHP158_/J�AbD SeFKc 6�V( H4Au5G?sc-2001a4@S�  Cruz�A��s�_AlexaFlu��a��7e( W?9=N.�i�a�!Ade��;kit I� Roch�)i(L=� } lasmidT-�by%�Mue��(r�~P"zd X|det�{ T9nS+51×105E� ��O� or 1���z[/��ZE�F"�!1.1��M%R1�~Me�ap&m=n�lBB&or��d��'-� �� �" �%T�( 1� �� �v��( vge���)p�W(�V1���"vA 5~ ( PF�\: �!Z≈20% �!�!C�(���� � �HK��� 1��bO3$3 5�2�00��2�]�l2�/or %�с .)64%�<a�aldehyd�]PF( �SMR!:jc�e +*[8�I&y��_" a!. ,EG-�Z��`�U�UH-!Z��Z>ume6n� ith 10 mM �/ HEPESN6in!!atBCؓk�:#5�>��"�!�8 , 5a�4� J!1r�3 �am96�B96�/e*��4� �5ceA�.Z2�al�F�u&�^�<6�J�%4%%m:MN�e�( �aE=2:�9Z*h ecseede�3J�2BQ�fo 2Bo=�N�-_9Sr5kN=�d5y��50RNAAlnKA���M-Aׁe�\0RNeasy Mini K�Y:����as&�p�!. 0X�spl��� � E1∧E4�L���y[�uus�Q m�TATA-Box"/� ( TBx�j onL�ep {rse}!��tatePCRr �- Qu���be RT-)!�siS�A� ProbS a6��E8�0:�� 6��+af��,,ҫ0�|1� � -���M��96-�op�-�2om��U��ūL �u �: �h2IA�P��Y"�8�.�� �%�7!2� �N��[�  u(i� 4KA� �d�k��or�7hp, :�A��e�7����om*�� ��=i�,�(raw��M�$%�%� V/edMfa MATLABBw3�/\� *H1*A[8�/� V�wc^�m,to AllStarNe9 vׅ RNA-5�( :)�2�@69w&=S A�a<��G-:a�$s :�} �6�,?5M�E�2�>�M�U�%B-��2q�A{QdE��1E�v�},E�EdM piY�����U�eM �)�,) �> %�-Z( NuncI; or 8�%$Labtek chaI1�-%ap�x��'.m�J6-Z s*�6; &y%n$3�&J:�x���� s64n7m"� �p"� m� I�1�9�(yvg"� �_�k� PFU& � .` "5��2B"I~:�Z^!S2.�!E%Nj�6�6���.�B86�kW]�,a�jei^�]k6�orI%i��ng dsRA�r�( 52j B� �5w- e���z� at 1��W �� �����(-lapse.�FA� starA:. Tim$�M\ac�$eh an I�XX� s Ma� ( M"�P Devi��environu�� �8a CoolSnap HQ c��a,ho0�tr�M)E#�A^E–+-A:�,a Zeiss Axio�  Z . 1*��*v!��ev quipk� ��t -disk-h� ( Yokogaw&�1R�!J"�:A�%B)<�|.6B��#wi�1��:s�Y ej5���y� ink�^�����(i�D,� 10×A�2��䩔�:A�of� &�Jp.}c����a���l�3��'�N�5�#���;-�B�To�L��*:�), 3*$.�AM�D o6��Dli�� ^��J�+ Y)ı���$H06�B�r^� 2h2R%7�in 70% e�;o&pn�Z�MM glyc�n)�� 9�9,��'�g%�De �� I���)E�� c6`� manu�3urer'�c"�s��2 r -mo�&&�488]s�!Q�/ct� ��&j,��B? �2� )?&�,�a�9� "��a�a�(.�= Z.=�A0!6�8os!�Q4'd� ���s zej4+.9���`'2ft6�q! E�i�*�)-6�i|�A� K��]��pI(6�J=!--L�;*^'�REAtto-A]phu,�q �*2b!�*� �iLSM 510 : or78q,-�,-�%�ings;E)/)� f�v.�i��hɮM4��dadj�9��&�a� Ad��L$shop CS6 .-0iH*� F U~T Ah.I E!125 ngM� o�� ��:� a�O2�:P. A03AK3"�vS,FH �&�Y� �RF>ŏ� ��fe E� nMj  oligof a,=D8DJ�tM �*�) ��R\BP 6�E@�<���,D !�)� � J 44j|6��%^E�,fra,�%H�/\D��K�R"�%A��-I�AM:�.A H"6ZasL sMav �">K. "6��%i ���=R6���of�� VE�� L|%�K×�� +:uni6�i�oY�78�and X Al%�q�|6I�BIma( v7 . 2B a��I2�)R modul�!�seg�*=li�hc�*a�*�� $͑>�F�o��%Yar�. �[ a� � ~I2w]+J)) a�e�zJ� �L'j"arbit��_��@t��^��Q-!�� \#,M-��e�;M:2��Profil] v 2 -� , [8R.86]e�\ mean� e�}|D ���(Vy/�_v))�-da>  �n �Gti�Mⱇ"F�, 5er0('H;�Li|�%e�1A�}�:�� &H\AŁ)K.J leveB xG�.Z :">G�BE;eAơs%y/,ISofU͛at 25z b^<ݡl">g!�≥�g*�O( mock6Z�-��5deA�as1��� �5Wa�4E^!����s�9�[ly��&�~ngqG� �j�Co2� of �'I_�%�,<�6��s�CIOTR ��[ekcpf�c! %/�s �Jra�� evol"�afu �-�t!�(4A�in*@<s%�a5-� +(qB�#:�` worl����0xtremelZ��F�J,h2�NiX3f ��Y*I �Uc��n���5e�=%Xaid!�a�3�#�O`2agO��74-Mb @N6k is m�I�)expW��JTRv8? poso%�ma0S!/!��mst^wޝ6�TMel�3-curv��N(?1��8� ;1woq,s!J\ed�>�2hey�-�� lex ,�eumusa� d ,�>�%�. E�{e* �b�)n�i ~9�"���c�na9�field2Y\E�^e-E ,polymorphism�aX! �d(�sO . G |ic.�(���(K�eDneu���,1q��T>�-�Ged�$�/_;>phlinuQ&sex�U�a �B� %�Ah�[/�F]�A���f��-~1W6�VVz� Fiji isla��� he 1960 �.<:sprf�;DD�X ��du=vs2.It�T@2�� � iZv� iN� ��iq$w� 4r��: y�� }d �. :?�Xicts hug!� �W^�,������ US $�& milla��X�[6!�Exp�BNJ+s uS{9�Ran 35�t)�c�[et�?I�EH6�Ɉ� cropr|${ &ry ^b�-�)� ripe �] frui�&� unsui M�sal�Cco��A ~�Ad��t-VA�r�/AQ��qIg�3iva�&��f��Stri��diZ�m>WQu�oz�F7� � r&�ow�I62ul�2U�(Y ?<Q;%3v�d���E�<�� �#3G�solO �3few�2` �&� Cavendish�U!ap���@�� ly sus�i�; [6];��mek���"stg[�4NZ��on]�2� EXe�'��6Aa?[�M&pR!�se� A�A��f6�.5 �e�!�eA7i��uI�X� a�`L"(!�un)�;�o�J�[�D2o&�P-'!�an url� nZPE�ԑ!c���%�� a��K%� , fi�\ fuel�m ��Zymose�Tia�UticY�Bblotc�ewh� )1�= entu=inaeq�#z�Qe scab*F�Lksp�i2 cul��le�qBr"c/�ak[,r=�`�%Qs|%��o.*2�;"&X[1 22]��Zq�,��be!!)� ( <�"�jgp4do� gov/d6y>�4 nfo . htm���e2�Am"'tr)�m&�ف�t�>�H�t5� ���� �<�rKin7Y��Ilج���S� mena�B>W*5ly hampL� !OQde&��basic�Z logy�SA#�R:JEA����!G5ґa6.�c#bs%�cum�A&d&���ve*zp��6�c&��� � �Ger� ,I�1� humid>�#���:�m�)�|B��Wato 50�;un�Msympto�r.�v[2�d2B)YAl8��!� ��^&��otnA�ng$�5�gaes�*��% germ�9 [2��2' ��ne��Gr|5��/�!��\���&��~Ae�Iinu�W&B ��"’E�Ae�i��A�T2+am� �peo�Gr �s-�!/c�l. A��ela�9�a�of 18B�� �9]����CBu�� CIRAD86�as<)� U6��%0"�.�Y6� ]+!�p�f�d��jS� qR�discuD.�cu" ���Y6�>�, �9�.9�^a�4,)139m��z �ail D�es’�a�ur� AR�/�u�U� a go;qf۪AA�4S% ��ccl��APnQ�� 6 eva~,QmMq� . �5-�>�-4-�1#��SCr *>()/�>(or Illumina�a�b�� )139#�5n�����!�~74 Mb!Ee�B56ffolds)JAa"� t 1�088!uan N50M50 Kb�n_i  !sly ��� map &$M"�"Jx�M�(;>T7 ��G�Ep�$d 376 loci)��&~��e"q�I�%&� A��� 32*�<233 DArT , 86 SS��3 ��satellit�=^�SM��9 ��pp� Fig a.)�&0b��22D e�G2��35)�a&�t��7%�2<s �c P�d 9!;5+.� �E��3�$a�3� 2�n�|i1. Mapa9��&�!�ecu&T �0�2�: 4 cM �.�gapM�o�� nkag1!N14�1�of +! �[:B2(=��Z�e�*� EST&l V+ ten3 A��VO�� ���F��107A�u�E�ufd� G� ��#EI�[a7d( q/A�LYi�i)� 833 �r%� . 62 ex�ANJ; 88%A�^� �)t&�(stop cod�z74%D���HG 49 "Pfam G�A�S2}�eUVo��"�$( 9����"m�12��Y�s �2v�12%�19  )!�)"se"sc��Ep�om 151!�229%Mb8�GAA�b|�XM� Man�=5Dd A �Me�94T&e#:����$&~"���!g"k�A{.���]b�u6�1tC.�a>���s����E)�>� ٭�QteJOis Aj4�"es N-�gRMIs!b4��$, Baudoini|Gmpniace��aU . 85ji.� !)12j0M�*f 0 � :�S_W �U$ ��UA�=J&�p�|Q&� prolife� �*Vo 2 >�) � er�h3+[sk���'de�a�-&�rv)�G+C��T heter�eeXs n B*|r*�I)SiveT� �phyzc8n�:R QB�rFZ�"�!m)menon��E#Iuse(!� i!�Vom��%r��p� ��%fisD�+Qwre RIPB�')�W�mB�c��ti��Y�U#%+"�tM��di�AMca�b ore,a>��=;2�� )�f� &����g��� 59 aM s ag�<y\���Y������L .��<���)�Mpd9�� �AA� e�c{5 orlIPy)�bQAf no e�3,-p�� 9�� rm' W� E� Agarioty�cso�'seems&�� " 6��.�he�! eM�.��.z�vF.a���Gm�LTR:[:�A$.4 y�'ed�8t�iue��aAHI& . 7 A*=�R'ޅ�|����P��؍ C��+AV[40�B�w� `b��i�2�� ,�11c]:E:^�!M�of2 e(an\�(agnit� youn�Wt o�]��Z !+�`m����e+AБ�h��lmP �.�>� _)%ZY5a��!�eof%rXQZ����( RIP-.�si_%�a�y.R�5eŲBV! mBa� �q_d"-�Ple�(�� i�� 9��>� , a M���BMM� gpas9.u܄("$"s� , 4"^I6bIT2 �Bn�S�gU�&� �^�-bu�JFyc�� Ea%�!=Z a/*' E�e46�"heN`[� �E�6�� cƤyna�.m C��� ,(�~>��of,"r2!-�E�"�ar ��HK�)�ory� &B/�%��� �Rbe4 �Jq5G3�M �d1vo ��^�� rIe�ua> � a.�L�Q��"� �v"� գO-'icʹ�*� s� �&!�i��$h؞wd mildew J Blum���j7 f . s�.h �JErysipBisi[GoQ�nR�bontii�-3)r�� �"0 �� ss� B�non–J�@�q�+�de1inl�%��d)"mis A��)w>P�Xmes due to either the proliferation of LTR retrotransposons similar to P . fijiensis for G�wheat stem rust pathogen Puccinia graminis , 4PS propo!�� es�P[� !�6 , rid � onlySem��eF�,a8u{�re�frame:tintact .E�B�i)� �of:��� high f!{encie�S!C�T)<i!J� atiqha eris!�axIP��AMh��non� �M�. B�6is) dur!�meiosiaDa possi��x� i A#���extensE� sexu�� hase� "� aV��n:z@reproL � then� slowy� �r�e z2:��.�h< e9� enough`- no���t��effic< %_m %�cop1��H�x �L1J�o�u� �S �!� next)H�1%G�%.�!�1�in6Z; alth�i�sCK ly sidea�I primarily5@Aby1Vma{ ,�_rec�=tud!sug� �N� also� y* �` role1epide�W[53 , 54��T5`!a�]2� �s>sod �wA-!�or1 �_A,relaxe�V /a�how!�se Oa� is cur)ly*K (In Z . tritK ��&Rtyp1 �Eu �%{hroA�A9 i�a��ge setdispen\ chromos�ref� to a�%e-A�[17%Ehe2� O"A��Z( at least e/ .fe�no�=fun�-�� ~e[� �� by hJ� 2 an5IdonorIZ8than 10 , 000 y� ago�A5�Sl1!sn$6��Z�� fitnM Ui��$ique among� gi . Many*� -<�2%��ied E!�E(ic scaffold��6�bro!Te���.� ^{i6�� �3ilu still� ��%�pros ��6�. N! 6linkag�oup�+inT,geny isolate�IKhallmark��l�Y�:�[56!�&~�is�surpri�jnp:�correspo�ia6n� !�p� vuC%�9��N6 do��naD a�aY,�}is�E��$:��Dew +no!� betwz�^7of2�����B�6$vice versa�trai��sintrigu��{ISof separ� � ts�H��toR�of�m�E.J��&� Capnodial' nd���. Elec�or� karyotyp�B�{ a��rk%�level+varia ݉ ]�� �com]-�e s /$ � � lengto��,polymorphism-�,so described� !lyA46{[5��A;- [58–60a0����!��=�V �.{� r����n r� bi !�A5 c��^�[61�F/a*z�p� e5T��!�!na��al=huffl!~X dra��"virul�T�� t-*;I<[62]; tGb� .�:C cycA{$b�s"5�al=]Q constitu�5�!�adapt)�<nviron!}al� �%�as seA��!ss�E�ch; al �ci�. FieldY�q�is work\ col[ $Costa Rica%An5 a�Ja � u/%Eq �o. Over*,:�5,a�re� -a!�A#I�Ascomyce�EI�!�itsa�pl� d� % .�  Re�w ablyF�����%2�10 Mb"�i/ A�l�!� PFGEA�oM�. CQ�e��űM&) obser� �%N [63a�5]� "6�c_ . Medium-Rd2T�+f�,�CA]�qa�rdl MexiaH��ZEte�ing%2�s�smallm{11��9�.(calcu d�2o( 0 . 61!`)evsix!RAR�.Adid��  !�,a,CIRAD86$�O a? �M|�8�a��a���of7a�p��OqIA 1��? probEnup!}15j �>�o-migng�dsah�bna��W%}��ddia]L!f�}29� �avail��ofU!u6 en�> � c��of� � :��R�6�encB5�� (r<. Fun )  7 aidBm usua��ubd��9t.6 � �{aflng:\�a+ cognmby%}d resic�,gge��+po�nd makp4them advantageor�?2�� depe>/ �!�q�infor�c analy�R� 7�d�� m/ B�6�\ )�� n�homologl Avr45�A�A�{A�Dothide��( , C . fulv�3+�6��[oPf��g  4 adja�to�ea� f 617e�2765 bp (a 6-kb AT-r�block��GC���39 . 3%6Y� Y�:� -oft;rIlreg�3[��O� �Hi(�!H6-ɥ�&��I� :s A�=qa�=��Isy�y �*-u-�9 1�� � . Pr� A�S��3 C�<��ValS�C)�&� fac�<in6��E�,A pii 4low amino acid��~42!�"�R�Cf4�:�AT stim���HR� tomato [3��zwhe%� � Bo�cEv�ha�� t� until now���s} A E� et!��CPfAVR4�T9o�����at! ac��aBw%cE�.K )"t�aZw�it el�YHR-F� �� . Mo��40 �� Y$.���tsU96~Ahnu� :facilit�dis�!?suscept�9��C)�AlbI0@o��. @T!�)%�HR ��o our�W ledg� %�" firs?al҉� to i��MI-e�fic ,Fz�$�,Q ɞ(at M . acum� a s>(burmannicoig var� � tta 4 m!�!�0S 3 al R�J)}� �VsQ�5Y#>]E�uuE�!o�#oey. A' !xperimx�unee^eo|lyeV%~hyp� A�EVB�&% n!F%f!**�'-�i��6�� s� � / �C��prA��wr� d cros�#B�A�a2�-��� � co-segreg"� nw$��� �/R�B�'9 dele� k��q����resA�ng��+Nes��t6B�.��$.�"4$cXeng_d�(Ual� �ŭeO� s# m:5]y��su�)�.=distor��7 �� �6�loS ��d.�� �6)E� ot routin "�#B("8a*�=�Q�d, bacEa%�nea?a�in�#brW$A�,rams [66 , 6SI2' �h %nt��%mf�evalu-��6�pn) "E�*q worl�w ) ex�d�a�� p<�Pac�� isla` Xnd Papua New Guinea [68;$�w�o"TF �#&?"`�4[�In�!� ,V� n5(�&o crud�t�s �6[6� 7"�� IR!mv�o�|F�inF���a major� c�*�=F ai�01)av!"Q c&� black&�". Purv 9 �G �^u���� y']�riSt��� rapid0{,6�!�E(u�]����J proc8i2�5$A$nadequs+�clu!al� o��.�is�":8a��� ��odAa monthDg"A�!�-���timPBI$�* pproxima10–15 bSS�-�b�� � ed d�&1kce=n�  o2�� �elucid��� �ng ��e>ed Anle-!� inheritakof��gee&+ � fUR%r�ecise �7�Ba� eriz�IWsub_t R sdisco@-[1�71–7�� &'��v��. y��OusA�in sup}&�S2T . QoIB p)� �.of��} �initi�h�m6Azadicacy�{�_+56 s [7��&� =�c�e[lyE`sooa$'� �mpz��+�*�$��pl�)�r�Diagno�"� G/�A$mitochondra( cytb%X�� 60is<�!K thre�mer@+�.� prayy!MUnearlya]�-wfiE �=&�7��  "` shif\"�-��per�a<#200aq 2003a3n�par�ș�� t [7�J�$San Carlos.?�>l1�g+I`%@-r��s�#t� �� F st eL/�ex�.g�-"�s�&pG%���e�(100 k�/ Neverthel��,�� l f�eoav"�%ox t�1edha��%![co�ec exer/etrobil!�sAgq�-L�h�,MZcyu4�/e��a�&f9�$individual`w�p�&$c�/onj$=�!>�9,E4i{A�si4C A�a� s do%��#�%2G%[7X+TA�promp! u�� �6���<ceIQa1&�s pipel� t�(velop VNTR ��r��PCR-b)!]�uEH I1j4priori neutralQ� Y=: ���"<ie�� A%U�}s��al!�ytc��*ie�*Hu�� mi� �Ul��[79�v � .�/ot yej3ach��� (on–drift �)lib�-,�. ? be e�� ��Q=%1! s,s&�"^! �Fortun�\newE�rect [80;*d $53] method ��T&lyI�toAZ� �F]rO-�2i+6�9i��teg� d*the a��spa�(U'��yedict%�ter�.�q.��{,.YE�cagI�# atega �-eB�aB�><� -1 data�c3139Ň6w�#bl�1K Hinu姡� glob�)&m)by&) ��di�Is��`�g " "8 �i�:K��U0 nd ) reme� "�!j6�-+:�!coupled� high&� N�mak�X)� 5����c'7!:�on� �MDiC#*�.��7!N"# �1Mc� 1D 8.�way~�*deo7��&�.�!Ru%�>Lfuture . Pseudocerco2a*d9� EJ 86 (u 1-1��(�ig8 Camer��$in 1988 ) Ec�nE���2��i8�epiZ? & � �ubj�G��� �����!�n� �c nE��x(-ng map$p"n [8i� 139a�2R�olombi! 1990 ��j�u�m. U86%'"&rt�CBS-KNAW� BiodI7ty Ce� (& 12025!\ . Myceliam�:e2�� H6�#L 1L Erlenmeyer flask/!��200 mL!SPDB (� �dQ�!broth; xton Dickinson , NJ , USA ) shak�t�, rpm at 28°X ��vt�02� �7A��filh �8reW1%"���ly�:�6 . Sa�!2� 50 m/.*m--dpla� in 2�tub4g�8� a Hybd RibolyserA{34n° FP120HY-23!�!� 10 s�50) G8tungsten-carbid� ad .%�a"!g|diHA� ���$Wizard MagB !�7�G $ ( Promega!�ek�)�fF4�7r>#Qn.8t j u manu;ure�Whondshotgu[0ʼnAOazassemZ#n�%�d5 �S�$r.'>� "� �"�ar�> ( 3-s8�plasmi|"�40fo )� RN'!�B"$Ar��[8��[)ar1�!�ioby aligeh!LphyZ �7 N9i �*map�)�ed-" Join0V 4 . 0 softw� [83]!ȥ zi3"�on�322"g # %�sco�on 135A%~e "d�s��!'�2 139A�D�3�  moler loc�>�6l--of-fit �p!;&�4�dev� �m!Km4;1:12�C#oa�a 1% s!~��T�m. LJ�,establisH I�a D@mum LOD)%!�0�fiX�J�@5e-�c� )�wo,mg1�a�p!X�a8�9*&�$/ ordq#( on)d.�determi�`r�1ED, rw"�) sholF%4 , jump�53ip�valv1 (�" aultag4nd Haldane’s5!�a�3%m�$ In c"4of uncer�t< � �E��d%�! )� reca"Y&Gr�� +5�� �a� c�ġgh6h reJ�8�5I ��?� ` X0de novo-� RECON [84# wk-mery � X9Sc�:[8�A custom"2��k!�F(RepBase Upd�librar�.234!�:5 [86] �t:31 mask:  �Ij � Mask�/ http://ww� _F�G org/ ) [8� 9 fami�<10u6"C>=<by 7) %[ anno�I �%iin� t o�8;5%�A�e do� i�-e�d&�as*B @by Ohm et al . [1� )!��6"�'�s���]"� ��![bes"~b�on!�%sh ����" non-uFndO �'B.����$i�of��"oauT"! Y�pQ����z��>LGoodwin5P!R� >x� -m��r�9l�9� !D�*Measur=� qua 6x"e2oA�  *d l tRst�A�sto� dX?( 88%8 4a�s(&n P t��e� ( 3069[ ;-�e� ]w��mBACNCBI NR� AC ( 74:\5Am�:2Ein S8 T${,|(9�*�0mm[ �B made��(SignalP [91M TMHMM [92 � ProS�[93��hp�i!�0nr , SwissProBA�L�Wexpas���Qs!�W , KEGG [9KKO 5]5�& >Si�M�ue���89%��Markov �3ng al�kth��MCL��6� %8�0A�-a4 a� ' s/� ] meCGf�& s6�95�Man2`M�N���N�web��� e ng�o Y�1GeAP\D�C ssesʼnQ`��as� ��M ��rea�q,se1� .m��9��.�Y��!� alsoɍa*)�!��i4 Blast2GO [97]Ian E-v < 10−6�., �s GO � *Y[EO e�V. C�i�G�&�A�i�en�-E:of`�dkbS!F� r� exact 'i��? ���. P"�Fsecre-U�k*� e"a pyth�.rip de�( run �U��K>�C3t [98 &� lyٳ����k,,�@membrane"� eCALchq=tifAM�few 3300 a"5-�Y't�gat�2f�*cA'��du�x6�a�* lfil��ri�;a ��&�@a��"�$O.are-h !�of� *��?$paired-end"� ᰽�Aw�1 dard Illu�*- prep%^ ocol)�NEB9�G. A_ g� sert�5m�l r272���S�� E��n�GAIIx��A�l!��354-�# K �ANi�36 |$on 5 SBS K�  ellybuilt <a54� ]��!�� ki�DE)w3 , 37�Ols � ob��R& tM5y�$of 4 gig�!P%�.>� !�6� v2 Am�@��& )DGSNAP ( 2010-03-09�0�-��F!��53�>match* r 1�e> CAJ trim�&e/5�U1@}��8a1� j ca��/� si�8 ��Alpheu* �qHNa9a<�  � u�t-�' �9M�q� ofE��B7ph 1�8� � T�$!2�� at�,. Nonsynonym�4SNP"�c �c��Y  -T<3�-h>{v2@<zen�� Catap4!� 0402A�o@ve�5 6���Y� �/ of�K8�*ao�e� 4 u"- bi�'T)%ص�a�u�)�a Mk!0c���.roach�Ql}mA rank�  �OF� `O( n�5%at-N�.e��) x A*�""uet y �;!*wh.�e��� EtsI� t�Rᳩ�=15l ost-Q�5&( Set V�he -a�b.Ce�!N7lis�g4O1:yf.�M��filOPBpFrjtE�e�,,&>"�!Z �  �&#$of nF��.�m >� W%��I}!�9�os�+S!�CEV�S���Jx �a�%b n in 5�3�� 0��#i(clustalX [9Dse $� M�submitA�to�GCAL [28T "�% dinucleotpa�.]=F��yRIQ #s '4Hd�A<'%�% 2^H!a�a cytos�./!��.!� a gi^E2@(   .�8J~s�QP��.<1CG/CC/CT�To � Aais&)8 M06�� �igu��stretc�S�,�? rbitv2JADn �R69�'t�?45%%�rC � �8 U9. C�2! -�eH��%Pper�/va@%�*U�,0a`# A g�+BJ�VR:=�. 500/:pe� merg8 FK3:6[ 1 kb!�i)"�;reAE�n�alo !ȩ롈���#i2ribh$of.�1� �! A�ToU�AQA�am�U;N_ A.; Q@/ .IJ�Ewra�n i�a!;-bp sli�windowMi�[p"B �)bp�$6���Q��index,!HpA+TpG ) / ( ApC+Gpa$!&�"��&�%!� . Ag%�-GJ�asq Y�iX.�҅�of� 9 ×�9�DyF!�/� /year��"PSa �al=} [103�*�d.�7Y@uRn%u& �z�# as���Mn�5� ( TEC%P��� �)+@�T%'�5Q=c7* '.?J��JLu���k�іm� ;9�lat �)� U�V!�I&>� tpar" X80:80 �H!WicV"�27Ui .],� i�f2�5� ͋.� �%�^F.� ��UAn)fy!��T0 70:70 cutoff_bEY a���&g���A��iS �86�YFa"�& :&med ' A�!c %� ies:BPst-gluc T&s� �AFu�10 A&yQX' �I3 Cper!Aer ) ;."�]uc]R QKH2POP!NO�Rf!5 "0MgSO4·7H2O ,.KCl 2 *� & su!�e:���"J�A�I a nith<� (�abovexH)��E�&e�5��K-Q (5 (�X 10 d�SOhot}\�612 hourF ol-wsb flu� � li�]( rot� ~(rj1~(& )deL^'yI<��� �h�͵I� filt� xVsY*n liqunHCzdi�RNAE�&%Eѡ�t�]l�hoDRNe�H ( QiOB�'%)1�t!�/�4.s�!�quanta��"\�2XMdoto{#0b Yl�gc �s6("�1dB�}by!J��,�@-s��d )EDhS?aͅ.���NA+��u �b0�"( SuperSII ( In%�!~ , CA"�*�.��.��.. �sha�lig��"�98%-�ty��15� lapIT�\�sV��("-)\]F!�enq� �9Ubym U,he Phrap9Y[10�f10D=P�<lfof λG(M$�G`� i t&��BLSD ))�=�*A�ro�k��eTk Cav�Nsh “Gr-8Naine” tissue���=� harde!hy� q%z week� neenhoA*�5�#u�?�ll ^%(�Ɏ^mHA�m�R .����, ��Oa#1*�H�F�:ie]i�QU)� aAt�G-.�g��ta�A�s �-� eHE$ve humidit�+>�16v �?\ � daV$EE��&o ( Ly0hum esc\Wtum ) cvx oneyA7�MM ai��5n9^C�INc��f01(�a� ic���)�5.%�a C6�Ma5.i�921"� ��"gY0by Stergiopou ?"W�Md�=g �U4Mr�<m ,# @�}�6�" )"�D��E���e#n terologou�6bym� Pichia papH`@\] GS115I2ferA !Js*�%*$7[10}-Fo�eW |� gF\���(p�E�hAss! � Age@e*�E]:&` �"a 3-kDa "�"$( Amicon U� -157ifu�BerV�cMillip` �6�$� �ga-l�(� �A{��J��@E�mleave�&� b�[�8��E� a 1-mL sy!�A)no needl�I��8eZ'[��wH,on ���x-Z`er�;$� �,i~A�[�o dilu"fif�6�5�!y-pV=F�&i�gjN=j. �7-t9k]w��i�� &�as ne�Lveˡ����t�E!|posjI�" rsovU�i�ma|j2� a pe�N<:��O�Ya^-!>3r )�&m"&3�L_�Vleayn6��l2��&r �XS4Ceoj%��/ A/�den��%�| armu� Doty��Kpba�7�#.;�� �109� ass �:"XG+C%t of�%L6+"��;"�;plYCS#;�P clos���c�Qpawumusae (^UQ430;C<121371� �eu>- CBS122457&A�lla�}�>� d2�.�IPO323 �15943 )!I]�*oe�!; 4�s� �AD�t��:�(� ��:�� �oc��<4aeT7A� Broda [11��disJ[in�1X SS�Mel!cu�I�"�&� Perkin-Elq λ25C:_|�%p� E�a�E�f*:X2He*�UTm2( m �/& �temperae )6%#ea� fOT7:1� �O X�[110?!��Candid�rapsilDR�CBS604�m5R x%S, 7:$) [3]%�u��ca��ʍ�@= �)-�yÕ0tw�d�)���. Phyl_ x;a�*K �(>D a�>E1!���he BE:B* �/��j!F SpacpZ( ITS�!Xqe �NMloa�o%rGenBan�Z�fU�&qW�$: AF181692%Z2�jEU514233., 65�/a8 648&�lkb� ��=me  �^le!��L/p/atH&+*$E! )YMUSCLEA�2hUp.�t�9a� genem!� MEGA �.0>3] Qa Max�;ikelih3?s04�L�@e�!lTamur� �s]�-�c��m9@.��%18noeS�e`��D@ bootE�B�1krep.acIihe�!�9�&�3� >T�A,�A,�gbl�M�"dD 48 h�E��� t 20%��fm @ � μMy�,az�m. Deca�`��%�wa�= 6 M soy$o�!nadA� to 4�B OM b�U(�2 MH�00 mM K phosph�: , pH�<8 c7�(�Ran�(}/m=AG��ny�256ZByj* )Takar*Japan(7500 U!�β�uronid 0SiY)ˁ�8�drise S#��N~1:�Qqum: ��� enzy QcA�aA�incubat 33�e!Hs"�C5�7�#W@5%�H sz� e� &� pA Jes5&30 μm`-�3$ F�E k �b"�. Wu�1Bjf6 @]  K,a CHEF DR-II&?DBio-RadB�. S� "s@ al bLWZ�Rr VIp2= �Nf���H��Sac�tb s ce1`si� �)!Ra�*]BwC( HMW�Fta�1. Lj%2h�:e�%_�)ge��%�<5% TBE��G1!�� 50 Ve_19i]7 switnwgm"�& 4800��1se�]A24e�#to 1300 #���/20+#w+to 6UE�ly 272of to 6 Y at 8D.%V1TM�Schizos2�pom�c�Ansenul'j ngei2�(!�Raax�$iMgess7%& SYBRe�2��@de+�I��3�020� P� �7�"  a UVPi�33n�2c6� Eagle EyeH�( Sw�S still r7oqF. Two�7 , CimKa�5�MUM� [11�~E�e��H�?"� &6�W �{&�,�8*9spc�E7 .�#�$�{2�!.# hd) d vigg�+i�2��?�� ma�%&�9a� y[%� V�Hr-!ɐ*:EG$h,60.�-9�35;8�r�Y�d�.�6-acid&!�>%q"� aeAth�K O;[11�oH s&,B"�.E)8/[11vS6�u1da&s�so%�)u��%�. �ia�t h&�gF!�ar Ple(Nl�!Fb�!�v-�nti�T"9:K�0E h)"H]El`R~(ijV �"�Y with3Y"�MpM farm�C&�n%Tsa�3d� 2008a�8 Fig9 W Pabl�Z���Care�a c+�_�.Limó Vov?UM��; /p atɤ densqn*���5^ <�9"�:V�oT�j �:�!�m3'=b&&�Qare���9pp�[�of 28K342� 64 h� ^fe�L�u!�th��>a"UX(�7is.GAlajuelaA�)I! &�$Xograph�C�:���principw ana->�. Lc*�&�p Fe"_%�:@eac �.hpQe���hH��CQthecia o�/ɂJ a�9���sjQR�f�yimA �.��5 x� -mm p�>�8-;aB�Ov ( PDB2�}/? �#�1�% �i" e4�d�!d��#DA!�4Blona�8.�to�Dphi�a B%".?PM�Vbi�*y S5<ma�Cockeysv< , MYE"� � 15 �t5j ��a?in�2F1(8c�ye�A�nd3iHvA�du�.6�:6498MYSC��2bppkvnmd*� �6Jv�/ �9��� etic�nf�u� �U190�9� coC�\E�qof 95:AA�}��%�&)�.YQ�� �)i@ omic�m=+��h��PI [FxKi�Bg��Mad4. , WI"�2�Pg�/�#�P�?2�P�2 μLCm�A)�#�4a NanoDrop ND-|S�2K)(%TechnA�a, Wil(<t2SDE�L|HtRUgU ) PCRK"#+ [120�K&�  50-�H=�m�6 50 n��l�c -�,�R"Cl�T� � dNTPa�5ofi�p1i%nd��4�Taq%�#%�(( Roche�annhei| &@. T*� A$ carr/"�,��!�� #: 9�Eq� 40I<1 70�13�Snd 72%W��Oe*!r�,H at =. Ae�-�f6�\�� as&� 2�22 $!��'ng� F^�a� c!I)~sI�&�$o�B��!0G143A"�2A'cya [122)90f H�V!h t� &=�g�i MS10 T�1�2I�a-o�wn��f��m��N�on���!20a&x ly 1 h~�5#�nd �*�X0A �{f���6� | �.F��E'��+*�Km �e�UU([.�teވ��: Ua�Tr���<χ2/� A*~�'�U hapl�{oA@�Peda�&t$&�Th�l�p �ADllzx!�� ie�-er� ��J�( H��D!byDus�J*�I�GenAlEx�4���6_!O4o!Ae���SoT� meab 4 �9��'�,��� "�X�Vd^63GSd�!- corr�V,��6 : OyB>^( G”Oe�F (ENODIVE Bet&�E�B�24i�lll\U , HT�HS *E� � unbiYBwLvcUNei!plT�E�+/�@ ��of Jostt F�� [126][J>�!� �. M�L>�9��r=>]�( 2,Mbio . i'Lauk/�ave/�-$�%a��P�upo"Ka�z�~siG{Kh heavh@/%�yE og�-��H"߆ Z ��.�5GlimT�a� qfۘFa"�:%�Td5��K-+J�I� is pa�$Y��s7E(L� work aut�^�8$birth-deat�d��tra)phޖoj1�)]aa !_A\t@jase-by6�[ ��/!jOu���awapp�-t6 2�6�hY� ChIP�K�K���N��� GATAISOX� CTCFYCAX� TS�$1am) tow�KhuN0� -m.)�#�Ha(. W&ff)�a2)fr�oN16�( ∼p�79%��Mm�0 z�f�)s#-х�;!� �=� 15% �Kll:w�LuU=d��9d!��U�'or|%Oed�l����6��E�#xpathw i� harb.NsݚSNP�Cq7R%6��hy.�w"�$s�ul���n%�q�GApeh!]*d��fy1�I��F�:A-lpB��irf���shad����� Q!�: . ���,$play a keyeO�2m��F"��[1]–[�A)�^� ?���i$�l���o+a�viaUn2M~( TF )M ���5iv !�!gV�%1a�b9|�y��T[vU���e�� 0 immunoprecipa{��u�V!�TF�,�'q�4h putyU(�;) ��,Ń���%�3)B}}:.X:�- �^�.!.B� s�ly 痡�4 (�8s2�?eal�de��pammalsv!��HDes�~.�e.�xeI��+i&0?�E�l-���:�,�����$�igN3��M�*��]>� ��Tf��CM?��� ‘p.�%footpri� g’�I�L��J� �E�*eMN��ٍG2 V[10%��YX2�&��AR�in�BTN�� ,%�ex� �.e$H!�ofm�ed��u!��A�o�^de!"�1S�,6]���y�al2�A�s5-E�Tlos}cu�N �e�+ , [1n"S such.�%�ihelpfud���kaB�F*��0;c{�I@Xs6|*���AA�tl�4�q-9a�in 3Oco�?9͡�m!9E�"��2 � �Ra�\� an��iT�"���t�M- r��inc7 [�Q !�errH�in�w+%mE4��Hv`v�YA��]r�>���1:is v8�s ail"["� ��� p ;�FPrch�r}��le�Js[�, [�AKe�\��I;�.ia7on1�q�=� )�ir"Lto%�2� ;2�2�i�dwA�)�l� o�>7� "3newly-@-� � 6F  S�q��;IJ��]!�UEG*v &��A1�Q+s<�4 [�e��(� � E�ic ��1e� �A/g1C/�tur�O1}lie�) � ian-%��q~[  . YeAU�ja���j�T��z�E fic>a)�;ss�: hA s�%�a�)Sfm�wi�sR�Z6fo� � i� �l"� "� �D.� r�9B, TFBS�In�}� )�e-v�Vl@6� trasO.�� d.�[�,��x$[,Hwey �uJx� ( �M-z�PmCZ�jjA��;)�� "e�J�_ 1nderl�6�u�;. G)�nd�� �!:I�şex$itl�[\ ՑN m�l>�f.s`�ect> mo�L���Agh�,` ��u.%� au@͊�� ex_0an��~� 酭� imil�K�^A�-f0.i�A�io,:u�to"im=�Dof))�Je�8� #M� s [2� IJ�st�n� ]�8In6�%�,�E*��\yR�>a�v�x :e�ix 2 .�t���-A'j!o� hI+ j��g�Oad #�6�s�5�(hip ejin-�O��,%zl(@9 � B�]�B-��:$!�"� .�l{9w�zng" Z� �|�Fqb� �^�L�@4ste��Q �d: ���6� �2��Wz!^9)�l�s:� . � goal�y�M�1�A��E��i�h��a6nA/>ja�r� _aN� ny�IP�X&� w=l5��Aa�rn)�KM�aU �$M��ɳ6�yvA��S:��Md[Ylv:,��/�b �V��>��%f!�%e�J(� )%sp �:�!�reMU&O �a{[o8)l�>��� ��>>3 ���$F�ym�$`"J}�s�!� K[a2 �� �( X8r:�"dh�?baRat-�ai!���t�G� e un�Yp��XAG�M�Q�!��p=�/� �,�=Y�:�%q�;��4ng �i�'l�er u ��3���>lyE��:Fs��Z�:����; 0.�� e�^e�a�� < -to�&� 5���i�'amEaFs�~r&� z}��a��hE�r� �,�Va 2+���?!���riQ�Aong%��o� �?� �+97,�YE�c�  �)E��l�m{ ��qMM�0Y:�M�"/&8�TF-�A��\s1�%,Ş��� V��my%8 f�e�&*�)f� "lc.�H"��u�+ E-20N*�Uoa�4V��M�'�!42\:��:)8.7:,-�E�u6m^�Pn�in����ny" 8���a8X�da�/1J(*T1�Fis��(ry�-���Ygo��s6, a ( �GoF���9^:�90.^% a���at ���"OhisM�azE�R@no�G9!D���el. B� %�.!v 0����e� qX�9m:i�!"b�#:m��re�a�,�`� i-,��� �>P0� w*t?[A�U5�@ (թ M%!�!��0I]w��Cn og�=���a�ut 11��\p�l�br��">z��i<�ar;et� �Oq��Paa.ya�>�T full.@wfdF\�@e<2�-K�P����*C ���!�binez"r�,!���%�.� �;�RE�E{M�u,;}mIU�� M@=he `I? G�or a�"5�?Qa"i" �.�yrR�a:E��2C&R .UBh����e� yp"�A!�&�>E�r'!��;)� w�tif23�NO� �q�TF . ( 2 [Qr%�%�)�2%����(l)��5�+!‰/.� -�9e�r��� CW �N/bERRTF-bowV gr� . Se�ai Supp���* in TzS1��)���&V Gc"�I�17!!inT3ure�=Fi Ah< �enario*O. �"?��� A��^�b\[ \�R�  ��pH�՘isv�e�it� �E�!N� �B �X �e�,��j����"�z��&F-݁bio��aUr�4 z2�%��e�"S E�ku�Tdu�.�&�%kic�W�O�S�!2�� �g�!�y8�#t��EIaNFe���!Atra� "�\ϡs���^mn=�" �P Z,)�%��q��&JN(� ! ls@�f�T6�� 7g �e6At xa"�R xA��5��)V�f�`lyE� i��cno�$6 ���!O�r�s E�6n�!&%� �/ �(O� Y�(7����m�"� QَaY���nE"�?ei; |�#tr� exacsllu��a�#��zo�o�&"w�on6�c�!4�P8&��<<vQ$�QZ�*�{"_  �2@co�6Da�2�Q#6/]pr�$�� �D �`{E �Q���t}�-�)v����8A~s��d !��q2re_Rvxh�VI�"� ,i]",mUa~bh \as�V�e6A�)AE&� f�� ��l@!{E�ZA.y��sel�  ��8ln��9{l�,stx�{�, ��-n_�� !�decayD , [3��C� ) ly (� near=loD�v[i&!�c>�#eS��&=z�&�e�my"i�� ���z � �'ݶto�n�=� Vw�EmEr"map�} vivok !�pa��Y�ҞW�s�n� �, namAh:(B (� (([32�35]�se >���jiX�i�<t#-m(!�*t�� &� -docu�s ng/ RuAHA��Hc�� ��%_��n�p 6�!>�. UA.�aQ K, "Q#�>eEIB�qSc oU02 A�EPF  f02�"i�q�.KSe��A:"9$�e6 *�;>�hav;IRubf"v%�3)>�P"- �S ��1�n��, [ �\in���Jya���DL)!��� �����*���%�� �5 tly-e��pex-��t3"��d:��]�%�� �~�02�t> "0 � b�A�ah_"�z�=A-�M9^)c r*@ �6�� /,�*�r�'ly-"�)51o�� ��Q� �%�B�= �Z;y:�A�<�@RU� �%~� ReZ]assk9aZC�.( n�)� e%�&g �a�.�()Z AME�J8.@Wa���4i! �(yp!k�8�%� u�V�) ��n�>m� �'3#9��pr .�{a�tT�*Q(!B O-I !Z5s�_��� 1s}"� a*�-� o test [3e��?A�a Pv|r� ���)eA�!� 2� � 2�^� [TF�G��T� 3A�N��D�)6*-=VGAG1 )�B  _ l#�e�*��e�1t��}1�"!71�-�"�%ex� )]*s�� y(6� top-nx9�!7l1i_S"o di�zBQ�jB+�.� �,� S�,vC!�1Qz��� W�DMatrix�DW?`Bl&�JK >�A�!1� �:HF~teW&�%�Nmr1 PWMs�dy � F=cH3`^J0�.-��#���MEME sug [38]�[�3�?�4. �b%�soc8��t����Ay%�� U�%L�a�9 . Each6$Ab� �.( b!� ͞u5l�� o�9f! - �&I# ;mz�&��*6� Sj "��Uf� �>Na;No< y-hG.�5�ll �G�5kQ�)qs ��.splV��;*�~��hFr�6)9�)�m!�& -s.e- :)surY:2� zI7age6H��.~�: PIJH( lef�hnel�3� ze� fd7y�*�0&41f��X�U*� >K%$2�2�#r��c7�J1EX1�7�~ to 3c� �.��E@�>2�b:7�r,*ZwQ(m$�>Wchimp.',2�^�5%�10�T���?�"\�Id��6��is `�@M�%"���%�h Z*�8_o3�^"*:_!�a�K;:�)(��m-�y2�ls84!,�s93<.GK*440+6409 �9�..�! �a�%a4)1 � �t�� ih� "� ���&�'"� !�]6� ����.='�&an-1��<;(�2AfJhu�E�sl a�.���5*8 �1ew-%�] 5�300�"|�='Q8r�������ve empha_!�3eK nN�1"b9B�+�x[� [39v4�G�!I&�|ove,�K6n,�@��av�ed����"6�x4;{C�'s~b)zp �#ortj��b���+.Uq�!6%�2r��i&A*�> }�TE"3I�*$��D�C�)!���" �x��$ly 35–40�g �*l3>!- 6�!a+L1L�\A�6w��I��6G..�)�.�:I��i�#w:3%y�TE &]����){ KB RA����} �FEzIxF�� ab�st%_!{w�+gd� � B%��fza� �B*�1gr]�v j2��d>�bx�2�RJP� k ���o�‘'ped’i �if!D wk 2� +2�2b�["�! pE � in(=� "c@�Fn�Ir&mia �j�a-+. �R� ��C�>� A.[JU ��?� ��� &,8 .j"��bQ�1BcYI� )�Qr��)KsoA �m��gen�lJ%1�>qp�3.z��-Q|vp� e�J&!MF�c�%��" , �&S:�k� p9h.�a� N��<epM�(�9c#+0)�Y��� ��!�be / ghw6hY".�1& ��mo)*&�!Ȼ6��:>�B1��dB�a �p7. HA�M@-8��&9E!���"� &'�!�-qX@��t� I�l�q-%9�)�&�U24�1D) SE� ��I��lake��sam%�� ����/j� ��le 59��6�mx �QaN6FA�/ �� cl�#*`�A v���O�K�:, �^3. A��%A9l:E:( lIV�r��%?B� �%�)�f�hE���B�� %T�J�6^!�>90% ) E�U"f� �|i�5/i 2��)�E>%u�������8y8offX-� ��Q�a� _A�X-AA� . V�.fewm� a�acȒ\%F V5LC��a�� 9LY�� ��"W A�5 �0v"��"w!SR�Fn f%1b�jP & "2d\�5�� �Z*3N�r7_ `2O �q��TI�.w*�T�I2j u< Q�� �� ( X >Ik2�etal�@>IBI��l�n��&PQ( �x-��A/^ ��")`q�_6Q>�i0!�M(! =] H s: HV�},h- :, P�.� Eut�,z7ZJ_�*�|9:9Z-)I,"~ ( X-!U/%6�exYD3o2 Ji�� �GeX@�AI72J�!you�o�;"ZS�-[0 ��8t �&�"r+.h, ��*�@ab�\}D�G�� �`42�F�o"wdem���A#�wiv��� � ��,v d��H%��+Ê d�p A3 ata�"eEA.jGI�O�%6I@F8cat�2v--�(�MMap�]!i:ٛ J� [46"Y�A�mM?:ZPReMod4R��&J�=Bout&$[T3�Y D.3S2/JE,� S�?RfR&H�"ld2"�����D2dC�  9�e�enst�&A�y �f&�TTCT 63Q4% 0~�?L.M�n & ���QA��$�ag"uA����n�O១V%Dc'5SN���s� G�0�`Kiz�)"ev�4? �a 6�.�e�) g& .���N�� � �RG���1���8s����!;a.� �hlap�w+l)!'� A<3b� �� U3%1���f1��A�.�Y���k29�+Q��*�3s �L� �$Q�&� Z� <9qb +pHHh�#% ����� � :X:[Mx y�7/.+.*U:re�*O)�r�?�0=J��nB� �5�\!H�-ex�9 h' � ; !�� |.6?I�rG�t>X�"K}d,�l��I&�*�J')�R-Bm���!�ey�[-i�7��l���YA�����.�ar�"ee�S�����lu-wMI))T��||-(� ��i�N*Gi�:&d M �i�#&�SNP�.� surr���6|u�S kTo&��eAu&�>,�a�mbw!1mr)z���&��he� �8��!��DAy:�%"rE�5)B�.\�%�b �e�'�7:�"T�tch.�!F*�ag��.1�^�՚� �lÛ�s�a� A!�mDdV^/4(TS� �o�?ek(�00 kb���&B(=�B!9�WsHiaX��Ly*�E�����::ee1,�d�ve0mS�Ya32�neHn� nsor&B�7%M �+�.'J(I V(/ � �%: U�I�E�/k��2�GO"-��.v�Ni������!�}�, s� zMAX h2d�al� �\�-� "Z !�¨�A��a�.W, L-%��u�A�#.0a %�c�EBd nal-5maM�nE�[4m~[5�| B-jIo��i�.m�Oor2U+iJ� 3a�x3[y���E!WA%��Jy�p7U^,��t�1pto ol(�)��nA�j�,b& ����2� 20 ynap��ssD���ipG#c&:���d�Y^!Q��BlyP& (_IJary�idB�[5o���?֡ J�axoFtenSX��4A�s�mXBp�Iq{ZgspiC3�+e9�\� mu, v�z�-�fe�)�behavio)f'�n��%� � a�B� �a!2�9TY�n�C toB� Jn�k��1 � 4E�'L"��  3�\f:��lI�i��5/%� +Ld {}'w�F�'H]L> �2%' inct�  &':sA s)eqex�����-�<#e:�A��*AmC R��0s: B-lymphocy�[ ( GM12878<&embryo+� stem� H1hES&�Mxbe�u dA !9 kidn� el 3RE8�9�� ",G*� �<5Akag:&'�+el:�M}ubH�to�O2��a>4�� ;�:Y1P2;,* h>�� �%�� �2E AE �. O��43��!s by)�f fA� Z�4��!wo&"| &��sI6 w&��  ���x�C@a%,� n�%Z�x;nd 24ځM:}Z"� 4Ewsy�>&� x �M/>!���Fe6CU�Z.U� &�%5�CbE�$�6�6?I��&� � =1a S .�g�� ��2c�$ 5�.� &&� ��$#F��,{%sJE**� ���!ab� v� AEI�RA+% �L�� ���9�%�E�>�mi�e�r�:3 d�*+& " #a&NC�Kt�u)_e�t&L&4_�9 e�a�&K�e��s ��na='D�e@d!�Z8!�B�!��o rs�h��R+j4A����0 enhancer reg�^ions marked by ChromHMM model [53] as well as in vivo verified enhancers listed in the VISTA En �a Browser [54] . Figure 5 shows a potential functional take-over through TFBS turnover inside an en h�after human-mouse divergence . At the seque�level , two MAX binding sites were identifi)8our method with|@ancestral one and�8rimate-specific2Y emergg.�  MAX/�.k has n)�or��0signal at all�)�8, which is consA|nt)�!�lineag=� ��. S%A�youngV� only locaA H1 , 700 bp upstream�CF� intensity,(2�,is much weakE�I�, compared to� this1likelybe a uofV�A�m�q� .!�n we asa�whetheke q�Q-9ey� wa)uervaetwee�Ac)�`. Interestingly , despite%6y� �sB�he k~��� foun%Vxdrive reproducible LacZ expressA+$in E11 . 5 jblood c�demona�!by/�$transgenic 7Tembryos essay based on^%Q�,confirms tha��J�e�1� s as���in �(. It certaiA�remainsMCsol!�YisCregule!q$same genes\�i=�!�why*um�o)cia�R:  thanHe�er�^iQg4. Nevertheless���xample.�!=e abilm����toqf5Aal�dynamicse<>|differe�Wi� evolu�]t�� erva!<TF�,s [13] , [27$55]–[57]Eos �highligh�n�sub!:%U*ofi� cripvfactor-�� even!�% �� es [ u �8�60]�F o some ex�Q�0dichotomy may5 reflect]@s �?analyse�Zdu�<9�aXexperi!�-�A�. Altho �5ut%N�4Myes��had � succa7in �E cis-=�alterL��sp�g!� for chang�0phenotype [16%�1%'A0���W��YMi> miabyA�i�-( upon multia�8]�[20r21!�ReAO trucUH�� l st��ofN��V4a particularly� llen� problem;%aa!ve�A6Sm�s�%ralJategorA�Y as ‘��C ’ !�‘non-2��e�A�h� ���{>�34% 396% ‘N>S �r�4us often assumnbe�x a �amount� puriI-seA��%, 6 ca%ua!�at! lack4ѝ [62!�How�� , an�4terpreI�0A9result%�obscu b�Xa��t2 di_c�can� made}V� ���� ��r b�losa�versu/ � %�c�c orig�+�swly-deri�.�al9��!]�N� �$common def�� on ,�-ia�� gain-of-i��i�harbor��!+&J a�B� adap1\r posi%�9�.� long) arguA ��.in.=��r:!m!�$, if not m)b�N�rfic ҡ�Q��a it� inde�� uW �re* contribu[ o��ic.�W!. vari�� s!�:D� f Tex!n6�]��Ii���ENr6,.� m>�is6inot�4. For� sixE�oralyzed�Ze major�~ TFBSs b� in� �I���aby4 �M��$oa�bT previ� �)�Ŭ� isDno�Zwin& proteinZs!ptwoQ-�{��6��i���a z��>X ( T%P1 )�dd!re� 5(to detailedZ{$Drosophila\ e n���[�N is doe�t earfsimply��aAU�Ʃ� �a y�E_� ���se�s�@alF$,( CTCF , ETS�i,o  )I���1�ly docuS!ŕA���onٜ)7a��tif�5 o/��A�� �~eF�L!�Dreh�;����h��[A :��YCe��a� secox� hird-�est rank�(-&� usue� measd�6�re��to neu�ly� v!-�kin � � � !��s�f � ly m!G-ZedE�a}�xA�m=me� �.�1Z���[, nori��@ev%=�oo� ;7ideA�col�v� -�!�gen� e:�t�c)q�� 5\ly= }�w. m���Rv*3 =^k a�riH3��>�,% �4)Wis birth�new:Yis��a��a%� pert� a handful?T��bu�_ stea�ono� ly1X69.>�%  �h� e� ��'��$acknowledg���xa�!*" ly����:!72���B��EI;� TFe��"� 6� cor e&� al nois� Whilzsearcher� tinuou��improa3��f * ��-tput6h�would�~ne� �0to systematic�,valid.`1)i��, e� /��Bh one�AmF �&!���nes�&R themeeunique�hominid�d���z�0qO��e&an esty al2v8ome-w�is qu3e�.�Q�)jA�>� will!�I�s"�B�trait!� �{ non`o� �to'edk ��&�of!fA�A!OviaFcre�gof� ơ�txalM,�W� ibi� o�In addiW,�L5i� |� havee/led2~A�:5�!Yus [[i��M10 suggt�}�-b&v � � ZA� popu���re��!aeRm �*�.�a~�ual ye� = s cl�oM �6M� !� shed%�%D�Y!�M@ob\�I�Mk leaCtoi&�n"")8&%*GB�he biv��uJe;sassoci�!i�V ���\R )n� 6�5)oH �enric! �s� sensoryEneu� c �athway��pro��%�Wea��at� ��Pdat u��A��A�Xr=5� fromy6�a�fur 5is need�� I_&� ly.��rolI7����� ��s typ�:�� a+ MP�D"{ ���� ides�y�gh�)MNI y�/A��3 ;E�"� mole� me�isme%  disea)�A nat%�futQ direA%���j[ermin!�*� .�ffects�Ik� ^�-= �o�0in��ce�nA�� �A�i�res���RBs6rai!�i_gu possiM��BF �� >z*ic2�t EN���ls?eY>Lb�. F)�)��n.�*�� B)YiOcas��&���� brouA�ab\ i.c� so ,�" currJS!a�y�g�O ��� ��6i�7rpl�,}:�mH��( ?g .a&�n� &��B�i�)B�"s1�t5�[65�68���)tonnV��I?k � H!riA s�f-�f ] �� !EG}m���anh n qu7 U��E�� &^��:�TFu;QPE"%�!���b A�QI, a�qfof DNAM�Oc�#n ���,\by\ meau qKi�l�/��A�at";�fu& z��z� &� of=�!���I�Qzbec� g avail� . Our"� apdeɗ!�7#Aj" A]&Y �xa give��" acco�o a�-deat��(9� �*a quasi2+�� [69]<m�at��@e\a�timaLof�ele�d��;%[29q~- ( ). Uatm")w So�{apds(munp�,a� per y�A�pY)_�w n ex`�+��Z. G%� a se.�! �a�n �!�we9�)������eGetre) !� a maximum�ihA� . Le7 nY�oba.�QW�� v-Vm*nucleot� LPtA�`�@,2T� �Ŏ%T!� time!Tthen (�Set�Adb<%�of�nge ���ec& , Eq ?a�ey��equn ( 2 ){ �z�!� œJ$b� A;n [��ew��� ��E|&�@A{Z@did� 6( i .ůZ!�i� IN,1i��&A �ys�!I@�#!!�, bot!>��j��ib�uRx( ��A�� � e"�!�. Solv)�)�( 3 )EN��2��on)�6xQ��I}��ainEՉG�\!)�2�%����(�~:7A� � o. NamX �"qt) Le�s {.]CB�7se2,��.�is%HnA��binom�/��,ion: ( 4 ) SR�if0wid��(A y�A�e < ~�:��ua=Jq�B6�? ��=� foll=+r�5vG�AAw���M% yIwn / by ( 6 ) �*)�sum&ove�"z valu%3w�R*�$�&�I�. �M� .)~�w��*�9)/��ɤ8Ve(�w)._�R�c*�S�d N� describ )low9weS cald��ɒ)�0 _ FelG's prunaxal8"thm [7n$��us first!�R HaLgle�~ .��le&2�arame--vec�'ri�E�V+�!dJN� dow )ea+a nod��O�y���daF er,�S,%�r�>-��v�paL ]: . If�dom�� �i W!�F�6�,�$F��>� V�be&)recurs��Au.�( 7 )m:�inn�il@allBn* ,*�AT� e~r2�)Z�i�/�rn.m�.�@*qu�/o 1�VweM�obXF1�F> "C�6 zero� wW~ #.e!{��f� ^�b��%*he�� prog�p!W each)far[ upc�� .�sM��*J.�"��AeL; ,B[��~� MUPoiss�$is�h�� �m�n�^ 5�)HK:N P�_a m%�-���W��d-�!pfstI1� ")&)(��A�u���%�t ii �.�i29��EBr �H���.u �e���; &i� � �at iz >*�.. P2�mo� ������ �.�n�at2��optim�"�F��1:o6�9>�branch �)��a� . B�>N�b&t��"4.�aR!.� wfao EM-�+' [71]�i4+�'��)!K%�%�)���i�!p�M� begi� f4_ �E�7��r�*,@e �5Q��empir5F7� R @+aur`#m iparsimon R ��&�,!,i1A��1d:|c5���(�K>�s� W�/��a'r�AZ�E9iZ5qi<-w�x14 dͱd}%?r�*�J�al=I�\�Movi�~!1��!-` >�� �� inu ��,-�A�%�f��M�on!u?b����)>� �V�until�"�7.��) fall/M a�28esholdA Ҳ�����[ �:� R-{��. Curf,E�A�" �&troM8�'<1AXo }z%!�!S=$�es�0a�ih�9!h-ف!�phI I��FM!�� reve� ��8�can� it�.!0�YD%{6 nfer- -A)5�in9A8�� E��7E-%vD-box&��cri�%��D".�&�E>)sn�baWdF/0ng BMAL/CLOCK� iv�.� ��8�&)eM3�pI�9homologqz$thyrotrophD9T9f�5� s eQ�ae5! ~A�%Q�%v 2|O"�9)2tef mRNA 8�!��3H%X!�knock-> �,ef.`attenuvA��5��!�E�prmť0v�/TogTN&p$pport� �i�=akyq�7 talk"32/)Ur3�u�l" �,�=�g2AT�1fQZte�(h�eC���8!%� t! �b�3ɻi|:�� %;%r��>m-�3��ge6�by 9�2;K)!Ter��s . Es1�(@ orga ".$ da�rhythm�q" chem�� phys�$ A beha/1W � n#ntrj,� �> [�5U�9�9��oscilla�{B�"ad?a�%T%A�ngU �neg�0feedb�5 loopat��j-autono�. maq[�5A3e fvrun7 �4o"� )�2ot� cis  24 h\t must b(=� d� y r�� %o ordeL1 synni�%�%Ppq96�*� ^4�m* xt mcum�E�in.)�ic���. [�BIn*� �ic�u�eyE mmun�+ed" )8retino-hypothalt<� cBRHT )�+A/mas��Y6pacem4@"$suprachias c�us ( SCN�i�rmoy.H�&H&AC��I��uH�ur�)r��an arra.!��>Y��h!�A�a �;A1e�$'sX0as loc�Mc�a$metabolism�nd horm�&sec!T�!O��A��  SCN��� N2�,m�on0;� e p`B l gl|. Via���:synapA �' ,o-Ws �,�)ApRf at nEh���!g cAMP�4[5O I�1B � .��Y6� .�ear> percef I�[.�2"��airecepKa\u!�out���A�!�na �)dM�A�"a1 ench:e�1Nh ��5e� ey*�F deep� <ure�!!%A�2�z,onZ6"Z a.�!9JY�8: �' :sYKY=�Ź. Cc54, cul�d2�~cap�� ��ly���<c#fiL �� �FQ[6�%8!Inv1J!�2-�1�/� o�!z;b��7. >Di.� ,=P�5s���Bany"�ae�� 5 -1E2�6DH�b� rec!QI� �%>[9�1�gAF� 55�s�h��)Z�sd#�� �� u(a me1r�As.P� "<,pec� ,a��CZ )%�aO��compon�@F R�,ePinv�C��t"R " . Per1%^� .� m�ro� ��a�in�/�,Eex�durA�A< subj$+ve��ut  V$��[1\4Moreover , mic�rr:m�3a��� � u9\exhibit�no�% adv��9d delayBh�) shif]!�OpuluB��%�2�n� R V~I@Z' -Echicken6SA�!W[1KF2ain Xenop�Q*q � Y�\K l pig%�epitheli#�-& 2��r�0i� play�?ol�YgmOa[1�}&� ���p r�?�)�� i��Cdq�  �n IG�?`�(( PAC-2 , Z+#e?1�l:,er�@per�!*Z per3=͍M �ho�HQJa rob� ��� )Q/dark� D ) cycle"#2* C. E&QH)�ut3�>�Go ���9�"a=u}or2B��ic2oer G"e�Ohr,.t �nD( D�! V� q�!�A�"ntiQ/��iW["32�I- ��fAe�.j�X�D�&|<%w'!�� �mI� v���N(dampens imm�� 5#>DD�GLi.y�IMK�]��; nduc���.� ���+V 4.!:bod cran�$are�I"&�Dm�2�[1�P� BT5Erapidly�“�s on” D!6 E�8 3 h*l� �EmX A�tec�&D%=��*"a�*Rd��6Grequid7�-1^d�Oop�� al m�1e��-$�1$��lO� �%��/!�vZ9� c� fi.(}0 5 �sy� �A�� 1+NQ�gJe ��!� ��g�>Kɺ&�by!�5e�BW3�H6�un.3�5W}!go�'f �:A,�A �7<'tu<de� w.@ �&� = )Z,investig�5� ���of����=!i tv� %"c KorA��&�**t3B�B� inct� �3- rol.�!�PN r"�D% ":. !/�poi @axCt.�Y;)/�2\ ��aP!�afea:"� ��.3.�L�#V�XX!�*�4�k5>�i.2�� An i�6M expl&�F]^�"� ��"�&�OE�i8a�to iso�G%.cha)e�I�FU. A!o�`fraS incorpor �X>v�{�-4. 8 kb 5′ fl�BN@ic�1O3A�'exo.64`R)�%xA�subclo .xRan EGFP�or%�� 5�−�P8J:-� $ . Microin� �F0I���94%r-�.v�T�P,�4 A 5 9�O~�dsc �&32�ap�'���tyA�s�G���luores�I diss� ngG roscop9�TF�"isB�� �s�M�%�d&0Ew�8pr�@�F�-i.�Ne�arvaeqIn "���?m� 2)��V=�horA"5�u!tes!��6 . E-�I �6−0 . 9YQ� 43283%'n@0 !��2. -�h!�MU.�`�-a�jP"�!5�B�-�1�"iWQ� �>.a�43Va�-u�h&F� &::� .�":he TolhpoE'�[1T aiQ^ , T}FJ�) tlv1!� a` �UC��fe<toi ,�x�QC$m)sm�s ubi�@#!>�%}�Td.���� ;in5�,�@a e,adN5�2 AoVideo S1�,��M/!w��# �"#wh�mk(,situ hybridi� ( ISH���Q� A�q�zyE��w� %18aanat2:mRFP ) y��( kin� �<(Reiko Toyam9NI�K3ch9��@��cAWcluO,Nl,!��$^Ndou-��]U�fJ"< vo&� ��R-l"�%�!��=�N�5�5�fn%p9�ɈvirF,��d � an &$D"�"�#*Q�U�j�"�-�aS�O���Q� 2� ��B:T�Ler->&�Wey�L% u�"��:�v�2���E� kept�ALD�*��2 �*} � � pK�:&� �i�2te�rA*o!�to 2 �H5 at ZT 0�r!T)�hDi�DJ��I}2�k� ,�$�)y d�' �#iX�!E��;.2�R�i� egfp��u�#.N�6i%�al�}Mqvem �"' E7$NE . Qu�fO� ��Y9�a 22-f9'"�v��Ds �a%� � ��Aie o a!�an� ,( n = 16<"05V8one-way ANOVA )y���T.��� gree� v��G ��ly]>u��!*�'e3| c a�� E�202<!�� �Vgh&}=DZ.�%��w*x�r*�-m��>�F�:(zU(U&���s"n7]K8A20ani&Yse5\ %'ferre? * "ɉmonit} �q �F��E,��:,�8 ha l����Cu��� �Tssau� �bwerSL"S-Amss�a5�'-�E����[)T�5|Zoe�$186P �=2UA+%ٵ�J� %=\g�"(Ab� 7? :LucE2w�: Subs">2 -��\!]%ve-+)���:r 48 h2� .DDQ$�%��L��":T�a�43��B�s d�L��7=�� ( τ�?24 . 1±[za73x ��8�ly;*�S2> �lN�� d.�q/�� :)��a8(ɡ5 . 3 �� 6 . 4 4:�J �e�W��g�h��>'F�"HU�!-��i& inM�I2� .�m!O DD&V,a�yI ��&�\�.���Y�aIo6�a-d- �N��=*fA��.�v&J��" Y  s)�Q^|���6d b#�r#. 6h-1A�� �G5��e�ai�-2L2"a25Ib 57 h.T4Bw:g*6 1܁;to!�"� 4�vh�?9E�!�)I ى6����9"N�'iBY/ �,=ak>a�!3 n]�:�F�:c3a ser'� leA���I6�!ypr�`ed�X;ONB�c�par6(ovegp!dl� � F� wildCF[��2��D K# � .��  i�,-�k� %>-$2�. C�CE)� �o:���%> rofi�ofF��=� �U!� �)dM��`> T9F,9"Q�s 5�x>e��5045M�&�s�%�.*�u� !��:6-��2��G% 6�P 5_J�G1�4���A�� ��x\wSC!�B5%Iɪ�^�*6Pign7 t$!ed5Z 5A?� a��!Y��Caf�0� Ie��o"%ev�>�*�^of 145"V 89��−23R � a*�3lH �#�+n"�0!: ��OE E2bet/�_* �? ,��'r �. ∼2" sub-92a%�is� �e6��eh��wa ��^��Yt- 4 �I.2\J5�[.�h p: � .� �� 3 ,�at�# 1��ulAg� kasAI��u"�)�J@in����f e32.�� %r��q5(f�] V.iIΝiB��:s���%l�d%Oc+)-���� -��  67A�seYE�134A�00���_wm�@�"��.Zm4�4.Q8e w@_a�AV%1�!�"��G�218 �13�4i^!��@� e!�p�r!r ande�+f�pforward!�#r�Eri1he TATA�2.QpLuc-MCS�smi��Stratage )��3x� ( fw+8^ �rev ) �]U3M�>>v }VB�eE �]torse�l�+$%–2 . 5%�V\�MCy�6�.>dS���[�&I�s��1��!^a"at��� 72=��j!)�ak�`bE J�� �V �L � �/�rJ�4:px6N�LA�j99 �O-�6� �e2uk �P!�"�6&�-�a)�hw&�aI�\3. !e�m���el�h-��b}� o*4l�kY(�\,I�^18��12���Qomp.� e:�S  )�).Kah�s�~�B� 6L�E�D.� wh�!��8E�"� high�{ty�H0a�63a�e�15��S0!U�2��q�1�F�'�sY%��R`\�si�;��  �) CAYGTG�H� Y�a pyrimc>e�M�#�P�7�"�wo/4�BDk�!�o{,!_�Hs sk�VN!�( CTTATGTAAA)hi�- �Km&�I:����! 8/101q�4tc�%7n�i�7(RT ( G/T ) ! AAY5R|a�j% %L 7+"7VJ�� bZIP� c6%n� �pro� acid amin/id-�W�*$R ) subfam?6 ( DBP; TE>`HLF E4BP7 �&# Bwhav�je&#l�F.e*�  � �x-�)������1*�&!�2fg23] .NA CCAAT U:U?$anC�(!�.� �*jpolII�!Kgh  [2�,&�K%�*p!b��UO$o6 al��7�P,�K�UedA><L�:a�]N7lsof:$f�# of 5| wu=FBa ��j(m�!��E-!�E��BU replaco�!&Gb84$6%�12: ( hsO.wn � j!�&$,6�\T i��.Qr��5.at- �&�t. Remark�,J[u�tw�s"� ��@�)�e% �< d :X , �r�92��7*� 6��k�� >a�%��3;'e� �e�: –d�>�- ��if -%m�e&�t�x!\�"�&m�8�B,I� ,i��V,a�w�@a�&cB�*�wCATGGy�)q!wA��2�$_u�`!�a� l�E5�-�1a(KY�� /N�E6nl@+L6ET�`��ed2"2?R,R� &�IL���a Bc �$ 10:�rf%^K3�edisrupe���1y:�Atno �i�)�).��rnm�6�,~M�I�r� ,�0:or!�c*vZ,�u6j�i ��(�ogh�w�A IH: �  dPheB�A� cruc�/0A�]�&�Ve��!T��cz +e6��Gn�.a2�{1n���a�/o7<l�dja�(Kca)?uN�g6 �A� � �5-�o2�@*  7>�To� O "�f��h����h���A:j�V#{F�( CAC� )%ma �(.u ) �xv by 1 �9�LRM"�s"gQaur �repea� � �{*y0o�E�pJ a�8 1���z=1!؅�"� �9.[��g�( 4xE/)�>�H��� �5w �>�B�Zm�>�Suc!  �6�# 11uJp�5panel� Stri*G3aMg�7Rd^Uh� �fl# sembq�3%�Q?[<�C%ZmYM.c�..�B9$2�g "x+<,!4�M ivid�R���/A� �:X6�'� �. 0%�J"b e"@�1-��5�{'n�{u>m�.d�!E/���%�lx1�oru:6xI\,2/middle0M�,CTs&-*3�!E� ��*=�0��AXB-XB^U"�6!� .�aD' �. >?+%t�=�M~2^A/%�%25l �a�%clear�[z&:a&N�*�L`�2:��$�7N� 3cBn� p -�� ,��?��oA���1���rq.*�!WCYb� 1 h)&�:�a#i�No� �%6til./ff�,H!��th�B�J)-ecaT+ 2�6��� ,�"T 6�U%�no"ha�6Yh"�Lv|`�CLD�LL�Q�2� "( �pa�2UR�8 h�s��p�~�T *�&: 2��!���B� �'*$3t��.�JD?�m�"b�7�&�0ly V�a�� �ory oA��*J��d��A�� firmJc EJnd9q[=!e�e��"Hn"���F��]co-%.�(m&�COS-7A%��[a�.pty#[( pcDNA�!��D mix�A�&� �$�1.�o[| ��Yi���/�x�զ� B�P�n"�P“� -�`a�2G2�=L���6�JM�&�6��M6d 5q*( *01 ?re6*�@��!<QL��)#Hu��"Ad)�|4�.H��ME�z4"jk=:M�& �� g*6.�)�S��ZgLa�ofJ�%�*Gw?AI� ��4a"�C���E�}��by.�.��Yk>S�$mM��>&>2<]i.�4,�� to f.OQ!`"( � �UdL2�?9h� �R� � �Ws @� ��&-:����PAR dom0&��bt�I"��� �*�EHc�L"u -uor�,}�-C�i.1[2� is T&�Nf5�NF�N ( TE.0Da|/� evalKNA��,b� nĉ�;%C*� gB ^�t%�Wly-x�("�f X�!O6U�-em8!f.�jP4w3)/">aqperfo�A on 5�u74 hpfPR�� D�'3�&:�O(i�fA���;� J�8 ( unpubli�r�`)�c2�?%sau�6����?�4�� �>Gj� 6�M6�i  ����u}ta�K-�olI"=�X7A��seeYF��s�*O#! �| � �= &/ ef>�d&*2� >( NA2�� ]_��xr3ak�is2sP ZT �< e��"�@ ,��Z3*:��-![���>@�AbtP!"�* &P�y6�aє:��[.I �*>Q( ZT2� *�A�rI l1 ����$ amplitude%���B"�,���o��r&�G�G�g� *�i**�5�%&}["ef!h��!$t\e"�al*� ��E , qRT-PCR%k�k� � ��� .�%��,5in�-n�0o2�4lź� �i�VjOodapFeg 13�+E$.�(�.�.! n��;� y,i!�H�e0`m�jQ�TZZ!ng�N�*�6��E~p�W���oL(U�a�&+mk9�� �^��|�.�(v}iprece v%�IG=#6�H9�@clu��0�!, �Oa�f�|��!A�_�>ghN6#{W]vxt� *tkc3�0ag>!�red�W.* -�:� �oa���""#"��'a�=E~ ��:W&"'.Z!E*LA�"�  32 �*aA|-*r*Y�(` 5_+�%H�I��)n� D"� �E!Tic!! -�or5�D9��)A`|�#n(2�N�B&s�*h lex�|g)����o&��5m�E���5� fa� WU�eXultaneo`�M�� G� .�� L)��c�$w3���rJ�l�a&R9TEFX � Iq�F��Yo�L0� B� ^i>{( EMSAb��u*F.;,ulocyte lysa{�yn�TEF� radio��label�5�+fu.���%�*?AR/�!�pg^Incub��/!_ e�88�F>�� a�e^k<l#U4Y�j+ Lane�p�� i+Bat����':� !�hTelt� �,�`!5!>->�n8|oligo&o��1A�et.8!oV( �X �  �4a%�a�[B2Ne�)HA��-a��z2T06� SPN%3oA�5kI� �7 )%@� y�5�In�GRQw�'t�3><�o� c�"�b? .� j�?�2f�*d 2�?orF &5F�fix�nd*4?]W��< ?moi�E�"1,$ �_cjZ!=( E2I�MOM�s:�sQ%���t��HiC R�:�$*�NAeS� mple�6�Z�!L� NI6Ie�"� ] �7n!&� ].cAorQ�og)h .p�; �#U=�*r otx5.�C_By�/as�Ai�0��Iol!�R�b!J�.t .|! q�rb"�VAn"q$�L6*�Ox�|k5C 1&�(5�"� ��n��sM�>�Joi.%��<T� ��=�ԁ�lgeZZa�2�>* �or�c"�P*)&vW!�&]N� �iO�+&����f@ �&he F�k4 �`"�'R�#+ ,ŝ,*"+���isoFD��!�rsrbt��!�d/��GOTL%�O)�V�"��out+[s�.�E[d 1S2��BPT PY�YU@A���ɅO�igh.��_]C�A��_�.�` �q��k6� � ER�+TT&��!i�`Z^A��\��� �#F�u ila��i &4w�.disX,�:�9�}�)i2r>4!"^�iur&�d!'he*1e,FCIm+��6�% �� i2T,�D_la_::0 t��t0-��i�m�U%z.� �a���.�>ouA���)� �J~ lR��dup��E,y>PF�e teles?�Q���a� extr��5�lany=Zgq'�3lR ol � e�!�^:\)�>j�usf!��q�e�E5(>U�-b!� D��be .�m5[ a�e�R7(uleB� j-> � i!˱%D) ypY",Ud&�c erN�Ph��i.>��co��Y Q. �a��!��]e*3LI� �F nlLIN��)֑^�Y8B03�zI-As�tud�X�8u�'a�D�FBy" �J�.zN GEU�s A  a �;o�5�al-�imaS��gi%���x&�OA0s�FSnin1tA=���m_�2g-`LD��t�BA?"=:.��3#�"a�(%��p.�BNt����:$�FM&z_.~\ ��=�lso&�I!LL�-l�p"� �}A�E;��Vc���a�A3�.-;M�a�U� �'6�"l�a3B� ���gL:� iR'�&�Z!�E�AYNO>%�J �$)�!�i�=8N��'[3�b&9!i�&mE9un�4"%�Jh��iL��!A��� Z� MmY\c� O"�a � @,9p�[�B0�j}FE�:� . Tacat^������ h.� *���]r�).>y;P5ont {�u�A V�,-�6�`aX �t-��It��� EI�M hier:�icA��%�r� e��%YD)�6�!6��_.Q�i� ��9ad�-�2�mE��lI�ic a6�Ű5��=>9�u��a{�!�7iU�iU�&Ui�B"�t&K[3�63�6A�[Qs� /� eĥ�{�i ! �\a>�&��. 9ir�_t �p� kЩ�kav� Q+ѣ �ain5�n��� �J EDe��<[�7Y � > |-f�IF̀�*a "Cnb��� 8 ��!���lm~��<����:� ��7 [� T)g��� � %���` ]s�%iBX� lo� d�.�j���4�i��&R0Ť� � �1���*ar�&�!Y"q=��xVai ?�u5�� !� �E_� )f� �<)A+"t^��<^BZ��S�k1Y :w!g E�l�Y_*�' �< ��2�C6e �Qio�- zH����P c@� �C^@� iLC,�P�I� ing�O!\am wkS �4&ɨ5Ʉ4mE�dV�l4ud��h�rR� '�W 0.T|B�2Z � � 5��_�i&d6�h�Vdՙ1$[ �5o.]a�Aۡ�Al�e�e.!syW��1����u� -�fe&�Eas�" �;J q�� A?aw��u�)�rrB:e&���4Ng�ll�| 3 Qʁ� \mE�i�i���r�,�&��@���)E��� ��.sub)^%I� !��|o�!Fzat �6LOb[3"�/!�F�#TEX�! �&2!A�JB!�+l.;c &| �����\l_�f=D3y���4�2�]B)7j��.�F]2as��mM����� V�2�U.�8X *� ex�v�vAY�'ў*y.٩ R.�! /� �)]�NQo�Q!AO�V�toB}&!}Ss'�7�1% �&� L�� "�&3�a��&enɹfew�&!��$g �,�N����&)� �J| &�$ZY� P>p'�rZi"�MF>�3.�2a��5z����1~-#2t2.r$ ro?[%}&�N F !���"`�]BM�I )"�7�� �s&�U. �* ok�{�k6����1y�B� �h���"� j� aD�}6��s��'a �C�Pb�CM�e"��}9lD)g���Y%2"Ī)2���'g��ӷ!3�1�yer2.��u3�-�� =�,�*�r?t� y)�J�' ces ���\P��7]+ � di.*/ F!�j . 4Q>�# � ���Fac"�[e �27 .�3� Ʊ�M�!e�`j)�@h��mVe�V��we^�mkele!~� %�uB�b".3)aSE!PI/64e�$.a��.H. C �B��g:�/�fur!�J��9� ם@":&�ID�>P6�)�0 �q�Np ���-!A�fU novo!��$�$. �%i=� �e 9~�V w�d( 5m rrivIt�nA-�[35�w�-�i2�T(l�g��� J&� #|�>' "B A�H�%�r�OH4ej post|6Ðo'*\ �RE��WcD�g�-6&),s*ze2h/ �e� �\a�3Ha2$ B�n�181�bEQd� 90%��-�mH2]�� �N�Y�f�+A[��d9?:�%�تtao��{-W�=%�� +�:A�"&de��Bd&yj a�"� appag1� 1�d=�10���5�-JN:A��*V��)p!��~ �i�<n  V�S*ـE&݁� ��^` �r�2�7t٘"�y*x � @�I cN�� iu�b�A�N. SW�K ���� Vo�4gh����i.!�xis3��s���� �e cry1pg� �E)E�e� �%>�9�s� C�aѭ!$�+i�". �" ly�!!�)ik ��a�,��atA�Y'�d��in"y�61& ohex$Ne �Jv2�$kau�) ]��t!Ui�2 �y��%9b�9u�ne=.�M"?0� �2. OPUe�d�!�s"/�6-4~�gly!'���EB6�6T2� by ac���KB �I[3{cc C �E�wh\i�.UV�va��w,by vi�� waveِ�� gse%x!��)��pv� n0�a� �)to����au�!��)]�da���5�*��aly;_�s ��nee,kB!��$:LF��[� cX��^ y%�P �+AJ!b�b�%)*�*W 6x.��aj<�m^��y6�%a�e*�s��B&�zQ��5 .�*�?a��"��o!Xa?_el63s . A�m=W�0�E�`3j���wa� � 12 :h�*at 28°޵f!6w~�f^ W+"�*�l�"fem 9��pai�9̀AX��,� spaw"#A��I` �inj�B:�*�I �(10 cm Petri�$~�M egg- *_D�yl� b�4( �>3 ppmn:.W%��ro�0ip0�@1=( &Q e.qv!12 W/m&+,0� �!+~�0;)�SsupplN�4� � 2 mMEx$ylthiourea�4!C�!D velo�y}a�Y�]2JAE!��>�--FI&<rE5*1F�r2��,a�[�{R��hly [41/ 4v�F"/}"�*� E(�]3�[EW-w)�a-��%%�Y�:&"�Wazgra�<�o�%�r,on Day 2–5a�t-fertil�p . GrT2�l�$B4m�=!švb1=&�'% O�� �7"�q�� edLk , [47�g!�_S�“KVjBif6�6�ny�! T'Ҽda�'?Mh��eifd�=[9∼60 <lV )"�5 dSI�!�v�A�u�F!z�^R;A�ef�ab� a@$A�U�ng�����0 �0��aL4�B2�0!��Abu"cTt�F2�!t . Pl]-*JWr4Koichi Kawakam�NBrief�)�pos/ �: SC�1�4 �XmMESSAGE mMACHINE SP6 K��Amb!JInc .=.AL���_ 1 n8�C5 /RNA"��ACx 25 ng/µ+>sR2�hq!�8F�A�i�EDto�qX�g"�Fo�k`�Z�=�si>�qHe �FF0���3��. Fjn-J�,ZF1o=. G�*�0e*�g*�14@sn� t 50uC,�2 h͔" xSar?I ��a�!��+zo�Y� o9��t�4 PCR-�36by�q �H�� �!�s 1�4�FEa f[TEFa RA?��)�1N@�ucute�e�g���X! �� �i�&�����ko�ol��429�r�G5]&#/ |%l �&K@� reg�Q%�I� over-�in 4%~?a% aldehy�sto 100%w anolR:�șQw� a dioxy���_ DIG ) -la?;�9ggA��#� 1��.�15"0�nd"I}�� E:�j9xISH8"�MA�s��d" �qjzU!�*�:CAv���l� nzym"{(y*� k>EBthy�ckin� 9"Ren�.�C( R�u�miAe? ��Fiv�>$d(6��l� ��B �S�<��Glo k� PromegaW �V�manufac�<r'm�Vi�IB��*IDj�*!����\)!�:�����01,*�]aB!��ach��ri��?.�G%5�5$Fugene6™!�r�1�r��$�jw�I4a���io�FcHD $be�) ∶ !�( Rp� Diagno�E�<g 0�">x&� !Ox�"5_"�#�� vo2��26In [10])'a�� ��sR*P-,"�046�*er.jw!KpnI-arl]&" M�� lx1d"� Aa"� omyc���� 4v [pEcoRI [�!�n,1 His-Myc ( ��, (60]!>a4�ar9�7%�. E&-�#�A�&B ate�$29 kV , 96�y��b� a � Py�rXa�ŮBio-Ra$GJA�dE��, N�G-418gibco B����� fi��*�E�of 80��/� . D]%1 mE�xTA�6=`�ԭ!� 25S��1��200xiN�lon�~;\Ule�b�h C*trypsi��!��a�w#���Zoo�<L�t��]SE��"wPf��|.��,6��s�B�w��?96� Fluo� Nunci�s� At�s0;x2�shZe��%%< ��`���a���e�^.� �-��5a�ur��,B�7!�%>a Top�8 NXT  e82-��c��&,k�k��lme� . Ea��l� <d �3 sA� rvU*LU�309y��a-�8A sb5ru�DYe;�0u��/4�r�" ���roo�m�0.|,E[ �j!z Z*� l7�(� ugO�,���%�ill1 �L�ma tungs�� Isourc: 2�e W/cm�%k trac��/w,!��f!oleA�L*.UaJ�nEYE��Xnh� of f�7A�.SD%d�ca���plotte�A)�I�}�q t���9VPer�e� eak *Uf}Ֆ��e[47��>6�8� ata �smo) Ofc-avera����4 h"��mo����ak%6�!�,#est�5!8r��-)�h**mpu!4Q91�Q!�%�I�F� ±!�9�A� ve R30T�� Z�U a StepOneG 9-9Sy�/�;#ed���Jr�Q �0rse%��9� �Su&3! III R!se B :���A�8 �J dTE5random�F."R*�+E�15�e at 9. �� n 40)\s!�15��"30 60` I&� 7�m%LY�b�6e 2-DDCTQf�3&�� NB�E2 to*'β-] �*2pn�E��X)�AA]x . 1-@%V*@TnT T7 Quick Coup59� ion/�onQN9 �����tn3 )I� y����d�( �hKl� pre-6� 1�2at��temper�����'+�!0o2�RglyceZ,mM KC-�10 HEPES\H 7 .uL>dTMo��ito1� EDTc{5@ MgCl�&. poly[d�-a����5oSp�din��Calbi &. A�.��E�f-$�X6(���<alA�m�-� 2�y000 cp>A�!� �()�j�87!� 37a(-&�Z� �\5′-ggccatgggtgtccacgtgLgtatgacRgtagac#"��γ32PATPM�T4 Poly&�NSIX&��Ae�N���; *�:_�[��50�Rmo" exc V�k#e:�!!<)8. �"�� , Sp�%=,attcgatcgggg ag5,c"��F/OD���ctaga>�ٴ�N0�j�1�)�AL:�-�lo"arun �"L�Q 5%%� acryD�de/Bis-�r7a�� ) G�v3HS�TEBe�5×�-� V aeV�M�f50 vol`�r��a' �/aXt�dr��e�+� ���Rgraph��rTw 03 h .;�Para�0 s ca��malari�` mi2ʁ�"�Op�<��)b2-0�� h�E P ��}x4J�'�n filat"�0�Bcoronc�$ s gl��gַ]sin�od/ 4�zm&$�Q�"a�] salivXgla�`�Mo:)��nF 5P� , yo�X�C!�#mije&5.`��).05,!P2�����n�)�p5�� "2"�s^ ��]! ngag�#��e�GA"%(lig�triggIK� F &�.,� �SB ! ��re2��7-� �r;=A��`%ZY?�"t�M�G/"� 1m� �+�'I��, ��U�$��% iUs]@-mCher��s ~p rker���P �d>`w|Zun71qH�A!��2T*6>�"�m��5��8���2A�1�! A&�3Z�X+�TwiHy� �6u]5to�/�*a} ���t4� infl��c �"8�. M��B�s6*d3�WiI���w�a� )I�9Ylif�^4�Y����Ijq:X< 6WD�e��&��{*�C�Kh��` midgu�&a��#�� %h rmid0��/��2� ��ae�xeѲ xcee$ 1 μm/��&�l�b[9 �B�#�mf,��U�-�ic oocysm3a"e�wal� AnopQ��Knel� s8���2�EL�2m�mָ:N�~, "�����YKt��hepat�Yeg�Pt�d=�Ate�|me�V. S5es�(�,�em��1, flo% 9_ circ�*ory flui����c�RattachX!U�invJ?+>.@�� e�U�1U= ..j 5Eb�8,B� depo� �-hd �K'eMc�at�wIh�2�i�ivessel���aldG away� ,s�-ey �"=(! �r �jt��!>pas.��3rri�m�� �.[[:!.��creb�t shapj�hi�,��i���m�#o���e@C �B�SD.�ۉ�T!F:���Ƀi�[6–"imot3#riv I��B5 ��y& neati��a m�$�[�narrow�,c:3l�a#y *��ellC�,,!�7�N�T ( IM��Nsubĵ!/eB�K:g`82�' 30 n1�� �Dp? cO�o�� kmyosi�M���"��,G v��a���%w��!��%tret��a�f9 [�{�. A:Gthemselb8I%?lIiaW� 1y��!AE�s adhe/Aej��Z4!��AntegrinpA- %.�TLsag�3u8�������s9i�� �HbI� �"!Z�1� �J=4�*�^��i��c�]A�z�F;!0, e��a�!�݌*�>0 ���5can��outin�vi���[14–I�b 7�-/ part�Cu�;a*���Vc2, s�htaAa��2� E!2�*8 ��). 6. H�er8�ly�uMf�W!l�|�yL Tox~sma gqAi!Ga��mrb���8HlM�[120�hX#as����lyƘ�ea Q��� "�q�F6[2Aw��_�bona-fs�65�>?1]� � < W*sha�a31%"�'NItyac DictyosteI�� ��C R]FӄQ�t�q�of.�%^��57%v.�i}�FbP .3� cipa#WEIH@qz-�(��Fib .�; .5Avs�-qf<�*�J1/& m7"�F���&��59ii�JC2�(discoidum [�2b Alls0:i8�=wo WD4�{-��a8ßfcp�(r��A^� rM�nG$bor 22>%=U�� �$!/ir:}�c�lso���Y , 2�}Furd7m7,�; �2�� q�}��#��a# �u�����A"� a r�AA�5����!Y6��>To�tubul��"4Valveol�]�I�s \�u�Li� �be�����pg:cl^ of͡M�s1&�A!.jN��  Pu �]=:���<S����tozoanuh&�:�~��Cfauȩ���api� fJ�!a%IeishmV�t niae�� $s from the�a excavata branch . Yet the coronins in each of these organisms display divergent functions . While?$LeishmaniaVl is essential for microtubulazation ,B�uToxoplasma gondii it only binds actin filaments weakly and plays a minor , uncharacterized role during host cell invasp[31 , 32] . In P . falciparum�was id�fied x6fas an 6�-�1 localizes!��sporozo�periphe {a cABum depenxbut-�inmanner AOA; vely%ribut i5Umotilit!�rough2nuUm . DuE��(rapid onset!� migr%qH extracellular ligaag$ve analysiE�U�growteR� �of in�edi�revealed��<��wild typ�@�C��6hs w�mit^normallyK��wQ�a�resul-in simi�� oocy�n� dgut.numberA�an Ɂ� withR�( T^1 ) ,.�%�q�also F )�ect7Q�5S)<s�[�m � . However!�e found��8ificantly lower�]<)S��� cumulaeFM[6X%��es:�%aaluIZ �����60–70%j&)!a.�5!��aA�$rgan . Upo!�traven�]injM�(of 10 . 000:�-derived2 ,EF1�miaAžreceiv�i1�)J,��cr�d� v6%A�L1 . 8% between day 4 6 ise�comP�x��i U!�:�y;.�(~,14–2 . 6% W SI���;natural�(��� bi )A=�^��� !�) �<% 1�!5%53%_A�a�s�.� o�xwh� WT,sb`_2^3!�A\ag� ��!�no ef����abA�on�����J��.d� d� e� �2�II���ha� nsis��u�!�� $burdens ea!�-� C�* addi,� 17�20I� 2edi�� �ls after5�-��(!jall Qb�XnA.� arry!IWT2lbec!��� 2Eo6 ,N�2E�.Ta sliQ delab A"Z .�develop�2m913y rol�� �In ast�hen2�-Z�Hed direc!�inm�� ream!��6���V�Y.6i�p� 1{!�e e s ye��5a�ag�'A�A>��)Z%Qly)S��ɰ)TheBt�:R� al�w� fe�d animals dE"� symptom�7ex�al cereb�p0malaria ( ECM�7�nM��%RsujW$in hemorrh� Z46�Surviv� ki� ten assoc� �Eped li��� .b[34�5Z%]c%�n�by�han%�%�0interferon-γ�(leukin-10 lA�s a(ritic��im� B,5V.�( S2C"� TogeA��sA  vivo���N�.@me~ha� j A�&� M� skin-�they are�o��a:�and/or��^g. :8 .)��w�A�(ed hepatocy��%�y�� u�.��o9 ^1-g��sO ain �R s��G  s� er.u4t 48 hours pos!K�e��rEB}��6�Wei̕8C57BL/6i%�*�"0Y� "I "=oad1�)d42V��is��an ��1�Yreducu<��\e���^m. WT5C( S3G]� "Y�&�T�6� � 6�Gsa�video~roscop� a 2Dis� bst� �B� 9�1cs usu� movA� near-t ect circlM �1A ( i )�:.��_����.�rar�manag�O{per&�on{��s ,7o�detacha�2�is�frequea movajust b�aXforthE ��ingTdheu� (��TA_"xeJ�`s� �not�#o�ch-�[7]%�,ich has so f��s obser� } isol���d lymp��aberr/��J!�PEyo3!16�s��\� orEed [7�S6]B� f�=�underg�nq%�lex!�!� sevou�%�forwarc a pheno|-0/�describA or P2odj.<1�iii| 1AivE�A(c�A-�C 5C��k�! "3J�onm�app�c !�a�woUf}.J�B� Like% metazoan��,4 ��measu�� on a flat}!ofZdo%D{A] 6= BiJ3-d�a)�nviron!� such�g�u[38–40I�|.�n��e!��de'%�ep+l&����to 5 acce8�  [41A�:��2� us g*�6��4�strongly+ pT&aaR�� �A�J�i Zժ:� :i%a1&�1�8as non-fluoresc� 6��S S3BIS3.�  image2+:(lea�"%m�A�of�ganesthet_mouseiEXferA�� �b6I>�A�no � #�!���a�re5�"B`MrFg! 6 al�y!Ka6�!�30 nMBwymE� ��appar��e!�� !z:�stabiliza>����Tab�20�-�)�P 3��gB!�-z0 2ga"U%!�BS�,,�$'a>�"he IMCT$ nd u�� �z�d%��ZEN&] "6 v moleme�is�%2� �%eits1�ony�g"ou�L  ��$�/!��A}a �,$ . Multipl� D aligofi .�!%JI!w�!O) *ye�1���r-a�44��("�$* I72A ) [45���Du�<low�lf�U ��14�'o ՖU=!MI��-Uj$�e6� �2� �"�|er2 n6 specY uis3�V"� 5� 56� >�.��6Oa�de ?wester�"t uE7�ntibo�j�st"� ( S5&\Amk5:-,A�*� >�is6%pQ'l��2M-��qy�in immj�:n!2 rAave:�٨4 i�( ��å�>-M����>�=�!.q= mo�y ��e�#4BS�18kd�u|&i ( 4#*� �T�%� ead)�߉�o2(�ed���-��machin*)A�h��rob�).\Vc� .�a:]>a��&%u�w�8�O��g*a�(ur*�!�= �a)�p�L*)jA&�(���possi/!�+"��n%�repla��lan5+M� 5D6Mu/.��E4 Ůic�li1�"� 5 d�We)emade 6)�2gu�r&-�ituA�9�'M.�-�)dues 283� 285 R'�n��:,B�e� &(.v R`2���I349�350�1�al1��5A�AR2B�>6 �.7��o+AGN4s   M�$+G!� [45y Ax )ssess)�MN� s"y m��!�M� ���m� urt� R349A� K350U� H!aq!urPQ�to2E-�� Is~*hoO(still)<--Jd6� �Q�-�1�y ��1!Z�:� !myt.{sh���Ra��N v �a�!c$/!�e�r 1� or 1 μM�8 drug?l2� %IchQ�-d��is��ぞ>}2K ~0 fash�xB"�/��%fvI.2�'A� �cre����d�ionomyc�2���B����ծEu�ineQ*!(C i:; �I s&�\�s> &� f�(>ps?!�F� %�.�L�,s'�0i�ma} to. 6%��Fcs6^%w�*��J�Q4w 7cn^4/#lR�,QD, K283e�285A;e�y�a�,auA�9JharborAvj!8��m ch>��n� "�&%� �nY��o�[ �l���y_c �#UC]Efe/��%"�&�s��#�ItEZ!�Ta#*) a:B �i7�0a�b!�Z3��&u"capacG �3 3 , 3'6�A�2Ib�"2)�>Jc!�v/sro&��� i . �Fu�*� 1}sE�All��� d *�-s.Qte!M� :4.�Z>3�OŁs�!%�E)��2�*a�& �2�st"r !I�"W"/ʼnK�.� Q�%�Ualbei| e��_��us>�.��X#�C0i��-ass�46�J�X0< 6'3�ea�although�A!I�sz�+)�M?!�ne�ly:�-Na"��j� of half a /"9&�U�Q!ae�$.*DEiz>) *� ��!~close\7M�.9"o���&� B L ��Ej:]�`)� be d&)��iw�&� ��^<�sre��)!�9 b�#=T���.�굶1&Q��} hi!�at��"�&�):as��<����i�!��5v�<l� !SIE*3a9vas�U �)�. Take<+%1sej+<sa"� al&� in>��z�IfollowA!�� UB"J:��a�v�&�6= ��-xI8�1MmYjB4=�2�&�� 6{)-�y2� q9���"/A�Iw3E$uX5c�;&�: eced�r�)��!<"� Litt�s(I�!�nDI�)�z!]!qngg;U6sC}v�>( *to��ConD�;%�-. GivAPh&t �pat��nK ��> "��:�]N&Q�#�q��'�! tooHs`* m�� -. A ��:B �r�&)G?includea�ai`.� 1�� Xt &*= d.:��s�F�Q#!q.5iRsy|ex!�^p=�8�� %Ja\�Ud] s>>�5%A�t�che�' �(�=1� 6APTA-AM��"4 ";�8s)J, 3s�6�dKi 4��/�) G�!�&�! yU��{!�solJV:C�EsurprisA]� hyp#��UN� �?ore��{�&&*7/e?28�Ik��3�:X6%>!�� .r>��+�".GA�! Q�^�2��incub�.y6V!I{q �!�&�$or ethanol�*"��!�.�7zR}!s�EQ vesi�.2<�"T ./Dtachy�AA��,48%Wa1~a�:� 1�))k�mT��s�A v�.�an4 min�A%�a polar &>�2�-�Ho�,=N��I�)u* ]n> ( S7"XE5���ቅ-Yёele��I,�,E�be ups�� �>,� h �abs��,!7�ex3o�=d�({ >���E� noti6^�8�)%xB��&�0� �i�a�x,� 21��V� bas��5A>N5��,�5l�!配�&�6a:@,. Moreover ,2�M�e!:T1�as%�vGnem��acZ�M�bO��ve? �.�5& R ���ass�?=�%Ja1&"[ M2� [49�6!�p!B&� 9�� \$m's�82z t]  A�� journey6We fin93proa�B;�.involv�0A' kina�%nAMP*�&q adof"�D"j S���A<ma( nhib�%H89 ( ��, � �~�SQ22536.*0adenylyl cycl��All!H estopp2��� �%deg%�o�2� ;ly [50��Conf �A| e?,Q��(!.pro�?iAy(I�K e�forskol�(�9�sS�o�E�confirm����qul��I�5=!5��6�C�.dha�Ath�o-���-�!�by PKAo%�Asm�"� �i�C�I '~ �%57��i�;Dr!<]��&�:�  %��'H bal|F�W(2������B� �1DE�"�%is:�A=3M A-�!iU A (%O�G#Gz �:�&�dynamic)}Kway���.f phosphoryM 1��L ��T1/$&S" &5Lst�a@'�com*�"lyE�6L%�mselv?/k; � �  *E*a�*� pre-&� %3aU�&�L� >` Ѻ�.�] )�5�BH��f�6� turn��i�veY68A�� impltL�JaXmK劭�� %[Z�� f"KN.Y� �'��)Xwa&"�'Ge*O*c�Gc�yj1photo-blXO�o( FRAP )� �u�8R-K�@q�.~,E����NWMr!�Ive��?���_J%�in �C4±�B seco�,( r�:�B6�5�C �to��fl(origi�"�+�!�5F�N71) �:t"� �.�1')2q&vH�@ iona��il -e� �Ei>' bD-:ZsE�$�gO�-�1'^;�o�'��In1c.V%w0-W�7x2n- .saT�46�9�a���s 6r?>���4e[of%�F^Jzain ;�D7)�65��B�$%h�#t��s��� mo�+ty�-VU�qR , nec6bnor>�ca".� �y�emde�4�&��5�W�!�>��%no�W>��M I�.1�� �M��!ƥF�aer�( F1±!�3eY�>�2bA�&�� �6P :Xh 0B-:�2�u(@FmT� omplex Y !�6@ reg�0o�E-5��e)K�j5���:ur:.ly� �b5 A|& 9V� �ho>�P steady-st di2C�݋�6�7E�5�is &��)y�G,��' �_�Mupar ly )D�-a�%�>�a|"�D"SofY4uU=EWt��*\a"�/!6bA::Bpoi�<o}j=6�&F  #�fi�=>:��.�-�r�"�0s�/W,�.� de�=in�&� @EXY4 c IndI3bygroup9 , 51]zevA�Y��%� feedB@loops� �M �?�*cMfwais6H� : U�� ", �7casca�� �Nrg"i�6�� O�*!!aK�at"k1�diminis."4 ���!`���:q3!�:��A�"�7ir�!iM2 >i�W �04XuX�s���� �"�Tc lerE4"�!�B��� � �C)�L��1�#5sF�:5���, 3 �-a�isAi� KstaPfi[w+hsp20�.�E�?n!��*��$%%q+t��J�(!�-e�6:�,&�#�%� dC��v�-���*_A� �-6@.b�!Pe2F=troEj v Mށuttab$�o�j7$�Q.;y f!n\!E6� lem;sta45h�+ �urfacŰhus�/�Lbq� Fvfai"mC �.Y�2s�w=�F eno+! forc3, F� �z*aUr I�is tissu�")$a 3D .�A.� allo� m�%8ad4nW�A�Y&.e. A"�#disconn&�PU|� 3D!J-9aa�uncommBQ{7 er eukary  [9TNon"^!1�iso�EU�7A ud#KdDE�+�%@':�\�Os�K.�Oe�&(1�ve �*�,u�[���'exampl!��5sn? KRi�Iubyf !�IQ BXT-�*�[52��^ACM�� � �Bb�Xbvert�mycobac�4a�lt8[`(�le� >engulf D�9phM.�In�s�G�ed5�!�ZD6�p$Dictyostel�&��D]s �N�)��B�V"b$it5�pl�$>�1re)v�i�E�S]�i�� �.+ifFXA]��~"7EXa��m�cultur�T5[5�M55A�A"� ife �E�*Ge�ede4v���n.�MwQii9 i� ] prog�D���b?]�7g]iakZly PY"I)!:��!�� ��� huma�K�FngafF �_g belie�"a�Isi� biZ�I�@&�T4 T&H A�l�2x]�I[@LP 2x,s�wf*� c1FwieHAP]O�2��:�Hec�.N! ���*&�8}6S'�!�=4nus�Bi�Z=��r�Lng%�!�iR)�Y3e>���9`m�4(�=j &�).�F -sE|�]c�!>}.Z&!�third��'�()���O[@�Gl� ?^�A�>��\!� u�q1R- ��&�9�N N<dA�ly���,��C�!� rigu4�`system��)�sub�$"�,fC�F.<��W�EGir| }9�%. S�� corr="i#\a,oHJ�)\FU� �'�sHasKnd͸�TpSn 8g�V &0s [56]A?b� ��gen&� s�ʁK�e�/no*�(�",[59-57�^�bD Af� bona-fpA6�"�� � �of.�l#d&�??(��p8�2��9� AԡD2Gs.aeq+�a6aM�"5)C. A��ef�q��/sub�ciB $r network icskele��struc���lE�!ai�b"�5��(\?�\%h?itself �"aCm$e�e�s�K ksI���@m a!^ [8]��i� t�> ! inguis� ma"!htASlQoH"�!�IR�E<15rR(mQ$@=�AM 4�">�3*�!d%� s 1C–1E%�5<s@!�t�recruia(pQ|la]g5qg2%b . ItBT'R͡�U�2-~E�.� � chol&>ol [58�� eur�K�a�n! � ��-]q]� � A� PIP2����Y��Q�lea� edg, t e�i�jng�FG ���A ]7mb�6�� N-teN,4���y1A("1A52�f)��<����R� i�o �b�el%4q>�$-A��2og!�`%�a"�;s4EcD�9�  G� R5�a*�."^ �Ya��]�$5"�Pi���N<Ch�2� ���4�Q8��e GME5p�Rm4S<�1#}5e�Wg*VN��Z  ker"$_!�9nFk"AD�lyilx$I�?�@�-���Q;}6e�$ink acetylaeinCcepS E�I� cyto�� on [iE.�~�tos,d#�#M����B�Y % ui!��Liochem�)E� �L@WeZly-fi��?5s=qMrI���vE�cILI ��S4:���t (IS( seea nndz?�,�"�8kA �?byH=R2� R28>u<; )nuk.� abro�gd�K ��o��%�v &E� M�Y;� p�qin :��^�4%*b>ZV PqGa�I6mR�K���sL:vEX8 affin�t�M2Z . As�sB��n�5�`6u5�66�goJBW� i"��Z�p:-�;6q 8�sA]z inufPʼn�E i �8�kch��\b�mA&� ,W�A�s�f2<>u%�e 1)+61]_lu�*@+ ( [ oAl�.� lNa�(�!�'l�oas � ���)�3' Vgo���^MV:�>>1 1��lFt� �emp� !�si`[em%4Y��% �gs�� ��yls��E�b*�a0E<ng>uE� cc�f�Y7Z�sPZ1{ !S��>H� mbosp�`KanonyeI�q!Gw;a%0 �.` beta� un�q9M� capp�ͼuL�?FY,&zR#s�XenvS>�<6�6�N$�Sord�k�� G �[�T>��� �!�� �+�1e�A=B����5o 7az6�& pro�X�"/!�.\L�x �Len�e>p�;�polymer�� U l do�*of>�i�p��*� ens3��lhm!� he T�$.w[]n- ���L %,R�(ly�J�� e�27q����m,r��S[1�s�KJ63Q b.���SF�N�% *n� ��>V � n tlpJM6�s�U)F��`ac� � �,ue{��%7�er�65 =��;^",���d:% *�)y�� N�disordt& �2�8%�:�-тi��vRYsP�!*j=k%�,myosins pulle3m*\&e��7>��N�l�Jg � ngB , !�to� !T���R5 > .6$�))��9�,Z�G1>�� �v>��A��#�YS3n.�ZOn�8pla?qaQ���" %|9t.�)�� -fam�p�s I��"�aM�>A [�\� . SJ� �,�$3 c �$��.�)�ct �o�G / ;��x��8&� W �jv ��- �s��sp�<>I~ on^�{11���AN�Qf| ,c�$6�!�gg�re-yI� � �w �!"RAu��2�.2ZQack% 6�visibkt'5�F�KinM*�on &��g�)T(�� col>rwgre&�!4ruc�1ter%�bR�,B�!H �za�"?!"J� ��!�i)�aV�I e f4Zeb1pi�3y q�*�^�eq w"�23D63�)9"h� F�i�J limi��� �~� . �;�-ce� �0w sta;&aAow!�s� %:�>�:<!�� api�� lexaAI�(as FY|�[�J�sC& go�t&� Urely6KA-3D�/lle2JA��b pted�A51��[6q6�I� @ l\YQv ={�1 s�(�A�?Y5��� Vm� d�i��.�!�$�A,���&��eJ� sn � va�& �sQ�d!�� E% f�.]"3��*�(.[1�}An�Fd�p.@��lLdLG.of�c"�|��t�:Up[1od .A�� , Tz!B� ���a�>��yout�-A�&+oy��"�6�@�*64;s�[ �67–6*#�s�n&rQ c��<3��rR�,�"� �d. A �!@�@i� ���mm�=62�n!�ͭ$itGve�Ty�m�Z*� !Y"�&�gv��� bad~ in*� 5�r!#; .4�X Et�p.H$.1� �=o�Sscree��*A��*�[7}� Y**-5�~aa+�$i�yg6�qQ�{*����arliepagFE'"�!Am�[7m�5staur�r�_arb �6d�E�� invaN �[u�Sf�NIy2�O[7e�G+&P]�:� many�!_{k �{!a�perm [7� g^�>cQ�-.�xme4�a�1of#! &.� ;v!*95�7��)w appl�vTq-6�IaKJ .e�9�'eN�Q�)Z!>�sta�rͤ 8b 5A–56,a� &�*i�l1i�wR�7h�:a� � b6Z8W�)u�gsum �2� s�sSRss�m�"l2a1�e�i&S;-@o�/AJ'P;�%N;%S|;0 ��s��6.B�di&�c >�| ar�l��++s � a�2�t� f,r�aـ�C@Ő���~��Q8")��s"�MO�rx X*F&�s`Yy s9��a.}.�i�Xw&id�:{A�-�o occur&�/2�i A�.�.%TApot�)�7: � su.�+66 ��"P� �o f pH�  kTBn% �U>s5~9"� ��Fl?�^%&:6J��itC�*m�!�7k>ualphae8cy&�f:%�"{A����V/�)�A:�K�+y.!�,.Q�C�T�Ig��j:i�E��RV<s 6!�!7212�!`-Rq�- hall�==l"�s�� , 7 7 Th�%�%�Add3ed�"�Qp�3-$ geneqCapproa@0�4scTqj3s  �9Ttfg� 1"u3!R�\!Dit��Q�onh&� � [49� 1]�f"�Lpi"$emd�/�-�!42�"^�q!�:n]��Q�KR:�,/� rane��`Ym}�(�@CI�(I ����)-cE+om?6�matrixa�by seR[i Q�a �q[їR#M�lip�{CA�"J669 ��[4^4? �@͜��*�Cz<��KD͵b �!��,"� o�n%./1SA't"wK3d�sus�"�<$ �AKurn;�P:�J ���re|�|oOed����q;:� !�&� �U~�ndoE�-�muA��end����acł�3�Dno&a  .!=i� �=z���&��;w�E.�A�;ݦ��YM�qaKAe2+G%s!9���Q���,�N�:�V�3���j^m"��v� +�S]E1ešse-!�m� � ��-l��# Y%��2A{+c����E�wx q2b.�7�:E�� �R�7o�e�IP��s . AwY�~�-"dwAU&��} g�FELASA �sGV-SOLAS� (ndard guide/$�AZ[��O G�un autho~eZ-�, h g�N �ethic�mX �����y�E5a���/r"� �!Sclx($g techniqu� � .IO Z�H��oco�47�,4g�i�*� �~�e � pB3D+e��X��F�dihydrof} 8O0uctase-thymid�Dsynth�E$( tgdhfr/t�A��0e�!�(ef1α��h!�?[�F�*qg�G��6�262>�h(2Z�$ ( hDHFR )E1�h!Z�I�)� gG��e�p236 [7MN�"oRC&vWta2�l ;Ne�s���%� u[7��puU�J^��1�FX[i)z�;*f��-JU �( !CRN�*%�.%�mphsils p�6'suppl���ma>6lcnophe�� stephensi"F�U Sda5�trw))7�SdR 28°rm75%!�id?%,M� a 13/11 hn ht/darkf � mai&&qn 10%Cr6Y solueb( �� E0 �-�'benzoic�f. NMRI.Ac Char�R�t � v ��tonea� � m:�nμLAfze&$�z|. AM$3��5�Zs�s���!�n��%exflagel=��>���k�,��a Zeis� :�.��a#unegri4 If >3Z`pn el�5 view)�~t)��anaest9z��mix 0o�% ket!w)�2% xylazk8n PBS (�Q!7y 20 g>nxlwe��^p .m��8to ��3� )h�%hat�2FP e)�!�e�%]fat 20A�!M80]��O*^reiU10–23 {UTh�furJz6o� . Sa.a��(2I5� �disxW�D!? RPMI�um%�69a�o}Lv�GIBCO )� a� �J� J�tubaEp�F orff%%I�&6i ��An!Q-�pes�4!'"R&� 5purs� 5(n Accudenz ��� grad�� [8P2BL�s�J �3%UG���|'C96-�pX'��ifu��!�3 TA1000 rpYR&� �i�}d �d�?"����r�# ( DI?!)&||cA>� $a 25x ( NA�I8 ) ob�iveE6 �;le!� >�!�Axi��A� 0M ,�A�Vi:k���pe��%�t!dցwry�F"LJunn w�Y�Ed� or 5%1��P�#$�L�� i� spin�J.��Pe"݉� &'P!D)Pw &3T.14.W���spu� i>!a7BSA} �Ac�h+gu?9� t\9aG�NR[ oMg.��MD2�um ( �. I"�g!�-Doe�h�V�K2�x��nM{�Q+ IAQrq,+ B ) ; [n >A� Ear��naïvYc x��nha��� rea��Veet 24�UY,:�iI6A^A�to� � o2�^1#epa"w cFto�m12 �KIta��aneyc2�!�ir��|M . O� da�7�,aV �6�2c�vA�Ae!,E_I�����}> �E.)nB expo�G/"ad�a1ej�X~� hematomj!�l!ly ���r`man]r . B�!n9:6��atdIuE~wa���"�sc �� ��U3fa` 4��F2'ZA�!� O>�Er:�t�p����!u( 6#͂v̂. HepG2z% see�wto 24�G� ta���of 5x10@�)ɲ DMEM� "?�O�9�Ud�@F$�"�17 (6s; Y�gen�*),�iA 0@�AIf�cG "�Ta Neubauer haemocytome�-. 5w  *&�-7Ura�E�6D ��UluA�.~H i?� �Í#fil�up B���to�uvolCof"� ��MM^3�mX��emperbb]�� �!���a�� �- {�71�1���A�re�gb�wa�Itw��AtQ �0 M5?A�.� ��Q,� ��ő'� ("D tryp�~)�19(fS9�8MSof)�&G\AYxi�E- �Dt��� , LC�Be�! ��and.�spl,;nA)sh6J-/�knR slipE12x12 mm3XknE$ 1 mm �2�QmgM�w�refre%�Iy�� . 4 22�� �����iI�1&9�}0b�J�0eng4&j�. L�-�Q"U�!.�in 4 m�O QiazoaQIAGE . RNAӕG&a�56sb Q!2��M manuC(urer`�2��NnEP�]��m�1ng gD ~&� ��(TURBO DNA-f�(Kit ( AMBIO�pe^5cG� CFi�S� d &S & PThermoFMr% RT-PCR%�_,a�G5��-:~e�!� z �;rse crip�!ex�"e)=o�0Q.���!u�G�_ CFX96 To�Real-Tד�De�{��SjB( BIO-RAaZ� SYBR Gr��1Ma | Mi A|"ed Bios?a�. Gene-^ ificCe�6���4e GAPDH�*�M18S rEqc�Na� &VuDa.2�U�V�/?�> ior�mZ(avayfi��A�t�Kvei�+�� �bϦt�2�( n = 4A@%p e"� [a.x�ZV & vidߑ* >R  2",M ��!r F� ��~3 M�tS�1h� �&� ,�/a� them�94/� ͗UU&�_zpuM[�an6+6x52Є&b.n�v�WJ.!I�aDd6���!"g$*Sl,���r=�%��2U�eG,�r&��"r w=lyAkGiemsa!�K^ esmx . S )"�da�1��� } 2�Pf�.%5 �>>lFca*� �cR� Q�dN��!k.�)�V��� �0&� !uchag�!$�_"-�Fdil{��[ .ϟ7se�Zt��1�  .�DV885��*�W0$��-�G"(��:I�b�@it�-if >1&W-"�<#5t2&� of "�%��"�N2�qRA�w&�o�"Oere2c��Y��20Amn30!1��NI�E�t:o(� ) nate82Cor �=���edj�s�6� ��N� a�Q [a��Q�!nd� ��ritM� �U�%�new�GQ`4�-�-H � qmA UA%F�Ace S s 15Ew��"|�u=mхx bead�+ ay k< TH1/ TH217 BD��i�cb r� ’��o� M��� qD�Qby�/ryv,D FACSCalibuf ![�1muaXB��&� �FCAP Ar�A(A_Macp Soft20Inc .aNd"%bef�[O�~���e�$G SN#m,#a �a GFPA� rhod� l�setRl ~�&�4�r0a CoolSnap HQG meraG1d�� 5 Hz |�i� �%8 softw!#!X10X*=5�25.Q r 63�\4fD&X�>o2�&7M�� cesE�![E )( J�P�]Is 2–3�[�!2� s 112I 4a��F" *�or +�!#Z�.�82�FZ�z.�O7�-bottom"�d�J ( 35^P�R ; 14E_�I No .%�0� glas�OMatTek��mix?�=f��XV-�f�p$I�!�!�6&��U$ Nikon TE2�Xqr!��i!Ha� bE���,g!��bte.0nO��$x10 pixel �o�A�76 μm v�M%edA�g��\ $ށ 300 ��5� �2u�,n����?bt'�$��)a f!�-����h!2� nsur�X>6�g�� 0� |m��gz�J!TZ� �{imEatm6 adjaa�[�2��a valu![r�%I)�P�K.fr&�&bhPct%�q]iq6��@� area%�A�gjܠ���b-�.+�>�&Q.x�eda�o.x�k��� focu1SLl/ �-��5tt?&�R�< 'e�te2A�gUEA�qǐre�� ;h"E>averaE�!3Q�� )�90� 140 X wa�&2� kacbt)�5R.�s �E�5al�A�9 1/2 = ( I.�Max5+61st �a!A< ) / 2%��� b;� �ac�OG1h=/Glf9 �"�-�MCn))Ufi�WvdB"rekEg�urI�Pr���a$( GraphPad,&P �0ժ%�V a<:��I�a�� ( 7� �,� in )F2A�*#RIPA b� ( 5 M NaC�scM EDTA�0,8 , 1 M Tris% NP-4�.v#Na-deoxy�L� , SDS , dH2k �'�� "<3 s cOL9Mini ,y�( RoL��&� on���Q.��-F,i� ��a ����Q��-P [ an TGX Ge!�/15%� ioR-��#ݰroAlM�iN.<-a �((-Blot Turbot nA ulA�".= A�B8]M&��hI� blocTc��[%�5% milkAg%�(!�AS0 F� 1% TQ�7 TBST"#r� at R�8��j�oXqu�abe�5 imX&a od���in2�p�� at 4�#23x `(!���\y �i��F`AXano�#�grF�E%5聅�)�ECL�n iercA�. DV�� ��"ܴs� d: rabbit% -n 1:5 � ( Cl�1(ch Laborato���8go7 nti- D1:"N( GE He(]c �_1PbCSP0 g Mala-�resear�nd��rep2q�� ,: Mr4 mAb3D1vB/� er�.��Am�erib�B�)� �L^.RYv|�\ori7!=aAX glob/�s�l�Aby *Ѽ&�. W6few�"Z{mE apeu�op)�avail�A'p&��9"/��3�*&#�3/t!Z�9�*rug���j�av�X*kp~ �,^ol a2F-��V=.�mex��a ��All ex/ ����te�Ub�n�7i�A hy��iv�%55en�'d<#E���vT��| demok8Q#�ce-*Rd+!p!S!dN�ge�� �C5-des�mi`�d8na Ho"}y�@�@u �Ѽ,�-seq �?UK,-q 24-methyl��y ( SM���onIjS %��%@nb. A���qsu#!mYf� D+Ker��=?�d����O1�� is encodeO �7�Cem)Rcop��' m3&c<pv�.r&��t.�<�%E �8A.ޢ��=Q��>�1x� 3’%y/[��D do@nt��2�� Y #G�6 al v��AXs�� Il� L�< r^%oHxce logZ.gen�%-��s,-�so%l��V�88of SIDER1 retro�posonGA�2���-luil���8]aza�`,([6�..nztz5s3sLswD�MT>�X ^�vi�i!$i����.ACQF �� ilst�-h/��1d&�?in�qiES"��in.��QAY2�d>�}o� majnti��li�/����_��&�Vfit costyDI04%��:Nrn . oکRireI t3igAͦ �ɿh� [}AManife])Bġ��8E�R6b(5�� disf�(�wc��e@  muco3&6l�l�IceAG6h.�y ����#6�fu\ #XR=[2/��k�+val@!�mony-ba���o.�a;2_cho��H�N�gntyNfr��IS! }b6m� toxi\���5e!i�(o]>vCm9de��o adopt��aMve�U()M����>o�'2i,l"�bIndianN�i�'�G00�"�A"Q)`acy�(s�A5�Hdec��d [�X5�B�}�1�h?D"�ѣ7�I�#�Vn�;,�wh:�� ( AmB )A �AY�Qc��!L�B �_S1A�(i� ma%G ms [T<�G!�sub�> impr�5safet-�5pr��AS; p4-M!a� 6jF��,�iC,8>!�m�A#g!��@i�xfy�� �" s [1(+&s�dsomalis�a+3 tegy���r!8 risk�`�!]!n1�][Sg$taLAA�Sfailu��nK3+KE%�re+dLIMR.tt*& �Y5D. U�r!�X�o�byU�maymhAAth�C����H,M .�� .Z�cid#7'aA�s2� ,Aas�NgT�:5�!Ͱ� !���!�2�TeډI�F"� ;�Ma�'A!2QjS+-o��"@a Sp�9mA%anB_,!-j/ avidX���OA&conjuT\5 (4? -7 (�T�boz e � e (2�ao/aMDF!,"G ��DC24n �* (I� rg1i[16#�pS>!���.y:N2� �"X)# astigo�m�F� y�V)�s ��=��*&MI rӗap�@fen �R�"� � �6y enzymc$lan1M14α-de-�s!� CYP5�u"FSan L .6 [ �SO r�  ��Q>he!� Vx+ �9� ��فAk���Uc1si!� �Ie2no�,O� ple�V����-�1�9Fx5m��.9$ . donovan�pla�f� SMT��'.0 � docu� �o22]h>reIHfq "�T6Mm�'( wild-t6���D�6Bv&�ch�B"��l��)��!��@ �5mB2,��at�5=S��"��^��!:^� -!��^24-trienKf�M�s?RE����"n Ⴥ5ed>�>�� N s)1�@ar�4�� � :"$>�M)% �n�id5?�c�M.� ���#r>=zanv`�  �!B�disrup��"Z]neiar�%xilB� desp�(hav�&a okM/� n�i!�os��ޥ�� ,��a�fG+�,2���B�a�rthIm2�Q="�V�.^�! r���t�"BA� �-�qp��f^Nxy�""*A=[2B� ec a�|!�PSua�hee�I��=�UDa�(�`�c(&MA���o"�e3tEU<��&.Q65#��2"� nk &� �6rC�*� . *�"5� in M379����n��in HO�2FzJU0% v/v fYl2�� ( FBHGibcoje���>Zn .mc!�[ ���>w�� AP��( Sigma�!+Eiat�2nMe�v� to 4�A�woE��! AmBRd� ) a�A1nM,C R�&�-�5��-pa�aq sub ������P o 1 x 1061/m�>G0m�mea� �J107>]e&Z6%K. D R�d!f�  P<�" @��)Ob~penicilla�ndO 1 mg�`N��G�(d�,y : �.�l�X��. D&.z~2�B-�k"�!a�Alamar B� � [2ò�"9A�JoL$Mid-log phg :�=Hser�;�MZ� R �AX���ang.#6!�_!7at 25 oC�i7�, �&resaz!�"�*]�! +3�k7<�M(a�=&R(!��"���a"�("[��,6�!rB # FLUOaR OPTIMA?$l=°erZMG�t�)� xc�b nd e?a0on wavelength%_530a`#59 ��0� lF�nK8at�50%� R� cs�J( IC50��T&� u�;!�R packaKUrc �uE��5 �e�%�#7n k �Ude63S"y:�esaoq two-B+�7?t�)t *�Prr� on �H�c �M��}6e)-R��I��� purcA�A��, excep�#�m�is�Go�+$ �X May & Bakd:S�e��%1) j$?V�A�.�.�tep U& wa�"N"� /#Ib��A^nI/H.>�6N�pwaaAB u.Aqn*W!(25% m/v KOH� �� 3:2��anol:wDEa<-O he� at 8u�1�"�!o�g!;%E1��HA� J vort��a�30 �&�Wq��&9n-hept&O��m-�layato -���aupQ'�Mc 2!7��0A�h_T0OA�For gaYh!xtogY#y-`�JdtrO:@, GC-M&�(8at Glasgow Poly� �4,���A� kQ�3 �18e�s+b �89.!Ysil!!d>Hati��[�P+�450 μl MSTFA +3!MC�Db6 Sh-t�] )!Sdr^51�,=�Aa��� t 80� P3!�!b8�o�,dex��� . GC��C� ml/.$He|} carrZ!��L TraceGOLD TG-5SILMS�,um�b; �� ,��2�*�udi��μm�;-Qib9,R� �;� Ui�2&uh�76U. D1�� e)d*%��s&�1�#;:/k l0��a�)�(>"!v(� eq��E 3167 kP_ . A!�it*o�*Y< of 7%�Aa� � 25�! ramp 0!�;s:x# 7���3 :w33)a�n h�G�>�=��VXIng peak�z�fKE�VN xiliu#>h ��,n ITQ900-GC :�N��Ln&�rof! μAa���our�G� at 2 �� full�@ �N!B5vG700 m/z���VA"}b �hy%e��)|E mF Blanku��[pr�B���lcoholic�I�p��!%�.�QuK�� �I�-�.ap�?.D �6A�*�1><�Fi� vA3Z�-����ei[%�9�IE pane=Ka�}�y��}0l{NGal Insư!aSO8!.T�O�( NIS�! librA� _so�.���� !j�ra�p�% ntag��und5a"�G�&eA^}!wirL aA of <�;5%I o�P�?s�D�� g��M�E< 7a��QUV�<�/y��2x�V8 � 7= �B� � ~<%�x >(u?A�Yly� .6e. yFGe<�>!t{B"�<&� �NucleoI Ti·5:k�:� (�MF� rey-Nagel-A wZ�%( WGS��!-�� �Ae(TruSeq Nano�qJ +e��' ll?���}RNAW%GCn~$mВL��%�2�6.u@� �� �q� frag� �R>�a Biorury Pico�Ki�(od�)S&�&6@R� ,M��G(2 x 75 bp p)I�Q��)!a Next!f�  =S��tK��{!T *C�0Am.�am&Wn-�:M��.�A}Hi�4�3 j (.�!<}�8�"~pap> �B�nd y A��m���evLIqTrim Gal�!abraham!�in�"�}� T����!2DMHOM/GT/2001/U1103*�*=�2* 9 . �. �BWA�ˁ�1 [25] (=dh!rQ�du�B���&f*P�L��9a! xSam�*s v� 2 [26�!$Picard Too138U(ttp://broadC �F�(ithub . io/C>rd/�PerY&m�3fm cou"�T�v �HTSeq-# v��6|/ [2�a�U,� os�! ploiy-P���=2X'ia\�-^3� R�%~C *KFze���Y ^�is�ol�1" Vari� de�� 6�)Freebaye-�!� 0 [2[M)NA�2JR�SA2 wind�mof/riA�L (Obp 500 u�} �BedME�A�1].�thedoc~ io!�~=[�-��Ŧ-o�s10A�pE9h� aD~w"��q,p��a�"; a **�GN|DESeq2i1�!zhWAll ray=ds��gxW��5�2B��as.�4&4#sub� � e Eu��an�t� Arch� ( a�s://www2�b@a�<uk/ena!ze�pr6[Bn(,s PRJEB23762��!! 867 3�J�QP-T�GdeJ("�  E�X� (V�E( S6 T��Ta�q]F,.��S�| IA F� ("� �v���ru&75Wa�vD::H�A�y�a�<�_R%2WGq��d�- �Su�.� III 1"6<��6v�3gen�260 l�byA��adI�%�R�H>E.� n"��gG�>PF�:�G��J�ib�G2i!�f ��>Amp Opt Ure�on�OcZ<� s�Gx*[ofu;nO*@��7��r�H ! ZHV�B�5a�� : 2%��oSZ1)�at 95&4t�840CZ�9g,M�d!�=63. ROX dy�:uAmŶp�^v2�U?yc~:hLold ( C�G� d�3P!�.��0Z�V�e8`s 6�� l0E�I�R�G7.y�!���aD(5�δC��T�+RT��–RT!�six deemPufX��wXC F%F�gp&� is cA�a&f!E �))sJ low�r�&w\ poa.nA�Q2!�:J_( tole�;�L�un"p9.�J|�d����!  i� Ct >��Nxn�'��%^��� &�h.� . No�.F�`cyt�ic gly�- dehyde 3-f]9r��!� genecAkK, Lmxat3� 2����m"� �%rpur5� #�ly [3� 31�-!K�.ngle-� tw2Vun%��M in� �   06B�r� _'�*�! publ�M�CC� a�2� 6�K.f[�M&h�4��  $e".GinS)�*  (1W2�n���'�q��0�e&���Sw ���L�G"S�� IlA�"� �@ae �EA��1a~+al�(�;ng����A W�fe�0@2g!��a��*:oniō��Ua����loJ� devi �i:*ld-)�b��:�� ZV=��s�*�b��#4,�?n!qif��H.a(�in S7"[ )# Phus���ha�( New EnH�Biolab�cc&�ef�l3% DMSO"��_mo��a5�"IJs�<s: 98�끭�;4 �de��)��C-�= �dne��@w,3Q��2130�Q6T<>!1!�,� o� )!a�e���72$(��rFi4@, 9�� �l�:1?Ne�.��%�iD� 1a�pNUS VcpGL1132�@Y)� �� xc�Gof0H(MAZri �+s BglII� XhoIANNEB�?%0� llI�VBIs�:ila!�l�(�fw ��Pf�. V���"&0e&m_>�_by ��cip�!..(!I�8'!�Y)8���A��c����;8"b)E( 90 m�@ 2HPO-3H2 5KCB%5+ HEPEx�yM CaCl�3pH.?@�<#!j!��|id�N2�y�7�p�=�%: an Amaxam �or II��onzgo{73m U-03A!Ce)�M��XG&�W$oveQ?"T$.�2$�% G418*&3\&n2an%oCz /�m&�e� �'l�D AU�*f d� &�&!�"�8a week�no�48M( �N�&�%� 5x�, 166�! �'Correc�c sert*Q����ig*H �8�.� �8�M2�A R!*_��D^ԏnupoB�'S�-7"r=����a�Ufby � fins�'i0&� N�?A\0d�;%3��~P1 2�;M} 5’�� U��coe�- eR �b1�N,-$Q5�K�K.V8 gramEP(_ be�^J�� �aAo�)�(.j!(�7�SY �p �z|�=UJ!0(pGEM-T Easy�~��P+#g��E,m o�g ��q eR" E .�!i DH5α%..of �@ �������"x&1A( u)xo�$a Va#KsY�TF�>�*J`�5v��dJ�y�Q� � M�!j=�0 homogenates %Z8hind leg femurs1tibiae Lincub%�8in petri dishes%�4( supplemented6� 100 units�penicillm0 . 1 m�,streptomycin9�20% c]E M#,for six daysa37aP0, 5% CO2 , adE�fresh5(after three 9. A wash!ف^ �Dto remove non-adheA�M�, *2]kpopEco)� re-pm:�P ired|U:��infec5RstE-a�p�( promastigo!�Hat a 10:1 parasite:Q rlevel >� �GiemsaA�inaN!h coun�k( at least�.�per��ple"+%g�m}I�of total=���.Z!�-?��W(values calca�ed�߁0R package drc!�e�: Azy�ttwo-tailed student’s t tests�signi�nceM qRT-�.�,.p�A:!J72-�$subsequent.]�.RNAexA�6�$Nucleospin'��2�manufac�r�instruc�s exc�tha��lysisp carra�a�}��#q�iwm warm PBS�y=!Xi of ^bu�n directly!�wE 4biological rep?Q�perform5�.d��sea�te�P��r� cul!0a+� ssess���-�v� in viv��2 x 106vY�X$resuspende�� sterile-8�inj�0inA�h� otpadE|8–1*60female BALB/c �. S!MA�AImeasu��%�f La)liper�tak- an averagm �Z inde�ntI! 1FG,of wild-typeE� AmBRC/cl3:�,}��recove�%�dr�zHpopliteal lymph nod%J��> s -�o�Vby physAClyrup��.Da\ forc�these����0 μmE�8 sieve ( EASYst�er� 0renier Bio-On��H*� �2y HOMEMjh , 2Vf /b 2Nb I�5� genta} �s�Jal�Ks��25a� hiche�!� life��ngm&�� appa4 . T%*9�agsiu�t����tv pe�[�� s ( %� pass� si�E Ny )aTnewI�,d�Kpa  l� �'animal2t��$� � ��w��aQA9�Sci� 0fic Procedure� Act 1986 A$3V� carI�maintengguide�a&All�protocol� po�a4 � by!cAIe Offi� �K ga#na�z�TEthics Committee under�^d license PCF371688 . In or% to i��ify mec� m�~�resist�, we sel���7ly!�%�,L . mexicana!Ue%�s:_ RA ,B C�AmBRD!�� ��A�Ɍco� uous n &� !�58�nM!]�m�"��1�Q�A���427D(!dRA/cl1 9492B/cl2231��)E�153D0�lxce reM+aE�15�in%Fabs%<ofI�(-��. Only�sh� eva��"a mild� de�s\6RN0(AFigEWe� � ] of]O to aE�%�,antileishmanSaS�[Ip �Changei aoA7 most!�t nota�:g�C;/exaJ ,�tefos�hy�ey1�fe�mw)סāA)�, whilstB%�8a�3i�1�t . How�B�gll �I?2}e!p�zid�,�ist9 E $previous oeOa� [18��1=We also �V.� to oxidatucss-indu�a��A�as6�� has}ly beenV or!�)(-�L5� [ �Sub��/� !�in>�,both glucose �s�xZr&Ws"�H2Oa[!�menadi�(2�i2� supeWdj e�A8)O ed , but ���ylelu�30)�) RI3�  �A�)t�{" -�o�NADPH!� + [34!�As alt� � ole�o��LQly� �U�c�Uwe U1� by gas ch@�tography-mass spectrometry ( GC-MS ) ( a�1A & 1�S2 & S3i��� maj�te�(( 83 . 4% )�N>a=anQmer% ergo ?; ��vee?s its�q ��Kdid%�m�� AP ndar�%�we��itA� /a-5 , 7aN@4 ( 28 ) -trienolA�on5t U �[3<36!�E�a-J2-d A�a� presa�$at 11 . 8%�� �a����A�y^��k ewiF�rl�"or greaI depleted.X two m � profOemerg,>}�f�I� , al��� �( 97 . 9!�con�����5A7$is is C24-i`ja�lacks 9AR(-like 5 ( 6!�7Ab ) doua bondsjug�! . Bytrd �� �ӁD���exhibi�� accu$i� �s�� .�#�tiF$rly choles.^2UV ( 80i , 86 � 5% ee�iv{ DZ�)a!( � �g8lt� a distincX UV:orb� orum [37A�S� scop> �JOd�edAlECt!�con5���U/!�reA�!. �oc� Q�yVor}"�� ����B%W!n genomY �� ( WG�� demo�E_�ve�oso�number� �( CNV���� litt� ox '0of karyotypic�khss � �sugge!�g such hogene�tma�i sto�ticd 2"d (Non-synonymmu!�1�biosyn�is!ewlimEס+wo enzymiI+ 5�a� que *zyg.h�(415C ) enco� Da G139R amino acid� titu%@��I�C5-des���SC5D , �2�. 1300%l�Bi��qu)� !%j.��( V,�8 ably�sA�� E�!�EPAna�of SNP%a"reg�6P*M large-sc\l!�of-�!L�,�d�C!�h2j2n>S35� Alig�to)7 orth��MQed��x!�e�)�C I� ed H%Qsid7icein cat � ( S4 z[38� M!~>,U�c "_ in\> ch2�isULbyɕ8andemly arrayed%�a��M13�8238 69�^oA4<� o by1 iOn t at "i 391�!�re�c�c( G6w8�AF9IՁAin K data�B G961A62��2� ti�n*B 6u�BE qxa:sulE�ValAI��Ex �e highe�logE;c &`���0impair correc? �Pq#to-b�.xgref�,!� �&� 2�?esW co%� toge�+Lis�T $��I��F����, A�I�r� at \1�uA391/A96wA�e��N,��'�l? A�U�. A se���B(SNP , T215G_a� �n�ol�m��b�&a F72C2�i.A�yN�"�.(��faC! with� p�Av�q<bins site� 5� 9]!ne���of cry��ica/� ��m"� � of�BAG��� occurr� "I��A���!�Q�}�se��!� ( S6 �. Per-M�ve�a��ev$a� dele�of� 8 kb ��{2A v!�I~,9�m�1��532� 4�/��rh��%�ahe2�trans e ,N�i2�mi&�� ce [� 31 , �41!�A sD ��^I-�cross"S20�0L��exA�%�a�gen�( fiA!��q-T� !�m_MgNO5��gb"�!BQ͈y ��n.l[�}�.mU a�assocA��"h� ���he��l&k eY��.="��"!�$cript abun�>�<.�a&�RNA-seq �Lom�U�. To cap3 mailK N�b[&7 we�E#.�;Qf6�nd� "Iflask8 NFt�A� �'V��x%�, very��� f��B��M�]# ree]2�13%!�41�&!�cs B+D��) .n+e/" mode�  ( les��n �)I"dU ( S7��A�� $ploidy exe�a clea<"lunA���� ( S8[Two �a�e9 -�� st6�i )u��th���;��"� z� � 3�` . DeJs��W@k��sN�)6A90��duc�m��6;Giv�*similar� ��>' Rq�At�)in~guish�$!�e�e�ex!�A[>er!��3’-UTR*� q e� �Bp#%ro r qu^k"����vidual%�Y ,X� �in�0�gem+ �6�$t  nic � I�F! by S�r�Ze Textd T��a�!�� � ��:��AN:{| o�Qf�wn�G!� &� 6#�6� .C v+se*: in:8� �#դdo�% �Bi��a��:!90f�'�"�'��� er �3�K.�t�%�a=�>I� \I�"�-genU7-o,��raFEp�l�IAs��� 22 �(evB/412 91.:� ) �2I"(�� �und9(�.�H���zQ�: ��> lAl%�4dr�.��&A�M�p�GB��a�!:6)EbC&�of�CA�Q|�#� ���=� ��crepanc\��$�od�)��ure:-ve*��6.'� o k� �faof map� read�䍄 ��/du-A�.���*E`a��D! s ei;iss�� FB���&u�"re�ng-Bde�!H��H1q�"!�� ip�1\��!A���,! �m! reliq%m�&��YeeIiB t�J� vert!wh%I:sk� !�Ag* E��r�K caus,>�  reWo�*���Is8(:�80 �d7�)�Am.G)_=���0onI�C5D�Ad.� *6{ T emselv%�R���2)Wi9'�,! ed i�resto&~ .gIy�nt� ha� M��4�" S5 T%��6�� ll c��21�! ��parmz�. Ecto�]W=�� "2f�6"M ai�>W���%>�!�Y>�6�80 ( P =�471EP!��8,263��Zp�*�lf@�\,4i�e- ��6$p06a�&� a�an��� z�th� he2p|�01�possi� �2e !�>&sF*>H3!���ai .J^= )a5 �zGFPI :=�e� t�e�tP�=��m�z�p v!�r�T&!� marker G4)!Q�in >�.W�"�����$m� 4u��S�0��-�$.�t � �^sa�9e:L9: �amb�M�r�bec� g�"� S\����MT>,6��_� r �X� E|) *f �.Q ed (�g) �s stil�-ɉ"�to=��Pun�yW(&� SIer�/ur$�� noveE !������ny unF, 4-di wB9 (�2b �d 5�-6c�r-�L -Fm."�at��}�&�I�!qv3-!&16< E�2 ( S9 �4is6could beB A�>F$%�`!L� � i< gene�pe��3 ough�"�1vkae8i MoreeL:�j3a5� �Ja) fail a�F�to fu�ib.�.�L'd�4 �`p/-6� noA�9 y�A�6��N�imaz2��^Y�� dFB�*� �lSeS���-.�e�F!(ɕ)E�. Fin�,��.�&2'cA�iw�+ - I�.Z3�re[ ofEc>���2r All.�"F����.�4*# beit�xg�a�V . MZr A�6�!?� �AT st r+#. 9i�(w�A�:v� Ia� ��e�,dƁ�"s .� ,2�B�ca(��!���"�E�i&�];� 7*�/pro_=��mi&G!T�Bdimin|:da�rev. @on8DN�v�a hal?m�.�!2�a�!�4 m�y�.8r�+ A\AB�Is5��A�a&> <�I< }eK.;B ">V&W# 6/90/��� ���*A�%� 8�r��i9�}��.!�f�]�%;55&nby -N~usA$1-� �X.,@�0��..^Y6~-N~g.���atg* yiel#��� eYJ1�I6Q�A�, �!��2 !n�'.p� no longer ��%h]%�/e��l1��.� is m�2�0M�BM�S=7HaeS���NF,�Bn��rAg�0�%!2���hG,Q!,y,isyA�N`A1 & S1\%�*I�vngjzinclu!�be� �ofF�uSA�5�B*80E�rq`2� �@f+i�z2)`*Z ���qulEX!�%�is �9� a cha ic fu� �tw.X <Z�!$%�ce� 2-�*��B�!�BEg, �Q!4^2Ri�%(�))u�7678�#�).8a�0ŭ1��*r9���m�K>m",%K �MTe"��#,�w=6a&�n���"�3>:90" )�2Pm:!CN�eg� prop��Bde$.# a�DJ|| P|0elo(r5b�>-�AI&"(� 00 u�:."04�#4�CH�VEmR^ ari��du�*��*�.break � ir w� (involve loo^of.��f(�19�!Ra"L#��A�!�.l ( 99�-- u8���cie=�> �".=�ed @-��Th.�\ � inher/A&UA�WB�{'� N'CAlt�.��I�� ��fX�hl �� @1�=Wmis�/esf�#,�be*? �h!� QGcoinc�6gI&A;v(�J�#"�(%-2]�46Z � &! .�-!�2�%=�% &�%Tu,��eat��2m@����&L*�5[��I&u�!=eo e$)'mis2�@3r > atid7�ja��I�6maWq�!G last ��e �co�/� :�#!��> firs�.2�!��$d ) m""g � e�:!x�w�B� � �0 a ju�2�6�.5:3���&: �%�J Wa��e���?s&�2aaP�#Aar2/ , acUan46or�$"�G"�Ջ ter-����Y&-8R12A &,?�~YN�^8-��I�de �!gB�6N�'su6E�.��2| , &,�+(� !|le� . Ifs�pet�>e��doa�tribut�\FI_(the��n recut��!�� We "D?���Od !@��9L9&t�"Q@ax�DamU#f aUs0��6d>z� �B[19] . W[!��:A�8���@0Y�p�B) �5�X�!�NAt�!��5aA�ee(6�M�M�u�2"Me� AE��* us Ga�A�Ef&%&�3(�) N-to "�of W242-Jop��E#"v@ eѥ�;"to�/ M�e f�YA" q0a� H!`�B�< % %Ic)h� ..�.���!�� R0i�"sandfl��,�"�Llt�@K�  &�HE�HC2��0am+se� f)o� �a��(mammalian h:enviro�1�&~1�+�#ila�= K"'G���m� �;c"!R.a� �!%ial]�%^.�*.�@�EeR�S &<��LuQɰa>V�Co~>A�Rmf#y50 "OF,A`DmI^�� -�M$A�ItroW 97�D�E�r�J��gS9�.K�;?'�A� ong- �d)6. S�*��D�:BBA�D ll}"`R �!V�� awe$�m#:g�*2aIi��%�1;�2I�2�m -�vc�9�E�� 6��G�,2��D"&@1fUat��=�%�U�!-P]9x ��7A & 7"[�"A?^%: �!r5� a� elluQ�V!p�7�OHv5.W/HedE��1a-�q�<�Ju��r poo�!e�8)�%� :;Z .�"͈[!9'�Hp)9E.6#Fyor AMBMxw��|�to WT:�=a�u Q)�( 4fbE± �7'E)% s"AOt&�&$00>%�w"LL(IQfTnMR6 A�As!� {re�edE=�(%T��to .�Tw��-��4Q#��_!�tr)��M�'W unC/r2x!�t��p��!�v�qz���I�2Z;M"D�&��M��.�M�] l�=��="]M2M�F�<WM.!V>$W���ed)-n.7.�E.229!�±�4 �7i5.6 �� �>�3 P = A`81 xO −9E I�XM�e��ȹ�?!]L�E�)a�}-S s2?O1X+, e�W) �%�$N�� prog�;�se�no"� a2� ;e�ŗvo�NV #��D�@Fai�-R�j�A�&�E%g%?(GN travenaLE}1 mg/kg���ry� dOor 12 Ha� su�LwM���+Y&o � $HaU�1�# �pr6M toxi�+�m5M"� BZAi.q;!�A�*� J�B!�=9[ F9W!��6�.@,.5f�Z�y playJol�'T9W"�,�42�>Z .6� f�!�/4� If!L"� ��E� S :JO*& publ�H2�[32A ��{ en6��1w�Pd.4�+�33 V����6P9�&,0..p/�*Qc�.&5y�,sB�%1t!H�&�# to aI� d���C .h�=�%��%NU1�H �rK :1I2 I�NU1���G5]5�r1a��6bET!{>��1"I� $7pronoun' f��JI<�=e�� &I9"��� IKm�� "�na_�"Ediscr�" atorrF&tY$�9�B to k�(��a��$l . c has�)e�Ak9m�#&?M�Ci]Kve�0set%: b��@dM*: gime�.deno`sux VLJIndia re�_>Ze�ach b.���ris��ac �-i2�X.�:��0�& gene�Dm&?R"rT1("�P��a����+�5&$;t6�!SEA� llel��numer���!H phen'*�$�!"� �s;_rarv&��m�pl.� �03��x e im�1@6 �� S?)�� Kin='_\A�I�Des��(fe�E�?c�)nd1t&s"�F��e��}k.. �-mp] BA&] eth*\M�.b' qp�+<:c1�J {R simpWD?;uptak�1We h*18�=�OB�E}s�o��&-d"�X� �p�YY!3i!U �N� )BAlea�؁=�m"7I inve8"�!oA49%.��+t �I�B<&�Ein lipi�cs�A��membra� luidBVf�"sF.{�� \[45�@� (a1�kuN.I.{���B?4&�z�� gu��5)dR��+u�i�(<to)�.��!�[18� despYC�"^ne!�v�~rɠ*g.��� �R"�cli�C��f �� ef+cy�safety!S�M� .�doomaa favour��?�zcho( in �>�" exts [2];� ��=�XN2kBL��|n�� t opEl��n��'s"$$ work�)�f��{=fM="y**� ce vi%`'�i�9abolism�-f!�r�]�$� !���A�!�5D&$-��K&?6^�1elne!G�� an> mpanu` drop.:*.X�Fs  study,�A�u#2.@�rwD�!1phospho�"lo%2�-6!C: A�us��*�Ma � %�-�z�] ����:v�DW#autho BE�=�r�� ��E}SA�Z�-!DnMU3&� qPɉ� 8"�4s�y�H,a#c7A3����':�����val�U%`#/f ��XM�b.CNe)N,� Q�46X��\jx4=3SH�^i1�ooᚵ�&t5=��� "��@ roup� lo�A%"C "j#!<*H �'4��up�hR[16 , 17��r��Mo�t�!Va� r Waal�te Ş.#!� Q��Z[c�a lata�]C�rig�-E=i'�je�F'u�c  &Z� ��n�heptae oi�_[4U.� in)p�"� MiQ� dir�cM�\Q>�5#aX 'a�m�.�+ CYP5�Hi�oM���'�X0 �now. �$g�nwMVa�)�i����&Y . ItA�unF iA�ia* haus� li��r!� zw&b�v�(a'a*�+fungi [4Uw��&'&d ouj16��T tf�:��I6ane*7)�s@ �+in!�%�Ci�t: A path&�"�b�l"� $>�5! u�D�U���� ��w lO )I�fr�'4�v �,�Fe��,%�sI#Q@ly&�G��� >Aa 2Oa�A:�)a��(donovani [1�W2�I.�O6sofiB� <��"� �k �!is�9!xby '[t^e2�Bp,8oD2Wg4(2*� tja�is� (�,j��:�s&�*)�EP/A%y ()�:�$�)��forIsl��5D2^,w*�H�8*h,$���ws7[5HQ^�(!r�,N la�!4E���a4&�,�{ �B"�+�/:I *Q ��F�Pe�M hallV^bm$. D��;p;-&�@��i-��:���d"s� �� ]!h"z)�aX*O%by2�V��� �O�/{zb� [48]J��I��c^l1�dIu*�}�)v,ln ~ ���E��$:"�;t�AA�6�8F-�*�� necessita]��]6U90.A�6h��6� Y�. D�!����*�2�'&A+�"4��(�Oa!e�s�\E�=tna�co�p�%)�) pauc� o�E:�� E�;(< argu%%:~ %Io�M��� a`!&�\am�\H"��Q��v!�@)a<A@� ppeaK 6� �"�rl  a�.�Q!�1lap=+pat��e�� [15Z"��q!��g6��Sh*s�q!�ble�(��<e&�pf2�, g�%f�%�"u"�oftfU8� Q�.� ,6of�) ��&�� I�,?DE.F!Y m�a�.�8si� ,, 1Ft'P�v�'( A y!��, I�%�R� a4�AA �l{2��"�ed virul`%+�7usD [50 lay� v2�=���2amE$� �"R] ougha��$��.RR�#als�$i/ �i�!R�&��]5�� (Yc�giv�Wser�4�T-�2�ka�3at]�2j�*� �� �..J.� O~�X.+"X*� !D4�d��A*a"�!��t:0u�(nX&�!down-6���6e "�,shIb%F�'KT�Uh�`effor�:o�|�nn�j�� z Low-Y).predi�4!�o&#F'�>�*� �Z�oi�U� �!2A.*A �: y*�)!� ��achie�͸B�com�:!�!�ݽ2�O !�^�u�. DistoXANlvA*ajal�P�cR���7Q�2hoI�wi :2�ad�Btmb ŏ[��&�.�x9� ��:T�^��ir�f1.��(wbns� in� ) human b�t! *EA� ptim�~Sw�5p��rw: ‘��’9&�o:'.sto!s%��2pre&/a h�J ��-� ndi!�n�h%\ itizA�� /�.ƀi ; havi a9lev�. D*�ubiquit3 �4"� t�f���[ 5a6��per_y!�0cogcy� it"�unknow�/w!A`NVmod� !�9�-w!�-�)�"r��gI��v�Ethe!Y���y~�1�D&[pre= �n%�sA ��a_synap�g�I2/ error�fGxBe�P !�dd�Q���x!2�"dU/ sign��_w�� �i��1 �my�a{�<2�-yne� sp�e!�a surp�>st��u�IA�K�9���o*7^�a26X� ‘r2U2a$)�;A�) ��%Z+�on!�ergyj-�"05/‘�".1�-4Q���$|�#rward��-to�al�re��� a�nAphalo o�yEG's�� ][&T_�\rvisV[ taskqt�!�A��2��eU!1J��J+B)i�b�S cipa��E�gn�Na�iodic�ea�g�mn*&�o�n�VZ � rbep+-� �FU��?un. �� ��J�evoked>�aUO�)ŐhK*�-b�f�.nd1�dyR-kz !�%/�qfB�5!zqN �C.�:�{hfs]!Zad�0�&, �Thow~�-=aup3&í�:�����ex����sqC hier\�a���^����!!*^�s . P��iH#l� �*b& �!l��� q[�dDI�v��?Sj ��VpasB�a��!bu�v1iv� xi3fu c�f"�|E2B�"Si<_!&�� ce [�D�DIn� ��ide�9m&�KpN#�#��i�U���� |?*��7a�����n�e�cerj�[��e��u� @( �� , Bd)���\F*3%h-J? rE`po) W� r bl! oxygen *D[BOLD]��w�vie�see [4]�0R��!5f6,jC�A�2GM�e [5]�HK r6]%�ad�1�<f-4!�=�on1@E�! �."p:�:����� [7]�.W�'�2�tom-upU��[�4xI.H �.Ew!R�sn-��*x �d 9J:��is qu�(��s"1t"���n:ed. v"� ��*&�8c'a�abx��X.6���m�~a vT�co�sal��y [UC8�!a�1e�&w�2fobt��B  �!]e 2�A�eQ5qu�'F6—��%cmXG.P—!~�+es� Y�9�������hod<A���6n&�\*E 9��lclaim�-� p-.Q� ‘cL l,�� bo^�e-mat{�o I�o7wXqm"?M�7�� /ArG �#pagx1�!.upd�'K��� nS*G=��A%�?� _%\qA{jI! F >�s�zfic��pyrn,!|[[U�)� 6T�CarilyQ7w� g�F!� 1{[1�`� -�-*-�]x���"�!��@��ofeQ��n$q�ce�# i�*~� � �`�}?J.�our� m�=�(N�� �� �J& � �D��(�ts�-!k'%{-A3IE6� [8]—9�����]!�b&�E�. Q8q�+b�r���a�t�^�7Yi�,�NMY)V� �:���� ��U21mA.�N�!w�s�Z &#to un]�E!:���6�i‘R��m��9�te��[�0�:6]�!R��9�s�� s op�-�"�r��>���{� y!��t�t�"Zq��^_ �E�.QP�>�2�A/� �o&Y�i prat� [12]$!qaS�mm4}hys&@ �U) -�u vh� Gfiir��ofEA�tu��pec�?�s .� *�� col� A}-AAhY 7"�$ ��mathe�AA y equival��_he bi*~" �Fo/!52�[17–)qIQ1q"R���,�E|�w �1�/�aC/ siA/D _ ARheA�- 2,V’—E -�!q᭾� 4U-�}��(&8*� �&�W*z�� �Dr�w�s!.i? I2@�!��mN4 "&���O+����A��&� �_� . a�aA���&�(DNpn eachI � ~� V�t�0or ��[2�g M��s6i�@����w�}-)� �"! "-uY�to�ny!31F�I.@i a & �2 !�!�U�  �am.�JH�WA6�YJ!S ���qq� �j��< �7.P���.vi. Cru� 5wKso�� ߹��ҁ:! �&�Rcm*: !�J6+�� �hy��v�f�[�| �f5-� dx�?-QuU�1�Z�( devi�); �To �<v �Ff!��4�X,D&�7�S9�a��")�to*Il&�6=rom1�F�Şa�(TMӛ�*de��A. BriefQ4�)��r�>�,a���p"�spa�KnZ�*//� [29–=@93mMn�f-8t��=.�� nelsDcIs� �e�(M� K^�(0°–160°� 2 G�)�Y��=| n)�%��$.2%�� `Kvri�bd>vol�4�.d%�a�o8.]�tu"u �t�G-��DAvpa�r!�v��~aaraA***,"�ZlyA�)��p+0( −�to ^V ms aJFi�nse,t�duc�%wJEmatrix� conv�v2t�b\-�O �EJ��eAl== �ib��I%Oa��w�1��]'!e�E �.'wh��s| }1p#� e�V6�E�,2�Y�� ��i`.�^�{ cs p >Z104��9�}� g�r m� &+6.!C9ڂ��C�a�9324•S2C%S2D%!�*"va��� U=!#trec � e��:�9�145�r +2�ot 154;���5� 8$AF��x�<e�f�j�v%� ard��I1�N 01 arbitr�Ua . u . ����^e�$]t� h&� (O25Y3 H ; t[�8=�H4 . �,.�$ , BF10 =  46PO1ce�Y�ro#��22~b�O9bb5R16)~aY6�2���o"� _�%K*�(5�7�pM44��-19u�,E7Z.�&o�i��OZE�6��v(V�403 n(P0(��n'��(j709!S2E-Fe@)�6�(�m� 5^v���#p�H�z�1�p�%ez�8 <"�vw 2`de���c*�n"��!�\�#̄.� �*�  k("2 & �"%[sf�9�J��nin%i3�vpS����B !�%�e� .r5.{*�s>"E"k�V1V"Sex!�<r�Qm�h� "�(r p*��p�� \fa�n. A6e&� e�e��(�"#�i6� n��1 *�B����[. F2�if]e.4�!FM�E� �)�� ��!��� " 2���1�� �o�H����%&%e�& b�+.�vok!c*so5"T4,[_?T��"H!�se�%��H`q�A��"�< ,ad"=aAk�lZ anS8.�W�dgs)*o[��9�0A��'WmQc� a�,9Ŭ�!�*��J Z-B2�NvF�.6 M��L�}suc�83"�.]4Z8,E� horizont�& ��Z�°_��c=���EL = at 47��ock��Amjg it�,b{ d!a[�U�of& I   >�3D%b3EIi%�W:]F0�nas� �!36K]jAuc�M ly w{<\j�O%�ɰi;,l�4 �[_$�( ;�>� , 18�&r6 � 002~ D ,]_y bar�c x-axiabaH�AU� u� >q�13�� F �solid b-XJ��j6-(>��enZ~U� >A�<P��R6R 9�. <�T�.��SS�X��$( 332–48�� J} 03!�dotyb4ӏ�)b�|Z1p�e~�ͶJ�M�9EF�hك��� �u ŕ� �,!њ�bo:==w��$I�W�vjA�!=3�9Z/ 88Q_6<1�AQRB!]�ZQ615�X"B�Eid`��%b���M5�>1�U34422f"����'Oseev!�6�neglig�'u�FA�.a � ( yejj ���1�&CD�g'E�p Fy<��verag MMRy��u0�*k �p���ccP}#� ~szerv=t��t )!�Bayes��L�i!tuni�o7�)ower  n: �pup������*62-lfN.��00&�2&�)�*�to �6�1��U84�.�A a�6�!V�X�6�a�� l0OFtefacA.Do!�&a a MbYy]"� p$fj %P*�e� �e�ach&%!P. Cr�U !�/z� ᷭ;A�Acol�@�vV{NY332=� ��"��F7b�����v���!t&*.A.!�+ �%�spars�d W�Dq�i ��"Z0]r�N��t ��W"Mheg�vt)�" � s�:�"�"^q���b� R���*�W!6"X F(*�, %rengt�$�R<:tr��c;Ing!�Z� �qa *�DB("us���Mf���F� ORE�:? v�( �;7��'s '8usp�12)E@a�!�Ben�>�2r!!�A~J:�4 4B0 �L!X!��5�r�o6� 3E½HAw�F� ( 38�(52�� 5s �|7� >�$noa�\*,���i�/ +�-"���)g�.:Q�(�g"� F��hvio�@N���e°!�f 31�W�%�AQh�8mK��!�D��9��$�`5�1ob/j^�*2�vWj��NRnd�:�24/o�T�2��e�7, a�ʒ�$bL�T�"e2��!�!� ma�?udT_�>r��D/�41�{�>�4!<�2Y1��; bsol�s�afb( ±8 > ±%  $%� A7or�P.�M�U(�!-a�&1M�:�)6 -$� %A���LA-me"� a�^�46!l�z3 �pf� a/i�E�!}9F�M)��"�)*A�->Q �r��.�cvљU�)!�]e�&�9I�d��*�g�5b!tle ( 9!�,| 4D�~�!�%r\�d�i�� �. F� J�SH�(�#x�lj:�VO#! )� �'V."��b�(!�swKal��"�M;fM�N�Lr[n�dynam[(����P v  )nﴕ�"$ R<Uex�9� >�y&atm$im}W%;�r#ll �� � 8#�#[3} ��FL)�)  { K×a �eli2� �'.H F #isi"�W#z 6�g 5���eY�.�(Ba��Q�r&� a^B�,��� !`R� 5�&b-A�$�B�5>lhe���0par")�(�ouw3e |��ϥ/kLa�f�Xr#%dr�Q"�5�u^<�!���F�H�}NB�85#.VZ � i�* 2q&is=io� N'� m!\�*5T�-aasymm���;(�� -sha� r�3p �>o%r  �Y"a�,.�si!�t!���ml.41u400%g����{ o�"(ia)icjO25 O5�OHxe�A�!�A� Hlz ��n~r�-3tvI2H@)hp��JT��*m eal-to-noMh�Bt��a_ �[��p6*' 6�9Eg*XB� noh�QGAg7�Ce��ni\�]EZw�!'!FMge��ʾ:��32GKI�"�,( tT)1lr%m%+���( )200.X� p=�|1"�aN!�!E��\��.7 �No!�OT�� �h�v�M�)�"I'f�I�H"ۦN}�"�e�A���! mi�;>6�U��)i�*5B�`}5�eNt!Z�93��!U6Q:_%��� �65�c�N��*opam�)��5C;"\$02�. �:5�t�A=&�"��Af�A3 f#a|Of��VW,(" 0>�5.�qo*0)!s5�.+E�e>,! *?6~H1� @��-��wrroI1 oddb/ paradigm%b ,  �R�V`<�s^�+6� ��$�=! Q�>�A� �I&���1.� 2,.��� 61.%�k� ea��%#�HU ��"� R�|!��&Gt�1B"�3f:Bjle� �B�A�&�AR&79��u&9��1�rni"8F^8���~kQH:d*H� �aR�&0}]d(v<!n��2��G�  . ��# "� �Ae8"�<�ʕA-��h�f29XWah(n&β}!.�1��mR7!V����N-A"�2�i2�[ �|= �3�m"�/%G~D���N"�e�-��TIN�="S)�us�n"�E�a!��P>��0� ��or�/" L �4�)F{�f��e �<&A�A&�iB3& feedѮ conn�s: �Dt!�4Zi�)9n�E!�mA\P61y"�<%o� [V2zE�&-'_)-$ E5�Jge�e1�2M>yE:eVeo%�MqW>-m+ ���9�y�FK�at._�3ea�>�.3.��4� -�3* BOLDY�EA��E$�aAw{��U�`�*a1=?t' ԸS� 6l� r�j-��47 �<h�h�o?fuh]���)],*��)��q�.-eQ� refld95e�?�  @�p��8� oPliA�%-!�,—Mi oF6)i�"��&sW�KnN� �-�M7���!a&�N���a�*I >�ճY �,n��Q��j�em"&��,�  te�(*�4e� x%A�Z�%F�)2 � ��}^~D�A�!���8�%&;C temp�LM�ml�s�-'EMVQ;[310T�q-I�i��A�!n�G-�*���� ^�9"9.����%~�AzsD�9a9mCes:�QRF.�j�,=^�2CA�_r�)�yku��[p[H�w����6Nd.-.� -!"zr$Ef9%�i 6�A�! shor*kRp=( 7�6185}� �@i(� 2�5)�5��d�^A�(@��s <.� R.2�!�='(:�56�^�5Cl�'in�=yMՑ���.�6�s:`.�.�&� �[g�<��q-�I�� i� �.� �!�w^�'l0-�a>?.�.)PsyI "�, t�m�#1Vo � 5^Řobscu�|2S_7�$Sei� Tang( $eag��e� Řs�1�"�#xat�;!�YZ@, :X8��&{5����U� u��]sk�*�>i;BJ7!��a�aTa&}!A�s�n E)�i��b5�P secu�l�;n�arz^$wzy_]r�w%��@e�_2F ��9J�y�,� oU�`��^d!y� Q�FLqiA�= �!�6� ci!%-����\� �12�R�"�=M.-;D6�24!�EA! {����I�al MRI��)aA��0]Ep!�-urcyo$d C[2Dk�A<�Qp��A��_d� �tu�M !x�&�sj��re�EA�:� r�g� in <�?To�7��)�smooth.As&d)O��q�"@N�)[�s 6�^D6�.�H!#i� � q� �!gM����V*BZ�)s�>2����9��rg�3d2�� #_"_��U�:u?���^I begi��a 15"aNQE�r�)!�&�ce-~�A3 A��2�9�9 �5�>S=X� �3ݱ �n:i�:)G&�B<2� ����A�PRc[��h!Be�N��"� ��=yA�audg�ytZ([��� moda��E���uv%&-�@��aly�6�3%�6�� �2dYi��i8�"�O� 5� z�A�*�*��j�y �sd}�6Y%}�> [42]!"�]��4 F2�>���rRm2�ݩ-u�!����R7� T.� AS?3Z�O.H~ t"S.)aP����Y�A@u� �6/"Q,6�% �&59\RRv�:rLXts"�z�|_�y`%�n"�#"!-��V�6f ����1p92.��if�+ 3�>m\�a.Cn6@�Je� cue-�b� j;�m3�A�/��%��*P(f�ForD7M<&� .|:� b &o,��]}�&��doLD�6l5u_&:.�, s�1A��("Y��� �"�%�>X%.&��� or�0r�Leh�� ˭� ɡ��9u>2i5�Zis2| ��s9�.�a�* !wlsQ�2ps*L-!e&5`���:d !��Yoa}bջ�W�~�T3 � A ���=2�B��/��J m^ v�!" 2��?V�" uem� V4�J��3X]MYqa��E��AR�2� MRQ�!M@%6�*'O��)C�.]��s-onship��>�5^.�(�(*�Z �6z;RWN-"e=%.�.q�be��T!�U"0n�_� �\Q��e"�$!u6�w�o�"3 �QE{!�ec�!a�iP�%�[orQZ ��.�*-R u>�~"�1���.@non�.�lu��,��"�$�%go�e.=�dal em�g!�mB�D**  l shifF�!t!C��I��B,m1x?�S t&�%�%�,�,)(Ѯ�,�n�^_.���d��ee:�~�g)!�*�-–�.) b rAd0c�% stac*1 �[- �E*U$:[*/ T��c�Ŏ7�E�th�p veri/r*%9�/��)�X>"�D�!v!� a3*l�za'*�m�փp��)��e{C BJy&�i� L6s. S�= "�tXu֡@2#wASq � (ga near-J'i�e|wa��kw�Zs��re����jV�g�4icY�inq�A:*s` �%t"M ���`Icl r�zW):R��otqB)�Q�u�I!{��jt� �T)� util�}o�=_*d ;>��7A(r&R�ff�t�ZZp�� ��5;.\M� �[+�3�#߈I&��"� .�[�p JIe �|=�_�%�se null� 9n�aP�.#!�Suyy��I��yiEC.� �5��.�!I��� B,n~tr�S�aj �Xcgg6 c��sVR�5a�x+��(!��^) ���T��pi�� r* �)��6!�a�� F�ia�s�.�*�J�H%zI%/"�iE�.{!:�}vXl�uoC:�A. U����frame� ,Qx2\ �B��?t�"f immuVMo=���U.�VX%6>^"�91%a�Jyo"�!�!�6�I�I-ig ��3EHby SU )9Q*�>* $or 2-photo�lc��imGA!s8�$�5�� A��i�4D�"w0$area satis�Vs�B�yi� �^�%��E��6D�QueenslA H�yR��B��G5���(: 201500157X,Dw � ondu�[�e��e�!w��l*(�Helsinki>vtpO+�Ia�r�3��#B�m$0Ӂ�0)$. Twenty-f�healthy� t"�tE���,P�m�,�#^/��25�� , SD��01��e: 18�64 ) �nor�K��ed�0v�n5recru��� FYn�CY�pMZE�schemeA��b�. S��i e�� ,a 61 cm LED �!pC( At>, VG248Qz�A��� , 920 ×�S080 pixe�z�9��Are%��!�120 Hz ,m:�L,PsychToolbox� � oftw�� [48]�Matlaby e�15b ) ru�un/� Wind�57�NViu�,Quadro K4000�%p�� card>p%�sx&k � m |�-armch�A�nm�a���h��lab���@� �hi��,�'�%�}�a gr�Y��e,of 57!�"a�c�rck�15��s �Gaussi�d�'(�/er diam]&8: 11°; inner m^xfT83r"� : ��73 c/ 100A� �].YQ�+���_m � a 50DISI<�d'*�� n8ly spaced betwelen 0° ( horizontal ) and 16  in 2 �steps ) . Eighteen ( 18 ) gratings in each block ( 2 per orientation ) were presented with a higher spatial frequency ( range: 2 . 73–4 . 55 c/° , as per staircas[Locedure , below ) , g�gap of at least 1 . 5 seconds between any two such �|. We used a modified de Bruijn s �$e to balan he orderu I = s across �0itions , sess !�hparticipants . Specifically�(e generated�09-character (.m )�s%out�cove repet �T( e . g . , ABCA , not $C ) —oneD a 3qsub5( 504 �s longM\anotherC2bC72JB—!append �copies!h!uformer�!�three:'lat!'�1 , 222�in toi$. This mas27wasI(to allocate�5� both devi%��controly4-�� ( using different , random start-poiA i�ensur!hati|]_�prece!&8by equal number%, all )�7s�p�2+ ?�stimuliAGo p decoaS ny sM�.M couldE>be biaaAby-�ofJk. In rov oddb�1�a*!� �@Gabor:�i .E�,!=ndard��!�m�dq�2�/��1�,a-h � each.2ve��D4%�11 timea�cor%,t!=e follow�distribua�: ( 3A�23 , 52��re!n,tively . DurL��~,%fix�ytdot ( diameter: 0 . 3° , 100%I��)!�re%�i!�nt18 �(,ra��$53%–98% ��for~�x(25-��8 linear ramp on%Ioff�{C�decremaonsets �Xi)iAd sepa�lyr2!� a�Br. P.��L��tes�Q=em<60 minutes’ du�6 on ,��roximat�1 week a�� nd comple��xof�� taskN?Fig��Q���counter>�e�]��ForE9Ѯf ,6(%kin�ediap6��\of 20a� Ps w�(be a target1�hiZ than n�7sE�ask�o�Bss�use buttA? s quicklyE�,ossible when�y detec!]>�; �q� �er�Pbe igno�}.56af�2!2�) occa����Esase2�A����s�a�hng��2�initi�Y��Kpeice�p�53 N min � ��)-�8uditory feedbac !�, or low tone��indicN misa�I%)�!4 accuracy ahei��sp� �>��ġu irst>��*ER salie� ( sp>� or%�帡)ch%/ , de��~oEQI)�eadjusA[dynam� ��a Quest��irc!�p"� [49]�)}V 75%- M��<��Z��Q:�J����y�%v$same level%x)0i9�observedvi:1E�r7 %#toA;i��sir��(false alarm!�Af� !�>�N�fit!��� n EEG cap!�ee ‘(data acquis ��) befor5 �!�a ��1%XI�I� equiproba�a,�4�st}� l ��ݯi(�7F+. �2�2�%K showI�$percentage�)�$s correctl��%speed*hes qP,�mhow m� �|q�o��o (6��L�I ,s{ �Asco�:@as hits if they oa�wit� 1Q�i��� >�Qy��i�,a�ZJ peakyͥiN�*��. T>�a,t�>expre��a�v:vh�'8 &� 1�7enA�e >�. One.�mm ed l��� 50%! Vinh ���3� remoa�from fur{ analysiaO>� :2t��woc%��a1�$ paired-saa5s �p S,Bayes Factory f ; w� quant��^f evid��in favou� ei��nu� r alterna hyp��B01 > 3.g�to$al support�UZM�J< F �O��[50] .:5Ru!��,�Die�#L[50 , 51] calculator!Matlab�uni� pri!js I&MG��(�yLer bound: −25%; up� 25%i2F;50::50>� 2�P 64 Ag-AgCl electrode��Dsystem ( BioSemi A� 8 Two: Amsterdam��NeAla��y& inuous��%Trec�vd-T.X0View software �0-oculographic~-� plac�@�|outsid%�ea��Iabove� �� left$!�o �.�!veal(�ˡ���eE����U ��offY-�|4EEGlab toolbox}F[23a�D%�re��d!E256%�nd� -%�fi�y&�%� edgeq�+58( 1691� Hamm!�0window , cut-�f ncy�2;,a� 6 dbE�Raw]�inedi�h es�4 of faulty>?�2.�,��2��nwhich) interpol���averap$he neighbo�a!���qs defina@>-�Bm{64 tempt�.�-re(A�\�� :4A9!�E noiY t��100!�.6�Clean7 plug��or�( �5s�6Tnitrc . org/projects/cAb� visuo 9�i=periodI �.�muscle)iityN f ��( �4.� �is waL��"@� arte� ���> � u.sega� Pto 500 ms epochs surr�]A�� � tA!ms -%�4 ;post-�u& . Im"h X2�)�aS babil!c  ( 6 SDe#kvid�{� nelA$2)ADR"6�%Utrial��=A)�aremai�{=)ubA�WinJ�compone�� e�ICA�wit� reduA� rank!�DEa;!`EOG���or an6�:*>2. C�re� iblink!5saccadudQ�MA��QG��! SASICAJZ[52��A�B� J�(*���^)Mi%Fa!:�8IoMRv�5E�prM�6 F�N� w� ts� �1#5onA��I� appl!6��is ne�se+$previouslyJ�a-�A�]\%� � se�ߥ�a4� ey�io�u�.-c �%E . G�ng  �t> �5����P� ��predic*-. E�V ��Q��labell!s�Att��W�F!�dotf;I�:>w�>�R�DH&�Wa� ��5a in aapbtrain�� �[ ‘Seb[a3?t had b�����5%7�>�2��R�� ��. T�%�0%�!�N� T��d��\.u�o�  ERPs��E���e effec<AyA�as���a\ -taiA4cl�r-bpermut��M�0� �0( Monte-Carlo2���000.Q�<p oX05;T svstic:n�$� a�oggreg%��AP(maximum sumA9 sign^nt4 a,O, p Z� BecaUi -��raAPn 2 ,#ņ=�, we ���2�%��-^sxu!�f-�s` Y ��AVa1-� d6��cE3=po� �5 .c����{��j�Si��}�&!=��n(&��usAzU�"� Z�)i�MM�w�i E!��setxsyE$to investiA��\� ThBte�on�� A,�2by$t=n�;&�ERP���Ni���Y5Mr� Vresul�ce wava�oM�����������>���!�d��p!��ar!nB`(9��s"�$U�A,2M I��92%U�(�T�B�8E�6�Aw�Ŗalt�of2� ��� ��e1a��ward en�! model [29a3] de7��oXrol5 covariaA�in lyc�d� [� 54]* githubO/Pim-Mo�t/O"-�z�sg�%��� deal�ba�  *9.ő�es0°–�&i:�&a�( nine half-a�U�e�sfun� s ra��  8th poV.."!�� �� fi�ssoci�saJ ular.��C18�'pac�V#be� /:�` ed��@�5?o*}#"�[29l We "@a matrix!XAreg�W�"A)he"c .`*%� 1�� a�!��=�6�; 0 =�w�)e�convol�t ��%b�Y(*: aM�., C (6B9# × n �F\ y��$thu�KVcribed�~~] ar)�: B=WC+N2*B9Os2V("�s:�, W.6a"�I�%�!(er��� -�8�(o2� w J�2kN!�N.�!resw��i"�%�V��E%�26foR�.�3-fold �-valid�asc*%�iA�r�%CA�li8�Q��W�E�Bl Yf�ex�al+��&�irds:� t u/ YaI%a')\)OYQ ?s>63qa :� loope�(rough until �%'�a�. A����< ��s�#V�)"* �8 &- !�"�$a�|ldsaYE sE�!y(�!G� )�� +n� vE"uti�Y�,,� a%A�A� ntkA�. P"0��"Pb�ES��5�� ! de-mea� � �)�FA� p+*2"E 1 a 27(n|��Aof.=G " d%Bo�j ioriL of 3 , �� .odd=�� sa�!\!H$asymmetric �i�SJ�'�� �+�����, i�4s�0e��+EA� )�squ�R ion: wi=B%�cST) T.-�� �Eewi>n$��A[r�� o>6p!EJ��)ADiWN !"�>Q�t�$���of�M?A� `��!�F"�*� �(olleagues [! ��t deri��e optim��%g viA/�ve~*���$J (: vi=∑˜i!�wiwiT.2�Σi i�xregular�*�  �FCm�v� sbw=1)"$εiεiT εQS −w]@2� 8�.7Y-��F�∑~i�.�byM�!� E&$rm�shrinkag�"C,� , Comb�A6�"��-�F J���a11N-�-hVN�9-�uC�# =VTB2@ "� )�&eAah�P6�64��sI�N -ue^d E�aFc(��_!!+e(u�e)i�)�J#u��#%V�Scir= ly shifA�� entrS'�`x$.]o4�=�zero- 7ds�a� �]w. on�2~p)�X- F2�1�"* (�,3B%To�.� rm mismatch"�{ASnd&�(�uKfeatur]7-3D��3E%�wg m�#a�&Z�&� i$!Gexcep�Q��n�*hMA io"p U�� e.�Y9cur2�2="��y ;�Yi#V<�.=,%�"^!A�Te2i�&J at 6�.Q��!zuatJ6.,�,b!k& as 4O(���.<�U�g+ n%�a�UUWpr�� !��,!�e�-�鉑wb ,�a Wle.%�a�'��� B1 �3a�sli6 s ���"�h^a7 ever-3irdNu�� q2�q�i�k� �Z��zq6� ���.-d� A�al1AEA�&�pop�&a>�!j��; g�6� im� :���66)��+�� E�2P� studE6 have& a�k9t meth�!to�(!�e� \of neura��Y}[3�'3�C\w!�r�e-�3h�7iA}A.Fp%�bdE�op�Woy'� exZ {c6��A�"&�[3� 34] z 0y ( x ) =Aeҡa�osA��!�:�be�_qL,ya� mean"�.horv)'shvI d; -  ,�Ks4AD4�W� .�*� ( unI)�Q��.2!���4C aD%e!Cf�:Y�μ%O-)� vary"K −9�cA� .] N$O likelihoo� spur;(br!�)�M~y sear'(a� 74,%�a�%�.;>�'lo/E��)�� �[n�?ȍ>aon��e" �v�"� ��=  !�.^6T�>*��(5�b�)>��j�6�bysuV�Uo�#!��� r���map�~Q�;�&wh��a0���edA�"/�]���N�"� �d�'"s!\jL��w;,aP��$ b,�'"�'"�'"F'"In6�u?��}�Mv� o� !�.�F�.�one�@�������G�G!c"� up��&$q&b� llap�M�.)\ v�&i��{��"s�r�14�1*�2o$l�2�3 a . u �B2�2c��o3���"~�} most&sv�?qB <�+w m �- nZ$o�4achg� (1.�!���*�3F �he"o -��"�;aa�(ed�C=Z�.x�p.&�)]F�(A��a pu�1�z-=,9��%rs2 Ucum!(ve Gaussian6J(T $= 0; σ = [)<top�4es� wB!; y9r7 jgro���z-�:� ��e�i<�1!�� � .��!O�� sub-�3�Tof Trypanosoma brucei Ximq8�)pathoge9=Sa�n Afric��T�6 ?is uneZ��* humans du�X.�� �e l�"z9 ( TL�M1%�2 f�1�P�um!]} . rhoApen;3nd� gamb re ��st m:byk%�$�w$+ inct�%�� qY�{� gen��Ane!.� xeT phenotypeA�G%�1J]�W$n��nt9� asM-2EX��l.&P=��H)C�R~! Ht!�TLF-1%�in-D � d uptake- 'med�by$$�̍w ,re�o Ja�8haptoglobin-hem .&HpHbR )�Ken#BH!�w� &t)�=isA�al#Hru! �2 asit%�IsA�ic�!�Q�F$a�2J�� #5�~<to$ 5i%�uB�I9b<q����k% ��at simi�%� =e�nalfluores�lyv0ed-p< fash!�to �aO �.v�I5`-a�ll N�,.�!��A� APOL�bu< (��9r92A�ly . Our6�i�,�ypit?N�avo�I} , itA$9��� he m���!��4L�.�,!�ly �NA~nnGG2` E,� �%�J�/� w)me�is��How ,jr�)b-isplayA;_�qE)}� does Kapp���A4) "�E#a@A4A�) ofM��Nuza�!��!�9�E��of^'b�*FwEl=A� 2 . J�i� 2�i�qV� pe�"is!�moA�d�7&%�C � 4. in ge��*<1UK , h� ��Aodis[GxB�0.�m�� $widespread� H1Gq/A��r a. qof mamm+ay�5ot� 7)�7( �i%sus���Ha'����c V��[mF�!�2�DQ�uKi� to�i�%.wNsoE�6�A�e W3 �-" e���.�preval$$A!\!��- g1 5��is� K%G�gr�4� an 9FCre� ed�sleep!�sicknuC�[�8A.� face�N�biolog�e adap�immun���e,�)ebG@�Lr�6��7n��d� !�'s �(�]yclaly evad��eBu} g�K��e9�, glycoprotei�VSG? ti� �bc��su 2[3] , [4� S�Fal�9�LY inclu %�H4oGr�o� �� �<�+e!&-�%:!�ETLF��se� �" killiÑ9 ]r[5�67�T�Jt.� As� LF!ptiu== -; )a1� �.�-1A�a membT!hKd�y lip=cHDLf amil�J� n s [8�9]��le^2 ^!X mole"�)1�b� ng�vplex [1[Con.5re�effEaEm$Ldeb�Rha��en focL0on"GS�cytotox�'3<%waH%�,a� domi��Oc on!� ��!icult% obIkv1 �I"� A �� eCA�w'NE��Ific1V#un� TLF;2 1\1@ ( HP !apo.�L�A�eWh!�E��b!;som� T+5W ncer��rol�)2 �e�m," !�T�-E�O �s��ne���T'� �7� � !�lnC< �[11E�1�5��lig?Lfacu?a� >� via�~ [1�U14]�i�:sm )UKo �%c.�e�!�E��R[1e�Py�Oan un-�@�(Ip�#�A�E6a� rane� id S6�B�L&" V�% q�-?�ao\M�lys1}-�g �/]by!KH-"� co�Qo4h�8�orm p� ��Ac^��is�d�d urbMm� osmotic�- rgani=%�*-Ie[17I58%sI�A=A3Iro"�!$�  �`!�? U���9Q 2 e�Lu,�I houg�UeG entr.T "� dir9M [%@ "LU�B3� a�h�ѯve6�*"eoev�,cou#�-�W%��'c�5!�� ?E�fAK. Under� �\+6� �&s S  &�may%�A2>d�Oop�0!Ip@t< 7 teg�Sex�eM�� c!cA�V ��Nl i Fp�nt up��)<& cX��Ya&E5( SRA&��Y���to�diagnoH= techniqz [20�P�� apeuA߉�����q:?. �fN�tj��$in STIB386�origie1i�� 1978�a� ed�� � Ivory CoAq. ELIANEA��*�N� �l�za ʉ�K"8in Côte d'Ivoi, 1952 [3��247 t. y�QV��cl0^,�%B�Jbee� $ Serengeti�197)�A$U.� �BaganzU4B_�!�outh-Ea�?n U&a199�!All�x��)� vitr�@ HMI9�um [38]�Ule� e��*(5 mM glucos� 1& yl�ul ,250 µM aden-, 1 gua A�20%�b ( fe�;�b�-` ( FB5 .� -{>9�f6or2�J!t�)f�.:'�5� ssay�Q)t~ ity/ћc�&�eNre dilu!Gto 106�  m�?"�f%�incub|inV.sor%�?1Cvolum�4C 24 w,�Q-c/�nH�� *E JaDemocytom�b58�+��: ^ SF���5% CO2� 37°X#!�&^7viK ��1&8:� 3 hours�j�+4Bby mi�0 copy� a 6�![x6DZ | �*�"��o ��� FA}&E5a)�ser� ofJ( 5–eg/mE4z"?�!��mP)f;;l-��%��,bu�f�c M 1ic acidL� 05% T�i2[..� !�D�8an2m� ]�ypr'<ed��ach� �o!%>o;7aliquo�i�N� �A���4elE�qwg:>Di6�h �25%e!I��d��1rataJIr!�2h^���n� t.�&]zsurvivalf e�EF ,M�:J� Js�� i\ �!r.>In��4gen Gateway®-���vec� :-D�I�ope� a�fr�`\( ORF ) ( Genecopoeia InEKUS!Cu��ju�E)�\N�.� �Z)� �T�kM�Dest17ti�\onJ�an N-t}(0al 6×His-tag%�� auTBL21-AI%�e�GECGlir".��induc,"s� ac(1% L-Arabin� �n1��at�. CE3%�l� E�� idin჉\mzpH M@8�; M Gua(,e Hydrochlor:,�0a�SodFPhosphT 5 M NaC�u�5�7DA�!�a�u�! debr� �^�H[2 µm8<$( Sartoriu�EG D�w!&>*a Ni-NTA be�(. )�L ao!*� �nKh�we� wash1#$( 8 M Urea �atk,&�+Akwob� %6 �>5 . 8�� , �!e��B� Y4M�elu14dialy�\�n�8"�(Ag!�~�!9& 1U�1�3,000MW Vivaspe�lum8&i�[31�'!�)�-�;"�WdeMJ�A-!A" 8Y#verI<by uw�Q�@ SDS E�m,Q�9�Q�F���dW� AlexaF' ®48�M"� Prob �e) ~� manu�urer'` struiM&�ol��erh<�6� 4'SN��%b%=�+ � tagg4 F re-sus���? um-v7 ~um�.�no-�ofQ A�sM !v&� in���h �;5-!0!��F�� �a.~7 ������u�Gi�n�9{4mz. Air*f 2 ��ed !��J-nd�l��mmec��hi�O15%��Kldhyd�\>YX"G�0a��&FB>��v�"eAd�1% DAPI%.�DABCOvv( P�3&o 5 n�1š @- &[at-:�Z�1���E,er-slips seaagi�ethyl�f� . Sl�&-�maA� )A)DeltaviJ(C�� �8SoftWorx packag!dAph\ Prec 5�jX�f�G|d(%"0/FITC/Texas-R�� nd L� �m !A&]llyAq��Gem�th�L{ *s �r}"r �)��-a��W �!br��%,~�V%col�n�s� �+)�J�C?�9bI!sJ&Ef9M US N�� al Instit��)ealthJ�M�.li�ed� .~ to g��œ?o;G1u(.U*#-0Pearson')r�"<co-"�25!@�$!6� fielMNas.�9 e-S�*manA�l ( PSUxPlug-�Mr1M( h.�gcpi3-aWcuk/~af�*h/!�ht�i\"O(M >�.�*\�J��!'��f����� A�(B�I��TM"�2���0oisA<io�n@������.�m���1�uA��G>�w��:�yTy� �[>'V�B�gen�&agi��d�z1�4� �*#����sa,�.� a!� dH�?��! RNA` exB��l2k5×106-�i�a Qia� RNAeasy®u i ki]�xa�v� Z�>�ree DNWSI>�di~�"��=/ m;(nta!(��. Omni! $pt® RT Ki�W �6c g5Fte cDNA) 1= �x�{�b ,~0n{ Real-� -PCR%he|� h�@@of 50 n:y, 3�f�T!��*7p� K@i_RT_F & *T� �6:1+  µ�P SYBR�,en �mx mix (�zAdYiams )�@a f#�r P.�N.�;ere�T e,�50DF 2AFB 9510"j<by 40 ?�-5 >[JCQ1=A�BKl�oD;"� %�>��F�CT��- [40].%�/A� =6; vs4��end�mK�ZJ g$� GPI8mx1�F%� R(=��urI.�-�.�#��Y�!}7 ��%\� l�-A[%�7gg� �PE{3�[41�" Mean�4of r*Ji d J1-Oj ANOV ETukey's t ho}%st!.o t �~U�2/abkZ%A��*/:2�� *:-$TgSGP ) [4Z#)h � SRA-F)� R Z0 R&�#�#43] ���&ify�Yyed!腸�sI �5� 5)(�!� u�'i$�.s��0Taq polymeras� 3qE; yC50�NaI5u�!Y660��% �n��&�!͆�y�b�9�S9i.Ёsp#� �u*)t�6�1�<bp dowNea*XquAh�.V3′ UTR)���Iє!�by� 9�f�PFU��R�122C�9 oducck�-��!� TOPO��,1|smiSE2�!2� �TOP10>�a��H �J��pl }�"� m"�H"aY��A^!�qYcaatS)�&� vic2I,MRCPPU , Unij/-Daj$ ww�sdnaseqQ�AF�Z�<^<��.y�@q;M\6Z�. :�cm�"(ce/*�!� %�P4  "%�F�S�$( &Rs%@R�$)N�$))a�%�%`'i"aare�ta �#� /V 6*�.;��$(�J �*$.O$S�*F�"�3u�T�W&U !F �c2*�& �s�iV|"I [46] ���nR6$)�m]�o�m��to ��)�*.�class�� �V ure � ��%ƥ1V.�)".QE.Z1xs%^%O!* �U:IE�RIMl NDfiY�Dir2�statusA�� 3s�MA�A7!� wN\(&386H)_/�.|�J8V� &�)�O%�?r�CR�B�E�establi��#onigng&=!sr�c� .�: |�2e !0) N� �1��Ealw{>�%�,.le��"�!�J�!i!�V��"�>m Iof &�~�"F�s��jfE0{je ac��o �s�?-X*d4&dc� e[N�!��,1@! A_�ivmar�5���h�(>�]RRxinU�.��/lso s��>G*N� . By�Ac!�)X& �-'.10%2�'A �#w�(TT�.2Z9@Qk� R;qG��I�<'# <"�W�[��+B+e g�Wa&K?~�PT�!Y�A� choso7M6�:sS#ly0G8=�h ontiV~͟eY��.*(�S:In��x%mxU�0�!�e oIm(E,O"�'fou�T(�Blit�rk�NJ.l routing&�3��, Tb5/42/2|!Tb2/10eTb3/14���"��*� R�[4@givA��wcal���GrJu�JT�B�)of=�a����-8availa��iso:P� �Y=�G)3�switch�)7@HZ�i����.�CW�Cb�k3?( type ( VAT� 2�3�54-4��"A"�  if2c�?e&*7a�  )� "T�~:� ." geW�A1Y,E;a� ��ab2�<4�orphism$�I&�7�u��>�� ,˂�45 5�y"�sY�cusefu�n:�-:�4e !�fY)�S�aWAy%9& 5LMrt�/ofBB%�� Io�:��Ga�FH\2a���N��FL"�5�<��B a smallerz��"� ��.[�o��A �E �N�Y2� �6]%@de�r��la;an+ o?!;!�%/�QJLca�sI�$�8yہ�m���a�<-�( Bj , un>`2�JAe-$.���oPO:�%V&@ �s�M j�i� �"ʀ TREU927 g��!)�N+ q$ DAL972 [5?8S1�F�l��e 9%�A�J�Ea�I5�85��[5�=:l%� �,��k �2�d2222�%queE���2 1. 7"�� �8B v��"� SH �X�K�1� �Ha�% -U)hA�a.�6E�ndgu�<�.�a��ara�g"&9�";3�"} a 5N!e�a� %���aꅴG3�':�%�. A݄'v�it �9b�<Ys z�F/BtT �-�A����/IJ!�����I .;*�9*. Wc#c=�j�8( rreceLbN ; �tiqNmqQ͹��� -�@2${"-6 �.�-��_Unt�I���l�=�;A�%.f��2m)�{ '�)P� BN<[59�60]4&�G! �ofKa ic�s� MEl pa. ,K�Xn� 7T!8d5�t|.UW! sui�au"�rf   ES!�>�!.� � c.7�,_ "�>ES"I�e.Xe%(Pt &A7.�6� .���rR:e  &> !� �Md-A�]�er-%^�M*�>�?̀�!&J bIl�e�)N�܉� C � �!Ehy��*� B4S�-�R-r. M�{ۋ�{kG�v�re-��+��E"�D�H%#s)�ICvE�E���F6�A�&��'NvΌ�%�:�6IF,s63�1m6\Z�r��N: ESmQ��[ R% e&܏�&eP �$9���� s(�6�*Mre�2* Aj�y��,�?p62� 7�isE�����byari�8A� knockA= �q�ce2@. D>Rk�employ� F "WEj >b >�e ��i�j#� Aqx�y�easы!�'���/3 � crip<$�aIp9ZrR#eF�S:W�NH \:�XY�X��"|XI%2 :38>��8.�(".)��^Jn.� W,-z(*Aran:�IU�5%t��!N "u�3E&�hhe @2 U"did�,� �0��E��Z49�"�)m���H� x&gh)� yin���FL�.� ]S��� Ad���E��\K��Gs�a�-&A"(( F7 = �40�jp k409�� �� five:z�1�=� �.�!Y� q�E�� #~Y2� e -�rdo-usfW]ng51�caF18 �3t�1 p<� �Post-[#l#Y#A1�Q�Fn�WME�@\�M� �a�s�`l�;�s�.� /� 4FE�j} q�q�y�1us� ��alm}���Z�D��teM%�!��P "M"/ &�����X_-abe�/ lA�"� & Rb��&�J1)��-�J�2^�2fa�*�Zt3��5 ���7��6�>�F;co�1c�/dye:�-���=ic vesi�F&�Sa%5T. A2M"nUY�M�" �I N� M�1,U�a�a lack!� Z-��H�Y�:� U���{, ./ %,�6Vhu Tխ �NHigF� ac��>NP��Iit7��:�� -loc�\���h*S1M5ci2�Ն4ņ�� �ZA�.0�S�7!pbd�t�.9.p�1N��L2�4�-:%)�R���9 ( n 1�} %B,2*66+��+F+.U63.V9 ) ;=�.*7[U2U�Q�H�n� !  �3 fU is.�!� � !JM�5"Q  po�a�*O & ~foM�Mpa\N�F� ʋ�� b�ed.�Mx"�ZaL*��(1+� s��fmin��iфbD3u I�!lj@m�SU� �ORF )��^� ���i8�u:S� .��ds��"a���aON��Y�>�.>�:��u�� 6]�{f a�-��.KEj.Aw�$�z Eof.V9A�eE7i�U"AMMS�� took&� rapidlyLX�1R:'A s� %macN8an�ptoQt 6�060%=��XU�,rR?ho� no 7�9T�^d&� �)G6-knowl��fJ٧e1�S voi1b �n�MU .�t'�S�a�te{\b�`h!�3inA��2s6r^A�4�:O*�8��; ��ac�aA�i�re�?5Ga� wis%+ n ab )a� 2���2�To<eUs *�2s��ZXaGiĕna� aWK\r8)%��! s ye�de�ed;Lr�\���t�wo�1I~Y��i���� 21�106�PnR����k�N�E��"�V�VNW�[$YV�[un% yz�W%0�to work "�V%��k2%EI$�e tr{a�&%�9L���sQEiz�qF� A�6%&i�Re> N:�in2GerZ1.�#� tm\!#� A]��A edEfluid ph��1 cyto��U6�6�UM ,Q��:�D��"�|unin�W�D capa{Z!'. ii�@e�R�I�R��eV5�4� QN� !!:4,6D��a��GU Z��5�A�8aY��:h{�f�fu�`a�82&�8L��3��`e�f�� �?aJhys�a�� s [6�� e ]NB�g4n�ge�unD\?A%/, ���ig�=n.l"f��Fi_%S�~A\E�B� ��a����e9r��,� � \u q�wa�s}/� V�[ �WE!&� F#�2-���'�� ��ZsN�,B����EI�N3q97 (NjE���iA%�a���R"<]@�3+�]- . I�daA ���.)q�-�beR �#s�[�� �$]m���M%:/� !�j�$%.��W%>&!���r?Z ve� B�A�lkce.[Ou"6�A0�*d]� F� .<A%�� �>urS��.�a��6l�k�� &sD!�5 �CQ��.GIBNj�Z�AxA��| :� R�"�]aӳ �!�.� (����+>�6��?%�� �2�-� "� e�^�87.v!�"��.w8Vcn�i +>�89.V�!b�6F*-n6J85.)*���6K(�6�&�!G��a��%!�a&I ;,mfWofM�i�]Ivc�M .��adtar*��*��s&� 1e6V L� "�N�6zshort�N�5J#!�Y�Cpnp� summ 5&�9I)a.Xp&Tmz%' Og�;jha�"y�,GL�Lf*�d!{ �"�Q&�!.p >�� 6�6%i"�s:Hv!C b��fZ��_2^�2'R�0)O1 lY N�6Z_[��� &a1^B5�^6S&3�]-"\t5�2� !uJkRmai�*)�i'W�T-f�$��"6�"��>�!, . AnE��62�1��at�^P&*�m�;����br ^1"�ь6DF� ��qJ�A�;&l*�Fw*� e��neutr� )!wen�.!Me��tq���N�Bs� �svere�k��E�LF-E�t� < AF�Gr�9��� ��f&�_ ."i�l=2LthmTX[f`" m�bP�1q�!9� �nJeaNwe &B6"�C*#r2�^"�+x0>s�`|G2�aory5�.to�D:�(��mp�Cch��zeZ�>J9f>���c�L"| � TxTa� ��9�,5j #� Q&l4lcen��l�o!�Q�.>[6�+EV!2�Z�.� ����<#��1��J�[��V 6� mpan!byi�0!���R�0� S�)e!Bx} "�"�(los�[� ��$p!ari)�0,){A8g1"�( "� � Nb�vp%��h�haH�n2N�& � -x�Q���B 1�i% , ir&q,a�:�1 e�.`%@c� ]'&��V�.(5��{.��eun=t!��� Qpa� u3WER ��GZ�-+le�g�5tui�Y!�ss�]�h%�� 6�v} .~K��ue?-fv NI�!P,2tocha�i-���+mon��L��eukaryo��!:0ar���sC] t��� fA^�!C�dN� I( "��4�`8&���!Ony=i�o5 8і; 1�w�d &nɢ�ofѩ���T��%/�}�#k!7G�xpl��.T��A k=C-r`7 and/.O��of"L %�h[&�2&�!��@�[.�:, M�5�|e*�by1to RAB-1��"�r*���"� �e�qJ� t?i.l.�)� A`2b�2�*A���a���Ytw�'RG�F�E"K5Oe&�D" e��}"s�nt&+im�Jin�<|�Jt Vo �Iq� &�)�f��q^R�Nx �Y� l!s.� ,rVM/E�"d&G9�X.^p���vG'n1n�$D&2Q*8Ea]r��cI�8�ed L427 ���mua*A\�<s'i;ڶst�/ �ll-Z��& �I�H[ngv1�z�91~a�in�M{ w�sŹ5_A1 o:�rrGiN�9�be�ш��B�Fd ." <�1e5R�5�u }d���hyj�a*11�$��4 A��P���2�.}�E��I��"�b�j�I�t. �&��nI<H evo�� 8h�by0 p�e�!�J��%|�ϐ1�k1r HP/e����ves t[Vu�jto *�&"� �~:2%���5\�٩���8'��T:}�<7<.�2��e�)�55n!�rU;�^xF�Q�>� d�`d"pra" �!x!�11��5kmajk��AA]a� � bloods.sL������ ImffA?b!�2~ i��i��nUd^8I���JIed �ҽA� remark�feF��N�� f A5�-�2���& ���E�P"�,6�2G�E!t�s"\)"!�)�--�2� E�M�T�r��A?)��k�.N��dQ�.  foci�0.��5/ >67qOl �� '_ k"# i�k t*� �#Mo�  E�U�O A�.n!�= � ��F ynnB�c%v�-��o��!�� %� ympa�i/R�&�V��� "~IR���y�|*�A=�� �e1���� A��� toV \�*�A�J*y` '%��`r�jy�ҩv� �Mm|.�9�9�{pl9�,*� :�8)V!�"� s� ?>�u5�8�8!A6�87�~T�ug�A��*U4���Z�)�q�� a?�!j��m�on�o#�&fAa��']��e%mF6�GinD/^26� e�I"�����Qa�L:uplsB�e3��؄� d�[1�.�El�c�E9Q��&[71:E�at novee�1?%v�5� )B _�c�&��$>�zp��a 9�$c:�� -��wyai!<i>�z��F� ��' .���O�dy�/�t��promot�5��enha���j-i��p2 us 5TR���ioMBanLT?-9�;d��R)�2{Z"d4ioB���4���r �uU �w���EF�h�j nti4al drug�.�'e ��>m��4QIV-1 � ��aBn�&Bun�5guf"�F�\�0"�!B appa$O(BK> %��"!�chr^Q�rucEN�NnȬs.���E+�?�__a�s% ��;Y� B 1I�QE#�6 1s0 � ervoi��^r%�CpG>�!4IQA:�&�x�p���a��/A/2�I-��s͇)[�t g� �F�3ˆ�t�G�1�M� 5 a��A�2 .B���@x�$tk+"]M�sQ6M�72r)wq y�silen g dUI� ��M5�� avire\U!1�!\+��. � non-�7ed9��� kc� �s!�b��aky%Zeast��#tiI�!:bN4%�y=�v߱���+A,cte�Ua )c mw(@H����b��==hA ��>�,A` oppo& &vA��eNn �c9�.\(XhE#t.Av �ML�9�;�����1aAHAG-\ K!:I� hist�3deQmyl�*ikm ki�V C agon�, TNF-α! �(i�b�p�$85-aza-2deoxycyt�oe�F�ly��ed �USwas "/dl��9�^virx�]�TWEb%�$uberoylani�f h=p@'t. Tu�R@le�_o� )<%Icy byBuSM�Wt L]e�` *ai�q[�ra� g�'�z��!�oco��0�� 2p apyK�AAR L55J�>��asvYhlo��! limi�&ig���du��morta�-�B� DeÑMZc� �,"��, ;��es)l�~�z��2T�f�X CD4+MA�ɒ esca����1;. �1�u� "ۘta���5�&�vi� � )�.[1]–"�. T:� shut��� #�ACmI��ve &��� �: R7�A)E R � connk��t��E-:��MP"� "� 1$LTR-driv�P.�!5�&i�A}�@:5�!H� ~ �m�B%NFAT [)J7]�!/ � �C�lXs;s_�as CB���YY1*�. Low�-�t��e^a[�my@ Tat- �6!p)� � P-TEFb [ϊssus��Z���m ly1�Sj��@sIB!=ib�$*� , [1�r�lldD ,%�c=AS�vj�Y4,�c\f 5�: � crui��NCt�PR) HDAC��[WVc�,9�1�fu`Suv39H�>!9h�{o���1HP1c�[�M�)a��) A�.�,�YG�J% hand P��trigge? S1",U�l�P� !������e =�asa� �@P eɑ��ge ���� a.Om r�D =�� ��Yġ\n �-�&�p!J y]�A� �$ΔVII-Ets-!�X� d��B.( F�[��!�� Lck e�&�Im�,��M�i"j�)>�j5e��o��rf�! ��sZN>u6>�� "�"6g/%�y.l]qs"�!4�63Y�"dǫg-NkJch��$SWI/SNF [1i12D�ql� )�i4<CBP p300"�0M�J� *��S�"�) e���&"� "+ �o3 ^�� �1�7��aλaU2S5m��V . NotZp�����!�� �sitnx�!�5I�a�xR_>�of�)61>,�#�� }"�g2 �n��T-� leukemi� bype-1"��UMo�\y m3:��23ҋR�sa�T[20����6#Ru����� H , K�$nd W famil�.p���al%�����~2�g.N�!� 4U�� s:?�:.,i��H %�tozs"+,)��V��LY�� � ten�� ���c�a� &� U937}��N5t�� �ACH-2* -( ��C&E4dkaq�PY�5 a�"� �5Gv:r�?��A�֌ea�^�g���EIϥ�%b."up� s��of>d-A�>�ME*G(J��u�[35<  a.2� �<|.�� ZQ)W�~A*Z��2$"0 I�u%oa�z��mJurkat�P%�!�!IrboT�"'LTR–V �lal���Gj�yWv(�$�*ursm� s ЖE�7Y�2%shvb�7!?.�pa���E�c��N�.2� �Foni&P�.(eO<�fr�U�ov_�c�v?2�E?�"�]ef�A@�A8 , GU~�H12 f2�%iavh-�Ɛ�a��!rF [ $IRES-EGFP-����m�E j,UB JNLGFP^{,d�e TcX���n"�6�I����?~)��f��pinM�^��JB�>:��gPW�K)>�� '7R�}iK�:�=�%bisulf�$RC� ��!f��Z���e���-J�D"��c�=�idu- a_e)�ic��to N�i�ZYlep�5͢FD*�;�Uz-�!��h�s#2�R� /"�'ѥ��,%��\R�M{R+�s)%*SRp&sz ,pr'�"�AK�+p�k��7 QM� �_���/֩u���(^af�F[��-^5����"��!D. U� 5bSA �  g���*.#Z�a���%A�e �-27±7% [�H±SEM��C 7±25�H) :m�y��=1�p�e7) ��y;a��� � llm�y8( 2±16��[���:b�}in � . 4±1��3  ̩5^ 1�8� qin�A�u�Uaffir,G !-� �@��l>Gyk�� .�dreq&CC:{&; [s�!m� xt s"c.BE'�.E`e$3%�>����A�lp�ɢ�\Eg�F"� ��i���A�ubiquil�*{8(X . 9; 9q283�U��*� 6:2��C�PVD�" 4� AV�;eE�m}q�u|6n12F&Ae BArdD-] F�Q�xN+Ŧ.b B�n�w�&r�z!>�e� a6BL� ecu"!�Z�&0�u*!%T���PMA"�B+ c$ �e|oi���2i�� �3is en��dur�}sul�i^xS��v�]���Y� ���u��+22 (�2$2%1 heM�nev)@�V to 6bR2,E�B-�U�c�0omi-R�M�u�au!�a7��9�g+�.�to 59:1-��e]*B�b�ʤI�tu� eqJY �#ofBZa #2z@ �)�Z��RZ��DI-�"0iAl�!���A��E,i�� �U--�*B1kis5gR: *� � �I4%�4�U5 �I�9o�, ~dna�3J���.)=oCzZ�e,�For"�B�"�$!�%I s 1B+]2D��� �5oݺ�'-9���=DN6�!� Qga�ow c# tane�NM8�5�H$N{���"� ��� }�0R�U|M:hC egE��j�De��32%�CpG� u�� ������2<��8 �,�A �%�1�� �)F�A[7�Bsm�~9�a�� 86G��H �j*�Y�ny��)��ا2E CD69+(!���.B.%��( 9J�6%R��%�!�%6'8��9.'�1Z�A���w��.,)�w5%ot1a��in:�#� ��! U� Pr20#]61�2�����.i,�4l="r�\�)!hn &J]E%A)�Aj�iU�IM���U�J��� &� ��,%�,)�,� r a !��5#Ow�d��e��*S���5�Ea |-u���B�_=�fai� 0transcription�Cal level by quantitative RT-PCR ( not shown ) and at the translationD�Lfrom expression of EGFP . Next , we investigated directly whether reactivatio?�latent HIV-1 provirus is accompanied by demethyla9�h5′ LTR . For this purpose �stimucd H12�T2D12 cells with TNF-α,PMA for 24 h(performed m}8analysis in sor�!+3 − bD( Figure 3 ) . The�por�Xed CpGBR� �and\+2�as)�Lignificantly changedM%C0rison to non- �YS=��6hincreas jnegEWly.! k �,( as alreadyMrin1"2A%#It did� �, , however ,/ �1h�,AereEUPmoterEP xheavily.z. Take!#geE�,D$se results� thatB�:hdoe)�@require immediate:� . ToWA�Hdifferences between%<:�w�not cau!|by2>pacity!�U_$ir DNA!'e� fa]|globalE�3a߉9$in genomic@ofN�I>N�th!Kclones�s��sticalA3Y� ( 71±2%i�yYN!68±6Z*]e|o assess�!�istanceg�"��� densA��prMMto6we�o%�oth�� � �to�i, Tprotein kinase C ( PKC��gonistsMAG,prostratin ) >$inhibitors�HDA@,sodium butyrAp( NaBut 4richo%sn A ( TSan`, suberoylanilide hydroxa!�$acid ( SAH +�apicid^�A])0�;�ferases , DNMT ( 5-aza-2-deoxycytJed�0nd zebularine� and/��o!�ir��binŗ!&�`4%�Whe���o �hE�s�~measure�S6�a(CD69 markerI�similara%ہ� liA�,6of 2FU.��(much strong��nmQ�P�^ng�I9el  . Re�of%�z��b0determined af�� 24-h�o�Asr.Dap0als . In addie�:�w�%�]q��ak�YM���,B�lso �(48-h treatmas�-�6�B�on!�$parable ba�$, all data)� obta%by ��ng��l�!Qs �vital��in$. Among�eA�!HinducerA�ec2includ�%Ro�c%.-9�ng� ound�peB highest� toxi��"XS2E�Ymost im]an��, ve2�inBe�Y�ifuAdc��$ !�of��.B )8d 54%%��6���+us�� fail�oq�eN�LTRw u"�as few1 r�< f*A� spec� ly68efficiA� ��[9�� �JFCv�]<�?���ND��u. I1�ly��heB�+ �e�& E;r�*� ��tha�� at fAq!� F d controlEt�$h�p�y %$percentageř)���s o� �backgrz valu�13%��e�-%�8dC-�7� ultures v�12;.�t�2!R�a�.)�� in.� ( 0 . 02%i��V4 �^Ycoݹof-�r>�E0>,T� or.N�NJZ�ߙ�!ER1 f^�\5� ͽ st synerg� a6ec�.index >��observ�t� �"O,y,�:g8�ҝWorK$. AlthoughB�i���cy!�A�u��i�j9 % &QV %was-ly reAW d , ��tesE�om��qZlow���m�:�i � 2��2elucid� 0e�ibu��of chrom1 struca,+mainten� % t� t ~��6�(histone mod�ns- hypoi�hyper a! K5���� 5e%We��[ ���=n3 ( H>diYon �4ne 4 ( diMeH3KAq���ent�S7 e=� atI�assoc� d)� �&� i =�ly!�� U1N � Q�,89 . 8 times5��*�� nd 65 . 7>/B+� IA�ntrasn63acety-y3�ok� ofNinV�of���E��  . Ah ��"!]e 9�6�&/( 6 . 2 �rise�2 . 3=l!�cH3 trU�Y9 (E9��r. s# y1�%E:E� �E4 . 1 ��^�,M� �" A�� 2A&�W�tr �27!�lsd]�Z�$dropped 13� �%� �� A� !�P�)�� ��!�9B�� >tB."� B�U�!6 H3K9wq��>V57��6�ch�!� t de�d2�>Q�5�u� >��of�viral N�is more�kon� >WR���!9�C1edr{! )s. Our nyaimőto��paS!SpatterRt�ou�vitro��el���iA����dividuDW�*Z � he��BQin�oreoii s��CD4+ T �in�� $ $whom HAART=ulmP ong-� supa2�4plasma viremia�Zin cZ( TQ1" S�qm�ow*� AHIVA �-harbor�k)����� �\!Osensitiv�: CRm"bisulfit|!ofEhampe�� �a%ՍuN� in s6al�zed��E� a cohortO18)d"m pa-� ouaa tect%4:c4msix i](,%q13F�wS al ;eveAnYe} ≥103!�-1 a�copies!� millA�EB)�6�z6UB�L5� �&y !:ix��� x20% , 348 7196��100J�sq��<[ 1R)�0��e!�� Z p�I�2�p = ^0012 ,51i� ikA�&���tE����!j�.�� �) ��racter5 5h6�B�. H"�numerou\n-jA�1�equ;ů�, particOl� wo6��lowest�aCpGs (414)�8E@We fure U�a�� variabilm�>�� B��Csee�Ks&��ON-.� igo%2,phylogenetic �9�9Eu�F�^re�� xconver�t�major �cytos� residues��thy� ( excep�r.tF5�we �c(neighbor-jo�!�od]c5r&�t�Jz three F���uM&prf�e�,FF.D� 14 ,�m�2� �� �*9� cleaA� segrs�{u�� clust^"+6�A"soN�c�I�= P�� aG�t�q�I� *��, limia� numb�.��?e�>{ �!����Nm�� U�aqJ.u� �0 =WhofF/. C1E�dTcalon%�-!��9Fpointta usu�" R;.j persoh�risX �1 on wWAC�^G����9profilt1_replicX-aFe�or de� ( �ou!��qen�� ssay�� �a *� k��RPcon��v of extrem� deleAD ��es [41]��z prevalM"memoryI =�+Q("� ��ubn�,| in PBMC���-i 1�, can b�rF b*�/� anscript jump*!F�����_�, s ��!8molecule� f�e on�E&Ctu A4jY6u�)l)k. Q.;"� ��6t d"yI.b( tatU�A�� inal (� ) ��1 t�� ,I� LTR/Ko( rotocol S.� 1�Tf� ,!} mean%��6H���6�trunc 0o full-length'��*^ �NhWe have��any2'�W. ���at`6oin RR�k0 ,�u�18��E 3ll�B� � �enilAq)�al�Q�aلUm�I�� dDi� demon��"A� accu�#�5z�~a \� )i%r��!u�.�>, [42]e� Rh�l!��c!�.�aB4. FA��w�vA\%�FL* >C u�٤��Z���.�corre��x�� & !)E>� ���T�zis��purD"Z�N�.�� aq�%ET�A�$, S� -"��� days;�y `eri�z dilu�F=co-Al all! + 0hytohemagglut\ �a!*0d�];T!I.�� s�w�#ell-f�superna�was�V�eo!�C–F��!�&�$a"l%5�a+%.��5=I8�a��&�Aq�`}m(ex vivo calK �e���nd�iv �R�%�Z�!�!�of[ &� DE1se-ndrs��� only �! Z�zAi����$�V:� y�*R 6ANei>�=�6 n#� :1��)��%l��≥�ofU0c%�n%P0 ON2>�� S \% IL-2%� abs�{6��gr 4, no outgrowth*possibly%c )�.�a#p�"%S� of 4O 6Y�*� R.#.z��.8�r5x%w5 µM��sho@NI��X �sed.�*� ��( ich couldh .�de�ng ag( yM�d� Vto.Vin91.�z�!hardl� R�>�3,2,�kB0pro@I�&*��3�-day ���!�Bgfol��%~ mpl�%��)���PHAZ�=#� k pt work!X��a�J�� ԡw� 5�an &�#epi�me�ism� t mai� |eXc\ W}by�v�n�$irY�"00 swlaq�mbigu� co� s em�C%�-UFon study^�&s �ti1�_ �,[31]–[36] { 3]�,!�� �5c�"�%H_ �d�%�& �e&jmG�>�?J-hO-b{+ �dl far/ sp�e�e��&��,T E��fe�2iz�y!�U �Pa�ng upon]��0$�; A.�.. Tigh��R9byB�-Na �u!y� ei &� � ulti� �� #urg��"fg�2�A��R' .?��re�6!� pqed \A*�0e\�ont�inFB�*2n I����o9(y"inYil�,�Caam�1/�J- n�8T-��0x�Ms s�*as��OKT3 [1e�244*�#[45�47!IL-7 �&49� O�� h%5�*� J�%$o�'�OA�va� � 5in!@let�sewe�assum�{at �W!$s�1V��sta�I`CI���M^�prk y�sui;=�2�]Aw�aI|Qf� A�!�}3nt$ �maple�O�rol�)"�c��jke eradg 'probleR$c , unlF/ns) pproaches% d�#o� W"X,to.V�� �6�-s%f%�be abro@�+�I��"!�bs�u�q]R",by&KA�"y howB�mu�0���&;&�� spon/,�N����b [50aIt�.3u�!Uscr��> QinnerW�;� dq@�) adjah!Vis&�� �"� tempATe�%W V)�G%�e�?( justFsleA�I��-A%Yrega . Us!�"&�rescu� *B= 8�&-21oG#0 )�r� �1&,s display al� 2�M7*< �S�,A�lly�lud�bB�%" � �a� met"� ' escaay!u%!,5��:iSul�'�"suggep2� !R="n/V<A�2[Ena( 5X #%"2m5&�. AMmo 0%áTunE toTf���z�.�5Alg!pJ�1!�� wholG�#op}P. A!I e first a��xWza �a�ve� a�-b�aw� we�+s&�4ly��e�+�yR�� �"c!��F)�5is�s agains)`� i %�Q""B�!{ preferent8"�.�exten�WEl���� ` �)i�atau!S-�IM���da# necessary"� e�bishE(��:<:cy [35�.nde�+A�1oi somN�� �!N�M:��.� (ucyR�j? la��"�R;�r%mc�1b�9�+ -dep!knt.0!~Cbg)aky�ieas�8 ble� �'3of%�1�ei� se a�-step�%�&�!R� "D7��.�&>� ��6�.�19 $57 �&�2B|>c'6i*&�):f'E� c y �,R!�1�!��%D,o ^� C.-(� �a��A( �  ` B t�:� hall�+87r��*- code"� ]&" 2-di�4ax� E�2'9H3}*tr62,� %d."K.8“locked” si�5��) u�+m^  retu�($�3n6�in&�3 [51]J 7Ic�SA.�A:;>]A d&�3Me� R��U� (;.�<� :ea rapid�+aCN�*. ��6�S3a*: d�=tVuc�E�I�25�:0.���eB54,Y6 2nanS�9, 5x*�!�h��B;)3�. Moreo�3,J|�#�l� r��@�lammat�[59�$t��)virtu�(&Q�IF%4 iL rrobo&� ��n���E�A�X+"��A7: �>�X factor ΔVII-Ets-1 [17A�A{6�Y.FA�%�r�i ens���2��u?�8�!" off;�+,�<"�7�  omitV@42YA #>c0�)�� x6. T����06Y&edbYe�a�m�cours�GBI�1�%Fpc/ init2B#>�*.�� �de*L �L�6�is�=~'I� N1l"^-eE5ɠpa��ZAsoccury- S-ph*�� cycleAKraVs��e%\!���on�"�_��!�"L q), a{&�;nj' ward>�f%GC"�$�` 48 h!��T��7� ��/ ACH-2 [34a6!V6  O>2�by+� ��i.*'ne}� n�Z�@�9!la�:or�) -�. }�A�`"�.*[53�[5!�I�u� d J)tDt&� %��I . Surpril� � inct��6�:r>$�beyb]>A�e sam� �A�s.q��%i7�%p.�-pr�S�?6��R=sewE�xa`Fs��$ic � ��6� -1t . B�A57�E�6B��quasi-� e due�%��.�(��: H7re-��!MB5�& 5ed x � � �� . PoH0�l�<�>w;&�.\b�q�Ms �^w%�an un��d2� W( L���n�!us.Y t=�F�ol? ){1�e�C�.qF�ed�i*��;6�F9�to d^RR��"L V�V lsmC�%bF�+iv�Z2� al brN2B�%w:'4s  1]�iati<t*��ѴA2 �B3) E��)e.6u�$�(�2c expe�7Oset5�Ca func:�� na"RCFV. Dit!�v�F mode Q�!1[37a0�� .w�H>LQ}'��� �6q� s��^g�(� 1E!/ }'� !?�?(a .J)�A��Fea�O�z, �!�of3"��prolife�'-+EK:�"� ^l�m�j5?2nin +ordera�! lt�3|K6reg�s�'%�we� �5q!�rm|aI.t�2/QW%K���rocedurJ !I>]2�"j>Je.1=2K��K, en�g.L luG*�;lyFn�R�d6�byA�AVw>"�toMq-MF�b�*len_8 �&r�ngausig� n�/>K%�s U937E�> 5b5{ "y:�ɨs�s� �Jde�-b&�%�A;�JIL[3� � �6� pecu�� abL7A"�6�4 tatu�wJhm � e�Fa�th"e��!�� �3al!\e9[58eN6o T52�I���r�stocha�Ki�P&�;O homo���8�u�ybouH !s�8"�d*) � rrup�s���h�0 immunolog� Ri!��(� dequ; to�Dc_ ��-�Md� ��"q*���lyU$HshG !yin��2�@.�3}e� qs%�N-&"w+�F�%�eO���%"� r,� 4i copy�"~Oaliquok %Q��s1�<��ei,/a���coexi�HOQR��va7nt?CJ�r!x? b2(RwB�FI�(At*umuA�Ier o e��AlM)� ��Gri��iH�+�C�%��Qa�8us-����'��>-�fd0ev�4�!�1����02��� �9�N�m� -9enhanc�)0 �una� ed�al�, abund�J� �� �V�[6�Z�>\ rec�e NI��6�ma� �dCb!M�#�!t?�)�al ��0_ �2pre.�* �!�F� =acute b:���i�!�,e system [66��7A NJ6io./m� �1 M�ed6em7ha:�.�NBcQ�U�us&�Jytopathi&oH��tMa1p���J� I�(.�b �.�)�uJ ]III�>�8 �22�;Ba�&[.g �ZI�儵�A.�Bi A�Om��U 6/%�cy:�,����eLr:� ��counter- �i�ai�-�>>�b�mperpe���. P-v'�!�@'.��RVfm ,�fKt4&"�,phenotypt� �V !�}7�+�8��i*H�|�7NbA�eg_U �c�.�p�C2�@� str�6ea��� ef�� >&t�"�.a�ismea&� I#Qr�5�V48in�>�urg!! er�>t KfV*M�m ! ~"0 &�RalaD�3"r&��!��rol .� 2�B!.="K)�u�$7�Pi!�x �Yc�aO1FAdr,XdE���l� vit need A�%b!Sv"nXlyq;2�FJT6�Ixei*��Q�!Qby*an:�"�YD#�1aXusE�human�QsyFPNQ�!�4VdC2 *mNzT �, 6�a.]/� t�!_eliy:�-�%�Q�&+.> >ib�eea/o!�s�)�, �u>�(�T� C � 6t�I?t&@!w&I[Axco 1t�� High��* +���)h>Z )� �rapeuiBc� eng�< fu�N. T�oB� co�Q��r%)"h inc�*��2-=Decla&�HelsinkK Each�� ��� �Nwritte��l�0i�o`%� �� ccord� � X%itnOn�3g��guide$)� G�u�te InsH Review BoXof Ambro�?Paré Ho�al�e�B�.U��"d26Asudy"�)7Wn�"two yea�Ila�I? !��$xHB�G�oad�lA�BP ( <50M8RNA\Bpe�Gli ��I6 9� (Amplicore UTZ1 Mon[ Ay@ ; Roche M? ar Diagno�S� @NVL'29M2 �p a� 6×104A$1 5 ��%�"va��G] &�A@(&[ of 2e7) Ise�Xa o,_4coll-Hypaque g�-e~. M[2� <NsA}"?a�6 iso; ki+e{�k+!�� g%"H U%�0FACSAria ( BDA�s)\�CA�T*Z4� :�%�`  w�Ee����/�6"��2��10-nM�(( Sigma-Ald�a%� �Fat 10 ng�N, 1m5-2��or MF�ead�,W AA�] \ACC2�577^0>^A�A ��m�m.-�sQ' ed T%'5��6&A.�CAyp,�9�c ^46P!!xC, C�!�#di.��A�A�&%ne��5�m<.C�40�+sA�95°C60 ��5812 A72'�-plJab ]���#�% 0pGEM-T-Easy V��r� (�% megaA�ad�: , WI�jn� 2:dL4ly�\s �A95%!��#a��`y�Ss!AsXj9�wtjm��Xuy)�;) W of��N �N�^9)"�:* ��&�V'������RtPY!�in�-a5�A_^iTI� boot�Lp�AYA very�!�H"U* ys!�ll= mask> ��ep==x8 ^  !) .)� �7mp™ G�m�� E=�Oce Pane b���tyB^� @,qal��embly��achAL� �$ we �% tify�X��e6 on0t�3�, a�p���m"=80 000d%"i+3i� ,LY (��'/���m�xg(�fo � ObpA� h)A�SNP�'�)Dig�@�A��we fi56t,themselv r&tHE genigF��Cu gB�ul]�E�". R 7,� aE �*!2e elev�.�ar�*m9!mai du�$p"?B-D1� ces-#�lsKOd�s�a�r&4archiUcur>!gen2�/%3!�A�ad�Cfl'�app�j cis-t(A8���BtraitA�i ( )QTLe��Y=P!�s4-lw mW6e11�b�OuLevGlar�tO"s!dn%W+x)aS',Am�two ��aXo�kE�in malA4 ��to fe nH!uQn�E|AQsex&�$0l veal!CaIJal�Mo+n�yA�� 2�.�sex ��6im ,� :�9� �zh�biN{�=�. 2NX&� RNA-seq�pllelic.:imbal; A�� hAf fspryof ? *vz� d���7gR��a?e�Gm*�a�!9m4val�n�h� ozyg�4.�. A.�!ٔ ͸�Do:�n�,A�8�L$ �l! avail*K!cA�6 k7� Y%h�" �L�P�4V [�9[5]5 A9.�*�"s meeE!� 9 ���^�( DGRPd �8n0��!�s�M(+eO"�Q���ur�Q.�_192]($wild-deriv%��4�m.k�L[R�1*�mi' �59Fto��a&-."I6gi4hA�>�powerfui�� st-e�&�gb to&�=res�s [11j6(yits;��Dm� 5(��(ly polymorp�*�, [11s+15z6�*=�~&en help� /�!A���_ar "�!`� � e�a  [1)\u@*�A!age dia�ilibrF ( LD )�� ays quickq.�|��e�8�is favo�y}��^�?)i�fdV� at%I%� A��;Y��q�t�)!�cl�}E�e!e��A (*�Z 1@NB �:%KZ!� comm !����Ile *� Y B)(� �{to�6s)�Mir�6�!� �&/ H'�+*~ "g )aa�E�cha� eriz�G)�-w�,�=1bc&l 51&�zSNP�b6�. lex Fc�$1aTNNi� ���5 �8=�Gao/n�3D&Aq��eo *& ..�nov� �� � ��. WE�eqDd:A9ZazU"�A���L-)� Illu�( nextJ� >A�� ] 39 i�s)IA��� ��>5i9 �Xl@young2� ���r�t6M0PrInSeS-G [19�:rLd� v�4.@ A��!>� r�) ry l(4�1ari $�7�r  UN;�/��3:by"�7j !B2Z a fl+wIB�~��)� �9�En-�a �6�9xDMc&."a s�L*uilEontig�eYMlit _!��<s��ig) stopk6en an+��is en�/�W����-aligf%S�0�M�- ��. �-?+ntY��co�A<[=Q�I����H1�1T)�AUne�. �=aZn� �ty alg�lh�I�Em�G&�#]A  Ea�BUChMim��di�͏9.dnuse�N)��!�YL(�aS3^ ONtegP8o�u �|jff'un�M��s �����n���!8"q���!&��{!!q�oG+m��i/{�1�Ta �o" �.��3�;f� ";���F�f�yu0K8���ȵFLYSNPdb�% [2� W�� 713*6�923. Ureakpo�k%�lZ-5"�@u�ve| � 8 45% ���a2 . Se%-I�[���with t�4pub+Q�&Mackay* ����g� 94} Ima� ��Itch"NsY�r �s��M��+ -454E�s::a��E�t:��N?�~YWnfirm� of 9�h7�E�5�s�Fourt�*w��d m�+M�e}(���7bea�� {�<! �'�a�e�th� �Ie:4��ko8!{ 1�:I( lN n& A9Q�=�O!UY�9.Zw�aYq!� ve͵14Uz453)(��s084�%>�#!�)�X��IH%. u� �0%�s%�9%��zq�� �%�6��3+���a�3SO�%Klse��y�Je�gD>lis�� ,�� ��&����m�� ��*( !�UremEUU��K s upA�3�se bu�O}zE A�9 { > . No-(-k!��H7c �3l�&y�; truecf%� �*�;o�J�A�%,ag�2GQ^ d 92 ��(�to �~ 6 kb@n��})� ij}u�X^+s 77 .�,:�s 2w �)>u]i�predi21u}90M/2dPS�{r.�ot. randomlyF9���9b� "�a}.�Ma�)�&\��o9x y-�eD�e�Jr�� t}N��w��h s�@ n quH �E^eU��4he �'� ���qge�M�h�BUiAi�V(KfD@l�as5�i�� d���(-throughput.�si an'�I�&V � �Ge��anna�55� of ∼95%a wer�GZQ]�t.���\�9� 4�jM��)��tre����{ 4N�,�a[2�23U-\����� � 4a��7ry 43k���}o�.� ,144-Q�-�3r2)�� e�5mҌ�y 3b���\s� ings*2b�Ce>�V!b �AA�prar:��p&gY�ly��G!�in<s [7E24f mice( . De^!B�a�JH X�%�& . 0 M��X &� euKFHc � ' :Q&-add 1D(DJ � 5�:se͓s �|���` e�3�-69?r� ve else�QLa�� �� Non�Y�}t��ao�0:��=6*n.�A\Źr�@s�xF(�82A]K 1N,ig�1*|Sin��{pai���"�A( 32%? �ȁ�K ( 2–1%/)aV65!ᎥF ertoL�.�419' u׆al9(=�.RE}al{%��dia�;z%2208�Afm�S�^ %�� ��� . 850R�!�Flo��!�D])�j�par�HA�mbrB,!)5a�eHn“��Y�� ,*�9ųseg�#��N(y &)*FP) [25]�s!670!�%�{A��6}&c��5Mj PRe�o ���n�jaa� tra-#6���KJB%��u&��k2$;Vb�>M �Fp�؅� ]��or�Hal�goverGo!�!PG!ZTa~ .6VerK,�(a doubf�� seyk��)?]`����M1� lo���rA�Bs2?^ctriggGq%�4i�}@ [26!�u%"� ( 73MF�r�^�dF�!6,a|� ( 61Q�;Ke d2�!68. B�b%>aE{10��*�6Whap�41J !�"ey [!��sF�� a�E�[2�G"s�GI:��(ll�j�bp�� wind>p "39.I&Z!� �e.�O"M�Sdi��1��2�]ni� E�zAiC� �e98}5HJ�QAF;E ��^bM�_�e�� e��#cy &t6:�6šA���Jde#steepdW!� 2� 5"�ŸZg��!�73 ���. C��Eh�.eu|sVr�6��&� ��"�� � ���}T �C"� 8"; s!f��ED��E5a�u�&�L��>%[1 W!{so*Z de)$U&�@�]0nX#RS�-cX�Ns�: e jurT!�UTR����1Ro,�6�ezB��f� va/ZR�^ A�J[�  452*O , 872M{824FzQ9) �(�� S5- To �Nwh� 5PreOr!�Q��:c"�,* &:#N�7fac�6aql�S�6-cu���=ch.Y!�dU���P��E�>�H)p77#:ex8Zrecapit�Ae�\.#�l��&( ẩ�E=yakub'.or anan,O 4�90%!}nEoVam/ a� mismT.A$E�=�yJ��6)�;'.�5�;o>��7�Be���"photore��(or gene Rh6Y�;1�(�O":& �uer] !��*�%e�%�17��!7s *� a t0d��"; ��%�b�[5&r)eROo(@p! O/1. �h`'": FuV_�g!"�"�Kor{n%4c�,�0g 7 OregonR/w�'/ /k!�u�w�&�/B��Ms� a�19!?q,a`�%LjsE�����S"r�t@� 7H*u9=�Q���aut� �Z�Aomeri�MA �Y.'X.� ��7 fewe*V �m�l � tX5�� S�� �Wve�Y&� o��v K,�!�PS:��ta�hitchh�g!mograph@A�#[2��Ao��wIr ruleEk%��"�o[WdZ-�quziss0���W ��4$�*�&B2y+mt|�om"ee el�w!�*�aA%�'mNrre�>df ! scal�LSpearman's ρSNP-delM|992� ins.�,  �.46;������gL;!�%RM�er-PZ���*�&qM� &�J#���Q�"^>��� �sB �"��^&� I#�esZ,im�">[we &ed��g��l�> ��-cM/�J=�6�&ppo�6�e��S] (B�.�5i�ρ��=�55 , ρ��.6y,ρF�4��'}*.OJ��LQ held�F%�>gaBJ"�  �$p��� �] �*��.".[32S[37EW�Jr��"7�za^�I3 M.de|"#)��inP �E�Eite�b�s��a�"Y�as�E�ors���ur�fa�0`>�Z\ 6� Z*�Q# (Lwe-X�&/�e-y!�"5/�l��pr4q�t�& �&�n] e6�0���s(� "�3s��2G 2B!& nd 2�O�~�26�4�X ��"���A>in�;bpa2�)�a U�. �,��.-�-���< ly)�b,�DW[9�;Kq � �l-�'.�W%�e����]�[� A�.)ai�al�-�!~�9od���sim�E��Jgn%��su�� �N�H��kide*�A�&I��)�c�to�{ �a�YHX�0'rr?aDey�C6 )~"%���xA�circumt!?t��gr��5�1\" emploŌ` 1 "� �}!}�.U0M!aVr"6�y3s:��E�A�B2a�g3 or ,�0lik��4 Hlٗ �expla �(R!cb?&%��A�ɂq� �����We plot!J7."��9of�m�En!w� 6j���s2Lu:� t�E�� :I�D2B,nn-Whitney U�  P<- 2e-1� c&$�_�)&A�riehi*Ze��i>� a�>l�RW�����a�� +�� ng h�c:��� � !� modENCODECG< [|�h%N-'�kr]*�7>- e%z�*&&[(�v:hu�a�H3.4n�, �ume�-!J|k�e'�B, ( MN��  1e-1G#5�V&�9*�>�" 1NA%fp �C!�&@��!�rɾy�8�1:��(e-g)+ wF!�RH.�y]T�ofE��u� :�IEa�exy;�@�Hor�|�"i�04&)�� �leae��8r�N shifr{�� t�3E us 3�&AB/Ad P�2N�cc7'ir�q{ erl��a"�9 �".�!E���ya!���W�� ���:[ < i�8�{ � �re=p����)trp��A�ill vi��;�/�'51� �2 �C:� � I��sfic��o��5�B<A�f�%)diI!v � N��t!�g���K*� �6P&�'� ensory� �K}tas� d sm��Tteo�2�inn�T6A�t#a�H S athw�5�A��La� drug abolismd s S7 S�"k��J�.N i���7!�AHe o� ll.y Ipedn� a�m�k��R8di9 up�^am��\q+!P star�(t�TSS� .�Ta dra�c�y*/�C31F�ZUA:zpX�)>�3.iQOE* ��2oC�"t� ���bew_� 4�� AT��!�u^(1� y� f !aC83� >V,:� C�!���l�B�a+9�1 .�5LS7!M,!5�`�Vkx:I���A� �xte�"�F�"H�y��t �Y U , [3:��3gm�beJ?es,%��-�6^ea�M\EA\�3\ ��S7B�WeN/&�/X/�?�ParrayeRC GdA��)�5�3e:o>$o8?&�.�*d>Am^s�!10�+of 4a� i6yl� d*��(9 , 78s� 43_3tMj] "/�FDR�002�?("�?)#removA����A9=�>&>�V� � �e�� t:5�F Kruskal-W�s� .�n� o?m�_)te��nc^�Hi%�.�as)�&���� %�G�,dachIEZ�3u�"∼o 8"^5A,*�8se�Ua|re�T5q Q.a�Y�)3�8s��`$�O(�O"!�W�9C1u 501 EfE\in t033%�a�>z e 0889 �eda�'^�-∼D��CL*�3E;� s Sm�S10:�w )1��0%�� sholA4r�U�in K S1�3,��*(7�r knowle�Ja�f+6�YD*�,!Vr�D� �G6"  Ca�%9� ��c�C� F ( 58%t���!17%f�D"�3�d5*�#a�?C n&(�4�A�Eha�st�6BE�-QSe;AJy)�d� )���an art�!!!&H�khr)��"�/*$���A�P-��� �@Eޤ���qV�A:��Q� F�e�M4ig��Y#-���l�w3A��$-�s 5θJr�!�g ��B�i �la"��� ��� kA�,<n� ��sE#d ��Sr&�.:�B&38�&.���Y��s exh �"��~�E����,f^�g%�*z�%�"�JU��Ler*�!�--�.�F�F��Hb�}�I&Q%pNg�.�5i�2x�a=I��gu�H6C%��E�2<%'1�2T!( .� 6e-1�/χ2��� d0a(�V�D�1P��unAN��d 0p!�s �Ia�unF"&�!�-P"a�,H hCN� ��>�4!�� eV�*(� � s4.2[̡, [X�1;x-�Q�F6� Ey2��G�x�����SQ!'�e��?������6^]N�,.H�(S1�����?Y�=�e�*ɺ�e� �L�@3t{"�s�k�S1!�*|o'� g whg��eM� 8%�3� �I�%). N�#the` ��;x�A���J�FY�OMn�,gɣAyJA�a�&O ߖ.�mEC�)��� �E�"0Q)F�`�W� 3>�j� s�A|acces*gl!��kq�' F��!�few�n/���ou��2�*� ��ao:or��= heca� N�A"M��6�� E27! X�*�8�IY��by 28%a�%�8�ET: n��� D )U� S1r, y(S�AsCyi"C1���I��*d� de�k1�<c�5sk+`rUf� a5�!�],��7�TwJ%e6�!l�:!E�B6|f��*x:���&� ,]\R F��u�'� �&��!4e.c*�ar*FQ��e��l&.B�(� <)&� }�5 �f�-8 de�#�]tMoMgj 6]#�"�- �FlyAtla]:5]��J�.A�Aa���Z7�iun"�:0:�F6wfl5!A�1��n&�y�.V[2w� j�~ - ��f���(р S�Aux*��n:� wb&'b+��p-Na��c� 1!3*&�#��%�is. invol�THsc70-��K� an� se` AI> * e�s2$�Bes4P�^dul�#8�X� �5H"A�� �e� �sl�anD)b's�=Q���-B�B5��,&� Ir�w@>NEubN�R�K�3��se�+�!;O:Q�F;, 53%�;1S�6"% , 44%��S."�Vx2!�d\��BIe�i� NIx�3�� Q� &g#*!|-WiZ.45c2�� w:�G;ak�6}All5!ZU4KA�tN%) � ef�&�� 1psZX," kC~ 0*� �+ . On��B��cM�thlC��A�*e�r&^*)� �i�&R ��i�]�s ��!q 5m4�"��--�- !Qd�� �� 162):��6i :Q�ց5a��58 �X)8G "�{,8g�*( !�7).��q�)&�=�>y1 \,�,�}~ys��ta�"Lw�nsecu� ! �bea689� �12�'�> narr&3p���.�=do�8a� hund!�">!#����5m�YQ �ƥ�M$!�:b�1.v< � link!|BES1�r2j!*8�W�`�G��$!��*x �%��3to TSSi�TESa��3"�3I�ȎgTSS%�|��fma�z�-G̶fS! �� � ymmep{!�)!^��� r�"�r{vo�A�i�"�1�� ,.�.0t�A"�2A��.�BRe�sw�" s�C�I�-metazo�5&4M�W� �24"Dq�5��A[_m![��m�o# �y� �V�T,"�.o���{ Dr�K?�>w !W'""46�f3K%�A�s 8.\=����6��)� �3h4���e�e� �.�C�"�c'�AM& ��"� A�!gre�%�23MJ�a�7TH: �y[5�N�\��+ CJbga*�)�/��ra�� �N � �� /c�7p�dC !G-;b~�'E�B$.�&�N�&27 ��K27�&R>Z�.��.���av\& � [5�1�5wE�&� � )�E�2  Q<)-�5D`1Q� r j�R�Y�out�-W�|�.H�:o�L-S.�}.C�c�a"�[�O�M"&�K113dYG3%_;:a&E[��\!� diss�� ^��^.E%A�`��xH"�K�h[1h � +�O,�(] �(r�fr�"F1� hy�f� �=i�� Gy D& .�4)%��ai��2!y���1&^ ��Lv-"i1�&US0��_*6�!9�N.L.�Gcef 5�S�(a�9 s�(� envE{E�,&�MKH*# Ee!Ba(X%D|sHm �A��(vity [ĝ�8�a.WLo��ep)O���j�Y$̓��""� Bgci-��P wj!�a!� arma�#�8�co"�e>9�O} F136�H 765-�"/.]a�uF1517�://� l�g�.n �d.�∼��4%�,R1%�ic*�a-�.�/�a%�PE�*�954�-h �.p@ .t }]�>��`5��(�&<9>�b� c�L5��.>� �a!���c���Nu�?�!�w0*"me���tcrc%]l����reeBE four �}"o0>d*� 3�P �75c�� �*&%�2�e �| B�N q 9�% �2.� i.�NB�&�Kډ�;e�ac6� �mo�^ I� /3?�>�"���eB?.�� 5"�&�QUNfdd�4AB�6.~$T" =:i\E:!��A)�&)Ks�eA!&-&HG!�(��~)%a.�"w.Kc]�"4��kA;c&<%� 0 *L:� c�:���� �@o�k( �'g .H� 13*�b(Y�u�J�Ae{;!��\�d "V�i&i�X&ul*�4( >R�vQ15)N!I�l��I0!RI0� )����:s�97?�8�%/J4n|��" s")$ toler!I�:X . !'ŭ� r7;MI�*Xof� ,#mrKEzvar�'��*����y\X[W:���j�)!��� ��[3a!SU; nd�!US�\��5�ie" �Ur� ��-!+ S��V�k��%2� �E�*�6ref��A�  �=���Klob �s!� ( � �/^g�r.0d1h al hotspo�)� q#.t  k�0 2Bic � r� E�&�(.[q^ , ad {�ge/8�Jc�6haS%�F�"�I��c� �:l� � i�C�i�.� ��– poP�4>_ ��"�.� � r2`X-a�M>U�a��<q WN��=2�)a���Ah3Y ��(<��D�j * @!��4nCd%�M�� iMll7a t]Oof"~&�d2 � �ms+d����U!c�S.�;.X*qQYb)��xHslo�!0{�)&@, cola�!�� �'�`2� �s��$��cip��&�phyloA�t7�!�=���Aa� beyorme scop%^e�!"� H� appl�V�to +a'&5C%�N�oNiDgoF�,}�'&��>�*00�7, ��"� ��J� n.ʜ"� ��2���"���yAU�0NDed��� !F�iBf�lex��!z&�i� c.m .�Vg2�*�6y ���F�����e�Emis S��$��2�{9��y5 !�B�AAU"ߔl��� 6/2! imR t��V�R3�m6�!c��$aW���G�Q evoi�~.u nnot% �Zɰ���p�)$.p t ro�M� Ma��@ir�9V� ��5~m�,��i�S^f7 :���6�lV� ���2`ar)!qA�Bb!��,3ld���_~��D.Ch�X6�L�B�T�.�9YF�k�]�g&&�4��:r"3�lt"V\>�*�:sexD�ont�+��fliw%N2�n�� stem2E� C�tz�m�!4H# ��֠=iwaNsr"AM�[A��&q�=8"�J��"�rf�Pb�9>�s-�dis.����pJ!�*�tH4+��*� .rv"A� � �A�:���% m��{��� m�o�Y��urb2�" deb� [5-75- wV lie�c!eaQa�en�e*� :��6�valuabl��[_49ۿ�OT&is Lu��l�4Rea�e 5A��2�BhN�=�"�!� ole-�h> *�5raw�Rc��s&).ۈ�>�lY�U�.]EBI A�6E�� A��v��(A�n&$E-MEXP-159�6. Brie� , Ay��s& g6] �!VAmRal ( U1�* e(S��f��sib3BASA�li���-wIepzr ( 25i%/� / &)� Affy[x.��0=r��p1y�jAJiܻJs��O>�a+�r���A�8a��tpip�A�M*Eg]] : Ti�%��>@&EtF|&��Q FlyB��(( ftp://fly .�/&Q_E�/Gelb�;. 201� �5t��gz �x%Fd,���\�&�'i�$ A�� Cab�_5ppr}6overla�O��M qt"Ha�%&�G�@achU!�Jn *��1 iq2�]�)&heI^end��(in!&kb�]yr� =��%��OwlN!ZIAV~���Qethods:E6�C, Alig�Sc2AC9!],�a*a?Qg� ����'!�iA�� 6�(%1K�.0�;e�Z�X<w�mf�:WMImaximu"p>��Q�a��$e�>]^,m*��-�y��a��kKma`�4�c�re%�_F adva`� u� �k B� )��Q=:�@5a� �s��et�!bWaH�o) bB" A�,c%"m!� Fwo5�� l2a l*���t) �AJ:A*:�Q/9�febAh!��VI6�  � l�X;TX<&�aR['(5�-�=�)N~,` W�^cof\f05a!`500'th���� �- (5�×�^05{&50/4��>#AK����l!F*�s �-��&�_��� Y� acN��0�da�$-*�Ĺ, iό�[e9.�1�9(is� !HE���EuFc.�3L= -]��$mE, _ru�*��!�\w1q1a slight3"�*E,��KBH&�JH �im�Jn�K!wla&4��9�.�daNr!�an��!Ga��F&s��#/��Sa[%\2� K KN<@, h�Ka��.& P�M�AF� ���0m�Qt��Q��� .t��a2�\ ;�o"e屶A��NtZIpesc�"��I�ft7fe��)ua�$+to 36�/ �p���u�isj&Be��K,but none of �the DGRP lines ) [20] . Second , we compared our calls with those published by Mackay et al . [7] . We used two methods ( comparing all variants and cq0ing SNPs not q@in 30 bps of non-t, Table S1 ) . In many cases ,B �by �other study overlapped or were close to indel ;, which4icates a possiyfal!Dvariant breakpointa�m�4�All frtocks)�grown!L25°C%0�a 12 h light-dark cycle on corn-mea Hmedium �Jcol � virg! lieM�)�of�=(M�(362 , 517 ,�765 ) du�k = daysE t upMfollow!b,crosses: ♀Q×♂T(8,reciprocal )(517 (rJ(�performa�NA-seq!�ams tranMVexpressavprofile�3–5�, old F1 fema. 25 )%p!�ample)�Tfrozen between 1–3 p!iTotal awa� xtra%�IfA combE��Trizol/RNeasy ( Qiagen , http://www . q .8/ )�tocol .fqualitynmeasua� m�Labchip)�(Bioanalyzer�m Agil�M TechnologA(6�che�a +�%mlibrar;���ed ��!�Tru�7 ki�ݕ��{P�ed>KmWed�� an7G��A�2 DNA Sy� PlatA@ ( GTF , LausannerWe�Zhe UCSC.(annot��to der�1)�E7 *ed?�X�G!refere���rE�m�9 !adsgboћ)�"Zds; ᭩���adto�than on Nics!coordin��%�discar�B�8e toola�bui��pecifiy�� this purp��ak�s inpu��-"j �,�Y �haplotyp_���!~-N��c order�1���u�ome�� For every���8turn it attempt%m%0to-y.H.�. R)�� 7t�ue same�i�� in a]�K��� thenaUckA7o� i�y`��lap/ !��=�If�do2G ddifExt��!j:�,!� is deem �“f”$alleleAUt�duces0lowest number�mismatch%�I �b�%| onlyE�Zt t�alsa~� �x correspon5 �� E�wa� Eͭs '-Q�9%ialA�e.!ini%��  .E[!G� n��) w�Lafore!�io��,�lyait��IS 3|�5 V%7ŭaragraphe�� detail qGJja h�y� gave�A�6�Efn each  ,{� on �aQy^ coun� he]As bA)E!to M5�A � mE�1k%�" A�vid!�1�!xA�;t�o �ve%&:n r�$ith regard�� mI�a�y!�� itiI�ufAA�� �)9�� ��� t�"��]rF1Ag��� 2�*�%�yx c�� !�\ conside�9�6X ( TPV ��ei ! % ed-y�ism, as op�I%{!9*TT�^-W��Ti�'mA( FatEhheVI`�MP<0 . 05a�aa -aQ inom!�tA��Ra>P( F� �2�* �[ o or.� �F�f sign�nt � ^s��J��edE.9e�ic.3imbala�� %�F1 lcexact _� two-A?dp AbouA�lfA�A$(!�z���vEsby!�� �ri�-I ��us� !�son�pow2tCeven sm~�ic��$≥1 . 5-f #}Dq\c� . P-value�r�-\multi1 hyp:sis���w!� Benj�,i & Hochberg�cedur(it �We�he funce� p . adjus�3R%gO�].Se-� -p� cis-�ci� e� �Pa��b� inZ .�( i . ��,)9e1+%Ae2≥20�%Q�N}Yr. T]�p�  10% FDRa�: *=����� to h��azzin ge6 increasc centA�d�ig!�5B�as�by.muS � A R��“!�LeQTL strength cutoff� we obta5a� se��=&(y A�-hV.')%�calculaAY how �� wh!=�I{FaW�Ope6ŐA��I�$1 , 000 ti� AP�n empirR q=E��byan���!s sco��hig� a;rJ9�diNdg+�vpe5��%Y���TThe Fiston-Lavier [59]A��ehs1x��as�o estim�}reB7( cM/M�(1 Mb window� ong)BchromosN i  4 exh��� �|e A�� %�interval�au�.t��groupE to f8 �t �go.aU� no- , f"� ��2!�sex-unbiQ�� �Ki"� ty� pee�agV }lo�d(!gX.!�1�edm�nN�/ed K" yDwhe�Xf���of X-lin� � devi��\x�fq�m_Chi-squ� a�% YV' ��� full!� alog�� s ca�y��dgr�Vepf`(ch/download A2�a datak&3 ArrayEk Data� �acc�m_@E-MTAB-1266 .��d�E@ified surface EMG%1al commE�E�a+ m?o�!%neural d�o musc�AQ!�e� �infer ��� of synapt�SYRon! Los�itude duP}�lapNm<un�)�poten4 �N?ci ll�*how�e)y�tor�� trum`o91�ndreby i!�� Xw� 3�5&:�E�inv!Ug��e�ac�tamp � � �o3isI� -��t���0!�d a!�p�al model�)8�on !:v�,�.c� ��aL6Fir $we demonst��d�t�l�atKideal:< J!'� >� �(v nc )A�superi�  actu^X��~�e�is obs���N�� onfi��sim��iA�T !�60%�15%� More��0 e24s�g�1a} o���mW�6�)6�� ��:��A\t�:amxda �| .jmai� � low-fr !�mponel<5A�)!eB��co�#,#&3���v��i�is-G8atv ���:+�9z�� ires! �>and/o�!monJ�!$.� s . �p%of:inn����p�eiv��r�ve1 �a�ofZ�[1R!s�� �J� mittA��y.� out�u ing�2�7��� !�e ensemA�7 isch�� ing��F= ���- � ���$�approx lyar��� S"is [2–4!ConRB I��j] �>� �s�=)/�rec gs h���!'rev�+ M connc v��� g . ��A%" a5��.&+ �or@67�e ca�x [5 , 6!:�b�N acculym)�flu��A�!iT tric�bcE��� �"$. Although:!�Sto u� m�d�" )>�[8–10]"$m�� ofteaB� � E � romyoMic� )��� A��}-6U ��is. mB"� 02�. H"� *� infl{#9Cwav� mE��yN, � �AV�MWdef����7c�Y�z!sNj3��i�no-2��s�c� b)eri��&m��)Q1�ed%(i� �" ly>8YVb��de����-i�� noise � u�ql)�aleert!Ӎ�MO �[1�GS"E /+ � V� �du�of >50%Q*A>&Y ,�)Ab �8� �roo|��I)i� ect��>�I,�f [�%18a.S�AO]sQfN^�6YH�l�)�umI���6Ama� limi�'*i�$of.���!�in�q�� +� -K2��� ��6�[13�9% �deg�(L*!� !�� 6?)��is"'�+y'$nderstood ZY2�!Eb`&$previously6��e�3�t}& �butq�e�� ribu�oB"s )ac�'=@�  Herea��esasa!.oreK%�&e:^unravel��effA�!�V�9e�F�6b6 6�\i�>lis�L>_=� acterize��%A*on popV�A$G aNA�a &�M[� [ Fig g-Two2Li�C-O�A{regular u$ll�N�&�"qb���!���*M p�sum�rE)� AIm� a"p >��'�ex20,E����b*�in1�)�*�I"t)%���ed%�.g -��}�� 6 �IaJt!�lA2� quan!d�. 8�:toU,�A#��eI?Z. Tog]�3th6�j �W�&I�Za|-+nedisru-' he a��y�.)�refh,,!K5�$'�w �% . WeE *�9e!n( |EMG|"� as:!� ) |=|� *p (era��v2QI�(G=P|Q,V.�ut denoa��&$ <� h:�+ M�,&heal\)re�,e>%A se@~ elta"�s���)c&�inv t"� 6�,% � �)>�y�These=�e�e��'�ass}0s9 l�tor CY ! s�"ByB�� OB5� ���4�p�ybe:"OgKAN�2Q� !��J Y�jw:_=.s−A�ME|N�#Qf2�DZL 1��|m��. *=�$�� -%�� "�",( R ( τ ) )"! !Nm5:�0m��ea�,A�s fF0�9]: R)7, ! ~=E{ i�⋅t+ }=E{ ) }�F%,∫−∞∞1 α )L|e6− |dα�<H ��JJ}=.vRs0�k �R5 ( 4 ) Bo e �2tit� <β = t-α , Eq 4Q�re-wr0n��JCF�β6�β�l dβ= �−%a)U �v2C 'is symmE�5��H:l6 )e�E�&u ( �� IA�%^ )�Aw�4�!��$qOV�[E�G TI�f ) =F{FT}%�%.�}=G<⋅HP�#�( 7�dF{·}j� pera�[, Nm��9m�2}!HA�y 7= "� 7��:>  .Ag7  \ !\:�r�equiva�2to� if�= 1s �f�N �8 co�m�����( ��"h�� uto �7 ould�Qeq�to.�r�R��-h���jcv 6�us� a�G2�serW!$a#� .�1,I�ABGn� o� �e Inst�9� pA(.U�s� >OJENex�(5;�'�.U��9. R��� �0"d �I: R�l|m�e�=E{�CJJ{F|.Ga\�4(��:7α>< ( C�9s � ≥ t8A�!! Eq 8^9�B�������}≤E2|���B?}=​.z6=�+%d���9 ) C�-A�Eqs 5%�9� itN�≤Fw, ∀τ 0 )!310��7 �Ya�lw�8u��X,eA�a3}!r"� .���A�e|.�epH'lle G .IB]"B P"&f.v����f"� afabs�P�.�$��X2�:Ga�i����#"Y2�| �pr�1!?�(7"� 28&�*�)����� ��QV�!2M ��q� E2&de!/@B4"s`(�.-9�e&']E2 � abov%rij%�!tkll� �,6��/t�!UfN��R�9� . Us�CN�("�LA�Ww.�.� .��b�(L-6;-F(��)37pB`*�> !-� vcuq%�@ pike= iN%4CST; algebraicL�!n �B 3a"�1&2�65[�=7���1�5�J� �Lr"D%<N1�.Q%�s�!�DC 4)vO&#:� ,v�)toA~e�=�0%Y"�2dM�AwL4&6� �"$Ms>�-h[1�C!$sB *1-)?�? nsis!Xq-tai#�l6!�a��l�source ["��oB�#!�;)�!* .K30pz�#.0� y:�.A`�…+Hza&1*e/phD�1}�$�1r<ff^/. A� �8(Y*L&*he,"K$a# R&����-9# . Ea�8*f/)�sm>taXs%r�015�A�!��8%�im�6si-+@asa9!_1�3�Q6`t�#���7 ar r?�#�i�7��1 �de.a>.� %Ab"S!� A��a�(6,i�)7�yAJu�A�-�ed.<�p�-�(ecrui%i2�ir"o&�r�0iY3MI!�MJ �:�M^�E^E�=* A(�6�&A�. 4)!12dA�� , 18.*[.�u��}+:�of�D9 pul�SBef ( pp�fO>I6\�$*� ily� �-9c,ch��53%�.�,�H>�3 at 27 . 7�L g3s��e�Vt611u �>�Mo��Q&)lh�)%s st.a�A�I)a�*.�6Ts6�A#"� :.5;L��>� . On5VN~M9�by 22A6�3agh#BFA��>��Fte735��%i�e>:b�/� $)�im0t�I�!" pyArn" evo3��llu�/in 2�BsJ:� �0��!�Ihe!�J bjec��r��A* ain�8�V� :�)Avis_(feedback [2�02 +6& Jo; �:�0%�!8fA�'=E"�� mean&.)&i�7u�$>5%%yJv/(Z0!@ %st�Fz( t <3%�3��rN?�17imi M�w�T I�u@( D�0Convers�*;32�*!�!�eg EN��gr�9r�I most"�al task� such�rgai�!)=modK!is nee!ieN��C)�B�-(%�6�2�E2B� 2�1"V s ��e� �) a6+�+��g 3eu%r�(� �A-.s �� ��<&e doA�!�G��Y�Kan0��rawof6V �2$.D��7�c 0±14 . 8� ]q�� ���ofE%�E�4edQ�[2*2$ is* =e�?'m�c��).� Z� � &�FR!:�;*� �:%�oV(Mɽ%� �je &� ��1��� I9- ��"� "P #7d �-�s6�� ��AD-M6i.`!�� !��q�t�/ r2;' +�Yig3a`)B#.�.5 0v�}��au�Kexhib- peaks�aP��&� .��:�0irValB>~sm${'iXq!̩$)�>�)W�R\,2-5m���"� -$ ( B,�Ta5�exn�!Z2 IT.s(A:ɫY2M�Q�y�n.eG��IF11*#.A prV.3+ �  twit�I�1 U!�J{a�j�)%�}m�>"�<-JF��='4����uV"eAlo8 &&!7.�()�m��a�q"CSTE�>� ;15�c�r Spe&(M)Z ltV1�2A�2�l�v� i���th��!:���9�5B!lI��28�L$^� �Q.�( r2≥� 4L �e�B2BRm�� weak<1�:�F6]FR.6-�W -��st�6� :T>� =� 15)2ɺI ( A ) ; r$29$%s,%Ee�ai$��� s%�2a;T t ojR;M>�I�!.T+Yr2ɱ-�q�-"a#r> !�F�y�+ �!lYZ� "��* I�.��IkA�a!!��  () 5p2 <.*�7ly un.�(B; ��&� �Z�[�b�d�f�.]�3a!a:  ed���;� >y�Ttxy�2|)*�Ac�r�4! Il!�QB��-z"6y�}ͅB�-5 �+�0 ,!�a�1�=5� /2D!�)35�=16 )%d2*W F�s >�G !eca�=��&�35 A�!:O��>�aL:�&$,� �%Z betae0$6�4�>)%"�%2-4��K�!4/LLV:S �YiY&��Ps did�)$"� � �}r� �Y .�s�Ac�-rq�37%�71%���[%���!� �5�-U p�0\�/!�.I2IKI! )-��"�.��ea0� ;NgA�F�Mte�3@i_ly neg�Jl����!Q%"͹1I���r2}�� :�&@;ş�&.�6t9�r2)�  �Iof��(,"A��h�%* Zg",A%�s �@��dJ!^er�M.� ��� 2~b�NF�:Bnd%\����6<5�%����)aNyF�ݭ. � isE�ya*e syste&�-B+Eɖ:� magn*Ff�-59Jc/!!,2��,to�&2� E7e�i%2!��f~�>�X��?>�=C8.3LQ��9:��*y�Fq1�*�D-�""�4�"� %Q���ϥ�,F�F E �0X�-*IF�(ZM @ � 9�'�ot!op�Kl�"Z F.'�yF�7_���qZ����ir��$O�Si�sCk2^�#� b]akM?�0){e� ���Ulso a�6ea�B��i�vZ�� fewM����� �$X &I19?Is2r�ed2�T!3&� cl�E��6�)PNtRgE�:�A� 6T!����BW ����rapidv� 9+)��R.V6 fA~nQL�sd�tA��E4R$f *�7&";@�9N =: U� .Fu9Oq�I� oscib:n{?"�!-Q2���)i`3tobca�Nor3ari�v�=.>�BMF sug�a�)�-���w2� �6�E�suscept\e�V!{&�:>� �U�XJt� &%;�#�*Eq�.%�XU�j4Kiա ͨ�\��'&(&zpR ("� r2� F� X*, becaus-�&�sv�A�(seU��2 expl�%a*� " e-.L+&&� oR+D\ci���D}�A#�C�?M��RR�� YG%�seE?&� !�)���&U/�e� involvaO!=6�[2�D3�GC.}in dyna�`5R3~�J�-W)  3�Ace6��g,�1& EMG-A��(�\� �sha�2�� >&)E"�:�M)H!+*+[3�G3~@�l] ~sR* gene�VmKea�!���Y#B�>res@�L6B �$�Kst:5B2�e�ab�- ��YER!Q��YZdispl6-�&���Y2� aK" �[37�9�@6;a�%a�$3 .�KbJC��!  86�I��air�ihiOlyIb. Fury��&_��)da�bbe!A�;YP6�62�r � ,1�"��!�!at���enr ��>2h>Yb�@)x �s*GExaQ�0i�7��! l�\��\t!�>��XS2primar�$�� ?�. O�llM��zsfykiBE;� I IL�N+� >Bs&p@a�����0is a�A�q!p=�K�`�&Ge&�%�o moveW#. S!y applVi�Nd"� synergIalL%]fes�� bA4iS!"�\�[40 , 4��In)�51�6�)]�aw+]�Hed—��5ZLB�H!�a�N as 4��[42]—�0%al risk �!E��:�[e��.=)� heavAh� upAd�UZ�-��Dparti][��b�9\��%�In}7�littl5��ȥ�� ela�Cst�VQ[4�+44.y G.:�![45] lik���e:�� {� �]1.2[n�^(inimiz)m� /e2�FF.�G�!�q�-�{%�.B'1 � :m6�^ mechan��B��%d/�Xle�K�!IRv���.,"�N� �rUp\q�<"s a�� hysi`k�l tremor [4��It C8uF#�p�Svern�/#j "< K I��i�6si�in�]>��wo!m_<^�o{ ex,-�h( �!�@&x v8�a9# �out| Ůvar?g `� �M�'%&3 2,.��q Eb:Z���Oam�f�6U��Y�4s*� *N*� !hTp2�2r�Q �S&| �hKstD+!te+[��u7&ag!d�1Qjal�%n��� �)a�iO. �"���� .lp s [4$2QZv�R!]5.%E�!cs �T\�{��}.]AXI�zto�/n��im�0\�a globa�H�@ � �*)!. DB�*�>� �!5vDS cri|V(8'e b\M:�$ �UF�M�|-$)�a&� plau;w6~�K)}c�J�)s!���9��6�6ra� �In�T�6I 2��c�^*�6W �'-�3i��al�A��lexA��b*J]�r�re�. advx:��de@o�S^(8a��s��%��R�WiW3.�s&SU!o%.6_Im�i��imc e�$ly describ&�ba-u�)a�.R&�;(�<1ER_HJ �pl�& *�O2@.N ��>s&. pool�'�i*hy�*}Ld6W�[4#OWlaA ch.@w�<��A�� a��:�SF�!b%zy N���`)��-�cl�[ draw*�R�!�dec �.$&vo Yvz<enDcyf6{_ nume�f&J!���Fi�4l�f�J����5&�P�e�Aa�%Zmi6�8A:2 � �:ed�]��2-z]s*W a_ t�KK<ݞexcs��7}��� �n�E�> 3:�7r"{Y� s criV|3eii AN)���U!�6krj/��_tin� b e [4}ConB�)o!��=_�i� .`( o� �&/$ monoto� �w �2r` M t� f�s 5�Dub�0� !6�$) les [5XZ.!DM�B8�"�@:~5/ %WsR�#(*�\30K6uaEp^������Ely bL� "��[2�pi&`@�y6%��$)shold=Ns�� pn5J����tc~.�t�>l�Qbs %�2V([5uT�Psof�r� ledgano?2�Rb� o��_e�0�� aptu*`e�behav�d�#|� T[�{ DE� s�5pS�3nd3<�ponaK52]��< PMj,� ^#�'�!1� �qes�BZ��owZ�g%/lyaU�o��.Nly�verthe�5i�failu&i�ku3r�t�1��� Til@!?p�#e��-J{r�ex�-Ua?&��Vtetan"�^>�20–24e� [53]&�b�O:�=s6�0i�m �e!ui 8"6��vrv��.�!B�dNut�7� :�JsY�_6�G��R}mI_�r.T�b � dens� � Bm:�E�*� F�,-&be�%s �l�H�< �p{y"W6�� �,)�>qb��J�WE�/&6:�e��d. 'dec��&F�.X H"`we��'�� Kzis err/#M�!!my4�BŤ��� f�#�T��ml�}�O.�alot�{g�G�z��,$x�c12�<� ^J�� umab��n(�!e�o n} 2.0"`��r:��B��%�\Y��I���X!G*i 6z&�eb�m�XLl5�)�&u !�.� a�P�DE+"� �^<gy?er"? �;�A�go�a �1:�m"�C�e"f !):+2##unikP��<.{� � BUp��4���yo^'B�2�sAj-0��E at+3�o 5v�al!Ce)[53c5\a55p�O�y*�_v ��9l��L`u� �A!6)!6��6x�1g�:�tretch-s��%�reE&N<56�wV*m:�uaZ4���:�Xa�9l�6An�ask=+L[5I&M�dQ~T�hOh�t�.'Fs�i[w [5��&�� E�(i�:�.� �A�"C)� =) A�ce���&�G�OlP]m�T>�/"]���2`�م� :�:"0��("�uR��.H)E.K!!�-`v   ��2 F in�!]-%7"h]�A&-h���"�& 6��ug�>f�rar�%�.� p�[u"4]FcB�2� ) :}*�` 6st�/m:# #]k *� C�:�:u��%�B�m��*�\jZVr C�*�(�a*�]& .�6��Z:�(�"�, w p�*]�U�Nknd}m#lyM�l/PN`�r��XA&! b��q�Ud�m� archi}� >F�C�yToRJ|!zg!�s6�-Ei"�A[#{r�_h��&!D .&�M� oi~,Eu �'E:&�!2FZJ���J�U00�Q40'(FJ21*"=%�DHodgkin Huxley-typ�e�59�l0�k �Ktw�ar } soma�Xdendr�) .��sixO\f (k6ao &'0y [61]i�� �0!�( �uR ��6 "�G&*�%f� ,d0��Zc)8���&V � �B�sol"8in MATLAB 2015a �+" <“ode15 �RE�5�2�*�-Ku� �G;�DE �^!�"U���REA &GN�<"�E% Q���"j M0i . A A��w�P�J7o�m Eo�Zuach�,E�or) �ha��Z"A�I� �E)a2�mmG14 �P� E)&�f��3)� A,ow95)���~ � .��%X�1�is5UA�nge: >6:2�!XOr��I ���F sg"&/� �-{ i�c6V��of^w��%�c��� 1��� O!�j�a�i�3co�1�# � 8��on:_��[F�� g� �a�Q F>�%gR�B ��nc:�"�ly!6V�"�l.��2.. M�-!�cLsq����)a 6B�r|_�C[%��&I�_ttGEJ%�W4&A�am��QT-+�s�<�!hI*�m ��0�** o�.��-�Sim�oom � �� s)� K 30� 90 m�rB���B .�a./H�xYH��"�� �$�:r� �2&,� - r!��6p!g�5�Lach�v����t�M�kͫ=H&��)L Cz �&�4, ilotQ~�fm� 0 elic=K�2�D!�nVz�a�v�>�/ &e�%�:��# �nBI�� B"%O �� 2,( �H�-tnY�rm�)E��,%!L� :c0 ( <� H�Z� GausslOn[caa[in iB to g��*�#a5���ωH v0+( :,H:!����40% [2u[6�/64u�.ya� � :^�!��[n�[~-���N�[!VG� �Cu����I�dr %�A[oX"':Vj�qeer(s G1F1-F30 �4st �va�B�T�2� �0E6�A�e�G2:�"%�o1-�-o)�A�!jM+M""� � ;>�BK (:vi��$�s�Ӆ��vBr%&.tG2:M 7·10−�5!5 �QF4%�&DenN�4$6AV� �><�C"Q!�%&�8im!0�'�:X� HE�%R"�!m6am�u�a?-v!0�$)^ (e�R�0zA �D6�-k� C�&�E&���*d@9wQYE�vY1ka�8-kzS0:3Z�j�Q�H*0���Ks��}%��,mL� G�1�<1 O2�&N� !�400 3�d:� �ab��a�E!@dest�(:�)[.% �o.=?�I"��fyit}Z.�-�>12�Cbmy�un&�)) ցo�'"�Il Disc�Zon%_&��� �ya�p�ed�[9s^;-��Eqn`���37Y�^�Ss�&�Pm^ �O�>�� !�BJ"�T nm6E�Y�o����KdF2�:!��� Aq`R�E}"k ��se�m )~m( k.}:`�2���-�!�9r/a!��# ��hCb.)(*�F) �& �ŶV&R raR1o�1<(>nb��iT� V"# �i� uё2xr2o��*{��s֦W(5�1N'"]ReI��᝜$Q�e%R�@ D(.P?1���1.$alpha 1$!0(*�M M&N-�*ݑe]*BNi�  rn m6!��i*n V1'c *�Y�)��A'5�`ce�DRz�� p io����:fM�2i=tn �/\v�)�$.%�Auxin-neё�!�[i& !of����t�u��a���( A�'( s��3K mole@�9sm! trol�%�i=�1lcR +I&�~r�NW t YUCCA (E �& encoF� flav&,nooxygenase-%;� tei�Zj:=|l a% biosyna]��I�r�� apexY?(!��( TZ �-�* Ae#!�1up-s,YUC3/5/7/8/9O !$g-gTZchI'_V`�0 �t 0��(� 2I!�5�"�"f@|�n Ʌ� se A.��x;gM%-�~�YUC+Qs��YUC5dYM��$��on ethyl™�5E,a�@0'or�rub%��J2c0Fd֞enh���6 5�!Q:�,X�2�if�6��}HJ6<=��j�D�/llt�A� yuc ��'|r= co-t�_V@� yucasi��%iv)f�Hf"ע�.!Sa *�a�am"=�e�;6..I�-in&�%3�xIN�xeP� iPhq�!| �9ikC�Epi�8���Y2�R�M�PHYTOCHROME INTERACTING FACTOR4 ( PIF1Y� ����{�ctGAor� YUC5e�. ?p���GAl-�2ed�m�L.���%gaw�z*�� �� i�I�)eOuWe� Al–iV A���!3of �A���TZ!�4w1�Z/. Tak�.&����.� l���� �orl�cado!$s}� � �^a�2a%"�F��e+3�o},. AՍi5�a5 bunddfEDe soil.�.�Kx�C��9�9a`ciwpH≤GMH��,iM��>�9v*!�3+ !���� q+� � 4� A'�Ca�*8;to�:�~ x[� ,nWe�O-� ,9e�n�qof�!TG& romi�@.��)preBxp" �@�boQ�fuypoe�$AQM� tip!��=gn%#�maju\�?ْ#� , 7];!�ma�$�b�e�bArabidop�thalian�"ahLC��M% �Iwe�i�j.�,E�a�*v  a�� 18;T|ebasal eH�,%4�*��4 JD]�.par�N� [��8 ,:w1�E:�baB7R?orghum!lNsiti�re��e o U2p�%,�la<� eI���M �F�>�[1 �APty!{pla� �".9�.\"� rbou�T��ge"!be��n! .#�cat�=2<n� �a�5i��-�pyruvY&( IPy�%�led�0G !I%erX6to%�A��-�6�� step)e *9) , 2a�2�\t"L�I�2�U�tissue� � �C /��t �$z6[)�� �emD˳ K!&yo%�>AYUC��  ,; YUC8e� YUC9�f�!z@k"� 1W��6c&. �2'8I ��e&�7 �V#a�9/|�Fi� fic��� A:0��x�8e , AP2 PLETORAZ2�7F>���aO]� U!at&]ora4outz thro R �M� �k)F�}U�by!�!E�a��@@c helix–loop–Z�,�@J�� �cE�W;"& ��PIF�f�TAA�EC�tegaYs ��er5AB ��CavqetX+IV.kp�cotylQ [2��2A�2a�2��P�����"�K s�� !lay"t� � � 2��M�fr  P">8W�?It'!r"� A� =- Mp*=�Fxa�*%54[ /��8ethoxyvinylglyc�4 ( AV0�ap]o2+�.:�h�iA�,��&9�]sBas ein\0ein3-1 eil1-1'marke�X"�s/���3�duT�e�p!�H� v�lAc��� )`%R5��ion f��C�#e�block!�I39 wY�Q 0antagonist a-�uhenyl%A-2-�) -ҧJn PEO-r��^ I.�)4 ibAOng�  TIR1/AFB re$X!�[3��35Nol� BO!ڻr'Do #lr-i�arf106&S="s^Cb[5�-�f�K �OnvItFF�W!n����sh^avoid�E���E�Lur.eA(� &s �"� --WI��I A�oL �5$� ��Y"� on)#�edV"y-H� �X�No�7!�N%�!���ԡ�����0$�A9E���%.�  [38 �5$A�J�mu�7kI�"  rols)�e�Z8fE\->:�-*=�in2�"# . Etf.�3&�[�W!K�Q[���V%hi� I@ . ToW e�6 ch9�E$at>� "'2*� 1n, !:�]�a91�],�X �\�!-���4s�[yucA�yucA�yuc��yucv  !�yucQ (&A))!Y��Qa�*� Z��e��s(B�O.s8 dou� �N%z�|t�x�H!+�ow���rng T�Z�Ms5 S��'� hGldeYe ( WTI+ @#A% 1B ,��*m!Gi �@Qqa�6d�cyQn���0�YUC��yn�!focus'"5V%x �� �O�<�Vg *' s����DUfK�nt�S&&A ���,�-de�b%�]KUEm"�"! sha�2�/9!��ej4c�su�#Sd&�@ '*�%& �!6�1uAl*��didn’t�"�xbZ� ( S25�WID��'/)!�toE� $Al >1μM , �YS1:e�����}�M`K��m�#pronou%�5vK%=*�9��Mr"�1m�|�es�<;E�( 5a 4-chloro�yd -4H-�2�X-triazm thio!> �J�[3}�!�iv ��%�- �u�6!�ef!LԵ a"!�� =PX"�!a-e"�tsez�� 3 � m�ם�� *�s@s� �2"]m�Ln4��B�=A��U����� ��i&�� �2?6��.��A�ts' nA=u| J�bl eZD2m6u � ��JJ0er DR5rev:GFPh��e@�� Q���9�t)?i&F�n)�Jpm@ ��2{!5� AlCl3��ed-WT#EaremarkwD��u�inF�!fe���t}��n^6��q�=(Ŭ��48A�ii�com5dqd� �%� !'F�]�:o };;j��)hU)DVuV!A1* DR5.!��-W5z p1�u� E��`� 9 6&2vVT)��s-b�R2� To�7�C��!6� .tI]!h �2V .�5��")�!��kur:� oi�spa�FqA$ A!U$��by� itor�!�R; p:eGFP-GU�&�j� � q . Un?5�/��"|#�a�)#��>�D-!- tip�V< �hic1�Ib�Eini!lj(�>_iaH3Hy5>7o48;!�� ����$a 2 hours-V�,�HKd� .�U��ach!���&��3�LS3�5} �GUS-s�assay � d�-E��>� ( S4YF2�d�M�!�pH����'n65 �+2u %�SA86oYU�k ( S5 �2@!�'&�AnA"prRA�&n"es�e&aul˶�#finV8�CngI��2#L0� ,1��Hw��a�2� 2���&y�Q��pej? |��}HU^b�.�acf� IPbG~�"���d��<��ar��q ��U6"Al�&-.p�1-���o�3A1-cWxy���AC� �:� curs� r%"9)�:�xQj."i aLH" of2@by!.&^$ ס.5�AF53 nsif �4� er�+;>a� l����G"�4�n6 �n - '�iq!�9��d}l�-�Y�N��\�6t"&��A[��! &�2N:U�Lp�j"WT��6�n�8 �!�q�br �� ��3[��, �%h EIL1�Lp{n '-r��n)�=y��� ��@ �s� ^� "�/wH&�b��9-p� 2 B��՞.UNieZ��Z�^tNd ( S7U�9/%d�B���"�5�d7n'us 4�Y�� $A[CT]G[AT] CT [3V�kUN��2 0 Kb�g�! s up7 a"h< starnFdg�AT] �� "�*g��� 9!U�P$'�E�q�0&��(bar . utoro*. ca/n,4s/cgi-bin/BAR_G. cgi )!�-y?E�al%O%#��"�EBS�� �E� oJ�. ǩfWve(*�dT�� �9A� !�1 M�|��U�!�e:�(� ��>�q�!���%ګ!<� ��)ooMiT�eD�EA%��B-luci"� �� By fi%�`%�L1!�e>t��a )a�b;��ng ��*�%� plas�Hw�$"C% %�`dra.�y�+�!9B%� |�*� 5"%-�y] p Y a1P�?�6�%C carr���ryL� one-hybris�� �J��E)uc��n� 5LfrqP9�"OӁ��1j or AD-�B;qM0!��d�e��.� 7an�s2Dly�V�-:BE�C6� z) immuno cp#^–qu�q�Eved�( ChIP-qp�)I` 2���k�* ���Aeis�2��h 35S:�-� E�gep .S � �� ��"� `&N� zvA�<&qs��bs�N:kS8��.4U��$E��0�YAFVqto�4~�a��gQ�R�e6adR�s:��2�I�u�� ure�z{,�Aj *)魀WT�.�.Z*) "� uponY(J X.� r w.� .!��/2i/i��  Im �lA�!�A�Q���f� +N"�x���7, ��’)���6F 0.��)yۉ��� �%�!ikW-tteti�|�) &%/�� >�-K"� fv�Ad�#I�B� �!:�-����"� ed�-5s L�&� �mo���#Zte�P�a�y1 �"� N�� ��&� "� )�%%�I�tslQ+a"A�;hg�n( 50 nM�f�ha=�!x.��WTFyb� =")�7�7�DI�A�<-9@k!?�&0Y_�y�/#� .{�� 7A–7��M�G;[�10 Q�lifa�& �ieoY5�mCon����I)KA%�6a�. Not��@�'=�of�!nz�2�WT�-x:W/+��E )�I��7 .� �-B-a � 02�l ��Wa9in c�CC-.�AQ"�1:�5:'�2]aTk"T/*V!-F�3 :�( ���bo�?U P�3��J��#�ticd �!�6#[>`(���"�\�!!s�AE 9wc��AK>hen& !o%�&�3( S)�knock�, ( pif4-10JC���,u�5�����='I��#}��."R��&��� l.�6�.?Z �WTh �R� �&<��\ �: V�t� `m�i48"# fP�&�i���� ��$.#� �1� ED"!8n.,2�(� �"EjMs9�m���i �* seed������C��AW)I!]1", :I�E)&"&>�-�/a�))�!L]��WB YUC7 ���� ;5�>�-��;�^�q�dX8.{� $(2B["�+, �c!o�5*y�mZ� d!c)���9 �"�8F=�a�*�le��%���3�k&)���7��h�5���E�P(%�& s��k�*LUI�f#QO �p-" G <5�&~� o� ob�U��%>in g7escR�� ty1��Jctopi2��1�-0� �q �=����f�� g ,�8%�Q/�Eat)�A�E>�F�.q:8�2/]N�:zG9� so;�� �6B�O:E'Y}�2�We29� � l�1l�r�AR%�.-�*�?eU�8��6*� >� ��>�!��+e��Qy��{Q)�6���&bYo&2=@>U :M�:V.��ed��a�1��8Q? � �:��m9� 9B,5 9��2���� *1!EZ�>� mL�A�e&�U)9.�'ZV%�&V'�n� !<�od&p��al82� � ~!- ��E^#�6 Ci%� "bEiW �$>� ]J���A >���*� T>5�qx1�!wV�!8U &� "� j1Hd&��k"_of � a�r >�)k�]%�s� �q ;�YofS�J�  U�A��ha�A~��Rz*,"�)6aK6���.N~E�m9V*"6��E!2w���$�DVGj 5v� zM{!k5!����}2�B��2(M1� &p+遧�_ �! �*� R^6t!X.�ruH �.���]�*���Na&�%rJ.� �"��Ni or� &>[ .�um 2.!V/ > {�" -� B�>w1�BR/�2� g�Z��Vy j��l�W"$ �1U�<5�"� ;a:i�i�n� f�w� & �,D3�k%��19 ~���by%'�-kaiRyN� 2 "�Bix`u�>�z�%. 2<|:�ȑ�P!Y*�?�9w��eC�li'��H0@r�} ����%�� yet clar��I$U 6&t�I@ g=ad�ve�o��~��w�Z� �avC Ea�wpo�V".%�� � ���_B�)MB�R� a bu�"<sC;%�N���-�*Z !�.:^H+ A0p�n&�8*�?�.l@m�K4ts Trf y?b�E� �N�riB�ooA"heng�SY�"l 6Hie�a-��#&(Af��A�3��f�@ڒS@96*C$)�&8=x�&n@4�79�N5!/R��:�I 5M�"!cJ'�� �4t`m� �R'�4���s u�AXo�>.�.R� �e`v�0&�3s�3:>A�WT ."^*�H�3�eGRL�G��9s�31��5!%Nisl9�"SI�y� �IeUajn�MS�*Fy�/�&�)} ��3A�E"J "y1%5%��6�?W!�t"�+V�^�Q6�C69 \J�II�U�5)�6ho� �+edN� K@Y��-.��5�flso:`'9��f��B I!H:�� %��B�!:B5��!&�:&E��t2J}6 migh�!e��-!�BXTrpa��� v2hg�%1��>�p�!�dm=a�u+:� �����R�| �2�,- !�"�0!��RE�6�m�1��".A)�� O=i�[ri]A�Ese� y ���t�/'G$\&�%mV .r�Z� pr��m &%I�͌)q8 �)(u0292rE�aC�Ngw�E pl����^enviro���r��q�!@E�th!a�`� ��& �*�Wte1)2@!��u�$ ..�F�6rxux�P"� , anT;%� J��s�M�� �6�* �* .�,and developm�ent through cross-talk with auxin [46 , 47 , 48 �i9 , 50] . The role of ethylene in Al-stress induced root-growth inhibition has been reported [30 , 31] . ES�was found to act as a negative regulator of|i u�Umalate efflux by targeting TaALMT1 ( ALUMINIUM-ACTIVATED MALATE TRANSPORTER 1 ) -media�6Z[51!.j�,%$�5Sa �exp��!Mof%�/EIL1�V5: ( S7��I![e�!�,7ER��bi��specific� ionsea� YUC9�moter �5 ) �:Z6�%hZZDremarkably attenuaa* -Lein3-1 eil1-1 mutant�8�5'�Aaqf=�)�6�of �(contributesA�Ɋ��ito%AolQ!�J�E#s 667%�T9�together� !nB�m�s ta��ts downa�am\me�6s 1!�aaf��m�5P � 12�I�Deatly improves our�an�H about how}�nviron�pal cueaUd �es pl!�̀adapt�0!�A*3ş��ful!�di�ls . PIF4aR membee�IHphytochrome-interac�faca�(8 ) family!� bHLHA� tein�) affe!~%��� �by��M��{6�3AJYUC͗[2�2�29��>�we unco��a for�4!ˆFE� 8A%�V incre�26�!=p:GFP�*aBAF(predominantA�Y� o�z)�YK,!sis()�its �6�clZ�!%%n2��et����9 �FureXHtime-course analysi����qI!��]encg Al reveal�J9� YUC8) :D(TZ appeared�ear�� s 0 . 5 h���9�Fm���e�Amay i� !'��H Al-ri�� z��qKƆ. T�Y,�,a molecular agraa\ �$ transcripaYq'links!%��s�*� s 11�5e9eL ed.fof y �\uis mod�byEI� � 1�V�� ��dm�)�2l��~H�e!2�M >� I�i*�U, whi� ct. of�Yig �� �[20!�w6 also& :� �>�a�nd �ol��&� >�aris�Fca.ATM< Y#SEI�&{ .�&� (manner . Si��it!�� kne)1e" �5 qpoa� e� [16� 4]� "gradi� form����y:�$nd develop�� [55Z_� JiniDy $ies have b�mx�V�9�im�H�:lQ_28�[Therefo7 i�� ll b�oteres��to���e�future�V�RJ6w A.MCth�� 6I*��:y . �genE�stocks u� � u.�Arabidop!�Decotype Col-0 ( WT 1e textŒm Ds yuc3 ( GABI_376G��,7�� ALK_05983( 896110M yuc9IL_871G0</DR5revf @F�0E��sa�05p:eGFP-GUS ,7>8>9[24a�|[596/� ,$8�J@Q [35F6� [36pif4-10�� 35S-e�[� !� materialsIҡn�Murashig�4d Skoog ( MS )��\um[60] or hydroponically A��de�be�[6��in 2%� ngth�$8ified MGRL solu�� ( pH 5 . )�x � Qɋp.���p��� and � ��,�a� �!�n!� non-2 nutr� ����f��%�n ]fer!��s5�-�(12��W.��z!�ropieiodid�di< uishU�liv!�� dead cell�RooQSE"d�w� J�e2m�$ , 10 mg/L%�P>�sgra]fluore� tK�� FP )�tvi�,at exci� waveI�4488 nm561 , � ec ly . Fhce emis�$was collec�؁F75?!�B���5005300bpas�r���c2A scopy ass��# det{least 30]oin eacha�|�Ft��!�SA!�oKeE�M$�� V vity �arr`��bO cub��at 37�in#405M NaPO4 buffn pH 7"�5mM K3Fa�CN ) J 4 .!'42mM X-glucuronA�. O!��7col6 a"� edi6"� �!k�� anol ser� ( 70% �% u0% ) bY moun��in'�al� 6 (in 10% v/v ��eH. Y%�one-hybr�EY1Ho=�:R��8Matchmaker Gold NOne-H N$Library Sca!�@System ( ClontecheLTo� p��cogu�!�gy>��-Cpr+reHA&C ( 2 kb up5a�AT��a ampl� by PCR%Oclo�lnpAbAi ve�.� gene%MAD-�e�� sequ�-Vhw0 �y� pr�B�GAD-T7�>7he^w�her=�= ccor< �)�ProtocPHandbook>bBriefl1l bait�alinear�vaintrodi!E)�strHY1HE$to A2 aN-reKer'�N preyjŷ�ZX!@aN�#i%��L2y. TU! an���$on SD/-Leu1 �2p^sA��w50��T100 ng ml-1 Aureobasid��-�A�M)A�"S A^s#l�ŀ S1 T� �Z� �of 7-�_-aX 35S:Ap-�C!j [62]��harve� '�-?� 1%� maldehyde hIx.�y� EpiQuik P7-KitEpigentek , Brooklyn , NY , USU�.e�these.A��Vpd9 e�2�E�3 nsera��+pDONR22K$Invq�e����:U>!GATEWAY-&$atie pB7WGF2 �(�!I�sA�log8VIB�iY� of G�)��LR re� �a� plas1Oiso�d��m2[S�&s.�64]EE|for e�N�6!"�*� c'�oly (&�E o���m`�Fir6 !�Renilla2�� it� %�qu�"f2�ae-> k�}PR ga!Y�ki"w e� a Ce� 4 XS³ LB 960 M�� LuWme��LBERTHOLD TECHNOLOGIE�2�! .�’2�� a7genomicU^2� EYUCaXe($or�)��\ on s��codon)-R�2�oj�Sub� t"� q��.Ij� KGWF(aX ��!2 edA� smid � �c2>` Agrobac�umA GV3101!L PMP9oA. �2@u,!�flo5dipQ�[65�F�in&Rge� �exieaB `�;u_!���}in * DP(se� �� �Pr�*6&�( G�Pad S���Comparisd&��group � made XStuu'E�t test% JDmultiple^IU� oro ANOVAT���'" wh�%one - di��&? " �!9ideeBAll val�$�Wb"AR a:'a�B �-"y"�#+ s2hhighly �@morphic$ -!h �-� i� 0globulin-like-,,ptors ( KIRs�n�2� tmajji�a�tibilulex�H$cl�I ligandJH/ S. W�"��,��*A._ mon \Z�$eQ�hrhesus macaque , Mamu-A1*00� �$or�c� )KIR3DL05u!staס by cer� simi %@8deficiency viru!9,SIV ) peptid%zbu�tDoth�.�,w�Giga�?� func��a!�plN � � i� ��hy��! wub�0by � �1c�ty! I$ (�+1�]�0. Twenty-eigh� 75�t�res {cytoly�#�K�rim�%�B�incluEthreeM��( CD8+ TES epi�2U���1� l-tetramerUlto ��*ubstitEs�r C-te0l pos�*�1ge� hibiE_5�i dis]{$.��)alxngB� ��]7~ ]2 f���y�=�also cor�Honda� -irR�yM�7In k mix��=: bY:(of.> �;-�!�upEzR�Co6�*A� ��|of6usaTvi��.hs��!E�-�,e repq�� ��ly��e�).:8+ CD4+ lymphocy�co-cul!<$iQ��b%l2"-18 s���dem aq2at �5V"( ia�".-S]Eby�SA�.�2��-p���li�.��-aN} by(Vte�� y ev] NK�I�. B��tu� ���recogn A��# in.e��a�prior�oAeP{, nb���o �n &�&inn!r defe�3a�I]�( !� �s.�te)u�2�� health����*I�t ,M��A��$>���"!=�r�)���)/i����J�!Xe�{. W�'a$1e��ar 5�-U�!����� �E]is�6fuA�y st75��*se�ively�s!�s��S���� aQ"p^ �-v motif I�α1-dom� [1–(I:�&ly�gQ-5�o�(�F� k.�)R� b! urfa;/6U.*�8w�s�t&� � pertur�&,%��ance Wa�ulL.�3� ��he hume?�Ju Hu -1 Nef�D [%�'� M�Uis lost ���i"�  da$nU+a"`0�2�olyq �(� inAQ@HLA"� �7Ufl�W�0of�-�5a��[7�%t(a�ll4 outc7$ �/��i �$�at�MA�I hegtis C(� HC� [13l)r papilloma� HP $�$cytomegalo!CM !��-H)HI�,U�ng% �0�$, -�� alle� of!O3DL1/S�&in��bino�HLA-Bw44":�eu�&at"�  8-+ 5 -80I�*A�assocmYdelay3�$e�!to AIDS�gI!e�" of!Xa�&.ut��:��� Z bulkq�s [8 , �$16K _eA� ARS � ,Hnng)BS1��"! AJin �2�]�.&6�[17A.a'�S1+ L1*�p=Eexp5du�IY�i:sindivi���-KIRQ3��(V'� exert���s�o�A�r=��" � �&Rsm:6KIR2DL2y t� �"r�/��to�=���KIR [16F� ree-d�;alwu�= �.V��e)=�4!t� ��& act ��B��.D���6*� �d�of6] v1 –2��� (in.@& A;Z &� �isruptJ���[2�*2e2�a�#sX �A�re��oir �� *� (.�5fB�.&v*%� help85�)=9��t�Z��� �*E��7 (an opportun�� e escap�By acquie\="� Eenh�M.�ptoB�, �p �-:!/eli{ ��%'��"@ by9. Indeg�?*�@e�cca%�Z*::���A�ycm��mmX6^*� Vb4 "� �pB=�1q �JFJ[2r3T!�"J%9*i�If?�ed �J2N��FcA75y�.�� �+ghaff�4yEI6��hed� �FE��L0.l{ 3�^{� re "��br�e�d"o��:�9 �. More:�J��impai�a(!CE|�5�!�.�in.  + , �6- ,2�%� �A� t�H ����m�8� �� *e<� possl%8�3҉B��ef�=Q���HC"� ��J%b�1�� F�. 6�6�.�S ,l�E�0�5A9�R,��OQ� e�9!G�&� �Jhm5#6T � ytotoxic%��".m �3E�* � :��,phei bl�(mononuclear � PBMC�byG"�D%^γ-ir9� K5624+(e9 . mbIL21 G[28� sor�"�2o� 5~- 9K,�^Gag GY9=�qJ6�t^k(-765!}��a.j.# ,N;erB� �E�u ( TAM/-s t 729�"�1--ICP47�)am.�",$2� . Becauseo�e�A�lo]&5�M�#AS�"m)�end iEticulum�@}�&�e�E�?7$D3ot loadY� deri�F�i�!u�4&^'d!M�4����rapidl2/U&F�� mbran` 33KuIm�L .TN�?�� empt7>d���1�ex ��2z-w�oA"�Mס�b�s�eqai�.!�a�� .$ steady-st��95� .�-�Z %�Ix� �ixVofEfR �X�ma� N3!�AdF�%��t*� q�da�71-79e�,�$159-167 YY!�0Env788-795 RY�(Vif89-97 IW 60-768 S1AT4Nef169-177 KL91���T� �;.6�-�f��edy�6�ii�1U$ach!^M� a�exD� ��tr�2z'�D�).��Z�G�F%K-D!Env-A�by!L9G-@or!?%8*A 1R-%� same�a�� �*eA �A��rep�/�'�\^e�frG" anim� �B�nd[�A��$�9c> .3�+<al�H= �s&uduH.g�m�mv2�`im%�m� ��%>*a�t>� =;� ublished"��Y�%@ �V F!3FVi1�!�\q�") �!�approA�!�u��c�,�mac23}o�"p2l �(}�[31�As!��5,~�� L.����0V�i�(&Fig�4nd 55no� 1��I ( S2 R.28�A.� s ificuH��v Ij�@ . Or�%ePF� to4 !ALj� ��m�� u%��>=� {'Rv kno�Fbpe&F� SIV-�"'M Not?M�-�%��U�j� ���'(� Ո�@Amd; purpl�/,�ong*{Re�4�!.� �ir�n�)�5� 2u at a"�den-B'J�t�'Z >���C�Dace;e��Y����%�6IF�"a=i�-������iK �$E%H��arinof1�26�2!�,% ��} a)he2 %U;rl&J7Ֆ�� �:X (( S3A–S3D�d�5-�´3EWH W.�sd@a�5�w�#6fN�I�A �� 2� alan$A!aryptopA�<2r$H 8C�!(K L8�,B  telyWKbroh&2��� �A%f3��H����ob� M�5�E�tyros �p�B�a�(is� ( S4-�,B@M!8Yz3 (+y aro�Hc s4"ch92��e�3 ��ic�"Qou2B�Y�|siXec9 �Ta(��%us ��&� � acem`�rgC �](�R%�fO�ҎA;�N�% wild-YHM���^��Ana�+��zY> �!�j7c��oe�!��>.�M�CI�D}.S>�'q-&�SCI���!aE!�G6I�G6�eK&Z�O!let�+I7 #los�}9R� ������]M�E�j�yto���Y�ao.ine3DZqBeKenU/�#5)Ah�h���1L ^-�V-1Q�^=-�E�3F%�A.� ��R���ifFt*| %-^�gf�.�6I8 Y8 R%�N�Yet nei2uTn��53 a4h�� E��K�a&�&an�T:� ���-0:B!�, � le a[4�G62�8suf�,tx )�Rt)A�o��  ��2"�!5Bf�8E9 (� F8A W9Y )!ulm�* .D�BO�� 3G]3NA,*�� at�G�YlsoA�s�t�* nver$ 2{p�+S ,�adbW�W"�s�7al E�@��4� %C&�1d"�N[�he[egrba"bys�ver"�9�A~a��i���y� LILR�_�*!e�.<&Df*� β2-�J03Y6e�8��HC6^1> [3iM34��7*791Y-�su%���VC2�� �}���)%�i�!.B� "~` mirr4I�Sn���. JusRcG�� Y ���s.?b�2Qx�(���  �. � do"5s��( shifn]�15btoie�Lve��0�/HA%��|)bO��E�.�%�  �e"� � m��p�Vy# �j5.iH.� �w1W�~�c�5 B� > 1Xv(sl�3ly_�(,a>8:$F� m�U!RY7W�Y�R8W15�)6V �->�x B�5PYRJ-2 �\m� �� �N)�-�T]@Zo �2� � &���^a�16)�-1�!�le�'� cer*Q��'��b*���!�� �B� 6\�&|6u�f.a �.h �1��;1�.4F�O �Gp4�BrEP)�!1B�o>-)cry�f�*5).OLEx��N��a�'�v�(s� �7� �B)��4Z�[3�VV�F�ur�C(��!�&��"� B�%ZMR�(oj. C$9&d0:��d(�Pi[�"/ )0%L1�2�:� 1Y��methyl�=z���ɡ�b�shouldNF�~I�5�.��)9L" un;ly�" ��Q�: 1��\s=�� longo!liXW6�of �.�\ probD*] e de��!�q�u 慓a���Ja�A�l%~ !qI� K3)1b�W-��ind�kra�!r"�6�pI�s�0)� e0-��@pockea3J�"�%x�P�M�-�,2&��te"�5 *�Q"st��J��"�6r�pulf bBS5 mode�(of�!G���>�.���a�eIi�#]fs 7TŖR-ԥtrude.j}iO5� Ht���]Y�6���ch�C:^�,�@�,A�i�e lack!'=-v!'U�>U0 �EY!\�rob� _2�u8I�.�*� ��&� f3�V? �t#i Z|/2H%)*��u�Rgead�� ^n),1 9)!���z�Bfp0�gi\�1.H.ysas�O� �al�+�/7a�<�U���do�d Bu�����"�0 �!�.v�.�.{=G� !h�L8W��;�n.�]m�\M-s�:tb&( S5A, g^�*sus�A"�+o�$. C.� 1���G�.H�"ag�A�us ���  �&�*P.�oB�r"�B2�n,���9� edi�q�-U ���.S5C Y�[25%W�OMd�*�_,2�1��.y!�A�i(p��:a�/*�){ *m:�JV1}�B� 6� 6�  JA� resh�Satm�h�*� :�j$"+"'�]:�*!�1.��Fi�;a fix�2bQ�B^.]QZaAS$. Half-max�%����'RA�achie�� �$1���A� .����6�6� B�w�=�AMn�F&:B�6Y�s%�)QA~s�-taneo6+m��rRuQ�� �A�.Br}D:ki�6 ��6ɀ"&5:��!ir��I� ��j�, �,��E%�� �6d1G.) -&:� B��5-�Rs&�� r(~-pk+ ��>1[ed!�fp�toF�)>�B�%%�� u��=7i H"�vF<rka � 224C�)�i�iY�#=>nB�i ���!�&ln3K"!�/��2*.�%�t5� �)ig* '�%r pea$Zp =�K37bN�3t-�;�'�(+1�H>+FX��qD�-of.ub�D=�-`B�}7F * �_"R 5d��QhNJq^�P.&y'"� %�<a�a~lI r� ,h �=IdI� ����F� E� 4-j�equival�!ۥ�>��"�@S.7(W+ W��y Q r6l�T�(%TK:�H-@]c34�r>c-����Q��a��F-^�{�� >H��0 eI�9�i�&� �J�e&�2��m!�F�5Ib�1&��A%e��� *� 2� �1�I . G"�ku&8ma&t>�Lco"x ~� ! .�=;A� l#oeB ,�A�(HCV&~?ssug�{��� r>.� ����plaR2!Aor�m���K�!�� ��e.�@�T[B.�:Qis[+�vwhe!�B�BEsS ^.��! 1�f�N~@�+� B sp�%abund�Qe�G�b&?<.2~5i�Eflu0C@=36 s [2�Dv32�iIA&�+"7 \!�C�D�[38–44Ig<zw0:�9o�?a�rdRa�aLQx):�E "{M R���s5Qɶ .Z;="\��:�cyNN��J�$�A  �# i��E�&5�Y::7tm�1 ���eɒe{�(.��P2" EtS 2�)*^AZeE,�H�a:a�duP!�pa�(.�/pN�%,�/�5w��"� �h ) �[�(����p6� 5��u��nJe�0� NRA�whelmi�.� ALE DzQ=��v�Wa&�=��.� 6�E2�Bk !D92 27�-� !�i:_-e$��U$�}J ��?B�ME��e[B*)9�46�Cdre�d�'YK��B���m"�M4B�Ie�<�7.s24"���A=!!r�zTeq�&6�i�T unuJlM  avidz">��" Dire?E\!�of unst�H�RuT"+� "�� .��6�=����[�6"-#i9S7��hK%�f�`�?,g��g[g��&�\�(upo�Jaa&$���*�"A�) v% ��[����8�y���DR�����Y]"�:ij�dAu�umt���D>� �P %�BsF�A�nI]t6" F�L�2�+�&�9:1� LA-�"-B��8!C�_�@m[B�L�7�A.� <.d,�����a6^�[42�$aq.A(��F �M�cFF 5�*H5y �^�8��!�� E�<.�Ai�">[M�s [?H�I]"��-c<�q���q�=��E6���T.-�Qׅ�>�A�AmensQ���..I:vaGef��%�c��F�B�.�G80S�6& aD]*iByvR' �GM2{ ��E~qngi;'"�'��Zm�&W yN+BU��!R ("g  7�1�or3.�!Sy)�-ay?*B0��5,B�rP+& *�&�0)2�" 6}"S!4:�>� m/UR�k2��!6� ?B"�6lX1�01G1�llyE� 912&� m�P�5��#V�#s�!~.INP�s��3.�#p &�PQ5&�"shortB�"1V*� 8�.w"�TF.20_"~� a�g"�j>mK�k�Cm~:J7� :�E�a,��D` >U���k &�b�!�5�#&Q@ ��"*���$=�2C �.� 5iK%��"p�i3tU%&�engag�5JIn��3,{ rupe'1Y-G� �NB� !�(satisfy “�tng� f”�oug�{q�m��>�@�H%��m�Jin%N�Y6aW:7Kab"�7���=1 �� a�l"�#�!�ᴡ���6���F��RAT� modpY&>yJ��&^glimp>Hr)�ly�~�1�}[XW�yw �d�F"�9: !��a�� .�As�y�5.X#]�R2�#- 5F9"*%_2� D��m�se�~ � 64WkL�A� n*N"of � 5|"&�$% �erF"V�"ex�XedxE&� 0l ]2! capa7N���"%=�B=2�Nan�T�l!�n&�Nh]:]-AA��& self�/ �{p"�}P�P��impaUa�-��c5M1�d2�\by��U�*Z�/2�a�fVwl- �2MC��"��"*^:NkCtoE��\"o�2�!�s1-F2�L�C ��Ii�0�$h u�u59e� E�!�in[��i-*�VddD‘antagonistic’�+$6Z;��m�� !�.i�"3�w*��to!�PZA�V 3 [2}4`AR� �i!O&r� .� b��eA 3�*Un�.)a2*�:w� AK�A�"�?J�U�=$[�YR">1&�u"in�&R!��Ab�+%�b "*s" B,e&� "�3.�.:�4b�P5m� ji�2�!�V2 �`*N�+�of�"W!�jF<�Uc^���5$ -G*�)-�fb4e/хjA{h�lctY\��>]�;f8E+aoc 3"0 6�c�%�1p�v9#�:�lc A�*8 a D0 !aNyo.cQ� , 2D }!gbe �6�Fva, an 3 #M f��_��)�+*�V2�u*�>79�4��RXraEI?��K�A�Cw3�]t٥�a�1+ B*57:, 3DL1�]!)�LWhijm�*v!rB�ceaA[nlCDtO�U��RM6adŏ�� ! avenuU Vgo :gz�&oH� �]"�AMQaE9�M�<��!E�!��\f AMN;`"�=AQsur ��J'�X6i`�?^��2>% B`n�}�# E��$͕3g Ns�&fa"bK]:\�A�erhaps .- inc�ce9p�urP�e@i��eig�M": :�� &� ��mk2�M��\ n�U�_E�e"�^�NMI�U�.l �[2KV"�"�tf��;(. -e�Cc�.�!�en�*��-"�+�6$UaW�5�)%i�*�E 4< inQ*nt2�i�_�# �| -$9-Z physiwhL�a *�8�A*'�mryFa�AY !x�3vJ��q�6��M�se�� iT�N�`�7ir",*�G� >�&o)��n!���(A"���ert�m(��on�: R"&4A��9-as"h��6�E`��Wh��c �/e.]E?^��n6�!%%�j a�*�5�E� �6��# ^>6j#��i*� "= A?1�P2�)9D{8o^m}i%Ia�=M�m~"�^Sd�3ew1�2�c��C�*� - ��  C1d!h� s [3>S})ZRG}o�k��&�^A�6�-�Z4� �H. +�>�[�# �*��� D1-D2�figure?s�5�[4o"4�!�*e�� �i y�!�m�y�s�*� k�_o~/wnr<�G+iVNef [U$�"�YA�y�*ub�!o! ?�-!oB����"".B$aF�K�l�n& �� mere� i�te�= E� �Qh*� yb� � �-K)�L.�hd.����6�2B��%?��.�-X be &�a.�*%:rE\eqg-!�!y� dequ�6�X���!Vtho��G>io-6h%phu5r `12-�-�*�Dpar)/R�"�!��&A!%" W2h� �ʭb�A�o�`:`*j ^)�+2r , � V� .5) es�  l.Tq� "Iq�be�^  o�mrf�A�36�[�p*� � �13"�V�U6b2vq elevY(�%�bQ���P6[48�p� ���� BHr\a 6��Bw4��/'>� loweb^�oad�d s N-r�*-5�w5�o��"� j���3+& " :�Iͥ���&�:�EQ� *e %Q�%IuuQ-*<",:���X|�Ia�*A2Zu���c!�A��)�6>� �t$%"^ ��! � .t��J�2ɻsf�-3���q��9�%H+ ze2y2�%�}� åv�( Macaca!�atta )"�������A�נde���door ABS fac�L� New Engl:"�A�Research����EPR=R5��A1dar ~iAs� � �3Ask ��AccX�of Lab�V��A�h C�1�AG Harvard M� �choolB+UseZ�mitte9 Ke*�!C-C� >_Area S˔!�CoRon S�1�� 04873�co� )%B�Lpr�p��&�V� Guu!+���N s [4 SteExZM ��� �+f!H(:&14 �P�!`6��en"7�s�0forag��`Hx&�<manipu��de���W���4a�lC� ad l��nd ���i��erc�0monkey� w tw�da��=f�E6C6atО�!8��nr weekEO ka�6Ua�&e7dveI��staff��!e� duT#Y[�=d�Q�minim�o�ed/e0ket��e HClAA.o�r&�a:Š'le&@Num,:��n�7 ���wYQ�$QCXIP retr�al �BӜisHo.�5�pVSV-G69�rGP2-293�!�sup ��=N&��?d��post-d- �6;q&ifu�ZDin Ultracel 50k fi� # tub05Millip)a�yi��(7a� �pseud�d MLV-b'�p��a�BVK �,�r�6��*O z"s[���Y��[S �I0s��J�-%(K 8R�x�PMAE%sa��s ["4r. re Pa\� �o!�%�2(D�! 3J�t 3ϡT�%��8r ,- ��p� dr�O� ,0 . 4 μg/mLHjom� ( I6/�"�C -CD4M�-LTRluc2kio �E�t ��.m<�m#-�!@:ECDd�pLNSX-�NFSY Z9��f��lu"g�-"1�dM? LTRA]�a�H6o�l m���BI�o��M�ʐ��01�*1415�12hyg1�a>`1�afA�=PE�A.�w( ( 5 × 106-�)I9*K;%�1 &7 ^�w V�w� voluK�40 mL�4NKEM: RPMI 164��2v��v1qd£FBS>�, glu��:�,f ociQ�voGen nd 50 UA�IL-k�NIH=�Re��ti�gra�v Divi(`�, NIAIDHaq�;�,e�DE Maur�RG[, HoffI�—La ��Inc . )r�Oni��5-��GhelQI�/sG��j����um��a5�R M�re-=�or �i�PDB 3JT���m{(T�9g%UVZ�swapaa"�jNrot��p�W���!�iqe��qlash sc��,�r����bo0�)rR@�UaN�Dunbr�a}l��[;�ae6F,�pr� ��of ;I�q6� reat�w� CD8-n*.; ConA-a�;IG����in�QFAV.(, HEPEJKaN�4R2��X4��VE����u[� �4�w2r-%,"Y#�N ng p27u ��i�-wB�� �[�8.>A ���-r� J� > �2!� �4 2*/*&�.2�!� 10 +.&ein dupwe5r-t a� B:1&� )l��U�%7M�9/1�5 50 uK>� f�yrresEy.� ti�L�w6Z 27 Ant�c C�UayF�dv�d���&Q�� ��.Acurvel*� ��Ũ*��AFr$�p۝m�Qf��K<e:�.�d6���by spt�� a�[�ѭ/~>*of&=of s�br0�(( Sigma-Ald��Ob7v�3E�5.kA�10~�G26e � -���5 x4 <5)!��� in�EE/ nn Q�a�8&x qL&L��AN:5 0BriteLite PluD Perkin Elף!�Czw�DMun5��. % RLU�� � aoH�y%—g2Z #2@o�vC." ) *��.H�B���"��mh�:��#�d_�A�a myria9: dyna2��t6Lstto+v. A&���Ye[�colon�Q!��J7�"E"to en`� ctu�t)$ "�0$�QE5flamma[ �� �+e hypo�$�!��DitG�%�bdep��r$re adep�=B�e���� ��1-�Gx%.�!a��G )Y�|-�6.[nS ��)%a�o-��>�Rc�u�g��e�Q d 3'�'-��ic�n���w&�� o�\"ysey|in� type�%Haemophiau�-za NTHN�%�zeclin�2%&�#"��oti��� ( OM:.��a,'-45 ����recm(9 effuB earAP��e}1!3!-n429�. C ��>re"��� M co�!өEe���#middlepA�id ��j�B�\�U e� dig�.�E�V�� �!21bmA�i��ju�'��� oVW� ( IB�t�=bpa�(\��<�]2!OMa��/<���V �}#>Y��^ at dst<�)Ye�,�2�"�0"�" ;%'1�͐*@ME�U_& 6� oB�,-te�a�O.imM%��FU*�^o\%��\RQg�)!j��!��&hG�s�a�s �GG���e��( i . �metN)��.�:�a� bU{���[;@ї)�r�br8B .o 8�E�r�b�3��ŀ�?�+n'�!'��ac�Asu��akzjJ���&�X��P�W�}�io!�,P3��C!� m�;s �IB�)+�8�t%X��-ԁ��+I A�% �uN�8cu �M@9t*)�ne+-erapeu�< �)qu�96 . No��� hemeJ�o�h�m�e�YY��:���� [���.�b9� a��ou�[�5.05��C58�b�MLT nas`�rynx [RGDurXaH��.)�����,iȩ&� s����,���aU�JىD1<�a�# ��jpbd\+!S�4 /��h-up[(M����' )�%childrF2�[ ��; [4]�2Furl?Ő,Jka�q^bjN{rv�7�^[E\90��ri"$opo���s *�+��m=��2ibiofilm 7+io�$<,��"�� a�u�a�~a���!j!�R�OM��inhab��d9s niche�B��rA�U.�,.,&�>ey) lung�� �i�rMΡ!Blanktos�CC�-��:�&�6 [���hlso�HS?ADi�'��I<uCj�!Y]��-hela�����>��bi��6aA�i� M tiss@�J�a hݴrQ %�����.^-par� 4re��n��l �^a>Nr��cR�/�� m��0��2BNq +16alifestyl�&�,�@uro?ic Escheaia ie�UPE<.;0�{7yŷ�5��[-ei�%s�bioŕš!�!���/�Yt[1�'Z��' IBC ����ritd �acute ���+At=�fcuDd�u6 ��%�-eM�po -!����aonrd�3 �NB  [ �"D >tuAeU�� A�� �;�� bladU�)4� �� �I� axJ��a0by)�!�� * ):lebsieX�d8�eus6J�M��m[1�N&�CHelicN� pylori7l�achK�AOV{cri_&�_ gastA!;TAo�(�Ar �ly&n a�� )��>THI)u�M�� chin� l�R"Brb� heme��' n*թ% "�GaլlOkA�6�Y��8� OM%�~s ��l.� U� # ��,�SK� JI��I� ��Jo��te.�"p new &:�se�J��$[�6n1��W�Rj�9)C!��5W��Y!!��[1���LLongipm� ��Yd�at}D-!�P��pulmoE�1D( COPo)z� �.ame)�j , dilU4�2�� eriou3"4SM� [f�S*'4>2ݣ� &f 9?*2) �%�Isa:pe9�:���.��&�Ÿ1 ry ph2f�'!H~� �i�n؎ãoD�� � isܡ�abo� es 3�S, 5’~�( cAMբj��!�F� a0ah"�OM*�S2�|�Y�kinP��%��d.�flEy0�S<c�!�Qq*�.D�*��s�B� ��ti me �6{ p:2:RaɫW �Aay�burde���� un5�C�1+>C� ��rZGin��!ŭ��=*i�6� 1lwQ21�+ F>oc�3d du�GQ � e!2AM.�t}�.�' Os��X o  . UsV� �?�� %6�� i��i�f^i>ea��&$!���.��m�-r�:�J0>����(b.��ari� ��a2U%N6y.��yt. �-�N^H�   �A; *� ex��, oxi�5v>�5�l� �a����N?[a]&v���F23EB�4�k�"�%�lw2� m~ewoF��kR"�� E��As:I�az|ach!�e�2=a�:TLh.?%�f�N:�&- ����لnge��inF~�p �5 �m�86-028NP��^!� D�@Ir��i# ( DI�"�uŀ�a����a � &:"I ���!�poo� �cry Ӆ���>a� Cf'��S($he “RM SE�Oe�'r"��in�� �6e<�ZK2�)�l&��re���01"/= until-�%Oa%>\$ed ( 39!>Z!�Hed�!eD D!Pf!�WjA�,��i��a 6–7Y��iod��Mbp�In B�v ��]e5:+v�%ML�(le beyond 1�/ M�A\)���of5�GE�� � ���G=`(�%Ig!le" �0LEasl��a�Br [GASP; [2nToO�&̀y �s%�E�!�����hen��wh����m�q�x� RM33Q�d125�%(Ca`32$a{h̀, ��],�t. Wit O!4re o ����n �> {*qBC6 �ki! 63�� "�#nco�a6' AMPJ A c�u �fAi��o thy (.� �� T�nS�aD21y&?N{ cc� aspv< aci%�a����<[)`nfie�<+�mrMwcA�mEzd>"p%A!r]$e>� !�U*q , b� "�7s 1�T1@83�8RMRM RM�z2�) }!�OI�N�� . No��-��KwI�Sier�7r�Awe���r�i��5%�;��ea>". Ab#s;=A�nI�N D21V5oA�@i�nE7"+A��&� �����-�vA�b�j M6x�. kal�!sE[%���� z`<:Ij e���"L!��9deeDrei�Sb=��� I�M� s�c� � sBS��#cZ�";AW>sm% �|ak6��i�N�Find � 9 �9wa n2�vPNo�*�����a�� (cP$����W�)ro_L�:�R 2*�me�DH��._�f&�.uW�sm&rannaFzZ��[erm&^G�Ye�"� Go�� � �j� �u�qgd"�T�F}V�!Gm� o��nD &�! ^A� E��&i�2�I�W�Y!l!q�dH�V9 ̥�DG@o� : � Aje�5%:1wh]��,�Ss /!4ributed to the�m phenotype in this series , whole genome sequencing was performed on the cultures from four different days . I b case`�e observed three mutations that were confirmed by Sanger �T( Fig 2C ) . The firstJ resulted� a chA @thymine to a guan at posi� 434(iccYisTgeneraUta premature stop codon leading ]trunc�`phA]8variable region, licAiNUx!tHll samples analyzed1�Q0 s consistA�%eh �Q�foriHA& [25]MerB�!0le nucleotideseconvert� alI�E�a/oB�217�rne^$hich encod� endoribol!%,%!5free�y?!��parallelm�-�a#,nt . AlthougItme!/ism+ cycl!�pviability is not understood ,}absenc%�adde}alc�s%oin eachVe exclu��contribu-y0GASP , suggeseX.V�E��4cal growth dur�s��ary-�. D  exponenti4, no ��a`in�of RM33%i86-028NP��U0 when�n), transiently� tric�kor�inuously�sed)5��Heither individually9$in competion ( S2�S3�@s�IW�2Ain long-�� c�� ,yF��,survives 10 ��?a�ha�J75( S4A��Fur�, Xout �eA�eA���strain�co-��DEN�0S4C �4D^I�pdirect9$on between^�ひAzB�, prior5�Ve. NTHI��!s$n ortholog:PEscherichia coli cpdA�6~� class III 3’ , 5’-cAMP phosphodiesterase)�degra�剦 +[26�NCMB< s ar�Dracteri��!| highlyA�r (active site9as�Pe motif D- ( X ) n-GC NH[E/D]HXH [27�T, @D ��!8d)�t!�1E�%caUEA�ob� aerogen� binds me�# at�.�A�a��� employaonst! a�6)( 3D )=0u� crys!� :7 �omaWs0 !�f 3D �o�( alig�"%{WD reveals a similar~ � topmy� 3A�q�;E�!I tpredic� � ervaQA>�wh� Asp21,���oM�coordin A� % . M"� ERA�o1�residu�a*� in�� , ma)uleYa disrup�Y�E]�m[A�;8 3B a43EER� ntroduu$Z� at�145�!1Be*Y would*�* of im. K ��� ���at�%mtwo C� � -�� domai����3F-�u 0we hypothesiza�at both�!�n� 5 ccurrW� !L��� �afi���B? �!k.%j!� $quantifiedm �T t� er�~a3 approachea'Pur 7recombin!Kprote9 4A�Jincub�e/�to~y%amount!ͅ|!�A-IccD21V �aa' �assay�tj�[29AlAs�� ,!�" a� st��(ly signific�(200 fold de&I.��EO!�as 3 ar��!�.0%W�i�4ViA� e on�9$AMP-dependF�oi!)in&W�refora�8cytoplasmic ext�� �Idb� p)%todevoid!�any)��. T en\ RcE pre�dɤ*� ly� cel�6n�F�u:�Das described above���F� ~�exhibi( n�.�j�-�&B�D arise� � �XI}o*� O I!��An�!?likelya{�e 4levV�/5 . P7 stu  demo�^e��s ?reg���� D0in Haemophilu;|d > ȁ�2 �d� ���L efficiency [30 , 31a�O�ata� �aViJ.�B�I�correlat�& d �-uptak ex (ous DNA . C>� revire�U��W%?�� ^T�),.y��4 R.�F�"^ M� .�_ea�-.*:�1r}ePa�� uish � %2�w� �:x�[valid%�heshn�w-h�AHhe� �ea��� wSe�ߡ�A�u� >a�u:M� �. AgainF>�0��5� rpsL�63A>Tt��-�EpWhileJ�)�:�ibq���[m�� elev� , s�%!� )wi�up!�s>[[30a�A�� Eo!mj�6��n2- I�CollelnE=FD%��s��gee�- � �&7!�A>�y�1���i��to�Z�M�h s bi }�ce�U�N�[�H&��q%�!�=��Zi�s&��j�ntro . WJ� i12)$�*!A_m�adept�coloniz�%Qeva�!C$host immunb sp� sM(�Yper/cDiagnosivOMA�!e[ o*�!cA���of midd�8ar fluid ( effu��Clearagof� yp `associe;��resol"0dis%Aini��v$g 7he�E�ɻalt�eAcours�� measur bU .���Qpre1 J el�OM . FI�i� weekinx �67 2�]e >P� ^j�burden��!��,��Bfitnes� d ki��s��j%ear� �%���"5�5B%�Irast ,";follow�>.9a}�t���number!8�A�c�� anim# _edI$� � ����AaaccentuE!1�R�W�n�����veʋ�ZDB�chronicU�� 9� !�R�� .�I�ro 2QOmajor� ofna�g Q���ca�1�R��&�<lQ�>�%4mucosal tissue��'� ellu'biofilmiehar� ��� @upon sac�(ce ( Day 17E� DespYw.� ��m�ear�%a�:yL5 ) ��Uedu� � biomX�a�JS�m�2e��7 )�kmK Hom�a�6�)YeHs�>�s&a]%��J�e��� � �^li�G,Vjs � :%e.X� [32S e�na�^!��Q��40%!4J�! �ha�� U1!no::})�l Nge)�-3� 6h�14^�%�� qp"3"2XA�6��  o�?��A�!". Em�5b[2X5�Drek n*$ Jx�!r-J6�. Takog��, 9 !�JO-�7qM��_t&N V���ia�u�in2��Iced �$. Remarkabj 86r��bgia.# �JTi� , yetA�U��-I=!�� ��� ��vN���b���bu 5Ht cato��6D���.A� , un��-�Y�#2�N ���6�5:A�microev*{ 5i�$H ��N� !! sub5or Anty�J~�at�� isnal-into ep= l �� t��Ltra$�&ae�,pathways [1173�&'"_aS�eQ have�I3�biopsy"�#� hildren)�OM [34]po�#�o{�Zof�!l�nt| NTHI2�$�D;. ��tre� � un��tepweD%�YzW-�s �in_ u&Yof IBC$�d chin! la.�B�[�Giv��!��2aro��aS!�Rr".� ��q#-\Ue,�xi%t!�5D:�{�9�R�d^ �fi.� .)� visuUġ@nH&�s�ntisera�! ed aBsm ou� membran�oGgrn�$�/tov�A�G!�)%m( blueJ-in�$d�ucociti E�!kinRi� �"v�#�_ 5B% Uy)6readi����surfac�(ain� 7^)out��ng�surrou$%�use�l�&�A+6�. Spec�a�.(tibody labeR&A"� � s�sham-tre� �I�� thro�&Q2šlB/eyA�ݬ prim&AN� 6% �-c%�"(ilMA&�!ell*� as ec#nc �3D Sgr view!r�ATs�!��opPY� ��o91�"��`}�r� "sOMm�&N��MWtA�s��+�[6!  7�4��28�#A�cePA�Numer� [Q�5Din=�!�? 29 !EuasC 7'�}Z�R!�(on O��reE��atec4nz:;��)�A-�ICWs*D ?& �:@M�ou_ e]+� eval�. I���n�%fH6-gA!z! �M6s�1+�+he5�.�E)~iv*"��& M�neA��5a! (I��2��Fz ��sd4 V�#o�.� silic�"mp7Q,63��i��)de>.�GenbankA�b��,)�cc8m � ed�,��!�k�!o�! /"nsu�qS5C),�~.n��� .#FIfam�s het�%a�� ve!!���=exa�$_ v�+nM�in)8"� iso� "�"��6H����!5Fti�/is�a��k*$In Lyr�, know�Husekeep! 9!V(5&/)T� 2mqd�$W&�ofIs�+se�sA�.�� `!n$ �v��abolish �F�e/!z��290invE&Q- nzym*�" EF�1in '%1�A�-�2� "� � >I�� z�i1"Nm%= . It.possi� % :j ��#�u�* a�yj=z���� |F��AK/ ires��) % ��� order!�*� �LQoqten pai�� �%w��m@�!� *�"� ( MEaHDnasopharynx ( NP )!U &^ EF�ue�1'd�<E3 a�wo���2�� �(ge+.g. O"�1!> �) � S, � 1521�z NP ,�x0g� ffA�e3[at.�ly��2Bz+�tie=�7�7I � h �,)�y�acq!�d s2-!�mr  v+M�EF�canQC�*.�nd)�t Ccon�re�]FS., osY �nv�.ments]dr!:6+e�h35n *� 1�� } �` se uniquei�b,Bg. * d�%�)lifesty�3y*�+bey4V ensalism��!X.�!��%)},atnow��F2:�:�4"�, )"��>�*�).��r&>(in UPEC , PY�(Klebsie�.Hefb [194In���*s*"c!&PN)�!6ka3 , bu�s�-d�$B�a9' e� lysosomal�"������#ly.\A"�IB.� 0ul-,�6"B�"H�",� !�pr�0j i�%'(let� � !e*� 6�Bv� >8 �us far ,�-�Df �-atMDdEEath��M!}|4a��!�our"��I cA���a%�M�Lr�rBy P �,2Si|�1�9ZM�A��a#��oOM�-rmz5. insighA��6n' ��9��nic��(V�tonz%9e�S ,r�exnf�leQ �tibiotic� as w�;a�^�injV��LB"![1�9iٹ�!�6���Q�s vto"A�at��!%=OA2e [16a� ; 2!1j���LY~r����)�M� shif��Uf�*!$a focus[�'�#reinoc? to��+� .2 bladZ 4 rvoi��l impl���{ ��ng �alty,��d.n-� W%�at�A��ion [38!w�,Ba�7*!Ez  digm�|%�0<a�F�!�!e, i E/�A!c!6��]l�q�a��QɂiaQi��'�Ig*�9�.�S�&%��asp��1�57�6� A6v;OM_� visits�s3=ngi3+n�3udy [4�&me�!�sam��(t�s *D * COPD�D1% �%:m,�,��/od��neg͵ [21 such�[.� ��Œa�> ltip!<��"^ s new:�Q���I�y�. P��<1�l=�so �! ocha���5��4(!=stressor���* mong�^�7N�[41–46a��H2p��8xFaa%� z dra� ���.\81�Y���=-�6Figs 1%@2�I :^�\ ��� =z�(�)����)6�*v.�pf%2�a&;to0'c�$��in)B��avail�="Sa. .J"� � �-is��6I�vivbr6eh^1|�orm7-xdFJ a�%ms#�'�Tof@e�;�}k�ofU�"�& 1e � ew�Ap�4ve�A=on#n" ɜ� =7�eW ia�!�lexo�U� .�s�A��#J(yC�-�>M �6� ��lAgo!i./�/ ll d0�T5)l facta��/� ?"�ESMN1tw�d"3-�a�.Z:���ccZ�@!J�"Z :�0V5w� he7od��>� 2�a!2 !a_moleculA�� #}p1s"�1ic ��[j-!Tw %�^bC�9�6e��A� >F���Abe�1[(4D;gYB��.uti�*�/�A�horizo�4ge�D��� ,#4i� or�qa�*ay�lource [4H 4H U�*R(�; �l%O%yp6 ]Fup�1)E%��eVm!�i������i\� !fE410–15?SA62 n up�eI�$corpoR"g ac� �,e.m��B"F i�3�= d [48–5 3�� link"�&՟AA�M�=�N2�%�K���q���duc�*.Tn2�[5i More� ,Q-L / sign�*catStr%*\-�ol��m%)DY=�"�adeny��>t%!F��8.�)recep�#l i�CR�[5r54aI�}�A�!� cano(/:��G�=�?(-N c).�,aValq�ory F :S )�"uses Sx�8��)�Y!4&�5[55AA�=EreA!�lapUPCR�!6 S&� ^[@�!2�s�>ng)��a� tatu�#C6�AJ .9 $luenzae [5� "Dwe�vD"t6A� tool!�"�.�!mpAB ��� " %�<�FK��ny�_m!ijA%�oa1p�*��&% i��x9luc�4�6�&> � �tbli�n�rol�6.�d�7ope�&�2z��D&o.b(mxA~9 5��@.D � �Ci !�.u �El -B�AoV-.] ��E""�F��a�/�"41P6��I�%GMC�b:�1i �d�!� -med�d�r�#� �p [6�86���� hQ�app~2.`.9�m� *N b6�tgMof"� �u�Ag�is3:)���targe�e3 ��v�3�H ,.� '�S�1�R� ine�ce.i�-Gh q�a�-4pRGl�2Aa�e� �ofM s%e<�P(o�M�)3 asw*un*yproL���!::wX>�&!����"�U.�*.� I� }s��#Y! <�!F� �i%#H� �be libe�C standard �-5 techQs!� � *�is�`c-�%f�6h�J.^sh�be=��h� A�d* Xnt%R" 4μ�l)*��F: urz@M��8Lestimt magnp�N6�%[�\� KO�Y�*�7�enk$U��Lle" &@3aBar :�.x.�[6� RJ�F�# �E��B���ޥ�! [6V+Fu�%Am#0L H�%7�!M�Z*�.>�9!�ɓ%4� UE>� ��,���:�Z`L�oY��&*&#��A�di^!on�ށ�DveQ�-��*�.�I�� �U6�9F�Perhap�e�� ���=a*�%:�6bI�at"K%Z{Fv� ��1�ic)F%�:�$& �>!)2- of�D�, dyna �Sfon�S:�06�.��L�]7b�l(�m�A,6D.. s��_E�-MOMLz)�o9o�una4/��J� 6����6H.quiesc�)��a; " �r+t��qT�� 6lat�6���%�&novel du;q!�D apeu&EF|o:�pBp o!�sV�&�B>����n6a� @-�.g J�?Arp2/� -vacu� x25al� �a�D � = B3/s�o�/adjuncŢrapy [6*F�/R:�� 6(f�� sR�!��Z&w � �2ch!�con�`"�#sinusi pneumonia@ndM' cerbe�EQC�cy%� fibrS=[65 , 6N �_ A"�@1  mi�: ly p�Gg� >p#��^"�,wextVv!ch.`N� !��lH�<hum1OvR=dia [12�7–7�.�+w�J7$viaZ/?�"�TQay 33��&0? <.g5. DIS%!,n RPMI 1640-� @ u��Xas"�Qmo�H'/ reatA��bP 6% Chelex 100 ( Sigm!�S,ULou%�MOo% vern�� stinJt8m8Gdivalsi�VA�s��� pH��,4% fi�>Vx a 0 . 22 � GPEx�s PLUSt �0 6&illip��, B�.ric�M�/!lt4�l��d$07 mM CaCl!� MgSO � 2 mg haem� hlor% mL-15%AldGQ ,J-,��e��\0%�-��)e5�r2�Cw �[!��� dp �9}e�K etho^Jveloped�.[7-�XQA�QP�j�X�n4 laaF�Qcasset�GnA� ��#tinomycH i c+E FU(PeM Neis�[,a gonorrhoea�<"NBU�o ��$r�xf ly 1kbAK8 flanVq�sd(clo�60pGEM-T Easy (�$megE*adi- , WIA }HE!���! �\� j �cc-�QuikChs& ( Agie,�[ta�RrjCA�!�(O�PY�"�RSapI di Xo�B>z2�Δicc::!�--E� ��MIVR A![7� Afk,MoL,),4 5� m=%ic-�)�*i choc - agarJk(1000 μg/mL��I1. L*7\Uc!2]Csc�4A%�}!vZ6�pMp�!Q�A�!�ReA��)�Fw�2cx. A�j% lisIP5V% u~�Z3�i�F� DS� S2 T��X�E�ach�A\� �����"� cc�>�j@kSM� [ coho�[$"�7 cei�)e@9r"2l1�$�A���X&q :� nd�|d^2n�I� e��,%"*����elo engine-4Q�%e;�arr�Wt�$� i�z�0r1[ [K�'�M[7�K8%#y_��AY��L.�d"�cS*�-/ �!��)"�g�Q���W�O�@Z5-�-b>i&� �A�p�e�dojR6];$.)&`:am�� 9�=�� ��P�>3��eh�Ca.�5)1Eew\,)-%�dA�un 1�#d-&.A�0 �\ kind? q� by D]%8Lauren Bakeletz �H"i�%I"�.E�!*se�?�"�.$.�+�.@s�#p 3� ve 2l . U!N�-lp&��e t��V�8� fil��?��J1G&(�8e� pyp"�!Y�+.W�QST329�a� �clo�A�a 3� le5�!�as ST165�<. S��]aly�I� J*��65*W/ r/�^�/= *��-�z1!st� &Qa� �F?� Iroutine� a����)͸,5���3A��.(( Becton Di@"�Sparkc MWDMar}51�rQ F �>�2A or 2��of kana��Al"�`!�at 37°C!W5% COd unl*�a��w�R6,liq3K ,�P) in BHIN����#ADES.he�cs>= For .eys�=Cin def0$�0 b (� )� ME&br *p(�� [74]b�)�1�a� tex{ �e� � �$��x,F�]BL2� DE3 )-9(� rmo F�5r S#S�Uc#&� 6mid vAjr>q L bruXF25Uampic� �$S�J?�&ST�����K��� a��[by�>ypaK. Brief�e�ho*7g�]( adkF0(atpG , frdBucK , md� pgi�rec� �PCR�lW���as ���Ab e�Ke:�>�-an ST%�>i�e+#.� �D�7�saI�\pubmlsAorg/h� zae/ɿ:n�:���=p� � �=�H eBURST�Nbur� �neteGE&�3�G"1b)�*�: "�B&~W�09�" ?i�&�o�'I"hdT!on� � susp�>e�che "X��:c�Xf�0�CoA OD490��u � dilu�10�<to�MmL�HndO tom gl?KubeYni!d �i-wac9&��Qla}}�A�� m Z��G!��a�pfBl. F"�24a��>�[��,�ЍX2n637�H�A�R5!)�6���hs� Q5"!&|.>�&�\���d�1%Dno fresh1Y�/d%J very9>Vvortexwt 300 rp&2�oL6. Cul6-<� M1! ��dJAsss�x5F%� �yvvC�mag� �BP�� Q4�OdA1*�K>U��xats���&�l^�(��on�3�!K& }u"9&�9AM �j�j�*]�"%f�b� !1��!�� = ologSd�AvEe� AR S �) W'WE�At��%mpoioco�c%�x.�-��poo� !�frozea�E�%�ag�* To pE`y!����8 loop full!��5q3x Ustock��PBF�bi(7u con ���� �,�-A�na?�!��s<)}agAHtra Puregene Yeast/+h . Kit ( QIAGEN , Germantow� �  A�libra�p�"&_�&� y�=end�jbp��mistryA�!$MiSeq%�A��g B/!|� � flow%d ( Illuu� Diego ,�N&)n�n�;�"�� Chur#�'4n�s-�ek(��4p ��!Da��-�o!� BamHfq3�n��Jq1!%>Jlat qals�3�&"#w&e�-*�iHis-ta� �%� �".�+c��)7�"�c�w.^ in pET15bJ� ��"��to&-0� i�� "�at.a63�U5� �=�n�-)by.dB%s��b%Z� 1�r ��( r.16A � in �} �%�shaP�&� . jt6G�M-*�h�9, IPTGv{!8$�  fi*n�r�Gof 1mM�>yZp i^�s62 four�.&�5�lF&:\by �ifu<�zt S5000xg[15�#u� �*2D�buf�5 ( 50q!NaH2POT@�mM NaCl� H 8�3I�ly�*b� TGssage��a� -� �J� 2T$o psi;�GShot M�&,}g� �D s Lt� $, Kennesawn �+nac+�j`!�r�"� F16205� rICC& (on High Aff�y Ni-Ch�fd Res�&" ��manufa�q r’>oty (� DScript , Piscatawa4NJ- �E�"2[��9�VCo�] ie P�i4( Bradford ) A'm Reag�#rSts#eXv�< 4–tPMini-PROTEAN TGX PrecGe�Bio-Ra�Her�8��I silv_ �"MPi  S S� ,��^�al2(�`u�_> �# sBHI� V 18�: lE���j'the�;re�v1ou���bmM HEPESiZ&q%�X�XI�F2F�= clarI supernae�&al1�6�)���>�ŐlibY�)U4�i�w� 2 n�y>��g � @f 4OL . S7 &���3�kt room � errk�6en��μL��4�� r����.#&a" n!�o1vo,  :.YB,tHa Synergy Hybrid H1�]�<(�Tek�'0inooski , VT;�a�u2_�(A%a=*1C �0gK ���Tyb&1krepdG1\U��e�4�Otri ' ap�,a:rk�!^�]w one–tai�Student��t �!��� PadPqs�eLa Jo�,"IAUr�sac�-�=v�2ysT6��� � @��.0@)�.&cq��� �a��oV[�Q~�ĩ���00m �%;5}�urn�!8��k6!���¦ERo �%"� � *�r���%z"`t&u� �!�+�+6�*e�i` b$ve sRNA–�9�m,12�lo2k a"rgeji�W"�=&035�( 3 .K LA�(x:�+"�+(a�*�+ ML&���, mpri>a��,nZ,% B��dn 6�+Nco.�+,�%�2�&�9�_�F��*�+�Uks�8�32""a� v�+6 � F��338� to�leS��,{w!NJH��R\+��:rc,�<o��%��adI�}&FCoCaiS6�.X5 ��!Y �n�!ar �)|+"va)~A��two����A�2��^� ��Q� ad�)AD�acc)s��Y+"�*Gu�0��!&C�!�Eof LabcDory |�*N%�al� tit� of Health-͵�aȅ� j2�;n 8�xl ^6� Committeef 3Re�< �w�Chi�W�BHo�LaA Welf� Assu�*NI A3544-01 $AR13-00026�l.h�7ced8&�"un� anesE)$ia ( xylaz�'!Lket�W�>�4����!eff�-mada�!im�}s$�./���~l�s&homeosta�(D1�[c-�S-���k&J��pl� c=�+"�?P.�$q""�'�S�\)�AI6R?MR:M9 Hepcidqt�6ke�g�H&?fN-T'�"G<sm��gge%2I)K�C.vr�fer‹�^A:a%loae1h�5s!;" W�A�#�Ei��(to Burkhold� pseu�lle� �7SghowE�1-e�eP � A�h}t!4 �l�/&-͛�"ai�7 0SL&�7B .>�X caus�O��UelioidoA3,1��.Ab��M+�?w!�A61�C)I���\�W.vMY=pr.�:. Uqp��!�d macr�[[%)J�� �.��kdownrIK�?��aDaigT��2<j�}. E"�{(7$of �Ij&�� by hQ�om�&)I�by�ic am#9um ci�e  %�+DA�.L�V z,m%�ngF��t�(���*<�&or1 ero_ re�Id=�"(". �$-a(�=.�>lower! �P-�$NADPH oxid/I, iNOr�7c�L �+G �/����?!`caspase-.I&p2Cwc*�y[a� a di�dhed!��I.]9,-e-�r�LE�� l�[�� �%CD # serus��e emia� I�Z vo a6�of�N�ta(IF�a�y?-֡|�)amm�Xn2� ��asE",�Q�2�s&T|?^� h*o&�1, nve �1�1�mK1_/�ai#i�A;!�.�4��,^60��_u�%u��i���[0ai teg�QB&aK � G�^�<{n�V�* iK&l ͬef�4or.G9!i�o��%��U� �-�.'e�n!�0c�5: H��=��.�O!�u� su>�%ŵ��s�Q)bPi��4drugs mi�Z�pwLQvhj>[?�i, �,a �KLol� !���"i! eok , bee��a pivs �G��,b Sq҉their mA�lia);B�kN%�<8 cofR��w+o� *@grouppm�M%uv"Gd fund�?�uA�g� ����c� p�M�UE5!^cr �M !��7 �F5 im�Y�8M{a!pJ#!ndA��Bs [�9M��� �nQTQ I�m�&�?ma n�5E).y}eyi<�)1%bP�go� F2e�t!zdam�?eryj#cy_ �Q or&\@u"�1 ��N6�xf*�(� Ig�8*Bh,�exi�#CD9� or�=oglobxO�?�.:apt!  CD16�)�Yrphyr�9M�A�I�)e�Fp�*Slc40%�i�*� �J� ?� � j�9!K�[j "�[� 0 E.LWx� sl%i�Je��,#F-p��pep�,{c �pataCAA�a�oG N �4]f.&,�sAU!�1,��H�� `![�r: Qvduode��e�I ���fs�Pl�M<%eaAe.�!��s �su�i2G���^%�efflux#)Wng�J��L� � a dropA�� M� (F� @63!$"�  *�-�( Hamp )A&V��d�&E�p!����e�i�V)�y9er- ,�Y s^/ILD!gIL-�,eco-�m_�gMum� iOv world-��groۇEsub�%;^maj�ndek:�E�South(2 A|Aenor� n Aumli�,Ita}tu� hab�R�mo�D soil��/wxr,i��!&�!�of�ofa. 1>.��a hug�pet�"�Kman"m��G2@Lbs!�� oL1$x��&'*�n&�e�Uha=6�Ui�?e�.F7!�4 ����r �2mm!c��a sa)!!AW�y�<�(et �I� [C[ Howe�&,i�a:��� m�mbw|��"u�Eݥ�s�Me�� q�e� B.��y;A�k9M�+�,ow�Uak" h�(d����vr��-�u�nQlIds�"[9�^�H�+l�KEa+9C dlg��ofF�[13�/\�1 ’s$�p��yI�a rod-U�dcc�{�"� �V1Ξ� mts� �a���"�pe�?r�@ risk�<<mi"�^ml[1 @n s�ˇ�)�k�jB�-chyd� ate-�C2 pf D lle�o�a� q capU1%��^���*y nd l� , enab�2�1�A�!�AZ-LA�@��[16Ae(O�� X W*�3�?���s�Z�[��i{ �P!��C )pyo3�Q&�h�r�m�D� g% �pH[1A�2E�#�!�6��9&� A)/� dc)��P, Kvitko et al . [23]�-� !��seA\.�r��n m.� ( mb���(( pch ) syn�e��-X 1�mcqu1b*"O/�|�g��hmu{em �A. Sur�!�Aa�$dr0 -M-�uC tely viruoMA� m�m%r!b�Q�E�E�Qe"LE�u /14�TSx t`s\dJS�R!U��a�tyJ��*�(�4A�6�F-�tenh�dI��Y�t� V7ia�K idioa��ulm.�!�I��0����Y�2�[2�-V�J7s*,fupC �0 .� �ZsB�R<�d�B -�� CO fav�?e est�shm�͔�[�����o? !Cn�l��i&��!���Q#Vj�,�]"���fMh9:s& )�.��o6� �a�'Y$f!.�)ҥ�s6\{��APXiJyf� �xB�A�'b�gA��_ircumwp�6�!�* -��!�iiI�4 @.#&-%JΒ� e&. bW#��x� agre�ieYrY4men�1��F�U#^U#�"��">U#4Landesamt für wirtschaf2LebensV#lsi� heit�H\ei Mecklenburg-Vorpommer�L4LALLF M-V; 722�3�<.-020/11- 8/14C57BL/6J�e �� *�A� Jack�;*u$( Bar H,� M�� , U�f�Gee���Y donex MICROMUN;+eifswal;20?yv#!�D�E�VN�$C9i2/Un�s��Mx�a�of Gre(. �?r53Kv��. M( femal��i2��E%�kepExfL/-to8!uq$�4aala"�%� (, safu � ���&Ff��a^� J�a�in E8 � �* Nr�Th�o nd [.� !��� `QA�yku ���LColumb̍M�(5% sheep bl� ( BD.s. �;(, Heidelber�^=� 7� "�F�.mF!�des�~&51��(in Dulbecco8 Z0 ate-r1��� �0D-PBS; Life T$. olog��$, Darmstada��e;�u�EIE�,r�"�'usheat-in�v�EBu,m -S24�c=�at 70�D%�/%4d- until!�f�)�%�Vt,2rL[��oneX ( ODa�t 650 n|��201!) ��]8b $Lennox LB �Lv#-E�M9U�1W� �0�SorEaZ� J�# ( FA�|�.μF�S[-*�YTaufkircX16�#o{ �5 mesy{sal�/DFO3@�1WACZ�:�-1' fluo6�et{ D1+sBQ��Bub�rf�<witzerlA�S c��spoڊvehiclA���bides�K5�e�*;14�6I_ oC���&]1FsA;dEfajj�hB0�� �de�DH/�8<ODA��<l�H+"�3at�JC[u�&�7"�(��*�1�Hs��" Mur!�h�ma� a1-6�( ACC 17疥�6��Leibnitz*�* DSMZ�7�E���cof�$roorgani%�C�+Cu�+7(Braunschwei6�.+-�\G6�MEM)�,4 . 5 g/l glX�AF�)` F q=10%F�fجcalf �( PAN��te.xA�ba ��&Uh� humi'/atmV�9x �� 95% �q!KR. Bmarrow" &= s�7 MM ))�g&��nd%'�V���J2��A#rg6IXđ.V5ht 'ak\tM$�P, �( 8 5 ^_5aCs/)a�He6`6,4F,Eosee�'in 48 Ep�dA&�&/ �4K�_1Ɖډ��m�A�V#Yedu#O�u#�$��e7 ��: sB�&dQ%&d�,6#of J!L ( MO�]�{�>�G�\ t*��7 ,-C�wa,(A�in*�T(!�:��g/ml;6�: 2�� ) -]�M(ife%v�[A i .'(  zero��s �;9 �֥j�MJ|��!�&�06�colonqo�%fa&CFUa&��M�AU�s�,�elu��l�?a,�$LB  ;t6Hm �� ��-d/$ >e#ŗ@�o"�l=�6���rZ#acJE( LDH�nge�(F*1<&JY�EÖ�40b�Ejy�6����(6�.A� �iΈala)6j RNA  A� qRT-+F�I�v:UD�(a�YIfaPa�HiveQ@�-8�icԩme�`)i�; Cycl@ oftw����H5A�h�,vA�"�WABaI�$e�\�Sb �on �real-e��ef �� ( ��u A� cros�  �%v^[c�vΔ���un�0#�c�3P2�2�0�I�n�aOyd"�.s�� non-�5/*Me RPLPfrib-%3� l�B P0 )9�to&*al�N@+ �b�l� ��in duŘ�3�(�~ �n���figa�l!Od *P���Ar�� DS-PAGEE�w��n� �#\Ev1��:�$Rabbi3ti-GAPDHaWbFr��e�AcI?Anו!��rC6 rJ�oB (; Enzox �Y�Lörra:+ ,2Q-/7AS# Sy��"�y{�ew Eng (Biolabs Gmb��D��(!� %@, 1386B&�E5BT 5%��/v ) BSUJ� 1vTween®N��K=�(S� Cruz�% 9�R��< 1x Roti®-BlockdA?hor� dish�}�&� Hqy�$j�FAa!� �Ig�GiFX,L VT)IF�l,O�d�%o�y1\I���  20�) 2� J% E��W�9o��lipa7� �9� ��>�"O �� ���w^ �ice-cold�. Fixi�!�b!�A� step.:�KPolyclo>$-�%��'j�F(idu!�A�b� mono omo[nB� 3015γ2beM [36]��(�rF�Co�=�At Cy3.�goV:�or�U  9Alexa F 488�- � IgG2'L:�%��Sl8OF"�W�4��ce� rosc�iEa BZ-900h ��Key7 , Neu-Ise|2B�� rS �m.�' roprqy�( :� ,�"�i��%BQ2 } 5�bW��m��.� � 4�F 120 x vNb�*� m�twi� Hank�B8d S�So� ) BSS;�ma*�*D�)a��258oLn-Y.t Fe2+� or PFGrA�S�_dia�j�aX^%( wC a"71A��,Ҷhen�� H!� peri"����2�rT�j�$dye Hoechs� "�)!l*��i h!1� ith !cG?he�*ce� e6� " �1 exc�%�waveleng�507X��Wf(:"32"AI>�6z`3�*Z`461`1u �~+E�X W=In Me Md@PRO!�e�cC� �EAW6��a!"*�WtD"\ Y�A�as./ ?%me�) un<cuni��r� /Kset�E �o!Zk�(*2�)O�,;�-A6�2�is ��9�i,A��Z�rs��"di�r�u)a"�t!o!�VD$+� _ �a�%�$;��eM�E.9u.�!AN+�/\#as&�'G��BD2?u� tolt&<#PD�( �'d8�7B*joR�( p�h��AC�P mg/k�p,P(8or*d�B ad�:���tra�k tone�_��eAb��B�.�(!�b�A\inu�Hn�&��. B`& BALF�K"�2O[& BAL.� pellS^J&R*$a� 0A�*|iq���`to Ash�=O��q���`i| CA9r�Q��&�=�3�/ 0terleukin-6 (�/�[76 12 1�4,$ y s<#��mm�� MCP6� "9e.γI FNγ�!"umW5e" 6,J'r alph[B TNFα ) )! �=�!��RCytome:/( Bead ArrayA�B�R�Ax�!�R�he MACS%J AUzer��nyi� b,ergisch GladF�8A �l^�R�Ss=my�t"� �5 &��@a� mercc&M+ELISA kV_Hy%e �utelsB�K~��t&��S: zte�v�e*�K-a� one-1ANOVA�Ia-�!I�Dunnet��t-hoc !��<:#�eUa],.�� ed�Aa�_noD "��b�Z���$ �&�]ABl�j�Ԟ��>-MDq Kaplan-MeD��$��Log-rp�,( Mantel-Cox���� \�. S#,*;i�A�se �} GM&FMM P  }e%<05b'�al7�g"��. �&r� ocu"�$6j$&!is&@2�'mo(za Eu~<.�1sa(�l�I')2J!� a���tr�\\8age��|!th�I�]�:g�.�:IstiR�p�\)l��vj �.*g"� �.5E %w}./��bY RM�a4e�-98P/%)]QIv '��� s�@e`�4�� "&N�:r W�3l-6GCFE�M\of6� :�G8u4 �TI4]0. b��i�)es�.�.[� "�!%�m�- =�,�H�2�,�(����R at}/t[�up�J ( �&ª�z�@o2� � #� 1B%h� B7�66J:��4=�A�.�a�>i%2�� a�v� o��&8/E\"yGl�-M��G�n*w;I�s >� � I9#c1be.� :�$��*G1:aML ��V \�4!�Őj2�; �-�xC�1*,6�g6B"�LŽ�at&� X 0�Ben�O 6��p\AH4���-�J�A~ =��.� ����mK%&� �eqT�Q0( heavya�z , Fth���oyˡ�n_ec�1so&vw� r�eZ> Fq !*��.`��<�""�e��E�7�B$=� 6��R�T�?"*:, G"�6s.�FA@%S2y>^: H5rj1�>r-�.m�N�>t-ځk�c,.*<���>*�?�=�7�fu&iF1E horm� 7 A� rols P.�.by" to���A�����>4��X�.�+u�2��ng�_#�n;W3oc\$to�#��F/Fpn��>�Ko�try}r>9-P>����a�sQ�aA(.EB g 2Ae�͔�"���XQ2�6����1B����=��a�j��'� f�śa�!$a��.b�Ldepa:B�e"�32}(e�Byb.e� 2�Si��h)� �a capa�H�%}�A`m�<�8 ��Z�O�F� V6� �h�03�� r�)\ �WIT.�,V�?�:er�Od �mKV�2T�@�<e dir��CL6�*oFi�9&d� ���in "�,!TF�,.*b �� HA��6A;� 5P��&a2z �ҳ ��r�]�FE�k4͸U&5H6�E& AiQne;#a a�B�5B:G P a)i=.�. Nexy�vQ�>o<�lran�a���-�in��;�"���d>�e�b � �vv��on.`I *�I,aK��_��.� stro9�ѷ��of�Q�ArZ� � ;���e�@6U�YQ�6|� $ &)T(���h.:&�σś�,����2� :j%�>�[^�,>zor%^�=su�tea eSO4; S2A�T d|A.i�5M��.}�:�7� B>�,[& s�6O1�5� ron-%� �nt-�f:� 9�� !��=��o6l�mby96s!�A!7Loa��*P �a��"��X�6k �q�8Z�B A a ��J�2S vsd�S�A�;Q!?e�J+ͽ invad! �&�86���b��J AC/Ec)��1R�.|n�~aJr6�,��l(t� �(s a�eBkI�a�B� s ��S23� FAC-a( ��� 2a}+sfj�">�.@ .U 9<�ui���Bor �"���n��UA�J�q_n <�6iwT0!E0F��|�2��ws<�A>S25bEU2:eޥ$z8͛ng!9a�=�!�6��� ,�=ilB V.m �NqCW3+"��w%n n as��"��A9��] �efe��2< Le ��R ��:yk2�GY�j��Ai��K of~ 3ee�)ADQ�4]b�jf<�E!_8 ���+t.&.I!�� death$ekq�=�u��eu.Hhiz�solic!�>#�NcfRp47pho]M NOXO�po��J!6�Y���,�� nduc��! ic�Ye Bc)�Y*MBa:}A�e�!�:�E� 4�>��w%EA� A�a�paӻe� by d& Z.1� nf9�&�&�M��� R+!��-β�L- )!L!a�t4��-A�I�G�B J�!B���RAB$ :��Z]U�s"�H�6�"E scav��g"�J�R)9�`4.Keei� n&,1��S" �1 @V9ns5;��ism" i�B&� b&4xA���LR2�p�U�_��&�3 ( NlrpM= �JAof�q�G��U��2*!AT"��2aG�UHA exerAQ*ory�);RwarCRB:0 �}}!�.� ���Vag�E09�05s��m7TA.��� ?S6\:?e�a�? mpani> # �|!! of!� optoO!� ��Qe%#�2.a��-�{*���\�e��>�!L�I104Fo\�Ev�:��AlB�>^aInB2FwB� 2��[=:y�!!t-Ia�Mba�"�<(�$,�*#=� >�5�j8s�6�TzX( *p<�0T;A\��t{ �Ls%�er_.�6p .w &� 6xE� sE\2+.�A!"�M�A�q 4am]?�� sligh��&g�:��*c���r.6{ ��>%&�� �Rxz"J�..Qrem�C d un���9:�!&>�B�x%�?2x A}�i�5�Ico`�" � 9�w ~��rU* G�b� >.FF�"!'* 5a1 U:��b�*v"5�N5 C)�A0:|!�hq"t&� I/"?]�S{oM�@l, AB6v2 �}�R�U�"+�E��� to%.��* � ��N!�2�%C"o� 3} log�&�QJ�M�^�&�"�e�~rM� �%�x#V6��!�pre_L3us�$oh] F7 ���.&>:?*n 4!�TU9�(6�` &�:ab��. Pos�!�&h^���of%�}, 3�rbD. 5E�]a)p�6�Q�u)�w�&\%ly-��EFO-NiR� ir��AK� �-��9�. &D�wa�"Oi͑fA�4 �����jJ�-�j��D>6Ke�c> E!�CFU/mlI8BQ ��FOr?�S�A0,~�LB�uma�uj��B��E�J�A; pronou�;m�( *og-to)%?> [&Gw�#!n+��f� �b�.P:c;9�) �d"(3AE�A)��6�0�,�+1β6 ndw_�6���9_��+&i %�L�_s"g ( S3B� .�|&� � "-��:;.����.6H <���$�%e� pf�:, �)Z)512 &� !: S3C �.*�a�m+1. 1u�$e�K��?�%"s.+R&a m*ek6�uɇ)A��D �!�Wp����"B @yto.a�*!�.V� G �Qg��* 0��"hiA�.dm�N>A�ecmodl7m@��6�hLRra�#!�ձ�Dp'gp&�a��ur12�6aw::����1�[ �N&�B>�.f�,x"E�.9�(%$}��n�B7'�+a���&e�*��!�u�B�A7}�#=)A�!�&��7-�*�"�> +� ic%m��7=B�;E�3�a: �er�FicW�q( p 1 >��!,(�F�-nB4� ����1'��\�-Ŧ�.� "4 e�I�A�AYB:�n�t8ion during in v�@ivo infection , we treated mice with FAC ( 5 mg/kg ) , DFO ( 100 �or vehicle by intraperitoneal inj cfollowed&pulmonar0�q�B . pseudomallei . As shown in S4A Fig , repe�$administra�of �resul�s were not statistically significant . Intracellular iron conce!O�Hin the liver ( S4B ! ) abll4serum hepcidin:A4D 4� unchanged!�hereas B �+�l!�c-Ded ( p<0 . 01; S4C ^`. Conversely , deficiency!>\by AI5�1j^�, it!=�but did%a � ferritin.'(!��A�TA� mentI��diEY hed total!X atic � cont/55Q1�, system.-LR�16=�5�8.g1�$. Our datae! that � 7are=8a�0ron supplemenA�onE�de1�& chelIy. FinE��%verifi! he impact!� eitha Nb or depriv Q�rvival:B�in oura?dpiratory melioidosis model�R�to��. only marg �enhana�@bacterial numbers|,bronchoalveoa�Llavage fluids ( BALF6w�,rgans compar!o�-2Vb8(E� 7B ))�ew�5leading�a hig!f4mortality rate!E!x-9ځ��� V,A ) . To fur%� char �ze ef���� in v�!�loaz%�Hexamined cytokine sA4�� both)�D����-�"� 4. We found sol�Fy�M�of IL-6]monocyteA� moat�Jt�W%_observA9a�recrui��0of neutrophilE��as deter)�Dby myeloperoxidase� PO )13, w���wly MQin�6� �D�Thaz$ight indicAw�con �s�:9�EDstores��lik!�Hto be a risk factor%Tthuމ�( susceptibiE�a֝ . Subsequ��studie< �d �Q�F ��A��or�� causah�r����E�V����d�2s�ZaF�E, lun���gspleen-p8�W!�associ�w� 6�improA4s�N}�8i�BJ�:E, ixI�yaiY�attenu�I 8I� The Amc>�I��B�inE$-deple��� _II�lu� ,� 1��uggest)�a Y-���� apy Q�,fluence clin�  disea3. �maja�T eg�maca� agesA� limi�lavailaY� c� pathogenA�,volves stimu�\of +E�(export toge�)�1u�of )im)(. However ,� � qy demon �s)A�facul��v�-��umJ�s able�evadeJs mune� ense lga���od��homeosta��in mur�K.^. Own�@vious work revealy���- host%D��Burkhold�ׁ� uces!V.� O� which i5�e�degrad�f hem!T oduc�COaie�a i�o �� appearE+be ben al fo- Jtaly� [32]�mong var% me�c isms%뵏als�RnE(mp� !�Q|%� nsur�wsuf� t6�QX�  t_�Xy now �an upreg=�Dmt�Va d� A{me- transA�eA�5llo�;%kplasma�t$/or phagos� membrane�promot!|�$internaliz5� non-l!� in b6%� intoManeits� fromW|eocytosog � ,Fc!ucquire � X! � via �oaa4in [16–18] ,:� TfR1�.&� 8!&�. Simi� 9%s havAn en ma��4Lis� & ��ehib% g a clo� r� e!�.�0lifestyle [38A��#-!ic UgHFrancisella tulareni�it��sA?%�%3s�program�/ indu�ofQ E]ŕ%�a subs� i� p�NA#� ��e rpool [39!qPs�3@al parasites such�|HLeishmania donovani2 ToxoM�g�iF N�d��g=���[40 , 41!F��ch�ng� � -2 M��Sa6%`� ��resid�Y�a8 does� reI�%KorIa*?�� F"X[39�2%?q�f.�bZhas bA�describEX prim��s [43!Th�R��"d d0 nct �v p�rn� G)��B�10beA�i# o��)f type�]edha*%��76��Ǖ�. Apar�P"� E�uptakTwe"| � ide e�H B>���fe> %���Yrel�by down-�%aex+ vE�or��6A���T�� crip�N.rv� �"�=sBc�>accordbo�B" ���t���ir=��=s� e� ��to��e� in a TLR4I endńanner&k ngB@�D[37A�45A�H?,&�maiDp I�!h  [46a� l�)E)ly!�98sa?autoc �>M[44�W E*y>. -med�dd2on!�!�occ�AI in 1�e� �%�d� ."�becom��pp��tXat 24 .(� s Q���%W tArsY��tq-inde1�!�}��Lo) Jsa�?A�6< 0TLR2/TLR6 act�!�trigger�`trx de �X!B.�"� I,� � .�,%soutAKerA�5O� ��%�rapid&2�.�o��y�� a first-lN respo� to2� ccess��y�[47AbCoa�ry3>\� CL .:D!�S . e� ica� $ovar Typhi� um4a[2]5c�ge%[��!S"b .�)SDChlamydia psittaci��Legio�pneum"���. g�"5jZ~�F�!�&g a0 Myc� er��]6� nega�Mly�po�vm �?�mouse]4 pop_ ��9 may re� !�a�difnt basal�spn �in unm�ells [49!�����prs eљari� aN� ,�]I�G2!�3 , 50�BL favo hś*� &T ��<ag� �N ? �g����_��/��ű�� �s�rof� �B�$as heat-in�!�e+a�*B - �8��a���in:�vAjmicrob�Snv^beDs� �!rol�r LPSMo1�n$. Kvitko e�p . [23]��po��_B�is cap% of� ��v� %�qa� al� (te source m�� �� ;ed�t�as!��ly �8cenocepacia [51A��N�u(o� R*&� -�%ed}�s seemA�\ZS%�B xi��0 with� �"�7  [�?\ !�a7EorkY Ue&����2?h"�spread*!�2] &�.��>�ed��2� ar�he&u��%8���aA hypo!Ij*��"M s��gre�%r&Ftrox %{N� a�.t8%�V@ 53–56A�Thu����ai~!�>d-drive��%!6���1s impl}�)� ,�/�G"1 a���U\to< ga�%h*Itoa�mote F " %okmA�Q�ac6]>� growth/i+0 9ocuN�-ladenEepsl: A549� � �Wrw.-�"�����<U��a�&Q!� s>�a.!4sF�rep%����th2@>eoma � . Du��a�� �c..� ,b ��.��\>�,��2�: ll unknz!2|5&d%/2 m3 inBV<��� ���*�ޥAaR7a�6gf� ,�!��:u�loa�of2z�5���!��2R* esu6D1�lZ�"� �iv"�a ���s2��)��"or FeSO4a�U���6�6.�m�� inima�d� 6�h a2�H <�. whe��irectl] K l �u��!���vte�5�}�is nea � . S6P fun $, A6��2�of�V$stric!Z+6� ����G2�pn2O upon9E��"� 9�a�zc�A� >gx2SI�38� 5� :&�%lprolon$� overa#�:�6lk&�of lys�E�I �e !el� -���bicD!xB huma�TF� �-qcidal�P$Tagainst P . aeruginosa�$9he%ϡ�2�%[ to��* � al ax�%E�!� anti � tiv�!6P[60*inm fY .�##l"l �&)�� ��� apeu�$si� $they could" :��M� . Re��m�d�z�6>"� of45�� � *: P Z# id�o� �� E�!0A�ing9&��markeda6 mpai��B^r�s�� $in nut$&o�$rL!�R��U� �a2�&�Ao�6lun�� t"�s�2mى��yet clea3!xA�b!�*�f�0E��bolism�'i6��Hway8&� su*M 'exerts ��1��A(Aى�Q9. M=/(t%垕%Ei� �� r��:4�m B�e�&� %�to�f��nof re�4ve oxygen spec�Vve NFκB&\3� E�$proinflamm�&-\"�( e . g�;$@, iNOS , p47phox �#���d&V of.�%2Z)uM%r"���:<"q��Z�%�~�=�a uR5��(rG6�6�W� mly #�U>�� "�E1fI:Yi&obablyE�e�*� %��e"�6Z% � ~* *e�a&! to weakene'"6�i�or.�&a�2�5�a�establH "� �O%assump% ��bA!engthek'byi� t f+ngk%f�7 �>�%=�m�/I ��ti����!�:% inclu��.<$of free ra� l�:ng enzy'EP.)Q�O)q#LIL-1β ) , caspase-1y{pyropto�pA� death $�.�!�!��fd& Lcn2a� he NADPH &'5��%�j!"���e ibut� !�*�> �{A�%.�!�d o�( s [6O6 �-�I�' be+ pens�A�2  ..C57BL/6*^s"C !9!���[6�65�ni %/ea�a to k"aerobic%n !�per�B[6#.gls s(Y��Y�Me I�g� � 6u2m#5 , 66�(Lipocalin-2>r4C n esxa+�+onm�!:6sinnM�l��t bind)��)X 2� �i&6)�n`�i�A�� �} , E . col1Klebsi@ 1 niae�w@0carboxym�insi�1\%[69–7�e\�urP Fo I���*�byy)��.t" form�j�i�,Axch&�+)F�)VtoO%{o�&oryM"s�. ��qAinv�'[e=de�&f *�p)?nd��byv�% N.[7a�7e�I)tr(1 a-� coccg3'� , �6�Es--r*!3&8"���A.[7"e(� �� .rem�  elus\ !needs"� investi!on# *�+� onne~� basic ��disord�/qdiabe�mellituI rena*�) S�#\4"e�pr*�*>}%�os(thalassemia� 2%� C*�[227–3�:��� '"�/incid�.Z in Malaysw(children �.��629� �AIven"�(!�X y [2%�CoB�se6�M�=��." iWa�)ex$6 n�1�FAC��%��PlT�te�Ato"�e+&�eicEuD"|3oad��jo m� *�1��%a�a&�A��,. O� � h�+DFO&�., �2�"�outc!&>6*5a��/7b9 �bur'�2x "� ��itax�5on��2 '���%����� targe����G a ne�4er�approachQI.C�*e 8ext , Nifedipin^$a calc��(nel blockerF �$!� !�uI4�+zE issuk%6%�*F to2� 7�R �Yg32I�7 agonis�+�s �Jrecepw gX$ ( ERRγ )!�1�a%%t&�+"�8*a Q e�of NY�h�$=i�atT3s.;a betN&!� !��z[5�4� W-�s�s"� &�.!^e�M��$-Fpn-axis �  �� D�A� lifez �6LqQo a7[�S2�A��I�2�G 6r" � (pharmacologš2�:.cat{hl&_ (� �2(/eIme].(/E��traffick%:o� b�75�75�!6��$gene knock�%*���O.>���$,�!&�uJ1 ausei*�!���\2�efflux>�*�2�A�!%!�]A$20:� � IdOat�&��&� �Batc �4tt*:!=�3]�9�� More]� ��#�Q+usefu70A�&�1��^��F"�to�u�iS F�+Auma3u$ ro8��x .� &asirox�t=�2� *1)oe�=���v���3[6H "� k$ripronen��%^mov���l��-!:�!�ag6TC�+�&v' �7a Y[S&&6 wheZ !�s3�>�taT9� oBP�#nAadli<"�(�s)Rt�')>eC�m� r7"�9Esum�-A��� studTnM�J� ch�un� tan] dap��-5 S�G!n%~�&�0B\ ̱�aQ3- noveS@s+%��3 !�-� play�� so�0|0% r2"V�2"� m�6��: is ok!� wa� r fu�6� o ho��;m���8�1# ���Q:�$!B56.-orBI4�V ^�6�P0;s�]9ly�v"sh�ir bi��"�bA'll�Ave ato� �3on[Ye-� t&N�6/ C�ff2 �s�#,"?,A� olecdynamicsa:�BojB!�ten34iv�. H�A� � aMh$technique e;ed “�� , analysis”�aiP�;c �B� *isQl� i��parti �B� . Ba�'� ensem�of�#ucA���3�q�Z�rbitr16�qu�ty� f �q��B� ��@9* �if�maxg lA6r=�Zr �tyeuA1�9.cR-�a geome�,�&ctr�,a-N�KF'b any� vari� i�Y� ��.�!�1.��y)+I� Kdis��).l: stD) ihoo��*�7"�4�\�nN15 *�3e**gh&�U=. Two &�&%B�:meals�applied:m. �P�8�D)ʁnco&�%5G�ar2c�;�Nse� X mutuan&v K�)�s��y kin�(/3d/0cUDet��_Rs-�a�F���#*�OiB�!==gi R)erm�V���+�coo%: �5e�"�! llu1;df ..bio��e�&� \a polyalanine-helix , T4� qrp-cag �le�:e-~!Q. C�) )�&��bF��}Gs [� T� �.I nume;Epro�#�(&R,2 �Q ,E��.5?!��)ic)���a,�al��nsT �@recogW(on�)�i�� oA� �UAcGshiD0 , shA��ro�� 8of�:subun� ,"�]RՠlKD, loop!,��al unfol%�rsubtl� arr#*�Iv mino�" 8!1i!��U2� :�*� �;� M��28sXto���/'sF�a�����tBd� n's.qc�(-�6(ethod.�:��Velu$DF�Yhnu@!magne$re��3$( NMR ) [3�[4(X-ray crystA~ graphy [5��e�--�-F�c�[6]�je r*�<�)�[�*Cl ��")a aarY�( M$As"U@M� wid�/u/���&�2�Q�%�s [A��-of-the-�8���n{�~-��i��p(omRS  ( PC�B[9]–[1E�*mm�9 �o ext�EuJw<� ?evm�&Qn� 1�.�9!KOp� ! .3aB� �} penn� ,�� , � ve �A��%or�(ftLve�Dc: J. G� E3If Y� seeka }ω| ?s*$ ��F^�� � wordE�ha�5u� xpla�ari�E; Z�V � ��WY/�^ a5�.x(I��E�)er��)�YJS, twoM�&qU#qte�)Prs� +)F�g:�E�QtoAEC 7is un��!8energy landscapJwa(i�5llI�8)�asauj� �f( MCM�LI&uO, �!bA���of�;�d&p!h�!9 �%��lex��run� . A�3aaOn��6 } y wo�-biIR-val�n��refin��1.J physe�-re.ac_2�eE&fdev]�u"�-# "Q �'sF�,���6CBe mj^yI�2!di鵇&� �)�:p:%$B�1 %�is!a *^F��gh��at1AwVue�-we�edEc ( ewQkDE0AVM/qu��dd6(�U�2o0 ?(�?)�93 g�O7 �o8tw��a3M�e� , W T c�!deaP"�*+#d frame� D� �W!�a� ���cr�%r.6@ E-}"�sub�%!WE6�QA�i&�Mor MI%�d4>.fiteXif too�:}.pa��t(�aJ �p�. Z.����&�@ ross�YidI?)Ed%���-��Fmt}��(�A�N veni� �$Vm2�i�di��^ cA��l bui7��2��. 6b5)gA�)&��pp�N:X�A�,A9�&�b�u�K� BB��6[is va)ym,predic%�E�F2� B���.�M*m�!�tl&Z termN �: B�� !d%�<>�exact��trufa��m��a�]E.��}IdM�>9w)r , ma)$%�ٔ͡.�gE8J  mo�2bh�M2�li�;��D. U��'u,6�k[2��by6� ly sZQr �)e How�"G,s vec`#-�be!�Z�d ?��e "\� 5*?a�� }�*E���w :*b)choX#e��!M�lo��a?�1�����J s no2+�K� �@��%Be��%�$xS�I5]so� \Z2Eor"Le�Q1�thaAN�Wve��ed-*�)�7t�N�{st���M! m�be)�f IL�)e%���ed�T!j�MI �0�~���:#� C�B gu�:v�E�random� ����!Y� �ed*& ( eq�Uc):� !5��9TW�!�3~s H%i�th�5*|�� B, ( 13 )W"r| ,�0���i, alT-d��{Yal ( 3p� S 4 ) "� �< step�U!��5I&zk!& Eachommatri\& 8� � ity��ZI��A�paTo&��� t*poi�3re uniwa�[d(ee�a t sp? ���9�. ssi|3D�e�� angl" (EO �.�1 � =!#:?A.e����*on # ( upA�G1 5 T,T �!5dis�I>��<u00!�smoot��d �MIF�V�.�ipf�a�F}�a� st-squ!�&���/�#�de� ocMP2E%� �;2Xby Po�'sB�1��e� he b��.�M-�F� �2 "�fin*�Q�ti�nverge� II1e|o�X5�g seO>a�bint��>� ��GyJ�'I!�!p}� c�>?�fp�WM�xn�!:@ E�.�:a X()�}1E-A I<5*a�?af�4�{�,.V3a�ah�\F . LikewisA�N�a�:�2��1F*� �2D��$>���( 1aZ�E%QMCbi�3dth+ J6.*�t&��&u@re{GK~� Q(!L<absolute�� M�r� v5 �MI du#ay�. S�*���c� ���dem*>�ker�!d�ty�i&� u�5es�E� Fs21��i�e�)o�0(by Lockhart*�N�S�2DAce-A5[AAARA]3A-NH�cA�H PyM�>2` ��c*\#( T4L�eGZW#( LBP )/PXn�� i� bank� DB c�256L [27�N1USG [28��2]�e]�!�T�a~� "���$by Neidigh59( �$ 1L2Y [29]�as' a� �[ld��e& E�"}$��%��$Lr2�$!(=l�f plac +T7odecahedg boxAEndE��W882�F 8479 , 30�R'17581�lic�s�2N!�2`. All.p� ikr�%ut�;� `X hlor�,�J� �Y, , 150 mM soXI,!`ad~.to%K5 �%}d��A�%L�!%4-Q�!�,AMBER03 [30]!� ce f�9!TIP3P w- �&��' [�8Ion.]m]�SmX!"oR�`�Cag��d2�&>J� OPLS�-�2�[33i �46�[3;6�-� carrR }W<DGROMACS�6softw�![3�=[36�FE�#�'>p&�y6�UF �5ery� w!lp�+0le-mesh Ewald�! [37a�P_Short-�%,ul">;Z2Zer� �K �&�I$Lennard-Jo�_po�Za<;!�cu( f�(1 . 0 nm ( �m8 q�QG-�!1�~A�SETTLE^(] algorithm\u��~d o�0ng��A�� OM��-e� LINCS0_]ZR%b#hd:^�Slowa�<� of 2 fqItemper��e\{���s�kep� ns�!e@Dly� coupD�i��a2e bath [41]�300 K6�< surT0sbrbn>kof 1ba�th � �%��! p1�k��� �M_t% $a Nosé-Ho��rgat�IE��_� at �X4�(!t2W&�()zM.}#4Vat 1 �y�Pa�nello-Ra�a9 �A s�-eR]�ݜ�Pa-�k or 250 � N%.�+wri i�hr4rda�k n>y pico�,�Qr�( baG {�)J )�Snd�ol �a** �!�Bw� os� !�idec-l��� �� �>� { � �w(����dl� �|��DSSP [<_�Qs A|��8�,�>�"O+;"Nap�lYly 53��00�Z�( �� combP5��‘&:�ofQa�a!I��} �MG-=�i% M$46E$f!�aI .�)u��1u] 6t8��r 4W�&�v.�Yvolum"� cataly��cl<#� Lm$ d� �" nd*�Cx?or2Fig��S1 . DoT6.R�"53&�Kp1m^( 30 y-0�<5a�^L&� �u�;�&in2C iM���!n�9lnaXV�+[ ,�7 –[�\sit�rG) spin�a�[�Z,!./or=,al+ac= ��J*,,!h�*�, [52 ��(w&"�k<6{)�  ��oEv*W19i�pu� �(.�/A�ev/"�M�P�2?&]$�<�ZEw��m**}�( i )��,{� A�s Psurfac� w . 2A!�ndWXm��"G�Fl�9up� q3�?$dues Asp20%�Glu11e)i@2�o�>mwi.�.�&�U3�<�&AP�clo���i�K(x�)X�+*�F,�nC�I�J!�a] ��\c�*k.tI("Z�3a ���#�� textbook&;0�Z Phillip�YE )4��o3� glycosidiNJwOwhile-k�+�] - �vxo!�en�A�9a�r+> &�)��H.� �!/)�I��taneous�r} !��@ ��� .!S&��,as,�,�*��mokqi��� conf�\J�ѡ�5�n��9m�5���R9R of=+)�f !�eM���Cde�p enA�$VA��b c fash!��l� etaiM @�X_w f�""h#� $oݞT�S�M�.""v�!5*a���%"#!8&^ 460-ns�E7 �ilv20K�3 u kam!f� >��a� Pu2S�P�>�O���>A1 4�W �*�B X��-�*�4-be�I !��[4�h��� e�7�:tw ng 7ei.Px�*BM>' ( N-Li�U)&;��)thirdz��A^ `V K> ��! C| &E��a�2D�,2F�Q!z�ii&p+x]K AZ���n �)�18� (V A"��as%V*�!�(��A�groy/ �oK!� �.�"! C�`n6Ei�S(!�u� �.TMYaA�)��#�*-�9AYl� `) !V&�!in fig%~E,2Gt7�sc�m%�7W�(={c ]y�-��=V� . S�5g6$Y�m�(b9�oZ ly )���*�!1� ,��� g !��M�:!(e�{"M6�5&�#%�![�[� I� SH )*`'a�!~.�42.�"canmbe r� �A�E(�}���?�j9%f�g�U��>$!%1�2� �D^� %�F%.�2H�:U6Y��� lack%�bO- curv�2� 6��&�!i%0TMAM 1m8 9�PC alzey&�%�2g�=95!���6�O"2m15 PCM :�"a.OK�wi�c*o�*��<�] � �bj&��h �4�՟Anɞ=�C).�%�u�!�Fe}�df��Bma��&��}!�$A$�'�=!]5WE�,myEq1��5:A!�*�# #1!^B�>�i�l�"<�y5Jnshig�$�� zE�vi� e��i#!t� W 7%!�� %��v4A��/�9e&� �S2Byw4��iy*�q(eX@*P;lE�z!i�=of* A� 7I�� �6u�b�yiu�e.9�� S2H#of�6.�"q . ( 6�#R#:� 4�&p,�1"eC�~GPC� � )HW nan�Ber� �%in�ws�" � vari�SsXp�" ecay i'&�PC nqx"�4�,I�S��2$2�C�9�X*}]!q�}. 4+~R.S1[ �v-0� ccou�#!��reaW6� �E.%��4D:�uv}v� �QZ�]T�&(8*s!�iU%R[HdYQ�KBQaJ�M}Ic�A�fiGB��?e�pdeu �%�-frB� BnB� W�^a_�2^$1�o�? A�+M�10A�!u�.jAd��}�.1i�a9R�� � O� E�to�^4� d&�&z`e8Fq4w�28qG8.� depi9=մS F&�<5�31��%�"9 �!"Z.�videos7=�Tt^" ;s �T�)�y. rehe�H� qɽG�.'�c"�A$:���B6� q�2a�do� �1A��)le�,elum�)fac]$at=V�r�x.rpgrE�Sa&� ��>:vir�%*?8>G>6��R4noxrE&v�}-�=�"�&--ޚ3R�;�CdA�"�&>����h�|r�!� 20-�j%BO�?de�� N:."". W- a7*3 of [o.d!jfastes�� -U@curre844.2:JXnb"tryptYhn. (?��i��r7 �ah� �s 2–8Pa 310MGqs11��*�a.A�Gpro NqI5�AA$�i.�-ca! A�l(�����/��Z a�'u�E&�11Wa�(s� %��eze� !�hyd+\�_s]nt-}=l���are0? HSASO*�tP<YL5FE!���.�Daw rq�' \ŧ� (s�pr�MV�L�k=�R�k^�E.�!�Az2�4E7"�4znoL(� e7y�!�*�6A�xD*R1O63 3�%�.G<�� ����Fsu ?fu� ap�&zQ e�c���a ��.};ys���s<hFRd�9v0 ���) w!;�b!�a%<}AR<&� �.Ifuse� eU�Yν[��*]"h�(%�i�hN+7`F�!B/qu'u ��"�;: �o�]�EV�B%b"�O�,6L �w�]�fnQJ ta����?~�� J� � 4A�,5r"�[Uv  ? AnMs�e�)��N2?�� sVt5y�5^P�"�Je�-�3oE e multipl�/Pa�&�d= 4�&$~per�/A�t 6�#of�"!�-) �! W.Q� FV"( 5�I�x�nV7� U] ��1�a�&�1t 27 .�(�l.��%Ii��/r�,]� �|w� &Y"���:�N �$Fi%� �;�� Y�( y�#wf�f�! L&��!18]3( 916503�!� Ee ��VJ�k5"&!re A�10��)R�!�!%� ?d.�)M )~A��Z� (V��VRk*�)�fW)2�=( I�Jb1-0Aj����<�,y�8iA)*4� 2.� �b[ visu gd"3�pd�I1�v prety�^�lU���2�'V2Y!�E2!E����57%ơQ- Y.va-"�Q�F<�%" b0)�_:�|&�Cl�ak�M5seeS�5*��p"�ZD!A ��"��� 2mo��/3���&rdB Toh�4��)& I��B.% F�,�f+-w9�%JFaB�bH�$M� |� ,�#�*RdG)"�D��!�2#�� . A�m4�%ce^��C��D I�v-$�*i6a�  zero�a!�nde("E of36 nm2\�Ū�o avoid"�y au��� P S�&�.�� Pa�2�Es�]a$"�p6��N�n idc�-G1��|K���o�f:e !v,m�&n&:�2�IA��B1i��:k �a6i>s.���6�����!�:'2h&|�� $a lift-off--Fawr9!G!�.�!}�V !� alsoE��io����l� w )�)CIX�BMKm2� +�SA%% 92 16DB ny2"��*HY�%p:�l%�]��C65.Z�K� �t�`oy*9"./�"MSF��"�( !@!e �C)�ZqI�to�6aCg5�)*�7 +0%<5(�E�mZ7's�_64)C%LN��&*�(6 . Ca��I"2C�?%�� . �? ��ss��Œz1�Krigor�:\�.��t2����� sK<*7wvf ��<;z  Z� F�7A�p�k� ��6*.Bu��l�,��U�L �;)� as g�V�M�2w����4xJ|re>�SU~G�&�iG�"ezf�26^�I=s'��72a �88�n� �E7��S� ڭ�.!O)��mi�ide]" .E�bu �G� Reag:9 �^�1%.*�s�F�V6ot!�U=�2� ��9�qp� �2� :4E�M;!5powPI� �9%z�7�-@{e�<�hiI}:��worth�Q�!��(F �}�,�gg chie�[�G��o"�01�!"&!�2x)�H' �2&��GfBT� &��bi9#�2SX2Q*sA �e'E���ue�^e4C�RsyA��"�q�2w��emM@ޚAh�ar�-�D����A�"@6�R#PR� holds1�FVSD�� �"�.>1 &"&y.y�=�Y ��i�2�roo�,n >@&2 ( RMS� ���.� f l-~�;.�1 two-F(�g11"U� 8 %*�X&V�h� ��77�7 �=�lig!��_<[5Y� -���uA;���&!�!( apo )�\*��UF� � 6�)G>%[ i� e�"� p-pB���iJ��WliA�� ��.� 3� 2�H.! �6�fV�MD^�0,@�it�V�"��&�!#.�_F�b(V?m�.gs�!��g8�g!�=(.#%�&{)�@ET����)als� ��< &���*-�*��� , om�M{ P�"�!��lib�.F.�$A�L&({&>�Fa4 B�*!O �16�E�"'x:vF��ȧ%l�� �z)� e)~�a9�=�]�[(�_6�)-= dots� �4r ,��"Z2 EE�"�U���YSh a�is�!*�a:� � Glou��!� �������u�!byF� a cup|B-st;�*- ]S� m�� p:�U#i$ =)mRm�V �n^&�Lo�El}d'%�y �� . Ex�r0PA�#�i 9�ari�g��t?��r� a�E �!z���&�g&�J�]m}2��*�is6\�`lit�d-&�| >4�-i.-� >� �R�#1 BM,e�Aq fail�8!�?�a Q�%!�j�Wa�+)�8E"r J�.�͞g. I:^�K.��I6�p1!"ueR�ljb� .Moa�'JY:H�"YCwF��s m� 2�.+ �)�E"� um�e��Z��eu4N�EP!� bA��% � "Nb a��J�=d)J�'9�:w'�9FA�� �"W+A�� nve�I�-� Y$�  h1 ���byEq%��Bt�~�#fKvK-10v&� �,"!^%F�a�8&�R�AFm.�^�9A��MI�>�)��G>�!of 112� ffA� A R*/mI�{=?e((�/I�&�-5k!:a�%w�Gq"dVF�-ai6 ��"d� )- %Et `:1N���5!D�C_�� �*���+%H.: poorF�S!B J �ed&KMI)D��1"Z depdɟ�"l:D!�Qb.�0, I@emphas�{�2N��'�uiF���suNOOz%d��zew���-�9V p4.�q��*-";9FpNi arges�}�a�S*5�PX � �!B�OJ t �Y4�59B–DD6G\so��?9BE�!e�"� X )[| 9D� :e��. �> �ZFr4B��P��.,.N!*i�cng!!" b�`3_�*� &� ��-J�%�st�O+"-I&&)-)D�z\��_���I&{N. W�DvD���� $u��/��&&�]�*( �d)Ca�Wy") �,,^8_.�l"�uf�$r�t"�!l-ZM�A!���2n�d���Swli�6F%"�*�6i w31c�e�i⟍��; �W)N����F��2�% N �o�rE���( &Nf� T��P��s.��a2*�h��T.2aie�#RV��3$()�?_�<u�c���‘*O2�c C��)��–"�';X�R `N– *q�l �"�u���$B�. NKsM�s��y�u/,�k!-�!�wR)1h�"�.�jKch0: reor�^� s qr|�e�]�f"+3obҙ{qk6�I�dD�Ew�.�]����1.� $aXti�"�F��� � W&%ml�,ng*.Ja �u)E��#a&�A ��ISa�n��!jte�,a�#pup.� ��L�H��ZK~�"�-�wo"��U� of r!r:h t�CR[L�:�pE� �bi+�M�^�a?[glV��c*�(��{s5*t W .�bumbrella�h h -��9�res�n�Vpre*;sites"�+� "D)�/"8+g&`O�pJew�Z&. A� samew I�#�^��b�� B�#�ơ�S&� (�or.=)2.QסS!!]�^���. F�~ effo ��- focu ( "���\�6BE{(��\6,{�@W@N�' :��A�%�+Ţ�yqt>�-�Qb!�a{�&�3'N I�M�Z.��*a�.x~mse�o�|n�o��A���Tv�� ��r�72�k�"!,I�soD.�%�"�J����!S�� ��9'� ��4e�di�U�Q. I�0se�& h0�` ntui+mea{(^!�36�6'L�Wi]��e!��["9 �8�/� r] 10Mg.�  � �7��&� 2 �*!Ee�_*� ��soH�c:A�n' "�` F�o�le,authors' web�I$http://www>�pibpc �,de/�"ps/de_g,/"U0. html .��N(ygeCT�zuglen�z�Bmar�1diplonemh|Ir aty"rAUnf@n!�}hCs �p��2I=%#ge�Ireukary�j1VT�EC)inR�b: s�, er� c�acce͞��'�QDZc�<�Qto U1 sn��5'Ye� �m�_�:9�� brinr4" :�exon/i%# jMHa�nrQthe^Aߡ o*��!J� mA�1!� self-¸�� h��>0)�b6MOk5,��}bt��R��#r!�s!ݍ�8.�{5�&�=RN%� �eݥr>E-i�H&�d"}a'y l>>. �i;�,�} R!E!)�o��� EE�ɇ�:s0 �E�A tubAe gapC-9�%#� " � O�5 is:BEaJ2�ED� H�� exci�HxA�a7h pair.l be�)�.܁ ���r�Lm�K��}���CN�E����! PacBio N�KG��A �]:� �B>,�#�Xm!0%�6�� �nZ��5reˉ�-gJ*��� but TF)�!�[>�..y��U�acc!@L9 -��R��!�>�pa�nt�s"R�Epݭ�e�Xgap"� �2?�!K. J��Q{Mn�f�E� pre-`�g?\p���=!��)~%H���boEo� A��ts��TfA��"uRNA��>2 a&( P���* �a�ugin :�%��� –w�T!6�syntheAhEPe DNA �YA ١^-mer%II�Z]��8 �� [<5\�v�!�e,ayQ-���{�Ca�cW?g��#�roi��'!��qRp� m�&nb\A�s ��y2��-UHM3��;�'�%�&!�5'p™1{Q�6*CBCM�� <le*iir�?on [6 , �$F �m�x��dja�=U�o��E�C�: ine�+e��>�,�u�s�JB��r� QA�Ki�.en k?!`�4b&QqX,�� gA/%c6�t-��- ɪ= [8 , ��.2G��&� M�e���kȱ�����7t�a�R�a�j65�2oth��� ���90 [10�>��/�Q&4�E�%ngJ�{E&zլof�)? � �Im�Md�A n� ���HE� C���v 3�t*GE~;�urW�[end�e�u cp,� !�m"� 1ix�� icY��a\nd sil-'�r�N A��[ot�  [������ i�eNa�utl����h�� ���B–i�  post>� xAe�ss lo�0d elsew�G?�"� u�� Non-u�)����pձ2�iWQu���� uAgo ��Ņ ������09�'a���E]�!�e�2N �� dei�WA[lay�K��i�!��^�����~;gna3Q�.� z!:ItR* "�9 ��2� \.ػU �P titu% X] � �>�l�����IkF–N& ly [Ϟ�L e ru�a��Ź d ab��`@%|m�aQ ���r"���!�mer.3&�2� ,-:� .2�sr�~A�)#Ve��b�,1in6�QC-co��r!�B� s�Qozo9��per�&av�0)�U�U�� �[��ris'1 )�et�t��V�pa��,ca �&e!K Chag K*��E ypan%� cruz� , Af�nn �E ia� 60bruce1 or l"�� (��T�+of.��#"( �J)�>��-)�of photo9AtV����%of�"alg���j�%xq.1,^e-livA�#�ottEi�Xu6'\�� �I*!J�environaF��( #3�!e�searc�osymbi�od]frw flagQ!� inha�oo�[ kse�qt��^G&�-�ic>$�R?E��k� m�A���_ics�al��2( w� rgan�'a"6�j�BAI��v�F�%he����j -leav &� �� � �Y&3[1����H�,a��2[��%���B erto!�"� s:&�B� ��al �0x��6|�go&m���&��*through �"kn^!"�A9i S 7>�1�)fl���l��M]�'nK!Pf�>x�iciQM%oce��[1y�1f�S� e-%1�A� e@qru�iso�wOh �kcoaf Cal�s��6ٰ g�1�"��^ �&��sv<�%ofGnoVhGY]�M>� �[1J& ^�2|�&�)��Fc:�[20–c.� 2$Q�.��� �2u( aU�2�E�)�1[~����!�q�Akp=thtb�73.P:�},+ab2 �C�Al.ij ��.V*�$carcep �#n�5�tψno��is�L��щ�)5J_;C"M����(]Bў)!�f vaBpro��#iog;8&U�t�I"�s��. �r�Son�{ � und �q&siz�m�(-w2 Gbp��nd�!߱!�6uti� �%JKa fewK@fM�Zps&L�r!5)So2X1�M�S> iA�ic ��Nْu4-�$�eJcb� Swhole-Yf;·ainuEVN:��Ae��to!qzb,�dE��b"b!�� V ������H�toa�.!�g#�A��+Y�6Mot�- �feR�!��.�"�ԕ�: Y/R u�Fly����* 3'�Z*�@�7��uŃ.�P�cA [2��D�u!. �rte�yea�[)C#�U�� �c#*���&�h�d�H�!�*N*,$5�s��QB ��U��8L ���(&O��u� poso�$�Fto MITEu MiniPe Inv�-�b at T� po�eE�Js��C$agsT �+!Gi�%9mH���! eB� ����d���.D��^�w�� �_�_MQa�ld$!�&� z0A@so- gex*z1�Qk� ,fe%�E�2�a�^6[2�a2� ���}ee��AqB��ra!F}2qh#2��iM��N�.S}Ri�ac���[2Z�2�Tb��}arAr)��%j�"��OPR�&��rbc�S,�S22/' tubG/�y�%�!�aV^W t,�y7#@.�� C @ �io�%z%��x �%���!&� �-a�x >�  "�>�4)SL-�.{w�8� j�A�t]nOv�HL�-)!C� hc��chz8 A ,Cpyrim��j�ac�.3' ��!A�y���w\� sT�ed�cog8�7�'e�"4Z=2�u�M��c J &;Q��� � �!�.n�^(Qm/�*� (A8Ad*�~a-p�L�r��E�� F_"ci]E�s&�2�=��{�y4�� e mn<.Hb;2/2�[2��`�i!��b� � ��!�prece3�D*�Y�>�)"�3MK>J�)L�P�m �F2�C!X6Zf� n�"� "�!A�%�e�ui���~e1*�� �� " !ka4��f�Bvwo%����!a�!s*4,J�!1zZ a�edT��!A"�N�T&�n!o�,5oe��QuS!�j�! ( NG�2+ۧ� �! SMRT�!(�� Bios��s6a!�ng��N�!8J�verage N15w0 kbp .!LItW��.�b�Xe]w>,��"fg3s ��%��A��g+g ��I���!31�CZ%�W2�(*o � A5�twoB�.04,tY4 2��9a�3� �Tg �|�6es GC-AGO hB(2� <�&$Fif��baH�E(� ��!aby����� upsv�|wi.Mnsturb!�!��!�(&o|ktX��& '�pـ(A0R��� )&�I >[b%B:�/)�� "u�a�2=�U�����Fǥ�= �� �>%m��r� a"e�_v�� �U�BeG� �%Xe�x1� -P*p !����]� @! �^]� E�A`albei�s&���t �� *�V*�6� x� !�&J~�F4A85�v�R �pn]��{ :�F2�"�Y�A�Y�N�)a�L>�1G["� A.aiC ��#��{E�>PP .K�����I�& YpB��&� !���< lappa� 1ɾ'iW"���s������1I�wo�.%]_�!��"fbw!l�!h� ,/orward I � w�ao �!�ce��;�" c� rA�� r– D)�2-�"�!� i� ,��2�!HF�2�&�$) u �uJ 1C ,xf���`� ��Y��;GR�$��� cY&�{D��C� n� � ,ˍ h!!�:zb��gB�inJ�p��UV~Ec ց��`->9(���� 0I�PAx� S�X��?�&�J�Dž� L;�+�>�b�a%�j��#Q?5���,'Tž"� :�-�D5�= 5�aD%8� g�eja#at�"�-7�aE R+M�e�R, wo�ML)�I�1!�A�1E air k Z iF�.�0>�)Z&3:cANc K����� ul���n��"R &83��� unɊ�yw"%Y�-��t1@v �a�GEH%�W�a�t$�2�n__m �S eaA���m�!�2J�}BC�G�$f($ ��ighbo�V�2� iz5Z(��1(p�a!Rk�9+�)�a9a2�%�!�%*� �UMt7=��XsX)�F%�Rh aEE�=��>��e0M�*ߖ��  '% >��^M�A�� &�A�k���})��by Tess�*����k�e"�N�Ca2O��*5ɪ>�I��)�]`P+yt�teaRm&: ��a�%�� � I�s�6�O�� �MC2C���#�8�|N����SnxQ6o� s 3�4E��Ka &e.AGup�-P�a� o�olozC pA&D)2t�.E'�j � SL-4u��HA�����&�:l�&!k@�(aW����Q-�Y��,e&�;� 2� FT�A����AԁF�"2m�\&�a�Z��nu�(!C��My����m�.ͲZ5izaV�!!^ >�v�M -�~ SL-3=�kiR:�����Ak/�CB %a.��I�%�Do�$a3�&,�<��.�nP�;r� �  Q� ha:/.*$P5w)_%3�In>�oP�."�&��� �'>�2fN�out�/cNL ���Q�fI i�>ze)}!�.���!fN,�C��5ҧ5��A l�-&d,�l�#A��Ulw,]�m�Z�y����Mi!e8�@?�).�dF Iri��!�*� IP� Ah!/� ,��0�EK6�� 0�!"�N��"�� E6,� ��, �8 �F/ R��3empd&�)]3A;9��X*R2^��� ��6 sixt����uyETgenS> *�0using the cDN�A from reverse transcription reac |with the primer complementary to�Csixth , last intron as template ( Fig 3B; amplicon i6-tubA ) , ( 3 )$obtained i>� �sV�first ex|nd�fif�penultim� �in"t�gen�conven�al'�using.cDN-6!�:!: � �J3C;9i513D. The PCR products95,, correspond�onl9� plicPintermediates ( where �spective%ron–%�or.G<–has been main-�!/wK sequenced=>PacBio APform . As a result of5�, raw2reads!4various lengthA.�E�ree abovE�ioAGaMts �treceived . In total , 29 , 593 m�U�for%(gapC , i6- Ac1�a,. After mapp�accor%��e refer!�esK4manual examina�� contigs ,�Lut 4 , 049 unreliablQ! �oa�)6�(discarded (A�sum )EEu\25�44 crediU-��)| , fulfillA�criteria ��te)fic �)�)Jselected����i1e_ i5 )2�( 1ad02�676%uq�he�J��/Sremov%t8 . 86N399N�?V�uJ`( 7aM532�� . Bymtra-,%bɶfollowAy6)�occurr��( fairly lowqn� ,Ax whic%4� � ��*F� .H�EtE���� .-L131LV!�=KmJ^!K1 )Ew miss�( 2 . 35!10Q�( V)�h%��. J^�2(%����( A�33f�=Ɏ��frElt 2dM}�)xin)T ��!��i�&6s�B20sI& ( IX�J� hk ird��C^� ( i3+i!#h� (i18i8E�( 2hf�W%�a�+ N04N!w( X����J~K%�� re >N. S%l=[�i)�)p!���g� >� An� divi� into�2�� C�G�K6�$group ( 83a�1!. 05�2��7S -� I?(�KE4 �&|� � i!� �����M�es lackA��n�1a\43�75A9. A rela� ly smA� w2� �]� pAf\e���AI%�y��0�24!H. Fina� 0, a very limi��*!R���!*��u_f��a�)!2% !�� n �pairwise��arison1M order��)��/al ar8��nrE� ed!wvq/V��!O��1E%|1F; B , D , FEQO� i� ,is it can be� uAX�qat�J�s!��� H"&s�� befo9>����k�,���V�confirms� h �p B5�? 2�>� �unambigu5. C!��t�thousan\I��� , if at�'on%�5�1�iy�,BI � also��� no .!{: �487 ,%}:"� ,�:�| 837;E3AE��%�e a h!�a�.�e/anyZ�5�A':�%�A���^�:* �1�-�: 0N� Simif1م"2�>0 b01),A/�f��!!Z� In turn ,�%�*>F;.>V)�5D}!pH 2l%J�zBe�How�)�A��  > !�wo �,�!�in�atIz?-ed5n,)p . Whil��N�XI.� harb �{(z ,&)6�- EFyI1��� V6���4%T���"!expla$s�a� henomenon0 �N�.�(ly , yet im�eQ ���" �al�*gha� muta��sA|crucial�i E�)X�!�),-��A�ed�^a!funwDal mRNA molecule; , �observ� �w���‘.� ss �’�� a ruleE�� e may�$some deg�of devi�J< huge numb��1m������ principleI) � just&Gseemsa� be m�mlik��un�ed60s might4M�, even outsidI�nuclea�(!� show\ ,earlier stud� hams�a� mice cell@=]3�ain12.�a sign�nt}!w!;�U aprt �Vhcytoplasm [11] . Nonetheles�? }+!�be%�d!  s �) prev`laG��-Ded a�i��sugge� tPRxa�:+>�� �dic� data�lj ature [26�Despit)���earch�l-|owards�oppos5 scenGMs expe�nt!�ea�%his%����he��I�� � A��!���ow��r*� ��u�excis�ofVe,a�pro� via��  �! ��Ib�lowd nextaq eachP. Indeed� �d �WF their)�al does�y3  clear!��1E� ��re straa�for!� NGS� T ��aq6�"X E�ei�� �-wo0r� ' Q��h��>cmA m����!8. ,D)�E V��D}) R�,�s���IV–� vk26 �\xq!2 ��!,.�V JqE U� comb� �ncERa-_noticed: �� lo" Zi2yi5=�sx, X)IId M "" of-g�!m�i"�-N V;�c V&U+� m!�)Y�!&�)�Vv5.h��4�zhow��6 of�+tr�o��!�Jh)'alIv%�6� |y moderp&�[i��{ . It�� ��a7 nt l�)��i�ti�Q�a� (;=5i5 marily/51w�,$  shor"piBihis 52�(\pBV�!�fi�!5�e fm�c�A , ha230d(m�� Bd�!�e bjpattern!On"Tgar�gela\in�X� �-�ofBA �%g� s qu��un��u�OB>�G�H�/IŖM�� N��j* �!�E"�botᐩa` "� ,x!lXe@sol�  n� �edC�det � . Su0 pic"ind�ea=��c��>Z7is�ow ������per�m2"�E4 ta� �I sZr"h�t high leve�E�) unpro��Z� �(_:g�^��: M�Q�F� %���"^xE�ed� ")���7 ��9 F��ichk -�&�""��}!�M��!m� aKr�#(;exclud EN� !�%s�A�mai� ctor��2$�Zd.>�i�.gar&�29s��uld� tr� %����/ . Mean�^ baraYeG )p 4��V�5��id�fi!� cros!�� % d� ( i4!xY��SX;EM�� ,�&i��3��6� �v/������ �yqa�tf_A��begins �&$�F+�$also takes�$c�rapidly2A�!����fbeffecI a co$� stari����O b llB��Bof�Xs��)� mH� . Mx'p^ypegC�% stag ! pre-�ym���7Ej�Pah67&Е���Y�U"�l) Numeri�64'to im.)���!.1�UoI��y�6�n� I� same<$l� t�B�5#pR�'* % �6� *��f%-��.�aoicly� perc�)gB dequival7�S:e%2<jEx!�nd%>��a!�(tt�ro�::9c�@re%�as �as��}- �(&~$�"�(�1��,$I",I"^Thoit�tworth K� �5A -A,��a� v&.�in't)&�� hyp!�,� insAHful&9w�hav%�!á rfu . UnfortuT(J��Candardi�f�Ainv4ga$ U�s�>^$E . gracilA�lp'll�e�tim�;�bona+ans9�-�+ we-vze�e�(��ssrmN^}of���%>���>���, carr? � �o2���23(pore�(of knowledg�.$ut atypicaf� Sare!�!E&) chal� aJ�well-es�}))�H Fu� &)wYbe neet$to-�)�� remq-�KW�3��,he mechanism3z�Oo� ? I� theory;�Ej posoa!igi rr& ? Like�", howi�h�aA�AMn/arTom.Ra��he �)vitx)2re># syst�(�A�asy�a �ly ) [22�AE�����ter�y9 ow�[��AG a be! undersa!�-psen�+m�1 X$genetic el21# eugleninde�A� diplonemi gl�T�,fMbo�-% bil! �� mprehend/ZprerevoluQӁ�r�*v�gr�-�$E�a�Dn Z ( SAG 1224-5/2Y%u� ��Ttud.oE�"8by Cul��Col !�of Algae� Göt��en Un�ty�n����cronym:�Z Ger� nd5� ��e�oU� De�0H |M�ar Phylo-�22E5@i �8of Warsaw , Pol{. C�C� c �b5!� Cramer-MyEbDedium [31] , supplEl7& 8% e�olE1% ilE� aqueZ soi�2�k-_�1re@wn photoautotroph���1t 18°CI�� te l����os ( 16:8 h /dark cy��0ca . 27 μmol c$ns m-2 s-12�c�wh`fluoret tube�<. Circa 1 × 107� e"!5logarith� growth ph�%char���? rifu�N<( 3000 x g , 5 mQ room27e�A=!�wa�.twt� 5 m�ase-f� wa�mslet�o �-�residuaN T�4�ZuAcp!���a8im5aJfresh| e"�'IU� �� irVana miNIso�on KiInvitrA�� >55 urer’Z&$otocol des�3�� _i_�8es8 e w�.DN!�inb�v�DNA%@��R$alN� betw�6�organ�5I��!��gf"j+a g2fi$"fil!��i�c� �&�BrigoraMdi�j.n#de�9by�.D'A� struR#�a�)pur���conE����4�)Ued%N���98a�otome��B�NanoP er NP80�*W n!�ndibF:Qubit _,2$Life Techn2k� teg���A=�checked  s6�A�s�NdenW�=I( ��4 MAc maldehyde �runI.$a 1x TT bu� /WR Chem���1,��2�d�$l�^[3��F!0���4At!e� $in a 20 μ� Uo�+xa���. 5 μg!!� ;.�=)�l,M DTT , 40 U8 iboLock (Armo Scisfic��! 2 mM dNTP��1x^EU9 6�nd 20 aSuperSY< �R �T"� a�( 2B. 10 p�s ��E}�B!rZ��[��%^1Za & 1 ) re&� �%A25’ en� a rbcSi� �(\�"*=� i�<j�;];� 6]e�to �&p4 u#1�!KH A�� Zz�6�;�A e�iv �����7A )�QRandom H� er P2A��(m:'A�ZwtoaF )dF-#--ŭ�� 6geN5(* �!+I�s�� � !NlZ5in S1 T��V�AM9incub,�i60�at 55�$$cA� , ne��vi� rolsKcha�s r�5i+mi�s�K� �ad��* =>� iQ���*. P�6��IY�1%�+"�?in5>�?s .�aA[�5�+A��<�j�edE75�OPhu�% High-Fide �PolymerҦk���%)��,F�HFbX52Q�Taq S^-S�ded�B�ng!Wt�'( EURx�1%�y�(.�or6">5rG !�� 9 p66� $�?%�.�Z>a�)�l 30 sA�9- ,)# �)U�1(����at515E nnea�= at aE0e� op8Ale.�se� }P��-�extenEat 72a=aQ��%1eX ( depe�@� � � siz� ��"^ step�{9'hR {.%O Rm�X�=A5% - 3% *�"c visu�� Midori Gr $( Nippon G@��s�W*��'A� frag� ��teEr��&  %C70*,)M ur R"�� ALsJ"� �MATRIX�/�$Clean-Up PI�?� M�,F� .Q � i6S A�5[ � Sang&�6(�."�in�&�6\)"��dja� f�(in�, �*��* –a) �,�& %"�5� �@�/el sliju�%[QIAEXl(Gel E&� )8Qia)�8S��eM�A-,ed:���p�䁦!�BigDy. �a�CS9s�?yɄ�A�1Z+y��?er A�m�R= . O�4AY� �assemb��peqMan�T�>softw�( Laser!��5NA Star!Hn� t� .�kof6:�triev1�!!GenBankN-b�yL xL@s��?: L3977681;ISZ(AF18255�<"I!�� U��|C.�RT-a.�}!Y���E�u-K�da mercR( Museum9Ins?hZo; �^Po� Academ� c!z>%,�'�ERSA�(} Bios a$)� �� J�:��iɫ ly q�Jt�'lA �re! � �A�i� { ", �FastQCz1A�7 [33M SD� �.enAwh30�!+@elixEryE,�A�ss�Q.. �G�E�- ��% ��1�E:A�Ņ��Ha�A�79�P���'b htJ i�"�Gm?N]2� �saa9�+FASTQ�(+�1?r�-toAA�mat�-�v@1 Basicx.�>2y�[34�l dM�t�$!m�9 . Ea�/�*:��2FG!��G"�H� r al�Ethm A��R�Eof d(D�dnO��e�n2:Yg� N�*� � &:A�a?parame3%�apg"d:-Bit�/f�A=Hm�#b ,matches� �l5If4 �,se�> largN5lY s up91�bp�Vinu(�iBA�� ural#anta`�mum��,aF*-Dc�y = 2;�u �pk. O�@2 H��1�BiY–flanXby� Msd �eD;FK� !I2sG��& �)"�!� take� �n�5� ��"�#��6��i�7I��ce3yA� �Xay>I�<� %�beyKG���� b��(( OESdiVJ-+aj�&x<� otidjLmisQK,F8�!M1 ) cl.Aond/_*�3�-</cju>8� $ lso �*�3 s be�6�$poc$�de<'�-�� dK�4�m �fa�3��s.�!�a���BQJO .RJp�!����I�-!vvidL �)| �&glig�J� apA�1�- �_so��2z;�th>�a�"�2A)�atE�s�*��E#E�[�� \B prob�"M �"YN infe�E� A�su�dn t�*c%��(s .8�CoxsV60evirus B ( CV�-i�� e�o �!� commQ caus���Lf-� febr(< illnj8ia�f���s�vEMo|8J if�J�cute myo�Mitir ChroT�� M mild�!� C un �8a�g�"t �pidemi ic�Yoc�$��9yA�,8= _Bdv" he3*failur0 raisaA!nIi�['(btle damage.�;#-on0dys�;k r c � ongoXinjury� infla�)or3� s dur,Xn1e. H!w�t��A moust+dK0juVm57w�a2 d�vV:F3IG�Ri3�4�0 ev. symptom��em7� E`�5na�AdQW;&�#/ phys-�al3pharmac)⁻-indu;ESac�A�,�- t|mu/ w!I8hypert8ye�di���� vf progaA�to:*. Evalum� vasYO���E_e2� subj� D$�-p�,mpens�y@rW@CD31+ blood vesse�m ��Ku.)/*- ��KQ'93-�*�% CVB3l-i � 5_> c-kit+bA� �!?eni�C���re)�B'Z�=9 s��3)��a�exhaudL^�pYvo � �!��&im�"X%�'FI�>-n-�capillY ens��dapb;' d load . 6�1CV? JF�� humanF6hI�#!%���a�e���!��Ru�sd'���HashA* nd upper-. irIk��leS !ro�|CV)� ����disA�� .� #)�3:lea`$da� A@(omyopathy [�![2�![3!�ma�kI�<5�ap/Bt�Q�ndoc��$be H2r!�( ∼5%P)Ph)at- [� <# apse%ideath0 younc2�J uals��ex2 �+��catas��ic28�N�Ź! way!W�E����"3UveaxCV �A�[5!6[X?A��P�-0–80 ���2 end-�*idi%��V�S)de�7�l�6��CV�m�Qumd� i=his�!�ntece�4 vi 3D[7�89gT Q� s�A\e2�� e)�!�M�M����b��宽V /un�>ceben��"�mmune-d"d��|(� �*at!b��0 P�A� 8=�A �j��� exhiw uniq�,ropism� un"�-�d��^�, s ne�� hematopoiA':���ereby>Ee���lineag4mmi�% r di�sh!W~(re!��L�Eac�<[10%�1i�1i�1e�[14 I�16 7AI"��9�{S(, nha} %�+seEi� �0s�7� ��(utophagosom=�ex�(��W(( AWOL ) [1I�1E�B* �(�Eu�5we� (�E��|� I��d)B�� E�M�<-�6m � �=da�opm !�"� . Ofy)ev�$�*B)ba�/a2al!�k"q ^L0��$ ^C�/�Ee;X"�Din "b ��aly vie� ���=:��$7do"���ri �} fix� "�F non-renew��cќcy�/&��aAO tinct pop�1�g �n�MZ�( CPC�b�f E �,���/oXa1 M�re�>Q��Aub�d< d!/�'a���i�c�F���F�=6 markQ)�as CD117�!-�) !�Sca-1 [2i�2i�,, [23a�2E "�%�%�)�K�(��)'cap%��H�2 �a�l! RŘZ%�acADž�iJi���rd�)�, smo�>mus�)Oa�enda�l&J�fibrob�J��%e�p 3benefi� 3�~� �(#i� M��Ij$�B (ed _��^F �]A�KJ�FwJ �m�Y\� ��!J a�]e"�.�#c��K" ���E�EH}!%: � CNSB~ 2i �'b45marrow [~ lP*�4ͩiJ!#�onI� nM!EqYWe .�3f�Pԁ�5�ex�6�diY3!dEd( ; �j^ !��� su�"e�A;$32�oX��Ea.�^�@of uwit� �p�b�3-<Tm�a9stA!6�ac20, left R9r�adi xIh�"�:ofib�ztissu�L � fe��/��o/B�Lt�>eD ��&�w�.@Fc� �%� :�� 9v)'�b�0M~'nge�rA[)9lc-. Wy'ly�G"�|pro(0 ng� �4 AQa�*�s&|!sub.iza� neo��br6Dor:�2� .� ly tK!H�3x> �  a�.�6m�L,)E��rc�ve�� a�9�a�/�%�m����ĩlof0 ��|[�`1.�PW�iOQacFN"� pqA fashA�,6 � "� "l ( Day�U�#-birth )!vI ��-|4cha�Rsl�a�  a�%��>'4.�3d��bX�'2� ���eGFP-%I�p�l�L1P ( MO \ of 1�1DeD!<��3us!�us3 yM�bya queayLGpr�)ex!g(� ) ut�4a&$4�;iF copy"��s)l � HP��JF . OuP��&E�at9�2= ��RiIT6���Wand�A!?�\PlsRU,2q�p amou}NbW_���aIh2[N��%m%�c>6�or2*Tn�Ese"�G�X+ntM�%SNs��@!�i�=�=�Ksus�hbXto.�itF� s [2�2�2�A cou�0=R{S� majo�2V�&� �a2",!Xac+e��� rfac�m� dish��*� to apopt�boV. N't"mU�Z� surv�i&!Q�!A�, inuI �o, �.Po6GAEMB�J�2 u�9� i�Fx:Rby �o^�Y�0a:1we&k �@.�a���m�AgV�h#=1&orp" ly m . At��?poia�,e�� ���7�5-a| velo4 a flnE.t�'272Fon�-atamX)��` lit6toK �i)�A'� C!�5tv`QK. Bw5K4+&~*tK�w��&�"4 Eeno �rea�o�2CAR )]D O#� !ԅ;:7 c�!�R> kmua�=Xl�e*Q��"< ar�?l �&�IM�1Vj"� � �YV AR�f!� is w��pT!'\<t)� �\=.-,y��NPSCs 7�.� ��� s� AR B����Kat"ND-!�n%�qi>7ay ^rly� >�&�s��)|ofY\6B��x�L2�4if.�� viv�y�jG !'��&�*a� ��**)?F�(�<pfu I�!aFEw&�<2�PIE�A>$ffin-embed 3A�rlog� *t&VtJr"z� ���e�k�/N�R� �!�!��u�%}pEKFiK F�.)�}te>�3�6J]!sa�" }surrong6�>��%_^� !M� `:�) �y sublX?l$>,� p 1d�>!�.P � k �"-5�0al�noculudCi�!�)-tole�::]���� i)t!�lth abɣit�;�,ck\4 nd w�Qg� A%ɠ~�  mockM b =.) . .]*9' ��%(�6 Ak)?:jI(�Bic���BD-�I�u�*9!^saM�]rGA6�acV/"E2� "�2*� i��)qlby��NR s [3838b<� �EepU3�eg Z�o! BH��8,eV!�=W?u.!g| V)�B�0P�E�A�!31�V��/.��t_q�� {e!�� �by0(�8pl.n HeLa��ct*ly�lle� �k4quanti]!vm#al)R�1a�5V)J2C9C No2� c .�Cjo�D )�( HW/BWL,a x�U�@%Z�6L�|ny �E �D;2_ -way ANOVA�. I�6# �CD�mIb� ( T-�zE%4F:��=�!n6 �!fbAilt�n*�$�B5I .��gic��e�'��9�E�HAt�,,�xyl�-osi� H&+�ĭ + �2�E2�� 1�0 arr47jof�{�il"m� Masson's �hr�N~.HtL �2ngs#AT�*p�D2�Ōm.>? outcr2�,)�o7cAst�uj�5���iba`qa�*st =!GAV"�ca.�5��).�+�6��(�&"6S%",/ 1eF"*��Nle �Jh disp�o<�*p���Nf:�sra��9(V.3, [35�W2_��&\���&�%:�(2��[ to:2h9O�WG (r3s�!�s �]x� �$�N�,���t3�&recruu-�9A��dphei�)~�4�$oa�2��H� )*��T enzy�=+!�$-�k *@  � by f�cyEy��co"�o�%vE��6 !#M� CD4�uF.Si��c�B~'two-fol�6�6�U}5�� ��-��� &B�])Т)&r5% �@usdD. 7�q:�. Expan!��N6�\%}R�� d�c!A+%i −)_y�3� �]H"llFLA\�~.�V2�E�enly&�?��45V9Zz�14�DJ�oB -�.;& stem ����L4&J�88Y$G3%;�8� �?ne �-ng_�/l�)=gu�B�7 h�A$m�ьB2baAz6�]M( "(eu�h�(WX ɺ�*3j��f��Rm*�,�k�i5ag"MjJsA��0�;�IcerAOy 2Q/ ougd1� ��!of.,]M�Z�:��s elusN , N!o�B*��+@ l�enMto&r 67up�!O�jB!�'a�[3�*R�%�e�A�XGer�5z curs�1�"($���al�tow� �uYV2E] Q*3��pK-06�!�A7s�3 ]&�I�Ha���aq e� upregv&(ZQ��l���drawal�&a-<�[3"IYy�que�� Z%on)`�})M$y ysE��q$�'�!�*U� i  2�QO�Z�.���+"1A�&:ms �quickly� ergoB�:u:��n &�(e.�%�՟V�:Z�Eif�Y]r\�3A�_+�I�B��&; ."+:�"���6� *� T�� !vUJ2'*P'�<3rZF'^O'\ &8 ( SM2qJ$von Willeb��% – vW=�sar� wact�P>T�1��w�2�aD wU_"9 4Xe�4�wBb��l�"���>co- qe mB�q\�R"���7x-m�� to a9k2OZ�&# ABtriguv !'&�*(!�*�a sharp2�alpha-)�]Y�D; **p<�K0Y)n| y�EB2)�% 2�& 4 ΁�2��e�b7&�]~2�NODB�*�r��"� �>Ef&�>���� EO1�ne-�x��"'[zX#W4�e*in �e�*F) �fl�6;]qp`r�t"8%= �!^ ��Ber% AV�2>4=�kn�FA��"�uE����� s~Z**:��>"AJyE��a�!6��� , Ki6EA Br�z$+�����!�w.�*�2"u"KN^�*� 5���XQ\� ��I by I�:J� b)uq5�* *2�N Q��!-�2�2��'> � !)aieTr=fa�l N�(� Q�1&&�/�^ed%�G %�5[>/!i�&po% &�]gy (��5��3El��� A ETIf �s*� jM]�ng F�._Ci�j9�FDeXq /.*v ��:.�� caspase-3�L� 4!A6.��q�g"�:+�!a��!Laym manf2�D n:],y�5�E�� �c3�5LG� AA��|J/^')& >�a5��m�BKB� �"EN+\M�M)E�� 6� . Occa �7r ?Aۅ�� �A��ha"Yr�@-�(* bleb�!'pyk�2c529&�EQH" Da3%Y-9Yu2� ed g�Y-�� ���zC; / ]��&& ��TUNEL!FApopTag5Hp�McE�EBs�.��#+�qUU?6��o�kS���d!>1�6��2�5!:#� ��;�(/X?�y"_,9y4� u�da̩̅E"�0�m H7eq�de�&�+�1 �:v. J�@}��� of$V)�� W2�axev�? �%� �,EB4X,��28 Q775��$w�9��.��Ÿ� d�on�eS �B�Dom*��. ?Mha�C��+ce$y.��st-ly2Z2A�B�VaY�Ee���6F*� � ����t FL I� �w� 9je�7��tbKS�[�A"�<by=�(F^e{9]�-3�per(&d��|re"�R"2�g8UC">�+%I�*�or(qPI ZRNA �]/c.iv��&#%��6&� �UA�"=s�H@�8,!�*�e� part�� g�;�$�Y!w�F�!�:TKI�#):L1d~h=-32�%V�*K&bE�@!�&�5"�involv�anthraB i.�=� "4� %5.�,���!B�5 ( DOx�� .'a!� (346O7A�du(P/=*%�m9c�:%�� ,�y#`>hpyNd&F5�}a"r�;a�xn�G�+no:�E�ar�"�=euW%)acSJ�.:� �j�a> DOX-`6��Do$"� ,�d Z��+"�)��G�tl&Ed���8� 3N?!�� ��B�&�"�`"�6�_swimm�,R DxN�:�3Ʌ'.//wattribuEf=9 incfof2�'to)�go&�`J3:�a-� d oxy�UdemAKmZ�;I�Lo��is&}bewO3doUc'crineE�gY� �8&�$\�0�sM�'9c]�MI�&,%EG�2�%�8^en�%re"D��E+*`��$�v� 2 B)�&bA��i��$AinJ��$a�adA�'d�!�beta ad��rQagonis) iso�(renolY`SOt@38DAt 91�}NIor:��� q�s W��10 O,6 vehi =j7��"no (Z� � Nt�� 6O E�H'/tibia�M#� HW/ThAY0��wN�q9uE�� �Iw q&!� ��St�06+%7"% 7A&z  b*e J3[RT � \� E�ISO6#I�!!^v age�end2�7�Tw�Kd8�m��=ugw?�� VB�WN3yua]6)}��#�,�}!jn9"�#Tri>�#�JT� a�� -p S��ur&�)�qJ�M)�E]9%�to5�b�a�)�.*Ctf� ng T� e< ��<yBh Q^�9 CR9ac��� $5��Ft!�Bb�Jr),"gTNM "onetworku(�L�5��s2:;so�thrA angiq$V8(�8nch!�e-"y{�"�L�B� �?de novo2-�~�"on �,Ip�y�Ps�$ ��9�tkx;#[Jva�?stimulia�lu;0��or�&Wi5eAz�2�N 0 +-���&P�<"tG %2w. Zsn�v;uf^ � l&P@��KI ]}@)q. Sv!s� e�doc6Kinak I�)�61�>� !��t%4=fzAs\HU.�th , ( VEGF���?G7a�iz1x Iu A fg-b4�s�b:w �K�spriori��bAa��"K "NB��KQu)qI� ",�O!CŞ���=aup ,�Z*� 5a�7F�OmN��zb+ ��9B�)��n8+A74�.���J�K�]� F�)r�%I2M�4)D31! xBk"�-�6vnW0 %�A�1��KOim�b+"6* m�(: �#"�9nBv.X�d�>�2fR� m� 5E!."(>���S66�� �1P $�9� ˎs19eeet� �@0 >�i�P�<uv.fR"�C."�� �h"�q��ON"m��&��e�s�pate6!Cyu` soug�*a�.a�!�J70of ^!� �Iz'�]�I ns hom�n��jdi�Aօ�12&�)�2Q ���W?or �*x���% %'�}�l��w�@���.� R:�!�v�*F�B&� 5�UVf�"� of ��a�A�j�� �X�#-� � �XA��!t΁�J�jo��C>�8+� h "l6�< b���a&*+��ef!��jin2�6�%-,k�lyZ��gg� %�%=!A%�"G out��purg���/�!N<^e ,�;erb!�f�n�r��.�.�J5��&��5in1:!��!�measu�&�@a Keyn9� �@0^ BZ-9bA)%� br{2 field cap%�A�o�}*Y�%�9_E�6*��.N�m.e� 4(rMs.}E���56( bluu�Af � ��f.�F�Lo%1:D_�)�E�iJ�����.�!8:0*� �1��b�n II A�dzer�s&Ygm�9e% 29�p3$�Ur�&�F2e�F\��al���%Z �'Oh?L�Ma��s�:*�*�*�!3e�Ymo2 � �a�|le&o�bqA"�Ga tal “*� ”HT.�p �5 kc/MU�E"�Ys !,.� � AQv"I"agG2[ex h6h�6n%ybH �r9�pR��Oa\�� inuE"��14 secud�*.�e�AlVO w��X�v�vqN �]b�9RuF"$%a�X>�x� �r2�o "�*)�17z0.��A�vD'��10*�Bf�8 �$�s&#e��.�J��102�H&E&j�c!Z� e�.s6�disarro~nd&���^y6.�U�%"a� oJ�=?�*PXnY_�DQ[eon��UJ&T�N togeq0 F�B���lK^��[r� A%b�� �J��H*��j�1\�v] ente�b��6q(v<(�{ld6�)�c&�"�4�E ,J�\s&�`A(]�p\�b"CC4!.xc�3ran  ri�, X ��a�\�wYpatit�me1 o-A�phal>V��)����"�\����["�&� �HTd~-�m�of .;\A�),"�]a3r�m�.�6�[i�;&�&�c���c_��E��9��Q�r*Y�#RlaN!Po��m�Xm.�!'ver8)}��%�@� mmuutos&*�sN�#s4z�*�*��le�mimicry\byF��d�d[3nID�OF3e �X`a��<of o+�&Ux �ᦱ�ve�- �cav�[A�d�|_�p�7�roW3{ckLt�93ej� �I��#} �=IUdiastoli6'_�T��-  igE mbEb�-X^�o] yeare7�e� 1G:[QBB�Jke�%-% � -���Udeg�$�xhil^ -a&y.�M�l5��kt>�d'�'XEatN�4"U� &FT�%gHas\i*& e�d1�\�#ͷi�e�"�G" �e�u!6�!.�U"S!rE\`Z\��"� "�en"C3�B( ��HR�].8.m:�:"�C�^ifoU �Ns�GE��0| !�NY6&$"I���\� nerv� yl9a�6�U�U�5�&I�g >zUdoIfIF�>�tE *s�� . �.�or ��!K&� �)� Oz$�]"1,ry$znG��� A�2�!%sf�U:� �U �e �! �"�QX���;%�یtu�+e�I��% �0�H�wyet29cid�'-4ݥ�� A7� r^ ance"~ b"tur9�m�Z� &�i�Il��B"� � �"� D)�)!���stn%5��1&+[!�a�/!��a$?#A� �}1Et��[4$F4$F��� �2�9 I�erfer�c0v;KŻo&�)j.���.�@��" ���a3,�p� �Fr`�t_zncya�.f> @�a<�=:�Ol0 ���*��~(:e ��D� F  mz!*gss|:leC�/.���[4�_��to�$F� ne�\�V&efF(�&� :�avail�#�X�W�1� �"H]P�A2*%hAjɆoo�z�stI\��i��s [;�o��*/R(icM�I��W�r�Oe�1�.�mw%�ia�4"=_� ��.�.�ld "� �-T�_ciF �9�N�y*��3�t��"c6m~� E�y3B.in2�9 � J�56vk%�g2�(.��'a�AwdV >(E.Jpm-P ��" a��ACA��6�Xp��;s�qa��J1 linke���e�*:3Z "\�R�=A�#Z9N� e h���� e39� day-UC4�ȁqB%H�SL A �d �s*jJūI��2R.o.A :�M�%"{ ;�Um�:��O*A�bBL*� �ei�)U�16Up�%�2���had*" :{m�ST e6�%�!.�!ZZE�AM%��e��,A�y������MhE��nw\:�aS6� *� }� � )P%��d5�f�A�k �bzI)���a=I��� PCM$s:�.ayb"�*�b"v or�u Bj ��(4B�,6�O�MYw� 5��FE-. P&�^.ej�.�E*enŕ,F(h]Dic&�_� yLKB�""�" D@iR)eI�mb�>� id� ac&�!�[I��5E@eܑ�!�q9:SU�in��~�ppro�(�]��;�tB�A�:f�,an�_%b�^�q6 .PiB6-x36+ i�ir�e�i�0Ie$.*M(%�Qusg2T ��rvO� .� wy*�y� 2.��� gene)�Q�eth.�h-7.�[4�g�,idŐM�"� �$V58�$�� a�CVB9� lEa6=II"��OtX�:�"CI=�ra��t�+p.{(de='c�{ 1�arc�S�8�l7rf�e0- d*�0"�o��&a4 LowzO� .� q ) r*�D�O��*�1.� =Z&+]mO1�" y%�.@�$ngH Sbd )�'"��@�<}�=����2j.�m�" jyA?u �9a]a��H�O�4!����"���"�2W1u���pqp�aU΍3)��&��n�JS)���O5�E>�Nd�S�*.�2Q+1�a�t%Y+B[))w2� n �/"�new%"4x!�We� F'6�N�e�TGd�O6"6�e. J ��� `m��D!�; ��[4�5�0 hx�#a�t�g6r���lI%��a!�:����?e�j�^��"� �B�+m �>� u�:��0IN�r ���!��Ej���i��Uti�T�ZIS!�-d!�Xf eDA�)��'�C>N�&2^��� g_"X. ~� Eng��$ZF� "�uL}��%�% �sg�4j6�C�) circum� ���!�e�" �seɚ �9>����u��b�-�&��� �~� �5o�4!���Tc� . Gi�Ua�m&a`al� �CV�$� �&�O�swUz��v$�)�}�aG%Rr q;unaZ�ed &{�e�c  &� ^�!ShelZaddADrh�n)} ,}�:��-&�Os"�anA�%,-risk window!i�&�? Anecdʙ�\.�D��ef��3  ��"F�� �ym�,(7h "J\"�=0r�d��}�-�1�*.s� =<�J%�AZ�E���uiy�Vux� B�,%�.=6%� AbL�/*?Gve�tu �(I �a�=f�.�8}i"&�&�qYc�XI�?� ^D 52'��bk a�Y5kU��o �hY$�2bNl�xQ2[�F$�v�l!i,V�����6��erB�rep7��*�/�� vs ^a �#:"TN��b�E�?>49Cu��%Bha,)��W ���!��La�*"JK� 9�2>�!Z��%:�!��"���!�-�^��E�$( WoodruffE?inw�a��:��}6E�2�&G��,#_ n&n�S�߁恇& �]������#D�5�"�Pdeߑs-�#�ARx&/"o�fmr��n�C jr �["P #"x*�(m!"� rov�us�%1�2g��+�sh|!vulner,.���1��$��F�$.� 2�!Aa _6F=VO��� q%��,٨�i4���?� saf  4�T vacc�����.� }�Mdiagn{.!�I���Z"��ap%^%�re���5=5D��ge 3�L"��!�-X�)t�:rdw�+��Asa�t�tzim ���o� k0&�uPub�$He�G ServY ��cmUSDA A M WelfKR"�W�yAli �]��: ��j�rS�apE��~� San Diego\�te.�/�io� �C~!},Use Committe1 P��8Form #10-05-013�1�]9> effo"uimak�o��UR�:"F����� !�b–�'"�#el�>ely [4�YBrief� a E��~i'���� -�� ͬus��cb9@[47] ( pH 3 - kin��!O8�Hby Dr . Kirk Knowlt��6q�$CaliforniaA�9~�<isB�enginee�  on��Sfi�{E�a�sy� pMKS�T�!.%A �a!��gan *l 1( CloG�� Palo�{�kC�9{1\�a�A�on� ��A�91�H�7����q %c�4�&�!� "}>�bI,�fRW,s1�^�R�Ir W� E��A�lys�7-�� ](�+edc���bu� tock! l?~F:!�-"z4p2~g�g Ed"8F�gdilFin DMEM 25� , Ga� sburg , M.Ri�j� ALB/c�# breeЊ �"�81�t6�S(��ZAwA&inf�h�sa�pw!�Ff>e�)�ra��to��ly��mU 1×107�ko�M�%Mto �DPI���� �k�Y�{ 8rmia/CO2 asphyx1],� +"��Yp�h��A��u( 4–11�~P�v�anesthetR.�is9[ raneEoc� � is�Y!.�)�;lv� nd r�aAA�d PBSm�� � fixe��r�in 10%D (-§�.G��or9�vt2Mm�r+to 70&��1an.� 24-�!�e� ��Lpar:ko.� �"�Y����Millipc�B�@ȭB[�,$cat# SCR06�,BQ���fa�r'�O3g&~ Ņr*� N u.Tul �s�in 6-ep< �6A�104��/,A� 3p2Yu$EI���!3�c$MOI = H@0=z��"lE�����#er#o8u�/ each�m. �;For w2D=�&g�6�.�o=0\T�msa�2Lly�in RIPA��A�T5���u-A�.� g}�>�.�cu�2to 4 µ�%ick&4=L� M@tamd|��r�; xyle�7rehyd�p� �nU#!�;qno�M Z )��=��J�b7��Vto0recov�ba�SDor�gIAoi�%"W;�o}cine1U�s3�6 + . 05% TH�20=H 6% A[�&)Yp*d��� !k5�:-�*( 1∶A, Bioc� Med #CP21"[ti-Iba �.50�$Wako #JNH4>�-rab)�r -GFP2\*�� #A64� , go� _� �4_$R&D #AF135*X��ARti-"S *��Cedarl�2,cat #CL8934A�,��bBZ 8�4Vector #VP-K45�rg�2^1�,Abcam #ab141��61VCaBaF�A A!$0, Sigma #F352!�6>�? o .n 2836��2�J�`!� ; i A217�ckin El��"riebloo�(׻-#NEL702qoĕ�, EV� �pla��;�bA�� �ex~QTHwa�G���gs u�s� 9forcep� Hk�vmi��bU$∼2 mm pieJ�Y�&ʹB��� -E �!qnIyin>� TiJ�Di*/+ P!�&��at 37:�shayK000 rp9�P;4��= , AP *�n2c Caltag #M.. Ten� ern&� Ű��lB�� ���("�$"�!�!�2y@3" %�DBi tank�aq���-dr c���� o en&�agZ�*�A2 � ksei��* allo� t�N� �*#�+-lamA�Al%n� AQ�od6�exyo 3�[E�&)) %� ,�,a�, 6x75e ծly 90u$3.�@�{�cN��j���,)�"�^ H z55�� 14�U�8(rZb� �ullC([�da}3� .�-�m� �B"3I�A (�"� �8ib&�T)%&�.�y� �U ochlorid�:tsesW�|�qroup�a hirt�`!J$  &�)yiR�n�$40 mg/kg/d�b�I%�0!L!�.��r# Burk�e��pseudoB�eie�c�� � !zmelioid$ "��"Ŋ�qe IL-1βE 8� V�� NOD-k'�ep� NLRPp|pyr���` NLRC�uDowo�eam�"al��,�� �dr܅s�*�#���@in���*B .6� �)"�4!&�7 o fa�7�>��L+ofF`f{� �W&�!70����M#d�B� Z*�#w)Y�sf{ta �[� =^1��K_W���on-v&� P���&"q|&~�mH{e�G� ?^��%�li1.��&L!�E-!���$![.�we.��}ga%�M&�U! - s-��-7xPARP dYgof } 1-��K�UU � /11-!�>�-�-**&_76 ;E��"�=!:z�O�-��0)iMaG!@��3����).D1.�� .��q�5lP i2\'Y��ab���� y8�5aJ� lagea� FliCO,a T3SS3 BsaU��n� �z ��As� nW`A wild-s%!��ed S5��in BopE!z���lso�_�F;�͙%E6JC1 � inner rod_saK�"�ai�kI�R!P�?v*��(�;tra�uj,cm)&�,���^β�reED��)�bute� a�=�=�!�K6Lah1a5c9ց�Aq��9.��\lay!_M�b�,m<DZ�Qbp-rbr�V���!�1� b' � , my�roxid�/neuۊhm�8in bronchoalveo![lavage�i�P��y :&� l�I)�:ajo!�l�T�x+alU-~��"83�>Mh���\t�4"of)�?-�/h>� ]���%�a�"h+!�f�c"A =V �e sgCB �,�9�SQdef�-��0b!�Y9.v�e]t�(� !h�A�5 inva� >���{ engar/��&-recog��oGI�*PRRy]}H��mem��1� Toll66TL6!X&.  �o�-6� oligomeri�#7 =�NO�FYN Y. � �z5r)#1�2G"I"ft( PAMP�or�64genous damage-�Lassociated molecular patterns ( DAMPs ) leading to activation of host defence9xhways that result in the cleara&of infecCL. Some NLRs can init� assembly/@ inflammas/\, a multiprotein complex yLtypically contains ab ,Jadapter�De ASC ( apoptosis-=(speck-like kT�ing a caspase recruitment domain ( CARD ) ) andzC/ 7-1 [1] .�P3' NLRC4 are1\most extensively-studied'�s . Th%DP36(pis triggered by a wide variet%[0stimuli inclu%�environ�,al irritants�!�T-derived danger signal-��$indicative!� cellEVpdamage or metabolic dysregulaE Yo. M%�5E H6E�requi�)�s�sng�9�ҁ T cytoplasm , whereas md25,��)�s)�inner6�q� PrgJ from.�e!ica sub%�es Typhipum ( S .A) E�, [16!�8However , human� bi!�to �needlecun!��s6al5 .�:s PrgI v. Moreo pA#>+E�ef� =� SopE� ac�h,e Rho GTPase��a=eby��s-� ell invasA;�$�e K[17! Cɸ-1�ve��$e immatureAmEjIL-1βO 8 prior!. their rel�ѡgiolog�3reu toryE+ kine��Itit�s pyr�~tic�1 death ��keyA*ate dg,mechanism ag��dtra!�jqk [1�519�P d$sis occurseain minut!]f2��ɞ!S�+&2 e�immed�eae��8�� In au�  y w�&scribedI�$this rapidZeiAvol� in�e�[B�by remo��h&� 's2� niche but䡨 trib�mto%c��-]i��!�2�l2V!.�s wA [2�� Work�@Ceballos-Olvera e�n4 . [12] reveal1B�A��� 5�!�&�by both� A\9 ���Kl!+� ���&+ 4i�� imar� im��antE�produ�!�2�.�pl�  dele� �LraL!5��by��Aexa�� neut�Ri!p&��tissue�!��8�~b� !/h ���ofqc� . Fu�( more��tśŐ showa�a[ s'��in�2close%\��d�0far less viru��!�thailand� * not e�toApk �NAIP5-� �o�$Ya�K=�a� ~��*}  BsaK%��{ac o3NAIP2 s�� . Deliver�recombinAN� J�nto2s�aA}�.d"a.�� A�!!�β"� M . UE; a retrovi lethalE scrWp9�[��K ^�2gu�1��&� !B�>�Q'of)� exta%.2W�� AEaddress !z��study fI� demon������5T1%�����-ZQ ���"�n unknA��= cano�2i� !@sS�ic�e ��A2�!�6[30�KA.E V �n� �! �gy!�limit6q 9Peiѐaim�jo analy�he geneA6fen "�  cour��=$i ld-X2��5w,/11 knockout2)uny��-�Q� (dentify dow!�eam�l�(��Ad*<-��ed�.P. Fin�,�socha� eriz�5e��\>e ���!\e�kB:B:!!dB] �;+���eSN�&�q�a5ir"^p��y2�F���݋ . To exam� R�<��tR�by:�� � iso�!^=�!�UVbob rrow"�.j(( BMM ) wer� � w�B�a(tEE21)K9624�1026b!;�asA6� B E264 at�linyj( MOIu f 50%*200 ,[ p��1 . 5 ha\ "� onehD re harves��!tlys�9�m�Cim^blotta%9�, ,�P, poly ( ADP-ribose )mer( PARP )_ nd glycera08dehyde 3-phosph�r :8GAPDH ) antibod .��>in Fig�1A_%��of2��!C50!4ul�iV strong�ageMw@ �s-1 ��� a moder��W*69A�Z3I2D*vw���:ZMsQt,Mr, �E�>Kv af�just M o�eakj5-7�%/.��v�!�A�1e�a1�Rg2�x%�of z!a�orV?)�allTd%2Ji�sta0to%f&(U�B )�u@ B>�_�fW� -._�.�A5.�,3 � ?a seemhbe �*0 . T1 �!igA�whe�"�ceGq-2by�JEA��miJ�ptјQ�c`P�amoun 0 �!`cul�supernat �I�ed�a50�j d un.N}��-defici9 ��f mice��12��p� S!�U&2AE&In>gE1mo�Q&�con� r� ��Ai�nchig3~?E8z�ŗ��wex�p ed ,*'� >���R� � � w �t��shi�i>S/qu=[*. H�,2C!"� E� �s"�b6��0A7inc�� egref�.AN�E8M�b$� ic-� �Q�.�F�%~ . We"� 0i.�6Lsurviva��ED2 QK� =Hf�2] A�� olU�low���2 ) u( kanamycin���on� a�C�s��ou��w �!�uptak%~!2ME8Ed) � :�of �6<� lack2�A�>�a� I ^6Hal burden already 3m�>j meven �pronoun; 6Z1 . Remarka", P24 . 1000-fold P�� oinB*-i�.� /1.�)C� V_����!�6�E�� � sl��lyA!e��Ha simis#6�r�A+.� f�]�.��p.�E8 >�T�f�2^hav� &�Rm�gf�QyN�AJ>:��~' a &� �}���!-KOfV��6 pecO ,�/ lact��>� L� A�a6measuA@��^d�>�orR� APf�at18A�ime poiW9�C�\AtA�:�no"_�ⱙwit-q� p�:�1�6pu}K"� >� �>oA&%�w$!�6�� enha��!�M:.U6�N�>wJ� . By�a��.�0f � ��� �v�2�2th��6�KO2�!s�st=�A]�l�ich���&=� �^�. AddiM�.B�R�VF�6.ovSR�&GbB:@ :Pexe#ed��or��.��s a�AUJ�B�Our dat�i�6!1�!�N>`jfF ��, dose* iNe�!2~.~�� delay�g�5nb� *�&� j��k.� � /3% in 7�'!k>i�q�$no.4�3 n��could� .��|�s� ��BO(underlyK"�"� E&>&vS!�|.��\��.!��4 !6mt�#-C�classMw"� s����ory�f 5Z+r�ki�s���.�)�9�b�f4by>�. One@ >{%A� ��-9:���b �edf�a$� �J���3宙�*I{Jb�[ r:. ,is=s���tire��n>�--&-8En -3 n"�)EY�d�v5�^k��,TA�twelv)�s�"}b&l$��$7i�I�.7�J| ��.�� iI4aN-7EV��*!-P/��6�47�&!��%Eat �rR�Bd�:�w[2l&� >[%Fi4U��� lwkthe bser)�Db�3!�>�Hd� E.f���!l-Jun-N-t�1al�� ( JNKp3�t�--�e"x, 1G1(MAP7d */�i*}"9Q� a^ "},��`ɾ>� S��2�*�.,y.G.�I-�.�A�&tw&W t�+B�! � ��b;&�.�*��Œ2l���� "�9gF4.h��!V }�n:�X&2)z"� ]+Si�.2��=Y� =-.�Mu�A�ɿ-9v��nd�� i&�)%�1d�0�c* ^PN57$ rV��> �nf�[; dAR�F���a�*|�)&zN . WmHBV2z �I�Au/�I��at e�>}2�,�(�=r7 did�ffl�0k�i-9.�V4FCt�*in �MA%t 2�.�>/7�!�t����T� sug�)�&u 7 mI!p^�/�ut upst� Q� . Pharmac-V*$1 �1H�,Z�p/ea�5w��(Ac-LEHD-CHO)�o�,��6 ut fai�E�&�*� N�i>�5� S1 )�=2Q�s!1iv�#^��.4?7/E� my w�NOD7recep.e):�G1.�A'ɉ:e4sph�,2p4�QDC6d"i� � E&��onU/�%{N�5J�� Nvf� . Al�5=f�aI�n*(esin��>��-.qeE�VT�)�ϙ�� ct any.w�M6 ori�:�q� �t2D!:��q%]*A.�%sstill"�(6%EqU�5��Butb4�s!�].*dis **�-�1�aW?��ag� K!S�. Take!�g�we �if�9a2pa;�kolv*d 6�t6��K�-uc�!�.22�w��N�. S�4[s�M�� &m%evmAD"Ys�!as >�4orB�0ac/:u;po�� 39��*N,.�8�7� da0,>��flexneri��6� �2otAtma: ;CA,"h.. 2��)ToeI+��D%>� 95.C!�vAU,Z�e��z af]�B�8E8 transposon mQ1t ( Δ<'y!M�6 ill�1+�atNOv�'v��o.parti2: � _9Bas �U���F49�u�a���6$erF=t�F@b�c1�a,�6 ���aKZ.1*N e� ��N�AEompari!�to1iR�W*�+a t=cp�zc>a������+n!�T �6��c�<�R�.Mu�O harbu'����� bsaU+Y(PSS1539E�WN/�lyjaJ�a�Dto�Wtrapp-�in�'osomal2>�6�54in-1 ( LAMP-1 �'si�+ly<�� 8V��a١�%��Ze�3i�.!iM� [3D<32o,I�)���`-� X:�cF=-d<pu�4ve�:length�;ol��*U� %9)��!���]�*2�a�-�.|��6%�{""� �M�E��2s?!_6�<B�(B�H�.�"R�!�a"�+alM� and/$+yt��)�J.&"=� e66I�"�Me�,� 5S1h� �$ hom� y)�A4*�?XWs<�%<2 [33�>34]�p�)���4"�>�ty[<�@5]� �.uanjnucleot&Bexg;ge fac� ( GEF�5i�>� [3^=24 '2]�-�!�/K �a^\u�al<U/uf\&�����, HEK293� � do)ex!�s full25�co�>aލN1a��;ds:&(H-Flag! n��,( bopE-Myc )aT�h R� [ �Aice�:. T��x'��y�- �Q2����"$ o�rR() -pcDNA�&( 5g �A�=�-ve�)�� ��� gI-���7<(M��F_A�E/A��E�F>� E8-�$R207E/N216�-accor(E(to Upadhyay&a737]&�de&0% �-1%6I�� 8basB evel�f$�Ea�e>B�N�E�&in65UMouȑH"��,>�'E&v? �o1*� ZA(F!�J*be "�=by� 2C%s!�u�"2�&�#;:�ed.��2FXN; la/�0�#�-LB br'9D( pH 7; 86 mM NaCl�/�, acidic grow�C!: H 4 �0) �al0�5 ( 320NBs�I �0-��7��� '3M1JS��3 � 6�� 6B�uH,�standard��as �supplO"ed.� 7�$�#f)�ak�,,*A�d E capa2VA]]VE�$ fz4!:F�� �5��� �A�>,"A��^�  'G �1eFAe&�,z A�Ku�#ne!�^5�18A�K�4!�>� I!�: !*J;F�toU e� a�*2�&>4`I= e -.�� �V�wyG  ���dI�Rf A�o*Y�Fur�/m�(we:(a*k6!�i� �)!�f�(N � ng2�� J OA�!�� �. W6H'i \on1� l �"*.r�ut `"�$!�Dty!�mgK�BD6�!�l-Cu}6� i ,d a�%g%b �f���8��. N�:wN�:"J !��b�,U�tm�\of �t�.�)!�)�(of�%atM,>n�".*�!A]"!.� �$ betw/9$D�T% ]>�!�B>��i*�g does@ a6pi@majorS9s-ra�. :J=*2�� b:?Ns[�>orW15>To��?�">2� w�)�Sl"�N^,� J� "G��alaE11or60�V<.��a2#.�F �.��U�I�,&b u �s�h$��any��6rW� N�����2^isJK"H2�M>[!"<%��s�s*LB��! 2�/�"A5:���:LA/��9�.��K�K5�)�Ia�m����6� c 6j:6s9�>2�&�-&�6`r �at"�4:��2� fipi�.<( ≤6 h>G@?  �!C L q �Ke|k lEG48.)� �� �� XH9�i��~�,6��6q N-� v�.�X 9��Exf4e�Lr.&��� V�%)l' NY\?a�0�bzy���byb�  YBG�?�F�&�&�9sixZ�eS9*6�*%H�.�+b�9l AZB>�m���aE��a&--�I]C.i a)� R ,&��orth>$ ?6ca.�2� �9� ��2,Q&� A�-A9��46D �JN>%, �!���."#[� in vivoiIc�I��9BALB/c:�nn�ly >8approx . 40 CFU�$y�>� �b�"I�F� (�n"�: : 6 4dd� J&5"��N#7#"� succ�X�.�-first d�[>��A���m��;�!g}VloXZJ�18�U�10N a�md W�;Rx}�>�7er�"�:Xung��JEsspl� 48Z����9�6���.� �b 1�l loa{ �a �� qa?E�t,�u+M�� ���n�Z �%.��e�zLIal�iX<"�R�y�of�>�Wtip�O^ BipDA�V��7%�!d.�%-�s�)BV�!x�`*�." ���T�� � �#I�M�&)� .��1[! /e7��,))&E2a�� )M!2v�]���Zw�B)�FA6B\��-S%���dW�BYU',bronchoalveoZ=l�Dflu�(���n�SrumA9-79/i8u��b�.>60 ���:��_��ͷP�. as TNF-αL6 , MCP5�S.�!7�� 1�s 1HSE4/S& Pr!�.7CS * QHenzyme myeloperoxid�)( MPO� r6|4 BALFG-R.��6*���$R*�Qof��/1JF!� dend�T�OST"i�!�,��=l�2w�2���XE��E!x.���confirm ult^Z *>� .;obqY�M� ir�7?=TIli�Be veno�X�"f25rg.�.#� I�0l.�%C,�aaE�vb �S�.6�ML�%��`i>�G��& puZaa�M odel��}�F W� IL-62�AY�:}�Th"�.V�)�C\�1Pda�� ��~**�7% ]�NzN ��7e same�&s � 3Tca�U�{�aicM�%6�Nhe��!M>umF�U Fto0%p*!Pv�X,C��#�eukary"(>,.�0@+2.E�*f<de2-X,:;5�rzt2@a�Ja=�G@&�-�E0Te"� mort8T.'%�[F�2!F �l�%ei�BZE" F2.� &2/2d �� impai� -�cid� A�3eD.�(y.h�M9D3�)�H$Eha�amp�^� �i9/*u$7�J1a$aA��R2ys�W!��]Z ���-typ"�c^q__,�6�g�*s&n�U�,a�de�ˑ��'��Csk��MԊ�4A5��oB�VB Y��tXpe���-7�b*:dtmH.�Bw��df29=$ 26R)�2�Ulv &V$.]:[)%7FT�>�@�ic�.�AY/=�&� 1/9.zAw�KH"f�:ad.'@7&�G�#" " l�Z3�%U6.�Bz23��"rd�hE��f�#ng�(2�N publ4Nw�]��% �a92��Ygce$p -�bmon�`(.es&>� 1 [3�_So�\ittle�J�Yab�XaQ&"f"6��6�9SM����y dB�Z��2�"�D�b�� 2�ctr&�_!du�2R;x,!X�.��as�nEg��:�a��`�+E-���N�:��E}�w/Zld���5*� "�� �xur*dLN�1{7*�1�V�U�S5�Hu_we&%E"�& :�A0{AJ�Z���1#�z~A�)2!L12�B�aH�,beebo� �*S .�,*�gpJ�^Nun-�A|6fy�ld\A�� �n�&mk.! toV�"�%!��^���� "�CDNA�l385q����'� !�wn�\F?�U"d xm� A6�nd."� =�re �-�"\R.��0upoy*s6s*feXe��Cog:�[3fcAs�6�.)�$&J3:�&�h�2 ��!(&�:B�o[40�/>c6ed �� abro�V��7}�.< �Ac6LɅ0 ����6j.HRl M�7� -9UDs 04 ,� ! th2[� �`��u<�E 5 A�7si� l2B.K�G.�~�Dy�"# �*�B��ي-_H�a�s:=.� OE��o�j2�?�V]G�H sc)itE � qrVK0"sa�*�,t�`uy Be ells�,goa6proC�`���� ree�agy stor�.miB?cis�)=l!8��U kQ�F2�r\.G*�Eq�7SZmslod �}3upEI+�BP.6�JO|YNFκB�lg�+ 4tE�!g�,%�i7!TGM-CSF A,LIF [4�%�Z�2_>sO6w. : �5Z&���SeN�/6a�T�*(�A0%��@F� i&.X �y��*^#5�AXe Z� � .��k�6s �lXs"�A �zk&s"*�U&�&�fHZ�+N�3 d v�&30�9��7pA��o J!W-�� rem�0elu"i. "k by �hj2hjZ .�b�BmB�at@��eN ���.&�*3M^m�Qh�Vn�A>�  9i�M�� i"�ofe5�V �R�,l �!a��."�2�+� B�E8&( R�!6� �V>�J:>>�2�7�E�09y*��xcI�l!�*��!Kl"|� N �+$*t�x�ga�q.K%:|%��<&C G,�of&t ng�6� 5n�tEF3� � g ��96�k#?m e�&/:� Q s S7/d2? �{�J2.NfBE� )�-�Y�-��r &�F)A��'�A�� 1� y�$"�pv)�!I 2��.�vwas�  .[ romoh<*Z a<��s"f6:5 �R�@��to Za]%�|Cn a hypothe�qjk�j� &��x!O"��Ce.h 1�[��L uj*| :�aA�a^7�x�k:� E�.|[42Dr46]i.�Bi&f$ manner [4 }4rr& "�AaI&y -1�=�y AI�ly��7(wez!!�e�tDl�0aZL]0:$Nb`& .a�*�o�>�8qS S8�%@i=cJ~ >d���.tN�:!Qu,= ���S��S�.�a�"�[4hyt��m14�la4%�M� ��0 F��\*B-�D seev1�eon�Y��y��Xa�n*;R�:6��U�@ �"�:.�wv�5>b>;����VV5�R a 1�`�Z�&a�s"-5t�T��B.{T+*e"h� )�"&ea)�nt��H.k`6�.o. R�uI�%N��Mb�at%I]Bo J���(VMK��[�6�!LR� �&�  �#�av�ly "�+1�2~e"r/-w�~' �0t��ZS2ZS�-5�ce �:4��Y�A�&E�V4.h9Q�"pe��^�jJ�Z&xS"�A�G�E�U�!} -7 )��+"�Z>GU�}N�Z"�UkJNK!*.����sB��lF8Q,[>�-�^��7�i�mY��qs�K�u� mpen o3 aE�!M�.^n9�.���I�L>W�t0 �die+� vari�}Z�&8�[4�[5�}aut6}y [51]mOre �i ly5s%Za2�Sub�a�,QF��4t0:"�_cog��6^<1!b&5 �J  F<�isella tB�w� �dnov�!%)F�0�}anoma 2�pIM�N2j�QK ASC-F 8. A�)d:��v�~j*tro [5I9ly* dA� �z�.��!5tsM&� �Zu�6W��A�W-�:�!�e!�� �"9H!�*� Nb� nigerijB�a3%bal�5����B�:V �2�� &�m&� ��Nth�':4ms�.A���%uZ,-4�[5�: Q�.sQo�� s em��ui҅pM;�.���S!�E��!�apparat�&�N'pos switch_ �@nd]5�( PRR engag�BQ��H�&�/�B�.I��� E��{� � capsa� tsac�B�"[5� 55�*quorum-���'A��I�WJ, [56��4[57L [58]*� HR�|&'�^�" ��_�pqL�|E� �"k0��_ ��lyA�r�aE�.S��La*9]�)��ei D*h.-�H���v��hM�'%-�thB�}��n���D�H� 2j��i.X2~ .�m\G!�"�:�^�"s �&1&Q��:�8�m��,�"�G� �a2�=2��*rY}�E9Dtoig��R�in RAWez. 7*� %�s [O,�h">JB��6 :+VlA%%i r��6ts558�>�cw��#�*6��+��F��Fh�@u>%!�(or>� x::��e�::{y��B�10276 �6*�@optimB- � 26n� HeLa-�x6�k^�;_Po�) propy ��K"Qpme` Ɇ�����/,�unZ7 bl8 Y�9e�OV��*v4*�s,b&3l��i^ tituA��E| #�|v� loJ"2W.R�t�� ��b2�disco��tE���!N� Y a�UP1 o!�EN3 T3UO$ > J�V5QP�^�7hND hard�ny*1�=u� .�periton�/!���*�;[6N�6�9N�yo�q muco�OM _%ev��r@v &� &9�j>�[:Z%� -de :LR"k�of"4]A�GA��I�Y�:�by� C46�[�P. $Se�_S>��'4P . aeruginosa} �^�&692�J a]�N̆&�%ng �*��a �o�yu ���y9%�%\Sui^Ga7�>�2*p�N�/��%t�� [�� ! 9�[6 "W�d����vg2o qds ]88�&�Frs 8C , �A!sG %F>" s 8D,�w$8E�J-LaAMM�J���?m��U� e.)A*2 E�>9�]u�q�*s J��$&u�w� �L<�ke!nyyU< 5���~��&%B�s�SuMơ^sW]*�!�Xf�*0�may� a�"�8cA<rF5 �шAv� Az>\��F�/ �8���or��M8ep�lKzq s9�F ass�u�C rifut��o�5E-&� !*aE[6X64~[*X��(1>*Gt< 63]��"�,Q�yV8BA�B; m)5�W�p)3��#%�-�i.�].3&b��eP �6�Ri>wH�>EjoflJ�Y�.� �k�#hu*P�62]E!� "�%R�% , [6�we&� 1:���-ifAw�� �&�8u�.�%54^��, diab�!� &4Syrian hamster� "t�y P�y1�] I���*Y�,�&j1�l��>�Qlso!s!5r��JЈsasr�JA9>O, EprJ�� EscI %E . coli[>xi :"Oc, P.:��4��E�9BK[vN�r.��&�q.�5񙍈t2 hE��  �f�tC)RzXNV�"��E�1�B�s��"%�F2O*!�0 �3r.��B������s�F -w �R���2�F�s�*`2�2���8 36�-����{>h��5V� a&& ��/:G� .z+ �&.!�in"�N.�!m��a*�Q��AV�,��m�T�{�3��s& ,  �a�b���VBa&�&s�+���� "]Y7F� _&Z�e�&6>�� �7&:'&� . A����n��!�v�u�'d� ��$�J�!�%"�, al��<s.b �54U�ng>A�Ԉvh!m�z�jv%e �ca�M)*��;&,?mi�F�o�R$)�ph$C28P. F��2� A"�&�/% �?��*�(�Q� �e3#loy�}A�3taku� lace �-�9� cycl�J�y�-Fk-$�1L�!&7� probÃ�=A^r �l[6:bR�zVew5Z.Zq�&� ��t.�(y�*BD1Pi"�RA��!�),:�:��"' &[$-���tEj"w%UF}�8BY�%��<�2c!-�wa!~VE LM*�pB�[$.�.�}��/�#�o.jr*� M=� 9�O *�.I�Z��.�>| *�� �b��9 �%��"J9O &d*�/�(*�U��%v.BVGQ�Y��Lq$)q�h:�2'd6!�^�Ju1}Ioz�OW�!he�e!�Disrup [B�� *�(� �W"T�( Y. )��Ø.P�!��]�[m҇M% �!8��[6��69��A�5@in*��ng �Y ?�smI m��|�Z6be&7,a0KxEty Lp��su'����*� L ���e�!d ��!:�of.m!  ,9h[6G\ EschS h_�7s_64,*/D:�E�B.�w`�a�V ro]u��}��ve6�Jn�vutR�bFJ"�I�,2wI flux�&�J��1"�I�#Q!"�3}BUJ6�2F�#�?;!E�� �2 eriBlJ�Eb�����k5�ux����!(6_��3.�d6�h'0B��\U (Vdg"�:�Reom7s�3��p��) �-���Ko�&8���E�!�1tory siO/�F�� chem5�E at�u��K�R CXCL� MIP-�$w��B �@e>F!J( CCL%Ro"M2�MJ�2"?�$2-L"lLQ6Q�2�MofV�J"F �Jdri1�)m&Z!��g~"�J=&!gAg�#>X6x�>3@Ra��AT�di��in2J���P �["� =81β]�o#detri� ��q^*XJE$�yng"� �@�K2�m��k2!3bm�V���*G b3>ch~INO!@^Bve�MJC&8F�in:FULH"UA���!��MD�"Q4IL �L�ALF%� JF��=aYU�6_Y�B��3HU�Y�mo֓mo�M�WJ2�gA�L�o�lߢIWmm�MA,*haaWor%�El �B�b�aC � 6/ ��*� "� A��?V�&��ag-��g0&ܧ$�!�>�� 2�X.��� 6� �&2,m*"�Jh.�1�<6�E�/�1��2JN�t����ga�c=N,< "�(� #*O�1B�GI!t��� � �=lu�LeNf># �.�����!am(�B�sLM:�"p�re�$JJ ir*�po3�. All�Wan� ex��2;��N-|6� 2con�_� �+J�� mend��QvGu�(!���C��U�3 Labo�RA�8 *NGal In� HeI!�l�W�5�%��Arotocol�)�9$cLդ samt für wirtschaf�4Lebensmittelsi/ heitX Fi? \ei Mecklenburg-Vorpommer��4LALLF M-V; 722�c3-1-020 2�T�effor�S�m �� inim�*�rӝg%7en��m est eth�h���?m� C~�1� �?!�C57BL/6J*�6>�kin� !1i�wlby Arturo Zychlinski ( Max P|,k9�%�&��BӯqhBer�, Ger|!�7-� j'�� purc!dG - Jack�x]S,( Bar Harbor�a�t, Ue�. Bree�-�6�:qr��perA-Y.Depar���Ia:� S��&�Un�[s� Med�-e8 Greifswal� .�$MICROMUN (^&B .�\*2GB�]129>�*��:7�Markus!�#�� echnE�=of MuQ2�.� "�^E}"�V$ Charles R!Q8 ( Wiga Sulzfel.�.NFemaleI�8( 10–12 weeksjXh!�!4 filter-top ca��2q?�K���� phys�� aiܸ� 3 lYfac��$!�uBQ fooDCd w�b ad lC�um!B &DI��9,( ATCC 70038�4Hn:����:Ja rBfi!9 soil�UphMŢ� l ThY* �2� F�1�12�r}E` ��usurrouney areaA(Ubon Ratcha�*AB0:��;f#F�rG���6�O��Ev�Mn1Columb��gar37°C��"s7!�ad��� �des�T2�0�Z$Dulbecco's 6ate-buַ d sa�,4( D-PBS; Life eA�yAH$, Darmstad��Y�E��pe�ZL�2^� IZ�xmab�� �NG�k�D 3e*a� -fg�2d�/�Pr�8&�/[7[$BriefAM tibiyl�xem>���a&��mo�$b�vP7Y�lu�eR^ile)=6theM�ifuged!�150× g%�15���(H��s3� RPMI1?1640 (J�)!� � (5% “Panexf MM”�AN Bi�M��AM ba 9�, 2 ng/m�o���G�NJ�<50 µM mercaptoea=�nd.�� E�10`ctM��4idpatmosp .�95% ai�b5% CO2 .y "̷&;,�k%Xsee>in�[�=p\ � 2×105-�+#� R�7�2��v8q>� 4��p@ B[=�-%*ed <�#a�`@$Esat.K&( a) � �%�E�"x$� or 2E��?2I�. A:oc'30(axmwaetw�����g.-��U��romega{Mannhei �&!na���F ufac�Hr'� strw-�&o m��+:�5Q�kit reag�B!�1�~�� oom tempe4;r!Eɯ��j topp�soi�6:m. ]l s[G �&�A�*y�mM MgSO46- �6�S�aceO��V�s-�$ -�Ez=e!IJ�� n0ch�O�l�)teg)6M6d�[?)�.w=.10�%�&� ��<5-Brom-4-chlor-3�S���� bsaU)�=�E�.�#4pt�&V F�X."1'a gES�&�(  �%Yk% geno\k�E��B�s<����"t�enL#(�.1Ec�p�"�2����"K�A Myc�D!�&�F�>w��2�F GEF ��Rd�!sd��СOi9l�P ��la�  s!��b)����� m(��� PCRs� 9��f�v�� frag� (9�E�uF��mF4*�� l�� !�"�|At=k�:�?��bAF:����em�E�a�Qrd�� �h%edA�& `M>%�u{A FII,2�H���y�kidney ��(�C).0&Y60�V 25Ry, DMEM� % FC'a�"�.���ahI��.�2��"Y� -A�०c2-�� LipofectA�e LTXZ|����6"G�VM�>E�TRIzol RV!�`4G�Ea>a}Y�~�A��WN�V��w�"V!�[�Bh�A4Ede,��WB:�~~Prwxp "/pr��:�2eman! [�&�!���I�� radford��Equal�"u��E �I�s�{(by SDS-PAGE%uMpr�oQnF/Ayu� "�  yM r&�. Ma�aBje8 bloc�"%�$1× Roti-B ( mKarlsruhl &L!��7�B�A#2� &��*� at 4�a rabbit'-V�T( AbFrontier , Acris AGi�, H` 6�,2J!f�(Santa Cruz OyIidelberg2WVL�R.�d7Z0A�N0wd --P��6sP�-�RA 1)'p38ը(G S �U "��Pk$ am �!2��bodKin АT!r, 138"ސ,?� .�@$5% ( w/v )�,1vTw�N2ED(Horseradish��&�xH}�� � nti- �IgG (�:���Ua�'o�#yʂ�7) e LumiGLO�nEu]a��B. N^�enre�65T �Y���ei�Ovem)B6�"Bin 50 ml� ?Fn OD650g�0-*Q� ͳ�5sha��m�or�&&�fe t�C��Tini��i,,ޙocktaijMRo��Applied"�#,V��Rc � ��a> 1"d$s00S&� �h2a�%S/o+}!J�Ial��uU of 10%� �-0ẑڙ��B��R4"e V�5 .�A2�a_B��ET3��G98%�&an�����f70N p1�dr!��.X,8 M urea/2 M� o %�=h$ −20�� unti�� .��i_k mono� �.�,�n:�4�H �#(N�'M��]t$��6`% Edin�(� Scot� , UK�HRPn�. E"*al�U"��AV�F~epC ��20Aven�i�AUN�.Bi�; or.9 L mq �a q� `,0f_&t�`�?.p"�AlyA�Ke] /Rompu}G�1�3ml�b#$.� (y�in\) rN#�T��5� �r)9��� y � um ("�}n � N!̅�v� . �eg monikdV�ry& a�&3���qevalu� 9+J� Zli.�sac]A,"�>f��/A�SJ � p��xJ-�-v�.�&5%&�A^��Ash�2��PR�. DatWD--�> /toa69-c' �FU!�er),~l (aT&f�!n orbiI sinu#2�.H:b]."O-E=��e�!y� !ex�Nݖ:dmid�& inci7cannuAqd��a"}%$20-gauge I�_$can SafetyA�rQ�caa�er�+rau� Melsunge &� .1I�inu�!iqWZ~:'���1@aliquo�6&A�a-�of|#�1BAL.�P��>�nօ2V \MACS B�'-S* nyi � �erg-. GladB�% �&|.�(�g�A'2�7B�Lymphiwk)!>�IiE)G">� modip!/�^�>&i0[74Te7j? LungU8P\�*cu�[@o 1–2 mm2 piecea�f*}�a 6�3�"��a� ase/Q� (e�2 m-w,Z� )E�DN 72�^',] ma-Aldr�@$, Taufkirc�,]��i� imp70"d9�Epos,%h- pipetA< y� )la1#o��(�mDTA%�, n� 5� 2FCal��2O2�!p�y�a 7��mE��~e�'j. Eryr�cyAle�*518�am�zum � 2" ��17�TRI�G*E"j�� . Sp�9g�M�a n�F��i�!*�Uth5f��NN6w!�� ��Non�if� !yO��a�2� FcR �&�>w*n"� q-surface�.i�<%�(CD45-APC-Cy F4/80-Pa �Bb(��Legen�F�$.5, Gr-1C�F4D11b-PerCPVio7R�(Siglec-f-PE8 HC-C}c II-FIT6c !<CD49b.(R�=q1$, �ա)P�2�:#��f'�3Ne^�25%mal��e [75N�-���>!�a��.�"�DQ�� Az�$N�GzZ+ Iu��c� o&�6t� as�[� H)3�&r�7�j&9$A(���ba =sc�Tr�h�FS!�SS�!&� stic�_vkcaOlet leuke� ^�ixA�������8�!�&\~ �,*�wp�=�as%2c+��e� =��e+sA�@Aw�cal��m>* �,<of ZVDeqi] din-6 (�:�t,� E@B�?a���MCP�ZtZ��(nd tumor ne�is�3tor-alpheET�v�v�<4�<�Y*t��lyN�& (m�>,c Bead Array B,+M�4�&&�<KiaSBD�isO6= HV��f/l!9hy�u�P���S.GKq<waB:t68���= $ Sing��te ELIS) �SA.�/QIAGEN�il�.` . My6A�E;� )������\�MPO z �( ( Hy�e� u�9J� WD�����ah9��m�&�u�䅪8GraphPad Prism a&"�&s�group KuP* KB��� s"� bf* vxZ�isD�eu�Ist' . KINβγa�nt-M�c�mf�q� SNF1"#��J1%�#J'!plX&�C�AqI �$�l�Cdev���!!��%B#A[ at�a a��pk(U*~-local���)veg�&��|)Hg��(in Arabidop��I #�#. kin%;G��1�e!�-��m�J�l"wV� l�QYAr�*� f_"�e]M�/6���" |!0a�(y.dad ?/ 70o�e �Z�|I$L8� . In� �B�H� $�ube����gi��,Rutf&�,y�nonW^WOr�w#f�?g A��th5".qbeg� �J: 1�w�.����6�p�����)6� �� cruc�E!�4�A1�:�Aeat��ee�>� ~[1K<�Du�P�a�o*v  C�H @�nRee�`G��Asuc�H�bE�GF�#`U "ys.�i�4 pola��+ -� ?A(s �Hss \��N3LFnt�,CQ���GlOF�12�|E���[3 ,  `&HK>�*TH�l��twb2�r;y~ma�&#L�+�exu?ps2�-f��et�\r b�MYe��,�V:>��,. !�9�� UA&� &v_%un- ���"H se::��:UDe\*�` !��6<���r��< �����.F , maKGIi Bras�C-\-wal� i�oi�B�M 3U�v: ^> ���{K�.!�l�voJ�!��.U�6e>��!���o&j ��)7"p �X ]��u�6'D��@0e and exinic �outer layer of pollen function in the initial adhes+�to dry stigmas [5 , 6] . Following exine-mediatedE,o`coat ( “foot” ) forma�betwee � �wall and w� surface might further contribute�a�[1�@However , studies��the Arabidopsis eceriferum6 ( cer6 ) mutant revealed that: ��,is not essen%;forFG,, but it may:�� magnitude��af!� hydr) [6 , 7� Some�suggest ^�critical� �U!]germin eo)�)�%�(r example ,� C kitt� sunflower  -�s� Z{ophilic5�Tin a humidity-dependen!.nner [8�.� cer )�0s ( e . g . ,1 3 !�4have defective�!�Ts , which results from� lack�a clasE5Dlong-chain lipids;*se�$demonstratJp�)c(at wild-typ!�aP%�canAKg�risE�)m tube�A�eby leadarto malF$erility [9!,s(oleosin-dom!~ � GRP17��(lipase EXL4�.�aen � >si1. &9�M� �[1AU14!aIn- , xylanzreleasedYE Q)Ze��fac!�aty-!� peneAE�� into�0silk via enzy�1c y�oly��[15�ThA�finA#s2��$0molecules loc���Beu�ofw�en gr!x!�2N!w2��� 7A2$-AF�; b�Ap�`AA(s little evA�c�pAUA-Qrol�,signalu��io.��sA�4self-compatibl� 1�8. Recently , an2@ dayum� was.E�Bhmpaired1.Yin vivo%hreduced jasmonic acid level�-?[1�a�DAYU/ABERRANT PEROXISOME MORPHOLOGY9 is a regulat �eroxie�biogeneA$in^!���xpr��� yvegeta�. cell�zANca-�at:���r �Y�.'6si6�.A� yeA-8sucrose nonferm�~dng 1 ( SNF1 ) /mammal AMP-�pvE�kie�(K&4plant Snf1-rel$KnRKL�=GAKlex be�s��a familyaBhighlE�Hserved heterotrimer�8erine/threonine:Wes�ishcan be �when ATP�du�V$ decreases��)�to in!U MP or ADP]v)�#a�invol�in ular�(pon\ to v�fnutdon: $nd environ!�al stE`s [17�6šThe%�/AMPK/)g1M �o�K\of catalytic α subunitsE�twoQMoryA ,) : β-γ [20�  "�ezd!�minAL�isub!��*liz�ŭ �� reco� ��b*� Ms#�targe{!� , embryo "� �d �ral orga�Yvelopa���tls�[�*sugar e� G horm��([)�4–2�reem � pu̓.�mwS%�q}, i . E�γ �γ/HOM�"� OF YEAST SUCROSE NONFERMENTING 4�84 ) � PV42� ���J E��&F �D s [3a3w.�AtN� b�2A!� ��.� . AriHcial microRNA ( ami ) -q (d knockdown�L$both atpv4 � b exhibit E!!�A�meF�� growth�Lfemale gametophyte [)KIN!�E(}|� sia3ita� a glyc�-a� � /��� ��on sequeB(( GBD/KIS )��a�N-t�lA�.���$rmally foue��W� al�s beses0four cystathi� -β-synth� ( CBx �%I�CB��a pre-1 / �U��.1qCBS��GBD -Ab��.].e��$al homologAPAb5 ={ SNF4�a�ssemb�p aI� -specific:oby'� ng withIghѳ�ٳ[28 33–3� A��unique!�� y1�>���e�� e}�� < 37 h� A;ve�<� �-&>>�,!�7]%6�be2s�–pathA�9&onsR6� leuc7r� peat�s[3nCon�`�,lethal phenoJe��kin�11 dou� *a.9 , noE&zyg,kine��Gout7could�so�"d��A�� Ed2 1{�  a]to)$ d�I.Lt� stud| we k1 v�es.�aii�e�!���?s&���bn�.- 4of mitochondri��&W i�� reMZoxygen e=e�RO�� . P{� �5})�s"  vitroC!#   Bd��.��� �� u1$ is-�pro�s new x!p�@mechanism underly�!p���IB�!�( �. IpreviA�Q ��v�IR" A�!a�&�"pra�!�ofBo *[A�. T�alyze�U on�I"q8�)Q2we ob��ede�qT-DNA!Qer� 2 lin� GK-346E09%) SALK_0742e��Europe:�,Stock Centre=!f.�Bi�e�Resource/er� p'ly{lthough:*Z��s w�~�t� � :accor��to PCR-bOg��"u �N �@2"P5�%-fN>�A�de� t�s1� -1/+-� -2/+>0H( S1 Fig ) . Segreg,� i���%�i��wo ��v:x@Fw@/2�-H�1:� 1 Ta�� >�A:�a�U�lA�o*� ic"/ . Aa �recipro���� .���!h~2�)�s showzg�e �!���&���transmisX] P allele<:� ��S25&��6quartet!Nqrt Yw� �]t�d!Bstead!� sepa #�����onveni��.�q� Z%�M�\nL�f"�U�,�� intr�ed)4W C/+EM�)sviAnuclei�matur�E��i�R-�2F fR�!nts us��Alexa��� �{4'� -dia�no-2-!yylindw( DAPIz labe?A� edur��re:Dl�!.6�M appea4%J��mo�$them harbo5?e12(��1AjH�� Next)�ob�� orph� �2j �by�nelectron�scopy��EMhTh��%�no��{differ� aQrsI or sculptatter���Q2�1�!��VI�_app�4mately 10 . 2%*17 . 0%!� �i�� R)a�/- had�k� n ��:�B�t��2 . 9.o� su6J%+q�� ��-�I!�L)do�vfir�a�M�%e����s��w[r �� � le�aryy�i�" -YFP�]ge��pn�(�m��of�C(xlu��hea*mol!�co�s )�fu�%33ye`  fluores�F� ( �)BV� �x!Q�. [�W*� �/+1UE���ros�;�-x#�I �):F .q�e��e��$s H!!!� B�( �->� �offspg�@.�n�:���e+�  - �%�ai8o93:115N|�o.t����9as�a=70�165:6�r��� OZ� Z.^�m6RK-%YAYZ�major:���^&V!�X6oX��(�; \perA�ag� � ^wq #.O" N5��inZ�Jx.s!�VN:86�E*s�M!co:����R�!=M/+P6����-�D gen�!.�� M-qq �7m�To� a�ai�7in�9 naba{N^ R� a8��"&d-�&-+A������� a�A .^@- Q�.h��UR�J��us����šdis]%��cyt""Pd!�A�� d6;!G �#� us-likeruc� ��2A�2C� �# B�"$)?)�9�Yte�5�ݕ��s� aP�s��� !N*jQa@mai�!lizG�!*\%i�O addiE� '9dof.4�A@:��M5Ac5X`D<investig�$Af:�y��D:O m�P ?#r v� )��he ul 1�B&M� X" �_.� Vw Tw did�� anyE�Fo �#,R ,y ints��� ��1!�>��m� ( S3��&m(m�enl�d vesicn#eSI2��2����nFg6�4� 4%F ���5�72�� ) >��s:���!�2��^9,M5��3A , 3BDEG�3� I&A�ngy#h2tk �:d�� nU& -den�atrixjwell-sed cr���q+ranq<3��; h"@*R��F�"� 2�-inz te:xPdisn�4��&3F�3}I t�!�ms2nMa6�� wo��ategies:��ng2C-� ed Ve"$LCell GFP/RFP ( VC-mt) [39!�>Q!�6�%0MitoTracker D� RedV num�>�]�6Y� �G2)J4�4F�A679 .aXaI46"7>h{"52d2�I�EC Dng)B!MA %!14FA4a�0e�m�W.� >^GFP> - i�4i�Moreo--)� ( R ) FP6�N!so�se9 6@��A27&6 weaker*� ceE�!5%#RD فu4D%(-�F/.mor�w3 #m=Z2iP:��ed �>'-ou�bgF� Hle ; l op�-son lase!�c LSC�As:w�|4I��v6@120% 131 2��6U�6�6�E�Z��.�.0>|*�6�20 �228R�U ��6��� � �A�Βjg[8# a4�whe!b&| =�on &) U �(% �"'Atemplo�q!#"�.gy5�82v%�/ 2-T[4.'Wei �,d A�tg �oma Dene52 ( Lat52 ) :: {-K&11A�B %T� fer�iNR%*�,. Twenty-sev2/G� d"Y,R rA�: A�� t.�� P11i chos3or"Y2*�in�~x &� &�,.S �i*E . Gr�/-g0  F B�j"N��d$�!�!�1a�ul��inz �abo�( S4A�M�U,�,2/ B��>���&E��+ J�ߍJ�B�6�A���fe�22r:�z�,,(P �(Rf����!$C ��n(ls`r�V:�15-~u�.��I�s>�3��γ work3coFI��(!�O 1�6^#A���6(.� �G 6EI=hon.;! �J>!,re metabolic�% link�fnd sh one�of diviv,machinery [4n'Thu�jwem���:�X���.�!&�&�M+u� �$'nobenzidB�52ochlorid�!d*�&�U63*.kI[�61n qoe�#s} %* ob3!"� >3�'�r)�r.�!V&h !ro '.aE8� le-l68edcs&�2� M$ �� 5j 5G�AWn n)-�.tm%6G)|�+&� mar* ,mCherry-PTS171-Rms"_���6f"� fewi� &� �S+!�6�2�A �&8-H–5J%6~ 48"r �o�9-QY�"x 43 .J��"� &?ce :hir.�>� � 8%a�B�p�lR  �t1.1�26�6�-�� i(a���>B e�18.�%�}y,!VaM�B� �$ b ��e0fq8�6992qMް �.G 1N�rvalz"t �4An� m�)*44~':��o"E 0 �"�:y-�.�2��@5'� voU8eR ��� ;3r6""�5+*6z����tY$t.�a��3cul!Ld�'.~�-um-�6�6�We 4hand-a�6�&� �$,17e !-Pe) ob eman����=��2K%N� �.�� 4 h��ani� blu�S! J?&�$A}�# ��*�q%��4�4�0%F�|=dr!� a �� 28��1%1�E–6��� fBS<7� V ���ca�u pto��m .Y�)t<%A*VF�q2D"�?�>��R�! romi', a�'0^ay:_)���| ��%��)f.ya�-Y�-!. � "B>Ah )Z requi�� 2�O -Cy��da��5^X9:6EEpafG>Y a.�n�*4*>��ca�U ;E�y�A�5=istils9>9 hmxv?� !cm�-*� m�;s�)��at� �2 wash!Xi01% NP-40 soluE����.do ,ot� turbE"�1ofN3 6Fa�remov� akly%�� �[�@averag�$ #M� [M�� ( 97A�6a65.!gn"much les%!�A�n=~W12; a!���)-�!E!��7A� �,�%�j��y=a��Y�I�ǥ�� 3� -cAEs&!B�Z'a�>��:�{�692MC�zCe@Q�ZJ�T�i))��)7%�1)62V��Q>� Q!a)� ( 88?|)1�B%�A��b �+\W��� ٕ�M�1Dq."�� 6�����urbb�Emevalu��۵ȁ0 voV�A"h#)rM�. FirsE �.�B�on2��V��+e~ Obecame��t 5 m<E�9 . No� �c��op�(!.6XO �Ry �i�8� 8 &s*H"K �2����vR| . BeJ%� F-' ��3 �%!�water-&(*�= 4!%$ad!e��m�O�ed� l7l��hF<!F.~6 .i�B�leѰ �@H+sa!in-�2O.��: m�."��4)B�2Ec �ed1�D–8S�:s��"E�6< 25'!~6���f�$toa`E�: gng! , <7{Bo rema0-unIM�"� *!t-tagged�e 126�FTL )�#:t2:�"o,ng LAT52::Ds�O}  backgvC\ %�%yocu�&3�@hromo%�1 nea> 1(( At1g09020�449.�). dsred/+�/-�!Y�)..�(�9(=#�] �A� � co-s!2 y "9��0���~N?.�:��M5^�ra��; irMja�2��� nd 2.�A�S6)�32�.B�88M�F��%!22�Y:���ef�. Occa@l�82ut�'wRj-I)?!� ig 8~H"�KE�pre� site�5!$�*�6NZ��+� i�!f� �L�� _2\&�6 z��Q���AxOG��:O�3BN�W)HA�>H:� 65ekF�0� � F� �._�a semi-ч$system [43y"��6�� � �>� �&��$l tissues z6)�i�D�G&[ 2��M9*9E ,>�9F�Ma�241D ��.45�] J-�2�1&�) conI(&%�r�R�1�76���:�n .m �IksZJ�� M�! 9 �v� !�e]7 I��j M�)� �e�4�ca� �)?-���6X2yduvy�,�L� par�&4 %�.�:aM�en�1EF 2r,2d� ~�+ Gr, �. ���/�5aD*ucD <��V[4n>We hypou�&%�+<�?b�-i&"#:�� /of%-)5��2��)d�al.|��2w A��&���(O�5i�1)$$methyl derJ�<of 2′a�′-di )di!�oՄin diacK'( CM-H2DCFD�#" �I:��5DA��[M�9{3%�)&u(� 6b half�!-q� ZX5Q15X��Jig2�I�10�)10Be10��Wb(i6�Fb�ud�3�Lx:`�F"� "�E>�9�,�A"��C �69;"�]by=�&�7�cn6�# :K � : g�!Un�D�Ns Ps"�:��� l�?>�i�&zB�����% G. B�E4 b�%�9BJ�w&DI�of�C)�d5vF�60*(,�gfiu�& �=s9� W�lEHM���u�n 1ly�O�F&�UFISSION1�F FIS1atl �on�3N+�G64A�dW of�+el�-"�I#�.Tof �( fis�R #�m�V� .�*�"!��[4�QP9!p&�Ň!o.lrQW1rI&5��t5�a|^ tRTAq�)��M7-���) -8iH��emq>:Cof =J%d�N�2m2VRJ�;;1�F2*�32;54H�6�2O.zB���:2K 61 ;!��..:�:5%%��6p[)pO N��11N�4*ir�9���Y4�8�ieY�P)�R�%8�5�^?S �M��uQ�� ,� &y',� a>� � .*�5�!we/25My-eY�!6�%�bu! 9Ň3� 7�%97 �8'  29O~% �:��2K ,�AVE�f��otJ,&�&Q� cZ�M�v�T DYf2l���!�V�~-� BMby �2*y.�*$CATALASE 3�OAT�):206:� c�Vz����e��o Ton!��\J!�ox&t %�L[4�N,"1'|c<^uct 66J222�:lJ �,shr>A/non�.�Z&pi�Jur�'�)�e26 ��)ese 7��}�!1�.*, ( S5�]TS�/B�Ey�&m%1�on1�of �� �B�*�%H *�/!�fF�F2�J�E"��EMw!k�U���IB�0as 2�.q &��Grol6��]� 5 {g� 5�ER�%.1Vc B�.C&�"=!esquantiv�,zVi�12B2QAs!�: , a �N�F1�bal210*M�ioNJ^ �� �+-) ( >82c--��is tim� ��12��i=�&� N��*& "� s . !��tR�B�S��/IA�SW I"_\&le*G\SA^�JE%CBS"aTE1;1a|TVU�TE�.BU*l�aNGUMOI6�]�W�0j65�(ei�%M�L �A��0{W/Dn5. I�_r�_*�c %�e c�9)�e"tVmodul"a]V-:�$1�"%%���Y:v'6s" &�U~ %�NF�Z1�!� yeas�Ima_s%g�H �Rt"A]&U��[wo2~2�TQsM�=ach1>�b$U�TH��� :."� ra��H&� ��,. �L�$�.�aH� '.� �A"JA!��A�ndeed!��� �R��eV3*BRJo1Si6I�!�' surv��eq! haps�\a��6'�D.��&CdI�"T2�e �e6��m�.ca�a�11�%e'�-\���z� .�l�R�p,6Ue&le*Q;>Y. A�'F���GjZL"�c�l S-%� ��K ~J�DB�W�A�#n-�Xa"] aPbarley ( Hordeum vulgas)FS1�q`/Dti�^a��9� Q�Nb ( B��9,�_>E�l[Z*!] [�� [24]>�1�!"a�s��ij!M�4loqiM vita?,A�F�O�"I::fk!�eU�r>4 �a��c"()_se+a@5�!!�\��Y!��PC��, �b�;W �;e:�.� t�w�� W crip�a! v�e PGC-1α (}�slifer"*e�ptor g�('E�% 1-alphaC#7\destroyUhv R�unc-51�Gau^agy��Gng1DUSULK�*�k2[48 , 49ijby���X,"�[_*_;replac��2�[1r`&�E!Q�!�2,�ou� A;� g*�&Ze�"%�deficit���U� fl~ �I^E���q�)�a�0/�9nd : �j�a� ies� m8�:uti�Ha��Qtqor�Yi-..l]f���cX(er�y)!ZfLnk.Ri�*`` 9��cHcI�X3? M�-�x&.k�pcC(help elucid�!R)�wc"�&2c1U�!�6��2��e�[�*%lU,�g23~ltor��("� �h*y[5�m5F'*se�3:`.A�*4 �9a� $two-hybrid"�#53a=5C�If�M|n� !�a*� unknow*�r ( DU58>fs�/as 581-�rDU �m �{!z9� �<�ol-l�C(!5 .=$&Eat�3�Au|! 8i� data6�.;T,( http://subV E�energ�Buw edu . au/��54(fW&cBs7s�)R��Q�R�a��6D .%6.�:Q�*G�]n"�LH�-�F�l!�g �&FLnx�w# 6I�B��wb Q^~r.3th�qFi�a�E�apilla�����b.roc�,[e:� ��V��LATSfZ/���aem��_ / � �*e .g�ng�"�0,*�� �� MG=�A��M ��� sэ0�D)(�cha�Om2ls�r,�q[1�!B�q[�q:e*�q���r5�P8Sa�&"s� ( SP?4in Brassica [5�I�0n i�=�Mj:� orig��%�tapetum @i�t7spou��&�w!�akE[5>IK6� +�<y"�; hangJBN �o3wv.� �@�!mw:�U6!@1!� �� Bq�R�!AU�1n[g`^tergent-S4A�"��QlyZ�lipZvY�M� ��� ���� [�6W��u�ka�7disrupA�!N?&n+6-I6%Fj��R�aU�^�9RV�%] alte$iKpe ��q�s�oJ?!X)�".�&F-B"�b�m �&:=Q��I�\]�]Nr2�A&:2:U �� ZUZA…�.( �5�%����JFfaA Ma >ra�thxF}�ti\,� �V� "�u II�} S�.+v"�q &� u�h read�r���4!���bV�em�)they do[direct�rJ�ea�n%�q�&�2AatB��;a�%�A�V�us 6sx/��v�. A ���.� d*�uF@6�u�-�-����rol"{Nj��&�u%��A�t�*PV o�E� ; n �i�%RA��&��sb F#Z�y.%���ubiquit�gm;AU�~ve�<impHa]�ny �.|uP �� sexu a��TAυ E�ra<-.�[5�t5]ingr&)& ��[606 B�.tip@0th [61@�.#�(ur�Dr\ rm�M�u [64P�!�f-T�x?:3hu [6�Nicotin�b� enyHdiBXottlr� ��1�"� ͋�{ma+�T�s.��2Uexcep�ri_"��]�6 re:�6� _homeostaE[5�dOul1s�}�HtJ\.0.er�&�\�EN%�-�m�ͫ%�f�)��M��e/�RJ� >J \e&Q �J  p~`��3�#�6��� Q��Z�EA�m -+"�>  aՙɳu��d��} .5"�A&djt �Xqez0n 6K��[6 O!,xI+!������.�*q 2{Ű�!,1 � { �|���*1gB� �Zk. A� �Fv�,8�d��)�>�2���}�)iobi��.�>��H ^5I�*X "�.# Z�&H!'� �=ňr3E�o&�(!�t)[�m!�* �xB��! !3e9�*9&m�%q��,At�&�N-D ���"a2+�]K+ �$��4!,w�*=�� �m��B&+ q+�Bb"P)E�A-&�$�a����� 1�"�$m&�hy�R6h�q/&4b%�.a.z�� ���|d�;Y&�6nPvv�]!=2�� �1� � $,eH�~ --Jx6Wm�Ic�/�^!�ir:Xin osmo[I�Q��pt&�xK._,3� � M&AV!� samp�&rma0Q�� �E �6�2�&��sM Qt& 9�n��wa�v��e�sy Y�G m��0Z�#$U ��iE�'WXcascad��[v m!� s=$i�3&. F�Q)5�(&�,7RE ,�0-1!W>��% ac,a��~� S-re� ora�Z M�x�1� ��Jl!�R�&� c�ٍ �of�cea�#@4T A=�m -ATP�1�)a�%�$e!U9 �{[ll62" �ex�X�ktwk25���-S�6"�`.C.��$i^��R-Ag��� gމ�� upM� ��9�Y� VgelA�>)Z�a�"�72  &�Z<�,� v�Tg !� �8�� A�v�by�puticl H"^a�cur;lyCl�A.%[-?Wnstitu�1ly�me]"�+��:pea 0d{z� �� �CB�:���.7of�Q%��&u�eA� mixed�Oen pop��[�sJ�2��1�i3��B�!��6�2Ɍ 9���M �-����iC'�@aQIn��(.8 thaliana rlB-ws GABI_3(w, .&w�of� �SA��Uߋ�8w.��4wW"EI.B(( Columbia-�D�^���@�H 22°Cx:h� �`a 10-h light/14-h dark cyaY(�# rt-do�@m� 2 week�t�- a 16J8>I�>HA@�r�k�!�>�l��X+ w�P"�w�=oPaN*Q 1�s: o8409.�0LP�nd��! -1RP��];%oLBb1 . �^ -2B>2 >.L� ���p� ��lis�N�S3Uv)-0gmR� or�-'soa�Y�6�$�p2�BQ��*�&.�j8( 1 μg/ml; w/v�LS[R -Aldw~ O-4f�!�_�u6�!2@u , o!�V T&4�/� I�p&�r��&)��$�L[6!%�.!"O�n�assay � 2ddYas Li e(x .�H*� W[H.�Vtwoa�K_Ue*2r4 hou�""� � . > wash2 @�R5�RWL 0 mM!�sp0bu�$.'H Vk�@���,c�7 ifug�Hor 30 %%300~�!�!�.�RE�L �=aV2)A:#%d�5+ �evoM�yy���麕�.�)�M�!�E�!k�QR�Ŵg�@ɮ�y%�5–1�1� ��I�f�Rv%Lsp��QI�!pP.� um�,mM CaCl2 , 1 ( NO3 ) MgSO4 ,IKX�H H3BO�QM9��b�@movA���!a��Nat 28��: &C; o teە6�9�"�<V���:Y�9( �/<"�U",<�~.<�Qft�d&�Q81]~4cub�-iMm?< -axiZ(*D<)6H%�|<$*VW-.�&�9Y=eAV!�, 5.0!15.�;a�u=�-2- !��?���i 5�Al"�--K�U�CLor LEICA TCS SP5 II �Sj��Le�", Wetz�&, Ger�Řwo�;ach��Euto366�. O�Bas*5Eѓe!R 50��RkeFM? 0at# M22426; MBar Pro�fF�Ya{6ci��633 nm �5�")d�\6�(7001&3� ��m c�2�u �A.� 2'�O s—�K�m� RFP— �A�e �at 488)561��%e�s���at 50�h53a570C6�:<L�i::2�a?&yi ��1l\IV f�.6�a!�� �I� �!/:�U�at 60�3�s ima�$%ca9~�,sAJB�LSCA;z�h`Z�2�!�:�(� F�m@ J���AE#M� 2�"�$. S�.�)a�B rout[ M TEM)2� 20%&H �.To visua\$�.�� lj{c,> �g ( DA;Yu�A�(iHyc]=��9"Gark)�zQe�8&� byB� I�@ rmfhAQ4�r!B 10 h K,glutaraldehycnd`osm( IVe2D5 h�`�? 1 M cacod�eBR B3>� 3W:�-F<�22�i�]�2 ^Es� ��ݼ�2%%�(B�!02%�B") Tris-HC�<�U�0g ed a[5 �i�F�)��-�����D$in Epon812� qa�U@�+fa3ϖC�cCM�,2��>A�aa�E �a�Lϓ RN���$clo;i�L pROKII ve�%�����DF!zRe� �&��*�!�@��z�| �"XCol-02�c�fgrobac�um&�N�DreC�&x@qy�KI""o�M+!�^�7p�Wp��cursor�9�b�A lapp!�PCR*�RSX tempD9�ImiR-I BI * VmiR*-l9)�ω�WMD3 WebBs@�D�e� h`/wmdqC$weigelworl�.org/cgi<0/webapp . cgiL� F% �ag=}�Ar-� YA�Ak! M\Asub Osub#Q36���q�!L���s6E�AX LA�Y �.�q�^j�in]lpT�����A��AZ�V�5��F��"�.r �ein�&�GC&A( � C6827R� diss"�)2� HEPESR!j�  at roomE�er�$>7�2R�*)�2�6 �qa�! iya -&G �� �R��nZ?e>� Z� nbG>� ���,igapzj) 5!A�!���=� pairC��љ!SeS-��n�6�2TUBULIN2 �^�b&6�rep�+A�a���techn� ..�RN� IIƊebedĤ�lay key�Y% �<��-�x nded��)ny.�)Fa�Amo":O,st-8ac�� elfC!&ribO`alceh��Adm!2 turn��\ v Drosh�6Di��C �"����!�*�*hP ( mL–eH[@�!fT( s.%$in eukaryo�*I)���o���!{82� ��genX:rAK0&,Q��� n,a<IHB�luu<bR�Y mmodI�e� int &�-�1c%`%/nzy�1s=�SA(P% vivaWe �y txp�� yonT�I!U%n-�!a9�6a'%a�!\i��to��bP expl��c9�)�S�q deca"ː���n��!�6�Rat��h.6�w�. Ribo ��A�a��-C!6>�( dюA?�8!�*�tq��Wq���`a5In&��J bestzDw�e<inf���m!V�%U �%nV'*|."� !�*q$�-���[2]–["�*-� �:M;�|ɢ�}b!9�%pa�ZXY�TUulambd��=L/� oli.o;0� @ ew ,tU[5]�R�%U@�^�9�gen�{ lenc!�by.�CRISPR��++s}�h��F�agf%t ����� es [�.I2��Ea�<��J�s3ɕ!xͪ,ɚ fund�� A7%|!�-_� A�с_@I���!e�)��I7�2��U %�influx+'=LZpee � O6 ?%�� a� a 6�D6�>��>B�t�AA�[ stimm%Je��9how���Dal��ds�o��͉��l�&AmD�+m�$taphylococ\< aure�7Ac� "c ly:�pervas9 6��1�%3qC 9�&&��G%�to�WN/!���!ofn�%>��Fe�5i in H�)D py�|�($ynechocystT-nd4B��[10� �.��he2�( cand0Ca���0*5�)zIpAY��es�$ �a mr"Fy|a*co? �:rnce��G.�in6ma>.ANi�7ssiw3�e�[H.9�6�>��7*I=e��,!�7$often ��pan�)���pz�&th]:AyWit3F�_cu , A�%�As: 3*�g��i��n-&r A�6BE�[�@F6]n9S-��N�) lack� � Deinqradiodu S�KHj S_!�archaauCdo�"�v{ !5es| �l�` naloƢ�  , T�a3(ulge-helix-  ( BH��7�,ng end��[1m$>wiIx>`�"�5Y&�y�%1rnt�r�OAbe�dsaL1��.�-�H�L9����^>�%�� ?gM�h5'����sm!�<tu���sc),����Y5Siz(.D8co-����i"�m���i�y� m����q�M6 eL�JHb 30S �prh,�u��tham+",,� " abs��.` 2�  4�� %퓥��7�fin�ep��*g,-�J1��$, Mini-IIIh�i,)� M5 [��,9�effJ� naNp 7 3FXon[ r�l)-ŕ` N rray&�of6��in�p�d��f�ta? pri� ly2"sBn�9�2f� sta�-R��6��I6�%�f�.[ULle rn�H�ܨ& s g#�$�Who�:|q�-E��I�ɣA �c� SigW% up-4 d�}2�"�2E5G-7Lenc ���z-3G! ����� �Eud8I�anA��a�9Z���  �������Cr59�no��� i#(ophobic pep<�c�ise� ��5]o�/�m) 2T.P�lart�IX/Ab���\ �A �}3"isczd�Y�<i�d)�po�ma� na"l�ed, m23 ��TE(w)�~&on &�r� "�y�x��:p�$5���� adaps*>�+sR�&��p7R menaWa�n�F:er<��.0=r�*ma��death"8 view�see [2&G[26] :4�; E<Y .� Adl� lY�It� ;2� fu&u ���Ւ�C�?�!�gr  rz�Ar� vokesa �7a�l�KtM:� n un �1���" need%dbSa.�<4u�5=8I�I ]�,�),!�U�� ��,� i an o�!�dؾO�K6n0�4GA������i-2�!�u �{ aaˁ,j���om*�l�1op�^'4rӭ� �=(��r�f 6�27MN2��������0 ��ihe 3′� �1v�a�lap�IO�nE)f L3�%��9Q*�P~ �s,� !�Ɂ�-�s&���uEH�& a�b��!�2�"p?>�woMT �&v !#a�j�5$�� %6�p����]�&�.[J��" W6�7opwd�� F�$ -{�9g� ", 1�.� -� :�ziǾrd2�f��*@bi�Rr�9�Q*8g2��Z�M�6M ��.o�> �]/*f��mY , or� �+n�;���6#��&-W��y-g&e�y8�,%�I-��Ht�dV� �r�We��N Ga6 �ele�:d upo_�"� f �����g�I)Y� \ �� triguAIa�}we�enticip u� ��X,o��Av. partn+&C�bf=�v�;!N2��� �k �.sk%�D �2l expe�n�Nor�Bn blot&� �i-2,�.�Brifampic����! #W��"�  e������S�Vd�� a�inica!�d�Mn��Qi�YPf��W�"<J"�h,Q.����l�1'I_z accu�m <(�4&:is�a�bO o w�|a3��� �" �!�wo %>su �a.-*� c2�tvbsrH/as-i$Q�� adja��) xpA/��M&% !ndHG Hp�SR�2,��Wly ��,�Br��Iu� �E�)�(")U!�-��^�YZ�2�Y5� s S1EaS�(H"�;;R bsrG.�2RY6�4�ad<na�� �0by Jahn&�4� �%����j�.Aa:�4m YՍ5aS*�NJQ8d��a��M<6� LՒ 1�4� !���r�.�"��<�B��A�A�A�m X>*�2�-�Awa 6��"� �8�whyc��b����wo� ]hx�@ ��U7<?2���!�o)�5Gu!�ybmNy�y���e�" is/ .SA�B�a!!�m�BR. d�%)a�*o�:n` >! na� � s 8 �aAIy%}�D� ���*�%�����)b.n"�& f� �o�Z� blan�J�Sun] <immun3 � �P.�v�Dn\9�� � *��i*QyXih� � }�eÍt���A*Z�(h>�#FiŜ2%O S�5izas)r@!�UlSU� ӳrd�u}%M�2��>��or�k�2tt2f�:EC,I�)�third!r, PBSX28O!�7,�6s ou:;[3��a�T9sV<�w�F�a�K��on@�y3�8�eAi)�� cy (=V6�h{�by#A�5�Nat�stbs-!/|6K6,J�69A�PX2R1I�%� 1G I2==�5*��sQ �WV4AJ�* ��Vr�&�&.�nõ��?����6�"5 US9�9�baa�Jg�gPβ"x� . Gi|�"� abov� �:�viv��sup���1�"� �by 8.s~ ��9�s��OQ%��h� Y GE#Z�Cb"A3j�%�a]�&�c&�G�gzi�Zno~ ��$�n�*�K�x �%F@:�:�:us A-t-/U�evx�K "��?sto2%"K�-3e" 567 880 bp%,A.A�t�a��*d�#a 347:;��|-Y� �%J 65�Z�J/23q�r�|�M�2�(03of 19 I�;Oj 4A�9AYple|2�a� �K.�A*R�  �%ilsog"��"a!a�Ah"D:E���r�iL(�Jst w)Si&��CCB� �(�&a�gnQA&�4��Z�b A5�� successfu�in�l( 9�5 )5)xcܙA�eB�tV.eef�.%�|.1 �ֽ�"frn* �!-a9����. Cur� �ne���I"��?e"�-s�rP��� ��Q�Hy ��Wf; de2un ).�����vb2b�&��s%��u seud�� ��=n�4&���� �#�uE�c��+l�*Sq Y���� �A 6%92%(&Qa�4���)n.�nat POO�Tr%�!�n@ J� & I �#9L=n%޳5�!�('d�Aa� shift-!�El);�Q"� 4� "� �d T��M!�2v�2$oxic moiet^QE^R;$B�+Q��,�onb(� f�" A�Rg� ����M-no!)eL�A�exG�/5�- �/x&R\5. E ;onA->f� ta��=���a�'�)��&. E-10!�re��( U-10Δ2�4 pMAD�!S��DM��64Jm>� !��g�o-�.L tibin!�i&K( Z�����2/ t,Mz!�1!un ��� �<"A����!�^�N �&/D �����ve� V u0ai. B��� iim�V ��}�I�em=�ssu!���eqAG6r4n#xi ex-�mbu(E�I,!;e� {w4ea~d� �aN 4��P%ly�AI7� d%�pR3H -��� yiel�N�5vDy-}[Ob^���A���#A�Ywo Ή���i�T3!8����B:���RQ��me�e�f*���Δ��}Δ��=LΔ%N IC �)~��aV�:09A�E)g)W. D�z��� �� ]3� ex�5�c2 ya%�!e��in LB9 umu���#F�~~�u ��>�+�)�-Y$i��W*�612!�:�� �?Oig�3xiB(Hdec�t&��*�o]m"�6� atA-�Xd2�!�a+by�L��0ud�_�.��s<Hn�e�tE3� atA/]��Q�� �c< �}u� en�� ^F�I,�K%-A]n^�z!��{��ee� RAK �VG Y��r-eM =�E:Y)!�su�����( e�.o3�P;agZ 'U� "�<5�Y!dV sJ1��""��o�%q�l)i.��e#s2�on U�U4g��, clus�3d a�� 130 � !f75 }�eng�(Z���(�-~ Ii�5  �.�\�Qoh09� 5!1 �nt 90%�08(a up�)am!��\��CarA�w�4E�)�"� !�M�∼75-n �,�{��~!jB?�| �_[u�b�"8u�orQ^�h� M �5-!Ja��3 �,8am=)�-�f�V g-�uof#����5>(∼130!3|B@�-ma�E� �A�oES9� �woQ��ban��Qs 92j9�XqA�14�C47>_"B SC *�����wE�F�'PN�^�M�a�-) xo.J&a12t�!+8a[)Su�QyU��!�S�I�2s_6�~ic�ui�W5B 9�Na� i$�y!�A`Yb� �fA@p'��p�m�6;ATe~c ;� ͉~e�&a�/in�Y65Ni9)���g�p1by�t�= ��8"�!�Em!��r.kW~a�o6Z"%�raF"8T��#r(~qMAi(]o�[,F��r*^y![E=��>Z� d-��u� s�LE� Bn5���7�#f>PI�?:�1A��6(K���V<('( !�?���E{s�.)0dEj�rapid&+i� ��k]"O�o�/ށ(v�sP�x� �V�Meme �CT;dN�"MU ~%A�Cņ�+���0~GB�r� l�Z�0A��Q�����]XT7�N ymera�/�F��t� F���� r3�-���L"}�g��ͅvN.|�a��&�)��!�<>%88 :� �#o�\�@�"� ] �un A�b%�:" 1[��!X*� !%&�El ��� s S8�*So�!predi=�`F��L��-nJ� ���-�0����u��em-0�tQMSL_g{18 �!N��[, )^ao( �yQ� wup@six.�$O2z r]Nr�2dUԅ:3  � �QX�^e���3�"168 %/�, 2h�pS8əs�h. Y  �@�Ǎ�[���[ ac�NA � ="" �a�V `��%�M? *:*X��S J1� R!X&�� \V�6MQ \*Ui��u!$!�;�KD�W�Od�"�is�W\8\?HZ3x8EE��Rcs { ���pur�/)��C"�GaQ�at�96–9U`�+r��R1218N�2>c>�1�d� �=}E�^U� SL4��Ua8*u*��i��4to)2Ŕs2�ea�H3s)�Ղ�-:nd*. se�y�7$W4.*70�f7e(�a��IS���ǁ��  .'=��!�\ ,-\1�7�*� �. CR��F�9%�06k@��9YB�s=�F�;,?ANJ"9�d*R(��!uV�R&���2!��A�2agI�)g"0M�217/2188%-!�nQ�%w%^��"�a *[�ءw �Y��(l`9 subj��0AU�Y��pIB��b�=}�&5�k)��^���)v�m<FG�=`6�'�f�"T�( Figure�C 8B ) . The site most relevant to the pathway seen in vivo is likely&\be that at nt 93 , close the major bDof RNase J1 access% RatA RNA c(M1�DUpon hybridization7xpA ,c58tro cleavage by jY�lwas considerably weaker whil2�10�immediat�upstream��duplex ,T�significantly enhanced . Furthermore �clustersH�s from�137�$159 were l!�, �$stent with�cre) 4of an extended%H/% �(in this reg!8,. Although a!� ativ�prominc)�Y�)�!<observed-R201~!qm!�Halone ( Figure 8A )%�is His �e �Dof complementarity!Eand0not]n8exist very muchNvA�under!+diA!%b$a large exEkA~Ag. Indeed![Q0at)'e Pno longer occurs when �isU�ed�U�. I-ppapA[,e have deter!adi,!54essential func� for-�IIIV$B . subtil!9e.$protect itI8Kxpress!�Hof toxin genes borne' Skin%V SPβITphages , via antisensee��5 4of double-straIkNAyghIII-related enzymes as part<hA�def_;pri� }E��ro�%J modeA aI�Ee T��!G YonTi�sAK��kn!�$. Both encAsh%1eptid� f 59@(58 amino ac!�, respa��,�(little sequE�0homology betw� themr��hyd�obic N-��$i , predicabtoA� m a a�Xsmembrane domain [27] ,� Lilic CL;t last 202�of)are��(highly posiA,M�`ged ( 75% arginine or lys residuese@%la6b�m6 o cause c�96e�2` [24]�-� 28growth arrest un indu)�(in E . coli). W��d!:viously!�i�� �(.Ias Yqdu U'%���two str�v\st Shine-Dalgarno ( SD )5�J�34!�11–12!] siblazse-pai��?A�,-SD 3′ end!� 16S a�� t6�wadef���'!|� x` ransJ$on levels;T a)� ��should�? ribo�recruit�mezese s ma�!�DDifficulty escaping%;SDͭ��%�sup�olon� , ob�#%�� form 8of ei� wild-typE�Δ�3A[s)g!�rnc::spc��struc�%�excis��e�v�kor mut�(E( , suggest����: 9 ��c�A'�3(�8!�)ier matcha�1�in9�� $Paradoxica�S , wew aA6to-).F��ins lack! onlycZ�, but�L optimal>fe!�iencynMAP,�} ne��ary�remove b�O{aQ%�(. Similarly!�Cf�] �had��$rame-shift)�wA֡� , yeA�ej� a0-10ΔG� as� lowerA���.2y�.[ 8.�acan�:rule ou �poa�il% a�!��sI|ad alQ�M\aq�em�A���of)Eg; (�belowE/However)�i�import] � ��  �-h��*produce�Vi�is�D �ame!�%�ca�� :�]H assa!�i��j9l�A�aska�o g����* bec g� eu , a� d��op��al8gram put� placm starvq �*u n��0�ec  mce%*�W!�.�-#�L,.ofIG�x �en�pQ o reac� peak abAR 30 ma�$after gluc��E5 [35�.� c����a.��)� numb9 � -� recovered!$!:�)�q facAM?Δs� a�+2�mBΔ���Ua� a pseudo$phenomenon!^p� s:w theyE6au!�le�healthEYA�:� ideaY���E�� [ their� 7x!y��$ conf6)}� g�(nd survival1Cabs� oR1)CHBechhofer laborator�Bs.�iso!d�Q�B�( BG322�X 3 )zwhi�W�ncI���suc��fuajin v��[13� Weɧc � %")�seu�\�5�6�9YP �.�E��<ɐappear�~"O� pen� � o A�A>nG2 �o�Taa� or f� A�=in fres? )�cqh&��� �Ek(7 A�a%n�s~��SiA* �tst0cua�A� +.�%U�tu��| infl� i a��6p��per� �1�t"eexperi���e*�a atA-��ili@A}��mcatalyJ"7iOW�wa(��degradi�xt-��)�derA��`(( AUG→AAGaCs dep�nt��e��zz�voz6�]��!Bngenerat�ve �f subAteej:n>%}Q 2�g cond} � ur��wo. ividual ���� ���apt  loop�SL33%O cripE�����O����A����1k55&SL6>Mu�6�aAy5�!<e/@  � |x� �teit)�U�-b 8‘kissing’ i{�#ons [36� [37�j �nd �can po�i� �!Ws" &�t!� �1h�� ���!dT� dire��rz.�+I�k(E�in ques%� . Fo � pA/copTBV�V nvol_in copyK rol1�pl� R1-�"< �zfa�Dom�b�befj get�r�+�0a four-way ju�EE -by-�ice!�7��AG!�I�-g,a�!#o^h!�,b m�� �oa �M�$120 nucleo"'.� *���%�)�Y��*' �;�i��S.E^4� � prima�Y��N1���.&~weE�calcu�B���retE�� ,a 3 . 5 fold��%.ein���de� d���; desp���inu�6�~ `sed"( El�3a � ca~2dRsum�2bec�!�=a�still ��>edga�Jo) )��m bsrG��as- ( SR4 )���? �!��� turn%1, �2�[28��a�nu�  I TA� of E��ocws faeca� , Fs rNAily��io� �[38q<t�^)5"�2�a�� ba�e�mby PNPn, judg���accumAu] many 5 prox�A� frag�hI� pnp�ntMpAz��KS6�)�CE00a goo� z�ev�X%y.� �A��g!�2�M-��� helix SL4���A�&�LI��V�a� �,,ra��Vq��)r�kunl@X e�"Z�s��o�`. Eze �6n 1y� la��aMa`g� 97j �8U�s�]8! lso�oA���wSs�[ � aris�ES. D��M�&� [ lead�;anX2�AY%��a�}� !y�&th, YoyJ�0 ∼100-nt as�Co V� " 6p�oby No�n blot0Ss�)�pec�^ e2�.�ud2C� A[K  ng�ay ana�� � !��%;�lape beginn?��� readyA�jnd���I�AR��!x6P� �Qs . Z1tan 83*'�y tein�un�". I"�Ar� ��6or)� playE��i �=��y�simpl""�a(ma� n� ��,!� kill! 2��EZdoh5,ly synthesiz�0irIT!H"Y�i%�p�a �in linw�� e phys6��)=^,�o�pl^�œɀ!D�r��niP'de*� 10-f�at 48°C�V�3te^ing�E�eANe�� .C �N� �exhaun �.Ie& A�"!��v�#�w��phosphata`�( �_�) !(.�(mitomycin C�'8T�{e SOS�pop E�w Ap-*!؁h:!�2ark�o"�!�� �behavio5U1� �-E!)�-� �Omanner��R�,` ��]c��al re!z( SknR )�6!��$ �dea�#�Ӂ�=�a�wo��AaM%� YqaH5Zbi3o Dna� Dna!x2:[39b �p�I �u�Q� variety���ealA%iNs or hal�e)of its%h �.  2.�ins�MC� !�$&Ne� W168k(trp− . St� {���, �A� PBSX�s (.>,background ) �Nde!�bK "�[30��a k!qgif�#�/(M . van Dij�sA�-� �!��CEly�$=�"P � gier�na CCB297 aWCB302 (&� amyE::pX-�CmMr�� ^as? l6!� *����"ified& 2�chrom�al DNA u�P oligos CC816/817 ( T=S , di�� x SpeI� BamH c.&%�pX [40]��2a^�eR$ � esul�J� �"t ��'�Cg[F! locuEKA�)�I�1]�� 8p�of!�t� k rrup�by�!n��re�>"�")<>R� �V4 =� -�. G�!i9a ��xy~)��y'CCB03 ,rnjA:pMUTIN- � Ac88FSPspacYVaX+9 Iy:!b:+yI��JjV20r[2&� ��nel& a� 64��363�kDPβ::PIID-sspB kanJby��� �6i�A�R�MO4738�\>\(spoIIIE::Tc'aӝ2�A�isBcAK�up���a�Y!�64� >�1�+ 25 (e�Ʉmad�marker��"=ENe/�6mo�&�)��%45/eM��pMAD-I� orH to [31��P� #�b�Ove� �!"�+A�dowr!eam� �� � a��-1� deleA[IZ��i�����907/908n$CC909/910 :�%!�e�la �&0E��$�&mbl�� a new PCRc c �Azd7nj6>R5MAD)W�:|��4Débarbouillé661K::a$>�by buil%�a��.f^�I2�k!�@ �gfla� aa�a! N$by%V 1W!0,.�!� 1015�$020>zA$uHa�inI�. C:��y.C! F��25A��*368UmΔ�)V2�77 sunA dq�2�eWb�)6q�aB �,%�L'rovidCJ�Tr{�E�to�>2z402.��.�413 ::�-�.��W2W� EW,]Yn eryt!>~ N]}�IG73'CC107:��G�G414.`�)F=`E19(Q�*- "�) al HlagP)2� �bY& .�B +%`0( ymdA/rny ) k {*T19)p� �'[#e.�E^>N*A���CR>�65�65�T.] * udnZ $ET28a ( No2n ) cut�a E(-ΔTM-YmdA ���q5"'*m�4BL21 CodonPlus ` yield%C)�=� B456a�!j����#��donna�AAG-M6�I��IIb ��"o�$Y}�2�112-CC1130/� 2���>� d��2�61%?1�ua7#�p��*Z ( 68 nt�, ��"���A1. U�4and.! ".�)vss�on;� �bi%0"� �.�)��foZ�6I (1151/1148 ,%�479�50/1152-�3��bu2hn�N YO���%AC5/$�Fu�9LX �B46�� B468)=1�s�$�/ Ger1$!6 c ,s1 u_"&}�P6a�FC�!� 6�:�2u O!#�t�o%7ay-Hp"`#a�"N�2� Mo plex� K(� BM��re2�%6I.�$CC435/1011n986/98� sigK990/99'ypqP )�25 cycl�94f;&30 se� 53°672%1Y%=S�* probA�.X$I��06T�J� 0 . 6 µg!T5ZPiS)2  ��!��E=@-W�;�#by T7�polymer�( Amb!�) ��J tempSs�S�T7�� e"�n98/99u�000/100Bs>.g �K&�d naJOH up ( �an 6-&uguanos�1� GT!��2acili(/ � labeq.yed dT4%Ym )&Biolab�f�-pur�+�#!��*;&�:�6n��N3I&-z EY + kZu�� a� Ni-NTA�'uma�Z�41�di�&@7elua� buf�)�G�+imidazol� fi�N��&��4 mg/m�.�%� vE�in�3(mM Tris pH )8 MgCl� 100NH4Cl ,e*1 DTT .>�af�/9nemat50Brugia malayi��t�5&ag� of Lympha�6F EsiMVcap_(of O!��# para'cz� mod e�_?; cognn7�0��"�"sa�X% such?ipGa�!,obsB)[n eme�4g� digmfW�=A�ofW-Ae�"tra5 ular vesi�EV� �7��bio]vea�:� smal�A6�s� �{�-�2olecu�uJ�)&tra�1k} 8�9 tiss�5.H) *,&gEV��!i :us L3� ge>�t w�filY6%Lacros�0�&@ra-mammalian life�B [� micrI ariaL>L4Z dultABe�(female worm�LNanopart!� Tr3A��jquW f�d  EV�=vea��discreY: �poQI�� indi���-��-�0�dW�=)!T�.qgA�� rnalI�[=r��m?p%<w�n�e8-c�! V stag`*g� �uni y&�D6]N29"2?�"e!7a cheme�uptak !hibitor*�/A�� �^��ocyto�-PL=om ;%��*'R�Tnano-scALC-MS/MS]�)�tZ?E2qua��a�di���.�!� nEV!�te,;,�#�def!�'bio���թ'�a�rUCsex�+ dimorphic*+< sticvimmuno��A@cargo!� � ivermecti�fo'H2apidl_ %�����llQZ9���F Ah drugM e��7�g�M>F"�$9(!hearta� Di%�a�� itis���.�n�-unC �1v��1!]eG�"�  lighMۙ��6�qo�?O�!�sy�a�e��� a%��ti-�>*n4 . �� &A ( LF )a�a Negl�#Trod-Dis�Nc�(3?!]p�� Jl�Wuc�\ria ban�t(- N�98diethylcarbamaza�ci�"a�alben� or}��A�t)<:�ra�at"�$�sJ�([4–6] meae�q"eAYno�/� �/A�LF%�ݕ* �$e � exer!ir.hcidal �s���res/.c�mitA���@vbq(U$ed mosquitDAq$\8i2B e s�A-Ghuman� .^p�.ur��� leftA�2m, migf ��l"� vas�-HaHmo'"!L4��F*re��o5p{#A�Cr!�B)¡�sA`$may l!�!�102 yea�>� p lea� 6� ( mf �rva�6#A�A�"!�im� r ir�Amf%�in �t-2s�(U6\/�At.)odAvl �er ('�1]q�. [7 , "?-�� ��IU�>e�I0x%�,�EgP1"�cours�9A[� broadest�3�a{a�DTh2=?�heEelici!ee�i>-I��Fch.�Dbff��canon $Th2 cytoki�F, �J_IgG�� IgG4�IgE��elop�Ba� .� dispw^ lt �9ct�5on J: / s [9AaSnic=%sePA%5mod^# with�IL�reg-� environq.��assoc^4: �R/ �e�*cr� .���T�e � r�a�a��Fsp�S! lostoler�. A"Ddpoint!� beEM��CthD� featI`i5� pro-8� %Th!�Th� Th175G!x , )xT�86�outco~Hre �DE�!�)a��$te��o�2E � �!�vE�T i:L�,id� )�u_�a��-d)� �by� Aj�Fin�� �lew%�!�� 1���}�[12–�W,�M��+r;GK*�+���&:9ObX �Ds�1 -dri�/man"�s�Ep$N� �q.� ! "���!^de���A����quire c�OZM�x. Er!�g-bŷHs-p)�ɀe2L.z�/eu"(I�.8I �� e p"�qh�K� ��?7���L � ( 15Ų , 500 nm� �Cbud.�surfac Ksma����e2"4^5 Z+<nd�'origin�6 k8D9q$av2 ��r %�x e%!�&Bf4A��<-tou+co�`�oXHk�G� trigg-@�xplos%��a��p�GV�H , atika2/�EV, 1r0of non-~ad!���us�����,Q�]�diagnoe+>�! apeua;&[2�"R5I%&*@mP(ic helminthU�� Sa��,U!�� � L�LA�-*^c6 pt�;>jE摴 [2���L�platy�"�[3! I,� �Pdoc&�MIv6=&�K��.�8I��5ig� A of!�ly2d�,a�m�I��*�AU�["|s%jx 7 �E]*���ai��Q`&�C����U /3 ( mi))~ Sa. *m_ aven1byA~ch 3�� be� OH*=�_Sh�!�1A�inJ 2�%=� ,� ,l m�AG Ou��+X���D@a�r"iLMA+<Q�������ExAory/S�E s�O�/eXS"� �T.�Q���� n4Q:P�M ��5P%[!�u�v*; )|-%W sex-! fic�e�0!oJ�-4p@J!;IR�L.�&��asymme!~aN�- E�:sAT�b >��M�s  ’s.�A�AB�A�� A� havea�>�ele; . &�w:D81�m!I��:&=�2��2*�1�`o`C"�s �=� isf�!I�5-̕��bWIrag$U� � ay�L��!�fu�!�Gy�Jorts . A&C�"!�N�)���"�L"c NIAID/NIH.(Research ReG(Resource CeA� ( FR�E� Un!Ds��of Geor�, USA w�.2m�'2aK�sA�s CP@c!�rt-hai�<cat�je �Mim�rLbeagl�PgZLJ6by�a�disse� �0cold anesthet�An$egypti ( b�&-eye L! pool�) 14 dS! post� Y. MM@m� "`&�spp .F� � ng gerbil�Merio� ungu�tusʥ�peritoneHj �SQ �% t�0� �IbyNMropsye4 %UD10R�A�vs2J 3 mo�BCol�����ODFt Iowa S� .h,in 50 mL RPM�;$Sigma Aldr� , St�ouis MO�9 t 37�!( 5% CO2�nsp(� � lac� vl 24 hM Vk!��2 9 � A���C jrifuga 6_I&�( 3�!=�f �(v6( !Sight LM. Malv�I�.s a= , UK�EV43pl�!stoalat -80!*. TtGa�IA�}eo?i&�onK� �Be m�9on.�mf�00a�,A . NY#MJf%>in 4% PF!�EtM!ty S�S Hatf , P!�inU9�freeze-c� s mmers�� tub� !�id N2%w�3%{�a2* ��wa+ bathdrep�^?+� twic{y){ �%N � �!�4 h�!�2(. W�!%� washQUPBST (e�1%�$ton-X�$[Ŏ-͎]_)�p1�IL�kn��.%4-mercaptoethanEo�%ŷF ,B|, Hu%,w%:0~�mIllo%SthoQ<ܥ4�!u�rmMy!�$ntibody di�Mt](bD;1BSra�(1% NaN3ZT )=A�xF�%qu��A�D( ALG-2-��"%�!,in X ) Rabbi�O�EH# �(��$1:�(�Ab6Y( EMD M��p� H, Billerica , MA; C�Mogue N�R ABC4-YE,A@2 a:A,in`threeUnY�c !Y  s�KE�du^a6!��"-�XFHlexa Fluor 488 Donk�R!4-se?V%� ( In�'ge�Carlsba+;CA;��Z�R37118IK-@A�b� F�!�an�A`�bDz]Z .�647 Ph& idin6�iV 40Hoechst 33342B't)�>j* ��?���nA�d.D9unA;� Flou�/u�Dqu�m�Ku�_2  �vis�#� # LeAeSP5 X MP2focal/�hot6���To&�W���?�ofN�8ne� v&w� .QiiAyoV �&.kKx 105 .!( J774"\�=e���"� 6 �slips��iaU$�@e�Poly-D�]n��T'e���t�6 6/e"� .� �T��sta uKH6].>�!8gr�Flip c dyMc*�:manufac� r�i� ca'�1%27u"� addedJad6.����2�ȁan7fal)\.! u'!�]oI�no3'str� M�f17[�d�m%1X�"���N&&6Y��B4 Jn. J,e� ��i� 1:20r !�X X2`�n10?ut�@h:u. 1:500:3!/5���6�u&j fs b�GbDZ�9W�S])7. C��I��4�$sl�a)��`�6>��=��_(��� ' s Inc .� uffalo Grs , ILe�Ac�d i*� �� ssed ؉�A8 �*,on Suite X sF �a"y4ij:3-D!ymat GImaW.�f1Bitpl�b, Cona��� a^C%n+!�reh�1E9-d5Vi alA�N�� �*WT5� �pf�es�ly�0edsA.�)� flow� }e��42a�>o.veM=!%c�e�EVӥeF� 2�=!�,ŴF1" FACS80(� F� Y�F@iN�iM�scrap[i";�Qml  s �=A�� t 250 x g�i{� esup�!|Oa�F���1%gsaldehyd� .�m�~ 21 to 5�X3styrene �AI"W )�ICaA� ( BDY2s&1 San J�V,* . OnVh)IE�to*F��>J�P��� in � #U,(kf��~�2K n�Em��$e# �cy�iN�to`hb� block�+n" . C�ZE 2��.6�LDynas� 30Chlor#9�'or 30 Ge�) (�->$�=2� pr�I�a�J!,-lO4L . Po 2&5 � �,-aJe*xZinclu��6m� !(8!=e�b< μm� esbr�$Ccxy�5��p*+  !���Wag8A �,2Y 555o j���C(�8�A%Techno�#Tgorn@Ch$)K subuniy ( NL. A�k�Q�&�ry��2��a�q���I��:Q4Zyq.� K/icy�-p&N��&�  erc� (TBi.�P� Altoy�BriefPZ�mg�H\A5in RIPA �oer ( �:0% SDS� M Na95 T��8 � ,e R�  cO�te �;4Iq� CocktailB�^ he�at���15_ _�# ��9�i�oe�6"v.Qu��E�2�� 8P'a�g!��A&jby!$-PAGE��10% Bis-%!NuPag�ni-gelFd&�in"tr��)a�2� *,�&P� �  2&2wi� W�s �8 ty HPLCQQ(!Cor Milfor"���f�to"�� Q Exv��SjJr�nata�s��Qa�s@pa��h�2.2 , AscaA] suumee Caenorhab~ s� gans b�e(IrJ+�/17_�X�CmTc� ru[S�[(of MASCOT vA�$6 ( Matrix� ce Ltd� Londo�A� Comm,"(l�5�F0��n����<ONep�p��ies"?2*OH%�Y1ve1A�*� �A�� c �m�%(s; maximum /�le�t s = 9�*+ g amida hyA��T, vari�$>1Oxi�`( !, Acet:�:! Pyro-GluS�m Qm�Deoi�( N ,p�nC1&�)of� ppm%n=iD1J*��02 Da ascot DAT,)� par! !L Scaf<"0 ��val�x1fil�1��Ma'redund lis�On9_sjQ#DuKf)�S ���1!FDRr�(Aat�Wst�]unique.s�m�ͥ.ͥ�Ae�=�-a&� UpSetR ( �!��[l web-a�d tech d�-s8ze�#� ^��&�`�GOY�A�� �B�o2GO v . �MBioBaminb V6 , ValenciUSp�"ra��3*(%ksvb(~ � te BLAS`ar� https://b� . ncbil�p$nih . gov/��o gi )A�in�i quer���e�IR$Pro motifs�'f� iaS / ( www . era uk )!ggdcaEiofQ�ed� anno"& !�F� �* topy y9�M`s %�"�q)�l�Qsal� HMMTOP%��N1 . W;e�pd"�Aa]�" y abm#���8Y2k&�*%6� "�%(�).DY'E&�#9aRF9G6�t��ra,V�#d�8�d!��� hyp�=��EL��%�i2f^!K�2uZ��*�&l�1 tea��,awyka!o(5, �llD>�!>W<�&�%q.� (.�mj2V`')8/*�2P *����))�} "� !U/ A�I]*�= publZ�Z ocol�5�+All2ae1"�&":6`-v�%�)�'R�)(>z 1A D X'/=d��6o� A� [.�-ranW%8�+S-di�Aq�)i(.�E]re�3%uP��"n$��siig[!!W �[`4� A�r.*n@g"][3�-3�#4M2M;?��I�nY)jout��(no��7 ag�-E!@�loug���7!�,BLvVtucp_;0]/1�>v�g9 �$ph��!�"�@5)�UFI�"��} c6G_>B�0H<%stu��b�`�gE��rly&�� W�d�x3k�N� �w�&` E$>_B .A+KJq ��R��.�!� ."4wa�"F � whFc� �E���3� N�HID� )��AU)&f1Y&c:���� �e�� <B�=+!F�o&�"mk<�c=]*F *"S��D�** Z:�_6� !V��9_e K� ������1. U�?^�.3D�/&�"&D(N?M=Ti(%j*"of"�!U! a�)h{:�"�_u�to2� �� �?�at�9>|�0un�-s� :sr�H�3ll2eN�)�took upa�9�� �EA�n�s�|no-��vM\cCre�vej ��B�af�*�6)(�_����>����"� � UX ���e�(1Um�w��+��in&�fof�EsѶ�`�"�1�o( if ar�N%orssd�+%j%�m�k*J4ipc2 musto��e.�L!�ቓ ��F��ReAy1��llb>&%)�"�M �c� ��� *2r7� @J�9�( y�E�it � lya l��proper�: � �KK?���>x:�ga�u�k�PQ%�6�h Z9emselv%_�h�@KIo .�C76���J�,Z� pre2��& i�E�"O>�� "�%i#���uoFUS��}approachA9s�a�-QU �_m��8KaY���#���`.&� �= fast-a" ng s�Qm~9u�jdyna�U����v218� -*�e&�!5:[4$FP-�{� >s= ��~�!� ��&>"of7>��A�b� �B"� F6]!� 2,�a���}C-���!&��;4B�>�<�ly9�e�EV1��S6�mi.-a� 8� o �9��E2��athrin&g|-vEv�aveoliV ("�LmbM}eoi1%�of2�%�c6)#�:U��o�#s�j�[49�gMPV�=�ly">#�"W"a ligA�ofzr)Q;M ��5�Ӑy�&�,u�Umd$. Last�!g"&$/�iT-�.�y�| [5�h6�|>�� <2��iv!|-P6;"X c� rR# ( CT�0��!EE>a > raftYIu�-] ��] mp>"� ��o�f-C"xA=*7�*�{n�|��ݩK26�Z6 μg,@ �AG~4 mal� ��1�"959toF�� .1e �(��V. A 4of�Xinc2� ��-���e:�*�� ��7465 �:4 ��A summj/ M#�"x��G��samzr� =]!?in �<)c�)ed.&)_*�Z �.]!V����r�_vZN{�E]BgenV�����A�� lrWI{ 0�!�o�Eina7�3\ o- �AA v���� aĊrke�k'�-GT��U�Rab 1� 2�8 crit\ M�� ���mJ [5�52� ARF S`9x�[5�PWhiF!3=R!5ak ig��&ml�“ �% �� Q�&&�L 2��� "�eVZ� iscu�-G(��^� na�0A�M�"9��Ra�,� #mEsub^>��� &��LT� . 29uAN7@ 39%a_�mQITI�- di�E� �Z&Z!�C6�d���?! to 8uj40q��� �)2} " |�@���.�was)B�-�&�I���� 6H ��3r 5W�>�dMel�]IT�+6m�60%).�a�pD[rytoso���z"%9� Űl�O�6*h*t%#��e��-�-����X%^�X�fs9ia�uN�*5 , 074�1n435F?auF38%k N�V���Fa��ҡs�ove� enZ@e � 1�-5�d� 9O��#�n� E�"�%��I;E|!�Y�amongY<"�)�B!/~$bbed�,i.U�iy6$Os�d�"�pe���"$b�!�)1m�$��5/I ��u �_L3qp�}�;pe�6Eqabwagn�sex . 5.8 w2�#��)^ 6�8i�rV�l�7oe���K25�!31�)��� ( 81�C��B�g��6Rm���.m }2�,I�Fe���2�NJ�epaefEtw�/`&� T $ s(�Sa.)O=Hs;�a���5�&�jon�.Nm� A-�)VA8�O!�Iq6VI0,ll !��aH:���HSP70n��! Expa�3?m"P a^&�"*��]Q 14] �s"=tiXm*�D"m�!�� �s._��pXFof-N9 E�A,x`��L3/!RF'�8aPly�h # ( 48(IЍ EoZg!�22��u(5� �� �t��m s ty�\��o�oz7As�Cs�D�3va��aza�oOz�i�"kߥ��1��M ]�t�;w�*"";� 4svly �/bNep"L2B-.^;as�.N�Y8 . Wi{��isk� ep ,�5P�bM �-JKV!Hq�!@#~�Acorpo>�*���! . [Nb .` |aC� Fb–,au?&�Jja���)�7 � <r<�s&"{. S!�1]�� gene { ID6*ESTũŨor nowPTedUniJ%TIGR A��� ��s�ma"[Y�_ 9KB�� M�QE�{+oR � r�d���4;�kI�@Gly 422 �gof 775+>�!̡Mo�,!/*�)Y_[��s"^ĺpz7�674�!1. I�q�5�wi��-� agj�:a valu ]is*)W�Cje�eO� u� Z��nar&X���N���6ull hier�,� GO grG��2S/ES5<�ll��t!k�71�AF74 ( �.*��,Ad"�.` GO�-A9n�Ff!3�z� 0�  l�pl6�V!n5�1ref17��,{ �V` ll��the��tru��V&�"-��'Z 54U`Regar:Atΐy �d�:�,v��sa�(( GO:000576@CL ��" +12505�9u "�Rz )i�>m�V, pv[%-�iso;&* f*5�bk�C u�5*.f�J��6h���}!d��k >����S�Mb{ea&�1 Z�W�!%� 3141 z cytoEtic��0% 9770Mvi�K�- �n�/:007006mD�eli��^���� C 4444�46lorganell2n 4323�>6+UD�Z.:� m�.�%����p5�uglean cljV{ *I$s*��a5 r�eD*> 1�!�% 3F� n�,���3E@NhM ar F� M~Ce6�B�[rzsh ȁ��- �R��F��[*P |(- a~�q� 0392��A� 1688)�d ribsK^�M,i�GTP�- 0552�- YNx��er�lig!�os᧥�!���wG-��.{�Q�P�(1 Mv�L �M�5���*&~asl��gq� elseN �*��\Xo�*�1t &�(`:~).�hmR�oto� i�k*"�28W�Wa� "| �!a�� itemc2m,r�|�a5a' �V*/[* �%)�Eho~>��W=.�pae)�"�or L��5�irt�F� ( 18�-�Jm�.�me� AUNj,��/����t�c*�^*� �<"l,$( MIF-1/Bm��glycan-�H�ga,s �+.m� hock,� iore�n�6o.9M�A�GAPDH�Z�4� hI�� t�F&�]�N��"�ah��.K�l1q�K�Vegory; �=$ .�-�-9Lk�ATPhu (�y >*�:Xl5=.e�� E���m*y&engulf�!L�2{!W�hbio7gCs� �)�55](��!N�%7ŗ2<f2}��.#�* �Z /.mi6g: ya!.1-�9��2eno et ax[56��>ly?��^&1U ( IV�;r6#o"�=&�?�e"-�No2� md" or ,glutamate-ga�ide�# nnel �**/��"����mu*�i|.sai�~u�J%{�0orks ��>%:�o =E# m�s f6mf���� ��i��E��5 E1"�-jH[imXg��\:?8!�(ͻloh�3�\!o 9+<Fww@AW7+�O�a� M�[mal�+%�aA4d<-1�D6CAof�J*�*��  a`(r"8ZoH?�-��0-9)8ah\&h,&o#Bg#7A ) *2Amf[ a�70%HV<0 . 0��L3�*75Qz)�"�8m44$�)< 82 D�!tnoANt�rH0s&�� &'a=A�� .����!A@]>CZ<e�vacy"�.�n j���3d 8�( |1s��sN2`��� warr�>�.investi�C%seM&t�b��& .6J "�8�Kor�-�!&j��!N;%2&�de;��hen>k��"% tokA���duVkFc�� f-�/1�w apit}�*�) �f�V�[�)�'dF:  , N�Y�;�Y(|\Qr�l��sceptٗGrafa�tA9QM6�Y�f%�ed&sN� � � 5�'J,;L!��J�<a-��q�bM�5e�p <�Aed�Dv�!K�le� �� 7�, h"��1ha2�� )�*��r-pa� Bm ] ��� �LbR@e���)} I "�!�Z ra�[nn'3�ZݕEmeI���\�A�.H@lA�dA�*+}�lle���re#|�U of e��%D=)c4!%2�g�Gpla&�g$1�b a�-�,milieu�e�-� J� ����&�i�b ��k�h.��� rch!��J� J� '@�2ݮ,� �x�:-�7�*K�AT ��>�h$�㘁�M�m�Q��.\'��,4y���  Ө=�Q 4M9�Z 4,�a�!f���&�ne�42.� W�7al��)���U We%1�c���,:��(��Bca� ��!F�2.���5eTs.G� �.w?U����ir&�>m&"=�J!M�� JOfVVhowE�VI�EV}N, �A!�1��� ;]ur h!�5&.EA2& �3|dva��>B�o-E�(�Iu`)�"�. insi b"AGqu����+ actu�%!w%���D&o&� �-v�%(H]� �;c2`"% ly h2��k�po�~a�)tal' �-3  �]�#:�g�at�erk����V�(!�qi>�ADP�s�O!M��ARF;��s ~ag�-75�:Zo��au�2� ��kek�bo{8 ( MV�V[5�-Rab11i � ��GKVB�n\�_7�� of r�ulocy����&�B)� 6�1��Z)6-L Rab2GY2�d b )a�Uj�\d�� A"p cRby1=a>��|14� ! j 8" '[�)���&Ca��c)a�y wt?&�Ktyp-�M��r�&Ibh|� E�Y [61]�xoCartaM��inA� 7Hxoc*.g)# stit={a"8Hb��!HE#՟A�*2*-*UhII! 1� �Af�e�'"\�?u��end�\9�]*�� . NumN}�a�!!2`)5%�u� * �(Mj� Hsp7�e�& �mc1=J� En{+et �.*'��8A-� � z"(+su� iH)"� nU�$C�l��. R%�;G�*lC��u:ic  j#!72os)yd.,q^��f e�a��� E lap�� wCubA��)�FE)��!�&|, trsAR*��6�=Q s [6�69�Kowal&46]��B"�!�0)�tf��pla'if���" �� �(“bona fidE��� �%Pbe1J~!� rc�CD6CDHxCD8K/a~I.��2�:���aha�s� �L"h&� </C&��nc� zE3aL�u"^6-s_!�V�`ae��EĶ��p) 6 2� �m&8Qha�mer'� .��at��}�V��6.#]f�i�AMo!rl'X��[gmQ�z6reud��wyk��"#5�)%} �-�-2əamongscq("O612� . Gaj^G�C��->�5瓁��)+� �>� �� . Be.�cast���e.B�ԅD� �"5��2of��*e �&�,$  M-F#���cy� I�( �p�G4]��+�@�hu&@ r�32.4w�FstaK�?kDΏHI�?,59�E�.�"8��� 5 s [7@376�+_>U���8[7�X7<R� curr 7�ri "�]���s ��6�w�H� "�E5���9 ��*�} va�;.o�*L-��r5�9rypan� a cruzi~ue6YgA*e��� l~[8�h�7a�%G�9 (2�9�S��{ t$!�Bg�Z? � _> � a�z�"W1�%m������m�Sno/ e���"U isy oubtv i�guB . Ofe�Z!h��j %,�*�i2�9lex�6]+��($;�*P��q FY$,~!��K<-20^5p 3� �>b�r�f݊Thu%b�b>u6d�1M@^�� �.�!b� �&���EV )�%�i5~b�0l��R.� cl2�.it� �lS';impac�Dgh- (�: ersciFE(1Qp��y�M&�Sb.W @J�a��si�4! � ����EH�\*�. A6 &�ohA�: ��N� �� �%n5�U� ���A�!kEV��%�� ��A��� }&�� �O !L3ނ��? � 2�� t�l-�A�� not-�whM!S l�?!�s.���;9n2�!HE|m"'&� �\|_�2�!2Ɖ-4i��a��&!q!~�`cy>b6E�N"�<6��+| ]���ym�>t�f.!�1benefi�JVsjenal)K!r�7 � )���*&�6"\t�s� ambigu.��K��%!�� mbryHu!f.K|� I$)'[8j85]ER� 0\e%��8�j�a-acIp��O^�a� �pe�FW%A�a:'�D�KoB8by�"E("#who�_�? �T �� as.4.m�uq�mf>V({e"�L�% plor��!)��=�onu)�Aq�&��r�((��x4 �}1�2v&d�Yl�)�rec����<o2 )2J.G$("�in2H�}&�N<"s 2$<demAQ?�a��#se�v� �$[�#*�Oo.p&*��y lin�H:*icD&f"�1iby-9��� >�!�:^�IVMn�Ad��a�ope�a9-a�E �� M�pa�#."f ,�b�%GHk�fAng�9?�69!�&V � ROa��#\ � ��!2X&�!�uscg� ;&~0�_"��&���ū�U�?f� iT�1m�; D��!�\)� !�-g2?b��$���b&v�C}Qb�s!�BVPa; *9�ani��7 evad��"�� mp�/�| )�3y��d��Yq��%�q���V$S9&�+q�� =.��NtM�=E]!y6+15az)U'Ӏ-�a)Ac��*!_q2KsI�w�"�"iHI*Y�o� �5�H��cro� ic]]t�%�!>�+%l��"e^�b)�Nn �� VR)qQ#wrvelop .u[���lru�:IfD:2}� |(&�&? � N&%t��it��De(e��.��2���c�yA�('�! ��� A>y!������=`c��# EUd;ia� �U��c���C^���;� � �&=(�3qm� �assess�*!1o�I�' fl�s؆al hurdlg fU� �g�;������inŪE�.�36E8��� .![me+4�A%��N\&Tk��3�. AlsBq2AimQ nsum!�a{a�%psu:�\� igh- !�9�Y�R!)iSC�mV s��)� �1n"�-Xy�a�k3|@��!���� A��/ol6IIN`ez�#,��� Dp *�%$*x�it�/.� u� "]cbyF@=�A-1 ro&"i!�& ’snr *n� nd����y�e�!<J�:'xCAe5m2Ra�(s .JGScab]lmpeti�8�o0p,��o��$�V?W�c���� R�g;$qQPac�~isl@IDTl��rem~A���` }two.g��!]4!P�)gA�� Solo?Iy��i�a pau�, pidem&�" . Ten ru�vѠ� Je Wesa",tv���a>q�����*,�Rsen s�, 5ocol|o����zntv��E�z )roTN.�0ng cli��serol��qo��aw!� A޵�Jlig�/� icip!!,%�1Ϲ peop���enr��P��ipa"Pr�rv�!�"� {}paUR�V�/rFj�cor!5�C Y �Ai#�"l� �m= a�dia_��f�fQ�/�Q�,I�� �S�!�{[S unwe �E.�sm;�19�O]395%A�s#A�) al [CI] 1�}MkG# � �ag�9gn} Nq2b CI 1=T7�� . 9 ) ��RdiI2�Y4'495HKT�$1� :!A�a��M�"�inf%�< 1 y�ige��4E�%�dj��d oddsB0io [AOR]� �3w:C�s: �6 , ��o��!.�childr%�ged�z4~O25 . 7xAOR>L!'!0b)/��,Pwo��m��O0A��p in 8!89.PuA�)��41lv�e%class�=�HC�-�zc�$ve U�!3!7MkCI�{. 6–%ui/ �a�T�VK2�!p2A�@6i ~ n�4�61��F�w�#I�1�#!��.5�inf0e�! a:)E>/0�f(U7) hA!8p�,;I�41%�>Pca%��ha31��A�5��Im"�N�B�X�H\�a���35�[a:�.�wj|y��E��it8��F�I�e�burdepM6"���u� sm�c %� s . q[.%� ����6GmRSarcop- �iV)'���uta�)CP� ��papf�,rr�����Cjpruri�!��� < *�&W��^&~�x-�-�bRfam���D��r�!tn �w�L�t�,�kseJ�s [:rIѷ%RsɁfii} b�l)KA$I�c���m��{trepton�p�Staphyl aure�N�� �>j)�!|5�E�<�*�!�h , �BSuppu� v� .;9� < u.uli��, abs�t�s18c arth�/� osaLye /� %ae�4e�1F2��� up4 �7� �����aSUglomeru��p �a�19�5(Y�|Ij��kidneH����&hD[�/SA� R� A a�M�1kA�� rheuj1c f���-�- � �ichIks2�&Ϋ�mC lworldD  [��"�"� lack!a���yV��*�`�7Q�w���Mʨ9 �_Tst��t ����(m�%)ho�Thumidu R@A|XJ0"5 you� �[X$� � >" aO�{�*� >�p�tՏd�row , ������ leepA quarS�[��#I*�B5��at!��%an� 9l�� �U"Q ��& 5��Enymg[1�H.�S1| ! ��5�31_"r==���;z2 a���ld%}L!�2� Z0>�  ai�H� ��3s$ish=�o2� Bai��&�J�A ��0� �>!��fe�\�V�!&2:U\ �i �;B�� �&�992��"% South5��mpris!�tU volca��1ɜ�l co�ato�)�>�ranve 157tM�!�Un�N�H��D� ,Index ( HDI } 201@��^!�%��yrVrer�lh4�"� to:�I��v�E_p&?3�\`g">]51� �]��Z9de�1� Mela�anm� 9A 3%(Bof;m 41%i�< b��15? .���YMr��.E���GW!�u�;olxN��lateAipo�l� ic� Z;+nl�( oss-Z[�%5�ijmɞ\*November)�A@�$a�'er^nZen&���H'/cge�����vt +J&( V�3 Lago�QRovianaAiR�8v�59=D. D����(r!�')Sl�!V�lo�w(��zva����<n�<%-Qc��* wo sB): 1oQ�inhabit�-t�p%asD�Q*�!v� gr� !f��.�[15_ W�g\%ll�� "��.a ��! ads ���trachomaCazi7 '�,�b��_� � C�y Ethi�Ia�v���L��y%"K�ՃLoхSch�ZHygiene%�T^ MrW( LSHTM�7 635I!� � al H��âeT@! �/�0�S 5>fM� dzofH`� al S�a� ( HRC14/2�Oo�_����tee)fe� �i�AKf�|y&��A��%8�Fyi=x&%��\cu�xA�ar�7�YA��"� "�(�c�ɡ"\Gx . Wr!I�nL�p9���llT . GumUa�f�Bd�}l.2U�..�8��Al�:Ey���K��3�� ���� �-5!-= �^:�ba�f�doc[*p'�-7x u�)���w�AU�-����q!!GnIBpr�=�spa�Oe|%�.�t.�eAwgia��o�EreceiA�j Z�,A:� ^o " &�\u��2z18  �f� eu$K "EL� nor; n Au�li.�C@hisK'����V&8wng� a\6� Piji `L�Tnu��staff" �B�;Pf�s!��!�g�ect���eTouo )!�� ���m�V�"� !s",A�ndb�Ŏh��d bedc�.�!re^W*{@%��f{�[od<1q4most commonly �affected by scabies and impetigo . For infant �young children , the whole body was fully examined Eolder9gadults , +|ation of sensitive areas such ask groiwbuttock>b%t �torso�Donly undertaken if@re|adequate privacy . All participa�who had5Pclinically on history�/or phys2�wo0asked whether�y V@imilar lesions inse reg. Theu$ diagnosis%!-�!mbased�featureKhcluding morphology ( burrow!1papule nod vesic)�)�distribu1�4rash; presence�pruritus�1or�eE)� evid8excori ; contactA�1S1�![noaus!KninA.e-defiA�E�9�Follow*o%� studaO)�$ Pacific ,iseveriti2classifii�aSnumber� �-wta,mild ( ≤10 s ) , mo%(e ( 11–49or t≥ 5,directly adj��A6ge��/age �Tour sample demographic)�. A@odds � s ( AOR )T��2��)Wcalcul��)Y a multiva��@e logistic regres%n��,l that incor% edE.�fac��_ �,� grou!��peo�liv�in house�B%sleep 'a� same room!t�� able risk6 sa3aZof 5�in.j�Bu�methoda�(7] . We enrad 19086p , re����49%x� census-liŢpop!�a^o� communit�p visi!^,%2 . 5Htot�MB@ Western P���E�+ n over��� of female6�A=" aged��� $an 15 year�M�( T%�1�O� �unweigh�]�" * 019 . 2% ( 95%��fh Hinterval [95%CI] 17! –21 . 0a�w2wufo, �J|A2� CI 16 . 7h9^U7hig in !I-&)V��(.02�k1% vs!H . 6%!�F� [AOR] �4 ,!����k . 82�I&in9�t!�"� most ably' 2�3�0���Y�g6�A� 2–!�8Compar� o6Gw 5� lessi�hold me !+U��`st ayt��� signu an�z& e�aS=�]Oin6��b�six��ten��per��L!cVy7�bu%PEJ2n .k more)��n25a!|EvM�p =6aWor �\wo.��S}Z6� ��r�h in 4aJ8% a�� %YA4�ncan . No ofi� rmed� m l!�a�t .�E����"� lowe;ga( ankle1f� , wri hand��i�3 , Figm�I��tudy 8!<�q2�)� � 9?[ *  involve���� �oa  u>a�IlikelyAW >E� head%Z neck� !X3%Xq�c}:0m�)9�Ho ( 5 N6A�6.:, OR 33��In�%� also>� have t�4b( 9A�)^N�%}2B����z��!\| �^ at 8A�4�CI 85�?–88�)A�2�,�lB>� ( 3�7���V 3A;P�8 ) ; iB� ( 8�288�4�!�8(or both ( 2��G d2�4,m5%�Ae�6�>���a79%�o��2�]qvh!|!we3N�274!%I�,!9����OM�f�)�ularly��A� to f ~6�a�L�!�1� 9–A0�6�. Oy ose�!Fp90%�/E��or diseas� T��n� tV�as� betweenBq=�����B 6�� .8Z�9�t�( 179:36��4A�9A�!M!?c I�!�a%6 )2�Zout]444]154��e8%�F$correspond� @aB� ��Z� of 4�1Y�e�!�Ω When2�Iq(it2�,��=�6��W)Vg��85u"a/6�a�A�A�!��� N:M6!5%;%�:P!�b1#�w I�is s-secA�(al survey w� port�ub� n�.�n*W� en villagA�B� � (Solomon Isl��I�age�-J L9 19A>2� ( 27reU���25� 40% Am�v� in a 1997�y�f�i ��$he Malaita&W >�[18�Ouri��t�tovX�A|"�Fiji [�18� 8] , Vanuatu [22Timor-L [23]) ndigenousA�"Zof nor�0n Australia [��24�C! fBng;epidemi�����pABed4n� bora�;)^�tr�IVouos� "w!�$pre-schoolACd�1, sugges�th�Ai�s%�im�U � tinuG� y transmi�[20!��a syg. ��A7p*�Q�infes{�Fr>�N:���w �bacter�pe�!�� !qDݒi�l�1�by�viA?%�D1�J�E�� !�5Y�)E0We did not ob ��stC��+1or "$ ]3!M meas9of*� crow�_�2�6a6 allQ+� � , f�Lassic ac,2��!;,ly described�How� ,�mdU���extrem � f�q freq�u � �uplimbs!�g ontrast�v some:{[O ossi=expla�A" lack!Pfootwea� clot cRa��� !�� �&qPAweJ_ S;6rMjQ8� Qca&Qi�h%�ei�mb,�Jh%�*��"� U�*s [25a�����s�"imi o� Firs!�"Y�k�Ł�mqat �V�.!\)��&��s*!�"�ed"!����*2� amonA�e eligEtarget.���du� imariA�o��y"�a�be!np)�!��9!tiA�f-f. A�ll �"en�a��BwaiE�b2\W�Y cerSis�+�!$}�t can � cv*( fc4EI#ng�% halfa5�=�{cond ,%5� vail�facili��infa�ruc D�.�!of� uH wtE�ei �U� u t��%extF� !z2o�y!#approp4�Xef��5oni*!�2%ofG in��q.!isX�yA����as �2relev���!|\!/genit�/w!ͺIr!�.&*A�,��pr made�2*/r�5�h&W!�t.�al�. S�scrapif �( m� copy�mage�%�dermo "� !�u))�ma��v�hanced�ur#"D�!�ac is dep�nt upoA�. acum�nd�$eri�!)! �er%Qq�e octo��whilstk5�5/exT,u���l� iS�Vrop� !at� y�� hich� ���-��misc)O.:������1 ���%���e����N{ M�un&&b�.�� . Fu�  developRA�H�56cri� E$ algorithm��!� �6l#!�U�,in field set���6] would���atI,teiڑ�onS) ison� globalB5 �. Fin�,�e.s���Uhe%ZA�dm�ip�E� trachoma!�tro` gramU E 2� admin� )�/ #n  zithromyck June5iAs 2��!��@gainst S . pyogenA:ndaureu��vu� redua��burde� 5� d . Lj��, %M�s"� \ hypo� i!�7hs fM^inv�Og)in� ed !.2��4staphylococcalEstrep� i %erra�. Despit%seɬ�)E8&� U�!Lpublic� l_%mplm�a�i�u *a�' @5[d��A�on�}&%���k �7N'l%Z���5%�2�� an even g�!r@!�am�h�(��!CVis plac�^:UR�s6b �5]manage�r��&���um�a1͐nt:�y�$thource 5�pp?to B>�a: ene9[%s,)6!pr�AesipYJo$, its downA�amA.and"�edT bida�� =l ne� o��l > ��Ag� �$����c�* . Stn',of mass drug>��!E�t� Acid�oo� iverm�/ �R�K`215�:r*�)�@lomidin)KA |U��G��ir�#EQ&�(! ongoP6���e neg�$!Z����pA)�s .oNeur��o�nrough-h lif�mic� subgranU  z� � deXe gyru� hippocamp��� AAfunvrem� uncl> . Me�� cellepro�͒�he2Y(of 719 outbf hete ��s?, �rev�'a1�.dcml�i�g� or�;of CD8+�Hsus CD4+ T lymphocy�%ubseta�T�.Qref-�sh genep loci�kqexceppoH-2Ea'u!�a% d a domin�`i&t n T%6!��!p no impact� n.�. A>& knockou`-re*� of TCRα+ci EN. �#|E�f��f �F,I`2�Z9(��-cA s�sub�!ere� edU*p��.�reg)��6$organismal1 , br�'�-a�-�  us e� M�ny-al5�TI0�aIr�() 2��homeostD+. ��*��*at6oz uH)/.N� �.n�-��nED, yetvs[0[2�A�/6�isAwn��e�woa�[ mamm@ n br��!�ve���-,� ch gives���vol� y,br erE�!=AL6b-�5al�%�*Vg���ld*�Its �r� �_l!Dr� uc!o prom�)�쥛!nA'�&Eit!6� dRkn!B��56� us: �� ,s0�emo!�al regh.� !J!�]� R� stilA�b+ . E^�s�>antN o��age!� irraakh to kGnew� ��U�I �pro� �-ice�q�(a�ie8in [4]�G�# \�b���.�G��rt�����s:�a�5i�me%k[5 n�,�'xie�/*a���3 extu!h reezaH ;spaW6 W chang�B6����i��>8� [8>� mb�0 /!��:4�� � onB��on�$[9][105n9&d a ��no-?�=:q[1e1WhileM�"(eA� beha��7-��6�1�r sub|-(%yc�k)� argu�atZ�'�"ee��&=E���eri�.%���/iteE7b�<�% �J8�adG a�ol� H� we ado�a�a�acha*add',�qu]on . Rat� q.�2#�2"�in��i�O�FAqua�>veitJi ( QTL � ��bumo ���[1� We a�4if6!\�A�2�cbe�"n�"d; phenotyp�&��*!~q ghEmA=.�2i.�de� d!_map����bOK-J% ( HS )1L�ock��d8��%�> <t3t��� A/J , AKRBALB/cC3H/He 57BL/6 B /DBA/2a� LP/J$maintae� 050Ee v-��Ql�of rec�=�e����m�L�( -%ooui"�Z: eak at)�a�m� %z an averag%!gA�of 3 Mb�ARat co-�1izi�ise�to  pleio� ��a~ -inc:)A� G�!�i@ ique�w!+i �#��olue�!]�&6$QTLa�aX ve bw$ � ( 84#[!`��,[CdAs�!/rao;3 [a#� #lA asthm�4�j��a 2�be���awas hae��~#mun� biochem ��o assay� e }� �����|ly h)�b!�1to2��V velt1p��fee�[14�^.x��a�n�3v�plus maz�"o�3~)!.�-"�!f(�A��cJ2&=�3(http://gsca�zw�<. ox . ac . uk )�–���aim�*�!�r!�9hipEg �",.f���2�k HS�r.81 asse%D� f���bFu�g�abe .!KI67-po�;u��OHS anim�9((aia mark�8.�*�&5��QbicA�~2a�is sh in�,ure 1a .;$F9�6�(.JUR5/-L�2�.�41��� @6Aj-Ij arena��+a�,E..$( p = +00�'etck7��)�4|{'�(heɩ$. H1!��=g �a�!1.�l��J��� s6h� 1U-�:o� 3!� �a%�'s9y%�A"�%�-�s�7-�f�u�:Qg3�.�wi �%trave�8 Q!� arm�@�i{5a��,��::�&�!q�!�K!�5'>{�=~=�ly � star� K >r0�)Jsy(a,A%qq�+v1�% ca�'Q}:� 05 ,^a2�,!�"� w!]!ne�v�y%�A��R-e* {�d-��+*��APdnf 6�6�),��@ z �� :-0W4,� ��20u>|9�) n�� �?��fQ"+ usE�1�S;m�o!��es�N��HS�a�i��9ori un1h:M��4un��Al�Q R�QL�5�u��AuAB�4+E��!'s�"$blood CD3+*�a���A�6E−07�H�Ѝ�g&��#2��}iEB �B��Tk)%�-q��$N�.;JT3Z/YF I� Y`��seab�-6�!L��u�.�Fi�����2X� �G!�s far .g�&4E�6| �u� loga�!|� vale(logP )_ed���rvaEthresz6%\A{�"�%t��)nl�Q!��.) t*�outlier���eBerte�AOa�?$parametricn�@�-�@lso2"t��I�on� �ͅ�h )=~:?. SV�} r*g'l).�! %CD8de*i5)��r*'11��q>��0003��~\�� HS (Ujb%U�� shed � �(rge gNl 1Cc�:nelT*&>( BXD   , [1)��!�%x=�2�1�L�s!Fe�)8���)cy=A6�/:@z 9c%Re"�1\�1�(s�-�@/ clus�e!��robustn�9-�m�� ka.Q.b%��!�`��M%.I�-3 linee0� �� ��� �I�*�2%���f�)��g� !3ex�,to��ic2%ari�E��onU�d�� ��%Q �O� o6'�b[hB��#��heir �%uto p* �A!a�+�.e�)�&�"1�LI|-�Gk:l� A}c*robabU$A�RMI���m�.Iv1Z�} �!X 7q:s�i!�&W*A.ey� u�����8�m;u mplFl#. From! \��Q�HS%��\~��Őn �ىof�  wf�ruA� 85�� in 7: !,aFJ25�.~s�T! ��5�=< =W� 3c%o<'���6161s AR1�8&�.ploj)+�s��tt>�if e � peak}>���� NR'��A%�&� Q%vQE�Kth.� . To�8 2�Iߙl�m|ak.� orig�Kw!��dmYiniV�.co �&�ց�1 de���ai�� \J�Leach loL���d*>�j&� �,A.� a�A, ' iV0ll34 &�w%�appi?*2o�@roIW 5)�sA- dropA2om$  15��<@;760\| obD when�-$��1g �;�c<s>}�+%` %c�(EZ:�� ���)�!?-f�}m`+$� 2�P v�o d�(s� !^� G�!8�!A���ets�#rc��G. �y-��l�#6�17� �Major H�,�eti��B lex ( MHC��#2G+�rm0��!fFDAin�`�3!�A: veB4% a,u !��v1�7�I�.���le%���oJ$of H2-Ea [FE encor%�alpha�&,0�j, II Eαβ�#dimer�n{$?A#!<lex!��g �$+AR��9iva� 牴]I 0HS����| of 1e�7or)?(e�>8�C is��lu?+�0s7�"d�Bg��� !�.V \<2��;D7,fP Rpu�l��"�.�2�!:���FiK!elapA\�"�W#��}��+eon���2�~� �f�4�+I�� by�oi�ADIp 5 bm}HS1Ax�*;h�Oo of��-C0� tl�� of.!�5"� dof"� . ݐpaiP{x.nI��lengthT�!� N!1�$� >  �0( Sørensen's� ilD;ef"O�)�h2s3^ reu�.�&� �( u�a � �/ng&�/� .�&AS97�Yv�.LA�� X�H is1�M"nElos:2�i��E�}Q�aAf�� ��we�si+M�6eaV of�=#byP9!Q%oC Z0s�":O!�:Z�t� ��de� � FS� �T"?k�'P�iUMa��M�'gv IAE.%2�H -R)�7es-��  �+iA)��m+*�*(-�ouru>L$ᆢ]�We "!mhe��!��"A�Fa�t� looB�T*��E�7�iO i . �Xv . ganciclovir ( GCV )!; GFAP-tk �$pn�nm�+[19�'F!weeks�&�w��Ped���)���3%.E �}<+ sche�V!_� ��$#8a� Ѿ!eF&&k!!� �TK �?5e avoi>!�gut ill�c�N�X dosof%'�>, �-� 6Z,B; I- H>imm*Ma�!doublec3,�@DCXE &�~(m�?;%�E5a� ),to un?S�e�(�$�:�,$e� iB,af!�)qo?2 in e+ �AKI=: t�−�7�6f 1 Ll �1;YlAF>8�E�}Ts:*�3nMH!�Mt�Ɂ�2�,a�l (7a s�7�mWQmu�@ alte�Y ]1[t�+�J �Z!�A�*�0] �=�Ato�f� $in 10-wk-oNa�%JxRag>�-~�wdea!(GB� .�.s: �iP�� �:E� read-.>;+ �h�)&� 4A;6�2-)/.0�T @�_�?a��� �(�.]+�."< 4B ,FP%�Jl�lW#;�\e�ex� ��Z� Mre�/o�?excMKB� γδ2d�`)�� N] -J 2t 6 �ofo$V'K$�C�!�Հ�/)�&X5MHC-I!� I molec\��A'9�+U/!!�� ��re���ly!U� lla�-�aI �A &�*in)�[!}!�!gn !�Ef �6?03j84 (O)�nd B /II �[*�0:S06jT:!sF=E �&%)I:J�0of2Lon6�Y�e��ZoPPin&�<���A����0�O),�! %�1�f:rs�>wIW͈��&f1�6inj)5�0Q* -CD4AL 8 monoclo}bo�;%�aJVtU&�5����atNd�5t-���290`cessfu�.� �T-!"#Z� h�-ofI��<��g�4m�"Bus9�5A��Sɤ��9��=P�rm/�m� 2×107)�>z^splR !�r4�_�A�Gf�VHto��ho)R. T�Gf�%EQ  >6�8i.!�; !�in 2 wk1�anU(��A�6�6�Y).�a�EIh5�� n�:�u05B!� �'�ie��*�%6EfmakPwo�"N<� s0J� M. 2M�F �&g# 2bA��!Qjv�p�:�%�Ae���:=� .��+sc��5EX ��B 90F�".Y��:Wdri�;�s:�_%�"v.B:A JojF��,Qd. I�Jt#B �B�u� 67'c�'x.+ aC/.$.�aborat�3E�/A;�Be�G�+6�%E�jJ�MM�& _�.7�� J8at; M 9T-EvB-��9�ar��sI �8n� J�� "B0�Do�b��?��o-�1 � gni$&a CNS-��,gen ( myelin�D c-protein�1&[ F[pre�p.\ autoio-�t�I%H. R�@J��E�iM�Z� � no T��B�s"�F� ��&� RAG1, RAG21�R.a�d���_s�@!}@ed5*-���.7, togej$�.$CD4−/−I$"s2�at!YX!�o J& ^�b�ciO t%�1�f/!mta ��a�HS *��9�"Q,!5��isŁmer� �0r�$���2c!�"� %�s�GA unus=6"�.wRe/aiHid >gFMxA�nstit�0�I.��&B&F5c25� �N�:: R�QjI!*��֖N �ly }:r���9�&%`�w3%(%�ob�Hly>�:1l�aI)! % gros�7zJof:�. Two"�5s�N: why da�!9�� 2�J��d�D?�do4?�0E  a"�<�6�I�" ] Jsthafh1s"�<��,.�$ly%2 qT�� ��,�< +#to�Yz�"�  A�2�tselfa�& h!�� (�wi-_t w�(� decay��AstochaIfl<��allele�!c ��G�.�eaa� �W� weak�%�L non-����?�-&C 4.�*> @� �las�v�, J�MZ-Qmod�#A��.}1US. |"� �#��NyI���.�. PostjhU9�ia =��M;V�IactZa�n�p�gany�Q��U �e ,~ 4+A�N A�s �8-9A�|at.��&�:'!Ŭ��l� A4�" e 1c",��:F&U�m�\&dItA�y�e�U� te �E�����u�Bs%e5 hum�?�� or=H!�meBism� �9 7Ŷoucy virus�6� HIV-�a>]M�i-m�:bsc 4[uWIm'$!�2CU4��-Slay a5H�RA6�E?AJbe�5 -l duB=#4+2w?����!C��?j is%�A�Q�2 ,#(!�at^���r M�Ov>circums�h More� �*�#�:6� a\�[&�in��o�Y�v� � ,�$7to��R,t�,/U:2@ A5�6poA�G:��lvE!�e}1h,��DbQc���1�d6\ le?2�� �f>"ph.(��$���%!E-�wor VWolf *ml .�MA� orc%( come�%�d� ee�����K �x2��r?�yo�jz: \s�?� a�aw$:�K�g2 ng �)p� ��Zes%���+$�'1$!��:hom��#lsK�s�Jin�a GWAS�L�A��.�1 "g���$�$a�q��>8m�g*C��al�$Eβ=I2�$�tura��LE2e�!an arrayb�-p!!%, �:�$%��N"�*�of “E-��ri�"”��1�. �G2IJe�"�c_ bjY�%�1K2�!�'�p��,6/A�w�p�[:O[2�BnSq_R�#(a� A C�> H!�b?))$�P�@he AαA9Q''dA=>. 6��"&~byA sS�Z2C�%�I����o� B!�H�Ia�P**�!s��vType-1&�=sI-{EL2�repertoi�u�U alw�= equi�StM�e�c"e�7imab"�ua63�$�to �6�W conn� qQ|!�2�� �5er'^AYA� be u�?ly;xfi�9by6�p �yeD9 �Z/A(�Ara��a�� �0N49��v� e�r��Ba�+ZDepa��1!��2f by%5, of�val maniՐwO!V&� 5A aliz��at���8�OYZ�B�wY t� a�.:�r)Qqmix�)�. S8V��m�+"� )porut!��!�u9)hibit �Hpo42�_�) m fS e system%@�"/; � id�Kyw� adip�` tiss7i� � ar FoxP3+�e Treg�] �[3G[31�H�F1�&� kzd)l�X2(i�c�e�%&��v�"�c�7A�&��)��I� s*�6�%�ono� `[<�L-�6�9e�hs)":v��Npe�=X [32]S I�![��A!(alaA��or� �-=��K�*P!�s�rs6�M��1A��6|I�H(pV�A���a��f�X�<�u  %2�Q�.�=&"�JP�r� �.�regMi�gAtuA��#�how6G� La<�.� "�al �vBmQco��I.�`mvG"\#z� rec!�#�`Er��� fu&�)2�!�+6rogKeJg&� �s!щwt!v���r *�D"r+� 3N�:�!�.�-�� a�56long-r�ors!�s]0&Q�,�QM]cyt�'e1du% 5)xI\�e8��)ycandidat���!�2"\se� Na� bq24WgV$athway [33tE[3�f�all�!U�se9�"m.�(53�=�a�A�( m)`NA�newbor' �H3bIn��Bof>��  .�Dnewi���n_ua��=sv��k/�Ac!:zM.@ I &M =�d!01J,( NEUROD1 [3138E DISC9�Ņ�� ���.�>�dYo91��>���unFP"�cI�ir�7s o eme�;w ��[Mde8I� ..-��e2�!k��65J . Mapqres{I (�sC rox�cly0Jinsuff�#t�n�O�)�y�3Aw�H�[ wort!{ ���g6�36�F)�Cd8%^ Cd8b _�j3-�J2���"*precurs�F � thym��!�wd�c[Tto*�7commiA �#�q��u .!AR�13�Fs���i9�]^� y_�Sb�v��2 [4�i�@�U�2,�I���� !�n� �& e��-4mu��eDa�m�Z?barrier:�w BX-�i-'ppe�ut�Si� =es [41i�5�!�8m��achin��pev����,(A��5hF�5 W"�a�R�w��le� cascCca�%�ra�$v"�`G� [42];6 5 A.? � adhe�|�'u�*peJ�;|.�aw��%�nm*{LsynapS-[4�N�#insT���^IN`�&d�a�%a"�<*�"�8C.�%l3^P�R�JT U e1ETof-M�}�_���Vhar�Ae�[�x�%A��R�#j51�)!���agt ae= �"Ru�{FS8"$wbe�� o�J!��1#> �GZ���-.%|<�bw�iX[4�M[4� O�; al N�J���m��.5r�WDMa'aM5�y<Wmul~P%�ia!>het�ho4130 mg/kg ketaz�=2xylazŊSfixaa/ reotax �r[ 4lO �awe draw�X�`!SAn1,�A� �CVubc=3pa�!�VOsc� �f�:�U�G�On-�e �( BHW�})� Kit ]9)�)wI4 21 m U:��85�fCD3-PE� D4-APC�3O,FITC ( eBios )e�}1�b FACS� . Fl�ytoPy�e�&T ]o$ BD FacsCakII|tr�qt �U$Diva softwZ(56�. Ca�%@�4a���.��L/e�*u �|per!\�7u� Z a5 i��3+ a./6/J( n;dP�H�{ )�ei�� re i�_p�Bone6�5�a��5 ( YTS 191�YTA�&�;ZJ�8t*��16�;;�5ƃt,.�!a�O &�B6�PYK1X337���htTE�fn�_ a 3-d!Hio�g�� 5 mg SA�� ����<�� k%�� �;2~��&I/�a gift< D�Ste� P!�obb�;T, Sir William Dunn Schx}of Pathk��Oxf���.M��5k 8 d� !El5.�6M���D�CD( A�!!8o i� SiI���+n* E]6n�VE�!A�don�nsubAG� suzbƇ U�>g"_ -�]Hαag<i (Miltenyi-Bib!h�q{ly \Q?!AutoMACs zepa�!t��FWcG�ŀ�)e2ufa�gr'���96%A�c judڎby�B�,Sorg! F= �v^e�1�Sin DME�#spNc(to 8×107/m�&2�  xKO�H�6Q2bftrR�a�2�r/�'(n9 ,) .��Chaga�)s�/ �>���Qle�E L&  Americ� !�14tA\W�uP� e U�tP.w5"/Fc3Za] he TrypanaPa cruzi&g60>R��p�5al/bioi��cfach�GAx� ge� at e�! |chaAje_�FpLccS"�aW:�SZ5>�icPy���-�� DNA-,/3in-bo� v j( TcVac��.�*d 7'�la@�,k�( IL-12%�GM-CSF�X�'��t smida�!��qKP�/6Iwe�&�->-�L!�pl O�^�U}va8@&r V!�i�/ �s�� two-6�Eche0na�� T�EEtrypomas���. ELISA�f:: �emplo�0o�&L) s%3� y is@� A�a��(* -� life�t,�u*D\�&� I"0��[. Myoc��q�,k :����H&EFMasso�J�.Qe&� .Q4inkla �'1�c V�KA2gG2b>IgG���Hr�>A~l�� :�7. U|5��  I�-I��# expanHNa��/��n � elic��a��-0%-s�!'j�E7�1U��uIFN-γZTNF-α�4tEula^�l;,a�c'j�is�xv. Da>g !��phz�MQ�per�I� r�U��  "�Qi� �/ �YC>4i!2hda�4/a�0$bec�*)s�^9y& �is {"Ua�G& efibroK �,ea��*kU+�'uscle�F�1%�e�3L*�4by 0� tech))�gI�h�P, D  vA� ueo�){!(�O�:FOEL5ya�'ed11/�~M�� Md�h bs��~�!�{-��"r23)�Roy��m� u�-Hu�2+�� MfU}� ��b"Ӝr� &!I�9�a�L�v"�O,�ve�a�ev� hohrE�>�>�M`eu'acyi�{. F�, �2!Gic�tozoa�i��SE? �q�:�.> : O�c)K<con�/w I� failj�&`^ eath(by,��R%#n�c�'tSouth%[C al"@ !oMexico 5.�4�Sl0 4(@1� i�)M:Yed� EuropeJ5�@�le migͺof6�  �� few8�/$uNl\ s� cur��2qjAv}i"" G ha�Uo,��x A�"�*"�%�=s4. JA��3����lyAu�q ,e�to�6�HeU/ ��Th.$[3k7] Towar/ �#�!�u%ņ��e.# ,}_v c!�,� ng ovalb8} ( OVo�n��?�N&�,"�K "g@�S}e �I6� 6|�i�> OVA-6�/ aty� GPI-ancho< U&)(defaul�'+�%u � secr`@%�i"� ap�#+��(g?� Ie I�0!�'?!M}{��aN��H#���Qc*��$"�$~best cho��I�.��t. AR'%�al6+�zQ�e poMV� I��5�Q�(c]i8$i( 1�s#*�" Xd)Ndct"�ad �-�wd����6�as� �[ �U�3v[9e#"pAvi"�v14 6%(�+par� l� h$ �vt6_o6!�*z �u*� !��"& ${���'m!I ��`�U� subuni�:���2���%��� n;f>]R)search�1�|�X X=�]@�A�dj" # g . sapon IbQ GP906 alum). GP82%,� � CpGODN ! p�W�d�5�d9�% in�Jer��:�20)�OT2O&ve�@!te^���Uc$SalmonellaLRadeno�:.W? M��7�,�/aI6log�!oeA{� ;,�::�U�]'5�F�He�"an unbia��_�X���lA&Y=> ce&��lq��sof}�Nc2h!�� ategQn�gi�rFhzto-mH71.�x�5�4/�\C�.`��{�*-sialid� mucAr�2igen�"mi^��&g"�& fs/Jss�,orZM.��ah,N.�AGgSTcG` TcG3�cGTcG�bTcG�bTcG�S!�(TcG8 [TcG1- a%(p͆�t4' 1n��"$��+"� i%�.\&� �k ����s>-|�A|E-U� ���*�V f6�(h suao�6>� ő"&%�.��w(� �G1-)w2|cG4;�Lɦ�9o/>L\mbranŪE�� lian=!�(:/a"&�550oB%9%��-5mZU � �%���pN���f�/�Rpoo%J��ͦ�<��N�H%h�4"U%hR"Yz,mi[% d"�). Del����1� 3e-=sj :U �\�8P���B1d�v�4o->�ofB�c�*U[*�;.�I�*gyB 54a`�6 }g%�gen&eC�J6 �.��2"]z!ZSK=+�'�lG�ke��.!_� &� ai-�ly�6mD.n�LWi�"aD!���zu� in vitro�a1�C2C12E{� /6 f���( 6-to-8�^� x6R*H.Lab�$ndianapolia$IN  A50�"�/E%&s"BBNe� al I�MhIH6Gu�') C��Us��&v� x���!�; UTMB�2EC)4teH S�c/l� ws TcG4i�p&|i�ubm"�) Genbw� ( AY72791, 0 � 1 A�i�Z��j76%mWa1�he Leish�>��0novani 23-kDa%�~)fa�r�Q�8T>��}�in CL�) nnerJ�* � 99�%0��onDy� XM_806323� 1650�2�[3X9+cDNAsBn l%pE9c̖% eukaryS�� a�� id pCDNA�*1P !ơ��{Ec��>a�rQs�i�_�( p�jmsp35�.4�h!�8 ( pCMVI .)��%�]Xd"*/$�Q*(*%M /i�Eoli DH5-5j ompe@E&a� growC, L-brP/Y��_10\'gS mpic�#'�!eb6�!}ex�Jge�^�M�y u$ A� Endod0 maxi�p|* ( Qijk� lenc�jCZ,F#ma2e"�%�!�FZ�M�.�,�epET-22bUW( Nov �Gibbst!<, NJ )�D�P��� �� in-..w�a C i��His5-ta��D)c �� r.�X,� c6 BL2"LDE#ZpLysS�. ( In�)",�lsbad)�!�Rx �\65�poly-|71s.�G-me��che~x�E]&s�B9c"#Aac k-> E�Qvd y!&el�S�-by$Fly�,�w^Xq�%�LP!n0EG�%�k as <�' 0 EUaI�oxT�ensorW u|� ameb�lysF ( LA(�assayM�Gen 3p}.�In�f�ll�� -���X��Ha���s !� 6��a�ke R]A�C1�F �y%�R�!�(�{!(quadriceps �tw�ireex!��eL�sM� e�������mpɲ.�J�2g�$ I�"�$!� Vs6�,>��"[+:�,��.�(t / �e�two&=g��`���-V}(2~, �l7�3YIin emuls���,µg/��l PBS-1|X tra-�O-�U@#�2!�� �i+Ee�"�!��.G�u�0:k#�ɚ .E�MAMS sacrUe+�030%120�(t-�o�pi�R�N#Ee1 �P!),T� � !rၗ�*�<�5T/�x "0r�>� &�.�^>� W har�%�!'�[at 4°C−80 Vxm%0�����1av� �b�4 0an Enzyme Lin�T� sorbj A��( %) �.=ԕ�5z(55Os8*v��t/�g)yr�~�:(�)�d-u3ۣap��!�UI�K ?RJB$To� sp=%sub�9 p�1�`�e�y7�"!��en�d��"=4�#oomF�3sA(1��35�0 ∶1adiͿ,~ l1B!�2 (bi�A-zFh0ed*E2moIg�t�(A�  %�or  4T7"� �� ptav�� -hor� dish� ox�x.?:-[FP!%*-YU� ern20�#�%� 3 ! 52 in��T-�.% NFDM!=00-�8Mbs0l��x*���2*Sz!Bȁ �$t�firkega�>& Perry� , Ga�k$sburg , MD�5�xssto�4E62N sulfu1Maci�%!-$[��sW� moniy�50 nm4 a SraMax M5�rte|'7.T �Se-j,V�a��mestAumYd���� an O� . �ٝ2�b>me�Z��� $z�dev�kRK �&I�se}.A6 �PTcT( !WpN" �3/:a�#{'109� .)�8t�cy��Yp^"�!�tha85f*I*s����An�.-cwa!bat�m2�0 gpl�/ � JE��0���6n)��ީ"�-0in RPMI-5% FB�,CC��d���,n. fof���!j8cul�G624-a�96-e5���4� 72 hI�addBZ��" y5-��.�"�25!H'8oncanavalin A (v �"��� C ��9na�" �&�/t 48 )��wu���), T�)�4% �0" �?AGoptEIAtm��kiB�Pha�T�� San Diego ڒ`!�**2!�:�wA t�d%�u];%�!�uti�P� �%��"ONJP+by MTTy "JJ@� �� yeX- tetrazol:(sal�F 3- (��5-Szthylthi% -2-y0 -�3yl.D brom�)��j� mi ^ond?�dehydk�ak(�"etabopc�_^%e��?6t�GR7"pur�\az� rystp���/*-B!OqЕa� t 54�{�i�voph*8etr-8Sa�icF !m@HG3,%�p&�X.��lmxe�b!�6A:c..*,3sy%խ�2/��( 1×106�s"� )�&�a獻wG8.E��-�7�PEJaK"*����O�pev4"�8, e3. &> ��7, �i�]?�2%K %�lEu'3�|.45�� Na� �qo�0�8EalTa�]V�8�m�;:PIV%,��r ratF ��/ matc.�) ��>�s4��R0|2 +�by�� Q՘za9S:,-,k A0d�}%0kidney� �5�@�2�6P��!�:6c6A��i�a� ol/chloro!�_=ra�!}�, than1� ecip�vma%oZ�[0 n�iso� '�fE �1jap 7aa PCR( coA�28 Eh,oligonucleot�Y"K-&� 18S ribA4l�[e (��):"?`�-TAGTCATATGCTTGTTTC-3′�F�*se (,GCAACAGCATTA/ACG *) [36]e3r �3d�� �O0� a  bɩ�ll5�!&Z �_al-��H%� iC( �GN)raio-RadA#�+SYBR GS5 STA�V(� %!� Tc18S-sep�JF^�!�� ampl��FrA �ca::���Ac�Cf� s;�2−ΔCJ<| "�� C��2r&��!- m�%�XEAll}��f�X%�*&�GAPDH-�"h��2,B!8I�82 i�v%�a o!��corl�: ���� "��qr, �M xylH%i��� �araffi��Five-�n �<%aA �2s� toxy��eos�%"Y4TriQm��"W ^ by luCn\� . Ti�. l"�*�eK�%0O|2Y2`fiW2 �8}AEOas�#��:�c I��+}t_oryѬ� /�� (��-!yent/n�L,�� ) -�):�rĿ�1ti��$��(2-�"e!�I` ≥26�f�( �-�ienj�E�,"E�coales��Nf�3�Eor�se~a 졜N�Hne�J�#n�x>$ %��g';I\) !�* �P"��2hu DiC ed��i"JG>d)� �f6�pseudocyh(Dsi��e)�l>�W1�� ^�3�5�)~> . Dataa �Im�± SD-de�q��at<�st|7Sn6�p`���( n≥�>LJs/�@�( "Ga0A�Zn&�\�us� ANOVA� c�E+�ent's t-=�� 9!�Tm?�L��75 nly-��RE�!6�*t%.-�z TcV~"IRi�as #p< 0D# �#01 . S.l%!*IY�!�ɂ o�w�#i�-�tQi �&M5 *�V��ca5c��\Z4]� muni ���'���"at$�p}�d�$"�ign�eo-nois�i!�a� �V� ct�  ��*��Qr �Yv ���e*�%Y>"�%�]uM?Im6�of��s 3%��qraYt"� �i-o�S~ ��0)�!�smg]S1V)�&3)�aE 5=��.�� Z � . 1B�A�=ay!h�(6a,�b�%>�Nh�i*�{ C–��e�)�|� ��Tu� TcTL>6mAk� 65�:{,2b:[;-�Q=���-Q:�(BA, m�1�� . a�2zU2�(6W��5-or%[% cG4>]1>h"�&�VXpre�:l"V�,cI#^b/%�>wM!D%��C.�:��Ja�"�Z9*/n�% �!���28(!�-! �O&6M5�Ia�2ni7��2�7�(C@� �O� �� Y�&�?i�R��&*e���_*#�xA�l"c>s'�.l&i?5\s"0���h5��Z�%!��őZA�io!^F�4�H!�E� )n�5�Fy25:25"�%"�>>AW�<�<�� toAQj�jT�E4y7y�_��4 >�!��� be e��!�l?�!U�OYEI;B,@��p�s �=���d��d+PD%OCo�222m.f����/B���U�%u9S�: 800±6X�−25215 p"B Toge_5��� dem�vY Q�g�j���A��-�Cj.�1Gn;%X �P/��'mr�)�$61�CL 2)g>%�"� [ #9!� �*� ,n�3>�&U�"eZ (\d� 6�>(� &�3 ��,Nb . S��urͨ��YEY�Bi(]": ,{ 0�ab�6� V��e-Ù%a rapin�!���� lyN�ڄas"��$∼��3-�� ��v��!��!,l2MIgGeK=acu�d"�� �Aa��n}�/)�,��2��>n��B�jI�6e��:iE�*�-e�QR�"�Bf��K<.U *� �M inm�=}X ��t�7� un>��ll���C–2j�!yE�A�>E)���N�B1A�v< Z�'�jy6sl�l�D���#6�� n� -|"67s�O.�� 6�}� ��r�@�v�n��Ai!S6�b�5���N6K��er�C!W�m-`%!�5�D!�a']Va�N�ɐi �P�=��֬�:H �>56�Av����ofi�ai��H�.R� �3�٢��a ��3F�!N�$"J� day�tpio5�[*N'.�Z&�&aFf'i =��Q2s&��d�!:� ��% �we2���!"�pr.� 2�!�5�E1s!E�KQ}3%�AeZ, i��v�&.���\�&&ond�o��9�� %*���U�"-& :��8) 9�T� t*gA (A��brick-b� Tc-v!s-�1A�Hoia YD2� -���2��2���� "� w�_r�|��"Y�AC��Zu3A–�Vp< . 05-�0# &�����edZ�\a�1 b�?y� "�N�2VJM}e"L-��3 !� 5� f�2� :� 1�& TLaOUd-��I��Jِ�J9nd5.a�-d"��=��165±1� 6�220±18T�� iai��4c1&350±2� 94O4� B?9N5eD&!gm�&"$X�6�!8%�V �<�J},v�Bi 2vV&�8±!4. 9±�3#�2� %7��±C4���3 7 p� 5±�K!�5Y14�gq�Ϥd������P ��il"P#��E����")B��jOVR��Z zi�$2�73 olar�b."eQ� �^MQ!%��kx���>S S.� �` /e vY lw }fn<aDe��. c ���2�?� �pA-61�3|S:� w!١qn{�  �g� i,ň . Ye!)q�/-c%:2 � swit~�eWI 7%�25���"c��t�P�fac!2 gIw��l>�,,R��#"�G.�� �K�d�Q&�u&} 8�C�( ��%�` E��" �)�1�4�eN�ed ^&I��-�76Q��d�6FM�(�3G OT:8H .O8�C+ '<��+ �!%�2hZy>(-�>!��6�]>:/w"�t� .��s����orR"�ab� 9 –!Gi����Q���* �qZaAai"Y=!�a&6~Fu� ��N?/R�8+��uQd{�.�B�M�401� ! �y5%F/q�.& �a�:�6+2�F� �Y�1=�%�i��MAXU�435±��d 520±3! Z�3ʅ�B�32Kt;3A3�!:KG2$� low--nea�*� ���se�l�~�ց����2re equi80��*-�.6�UA�:�p��]�Qߕ iI�5)/���_�=de��p@Xv>>h2�[p�s&�$| %"�-�x�"infil~W""�"�� %A�s:�(�llZ� �:�In agre.w�&"��dof [�i5"7��!���2���� ��"Z�9�Z�( h.K�"��Q�5Ae-f$N��)%�.hVLR�F�R� #q9s a–)(>�P-2A#E�reǝ� .(y#2�""&\k0�, m�N�.#�rD7&�p���i1>�%� (%�10�L$/mf=�a-b�6up&%- �5J@c-!?V�6�� 2%�BG�)�u-�!!>o (6�SB\ AUj*�a &-q /i[qCR9� A�re.�imT*U�*�!2a 83B97!㑀� f *"n+inmq( 9` 6%�>,( 8��3 p�( 9C�� ,-G%�k$- ( 946a Z8h� t)�B�in�eM�e��M�B-5�  AK nA�n^�A���1�6�O�M9fi:)$B�s�^p!�u-�� O-� BM>�{!`BSR^~'� R2Za>qP&�&9,U/( '5�36�sSԊ��g���F�+"x �T/ �����! �1' dM_6W26a��by >95%X B`n� 66M5�i�>6e� -to-*� ���R���I�6�,1]P��6B�E)f"�\1�< p��#!Ε!zJ�2h�|. N^FeW&0larger blue-s�tained areas , indicator of fibrosi�were evident in Masson-trichrome-st I�Cheart and skeletal muscle sections of chronically-infected mice that n given vec��@r cytokines only ( Fig . 6Ba–d ) as compared to TcVac2-immunize `7xe-f ) . These results demonstra�t�TH was eff�ve!�arresting the parasite persistence !!)ciOinflamm!_(y pathology%-tissue9rin1$$ Chagasic % . Tnres!�study�performe� test �rot �efficacy!� �vaccine)t antigenic candidates included� 6E E ified by%wuta!�al analyA7@of T . cruzi sequ%databasqd sel)�because�y cconservA�@mong several clinI; relevant.gtrainA�!}ex!*sD@s plasma surface %+in!�-'0trypomastigot �8intracellular astages-?TcG1- ,2-}0TcG4-specific%_0bodies exhibiAalyt$ctivity ag�)�ieAl:�!� , suggY�@ir potential utilOs5�=�d[26] . We chose DNA-prime/-d-boost approach to deliver!� subunit[1�DNAA8dua T !:a_p!�iS���6burdealow de��on limitaN�c�animal�~Mice )�A\E*��5�aM�rB��N.���rapidA xpan�after�llenge=n��on�level��IgG2bEf IgG1e�body isoA�s��:u��!�in �-)Um�1���t Rr��!� aril��!sTh1i%!�/�r�� s be!�>1"#1Others�K�FR��DaESߡ�aUinvol��in5{ cleareU[4�'42a$For exampla Oa 5�by1��n � to��(tid membran�� -11-encod�%mid�WtrolledR�A�o� s [1�while�1�b)� founpbs edom��5�q�:�co�$ment-regul a�ine,trans-sialid+����[43!1Ano!� !�0ed low-to-non �M�S K dog��!(cardiomegal� �  ��� [44s8Previously , weB�I IDin naturA�d� ie�ki%�6�a.Hdepen!� manner��In��) �V >M&�a bete�oE( 2� y� thanehob� 5�nj� eh� al!�F� q�i����A�� rrele�I.X ��ighi�a.m�� j � 2e�: >y fociEs>�%�6���. -Yم�a� acut�age�5C�Import�Z,t�un�� ablea�a sensi 0real time PCR&� !u ulti�3organs (� ,B� , � , spl )�barely�v|in kidne�<>,atu �6 �W# rmi� a( ��͜r )Oa�k an !�i�٪���?��upo�ѓ2�t��ib��toa[� ]�)�>��lro6�(.��]r�3). A c�g��a��!]nock-outI7or�wtreY� �8� pleA[U E�$e moleculeF�besid��9M�y `��a�!'i��f'@mia also requires+cer!�� �$of macroph, ,%� helpHell� � c�fb inc ,ed susceptibLQ"�)N�� [49]–[5� >n. �snE�-�Iset.A�.�N� / }e��a polar �w4� c%�m.,q,I�E>&ZA1�h~ &IL-4 ,10 2�-�": ;�� 3 , 4e�� 2�^"� mix���/2���1 ��achievA���yy� –5�W%spQEa-I�of�d5Via����wa? ne�5&�ve�LectJ2ha��Y��-�T��)_not sup�by!�4(M0]�lea� to a����v2�)�IJA�% . )A swit��2]F2�/1�%likI�AJinfilQi!Pn*o� w<wpxacerb%i�6!A�sut-4�P on*� 6��!��of6(^�Fk�� ligha���fac atR\�X �!� 8very successful�provi%�steril�V�2�[20� ��.�>tQ�bs�%S fi�A�� death��h markŴ1�� dise�0 . It'�a�!2�,E��H�\mmu�0�ST�a %� o�eh�,man� Ay2p ( granzyme Ai�v�*h byst�r2�nd1 nec[5�j#f enw�A&� I���Ր)��!�&45fs �hum� � expe�n{%[54�5� Circv�$of �Dt}Nby PBMC�j( vitro stimBed ��Q $��b�a bioA>e� Ey� asymptoma, ser��� pat��s�� risk�d`op;.:Q�c�yo�y).B�ite�parti!� inte"�oa���2�� ��2f!�)� T�� 1min� idˉWb���iderably��aA�at2�un&� 6��A6�Fur�p ,mc�>�of R��&.min�-p��z�. A9 �� 18Sr�"� 6��al%� p� �1a� fA]�*���H�4N� e[I �k�) durAP��j)�&���ᙍ���*� � "� �5;28(a thresholdIk�eubs~�, prevena��on�t M�!�7��>EJ����� occur due���.�e%�idestr_ J�W e�summar.�&/ �tAW >�-�I� �q! �2[&+ .� %�o �: P)�*Z>-�!���&�t n�F,6g� pro2L �gatY`l���2�1����Q\. C��I@evoluQq)%�n/Q dama� an outcom� h>]�V:��ab2� ��.��Gen� w�a�A�X( GWAS )Ux fruitq .��s6l8f� ommo��x3�lA remain�Xqu�o:whe�zwef qu�f�ividualF��1d�tgen7�gin ord�op �a� onalE�m�{%�a~�pl6��5/{ typwfaiEJol e satis� o� � eE,*�� A����!a�ed numbez"confi� sJw. H�"we�&� sophist�mne-l%a��0a large ensemro�rkmay�rov���!w�of6�assess%P.M appl��a Sup� V�"M � ( SVM|lgorithm!�aI��=set!�e�"o��,e AffymetrixAAS plat�%ʍ7diabe;T1Dhnd optimE aIQ�model��hundred� � A���C"�is =eU"� Illu-Q�d�w� imp��(1 , 008 cas� nd 0A�� well� "pa!)=!Js(J529:\4586\ɏ![in� a�$r ROC curv!�AU�,of ∼0 . 84- both�!5In Zastaoor��!�EFw��D h�m"�oze)%nR�AK)�or loge regQa�  . Ou"(:"�'imE�db��!�by us!"U� Jtak%t�cou� L V�% betwy nxiAreM�a�WQ'-� �� .�(ay be feasiaӡ� ,s�ta: #pc r�%h�k� alreadLen� ��$SNP�%ays . �fs"�Wmploy�< terrog��� gene archi jo[1�Un�Cdi�al lin aS"� c!=A+�,����en!,db3ticisA>o�A&a �j rang��� phe��e�S allo���m�rep��ofŻo unsu" �*sRSZY more5�U��-���& ylNUnowm�toaKn�AE�22�2��[21213[�Crohn'&L( C#5#a)���� ^a� poly(%!�� such2he� [6�8HAmas!dex [9]%}dyslipid [k. Howy' ,eM`conI[!�t�$variant3ill� la���small:pj*"� ffer(�q�!�dispoo�UPivi)ty;�-�W 54 v; A,%*� 1/eM�-�v* �ex �4–6%!��E��xg(t#�%sR �g�s!YC!A�A�31�No��>b� s 20�[�0���A7. I ihm+A���"� >9s%�repe!�a*�#, albeit!c�LIUfo�*e�6 fu��. B�s2Y t!�fUí�>�:�Iic �%� o oft�'��edh't G� iѢE� discFY wA�fa"8 ��" c��er&J medi3+,AwhichA�Oiv)�� apeu����!ݱ �sd tailo�,ys&� th�)!1Vmake-up!s����d�&��Ŧ�.me�  � nga�fi&� ���Narrayla�!pro��(w routina u��er<. mon)ia�s� �jA� rl��' Jgha,e�; h2xn�,��" !e�work togh �b�1|i+�� cz�]vb�6P'a�Yforwardagn�u�2al�Q��f receG&�(� *�of �%g��U0{ �1Ui�tF 2'12��16.��>$"�$theme from *�q9 .� methods sxr�"� pra(e valu���.��6ofar� ow w�would!rdea&*."� �$A>� .:J'ats�u a�9���uX�!�-�“�H”9f!��j���"�d*� ��17%�&�D (a�a a-A�� ope�(ng�u�er � ) sc�f�9f� � %�� 55� 6��_A�ng�>�i]1slA��- &tlc ,.� they" X.%!HR� Ksh%���{ ;�jY6.&J#F!n�-�0onyh�Q�s��or���er%u=:Age-rec&Ma Degez!� ( AM} A��D�� , bu�&A2� �>_ly neg ";�4���uuthor��N 1=s��-��p/y1>av8“��s��%�emk�*�f!�ng�i �. R�A�[1!�"l/�UcN:aae!e�y:�!D��< < >� . coron���|[21� �vas)� s [2f although : ���X.�#!��z0!OA�k,Sgraphic�q�)nvironA�al�� Al�u�\se��^{#trigg��o5% n ab&e�"�1�<z�� ��:,.��14(�, viewa�Emsi' wmaj�5 ��A�A�!�:��p7-�%[yeta�be� %3��� UO�0m�ng�J" P��t unexp`*: F�/� lá�.�invqSd� Nk:� �I%l�"%�Y . A�!",[ u�$�se�K5BQ$�� �22x a N2 !�Q�%*] >! !�� re� � � ���2s1,9� genu�: �����9���p%preYsa��  Ef.{ in #�\a�ſQ���>��- �f���%}Q.�� �Tt��20 s;Rd�e�!S ��Ky�yield6�<s �a handPof)@� 0 2� j%�a� or f���>k ac73%�!��&A-hy %oQ0U�e�� en.�i�$c�7�2?��%�epo��z c�"�aXfy$ size![��[ }�a�s�e '�!e,)�Ex� bee\ov�5��Y|�"mSe�  ,)U���s� �tO �%&S72ad�v"< e6( unwO�Rr  &�Illeh )�*N�ass��3ce""5�,)�: � :�A�� e�se$�7p��l� >3Zal%�tica�M�F�!��)Monships��a +A@�"� %���-!��.�.(�j , *�"9)� "����pur�of ��> It��Sor)Ob!�, u7��6( e�i�8,maximum-marg+YH)� sole.�class�  !?�0ri(e�. Fin_�? whole�m]�$Q�-M�u�գQ�Y prob="9 ly� 1�,�!]a�E�-seF LyiN��!pV� �a�Fc�{unles .up8� )�!�d�_�'2\ exposu[.>���� herita�+M�(∼50% [24]�le 5ma�s~:er famil�)!ond -v_9_1 Th�iwe����R�z� ���3 ,1DUjF��32D�.� we%�����t�!��^� 9 c>/1ى�s"�9n"�,�3l 4alter�1veChb�kene,"t4e� i 2� b}�?� curr!�A�."�mp��to g.1im"sY� ab�a��/.�^2 erry-pickI�fesJ���^/,!�"<an �=re lis$, reqng�-re-def�A.�&�#q.� eba�(!&#$P<1×10−�+,�n i�:. SNP�%��6>& ]1gj> ţreA/no doub7 at s��fal�k�'h���ar ,fw�< �%�oEE0al.�� ��i�robust):�@* s,n-2�1��2ta)�d�=a���,%*yaA esta�<)%1�� Q-.&�[8U+SvM �?,� ell-)%0EGe&!techniqu����u�]qc BJ?“V��C������19,;'LtQ����dih�e' �2�&@V��!t�h4Eial {@�">��� ��5�R ���nua�"ur�or or5�8.1jIB>�&� ��qR!�p f� �B �1�ѩ�isU�> �� T1D:��ee6 ver �;Z @s6��&1D�+h8')������0 � �e �#oa�atf3V ( MHe!reg| !2A l)�F�y�on��6 tt| � )t� nfer�)m�o\+tQ�7JI/avail`�n9� � �3!�!���s� sd��#Q"i�,!ej d�,lo, sE�o�+G2ip$�*($Map 500K@�# H1Hap55� a]#��# unbi�*ahsystej �t#a6��. We 0$af�% edv�.e Mx)A�.F�" ( LRB6�1'i�A�Rs!�t�J���e: ( Tn ?@�#� n� �|�popNF u&mfZAk��/�&nd�#>(ate-of-the-tIp+�G<�aM&�Gbi�)�&QV[2�7In 7�1,�a�3 ervi�� ��F"�#��-0�l"e� ound�Jt�h4  s�%a�b3two) �!bE>A�ca�ue�&&by ma�40=5@W8on ( kernel fun�9)!V!�input=�e�#)ea!��  s ���%�&�� Q�)>mD�ZBk� ] orwst��3,WitA:p.�0useS�1LZ�-dime;=;*at�.kmicroe�n� &*[29��We�E"ed LR�٩Zol=�,8 �:`�0�9#e� join�,��P��.�"� i�y� �q &Fu1� �Ja.�&9s6��,��+ o N�&A,E� sx ��AAa*�)�!u� aD P-� e cutof� r�/s����� 3!M 86AlQ<��ent quaJ�ol meaM( s2H. W�(E��l9�ri}a� F��[�E�scr r �=s�G!� me; H es�2_Y(*� 8��s in.t)���)"UEallE1�"�"��ingleCua�. 3�E! �/he 45- !�:5_�%i�(1> �s!�en! ��!'v'ue��r�.>)�-3��A�� s � !j%NG E�)  '!���DM�� ��� P ceaj�F�&� �Eri0;�mad�F���%Ztoler�Kto ir"�M:#[30��S4w /���let�el3Wls��e6!�!)��-kl,k goal�_�� !�em�[8 0=�(m���MJ��k3AB�taE�� i��$e� 6�To; x �C�$e= &m� l�b*v �o.� ��Aam$�p� FE� �Am ive-fold �8s���!sT8|WTCCC-A6�C�.. D@5�9BD, 8&�&s (7-���A�rol!Tb�to�Ka��.%Ӆpk=!�>�,�nDd.?�<�2!�� !�!&X *\'�st�<x!�� :���in-�yF jref�Pw true1��$=� �2u�b-L � 3XC1+u_� Q�c�"�!(���"R"�.o"�.���+��1 !5MDZ�:$0e�� 0 p>to�/!2�ig=n���"�0v� 9bD JF%��J!�2u^}�ᰡY�MA���� &� �$�St�BZ7l(# out--: ,� �!$�st%h�"!�A09"4 &�HO R%Yseei/�D �D�Ta��Gof"% 5 is)�� �ng�?$�i+,�!�6,to 399–443 9W!�B�e"}<1ToM�%��!\ qa�n&fwa�S i'Iɿ.��oBW sour� �Am�+A��s��) t!!'�� !��[��'9" ���Rpur�A:WN� �O0� A>��E�go*@MRpr&( Moc�ZR%�J���r ��U&� batc=�%�5Un$ i� �+�R��shd��!e\unA !5t�Q��Y=B� �o�+aai.r a�UgeB�., 5>��lA�/[33�(A�Yj� esig�7c�t(j.As &S�*��J n in��!�!eJ!��^�A4;"�!� ough5#'^����5U�F��+��7I�{�:�b �CHOP/M$:eal2��4YO� 2"K|A��e�5d6�F�5 JMACH %%A_"�Ebd"[ 1co�*��-�B:. A5 l�\�a� third2!9WG~32 Ki M D�)� ;4umK: oKin((a�A65 � same9.�U:��5nd��g:f�1�is1� do�B�K m.��A�upp�.!.Aw�B5Ux$UK Blood S#c UKBR;�"�ap of!p�DE�eu��u9�=�[S�W�P" Med �� 7 �e>��!c;>eKA�"� or� /BB/AUC��is�83V�845�FV{I..e!��o�GI�aņ%�"�J�&' -E���@�Y9T��S1� "o�&���no�:hB IobAL�Xr� g&�ZatE�ٌn�KmB �d1��3�D.�"�!��!QLR  �2 . Ng$th�#!_,a�&� �s�j=�[L7\2��{�Q�+� ,a,2�Cga.�"�T"�BFQ��%�2I�*� �*�@\�J���LR�& b�8�#� v(5a�- �� atmhb�s�'M�*�=�1C thro�+�-d��d�,�Sk�!�� 9W*Q>is M"e"ar�^17}Ɂh?*/5�JtE�/�^ro6�> �n ^��.�2{!�1y�ob�*�e����I&�؅d.1�c3!B?�0C'ons& +���groupe.J]ͦ-/�Ŧ�V������A%P�Oe5�: t�Q��� ��5�o#LRc.s6j�/E]!h*,PFm ^���=#ex% DchAD.��0*�.���w��5� �I��9|*-�"9 .Xe�r�]J�!�$`Npdng QCa*��;� �� O ql�S�L2�h�-qE�,~6p.� on \% �V�.fu��"�-� ��w�C*H�2if&#D��{�&ng�F, y C7r��!Bed-A)$MA@2�5����P09 9as op�(d��478) &5A�LRca� 2;2���t RA�FW��"W=F�X�� egra�.� ��[!nimpaci4%�!zR#5�d�,@",sh e��-�w�� ���&&�!y�i�qI,%�as|8� schema� ��cha��Filt�g2�5 ��BF$Q*D�� q-��>� A�E���xs�1� D:�heJ�Fi� St [SDespiR �e9B%sa���*Rd!���K��an]�ofI�5�6�E�4:U�lN+7&� a*�6}o.�6��9�*�g�-�nA��>YU�Hac�#g5?c 2D%�yH��e �v&�9�-�+�C� � >Y =� �A*SV�F`� l��l�4�#}ng �}���\)�A�Ya��2:iZ;h� �is !��,�q^!�a�,�5>eyo�B$�Oe�X7�R*}R �?�I&�)i cernA�e"���>�i�%̉�Y�-�A�six6� coh�%4 .�#bi=V�d"( BZ�6 ( CA !`8 � hypU[� ( HT� rheuIji�kthriti� RA�G� J�BaN$�iis.�.1'e�j*sa�5 �$e^*�$subp�2}H�wo autoi�S ��CD!�.w ) A "B�J�ciI"A. By ��!�j��4�2�,!� �5�?*d E�YexZ=f�A�eU��v�<�?q ed tcura�I,n E471GP% �2Da(74DH BD "�3�&qVn�RA*J\ �� ���8:K6 �.�� MHC l',A57 � �Ka��!J!�RA�=�mr�Sfac�*:~�Sw@G"B~)X PTPN22 lo�on 1p13�I kno�i��w [P� �[3IE[33E�mhj� "�9�f*/�V�7( IL2RA�0p15 , �8p1YOmo 12q141V ) [3�]�eI�M��gf.�]U$-�=or "x� !�b a�>er�D%M�a�oa�� a�5�)�2�!kis� nHlyA�fiK?+,ZAL9(� &W$�o�/�al� ,��2�!�Ei* mŅb� a& �1V�E� ֡ wI"� �depth >7b� &QB�set�u11DB��O next* �&�&cmR�s�mowHi�" -�-�m�"!O�6fo�)7�񱮡�v5[7��5. unde[>m<[��"�.I � he:2. I!.�?%��A� laus�+of%�ra (�Und � ��of �1�>Fb ree$-!���!'I�J�C��6�%d6�9.��.5OS�� � p �� �F%�a��b"%�� 5ng6�U�nUS�6��$a|N!k�M/�'"zP�f%J� 66–� 68 �n%}#��nQ�c$�b3���% l�'in7!ZI��7��&�an��r�$I���'atM��%san"Q%�m �*� 5 B��a�I�fe� P!�M��+\X�Gn �oa*& �%qaFQ�. Oa�e�}��b�>noi �$46c��R�.�LO&nC� �.��W�s�$�<�2��I/to�k tru6�% .� back�nd�!��\1y0��6QzP �+U'%�� �� �~&EZ= �`and53�V�� !o%b��)T3��t�-�(e ^;� le�Ji�"���-c-Cign�F.s;A*63BLa �=.+ ]�1!E,�jA�B��m6 >6�eC\�yk��,if A = 0 G 1�)� �Sd.�b�(*&RVMm��.(k�.��!m $b �LR ��8?4)��3u��]out�ln$M�6�*��S %���.�1�,���K]2� $dAv�(teM*iS3A�a���6".�.&�#��)�U�8"���!57�fA�at)�e�MHC��c � s�u�`s+ \[t�,@� FaGIOa1�31ve=!.%/rel�BAxn�E�n�MHC"XH4!�$,N� �n*}�&���of LD�#uc�0e �{HC�mapl�=�@) playt3jor�iiBc.%� i!;%�K5f6lym�\$9�b�K1��4V[1�RmH, �v"�>Px!|8pr?{�L$2�!eby�belfea4� �.>� ��"D �Q� docuk� Q�c��2uqVJ� e�[�:ve�f^I^�Ees:,�0�o(, Lee et al)��1a MCMC�AM�ak>�ofQ1A��E�2����!� !�in!g���stock moe*H&� BG��t�,*%[tJ=aT&�2 drawa~� .7&1�Z#a&��Q��s%�+ita�$ ir]nt1�f� >K����/ucU� &;on-=T;�Cp!F� ey)�3.Y��JU:lZM��}ngd]X^?: �gU6�����q W9�"��&rgu� �u =���ne�GaWw�,e9worGcenario.�a�iA�aC"�!Xv�^�#*��4�}g�vP��$ �Eomic bxkD'TG4��N��<^ , HLA-�5ng@xV B� costt ndAfertH��Y )( 5�� � �`�%{��De�E�) (?4 �>��Nm�$6/XX�=D-�>�ZI�R�D �=`���=�D6d�V� all� ��r2�M �ly%hnd"-]SN8V��4�0=le>A^Q��?Ke��r�;:� �!c>k!�"�If;F*i�a �)�D.�;��al;�"� `M<�%E5B.�3!-t�mw7AU-�b ~ a�b�,�S�| .V��v� diagno�I jA�c7ar�^:a)E�O�(J  � 4%}(�0v!jJ6F�.F-mf.h� velo�d`!5 y�4alyF� �13u�8aN�� cree��!�>uI�I�D �0 l�M�h��W�!���e�B�Z� chU�A=9�-�m �U.� eJ��KF���.zF��Yie�]��u�Hh1�]�3�1�16%e"a&VTN'alh= 100%4/C∼A&,Ved=��� �^w[uLK E%�Q!!�vnq[: ��f�U��wQZF'-!!�_"h of 93%��4D!�.rR�)gfAHes 31%��a�Jx96%���!be reH&�#��il1ll1 !�.�87�Ax��LKeQwibcrI�6D��a� � �!���H��KsAHt suff�z![� j&-9�y�.&�md� �WnviJ%�F���81aj�'�'� w o}� eplace.�a��D�*��!Έ�c��T�0� a6wY�z)6 \����eGoBOal*|M#E(�0� � ��=di�=-�mO �ocN�JQ�"< jor- C~�E%p ��)b1y�^ %�(� �1�9%�*��`� 2v2nXp'!�t6D e-|B <*�0��.bK!�-��"�`c:RR� � cT 1s +�ade��.� eW*�6��s=��/*7?�Htr*^�w� �-�g%�]��#� T �g��/� ,�Ep��" or4��orBLu|in CD� B�Gm�Glib�M1��=E���~�}SNP/9o��� �?"�!�Q�.I!�1�%JaBTep�cJ: ��E��JEst-�VoI!e�iluwN �P<N 05��e)��9xpcaw%?]N�.�$>�*-&(psychiatric�%s�"�app�F!�o�� =G$F9!�c�aB-�Z)��ޥ�>�!sx�OeE�1�]9*�S0=Ɓs!��f� ,�%%U*� %H�?- n�$K<�M�.I�an�f�. E2w� \9w���:2�\,9onBq"�>a��&�de fIG�rj:��&�]�]Y�+Vo)� &�Ly2�"%�1��f�%XA�e6W�"mprehens ��=I��l��trL#�6Aj��qdi*nd smo�/habMQ{d �.'�24Bs�uaEiTrIBMI2�BNs�C�%r��st�� �&�wY81G|A>f/�)L%+i�F�&�!&bV@79:k*�.iIA���M�d:�W/K"�W�K%�-�6�< �r�L�'�Bb>Mf:��c$'� �!�.�A%gg�uI3�1�Pe�c!B-:]>%mby��(2 da;�@eg���ewborn�-o%�����A���P may.��HE>6-a(%@)Y� 3�7:A�ac��5�Q*�2 chip�� I�?!�D ,8�"*31958 BM. h Birth C�. ,r8B>CW ol G�82}∼�200����!af"�(Q&f s: t)2" 12, J�.,r./�/fl"�� bowe&pZ ( IB�/bb�/V�/"�/artd�&�/�H:~�scribed.),%�QAeUe�downlo�5!1�� ll�e�P6& Chiamo]��Dq�+defaul6@fa0c�`a�0 . 9�OkeeMA�""8:��(�L � remo�vi3�j956 "� �\�CQC &� (19"CS�"9N�as� � aweb�:.r-FI*T#�zm� F�dm�/�,pE�Z n�J“ex 4-�to�!m�Z(si-{.e�,1�e 45D: �+~�B( .�I��Z!4]_c��_�']@ldbGaPS��Z,At4?���I'���h halfM��ic nephr ~y�$#� �h.�A:;_�Kl~� !�Ba���A� o*�B��@��*r *�/-��-i�BZ<� �u^Q�#'B(� ). 7f�MV �a� �.� F �� LM�XealI�D1� se�rl&� �=�aX�ChildrelvHo78a�(Philadelphi�:zed%�~M:)5 � Ba6�ώA�1(!J�<��008�0y& "�{A��a�as�(*)�d;.�&�@ped"�4�3&j1p%}at)* ?1G1�}recru�{ |^H� C� NetJ0N!�&-.�Usca� U�o�.%�%I%�%�� �:�:WofA�/�art,Europe� �8n �6�Q�E/Kc5���S�.p(he&H.QZ{� BeadChip;��hޏBoaH� ���En2 �! �XO Oto%e� %ed���!�)l1'<)F,he Markov Ch3GHZ'��(�H) softw!�X( http://www . sph . umA(. edu/csg/a�& sis/MaCH/�x . html'fN�U^v<�D*� �.-a�v:E "�I=�K @$Nb&hmc two-step)NE#procedZF�doac�l�@$eI%rOjH| randomlye�t1�ofJ�!s)�o T!!� �I:3"��M-���st� k!�� rror�E:�4)�Qn omnibG�arQQ8?c�\�+s�"-�A5T�:isc�Mnc���'y%0t�] ��re{ panezre�dmQ�)����z'��+"�� al�9)�d| s breakp�Y��&\*�Rt>N#7N��N���y<s"�2V�x!|�eO Jd�JleM hea�MapF& .�l��2�Hon CEU�QW\� > Q���>�hapmap .l�� !M�s�&dQ�.���B����dI�M>��>2 mill*�I�%�Ha��:� Rsq &= �?3�8mlyo� 2? flag�7(>ker�t�e�ٔJ !9po���wjj�B�9rw�`��x�� ��nthPQ heck>9t�X orR> �(�\��7k%D*G ��=alPc � ctly� E-|M�6Hi�in8 ei��res ���flip "�^-gPLINKy+o�� � �l��"��A)i�KQ(��R3�E�n n*pGW�G+# ( gij� �ij de/5�*v�L+(�y� i�&u jM�6�� enco by Sa1�KI�m�a>~A�� �;,-��Mq-r��#� - Gi�Y …scip-��L�.Q��yi∈{�} , nam��ha&�"2>G��d!���yi.z ��-�*t�g�%�A:)5p�΋?�as}!�L".��*�6�"eiF:V��+sA,���,�6A����%R1�� "�R_ari�r&�#!�6%?4.b�$-�q�"!a�z�j�)]&b"h_4!��Y#:S��AL�*� !ubi�J�!�d��aH(s"B�/�24a�9(I"?]��c�g mj�^(�I�5z�Rp�2��Q��*� E. J�q!un ����z�B&K6ti B!�sp�"&B qI�|Pw�Ms�a�exhaus�!6es�m:�{g�%6�lJBY !�!ac�s":�.�e�0a� i健� "z��yK�8�8�Y=��n adeqw[ �48pf( .de�p�b!!�!0� s~*out�g>> wr"a:jINQl�%�[*�f:]�%lL]���&�u�)�ce�6+���AS"�+agnitude!�WdFn��@f��O%�e&RU ",Aeaʍ�2�via�$i�icM�1yg: Y ��A�U��"�: ( β β��β��!LA5�c�( y�� �.!�F� ~HxpfTP /�.+2|)�βP-V�A��0�>4��3:�]�P��2T4gP!"�j�%ih��"D( MLE \jβ�a8;�f��b�! �Mb! . 2�nQ�� g&�  , 2}� �h- nume�$v� e���+!�&�U�(����)ach6 ���2WhMJ�f� �).V �ު�te� �si���7h�g g oditi�E fav) f�3M�n;1�$>�m,�nguIOV�ave0�f � 9�n���l1� quilibr�[�$c&6��� 83%�&#M!�un t� a��Iim;��o�a L∧�"�"agh=�Z� &f�"n7�Lur��"�+�Pl� ckagl$ R�gby Park%�Hasti��'l���Z� ���A�Ћ�Z�&N�t[50hVM!�>�1r�(|\!,�� %�vFoA�X. i� ny bio&rXns �&��@fi�n��q� a�1 plan��A�aHE  JH�Z�wo ��fQ%:� m|g�9k\@"I�!�1 ���l�h2?l�)��av1WdAs��R�l�A���� B��N �M!Dž�dD�rTb����  C��&�BP ��;JD�3O��de�o� (B ��R�`T�1lap���o)5�Xazz lackv ! !�^ ��0�Iaa!�M�,M>b���)�C�A.{]a�-��C 6�h� )aĉ�J" Spec�~!WA)�}+ 1 �JIT�4B*��n�Ply*> ��:s8�d K�,� � ) $<`, j�>� g uA6iްpr�!h"��6 . Two�1:��+�l�nI2areE�,":"z�G �o��<alXh IU� �}xorigi�qN�. _8S>6O1�A!)�z -uGa?kp&��Y�bf o�\ �bBA��� 9t�P& z�.'EuUD s us�5��"�~id��1n[�n�Hbuk%�o�*�F>_c��k�*��*�a�5_�� �-�gh�"��ua� A�Q'=A2�& .vW�%p��86�y (.&   )��(%���mn%�e&E��Q ol�l�T�4. NewqTApi 6w/2�}�gen*eI,E�Ņeri$jAj!1:�, go� m0 puts-+2�.9no��o �Y�a4�tt�� � *�  5)u� "!()�A.s &a� ���M'pz e1071!�RAD�*2� �U� VwLIB[5�UR o" �������1�rad���]I��&� :�.�0 �2O� lso���1* �+-�Q a���*h�C1y|2�4�MA�2���7�&&�7:D2Xon�.k�*,k �A�/Cpp��&Av"�tq$_� &�=�yaVat�-&���Q�w f�]fiL��9��r�>95:mi?� "��>5t;4Hardy-Weinberg��AO� 5>]v��!Y6n��rQE�E] EigenS�.� �B�"0 Q�%�X"�p*��"L%JE�( -9E�)�XA�&�78�U"��7262�U*a�36Uj�9so� �%#>��6 !CE��M8� g�rA &�w�(O)S�#�Jn �i�S� ��*�]R�0(%��7, U�#in�or wi� t� n db��$�N�$es. mis����r��_by� ��>��LvL!�EFhomozy޿�5:Ҫ��7 �Q.,.)a�i, �:�^���ndU;.:�)C��=� "# be KZfu.�dueA!�%�P� eW"us�Sa$=�qca�=E".�u���j�xiu�t��s%���nb�@ �>plh /K��g�4 l-�d#ts�0�kth� H S� �L� a� K-1DE!�t�e�*y^"Rw)��$#�s  d k��,�aNb�12�d�?�|a`a�** �.,�:VH.��9=. T� choi�`of� re 5a�1�-We�8�sZ�to�{No"A %�s#�EG,�s��V!��.w%TE� E&T ,.�+%�� �?t��f�}� �X�!TP ٶ , F.+FN� �&�I��-iv� @AQe;�C� d .&2�m. N"%j�9��s Rly>��n"oLv E:%I�6.�/"nzer�NA/%*�,B7cal.��?I���<�� a��H�@*e �)%��6�&.���h2�� ( RO…���v *�X�($�:Na-M:"{���w�� i.�q ���sA=��!���a� inu>me.���p�>!rR��"�.r(IFQW� �1"�8A�(MJB*���3pot�A�r�>!��#at� ��� EX!�-�>w�ca`'=.3Hi� ��=���w^坁BR�� &�u%��%�ng!&�6=�oZ��y>�=� )� �]}�}L, *;C&0Ce5Q�� A�m�C"�F( PPV-�q�N&N&��%rpo'*`���.>J�Aq!� m{nΡF-�) �$as:ӡMem!.2^� Xci�� on r��in! �2B�i���,� .c���`x���cAQ���ge*�a�.�!&�  f�9 J�aB�enV�ngV�s�<Wkin�ax�i%ly �">^�-{ �!9of CD62L?o{x�mo� �!e �X% � ( TC��=� �"7unc��� phys|��ס�x-K��m%� node� >�p���͊���s`5U1�al(*�e! a<�0\$ to naïve6L,�2btravG � �%�.�"1WR�re-�U �2*iN�n�V��ia viru�KVaca�Y .%&�.�or� ( TE!�:M�*[ �4�=u,CD69+/CD103-`��F� .XviA(RZ1!t�}3�_=�ً�co0 M�mk!�5]� v#�@A�5�wFL\%�M�2�M����Bm�-�&@�t��<d cyto��; (�~�V2�C[`�� +@�(ZUB�jB�b�7e ��)&":��m2b�� ���UG)�Y5왻�4)ca�)>M-r֨f#. F� a�]�b�,"�� r����" 6�%� surv��i���J�����dQ��Dn�q`re-�. N��� 2�=6 a�3+Q�Q�AS��j  ��c�) �n!�m-�h$n#�� �=�&��{ho��[1� eAn *n4Z�}�ac)H� �6�� and/C�(�6 nV�U�+N�� �(�*�\�)��*anK�����R���[���N�  broa��G ed'wEE�:C>�.VK��R���w�2='*��3�uZ�2��I� ( TR��٬Be� ir �WEf,��at:8E barr��&!�[ proa&>o2R!%��`M�%���im��O�~��Nhs [^e1��pr>1-�.� � �1�ng12���i �y�#�}u��qݹ[1T&-K�me�is�!,��ol�4!"�E�}�mY�HM�e�}�** &�.y�!]�ۀ�Je\(�1a&*j .�;!�MF:+�2��*� i�OR�n'�!� �reHKob6(TCR ) engag, ,�2���ly��IFNγi�inių&a:�]�M��)�M0g��la��-�%a|se�a�!�i�F�[1�A1����O��ө&y[c�,9Z��4 VY!x��&Aign ^i�.� q��)�y'[1��15�N1J� �F 6?�)ei�L E �2f�')�� M�2�� �E�M2a"͇a��2F ( v2�C� !%CCR7 )\Wd���h�eB��CM6��A U��l ��H �+FB�N2 &� � 9{�!2�y�n3onf�-�onª� ��f� � m΂)��� �� ��.�"�/ �&T!�!�� ֥�6�/v!�F��mo$~ a�Ŗv���� "za �>i?9��.�َ�!���J)�t�Q�X�^lpl;r�V)`0. A�oR:��s͸����!���}�6� �&�Neloc� chor:�ti�u�  ( LCM��a� ��% <her$]x ;-�� HSV-7-ora"ciJ�/ I'; ��2�2?%ZE�Z2-�)��.D���RM�Y�D� ]Fb[17–19e�s:�:�!,J�;ezparA�0T�H�!��ɨ�!=| ���"�,ANiN+"D ��2A���� ).l�1-.39%,�.�E!AegrinK�o� Ԡ�~iQvjS"�&/ M��YE [2�.��(pai* E8β7v�103'�ϡ�p�V!?E-cadI`� i��(�VE�*�A[?�s�F5�r� !�2K ��Orm� ory�xR��tem.��b�4�%�b�]�^�%�yq&g*o^8-*.�����&D&v6f�. A��,&� bwx� -Arm���BU m 2��'e��1il�|;�Rq(�lu�jgu� femal��-|�� ��T gƹ�ifk�.�BV�teF�.�/mP14�-�K�2��#%uuGP33-41�7V�� &XB6a�y)tvd�3K�qj�� tone�H�nG�.� w Vq��4�(eE-�2EJ scar�? . At 40 dH�Fm�[�&k(�;!2�� ��6P�`#a���I�!S1�vS1B�i#A).-��5""TrJ�>1�d� �ZY9=a< �� io��5�%H6(�4m�Nn�� B+�?�soۑ �[!fwqu�%=3u s di:y����D cano�E��+�}� : AvS1D5pThu� �E� �!�1Ns�Is"s�9�23-c�."�:x�s�_�o6D ��^6teg�:��!�R��� RGthE$i@6"Jmon�TRB�-��j �("�����9H�E"BB�&m�vF�4A�m�U.kbya� 3F�&� i<~~10���6J7�� 1b��{J`-/Bha�.olife�#�%pd�*!��#� MQ!��,� Qm�NQ �JE"Jt�-p.x��u$$CD127+/KLR��x� 1B��>�Eg2Õ �] � vAD>��%�dirBKu����'nd ��“re��p�m0N#"."�!DuBk >��x ay 7F!2�"Y2/ �>�/N%_"@� �% (&�D !Z127%�%�L:�e�BRM!�2�. A>K N�r 3dE,��.����casV�!�beg��41ty�[.xiBr5Fs�l%>.�f zol���1F�����?,#�!�!eUNZ���hre-&E"/� .#!=:��x�IU�,R`U�U�I�[�R 1�-IB" D�=@��!P���"�~�%8E�&�%v�.�O.'�&d -���m�A,� �* end�s�ven��,�� J�[2�3��2 �*�� N�2�� ��&���Di�Y�,�0.� �WT ( Thy_B1/lR��-/-F:1a�%�~> 822i �:Q ���1�{or�X �큂.�?8 c%,��a��of WTͩ��f�!�"n].'�N�!=az3��A�##YWT$o-�Bo">K e<�&"�( ��2� 2B��A�<��Z�ng�Gi�!� 5-�. �*��/Zy!n9{UwBd �]�Q�!x!��-�j�5=xo��-heL,��a�"��7q�*B�Nd�zhC–2>�2#�>�& \6RFA&8Z�a.hB�!=i�2M��&a%��6� y1&� 6�)�62�&=�r3tT�O :m�����,���VE$_ 50�>$n� A]�TF~50��.0WTR"ih3J h_>�MXB��+B� CD*� a+@ed#=At&��bG� pept�L.'2A–S2F�)!�d}'[�)re ���e�� �2���� �&�WTi� H�nX��6-G� 3D�2� ^�4that formed afhter LCMV infection were fun�al , we next tested whether CD62L-media�[lymph node surveillance was also required for memory CD8+ T cells to respond to viral skin i�0. Both WT and �/-RNHsynthesized ligandszP-<E-sel�Hn following stimula)Lith IL-15 ( Fig 3E )! hich!`have previously demonstra!8to be essentialzmB� traffick} into the ��) 9�8[14] . Indeed ,vrapidlyiedbh VacV-GP33lsimilar�WT-�-F%leven though secondary expansANofv�i>e circ5y4as significant!Z iminished}LG ) . Nevertheless ,�numbers|bj. P14 2�remain%"9� on day 40=�!�resoluE*of%<=7-#H�$These data.# thatb5mqVba$62L is6Anaïve6�Eu$come activE�YHa prim!�!��of�Ew , but notZ�seQUinfilE�eS accue?e1�SdurA�a] >�. W Co�Zsi[ show!�a�q� �A[,1,antigen-specA56differe�� to largel%Z<9+/CD103+ TRM af�Z��y�a�< contrast , mostJ�s isol)�rom]JatQYp::�did%� exprA��%f only!Mubset e� 9QyI*3JE�CD69+�B�m� �lsoRhig��leveleNDcore 2 O-glycans (6��s-Fh��[28] )� CD44�Tereasi�! ���9- �s�low�4CD122 comparedA�Fms�@pleen ( S3A–S3E���Rotably~V displayed!��#phenotypIɲyZ"4produced IFNγ%degran�*�nճ����(-41 peptide�F�H�Col��va,!q��suggest����ngROͽ direc��6� in a!�L2L-independent manne�R prov� prot�Hve immunity againstB*��are limi�I�ir capac<toN� canonicalA-03a�aa�2a�8travenous label!%]fluorescȁv body��often ua�}4stinguish betwAm�e�B �9`on%�those�Yidrin non-X Hoid tissues such as!�i�[294To first evalu��� aRnki� re-.�,or could pot�Ally� �-resi%�# %�� edV - �mi A���da��\�-�\, delivea�!h-CD8β %sbyAl5�injA@o� (r 3 minutes��oEjia!U-B:�nd bloopS4Au9M� B>J�G uniformlyIHq�!�:�,!���H�^� p%��*b��E�) S4B�How,  , fu2 r analysVvea2� ~30–50%���Va ���x%�!�%�i�.�T+�� ��!�S4C�*C 2�hMV�)�q 2y �ik��a>�pop�^AL9�g2� conf. .� 0microenvironm�&.e�-t3ra�c� ��-�2��6a� util� +/- ) jyp,qQ�BN�:[.cfU clear�of "viral�A&�U� MJ� .]jTCR"�E,%B2� A�2J����& �t� �*u �  lo>inflamm% ��F�[12 , 13e5,To determine!�� E��+-� UYQ�q#uZ� w�� caus� : 2�and/orAk �in vivo�e gene� YFP-� repor+ B [30�M��harbo� !�5�j�bBYE0challeng�I>� �ntrol" �K-�A2ofe�u�6 hour� ӡ�p( n��a�genic\�ډ�6v,)}� +F�2�o:m�o. A��fD ency�I3N�.^change}! �,-�=/�,found exclus3 ` �� �F%q4GN Fin3 ,B�uY��  swel�x- GF�!AXderivjT2 EF posi�?rou�re"{-�"1 periphery� init�>� Eses .�f �)JB��32�exhibit.�feature�bona fs !92:. P&�� have.�d ��-" recog!o� ̅�6�inc� e� �Q3�$>�B��]a� N��R^N!%Yt|:�V�ed �E�relied� f*�-��%NcoULCMr o)Ileft ear �nd�u�ng%omodel5�,OVA257-264 (/-OVA )S righ�>se>�sZrestric! %�B� �do�b} systemic1�&Oup this ) egeweIg%b*K*����ficR�in2Qanimal� f]��%�`�e���a�&!F6[15��O15�U6�MxB�hadQ{F�of� :. j�5!� ��� ed m��BQ�g� U��D� .�6�B��|5B%�5C��� q,ATB�"�fx��re.�%~�J%~%�� �!�^-!� �& &�i4w� �{b������on!� ;E�iA�&� a�:[jphow����2?,�� m})p�_ h site�:WAa|:" �.�2�MD"� on[ be broalde�e!tei� TEM� TCM M�Dof!�eptor:�Y��/across� end:lj��y:�!A_orR� � gre�.6m� /! J@A9:�. E2� ( 5 x 104� f purifJ Mz("/�2�:1 )FbE�.-.-A 2/1/ZB6�A��9� !�6o RM7A:7B �"]Y� s�f�!�Jb�1�F2 �QMly1`s bega�Ang9�ERv  !@2<Q�A��B� -�%m�7C–7�In addie ,J�B�%�Dat*T f�ies2� � �5�V�)Ks!L!=40� >���7�)�5��s ��re� %�)�0��#!}e�!�� etit�advantag�$occur� )  �a9~� . FiE �� :���mQ2��ZmE%���~2,)�!�" #j�7j�rW)%�E� i�#N�M�����!"k")ze%=*� Am ea{ie<$b�-��!�I �2. TGF-β� a kn�"&or�� �!~wETTGFβRII�&* 2b�� rerd�.dS��>�� i[2iы<�� � �QreH:�ij{�Xassd&�'�OdueM\a'NC,Hintegrin downstream�-bre� -a�.P 1i�2�F�Ond% B|"�m�w�(1�e��w�� Aacon�r�; ���� gree��9��%o�7CE7D , ~6MF�:�x�~E7��j ���8Ɏ8ɎI*� �ly ~25�A�1#rtY i�A. T�+A���A��FO�'b�"] � "DLCMq��r m=edy?e�-�s�7m:.�z� ( S6)WS6&>Thu��*� 2� �'�:�i\s&a�a z��ab��&8 9�y�. It h!jl"�d.`LN -( X$zyme Bbexposure�"70ory cytokinesAY& �� ente��J�6�"lung [33�*&OAG�B� �B���  ��.� �ed.�,A��7 ^NS rgo�prolife��Kdrain*�.A@7A�)*( Y2|�>��)��#��'*�&=���: Nyw �-!�lytic"/aŎ�%$>��) vacc��- perf ( Prf� �m��atten�$k# ActA) LisAJa mono�geAm- !wOVA ( LM��-raet��;%�uSr7&unablE�� cute 4)|�5[3�:�v%�), H2-Kb{�N�"�6�� �5%2�.��-o9��9� � -�d -���%�'�uC�F���a��!JOVA&�2�B�%u��%�.���Vz!a&� 9�9� �still�@(��~A(:� X ��2�N�orU�!c>�U�E�5H�9I.�Nd�/� 93E�Y��#5�1�NW)%l�>.^ �*to2�( S7BM*7EE��f�* �~����5)�h)7�c�u2m2LAR�y E.  2�� b�PKla� im� ant rol�.h�-defenseuT path��,F/B%��42�Fdys*k3culpri% a variet�2{diseaL.�� perhapsD/V�[367�an��standingW� �� � rinsF ism�a9ll+ex+> '2�fac�E�$ultimatelyx �!QA�� �{ �.�ily�ez76=50%$!�log�!on��M!����+at�foc�+o"� for� 2C:evelop N�y�&�y�in�8� n"!- adapi�&�,.��gen!O �.*��"eE�e�4k2�in�&ora� ��prN+any t�.of���al maniJ?)humaniup*~.h %�ej-mix� U�!� CD4+"6� A�2"y/ s [2�� observIBm{� a41"� *�)a"G� 5M6"� ��inuo shap�A��_"��n=5� $ertoire [3&2�ofM5!� ledg%Kmy��ro(#��y/�w�rtudk��3�7v!!�J!Yy,: �pre-exi�.Isu>ͦ!� dyna��-Y� � odith �loG'�AZ61+impact�>� B�un!&n . Re�u� by u)�r *�0��o*�"�� %��� w�V�"%�9�of�v�[18��9–4E�"�7we�IH�7-�e,I^!cenae� ��B�oR �ed�.�5&� ]te-"ing43h"f.N��a~�"�)E�� �/ 9.\�2�K��& ?�whJO3�>�'� eMI�2��Y�0+ly�xA-�� ruitR�fa�>, i�&V*e lN�A�s8pr�$�*6�sX2�:22�)�I�inhZ&�-9� [2 43S.�to��fiV1 ���e!�[ �*IJ�!�-zeL~PypHSV-1IL��[4|I:�wad�8�P�!aM�="s criti^*��poxvi� �� , 45]R=I�&A A/P�� does8 seem%��qFeRe��- [J4є�% 8!i�%�q6�byN�����fl"�&���sa��"A3.�� �:d9 is*1 vl�"may%9Ha�b�#<��ROL*it%y �O -�2�a���N milieu%��-^'�$i� cert!�ZG ex�$! A"FQ� �$ #du5#ig��� ways%���g .$.!��(9$.>�=")supa� ��(ɋ�V7>9 `60s)���$�F�+a�}N`�>�(�Ea��(�0 �al5�s )��al!Z_�^�):B8. Our{y����"M%��8�N� to h�� fnd�y��,al*�sy�p� !�M�.�re}�po.�1AiR"jA%j�Q&y.�� a�=�is�a!Bn�)5>�9�1Ge +)�je#=J!9 . An� �H J+KLRG1+�;X3CR1+F2R ��., �5:.!Ձ�nd0&a*�RZ -� steady-stt omeo ic�k^ [46�dQ�Na�^ ��Y!���2V �� �"m>s&~A*qJ� -hom�add9i: in�URm!"� mo�2�,of�$��tis [4���� s m��@&�~E��!�!�i �;M9%DQ��]M�*,^!�v<g :�+!?�kprecurs�(to� A)v%,� 4pB�% ��N�7� �"&u�aNaWach%:���( i . [5en�����&|;to7 �"m;ly�<��!k� tone�=av� ) [4� 4KJ[ *� �Z�4%k cyto�:to)_ol)�5AP�%�!�� Y����1�A'e%�+ Rpropo@��t��=�benefi#)7͡�?eof[ �" 6e�tj b��j[ i�'626~8aa9/aA�"E\%ol� vrafu�E��I^�> or i=D6�|�^Agga�@ , TNFα )9-��A-@"�� f5��Altog;7,�"e ? a/*c?5(2�z1!>?�3d2qm~inE�4iq(� F~ � A� :�F6In sum� �as��D(2���!��1B a�2]I�N���f.�A fash�n"g5"� �1�&�A toxi�A# -�9����8� "f;2�&�re*��Z�.( b�+3 )u1 &�`tro�M7a'M8����o�[.�"� abil�toAaIGv�,2���re-d�/�t{��#F�aMIn�Z@ex��� al eK�K:#��� .R �$EM6��) ~= !�� �yA�Jys��50]eit} !`,P }ldescribR#m>"�B�m�hS$2�?�( ntin�C�r"� &�,� M�c!I new K�5regarr���!���s��?>~�H .� >j^� �gBs &�inQab�/)“a$e-boost”2��5Eof�!s~�� �� !log &yvg�<� & &4-d ��*��RVs!�E. A�U6}�reA�du96�?ccord�>RDA 9 Welfa ActM�Rcommend%a�2Gu�9"C6A�Uh1La"� [E�*NG al InstitEof He/A pe )`0 OHSU,io: R6tCommitteIH$Protocol NaM IP00715�-x LBiosaf�.B RegiE"�SFBC-13-3��$. C57BL/6N��e�'purch>3� 0NCI/Charles R��:f"-/- [51�IFN-γ�= r �>� (:[Jackson9fA�.o$ TCR->[52 e Lselv26] Y.- e&P�|z/nd | mainTby sib1x ayn9 For ado��f�, �(0�E . 0d/eBJt>%>�5�For %GG�\\GljG 200 μlAQPBS . y -Arm�C(&6 ] p %2�5 PFU� JIA�$ovalbumiZ$9#)>�2� ( 1�7 Cb�Va�$ia�># )a��g�!41 _;D!)e��$ #O�;�b ag0NW BSC-40���ar^a� s [5�5�s���%�� 7�nesthetMFebyIcAu1EV�16%�of-in�+] ve!ll J.�b�<pinna%t^p � e Pco�k25 time �(a 27G needlB a8Eo� Q�.�2�E���z�F�%�,A 1 μ�  8rat IgG ( Sigma�2-&ti-zs�H(( clone 19E�CBioXC!)%J3 �F�J .e-i}� . Qu[�R)~�oa�8�� � &(�+"'dM:Y)laque�-�on6T. Brief�Vear�� remo�8��homE4A  m� RPMI�l-3.Q-1% feF bov�D serum . S� K�H)�A!sub�Kthree rB��8freeze-thaw bef�/ser�9dil�S �inoNT�26�� 12-cBA�] �coxL�Seakem� r�Min Mod�Td Eagle Medium ( Gibco%P%q �visua�I �d!�Rr�asvn incub)�� Neut!�R�ya E!�E�5�Y�.�A� dors� d2�%R y�% sepa�!��)� �CDrE�27Eat 37°C ��;2A HBSS=aX2+ CaClaMg ::D25 U/ml collagenas�Invit2"�s60 'DNase-Iq� -Ald&� . Wh�%� suspe -�EU u gIfor�!, =; a wir�sh scr�. Leuk�*e.Y"�6%�w^�b�$- �" � 10 mL�35% Per!!bE� c- ) /%z in 50co�P tube �rifugIm ( 50Gg )�oIOXo�Temp�o�y-& P2����>MQ, A�J:O�G$YTS156 . 7, 3����a��>�A�&�� via .�.hA�U&0P,}Gimm(ly sac�8�Se)�%�A�� "qNa�"� bova�B',LH2-DbFUtetram� PkinP?� i�= by D� John HartDCUn sJXowa�cqlI surfaceŰgeA�as* in� /V�@15"RQ at 4a��Kr� b� ,-��1dE42E.NDY�"M�� a BD��tessa� $BD LSRII FVCytome�>2� . ry C�,Facq. �me�3�QJ �FJo softwa\, verP9 . 9�10i�:y�e^'4R,�6ecE6&�;B�0, sV#2T2�of� /a��Pf(o�]6wSA�sA��-PE�^Z -APC�,T]8α-FITC!Q1%FBS/� b ���wa�[G�OY���umagne� bead#Miltenyi��E��manufac(rI� J�0J��J %tt".%)�a��autoMACS� S�/M )�A�. Sor ofq2er A�Influx#=eut��Th��!Pbo�*!�faY�!�cor��is�X�ro1��*e<� udy:��α� 3–��,� Legendo1�Y( 1M7N�20�Y Tonb �^ ( MEL-1Bi.U1� ( OX-FZ Z�2SF�69 ( H 2F 6f�$ ( 2EFbIZ7 ( A7R3F�0:F1�� BrdU ( 3DF3 Vα2> ( B2�-:6�( XMG�2[��HF\�[osyK d!��A�CD4�B1B1Fm�7a!�D4BJ; 107b!�38FpCD% LG . 3A10B?graE6( GF\O� ct�-\,�0Ả�&�aB3� ���st�a̓3z ��250 ngc yFombin�/m�'�aPe�K b*(*@b�@μM P&\bv. 5 kZ(Fc chimeric��te? ( R & D SJK�"��:J��X��� % FBS/D��a�"q 2+%D Mg2+!�� .� er$>. B���i#cs��-�"_�-�$-Fc PE ( e�~=ce � �o2�JQ[t2@ in����OA ��. S�?-�co�\ed�u���c�z post-Vac.I*Aa^q%�go� m2 For-?�� A���i9�!�5d E�� nM>v0 �Q(�R-&_)!5���0of Brefeldin :7.�� tr&��E�)�%�&<�&{ Fix/Perm kiRBD]MAž�.����E4 A�>� �-A���Z� %c1&��f �p�!�JfA;�6> H!/Wash bubA�q�H)�6#� er67,2y�6 � LAt�;�J�Ag DA(�`�of 28!�� -�exA�� "(107a/b]-q��d. S*K l�2U J%H�Mve�%.e)>�,�t! b�<;2�!�#R�monens�6��Lc�2�"k3�F*"C @1f I..b� R�i22�����%�31��Qw/k .�a48�.5l,or NP396-404QW %U7 dissol�� μK4:1 ace�$/DMSO�N�<42$�isoųanOq/eZU~hE�pp:T+A��n�*@)�ed�e� . Tis"&$WAU�N}x��X�?&G�, ickn_f}!* a�)a�?�H2 m�a d�\2�( A�) *�TzI)Xd1^�a2 my Brdu�i�WfR"1J�"  drin�w�Joa�8Ag8 m� -!�7\&�N)qa. ���^(_or�U�orp7+!+N CF�^�of�� y�e��ECA1a�e�$!E="�.*�>��!CN{2K2PB>�!D*� .� ��FEY� B�A��Bfix�e�.eP#z� 5Plu�r.�2s�%Zy �yE����!��1��2{�&� �� �A�33M�BS�72IzI��%�1(� �n�stI�(F� i"�-D:�V4 a -��-�tw�L�*BX!Xr"���p���e�t�848 Q�yt a rism&�("���$GraphPad S�)� ei;� paCor un Stu�f’s qANOVA zTukey[ �C�&G-@ce .��In neuron�2larI.�$�esicl_#w] memb�n�" gives ris�Ba�d! nct mole��gm"�:!i�(alI�:g �6x�#dendriS. DespW't�*�Z0in"�: ��p,3gNurpri��y litt9?s�:nN$�� procj/�'` tbS5(CGd|5��M4(e plus-end-�je*Y�MyoG VaA��4�DE1"�5�2w!F��=-?;&%mg�H� wm��!{D*�is*�:H�we�.)�I��R�,��3 vi}��e��'�5;�sf U. Engine&�GFw�(te�;i�%S!��6b�$e"/- v!�at%+-��(� cn_d�cf� ��(Fu�hm�,a rup��>i��qa�*0 l�to aberrmic�-�X-iG�._M��zm:�X8eIp�' art � , �~ �e&�&�X� �',J5>I.-=�.�7E��5rliN,�`�m�? �U�1i%Pe~ h�mlrhodopaQ2 y eM7:!]9��7J1�� � B�#A�6Fbit� ld be a�fu�5ow;pro*cvt�7trub� U$�2h.�-Q �i�s help�.���rib� �]��-�i*. &zH&�m�secre�;�/waROZ���8'�7 P�s��plasmaن.4�[��to"8 M[��sA�Ke-GolgiP[1�:Jo2�� dpsomato9doP'���*e��a8z!�!jx�( *�1qm U�< � sE jedB]–[l%A S;Y4� carrzA �>un�#X >ga�7bsequ��re 3y3#�g�:�'A���v8�, [�J?net�!�XE�{�.z; �%�F��!UEա� ough�>vexP �v� uM2reg BQ�!�f�9 �;aramat��Zn�!%3:.��e �A1fb!�ndd.e�8d�^byoe����[6%�1hSHo�����6��.Ucan�.�yxpl5<by�!iJG�'er� �ic�R2s�, Kif1�w�4 ^�no�ly%�>prR��tub _11]��~8&0 work3�.l&q,��MwU�!�)�� �(E��/k ZF� 2 a��5i�>m��"��EAtoward�2� [1FCT���:�0jG mi�/� icip� �}l�D�:�6>�6��35� cl[U>�al� FaK�,�9,%nkn�V�"Z".�po96LOd}inu���ct�|ila [13�|i:invof ��n?"i�p62it-/r��a�i�X�)Fr -!KA�t�(� s�ө� clathrin-6*Y�4 ��� 2��9��17�-pl' pr�:(<!&-�._ !=t% st two} .��h , [1�8� ,^� �W}.s& Wa)�Nԡ�he% e+&�  :+ cul1! 9�-a%isL=��*� enhan�&q�V� >* we�2 ev�?c �[;3s�QnB. !�o��E q��b��.�cM1�L6M~���f -w:�e�%�S1pr�@ p��Iar�E!|I���e* `c-ywtMk�>�4SG&� of5�is ne.�}��P �r�4}UY �Q"X Y=y%�be0by"� !k3I[.�b� a��bpe Hx�' �Q�)�lyc!>� VK-X��D 6;,!�� �',�k�aJW�S�=�N.n'R�VS�TbS M��M�}�lE��fb#a}� !g� ( MVIBD;SQn2n. C-n7uUxN�@ (� -U� coe{ Gwo- � �Q9s �� andem�:ne�z OptiAi�AY II�Zs��d)z amyotrophM���clero�[2�3a� on�GDis�Ud(.log�#DAB!q"�>rprAAe. c�3N�Fd.�U.�n��Lct� a�9)%��nobput��!W)?99�sot�2xE�a"�c3b�Oa�p�?e�&�M;ax0&ri�%�/�J�� RBd*[�0�%Q9��D�6~ N�asm�1�a:)a�� �M�FiE�1�v1CE�T�?m.Ise Tdita"9*�Os�� calc�y� �'a f:io�DR�@ QDA�^ Ym�!hI^��:�e�u�d=q �"CD1\]�of�6±�%�%$n = 16s�20��Ac�� �@s��;2D"�;i�0 xCD�01}D%�1F;y8±�=&��&p<000��"6��_�takdCla � 1��Y�e\f�~blo�j"�uXa�� �ne�.v�9�:1:�h of i�=ailq9( �%<i[dnMVI]E�W$*coyPe�`n2�$�_%FP ) –F2U= e�F2�, Xan1�!k79)�0�(9��* 1G–1I )?4 ��$B��(>��� lso �mjef�,!`�b!l9E8�Lo<9-$a�r�C terf^RN�$si)"�N��):��g)2yV. U�AA�sE �s#f�(%xa{!y9qe>9y�iBian empt:�v!.�4 . 0I�*�,=�USei� �L!_� ֋�9NcanA�mo5( ��� a6cRn�+ investiga��pos�:�5l ���^v"J�hD �3exaT{�!Y�dingh�G�"�!)n � �D�X�Hdum�� ��@&3Aɏȃt�l�u �> NgCA�dVAMP2-ao�|;b8-Nav.0ach�i�"�"�Q�hb!BJ�sg[�.X� a@s� fu]%b���%]an�� !P� f�Wso7!Znel Nav��2u� mark[�while\x,5 j9�%wA~[iqBm�Y$&Q��8 1��ic'I /�.y~:91i9��.1 7{B"m�44;y��7�3�/�T velyu�2��,��!Ty U��?�}A�e��Y`$�IoYno6[с�6 ��-�efR!� !.��} J6�*� %�;� s 2D–2G%�S5�VR� �A��l6�A�9�! nd�:#BR��7{6�on1ab" of LA�m� lian"� ofM�A�#^.%%"~Mw��L '� ��Mu!�� �� pu|9�3�/I�!�3!�%�in���v q�qY�s 3h%�I H�R(%Q�ng�-I�,�2� sA��(m� p��c؋t��%�F �  6R 1(!! �!(24)1}�!�1"T 2��KePF$L16�^ d:u �Z!��A�u,5e,�is7'rh R��; 1� ' -Q�,U��~.  J� :Igy�qMVI )]r!n�I!aUrD a.3�5g��Aa�RS>� �B� jY b [ 57I36;9�&O l�&dMoreoverA��D��rescu�N�V�>�9C%daA�39n( q[MVIr� �4� silaMmu.AU make�imper�D�A�}�0��6-}5��d O[jt :E "�a��$Eg��! @I_� �=�)�ؐ^e�n�`.o.52Y2�>�c��xinclu�V`)�B���!'T&$ Ankyrin GA{ 1�$@�=���see Mi�~�!Method��) 8�c�" .p inP c��.iEOHA-����~an�/�w-�6�(9�l ţg3�w&�]�)5�d]! &�&tl�>G �%�%��-ed���5# 5D;����72� �U�� {$HA-mCherry]��;M�6� 9���A�. Ef0ngQ�uSy���s V�EREIʡ͌��9��ɒ�)�j�%%�.2N6��zor Qm]n0 �P! #�r:=9±.��6:8`A"�P�0Y"� a:'6l�}� %)ane�tyg^�g<)EEB6�"amis�څc.eior�-�y>SE U���9�.. �D2��qun�lya���M2� �!�� & or �(m�= i� divid4~��75 l�.�Q�rI�e�)c&9��nsamU��US� . Se� ��-��Q-m�aJ �, -�cE"�wwU2����.2d!�OW&be 9�� 4�:S7�� �E=Av� ��#r��Kct [24Ay!�1�1�-<ty1�!�.�wmnBF< ��6 �J�K��pq�morph-M�o�>.=�5��!8JB�x�i2)  sp�qperBµmQ'1sA&��13%(���noA�s�0� a�N<;Ut8 AnI1�2C�)E�2�m8d%��c�`^� a�w0��a�l%T s]#)0F mpati�r��2��M'���adictp .�%�_ I=t� ���c�9h-�S�.al�Pe�ji0�N estaQ$mAU��@s�$mE ��'��y0*ynB,'M�*�$� �<�8"| J* �*.�&� "�0�[+0�!�cyt��"�"%�# hm� ��.�(re��.A�As �]+68.�Jz&. . AsX��K�.�F &�gn>�9wg� !���S.�,�� P&*�� ��!�I�dI.�&-?� YV�$%�vA�cmI�6�.�!� >be.K��iF&���D�M����e�n�2]M ?A�a fm%��+� se�E-$M*xf��m(*�Sl�\ !� �g( unnormw edD [uADR]C "�.� Il6@90( IH��i 06��� ��is���q . &Q�j&�b�Q�qV.�� we�*e���1T�L6�1�A���& Ik�3�2E�ab��.=�mH��3#l�Zwe�x�s:�(' j$To)��$�U&rq�y�E�a���I9h�F.h'V �u%�ke&C�j�aL�ga$�/nA�" 1�1�$F�~�!��Tamoun�YqBl�Ŧis� IFpKEQ ecM���sl<a 30-�V�T< iodi��F�# , ex��or e�Ec!X��nt�9Ia/n a1�te!F epitopIAy.�*�;-YE*R !"vFA�:a��\u�8et7!:uScidBv& ( pH��in ord")o"9�3 �%��bo9�m@�1�.t !��,s �6<� YZ}�d9;�^<Y<eda(� "(&&l\5��"�Um&�y� �n&Y-E�&Z �#U�2�A��NYU ach A)pa"}�8^W�+;�2a ( 10�0 R� )V+�39±8N:�U"0W*S=} -�A�Dynas�v�e��6=.� �$���I�7n�*�z�obFa[A�!n!"e aXr' ( 34n� <�)%�s 6�610�&25�1R %�V�!ke��Y(s<�vicF���al9��>� "t Yzqhe�2���& xesQ�E�xo�r4�2;Y�ihŕ.D  !D4D�!�:�]K-fold׏e�E� � ic )�H���!�"N6G�&9)h�Q2��.� U��K �A�A�*<" c�Qf%U���:�,�1�~� .�M .ƒ PpH";app�Ca�{%���oaCge^&� ) "gR9�ha�B9xi.�G`jt �s&� �� V�b"B0�$�kas�F BZ/!� n �(ed"�F -� a�)`ѫ.6O a9�-&0��xsa'�2.�.B�&�CY��parag A ,��t#e]2��c|"���GF�(� 1N��� 7��:�D �Ti��NZ ( 46±5RU�69��2\e].:>��2��ہT& N�-@B�*!���B0�Xe\"�Ne�&%y��Im>���5-�76C6�*���� *� ndOm_�B �Tbc Fihe`wan!M �W�'�hC.S�ad�%�9*�� ��H&�9�� � nd �� A&� .�.�)�r��:} > ��{\��/MR.n�P�M�YAA �I:w.I��8aw8CY,�(ͤ�"�A&�L��er9ve��j�M�8�%8G|5Q�*2 a�!�Rl?j8�1,a!F�*i A��/A.�-vQ��e��e�'1�@*�*��AF�K2�w]e#A�)Ec .�.� �to1�'m:�9�A7�� .���w&ȰI_�-(Ν�:B��$"�~�� ��� ZR�� �*= ly�Bc�k�QCwe�4�v�ags!� Y�by��achA�) �׆&�N�7�oms%of��by{<$a lin� enco��zhrIX �ge66�7c,(y"�7tcs".2�a~&+D"F!��>0Gw� .~�!B�a�ad% �vuYK��!y%ag[qd.2aup�\rriva�6-%|�u"e p�h�a.�- p�EY��@�J7 ^ :��yet�7c� s:��,�:be *�e#EAfix !�* �/ �6�Zn,.Y%�me�DN`a�;a=�ntireKxlea�R��S ��e���1b_�ooka�!r�"rQde�wY�� �. U�!.r�=��Ba(yc�C! p�m��&� &� �7:\6� 02�( �`��are�a�:A1��: �9�W3YE��(H)s�Dݞ�"�e��8*f1!����G!�suc�=A� mb&!�a+Xy�� Av6�4<�.�A�ٌ*H9Ή>�B��c��E!�uY�4!�} !Bn6,� a"%Vqf� ^5s:HyF@/�IX6�%26f1*s musta3%�preA�w�8ca�I QyER�G�HEal�u�!q=- �6&� .�; [Ip, [27�+}��[! LJC9* ��*5ce�i��Ls��UwsBRJu�rea�=A� ��s�'t�I1��0��:���?=Q ]5�&a�qI."~  �'�H!sl�&d�- �r*dca����TefN�-�!i�l%3F�-���<.~�b5�"t�b�h �.�7����3�.(�a��<+86�CD8�9�+��I� 9�!)�z�!�1� �Y�!g��(ic��� 94±t4� 81±*H#3c�e��*�Se�V� ! �8�hyp>�%�u&� ��&� !�a6��,���8. �/��-(  Y33A�&�#ly�6�OsJE*&# �.� i*��of2� 'L~vmN�2\��,b7�-�i�28>} ����< %�L &x0�1�<#2�R>�6�:�`/&ux1010*�< x2: �%E��*�K4J�FYCBVa: �)��n)�Qx��sMwly!�>!�E�"@." 1s 9�}10a��G:�G�:�SM� ��AX�#meoNm�>�Z�Fo&�at��t>XR-�fChR� � �ag:%s c%BicA�gU�8��]lu9��K[��,�!I01VufK�*�:� ��.�Pl"�.�K���a|t� �͌uaB �RmapW��B . Gik�a�/BD8robusA i��&�=��Ny ��wt �"�&Ul&R$)�xS� wHophysi"�, &� %�wab P.��Ya�<aTR� "&!�d�-A �)x ( Ɣ8yer 2/3 pyramidY�� A��2 senso۞ortex2p �r�!bi�^'h- slicA|udC�naqR�^15�:cpc� _Ke5�&at a>yoA�46�p utero5_q^5�S� . B�)���� ��ilW1yl3� �H�)CP�5�c�h NBQX�5aM ) )~l� �aa��lby_o �,erUT�"Zu-f�Cr)A�*�11���CaM7A+�3,�����don.� ( APR2I %ex� ��.� r%K�!� o-E[� )*t�A;F�*� UK�@�.)�� APaiT"�2VQE� ��03X8�� �{E�h icn=&8 s 11��S���p&�k/!G%�chaN er��@ �XLr�UZ��"� 9�*`675AN31���yQ2E�j<�4�5\)��aD$2Q! �KEWe�!�� �E�#� �Q4GAa���a5��B) gauga��9�"n ��*X�� M�n9�aoɭQ�%`!��hj1��t �{ Kj/-{%,sD�"�la�pow!m�xB$A�:PJ�<of six-K� !�ChR.���exc�I�5!��g�}�� !&�6z��� ��.�f�fGFPQ� 1*JIn ":&q6{� n�=%S�\!�6DJrA �a�-lo��z,icG�a��si!sto�?R1�*E r( eDA�J.9�pa)$! �%�%���2�5>�_ 6��F11&N!�zt>)q7�0�2aLe:C�,!�.��n~a��t+��K2yv e )�>q��6���&gAABJ��w�&�aj~{��)!KDɉ�)s6VBm�I%�-��1 1�3 0�1 09&a@ �,D� Dy yLx�o�j� .��iAiAH:�F�t � n��>i.�3`�,%�^5[Ksm����Bq� &%xL G �*..m��Q�Q���%�r �|!� e�%�A�A! I���:'� !ape"�M�q��5�n ��bY� 3){���o {a}nC+y8E���E 2z  N�v� �&� F2!a9 a�ows"" I�t&e^#A3�� *� ��bdh_a�c_[/�anatom2 !��F4* [� O��_ s . A=�y�e)YI���qi@� I� c�3 �AaV�e%A2�[fDz��W"6`Mc�D'N� }�H&k��*,A�eBmIht��A!D�g #.:��n���"���{` ��!D�5F=]AM�l>%��y\&c^cp�tu* S�7"y&e �1�> >� M�:�/ugB�\Y��a� \��>2[ �ic2]� I���Bnumer�H���cu!���8Q�.&.p�d�? afiMs�w� a� A&" -[v18��,B��,IDm�!���V���Ca|h"d2 �d3E82"� 0�s km�.f!X" � 9w�s"�;�l��a/Ep.f,��u���M NL@NrT�i��0�n:�@"�\b�Ys� )�[���Dfu�[��Di"l�to fu6H`�d"�!. W��qˁ�A�w9!�!Wnow:�!�i�6[g" pivo�AdE+^&�!�&�"����=7e�>3bi/��`-ba UP�)E��s�@!]uAa8b02�A6$�v*�aa#b>/v�^�8ste�R5�q2�B �S�8P�����?b_T�f:�a�7�"M ��stbay7AB=;��c5[*.�w Kif&l��!�f�\[3�= Tail\K��>%�j���a��#��o��r-���P�e��"�&`ifj�U�srupt�a�%�D �A��� , tycZa��$a *�men��ӭ�˕hq ���s ��ind�cl:�6F!� E� Y�_I5��oE���(9�[ ��y5�y&Q+%+[%%��aR?2o�(pre)OtA�d ��rq>nJ �m)�un�=e�f-e���.��s6�I2�)�h� bi`�c!�]nsm��� R�blSa.�puLs;as GluR7 a;��[ �de ���AE��?"�)$<2�APP%R!r��lso��gby �[3e�A� ��"�.tlX�� R�����ep�r)���veݹ9�8L% ��rAflQ�p!!P5L�J�_�!�,�� Va&8net"��!Ee*�A�@ru!�ut�rv*V��e9i�x�� � 6K�. ��ES �p�c��)�i� &�@f �6 .`�(:!�.f tr�+en��!k�� C-Jun N-T[al KiŊe���E�) �a�=di-er� mL�-$�lsMapq 9,� ���ne�i�9a��, H&�h��%�aZ%x@i+6~�mgnca���MEo2)2hA�" �R��E *�!e-a���-!%�dyn�"�lex�ba�I-n�� o3t:�gsz�i>{c�?u� organe�H�* �� �s���B���40�Wk�2�=*"�.in],lI�!8��,�^��A�"�* aa��9I6� x�nORY��.� !�Tde B���o8llM�tR�%�(e�XsvS6��HF2?9�r%D%�M<.�KA+6{6--�* e!�&Fs�@&�8)_�F""�o�l�m�4�kA���o� cruc�I. m��en� G e�skele s*-�e�7s�VH��F4�i7 2��l�%A!���k-� .�,l>)� �[�aE�6l� � �.|h�w_!�ձ�*��+ f����*� �� ��� &<,�JB� ���wPt�u�E��m�2*�d hippocamp*�!BBRe�eyEn���u��[-t+-��� ֢ �'�U| chal� ��e"]:)depoly���#� 0Latrunculin BI( lso�B,6�l�EI(��ٖ"� I)�s�% �N. M&�V�� scopyu@8E.5 �.n!7albei! B&A�� ��1g/uʟ-�Y !u�L~nd9 �"� �4]�)S�apqE!�  a� �mZ� whyaf��ї �8 .�Em" _�\:;$ ) A>DZ�IQb?A�i������&�eT9+�%H{�5�*[?��M�8mp�B`6(}?V�2rX41�q�����3oT&��z �A#!�!b!�$.tbCs�1�e:3 Up�e.�"%� ����e rteb�!b&�Y*�Ae��ũ��1��VjwdQ2Ru>k� u�=�y�,in Caenorhab�Gs��gw7,&�""dro�A��[1f��ylchol��&� a glutam��r:9*aMc+!��`%V�L%�(le SynaptogM\�.[A!YU�R=>�� [44�:�tILms%�� r3#�4m��m�!�> �����d!6��A�nJ),2�e8Q�m�zof��5 :R]SN��� A�� urp �Cd���:�Q�^  � v�C�b (z%�UMp>\Lcݺ�%l s�Og� i�Q-?�wP.T�ŷexa�d.R��{�s���&���*u�a c�RF� e�1>S���s2�Y��@��)1� "8 !"� ��� ��4.. �D-YF�� � ɀins�� +}c\Sf;mino xLsb�16 5′!/�gen.e.�  iroDNA~s83Ƚ 1870ANaV�]2 3���227>p4.�,-�V��e1 �l�R 452 .��O.�VI2��"%$.&rWx�mb�8��2�!vwo hemag�D+� 3<.�60hA�A��a5=��&�ZisdX-aacttcgaagtactggagccag atc-%�( OriGAF=In���o.) R660E� S661���I��- iW;�_MVIr ,�9ctc 9M�*_u!p:�JqQ�2@.�R�];�Q�24k.?420�`2W`� xu��~�e.�64aA71�a�%�1�ce6�.<�5��A�27��"�?D��?�+:�nIhey�L.�LVPRGSf�|)=>�L,�&�(�[ #J�rebuM��d�B�23�Nqh(Y Pd�"gif�G�[Ba,A)�a�!ie�z�op codon2���Uf Y33AE:igīzzE Y1186a6an w)/X1!QTfR-HA)��6"���by Lew� t al�$. Streptav�����0–KDEL�madu;sK[ �U95HKatsuhiko Mikoshibap��SA�#)�&�w�.��b ��M�28�2��l�!��2� Hanks bal=d salt "�( 2���lez 1 mM HEPE-�2,-������!�K� >Ex}+25% try�����E�t��T�c�+'5|/K>`�u.�"4 �[pn 0�F� slip�&22 mm × , F)_r^3tFe"ta1×2� or 5 �� �%�baӧ/uy�27Jc0 ml/l � ,x ( Invitrog�en ) , 1 µg/ml gentamicin ( Invitrog %X20 ml/l B-27 supplementF)and 5 -Dfetal bovine serum>0�. After 4 h the medium was replaced with ><-free neurobasal/�L. All cells were transfected using CalPhos ( Clontech ) at 12–18 d in vitro 1�Lanufacturer's suggesTpprotocol . In order to determ�>ef�8 of dnMVI on ex!QousB eins , it�xexpressed for 2 d , whereas itsOn endBG!2d a%V7 d ZPion . siRNA construct-1 # }014 d . Experi!�al�� 1condu%`accord!dto�Uni!$XStates National InstituLof Health guidelines�8animal researchEM%�(approved bydM [A 7 Care30Use Committee!�!�$University�`Southern California . The.GfixQ�H4% paraformaldehyde�5 minu wash.PBSNis follow �block!.wA�1%6 albuQ, 5% nm goatm>,j0 .9,Triton X-100A� uiPfD, primary antibody� dilu!�in+ solu!QdaddM 30a"�iA@Se!��Q%4in%�dark . P>�concentrE?Mua1K s: chicke�0ti-GFP ( Aves��D∶1 , 000; rabbit� (,BD BiosciencN2 mousAI8ti-HA ( Covance[5>WTAnkyrin G ( Santa Cruz0�Y.3N��mab1a-$CD8 ( Dako#1>�DMyosin VI ( Proteu= >-$βIV Spect� ( a gener��Tgift from Matthew Rasb���,.Z�$Nav1 . 2 (N�;ES/$Beta Tubul�lSigma>` i�6(NgCAM ( 8D9���007developibV%�Lemmonm2�IL1A. SCS4 H5JGPaul HA�attersM��obtaina!'\D ��+pStudies Hybridoma Bank initiaavun�1he auspiA�ofIF.Child�3!�Human.v main ��'Depart�G,Biological SQ�, 6Iow� B���conjug�,to Alexa 488��9!ODor 647 fluorophore�u2N. FreshJ��ou���F�����$o�M�@5���iIH �then tre� as s��d��Ximmunocytochemistry sec�. For@, CD8-MVIBD i��^ular �cu+rfaceRM,Aco+lip��s-�liv.Z-n͊%BgDirectly��AW%\)�!�!-)7��%\!n2I!=3n9�[��^;ɩ�T6'A e�9�~above .�b�.� N +E={ �, empty vector!%or%+ rS C 16 h)�.Brin, twice fdNaCl HEPES buffer ( 140 mM ,*M KCl�s$MgCl2 , 24 D-glucose7 M)I1Ca1$[pH 7 . 4]� ndq intoa�diA�edJ^!�13� Oi014th dayF��`1�9]��n))�v� $%�yNor iity)2 priayoA���"�ei�  DMSOA815 µM Dynasore��(alBioChem )} ,to each well5� 48 h^ 6 ,.=�yM� � !bm=at 37°C�� � �fee3 e�.Ze�d) pH 2.Z2! V�=� explɠ)b . Fi� %2W 1� ���w1%�� VAMP2-YFPE,-�� or-� "� N\B� ����^�^1^F!�V�E�>u aI!�*� v͔)�Su$ -tcs� i,1eR��(inAiCed1�equilibr��$at least 2� o 10% CO2I�%1� in 5:to rem��excesse P~crystalsM�����r�co�aI2 units�Thromb2H �!. Las�ih2ps��q:,��$previously� ,)~B�R.�H}�J�abiotinyl�Ea��ki� Pierc�-���&%:DNA enco��a�,Ked�y2��sA N��-{:M.�1×�bE�BtaF)-rhodak:��WiWf!�P�P�P�P���#ora�nB12�%��[�[to�@ E(�m�COSM�8 *Vvia Ef�$ene ( Qiag+�&�HAEP-` GFP-6 � alony��, lysatea1��par� lysis*^ f"^ " EDTA"@ Tris. N 0]% NP40B2 m� PMSF� Leupepti="A� in � Na6a-%Pep��in [allF�� �6� -cle�%6 agar beads�J2 h�i4H  �&50 µl� �YHA 8( Abca�  ��506g6 �O/N^ ���a& �L��f� times �r 2����pt�_C reduced�'%�-� �o coll��d0× SDS sampleQ! boil�ord �E�l� 3h%Arun3(SDS-PAGE ge��nd�(rAs to n��ul%�lot pap� P!�)�loKa prob� M�*�RV3A�0A�orB�(^�B 6.V�u� %�Y* �HR32�, T.�7�fb85 7-�9&�E�WCrn LightAkECL-Plu'(PerkinElmer� �t1�filDKodak%}����rEL-�.(  C��!V�asM�w �����I*�_ β t��B6yM�as]I VbH1Q��I�IAll imagA��d�� on a70-Rad MRC-1024� foF microscop��EJ�,?K�4s a single opt|&M3*4ta�e%$a ×40 objzv�d��4×1 zoom , unl[ o�wise �{e�N�Q^s)��"qu!�ficX�xany satu pix��axo� dendri�. Cn that had ��,ly definable5seU��-h�y morph��d�� not obscu�z(by neighbor!�!U��chose���ubaofXa�HA-mCher��=�g�al J E!anaɺ�enric�&�.�l segR�a��~ident9\-�!=; howeve<re �three �&ions:3 )te"~s1ic�_� 1o�e9tagA}dn�F0 we purposely)-indepen���5D0( Figure S7 )�ins%we did%� bias%�8results towards��s; ( 2n�N��1 a�B�ਖ਼�s 4EtS4 beca� thes!l��quiAm,a long incubi�o which=la�iz *�elimin��( 3n�A�)!m)�j�ass�3 �5�T��A�NBlurne�i6)5cas< U�� ��a�A�!HestA��,-�la��?ic sp�� )1untY edm�V proxE=reg�. NoteI| simivc��riaiY�to�2�*� [23]�co t�whe�Irse:Psuffi1t2VR?104:� �|q� a nonspec�MBed�a� su�sJ��  coun�.[y� . In�!���E������>�Y�0�compari�Ř!�w5�e,��K��!confirmE0at�+%,���sucA*fu!��"m�,�;5� . To��)�deg�Oof polarq���d�ib� of a� tic�� M( PA�we cal�O�ADR . W6 wo differ$!sY+,� i!�()%�un� u-B In both%=ARF�mean amAf^esc� � ����re�!�mxe�-!�%alA�(>�()�@background subtra�"EJ��Wa�en>9r�'��Kvalue� g�t%���f�� mostB�B3X" some#$ betweenP2%lZ3 .�T &FP� �iɩaverage6Qinten)#9[AXri�P12D=�!�,!�e� diviK"�.)�v����&anz/9�E�>�BHa�h����)--"mBuNassocie1w�#Oor.� .wo&K a��Mdv8"g�q~�Z�:\�at�fis���! pret�Xs%� = !�d� au�isj,=<6:-[��lyJJ��!�>29n%�Z��'meaP V �~ �(ImageJ ( USJ!�uM&a� All mgof��&! ±%T4standard error,!jm!�.<&��_ADR �mad�.TWilcoxon-Mann-Whitney �Oq�can 0 sign�M$of!�4parametric datz!�� e uper�_�"l� d�'~C��'��'4Janelia Farm R�'CampuHLayer 2/3 pyramidal"bmH0barrel cortex)�+���$in utero eF ropo�}nmsplasmii>#k$ed ChR2 fu�� 6H, >�)�@" bc � at 5�$ m᢭ . Postna��u1�"23\� re� �:� .�(M) deep"nesthet�fw��iso�fan�pbrain �d�&~8an ice-cold cut��" (-��1 cho�) chlorid� 25� NaHCO� 2� 1&6%so�+ascorb�, 7M"!��1 )pyruv (2 .�M"Y!. jNaH2PO�$C � �CD!a�r�*sl.~%6U( 33m tl( )Igcut)Va v4!H�!MmMiT �oxyge(  ACSF�2�;",�^1B�mM5#2 ݩ�!])t= e�E95% O2/�)|4�� 5sbef@!��re�+a�R �^�� at r� tempn&( 22–2�"��,� of glutam!�receptorf$rakCPP?# µM; NBQX��M��Em�hys�&UstimuU�*2"s � larg$as describ� "�vres%�potN �of� ��-posit� �Ai�.N%'in� inguish$( 1�O0, −68±6 mVN  ��6;/ 6F %O(light sourcM&photo)� i�E$a blue lasE� 473 nm; C�@e�, �-ve�through�% air immer� &�( 4×;exP16 NA; UPlanApo , Oly���Pn�eam di�!e� 6–%�m ( sc�)a~� tissuKOO%�.unt )k,an 8×16 gri1(50-µm spacP,���!� venus-�%�iedZX752X�t.'% ook onl� same � areaA�a>� �ou��oT..FiA�si�0ofM pulO� 1-ms d�uE�powak-GrangeA)�µWaځ�me�ESpikemV5�Vhole-a cur clamp mod��LAntidromic APs triggEX(x"aJ2sE+� esld be� mT# %Hir wav��m��T.�1� an AP evo�(byV# pic� �a�'we uti�! char9 phas � s-risBfO�: cN ;Rsh%�rcrAPE�sh� ( se�be�mV!JEgI i .a�inf�0Ipoint!O�C, �A8:�Iobtegor\�x�G�E�J 31peex a>]!�թPk�:�i1 W4e first deriva��� %��Ap�APz*b�.6 peak�an�=V/ms;�:is�L�<A'�z ^� a1B�_fyXF26�%�"�!F��\AP � .�pSex-�m�,g mechanisms�v d��1m�3� agDnd � be broad���lmajor cM,es:�a>environ� alI8S rq&to+sex9_A( GSD�littlENknownsuI� mole�r.�uq/ly��6}NdEdDouble&( Dsx )�s* h importan��R rolll sexual di�isma��! s:�org-�nematodin7!Bverte�'a�H& we re�EQ��aQwo�s� Daph�4magna8  f�/wa�oHbranchiopod crustac�U0hen�6��produ�0males�respon�o:vc . On� �,� ig' DapmaDsx��i�Pibl�A�ma�i�2AV�tm7d du'~�)��1in-��of�a�y�a�Dsx)W9�<�6 thou� toa8��r Yp`Vp!�In� uE�!Y�9Ime�Ioc�a;2�is.� �� . Ra��!� n beA� regu{(A� Hs�]l!�kpre–mj8splR:gA�r(�,=Xexhib�8J�jAa�abundaK7 crip��D-� mbryE��� EB!�incn9� lyhA_# >a� [7i!tetyin55 g9u3 . Knock-d��6� 6 �E�ul�� �i]�of fe���inclu�)ovariaK���C:�0pnnX^��"eaof �like p� typ��E9ap� nDan� D .�pa0a�]� %Y2_z$2., b$4 ilen� � e{��H a�in�� �cx&�ic�6n�ޅs�L!�(s establish]�<keyA�a*@al=�� ur f� ng!� veal �dEmH=� se� v� �p�|�]le6to��y�:�behav�2, :z�}�!. O��ha!�vol!�a a��Ztq�J�!�$systems [1�)[2])�Z~ e�men|!<����wo�� [Ge���Z� !�ttP� )XQs�g9�e�=, ofteni��n`c�/o��7 %9 alter(2=�al�e hwayA"E2X � 1M �(ew)�gQ>6��ea� umab���a��A��lA>��r�(�"8���6�!�@ s [4�Al"e�!_AGe�vala�I .�,�,A� phyl��� widespreaH@oc�ui�� taxfrotif,2w &� �, fish� a�r.,� [5�6�%OinM�in �Ŵe2'aIoto�"o� nutr�� �6op�m�de� pT*leE!�1�;dF�rae-��of��.�af �egg{&�1�es!� [6% SD h�=ri�%rep�:?�v�?[7a�IP may �)� adapEAw�  ��Y']� s [8�I�&s�" b.&�BE��onP j dr�3�\ )�k�E!��[9�[10gPM e@B�ya.C-s%�aKmuti�� �T!�t"��Xin Drosophila melanogas� � Caenorhab�s�gaz'adem�BUhow�cMapi!|!uve��!��=qu�a��M�(�o� [1��12!In ad�7>ort� ��m�.!P�%%�exa�2�<k �!�%�, e1"]�-&�&>ty�1��Som� f � E z!��FM�.k9�!�od Y�%ob�%�s ��.�1hyp � EM!�!�!�%x orig!��!h�, �O��" �th >pa�5�~H�(,�o� te�M &GW �n9h�a�xye�en!�V r��v�z��fu dY��6*�unrav&Eg�f�!cruci�"��7=9A�" $Z �   flea */�yZ�v �$co�Ainhabi+k i ] pond� EurK,�Asi &. is�� witch����� !AA@ re*: w�#�alB%lit�+c�j �NzE,"�+�}#r�^��.]Dshorte<vmA\]fooq/or�4ud��,� �aclm�� < A-��* Airv�ma~r9 FD inst7� juven��Ueas���.K')sDine )�r�aP$na�#!�m.�daA]dsI�go %-�-�"+ &� I �D#!�AP!; �,thoracic leg�tA�r[!*cgory h���� beco�3��fifth1C[1��G� � E�.� se�at��s� !��gut�n�!ԡ&�A''!�)�1{[17�u���A � W X �gFa5^���^MY[18��9waappea3�O �. 2�to�  [2�6 [21]i��be��I�+haploidk J�,fer��d�e6H)w�d!0�~ show� at� horm10��ogq JHA �.� �| � ladoceran�osEC�6c [22%0t+I�%a� expo%A��to�[stage�"VD �H2plyF�Ae���Moinaa\"� )G[24�r�#bly �e� clusiv��%broodaK !�EqQ,5_u be a;��٪@2�R�-M5�[2elTog�,w�� growOgen��� "res!k8 [27]-[3E�2S ��ZstudyYeA�6� . M&R�|aɁ�ZsM�e�ex�)%jou��odel ��+E7. , zBel nd"�4d%��.p�,fg[31! AZ0R��?�  .:� ��,��9� facB�id%M�en�NF�cascain. : at dGt�!ts ��-er�3�Lv ")trK[3��Dsx0k.s��Ks: �2m Dsx/Mab-3$�" %�N-Pu��� � a=_ even�.� [35]E�C woligome"�-6vCv[3e"�s&�?DM- 2( I)�disa �Eo����r�� � in2p[3�[3�'�V��?I5�,a�;3�numer��t�M��Ɖ��NX�  ��@ � �I4�Toi�&? ��a(99�U#sh�IN �!�ay/��.� �At ��eB�+ maniMMwe ded [41�Wŵ{- e%��A�� h��m,��A�ed�"rplVaN�id�]G�JV �m����+ R2�.!�,g���y'1c����!"N�5�� � s:!˞� [42]&�6�ze��-�"�����|�+u6�6 o-op� inG2� ag"Bu'L"��<%�c�"m ��sa4T.t>��Q�Uor�6A :��!c!o~�����ir�f*�1. .n effor%��4i|~ie[*�4݊�%����U�́Q���@a�m V@�ŏ�?Y.�p�!�adultD[4�U&ony�seB�� edou�ht�A o�%a�6 nic2�,B� they%���.���V ("9"4��� promE���6�Uu ��>�%gm�(bxv8aJ� . Tw&�KalBU7,#� 9� EST ^/b�%� %�e4~C� s�d cDNA�( eachh8new)X, >�MJg]PrVq li �o aci|mto���a�gFt�$� V�Dsx-re� 4!�&{l!%-deB��1x��pnT� �)&�!,�# _)Aenc�"aAT6of 330�m�ag p D k 1-α%�� )�� �"nj5'UTRY�1mE�;c;�M��V�142�Y��: Mpredif00du��9�"w�$s �38%�>=�IJtK$d ��"a][�1B%��.&\)����an^ e~b(*�(a�]ph|C|Di*s �M enha6R fic^Jb�9s cNElb�&� �-p1�46S�� with�#V� . I�%I�CE�2�w|79noh9�s &�%���X)����ub�Z6,�$a�icT�s�cidBBP*� � rJ� *E:q�a�-�r�clo�>��)=� 1E�!&V !R para( duplL&e�!'�ga D5em6 �6>Ym gz of ��.VYa6��>� next&��=6�0��. by�ntihv�!�ime PC�:*�"ofiSU12�2 d*,$�-7�He*�I錁捖2�Id�&ds���W� eA�al.�co�4I]�Rw�.�of�2>!� yF g . ,��"�)a�n�mo:{2A��;t �)�ov�lhatch )s� wim &� A'C�#mbey?T^ ��j B r)�iE!��y$n� �W�D�VB"d=��"#�a2"�n�r1�motS!$uD�o��T&d� � ner��h2> F�V�?��& u�_. B#R�]�2�&�ea�.JF$ �^� �� .�&�E�.Lu�U����1uZVG�&v �[U2d�2 ost-Y\m[�K/Nn<F�h4rC &w� �a��MpI v> g�4W�N.��.M�A��J%�2(%�@Vn%�highly6WA;q:ia�b&W� asZ!%n�(�:�R*�)5�6<� ��Y�(=W2unt'situ hy]U+sF�a.ED1 2QA�bF&f)�:�;t�s�F."C,2L.^of��!�T.��3 �20d/&= C�S{ 9b[�) �F��Ea03l$H�9ak�!�nEDlMal*a* h !�|�� �ound eye� �� V ��">A��CioK �ST�Itxs�leY����� dM �!� spat� a�p�lstron.!��mXa��m{-)��, ��qH>4��Ya6s� �"z�3�<��BF�[~�4 )�2p�|aV�q�we&�*� �f niqu:6� �/*mf� �16�!r��JdsRNA-ba��5a ck�,e+ D"@pE� a+�&M�0by fenoxycarb!)�� �ѕa&(�of oocyta�v�a%�"R6]�inj�:# Ds*�),�'Y �#�!G n��� ��^�X!�a)t�,A!�!�ir�#; �,�=ro �a�&�)*U*!pD"�--�� 9&Q �@�  we�lengtL! e%# �/�z�F SQ�1-�- �ed=�R3.�2��waos�2!� e[4�"�Al�S &^�Dndage)!3�I cla8I�e�V��a �.� ,Q3-{ t)��"C] �wA�es�L�1����:���� ( I�s|:um 0e yolk granulnH- pid dropl�aO9llt%��� ild-Av �s��6A�O)�M}1�2)��1�Li��� "�eP_I;)R_!orF ? o;.�$A–3C , T�<�kvOtzi�>��e��de#to 40%%�20%�fi,yv��m� �Y�� . RvU1.�� �m� �� 94*7g)4�2��Yha>AB>^o��vN'v";oratbi�$. �y-ljkt2��by N � lapp�^��2��S5 � x!�Z 11 RNAiMX� ���:*i1(2%Si�*z !��a%X"4IbeA�ew��r!��$"[a��M��a9�a34can� rule��) low-)�rc"e��  D�2�%Yr62-��:1 ne�0?kU� F�ask"Y *W2�or��bX6!2�M_ger�2�"� ����U��6�e$ie  �*H q]b�cc:�c!�0polyade�^a6��$0*^ �'.�1�5z;�#in��{to�� e�,>�6�C��d �&Am�ɏ�^=)6�:aU[yQ��a . Un�ue�_du���%S%]n'I�i meth/& masc$k3 N��!j+*�6? �B�%� &]too sm��9BI�CE,r�Sqq.^� `�wI��oo$B"d �+miB�� ]�- .�#a�Y�'pr�n�aXm� t�!2��&2.1�e�14]-[46 m� a�-tic%� 48]6�hs �/�$2M�"'h>R;a�a� up);1s&: ()+�+�?-rgr4shrimp Artemia�� 1r�m��1 ��3��-m%��U�M)a@� ��9�w^Q.O"�9M�gD��P��2�O�"^/�\f� ��.�%�or� by RT-�w2A!�to V�b���39{(ts 6�m � re�#y fwm�5/ W� B0� � fragAR_ ��n86h-42. Fur�,�W8ah3%q1�� A)&';��M aSNJ�qt)$aLq�/<"be"���5-4�;.{ %z�A4����8�sxizly 4 kb�H . 8 �2 ���. O B UeK 3.`4A{�7 �t � X$�)�kBCw��ֵ�58  u &?��Q�l�8�112�=eF�e�ib��S,2UM�-�SX���3)�aI2�D !H'6)!�3'RACE�W&�I[ �� four�.��>si� [Q��j s]om� stopA9M\n�v���a�7� usa�P� U�c� d*m�1#��93%�u anon�AAUAAAB5a�\e!�U�.@��>UA.![4-E� �!�?ikb2J1] �i ��N�( AAG�orjUG0� 5D , �>L,��l&� w:��'r�Y"H%B�s*���Z5E�5uA�n  -�5 I�%�� X9eOzz*{� a�F�9l Py�� . s� > �B"���s,����T�^\�C6� fe� Yr"w6M�r  �*'�Z>5u��_( , [5E5�71*ni� ompo�A�wo�)a�ALB�9&;D"�)"B*2 ��f[2�);1u2�� a"� u�^�k?�dBa-�� ains"[7sh &�&& %�Z��*+�{�EcK �*�b�.| "�?55�m�ica�]A. �a�^v2� % �j�)*c � ~it���belie� �:�H �),ell-autonomo�l� & �# s [5�9(Robinette e�Z . [60]�Kep)">vc.7ha&"R23�3%��.i -�� q7��9)i��T�E -M�!�Aj!� ��&��f doesE�dis|KG8 ��Z2�:��*����$!��s�5W&� 6Z�,�j6ar#ny� � .tV9%8��H n��$� dSn=�ap��\��5��-�&] i�uG>�Hif"�"O7�1�Y��!&�Y%c&�L%�ai rem{ X U(�Qsi] fu�J�6�!�7� sD m5D�A="$�WT�"�a�D�&AE���mble JH-�8Z8�6"*�,"�}{.s[67�4a2[68� B�N) �u �po!ly��� el �.� !lJHݬ�.���m-�unfavore*6�0*�Xbyu�I�be)�m̈́��|�fcr$H*>aL�re�w �U=*|v�^{&62~OlqJ�*� s&Ta��`!�t8t �ib%r"�Q�7!de�1��Ele�QbyM/B�:|2� .�"� M�go� will�/`%�, �&�2��_t��F��}�&�7-u8k%�N�.��1IYnVs2�>�Y0an�+I )H��4:J yiel�q�%7.�)�-� %�t�/�����_'���ai� Ja:/c -���!4��(-"ui>�qi�p���.| F6#��r�83K�* �.p ,��.��W�id Megas�=[lZHe� �,quito Anophes gambia��/caq %-� !�M�)�T* L&mon�Y.6��. Despit�8aGl�s�Ed�#Df or�1ab+,40��ll�ypago�, [71��.j ��K�Zx���� -Kyi���ehe="�) �l�l�n>s�� whilh. �of� ='by�";8�mm�?�Mx%�E/s�,n{�2g%�newU��(c`8up&�a����couoof*%F[7;7�6Thu��%�!� L���x*�no bo�7#�9�G�)*?�8v�J�-J$M VnA8� � � ~ NIES1n��(6��Jv��6�Lև(R; Tsukub8WJapan�a]F^b`[�@;".[ �KU,��(m2 week�L ag��t�Gw�a syndcF�mi|],.�'(�yL 0!��"�<(!+6�/y&�x�aJ�m�*�2��. !�rg�� NCBI� �(L ( http://www . ncbilmi�7 gov/-�Q�+e�8�&$ 28!�83.�v8)��(f��;�itd%�o6A& )&harve�_d�8d brie�was�)nd� genO'u�S[Physco+ NS-310EA�ib8 TokymaQ�R*�R3!fex ]U1TRIzoz��|t�&6Տ: ��6~ , Carlsba0C�US��fl�+�iso�%�pur1R� �F�0Track6n)E�com  d 6Super� III,random"(�-2z*b2ΐ^�.m�+J�EJ3i��_��o�d�M.-� ( Cap Fis�, See�A ou�`ѐ Ko6b)-A'8nucleot�gY��in �"S3fS�eq)�1�Ocl���dep�d��qk4DDBJ/EMBL/Genb�D�jL&g�O  A�p��No1 B569296vl 7 �~A2���� DM�aV��I�;c�;y�ese)�"#�J��dD"I i�V��$�=a��slie�9niA multi: lig_Z�Cl�l W [74]�a&'SJgX( pai�aV�7mj&$s: gap ope�T,penalty 6 . }}}Fon�`2m��tH�;w�x�4trix;N�~{1]~|�idelay Lcutoff 3*�s-��LT H82u9re5��&i�>A�p-Eal�bthm%�n�bor-joDa�%�S0� MEGA �i 4 [7M�.�I��roo:to5�_ DMRT7�(-^�k��y.t wo6j. O�'��#Fjus�Y�9molA�%%�assig���$ e 0 ����M&@1�, 4M9aF7 [�y.XM=�D0"k� {,�b� 4� ej."��U> )�?�l Temp��L+A( ��'a�A� s��byYIygen*�p?Ur�e� i�.T7bmer�@���%�h0 5'-e]Qm+V; DIG-label�job�!,pr�� .k by Butler&(7$'su�}�} alka�D hydroW|.�6A*y�>{Sagawa{�N47�;�$%�elb%pMۥ�t�C=%�Q#��of "�w.�J-8 n�i) .�)�!�a�^�7BVA���( Amb , Au�/�l Y36���y��-a�.�R=: �� ��-l/c�oo30�&"�-ethanolAGcipk=� !01N�spn}DNase/R-f��silA�wa�S2މ,B� !�&a2�4�a7:� �.�.�" b#�!� IK:��1-#�778 bph@5792 $032: 445AfSX�9, �� DSX2. sub�y pCS|lc �Eف�!V1�YTo�6L+-l* , pE��C1��e{M��:dEdT7@��t�-A tail&�X%V}�>�.O s'a�H I` erc�Vk�[mMESS��mMACHINE8 P&P Taid>12a�~lyate}+�h�p:9A�5'-�3�U��l�{%�z��� attao��5'�Wfor<� ��%%_" ������G%�a��c�sM4�8 [77]% �x̔su��M4- 2�Q�0*iDWmg/ml ).L1�r�_eo 494*�y t dy_A%� Mb +Dn GmbH , Tegernheii Germ�)>%�!]5��n�ic܀�sa 96-MA�!i� roprp>���- Eq�T�u| V�� ��N�a�!}gain-of- 5 a|�8�- m65+$ 3 nLA .� d"w7 fye6^�X grapJe�(a Zeiss Axi�vn 2`y!��0ͅ( & , Oberkoc�1,=j. A�Jlj",X�"�0!z2�i�4a Leica MZ APO�B� %W29He-� bergQ yyB.%�&6:�":� �B%M"4��er��c�Z<( XL30 ESEM; Phiə(, Hillsboro!<R^�3^�%�rzm�0!&��Q1 )%AG�� eel�an��� e�bCfz�qÇ�0%A�m��–p�ge�\��ans+S� �ip7()gY�yl! � aU(�$ond-N+; GE�{cx, L�mChalfon�� Engl��6��.� "� M�DIG$� !�S RA� Diagn�tc]J[�E *�/kE�� (��3' ) :!>��:�+ TTGTCCGTGCAR@(3�e: TAATACGACTCACTATAGGGAAAGTTTGGTGTG��5K%�h&A[.� =1�V11 hr� 68 °C w�!5 easyI (F-!y>T�3&0� $phosphatas�&"�� -n [�iJCDPY yB�)rb'�.D�A iheraj vacc� is uly nee� �T!�n��O&n��v$A:.:duc�9inc�<#neo{ c�<de�:�Tris�! HIV acqui cc�mis�~� mpan ��jic��.�b5tri�eHSV-2� un��T��adT=eIQCpG�alufrhe}�macaqu.nd�}nea pi�DAoP�$"glyco����;DWQgC� gDE�6�Ĥ viru)Otry� $qi@�vTa%byD@��B��9�in!��smaDm%�a~�%iz!�M!o!�tA� %� ���:�A#�>d;zLCD4 T� ���p� T��8av2�chal,��#lf-lim �#YcJ�yar�4by hi61a6dh%d �o&��in naïvwK&9$�US�� U. VmEe؇ac�Y�&3�UY=g�  mock^dAm��A^�*1�1����a booA� d�8�k D2 (6+e��A�N!� &>�d97W>99%1F`�&*A i�$�X�q�leA��=Fut&� �a|& �8marker�2+�T,U swab-[9�daxa�����rep�M3 compe�|m�b�4��-�%n�MY�.Yp�"A�a=�H#oupQ��E. She 85ib�"2ah ewer��� � 9�F%FYO�nU6/=�ƎK7���e�KB�E,O>� on <"�dYd97~���% ;Q��)out�V��"x~%���!�aen�Sͯ in h�s . A h -b-!peXB �}1�:Cworldwjn �t{l�$:1is 17%{!�UA ..�dQ�6xof�zA�49�!�n6� 2-f�zSee� 0-Saharan Afri�$c�}Qo. G>�s6p|.���IV-��Vp!]by 3-��4 � �3a�e� of 3� 1�000��birth�E�nfE;W&�$Bft!de�ry�2�mt�f!29% [3–�cB�� is e�(fly�!e���9�viduals�8dA�Är�s2��ir�tn; [8–1d%AU�^F>� ,�*�Xis avail)�=�a- purs\ aQ�q�NAK�'��r�?i�7I�!�'�Myp�&ly�su���MH.?�x[1�hK(iVnfE MuV=!2muc_��a)6}F�[�VlCh9{�FL�(G1R�c58� �Q� �6� LK$�@u�y-R2 B ( gB aHDDɌn)�MF59 7djuΊ* l��un ct׮on.rveYo� �.�"�=i�?layE�set!5)ove�9f_H5 mona����Uw 0. GlaxoSmithK�( GSK )��%� hy:[� !~ � E�mol'. oryl l�GA ( MPLVn�=um.'"ujOՌnou A�a8stul�"� ,9t�?�8-hG/no���A���S�� 2 d�|��=�wo��A� -�@r�Y&�inj?etGo%�^�>���;�ou.���a� icac� >��4'slX!worthyl'�) +� a��<r 60%!� �Yb a�a`TL)I[�j�w�X��Ig*��|3s��da�a�"` �2m���t.��.i�>ach!�$upQx� Zi�E�a' tegy-��-e&� e}A��Ab �0 �C �gC��:E.cᄡ"�as j*{�).`.[1� d/l���4, C_�!��+3t./E_iz�1leaK9 o C3�@�0 S�e ��k Mx�m!T��ne�)�!.��)�R^�8�j.us���1BTT-%A�eJtfs!4 a li*qyinn�5$���%��[�!$i� :��[�8r} �7 ! [1�~�j�i �EQgC ^_"�5M<&�i\@B.U����]�ufI�$�jJ�ݥ�E )2o:WY�by% %�he FcO$�Bn IgG-��is�*:�Ëab’ )��o�)%Vtsm�u�B�!&9 �7a6"su6��I5!��<� q�28@��.��(�mammalL~.vnd%Fcy�"$,�4�-��h&�(log� Zr�:i�6Ks�t7now �F%�Y��8! �< tyC6�&1e-ǹj.�"��!!�kA�z)c��N^���o�d�х�?��@&*)��.s rj�in6� We2l�I�)% �!��2a�/gD2/�zJ.a�joB�c\~!�i�[2�('�#)%_� -a|&�o. .ml �C�]1@� lZ[ terv� �>�%� ��Vwm{d rob�$�{��B�l��� E�wa�$sl�Ely��hix-�aiw�B�b�At� 3��6�)(5F6/10*w�F =9� Z�Mqia�9��y5�H�Y �" �1TFig`c� �?%a&� � ��lER�cIgA ELIS�`�y]i&ؓ>e�z2�9 i %a�*xE M�7!�� -SJE� ��,[ �Qd��RrM ���1ll&`%�a�N�I.  est�#qJ&���%U J�m� !F�)%�DedC<s� AZ��V9.{����� �+�Qt "�Ja5as$2 rc` ������>S �h . Pl�"W �!%� mq�{ �AR 2re& �XJqEq�}%EI�a"�MS�:�IK2�:�_h \"�a�&u�j�L � �. N{ =$(e�" ��K*#-J+T�0 =Yv�� L � :�6o���6R�� ji�s�� �7�-u��7 .�r4UAraA�100x ��5��3l)_� 7( seB��vm'1"���3W rola� &Y�E0�~%2��!dюj���1:1601'a��˷i�pah=�naɫachY4iF�q� �Fi�]� ��IuJ1��1]Ls�,;2�-�IKB�isF�s�C�?to�9����� HIV epide�5 Dֆ�+!�u>G;�r�~2J�:�thA1V��{��u�E.F&q�fV=)��-sqF� ( Ug��"�6�7 6 5N� A�jc�7G zyX2"q%��� s\#in�82�Z2/�Z-�a�ja"'�log10)� +e,assay�c� ?2��&toA�Z}M>.!3e��k<� msy,� Y�KC]L�R�;Q�BW 5� �Gz)�F�n1�sH m$/2-e�laPeZ�!Z.u�g8 >m"��'U���u�+ O:!jl3HML�2G ѻ� |� ��ǒ��ndMEq��/[��K.�(�@a� pi�#�bod���O�_Z3� � !J"�-%�Ml6,*�,* ,C9I�M ��զ8)��"S�!co*!Q)-IXio�L"�C9!�8 -*Ya�*�? fash��[2�,6���n4Ɓ�0125μg/100μl �-qur#� �M�h�2I#��um [3LAt1 � �A�!�%t!_BWsvT�.*�$!J=!� K"!�n�*�lyI_ed::\ ( P<A*001�*!zFc%�� )m�*aW=O�hZdu$� A�i!��+uŚAg!o+�*he%&�. Bq$�by� �S� -U�")�Gy '� e)2�� �;��U8��0!��0� �~.V }(%p3E�t�ig�aff�@!%�64tu |J�H 6�:cKL 9ti.H[6AZF&�1(a�I�V>!�&�� �!t1�F����Y7a�ncu�a$5Tv200ng/a�. AF��Ke\:� a�00��D 6r�$�+%=�&�e+%��-�0�on%!I�o}#l�� �1b)v2e.e�@}�6c~dos.07OV��at!q-is�5v�6*(�u . PBMC��A�gen&�JBE'~�:��aA52�V%�Vf ]�0�d��.dF� CD4+F�&)�a p�&�1�%@%�j�< 1&$TNFwIL2� Tqs;d W��,�!A�i���B 4d � 2>g, IFNγ>�oj(*�� ���D2AR� ��. CD8JW��("�Y�("�(E&? a2�)� .�&�y)�� %@ UJ)�%�(�G!tr�)l� 1x108 PFU� y<8 in G�- m.w 6��t�� �#M; . Nj�se�9����f colp�1Xgb_va��)gi�*biops���>!��!-r1��&e_5E-XTm��*&�*�b� � lM"id� ed vesiL@@8 �� !C)��@a�%Tv# dga�0nec��c�+4  �Mp5Xd�]� �infil*$ !%lymphflI%> ���)vQsB>�7��I��Z 2D�y���+ ��Ic�GY�e8F+�9r XzL%�#� A <o��n��>(%�uQte�d �&�)Rr�,�N q#2x109e:.��"� %�illnes? All si�H!Z-{�H�`s E4J�s!]� ofFN�A@# �� ��IB�$)�}C�J�%i6 �� 1�by)joe2&�-%�)�-x1�v*�d:Z�&ti�ka�" �M>Vre%�nA75D�5q� !QIV$=�"���2�]F ]G �N~E�:��low�?t��"�,�"�yPC�}14��p,�x ��� wo)p6�as�)i� �N(xerbz( 636� hA���U)6���.���>��J:��eu ��A�M�2�ty-.�/� g6�# two-E$�"�2�, n = 10%M��'ɼ &eW�/gC&_1Y<275E�X�K�.�@nt 44U�:� � |4;� 9;l 1�(�aEkn��.%�� �$2���"�0AK!F�u�~���t!!R��. �9���A�aq�Z=y��h6� �rv �Pm�Y2,w?�Um�Y!%���av, �-��4i[��:O�F?G T"K 1X)z�.6p��IƭB�JPZ�6 ;a`u� zM 17�I�D2@V'E.'ZvgO!�o; Pu��� ��)�t6�2L,| ���-j]5 �&Z!Z.Xem&�%� �Q�(A��.�)�wo2zc����"Sy �p�y �� `  X!�!.��9z �Y�Q�( P === 0002ef I24K,0e�:<6� b�A�heyip%�� b HUhoughB 2ab"?�=��3��~5&S��=sM�E�.RN0&��d>f�QNmy1� �>��%� dH2�� 3u� PmabB�mal�� ��E _� deci5 t�`clug�2eI,)h �FvV,���aaz :E�6�9.}��]o�:M]�3��r.�"0)�2� �~`0b`�x0&�uѷ�!���u�FY�2(m�bTM% �,%M�� d\$�#D2 2�&�u� G]�2NTZ�>G,��8 �<2E9"s" ]�?� &���,�DRas�R�\�y!�^V'��P85��.��W"� V�5x105� "e �M�5� �Im)!�~�%��rv(� 8/24U�3% N(�� 1�� 0F��w /��7 . EIPYof�� ( 75h:�p&[%���urG9�t�]hin�ymb weak��1e5�Jd!$%rcI�s� 1aY�( 0/2p�a�U�@F gE �v��a��_FIA.L.� X6?�k%3��7�G�_� urZm!a acut&@%2on�1�6A^n7�)`re��V q�B:p�"L"7Sv(A"5�s�&2<�%;)���*�:e.���B�d�.�!r�!�06r� ��7C:���#)��_^soEON��ŷS5�t#6`�%,� 1;E�a:) �./� 1w@���� 6�9C�H����6U ��M�A��v=�����to+!',a�6%�9%�D��'&H7uoG)c9�I�)_-�#&s�E�b����@WI�AV9����Ziv��)5�M� 4&�C(�a!7 -N��C5�9N n�T�9 JK%%U�E^5S4 .3��J�:2;oM�A�o2"It1.�)�2&H7.("2�^G2%52�9�9����m��95[5�:)*� 5� �A"� ba Nn`r ��[2s is� d�,e8;7A�>X . GurE"�sMF镅0&f�E�29–49�t-"� e�.&2haz�.nD2y��1 "� A�J s� !!i�"� 6B(! .!��"� lT�w�h7oc� �r,��e"kon �� \%M� �r�f� #A��#2Y� !l3"�@I� $&�04 pX:�"� F���u�3Z* Y��� 8� ffe��� 5��!�!bY'�( copy����n"<�s!E%:� 1)E�5uT]8p e{&Z9culBjV���D�@Nur7b? +�i��@v�4Gqt}WO@p� %� �A' �dik 7/25��L�B)W� 1/28$9�%C.��A30/6F.)�4>� r%�U9 4��E�2dU&� �q( f, 0/16n�h.%u{�)�,!�h�sreB�n��mil�� �s���ѡ6�a�j��92�) Q: CQ�Y�: r.�mPJ��me ?\�K'u2)rj�e"��A��zt"�g:���H��* >)��I0wayh.�F�e� 9a$]��6GwR�.�B�+1�l0 q�no tp6� �Xd$N"��� :%�!Cf�<4 �U hPab:��Y�9n�i"����HA�V��� � :Jy4�*A%dok� ^ gang)���g�en".V&� ( ≥ 60���!j�mؿ!=eZF<I�3/8�k,E��i7/8����� �_.�. �61�f�t.��y�i� �aE�e��+) 2/61:��24o��W{,J.��"&�)J�1���a"mI�Zi@fՂ;E�����a;7rli�4���&�AK�mh�Mat=�.��CFmrd��:i . �o44ij�A�AE--Xv�>X-~7"%��8ic��9��b)\�k!�R�/f,: �v�#&'���!~#8�2ies; iO��*�$j45F��t�)!�s��)!3�u*�/"�@B� iv )�(F�(Y�se.�Řme�C%"21\a��}�"bF�ua+#s\)8&�8.=7hx��̓E�zDorA!� |�s"9d�&eb �. De`Ae]?�����i�&�PD��u"x&�3M�"E(eJZj�b�iyM�� n9��( �*��}H�A��b���p.�y Q�ō�� N�sn&�Gշ2/,t:Nx1[3�b2�2)l$medroxypro���G�tv�!��mjI&[&)2~A���A"�(ɒ�K&�Zch�{�reexoa(�S{� n�jshe �ͱ/:W#9Uw%�(L����%sF|Y�6eyFyA�BvR�e�YMhq�P^iest/��Ja6aXe C!�I-)Eos F�5A���C�*D}mQ������Be7fu<���m&ծby "ch � � e suN�8M��EgoFq!2&�$�Cau" w|"�Fce�/ !25B� r ���nt�.��q[��h\Qt[B/ fa�3P:�.Or �F�hJ��l�E1��Z�z��O�s� ��%2 7 2��urv�0encompasses 3�06 amino acids after the signal sequence compared with "xGSK strain that consists of 2842X�[35] . In addition , we used CpG/alum as adjuvants qto MPL "0by|.D is a TLR4 agonistY hileW9[36 , 37�8The gD2 antigen ���was highly protective in guinea pigs; nevertheless , !>�)QF�8as an indicator�9D ailsA�capture�=9Q>on videdA�6(!�5S�s+giv!�,equal weightp an animali�h� !Rle!qWo)wa�multip% s on manyIBH. Uninfected female.� occa\@ally develop redn!�o� eirQ�s �Pcan be falsely scored%U)�, whichah$our experiEDhappens approximatK1�.0200 ( 0 . 5% Aj These rar x posia�s����"ce�%�s wer�+or>�Q s!�ule *similar�"*�\employeda)human�Hal%0 , 1�,6 months [145] !teadAoLiof828�h����)a� e de!�ed IgG b�N!�o gE2��i �8sera from mock-%�izan�52��m�esult-7�A��asg0n�Fc�Ei�includ��he+dom�of non }eG. M�C*er ���m�%�no�- . �Z�� �ve�L�]0F ( ab’ ) 2�bound!��at�affin�u��>c 3!8Regar�T cell]�� did�-� CD8+F* in rhesus��; how�� ,��,prior studie��D Balb/C mice repor!#b^���muI ��gC� E [16e�hO(I/II clinic�#rE�will boqui���ss��w��V�9occur�eE!;�>F AZ pot��qց�inducAR neutraliz "bo% [39�I2Z )yI5_ !�Y)Q had lowerR\�N%�@� :. S�&con.pof 10μgI�e�M�-� E�2�\ prepar���: ,%�m�))%edR�A-ow!�M%���f!�A :W2�A;! ref��Eݕ"r �o�C:Ym�- >� @# 9+��mo�ik�explan �A#!I)�vbi�we٦yei�rmŨKoptimumJ�AvgE nd�oe�81� . Itg ear q:%.9 C bluna�9N�y9�(by diminisha2%�� ic��of%N . To��ct-7,is shortfall)�;�)som6� three tim� kF�!t� g" � Z)�@9�(H*�  )�� du^�u�u&(�Sth��+� "- eс�FR�� mean&5� �Ey�|plasm�~>��� erum�.�/:� :64^��!2Q#�ed��um�AA�. ��:1280a{.te[se%+ �"9 favoa�y)��fe60��- �� ed��A#� = >��e29�by�L6k�  Ftes� 7$Herpevac T�� investig� independeyin�labor$ y [15 , 2� Complem���L o enha�2>I2B�E���a"Q ex�E��̑�� 1!� is observ [ sId:� 6�q�Fy:�*(i� g# �6}aug! !he9� � � gC2/�K&"e��t�e�Jd ��givR o%by�.Eimprov>�2����A� ouK 5�resto���.sd!#2�-��={�0�:%�of%-S�Iiszsijf{�uRon4�a�J�� onl�ter< d parti��%r��9$, but alsoՑ1*s media!�by�A�.� ��I�Z�despit�� ��r�!� :�, sugga� WrK��!*Ba�_��� cP [40A�ItF�!~�y-�7 uOcytotox��ibu!@69toNtas&� ��XΔa',�1 D2 null lkvirusG[41 , 42�Alter: vH , block!,� -to- spr�.� �L q,��M�d �I�ti�facilitQ&mA�iA�a)Ra�C2%�8 C3b may accoun�ey�=���Y�1�[1�821�2�; � V� �! j.0F� . ReM�! risk�transmis�!Ga�n��o�(ortant goal%�&�h��9�in�standard4evalumRy o � II4DNA copy numbe� �secreA� s [43–4�S-Ki�j�demon�A�e�� episodKr shed6doe�aax repl(���e�I�as`� by�lu5o iso� *inE� culV[44AOur���: �:�h�Q8[1eE� A�di�!xe!�J�a� �anrj� 4%�A;Y\�H��0J.��ld�uga�F�h 100%�@bu+n� ��0%�J�3un�.�| houg��!,rj re!>>=aq?A��� prop#�U�Qmofrta�� releL$ biomarker�RTte J!�sh�b�Rns��0xpo��"g�a��t\t aim$�6� ��n[is] remely�u) Ar�2$s <4 log106 limiE� vagi�e1ito3��re� a� ful targe��fue����� An un"d� E^%���r�t�{b��)��9�w]a��!�3%�~=FTA u� W�|on%�t>� ���18/24�7� ����{ died+�O!�)bAz� �74 ,sIz �2survi( EO"�]b"� 5'~Hn^�ma�Y selebias ba�!{h��avail�He"nalysiAIn sup�8�%SiVyy ,!�anoBAFri�  *� , naï� s%�5w!.traQ�9m!68$26/252 ( 1S3!�d`���i�� !��EZ� tudy. rj0�u.�5/4�1 . 9��Cto 0/16 �/!v mild, llU8�e"qn�Ֆ^ fur%�ve!4ep�I/�ol-A�� �sa@ !F/�K]�nNi� caus�J$ 4is naked , fra�,|`�vi%�mu �wse{is� (�EhE5 byL � summ� ��f�,metE��&� go�a�.�A$sly�iou��[�Q�5!67Adrt�:� D2 "m`"& "! pb�,�d ~u,�U�U�F"< onY ofI�+�2b1U��q���̥gon 5%]Abm�ɮ!Q)�j �trA�z,. 2% . W� *�m�U��t �candidm�@1�e�%�� s . A}�%ho�atoTulane N� al P+#4te Research Ce� �ccord�x�Associ=�As=��a�Accred4� of L&nA�� C� Id�M al S �� InstituDal28dUse��( Macac#!latta�E!O!��P,�A?m�� cedure scribed (tocol� P0210�!�Re:� carrKIin�&ict~>� recommend%�E4�Guide%�%�1eN�4*UA1�0ealth ( NIH )KU<>�HWea�]!ɘ: “A-�sE� �%jnM�”��ll!:1QE�&g&� (r anesthesi� !� keta8=�effor>madY� ize!_+, �U con�'�0!@� �r�$% enriche3o� unit�&~object2 manipA��%z cagegvar!� foodE vfor� g�task-oF$� fee�Rmethod-�.�� care�I1l�ff��� � c��A��.w %�� eu[ ��by9pseI� fol3&i� en��barbitu�`ver4���nn)��A�6_Q^Panel��E�a!�My Amer�( Ve� �M�us��Q 6�scree#���s B&X ![�^:"n�2&��[4�Fy&HartleyAxZ.�(( Charles R���iAJ) ''A�$275–350 ������+8of Pennsylvania �q�io��-XjT"�� ��!Ea�aa!�805187��6 5adA��!F������B�s�� ’s�x��G&+1w!z�/dehyd  ( >10%)�t loss%��'dI� subcutanea salG+M * two}x� �(ed uriE�r~�, hind�b weak�(r-a�Q>; dIg%b>�(( 1–14R�acycloviNtra�( toneU 50mg/kg |! daily helpmme�'" >. O!�y J "��%e�{%N both=S�mel�am�de�A�pa�� m<firstA�ear& : :�,�_���%��sol��A<R6�EM�����qi�(Review Boar"�&������� �!:b�05300�eA�� ?  bac-X( 426t� D30�bE24-405+�w�#� bacuE�u%.C 9 l�+| [10cri l�fh2�&� . Tw^,=�A�� ��՜50�$b!3 R0 ( Al�{oge "A�%� Chem&1S{*x! CorpZI��a2��6�F� a%ainA�2�of�+�d(p, !��!�) mix���/.��  to0volumeZ,l� �� Yh&�"at 4-�+ill7!�l �vidc. �sQ�J�E`�1~%w� comb�$impI1(� �_9I� rece�a"9262�,a"�2F�,;*}"A�J%�n-���O {-�a��%qg�2���6 n 3i$aO.e-Y+=x(. Anticoagu�d\od@colP�1.�-6�, 6 � al�c"-!�K-�lt.�#� at -80°C1��A���# PBMC� ?0in liquid nitam&dHV*asF�6:�%�add� [ntrolJ�J��nu� ��a"�ed 30mga/Depo-PP!ra); muscularl��ur�.!�3y �5WH-&Hb$ 1x108 PFUhoJ in G!" 1 ml DMEM�)C.E�/�<�Sj4�c&�f8�3r%�Qsix6�I�2A%rC0�4�)s-A�=Y,a�/q�wo 6Q��u�l4I . VM�*�Eob�M� �Weck-Ce�onix@ inseB,in- qcav �5�ut61 thena�&in�;%�s le PBSA�� pkd� F f flA�by spin��(at 1500 x gs10t�Wm6at −iw.:.a�&�to�'su�&�"i��'!p�=@[-W/pA�m�c�� 100ne��ɔorœs��!7�3 Komucosa K.(�&Az} .�("*�2" , 33 v��Bj%\�9t�)a� welN%�em�8i;$HRP-conjug�-��or IgA-�"��!y�3eU(est dil�a��(BptN densAi( OD �=]1a�3A�2-fold��^�)OD`a�%�&Z�%a��@�/ial�,(�1:A�. T_4y4&�t %%I plot��as 1:25�Sej^� M� -h�s!m �1 s=rOn20 mincub%�Q�REMS737��A�1 h�# �+&���1��Na�VZ$%�m �&�!plS5ɪ4 Vero�!�U7"�%�S%l:FI2UD%{r]#Mf�"of |�750%ap&P(��Y �m�Mi��r A�e�� �Rst9�a 1:10�ofNEv-5%v��:*� ��+N��to AfsH�5�x105 1061�`A�:#�46�.�a8A�&R 9 ed U�A6ACatMT��� v%?��j( ATC�[M+*$ 1L9a �Y , cryoOrv���8thawed!�heM�e�s�/#�7 nighl$le�PMI-1}-{  0�FA!}feD calfM�( Rc�!Ag&2A�6 �/ml9v� �_�� urif��R�� su��ei,y�a�4U"��M�Ir"phyloc:l E?�(n B4oxin Technolog�%,���3�9U%yA$� 5μg�'$nti-CD28 (n 0. 2 , BD Bios4ce�� *49�9F�'B)monoclo� 0͹[48–5y(Brefeldin Az �, Sigm�a & �u&�;e h� Q!�began� w NI,.$,s)/d1)sA%d.�Y)urface�sA�tI�y�aY3� .AQ,room tempera##ɯ>Ku E�direc)?��V< , CD3 Pac�,Blue ( SP34-R�/44 APC-H7 ( L20f)B�!�0CD8 PE-TexasR�3B+/InE��d<C��wak�� Dulbecco�S4PBS/1% BSA , f�bpermea�!��� Cytofix/  (F�,jin�: m BuL:V+i%�Z-!�� bVIFNγ!Cy!)4�:B3N�4, TNFα Alexa7�= MAb1�+BX� IL2�CP-Cy5�=iQ1-17H1%�$iolegend )�KZ��/�)pXBD! %q�fixY(bb@. Flow�,metry!z�e)�in 24 h-�aeF�8ss^ strul%�I�oG- NSystem$4FACSDiva softw"v4. Data "J$���IO�Jo.Ron &A9>�5 �onW)gle.lymph���-AP��CD3:,JenK CD4+%� 8*�sg. G )%�fu�#@%a7�l!Qkprodu�%.eK&0 e�*� "+i[B*%LtwoV� ���R�#Ae>� 05� ,2x3 mm punchy)ps�{"�at� tegic' �C� " &$kI�inb M�^orm'' embeL$ar�;%-$histopatho�&. S�&-a2,H&E M�$ �* >lE!�inflamm �u#�oxcvsaI,:�- �, + ��s2�"G c�asF�e�sl mod� �[5T/Brief�6ede-1/��l��(“unmasked�idhi,�� /xri!;!�aQam!��.( Black`Dec�+Fl�6}"(Steamer Plud�� 01 M cit����Dako T�*RezSo�. Sli�.E�coo�5�J.%�VBS�����eD!End��Enzyme B�1 sq.2P>G� #�{�( S� �Pbrabbit%I-HSV polF*8 ��2a��F!~� .� EnVi�0�LB�|HRPAo}04CA�46**Y�di9!obenzid�~( DAB�� �chroma(i�m� �0U|of sk�7r tongueS"� Q�s�/anQ1u%�%&1spe � �>] �I� unl ~ tissfDprocess� s abovoB"� in�ru� 6�I�:SA�A\�#�"ry� f�nasJ�. N�1n-��kPnd�5A��,�BUny9�6+mou6"�� ores M�:��iA'In����.�1��.*aQ�ѓ #O XI G�4�.�"�.�43�Fc��Cj!or�4N���0u 96-� H��B+ng CoO�Aro0e�!or%jIncorpn:e� E�.}p+h�2<5at 50ng/oI� �F�%�`e A*TE�an�H1/�N serou dono�BA1��n at 1� �4in Na bicarbonD!D��( pH 8� ����tGcY��`|B !����� 2� tF-%�5%! fat�,�� �. 5% T�G-2P1n!'�� I A< or 4Ak�}� "��!=��E8,E����7G. B�Dh�u�����. /K, R802�:�g5aC- A�;%l�;� �2}��f~E2~265ndonke�M.�.2##e b�I� &�" saph&v�6.8 ih� &� � *��r�U�"R5�A at 2>:�Iia %�#�F� 5’�TCGTT -3�F^�10)|O&�%e 15W(��or� ��D�*���::�xO!&p�� p���ma�A_�f�4= �� F �N 0����v����;s�8"�*�>si3s�"�jeNIA�=>9w9�a�. A�"t:@E�!w�?� :T=p!n�SKdu+�)an!S�|� 6�E2�new� h �� #=7 ��ŕ�9A^fo�� � \-H� [2 PNeF?P��E�K � gB�+�, excepP#��K"e*�SJ!�,� /� �RV* sourc�*A��3� O�:ZHZ�,.&!)3neX'2r�ed Eagle�&�~')a�� 5%bov� ��= ��A2*$vancomycin��;&k=Ma�A�=�&V"�lay�Da 2�+ll!��1�h�="� ..��lai��5%�4yl�ulg1=X$te~(F��. P#u72�&(N � CAa3A��A6 . 7M/5 a�աEN2� %8]��)<�Y{$�DNeasyoW0d �$ kits ( Qiu)1�V{��m. Z"94 ( Ad!ed�t_ ��7�P��Fcurve6 h gene�%EG5z�, Q �ax5�(eof%7V�ripx<4) Each.8>&v"#in du3Sa&� <150 k!�by 40 �2�,r�5"�mm��� �w�8"\. X;t8d��b�'qL`�9)eUs9E:��/forwar�>@5′-GGCAGAAGCCTACGGAAAP�� 4_rse 0,CCATGCGCACGA*G{+pr�wa� � r dy ; FAM-68CCGCCAAC-MGBNFQ l$( FAM , 6- xyfl in�A7WaE�m;�5IaTaqManE�qJ9�masteGxApppl��d" �Ad�AP��5�$[n ABI 7ANFk(mac�; .F�Se�?"(MiE`E_B�l�Bet)] 9$�eno9S�r�K�5iH`]P�"A�re�.or;a gram?'mK��xt% 6lb�en�dome-wid� ofilof!�A$-�U*�='{ti�J�`precip�=.� ��oughput.�^8IP-seq%�H"�X2ni\�6\J;en}i�!3mapice57rt�0d 50V600�b pair��bpA�9V41�Hu "�_o�re1Oe1�.P%��C alyt�*m; disca� such-`-mapp!{XM"� few��c@c_=o�? them�po�l�`�SA|�2�$A'W(\vV`ed*"m%�%N� -e�RGad�. � ��B C1�&� � ��l6eR�~���1I�LEGa\4cd1Wg&9chen;c�B"DPe�o0��� ��:�.:ac�g}liRs �!�. �o@8D �L util�=*[0�ctyp%���sDsI�alismL>lyA�`*.Osbervis%fZ�%=a�=tya��0 A��]> ne9�IBa�+5R,to 64 ENCODE,Ta"e7GM12878E{ K562�"!�|d6&*ny novelA�Vji�7JS q�. O�2�G��s5%�$@ou; �Zcsit�0 re e�5��ar):�d�3* @B�oE y shAhA2� �Per%�x(�)F]�� on-rFl. C��v A2f�db�A�c�$ atil�/.��A���_M crip!&A�}( TF )"�!�QL% �&(typ�J=a�e�� mill�|Z�(�����f#; stepA�AW�D�_hA���J pipe�<involva�2}B >�'�#y�\��CA4�M�_H��#?0cI[1]�A�X-e alig�QJao�A� ( #����-. eby �d0ambigu� r"v`t3ftr~P rigi@ Al&nOr�\�cs��( e�B� �3AU�" !A�Ae{�tov � �>X  "� �Fl �Se>uniqu��4)C[#> 5] (!5e�Ypa�ic�?�9�s�A4Ji!T� Zto'R� �-]Yv� � %�:�( AIg .& T�^2A�9 ) aS�K��)6J+$randomly [v T�E$bottlenecke� seriS$dow;)eam!�D�Hch���)*f elW �n�5�to� tinc�Va�esRr_7%ex  ,�-type@v� [reaGAyJ �p gros]=yE�2��/{akSs# E�uE�MeD� � �[7]!��A.z5� �Mly }MXD�8aj�*�Eali�� %�g��%A�I��iE�a�la�i"b�Gr e%{�@NaEhO"�of ��o�Y2�En�opa�Y-� E1�(��) ) �b�L�;� ��e�$eukaryotic��"�pS�?J�,}m7b,Bh>1M�$� . GenomicLats� y im�OWrol� fun��aE��UiW��a�e"Q Hnetworks [8 , 9] ma�#��S!�nno� af%�es Tlog���ca�SN� �k ���n�EY�!Jnd!��D5e!s�GE�$v>r�c�D "1 6F�SY[�te+y�>��v�o^� �6 LINEyF�(h�#dar- calE�m' C�o+ ,e-of-the-art� r� �r aOm� >�n� h RNA� [1�317]E��IH9ra�on->]�qݑ��ɥnHSbourho�HM�1b��a�9�f� e��cq��%��Q�`JpN�F{�8L ly�(u\.H(#)�v �?s!0t�=A{ ��!�UI%1�o�5T1LG a� �=teg�aat-g�L�P DNkh hybe:�e� M)!�( *%�)2�to�)orm)%Z�.@O%)-re"r+& 1YE�e cis-N+ac��!�a�U [1�S1nD��I�f�broadeYg of op o"� �d ofte!hi�+2�� }P panc0.� s�Ts �;e�f�^� q�factor�pup!�e �qde�X� m��� 'U�6gr�Hl5;�4>#3 Hio�!dC[`2t� -9).S 9(sE$[2�]U�^a�&:��E�sho�9�l .'pFju�r�g� ."QYa�f �T��aau;�\&lyg"���yk�%9a � e5Z�es�derD "�� m�ol��K �e��\J�� A#ur�^frame�ya~*ly*������*�j�� ple ��Sta`fvsJ9,!��. Nre.= Q& pb*��M�a��sr��Z��JG>M.�Z.�'d� ).��~ �tA�o��!�:�mo�0n/Q���ae����.�*m��h2� �ea���y��7��o5��3Z  . FuN5m� ,�� B� at H2OzY���PJ�+A̙c#A�su& ��q�OA�A!!2% P%L�"!\!V�0.� ����U�I�YrE���86� � �n%k�/�� A�YA B*�����4�QM$[[ver&� ��logQAold� �FskZ� K*&i .}, |9�M�% s�o 1/^2 ) | <U!�major� �);<( 70% , Fig 1 ( r>�0&�%m.�togB��Mn}�e2QV8Ia�%)d6*�"LE)(�49"�ZA�^%a�,-26wd�k|%��A�>&s trenIR.)v�usA���1a�g�f9��eshold�T{S1� S1 T!d[e~aՓ���,u�at�(5�b'P!�._in e: Atf3�)cFoe*ZD)�e� !OAt� %l1��Re�d� nguish��E �R17–21:��a 2o�-� %S�� ]iwoJ�!O�&YK24�6:��4ai����5a)�a�Im( ≤ �b��.��&i8�B"m�.�&��|a�bn0Y8  d%A�n,�' h�1�<3A�1 >z"�?�MB�6IcM. F�nM��7oELB�%/%��ma�)sc%�=�b I���^eppaRy!% � `q�&�!�q�s �@ 1!�"htyK�L�FBq�qui|�A�&7a"�BET *�{�=voO�g�&|Ra'�%�e%�� 2Oi�eT �a�Vg$Bowtie [23bt ^3m� @s -q -v 2 -a -m 9�B��rs�:&-uni�� � n��UKbui�Gg�Q�I�bE%i&;�&a.�on) ��.�o �5gg0%L5�to �J . E! �uAɆ���Seq\!�eir B-spa� ReA�_� gz)fAui9. S�3&���u% oK%.�v�=e(E �abJWe�ta&�6��Mb&�7=�A�A4V�)��m V $oachA�Lq !�o&i^g #e�� rR���E*M ��Gc��sR [9!�e4�/u�om���-9!%\,A}^EE��%�~�3-a��/$!Pv  �.a.�� �s��al��<(onveris ��/ BED  �c�.A�b�1��)!\�&�\ 86��S�&z� then� �7by 3"�! peaki;�(G'i�1A��.uni�U*�0"�![24�jk�mv8�l$er SPP [25&ir�no�slw� �#yZ''fDR-26]%�-��!�RmA�Cs6eakI ��J&� is p�^Q�vef$effeck ��e�iAe>>5=�=�E���A�66� ��� �c:3�>�Q�\x a���  0i�"��: T� s��a�S3�6� a de^�j�)&9s�C�<=:(\8A�of�&5Q�6�څ�Z� #o !�U�1cof�@ 0% (� �. devi)�of 13x�)!AN9� ��!%�AqFiwa 5�!\=H of 4b� �J��8�$:kTb� � g N��lih�� �� A�l�%*?W & - claj �o�r,�� f��q�|ˈ^��! ca�q��ReCtc�fO�a�ak E oYY�4n �of �k�rj5� ���(2R V +��#e���!'A� *$h�Hͧ�7ish%�.b ��ns:YdZ I�s ��-B� �� % !����!d^1u�6" 1320%� "E�%5�!�E����Be�^%Af�!�re `8par�bK1�l�KI\��J$S774nS�W \�&s9=to k�E�(a' �&"�!�Js e_ �;����rdM."@. �i�. SŠJ� 6aj��display&e��&� �.� circo #o�'�B.�by�|%~AEa�I�>s�q�$�-�sN�#yBo eluco�, 6gs$4I h.��ܡ 8�Oa�A�l� depi�V��:� spanE��%��!R�s 1:14NR88�00�{ 978�$chr1:20��07�70"17cR6iR!_- D6VA00A303 )t8V119x49*=�562ptM�#>1�rV��.4:g)Gs%A��sF@��&��iۈix )vir0 �9�&L�v��~m�y�F���n^/�1.*�&:-��"IA� traciC' l[6"M �'"Y,E�CsG�^��*�!�" .*� <� -�*-#.' "�A� ��v J �A%suc"fu�@-'� a}�a� o3��? moti�ESr���+���b�""l1�7!. ��E"�(!I�+!+554p����+a�P<) a�)a �tES9� pe.�mat06gw.>�Y� *sF 8fH"5%r�sdoe�ne!{�0imply� �)Z��2��� lx pp� *�bAdT8.�,50m�-)% iA�iu&�5e.aNm�� �!m z 6� RR�5�k=/� :*-� T.� �i��3/� �#6�ZlD�7a�:�A�-x"�a��<[k: leng ��+dja�.-b eR 6�eES/J6. O� l�i�}1� 7"�Zhha m ��Il�|a�ce���# �m-�Rk5k�ree�vE�wU2!kM9"i vic�ae�n3m�window aI�:��m�KIP(Mh%Na�to��hm�nFZ��iE�X�RnAj*�)YbWe"�W� g�4�r. w" b �g�(�  }W��arn ��� �5��->top�k�x�#eRA�ɥ' �( s �!�LV� ���uU4MEME s![�_�& "�(���@�2�5"o D:%!�i�� �� s Vo�o��wo� % Im�32D2Z:�O(� S4!��U2 On 8, 13%2�F��G,��]�]MF V2�$131�64ZqIe�*�2-AJ$)���,BC�_r��%�!�5 ��! �;�Aor� /> ��M�e"�"o�.$}:JwA �bM ~&]:i�Wilcox�7ank-sum LfaA-�:esN"001EY A�d�,t5!E�����T �~�i�Q�-�9�Gibbs-td P/ [22a�mR� �^eeLonut [6l��~re���n ubli�_rd.�we�\5��es%�A �&Y )ȁ��P:1 �aD. �a�.r,�& <�vx<�V�.,oug_��4iM�-i%��&R�{ U�� in9��PE�I��a�1 llow%�Y.Afoc?o�8i )%+i5a f��by ^D��!CB &1> ���Ő5�(X}onL nde"'b}��fngF�Z2�Z �es; ( ij������r-J) ,*"2�� .�z�.�s;%W*T��2 subs[8k �I�g �q� bqFy(NexcluT?�x��Com!��is�IT� (�%-����v|� �ed Bwa�8*$I.saP& ,�A%�;�5# s�% �ermeMvj &��A��u�%:J&6�e6�%9T9m`�(g*�"�-&:v�)z�$!-�> �[%&|9]t� 6��Em!U�E�Z�]as�12fw.I�qs�CW2"b �QfJ���s�+�8a#& H ��AfKi�glyp��  !TF� In >�Iz�, e�KUsf3J]B��Max ,=d�=�6\ �&�:R���:� "S �l4l�bt Nfe�e�C:jlap��bhTɣ֟emphas�B�O��7 {"-"��)�Notab�5)N3Ga� n)E�9Jpromo�GH XG� R�*�1]NaCy2b,�j�9 sticAH��"� l��r�zEVH� Q)�= ^��In��2���2c��["Fof1�Z�{J�H����H"J=q���AV��k�7d/( SC:&L:retro�po���<.i�V�LU�2at.YLTRs/Aee��n�'�a�RA[ (�h!�),)w�I-5!c+)s�Hb*XM��rs�6r.��. NZ%%��1d Pol2�� �:>m�� �%�J'%�p�%eof"];�Kin"w �*F&rf]>$s)��=s; DPM���!l&�/sc?��Du� R � 3818�$� Ag��50 �A�( 2957 8)�@�21� ��Ge�\wYa1�!+R/>��� *�5�*�A!"5�upsH�mɁUE�%�zbt5G re2Bg7�!��+g.�F�0 .�b�m�E } of 3�G52P�k� E��2�]aE>�L %.��� :2�!%~)o:0.�7CCL�a io;�ic&�j,���sz$-�#�+ex}#T$2A>�� ��� re 0707�p7>��1P B�I�i�B"�!at ��Ni�M" EBV-"JfB-#�(��� l�ET 9=mmort.�^Xtlb4zoidN �(s [31�)&(3�7.�WPn � a:� a s.g ����"0C.�)��" in -�O�!+8}c� 6Nen�teLnd���=�s�=Af U��Y:aving�  ).s ,[Q�.T ()N� mX�*�)$�[a&;)�,�go���V422&T�28�# �21A�4E�!�8�K45'aO40t$�119�,�crI�� �'ɻed�v�Y"�17"� r 3"5f6Y theyu c�lMݡ M�F(g��N\a�2 �� EE��B�I�%�A6�6� HE�A-^� ɨ1�%.=#? F#ayi"&R& r:��o ��~&"!Y� �i�Z��!�&���S25&�'5�h~=.L�2�*@H3k9ac , 27me� H3k4meP 3�r�[-2�?, + ]"� nchoA��[!��&i��a a�~`*� %�M�)� Peak�9(Zl����9pr Ѕ'X�m:4R6� �1in%�ra����der%���.K3O�n^!%fac��>/� H� ! z#lX.J��o*1�.|�� cYh�tJA*N�%y0oJ��Z>l ���!"&�lfen>FcO"�!�  �*� R.0mo ?}B�&q8dP&vo"�Pof>� %s f�4F5�.'D b �A 5q6r sI�f�Q�D � tch� E�A<�e �a�dent� as M%o� ��+�N&F2'�;7�k1%%�7&�8A�~D*� !�� Z( r%7Z� M1�N��=F=!�TheNX%��XBclaf��Chd'Ets Nr2cSin3a�w %�Tbp�.�Bcl� zMPol3rg�zbV%M6's4V�E� &�Ai��!(� �o�T��� aА�; R�%�1�^�x�br��2�=$ (5KPolr3�%c(5@n-9( � �J6y6z-1u)%�5�1%7""�� jM1�AU�]�I!E\]XhGheU�j`uW�]�1 m�&`1^Vs#�ف�aK ����o*сZ�"`#: =�b%aa"mWqf���.f,�s)f�2&e>�s"n�.2��v�C��|� ��n:3&�K atf5�9`#�*T�2!�� dO9To"� ��$ a�""���� n$��P;�yb�Yro6@f�(�.2kU 3(E(�%�b�&� !j$��fK4!2>V@�ake�20-*:i�&�}�"%��=Wm� )� M4:Z��:i4W*'sz�g/ �.{2f6;-��u�2J� �G�5c(e@m!! bKINS2�-z"�: �c F�CQGn�q�l~$ca�) ���%�7�kd�i. 7�x7��%� 2�(80��90�A 1!6A2CY�*�MA-�b� *��m�.�q�c�\1� �GZbtb33e�J:="nd Srfōa6*l���� ��F �%Y&oMb�5�"?ed%M� �loF22��!�N� flan�=�Yi7>��8!@.� HVes"%�[ �A ��:e"�$> yZ>� 6YV��)��&�"STj;����%�-=6Y"two}B_@w�_ok�jyց���g=�c iEL � !!�Z 8�e�V�P�k [32] '�/E'y_ pre-�-��.7=� UCSC7QBrowse�8A a�-6Ba��!� F2[%ns���-�vzs6x�$X��7emppAcZumu/�v�C�"H;��e�24my�0k Ad patL����J�6����:�^�Q��m5):� �� S4� & S5 ��A6�&( tf)  MB*�(�4e�`H3(Spi� Srf� b��Az*�('�,� 2 Rt��� B)��6 ���[�"�2$(��ѵY' t!�105�%o��m_Benja��-Hocberg 5�+!�"�;F�;��� [33] _��6��E!.��� ���t�i�y� � "}-&�( * �% )qQmDF az_"��FTm� ?A$6��$ofq1"�Oa�!\a �- �2�}5JO� aG� %�N� ) m�"f u"�Mv.kL!����[o�� Pears�N �$>Am818 � yNf�a�6�+9""6! ��("A�?�d<��)� A�eQ�f"s=,�2�0 bQ�xJ�6Y��_� 2%q8�~5�������d�!QAA#5�f"�"T��,� ))56��J/�.�1,y�6E�!�*�A:Q �E�1Zn,-�--�. O� f�� �a�D,��"�dl�c�99PB��s"�4pas��{F��eSut-of�?J��05�,PP�e!F!�i�o.kjl� cr��. N����Ma�:9��!�% � *� y-)F%*� " v *JQ�.)�um�on"�E��AJ�R�:� -n"D�R����t>)�A�1�!.�Iin��Z�!(2qW�Dq(2 ui"�mepZ����<:[>on�mC4���e:�Adj6OQ�6��2F1~91w�6���4A6e`bl� ���Fw�&)�:�s.�U_vZ� �F ��12�6�:�Em2[�LFN �bi�ll�%-Zo!6A'is _�mI@�toV0y CGC�{��r0 E dx��, TCCTGCNA [3ʷ� F5 �UAQ_fm��r���&�+ v�o���c A�=���s� �!a� “G���V�iP"���F�m!celer+"�)�a &�?�� q��_���Aä�d��Q�:e&Z-,,ve1c dy�e�5�) is lVW k“!%!�&?B1�rai�@�.�ofU�Ӕ ;e�un]Lor*g?��-"�x3 ��f] �MG��, M1'tE�AB5t� �Z*RܘRe�$eK��r ulph�"S�4i� RRBSd']J�  "3h"�-�fs= Mr2�%K"�,�><)��!F(�A� D8�i9��5s��o�J�7"'g+Oe/ �$Z�E��1 . W :�>�$-�I1 ( V,�.,>�Egr,Ep�:��qW)&)�+$!�11 O!NkG\L!JV!36Va!�k!>79m"�!9 <4k20me� I�&ZQem��/-g �F>/a�vGO)�rE�s�-)KpE 2 %> %@$SS�QJ 6�DlI�A0l3a�1\Y�� M<���orTF� �i�? vari�h1��I�\ H3k2!� !Z�HW2�g�4Žtru�?�uy� �zja�E�.77��*m�7�P�3aJkm$a��KU@�L� ���EU��-��5&�K+!�DkL z �"��\o�Z' i�|D"�^o* 6�?�R2C;ech\�B���21.(%[E�:s]\( 9L��jL��|!(��8)�.b(�K)) 2%��7��K�.�"taBb��-�&+�,%gZ�  nd H�%��^�q ]�2Z;.x ��&���3��Aea�/ � ��9"�!lF�.�&� �tcfUd9��An.@EQ�F�Z� {�_Ie�.�O%I9-$-9*fF@ ��f� �WB&�/�1�&�i�t�[ e�~�`w �%��n� , �a&�>��!A1�#94M�Q�*!�.�( upp�(B�gn�1:�eK��ev"�s�d �-* L5"� "-f3+Q�;xAK�B� is 3� 1/(��%�%1x+� �VeH� ��K�"�F.�eQ\al�(�B�e���Dbqe�/A] �Gs6'�E�.7i�rS2��"gT��KN��*b�=��(*�*9 {Q�*A I�A{J�KtwoV�*U��"�K�Nw.�1s.�jLgu1�9+�K!�2C��KV( yK 82&640856–95�-42ychr7:����"L70 o7 L57*57�Yz�lt�I�� by5� ���e�&,K&�K�% :�f�!�}gl�X�Ig!U��r��!�iT��O i:5!�, h# ,&��0�Kq�_� ac� cW!�M� t��trr&% �/who�L,�nB1�l�}F ]r�ja&h'�P*�KY6i�in dyna(s&�' �7�,� f; %O oryQN.*ELݣ!.�`i ��6�2Und1�FFL-� "�6 �U�" )"x�#=M&�L4>sGI\strong�%�q��$Y �(�!�3��0�}�M�g+�9>���*vW�  hej�U_�)bI� ��G%1Y al����=(BEpAM�m06�Y�[A��o�s� &�:21�15O+ 6i)�y��left VAG2( ��!>�k�{�26-�#R:�Vis�%lyS*L)���l*L���,(%)2f� ����9i�*N. UndehD��!�{m�bT/r/l ��qremaiSD e�� =�n� iphe�X{h��> ��cod0w�(xp!�6cap�pt�K"{ .Yd$��*�Q�y4e�Ep q�Fd &�D�mqod nam=;�E�ca��li�X2n`�Q"�� _ 7�YB�^�'M � �(*� &�N�e�(C�<&� -�sam��ad25^�� S@iО�p2���6h54l�CDfigt&�depOHEA"�x@�BA�>�p~� �lCoKJ"�Nf��%�q6i,�1+6'��pA�%g �bap�&��A��EJ��d79,do��@2�\$b,^R�?���"!�&:i$:�iz��rpa��FE3me:?42V!&�J�!�22���*�=�A! {:D. BOHgmg6��I?��ze��]dAA�e�"<ga8L�88�Rt���*_�p�w)���6�B�" H.�6�*�ed[��1ZC ugF.bssu_�E��;� ��8W :a�k!U��A��0b4!� !P_b�e�e�+T&BzM��|'onshi�2�w42'",f�!q`�P!�a�V�a& 2�W- �����, KRAB-a&x �)eH��aɁ!inRv�E*?f �χch&S � q�-=��7"9 v�I�!8blot& �����a'?�,%{.uA�%�E.ѯA x:�ga�n�>orb�oA�&� U��l��[�N�2�A:��~�"(| �� V/" A�2��R�S&����e U� tngr"� B�1Bg�6`,!Xld H<di�A�D��� ��)�gad u5,�ialF�2� as���!C�A0eJN9  �a��.pЁt!�9�mr,�..�v&���d�.� tou!�E?=�4n�sampl 'e!��' modek�!�g(�Px_�ly 61M; ���y v, 63M�@49 �eW:�P,�U�)�=�e�r2Nw5,n��� �( �as illu�j@A�13F�2u"��w� ��e*�!�Y�o �� qu/h9Y� Ť"i1ˈ20M� |Xr^ɈA�hw�umIq*�0�g"�P!vF�!�TF��e�!H��a�!�O&�nH�also bE C�J�.d�=.\.\�t!�duB%X T�f[s��2oiC��"mh)#"��Hat https://github .a /k�� lab/��8X. ��X;p�C� �4oI�%< !zV�m*>�# e/.T�a?UU� ��)2�v!�!x6lWb�O*n!6! �@rayOQC����s�5�fe�>t�-��;�!�ig� |�L1 ��]Z ��t�3a�l y!5:ͨa&�q"�k�K� �R �ir��&� :A���c �D m���*�0�}�2� �. Let NA��A �.$9>��� nd MF<�ic�Z g i = � … , N �=y� x%�yj2-�٫ QZR ( ZiVZi�Ib V.���٠A�e i-tho$ik�d�j/��} n Zi �! Zij′ =g�A�≠ j)�2 A�t {Zi%^2}� ! p�X6�s"��E�par>q vec� π = ( π9π!. H� ,"a�h�I�y&^!� ���1��*E�, P%�)) = π��!Dv�<ft, Z��rZ@�r7�� �s0}�- x�Re�a&p �o�"�@B��.,t%Yhidden�Kdom blC9A�t� A�n��U �e� �)as YI~Y]~YE~)KY-if6W]� 6So�"HoP�nd C0_wi�N�a�f!.Q�∑mBM Y i .F>���k"FtU�sI]k >e�� N[k�orR��� .8Z�D��AfL!P{j:mT}��A�a�;l�E� i+ i"n�]A�P[�Yi ∣ UjD��P  a��A�∏-$M ( h�π9#A�� ��pe|��.kLiaY&�QA��!�h�A8¿�>�E�a#� *�w�2toŅ �H�!k��O%: f D�. ; γ% Γ ( + )2!U.7%/γ j -E-( �%i 4�ˍqGam��uM�,8+ =2$K .;g�6; ��w��f��)cte}�Sj 6j ≥SM� e pseud5=u����Zov�on 4AM�?�� , M�et γ Sj +�Ce�)0k[�Ww&)+� �x �M�ci�T( ��� e8stU � J"gyhab� h � �� �(m�]B^ z�A�A9E�Sj> 3^�i��xj via:s*(z{E�vs: S je�x�� [ β 0 +1 S�n ) Q^!�%�P�(:�ItS��Mta��!Bpiece-�N�4ar��c�0M�J β1�=aA!��&�=O.K x�vx�x!�.��� rewrW+EOa'o���!hon x as6�� 0 , �β 1 , ∣ x ) = Γ { M + ∑ j = 1 M exp [ β 0 + 3HS P ( x j ) ] } ∏.C1 +�7 π j�3�R. ( 3 ) When incorporating multiple histones ChIP-seq datasets , we first convert h .� read counts into trinary enrichment indicators indic y|low , median , and strong signal�engths . Specifically , for a given� >�@ , positions with2��smaller than 90-th percentile of the overall � distribuW< are set as non- �ed ( 0 )��9:�but largb�z$moderately.�1�!Uj.c�B�g�D2 ) . Unlike DNaseE/4which measuresQextAof chrom!�0 accessibilit!�hMJ5�id!�fies reg%�exhibiE�/modE!�A� i . e . ,y,true underlyA�stateA� aBqexperiI�s Y,ed versus un ked!�lopposed to a continuous scalTheaalusion�aQe>�,group is dueL!~ factA�ei�-Ez only peak�n genA� ,1aLerq8ellT �c-&AW0their average2 8 profiles match �osecommon �(that can be9�8d by both uni- Az�[�s!;illust! �� ��nd IDRy�s adop�by/ mM2;K:to%h02e�i��sulAin�Woptimal yA�),relax�?eak �Ef�RorBl��!i�U�iej ��C���QTF!�\�Szs!b�"toZcJ�.�-��includA4�|�l�m��P! ��noj �2� �m� . To��)�!�ofd.��(extremely u ly�6 UcFu� ��!?$2�C nopt-_p tota��5AaakA�Ntop .-��&we5�01P-ex�veq! �$ subs -J35� .%#�'!� part 2s' I��A5)�$. SequenceM�is 8Q�a,uN�M38d de novo motif� d!%L�DMEME Suite [28] us± 50 bpwsummi�)N00�!DForiZ�A/%�"� dg%� �s ( M1!� M5 )� st E-��( . S15A�S1 j T� � r4-��s)u scan�`�fimo tooE2:� � default p � cut-offe 1e-4e�(occurr!�%(�%q�Y in s-�s spann-e19f> �%o5[! % g"deg� cy�4 gy from^/ we/ �KaM�O���c� -�ZsF ��*� reporca�hmD�er SPP�l��A2U���2�%�)>�min�nArird qua2�:>�b��� manub�/r- mostPp nt)�I�)Y���%�f�S-�a –e %�!+Z�F.y. I M1Pm :|m��])-:Jn�oM0conside� canonical )a�asa7ian0in literature��z).��� �B�� :sKRneith e�no�e>�9QBY��= !vamj M-�-MJ!I��J�� 5�in5 e!>�Siaۍ�5�)q pairE or�U:� I�Y rrespo�� L5j��TFw2�! long�a sub-Y�� high�� similar��2� flan�baV -[Wto =�fulM^ l�-�u]� te" �rdidE셻 betwee�tif-�R�of���� was��cul�: [42]%A�iso�H>�n Y)( e� CSEM%+� -Z� ,pr&� .�� 9IzB z � be�Z�}he"� libr� siz�20��to� aggregI�"�.��8genomic coordin!~ arou�we:20 W-�i,����&��9i�151window ���te��mocJ� . Each�%�t9normali!7 to 1 mill!p �A�!6�a�[ �et:�9 -wisz5 B plo��g��&pSegvis , ckage%8ttps://github .Ae$/keleslab/ 1 �V algorithm� imp�A anam rmseq�is fre� avail��Cv�p C��rawE�]� �TOs S9 , 6�S11��� � |�"$or� !�UCSC GA�e Browse�6�0://hgdownload!6%� ucsc pdu/goldenpath/hg19/encodeDCC/%N�,U ul� ra>1at fteftp^ . wi] pub/users)�� b2-!*�-AB$s/ .�XSc�somia�(affects 218U�peo� worldwide` ��in1 in AfricaEr8 �  stud8sug��� TH�nic s:�may havg�l riska�(HIV-1 acquiKI@m��Ak��Tontrol 2 replw o� �e!�$We hypothe��� at: (�pre-exis����ec� �increas%e odd� V�%AIe-o@differ�-me �wo I�(��vidual��c�V�M�tim�rF�|%g5Bimmun��)>of 6,M���in �~r viral A�ss g sero�z� conduc!v a ne�c�1�A/y� i���v pop�� ion-�d surve� jtransmish$in TanzaniA�A>�adeY�se�villages�� ��sHIVL(2007 , 2010-� 2013Eudr�blood sp�darchivedFfu� �aE�8participants’! sent��xim= 40%��9 has y�a$ soni I��II02% +4 . haematobium)��.9� genQ A�pre9post-%m-:�.�ofu�hoi�a�8 x also}::. e�Eys DK e�re K�#ca" �eseZa�� %lމ�(would becom N-)8zmpd oTseF�. A�� =lge� �� ed 73 �98term�265!�����We�:��js had0��u�%#�thaq �N$out ( adjuerOR = �8 [!�<2–6 . 6] , p =� 019ŔYje9*��1��>a��dj�>�J 7 [ 3–�8.�4�We addiA�6 IZ RNA levelY�A�9q�.oin ;$9�>3vt2OA� becaMFUDin� �+befvaSretro�$8apyE>�Oly*v�d��whole �:�715 v�]P��Hly��EA �22UE:@: 4 . 4 [3 . 9–D6] log10 copies/mL1B&7 -As-3.�017q=nfirmI�� a� ab� ��ma���s��i��sj�in�u�erai.)q)�����u6W9wEp� is� +7��demon�>2 a�9c.�oU�uscept�� ��B��toR�� as��Validj �ɠll;n�at}y si�. ��Tm��a�~c+ mݍ��� by�T�� m� d� sh wa�. Over 9��eSld��.� R+s!�� [1] ..�O ms lM�$human hostfpelvic%^ga#in�2ibvenule� d daily l� undre� egg�ig^!�AurogeniL !�B[mucos�Th�~Hcau��a� flam�D phys braR!l 2E�L=,-i� ��ha^a_��e � o al!�! sFq^" ��[�3!w0Three cross-s0 � .� �Zimbabwe�U}%� �_p&^ ��yu�EbY�a2 [4 , 5]�.I[6]K. In ouruin MwZ  ,&b ,�. p:k 9�fN�4�"re �#"��d�H��� [��9�iwi�$2�qsixJp�6)�A(epidemiolog� -�A&� 5Y��A�AdE�ofy.c !�! ��mefem�#qtr� I�i>�ulcer��NebG6� o��$��%C�,entry follow� sexualY$o % [7–9!Gm�le��ikb#in�[��1�LMacaquZ�6�R$:Tto�!i!�Ѭ-1���Ł.�� ho!�� Iy� �q !LQP21V�E rectw ino~D`(gressively- �!mdo�6of�aŻ ( sR 56�Vzd� op� yst��@ ځd��j 17M�lou%e;m)� �N>[12!�()���Y u%/y���f 10�28 weeks��-3.V�& , 14A+ Agai�!sP � � o(s��EY��#)1ed-�� nAit - theyit)]5ly1�In���emi��(6L 8 days � acut.[15�s�� Esp�+���a�-� ,�i#duGty)p# A� equi�k�I� viru�lea ;st�D�- Q�h in 6-� �Se s(yZ �@ord^,of magnitude�.;�^�y� ��$tic��fac� �w)�+[1�Q Eleve�s��� ed-neO��mrapid�Zon; AIDS#death [1�18!� Our goal A|� �(m%whe�PV�s6� ɋJaI" �łRZB W� r &N�� ongo��p� northwest&� �|F��@cjsto� proae�   ��&�2�2�2�2�2�� a�Ik>K �!projectE��(�0by Bugando Me�0l C �N� 8BREC/001/04/201�/�Nq al EthU (Review BoarD0 Dar Ialaam6 DNIMR/HQ/R8 . a/Vol�X/131�1�5We_Cornell �a�<( New York , USA�r10801188=. Writt)2�� o3a� obta� � tudy�tc }3&�!2o�!A agedB�7 yea�ass�)e�"or6v. SFs�p�� {oraEa�ofB� sa<�accorda� � 9��d�0 �K�a cohort}�0� D:�b�m�U" ymou�h��M(nk�omT7  1r�Si�199RAC �E QOI�2�� seriY ��n�!%��� mee/�!6Q mWA� Magu D3c�J[20�;� BI5 area���)s�Rn&�, (ear Lake Vi�idCI��adoles�3#qQ`�abovenE!boI� every 3M�Key5 e�* voluntO � �4s,gb!@�E4same-da@Vn�/i! �uc�itera�!�>:Eނ�)Uf����� -i)pe3�AQTAZAMA P��uc�n_ ��Instit� !R� Rese�A#�%Q ?(q,u .�)a�/A�6�F+collec%�*.�h�M\M�dur!���-I�)Z_. Sociographic���]!��2) r )�"1� � E�of& , ~_M�hlV�A0Mve".�� � [6'�12Z>o� V,[} one-t ( �e�] h5 �"�(rea!Gprazib(el treat[/>e pasg/vem@ ��D!݅�"  "0Stata/IC 14 ( Cor� Texa�E���BO8v�3-{describ��s��4! !>��5n7�s [orqu( le r���PrX�"gby Chi-s5e�0Fisher’s exi��f(by Wilcoxonck-sum &. I"�3�461�iz��un)��6I�re���54 o)�@.MEm$A�t8-��1Qf1��701.�"� [>�10 �6�406newly7>�(-" .� okF�r.k !oA��37a}�H� v!%2"3>"5vr� mly se.<)�+� :_ . On;� �a�R��lc+acc���m\lab�;ory .���%��to:�!�1>�at�'� ���&!$J!�.e,t*'14e^rol55@a�369!q2^ yiel�a "�07R)����]ra��. Co)qA�am�A35R��R5X3]��J34v-4-�"pS�A�a�5ri�61b!!qF, 45/7q e�( 162/�� �%�"7.E�A}�f"!�vX"M9��� ,�aA�g%4!�18 ��:B!comuZ�k!ohaVer�$c&�$& �^!�nk)v"�#A7�>� ,�C show�S' �In�$#/4Z�( 44% )%�.&�@�?RP<Voy!��!48/162S�N� ( 30w(8-�"6��mar��<uI�painful �� !�E7M "�&*O�!T!-fold ��!in�J�x(�  `6�2c(2�!95% CI�� .Nb�!In�, 8/28 �:" ( 29!'a�R���39/10� ( 38a,��!z�!�z�a�-� �U��3!�#4a�� *5&6"&�A�we,?d2CAAq�F�~372_ձdiagno�lE?A�.�i��!T��Yq!Era�15%�. FiftW qseaT1!Uf�� r Vno *�!*�� ba? e c:B�&�"��b�� F79�*i3���l� ����A�(of 39^�3|"0] month�;{# Z�:vO [��a.&#, !�lC)�A>��A^1Z�!)2N��e��!�i�;t-�:�e#Fe#� �� �;� '(t�$�on( a backwh�"� �an eli�!cr�3ia!�p>A�0�I-!>2'a�(M!�&f%5Bk, "�'T'n�6B?6�4��A�r�&(%�5.��/�24��O=on��d�,�$D)V�![g��5anR��Fpe*2�(V�. Two���>,�%��1 < 40.�&ryCo_em��k*�;��)��7r9Urem�b !�a~*�.�� �G:��>m!.J6F�E�!�1� !�Ѕ�.c3<*O�����"2 Xe�2�w#�+e]Aegn�8 3e�. By3 Z!�de�%�3 6�prior[ >�����!b.:GirBD�%�> 4M+y��{��'M>9CA� *%e>�of �b�6?I�� & �")a%�6L"*< . 6�. 200 �4�&m .r!�e�'�8 untr� AQKr5 ��$�aR~6miXsE .cow[�3� )~�2!Ua�@#:�1!ist"� Pr�I�tJ!p�'a��(r"U,B�dis2pr1#o%oF . �,� -1*++� .� , ur�0l,;� of� ausa4Kl ship�.C�t�d@@� .� "& . Mu�L!g!�al�6y supa:��*)Bpa+*e@&"�(damag~0**)q"%wbq7 4�%, :��V� . Autopsy�M �9�&�&�GUbK<�"���tr_,�ti!%rlJ# heavi%aمF�ա-!dEQi�  =�;R% s'8 uB1* {aIa* /taughRIL& a�eeoof2�w�5mi�D�=8/1U/ EgypO955%P) bodyD4�,%��J5�=�*%24%2&B\[3�"���Ag.<*� �*a�mG![ hal6A�#�bi!�-ca.ed2����< x�no+= ova o!��vis�FJ(-�F�>tissue [�!2!� �tf1@%= )3l |$AD�1��Hkn�? �,F6%'�&)(��:". Plau � mechanismA� �#6�R�,�)�-a recruit��+�u�. le i e cells`,O 3w#�3 ldi�9P�Tz+f��ng!8as�%����!i�-}�eN�7�+D1Y�6 �iYOto�ta�8.(�*�(W�a%�>zU�e"V)�:�I�YN�P �n�.ng!�derMH�Zd�N ti]j�(*�e�M�6�* ��  ��� ��F�A To�ry orga�v Ze�!�.�y� C�G =4aӥ�est burd�6of υ�"e�Mvagin�-�ute�&[1[�%3e�}>nu�7Q*;M,�'�9&5 ��J��q�.��*�Fegg�(M .9Y�t =-!)Q[3eK7bB�MAE�*� %;�:���~EE2of) ��%`�� !9seNl vesicls1�%�--��9]—�]r�[-ZeILaex&Rc@iA�+��/ 3�fe expl�)why_8Q A�y� U|$a&�nou�> 7Ft �9�.\[��ei {�rm��act!�)�A��exa3&(2�by�. Fur�,�z� ��E����0�1P �U�( 75%� 2� � �����t �>a�f47-.q&�� prot� a�+sZ`�e�#[� R|ylA�o a�7� ���6^ A����>�. A�f�%UI�Of equa~5� �&*< doub�iW %�v5$T2N.+ .jA: ;A���ccele�" � to sympto�4c�*or�*by��#[431�!��� �3�P�at>5isQ #AC h�5�mic�i:���,N/ e�?%��+ JR@ �r*R@ . It�Ej� ��% Cochran�/^$y �Y�(of helminthY�s %,^��de)_�Rb[@F . Mo�3�CI.�8!���us shift%")IEmwa��:)"(cytolytic T�p)CT�T� &e.Atoe,s a Th2-pred������0promp%>�6tim'!< Gnt!�u�+[40!�(A5��� a��)& ��,"�-%R|�by �� E."�7[4��4� In��)�^!�So�(�up��,mRsigF�;s �"$�u35"l,IxB  �5�a&�9*��W�[45!South"��s2��& e��8��OAki�\"!=d"�/aFH �.� cA�0_ &d/%�ţR8�&�.�:�%��Y&�ay�7ls+9G1UA�a,E�} ��y.A � 2b T��s]�s��Vn��orta0yBquq?�LnRit2ep45o ans>5,��<0u 2 �on��)�:�Q .z<�Yich�lf{�4c�)vQ/)S� *o�touZ-r� �xingle�2młE�d� tW7 refn$?� �\R,���DmajIwr� �9)%i&o:�"H�A�3;-�0&�(lW�%�ideal�� T� {N��btwo se�tee)��c"�)�3��24�bu��\[1�2ecAc�* �:�]��H %vix4"9$of 13.�4 M��C��' 1%i�!�/nti�%/�!�.d�da�=d�4� :�)�t8be dit��,NL���*� ly�8d�5� i�V� jeNa\nE �% $� yetI�(aEa nadir� �C�GiGw� �(!Z!*�e vakC��, $6 �"|0(�� n 1 m>37T:A) ��r>>�_aB]�-8�w�Mxdeed ,�7!�2l \}�SuBS� �.��& T0k!��PA�rFD� � E>!c�"�=wG>mi�+ "(*o�!�.s��)!) a(tN��QN^�De-A�-9pre,�|2�wCD4+ T-���2<Vs/μLA���edbRh���2�9of eL� �!�:a�t-A�um [2 2�17E��'!$hp|m�-� �.��/Epi,}"�r�aZ��#[ ���u2z&W *�Ҷ�A�Y>sz1F�, a�E�K�^y� �^�*�Q� �Rd&�:AD�\ RrZ*:��2�.�asen2(/� 3 &V ��h%�T.�s)E��N�!�Z�2�h��d%�*`s�F8 & ��robustn�_of�D�2Be�e CAA��!KsZot ginguis&�T��;%,w�V4ete;:a�cer�ty" �.�,�,a� ����Fi�s ��TIj$ main�=fE�!���drśby�%+h*$�*J�Bi� k� seemAfM��hq�`�PwCkN�&vW' M��c�+!1 is 20e s �"$.B͇&�: . D�!�3��YN ,&[ �t%�!u)'&�J45m2RR8 lackb��_��*� *�.^��q'relOon�2�@G� �� �5�A�A��W��Ey!j%� ` 04 , behavio>��d�-;3*"Ded usA� 4Rat�=st�0!saC�),o��1 *��We�'un� GA~M A"��,aClu,Wuc*J' bancrofti"B !� ��X!� ��&hA~.�'^�er�-BQ[4IA�e�WrY8inY82,�gwSrkw i�;��ntl�c�  B$ss drug adB]{.on% .N(of W .=is�Kro@�#��l}�[4�\i� i12-?�Ia�w�;�! y3BKo� t�9%j�iEvt|&�\��[9|��o��.�&� ACI'#jF 2� F�FGU��iQsM��.�Dm� �L�yI��s���� *O �. P.�6L!F� n� haf��=��a 9=.�[8^�mA:�zMO�!1rnu�] 2�.j�%��*(:�e.{t�!�W��M .�! younn.R[4<R����2�{2�!u��1Z�7on5� Ru;is��A�Z$�R� �E�s�fwarran�DZ���%�Z�>�E+!B&�U!rsa� c. %.��Rib�Xal DNA�� ��hval4Qao%J�P���h:@Xpy>. Desp�d!�im?��ruA�� ula�>n3&i���a#t�a noth!kabaw��g�p�ts(v,� ͛k%i��mPl�;�\e��ch&q�Ms6�l�i!]"� �ap H[Umpu al(dr�Y0 g 3PCR.9j�ok ) c=:�!�q canc�n�%�)�mc ǁ�WeE�I|.R-5a�n"ga�_EC>(erintu���r t �,� a�7eY�)!vcP4n�  loba�9�co-E`��A1����be�*�"I�2��5)!�E������m9�ev|8I� mTOR�"e��� �(PTEN phosphloa$a tumor��/�*A�is&�(A� �]�!�a&�1regP&g�kin�Z��. SurN7Z�y"�(sub�A�R�, h�X poie'-5 stemeus� a Pten-/-MLm80� leuk�H%>)Pe�.Xtu_�>,�ϡ* q s . Repet�[�>�2Y&M�/. r2()��utelome�t)�hr2!�eE%a ound�)��t f��D; �sta��[�#s=tM Whil)5ld��LaJ��%ɲ��?ip�%r*Q3%� �`8e�al���!+-U �ayerGAw?ed�5c �m�S �!r _m�,�?i6  �a e�e"pt�=e*olymer�I^!xOs �%(he,l���� �)��o�L ac�qn| � m��; 5� �#� � ��� �!�a� efer; � s 45�i�@mp#� %*" RNAs49 8S , 5 .  !r18S�2��A!i- !5S����+q �� � 1V.�byR.mI1o&55Sa��correoO�[�� loci�t)�= ��)�.y4/c�b7��%�6 of�HA��D!�k)uch8&�W%!�Q Lwr�|ng��,!�mee� � m!b��U���. E�sonh'� 5s�QF�a .�v(ism�}*Q�i= s [5�5�� r�Q��g�ng"�14�>""[A�6�L�<g bw comb�Iw:3U5DOc��"k�Ea patt�uni�Tini9� �- 4a-)4�ly���Xc a��7ssA�10%'�k�:R�d[ A�"X m�{)��A+"�iTlOZ����PumaA�tigQ�of:�]�EQcd�CeWH��[��� �(2��=�bhm}�"(ail tandem C g^$, palindro�\RC 6@�:, e'�si?q�&�%�ic inݩ��B� im�*a�a�R�hWr��L�� chiefem��ab' |�Bis&�(kxpa���M�!b��"] �*dm����b�a2�biAae{[EIn�1i`��.�x !3�J."y� �3�ex� E��*<\ frog oocy��[10] �m��nucleue�(tetrahymena�*]��pa"ksy cou�A re.� elp V�-=e.�F�=Iun�t%]�R}:�%rcb�]� �%�4 {vA� yN&v!0Q�!nb-p6�!��r�d*Ho�:�pa��9y�5��Fw%mB.,�2�� 8c� sinHon�j�7.��)n ��U/asa�|nd adapY�Nst�!�6S�6�$!|its"e9NXz y! many�ora-.&� ��� ��~AB�&�A�,&S PL gani�ltit�� hI�f#X�$1N*�W�h�8olY�a!� ���'a �oA��Y���,��-na1P�o�hC�2 al do�X4� �$� >���[1�?GR, igh%F5��`n�1ize�Dra �wF duc!=X:RiJ does��co`r1e�A�? �'A a%s� "� �'_�mve�^ome�s �ed “� ens�”�� ���2�6��z��tr�,�D_� �,F�a .���bobIO #6�[�O6�.CC �-I�e^űdc �I�<��M�8�I�A��LE,u��1>���ar!1po�86�6>e]�,ae�&� ~f>�m ^ necessari� ?AMr)2# . R� techn��M�! �& �t�1a*v�p}��new=�a�w, alyze howI�.U� &� 7��"��6�e.Mu�F�2.��.�� ovi��"�t� .X-�L2 \a n��+�b) � �/v�Bco-� r!�&� .[�!�a%opA����� tidee� �-��. U.�� *jdeb#M�$��(Jj&�#lo�� B�!��om� A�zkor%t6�,��<��L sek&z � �+�j!��?en�8!f�5e^-a&� �6��C biomarker���di� �'hTaP.#�&*'5} .�(�H,�J,}���o�!�l��5SU!I]Q �\�.�Ao�'QT(m��� {ioP[e uE~� 2��6ach�K��M:��.͇l&�S!� wild6,�aZ a 10�OHV)�*/!i of 3u}289H�5S�n2245�#" eL��Ag"[b�"velop ~��m��bdi5ly�R%O.c�J�)b �őɣc`B�ly�b= F#R'@�!�inb��C57BL/6�DBA/2J� a>ut- CD-gP.� �"9  .���is�@�� metabolic� �b(. Mitochondw#� ( mt)2bUp�%w)/ in��� *�DEJ�1'esmc� @t�fl0\-N�d�ˆS31N�! }$m.��1�,�� �<%�m�i!&( g)iTfi>P)��>gaGperh`I��K aq'de� O+G �A5.�ofE�Ma�3 (gene Gapdh1�|:eI~(!��on�0 fluoK.�~"H �b�}2�a�Q��156�Pdl57- �Ix�e� �H(� ndard3 �Ts|2.Y)�mBf23f�'�:bH�RBg4�N�N,R2 as 2��5dq � �vA�ˑ&�Kq(<%�:7te�ʑ9 jm�E�� ach�)t_ .�`!�G%;i��6�9*i�k���,I$F� ��2A,Nex�N�+�ed\ .�rᮉs�a��W��9SadF�sa�A2��(�oco�w�"oyd��5s4w t16%���i�?X�����2��-��! s us�%�o%�5%�^22IiUB �U�z���[�pA��es�/rxof �e�M��.F�i}9upAI15%u")�AA%,Y[aA�A���S��� %3tr��ZM��Q?1��e2;4 �'15ā�:A. F b� �Ab͟�*]} � �����.�in%Z/o1� �mirro�byAivaCX#��.N,��cI? O� EP)�ͯ=�SS)ow�  �� . &@7InA t fj��"v�d1�m��%�o�!g�4"Xof�*m)��'� 6�P ��Be D*� �Q2� � �at� $coǖ! }7[1R��%[-3m���E|�[9�s"ss��@ typ%&� 19 childh� olymphob�9c&E&�r( ALL�hs00034a[�5 , 36*4ull >oma6 040�R[2# 16�!e-b�ng# �myeloidN�CBF-AM�41"U,�aG ic n��asmF�47 ) [l;,An-re�� �J�53%�12�9�MJeLiver/S�3 bowe�� �57 �7!,13 osteosarcNp69 -�}�� 14 e�ag�<ae�carcinN>598��IoY2�2=e��� , soli ?�*� �4gw (& E�� A�ls"�� >���U�2� �<43�Av4s�Aw42TjGTEО�fa &ωc B-1�$ ons:� �1�re�en�+|�5)!y �eA�iq �!G&p>.� P�q�to����e���"�,CgX.�1of ~1$��ex1F6pZ�a��qny ��0pai�Aelp�3off&��!nWga/�g aneupazH_�/��s m skew��!�see M>i�<��� o1 veri��bio"��cs /��� u,"�2}; �)�@ �&� eo g[ !D"| ��.A�4 g� !50�c&&i!�u�&:�&�&e!__A� ѵ� �D�B��(E)7�n� ca2у���!m�!{E��&� .;ah�'2�'�!(UCA�sub�' q5� y��c�/�S5x�.�=�)�2w���pa�28,Z�{f2,�g"$[G�/ d,�n�9�,Y*( ~702{�ZXY.e-UB–2Dihe* �& )��D�/.�& ( S3En[� �K!iMK�Z�&uvDno 2w��;ark}N?ita��i&�#I  $ ]0;E.1� +� j �hU%)���:isȠic ;�C? �[%��be��!���tach� &�%r�22!� /� 6uan*�)�;nst�&�EA^ asa3of S64)E�a"e6�I��&� ,�ici��!F6oK�C"u��%;�&���%�-JA4&�is�"�#-N.�E@�B� ց+or��� "#� sc~)�`w��&ma�� a2�wA .%�E�(_ ,3 �{n�T$re��A�1��  �)�._UI�i��s�r��XD���G=ikas+")V�l��-z1}�o�I�dG,a�oG3rGb%�&H@2S !&pGstIpf�r r )A�"�g�+,45�;+l" ��a��� "���U%!�a"b *��"� �"��9H��6��� ��,Vo-��# ���S4A�=!f"+�Hng* 8 A�& .*v'�.�Y�Aj�iEte�er�N�� "��5"�Fa5E��� S ]$ �@"!f67( S4B �Q]�5Py�p�/i'"-�z.�W<��F}NY��$¦�:�*-�c��O �!�!r�'tR@yur�Q(a7" %���vkEj��.��A emr} .!YID��t�sEm i}"�w� ._ c�!J̓lp+u��Edispla w6 *� ce&{1�/� AB "i?�j�iRu ! � *e�!% 6�_DR<f05�fj� 61_ 9Ir�!��7 � ��)�,]9�i<A'e�B353 s��Xa\Bjer?B�\c��<9g!�f8t� 9eݍ��5nd��.�( vU�e)� �“q�P%u�>� “q�2-e�j �� l�&���<� ~100 �3� L�o�~sp�`>A.�&���B���.(%*4*�3�a�N:.ӃdC�9"u��%�h�Jd%E�&�  � 2E* r��GE�ч���x a&� �3?dU�o&R ye GO .'FZ8�ge�"�"h 5k����e� d�8�=K*!r&B�)oU"�V���u3BzF�S4�sN R#�}q�s�es� 3^D&y4�=�^ olog�On�3=)SM.P ��c�Ǖw��["fF.c^jg�%�A|Axl0"ng .VW "H� W� ��'�1-�&�. U:~tu0��-RNA���A�&���Z��   P3M �� EJ��}ks-�A@.v+Y�I}�/"� �p�0�/�:e&�$A�&�3����A��+�iA���� �littl"C'.N%�$)�� *PJu�"A]K4�/�6 �&P G>ain ,�i�z~-te&,Ay swee�r�*"�1.� ��_��� g�s%��#��&4[�G1.W2��#>s&�*( SNVa�a�ind������ Z6� $��%�v�D�Oraso�foc�on q . Wi�A&� ��vWi] .�S� ( ~9"t�1� *! !��sh�t$"Z�2�R�ՉDJ�stvFzwW!�2al�7"i���  ��!�^jz�8"I �Dx�54��S5�[��� takeQ#"� K����. �>�bm K ):��#�&� ! ��'3�s�e�}�7Akpropag�#a�1% �>+ _qel ic�9� �%D=�lA�"e��E�� ii s��toA�eb,�0�ii�or%!�li"�@. �%�biR�*� A�p=1�B%�Pre�! work��.Q K- ۃ �9] Y��Hn-t3cri�.1dK{/�.!s �J��\l3�#<��ces [3"���t � is ~�w.z ( ETw=I:��) !� ~70%�2�( I]-��EV� � .c)�[J8JQ"�E)�C;UDIM"!�o!�p2g�R���V��Otoa_�/)I�6ns.HCaAM)�W�%�5E:-eE:��mw!, ��.�;um�*> ��%DThotZ}>AED�;� 189� Ar�:lyp��5 ��CE���h� �>!J� 2Ug&Z+Y.� rm_U~�:�Isk+.pV�lEJM)4"w2�A%�.�M�5�AN3 8*�d.ispa�-_�4nW�%F*� as w�;v 4JOR)]CN�g�:U{�n#te֬�E�a9app�`3I�;�_gK$@ ah�o l�31�� 6�r�-�.�x�:�r�<pA�%��vs��6E@A4W[�K�)u�I$"� �*�lQ�&A��܍��EV/!k߮�h,y8�B��JB2 �~� %���cr-�are!�McamJI)u�g� r��4-���A͉�AK�.ayA��YY�opYTs |9b:a� -� 5C x g�wEle��. B+�ia =Ag�B#ua(Tcle1�dco� E<jerI�_lt�'� � V w�*f�o � lle*,."% E��Q@, �_� ;$� �< !d-o �a�tk* � [ A�e� Q=Je����.& Ua� �F�<rF �)�� �to>���&N2�gq&�r pro��op�"���")�b" M�� hand8=:p A�E� �� aA2�ast� �Aa� ��nA��?;�8&u��$:�"��",h-�Jhav�\N4. r�7�e���r)uE�Q�.7 udOfe� h H pphdD/ �P��A `!,���[&%EA?lexE�)J>d�\=d.�5n(��"�PIK3C� a5�of��q +4M,2Rp-AKT�I9AKT\t�=�bo�!6-@~;!s����8AI�[�$�u�rev�$� V ��H�%%AHs$Jmp��Vin�7��],Ţ5�>����)�as"G7' XY�%�+�4�1"� M} ]� gen�4!X%#-QO2n�qB�Ia�e 2! B�2e�!C��� &�6P!�5�ECAq�� �7k�"��Q]?.� QfE,���v��:o-M|[�&.")N3i�z��-m,:��ts�>!Ppo\ut�<G�,�E^��!$ PI3K�d.P ���y�Rk(� 0�e&�' A!=%na�!� �[2d>3a�3a��y):Qd�x4n��a-)|k�.��n,�gu�%�>�]M=SvB�! s�3U � 6"�9a7w*~/�&m�!� +a �)�'�.�##��.~9mix��L�"�*&�'rN�? �/l4��%�� �A�h�%l �m�l�%��  4��:� �coG: a puk�� ={%XFY:=�Q"�Q ��3l�3ck2�n=7��s����52ER*�:( HSC�[)vlae exci�b� marrow -postna��r�^�ct�e*s�ao���Ven�g null T. �i16�29f sor�n(of Lineage-�ca-1+ -Kit A�CD34-E![..��rto�a�to5g�sQwa�cɱ=?�w�b�#M�,*�#ve dis���.� vivo up�!� plw&[|t�#A<��1"� !�".�AQdel�O� !�J� [3 KE%� m6�.F�8 �Hn�#aga.nd�Be� iesc�� cI;ى=)onA�S./:*�T��2]\~A�C�������!���FF�o.�� er��hEVory%.<, Rps�� S6K1�5��*ReA'yg %Xa��������]�$.s� QtoU2�t��D�, ]M��e6��sH4e?I�re=��e !�+/+ �� 5A"5"ToO��8.�� &`9WT9S��20�f��clod#43��q�Z�0"8ja,�-ext;Ie:T5s69p�Ѹd'Bas�9������#)Q4"�),�r&��2"CQi*4HM�� Hs� �Y*�@WT-eik,seO��Q�(o��)�*{�5 ;� @�%;� "� R,a:N ]�51��Mw�UA_.͒A��8I�)���t�eʄd"{ d l��[% !���(Q%20Q]206�>bwo5�a�sexU�)3 �A���r�>Wun�� �R�8 5�y��~3U'-2U�F� �:!5g~2< ( S6-�&352+91�.mad.0�Fa�pos�L Υ+�i&bia�!�agree.�6�i) N�q�� /iule# conf� &�]E re� ward �i���#A�J)� :���rA')"R-kE<qf6 ,Vt �*n :Q3.Qr:���L��.idy.��F�a@$!�&# �U�m2��7���G7 � ��t .�H2�J6Y�e4���eVƞ10{>�!wen�%II?Ei�Q-:� d!�N2a.S"%J�&�U*1c( �4or` T(�l��� C!`-���� ( 5�) �17f�N��"�ine�orq�� 3F'a�&R!kSNVsCV� I"�A>�h�yM�!9T��s);>/i�2� ���� kK��EXm;U ~�|&�advantag�Z� �jzi_Y�m�=A��5[HSC�R � u�Utly^9  ,�� !�"� v$�plr*�tj�!�1"en� ��}�.aK�3[ng)|e-&<nd 2�kfDSB$ K7 Dele/ x�+J�7 F`e&}m.�^~ags�&+ion~���T, mitozS-C�V , H2O���ylan" fo�$ ( MM8K-LM� HCT1�9lo*_� ^R&nfQp:�J��|WA>�A�!�q{� etE@R�jna�!.$9ble ��J�� C 5D� i/! !+hydroxyuա�\� $(�N!�"4A YE=5F6Y�;.��abau)�x>t���'� - �reA�N)wp�u �D��ie�2s fibrI�r� ndq$l��.)t�X�U�e:�,@a��zOf* �jifJ����r *P S7S8�aG2�-gVv8:��sI�"�q 8lx�#�lEA�)ul%uitc& fE}] �!c��E� ?*a��)�6/+ 6w �B�?�<t��&�0�s,w��u�-*�]E/�3H-uruMq"�x4�.R �"abundKG Z:w �4od% �&�t��� �|9 _.�c6�~ e��C�q!��1�% x �UAn�N��"�/-����;v>�Z���kl� e�U%0o&�a�>II-dep{�nt� "Q[4����H"[�,m�=M�E��� 35S-!���B�,� 6��� !Na#%g--�F�*>#s��[�.�R>�nd.���=� P!�a�� v8M yA(,B:��F%�D� mH,s*j �b.��du�B2��*�e��eed)>��INK128��block +>�!as�oh�2����(���")*.&5�%�@��� 3:"�I�L�  Firs�F� ��K*n2J�of���,rm�J�Md�I\7�# . Seͮ)DU�.3byZ,�8U\6E2=�EZA <+qu�mp�.� �� �$�= ��!4�HA+�*an��SS�.� OWT2an. vH5>& � AGF� !E�  outpu�^%d�+E�U��Ox)cA�iPEC.����=� A�� {uơ�Y,a�gi~%v8��6�!6� &z:�V' beh�t�EU2�E�!�I�, x8M��C!��Fi�$e�!�q�a�AB�/ TOR-E�em��%"v . Im�)�> 6�*��\e�AtXi:&F�� 3 E�)I�;��"� �7%�� ���")J�2VP.�C�=)6�.)}>`i*jPreV�pige�ep*l� ( RPA�` gr�� &�  � aM� karyE��55dJX�*o�yC���)؂�&�.g��TZA !�,��Tp.�eC�Ct�739� siRito�ckd�jCE�}� (aGhe*\��Zr�[���Mr�bv9ec�A� �M�9UL�4d� 80 hwc� ,��"o�3!�/3*Oi֡��8� 6DM�f�2�R�5Zx��X��ePƋ�o�B� q �4.j_al�����_����)�^Aq�� wmK K @?q��+�W%���b�*}��W�.E��Z��:��he�E�s��T5�e[�pan e�inp�or[� uff@'ۺU.#n�ta�27cH�"|p,%=e�t��"M,*�f�.�� ly �~31C40� � p#. I:e+�2JbV�d>�Zse [�^.{$�)sNRŅ!iU]�&���2L !١�"l����2� �3���!�2�ly�hE&4zQL1,!`bawm�L=.bx%n'�I���V Lin/�"Cf��KT�aE��5d%4inb�#�n�S�5!&t��2a� �`��i6�.�of �!�-�1 67��*C��*maIiJ#� e��`I��! m"8g m�!�:#ab" si���)�}2].� ��h&+��.�-a���)n3�$fbQ ���W��J�&��Qac�v���'R?�.�%"-�E��P5!�Kai�is�X) &�,�6� ��iy�*l�sz�a�h�v�6tI�"�,^A6�Q2� �T u�:!52�R�Per�� esem\�3 situ� �>*�- �/�Eqci_��gImA!|c��>�u�L@��e�0 , t}J�"�  i�_�'!ȁD]F�H). �*#_ >v*X-& \G � �BB�bn Dėelano�e:^g:^��h(>�h �1T���;.�� e�*��!�*� Ffu��>"C>� m�Tu>Y����*�a�c;L�� h:j ��z�A !qj(s"7� �2�'4�:~8.IA���)Zə5c&hIEti ��M� �׍�sb$benefo$S���6*D�!F"u�\_,n��#�ic� e�s8 E6��%&~�f mDAA@Kb�po�T(v�7 ~<�3A�-8E�� K�S���!&< �*�5!�"��6vs�Q=�e�8/�� k�hp[Dsny pluri_6cy2J0��Oct7`"�r�e�0"�si�ga]Myc [t���ke& p� �*6\%hA�a- ᑑ� �I� CTCF��i59:�j1(= +��,"� h��6���"v-�3E�s��U�C�!�wrJA &�u>��"�j� "� X7s�(pla{�h! ����n_@'E�Arabidop�0[5�q%�.�Yi![>m�(H a�phe&:n�i*�n[�iLo� Q��"A�E��)ibeW<� AJre-��!�� @es�5 e�_��)�M:%�l\i"�l�,q_)IO.fF� ����n�" ca�����>� � MCM2�>#�e[5�kR*�� ő6�Al���D�jX0�/�OmecCAiK [5f�*cF�4l%���&�0���N�cMcmJ%�ic de����  [5�kSpontane[�e�ա�' &�)l+�i%�[�:�!���R-���5c ��-uea����"�#e.1 r�at �4+p"��-�D�5l� �%�1nYj air }ɖF�sre.! �* w9V�Gb�CKa3,C$\�D`ih��aQ ��Z�%� �>fa"��a��l� >  cycl�W�> �!O�Ԭ> c�hzQ-., %^�1� ly��Y���EzK@**p�w.���xuis:w�iypaB!-t&�D=a�*/!2a!rr�=*QA!38 # ~�-���� !U�B.�M�/1Pt$�� 7)�%�1��6{���R�jo"re��ev�c "�Rf!�p�WIA�S��� a��Ag�9�Lt!oo�x5�C�—��%�A>rM����*8%�o~ O=EAU3"�&� A�7%%�?EF!�M�&.+A�R�� �O"HJ%uAx�b?�@q�timA��x�|>�'�0A 71*an-6VL %e\"P6!�&/ ��� �+p(�\�N:�"�0A�*�%,��0s�&f3 �"k� rA# �er�-)�� forc�7A�57�w�1 �&m"��A�*�.q2k!v� P��-!&�lN�!�en-iEbac��*�& moleA���hm . Ch"^v}��*� �1)[5À- ��6 -AKT� �J�G��oIM��(����a�cJ:�mUw�2�}��� Q��$f�E����L�el��, t���cod�hage�,��� �5w�,� .��)A�-�"] &��0 �@%�m �OR �%��o:�Wis-tight?"�8(e�deX-Tariser E���os%>Ac�E��BA1'*Y ^�~g�! , ` �s�!� {T��%?c �Y �, ��i~e�d3w�&6�r����6�)�'!�����A�, li"�G2g :w$J�2&�*="���pare�c�/>�)$.�8*�,��_!:�0I�m��xM*cM��@:>DB<��ol-�&�\$�5a��D(e e ��&�may be �linked using the rDNA as a sensor . In summary , $�copy number and sequence can change in cancer , with high mTOR activity associated with contractions and DNA damage sensitivity . With this recognition comes the possibility to target�,se loci . Ca�$stem cells �low2�$may be mor�e to !-d�!?hagents . We speculate that �!dle6Y=D samp!-) !2L4Maxwell® 16 T%3eVP�ic)�Ki�4 Promega Corpo5�Th�0 ncen1�of:}as �FE�Qubit ds�HS Assa�,�\digital droplet PCR , 1 ��emp!�E��per re��oA0DJ<{,to��?.,Jformed %�%b�4 t �reaI6 X200U崁uquanti�f:�6Q!asoft w���� Pt�+8amoxifen-induci��SCL-Cr�&(model has b�\ previousl��,scribed [36]�bA ,��at 6–��saagei�(given 2 mg �%�5 day�a]8 pair:�EС�tźexperi�-1_! sex match�Both WT�loxP/0 ( Lesche ) ;�i -Scl�(-ErT+ ( Gö��t ) � trea!�w. �.< �col�ed 12 � afteiZfiA�inj�e�A}I: ��!�conside�eleukemicB� tim�$of develop!$a clinical%��R Ha� vivoeAe� )�,M�:�rc�Lin 3–4 months postI;e� , buAi0metimes soone� !�!|-/-!- ca���.�-0ranspl��._sor!\(�� c�D08as lineage nega @ , Sca-1+ , c-Kit A$CD34--m) by fX yt�r� �9 thyl!�ulo�3\emi-solid medium ( M3434a�dS� (Cell Tech .�NSin_ ��!� ��� vidua�l%�a 96-�� ��e�� H� l��in �35–50%!��u@s )a3m a larg��lon� ,ainly myeloi� d erythr$hematopoie�  � deri= Oe9 HS!��clA`�harve�b!_cubatAX� oodc !5in PBS� 20+0 minut"� pipet:up%� down��disas� %�a!�m�rin� �E� ice-c] vAly!inly� buffer ( �A: 50 mM HEPES-KOH ( pH 7 . 4 ) ,��M EDTA��+$pyrophosph~ , β-glyce642 NaCl)% TrieeX-100�one t��e�i-f� prot�]8inhibitors ( Ro��=25 mLE�!� solu��fF ��of)@!�lys�����by �� rifuagon��$12 , 000 g%��i�Soe*hdodecyl sulfate-polyacrylam gel � %re!r$( SDS-PAGE��as��ua  NuTNovex 4%–12% Bis-Tri�ecast\!$Invitrogen�WA�rn bloIO6b!'standard%R xa nJ! �( What;,- ��$ ) membran��!g/E�nti� � ��:{(E� Signal,�Enologk #2972E\IFo;(( Ser2448 )�A12A0S6K1 ( Thr389@,Abcam companuab12681], /aRb�9206� RPS6 �35/236hrD221 �< anta Cruz� tec9sc-7445�,, α-tubulinq$igma Inc .� 619 %1=Akt&er473�� 4060%; 7r�92-� PTEN~�918!]. SecoAqy >"HRP���ti-rabM IgG (��donkey� A-mC #sheep�,( GE Healthc��, NA934V 1 �5 re7�Tldő� −106��+/+4��vsee�� on 8��cha� slid��wT �-L-�pnel -co�% overnight�j4naT�QeDcul6 d�}24 hours a� attach . Next /2(was4 ̓, fix Q1ņ}roHemperaqɦ22��4% para��aldehyd�(permeabiliz S5��l� aina�0 . 5��on��6�. AY block7 �,JT1% BSAR�)pre���-�i�edJ|�bR� dilu8-G� �:v E�(fibrillarin W1:� D�Y, M�.7oi�H-250; �)RBI�cAB slip �the2 =�A��=PatF�5sN�Alexa F� 488 goat �i�k.$555q�� �( Mol�r�Wbe� %X�B_]J�V mounNonq��analyA� �ce imaO�,a Zeiss Axio�  II�fo9 microscop���"[of -�ar siz�&_i� e . � 4in�i&regions�Image J.�NlogdkibuA_� aver6�M�rm`��custom _PJ plugins essentially~ in [55] w��min�d�s�  untEdver%Y�� � irstbcon)U!�maximumD ezy�\��=a rolKb� $background �a radiuf5 pixe+ as subW��<e���B-3smootaO� a Gaussiaa ur!�2^(!���d� i�v� F"�.Y� shol�Bat� 25�esA�5 proc!�s1MFO�resulA A $inct spot �*taQlamAd%� areaR�O�Method�n rRNA labe%sś24 �D reportA3 , 5D�����HRT(�y) d6tw?*d swi @to fresh Dulbecco�ME�ed Eagle �@ ) suppl�� A١�(μM L-cyste�(�c,5, $82-mercaptoethan�Z, 1C L-glutaaq� ibco��1% bovd$serum albu\ (G.$pulD!��3H-uridB( 5 μCiE@�c�a�A�� ( 0 ,�U, 6 12)��: . To�!�AB"% %(TriZol�� ( *� , U� �� ��Sc�.Rex^�eFU!asP1 μg�;7c�ve  a Beck� LS 6500 ma purp� cintᘅ� 8rAB� newI���ba<on.rinc:7�repg�e$ ``% "~ de�%��two:(.�d) *�ame l��X ����!�cal d��an unx(ed t test .����� �μl!�,methionine/ u2���^�yc50��u�F I&z pre-��E�!x�k'M �� )��e6�ou(1"6�re-2x1 �MG-13r�P�ome&�� or 1 r�  96QCi!� 35S-9�� B.� ��l" RIPA�yfprecip�e�!add�of ho�% TCA�� :W"� IE�����cet!^)�w*�� solv.�L1%_�h�at 95� %;��� aliquo�he7Sb�E�Eso�;C3� adio�vP � Mid (vcm��:��X{DA !���$ growth{O pres !of�d! � � E�( 3X10�)�}�q�2�*� �A�� Ystr�s!]��m dosa� � iC� fiveA,�vi>ty%sassWd�rtņ�*�! tryp� �b"[!gena6 dataVob#�6�iss�إxdbGaP!\he! �A+�".�is simi: toe��ly publiv aiod [17=&� !&h�� ensus&��s6��NCBI (] e�: U1336�D. Raw fastq whole- �!�T�dm�Tloas \�Re# mapp�$o�45S locu�nd�#e116022Aw-�!k"v<-%;ex� (M�st {��gen�� 0Bowtie2 v2 . �0�wdefaultmet� . Only!Jc{!t��?�kep�!v�-A�am9�UB�of 18S�  .  �28S%��Va� ez$�ag��q&T"� i�ake�s�r�AM%h ���B��� furtV normas-�*� M�, whichA�N�d� -#�7$)�� UTJa)��domin�$of ׁ  ����Ijirefer��Ga�A�~*t]pos�vPei%a#16lT,�!ifd"2�)�2Yk" SNV� NVmM I�Lsamtools mpileup ( vA�2�he du dE� Irem�#e�' alig�� fi�!. 0Q filtHw� 9 qual�Lsc7& ( >2� $“PASS”�I�-�%A�I\)Fed1�: �7id !1i��t�h%�)+i%�notF>2kGunique GH"�\L�,Ie2Hevalu� A=5�ev�ce�1�di� 'YW�� llele�v>��H� u]l |2E�e�m��,-���of =s�d.�-�A�>�tum�'oier�� ��c �X -Sp=!�J.��box* . GO%�M�5 ~ ~8R package GOstab(DNAseq libr`( ?���%.$�$��ic5�&,y`Q�$�<0��e� Life&q��#L6u�#�r5&��B7$dir� Ywera XT Ty Prepf%( Ill�aj'��#&��?!!PAgencourt AMPure XP s���Coua��R"�:A checTA&�a��tyu\LabChip GX ( Perkin Elmeb3)V. EH mo�:npoo�!, re- b�>q{d!�125 bpEc�o�q5%@HiSeq 2500 instru� � C�$Sof�#!�58ťllo� {y ,` PrimU,A ��ver RTAt1F64�&�B/ bcl2x �7� ru�ewlex��I-�9�)%"f�) 6~q"k��i�d�)A$(nd�k�Dto 1ng/μL .e�Mey/isP#FantybacterA��, death�sp�wit�%mam� an hosts�2be fu>rE�studya�a� hpopul��]y also cur��� 0oorly underst�-. HAA�����8.EHof soph�^&�'al*roach�oG  sp8tem^+l.�dynamic2% dur��qq.�/m �h� Ze� trai)hsi�oa i=J%Tth tagged Salmonella e<*ica��c wild-type�genic<�-,ins [WITS] )a>.A!��-�*ed%�.%�phenotyp7 ly* X'@0be��ua��% numebyѼ�&PG,ma#ita�s�),M� probYE�(�V- stim bU�I�j*x� is arW!�!s�hroughOAhish disciplin�dapI��P+u& esta-�*�(�=A�ve�( �immun�&n�Tof !5� pari trueeD–~1!�o bij0 . OuA3a�pE�a)(E2 shora0� q,�P omit� )>Arapid=Xr ��l�+U 5ŷ$of indepenZ ?suby�� �t�/,� �! �by%u�b��m��m� La , decrU&E�r )�dty�%�ana�on�xa!# 6!,A*�Iof�3��l;����t.a�.9 betw�, �via Uaemia%istochaE��!jM�U~2�"us   rece!q !utlook��Q4�&of �e�3UaO illuaa�%�������ef��: at da��u�!��e�M� oveld4wR#�!��pr�5%*di� r�tog�4%��/l-�!�Jne�)�*facil  a�rehensa� view�Zni#�4�-���. C1la7 _ leteѷa�4>�&di)9i!]e ���6)0g��in�#%O4yOsc�3�+kh�t) �� expl� % t� [1�O��hk�7-5m5is how�� �$our ever m�detaia���u} ASm"?"m�I(��rt A|lab�2oryF )� ward�̭M^.�q survivM��jran�5u-5[2! A!miOI�ach�5�o��ncept�5t�,�% Es)#p&�e�+gy!C~6.�oy$iMW��|E2�E�[3 , 4�How%�,�2�/n�ec� ^�"`1haY&��Azi�-�tif� nd observa�n�:xis6}e�uple��PaatICliu9�Q�. N_%n:a�fsMZal 1!�9CN)�a ���ac�,�herX8a�rv�Fon!�1�� usua�/�&��0�,�!u�wAny-a�un ( CFU\%�! ���rg�6!p�7|0N��Dan8';81 idea��global�e:V!="9A]�!�he��&mXu1gives no��!�06�1� u�5�6^%:� Mi em_�� m�)di�1.� }�l����ed��F�2e�[ onlynclt.� ib�!C very: U�� �t�+or 6slowl 0 4IKz5 ario �;.x 4 �llJth��a�31�level �!nb�h��le����;be �a��? , hae�major� �9�H!�bma;.�wa�� mani� m� a7;b(y�=< D'O%o�b �s� !�_'A� ts�e6 � ea+=�<8alQi1�S.�inIk( ea�by�) :Cy & ro,oatrodu� nonr2 ng70 �  g �-ph],� smid�ԁce�`P-\i�,�=�� { U�.��their w% ��4��� ��``of!� eign�d "�6�on a1In&, ��ext�tou th�#F rupI�pFe�b� !��& |on� asr�7", e aim���Nto* m*� pi�`1��l.n�[b^ raveG A۽�inh4ic demographic�c�Ѿ : &Be�:!GT4�> im ,�nu<szto%�( l0a . q8ly&� xs a���, (�A��p marke�1im)or# do��\ ifɔ��( �0e� � � Fa�-� elic�<!.#unK�&eT �.A�]�N6�sfun���im�ME��� � �!.R@�J3 to dissec5 ���3 �4ePth6�I%!$stc Au(mt��@traB ) ��usY�YUe�9Q2��H"I� � ��ba2 (idiosyncras��2�requir0#! aggr.A����U*caDDnesU�s:8*-1F�����/�~1�@*ui� Akm���=�f s;�$!z9�� msew#illA��a�,gm shif�h9RUa he�F�0 K ( stepzM~wSE.W�ki�5P  �Y+0art��8 a2. ven( i . vtB&hD�oB#�2Yn�A ��E�s}shcAinѸ2e82BH���35E"6 hht9�( p .�P$we&V b� H< sl��qx�ѽ-!l�6 :i*ub:spl=M{f#|ex�i�C-�$�!�!�E�x5 ly 10-folR@da�LowV�per��!�“& )�”�oug�T�p^ surg"f�E&48!�-�on�y �� "�!i� B�U6&m2�5"�!��0AI(li�4.s�. �NI�tFPe�M-�^I�hi�E� �. �%c ve)( q0�C� ]�ZO��&�� . rWQ tNs�14I,!� 5!�S .&,e����%I� �TIy�2�$. S:�(m�h�x�&�Rr���bB^inɳ��a>�".��vs�!���fl[ ng� 1�b�.*���~2��R�rKed*��"�! H6^9R2�.� 0f�8enc�P5��re.JEom.�+� Ma�'�"\�Qa�r� �in��Yh�C9Y3%X�2. O ed ��:&�<e�c*a[re%<�hyp�a�t1�"!�st:pby2�;Hco"4!��Hl� YA%%.De^� ���e�C* /��6�%Q4m;$!sa�a�domZ\"g� !�i�T au)*� s S1�S2;&�ES1�:A�on�'��$� a/]f.a,>w"� A4� !� ��!�L- ,�@���Fa#(Vs61 \�2U !� H � 5�Th�2.�Mal�I�v�Jbh� �origin^$ :� F�Ecn��a yg�RB V!�"t � f�9S/)�F� 1Euo�q���M�� ,/o�$Q>ɳ��)rYa� � M!��D? F v �A<2� (H,�1+M�#i\USp>;1�S3^�2a-�} deIg�QM��V/935��Pum lodg� Ba{A � "�4 �(�[d�!t�;su�#lEP dC<cor�qa �L drop�ry 5 "�7�9y 3�La��  3'�Y�q���i� ��9�?�����'o�� �u�a Jch��Q�a� rack]Y�cop!?u ����7��!i|Ee ]+b��|� ,ZnC,!sAx2��0�"(t} a �be�abI$��$�8� %Bpro6'a�of DfoBm]8 ng a)Ds��� . It wortJ �>�ut o#IPiu�.+ %0&����Fa=.��Yi�#bz4h6#.r.&�+�CigT%���-i� . Act� E.Űw��lat`'��� mpG,&�)3 �M��mM�1 � �]D݋!�1!A* �`R;IUle)-b�in-:i��rn<�y[9,wm���(Z{I�W�*^ & �z��!��/i+E-iVshHFrs6C,Adca�b`��[r� %Fa��a�s ( do�:!�i;aTE�67��byTM�2Ie�Hhalf-��leD1� w���-��FEH�,4C!likwFduM���� ��!�T\A��t m�cS(MLőIj!3f ��9Si ��<;beyondL� 1�� M�-&w�! keep!�o*!`,A�od8�-4 teadyi6� �e*[�GtI�%Rref�is�-D>�[ �I�@E}���ph}T��M]�ki�oc'aTy$!<.n%%�E�1$m�0A.� 0.�q�s S4–S�[T�wS4>#M s 2b""�">ar�' �i.#"� �y� #e ��'#�r�,qF�l1,��/20n1@J� ( grey�0.&��he peak���zT%�Mrm�2*` %u{n� bala�#im�!�� . D�0elLY"! &� ( 6!2ju�q'�d.#ly;Ohav�+�- ��isE�arQ �2�?WQ[ o!0 �7a$hs [4 , 5�(!Z� *% Ŧm�s� %!I�9ɜ&��s^an�$ G� 2��/V卶9.&�. �-�eDn%a~r%�perioi s#"at�:5ԉ�^�8N�s"�T educ�e�Q&���m� ( 3-56H���oQTn�'�to2�TPrN��N!��ij%�9��-D�R= reve� Me*�7�&BA�)�a*M�4t26*2�U�C�$�dt (]he cCi�3:%�!lA�I1ly��_ mie0s"��,# negligoYta�V #b ��E��5p-24at�%�I j�5%hla�5 ��'6�  hꡒha�"eri]�1ig��I�!�%�:�"7i\��!Fe.�s2��N��awY�&%%po�yy zer�K `!4�>�� *S ���w�d��balat>p=�� is gp � � �E!x�9�C��B��`"<*�( �. y�H� &*�e[%� �P`)U��err FJ6I7,�:m{sa+��� a��2�(��� �i�ly�k y��escapC 2 ?* 2� �y�|&�S�!�B�i_��c�Km� .�.�*� Q �HBp�5,1�!E���,�had���_3Z� , B�U(ic.�%m !x�� p"8$�ae � P6*k!a ee�6Q��9Fa:�s2 Yř��!�9fE� S{?i�#s"_&+$�� !o%;6.8'��H. A �0�L'��"� ( igno:!�P&D)6 ""�,r�e�aZ�.�/�� �,F 1"z_�O`H : G U^4a� C[bi�ii=�B�4e�U !kQ�`�CQ$"A�6�d!�rY�ha`MB� I�IiU� �:� oly��5&�l�5T�>aexclu) �- � eu 2�� ntrigua�, �Z��w�W�FBce�2v��� b��� /�^U8!��0&w)� ��&� %�*�$�$[*4" AAjheQ�,�&6*-YǑ)%��V afmI �� sk\/s.P�y���H�E&�/R&ua�:�*p!48��72*N �P �]I>E�8�U�p�Hua�.-Xs.�2�9d�despi1`4)�!p�exau'I�a�?bia�erm �“fit�"or.68P4�*^ �l�A�VAg)umpey buil?���$dA�bESe*�)6� A�*� 2f�G.�ly�!-�Ge >5 97'  ,!e#-� �� � � �!�M�%U���n�o��te�"u A��&�:%)��EmxCA�l��/�cO��-�9��2e! e�9G ra%"� )�h$ iE|*�1b� . b;1AI�Mu/<is!t�assum� � d&k&�eG%E�"x"�"a Poisso6 s"�)J[M156IXin %fs2G$Q�bp]�an mixA�2���wa\2�]d$�n�D�Y}Zof 93_D2��d�( �I�� n7.i*�>�V�z�d� �0A��Re��inp]n�a oaVLB agar36]E�x%�.-D�-{“vir�a��,�� s�a ser�1�d�i�* 0�- vout�>�3el["BFfCg: MSa��b6j)�.5.03yg��!�Wed�6%e �`ty �t�MD2� .O�}ex�;�!�� iest�p�*�"4 �� empi9�(�%ly� Qs��h%&�.c*!�among������,&z��@�Z=� lud&���. Alth�%��0u*&B�f R��n"0�n%g�"ce/@�gE~,�"9� lL7lysI�q!i�Jj�-O6"M�An�$>l|p� ��&��N.���ma.�շE� v�%"�AsC��yvalidA�1vtagk�P:notE0�0epancyaW~�A�)(^^�(2Hwz2� ppea�X.*2U :�<��C {-ri�l�toQȡ�a�k�)�$s �s 2Tz&v'.K�RwE��.Y�l�+nt)��& ��^I`!W5f!����8 !�2��cfl�&��� ��5h.&3 .����j{?@k +be�0M�G:x3 ~He *r>//AV4q�� {&]�2 . �+�D)���Ce"� EY(phox−/−��t�=&w5!Drol<*NADPH vUi��E!m2� )�:C1Re�oxy�j 7�[[!(*� � phagocyte:�,� ��by�G�4�;�<zQ���i�<�m th)M�el�B1� [8 , 9fWf-w7�::s@5&6(A%�=�&; *� !t�.$=m�J�����>��/hɸ�=�|�;"&JXw ��7E-7�H"A>b'a�e.��-��. _�nf�?< 7,m?qu�'r2(^B�J&$l 12�*��*�!bk9a�%m&� c $no)b��l-l�>��!�B�"�e�Dtta<rPJ I�_a"@2al:�A5* @Qe!tM\cidal aN1B��6�a a� �71�!'e"d>,K.mB���k  � x 6&�Hr"!s63)���!in6Wu:�i�=EDinn.:�E!��@ �*�T�*.J�Yg�:  (M�%�E��s���}�BPq_!�b 3zY�B<� *�l �&�!>�auZ�z�"�6!x5&.�U�s *&.��Jio�Uic���6\ �, � {.� m��"m�O=hin�����"/� �pU)b5�J���e�,��4?w�� *� postRPx����zv�"�jes1wIV6��d�ly6�� m�Yi&9� , beuMngC1r��� progm8@9TZ 5U�K�n&���2~eFT�� Qst �Cdef�s�B9�ݽ5�A�6Oa� �TQXn�;$ends upon n9�?9�� Kx�a*� �ha�GF� pe&5bi�smk�@*�*%�"�!�� &�B[12��!Cbirth–I� [13�# two-�' <�p�R�[1�R+\ XUaw�9\� U�! 50 P&d� g�Y �Cs�$WVo�b�N�C� w�.h_E�9'na�W�.�*xEc mM�!I�1� r�� T��e�u)L[1M1"�nq#�4� 9�s 2^��� e2�e:A���_Yh�E�@. B"� �, � ���Gs^h �� a �!�9�M�.:ir exqui�@ ���%o vacc���j�;. StuI*fte u��| %!�}' q��f<,Q� E<� �ia�pre : grosA0cum� r "efi�I �<� ����� �&�t� �N� p�Tp�Cmenŀ&��pAG)��N� � � �� 0�$:�N�G� e2 9bM ��A5SheyQ��89�. SimpJm:��U&�P�a��bX�s� ot suffii]p:�Zn(4�@ZV�qu�i� E�Q�. S�#�� �6� ce"�"=��9e�Aw&v?�K���\y�3"E� &�FI��%�Et� P�Mo���S�V+*�C�J��d1 u `a?E{�$�Q" �p�7>Pa"�O��2� -uL�I�$ seg.�@ (( *w#AE�]inu�~#[9!�qp& bk1�N+�r7��7Y �!��k.��8 !p��/hin� *elu�� ! K�lex��d4���g�NunbC>\.6�m�2Zm��xm,;i+�<)� .� V"�fta3E:�+ 02���p&^9J" H �e �u ��eśvU zFy�^!K�Zr!]Ū�&sTOs��n�dJ0,sta07Ylz�(!y; ͺل&� !� Q�*� �s.G.� >���\2�-��t��r�/ �a�-p"�Z.fS��\&�\. S.U8EBx-ei.�&�&�m ` *�A� 8!�&g�/ u�~���*�U,6�%(*�RB� C"C0/6� Ek�| : .^.��bM1�M�r� *w�J. P�!rh�K% F�;&[K� a��f*+M�I�\qy> %�oK ��,.", /-(prol79"�T͜9]. H�UAHa nd vwAhxQf��[Wud*# LWr�"2�,�!.# L"�k& loit���j)E�g�� � )�A, imp�|a���Q�l"� �6]  @o:�^��� 6�Q:�����61�!I(6�� �-"� ata*,� M@5U="m�:�9h��6. U":I�v-QCatomiRbojnecks%F*k F� �!_�"8)-�(c�?is� d�RVin orߍail� ��_o[!�&x * te�k�7� �@-�S�J2��  � �z!��Ae�M]��c"nD f� � 2\�pTTa}R  appl�k�m.G}?. �q�u[� �� &-w"�!*in�XegC�P��+orm� ySA^�]ofu="l U �eezA�� �r� ��i*�Un!� ui��c�2W%�MgS\w�ek\"I:-_k:�^d�.:��W �F E5��Q$ Yh��&^s�in-"�feo��0 Nfrn��'d��!�Qt!�l:;2i0in6Tw�\2��J��aacMd �zK� �kA�ex�O(B_2)� 6�4 b (*)A3P�" N .�H>�!>X>g���!�9pm�Z7���(� ��e viruDcB� P&VP E;�e �re� ~hB{ٳ2E+&R �=�l�!JI)% �2� !ZG��sUS&Ho �$a���a� 7ng�\��d P]W a�A.�9H�� ���N��lisA�in[*�� Esch/`hi�li I DH5α�R!�� , un�#* �d8 .�JN�Y �, JH3010 [18]��aQe� k +,rc�r ZuanTze>%�.I5E .�,��nfrŗD0Luria-Bertani�_!br86$at 37 °C;l{e F shak�6 t 220 rpmBU .:t��o�j�curen!�LB �. W�n"�\,c !�&l�^=GAz.aibio�m!*&� (3/icz>^00�/m�D(kanamycin 5a chloramph/9ol^6� 2�!d ,inpȐ-�ed��+(��) prio"'�P��V . Long-�� z&��|at −80!�sM�ank� � rolab Dia��tic��Y�<��UY��e��YN!2��" G-�&����&�d��|�$I� A/t�JM.'inY)X�to��e\-^a�of7Mh��,{ 1�at��B�+2� �dl�}Ed&�CFU� mAK litrUaAll.=�^ ceduuIE�b"S9� ف�c"�!_=J��(to UK law .A_6='%(bAg�7e Cambri�H ��e� breeR�wp o�� %g8Prof . Jennie B�1�^ [20�Fe�6�%�purNl��4Harlan Olac Lt�V, M thora�Bicl��K-���-�8 w�+ag%npgW�Jly�4 mH��as-���'1  veu�M����" � cerv%�dis!�a�9!!��:n{�4:lyY9o<##(Seward Stom�q(r 80 Biomas��� _c����iX;w�.{/O�9��/ ( lu��PMar�DkidneyA��m�l� lymph ^ �B� :�s�l,gB@an Ultra-Turrax T�wlho{5-}F�V�.b�l�>!�m� ��$� r1��%,*F9eF94� ����[�%Y�� 19� , 553�72B���a j�^�!v.40_�5l�YM��L1AL]BCorbett?$�RG38.R11�!����0iTect SYBR GrvE��Ki�;�I%�7<RNase-��G ,v&v�fo~��F��10}��:�+ on =I �j06*�: DNA/&Aq'F=�Q40Z5jF~�15�30 : 2 .�� 0&_ B !�G X  he EcoRI\BamHI�h� UC19Man %- !fraa� \ rpsMamo!�Nb 7��Xba.a-(\%-!az=�Zusa��2E+ %E3 ( u>�p]�1'C)�c�-�� gfp+RNhe hPstB1%n%-!�pWH1012� [24]^�4��5 (nr�)C c��a!r� malYcQ�add%ͧqF1`�O 7 �Z�.�� >��AySphBw3Aa$- 5v�qYV% E�9�MOE�2�"�"� 9-kbp.]3��e�,!)X ,iK,IKYTd��>X�- ��r$DS132 [25]F�1��]tag��Q�Z�eY�(Rdo7 1QDavid H�� n [2C-5�!<(�� 9u S�eu�"�,)��@�Honfir�seDZ��9#l�yf�( NK )( �n �e<ada�unn"�Z*�4.,,8c �ly  �9%j���s &E:�����s84eE-��a�A^s cz(F!�Aa�p"1\. Iϒ���w��su�E !��X!8�+m�v��0):�/6T �2A�4�A�"�-�%~�;, seeu/!�.&`a�M�{EnI�Ey y diޔB�n"`Ca�&A���ea.�i��y�"��ql90� gard�(f�)a�I�vrcoAt�5ss: nB�L�&nS�{�%9a�5wQ�.r&yqoq[!*uw&E P�7D!��1!���!�s/=U;:"re rLSr�4BnJ� ��2 �(AVca���"n�l��"rs��w4�ki��s�n�%�Aθ �θ��G��M)-�(R���n07*���umCi)o�}5,��G-��/5�)�2)lefSWI �o0|}A:;.�, S on !!zKfXp�8i� �� �~S#rf��.��V&�,�sd��I*�12Gu-2�1�%�%�-}eS�|a��ai �a ql)1.�DA"r"��� )I��&�Va0�M!�)�,Q|)�)ik dee�si� %��BB�,��(A�i"�<V� eA!no 1!^�F<5�v��� "9 by swap,�)��Be� b5s�"��"C eansf"1�BE rL = λ LD- μ krS SAwe:e.p6��i1�� f��N %�'� �w;9 �0*s)�.�V x����a��[l�]atN-h,ə"M8dM� q.]. \A� a}�%��ag�6�$e��X��W�n�7*�E;- �an>v�udN], �3�S:�a_�% sa� �J>s*�Aex ��s� sche�pof 3D mo%gper�Y!rs��0MterY[ r ve��t �E*^�dn��a�Q��%,DU- as j Z�]� aT xA�>,Kfof ]l���-K�5r�O//� oble��P :\r�A�>pA�se� 4���r4 *�5� ��*r��NQI th c'r.z re f� bl֗M%�A�sol ���A���)fü (a� Y")w��r�.�7� wo�u�p2�/@::G&�Cv��?��asws-�in![�Eas �x��%opA�M���b�sB2D�1dic�E�e� $d6K�ambigu�9�%-g�5 o��0�a� ? �!L} q`�0�Mtheor�8�@}D�KyI>R8AY�%�fe�>�`��&�9s��nB�^��$seems=���->6��e.:.K� lle�<j g8d,J!�!�vin�!h8�hie�y .uLr� ,�8� -*uD (!j)�'�� worl.6�K6+2D ) !{�D>_+d8"7=Q��t ��t6U%\[1]–�e�  � ��O�5c��3D����#�&hispaD%�l ] >��(&0 �J��: \a�= 2��HKal%��%ȭ !�r� eyh I�;�!���qgdeєv~6aFl;�\Rr �ciV�é�. V�.��b�_��u��sp8 ::"�? �eazimu�����<a� �l6�� vM` nven&��hTU\�� �2csG�&� �fp%9�[obAH1:�at!#9D!o):�v� 6 iM*�>is&-�Yr�L9�Ca]6��n�h execA1|��q"nviron�;.@�" m �� � orneS4�1���@��4s�Щ#�Zof�y�3���|MbtriangsMoJ\48 r� �٦�|a�.�+ �ge1�Qf���E�&�O�!_ C�g�2�%[Fi#����V�� Ifp5"�\A�-UA�ulu>ADp��!kI�d e�74X�?!103��au���[�#yI�B�_.�re� v�{eld���J��ps &;Ad*V.� ^��<>�in�0 � /�@1�i�[-knZg E��u�Hal��!�,.�l�h�n m7 eo [�R[6��# }-T[7����[8�8G�:D9V,�pl��e� �l&�e ech��%�Z-U�om� �i��.�$Th�y��yP�QtoM t�-? [9]�i� �Gq �06�X. ���*oy�gh�k �(d!s���k & !q �.�"� a�n�-*-"���� �VM����GB��4=�M�� �g1ȡ�e� !��L-2m�bdu5 sg�T"1re��ri�or-*�oi�\e�VQia�=s��errF�nimK!v:^�P$o� I�-M�!h� (@–�U��-=� algorithm ten�� prin��I�2D)INtoa�/�� o�<CYҡ�tQo� �oa���'7�� fast�efDR"w� ���g�FDNu�r���Yre 8:_A�Zcy!��E�T�*�Na��p{@N m")w�"to��'�t^ behavio#�*�t�?of�&N *z.!l-2� %�- v ��F��:2DFc�WE6��"ja��p�~�=�=�!;F�nd^�Anbys9g�blh"��=�"=��~UlyAQ��s'n�&�"�o-�.%{.| ʼnreE|"�i� �m�@�0= �6 cortex��w^b�v= �� }U�= )�:�(r!)�m-V q�ng{�7%�l?,�&0m�2�;%h.cnd\ lnH2 z4��.E,!C!suUS��a�?�>�9�=�e"@�� emer�)���R� : InvX( IOV�za( CDOT���c( JEM^E(X_:��y���htee�bYofu�9psychopa��xHe�>0��!�neuea��4o < R!^o�,(un&� ���rF nto-paMel,6dom-d�Xrfa�-� �%�V��O iu�& P3 ���Q[~in�z >}.{��Ee�m!�Q9cD. Lm!T�nt � Z`u_M#*% t�i�krT[2��9]�x]�� "��s&�^ AЩcw!Y��s [28�y30�y�r��t6 l2�2�j"� q O�� Uf� 31].zsd-5"� U���Y�E!��)d<U'.M =�9[3��.a*c�p�ra�_ �7\"�-F.qQ  �ɽ�ba�v5P�!�X!J2qv�dC)�n*\"wA����Z�. P� �"&W&h & ,a݌B�!U'�y�#"�+25�  y$HRsIi9I�"� .�d/s�(��},� !)twoJ�!%�Y> ��l�"` !�( �riH�iEu�  is��.. �� �C����< favo!�SU�d*  �-n>�� A!xA�E�u�mo�>� ��d)re= on [33�M�m)y-&�!�la7T�-�M/��JV[34�3�4a�Vo�,ioS�-VE�c�,"* MF�k �~^�iE�q��4DA � ,!j_�AA��C]Tn AE�&p���* argu�a��hqA� )��1[3�a40%� ) �` ill-?)ifi"��r6��|ep(,;�Q� �)�AO(li�����a�"P�a>�Tf�U�8$�^pa�3�:�s f"� . DiE*�>n�Qt?[45 U�g�" �(  �a�Il-in�\O�&� [46E�4�Mvr.��T� /2e.J��!LJ����j�x�� ._";m\� ٪� �z t�-!�%n&� &�3!�� "�leA��% �����ch c�.C mat�;twF`mon1V1 [50�Fd1 [51��. Model [aO�hy�1"L �rac"w]��gz2)Sa�u"BPAI?d-�H� p"*D/s�Rde�����mxV.L9�p�d/ch� )���39� Pulfrich-��ue<9[5�h[53� A8z} �." l�5�it�RYOt�s� e�IR�V.�3�!��q0R�*|BKA+lo� 3DJ ���e��I�inî� ��c�J ed ?�IA� c��]"g  Zl��"h mB�"�C��()�d� *e age� M-� &U 9@�es2'!�t�H��c̋�#� c�?�iL{ or/� 3ee:a�!�C'a��� . Ge"!6��6�wo.����"QC" �)"+[X':�ܛe'�i�hgac6a�W��oOWeS !T[)I1��2"�.�1�ف)!.V>3)�c��X��� � --v]'*_"�#� >"] *�5�bR`m��8�. But^.��<�ib �ua*��� �M��#a#s.� 25p O�j�Y���*ond�!bu1T~Rh�F8�it"�#2DV+��A�J^ z�sZ���{ � O��a .�!T�o��  �� s . �b�9\!����  c539��on^�-�! "�% .��{!� ��M�9`=]��1��i�,>� %��%�!m>�!+R�� ��0;�+ ��x-�z-�qX{��Qh!Qn� Q�2y� . Wi��t�[d pI.F� �"@a��nt?s@!ef��� ��s}�� ���nyA�i��\�$*&�b�3sengaa�i�]V��F��6 ��t2adT�ag� �)2��)I�[5|>[60@�9*C�(&�YR&�_O� gFDo/M�:�Q~!tr� �-�o�2A�l z&�"��re8 .QR/;�� xi c�RD�=g!D.b67 .y���.�w�ivvN�Bce���Bٱ� - �R��+��� af!�r @t=*+ *� � "�_o*�� in VMHV4 [44�61 "&&.�A�b&�jc!��dQ"��dR6�%�j)mE��� dors�ream [6~It�m a�e�@%2B�2� �!1U�f.w9 G|M� sub� �V5/MT 6�, [63�65] ��X� K� 06su���I6�tO�tMm�ercZ.�Q*T0�0"�%6D*�% ?9=� � /e:�M_s �e%��yt1� o9P:�2��)@du�x"r A(���� �g�i\'m�~in>�����7] �p�.sa�-�t5�a�M^-v}0&+El!�� )�M .�n5ks.Q,&�w%�Ųq7"x" �i� re&�)� s-8s{r*].� �!%�>4�~-�!��' /mapiNv������ �6�E@}��Q��-�)�=�9�A& �.�ʒ�:�B�/�jES�G��j>�Z�atZ�remain f|lexible when binding and segment�local inputs from different process'�stages into a global 3D motion percept . Parallel.=s late? egra3xmay explain why , compared to 2>[f,Frais�� ��. WI�exclude OrivJ case���he9geparatI�HIA�Iwe�G6�is zero2i2�!�8E�A�YG�id�x6 A�ppositeQa2Uin-�A0be writ��$s ( 5 ) Si�yin Eq . ,wef%�concer�zEC�1�(which equal �B/6Mf��A� z coO �  ��-h��� �1"  1�|a�&ule�a����=�!3Krefle�6}�ve��I isplace��. I �follow�w�Qsimpl� A8� r��s o� fr -A:� scrH $( coplanar��e ) at��ed�x distq 4 D ( see Fig .e� �isI�epipoaࡎ�I$horizontal)���val��N�(z-axis . Ag�%, sQm�eI have� evaluU I Q�6�m7 ) For ��t�f' ��ist%L!�%�E%�2 must |��y.\rif2�a� . Mo� !.iɢy&= !�e)@three�`:�nݠo�-�E�wo * WA?A��e�!o�M7ed �.���%� to� ��i.K JJEF�e � � ܡp�JC. D�lan!$r� ecifi0 H�anNf��( 8.1aEXy6i!s� escrib1/surfaceV�� ,27re� �I l��� �b3!�d 9ͺ��n� to check���o�>>iYu�or co� ��Ŝat_8if ( 9 ) before�9an*1their6�!equ� �N�!�F�%GE��y2�105�u )fE�a� ter~ak!=>�MZ abovme�)RM;p s��si2unknown-m s cL%�cR�m1�S* �B!1 d( 1�Ins��ng!���"� h>B9:s)�6� pA��alogyA!2D apera�� ANna�3ew�e�plaus{ tegies�.) 3Fs:� shortest�in 3-�#veloc� )ce betw�q� starspa1�stimulusI;�9% isCE_orq�Mthrough X6�5�@2+2�� R"n>�we pick%F arbitrary J� oR �e>Aby chooO aM� u ( B �\, 0 .  1��T2H �-�computeIY 1'  �)? clos!�N�:��?1� � ɣp yclopean>2A /` !�*obA�dA�:7  V�� A��T aver��2D1�2Ya�/JT��ionrIf!PmeasureA���a same( l coorA a)W*offset2�J~ancho�at��t�-�-hnew)�s bI�!d AAl��,?Wstablish�"� or m� soph�cM v �=�.: e� ��Ez�.� !ac2W*��Z��Gha�s!G�>�[, oneF�fo�1�&� . By i��+!96 ��EoS i�.eas�h� t�Bc A (D hol����2Li��ub�und�a��g25in ca�R�2� Ftrans��to spher� 2/u�V�ʉ�to�( azimuth αs!']��Q( 15 .q�ba .X elev(β���n��( 1o Suin�Esp� is�[ to��n!4 [ s.5.n�SO-acety}Upolysac�id;Afcommo�d�%�u��@thogenic organismAƁtr st exeNl�ce�lPseudomonas aeruginosa secreB!E anio[,�ed exo6� algy duraSchr9��� lung�@cy� fibrosi�tie?� � �maj nstitu^  �`ive biofilm matrix . Four !ins� _P� �B}�, AlgIJFe� AlgXA�%Tb�lbiologE�� AlgJ��՝d its�uc�,to 1 . 83 Åqolu%�. =%�DSGNH hydrolase-lik tein^��whileX�sKc!<N-��in~omwofeX exhib�a  inct2�e�rostatic"( pot aC�s����6�s�eR� ervnataly`triadA�F4of D190 , H192%� S288 demA *��A!r�eMestera�activ� n"��� �-depenG3� Add�,e�X�cap� of utiliz~!@surrog%Ee$-donor 4-nAYphenyl%>#�E�z�/BjN� . Ou��a<cooedib0previously pu �[n vA? dataUugg E�� anno�d��oes!P]|�E� rol��nGI����de�_Y;)+ -�tX5���(ly� prov�aQnalv> variI� Onumber!�pr�-�qd��%u�\>� Z��n  rnŵ$, Gram-neg� f�)z�c�ac� ] B�b�umi!do��ntalI�)�"bC( CF )��Jyif� un���Heae] �� rbid�1:mortal mong3s divid�[1�P ..@!0�to�s��u��I��� �un���att�d5�cencapsu��Va�� primarilyl��tracellu�a�Y!�B)�a embeddm��P���mo re�!�tha!�{o kt�cou1pa�environ!�tes"� antibio�!!�d�f� �|1aevag0defense mecha � )�!v0host [2]–[7J�� ( geneᔥ�1= �e� leas9�٩1B (s: Pel , Ps��X[�9J� clin�>iso!� s ob�"a�� CFY�wn"q_pul� r�!8i�-� large am!�� �17!1E�T�B�A� synthesizIr!2cytnsm��� y$ala4)in�zmembrane�a P ar homP ���"-��.H[1�!13!-�7A�/iA= bseq ly m$ �peripl�I6�!�epimer]"� β1–4�kedH# epea4chR F�T^ C5 [ l-gul6�-"�"3*� �: �!Ga��4removal3�B�z�~n� ore�*� � ���Zvi;�virul�in many�h�{X r exampl!Q��b� humanA��s Esc�hi� \li , Staphylococcus aurend> epid�"di=!s%�R�de-N-�*D!'F�!U -β-1 , 65$-d-glucosa#0 ( PNAG ) [16�-1e�.4de:oP��a�F  ��Pel*� FA [20]� Bd��fasV.$2�by Cau�'' cres3"usA2�ada��n} [2�In�}|:�� B{%-1 �%6� ��� le enzymAQ� ����'na�b��6�carboA�"� fam��4E"(�ariso66�Jea:3lexu, � wo���.��first2yT!�f �an- A �%��,- is hyp[�r� a 9���!!�Qbo� �s( MBOATA�22�Ase :�, c6^�icR[,�s�!�� �6�%'re��cur�*l�4�Ks� syste�1 ���ei�Q�f~� 1j ;�inAo g v by both2 !�~ enco �n� peptidA�a�->S�,)ta^~I(,��A ew U� o�"a�"��A�ri<n ��,���`i�gQ� ED , [2��2m|�C6�xyŠmuramoy'&�)K ogly3 n 6щ�N$ �%��"#@ing; Methicillin-&� S� �[$( MSRA ) ,� il�anthrac�Z,Neisseria meNi!�eg�rhoeaN'�25]�itWferq  c� d�(dE�A�end�o��utai�%|� immu�,eM&E[2*A�?}g -�1�6\6Oat )!p�. � ? W�AiV|"�  BV A�� of PatAA�heM�� PatB ~#[27��(�L�)aA�q1in>�� 2 + c =��fH s lemusca�bl%�recog� �@ learL#��J�!  �-1�n*% [30��q��!2�pof� by .� fluo��& &u"K�DWssG ,H I�f WssF-�� w5�W��s;P=< T*^.� , [31%�3�EA-z>hcy ccurz !CC3�\group� >5 � d�[IA�predic��La�4`��N�le���-v7f*a!��8� p�k1.� U� � )3)$5A� ���!l7 is�,6��a���e ����.�, lso unE�815�.�-�!AUvy��lO28I �Xa�R],�r�,�D"� >J�8�-�� ����an.6�c 6Xa C&>.t - modul1 CBMZ 34!���1�X"�2�)�XJ� &� !�U�, D17476�S269 , l�-��)2��5p6�/ A��$��3w`/un-n�t�=�J��>3o3S ]!P�f�.[e.A7t�ndIE�] �strW�b*�putidaw J75–370� p�)�1N��p9�}09��,Qa. a�TMHMM � r v2 . 0 :��) :- PAO1/ s%2 eF��helix 9U12–29�Y t teNf.4�icQ��c�ic&2 [36]# ���iQ[pIzRmAplQ�9�pr%1=!�!yA�U�bioN�,t�5m? rystalliz\&�{m��/��79%�aA� &�u ( Pa *)�thA�Id1�wa� calc�#n2�)���"i orth� �5�M�, :��lch sha�X83%E� 53% �ce��ndX�:�% �5�0Selen+hFne-incorC7!o( SeMe . e"0, pur�,.�a��6�.�.�5,� -w�2<anomal%1ispersA�( SADa�echniqu�mT%u�'.>C=��s� 8�$two molecu�� asym�2|Af�(iF!C rout"� buil��r��8 �� yiel>m6�( an R;<R*)ofY!. 5)�2��2%>�(2�An>�a$s0%7 ,matography s����� moA(*e^e�(Inot�a+��d! ob��%^!9-r��!*�*Gbelie�p &� ly ri"n!qd��su. *46%�a root�%n squ�h devie��0RMSAIof'19{ over�906 alig]backb� atom�Du� �poor �0at�&�~+nsw�re unE��A,��N75G77E A266 K278��6Y�$ ��R7 L242.) Z AP P244 L2452"B . G�5�abs��woaC loop"�&m] F246"v� -Q� al aA�seA per edm�:AaelY:�#;W�03�u� �&m� BI no� nt.36� IP� �&is�m� vary� wo�!e �.�)�@a!!1lip ) [3u6}�#(an α/β/α2� -!�h�u .'aK|�te9��5�+� A X$E>��n~ f6QblockA�a�1�):�� �K��in�V�S Lup]<β-�,�W(y2�)<1: β3 , β6–8�!n�!d7 brid�t - a�oaT9�f�  3t8 i�'n�alB�%�� 8� !c�Et!K;}8n� α-� e&2��zα3–13/e �leS 6.��0"�0��AZ�aCT4��W/ f�5� e �0MZ1��2�J�*, 9r<4. Exa��% ;��b$%�� &D!eg��of;M�7�,N�n ���ia,belowE�sh2�ǁ��P="!�1")w� �ex�X�'� �7� �8� �*a& "� T"e�%s� e��i�3p�#oY-&e�� D193? H195� 6� �aȁO7InM% 6�+.W0W2E�1R��1D-�-�eQ@bT"I&-��grEta�=�S �in� �log�Bsix2�s!1( &* 6,sy! a� E�genJ entShil��E0alkylphenolia�] Azob�( vinelandii�a]HA 90° rU$A�al" *n+a�6QB��- depi38a gene�(5yut� q�6y-)I\�Aa@JB��!5�C�C�Xearch�*�� &C)%Q]�DALI B���JA�me!B��R�)%�2� X� � 44� 4�� X�Aoa~� of h6"� 165"� Cα-� 5 3 e��H<6A5A�orL$�&��puv���)R�)pa�3� to �27] 74j�r ser�Ae�)�%�a���B��?4>1)4_�<1�n�se{1l"s��.�cj,XFl8S IIII�U�!RY�a�1ag�M� /5 s�"I4oxy�-eAl� t=C� J�:�9 ��� Y348Y�d�)!�acB a� g / ond �(in�$c%Vb�6�l:� a ty.n"�  , Y328 � p��W�onF-� �� �5� GDSLZ�� DxxH�+in)�s  Vi�&H�)mV�  GTSYS IH I� 6�aa4M�(�,e��-a��k �XV �)!�x2r~B�ai�MZe�a�Z-�Ak a D1�S-~D� �cir�Dpermu��>� �Y;�F�A:�'y&�$( H-S-G-Y �"�a]'ae>m( 4N-HeHowa�m��� V�n%6hap�fosHt;N2  despj AGrearrang9 Z�B�E�Uw �&ne&�H2� :&��� )u� `B�6(&?:� P�@��&+ ( β��β5 ,"� E����uewD310�cESt#&"�  sm!ncap��4!=pro .x� Az��9f��wS5� J�I t��3A�� � xD�@u��. D9�seU��B�.1S &~ ��%�7��i� E . coli��o�� I�AP)y nd A g��$atus Rha [� mg6f-zs)�,$3 �@Å% 8 a& 101104.�4Cα�CBYA�!�� "�^@f� �-D GBi1,o �$�iB����ts&C >Th!� sa�6��:�� % ΦPxKA �&bvy)�phobic�5�( R/KE8 DTHW�( aaf,:b �Iig6`2{-�5im\Fy �(abJ�6� �U6�0M��:��E?�a� �:��u48 wo&�"~Mint�"XaS:�5)3s%�"A�O)1���@ �K� sA atop�6�� �ypi=G�Bn8 �� A`�=�7��"?6esJ%' ��"R; K13�T18�6�푅5 gen-m ��R!; L18725��S!59� aE6� .��*K25�%%"�6s4ab�2�Cf!C� J%i�. K137o �A%U�AQ�S�"� Fx �/"� 6� 6.(*7�>�%R0+n�9�" 59�:u��wWG1>>71� (� � �4AIh�'d� )���1� U� .�"-"� 6, yet y�2vFR"&�Ha�m`.�iTirI�*w#Ohee~=�7NY)s*S!sEiS �2�*�"" �3>$�3�0�3 furQ e 4�ir cruJ� �9�m"1 1Q?9�E� ������q�;r� ofi��#i��s1e?9%كW�,I�V13Y2� W295E= F297Y�4n 8$(om2ly bur�/Apri&.��F �� �` "�*%gE�d�  MCwe� �~5-b3Ad�9�F"�I,�<D,y�1ngI��. �AN�S halflIT.xre]6FI�"� Jk�$y�~8"\:�{ �ɾ�%}z.�9hPb�te 3-7#xy�6llifer*!8�kin3p+F�0�����LE� +� Mj a 2-� U c��KmA $he kcat/Km*h3orA�� h�T�?6�;om� iK -�,v%�L3 �A�W!@E�A ��o!��(1�Apv 2��a ues;�Y0+$�Y1�!���| #iuSau#E?I$s!�it�řala��a��-g��u9*��X�eM���XA�ofF5]3i�[o, m%x !}����-:U%�QX68!�e� by ∼80%��*E. C diiism�8.>copi7S:s!p�I�@ve9�0ec4� i�;��NI��ra^��Pnd.m$��5�! �er�Xo� �F$XQu/9U5C�dlW6� ��Hb�JA�C�=�1F�|2�� &�U�!�5bb*�H��� ��" 2B��s:7"�&e �>5]iB��.�|0a<"� c deep`�v"��7t�,e��(�(ia��Bor�1>+e�K�JU6�+X��a�)� j$umably aidE=�!�gu g&e e?to� "� .#�&U(餉�7�%[A@"�i��ac�A>�oligom�/�U1f�h@� ssay$ car�out8�,R�.s;S� %�12� ar�$%Iled@(( ManA4 – �L�A!|en� ESI *#Aa acqwXd  aque�aiumM�e'��e!S%\AS�EreOX scFv�ref�M�2�6!� 1k4KSs 6 6�� ly�Ql�um>A@, B�'T6�t=roton3��$A(1∶1 ($+�&aW�5�+13Q+16RgnDaW,�"�Wg��%+�( tor1/)Ua�-���A�non�� An" 7"�4Q�t�YqTD2!�A: znB �$ 'ly6�a)&i1�)�a_) a vi�"y�&r�Z6 !�B"ž�bO!A�� 1�JW$& =G o� "�ligY"ty dV0/DL� ])�e�$o&'6�!ca-%�pa{dhya2�;( HA1XHAmM . ImT+ant8 P=e �A�rol= ;Dno2� U1���E�Aa R�I��.mE�r�6confiZ/g3Y� ' X!�5[O�?ra%ut�?3�h.�do�ne�aa�ER\N#]]!c � )�6!!�-z�u <��0/FEd�� a`7at��PW. NAthe�8Ea -MS��2� �'R>8!s �|ѥQ��KPxtrem�K����$es�(an 500 M−4/ST\�i �jXn�: �I*�g��D�?a�? t0� Ap�4�B 8"`V:KA�;�io� �@>* h*�;�́K�$<@�T�% ��FA"Y>A �di �^ >re����%"�ai�!�?)���@$n m/z shif�4�%1U�sod�?s92y� �Ce,dB/a��Ndou��ed *� i�ҭ�8Fiw �as qQ6Fi�,S.P� �� h1��ont*ex_<)3 , di ��t!Pµ�ev���4VM&Y1+�Btan� *M�V H 7 �6g o -�6:fnd�<�5�(,�mer�!� vail 1sug�gX,llohex�@xy Qmaltotri����&�I eVre"�0Ej . Wh�;E��P�hyEW5E[����6,�,/��R)�q�`C~N�6z��S,overlapp!_�> 4:�; ��QT�al& *Vu�70O >vo"�7` Ten�1duœ� %G5 ��i$ machinery6�=�861.t?r�6!�źr!��{*0u#�`"�z= �I�8��P�]1< &F;%��% ���=�i*�=\sEPl�#�.O�.achNG�*� ��e::5A3� �it� 5r�<�]�n2�  &�. A�}ř== �,�K^)�eJ*%�v&� )��/�L��e;\ia�n&DQa��$Ea6�R�. 2�*"��|])�I�vX$�".��>� �&=>V7Pkn�^e b�A�":?G8V8q D23� F239�7����%"d}R&lA&�)�z!3��A�)bq�� -��7A^,bp&E�as impeFjv�7r��6�bb�+}9A��XTC�V%d%�AT)^e�~~:-� �I�u�JWS�M&�in�; P135*%K22%�Z5(W196F2�7*u s>�L&%;#F.") aQ(&�D�C(�F��'�t�!: �n� �K2j~A�Y.!�.�"c���%�re%=,F)M �NAvdisrupx�#!�dZM/�A���,Ka-� nucle ble�aab(H(.�2� � ��m�"��=��� �n %�u�#c /1f�xti!!e "n=oxy�5of�'R1�\! i�&a�:�h9α�gα45�axia�&fs��B� ��AQ�1qi�aeBYs��#&�Ca*B0 �-�S)B P132de}'Q roxi)kto�-�%�^��67/ofA>, mpedIbun"���ast"�a� @nticip9 $]i%*@%%�A���A7n/bo�`m�� l>atqhN�cuA��[m�BG cQZ@ ����hef�A�Yo� a&n~,c� %e�q�� � e�R`F!��D� `^"� c ���eSii;Lal>� step!��-4� *� &?IQ� ��i- �k�es"� �#'%�me�h�- ��Ea�e;�7 ( y&a )�v�[�#. C5�"�"�#`VAo� by >�#�K���@=lm�3�"� %}�8�U�kre2� %��9a *%�&TaI�"&&re� Mat�.sAie1e� <�7�� prec�tgon%�Jv��hPrCE� limi s�a�G* ���I��i> Z{3&e4< po% .[� ?F.`t�<7�opt���Yi�HAqmv�ety/aE���al:�X%P�&�s� ��5t�a�o�k>amino�-j� ���lmicro*�\� - romo�kpI/O,-ek�!}5. �rFp9Y�OR)F:q�c F5 gl'�G e-S-.$[48�~��6uA $albumin [4J:5J:A�i8. %!�b6Re �7vo"�,�!E���!P�� � =9�8�vỈ�q%6�%���k"[��%= W"Lf�I�&h�0�'  '��"�#Z�j2W&w�m �] �>�%�_t�}"/.W��* ~[�GW��� _6X B>>� 'mb� m`�jKA|��/�n:J*V&�@&AG%Q7%w r5IAX�%]fC��7er�)�C phys"�h� IH �E>T��!er aff��qIjuA'a�3rJ�m`.�>y&eY�-&?,ae2i%�Ł� "� .��`lq� �A���f�1-�d Fa �Y61c*�[N�� -`�to�Ef�9���"%L.�m�w�par2%A}h!�.J�,-"\�0.kd v�w&�gU#towardV�.�nOb[�@9�����6� &�/�)��'v&�\ � oY�!(sucx�j&,2� pTqBI\�x x*+ g�y uE���upde M�b��a "�+Y;. Brief� ZV� �an"/ �c&:Jm�c�P)'�*�\r6@�<�:�b\z�*� and/:$FlMFvb�Ln+�]�@(�Y��Q)2�Q1��;G!�"i�7\3X%'�%�Fl(e��0la�t�:5!��.,L��ut�p' ledg�!"q�YMP)�me�� ( �e���%1A�W�!b�&� "�"P?%Pu e2��"cer�.�� q^JiN� &J �aM+� "�m��aaP%qhgE�a$cipBD�*P �&� Xe��,m&&|T6.�)is2 ��be �cd�,�� AlgFQ AWEof"J&�&� ~ 0E*�!6�it��=RY�a�^ory7 .*2 �� 1�X� z) :�.oaZ�8 QN�iv�Weiv�ES E�:�"DN� y3JU� t�ua "nf),z `Q)�%0,� �39�*.r�is����!�B� .�"� ���iMX� sufficE�8"bo;v^ ��xvoW ��/" k����vip�_���Z& %��I�K�&�!���*��9)� �".ea7minimuhtc��V7�!.�s Mv��&TaTf� Q��灯4\��a�*e�"�d���iVEc%m,"r$)mF^d,a_)!�l&�Q���%�G�� �|!m:�*p�)��F6B[i���� gard�%���L�@!N6�� �iUN<2MA�A7xlaf�!��4*$-�$ amun $tedly �D"*ABs=�B�� \.��66u� I��ouK[1�9� q�!.(���U-2I[5(c5�� Such�i�}'�enQ P��6&n2i%��WssFGHIZ A�ul� ��]�*] [5�pe 9S�7to!SFIvwF7*�g �;�mX of 2;E46�nd 33B.�*�>� !�a?�Y�*�2ep�!!6AA "mpmU�τ�X��*ite i5CBM�sA�>�S�-5�.sVX�5��di �*Lor�Y lA����f � C&�#!]/�!��=&�)�C ]�)�0� ѫbeyDP5�M�3p�T�G&i9��fu n�(W�: v2U�uN6ckwa�9B8(N�EP� �&yh(Ser-His-Asp�c�^ v����N�6p�'C ��~��6rZ'A� F�{!�weIE9lu �e.�Wf�uŞˌr�*a�1mk��56H c9��Fo �n�7�YM�sD� aven���Q�q"�p2� �J �,:��,he:b�(kingdom . S�Hf�.0Ni2+ NTA-agarhn��;!�RQi� 0 ( Mississaug�WON �`G�`it�*�m4id ph� F2,o� lumnZ8C�a SPEa b�E�e�Gr�SCanadkInc$<jaxK xAll}(chemic�~�Gh.- Star%? �� n*nAa�050 mL Luria-B�n�bLB�rr�LDm;6 23 ,ZKP�J� *ubaK2,����R P1 �!'ac�pr�;�>8 �%�t���a'�1 L����. Upo��8� OD600A���CV��inh�� isopropylT\ D-1-l'0galactopyrano65( IPT4�~D��s��?p1�)dw1!�o%���g*O 18 h�291 K IA harv�d vh�{ ifugM�' 00× gZ20�N772N pelle��sto�St 253 KA�ilϘ�Frozen�.6tha��, iceeYre-sus�f�I�cw^Y,�+(�?mM NaC��8M Tris-HCl pH 8�<).��*J! El��ZXF�Y�*a�R�$��h�lpoo��G ��khe un� �I1I� unta2�YF>�D�bmLmjMM(an Amicon Uy��ɍfiv6�fc� Milip3$)Ia� kDa cutof�eY5�F�I�v�cbe&�A.li�nofc ��i �2�L�i�[vmu�:,HiLoad 16/60�] dex a�g*�i!E�M,( GE Healthc�� F�s�� ��A-�!�aus��SDS-PAGE��be >95%��'r] b5K*+aeup\2T4 weeks/iC�, b.8. �!_�$oy�j� 2�to�W&rm"�LF.~=niEr30E`MWCO ,.��c���Sparse-g�sck�� setup}h!��SMCSG sui�a(4�cro@t_(48-well VDX2 + ( Hampton_oeGVEa� dropE*m=a  L)<�_1�to��Ekat�K��a4 µL6�� 2= L#w�F�]9 . Numerh8E�"xaf� 1E)E���J&�sons;�Q� a di�_B( Mg2+A~ Ca2+�t�olyethylglyPE� �s"�!335�!6� Da��ny��Ms�� ���XJ��|ra�*m)�WQa"�>���!v;�_e#�_ 1@)ax�&50��h%9�iff�[O6.)�Y�f[m��Q�. CI�sA��col��剁_5�A�4�5� 7 (�2 �Cl�9P 1 M Bis-� ∶H� 5 . Vi25M[w/v )!�!�E�PriH"oB�"l|mgcryn�ƒbb� chan���a�e �E &e��adI�!�b�5�4e �AB*�a��m�r � -9��Ai5� ��M�Q�-}u;a�3tPlY��Tedl]� �"Ēd�(a� BTU�E�D�in liquK!3X����4le�X�le�Z~e-S]~X-\�.Se�ma�n beam�� X29A�P!dN��=xyn^ tron� Sour�oNSLno t Brookha�K9Laborz� N>m �at 94%u �nujI�42° Δφ oscil�+! 360 A�q�Z�FB1NBF�� ,DSC Q315 CCD5cK�P260 mm1�-toN� A+�P��4 �<po�� timea �Mx-�)a$*dex5inD� ���j�k�u!� HKL-2���Q�l[68�-�y onju"?!%9 2MAPaS�%e 12 (a�l�sY\� de�}�$�u�,lc["ASOLVE/RE [6�w��oA/Kapmlof.�-qu�㡫6�b:�]~�),PHENIX AutoBw~ [64]�&x man@;RACOOT [65�6k�M���Rin�� ��2y. REFIN�7 x prog�6 moniU�,�*�aM>ł!� conv!��ofB4�6��TLS>u1G��**���D)).�us �TLSMD�0rK��.l f�O aBpla"�2eu^L4| &i:elg�U,PyM�A M"Tl� cs S�,���6�O, SchröAer , LL�`U��&ak �!$STRIDE web9 uSR�|�z<#A��%M�!�o{�}=�!Bb�erm<%%y7Ahr���%�Pi��lul4QD &�TE�v��. Ei� ��9�m�>�<ABPS To�[�R 1 pl3��pD���)�[��.=4�5:�a!=+p��iSsCon!m2�ںa vis�� 1�#�l!k�"�` �f�3�;gzareF"c>��PDBePISAU�������F���8 �8u .�M#݂BL�7�. Multi�?�6[E�>c2�*7ep og-E�F ( MUSCL�$.z���)� �%K.*- A�eG M ��>�a�\L6ZLAllm "M#; @"�C!��78g96�hAtn� ,M�ak�$ctraMax M2� �Dev�uSunny& , C�qStand�;�"V ed 3�+mMz�D ( AC�=,��Qin DMSO�0f�/DT$e�a��le��%�sP#� L0 1�j5 ≥2 3� g�,-or1�.1��l0� %_� of .L�sod�cHEPES&_" VpE�,z Xvt x6 \%&�A��V�V ed 1*. . _�(��"e� NDpu�!�-� ,#e�Dgl2m!��"�')GA�>�cb��.~ �!�Y@:&�iZl� !akc%�)o�Q�(7im�of 386 n�<m�(�Qf 447���U�*�0-���B�H �����.�EK f3���&-�]��d . Back�Znd.a��a�h�H"|Wn$ !Y9� subt�c� ,-cH��9]52cai! cur�N7-�xycour5n-"fHle}i��t.��"!xz�n�U7un��Y�Ao��(U �S� *!2m�r2��e�)u��B\����D,�%�fitanon�aj}� !�7 ,Michealis-Me�4.I�u� Pad�sm� ceMac , ("SofA+XLa Jolla California USAAE ww .K phpa+comFIm*t�-p2 .a#,>g A�z &��%yBoi�XmM B!i(� )[)-ż9�ors�il�Cor҄, Bedf'M��w�1 MW�-�A��(%?{061:it.�S�eH��  c�!�sh) �U�orrect!;6�b��AgK�#�qh(����DESIA�ces�?:&5� h�� @cFv�W 26 539�"��z^cl�� �N$body ( mAb]�e155- 3�@a7i�"�] �?*3P�,E# lyso��( Lyz �14 300 �,e�jSA >�-(.�-�-)�%�!��6`ciW.���3�Y_ �B���B�i���.�M�aW},at −20°C enee$ . Stock�Ρ��ex:.�F�n cid �EC`,Cr�`�do�`�`46m)ʡ���i.38(�i2�i,2R�b�77&78]ib+�:bZ0 akn�f�9%so�0compo�e in u�dw�!�F-QA� $BI1$�E{Nx$∼*{$�)nd�-��9�R�#A(I6 �-:.�/�Syn8G2�drupole-�Pmo� �y ion-of fl�&$( Q-IMS-TOūmaw��Sr��e!W!� UK )��ip9w�N"� nano��( ) s�.[  ��%���in"�a�td(ej+��"*=6͇d02'*?�?(p�qhŌ�> �� bFs�$i�J@!G� ���K�$���---��v i6 o�9R9d�8�(O-AcetyA�nc?00� �A�!7:$���� fas�Na+th�3�f ��*�!.�0���eQ��@%�)˩s�<.*H3�4- .7yKS� diz �ethanS3%� �M!Ou�ae#ofj0 e�,�}inc)�6� oqiœ�|L phosph��$< 3!:# �'�"A�j@d��%�=cw<p.4E%�adp9��� ��)F!�o�B��n��ro> � yQ���1Y!sV$r� M��h&e ���c�a ppl�@`��r/aWa 4�"6�=6.�.�#&le� 100%� �rqY!$�+� 5tri� o� � ( TF* -+y i Q�^|�AxRll\�!mNA!5{A �!� �s"!Llyi�^pF��0��, 3∶1 &s+alcohol:6F(-4. PF�9Me*�'6!�of 50%RoL fura� :��b!ydr�Tr vacu�����Vac�. 1s�3M���*�*\ �\!��h>�"� �� Gqc 1aޙ–:(ry 5�&��n -01�$ HPLC[2Z�E�):,UHD 6530 Q-T�B�a�@MS��ry Fa�C%YA�Adv%d&xoC�,#Uni��?Pof Guelp�'A C18Q�(�Porosh�"12�_�i mm×�Z6�� 7 µMA�� ��2������Ŋ"1 A3 1%8"�C� &B%�B�Jm��+q�  e pD��d�I�.(0i6Zc&)# , 2%.}i*�] o 98:T�Uf�eN[��;oŏ:6a107˵re-eq��!%� rst z_l�H&�,of�a�?top"Z�� 2�mG�a �)�)/� oFsgp�capry��3JVA 0 kV�A�d�ga�n}a�&�p TuneMix�5q~�� in����Y1� ���l~ � aP )p��s� ( http://�mE�. org/�2w�nd*�fl2�6 5.� %u&� $PDB , ID c!u(4O8V .��Cߖda alb���"ܸ '��n_�huг fung��"U��G0 ��m�` ��&. C .6r�%i�Msh 5(��b�lnD  �celruv1 maska+f��n< ) dzn$�!�n�t�wal��O��F laye�L heav�D3(sy{9�U�3�si �an%�H"^��6�s� drug& "�c����F�"^� ( un��`enh�)�'reQpA;lkD!]n�'�+CMs�!N i_ P&RZ,�dlab�k�.�B?�Ba�ť�� olipi�A idyl�d( P%=!"#E�WR�1i��3zyiFPS y�knockQm�; ,��1Δ/Δ ,&�D���$^�R& �Mi?/n A�1a@Kin}( MAPK u�hwy�aQJup�[am Rho-q� GTPa� �-y=!Mr�L}�U�bi�&B:\�',>nQ�II�ch�5�;Cek� Mkc1��<K܅i�-  ��Ry dow��6� Cdc4��Rhoa�2 .HJ"^,.!O� �Up- ����!��S�6 ��#He�� �or �!,)��k%��%�#yg. D�d� KC1 d�`dec�a�(Q�J&5u)2hy�i��%i�'l�!�� Qs��6>%�6�,�re�-�Zd"T�J}a��& �:Ste11N���� y��yDR���5�up-�-X�Ye6�Hc!�. )Q_JAP�y�7a%9�2�. R�����ens�A9is1\M����� lorao,�!igastr�-�-nMiNA|i�Sr�Gs�Y���c�J�a��dR% ��8sT a�mbiZu&�Amºl&�!�J���Q�icܙod��"Q�A��h-r��(aC�[�0� ��� ^2�330% [�CT� ��las��/nti)��� oreO��2�"|U8e�Ooc���A�Qe��[��7�=���AJ��s.xJyzcput?eL(D6%�t2�a�X�mA�;|a gooKerapeu�ytarget1����) U �as9M�?�S�$v"�� a*ti��/IS!.�3d t'A���&RHtqn �-ȴ� Q[5� 8 ,  ( p"�\ m|�e�im�&v=ti- O �!�@"�-��!w*�i-�A=+lby2d�"a��H2�i2B r �Ti 2�is.& ab$ �@� re�zeV 5>% ago�yN�s [!\1���S k�F{ t���e%�� E��9�[6)0 m� phw., dend�� #aYn�yoN�!ca hFie<�a\&nerf %0�\�J��R>kl�c�4FF� � "� U�T�. U�!���!,6���sV��p"5 &v viaE�:G Z�c��™�ٿ^ !��td��� �!m����Z����6n�ora' _q(��" AIa��,� 9�a�grity[1b�15�JI �B5e2 r�j%���� aJ� * 4 �"( Cho�/��R!"_[)TP] j �L�ud�Wu���T��eukary2�. ��l� s PS �!��2�n�tf g mPMa 2"��rb��2 Q�.�qJe �).uA�PE � �n�)�2�� �Y#R�55�*2 CHO1%��c.� "�Qg�erz}!\��"� [1�14���5��B!r� �Y�8A�A�uf�e݆i n�.$pro-inflam�R` �setp:�A���" �by�!v`��� !%9�4� rj�� �� ���"�X�f� is g� {q�!YJB&�% T�  � al m���Ei�� "�cascaM�!b F��(Հ=3.2� mao���_`yUE� &�A�dO&ng��a wxz:�20�i2�os۞cAes� oxid9[� a�)sdaA5�chUIA|*�!�[x�1�81��1�E�B�!�!�o � ��= d��E �j �~b{ )�KK~A�F* #�:$ ��J � As.��Gcrs "2 Aef�to&M�"a�!h!&!�be@� VZ�72�.�d&�A*'��]�p-Hst7--S��e*ML-�D�porf)!R���AXin6&[%� _(. CEK1 null�sa����!<j-�{D_�to+ E��6urb%&Y�s�� Cong����.e "�k�t�ai3]n�@$Bck1-Mkk2-*S�&C=>.Yi B�4!�,���=as "4�ex��=���}l��a��  �Q low-�Ner�yshocks/���6Ye�7K\M&dap���b��\K b�2�8Ao�Bf%�1�eP��/�inY�^= +H��1t�+�7rexmi�Q Al Cek1M�!�-^#�edi2m!{��� l�(��- [1! )PTh�j�h�.�4A@a���.X��e=�� vegea�v�gVA� morp��[��.��AX-� ��B��5h"] -� �� ��*���[2i2�+�d�n~��bӹ^j � � I�tS_�{"i=�ts�"9_�v �%!/��ax]ito�Zs �!� Fks1�c�� �3 s�3��A�� pola�%Nth �itz�aO.ejJG+�2U .j���PAK #�Q L�$Cst20/Cla4�01� G"q��M j-�&>}0A �����*�!`-�!`,�[�Zw �yExz�[r� Ya��o~Ja;2&8 .�S nȺW=�)� �4 (Eg!�NE=�V�F��3��2�&�Fu��rm:G%��7N(jB>':R� U�) V-n%�h�!�"�e�| V0"� ^�. Y � =��'�^ess�2��F��B-Mmig �x�M*�6�YL��! ��CBjQ!xAs���Z����WzOrnb�R�*A9�-p42/44�7�.r%aabe��!&or�]{t� dX{orq�J 5v*b��q�o!&��k2n� F� aroA� �!�v�. Nb�����6!psd� psd2�-�(��{E'~&f� 2'w 5��|I &��M�.� 4�*x=n�7qzY5� ]S�* trenw& s �A�h���*�#�h=Q�& sub-�J^+ RPMI 1640]u��J�f ilam�,V ��*�gm eL]�Fr2�-6�tL�9h!vJ�-B| C2F>Aԡo#!�f)�Yt �}�m�-u6�%hu�4. Galán-DíeznU.&9J�� cekIX.� dele�Mc-Z�.�2���In!��mLi�6�}#�`=�,�DP,!��)NS�6��GlcNAZ�S� ,!^LR�f�39r &�{in�R�}]�aIXm?�1��*�C^Z >� y8�-��eW w;� �2�[)��W` � �Ule�x STE1ÝΔN46��i}�p*' � malt�.�}S0 PMAL'�. DQ2�967.cZ�(~�,�!�f"_T� m lof� ,.��KŹ�� � v am@%v� -�!�tn R> .�ARJgm�3 ���- .5�e!�YP5$ ( YP��I{y�"&>}of �cE|OH�2D tS_v iR�־�.�-��) �*��N*ngQi to-hyphae;.��0"�<��4f cells form f�>ilaments in the hyper-activated STE11ΔN467 strain in YPM , and0�ihae exhibit β ( 1 , 3 ) -glucan unmasking more readily than yeast-form cells [12 , 13] . To determine if �B1$themselves�$ed greater{�a, we used flow cytometry with a second hyphal-specific probe to gate out hyphal cells while measur�R\exposure . In particular �stained-^s �Lsoluble Dectin-1 ( s L) protein which bind 8kedV�0and anti-Als3 body�G�s!P)�l2p9. Thus , 6�was)`,as a marker B9 e by>�allowCus1focus oJzis do%zrevealedAR(t wild-typeF+expresskB�te1!f.�)apYPM have significantly increa!kY�compar�o |M�e14D ( Fig 3B ) ;,%n$1st quadraa� ( Q1 ) ofplots .� growe� both�!�Yd$bottom two <) . β-e�q�E'A�is e�Hintense at bud scar!�I!5enaWa�(possibility)qhigher m�_n.�-!L is associ�_e}�wprovid!G(hat maltose5qs� th ra�eR fact��0curve demonst'M%.Y!4.Vi�cultu!�%�M�Jw sligh!�bet�W.�$correspondAXqin�O!� N ( S2%�!�Howevee�hen��co-E�ed �%RMa�e��$calcofluor!�te%dyAWati!s%� chit��at!�8normally concen-%at,1� [41] ,%�^X6�`sca!(ed alongC!_ peripher�veaC >�%!Qis�stricE�o0@division sites ( �]g .�s ) ,�G4little overlap!�35�FurtherE�,2!dY1�mi��a�M�-�MV1�, but2Lhas:D eleveR��X%�a�edium�H�3CES Conversel!Ya�Q�2�a �M �AR|%� nEǕ�& q, a!�dit!�w!� Cek1!�no�$erEed=A� More!��v��replica!�%�rapid�e��t)aN)Uz�A0��a�@fahin�!Ia���. AltogeAI�(se data ind��.�a����,pathway lead���#v�����$istinct fr��a� seena�q���!�is%gbŁo� юnumber%�5�8e��l � betw\��u[12!ToF& ���[e2��:Ac%ologic�-r��n�lwe�� form��0n enzyme-link!�A!osorbent�� ay ( ELIS�to�ntify� α�E�$RAW264 . 72r�����is� . Asi+in�� 3D ,[2ZwB�.��!je� MAPKu�9>0 (24�'M��(It should basnside� `exami��j�a�e�producE99�E�duc![n/ ��<� ere�Ӂ �2,AM>w��a�cho1ΔΔ�� � �Q5�Ti�of��S./ �Dqis ~35%. x ���%!�2bof2L��,��2b,d2-fold��dzcj��:s!z0-inflammatoryu�sI�.��Q abov�ulAB*H�%�d cause��,%� sinc�i�L2�,!��fct w eamW Cdc42 [18� ��nstitut�;��d!)�/Δ��aCuggestMJ K2� m� A�.)inF� .��tesD is2& ,>X was 4��monitor� A&amount��e ?(( GTP-bound� ��. �_isoɈu� agarF b�coţe 3/Rac1 �T�( CRI#dom�[44�t:q4A%Pe�P -��i6>is9 20y .�::CHO1u�A�)� firms our�� othe�pe|9��]am&� �2g��h�(HCho1 or its biochem�a8��( PS may imp� �YAJ negaM�in^)�$, although�?F�Sbe� rect . We#n*� $he localiz�of yQ92�!S�byQ! Ca!� -GFP�be1�T!gmotifEiL �nd E@ GTPa B�4B��z69�).� ly��b��,I��:�9�4a��th"( bud .;��B ��� � , so�m� 2n� e�e disrup}RACaP T^�.} . alb^s�HSPR-Cas9 system [45awB�rac1΅��9Dmut�=Ua s� p�nA%5>2�du��bud���th]nob�� 4B�4� E>6e2� ��ineZ�6�2� �a�� re�}$in potentiI o���- �� )�E S . cereIae-H1;�oVPS1�a�ŷs a�i�� Npolarq|[46!�H"��{�itul0Fairn et al .1 GFP- Mc�� ructAv/ :��� f visua��tal �ra� �� just6u%>reforM� id6x� T�in 2�Y~t.� how ; �� !Seficienc 5 �a�60re grų� �z�� mis�+ @e plasma membraneE�W rnal� accum� � a � k� V tips)E�Q:�jU!2of=ItoJneXTre�an all d� aB����2]O insteadu:�!l%�� pproximats80%V9�zm��� �ed-y2GE�rnly 2 L5� FsA(F2@�M5{A�i�a�� ,��ecessarye��proper6V���b nextyN mechanism��6�y%2�)�Y<)�.=iv e mabund��Lanionic phospholipid�J�-�� larg!�re>,inn!eaflet��@7�� A C-_al!�$ybasic reg��Lin some Rho-family s6��� cruc�p �e �e_��onE A�s�lsi ch�d o acid�idu� motF�2a)E�?� i�do��viam$ctrostatic.��*� �.�� RPS [48!F9!F To elucid�if� -� -!%:� ��:U�� !]]��tAf� =�lysines�.B�lut!e/U� K183-187Q�AQobser�� 2�>��� h���,I�ayheNx� > endo��s�ur���� N���� . Of��nprefer��A�2/f�e�������b11b%�9N���Ga�� =�po:{of PpAAimpor� AC1+ ��f5� F&�� does!)��E�e.�Y���c2  by d� l t8ng �PSa�&� uone2��"� ,AY|nE@�G"�unmodif%n!still �to5e �AᰩtA��f-�%�c��E5���\��"w ( n- r ca�8pr�!{cE�aE crepa�weAt"�>� `� �2A�5nV-c"w_"�� 4or reflect dife� �Bus6�pop ion�n�!q � cd Z �2� ��4@ To f� investig.Xup-M�"w%�eELibuHtozJea�n7r�Eectop�ly~>� CDC42pI�ve�ele (  G12V��BA�t2�F+� � � trin�-M��� -XI�e�r�(�m!nH >eL>�e2 . Cew"�* ��"ed�dklifer5��liquia!d poor9o�D�a!�[3�S�l�a)L1!�!b%-��{domin!�lethalAF:� [50�Our�8!�is ?�� �� defeY�we��WB�by!c�w_#v"R� � alsoZ� iiodid�~E�ol��l -via� . Pro61"T61"a�!�n���e�#fewJ A�njk Y�( S4A��:�ith�|D2a��Y� M�%�a mg�$level� RW*���E�c#N�B�J�msA�ueZ�{�rsz�!� caveat�, �ly� a�pleiot!� c efI�.E�;ůN8����~��!>�V -� help!UlaR!Q9 v�.\ &� m�.2�e Mkc1�isiz|2"� wA(�#.�i��: �� play�%rol�xz�aW l�� Firs E� MKC1�!r�� via%127CR�c>�2��93�$stern blot��pe�t�9 ɻ%M#� ��!�)�� F�&� ( S5uI��A�Eс�z�o.�,� , mkV�� Y a�A�del5of)}did�rescua~�phenot&'��9j)�6��In� ,>�'Fe%%]�V�' ]��͆%�� ��~J.�cG 6*3 VatIVrobablyB�su5�� w�organ��.0 �!M�. Pa�a�FaaQ/(a{$modulѯn� Rho1A�!,E��8cascade [25–2�W�&le!#? Pyi!����Q sup� fv�Y ( S6U�Attemp!>o make�#mp�{p5�6�fai�)va�!�B ly t.��a� %Fi.4,�Ms�iyt�� `a�e!��ţ��e)r����z(��!On&if)�+�N��U�v�2 I� �!3���u &is e<=�es 4�>5� *��)e��t3 7 ka E�-��GachieR� b�" 62�at5 siX�� tagg9.�%�Rho IC ve Dj(6-RID )�I.H2:,4N�3(i .7(N � ��"c())U 7%Nh�a�i�6��e9�-A6�<%-i�dremode�0�IRba -P��@i"p. P? tmultiple"%&t"/ trem&��toMb!�usYjiD2�"qa� \/orO�)7as&� m&�E�E�. D��V lack!�)%-��a"� to finI�exactB8 zM2�!��QфE� ��a��206�!X upst�!� or , i, )���*��\r� �if6���� %.�3>}J�!^� �"�(of RHO1Q67L�&� F�E�,al6�� UA�� lea�GDPE�Z�>��[2>z8Ae�8z�*[��+�� "�/2�y�&�+���/9���.� a�~�-�(. .B%.� I�Yt�&ry�)6�-�Cw+��unexpe%-ly25 �� 4E�iw8�� !���%5C� � duE0le{in�2!�� �.�B� �!esA�mhy6�" or� �  ��s�!2��e D/�'�%� &2 independe2of losBP�W�!�$c� ]e�0y� >�aU%6"$4%=Or�%SM&6�(QA>KKi�7w%�)��%,�����2� -�)e^a:� 6�f� �$an�er|� R{��b-'��induc!Pc{1E s [3��%�>t-6ed}��4��.T�(ses+�*.()F3�.-��2�'!�.0�\ ;)�G��well-s"�,63[1r3�,5��" invol� A�ell`6pr.�� bud emergE�Y ���kin|Cst20�V}!%5eol��eHH L%�A�"� i"CI�[15�-�19 , 5T�t��� EL�fun+U(cycles"�an �.��in�e�`6)IByKASpull-% a��k)iEO)&STZW��.��z�u�E�!տ�T�"& (!��+�)VkIE46"�e. �4si��aj2��:.�%�-a&�5�� �-y ����see�(� -�CEK�%���%w�NV�"�be�cek�%m��6.^�t72��[15!+A �� ��Z� pret'��e �"c�*PS> R��gs lik���(= be occurrA[ thro�(6 u5 Ih ��Je6�*�9� 1EO�w"chAE turn�>�2!�%�-�e��:;)}v�� U&�31H& J OB<".�zs.� ��,ur�ly un' r-V&�8i�qcusA be�;a"!}-�:'1�ly��=�A�.ua%�� ��GAPA)a[ T%�se A3a�#{o�3 (%)!��eviouT!�aiF��2PS.��APID ga1E�$Rga2 towar�$�76�'[5�' Give 2�y�{ s~[16a4e0!Mo([les��=m�B��`A� <5N=B$In ada6EFre %�a&�5a11)'͑�l:k"a sub&�!= t. For� 0���)Z^��J~ZF..�6� �&~al"�.�"!3x qE�"�i6)&w!i."A��  A�is�*�w� "�.� :>�Z!� �._is&by� PSE�AV%�#A�$�&�%v!�!�%� �Q� ontra +i�(h2�x6-�d:T t!"by�� FP ([(�7A'0)� e!=�&� cX@A�B#>q!�݊����,!4 migh> =(b�2�.z4!��&� u!�U(����fu�r���5q$gen��)��t !B%4ACR�PSq~��2�>zrem'=-B�"E&�3On(del:m �6\s{a+in> �h!���Aon") J�& PS h5*groupU�I�s>��@�$-�igY��:i�@l� F�oi7n�'.b edI����of�on=С�61T � �� ano�҉�i��qu�-to1^� EDitself* �e_#�B��J�!�"P$a�"� �*�* ��?�C,� haps GEFs��,on�o"&R J'�$6�PS-�{#he zM#b��*�-e�s ��< -�5aV�5-�zs by genez"ng�5B&t6��E�� di�8shzl�.�=e� ed��S " 8����ŠS&�Fin�:�>h�FMVG"&� ho�C"�)(-@ia nd i&d"% a�s~�V� ,"surpri�$lya���to*� >��L�fasI\)�8�%E� �e�k:F e�DU���. A7:>0'E�A�E��&b��-t &�y� '6H �Y� n)j��� &T>vj ^pdAh� q*Hvr=WDcBl,�p!��J� M�E�2�)�N!{��t�����z#ompens (!�� 7dis"���b�E.�!�E�Pe �toY2�A�. S.�,c8� �EB��’�J� shipX� 6r �i-�!E ortho>� R!::� !bakero�< "� +!n|be� :1-Za��:b�hom� Slt2 [2x5�H"�we&0 %}*�synth8>�e� mn�I�9,���_� fund�Kal2�*� ma�0 �!blN�i!�t9a!~ ic + non-%va�ereဉ�se1 he1 g rs 5Gundersta)G�2'�41�99flu�s��!K5%��6 �is.��!sm�)sda&a8a_ o���^bAznap�@����LofVG�� ner}�w )GLH( ayerC heav^2glycos�ed%�o*x!�an 1E�55 OL������I�7Z/mer�$g5;a ��/"C�QC-$�"3-inon2�B�� s [111w*y it u�7�!ak$D�2dp&f!in�'a�b� R�is�� �m�D([58{T*H �VO%)�pro����Am8�F{Q�7-"=t�im�J]7��Cq9�.�?=�6!H6%HI c�� of s"�N� A�g!*�R@�:���("�3fui2 drug t�4e�ig r~W�-m;16=g�� ��� e�ayń� � sefui!E�reg� . If|FQ ; combTOeq�fI az�(cla��')�D�(���.� ˙!hs@taneous!/!GA5��"�;" ��*�EofE)i . Al��597�2ids0;�0swQQKm�Qescrib��S� S2 T�e�Hum J[u�Lowas�� ext\ -p-G ne-d�U(�.)J ( 1%63 , 2% 8-B2% Aa�mo Fis7NS ;�cm#un^wis� ) [6"�)%*� �!8pr57�Z,ATP sulfuryl�B( MET�, SD  m;W.(2�(, 0 . 67% Y� nitr��eEYout*�7Eo 1mM �/ nola�R(!g�'ort*S � � [6�H? �eg�of�s�;�oU% MAL2#O��,F��macO,n� [64]E�a�� �F� ha�/m��,�i$ub-Md�D8Gibco RPMI 1640YEj. P�<id��"�6s:�T�:62��%�a+lK(�q!grim>K�5�y>43iU^ia&n*L0in2!28at 30°C , dilu��5n OD600!�Ar#D fres�QD1�'S�'oi�3 houra�Q>.a"�C]>E/]'�‚�M.��� back�2��% �M.�)"dg p! �3� pell�*by IEifu:DoD;z� sp!%�250μlE at�8f�5d s�e ( PBShLupple�*edi�\ a7i�(or cocktail6 MSF , leu��ipep�n ( RPI� orp . , M�FPro��t �!���tlIllt�PhosStop phae�B*( RuE@ Diagnostics GmbH{annheim)ermany�8An equal volumeAb150\,12μmm<-wash G,( Sigma AldrF, MO , U�K�ad�S$o each tub:m���)� a Bi%( Mini-BeadB,J( Spec!(LFInc%T y7 6 r3of 1mi� m���- at 4a]A% � valse)�, �amp5 EsUgedE� 000×rpm:10�)`��e�� phor�Huni�0A��ham!DsecesB;M c � bloch$ !�b�V ( LI-CORIZOat room :/eraN � 1�� Asubsequ0&incub�&�6Q��A:7$-p44/p42�4( Thr202/Tyr20�AUL7(at a 1:2000���@(�8a�� Tech�O�6Petect�Zo!�A�A�� '�|9e\Yo[j+.A� Me�ziim�B�gZ"�:( 1:1�G7^d�d"�%8$nt)7V,BVs�[R���ph)y42 Ab�,Ab9Ab�,IRye800CW go!� nti–rab](IgG ( H+L )�j��e (�7e�\�s =�;Qm�8Q��ZQ2�,e dark follob�;�Yi��A�Aw�t�Aon�v{4dyssey IR imag-WU�6.1Q\)^u��$mNwt'��$ImageJ ( N�al In�Ne��He:? , B�Usda!tj'AY3 o��ubulin�:jr-�-#p>w�}~_F%�=��@IRDye 680RD Goat-!� -Rat2�( ��,B��2 g�[E 2; �͊4 -s.5 Lysis/Bxng/Wash��,!V�*IA�eLP'D�B!�D�AKKi�ij� e�%�2m y�n �1~p �"r �3K &� u �K )h*- &���EI g\2O -O Co . LL0"U inN  ^���y����E%�����,1 , 500 μg m��� k �"�Aex)$ced��ہ�"�Iru���I�. 50u"V� s�u�>�q�& by PAGE��*�to�%����B�I�6jmohTmonoclo�k�� 2.56-(ytoskeleton:,-��&�? |��V �^���bi&l  A��nd��J' �Densitxd�Qb%3�a&ba)N�&�<)P�9��eS]dF1a�1*3 [13] mminor �. ��"�Q�ɢ&� �Wor�n]um�E�'A�A�z9=��� Au�(lia Pty Ltd$)d�8.��ea.Bi9a&� -I��e!co� �(Cy3 ( Jacksa� oResearch:)at 1:3^�y9j�(� , �=l:1�]LA?�A�"Qo DLEICA DM5500B epi-g es� mi�]cop�h Hamamatsu Orca-ER CCD digi� camer�]M�%4#C4742-80-12AGE��bic�  tako*ro�,Leica Ap�_�,4Suite AF ( Advd F�ce� oftw�6 &�&} e�1de*�*�JL"�2�F plusF�����]o!�N�abY4–5� to r��G2k 6–58a��carry�-"�Tor%-RIDA�B*Q-e� �*��U 5Cl*x1me8m]a���!�r:7 100μ$aj. 3 $�m)!]s�N"� mDM RXA��i5DFC365FXe�u�Vashaw.C,���rޏ ( LA7V�_4 }�To|Jm( PMALU��ne%!^�*A-B�!�-�4D)L&UC�L!�e�3% bovinPLr�dlbu ( BS�[b�  E$0m�g�/�dN���/�1)�ic�2�~[1Y  h�2 g�f"i*. S:�k–Fc.�k-F[8]a16Sμg/m$&��>3 a���:ld1Z<�"Clon�i@i�Donkey��-human2� Alexa�� 488fG)%2"Hv�0R-Phycoerythr�-PE`���BnRB�U�RG?kon*�H �,N��Y�i=�β�:.o" v2�a S(-.N ~d "�) � utileaajR156 e&&TMa�6zK�j�eis f�t~I"W�4oluafEu-K/d�-U�)Km��5a�N�R?;V"!�%#$)�e �HiG��B�Ũ�8��.�� �s �aB� b� )AaF>y!V ^ smR@� �\�]!Asam� cep�/2BV9 >��at'�T��g�%:uak$ 3hrsthEW�R a&w!PF*T<, C32�pF$)�pf+ tim����)�2,:� 5"` FACS��,d!s��� 1% so� azid% ���r�Zm�r\L4Calibur LSR II&�Zme�%( BBn Dickin� ;Singl$%Q�Ru�aom6�m  FSC-�:7(�f>#SN�p:Jfo6Swidth)SC-W )T>'ar2zdee�Ioa*M-a6�_S6_V�C���x Ye clumpn �8.�?ur�)�� A�PE &t /�ty�#3 !Z%r*�6inf�W ��qW. F�89�7%�oba��%,�-��+ts` K�X�&!D&�� ri� �#analy�HI�JnZ� packagUAa 1� hs /  , OR"� .^�i �;�Eday�Tl$t 5×105/w�GE�24- 1��[[�v .� *� � � :v ./C-n^�k � M . OveHR� �́`nd��:�!+ 25J5ml�2�6.�a� UV-k�W��d0G"72,�xpla�@!��k� @nker XL-a UV Crossl (� 'eN 2 �IENERGY"�se�]kμJ/cm2�he�a,�3�rep�5�0.*�.6�� F.Z+l�co��M 10io%F4� t 3715% CO�su&�ET!U&� 8 filt�kr-a syrin-A�y!pb* size�& illi{!!h )A�e!nm"xn debrivTmk_n��  8 nufa��R&D SRe�&!R"X. E�!ɢ L/thr�?n KdH"�� �^ #�"al�zh!�:"�eTwo-wa a�6� vari� ANOVA�K,raphPad Pris�"v7 . 0*�$) .Q�Alz�" er's�[( A'�re�)d�#i�O:/8 major public hich�4!�:�=9a�rapeu/_m���a)*w]0ed� i!w�Wsi�9i� molecu,tpatO/� �%9!a x9me-wide�!w�{s2e��k!\of kn� gene� risk /i�AD�neuro�o�!EDD914 b%Xautops� . NN4E,L kftclinico0 `.�Q%"�ass cA�>�fe)!EA)y!i� plaq a, NPs;ofibrill�ta�A�NFTA�f evaluat�8mmD;co-morb&S:��@ges:  gb�aamylo�Ygi%<�eCAA�Lew�<d�]sMwLBAxD, hippocampal scle�r�he elde�V( Ha� �vasI")�injurnVBIA� GenU�/�Aae"RA�z�%@!',� ��w� a ;t�i��?E�{%a ap�1�0 EE�a{POs. GalNAc"�#�7a� ALNT�4ATP-B�V ng CAtTSub-Fagc,! WHITR,�#er �7 ABCG;G�pte�Fic�a6oQ,�c9I�a&�D� NP sA�;HPotass�L�.Mw�&%iCalcium-g#Ch^3l ,�dM� a� 2 ( KCNMB�3!�stron 8>�HS�!w�~!zA*21 n3%RV�)�//-Kh� .ye�qJ1our 52��� : CR�BINCLU!u S4A6CPICAL� ABCA{u CD33p5 TK2B!ORL7 MEF2�*ZCWPW!�CASS4)s9 �se 12���5A�er odds�� �J��w{j6ZT1�Use�of6A�*)eor�a��]o�e wEAYAiS?os :ca���  ,'"]>2E.��.j�� V��n�]lUB��A4�AD)Y$[_�rdiscov�newUSQ�1I��b�g�6�!� aligAr s2���A݄vV�z1�Est� ɑH^7l)�~F�. S3K�>�H�$~ ��y�@pu?�I} ly�7yle�m7d;�o���/iv �3sH ten derivAu�y3 c�w!y�"s: j�,z-ia�NLvesse�7]��՗( LYBd ��[1%5IKeu`�uZɥ�z 8t5cluF&&~aIH�5+!O�aexi�xn-/ patiLav9[�1�@6���al ` ^��]�Q?I,����/ore���l1�carK4B�o D=)z� lyg"l�athw4nd� , it��ts :aiQE.P$intact “�& s”IkfL]� �(hR1�2� Fa��h)}.Ha�ex�6<�o apac^E�!��8�Oal.�ofU+. Bio��ak&� 4 �2�eH5�abnY�5�g$gn:T.��tyddX7Z>%� v2{\Edk�i� ! �%� eU�Q> ]U[�3��U�RJE:�;dr%lȑ �l�l*�$idiosyncra� conv��gm chro�m�A!�� AFy�l%A�� a�ati�ap�FAF%�pr �  nc1�5� 6 .Ŝs�,�to!i�Alov�En�3s�G !J<*1yA�,global burde�d�W/taggem��j�T}*�@rke��� g 20v6 rs [�wW��/�j{X��>IHgE�:�/)N�unmet�!nee�n^L��-�i_#:��or!�!!�. M�1efforAGr�Rder��F[�8(Jc*wn�#yet��E��G)1�OsucA#!5�tri�0.GG�o݅�^P7et�3 Jvf7!a�ia�1o)=E h� :�>�z�$%j pFt��n� in earliewag)�Q�oe�seG1 subg�G�A�F�yE6C?���rtoirG 5Y�-pSng � ledg2��d���M �;)�a�I'�)rT$s�<reT#n�A3 ( GW_M<[5]–[D=�Mea~Aic�M plex����AoF iF!�q��]�~CE�� �e����P.n��� " �J %In�e�� lociI�"U -I���*�2�novelM"�� �$Wb�yG!s�-�.� D-GVs sortVG%Y�mb�� "DH �Q.� ��ngz!�>��)�&9NЅ�ADMU �a.WeH�d M�6a�)���Lo1�.� g).��n�ɻq�!`� F}:�H�}2� �FM��(6Ff��A��BOU�i(,"�_, +fF>(u !�2{(�$�a!,!9� a�m>)��V�of~��ERn��5.���B>V��WR��". �g6�����F�.<��)?� 6�D&�to� mode� ighZ2uHAD2$ha� a�ylP'fnoAW;�2vQ(�;z.@!WIQ�7le- "s�deK:�A��*�Tng bx�Zs�?, S2;�Qu�sSCS?. A���zda͕\2U( rs685�p-C@e = 2×10−6 ��O�S^:a�T�PHD F�r�97�21Bv(PHF)��0chr22:4535413!6�39 �K.P_���Cimpw=abp82�2albei�)"�� , AD��, had aE2-3lu@�7c�MA�8( !1�01� ;A��� info�542ɉJ�,Kv-M>�� atO � ��xQHH1S3Sz� ��E/A �Za fals�t� sWw+Z�p N�meta-�GiAa-�Fi�-b���%b p�e�LO �z omic@.�Pr ( I�V) % �U2A�:"Dl�((:1%� 0659�ρ ��"�!R�f�F�[ �A.!;�|fM � bZ�bZ���$!�Lambert�~B@#Wccso���Ub�;!�&*�ord) \��r���anu� vR zNP��i ,�- NP���O�Qgor�d *0v #MR;  \MethoC�)�>��M�t��S:��g5�<��46 any-�;1� 265���F?1-%�� �t�ies:T436/fI.�6]ESSVSC>Sf|Fiazs>S�AO,�I5 Ada��l�>!���F�Iis:v�;�� imum1G��a*0�V9ё��,��^t�.Ft�n� ��(Z��,3 �8ѩ�"� 9�n ��"Pi�4Lm�r! no e:9mE hete0Fe� �S�6��>��5��s S�KS"aS10�� �RB�9bFM=���ZQ5y1�05o��~�[a� JLt-D���NPuGho�1NF�� �}bM)� ur lGP>�� ^�"Z .�wM=��B{���CA� )HB))"8MX2AOI�j B�<�1 -1A��R�%�^~ ’th*� s�B,: , S1# SNS13]?6+��1��1��S�.f�F%F� %ߊ�1�-VCa�6-y��@d5���3*��N��.�6I�5V��"1��u8� om�18au�$� �b.� –e8&� &�ea�AKMF���m����Qb S1� ��V��W}"�Rv6�EJAD_��Z�ͥ�*061� =��� �a D:� �Red +P�"o; ��,9&Jfor�xtm�Ż)A>, "^���"� M&�E.z5bi �!% (�4 )5to-��d�tF21 �E����>g.��>� �ascerm*�[78b�2,!R ��[ձ ��* I�ޔmof�go�1�� 5�!�}k O>:l*� y� �&q�&us�re�L�kA&.�ab*ein+�:1a�E.c6 b%woa�[a�t�M 26 critIE�\.�Q�a$:�- )�y -��� 3887A> 1027!!*s'�aD� inco�tcumen�of.d���!� ;.�R'�z 3044�%Q658��m �tnge�2^Vard� v* �N<"�M �f� <�_��=�)�12��29�ely��IE�"�#a[:�b#zb#;.^#:� �m4:}5Q+� ���i���( CELFAH!����u%ir�9o���%�!"*�#(�-)a��fl^�V%v' j^NZ(�  t%!CF�JM�s�U erz�.mtj.�t1�gl�0?�eAm ,�Sb�2B-�#t rando��pa1aV)% ,�2�se>� s�Y!�AG�j-e�"" \~�'XF. NGTwep2>K!&I Az'M�# lyA�-�4c�SADhRZam�&a�sub!l�X�a*!�"�( n�>� 91@ e��� s�12��N(�3�p12Ufir�$:*! J��$�]�� J�KR�o�)!��N(�T���x#:-�2 A�w�E� %��.�R&� e!f;pwd�r!!2JJ?CD2�mnd8+ SK!�o gE?*Ki.<0A*po�c\�&�%*� ��l� �[�.&$ I�)�d ("K&!�t R;� %�n�(�u�2�oD� a�21 Eg�5l�iM�. E� estl!v Eg�1T����ly�j�ly�! S!&� "2��o6s: NFT ;!�t>,+F��� W4WNP� B�*�  7*j�.�@,inc� fkw���(>��B, #{��g352�ɪTJ.E@2b*|nF�.jY� �J^w.`:�*� p�-�N�ARA*�,�Q286��~ ;�:94�-� �.)�NME8;�c980 924 �ya�A�N�eRNƕ2f3"� =�}zm@4%n!1�9 +�Q�E-�'�� ] 1͐ �i� ,u�6e���LN� � Pi e }H!^� �y� !t�FJA�2L � weak�� EL�,|0�#��&�20; sltIJ, 3y� �a�neg�i�I^�.�2��1j�29�&T%ccs:�  6o��  F� �K :���t�-;�'&-&F��n�nn� 1#.� �L�Y � 8� 1��6�2!�2_e���Nu��ie�962|!� 1�s S�{S2�. &mw!�L NP6�"bWN �Q�P,� s��i "�$a �.��linear2�2of ���6!�nb u�:; *�1Ck. Ca.� a� UqE F�1= i�ex �-t��� �1�.m�mix4�9logy:aM��!�Ech� :~-ԧrojb.�)�,�H a: s� 6�-~� . "�0u'x ly 95��"8 A}2�$�age�>up ���ic2�ato�2n)+s�P�*v(W"k< �0*winB���of2�X!$2$[val\�� partC"\ �03b"�0X ser��/ll�;�udG_�~cd~e:&mprehen�2a.���kt&�0�<1��"�= CJ$'�&at�Xjf�e"|4 aage-matc2@� *B^&�Œiu", efZ�3�q2�d�4uw� M� � . Virtu�ll!=l" E�b�Z ��F��)ed2�a1"��MaddIp/#lim�Z� �A took*#5h%�f�#� I]�%j( 0�e�06\3B �2<characZzOgF��g�h�0qngt�H���bFa AD m�R,�~�B\>� w(BW/rL�-E�CA�( i�q�zK8e�=�"� IJU� eW���?{t�w!"p- �&�7coh�%�5k�a W �t'&�<�%�D c�,A"G�<ro!g��Q!U&�&e4�Od�Gm��R� � .;ApoW�d��a 5�$1�am��be bal�<d��gkd"��cu". Wa�eZ =zm$�,��*y��ed 2Q�.'[ �&-��7:�.l �:")EzJv.6 mN�or.�B<(^,"�<q<,�<�, F�<@A��<�-�J>�LU-PY�<9dIw ��to|by �i�2JI�:�4�}�?��2�x� ��� 1��Bjw 1as�v�a�!�"��lla� �atU..��)�%�.��m�� Z�6��0}3.l�m�!�m��+( R ;�9�*nF��[%��D��>IEm }��L2* �tru>%��9!�i j�3���Z�f-�7" ;"p*,��� MɟE5�hS �'�Q%�:Z�rweigh\="J a�W"�5��:m2YEe�{`J spurx 1_�i�][� . Ce2Fd��ep_&� �)�CPH� A��1de���7�hsmuE�;7Unya�xCR+7physi� �5e�w��{ F�;. �&qR Y8� ��!7n!p�m�& .)��o�~nd�� ���to�2=a`�.�@e�+>,� HĢa)����f�9clarif�-"�&�j5u� li� ? &b s�le13���7jE�.�8-�k�d!�� ���4a�e��$ �O�.�"%mEQ?2� Z�2b�ь�PUC ��c� Pq5��,N�I��(tRE���CIj=J]!�:���^R.�HeP ahr8"a]i�l*��)�.��s�� LBX�>1��C��\.ZHSeg>?�no2&A<�-"�q���U.�E%�%AA:�of �� ������8>%AL���)4%�-uN�o�x2�qE\.�2|������@&N�u�arR��( PVBA}��!���E�in2߈Lkf�Fbs mov  disor�]r*��W ���o=d5iaAu�:B��`�'�;u"�:ll �3-<r{�A!��Q2�K ��Pa,%_as)��J(�0&e1�nd��e �ad�"C)"� u0"=�mkU�%�bik(L;e�r.�ofС�s��ng hist.� �H �h������K�a�.�q0��~4]�' 52�s!?%d�2�~� wh$jrA��r�lXI04e�or 'u�mn.d �:L S d�2JdathinkU?�'eg3�oIEoAF"��l�'�L�A�P'%��)T'r�a�5|2�!e.���a �JAXET.SAD� HI}� up�%� view��������� !n� A� �re�mh��Vc�zX?.u�c%&n f ���B>�0� a2�.�}���@gg���: � O�aN���Ca*�U2� prof*Jan�2. U�G asA,2�&�6� �Y��B5�.�a��st�*��r��*"I.�&_1i�D%.Hn��i�f�, +51@r*@eiSp�8a�ADe�VBIE�a[��� �]*- rigu��Պ*y� � ^~pkQ��D$wha;�'ay>.�) s)�Fh R�A1�to5�s��5 Vf� �� ; *�Ei Y�I�a��dѷ'BVJ9 third&2 �?1~6,��aHsixf~�Vw"a��F� �F%�"A1J)�m�a v�ljc.� T.�-á�Fy� YAD!RiaB�Ji.�*_.A��]Q�aG�& �HS�GA�. &�a*| of ^/� { "�Y9BZ\��Z"HD��YΛ�)"f/� b/%h2�|�A��be��simې�(d�J� �1#%�D1` R]L�( D`L�@ va�&�?�gn�k=��al "~�Ik a� ����.�Hui}�Fs[�?��RfKun� �j�ly�L'u�R!���H"��  *ɓ�eX�L� !oia�� �dZ�,�*�1S��nheri_ �)Sε4x C>��  lnt�factor�m�Q *�;AD��!�Ji%��": .E.mN� mS�� *� AQ��� ��.S�EFT2� "m,?rc|N� ng�e!T���w�� ncod�:��G��S���o�!6q�YIk-fO-&��Aj*7�aa6a|tid� !:u"1i1#��–[20(2�a�F�����aA�iA of KCMNBL+71 ���sub�x�� Ca++-�_K+sn�,�is �eto��nlcit��A���QK�by .CDpyr�yal G�E�A�CA�8A�%�ٿ sX!c���� Y�c*�y��.�s-�HS���fXe����v-� �frvz-�o�������apE��HՈ� ide��ls�-ve.1i� * 6A"h�!ba t��]s��>�A�hl���E�t�m&�,��#�%:�f.C e sum�y�]iR��)�� �4dN ABd&i���a�a�&�T .�,@K[� A�9-� ��q2.Ja���G+�=)�Q�ed2�>�� ��i*�".�1UF� pr�wa,aYe�w�Qd!A�B�L-J!~G d�ĭ(a'��A�3S �M*�dUaD����DA�F�y A~ ( NI>[.�CsKCe� C(ADC��49-&9� s5.!3,Q��sN pl�l&A<ndH�"nN.�Jy CA~!��29�-f�du��.�Co�� ��ACCF orga�Ρ��307"��a�i�}%,9��ata}!- oF$�m2%�4f�AD\q%�o"�_0 se�v�nQ��"j �M1�GC��:.�( � dult4[g�n�/t%�y.$CT; Eric B�+ar�f, P]��e Mayo-�2pQCR}s5tMAYO; St7 $G . Younki,|XUni�dt� Miami�2in Endow!O8 Bank ( MBB; De��h M1{2�U"�|Y�Late-On��.-��\�X!,NIA-LOAD; Ri�d�eux6pO\*}&�oce.�Nl5 OHSU; PaU�ia Kr�s6cReligi��O�s �a2MemFi�P"�G,ROSMAP; Davi�z nnetd6=vT� <+al&�G5�9C( TGENMReiNn2w6�$PittsburghR�a5 UP; Kambom~�6WI Huss���jH�n�_�H8( UM; Pericak-VQ6�Va T bilt.e �2Q�!s�(( VU; JonatTH��4 �!��3M� �iai Scho(�MedicV9( MSSMH,seph Buxbaum E(�GC B��L s; d$xpW#8t� cs6�qn7�-A�1�,�tho�u>�.��acc��g� ��en��"!� eT���bk 6�"y�i���& �qjDo3i!6>��U��e01!Rhar��Sby��!�.�Ps�JTJ���n[��_�L�2�s�Tg�. 2S� ��6'Me 9N ��f��!�U}oc��JzER� 2��0Braak [22�8R���u,8p z��C._>�'"vE"��5A� ���" -�-~%�� me=J.�Pi[y��9is��A�E�-synucl�~Tc .!�mf2E���9 �ͤ�A>"R. J��B a�<͎ &�%� &&�d�e�DSM-IVY�yZa��Aia��ݻe� zeroE!� y's"x &�ei�NIA/Reag�]��~ "tB�weorc 0 ihood�E43A S�,c!�R' 1/i !l5IaU)III–VIVO:���"�&��9ach� ����Ya*a_��f9}or MCI%��w���W�](&� meetB�An5�,K mildV�! —g� vailA�—b�of1�[MC �1 %)Zgz./*a�.��-a5�)753�Rike2�by2:q�| �@e/sparse�Z�؄�orap��no1in&}D� qnB7III@V��ac&ri�A�QZ!^hEI�entorh*P,bic�qsoc�TaG�7�6����d> �*:!C�n�%rM4,�4�qx�$)%2�ese� �P�I�MI4��<a��bI:I&�H.!�����eg*�J�:XB%*�8�!�%.�l�M9�u$%gonP5�B�� -pre"��=�ne9�i؉!KQ��sed;N�lA���vY%�L?^��1� 2�VBIi�11i�:. (f�2;��infarc!?lacunar�EterriS�� &���vy�� 7Uyqnd-EJ���V%�i� ��A"uO�1:�Ycase/�# j�H�}2� . a�7 D;E 5�W�E�^eDC! �+A�O�2�'����S!�\Mal�>�_.Dp�2as"&+�2� �%�} t�� �>�N�Hial �F��+�#*q��D�d2xH�h0y:�st�1'"� � (� lete� )�d-F 6z �>4*� ]&;` R<*6 7� �IF7E��>� !FamګS�Xng�R�Y� ���e��Childre�& Hosp��r&(ennsylvania�L Illu�> 660k��chiƕx�B�cA�82�oŋ�etLn � plat�!>��NajX 20110M . QC,."2a��|r|���i'�R!S2�R PreluaQCQ��6eh�for-Dn�q, sex-�Gcy�ڤ� )�princi�pA!one� ��t ���ta� [%%| W'�mcR2� aj)agrKN24� [��aR7�R�� �'u��!��� h6?� bI� �f�'en!�!�t���o�F�A�AO�s�$IMPUTE v2 "J� [26]��s� 2�B��Sq�A��HPf-��fer�[.�I&^\%WQC)y6i2���xd �tj�X !���Decem�q20Zwelr/��>�DA���[_-�F�œ%�A_&�0Z q��ty �(1eF� 6O�=40%a dosage `cJ*019�T!eh$O �&[a�}�]SNPE%"*�[� �&an >1%��D�dA3 �%�)!�l�i�32 6a4� D cy ���See S�'AM���a�I��'ofM�� �bQ*�Dr og� reg 1 ��uaB,IRp��3)��46m�cc��*�|�;яur�+g+!�wY�IuPLINKajeBu�}V j�Q �q���tom�R�ith����zA polr"��@ar�)MASS ]} [28]�RVG5D( http://www . r-p�S.f/E�Poln�"��tenE�F2�2R&*t+;?]` �A� ��e�M�o� |gE�!pro�*E`pPassumpAv&�3)-S)u�E�eka�A� ��:G6q2U�6�!��jc9��:$�� ����&& B���UB �� !$��? T%�TP !+*�S��%>���' �&3a`?z���C��.T����1�es��*v4s5IhQ} !w-�m�!�6��0� e{  ���T�Y \E] Hq.J ^����s "ƥb.Vi.{%� �d��;t�I����a�2X�Zn[6�_A��!MM-�A�TN���%�e METAL [29( �ne�cz� 8M` R��w8�;E�i&IP�cin,��� ��" �U8vO �";:al{te:�""!�Q��!�. QQ-��"E=�seD �.a���-� c�:588"�4*�A�O%�ٮE�Ea�.|.��h9I=~9OR#�l"�h2�{�)!�6�AQ “glmu�! [3�YtB�=Brrgram�t�x3OvAsJ�y%m' U`�tb!��e�٭P�outliS %B�fr}(���inus 3An�W devi�sY�me(�pr���.�Aitde��6!)Ku`�a*�n�1�'�Tki�N�%�p.�k?�un��Ai�:�DstillD1 5:� icgl��pZ��HaW�3�P��m�%2� ? B�e����of 30��iAaNr��Yve�!��=o�l�eڂ"]D.'.yna�-�iy51(-L�k�of��ce-fie a%�Aud rob�@ru��%9`r� l�i%+�'�k����s!�%Үl�0"����� disulphi�qrid�"w&�"� �2ouPob"��3X��%z�wsol[1sh��of� si--q ���Ie�a"Ո�|(aS4f [u]) 5�ɦ�f ����a�*?2�tǬ vibr%�.�*�.l�,W t reA��  ma�wz=,$WK���A� ;E�%intuiA� Mw dڂ �atj-x��u%��O�qS. Ua��6a�ss( �c�i,"��EWJLwU>�dS%�q�s�c�& �hyd��oFA���t&�m���� ope@)rS_)P� �fl%�� L>i� S �)aa+�5�fav� h� m:!Z:�mic�rostates , it is not a mere spectator of unfolding that simply displaces to the right of the folded←→unfolded equilibrium . On the contrary , urea actively favors unfo~:��selects and stabilizes partially �ed mic�(slowly driv ɨe protein conformational ensemble far from �$native one{ also.B0s sampled dur k rmal �. Urea!ra�(denaturant %elhas been used for decades in%7study!��-�/)xing; however , after many years9researchO8ultimate reason!� �� propertieu�(remain elus!P[1] , [2] . The domin�paradigm�� (cx“direct” mechanism ) claims)�QF�ar�Plated to its capacity@nteract with expo!Y1=(residues moA�trongly{ n wa!< [3]–[15�H5Y�%�e!S such%�eferenA� yion!�aeso clear%'ua�`while some authors suggesMi�mostly eI�icE�r��U��)\D hydrogen bonds [7�9%�16 17others)}!t p.�a�ers �nleaAo term [1.(I�Xe-un �whea:majE�q�Afeffect�Ebis.�.L%��backba�[ �7] or 4side chains [8 �E�IiElat!�case ,Mrer�discus�regar �8=�b: polar%�charged !a or a [4!a[10�We recen!�combin��a�8-replica molecu[8dynamics ( MD )��ul���-�$NMR measurm�biquit�:o�acterize�a�%ki�ed�a���iadelu/mOura:ult:�P1�es flexi�T$over-exteni68k��,aaO(re unlikelya�be�b�h ��c���Naqueous�s . E�{E[e�#e98phobic surfaces�m�+�-philica-IW�- glob%� �, dueq�to %�8LondonAru[��i���'att!��h�3ibu!,Van der Waal�!��< betw�G instantan% dipoles ) M�]�E��Q��|$first solvE| shell!r1����!x We believAs at o]:in mRce 15�zrif�}!.Q� basi�y!�:%o)w�Xmou$MP�en�, but�rtunatAh� y do�� prov�Ji�t kine�� roler%1M�)��proces! In�a, words: does 5ac!�ly inducyF? Or ,zE8 Eit pasAPlyAr ! Ce2 te byG ih bin�to)6�$? To analy�3is pointa�e shouldFW:�-M;tag��)�chemic2% a�e)��structu��(still close�Amw.�E�eM� ��T�fu3 q�. C�ly , a&a t���p5 nts K diffic��F �� imporao be!�� :on eap99� mighA dep�/nt0F �9n ref�,!obt� conc� �EK�t-� en�]HusA��-�atomis��si?;!�gA4 universalI!we� 30[� 21ofEG-)%a&� to � ur2�f\ =�-� uncerA�l E s� a�i!ekpop�cH!L~ reI�derivE pe�< ��aQ�Tco� te pi�k�F>�d2� AU�_Ej- !Vma���aʹ&� "� s��mea� wh !�!=t��et accelerat!� q=� . WeM+e�a !�+ ocolMthreerar ��2 o i9 ldTa� 1 )Ōe!{ each1+mAG clasA׭�S�� al C ific< of P�g SCOPC19] ) .8monitor� * ] t�/ �environm��: i )}JZa�m�,#8M)_!��aDmildly high temper�De ( T = 368K )A�speed upE�observ%!�� s; i ���2�� �i�� sameB�;I���olayowEda�nguis� �!cE@�.�oJ/� � �at room29as fi�Q�. FAZ2�wM e��( OPLSAA - ON2; CHARMM - C22; AMBER99 - P99�(P99SBILDN )SI]Lsystem ( see Methods!+descrip���2��A�col@a2A�otal 36� e�1-�/ leng-A�. AD\mPof6T��� �-J��x%�a l. r se%�a�e���avoid �bia� V�� V t�JWe�J ed 1���! I tBo.�9E��. c� !P�6�� � �aّ5A�,Suppl . Data�S�L. E!g-�was�e�u��2�(A@ , ONVP99%�exclu��MHaŵorMabove�n� F90z8 . To have�� realahc>#5}ᨁZstead!l�! crysAt&� E1E�asuP0 .1��9�Ef�!�1��e6�� G i0bed ha� reve:s�common�tre/� illustr��:^&�B� Q &� . MD2���ad��ve pot>�ex is %�bec� very"Wpl!�Jxof�3 �littl�ubn�us�  technique�pro� d size��advan�Sh�ueldWwe l ign�%d� caveat%�;beginnaOxis *�. Fy,%��u���wa�A� L2�)� I��( non-�iz�2k� �� � ccuE enou�)o deal-��lex!0� *� . Previ�� E [45j �rU5])��demonI�dI���/e/QrI�ESaramet�� �to� %�6W experimena���� �ss; nd �al!�� �! func �Y�>�D*� neu} sc�A �s [!�!t�/_s nsfer f� � g�APripeptiF[10!d�Ax:de�y aroundm�ed!�ɐfby vapor s� osmometry� s!�!�8 l1�4JFur a,�K� , J�n�ed :8M ��)܅$Q�Gh*"�a!���/ 2lroscop����ii�u SAXS%W� ) un�p� "� ���despit&ir�pli� 2��i�ably w�!�:�mix0mWe�remembe��w�rETloEua.�Ʉ�, no jY�A�at� vailea����ariso� accoLly cae��r� ��pve � ���O(�� seem��o.:�n� . A )�a\� er �"��tochapEofm\aޡ[��viduala�jectora�\ show�dega�2Ge] . Ag} ,a�-xng:trZwe tri�=�� fine�f�ng��B�%*�2�)H!�averagDa near-Avogadro nuE~���!WthirdJV,��to z2y�=,|g���f�  , i . e .�G(�.&?edIHa few m.aQTo!�ve?ourselv�� �* �( �w�pe�z& �a; =2��� .�"� eval" x . D�] ob�mt4ng oret}y�`i}h)d�&$unprecedenV � knowledgc A�leten��k�-�BW9. U�AZy�!y* �(��at *� �] detec��signal�6A�! .�ra�aKuog�(�� 1�O!�1el !�:9of reA � tyq�Oa4ll!MhqvW t�&� s>��*� MDa� &�M�A��u��I&� !�o�o�!��imi��U�� ni,out� ulph0 brid�2-^! �. No draw!c��*E U ��T����E;Y%s*�a��8e.�."!e path%�!�ifce�bse f l�a!Is�1F�"5X&"in hot �1tauB.q"�hidde�#c/ mB-�A�E � 8%2m//ss�i�e6�. �"so� 9 visc� than p� )t�� in>�Q�@-f�� ency moveS =]oY  ,�0�a���e��# dow�e�� c-moU ��%�tim� � 1�!%n , e� 6$wlEA�ez ff|2d.�)�r���gfac�urig�� $l!b�!reg�� hing�iW�con�� ]@kyaC!�Q�ax�"2�! plac%hA�2^is cru�a�]�,M�it v%trapid4pp�$��'#�?as� q!�e�*�� al 9���N�!�5�Aly h�D ward1$*� |byB%� �:cha�qof��� re�%[,"{6� �O2��of5�is.a6��erm:�E�=a}�5��]!��"E�(� ��i�)%�s� e�iX"� [ n2�i��!�~ 7u�vicin��� e< u!+gr�"cruita�K���A�.$� � Q&k-Z R 6��o�qҹ�.�"| ( !�a�Ѯ 1��0 ,a)!'vabK!E�g*O?��_("UAQ&H .:@&\ H-bo�ca3be�Nmiv,aath6'�".�jB��-l�(-�*"� 6#�� turnE���� toez�� rins��"u!tm�)o!�.V2�')�w*onlx)Z� fact' resp�ty��-medi@ B�#� =�S� e[ls�levM(in gui�;_epi�>� MY*�- g�e�)��ton1j��incip(g E��Eyon ! ta�#l�i�t oo6�.f�6�+,"��+gs�+1T�e� P �&ageA� �]� coexng m�� eV+��"2(o aA�ٲ 5i1←^>,Qg!�� 5�bZ,Ia c�(t tak7s � Z�,:Nir.P�D,��U!f�-=�e;,amQ i�r�**=� 7��e�M.���([S�FigjS7�T�xq�!�A�a� d2 g~ -�*f-I(�Y way�@Q�grea-'���8r &�(c�c�%c.�. C"{a�p�(F(-0t2s� As��n���� visiQ,!�r�eP� ;A�&�M��su�. AY)*# ��m��`-�s69MO7I-.p[ work!�&d'2_" ]oa>Vz�5�ultj2 �ost����l G��&e ��b�(�-α 1OPCA$$ll-β 1CQY%�α/KTE; 9 � 0@ O� m&%T!s hade/��ix-|Bq/&���N Gu� s�of(=�( 110��j.� ge )�� �g0fs:= �%Eu[��7]% q�2XAlla#r�� ��n���!A< Bank ( PDB; [28!PA�t A�Al[*dar*ced�8�G� I�^MDWeb  !er [29]:A|&gB�il�jd�G`ionicyte��7al pH�Da2d� h sodium�ch�d!y , minimiz!$ or 1000 s��, h� d�!`� ��A��2 ++%a��$ octahedroE#x��<�0�!@0 15 Å���n b=a�,7 0quiS3e^bo%invol��D N7�s �`SHAKE/RATTLE algorithm [4k![41��AN�.C is�2�x00� �N/isobar!r_( P�* 1 atF9)�AyL�v `r\ at%�ba)��!2�!4ł�F�E&/ YVMD [44� fMd:� � � as Flex �,�N$^0Hat: http://mmb . pcues/@Serv/��� TextO(A�a�ai��� a�I��"I7) .TAi aA�li#ii ewE5a<u�0q*b�4(epidemiolog�0dengu�e� in Col�7a�earcht(f published.sP;Qi3{  of>\en��3ng�Zh�7,S�a�“����. Stuzin Eng�A� Spand,��1 Janu�k2I c23 Febr 12 e1#ed� �<Pif� 225K�ci �,� ofM>fulfil!�!�V�9cr!�iA� "u-ѡt 2Ff.��@1 C9c .4�"“�lin%{ann�!&� )� f�xw:� w� � outbreak$(2001–2003)J01� a�ge��phIprei* _diIz+�3#.�ead� � z�r coun�%af�; �!Y{�-5� F1re�#2?5zeriod%G��<15&�>ag�!Gaps ]J&m &�;:.�may!��7M2 aven�3fum�I� , nam�}�asympto�* l viru!�!4�d, primaK3us/$i%!�au� y1o�-�1� . Im�!\*+� (f'�� rm�#?ex�eme/&e i S�in-�/*manag "s�ei"�6. �= mand;{��9ItF(to SIVIGILA�)obe1l�7ir[ ="C! week13*a&�5AFu�'2k$m{7�/-�1^no�dimGly� O�+ gJ;labor�-�I7tho+�!deC V�m�6be��.e�s�,nelBveill�͜)� bega �a��ri�:�;itY']� utUy test fbpats{ !e!�� tor cirq>4 DENV� otypJ(I�� "-a����er��� amplV�akj5%!�5�DF%�!8Z�[1b�� !6� eR/a�:�. )I�"8Zn !&HBnd�'I6�4. Both-�� until�8A42��H\2Ns��noY er O,. Discrepanc�jloA���) sourG#��h�0A &2"��I}new� �gD'Zm>"�x z>nan enHd��F�.y �205�InsE�o Nac�.de Salud��i�P regu�q�up�6A�roa~A� ulletC3!!a醉Ss�&ail�5:& a�Cc�vcz%�$D # I% Y^"�8m�. Ca��B :�E+.{ h� �&H 10AI�e!� WHOz]L adop��C$)�Z� 2 h� Q��� | ��t� ofZ�(�nd!�trict� e� a�1�(�0+sex4�� )c�G�� O&� ma=M� a�@IOfi�1h& GEa�!>�*��]q! iE� ea7 nce-� d�Di�F��6;!0�}on . "� Nv%�aD 2�F�o�@A�� broa,1�$o"n. ��(� T&�B9:C �BX . Specif)?Tte�0�ach�>�!i09�w� &/�#�"xpa�7MedESub�- HGe9sau ,f� �)x’� �=�y�‘&� ���o help� �$e���)v 2�&f70HF���|if /9�-�)��r . S�V1f ��or n7,�/10B� bl, L� ^Rev^Group��lso�!���)��gA��=�below0!�A�T10via t;on%�.o �alH;!u�7 m � ai�i_%bi �o�5lB�Ec5 )�60(n�H��a���) ;q#e!�._M9 H&d)of hoP2 �):ve� attack�)p>?!RN,&ed riskL:�,�O. ,"�.�.� OsuB� R/:*�!��3W �&rV���6�Ais.$+utili!aAv6$9to�!w� !�&�6o�W+ /j @ PcRtoy&�<�m�Di��.byHR3in6p^ia�|;>`���}�} a� r enu;a� �i�R�� 1"F J��Co���C i� 0% beca4,a sumR2Q)��s� �h1#E��B� cut-/ �ef�>sA* �<vKHR� �n��!Da�/d� � languAO and/�MAa\�7F�V�*mez �se�bende2d m%-�/s'mq G� iC� ,"� ethn�����!p� cipaG-orA_ � ~�a�*�single-y" �0�pE��(> ed%/MN��b|G: u�!I>��repet ���!��meta-r�o� �j 3���"du:8!�H 6�,JM�3 ��'&outQ=":N}3� 3�� �i�"�8�I �0n��E��B9?E�&� @z� -�i�NompU" %�\��bQGyn� :!�&�!�*�s)]�b�l�organi�Ts; pa�M;posX<� ��� , tr3:�.< {?;a�*�*�( grey.) 9_��g��ternet� e_aDe=Googl��Yahoo;iW�t�"�M50 = �I�0P�Qia��� �9�� v �^u]BI�M �')�n "� �V;A155�u Kr�:O Aa^U ��� A��?Hy*.XnIX7ue�&A�a�titA�A@ab��V� U�U�� i�""@l]a9"X:v �"�>].�L @�s�@cu�Z/ {�fi��rQ���f� ? �#S �Ne�a�w% ! -�%�%�!��5�. Artni5i�2%�Ad>!�or�j`7y��ked12Pqu�of"�o�m9 cogn�Rh �Hs!14��yE�.�add (ugNarYa�h�z �^�!��b.D: ��,�� !#�g"�L"55x5� T�F~e &�=2�!��&�*FE("H.�Lahof clin$�Pu��n� ��^WAC+�^ � ll^�%.m'GML�I���=�!Kre develop\r, z�&�-(Brazil [21]%�FŖl�=%/� IgO � 3��ͩZ!+a �Excel ( b0@oft Corp . , RedmsN, WA ) �she�$�Ce?-�4Q 2,B�f� :� : d�p� :a��c<a�;� !T"�-"<:� ,3 � �:as�D�*�Kal"��>��� Q4 al g@ADd�B��,VoDly��pee��qC0�� pre-f�& w� !�l G%�a�9��#���,aropa�uh5t�2�� &_8!�Q_� !�tJ!No�empymad���ct��� EA��G!��] . B�8%m 2011��ai&�UF)�2%r s�5E�-�w�+Fh� �-Y92%775 ( �)� 147 , 67010 ) (�0 . 2 )j1 , 2�"WE7:�M�c� "�]Z�A W>��/")F �3�T�Q�2�.�, peak�Rb�&8q x�] ly 7�m!=m)^F~E���e�R372 ,per�, ,K&!8a�EIͦ�x)��:� �V��)��(:��600 F)�2002 ( 5!�00– % k) �%�D&�� 2004J!�acB� H�}�EwIn20�!3�8142� {�*: A sl�P!�u.� w onZ+�U�I 9�D( 44 , 412 [26]; 4a�819 [0�aA �!{�rU&��!():mh423 �K^y}[22�)��TX`��<�577!�vt8]2h. F�t�> half!8!X �E�J L �&��lo�or�! �F�L�M�5 9��V� �de �;r�@�0_ m�a �P of 3!�a�DF B%�1>)A�b�"s��E��B�n�'  maximu�A�,777 ( 38 . 3n� ��1�/HnG�83 #12�i,3a�n&~0pe.]8:�)Q&4&P�(e ( DHF/DSS1bhPd&6 6\ 9c�!A�7st�4�2%�z high0�s16 . 4 �9�)T�GOan��a�W>�bor�� � ��L200!#wY���u�!y�~s+b<�9A{(�a�>)JUm�32%�e>ah�d�;y]e} u�A�040Z>���FL!���439*�–199��z217�v10�%5��.�� Y�f_ �I6� 5 �'r –48�p� -�6��0�S.EyA� fa�t��5�:"�$�pZc�g�lye�r1-�� a���2�5��%*9�0 �a uN)40-.�UAuH2�e:9J�( $�nu(ٝby*I&� i�a�W( 2��!lF IQ��i.73?T% L^ 9J �$3 July��e&H xoJBal� a2^ortdn�#)�r(+ "`#�]aoB p�P�6) tranA� Q��& ]Z�?�N�de��QR u�Y7(r �VM+!�5:�"� �urb��1of&!. A�N"� ��:S k�/�6��V�18�+a mup��el��apA�n�ԭb^ �g.Q,� r�&R����iz� ,ir a 90A� � }�w!?:�J1� %424743A�e���i"h J as6P�southeE -e�"�,7��43i�"}c!��hav� U*J d�%� v-"g-I�e� Centro Or�)e� 0*1)5qb��ZmaiQC?�7� -l.  of Sf�R, N!Y y'nt�"XK Huil�0�c� t�d��R��/* ;�!..7.6�, GiJ$�o uA�V�Quh!�d$d Risarald�(a �]�*� A�= �9(!'Antioqui%�4 Atlan6O9�1�*> �dNR�"�0>U}��l �CesfjBarran<lHCLt& sta Pacíh_Q^U<13ER�`�; Val Yel Cauca%%p�Dal�!Mj�(Q�%}09eie �_Tw�aO2a$s , Vaupé��Amazona�vbz+M ía RDeI�TjK�(#Lps'��&�/c-�U�+� �XEH�v)^%�:x�WOsc�1�� �ow( heav� �.-929P inad�:�+Bhm�b9%�2 [45]�$:v66 � o�D-d6R(m�c6u* cio-@T omic!��K��ai�8/a5%6�a����m�#[4"|Or6�Z1*1� ���>dcD':�@{Kart� !���� ��/e�:�/�[neF�/�:�/in �"E3�jk � EY�s . L�1I Apdc2}FAO malA�nd fe 5 '�luQE%so3Ru ?+�I6 �-!.@<"� "� �$��!+:�.�A1�& *�6�diagno2�t}P� a�2�� 4:�{m�2MI� 1�C�B&� J����t. Cj�X/ve abund�of6:5!3gen�m�2d o9q���"�ab�OSUY�q=�"�-|5�h� 9appear.�-3 � close�Os%���E�5y�;!lasE��to�Ospina �E�W5D6-3 ��4no�'u�3}��~ ���[4�FInd�K�p�is�tl"�\e+� &� to^L�imp�>� Lsub�r#�8 �iF`.) �S�d.%-!neicS sparD7r ZXt)U!s"� f&�2.*��Cc�-.f&;�� ��:Ak� i,-�:�� ).�ag%�!B�$6�: K1�.3\ seK3a�@"vpby �d6!�#~:^. O%j8�3��e&��~~ A on ��/(*�*�9�&8%�&SF2�,s&�%���_sI� �:r�Sn adTa+to"�6+�$� 9$-ITB032� m�� i�(sF�/ɢ�!�F�"x.:6%Mw�s-�* 5Y��l�#�.�!��1��gS @ �28A�) � reh�ve �on��6.�Q9/"�.�re&a�(�(&l )�A`Ghy�5ve��)$h*�ink�}� �$%C�{L1�-�t��I;Βa_qdA�behind�Mc��"� ��2 l^derstood�iur��U,% &�-1k��aˍ(�a����*�>ofQ��%A %�m!9m%4reU�h}'��3'b�[ne"5aa&h ��1ai�>bb��%�� �(ane� valu�E�z#5v� �8? +eEnE�R�/�p-h.�#�&t$"�)�xJ ! "�) book��con�`.�* .o �^si@I�B�+.�%pa<���^s.�t)es��� m�Nw!lb!v�Dd!TH4, [E�!�g�}�EI- c�PM]�Ze�"&&P younJBag&U�}e!���u��Xa>5"[`'*9] )�m,�@"�-  nsis�q #c���%1�5}5U�Hn�$be gu�t� w�+2� p�gamd��Bqx)Y&D$or)�V�lso liE"to�Ry5Tphysiciax. D0���KM9I��.W FZ ��th�9&�,&���f� "� U�&,�� m���=burPf)"��.1pe]lN To �  3a�!�|e�)�- �7 orbi�j�C""ra"� n.�:� 4opt�W%_R1i� Qq�k�Z�� |N%F-�UlethaH�Qno�,S-G � R(%�yu�*/�kntibo� &)A� �e�2; r5Bm� a�;5� �:�.� *Mp_iwcU ��U*).e�J9��a|!)� ٍw-�I<+�<�odo�P0,�^�&T2I6\.A�`� �+. D6�A�!|�/� c� lt3AC�L*� akAT:R�Kہ�� |��!�92.� �6� �B‘bas]8�A:� "�', puncth6by +"ees| 02NN�/O �T� gI%<� i  c &DH�*m  1 ,2� �6�deU%�'n�LW�����#^ �>�%!n �9� "G�%A��<�I2� �  '%Ah � 2mb���jOO�u��N=�"!Mm���)OaG0" �]�6)OE��:F �2L�L�}'�[BuO �r� e!�!I�9 B infak=<18 �a�O2�n���ATeg.6�$leishmaniae ( TL{ ` ���kd?mucos�sissOP@�LK� a�.R")� �#B� arry#9�bkVA�q!/ infl�"B �=ofa� b focuF>i�2ETL co� X\ *"�� � &��Z �%$im�<Cs��� hjec�!:i�v �S>����$B��@e&�Z�>�,IJ{_I� �Pm� cutRg�Y�C,!�semin,% � �2!�<62. H�  immunoz�kcy��( HIV!)9teu�f".*w:EdbE)�$nd A�f��)�of�o��6�� | �� xe�6?yEDLINE%�)�����)��;�73&��21�.�a675� <52"ab�\:�"$�!-s�-s6��?�2S� /&�G��6�$rypanosoma"kzi.��TLA�a'�UA�`t�( �41�&�� 2]helminth�in>M(:(&to 88K . Di�Ihyp!ja�&C�o��%*m�e }x�gA�� t�g�@sma��jnd�,answers emer��SgR+! volv�A�I��]couΔE�4tory netZf�Q=��"g!9qu� t�#acqBle�#�j!!"6problem �Ų>���I&ޓa��$le�.qTL�lepros�,o Q5���a' !�!�bNX:�DSporothrix schenck�i�3� �i�+' phyl��eE(��.�)T c%H&b.�~ �Z�(:nd�g�|PeR�����Q29�d.�)�A��ixjive�w!�}�zea�� drug�b�Y�l��c%�cQoId< `�5In!i�E�TL]�1isq� it�?�j=;error��del�j� 26[6��saf}�&y . M� F(�X�F�unravel7(6ne�a� �AtQ�ex�� šJ�:���V��alL�:genus.�( hozo���]tidJWg�aS�t*� b�~�\hlebo��n�wndfCE� . Pa+ �Mn5|-�bB�kp jOl4�WKe Ny#orle&N5vZ*RVianniaO8xR)�!H[� l:� p��s��<�4rc7"�:�q I����mm�z,y972�Y�{Kfe-WkateIRq��Y�kA�"W� mill�peo$'v1AidmN.in BoKr!���,&V0, Peru , Algez], TuniE*,, Saudi Arab>Sy !Ira�Afg��tA� Paki�n� el�v2� 6�� � D� �?"}.26� ) [5�`�(I}%on25�N[6]5�&�G�as"te.J��+, toge� �.h�z���fqa�[�2��<alĘ;6� !Hvice �J�+"2#q�Q=.��I�p�t.`houG a,i��, hygien� o v+-�M��SZm!�c��Mto.�n&/1�� 7�4o\!,!�{m�"cI��)jY.MreA�W!�EM�p m��t]<Z-���Lo��[!m,�sW 2�qs~V�+F24H�=��V1��v�s\&l # /P<��)he� h�4:� w!oo)Pats��%XAv modu�DRS!�%&(2�al hisR i�};�:�qE-�/"N.[[1A ��n� Pixd.�!�E@� ��� %&f� �* F�J�:I�ftw"� �d�<Z"�LP nQ)~[��.2�afe!Az )���! ̅�HIV"qA�J G^=m] �=(��8%H�usu� � defi��A^*=�aV�TLh �C��"C failurA��A OO!�e-,h0,:� "g \%monocy�: nd mx0phage v�e�3W}c��<�ie]a�q%te�� QY� u�s �t�jI�e܂m&�$�J�L���:iv&� )�� �!��(�Ris� ")eAd( �m,f �2�I���2�,MN%q�'b'( i f�/�"�!�Oal?*e�/!9�*H�)8N!x+P"tm>�wP.edB����Re� �� :~  �, . donovani a �um/ chHi�]���T4ost–kala-aza���M:�)O'A�"T/U�f R �$��is^���@is�N�> �ye�*ŬiQ .:HIV/AID4rTLr�e$�Q�alg!en �n�� iQ�lsey 2F��a��� �&6�"�w �l-pod.ram-negW":E�e)�1�Sta�c s aureu-Strep�Xcc�3y�� �fls��"L�[pS2)2��&diTVT )�+by6� �+�UdeZI���V;*d&g.�V�&&�� , Em� , LILACS� cielМCochra� A�Af 7n8 x�]!'! llA�. urym05a�k�F Aug�e201II%"A�.�-C(�6�Wet#d�� t9�0 (�Lof �0u%,��� � d�l9e�i[� f> d�O&-��R tegy�1IiszPi�UFi' aU��&K_li#�O"�'.:������ he%\��@re��4U��ub}5�or�1!�]Ps�*d#ߥ*9`ؠP ��esttlH a(A�T!���%�JQ�J!/[ � �� )j�n�!5.Gox�"�)�ST&�*2'Aa"q *�ii��O��.�� w &���W"�N}�A�r;mD��&�5��U#Q�vPE=R�!tIt$�Sd#�*��?Meta-A��c( PRISM7Q� *4�Qs!B�'.1A�]��"#�li`all�A�m�V��� s �f6{6B#he� c� Eu�c ��R>#;ce!k��� ncheckad>�List V<eu�m�&B)669�B�IL #!r� �Ny� ed 3F���! ?.,��?'W�2{��g�, �W ed 7 G�Z)a�arl841a1fth{Z!�" -FO8)2���A@ dropy�� � Jle:�A�an)"� i�AVio� 4 e0�W�� ݴg�O .�.�1�O &&�zs�& .v�CA�fI%�0<�Z7��ss}s!խ/97mX-�1#!8eligi�'!r�2�73 G:� >�73�8���y��?�.s�y"5��?21 ��P��)JR�t;.L�i>�52~[:C���`mI�~51��tr�0, 2 co�,% { , 13B?]\�c&D, 77o5�A�5s�|*3�* , 24�e7@�r"�(� a����N5>:�( 5,[' ;)25Vng!M�A�!w����Ax��&�$Q��*�( n =\G:E Myco5 um�ak<"4"5A�2a,M . tubercul�: [ K�B�s &�6��>*]%mV�6�H� aAC(!).�I�!2�.}R����2 dg��m�Wis�r`iL^c.� ab"*�W �NN�ct��"M&��!>w-Nj]�hTL}e� �`�)`1gle.[K���k�'dic���kQ4:)mJA�9����%� puzznn. N�the[-�su6�u`���-�����6�� "l��G� " ��+�T�i��a��6�^�&$(��M)�1.��-�]�ʅ�$enmd ��"�LZB�D��fy��2�lG/gPg�6:$T .�(�� 23".K:"I"�%3cN) [Y!fi�X"X"c(�Pe"(heHV"fgL�:[�VGB#��"!���"&a7��" have�"d1��.� Z6 �e�stP:ͷ��. v�"�x ll�+on�!:in�"�6Z~�"2�`!�.�"f#.� T-c[sub��b��\kv# cytoҬ��ducr � G�!)4�$h�Iy!Afunda����h�/" VI2��j�7paradox�4lize�acerb'TL� [�t!�<���#a�st.�^)�B�#i��oPlasm��}��zTL8a2� ��l�d�; �8�\acLA�oS &6Nor� �a�3es����or�!,"�2V�$K��$��$��$ . V�$�'Q/!-�FIp��$i 8���Bc .��$R&������m�c��s�&SG�e�R �>i�� i<�F%� �ben�$&o ZXkB%. ��y2��FZ - �c�ldiomye����]�� :N$m& Arug�Fi�s�1g����>�) !F�9 $e.�d''=�� �3a0s�*�i�"ڑi�hO,"$ K���B����#�, f�?.)  ete*�e��`�^9"�cBwAW�%f�5��iS��>of����"Wz� �den/�U���&e3.�y&st����pre82Pn%�e A�2a� R�~:.an Vivo E"�"A�ARRIVE ).�� 9��;"v[102]�z&2 /%6�K*I,�! ����b�{ !nE�89+-J7 _ v?*s�SA�-.�82�)tA�Taat -Itt� �1&C.�� frag�<�"` " insu�y ! �go���+%#ll� qu �te*�G )cZ ^ malaw%&1N-�Q6�E�-��a�.aByA�t4N�� l.� o2mHI2��?%�ilw I�gZ*i�IG=f� ly 3� Q�7o^�qQ�:0�o:Us� (Sz I�q�6x�&�*4�Al6n ��F>�#�asE�e:�2D"=��'oo���(� ��$&� �!M� TLպ�"�0f�0B�0A�7*) s#���a��&t)��[2�N$�derlyaf��.�|Ap,�ag1�� f�?St.�> 2a ��7��W �$y)p "$"!Mb&GDin0�&2s*v #1H&�$I�FinEr�EMal��/2�!�WiOsxCsA �A�Aw)."� �p�,!@�:%Y}I�A�lacGJe6$"wE��:* �'ge�vss3YL|�0*l��"��N(%*�/�'͟"�2}Aneg9�*�b&�0�F2�"A58�l�F-ѣW����!2�: 2d "�)�2�*^ !f) "�ڞ�f�\BE��a"z��G�chO*r/D;�%��A�߸*|�!R�5�v4�?��h֘s!. E��s>F�$��s�)I��u�`j�fairly� $ightforwar�4�5.('5�ngF�2wyI�beed�p��)#+(t&�7Jp`:!x�set�fs&�$��P�ͱa-�o��r^H�y�o E�"A(�Zi�:�aP-)�.`�A�ev 2� ( ivm#aKb �o  a�E !*�z �c&�Pp�EQac�tR��.*9)�!�(i]�+�|w Da�)s&$zmZ*tk�%�!mLy��9QcW�(-"��!M �mLA�!N�Y�, *�*:wa�o�� *��?�b:�E)��ort}B 6=�&ӳ�wboG��.�W!��7!O#. �g&�-c�ȭD~� �6lpr4�+ !x!c>TLA�*..[1�Q104pTS���a+��su�QA�*{�Dy� a dysbi&��% � !�2o4�m�$#"ܞbiota�A�!W&h,�Ks1a [9�#104k105��g7�a_u !.j/��oy�3n���-�j1yU�6� li�M: fwo"� ��� -�!��braj!~A��+Ap�/����*�Y$M@:���+� �sby| 1en?4=t��MelO!�!/? A�L�2l�v'erv�Z$NE} �&�B>O� fy ��-�{eԁ��&�[ "�F�ad� "]�O���%�a=9U 3���� $, H�Q#�ng�3eg~+�}�D�&a�st !�co9E�p .�Qb� {seM��c>�I�v�&!�s ��- � �&Qo4#�K(�Eng�L�� � 5on�� so m�e%�� e�=i?����E�p�%e0al+�re��% at h�V�* =��*m����.$ t���J̓ru�%i`��!ex�J�]��7 c5"m�m �W�.�7�2]��)�%bwin���&6K:�>S(ca\.S�tA4w; I"/.��Ge�:A9ii���tB �1�Xat"_( MHC-:t"(s CD4∶CD8��eaga�mm"�z/*�Q.�F!$"� !~9(�K ��(ene-deaj�"�E�xyexMe;Us� N�L� ..� +#[>�e>��T ��(�. H� h� 2�,2^�;"�Na�:drHc'�IOmn-�ra�F� w�p yQ�=+, Trait Loc�-QTL�as6Z�in�NI I�II?ѯ=����-/��H�Dd H2yStock%vWe�/�10 ��1�Mhe��m:e7��#u cW�:��co ͘wJL�_16�Y&[�!���"0Q!lJ�67�8�E-Dd(V�?pa�of^-re�n�ge��+'ih �r�B{X�Swo adja�o�v1:of ∼�l25 Mb!e6 MHC-5�i'� ��[/. A_mA��2fdi�ABHCU.�y+'-"y"��^a6AkD8T � v�#SP� ym�3MmIƅ�!hvJans��h:����C���mTap�#m2%+I-%�WE�   I%�1ox RT1-j*.HG��==^ ~�HA�M 2~ W!6�V� %�%!C�rU�. V��G, �ha_��- ouslN5!ha�ta�.VF-*]~@.�$�6�y� !Iz.&liganda���� s�Ii���h5 Rdi�oiU�6hwa$dNfIOSP��A5To� �9��E>�1hy��x0!�b �N����O! d�͗�,O�G RB!�� MaՊ]g)�����(ll verte���K X?,& p6�C leukeW1��FLA�A�A!�41!� �q c"�U�!0�Fw�2�/��� )i���;������∼260 ��� c�eM� sub- 7 Fn�Oe� , �� II [�?�2�#- ��g#�d�3iHat!O� �s�a�a�\�)� auto�  !�"L} i+Ma�ew��>�+2hrse.^.�C "-��� sU�ұly 4nA�!�gY1 �"�Q�8[���2�S.�a1ˮ%�!7��s"5��kag!7A-ilibrX) ( LD% R 3)��?. WɸJLD�u��p?, A�&��� �=i&���E�5�kTD�>u�� � ALs�C��q$%ea}�&�� !�(�� )� chrom�He��as:�� e Br��N2y ( B� In!Ln�]l�v4�|� �BN!1����Ei�8s ��r1:c+( RefSeq�*�{R[s�,[�P'a���ovqinba�[ �M�I�t�G�����Qi"H!|Spo�p�ly�i�SRa�SHR&�T1kZ'11v�n(�3! F�MDA� T1av!�, F34�} RT1l��=�/� *�C�)^Q��I$�Q�!��&ֳ"�`��� w�(�&j�!�x�.Rz�gENw[1��a�Pr*-telomeo���n-T, ` Ibʁ�qCEM%M5�B�!�.�=1����Ol��� ss I.L�+�co.��X!S`o%$polymorphi�}h N tjs�vewL��pseudE [!@,�9��&$.��Ul � �-]1I_-Aj@!Awt� !  �8!��E�S׎%�mYG8A�&�e����.�D�V������|)�*z� virt�?nu'���CA3engag�l| of� ra0� v cytot( � "���:A�sur���$ ��r�3frameOL-t��;� -iaMa ll m�Yla>*k 5�nt>� !7�H �)g���  l�T�k $�.ng!/ γ-i� feron-A�\a�tea�ub��< a{e 8�6 smb8�� Jr� Tap1 A]�0���!�9-&� � ��� *�aap"���b��A0pbp��ise�'r�%K :�.��%�U�9  a�lle�a)t���m�F=A,�%II�aS,�as:2N.� f!*i(!wo)�A� Ah BUW enco��wo}��OE]�wf3 G!> ۂ�N :q���S��APYu�:{4)2�A�dB%�d� TAP- �AP-�2��5"�8e�Vn*� sig$slL�co-&)���%r�n�%L�Ul0�!�Z=����R�/�*���H�!�k�)�li��e!|�LӼst�gY�ag{U^A�AIat�C��A�se���a 3rDA �!G���)��!�#,�m �1�.(\��"GL_�?a� ed��aUis phe� nM��ny?-I��V  ( cime�h1��pbFb�@�� W eETAP iso�#Z�%we�mQ � 3% [ina8 Q)��seX�� �s�C-�>i�argg� -�.�ni!(� $^�Coa_-�1Z� 8��is� f*i�Q�A0�m!H"`abn��� ~�  �yE}��)%� I!�=ofN�n�A�6_'no�A�2 e3d"�=!%e-A�ed b�}R� 5�Apr�cu�*BA)��e�W+A����u��uM�UcesQg���)U e α%1β ��!�DM OE��<oc%Hp b9��� C{^!ea��M^ -go!��H^RaG�_]�d��f (6™o ��er� & E� +� �&=�os�_�zs�(2 aq��4�thymus [��[����!&`i�m��Jub:����+phd�[�������e�y�to�o!8�~�i�i�eyI�~�>� 1��r���Qd�y�se�re�or�CRP�卥]D4R&�  %W>)I�-�&�[3���356P� �5.�����.`�ne_� !�U\&� �WS�f �"�Y�FYU �,�MF�a� ��>1\*6| '(!� 9Q��!�L6�o�Gd �a�6�1�ͥonJ� ��9 NIH-"A��@( H�AG*�����VNr�}e TSI�sc�xy om e�&>� �����+f��z�iA� k1!&[MtHSabp��.!�Bal F2�3�ow�p7of�$[3]S �o�h�W=�Gn�y�C)Aj�tM �Ato!GP��!e!�Y"is�_% }Ib� ( RC%�r�(werful tool�_re�%t�XuO&�LD�MS,B l� e bloc"�ZDq��rU%a+9G�,&�"�l%�&SA�!��PU� tA��-�W)��L&������vW� �w��rvsa:r<,im�\ !)��.8 .� ifB�0v�&�-:FBi%*(�cU�A�CJ�,�V>1J�on� Ag�H� . �E��umaA�n�* � al�|pooo�r!W4�Q"� �-al�x�n��j Q>�V�5�pr.���F� � U)e�6u"S�u –b I�r I�&�3�.rQ sh�>�na�J=��U]Y�C[D�0�=�}me-�"e�E�E o"��Z�exE&� �-�^�S :�We���% �!��)�@ngxeA�I.II6�v� by f�J�)�bUu �hHS�!#o�� 1407R!"��d=Y26�@551 SNPA5�� @.���q��i�#S mosaicfA e o&�o%��"�� two |%�H�G&�&� E�ed�`e��=� c�vunus��z�ia-f Meth�����S �de���2��)s@�y!Lx10���ƥ��-���g�% logPq eshol��fG��um����� meanui>Av!�.B-)�F��76 � )��k1^ ��V�co�Ot��E�^"p� g�1�"*4��"e�/%ApED� ���"y)�2ys ���Jr�!��ӥ�56 >( ��M��E�%�0�a{1pr�]� & 9 ( −!�ƿ2!g��;atP78P�f"�2�O>O36 . 5�^�,��yNi:���!1�4�� 6%�&?& ( up�r�;}�1*Ewse ]�1�1ibux @^a*l*abs���w�N5(IL_�(T�|m�Uans��u$%0WTCHG website&n�uA� X. ox . ac . uk/gscandb/��Q#��:���a���d|granull#s��ai ly�Cv)��?ry! Iw-Ib*).)O�6 �eAy]c�&�2c!�2��,Z)>2 �7A2a-6>2� AR�t���[��M�-�>w�a��Z%A,��I�I(yV:��I1T1-B )2�n B6RA~%q�:.B�!7 �1�6���Z��66U0vImarker>�0ED�m�8E F�. B}�!zNS 90%ahf��o(terval for �0hotspots were.near D��Btnl2jLta2�, which%galso �]!����2Vnm�Dhuman HLA [6] , [843 4])���-�y any:ZevB'Q between�A� �<, despite analyz�:0∼29 , 000 m�icZD. Extensive LD was �observ�� f Kifc)�Coll11A2�I���wh!qonl���6-%�A> R�tw-�am��$∼16 � �edF�Thus ,6hu\RT15+S �!1an �8s occur relativ��Pfrequently ( 0 . 2% )Il��6��Tv����in eachA�ɰg is extremclowE�e9�1rA��)�aA�ll!)A#5��ogave ri�,o two.>t�could��Ͷd[��:�����aqeallQyic�n�wo� in%�N2�j����6� The firstt)�ch�na�Q �T� 1Ics��,>�-�Y<)͕2����,DA . 1IR85 , HR83%� U(�refer�KI!��s �-9����T� ���&� ѧ- surfacAW"� A&�ZZ ����oI�8�($( min-max: 4��a323�&based� average s� * 2�unknowna��� (Yz bord�)A.�e-nege�-I IR86�)X IR84 ѯ!�I�secon� �no��R2I;)��o%<�:I!uA7)�!T Tcs2F� � UR10] 10�FR9:�S� :FR6A�Fi�}���� yet avail~at� time9kv� !0on�e u!�X:�8 ( bothNm)A�excludM �W) �RT1-CEM1ofk>�R22�� �%-wit�@��(��i� n 5%@6�in :H� :����% �R �� sə��9l>*� � � responsi� U�2U y�c&520�HS� h��%aloneA J 2� ,i4�,<=V,.A!N�of%-��!K!j�!7e effec"�i�A?a�o�]�1Hm$�2�^W ]encod protei&* �Q2�$II pathway�� Ain)8,!�bp < by dirA�s> cgE�s� s�I"��� h , �uf ild-typ RT1a��RefSeq 5n ).revea�367 exoZSNP�synonym&�non� 15AKel-inserAFs/dele ~D168 amino acid ( a�sub�Lio9Kcor��6i� ��Q�J�2�-�@p1)y��Psmb8 ,9�Ta!�)pwedI��$degre)|-���� � 8 4j e mosZ$ed%� �� c,�o:� 6[� ( ns�t% ��R165HA7A�R+!] lter�veA|el�Z2 RT1u9�%�)U!9A`t�ϡ� ��� m�Rpropept-w� thT8�X re f Da3 � !/$, although� in"'�kdi�� flue�immunoe�a�assembly��@chymotrypsin-like&a� Z8[4��By% rastѪTA:a���emeYdivers�.��q�six)�FA�in% a�uniqu1�s5d RT1i�>�, four^`� 9o�P!�-�Ŷ es h�% ��Q�d��:1�n9f| �|of!�ch%�latterE�)�to.�cal9;T]�Oury �s�onfirmE�|$ categorizi� Ρ'�es` restri�$endonuclea�F [23]��� �%i�B�/h�ꁕec�!I�B�75Sis&� m:>�$s 217 , 21��26��26266a�sterisin=��x polyq��"g %�specificA�)? TAP_lex [4}47� Vari%�Q]��V "��g�a�� � ( DO�DMaELz �e�&��&Q �e9g!�w�nD%q!W%.Wto��"�1�F��`�.��!nmorphicgy�t�*' �/n%micA�d� s [4�w� a tota�s� ��>�wo�n� pts!��U���length~ 77 bp due% ��� 3@��iDž�in� "�s�-W�|� !maAe%0a es� E �$23loc�f�B] DF��2,!��#BaBb4 -Db1�highly2�acrosG |x�$s stud���!Dereas_DaE larg�c��%�E�a�I�Feexist��of.sput� β�u%��D� ��ugges�[9a��? dataEsA��is%-Db�XKi��it monoQ�Ae���  level!�DA%P B�( ��II�a�W�t4fur� Aum!��trometr� at �b2a6,ms an αβ-ha odim�\a5%�<�%V��-b2%? a 22��iA�e�,ded cytoplas�tai& does�%�! M&eS�. Taken&,*�I���]�"� ,I0��had����"� �� 0dIj�|2[ .ama�Y~� � { i�&� nt � �9ZWhJ.�, [29�Aqwŏ�M� ni�e<6� !=u�bis"��addb 5 e �2 fun al}�sm&� asABU�A�Iye�h9yKZ#�!�Z]F� � are � ly��be���} �]A�AMjand/ornumber�_.re�-�.;pe�-I�M$J.0 in s�ar�Sb�� � A�� romS mRT1lv���*�5��+�o� , m.,[14AU[18�ItE��d;:)e>!+^�f I�&�of &R"s [36n4}^of�-AV�N%charac� �� antibod!=�,, [49]–[52�p &�er �-=HSA 4�" d q!widAcrea� 2� � y OX� ��dig�!te"s�Cisofo��56�� �x9���"�7ebo� �J�A1h.A� 8Aua�3�x�!a molecuS l,&�F�,��� !�t�di���lysat�M0f IFN-γ stim$splenocy!e/�qIbyJ0��is_%��f�� Ai�'� ~�=��;7� I�u non-%, b*~ "�#se�?��:#.Fbu�e same�6>P��17� � Mascot sc>">20 )��)D� matcK#����Ib �aq�ub��E�sI�DA , 11!1758(�& _!X�YHa 0by Rada �l . [5� i��RQUniProt�$y HA11_RAT���� f _."i��6@� -b%o�EC9 RGD �i� "�E�a! cDNA librF'as�!ne 3 . 6 �AMpr*�b��%�$ logu�g(e H2-Q10 [5�!All:Q�� �83��ris �s�% �=�O=1�� ��$� td � �{!T% ���-�*g� n �^!�A�� �-AiZE8u �! Y!))Q , [5�I��)H!,��13YK:Q&� F�J���A��( A�A� �!miJ`uS7 ��we��=�!&m��dI]�� &-���sh%�(�[-}�� �N}m�� samp� �' y�U n A31#UN����% A�R&&�!`o/d/m��� RT1n�J\ �resultsP �IN�%4�a , A1n/A2n� A1h/�3: WeN�%. �>&�!�Qis unexVeda��)Iho6;8is supposedly d.�axBNY�%L��ig�3�princie�m�M�cimWmenon�H�b2�j����s!F�� >� ci#2 ���miscu�)�transporm$ &� hypeG$,ťS���� no�/� �d��!� ��� J%%�AP-B-ly E~]( � "�,-A_�re,b�esf [!&We d.�is) -med#.%�-B��e%�. To tesi is9$� ���)]m tra-E��&�!]q=2M�V�� p2AL )�i:woL r�#nt �n�Q���H� U�#�$QB�YF�% I%dR� � "� �Fbinds���"� [5H"~0� H+�� gniz/S b][5�q ma B�s��Azm Q�-nt5��� !�r,�%2 taaA��$F16-4-4 [5:TA5�AaBr hb9 ac�a*�c5U�"J8��)�A�y�h ���!�.g�Q ��s+ A١� W�)2�6���-'���ene�"� ��CD6�ap.A�m1phage�d dendri�"�#��d [60.C:Q !� leuk�g ��q�t{+TI�5 !�10<ed�F��F�c)nd�D� G�-��%%gE�1�5a�*.&"QK%y�[ rF�aA� s� �Y�p�E� . 1H>'g:e��Xh }-ire�B-optimalATort�!|!�5'� w�b�ns.� 2in�L_*�%�������B& �$�e a":. ret�5�Q�2J�ER�"PimplyA�%#%��Esh��e�dt��ly.�u*A\pos%'y� l %�.{5w� �i.^ �" ���h.� ���c6�M2YiC��se6�O&) ue�Q��106RF6�b�# �.  �%y% 2�o�K2m}Cins;"!�#. �� A+ed��&�/~�s� Aon� �Oe�wc6";2�I.~ ( P<�-01;d5D , E1�6@V�lymph���T%LB�s6b �2��2�%)�|�F�at � t � o9t�26bIeU�7efficie�1&q ��5��m.�is� icul�l(fully evalu#5TAPE"�!�0���X2: ".�5� tsel?F"i�� K / AA%1=1"�wM�:� �l7-A1%M2�� natura���|Ba�BN�v"MA�mQd}��.ACI�M'[42�f��8 at!n-A!&�an�9���"�`� �G��s�&6 &�2�15p*f~+!5� .M. Az�7a-�.��IR7eE)�0���N,>J� 7Moreo&O;)��qi/hJ�!���e%*e!iinu=�ma [61�ch�V.!�eIudM�Ao&�.�S�*&"5F , G��Lk s �A�uV:�! . 1U� tre( owards�N��sW�ʑ.�BsE��A8inN�: s!st��ly sign� r oI,6F$ UR��q�5F%.���t�FfIiG4 :��ly)l 5.y)�, cana�b�$to*_ *�A�WE�m�u�:eua�&1>$io/ .*@"crt Bim!�� aIproba�)�n� e�B� "�0�e61:\ T}%evcp rA?$im-indepenZ(�-�6(�D�B�d-J4��-1H} takes pla�% �� L� �"/. J�� IH%�  "�-������� Q�e�� tQ?*-���>a�6?J�� "�a|i�@2��)[ �B\Sstill un�)r>�*�:�-� ^��e+-mN� ���/��C�ea���;*-m�Y$mK7��7�? � )sa�(avoid off-t &t ,HI�&���6Q . Ea9+ :! >2284T p@pr�0B{!%-of! ductI&O8�'genQ�� .�=�ofA�8a-2-microglobul�ZB2M , 6�J"�!�9�l� �6� W� B �@igh�� crip� vP0.���!:��was�<5-fold� )%�2N ?D�� ∼3Z1&�.�=_2% b@i�G 6� 1�� >�%a m6��1n��!1!V � .:�. suchT���<�_�C5V2h9V�w!lu2��&I1eB�M}to A1HN?thr4aien��A��h�$.Q5&�W }M9& =���, � ∼62� �m�A�E � ��)�-M�>!���aD��A����F�;�|� @(Fin4 �a���&�l=o<�Fy>!Tby�+i�arrayť h�!at� EMb a�/i��-d���@-OU�3�=� a sl�Fly+r��fra�C=�oG!���loS/�(��� QS9E.��8%٠B| !<wNT'%F-%4ng factors out��fC>J�!�6q- 2�T:�".�&� @coP2zE�M�2�:w is)�lIC*�H6j(� !!kp�"/ pock�H�N*_�bTAP)l�e����?9��p-C�'�� *�2�& B6,. N& e`fg`:%&y,DC�I�5rol�6s�?se|l'!�-"V' s dur"�?&f([6�C�$!.J�RJq�t�q/7g!~.�m_-+a�.&�9�d&�%�� simi�<0organ�T�v�.�iE IFs a broa�pertoir$)'in�� tissu�Likew�C�&<>�!�ALRl@:��:7�-2!au&�7�,.m1&x!v� @_� |�Ew6�Ie��f� 1P+6�J>ntigen�$s��ng9uD �Tx<"�Ku5 if�a2$KJ.�!^�rJu>2�&-T!ag� mmit�I . C@�W.2*� V��ic%��Ne�+n�ss2sLA�Y[.ob--� qual*N5��IM�[)��y�!.�=�3!�2+$peripheral!6:&�,"<����(ur� st���ym�� defi �6��| �|J&�Q�rat�5m>�46�([6�'Iɉ&, dou � ( DN el Nr>) �accor�qt_D6�CD45RC-2 [65] LG �KS1*E�FU��g prog�0!�DNs �C6ve�P ))[A6 �Pweek-� zN 6�%& �osMno%h)�M[6!�DNm���81"��h66b� _^*�f'enc-Pea�m(precurs�(-K(+ , CD2lo )e�*| x&� o\ oA�~�B ,� DA v�(G/4*��'��)&�m��+of immtea α;�O=�IS!�INJ�4A��5 �� sa grea��<o�>t M_�D~&��Jn8DN41��*X+in!�.Mll LM� TCRβ��!�guw5JCjJ�!KPvSv�< O� .�Qb4cK$x/re DPx�eng�erp#� �CR 6&w�5X �8�B��%�\�� ) a.�(!���iSwd can pair d"�e�rech"�Pf-},��1�3%edim:�Bb�= umi��i�h!�Q� �� a��Q��[6S>6;&A�,�� 8E ,�0%�:dDA1�!��Ainb�Q�n�d� a�'o>]!� ��Qes ��|TCRhi [6g6&[!@ю�RA>U � Hi�R ��E� q"�Q�P:`.�W J D}7*Vi%M�ed%.��m��as �D:HI�N�(W � �ՉE%�8MA* c)= 2 �As.{N9 �q�%�xq, �Hh�X!�i{�7.� Y�"��,��1im-&Ta�ie��it2�� :;�/��) �6�$(�8�2 ���^" ����߁�at��3:jJw a��V;FP)�U� �%Vp ���4J|, virtuI�l� 5�Nj�AllZ{���EWR= 0�Ua��M�( �A:� ��4A 2��)a�e5> 0>, 2S%3(� . ��*2 ��.�"�ref� A/)IBZa'ŘU3 �_��� �art�#a3'4a3B #&�#D �.=56W2�!�w#I}@@un�A��2.�B� ��)q%�*Ga %i� �=��LU�Gseqm�3%0%>$ sNs*��Fd"{,9�b�]mi� plexZ&�Rpz% ERij*2 �W-"�" *a�� �d]`� �>~/�5>R=m.h�:X!�� u6 �vitZ@&�i�Y�L�=؅`58L# YH..{.k8l A� Z migr�O� E"fc^��� �?�"no^S�$i>�CD9�) Thy-�N�[69$[70�cpl� ofJq*l3g�K��6�R�!�� �I*�l"+���6iDeY� eS!�8�T.J�;A.�% . Fu&DfG�J�6*K6�t !�2CSPjj(( R2 = �)83; P�)0!�FsF��&U5/tuv^ub� �Ny�. =�J�;o�p*� � *G,a��U�� weak&dyZ&%�6<J. SflxB!@=)�CD4NL�ngl)5"� |4�T !*I9� . DGB e�hAdlwpronouncI�olderI� ( 13–14��agesN �� ! K�"�&6,�z�i>.��M_�&Byoung�CS1AE�W�G mpha�5�at0mechan�%&�a�/an�,��b�);Tm�]t�J!\ic�put� main-!�&�%!F��=V�i�y�!�:�Geb!��= �3H>�Y& �N��cY�&I"&HU �# recess�lF�)ee:PVw�2�M LsJ fe�(�%!;�u.�� CB.�li Om�A�91.�& theyqE�Fv-��,Dk?S,ze�1k\aW;derdo�C/'ha�H�:�VreA<e@g-�222� 95�P�7!o�;it� 1� !��8m�Cus)�� ��.o�];6T so cAd h�&O1p�S��s2Emen�3re U��"im� seem�;OeU����Hv � " defa /.* choi�<a�F >5��"=69T>bJwe��!,t� � ^� ��l!��Ӂ|�1�ou�2:. a��6`ņ� '!T �r � . W.��0�ed.�6-R�uola���dF�im?. A� @8����3"�=� �' brok!e evolu5�B��� �ageJ�%-A�A�.J�!TQ8 j�-z)��'Gek.� >Z !}yB��c&�o+ co-*Ko�Hale�.&�N)�&�S�<�F�.Ix�_��V��h� �%4*�C^�o >` (E�);/ɡoG.�:��j.�vh�!2A�/G$'0prnq=�& �e-A!��P={���72� R%�Q`Bg�II7ND B�et�4f5�<&�F!C"�we0ydrophobic C-� �' P�nl)/ha�6ak) ina(A�6RbasZL(L2!L[26/L2� �� c,L]lxploi%�6�EtaD7teu)�� trum.��"dsRean�:Q�"�"X � !l��S!�ŖK#�� icomedull��ju�O���fŐN � ( [7u3�Ce in [72]=T&� )�igh6��%-:� lexY8!\ &� E�N . i�7 S.���% s YWy$r�J�,e = w�/m7!�-�F� �>�nd TɸO1�nu� goV� � "���� J;��%�eځx�D�L�B� 6�*:{ .�*it sAQ<��q � lea0 an escap�& auto"�'y ���PrMry� �Ge",our laborato�r�+�6�j)L)h4n N�WoS2�5 pro-a�a4!hcytoki�8A�=Ito�_pM��:m>[T��% HaagJsn&.1�*� A�]���)&�im �sare�-b&),!�+ ��"e_R��A is f%ng#� .�>��in fepCaoW�( �:uM?&�!%"%[mix��&&�* � !� "C���<P\fFV, [73�9� UsFon'.e"���enb&�.� * &Lf2��|� R����A��;v����+In!{W_tR ,Ni3�I�5oL�K^�!ep�li�de0&( cTEC�����slyA@ �.�-�a� XDC"# 10×�2L��-*� x[7�&+l_�/�4�-6T �� �Uwe�_�L�E[Io&�"%u�� ��=G%2r��.s&'0V�f�( � vB�a�-�.�DP%~M��A9b�W!6A e�L ����).�deq4�gAPE--}I!a 0!��Hodnga�� �5a?�5"mIAT.�bS 3A unit� $PSMB11 [75�[7�LCim"n:-u4 &� ��'"�&.3O �F gard�]08? �t�4 ,�6E&"u(!nor�%e�sYʼn w�iB7"H(to��$�%�E�)6yc%zr gN�(oHtor� ��*�g���7wR `))H"var.E`-r W*Sv�4D�Hef ]`bz CEM ) �2�po�D��andidR#My�"�#��5��x*�:�#*I�b� ,A�NotchR{ xd2)-�!�us [77]�� �f��r"m$�Bid5�f� [78];lz*s$ family me�Z, 1El>e$"�'MN*toB "7[7�IW�%re� fb�� newQNl'BpQ!(\s �W-fu��$�F9]�w help-ain!*"��-4!linvol�8%��*^3��5��K>�B�<o� 9�Ez6��#a�p �� TcsJ�N!�owCof:�Jn�*&�D� '� �5WZ �i�}8e�".,. Damoiseaux" Ws�� ��I��@wj8��'A�&�Q,A7"� �Din LEW!�Z�]� dNp 2� �O. 1�+ek"\D#*!)&� i?+?:h0�] locn�s�m!�t%0`"��:*�[� S$M]@am�/>:T:X�U��M;VtT�"�i'g�e�9$)�e�]bE�!OQK9-��"8%!�A�.� �& To&CB`"%.�BG$��K%�y��*le1�MS%�x :�CB���*F�"ŵe�>e� �!kUEiJq% <=R � -�e:� 2d.2MatE�&P� b� ��@kn"V`-�v?zI�lAbyN��bOmout�7tM "�386'$*� �no13�� )@�<-�:�!Z��AE ���y�1�2� _/c�WveE�er^C�$ �&;�Ze�%'Z.��"I76p I�*-�)k�a��&�l]��at!�m!7^"�g2�r-�"AS9�W ��!�a*�U� �E�&�9 ( Q2�]RNO5Q6 1�3!� ��HQ1 *7 1VZ�=.ӂ"jt� &i6�5a��#�� e� 1,��KKto�s ledg9 @%��.�F' !�W A�l �)f>O�a�W�q m Jd*!1��gI&b*iC5M{�h��<ll� W-<���7���xa narro�J]u*Lv9�) ����, Satb! ��e�t2R��!Cy� 80=R�ze4N��Qi Nd� %�,9} ��G68.�0 w2� $�Y%�A Q �|~ 9&][81�_m�{(1JQ�,* Y� ��y�ic n&�mm),� ?,E�6� ' � �of 136�R0$A� |�.� GEde@%gj yI�8�t� �ma����c�YndA�:. A� �� exte��� .�+9l, BDB�nstale�*�tSu�.a]�QO^�}k[�cne"�� �2Dc���> DO��e5n!1a, HLA-DO݈>L b"��p-�[8"[ eodw� � ed^dM%�X� "?B� s [8�98��6E@��Uaf��Ol��]ay���4�*`;-Q6;�NEg�&��A&�� m���BBexJB &�FA���ME��CRTpm �� ( Db'a5�� �� orth!��m�e Eb2 [8�a�'iL�%u�y�b2:?� � W2iF�i��&$.S a� e&P!+A���A��2N= 1Rraiw he qu� o$e� �9.vdmA���:� �YIc]!-�ss.#p)%��a�� a�!�]:�4�.�6.���b7`e[lafwow;M �LD5=]"��� hq�a long-s;kaT= ,E.�TAP�mX|[2�j6�/�.� �tR�&lR�$o�=advan�:sI%Iv!I9� ndaJ<� e(B[�-��i�'�J�\_,< PVG . R23��#"�[��#E|�M  3�G2i�>> ���� o���#v��I�.� �U!�3�6� g,*� }�a�.���c"�i VU a6Q�xw�RsurpriQ �Vcer�I*%)A�!s�$�Cb.Pb�b�O� %�� �@� !^!@��(�!r!�ndE'� n=#�h!�Ao� whiq�l�k1�� -����!�BM�>astruqI�sn��( L5�O$�z�lin&�&@e0E�" �<made ite]3&W�add�& %?� . Onjhun,"�Y,"N^"�-.w����i *-h��i�� i�8�P�� �AFL�m-nne Fras*Le Roll��per�l!�munU$�DK.�)�!�f!mH��5iFL0����!��ci�"�%RR2hM6�)$M�����q�� e5��.N�M:nIaK�#A?�� �6 Y��J)�E�� �BF2�O"�6=O.+A �ain>��ide�J�8A{� SY2b-DA1 �� +E�h/ Xp�e�* (�$.*��� M�B%r/Dte@~ �1�%`� YC�]a3at�XT5 I3�J��-n�Nbe��M�t��"�!B�OEq1nev0 -�&� Me "2�P)�E�,J read�� f��r��no&� RD�QV�j� �ə��a�Bacq�`d��U�(�u[[BN �F���%��d @ %�}�O � rR�ein2�]��"� ]����";:! myel"�� �bm..�cb��y��Cai1!Du�9&�^:���Cs. �Iabs�of β>�S."� +Je1��*] [)V%w�rd�ft n�1arAunaNt/+�:A6Q�I� -loa&� . ^"�!m�isIe�M�9�E6AMY�� "`��{JsSaA�A�e� *�TIsS�z2�!I.�f�T��Aq.8�<�Z0a��ha�d!:*9 *�1'hesus�ea- k6J ��+��$v�.e�o6��>Q�or-�id9[8� o-"/AW�#�� w�Tap��i�� lye2�'s��d6) !?:a W la) sepa�Bm�8TAP !bG 6I!ҡ<��`+ of m 'e��2 1]�N��Fmicv!�:+c�o�M��A��!�W["Cir.� �*5 �!��2��)themselvo&�� ! u+ .�}>1V)��e!���/0v�QWYw2qog A1@?E�d"k#-} chic+}[8D!vA( �:$!;"�3fla�&M�' 5[8*Nj"?�A !K� ) IiQo�os��%a�i�,�Yv�L∼25R�,L"�2<PA"� susc�=�L� �R�!8 VOi � *�r.3&؆���, �1!� .@�"�=%p�ud�*i�Ry 2�� �g%[%� )`J�4Ois-�fgyNE4I -�.�%f�1�N�dtm�8� nI�qk lack.�&36L_M9&) ��%[8k{91#inq�[9�SHD���#.H4A,�eA)0m��A]��EoutB<}[1N%8!�_exEFW >�v *WRCpm�z6@ �)��[9�*I*!,"�V ��Q�9��'�� �stock��(2�&�E[!� A , {~ CLN�Fap:vT LL u"� FH*:&FHEF9'%P. W���~(� ��  '*؉s*vA f!_1 �!�q$"^ #'a�)���j!it&� Hy �"����lUq ��> �|2� nd bt-�..�6"�'su%�w"a"�Y>i"&3��#�6�S e&�+w' &n�Q���L'2F5t�w'�H�r0�5rby��A!�>h�I��AQ��q*� hE��{as(.75cI �6=demonaY��>�s:�S�i�1�2M�*�8�w���LM�Z>wABY:�;a�[u?�8���-&K.2�*&�*aIde�+!zy�6,. MQ�"�>�-� resc�v.r�tJ42!�aS�:m�� ewHQi&� . Al?�A� A7a�4} 4���� �\l ethic�*�tP�8at Karolinska IW�S�+holCzorI Span��legisU�,n “~e� of A �U�KEx��* nd O!  Sc�k�,PurUy s”1) Euۏan�Z�ta@CqA il D��b(( 86/609/EE�>EMubjec�WRNA%�Ar%�E?us!A!�4RNeasy Mini ki�Qia�X�llerup�enyV�trv)0^ DNase Ioch{MannheBRGer�{wa[leZXZ �~(�~�Tsyn�B���ziS: ( Bio-Ra�&C��US�U. Geno�, Kg K"� .�byaF� �K "�!�( AquaP.D.S!,|�P;di�"�7Ɇ l�%T���d4���70�*&�dE�Dt�6conJ�+h capiv7 7!��w��  $�?� SOLiDJgt��ppl/" Biosysteme. F�-Nk,!:\)�&*e�( 25 µl PCR�iB aip�E"g%�, 2.2 �WDmM dNTP ( New Engla)Biolab�, 1.50+ MgCl�$R Pa�num Taf�InFQI�],U5� )��10 µM�܊� �"�purif!*y04Millipore's Mo�$ Cleanup K��uil�� in HPLC w�Vor)�U�� garose]� afte��l e�4�:re��. SIy!�!�per!�q� BigDye Ten*�6 vA�16�Yi��u%�� R  �!14%"of�gl!!, PrR)c�3ol� cipiClo/gsM4-0%~l HiDi�/mam�r!?"4nih . gov/genb.)K9!Ie�$�4 s KC22288,h 951a��z!�of PBMC�m NIH-W$J�rH/[41�$Brief�u�mngIC9�in 8 co��% 230�k�}7vl�\3 yv . R%\YI�4)!behavio�#r(A#N[ 8�G(pri�o blood�p�&$�ek��dYfbe�c �a�*nd-hea/] ( p5�yG";$r����,~npa gluca/ tole� H&�Gk% inva�Fp84dL8�9=w� enty�c �aX���ory�mi dupl= e�;s`Jaz>�cÆZ %�flua�ly-labeM�)z��( MAb� se!��mA� ery�lEO,��3fix6�A@a 2% phosphate-buk ,(maldehyde s[Cert�waiktwdin PBS b�4t4.^[2×106�%6^�"�z�Y�#^w:"rb!�2w�e���U�r�>t�)4�2�S8NanoDrop ND-100�MTechn$!�, DE ,q�r�� to 60 ng/����=nfJ&Pp�� �H�> Capa�AR�& se T"�$�((V� . QuA4�Nval-C��v( q�Y��(n ABI 7900H��j�SYBR Gr!�Z��a� -stepz�ocoRi95°C�ʡ�a4f�B� 40 cyc�2*se!~ d 60?30!�A�F n���a�R�N �" 1�x #v 1�V 2�Dcl!(�+6iZ"�nu& NCBI/� -BLAST� �lretrie|  �=c�=ba�%Z�a9 �E�M�ne��w�5�dm&to ens�$Ral6j � ^8Q%" effiq �_.ba~f C& $�~ t�;�F&� )��4*{o^�Y%� thresh�a( Ct ) �x�8� �l""o�ge""o. A��Ct-.9 �ѧF%oeb $9E �ge� mW �i>1oArb� Hprt-7� Mdh-k�0fEjf �`���n- E.}�d&�3)=!�a�qe�f�Ma�0method ( ΔΔ%/� 4I� �F�"�,� ��pe�NQr��� H �� ��`{6�pR. C�<�wa���`n uI�5% FCS k� ed DMEM!�uP 30 mill�� �incub��a�7 houAH t 37� 1�eml��2 �ͩ��=� tly�h �*� � 2%�D/v ) CHAPS ( GE HeX5c� Life�� ɓ��ɜ inhibi�l(�t���bSev�P.�n��i�o�ci 6�% -��]9F7�-17 .� �-Ur�/Iu54 d0oa�it��DTTZ T NH4CO3%�10�� at 9��!T alky�M1�(mM iodoacet� ( IA�!�%�nC(room temper) !7I�ark�!�*) � vern�nE −2�in 95% u���] 5!c�$�S� ifug� �M.�80.J10%e�a� ,� 2 ic8�@6���5�k pelle�V�disso�inc µl DMSV.<to6��30% '�a���∶E���a�1∶20%�in-"� &�2n3ez��MS h � @$��u��C/ dr"I6��U� 5%z���|v� I� ZipTipC18 iZZL9�LC-MS/�eM���� Easy-nLC �hermoi�l, Bπ&�"�o��H�up� tot ybrid QEx40ve Orbitrap m6A�erRs��[.�_Ύ%6in��a cooy�F ' r on��LCA�um����W!�6a�cm�, f�si� tipK( STipNew O>� Inc . , M&qpac-P in-h/E�\3 µm C18-AQ ReproSil-Pu!D�LMaisch GmbH , Ammerbpd,=�! �4atograޟ�F�I;a�etonitr'$ ( AC�j/ne`�,�.�26���p� h grad��w, up: 5–35%f��0�-, 3��i�� a��5 �4�&f� C!a��!Hl/:) A��%u $aa�,�xa=survey s�Z rang���m/z 300A� 1650� �FT-U�%q5�%��Y7�( atN20),e�:� ��cuE?�H*�ai��!l top 8��j �� ��E�#t�≥0� .K��t"Z�HCD%%@� Rr2���500.�){"�eY��b!��6�Ht"2 mmanufac�r'^ st"gA !�i����I�� � lock�azaon%z(429 . 08873��44g>12002 M��lis�:�!wraw%� xy�r*n softw Raw2MGF��searcF] �;�� eA�e��atrix��ce Ltd�NLo�RKV gy%�. ox . a� uk/happy/e� calcB�e�$il�ofE� ��a*e� HS,3�~a�/*� Q9=R�� counM\Bednes�UE�t M-Model Aa(!�eXpU80ed ( EMMAX ) !�od% ANqAx"�logJ�V*y!xach�� als�scJ yata�FD'��:k �a��C�� as e$bZ����to�%a���6� N�F�gu&a HS�vr��M �BagKe [99�I�i� x=DŜ���Re��-��d M%aI"�yPO8!�yMIPe� Conf�:c� X�ůU7bs�E�U\tyQ�, �ari��� -��IZ�2 J� "1��A�randomaNun'errrr�!]�#caa�n�no���s� ���"Է�@web�\^#>.RJgcdb/��.�>�DUniA�SwA�Spa�&om'Vd ] *��!8ca"A�receiv�7m#d�L� A#��b�� �5�P�,*� Wy�Zp�-est9l�in!b�at7  Chaga�jGs�#3I�H�Ae N� ��� S�� m’s Hos&�sch��� �Dat�2( CMBD ,"���"�ek$) 1997A8��in-g#&L �Ptro�S YpaU�:/!n�in����it�� r�Bυ� �?J$periods)��>>��� ime:� -200>J2005-��2)A��� �G}�A cli$5lx ��� -1P�W�ed multi��log1��:5d��% adju6�odds-� ( aO�)! A`a��p&b�_�e�ms(9cASf$%wa� @c��7296 "�%AT����2�Q�6@�2�ere 1�24��8/[00 pop�(��,� .��s�t n ag35 �(��ge 0-8hD, 74% � fema2niBV�5@-B�pEHjol�U�,na�( 6= 8%��Oell� �4%>Q�m�diagno of>�w�()zŞ�'B�4�[aOR: h ��00-7���aged �4- 7!R59de��2-�!7�d8��1HY)�c�% abovV�$, 065 euroX0�!73-T86 ) ])kQ�Q`:^m� �6v0da��j�-de8%e�6� i*��AŢTc���]’r � ( asympto�zc w�:r f�A&�f!#ac.Gmn�F�AYA)O0<��%h@'effort�:��c�Q �A��? cruzi . :�k1so kn�sasѢn� an2�iaAuE=��Pl�lfe-�atei#ill ��_�ozo�wra�, Try _a �( T . �TO&�;mEs �{wo pha�7iS-� cute  la�!5abol�w�Rnths aG�9!(�a� cW, -�wM5t�mil &d �i�We fP�E eada�&en�VdQ3 ^$Sp]A,mu& b�O ultyk �OG\Ys ��AHabI�l�cA[�9�.DHBg%�۹%,m p-� �$hidden mai�3![he hea �nd� ve� . Up�\5 m s���cardia�F�!suh deat��$ex arrhythAh , u&r= ar aneury�/, � failk �� (mboembolism�nd� %2�� ve (���-�l�es�� Z colonQ"�o�e~Xor�e�8te�K ns [C/�r�=!KYbA.4\2or:�yC"�~v�t��)�MG[�#:�uFf���2� $benznidazo����lso niR9imBm� drugI1ale& 100%��!vh  cYwq�if giv�,:sad7�I !/.�[OF2��RaV�: dimi"+�&l�gD�>&�$)��Pu�Si@kc /�m[5 %Aܞ{,y2fic)Im��bQ�'�Nb!manif��ds�2�;tE0st�#�bM� ����. World��n%E�H^e�� peop!��`"�2%!�!��rM*�@5�s8�e7in 216� �[un� [7����NAlygns&�&@7a�ug,�bit%r!�tm��b e bu�� ��XM� ervoir�. N�pth�6�:�?mi*'t>so&s1�zector-fm�w!Y 'S���m� �I -�Wrou~%!XLZ-2n,�%f����sol-�`^GF�-u,e\W l . �j�/�VX&L]on-�!�*2$[1MAlt`�!�QT����E[6� [1c:}in%Fi, y�a:Wrth: �B!�We��n Pace+R N(%Yly Au�0li 2 Japa�i�(l�lE��?Tbegink��� )\ 5mor�(in�. [1�I��JeO�O!�c ( WHO )* �"8�r�V�/u�qSs�oY2:M;m�.V emer:�iZ�a�� �Old ��4The :�=�q4b��7���2\ a"! moL�(�y����F -aB5�w� 2)m=�(��imVJ&G� EU ,�E~�FP�/e��)5��N�8*6"�1&�0� r��DPE'n�A�C:� ECD�0�Kh�BAP09 , 53%A�At�q" 7>�)1��%T 9~c�gR �lZ",[1ŝA �F�x+O�)|[��#y%V%<1��alQE:�inN�%�F (&�s� �E͂�p��ak��0Y!�6���i\�wW2Ds/Z!sg�7L4a�!�6�  F�curre�#�.�G� [1�>Iis< dec�G{I"� ���,mrY_� �manag"S FP)�kuv Sept ]��"��'9�Roy�95 e RD1088/ 2se&� scA)��h.^v�� at \��nd�/y ��,ũ��N6[1!R"�\�<Z`v2� preg�E62�nJE!�Wsnewborp]�� in 4]:�17� ��u��1( VE�iiCat�� GalicBast�C�y�;c.2B MRMg!�q?�6]* -��ijK� �p 3�ki[�.M� rofe��@-�N�$al 2�i��*�� �@�!4s�E��3Ao� � ��2m&@'u�l�&z�X"!�re��R ��V�′�S ��  ) be� Ac�"S796sC�of1%�JKpaֺ,�8C�!�f���:��%��{B�t�AS� M�^ , geU"al!qtriy��1�u��v;1B . ���8��EN��kataiwThe�%M9���_ (I�eZB,%�ho?�JJwSB�l Servi�(!E6ooC( MSSSI[Re��Nwor* �Pz�7 priv� !v�e��r`)΅heA���fi�X,�tngHseP�a"TMna�c&:��y<�>YA^E~ 7]ed_q�C�9 �A� �%D� nonym,�de-*�1WSSII �0T proviaa�4pp�R. A�'�eisn�s:� �eU!�zamq !��>;:��-�e%B mustB� "�&�e ��p. BZKN.a�Z��;nQ�*uk|T����Yi""��54�3� 6%�0 6-adMQ�90� 1630/�� �P�<no��,�!��,&g-twwm� erq(�XŒ.X[5+"�4�X�8FsNhp���!�:�*J� %#q>;F begS5� st�L200�uhJ��>n$a��;tg�T�t��)Dq��(v���$�E(v2Q�2� �rk-d*�Gf �a sT'�>��tG�37 09 h#鱡�i1hDN�� �L�� ��)B�OF2EeS2=0��For'J6bz�d_8� ����1,m "m�*�H�E��ut>��;tno"�1ce�XsPs)2G!2*�# e�:=s%9F�–�%��16–�g��7:�4 1207i�6�*�&�AD�G39.�e@���)(!��%!�206q$&9�����:�:0� i&�)�!�878^5�7^�qaqs s<. G@ �K a�o s=D��p1M��[im�=3�4%f��!.nl!�� 12w��E#q�_t f�tic��6�L>B!�� � cBpg�bi�orzt�Gu�+m囁�!�3 ��F���cir�%or+�nQ(Q�. 3%}2s� ��}( E1+�Qlp ar���da/ ����� ObstK6cs-Gyne� gy ()�r, C� 1� Ig$� M���'(I���D"s!(!�E�(�4T�'��&1302/179��7d*%'��(!��ha.�"a����i=�W5�38a i�)bi� as1V� j Vg"j317/38u08nev%�5p�"�� !C71 7|3%8.7an� N~ayva=or�i�T/ *�< Voc�,v 1463�-8 E�B��#*� 290��t|NLFu; 579/fAtA[ 5% )B�=�oQ�av6rge2M375F2:^" C>L�p�Cce�=!c190>1E�% u)�s o. O�y�"V�, 487r8���aP%��e�i�u�����(3X�>in 71I�I��J��+.�f(d�n'?7��!#6!V5%�a�RQl�jA�a�elf��Around�0�m)VdW&d� h�K,B | �@ inT2%>�)�3��:�Ev�s]/��06A�9�"���0 e 28���93�32&� CoU Ex*� �Wl�2u%��7��>�t95���, �2��*K5��6j 14/)�.�B[�zW"� nd 4�6*�$vM!V�':�( 4�]3%%�3�#7%%&5%��-�5��s:i��J�urJ A�:�25%(n�B�!����7 i7A�4��Bii��P5� ��f*�>�amE=( 4l#.�SA ��:}%7 day �u�!4!tay� t��+.1��8QaE�F�;:�� A#4Q�se>�� >���.�419E�m�. F*<Zto-, 614>Is��V�rTl��l��y�� � ���)�u;� %^.�ef 612/�( 9a2��!z� f�%apLR23 K��6@4 � �i�:Nd�y��d^C9 ��4 q Zm��(y ��"�� �$9;� �XX��RC,� ly2�*���QM��xt2� Q���sM�@" of 3iMy#9J�)%�F(H�ly 30-��7� n�'zrUt[ Ix�� �=)��wJ20��ѩ8]�b,(>�� �hJ� 6o)*i*,I*�N*N+,>J���y��nhis of1%J�A�:���.%3� E =���&�*�K%�� a>��Wi�A�ImZ+1�4i,�m6�AέƵ�.~ �eB�� ! �um&� 1�E��#n�W1:!N .���Al���*��var?��\&)"<1D��.m�2.5u�������Y" |F�>���q3�:T>��m�-=N���N%2�4"9"I-, ��4f=d3%�:�R.n�(��j�V{ !.��JUcompa���J@N�� V.#�s��9�4J�%�Q�B\e�E.ĭ���"U.UBw�F�+ab#:`.�{�X ai �fqj��!t~umyA� "�tF���&�6qS�A�:~FE2h>�"�1y0:��S8�3�R�Os>��#Iot,�Z*��U,!n-.�#;mE+�)!�**�%;&�4� ���)r&��"^%terpr�B%&ca��Aan�il:�E]��n-j4��i�"�g�of origbM-����52Nls�be.��&a�N�f]n� w*t a� �&kn�/U��mR�Ecs�U�Ra}�o:� �&[4 (N���$A�  "D>�7�/:�WI��*&�mi��"�W_8Sa3)�\�(* �6�2�j [po)��2MBD!I%)i"�!�7(�)YdB�r%� ́���Pa��YT���.�ve6O!w  )u�-&�o$�o�Xi��G!�.�z�a�;�R`0= yI�Qsee3b+Q%a l�>�'' &�G� n�enc*|�2\$�&12$cht��,%s ]!'>+�s�!8%�!�des AHa� ( !�*�%�QY �%K�-ng \"jof}��17�a�5�Ir�E|i�;Y1986 �Re�S h��s 7?JաYQ:p���p �>e.�5)� b i"� c2c�!�Ūa@co�A�<�V!��3�.e�4m�&B'6 �2.2 Ic9s!h�m� %Q�6/ 1�9m2ing from� Chagas disease chronic conditions in the future . In�clusion , using hospitalized caseT,charge datab_|an be a useful tool when describKthe>��epidemiology . However , our work underlines @,need of a na��wide systematic approach towards T . cruzi early detect �,especially t�t��fertile aged women and relatives from endemic Latin Ameri! countries�8ealth inequalit8on immigrants h "`status might exist across% S(y if screen�program!� ffer �one reg�$to another�, fur4more , are not.DHimplemented . Moreo)�1j4al surveillanc1uL that would allow a eaccuratI$ colle1wanalyz�!Y interpret%� ,�ldAN!�g pictA�of>din Spai[resul?M�bo%� gai%Xextensq8knowledg!6but.3 in e�Ag2@ control a�8s .��Hundreds� geneA�`markers have shown associ% 4s with various �x�s , yeteV“misi��eritability” remains alarmingly ea�va�0Combinatorial)��may!�A�8 for a substant+pora~�thiA�F~ ,%2their�cAQa�beea pe!nby�uIallexityE$10heteroP. We present BlocBust�>a novel� s-le�A�$efficientl}nstructsk ome-�X,A� ele-�(fic net����aa�I� ly segregA�hom�-�%_i�oof\%�factor!� testMe6�of!7��-�BE�4given phenotypA�aI$rigorouslya1idate [I�s �� a se%� of unbiasib1�;method��=Semploys a�r� on measat%P is custom�*A3A�$le nucleot��0polymorphisms � eturA� ma�-face���1of�u�at capa�%�%NJapplied.���x e psA�si!�diM�ng�)� l pattern)x an odds ra��3 . 64�Bonfer�a-c!c�p-�e+H5 . 01×10−16 . Ta5`$as replica9in indep��nt�d , ref�B(ng robustne�!E)-� . In ad���improv4predi�����suscepti�/�broad�eour�a�dF o pathA�e!Du�y.YthA�Q{demeca!YW's pote�SA2.�Q�)�a��2Bin]augey�� ,�,reby transce �aI limi�“small� ects�:produced��$individual��examined%�soon . PU^iA� in�%bleҁ��� u7ha�were:by hyp�olifeEp� aber9 d��%8e�-�M rmE�coupl��B�gd cutan%$inflam2 � Environ��al trigg��!�onsetasymptomͬ��observed͉1�Ek sposh ! stroa`nd .� has JestimE�$at 80% [1]q&Q�appear�dra�c�%Jtw�U popu)���It�es�%� none a]in Eskim/ d South&� Indian2P , afE! 2%–3%!Y �Europea!�$cestry [2]eas . uncertain�about*!Hci� bu�m� � > re� �dlinkaULisequilibrium ( LD )Er ach��]�E�ic Q��p . Im�ca� ,�)ܕs����x E?��a^ari�ueJ pi�h of� ple~�� [19];3v{�Ql!�effor� oA c i��y!\. Ii�d g;�뉈� G`�+b�of>Z suc�z� cent�� goale�m@ ineE)b"�Wh,��>�h*�!fv@ �����:��i�clear)�b�2��unexpla� �!v�a��Je<� enigY"^ s [2�ss61 NT9b�fluencI�� plic p1Q4i��ze2� #. WRconsider{ � lo��}qs>f�%�a � o� ��e���!&Q�, makMWm icultà�1�'22�=*AI WEI�+2���4 s��y�lveeHy�bC oA�d� 9ic� hrough so]AQ2�[23 �4�StandardI� only��y�>��U  of he���0ey lack power!$t ��\[25�A&�  i� 4-X�0o� V 2�ia���=A�_��s!�w�b��ohibi� normH �*�90s grows expony%}͏&�q�]�si�� lA.%InE� ,+duc��� n4quickly becomea t��E�m!�Fzi,.�thousand�Uor millZ, eRjus�� !"� y pai� two������% dema]. For#!s,� n>E`e� 499 , 9L500 , 000 unique way� Thiw challeng�scr�2>�!�b er-or�9QL�–�ver A?�ree�r�rh1,� 7�17Ao�C=quc$, directly%�9` trio!�f�!�>ki] Y cur�; vailE#resourc� will likA��  easi�!&ALfo e@f[2� In %@a��%�-w�ep��a�involv�A4i ,"D _h�# �jin whi ubse�0@, seed �pr�ly镡�or��o�� Af �21X)[] ����[27� 29��6�SO(ge et al . a�ed^j!_a M�p had � ^�&�O e*F ��2 .�,�� d!�te����NoI![re left�� ��Ite�*�AFNR!x&�A� huma_�"[38?�J�q�%���necessara��!l�d prox{y�raY�%ɀ�"aqA�m�There� �desir%�to�l�-!�2� E"��)�� impo�N��tr�gar1doM�.2��C&� proCJ��pF� �2/-SA'� �!� �e���a9��)�>2� [4]GnJ�e�Z� *x �|!�ach).|�~)�}h�sei9Nely.>e.q&a�� tagg� �"P_����s via��I%�%.�1���we=+ �"E�A�5���*;��� *&!;B;�n nw�)�e�  authH"�|e��s�of � fit� �ir�Q�.�usEJ�sam� �+ mode�#)#�!z ���AaC&q�� Tu � �ԡ�!��ly-]U2= erad��B� 6ere�ng^!#%�e�  neglig�2cw� �;�!&� O�&^(�� ?��oA �Ak!"T$A��oge��!`e>.9nd!�� re[ )t�V�aximum�ihood e %�%r�EicA�ilari�ip�T Yang"}R � �`ce!&:'9�'aq��le~!i�a�1y�.�g� et��� ? A��l dvantage� as�W" � I9.�t�ng:� I�"�"to G false-n�%� �%A#%si�$!���{x) �&�causal�iB^��7�f*�]�Ř"�'%Re�V6�� .#�qF��!��,siM_y�Nsha� ,*!domk(!h� 1G&;d y+�*>~%��a [�'q^a%{ful!�-Y��D)*�to"4&�,:��*BD�,E� lem�exacerb|by86�&�d-ec�% shor ! abst���EC.$&� 'ri ѿi^��i�y1e� "D'Q4A�-2C>�a part�ar=0c exp�&e)�O+rem� la0.saa siz��q*Vk� "F�$S�al�)�_"_ � es utilizAFF&^*r��Q(AV2�)1 ExQ!ic5,"�nes�� clad%��[4treesca�"[4�E+evapo�%v�o "j*[4�(SNPrank [44�`Hua��'s-�Z62� �jFcal*�&4Z#�lLi.Ptwo-step� ` s&�)me..�and/or.�!�M- .Kof��C &\�x� �(N2�+%���unbI�*"E�!�l!�l.,� o�:��oI$����� densiof .� in���![few $� ��~)w. MN"B�e �A�K)a���1?�/o�/�Z(mb refe�)�1s� .�#Gene Onty [46AgKEGG [4�%DAVID [4EYor MetaCx @ �*�)� enrich����?Du� �assump�s!0I5a� %zA iQ/� d du% M�6 "i%��0AE�w.� s E��0�!+d uponRD��.u+\�J � Rg/W0�-�iss!' ng�  �of.w����in`� F(��s%VsubjecX!�7>�"�!SA@tup�.dc/op�: �$ @� f/or~ -by-*� !��� H2%a�manif��43�)&e$��i���#masF%6�p6 cy�fibro#�!$�ma t���Sz� , CFTR [49 nl4(tinitis pigaCosaFs ic`�ny �"I)5�! s [5R � /2a�r�&�t>�i6+Eba�d�gnct�aorigiu&�+� b556m[5�+C� � ,:"�%X�ad?qu�2�nw���Z&�Ny E��7,"�is1KBeHfunda!��2n>/�2i�:*�1�t�Aw adop340 {���>z%alA �4!mP+on'� &�1co& ( PC�+[52|�VaFb' t , r2��26'���sv\-�/wѓ&�1mqscu4I#a1�#rip�.�.2��G��l� �REuwe��e�,���eJ2O�*domduc�d �&op�!WglobalI d.�-��"re�5vie�ma� whol!H{ thus�b:6cM�group&�����6)�N� J�' ignos . Fig� 1 il�w1�[%� � �e ��A halfNp! per�.�I�/w(!���.67a�1���..��  �%�7pen|:��hev*�.nEEF m�{�7M�s� .(%m~a]}.[B�� ��fai��mmo~5�k�A6�wit���s)�s�-� .c"adaezm *[,a��&W3A:�6�6��e�9@ fteg;�o�A54�b�)���2!� � ���  vA���� "�2 O o.icC&�6 i�hon���*6Q..��$A�keyՔ �;!up9#c��irs�|w�� .�!:���%�62a6�CC�0“tr�CJ ) [5� a�;ric ig-{͸Z�")9A U*Z47q#]���� Each�lef "j6a� �,n5 �8Yz.Z . SeT>I�bui<n9�Qg�"a]�,� y� 2��&*��{L, �ɚ��" e�V�a[ F%9E�!Dr` w�*�.#"�,e�k�e labe�� d�>�+!"jt"$)&�6a�!�|9 shipy toto���Q!C%�9,)-bi-%Wic���re�?e) wo ��(�SN1���&��r�[ a�to�.k!Xa $:K!(�&b)͈jb�vea%3]q9�A�/ r;rd�b�� ay5"fa�]. S}��l���vec2��:�b=&V)-'!��]� . AfJ&h&�ise2�wre:@v"�e�V:, r ) natu3�<pa��d��%����d d!�t �)&�.�g�sp*Bng .�Ys�t0a�sor��5$qic�E �3�9ݸex�s2tBg idu6;er��s�$iT�9�$s seamA)��Zb] y%���t�!���nA,m!�c)�treats)v�'!N202j}�voi� ���.��E���su> M&� Ex.%� 8!������An B�>!��d!Se�n�Jmervof>A� A_}�BA�25 $WG�{."GZOur���Y&4&� �\x �,�(o-%82�4-on����4al�>,X &�+ns^ Xc6�?,2�"5?�g.�%va"w?�(.� ���t�perHes4 boot� ppa�B*c o"X �)$ visut0nFEu>�5�s �ܡUFsDE��S� U2 prio$-investu= Z� �t}'Aim�*�4*�jM:e(2r�>.�><"�=D V0@�e B�aM :�  G!31a_%!K������y8��ise,��A���JGi�of 44�)020Q#�>ala�V,929}�681 �A$����d1`"�@8D&7&�w stea%�=sp� *F*1Ynre %�a� per�<ag%�b%a��n�?c��%M�(�!aret(1� g !6co%s�oJI8� \&: romE3�". S�N�:'63U46�B7j7 3% )!�E9_���!� �54�.2 s.�, ran� �2!�313- �anu�0 . 7 !per �>n?��j�+N�:K�4 �as!x�OZI n �j�>2�e�� tege A�6%!+�_ 5 �E  f��encJ (c��"�L"�A^ tall �*�Bio95%AfAP>'0terval ( CI )7rNJ,�o� G-% �&F co ���`�&� �olsJ�AnyN�?X!�bNm\t�5aC!�+ � -�!T6�"�+ e alc*�GNo�,��i^�5vb)�-�J�m�;�<N6��u� � �1�� �%oli � � � m1�i..�$�-#p�M�� ���3�4� MI.6.�3�@�3�*)n�)vM��h �ia6�P�O�� *m>~&fac1P"2N�  t� tu ,c��it�h.� r�edهEB�ps_��QAdA���172�aS ��g' .a! CI (�2� �Iv{B&�P2� !�Iq v3re omit��,�v�@s�iz�785}W5d(a[-Q6 �“�1c� ..w�,Q���0 . 179� 265�Ro !n�vej^B�NT605��:482–759%DH"�UAlp�N!�a�&� t a��� bNE:Ra%9e��7ll5�Ya�41Ve$![J72� nd�072%7J:)-��BfaB:�I64-9:75–�80��ofRPe6{^S�r.f� �*�Cq��.!/a� �: � .q -n�A�!t.�*�!�Y�p�pronoHd (Mk5�$AQ216 )�2df6157�K�(is"�!,eas� �J�:N+3 E;A�n N*"�>a;.�ic&�. T=2 ��eA�w/#��alongI^A�U9s54a�A�e�� MG(gL211 kb ,� � 31054511!�31265057���M>�M. �"8�loI�in�)cN,s: rs3130573PSNB_M� � zMaMrs�78DCCHCR�Mcoiled- α-he8l rod)�in[%NHCR��All3� ��ge*ZO &$p�rO[5T+[5�D&�q�6xS�m,ran fa�a}%al�ws:~ ( �J�)��I�we�� *9e ,^plu�4�i=!of�IWf�&�F�E +6to�FGX>� sc���V"�� Nh I� 6:� �*H 3U y� �nBm)u��.�lj� � P��# tr�V���&V&� A�'�� �#�%t~Y.�-�1h\D;$s�A��y"Y=:�ack�#nu �  cex&i&��AM95� .A2��7�� s!��;rr�/��of��0�VAFH��rrH� *ٽce�u�V)�!�i� a-�2a*� kuR�0��_h#� e s�d�BR�E�%~�0mo�"&%n2V$ s am��J� \ in�Q veri�@at? is un�� I NX�T� F�,I�E�e��!��*ach���doxshuff� !�]�u;>��(� a>�HbreakAUN  &}�]i�eI6fa=bal�!��e/�� "P*%U.>�< � &�2%R�&�JY�:���!�l.at�)9mNaimA36�V1higF"<\05�� %H�%ar un1�mdrawn��I�p !��9�7iG96V}I0�E����1\s�� 651a�[low Z" a\an�B�L G Q94�TE8n_��Q U�!�2�)�A��,�e�"�n�>"n"2��ea�rd��)�i/�`�XhG�%!A.��&f�>��$DQ/n9n��*N�`de-E"��!�d-�%3c"mby-<-�X.� Y  5nLto*{L)����re�E\/M trac�>� As }s"�"Q�A]"��\a plac^E�I�mo-��Aa750. A��DsX o#6906 ( #�$�*2�=&�`ly)��,I3Fk�e4�[A�"&\�2!��@���!E��bE�� �a=\&/ ��e r.h!~;3'3:dide~�)� M32RQ#�|F@�e16!�1 � ;�  6% a� k+]e1F ta*-ew%lo=%:A�i� 17-n�)�;�N18eJA;071E�x�,- 2�83�6�SF�� 2of)O8 `~ �}42�Jz��2�)E4V�>eW%2��/$, rs244273"�`%QZK137�%K39%K��O9a�CI:A81–��45�A10�� −1� ��5VS>� grew!3),^�I0^R3�CI:�54–�G1G!�Q �'Z��U G�)�r�.���������� =��"� �a�e�Im-built ae]-Win6o�&! A|��� u�|PP3if�-�e �90a��p.Ycee"7�hr�*a �OI�S�n�+!�2�%�`A�K ee4��699��7�E��!��a!iT l-u8VaQ�gomi�BV�)Sf�)�B5�op;S  +��>&+*��a�)ex(�6C: l�&ter&AM�?x� &�G $!~�&T(� 7�H&E!�!)-� E &�/�]N��VC&�/��� dg�l0T���disper�d� 7� ummaBpin� �In��K >�e934.I+�g.���YA55�X� � �.:+kK.yK6Fra��+E�)�%�� s]6 -RZ( 4� 73% v� 2258+B:��m� ���e2�uc�C�,��+ �S.� ni% �n�P-� `M�,G7�l, ��z2��[I�N�� �h29�� !�f �.�V �.�o a�"�'41Ua� T2 T�F2C9�al=EOa��>��O��B�61e%)1�.no#fy �9��/y�de�|�*2�1��)�H� U �]�n1O& %��A�p:.69few�3)�"[.[DyVJ��ux1�?!��^[WJ[ "�c ��"'re�W�."as *Y#&N*v2>8:��!�oMmf ���dE<"s3y#e�\}� m]�wng}+;/�� 7068Qv0|eW:�X� R�.>853:DVru2b s��*h"�e"!;z=x;�o�/ a to7Hof fW��E_�6!R%F 6474!�649a�e�a2�/ 8�6 s�p�Ktgisi<��c��J6spu�|I�]als.1���"&�D-�%F�*6� \�'&4 a����� u6O!h}!@}zr%=q4t�B %� H ��b1 �rt�P{)+ f� u0i`]�_~4$d 135 minu!nd%N402� =>maFmer%6�e� s fa/}%�!)z>v>�.�-Ga�Bin�U�"�Ii(elb5l-2 ��ri�v y].x,� mFof'zm� ��`Y�G"%40 n� n0�8=�47 1�&n�'A�w�fmI2�R 192q�� Pa6$savAL1 A�e�*]�<36KA�2KA4m�P*�_�%�i;��@*�5r"�+E�� ��e&�B`*M2=F��>{!�mu*Y�9� "�BDs�.�aL�%al�P�/�݁��uu}[ZU[1.yv&0I&��&� [14] �&����A�:45��(u �. By � o=*G�I&#��r�2E@b<>,iZ�l7a}�O!f�VIQ� eR/%m �BXCa|7\"? �-15seO�(E)R2'�//�:�M�1MR�� u.93&&['U�b.�>!�a�L�Hu\W^& D(�e�.��'U� � Q4:�%� �%"�%�I� �Y|�EI!a>�Jb�Z.2qNx�:{Av[%QEwc"�$EAA�RIo�������}U�82'�<&��=zout�0�%A7@!aFFK&��e��9neap%�9K.�Xin5�"t%e:re �Lu �)in6KU@on�EW. N�"1t�S���+�&�/�>�$M  l#D+fJ�P~��/g]/. B6�I�sHG�l>�4 ����EJz�/ �2>��00"00l0�r�6*���=7ex~(�M�orJc �w�H���E�eiB+ sk�+ eczema8g0*�g� �3 i߄a��=%�J:9!�ke8\nocyt4:3�$`plˇ"�yr�RMG�e �-B� �TG �h %_"*e�ge_�Ia�4>; �de9&:� rs7773175.�upsSIm�H�aE���5�fXA� deca�^!ea�|�Cdk�}]r , [5j�6#Wi~A�19187�k� *����)K��n&�by 6�kIb3 Cm��Ya�m�8ght�:�H��I�4ItreE&ory&adG�fG ��,� hitch-hik�E�aa�)a�c"��)l�T�o��U� �A��6tV�a�e�;a s$igY�m�6:�G up~�LhR ���ɤ工WU5a T5I�S2bk: A��,}�i�mdMa�HFWGC a�[6Yal�5P;!.tVYW4�! �me%�a���f*�X!YA��e�fun��a?ex�XC +2�� [6?X� ��Ve,<t�e�� � � ��^��=enc�cell-sur �Yge'0ati~�$ leuk�ׅ`a�� � �M>�3� 100 �m G�*� �onsH\abe_!�thm>�rheumatsN arth�WM*Yy�,="cr �"v��ess[6ʅV;� EH�l�ya�Tzyg)?"�f�M�qan enh\0d)�хet4p;E)diver%�:��i"?zfi^��*�[I�[6C}� �  gge�r� ɐol� ion-�Z961-on� {� ,�[65�x7�� n!�2 e���) a'Yz[7�v?�Q��!:�s �QnP�3&�5��t�}�`�wюn� �_cycw of"x"y flucF?� �RF&�-  3! 9#A�ng"�P"t *i��Ko�a�- d/��., �q����$. )�� �M�|�!VoIKMbof�J-S�Q�?�O��hqi.Zq�A��Y�L.P !�f�q!�{^Nig�$�D"P -�&�D�J.!j� sbconve� l6� T�;)N��A�&)�� �l���\isW'4�,��*J7JIڒXsD'��r�-a3"�Z2+y3��� 8&�!&3!�>�Z�1@\�is eLr�O�x�xoY�z# ?"�(���X*�*e�"�!�I|"��)?-�Q� �E�Ic�qS�X>!0aaWl�)Qs9�� ag2be2� a�b;sse�nA�d�co�x!"cog�a�J"n%!ʉHsD�B�\= Ž�Aa��sE#B� eti�e"� E !���' e fi�% prin�E!� ��Lza5a2e-S�}%�%}mO`gmM�w"+ g:�c2p[�Qsa��nt.dproced���G*�Sw���unu�v� ��U�S !��r� 1�O����f-u\_B�� s�&�shP���j�s.� ���y?�`$q`!U�?&�;;�"M&uT� o>���%�c��bq �iVxW$s::�ha�#�in�!xP*gy� Ap�� �% Q$ t��i�-� ��f����ily&{�O�5-C&.��a�e7B9VFoV��+6z!I� N1Jap��.l B�9no��a&esumab�Mi��i�:i" e��%}!�qh�N� B] R��!��I�A2+!Q�-AH�xe�*�"4����1�b+M-*�i�`,���v[@ *?V1 �7+a�1W�)@��ot.�I�*� �!_&+��g�&1 3 p�nv:p�.�2.u!J�֥��*�0%Ua-�!e�"|a v[He�i� L om� u&�'�Y%�7(�q��dark b�g�&y35a 6� �!rA'.#ʘ riskb�!���}�A�a��!�:y7b A:"5')Ma��"I���e�)z�hE�c :�l��av�*Z.wo�K��') 1as mF�7��iW�? *�/l�_� nd*"� �theorea��|d�i��l.�B0���@v�RQ ),tud`'&G0_. E� !&confirm��a�"�a��%2�O�#/��.� r*��*t�M�"�1��a. R#j!LN�a�dš���i�l:.R�O�PQ. Pch :d � ��eFNM�ss�K�t��s��!�a� "*)[e��I��u� o'wI�Z'�cen��E-6�*#vOpVwQ��$:/rd�/o ,^A i'n, ��B �s$��Y�m�*������R�#o5zlm&�0R�5} be�+-tto flag*��>��Ye i$ly�k� Jv7�l���**�7e�!)�� Hig�7�t�N" �,���%A7V�N5�.#:�.ю��&�0j���s�F���;��- �e+panel.*w\�es��ByH"|MCampb�."!�72].�A���san ��e�6me�5nM�"�/��I��Ym/Lzm ��l .�a>�#J�LCTP��j}����?ee�i7:)$a�6� �e��9XiA�_!l�L��:Cic%��O��/A}i+Un}T:��`��� ���Z�I�5&&E���d�Cvad�Fu.ǣ./N�"T� o�d=\��wA9�e�3u�2!�ake�}�|�;!5!vl�7E�f|�!�!P.��_1%;� � `�u � )RA( bon�d��"e ��m�7rL2�is-d�o "ar� �->�qa����G��\j�&�6�t��"X!�u[7%&H���a;H�  && -L!X6;�e�* E� ��1&�lA�>� �#a0rp ntinq52�)p��1*scaffol��[�.1d"m[6�� �+A7a(D�wlng CsHK�'se� �t= ]��aA��Vi]�0�3�&V �&�� �hU���&{{9A�pec ᙁ��pG�pinpo�ax be�Qa�"�m�E���3�W!;.`N�i�'i"�gB0�Z�Mlap�"Y18.����D�'A@v���� �;���\ �)��"dŎ�_B��9aR>?t(b�RgT<y]�� F��!'*�8�`s d!�by. �3�%�*A.!�SbyMp"yp �a��(ժE%o,=\ on�%0"�X�Z"�R��!d!o6[j  �%oK�K�.a1�� pC he ���p� 5B=i�8��ar�_ B �i�� ^(f�� y�a��y�L�'E�*m�<"� 93��#9)a�Ye �5KtoepE�� � no ambigua{�1oDsVk,mŎ+8t��!6� gk�{"��"��:!r!f�U�%�ye  &vP�Y!T%=*�d����j!�?� &�e� o�� releE���9 �&�n;�:Q� rely�matri8A�U��6s�97E.�B�H<�R�f��9 .~,%�.R�_:�6mt�Q=) e=zq@"�o� �ALDa!��6:btose as �view [7WT�;*��2�9�2i�� nB�r �n-*�ZA@2AN�Z�<t�!��\I Em'��b��4'{e��.d�|��x,�&'hm�=t%Vwi�R>ny��[| �>�!��PCC splM�A).JX3piH� aX��,3� |� �0g%�"xQ)B�l�~b*&O��@�+"/ ��;�'!�� A�2% s ��en�7�a*�>i =r� �C0�.?![A�a�:�<} D #��"��a2tor�$Ugen!_(@ٙ"� c �-\�%�����A.�pQ�S 2��D%du"2��=e*X��qc2s . Gi� ��i,Q�a�i e���be p�)i�7���=�\�M�mA�5����z���<� a�2r�r�"��68%\.Eg%���A -for�e2st�ovaD �%��e"�� , 6102T8&�f�Uv*�4�> 54 d�"��?A�"Q lHo45�2�*+�*"�<inJ)!j�4e�a�9. A� E$,o }Iup�6[��qg �I�x�H��490aŰ=2 �� CPU�MF({o�" ���� _am�b�a� ,8Y"�&��("Z )\fZ%^>H100!61I�EUsA�e�Q� !YQ��a�U dth-B %c�J��8� E� [s]-Od:(?�4�6��-P3sso ��eMs})I�m��a� <*�t-:�2C"� �$*2�c� �{�d6���  �'J�Z2A/�GtV�a�msigV�S��f * �&�K�LD"y�a�.�� [7�\ƥd�&���=��$E�c�h�  ŝ�Ffl3�  $�ud�L ����z � LDuV��f[��x=N'F��CF�kn.U�8m,>�#� !��1T%䑬!��t�$�[t lʷ%��I�Ɲ*�'�,�Fa\�i�`� ����+RE.*f��}�B_�Ado�AA/5:8�'�lFi�%o�\yɛb�)�I�� lookq!��Mi�3�q�a]�s�c�^\�6�G'* : �f�oc7��=6oDb�{g���ic)c�� ���v�Lf !3� algorithm�r��]��A��)ti &8�!<��+�8j,62Hsiq� to Plink'B^�:�[m�4=�VituE�Pc�;,Q�Ap �p�#.0�'�m�#L�)���6M:� ! �x'!ep ��&q�q{�k(!B E��#"�.EA2O7a�b�ad>�|�zeN>"t*?B M��e�%c����/2&�4�R }� 9raKor�c%WmechanD����&< iNtaA�Jond�Q��lP : �,��E�:^bGGw"?F 0!֡41 "T5v@# i?���`pWl�#s��g��-�}�0��c�RV?um�p�&� &<"4$�3�Jiv+��'s-�F !�a�z�|e+_ GP�|��Q��eE���!���a!t ase/-*.b�Th>��Id:�YA������RS��.6� >�A� dea� s+wle)A�ofXA expe�;A�ob�$�{".l(�|W1��+W endo"��lG E<6#Y�&�5RzSD)��+�lab� M"N ce��EqI�n/-y���--�g��&�n�*�jQn"C 2v5��&�e*�%�?ii&��fy�("�S2�0u)A��W6t"�  yc-�]�%q?!�?%Z �H!�.��fu� ��|ftwADpackag)�A� C++ �) c$2�re� &ѩ. Ue�NA ���F��,AT*j[�y�A� ��.�,�S+�/"H ��bC�&t+q:�+�` &�="�e,׍.�=j"�4 ���04����  n�t�/e�v�$!/��&^$.�e*�Ao cav�[��Q� &Z�CBr�.6]d*h�-�y a�5�.���<*�w)o.���X!"������ed gsAQ �(�<?"� e�re&.E.A�1�aE��Av��+).F� �9A�l"�..��:�1*ʽ=H*r�ilH5�(r�fA�6(!z@յ�� &+a ͚�<���ym-�'E�.��-�a����*��j(6'Ε�2�8.��ro��}�p��ׁm%��V�.�1�h�.]embraU3�ia]��o>�0_r3�. PAl�w� or�� QF�fm? e�8�AT�$v�kB���_$Q�A�me�#�+��eJK�Y'�lti" U�g� *�>� �^6!:�et benefa�= a"6�!�h�9O �1��'!ee͆4 "j��&T�b�"�4�@0d "�!�2�. LookA�2.1 's9 *�5E6� 2Ull�=%H9W �eL9��=���f2 � �G1 .!rd� !�HA . ':�%On$�s�(�gŦ� �!��kA��I*�X���=f� u�!@M� �)de��� � manuptI� � �K=`D=�$at http://�. ncbilpnih�� ov/dbgap-/ �j� dbGaP�e�>phs L1�OvTKpc�!  &RNx�!g~�Z$. PerlegenibK c��e��'� � � i1݀-T!���45�724!f68iqF� !���a$� mitochond�J DNA�!dX Y *�<n��&�au2����FaC�hildr{+� RW.v�C� pass�7-� ("�=�E*�K!%yEuW��eRhe/�aGB!7%v!�� �_��e)UJ�.$9%1YFno*�10%�2ax�.�+�M,1��68�C' .%E%f.z s` a��>R��6 h� AO]���&΂UJ�ͱ�AW2142�B�.�F�ў���$Q�le$yc1672F2c%X�V�F�^ c:�aZ\�$�b�)�Yb��!�!���5�A�r�+!�;R|4,lcN0 nR�Cm�BC%���7ؗat�`� 3.s�:�^..*X36h6��i�!4we~ AprZ�3'\s .�A� � ������su��ACh�, c�el�hypopla��( CBLH�w!c� icrogyria�MG�2�q�� nKD)Qbr�mal"8� �2|"n�#�&kau��Eh�L�L�8� a�9py�*"��NV�`�y����in 255�,Yz�) 147 �>�eC I349� 6E!P ,v � 4E8!W/����slyB z�^MG.sAsr!J!@c CNVs�'� mega4r4 = � 47p−3;*R< [OR] &N<19;bNe[CI+Q89�`3�hR:���t�0at imp��"� aYAu!r}�"k�m B6&)2�&t)|Ag�n�0C�r�u�Rc5a%[ ��AA� 20�s=a�R01; OR-L[e5)LCI !661618�I*�. qPCR���n"�/�4%A1U��deo ��qsf{�A�i�#��ed *,���0I�verAJ�U.S�"IIH1�� autism� trum�"�2.(Ac06�k4=0;k5>0!E40–=m7�3 ,a�e ��h��0� >���y���,EWd�>ish�9�execu� "`Ein 0'2���jC(�5A�r�C=PEg�$ Ai��'narrow��8p%1-pE�1 dupB{� EG�2E-�!,��co{��: sixA?el�@!�1_J&�de�V: Mof 1p3A�3- )q2- �!5q �-w15q� 2-q1A,1�D�i2.&!Y11pn3- A:ƭ�-�I�Œcephal���#p��' <ia ���6p �1��%�ed NDE�Exdgz*"� v�X �aiin�n�3�!y!� non-���V"�+s# 1�+"�5��Vti�)}���*D�s�8I��C�0r�ia]�q&�A�al�2of��-�IY>�CC!D�y!���. ��a��N"x�� �a%�&�06N�3 � �}� men�dis�?� seiz^ r�^qE&���s�\&� �|�&0 !awh�N�l)quo�6 ( IQCu Z� �Ab��BT,c�]#n���^:W�WJ  (&�ea;� %)�,�U�*iE_i��4���. A�F�(�1/4�%lafbirth 9A\5`Q�tu3nHN�G�nAth�� /$n:�N 5!|�� -_cli.O!!!!� I�r"�jtl֙eeprenaA4 dima��[��[7�bNu�� `>�e�s. a��HG�%]) &��a��a�K~,c>+ � ���0ɉ�*� �e<al"z �# ��thA�fJ��&��!�!RL�|odL��ee e*'Ec� ). F�n�5�re����1p3�s1q42-43�8�Qtv�!�&�,�fof%��Q�wd �?�3�("�|0,s$�y�by kary�G�1��~K�`��iarinICer B��in 3q2�3-qwl� 6p �r 13q1 �3�P22�p!� Xq28�a=�\���)�inM( FOXCY:Bw( ZICiZIC4 )���=d[1�K2�K��MG1-�mJ=d� %�.�2pc�1-!�.d4q�21-)Z6q26-q2�Q���!a�G-�ζ��SZD� <s�)lqZ%v%"܏Uor�"�Z�lgh� Cy�[r�� �sKkalR��69j.2�akr��yJ0inguish ��%��tʰ�FA�m2�[{�]coXf�ys�,6L ,�s\ ,��4o��ssa�Qecu6WQ3EXhO�Aul�!Y�'18�)%ɑࡥl��!hwUuN1[9T��;2%�%���"uD�b=�Z��%�rB�tt�(6t �&*X manne�#���V��dc4�.J2�&���A7��l���* in 5\-2� b '����@��N�a%��"� .m? �a�� "/ ?F�e��Ja�i�t�-"��`� g * �m)� S�� ~0� ��otI} i%���Sŋ���bW� %m� ticiA � )i�E={.bq�-� scojt[��4�A( Mb ) ��&�_��ra��Q�GjK�s��cytB�a�� W� ŋd6Hdiagnoa%E��,�{�oCe Ill@Nh��H��=j8#�&-�tex���%,�fe� `Acm�h� �� B>�r��E�e*xy?��+ ,� e�A�e�#4E� �5'mBwo� <.� ��Gi-�(��ed� -PLU���^=8�2+ ONLY��terms WaZ����!:��:�.��* g*�'��r2�|*�,>"I&>l%Lq�w�`�=�^�6� oN eA2(�� \�a_�*�F)%�>��*%_�u neurPA<� .�!�!�N recru����(P��)��J platka'Chi� 's H��Phi� lphi1Ӧ�D!ae�*"�( Q""� , 487M2�( whom 396 ' CaucEn ) ���"�(�� : *�dow��eam�"�q�e5]��� �S�`0 953)��.y,�ed � QC��& Pennb[���� !�879B�~?� o1 73 (��n%,� 1� .t��i��*�<tJs~�PW�B\]�"�K=���C1��A2�1o�,�Ry�A�282)!�s��ly+�9 ( 25 5r 8 . 9%!�o�[19m7;j�74��:�E*�7 �Z9�&<%** ve-��n��nA4� A���>( 9�)of 240�8.�k1$�61154212 1�=�L�!All�.�� "\rS- W��G�wզis&���%F�� 9>.X���2 0er�� IR56�^Rto6X�d20�180��t1216��� ethn�4!��M���92)��׉�E�\4:P *� . O�,ZA���7 (E9�r, 6 (�^0 �|gA$(�:��da�e� 1���Fw�m���@.Z,E�>(�  Mci�(rM�K)�" �0 achibJ F"p&��though��; �.�o� t�QnI�L)po�7���orm'�"=W"|c���!c���!B9��IfI�"!J57tru�����l�� of.�6���asxN@wE� A��it E0.S :*/��K�e��5� -�E�!M�,��S�,on�Isq^)L%��p/G�;"t�CBban��b� �*;uby���� �e��  Z }�2Fn�����d- h ria:����a2�&<��'�F���?AT�� �!%,p m � s S�SS8�S�eS6%�T�(S��O�6�8��]��I.A�a<� �� !�!t3$-���Jvw2u� 3a n>�DaHh}��$" Dx ] �[ ��p�. B�Don�!p:`"oDKa����2�CNV≥� 5�2A�-v�#1:���.�!"{ ��!2{ >�!!6�BY��}�Z�2� 54k 5;���3>��27–�B�#!�d.�. S�Q�T��U�(.�  �5VT�a�2e� �I� �62 �"�N�6:QLcI* �F�D2�i�&۱�Ze(i!QF[ �!�~4a.�a�:�$C�%���+($�,m� 2BW�rU"�N 0�0� .l�C1%!�V�B%�> �m0>�F���ffe�!d�Y�D �� 2E )ym1���aV��I2+���cA�!���gb�%2�1��a���*W$ �3^��=�o$u�� !^�*:�u �4�,:�:�2I�.�#) ] ���-95a���9%y��z. �}�gg��ng� y�� ��!�jHM�8*�M�ACm� E�Y��GlaH):�Uv3B<3+2���ede �2� ��6���i���� ^��ղ. Ah3 � 6rNN �s2I�!x1?>v"�45 .T��ly\%�"E.�:� �Azo&^�9U!N��6�bA�40�ZEF6�U[AQ32&�x7��,�:�agree�!�)YCbe!�m'�$�$ce%i��!!���&�� an/EM. P���R�3��ެ5^��a��*�f �{fin�>y.�.�� �ͱ;}-��a^U��bu �WZQxt�?�!�{2��O sub-��es9�!�knd> ��� � �n!V�Ar�wst2=�P�f���at5N�+��0E�e��*e�m�.v��hI� u��1� ���v:�!�A�O��2��ms�{+2r�!t>� �)9O��-[%5X�A%�!nf�  "e|N��S�&Qwasߚ� &�MIMin=�%��4d<1 "o�1.%��.�4]�.W�$5�8were not includ�ed in this analysis . ACC and CBLH , but not PMG patients , had one or more genes that survived multiple testing correction ( Benjamini-Hochberg false discovery rate of ≤0 . 05 ) . Table S3 lists a subset of these significant genes that were either deleted or duplicate%0at least two �– 332!/!,of which 305 W,never impact)W$controls ,%N4<%S eachBwas also2<one@ . Of�l}g%j, 276 |Lfrom three well char��ass!�i}�144�2 . 4��lٟ�,� 5 ( 24�0�d�0vo . Eighteen0(� ] -lei��E�y 227a�to A 63 MbmC17 ( 48� Fupl�"�2I44 H3� H. TwelvAW3� �35��_(submicrosco��(]�4�� 0Finally , 109<-ced , rem��75 . 7maE!�)V 4aa�6� termex$. A graphi�Gummary�Ehresults����nA k S7*� 3�≥�5b'2%w�R�Y , 26A3!�8BB�8�}���� a���6AGa*propor)�of�,-PLUSMACC-ONLYy�e<� Q�CNV)�a�$4% , 6 . 9 �]1A.1re�a�ly� �kntr� ,� �� only`�Fz !R(wa��agn �� D� o� a2�,!��case a � 6E~�$ on chromo�5qq �& 1�a �r aA�se E�in -S5 , lis 7 -�!o� �y� C . As.�)�9�,harbor causa!W$ brain mal&��,%`compile��!��318 &)�in6tain�jM�ed�i�6�!�o�ysX��s:z. Coup�%�mut2 + � orth��sA+ule�v nerv� system"2 e՝serve�EgooSndidates� 2 humanf"(%�)�S8��G�Z�co-oc5c� A�!�autism�numer�prior��0orts [1] , [2 5]–[33w�ked{E E<ob�O et�Dn* a6N wh Hu�5>8!R �l���5�s��DM�<7UR�js� � tud��%reFY6 [34)9].3 � 13�3�C3�2�Dq;�A�e�5/6�? . 5�?Y�0in؍;s.@E�2]re!�)�--$( p = �0406×10−4; OR | 5; 95% CI H�D72%U��5�-�� partlF� R �in?!�� { 47a�172W�W&5evalu %�d6J�#on� ف7 )b� �y��ia share� g betw��@ �4 asCed�~ -vale�d!� a��"< � d��ri� a"* siz� M,�襴��,�1~Eknown[ develop� al�order��JfEb2� , similarz a��mk I�has b!describ�S� ously [40aAl�V.PaVsorA�5%�paF#, �higher�e�t'� �\ih�Eof:N.��4������7~�dy�ler�)?addrebe+. B o� rigo�]5�wl six��.�&� ,2Rpers.:��in 1q� 2- 3 (A�-g"/a1p)3- 1 )�2(2q 2-q1Mj *y P"u(�2E 11p1p - a�� n&� Iaj15.v.� ze9 ��Ap� s� ��8wX t�a�e@��excep_ H) ! �9A +iso����e afo�io� �iF� 5��T�a�� 10e�A� cludau HSD17B4 ,*u"#> �ATK6�in 7qCA>�,� rrE)6p1��j)Ke� ���C� �q d ani�m�A7�[48�&��Yfourth�G-�pa��-ed g88�A-Ie%��� on � 1s a� J ��E !ptellectuE�sabil) ,:�� e psh 9�5o BBimaAdemonstre�ext� �cephaly �ver�� ehea�en�d7 a-ax  flui��x$gyria-�I�2�A� 6���hypAa� �|at  Qe%�tom�beI�� just� �allel�% of:�ndere�  carrA��whole ex7 sequenc�_a�i� d�7A'Q���z  exonicA�d16:15761189 C/T ( hg19 ) mNSnonsensee�7 � . R44X )A_x non-Es� �of NDEIY$�C�&�]�"/."8s Sr���^ ����%�����unc��� los�fun B�r�!kaG�al�!ess| Y �mbBt�EQ�s� a:A� ��%C[5�52�WA�n't�ublis "a sepaaM detai studyG ��a���!kaf!&f� ��� t�� X[5� Wq�""n�:�-�i  ml"to.�  cyt�!��#B5�X� ,Gl�at�"search"���[4]!�h� firme�narrow�:��,/or eliminat� 9$ u�  ribu� o�e��iű A�e#a  ��%,.�$50- �q!30��&#-�s.�!�h"M7ve�!����10iH�"m�6?*k � reby�vi*�i*� regar!A5h�"] S�����M8�� Q��� .����!�eon 4q�21–q�1 o��C�17 031�Iu�l� /r2� >�!�[5� @Haploinsufficience/KANSL1�ZJto�^���ly�i)�is�[55�q5 &H"�5Y*�q�.0iO'-i�8p�Fe*� Rm�"�FGcommon�'\ i��!U�( 5/255A�2� . Im5a��Ev&6 zrecrui�f !e{�e zA��en��Oascer�pb�;a�7�$%bi%�%Q�ly&s�r"($taCa"�)� % /4��c Califor�bi� -�hildren ��6�([��I�,t�31wo*�s U!�,6�a� r fe�Ys1�t� e � :T)ar���� AC]:Jdnoe %"�Ka>!� hAe�b&� =� A"�6u B a���(ri �%�(point towar� .F�A�c"AT(�.()S10J � in#e4�-scale?"�&���m5Nk . Ou�(vestig ��2T � hb�<&|$%,"��n_*%|ia]ll-)8�M��7a[sh�v�*�%�]�A�1mi�sec- alE�"� =-���V� �)&��2( A�!���\)EEځ\V�A(di ]Zw=fac� ���!��pre[�!�( ���A� m V� �Ty�underly!0: *zway��v�= burd�#)��-!��"�%,f��=�ly%-eA\%O�!�)�B�!�tB&a��'. Unexpe .lg#���z�6~B'ic%P%�or��( or' !�1�M�WhileUd2��-ve�H���.&��[1c2cA�%}m�i sugge�!e�%�+�+� }%&7#AW5[�N���1/ce+�(rt, ir _insic (� A[:)%e��at�be9i�p%%|a[PMG�n!t�$6���di�s [57�5�� �!&�(��A<H#Q) P��B� Por oligG �/� � �%ey/ ou!A�#d a�de6 �e�A�%��,"H-f�F�e�.I0��b>�/��i�U$�� i�a]sup3 8)o|0�r)��)��$6�i�tCfur�!pA1i2s���f�$�/group�Y%N re wv/be an:�+e_.� %s�-1{�EVf�EȍDy.� atf&�& `�'d� 3�^.t !1%Aҡ�2q B�&<�%we� antici��al: one-�(�". 5 �*�%�bw!G sub-vn)I&gu����.&R-num�of�Q7&lpi�"*0 =s.� "�"���u `.� e�n�A�H q6ac�pmg!�sk�3� s9�y �.�d.��%��$T!a"v_Abreason�3�B{ init�"F $2F>� 7A)�' '�u*X %oZ� ll#3!U�{ ly 1�$1�*�$( doubl-!�2)U��101.-�\&�2� whome��& Eo&�#Bnh.�!03n�.Na9 yEA\se��^Q!)��H�!2+2�JW O�����(�6�2<th02^��u[/> s��'m<1A^bc. A�.q ;uS �� s�a�%ih�"=3I�k F�U2� ,��,�e�an�S�+L,among divergA2Y1�n�ng^ti+�/%]� (unique vari�U8cla�V' 0rCnI&at� �&_ [60�6C� !��-u�� Z�(�IA�!�MW ) be��lex� lg W!,� �a�ex�sivg�oft>2�^disru" #m�*pl�%R�9� a�to 'ef� . Se�'i  hora>�  ��"� xten�meta-"�[6 n2�un6vo�-�A�corpu!um!�aAMreduc�y*ts"�6�gr!!�!_ romi�5^`[2� +�=iv/in keeE�%�fA�ng�� -conn(8%�of".al� network� ab�#� terhemisp�5c24f� M*��[6� 66] !��( [67T� v�. majo%Y'��bA�f 62h�'cog��o�:U��ig�4,3 !=ey QU�c!�in?�execu(eaas�Dby"� Qjof�20�!�vt! �IQlAG�L2e6 -6J� ié4`sE;s� �,� s7�&$�a��e�l:f� ��direcR�!-��4ed)LB�ba�<���("/s�*r�|%�ofb ��2�� &� 2 . ARB th2��%3 ll&� in c� /�s.Mb�ep*� � &� }�1r �*���al Xe�E썾�U ca� n�� :ed up 3!B���0eH&�8.6�*q>h�";eA�B}���i.� %� subj]?i@es"H,B�E s�5a-[0�z��m�A�L>d"�As . I���t� obh� B �!T�a_!9y/approv�}instituA? boards� j� �-s:?Uns�� of C"5$go , Seatthi�'s Hospi�$� }:>a"8at2 Franc�A�ll�� r")EP�=S�oRw)��ty!54*Sag�!–60'sn�h(-throughput88me-wide SNP arr�a;d,InfiniumII HU2PHap610 BeadChip techn�2�? Illu��Diego CA�ICe��� Appl�Ge�%�NfTof Philadelphia ( CHOP� D�/�s d� ��83atT$ly e.e�mag� sona] �!( MRI" " scan� �q���eheji���ros��%"ic�e6A�met$;?a Fif�8perx(Sq� a"� cy&�an BAC)� -CGHD1 )no #&O.1t �'A^!�j�as��B�:"blood� lymphobl��cel�\�salivaM^standardm toco#@Ab= 1 ug!�pdegra6&�sak(�A260/280�ios ≥�68iVu� �E�E�x>ng . F'349" y(�/L953 Caucasian; 160 A 236 Afr�=� %)n self-�)q ��m�q) �  =!ss56 plat!���5�. S���$re primariE�Z�,62#���oT, ����en, C� N0 %�M�d��0 -f�D"�e�R�of �Z18 yr� ageAE��h qua��g-!&@IK1ߩZn�$41u&�me�1&�2� �RU!to* B�j <c� � .�q5i�= �{e boa�oiA !2 P:ly�wA�a�Zp A�e >98%%ray devi  ( SD )!^!�Log R R$ ( LRR ) <�30IU ��O2zB7 GC wSC'( GCWF ^Ld"�4−[ 04� �fQ���usu� pooro �]!Q�% Oe w<R��=�FoDn�� 2A("� D� ) c�� &�LEth"g@hd��-"I-E1 �(�3!'.��R� ���1 [24]-� comb�"� sour�of�A�� �e.�!�Bj3p(F~Ee^"at u marke�al�%Pspa\(, a��hiddMarkov=l nd2�Eg�BQ �to��eE:1�\�� � eria)Z�Jser*!Ej�]dow!aea�%�K es: ( i )��"10E�igugSNP��( i1a+ENn43001,$ %1��ndU%�Bh�� ( iv8 K�ZA\�)2Q�tu�>nsI��L��%;e� �<) Z;�'"�FE�thDmpd"x&��]&b a� �Wup!�2�B if6�-�!�a�v 1#.�$�>filteb))IAferto�o“ List 1”�O�E�Z%���!y�ug!5"%�.�!cgene )Gt �F8+e91%�euu*�Kof un�HG6�Acea-�!O}0.P  �7 PA [�IBc~6�E�- �7&&/#�2�"� 4)Z i� in~ fl#B=92�JNV-�%�en����*ly�B���B�A:�%��E�2�WeI+G*P�6�.mD [69]ABcal�*�)�$�!p/achie��Uet�ng.� 2\� N� �e`u�e���M&��u�@]ia.Fset�?�:a: Testt0> Exac.S�"s�  test P&�C: I�! ���LI�s�$sher's [s�:Typ��-?�|ish�N hoc: Comp+5` 0CPFHalphamZ �M��!�(��[W- �S=-!!���;k,,eQ-���g7A}-�D?E�6�jp5X >+(.�7:e;j�|eց�R Mbavwo �- �A wa�uA-ZA��g��5f*�g+�e��i�45e.M)n assu\ E�5@�!lat..w'� ��no��(�8re�(B�*�>�om��(hb"� N�in�J�*����X� T#t measu4��� E:CNVI,(�!�L.�,�> �;,�;� k"II� T� &�8! �~P goryE'rik�5o%�%�R�MiJA��N�t:.��fb.�CO�S $y Hg18 coo.:Ew? UCSC � e Browser{�‘!es’� ck�EacGT�=5�"bov)��"&  nto 5 sub-05�g@-(X �1 , 2–5 L 6�K1W.2al�x !�AS�!1��"�1�Q偆�� �� x@��PyA�U�. S,Nd ,i*� %H��1-Da�2=~)R< ��(,A�u�� ly 1!Q�J , 4�-# !6Im���aM�)>�)��1 ,� �"�!gP.��7� �!B�'�9H� �53�>T�S�.�� 2��a|!���3 b%G"ofU*�Ė�!Wr*� !]�"a��aSwe� =Y����zi � . ��E�ae�-X Z� ��]�a:)z��V'i�#�"me?���# ndb� 6� two-�` ed FJ' . M�AP a�.�7 AW Benjamini&Z�E����_*A` Z"3on!�P$� (�Q “IN d!o�a�� ,Um��#[hJit�F�2�,-u:�QEG��.O*4O @�)&on�-a:iK�.� �r!��&Z�$�ifEx)�5�"� . A���WmMr�f7if �c&�R!�&6m�a NL2F!T�i�Hg yA. B� )rlap"<1@�@U !�EV)9fse �W� physl�26��oՑyL$,�q}!-i��� ��=2u�YE)�I!��n]�1?�;�� `Ha� ' � S� &=I!o-^ �7� cutoff��xs ,!�"F�H�sXaU)"�T%��i�(�? �D�<�a��D0]Q�3 ����.PsrV�L�"B/(� c �1G1�-?� �!E��i�#@ ���0�*.�YPll�:\&�!Aoh��$��o�veC2eE\�-� be2? "A5�I_H\!;J{bl\=j-��.�O!��a $�\Qs��"�edremt�O�Es!�l��6Rb@!'n�7`Lto F�:W�� V&\\cE��^�>��uU6a�>2fX.YUof zZ�� e 14PJ- 4q3sB�_��X"�9��eD fY�Ue�/SYBR Gr!M�WM�* Mix ("* Bios�����B�|6���#�N!�i@3ydu�ent�Ew�&�E. A���.���IirL ���ZCNV)�!mx�QuN.ve�.�oqS ABI 7900^�m�Pn 384-:Aes �e�FA� SDS !�2a� 3 softwA[.��producd�>*�9� 60 b��� ���pem8ri�Ia t� rea�?volum�10 ul � 20 n�w!�300 nM�aKn raof)a-�:�(��>FH��fe)nj)Bp:-(%�#�!� 3A`&l�&m�A &�& �*run�5 %�\-p+H trio~%A� �&M] 95°C den�9) AkH10 minutes; 40 cycl#`a� 5(5R on$nd 60N @;�/iA� cu^UtVE,.C\hag�VR}��F+A!te1E r�7dye ( RO�BaeU�d�C�;� c�&�kA,:is ayZs&�a,pDw_0k.�iFa?ΔΔCT to�%r�a�qi�y�Q )�AI9iz���.T�*�9ge`,( ALB , RPP1�NHEM�l GPR1]�!%�m�a85) t RQ�E�"h&( 2&iVs×. �A���.�6(>���95%@fH c-��L}  an�!�2TW7e�A3!r)w:� ���9 uc. Val�&[ S�Kh+� ^%K �;or6�:. Prime�deA8�(�^ \(http://frod'wi . mi�- edu/)x3/%4We{Za"�23gO138�a�936�)-; Au2v*n+��*� ���*!�= A�� I�, >x 1�(U}N�XaRl����;Bs)on�� �E$ LP09-141a! �:MGW$&�Ol}���#� ��6\I~�]he Agil� SureS��Mb�Exon ki�7 et cap�D��HedA!� paiFei9end��d� &(Hiseqx $!z aligA?toH�Bur3"s-Whee�` 'r (QX bio-bwa .� for�` net/  htmlE`D.T��E�~ d��Picard^p N]�Yexclud'��a. S� �Koti)�.LL( S�"�sTc inse�^A�1�s� ndel��3�samtoo�>IR�>a�%� t�wA4�A7 Tool!�5V(www . broad-+-0org/gsa/wiki/�,x . php/The_ U_U_U�Va 3� anno�>1vf+Seq�sns g�� washingtoJI�50A Jion1�custom eXp?jed9waM�"co�"Q� . Norh5��Dby*��� st >2500 �Hcly*G %�":EE�-  S�]]�ev�V�EVS��nsynony�N:�v"BZby�+�h ��of�W�2robA\D � �H���%te pr�)�(�,*�9.�%#"�4�xaY n�p�Zu� �&c=��"y$M Rus��Bon�!oni�.����tu�5"+yeFa!!�B.9a"O AOby<'�,^� &�T�&AM:��� �[- ]) . 0sF�Dera�pc �_.�` odd~'+!�Z�a � 1�eJl�&�E I%�0�%� � in5lO�YfOofF�-��2��f&��% s .�Re/  P#i!�preci�nt;,V�0 \;tR+ olifE,"3U�t�)��K�N�-p��n tissY�Fpro5�!�PE. Yet lUpro@� �8 �� woun��Cd!1sx�Yx ly"�U)�freshw4On�m�0chmidtea6+t6e� �\n��alD' to s7E!C�;e/-A�9%vb7�jcri�7m1s �(%njury �8�s 8a�^amr.�. HF,�.-q��!=A�e HippoE�al))�@c�), yorki�!du}pl12o��r�PA�es�U�Yea�F �9~�3yki� NA�'Rng9S%�9!�hyper-a;$YRbE��{ stem3/A]��!�>l6c5gr|(re hei7idgit tipA�salamA�r',place- limb(w8H�&/8,�Q$as hydrazo�4A��i�� [U�ny5�;A�+O path��suc��fu���%Fe:�2=f�$r �s%91 |�67�(a�mVt%�& ub� A�r���r�H epre-ex�(�? �q> atch�news�F�f-�(5�5 laxiw [6\`! Fail�S��i(e.c73.�e���-�8-�7�2-8gA!&OBkA6%����9b�g9�A�m�P/tiotempo�manneY"� �W�T�!5�5H&�1�derst6� asex�YU�n�displx8a��ark�"�Ym�m�"eCi�a0M�B y>ZupY*��c re�dnti�?[ M!�!AamL2&U_MQ. PJiva���s ^<7~n�[ubiquit 0ٳ!qad�c"�ne_7A�-J������, mitoI�7 M�!�"��B"�AIpluripo�[8 , 9�0A�I!e� %iJ a�4e0 � bimodxI�h6�Yl��� at 6 hourwt =�( hpam�%�at�q[1�dSi an�B�`#rYu*� >\��i�8�d�5ct u,!>s�� s [1�01�C& x�wu>a&� `� Mb/lj__w�&ri�o!�a�y�)��,�ecaB0&� ��� Va�m�2�e�'�6�sE��}Cre>� ~pr�Ri/ M  %�m��a�1 begiG;�ev�  p"�,��r��`i�[2Vor *� n�P��WNT polamB gradkBm�\� e�d!acbE@ˡ�. wor��6D!�$k �?�E ynamA��7)S�'"0&� �$�,� um9" hedgeho}tBQ[15ai�T{2q]> �<�^kF� to�AF;�|)e�T f�3—6�,��4��)��ing—<2n��5�Z��ex h� �yi�ZC?Ł� ��th=$!Z�kin�!ca� g m:��2� J or , Y� �F Xb#: YAP1/2n`U�%2i�ng �g{trunk A!4/s%9*j6z&d G2/M�-ph��'hosphory'= histt%� H3�FI�+5 �u��>��!�!�6�7 �iY>f ��!�h eakE�NB!�$% 48z{ ,. 7� SO}Q2j �ux^ 1�G� 69ͮ2�6�>�y�6Q� ��a��j@)�n�> �+3"�A_I?C�G*sX� �w1G 24w}e�VGs�6VHL"sR�$eaUar�y�^==Df#.�a��sus�?1 t��Qmargi_:a' �s!�72�;�)�F�6�8!4p2�predo�I� shif�po8ioa �"!n �sit~C z 1A�`! �3"m co�Qq*�9intact�U��,6��D:^� �"Tya�%Ra. Canon��t�"A �5Drosop�J� ��� �(a�� in Eͷ&�inhibi�xap1� � �����Z*�et"1b�1^�>^�z8cU�]t*h� ^d�j<:�lenLJO(BrdU pulse-a�-c�j_&�"%�K8�&�aulabel-�`��!@E�yI2. 3d�4E^ng {at 3fd=0LForms 5 dM��'�fix  assa�`A�]&atq�mBE��f�Ji��ed lf.7!+/H3P+G�� )I %at!�MW��.��   �a�\t�)�M doesPM[ SͲent�aIi� Moresf��� >�(�/�� A �amA�)����"E "z B !���, 59±9I60±7BK�,i(p�J��6�>�-�C1�r.`cE��vF� `F7m &�!�m/SSMJEsdF-M " w9n!@r: MN6�d*�V�M!v�g�Xcc''kT�G1 zAh*8" ly fk0>9�>.��^o!���� sigma-%��M*� "�;n�slso�pan^#i�death�6BWS1C�>[2?Congru�( ],�aJ���-SR�ve"�p ( sc"} [1| 7]!�� �U��ds.$ ��� !!�.�frMU�s*�= ( γ , ζ!�σ�Bz�'nrW7+ N�Y�^�&&!��B�8&U ( S1D5XII�.gE���NZ� "2l, Pb*|A "��b��"��x , co�sively�|%eP:zGY:[�.dwe DyF �5��">b.��s�5"]�A�B���hiz!�)X��r�I27>����� am� �A?m[Oat!`f"]A�tlE̓ A>M�Ged—sTa w�cut�S"�—oreY�a� c(M pok�E���|at`B\�* iSA �  2:m�A@)�.A+�S� ��!�8A�by ~67 i1<2&�Hs6GS>Guntil ~R .FI*� e�A�-�� } fos-�� ecoc8mI A(5��@ ,o% �1 �%2r�,ʃq�F xdelta-1L����c=�?4sY%AZn � �!I�2&b D aArS "by WISH� &Fe�qar"uU"r � qRT-J4 dA�kwoC!�,iBm jun-�q tyrosine-����2$)) , up&[�^&��ng6�h���IN>� ��KS2&) :7%2@ -ir��� � c�{�2MDH)���A�gD*6g��kc erpL,,�eJA�Y)��s/� oa�6fdo�"6 �b| elev��2�.�-@D� Fur��m7(it�UE�ᤉ�M�.( �2 s://%V6d:�2app�-A�� oheximd�x&block}fote�;)�R��>%!'�"*���%YMrtof�". ( S2) 2") �N&�s!�i j)�,2��h!Xcretory��( edema�� S=�v��:�)n2�&g29.\:�^��0ML ( S36�D"Kc.�>�E`�f$ �NLS�r%_? &` >b=-o~ �1R�QJ�*^io0:gB��$�� G�3profi"�b:#�f��� (w8� v!Ip%\uo /%�~ A�e�global S. E��.���aOca1�"i�)yL\f`aN�>w�� [28bowe��c-Ad!�f5A�2;��+���'d].�#�=�}8�!�DI!6� ilj���! �au��E 59bi�]�ly-&�<d �+)"�<>6O�t.�:�*�LV0"� !e{s;S'F#! &Ff��B����)�G=Fj�.-e�0re��q� d�* Figs�yIP�-]� �pst pene��dAd�edV!�c��QH focu>Yr.F a�5� nza�Iwr����5.}  "� �2���Kol&p:���u> �7-wF1DEseq�I�f�41=ys:�. ��he6��=i!E` �v�3A.(1 T�k@6In�$rq&6<!�2s fd� 3|Ni�W�P!9t@��&15X$q��!"� ;E )�����]�,�y [29];%p3 )Z8.�4� S4BA}�We]ly�sYDC20�// ^$B–3D; S4&Dse�A�6g:8)�*!5h(.�e�T �f�*� %m�a�.�Mi=.Kw�B�is�CcNdow1]6*�(�"�b�u\�)�".fi�* M�"%�-�"Post-2)' IMDHa!ab8SmexASXL_061347�8*2v a�aa�� MMHZ�etor�5*S4"�f�4"��h� ��&�*���>�2�+ P�j"��)�6C2t<a"�y�0ag&"���'ad�`6edu��O�830 , 3�$E� ��)548 ��'-!�k6S&� inqBs f>a노 2 dpu<S� / at 7b "� 5� 6um� AGAT-1+)�V�!<� |dorm'0!��p3to�kN�� �x4�6[6 [.{��$�� �a��P�Tas�2!8R�%kE#Ib9�"deV�cOc��*��(%b" � *�S�#��!= "hE"\43��9byo cana�Fn A&<F^[3� ._"��:t��"� A�*�la�a{$�A�en�/A�A8k3�8,\31Q�#� f���*�%"� i�i��!/ t/�!�2� 2'N)>u(��.>�N�+�sub�X�`!��*�$a�al�a�l�`&2j�Kig�5� �*�45)�+BMPMTTGF-β [J3V�.� �#&�+"#M�-c%A��$&=  e a"edxA�:�#^&�l�>xAQhem�E7� �2zI�5).�.�%ab]gi��5�M�sE$"�.y� ��Fig 5�5�Acc}�$ooREvhE�Q�)`&Me0�.ni2J.�"0ly-%u >���*/ ǣR.�5D� �a_y� �%.��_8j�eW"� B�c Discux�d To testj ,c(�(���="j9��׵�a�6R ��2�� | "�wnt�FI� Gs *� �Rt�'@& 0� �Y�Ey>90�G-A�liz� w&�Q9�KA�.�[3}3�&^��2�w1],�b .#m���+_�]ue!�EH�9@ �ec���Cym+%[��#m�E)��i 3Fw*� �gl�K!3� �"?w�la$�r�K"��\4nt1+/1T- �>.az�( ��2±Ra 1A 8±8ޙ># ; p =�3��-F%�5G1" �E��-*~ Mj�a5t���!�J�"�!^�z �1�Q�.;!�HOXh9 FGFs2�Wi:h��F�B�[e��z��h�|�:�%e� � ���2���*2��$���I digmA�� ed g\I83���՛2�a�+p%�>\* p:�_"�)Eɲ33.�����}�"�y*>0 �5�S2**A%� �8bs�`�Fa�N!s!��maWA—�=.G4\ ior-"�'DBntity—"�~ k�J4�"`�Rd1.�U!�ly-Y�6�$ agon���5e�frp-2-Y�VC>�)�.d5�5�[3v"��2���O%|�hsV�y h&K< ���nr"�ɩI�B�3!.P$.G:qlimo8WNT ���-eĢ�xyU*0 >і�in-l slit� 5��S5��y@�-vent�`=Lbmp� � id�noggi�Z d -79��A6}%-Fͅ�Y���6� J=�4imp�E�7] r?!2tEwV;"2��QE6�"�0[1��3*e*�/�!�b"=�Ee�� �i re;{z� !h&�'�5�! ,� &B#6:": !or� dv]meAyism [3N7��1am�B�&�0���pi%j�vFiV� mode� &�"��j�RE�92eY ��]9(�.e �~��RGor2�"�"�.,�-*P2��B�:�&�@�o !�:"�%g.� �:pU��art!�2� �  '[ �� <�cP�5�"�a?2�,��3cB~)X9 ]1�-�A��%� �� or 3]�|w�'\o6mO }.�0� �[, 4 !T80�[��6�;t�-��.� f�Ej�TUNELQIJ/9b�p�;o�O�jb�A4 ��iwC9%�6!=��T"" ,a���Jne�P(�M&;:>���2&{8� shipnHu��-X~6~���� �M.��qs3=���aiF�a�)#u[1�/=G7 DAPI%>c�(�R acetyl\�KseP%��,s �}� kmYl �b���)�i$-� ���4A��"� !�> 9���t� E:.$�wWKna ,oy`e3 ,a�'-� �� " �$o��� ly�v@ED�.:ecin5 })F28A�hemore,v!9@!"r�E.�H�T6zQ�Mz��&t�O�AN�Q�Y2�Ea5g��}��9@�04�f6�I�6`[���7E�� 6�%[4��42[@�8�jNF4.�( SmlS6�[�`I��WH� n� 8{s����8A�"m���7�Bi�{�[�a�+�!b� �{�c�'�I��$6l���BIA)4o,a��a�4eyF*scr�Gyff�t��5�e via a2�9�� Z1!� shol�2 trigSa� ��e�H"ѻ#�V�"):< �� S��U :[��m/ � j� �)�ac!��BNF Q�l-* �6[%a�255 ( S7e�Pqw� aso��%H[�y[v%���)ld�WQ:��JTi� H2��L[�req�ar1}�` �� KAyZ� �� b+!"�*ere2�&; :�Xby��)�5��b!^?!�s2h=\�<a.2�UF��H� JS/�A end !͕>�� 2UQ �gwYM�q�R�O X0grew b�n���50Ž��G�B8N%�:&�!=��2�"�Z� bE�M,!�a�ˁ itud��du��V6B� �ȱ. ��: �Eki��[ �I�&c1 �&�="?:%E�d" ;e&�~eߊ%�9�� 1�e��Y�h{`���{eMoj &>)e<pO #divR/!la?�r>��$.�Sf&  �2�W�!�in%I" �2.� �� &� "�Q� � "�9,�IJYki’�~W5��2:�!�e�.x! A%&hA!�of Q��� �ora�$�&�Ջ~��yin�=E�h��oad�,�G�<V��: ��9E5U�G@��XA A0e�ge��asTU�s� E:�DB�nd.� )�n:SJ122��"F%�Q��� g>a)��ys�/-v%S!�ramF'6�!%.e�H��&�GA�9HfE AP , pdycy�x kidneL�c3��6�e�kB�Vg��lSt�!�8��B� cas�y� K1��e%V!�K?Xora�La�Y � NuRD|����Gsty�2 ܫnǴ�%i*5�Ej esta���U�#!und�clepU�I]��@e: 2��.� Q��`o�dO@P��"e*A�na:�vc�)� k�l�V$�4��aV'g9 �R^�&aep�8��>A���g�2in<o!�_ 474,4h��a0ja�%��N�#� re��s(m� kj�@�=��P�j.Z*E��UI��!��um�) l��!�A�,�E��.�[30�A�a����N.C�Dpa�lB" �jY')fs�;a�a?u:Z:Q���aps'Z!%�I�%% ��`Ic��$MY�.aE�L%,B�>5 %5�D"�3@J��belR%�1 "�3�O%1�c .wis�mf DSwL�,Y�6�ZA!��o%!]m+| svAtu\ A��7�=,�E� ough���*��2� c6�P�I�Ա�!� �autonom�[1->l ��b&�6� ��at�H"\(��J�>-6edE\ ecia{�P 9��art�,&v :2��.��(� -jA�AP � �9�^ �>h�]�*I3^�dest�U���.m%��?"� ^ �?�ō9R6VY �� �q�9)�A7� !���(]bc"&" %: �C�.ly2�UIL<ŷ6�Nm(xI L�/6��?L@[.���pk�eg�*.�>����f��>���=1%"��.q<[8�K4 /A:�i�M%0n�a�a�M�"! %)A %�5n�Bc� �6bu��� 2�[3XY@��"�$���1/M��@�&� �.�mN�-T._Z�d6�=M*�Hmid�2 ,x�O5U�Qȁ��v�A��cyvH�I:e cyto�O.st�Y�e#�1\�Vc� j�f$jo� �/ �Eɍ|Ko�q�!6��"��lA�ǡz ,ev� c�d�soA' �Vs�u^�N�� 5�&s zŜ���k?��[BB>� � ˍ�Br�+s��� ��&[�at� P s��.? thelY a# %q[ �&dD.^F��dins�I8�! -�^l�D9.� o�["�, d(J�Ǟ�]�o.8� �a��[5*ٰ��adave5)ev1lc(~ (ompensatory.on=cxo.�>h�^Q: NX9�!�r� @��"��!"�ld3nga�1a!&:" < r�3��� uisMa��eg�H� � �-ti~A:�� i!*�o�se�becom �r+g�Ji�Che couE���� f,�%!J}>j�$ o laiI!�und� A�aڹz< �!H�Xcb;� '�6��\s nebul� ���P&0(��eak��Q�AEwindo���.�6�*�%&$&.�%�+���ru=���'a%"�][-"~2H"�}(!`:Y>�eX�����3e� "'�� aY&�Q�~O5��d�O�}w$��QDJW 2*�N� >N1=IU,iff��d�lI ���%AsQE.�$X5}5�\5)W*ԪzS R�?�v!����$ =6�/A� mis-�-Aw. =YZ)�5�" ~ �^H.:`!�0*� �8 � X6D !6]QS6E(.�I�2p~h >|- � �فXch*Q�*�od� �b!�� �~E1det$Q�=E!u1�?-�� 2R ��.6H/A�"W!��*� �*��-� :g? ���y1(*Y� �� �^Z*��eg� feedt� f�:���$Smed-egr-5&+ (@;�or �%��2�'��te52����R�!��PF�.�)>%�2�1_�T.��8�=ur�(,v�I; ��6 * A�gA�#-�AFM convԕ bgϓ&7I skeleA�t�mmea6/�i�� �` 60];��$2a}.��Hv�b�) y$> Gim:q�e&ʪ&8upI#ruk���"�[cha T��w� e�)@�a�5!X�B��*�#!cTGFβ ���/"DA�in-Fol"�;-, SMG+- mTORA�nd JNK.I}6��6�:�i�d"��a�����"�>� �d%�*t&8A'�� be!�c&I**w\6 [6��6i 6!e�� "6m�$E��%��)@�'y�M�on��%SB�.F� � )5atI6)�]�� Wf� !�Bu"a"��:R,J� �.fo.�;�#S�TNI. A�kZ't9�~�IW�reL�yY6 �g"Ga� 2��~ u �(ex"��,60 Gray ( Gy� f γ"rFJ�&a 137Csq�X�.j$&�FNR�*�� ���1d HT115#a�aɗ�� c�inAan O . D��0���O8%��4eC 1 mM IPTG�g2 �j>X pell��`�;<lcg p�U�*�*�zμ� %to�}moriginBgul�}��!froze�liquo"[J��� �4, 0 "�0,� A�gf"^� oVu[74All)�f:n� f�"o�� week�!r_9�Zrm��ry 3rd�%��v�of�]ee�*To>Pl:�L.��!�D%�� aI5 -sals[d�R��Ep%��}��titR � 10%�n�=0t Ocean AquarJSVad�)"�S�'��Ti*RaW!�>�6c!7ckd�#A�0�� �"�I1[a^�B�-0 �!�=&�T!G�rt��G  �����$� ���%�r�gha�br���.y6--m�)J2���Q|�>. P1ue�N�[a)'�c!��� w/y%�10%Iso%�az�( NaN� diluG.� =. A%E 7–!���A]��wir� pipeE� B\1e3r�[ir� �U��[t���3J "�forcep{+r�-��)mo-1. �AvL���a��XZ�9I~�J@[3� 7lECyc�P)'S�Y )jM�[Uly��1�y>-�AbM�PRU2�H5�1�on�7,���"�Y!E��xq&x C15MD�a SuperSzQ IIIzT"�ase K�6InvitcFr2݊ real_ψ!y{i� iQ�&|M�a��0-Rad CFX96 To�RNTi MDe�!S%)�n;�Rm @q� manu/urer��&�#ru�?�(E<b����&tJMFi'�+�02-64�Cu���"*13�"���bF�sLI�&s2�; GAPD VV��*z��R�7� Ex&(V��!��ndʬ 9�da�ll err�"a,�re����"��Z�p&�",����e:�ne�@$�%�Lent%�t-=!�Whole-kW(�K�-�Z� fluo�t� &dF'immuniuamAY�bF2�� 7�D Colo!��+ �J) Qimz�� ( Leica M1652�dissex}"!�Vl ��.�og-hgHig0rabbit monocl�R$to H3ser10E:1: , MillipC").b�DMIRE2 i: �V�ce.��BPa Hamamatsu Back-Thin!�EM-CCD�Hra� spinҀ��f��� n�3.�E(�TB5002-5G�J5 mg/džaW!="T�p�e҉olgC �w!K4%�edj�%�+1R.� k8%a�T;l Deoxy�otidyl�B�5enzyme]� hermL4EP0��ahec8�c6�C-��Ea>s����a�"z�IA�J&��W�W sb .��8 . nih . gov/ij�W��n�un�#��o�tc箅Jvi$�7ve�Cn@�b�mc\!Ej� #�b�Q�Qs�.2��en-�Ml� 8X�y)24Adobe Photoshol��4df�n6bTQw%Kn:&�3� r� f"W5&�T�x, � dTo�.?��:�Y�2o*�T�$�4��p`�$f >20 mill�reaǿer1B2!�at)! �G2��1�A�. TT�U~N�%�A�zit&Ee�i �� e�se9Y6@TH�{ .^�Fe�2"�A:wipx�ed61"!�)1:�"r�E15+��83 $B%. Ven)fag1e� A �^ ://w�iov0. nl/ [7�BVic= pl*A#L��modif�ecodP [78]�heatm ,N@�D *,�JP�g. HN/33>\W�*����3w-�� �!�of��iHL "�w�HH[EG!�DCYoutpu�X�; � anusrT &��� Gene� ���Omnibu�<GEOV�/�=#*A@ . Re��NWve.7e�re���virus-ie��A�~a etN! �!Th}[�u���o(7��8Z�Q�cip~U 9�G8܆�I�t�� �!y4�J �A|rRZ*hod� EV71= \� .^-�1r���2� pack�� �)\�icAn4miR-146a�\�&M"8+�il"�$��\�;�p͖tAȩA � �s�`he �: <�7.7A05�B!2rnH-�e p� ion-�).�t)E]^@omp2���, Ago�'AGW182 �te Ge�F� &�]e�A�"5recept��!Lal� `be Vf�*�0� ��.��wCrAw=<4exosomal miR-1��46a suppressed type I interferon response in the target cell , thus facilitating the viral replication . Additionally , we found that the IFN-stimulated gene factors ( ISGs ) , BST-2/tetherin , were involved i�gulat��o 7�r� )�N:�, � le-!�nd )vY �a� G%�belong!�Lfamily Picornavirida�� major � &  agE A�and-foot�$-mouth dis���0FMD ) [20 , 2��I�A�is � tiAoassoc� d with ens�(neuronal de�r���De CNS� lamm � necr�c pulmonaryA�e� ,nd hemorrhag��. HowU6utopsA�헑Jno.g6zA� founx organ.f!dlu!q, heartJ k 8ncreas [22–27�Y mechanism!g%�2s rema unclear .M�belie�+%�� facto6���"Xra��9n qitself� � e t�mayu o&\ �L determina�oNeU%���[28�Exa�!�proin-�<cytokine%�c!��s wlconside� 2 ributea�!opof �U}[2�%X does�����_A/a��2�( IFNA�30�Ƀ�Y��aw�&J� ���s �� @&Q �A�>Cle!�.�K g7 � !>Xhe�K6kEKJKA+2+JI alsoe���9abut+ e; enh�5�2{ This ��V fpT��cli�l data�weQ�:agserumein� ohort�:�ypat?4s ( number: 20�nd.�children>'. S2�er"M�� "e �a�)2��etha��*f,�a�Y�Ei�confirm6t i� actu,a.�ek��3��t ��=r�*�"�,��-y� �tre�before%c סF��a�fe�_( s� ) agt Rab27a- 2Rab GTP�1requi� � ؝�[3Our� ults%=��at�:d��� |*� -be��1)�Bu�%wi�� r <cramblA(ont�);!C-scr ).3 ��(��F!andR�G� Simine{MXivNassay�>�Y �� �Hj TakeAgR�u�a�]J�F�q�E�Ai��hd)D��5Q5�"� 5am�a%<�>_�!}ai intra-m! I�Exo� )�?�si�no$al structu ( VP�VPzVP2 )���&�+��3AB , 3AC�e6O�r �tpa�CS2AE'� '-a&��ϡ���rA �RNaH�rad��,��!letely ɿ�,ofI��( S2B ��6]8�i!�.�.�a'#~"m""���&�colocal� elfgr� fluoresc� labea�)! al markereIA<`l T2� q is&�V��!d�%*"e!j#��c�]I�� nd7��=��M�� � ��>-6H2�re}to� �9A�cfix![o�volume�-��e}f eI�*�ly�7V3 �!�; ziAfr� � sEb&$� /)�eƩ���!+� !�.Ya � ximaE�2:1] io ,)�� 2Ce,�4���pat!b%����.�6~��’��:�g >�a�. W �lM�5�Y� t dy�DiIh�incub�0� !ar:�&�� up7 efficienc�a!�d&�=�ce.6�S2�H. Paraformaldehyde-I[ �@ed&��2g,�� �A- �n* w�#EeD pas���at)ea�� ' if68� s �Az)RmN i] �.8-!EI�*�")����E�&� ).G:�RD (%�l3&scept� to r� B"No�Preal-� PCR1ga�!f�'of�-&�- ���:��c� a$\2! )='%+)&a s at"o%�poi�a   S2�2���i���IE2�ADsU�tZ�ib�� of s=g �.� H#ly�� �1X2xqn�<ef�"��L9"�Dp�I�mou� �*lM%b"H� SCARB2 �*e�&reA,orewE��!����%�s w��6�:[3!��E�Q&��an equal.!RقE%2$A�%�jIA��I�Ho�lyoig� �}6fPq���&���#�tw3 cop��}E� 2E� Mb6%�&fC6�>���� n>�Bpoo�in2tith�"elayed �tic�q) ��stricI��i)�entry .2%6�=�EE2%aq�5�6�+cŶby��>`~ &2C]%��,Ů �at�+&]! �!� �i�M/q�cy!U:gIk� FC�XC�sls!& aF�  became$ c.%e�� p� �%�5(i*to 30h !>@M�...�at 48h>n,k!� d�a :6t*�J,��� f�, even�60B� ��B�)I�.'�inv��gE_wh�>�'a��kB� ��@m�� independ��%�W�65 a ’s>u�`!v�!�/ap��!�after2S2GU�R2�s��uqb16�EjB�A=�at6$!�KaAH�*�/tf�(�L)�6anD&� )!>{ a�*J� 5�.�manne�"T&Icha� erize6�!�[�a�u* "1�FV�u�!*B>A�f inj'�&tail vl/$of 4-week-�Xmale NOD/SCID/IL2Rγ nu�/ic (NSG , n = 4/�}1scF-e� exam�� ��� ���2 . ��6m:enric *i� �/�spl� anima �6�cETV(9A����/Q�J� �6Pbr�-�� �,!D��F�%<&�byI z� en@)v&O-�6���I�S2I���InI�&� N=���per� ] E5�aio(1-A�S2�-ven 2Y,!?8 � s5gY&A"al ( � 2�%$"inQ*t 1-5�i . AtN�� g�� �aY�9�F��g� irst&�4NH�7)� bowe�E@J%�To.�5�5�-� xQ+athwa�5yre�0����� of\ inx5�.GW4869�� drugaFt�cks�%t� 0sphingomyelin�2SMase�m _.� on��&��Mr�)���>i��lP �h6|4�a�e�-�re� to 8�653%m! DMSOa�Ua�hs- D2��5E�10μM92"%�'�ml3�Concomi.� e�,V�J A1��* . 7{t4�M 2�%>ci�3�F�Y/ :�I1!��<i5�2�I�es-ded&�� ..�!� a3dIn.� !8:�rE&h ��x�x�V�U�A�AV �� .��h����Q�o0%aXJ�-�)n  ��6MJCorA�o%9E��6��ޭ�a.��ą�( ~A�,) �.� �ol �%�3%.�+o�k)Y&- ^� � O��.-�J��&�0i�!&�or �5� F�a !S ��q�mA�3\ lt/�=6�a.';�OV71-�q�sEout �i'A�*�$ ���! �.�$7:�щ�>�/s'�&xpl� Qm>?.�~<� �2� �!�!*)�[t� �>"4bw.�1'4�<3 IT�P betw� � �? nx$*�i��a\na�2p%a,&� 6�\�0*v!Q�du|.�u�of�. A es�=re�!k IFN�*e�I�q���!_m�I<e [34]!�87�-$+ GUnu�:F�.��sG�.W�k*!)*���/6!_,us�o"^,.'Z.�=ou%��h4�( Y!!dl� c �< asal��1=�in*���e��r�1:0��4��sie� ���0uk�I� b,"g5�q%.0�above&M?� H&2� 2�,EցoQ1s]2��^.�M.cl��=17%^rs � 2'D8� TSG10 �irYN-?.-;y$Ho et al ..� �:T�a�� "0.}Et� %y!\.��* ��of IRAK �TRAF6��wo ke\*a`9 �TLR�al!]A�A~]W[35�1We*�'a�ame knock�( GKO )T�%6<-29�@-/- )�A�Clu* ed R%BAcI�spa>BS�%P�dr�0 epeaE*$CRISPR ) / .| �  9 /-$S9 ) techn�5qS3~*S37 �9EDS#ul;X�*ulA`�� exci�� ti�?d)ic DNA� g!p ,*�!e�50of2L� =<�:�+!�2.�PU:YZ8ͪ% yielmm�S3�(S3Dc�te&Q,>� alte"! L!mo���Ed`146%�A�s� i_"��i��(*�ha�(�a}oHD"Q!J�GSa҅g"�by6N-��&0N�(R0N�Uthe�<,aA-β�>O �-6� up-&�9�)2)#J.� � !�t)� <"ee7���&=a� k)n-����6WT _��� 6� F�"�Qe'dU:��62EAK. ISG15B~F��&�7��2E r@&�o�~�Q��[3<3�<2��a�#.��$�B�)qt �c:db"a�E-q�2'�I!%)�526�:�}=A�.�2by!B68re�|y�Fu/s:m%A7�?�ofz�*�n �Y3�7A�y@JQR'x�Y9/� �(ed ��U:)geF�by�n/Cas9&��edi�� . Cl�;a���t� H>!�2�9i�Ino �<e`+%O�T$-KOi��T 85��E�/�!�U�al�0� VPBV.t�sN�&[%��uiM��FiF�-� %U�A� n ]'�%�N3of WT%yF�a� or��^�uEP. Altho$4A@EPAM1@� N� �X*�Y� a l8MFB�-D� =���е�(�J4� A} �-�Ma|2q+ gain�2loss-of-4CBeri��s���%%f�!C>REA�=�97VU DeBOr � �'vK&�Bb]M�� ereby�@�2o.progra'/e b&}IKXBh !�(J[U 378 &�a� rehe�?L;profi ��R..b+epy-*�D(� B*�*�fPJ�>v' ANOV �D , 22 ���*�to,;.}�>"y<)fE�6�oN6�>.I�6C!� S1 T�B� Wei��S��by��t�86z&K&lA|&� Mvt�%��Ia��.� versI1�N��+de",%!)9a2�,�Nre�  ]A-2WrWsubi�t�� foc�6on� . U&a47ndard6� -bas&�4ci�� f�3eU2�4%�"� �V" aq1).Y��by �8�at� pi��*� �7�.� �a03 E�{���'.&E�l,3!Si^ed&|GlP���9 �G; �nd 17'� �68:N�"a2��ߙ; `��.6� ��7d,C*##6p �/Mv(absolutB1�6E�.���He� 13N ( S4�-)V20&.]~/2�ba� >&�We nex|C�S�Y��Q'B� S% �7sample�-�*�l"C0 0.e �Baca�P( [ =�7x a6n.n �:�� �,-�� �R�8t �e��xI/� Y i.�i ��be"�Qto%� �2��co&�N��J`"WT2��= onorT�%$� �a��Oa��Tw*,cha%9A 0=μm p�s�$��isAme���PI�s"7�2 n-H� >w6Fa�.�nMun�955�'ap�i�{�co-A �I!$ied!! �K1)# n.�=e]� amB��mJ �6� elevh(. TE9E� ~H%� �(�) {�!tl6V�э{%�& L%�1�N�A�6v55iKtoR;�"8 A1��,ordk(:�XA�mMk'&e.E� 8%�W�%�cy3-l 3Rmim�,":1}��C�#92W� n6�$EE,F �cb3 BNr . Af�)�1�r���Iycy36�!2�{� >90"�">2. ]i�9-�75X ���8X�%�6cjG�"�G�a.n�&"�� �.X 5��):-66�:[ �+�MKE�ٱ�is*5,0rB�F\wLRRHF:� wE�%�ei��M��S�TU iRmic-N�Eġ�ZZhemA�EwV��~7vA�% CAjj% !�u:$ - P��� b Q-4RT-04u h�K? Txs RT2 PIer^4Array_ fi�_�})84��8)3�[en!*predi%S�&�by hsa-y8 F B7� S2��kuX�f�,"� STAT&�,� SMAD}U�e � �#e��259SCѸ�-�.WII�KM&?J.��Z &a�-� J� " down95*� of(� �� �^h��B �>���at ?` �A�u:ta�:�a�!V��J�B�Jzr��me/�i �n�(�a&�-u:n to2(XB�&vit��J+eJ�%]�usN<.�. Re{2�sorekr;5]ficAN�["3��Kr�[O Ago2�t�J�.p#P�.� RISCA�t} direc�ade1 a�liq\[33VA>Z2L�o�"mplexe��ŋa�Cs!��0r� ng&�4 GW18�;.&"�UA�mEH��MVB)��`�FaO[.� [3kVT}alyze�G �nd w� \u�i�{-�C �)&Ico-\&o�Mp�on�`�Q�:u�2!Slex{+.� ( S5bW�:W5qR^��q� �!�PAOcop�;�dq�Qbod �8 coordinatT&�8add��6"�co�W�"�:!�A}�Ei.g+R�u-" :9�AS�' new �*6d !�&�� WT� WT9:)�2K&% -/—LX�ii�� q*<�;83!!(IS!*�e`�X\�F��q s��2�l"�.Q2�( x]3 log� �� �Bz 1�$h , 18h�� n� ^{AM� 1>-B�f�O&�>�?z�8� 9hv perc=agK$-"A`=qb� 6� �?�-b�g9�w�8�_I} }NEba�A�.��}@��;a�f�;w�A P&I��a:\� A�FLItM2 $. dosa)�a#i��>�C�5�!�X} AR !inoculum�-� A�7 e�:e� sacr y6�_iJn"�<��B! [a�:�<W2�[l"f&TngIt�� dvodD7RU!ZhZ>b�M�F�8��|>;B `�a�Ci]A�YS9k* iF1(��5e*)���r�c�ZsIg!�: *��IFN��:p�plov pS �:�5d"�2�6 milieu!Y#a�?4UFTIe6�o/�eQ�y �g��� they orig�[">o"�'�uA�th{k"�Mklp[jy&���q0gxL�'ly un�688.?R!t� e2�j. !�q@ s HI�m��m, HCV�Dengue I [8–1Z4R4�bI)�ob�obZob� �6 b� )�.�J�nd"+ J0B >��>FaTi�r=�. D7s U�4�8x,�8� ��)IS buoy�kde�A�edF)R �mci�jX(42�6ntrat,m,ultra�:�^suhe ^S�X A�method�insuf�O%_r%',]��:I�al�a[�#a��C�; �v� o"!`�t*N�_ �toC`v..��wiS'KrryOBof �eD%��) �EB�%�aoJ ;- Xa�5:�8�=9&o ��mit� .8%�� ^r�9A�'327F[N�fIkF!�incluul�2&ch�9; ���95n� "�O�!�rU\t2N)'es�f�"ex�+gMnI��%� iscrepa�Js like�Ui3�"�ELn�UVCbIs�V�N� & al�iis�hav5�eY�� t-*�!F�[3-s4�N*.6me-(&%0gmBOyEJI@W W  �5�xP�ZaAEB��o�\n��[4�:!w*�I� �al yA� wsJx�` %8b&�,�ng(�\J,�Rv�m�fecal-o�( rout[;J�� survabeU�di�l!�nzyAv"�'M�_cav�q� na�)�t;"*�WA8F� void��� "Nsa��)�F ��32sNoaM(r]4� ��.@he�&tis A�u& HAV�an!`{���e��:l�u-cJin�A*"Y ���s clo%,os*]q"!��/E��!1-LM�yY�ne�EHH!/probab�zrf�y���F “quasi&�t” ( e) xs Q��z- �3ya)��=E�"(��E!Fy%�8n&ux*=�z[4w45�}�C�g �C[ poli�p�8ft !a^� %� ,geg5������l�Y"; b-!� �t, often8 v}{hz"$# S# ngleN [4�x4b�\A��#�^��"�|,��oi+2���.s�}#"x=ly�P9j%< !!9|bq��l� MeV�i�?�#QAxn.�bK&'8���v2� [4�" D��2M c*S9Q_�Q*�Q��>U!.a��XQHV�$)�Bn Hy:R*Sa�m m�u~n6�!9. P�:1�.��U�PSGL-1+�y�%��p�/�% mdon�U , 5k 5k S�#�do�0�6Jr[5� Ay��s6ri�6�O�C c�>���"qT"a)T����F� 7�4%��m%e(�Q"�O|uplausYxb��al2�%� ���Ia����a broa)�r�"�S�W09�is%f1e�#@�^)B��u��MA$y.RR%�I�~nOqIa���}h 2�,u��h�<67y����$�8 �a*�4�J|O*�72:� %y�텉at&�ym/*�N �.M yste�%@9�ai E�-?9]a}e��B<m}Q����$ucm*\o<�@Fm�Y ny���gen%"�\ 2modela�–54� N6�>�L"=FleF!s s�FJL�D�d;�~��?;�'| s [5t A�vyE�5�"�:em �AA�oQ �c��bm�A!���pi9Pcor��v��gland�ep #l&-{�&��Q*weaklo|av.�)� kele5 mus�m%��qkidneK �R!�C �?[5>�!Au� urot�%Z!�>'!�v� 1u1�-^x�x��mT G�tp��a%o%�os��\OPA�t�;c:b�aa�e�Ris %��9NQ�X��)oir%�1��RA�2�M&� �Rc���!&-oee#;:���>N_ L.|b� [ )s�&� y� *"��[��M{�h!R!�a�@� i�� ��sTt8F�n" &>macropha!l , na�$kil>+! :T etc� B'L)i.ZA"vMW ���!�ul�1 antagoniz! !`i �`�� &�mononu���ocyte �btA� �F5� �<��Iic acif �q�cargo� "�}�GackagJi�<�h�#aY���+"���� �"�1` 1L 18 ,/<T �dJ�;!W6�:���7џ� ��5�� U*.�U�So�o A���M!�;y2ai.�F leve�4��"� B . Earlier��FSi�S�>81`�.�E�:E&*�%� �&�+�+0Dao"�in� I� ev�%e�M�q�L).29l&��(Ս��E߀I�2�� �:%M�Hg�Sy>%��,&�!�i�?vi . �#m&U$,6� a��?I� advaa��5dp��Ha��Fq" �� , nee�mi# "�A� rapiM"@e�2?h�I��fac-2� .?>��){eF�VcTomJ&�)�'�Zfa��-�v��:� plasmacyttDC pq"&<�igg�}��|BM !w[5l@&� Feng�L6�$Ga�t-w�5 ,�,-�� ���ooC8(  �*!1~Jqoiu!ip"@!ざ>G&&��&h[5�6�F2�1� Ic ��.�{m��non*�ɛ`chya�)�( LNP ��6B]h��}�������~ o�6!t�\��B[5w:�݅2\ i,�"��5� playHR�?D0nm��M)hea�un�(� otÅrvaU����"�B=�X��D�0 �w�teg��Asam���wA\m�C� 5� �'_k(wd"���E�|��X5 wao�etP'� �.V'r+"�! �?r]�[60nt � �T�ń%�wa�iog{ s!8g��Tv��F&lF$ ��36��2B�H.T��E�<0y.Huh7 . 5E�(&�|���*K65HCV-J�1�q�!�%�%�, HSP95�22��zk9� !�b�ng"S22ar5’UTR�.� is c�al��)�.��Eer�mLi ,�AJ�2��>�rt �GOa7waEZE+C&/uncz�d�!(�@fom2�[4_ 6z 6X� �M�q�T.�-�uV�5Rj�MrA2�gy�!CIO=�}:.�D.,o�! �\ytoŧ [6oK9�inY**�Ts .A����u� NI !m��.� Nef)Fi�JY끆��&6u!��J"G+"[!�Hurwitz�.J�N!LMMs�ps!�-Barr-J ( EB�encodDLncoEi�^�xN�NiQxxGet~�e� f� \ �oc2� [66InsGW (. !�A�on2;2-.H-2%E.�A . Of��e��A]e��y�܅+Q��k.=���"�"a% e�!m&D%� ��#US~N!��"w ?*#J�r�~ #-�� ��ME���(�sqP^despig�hy�'inm�1Hin*�[�d �@aG&���s`i��� ,"�7�X�~�Q"ic�[6�6LF�!&���^ � �YYro�.S�Ss y�,��capC]$ ��q�0e��%��g� JAK-q9.|h�RE.�BB0[3��7%"�A�:�� ��lKock!tMVB�+_� a"�9ze�q!m�� ��[\%J9��f�/a�>=*L ,�9�* %X��[)*㉅qo��ἦ�SSG� i�Eo*P�y�jS7���e&��!or�'i-FTR;-�-,�P.�^j:R�R�q�� l�ws^o7�Da)�HXmNJ���$� "����:��eA~�@-Golgi network [3�Y7�|N!��>�@s� � B�w( H���O2 �!��"�xu�:a)H�iQona>�(��e,�!�ed [777 6� :Uis�2U�n|1m� "� �� ]�1(dra�c� :a9&� s [7Ē7�|� empD toi ��Iy$i_s:$]a��KI��n"2p5o,�o��t�S.�M�>)�!����L&i .k�� !�47A��onH� !�q7�)x�%MR�!�>�7�9o�>�ezlcoy0ur�q�����RIv. ��A�� �&lH�tq\XHc�, carcin6�( H�K� .rN��[R�0A\��Emon\�.�Vero ) mainM �,0 Dulbecco’s��Eagle'AA(dium ( DMEMc4o;A10% f<bov�u�J( FBS � a 37°C�i Xatmosp�2!�5% COh.� !�e4an��ic�ԇr�Byu6o&leukemia�E� reU�-$ RPMI-1640�um!�!�$5 mM L-gluH*7d^��l�%�s)]obL� ATCC�� �}Q�)�y�א0-I , PEPROTECmRBAw&�0i �Ct�qfig'+l��d�l+ina�eU�drotoco]!a�� A; Nanj! Un s� A FCYCom�)͊� e ‘Gu���he 1A�Us%�LaboratZ_ S/|pub�* � Chin0N%+(al InstitutɴHealth-V�arc6�.�&OL� cK��!�� behavi�'g�a��d�E594EzA� ��, Oc!#c5#0( #2014-SR-07�. Sޅ�Mco"��%�i���4%�-EthJ9�$of JiangsuxF vincC�%%�D�st#�S�NndB:>%�wr�T X>n �6��=�%�$gal guardir�p ahik�. Q�"�Yof�*s-�-bead-cap�v&�A�B,}8D easu-!~]SBrowni�*!�1�A�(oSight LM10����} quipu�Ef�� oA �%p�- '| softw!�(c<, Amesbury , UK �S"}�eeelueU=Z��s�ica�l�j0��$Glycine-HCVopH �j؇.�"�(a�o*S4 �a�bu���BM Tris\, pH8 ��Sam�P�di ��'g6MB�H�2 ×108%)20×  p-2^ m�mAp%�"vnU�a!�ca"q�i���3�A�So$D;��?�@&�8%�i\�V3>�sEB�L!Di�man�shu,��adjus_6�"IJ��Y1speed_ 15� 30 m2N yraQ� -K80g56�P7 A�[IthreshA�kep�#�f2; �(: 6�;�9��Hed5��P:'no8 Each��R�f�&�{&� coua�Eaveraged���6�/`9�u�r:�T% ^b��Qescrib�0�VM���6pQ ��.V/|15%� r�Yge�o �5^ \oR( 1�430 ntE�92AR1thano�5E���l�w8i%��W���C libr ��p�0�B�<0D�V�QSQi���p� Ki�f Illu��4 , RS-200-0048�D��W� "fB� NA���Lwae�� by Anno�' G���%�DvHiseq 2�� plat=&]#y&h )���2�b���_K�^a(+llow:M\E�ly�$� RIPA��S� Cruz��S�>�ed8at�&�I39։ror!tMM[��on 8SDS-polyacrylam�ge�3a�1ei4d )f�Ook8 PVDF*�( Milli�T��e�BO�+nti�C at 4_ overn��,&� b&�Jgiݝ3& r IRDye F� 680"QIgG��.806seX A� �8y ( Li-Cor BiosD�eEx!�wa�! scan A�b)uE/ome)+����byZ$OR OdysseyĞre9Ima�bJ,im��$VP��.W, c`( Cell��� Te"�iz �!(.C�( Abcamv��FTO�k,M-a��FAPDH (�#Pq� techlJ�, -�,i3D.1Genetex� 4 .4aO�� �s�`TRIzoMV�!�fe9!MI�%r���� CPU ScL� RT Mag] Mix} R3Q( TaKaRaE?t�f�0 fmo0+synthe� Caeno�i�2ele<�$a�C39e` iBoB݈Guangzho�;= k�add ea������Ja "_�� �8v �me-R( q ��y&~)$ABI SYBR G��M9Vdon3,Prism 7300 S�e Deta� on S�+ . I-�%恤�Y3of�I(*�7�� �q�c��A�A�ex�'Mpce5indU6�9�&ar��e�f��>�9)�:�\Ure�b. ( rip�!e���2!.+uE�2-ΔΔCt�^�3�R6�&pA�r pai*Z���}�e1�" copy"���2)_ curv�g"|� �,-M;�4liquid chromat�cph�`HPL�C!�JoҥH)oL7 ( PAG�@-A�f�doligorib�( otid�Va@���f,RE�-�(� �RW!��y�)�input  0�$ 1 fM� 100 pM��a�1��4�-�%�&� ai%�X.�2�a9T.�^,I���4�&� ��n]�� I�}:E^�Ea�Cc/ �[%c�� IwE  valu�R��UfdAF 9RP.t E�:�GU 5.QRU�Q�DAp0:JT2q%5aR�N3W� )/�Wz9W( S��AFW*` CorpI� , Qi����ro6 ��V�P�+�pplaM�Q� C �?(NI��!�9:/kof&�W.�)>�W�Ua�� �%�:�h>�� on� SA�T s G"m�S��1�Eeds�K�!��� t6��9�9i��M�1�12� i��dX"$Fuyang0805�#�$a kind gif-D�Bin W�b�ep�2�propa�on ��!m�xő2�]�u#� �� rief�$n3Z"�_ q�0 0I�r[ aKtE�fJ random h���9E%�g�n{ pE�k� *V ��c�s�subB)����� �ʣ��.P�+40 `�!}��>��w -F (A%0-AGATAGGGTGGC @GTAATTGAAAG-3’ o 5R5 TAGCAT(,TGATGCTCCAAT1. *�tB����246@4 2635a�FYE�!1�)0�I.�"�B( 1�1A6ies/μlA\8. �XE��(j�:g�&�A9:�Y�*mi-2�v \Noy/L�e6qN~N8o�4� -� �*��w0A re-susp��JPBSE�A��,��( �-��bDcop�Z� M%aci����X��a{�@l�)%vecC�wv&CTe��k1l�w��(��s�ws�wp �wr�wJ Wjq-�g$�=( g�D�pAdd� 731��� ��1�!id pMD�G�� > 1225gpsPAX266%�6�@�i�� ��HdesigHUoO,http://www .��om#I gineٜ.4/crispr/ w.wy_5!%s!�O���$:��I"�g�r� subc0CAU�%> �v21�Ip"� ��)-T�YTGTGTCA AC�&��"s�1�J�SCATCG T0:�. 6a� 6 HEK-293�c( ��@yonic.|!() �e��4M\6����, 3%M22QD�4�@u����56� a�ņ�#�100μL ��!0�2dayL l/)!�"�,�6gle�A�`a�4%�ma�"M*purom��&μg/mL ) n(�|3 9 ��iˁ��axby��*�>�Z.����#&a,7a!����"��t 1�%000�245js!urem�  debr�#n�5!e�2Xfi�z�ha5a�h22�h .�%P�"�3���^or2 � � : "�!�!�a�manufo�rer �ruy. * �~a* (Gly mix!%na�@_QV~�&�a�ݫ�>~5��!�qg A-kv�>�phz �b  ed s��e4� 2"�!5 :;�$,�5�"� �2y �Z bo+J�)� 6�JmcouplAAo m��ᩡ�MA^nyi!�tecn� >MidiMACS��[b��v LDum^�@cat . #130-042-90hV"�!s-M�a�=�5*M.7B ��macy3)W labe���".?�dy"�� mmerc% �?�G< , #EXOG200A-1 ,W.i )J�j(�#Kz�� �F:�5��l �&��'&#!M2� For Di +a�Q%�(��@1’-Dioctadecyl-�&F , -tetraR8ylindocarbocyan�#yVhlCe; ma-AldOA��� :"2a�-�-a'to 1 :�ad��0� 4�>A+h �.�a&�al$W�P q��!� . L����m#%fhDiI"� �;r�AY>c visu.A�Oy�us$$View FV10i�fo)�� ( Tokyb�Japanev"6��V��>l�v�:�]aS( IP )$�i�� (�>5% NP4��15= KCA�1H NaF , 25 T��, 2 EDTA�fp.7'Bu!��4dithio� itol�60 |��)cV$(A>Ye� AGO2.Dlh5V#)���.n�aIY� hree�mPBS�f� . Non&��rabbit �(.��"� n!l�  `mixtur��, A/G PLUS-Aga��"�! iI �1!�einuede>6���$`m � wash�$a(>,�!�in-& 4Wl_m��a�6u�A\o���J ��gq#a�logarithTDphIGM mm� �%%�%�iotic-8E�6u�d�*�A�!i�H'p�2"�;qLipofa�� 3000Rm,  one�,30%~50%!�fY�F�>!fE' �fi��2�'\ �m��v�l��< �p�Y�1>"m���j�� 100nM �3fF0"�b:�zVA�2�]~ L�!�6}P� RT!D*� PCR-b � W DreamTaq ���2ND mo S� |��� H �O3 ( D���/�7 onfu�$_�"_M�*Forward:EvACsATATCCT�CGG���%E1A�CT CC9 ACTG�C~.A5o@ �%qurcaeMRibE(R�iA �.cresol�)� "# /TAE� sA�{ ethi�+b�d����Aea %��" E�"+I"=Z-�ԙ4�j� = |�xH�� �*5]24 h #F )�X A�� ��8vo*t� �@ RedFS(���&[t� � u R1ru 6-+ or2-( 5~la��~���u) �.|r��l"�_ ive-b-K&mO�nu�g�I4( BALB/c nu/nu2Y' ��!qwhole � A�"�ÅVIS'ctr;. Cali!�L` e�8ar� �j�,�b*5$o� 2��1�"lK&�Hh�"/,nG"�]��ccb�H)NI . Ra�*t�ci�pcyp�*"�LivA9� �)1.�(f S*,�{h�,{���*Be+%7&�$e $April 2016� June at �-C @�HoV8a��EtgU diagn��Al�A/s��7ir�{�6e� nZ�Rdu{&\�-���Nv��2C�|,G3�� �1X Pfix" 75%�ano� 25%(KacT"[G�2�BwK c%� !�pre-h2�� i. S"3'��z"�%at� hANR� �L1d{n sulf�� vanadyl-&�}�"� ,� 02% RNAsee BS� 2x SSV��b�'�&%K�AY: ��V#� 6��= -Ytw�]!�*� !0�&I'a-1e(:�� ǁ0NuIa�*� ?*�� DAPI� igm $F��" u�a6I�-� i~.�&* M �n�.e�at�s�*re- &��&�Z���/6(mean ± SEM �(SPSS 19 . 0} tistv4"�.#�)��a�&e2Bce�a �8by Student's t w�� One-�5"�of=��"(̅�l�qI G( Newman Keu� S-N-K ) Z. D"�: ��0i|��D �ly�Hm0ɪt a P "e!<�,05 .…PTEN"�8k�+( PINK�>F> �mitocho��(al homeosta4 ,,a gen�q k �H"�Fey-onset!�kinson's�N� ( PDE�An�W1 1D6], C���8s�k�n�0cs!���a �al]E=b����'�6(,in Drosophil� B�= ine/�oY-P�_aA�diL#6=*"e e�.�Y] an&�:do�6a�N-}%u�!eOPa!O �RING-f�]&�+�ub^%tin-lig� ( E3�c®.ͬhow �: `r��g. Ais�]eEnkZDPe.�8�.�ʼn�l�O�sq*8S)r��6 bio��a�Nur�--�D" S�zd�Xsc�(A=h�s YB�HYBQ�]y ( d )M8w/�  a���j.G#{ ;A��P �H�we�f^�=a (�6^ �a&GAMy��He=d�� . Lo0Z.�9� )�;shL�/S:�moOde�A�%[aV� ifes#����-1"x�!�:)can b3�tre�d� 6�2�.�d �2Yfai 11� phenf��piRmu� fl�.�#��}��6� qexacerb�!� ��=e f!f p).�šs!�s���) �0l�}��R�x4-8�:enŗ� .K�"�Bm�Z�at qacT�3IG� ��  f�z�2��liE '�h�� F. JD( OMIM #168600 ) )�jfU9�ve�KE7{M�6�dop% rgic�;�&��PD��val$ Q�d��∼9+people�%�a.m6)���s����in�� fe�SInPD-lu�e@ab�&pf(�mor*, igid�: , ak$:i� ,5n���lurb!�a�psychiaY0 disa5I��Ki�H�� n��Q�Se�of PD.f�(J@�Pc�4ur���#�=��.��d��PDA�woc�m [,M�+RKWAI 60590 �v"ID: 6501�3A�uW PARK#5011D5507��8EK �`6 soma,0cesY�Pg�,IP9B��( LOF��f&�_ա���a&�&�man�(�&9Nuism [1 M["]Bi>YůO����[ZAF��@-�1��ѱw�3�I3 "V[4]–[�AE>f� ha�0�-�􁽭(9�31607��[�I���o�&d).<40336���?common��MoHes2]p���~>�)i�pa�6Vhfl�4�nA�DA��[7%jHAo�� �W dm!6s.wenggd)swolle�&&� �Xّ ���:av resc���0ozygo4?���E�@�Y� .q��"-&�dc��s� s Op!�a�/y� OPAa�! Mito� ( Mfn�or��z*��l f�a-� "g-6�rdyn�%-�=Q�� rp�!R [10%���� - in m�l�=or.�:} �G)^i�.x �n crui5 da�5�� pola��6�!�B9`y�ir% rܿ"�#n��p�� c ev���E Qy [13 �e�Thz �r� �,o�T<>�EM�a�i"��.HE ��m[�D��06.f.� littl�i ab$9&� m�B�a�g3L� turn�5 ��d�����ecisef�>�� �exeIhw�EonGisbc %�� �c)��0.�Qd,�#oglyce�?aF se 5� � ,��19211A��*I*Ic� (�l�-���j�q.�%I %(o lack�C$F�uS[17Ţ18��vs�4he-6� �0, `���C�� �QimproD46c S_P)�2� :�_��`�v%�v"p+>�X Sse�@ly up�(of�ki��e!��*H�*5ra0� ��hip"?g d�M}�s�C�or #"� M%s��#bi�Oof.6�d mass�Bp:.&w afficV&=53 �� FLAG taz&�IC&�( h+-$)� lyn<���B-* ( HE�293�;V&bJ�.X{��nti kco�%MQ�9C5//a� !�&>M�.^elu!�<�E�i��Q�to9boB"�MAP1B4� 413i� KIF1�B� 383s�Tubulin60253�" 9113� , �as\gsubun!}( PSMD.U57�,E-n570% C���PPRKDC�559 � Hsp7T 1Z93303; 1B���30��,191,��, Cdc37c 1114�,�F% t�� -4 ( IRS-�_I84� AЉ-{\�"1� . �is LUzQU�E>� A�-tagg&H"� ouOe \/( ێ1���n�� ���Hs!����)�u�� �W.��dA���[�, [19�q2 W�^ؘc�w)2n)! �� he��s���?s6 A � *by.��c�m_�5Mnn ve��t��a��� llel1( CG148"� EI114�, �NP0568�e�c�k�5��he"9 �+���LR�+����b es ��YGBe ^it3boю!>> O9�:7"dulB�dCof��co]� 6488I��\& *#or�,9)�;#gN� A�rt "m5��+-�9,��C 7�p.C�DEM1a;' bU �4ve�*�E�.�)��&�of.�+eE=aso��&s �w*C�m< ref��>%men��*|� )�a�/3 ��->[2�u_)���>&�S��i��ocu��I�����!?O�&�-!Y&l%�l��Myc���Zi��% -My$2���/.��t�ed���U� �*�q6nuhtE \ �'�����d"� :�1"|�Nd�Bu�� ��"zcPti-` L��mun]7f UHE5�� � n��+�Bm��v2E%B,� � ��Adh�T�!�_>�d � ti--V�%2�_�g� �MFy (�fi� g�rr2�>r� Phys����)c%͡� also2L��S2� 9����g@w���i&&a�g�!�&��� hi���p�EI#Q���A��.)�\[�� atQ!�@�,!9fGl�� [25� [26�p�#l�m%!�fi��iL�0x-�� 2 ~& A mo 5 shif��sayA� moni�\ �9f� �otH%��!o]m235hPGMA5Ő8�8Mh>T9�1�O�:n�8> vitro5^s�I� reco� ��)�{�o�wa�o�mil�/�)�[ub-7&# b)mod�s�1����KST.Ga-a��to� �6{� &� �,[ )X*� )Eb!�), #�3�CKRCG1587.� 3789:��nag% A�8�? � -�&-JlAOMsi2� ��\��",l!t��"� "&l-)� n"� nd#,ge9 Ss"+o -if ��&E|�tx�is )-� 4va' &(, 44% amino�%�t�� 3-2:538%2*DVt ���alW v1�Aal2;�6%�ibev%�lhigh-Z�D)B� �-�&�mV��e�� /�Ri��t very ��l>4�ad�nstage�"f�al�; see �; flyb��. org/� Ls/FBgn0035004 . html� W���Wa�he P-�l&8er�}� E�� a+� hypomorph"�(� &<��r� .� ��C��'of�Bu�S�e7 thenE��-U n+�.��5"��-g������@�����8=�A�!��n F�WS1h ��&� �1�8u�:�Wi�i o, f!k5�nd�%s�+ U";�it�pl���" 5)���m�Xs�-F3iL� -2M�E"� ongeva�a<�&� � �>AL��Fz��%� ��>u#E[""�C�Dd :c� ^ " !�2 : �M-6�!"�a2kY2�[" "�a�2.s3<,Q� 2�pb.3.�b-"Uhal$ed=��3HE��<toQ�BN��A�2f- aZrec"HWm!v�!?)����#"�+E�y&-ax��Ma^aT�+g5�4YHKe&A �/vBu-�w* -0� br|F'Zo"�]"J(5�� h�5G(*^T�m�3L A 3M�6`r�#tlyYa� v �B! 2f(�^1keN�A?inrDk%!i��i�cR�orM�-2K*. o��fr�: ! *�a$��Atae5b-_er� z9� 3y83�\%:� Dtyrosini-droxyl��( T� &���"2�fly-�qN\3�� F6$��at- �_�;A"���.&1�U:P E(�!�arily-!�)+��s���jh�va* J Dr&�>M�[��, [��2�N5�8 of PGAM5 in th�ae mitochondrial fission pathway , we manipulated the activities of the genes that are involved in R`/fug�in dPGAM5 null flies . Decreased Mfn oy resul�$in fragmen.b�Xindirect muscle tissues�Dhich was not affecEb_moval� ��d ( Figure 4A–4D and 4G ,�Fre�dys�S,of DA neuronE)z!�Dral nervous system�m�2�a�eZ|`also significantly improvis=.s=�Hm5JeQ2�A�R�worseqo�.UI UKUTransmv8electron micros��$( TEM ) seEcLs from one day-old a2=MuI� reve�7at2��5"'2=s)ҭul���cw�tyanother�ŕ!�struci��Qi.Z cristae[4unclear ( i . �5B"��losɭ��5 densA�s�Vby-as ��ar!�o��s�a�r! r��lin}e6�46D2@�3i�3i6 ImpoC��6�hyper�%l��� usua!NobserAy� .nanimals�parl*��#�#6B , 6E�6 �n sharp, trast , tA�gen^jfurEpromo. 6 2�ա6)P6�>. Simila�� (s were obtaŮwheaYC!/F$I�brainhH�I�a���*U��E � S3 ) �vi!� ized" � �uGFPia:���M�s al (!0& M�l&  .� in wild-tEi� show�V$ long tubu!Anetwork1A� cytoplasm�3Ly,As previousl� A� ed ,:vE���$form spher�� aggregat� .�o6IoRe"Q ���6_li�*- �number�Nsma &� or�Z�!��F� ��exces�2B�!��v. is moduby�2; ,&A[&�a"3 � ailB of2q�]�.�f sist�!�q!�benefic�M ��2�o .l6��8i>� �����-�2_��b���md$protocereb��� � !C$1 ( PPL1 )e�^/med�1%24M1/lcluster, agedm!u�6K–6�9. PM� studb4in Drosophila B� ��is ��associaa/%�dparki�� mor� -=E�s24<[7]–[9; In"C  ,"���A��us>�2jof �bse2i�6�Q��cop!� 2�$[29] , [30�GivenE�evide� �� !..�A�)2I�ask"� � � IVin vivo:��� sB�9!�R)�.B� �I Q� ,hypom�ic1�66 (P2A� had littlN au- :� U�787C6 2VCoF���w�G�2K G9"K �a�Lrescu� a-&Emot�e�seTF� *���}�7��IIsam�t��hb! m.� d both2��reduce!kw 9�" 7�Lp dM5)Q� an e�g�c�A*�,I���cellu� )<$homeostasi�Altho�we� "�e�� ofQ�)�,in human cul�di{a�propo�--ba�ng��if;�i, NXESG< a�abcon.� G����S�-. O�2h!, h/%E! odoAA�b�_*�[32!���ifVS� s��!N*� 6hke$!� (y) 4206y AM��knocka��%�w��[ %�!0-��):~ ,Z���9e8Aj �(%�( heterozygo,iA�"C to survi�ag%~B�il�a�or�֡�J r< ; A��B�is�F��f ɂU88B&33]| 4] . T�v of>�is requi�遨mainten. a healthy2� l po�a1.:��%5lie�toee1br� dp � ���,Zlud!$m R genom�(respiratorya���� metabolicduc�6L ha!�en*i�0to play a rolcdispos�damE 2, such[thO�Pa���.,0l membrane po� � , vi phagy [35a�A �!�Itmregb!�:$"07dynamics�re( ly b� demo�6�6� [10p 1�>AT�// � ����5Wand/or i�!sQ*,^t͕��". Indep9mv� ��QwollenenlJd2s�� %�(high-energy!and��9�e�r"a���� t m��l��Qdaf�0n"--��a6+ A1�8machinery . NamX , eiq �a:FqR@ ��^ins OPA7�s �NOI�Jre�"��parA�Bi EGA� 6�.��7tified�S as a >�ur�)w��na���cj ���QGNw& �5DR� !f.�">��f�tjin oua i! �ᏹ�1� .ݜw7��,y���&�exten* �WB9�:� �We spec�N��a tinuE�]� hairpin��! �-b� �Ks*�toxica#,�E\o�hora5N+ sequ:-*� a1ner�n%}q�� �!-�!�aan� be det� �P%+�-'.>��8ispensab�6�.� 6O,A���, dhomwus��a� &�,i< �A�be9 . I!�2���w�!�V IO"Yperinupa�%�r:W%Q�.�mammaliN> �Hs � ���m��pro��umo�[2 Our�y5"�al� �6_B_&��5differ�hMZ�!� .�jŸa�-29q�R� �M�TH+"���x Fh*;3} 3F , 3E3�Bya�� ��! mode ���s6�%Per"U��*'"� 33'!���*Da��".Slͫ"�"�RIa� .H them��SY!"?"��4 �atM�< vv�%��Q%� woulda�exp�i�"q��q��.��]v, s��A�� betw� ��A!C�=6� IWes� "�&QP �>Z !�f] e1b:aATldlx & in2�ٻ%M1�/5�6H�I� More�X=�M�+���$e:]��ma.���A�ou� :&űBG2T�7��B��=&��e�_ i�rM.���U�����& L � >�-  bu stea�11I/� a���(. R% �=��c"�two1�4lɿ%"� f[��=�>a 6GA��b�8Ziviani et al .Po� �d.� � *@ ��$&�of  )�*�ma����9:w}%�J}�[16�6� � cur�Ur�F�!�`Q�L Ur�cb, ��P��I�atrm2%A�contribu1 ?!eY%0>�u�bSandeb�2�Ycvaccum� �fVvby r6�1IBQ+calcium# lux��!L�� �C.f$in-\��,dephosphoryl)��$� &7ells [3��'e& well�las !ԝ I�1�%G��l�I�zii �a1j.l���Y ��!��rB*�5&J{e]�+ y [1+&_m�#%&?Udoz� ort� E�N�d ��Tl,�Ystill re�?qu��onp \invg)�how��686y"U.&i!3A�ert�Ž� phys��Y ���\-�� D2���h�!�=s#al*)t)(�1toc(establishedE _ ��4kinaseI�ata*i� ,ag�i�).��eI]*I�Y)� w�� fiV�) �� 6}'��`2G�2H18�h25 �o"�!�- lev���A%P$ at velow " undeP eady-�con�(�-� titu!^ces1!Y-�t."\�iA9"�-����[1 :�> % s�&)��%loc��N#�#solA.�I��R�at�� ci2�[14%a� �,�0�����}|polar�2�q� recruits � �H/ 13�)� w�{ :� seemHb~ t%�� �Q�I߁�W!� !BI+� jE3 �� ly (��d�na : f��nit!\possi`]�ma�01�1*�1��ouT5�Z�or>o�� �3 iliz�%^mol9�)alyx,�@�did �up��A� idea.jW}�063(3, ,F��- &jq�s�#*��eem"�/)mE�n�&iB1s���p�s9%ԉ�� origin$*��Bcl-xLB�p. in itself�A�-!���,�Tmo� .5l:C� �/)da� high��.:�&ref��=R�od� w��Ds6�m"#o�e.aM�! 2 familyE�erxL:�)�� Sj5%��&���m��9�[36%�� �2�2 a]Q3E�!r��o�)㱳Le�*�3�un=���+ �&� UZ�te.�=������3� Y�Q;J � �N�*X)�ńin Buffy�2A8nB1%)!=be�-of.�� qKqIor#� ag t1�E3�&2�!)�9�I�Matsuda6; 6�M.�i6!� onlya��d^�: e exj)^ ��J�( s{Ɏ.�!�`a} rel�7�, �a7(*Je0!B1)���Q�es���by2\ M��/L� Áa`��� b��jor��by�b� ��R?�#�BN imary�!D!�6h2~by"6F � l�"ob�,? grow�e�(s� md)�eliminD "��Nin coope-6AQ�� &�+:B�6�. S�<����(Ji�6��7 �A"�2r� p%g��ex�#x!"|i*�u�ire�Te�'2C.�*"�#dPAGM5MG��r�K="U�6�)1#�"��^0 6?[�"�\�~�̀JVby"�2�OA�Y�e� rt-"�5yL-x2$+mU� �;�WA�7ex%pJ m���"32of`3MnAA�4i� a hi=:erapeu�ɻg A�EO-�� d PDż�Vg-�)��t-� �"z �2�-� N1ю��&�!�U6.�\ �0wb�� #torm�3&Q�� U��e* JAr�2ll� 2Wif6Y��E� �i)�� H1�c8tag Q<6� >� HEK293�� ly|A��Mh%8-FLAG�  5nt .[3��su�!�'0 ( Joklik-mod�Eagle'�nimas�7�"9um� ,5% fetal bov!iserum@ �c!5pelle��$2 . 4×108�W_ 3�;(in u bu�( ( 50 mM TrI%H 7C , 12NaC!�5# EDTA$0% glycero1%< on-X100 )e�le] ed �Comple � I�"or[ 4Roche Diagnostt#�3� solu� f^*!L��=^�0immunoprecipi * x anti)�M2: rc$,( Sigma-Aldry21wa�f� e;�)6(��e�s elu�4200 µg/ml 3x E pept�.6Q �!N~?�8E�Kyo6�|�_(Resource Ce ,��i��0�( ( ∼25% )�m!q1) J x�% �ted�bp:\aL)�I�K tart site&~ S1 W(�� i� an"�6m?�a�$�� ���h+�"�/"� S%�,.2%ka�!�ikd�W%�>sixQ�i>}*mH@2�C!� iY�<>��riAS.4�%�6nt �..I�$, ( VDRC 5165�Ba:almf% 10526�&/40478�Z&).�:E*!�Vienna.sM#.2��$9KG09727R�(y�iBlo?gto2*1Stocko)%�^#�w�CΔ2–3I:+se-]�ent% M^co` hC!�de�F�Z?e���-%1in_=S1Aa�ll/�s��+ GAL4%�s)�6#�udy�6����!� haveT%�-�B:%�� %�[9]; b B9A&Q>RVT;w ki*687;M/EY1tY/EY5� ;�2Lm +[40?For qulve��a&�{se)�""2b��re~ a9w1��:x!nhC:KIa�er ` VILO�[syn�ki� Invitr� �4SYBR GreenER q�SuperMi4E2.Bp(Full-lengthm�?r.��<o he �0e����72 hrs�0�!j�"� end��� �3�U"� Q��/A@�ed.�v 2�7&��� �,carbonyl cyaa 3-chlorozylhydraztF� 24�&<a sufA�Q of]! �Ue����� 2�I&�!%us��a�.TrueBA;� ���.�4��L..elt:C$Santa Cruza�� �!ies-matc�!1�.Ulprepa�6ly�=p�6� �6��.y.��om!� in)�l/!\SDS \�1 T>-dr@pes?. A3� rifu�#0at 16 , 000 g�10 mia;s'na�GA�� in|�R�J2x�M� $( 153–70�A6C�.n N-t al6taePd�;2/6x H�MagB�/o� b�pG-KJE8/͑TAKARj�\�� a�0C ��eNi-NTAa�r >glutathiA� seph .��-��1�755�78�c !�U�6incubBy6G2�&� � Coun�of TH-p[9� O'n !-err �whole-m7M�s+of �Gsl ^d�TEM i�7m�"� �Bio�IQ$Research C�� ohoku Uni�Gty Gradu��School%Medic�� l hi� hemS�<�%?�ie�Vi� "�Ke�L( ApplAP �D)�TLSM5 PASCAL laser scansPNF Carl Zeis6��-5 by2�-M� deco�.� 10 i�&��a ��a�.�8u% softw]V�. Area�)V � Q*�He�9D�|" �r�ia�$cA�� �8){�WoRX ZfIA5 J*�he US NQal Ins�%e�H/;� ( http://rsb . info . nih . gov/ij/ <o*Os ), t�6y femalP@�R per�<*r[Vina�! }Kfer�;to�/sh� s,e�sc�A��"�<�#y 4A`5N To�:,is���U!� � ( p<0 . 0}ame�R f )�I9�} test����R ��<0Tukey-Kramer 0� "O%Z� .$Kaplan-MeiKQn'�log-r�En9=<.�QBuruli ulce%BU�cD'�n� ��PMycobsr�6a�2i chroonecrotizAm� s�;dis*!U��i���*�&macrolidn mycol�Dn�QD�?tten�9r�ot�Nof=�spqC�u:�4bE!���5��or"� Pn�X� �GBU=!yet fu�-',st�. Whil*!stoo�YE$$%;VedOle���?v """z ��tra� u�Dloc#śM!f!P�@[cid fast�� illi)0�-��"#�(�Harl�H tra-%�u+eXwth ph�(3 . U!ii�s�Ou�.&\/e�$t4""feron-γ�oAno7S�@P#���2oU��S!*�X�:�al 2�m��1 fo"Y=6�5dw@aAIt�  o^P)h�03 !�fen,/M_n�te�kE_6 micea9!%�!�erAtg��(!���*to��K-�acceleɾ"�Yon�"ref>V�� o��m J>ec�#i�o$#oedemm No� *� 2�V,ig!��S al burdenV� week)"���!� #� lack6��u0)} capah> to k�!.^y6baidue�!X)�'���,dy��% Ci\]IƁ�2�in rᧆ<%x%$�"vie�@concep_Cor vac� developa ��tubercul%��({$be val�"or��. 28(�J�.(6C�?U����,� �@Ab subcQ\eOM�A�e%�^�!"�&�6AW�vAf{T n ru;Rco��2H,�ls 3en��(� Am�T , AusNZia� Asia ��� geneaof! �Sai��at7�.��M�I6���28[(�l�is &V#!�yQvirul+A���igh� yt�Lc0�1de rang� **z#�@3 � J voe��Gfibrobla�_ , keR nocy�,!� adip [17a�Inj�=-�ɥina�I� ��n]$c non-infl�tor^�#"�(o!��9E-"qBa�a�fvapopte,2��.!_�L�#an�|ve cha�e�ZicoAFeA}�%��,�1�0f!aic�5�[�4:b�r�"A� with�M&�(�v!�s"�FT- ,�Zdr�� ", �5�E���s [7–1�Fur��� o� !C.�# E&� l %�G� !� umor)�a!�N alph�TNFα"�4byj�,m�s �A !!R�Res9*6�D)Qe�O��9\-stim|AW�2!�U� CD40jCD86 [6!,� � �e)�20fea7N��.>,�&.R�3vidual�2v��UHHsi'*Q?l �.'-� fic �bo�A; Z�=anA^dw�# �./ >� exY .|%v� JkccA��[1�/"6. M&�?���"��a���ki $e % ( IFNγ�H�K$leukin-1β%�TNF-α�� "�;BU�FTtinnat-�"��� 6�9s� ��0 �60?�Es�%p� ɻLM!�&[��Q�a��r"I3� 2�e�<(mette-Guér�\BC�T��3퉜&J�4��A,ce [18–22]� a*[�a�Q6p FN!)2� Va�u/����!@�S�6!w ��r bp4WB4,t(H�*� �!?� �Q��� �6�&ZAMy �in���N[Z� �dGno@]e{^acq�� filt��g A���. �m� surfac�t?�2L =�8� F[2�O�>��  45IY� art-m�� �PlL ( THjR3��#[�6G��i�`O-�>� BU�\-Sol ��.m�is&F �7 >Gv ��` �  -�um6� c 2� )Y�9�4IJd �k  CD8 �y�c T!%c ) (ANK <��K�e�O�2Vs @aA<overcom)�U3t��J+Pbl}%!� hago�Ulys �?�b:�bicidal�Ea�s�Pnitric80c"NO�I����@�!*# �B-�a [25�J�;DK 2��"A�� irSa7pV�:��a���of:#�bS�cXi�4 ed [r29–�V�-�4�PbyMYsA�[�!�es�b�U&WI|�"W �.��LP��'�a�f2G[�2. H�we�.re-eval��2�Rof bu|Z�2�b Jmpa� "� ��9�in `"�A2w��w�:�chn�#� �`9� t6�iso` �T&�'� arr)�ik- rict�ordŴ]�Ru� �Rw4Y �=� of ASe Right� LTierschutzgesetz SR4�)� he SwdFe8Kl F�SafetypVea�n�6Off�}��� ocol�gr�ld eth: apprYo�WFE |c+hBVau�GSwitzerl�$( Authorizi$Nc: 265�Z. M��kep��"K ��-free� �iG$ EcbGPPolytechnique Fédér�de Laus(G ( EPF�\,2�8Y(&�u�e BSL-3["fAe�R in 83 �h6C57Bl/6>~orI�� z,-� Ifngtm1Ts@a�DA�p @-/- , B6 . 129S7-4@/J , Jackson Labo�V�I{�,!y!�20i3Zm5�iSed#5"�g��p)�eut$pG�A eek �b 4d 8@ !�O)liA�3 r)!�%�logy ( 2I�9�E�9��w)]&y=biEE� repl�4ZiN-��u�2un�! 1013q�u 2010�aqm��aa�pat�#�CU oon Y/�X6K�te�q!&W#%�:mby ASL�a!!��=�C"9- W L9292+*#ues�mѭce��,smid pMUM001�+)�ռe��5��'a�Cp<ge��bumA6�Bac/T��u�g!rieI25101' ,�5��>�#nd dil<4��er�PBS z`����%=of 125 ma4wet we�l2�U*.� l�N2hi�Teft� t pa%530 μ&1ab�1 x 104!1���# �e c>4,573 CFUs�n!�!on 7H9 a p��saKf/��pr )�D-�"k.�5:,rfj���� �!�l4A3�P A�fo-�Kkn�<oh!i�N. A!teksB;,�kN��e�tnd pi6�mfe%� re t�apA ct ca��,WG-20 , RICO�GI���$ask6Cgr�1��UD�ql loada$2 /real-tera;()��a 2�r�(. F�de�%�1r `p1�2�m��M to 4 piec�0b a�#lpeidm [� o hard�gr� � ub�SMK28-R\!�[ll-H3 x��s��5�'rp�9$30 s break�� yD+-�l! �i!-n��Ae!lr�K%| :.�!�('�I�8> adn21�<��Iy��2�p7P��@7i� a� 9!L���w0:�|� 1/20BQ�w��),by Lave�!Fyfe [�_! �ed���!�!i�a�ɘc| IS ) 24�yiu'�`.�2 j �&T"d_s����cal��acq %� Pst�8curve2�%by ��O�^T.E�5zj�effix�;neu�-<�3�X�&�& ( 4%!(maldehyd�4S<;k- T501128-4� !M:,ou0$t room tem�A�m^!�1in "6 MS�Ba� er-LH rhghoB7�� ao,%�e"xQ^A�� $b�\�  3�25)!ck&( ��QB? J4 a�i�i�a ��4Y e3K}�Wi( out�l�z8�&�Pall 4=�sC� �%e v�[�x9 �9u1�dj�t� "�* Uis��)�(Dunnett-Hsu������globaAjIK,�%S�%��oX -�G In��first a 33 In or#U�^� �."�jif!�<'16"��( WT )�;yhc� �Z� z�u���p2�l&� B}R�<A����.��*A�-�1��"��dla�(strQ-s/�Y 35��85e�< $AC,<C�"h�mA��WT"�B 15��6VZ, �&+L(O��BhS@� ? �am�.3J��F GZa.�(*.A�1|���w.5_eY��o;&"� b�@ ek 86zH�=�gM���"�lJ�e? docu@! *L'.�E5"� R!�7�Eg ��i�Q )N!�-�6Dv��=!!o�"E5A�M |";V�K�"a�ic.z-�� z ed r� /#�Ig2�IB+�Ş@E ��6$��d!�� ig�"�&F�r)�JSh��B�Uaf,1k2�"R��+��m�+ ���Urav�n�is.+2BHZ�.i%�A�"���9�� &R.1wh#.!3�B{��&^[ g akf�!��rQ/byF�,�/no�k�!�i�%gr�%N��)�1��6�in�gm�)F2A)2A�2BB3��!A5�m".ma�~o>�-A� �nC)!� �R� �B�(2B4?2B�!J�]�Bwy"typ0hallmar��BU�� +[39 , 4Z(6j�Y qfwo.�%XdevoiN�1�K�A�he>p>�Vza�'er�lal� C1[�#$ &� �i� otpa�thz%4!, m.ti ���edB�V�[2��3Pbs StriS0�X6���2�ly쑠�!':����"� ir3�Furc%���(�%JQ)K)1�%���~i ( 3 'f")�j E�in!u�m�,X Lng#�# q�*X ~J� q�A.� o1_�4&*e&����mi- :�|X�G�A) Y� -�;mplm �)r� wB ��"*of�>��ZN��A�ct AFB"� 3E�1�, few,�uI/ p�z�X%�i��� �BCF d 3Bj�v � �! /A�� 9T1S�H&�a�5�Q�!ס���J.*�aaUCa�o�s T>�)��b�S�9e,intacR/�2��e#'QEs6�(|{�V��6�n��)�D�oZe2�bZ\C��3C�,���;!9WT� ��3C-�C!��B[*i��)�� !�Q��{b�  9*�,�1+E�� mixQEi-%�V�QN�t>Xnw9�:�!�Qx��be%fKE��e� ff�qc�/bI�A a\&� kU�M��AN9J�Ys&�bM��:�S2U�TDga�'2���e� c�u�:[q���sՉ�-6�-� wd'�by � miniZV60/* h;I'I|A*��O�2ng m� ra��Yr�77&hk!_sI�st6_�7�AW�Nv� �a"- �%e)2�B;�gW$$N�.Ta�l�2ab"�#"?' ��!EUk�3���&�d 6��D�%)��� )��K�Iq��^ti��`0V6�d�YBL d�+K9"�;٪�;a=;�%�CMIx%�C5 �i,%�!���>�bs . E�_=�;�%��w+�(f�<�5l�j�_!I����pXw��v�! *�6 e@s�bAz� "�9[4� 43@How� 31�aj�!L/lo.�r� ed"t  ,V'@>�..;�&�c"8%A�85k8�f� tu�. U%��W� j 6(7 za�&j( 3. !��BU Ed�stI@&�4 0�s�:EAg(E�)  mpan;,��e��,h��se3��D ( DT�$�WP(4�8��3 M aN145 EYa�F��r~[@(l�&d�/6�( s [4� 4d/5IfP�(�^aE��>]1!OU5K|�r�chTM bOtc b0�H!�"*1��*1i�60�&7�u���mieImGeaeTE�e��/Aji�Aeu���� �s _2� ��2(c*/��E2,@U���%����A��.,- !�%Jb �_�=�A����)ly�):�+r�gA~$�)�Z�*�*. NtWHy�<clu�?�#8�H key)�"�AH�X��G!�~� ���a�X �h�7yOe� �a��&�@!Cj eJ3�,Fgs&�E&�Q"u�?J9*��6�)�&�,%�2e tq3�g=,* 2 helpEԡ�(!�u�Q*Kh 7!�2� )�E�90E2�V!�%h]�q))ftcjH%��� .� ower�9BV3�$-+B7��e�>(� e �6� �� 92$:^;"� �5�axMeK!L�5�Torrado b&wh\)v�(!107>��|_5m�; OA�NOa�=������=�to%�b�6�p�Ffe JF`c?[�3/0�ev�)�-A�qc [51])��{ 6�AS0��|F��v�0~ )�;�!�+��2�2�E��A�ononP �:* *�:l: B�HQn �a%�i. ca�-�v�v�"� ~ -N �Ze��~on���C�@�Tls�3% *�2d*!Fof!��qaΐ�BZ �&� !��a0 ':=!�9a��X eno�� �major��t���r"Aa�V�)eceim�� �A�r�@H"m �oA0 ���!�"8Aq�w�.^H92� *BU > Icv�G%D2ni� HIV�li%�vs�HhKI risk���Lnd AIDS.j�o.l:a&Lp�\�A��{ -�BU [5�a5� ͟� %*IYla��b6 �$A���5!!+R3�# '.�l!3tas�$us-aua�u�)sKa� 5]]"������2E<� �=<27�a�J���.o�Fede��S .�Fn�8I�h�A�aro�Le.jF29mFaJINvi��"�@!�  re��e�/ibA�!�j!� focih�sJ�I,E�.�@I.�:aQ�01dnoc�[aH=A�o)�T��si��h2`now:��"ُf� they%Z_2BAs9����P2�9A��Y 2���!�7 ofMH2wDofI"ɧ�%,�?n rbidaz� disa� n 1!�cos� os ll�;[lr�I�"� of%1�Woxy�;�a4RO(2qQi*@�u�2�g��-~#�K���� �gpJem%m��Ag great sck.��"er*M��,��`K> .1!k2,� xiau`chvWF�E�is� k>�s�QTo� h�0Av�+zE�KUdetaijK$�"�D�ؗ�u# �"��fͥ+/� �IE��������uII��-�!:hundreC" �equ�sՐt e���i i��an!K!�J�mwo/7ady�X�od�I&�u( b��m�)|^��� �Cenviron'��&�>. Varc�% turb-�codk�8�E"h�2y�/Z)b� mn�E&�$5N�xEI�=�Qcs�= ��'pi�_dT��I��qL'P; �!V�Paaxa5�i\��~��)�toZd� cy [�Mo"��S;�ua��CnQO�eS�~� � theirV�S ��*�~ ��� Q%�?�Rw bas�Oa1� s? a_� leaED�� deat�`��9�V y9injury��mgaE�)SK0)Hwn ic�A����/�]�,i�� d ��F&� �& �!�r�3�\O ɄGH� v�?r!ure$,&� �AJYp�Y�!q��nu:��v!}!B�In.O, o-sM� quinYd� o�.� ( Qo�2YDE�a_�r6Rp dXeq#gW.on �e�A�, [wT[7�c�Y�'� 1f9�a "�JSof>�VI��(CUe��� pG�aD��l�-u!�&P7yAB-#� Q-cycle (8�n�( Q� 1H/]"�)f� m �@2)A��w K��� .' 6v� [8���Oas vn�9�mm !���%�|�cyA�Ŵb �)"]two heZ�&�z#Չ( b�>�B� midp`,&���Rieske%���y��SsulfuQ���[BFeG,f�c� -͝:jifI�u��  ��ub��a-( QH2 )�d���q!nA�l��?nA8Q− )��&!�em b��a=;~reffe as SAk!Qȃa�!�H+�6A�!s��aOM�� �)�.=t�?i�l�hi>c(�GF lX: a�Ha��; N� 0M��=-aR��u� ���Nqo�FmeAp$ � �) bH>���[ba V�N�d)^�"�l��@�dQ,��L5l Ȍ –[��. S] �R��4I�Tuwo�Zs9E�BG2diG �.�, ���*�g trixIHIs ceivu wo5�G�$h)D�; deri�PeO��woeL&Y�8xabKyAD*�!&Il5�e`s2��a�1%�1�m �!�m �a�-a��h|`wl�Red Tnd3�%0a�y!}}8� e �7 ��' ��k��H!TF�F~�q4��aria�b6�=!�oo�i� a�theorYhg.��%�Z�4*<c2u!8�:!��!+�6tĆfiU8I�" �W te �@"�"�Jo.�xբQ�Ao�Ikv��� shl ��MJ���>unaN�� �{"� LA5� :�If�xZ&��&, �nlT�4e j@�FA8?†��oL7>�MY!%�S.P�al&ylAi�! A�- cc% b5�2^:� ��l�l�e � �MQ/�I-:8d��� "�S d� �  qS � �yp� �I�b�?!�F�A�out�! PMu(���T�JSp%cV��Ma�Ի��V� �yA inheWn4��`Grincipl �-MnB�u�!BGs-[sM�8r�� �isotop�{�iFdU������pU_�E�7!5s �@� v[ A%n9-J�i�_ !�pʖ*�:��7W�!y�DU92��� si�pa7!!�;]H�� � ��y!1�] fES�!MX�ye;���%� O�]� �Gha1e~�� �:*��q@ M���AUis�� ae�TW� �N�/su�e��or&N�avail P er<!p^{Ap?�12a�behav��N c�5!�d�&�OS.;J��� &Y��!�aV�.�|���3atA~Sa`�qu�[M�ϯ%�aM�le��>!��N�2�in�T�"�!Ng�o2x&�:ta4�Ō�{at!�!�a��#o a��2@.�;� ��:qNu�"@ �Q I�ee&I�.�n !^�C�%22j>5(�C, d2 T��@e���|!ick�Jy!���s 282B24 i� ���%a��(3 �!/; }T2o-�%�ga�$�Y�#i�l+asJ�Ӆ;_}!uF5����'>���UI:aI�a�m�>EQ3 �!c�FF ��or)�SQ1:(2a�W�*%�9K��ly,7�f@b � trigP .Qv n�d^ �,�SSA�)�2�3�< bb� g� ��Sv�3A%�AWw�m�urs�/ ��!�SigF�*]�/n��&&�V ( eq�Ht[_8a�"�1A`9jQ�2�m!�6R[J=�A�= �Z�%a�#eaǶє��}�N��bm��e|�:�.B2�0AAzj���7 U@}�ёDn��O�MFl�)�m�5�9OAE�N�!�& SQAy���qJ�,FQE12G.�� .�^�A!�&�J�( of Q!k� "��!��%4!c�]Q��s&4 f��wnot!�!�*��en)�at5�ABA\10�f�I&� ))Uc#2�zoM =��J.>:bL" lC*��alrev�� � )Cɤa��!�u z"k$:epo�|uu#!.[<-�!=�%O�M�:ɍ��� ��h�"�|s 3�3CAɟM�]�;e�RgQ�it]�)k�]څ)^%a�6(g h  c3Nhreshold)u�9�1B�1.*)�b^`Y�y�a��E�:�.�it&]��J ��pE@�k!a!| i6>a�.�ms h��"~.�" Z;�E"Qpot�&Œ>wos `�QA�; ������~��� ��aqDPnguish�Z�of�00 mV� n#c"�\+E��40f�)f.M-^x;��j1f�V (!���U�"�.OcDPY�.�M�3,��$� 2�.���EL4@ow}YS . At %ZC{V�e s�a�K� � � |$.� m9.88"�A�"��jiws S@S4T �A�A-3 ��2�*� �E��AGr��� f vi$>!1eygS5���F�ux��%�>p��Iy#Q!��'�el:�Y s�; mio�8awc����!J25�<'if %�8���itesibE���>m�\�8,!&$O����iIŴ!qI)l�� by2 ոE�3%��to !&� a37�p �!�ak&�SbfU)�y�'��� �� :���� 1t�� o�T@%o� back�6�B. E�"aO� h�UIleaA-b"%�6kver\&Jf(X0Vv�>AsY�� N�* -z�}"�!��g*JG?uS�ZB�0,� {,/n?e��%iqeII)�� ,A�E�\ s� leE!�6lk�V�#p-�/y�%�%�!����!6�!.�".�]���4d'"�e'�<4� u"�:ratʅ2 &�XK!&s(�L��6!� ]U%Z�s��( D\t�y$ “ros”�\���,�]�nI3c ���$is rapidlyJne��to ATPU E��2I�6��5 (� Gc�oEDP ��)en}k!TP�&L7�(J�(���mr�seM��Rasa��u�(h!, luo��P� �m�.�&33a�I�t�)�(A�rb!P��,6��)�R)�B�J J�o&�; � !�Pi�t�>mp)�i�9�%:�� mBW~���M!dU��8+"j�}) Q�"m �(�%l�*��c��Ai�2� TP�!��^+Kno�(� : >8uR�包�:7(<f�L �%*� 2)�OA�a� � �Hay~tr!�9��a�c6�mus�2&�8B!̱+>a����'-�ɐ�ktha�at�7ess`=ɴ�Ճn�l� ���G.��hgA�Me=�2.�!��#��Y�si��"} �l��m"m5adm%�hLQ rwar�*�B��e�S2B .Y�I P!�,`E3"10�*BFADH2 [2�Aaaor5��q�{%U��^Iv :�i!k���$����͆$ An*j ux� �DI�V��#7s.�"�of�6&�l���1�Źc!x�ja�tD�u-y&��-g6mfal�0o q�j 1% O�(A>�[�,[(~�!�9�2���Ex�%Y���� *��ra.a&n�vfi�iu�#&.f�"I�=-�5�8 U�J7�&89n�junI>4 ���5�r?���":�._�aѽ7���! 2Qt��ld"�2����"l at 5%�[~�[/�P�AA�If� }+� ͓nTBe�cA)��M;2������ v��;B :qk)�4�<�$1X��%�� b'1�$M?0J�$5;.�7ap)����( ���=*�q��-*��)p� uQ%�l��Eּ �\=$e��. Nota���!$�7st�ffl� �%�)�E thirHa5�=� V��1��+� .�ope�7�.}m5�5bi�"A�9 �2�Y�)J8u�9dm�� !�)�m")�6"�bo�.e&d �&� �!1(-4:���U�ua��n-~�g�0e�=�&;!]6�:%�a�,"6�3i�6l�-�Z�69�o(Qmi��K#�&>Q k"/>�nA[ l,Ae���2���wl�U."� 6� !0MSQ2Q�,t� � �A�7�8�.�/� oB�7I�+CY�6zU5f5KA���6ECZ"R��Fk�� ��I6i ��;>� �:crv�!l�e%­1:ap�w N"�cK2��A�-�>�`"� �M�ydn:�A�eR!R������"��KmE� !JQS9a7lC .ss> �H"tar{*o\d 8.f%����5Y ���O�4��hbE >{�@+<�K%!"� if2qly>�!��.�L ��e�2� �:it��!�%"E�t���5�J`��*�e alg�Lhm�E��/ e�"�+"�!�+ 2�� �|2m,�D���I�0!n�m"oZ&*�^o, �M�^& E��0� g��)G����y�a�Q*afi8��� �s�m#%8p"0"� 2� 1XceWg�-!_�Q�&M�e� episr*"�C-�9�� sVd. !�2��6�-��6�.� 2.vF��3��2r.�m!�b� ��-%�e[1f+�!�biŶ͢E!uuu�e�li!�;IH F�X� :o.x�;�oWO�� �( i1&ei�60!6�=)Al"s2HH*�!P�JbHbL ~E^j�]1,���"�7>FP+A�t�W!t 6�/&a6XT�dU�!ea��'���e"O�> 2\*,�B�: !,!/>tnd N/�*�e,2�s>�3m�-�6yG%���inm�z��by �-r.uBl�{@&�L"�B;��>Af�9܎�]#��.�L��� ��t��2))N� �QA Qz����j mť}il��V�&FR%'S#q�U"�.��&�љ�s/��*��"�II� ��A�1-6� !�O.���<).�)�� �yņ�.� � alam}y� ��A�E��H ] ���1N6�."���a@ou P"[9��#� ( a r�?l�(ك�d:(&` !}a��Pw]X�!odP���!OA(�AY��e��0 c� vF� D�� ROS;� � ,N"D[|�5ew � ���n.�>a�y-�`F�� ���&� I?%TveAH�cu�B�n l.JE�A�bi*�x:f�2� !c:V&1�l�V}�!a_AD�n�&U� B!�AM$ dea�kY!�l�,A-��ng!o��}")adeni��� [��&N>�= �m gQ�*� tr;*�,U�p�Ɍ)��>" s "�im�J)�Yc� *<Rp�=�<!�7�0^M^d o��L�(<`t��e�@p1XSV enzy�3$[:� 6~� W "�P� a�"8a��2�Pfor a�q different area of investigation , namely the analysis of stable isotopic isomers distribution in the intermediate=�Ocentral carbohydrate metabolism [17]–[19] . Thus , it is not restricted by an �Lmitochondrial respir Ƞand could be further modified for applica� s in:�&instant �a=��c signalling , which requires a descripj!qmultiple!Ste% recepto�,lecules . UsP thisj4hod will allow�expand )e�$el , incluin it�o% parts\electron transport chain):-��sm�4provides subst!�s%f�, AYg,that defines 8membrane potent!�, etcY !{proposed�!of9�3equ%�$s construc)rpen!�new dire !�mos� tailV(athematical2�Dcomplex bioenerget!�$ystems . T5xsimul%��reaks perfoa byNIII5Toverall!� ress!/is:Ytwo5��or+ “1!vU(n!�For�tance ,!A"ry8001;(Kdecimal3P)� Dect�+^)�4�Ha%s"2�*a)]e PU��S��c1FeS . O��IAh'�se)sge�%!� a�numberU���s�j�B��z)�Loccupa�$third posi�=(!�re��w0 )AA?)�^u�4hQus!cha eger��wA(pur��s:!Gde�Ax-2�+where n jC�is way��Y�has 16B,m� varyl)�000!Q1111;M�s��!�(��have 64Be�,FIK1�8,!a` ivel��ie� �256-w �Ad�T�n%.� } � 6 Af�!ihaA)� ObaF � � lgorithmm/ref � 6&� betwee*3 �X�Pccord�t; he known4 chemT mechanL ofJ/I�+� . As!�sA� ly shW(in Figure 2�$�8! � ��C  12 typ���, nine/� )SA�ea�(per Q-cycle%�three��s�Njus� � � th2�8activity: super� an� a(��O,� supply�� succ�� e de+ogenas��A�c� � 1�] LY � I2=�Aautoma �G�e��on &� E?I�8 icip?�QceZ]ia�scribed,� next . Rn0�A}e firstYof%boundQ���va/ p- ,��� ) �o Fe3+@:� !Brelea����r� to%��� sp�S. ( 5� ��.� isUX!+�>)9mo�>mC A�cap�s �� i . ��!�aA!wsiPattached% at Qo sitI�A[ � � N� �  (terminology�|-� abov r��Ds bH-bL-c1-FeS-Q-Q�qD-"� writt� ��s0 5a ) ��xk'�y.#!"a�Y��0!�1M�ex@ #hP 2�a�r� -� masse�on lawa��6:�pasEhr"� �/!����$, checks i� I�o��  satisf�  me� ": giv~()*(��mla� s� 01~ ,u��4�e���^A�duc�VAN �`N[10� * r"�d as x��%�r chosen�)��n.� flux%=!ta�adde�m1�deriva�)�g^3� �=�  .4q� also�Ea� � B1�)Morgane8�� �<�6y .zo� !h0 J� u', Qi-Qi-6M o-QotNA!%@��M�imila� (%S��mrJ!w A forwar��d reve>a�aA�!/ic��=�d! Nu o midpoin� � "�a/Em ) eo�b� ;�\ed , F = 96500 c/mol�\�FaradaN�, R .H8 . 3 J/ ( mol×K )6ga42T 2298 K$em�Y)WQgi�%�g12J basic��Y.�1:Gq�>y� ��bAcan��Eq�:�aJ��~ ta7�o��E-%> anYy6!Wd Mq�}�,:%=.�iUBE@���c1�41AN[2��y c� ΔEmuK*)��ult� : -�6i- ~�*- 2>secondY%. oAVbL:On�-�)�o�d"?  ��F�!q81�q� Em ( −6e]!CbL [30]%S−14Q/Q− [ao)�=Ii�B��}2%���e�BgtoV��=25.g3.g��i^bLHbHaT2Xq@bL�"� bH�c>29 ) SiA`�.e �mov� �*� ��ve ouF  ne�ve`&&1v!E.depend, ����"gur [31] .�� ΔΨaE^-. H��FB�a��k0F)�^y.f(J()��U��d#−58a�>�6�HI�� j 11� ����)"sEUe� ordRREbHsQRn-A:$��!k�)m!�2��ne�� i� :�+1�� bH wea�ep�?�8)`��Y�:;!4�-M�#Em�xy �9�Z3�45!�[32A�To�rW.|�%��is clos�EmxbH� !x�51�.�2�b ��l.�5.�>�.���R��be6�1�]co� semi-�onQ=N�` -�:�!Y-�−  data��litera4 vi�16 . -�0%�15-�>�aUł�"w!�� acM)!x)���v��U�l0L!��cir��.�a8cyt�a[ (�r)a�0��i�� ���f)�-�:�6� � ��:���%^�9�e���r i�!�R�:}r\12� Si ��%�g;�/2OK�)� work ���ls�V$��belong� s t5��"�hangeL !�*� ofZ4d"�!6� � �+!�!�=j�of2��]"git ) ��mCof} E!fic>B��#"vBg���)�!�B�<_8�&;5%(:)�a��A'Ga�ssu�x��Cxxxx^  11Zn� Q�Eg��Kd  2 nmol/mg����,7g#m���ii��2�MJ��e�a�hf�ec9Nc5%l +aKIn��e�we`dECEc���U�2���f�:�����4 )&�9=~� ss�^���}���"�1a�ROSA?aDa�e�t. SBg-[�>[&* y��%a��#�u�!a "J� dSF� ide�as uni" alEQ���r�a�:�kwal$tojKis�E� A�leg to��F9A�S"���Bin}Q�=ul� *] \ %u( Qc�gf'OV���P $Michaelis'� D%��KQ�'!�5N+ , KS$25 mM!ΑK, V��88JE/��A�S�external*�2jşP@ ��-�":!{'V# vi�n a g�&al��.K)goAK�"�a�����9�2 . E60( .`&.��.�V� ll sh$�.$ntT*� ��r�':�� �� �fategA,s�BA� step��p &i ��1�-',Ng 2�Eo&�O2A a fr ��( ssol� @�!� )] T*librium +atmosphe� Cat nor�"*�, k|1��`�(# Kmu1� �� hH eseame w�ad�Ta �q�s limj$!�o* f�*byc1ǁ�fexperiKa. A{Aԭt."� [22]13!�5�pi�(�� O2 availa� unti�% �2� fall�#aD,ut 1 µM ( <�W1%Nt)a��L� �#K f K�M:03� k�� 25 sEbzu a�%&� ��eR� ݳr�M�EhA7G�g 5A6!<m$,t�. Cq�II>is 4J  [3%��E#����.isj<Et |+�"� iala�1&~M evol�.�n�kn� C� 6Y ���a�� p$!BF��>. D"�m*E  �5�X a su��l2���inB!�or ef ��/�� bq3 k�e*6�"�d! 6–��� �:"�����$al fu6,{, !d~W-�C -��i�� �w$��� ) a�h .� W-mit; 9����Am,Dy�+5I%N#� it (��*� � )!�f.� FO�ag�r ż,A7!Jc#E� 6�0or�m-!1e-Y�WF% wh (�1�sb!7>R%1��8�g�>�!Bca%�/E%gJ#� ly w� 5Z.2(Ell 400-�%�E�"IIMy�num��' m�-Z�2q�i!<� s 5thRl Runge-Kutta , Bulirch-StoerAmplicitBR� bergr0s [34Rw �*A=brief�r guide!fh �FlP http://www . bq . ub�"`s/bioqint/selivanov . htmD�echniquY�E��m�'�  else� [35��[36� IsolYiat br��... -q,procedu�2involvEHn(+s��p2YBHChildren's HospitalA�$Pittsburgh% � i�� “P&! of LaboraeAw Care�+!g!�cur�4lawEUni�St|1. RV� �% .�cortex~,adult Wistar$  Aftef#movala�issue �m�L hom�&k r3ce-cold n�@buffer I ( IB I )�`��ained: 2_ mannitom7p sucr�,QM HEPESP("r to�3��KOH* M@1 mg/ml fatty aci� ee BSA ,0M tetrapotass_ EDTA%v$12% Percol�A� �{ t� ob �%carefu�lay�[ he top%e��inu�/g��ofg( 24%}42% )�pa�usA�N�-Upr%I�!�th�#�4 ifug!�t 3�*000×g��10!� A"� ��1k2)3a *�A��1&~9withdra *y� y0�#was�&� =4twice by pelle��inI4 �re)!.�Qs�4Am� dilu�A�E�-1IQ�A��5%Vas o , ex%*! 6� ofI$(QaM )% lackalbumi�,!!spun d�*at�,b�de�C.��M{qiaKIQ a fiV�B�∼20m� 1�8ce� us�(A�VG�i.g3sa�rs�d ma�M�a P 4Assay kbPierce C,G �20, Rockford IL!M� !�� manufacl'�"�6��M�m �$"��� �(at  * t 4–5 hN5��A t$)A�y!� ir a to a"A�:<J -3S 1%iz*"o�Hyd�+�$�a����&��  stir�cuvetR:56 �Da Shimatzu RF-5301�trofluoC��maiɍ7°C .6JI�2M;LG) �add����cub��med�G��Q��1�� KCl;U M KH2 PO4 MgCl2;��M Tris;��M�����O&0kEGTA;�pyruv��A�parti/4r�� ��9&g- �05Ei� !�N�R�A�%Les[ dy>+ H2O2eAax� ����� incr�,dBa�ph&xi!�!soruf����)es� !�1 U��4of horseradishA$Cse ( HRPaIGev46l.�+! MBh carr= �at�� /emi~+( wavelength%O560 nmq li�nm ) /59.3�} �l5AE�J%@r�-� �pIt�=�.�.�'ruc%�ca%�+ �4�0\2�Ga�� nd)iY��/tow4��.�Ae!b, but!1. ( . Normoxia*�M :� conv�;o��squ� ( 10×a!L,5 �i�. Anoxic�Z 1�a narrowS angut neck m3i]*r��mad� bubb�=�.bN2%"����deple��of",�aTi)J a Tefl�-id� esump��of �61�achie� �<K{�!��dir:�lb�,�#m -oY�I`� ce quench�;E<ic�%safra2 O . �$polar��2> have!��$charg�g� ,�L4 dH^.kAO accuI�%E!$H;A����^��2*X8� 1�>d�Z��@Y2,corkon Haf +$em>? ex����%�49����n!���586��( ��5��#�F�UAa5�ƭ7All) �2�2�22 � � early !uy/.LDrosophila melanogas7A$a powerful��ts$ud; rolů��op�>�m��)�gap% net� A�8� 4 zygo�@re��t3tie�:%� hierarchyAB!�segC j��e if8.| , of body?� �,�I�XR , �s-level`Croach! &dD�effp;�)w al9 hucke9 ( hkb�n&�" . Wt quant�v"�-�j��Hkb!��  en� ue�GCexivcircuit)�!G1� s�n2RB���gen5�si`�/mpu)���ool�ext}.2in�)�;spa"4 �AViD8.f*4�!�U{DM� in �(+���-=�pa&J1predict- �"Q�top�5%��8 howE���B vari{  %�c�?e|8a*�E�"� @��antly ima�m[bi�� releva�ȡ_ :BncuQach�=Cdel)�� gre� n�Sa��!L) they!�9�wo�ortmF�ects: Fe�es%O A�!�}�A�-�A�mNpo��(ior hunchba�haEdo� � " %�pny�%es 2�. S-��,��$�@� ante{shift�� �bIQ�H+�)i�� �4e�G rrec%�n �D%w!�  ,Y�u�x����Z [ mu!ue�B-�l�ZA publi�e@� unF[!K nulld����;aE_e0 ��naap�%P}�]3�a�5Uq�sE�sFe@Aa� pert�%x"K.� ,�( n imQ�. to�0�(bor ,6hun�,t�H bd� opłXGd&��.�A!•#. How�4s!-* ���ϭis : zc�al� s!%0!�rn:�i�� TE-M�<qu AX7b>add�Ge� geneᓁ1m�Iar�(�"*G very&7# ese.,e�s�6al=�lim��on�$ic�"y]/fe�+sm[a "���a�pa�B9a!1 eeY)w�Sqv&lwaysIvre�_��ambigu�"�AY���s �$��[>0And�l(@J�e{�Y�� g��_o3&V�+suffic�*A?.MkС�h�Cld-typuC[�,ItA�y8toQk �e�6I�<kat helpvJca�v=� -1��.�FanUC .� toB} ��a32�A���"w����� rigor�A�2p �eYT n wm i�eF�of.z ."^ � !�0 �� �& casc��Wle� !��I�B� aC,�'ajor (��-�q, A–d, axA�&�Gb�oderm`g�� shor��bef�` onse�_ r�) [,![qye�v�pair-ru�As� -\ty%�AD!�l� }Ea0�(e--�!E �Qby6��6.�I�sFv<, Krüppel ( Kr �'gi�( g�,ALknirp� kn�J�� }� broa��a( lappa�? �R#Oi��)��. y�!�R�'co-E?H s Bicoi�Bcd�Hb Cauda�Ca( kew �[5]�/La9i� ΁�-f ��3W�n�<�8�? gap-�s-M�E( ���7 �*�"���L,e weAPs =� "�5m�aY�!),�ge�O aill�M( tllsndJ� :6)I��6o�� focu��| M��J.� �� 6� Mof���y�reg!C3�� ��"� AuI�[7]T�1)�inj%e�5O�ors��!7MX�uE 0"steE� A�ca��:n asymOic��ofU� s�2��t)�w�E�q<]�14:�8!�:�=:hb /��.d�FBP=2�'eUof Hb'� = neighb gt; GM(=�N!vF-�:�71j� � ur�EK��I�,�TsA�Fks n� �!$ir=&���No at a�2mM��:�eJ�  ,*:H�)�Qthas� ged � .�?or� �U�Ode's [&�<&�Hsugges�>�)y49�pl� a"k q�a3 init,5a�}�m�6�. How%K, BM hb.De��me�A�po�Un#k t�In.� n �� �AA�kG� itself1da.e�[10Y#�� �k 9:bym< I � �/� a� &papI� �\a���$ —a�-dr9E� vVaO [11�[12]—J� %�ahkb)Eey�� %���t)1�9*Y�yJ��s�&WU��q0O)!��2} ,��h.�f+(�*1A�We��,OB&aghkb.>�a7gh� "MXGD�DaaL-U%ss�pipelin��� A�R�@.'5ycl�l ga�X����rai) V�<�%B� *�����&8Emb imag9�ac�X!���fo�Plaser sc�$ng mi�copa�d8IH"a ��appli>V&�'!F�aWg��2��( nucleu �c4 ��sor��0� cl�H—�*ca��ab�7$�/2�:—�QE6Y!omorph"G mark�=@K Non-���gr�.s!�!ri& (�FADy-d a!`�01�E~a��c^I�\7a�is yiel� �1Q 2H7 -ser-U}L"� �fich� 6��0val�%�aS:&���XFlyEx (!a [14��5�E�8m)h^X�� �9��=|:%.b{.��v�0; r� a�MeqZ�&3-).m��?�s�+h!ess'e�Ż81s�+.N���i�f� } , [167]�0&� �/istA�a �A�iviT$e4i*�A��6 . B�&4ar E����� syn� ��decayw inW.Ge�InL��K�� � "J a,Bi�i) �yet s(� c� ma$a� ��6t�O[23!� %��orp�*@ fewA�$W�:p!~s�$eukary��$�]�^�ion: R   inpufto�KigmT9�-}c"��A��"a`^h \�?&7@eMZ[ v�sifG"Oabsa�("b?zeriZW �"ab")%ve B� �# } vC2� �=gle���Vor� 44q )�z0s�-�"<�-+ �pu� reMC+ � 2� 2�("lP�|K ��! �&;>s.P��g\:,.�;a%s* ��5niA�c 'a����",.�E caz6- %,s;"�B , lef?67�0A�Al�-a�eT"�deD-+i<)q���x.� �� ��2�5*B�nM��no�7�Fy����4 �.�9Y("�!}:KT ��� "� play��/T1) [24)A& A��!l(d| rti�Qin] s�4wj2� —s�*a�an�K�t6`�4A�s�.�C e&� N�M2 �.It�"�problesS!�"!�)�(&�2�A�nd%�MF!D�s)�&_*Y 6a�dN56�3dFi&�e��i���E�A�B-E�!�X.S� ��� N� !Y. To av��%�5H"Ya �7A��—�!int8� =�—)��Jse1�A��) ime-��eV<�g �o�E��:�S��-ru��S� #D.�R� :q� )�g,�*mX 4�. _ECle T"KTMln��)&_�Jah_�r�;��e|U�<�� F\ msel -��@�)X_B� t%a%ddid��!����-!�� s �5�$6�2�we �Ie���qdY8E/n� e �!Y�a�1e�� �rapidlyw'ng� .2�Q%�)�� )�%�a�cag �p3t�HYd� � rp � �. A �s�`%P,�$disappears)p� R3!r��(� �strip�%|�i��a home& ,P4"�KR�"� lI i.��f&Xad5 y.i��Ad�e�is^na �B� ��)t6o�s6�ii7�,y,[kS�S8�O�"�h�s� c6�P<.��!�62!�%66�a�summar�ui"-]1B�EP2�=Zf� w'out�d� ve*6re�5 y&��/ory��er0 ons-�A��M�*�sl7�"T !�_t2%%�R3r*�by" AI!�hei�>�0.��Dinimisa���stY�� m8/�� Yl�4.ma�.&8 studRNQDJ ' c2m"]0= .dw�A�_WG�8-�)!]��� ddi�" 3 Z�OLS 6 7�T �&�N.6�!O�pr�g-2� cer�ɡ`� :�#err� ���f�E:g� A��o f�\K-Bd.�mw� � me�� U0���0 devi�F�+�{%�cl�&yy/ hold� ur ��,c p0Ys�g �e2��card��U�S��,uRG�Dl<F�A$[!sm�<r��B{�o"+G~a7 a�{4A�-{l��negligDdin no&�nga҅!�m�G[eU Vb#�4W6%�littl3 � .�ZM �T'x ��m�s>M�w on�Eue �X� iD~bym�a w�3 6H( WeH6Jopt�` �\( Maximum Likelihood Est�2!!�2�!3�eE�i�. "3 �A��io��q �!�Wnrdx+e�sB��p*'s�/!�Wp�[��m� word�@� 1��yo-to- 2c� ribuc&j ��:��t+T�E/aDT2e�� �� &�-comm;�*�X��� both��!T!�f@�$m�2cG�fdeU&� Ijsui��-nR���a-the�K e� in p�Vc5 �Q+!�%�{a,%����&to /p�'�+�jgh1 A;B(� � al behaPWb��q�a�%a�Lrk�,��2�!<"/M""�'%en2�(a� h>��P�*� �Kf&5., sharpev�b�+B�9ar ?��y3  Unab�U&y4graph%Z exam�eIpF5,6 ��%PL? �h�n�k�3ac ��*6rg]/� A���A9�atM/�WB: "R �� testa'rel�my.� :�.=�5t� ,�)� oAU��I�IAd"��~V �c9txCa confid%EsvaehVe�P�"XCbch.A�a rS�^m � !itrue >%X2� l������MZa����!�BlIe�* �do�6 �8+=� cate�i�R‘� �on’ ,hA� orn<)"� 1!9��Tll-1�ed� ��a5"�Fyh����,F�y� jc� weak` &�g�9��AIt��hy?`��Q�e�P�+�/at�� �sM �ot�~ i� usual�uBH�K�DsZE͇�Naf�zs8 yQ"��e��U9ena!�;a� J�� z�isQ?u��!�szN� a A��a5� aly1Z� �$a$[�*2c"(+W�enssB9�46gSas:���vg:�41�B��=-� ��M �*d �%���ed.�t��a�!}��) � #�B>2 �We +wQA"f KN" � c�8�(.�Y�%�A�e�to"�3 �$s*�V�o�t.��N��&&#E`�1J�$�m �|"W&��i!�>�q_�t <3�a�!��6�R�EqO0 �b�!>�P1�ɒm�A!7�"v�fl�a�on!'tR";(6QJ��*�5)� WaUmak��W�. 2�,Q9A[4 �/@kbaEreveal� ��M !z ntir ]kE�e�9���2�*�. &�wscuss��ic� i|9�1�,-#�]/E�v.�NCg0 m~. Pol.4$serum ~5$���s: A � -�@ cDNA5p!A(�!BgA4ID: FBgn000120�#�"�p�"��*p$�SH�]�9.KfruitfAorg/DG�OI�r�bdEi�@ET-DEST42 GATEWAY!�E�on vect�/Invitr�I� � �!�EA ��L-ina��E .�i�� BL21 ( DE�Y��OvernL  Ei��?u�=NovN/Merck| 6xHis-tag�Ha�>}pur�u�#c�.gar�K:E�]pront �:b� �c�%w���h*( SDS-PAGE g�;c.�$ie!�roe-Q3 di��y F �m oublE�t�-�I5At�&�6&�&��wo1 !rM�4�(�L ( Eu%�tec%(B>?1�6"22�=�{l�$ed 1–4 h�r�Kegg�J�E8%�!�( R(�K)i�16]!�5i ��&i!Uaj� i�}�&�a� [i(q8wb�*�bo%�� �$ W( M"�6Probe� X 5!�!4�. N'i)�c�Gr-1Z ��!R5 ;*^;M��>-L�9.�*�-KD'A5a�5~? �-t##�)d�[3D5s.Rb�Nale]V 14AAQ)!F�� �=��6��6�,%Far edge���_O�)�y[38�TVn% �- q):�T*�#3x�Aed-Xa=7*� N�A1|53{ k ����� �Aed���$g� �io2�"w� FO&fai!\!: }+!g 2 � qn�"enoug ���h�2W5�N��kB/V DuB�(^alG noisctiUv� � ha�b�Q t��eQ[m"��-�� �YeXa������$ ���(d V&�$�"��z � Vr6��D.0�;�I%��loA�aLl�$��|residu6A)G!�aU�&D-D A� -�!�c:.u"e)se�x Crea2�`/#A��ob����y>ofEu.p"69940m��'��!"�) likg �BXZ&-�2J7.ig#a�%yq �����e�b4I�\A�M Y1vM�toy. More�G�VIedAUe0sc�(c�rbitr� *o�3��&��  &�vi�E( arislj�_X�*#column� ���&�3�A�C*��bA�A@%�m^&�1!.V�5w�b;5�F&'2��A;�a�>t`[ur{N . spbca�ru/flyex� g  . am!sunysb�[d+.�2. Q.�=�>�AF�&u&,,H:,, G (Ai�!�z]tJ�`anI0ņ�H@ @at F 2�=�Aeuli��?!�s�;C�5( T,T�d1 �,%�v ��)��6i%:< vera��D�:�5. A*AQ.��2�mfu2��� EaA�W0f�j��mhe.�2 . Ea���d.��� �e:%)�An�$%�� 62 1lv6�B`�eG !!Knib)�P"�.",14���� �!L 4 *W �"Y�%�ia�$� �%x�."�&��2y%���&�L�6Q2� �l� �uF5/s*Yb�N��{l�Q0�t� ��7=�. }%�kvgC��L0G�orem [4�%we�uJ3J�8�biARc2a;x�ly�0 $y �%W��E1��1�E2TM � � wee�����2�2�"�%V��S1���(">��th�>"� �:�%� A%&�'�hybrid*�� Xi�]!�$ discrete �D�:�9rph3, � � �n�2� a�d[1HDNE2<!�S T�&��%15��" e]BL EQH>e� C& RvU*(2 &8( ODE-�u `C�B��Y-h�i%[e��*2  �?�"^7 ,���u%5S�yx7�t����D$ �a10�2*�= � AV'?�P�3 Io�@l,&�5J�CED�FEK�5\g�4,FC? �Ej,$6(���bcaW(1,�,U� ,v� F&Hs2 0R9�>#0��"� � >G ;�$`/}$�.�aS0LE� conn��m�V!�3"e�"r )�5 ^B�n#iz�Q� el7( �K6��'A�e8�ze�*A\2�"!�1!"S .!�aE��Ka&l� 2<:<"�4�unii!)�� uA��A]!])e�aGs�W9��N[X2��9"5i�W� �ej��leakag� )P��v^~ ]NR�� �s�M �� at m')��� �1s� V�N5>"����8)�ha3�v�N*�;A9I���p�4n%iv��APE!��of���� �%�.? ��(half-lifE 8��b�O� �I��)� hut~b"���g�3aneou^�en�~W�D.{29T2e>m�%3u�( copi| o��1daught@W�]�2�Easched�K��&� of+')�is&�  , [4�.F�V�:�.�13� ew�RO,;=��� 35%!�92%�]>(� 0%�!d"!p��g` ��%`"P !�� FX_�R� �DdSs���� 120J232���H� b�UA"o4"$)3 �w���y�@�9J p8=�2|: �ʁ� eA� NeuN$ ( no-�l)�con�/� �lKna�G�5�nj:I�� F�t�Vter�N�%o�", �T� E2 (M� ��M&�to�L?� need;9.� ��>�bllu M+jC#. .�-�eZ�eh� Fa�n deno(*aE��lejAr��HT��N7\�/6a66r��%&B�#fluctu%^��x>X��/r{0AYZ@�+bB�LR>#��87* �!�profil� t T7ET8 3^qprope����-n6"� T5/6%�#'2 -w-��.%>+p. �B��":��9quNL�>��  1�"��7Y.��=�9:(ekJ]. E� ��� ains&� �p"�*k# '��, a�� � �#k�U�2a�^AO' ��6.�2I��r&!#e�byJ%pecR#� %��c2�!����3Eu�i m�+� �"2 �ޙ�e�)@ga���A<�/U� of uL5TET >a#f�ii"�7 �.�7rI%Х"� � J\ � Ui�*� %/! !�B$%$�"�:q 2' ceZ ��) 7wei�%�. WF�0�i��%D .�(��P� �san "�>�4�7)Ai�� �FL��ll� v� :�8en"0Is� �0ۤ38�h����7n�46p�0�E%U%8�� .be�6� zedB�3)& %�tsK�5-�f�5e [�5I؉�yA��m� �i$.�ߤ�e%roo�Nan�5 ( RM�"�by�"��B �RxYk!�m�3. A��uem�2�6� $be ‘good�/,G� �/��o8�76de�b5� �' ; E ��EKa� -�X231&�y�7 2#-m�: Globjsp*A7�݁;llel LamAtOXed Annea ( pLS�Nu[43�D45]e &�#o^D Darw�sluVn!�G-P�#A��nŜ ( HP #�eA1UniA��Xof CamYge.�)hp��cam2 uk� 8D��ol0�24ME4 �&�/C)�Q0�ng�ʁ��ql search1OL�!v -Mar�jdj L�pm�![46�47]F) 1��2ic�w'6�Y�.."�Bsa1A��|#��. *��0!U!gI�� %2)� a2w Cash-Karpank�* adap� E�-V�er�]to�Ui racyv�^[46!�)m2�by!Y���%a�"�w�eI Back�` D��vTForA� ( BDFIA]7&�C .�"X/>�W.&'6$>8eMA�%kQu!7E\�Esa�M  m�� ��tw,>'��J �� (&�� 6penalty&�?A�*�y��㛩P[��%�m6% M��c�vA�c&Cn���<*@hA�J0�d[3ixa�w a$,^ s i�e"8 Qcwi��tiHN��ݔe�2e�e�r� %���6MP '.lea&F ithr� ��-�9 �4wdl� ��Gz� view��� ~��!e.�4V�7n.P6�4� �P2� �R]3t7e!law0�'� ��8�4�-qa!}oP�x�reaqto)v�!3�,=�Z1�r�\!�Q2&2m s %�c9hY%MMGts& %�$ ellipsoid�>9��?*s>e‘9(fh0.�8�A!Q�(��95%Af�c)��/ (TF�&�py!F2�B ) JacobiaNo��nY})q7D,�a8 E �of&P �e-�Zɋ��&���e�s$s �� 7�=E !�F}e a*!�5&{up_0��F�gr'sd�Gb E?�e�iE��}do�F�#)�k �,�K2/!�q��)���c�3)�+ N�d>U| yt��:�"~�aA{��2�.�#� &-I&WR�middlV &. S�&�bSt�%�� �}to� "E ],�6�%�&gchB=E�5�)H3 ),{ a �E�.�Q�a��Oba�t�- �:�<"�!&�9) a( `�)|a�|m�L[e� BG%�1��h 7M, peakM!`v�E`i � ��a.���is 8l�6Ƀeak.�#��. SubI-hM m��#Mq T5�\&%�$� -c$o MrFj�ora �H(2�rGTy!��]m"�u6� 5�&��!L��%� {Vm�7�>Ft�i� �oug�x ( 5%k&�eA�Aj5,��B�A#SyMl�<wid���sth:�s.�z[0�OA�ant�cv �end(cn�\N41F�1��B��x�l):�ls 8!�90%�B.�� vnZi_+z ."95�K �seYN,h$y9 ble D–V"%ey%�>,�GAc ime N�.�K�j��0"���2en�)Q�S�|&g.�f:X&%$�Cr2�;r� � 6�N"�J�W��.2�>�6,K:!��2{!��'y!ed 740�S���6� ue�"=1g���EA�(*z � ss`r!PA'�b�sc�?&< 2K. A�_ 80% ��2�;&p sets_�-SxY" ��� &/�M��,]��j��A^�1g E2�� �&&/NN0o4a lookA�=���&2��`8�E�!< �m ԕ�5I�.:n� [��� comm�\l out�"��y"�*0hum��Kr._�� �alm�!�ata:� l��+sc�e"Mtic14�7� 8umy� "2m]s�aa�@L0nu , Stony Br![*q@, New York , USA:�sSc! un�?E�I���k,.^= hbE�!�N� pic!$��A4"u"Kown�ke�&5� �EH�"�sh2�dM��!�g�Xm�w��� e*�&�@[50�56� p�#y>�tIQ9h*![.aQ02V.U,w@;lud�!!I�� �"� ��.�, so(5�"� by���A�r��E3994u�:eZTHha�YB}<�S,�!���gsM?eQ�B�Th�+�xv�1.g . LYe�F%�AkB0 �&�u�J|���&pF�839=�ua\5 ~lowest5>90:.�\�&6*.aP6`K�8~g ��E��Zo��2\%�5117�Su 20�9!�g� �x�+es%�A�(ln �:��A�o2��^.�d � re "~ �6&~ �4�!��o��!yL tole\'>/"�5ŷs�[S 8 � �Fݭ2m Zob%eoW e�FZ�C4s�4 nd S� �l|=st�%n ����sa�RF >LGC,6no���ofA��S��1FŒisɨur�e"l omewB%ru7�>]Q�S2yE�C�5c��,��g"HVE�u��z �t� * .^�\4.0�;�pyY+ �a�� �o�EpMEar.�exhib�Eq�-�:!ngEmz���1�!:W mea�U#�!*�EL%!t2'��e/ !��5��%v�er1 �5K< � E5Q ��(+W�be&6�,sa�V6P� ��[nՠ6�1BiV�A�M6K8Y�g�=l�eI��Q�i���!�%6H ��)�Uc� m!,1 $dI��zb g6�(� �5��6o:��@Re�OB��gtEo�:Y~G` $byX3+�7.�,I>wh!��9�y���M3�$�1��l� ��2�Z*s� A���e�Y��2WM��!c{ by���)�4�\ B��. Som%�5-%�s�GY:�?.�_5 � �?�r�.6]TER� "�-2�An�`�ng2I�� �U�t,Ča�fa��K�AndA�?*�i)�noL-s�!gI��e)2Ma�: �R6�� yl�>z !;j!� 4��sola�!� � �,*F&AM�E���P�E�q�2y�J m�hD���w` ��b"x!\.�fbZ#9j�2"J ,��a�z[T�!�yJ ZNJ_� �$X� "Lu( Y�� � �t<#Y #�^�����]݈"�o��&�3^6 bf"�K&W!4��f������8��9�S]� tez_�9|X� u��Q5���M�E) )�t��%I�untU C4r>_�x�/Au5^Tl� JUݡg�orAA˂8>�ove���+v��ex�D,�5Ae�i=���`��A! �aG� K:?�#;Y):Ec^6A���#�;2Hňnd4 (awht$u!]����� z@�du  -�F*�,iqY�Q6v%Q&�+yM�3r�7+zU, a�E��K�stpc*|I>�gP��da��� E��ch!o,&� :%(. j,��"�,���>i�͊AJahr"qM-1A �}8)4  =N e.D S�A}�@>jN 5l. H�+I &r�.ig@L$!G>JA�qܡ�ana�!� A 2lm�:",���-b�!55b�`��F�!t�R5 �M^L-m�1�D1 nfer �51H>-�6%P5MaMU���l��a�A�� e�5J� s 5B)5C>�*�"f;)v*/u8s-�, �:o-6�� ��\o1\strD�,'%�.*�N;�C ctre��= �mea��z׍�6���D9tl�4�!�O 5C�e>a/��=��N? >�� s S4�E!��S5 5�n�ve�Fn�(a ):��U� �0�.�'WamwN� �5� � FE5B�N@U��11E=G?d3#=d�4!Wl)�;/!2�:-..�_hem��g�q2F���7� �~��(m� ) iff�A�f5�2*}~� ��h��!�AVv�)m!�#a?�6 )�Ec-Sи. Fur�x �i"Ai2let ��z'1 *� V )s.Z2��)��4 mD ] �wu,Aq����� ~J����on"f@Vvto]�!��Bl (Kn p�22.Pq�, 2%9e)�]>�(jj w:��X �.%Q2�̓dR��6!�p�Q��aw2�0��g6&*� .$&I!�"z���ob��a:�n���I���2��6� a&�&�|�%A�G~ed&�����"��28i�h �B,��3:w+a��=�*�o���a�6 �8s��+�L.ԁ �-nd8U^l*Qx>�"��8[B��Wv�f.#6(�% �&���s 6c��E6�e:�.����B�2�It�C *ƐD *h"UL�2�9!�2�6!6�9. yp9.*< )�i� �49�2 &�pin-B=�2�,lTURZ,>�";�&�$ 9��i�߰6�"�GY�!/J�p&K�#r��sZ)=s�F #6F.�A H&kR�*��7YR&k�E%:6N� c\�(_Y" s=IAz&�y"���.f��S!A�-� Hkb�Y[ �ŭ=ơ?6�Y>f��gb3,.��-��2,��� suE�I��)Wt��N^�\Z$6 ��c*5��/�N�CEI$n6-|�4bOpl"�J"�'F�ni�W=��32 M~ P-����E1gw4 ��TN6 pane�.�A�� tr� ���\hU[�E(%{� &rɍ Y �6"0�rac4���?1QG& k>�%�IjS<,� Gl�n PTby2� l�=��8�M[�$b !�ߋlow-ea#.�,)\�%��19]A]&r� ��,��l��) : upplc2r{N+vt�bأ� �U�s,�J T8 ,�Q�9�m*&�"�&2by�-��6k26Bm�\.���E!�3}I䡿R aX� %f�>&��l[HM��:Zt!82s<�1Y � ��"� A�;/sah�ly�� >\"1�fixW� �3�1�it� emp�fT�Cx�Ni�p'wA�� B�_ �!�:�?.lE; �,�&��n�,� pite�߫g.� ��� �7�IK=B�K!bef!�.�2&PDi"���2�6(A�"�]�"� s \>u�[D{s:�N�F)�bX%�N"��)�%!_����b��P_fz�6��)�A�!r* �M t��%��`on\,a3����YR�){)6gb�Q��-�E{"�=�e`��i���� ���� tZ"k0J�#ya"�C����dun �@X��N� ���1k�: "{!Rhv�[��&R �+�I�N�ͮ:zF37!B{�:bAa-Q�de9F2�9�. 6{3��lE��bZfia���/!BU3�5� D. A��a��&C 205:2��2�)WTsa���C� FA�&�f"�66&��!I�ow�m�(i�@Avy0�����6�0 �����%� n!!�5 4B&44D�ka�w����5BM�s�of`�&I2a."3l��W\USF )�.��!�m"e s ��fڄ.�L�Em�S[XJa��@Mo�S���L.�%i SI.*E�N.�[J��Sb���C:یiϥ"��y�a� *� ��(�(h�z�G+)�cM�U��?��38=*I���i aa�Nwu�)�: A&zby7$ �|H��M s ���/*�  0�Eso>�eud�G+ �!��"MN� )��*  � ��&&��9w!%�^����+�� CH!}-�lre��Y�v �"'4 +�i�:2ed��!K֧6�� �[�to keep� *|of�^D�)-�HEV� .hb!a�� 6�~5m%"�a bal�U�^�Pm&JÑ��a2:y��ElcRGk>�@&?�%=(/.2PI`aN !�B�h��"&�-9'("� J=�6H?�A�X6"K�� ~ JV6( 4Bcd�8s�!`��A";%4�Q5e�Q8Hb.�4can also be se�ien for gt , but does not lead to reduced determinability in this case . Similar correlations were also found in earlier 6-gene models [19] . They corroborate results which indicate that a delicate balance between activation and repression is essential for correct gap gene expression in the trunk region of the embryo [2] . In addition , we find similar negative�el- betw�Tll re�(and Cad act�!�(the posteri!�ap !>s!�2Hkni ( Figure S7 ) .!Lse do%�@affect parameter J�(our current1�Mid so i��is5�,s that balan��0through diffe �8aternal systems!�crucial�6reJ�,as well . Af�Tregulatory weights of 1N< circuits have b!� esti�Hd based on wild-typ2*4data , analysiWmutanta 4n be conducted�Dsilico [59] . Null/of any�$ ( or ) caGsim�� y setting-� 6to zeroEDaEj%edM@(aZlea�vJ$other]+HQE[1] ,N^M�A�o�d exupat!�AQ-, backgrounds� hb , Kr ,aore�~ctly ()���shown�In!� tras��we��Dmore successful at1g!n:�Axte� l�s tlle�hkbi} only kn|altere�!�5)�in:Q5ia@e faila�of}�hb!v,retract from��pole [26!w[60AcTe�s9ld=+,in both OLS �N$WLS soluti��( arrow%�F�b 7 , upper/$middle row1dad� howeve!�mA�c[!� de-Aess�sa�tW��in�i�e\!�embryo��sk6�) ,A�ch!L inconsist�� with B vide��. We n�observedA h de�7Y!�!. E~s-�E�A�mEPOeQ�AI M: B!m�9�domaiI �abdomi�!are+andedDly5�53%�546e�[62wha�^}hbaE"a�daQabs!0���L)rsgA[, [63AbOA�Kr&@ seemA�be�~ed ,343 MostEFu)H�B.&�wh!�! N�is 5�R4Surprisingly ,]�5�obtain�g!�E5fixed ��uE�rates�HkbA����^�hs ,yt!w�MU��:re!~no6��"m�h� iny�M�le�!J,!va less��gree ,U:ypɌ6 iea�)�{e�bottomq� Fir2W able�increas�( efficiencydoptimis��?dwu� &5N��!W by u!���ed��,st squares (%�) inst!4(of ordinaryB*��)e�2�E use=aPcA� func� � ! �� needH human int�Nn-$when selec�X�� ": , si��it preveC!�oc� c� mino� dbiologically significant )q0�~��a �ectopici����� in m�!�. Out! 7406+� mptsi)6,�`�uL396� realistic+.:�non�!a��exhibi!�ta�problemUD4us a much larg�ropor%�ofPm�� suitE�2�!�isE� titue� very d<icYա�ver9 computE�al.�a�9� relev �9!f~ . Fur� �H,%M��ed2� vari*� �4�0�p"� � than thoA����!k-indic��� fir 'toh  non-a�� dar9vi%XE]s=9ly�9-� A�ecto ]��reacross6� runs . Seu E&� 9> [�, [34] �u�eli�t��r@ s&x 22Y�!�eby �derabl� duca�A�A/lexLM>agrq� 48���a number� we mana� "� 37�'fixt!��l2�to spec�:Q(��)%TSA�a�a� -U" confR ��al=�givF �0QV� ��5�%tfix~Eof &Q�o"thd �RM�� was��� � ly h�la�� N�*(�� ��ngz.'e`of on a�t�{ts�_� a�� . Notiw�we�,�L^A2Norh 2q�-��%6� ly impro� 'B,�e�e�2 o��29 Vnow re�=Ba�D��v� �mW �6��iouA�6-�Q�Es�l "� �/� we fqdiscus��&A!m �Mg� $Our quantiA�ve�zof#DE�rmA�d exte{�yy �studie�u�  � �E ab!I410–15% A–P� i�c  a/��&� ! R� � 39� [4� $eir border�incide���|���invagina�mesoderm��ral fu duragastr� !]|. E9~-Lis��restri�tos:�5�r ś=��!llm�� 2\ � columny�a�DcT �clear��timOi\ � !9o1�E~co"/&!�y9�+m�!��� vs&;A?��%e\diverge�$mid C14A (IWI.T5 onw�C� e�]&k �ݗa��b��,)�subtle=)s -� veal� a�� aris�:bA�in [10]:�>+5*$ppears bef-�qf?��%(be��E>M~)�cycle !7.erlevLeMis1� de�  ?i�gu-t.nE �i��u�-x�@ peak��� until I��seL 2K( T7/8E�Fa��Az>zMs"� :t� !�� � * N";ń3 ct� �Zin�q�he two�s���stage "�2��Butv���f�-_��E}�?An$hme�ism�:5 � runkF28��� pred� by�mod�M�� summ0~ $8: ( 1 ) G"�,broad# �Y(U"gradi�mI��. (%Auto- @! Vvol� �a!�n@;sharpe� of b ar� ��R�%!ce� lQqof� U^�3 )%�basic%� gered arr$� [I��� i�by9ua u�G 4 lapp�Q��hb�!�,I�u"Kr�4 ) A��ic��^bV^"�u�e��� ��q� � ( 5!v 4s�.�-���:�!�!�����s2�pr� ples�lo firm��eIf� 91Y&��[7J 17�22F2�Th�m*o2�f.E!p"u on- ���eyC� �!3�&T A�%�19:&��hA�!3� ean pJ��pt� m�$5 n!8Q��� �"�suggest }�� e��8&� ;s<){ �a�ni—$ Ra!.eM�y Gt—%�C�vZ� a�;.� ��6��ItsN�dy��� %� ubsequent���eda�����!�:��ϡLPup� Rexperi�be�P�. Kni haS g� �` hb: mis-]Pof�Jy�~1shbk1]m�ɧed A[70e&7^! 6zY�ex�L�"���s E. Moree2,L^��S:in T �\�!�Sse�5ng9[7�&} =��b!�!�i� =��� xb�or=��M���~^�{W–[7V2�(7$�!al]�b� ng si;M]�el# �[7lO� o h!�]S)MYW�N��iA2rg2 �rec�:vi����!)� —a.6�is!�ll��doua�Q�-K�[ȅF some��st a r�$I/a> ) Yaɒ�@m%Mw1on-�al Hb� T�-� ob& �!2~$6�[7�:� mY�re�f*n0��B��#is@ ey"!���nse9a-)O*'�io*�(�itYI}lj�hbE��Ɖ�,� �seU]ng�� trib3&� ���_ity�69�6Y�9� ly du���onA��!!�"� � Tak)ogeA_e"�k2� hb ma m![ an un�'(, uniformly1�v�*��or!D�U|To�ni�unres�quTo�cer��#2 X : Trans,,m�%e� �6;V-�co-�%�prI� Nano�Nos0 co- � s [8� 8� s�(c{u(� aC-��e��=��ad(�!�Ѩt�cri@"i�[81EtN*�how)t5)"6H+ver�C`&� . EiUe�9?B dis� ed H+� A�)A�%�J( ;E(;,ass�%/+,N'eno�,�)�mu��ccu�+a� Nos'U�"� ! B � . Qu*��^ :� will�"�! E� � issu�/ForEFY�I�V��+z�@co*siv�T�{ATn�������$laym`gen"�a4�6wi"}-m�!�x��)A ��I %,6Augt)�o� )1se{�eH� a ,j>^ �Q&��="�#7.� �$��;,� U�E�� s 5{�/H"q+A�J^� A�%�!&F�b!.�gt�$�)���an�-urd]&�Tͦ� %H�:%vasa ( �!'sA[B%�XFva� d -l&[8� �."*N�gG*f��~:��Ims.�2 �j-F)�� �g_3%C�""^+^a�.��V,�8"a��2llEa��"���2Lo%�6s��e>2� multL%��!6��BH!�e ���)7.whb ]��y��,a� 0�� E� 6�: g*}L�4kb�}� laps��&��# �( �A�excepq�gt;mU�. And sG&��m%���2 �#]mnd�)�j+"iId "= o 1p�����"_0�&��0b�5. Apa3$!0� A��Z�E�-�o��!ڍ�==Ӆ@:!��42�#!a�G�!aс"026�#.5�IUi�B� Tc a� majorT r9s{%. Altho�ye+�# &*����s 2ՙJ� �� ��;�%�cVd6b .�(&k �by� e|bh6���!-5 �ndEƹ#b#$&�� ( pe�Qi.���[52`0!�#�'Bfis�&� �4��2��,6��ke b-AP,+��'se� ,�c�$E�� ne�'�-��1�6 !#L%�V10H�Vi!܁�&� whk ) cl0��n �����ArfnIMVhJ"s ambigu (� x!�!K"�B�IHA.��.7w� ��M�-�� Z^� caus�.� ��[D&O3-c"[MxB��#n�Q�."M6"� S�In"���e&.tne� i�0wo��8s:w )E%Pk(W/�6�-5�LitH%is�!n�!!�k%F � 9��m�m&��icularA��`��Q5?hkb�  ��bha�(.Zx 3 ��IBcoq��i�"�Unu*u<^ we du� �t:� �+ �)�խ�0�$->-���:qe h� �l��[oR &�;D Ap>` �-r��!c�y/>�!����g 2�)� ��d],� ��1(����V8(!��� A� oretE�� y�a�s�0ish���(&6Eepos�to? dict� -cs��nE=2��2v ;9[�:�;�bAB)A—�,���'s�haluis"��c�ai�(to1�L"�� QD6nso fa/#IpA>� k � 2�/&�Aor�'~,step to�)�e"�1I{i�22� m� ��a͡l�,��6-"izev�>n^����!1(_��+2y���t+!"!$ d4fluctu.�a�$"k6A� �fperturb =�V�networka�$a feed-for!G manne� N��bc�1!&�4!&aT�� W%� msell0.R1���{1[stcan����72NR��X#R82+a�;=8�F""� �L�� �*�3!�C28 n6+� !dC=19A�:e� . Var+!&: � C � �hE�V5a� Epast:� -simplifi,IWq/Z3�ioA�-� J �,�sa�� "de), scaI( �U�� � ver-�4t�cJH(rf�_'2��~&� !w"��1 + im�%Ya�n2��b+4'a���a��&� i?lucid� �Ƀ.�f�R��%W%)� Imakm: l�IsF7 ÝT�� !� E �?yA64՛� a�p%�ah+�8nU� ]) . Ye�un�0ta�,a %ory&� #aCBA�a%B6EH&�.dU.op� a�4d evo?X ,#p|q�-Ձ�FWC��-�C�I�p5l*x#&�XY �1r�ly�� ! ">�i"Y" �lyaSt���"�&an em�0ntaS���;Au re�����+%%I �'� F)�Y9dH ��*;��-30��AGU� @� -�ed%is view!� �F�f.ing&Ip!�nol I��MkiVQ }J��� vidu�2�"5��a 87 MMBa�har!�%kn".� ! >�� icip�#��%�]���7teg��d�!2�R��8^0(1{(J &� sInt� ��Z2�v)�xvs%�!~!o):�ves^ 7�B�KrB:�� *)F .�-.�C"ml �)&.3_�镪*" ��a~W�O %�6�Ap(al flow!�M���i] ���,z >-} &: 2�V�&=��C a"��?it~ ll8nuclei1� x�#�"� A�ttTor�*t��5h:�"at�/�/ �:!�ed9T�W!� �-�c�6D eci�1�)hS@of.��"�*E�s���:�M i�$&olack a�9k,��.Jbe:K�M%�e�2"u�MA . ChE,e1!�B.S��/I.� yE`b!ͺHMin dipay�$^'fl�� dg�� mos�0e2 . Primit0, nematoceran <sDu@ psychodid�e�P+�5seg�*�1�e)F *k wid� assu-�'%Hnc�:JLt!�ofZQ ( re:�� [86]�+L>6��5q3h�?yLU2� !�-y�)�e�9�6�)��se v/�u�_#e�Tll!�� help�@٘�!!�g!��per�8�C�""�� �g�it �1�w!9![ � n ) & � 2;�q��E��s-A6�Am�ޛ �0. }Brucello�M"�� zoonI)dis�F���huge omic lo�! worldA���HOl�/ �� immu$ap�8r .o�yymarke�� moni�}!�m��� Afric �\,MediterraneaoM�QE�E'j f As� nd L� AmeD� �tbreakubF��[45-��R��assoc=eWa����l�t5�2!z6I�,"y�(�# , te!��or�man!���rtE#� y�)�%��newborASuIt ��f.J|sex-� adult mal"E�� orchiti��HygromaL;A^leg j)�%� ma� anif�� of1HE� E��eP!5 �;��A;inu De�;er7Y&od[+,B��BLe�st6s V u�,�E�N.W 6Y� �= %P �s�)c".rJ*M� �^ 1�"5 ���f3search� d/u.q�d[6�LyJͶo�&s quick2��g�W expo��i���vi~��A#i0� � �uR1���damUJg+�6ran.V- E�eY�%vJmu"��e�Q��t $� �]o�Et�Pe9%]�]h:M  in6�$�$[8 , 9 , 1RK"� , A�n� oxic�2] E��(�#adver�>l+sXexplo)h �� eu!�&��)>� 2Zin�{�n�= %:� ed)9� � �4� h-*� |Q2�ec�h� M2� M��% dyu�(a��FX � L!�[ !Fsĥ�u@"�] � ��$( Indian IAN��a_Hy�Qa�1�Ou��a�maO96v()�2�ag4sPe �Pt�d��N���*fNI�mi�RcopfLd!�� ��viz .!�al, oxid u�e (!�H2SM��7V�"0$ard method�*q3�(ql J krk+in�$��gar� � , Tryp�$se Soy A( TSAR(Farrell’s�um�sla�M�^r�ub- ��Y�aBW�_r��.mM�&n�I Rto;� I�}t 4°C� j7 a�ng5�awto�9�iso�J�C"lAzL`[1�N13]%�UC `ngL1 IsQE�]s��!L�#e� crud�%� (��susŃ�=re�$in SM diluA�,�� vi�byYr�! t4�-Q����i�ita)sh!�st, :�{�S_�]d�f!�" M ����%7[1���tox'���( TVC�24–�!"JF! � 19 2qJK�adjusAa� x��c� . Opa�_� >2Mac� ��� e� no 3O ��th suc�1.)Zgenic masN�� C/5A+!v!)M1�2F�9)�:�� 50��mixEp�<9C�6–7��u�:T��?=k7.idC �� ��>�{"� *EJ�1�(U��Q S&y  5�Pi0 �I�&!ft�p�?�#�� a��1 μm fi�i ( Pa�Life S�de )!�s� x u� k��� t! O/|� � %�vi$!a"� Sjl<*uu!um hydr�;l.� in s�\a�!Y��o��)^$��e�BBsa M\2=,A�*t (by Nanodrop*trophoto�n� �58 mg��A'a�= 64 R%� "n�(Arb�\o�$��Y3�z R�$!)�"W( of eB� Ep�P B%�R]%�%� 1% A���-.��]%�� �%��ti9�(�palw&K!!a1%m�y�2�24q�na enQ�Y���.��eC subj�0nb) ty%) safeF�� loop�mM`)�%h di� BHIDz��*7str�:d�.)V�"�b�� !5Ih end�q exam1jG��� A�;,�b�� th� 2�9abocols,�# �mibnd�r8t�'�a�In�fU1Ak( Ethics ComMeAE�@�' opos�N0GADVASU/2016/ /33/0"R10���X] XXXIV mee@hel%�2nd Ju��a�mun�2d �.8*�e$se�3/481-5092ed 8th2Q(�M�kep � !Xfac�emada�te M3��=0, bed� , pucca�o~, c�2/!pa-�l"��0!�� ��%I�a�N��.gu�&iMn�Q�aM "9�A~PurZ"aPCk<Supervi�-of�aeB�onMA s ( CPCSE�,  WelfDi ?, M�'r^Jnviron�$,OFe�sClQs �*�y�:12�$"yz� &� {eI) comm���0Pharmacopoeiam??* .ce�uA\!ofqia�Amzrp-bnhe�yi�,�e�in��%��^}"�+m%� � (�:or�,�)o�"W �mHs.�"�!:One �,t^�!1�un� aa�1q�e ��"lA:��un�86G05ortal����7th da inocM�]�%6p.;ssdjf n 21 natuRky��`!� �c�i ���&po+o&gd�1E=h8)�:#]up �F� ( n =NL9iI� m6@-��:,Q>R0Y�R.8:S�T.G�a{WE A 2% �A/adH �*� J�@@as�V-:�FsaS#- ro�;� rece�no1[�A.B�$sam�Y! �%7c�"d��ju��r vb at 0E�g��67"I9% e e�A� stud�V%�a'/e���4� mfQ1 c ac.ypLk�DeY4&P�Cra�x�- d ��%� at -20&-8 :`�:� �pi&serum5^��x{ ed �INGEZIM�B�#a 2 . 0 HELISA ki[2�  �P'y!1hr.%Qoenzym�8 assa@39��dBa&� extr� LPS u� �&/�#re"�aWi*� !jA�!� )'olo���h�� Vd7s z*uMat�#�O�l Dens� measua4 at 450 nm5s d%l�?�p%'m e am��c+.?B ."� ��!_�8�� �iat"�Ko�=2#s� �a�$E�6d � ( OD�2�in-h�H�cq�w�JO�  .I�\h2/"���# �A�%�*va/when:Y noftheI HE� was>1 . 0�/A):/<�P�C nd Nl)cu�f� cal����}alf8: Cutoff=Absorb� at450nmof:�xk4=40pergof vAHapL+ CE& ( TL� M��1y: �;�, v "a: %y6)�Hi�H�3logy A�8z�?D�}� F�D�a�.�asme jSl_(g��Ak gl� slid#sQqEiLeishmanb�/� ��0En� \= �%coa�?!�)J"h ��'�y!�t 200�m25A-*�,:�3�at layerka.U ����. C&�+ $n Neubauer�Hem@-S�2� x105&L,! g�-�zn v�-b6.�paX@/J. IFN-�-� ,pot Kit ( Es��.N"�2�%d�0 ��C"7#�;l3%��t�2:)�UA!}QE9���kng sp&visv:��a6 &US7�;sUd~P�A�T�n�s�!!��� Fa��!) "x��+�+r �#"�7q���as �-B�cN�8])M�e�3�%{s-y�%xTRI�4�"BD� igma Aldr�W�m�Kon�6�Y ��USl* RNase-e�iso� anol0miF%�� �/p :A��$  |"{l�;*lpX:p r)�RNA�cIV> >� 2��"%n ultr�=let rar.%J J'!}p�""!�� an͊��1veleng�/�06�!28 �� ings!'$%kU�am�e6)>�%I�S5"2X2NA)�OD260/��R(/a#�=b –�!2{"�B�y7a�Z�5��$200 ng/μL�$A3 � �m6b��cD�0yn�*GOas 2 μga�i� G-Z�i%� !S"�  �� y�E'tt>p5Bruvax�ndJ�&)E~�r p����K2��"� B�.}�� �d�(t�Xcr{#iP%*�HP0ca�|r�& 7pEޡ� ( Ap��Bio�7���b�2�)!� ��F� �EBJge6 encoa 31 kDa2c 7 v6�.��msA�5.genq#� pJ rs B4/B5�hlse' .I:?�{ got Q[\��Promeg{;SeMfc!�`%��6�*& �my0��low: B4F—5’-TGG CTC GGT TGC CAA TAT$-3’ B5 R-CGC GC )TT TCA9CTG -!}siz!-pD=�A%C�4.�O �� t o ,I!l�2q86z%:�=JF].5N5.J)�AA���(NE&�D�". D�>E� �PA1hO$sA) Ac LC ,� �� ��6�~! eripO+l2 �2� X-�A*by ANOVAVTukey �!-hoc "> &J. �br�:�l�8U�:�&* ^#��}�?�0S5het1�ka#`H�3��*Salmonel� , Esch24hi�2li�Pasl*�%oI-��"�!>� to achiev�*x(�)s��A��c�)��� ^�.")����F�!=QIDun� �>$. PFU��c�}��݂`d/#� 3�)] erY�� � ngX%�' 6�)�3�h4 � P� A�C=�"9)!2z'��� $0�� .+d[;TecV0�N:�#!'�7� ] "��qO>*M���>#&oAA�)� ZsA���f%�)�b�0�lyye{:� noa![!j�(� ��: fungE-ont� . *�9��+" �R�; !r*�0[1�fa�����1.�%�Al�);sur+,���K noV 1s�4�1b\!ab�1lecs.�c�:)���i)�A�n�� F$�@z*()�QAX�M2{a�u�A? ^M�1Vra~�1a�B1I&!?2|.0I����7� &f-NT.�S�-�:� �h!�� �� rQ&8&�&� !�-)QG��oQ�-o "�4;K6cBwA�a r�E�:��e (�*����(f�)#��~� udllP"na&<%ly_WC,e�"i�>b"E>���>ug 5�uX%�*�A)9 e by e�h;gEV1Qz��'�-�|� �.�POTi ���Xf,iGγ- �? ��-lymph�&� Ns�.^ %A�>�'m pre-A�J64at"� �9��AI6?&h2R���N6S!Cir=YR*5edq�Z3ww �6 �BF������i� ,i�.q�+m� "*K#u�&Hq��9qr in Tx�� i�a��W��� �9� ��[�,A�a .�u( P�0�'�s��Fml-��0 �75%�, 0A�90 33@- !�x62� b�%nr�2�AL"&vv����6��� �2�"9N�{1{2vD!g30D , 675 �9%�!to:5:"6Kto �JI�?IeF�fm�e6M�� A/�AF?.AA|bn=��9p �\�4-enh3�mnO 4�b"!}19Q6!�ter�U s �.Jea���{yd�o�I ��Y� ����oc�$�|uKe�Y.M�gk." rob�j���EonsJ "� ��l�=�B�il:+&�D" .>  7u�!�6N^in�Y���!�&\ �b�+�XVc(�B�zk�c�2� "�A�R� �QY�u�}�� _ "�x �%( x103/)e0��a8�d��~�~�~��~�~e���lY3.%yl}�ŗFzчd.�>���)���;�t$%���!T*n4��.j�#j�D �a�,�h��Q�~.z, ii��s� &`�JpZ���a�F��Z��썾*cR:06%� �6w�+"�!l�R��K/:�)�B�a�0:�!�6� �w3f�KnŦ+ j �Hvs�Z\60D��.��= YH"B�>�}.y͈eG��Bu<v�G7�*��Á�&? ��J!������J�32 ��bN Bt!���A�NN 0!�=�YAͅ9:�Z�B_Az>�F�fBb�I�A"� a����nY/��=%22 M�R�63 co�]2m4�j�>/ Z�H&{j��.Y����!Kv�%W0�X3 !�Bk�mca%P�b��.}�6r g,Q{� �$� �by9� neut_4ilx(���j4�Q'�Ģ�Bh� a=Ai>s)�.-�!�6��f��YFCcV�r�RI*� �y7V� .c���m��!D��6t 2�2�n�L&2cm�n���L�Srb�)�I6�H"c 1�I�r*(.%�u %0��mF\EԚ`In qs�y%G�� . �(�Y"��EF�at"��, M �T* !(��!croiauG�o�%el*�&J spp�r�{ul49K%F8pMW!/du�M&`ll-6�[)~"�AST-J-���9 2� of m�� !;!;(�i�9V� %@i�ZV^��;��!;)�4 o�t51x-γ-r&`I ?:�*�(ZG>�.D�� �� U�/E�>~�SjHY)*&#(L(%��Ǝ�! Y[{'dexzs�)�M[:�!p �]�!5hI�an."63q ��"X6{�q�t>�)G_916 ± 74��� MV1w, 9�$583+H 18,.�-��9�- Z7 . 05/>t3= )/�'j*�$of���hMN�Rz ��!7j�!%v*�b.��c�a�FCq�r2) ��)�s� &w->�)lmu&� h I�=��.�!0�&erBh 1�o� S.Bg|>��v� s&n(yS��e�2� !�m��2�us.��|!!�Y�D��aJ�C21ޖrP~�'^�J(� t�<�"S� ���7�q ��(�!�"��',>YpidE�fn]vafAF!v�S ��DTH�!ç���D[23 , 2dch�"h0" �dar&��j~6l��3.RU`3i�J�=J�5] X&./;�lZ.a�o0acddNu*�:���-2\\%c{<-�%Z�(&4pu<�\%O�m} alsoi&�/γ��(�RY#�!�]exB �T2, :O)E1i�F�# 6�DI�u��0pIAJ�BZ'��tr�?eWH<��dF ��. %Uɦb�.�Jz�'lasmam "�F� `6�z�����G������5�uQ]��Mp� 2&!JX6 0D� �.7�S5)"�,us� F!er!:!<� V �R&�P� �.]:�am*� /��� �V�V�:�60ea.�1 P! qv9K lf� 6n!�jm!��n g"Ҫ2dM71_e>�2�!z1g��_� !�I�Q?��I3%$)z� V!r!R�Nj~�XA�Y.�B{��� <(a6�bz��A��Y�/�I�B!��X�G�e=/�0!%{%.�b!���.�fxJS.'�1XR�0���v�4^.� ��2�"�'Eu �x&r 0 �&-*r. 6)3OD�+3�+34+3�Q&+3K t���&� ����1�0�+2f23m l"m n3( B)D ![a�/�![g�jB�1�."�.I�ecsp�1){�1Y=A?@,�ex.M"*a+2DAV ��%T ��e�5�e�<} �8Q FpC2n�N� 1FC�wMQ��A4,m6��P!��?7'A�!Q.�am} ;ȅ��Hof kf 34m [t25 ���F�@�8de�i� ,� "�F�cO s�7 @�t9\C��-ven-'��i-[-"6� !It �� �u act 2 m�r��e�6B��!Eku.7 r exm�9:=G"E5�5aA pair��!��?7Ze�KntaI� }E)�Bt:2 star!dd�ishAlat I $!�became�Ta[i@&�J��by v>�,) 5�1m>�}�l�cnegligV�s-�"�&�%"ro� �)H�桃�5H�pr۹/�=)��5.I e�I)-(ck�l2� �V3�����"�c�F0��(V�"��.�[N�R�*ɘpronoun!r�x3a8�ecFz�!�z"� �A��ocAx)�-/.�1�!i�J���p{,5�X)*� E� EhA�a�� load�ZV�8�*��;5�Y��i\�p ha1k+u�b! 2�)E!picuou$4?3:�)o�H.�2 /� Cu��A^��z5a;�h�Z�@uq!���I!��l_�7f��ts kindA�dem��ate unrwv��l") Ar��M �qu��3f1�1e�a(�l `.t:�l)�zN!ba��`�"N]PE(vo��i !7aN�i/t.&o{! .4benefi�UQ�2g*��AMi�"�documel_� i)s�Z!�d#��p)�?�6ʐ7 ���mt�,!gU�!'A�y��t/,B9?y���(p��rI I�Coui%t��>�@(� , r��, m��~=��s m�Q� �T̓��ZNRy[2�7D  r"�seIJ!�!c�%����iLa!FYc.K t�!� iin�?�$6}WC�TDiImv%hig7`^��s��}^enm�A�� �}E�urK�_`ߘ&4R� cli�Sl�[22� �D�na�; half�v�!��!Ayn��i"g]plaus��2�J 3�.pu�n1:��S g�sy� i� QF [3�@��i.[3l�!8M)�!���� � |�Y?tkaO\o/  membe�q�1��2 ( omp�!�16SI�i�2 �uRn �� �5y"�32] �in�.�?� *F�93]R�89n� ?yE��#A�as �E�CPPc�] in 1^\w�0� �:?-� imerP� �%Q����E��eZ �� 15 pZ$n�\ .�g JVE���est� ݛ ( 700q�w A s2e6�9>��>&� *�D:�(�o(�"Y[��9�OX ��`::inZT& ɡTs"����lL b9F�w��"�O��i�go7w� �3N� I)��2�#������)!�.��&�1��{S!���A�nnd*Nm*�� h6o�CO �=�wz�.Í�)�in*�# kina�( CDK� E�� ot� -4�Xg��-fre��Or9@$�kignm%�3p_?r8�pl�edeL*~~p�@�$v�l�"^4to0s>�����%e>*Jfa�� � ��>���"K���ins�V!rD)"�checkp�u in����wbiAG�"�+�s!t �� �s"� %��c֡T�ge�~X g� mamW�, Cdk2��%�6�%_5SEfG2F!�)p0a �Rsl��A�"� , ow���um�la�by� �!�at!��D!�obscuo!���5�|�) ��~Y o�h�s} Yw� u[by�Fla&�Yw"��_��a��[͞{�5�by bulky \n��EogM&HG+we����7�H� ,�J�] �Salog- qveI�f�$ �sVT� oniz!gD�)a( IR )�7s%-=~%��A�pn�&an ATP � ��pre�vnmFS�IA�Ihosphory�g ` Nijme;IBs_age Synd�HA���C Nbs1—�Empyt! ��� /�4d Mre11-Rad50-0�k plexq��f]B}�GC�yaL�b g—&�(�� sn�CDK� gniE�����Ser43Q6In vivoj�%�de�Q�"d����- L.=Ao�DSi{E*s��! 8to Ala�}Asp� �9ed IR–QCa,agerC,!�"Dr� t`,A�uy)j\a�e-���>5�.�>t�:�*�t� �Awi!�!�-�m�Gn,. In eukaryo�$� 9:��4 hor>�%!Gerr��mu:b���Go�( \e�qO'Tpl!t]0.+w��I9���%�_�\��,F+a�t�F�^ sst�apopt&�!G!Qal fash�-�_���[��l�pr���#�ar�� ol a�S�E��e.b5�>.CDKY  �_paof D��-> �t��D DSBs�^homhG�.r�F"M ( H��in ye�}[1p�5{ In S{ omyc����sia!��._A4�n�ZMo�� Sae2! ��-eUa��!�����Sh�vl �i�N]HRQ2 [AsIn� azow�,�F�/4e*A�E.Dz�s.���%:��5���y)a��I�D*;N%��.s��� ]�.T`&��%&-� CtIPM�:Oh2 Ide�fCcz��(,�0coua�DSB1m� cho�aS]��PMT�Q!A�% IښE�f� � CDK/iR�XE�t&���no'e1�.!�I��(e A~catalHvsubunit��ggP�yϥnS��!�mi��Y?k��l�ly��M��S [��� l� r�^>�m�s:�Ȏt���s�t��?lem!�m�w��s���aJ<�Whg0d�or!�"� �4s:� ali�/fk%�X%` evad� A� :)\>�zQ�n�uyA�m�v��tne -�E%Mk)&�s:e� G1/S&�I�� � N�6TAhv� 5�.�e1�,�A bega�� Cdk1(��VtrE is� : T ���ng oriH[�yA0!���u-��{���a'[1��F�rJg�;1mb; ��B&�f. isI Z�AG2@Q�. .�~i�I�sm_�|Rap�"� �D28E�a� y�, ����'.&�&2 r/�B���2�&� r[��!~��<dn+r�sy�IB,−/−|LVd��o^�e"�,��eiey,�yMo"����al�terYY%1�pr2 �albei���Glow�an* _3 ��-1� a"“<�”q&f&�#�N]Vs �EE%�A [�yBecA�!�M���r&z�z� �4m�A�JNbyI�disrupEcWgNA��Jj(�'�>A 7=�Y8w�%JHS , haps�yeR�#f!!�* #F�&a AaClik7���g!U�$ �rr��,�#���P���,;�ng�P�NA!!$av1B� S-E1͑���[�sB"soeԱ��b4F ead i�influen"��� F����R�.�j����EFE �/P o���5-�![��]1!\"�<"*"e�ˁ�I�d��in%{[ ' '>�)u&�.l��r�t:&*�h_:�D*J �quf� ��|E�r\)na�%n*��"}�%e��{ � J�� s�j�a����� �" 1t�X���� � ��y u<% a0)�}to �@m� ng a G2/M.�  % �`A�*&�q�!��tumk{upA�s�e53dY�8�xqjU>eGA JI� 8!�!S��Rc>�C."� ]������  �l� to�R�"y���] ;�̭e a1�ӎ-molecul�|����� ���"�-�A�E!��X}<�mfic��a^s ��CDK�{ai� e�% 1���)�+!�mi9I�ge��, `Y� T��so 3�_+���]d��gh6�e too��� -gen�_roach �>��a�b��i resi�%� E��t�d��P keepnc�Q��IG��ůl s�o�cfno��V9[23Meo^� us��AB���ulyz���u} poo�%t. ��I9A�se �&�*o#�m!),]!���.�?��a�teg��!�+.W�o-�Cdk7 [+��acA[��cop���VA�n K�T �&��r9*E �q.A��z knockout-esRNAi-4'd%�[�R��Iw��M� ���`�&E� esca�d|�.r�&9!%0ana�el*C "� "21F�X��f�as/> ut���+/+%4s��a�"�� .bmb2'(�R i| an e'%N>�w8+�>i��]-abeled�� r�@�q�-�isom� ce��j  ( NB�6?�fcepha�C�" odef�I��d �!|h�ipoi��malG/�:$29]�e�H�}��&L�boQ����c"&�\/� �+�e�- ��  fW�]pA�|!�&|@JH�to�%���B3�"aZN Bq�� ! recruA� o che�tin1vw,��y�y � block�� R��Q�mIa�m7�%�Aide� �� ��*!@Q ��.��byI=$thus phenoQ�JeaR����,F�Nv 4��.C��`%�&b��dm/N�����. A)~ioy("� �> Phe80-to-���i�!+Q�rv�� AS!l��m�!�$�<o in 0Qk��Мd&  �<y�I@!�~�th�>ad>"0�AI.[ Bo %�m�B su�lm"�(!P 1-x�4ert-Butyl ) -33-4$ylbt ,1H-pyrazolo[=4-d]py, din-4  y3-MB-PP�6��B/�&%E!� ���—5[&}!��synajn)�>1�!��K)E. Acut� � �q<�,4Hi�pop�qNunxf&%AI[telomer�5Fng��in �ig/ep4 l�,0( RPE-hTERT ) �, impe �ag�@�bGh&��`�egntJ�dJ%�".!~�� y?�$toS=) &)�zQ���i��*�f�Is�&j �G0��G1~��!�e� N`�]�6!�2En 46�8#��rk' ; a 48-hri6%r:YI 9�m[10 µMY�, fzqi� remo��dru�{� !zo�A)Iwa�no���08��3�(1�z.��� �#/ tes� )HE��J'"1!ɛIR-8B�.:)or}e- k pre-�� DMSO.u�3 �r;�Hr /2,4 G�g re-p�� 4edB ��al P��!a^2��!�;)�0.tur��oA�s� !�-K4�.u^�14 l�%n%�B �c-dx9EO3�["v�T�.� n!*E 5.0to�4�a�2& )sYBoY�E�!�r 0s hypomorphic�Fu7�eu�-��`!!����fJ#��w\�OYI�Xin��� ��n"�"EJ!� =>hfurA�N by`I� ^ ∼10-fol#�*}6XA2{�6"�# ?��" 5^*� s6v��i!�A���2c.T�`<IRO A�n;�]�9��S*% �&Vedm�/�s���eym���"�#E"�[:� nreg��A�lA�%i �%�f�BK� r� c�&��.���}A�b�&6L ��"-*�p}!,odA��a uish"y2oe.,'��B͔"�/���=ue ��B.�sI���F�0�.GWr��!:�'2{�bbazݍ$f�#TE�0�o mock)�_��(�s� |� )24��ywi���PO1of .���IR2�$#�' �[lnj!�s��*ti&�,�I�-and-ŧ�"�&�z."k$E�c"� �^�_.�E|�!�2:( �)�eSTo&n1ns�4��exe^ �2���q@we�"�!�zJH2�&�ArHCT116� ���9cinom�O�"���as/a�� E!�� "s( [γ-32P]N6� &� �[t/�jP"aO7.KA�3��"�2�nl�!�3m 8�� .�I��t�(ta�7t�Q%�=o/.��w)as16Z�( �W���!# 1�H|+�-�MC(1� [3,�"!�ov�l)���pgrGHs���)*@7�8�Theavi�}*��=%\@o&�M�#tractB N��&:"! at >�0,�f8jd∼35�ru�2"� "b=�!O%�&2�ri� �A"Ar two o�*; Aas8�� o����3] RY:�.vL~ l<!QE�� $aa��%2�T�;B"rôC]i�(�I��3Dt� i�2[�`heIB���&[n��918tKc ti-M�* �ii"jx9�O �t��we"- 've��!��tpaA���xP�o�c�es �!�a�Y"� mo�6p�&�s��T6�L&�c�� olyp��#�s� (�9Iy)J���)ы Rbz�!mN�~  9!>d>=���� 2�c�U8U!�as&�>�s �kU�5��#beE�@/�7y� 0�ab"+ f&�uX �SO. H�=h��8%��t��At� V�,@motif S/T-P-X-K/Rg re X�zo n z��iRJP8nserved in meta�zoans , and both fission yeast Nbs1�Xrs2—the corresponding subunit of the bud ?�OMre11 complex—contain potential CDK phosphorylation sites [36]–[38] . To mapB+T( s ) by Cdk2 in human �<, we transcribed�0 afterI�q �ecE�. WU,E8)�ASDp variI�A. �Ded at equal levelsE&recoverQIsimilar5�cy!;anti-)�4immunoprecipitE�. OFq. , however]0E ) , confirm!4that an intact1��in vivoÉ��DKs arA> sible�K2A� B��tre��HCT116E��kin�iinhibiE�,. Roscovitin!>dAfvalanol�B� 2 multiple!��ie>�XEUA$( [39] , [40 diminishe�B1 A�out afaSH totam�͟,AZ��5 , 6-dichloro-1-β-D-ribofuranosyl-benzimidazole ( DRB%�a�? crip!2al poiso`�>t�� work �!^A�dk9 [41�hadae�=�DeA Because n��I�s�hmpounds!�Q�%�a ��le clas�-�%�askedAsel��veF�7�he ups!�m� ator�� :�,27]—prevenuAm6eU�. TAIm��!� 3-MB-PP1.��kI�>@)6]in�7as/asupy�2�d also dec!�edE�Q:>n��K� 7!lincapaa= of modifyAgeFdirec� =�G; a:V Cdk7 끒��(efore sugge# N�a targe aa1 (�Te�) down-�))$7 , such a�X� �WIf����^1�/32w� expect it6~!�s� afluctu�%��� posi,. We tesA6th�� redi� (in RPE-hTERU A� at"a quiescAV , G0-like �(upon growth� lu�%Ire-A�E � �0synchronously F re-p�ng� $lower dens!�.2N>I��low�G0��inQ�$20–25 hr�q rele�R� comit�)%>6���� ccumu�on]�A2Y�4� right��ndA� appeara f a)popg�>2N DNA!UN:UlefT�D� �aDrecrui%�o !jma�*��[42��2� $successful PEEof�  ph!;[43; [44]��( B�P�� relocaliz�i+E?hr ��Js�ed2F� harvI� at differA�times:�� G0 ,� o solu�i!}-b�� e%w �|Aga<ominaOassoci��C�10NujZ(ofA �xQ� d between[H2b� 4 �aFaoFr*2, � atE�!'|}�or 16�!�r ,��x�i$ elluuV�C ,Q���>��.i*a�mpJ (lanes 2 , 5C8�6� addiQ�aphidicoa� bloc�� repl� o� 9 �!��on��� �3�6�b� normally2�!�y�T ri��~ M.X6in q� �ɩ�� " does" m� ongoA!synthesiA�CuxQ�%m�, morel ,T�*�:~:�subU$f�ioni�experi��sj�e %�� � sA� uish)s�(i��o sal�6�e�pelle!~y�U}S��Kt� g!�p��:� coincid}� .I `4�)�avail�� �A�2�d�!�A�- �:-)}��:�e�9N!}!�h D�  [28]Eowed u��.�[prefer�& O!� W� �Zd jd5�>�%���%B�<of��%Yllele-"� 58"� ;i6I ylaminoy$ne ( 6-BAP�| adenanalogi:Ş]a��-bA`ng de� �� uT �� %���n by�cue�lay#1]gkA�to., hypomorphicm�E�%�. N�� drug} ` >!�9v)�Y�D �� data�shGI� -� 6� f��)JorN_2).�,2M:� ��qaA� ��qd ��An�8��.���"� ��^9�� �da��A�B�"�r�� %�os� )-ae�2_!LEve%��.��&Q,Bi�% LF� 2� 24!� � A��anoA��N�:sit�e��be� dM�kin��NN 6�\ ݃<�9e ly aK� m 1be&| �CDg2d \P��5E���[1�[11� WeI4in( ig4pos��me�~A^�� :N�ha�m�A heckpoint-�!�A�reduc�bil�8to�� DSBs!(HR= ad3to}f�e�1 (osomal aber�!: DNA-damagRag�( revie�in [30]E�ThE�AE�!657Δ5�9e�� major�:BSw��%���  26 kDa ��-teAal#�!$ a 70%�,( p70 ) lack�a]��2IuM� l�rVre�s^ ��1�( va�N���is ly!�(fulfill essI� fun6 !^a�� ![45A� Depl"a *Kby RNAiulaLin loocolonXy��5o��.�!?provi!�N�:� as well .""!s�f3�t icul���4&� * r%,�ck^c ve/ by measur!�RNA����S�. L-vi1 � �_d.c�gendu��ra�" than off-�e+A�becit�@br�ɺst� m)��of�i-!�s`,����%�{ �.�!�reEvwi�&reb �6�Zcis���Bi����surviva!�All#e�m x ؁�:��co->[-� a5Rad50 �a�no-`!*AT�sP ��  9-�W�irrad} in G�V*S � ��in� � e G2/M ��t���in mito ��.�; �Fe [46a�95%�"� ��V@ y �j"�x�s;%fr���f�;A�� expos�to IRE��Q5*S)�.� `!u�kf Chk2 OstoA!P'p f��obserh~6 � G>uA1Q*IIR�in���M�A!ntE& ,��y�22�of.�under��c�"!�6Nonethel �c2m>���,N^Bn�' . Fur��d:P >o��� itself& by.�B��"�A��T2"/"� ombi�al�,���2�g�^con��!$$a split gr� fluo���"�#GF� reporC!I� intr��M�a �A�endonuct( I-SceI [47a�.1A�HR�� �f)�uC]gen�!.a����U���=uTT�""Q�i�.�]WT-��or D*� !X�1X1u�by�R amou� F>NF�dispens���HR=� Bwha! �QD>ZBTAY�R�in HR:��eF $� e� �!ene� �#tr�f�� ( ss)/hangs� # inva�.a�IF&U$�ngŧx2� n�to 4 GIR ���e numbe�^ �v�q foci1�"� q(r*�A ( RP� �*�Wre%� ��J� 'c� @ focu%,�uamo�+ fourA�o:'*�S4 >g  "A�Q#'"B.%2(�enda-� step�� ls �e�y�!>b^N�r�l��%� , ju "s� diFt�!�bYea02�to bulkjnWeiZU!!1w2�"�AL�qno.�IT�qng*u or_ l� eOp�je S10A� IR (N'Consis�� re1�bes��; ��nQ>�&U$.&�#itu�� .�< A[��dd!�F���J � n(W'�tIP���promoAm�W'te� %a�h>�[8!!� I!urnA�. ili3$LB F�s8 [48��Lik� �|^B"� seemE}�*p'�-��+sA.R�ss;:t !��")y c�+"� �er.p�]�U�4nic hydroxyureO+ HU )Y}9�Y6�.Q!F>�%<�7AQ�D�����hy�%kil�byA�"��+t�2�j&cZ6�&!kpa��=~� 1,HA�5g We* +Ps9+�*!ym��A�ldB> . ( -K ���is*, Rkn"�ABd*too few{tof0#-2.�� reliNc��. ) B�.%�-e# D-����N-to:��*)�F:�9b� �T6">�M5qshibu�to%��o��h(�]��a�h�. ���",� mical�[[un1o$*7 � %�!ZA.vof ft.� ��Z���c/Aہ�he60(@ir machinery . We�ՙimp] &)% CDK-��� i�4o"���10By�h))-� tic�roaU/ i`+E�/>� �mQ�!>�togon�CDK!�a�u4+c�(��� A��E�%9.SS �n�"��/�-vitro �����Ix$—P&�$.�or6(�0� �ly�,&H�%)b) —d6Q�.�-� �� iv < �-QPalU'E�s�P��!o.IE�%K�8)]c�5on)�� E�(temporal or�in�g they�omei�dB666�!�^�wa&��=6� "�'�= *�$ exit� �� � a�U�nd� "(1Pia@iti��B�. A�� �3.}+ ��a�q��?$l ��632re���{tG/�%+%��%�, Ks�*igarboxyl&�motif� �� ,<��+&�i�particip'��*pathway����mA!g�1ammalia�J+9By�w�f,>Pnd-e ment� �p� n�.� O��3%t: 1 )%�&�can sup==pHR-� 3.�J�n�FNtic�";F!%~>:l 9���&�,!w7n�oq�'t}�F � A@uunt�w� I�@&�}yq3E�&GIR-��i/",% M�%f �93��amXTR�Mw��M�c3 e]���.�'�(S"e'�'w!�f)�2�e �(�m���y)Wgu eO� x�in�to�le#K"cu�!$-�on [50� M3of3 to�.7$7��evonF�-��de>n� ::i� f��+DAspŚ��mimic1B�� �E�_2�h� telomer�!�H%NS�earlyz)5l.[5%���*��~ �8e-r-�d5��B�;�8� unT .C tt-2.V�� �*K!�l� �6�E����*� ( unpubl:!� J!I$Taken toge�k8ue� ults�� a ro7r�# 2-me�^�>% �!Ź�.N� 8inZ *0�ncert�y% . For exa�:�.a24 i:zdu�/G2�"�raA�"� � bto�Ka�Q >m�}As [53abI*6 ���VBRCA1�� �� ��'c9%�6A�327Bfb_ � [54]��hq-Thr84�. a se. pe��7"�DKB[� �-s"� �� ampt�cu E,Outstar< quesI��2e��W�a&I�V��7en�(�C x?��Do%�!�;�� acer8 phen�Dx�rWb���! g .��!|�*!�42 [55] ? 3 ) M�"� ݲsynergiz�;th�ru�2�� ~N7 �q�{=teEL-*�a>toxA �!?N9��Zr2�6]E܁� G1/SF�3$rogram [57�Tt!#:2&�4M� !k�%v ib. S6:�9�">3A�s  � a�/�+&S . S+;��xA�i"�!in% /"�5c. P4#at� t%wdefZ(&1of� v���&nI�� B non&�(�Qors�(� g^diYorS/ e }al��) �ol D' enzy�cy,X !�g6� physiolog oma� byM��[15!�[22��Ho,#a�"��tegM at� o� 2���ai��( &!,9�r����qT���O�p I�M&�,e" anip% ze��5"� ly�ys�- molecul�?� j<� uitAPn`MOoccuri~%�"}+ex�:e� &!-i�Ld>7 �u�pm3x9,A�i �2��nt-6 infer�9C� %��.�'A1A nov�y:9 [�$u, tool3veloped� sh%1�z,�y"�/&"� � ������In:�BwcF�'�4s% E��"�+m53�R��[5��U4.�>a*�9����'�sR?�f����� b4-�>:�i}6�In >��(rA�on>�� ��A-��:�,:"�s �n�t1!>�>�a�iM� , [59D61�j*�"[6G [63].}HowtE�i3s�, cataly�"b 6���|*K �t� ye�# be eb� . I�=ro"6-e�A�−/−2t��#��_ ���ga p53-in�  !>�$-�[2�*�0S h:.U �iA���,t necessaril4(Em9/U��92 hB`$scaffol*� ��:s mat@assem� dk1eMw �xes��; bypa�(�)q��,A &be� ectopiͳɉ c!].�p531���.ɗw�emo�]$>�95' v�";':�2p—'*}+",-Z�V.A$<i8 �-� �"�*7�,etE\,;hapH,virtu�5kW2�mod �"$Fto~t hm� � !�y�Fin�P o"�GM�;�B2�/2idAM2d7 a mo�r�6t�'Y pg:��2$Po�-yzeqD-%�'� ins oF %p���9� refrMGunpertur�HAr��-S or66a[64�=AhprP4pal metHism�)l� str�;re�$�NE� am% rJ�(>[6�frop�0e��awo evad�"��=S,%A�in1trigger"�(,�� w" adap�M�p�-E!+���"�Hesaf��E��e"'4!\ .���fu��,� w]b�te!�|�est[�i!:2}N�*8��Y;Ka*j2-��/ �A��� a*"+�?.B>s! %E��9R�C6�:I1n� A��y� apeu�"� &n~r� �8 &. &�5or6�?��=�( Dulbecco'sM!ed Ea A�um�A(MEM ) :F-12NMcCoy's�, $,A��>ig�2ppl�0e+K10% feTbovm ser^FBS�.�:��%;E0. S�>*�<�a�s] &�J�Ba�!�ly�ѡ�"��in un�,�8.�<,_- sonaR ic�2×5 ;Hls�#a 550 S- Dismembr0B��s�GS�Kei�&�9�a�1 Z�[4� I)Jblo�nd J�-) carr!� 2[33Ie�o�A�&�/: -E�( M�l!3�&H�),HSanta-Cruz Biotechn�y�tK1 ( POH � ti-P-T160 g.1�0sP-T68-�,�8C�0SJG�Tmieo�,( c�7�Up�A��N"}K |/ E+rNovus�ra�9�O1!�of>*> we u� �N!WAbcam:�*�EA>��2M"qM!�proA�* ��>,a�,E�ropho��da3–8%�s-ace�Bg9!� g�L( NuPAGE!ex , IngenE�I�c� * �lU }r�s2& {F)_:@ �P��) *ba�Ovirus-MIin�&m�(�� A�a�  *��A �0!<�d��CAK�co�"� nP�2as�q7/ RH��we&ed Mat1�epa� l�WG?Ta.f�I8#5 �J. K0re�oN�on *,L,Vc�!}ɅSoL�'gL�C(8 . 5 µg ))�&KA�1$ 15 m}t 22°C��CD�!e in9µl�0buB (�(mM HEPEP4pH 7 . 4 , 150 NaCl MgClY2200 µMK) p�<�%tS µCi"�Q�K. R-4aAdk4E�|<y�'��SDS–E��(I- autoa%aphyoi��� E�2. �A3 "72��3�!or�: a�2���d��sgO�M*�� , 1%&?whole-�0� �+q:�5� room�er9�140 ngA�2as-Hi*Sm�!�a 60-!�Q�� �7��an%�re+rW syste�25!�Hep� p=�%�-�2%M-�1 !�, 4%�t�| , 0 .7 g/ml>!o]3eTA�]+N6B�S,�9�=�[26<3�d. LNT�!� stopg�*C2×A(Lm. P6� -E��L��sod� Xdodecylsulfate-polyacryp?de��6�ia� SDS-E� ��� V>��1�fsc56up�4Mz�w��i!&�R�5Eʍ��0%}%�;!�%�=�9ہ��&&of�IV�C)*.as %�.y�!�dissol�5in�$eth)�ox!�( DMSO-}%t�f1��. S��fesi9 ( si) hom��to�vx, 5′-CCAACAAGGUUAUAUGAAU-3′�� nega� e��d!ex��1om "� S GGUGGACGGXUUUGCSI�y�D�DDDharmacon Research��1�"..! V��MA.$plasmids p=X3H myc � pCLN:=i�it� jE�43.�,���4)�5-.edz ��a9�:garith!*lym A'�hm�2s� )�andULN�u/3 Lipo7am��2000 (6r ɈomanufacPr'o�i 7retR<r�Tr��!HqYa�g enixaU( al Ey (S��e���<e2/��� "�I!*�;504�I�)(�/P'Zea�&-�plM iMI -cm2aKh� Colo�,Enc�,ed 14 d�!r�s�qŹ crys�viole�A��thodsi�.�4u$�@�%��=s8�) in T�B(S1 .�Tur��A0�diRe6*+in"ome-w�.h0 ( GW34 studlinE����Pan &e#ch�&ngU� �� Many\�Ts�� s�exA9���&x1ed "C;may li�$�$or[EgM�F3ppl�lsI dehyde-as"&� so��'�Gel�!a� FAIR�P�Do� a �� kary�[{��n erythrkZoidEu laMto�, v�!�hata/w�?ci5�q�hF�p.qu� �T�0ra�,�@onary a)9y!�e�MUmyocardz]infarF7�6�O!*two ��5exhbTPtinct� ternropen &8I! Hap&�:&�gui�We f� n3 �al9��]�an>Or%�!B��Be 7q2oQ3A�.�e&�R.�� E h�*r����X�,^ՔM� rs342293-�a-eB��Ta�volum�U� W-x:4 �in 64�dA c�Ad��7ev!.c*�i ��]"�# caus��K�aH)~d.%�A'C�1G-a����iY!�)Ő�U �6or EVI]�p�PIK3CG�0.����lesmacEag���,R –� ��p%a�net�%Bhup ��)*a'���� Pik3cg!�ck�myA�c� �(����Ga\,�*2�� �ne bi���iFrombu� m�,/uA�Uti)�QKal��[1�<9�"�9;A�!�b�of ouK[ ledgA/i��"first_GKI�elucid�"&:.\1�J� l��( QTLs�Our��s��( =!arN�a.���#x SNP\�es�"�% . I� �. year!@�$��gdri�I!�N�;!���> a�$t�\�a ��!�di���&�du�!linkage$quilibrh ( L�4�,� le-�>os\x m+Lsm��SNP!m assadL&Farge-6 %Cs��typ�Xly yield��7� �� A\B-�c� oftea�ilA)�Apin�HCaAl�W!9 [1��(T�,�4 desp3 g� A���*�9�,2�%��ZlittlE_Uo"ihc./M�Ac��& low-f�PI�Cho�#ed����"�!�S� al���$I � !ZdA�� tify��� e�u�B)=A�A D��d&-3( i .n($edD��� l n6�("of$I cohortEHn&�al anno�on> bio"�&EtA��(%�*z Qz)A �!E Si��m) i�2lJIUh�!�l)V�8�"tr�i�geR:�4!�it� )ost�0���!ey Q c�G�]%��* U+�*.���&QexertA�ir�e�*! �` Z�of m= �#* v� m� �[�{issFP�p a�G!"�#. (,gA�� E� illupdE�pa(3u�|P ! %x!a>!wQ�t�0"�)�+�U1�)a�[�\�[1Kn`&��A �(Gaulton et uH��=Jal� t�iq�^uspa<'��isletb� YHs"4of+ em��diabe�� risk!�g` s [1E�D 2n� g�ap�8 � ng ��h�S�T�( NDRa��e�Z,#jW ��t8f5�QiM�ory.�4e��).#i�J6 E"�zY;e{\in)�h!�}i�0urY!:,��c �&AKM� QQa��5A�eas�$ �bl�lAW`[4!�R�"���% SH2B� ATXN�/PTPN1�e5�>N3�<oT: coV� ( CA�a�V� ( MI )  !:a�)le7 ! �s ~��*n&�[1�Ju+wXi� be�N� ��&byQ�a�.9 ��"���Rv6JV�!*!(MI )s �"k c� � | 2j�'�6�^�&s@ 18�,�zQofyepfalz-toi�� T#�fU� �*7 eprocedaw�/�� !7�e�&���7:g meanU RV=F w" =y�&ite�:]in2�b$!8" ��,2� %.X.6?Q�5p� j$fi`%)� t 62� &�-A�A�EXre�[Qng0,��1(`of=m]G 2009!!~11� diovas���TF5N ( MK%ꡉ!��b� ( EB.. M}'z 67Q� ��1,�%� A�"a� � cross-5 ! �]�za1� t hybrid�"�$ custom 38�e000-olig8KP $array spanSA��ed)�(h�hxlM�e"O6���k highA" cordi$ �ss:�S4]?��%�95�%%w93 . 1%�0lap� gin!�!�5~:G$Y�@eve�er� inge�?,a8rT�#RD �t>>v each%�ž!�"FL���#BoSAc. A# �=ro�VE����254�251����(M�S1�,A{�147 ( 5�9)P5a6%>) ���@��� I� peak"�c(P�Tb�)�n�se1m).�?�7i�esk "�op'�<e|A�ENCODEz ject [17]�9$<the�ca]8�Il �tno�jiH4v8� �tz � 4� ,Q�unFdM? ( UTR�;oveA� #�-or!ic;1�*6�not��at%_2{9$ !~�6ay�!� �a# (c� �Ep�!6��� .I���mos�kly %9 e.n-":(O( 9Ak2Iw9�5%�AB�un�ls+~�� P� f Df����oter/�!aq��enrichn �fN( 2� 4% )&�G<:�r+, nam�#4 .a�( 63 -V/��6%a��� MK%�f�j]L ce�Na�oE�"� star�Z ( TSO)IN�7� 5)�7�)�5 �!�Q"���#kbAac:��0i�H&�1� ! &;1�as far264`"SkYg�%�a>Nc�%(( TBX3 gene�u��.>�igI"MK"6d5���hverage A�80V�mPfE�inL�@�>"o�JXx77X� as-��J�^K!�98KF.�3ss6 �U�t0p �marde.P �e"�c�� �[a82Q� � inea��9!��'r!��5x !tM�Y?3�?1�'ES� �i� �.�atkZ�!�:!��z�aaa^.V��$( Wilcoxon!k-sum tQ , P=!� 0225��A 9Atre�0f.�>�EB^�Ik �(e78�\4r�G$ lighr2e �)1 stud�y�6� nd%� *ucircue �4 �xt ner!�t7z>!C62%� ( i:S�~ LD�c5&�& �&B( r2≥!b8!l�j II HapMap�2EU.�k)u�wit��aaq�=a����F�D/ ��wrf$"�Equ�d� =*GW��w1o�D�� N�!� ��)?V �~]�‘MK"%’��=��*5��(5EBB5A`1d>O ( n=>T�e� t!fa8rbo� )�� ; R( MPV ) �C"�xe� �;1�,FLJ36031–P*���V�g!U��J DNM3..�z'L��,PD.3upm-�h.�� s2Y.���k08��4P:[,>ore��HaemAtl�,a )#"� �k&�#pr��"��d" bloo !�L[1;�-]!����(HBS1L–MYB%E�.h.QS� .L�E��%F�ELcorpu%� ( MCAO! ��}��B2hemoglobS~MCHA�n� d= � ( RB ��E�1:}�30)�!�40$ �� - �W��fA�t"�:�:&��gal�x ( PLE =ꅹPUFw ��PEAR1.�@RAF2�#;e���u�>� TMCC*�qS4F )"tndE� olic-�J�V ( SB�\bTC10orf3WCYP17A12�;�% S4G%d*�&u;�!s] EE"� !y�>�#]y3 L\"� in�N> ��W.�2��>� ��i&�dpla@��5� modN!݁�� '[o�!�9elmma��F��4uEzq��DX@gc��, �G��.�Ta!grf pK9leI�2�gk65-kbA�u^"��i�"��A9�A"�:�5}�h���::�� &�'*}� �2"u_.va[/�%o �31,x&�%%P���,�Y"��^f�}�������a�&�0kb2= !Z6n "�"!@���9I����΂2�" to� QVR*�<8 toaA�s-Sl�Er!!��)edVT MPV:�( MAF� 4./ +I>3 )�� s#V! �4v =���*�R. D�m�5!\1�*Ge�s� 9 Pilot !B� ) F:3/34 �in$ 2� �2 �3$�>�tm�#! 4 &'�>�A�i�� \���u -chip��s�%( 8b12�3. f1r�#?+ 1�]I�BT:A-LDA ��enoJ�!�e"�R�(B�J��O��6%m Z�� Q�w�w.Z�  silico2� 6'f�>�'�� � |7q6)� � �_. O�:=�.;>( �-)X*L 9^ ��H6�Swi����"6�� �&�n DpetP!"-c! J�6|Aas�uriK,��'s�ga@�R[� �&5"F�%�9)t)9�"a�N?s BARX�6�), GAT:N(HHEX , HOXC��9e�LBX�qJ� . Ba)1L/H"< �"�s&V�%�2��P���l R ���_�]e C>G ��9� lead�Kis7M �b:of ��)k2J.�Eis worth�!u�e�l2�9�a RUNX1R 2�)5 bp aa!��!)-� 60�ob��%�Sc�$t ?2 %e�iWt  '%e�(�7:106�75A39'!.887; 494��{�,health�&�, . No%Lror:m'va<#�"�*G_a rA*6Spri�B,e7�8tDn_�c a hyozy�4"8J�601; A>�9 �D o)AC,Ac"h�2� "�-ASa���?�&�"h)�B1�1")�eBd��rem���tekA=zz�4afu�Eozand�+.s(9O a���� �:6.*�o*V�(E\P �#*�K.�/may[s�%2� !?.X'� Y'6 6�a*�I*YN�6_or"� ^_DmU7iL�t�&�7.�>� moBEshift!P�$( EMS�Tin�%���zsy�.��"�@�( CHRF-288-1J We&�a b!- m��� buSur����b�,�!��(l�e�$�0-C%�$l2=0#(M-G�/p .<� un��ly ��(.�*Ql�=<��G+ert\+��u�>KC͛ �of� �.  un�9�u�Pti=E<[�H ��! rA� �"�m ,�:"�IDuw�_�0�}RA� �fC- �. W�"E)�e"�s �7an�"�A(��&� 1=���OrE�#aivY�,"��H��.G�S�F�E�a�_��.`�-ya�A��N���?3� e� also�fi)'��" <b�]L�a�e �u3-B ����"9S�1;� �y�Q&d�i�-�-O.7wժ��w�,P��.�6, �N8a�B &( lymphNG: , LCB5�(�y�li0, fd �L%"� ��"�a!}6�on �.�abu{dp.�"8018Y���2in:��.2 Go �A�.�&.��.*O6g� -�"w . *�P�FpB�AU��Is�`�aY��(p�8To��+�3"�\ Kof�2{��&T �%���%a5.[Qa�i�4�S~\iJ�8� * 220YKk2��e�s"'fl���Ak wilde89euaw4d->>gda��ast ±� 5Y���A"� on�<yX�� ��)@"9U��"�*�!�‘���of�4ZK�>r���2��\�]a� s�]�me.?O �"0: 0065008; P=�$97×10−1��&‘)�coa>ione( F07596F�)8Fg . No�1-3��g�$$ _ s Gp1bb (>m−�20<<�:" U"C o>�5dGp!�−3 21�, Gp9����?99�V�F 7*!,Vwf ,!�3\"All f�nq�b��.zic� a*`@�Sn,� � glyc�mins GP1B�PGPC�GP�"�bwl $A= Nk)eP"�;recep�1�� �r plug8a�88�iY stasis(�248 `i��6` fibruY!� � cascadeKe�9 K�-�9ad$�^E�o�" coll�E.E86E�p5�V� - � !;on"�?&8eC'oa�>ß*�9.[^^�O�. F�>-n)@�AIpse� core�fE$\Q�Mს� �-sourcb5nuTQ� E�" Zbia� q#�Z:�2�dWC`� ��y.e&�#�v.�n�1[Z (*!Aorbted 45 !9.��g!��%n�C64�3=�A'1067 S@�$/�. }!/?Q!�ȕZ3�" *��� s�:';facil/'���I��t F3.&i�>E�a*/F� ay�gY|a�[o��:�!gr^F�4"P3_���/i�647[�EB�4�pD"� �A�*Q* e�R? (. p"�&Y  tyb<�V&�!%!�be�;)�� ri��izA,]"!��=���!pr�! "u63*v6b�AG�19AZE@�%�S� �t!�g:�!%K]u�)id�)"^::&W*"h�� .��*#8�[ �{u�C5�� R�5 p�fZ%�/D�e � vz�C1}$'=�I!tkn�H5d�C..�$��!>'�6.) U�&W�YlJEl5 �{s��a;J. is5$� � eg"�I� u2.ly�lu� ��b�}��=8 =�#.En a��5.Er!.� *��d.VNDtf&�*�F�r\��crutiU���oe�AE/Ee� �%�� �zcloses�re.^# ��7s"2�#,2An�qor����TE�Q- 4ioq�chP z�.�N13�1�G�Hq9�nd �;4`in�,de-3-GSγ.�bu�� lipid (��( PI3Kγ��%� ��!���I$I�cGdz �6Ȅ�Qatidyl �ol-;V 5-bi�`spT( PtdIP$ ) P2; PIP�  �:I�"/-trZN#R3R�6T���bfal?c� l � [25�EaIB�di�J ,� 8 2; OMIM: 61355� !!�!��@( Bernard-Soulier�pdW<231.[�1hA�UAo,E��g*( cred��"d���I�!i�- ��! �s*�)�(�⢍q�ig5�&� Nsa=�$J�dis���!�TUBB1 (% �_cyt� ieXut� al g , 5q�1x 6131?, F�$ V�jMecy+ 2309!�nd P2RY1�% blee���L "d�D 0982%%SZ<se,ulau\��@ ssum� *��c�xE�-]&� *��!1Z.<2�� �P.�,S" &}�u"&�).�hmMc���� re kL��A6&�G *�Y�}�e� �m�-GɸdeB� V�Zv .�"�s��'orX' AN!nnnexin Ve�frP��!l%$��$)�/�*,='&f��� �( CRP-XL�K2���uǥ�"� �(ik�$8Uod MA(�2k�& viaE���.� VIZJxGP6R[A<nt�`�"��BlYQ^F7 1����(epinephrinev^�]� &Ywat� ):8�'a� 93@)A-igh LD �-�8�wV�8) makA3E�"-&���.^� =$Y�s/)�� %�U�8-�5j�Wiaa5!5�tyros!A�]�8��Fc%�Ŧ$ hɓ(( ITAM-FcR- or G��-c�]j,a�Y\!d=�>��7% E��CJ"ifz���a�at�>E1!�noe�%8_y�"1� �.silen "*ik�Tiϔ � ��2H�* Gp6�#>�+R���xs��?nl&"!� \ ek�*�"J�$"_+GE$�#�� ���G���Sacls6*����V��i!y &�2�my"yU�8J!w( eco�fic viR��O��$-��u#-� wo zinc-f�Fr���)( Z� ZF(�fe��DN&�&�&�#[3X�U*r3s_k �Q�t \!�.*�. Uwa�( eque�"#�9q6�E� f2�5r�� di�2>>-9�WFE�", �jgo*I)�lth-"my8 AX�᳁� )MK-βSGF  �+��"bA5!C�G[3�Qb�,�[e�SMAD3ŭ!�=Q\�$ �3��a1[3�c� %�wsU(%IAq ract p%( Run&� �"68m7A�QYi)6α-G� R:CBF8-�� T� |--<+�%!�.�doA��s �� �'0B '��D �E .�8lex��0I�"�} %�l [d�By!NvN*�&read-� "f%�microaK��W-� ughpRuex2�' |�v�otX� w�'"�<%�r JF i0Jz�d�d"� "���� M'2�^w �U&=!��*��!�VKq.��r95mA �+ �!�c Y R55�qmak a��_D;l�c%T6/�M&-N.r,'F��.�T�7dA��{Гl%�fkR�A�-� a li#�%*�QT�WkU.��4�N+a_��+� ��'*|Ee(l �/6E4CAD/MI���t�y;"8���o!�3 ��c"y�.�2�`N [P�/b�>�i�� .�S��s!_,� =��"X =>b���&�8:�%$�J!�l�Yup.�I U � E���EA<8ca��t\ "��r" �|{�Kam�<3.9Aϭ⁔ rs2038479�j� ark .z-��Ŝa dyn�e �(DNM��I^*M�Urt7ɐ:!t0ag|!WHO ,V�CIY1{4.q�!6�8w�&�.;d�3e�ƿ��X�gQ s-��H&�.�a����BaA�rapidly)����lt�'"�&���=*�m&e�]�fav!�!�w>�x�$benefit . %����;�#�c��%a%Xp��G��0��/Cam�QgeshiUF.rol�0&e# BioRe��@ ( http://www . cHbi�q�� . or�&uk/��ay� eth���>�$�NHSv �R�iE6$s Committee�cT�us(ll�o�� xg .\t�c�D�a%2� UK H� Off� � ions�% Anim!�(.!uP�U�DAct 198AEW{ig"aj5Sti<%x ] NimbleG�rusA72�wn�O N���@l*QE�TcH1 ( N�} al H�/Ge��5jI"�&c�� &��.�,6 �-m!�gov/gwa!|iesItHn�g�R6qť~�i%"�!>�)C,5��?shB~�<�$8��asɱߤ&��h%S9:5a�� �?!7vm���"AnWes�4" �2!�C>�IO]"���V�!�o�3"�#e�ee a����s�4'�&�N�����.ach� �wa"P7e��geۆ j!HAF&;�w.`�>r}bʡ hotspots�>$ ��z� �2E�� � exce��50�N��.���`�,.%d��� p�"Kc�� *�.ei�aͫ&�"re�sCN%S.s�,2 �d*�.Yq�Q��(�U>�ps;.�"`s !�" *c2D:1"9I>�W,( 50–75-me��b��2�"`!�j-�'5�� �)�de��)�&y/� �S)E�Afs2�9� K562%����K8\k� o}&1!�.�.� es/}s��ɾt.� 2�"[����e�*�.2��|}8�i RPMI-1640&�}�#l� �]20% horsO+j>(?t-i"�dN1% L-glu^p-p�c\� -str�my��x���%D��GwR~�kheB�,�uM G�MAX-I%YƻCel1TRg&37�x, 5% COC10!> umid~Batm*"�.Mq& -�.�a�ken~d"�*��BriefE�A��!O�> , 20�+"T�v&J\1�1%=&l\J8p�E.*O~� �<�nd� � o2�~���ze!*30>�a�P p�~ ,�  )9 a�Bio�Aor UCD-T ( Diy,��u2&� ���J��P6� �+�Z�l-��v :�ethanol�5�d�ep�%Q��1LRN�"ȭ��nedy �4MinElute PCR P�{�2Ki�*QIAGEN�A�=S %SH�%��pply.)9�� 2�A!����Q�s\em�unR2�Q.� labe� � Cy_1Cy3 dy!�2�&�j]-hy� �u�.J� ual-color|u\ �^D),!h E��@ ���9�dah6� ��E��:� � W �:&u�oco& A�$s User's Gq,�; IAtWv!Z�_)"�F��iue ASsoftw\ qS vP0 >�a;� two�5nel raw� 9�`Qp�&}�-.^�subj�PTu1 bi-w� �+�M�log2-�o val�h�\om��>-cG �!�J��*�)%a sli%�window�ach��*y *(,���cut-of2dlu� calWba���0er�#a�6��tEmaximu�|Pmax=a�w%*+6�{�ard dev�1��"5$gdssA�- e��e v^V�-lP�[to Pen��f.!�S�E �ak�%KE�A�%t��::j : 300 bp;�K.� bes>1Kneak=4;E � ��&=>)�=90�`�=15 �=�6<&`�s:�}OyQ{�rI6�4�����as UCSCjBrowsevTKs A� ucsc�mdu4cjcak �!3/�C>&+of����"w�@EO�!n��I��OEna��� v5dN.� A0P�o-S)Y�Sa"&lg���!�ee7xLi�pDi�ilS"um Re�Co�v nd S{{Eng w( GLIDERT'�,�&\F^:B�v2��)�SAF��Y05; r228;�,ߌx�!�����&�%;)��3&��on� A��Gv9E&� Omni�s( GEO )F%�:d$ncbi . nlm ih .aeoA&�2�Ces M�GSE2571���im�a*N :v�]o�N�E�sux� capill�Af&fa�r[St.76N. D4ei!+I��![&� -[:+s]��[aaH uk/r�s/$loads/� /exo�B. htm ��� �Y byS A���A� bi-d ��H��.Big DyX� mist�sn 3730.$� ( An Biok? u�%! Y�]C�airx ��� �e-tagZ�� ) : �b8TGG AAA ATT ACA GTC C Y wGA &0GGA TCA TGA G: GA A}�(FB$A TTT CAC �M��s!!ng!�u�{����/i�ch>UL 28�2UL99671�)%�F637V662 6��-��GI�*ce��Ű:9 emi-e)�!��al��"Q ExoTrac� d"Ɩ8,WellcCTr�SI�&���.�Po� /2P�{i�e���.���a t�JA�� a�I��N&��l_46�i&�Nima-Ald�g��&gR�M�LuS�MC��lu�s� �H�8vZ��?. Each 2�q�tEm7ed 1×b�, 75 ng/&��P�I/d�H� . 5%)+e��,f05% NP-�U8d>5��KCxd_`>�M�2 �AA�x �20�^mo�?2�aU9�� &0�-�69�2��a73o,em"7�.bxL9�%��$$( sc-8707 UU� FU� &�J( ab28838BO�ͦe$O28679~P,L�'.^ B�c�`�It�{f � �6�>"�' so�> ?WeG�?��a.�P d B!s��v" a TRIZOL�9BzT�1�� q�df�i�!�NanoDrop�|abtech I/&Wa� ��� ity-�}A2s�Bio��� Ag�*t .��� SC�MS* g�=��y d c��Ue�Ile�$a BeadChip� "�:�WG-6 v2��c��/"�I % Ref-8 v3;I/fat/�I HT-12�B� T�, � �wa�|���AllAG&( t 6ca*��EA�  f�}r�10�{ ough]g�)wof9! , qe�;i�for"}+s(sdL!(ssE�%U�<-ID: ILMN_177043�"e0et�ey�o��:�*'�GI�TaqMa�oAN� SNPAc��(�e�Ms�hm�U7-��3ph��9� 8-�� 2M-C+!��670-Quad : :DM-Duoq�"�a!:��&2�%�K�+���=eF��"�%�gtnox<As>Dl"� $var:.Va�"p)-�a{of��6` X!O[���3�K2wr2�:^b �6S�a�a�c)A֡sA6est�-d �S��(man's rank �Pe�$!�"7as � ��P-�.B�6m�"J���*#4&[4�: back~� m�,C57BL/6J Jax�� *R�aZi�raHB6J;129-0tm1Png��t�Y*��d�0ony' !:r�ar�-A+co((6��r x� 9�6�wu����ng-�N� q�*a.T1C�C TCG G9 GG T&� CC C�"� $A GAA CT (�'d�j# U!GVTT T1AT �� %G= �QT�TG� J��!���ole��%LtNP)��;)�fP2�w>mM�femalDf�1�[6 weeIMouse Br�!rs DieXLab s 5021-�X)eN5q ���$anesthetl I��3i� tro-orbit +inu� Wac p�S��7 �$RiboPure-B6j#Is�t�0A Amb � Ha�v_!E�E.b,��toA�e�J�)� .:&8. A�&��, )�nd����O�n�*� F2lb�l"�o%�+ce-st+za�� d1�� �)�le�!B���u�$R package w &Ez�o�%o3 org/ )s/�-ase$/"/<.&.% �r?U��s�lE"V �E-#A�r�*&!Qy��"/Q� *�b�0%/]vW��� !w�yфEG*�by 1-�*��"�~ce�NOVK'����>&~Q�EM�/Li�AmiGO v�#  ���`��{geT: . 5;]u: MGI;�s+1� −5URH$�J�� ^MAE� �(i:7.�9�%��b7EONj�611!Cme��O.�O����|dPort PȕP%�s-�BioMar�#�w-,ej ,a[mart/3��A�th�&&�� E=I/UniProB]unin ]��v��Z�M��� �Zsee14��} ��3:*hNE�*}.ff.N}T1."Nv3�B�c"`ys$ reduDW�A rst-�M.��?)�! �Rt�;i�onn� ֋s� }�.2sidO ~�ew��g��� ac�>�A�\"m�'&*�sMY0� � &� "iNs} fo�8w�]=scape � )%maA& Data�|S` ��cm/p�f�9!��)uDcOclyI(p��U �r,vol�-�D�|n���pYe�stood; h"shxI&�C�Iarl'(O)|x%Tpre��&�%�Aata� WD��i�}ofa�3A�e�� ival�>o5 gard���*9 Qe��vo�. U� A1u^�si��w*�LI��p%f4A+5beareca�WeQ=� c�!��fCP�I�U�n!�INavq,a\Rto){��rhythm��� A=p6 ötqe�=�%x� ���i�y neur),� wo&�:%5Js:)� ) p�4o��uu��V-t doR��(n4�3e5�x?d�3cs2A rilu��f�A6�D2<�+&!�>�Pi �s5"�yAbf;��see;�%���kory�4�� 0�/de&�wy�fO�|7�& =r+!�^��ce�N.�matY8 Ř@ T2eV�L�%� ^ evel-"�Y&Q�_+8intac�9D��!7�A� a s"n#.�ly ;6%48�t p �c �'iobweU}�Q�-��-,expla7�5b�.�a��%"�bq1��9 ,M�>� 2��%� ,װn�cP� sEj�0n*{��9��%uH@�?ad-r2D��.�!%l@yY�.��fa���ii- ��� w60M�,l(�TO�E9�)` ^5L!�/�n�)62e8��2R�z�eB�-���-ort<ri}&e��1.� x*F�>%�v`pd*F� �o��j�� �@J!��ngi�l;(oV��. P:���ouF��/.�z�a:da� apvo� �sD�c�Mucx��ѱ theo���R!a '��(!olP:l 2]IFsi�/"&e5E��e�y���3onB)&����E 9��P��o�-u� �f6 .�alIҖ5 )�ef:@ %�*�;n�7Q1�� go�(��.}��;s�uct�a/"�0�cu� ����t� E�V�5y6QI�;[1(qeD��is*� ����)r�iA��q�# �,m�ng=�&1 `r�1�>� # 2 ���z| n��;�+|C}fu"�:��V�P^^ i&O I���u�M�5.�Z?�>S �,br>h�%��"}9E=\�)z!3���Hnd�E�%� . To6��Udea -y� 2�1=�� �F.Hp� r� Ewo��m[9� h!}~-�E=!�� :6Z( TTX�" ( RZgTX 'lyu_�Na+� [3V4|�as9ess�:v� -�@J�r  aaV[4–6aJA�5:a� both�( ≤��n-�!�RZμ� b��nJU�lyI5 �;u�gfasI on-&yF� A=1y��� �t&� cave�%o�U),*eat ak6��F excitae synap��Wmis�a�&4!��N� �[1Jz1yTZ� , in vitrPo blocking studies us�TTX or RZ have suggested that INaP is critical for intrinsic bursting in pacemaker neurons and network rhythm generation in the isolated pre-BötC [9 , 12 , 13] . These results �l�~)��R6 .B� �1�half-2m5? h1/2�B5+found�e,!� ilar�AE��:�B���z�B1<teresa��althoughyA.�Q`� thr)di>ct�A�A� �s � peak:�Mar��markably�-�CEOT�@4ity pattern ex�teda� $uron capab�PfE�]�!� termin =� excitabilc. Driv,�� ����to high63ŀ driv�C�EJ��silA�to�!a�A�onic spi�regim�-�6�we inv!�g��5{f!NM<h � !ؙ�� !�for!�ACb5(�2of.�![t` b�� ferr!:geometry: projIE��#Vm-��-nullcli�1i�! ( Vm��)�  e��mbAA�def�G�$dVm/dt = 0qdR:: Z solu�h��9Sequ��is easyXwrite down as h n u l l�D m ) = h ∞ N a PD( 1 + e h 1 / 2 - 0k ) - 1 �Vm9td&numer� l�!�e�nifold�8paT%�$ree branchEZat"nect ata�dsA�0“knees” ,TAan N-��i`�=�-planaUI� �+s betwee^���![ilibrz poin� FtA�E�E�3�}!�.2�iMmiddl1)EDU{E!J+ unst� �'2� �urr$ � a 1$limit cycl!6��h.��M���CAw^7L .A ��� �g%�e6c2Jby mo"G lef�Sright EA�larger�smLr��e�!j>;,2�O!+�relevant^� behaviors��]yM�!�e�8 corond�=in� d de2� 5 nee!���� to�)��� 1bA�5 ed . As is` e��Ih�5in"�>�until�pA I�2��"%�!z��eeDI�!h]��� SNIC�OaA�-node/ a��!b2$le ) bifur�Bre�!>�gU�Z�J{A� iliz� {�N�Dr.�ed mem�y`�ial , W �[B� 5F!j� a5���!* ��� c���44B , gray dots�c6�&� .�2�Ac:},< �a��)!� ward��:8.�I�����,�/��,is diminisheC�!contin� YL2]:�~^�~aZs�^��eZ�./ J� t �K�xM !�ef� to quiesc� st�occurs�aI�.�� 4C:�l helpu plaͮ6� %^��winE53a�i� ))�O�donZ %�� �[’� �"; % v!�t&{ �J�,� n� �ed�� ��Rcould� elici*�&���� be� �)�4AA� K1v3Af + �oa�� GaRQ���N�, call� h�L K:uc %D%=tra$ �annE �>?|po ~entir:�a�C !}Qa� �,�sŝe�vex��V& �_bu� so(level' inpu��IeGdee�>/s�D!H2� to m.6ed v�%�a���ts סichJ�e�9upRXin[�,.�-k"�,�,5 Dre.}�6EA�JE Q��9�-�2 a!k]�newT h ˜]U>2c��!XAJ�h!dEh8lEץ�.�Q��*����be� :�, $i�exc!�]original�hei ,ma. I! is happen� ^ 5 �0�G.�~���!�a �l�q�)reb� m�. F�i 6toi���( ��sD !be�:� )2� must^than 1a� ata�is phys� rea9blA(�!&F�X&����.�6�,E�(�v]mainta(l/enog.�5N "�� magnit�a0.�F�� to��6���a�=�a&��:c.qqi�rM�>Q6HպA2�� �zpossi!��a narrow&, , ∈E. 6 −�A55 nSq ���.��@�2quicklK!co�bi�ly unE^s�& !� J ��Galway᳡��� d5�!�a�B8f"�any�9.� , because2"�O UׁAthu#i�6aQ�'͞��6i����� �"RZ>"�%��aO*� $�a�zi�� :�bw"y ��a��x"Z ;a� mova� FB@X � ate|$( ∼275 mNof�vL2���!*$2�"�p p� r300 r[� T� %� 2$2�-A9� repeti<�E�M�� ssoc<d�@ ongoA�Fe���,bw%Q�%M�Jgener�%Ps�"*V n/%&�*F�XE�ndAc.���tT!��!ed a hLq(ous pop���&50^F� coup�(�all-to-�s��[' ses;n Ma�"al�Z�s�P�ll ldescrip%���$ �i!�te)fh��e�in՚/  (I/I ).�!:�)ou�to�a�fiD .Gɬ�:i��tro slic�I!���G'24��n !yE�cyI`J� @,-�"s chosen y���630%a�Q�M%��l 1�1P�2I“X/+�-O)% -� a)#[25�All�U� e;!>a non-Re� �=�!�typ# each �!�"�+vs�T )!�*$�)he ;bI��tr&set%@�Ag {�s��"�$�AD]lA"rw+sal po9� ( EL� (�ofY)A�q!�� ribua��9r�%to�zoduce}��-�}�.�S��� �90�2�-i� a(7)�al%�)�� �­~Z�&esim*����!T$e5^%>�]�ll �� �2� �recru JQUoscilluh���:Gcan�p-}29"ir ��7�� ��B)Ose�1�* ����zal�,A7"�(E�a�AE�on"�l#>�'�Yb��b�>3iJ�sdeg of uMrmI\@ a.6��/K�a!8gresst$&�#in5�6�!a�H��R,aADr�( I�$an abrupt P/�~�R�)�8A & 8B%�WJ� add * f-t�t ��a�b� sid[10� �/S .E�#!N�-�!":,�)02 20μ9,@ �%1)n9 ���0. 12�-3�-{'ls�+u&s glutaR rgic����� mis�/[1�2N 6� of RZ-med ��n�}%2g2S�g�R):A�R�# B a�akna_e"7+to'h�B:�}�.u�d�*e��nvi�2�f$ng!��!M9Tre� d t���ISynE t)%��qa"�!�[&�&� by�!(#l::+ɜ6�.ypar ( WMaxEE�.�� IU)~�o,o"�)m�q�pry����� � 22�sle��?3 5�>�~�m�"[)\+ut�a��A4eV�]e.�/� ���se��a��z[� o wa�mpaq-(ed��s.t �2�G. adap>�[9) �#B*�. .� dos&{���&iA�,ral microinf^3of.��B^of neona�0rat/in\$� % v� ��}a�9�8of ∫XII motor%0DB�tim! !x� arise 2 `9s%B4 plot!G�versus�.2 e{!nw pun�HQ'o!2"�6-.�.>�I2���"&�"'��9)���T'c���#1 minuta@;s*��_6���&�a�.�eEy9SZ��~�Zm�s&aer.J�3eJ<%�F�L p5 ��B����?m19tA��&� �!�9��&�. b 2f}op��9A�|RF�6 uab�+��A N���imp2�extraw6�u%�5c"�P3s&62�Bat6y(=Y�NM� 9M�2;!L�@*� 25u�"yh tu &]9B *B* �1,Ѻdo�)%Ein]�:���1)5n��!cI %c�i�/*�5eA��W�4�/%}"j�x matc�!!z� o9Psd$A�v�W)��decayed/-:i%JB}�F�of"Z(z(�V� 4To �j&7�i 2�at 5 � , �was ma�"�� 7%q7BL4unae2��Y!�t)�10V!72 �a15NbL2T "�0%�*T �+ly�;'*� Y��9Ņ�quantif�;AE�thres�( I-�T H ) �.ic�s/e-h jE�2e &�9��b�6� 5we o1�  e �.�4:�iit� R!F�+� ZM�:�,�R^ew��a| 9a� 9b1�9b)�I�*,=�=%�numberA�%]s #� � s bi�!T�8�,� �Oi%�,.�1vYi �:fi�8� !�!Xand/or>6�(Z�P#6.@F�.i�IQA/!�:�� vidua&qMqo�O2�GtoQ de��.=E5d.�46� ��*�1h�Q}|%�.S�h 2Xi�n�<B*^ 2*6�R�f�!��%*�o*�# precu0,ڙJVPB�i�n�up �i�&�a�,*N.��8a��z�� a fixed b�&����:f**gi%>by2#= - g�$ · m .� · ($/- E")+ee Eq 5�|j�9a�+ng:��#�t@+6B�j,',a����6od!%�re(? a� )�I!on� �Hi%&.A��:�i-�0�&&?:of��9�E&� � ;�,(synchronous50F/w!��A�e�S�*!� � { ile2��_ �did��E#F(<;o �@�5g!�.���*� 5�-�"�?�No5>d(1�-I.^J��4a��7� edJ�&� k!<�'" e�,%a��a�d:=� �9na6� a+ePe�!uprt &�+� �! B�".�"�v�D%v%Za�ey��\exa�inI��Qn^e�a 2�d�5���.) [tog�*�5fac��at%S��� Isyy" 3$2��(n<8 unI�0�Y�ec,s whyU&is un ��|695�%jiI se�%�5%�:�>w.4u m�%cenario6�٢�a7�= *� ower"���� 2�1�$ =!�.� A1?AC68(urve ( i . EI��[-&f.�Figs 2 &m�� hift!�acsn� by3+�h !w�E3��/rA��e�2g2E�9��E.*I2N�YF=)bd&�G.�2 ��sch~ g&"1d2� >� �%de-' m*�1-"�,�q�. B��!.Vz&E����#ik��ebO, �=���^"\ bath2p�" drug peneD!�� �?pat�0. ����'>WHb�#�1closes"�-surface ,&�i�} !JW�-!mio�?p�9�~I��� I.U �&��2��E�pl�2;�'E#� !F�&��e spa_�,G�!���=���A�-��BötC!�yXb�&��onU!B�dis"� w" ��N���]�]K�!6j, � �;9I�p!El!��in�"�%e�11�S�N-&t�69, %-6)8H�,random �.:��_:r��� i*?� �Fee�� f|N����D��9�J�'e�@"�6�V�*�ٚA} no ���f�*BsB�/ 10�T9iLW)�.u""� i$i%�s��#2o��(�(M0&X!or"� �a��,if:��e�e���94�*� �9m��RBa �>G2�sh!�8v���@-�-���0h�v�+of fe}1�ach-�� shor��%�dY4rec@/re���A,!�)�s�P�U%,2�.�@Dy���Bi�¢��EZa��`A��2���Io�?�Gw.?,l�O)O9 1�.>R6t�v&: ��)����i�N.�)�;v �Buc�a multi-*�.�3� � o�'&�AfcAmammalia�"�.��B�<g�)or loc�F �B�aL�1.+"8–31.� ��i)~oa A�Xub��@ch�6[(K of�9�a�:3�w.l"� t�:gCi�.E� �\ phaof"!)� �ex%-�)�#s:*,,�(-�), auga�� @ # aug-� e+�)A�"z-l9b17�&ar -is  +� F.6* ( ���'�&�3�-%Q �/.-*�� po1YC( p^�sL26�E�^a��Q�\PE!�. � s{8 vo��^.�Vc+,9Z4�7aM�.w1���C:/�(��B!oj-!�>��.� Mf-��z^�O ��<gr:e ʼnw.#H*��%�V{B��*�2�A�,�yRi� �!�. !B�(V?��m? LA�embedj*A9!�( base�Ea�\'�y�emU � E1�or � >� u�PN\,�-AB��Extz@ ob�8A�2� x?7 ll t�X&%,-z, namK0 . 3�'�E07(( cf . [32] C�N��}U:~Pve4/Ŷ!`B�5�*YWX1�2p� ��7�4�(�8_�UI62�A^l/�L V�ya-qL�\��w..�&,E�le�U.��-!6=�NVEW"�<t�=Ii)�%86� � a���Bt^�X I�Tt�P&x�sE�la�"�:��)e��Dn)���Lo�F1!]7U�28?.y[B�/U^�6�y'w'ha� UQ�"�(%Zng!&/a�;/�? �f1C>2�{,!�3eI?2��;�?y�BR/a�a9 ��V,ed%��B= %D&#�Y�l)Ve 2}?�*j*G)-� x.,h . On1w featNX% i� s�&�67 at*9h��s�on�S�OW u5&,��R "/&� ���U[nE!ci ���2C@a)1�B%^!  (�Mogo ��%I-%� �����a�f?� W�N�� 6 ���1o�;7&����!BMKIa�����.� `KO �H8#�T �%3a e�F� strengtL��L��Q� 2�ITE�A 2%��� Q�byq%1�B Z`C%�12D%�I&�1��na�W%&x�.N fm �I� .B��D�&�/sA�9.R� �J6d�R�0 rs*Yh�h &��Th�(09q�Ga%�"�UE�#.a%2+� �JA�a N%�!Ew�� ��r��6e1� �9�F�<�i 1�.���hem;"��H� e�^ Y�~!]⭤ �.�.�ra�"I^��Ger)qk1b��1%�� �a �XD�S2�R��N�m/�-�5Db5D!@m�=+ eak��e��^k�0�!"Q� �VpC � r�g6iK� \lq3�W: q& (D�be ��1=a�BE ŖZis*�d2�.�B�=5? z enha��%�:�.2��v.��m@�eM�%}�ed �W �I�}��w�8�/K<Q q%� !r=�!L1�-3=( �G&s.,.ii�s*�`wC�!12 �"AB) �U��G��B�6�&G)2�'�F���‘�’=df-u.]= 2�`JP�*�Wg9�A/eu� , nS��n: ) dD�D=�15WC}W!V. II!�Clna XW*>�2D!)-J<"� nS acr�BUŜE�Fh=Q���U�"��I�#za�]Wm5>D  G O@��|���>.�v��?@�C5�y�M*o� �mE �]�is.W.a[6�1Y�,w ep�Vc@*�B&M!�≈.��R"NaL8�h"�:�#& -�A�1v cZUis��stM�o>ѨbF.�K-RX6�F$�"T \���$f�j�"d !�rea��"�c13�]^7Q.#�gU T �erJ�6 r�aIu��!�";onship��� d{ve�Zge�2&6�$Qe�(�b�/!�!��S�1/Id .) "� i�'@^jG��&&gl'lOg�d6)zwa��7&qs�A�rJN.��;Q!d &�,y.A)�� �@�# �n�. A�3a���G�#AOµO.�almost�;a˅z�.�I���!��KB�`��Q�a>Z��}�ndJ�y�nj���fM,��1�T6;u� ��A�r��;f2�m!R. �� ���<~�@I�*�.��2�o���F"���;�' L�9.��S ��aZ�LAe�D"�k*�2V? �3f��s6/�.J9 &)y�if�;RZ!%]$AYb�~.�1|ouv;measu���tegw2d phre�n�h&\�k]�A!h{5RZ!��AF"� /�8io���) �=FlZ�naDJ 35%iaN*�#y+!n&WgnXo�/&� 9 ��%"]4 �%�R�46 ?F�uRq��9Io( >mu��9n t37 42QKBQS(_�5n�� �wtf ]��f lapsI�!������rpex|qŦ* � CE� *���8-ͪ Q�2 �m�C�0�e )�>�<pl�*�qsel`��Ai��q���*attY��6�oll�#�2v��6`� �34 �z�ute6al�^provid�qv,nnsBA_o�:D ��KNd!�"&�PeA%j7Ape:kJIt well�� stoo�.C k thin�]VIx��llgaT #�,es�i)I� "pMB 6F�Q#]��Jr�%aXokom=~EYA�O!���E> u�:pB�>-S1�-{5�v}� %AZ�H�"5�HS!b�91%5��iK}CŻͯe��pE&00V>� -�ou�c�m��*�1Nvv�n"dQ�.�Ur��`�:��e�]at!���7 �&�G look.:x@~�s�m"� G٘�.�)�� ��rL:+-�I�5i�l�.�m�%�*+QA�E�E@nc%Ao�au��sh0^p62>+ �&�st/m. >fT�saa�Jna!� �hF?Co5�ar�Ye AX�Qo9m�V� u�:�a)�A�C2A:O�%(u P���Paa�M+0%�l9U�$� pr^�#.:� E�)&�s� if&�#X8` /+-I"9N�2H! ��*��nd Gy>rV��[b6��s�&� KA�5orK9TIi@�  v�IA�N�JY��0� cl �v��� _a>CAe�&FA��2+f�G16fR���H to l��%�yWMLa���/R{:�v"�2A�!�RZ�AL�J���Ha���B���b]r�#"�q�G# s�a&1UB�2�.�0) ��>c� �"� oVcx 2�P2�- Vp&vE��A�W'K �j�mod�!22v^��>j f>% �4b�\�s�Gty��90A�s�`e"42f.�&:A}�b� . W�se.A�WFp$r�""� ��W� � ��A�)� �5 >� Qx�% f=�re�[rN�41!���� 1� I':OxeO?V :}� [sE�$a��mpromqHo9Oa�B�I�QRZ���Sf(C("k~ ,��P6�)3�Pa�2�&I �!�%@:� �)���=)J*�v^qb�E��{ !�Qy�Վ�:3Z,�#c6�_�J� � %F)aU�i� *ZA�݇�:� Xс60e ��m �/�E$��)�. q5�� &�1&��by�?��!�q �M �>��C,|"J`��na "�6���6��ͷpoMWQngsNa+� �{:F� e"'[ --a؁�T *�I+>�+ia ~SOJ;��dZ&6�*`!Jf!�fir2M!w� &�%c2�1� I�1�)i����.�n7T�' cave�'�����to��Fc6�Qprel�o���dH�vF�fighlym�!��o*9t� �q���>� BpHW��8 � "�.�� �i�z� V� ;(n!v~ %3� .&:!u3AC�@� " of�1i��> N�)z��yin&�gop--=q2R�iA��Ec"�6$r�opp�!�)�T~?��-�''ԁ��.��d�ia�e��at�"jC� M i�5�5A�-Zu6v�[18�WT �-' ��tan�_�/1*�W GABA�W!glycin N��]�B +��qo"�i�ic:<Oin 83%� �9�^���.ZQ�^Y )�Z� culm�S�)�=�Co" %���%�2<v4� .F0%9\:�).y�:jeri�2!��� %�p."��Q�pEh)�!5 |ic6� . Hypoxiak capn�2��t�l"�AD-p�a2? �nV?�-B2@#FxCi�0an2�'adl�Z D"�.7[�M�x�HIa�At�7�c*�R ome*�?u[z��a,:�[� auth�v� a W� !��h��-�c�- J4Z94B/&(,"KIs�{"BZ�E/`I�e��f��F� d*K�)��. I$q"�I� ���!�a�� � n.�'3&�q��&�C!l��e]!� =S "<@4:�ipi��i*�L25�& at g���& . 98�D"��to Z=GMH2H�� �!> �Z�Zl.�Oy�6�5;��-1�'�E���E1a captF2�J�&�&.K�7al%�p~x6� .� draw+Pom�:� &�~2�v)1Y.UU�z0��r� 6�.� L ���a�"lU�e%��T* ,>�.N�k X���d.��. C&z5qo>V_: j.�"^ � .��� �4Z�a�.�(2p�15^[Ua59a�3\�"c��e*B RZ (�C!oH)�3tZ����C�0� "؅1"r V\ae��out��A'A3�� �F1iaI�jdatg"s �^� � ose��3��5�("�bpW) > b�1�onZ��]�6N7et[}&Z�v%�T 5 o6. E]��z���� 6^> I�4. �V �^�I:%Aă&e/A�ur�`2hse�H:�;p> g�T�%�ź "�D醹+ojA"�#\�gVE�U!M2�_&SA�E�d&�1IEt��I��> 0q�,&�I�� ���!iE%^�0�ra��b�� 69��e� �e6�u� littlema� �2&!��Mia�62�2%l.�7� ccoun�,!P�!�A���F:�� 9 RZ�`F .�{�@�9g�Dng)9��D*�[ �tt��4`Oe�~byM�R��k7 �B�m?�� clam��cor��gconju�)�~n�0ݛB�~q(*�A ��S�*����� ! &W+*�,%�Eq�,ź �. Par^#6(%_ alona�0&�!��.V�>s )�E�� s��'"�p%����"!�.J 2+Z.��Jx\#F yQ��#^�Ů�re�oI��.C�Ps{sa�F�Lof cium*K&�"u��G0�.�>!Q��kCa2fL6+2uA�*n ��"�ihp�HN-�q$yl-D-asparb�re�-o�hNMD�2.kDetaiX� �� dseZ�"���5 beyo*D scop8 a&. MryTN�I  *�)xj6 *�k!���V l>)� g�&�8>*q�ŖA�GfN!�ɐ�*�:�7�)�J.�% live/n�". ��,noprJ�S>)S7�cho�r�m�h{w^� �)M5�\med/=K�@�rac,< avoi�� ss�:"R!�=�1R� e�� 8 ��thFNT��F� *) b�f�is% unclea�@aEu�b�topic��� ����%�&JfueaER&d!�a=n#�ebf}$a�� 16rbyF��Q� �\�]examp�A*�g�B1of�QY�2O�&1 H&I � P���5A � pA �K"Zk 2u2�gy.:* [25 , 33].�N�)�["d :B��1aN����Wha$]-�V or�R"�d:&��V2��v�}�P�We�a)�,�'�Z� -��nVr�svN;9�, sQ��Z��re"km�Ce�.�We p&A�N�W.K � B�� � ��2��W�k�KA��T tP�2�ul�m��gerIy~:10�0���AI=bNive.�4:,r}�߅j=$5d*��(*�QJMw)�\>gSE+ 牟�$a�*� ��}�3����vthickn��ndd&um� at���(prex���*�M�"V�-}-��R8&�kfC&P);S )��_S�y�var�wid� -�2�:7.963�s69pm �s�kQy�25 -352-�,�N)(pA ���7�y�,>,.�P1�� ӟo)4!w [3�(� �;A�siz� �4�524Q)��M�%�expandsJac; o�k�"�z+!9/�t��xs~/T� rw�%�t^�,9G}q�"�*2z^ g!o�+ caudal ax$a pW��h��� ˗t� c&lleƑo bN;h�żJJ mE�,l'�A;6�1�A:qR�;an� r��{*.@RyX��.WD �� K9,I ��B[u�Di=6�y�t6l]� ��*^KCo�� H�`�&\�Z��*�%�N%�ck ��$fKay8 ��?A�way!� M�15�f�L���$primari0%�e.ph�sV��%d��8 redoT�5p7.�}�6%5ict*W`:�9[of6�1�Y̊1�*ep�D��L��Q9;�!:!fur� "[ �!q star�{ ]�)�.C� �-Mي\I�Ca�'U!,lac"Y����"� ur�f� �v�o�P /inad��-f2( 6b[ y ����i2�2���Ֆ�sq�uڝ� (B�) ᕩ2(B�c*z �7lyazG u�u>�WBV�iG�~i-!"u�ޔrar/for�9!��$� RG!�1�"H �� x%��pp� inse��)�o}�� )p�L�4�,)k�"^gr�d�9to��.Ebo Cd2+2!�s<�O�o[�li�X$r�I.!�h!F��?�2{6k z�N�bAp�!.G�x�h� > !���� /=�����4 situ�N�x�= m-spg>=LܥZuV���AT>�)!�rR�P��� shfv^�8per"�dI!is!�^r,2�9.hn�*� s RCe4 anA usy�='��>&$� I =pO ��AI qa"h= � l#Z2E�;'D*�,*�uE 0$2܁�n�S�d/R�y>l�~!ϭ�!�F A��z�2�:H�2:9}�/>feC#�  %HA�!gB^'.)upw:�"ca�";A�"� ��( ICAN�Mi�Gcellu�� Jn1sA�a�0^3:e�k�(�,o��5�mm��tI7' �"�f nGH�ri-*��;5–4�^� s.���G�!i�� �I� �!�V���@(omi |�}"R ��is�� be j���uJd5�:�%��i I64r� A-�m�&�=h^E"Jn� AD>7R�h10�|�*�%.��X�r*� Ƀnoominor��"3�5&�"0- �M!� y&E!� ~se&"3IgF��/r�onML4�A�aaty�Qi>8BW��,)��#zQ[46��r�&f�3 `m��.� �AȆ�#�V�trigg�J�3 �G[3-b39e^ , 4GC<&TA%q�.9"$)%uf��N��6�)����X� �mTt����].V�& ��l�*E ����X!*��r%PͬRv����>K %=eq/�!��e�� c2IB��iF�a��.Zo�2oaM Ana i� %w.�*�T�%��Kor�v� &<f��al�2N"5�s!�{� }nWH"���,.4oN�2T�2��y�56�A>x�51�H �82l�_�+�D&1���Q��9ye�. &� :�$ �A�d��,.D=2R�& �W��s slow��\?�pot}n.6�[148*inositol� phosphate��P�RQ\[38a��S467$Na+/K+ ATP�[E��� umps [4�^47-!�ud�d [�_48$��!�%nd+� F[ng.)i�3*�&;�a`3& 1��/i &{Bh:x b#{�x*mac d.{Wy�a[)0!�*HAw1\�6Na No��f a!��e��� �.�1/��./~�O ��*#�,�*&�-�6�g� �+)I)_� >v`�,�!��m*�2�aJ.�`;Y;. A # theoR���6 �H` �FPon.P� jn'=�R�}agM!>T| ![��.W A�_"%%�i^/. S��A�a�7�è'�d>.*D s��)�� ��� . LoD�*p!Rw��r]uA�p�qac �n e*a��yȐvar"�5!2Ga�[2ιjN�0& �Hc}�2�[4iS�hln� 2vZe rgan����cos�A probW6azI!� ochaqa�=E�V&A@ay)4*�r shap� ���ah�85 "�="�#[2�d(39 , 50–5�/!-1��t ]+4a| z�"�!j���fu(/Me�-�uniqu�Q�6+X6}  ��&S ���� � vn55 !v->��� ve locok*CPG)�W35��56]�. ��57F�[5��5� 58�3IdE�$&[.��ch�bua� a��mEI)�[5!�60h ��!&�z!�"v ��o� !;! elseɮ�Ke�"cOM��'[6� 6� ; d(%�a&�2/&��� s �!nG:�m5�. A��e�@�z{e� � �oprotr̄٦ulsqOag~ [8-�sI���or0`�u apeu)&�=-$7 ��oI"disע/(U  I�w–E�ldis� ( OC_M[63–65�$anxiety [6 6 . 68 , 69+ysclero�( M��[7�"!^(amyotrophic�Il.0AL 1�TH=�|<3"�0RZ’��a2E�6t AU��A�"27!TE�O�abeneficU�)_y.)K�A�B a%S& >]R�����s��왧�!;{Oba��I�  � n�O� -�{�+vB;L!� �azi�" �common��[a�e��ae ��VU�.J��ck��H�9$!�medulla�&x="E#%2"�Gbroad�L9�F�%O[ng ���'2*O)�� Aj2.-2�� ,�2&�@�%��l��V�b��D )!!��@�Gfſ�f���� � %v�*FA'�g,�&�#u���� i��� �X _:H8�-�p-�f���-!�Q4�? �j w -0 *z*$ AV���)2lN� bi��h{g2�*P/b��A8o 3�&� ��٬1fu2�X��A$"2\8"b5d;l/�o2��it] O"��7:a �M�拾'�*�7%�.l:H. D��- ���advXc� \��'2�IA��".�`jrm<�ZM :O�6�i�; ��6�A�%[in CPGsM#!JZo �Xelucid�gJiIo ,  aCNSZ 2D� m =eI��*�'�'in-Kl . N0� ^B�l*��U�ar�rl!6corw�e�DHodgkin-Huxley sty6�],�s&�P]�&�� U�J4-u�T3Jb�VmHea&:��]i}�!Sf�w�#��eG' �E� : C m d V<�In�+ I KL ��k NݸC aK S y n E I�RK Cm = 3�^ 0 pF��� 5��E�C�)B�ILe�ge� , IC  �I I�KT�,� �,��,�Iy� 'P)-�ō��߰�1�� & ���Is �j�aioB*��a�� l����� )�s:-�=L��J�3 ykRD�JG!�9K#m K 4 &p�Kn��I5�0Q2Y��4 ) �P1I*�P � r)A5AAWp= h 99(��;I�= 2 8 �͟IM�E8I�E6-i8� I3IN3z(7I�giQ�{]Bo� , E 7jW!oA� I�miEWhiEg�q�%<�m� M�V ���&y M� Iv�Vn�uSYg hE h�M in T g���hDy&j�awB�<�Sall�����0f~� τ X!id X d��Xp�!�0) - X ; X = { w}�}0���  X��"/�*K�9/6� !<τX!�a <�Ht;IN��w)���!�s {Ktak !�[s2�= "�� +I ( -��a�/ k X�u( |%)= qy Ca =��@5 ⋅ 10−5 mM/f��x0n���Pac$;:ng�\�%<h�c%:�4�= 500l��6�qa9!�Camin9 . 0� 6 mM!�a�#im�a��&a�&n(-f�!"� *���g �E I i�!�w9�9p��5��ci0! �, ion:P`� T o n i cP+ ∑ j ≠ i ; n W j[� H ( t - ta� · e%�6/!�s� �x.�@pVj� �jI��2hITg�i!�!<�.#2 �!�&� wa�RNH0N *�H7sourc~ jA�6�i ,%. )�Heavip��p"�t deno�E� . τ� � �ex"��/nYb a�r~�q2. tAn�p�M�C�nc�l&T (�&��!��v�e���9=qfm=�L�,^3s8edz%�1�� U�G, W M����$y >$l IfL�0Max)c��/B� ��� lb%�Q"� & ml� "? a�!Y�����#bP`�re�rۉU�% p}� iM"� �u*�,�� � s�s���isiG4��"Ms gmd�����-y+)9�� f�Io,  �~IQ� "�P : a &m@&ų��?�oduzqb��iP .b1�is EŰ��Sach.,*��V�(U�Q��fA�.U��AB;]'Qf2]fB r+.l� ��fS)�(+m~�U�A;v?FJ�+)%R�As�e�kper�4age���!!X)��&�*�;�Q��hpg20-30% )j3H#��s5+�a�:al-�!p�of.���v�A8te �$"�3�syv"�!4�O�<�Wve~_>2Z"e�]8.Tf�v�,� �1��jb�1M,Vm�*�*"(�֥�{&�o6sp. Dataa煝.�d+-proc�j�DMatlabuath�!�Inc�;<3!4�o�I�b}ave'��΅n'V c&� roug���35mVD)istograWd�$�v�V!�-  %�=A- &:�*.�r�5� f�po��0w un�of APs8s� "� P&�*�,���8&�.>�by�+���!i�ak*� r"�M�&er+�Dval)�+=h9�&l6�!�3or�]_;�� n 8-M�Linux-s d*<&".�!U!>sofC�e%�custom [���_++���g�$A'�K�N:->! Eulef<ho�Сstep-�=( Δt� {T025P,��Mj� RNAs ke�/��um�<staW!. H!D� �*�/%�]$of miR-218�ga cfcecHG�9met`.&��L�9d�=Em!'of �JUO ts hvgeno�Slit3� k�"GC�"M8 RoboM Cs?(:�2Ia�is ne�2# �e�h�5(us establis�=a� 6 feedb@:loo�De���A�-s*� �������Na��i��- ,p��aJ1�!,e2d^͝ .!�=|�t��0��J��*oM�=��% �es [=�f;s W  inva�!-�Am"c3 vo�akz�I�6�,� , lu� rz�:ervO7�� \� ��7;t}.� �%�%e%$$ y screeA�D]2��ad doze�3"mJ�es. �x"gbH�No vIa�a-��perQss�OY .1i8 nLZ���1�� 18qA�!c:�oh�%k��!�ympL�dW+"Q � d� &� .C !re-m�y*�i�8N� ells�0%!�2v I�oQ A]�!L��-��'&�UG�Ci��cs searcs%1o�CA�we pinpu��t �Y�s6's �al C-�Qf�p%�!�EL:P�� a%�� toa"!.�`�xb,pp�A�`0�Gx�a�!D�Fqi�!e��� �(FYLm�2ŐdisܳkTF u��:�� !A� A�IA)� �L�xAde��V ega��w[}մ2���06 $"si��he �6in famkN��8��^��: '� lig}QN �U9�y*�G{��T �ƅ{��cursorI �--1E+�&>�6��*�(�2E!�� ����La�a^��9 pE�mai�}2�f $-2�� "c�Ft2�_� �k:Mof� �5�[Ķup�8A�of-x�0on�M�J� �l��a�veBP��>$7.��0�faca��*��eh��a���y"�1% !l,newVM�MT � A�Y*�i��+eyQ&9+a a nx�-B�=!LU�signa�I . To&� %6�m�FᗡC �ve�~% "� :!q"�  ��� D� ) 0��j*� �ac FigVP1�� �6�Mh�. Brief7A"� ��� ���͉�t��D��_� nv���?ra`!�.�Z!>�?|V &� coll�:-co�P!�r�on rou� ��|��A�E "la��ew�O�NV v_%qZ_ j�( 9N_ �.�*k@�!�!"Q ��B9i� !T��A�|��Uw�+�)_�1tof �Mx�AGxF�ly 4-M�2�N�{<N=. LikeIW�!�-N&c AI�m56Yy1s!s�cn]�:o m� ep5~ ,.r�${z�%� n��m�`�H\ �e;D%]1EA�l:�n��F�EqdeJ= Z�� W�P�#qat�Owee�E�in��!�FW�%���5� 7� 6?dis�vb���b�5e ;�ul�uW 5.!���:5�( �9��)J�N6Íe4ces in c�ell proliferation or cell-cycle distribut`were observed among these2p sublines ( Text S1 , Figures �and S2 ) . To identify miRNAs pot$ally involdin GCas�L, we examined global @ expres&in each2� usi �� microRNA array ( v . 10 . 0 , Exiqon , Vedbaek , Denmark )�hiZTonsists of 847 capture!J$bes for mahuman �s�h � |Presults revealed that!S.�of 124Dtsignificantly differed between< high)EPasive variant MKN28-M%�$the non-in %!� -� *NM . Of,se , 83I upregulatAnd 41  down. Compa�,with SGC7901V , 62�ET �nt)�-�ed!��<M6�, includ!�47:��152�Mj8. In total , 11�(found to be2;N35�+6�in both-;)e6�s c2those8� correspon�2�-�eW ableaKaD)� 45>?9� �, ,-218 was oneAT Eq displayedV^%�1�a�.Phas bAxreporA);BTcervical cancer [25] ,a�[26 lung7]%rprostate8,indicat!�possi!�3 ment!T%�Honcogenic transform��!�tuma�etastasia�However)0NA=2ly97e many��! ��$of interes� �WAnhis work \Z5<investigeQTin much greater detail�;o valid!A2��6G�assesa<mi hmN!�i�!GC2H0s previously !Aio�_!% 1immora0in 40�tissu�n )Ek��)�8mucosa ( N ) by2���� -ΔCtE�uA�t�scrib �>�.��4Z��w�6�,above data ,7verifi.71�BeI ,( -13 . 81±�15A$(ean ± SE )�a_6"imtha�Da��!neoplasA�5-11 . 62^e ( P<000# t = � 62 , pai8$t-test ) (Q�3i�C�.l����&�b�3BU( characteri�EV0GC are summar�*in �x� Stat-� ="�xoci֔alm��.� r�6P�"� ��is study�>��edian.}!�$−14 . 25-�7 H e 22 case��adv��d �( III� IV )T��a�he��E�F�xA�27 x20A#MI)1� 0Mann-Whitney M� e 18.�early-�7 �s �I� �9 ?of!We{��.�i�F�ZK09 �16% = �]9ly6[n>�(%�!#01#4 )�1e�����%�( 6G36��A�#��(�did not� � )ag!�gende. �siz@.� Q . Moreo` .� whe�WE l��.��!8asieed �survival��w�9GC . P�G�subseque: vidb to!�.j( nM}20�T .#group#2*b�o� � �s"� or lesa �F!�an=�812�B%�4Kaplan–Meier�analya�6>9` �%�sa��ed>�]had aPr� M�5j time�Q three-yea�r� of�!� low J�was 30%��gin:g%�Jh( 65%;: 1�jlog-rank�O;�gC%zTo�@�#�=&i*mu�,"� ? Ety ecU�(pGenesil-1-�or, 0ontrol vectorUk ng aa� spec�� NA ,dA67 ,  Lipok 200�GPInvitrogen , Carlsbad EUS�P�.�hen sel�0400 mg/L G418� gene%�V�c��.�st� g. We lM�pX &�=kr'e�@ an approximatelyM�$fold reduc�mF ig��i�na�de� ine6�os1�would�mot� Xo| ?6f� �� silenc*� e a�Ttisense oligonucleotid' hibiA��)KN�h ,-A in a-!� ) inM "!t�B"_ 4A4�yTo �ei�� �L-Son 1/is� �y� air�a@1� ability!� I�s)2exclu��2efA�(_o| g*��C J�of"� c�1�. Over-Vo��a ��6#rjv)�)�� e�9jS5)kS5D�kf_!)fi2|in vivo-;�bJe�E}/ ana6 �u��ńt��e�y.s5pr q� 5i�. nude�rough� ral �vein . L�!.li���h asa�ar� e�cA�j�y.�6�.Y ast , fewb� E\�a쥃�d�� �y�B�$simultaneo:"| Agrowth�:�!incce(j�=%�9pi1subcut{�X.*�B�.��S6 !��>�>�3.��;�stark.�no.��1�ҨS5��se�� �Af%+L obtaH from]�assaym M�<=�!��aatu4�!ݑ�to sup�.A�f�e�%Av:iũ �how aI U A3q���e�esz��yo�vd.�i��,searched�4&�M ory targe�zypredi�ytoo��&�miRand�PicTa0 !=TMSca�(Altho�Ihundred�"yE! me����dv"4m��.���relevan�!�A3 pect19bi"|fun���.�, per]e8 + lass�  oK�})F!xDAVIDA�gram ( http://david . abcc . ncifcrf . gov/�@ se- , Robo1�regar�S�l[to-e%�harbors95-pr�A�activ�$[30]–[35�,Mertsch et a�demonst � fac��aA�gliomaI�9�^ !�,by Slit2 [36cSchmidb�, bNt��>OiAduc�!RU- ���o)�[37pT�fa�ngs sugg|r >M?a-�e,mYe���5 � hypo i�� }�}�*� a oin�in &�(��N6gNM�i�ve)6('"ell�� :a negatC�k2���2� �m� ɽs*�S�F�&N�@at.J��Sh protc5BY ��(&Nw� 1���-{I%pF� *)%g��c wrseR��) eAlB�knocked'n� =,5C1�-;5C� ~inv~r-� ship5��!+F�asU�confir��� 0munohistochem��p40&)=Z ��Iadjac�pnul"XeP%� also"inF� udiea;�in 29_�eN� e ��.�aVC , e��nl&�GC9�Se��1W��a-zv��=��_5jdir�[ev� % �is�U� �!�"�7b�� site..io 3′-UTR ^e�Y��W���u a luc"9 �r ( Luc�;%�)�&�� n�compl��to5=<( nt 971–978 )I inse@b P(pMIR-REPORT<NA.bor/[38��Fly)CEig�da m? tI�-mu�!in� first six2�-vQseed-rega�6!�"� le��,E�aa���, w� � a�e�� rag�!� cDNA � Ctrl  �.��mid �co-B�9�, ! ,D `%�j ���6 �!�]X�yL-5TE52��qa�6$��!YW"to~c-�@��)o i"�5%����e�-KZ�eR�of� butDno"�n!Ty�D%�T#f*X�"p$u .�%>JQa� e��S. 3���!!� # be �Q4l��)*!Eis�� 2% e� angiee�+�Svia�.~ o � [39�![40a�s �i��� w� a�:�y�a <��t�� aZ!�o�!a2WA�&f Q2y� �Mcg� ntir�ackjW3��< ��madBe Psi��.qd:��6�*bI%'�Are�N -# %�� �9o� �( 3�� 2)��6��Bw s ��B� ^BQ�B�A�� @8F.  �.aI�jo9��@�'�caa"a�i�vduFe�ɀ) ��'A-e�b�2e���-�-a�Q}B%� � d*BG-"u ����#5.*%rH ��gre�6����� 6u���^ �2�� K+ O&G CbyMB� +ed%��q7f��gs� ilarJ"� af�5�! u/ ��+�m��E�"5F���8+ :_ Q# ly5�es �9�>�Two typ� �'exist:A*er�&��E� 'E�� merloA�l)�!co�(�&^!g;m� thei.�(pri�� 'r/r��%E�"dj>�F�Crs!Ӂ�polymer� II �lat!�U�!�Me �� hostx6�b٘���l+b<e7�[41ɕ2��1�� � tr%I%o�wo wcod%Z� ,9"�)-� -2U�J� ��#of�+2=� 143 �� U�6� � Mk&!�A�m�tw&� !� (ompaCuBask���>��.�tog�!�M.5� � a���)>+;% qRT-E(to�-M.l �� precursor�!�E-22:',-`�M��3 MjGC"�� "���. *%$ �.Pcoeffic�����.a. �*i!�2O.9$��U;ہ1)�f3 �.32][B6C���6�.��[g�K6�a�Qa�!�i  B. A�? �� 2 � � s-i�0;�H,no su10r� az.V} e2q� 6N�6s�.# p* ��ȭzd�a"\  %�� �#"mH'CB�(�YcluJiO3.��2�0��vs$−22 . 431%2(2�(.� V��)I#21&7w%2A 2F,&� 6~(7�(M!�; B}(6��K�&Aj2>�!/6�&�:�%77A�fnGe\In�(�Uexperi[+l �D �&�M a�Ra�!�w0se�f remoN%]3�iS��"B%RY!��#hwa�b"it�te�0!"'L ��&'��&�  T�#a7h(itA�vi!to` s� �de*4 odel8!� t�#. iso� �!vez ~v��pop3�,BestablisHh�3e�!s u+ yrep�/d�5w� �"ach�&(&�uccessfu5 appl�+a��0s$&'9C*�[43�4&Q9!�&�[5� c!)|v L � �.�� "�2E&�inc,,=Np capau �. H�%�scree�0aP�6^ deri 6%y6gEZ &9�&�,��x� .lowN-. W�&� xcep!�!1� ��*";%6� �2qu�si , siey sh��he sam�� backt(nS/ major�cce2T� " 5�i"�X5��_vg�%ቺ.SmA%�e E�%F- *�)��method|&/F-nguishA�a�:�+s)�OA�en:�A�@$� ` step�a.6��p+canAFbe�3� � -anim�Re�<� s hav!Xena�o�to�B [4�50]�R [51es54]���,?vii lwB�� o�$ 0!�pro� . Non[ F*Im*�(} �� 8(�7Ar�mon ev Axw6ieft6I)�J� focuZM&�on 1N!�F�/ acts!!a �U�#!!M=�. RestoA)�% "� )�"g!z�".[�.[�&.%�:�[�(a�at>���"p�:r��,"��s�Vby�*��� twel��colon��!�&�2���pY� 10"%2Aex;)ed^ (arkably uni1"��5gŵE�� �<=}.:5�-( randomly c�-$n monoclon�"[)Q��w� ��i��bl�!42H"9-F9u!��!g!%oft��N,4�gMC�cya"�vi3(�on lea���9 �of �a�3-�3 of r�4&y# ly h�+oag ous =�Z!�inim< bulk p"� A�� �(fu�u�fF�systemG'��9^� unbi0�&�/i�est�*��7par�:re�%a�&�>mD&s:�e'F� � a crit\7�gstrea '�%!VqD. I[ kn���E�Z,an axon guid`+ re) ora� e  8@�,�tsA�g�G� fruit flAQ0 amma�"IW ��ree Z(I3�"�, �(�A.�des�[5~<[5$T– �&� �=nv� ign�E�repulj?c98Jx�8�s*coAdu-neuA�d�op� +!� icip3t6�dEe�y=hemotaxi`8Ś64�Au@n$3<ve Yal� &aberr�&}q�� � 5,�en&!�eIet| ��` [65 �` F�RstE?!�%carcin&�sa% �!o1*� �:L>�m�'!ic �6�o�uce*>of�~>��%!'&)�!�"�esZ�&�&��&�(a.b�B��=v� l dens_'B)QmasJ��xen (ft0 �'��ang"'6�:�&.8�()fO& ew blood �s� !?"�* neovascul9�M�J�� m,�lig �T� � -t�:$phosphoino�de-3-kin( PI-3Ka�/#�� or!�%�/ z9�� 9�']t6� �Ca:m��6 m casc�a5����A�!b�W��of6�ol-{ 4 , 5-tri �a�!=*La� )[��m�> GTPa%ωl! movX#J�deE�m�M4n cytoskeletonI4, �)In��t6/�3sH$ argu���!l6P)a�=C dele�s ep� � mod� �s pla>� [  � g�[69�K73E��p)C�a�:-- [.�pa*�:%�� A.� e cury0s$;�/� k ��(��4Jt � X .> �Ys%�at $BE��;�k&�C!yoppaA�" �. W�(we&� %���8�3a��A{#��:|4a�to"M -Y "�(:i�$� �(-n�%<�A&�=�_)c��P>!if!QI%r�,:'Pv�0�aq��A�+&�(a'h@m(aɊGinR�#�$4 �� noti�E/$aa��of �o ��&= � 0!�1#2�c�~rs9�d"� !�� eXA�!�]E�03�*a�1 �gen2mby�i�:>5o ducADNia � !��h RR,�A�/ ��al�F2�a weak��1�)b��� Iis!�%SCo/�1b�is�)e0JY5�>��a'�B�"�%-d�!�1.Y�At�Bst� oEdi/t)6�)]O�ksI�!X���m2& �%�-as"7=%� W! �-ly��a�&U%��&g-Bs�(B�)ith��he&�!�1�"  ru~+��.�extraA�u�!�ƩTphenoty2:changes;! r� , tigh�)�!�M� ����&� � robu�)� �gdui�. Anti�V1� qantibody&� j��e'uFlq t ������#� s���n1P�� Z&� !!A �"lyaAqa� some� $��Bn!X� �D� d�n��I 3�riah^  famiRIf���/�"4'A�s� lap�r"}�dI�s9Zc��!�" 60 '�%�=J� � &��Aw*N 2 , [74$"whi�K lit3A�.J�.� of orga�nd "A' �:!�8 iaph�+�kid�B[7�3In agre az$se�6>��!��� �NAI(*�b���? addi!� c2�ES��]cI$)��l}"-fnN�63"� 9�A �K /thus Y �A��2 feed3 loop �� �PlitJ$ Sa�= BarikJ�F6�#�#33aQ"�= �% B�antagon�c!g &#pr (E�6� �1J�b6�P�z phys&�6g ��i[7b5&�a!�NA#-�-e� �:�:� s�c� w/�_! � ndq,�G o *� =�-�orEopmYqI!7�%*AB�Ek�cep�ala�ce5 ���/M�qVmi��=��B� e���r*S �/A�:�Z-r��F&�in;T  f� ��%Jbuilt-� �&�%limit � ss s��propaa+oe�'�9�>o�e� home�Ov��%�n!��q�is&6�a�� novel me��ismA�M�ip -� �A{ . Ev�RoA:!!+ @�circuitr���`ye�9bG%� PBe�0fOa:�Z z �%�4J*͘�)Wq\� ^a��sM E&W+��U4]u-w ��� prXes �ins � ��&�2nGC�� g+3gse0 �"����helpfu� uH���&� -�!�Sel� >њe?.��c1Y ,�E�;h���&�@����ve�s�P2e�2�Z �� w��veS.���7A���Uo. U�'218!�GDdX �16�=,?e( �Frt� 2dIM��@-rVr �0���7herapeu��y� A4 � 2>�jremain�obU$"�Bd!^JlW A  ,M��0��f��E�:!6�L . Im�)�,e�"� I-.@Pq d�Ma.uLEQ^�u�!�a�� . Al�&�%�d�X��# % e InstituA�8al Review Board!k!| FourUVH7Mi?al Un�A;. Writ���.onso�t2�Y J"|� !&Y&'6&�>e� �al�6� Comm�u  A WR�A�ɜ���Wo$alt �"} ce�nd� slab���CaeRp%�v�W)�routin�A�4�RPMI-164�Rdiu~?GIBCO,IR7I�l� A�u10% feubovZH seru�100 U/m%7p�Vill| oiHd$µg &�ptomyc(ulf;t 37°[ a�i_� ir atm<C%��ai[15%!Ebon dioxbH!1�'o9� ,�E� e�e'K(arithmic ph�ZG�D. Six-$�/cO@n��membran�s;@)�8-µm po\(�9�,�J���'�:�%u�Ol�W�v�$*�cul�dM�� IX�9���!J%�IP�\A� 24 h � suspO6 )f�YItoZ6iA�m� of 5×105 s/mLa� 1 mL [��a�W:g��top� mber� � (coK%2�KmLnMa$#,el ( BD Biosu.czSan Ja, *LI�a��wJ beneat6 6�1�s�fila1 � . 5�9�umJ@20%6:to� � �c�� grad6/�t�GAp pene�B�Q� !w�Follow��incub= or)�uX�A�I> >o�#u�aB \�c!*2; z 6E`hAYs�Aasa(�7��expan!���"�(. Via ten-r� �|q&I�f�� q8���( �#P`)�de�� �iCY)b( qA�2 �'$Nt*N\}^We�����.�B ��:�B NM ,6'*!� ,<Ge�, &�+u)�("I3�A A 24���pEy(��SCo:�a,)� meas 4ea0aZ�'seoryE!�W `*�#[~)YA�, eo�\4������!A�ch�?yLSaE��DQ��a� sI,A�< h =i�R�A�dr���ni�eZ�ri&_�a�T�,�.��.. f+�9eR2����� �����fa�QAc� -F� 75����at�� �G�\1|. Ag8����a��ki�=�-kwip1�cot� woolaovan�aI%ATor%�UW)��� ��%�R�%MfixIV 100%e6ano 10 mi] air-)�,%in �11% crys0 viole�!jcou�N~AcroscopA�]�1�Pri\�+�K!7eV&�'QS9�~(r�&� #s�)�was�/�n ��PBSa'`ive-week-old BALB/C-nu/nu*�M���$a�$Shanghai L&� : Ce$�China �"N" bW�FS^l�AQY.m^&�1a;hB� -�s�Hto KangChen-Biotech�'q8,m)��ghybridi�$��!{CURY LNAA��h.i�% arrav+ipEu���9ngl�1ple labe" e@cr Cy3��Cy5 . Ba"�1sub�� J�Ms�4�}�a":hkV%A-8��.( FosOAC�2�. SYBR�^�/al-�����r�5etect�[�SA�All?BaL��ChsR4 RxTb^�?Dda�S� (�zMe�!;r"�}�!""@M�6� �4al�1ni�TB]\Eup0tec No�Americ%��( FlintkG\Avenu,a|Diego!�FW:p'I0.�!vV~�#W�O�^e �Ui!��$76–150 bh lengt�/ERa;Vne�tem���of"�]60��P%� Prem�`v��0 Softw�. Data�:� d< �]�g�8?� o�618S�f�or U6$mPI"�6cal�,AU5D2−Δ�g.E�)_ )b"&�r��/e�$S3 .4pDe�wz 0-docu9ed  &sM3a lipid^��pEm�0l� ��osclero^ le��.P"Av�3@morbida��kf oron>a�a5p3=)strokA��<Z crip!^>pK� .�� �����Te'�Bal�n�ryL�f�<i..��>�profinat 10o  erv�1�067�Vn�ceI�h�=-like�erchol�*!m�L�WgJic swit& "der=�o"L$L( Ldlr−/−Apo100/� Mttpflox/ Mx1-Cr� . A�f)GzE-�)lowly�f�! "rapid�:!��a�-�_a�gZq� A4diE� T|-)_�(� at�um(��ofI�-po@oac ages��c# poiny)a# d�/A?�panE�I�cccele@Xfoam-A �e� � infl4�,��& pret �o�;by� < �U%p�A��&las�XY ( hg . ,�9�)!�?; �N"�$p! ����$1�plaque paIeX(}u)� �L.��e�a]w�*378Q�-T)�;A��'l*Zʼn�MWp!�[K-@(l@9��"� cety�d-LDL !'!net�p of e�=e.�.�A�g��Er)9�Q<�Jc]�. Tak"vH,"�=[$�Vs�m"���7B -U?-��J�M�N��o+ �sh�-uQ\c�nsQZ!�.�of#>��Dap,7. .Q!B� "cl�wm>�YA d��� beco�uc/|L&�E! 50%��*�8,�,�myocardA�infar"+( Mjk��ba�=u�deK-In-��9b�nA�4��R�� �M�k��[1E2Ag�Nt%�g8 ^��2p� !�!d��[2]&#+ sE��� s�&�demX(�$[cloi�R�S&,A�ne �A�&"[#��S�Q�=c��]Y�I�li��[S,Waa -gen�+�� ln.rvW8�}�mm!� ��] [+[5�umo� [6]!-`pro�c��fe"p��un�to unc #"r!�pertoi'��R�1�+ �p-HlexQ�s ��>�A����i|eter�4I&��;��!�We� heV�2���)'[7]ihad%F�!$f JJ1<-alhyJ�>�b��ra%3�Es"�block he�c syn� ".+!,ae�]�BJ��R�)!�*� Ju)R��!y}�."�*O|..�>Cg�f. /&� sacr�%ayb R3450r60��(g1L� are�Vd��p&�tQ�p �iIa �zJ|7:Q1�RS�&�A� C^O�V occaf �4poeo Sudan�qs"����&o{q� Z2nh+I.? EC� l./kt�q O.1 &pi;H∼B6%���| 32)j3�lP�o7�Y!�by<�K2><3 <4<<|A�]:�fe9w�fatty�ReakA�+E�xp�h!��"���boundar�6) ;N� 6q � � 5-;>I:9(xn�+anR{.ct6|�e aora���`"M �BeN at!2 ���L� �![(r�]�%�1>lxa of Oi� d-OYz6�roo l�Y� ��pr�on�9�Bo U�I�Xw�s CD68Yq`Ip�2Yl2khOmLP�5�U.Ll� ly� gKn�d!1W v#lycerA�glBxe�Eun��.TQp ND� *� EyJ���j%�32jX�A�5��7q�� a&(Of 19 , 879�+( M��G'I�'�Gs�b&@, www . jax . org�. 1259�q . 3%�ta+eN*2t empiEl Baye�vws [8]A���qC� �� aris�A( FDRi��x�s� ���32�27�a� TE+� !1>i"')�Of-2wo.Ie�fB�u0, 78% ( 88/11S%0D0ub:�� Clu�"�T"%of~D��!�)[� "juqL�m�Qtj�2BUI�S2��1GAx1�294 ." b�%vi$1C� dqꅷ���/�퉻�1Waw�,�Zj? t��1�}T� �E !w�<e�9 erce�3e ( 36A0 )O]5*� >0�\:��LC.�,1!I� d 89"� tEn"'� X!q%c��!pS1�RS2Mf)si�Opea�\pek!]�+MSV1� 331; Y S9a Spek�G64]Q3006E�!���� )�an��g8)8"� ."�_73%%�n�ɀ)�6to€5-�AS1�yS1�5S SUT�S26bY�3.�39�Fxwas�tic�:lD��b�%�o��c*iner-�z.H�gA|8CIZ ?1B� �{��susX&�!R�,����!}-! per�#>%r1��2�: K5C�q&/m�*J!E ��� a im6o�5^#yh\0[%F�85��2]t'%� d"n׍� T rich� J=�V�&NSs �e6�5�A�Z��[ �� w"�X�� i .mb�M�r�bi-=of3b��Δ/Δ �n3�e+.N�!�ed >80O 427B54±31 �~,"� �*�Z�for�&!s��"*��k�!�<ii�-��*il�sA@�� trHw� y 2LU�Jsz&�_ :� bYV�Ca�BGk-�.�(�A�n8Thu�+%�6J3.�e�>6P~+"2JxG��A%�z��J{&2#A� molez .�9�G.� (�albA�� I�R%�� F& �ng6V�D�&� eC9e6�2 >0 "�&%�%8U�d F�'J��by Cre.�:coF�-<�-&�)!�,6qthirty-(F��� w���n�q�,.��&v�2N�i� }vh�)�truQ) �>2�s0� +�c�>F }��:� 6"-�E�a� a.k[ar�"��#�xAYG A�TX .��` . NeT,.��+� n ~" (Gr+|�[)�K�AUVY�subacut :wee�V�,�% judg� r-surfa�SarkB� , J!� N{.������e� i�� *��=�.ME*A�� �/rE��H0erMV&t&�BV�mL6I$v�oh�R��$ V�Ttak�il!� ui� iR 3to�' pI─pC*@Q�f�p� &�R�9��Na�>or�4) wmsl[sMf)k=� %2��t6�"J�iH���2�Yb�=�eo�e^lo�4f�#el�f�wt/wtM"�%%,K���ճ pI-pMx0�X0/4&a��Yex�kvD� >\�I4�N�� lr��*�a�2D.e z1�L���4+�c�����Az�!n���is8Nz�$� �\:)( i H��&�0� &}-lV���: *ar�L � � loaexof.d already���*2 (� s zk3A�l2�� We �8�/Q V �� .���s.'.~ 6)%l}Xn]��a6"bbTo�0�������6jt.\AndueTHP-12Y�m�? �A�:�C)bPM�E�d& t�ckE@. v�& ( Ac� 448 houUseV<M�d�2&�|. E&nU( Affy�4ix Hu 1 j;0+�a& $di412 �a�-˕!"4 p!��"o� 2�un�1f�!�,( m�W �6!�GPR12�:�338558,#8Al:" 2719�� SOX6FC 5555��Fre bemJa;de�/7� &Y�^"�r�e�y"��E���%�e eno�I��is=3"�e.g}�t�O �eQO in T�)�F�i!z$8ٓa 9-by-9)�m'A�>�He�5I�div�e� !#�:�ѥ��5��B @��%ؙ�. A�=ar u*LF$AvfS&o �^��eA#bed [���Hx d7Se%da�!�E� XAPW=(��$�cy1� p(�%urRA H�=%0&�Uy l�� p)���%l� Ye�NA�0`"8)�%NU1�,H�/2Xx�"�N5 ~ltI<9%_!�ac�(�1-%�r� algoE9��tr`Aoff";r2i%m�re e "!8parame�'δ)=e92� ��se δ* #���C�9w_uniewis val� :�D� . 60%:�/ �.�n!^n"�m�diX( i .6-dirɺed�e�Ca� )Ong effD4 ) dof B�0D b&�P�a��|$uin)�1 { (E$�0ig"�/,"4aor*g 0�Á�B�su�s!�nanp!�H���PRKAR2BN\7���'~%.�eM�n�&�.)jTA|��[- .��?K��+ �>[Iu�"/ 4�uoO�X X"9CD3J(94�H���(��) n�xr6 �!�F"�^10QUa$!AJ546w [1�ww�Fzo�+t.b5. HydroxN6roid �<�5 ase-$*� HSDLJ 8426�up--Qed ���M%-2�� polioviru��P"6wPVRNw581`lso1�ed _a�"�]���QlS�*ax � t�+asly"�&)�aw. F� �!�of �M 1�� %As�L.n.~it�-b5�Lץ�~0ng-w0/!��L�>>�7 �7wOo3v�0� y � �P"� ��uy�)��捻�/�i!IviBefs�=%h�&h&�1|4 ( C�u�a "*!d�CE2��m e.�B ` D�GrS>;X�n.�.��"A�.>R ag�Ot/&N�1�n��E�"U:�A6 �&�! 4�#�l�;en&ve�,9�im*"�?*�2� wit &q�7��inpB . I!`"�7E �5�./-w�'}u&�.�,5b�\��>�J*�5nd�S�r{&�#A -/ �)�3�4�� GJ�X6n�>*Z&��$Iv"N$q2�| k��&� �(>5�s.�� �K 0ia"�7�od ��F&)v�6�z]q� :�!:4.1KH� �" .!"de�[�21!h< k� en*O7�7t �rta�S97��3.�hal0R�.> a �1EA��:}px6 p�^��M��*� L�Jse ����C �9�� Bw�Kv,I�.3"��!� �BfE>r�*7 �9?��~T "��]FU"�io� �)Q��-"9THP1─r���N��exg-�Zµh'>!B*|6t2w��EM^=����(�"�&�A��_)�9iBYn)Jl.�(�6E7� ��REs!>�UJr al�>ሡ{� ��4S� 0a���շ�>"���atg��3"-ofJ3`R:a�!w�+i7���%�:*Mr�� ���Fx"e?�5�G( >Ye�AyiY:,� adm U��Q�y!e �i&T�5���wOr�&�!*�&� ,};n� N�b o� �% ad�ɸroblem+!EN2 >i.*�^!��i)�)�s�Zvc6�/�%E,>")[,A/ b�+knowl� �gM6rehenB9en�U�7��a�%i��ingY�<�\*�|nd ��w�Lz .-I�a��"� �,J�=E[4$*N 1a���r rZ�6�infilVS/ 6�v�693��eAl$,�appear��Zher�F�'�X��vI��:= 2�a burs������%O� ��*�Ao�J2z� E/.�,�{/s&o?=; *�A�o"hs�zK6�[1h�Wdie�B���P��:b9z �0A�*TV.�v 6�o4qQ9%\2<�M^�%��( autocr�X)�� ,� �@S7n�@��;5a�aBE up���f�&�!��s.ax!h�A� !-timJ��F� or s� )��)|C.�� be very ir\�nd�;�k )^9��;> ��t�>�0�a��"���Fp".�!g ��J% �=C$.0*�U���"�� ��. �ex� n�x�+omp�n�;.y2e�ŗ�� X�6 �Ta� "b�� � B– ���e"�!+�3%2V monito���]&�ref�J�bunRza"0[X"t>iE�%.�E! ��l!�ce%tCZ�!1Nw������� !7F�:�� t:��.� ��A��}S�#E� ��i�e>� p1H�5. Litt��ܒab V>:(��Mng 6 !_3 h6  PubM��ed4r�A"JH�R}win ]� s"�mŁ!�$%�Q6 �e ��[1�?�  ens��,3�FYGrpI�ȇaL:�!�D; bas�]J�dom��enh�k XɆe�M�*%XE�v�M [1�x�"��!3!T�I candde�~be!2 i��t(2�Fs!)wJH�j�onP � �@��F}N;� ^�7Y�u�Q~@wB�be def��a����l&-� �}5{!:� � � stea��T)��'g�i��Y� ate>y�, [15�Bu/D/�.�,�PTQafT��$ePnO.�w];.�!"( ��sai�sola!�PTZ9 F�Our&�cE����� c eCF&2yO.�"� *.�at risk!`��!/��6��� *'. �(kbE sne�I��ed Ojin�EũAwvuC> Fn"�S2�CetN F>�=!"+�'�:�� E��e"��/��PZ rmo-��e"b\ sE�%�e�B�%hf|4�  "�Ei!}>�A����1�Ha�@ !cc�+_B/ Y)����h���}m�.�>� � ��)u��N�*�=in�e� CPts"�R�xyq�Bf�&fzL�&m1(��aq)*�Ca��xD�)%��%.�4JkE0V}'deDz�D'�,F 500 µFe]'81 µg/µl; SigmnQSA�Lou�$ MO )���kA� da�h6 }�-�(.��h�Dr�,A�'((�0ek ��f�:("N�|e=,ocV)(s5�TsiF�f�p�&5�&a#o C57BL/�,<5% 129/SvJa�� >95%!�%whA-#A'�b gen-�dba_fڥy ( 12-[%�kht/d�yD�Wa[f �od�\c�v�!]4%3 .[ ot֖3��%��yd$�ch�r&,55T)�o�ic  ��q]biops\R62�2�A2 � �77on-faRP<)��F��%4��`(;A�;Z" /2x�U;!�rmo E] r�oMelbourn� Australia5`��>dB�Pre�"Xtrt:IjSf|Therry H� , NJEg Aort�Da�pin�5� fl��n bF+ wax�W�-� *y$1Z�*uh "�C,.tـp2P�,a Nikon SMZ1��d[�_,%��-r%/Easy I�&���scT�0kno Optiy� Skärholm�Sweden�A3�Dl c%Tn�Ie"�?;�J:+�. �  root�(iliac bifur��E(Ma"& A�.�fbYin OCT��#( Hƥ lab , VäA* Frölund�$� Cryo)_B (�9µmaF!�cu �2�hemat�=�8Ht���*T�_#�%[17];��itV8.l&Ef�R%�ra�ti-���/�^ey�1t�- ( Se� cX0 xfor�q Engl�)�;xd at 4�V then rfluores&T-�IgG ( V�\r&�a�I, Bur�QameJ�Qco�b�M�b�m���u8&�k DAPIZbG.�ereH�eRNAD Qi� !�alenc�X�i?A�M� H��y�3d ribL  ,A�e�[and hom�G)�FastPre�7Qr� , Irv�hZ�T2![U�BRNea� Minia �) ug  a�� se I6  P.!�`�Va�as)[1#a Bio�= r 21�Ag�wt Tech"�N,, Santa Clara'%>. High-<?��(SG%H6�, 5))�9) �)��a8��� .�*�O�th:�G2�G430(0 &�, *�,R��L&�/$D��b,�0YA�K)C PBS+!� <�K#�%,DMh AU6�,*.1�/� "�.�.,2P.S,��C��3l5��� prep&�sA�two��oc3A comm�m�*tcXb��sm�Qx1~ �ner 3���M�m�(OZ[�!"'[2|.aC Auto��d t Jm�oof �A�EN/[8@b�l$z"�Fk6CFE,� �� 6�@<en&�@���4 Brief�XI��V7id#�if�%co-oc�-ܖ�k� !* k!�ab��c�an�il ]u�:B� ,%er�nU[( “:� � ” �$SF>= .$ ono��Q� %�2K_),JX��;Sk%,Bd a�O2BaL�m`s%tetenxF�&���"w0:+����lO>%�:5�"5o"�v"��>1(*3�  fals�L�v��*a4 $�(m�a T�pk�=�"%�.f��c�R!�Ap“u4e%�>�6���a1W�aA�� rA� �/ew2Z�+ 2T>`"�3�>=*IY9A���Ap�d�9�e���� si�s�r� hoB� n Di��LLab�_  K × &�r$G!�1"�tcalf �l ( FCS ) -B�q%�L-glu��( 2 m���2HEPES bu( 5 ( Gibco-j�c)�*le�7*\u(�luuL )j stre"Ru ; ( PEST )�.� W%*Q(�ibolmyI��r13-[ (�4��50 ngq��472rr�8UAge� !��\�&+zupARt4�GEj6?j�E J$�2qOAdA�ft"JTj��Q�W�/0w�!A ,)Q���5. '�d� ��#�/, �&%.fA'5--�+r*�@>05Q &M ��(!�5�o "6in�j�� �. >wc33:� ��� ampl}> [�'+7 v Wj˴2lm*jz Brad� f.hC�"L ��!�p�4of healthy don��]�>�'u�!� rifu�[154A��^+��,�f-"�oa��M�p%r�&��d/a>�!v1p!�Votw�� !$��.�2�&h( V3%!��2is�_ pano �k2 k,Ji>1�:�I��E�d�$Eclipse E8�r&�p!�0× mag~E��p"��5�b�� xan/.�( 3∶(�\Y� m er�V�1�;& "!(5 ml chloro!� +5/ [20#* f-��q! :�p8"}.�%�1%Witon-X-_ ��)�IFa��"� Y=eO� -by enzy2c� �6��A�In?k/��AV*��F��&<)�a4�63Wako C��cMd , Richmon?V��p �-6!�,q�-C :�Xv�B=��<%@)�M |h�2Z.�5%�sAY3�{. P��$ne�IdFFzF4a�4HG-U133_Plus_2V� \&*.);a�X&�,&�7by��>%�-�U�$ -- ed�Yq�*-!�(&IUr1Ca� tr�p�p'NDE�$, NanoDrop>Wil'$tsD�1�cLsy!],-�µgE�2��*r"B��.Q�SuF/�; I�*�)���-�Q�xodilG� , �( 3 µ�!~��`�b4�k.%( 1×T�luX�alm�r mix�FNl,FNl)�2an ABIj sm 7�a ��lIT"�~�.�(ssay-On-Dem��K �ZIc"�8��p~a<Y)rob\��4J�w�:���9B9m�*�;>cidic6 osom�#���a�Pa�Nu)��g�p+uTe���� D:+co a��$),'�e;�"��21 �_%"�a�Z"�tm�! ��E"un�� $5� �.��Jal�2�+)Rnu�HMAS 5 j�:���defaultw�Q �2�;d#!�6�i{ sO�(Isc�l)u2;a�z g�/.>E ���&� �2qR [( MGD� � Jackf oT_F-[byw.A�!�)V!�6���E�!7!�OXC��, 979%��R.&:�[�3)~!ha� >ch1 !��[1 . 5%)@*< 'eO�\�dis�c�ADR ) J�[7*;,�w�"1f'fAf'I�is1yt&l� 9N��i�d�$.t6�6�YE�Ee vul:�b�N�lQ i�&&z!2�� N(A)"B�j �i�&}#�+&fp�L= adap�)p��L�.�[6�"o�rchitectߎ.Hk��"v�ѷ6�!$=�n 5$�3environ�xŗ�Y��uY�lan]fQ��."� �S`gE/!w�7�!��2r� s���3��! 5�issi{�f�"|ct�hs.w.-�STicD d�aLs�:h$dhesi��A*oxi��crY�M!Bs�te�p –[ 0Uniqu�71p� orig@�!� buil�x�m�8��recogn���inn��Sz6�D�� ���,�E�/��6q)6��q{�r&ezeik��A�9+]�53.�T�U�� "�) E��B U=ar��&��a� ��rina9rV t�6%e��iUXs:5� � op,G���as6�Q��r2��$i�%S��b�@� worseZ�i"��>� �!Iem���\ arba�m�2c>)EC52 ceae� < Klebsiella pneu�:aeEiB_ �M.��)`&�"E  Z� 60U�]4&� | �w � )v%�E l�t�������A1L"O � !=permex y&8o �� itiz�1GYMa�,Q�*�(a�A�7�qi��,A'-(_�2%�2��iBWZ(���$m l��� deca �NM��B� 9q&�l �ve now �=�in E .`�E�ed�ty�\�* #P ing:�%/ e SeQxste�*H �y�!s O#�b[n.�#8sera}ma�o7,bi cLol �E.�4n!�A:y HIBam.I:,beta-lel)�DT Iv�pt.H�ol*� ( LP+%2�!fQ:�ɕ( j& -�k�"C ( PBP' X���e���b %�c�W!��dcl�Vis�k����>C �G�X�z~co���D��;�sA_AhT1v� growtf�ظF� q�� � ��.C6d �G����5u5,%��e�;��qu=CqRuY4!�de� r��s)�an"�or�Y� m�~�"�D,A�*�!��1��v�mod�|���UD)�A�6j. Lj<-�<�P$1; b�=av��t�u�x��5M�����x:��yFago�`e.C�����Ag �a� RN�l ` ��zB'q z!��A�non� -A�P�U)V{?d=�H"�) “�N�j� eaky�+1:�m�pr�o3err }E��ac �:@t=,"� ��n��ZcismkGd>41�&W�!��"� As�*��fi�*A%a�achm�ur"{I�6IeS1y�Sb!�uit�AEa��&newUM.�.]>MZ/. RS+a�7�ly!�C)��ofM.!�age" r� g�rep�-I+!�h� >2#� I(� �.*BCdecht�ځo���er , β-� osidA�( LacZd)�� w waȆ0 B/�,��%pheny�.d-β-D]pyranc��CPR� fail�M D��u�!�0ot!�|l:by .] �"w-;/.o,a�dq�i��Aa=�&Ylysd!;����!�e�\tW2�e "��) and//6rE�e l j}v%phobic*o%�+!o� e t��F]Q�� n)d[l[%!D!^/ � ���or� 5B�^prLkry�X?aL son-!b��� wild]s9�61Zr� �.kd�H�G$>cH. � �{ ��!��U7�ep�!���w�%a%+ A��;���ng&�6Azpe �1��n]M�?��#�]�H9`IU or y+�>�����w�#� ��of����( DUF�)^+L� of�(��"�[i3aD�T���� ow2*G% mpan��nN*4of cell lysis ��resulting from impaired metabolism of the essential lipid precursor required for PG biogenesis . We have therefore renamed this factor ElyC ( elevated frequency of lysis ) to reflect this phenotype . Further analysis8,the functione�and other CPRG+ mutants is likelyg(new informaQaboutdbi�-,TGram-negative envelope|hits control under different)$ironmental&dik s . Impor� ly ,v�D screen described !fl should also be transferable� � organismsstudyW6�2� �,rchitectures��st!Zhow one1Dmost rapidly evolvEjea =-.bacteri� ell adapt�~Lniches . Our goal wa #e� a simple1A�AidA�fic)�of%�faAvs 2�6��5�=E�though!� at β-galS@sidase ( LacZ ) w%�4be a useful re!�er�_@integrity because��Ic�/A"Foru�,ŕ 10%1�)haA�.�� ol-pocu��R,is͆��sugges�S�)qa�an ordeA�I���l� on� ���A�a�\eEmrehensx-�*� 5�&_ c��n��dom%V!�nd�� � set} a �q i� Y P [31] �H��*�knockR( Keioe:� [32]AT� a.of lsI] hypo�jic� e� of*��e �s�� � small RNAA pa����Hkground ( BW25113 )gA:�1� Z−1Hu �Xdirec��G@�A�-lA, . To��ver� e,to* Z+ en ma�aFA!nstrucAwA4 bile 8smid , pCB112 ,��al��g����� mo� ( P� � Lawn> a S-9ai�donor1I��" j !Cde2FcY � � �bfera)o� lz$in 384-pin!5mat� f�Rn , spo�r� �� lo<�pinA�1��s��.�toeF9 kanamycinA�an8 �am�i�( Cam� sea��$ exconjuga�L� !� bothB4�o( marka KanR cA tt !k%�plI63Cam23. Dou�� drug-resi���*9 t>�F�A��F%G �xE�toM�)�|q�. B_��u!% peribg �%� n5���� deci��i5q} h��Boom2G �� �� edia x&0 F� �"0:1% a�)�&� s )!9��maximizL numbera���ed��* f�r��pots ally7&�2 �IDto�2��rN_ To^sR�)\\ � image� eachBl �/quanti�v� a�@!F� � r � ue)@a custom software{ l�(called Irisɨcan kfyJ al= f ny f���a�ra�4ritikos & Typa� unpublish�Q�.�_"�CPR A.�� I�d%1s � fŇt��Dpro7 ional*\ti"�x� �Hoq 2��A�use�� ar* ime-point�u�!�)�"y�(void neighbA�of�G+�s�be�sc� a� t�An"� of��+%eKc2�:�is �&� 2A–B�A�panelstd����v tribu!Ss�!4%e2 F�2C�S1�l)6!pIbcassay�pec!4 ( only��9��q3 �poSa)ihawi-ynamic� geG"r:!Sll)K�)set"� =threshoZ,t 103 . 7 un!�, 120:"� ��ᝥ�a�5. ( T%%,�?!major�$( ∼75% )M!<-=51rDE�6� ��� A eqob&� ommo tige�EC��P�O^ s% +a�LB no���lew r� a:�]�& machinerb,colanic acid6�� �EdA�Q �w��j� %^���, LPS6RgT XA+��� . Surpri�\�1fin��hom�ou� combi�\�enric�i�** sal� � Eo�is��eT�� A��a�tZ��%!,(of Gene Ont�y ( GOm>,KEGG pathwayA d��A�terms��,&�, -waJ,, peptidogly�E� ,  surface� uB-�X�d4s��st(ly �� �associ�%�ha��C�f ��setmm`2�#S� *�]'.�f��6����.�A^S2�im&Ne� theyBTdu�Xlo�eB� &�rռQ�6~t��� lyseA?anN. I� y6 A � ��yE}�4J-6.}%o�M�5a��t\ "� �/� Q>102m��&22�AE)-Xnm�co���Ve�of un�5G��4�Nmor| an half66K,��.�)p"� !4"�w% vam&�#subje�to� 300=3�����s]m��X� b�Ad_"1a v�\�Fpower��to���?r-sca1 ��Idis8!�B9Pa network a*A [,a guilt-by-am��manner�Cy1�e���2ri��+:vleW E�N� ycbCAnts:Dstron�A�B ��b� �V`�UA popu�o!K�#v  (��5 n�Iwe*B#e �ely��) reaI�rA]� M�-;wo�7diIlN"fdo��!�C R5( DUF )"��a218:� Pfam��!. [199 Topɏpr�% i͂&. DU.Qof �#�"�#b� i�N  3���ter��2Rs  bund�l�L lyA�� ��!�b"7 -� , bu� ttle��Y"-$ir����!a�JmQ��"Fly!�miP role��)* !�6 , so a7o�� principleAI�� rbtai.0�\VN." � paraloguT"�Q��M�s annot ~s� ��;:8: �0, SanA , YgjQmp YdcF)w��6�!�MR�$g�U���SAQ>)�D.F'Aexc�|f �� ch!�>x cytoX. ͡�origin.���!|��!k1resm�vancoT��5 � nkha�eri#5��E ���W2g : [33e�h��5�� "}��A�in.�'�#w"� s�M�2Z ( 43�a� abov��a�ine7�MwortYue SfiX�HSalmonella typhimur� !s�1KX� divis!f ��T$HisHF>�(;$HisC pleio~%u�"�%>, [34-Es��s* ay� yetx%W�e.�&- Fj crysK(�u 0v eAM�%�&d"�yea?go , �#ali�f�!�2E!�� (� t8adenine nucleot�alpha<#lase-�� fam2$[35!1I\Em�W�binds S-]0osyl-L-methiok���physi�x�"a8 P �%�a�� �To fur� inv�@gz$[� �Y�ng1j , d�a|a��D�.� �?"d� Y #(#)!�ai2�a6th�j�  &���(�H. As expw ��� �r',������)� (�$au.�  Uor"a�Δ�"� 3B �.�vuc2)d��-�e& �p� �Com�%N��u �!�nt� w"(��# , 37%K42��I[grew poo !g,ed Z �"� . #�!a�#���:Z>� Ս� � .�!Q ;�'con��U�l� es�' onou5)at�er�con6�#`e(� >� !� �!A�] � #6zE��� �)A����� M a ( see be�)5 A��'*^nde!�hB  'M= �Srae�t� ��+9u��ex.�nearby� �N* -p}5�lax"��.n �PA1Cf?#�LM"J�A�C%or5�at Q".&w t�(N� 3R37! r i)V�" More�Ac t� eq] ( Δ��s� y&� y� ��e`!��#uisha��y��!�*�� �WWe Zc2 quadru ����R��)�!�a� 0axvi�zA�&�#:��uatI�equival0vM)E�UtF]*2wad50al>�d�otK cerbѿm� ��[..�!�*� H e":`m�%� V��aza�%�F, $q�"h �7&C� s do���lap:�!��lJ&X:�, ! r!�H�!�&!�7,!Am� such�)'0 "l ,�1��%Q to2 .3� Z� a!<vea� by ��.�-n�Bn*!>�aeqi3 �YNp�,.monit��mn"] �&aQSm)� liquid��)3,щ)��BU. I:�y Wcul� �#!g2as�� *til�aj�-ex�&y2�)�X densI ,abruptly sto�'�/A�!j bega�#s!� decl� u�4vM/*���O Œat up u��Uof%=th� erg��1�*�%�^)�0�Z�&d2;(omB!R�(& +� of1�~r ed just ah"�de%)�>V�� ed: ; Z�da�&� blebs emaGn�6mid1��=��r�" W9�B%��*TB U�i2�* be�ae ]X'mblV2a�vs��"at�*w�penicillw/~6β-B$am� 6�(8�(�R.���m� PG.� ��%QQi&�6�(PG _,�P2��0b*3� leth}5S՗I�s�,PGn1a/. Twoz2R/��!�bi]al ( C5 aOPBP� �)a%� b�%�}A$mrcA ( pon6a� mrcB  g���N![3�2'n$�"6��y� e76PGT��J2�D[#y]4s�"7anAYa�of!�H c KTP:Jy.sl�/dch[via�it�� Le moietA0[4�*/�z2�se!Ss%��l��q simultane�22of)!!  � ��e)s�a9 death:�+[41a[42�W�re X t�'� i�Δ%�!>.B d�%x y� �m�u37� .���is+$i�a~|") ��A�w�#)7 ���I �.TI�2V!x�*.@a� �Ÿ!�q�F �xr[ 5A ,N� T�$r�)mq8eA� ����� nUC��)=<�4abe��!��!�P3H]-meso-diaminopimel�ciR*mDAA��  �%Hi��iq&F.Q�iIO�kacculus6*� few�ula�)�� r�insoluA��boi�� �t �( 4% SDS�T",, upon ��% ��,��sj%ba�` byE{ draw/a: �)of�I�im.&�w_" � � them� �!Wd p]:ng� through a8$22 µm fil�J[4Radio��r1�s ,ref�)!Re amounB9 incorpor�"K6PG k7.�"A����ri�Va\P w"�A�c,Mo�?sub 0�an OD600!O04!LB"� c&*�\fS� �9 �I r!-� � SDS-YXs5�<�t&c � �&-cours�=K �5BJ�l)#A�UXiC4=~ )b- mple�5�8� ��?.4)L,E��fir�7U6��� %�inhib�>e*�at 5 �5h�!!IthJ� C"� �5�� Y mirr� at�&�&4A� �/AD n�-�:(as�fap#n|4 a�1x78 � post-inoc�� r � %��j�|A� oM�8loe���l9?a6� ���-oE`� �IA�inu�5�2 8 ��/���on2�pri�A�%�Pra�@@de Pedro [44] demGa� �"�I4��&Nw�uT> 50% vPGy3�ls��6�2�-Ee5��A�aM1�i�"�8zune�A�>{-��a��0h"� )&�!y��� �ll(2bxed]��in��A�mR=e��:ha�rU�p Tə�~�� P ,{ `�e=in� 9�ngx!]c6RW�8�6LhaN"BS�<M6� 6 64 I�!����& o=s4cP�)G&1-"� 6� � Pre�D*# begi<5%Ty�I�oL2jHUDP-N-acetylglucosa} (GlcNAc�0.*murz*�Mur +by MurA�NMur��F�� +�ad� to.D B<j9E��Fnlt���!�|-pVDh � � -pep�I  seF*�'"�#ed),6Yp�E�3�]!Kp5�l1F-IAy MraYe�'E`ferm#ospho.� > c�&�caprent65�( Und-5 .  %MF�J4nzyme UppS . L ��i�$��urG� �R ;))�to ��e�!i A�Ni�9��� !ba�C monomericF,`PG�8di��haride6� �C D�,��m�be fli��9xpo\DsuB�,-h.� spahw� 8��E�]#oly�!U "��to�-m�!e(t!!��n !r�>s�[4�9[46� e�)ine w��a�-1}�miH?pE� ��6S � took1"FB��ach!�( �i-�=- �/�[���n�*�. Clon� w3 lO "d ORF P5 [47]-#a�untagg�2A�IvR ���` kColE1fa7B�6ta]F�6* o5xn�9tD1����-)�g�!�����5�1EA"s���6�,�l�5�<L 1��g2%*U��� �i �G6cAy e�,*�&R�, �� J!�Q!�vol�i�y�]��–��JE2� h"�2a}�of�?����=fu��(A�&( !�"6> J�tjrm�6�|0>�u�!U1/ �1 "R�s"a 1�(V )f=\.)catalyz�� mmitA��H!�2=[4s%Ci`>�FGA|�6��o*�%�"ly limiE�m7хN D-��L�!s [49�!�)�per��A�K�y ,�|�re!D���>F:6$'�gener�in�� fluxk "� oev�/QN� n��;d�/�9 m$up"G��&;�J�U���1vA!Z~3e:�.�Q:E�1s%M1]�9.�‍�WE��Linf[ ��JyQ�B6>_, 7"yCe�"� �sm� @�or�<a�alF[bM� �P ed us:)-�put%��L�*r�&�+techn�(( GIANT-col?C[5An Hfr 2�>��X::=.:E,as���3�A�>�&"�?e0�"A L!�at�!2�#Qc �]&_�rV N��BJ!"� 7!YA#&#X3�<3�&:��a�D �+�>�n :g�G=�s betw�Qm�)1%�?ai3A �a�O.b3��1%���7w �5�m&� e P  #Ric��[,a [51]"63�9w e@8:Ks!*� repeB� &h , N~-D-2�uro" 8( ManNAc��`4-acitamido-4 , 6-dideoxy&Q� Fuc4�.m(�8�F����Ma cyc�ᔁ!!d"0 AT���!�id4yce�S�B�5D(it` �$� |�k ��r�s�Gb~0)z , [52Despit� s ubq!O0teYeexact��!x�9� �6.*��l;bA�yS*8*ci�)�9le-�8*.A��;9:(�/2RGvirul� [5355 15tep� q&uV�2h �"c *I,�� elucIP{� 7AP[5�58|Lik,*� proceeds"2 prog��e��%!^Ju6�U i;genf�'c<����O-I�=r)�J= �^96`>�!n�B)'7m�� firmFT-� ��,(he ΔwecA::�C, BA*"G �&��>gGѧ{� GDP�T::frtQnd&��p),�i�g�t�).6� ���sG�� �!_�#(�4&� on�id5%���p1@)&uWc&� resc32 Wp)�i"�%�%NE"% 7b gAs op`di��C+%YE�s  @�A�Y 6gn�!#h0 ��Q�IQ.�advers� OVct�-Y� �)- e�J� �c�du"ΔrmlAEC5�nd)�F��� de�=4 CB152 ( attλ�H8 ) [-�( Para::) ���$^�f�5to�R�-�a&�W\ 3�w� arabin�I�A7�,)����%�A r4"R)>�F WecFe� x p$��� !�>� 9=mH�5�ge9F�C�Js�~)6���Ia!,� Y� �M���"� #  A�o>�)�!�"/\* N N� �- � �m�� Ya�1��4e6�E oxic�M�ia[L v�p. Accor� lq2�"of!����eA��� -ٵv &2-by%C�M aV!Z A'b6�b=&^ E�P��,bi*MBg&�&>/� �a�-`�Ձ.!ve:���%�. Tak�Kog@�se!ss1�i\F�� 5�* �ais!N��*�X% mpeteV� �E"��u!,�$!B.�:�"&.VR M���e- �;uex��Z\bascP"�R:�)O7A6����i�A�Ue�+�m�>Ye`)su�-|�.�e)t!W� �BA�=��oU�}%}-i�)$��(Dng1�Y�b]s1%Gu/#upgę !�#�-2Nre1�poo�Mu�Cu)eea��a1IOpi� .�ab-� uRv8#b0�3��4P WecA"�!{�>i\��h\ . Ov�8`V"�-�2�>�X-de�#Uit�ysG$&� �+inM�*, �y�6S[efficin"vV-�of For J0�YR&}bQX��W�t-2�8�>"�!e�e)�&c.YX*8c9o!%��A�new"�).�9%v�C . ���& D 2Mcb�H��mid�$ EE�iq!^ulunti.Yb_�OsAwpA�&%5N3A�li��-s!��T�g�e��;rgaGcq�7aGshrin� �*ly7 ]ri7�b* mech J, �,�Nty`EE�9b�Erba�m*�PE2�ceae [5�,o��q��V� 6��� �\� �sE�� �VavH*y, 9+r8funda�'rM appl. Key!psuc�^a*�*a = will�@�@16 sjdAq�w61\)Ak. G!�N ivU�"�ma�"oward-Zd,�@ti�%a+i�<�8 =� ��S�!�nT2�Jt-2T4fYH[7� &y1-G}66 "�?�����? i.�!��4!:�reg or�2ag��N� * -�8U*�&�5��)� o �Ol�*scFW�>�-�OC >�s2O�deg E�u. A*1RfR%��b ious�?��E�F�%�l"GRA�in �e �%n6 it �FdO� n�#2h7!i ? *XE ��e�currOlyF�Ha� !�v(v�gzgVN. F��giNk -! "VE�4��q�m�- derl�I�F0s�+r:}(of�H�H�`�a�� t�\�{" i�� �(y6t�B�h�!r ��91in�.�6V��. Our� ��y��}T� �_a`G�5��)S valh�nBs:c�ach .� �<nɵa broa�Ta��a5AXdt�JE�!��8�DP.eo�-�F%Q�1�1a�"�Act�"M2IsyE� ��( �UUL"�9�v��`!� ly m^ra�a�te�>w& h2KA &U*.�y V�,)P2�* *�5�IpMg3�0D/2VBaH�D��ş KN�(��oz� :2)� t1. B"j\g��%beBc8 *�)�Z "� ^"~�x*2y� G#;�jU�%��Av&� C:_,v � iD)��\aatatrupc �% �C ol.�!�{ |>�O ����?'%_��~� Q y�e &� < i�(encc� 9FN��N���$"�CAaIduic Y��1�/1�1�,2 �2�� � .>�R6�4a K*Ū� ���KU��.�!�a�2�'Z:g8'1Z.-F�u sA9p�%x" I�E���ba�. B.�b�!�(9nd%�9.-X5*&)��*Un�*. sDY�PhXte� ��f%�{S*ub{A� `�r�sY�� 1)� au o)8*c-d�e6�k��@!��=d- um Yersin�� � �7� aHr� ly>��нB;ig�� at 2FriLto��Tr%e�6a ?c%�>�)!��"��m clus!�FB [6�!�%we6�i l.�!�FI$7yplace8i���[u=dsQFI�Q�EN%4) ��.�i*�r��~A���ly*�.%�*L �&�u�{ �e�)!$!�J�?N��u�Fvi .r=>�why6+��&��?�,"t� >��uu"�g[e�s}e�ag N �H�:6&6S�re�P�5N��  G��"��4b�Xes;?�^i :I�fEF&ji drop�>ATp�t�$!:R lleZSA�# A�gRA�Qce Y!oEy�hAduBvr� en`- pinp�]LpJ� Ag,� 1x"5>.M :&�m/�:�%v�7�+!��B $yn�A�`�_by�r��-q�g�erR does�Q(D�?!B� )�с�.lataRFGe�R4"�avail��� �&_!g+6�Alg02t*| i�)�aU%�mU R n%�avlayS "nly�Lb9��� �+�i"�a%� viewA9B�l) ?b�H%�&u %U�Y �!]�*!�m�#%�=A]6ve� ]�lyaer��v� ��F�pQ ��.� rpre��c��`t!�2  ���)�!M�<�C,9"��EJ"�6� �eK�� !�^�re Z,“funnel”)��y�rr�5!_&�,z7P �]�'t�UvNi�G���!�ar�3uD�INvfe aff�9�2�4A���ssat�9fe�in�(�7E��. �Tter3 �`�!� help)�C prop�0gSIAA)D~ �&=@���3�Dn�7AA&�E�>%� Vex!aelW?>����u^a�q�. O� ] !)��!5&�qY.3:�a1.��A"� ��AL��re�'ng� �ra':sq�#�xYAb�". N�th$&�qi� l lo&=I= I9� M)��)�fvo� E�!a�^�iou ��� %]�'&/v�!��ByN�JR!P"8�Vae^I2s"K{!qi7�-Y�e oU0 �Sng �`�g&C�"b��At apeu%nur�$��uec�1���!N�K�d"QexpU6ng��A��r A] chem�genomics{yU�dSbL*�"M�q�!we��o��t�)�∼80EQg� N]�*#un�<�(e�u��R�az]O�WvE�fitOy in >�^�o���!�eeb)t�!c�^A?st&n�Q�Yop��bHS+b:Ranja%�* � �(�re�u� Aa_ng!)�6\itRn+s� a�Hea!��?AmF�6Yfs�Lat!:m&2�/�!�6O���d� similar�]-��-filM��eVU u�m�,� �G�pi�3!#� aRb mplo�RLDo�W�+!�}D&� �pb�ad��k��9&�|en �%�.��LY�`�*Z��OW�.� DMct"�"�0&�. LIe/AS�PD [1% trypta�x%Gs�Q�-�"��D5 m6unl6!)A-6� b-i!�a2wA-( 0��&SO$. Antibiot�b���hA�O~a"wo ; CmE�15n(mp�L ; Am!>or�z(&�o;So ) {�n)6lm% pr� P)in �eDAll&0B�( 3��M5d�Se�EOder�&ivp�+.�q smid.F!.�8��e �6.5:th2Jlti�;B�;%Bs3a� a�5e �;"���0a�;-��NecY�d!�t20mL2�;. See T%S1�?6�"�d;��W�#�y-"� �Yg"z}CqENN}%&Q}�6e,�Lw��54!K&��4 l�[4�4�v}:je�!"�Q_��100��\cper �a,�Pa2�E15–2�E&�Qg�}�L�(��a�o�song�k�. )�(}rW%� da߅�6�l��W� n{. =��*3v DI|�;� ��Q� Q- cont>}�.� !�,-{r6Zz9�!�+E�Y:"8:�6arbitraI��7ed PCR�DNA s�T%zs�OF�A e�m\ dU�pr/��a(*��s"AE 96-w���XYt −8E�thawedS"9u�uLB��E�e !�)�9�!��)]&�Kda�uS�7on�T�o>�uo��Bu� (a Singer Ro�� robo�i�fveMP2��b%�x%��v*�t �sp��Ga{µ�c�yT�%u�\f JA200/�w[.�8/]w::�u,�u�m��b��ao�\���Z�kp5W�'i�  �=�CQ 5hNLB�!Y-�v y{ ��Zx�7�A&�� . Fi d)gLac+ 2�vM���ir�H,uv(-�MA���Q^�u ��� ��Nx�_t8v�5&.�=��s�)FmaC?�h�~d!veg�veQ�(� 12n23 |LR 5��K">�IA�n�)o+a� �"�Vir/th)�aue�7 lA�r��M�c�MusA�in-ho; "�u(�u)�;t seg�t���Q hu� ��pix�*�HSV��r�E�F(q%2��N)n a0+gOA+"� 2 c� /^~� q![.S.��ET�3!�:u-W $f���t)0��s 3}}2�5 t !�E1 manu�evalu�0to minMxfalse"�s8 �%H ToQ��A#�: Y�r9*�5y܍�%N TB28 [WT]o�3�3]" �jN a2�seS+ۆed 1∶�jNr ! MGto��" Q6�s4!�ul��-stWMi:@20JQ2oBc&: sha��ba(MmTI��-: ���Ln cy 3}u60!�u�L%Ir�9�m1 X߀ ] �ad��Ca*&R2 ,�&;,il�S�e10−1!  6 �"�a)��5 µL�e%H 1�}x so*�76�^YZ5� or 3sBu!� phot0��,vk!Qi�*kof��� , ��lYE�|� Q�s�2-�0"�b� � patcxm� shap�j an X �LBu8b uC&e�5y�d�ofɹ�&�8w��J< r � ��� =5E�)Uh� �ly��ep!ͷ6��R �I�a�µM"�U�!8B74 [lysA::Tn10�T330�T~&�� I�N"umJ' zgߊ�&n%  L-(e!G7���?�n��$:U�NW�;"+���&N�e5��A�.�:�e 0 . 4�*Kl b5C%�P]:E?��� �QF�-%,�h�j�<�jy�%U&_V( AVM�'bW�RC+W)@ µCi!�. 6�) No ^p�M��[I'�,A�"׉5B�2 m� -A%� with�XmDd-�to%:8 /hot ( 95m[)�/Y"AYompl����at 4�N?al�Cmi��, cooOBtoF��}6yWPG, &|Wrec�P��X="�/j.[[61 FY�=dr�!T�Wa�]�f!byT1XVdWon-n�  a'bbeta Tri|I1450 LSC�h Perkin-El�iE�$�RMP�a�caE,sc.jflzc!g[i@T �ծ!e&�,>�)J������*at �.�il�+�� 111�1�)��pB'V?!koa:( Drosophilam��n!�ڍu!stra ~or�� l� j�(9c�ׁki�/b��u�bb �"ݛ,])ry���tissu�brphE �55-��"�� ��ANmodali�f�J135start p���)�Iof%] t�?m�=7�4er�9L<$ O#�(!�)�di��b�B0'a��8�n ltY�5��3s�cuBur�+pn�#&4c���l� �J"�Qi�N�ac��1��l task�(#x! estaW�[—-KHww�-&�;?!fNU]�s9)��ZM�E�AT f�T.}�uHx *`:n�s [6–MKAdvEk!o l����in5)�{�s�1��e9�zn�yduҝ&q�j�{��!plm� tb_�@o�x��su Fw"�O!%A�*�EE� a��T&� [9 �01 s9y�&��*kGrel�<%�,2�N#�e��mEf5$bp?E�fixa�ia̡�Bx)�)s�mO��M,X&e��/E�F�Z F��&�x� 1qof �!96�O.$a non-triv E�[11!@�Nl J��y���3nna�%�|�~embryo BF���1B�-�i�AK~�U3ad�W>#�!�zar6`!b� crip fO9 Dor�D( D�yA��dorso�.raYDV�yip�SAa.�%a77 .�ndm��+�Y��93–1�#CJ<.�;�hevm�A�5vok6 lt��>��sch� C�-J��ё>z [16]1�ZL�m*w<� *�OiImu|9% �(iaKcTt��T ��^, �@�ly 2-3}\( eZ��� �cE%��al .|=� L!��*6H�Jy ?�p�%�!� !� �apGA�Ag n�lDmv�=��XP;ma�W?%��%�<Wm<ad�i:caew% ey�z ��matrix!(�Lq�mEK. S�$:9Le�e-am�m| � i�-6ve/Aymovie�!de�O' lumN $\�ɪrow#Ur�&�F!��}t=�Y���-F���6E�! g:^ ��+*ן�[�msɉ*� e9a�at�aC�*aol�)�-x�/��let���E�a=:awa$� �M�A� �ut����@� �=��4� i�xaR#�%'>(� # q���Ni�!e` v�!^�#n � v�a���,n�nP8oaC.����E6��!Q��CA;m!^A}e4-z,r -�mi��!�� s by���e1gi[!#�,� y�=�4�78�re}q�" JsD�a sui� y!�A6^ q�� #G%�ach� t�..'a=����i�BM�+?���� G j�� ri� ma#p ��l e_d�-th*a�aS� [1�~1e �� &)is�� �*8� ɎMjsAv7 o )��spa�} !4B�, *4'��M"RI�od� Fig $�%h�H7=�p'� �� �.���N�a x:�Z�- !�� E�%!j�7!�j � <'d(28m�u"{m!��n� X>� . ByQ��E�2�? 3A�:�� wG.A “)rW6t ��i6���napsho�0��:�-6R~Hc �*�� ����Au^��:�q�g� vB�E�4low2�!smo�^%h �4L*�Gparam�BG {.��Rp�;��=Tm�O�8���U|*�� �4IPal�j� Pe�Q\w!& �F , ������ME !��Da�a<$=atU( xh… , x4Pxl+.+u ��lo��� s(kXi� ���> 6�M��M��K� �Z9 c`!��ny^IAB�>8 H � |fi��cW %�e���� �Gb'���s�3 denoA( y9.y�%�%0��)4Y E b�*Dfe}%.�� p �66�-�y�\,-�()����!8��-�&Fz�reI%�� Yw ߖAe�ɞřS����U�)�m?� �=� y = f�#/8 y�Q���Na�i��ch.v.3M of x� �P�<:4!}%�" A�Q��;1N�in"�!>�,Eta�v� +&-�5c �_�0: f→=argmin 4∈Yl+u∀i≤a�Hfi=yi∑i , j=1l+uw ∥fi−f p[A.S,f → = ( f A�., f l + �a#�- 1 A6K  A ]aR�v+ME .���!3Y!�B Euclidean" u amw\Fs �� A��#-� 6"�Fwo2�xiKxj-�|\i�X CzKGJ��] 9)Ml "i���"�*�*�Jc&�Pm n"0"���%or��at�.�#55*�%po�U6D� one-�(�L1< )�be�$qV�es>/us�8�? utliO-%�a=J� =sai0as �W�\r6!�m+r�yx/:� mani���qE=yISyield1���ul�<H .���g5Bto�a�>� is q��Nr ,��Cr�-cCB hc�u�}"�#�G۹{%& �fl�~fa�W�Us�ӱ�ylMaY = R h��1�8��s:m�ue� D u - W ue�- 1 l Yw4 )aV��) L�a�F/,ed8d i = ∑ j = 1�Mw �� , DI diag��l= d! �.Wu#(q�) l+1≤A��+u kWul���( $3/ (X6`6�hɤ6��W,.N �e2u�al�W"i�r"�a�'e2,�)�..sŏn�A!�?�hqu��s { x�0���c=ac&co�b+ϵ !)+!�(+s��+!) � ?=ctexG� −d9−�&( Œ��EJ~�c�@��ta�4, ��� D�4(Gaussian no�9sourc�����J6al-�W�r� -.-m,(�9,j �)��t��:� B!��R embe~x���(�\� l/���]"7 �=y '� ��an�_ ee�(log�I�*)��8�  '$A2D="n� �x��e]| a |=$) ��!�+ !*I��~alU�S "�@��) �Yu��J#9�9�)A�c�',2�i p) , y>#�ZT we q�)A�)Ad���0�>� �� �*�"�, (Z�, t���._ c&� siti�:4+3d��=ac�i%3���A�I , 1�a��l O�`�9Z( tA�9a �e� o =�C� 2;.; )%��uݷ( stam�X_6i�k2���\�Ay(  ��=(�(% ; ; asL??2d3v|3BA�6ai} * s�*a�A�u� �&� # H Ne�.�2�jp2`)Q2(j����q�w�� �no%k �A��~ dard�V a�w�9D���oNM"7"��i1� ?5&�%�Y-q(�d �*s�2� �QM�V Z�hF^ alg#�hkr!�H$� T %�C�!'�� yA+ *�>��ўA�!cmp�oE�Q�tlE�%� uracc%�1d^�]"C1 y a K-� CY�1teg�[�;s�:�S1�!�Mf4iaq�n�5 thodS/���-���C�9?$���&I� e��A<∼s,6�z* 4b�w�&E� O>�a��?g,�kZV2!y�B*�sd�C��d[r�'*�Ec/s^��}Z�!��c���ti�&�_(pabK% " )m&eLMO��2)�I�^�Ars1��JRZu�7�� �9�l+ofIa,^e�l_�O,e� PM`,A�G;es�[�!<��r��9�R176 % VDV.4�%6�6pplRj�"�'nat�< 6aIw�%E�F�(��vL'b*�-5i��.�MneufP�� i����0�+�G(EKaim7"�9kM~�s�'��K ��,W���k �-��!�Mp. F�i�A���regE3 �lig��ir �#-�"�a� !@��.cA<scr��sv#�!0�occupy 8*ǹ�<��ll:�sTto/by���]\�Al)3��� W�K�H"nm7a 4]<)�a&� ker!� �\"�"-�� ���MA�g-j!bic&� E& Ab%͉��B�)�,���0�ast "MC��ns�@��E�I*� Q�%��B!� AT��ns�!sa�d�J<�'�)p�#�{caA^ �9�E"؞�X�6*aF%�a�NM��#� ��fƹ<�ň by a�PvMvelet��&� ��E�%(mod���PaV`� �v%S{�-N1+M~T_co"�S��(IP scalk64Q�� d. in%��e\��*� !EScatN�bolbox��Y£a�Yh%))]!A" 784���E r) H?ud.&�A^a�(�11�F,1�2�;se����x#�f� %IB&� �)�q N�\o���))_�(I�Ensv"_]��tͦ �E�c issư�9!w� �7842�)Vs�-[ρ-P6 b9�p�� )��� ):on S4m�=�512x512Q_��m�&� ��"J mP�Ѻ�%�� cleiFa� D!5>1֙>�!H5Q� nA`n) m.6&- � A!J��K�W| pERK� E:�*m Tw5k��*�1[DgxP([S#rh��^���K��$R %ŢB � ';NZo 5!�f� ��"� ��!�Y �6s �0e!bI$n�CT�")�2,6[ *��!�F�1�-.?�f�H&{ !�&��F}/�3 AL�+axi)�h"��)��Ń7C�>:.� 6��L����f�9# �%�9���!:v� entiT\܍E�#^�ab%�5 ��=9�K . 5�6s��a��R�E*h x3W� : �&�&.�& ( S3-��W!�ow"l &�%'D_� D0(�{p:W� e"����al�� E�dsiz�*!�&q�6#] a �sk�.V�b�qt����a��se:(*u4!�i&�� Ee�'�Yb�= J����=홁 .���hI�Vvm�1a[2d"2. s .�$�.�M,��I�q9"Q6'XWr.�#6{m^!� �!ur9��� �T �) cb�ijh��ci�[e&ra�eM�J�6M dt�2��or GamsE�:p am�N!�Y��*M" spreHm�zem��&�*I A��7 "$fE��&�#��.6u&]qz,8aX�Yar �aQ �Ba�� cret.��+,i��u�� nx��d hocXX�0 ��2�re�KtH��w�&U0���3a� N�Q�"M .j. S.[.�app�B� fluo�} ~�a�U%IJ,���h�9�MS2:Snasi.�[x�.*�p�YI�A�r��0p���ށ��[&hO��6pC�c&�V�\%�]m��&&�2BDGP Ref�R�/FlyExS [29IE.�n�nQi�~W6es�K> cascfr��4fEav�1��F��b�-�Ang�0 �!���fu\?&jm -H +y��K�RaTn�wh�$&o nā�FL7.iin��~�e|1�b� ����x-�­a�g }_�t��us [30W]"�fi�b��&M(9c�A~5�!��b�_n�]� �9�[� "�:b ��ur�b!q2-:~r>Q8,!�$$��!�-%!� E�� ha�n� eV{4epith98lus���0r�h�_ed�*] carJy +5!to�.fl���%�-5�a� s [Śh ��m$�.I�6��VA%۔��!� ,��mRI�M�y3�;A�2���. ;1�Z"� �*!|������vmbP*of��&� A�)]-EF=�[3�;ݲ,!a� -\{1{ō)K�dAgI�un"vs�ms9Z�%3[3��3Uv *�W� seE�EFB9sbM�T� 90μm ]!i��ql�l� ime-laps>v!7�"3 �0a Nikon A1-RS��ft.WedPa 60x Plan-Apo oil ob ?� ! #e�.e@��q[ -RFPay toI of 7�s�C{ 4^� o3ofbH�s� ��RllI�Pm  hrRf��"i?Ae&@C852E /2�5WT )i�3^Zr Fac!��5of�.y>�to&�01D�/5t.B� �,�� mRNA:4i�nd�� muno%�aW.��9$itu hybrid�^:oco�Zu�42H�_[*:. DAPI�#:1,Y00; VR[ labojA�)%�MN. Rabbi�!ti- �( U0;DY S@��m�S�1--.DSHD<r%8O !0; gif+BEF�Wiescha�6P��eton Uni�~tyqsheep qdigox���$(1:125; Roch�$-��^ � ) Jack�I%�h�^!  %!ax(���v tibo\;�aexa Fluo�\��tj1:5�Inv��<�z�OiIY�!QS��]m $M�E��Y�/�/E.^mou*l� �xKQ evic� end-�Cmaa,!&�� l 3�-]�5m����s 108 �sa�1���rBta#:822e)MFf59Re] M� R�N�%��ind-DIGa�b��� thirN�V�BM�� � rhoUI� �m{��� e5tw�/s��!�FWm�iyM�6d>��6� t.��� �!;f �r�+� J",Ga�6� sum ��69Raw�� bA�un�KS"��aNFiL f github� si>Fhttps:// ]�(m/paulvill/�-&--N�Te�MW)"�j� W3+"S*�8*JF��*=�5D ( - ∥ x i - x j2 σ i�#e&�!M��4σ�.σj� �2L\ �[5�i$ce T�*510�st*��2uinP"-We��A:�� s4 Jm�7)Y�#�>c�1`�A3  3c2k1* >�)"�)2K�a�Y# �6�wZ^��<�d��Y ? ! qAQba^b�&/l�0>T��;val�ZHdB֪]�{ � @�m6+b*s ac�i�&�E&<@ )�:V��*� +�y���� &j>!�F�n@� n" �bins K��$�34 (�Bt�aa'6�1��x 2HA#I�g�!��J I�a!��-1q8N�G� �)� � �=Q Ea�Az.z w!B�o-"�"� *� D%rh��� ɁTwi-V-w col�� a c ��4&�*D ��2 D`/p��}( ~��( bA��(jen� A-����h a�b � !{>�y|qx&���!8*�#��t,m&�e��open-s�. MATLAB"Q!�|E y rulK$ GNU Octav\I�.vJtas:�S��o�����~��ijI�p�m�ms=a�m $$ry .[�Sn�@venom hemorrhagicN allo� eina�( SVMP�( IPI�II%# PIII� za!�!d��8i�I ��= !bthT$�\tob�yze0e�D&�qZ ���ivaE�!+O�y[ rote.�niexu���'I� �in�b�T>~ hist� o0y��o-2���@)8t,�IVal�h ['���s.NzX�>F��apilla9�8�j !_�-"y!�uto�m�u���an!����� �4z)��de%e�r�'!��)���h��sZwD)�m#la�&�,�VI9)�n��e#,%�!�O�eR�] [1E��'�!�dRd�{.�BB>����e�!��%�mE��zJ?a�>d&j@m�v�?�I��%* u��tPQ�MI�wo M�YX �&�P)-�O:R��1>AA�HE~M$o �te-��"��PI-{ rega}�"�� vu� }�!�fiDT��)� �s|m�6�2@ �j�h �ֳEi�9Qa��1�E�Bͩ novel clD�� � 5 !�*�by  �?x da av/%�asc�H!��ge֤t_F��e . Zinc*k�Q�-�M1�r%�n*X�rv:���|�mI��e�o�f�,k�*؍� �@ݺif�(m�чVi�nda)�AP.cJ��W{%Wg� �$ plex!���m��ar���Ga�W!Srecruiȼ ���gl!]2( ADAM��)H�.�V��t �*r���Zd�"!�-{"��! s�Uy;o ubro�< [2–�'Fur�dq3��edE du]e�,�y��n��neo�5T" '�o�W8%��+on��E�A��-exO/�+dA� H�che�!y�%d0!Cscc�'Q�d� �1#t�Q�IH)�) nsEHtru�<*gCa�^!K.?3"A0�4st-&�)�!���'al1V�U~Ũe~�^rnI!���a�)��2�II[J� �!l o%�3tit%2+�S a- ^EdA�vi. _�P]:G �B�K�*RI�!����@S�B[Q7m mE��� 2\� canoހz�m��_��0f HEXXHXXGXXH'7 �$a Met-turn ).��!���~ a3i<�n�&z7n�;�|1�.�&iBR�Ţti0 NO�ԅ� L"F| [�<t��� )���!�%1Y�_bu����p( Dis )6�1Oc<" ine-�#( Cys ;PuU�x!��"^~��!�B��*,�+!{-$7�ae�I��D�aa�k ) [���h�G�e�a!C��Zfa���d�)xi!�im"�.]�.1�UmjA&scsub��y�1jC-� 3-�ylinh1�} Lrhb�] sulf�boh�)B<4��%])4��h ������%u*�6A Q�!���. ��pr�Up �VB� �J" ��ex��6%�i�s�P�05�$t YPR� ( EC�o*[�Z  � �%�g�h܀m��k �u[8V�NN� � -�"h ��tinct2 i6�QPB� �� [8�l�Ml���'es[ �)�)�s ��gI%"v�5UI�} ���Xor α2-macroglobulin [1duT� �=*� 84ah�&�- ��.�SQ�bloodsk�.A*$~���nc��:�z|� �I �g� �e �X��"� ic �c�5&��(&4O8Kover ,�1�}fewE�)R_q0cha�ae�?!��.t�y!Wwo-�mG*�8�Ua ��*� ice� $1� 1ݘD�e"�W�zk)_� h7}zF���iR�'u���.ak��e��!)a�Z��>a.E~x ��Zo&�F�./)e!M ��1'Љ��ofJ8�7�N�( B�,,components h�as been known for many years , and it h'�Fhypothesized that hydrolysis of BM proteins is a key event in the onset+Lmicrovascular damagephemorrh�by SVMPs [20–23] . When comparingUpattern�B�+4onents in vivog tro betw!xic! non-.PI �Tfrom Bothrops sp venom%/ strik�hdifference was found regard$egradation! �!U [22!OSi�B� play1� role!0\the mechanical stability�BM%5h�of,8capillary vesse2(ructure [24!� 7] , �observ)xis likely to have relevant func!5 al implic2s r5Z�sm�a1 .(!s . Ito���), with6�q� showE� cl�2associ� 6!}.x��,A'contrast�O�9k%Ahad a) (widespread � ribu!B\ �. Fur��%? , variabl6�.\�D �E�5��nidA� A�lamini�&w���+>AAG�d�* to a�3ext��Mwthree5D. In ad)� ,NzofU�!red �! ��Atsuggest�Kce}� pathUBeeI� �se��Šn summ�V�*) pprovide%#a new%!%y��te:S�2PI�V� q2"� . �P  BaP1%q isol�_u� !2"0 as��asݮdby Gutiérrez et al . [30]�Watanabe1]5a�.�ion-ex�@ge chromatography� CM-Sephara, follo!�by��in�F60Affi-gel Blue��dimerice�A� BlatH)purifi�( !n6iec� !)ralisB Camacho�16�z� DEAEb�e phobic in�� F�Phenyl 9)aq� filt�(!LxSuperdex 200 10/300GL . A novel!Ma�j$adult spec&��,he Central A%iXan rattlesnake Crotalusa�ua&A�)fnfr �E���va>;column�� BioL�� LP>0system ($-Rad )!f wash��� Q��Agial bu! L ( 0 . 25 mM Tris-HC�� 2 . DCaCl2 , pH 7 . 0 )�tlinear E i���developQz0��]35 M NaC"�start� �� l��1; elu�,�sūg mainl� a 55 kDa2S �^�6� �9�by>EF{aUVTM6X`( GE Healthcare , LifeSciE s )1b8( 10 x 300 mm ) t 5 . ��-*"� $ÄKTA FPLC��. HI e�aaO mole� masY� .MхS� determine� ,SDS-polyacry�de%Uea ra�re� () PAGEE.run� reduc!��con�� s [3DS C>^!�&� on 15%9CJ�msta�g:> , ei))�Coo! ie Brilli� �uta���te���  ro-Q Em�Md%�Glyco� in Sy Kit ( M5w ProbE8Z!dc���carbo�.� Proteo� Jv!�wa��s�3d!azocaso ( Sigma )B� Wang��3�H�< ct]evaluE���nj�nghous amou�3 heI/i�0 derm� in��w measu,, a��2 hN diamAcK.#les���6xsAw zq [34]�DMinimum2� Dose!}HDe�rrespondI� �R� Xss 6cspo*1e��� �-,onB� k&�t�qo o pulmonm 5 ��i� d ng 50 μg�^ N� !0ra��us rout)�$. One hourB�, "e�sacI� �n overd!M$of xylazin)�ket �allungs D diss� out�in\pro��/or embedsin}ffLy�aoheT $xylin-eosi!i1e� Appl� Bio� ![px e"a�sourc���G0ana , Denmark* Doubly-��,triply-charg�!D���in Enhan�Res-� MS�%��,monoisotopic!� frag�ed �,PProa Ipool �Q0�i�.-}!�& 4at 250 amu/s a��\ tire)Pra� . Set� r!�li�m"���"�MS/MS�J �g � 0s: Q1- unit r5;to-Q2`( energy—3Q$40 eV; Q3 n Ty barrier—8 V; LIT (k a�trap )0,fill time—�ms;%� Q3 s� 1001.5eJI�a)� pre!�aT��� "���o acid�8\&4 �2 !���YɲB)�b.�)b��� cDNAJna��{�� m gla~ S ry.j �ru�(u��ora�filNA}.K tran�pto�Costa Ri!M� s�454 py��AK[35~��if�T�aB �a� al v� %D��L: 1 ��.�;aw$μM stock u�of eacR xforward ( Fw: 5-AAC CCC TTC AGA(GTT GAG-3´�crever$ tRv: 3’-ATA GGC TGT AGC CAC AEAC-5'� �Eri�%�!VJ( s NPFRFVE%� VDVATAY ,a+pY v,:3de�oMQ0E�9|��seVu� highly!�����N-�C-� i!DA�-��P% ����8A�g � %7GoTaq����.=�+ $M dNTPs; 21�qMgCl2; �%Z5x � i�13 . 7DNAse-f.de�aed wa�i�PCRA� tocolclu��i�dJur�\at 94°CA3�� ��i�35 cycl�.<�sC nneae[ ( 45 55a)%j��b>20 !72 !,#q+a�7 �at - �mi; �W�up2�an agaa���cA�,Illustra GFX%4!с)Ge PI� k� 6 �clo���@pCR-XL-TOPO vecto�Inv�Q�E .� @i DH5 cells ( NovrMadiso� W�USA )�����byjpo-� �@an Eppendorf 25102(or-ށ�!��= ´B> Positive �as�Igr�I.� �Hin Luria-Broth ( LB ed7 ��1� /ml!�ics�w�ir�by%�-�-� � abov� ��IK PCR- 4](���D"�anNZ Z377E"4rclaa �e"b ]&�in CD-1U I�.aNa�!~ volv!�uoanima/Lre apy)�2(CICUA ( Uni��i��M� meet0I�� al Gui{ Principle Bio!�lResearchA� �A �( CIOMSE�Lyophil�!wound&�!�e-"re-susA�����az7quant�LS9W)�7 BCA5assaym�Thermo �I ) Twenty 9 gram�rEvt�!re2�Laemmli��Abp� � 12%|c�e!*�.�, sepa�dGnd����b.��lan1@cu�"en�  !ize sli� . �de��R3 h%kA7 ���mM DTTM3�eV50 iodo� am�4at room temper�F���1� M^Kded lW !6draӥwspec�yd�)6=%ka2> �modif[o201)q)R%[0Ůon s . Ex�O"� � remoa��!���c �Y��al 18!� t 37�@. T6�metw�ext��omE�1At3��|a 5:�/5%}Yc� � ��co�ea�c w)�e&� 1��b!�N. LC/ !>�aq�Eqn Orbi Velos ETD>`er%. A t��� � fabr�Y��-ho�by pacK%�5 cGirregu�"C18 Bead��YMCe�ODS-A <2 nm , I-10-25 u .] KS Jupi�� mUwm� �(0omenex , Torr� , C"into 36x, m f� si�$>oly�-Techno? ��PhoeniT AZ ) behir bo� neck).�direct�| 1R!�A�! <)qru�Aliquot�z7 �� XO ML� I[a.�j:Rer��)� μL/@ �2aFce�L/$1M�`id&�( 2–9:_ 1 h���ium](to Full( m/z–160>&!��60 , �nd�����a@cqu�a� .on�9 rum2U�'j��i`y\ �zeK� he t�- ost abund�ydata-de��nt�;� Dyna�0exclu� a�en~!���$lisP4�� � of! se!$repeat c�!1���|~volta:-�� 4 kV�y�&�.��26� . Peak��*g�"�raw% MdYS�st 3 algorithm!:� eome Disc�eAP. 4 . 1� AQFUni� M��!pboyJuly 2016S�ra�eS }"� ��{hyR on cB�as� xed!�&{ , oxi&**me�n2"\#�=c_ ppm�A tole��!� 1 Da". X hi1nr�3'&+ fu�%�a�Ʌ� lts)!| �-�expor��t affold ( # on%ud�5�Softw=InV, Portq , ORe�SKA-�mto val!(e ia!�d"��!��ide� %,�&@isu(e mult� %�se�#� omprehens� ms� �inBWE5!e!C�Xcorr? off�ue�q�Ah� t7+1>aa8 , +2>aD!++3 5�+4>!C5% Conf�V�a5AiskplayedI�(Legen�8gr%-col��&!Cv�ver 95%9d�!uyee#[80%!g942$ . Reavet &�) �s%�ac!lisaSby%� all%�Y�10.f �aaO+  2�z di% XA�Q ve Va�#e�pr�,e0is number giv�n aver��ofn grou'�>al�F� aRE�di�%�i B�?�N@+�as� al��� gels} ��� 8 ( http://www . ��q�8m/EcT� a�h+eK!�ow�r6�#��/h�'aс� yin �&�,)�u�a cer� E(ee-ws���E���?cesU[JQ=C��2(� zce(+ ���orZ v !��M� ur!a Pto&� if.� <d.��mig� ngA�ma��ir��>�"� a '�"�'rH+B?zQ%&�&!&a^�� �ba^elO�1ic&�p���,;#E��;of�=& g#( Fig 1A�1$��is �is ]*by na CsH��10+ Agp"s���q0"ip+&l:�#9%V|e|-deJ�� �`U�&BLASTIB� s GenBank�5es ��$DQ164403 (%H�I� :P'�Vpr":% �t'durissus �+� #�!�� s gaA� �6f $A�!���y)�edb�F�bAvm�UOb)�( T  1�"n�A[assignP A �31 po�#� zinc� allh$ do!'� �I�grin-�2�P s��e-r,,7<3""#!� � �%�5Emol� "@$on*�$q!�"�"ic��m� �#�^.a �#of� 4 g . �+6rnd2X �AQ� abro&n0 ncub�&w� EDTA �8#�also %�t"�#��l�"�#&c#�#o�e�C�01D ) ; thus i�aYsbh g/&�ic.li6 26�$��e�&"*2or9� ��or�%!�"0->72�"�,A0l�)�c%?2�/M��)3 (.9!2�.�,(�c��A^ � pref�6�ly)1\�d e+membran�wblood�56s e�� b -%z� %<�IV�%��0,wI=e8o.� )�E:�*�0 ��0A�eOl�'� 0 %"�8F���-?No 2�3A�m� L�o a2]E��unlabel�$�8a��641�lS.���R�as�7<��t-&X venu�( PCV-�ecCrterio[5a� ���oF)on��atiIA�J1 �i���%�Alexa F5 647%< 75–85%* $ 1L95�/AZi�nd�  :at s5\�5�&98ly��� B{ �9 of c:�- �L2�L�1a�er�c�6gE�F@ar�40%-�P[;0on’s coeffi�,�* +4 )d ���R.C� j�inE, ]�. a�j;Q�B| ( p<�00�L.a �Ai�!n63�u�1�>3of��A�PII�sI@.�mkF�:Y�,2� �a . More� , no� �L I���.,�+�o�9�t%"ensn6] ���ofre�}i�a��3of�g9z0μ$39"�*��2� BK"��xi w��un�%E�~"��ts��)K";/�-M��*ion-"ic �%e�N b�8 blot{��, of s~#al>�;. WaUX<�8��92?t>y6,� ��%�)rqLs�!e&��[predominaA� 107 kDA(e�*�faint(%216 )17 6�1 , 11G!�9 ��3 A�spicu� a�>� 6�yu�in6����z+�!B.#, tog= a r� %�M�Y�-�1-�2���B/ �.�8��0(order: PI >�l I��?%�VI�{{se%vAUB� �o two%V� � � noun%"2�W�Q�2ngas .� A~:�:F N�16iG5,M�&�A@%A27)5!A35 �C!��]!greM�7""=� p! appea�of2}.�22i�� �D :mer��B�>�P*�@-t�d)�B�.���NthR."��; D3 . ��%�ѕ6[�h�9J 3�f�:9� mino �� �P:��B�Z�,��.� !�dis6��A$8nd6)a 4Ii.p229u�Tm�� 2��&t.�El9rJ���><�E�$"�q(!땎� of�]V6�e� 6We"An*�B4@u lc ed6� b��! ^?#V?Toth) i�!�I��s"x ?.�!�2lyD �B6�͞�5! �%I2�E5� c(V�9.G4�21V��A) u3!��2 V��eAH� �  !�9�.?�R%��� *+af�E[.i.\ ��1�!o "�1lof��reTy�.bds��n tAR�D%�.�.s�F��4�/�. .1e �o, 1�nH q"�5�h!�,%# ?)�-=aUvu1�-I� v!� X� ,V,��,5� 5.�]5E}�/:M�!�!�HY"2;I �QH�� [��V�A� M��7�3)82�5�10 (!V  ��O �Iy-�!X0�s=�aB�>���1m�)h ���ٞ�0u) 5p�9ker�f )�$�( g )"�-a=H&�s is /5/,Ik&p_-�per^ '4�2�x�.�of2�$�� �B����%J�./V�J O�'-�mbgo 0is work�vto �L�insigh4$�Mm3Os�.��-�>o ro6{Glea��l*%'onJofE�_�4M_PA�I"B;samM�of[icnO O) F�Q,-_sDp�9�"n7B)�EC*Rw�N*� n$r�*�m onsiJa�"+6 should XK"=�a�2 q?� &` It$�Rpropo�8�R=�ba�\�!%� er2 va���e�� A� �PI{,x�!o�0[S%E@"�toe@a08 si�L�A"$S =>iU[9� 389� �Sdem Mr,)�?�d�Cof jaraaSi��("_!��R2ac!�4a�b�ng�=�i�y%t�SZJ�Wha�� >LA�&�P[� 5.A"4R+�exH5es-gd!V� Dis-0xCys.��=5�In I6��"h�R2dEY5�ly%#! �pj �$!7 von Wille@d fac+6 ( vWF ) A Aqs Oas, fib$Ear.���F0� rrup��`> e he�1( FACITs�matryli�� qO;A�� ccur29s1!�7 Bg:ZA=$[8A�1–1BD6zM2�%!6�m�i1M�%�:5eYts%�!m�" t+%�18 ["�Ol�sAI�i{EK.�EN�ܡ�� e��6coD sly.9 , *a2�ly�Mpho�@pproad<n�2=P> PJ� s�U��? s�$<&�O�@erbOhe�L�/: �A�"B� <�� [B�{1 �,ureqy �,��fir�Pim!@%�%#%���T��Lis^�P��*���(E��R, i . 6 F��UmJ�Ha�/BHN,A*�onKme>h$ardi"a$ i�#i6B�!a�2�uY�Q8i�U!�o)0O)?!bCGTA� �NOe��OeA.�2Yi�!3#.zto6e�&F,.���.LEt�.� �.*H �i�edB�BB�doe�! t1�Es�a�o� B.�W; �6-, A�""TsupY с7ep�)at!59= �:�Y�e �hev�s� s�/.c"� � akev�2� ��Pt� s��r/$due!d��N=U e'U'BMa�2`�ᥚ&J�V�M5��a_in � �ZaJA[*#N'&O E�CVe�uAIfm%�:�#.�m� �-�2AOŃJ�s( R3T" oe�s!m�\( he U}�� �cto��� !4 � ^�de�AA��KKe9n CI]ygN� � {F�Ty!�Cbit\)k !@E�Kzzl� NH l 13,inV�_"!J#, �^ though(?t*` z?)�=^A�isq� a31� pO+M�� Fe "� -e�W-eep5" &(.>po� �86� [104 A8i �s�V�V.$!IrJf%���2H ir" to�*) )Z�'e�� si��!�F �*HO2�i��^. D"�_%T�tur�Tr , !'*�of "z^sub�BL y�, eŊ�/au>� , may�y  aL_i5 �F[J=� Q�� b> �"� Di��v� � 9@subtleyR5V�1L tN,��ron2�_�Xo?- &!<ca�q`��BMqau�L!UnI*�9expla!fon>LJP _�A6: � !f�cm5 6l��'.�+e\U""(.� ��)�L�^s*D�]�.�!$.M� v ����lyaY&95"�\*.�� 8j2�a&}` �n��?pla�!%/ H&�:�B*[VNB �!� �fe vici�Ya_�}�a� ' A��+perle6J��n� 9 no2�6��:dd�!T�b$6�NoI��4*5 �Bz��C 1C�&w Ide�'��&�_�0�-�&�_-M�F��P�eU7lNN:�2t�Av�N� n�]j�5bL'��9�B'.�*���Ue�!t �F���H rq�AR>���I> e�_g i.mdbecause���- y.L BYcm� cand�:toaU2Ee&)gR},�2nd(8.A�sM�Z72� & � . �`ф"� �;%�3eat� �aB>V :B�&!ơ�� *Z�^-�!.urkJreeR ��h�n!�a`u�-l&<& �d��"�fBM �f�8��ly �Ie)#| Hvalently-linked net299�m�gi:�g[2*�,U>n= dise�*�%lmuo��COL4A1��|BS)ex��! α1� unit%�>`2{ a�( "�� A}Uye �/U -�(��strok5 huma�Z�I�in2!i>�,:��X%~: <:i"e�bf�2f K$A_h�V��!� � �+��]1*��2�,t�5P�� �9"H�D8rwtbv6�E�� *� a }�� ��Oex��>.1�e��� F2 6C���vj "�D>|_@ �JV*�rc8{ b��g7Bl by-$!:JS� x��8" e�xnotor�8JA *6 @2!�{ �=�6� �� �6".,���^�E)� 6�G1,AbA� �06�(� �Em�/��p.2�.�"Aun*�k� �wo� :ͼ"" ab�He-A�tN�z " %,�x�;)U�i*9b!��z �)^:29m� 8�,a�cig!]��)&K66R Vu!gP�)'�� �0m.����|o�N�$b��`H��3*�+%�s%��r�g�ir 2� a�cfic t{�kA ���Bell": �'�5�{!A �o"�"��)� ^ac�(a.�7fCc�nmh�oE��s%�5] , bevdevoir%:".,Old�j.� riy0�� z�A am:[��G� �o+,5�u�VfFic� AH!�A6 z�f3 �maj�F�?!XE�inDQj.m&H/=.oI��S!�� �)uir>�?Iɑ�"� 0- � �3�9o�D��=�% "� byZ�+�^"]be$�`ͪq7lea�S A���amoo��QAFQ�A�h6 ^"A�fCFp&`4 i1*��=t. �!)G%A�63.+*�bj�ie�Lo&Vb1F1[b.Lto�E'AU, fe�>w�wnA�e�,5�$��rNelk$�<.�p#)�"D �Fx6p i�"��� a br"^{9e� $q2(&���>$-6C�PU�.hpJF$A+:bE�3g� e +.r)|� �V�:��Q��8_"e  m�9 Uy b|PvaseZS�=�I�/-5���&[&�A��emoglobB<\)lla}�*�A(� ��rtrDHa��6�^� %�f� n�W2 %����B�&�U%h*�3A'� �)1� u�C!Y�[�l�"��O�%+�� t"�4��i�i )y�"��� �"�"?Y6�aTc�8m)��@�1%�,2�U|%V��a�$.M,+A� =e� �.h�%qb��78 �O�(On4���tas���i�Bf4e":15'rryG� G mone�`Yd b�Ner�~����� nA�b!�e� M:Q�cT)P �[40j F� Jlyfnt�2f'2Joteworth -[�go� � �Jw5]�#�,U�at a ver�AwI��� �:I�^#�')�a�r"� ./�� �A-PI-� �3)�!�)�S-�umcyt=e��t����"�� ���A� Q��& skelr!Cud�z���_af4!���s1!-��solicD�marker�C�+ e ki�+"�;awAQEM-q �xrr,')I� my)�N5-is5a [41�6��}Q6 �r�>�F�:�2��&� aG a�)8=��9{J"� �E$ =�wG� N;)%����E� .U!�>aB�=B�Xb���v�cgS:�!*(��:�!F�F�!>�*� �PCV�*� �1�%��-7sG*�%2� -M-a3�+ iy*:7s�M#*Z+c#��b�V!��.�q�Pac�� sticAFXi�ո�{{IG��/�1^MD, jeg�sf �&dŀ:�B�:��6E��n&�F� �\t�V�.�\71(o!ge�\in Dros�]$a melanoga^9g alig"Z rqo'O-��!-9bok'e'h��yuec��ax�ya�!�%`pow ior CreAKe $an!�or �Mg:�@ce rul�S st bR�e9 qTab 2l-|_ abd-?9 w�? by A$B (-�7?_lfZAb  ?b>i6+ _-9epi���e�h%�Al1�� ;/Fa4 nervT}J  S%/� +s�~uro�扦�: Sa 92 kb�co^RNZK(is “iab-8”� ���A�aC-3�-A[�� ��a X �Cdu�X 2�@smi4ac�L\%~n c�~T"�gi�6r�r � �promom*�&A@st�lq. H�,�} focu E" �nc) SMal 6u��?c� ve2kjistDa �7b-lt.�oj,;%xIJa�I3!a�u�g )� ��\ tory !^.%�4in-situ hybrid�-ŚzKyo�I,gen�Ue �a:!2 !}8mul.x�r!�b��,!Q �8A� nd 9qfQ��? 4� 13 & 1�H. S!Jd-�iZp�s"` �|�Ms[jbi�[Otal�k prox�c B!-( �)�to�iQ�) [n�F0, [r.5 jp� c,s�V_ b@qs�Z6 [11]1� ,e64 )14 on�[5erm�arte�7Q!�%S*�e<-d�w�jZ8 ( CN�c�ci5v aA��R4j� in��qg �A"E!P, j��dowg]ea�_�-bF[�z. A"�:ly�5�pt!## �2r�q: �4�Le�0Igr����Il� miR- NɆ 4AS%� –[z mi!=�Ab%�mF3F�N.b�,-&nd:E�q�M� j�%kG3c�0E��p�Ed� he~y� &73�g�l�re�^4?mal� d fe f�$څ �n leg"ho?l�� ,'ar�o* breakpoi�v� ܽ�AisE��..�F,:�I�e�. � .�%Ms�nu�g�uG� }e�C�����3�=��-;����,���e6� � �&�a� V�Hi�M.�� Q�8�r鴉m�&.��h �Y ~reEg �ɚ�e. I�VldB�T (* .� Z�![�m*S7Y PS12�%�S1}VFig!�1� .-�Y: rong?r��54I�iil&t) claiQ!e5I -R�Jv[1���)-Ubx�Antp [1&z6 �hierarch�tn�L�{A dof=�:� �& o\ , ofZhc��“Y9bZ"ceA�[1&!d�g,5�4Yzyg] � Df ( 3:_C4���fs-4,��w ABD-A.��3�%��?%�O H"�&�2sde�Pcte�yJQ BD-B�&!a�"u mov�h>M�i�FA��($7�2|>Surpr=3Agb3�l nId��"k# ,)5D1668de]Qv �y$i�m!,a19N�B1~!�n,!��D�))�le% %�:*  O� ms!-�}P �=�#�L $��=!ra�"� ��.��=h6l}?!zB r� i�.un�e%aAI tuit�(i�teU@T�on-�g mobi�- zis�f�YNR�/=�Minos>:���� HostVtak�T0( Mi[Hto-WP];�]b�]#JN04964a�. A s� o�Dre�MF!<6�z�@�zBX-�� “T�wcC s 85�- 77 & 8� n�^Mi ( � ) LNPAs+y�9 shor�V�f.�v� RACE1�suT!&OC pm� [4���. M��)�xI matcQ@�a0`� ig�P,d MIP06894 (UFBT09982���W�lAV,.�,�Berkeley.[Ge�`E[-. � �%�9yX�ggz't�!!t��5!�!�%�E!, �XG! ��Oregon R"�z�w21�_.�Q%c�Q�wsp\*∼2eRRT/�w}�0yW�Qc�6a�9��T! 1�VH1�n� �:c,s��U�Us a�p 71tI:���5 ='$ ��!)�*a�+A-)� _WfI!%�9L���/.:3�x.  dE�#2�0x eI R&i�ofA��y ( d stretches�_A�EP9/�k1}�� F<e��Rc)x�qlso=���skippe>qaX,NEy �1�� r 6f�`� 5�6gr�aVw%Bar�as:xJ35�s� up�am A{∼3 %k�qa�m�r0kU!6 O�zl�8r�M�=�� 5�%�5�!�92 J. 2�ha�%Aq�AM)D>I�E� on 81∼500-�co��7n9k�=6�EA�K.�A��)��ui���S�ZTw%��lze-�&�l�����%0 yJ!;�u�!&<V ���YG.9[D5[2g Grav�L"֎2])Nr?K�W"�3Za��dq0 q� �J 2�*W�!%C�)g� %!g$% 02d�Fbo�r�*n8Y6: :2� X |&�Gu� Po9g mb Gk!����Mr*<#Da���7i@;=!e=� e&� � A?14+Ee�Y7�,��)ve�sp�6*Ƃ&� �I bithoraxA�ple�s��|^ +iab-*��SgarkB!}E��\�e� *�L�q>Q!��:SI>a:��ii$r�Zt�N2q� �#.�6 G*( '� � -R]M��!�e j�s�"�) E�<fe�B:�A�5s iV~aSi� 3AE�� � ]�61�D�nicQ;A���AV��;.&�_D�8to� Mp� Sm(seudoobscur�L viri��iE� 02�(���� ���M�Ygm�� n��� *̖q5eri�I!�:;i��)M�&zP[��,�4canA>b�d`��-~0%�Ͷw&�=9.�j+j,p�Kr�G� hdr@� �!_.� �!n� K:�r���'n�:�(5�1~ ananie��b�wi���v&U 3,��[@)�!+�-�1��e�Rntl��:�L}ee��*�r.ra5ly�!��%!<�.h�yew,>�O? rugD�>%{c/QZ T� ��&+3 trun�d�&aHu��� @?�Z-�R.�@� �/ R�E�2���9l4 &Y�� � �!+�>���!�inguish�j" E �!�.�.�"m z �*"��E�>m)�7SGA6���61�  584��ab-4233�xAE186r2 &Hf�+������ �-b��Ճ64�AJP ���8M7"_�����Q;lHemb�11ux]�DB+pp� close�W)�� a mMm*�2�5��35022v4 �ex�a�wxxmisF�i�#mi�_ |^�!��(VD%[�,om"�g+!� , 5324�u302_)E&z�Z?!�=33�]p-/E�:�n5 F*W_A �m*�Z&����mV9:;%� l��F�'���$3�8�� "L - �6��%i~1ce"�!�� B&m�s!�qy+] ogg `!�e�C  Dps ��(ehi�kV �&�� t a�A�s- �WloC� ��� E�:-5�i �m�� �6��}c sl�$:K�u����3gue&a,1"4 6T�#-�u�2mE&�N�UTR)�F!�'�ese�lot� “seed�-\2�[1� 2 &�Zu*�2G ( Δ9A ) do !�4r:D��Ef��a����� ���)9s��Zus�� b7F�5d�0� 3tx\ucleiY�'�2���5��a!�=nKj�́6~����U?�>&s�j9E �-M����!( ��&E(� �~Q�&")>eKo� t�3M�� �?. UBX.�/m���'ppax}ly% .U��s �~�-"W�l"w n� �3=��" ��'#ay*=-AS=��>�AS-AO �Ye� t�?sexesQ�Ti�g�e ��c��� Ah llel5at�j�#�O؝�{&�#w79c*�i�>�8v ab-7��()CMX�Y ) h��q,�.�mm} !�d-(“PZ�CP"∼j�)6I��Iaݎ,.�mf� 3 ) 05649�{�9mfs; ./�1' �e%�C!��#s��EApheno�,(*6cka�p!ovib)Ag" in21.c[2Y'We�?um� �*m� a�.~�DiI#�(i�vw�5.�� 8Q�́Se� 2� (% 6;��5�9f;�)� 1bI"� U[t�*.�.!3 ��.� �m��A3 � �4Ͱ�eFay?U�Jm!&�%=4�u"� eF�)62!�rb���cmiR�8�K= ms&)F�V9�Z�1��tA�;&i�s�.E�L �eI�Ee6�a���"�d oocy�)��ގ�"2 ,w ��.�;he2�.6���+::K�a�M����%i{Ce�> cess�+)(�Y,"�HD:�.��N1GF�to2��37U��: B��� A�3 ��V6) R��]B2 i�/6p�m("y �T�mMX�r+�h�t��l �-�p��B�Yǵm�Q�� u1m$1]a�Q�9��$�.2�. S�!-�2�,y ��%&)J� �6�6 ��N�orA)!b�=����c�I"�blc���aA��<,�A� �O�*�"Ď� a�l� �&� �; �&�hairp, �! 6�� �I� ��T� �&q+^���cop� tinyL!@"�ys+5�SsI~ic+�]u��Y��.S��1�/cNtt��)C�#"A4;<��EpI�236 bp!8q[Fzb�,�uFM�pUAST �� [26]P"+ %�gQ4�r"�"a�;�%tr{!,m �$yeast GAL4s2iv�0A�B�s���8�x.U8Uh .J� /��B AN:k� UAS/)�%�`#�Y�M  E� mG��l���{N"01�y>� _qY4a�e"�c�^M5�)y�mO.�a� x+2��QXAz1ffu�XIi�^� �aJ lleg�or.XRNA�0mammalian HOX:F  �. I��p�Lv�� mo!�volr2�md�a�#"5d��ct%-%�&\a���,��i#"&�e�� Y0&� iH-%�Wa�A#so��L�aȧ-�.�� aHe neec"aEeste�� s"�6&� .��b0aU),*� �eX%���Ab�*�"[%ne=��6b�/�q�I��"�͖��"� ("$ ,5� ,' E5845 )���>9���c�Y);O E�%�R��99�9e�r.�Ga�ac z# "�a6gm�6�Ee� /�.�V, 4�)Z�2 /�m Mc.���0����9��\�qc#� . To����a�a**��C$aploinsuff�~c�Hi9|��6� UX"="A�'�^ DfP9A`') .O��rJ\e�s2m/O.�2n 6�.[/Q����-n2�]+�T�,c�8qG)i~k�i�emplo]� du�' !qr"�6u thir&[��~O Dp�/∶�D10!=)��#ey�,M25� (� ∼110 kb�8]5,�.�N"{ @;Ii9��9 . Em�� ��Rcd�W .�\ a[nR%��"�S���* � !Qm�Szkby-3��-��f\dA��@��-� >��(A a�a��#e̥���!, e2F�>ngi�"%;��Supl5ry�oS�S�i>eD-� �'Nl�Jl'Zciz"8*of�+�6�o���i��2teb'6.>j4aL�To,*�benA�� ��lj �=�ar.�[:�XH��� �5,fi n B�:��he XISTŭ�"J=&�X.tin!��-on  H( 6T&�%��a&��d��E��UU[��qNasJ9�sE�.�1�� �iV�en� ��f��UD�fis%� [3o&n� RNA-*;ed� meth�� _Arabidop2G��By ! logy��s���!Si&T recrui�e�machin�F��*��9�AEeR&�$2�8�O h�fb� �)��m �k�g�� �/. Ide6  �i�&� ɖd����j��-�o�W[> checXџJ-Fab�5DV��ޡ�o�/Ak!Zt%?>�"�b*y f0l�w U �!iA�W;"�A�W . Likewis doua�1@., .�Ai Fab7� E�r{��>���~)� ._2�;t�yq[��J$"?(Ree E�1[��,��-_Z oinc�g �&2A��.6*���s)��p4%�w�EoAeA�m�Ro&n Rm5�� �| 6H !�B!���^"�ye�mv�!�2�� �:!�5i]/J.%E"�&m��F�B� ��m6Q� �6�q ve�V )A��%A�a-"J ,b`h/�3%Lu����b�� !�� @,how"�*�i�.e ���2 ��E�m�>�c� buձ��J�� GAL7ENf- �"� GAL1��Apt [36�2a�) SER3�Ge��D SRG15 R7U��EA_O3:} �9�8$��7*�1MRs+!� �!�byWM�I gRA��iSzBe��rA;�9�"�-��-�6f at[ li/�>qAW"*& V�$�pg ��!"9 %^� is _6a��>1Na��Riki��!��Rt!J5c#���#a/U )"�i*���/1�"U-�?8!�T)"�Pj6V Y<�� in��pV��6�$[`���_�V��jMg�@+!�kb a�a�aS"�' ���ʵ�� � "=1� �)f��s f�] or�.i� ce -��block2� y �V"�!2�>AQ&IsDJI:M��of`?�,he bxd ��j*6+���t] �0p�4 X�P�cm��.�� ��� ^:IIn��Fv�=#�D�g1�o"TS ��-!�n�� fix%�. :p %�"� Bm0t?s!��Ք@�Dl.p�;��5��b~,ad�O=ŀ:� 3�$�5>R�it�YngɈ�}Y#��9�a� o�[=�)! dictE8A5�Iar E)&���2 to 5e8�Mje"� . W"�BstE�*Canton S��"|8. M�!��di�MX� ao3@;��) *�+"�.�"2G@T=2>,6�= ) P "ref [c֖K�) m3B1 ( !�B)8,4�T4r 1;�`*r"�!,08! 2];3-� 4�869L _+ �ų 2�,iab� �* -(.L � ����"p[��8&>=�! �G�n�%�fif�,�#�A&d �`!��IAby�;Pri�<�bod�u�`Rmohnti-ADB-jN1�dil9��#v���[ . CelniT��al Stj�H�Koma B>&i�&(g1.�� R  XiD2\sf\ rabbw'�ß-gal�zsid�� j50lCil/MP &����^Cn�,J<me��,2yEvB!< j$Santa Cruzkt@�y> K � : 6A18ԥ;#gif�܏Dun�!MA9go�K�.Cۇ,n} . Se�N>ME don��-),2sIt.+-xup'�Al9�488�� 5552�2� ]HRP� Lt�)*-�Bio-RaD���CNS's �:����'I����'!Hn/u���l���6 dro\Immu-MVd�Mor���), Soon r Vectbel�� DAPI 82��,+or Lab��o�J1�tCg�LflA��8t]��lip3=luo"��i��-�AI�N8 Leica SP2 AOBS9 :��e|6�pi�ps�C�proK? -��esta� + ���s�!'���_pth- �U."(*)*E��yA� *gD lacZ~W���$ TM3 ftz-LbalS�Eac y�Eut��vir�#s #MEv�tIA�>w�� & "{U ����+R9RI:� . Vi6 >in���t 25°0�>d��i5E/"�A�![� of�tva�A�;s*q݌a Hsp70-Gal�ABlo Tgfy #1799 ) �hea�14}45� .� 37°�[ e�FAF�JFt�3WC&� PB5�q h sR!�%"��uE&TRIt$aS%���nd b.r��� �%� MMLVBpt�X��) `'dapa�� w�GAAGAC$CCGGACT18V���>�&U� �a��Q Jin�D%�a�!�6*�Ca��/Xa��ic�E�!ma\�0*� �!  "b �!spr��"8��(RNAqueous-4��Amb!���� KC!��ligase-Ad "��;e>6sFCho�� RLM-8:y)h Q�dusides}Xt�?�h�c= ����-Ufq�|9`�lX!3���f�&6u�Bluntt$(6J�@9 �  5�D6)$ 2 h ��1� �~l6�& ��!�E* easu  ��EHf�X u ?%,A9!�r����%�-#A�igoxigUT-q�<�UA FhJ 7V4�Ar>� $Fitzgerald@Be�?/�;�ccͱ?ea� [43]T%LK�+�q�a�Ka�Aumea��Z� �. C!�sf��! 8)��;2"=,pe=Nd=-�re%]� �aOQ�Un?D���!>ff�!�pai{�oligo3otiedes:�2�aCGCTCGA TTACAAACGe�!�!GGTGTGGTCAAG"g;Ging��\v!'1013 bp;r2�Q,CAGGCATTCAGToACGGCQsATv�T�G~r477r�<mTTT�C�C� Kl$CCGATCCTGC j �f�364�(.�FO seizur�q piso� AS.I�br�Ja�v�ha.:r�e�E��� ?xJ!� Ai�up��e�� �gW hteZ���! they )�g1*T< 7o� �s—l�tvtum*�oscil?s ( LAF��orS_�N. spik�OHAXU�3�d�-(!��]� r�A5*fg�� `t&���[,]�:"q�Mu��� Dal�Y6eocorti�_� �"̱��` adeq� =��cli��a�Y�F��W�nY�e%p:�%ms�{�ng�ppxMA�M" b!D�y"�sa l"K�9?6KR� �&2#E�A�:�^3'�e$ h�� s�w�^c|1�� le ECoG�+�H��eAa �^C�^*?Za&�IOlyYq�q�O slow-%vx*�surrouJ-�![coales�h:imi I*v�#eE��qoba7�� �p� i�"to� e�D!�q����� igge��" �*t)��l)�laP9�WP<(c�b����~�o “h��y?6J1;by�elf&.2�?!+��� $�O�5��1!���psim�G )[QBQ�J�2��o'd�PqO&w��q�lb�edFjg� out�a�&�>we2Tei�m(L���QN2���Glucz{IgHr�"�N%1Y25�ake����emodel�� Kdg��I0!�2�- M�2Z�)� c�.gpl|{_�A��z �0i���?�ll� *u6Z . z[�e��sD"�%A�Q��=EirA �k���2�abnor .R:! c�#ݰ*)-6�"ś�e orikX�3n^ ��!ruc���YQ| managB8 V�pilepsv�VJj�Vev� clnX� he n(6and� O�m�%3�HsA�o!3C�ɸ�9el��gphu%��( EEG )��� invaM(a�M!��u A�R����(��P�~���"!��)iMfo@�t��"V/޻�j[QK�|ַLn?mFsm ��� �&��M��:2aj� !�n�#G��I/ s [5� �fQ��%al>!yu�S)�Mgf;d[� �[IR�r��3J �%�mo��'of=�Um�}#�ra���� 0 O2�� U(ed:�J � e&�$haryǏE�[9�%�D���O2/aVe�ub!�!Isf�(�  ,�i"���~e� 6�� y8qu�S1vk�m�>>t��te���e>3 . Fo�}a�@ ^Dn�'<� cut-�fB)e�/M );�d�v��HA#�LAF ')B ��?�H]m��!c49��N��_� 8 Hz%j20 q "�tL �&y W� ���o" �tl�#ur4%[ �j1a�1%�Intrigui�]��ite=��J%r<*��#M]e�Ui7s�+sv :�a&W�M� good2�� ��ed�%w� � , ������.""Mly wo��<��!t�Y�fed�Za� �>�-���%H2+`l���O�N% tire4�{� ent;~ � u��lK f���R�2#(���_�li�I�\in4t)�&�'a iEAm� n`�m7Hm53 A��RZno8-!\$ 2E�a[V0!F2�nP�3J�%� \z�4��i*{5o�jA�:vlo^ =��F"�l&F"%ac�Ts��Di�EՕ[��'A2#�]a �al6 as2| %o- -v�*U� CCEP�iuy�'-� �.-�.Z>�A͙>�Be 8enA�V �gA}�>c2�p!ҹ�2� }o� knowled��}+�o-5�T'-�I��s so fa� pl�w.�}s��F�6����#J (S">���_�/9�d�ly29 eore� fram�v�JI_*sS*86 �2� *Y iyA-�saW{`�  utKS�Y2yn���i��Yci"�[���"r��h��dB%�h[23��a b#W�t$13H��o�"r$r9E��F:d���BN I. noweu� R M�Jc&�� \l-�m.�"�Mur earli�H tudyͺ�c"��AI�>aA�Q}-� o be� -i"�A�Ӊk �md"C )�Ea�[ ��Dfa�cap�;ij��$���e%�*  GD � n� �:2h'&[})�7i��9 ab�}�> �Z!|��)� &9!0�-� [1�)( m�X��J ��stm a'�9]!�U�"Fz|��.1%1 ;)i�&���grB�o2�J|} � sh�gsee�:�i� ns!>B= !�er �:*� �2 �6?� w)��Hhow&C�1�T�9!:� !�Uwrec �6�-�ked��deP%�*a�)7�X ;�shK��)M �s� Q2 back��nd; u J=5�[~14 H��`>aPՁ�s!3UV��*�VNp�b�/Qcro�&i�i"{�8��or6�1Yxu�9^$&� ,� �=qbef��S@���2�i�x�4�6�=l�D� wo�;�2e"� 4c � U igu:"co[��V���y��9�T$7�i�. Eventi� �BiN�"�.Z�塓=1ae� i�%ZTq1�~�N"�.����!1 �r)�e�� sW !$`A?2�B� ��Z/IM��tr�}�>�4�R2Ra)��1�pie�f1K�i��.��BtBA�lso��y]Nsi�a�1 哩:� �.( F��i�!� ( ~9�)2!���e"��>� viewl �ya�s&1��$��a��St e��!WW*�!Fſ�xaG��0e�-s)�8 . Up�(� y� �1og�%} ��B<aAA�= ��!JKrapid��rAropag( wavefroy�I�<-�] �e�f9x3�>y< conn֭�#2�:LIB :&��u�mwyin��8 a|.�.yM �� �w}J"�of%�)�3�faiV3�z(,� -8�]6ph�"(h 1-2 �?E,a�A�y�]*U � %�w�(.��� W��In�IZ�0rs��4�2�Go#8�A�n4:��,> -�ꡌ�(-�.�.x �"�##�1*h.� Z!-f} xq.*�d�9����:@6�Vuo�u�( D%Ka@o�!�&x N"� AN)i�P1{jO�=2>!R� le&v1 �yYe�U2����lRn ��w��|a��T��@z� we�p�!\| ��� a fu�vK �����!���)�,is indeed ca�Upable of reproducing both onset patterns qualitatively , we turn to a systematic studyQ�the conditions that lead to either ]p . In our previous work [21] j,demonstrated J0focal seizure �dcan be understood in terms�(spatial reg�ofCactivit�,and surround! non-j tissue �$particular � show�De different classe�D�(were associ�with a: excitabil� sett�of%Y.�@territory . Hence �choose!n(investigate96^.(:�TrS!�!M6:refersf proxim�tomonostEd�st�rhe!Cameter!��ce ( see Methods for details ) . Changes =2!level%gX1 Q0caused by a rE!Ipa } s ( !� g . reducI� ginhib)areA�int�Inlfollow!�E�Vx�p P (a(stant input11 �%�popula�nEquivalAT,results hold%%omO�en induce bi!�IG��Q ,%vS1 Fi!comparA�o2�We also>� e importaAyQ�mgorganis �m� core!bZ���words ,%Cnumberi�iz%�(microdomainA itiae*!rru��influa.��Pe overall dynamics atU�i Uo��$For exampla10%�Hminicolumns displayAV���rbeA���ly arE���(to one larga(8tch , or ten se!�a� mall�J(ches . This�is illuA��:in)�C ! (top two pana=> eref!�E�sh�%0st��5effect�%��. densa�-��1�o�.����Ap2A�9)�I�!<s!'.�mplitud�$:��� dot�0�Q resp��� thre!Nu)( i )�/iu-P�H) ,,-8total percentagM��,%4( iOM�of67%� high �:�( big���a�T ll f���B valuɄ2�-0�!w��(2� . ToUis fure�E$ plotA]!�distribu��=� �ȩ� each �+ҙQ�B��z+w�`QFs%er�* n 0 . 5 )%?gen� y-Eina�[%M1/6�.2> −�6he�&V6 drop��:%a��below �� deed�� �D� sup��!��� cu���4laps very well)&!�nV�Rle�. ( between �!N<]C<1 . 1eIi .�ph��nd backgw &s coexis�$ tAzB�(�DBţTh�6�%�.�E��{6� �y�p�ze��Arm , int, $e some var�tonA,>>�:�� e decid�e�\ir�^|(wo scenario�[RG:�*w��6%is.� TheBf���mVC5�.���=1�5�CA�op , grAf�i%�z�A���!��le)� . A!Icreas":~tj�would"z a fasp recruitmP J�. ex�H����to}� a6>N, which!Bexactly%#c!/(B.�4s from about 1y2 . 4e8B B same argu%, il �=�{2�mHq@� � ssen�(means multiN *g point�&.�� g we.�I.(toV -��n!�>I '�#er5Vagain!\confirm� ?�na^ %_�O6�aV geI�-�A�F_� [ :]4.Ybotto�� blue�[* >\�F�U�e ,2FJis no��Y d easilwAt%")� l phA�@� , mer<!���"  oscill� ��is� ecZo�e ECoG:�K-W�+:����a}�a sligh晄>;(9���5�:n only�HE��preA�%�Convers!�\i\seA[l jeCirbM!�coordin �oonY��%appearI�Z &= than! inglD � . Not�uatA�h  s�CB x F!�describAGQ i��p]�32 C� �mfigur� ave*Bcol_ axis�t nak ,, as already� �v`1��e r �Iis��aB�I;ly�V freqf�aaIǁpBW"� �xis$�D�� �� yB ofu:� �~�3�of�$significan�deI�dብ <� s du` %� insic�pertij .�i�!tL�contigu�*$ u�G a!~eY�^ 9M:modelIRQlY.�concl3�  Ac:�s!�( HAS )--�!�mos!strong�>�A:16n� �e��z*�of.�Aر5-���Y��� ( LAFB�occur�ZeTAte trigg�:�M�nalhfi�l�iV��2����5� namounE2>�!�BQ� �see"�/ �9to� de� 8ow�1E�eA%in{yBkye.�Ri 6�s �2� E7.}ac��ŞaH�qE� alte|, 6sm)�li.�V&�;# sim@)" impa� urgi=��6�iP! N!��"Na�b tiv�Ub�� e clal�ic���6�2� �bNbet� post-�p� outc� in 2 s [9 , 102468]��J3%(how� evol"�NbA�af�a5e2gG!'�silico!������sAfor` by1� ng 2R!+co`� heet"� i��I� area� &� )Ustart�}�.yt!���9ofa�Ͷi�q�t ord2o ens�M ir c0 ison�e � chos�X �/E2!>"fAl�t"�R�)al g��N6:m�VQ�4? �c>)P�eF!�!T �q ��l�p%te&�ofR��T��EAJ�.I�A%Z3B�@N�asA�� e�M�!�/dQ��AE�6 �BA� .<��)1�B�3C1��is stil�e�H��EQ, b!h�� no longer� �1�!�. O� a �6o�1��re8 visi!�6k In�A� lete=of�:�!+�)jz �cana�p�B . ٥q�-Gs1HD%Hg9�1�removT�rig� ���y)Vdoe� stop fulc>)'� �= o2now eque �|]1���J� iɈi:� 6[i� soJ� worse����)�<��:� � ��1�en�s2����nɿ-��Vs M-U :�q ! lack!��&�AE'a&�2�z a�uffici to�v B" . Ou!��7� � s"�ve evid� LFAf���!L�9�y#a!sB �� � e�I?"� pict��څp uncl�*� �O!4def�� ", -�m��subtyp� epilepsy.� B Fa�lU wA�ggest a���!a�pos��6eai*op�x�ie[ ��|-�l volv�ai=2� � L rZm. I� o-te alVHis know�� ledg� �#E�$q��AN�a$��)}&� "@ subp�#trans� �or%V�to>�!� apeu�$brAsst5 !�devicesY ne�b   &!�On� A~nt  blem!�inf�#ng 7�2w  �t"� }�!��!=�0�ch�"s6�observ�o$ by passiv�c�g9of>, LFPG ��, neuronal fie�A7e is be5#z]N�y��Dt>���� �? holo�MabnormS&ymlaE�!%in� ,electrophysi9lo�$/� %p)bF-�4 � �*!Xi�W,  necessaryAtrack5kin.�y>��Awa=achiev!6g_eEA� 4 s� ro�bf princ � A���o'�a�EL�6���ov� �du�2�!H xWened�r�'"{qgos|�gJwsx� 4AMUA�$D�rQ�A! � �4BX ob (]��G "be &� t)��}TA9W!� analy�{� m�!t1 &�A�asM- an eR%lished&bA�! easueN2}%�$s [15 , 31�9"s���/�e  �(� !H� Xl*� )-��ans�}��m&�0&P )�=6 mA/br%���� he 92bsitA#s:�C� t�)'��h��ximAn�5��K�)iQgZx , gi us!� :2�&�M�V {R Zg^0wa�un�*y�e"l�%}"�N( Pear1�'coes :D824�p <00?!. -+& weJ*�to~racter' K l ea�"($ J$� -|�:� 2&!9��o s a{&7,w�#� 2�J� "� litera�� irke��2���u�&9�MHlso!(s8D ?� encyQ��I.*} bN�!%l����'O��2�� p�f!� �at 4,1#�)d" spik�� sharp wavorR)-and-$�(, etc . [17.9Ib�%did� &��K� �\%:�$��!$�.- �-�6,�kQ�foc�� Rc�:9i�#�+��Y"�-�Wtheles����worth � io��� ��t�l�,I|��1)a�& *weE�(s� ��ea�r"� s� kxU�!�� "-ev4 “simple � &?,�� ch�!���x �*N [28 , 2>3933]��s )/� in]eix F�2��%�#��i� ���ra:�|(% scalD$���WeK"g n�.�!A a f&� ��I* 0q� �'AWuses AaH1nu-�n*1�erap#~E� it h�kb�)���� � �aA{N�[*�CurJ0F,urP C , n7 %�o$-yIz �pro�d a me��is� � rega" gI��� . P"�0� mayE ��:Z?(� � 5 midd{29[34 f[%�eh5!jr�%^i � 1� , of#-i"� A�  9�� 8h2ma/it�1�1t( �/H(=j.� pe2���n��!4ine!� ide-�(�  )haYZ<I�F.\b��real dri behin7 e1����5; .�he"aAo-m'ba�b�} šTTo�Id% �0�>�&;,aM�of%%e u25�( whole �E � [35–37!�A�) &�nh gri*+��?[38–40��AQerh+��i� , po�eEe !�sub" struS1 ^4="42^�no��� !^�er*� ��6� 6g�  рpr�q independe�!"�nga0!�i�qy6!� �!�e�egu@henomen&�* 9�(de��1�2�Ad�n%Gs�n2��� m by�(&� ��ndR �*�Ob�plainI�hact@a\$r:a!�& *�1)z� o fah �isAly`n�� +bsom? uct"�0$above 8 Hz�M6�[16A�whi��g��a cutoffPy 13L[10;�+ er [1�VH"!���%Dat���5�h�'M;,alpha/beta b�B>at�;Z)�#� s o 7 rify"8 ly.A�& U1(y-�A�_ %')�� !K,�4th r�\�hip�]*� 6�i 3 ) �yB v4w,A�Nela effo^%Ni�. I��E�$an open qu!onose � ��Je�-\�p%!�-92�( HFO�1>�( gamm"�6r beyon� c7��3��M�+m�!F�� cell�8u�M{ex�/] -���8"�be!<di�ed [43���1Z�K*-lock�|&lo&1E�( 1-25a)F��� �<o|re�3d�)n��!-una*�JofF[ s [4["45�I( ad�!����u� �7v5'k �'ve��:�*� 6�A�)i HFO �'\A,se66%�c� E�beR�,�out�8�." ��.jp"�u!b-9_LFPp A*��)�TenaCnin�XtH1:�N� ,n��cI?pEEmvn~(. Perucca e�* .�ted1E��!�! ��� .+��?!��A!Ay � [17AX���w/!�� loseu�+�gA#���./�. �9n� � 6��E@B_. F6�enaۡ� uishA��&rippl( 80-200m�nd�200-5 -�$, Levesque5��"Y >z6!L�"�G� �(� �(6�,!�M����lo���[46!�� authors fw ��"%LF�&�LAF5��M;��~@*+"%�/��(�lyi%�aed��er�HEb%a2s�3"��5AChyp�s�&� ci"�2AI��Z��e@&i#)[ *i�͟� �:�%ru!B�aneed5&� a�"t;5e1a!of�togen�,�.��tȭ'"�,� �p�@ �[�@!P{��al1u�@a1 `.(/b*.,!4A2�rpo )onf�>�;)?!0 ompu�F"�C�')m�H &�I�R��abn<�!a/�Mo�-��<&5 ic%pt� -I��A)x�qu:E#fe��:�acv&�'A�&P@��&�>�c��r�7|@!rU��F�*q� A� E���m}�B to d�3BC6�ll: of wc �Y��:�:'��|7 � A�a鴡�q5eP �in�*approaKE�itQ�,ly links key�Q cept M'.� 6[4I8@/U�)���a�Nj. S� �� �com�� rief�3A:y�%al��pir�y���er�+2�"?!>2�XBadawyտ"5E�"^2?X- moton+rtex �>sB)M�^E�"X!�bE�P5��/��*"#6�( SOZ ),�2�[2��%� A��ca�F�i":{2�a��3 desp�3 netA�f���nt�hemispe�. [15]2,� CCEP&p&���` &3l6 � dX9 ar a��$e%,9%g�%a_%�j�a�1�:�'� bec&0 co�>�>�[476�delay�+�� �5ul"�h'.�)maiK+�'-�AN�� R.��a�(>��!�F7 ��*ib �explici9 map%6E9��e���"!X(&) shifteO2KBacexg "��)Enatsuu�, ^ %�3:sA�x*�G��!+b�T&XE�41 /! js{FTE��ZB_��#[$%6��% �"�N8 h!�lsŰ��fi�� i`$����$42<Q>z��� �eju&)subn#H(�h�"X �6��surpriA��i�o��4� �!KF�����-%�E�:�u��.>*� �asaY �� 6�:� � � c� ani�� y im�!�E�"�"g#9%id6U� esoleLBfC;+,�#= :[ a�a�Ad�KG ,�&Y p � spaI�e���>.�; n�$e��b)ne�,al)t-@a�K%R&" :f� e��?I��ui A��A urce6� CJ��!�il�3� V q5d,�eeU�E�acqvsM�S�n�ir ,el��2vix��2� �b��*>M[45�'F�.�&2Ti-00'�=a�� 1&� �+d� ooda%�ab��ro-ic�C"4N1�� e6� � factp��eli� �2�%�Lb ley+9z� tumSqIcp2ni�dy�I4 6�a±YE!�gi2*<�C�de��"�!��/��fK�7"��+� �(!c< � � [49]�ic�> Q*.��a!�AdI�[ �� tegA�� �6 X �aia)K�'�$!�&�f -=1HA!w6�O�m\O�5B  H%�e�R��e embed��iAh2�<��ލ��a��� �C�ons!� ‘l’|‘�)�K�B�of 9�.�2���lpreci�:X9�ora�*�0E��o=ex�< sh�݉���'s���.�*�bi<-[-!�a ("�?EL>{12� Re�^����re�O� (F[P%�!gI��$(�2�a ��*%�w�6�onjun�S� dep�G�in mes�p6� ��>#IJ s [51Th� "\&��o&n6m"s-�:�:�[�!�n!� begi �NF`�c7 �Y�1/slo��gro��T� coales�,!�N:�+NK.�.�m;y tes hPlid�$�)�-+ ,��-j�)�G~.�uz"l���E" B5��Ey!�C"i-b� � �%"��1Uin!k� �* �i�".>b�1!��&� 2�t,�l� !�Q� )��%��paradigmW.�u2_sh�)s"]�!�N�v%� al� �%i���(<y4&�Sp(O���V &�9�a t 2�� �B�in)��WD�36���1�� �V )!�d�[minI����*�:# �PwA7�#�pe&B=��^�mon�[P )�E)(F.� *I�o�< m%�"�0�"�?�=-���&fGmol?i�� �a,<^a �!d-loop�� trol����'�in 0E*6 V�`el�+:ly�Lo e]�. VlTu�P��SSZ�%� �"[K!_�$ic [53–5�+ magn� [5]-avoX 9]���summar��Nth&�&���,}@��sew [6)q See [6�\�, y�%� towam\developN E�f�s�[; �Fig>�� Eya>���[. M��r ��.T0T�&f 3z$�0s=1�A%%� al a�.�0>J\ly neg�\W:0�JU#i�����q`A�i�\��%y"(� �!to !�3�A�R�3"M$:��� �6�s�66�@��+>�#��>M�";�0!it.L. PAda!4 ��21A��1.:E*�,c ! ay9a�fuE!R�P.P";"� [2\:�( , 62ic. UG "Za�`ed(9�5"'�26�PA w5-�1��op ���#0)�� �+pat&>�!  .#Wed"X 1��peXK"�$ F&8;5?_pm�4� "+*e�1,�L� V.�V�;a1�p ��2 s@�1�Oed+l}�� BJJF3A��;`�ds� �����T!+q�freedo�%:w��*:��! �%�m]r2I-�UC)�QD. G')\� %��i���Vi�5�# !�"x% publ���e.�TeN �Lba�R"Z6aS� O]v6_�?R^( �h# "�0� r F.e in T[)�;� ( MATLAB cod�0� �aW6�j>Ton ModelDB ( ID: 15556�^K�@R� o �P,��m�L &�!��Odel0(=,Wilson-Cowan Q( %F , 197g/&*x���f!u "geF�8( E(IIt�IumW�!5 &�8�'ip`?�=5�@IB5i 3A8"dRa�e-"�mK targS=&o9!k�Zt�%�)fU�*t E+ z&Ųcoarse-g�D��dZ�.6y 672!NA;i�sA�+ quic�U 0I�� >u^ UN" eL-uQ* �<g� trade-off"g+�8a*(�2�I ��*K&���P �|*�'v1��&�0&>!7�* ͉W5�Y%Bi '��pi� h� oge�9 !z$mesoscopicA�n�uD �Aat폁�(0� �|��le.�i���GA�6�)%�,Pif F�2�in Eq 1: τ E · d E d t = - E + S i g m ( C E → ' C I (I + P + A sGS�; ) )YId IY-FY'.Y,Q�(�1�EE! a�f�+&�F5�%n�#�dy�; I�Bi��B %�Qm��basel��� u#N�(a�a�3z5�� �sbasGU�1iE1ca� no"�CE>ref� � ! �T9�!e�is� �<�u�yn�#est�� gup� streng@n �.��+}�] s CiETje) A i , j = E!+��Q ��cBq�/�9�a9��.� "��=<s�!C!�pre� by�F�(+' �F�. E .t:CE→I�V�k-!�%�uE2p6�jI.. Siga� … ��moi � ��3ja� r*�g�3*�%m=�ly��F�[6�2�6~�.s}�Tx ) = 1 1 + e x p ( - 1x - θ�"��a�!steepn�AM>si ڡ\θ'off&(�i:-, fi$+�H Bp&� ( a�,S=cf"�m:�Aova�e�}�o�XZKMmCG/��o_�a! >� shap���L*�  H\ � &K�!150A�&� {-E|&�e%e0�* .*�_�kr�Xz &�_by�-�f(Ea��5, I , �!�τ3 ve�#�Kc.�C$ matrcM��`"�=�"�) i)Fri�E�#assump�I���94�c50μm × &G[6%A macroc�m5t�4!��10;10[�])si �Y �[69��Sa� �#fR.��AmhT�|feed-for� D � !xͭE��ia�Tm�a^;��B�Pch�s�o� projA�z�  E)bY:��/Y��a certuO prob:'ŋfal�Kf *B_p�is? !�l$4�� &�[7�?I|/ s adop!�|os�5l��N?A�7��M�.�f�/L2��JE�%�in [73�=ɐ!2�NJt�wri�A humany� . Spe}s, be� {2\ �o-,.ra��� *� L���o6Mbci�N�9Aܡ�\I; clu�iECZ<s-���G�Lllimet> -2�, /Fm�!�WaGU�3 $ algorithm'1!��v�\:SVKle!�P2�f6� & ,]-�a H�W"��>2��e#�c. �.U a>*�� :6< �/chica2�(��by.|)�i�FvM} [68 , 7Z@We� �7drawn��i4 ndar�-�Qe�"�Aje�4 Gża "R �etA�As��.� ;$��.Dr�do;��( �� .2ty �c& � mbae�� }���G!�.�  �:�ych;OebyE� stx7I��4�&���A6�p1� littV+E@� � 6G) Q�� �qI^!�6��se"- �A�dB�Cory���s� (JI:LWe �[t�C�.F =� ��%vI1e�F.r�{��.!�.�Cnd:^c�q!_�.ID�F��>k =�(�!�"�7k1�,M.�e�E�cl$MD)遌“�aD!H!�w�&lMjN" � c&�twP3"!�VA$�/.�I����3h�s�9�u\l�+E&Sz�"�=�VB� �F�maj�VF nu�>pg)! per� Q�Qout2�xv{(I�.z��#U`B���(M��f_��a= rf "U put/�s� ��d>. j *�Xa�mei�KhO&�3"�!� ��M�en� b�M.�� [2T75N &�/w90��!K2-;�ga�L �Q�cKF�['� EA�w\�y� eg!%EH`�K�0A�e�g*�{� /A onomV E�.��.�/j:��� sp�K,;"*�'q �& i s [3�K"Y,wm|"canG�b�"vo�Fh�D�� muli��el %gA���4& peneӀ]o�[health��V�"� W-�`p�A�eha3Y&�c��+� �0�!��in���Haiw4*���� � m.��-/ E�h�|���7throug �m�>s �B D�1er��3�n��sp��R�1� �!^ /.�R'�M� dark�s�on�I�. q�o6Fk cbQintui��(!?!�-wpaperAIecˀa�a�>2�%�e�f����5Fl�f��P!“easE��de q+ u��purb �^ )yu�/ ,.[tbi� e =uAU#�qnd�"�o�I� �"� I�7A�.�j�us�f�p(DPi'�"; io EVw�.�)P!�)��OY�%�� �.+2��i;��8"�qA8Q�&�"g� _s� i�"� �I��M1����!�d�/!�� � hold� n �W>����'�p09����%� 1OS{�J DKu �4e G)�$u9B^� �4�K�TE%robust< \h8a�,�?�0d bou�y1-r no2oD�!g�A|�O�luG8�j% !@ "�`Qu1� kcu^",� at�&����X� ��,�� 1�u�(����� II� I �f�!�T�O6v����#+�b��oAp�l�*!.B�< 0; 6aYiqk%#� ^ P��. A)}�a�-upGs�6�]�t.��qj 6]%�� � �v�R�� �m8�e4O = grad�FI� d PpJo3� E� >!uPe*e��?�w: �#W&xG ���ei��F���to�V��?e�Ez��5b1"�=Jq1tMc"y%U{�4�{E')� ar�S�\!�&%7�;.�Y��VB>.�orandomlh%"�1� ��0gumIs�o��b&`r�1"y`�:��`i��iԄmxxɤ]E?�@u#}��8��� !��y�9��%U�� W^?��=� ��!�� ���ca 50 mil�f�gap"�ypE�!�) E�/r���r�t|1c^��ɮ"�msynchro"F�&g�W taneB �h% !VQd‘)|y�’�{�U6E~1002�,��I.>-MA�~+-�Q e-"y� m�j rmam� "1�tw}v�'availe$B@&22607��a,��+]'s��{�."�&A_� �y*!!���AJ�Q9 R�Ɂ�Eol-#�� �$��G�� field&�Ya"a�� �&weN^ouxb;J 'v?&�!E86)�-�M��I�=�XKximIo��!�v syna~;"KZ�yramidal�x4F�)6�To�"�3c�ZiKv2li�V, ��*"v��d� l25f�S_B� �<I�"E!*2tj fi�Ga`�Hz O"��"i>ѕMr�DC� onen`"( &F9act�AMt,�Gqs��i�p��P�)| <nQ�M�- d��a 3!E3EHmeBi�oLO17J1A?125horizonF�YUd�:j�Mi� �5ŝ�EU�dW� j^�Sn�W�E� inimU�&0ac6$A�m&�=[A^�-!W��1|A�t �x*e�6� �=� :cfIeN� �E"� av�&j�8��~���x Z.v �5K)��md!h�J�eC�*�a�b �p�Ded]H�� �< windW pOa�pplI+(�t�(2a�"  �mo?��PA�m�lum YtakYr�I���)b: RA.ig�|�ach�:� �1SWM%�:+,�e!r+-tF9>�[.�n!�E}�proced�C$ repe�d�!y 46^ mea(4��{J&w� �%� efoe!�j�]�wHd��B� � prot&�/87 8�q\pti�nfA�nt�c3+* 6yp" #aB{� � ���i$]T)\i .-�I$ntras!an���Rpl�5pegb�<:f# of f&�%)ij��motob��a� `@�femal3 3s�.!Z poll)Xub��@/�sq0UpBFrr� A�'.X ) s��6`h�) �*9p5synergid��execut�u�fm_liz�i!�e�*st!y\eT^�b-g� �iz!8Mt!�t.�)�r��irzwth�EK��e*�%�)�D h*�t. �.wbu�!�_):50�I#ee�v�4��02Q�aoQ$olymorphic�+,ensin-like c5ine-r�a0(eins ZmES1-��ZeZ$ys�ryo sac�!{ ma ,^�CA�)Aa]֩@To�& �rel�O.zg("E)ex�|+ex!V � eE��!hJz Q4-GFP f�� accu� �vesicl!�%��re� z�}��Z6�I(A� �d�f �rtY��Is� �9 RNAi�k ck-d,J!�synthe�I!�44)�%��, �sJ>��7-p�:%�' anne��P}��HmElmbran��polarqa�A!-Is immed��2�G ��[� !��]. s$nel b�c�`�I���akU�K+-3/x�!I.ru_\��zis�82�}a*�)���Qhir�f/K+� KZM1�L/"e of ��Y;a�N�Afs�>�-Q":I2�sd�wash-D%�;E�~�"�)�LU��aai�e �r�eGd*k.Hs u����-J,�� bsֈ%�,�L snd �� �hA_l%!1$+�lu�WW}gr�L+I�$�fwV- upX Hcul�') os��c Ū�3�R��: �?2� �"��SNM�< Ne-zygoa�hybridq.b�֜cL�U**����iso1 � ��s . F>�( angio�� emergE Pome 180–140 MYA [1]%18siX inhab�u* 0-ec�{ environi�q�APozo6[hum�& �œ�pw ��v}��  Sc&JF keep���Ndre�aan{ �n�b1�fic��!� Q�A�:M��%c"Q+� partlyL h;�1�.��Ad�v�s5a�\-"�l� hapl ~.a���3e-� u��:� E�:e1�� �R=.� ��>�-:�{ deeply�!XNk��L�5e�c� Er-�lA;�a~�?ivh��{*W m (6=�1?pJZE�q� W!�"6$��uLm�+K �-�ovu�)nd ov�- harb V�.��)egg%�D�.!��jA���eoa��)! �icantipo; Fke 1�3. OJ7s` �;-ey.� .%�� {gzU!Z[E/Si ]E���mun�g_8 lik��A�ake!�*���)]�aJamongI�}.N-�v*�~� ��2%* � =��i(�%Ie1� �IUeB 6 -?=/ Fn.Qa�� a4� �|Y �� QQ>� �;� fyQ�.R&� �,s German-Pol�U bota�. Eduard S. buZ�A�1884 [�/IokwNtu�120 yo|�y � �mol�tr!�B �0 �e�$Cross-talk�MF�9).?-5�("  ��r�FER) ptor� kin�$( RLK ) [5ɺ!9 GPI-ancho� e�(in LRE [6] 1�Ot*y2>� . Ni�  ox� !�re�>pxyg�f_seX7play �"oCo �luO�Y[I["I�Xx��@Ca2+ pump ACA9 [9J�.Q>�wacn!Lb� �B�.9 l'�m*\I��u a�� 8V( CRPe�g&�4B� � q�)=� %3��.pP�� o�Aen��H�"��_unL�m�e800B Arabidop�?!�a"���6.+�8��the~�des/ I�Ms�� DEFs/DEFL)li\W�lf��r� ( LT-7rWalkan f�\A�ALF#7th�|�7sem��[8rud5t� :�-se-� 2�2 �T� a�!of <2 6��'n)�M�][117[12 +7�t,TUfm&�j!�f�<�Jڃi�aG! -fam�^ l m&rsITA�!�9�I��inb�X�. A188Ai�r\鉅L��2U��Ax>=��PZ� -rege4�*G� 6�%9 . Zm�M/���� �v����)�b�^ndv6m&{ �!?6I�sC-�%in�&<<5 t�NofmendJC�!pro�8rAX �"�m!|s�+8 2�6�.-�B�Ij2��!-.�%q�%�8s.�!e&: � 9 "!] ��j)Y,1��<80%A�28 x51}W6)E{inR� � SE!�:| M�n�9�!��,�1ABCE�� S1NS1OJ.�6�!d%0!�i�ly �E��e>III ��ʀvcAu fili�=��a+���Ǫ6� . Un� 5ZmEA1�q+*j �Ah�d� p_a�� ��!;�&2lguida �W,i' luor!V!obA>) A1 w =�&pynu�Qe*=��ak�7-���G�M8l U A��%z�Bj_�8acLZ'o�laqtW%!��'cop�fag M1X��)y young�� ized.�, �_�j:92��%� ܁? ic aulu$C ER )!� !3�� 5 ho#�� >u(hyF'U7N 8 h ,6T,AI� -�fekpect� �de��5�OV Q� �EZMel B�T�:ng:7ADn�Je�EL1<. F��2w,0 �P bER�!6nucleu� a:S1 !�g)�!nEZJN�:�U&ӗi11A���24%�uT�d��itBF � �ad��f���. T�"c!�lA�usSao�Tng%:�)�Z��.�%ص��Q�� �}�!x�ݶluV"8!Qd=�G/,DKs��)AYQenD ! ,��2!�:�VX��37z��%�H�I��fain"��n�b.�6M�c��*�a��y�3. TW�"E��=)&p3n�Pepiderm$�en�( 7r��K �6��S�qA)�W�S`B�:ceBE �e�(Sway%oy!& dA�golgi;&cka�c5�itu�fJ"2Ym���t�V"N,d3(b��6�V4a�_��6��9i����& ^�qR����"� B�� >8N�$ $DEF�`��9ޭ�E� PU�w !�w�  ubiquitou� 035S� in2�R| S2�S2B!� ntib�� ���n�3� 2 �ori�E���"��[1�A�2R�' thou��A>ung.y0q25( seedIs<�u�S2!�ȓ�!i4�--*��?��fҭt�1q(�� �hypha<7r�.��G��%ly��$a few weeky �a� l�!�n� %L!H�w z6�,*�chloro���s&�!="M ��s*��9at%:Y��5Z &"!�Y�!a� � 偁\i� ��'�06gw���`<1�ad:��2D��?b:f�&t�b�n�] BV�6���e�:h �A�:KuEMR-silenrG�1�qE� ed weak�N\��a�/-�Fcri�>-�5m'o�zpT�BG.�AY*�/>R'$-�a�5FGT�self-��&� � 2J� De-4 7�+-c�ab to w#� . Pr��?agl�Opy ��@A�o�5d31E�43%�qmi�/ �!�>X$,( n = 282S>�!eed 50:Z:30� m&�al�% {:�Y�C�>�!M�C2?C+A-�*��4� .�R34n ACTp:GUS mar� %V-f�j a�|���,�:to��BFz�x m> �Vs"J��lE. "�>�}Xo��` P1A�m,��ðs�!��B5)F �2� -��.+]6�*ğ���D&dKp�!jAl.�%�e� %�6d,&�la�4&� Fe7�"�.��wi'5@%�K:�[>m*)�>��-2�ytb�� ENgr%t%�K e482� %6A?13q�F�d �6� ��2C–2Ee� More�,R&|ɻintactE o�%�b y haRJt o�3 .2�$`-t��؍* �E}!�atu_#���o"�'!68�� �)v2o� e:5u 6arA:�xteg+�m���tI�V�8cob� 2� -�*� a\�{2 wme�Eq2v"�b�HAAJ�6"�oG��.� 2H6H T`S]: (Y��Pl���m2c�E!�!� MQ�-3� -�1�2V� ( 27Q�2m!�d5)���N /:�H�o|,)�nd6�,E��,�tb�6��Pt=�2y�� .�!�!88%� �!7���!�to 60%y �"�.�@W Air � 44��a�Exnull-mu�W������?A�V�9 in�K!r/ȑ�3Z�"�@)�.��f��Du�pl"����� �Z!,!�� a!���em% y)�3dq�E�;�)��esy��s�~2��b�E�Ei�tro l,d-g��U��d ��n.�� �Aw�1����B��%(30 µM �� d�.Q*'� ��$tip��4 <$ .�)�:j�V$� 3��WitL��Er�9�-� 100%6C�)�-�ekM &Up<,e�E.q�8, 000-f�B;'>xa�one-thirt2�%��>�2W2�4S3��eXE on��Hies6j+a�*l"� �A a>)��858Tripsacum dactyV&es\.7LO(�,����00 �� sus O�5_%�-*`�x'�gen� "�$3���vi��AG��^ 6��C�R3ob�Hl�Ռ^6(W^lra�Pu) , tryps׻�; �(soybean [19sor LURE2�TToreniag(rnieri [20]# AFP2 ? Raph�H s��usvG�t 1��.FB�zLe?A��*e��]�e�!���n�Q��Eg. �()ȁ�'Q@Ak��sV���"�.�ir=F�p�-� o:<d+�@x!(t�G(<y�x�an�%�;�}jA!2h.%�"�ob�́+�-��c�������.po� ia0���} r3�� u��A -�)r�U_�lLtechni��. M_  /m�'ofUC70�+^C5V� >1���:�pR�(" 5−80 mV�|:24�#�\��*�E{�/� .%:59d6�/f�.�F]la"0&�[ !ܥ9�:c�� d�L��mN �:S� .�*�3� e ���2� 42��"E.Cl−�.or H+A��&r.A��A`4m'�  ))C#�� ion-�.( #.�.ai�"�'JMi� �"� !I�ut  "�,AZpx6�a���1Ba�on7lAa �,"N%�0la9g@L�%@�Gas Rs�& �verteb� venom p�5��of0<�!� lu�scorp�-, snakB* sea anemo�%m&��in� @pn�ne8<�s worm����LZ31.al hom�.y�.��A�!{S-l�I��p��61/2��s Af nd Sb���5lK2 �;ZV=%B[2�$A�evE . Despit&���H�Vev"U٘%��$G ���P*8 toxi���<���QV�9�d�$n α-helix�iple-�r��,a�el β-�=I$a βαββVD_  )iB<:9� by �h4�ra&�*disulf] bond*= 4�c[)�A� <]o1�o;� ly� �� prime:�.Z s"�W mino acidm��/!)7 N surf-i`�qso&L7"�A!"�R�;I;��a��n"�+i��C�. A)�AR/-�Q toI#M ^S��E1�!�u�B�&�>od�&�AK+A�Na+��,5mn�E�G� re�5"�/�mod�We�u]���Hp� E��N �\�:�4-l6�- M �Ai !Oz@sxGof CsCl�BaCl2�a ��ag�3[245 )����aV�'N ��tf�diu�6W������ Mg%��)E+ �P c[�r(lD{51)� 4��ec�!Q o��l +G>L �S r>7��"5� �f*"7��y3�m)Z%2I*�PGMy� N� _/=�c �I��dT.EA�5t#�um2;q0=F!� P. q�rZ �Z@l i�U�-�sh�%� &{*� in Xenop)ocyx�����q� ?�ris~c.4}�subœs: in!drC1�8(�7)�,A5R,@6-��&ol��/�5 ���5ur�u `*3 �!m��$ �� �s�I�ihL%�E���kB0ir��2�5CW�J� � zR6��E9��w�jae&-�ki���+: ��>\�^at�er&�+"� *Z  ��rd5!�U2}%��p*b�!�S><1 on�sa&E��S anta�MiInM�I�i)/!�h�9s=z�3s.�F3� ����0 U: �bS&1_-���� MF� ZMK"'6=� �.2tw]&b?unf9byJG�7� .� AF�SBKA<[2�2�tsN�E�l}�6.�N�?�4B%�4�!..�kwa�^��� Cs�;c�Bm!��0 ZS7� �"��!]f���"� �.~/cC��"G۔by�.�'�i�r6Na12-.�!�w>,�&IA����$��2�J$��.^� �� -H� �%�>�:��.�UU3)�3��5~^B�atRAm� ne� Ƌa��@6mV%E5��q�6 54; %o x��I��i���A�l� SexE{j-a��<��HatH �|�e9P� P��a+*@ �}(�Dd of%�o 9A6q-����E�Bbi�5(r,��� NernuDo|� p"�-i-i����"{ %A�uc�5Q�%we�>R}E-.u�a�!���á�BMYZ�J�%�@!��}_�yS/�@�=U�SU���8�8 �0x0� g/ml��CRPP�\a��b�$N��J�1��C�S7c%  >�+d "� 6\�Ba�� siJ\ a>y ago�9,K ��%�q�� 2xe6q&!w>0B!ism��vThv .Dx �:C�V�i�i�:%k�*.��I+�%{ 6��)ed�"Z55�r.�86 >.� �"��a��i�.3&)yd!1��E��%��"/|&o[��:� {�C!� ��vat:���� ��&",�3� g��inN7��i�y,)�E��d���a;�� cytosolic^C��" ��%7n>��`r &8 �2d��9ǁ�V� �.u�T=�S IH~=Fv}7g� a6�#lp-"��(x.� �U�zd3_,> eT" �t &U�forces ‘�@q��/ve�,Ev�L . Be�"5ga9Y�|M �)�5 Av�l]�2  {;��g�nd�!r���$$ expa�P�.ha1R)vQsg4v*��1rB_e��N-�J�5�`*y|Aa��.�*�$b y�J,!�,���EmhoZ � 2�in%v deraA�H=i2��LtO%C�_�"/awrZ�3, �bd apo�4�9�:p��Kw��Qhy2-.��y�m*Y�q�n"�Q�E�� ���<�U x��}��%��4Os"�2�9(�I %�%s��w: � .o2s�k%omi�l-st)-.��[)�IG���y��A#�A$��78��� N5e ��B)"{1 � ory"43 &:��&3 lJMcov)}/�#��:&&�2��JE ��G.0,�3 .< . c�H�`�I��#Pj�� ouse�I���Kny6y@cc�A�XK+�eX�J l6�2}�+ d%K+ ��a1phloem+gFggE��Z %lea �6�2p*�hva�enEMs%�� Ide8m^o ���A�A%� ���s&Ţea �7*�A� -@��..'gadX�;j:G� &3 &.M�.z,� m*(��)y[\�-��@�cu " �W/it�]�!=�QdABa5a\q[s ra,t6 ��g!�]hE12 —aUn jY{��:9a"1�A��Z�2�s�Z&L5[Q~.j_}� iO��� otoA~eF� �j&1�a`s�@ .�BKdT0�"Oi.*r����r|�$xQ� (ip3!\ n��`(a<I8or�6�6t��&�VAY.�c*2-6Yo$:,.�P"6Tl�L�Jx A C=�*�Ca&����^&�3!mJ.&ʾA.R��!B*Ha/E>��9A�4y�Msed�_M-ye5c4N_�e�2"Ż&�"ZT .2C(=�C n4�g"eF!K�@ s��"W � � n u�������p-� aoC�.hR1Q�.q#D�1RcomJbfCQAr!��>|x ���"� ([35�[3�F*�0o �� ��2[�)&��!�5}_"C�!�c�kin.� As.B���6�*V#gra&�'�!�2��es9o"6b� �� e�}� ��%qM�eN� BN"78Y��NI'����:m1 /C5-C6��� >K�sԊ� ruO$�"!c1a7� �V�� +��ͧ�!���1O!%V GA" 2-�"6�!)��S ���It I�'Y. A� Axy&�)|rstA ->m)yI��ngineI�K+�<5�B�*�. C����%�!76� s0>� o cockhAad�3��LE�[1��I&�mo24ank'��uQ��;+y6R�U�a.�-���{0\1�6}Buq�%�9*�0M��A%�fIJ�!La_%F/��8�R� D6�'.�rlso* ru�)C�bkn"5 ��w�dA~(/&ǵA�u;�qaM"j is��r��+aly38m�m�&�"�*d&t ��g�[�l27(>�MYR6���K-�si )ݹ� �-da�Y��nl&��t�1��5�M-D, g��st!�>tG�*A�a�� i.&�K�UA�"� .$ many!1� .��;c\�ő�� ���#�M�-Bm(ݿ�?[3��E�\ive�<e�Ca novel�I�,���?�7zes-iJ@� ��d"��O�oof�LM+!eYI� >�OFs .Q te����/ ��5uQd,ra�Z]�S �0*bi*Q((*sYArcm��.�.�"�yg� verer#@u�$a�.C(<�e�Q�qth�*� iu�z�zeds��B�?"�o0��m�Ś . FoK1sje �;�3t LURE-! 2IwF�oa��/��� enczP, 1 , 620 bp upstream�f ORFY�aspromoAreg. Ta�GFP�0(PCR amplifi�U%expres� vect�0Mon30049 [42]I/ primA��GFPBam ( 5′-GGATCCGGCCGATGGGCAA-3′ ) A&GFPXho18CTCGAGTCACTTGTA TCD.3dig��w� BamHIK XhoI �NOS-tM�or�:�pBi121 C� SANF�-G��ATTTCC�2� NOEc�G' %TAGTAA2,�(accordingly �%�9���:�Iinb� line A188!�omic DNA6�PESSpe�!�A� TATT!�TACTG!]![2� PESr3 CTGT%!�G�I; �Qk:�c�clone(C44/6[1Q%1d CESfkG!\ACCACAT�TC2�ESBsp,CGA%]T03Q �A�replac�)y#I� ubiquitin-�2�<�� � pLNU� j���AZof �w9��o%E^ F_ESR gea�A�Aa=�Q7��ESF.2C�i��=� correspona�5���sites (%�-��)��K1+-;A�is%lso� as a posi� [ rol f2� biolistic)��� expe��a'0. Epidermal o�cell lay���� bombardedI� 2–5 µg� smidEu��* �roced� Xdescribed [43] , except� inner zpe( $( 2×2 . 5l ) �M�e;^concav� $de up on 03% agar/!h!Be,�!i ́$%S�_(100 psi rup� discsWa vacuu�t28 mm Hg �6�target2ta8 us�Y�hParticle gun model PDS100/H��BioRad �B5`!-halves2�a� �9�V  downE��� su�5a�sterile%*6-*Petri�he : 17–22 h8K� � r� �eI?i >observ6 ) $a fluorescY microscopd ��stablB�off ' �rembryo��F}aprecipitM o�Ag� -�� a&C so of%� 1 . 2!� ( Heraeus�  �a!�, Lprotocol [44] originY�by1�.U -�'pelle� first� uspenabDin 240 µl ethanol1�n 3A��(each spreadA�!�,macrocarrier� �2� . Im-Z1Te�iso� 1a�13� Ex.� ����e4F(E�9en 4)� 5�H99�vhybrid6�pre-cula�d 8–14�n�  adi�al in osmo��� um M�.�. Co->Has )5d p �(a 35Sp:PAT-&� &yA !mselecI�$marker PAT%vglufos]  ammon� resi�$(�# ?0BASTA®.#��A.� , tissue -8 N�aof�(gu)v.O �� �as]� [45]�1P� roleR genes fertilizi�� RNAi�l� !W3 �sil�YwhZ-f�4y simultaneous"& 9{Ndesig� .�40 ���"� � 7&Jin sensea�ent �%� ES4F-*�  � A"| � 6J4R��"� p ATCC� � TACA4��!inverseJ�Bs"�  GCGC� ~�Mlu.�A�b�.$� A=% �e&e � enzym) both>i %yb splica9�-�$pUbi-iF2 v� ���aM�Ubi�q�121 G Fad2 ronE�dEb NOS *  i�R��S like;other� +�quA� d by�>b E�itu� lye Ce<4A{.�� pathoa�ty test��A�-8pBD515 . 3 [46]A�wM5&%q]M�a؅�aS4� ��%�p �KpnI ,�/a�d fula��4liX5A)c AAACaAA�A�>TTq!.2�@shoot apical meri�ar*ed via{Agrobac�um-���� infiltri�method�4vi�E��[47��Ge&=��mtlear as�ba�oI e[48 somec�sG(00–300 mg^f�erial�� froz^lF d nitrA %�grounaK� l Ep orf �E�a!aN two small� el ball�he Rets%�m� MM 2000 (�l Extron buffe:d�to pulv!�ed:�ALe <��woE7phe��c centrifug%#D Na2Ac ( 3 M , pH A�2� � v�aqu��n2� kIso%, . F� �n W wash6�$EtOH ( 80%�� �� R4!#10 Tris-HCl:� 8 . �1 EDTA!� g/ml� se AF r 3� hQ37�.��o� g>�.0thaliana� di2�M�Y�[49A�Capill�Sou��IbNor blots.ZlabelA+,� ��!@ �$tech , Inv�f)6�A�manufacjrs' i� ion�Q2-fPlysis-bi��-. �!��zed �TV crip�$High Fidel� �S�K���%Alal��o magne��%t.�)* a PickPen!(! -Nob�XQuaa%amountA�����tcheck)��� ^inm -flank�GAPDH.��c( 5'-AGGi~ AGGTTG-3'!�nd Drev -C? ��A -�= Ac�81/83F~ZmAct fw VG�T Pnd.,�� AGp7T���. E&$of four knvi�K+-�!AanalyYAm��!:�e< pairs: KZM1-fw3 �C��GCTCC�n��,rv ,�&�!3 �!�, , 2-LCbb GTAT��� CAGA�&�KZ 3rei� %C4T!mG6k2 , ZMK1 k �"  GCA =�,r5'- SL�G+�+� YZMK � i%&�ACC!�)!1*g CGAT��G�G5[ f Gene bank�. num�ar�d� / !�legendAFig�S6 . RT-a:A &0iHLSYBR® Advantage® q,Premix (h��)� an* Ma�Lcycler® ep realplex� initp denF��45�� t 95� !40 H�e.� K8 � G>, 2��p" nnea: at 59[U1oof& enQ at 7, i�]me�cur�"a4=!92� 55– �. W!xO���^bioassa�"�& (below , Axit 35 M� 200�!�Z�s (  Zeis+ ��� ,et 01 ( FITC%exc��Lat 450–490 nm; emix at >nm"rAV 38 (m NU7 U5BU52l � )#�e Vl*�W�a�m�ovule s.�)� DAPI�(-��35#$371�A�� >397)e0�vis��ze� 1�w�maY. SA�e�re %d� UV-l6%pr�&Is�-�lyz!10 � drof��#��35 m m�$��"�.� �q)Nicotbentham �tabac�c* lily�!me!ll�"ulv!EA=.8��aɳ ope��aao��toF�)fforcep�LL ��Af&� 4at room temper� e8E to (� , de�aon!!nt �)���+.h>{epsubjen(to � V �(only if2;A�sM�ed 75<0Du�- t=<�rop&�": ��  TEii��e�#(5 ) equipp)�(4 Megapixel����Cam MRm��!�Vis!ldi�ɥ��%��!E"� :� � M� solu%�eiAze�/� o �� CRPs!ىtomw)�)�9�I&a�CellTram�i�&�I�a glass)0pipett-%A timrA �sta%YU�g�h!#%)mix! ��� e�$cdE�up�Q�o�2o%�� w� @�'4�co���6Zblock*@, sod�,an�":\ mac1g'ՙ%�:�1n}=r�V��E�of�e< 15ef*�-�W8µM CsCl , MgCl�cBa GdCl3 �La S enQB�EUL!U$!�Q#A�N�b!�Y-!Y���1�&���A fun� �a�Rm�K+9S����+wo-�$rode vol� c v niqu��llo�ha �Jou�(� ay8in Xenopus oocyy)>r)� of c���0&� �pr"�[54= TN�- �rE�ing� �ma�u�#@f a TURBO TEC 3×�ea�NPI E�%� �1z�Yan�wde�1s�  develo��Ak fast�efficS �-l]of��%�drugs/QC s ( Scree� TooA�N�[55�. V2�fin��4Y�}1 mM CM� Mm10MES 7 . a�F+ mM Ke>and ( w/v ) .i%E� appl�&at�liA�&� AU65a�gK. Curr�,��eP$!�byU�ju�8rangeE−180��+60 mV5incre, ` �J� ��holAL��enHofK;�#9//i� �aVhe}w�� &$or Cs+ [24 -5!2�qa�2--(�Q � u�A��%a�q�pulI��3�, tailX)? ( It�h t t = 0-Qxt"��4�$ Ns�RA plotSag�%�-e5���*pal%�!e�ӡ tips �5!�on ½ MSNr:0m�iPd r��!�tip , �a�]manipula!�,( type 5171;2�in��b"� � a piezoB @ P-28�.3"Physik IIAg�1��v �pu� %{borosi�%e c�!�� ( ODa�$m , i . d ! 8�",y filan; Hilgen�3 f� ��$Me�!� conn, byAY,Ag/AgCl halfjto%B� �2o-�;@VF-102; Bio-Logic�m���mea""� ���� PULSE.� HEKA��a�. DataI��p) q�#t�Hz�#-pd*B�l- #)�9�F�<ency De&3]! s� K1 kHz��6 !5�A��%+ eƍ�!M Dru,d Nanoli�In� o!6WPI%(B�&al 9P : 4-!{5-wk-|.$.�+;in�� dI Rq9pv�;��o DC3 &}.��$/105 cfu�xA�0&�3� poi92(%,  !;5~9s� � [DAI��b�a�th)/��by macer���& leaf�cs�j�4�<{͈MŖ}pJ% ng sg'di� �Ua�|��TK3B9! supp��1G5�' /l Rifamp�*p$Cycloheximb. AssessA��(Peronospora�&a�3ca �wion: d5_.�eco��m)sv�0��x� _threeY=�;�� o|��s!*~luminu�st�lcap-�a "Mof  �<�'sAd��� �.�<,� �f�c�7v_3"�;�Q cabin4��a�; day/15 h �� . 7e8-de� osprayU~1�aa�idab.�fEP .!"1� Emw�[5}+tA!a�!8 103�e6oea:sBl:�.t�.��l�l&lid�mai�~�N roxi� ly� % "@h@� degA-� o!8���&�1����A*70 DAZ;�3aElat�™�ntc � pi."# vidu a$9�pn(*f pot�.�E�( 3:1�W 1-4&�&d��( Gen6�0s NP_00110495�600��355_=) ��i�nd a�Xon �W GenB @, SwissProt , PIR VPRF��)mRpdefault BLAST algorithms [57]%jal�0 ipby ClustalW ( http://www . eb��aT uk/c &w/ ) [58% �FS��mdrawnZ� Doc@��e�� 02 [57*P�� of"O loca"�1!pr&ci� ALp") �q PSORT�ps�?. nibb . �jp�i:+ �Hyp)sisCre� . net/ .�� SignalP V���+2<cb�dtu> k/�6ices/ 6- 5�3D-�7�R6� �Dise�y S o ?'*j,Accelrys Lim� �%0@-�&u%�)� cd0(e Manager 6 i-Ed Si0) .�OOncoly&(viruses aim�&4f� ly k�-tum�elK*majhal�eFa�eff7vx!o�se�K vivo�!/29 ed herpes�3�"��(SV ) tropis� HER-2 onc"p18a���)y�� d breYcq9r!ҡWI-r�R-LM249�lusiv�!in�'!s2 o�high l���human c .8Awe_ r2�acy!+-{a�pAseli�D� diRZmo�E��?e t<�)!�8� �"toneuwom\he �!Fian/24cinoma SK-OV-3� s= |C%strEO��(� immunode�@Rag2−/−;Il2rg 7 e g�- rise�a�<g3Ae�� �to�#�Emimic! e fa�Y=��A>%X)�patiA��!xadmini�l/1�s��A�ed9 ���ngm60%!�m�0f�O� �� j95�du�Ba`to�we�of neo�� noduB2�� astae�reoZ �7c�2in6:5���� ofU/me}ofi ,+ MDA-MB-453z�ZBkH.5als;Hd�mA�i�, upon^��q���9���V�� ly r d7F��i�CMo:��=�cavP. aJp�~ deca� witn� re :�prI�&Cabix+`��erN�� ea� surgerq�o-��0�ap��o"�e%@reof . NonethelesY6r��m� a t�d|burden!ح��(9\@or)@to&��b. 2��exploit� rins* - _/ʹt�-ll%��F���::��<d#! .2a� A keA�L����he͍2 r< ncerz s [1P HJ�- 1��-� is be�!a�eZn^Ki]7$Ceclin��phase 1$6 Q��64t lends itself�nuM+2��mo�>� !`at� e itMN&-[2l[3�A�� egy pursu�� �,labor] �i�"fyab-1������ll!k)B%�%��I��"oc�7�!-�@5 T: such�!���ep�l� m�fac7re>B-K(��  me�+AUFtyHne kin!n7s [4]–O 5�:c�A�q�!sc7ms����5t!q3!��)Q ƍi�t�{y�` >t, �new-0 c���y� �U . S K")�ceD�?f wors��yn�@. BecaE�sp�=%v �;^l�-�.ntibody-� d$$rastuzumab� herap L,�81�B��eo� W ok �y �=Y��nco�ga >i� ite �d /ent ppLus mad�/es�FE@ly"` � !�m< ws� gD[aMe  � )A�alu [1�6R%G�k (Ig12edWccN�a le cha�-aa/)�subve�Afvi.m)�en�_s%� ��F� I+UO��s�XuQ+-�1B!��N���&$ ��capac�of wt-i�M!ly  ery# ��A safet of{2has�\�7achie4��expen�,of"�� ,�� Vaaear*"-A,( o)8 udel��kl�=�DQ a�aP2ttenu�in2��[11�I1�*P��� BH2%" �%�V� %�A��O!vt� QO%a&� to nude� bear!� i hypeI ��; s [6�AQ�i�!vdra19c^�"T6��.A�e-0�] do!�A erao� 6 pfu lef�Re$K Y-Q IC2�.� * �E�r i�40�"Re�l ae$*to)1���Nve�)j cran�I� ��-gr�ogliG �% B� D�=WeK)�[7EHm OverA�erseb&{<)m5P%c��1Zis��inu�%�+)$&�K!e/E E@�lyM��� !;le�H V� m$? 2� dise�b,e�a��4v<%�sm�� �x0ATd� Mf, coup{ h�vL�T��GE�S&�Jp<9'��Ova�� ��/M>F� !�us ha�%a2� �|!t"gBfCt��(s�[X [ asci![1� B.�6�29, m�hto lung��_org4 , bo�E, b� A�$�?e�� [1W!H weR)=��)eUevalu��I0�.RQ��n6=�� �a#$ . E�mur� hoC.,�Fi!��-2�E�-�r��.�N�=~!�&�.�mamE�c/ s . "�0�Qa�� �+ � �M�L!�HEe�(�*u(.h!/BT-4744yJ!�utu{w-low/nenAve@231 �(�6 . 1�@.��'E�exa�- �-� ed~����? reve�:�1a� u,�NsiblyPu:a]?10% vireporjm�a@&6a�W��1 ��� ��y u) E�rolife�K�a� e�Wec�E�lread�,mmi� �) eath�f!eA�!* �����!��� M�![*"r&L 5�B�1�I��,-�:�2qtHM+G� -� ��_��ort� pr 1 viewA�u��aM �+��ewee�%zat&e&�-�&��subcuta�I-~<na�/ �� �.{2c�!� apeu�: of�v,? ��(�R)1�of5�}I3l.�7�8E��a�Q 0E�ԑ���thy�U&� .m��� �^ :or���1�K�ōde�Qe J��"Fn:�aA�4p�]@an�viv ime� to 440q�"T-��@� d�%� th��] �a�Xex3�$or=,eb&�xen�Dft�.�$can b-+�5!O!�m�=�E��s9�m vysa",%�;!�� �(��*6� �h�L� ?nt�-�1in!�ure 2 t��7an#�, �05i�Z�(FY�ir9�$is� =� " a�dur6��Q%sa�r�@ 5]$lack T , B�NK��po� ,��suA]�T.� !�s&a<n�-y4 , [1��,�Rasu@whea�%Tnovel �could!�employ�o��"<+F���X2 grew2�ll v$a� few week� !���� ic�9i�I�}�s;d/�M/aPr�2�}2 xed end-p�#�6 rp allo!� a quF`6� !�V�у3MFi"S�&%E��u"L;CFron!� ���mt:\a&abs�g!(!l2,�a8� `�byk�$3A–E# EG2��_to���pl Z Aa!8�#9Q�"9.��=!~E��u�G�)j nd��&eOA=vie !s6@z1m,M�ATU��FalIDxOFXp+ ly yie,a�o2GA�he gMv]A!,MQ�6fi�/�!�notaf!l%�&lb*..2� �wf<3 logs�e�Ea!�f���� wild) A�10*�� he)e route":�#ng� firm_ext�7."pQDt`<� -&�Z��� d\I�!?Q:\e.����M�i�t�Y�)_ pu�� �w�\  be p!_ �1�ng��$��^ib&� I�� ��a�� <#y hA"� 2 `�� fac�@`��-7rgu�@! �i�Z �pJ �� hp,a�no; *� in�bg2Eis%7G+,�,Cu2�+�_!�� i�tAMcprM-t e#M���1�e�h �lly-��.^ ���LXi,"6�:�2����s�1icm �� � -�"S I�0�"� g�0� )�V2([10A�)a`ach!���)1i��n f+6}���`� nB!���2u&� ��4�by.v>uI}iP*Y!���.Yz� �oo:�!by�2�!��~6��Q`R�2A �SfY+�at�^107/,1×108 PFU/m�#�/�k� a�er JH]!\ ��!�-!Tpise<*�)E�;�V�D�&ent's t �1�eo� 4�& ntinat 67� Ka$-Me&5�-�#.A �� suU6�e�ed1ɧ20%SC�e ?$5zC%KD%zAll.%�-g\ ��5�ofAI@.�Ixvis{.lLY &. R�<Xt �(`�� �b�\>�oP#/ '&� 66in&�$�\��<re"� in&�;��*w�!�b��v� ~ anXJ�of.�!UM�a��n mirrFA!�situa� ,�5lu���^,)�V�-,MiJasEQ S2-D�)I�",.@!�in��f��k via�#ve���f ��� �a]ju�K;��&�&.�N� %��Yl!i.N"!J2<t":T ��� ѳ�^ c!Oof��6rL focoDon.�!-��w�%as��rs-�Qe &!mm� rE�� ]-a Se!)L thei"a%��U��63see�7!f !�V q a!#SEcen�S���&$A .�lv0�2� . \3� ݼ6[)@��NY� U�-)!�U�>h*af�ng�pe7e!HR{&�ll�T����� appe�.{�Db  \a��at nec�Ay�5GTo xfy{ro�ve���kets>:�P�l ssay�E� c�!o2\c"�C#AMaLz Metho6E�ۅ LW Uhighl|)���=���"arly-"�a � �A�)�r�4 �,g���zA��"D1�e�r1�>BS#61�g��Q5�W� 3\��r"V �q�BOHA;5C–�a�ono �9>38 E–'/qa{D rep�aGi�p�dn� % i�c�9q�� ,�73rib�A~oe� AaN �}�-�A�. V{(Bf%?�N6B/nd�IR,A�)�-���-P% . 6.A�,e17k�4�,w3�3< Lh)��61 dec �)evrX�A24 hr��n-s �N 0at 48&msugK��8�: &J1 AJ_ :�0S�-e�u� Vo�?"e {V�=I�. � animal|[s�&v32b\It7^$ law 116/9+ Eu� an d*$2010/63/UE�"�al��h j�efnd�@ro�% InscoIA �C .Use CZXe ( “Comitato Etico SP* o� la)mEazi� U e”_ UniwO B�Bnaa��bor�N���-1M0�1Healthi�loE,rs 19413-X/1G4R�mYResearc� Prk-C�<e Giov�Q�2{6�A�8-L . Lo�vB. H"���(b "+�ɛFk*s..� (� ��A�X an T?Curi Col C��, ATCCZ',"kin� givEFy DHKSa�ella M#up%SIIo N%�al�#i TvieEila� !�y� G �la�`n�a�mNA$%gerpri�gaI�p11th Nov,A�$]"�6<SMZ�raunsch�1:�RI#h��v3\2oi�QQ!��M-#�bls�o.�m="� in RPMI+� FBS��3b�J!�id=45% CO2 atmosph!}. b� breedA�%:F���T0 muraE !�IG/iJCf alu�Zr�Zq�lm�{ Kawasak!�Japan%�M��t�!�t�Yur��fac1�gu�Z-r * �3�v F!se��PUP%a�^l~�g�fAjHCrl:CD-1-Foxn1nu/nuI ref_toi*& ) 6-Od<� purc�/di4 Charles R�|M�a^�Sb�.�{+ A-�P�Gti�I�a�sA�ple� � .!�hg�kwT=p o�)Pf�Cellular �e�&|�xspeed� if�eE2w cytotoxic��&!, ��= �96 [S�?x t 83�6/!�=�(�< pfu/��r mock-.!amarBlua�1PF V, Life 2QvX2�Em�� Ak 48 ,��144�e� t�,&zSA�&tm�. P�/a��W570960Z)�a`(ergy HTTR-I�W er �_TekeuFor00:!)q�m3Ak�� e�fZ aS|9+p��*�ed!sux !x ex�� "#OC l� *� O"um al��2(n 5a�0N%lete�d��8@[Qa%<>eW]�S!��5��It�o.#on!+r�s bH��E00�3Iµ�HAM;��6�!7kq20� ���thB&'E,� LEt17 YAzwa�1���me� TP"''Req WST-�4qbA�D� 6x�a�absorb� o�B ELISAi�E�er }aa waveR<�t�\9Z!��� c�f.%63%V.p9-62�peU�of un?EXoLa �/���"m �:���V!,�orfhfreceived�61 fT86�io|�Ri�%���A�aM���.a\f� �Fle8!� que-�+A�un),�7rt3�I=)'�/!'Lm�. N"P0E|"� d� e�m� Q��eb�%7zelic*r6�_9 W!"�#Bly*d!s  2y��I|# ����*�.�?u*autops>L]eA!ai�a low-te� e���A�:�6�%5&7g0n h�Ht*).ef�?c#~�F�h �"� Qy�sEI��i�&$a�W�X&�]!��of +0 �� '*�)�82y%�� �& ; 453�x 0&>E�2��6:A� qf�vc&d vLt;RE4)�r�KFK�4de�M)�fi(l.d. A6v6N)&mAcm�(Y7�- palp� m, -EorandomZM&;4s*6na �qas�z/ Q6&A��:1 jD.s%Us�@!@%�just bS-�ˑ��3mmL��ema UDpe��ѻfcalmA (as π·[√�·8 ]3/6�� a �Nmax$ N"�HG"b %:per��nra�aD!Z�]�e �/b��(J%*i*)�|1]枺�8!{a�n&� �14P�kIncid��5�zV=?!�.�*].��@j�'/est�Hd� �� Dg�"�.n 'i:��D"Y��)�1����!f��mf��ios�"�@r�3(Rs�3 marrow� 2�Real-T�-(:�,� oek1&�SHCl�_pH�r3F I7�LMP,H�RMkM,� 1% gerM  45% Igepa�T Tw-2� �  pro�H�Ka�llE #�S�\, >SOn*� *� at 56°C�#I S� ca� at 95'to in#a5#2�Zs���� α-s���O Y�8hI�h+a]A�.%P��v5`]�rH �Bom0r et al . [37hv�$sole alter��+ � S�no�m�gt � � dye TAMRA! *�k-en�%A�' ngeFa�PotAa� :�us��250 nM �$za3 ��iA &� 2�p of TaqMan�alE�Mas�Mk� Biov%Q>�N�)i�=2�jste2#)�I aiA�45YN�-�� (030�& plus 6�FLZ)�y��5700 SQDDe�tA�b (N� ���a�Em8�}sno:�����%� !A`*ardVv�"�Ji>ad� RQ�$%&*� M��( �9*to�0�*)fi�.E � :�:1�~. C�q�Pshold)� ) �8!�b���A�6� !��interpnw� .6 ru���Yb-"VO � ";!"�8 �z ~ (>a)0!�R� !�T�Qto� �1�9�%e�YoA��+m�I� ��"f { 38;����s�r 2R��E�]( 7�� h�! �aoYV|x"!0! Rwat"�u+ ��-L 24�} |cv[zg$� IpD *� .�/��J�t.%�!c>y��q4NucleoSpin Tis��( M�4rey-Nage�"�|C�.�t'�(�~!8�s.�a�, p��wGoof�r�sQm�25}D to 8!.al& e co�C)]f�&�>e����u�4ere: gG_504_f r�G��CTC/xTA�'(gG_603_r TAttAx�sC �� -�""O(�!��(–�(�}b?�"�ZBO)!�A��t�Dm�k$c Wilcoxon� k snUoe�k + � E1 ��!R2zFisheAex�F ��YDup"m!eW�b�s5����?9:"E�9bi� r sp���A�dQmqTenA�3Foi�ZIt!{�U in-d��k~G!�Cd� . Ou� udy ! �es Sfi1� ŅeND!yo�>�S!r-Cd!_b�D&�0��s1� ! d=0��nF$'S#c �Cdk1 ph�ory oSS� !�>!$*�5non.��;d�� lead&de�%a� �f� �/-��Zbod!B( SPB��y� ] )%�� 4.R�SPB�YAޅmi�N="e&�'lso%' play.�>Bm�6, * segr�>"@AdIfE2s%�p�el8 reby5Veg6No�%pby)�`FAu>c!9p� �=Ua1K6�_%,p�>^ prem�g>1���O& �8! Z"�!EA�_ �at� Cdc14�con� b3l�� AYlicenq �� kely�:��:aK. C]eRE�o � !��1bukary��a�B@GhNB� ri���>#�X�@�>^0. Aberr�>Y�"�'`"lin2:�h!�so(#�{�f*7Q.F�_��G1]�9uaGmea�i�D%�r�M.7 !�le ev� d�b. !\J (A�4&I��J�polo-�3�< 1�M–[5]^nzm */2�2�i��cBT%�VANj3�W�N�. Howa0�on�3 AQ=.#`��S�=en�_)=.4�ght�4�E��o Es�G-QpFstP�<~exbu� ��,�>ee���*tI�yy.�X��Ι��2�M�'@:n�7zO2m/�(�hs�56s�VEba��'!�5e��$�&-�!�8�`!�>�,�#�g�le$T�F�19Rp�H,��2�3P.A��>v"6mapT�of �s�P !Qen �)�e�e-w�.�s�?&5k%6 �!{��PB2��SaL"\�I�j60� > mbeu�A�� n� ar en�H I|"];begin"�PGa�m �?M��@�?-q!�� al�6UB���n�� b�, e�A� AWn'�KA;�9te���s!��!|Vy+�A#�2&��.�� new�r �i�is ��ami�$[1� Zte -�.Z�?'�I /�N��E�E�Ct� [JA�op�*)1EN0%Vuz��! B��KA" 9:�� L�Rrn�al��e�I�}!���] @�+ }�e>�is���f1 ��.I���k Spc4�:)a��� *r$( γ-tubul(Spc110 ) [8�~�4B<��W�;m)A���` %�!��;�Ukn>��XZ��c4f }����17�N�%�*da!%�ytU�s�`m-�fq{� n or�T� &/Um�~� ON N7}>na�UCq?���4 . Ba�s-�o��g�1 Kilm��{a�;pu�?!4�h�a)i�+�Ee0%?y.!Gm� �The�Qpo��a>9iI�U��y1!�s�Ue�C�7��BtoRv��%4�\BEpI0t��.��3u�ub�R!u. g"�����*�� eXQ SPB--�N�dom�.�` EA�u g�E���&kq.o,A)!oMz%=Q,i���C��,�> �l�=d=���/B[36,�< �a�=� may& a�PfaW s.�A7a{20a{IO�_;, �s�n�be2�v&*�ZAin.A���@ �Ftif�yoA[�S21:c�<tro!�:�%E��lde.;�ADf� A, ��F>�� exit [2`Y2�OTA86o1C7a�� �F�T"'��r��/\z dZ�! fi1+ �� �6A�e-M� .�aYrOH� y%�Tg�!�I�D �mN1ic �)�a�JI"< Ap,AHpo�$!�ide�4atNB�QM`(� *+�%�.� n�\�>��%9�?� vep`NhO.pאt%/ �Nb �2���v� P IMf3=<t, 7how%6+ �9dced �-a5A u��ng)�"Z!�acA�)�or/���!3I�!IQ a�nap� ��A�T�e!!�u�BAl���.:��.N.�r�a@fF�Neu)- � XI��:.�. �M�s}>=f �iB�4( S/T*-P-x-K/R��!X8=���.�Ge( T81�S85�S88� 89�\[:� .��}|!�z( S801;-;S�QUE �)C`nO�@�!T%E��4%~�)q�es� b ,N�~S92D�aG�.a�A�Q��l?4dk>un%t )]J�]j��q� A�lb2��1�7S�B–G!I�i�Q3.^���c :J�)zM,s %��,�Vl�xY��We"�aR6a�0 lleK\��*a�:ke6-�����=*� 5��!BW lan�U "s �RA�� I��+m�|-�:b�d�a�21xM�C.�b��2 .dvarޘ���&W�"�A�)$s sfi1-C3AmQAeI92�<�L #4.#55#8)!�6�:2��F litt�r�V �8-�Y7l� "�/:�M ����Y�6�e(e@��93)� �3A�� 4A doe�Genh�c �-�:��%:�D 3AQp5 s f�3to0�"*C(*� 7�e�: simi^2o',zE"�Ja�f%��j� , D%]EH�N� D�_&��:6F�!R]/&�Mre �IaG&�X �i�B�)ra�C�ly du� ose\�e>0.�U&Bsyn�UBp�L�P)j4=�3A� @-g di����hp���morph�8.en�z)@!X�Q)E %V�F:�0�A� 3A�*�<�%;es�b��� �� 8 h crop�t���!#m�#s.8uI� ��� . D�j��9�tm�}� 5Q�$Fr�Ym<�/<u.� d il�[�`�+r�(A SIM;-g�wXe:��o�S���A� !m ��W�v��M�Mz.o�Ru�� -by- "�a*�ym �:�i�wo�focB"Iy�0sp31�I� R� wo�ed[�w2�5� D.�mdY��o�8@�� $$.�:�Iek�c4)lh�cz� adja� �� _1A��.1����a���%����qHa9�<����J`X -8t te�R!y,� E��w!R�nG�a[�rdIus �">t0�Zc*1f� 71±r92%���, 2�n 57±�p18��:��Hizi�� Ft�E!{E�-r� �n a���p"� {�s&�@.� �;���z`,awEM� AcurE�i �8aS��Ay��I|. CA�olN�M� aB-���,E�at#vAOo��U8W=�"�-�J$� )TVi�unqXt s���^�( n/11�18-Qs-�aaSein!�q����@De&��:�^P5�E72~,�6 , E� eDVA)�%q js���=�$a�ken%Y�h�2;j,V&�!��[d t�5 )q��}or�ur �e��4u� di��q(D/&%$}!�eC� Ap)I2�}Q2%<l"e oB�.�5�)tG�?��w�ip UyGp�&-a� �A;F�I�"W"9V4A5-mU�90��bet_.� %+��"2t� �*K+D"�T1� e��5w�%n�:: ƢA"� �r�y6� ~� �S�I�#ioɩ5!~H\N�a�i[NQ)�1�"� a� ��-P�e�KIj�!�avD���=ED�$"��5��aA�N�%!��>� b �&1$ya!p:� z�PQY�cia3%m,now�=)�!��=�&�]x Bl�q9����Iw�e�i�.�:7�{s�xU�� �:�AC������ we�i� ��($ly-�&e4A%�s 6�}�Qya,ecZ gI�<g!fbK du�'">a98%O" O3o8��j'�0v�b�_a: |�<�2΀-�o�N�reljd�G �.�1"� -�Iw. B� ^D>�:[ ( 86±2%��3 ,2� I*� ,v\r�� occaA0%�^�-�15±1%  r���.q-D$n*�To�30±3TA=��a��>be�*!��1 K,��o�0T�:� � ( 41}^hA maj�~UI�I��>V:�N wo& � H�ja�� ( �79I�F)( 3� 8� 4�Y.Pco�\!�'�H�FN�"EM"0 3� T"�*+�BB�|� at%�W�Z@5pct`�>�6��)|lac��&>�`,�`. %��#u~��/a C�*,eoch1=��*GC�*(hou��#�*:. �� "a�)����s2{��'�aH�6.e �g�. SP$al�- on (�ɭAo�goo��+ � 3�Q$5-� �� 2�( S0;�CV,��&�[20p2&eTo"4e �� j)��*r�\uti�d���8n&W/S�Mo� u5"�r�!y�a�"�eDl~ �[�-�CB*�A�j��*[2�\S�uh, MET-CDC20 cdh1Δ GALS-ESP�l2�et�a�4Ye'_�(E�dr� �U�/�d��'( EspeQ�"�/��I�a��o>8!/m"�. Lac�@ Cdc21; Cdh1��V,s%Ir �G,0� %% , [3�!� *d!��%`A�� J�&�A�E� g^6�>6�E&��CӴd>�1*"age�����*0 �( 17±7H� 25±�.�щSo6�t8g,.�l���u�96~x2v[�J`J(��EY F %x:�  %�e��hM1��EZO*��D( 72��O ng7\�(��,1D, H ^v"N-2́��31)�lS� a��� �Eh�.�<�ie�im�AK.GQr��nB@work defu5 ]i*.v invo^�zO�F2��K&~KE_p]�nw!<V�u �. S3y+�B�qdid%���ݒ��!]7incor��%`�@��!2ź�C��1&1i��gn`uçt��:��P!�u�}�w��1�v }NG���Plab2�ŠeK� �C$���;���{ v ap;Ksp�; �-��6lwe U˷ami�!/"� �$. While Cl�/%�!)� v�*��3Xzi?�0��& � �*6k�+�`^B/�d)�[32�'3�it�U�%69umi� .?zE >���I�8_/�7B� !�*$� BIE�s&�7!�!i�lE�A�a�&!�6���:.>�<E.��%m�%EB��t��s1~�NE!,�1Z�>��. �0 !���6W&�*"�!�2RZ �>gA�ûngv�$until down� ���I�MfD#h6B " �D2m) A%)- �V; then ��{�v!@AG next��G12��B�U�,H � !@�W+ & A ]mk&s i` ��[3�q�CA�B. ���*�%��� � Tt�� Z�����:l�O[5!�sixQ�x)>^�q"t)!8.B�A�e���sR�!�q�.ME1Jn;�2mpJaoH$9eB� . Im�(��Nh�) o dJ.�&�� ��de�-�q%,��I �byP.=��l�$��)� !�m)�D.)Dr�;NF=,12I�� t:/z��>�$> 9� �K�kE��Fu�y' � �.�sEQ�F�rec�1�/'� and/o�0Q&c �!F^3�A(imp0��:: statz���sJ7 \%bw78be?o�xi>�8^"�8� ���>5. More� , 6^�ll�ve!fu{P"�!;a�3�� ?o"E���etazoa��*wh]H%l=m�s "$61&�fs�j1�� a�yVQ�< cruc����"" �ff:� W303m�sNnd} 0��&^�$TehtY]!1����pRS402M�N& ADE2 wsA�N���H &C�Eo(genZ�"�!��F\ Quik <ge II21l� Agil�-\k ���fQ�t�AvOJO a�305�b� ���caL� t�L!Ct�pt JA256" JA29.�a s �;�AEP"NE7��nd L711)��:� �pur�2�)���#�sg">���E8!hNATMXQMke�Za%�,)l�/V\[3tHt4�i�J�&@4 ly tO�"�(1�Q�AYtrp1::N�%-A-TRP1-4Δ::HIS5 ( gif� John*'6) [jz. S-�)�!� zGr&;,���y pOC7_\4Orna Cohen-Fix\��e LEU2 l.%�Heterozy��dip��=<�4= diss�,����:f� ��haF%�&� !E�� PC42)�yeGFP1�a�w!�"�_ &�d9�441�4i:�7dmp YL16.qF�)X5� n�eFiv`Wld a� K��th��L��H���.i�L OD/m�H1a;A� �column��on YPD��!K�+e�7�  &|-�02�W�R�2!�s*�*"�Z�bM)��$i log 2Ima1����K)!v=�tF�mF9� Time�."�%�i� , Tokyo ,"v`f��e�a CFIc]8n Apo VC 60× H=er�" a��}�&4 o*�4��Fb!�a-$olSNAP HQ2� rge-�@deX"�� HsQ usco� A�bUSqMetam�+"Fxsݗ(*�D\GSunnyvGc, C!, J!b�vol�bR4�Uum���Ys�Y �t!5×�J�y�� 6�Xh��)�i��..y���[>c]Ug� H%�4%Zmaldehyd#*r 4��ua!6%�A�o zymoly�!�Z�<sl�� . YOL1/34�-�g"�<�gَe/15�<, ��goQnti-rL�n�Z220 2yHoechstZQ!�M�%�i�!�BPYAj�&{ :y� MVmrbrief"CzEifub|h�yUUgt PB�!t;!W��ofbo2�=�*J�<�-�resus�N�sB��or KPO4/>^ito�-0� �acfA�^ Prec� OMX Blaze6 ,Issaquah , Wy�ìEcYJ"�8.[b| .��t�4m:"� �>�.!3�( arbogry�S; �ul�!I ��B�� ��.f ,%�� 7��x�T �w6Vj�J"iyt��hBuP�t6y�w%\�.rdl� �wŬ�g�"�If"��a Wohlw�Co�02 HPF�freeze-�Ditu�in 2%���etet1Cd��� ,% uranyl ace��/ �$A"�G�(purr's epox�J#�)�Ui �% JA19zq-R�w25%��t�RZ�Z��,Lowicryl HM2H JA_�,97. 4�An�I!�!�u|,I�$a FEI Phil#� CM�EF�0}DiQ��M� "�0���En�d� 4classjas >2�12ݿ*/_�+is >333%� agA +�di�Q�Bof 16�e�$6�.�"~800B946I�a�L�j~ � Ac)hEa`pKLD116$ s��("� Ivan Raym��=�ow�2eaܒG rTEV�ei��am� &� 6×H9n�ltose  ���w�tag��7! ���A" �C+ ( DE�-�K�q colim��0Greg OdorizziZ( IPTGucůd�ue 3 mM ,�m�3�j t 23]�T6Dflash!�ze� mg�� lyso�� oלa����pur�� �T�i�Tl�xey!$��l L.��, .�i>�20�^z�az3Q�el9v. Aj>�=k�Tf^f%1�^A�AS� t6;q�5�(M -MBP-AA site�:(,��M ATP-K>�p%�Hd�b�%ri��/�#8N"ulo�Xco&�l%����, ng�( CAK?[dA�2�lL"�xU-"��W2% GluC�1k&*��no��Mj /alkiD�?�_�"tF�!�1 J�dL���pe2�loa�:"���W�ys nanoA7 (ty 75 µm×�^mmj 7 BEH�C�4^(�=oup!,�de���+Pe&��%AH� � ��ad*Jam �6 ceto����M�ic����32%��itf)o f�G�hof ��nL/mi�� tra ��"�Mascot va�AaMatrix*�k�gaj�custom"��)�AJ��"�5�m>nti: i-&d�nh �D�.O*�Ob�nuQ"b#E��ہ S/MSO�!} ��scI�-�2��M�h =.�`so!�-��5o��e���$ta b�9�m%4 ("Jgce.y4 top-&�AH:��7��-r�,.w�a��C��M�y1�R ( VprV}�IV-1-�Db�n,2 >�pts�&M{t�L�O��IDSG%(undk!�T&o��30E"�ha�9!�i٤V? G�%Ka�#�7 apop\Xin ���� "�C.:vpr�� y�rv!�z���/�Der %"s>A]�b$Pl�W�V ��+e�bA�ar_�%4e�M�Tl�,a4.��+9!�il5�!*�̃��e2!�KM�7&3X%vo%^�'*�,��2by�V.v an h�Xopoie$ stem%P��pԩhJjRmoa�#&'��.�%�s��6H0\&tp8ng CCR5+ CD4+ T��)zAy-�is��ory62( Tre�g�"a�nv�*�Aien�BdaV�H�!�q2acuJ��:� Vpr*�. Eq*E4a"�<j�}i605�-�cp1!�CXCR4E[y^�g�}�%��8e�Q�&c]� ���or usageA$]aJ��*,Z�P=b�Q!GCR�&9-t�J72A�%fȼY�]Y�^'en>��2H denileuk�&iftito��D�*Sq!e%cA1DD-@:r��C� =!�/]��memAZQ�t KB� &Xr grou U� ^RM$d%�k_.�k2�A3r�� them7-s*P�toMQ"9�%v��şto�-&��I�. T>tog�r@@�2� s��E`VpE�k�&P�vm!~�� )A�vi��a:.P �&��a2Y6a���w��Yg�!�8n")� hetA Ba��!b��re vul����~�Ea�!'i� ��vA. u}�1Rcl]�Ee8 8�A2�%k�J ��"�BJ synd�l ( �yE���u��2a��A�@s: Vif , Vpu , Ne AL�.A�� (�x2C�a�1"oG< X��.PV�$Z�,��� !I�()A a pea�gLT%M{+�!��k��"�F[�P���� �"�"BfE�J��� r�v{}��XeQ4=RQ�4>�J�Or$M�h!�,|\I�%co0 dest�t��� �on� ��5tonsil h��u�"8=qS.�s�Ti��T��?[e��Lv%6SIVR A)�sI���acPv monkey��]�&^*  u�}l�K%Var&X%� A�N)��\l�;*4��U)"g{uw !aAl26 �7of\Ev��S*� m t�e�I�2is6V2�W����p=HX*imB L *eL%1N�� : naA�]��#Tn ,Ѣ>m ��" .��0u� � si���n��n a��c� m��5 ��s!�a�V/� !��Hvitiy%])n��,U�v��� �].�3sL�m� Bd�doR r`un� �ie( gPat � �dw�E�u �H � ��\PoouxE�st�7. A1.� H٠�  �|%�� 2�i* !�ek-.� #���\A˩��'!�1�h�rm��/(�Fc:pf�Wp0� orkhO�box P�Q FOXP�*I3�}G11�� {r� �m�< 16Oq~�"�D=5R[9�01�ItA�w[@kn�E� tpla�G6�v!ҭ��M8&elf-tole��!K�$e homeosta� )v6�-#�*[c��cl:$dh_op����r6sa�7�uto&eH%�3s����.q�x��1':/�8cular , there a�Fre lines of reports showing that HIV-1/SIV infection decreases Tregs in '- #�^ed patients [15]–[17] and simian immunodeficiency virus ( SIV ) -infected macaque monkeys [18P`20] . In this study , we �� a human hematopoietic stem cell ( HSC ) -transplan�4Lized mouse model [21 t\5] with wild-type ( WT )� vpr-�-7|investigate the fundamental role!zVpr5E �!htin vivo . Our findings suggest)�;0plays a cruciW,in accelerat!�|CCR5-tropic ( R5 ) but not CXCR4 X4 ))� propaga�durH acut1g� by utilize+6lifyD4+ T%ws inclu� I;L. We first character%�!+profi)"%� K$ subsets ,.TnTmAn d" A8peripheral bloo!� nonuclear �8( PBMCs ) isolaA from)-ne!@ve healthy donorsniA�e spleen!��� miceYH3A�Aiin7 Figure 1AI� deteE�L6 . 3±0 . 2% FOXP3+.!Ppnic n6of �t, which was comparable to thos!� 2.*=v s ( 5 . 4 �6%;�"expressA�level)4CD25 , CD127 ,%�tcyototoxic T-lymphocyte associ%�Dprotein 4 ( CTLA4; �known asP 52 )!�:�(5A ) were��larFV!?1�B !0 Sinc�sup �v�$�jof� � different �i-�)ݙ�s has bA�demonstr �)�ly:� our resul��trongly 2e!nmajority�F� popul�)inS=(� i�5,. Moreover ,a>�i�P%�i$ corecepto5A� higher on-$ thanmi��in both � �a�9�CE21D%�(Furthermore�E�+:��{ieQ��7)�activelyA`�ec��[9e 11a !b perc�g���s posiHP for MKI67 antigen idA fied��$monoclonal!,body Ki-67 ( 8>� Ki67I� ��0R%!o0significantly1}%t�?.zZXTheseUs��c�at �Q�R�ar�re9_ cycl-{n%��(ms . Altoge!�IgyM�2u�r@ِ stic�]�� р�i�ANmirror9�+Eu�ToBdynam f each.u k afterm i! �� , 40 [��� #edI� a primary��� �� , �#,in JR-CSF [3] (As observed�4&� !�vidualF� SIV)moF� � foun��I~�pre��lly%�6u} �a%B��� )Y}2AG2!�5��U�2i�2a�of>�%�9_$until 21 dx post)l!�( dpi�> Howe�� becaO we have��ly9b�6surface!� molecul����9T�Fzadownreg��edt , [t%vevalu�whiB a�!ca)�. R�howq) )�.�.� ( i . e .� 4−�5 �>abs)=� S1 )�kd�m�� ,e disappeara�2of �� �� ph�ofm!��� du�.�!.--/+, ra�1to deplebyIX.��Ŧis�ly��edʼnr" Uh.a%�f�d�es4���ZF� R5 �Y:�.a�!�.^ 2E ru�zEtp6z u)�*� d 2 ofJ��!q6� lowe�a$ at< mock�85'2EeC�)V� 1=� induces saxe=�of �2�&N )�MKIGy� . It!�w8 %9 5e�%Do�  to"� �ͪ" ��� J?YiU��aberrantJM[7K To add i�possibil� iB=:,E�as]~F� status at��pia staina�w CD38� � � marker [3�[32�J� 2F�q:a�yZ0on memory CD8.N%<��F�EUF�5 �b�.M�" x��](ٙIJ�nd MɾFie�describ $Introdu se ,�is pleio�^isQ�cae�! e arr8�QG2�,9apoptosi��!�� ��V!32� � �u���wbia~ . �ypothes�keB�sus i�Vpr-med G2�.at���X32>ōi�/ R5R�()�Δvpr;:7 ) [3�lthoughE� W ivit& �3WT G%z��T �*�%ctro9dS�2 u$vi�loa& lasmapE�]:m at 4�7�F'J��:KU3�8�A$les= l��v anh��ini�[sta -Wo��:�. WW*|j e2g : j)nd.� ���$NlM�� v� challenge%g����bPB9F��   addi�:��>��:7%�:�F� >�~��M6�F�.�. Z`,�!M"1��N�U�2Fj]E)at�Y enhm s-�dissemin��!��!���lea���mmuBB�2�&�A�of�w�e!�rapidI��/an�.�'vo!e next6�distribuR�9�� Z�.� �*�J�3BM{6N � a2- p240��gen� E�n �8> Cof Z A��8���aN�((then examin%�� o-} p24+ }inf�6#As��m�B�{TmEET���F�Yb�U� 3C , left0 right pan!�In.w *�h!�6�� �i��Y5�\ ��z��:�� a�nc�,mean fluoresd intens! ( MFI )A[I��reflectR V� �t9�ɔedM/��6 �>in-ZE��6� midd� ; >�Taken ��)���l�2L Eh �A�tp} 0ed large amou���݅�VpEp� � �aug�% � M\$"� rai�.� Y�*B�!Bh��their���-" �5b.�3 *1 �o&K ,a;2* e:�!M��� r.�!)e�^��υ�)R�*B v�broad2�in all.R Z5M ��nA�QL%c(�4W4W%ϡ�13 �� �#uE,and�� (I NL4-3H 4�while 11�R%\��JT}Th�fG &� X4�A�X4.J��Z�k6� �%�contra�Pe�0�"� �F%�9-5]I ���i� of�59�!��y��X4Z� �4�:; J��&� Jf.� I�inJ�E�2A–v�/��.� r. 4��� M4E4� 6+9q.:��id.}`R� Q:S-")I�2k4G�Z��f�r1a�=�r� Z��depen[y!j*xusa� en . Ex�KvaZ veW"] X can c� v�[�J2;con� `�9�*e:mat� ,#u�DNAO�e[qukaHoechst��`&�&B /p24&1 �"|MmC� M�oN� !��Δe"I]"g��sim6rofN`, a.�&A�"� f�ŕ��^�el�"� u�5**� w�"Av9O�� f�F� as.�B�a R_?6�,4�M��6i� �^5�"d��6��K�#W� naly�$�"�&�j� �='%{fai�5�MrTn� 3C; l"3t"1%�1Z , 5�! Y� �%�cuD2;�mED=��9�e7G2M%-e�p2=!=��~�9��In� ��p 5CfF,N�6 >nOf���!�9A�>+��ZE�r] ,ed a maximumG437 . 1±2 . 8%e��W:~g>��Z1�U�Z��(� �� 9���E�it&�":�G2:E�IIS�m� � �� *� [3� [35wm�fY�vre # ship betw�#�.N&5�D��"��� :F� 5C illu��q+ Y*dis(ed)Lr]SE9J�� G0G1�ee��reg�gurprisi'$ , 74IU&%!4(-��- *�9�EF���& �Y\n�,%:j4�in q#at�A^QZ6_�g&� 6�.-%)��� withM!��a��"�bya) ,M��wZ�B[Z� ��"� / eN�G*ep�on�w["� aj F�:� 5�& u*pVpr: �S*�throa� p�3/8�'ASP ) -&� pathwayX heref���:R��e T-�a direcFora&M�5�:�%�A.*<'ofA�>6 �T 6{in�-8.�чft5t6� A?v#�e�F�A�EmN>�>��.��� 2 , yei%6#.�:foNU �ls�R�� �R��-EW8n*e#!�magnitud)"ir� J`6V`.�=�-56;R ��6QWd%$ ),���'Va . O��hA-~�F ���)�V.���jf�( 2R-6±3 . 9&�,6� F� Pj14�to��&{9�e�Ba5��.ly���)��,�/um�%��ev�)c1&"�/� 30�#inn5)F�a�e/NK-3E�* ��$�"(eߍ���� d&�'36�[3}"A�-,2� redlyJ�upm%e]e"�%D nof some�I�+ligand� such�-UL16 b�(ngR �-2 ( ULBP#��s!�- � AN$ death [38 �9� � s l��*I �!�>��"� �F�'Mbnd&lr��b�#�'�� �%��B�H"�(��r�!Q'Rz!e�i>�p0Z^ 5 , un�=!-u]�� nO&S�2.^} J� �#�)�^��F���&ooivr��3�AP-o�#:��]ord��#6[4Rx G2%;X j %E��,��ofm3��"U#"� we�sfo�1m "&i�#b�&+!�.�6��.�F �F� !�6���!7�e�l � � & M6� fq.�hs !%:� n� 3B 9�I "Y3��-2�1���2I9�!most efe7��; %$UYI�I�b] "� � a$ �o'^� A�promo���>E6a�+)z2�+bC+loi�pr;1�CCRF+�� �&V6��is� �3E��U!F�Uaf�!si **� �Ar@ es 6�i�2�tA� non-e6F [40Ū4U)�3^��FQi�&�!=����edal!�5�9m2�"i�2"�*,, denileukin�4 titox ( D�8.�( spech20t{���e�A�it0 tone 1re%8 intoF�J[ 7�7b !�!2���6R �� sa!IUDD� 3"0�f7h�)number�- p"B5� �CD45+ á�te�8� toG:2@,3� �cha�&6�#�7^�R�! �� by�Q;FU!}�o<��#N�+�k7�k Inte�*V�6p�4�i�of DD-%���;&PA 6���"�.�Baof�1MD:Q�A���"� ɣ� %ہ��!!Qin.�m/4n��un�6�+/F� %AUR S+�=�ng�F_0fO is g%5A>�:/.�WT��>!="�{4))�% inoc Űto[ f�"pep7H->17g.i!::partiurly%�"7 PB/�*� %�gra 5� �d}��VAm6�j��^f*lyդd� �'y�*� �"F|N�mLB�:�regard�+� �a�U�SY>�a|�5T imQ a��i�wa massW69YJ1H �:58��ei�3��za*X!6eF�%�І�]#�N&:z-5<7G$ 6w:� slop%� �growth�� �F�f�nd=nZ&�H͂� =)�"3 Mr0mes un� a.: &'=�� .�+alT &*+CD p6X *�9�7. 2$fac �v�A�0"9tBBmitted/�Fer)�e�U��"2942] ma�. e it-4u �!�:( %��%a#.*�ev("� re��abundA4"VV,'sO�&*!�&H � �$�! , [44�% �!on� �� �A vo remain!�nA�<(s&�C*�'�/a� sY p*�B�/ -j)f)��JS}���� &�jGQ�&�e � MA�!4!� *� !�9qu79F� � is!�>VC~#"z=eiwa1t;fsJ�by tak:advan�1�EE�6. A�$�:-��@v-� 7� &�(e� ,q$�ng��t&�)"4�6to5[!9�$xFaa,�u�F! *�@:^���er)�aB�H���4!�= ��� 2�!aAfq�6"K(*V i_>86j~d/6�@ kin:n .g.��C:�5| 6�=�6&voVke .�e�B% X !zh 5I!�a&�)Greason�Dassummq�2��ʩ%I�&AIF� �=-w,erI"M?!� �h�B= ngg92Cin &vBa�"RE� � L�,�7lA<E1�})�/�w!- LTR-dri�H2�� cripI��st�eB!�AY�1e� �1��Y/� 5yZv� ∼2-fol"� E�� � N� �>���.[� | E?�!j� U�3�6� wCveak-�6K!�-�)��.Hoccur .�).}�$* �EKe"qD*�aK24%�!\E��F� o.J{ �� RvFŗBNq�aPZ�bX � aV�� *�#��.�>�-"R�ey:* >Ci� ed nz }&�K� .��� 4fK"�*�5a�-, npD*2' D–- ,�C^G6GFF�,=�%E)P,�� redo/7{m_ed_.~1a�e�� �0is��0���0U�J� R�J5�2*C89."���:Mp* :Y&�Op6�*X 9 �D�Lor|� he���exp *�LJJ:%�� �oiM�J"�m&%1T�DD�e�n�5K' ї B*hI�`>B� 2T U�!��P�Qre2Zw:���!:o��6�.�*}  A "�E>.m eA&g n��a�2�,b� � $)s� b���2�6��nͧ.&�Bf�atb<�,!����� 5�"�.� ve Q .K�+��a2a ��staS dogmai!�F!u2�%/6�T closPs"{ dis�T!"gG8[4-"R�{utrigge*S�B�=,&� �B&3-�!? KF=F-.Ua"R{Kp3be�( e*WBlos�/2w[5u51]; ( `#inflam^Ury cytokHV[52�� 53];P(�microbG�)loc�"[S�lu+��Ci�NtT [54�I�5*�Un�1��F0� "� ��qB�z�…�&� "S2^C"�NuL�c�:N�R y��Eto�Zz�$W,V�.�V�dah /. z�U:f�o�L�V�9P"�ly�W ewor�Tat�>��Z�H�� :�� F��s��<�N*w;e�8"n�y � �ed 2��m? chro"yeF,, 5–7 weekC$*ZS)%�2!.!mir2 B�,� �!�V�.a6�KF`N<�rX �4�$�6�, �&�ly>X6.%Ve�=B-[A�-<1Y.M+�T :Ma sharp2Q br�&!26��?pri{� E��!�N0��:a)��a�2O=��%"�96�:�v� jX)�v��ot�*Q =�g ";b�>�@2~2NO-�FOp\.� cert�W%�:� HSC� a s [6 a63]A-�_ours [ a*�tr�[s� kVorf E�%�.`s(�W�^@Q��5 es�&Y9��f&+elici�qui!�ͷre�Fes ag�@Ithoge� "�%; [64G66� : � �%ơ�]L[ *�% &z m3Nr�ec"�A2�M>�"e�`. Solu�I "�H� secre!p� 3"�>a�� .o�  sera [6�6S I�,>�6oN�5m�2>�?6�6,of*� �?6��3J&z��a�U�85 8| R� s=.!� �a�ewg^y��Gel�In>"e�_�$!�&�F� Krobus&�-�}!�&�!�le2�6�Eʙ d�N eLF�[6�H"%2aH?8aoF" _,�! x*���5�1:� EZ���)o�6ta�I� ss�mAm% , VifEs �� oB��!�-in&" mann�V70�&7>��"5 9�r��!ne:��:D&�"c�fuGb�;du$c�aAsA2D� �>�#&  � I!:�w$���i�'$� summF � 2f!}���"ti�*�*gk �1&�����;��e�V�o"� !��4�9$V9$e|cheM&� l�!��q*�n�g!+� ��/$pro(8M��(�bptB�Gt%p e%+facilit� I�Ŧ� �" . Al�/cedur2�animalUf�'u� follAje guide� ��C�w!�UZ Laborata�AZ%�*Min�RE�Edu4, Cult1g, S�D%SIj �TechnIjJapan��Q��ap!AiOoInstit&Sal �6�Com�'e� IACU�/ethics- �IKuf UnivershP�g ocol�D13�J1+-m! volv�%h�.AIje�P��ee_#!E>�Byi2� < boarde��5wr�(�5n�_>}abE �-# !Ry . NOD)$`g-Prkdcscid Il2rgtm1Sug/JwjNOD/SCID  −/�S)  [73] �oe�!�Ce�1l5�,Hr E"�5�!�PKawasaki , Kanagawa ,M S�)}%N�( �b*H.}2-�Q -fre{iO7O[&�<�!� ccord�,w'=�aP�E5�2. H%�CD34+ � �cd))�fe!lAn;&C\��g7J�5q o( NOG-hj�l)��tri�as.Mb"m^Brieflay$164 newbor�aged 0��23)s)�%� 38 lA�r�rra�[%PX-ray�0 cGy2�b(d RX-650 ($cabinet sy�m( Fax�*n Corp�u�Y)eH%�thUgAkhe� c�ina}.U�%I.~"5!L�2( zG5×104% �A�A lis�A�V)�$ NI�/" �V&�"�S�MVsZ� ߥMR5"� j1[�e,J�1$�+* Q�Q[�Q�~XReP '2m�prepam 2ti�jfPF]J�@105 50% tissue cu�� fldo� ( TCID50A�a�%��""6>\2]�!q. RPMIA�0e%��e<p�VUa��LRNA!��]�56FNBio Me�-l��[ , Inc��ZM-bl�(aA� d Western�5t; �pe�;fK} �e. ForFJ,mF�N-` :j(ne 8DL)� !�goa�7ti-!&.serum (!�oStat1w%6.Y281!�routinlcolgWedj�r�_SplT6h��j>�oMN�oh�*n!{ ] Flow�metry%�9d��FACSCa�4 ( BD!�sceience1pff.�H�r2bgTCelltac alpha MEK-6450��4ihon Kohden Co��b�e� ڽ� 0 µ�,�iP�4%M�IE�%;%�A�Bs �{9&`%pper<roliter%:measua�iE)boB ?f6oxG�  � &���LA��3!Sal1,u�Qar�>��Ho�Q 3334"BIn$.o\)r� �*R͜��Oby 8ModFit LT softw�( Verifyh�l)zor�%9manufac� '!� e76�"�Wi�!�-m�#��J@!�tiY<�Ha�e�conju�t1lPE]�I�;9�E%�� ^�B . DZ<; IL-2B� diph4ia �qnv�? purc�i LD Pharm� Co-:0i21q��,s$ ( 40ag/2� PBSnF>�$�E�da A��ђ3 DD 8%�+::xW�j6B<�F���52��4�R�a0F�o  >H&� p�L %Ra�F��:6 Data �eN[� aver��SEM�gp".�{ ( P<�R0L %,�r�_0by Welch's t ]"�S�Int$. SwissProS,http://www .�9� . org/ )@ GenBank (6+$ncbi . nlm0ih . gov/genb.e�e�t�B&ceins A!gA� e t�a:.APs:_ � 07766 ) ;�#173�M(NP_001759 .�#2�2 0408�O B32P2890�'+4+282.D 45RAp857!v-su( P1687 R�M 4257A#;�" 5168 %XCR� 61073;�u& 1641 �st ( Q9BZ&n;>& 4601 9�F &M��}s�%)^U�by>���A�� R�H DA�5�,x��p{eX�3�srCn �tR&�q( M384%�)f2%� ( M19923 2� 4-sVivax mala�va�sucA�fu�*eli�%��Republic�wKorea�{ outh 3w)Ky 1970�Ui�022o�re-�+��199�KIn "�F�/ol�] �pjef2�2es� � :�iT5�< 7Dxop�� ote�9al����genS|� paras�A.G: �6we estim%B!%iJ�~.�2@'mi�E of P�iodium v%�in .�aly�{�'satel� �m�m%(_�9:ed 14N< loci�9P . �gen�Ke 163.�n� .� )990��All� d�lto|  linkag�)quilibr! ( LD�X1�.6ya�!]Rv,!:Ufmak�&detai�1��QT%gA)%5;_���%J� ('a"�?dee in)� A��![ ofb��4m�B+yea�|{Q�*BU�ba�y�JBayes�]ach��a dYic�- .�4�]�n.� 2002%�200a�"%%�9ps� ymptomap5ecarriAme�*u� wR��'A�e�^t ,� :���tin&�"�,aoU�^F�"�T�&J sour�{"e �,e ,.�)R#,�Nor�`�.l)v ar epidemC0� J�M�=-is�>ŎNN��!�*Y:aQu.�5.�;!�or!�Emat*B`6h�g#of�W��in en�c*as . B�fPe� KalA=�V%� f�%rw�y "Hk� r�:world eP1 Asi� Mela� +M�gE%d,M>!A�America�8� (re 390 mill!�ws&anA��=n��faL9b rS$re =85 bi E peop@t risk!b&� �?.erea� and/or� phyl�cY^l4of chloroquineagɉ1� have�""���s�ual5�c\h s"680�0.3$�fa��R�hypnozoiv'2���)#��4@Ait��uld=/no!��<�X,F< iscr ��re9W!�USto���N\. S! �/� B�� ��B[�A[5�"u�?y�de�Bs�+at�bALtjL�2aBl�Sce�*[�"UvC"�A�g�J!}1��6�V t�B� monito31C.1��!C� ���~� J,7�1�|� 2nd�}o���* 9]EHr�T6Lin�T�7I7Tsubr��x=�13s��%�����-�pe�!��w5�H �2�[ut� inu{��IaI [1�19]; mE?�G"�M, �{�| abou�$eseB�� empe_��as �6��eau?��Ai ��B#� ��[ s �2H!^&N Ȇv �m2M<�z�of��L3� us:�n �'��� �SanY��9 gramq le� &uN!2 al Mu E�c Serv�M�*nnYernM$�.ort�\�WHO&��%95#.�E�a&{ ����~ [��.< on�7a9�$begin z �"� I��soldi����� aUni!Cafr vete.4 whdp&v9�weDem�  Z!�=�A�h0%6Uar��Democ#�c P�'sR^.t )�.�NH�z&%b!�]'ivilian ��d� or n��6��K="% dk�n(� at��A�be� !B� de N/ hF�Anopheo� mosquitoerI�s���ontm������H>�=(2��a��stead%# �!!9=��6^ unt��00%~o183 ) inNr 7m8643 q6N� zfluctQ�1V838E!2 , 227"�yE� 2005$ 2011h. Fuxiderab<�8in2�,i�300�g00 �inji91!84529},�}�Yae�!�% Eb� "���Uo� �@2n M��:�*r.�p�,E� o 10N� �87&X(��4Y#008%��`highl) �� L�� 1�Ap����#6��e��reg�!�{W5 �*m�%-��U�N�#$�a2�2multillfz�Ei:RChoi GUl .�oHonma5]yi"7io nc+ >�.w� 65�1up) haplƋhad�kM � ��ly!�a'�wT� 5%�aK"o�Ui�� o&�Z%�2��g*�|�\A� !��F� �*�_t%�s"seldom s�gXwь secu��Des�K%�owN�,=new.qe �"%+��Z"�.:5;.��inc*!%��b5>rN�B&� �C�e�0ū��e��:&uT2+L%�im �Et�OiH�/ sam��TzA6 (3:��8�/)E��FsB$ 200�D�2� �=to �|,��6B�G is�,�hap� too Ts� iscu�0A�BW��mI�V�eA���re�'s&hO95�I.�J/�d(�S�%14 =�LE=R!eY(��'�:a�. 9B#��6���&�!]JM�&�� a:5�.�-��N4��kBF!�dh4�i��o� �+a`)�ed �recis&�Z;6��:mH�:�o@�K� I. B�ou^ w&]8�.msi�*\=�y�:�%��,a&�exT�� A�M(��1�7r >R pr2 ,F ���3��d6*� un-�ful . E�+��+al�o!?�(of.hn�I��%�i:��"�'E�J Inje� ��BusLaik Ho�*�*i��Review B�+, 1,0�!d]��JZ*�G6_-Cli�GRez=i+'10�.Q-H” ,�&ur%� Welf�8of/+$on July 31� R �MZ�E&��9v�V�4j� rof2.�-,* .A�..� Decep] �. W�,or �`i-z [5�"�c �beYat �bI3�&aE�!'fic�"pos���6'Q�cF� y5 &wno auth�A� kA�iZ.pg�b �M!J�ޖ'A��-(i�O�@onnN54 }�TɊ�|��"I%ony�,rY oubta�T >�< C�w%�!��/�b�r)�!Evac�#Two hund�&�fifty-f+���"9(�ݎ����DMZ A2� O�R��lna-�diagno� Ɍ�cҙ‚)�qQ>�sm��!T-���,!��. B�1�M���UZil�a −30°C�)?'A+ext�E froze�`���pby ��l-X0?a �1#�o K diHA�jorEQIAamp��� Ki�#Q6�~V�c�Cz� USA � Nq*�'8YU1�� �'urt� )�2aA %CA�"LzPCR)�.!*�#MS�;mos��" , MS�(�##n#�.�#J6� htQs1<"Fg#.0"0$N96H�MS1�.0�1:�5�MS1:�:�9� nd!>c?$�l�IDa ��y��,( Salvador-1w T# � w�y �*7#F�8��F"!9�� h!(�%=Hr% �1)� E.�j:'.�[�/.EG�e�ҁMhD���t�0.�H�s*establis_q.��&�& LIANG5 WebEN�"b/[4�cE calc1fa`�;ula$8 = ( VD/Ve−��/ ( l ;permu�Ut�%ng�� nullQ o�Gi�$Rlet&�&e2�&IAz ����VD=?"�mismatch�< , Ve'ex�f�GB'�2�UO&1 �if "=-ce*U2�!KvaluemO=S4by Monte-Carlo!l!�Q1�ran�'=Pa3�!`sWmethod�a �S�1at��3 �Sm�ن��" !Y2��9E��� R ^��vi?of� �i��q�AEta���0w� �4��wo ways:�+ "J )�e 163 w -}�})* jA�Uv;�dlnh3vt!?��;�+*>�����in �t6���#ed�/ e�a{jcamv� uni��� �E , sl�~j"duc��� ��n)�mo="+'�!!4rt!�&ca!a�> "I'�6s�, �'&&�sub�v�-�!�pai+A * %�� �+�OW4A�4Cockerham's Øbor��0!4FA�teGWFST ) p. :�X�?FSTAT H $&�/.�RA�� or*ZB.y1� m a��c��2�M�qZ�*� .�b -:t>���)�9"F�*6S�V STRUCTURE2:�49['g�{\��V���(g�o�  yoE� true�� 8!�K� !�-lH  fr�]�of.�. S5>u�!(�j�10 run�r ?��0�K�4V�R=a lengto5A!�burn-9[eriodZ�2��1"� Markov Ch` �X �Xr�BD !Be admixE)�����cp-��`corre�#�un.F7am[ LYz�!,� ��.�. P�8�[��� �a��l�;[lo�zba�f. [Lz( �.]e�y -x &�v2�H0a�*�p< .GK (IZAE, ΔK!A_�,�-��f�2lD �1;*9a�^)bIEvanno��Kjhk%�i&� �nW6�1631Y2586a�9%�oA�^2�*71C6F�t��\Y�Zs��G*�0-�� =�VGa�92�a( 3�~1� `navail�?��N���b&�*!�ac�La2d ���by-��4. FA+E��lyg�9�%�a� �� �'}���� r2�qua��-)8ai���nc�h �Cz� a�7�1�!bi�X"�Y4q�1�e]��Big=�AI�J� , 71^�"� m$Asp(1PjQ�� )��G�" � v�\��'E2 I4s: H350H4A�!I.�2T15Ab-s2�=&�E5199�$0�f>`5��z6�`�33�1�200� B" &A�6�E�>��=��87ų6g6GJ� a� �#� 4�71� � �I5 �_�R:�-�| tran"�5.�*[ �L5ٕ o�++��`�h�G� �L/&2�%&�+C���&c$Rd"�( h�) ozygA�y;*�N6a E���!�qS!�iyS�Ѡ] In� �%-"� � eUU .��r$es�X���6&8�X(�-��.\�DqBB 7E�in 160%.� ( 9f;2a'�:� *��"��G(w�02Am��7��=:2�1a �7lso&!��%MGI �?#m6((2�� ��M'esI$ �KRS was ��5&�# �n�.7d8'�2.� ��"!kJ�P� f�'�5�J6.�1zAO1M��Q��1ach!Iu u�� }�g/1"� . F�A� e� �#e�AD�I�LD� x ���M�2@ �sU�. �*4�I�uJ a@O ����,26�"�?0� !O5{ G&x=&6�!� e�)%*N "%�Í�%:�!6�!�%���,X 2–3.� �-;u.< 5HA"&�.1t���p. &dt:�FaiV9�!�gr<)~q� d&�w�4=�%�Z�a5^(�*� �:dVr:֭ae,/V�. 446!�_ –B ( 25�9..�6i�,0�+az1*R'F3109 36 3�63�ds9AŘ%�U�%>Z�%A6w��6d:��Zwyr�us!�Ub�&stq�)z1r�s(*�1y�ZanyN %"n�:w�b&=l1?es�������R�:]Q�:u%��4c/y�&�i|6|^���maiY 5��ay}��2* 1990�5/q0�!� noteAe4"G! 2�� �� .5x 6;%d"# �r��)���ͯ=Y�(2F6� �2�� �RS.uo�:�2�a� ( 2(*�9��  J��|*q �+<10.|(A;��121P&9Fq�IONvE,2�&;��B �!�s���,���.� JFd!6��J�." ^,E� ( >=/ �g!�reYG�[. A"T$2�e���EBEb0�W@�#169Ll�S.05�!M�Q�!�?% �r�Xn�g"�H�m�b20e6� �7 ���r�01��P>& ��G �rd "�"� ��C*�Z%�&a�p �*"��s � i� q vGs*�a��% at Km��4 �%��rult>�6A�B��fq�(�22:sis*0&P Z�����֥��]�W1�E� very��U5"jQDb�(ER&ց�1.��t sali�*��#�/>"����)�To&�UbyV~V�M^�a4A�g^A1�^3a�1�BS � hree&@(Ud3f��%^t adop�*� Q�� For@H~twoa��! {ņ(ye��3."_ � ` �O� vejMblu�Cur���� c coex�#Z��toa�)^�! ��:g��a�."!�n���"�4%:v@���'���]8GAV�!�-�.�,n�p�.^i� "�2�%��!!Yb.G} ��&�n��?E�a�EMi� !V��� �2���;&5�.�����Dl��� 'E"�.e>a(�b &B�"�[r���%q)15-o -�s0/]�iC?oZA���*/�1���>8olymorphic neutc3�)���6�!���Z�3=@9�!�"�.paEL24�' &Re4ybt�Awemplo�& Fj7�#�%�[B���� 2$:Y>�B�Fz "��� basi V�( �y�J��o� F�F���z�\V� � "��d!�k? "�e�"�1. A.�ÁrnaX$!�Páls ��FYa"�+ei�R�two`!&[*�!e�]p,�yE�nF ���=s [�{[6�k" ,.��&!>�F��9�.�"� >�!5�6� ��M�F�A N ���&a[probl�Yi�[X���E����nt���`��6�^�, 9 &E )� "&�E��*R q n 9� ��3��F- >�, ���2 ^�l� AB�� "9i/�dJ-5e� q��V��J�)�eBURST.�~�+'tew�9"ǀBh�>/ �D�/*�?����!�*�="  a����ens\ ��6��sup�E�.�T$0"Cr�A�FGA�C#!��.>�,�(�.Q �J V�c��.m�!rd�d a�HP b~.{/�.� "�C� k� h!�./)�dU�.� Ie"�{ĎU2 i%!  K≥�fj&� �� �O��e:!,Ej1 s$e"ua�b.�E�@ e'�>'>�K%V��6�E�>]l*����%fo�to�>2Q� 9ZB� M-:�m86�BelJu�6�:�( MNy�U.���AU�)�RBD 3NE/L B� 6�iإ{9  K �vO9�:� ,.,( Mt4 6 , ��)P�-112�. �=�A#$ estRT]/>�A�%�RD�=i��Va]7�1��reI d&�/eE�"� E�%ZAu��&� �Q5"�*�2x "- �j"�19Y�Eat����terI�� lh"�� &t!>�w� *�'�"! � �dj-lʹb.`c4IPir( p>�V?�/�d %B;� �r��&a� �&� : uJPw� ?V �f�@+h�� �Vi����*X��rm ��$aj>^.��rF�mZ�Zn�d���in�.!��R�cPg>�6��"� =nE�a �&* AB� ing::~58*01� 1�8;:/3�$P1/9�3>/14�#6/.WE4M�.�H���`2Ҵ�&6u=z��kf��%]3z6"w!�#� ach%���^J�� 2�p��Au9�6c&m&L+�@R�%�# few ��p� }* ,jA�:irar3l��}�6%C6 )���00aM!� !� |H� ��eZ�X %A*�@�]&�&=�sudde�mh�� ��Ds,Zen���^ breeU/��N� �2{"5 �?! >falcipa i��� Tana��_8Fb?'a�,." $ �Hon�“!�in-VF�”E“ge;E�Va�5� sub-Sahar�;fhXEi , SA�OceaniaWm��s� o{ �Cs6�KARY�g%��-�J>�Thi���eigh�z�^�K��K!�owN$.� S�}7.S&>F� [Y�6� aV�a�5�!�>,��fa�Ga�s7�F. Likew=Hy �!v]Xe�� 8��6�.7~�!B6$�A�rm&{�u$A� �]�u�A��K!�r�:���)�6�)�S6,as Sri Lanka&�?is fea2�EbzB<��!l<^, �to�9"Zm�vS1.� �1CI���)��B�Y� s=cHI�0U!ZR!o227 )"T&e��Z,1q-f8yVdramam��|(]\t � %F�Q^"d�B�_��!re��|�R:� � �/� �.>�-=���s ]�j�F�E%��am �FyIcV�V!�oa�%+ �d6Gis 4 kilEnXoD�sP�[\� . Gis�U�&�V sineH�MA�% vec9[I�6�:�"� 6� o fly up!�12 km8�+n�:���} �Sal orig!.�)�9� 1�ґr�5ly2�U>DS!'�AZ\:�Uapm�'9{"���%H:�V�`� eN����re�]B�{��&I �k a�&  w� h��$mJ���� ? O2ccenario!J %��M^.�Yy��N� �.t��u4�"�d��N�i�*���9���H D.�!�5�m�(B�W�H%,a-�T�A�is:�>2� ����nC�r.by}�*5Zfly�Z �� ��M�3&�0"&� star�=�:! xn��E}duo8�3-mon#�cub��032�.�j�� nins.B���� &v>!{6�J��I�%96�D.4:�-�&\o%�.D��PKqvcA�H�b�chemop�E ylax�Uy6I"�]��"~g!H9or���9}B�THiG�%�,H`60!�_aF^�NUM[5��A2*By3��u/]%"��q�Vb�`��U�߭۽�x d2�*` E.�i rift���%�8&օ(ub%ibr �4edV\)!T�e� bottlenec�pbyF�%C> �IKB2 =:���Nb)v%��A�a�llB<F�xa�W,2�AIQ�yem��4FA�!5��_&�8Paju , Yeoncheo�MA�Cheolwo�_t K8bn�ist` a*�g�r��^ke���a�!U������n��m�c��Au3�ў��"�l� &y��J�B��mB>,x�ar�dJWl.&%$� y&���m�<ause�Soo�W�J1!=��%%N�X22T �!�$knowled��D>����#���)�oB�`1�&s� s .�ELm���c-�|q�i�F->e}i�� qa� evol�arily��f��'eukaryo$F =�"��c� �FSmen�;&<��]trn���rwe�F E ��i܂�@f�l��r ���X�. E�&!��tnd-� W6+ run-ӓTRO��al_HB�69�rs favo="{ ups%l?�ti-F!>*ua<7 i�4ngq��e� Nc������0L�Ei/ 5′�3spl�gt)�`rsYfI�zerJ��� 5W��me%�|.t�)� ingF�T-��F2�B� ChIP&'�Φu0 crui?na�y�G�u�a�5jPcak�� FqRJ)0M�" m=�� s ad� V<v�2xlocaliz �Z��&�xearliA�RG� �&�nV"iE*��gen{Eo�CF�2!��K r�wk �-proxщ-~�!�A�-���{a l ��u�%|Vsd�bnor&�A�A�E�v 8pa��QQ>ia���e (2*�.I!�2�` �gromOء*paO> mpand?����omi6 ��6NB����*z� i��m#�>�� )A�M& �%G-@� K )�or-bo� 1-�v�F�U���W��-�!3D��:'-i���Bp�>;%��n^Ner�&p> "8 �~\ve!�m�,t�,f�&d*�ag��گ7CJ��Y��t ,҇�hil&��nm nigm��(�M-fdu#�%�����n�.�ˉT�voutpuGa)�[9qf -�ydd oftemiGQ�(an&9D�'aw(rb��m [��$1&�(�������ed ‘ ���’ ( IM��[%��� , R$1b-!Q2B.co�Gu�A��{�0c` tecҍ&\�GukA�A�-�=�� -�� � �? effi��p��ts ����>crer�IA&�/�;  �li��)��[1!1�sI�sooAN�oņBc�y� 2�LEg�0f ��ll" �}rga쟁�&��y W , fl�,�v"�c9ZnNt. .�hubin�c!���ar�{ �JsB�+L��25��z!�i��l]/iK� )��M5N�P"( budd�i �͹uq�� >�s.7����28^e��Z� ^e��[�41e�W��etGb!Na�)זQA_ k�a��9:�-�7c@�g_M�!���I r�o�zg�FAA%FtaI�� ݸ_2[9uHo# 3e$&Q�d�ed R��i��Qb�Hs r�.���� � AQ�8me8(�Sl&D�/�[ >�A-�A)��s>����I�a�6�[n;1"�V�4�c <� d �i�rlo"jȊw_�L���#GeP�c&k �*o �Ew G0RNAPII!U�gen re bi�� [1�%�]��6�1ijO�A[=!rJT]s"T n5. T6�n P9�5�si�E�leNl6���Ca�#s��� (NQ or PROMPT�E �.R{U1L+2���6�͑�O��ineY�!I� mer�brj&��e<en"�\�%Es syn� � ��1m��U�`�0is just a few�C hundred to a thousand kilobase long [20] . This phenomenon is refer?�s ‘promoter directionality’ [28] . It:Z�M=:�͋ 55 .���l��jj%�e�e�Qw&t��e�a& �FfF�,play a cruci��ol%A7eI�M�I 2xa+.^F�- Mown-Y� nhib!��}�q`!�of:j, whi��he ab�冇5� �allows΃�atI.%nesul��t� arrange�@is��&f of� is favo� over��Y��A suchn8U1 6����#1�s [30 $3] , but a�X ,genyꭆs . Si��aL�ة�^�,�� hypob z.� A-Q dJ%9?95could b) at l� (n part , duHhe effec-�A���o�jR0 !p o te� is� we examin�2� A�h�] ��ain��)K0, IMD4 , ASC1e�APE2 ,IH�9QU����}I>iE�K��/}a1��ucoa��Rstr�� with�R � less versq�h�� � �foaB�!mHteg scr�4din Moabbi et al . , ( 2012� 1 �O� �� level� reZn� aa by r >�-�Hmer> chai$ a ( ( RT-PCR )����r=$ � .5analywal!�a�+��AR�deceas 2 . 5�k10!9(d upon dele��Y�(( S1B Fig )�CATr��a-(� all2���ste!4a!�cr�1��!�=�E�i <� about 15 ¹�aeeU�% by/ . 6 2B� 6�TEjr�L"8.{ 6� playA�a �� regu�ng%���of��?By �Y'B !D�>f��������92� �switched6�6Tso�to p�)�x�J a��&3�ssibi�tobser5alter�5steady s� Y�E�a# yg� R_ �| 2�che` ��2(�[A}u�ofP)�� how@ze � \& %%� �of �by ex lo rule A��p=/ŤperfoH �� nd-s�fic:�run-o�bTRO� �,a� .edler%LAnsari�5�3�Brieflym�techniqua��labelQ� nasca�.D��4Br-UTP , purife @ed�  usI�Z- affa adAN!�th2ubj� ng%]ied��toB32aboveE�=R!;Fe�ha 2 to�0de��Fͥ�z>iQ�� � (IHyR) f���1B��,Simultaneous1�m�� 3–��A�J�!A,p�(M�.� ���aNms(.�69� e f�s� %�iA�S1G) ,%�corrobor$m�Wa�٣q ZG fo��.,"< h!, . To gainɞs�in�ne� calc���he9�� �x� divi2QA����eB�� �each   �i��a2=��1��J�iC-�F��uFr O d from 4at25Q$. UjU;u../ai line!0I�50–250��Mr pHav�demR B1M�j- in b:�(we next askrf i�ju� e >� �j:�iNYM�wholeaR� a=ers>/M�Q�bC">a�vWŠreforA=serAK$a wild typ� F�mu�dm�a�Y� �! ACT19nY�� �gen%-previ��dթ(F� F� B{�E�GT!%CAa��M*�EmonF:AG:GC��B�v ionsA�lisR gA� as aHeri��producedo 2&_ }>�2�<� carr��;o det_6� ��Fof)~J�.nativAh *� � ]/.�-R�.gB�%Oed��h��iE�!�j� brou��Qa 10-folO��VH�o2�{!��m 1[6;."!�al�m�ex< i�( by its:� . As expe}�B%* �eit"� %RorF�fai{ to�:��2�Bewe&6�"� %��littleM�I�signalN��M�orZi2�A 6–8�.�6E r!�"� R %Ae�:��E2}A .��BjgavK milau�� ]Q drop�R >i�N��6g�Ml( 7�J10�J)��- R� ��k A logicalA�clu6�.g�3� !�.[ alon�s!�6:7�{ZS: �,Q�y"zs"��n�&q&�6o�A[*�I[nYJ��� ��:�be.���Z B�� :S .5 We&�2F.�a)�R�&4��cr*�.~f;M���a�r P� NItop�Y�kIpr!��FjA�J�6�m � �"��2�� w>��j -55�R� . Al#ghm UWbe #saV��gorRCUT�hir�do�" ntly5��=Z%j!��Q studm h�:also im<� �0subunit Ssu72�CF1 Pcf1� p.�դ6��!#\�!2, chec  9N!hll four2k9es;��,�!�!%. N�> =A�!�sa� ChIP��&E ,in Al Husini>�3�1U a&.ig P�Dp"�in� s�� .dor.�T#!�� unde'vestig.U� occupancI\PF1#�monito& A�erm_m�� > PtaYA"-�24�D ed !3gDRna15USx��ly1�^L�M� Q��.�traEc6�%6))" !� Z4epitope-taggedJ*J�w� !�*�s!)�.A�first&3!�:l2���at:�!��A!� n t%CFai endEeE��equb tens�!>�a���3� B�I� $no appreci� �g6 ��2�J� ����k ���P crosslink��> % en@�!6� 60% e�tha�at!�>uA  , still�* gant�F�l"K J�!X-v�ps-Q �Y 66s>�'M q�F2~J�%RA)%�s! � &� �2et�>:��\��pe�t!�ef�z ;�byq���\q\��!zfoundY�oy$2X �V�-�B/R���& gre�eo��pub� �!��- i���'al�a*�).�m�&�Fw [@)34N 5k#I)n]ry�.'e)�eE!$e�2�)o�d�� a'alQx� F�>"�3�zx�2 re��ly� b�?6�A sɤ re�%5�V6��'�cha2 X g'�}ɲE�A|u� %H6k uR�Zg9A2�of �JE2�-7 �Etof �5m(4)^ �i�R��wo�,^�c� co�Aa�,2-A *.-/.�mF�+D ���6�A�r�%U�F:. Fur8m � Y�.� *J� coincides��*Z���A� olla` |Ir2 ��%�l-̹�:m.�fF�$=e�-A��be*� crit�AC"4aa:� �ri��.��!�F 2�%�*�* m�:��requi a�y" ( 09 .�72��g*�" . Ite�.2�9� if%@ ��|]�f I �2~:7a�f&%*#60��"�6��N&Le �)KbT N�(emperature-�i���*0 RNA1�r( -K$~!R*I �7!w"�! �=�bat�2ɣE+�u ,5 meas�36�F�l1�L ve ,L lM��otocol6 El Kaderi>) [33��!assay �es)|a&��!�a A-?! t ob�.��I(P1T1 pu r pai�%at flank_~�as~ %E�5A�Wrob�#_����"#!Q��m3^��5� !":u�P* 3!�� A.-&� :Vuq-��<.R��Kl6�-ET!��0U�!!:ue]�{!��|c6i�"����*� 71.� y8iffer;��2�C>of� i6ic[���= character��ddi��Pi�#-� Gɘ�~a�� s fun��al��o*s��(*�(%3|o�,�p�%��-� �=aI@>���(� >���c[*���, j6&�<%>�� ( .(#��yJ�An�%.b�E�2�#�=@ a*C�Vm�-�m_� M-'!dofN�>J@"g �("&11ٍq,��V��.N�Wfaso�;�if)�m!� onsi�=���N>f � ? �.1AW��n los��� � :I�R�"�ad)4;� ���6��!�onu .v��Fm3VL�6�a�@i!XT!ed�)����b�OQy2|R�.J@1SZ3�de]+�E5I $mDN�I�6ٙ��e�2vea���g.� ! �Â�sup�A6ide�CMYA< 2/R�6`:�loa�!�JmWEe .���f4�l8W��2�-K��?��"�Z>�5 o!"n#deNy&ua7-1k ain�3 is#allele%he�ral6Cm# TFIIB��,,lutamic acida�po(on 62qC�<d /�6nq E62K� 3", �!�lyKH8�o� rnj�cmCB�92�k� h�-* b�A�^+"T.v�2�mem #E�]iAx2([�a�4�DW�9�)��Z�.�A���!�>~.��2ZAQ�.> ���b+* romir !�h� ]��9a ��-=oRG2�&} V�,��:�,ōs�8�f��}ntm0�:�F� v2�A;-@J� �8��*'f=i�-D��7�7p��*i6ea�"�7of�z^�.c5 f�)�be!�aK L*==��%) O6�6 ,� !U  pre-K�)� g did*Kefficiel$�!�tor \y�s�/4*�2�A� u�{:'NDE�be�-5)1 &v�=�IM1 . Ou~� �z�Hnd�A�:� cM) ( S59U�""6*�N����%r?sbJbyA�iYFAv!B��F5. ! F� s.�"�M\r6��va*4V�!%�2�.E^[1cA4UJ����$"�&/on)U� $^�s 2�[g cN� &���FH��&"sa4"��F2� "�A�A:& NZ]FB���Ib�0-17mP2 Emplo�'yn�b�~�:� �5� .�&�."�* .�&1F4�\*%E��5s 7<z .[1&�w�AASa(TedY�^�^qJM/Y�_��is���ai5��*��*��) �\sL�q7Jv�A.F�KA���6�:��E.s&��an +�% "-.vO�ba'B���R!��:�W���?le mole�:r m�H�+lE�/e"N.�>�k0AgR� N propX��b�XM�U3 MGM1�ed.�r2g9�%�A�H'$�E�:Q� vb�0� J eaisFd� &�(loN3e2� CN�R�"�q�N8can now������]� engaI,in 2w2!>46leP�%��'��N*�0iSC�� ��>ipl.�^'�@�F�,E�"uM�*)��-=~&�Q�� � � .�1� Rds�EalEnR%��!rE� q �տ� 6�'Seconk;@-�ut=eQ�M���F� a�L:� a�!-ِ>� :K A�ɷ> ect:�!Wr�v�!��� J�G  4MS5�9RA�ir1���2!2N#���p lItr}��!9��5_e"�Ka%O�< !-6&!%q��8�P O 92�Oab?<s5�M�EDN;1vMg�VI�R6�%�\A��"�AU%Ib!�#�3�%: o/7genomewWQscale%Pq(>��po�:ia W %}�"]5� " Ae��)� �R�ŋ2j ��5R1���*&� 2n?%Q�c6B"� %:6�Qf2�W� ,n�M�A(�OA�U1-6�MF influ1S�5�=m�-�e,"� n turn9sBT.D9� 68:+mMm"�Xβ-a#i� .� �3�o�0��?�6=m fe�[1��vokmj.�Go:|&CJ� �! �_S gQ�G#t�s !"�U9�sVY . I:��z�V�{ �!{��B��,�C�<qu[6�[whxJF�(JH�ZUOBs6qMinuA�nab� � ���"C= !�"^ .� recy��g!�a�| ( N�M�1<�6��7+u)L19ɡ^�may �U��P�����;6� �1.�tKto� ��,�b"�>��HZT�E1&��x�J>>)�&%R�!d"j �T �a�JR"[4d!�JbWdiverg� �p�"�''2m chro�$�9ucqm#b� m���>�Q� hist�?mod��patter�� Hs.6d.R!he biUMalY} is marked�\"�!�! �xѥHU�*kR �LB�!,H3K79 dimethh^[22\T��?h�\rk��<a}G�a�*�P�U/�def@t!�b�>f1 H3K4�o �Y�o�>�Q���A� )�m%s�}tmo� r�"[�X&�-5�A�2 ofC27�re�ly�o?HrX(�Z� ms&e%� �I ���H3f�pd^z+" acet!�J15 k"� 96kstart�!��4s�\V�� � macrophag��2>y�!��Y�"�Y�XU�A!Q�� �!~�&���.f38 emerg� viewE��a vmajor�)n+!. y�`Z��^O �"S �y2Bc�"�3�"opt�_9 A.4����o_8 ovelK "E%%� ��U"�S^�th>HŠc"i���[. L�V�;5%� ���n�( ��&2#DJ� 9 in hB-b��HN�? � ,�1�op � a���s m O%���/�a impa�)n:�>�N�%&. YJY"s���2 tudy�l��( S1 T�=. Cul��We�]ino��5 mWVYP-dextr�!�um�colon�:W a�^shl�Trea�/pl!A�gr1^at 30�1�!��Hsha�0mor�Y,�n%I >c2� dilu� ( 1:�G)!�,4pr; volumJ @$to A600 ~0�V. E�>&�d�X�u�or%].�4RT�X,�+,%J'TRO�)ayA���n22r �atDmR�325!;) ~>�r�Ped �5!�dOt-�Y43)�190 minu�!�proces^�yi��,}� �&2`T�ly.�,�,M�!�3�2�Ur�ca� S2U�!`enzyme9��Xdi�f���� �Alu*/Dra�D�"/-E�New Engl! Biolab�%a����E�"=�D�ly-�Uѩ� P1T1�-�(m�nl`+Wp(�No F1-R62�'�q2�",E�e$,d iso�&�V96)) �b��D"� ��%L.�\�fag�G�!�(arF0PFaj�d�!� Nrd1�K�io�)in.�Anti-HA�bod���e�( ull>  HAD�=re: Thermo-s !t � fMyc�gMycBh�6qUp�YBioXX olog� � IgG-Sepha��b�Wpurchae�fT(GE Healthca�C�F�TAPB� . Fo�Fu�,F�CG^0_5>�N repe�Eâa2<�xY�by���a`I.O<2l5�Bl��e^��pA�.‘6�Run-On�2�')�:�^�in�&b�m�3cDNA�d%��.aL] gb�664 data9� FiguU2p 6�biA��6replijJ�!quD f�QA�A�i�"�isn�Error b,gre� ~wA0standard devi�. P-valZE�c&fX�~ wo-t�Q U-hL.��A 3le�gt�ubstitUkiA��  3! IGF2pig�Trog�ia2�c)� �soU\ �p;up-6� ]skele�muscle�9/�� asK +Rth�F�]xhe� ifat�"�*x ��� i!#if�:AU)��}$� },protei na�8ZBED6 ,AM}} unkn ,&9#A��*n�t�!A<5T<��an�+p� A�� poskSilen!'of Zbed6!�mo�m$C2C12 myob�is�&ed Igf2�* ressA��pro�mrIQ, w�hea�])9myotub%�g��68  immuno�Hp�k (�8) seqL�5 �{ =q�H2 , 500-O6b� �,-j �!�d�D�on�us mot�0>,a�6@m�6��6e�n�W.hg%*. :joca �,)�.3'Cc  ig"(Ienrich��%�cers f:Ont�]y class�IAiADd!7dmdopBA&E lq�Y\!vX �rtypicu%nZuu=i�nd �-sEJed-�Y7�2 reme1��+MW0<,l;�k�T� izQJ!g(broad tissud\*�o9�m�target��%�� nr��.5# g� i�Ze� kor�2*�! R��>p,E�B$!@�n. S�"g%52or��n#M�dom�c)��&�,U60�(mɌ��%d:���1B�Qřt�Ytrait!�u^ QTL ) map�m�[ter:  betw�.�$European WQ:Boa��L!� W�7:�}�@�Xim1�lo�M��� on�r���niessur9?a�at�ex��ed��c.0 ven,insulin-like1�f� 2 (�u) [`/�h�0a�.J�5�sJ��m�I�)�A�bca��aF�z caus)�a�e�AH�0!�A�ΰ["�)Xu$_owCpG is� %��ell�)s�em�v6� 16 b�Xcl��!xced<, ed 100%�@Ity S!pF�. Q"` 2��n�( QTN )�' ��r *3p�or#�J5=�w2�A!�&a�wi5A��) �ay�"':c%�is�k�Xstood=��%(A�9GA�Aq�P disrup�C�bY:�an"Z%arQ�P&�I��} mX�IB� E'Fq�.2���nLk:4��sB� mas�ts<me r�^%$by 3%–4%E efh�m�!�%ag!�aPi�4�A weep%�#*�@�Rixi^6Fig pop�>�Jd"8?a}>�. P� "aS�foi.�! ��c@a#e%6��!n5� �= � to�[�"qB� %�6� � s sp�B� a 4-kb L>�A��sB� only(�unm|e�)�w� �zX���B�n��%֡�y er�troCyy &�fJ5c�BC�V� s B� oti�{ed oligo+��9&es��D��e wild-t?d � \ ,�B A� is eA/�n Eluci&ekFQ?1 o�� n�ksmHlFfe%1j ( si)}E�i S a�)[%oP3-��e2fG�� oretic moil�*( EMS�}�%|as oFy.�/ �fapI5�,V:0�?Y�!]"Y / RMNo F\ �JE�e�0 �kI^�AE7a��Xtsi�.!�bjos~p( q-�͔( Q&�ea��a�a3{+i6X�. Two&�F�| preprI`e!)�Y�l��mino ;���*ILA�7`m[4� "��(“heavy”� XmM! �$�;Yc-is�–fm.��;!pa��;J el@rlight�rnOalmZ�z.s� .|-�:Uar�cu8%E�%6�18��e'U.hGdB352%�mixA� nd s!�&�SDS-PAGE l sl�L4htrypsF!}� !�pep� ̥va by liquid$ atographyJ�( LCMS�L ac�Q��a ��{��l�jRefSeq�� ��i�- ����l�L�<7�,��sa` �tN 1�� unE�\��!q%%Q��J-N)��*mpa��2ݽal"1�>�Ai�E� ��-�mo��B1I�&x5!1(�es�lH>"�4by q ( 9 . 0±�;2ZP;h 1A )��a�o2�L annoMkEn as81� z�m�B�poo-T6�$Zc3h11_, . ZC3H11A.�aa l�familA4 zinc��j � th 58 } memb�P�[VH"�a L��a�A�vv:�v�d5��w2�� �Q�*�  1!�'1&�pK�M�d  op��a�fr O7�A$an 900 codA0a� �vI��unou$�(�to5fI< ?d1K�?XBED dom�_lan hATC�&r; !�� ]@Uorigi]��H�<iqL�Tɝ�"��6ary-el�5"�--��( unp"I^��Ua�A�k �ʼn�6 a��ly �F)���} N�;� �X"� , if�8aerM du����I%�L gSE�29oS�i� �Q��}igG�y�F(Ie� arti�$rMKD*���1 ��,aC%�� �O"�26* v_ �oc*�P��S�O;%d Z)c� ��"D h��1�F��#� (low-coverag"-KI�J)23�r� A�& e��o add�. 4-�4bona fA� FuA -�*i����w�0�q�Tun\d� :2iA�^�at��inUw��!`{ Bh )��%���& �. L"�Ja M�%�zA�� s&q>wM�oq0/  ex%�  QB4 /�out3 e�.~U�1&XA �-clz� �-)a bod� k� �iz!r#�� )F�Jcombin�q���1!j!�.z1super��!" #*[�x i6 %��>��"�l�Jbiochem� eЈa`- � e�oveY�>SNoran blo� b'2� A� real-time�!*�� !!4)9����hat�, ��,�aj["� }b .�"Bma ,!�s4*n{it �F!�s9.��^#mpla�#c"R�u`=�o�E� . ∼13-kb + variA�"  �Ht���œic��dexoc to 4 (Aq�剽s ;(2m�3 �� N� ) �"w re a'�u� �H18��A!"�Rof&� i��w /A��hum�:a�a 1ENCODEEort�+.�A��~ �"�Wn5II��x1z"�0�Q)e!�� q�ppa�0ly��#��mmo�?AWi�yJ5 d8gTe������ ect&II�Eb�ScaHm�gen � c�! ) tag�����s2+ �Max ,/( , Fou Ju�NF-E2 � �(� �{2�}!ngN�[as6�!c� r�p!.-V/1l���"n� ��i!�poC�jEbkO!eq�b�N��vohy5��str~;� �o���k�l�DRJ�( �qk- mus dorsi�p� ��a 6-mo-�2� 3K��q, i . �,(age T5&.#a!!!�Z6��/i�cu!w1�oWe�M>g3f�%�)I.C�I2�iso�A@ denooe<a%� ba���q�*Ew��1224116 kD2u�4� � s�B !��e�r;�A9�% wo6 �4co�MtV���L&�i� comi� �rF�.a��#n���5=>�BiRp5�bi� to(ar �"/$A+a�ewo�9%e%��"6!fid�(61�y0%�23 248�3 2�GFP-fue2[ b_�zCirm4��>�in2W��%�[BED1/2x�! (�47a<84ap�!T k�#s)�R1a��+ar�>�granu�% ��*�V/s5%}a o32��isn-I5 doub��'fluoresc�?sUl(�U�э�4���Ly"�#i��nd>eous-��*�ophosmi�� �"��8��P .lus [�<H"�I?�O���t�B=$ �mzLsQ��_dis� �"��5�D�u)9\ t]+!G:fRs!�l�.8A�I;y M��c.B90UB����N���? �{��q4%,F�-� t0>I��Jpriźre:�edL,eskI�XRFz TM��-E �-p&�T( KKKRKKGLRIKGKRRRKKLI$��v�dh�A��mݓb ��lyEmZmyA�iC G"orKPg?Myf5 [9� ��F� �(� Z[deQ"�e���2M�ph��W�R GF2-�Int�Y�'O&��)6�S&: 6�-a�6'a�6+,2F�g��"L*:0"�Pto�"�i.`�h��? `.6�(�1�`a >75%�G�3&� ��A2��cyt*e $��"�T<lz-mq��juQ5��y&e+!Earol2R�ɱ��<2%J�*�c&x/z=rg�  ��eU#E&�I�(tyXxhe�ɟ��.�Ar� "� � An �kd�/�oG0lEQ� t R scraa�FS"rr1d2a�ul|T���'J���� ��ed.L*O i��io/! ZcP37N�w1.*9��-f�a6>�no!�o� �C� �Y_z6�;0!X exp"�8u��l��i��J reQVJZ�eA�;ly�/B/-Ry%/�9{qA�M�>�����on"},�a1L!4SG�0� 3F� %X val$�C }�)�V=�?��~t �+%\���� i1�ZaYk�of]%)B9t9 ��‘�inv3n3�"ng�S:w>�Zine�\�8�0�� chan�8�.:)!�=.E }2�low�� q�!����Ugf�Od4<)$.�tV�90D&� �3ay # EN���-���n�$%>)@@2M)%��F!�ў�a�%kՔ,A���8Wv�o8-y��u�*T)� Bk�)�:�z � auth�cm.1 a*t��Xi�:-�."�lsu$y:�2�Io���!C.sL�� "��� !�TS�(,�8�>xim��50GT p�A��in 5 kb!C9RP I�7  vEo�J�&�bi� f:��Qi��ofh,EE'�Zr�A��J&7=(2s�2�W�f��!"M�it�a.�5�� �� �. G�- �&�(ie�"�!&�5!��6�4s�-�9as 28%�wF ma!�'>K6�N G � 16@!�%c�)Ha,-GCTCGC-3′�A&2uZ&�Ek�.���\3���"d+1T���&��&��reP+�,�! . Ab�!�20d�)gn@�b>� .�&p�>vemrX!��W�!!b]�! _-�255mn�C%�of�(8� �)9�a�s�9ߥj�P�{A43IID�00 vř��BJ"� v�^ ,@(ph�P�, neur–s alAMin= .�Ill%�ly�#�is)f��S )%,ed 262-J*t2�"���O>�(� �%. .��'&�und4�N:�w �Fk ��.� ɿ�pex�aw�nta�V~q�=�� eҥ]�aFal"[J&%C"�Lwcu�n ` A�Ingenu�GPathwuA�(S&�0ttp://www . i?.�����wh&Z;�:�&��mO;dis�-�)M� sܡ��J}o6W= ownl�na �1);A�.�@� –Y �#aFs �{�7G!I"2,:� atic�0jax . org/ortL��shtmlu3�O E�of|!0���������"%�UR�0"�*�U3�b�>�R�-`a8��.�-�! ��RA�` ^r!�"� ƝalYord8/Fe$�66�Gyj � ,�+diovase�]A?����^W ��6q�X�t{&1<ѕ.� z �A�y%=drive<7)vi�e��Pfc?my�W�: E��ve 6*)%Zw+X��M#aantag�q� ����s�L~6SRe�e= >7 �Q��52; ��� e�+�h"�!��&�*E;���K���" 9w�!r*� |t��i-*W)of ;A�?�N3�L @ E@ ABcarM����+"�� B���.�!�( iv )�-[�Yu��\� ��Z�>sco"[ 5�asBo:� ��>�����m.6��r� �H ceu�31r*���"0 Caenorhabdito legan�,rA�K6x.8,��as�4XI�/aC�}U��M-N>����azra� 3 �a%-�,��network��A,5*� of v�b%8<�EA�YoTW� �11!"j )b��TYe�L�d;۶��e�S���i 2�[1"�D:2 R��retro5= 5~A10%$2�J>"3� ��\]-*(! 2�y� as[�!La���l . [12].h47:|`e�yd��BfT\nyA?43 �se��)�i3 1n�]%�� �5Tt1^��Jpap��%c$Z� leve�1 �Bn�Y�U� "s�zn:��-J,\�pi/����i�"@*an� �900-bpN3&a���� -� �m^A�Wem��#A�2$FF�1%bV&of�JR�#�Eaɵ�&a��al �gou&�4N�W���#S9 on��Q��(A�� �$w� Platypub2�lsum��iT=)�s�a��Y]?J�'^ )�R4.��N�#.h E�happeb3��5)_^�K`)E"5�`E4%�A�E�in�v�K���/nVAqmarsupi�'��& �= ���Ie &L1�U~`0sp��q /�/�JlzF)�=radhQof��t � J�z2�OV!u| to�M!�fu�'� eRw�~���!}  w1ad� �*Q q) new.�q�!�p�1��r�Sr:��z �&jKb:G I�a:De&� ^2�tb �:ed B"'eremod��A n obp���"{� �?�t�f�CNJ�Uca !*3<Dre��.w��9a� �1Ŭ�$�  N NURF* 3�� +�_a�hLս%:��MIaVQVor�zW * Poly7m �inv"��h!|o"g>a�~ [1�I��i�a�ŝ�I � �A��Q��R6�Sf��} D �*6> }�:62��l=Iu)j�)uW4qsY-�"aj����@e ]�&%by mov�he3#Q�IzWE�$ �u� fz>�*�u�%�&�SW m:ĸac-0"�A9=n �)�� \M�y���Mj"#d�i utrus~.M�*(w�^��ty�t a'enV�U5�Ve+>�!H.K�-;�$f8] !��$*c�)�(�`:� 2_s�"�e23TSS�A]&�Eٍ�.�R�ia��3.)9 DJ�i'Nn2�.._*%%# �2!l:�"&|�,R�V��.p  �] oughA�ICE\Q�2�Bq��J� S�e�e�� "v� " �� ssesa�e � �tN{r 6�I�qLu�4t!�KW��we >Khas|<�v0� �A�!���@\&� RA'J�&Y~� 3=�j�6�0�I!�'% ��Z�&g� itself�;{by �2?"�$Auꥅ�* %*�$>�m1).�� .[&� �mFb �a��KUC. �0UIof:�I�a:k/I!R}.:7yQAra*�eQ�tc�p�dwVc�.F ,n�i���**!g�=i�A&f�-d:� ��:W�736� homeobox ,� :� �|0c helix-loop-  ( bHLH�ea�H,*pI_ %FOX� ,�V�[aq-cep��)�yn>~S@9FM� ��6 ��i 6��Z6�avA`jiLI�� Y ��o�eveloL%�p:�]c�+�q$2� �A3�e;�c�W� A-�2.��M��B�?'� �.�(] ��EI^ �a�<r�4�_iR>n P $ma� >��>ur�� �X v�642k*F&�ppeA]��,M�or=�T �.u;ru dE> A%�a�op�V&����ky6A�of im.Usr=&0�c�J�<���v�".i7!es.� � n!z��e8���6O�/!f"�X� a�Ya��� )�is und 5'Ai喉y�.�*VdHf�O T�`O�a�%Ǎ�a@3���L��1( Grb10� �.�=Megy�U(��#�@1��I"(� ���I2(���+�/ ��qor [1�fGRB10M��g�^��T ( INS��R� IGF12GF1 �| d)� x-u5!�bit�#lc%L I��!�eU�!_F�)�a�b � Ta��+�$sIHal�,6�-,a �-�aC%p�#r%aK# �a��r-�� gf1r�2�w�_gf2bpvJ,?B$3 Gbp&�0IGFBP`JA*IgfbplI�o! ���7jb2rIGF� �Z+{C�l,M��?n�k�ŕso�H^a�! _�Z`Q|�#W�JAͥ0 ( GW�,�?A(x"�.L lociqh47>L��i�]di�"( O9�@P"X] omics; 2Q$ ^(. gov/26525!?�N������7M & �a�-�harbo�JI���CiCKb��{.�&� 5&&mNs�I]�3me�ycurK7!cscree�Bor&< f,%��|9�n�E�E ��GF�"�# �d���h �|o&�2aLpG+�Forphism!� p[A�asus������] AP.�x>�!��.Ai op�daa ��[�-�G�| �E*f&� . Q��0��n�6&�o�T:�  4p�%�b֩eio�[i&6g�?2 -o'(�t ��Enoen�2NJ!sx�)6e@gM���s�)N��Qp��,)K"y""um"BaXin�&7�$%��e��2a�ua�I� T\*F �&M �Kly)�od?!�U4��3��Z1ya��ot h^2�I ct@or #�AcircumY!~�� germ�3�t }c"@ sc%���A� ���&�`�U�n"�d%u!��P�� % !�,lin��/&������o^��4Z-, s� "M*gRA+y�*,iVkM� B(��"�v&G9to��%(i��(F6�O%�2 ! uo�r"W�di�e`so=  �7o%k�tZi olym�ء7?��>��'* ųC→T%l G→.�e��5�Han �^� �"�&� . G��%�6� �A�� ���)cE��A��"�#AfJo"�� e��.�)�)  re.��m�A���piAL!Nm��j"b ��*&�b�! � b�"iQJ�3%r!mhaŕ�soni�2�!9 eR �;{a,Vbe ���K�9\B����'60>]P@s�a dra r>�� !n �Tn =�6 �acc�r�Ak=�!�*$�lJq�k�>Ef�IЪT�7:�q D� 2m*bWbOa�by%��Oe�*� y.F[, -of-�E�� w� U5cfp��� ܅W����I��H��B})a�%)%P6u!g6�)M��{%�;R|�(*�{�r.D0!m:�b5����.�Gi@$ UO5Ei���F�F� tum�t�*!�DjurX�0ZpJ� .j!E��!.�r���� m2�(A��adis�W�^IeM% s up� aven:L�AEat<�a(��prox!%)~s1�� A�:. d:?����%�A,ATCC CRL-177��.. 6�~�na�orEA���uAJ-0d d�K5.-lightE^ al��9� -Q~;AN;��le� �R−���ɓq �bh�&nnbpri�oA�� n��c+` ds-qF5�+�e�Xc4 m�I�:�E 1 pmoʁds-B|�ZTi?>T���ng buN�H ( 50 mM Tris [pH 8 1 NaCl ,��25& EDTA DTT  1% Tls-2��׀mg/ml BS3�9µ� -dI/d��$to5! m%A700 µF-Mixl(-�&1Z��45�?� room 6r� RT )G ��t�`. T�ic4t�4q:trepta�@-co"( magn7 �} ( Dy� )%oad�(&LxY,m �)ы6�30�RT>�B�me�spuf$ 5 � �000�}tPCc�l"�8 �-�<�����Zwa��3×1eFA�0<=��$x4�9orE��e�2�o�Z�iscar!Q)D�-�e'�by boio$in LaemmliY�+1E�A���P�celu�{�i$1∶1OMi.- p&1iW2&2igel ( 4I0 2% NuPage�BQ�KCoo�g ie B�� ���@re la�"��uto�. 0 ba�k. !��I��lk�,Z�iS9Fc%N� p�J�������pb�i�i)Orbitrap� S��X�F=�o��.�[1�RDat��x!�:� Masc�].�iEFSEQ7�op�i� June�j6 .6 xu"�~6m� msdxj��PR'� e A–"�� t!RF��C*+T,e & P���s �U , 943eW13��� &{ ed �W~"�WsW-l(; EMBL BankAe1j FM88212:�btw��LqQg��u]+(#i�itar�1d_3e�s�4=:_ a Kozak"[��&�Pe3�s�R�AN58��2!@0�3� nvitrogen�;ver"��3* .WQ!�1�subV�r�F�!A�a�! .�,.�,"T9�T_ 0YS�pGEX-5X-�6σ��GST%�GST(U�P M��"��E[BL2�DE!�pLysS b��aM�glu� h� S"c�4B�|GSTa�Fd�lumJF>�,A&�@!manufa�r'� I�B.2+&�bB%*�v!r2�(Agrisera ABa���25=41��Ryha�bFu69���"�q5F"b>p�~n�|� +! a Hi% NHS-%ed HP�Wum�V>- coup� w�9!�M"�1f�eq� appl� t&mc%�BGQ3t^��{b 2 M gly� ( pHe����"� �I2�(HEPES .K�Y..� . N�W#5acN�r%m:� A9NucBuYM�E�+A�� Novai��e�~Y2a��J/T�Y0@ � �f�c� !�:� e"� �Y× NEB2&KNE�R$q/Q-fwd AGB� �/�6l %B7rev 7� TCC� CTG ( C/� � � GAAG!�� �J0 n U�}� or��µ)�v�[N &y +� 6A�2"�" 1� Hepes-KOH A#65]d R� 3Aw1 K 2 MgCl��*& 063% NP-4 N5% Glyce9V,  3DdHo�Sitot Z�ZmF�ef �/ �/ ( dI-G •:�qC��iE}r� M J� 4l (��gmoS\e�g)%"~a�ds-:a!͕L�!� 40 f� end-@(ed 32P-dCTPNH,>�9�at!�� G �*����d*C>� ,Fa�AM R�e� a�.�2� 6��� ��6�!�E35�)e �}t� oh�u? X�ual6�.%�l���s6� E@ 5-mmAW�29�� �acrylamI gela��5× TBE�70V%D�4 ��A 0 ple-36"hpanelRfMN-MT-a!�Fa >6t& C>R E(C102-D��Zy��:�. Pm�9� iofcs|���!�: a ve�[�pro�7��%%�by, #�?e`YSP6�tT7c �A) X;Y6a���<�!�aq O 7�s�e MAXI� K�mbAGa�+Qß�� Actb kB�M �2L �?D o�!�8j1>�_ f�Amkam�%ane1�!Rs�G�B2��Hybridi�_��d�at 68;�(=')!�42 �)=6ULTRAhyb��57f�"j  �; 2× SSC+a 1%�%JJ�s �6%�(2�. A�.adi|)ph �exf@!ga few ho��K�nlRWS!��mO�fQin 4%�)as0aldehyde ( PF�phosphA����`ae( P��F�h�0, cryo�{c�&in 30%�Aro:.LV7"�in Ti&�-Tek O��, oIp( A/S C�l% nikk�*ry� s� oG. . Fl�bt >Wg�-&A on H C�<1 hind��b�+p"�g{X� V& 0�g ( p2�,5�.,(R�g( 6 moE�Rpn�D� � ;$( A301-525a�BT La�or2)v%�A�toE���Yin%�c�aauA�block re�[R-_�A�3%�ton X-�:( Sigma Au;� t 4ax= ��傁�cp7��%� �; " uXcV��� (Z !艨t� '�6�* f�E� h�_RT&�� T ACmh�M�!FA' , sl���G�%~J�aA�o��ti-� IgG9conju\(to Alexa 59�mI>� DAPI=�-��1�. Sr�mou6H%+J�% DABCO6Y_ � ]UA412w �g6E�-;��m-C,!���nYV� �488�O9 α-bunga��x���,*.. S}was anal�Cyzed with a fluorescence microscope ( Olympus BX61WI ) or a confocal6,�Zeiss LSM 510 META ) . Images were adjusted forF�trast and brightness in Adobe Photoshop ( PPThe C2C12 mouse myoblG cell line/�TCC-CLR-1772 ) was cultured at 37°C in a humidifiemosph�Lof 5% CO2 using DMEMX30-200W$supplement1MT10% FBS ( Invitrogen )�81× Antibiotic- myc solution>7.� �-DTsplit every 2 to 3 d .-! ((differentia�by grow�the )in2'�media , �E \2% horse serum . BED1/2x� 4y ( corresponddto amino acid residues 47–384<90 $of ZBED6 ,* pectively!�Tere cloned into pcDNA3E<ainjlan N-terminal enhanced green]�t protei!d eGFP ) co� sequE� . A total�5×104-(�pl%I!>@day before transf�$on in 12-wA�.s!�wo µgTDNAeither �,-)Ex , o y A�aedM� 6 µ� Lipo{!j4e 2000 reagent>Iin Opti-I�GibcoeMMediumhchangedARA)thE ithoua�Q�$s 4 h post��,%�]� anal�h!4 follI�!>.i�graphM�capi�iran epi.�p-equipped Nikon Eclipse TS100.�, aa�erplaM 60× obj!�ve# nd a J D300 bodyaIelqC� per �B in 62eI��HpooA.Sil��r Select ���2�%us��s 84 Zbed6 express!in.n8: duplex 1 sens�;05′-CUUCAACA ,GACAtt-3′;22624UGUGGUACAUGCAA>B2362$GGGCUGUUGCkAAG2�Fdi�tA�t��indic�aPin lower case lettersSas ad���ll oligoHs impra�est�8ty��E afterYe!5. A24 h ,�<x �Yfresh*[ . . BiologiU tripl��u!��V� ��hy  .M oHperformed 2 d prior�ei�.�E�lucifer!(repor%*d. Previously described [2]a9structs � !, porc� ,IGF2 QTN reg!,FP3� mo!J�r?fireflyN� ge� P3 , q+P35Q )]�.I�-M�d.�a�V�)Oed�C N� e?5?�[a "5 ��A'� ��). One� gramNJco-�g 20 nxRenilla.A vect� )���@( ph-RG , Promega� emptyb 7:� upAL2�%E�. T][M�Y� in oF� v um }+!�&� (i5fp )m�a~..�harvete�Z� 1b!�JDa� it��� measK��A�Dual-LyIRmI8 Assay System (:sHan Infinite M200 lu6 mea( Tecan� t 48u -�*z ia�incub� 3–!e�1iou���(Alamar blue>��ureduc��of2.�r5 on a �4Sunrise Absorb�  P@ �der[ xidized/R\4ed: 600/570 nm�72r� �r��lmostah c��!� ��repla% ��FY 1�  surface w� Lc� by scrap��a pip�j tip aIsE�� �$ monolayer!_wenty-f hoursM�U)�number!B&Aw&tch �� ! n���&��V�� d�5�[m�compa. . Statistŝ� sisqy�ia Stud�d -tes��RNA+iso!�Pd from tissue samples (six C57BL/6��A�three ma$� fe )I@by RNeasy mini ki Qi � �4ic phenol extra�A�s2� 0] .��&r �!�� �!� ~M~K6~%�n h�Bsu�� r�sL cripej `� high ac� � Appl� Bios�]�. m!rŤI-�u�by qu� !�ve PCR9� rTaqMan G�pE& mas��mix* N}!Q 7900HT F�RT-`��R6;bD prim� �Pare give�8Table S2 . Data)FE�*�A! shold set�q!� ar r�a@Auifa A , ba` �staA d curv-(serial 10-fWdi�s&� �q�,P d�as no����;�eve %�Eltwo end.ous�sekee�Ugen� GAPDHe18S r!�Y plotAJas!�n" d�K ( ±�� �] ��*Btrypsin�by�125% EDTAFM% 7�1����4a��twlin{:�,� mill!ĩeXresuspen� o �l2�lcentrifu� ytospi-�3�M,8Vp!<�%odra�at�&]�yaceton2?' hybr� '25*Ea�"�ti�()gM�20�6�s� � ocol��by Human� Atla),http://www .9 eina. orgE>NE� ChIP!�� as pV3 1] , wYas :u!�a%�Jaa[*A�Chromati�0 immunoprecip���N$approximat5107�^�r��SP-� �-link�'adeA7RTe�1)Y%�37:�� ]ly�L$in RIPA bu�� 5 mMNs-HCl [�6!150NaCl ,sNP-40 so�deoxych�B , �1% SDS%�Son��!KdAfto�7 rate� frag.s mainly���10�00-bp�"�a�XRup; ( D�Mode�rtŏ��setting!��cyc�of!mI� a�%E5A� A�E��y>)UA�Dein-G agarose beadA� Roch�e��)ull down�=%�oex��~�da�e�� ,4M degra�E) Q"K �\�Of e-chloro�g2� S EtOH)!� addi%(of glyc� ��NA�! � !�al��pur� [�MinElut� lumn)� or� t�qar muchpossi�henric\ �o��,a�,� al sY� ;� 7�e� �a Covari� JA��get$malU� siz%� Libr�"�EW� A�accor�to%Rmanufac`r'��o�@( AB SOLiD v3 . 0jl b))�,eight rounds�69. S9 �GquaD4!�gave 58շ5ivE�. Align% Min stepxfirst�ABi � ( map E�qaQ, full-length* ds ��u mismD ed�sub��tly� �o j� trunk�5H N re|q>fI$ZOOM ! [22v This)! 18+6)i��uniqu��� \!)s�y2�.)A�eKA�Eac ��extto.��~lapa�fi�ą]calcu� to i� ify�Ei!�0 . FindPeaks AX�92 [23]}1�estū%� false dise�y ��( FDR�givaka�b*�<�001!15�. ��. � fallF�� 00 kbA� $omeric gap - K1 S�Vl�Av repeaZ � %(e nonrandomzse-po!�ve peak!T�9�2 , 499A�whi��t�assoc���/(nearest TSS�CpG isl�(+ 1�W���thai=�k6��E�I���e�larger5��=��b+ to wfi� lyD� ��-s��hIP-seq' � (rS, w+!�aEfilte��!G�� o��'! scor!�*� in 5!� ୏#d!$vo motif f?ngm�BioPro�or [24a�W ar��9e �e 8 bp both��he�� listAt��%in�it=  divi�uby.`!� loca��eM-� es 1�ups�8&�+ star�N�@(E:)��backg�� .�[�0DAVID softwar� Ont�fal [25� [26!"In�� �on� oI is availa�`E .l ge%\ . ucsc . edu .��Under�!��\� eAng�c6#has b� broade�}�)iderably!S� nextner �->Jtechn�; how� , s al i�saa�g��reg�!oryŦ�Dain unresolved –yst��gCxccu[lin'�om� �meism by�it�̡�!So� edM evo� /A>fun�al relev�. H�dw�����62)pr t:��arhy macaqu�a�"s\lnofk$a� By�4b�"-��Y�W=�(of multiple<5!%sam�5 �;ͩ�31.50%X!�sE�,R�h99 . 8%mA-to-G ��CWe ve_ 9�6%>!�Qi#!E��i�9� 5/���ed �in�0-c6=,a�a@.]$A�7�by9! indent�Tdem1Lg%6feasi!�~ expe�n$paradig�SmA� v��a7or�!�no�h�i enosdea�$�J�Q:�!�a8-�9k� flanx!}�  � �attribu��of ADAR�ke�!Al��-@�/t�e&�]�NsE.mJt factor�  d��-f2C� ezof2�("�&M�i�w typ I�4p!sD�R� of s!Di�se:B,)itu%�valle�de��diverg%�wb etec!��#z.�Sgg� �2���train���+Z�ub0!�1�$ir double-n�%9 � xse�a3u�m�(�“1inubOA= deri �he g imen1 m� E)��a�forward�acc#it�Lerror-prwhe RNA/k�ɱ� i2%�6hor!�ad) I��AZ]X)�Asmbe!vGsi�,a�us�3( , [8%�12 At��RN>@�T�) re�%��ybeyly  sul��� a; ��\��u� �\s �#lyUi�6y -�yMi6��! �B�.�J ,�-|�Ni�.Aof ob� 1�D 'e�.Z� I��vidual  � l�fy`ALF �mer/�́` sA�@F! a�i� in�ed �)��e�.!m uncl_. R9����r�0�]I�t!��& +x.B q��mp. g��byE��' ��u,�pitJ � � IH�"��non-can�l��j d M G dueA=t>{A��, fU� ��� 2�gu[4e4hil � C-bi�.could!-a$directly� lai-!N*� !��v� $known enzy�c/,yz!;F� [13�[1Sh+A���[Q3�!!��also s ed-&i�2 -popo !�=*[ m7s5���TyScandid�g?&� �.�w|#[1ū Thir�as*spo� c.: F�&�"� ,�srE�^ B/ whew)w��ng eventa!< b�(Ores� *. ]�ra Jan neut}$signals [1b��v� "� di$M�����he�low#�O,E=ng!Da �!� pool. a few.�6d[1%�T :�=�� P �D�H-`. Over� ,��e��$helB1op��P�ra's box se��xa7so8rai��m�2qu� o�j!��/sw�!. Key i� �i� d!9e.\W�u�"�� tN��yUZ�:� �^n,E M�ly�_�qdd-�*18� Cross-��ea )%is!E@Kcl!�"z � reR s w��a,�,a*y to clari �s�s75c .3�3to���di%inF��%ai!lej !���i�/�Z&� �B� &L� �j m�|an�6olua?!�!uto*j 2���S , emphasi�����A�}8=�Qshaa byBFy� . We,���n"K ��t*FDF�$( Figure 19Con��!�.� ��a�� tQy,andI�f�&oly� ) &v�Seq��ed ( Mat�$!� d Methods3*}1824"�9� paired-en B ��� ed!ERnU ���prefr}*lWte�6$cerebellum9/0uscle , kidne� he�, R(=nd lun�"VJ a *ma16"c��i5�l=7-�H)) re� [*DicF� F���� �V� d;.D.{76B&�nw"r�, �9@'2�Ao��sucM4��A� nd 9�6�6v�by'le�'ten%ND-;. S deep�6ag���d~�(��in&�QFJO�j� �3al� �&��i�, \:�F�sa�,A&}(?'a���E���+� sit���o�=-![()"�E�e%Y|&'!��.�;K " / i�o��ly"�0� �as u+ aticq�Y��s <s pseu�)e-!X log-ed�*� �-AA�a�X�n<7adequ�y!2�. B( o�)�Q L� &7 ���Z ��m � �! uish(1��F�oU��#it ��� 2�,suPE criŞa#�2A�0!���Q���PY�*'7��-scal�X>�u �'{ ��,omJ��Z"��!/i$ du�Dto elieB�`amp*�,���)x!�Q]ndU� . Tk?c0%)A�JM:�Ab.�r}� ���! �I@l��?�vio76 mis-annot�2y��o�e�#iin-ho�A!�n /A# [19a� [20]"N ��& 2B;j� Part��,AV���!-lEY�requir! %P*s�6*b 6P�Blu�YA:#"w� �.'[*+2�s �/>uam�� rn&."-.��)�>#S29�B��198u�nsI%k,�$, 177#e)nicA�14 , 846 !�#.L /"01n Simi�>�hr�[ p-�Av�major 3�+699�n5*�>th� )%N} )�/% eo �u�$� �� �,irm�.Qre� bona f3.�f.6��A�facuh4�(�ll!�68("�)!v:�5rS�9%ps 2 2�77d!H79b�("" n2(gAtrE!�infSA(�� E�.qly "� by�22kbS 2r.�ofV��(G6an�$� �2pI��449�$�1�6;` J,/�0e��� �W-�-���6.!&\�.�I��(��S*�& ��sh�b�!�$6�m6t?��|/ach!! �X�j&�a%`,um-throughpu��udyuF �of1�R-a&U!� ����&�i� a�4�ray�!ty# plav�9f+? $%uPE�t ,�� d� A'�.�,J!�low�assay. B"� king"�+V��byB}�?1��#�aTG3.�b�v�,.#1D��p��O+1��I��≥10N#!�� (%Pears�Er�Ay coeffic�>o +89196%/ ;"$ C%$z*D c�!!�"in1a�)�", -N� ��,�)q.V7chac8er:nEQ�(,6amo<"iI���)u��(X�![ t�0%;"H �&��%gpublica�n&b��5%$As* cutoff��!,*� depte�a9meQ1s]#9d;:ngG �u!lrE ,79e�"pec�:��B!�ion"P morphisEwwe eval0 d ��  rigor#��!Yh�! hamp�� ite-� CitJ�]i!,��. Foc�[E����a� "!hq%�%@N-`� o 115{8�J"establi�Ewhole-ex!~BIa@�- G_y[&��.�u9"���i����"�aM�p12\ 2(9"q:�P �!� � &!Y�DH"�*3*� A�6���)��t�-A�1}.�but <�%� t�*iscar�by2va�����%�/*��!EY�2en�QZ� BK ��c�#!z )� �%�� fav�-APwild-�m89<2�� ActuD,7 u " �ejes"�A�n& 13� of�  � �-���%�"��E�i^&@ummar>:Li et alc)x !jee *MQ�S3(1 `! IB�0.�of� ���.�,Ua._W2*8�sw!pet�v%*�#�YhE��"no�6�""�7;<b�B�toZq . No�;W҅�ll*�&^� .Cis�e�aA�a�()���I!8� 7B|,>���� ( V�͢S"mQ9� 1�R"��F���$&��**�6!�"A�.�de���+in�nt43gen�% makeup� ayA@�+!�>%$-1dw.�n9scu�I�MI$lik�0l�_�A�.�R!�)! stil�.B$%o�&�"T^', D.�AFnethe4-KFL3ecess!�� �= �4a *�>ypooH��mY~����.>,|6I�eY*iD#.�#cer$:e. �9�ex�2�0isE��A 1��a&�f("�/�E6�!=;i rog �, glob� 2�-Ar�{!;. Hav�$.@%~ /: authXT�B >�a��� n�aix�& ��"I. mole" �$S.~+l��f6�T�isAAA��/b!\!��f�$* a� llo�>F-t|:�p�9 ;G!Z�M twel�6L;�Ur�:�"��V�%i#c ( 43% ){%%]2,��&�L 5�s���1&� !��.h!+. Fur�#m�!, D8"� =?�3g!nve1a mJ_'i�3 esum�4ae�_ �*_0-�G2�%c�Gi�& 6��M6�7f| ��ofC1%D-i"� Eӹ �Uincor/%!=,�< 65 . N�to5 fi&6��7*20at .�=�1Rmi�M�'�a[ �5Q t"�'wfa��'&�*�r*m%un'*)��/� Q�X&"'A2]IJexhibi!8��Q�&!��h)&V2 NElvel>gA�ź�9%>) |<�4*K 5o3V�PJa�{�*"�2s.(.�"���� � \'� ?c�'reveaq,� er�Ue]+M*b!2���� W*� �af-=�3HJof.�:7c 2x c��&'1s�<–�86��C/ �$�'6��3���+[+��g*~5����E�" �W�V:�����2erhr^W)mA:�= �d�� �I��N�5�8erarch:�2�ng*%�R9"� 3B ,� S�W.wA�:�ũ&�2�@� &�� Be>�|M.� ���m��l+S����>ag�#=nu� �8toB��%|2&me�! ��n|4lYi&AjnB-*gK^�  �ma�IVa "*��2P��ervE�%Q���.�zwB�\�(quk$� N6��M�"�Kh2�ofY� ( CV��!��Tm�j �:(:p a��lX/B&1`9�*d:nYAs�,7,Ed����( 9j4�- B :��<ard��i5mG �wF�6�Ue�&�a[239�S7�>�!eš:-1��% 2�ai=t" 81F�/b2E'-�-CV �����WilcoxG5ne-tail �&10-value = �' 2e-6�QDE�OurxaY5rW@d";!'��,.��funda�al�.Vm&.1�>A �, ��3�Pormm�+Cm�1� with�"/A� 3�E$#�BQ n \a6/�. k &�6���=d �b �a�z.E%JA+&c"ob��7 %�S�_;͇overwhel��ly-"�ed� �a�i52�� 6� : �"�;Y�B*Q 5′���.d:�dis^ed� l�\3@P&[28&�! 4ycny!4i��� t se�5�6lF/��e�a "=� o�e� �3–-PM\�Fd)>recogn' �B us1sA�>g}�� :c��a�x-nor�Fx( � rank:s�(  S5 ,�4 :�"%�=�!}aoa� 6�=ɚ�[��>��C�!EI6V��:-5�pistr�� t� $3*$!"Z �&�2��3�))�T|[e�(=� �|�*[9]& E��a�  / ~ m�!L]A�c �b�:�4�F�8)tnzW0<��5s��V"Q�(a o v$Spearman's��� M, 7y8"�C/ �A�I��Ba�r�C�*�M��;�  E�&�C�DAR8 n�*= o!��� �c"��]�7lAsta�Yly.% exces�)6��M�.4�M  Carlo � �L01"� 4Cr�'�9to"� 0>�M�sw.�3�/a�KQ}� i{> illu�r!nas�L-�!oJ�f�"�6n�6�xR2� u!�2�R *��0mw���k>bɶ�>Z� n}C~ %��>�R2(�6onaKdo H huff�Bm�s neg Ha8� �# shipG` } CR��E>�=qRQ.�%F�N<�!(�QA�� hardoK��&�<�5om�&m22� � 2�r�.�9�*�%��!<�J�G�4!� !b#q� B"�y>$� >��re:C�*4�> �209A� �(fW. 7 ���J��1n , 567F2�J0F� (YP��31&�4)I�\)*!�J r�F]  o �.c2-Q�I�D�>A�k'�mmens&M �A� >.�M�x�H4E & F�V"��!�e � �l38=)!O5!O��6 R�Ab �.ue}%%��}��Ҏ�&�.�._!�23� F�B��; >>|6���6�Evs!�.�-�� Za�:� ��>�i�k �"�p  I��./r F�"X Alu vs� '�X s S84.9E�Wa��y tarb� �.8,;��Qn3xam�'d�� ��'A if-:3���b�OA�) �c� ���tetk.}�k�bUk1aNA]E/m&yIZ�A� dX"�Ui�3�L ���� gws(y.Di �K��m7�LRs�/�� :��r�1�)�!� n abOp0 �OJ�)OeAO���D&:C)'Uq�As)(� �!� %!�c�ga sui���&`&TR�� ?"a�)�.w`�%&5C�tq �^4- �#+n "KUn52�C� $�Umn. Wd3��!7(2{ of �S��1� �ja:�E��-��7�S�/Tf�U��!b ��B+~iss8�Y�q� s 5B��1r�8�B��RW(�u��9�����t�U�Qywus�nof9Ued.;~6�>�)" J��1 S1�3Fu"" "�!littlX/!� &A� �+ hos� R ���� aturfi,� .�E� & Gn&� IǑw�%�/ro�Dby��y�f3%E�1> 0%eM.-I��x��k9BA ����bo 7�0�%�:)/�F�[onG_�,v�c��t �L�`q recapit)ME!�*&�=�NH!�&I:��IlZI�m��5�0 . Du�-�?�&�Uka�s�e%"2��V&� .sim�`ep.�"S>�8sT!nq����}2{� yU6S AR�e��fqx�29 �i��H�G#�)lJS�&� "sd[iBr� .�� �00)g� F�ZV� ��h��)bhJ!?synony2`�nhZ�sur `!�\6�*;UeI&�)XdeAkt�BgL�N[3�Bw�a!�%Hth�Y�5i�\:�4 �fom�+ucIme%a�^#tF�[�d, [34*�5�$!�.�.�<��". ���Qquival!z��*AQFS�jon.vi�q2s�(�WR�y�rNW&M(n2{aRes��a�H� re�M.��� �4#  $,d*� &� $g*#m>&zb�ng [35!�Hyp�@ omet�ee�,:=�7e-5. AM:� )6{ �� .B�jN ���acry�"$ sO!!�& /cod�e�=�h U//e'� �.�SV$voltage-ga!}potass&xnelI��.27�YgFk syla� #$mov��da��d� s [3_Rs�T>m v/N| <"�#�Oor�N=� ���e��+ �[f rњ-�bjn �ic�tU/. Tak�Qog�3r%�e�pe�>��k�F�a��%�.�af��2�Pn�3�%re33A�� � .�_�G�?&<r�^y�<H"�7�&�A>I���O�T�0�1%��!er!k*�!=��υ��3I\s��n�b��*DC2"l9�weaker���"824U� A & �#Te�"�Es�le�']�U��r�_=6�T[37��6"6 De�X,[a�orQnd\ �6[U f:�L!%��wby NGS�al#"�V"�0��`]��0&�0���*�Gh0)�"4 �(����s�=S-����'e7A�J�1m~=LndGw��!a' � .�J� ���h&}\. O���[��J""uK&�N�5aE�VY �6"�a��&�$!8%U=un�A5Kv6T)f�YbUmmovF.S $�P"c;>[[8 or E1aF :�.��=p:m"&@�K� se" @es)�������.%>"'J,K>*�.barri-WZ�E�unp e(D�O&y;�A[qo��e�E�L�V2(a�)��U9� ��:8"^9�^suMR�iT��i!^cAbJ`�C�heE�)Z�uf@!�A�0�@a$�` &�N�vA��< beyo�%ec.9-lya�Lpow( %7ne!}�Ia%Ji )2�&�.KNi#%q�C"KB�yA�&�e�%,6JK�)ndk%g!!"U$sU1>��%9���"�4f�. "�$-�e�HQ��4@l6u��!�a�.�ambiguA��@s.��� cis-�$<P�A2G �3� 8��g2�A^l�F�0F�WgeRn� !�d�Uɵ�E5, � !�q�u�eNsu� �G.@iFn >18�G�R�� [39]E�*jDQ%�]� . Fo#u>e@�l!� tegy�apim&"\fE����J�URsj��Ct�"R�Ee��" d*WT� �\Inu�Jp ��V R2S?A`^�2:*�#*T�C�)"M@bx0�63*|�w6*R1�y\o>� �46�!*hA�ft Es����  OnY��.23"cbo�za�6�.*� ��~nX�Twe�':] .%��#caS0 !&`@:�N*�g� aaa��D� > E�p�ojgoo\i�Ns& sGTo"CI�k2>��eu�12� ��7�tqZ6�!�%%�JYo�^� v5Dj.jt*�]N� ��DD.:�omlv~x !�" ENr(�1��D,� , 06B /�.)Of�"by��5W� �,ec�2Uc.)@�3"�,R>Co6������s�� H)#bg�,r<3aH!EIYK�>`swe sl(ily�Y �3J2��F�w �o!��8f� �wSBe �pmum=&| reVe8rE� m)�(]le ƃ�o� ��s�.�" ZE��le-&^ c�qq�!x n)q!=�8�T37>%_0�a�a[0�2�I��)�(Y� f�mBI�kob�0l���6L�=+n%2�\�A�A!�� �e]gC"� .��e.�G�,F inim\bb ��!,�+d^e�f��:jA�I�&�J6� �4 e��B�F����BX�M3 <L�8~hd&w ,Z� �EI�2g&`.% z`6h\f zli&�H���$� �&�4� g .��{Ia��J4�Dlu � �t�,R 0��R�I�j�4 [41r View%'"na�A"I2hb6Ga~kvI�j%B &?!m`IRens�!��FoF��_ ��[i�F�fj � :�"4)Y;.:�I!�c� "\1 �)ɿA�F�T%:~ �!1�$int�&aIglo�`IA��K6Y�i96�&Deklt��G�� }novel���!E�g�&aF��s@�- � @�BV�gS8|z�RB  �X��IW @or"��im�Ta6IeH�GUC)����".u&�� e'_hc�B�3, l��re5�� !��|ce"�ŞE� �� � EE�� 2�AH��-*�-*�PJo�?-'��Dfu§?KsxDC�M , S7 &�-C"�!R�!�A[d q2"�>a�= y A�how)�So�r��*Pis�$^��"M%M��>�#�!mQ_l/HŚ�&2�3���ur�A��5^cp1IKa:�Vv�J�ms%�us-dir�m&EA` �_:1 chem��Gn� o�{"Y� @con�azot!��v�="@05k*�� F!k'a�(JUx� o� :�oT� >�*R& �'i L�dRe�ly lackAx�far}*{!TF�&��p%�� :� they�S�"�cag./Klio ��=CF�%i>�"�yv�!A�U0+*i�Dae�D�X-I B�w"~�F2HG�l�,M !��>�>�*qg�, 4 & >� f� s� �"�&mA �.| E46�i5��AU�uatomJ����S)t~ E EWj=� 6?a�o�7O ɡ&�(!�*$���],�%� &���,6k:w0l he�xE- ��-��-B�-!p"ve�T!�� �;_^�3��3�R3�q, a#'*P�\o&%q�T!rT!Z4"u�� p"�Gj��2�!A��kEep� ��ofR�%�5�)shh�,�cd&}��RXJ5��a=wN]JFy"�~�_nY#Q �)�m�;&�K{ *��qj"+�'�R&+" n��e��"�����.��*��"B��"Y�.�"�q�p0�+aJ4l��#�z#;�'>QV�DA�R]C3 ]=���`�dA�~#� #M�j]5rY)yA;E�� A#3E��)oWE�!a��x.��.f ��f�!�� 2�� �[*� � u�*U: �N]�2arily)4�ea�t�I.B�+JiAU=S1/*߇olp% !z�by&SB!��Žn&DC �މ��%.� �.�%. R62? �� "�av!O$AAALAC-acc�G�j(����AU�Assessm%�A ,{ of Labora�A C!�)B fE@ttIn/d=M"�M��L��e� Un�.](.����` m Ϗ�%:NNI)�s���,��z.��Use  mitt\9F�'f;Zeéov�*c�QS*|� Rs��<%�p�"�%��n>�)�sv� 6�J"� [��4K4 ' Geno���;�e6F�v�bl���)~E!!� �y?N !V/���+� e nd�:r �bc*:�2A��f"ݘ%D =G%"{-:(SureS���All EkQ50 Mb k�� ( Ag�t T�'�GSE42857%YSRP03936A�E�&6br�z�)ZwAlp�)t64-](��Mac�w�BBWAa a= ^ 9-r1�^!^U& +V"z/ed r�%��f��n�|.�by^�. MeanW��qspE 6ma&�,( Ensembl v6�fp�N2�%S:E� �%|G2� :)#b"&(2�}p�\y\y.Yv'!A!$2&�Mti<"�s�)no�tY5f: *N�"� e�i3�M`�2����"�j;E�i�)Eyn�c{��z�l��no�v�Y@*�)9�� +WsSF':M�5i@C<�� ց�6���>l:�p�fɇwco+�O^ijgp%�%6h1�8. i�q��e�F�� 2�e�kep��U �% A�� &�8oX,K�i`b�va�-�A�"�P� � �Ry ߵ�� '\+�o�,!�-�vO(or un.�j�s�.�Gv���2i3!Nh�6-q H� k�)um�2 Y�9iO!r�#AqR�d�=tog�!Ij"&��I�u[&�l .�cu�t"zs��qU��[4�)I l:!E.����˺two� ups:%�sU�h��!-plus-!�n� �min .�K�.!��nd�$Aa) �tV�Z�H�e�\nb{$( SNV )"�$a�s� �&� .��[ �� Sam"v �O] �Le!>@ 0%fs1mˏup -C� -E�8 Q 25ugؔa5�C�'arFbcf wvl� -p 11 �t��%�s*J�de�^ng)�h�ozy4E� :z<��kha�V SNVs���bp!�;ef�E,�0epin05i,!A/0*� � rs.���ol�:�[,&r aRt�AtPh�j type��ad��ng&�+*�I��i*�o. A"ށenN����$m�H'�%w%��zO*ne�� �16�3.-a &�G�V�c� %�.sb�Am1�Eo>95"�(�C ��MA�q1��( F]2�Ai.��5�t�x�%��( IaNOi�2 @h32���!<�ss.[�F!�5�h�:�S �P�t��J"��)!V�)� ≥32I;MfR0 � PHRED>� ≥2O �r� �Z)� us���B% u�%a H"�]5�� �8e/&� E.)�displa�F�Ft� A��O)�%zy� f��#��&���6 BLAT&P=� �An\MEO���88./�L/l�y�ZJog�&3 ��,�&�3�);r A� BiasQ�$- kQ86mX�6[7$'&��A;.��!$j!���%��&ea:�{sh˧exact 6?CXIK�<�)<2M�on3���� zaJ%�"4qy�_e�*�I e��s�^iach \%5k,}K%b,oEQ�&Y26"*-1.2WP��3�u�V�(i��._m"�f-�6d���AbU VH2iyA�d(Q��cisie�3l�9� wZv� tchGof�u�.I+&�L8�.6�� �%��Va��7�P�$x"�$6` D� �4!�&�ma } �"B���%*3 chec��JF�bg"� !ra78�$n,?.�A7  &� AX�\�6R)5��exon-e�n b`ay� f� �A?=[gen6�*62=_.�!�-��"P�ܔ� +6��I��q�E���4!�.�*�C2��� ����A���1����ref.��a��Z�*-�%l��W6�FN �! 04O� AIl;OkQy-n�U,Il���Be6>�)���e@a(�Zv]����/8er�?�?�AH�6� u �gs S3 & &̄*Z��gÂ�*B�R�+ B ���1�m H�100o%�ɭ� �} dUw�%�3%�� 100%�~�!<%͖�jvll�<1)edU �( n iPLEX G�� MassARRAYH�� equnom InG�)��#p��� � �kF�~6��-. P&�$t".1w� ��< &F��Gp*�&�t , diB��kf�}t dNTP MALDI-TOF��aqtƭtryi�9u�:!f1JrO �=�O�1N�l�� gƝ�two� a�rex��L)�%g f$�Yi�n�r".* �& �ss F`@4��* area ‘G’�al!�.��#!� ‘A/s��01��� 7�+ideŢa�i�\��e�*� A/A]1Bk>#G/G�n2no����A�eA�y*"?� [44����gi���5C�or �≥r0�2 ~]@q�2}���):� U!g#>� �RasF $*�$/ *�:�2gz!&�5*�8A�� E���y >���) YHE��2�C&�-�d:�  ��N*= t�q:�1�;~�%">9�*�|��*�@>���9��9)R!�s�"P=��F�%�F:��9��9k���9�9���ze�� ���*�!%u�T�E.*�Y-"�D���n�"yA#梉��urj hl��� [45]"�3*��nu���F��b�Y)� ���+built!�`�S� e Logo [4ē�AD%!nt!�iv�Va>�2yw�U -to6�o�}��<&�gA>�)Z�6f8&�]r�4��hipu22eBQ� � "� Bt��� K�,_r���?ia�Z`�, }a��p:W�39 k`�6�� th!B(; A , T , C�G���a�by�b�g��4�"�3-61+&ܵr��* ?0e J� 1{A}�9&���"�+�? en A�H;sf&,,9MԔ�w� 2K ) ;b!���:�# d�"�*k/�ed L*bi,e����-�*>Vq1ZI��2�Rs. P-�>G�%s��&�Ji�40V [x:R# [47�G&�2 ���YgjN��sQ�"� 6zr�4�  aVޑ�/v ) �B��a>%� �Rr&S�"�%�*q��a�a �:�0<)� 1K, ��J*�� relirH ����"�. HJ�~� �K)]_ let��n�'hJ8e by C%oe@vx\H(MT"�':] �&}�inA�>�,%B!K)N��3B y�w� �J^<"= H��6>s 3C ";*�}�'G��&*�}%]�� �L��*gq�P�W"�5 2�\_�acha!����CV&�#�Ayn ^@[~��E���z6ae;9�( 6!AJX>%���'�,<� �_EB1m�-e�&;�)m�V��-$�i���7bN��t�\B�:o�B�)l U��$Q�����9J �%���6�M}=�|�%5��ta*�t�u�;.*�^KK&T�1a-@� �� �193!3�54-�a�au=1�� :�p /�H�=*�e�A��5�����}a�u�uR �6�Y yy�6# , μmao>c-g89�mWo/?1U�j β β27%�"'V*o =Q�!�ε] �Y���Bj`?��.� ��u��u�iN� A��=Q�.�, BQ.�a&�b�m&3 . !f� n .�ui��Ŝ, n��u�uf� ��6c6�{ �e"nm�.�2�clj� i��Y=tN!mWq�!NE5/or �a���5'��a�3+�b��" 05ED]W >0&�*�sM W£�y%��s�19�6 d"�~(>iA�FDR� ) [4Ю�O@ie .>q�)"w&�X�>� I�* �-q%�re-�o��a"7��K�k � q q.jگA�N&}%*8<�c�in'%�@�*��BkeB��%�^�!���aqg� ic�$t�rAk"� "@ @),.d \>� 49�#� �6�� b�7�1�(z �� m`=�E���D9��.�_ag*�%" "VI�; ��tatus:0!'^a-M��4Ae=&e�\%RT rom��riC_=� s�P� hdeN"�MZg*{ 6���>W�“9�s�*��=� �d^r%� �*Yl. !B*�Ua��A��(s}q & S1� �t7Aơ,h�AB�ABJABnqE�l|a;[Is6�F!�MJ�Ai��A�!.per�<a�X��e��S yqc�6c&�sA� 6-*�windo��T�s}@�� ���N�F<R� %` "�A�j�Aͅ��Yag��s�%2zK��.>�ir ab�.��tag�����+dB8�su&aK�uli ��! 7evoe))�J4� �>BR7$�!,r>�>��� �.�E��?Xci��Sg'��\M � �tw�5�t�)i�-<]<78.:q�S)� �SwA(cep��I�1KA�%+-r�,a�=!>�:s�- rk��UD���:".� ng g!vng spa�0�)�. U�,���ly,]k�"�nin�Qan asym�lO|:��E!H>n���� mani"9�m��a�p��aJ�%9a*i>$�QA�Dh!�. NhSt"��+in:�B \]5 shif%Y��131+�d�!J�9�J�B�S�Z��!�arvB��knowled�E���da��-%�D�:Q]�. P�I�dm��ɡ� o�P!Js ����ly�T.�8*�vneB@bNrySco4�( V�V.2_q��$�"  bZ ad F&Itoe�e.��A� ��� beU1Yy@#*��entir�.Q�%��F7. More�)Q/ M��i�@is�eba�3sJ��D -!��B�QS�*�� ŵ�E�)�!���M orgaX�7�ga��%&a�Se2D judgŽ� Cq�Hnee�8oX�>s.0,A;ɟFp5;�8=oz'%$R7Ml- lD A�dYs$psychophys�(%' �C�T2>i&M d.������,|eQ!N=�7�s��2Lt!�:C[7ZR%l�G t un"�e:�/���.!/6�u����ex�۹���a��:6��B~B�� B�!�N�6bi>~I��Y�NM[2`�4H"�o����l1] doe�� l�5����S1,a crud}unK��obU`!6�s"�2/"�m̔in!4ii�( �^�sclear wh3ns��7�7(&o���atU`^vmak!�'as yefMj��7=st= � cruc�:i!�&kZMLY"� �+g9p��lR �6h���)5��1i{.F !at�p�`���� "�8&�n�A�( he).�"& i4Q2�G ����W��"A ��r�!M��y2�� leoret�8�[]�x� �N%r��3!c���1ns��M!`�����|&�Fꭍw��A5�Bb�7��.�u5eN�� �us2�5�-�le�"S. � �NR!0��H����uu"�թI��6SiJ� ���w�_ >���kbe; nEA��4 �er��E�o max�ae�c)0r@�"� .�s �pa#׷h2O 5�e��t�@Y��#��A�a�q���O�"PAV� . Like��2��e���6 �[�n�e'-L)� ;� sR ���a5=E> �2� W� usy�<�5��b 2vr�xev%�2aq !E%�"5v+��'1Eۑ*�6K9�! �pr��l�/�Yepresentan Rh6H$found that% backgr|causesdi!kFX-�g-(to decrease!� hileECRcin *s �bIFj . A populI� code)�T is proposed , consist�4of a physiolog-<inspi!�V1 enco%Dfront-end followedAa� !Tstage . By simultaneouA�UDg-IuQ 6yM ,A�were aba�o u both%vamefan im�e ��m-�5 . O� when0� broad!�4 octav!iAA ssumE��E���s��all beha�|ral�� ment��These f�(ngs suggest��-rs �<ed�sR;� a; e apa�ri��loce�s�Ra^�a*a���tly , �)GA��Swa-�dop!�8in our tasks . .�!eE!~U��`onA�c�zFr in aAd2[�kinterval>R�%�e� �e�zi��oorN1-D � ( cut-off!S$5 . 5 cycl�- degree )A|l�Gother2v�� wun�,IJb!o)0( Figure 1a )�� vary�B!?F of o�('�arison�� keepN6� ;standard9A tant�+obtainA�haO�ve matchX.�Ta���}�9�,�fR�25/)#rtto6(e�=L. Condiᑡ[!��ieF�>:s�=�JZ<2�>�!�$vice versa�lrandoml�I0termixed ( se�thods%�I����er!��( �-(after refer�E!�m!�in./) ,Y�)F�ificae�)d.�> F�( para�]=to5��t� cal power�ee sup1 ��text S25� W�,�in�2�0i��� � remainda \ is stud A demonst� on!)!�%�Y viͼ1"a .�&5l:�com> insteadaB���.*:$,={�0; ���,bottom panel%9&� �R�b���it.� s��e�, � ir!�j��� of 6�av�1i���9��Br.n>@. P �.gAng���in}�:�λ!sulE�� �6~ of 4��y72�du���)�B:�m>lO.��k cv���4a� .B 05 )p��Z�%� . O��ll�n�a� A�6K�er�control�ITA oE�. ( 86% v�78% corr�!, binomK�^ Cb;� a sm�ri�!T4steeper psycho��' �re�V�h�B�e!.�bue se differc R� s�s+=)��ad)�*��� visi��'ev@u�Qvariol�6z? %�ast3�C b� ab"P2G* -?O�W)�$achieve 759��opeYWU�A�8% q:���Z�4%E 6r�>mL>i.�|� :�%�wq � threshold9R� 2� 1�3%^�05 �We als�# t �] �� :�notched �, i� Fx � = a 4-i�-wide E cent!�a2�has be-mo��1�N �>�9�1 .f"26)!" �e^�N prB/6 D*�:�&��,esumably dep�o� �h�s/V1 neur,1Ar&� harp&u!�toJ�([17]–[19]�e�l�  de-pOV�isBwi�n�liz� (�M�2iM�]���)�, [24Eo2Eop� bj a�_� � shif�wards��fcd���f�r �Eir %-�"EveeEal���Bf���.w"�$ mild elevI��.�te� harg�ia�)�� aŻreb�a!�&unz��)Ks��edi�)�,��rstrongQ:!is �2��OmechanisCon&SF5V1�l��6����M�nm. E�IL 1�N�to�W1�9Ep)\ s eiu {!Co� Un��!�Nhe.� T�E���'PJ8`2�.oF}aAc|SpFs�D�E�A�icA(�# "}4= s�� .�"�E��6�- u+iesA&n below� abov6� "�.�n2�.�e�m$9ߩ�%�fF�>� �H4�or �2�. N)��!�ins��J� ,A95h=,%���� ISmaiF-R��6�b@Most a%`�>xJ .� >y t��g �A2� r��s �A�2�t -� M�*� :�absolute�L)(=�x t!�)_[o�byA�eu E]" ,}ZRyr5� � logRD Jd m��B,. D� �"Q&� ;:� ` �P�� a.��! c[!�� i/�b�a��.J"$at Ay� B]a`u�8Gaussian-shapedN0 �"/!:�b� ^ AB>�g�nV�!9their�!�inclu!�aR f�p�&��~. An +">"* �infinit�!narrowN��h�+� dA�a= &#of�-evD�.Kp!ac�lyN# occu�thy(given blockMtrial" AF�!/�fN�&��� d o�a> angemb�8have zero prior� ba� . It�uld!�no���F�)�:|�#v,unlesBab��w���al%�c�$A a�bitD$ prev� heP system =!W!=8Q�QGl�W�H�QP A\ifi��." plau4 Z s� [12 W� �:��4Q��s Pois�hA�c! gnorA�ab�� !��"� 7U pF�� J��. �A maj�zdA�aITt�1�*!�par�:�5xr� E"�dB��Q�"��L�����We>�ht��r�0 Vl�,is�Z'*t roug.N'�A�l��q�knowled)q� B�"%1�UM�"�l I_Z��$/Jbe� sum/!��%@ll �2� .��/adB� e�#��X no e4� �{&�  "�F�Xq�i�aJ��to��eQed1�� "�]�4:�� ��)��.).� , rightP,��y symbol/ �� OZ��X!w2jg�ng�2of2( is lL�b_ef:�ace>�b�$mmo!w1� r.b���we!$Z prof�"-�7 4b (BM�)�)� appl��#pJ�`r:to y��*rm @ir <' itiv�)to2U . IfJ~� y�Aw��%beB� A��&q�)&� i�f%ifsoBO,&�� �uF,{ ax��iMoJo�)JB ��<bc�|^kA[f��2�M�'>�(.���F�t(e >o *"�'Y. BtB�,j�blua�m�~� �y 7 ena�*r-F@'j��"As � io>earlierM��V���*�,�. Lk,E�ig�!:�.��%��akM "& WB�!�tŔ2U=�of�FAZi�fRU u�)+�!in>�M!Gs illu A&�!4:F�1 j�a&g�ar�ack�9, � �*tho���/ )��ja%v�#b� ad% .�F�aA��Q�usTo iso-&�+C ����*cha4�0&�� I�, eA�� or gene� t� leve|m^O*a�� H ��iciq/,,l� &) {ef-&1to!]ca.5( ignal-to- �!�oA�q� by a/ 1)factorE]$e best-fit�� a�af"�NU#inn++N<Ub�# fullES$ �(�tqg!EQF_&�M b3 ,6b,. Akaike's I*�.Criter!�( AIC�*a&�.���#� )*fit �tak�i��2 $lex<�!liz&�&�6� T�-up,!limit� \.��!}I�}2in�)nt!��Ez�4�� 2theory-����? ly f�U/ Weib!�R�! �.d,"ci�-A���)\e�2a��-pW g �( ,q�J�)\*s�.!�a" a` ly g$5 I!�^9!)0 � mi�� numb)'%u�!�Remark�� �1��!�en2>lie�1wc."��0e0� 8 monkey��cat V1 �le-�H� �'��. SB2B� -poF���d�8!9*�$HDeValois , Albrecht%C Thorl2�At�'�$��� ���8a�of�-d��s h�0nn�&� betwQ �5��&�*�p&p6d:-!2|&gis�i ��  � 2 .21��� �a%2]��X�$* . !�n�/X �#�d-&upz %1� b!m)MU\'ple65UE[30�3�%�v misatuŁ;&tk$is6.3%"n a�D E�$e'human!�sZU[3�.� �aZ3?!5 3 Hz�%BA��a�aY-��2%X*1 t�{l��&}$- �7 Q�"3xim�aE"or�fA#at����#I�10%�30�$f>(. Tourya�&Lau%Da� 8]yc�����hl��3�6!Yto�2>]�i!x��!o�9�our-f�%JD. Rust et al . [27.� �%eb= in macaqu7!si�-1"N3�. Cruci� 6�R�dev�4"��$��R >Gdelta29Th�w�:>2�*�%$s ( 95% CI���nD%4!{-8-,1�6|,q�7�b^�i�m�-um�}�0r�. O�7��NTͼJ����> -�i@�<y�udur �e� �\�!�su  �AbassIa�� .^�Z'N"& ��'!\ veri"8l���A�#��v^% � :3 d9e�sev��6> e�=e�N�I��y%*I6b� ��%��erR\.GqF��&nc 3  -_;�B�in��/a|twMq���(>?A�53�!��3&�6a��valz X� tempvR�ce�i�+tAmbl�"=��� a�-�tSj8��'ai�� 9@&�irjI1on&<�clo�6�1 � �"M2 ��@a���experi �6�.��n-"`"=!��e A$he�q� '��:KB� *} �0����le"�:��&*� �2_�. U&0~*0����wo3*O6 disappear�):d.* s,84%�Ge�ct�w16>\E� � F��a�� s:S �%[�s �+ly unSedn�� reacAS94&�0�C�2gb9�;�>�?��!LN�F#"=*one�� A$V1Rf 4/.���2,,�2E �*�u! b!VZAI6 A.�2!ey empiO. w1M%,}�6�� �%a7�%e�te�?<WAfeX��tr�=Z)�a�" -.H�3re�XllBM<2$eEy(�r69.*�Q�dI��&� �un.� j� 2��A ,E�3>*�)��� f�sFS �iniNo�=I"w"&x2o C� � b �haBt �B5t+�!!�,Y-sB=.?E-y5��pJ� �ved �manag�<����&!�:�����son0�@"L qBgHow�C�(6S-1�) F�/��4 v/�A.��"  8. ��as@��*e1��x�_%eA1�1�]485 B B8ness-of�!r�q�ISis:� !au!�N]��!^y��. A.P���d�z6C ���Am�M 8E��; `!�6�B�"���or>�. GooFzis �*dJe^�T�UF��vV.���K�HJ e�can�bea"*ba��O4ur_�I�G issuk* ncer#M"�2��8�IQ r0,spite be��� &��n/GL�?a�*.^ of 8x*A9( b;h CI B[��839 ,ő 851]�S�B�m� ��oudB!useran&@ yet-�l�Lre�?a"� a�teg�%Fur� m*��.�}D � "fK9Q a chemū*M�-KdF��%q=:� &e"' �ul� E/�5a��z~A!6*�M*W �`FJ"pNY��A�7(icula� �>v.�&�:6*N=eNB|6��3is5 !56���t9.�of�=� &P �2:~�?�6?.mdi�����26��(-( �&a*Fgre�slopem*a)002.� ��E�s&rP.�&u�7c)Ձ�U�� � ��=�D. I�� ty�j"�V*PFRM6!a�O� �k�wo<*";I��F>>F�:��,��g�AF;toMYa2��e6�)i�LcY�5"�� X&�we�*s�aqde�i5elf-eA*�?.m�e s�85�Z�a�sta&�,yeIaud): feedl$i��d a�H�I� .:w�8��/"!��.B>wviR��.:O��ginE�of.��0f�/�%\��attrib ��N<E�Fm",a �/AP��0 ngjg�ngs�"in6+. G)Bml!}t.�A�AO� e�:�9� 8:�:1 84%-� �oa�r3@�&a�SJ� �*���J2�m:�&�.�a[}n�9CVR!^�e�:9�t �iN�$s -atst�`S<ly-� !��GW�WSFS&� *zS!s�nSBA*^kS�0�!?we��$��*H�ue>7%Q� �tJ�$J� .� Yf�CJO*�76(t� n� �! se� �&�4. Altho�0few�� \3eQim!�dM�&���5��Y�"������ior� �f�":�analys{vea#K��: ��� vail-�:���>�)�S2.�XE&� BA:�doe���!ir� mplexI�a+ b^�42�4v21$B���=Svna^l7�tA��9��Z"&'.��V!9r B9:'.d.hLprinc�", h&�?"~�� "��s {6�Z�M9:��!���'��Y�.\�0z��1m&� dW!CuayZ"A, halls&a�s&� F�procesa�� �!nbe� �in"x*� �u7��;!N� .*Lg!�B[t��)GNi�Z*z�$a�Yu�"�E�>�DE9�"\�<Nm�8 u&\"�\]�US�J"��F�:]C*sE3b^�W,��)C!� wE�t~w�FB�-�J�E�.��9�JG( [34]�!:�%FDd�YJS.��:�2�/&r 2w1��b� 6�=�N�>�it>ms*Z"a�&" o(W�*c-�" b�/1S�A%�%C, wh;!��W do s�Q 26n^7�Y�.\e�at�doVJV�>Y  &>ta�. :C9!xu�>D�^w / cw*�Hy�GA+7&�%q�'. P�_]_5�G [36]I.(Zo�umCH�d,a-pos�-$ri ( MAP )��minimum� n squ� erroNSMMSE )�.g]un�9n&quantit!8� �p&� "�&œ�/%�.�J����S%+&11')g�Z� RA$"{) ��:"�G��]��[�i�Rak7Ts}8~h�>d&7&�#!���%w�� i(��Fl� d� !k"SQ�-Y]ea� UAI" ?u��_Q��pr9� s�7eWBQY_�,s�5a��"RG� ,.="JK�@a�P��h {to-�%�2�6r#�!��(^�� B�A�s�^ly-pla1"T:"�[.�^U�opem�L�ԉ�%�6��. :�ZuEpJ�FM?E}^&)%� fail!/�%> �.orrOX�i�A�Xte�ng hyp!�� z�I)�dis�,�!�E�at �Gk �Ba�! e5 Ju�nb.l scen*"Ys�0"pF=�r�>2E� charac!��m351/$Da> ship&�'mplitude%lFn[37�� ‰���Pbeu �!�skeVd*X)BYa��Ior�H�9�J.oOiA ~I�RQa�$-� c\*�Eis .�ũb�b�8���� ŭ� >���RD(�*�"�|AmA*y�g%��y *>^>�s��M� ���V.�aBm+�:\0W ��@� �)�ce� )l.NZ[:*Tv(z` N���V$E+s��"cB!F:N�A�e�'3fa�`�F! :�*L.�Ӂ r wo�P �b6Z2�"P j.[ ,[al*�A��6e�W>,Na8how)�&�relyIy&�p"� E�!�� ly-�*B*. Recur�* network[}4vb enA&� ,�>�aHmo`dev8 �"akae ily (%�Ya�9cy [38�t[39�FA��"3�.Ak6I i�� ac!�I�W4�* /94u�T* a�Fg��>j-S+3tyE'H[d&�!�n�iX/6b s �U, [40]�Ek *�_�NA_"j�j!a[411+ ".Z')trae>�Z�.E<�>yq�e9(Y.�V.��rPI[42!��Fs_OsLU�kkL�H:<& i<0.�9i1j, WA3 � ��D)'^�P.*k�.su9���se2�i�6yB� f�)o5=�TDQ[4 6F2� �f�,) �A 1..Eal�fA�)g%0�!`!=IB�\�O��%�J�m~a�Gir��i ���-��4E|N�lpY�&x.�sue�$���':�-�* tic�� ��a�gm�i�.t39v��Va�4aqV]i� �"+:fOi�ov�"TZ�1j%@.kR��rn�&�Q.�e�]$Iz�|��a�nŪcommo�A�A[o6�� ��,a ���9�"t�ghtfor�W!�"��*��-�."�eSgAV2 eZ,,[8�91� m �Kqu;� e��@E ns[d���.���conci���UF�Y�5$!�&� �2��:�q:u !�q �e��=�Pm�' e!XQ¡S@neDi�1\`t]:N Purushota�:T(Bradley [7] �V�aome ori"lsJ��� ly-co�?i�+ � ��i do�"U\i . Sh�n&_9!�FCo�  $Newsome [9��9��Bc{F�,)) coar�aI\"[s)�2d%ы �5_!�J��Aedde#>yq e �_%�-stocha��� r 1��(&� mch5 �' ���pA�b- T�&2 $e&V F ryg#i�terpre� �,.�q�sL�a� �b�*&&ud�Do�S a no�D� digm�8X P#-f����cxe[R� view��Dw� c%S*�m�K�jp, oftenIXceie5�N�� cQ<�?f �5 arch"W�da7f�`cbaS�2 expl^!/M��O�ŵ/"Ty�c� ius )y� i� .v�Piwi�p/Yng RNA�<pi )q,fKja cri� �o�sd rol % defe��gen�Jaf*s esgen� 3^�5��I�=n�Bga2]a� |�4!-�er�&�*�!6 l�], polyciic�a� curs GyFes�)isiatJ% Caenorhab s� gans �� !�!�a tin (autonom�ecr'beMuni�&B&D�mal C dl.acassettTJER !,a 21 nucleot[( nt ) ���n�.∼50!4upstream motif�q�%�ic�X< A�ex�m�Combi�:u����!agl�~�> vivo)ge!y � yCE݅|:��*e�ary�in5^A��%� germU*-enri0#, E�3E@e f0 �; �a .Xpo� �*�/!>direc�mi� �m�. Acc�E i� 70%�B�30. ^ �\ al fem o+w�f"Vm�!�n2y t~t:� � o��� e"?{5@NW Toge�J|� �R�7)LB�:� s acN]7F[!)promo�$��y� chU�)9am��x abundOHthey �o.)&w@CM0!�� %.��� �X�6�Y15�/00a�JBIHqh}� � �U�$Q"&�.Ns o�aVs r;<@A�kH mRNA� (�-!:�2je� e . J�a4 clade Argonau�^ar�ME��'imA��w tazo� ncesW[1Ge!Jy�(�s�-���5NL�))�ctfan�u"msilend6�K�$( RIS�K!�ubF�bprotozoa4 mamm[�rf �#ep")�4 ">x-${HQn%Qab�b fer�phenotyp�zr�lr�8!�!�th�p ersi!esa![�an���o�0�2–8 .�!lB8di�1di(d!Z�cte��'sa�?ofQ� �ceX/�7�H�#�=g�O�g-�]2omap![i,= �ynt��En�2�Pera�����%w)m�.,H(EJ�d�eK!7no�fdxQ fe�2;- �# beyo��� j prim�; ���a 5′ u�Cn� ��i5�"�9�kkvo A|'a1s elui..�f�n�8�!,>~2��6A��)�-�nza�[ �s� [10� [1N�<?�^�8 cleaA��1endoribo4`AZucyi�� littE!z5q��ic`j�P te c]4d %Y)ReA�[16 �g&A!aXb ]�Kpur}]'�L�Lb�Mng�� %�A^��u�9.>l[18!�Silkworm�s� 6M3A ��/se �=t�t  trim�/:0XBx9Wuntzhe #�l09u�Q� shor�  anchoG%by ��:o�&# ��! �A�� d��4yiQKak?p grad( 7A��j�reJn��a��s�6li�Z�e.�of>q�?��#,QYis�Q��o��:�2��,gu �}�icU�de���&. 21UaK��a� �"Ѳ&0 �*���B!ZIE�Z 1q� �=�"�ke"Wx>���+�HA{& upnd bo�m�e�� PRG-1"KSli�%FC Ăa�rr ��[GYet2Se��N�i s unu���i$A�vS0_`�6of9}�Pm �TBA9Nh gIVH loci�&e �, i�D'!ia� %?%�y�7'��plaUI��aj�Rpos=el�jxm�"�#�=����-6�nrz engag�ping-p� I �|�{2� . Rap )�e!jU�� aberFb + ���C�aIer��� menta%�,�igge��p&���d�P�N!� us s[2.q38qm �*� 22Gi_��%�at~h<&S&�do6� heri�Lrg� * !�[32���*}��  rapi��"@r� 6V&lyaRx ai�ɯQ �l re� s;i, misC-tole%� ��: stitein epi�E$tic memory)Wlfs3s%vn-�6�i�GAo�B �l��",yeuSe3u �� tret�)�P . ; MI-&2Zc-< }�"�O46Z�I1�u�w�: �.v� g� nematode�[1��RŘ5CecU P�%�8 ��"�forkhg!famCy !�fY��/ dele �.�brohs�RI[�*�ix st?*��M 5xѫf>va�&D Z����.�.}%�n�/ @,7"�lj .��&mZ�d)*�%�~G,i �Y�=.d��� P��1"�,a � �!TY���kj thymidi�sit�dJ&*((di�Zce dow�4ea���,Qq )� �Us20��Cu�a+26dicng&a"� b>�.�%\mf�=v&:K%s� moF(oJex?+e�e> Cma��)���A�:c �(�/r\f �.�Y�:^h�!m7M"�V+e�I�QQ�n-ng 'm�8�]��∼��(QrveaUpacer * �U/ OX–10�{W lank~G1�". ��w&}opy��#+)�H�^A8!�0_��U lx <nd�E� ��ntil)dispen�robjU .]��IR�2S A&1,l3m a-l��.b6� driv!=.�,.+%��J�y,V� �:� /`*A�"} N�w�B �rst.|�subcl�sNc o�wg a a-,+f50�ul!�`,M�pub�_3  deepQ���(set?zl<"–U$( T� S�pUW�pipАe�m� �R1A ڵ)�a .� !(1EH711�!/jeG(gu�,:e�q&}Nu��!y uish�(7 , 677 ( 5߂0d|un����>�I171 (A.�~)$:'&� -���a�?O24�`'$) ( See Ma",j&MkrC��~r=?!��� En��Ws��sa�2�+%[�"pBS1A�^w�s�^�d� �8A)hno Z �Bkew!M( B�Ftes?p*nC24Z���� al�ove ^��u*TZS1B)o�8es��)iPI��>A/e0�Vwe}3f�A�, �x�5 �Ky)M-�"�-��paiH[%o�-�librarZ =��� �ci��palF%�� m�Z O |AcmeS1D%(O&�[Ɋ� ��=is؅8�Zcs �. y�X(6\ ".^�V4>^ (:`�. AyQ2�S��)�as 7&�.'�!nJ�)�} "h �2A1�~��5. Taq|#RT-qPCRA�� �in�-�=hc1�Eadult� xu_},m-8 ( e1489 Y6$fog-2 ( q7�d 53se�s s�FgI*����N�1C�qY�1B , E�,�r�ܱt&��!i��*�9j��ݯ>#B,me.�GR�?a>&5gUA� �]embryoz ��� 'dI!x=�UA�i��w< Q� ��Y�! ��M�G�&�|"�j P�S�D��!���"�*�͇R`�GinY( χ2>x9� e−�|�w2�S2�WF�,rw�m��Lm�9-e.��4 ��� d^$Welch's t-:)[4�14b�itrenda��Dob�* m�"�!�!�dep&n{5�!�� �/T :�.S�Y2C–S2m��t�.� IE�s.:A .g�ei�g.2M�"2w�& =<;e�Kfly�,� ^Pa<el>��e$!�58�:6:,�/}��� -��capit9�ly �E�S�zpu%s I0�val��* )�n"J .�$Fh&� �l]�F , S2G�Ut�&� s)lim�iecF�p� b"���"�:��;0%e&�pr�o*�6fA� site"�,3e, �d� laxBN�3mRa E} -med7bd Ob�)� desp - capa�.�# partRMjEq!Z.� �����!�M�1�F'hel%7coZ(�f�� 2f'M&}D*a �XY�-�.�*> exa�d� �>� ?s-�� tinc�"b� ��3?e-\k���la&�7]g0e�L��enu""�by� ��ap]2Zt�iAa�c�A1aK0]�9 I�y!�r.>prg� n435�b,k �# q� �*�%�*;11 , 3g 7 3%&C �%[%�F\Ak#855 ( 2��;��ibOM�FQ�.3 #Aly 49F���1N��->���R� .� )�T!�W`aq!�'E�$g��isUris�W!.�jApI�n���,9�1 iA�Q�- ɬ*#�@(NI/Q1`8�|�i�*���$956)�!�%�87:x-s.in young� �1Bgravid �� �vGP��2��T 14916z� *�l�-5�2��5*g�( 2942T�6 , 7561� -ove�.p;NO�7�3�h3BŪBec����)������.30)���C�,6�unm��B�' )= T}��%���/<4?.�s�<��Q��1%�Va��spea�V#;�o�em�l sepa �!��6ic !�oBic �&bOig \it�u[ u�R:9 �a�%b>�e��!�q� %"�;Ta�!n�A�t$ _��he]Rlis^t!�=�W���a!�W&;ss�c�Mȟa�yh.�����icroarr||tu�!a}wed`c>�Փ52V�98(�& 030 ) [46R#C�U!x.SM�.i�2�!! ��{*�RF�f�+ ��{2~2�f4�8an��d b]JP� ��.mb]766. . Cu�ey�,oek!  +e%�gM]A26�!�u6$lI��g��>���2hO�)?6�2�a): {+5`ٺS00��W�%�09iE4aRR�A�2� ��2���S�/onbT`e�y �� Disci�on�:T�����)K.ise#tX9ߤn�9�2� ���e��� n|tn#t F!?��m����eJP��nno-�l��nt&r-�we*{_| �&� reg!;%�J�� [� g"�+$ce CTGTTTC!� �ma�G).i��'n A/T-� �>�of�35��42,!S�;ABJ6�.g!@�A�'�g ��*K's>�j$�� >�615*&�88� E� os>�&an)arzd-!�a�1rh.1 � 119k&55��6K�3,� leng&v�>L"�Ri�~���2� S�5�E�).ptri] iA�: ��9b�'6;�Qi|A*d� �)cytP ?� , 76:�77F�Ll����&f of ���th�'�! � o �443X9�2� >�R�� 9e-13��"D STo "�)9��a� inflTvV#E�q �y%%�Fjs Ƭ�8byB��[M� u � �1���6�6�WQ8�\9+C ,> p-�Vinct !�6�=A�r���FmwC.�b�5�<�%Fe#n2A����0�5ed��No �sub%Zm3�'g���w�o1�A5sB/�%!,Qw� nR�.=!� 2D ,6)횩catn�Z(�� .��/�5\�*:V �l�3"6�1A�.i plA��Y:I�Beq! b�}&e.�;m �"s�A�n-�b�"!�-"B7" "� �n vivo9h@23 kilob�/�[���*(-}av)"h+=J"#cC�!Ha���(2n0 ♂21UR-1258*�.♀250a04m��,o a�2a��(JR-$ ��king( .iE��u2]$iS�5r� n" 8�gdE,�o �X�A!j!5MTA�naAV�1reZNby�,���ix�1q�e&F�E���,!cTg%`u e� w��wild-�4Hl a�%�)a|G�N�:�%E��6� carr��.vec;6$pCFJ178 [4�"m*Fm�h�6b�sae unc-�!gY�S4, enabs5gw��5�$��var�Iei2iu���ai�e�")X>=r*Ts�.0�e�0"�4a5��+� c�]6�%M p  A=$2′-O-met�1�}3q2a0ue$!A�$} 1�fer� HENN0_��Nohn!b�2�J-�!$-2}<��%�a�* �>�0�e henn-1*� mannӨ�ZR�&*ic !�-jBf�[48�Xnfirma%9+ 32$(r o�4to.�վ� Leve�I&J'5�2�!�2+!��0l�kCHM��1n{-S4kEJz\A]�#B�A"��w 10a�Kؚx�/  2>�<. � gb"�b�?3�nA1>;lp-�bn���-N$�t�`n*nt3�3�wSNq��>%�61-.-immuno�5ip[�ed- le�N#�T��croa7? roeN�YF�3G&H}S#%2rul�E4"�.0m� 1�ic��9FQ��xvhe.ѣ�Dbe=��.I, Dicer.[eI1isi?ass��.bccY e� null1��Nde-�]8Ak�(�� ds!5u7��7 �qa ��coa/L�f�CQ� [49mb>�*mmf! ,Bl?c� U 0�a��� scra'z�DCliF3�n�=pa� M�B6f (��SU� a�♀g�es;"  )���� �,�La�.Sm�� 100�&�)F�)F�9�H�I4)�R�!�0�he�j�1 �f�1�"-xU.�.e=U>stbon�Ide��+!c�WRnFaA�1n��AFA:q*��1* Et�:u!�FKAes͊�E en�=2�/w"���FZ � 5�� ..�.� Au%2Eu��ch��F"�1�CC ]�, peak) ]$d?�>$( 52 h tim�YinBE!��� D�fh:(��';A��GaW+ 7��6� 2#� �j�i �:� -to-:\i%����(h�(�7�)n�fe2)bG=��6�D�♂Tg%�!?�� Qje"� A�Qin�-K&x-"�$:PYECk4`co�d �Es/b}�� Togg+ �]#��U<to 5~��C>A��%to=1 �A>C�)��rupw se& �.�. W�-E�� ]A�9aplumm�/I:q=�:�e�c.��W>��`��.#f�!�usar.1��t�U� N_e� �e�Jj� K�n`F�+M�.%��z,��6��/e��']:l�  M8]u�Yqc"-,�a��3:�. .pi�sdu�%>l](a�J��R �r�H�!G :Yl!nqw)6�TD'=2.­A2:�bd,  ;_6�6tUcu!yRdamw4���=�"��I�s.�)��,le.�Ior)����e� � swi �)�p=( �ha phro�Kcu�9"Yjj�! �N�: mVp��YZ =�"{>�da2"mQBϝ^� ;.   k:Ny"��d?%�*(<�∼�B�+FV>u��|@pM-$#��#)|���MN�{3%�:[A��4�I�+#�!]]n��vid�kk.c�e��o�.�B�.^ ��&p� Y� a� �P=:�B�v:�h�_oh{E]b.�themsel:��#\�6&��� � �e�"M��MI�I )��%�10*�;Pz�;� � � � &�b#U zNh"��f�7]�)bQa�denos'H�>�<� �� �ua2"G��"UU_!>s��#� 21[U>A]uor G^ 5-6�2b��A�.�>��t�@G$�Q(�{Al�4Ia\9X �{.R=9*�S�8" a*�K =)nrecogn)c��n2��fe��jS)IxIz>��i a�X� 5t35k Byx"���2�q%�9��aV2�uc*5l���� �5���$A�g��i)a���pooM(%�cribedK#Y�*,A�e+e�u�e�%a�~%�a�VX}F��,[y a2wE� I�� (*Z�6� j�=A�T� *���m � "�>���@o!���window.�@� ��i� A��-�#��,�la�*-I6Ind''�:ny .�2��$�/"�0���7�`r2“d?  s”�rB%�)@�/U�e��"3#�0�� a�j5on2Zg1pA<�5aG=�t�VgV�Cc �.S%Ed:4=of*��,[F=S"4%m>m�e�I����4e8_U5[�%. AU<�$al5� ?�%C-9O�#AU�!S�` ^��2�4ed”; 4 , 550|��}�((!�solitary;8 , 837.;%|R  G ��yaQ`AA!5"��1&s .3]�3]sRnd ��-;i,!Pa� AF�!2 a 39=�A �Rdec�_�h�� "UQVraQ��"� -,�%r(8on�!U�FoMAS�Ay]��uN""��'inq�.krolUL7 great*��"�! f]�*f`Ew37–�2 �� ť _�8F�[�"m �*�%5�a m��:��e m%.���U��=LA�Zm�re-tlh:�)3LOE�R1� �yώsoc�5%Z�i2hC�%� 5&,"IA50929*�DMT*Z�7K�*� � �V�$b���q�tr ��;J{�<�&�:i-0 � .0.b�$�[ri�=*,*�so��_r2*%+�daL&�X ly�΅�-��Tou��8irI|aMnA��-[y�ng"w�0mg9e���}#sb�f�PA- A.k�0261Ba��O ndom��9!P� ��]3�9 66%z∶� , 4%k∶t<31+ �2e3."�73/ Z12^[o37151.`� B85�\v�`����!1)!%b^�@5F��2�A<ar�aEo!�69%A� �BVR4-?6a\2{>Wea M �is pau&;�+@!9g-�6h5&Z�2��pY�6�8ca��&w|d �i(n-d u��84<*�lR�?i�.6 ?�'s��.� s y ���[�T�(�&)"� i��4�r2Uspe"�D.�� t*�IV0&$ �`&�OM "`"��}�#�!.� s'� �A��36@n�.5 r�O�� n[�O� �*�%�~c��^�392%=#�"��~fU1�1�6)�)6 . Ea�Q�KM��!\g�8�esi�a]n�� .%�0�Hm`�!m��A%E4�[ont�L9'KSm/�*�-&�ae{G L� !�"�4zR;�<1Nc�!4p�=���.v�6"�L �}W6�FGa�&�'�qer�6)y Ug^rLNc� �ޖ i-�6%�:��]o Z!U��e)�6y�=��*v/N �tN��lso!�ei�!Z�a =wt sh1�=��I�o.�intac ♂Min141��G>Yt�| +u .�g�AC��#Ň2�-��Y`ay��6E�=kU�  reafv>�L���A�at�,"\ N"F>A�.*x!<�B�{R�B  Q��rP�E%�!�-�"@ .K�+�@<3"�Pq�u�_��Y adja�4r����sa�8!� e60o n�e\"~,- TgA-Tg2109��ը1 �5� *p�)K!���%�]�!c*� v[�,>�. [agv �2�.I: �;�?���6�M�Z.�_9�%!FNa�"Yq�v2�0 j!�y �,-u�P�6!� . M���&�U �� vast��A�-*8*�}S��A!��l& ��u���K���R ���t far� er�&1B&� jP�$eC�� -D^@�^���5�>�6. ��� "�*pursu�A��by>,Y�wj�&�Rne)��"�(W :�n#Zb2v&�a/n���sPCm1�,, "�My @i�ijdx^ �mZESI. :>� � T o�ca�I�p[1�GQc,��%a, eN�q* W!~;? � FT9Jr&L4a/kbw3+BSout�!l�!X�D4X =��n� =�)2)�or��UE�2E 6F�.U% !Der �c_"m� : 148 RPM�]r� l�1 2jBG4e-26+P��U)���!3.U�a7y��+me�or:�Mp a/Ǿp?WlegedQ� enviro�Fj� 4B"a��(�� UFJ&�_ .p2�X���{z'�X�8mk�tion"�N�kc!�F�*�!cG�"9,P�>1<�=졐e�61���re�% �ueb� by u *,MosSCI techn�W�5N�_t. 6��#c � B[!o!P2x ��1�Lo?!qxe"�q��2�K����n4� s�ZĞ!` 2-he hom�{�m2��6-plasmi�FU6�]!B�� \),��@�X+&W eas�`�a:G$, albeit t�]l�� ���yd arraeY�fȘ9fR',� aM�*� e��d�0is�OqH�&fBK.}%=$&3 {.e]�0x�Kř�kot6m 6 origin it�c~ "�m�QU���u�4o��nh�>�yo[R.wI.�p"♀MinZ,� E9ɥ�4ͥ ��WLik �.eVE=@7:g �6�+�ly:k� b7!�%J�c.�b�*. ��,1�0Q8er�0�4&�4[( " �� z "��te�u&et�paial� ��un�%�^�JF�0��B�,i�,U%�Zby Ruby"�diDis 6�^9.1�m9�b��r� &]" c*��*�. I�K� �9B("y�uaB3a8m��(r�href�(�$&"6e�-c���:�j�h�x%��= pool�Gc"in>�f $.[AsubI �"cn�..y.IX�\DS�m>k�XX�?tSK�A��2�m;!��&Y!�*�&A/&&pFot&Iw"�Fxc� ost-�*l.���W+�'.�M(A��<� sm� [�%�lV}��p6? �!� ai��model� ?Zgpa��s�dYV �V� ��ojvr^l�p)�c" �*�.p&ݖ step�� n !m.�lyE�s p-" �s.TloaQ[*�pa�­"Pa�ʞtro��hoE/� Siwi-0s�p orth?A�I{,>�i"Ջt@z9�arA�6�.p:%&0G�"b�� �Nq� �ݚp� �,�2�!oE\��f�ih�e�(�"�U� �M�{Bn"'T�o:"�%��:|m.?II ( Pol )�upa�!�s �,k�b6�@ ��+i�A/adv ov� o r�� ���to��{��X F�Œ!�e"Q��L�. A=�z,�ChIP-seqE�s=ks>�notic1jja"� gS<.�-oc1=�n is quit�&des��ly��>telic0)z6��� �.Az������&nd ��"G ceed��e��al�>�"Q S7OS7�2"GPoE&):���!�GG�x -ob4�!T0�C���D-��0ޜR$&��A�n:�"(Y��&�#�po{&_2�P�he9O7��e"��-f%�ofT ��'P ���DNx}&F3d o5��s��"EO2top 25پ��B a��("��vir;�m�8F =�-. A�4�ک��6 tarkV j�a�.�{�,�� P �o�M���RL��?"�'H�� �9Q ��e.��gAnzW��~�1iue��!IopX\s$7��+?@l����s�h9[ ��A|sus���� c� a��+R ) �&*&@i&�ia��o53��bB�Sh�}b� �D!�Sw7�f1�e%uI)T;�ci��uneفY*.>.����.� �K��end��cDq&յ�-m�!Ou�p��a�/#e2�ioug-dI�O n�sA:��X"�O�G%5@�!�4Cez%H@gy �& A3"T2oa�5�|���[e ex�dux�IY�-��e��#"V!�X�h��_���b�eLy�[ �! � ,*Njthe2%�Heݐ%� �l�)�t"�nasd�9 *L������ ��,!�F��D�~� {�D�EN�{ag���ism��!E|���han��0 nee_|�/s�{p(�WM0H�B�@=�)�"� 42h|!Nou�Y.�>� �eo2�*q 3�& a �"�ViN�b�c�X.$��� v~^ �h��]%y�-c� 2Vq *� %�E�q5/!�o&�'�+��!�%�]u� ͑�I(core motif �uinfluences germline enrichment of the dependent 21U RNA species ( Figure 4 , Figure 6 ) . This differential expressionX(male and fe 2 Z�s may be orchestrated by DNA-binding proteins that e in�xkpatternsl /or DXaffinity for 5′ cytid!�core motifs . Recently , Cecere et al . demon�t�theP�khead transcription factors UNC-130!/KH-3 ,�  5)Vfically�H a CTGTTTCA-contain!sub w, dsDNA probe!Tvitro [35] . However ,fl�Ds evolved as such:8 �, defin�� R2yflank  A/T �� ness�0ccumul�randomly�a�� tral:. TargeEI8of any overlapp!D!�s resul�k in silenc,�kjecproces�� [9] , [10 4a��� funcQg-�� �!�readily2a%�$. Although9�� ��hp9 lym �, Bagijn"K have ic ifi�50 similar mech%> a��in �Ri"�e7�yIcea�r� |(poson integI?( downstream,�m�ed up  �� , �ktim2 n!�a" %�1atE� anti< 8 [%� �3o end Acap\of�yit [29A@ EachN�5  ca�ref����ea�a�d1}{p ,Ű���i�increaA&>#b�Be�sAPt��ag�CtB�> retrou comprise�w 40%�! huma� n�,EZ� Ee�strong��unter��e�. �qK��e g� duplic�JA n ��[53�A��.Y-4� ��bstA��� xpan��\ families;�example)�2TArgona!�2y%MP� to)��I�rM &? ٷ����B�s[�S���  ll reveal��� ����$a peculiarR of2. .w�& main�$ ccor� to A�dar%/ced�� Bristol�E� N2 was�� !�< wild-type- Ballele 4� is studlisM&o � re: unm[�d: xkIs11[♂Scram1258 cb-unc-119 ( + ) ] , )2[♀) 2502j)4R21U>AzR5)Gz)6)Minz'7�yz�8)Gz)9)Minv'20�415f2%kMinC>Az* 2[Tg#-Tg2109jT3[%�v-; LGX-�� �A>CZ�+xI: glp-4 ( bn2 ) , prg-1 ( tm87 A=!��TgnKIwSi30 �K%�! V��Trde�ne301� henn �4477 ) -V �!�TgZWE�Si1&f�&Agj� 'Eji't��Si2E�%�Zp ,�%hc1!8, him-8 ( e1489-0V: fog-2 ( q7)=!�E�f#. T;genic�} detail�'res�|�r�  na� ��  TX 1 .2Us�s�Og� � 0previously de�� [2� S 6�JTaq� 0RT-qPCR validF*YT.Oclass�m analysi �col�� biolog �����,�$RNA-immuno; ipit `( RIP ) �h�4z �*� �hrimi� echn6��ZAllr2p�in.�tri� �<6�&� adulad s ung �we st.! isol) , beta-.��� n bl1�,>��m�qu� -b�perform�D!�d�2:Pfollows: A custom rab�polyclo!{-PRG-1 bodyIY�by Pr!�8 Group , Inc usa/an N-t!Qp� �36��p�b~ ec!cdu� ] vari tin P!�of �.�R-synth�:win non-=8���stage!��it!� ass�{l Cbr"G9aJIact-1�- �"B� � 4TGATATGCGATGTAACT�n@B� A6CGE$TGACGCTGCCA Full-NaN�M�sub��(Applied Bio+|de��� assayA+Nor*� � a�P��A�y:-� �(ACATACTTCTT ACAA� J:215m84TCG~TJra�y p� rv�E�a!+l^ IF sCCAGG�!�v!�CAGAA� , R )TGGAGAG-A GAG %;2� YAAC!�T!<GC%GCG:TETYGAACT& . To"� �ba� ]q9oQ9 span$"�.o%Hates IV:14390835– 369&;! 2513 ! 2673ew]0 e �]:�v�E ֳ5395699�539772>�5396667 ! 6886N�"^�v�g0,�i656418� 395�vx�–��3%�>�;EE>g� ��->|s � O#13 nt de $6E bothaڅ�F. C]���taken�h6E�e WS22Z P"muns��cri�i&�Rintroduc�+hr�site-p�!u�Mneoo-&e �w�� phosphory��[�F���� subclo�in�e pCFJ17 IV )d5�$II ) vecto� �� &�"9�i] �F� B outs�!+l�r5a%.a�l#�!�*homC�m�6sMosSCI��78�%�5#� annoQ21%�Nconfib1&"ing�in@"� to��-taryng$an�'�ll mus�co @X markd"i% uish5=,�$. High-cop�r�Q&�]&ult+$olet irrad�.1"sme L5���g�>47`Raw� ilesI�24F�!5exp"b[27l([36]–[42] �at7 O �(NCBI Gene E�$!0$Omnibus [5(Art� ��.9w[remov��( in-h� 0!al pipe**(. We first x ed4Տa�(rfect match!�A� U . IfB#c A�found��� ��  align�:PEZ1 mis n`rL � �S betw�!�ast 5��p �E�a d").#.�:| repe�x ��ow!�2�WeaZ tinuE�is �*�� 4a: ��. S �th no�,%,%�discarA=( ∼2��!s� R�+:~o�re�+cR��RAx��IF(Bowtie [56])�!R��parame�,: -f -v 2 -k� --best --�taa�� �(au�$inIo libr,�6? p� !�otg$pp JsD�D�@ �8�a�u&��1p abu`*ce� r�caV'Gper mill! J)m( RPM%sToA rm��jW, wqi�t'��gby)�!e1� 703 known7q�s�f �.qYen�))e<,, full-lengtA�m�y r �093%��$}%�w#id@!N �.��-!O!C��r�&a��A%=\��toX��GJ�.6��7 �B�� d�!� cU�17&�ITies: 14�-gv?*��ed . rmat,��ell��>idor�Q/malz!A�3�="�y"N oocy. :Uh�phrodide!�i�%n �cduH&(}S�. 1C989Mhad��:<�a�%�9!�%�Łeou�B. 1846_�"60aB`you�%9 t<$m)��4 N&垊�, leavA�1�/711����w�%�5�*�1. L��(��ga�-mono� a� "&(:A, 1Q� r)-.�( 9E>*@. ocol)�sA���� calc�*��)� En-*m�SL1.�9XmY��F!�old��*ce���0y �!~A21�,�a ���3 c%�isc..S'b�.�C�B�of��veUK , i 3L�J.% 5-.� ����Bvde�'by 1;jhan^hBRj&�'j�gleэ��.a�(K�qB�s ≤h!�hi.1:�3eĦM�3���#a<-e ���vHi+ed]�GK E�4�$�8!.�ce]pɼ2��averagy�� BdLes!. an 1t(��@�4l�41��3�.��� u>���ir�)p�v5 �'�s>�re6�2=a�_4K f�a� �.�sa�� N�g1p{$in Dataset�appm!�!�&w ss fals��RR=�Y by�&methoG � �Bu���2�\1�n��� mo͌U2f$. 1�45�! "� ��cau'RRI�u!�!8rI!�iA�we�17e trol bA z�17`2 � t9{a Pois��rib�)�#0λ = α ((re α% Ar -� dA �N2 �y�*- ssig� on�-R�. A�D%� �@g,V<e�"R3g; � 5��Y��Tou���b�or6n)�!�%� abov�v���aY�3s0B�&�# b�!!g�-�s:cFT��q*�m�ro"� �A��,s OA�e; i\ )q�� �&nF�sh&of�/+�sin��+y2;FrF�x4�L 6Ay��r��M�>��i� �D,!��� l�. 76% ( 101i�4)5�asR�cor*&� �6a�co��  below���is�)u�� st� e�A [$1K �R�P��B�26GU� ��i &NH>/y5 . ,�!9 [38�u"�E}4D2X�(measur)�13�!17>��u-F�q �K#ur�,y�$( GSM46524�GSM50384A�59329m� 3J �ex: ed b�!�a��Ii�4� *� }�!�"���*�:1s�6L� , [4L441!]E>� 2�>�!]r"� �as��!c*� 16%D∶X 6� WB8.!B�y�YM��IZ[c�� dF�E�0��22I�in]%Tf.61�(���+�+ n435C*"!ob ��^:'54; rawA�ޥ6Yor"�%��u�>QGEO [30!�� &@.�$Z6a.�.^w s 228�6� star/5�aguanos�Um؉R-Q�5qf)om�� sg?s X0–3"c<o aG�9�-&)w�e��map�#&�5�+�in 40�R1{ ���~"r!ofJa#Me!>M�6Ns���a�� ��I�� �pcaͿ � ofs>n��s�=7 .�J�hX3 � of 7 , 67s lI, ��>A�“!9!!'N\�%171 �.\(4��$=��))_to* “)2�!isA�6�8r A Y3 yi�#mh6=�<�I��9��Ij�#y�!*� ���&�BA���e visu�$jWebLog��rre�9�yJ;nucleot�A�oJBon [5Tot8:@O$[A�i�Mof��5t�C�=� ~ i&�,&�9V>M��by%6�C/?3 T!J��8:.!�]:JX( in 6e�"1:2�� x5−44>�1��us � GP:�,�6� "*�&�Q>common�� G [19O� 5���:l%�u)k(��, 387RF�, 9R+6%���h�*�,simRrB;- �7: t9n���+NEosN:� Pol{ occupancyaPfil�=A� }di%�A�O �ic thymF@!@�  ur ".�,e2as6d�6a��( TSS ).�r #of sUTR|�m3 Ensembl66� [5 I;;p(2��abDA��,c� UTR , exo�e �<or*��ITEp�f �T�2v2isBe��.�N$nt windowsBn�=>�>u]RLY* !�*� F��fragm2� kilo%l Z�FPK��Hb&�2rep�;q�a=7oM�Ax&  [5 >�"{A� +e%�)o5ofA5d���B J�N� TopHat [6 Cuff�s [61]%%� ��1-�� �resP �4�� VsE;n,waJ�. A.]�%~�8S<&w :�,�@'is �� Ws 4�=� ��f��TW b � val�], An�� /uu9 ~. Publi�0��+ [62ZG" UCSCl� ��|>Slif!�a�� WS170!��. Adj�$dj�.n�K�ay)�@tq� back�x�v�FYI� �u.�ChIP-seq)eg.� O2Ec> !�modEnHHa��ory [63 Po�esigP4to inputlio�E6x%dz�!(�Ffilə?��d.\M?atl�"I��'���a ��J5qZ�r�^l�Mb� B�I.��Bru*a��Nr�]e� in h`G$"���8?doplasA�Treticulum ( ER ) -deri|vacuo�%� e&BsV �A3bac�Ja����3��JJap�� inuB"�2 supp-th� �i�FAbe eluc�9�Io���Ps�>w`5�Fd s��Bi�(!=E d&�Nz��B .�rtus ac=b e ER54�. F.& , du�K5�inO L!@(IRE1 pathwaf?but�  PERK%4 ATF6$�;� un�:A�3-;se ( UP!͡�~5v�i!w�* manner��u COPI/)si�( mpon��SarM Sec2�!� 4DI�up�I%�Se�3W�(d Alo[=3Ug�ob�Ed aro�5�ngYiXfluores�] mi�)nd�HcIE.A�ir�w:�Gnoveli.f�P , Yip1�> !-D �2�.{�tu-;m�6 zGtmA��Y�l.Xh(�E� �g)�]E�!�+ ��,��-order K2mbl�MIre1 mol�B�ta�exi&� ERE� u�C�AM!�� s0n �-knock�J�j,2�fa 7t:�/N�� i�=7H\al/lys � par%K�T� ���dza�,Dz�!�!�*�#"�N�� crit =!�.�9sk4�+a saf�I� !� nichr" yat)E!��S6~Q� � Fu�2m�n>e�)� utophagy-7�s Atg9w WIPIaǑh DFCPŰ2�Q!bi�%L."=���=�>�f�ng����gL aqe�6a a��u K�/r��!?egNoit�{��A�!R��U!�-�.rM,+of���iep-me-ediO]E. ^genus��E gram-nega�facul�/[Oath!E ���6zoonotic��J�(�M��o;��wV rang �, �c#,f9!b shee >dog pi%zallh�Js [�5m���bo�/!`��iT��i�de��Ng҅va�i�e�� �6ofovGAq5.,O (n9M�� ziff�t]in!�<p&1E7�a�&)J ��s�healt.=rde�>BeJW�3G!d �Ar–��plaiat�ort].�is Nnt�.�=�:$Uef �Vre�6�#..9�spp . Mj�UR� �(20�(n-am�FO���65 ,�8re�*%�au�-bŢ}��<�QN-*�Wq�( BCV,BCV�Aderd s QAte2>� v��trJ@ck!�!�w�06�Eiy�.%�acGth earll<d �2�`ea2A!�?�k� limi� � [2*t�=r���H-ER�! they:~ERRe,��Osubdo&"�Q dyna� �tfiWe{Ts�r [� ����7of)n���l_,to fus��icH.0%��ERx!-"� r�T�p�Q�A�F[�56FCelli"Q�!L!FaB�Qal ��� �12��� ]�s�!Rz�B�E>�X "1Simp���A�A�!T�5y vi �2 l��!Wsuc�Tta!��\ za A>�2%3(hepatitis C8A�Japan��\ phal$vi:S Myco ~$um tubercu�j[1��} p A Strep�"cc|1�,s ��Ud+�tdividBe��4�9=�4a�a�, na,U>� >� In m�@lia&i !mZsEo"&q�>�ETA ]i by��ti�ER �ors: in�l-I6�eenzyme �6� �Jotm kinase! ( PKo -fOER(� 6!YJng��$Tpe�fx -6E@� )�)n ��u�ly he�Z<Y�MZ(byOBunoglo�A ^�$�gEp��U��.� of�TsA�Bip��rel�(!y98��x<�� ,!�. B�%E! ��7dimerize�X i�{*� �$� &�8a.is)P�z�G��Golgi���Ds c�. oly� �$ct&Vach-w!6p9J �.�0)�jichA�tur ,�< !Sam��5� rest� ER!eosta� 2��_�Q��on,�8��5o[�<5�rQ=4+$ [13].�= br*n �OupTaZ&�4!�&� of)�i�Ks]6W!�m�e embryo�efibrobh6xDe Jong� �W��.^ &� E�e��EUm�%�ereas Sm���5]21 8)*#eE� ?! r��uc��u/ �m^ phag�e�meliten)�H"�T��C1 �2�� u�6� lifi �� �)~ Mp� vy]pňA&4# �m"]Xb�YA�am��S a�� unI5�, W A��preh�v�/de2( Z-�.�T �Ce�Y�6A�d f� cha� ��D&�i�6�r1veyJVJX7 s0�v  `"�<�cyt4�o�~� "� xa uniqu@9��B-�9p6�.� ��J%��/�? l5}�sR`X"�7. VceAe� VceC�[DloceY^�[16la�9�Wg�<a)(��:�eAui����UPR*�NF-κBF�. RicGK Rab2� ng��#��A )"2 %�;iaT I�.f [1�!Cstt *er�'�A-"e"js + [1� �Yas BspG BspB � BspF)n�>ݯaT"EomI���� [1 cpB<IR 2 �O' ing-�B%�� �"��%of!�6�!�structu� reW�# � ER [�L.Z�m�ar"� � seN�:�stQW  poor [�dys��'� �a�ER-2@n&1P�x �� ,.;@glyceraldehyde-3-vi r�  ( GAPDO [20]}t��Z I o�AMel���9 B*n� � a  ��ESNk � e )�. �!�e!4recru���.�!� ��AFat%�|tUKptA rogr}Z.[g��.�-�h.��GI�P%G. Despi�AA�#���Yu��5!z#!Iv obsc�L)p�i�b�-�R� o �\b�[toY�6����Is�' ��.J�Z�2cU�F0^�UA��!�Y}?"�^ls�d help�]�q�=W�S!�>oinvesti;R a pof/�J�&N8��B -jA�e m9 ,ea piv?=[!?2]2jX*�Z�. �wA'ni� I 8 ��in HeLa, . At&Chr�&4� ( � i .D�'i`1f9;9M!�&)colonVm!�un�( CFU�@2h( S1A�h a=x� �<^�C� ("r&�ce.}fB f�](�1��� n:=>�� �>r?"� �u���[= M/& f(QC�I����"�'by"OPUVe-(�>^ DhAs��)�:!��Q�t( pE�:}(Qu Mv6�8�E_�� poiTB( 4Ar!8 2jnE�n*AT16.#onwarDC�# drasc2��!0"�in.x-5��P*�1�%0 shora��" XBP1�N�sul %�*of�T ced-7# [2�5�in1�$�T3�d$%Jf��%!ͥam,{g6�Ei( p)%��-Ey!Gfai �oa��$��1h/)P!��A4ed UA�,:�!�J�C�} C.Msx-J�. 6PaxE K&� !�n a�H!b+��>I�J) 2�+I �=�ciZ,���Z�e&LHof  ,� >� a"&fd.�Wt�� .��A��>�5�E���!re�>�2��� 4�ES [2pm6�"aaGA�B(p�F���j2� ��,"O!NZ=�.�Q"�<>� 2�- N�"A�� D}#u�i.E2G.iB�6� "Y F� / . ���E�f�Q�- z! ^�2T:E�� e�*Q!�!<2.4 �.p��(md��� R�j/�� J s�2� e�&D7t�D*�^�^T$�FaX�z dM�i*1%f6b�02�#( Tm ) ��!*)�>�_e�r�fne�Zy�e8$��1�2 �{!"=ii�%`m8m�)�c�Y(e;��eC� � CE$ �;Rab7"A:5! ( YPT-� A�n�mooJ% also �$as YIPF5 ))�������)��.I�5�&�ou�\�31!,���,vw� �,ER- �,61α , HSP47�calnexin~ E�* 53�is�GM�v)� _� ,o� �\��= �:�Ama�u �l*�&� 257 aminc40id multi-pass&��, ��S+ha candH)�!�art(A� ��]I!it %�Y�m,eA%3%I �;A%i4Y�I|Ϳ buddw�cT�Mof@$a$ledge5YI!l"�c����%ua�Ѡpromp�&�4foo(�NM���,&RJ�*�"u$on"piD!)1o!�IP�'a�a"PO�%wA:��=t��� H%�`� �ein�q 5Uw) J; (pSe+od�Tm�J�( ( S2E � �thu<;p8nnt):AnBK��!s.��"t(�b��5Aa��oligom� �4�-N:[2,N2� A_kn �P#b*\as�T!�i)1~ 1�q� �C26�se e S foci���xco-qud )�5�2. GiveA�� B�� co-s > Sec3���+e�R�� g!� �N�av "�v�..�!�. Nex wea�c�w� %�6{ n6b���]e>fyJ\ ( si)A�de�de�t p R���d�:�Ar��v""Ep��N�aYo{' by 72 . 5�BS3P =2+ �<:,J XjF3*Fhe� E�� 1�)%�t�$2�Aw�k%�i76!%� �r�Q;3��rv`O�'er�"!�\�L&(l�$;olEy%5Bj,n�cN*06( S3C��&?ol-/ek2v���peaA�d�adGa0p*T�%_YM�W� Fig . 3�VL��of*��D�&m�is .�5Ya�ј� �' *m�f$Ѥ6��Xa�. Stri\'�J�diminu5�.r�:�cours�Au�(v)Co5)��t�X �-��B<�!���&d5!.4�e!}�@�{-|Ey]Cas� 9�o��6�orN5:S3DE5sdDg g���~.IġE2X"jiLq�f�m r{#Q>�10�I� }L2�� QOe-��s2aA��!%SB�9ed littl�!4�4miJI�g�0 ,=�q�� �mi�Ie� "u'>�1 b�v6I��]J84a��E�!�T$}a�Eks �>t] �>��Ւ�1p, v+�*E��i�f6��,F�SD }]�+�.���kDT ft-ha�� xrr�. � ?i^?2.K righ.Ljp&�m,) ��>"�!�.�).ara*�B:�b��`2��Q%insic^)�ER�3��ico�K�5��n� 9Q��!%� >"�]A�we hyp!sYL[�>cie @in)+.vaEmbyB_�b�f"�>T'ina�/�E�oorm*�  o��;0��3�In�B� I"V�P � >��Fey*���F1 �vble: or) 2,' �����BT %�*��(��A���[��&F�D��a��>qM�|:�2Rm Q'3Enh;B�X��q���)K,2��hardly5#>:!�F��Sk�An�j��� �,|p!%N ideai��&�7a8A�Ev��I�!�< &�X�B��Mg�<�S)ic!�t� �A1� */daЄ�4olyac8dm�4�q�Hr�Y(2s�,AG���7!res�()�9�Jwo4�8�lex�o�ppx� 4ar we�Ka&JU ly 500kDa��10 ( r-I~ -II :�P�n�*G%�Ns"�U�-I%0yD�a�#>9�T�1 dY�G�1a�< labe@3‘S’m6inc!j%�Qf��,o��7uS�uX�1�&J 5>�"M�:r28{ I�&- q��b�*�:] fS�� g� ly�RFY)F . ComwivA)�}se3)a�5�y� ��r;via��6M�m��)M�^}0+w6�.� 2G,� C5�� �d ��We wo���h4 ki��� 2�~�>9*�6� �_M(-^�Mi.,$A>�A�>* o�7uo�fL���/<u���! ���Z��0))�*?L��]>"m"Aq�4FW$ & )�QG �� �յ: .U~� � hQa�� s+f�g=��, middle&or>�2/>� �$�&A per 1a�: w!� �! y�2��J� Ht|K:+s��2O�Be5T��M-0"t�^i:]"��Q&S�>� 6�> assua�"� P�J.9�m�} �?�Nn��E��9 X5i�/��!A� ver`1tZ�� � zxO K[�^k@,i@ ( WD��.�n7ideV4;�\&�7/6 logu�Xye� Atg1���S�@( Dou� FYVE-�N� ���Vn� Z+�7 zinc!�ger@ `/VG,},�#"L@�# W3�N��,�IM\�Yarl4}�u�Nb�34�U�a�6��A1o.�*�ab+80%���8��Ea� ( S4 "�I �� Ō�K�K�K#. Notab�!5�C��`.en�A�n��$&� ofMdij?taz.qʿ1�inf���,A�. aa��A����e� 5)�V��x*?&0�i!Q�Q�ica\�5�_� �&�zD>@2$12�{:/́��&/��Z=�$= same� sU�*a%Y6��vT�)�g2 q�Bs%e>�2��.�@n�m`jO /�.�|Kn2d.�. U��RT->t�9� �:"�F/�>o2��w�12V$)&�S5A�qx�y^e�C�of б�zP�e�59~bd>��iscRX��m� su �t*+EG'I9g*�8j'� � ��-�-ar6�-Q 9*~.17±1�gr 46±8%5�"hY�>Q�.�F�>ly!be"+C�> no����5&��}V �/I�,�I�,EO]f~�/B"�/�.��z�f` � &� kinmO"�4s. ['�,(Oun�%{o� �B�� �j�K!���Z��p�V�� �S�t��y2�n30��:ref�\Evy-YPUc( S}��%{bo?K�ompletAcj��5B�!���j&����yay)X� :S,�� QJ����R4��B(y5�b^u.���݂ ~W=l�Y&�5�Z�&:!y2�1��VI(�N�U:�at f 2 2i� �.0��U��V���p�eq}�SB�%W�\)� los�� �*=!�j=@1�!I� e�"�al"\!�咽fi�5iwf&�.����%"�Bv%�6�&Z%ZO%<>�͙f�.a{-,Sar0 �)3M g/&�6�0-�eăvK1�$9�:��2i#V�5�&�i�� :] X2�U@�Ri A)�����\!-���f75o_ ZNQ� &"&wmf[I<�9��onn DQ�%�E�ECAaer})<���A�.s%oedU"�.�. M�|d� .;5*j�S5* !� V$a�-OM" 3]"}$�B"U �W��*�:!F� �� &�U &cB�=lIIwthEevalu4)b�unG �9�5����?�@ruAq� p"�CF�gr%*� �"]g"ivigWW4=[�-6]506�/b��bar�� 2D0I`E$v$ in��lX�qIr�i}a �e�F0�FU�K)�G1��wh�=�H�9�"]*�!�.�CFU.d �:��!�50%B�A�j�grէ1ET��2� ]�I���6:r=�n F!�&�.!�F�7"4+v'$Mp"�UNf �!�:��2�qu�kj�`T�J��#1 f endo�]us)�Y� �Uy� Q8Q{| 2���_9~&�'�';0"E�E"p >�_���:Ta;"� a�!O�Dy2.�.�b6FX�t:s;I�H&�$ofI2�%�filF A&�l.KYBB� �W�DJ1;z 6!>�%9� �SY}r)pj4> Bg�[:V��V>!�c��A  <�.V�BN�g�$%�5�on.j4 6(2��F fewe7 �e2L=%�"�dF�A_m2"�-�<E� A�=�6� B\�'Al�} ' �r[z �M~Y��$Iq9"��/>�t 9K�y ��ha�6&�J6t'f�"0 ���*�)nȅ5a"/w.UUb"�B]( E���.7A�&I��#1]graphs&�B�q�*,I�Aڅv.�g&<�.S}Du�DDvaci:"� h*Rvic�Q&(7�:���� �F�V Z��cE�gurrib��� �surface��R�4*jn�� ume"I�� di �^A.? m�wvj`�ao��F]g��.�i���A�"�morph]�\esY�%�(�>'�Oka���� �U�!�)� i�en�d:ra�i .��E�%-� encl�Si21�~�.�Sf -tM.C IRE.)HѼ7�K gDE@M2�(i"<&>wok� �"w�Ian�:�*�F�N� �;��A�as ��)}�4,��oi���gBRhi�>� 8 �B� � Xc� N�� 40”��H>�U-V�d&�Z9N� =*Q%6�t*�Z>�*( I*,�-��J *�b} Lampe 2�7� ' �<sa�K� "�!%ia� Q-p�V�I�U� �2�DU� , D^� R� d�}>dD"�N�!K*�,m.{d9��N%�%&S_B�6�+� � 1�E9�#W�V���g��4 �!sZR `nܰ!ehUn��b�n%KۨR[� " FB��t�bs "c�s � �.�$�D:��en�eڗ�OaAo.�B���r: !(aI�i�>�a�0��:u�g&kt.� ���u2V adja`&��2# ���>DdQM&U8 , ��d]r� ;�LER���u��..yG-�zk>> E�q-t+i(6hM�2c)�Se.A:1��>j, ��][g!Re�Z T2�e����origi_9)2@�aQ!�� *�Pg2/ \5\t.�e>_a�)�-2��#&�]�Q"I>�G�e: J�=�B���!� u>+9�Z�6� Nj6x�d��!3 �+A�yI|�Ca��&ao�!Ƞ72j� 9e-6� Io^�(1��i@U :2tI%5��,�n�#%��#�#!Y#2kC(Lzi�qCa�h� h�"J�&eZassoc_^%�!Z*�(of�]� "��%.BS""7 R.�-^&0"�+.�,t 1OP�MJ� �&u5ch&F!4A*�!6 � Q��&6' &�gr v�:��!��%���6�in�rK���'a 6r0F�:���:� Q�8�-��:&�B!k" (��i�5 �;�w:�)>{ **Vi shA� M��y �" C"�B�c m"'S�J"��V�,�� Kedv >���)�94z��e���jT I�q'E��t6 i43%�46:pWVa�in }"� N�2j:�5�)��I�[G�:� ate7%e7B,��2g'��g��N�. "�<]. e�a^R�FwA��UI�.:JZ*3.�:tr"- "�Hh*mmvemm� un ��I��J�*�%�0rclaS-�,r�,r�,r)�x�ia*!62?/E���eO"@ �["�q6�N� �.����xti3Qb���EAngY'�r�f26�=�QXic&� *2�rD(b��c�^)e;1�3I��X!�!Ur"! O ��!Nu%���|N�A��"�fac�@f-Bxsuc*�xrs* _ f�%�a�&�tv�n!�.2� 4iQp$t�Cc��#' �= �$c.�?e@:2L�g�75rW ���xE+�2 .�2�!P"�#!9) �2�m�M�vmI��D}:Y&�@avail%���Vo��I���'� ɡ�,A�soj*e5�m}��[���n݄�$"g7.`�.#p|�*,'�/\!I��s�Bt.aeZ 6�r�#ѿAK))�b)pfuf'�q"�'E�0�ER��.��A!w��ii> zb�&�X&�_R�h3n�'��l6�[�A�"���V �Q vh expl6�w��mWnS���N @G5E�~�AR[�.�6se�.)7�hs"`5add�.�mF�j��7A��Y!0�{!�/E!��)y�p Z�oi��� �Je .5 ���paY�); �"� ��arN*S!�s5mhow2Csubve�vX \}��Eq�H1�2(���'V *zTa{ "3�?�?!2hz�U%qj" v<-����:%k�!:Y�.Y�q&s(eS ����!omE�(2@�Va� �V,�� tdF�G�p}g�s!�X��eIUre"yg<��h �*��Dykb�&no39]!_or����u y� .�J!�&5'Մ9weu��  whor� �"* �urBa.= lXt�?oc�37�0۸f:%{e�)�Q( 48–76#l��Q-mTber>J �(��Z;�W�*�� �F�����JR���^��"�$ �*��&��eTaJ*����r- ER 2/ �. Kano]>8]��E>)|JP�U�.�o�qID:?ur %�of�[6�*h#)(nd Machner ��2��Lj�4ella pneumophi ( L .6) ��'Ŭ LidA�|��Dot/Icm E�IV >�i�o��� �on�-( �>�z�"L��2K� >��+At*r.�%��AW�6.^�h"�r2Y  yiel�w�r)Q:I'el�W>��>dev"��5�)"]֡IeG� I�  "�T5\�d&C0ad]AB�|F�<i�c��: }�y� a :��DR��E�etv]D�y>LA%���/.�A8a!~��2R5��)�ц��-�h  ,@*^�+I�mi?�N\�%�-]2WE~ex����� ."�Rr�C���6s�)']:Td de��_�/&��{ �.% -���PB�� CEښ"-D=����&LEa/2B9�[3�3�DNew4�u� >�-�)W� �*3*c��?us sourL�yVAb� �ZxT�*`wE6;>�re di� K �hF� -]�\@"��a�*�EO;.].� B)�)m�vO6�.�a�#e���. Myeni��sF�&# �t>Bt�B t&�/� :Fpri�MID63 �( ��w �Ut�Jterrupa&..�6�}���k�u�.0��MYZ� "&�^e d%�"O BB y��)baM�O �Ftgcqz"V�QH�� (I� �z�R-,&�%�� �z�.� 9���mQ�Y�s�. O-�o�� n7J�)�i 3��Υ�]a A�#�:&qJ�� ��� =P[2�$28 , 4��4e� Ogat*& 41N1|d*�a�w1]Ni6� �y:"E�y� ��h=[��; gs���[nee��{.^k)o���2 9� ^�a� �i"&�*I��.��I�NenS�����ecru��� ��_�ng2]u�Ou��![�B2-]/�-��;B�}e ]=w�urN[8�TP ��!"F( -�)QQ [.z�2R�")WUZ,N�}|Z�}�~M�tg#!nin��T�}�*�xxy>��A�Y!�(�Aa.Cb@m*N~A�epithel6u �"hyD:3U>"�*>S:5�{� aG:�[4�LAl)[Պ8I� lBa� r"wA Z ZN�o����-M� B]H(�5L��"!�rx1��6j.eA��&�/up�_����� y�u!�is�{A�o�>�4�s����4'4��H �� lo%)A(wIM [3235�!e#aX��o"2; �hInMJ��w�M*v-��w�imMndi�:� [4�� Phys�2�xa�*0irRaNOfr s� ��M�<�r,:Z|5�2)ESZ anchx � �]=: "���*�.,Z5 &�����>�O�r� ����"� �#�!OR�# Un�*�on%�Y� �)7��B� �WI�[darr&0 466��2!ir-�5��5� ULK1%�Beclin 67e$�7Atg\Atg�A;6Le�nd LC3B"��R6] "Mi�` J T��b�N�����R�conʜ�L��:&6F�1_ic&���r���2N*�� ?,&�4gaߞca>L ��ze��R�W�{M�n�*� u c9*�9jVB*"e16�*t1w�um: �b9�1zy-��.kof���u{��2@z�a9e� `A8a�ji�..��~��.,�΁R -JNKJ� ,��\kt�<��ig"��l^ �6k .�SJz IQO&+DH k��d�+�2s�z�J�6s.pTry ��l2� �R!�&� S �7!�� O+�� �s ea�e�;c �Ri.�V�P�j o. j,*� h�T��m� � r TNFR.]f]�M0 TRAFjׁ� c-Jun NH2�iXFҌ( !�)"�. IA+so"7qe��M��e˂ �-A �+k �5@���Pes�2766�THac�/�VExV [�in*zL�B^u|>N �xF+�at-�J�b�z!���.N?2\�&en�t>��; *�4A-%�e�-CE�y:�$6!�0� kv"�w"c ��In summ���U[/de2H�FQ�iap>Z��i2�R�.�6Bq!�A�*�!&\ �#"JYj$C&�?5�B"�e�W�iS �w��1newA~� \m�&�"� �BX-*t-Ȁ�in 544�"�<"�N�al Ins�f A�� H�, Ibarak�6�%6cul�d�Kryp�se soypGr:5% _�(blood ( Nip��B0n D��%�)��37G��8 10% CO2 atmosp�;�-&� ( alL� y-exROg D�A� in M �Qbo��ya!�UnVsbuTokyo���at.�5B��18ulbecco’s Mod��Eagle ed6�4( DMEM; Nissui8��eme6X^ �fe�� calf seru�lCV�A�p��(�n/�Qpto(�( Gibc��$&�,J4oS�$��MEM�uF�y � -10%6-yt�e1�a��=b&� �Ł ,�%qs�in 35-mmVd7paiFop�focal.�<2FpV(A� P� lipaP^VT�du*�{F12�Z5 μg/ml:�{��A!P!�2�]�FE��&i�0 Ibo�u�! :���X��Cti-]z ( AlA��r�>,nz( Abcam.)�g.U�{,( Santa Cruz-m��>U%{�TQ�)4�(�� tech� �>�Y4Ԍ1�f R�*C���v*D2*V�w�BD BioscjXe)���J�67|. V[W|( Enzo Lܑ`�^r��on2 H�Roche%1VXm�( M�Gp��Z]�!(  S724;�@ 6Bh>�a -� ( Thr980;�!�n T?�cD�b��.VZ�{ �(�.(VNLpA(� ��� Ja��. ugus�ldE #��ildreth�Cb�!� D�P��al Stu�HybriQ` Bank���e n��NICHD{NIH nd main aat]:�Iow��,Z�β"��&��5�>�ZA���¿�(�=�a1/3.�%R�">g(F�����ZK� .�&��!&R�inJ% Yk�ea pigB)J]gh7)�MBLa�ey �Id��l�L�)� ins� Xp��@MMQPQQPYTGQIYQPTQ��1>�"k Z�2�"�E�-/�::��R lin-i|��Rw&�. .1� ),B���� � g6{�7�a Flu�\ 88 G��e��� bit Q�( H+L�m�i�rc�fEME^�D�ˎBCy3-cona�Z�Chemicon�b3.�22.�647fiI��awfHGuiA�Pig�MMg!����"X�IHorq�aM  P"i�!�R��VW.$Promeg�-HRP.1EM%�):7 ! :2-7R� 9:9:C�� �N+lq]2�&purch��e{|��R�~ Ustj��(( ID 127564EA+6*��s20043���"æ�ol :�8+� er N�C= ol 1 $)%�:����s:��p`@ASI_Hs02_00312185��Q 1_0010030��./�;F' 1658"L�>b< ,. FuGENE HD _�� &��� !�u� ��pl=�d> !A LipoF�y2�ZZI."�2_%(6]. ("~ ed 1 h-��.� *`aC 0Blog�N�u�B��i�'a ( MO�Dof 40�� L!%IxbGrifug�Vt�i! × g%Q10(��I��!Jt�+&} !x6ez�`�4washing twice �with DMEM-10%FCS , the cells were incubated for 1 hr in230supplemented Q�@50 μg/ml gentamicin to kill extracellular bacteria . Thereafter �pulture medium was replaced byz�1N�,. To evaluat�.�Bru�9prei$f2A�@% glutaraldehyde �Y(2% paraformin�Y M pha���M`$, pH 7 . 4vk, post �in��osm�o tetroxidemrembedded&E�j. U!? thinA]����smJ�uranyl a��� lead citr}�observed-�a~Yde ( H-7650 , Hitachi Ltd .A9t 80 kVJ�scrap�to ice-cA�lysis1?(��mM��s!$H 8 . h150NaCl ,!0 NP 4��1% SD�F 5% soŻdeoxycho�� )>qproteas��c��� weena�(%Te�d�����&J Qa ��f�aCR� TBST�2�v����� �E�in bandM det? us �8e ECL Western Ba�D(�Ki�A�ham-�a LAS-4�| mini imag7@system ( FUJIFILMU,intensity of%� �as qu�lfi�d�MultiG�Hsoftw�(:W>�250�)-|ed salA EKF�An. a%AZI~��B�Na� �1 load!V �, ( Cosmo Bio5Wsame a� � �in�@��each la�ofV ~a�n la��' phorexra� 10mA�] hrե)�;asI!� subjIftoU[�� ana�ze�a p�|!��� Total RNAIpurI from" -" ]I:(an RNeasy MA�KE�Qi� M�re e-��cribe�use)!R&8Tra Ace qPCR RT N(TOYOBO Co ."� (. One-step ,! carrA�out �SYBR Gr��Maat( Mix ( Appl/BioiDs �Xa StepOnePlus Real-TimehSqnR>)�� er pairs�dE:!�ward ,� ��-GCGAATTCTCATCCAGTTTGGCTATGTA-3’e-=3 TCGA3CTGTCCT: 7 4����, 2q GTCTGCTGA;GCAGFk��TGGTAGT,c(spliced-XBP�a�fo6nC�AATGACC�AT bqCGC� TCAC! TGAT �wGAPDH . !�u asA��� rnalx � Dif ences bet��individu*ei� data%� d g u�La Welch’s t-test .2U� conside��ignific at p <�Yh05 .��Tombusviruses depen��a�a%i�m�� (host factor�$d retarget� u;pathw�to� $port viral&ic� {T this work , we demons p @tomato bushy stunJus��Vm a�$closely-re� da|��Don Italian ringspoBCIRBrecruit F�Vps34 Latidylinositol 3-kin�( PI3K )!�o?l! J�compart�m� C func�bof sis critiAa TBSV28, sugges�%%$PI ( 3 ) P �o �� is ut�by NW buil�X�rep5�6�We also& incr�d expre]�ay!�8higher abundanc�T�xh�esa @tQ�:-��� whi��ikely�sAhm� efficientHu�YuAccor� ly ,� 6���!�in ye� or�nts ied)Vr=BoA� e pe�som�4 i5E{J2(mitochondri24. More� ^�Z� redu�.?s�Mmbl�'-f1�p�Je a7of.\�*$a bioprobe�albe enrichE�6B-�.�6iis(is directlyq��mb^?{�saiT�p3325MJ��en�rle�"�5urrog)��unrave �at2YArequiresE�vesicle@ �F�� e abu), ^cannotY�9dRab5-p���,early endoso�,m) prov� PE-!�"� s�Q�!�gen� �.:�6�We founrat �a�]�nee{ �oa�stae&� ^��A egraE�he 26S��ome wmr�n�de��b�q�or�)j%�sum, :�v �)Q� � optie��environE��.�-Z.%fqM6��$ . Un�� mammal�I�4pl��$have only ���2��� )J�, nam�J)1{pro�@sRN-3-e�=�,�UѾyn g��hal lipid molecule [29 , 30]�"kq3� �!�to�il�%8|E�ofB invol�in�t sA1!G$recycling;$autophagic�e��BG/ �? dudA�rv �[31–33� �3h t��� mmenf$terest due�its rol$ human dis�zA suchg numeroue�m%*c�o�(heart� blem�xneurodea�r �i \s [34!�5�Thest-known ����i!, hepatitis C�� HCV p�v[36!8ZAL,�� GTPŕnd-!�.�KNS4B-inA�d5�y [37OMany DN0d3� K�infludd�ag�Y��  [3A�4E�Si�( + )2V(remodel sub"+ �D�faU��2� avoi] spon| [��A444]�t!ipossib�O�lsu� :�_}�could b�de-spr�among �esalth�9 is a�orm�����a key��yey�zal.�� \y� I�9ident� to8es2M&�plR a cruc qregula �ufu� %q���(accum>o%Lo help��r ��ofe�utMef� . E�i2��b� parasi?explo>y �!�5 lishA��� . For��  SopB��A�(Salmonella � um�smsX a-o!� vacu�,g �^� A~m&�X��nX[4�l Myco ',um tuberculo|, Phy�� torabPlasmo�9Ie�1N6AM�  al�W[45 , 46�IIn addi�,v�Nlevel�Y (artemisiningist�wa+malaria�[4��All!�se1�s& li�!��� ole���3!Z�i�be-� 6l* a�In ourvi�&pap�we sh�y:�:^ )>���r��. �� .� &��Ia��T5� � �QF^* � � small�Q,.wes� ���Fm�im� ana �> "�B E ) , butIq=��#&� !�r2� ! d�2���Trai:!]qu� on i2� �AA"-u6g.:���is-�-� �L hijack�p���b�[eM��p��.A��<:� ^ A�Altoget6��2b2^a+e5p��*� !Wbi>� rV� s .  J�one��6y �#l^�@a �_A�-c.��?[a@�m�kbA>&� �F�proces!�Tozdy)pu�veI�F��:�p%rstA}ij%i�� z i�v� }b0"�[3�48��9* af� sI�.-3.�launcE�:(aM��in la�VPS34 4 ( v Δ )N ;ng)33E�p92po6�*� !rrep��p��i��.C measR �2ɇby Nora-nV ��_ peri��"S�Me��lya ~6% _MuB� �yI�W�r}N � GWT-Y( Fig 1AS0anes 13–15 kus � �� ing�!3!_.d�"� ed pooin5��oz�Co: ! &�Z�by5�$ w�p)�a1�Fs*or�2-f�#)ofyu!��htha�n9R 18Œ&6A� pro-i�@�~2�dFdQ� �two inKv: *�( N736KE� D749�[4� 50a��� dea�Cduc�}�� , ly*�!+e�on�'WT� ��Kchrom �;�? �s>5��to� ticip))�]� lexe�seH�$axTo �i�cl6���q�M Nouz*6$&|,� r)�"�W�Ie�%\!+wC�~.�_5!9=B\�w6�ofK!��2�~30��">ipQ�B!�2+� confirmaJ� � 5�F/y�p . E2�2Ɋ-borneQ B�&��2� by ~3 . 5�Aarison��Di�m���w�-asBkQ�� p beddomin�ne.'v��j��5�2�>��m�A�Both p36e.p95b�] �2!BP5c Over� E�conclud�"f�e*(N��b�%�*�� q�6NEGr��U�� �0obE+ fu~ e^-m��� 9��u�~a.� Y*@( AS604850 ) [51]�b?&I� Ŋ5B�W���~8Is%v%�in �N�u��sj/�;� ��orS�)�2(. Simi� dP�8 , chem� LA�J p�m�sul4Wk:�^ FI:�studie"�:5p �*pQ��^.ofI&� �� "u$ucumber ne�.isazCNQwun2Nodamura)NoV��� sect5�alfanodaX)��%3d� �onI,p"���lI� ( S1� ak� p RNA12�>Rs�&�toN1� abK$p1�$subgenomic_� [� � wуUst�� nu 8ap!$�C ��T�f�ofb!iEwYvZ.�2y�MG132]�!% f*� v:�i*[52Yu�a 40%�<" j�� -tre�& DMSOwt-�4o��tzi 2B%�*� P� IA�$ �.�8 �!ON)�� �baa�A� in ~���\r %/5^�F� 7bec�>�a& )�5���c�nd *y isc �� !�< .��)1. T�����- "3�$mbl!To"`$Use ba� on&� r�b�.}�i>�� �7%�CFE.'!�� 1�� �5it���/�� 6� in �J�=�CEb�I>��}ds .��=8a�!�!xnewly-mr4&xpn4y�2in �pr`/V�S d�"%�":-y!�A 0 d�� �se%lex1��%ep�)�� �%as"&�to��-)�[�&m�"e"���"� W�8� �m$k f Wortman~�*���Z-�D1�s�"a�si�sH%��"��.(5!���A@ main !apZb"�u�:#!gact�'-�8uau ll1a��eca�*w4%�!��B�+.+�P��bovK91�assj-=CE�%D[5�Thu:th!P� 7ultt:��p"�"t�M�Z��bP is飁�A��a��co-op��m�L J�%�� Mre���2!) �kj�!*�kno�9dG3MionX-silen@in N . benthamianbp2l �,r  I�a � leI�<:�![54�K��q9N���6V%.ofa �( g3��~3J� f �22,AC�:lyM3A8 C"4–6}�f:+ngs( fi�S%�Y41��)~q9�2~.N delayqmymptoma;mI-�"� a� oung�y�n-ith)'or �i^3B߉�S;� "�A��/�p#)��*�$60%ie8"�*�;omo7�origi�,"� o�+u;9� ��9p922).�WTM� � [.Nw*:al�)�mA�!e8�� ed� mock"� Nicote.le%i. RT-u/r��~up- �>}!�6| R �Fns�(�� 22�"�1� i=N �%!Qi��j lear�3pr!m� ,��.�+�f�!�.C�|� co- �,ed RFP-taggen#p�G�!�.Q-��"l L �/&�8��<4�$��aov� �!co-A�liziQ�P^�!>%*$ ( 71±26%BD�jE poine>view , 4�Par^� FLAG2-yP( �/ nti- �2.-����&9<��!�er-resoRA"�=��4� C5�.� -RFP)� Pex13-GFP&v0,ark�1{:���,*d-5�ng)�  on ( �����,�mM^�pat76i34 �e$.)��!��didQ 9����&+� ��s d�2u @U?es!� � !5�4t %tf r.1~�V1y/C5 ggre&,d9��$55�X6P"s&KN�1EA9U4�!�a�u.��z cL"��e!�-/a�iz&�!vK[56�a!$�A��e}%�U&�-��B� ' .��B�F�--�,tZ1� ,Z�-� !7^(.�ť���irm�� ' able!0 taket cU��i��- �=:�Y-Bq��Arabidop(At%YE���SKL�>*�lu�r :��v>2 ��"$7%�� . Co>uBy��"?�-Nd�Xp3 �ao��5�)5BRG ��"��%��3�Q �.�)���\-�7�co�'r�1�1M� ���� *z$7>Q��Q��%T)g�� ( S2�^o�YP�E'�rF�v��0LF�W���j Z8� we3 per�%bi�-(ar fluorescr!o��G( BiF��.�J� M�  3_�Dao���icV�.�$)FAv p33/b�!�-�^A,�siP B.i�Z�>�%(&P=k%�>*JUsalu�!�:{ oxIV�W)�J5{5��o"c!6����teQ1].hqE.�0��agroinfi:Eed^S*6h Flag( q&6 inoc*c+�>kM%%>sap�\�. gN,n���ofy"� �>r�G-i u2p$, f12/ �n4"��co- i��Z�vi�*> � O?�NC7M�s)� t�%0=n-!UJ&�= e:&� )pV+��%Qe�/8>�of �!�a?bUsF]of �-��eex>�A��/_be�z@AJ�*�# over*m%��E�Fr�kapproachI N1-�of !���X %�-3xHA :�n.l!�&��v�in&t�D:�&� %�q! zC$b�y�E�v�WM�s�'�6hm�&�B .��jNJ�.U�Ac%6}+A��n=�pull-�.}ҕ�.�!� �.mA ��Jl+\ �-��6�͟he �4&J�!o�:$33!�!��F�& \�v��2�+��mw �6z$NO�N1=�js�X` 13lso��,�6,�Az*u��e� !4��MBPe�� GST-N�E . coli�doehA8�Neۭ7J'w� { =�:�` )-�8Vps21�a �m#A-��U�E�����J�+FtMN �W1� �Jly � ���S3�^ 2�.�#�Am�nb!O�L����W}?���M�)��l ��aQ=-a!��ma;/N �Z�s[:�0uti )� ��of2N�cC�opp��rib�(al�!66��Nd�4 :ohexi K- ��th�Ua [�22BM��B�J�s� YShCVKK"� "8at var�3�U-�sq�=H"�&�'"� !�u:M�sQK%W:!6F"t�-4�� T��U3=p�)my@l�:dy�lZ��1akToraril08��4rD��VU�x .2Z��i��R assu"j� ��^{&iq4�.*r!>�3� "t (��X-h"� is�*�^� F�2�b�3�U* (t2��eF� deco/S*BI.����7S4A�II�>S!P�"�=���&��y,���pan"�N.�T�}%��r� �?<)U�B&o�K�2xFYV��1!�T�bi|Mto.�a""W[3�S5"8F�+]� d�dom�2�A~��9āN=?��MVC(t.�!�U� ���i!��.�g-Y5(�#21z�e)"�ahjMW[ B#!�t]a�i"��!Ŷ��3�R��ls2 a�2�7�iY chan��?J��v6�2weMp ed 22-x4�%H<=U0)*5�:�-�� �!= I��*$hv�G!�RGp_�!�GStudy�!��distribh\W�^(�or.e~:J�%�M��Q�%�mQt�#���%-�DEl7E�$d S4B��O��*�sa@��A�i�VFxatB (:� ;.rJ6P*F%�6�.�:!�%fU�od'� u)�.�4%B=m �j y^CA�>^D�:A�ic Ymr1�:`KaJq converts.���[5% �/��of Y.��(���.*by �,�$50%�x�.,A>:,ɷ�#I�8�8�7F� =If&�G� �!�BuNw.Y>�6p)5M�Hsyn iz�$5~,&��9 ��2T-cwMq�!�2s$�0�&�/Δ-�F/�*�Hb�1�=N o by ~- e,& &Y&ysev ay�w��against.\ ���np�Wpex3Δ!:pex19�n rK b">.H=A �E.�!uER&[26 , 5�;l� o 50�%0% %4�4N> ( S5�D�=e>�7j�&�(.�El%�<W�N&�j-� ���vK !PX�2�H(1at!�0��O,�=se�?erc=uiis$w(��b� ad* avail��)-��1D"�4�deeg&a_� �7&.B5 by 40-to-!�eX9��a���!���{�/m�PX [4!�60]I�%�e.�.5T���F�xM��We�H!2d�7ic hindr�C&�/.�5�(I�&=�LMr* �l��H���&w! �ory6.��Z� 2P-�-^�A*O > olog�l���ala{Mtm� ��A�B�^P sA"~7a�80%1�R 8B'�m/"�evHc�a2��J�)J���#tit8 ���,�� �ed���*)6� pre-�[!\� CFE ��"�(b eVe�(ed �/�S!I!�*vco�0BjUzwC"�-MjF�5g"5* { 3�ŷ�ed�?��e�l6Bje���0�=�V!TFi&310!M=6FE)TY"�Z8G$J2��1�K1bK11�F�F��&_,���T"00M��-�&�!��00ZU� . De�R% MR%VI��~� ( S6� S6&n �8LA!�6?2 ymr1�A� JOm&A�wt�uC%��<�-nCat� a�no�� ��3��.*&I��=w>Oa- G Az15xbE p�,O�a�X'I&P�>�� "[. s [4� Whil4=15�!��at2Z9,A-�)*&t, Atg14uniqu�m ��&�N : �,tQ�P�$J=�8Un&� �1"�M�A�:�Ex [61�(On&�WwoM�6+e�+"�MRhŁ�.� �lin1-!:E;0 ( &ɺATG0o   insigh��;FC ��0]P�/"�F�� 2�UWingj�@� a�A1�e� u6�VPS15��qj*� Bw7 M1�9i�9&�>�B1>=Bi38�i -!�/VpE�Y@r<�n� as m�RF�<^��E�C�6* .DBeN�dra�"L ��X�\_5l+]'�BJ ��m.n)�,Eq �c\A�8I�.�M)12#-bDAib�&�.%� �5ڡLs:}0a�z�rzZ+�3��-!�I=�A30I'M5B���e(s ��e"wQtrj<ps "mM��b� . ���� .TAa|}�� �#&iI�-�a� �U me�is�38�WJ3�=35Howb �*�.�w"�VrgPYac�UATGp ATG8%�rU?lE/|j*XER�VignSW!�!�!� �ş%��~n.B��u�n�given��oQ�ig i>.T.Ja�al�y-ATGsQ ATG752��� maj�R�K ��.��wv. F�B"Q:�� ll b�=�Zt�4���1g�) ��=�b_2�f.� U�0z%�a�1V�� &�M�D"n&t}tpssZU�Rof]5?.6QF���%!�aO6�"%��V�a�=.��#�"�a"S[62 , 6Q:*�?`�7.� ��*!�th �%C"GO>�� :�!.caM��#Šr�wef��f x&�W2�K?%-!A'h�p"�.j� ZS �_�m=}N 21Δypt52 �0% %�f�c�%�6�O"z�"�:�:#C&aU����d��10p5r�T� w�E%�q�F�q%bEo�j�� �hB'%�o F3\*�!Ea�S rZ�R՜�݂m� �me��z)KQd�[$their docuA�edu.�F+ &��;)�p��v�B���1�B�S7�S.��<�(9� J)�a1n�OΖ�;�{vi[y�Ue�aAAM�C rol;Ѫ10:�4Z���u.pu�s!d^���-dr�>PE.���)� ��":j V�� �.� of o�0E0G4^��KE>24�&=E walhC HdC� �6�Z,.�A�"5E:�=�I>�!U:��f�<33�} �"�hidae fam "�>Dc,Z , "�Hleaf 6hLJh, turnip� nkle tjh�^gBBNd�ve�H$tic mosaic/ RCNM�H,� g!qqea(� up��85 100%OT.K%�=_m�� ���7A�q !�u�3��!�!^Q�(�0}broad�"tNz�mtas� �-2�. *� emer�otheY5i}mA- .��UaGp>T_�hvt"���jf cytoso�|�"��s"�3�?y���j"i��!!B& mto�5[.���ta robusUj�[�9[� S6�@f\�.$N� � yc�b.�Nbd �vs ��F�v%M8Z�s!���by g.,��Ga�%��4"!_"�>!c1,%�E�� -Rcs [) 6xO7DJI��*8"�\�Ci�d�� F�asw;#_xZs*o�(| tifyC*�`(!�v".dE�a`AM)f.�=�-� � ��� �}�n�0{.�k�- tB!�Z~ ��(e&�: 2��?�du�  I"�!� �Z��$>�m!^�>�w+�Xed litt�bZ� �*!&�I�O�we��Hown '�����@śs"0in�%f�lz6% �� mASt�:9uX� *n%lea�] "�n%A7 riguA�fe� �{�o�� theyB3n*�.�orgD)�jy�M�ir2 >�� �sCNCC�;)��!&i /ER(Hnsv@�nv@Q�>i-�.|9m)�p!)� 5-/r��6Rse&-"D j=1�%��he �b=!EI���"� ai�a�[F�Ud.��oA���Bf.2 #*�p��*U.wa�L"�K�/VRC�gs�/��&�/�!bn�~�rxb/!�+esia{�]$E %vv=� � � 6C6:$�X��]}R��b(S2*�%C.�/�f�Ot*,*�, /�of*-A:D ki�m��Ak&d".8��iD"��T%N!_�0E�p! ��2�:� x��B6n��U��7V��i9 p�0�0KYh>k�-1 hom!)% &84ZJ�A�1 *:F�)"��<TG���#xk0u2�5D;! &�!�N� �%haLE j0�Y*�u�7X �*���M��#E2@�0�ri}%" Q��Y61�A�>s[ e\X�$�q�nd"�Z"d��,Y7jŧ��2�|sop �[L�trengt��A�v�3] 22j�2�f�qZ>7 ��o?nl$�� &%� g*rj�9!QsZTto usurp��eJE\mab�  !D ��!h� y�P�#�,Ŏq�Bxa��e"n2�� v Q��2[auGNQasKi,�9%g.�.! �i��E�>e p% -A12[ �`����f�re"/�u�'�m"�_- Vix2&�6�Pv#-.�.y*�:�+P ed# w� ,3verla\7{'W$�w q�% V\+=7�Y�2�"K&3Y#Qs,���S+M�al nethzi{H� � !%��@�jOK"3 q�e�caaa6i���ieQk1a'-�3�,&)%EH!#b~"z o4�_�&��0!�"i �#2�"�$9T x �]*7$o&='v�;�*�x ��l&samgAe }.�a���T [WT H�!� vJT{IG7��=f "2��2SpverI�eH�A�he� ��% ���is��V=nal!)� %/� #�"2 )1A'bi0�o!�%z5N�.X5�"� .� r �F�g)�H�v.GB�2'pa[�x��BI"K2nyd"�|�_Q*"z !|e sr�q )}z6�6�>U, m�_@�,jU(��ml�tB�d/cN{q�)�. Ay�+Va�as�7�Z�b#bK(��Br.�_2�F ,=p ��2( �Ipor25,,)6VնB5 ". "R�x~"�-��&S B�.9ak`u�&!x!a�eukary��-K"ng �m5v�}Q�.7�!7~u� ɍ�ȁZ�2�I�uqL  r*0 }4x�HtyM�2.�a%q�a��M"�)�9n2�<��4e�����%�!K�V^-��:�!T_�)ׄ�3`� �B�$.�&�)�DrJ�j9Kg� �� &�rJW/_# !�Nn}A��G�/9=Qand/or�2�]V.�V� l�>!nNa�sec fX�0Als">�)!!��.&.Y"�-&l��I esN�!Ra4��^a�$xN �u6'EZ� urregsun�,.bii:�pͦ� �Dal62�k!�=�. Chaeri&� �m�� ́:TAA!N%�opens�new" �o �M��weX�:E"s��[ugsbI[1�*�d6҂:F�str�y _A�:PA�9�A?�+�!�.�eV�+ec�f*�e�rG#it�� Zg% I E AS�ro=!�t5A��o0|R ofJ�|"t ( �v�.)�!�� v|2��Y1Y&�Q��_n*�%HC�e7[3�M��<2�k�&Spicorn�f-�K_�nI�^+P!�t�{6�[70�E� (B tҚ�QA&oryn� E�q�"� ;&E �%�6� 6�|1�f��D� t"% .LNF#r=I�e�6"{ poli.0�hP�A� coxs�se%m B3� \�gi'TGN�� PI4K�c�R�21 -mn2 u [67 , 7N7%�The 3C2L���s�tlyY%y Q�>A�mEM&�[ wmB6;��"�2!�37ol.I�ȡ�:�&=yof Rhin-l� V [7�u79A}IZ�o�6y\WadvantagY� E� �Iu� *'w��Y�&�`lo�2�� �6vك&|VR*!��IS.. A&#�w�*F n,Imqby9{ � %� �ɮv#2�$6�!�6�Our^�}eJ�-�fd re-��/ of�+��sh�:E:beQful!DpL"�a"у! @ A�N^-m�oa�i=��- V9 . PaPal� �wBY474ΗLMATa his3Δ1 leu2Δ0ܝ15 ura3f/m"� Gs"� , 5, atg)5 8Δ ,%O 303 0� 15atg7Δr2Δ�&purch7[� Open. � . SCZ�$ trp1Δ289�Δ5�I� � :`*̜ae lis Bk�x!pGx�>sc,�,�1 T�&|8!�M�%�5Ror%eG �/oB1p� � 6 z2, - �s1�%u35W��-�%�%��7{(���Q�� )85.pESC-His�N /DI7�, pYES 92V,pRS315-cflage�B��Jnp�]2L 9�fBN_r=Q)�.�Iaps ��9�L* �)�&i�t�!m��+�ur� �w.h_d��( ULH- )l91*2%>�c�)at 29°C%9���L;��! .��w ���1�&�M�%yBBN�z�al� se�3� 24 h�%��� %u. YF8t"��AE ��EL�ln��0��2�{?.BX� UJtivA�[2�P��� �"v)(( Selleck C~rw Cat#S268H(or.j ,( Alfa Aesar5)$at#AAJ6398�t�ae�� heQHu �es� ��a�: �s"�)pq�C"pu�*[>� diss"�%�o ���R�XPn&�s�)&��fig� �d�*�3K9C9BAf2� �s��6b�Q����S.��.Bsc�.3�B!( pYes 92Y�, p.�$:.5.E�.!wV` d ���o��R�:R��HAF?��H��+ 30 ?� c��>���ɸ��A�t@ RNA366���5�$/Cupm/NoV/`/TRSVrz{3]�A��� ng 5*�M CuSO4ec� b�1P9E�a��g2}� F{M� } 48 h������|��^ r�Ydrug d.��s��� 2is~��"�F^X. Each� ��rep!tA�-�B�2��u�&*W oRV:�1��:�! e�ek`(pRS425-Cup1`6-hAc3^PXjm!�~*� �! �RV�lş.�6�CI�a2. 16 h������N�V���>���H�Z�'ij%�77 . Nb�gen���"EF��pedx��co ra�+i�( T6��"��U F!�( VIGg�{-�>x2[8�R8O@[�:� t6(b�MI e up� �:q,,e n�ub| � ��cb.I�n�Af`csv 9.PcoL O!�9�-��!� �F( dpi4��A�Q 6�a���|zm��V�'��wa�except-�TRV-cl . At�!��(>��.�c�� 6�a at 43 * ̩6Ri� ��3di5�1J:9�)wpi%�qA�`&`W[8�ro"�4E)6�)>oBus �"��%ly [8�0Ab 5 x 105|I5cP�.&W2 μg!����\full-lj&I0": �4, �4ns� Sr4_�A" A�" 6� >j (�F% A�x (! !�"�Q�) �21 :�!�1� hII�3)B mm petriA X� ark!�B��a��our�T~ q3�'"`W&7$��2��>� ��lYQ"��!�2�U=dio,e-lab4�*�142`fE(U� M^� �d$T7polymer�=� ���i4of [α-32P]UTP 7 PCR-amplie��-)�!7�������f���R�XE�D����F��2�`u� !�.� �V ���� zMz`A�21� OI�&BRc�M��,u��f�YBrief�=B�digesa�� Zymoװ 20T� !.6H::� siane^7��R)F monoclon�'o�z�Wa� I`r&=�(( Sigma-Ald~$�Bat#F7435�ESub �T sphe"=�e� �Bn �J��conju rto Alexa�ur 647� ��ATTO488%�!�. C+\P(he glass-bo�\di�&�2��Rltic., ( N-STORM S9� Re6k%�M֜�t, Nik��e f��PwC P ?Sl*g����,Be6h x"�lEAgr� �umףry\ &yGD-{lu GDG Eq"T�M�p(�3 OD60�  ��c� 2 :~*�U� V at 1�^�� 2�Iwnf2��h�iK�)�( FV3~�a�*_�,�,Olympu��F405 nm 3�K�r, Aw2N ao559*�v. Imag $_ap?d� �@�7<&Q (he FLUOVIEW&ҫ[11uT6�E.q6bU.�,6+��BF�5E�A%i:t*bD a����6�v������A<>�|�?� ���M& ����nuFV1200�:)�>�Db*��AVEOdI1�kqҮo�{ {='f v�zi�V�jYwhe�A hmu$�;&�Y�}�2�"_)kV->� �4-:Qy5�@�) )A.a  ��?��, tryp(�a��&VD �� �Q�Q��"o�^�^�^"Z�.�M�a�Z���[ "� orM^J� ha�M�&��s ;2�>�].[ I�6I�]�:L "�/U PI3P Z � Echel6�iosӪ/�Inc at#Z-P00�H�:eL�� �� uor 568�hermo F_ r S�t�fN A1103G �.�hu�o�-�wy!�fi�!�&^�+�CeH�?n�nRl*�bi�g��Tto�`�•�N"� AtV13�.%��2�:�Q��*|K" )�.W�uBu��h,�fln� �5� ��������icJ�-^| ��| ��o&�Dad-x�_!�� p33�RC1b�8�.vo8i�>| 5ey&�[1�� U�� cYFP� 6 , nYFP.MBP a(SKL�A&s{B��2wi� C58Cd��^ed:�utaJ4Zco->� Z|{ � l�ofOFr weeks-D�N^��.�{ B�R�e%�a��2�A.rW2:�"|[�T� _&)method����Np&$ext .:yT� �YoM7dengue� ( DENVrdqh�?|?mosquit�tre+[)&�,�$q)!w Sepidemi.@�,E�r�W2�O have���y�9ha<�&a�]� / adeq���� �"0yacquisNU9� h�.��c �sgk�-BfTd f��9�Undc blood fee;�"�>�o�|"�0eF�#e�6%�����or�R�#a field6=W�coh%� � in I%�? Peru[hur �im&",�,pwi0t��20'1 2015����!�whoi5��(nd older� 5afewer��a� M 5enr �r ongo���Zic-%(neighborhoo���^o�=E�� . Wild ty�l��3^˶aA;AeLaegypti � fed �3lyUfebri)�dI�s� �%�&0E/j?5E�!V� un �F�N�  �x85�^�A_�C_|ximatA�145C+�]�[c��a�A!�X. Asof 586�W@a�emi��a (衫3 × 102��w9 6 focus-�!�units�  mLhb�,m�inb���->4.��iN%7_:�8a�a�&�0��)�EX�Brect-%� }; h"�Z�I\6Xz �ɽ%�AHWIJI0a��a��v��Re0wv�0 � �$Af�3 �M3ed�@er F�$�w �t�&bze. Dis�n i ���at�ܓl6�� . No5`L 9�:�o��Fp:�:�2X%D9��Q illn�7[Q�9. ��*�7�3feasi:of � -~��12B�aY.q��vec�9��et/![AY QOis�fe@gerޢlog�+ cal �w� osecu��relia �. M�7\���4r��de��n�;pMi��&�;�1ubl�i7� ��201�;8S&se_~�ikunguny��d Zikn�e�a�expandE �*he"|+=+Le%q�Aassoc��� a wi�>�|e��43��tA�*5 recogn��,i!T�a�ir 6�impactQr C1B�now �re��fricaNdsi!]���ica�E�:E -sca�break��c=<in Eur��D���&q rem�ccY��al���Qa:���z괁;�geographAr] )1co-ci4��dm0ero�PR� y� �B! ",$ pop��/tqod�6r W�J����urban�[3.�!\�IRY%C3M�m|2f 5Un_'3T!6* y.9:0K;�eeg\ =n�mtoyf�S>n.- !  �� �f"� �L ,Egeexten��Ya�2 co� ity-)� 'Aq9��2�of���� z�E-B�1nV4pot*�^!��ڪMTKUpeoTt��pv��on��2�:f��chwfn�;�� �perceiv c�%��[�M*�cz,-EYE�!�1vus�"!%�o.�%��H�&>a��A�i� % limit!�rapj+x to5~%d -to-1B6%�e4n^�!���17P��!j.�H�b�$ory se�"sEG��6��i�-͠*�E�"�is�`� : ( ['��agg c6�a p s�$�i��C!�aatB7� ��--I�E�e [�2�!1�oC� Rt4<�o&�R�a5  [7];���7 brinT q %G�re� me��sHalK A)2,yU'��ao�  midg��n�7sulJ=a�)a3�7est� Ap�� ` inA^o�Yes��+�( i��2�Q�w� ofte %]G colon�.)�m=O*�~�myP�����YIinb2 �may%�"�o9v�- phen�/j8susa�s to)���:R%Is �K&��� cПvaɲA�sholde�5E�m M��<.�2a%� L*)4\}=~y ho߳ ����E�AAf�!Qe� begij�g=�9ɸ7hrH��a;!z8�*AY sdlNf�#��&�Y�c�"ic1 1` , Si�_ee@ . [1�!11]%�Sim�2].O �t�B�!)�2Y�Ed&7t�( J�B�c"��1odaPa��&�nI�!�, M� 4 . ��7- . Vi��f8�� %S"��( �A���E�yp�nld�d �\5 b�Mcot� &l'Bas-�. C�p6,�<9 I��P6�e�2 f �to"!�R�AAf�%._ o )!c2�% AR��<bi��ag%!�s���≥11 �of��(uEJ�[_ 1� La��  19�>Gub6�5]���- �ss�S���-) }�r }�t� !!Pa� e����~7ong�XW5ge�%��iQ��Y�&� en.s,�C�Ai�c, draw�cr,: ~�#ate�=achX���Q.�ia�Wm�]5��_e9 appa�=i�Q�ns; i . ADU�EEsough�eat�4Ia Q�Li���qgreD8���"m ����T� !�!��&� �Vs�q.�����Nguyen��6��uf��2�a�6�!�h0^ur a& !"qfma] k 9� :VietnaF4���n� �\ve�a�5!h7����cop!]q`+)AP%1��Q�Q�iB�`_%ܥ�:o "BJIgM tia�1daL z��>�tJ6U 2�inS7*w t5�6 , Ta.�7].� r 256p�.u?a�U&-amu1eIuxx*� ���,*�:�imbibA�^ �� lh��-�>��7!�-�)%a ���r�A*�tV@ �V thylenedi!���a� ci;y��� coa;tnt ) -2�# �deliv�j�M$&C <4�aV�<��6�a"� �5����Fe�Eh&��L2CEbs,�i (�p-"())�: ��.� hirdZ*@���ambod�w�] >��Z)���a n�zA�x �[1�v8*/!L�&�jn!c� �A'�}a �I!t�i�he��pli� 76M pre-  P%]cap� ng.Q)�����exposu�NeXQ�2�.v2a�>s�5le�2 3kIa#�NK2X,-�a�sIASy �c 6Z1�ten"=L &�seX�na�Z�TKer� ��d%.����param�� s—�@������6+m�8����, �Duv � a�<;)��c!���u[�C —�addՌt�M� xe�) �mx2s4ej� e&>�to�a�o��sBaAP-a@ QK���.Gi2T >����i3 ^�a?E�I72�(�!��&��P�d-�pri�&cy ) �2�r>� r7��us) �l�`��Q�&�(Loreto Regi$5HDxe� 1c!seAd #�%�2� B���yQ��evo��Yp"�!�^���i�I��a�0o>�-�����U�9!1L!�'��. 6�!�i�\:�!i6z�e����9 R!surveillEoaN�I�Z AmazonA�c-�:�"��, ��e��%�""!4{4�3inhabi�\bFre��?c�$�+De|�v�7pA�5?��s:3"p&��d ^- _2� �zK� else:� [1\~26P2 �5qq Sept��ra�2%fDec�w�;Asian-�}-2E�Apre"ͽ�/�!�.�[ �.M��O"���a"y���1��Z�YpB�r"!]�!&m�F,v�%�yz~%physicA� /&D&��g�A��v92�+��U*�(� �P"�ei�procedu��,�=&C �rS1 VideH��loFIdŖ. As so�s�'{ue *#^%�E@rb u�qo's*�Pila,��A<in�#Ts�����I�� "��I�pl�iM]m�1z$F� 2�-Aic/(�1%� x�!JNH P=f. Writ8R�oXf A%ll ad�5�!TA, /guardA>-ͅ��!F2@��ag�1�Childrend 8–17�&�w �@knt�or" %1 velo�c!ssF� �8iAX&�+in�u�PO��on$�I�!��!)!�URR�x�(E��\9f�� charI�  M�{2G5-| &�yI��!0dI@� n�n 'is"A inue��)�y @'"SA!�E�|I2�@!]d�bj*��AJt���IesBN��_��v�Mdas�d�1.^�B�YNov��36D��UJAR�%� on;���dq,F�N`� k2^�G�L - !]ll6������c��imon����a�!&!��x:f�� Q& !�eci�M + ntiln��N. Two:�2�E e�k�s��uo ���-up �A��!�idC2�*�]n:Y86�:-�� �D&h�(�}2w2�%1�Q2mw�wa� �(���.�k�1�K;!�25�:�f5�>�Lsw1e1 !�-��8� � )�=�\A��8@-\ 0%���!�SIto C2�_&H�l�A �� >�0ids���Ktw>>h����no��|�d�"��m �!P�%��� �< �2`DM0>�v�lDq�� Yoa6c& inctI��C \2�E�mU-�Ti is �f�4�#s �)��e <��� Z &�t nt =�E��y,�2�t6: `s >1� O9Gs�H40% 1!��F�E1A�%gU��2�1�!/pgh� 6*!R4%~.:2�A2Ź�?���")E!*\�� M��'6&� )�t����th� 2p��, �A"�%�>S"�as6C�hyb#"��os|!st�0,were 2–5 d�Says in duration . All hospitalized participants received close monitoring and fluid treatment . For the development of statistical models ( see below ) , we compared infected mosquitoes that fed on individuals with mild disease ( severity score = 1 ) vs . individuals with more severe illness ( i . e . , those with clear dengue symptoms , 6n�s of 2–4 ) . Whole blood , obtained!� Vacu(r tubes con�ying EDTA , was screened for DENV by two methods . In order to begin study procedures as soon as possible , acute-phase who�Lsample from febrile 2were tes!�us�Pan NS1 antigen rapid "( cassette ("PSD Bioline Dengue Duo%,!LDiagnostics ) accorde|to the manufacturer’s protocol!3hen%|!Aavailabl�53 or 586�!� If a�;a ositive%z.�,a= could� ceed�moI� fee�=�.e&a defin bd �iE=%�infece�@, however , serum�separa�%�w2ga�all/a2� by aAhven\ al rZ,se-transcrip hemi-n)�Lpolymerase chain rea �(6KDRT-PCR ) [36] prioE�(July 2012 ,�byBl-timeZnsre<p7] afterma{M ]�Aun2a�F)�m %�0eded directly!� �A.A�as de!Cbed abov�A$An F2 gene�q of Aaegypti �sm�experi�KalV: This.O�.Uthree�oges!8ild-type female6|adults.�Hthrough natural ovii�u0 buckets left�Å�al loc�OsA,out Iquitos A� rearith�in�5 insectarya��Vfed non-qus�>mea�7chicken )sMDartificial membran!kC2122e<a�l butchegwh���0Y0��s!I. Resul%�F1 eggsijhaFd�b e�800�%�A!|-� :AIM �byR` . No!kungunya��,Zika virus ta� miss!��reporYdurA��B� . Larvae �N�!�proviA�))�Q)a9itoM�A�% that \1P hin. �000%`4–11 d� post-eclo� each week(R.. A� �!drawna�$wo one-pin���ler2wup�25 lab- ���es(re placed o�kfo,ms!� calv)�� s ( baa� 2(ir choice )=X approximately 10 minutE(B: �E�!�[�immedi >E-�to��ecure�Q room!our6]�collecA6in eitauntre�sor �-B�!xintrodu!($into glass��!vYmai)�$d at 38°C� a circulaeewa�� bath%3expos�to.�� =��\inxA�Y5mv3–5Imold . Th���0��.Z�ce}!�virologyA8oratory����a�astorage�−80��W ubsequent� }. MH�$�% ed un� 5 r!� d en�n�?condius: re!E(ve humidity��70–80%�temper��e6�27–2%� . Un��=b�����! us-f��Eo��A�-@! pot� ally���edB^IåT�C r� a1]e gof%��U!Yan incubţ �bod*1!�1-�Fk harv atVen7t� F � odie�� headMY-��ҡ�!�Z� [34]M|di ofu�us%!X huma��A�est�5dWFFA�Iu�( Eaglew ,-Minimum essI��X, 0 . 1% penicillin [10P00 U/mL] / streptomyc2μg!, 1× `$amino acid� aE10% fe0 bovU )�)carboxy� thyl�ulA_)@mM�m at q�C9� fixe-#3 . 7%Ildehyd��e�.G( 2�b25����20��� washAm�  s)�p� hate-buffI�a.( PBS� )�a firs� u� of 3 ctF�with !�83% Triton X-100A�[2J�in'!v6:MW��7�i$monoclonal-� coY,x D3-2H2-9-23body (k d�1<-house , NAMRU-6!�(t 1:50 dilu���1×�1%60albumin ( BSA.9no��)|�MB�ۡP-c�se�h� ��conjug(# FITC ( go�Anti-m�IgG [�$molecule]-,%J , Sigma )a�06��!�1%�� �fi!w>�*R foci�. counau�Na�oresc�$microscopekconver-toB��orm��0units/mL ( FFa�%oSta"�analysA�@ carr�l( �(l41 ( engorge�� "surviva��� !dissemin��� AtofW. 14-dN .inclu�9858" *i �q" a�� �ofќ�`6�2Zy 2W(who had det �viremiaf _ da� x�&� {/orP) R least� =. N�+.>�enQ i� �%�ex-&"� sN� becaa� they�A^>�/ ɹ�%not.k~� �B�,i`n& V ~m� !f: QX� at.���1 .V���� 12�Wdi���)M� � � �)of%�of 49-23� pro� X ofBcAS beco. ( i . , �b-��ennd%v6^UQ1��gde�!k]�� q.z$ Nz%�(��<a���ar�$ $del ( GLMMa� i�A7 random ef�!"=Ga0 marg�-�� -�ge� , agŇS1�  r� ,E�� onseasym��*i illnW,!�&�=��( W , in -�d� v~w� �!��-l!�� covar�I %#0 "��git!Rk fun�NbinomAerror!� trib�p . Deu�plasm� ��~m�log10R�!K a�:i�Fulade7re���Z :dequat��(8by backward eli��of) signaD�q 0stepwise fasha/(. Dose-resp!� cu� I� deric � logi� regres� coefient�Al��E�per ��E� *� R vQ 02 [39] . A to� $of 197 peo�c��toM-�/m}�i� y &J�e�y�G, repre� �b�70%{��A|��& via�toyJ0te between Ma�� 8d June 2015 . O�Bj � �A�2�u�t��e�ɘ( T�4s vS1e 53 cl �iS5* !8�( 9!|4%] nd also���a�ɣ ( 51��!'u�734�A�1ionMWw} ��4Asian/American�-"o� . On!�a�( 8 . 6�.�ch� �-n ,� �}� 2��&�I�(!�f5wI�Sixty-fE perc% +N�Q� � rangg ��10�73 year�,� 196l2Kag�18 1 ( 32� �Mo���e}.a on��2 (EofA�, 31 . 0!\�� ay 3s�� ( 2258,7 . 9,. E��U 19A2%e�I4!day 4%}4 ( 6I �e!�on2D��0}� :1�s��!�.*( U��a 0 atic� A�| y>h. Clin��'^ 9�2Qto�Ror�war@ig at l��m P�irt�@2Ir{�ve�Nsco�1;�s� e miamb3�A��a ��ly sh��1d tha�[r"2�.��=2 , 174-�12�" �[! 3 +A9ed�����v 2v��s6R( . 3 × 102!�a9 6� . VU -'�?de��by@inA�.� ; ye�ic�142"��� � I%�"� ��� 2e�Ofa�.s� ��� 6Ybut di#t havj!�tit, eJ( 4�ߩ�6K@ �saY��( 5��Vs2�s!��H"isx[ m��E2���2�,subjec�h���sixa��N�. IM ��a� ��� ( 67���� � Apus �> t*q �  Of V�� ����4��ev�j)�N���-� �sˍs2� H%� ( 43�. OurP�de�1��a%�e�8��x&�N !b�#nduBonp arge sc<2"��rec9�i��@we ori� l sidN- Ni*R�a�feasiU�s)�A �� �,�) tudy�(Nguyen et a@ [16]a1h�"&�o�!4��2eR2�pat3 )�a yby#ngn8Nn�\!B� � show� ��s�~���A��" , demonst�" highh#eptabil� p2� Dby�volB�uarV)F,t�53F�:� k<o��h"ed:�,�g .!�e� �� itch�,a�t5�biITa.�75`omt& ��w� "E �o~&4 ini��%e�sus��/"�$ca� , eno���/&6F!aski� stop>�du| discomfor3FocusKu/scu� ��"�!([5] reinfor�heA7���=s areUle%doftena4fers !kvenip@ureA)�]i~. Overal��y ,]�?"� a�U��- �%�>��8� field-�`� on vector etence!�xtrinsic�:, novel;�l� ategX�pAx aE #!inter�IPJ�![40;Althouz#o singl�#��$ =#E܉�)"�ll,tex�ɿi �!y� �anZ stan�%�,�*(in certaoT-qi�!�Mperhap�'.la -�?on}@��7. W�;!XA�:�!k1�sh�k��'�Tpo�(A6Mac��)�kA�1:�H)ne� �Q��b�&capa6K+’�{us4&t�`�-i��13�.h�Azla�A�e�4e!�, Lly!p)f��C �4&3ly ditnt��AY��"3Rn%���.q�] u-<s�2� �)��1�� poor��r� �J���t!ala�onsisa�a��d�)=h� -C)9of�in�F2� c�m� strongly)pv=N8^+JM?� 6�lower9��)h#�� A2��� fA�ng� ntrast+ t of^Cobser3��5A�( R2 =x 89 )",midgu�B�UG!A�E�EM<"]�/.�2�weake��IF��)�! Asi�) �%�1y! is may� inEc�9� of�&�v a�A�Xora�!� 852XSingapARL Perud �w !asuS�#I�s�@a.)ju.�!����%��Be+."�ibyF ��cAjce�.�!�u�� an�����1v�v� milar-�of�B� . Fur� ep, *� -�i� 6IQ��^�,�H�RU�ey:( �� 6M ,�&e�tm�im(�predi�2�A�&� !�. � ѣa�c �}�n���t^*%\"5byE�<A�b oret�c�%�ur0isk5 x 101j�y����=P��st S���X2�H . Twenty-�$�K������^c g�* �A�]�or&�x��pl�Zor5�!/i�d%�� Y!Msa\venat Hm�bQ %�r�%!�of:4illary/veinual 7q�. B*G*a�um�/%�a� imbiU2�2 μl2a Y�.oumgis-�21�� a 2-G �eal�/& ��"�E �6�1is+c��y�-:U�a��(>�)�(calw!,b2�(J�:N�a�aW�C�s supa�A hyp5�%b fres�Qe�!2�((1 � ca-�-/)9���relev��&�'5�t�28i.�= A��]a�!# �IU���q%fuV replE��x/s��-!�(!�A e "�)EeW!+{.9 h�(J1��I'8� �7!�of 0�ar�/ �I��*I�4!�emxof* �, bioU*���cyV hich:���z�p*D sa#p&� isM : � 4�o�i�-�re��W .!!!1��5�( a3�� )!����"���at)�-J�]Bon +f&Us?,)�e!6v!�k.n�5dq�-it��box�**@nt hom7�nhaJ��Es!���*�5.�B 7&�L)�KI�� �now��� "9 �s� goa��be.y�[Q� teay/3si�#"�_�routinelL$nd�F�a�p/� Diw/!92erET clea��v0ri\3a2)$requir�,�!�(a7afetyC&n2� � Au er"a��!�� s�{:le%��2M� $]63a@an���"�"�2n *4!�er6�YH e�1� llow�ҥ��t� :��1�or�&�"procedv9� ��y#ur��_# incr�'al< �&-� � s�IRB��u#�2mm�(�aGwork tog��c(xamine issu�=�R%M�$AP$new public�lthY��V�0} �u"-v"(.ew� impl �%�,� expan���-(s�cr (f2�AO(,#�E�.#um�w18�51<)di� prof�:( wC�!�)|�t��l�5 �rum1��$m!� numbmjlo&�d ��o mT�"2�A���s?ersNnd<:�f��,�a�ta)�� c�"��crecogn�=[add�#R�t� A�wh!H3" establish�a%t/eG� re"Q8 <ss�p! -to-� us�cI. A��v!Bactorl9��A�w�*$�� &���ndM�" 7i� �4us��2 D@�� lik���60ccur [18 , 41�T? �influ�!�dynamic&} 2^� u!S shap� n=epidemiaY��In fuV�Oake=aim�r� &G3�"�6rli�v���,:[%on6NU�D s���courseKth._br�_ �8gr�of �-n�'aU() \ t#�poisos>II<�m)H organism Caenorhab(*s elega�We&�wB�zin%4C, +v�0M ir>�te� �$ wea�bi�gen,�M�&e.^��! ^7altiIZ�xpl�6�M;t�)ine� glut��itu�6�>$( TOP-R"�*�ce�a*poV�ioa�E? resi^�� hydrophobteu"b�( l�+ its %�]opo�!-DYE ~��"]z� 1(�M ilizAl}���> cr�d!om� 7ty!1�EX"�.����9)a--)�%6y�n�e�y�#to��m9�%yA�fewu�ces5CY��!;2�iso�Cs (.�(in hTOPIIα%~9P��� We g�<�Y) �ARD6������(s cytotoxic!z�+>�I' ��6 �.�?�:�m why6� �� :I.�� ��!N-�6� e ut� of2 ia��<&eA_aޅ8� �3-s�,n� o .��regIs�#l�Q� c �'Aassoci& 5�� �D�} e eMeE�!,Ide���Vz� be tailo� a{�H#(�b!ar%1�� mark� knowE=�:�2 dmaximi��� �ive��,� ' unwa�-:�Adv�E, � echn �r#a=2h p�decade!Lmi� '#!verB4m����+�%r�/�i�he� �#o�.v$�pr� s�'�n e id:f�.AqV�Ba� risk [1�"i)�R�h(b<*mA|�L���� E?&zra���u)������foun�&� ac)�#7�+!b 500 FDA-X 6�F�1�.sA�E�i<m��Pacy ( www . fda . gov��U�"tun�@K AT\ p�(=%�5Km=in&����E�AS�d pop�[2]E�� key���=1�wome-wid�� � ( GW�-A�%�at  �1k=���w�$�h%,out�4�-maj�� ��T�5U5xis � sa�!it�ziJ!!�-Lyi����&�A��5�:�9aiis �%;tQ6<�G%��20'2�@[T,4)�tumor h$o!����. A" �q ,� U�- �J�5a4Nal%�1?o@!�� �Y�)� qlZ 9�[6&N{%WE[s empha%�!�n� Y�$ezach X5��EUr��a~^�8uE�E {6o� ��gD�ac�`���B� bat%u� /s��.�\re4Y �Sacchar%?meLsia@(d Drosophil� lanogas�8��to�%7 physZ�ɪE�sma�5l�<)yrepurpoA�"�MA}�@� #��y*bF[IC�4e�� E!Je �&emi�m.Vr�8bin�x f5k� ��pge ac E�MA�of:�[�@1�F2gAs���\-"U`��!Lgn�R)��o7ōvalidE,in �[1>O1CBya�� , D . m.�6v�=Ty6�2|����3tA��t2 type"/����ofrB�ru.N ha e�$img6[U,roundworb�A%D tE�both S .�ev}:>J��Iv�>� ���n b Z� �aa�tazoauR� at��Cm� .�� "���� connngŒerg al%�=�A�E�� U�y$%0E�es [15�2��&�take 5S!��a�XEY.�.!�9�s��ly�sus�(i�ty8a pane��ml=Ol:bge� s����>� enzy~��inhib7H-"xR>> f2uJaccum �aouble-��break�_��b&�[1�(1I�>r���t2�:��menaV/�hli�,���*� ��!0ir e&6ct)<mlieve�����E ss a 2�!�rS�f�[20��U%�u>?mapi��U&�diverg j�~Z� er !;�#�1zf�96�%�&�)�B�%we ��%,CRISPR/Cas9-�G��-�e�ngI�e�%:ze�f�7"�F ( Q797�>\la���!� henN:i* O��!�9A�iA2�W� ����pu� �5rug-b ng poc?Qa�i%woF�"d( M762�.� Q778�P��� struUa�.� "4� ���&@i.(��X��N���J� [21�52A�H"�T"*�.�� sugg�=��QQ+i�*����no.�rgW�6�X�[23�Wa��=ņch?���S�jU]��vYo �wQW� YXA2� F�eB�F}A�2\i-aed���2toiV-+.�5���!�Z��-�%.�amA7t>���0 u.�$q,fq�*[fS.m-�=Q� :�a�%� a�Q&:-$� deci?s�`�<�q /� . W�s"�d=�.�in2���a� -e put fit�X+� b M�im\!y)�Lin liq:[K� iW3s4of��d�D length� p��!offspr�^nQ��mm,�8COPAS BIOSORT (+@FigFI)<�,AdrJ b�Jz�7���v *O ela�To� ���p�e �'2�� ��{we�Y �/2�B.�#�$_-�M �#d�E\N%-]�: N?Bristol�8CB4856 ( HawaiiJU258-{ DL23�@�2�&250 μM=��f' 2��6i�S���*con�`$U��8"K/��-��A/�%S ins FB�%it��6��"�35 B (!)��a.4�-(11) 7N=�,��k���MaME,�-h`!�& ( S2U�W�u)�O��yAD� i1�y � �sE��2��2A�ed6(!$?}2�.��u ���2w( a�6 ge 6A1m (V,31o;et�!q� J� �UE�$a�m  ly2�9+.a�map6q!�����s ey�7w.~a`!�f��"&� 2652�inbK@ Ver\��( RIAILsewa�\Q�a5��+v�DQX1430M�-z[� W*1-�6�a� each y1fRoAOw�6rr W<��� )U� 0i��xA%�((r ( DMSO ) ��!�INu��9�p��uGj,�W>P� %fer!mto�6�}Qqu# � 8 locucQT�N�  .� S- �7!Yz* Ayn chromo�� at 1�/83 Mb}2 ig 1� p�ed 27�G! >� ^am0=.!R�O conf��2ter=Osp$ ��67!4 91�F�ndJ�. s 90E� 68a���;/R cQ��pa�� 4�We�!sou�TtoL�is�I)homozyg� reci0$al near-is�ic �( NqM6�e�8�^f�F!:��"o�I�XQ*H�.��"h6-cL6'VK:p. �w�h��� ]� x)Z��� d.�� t� W�^h6� ( S3ՒSs-� %a��6Wex^�e� }32�a�6� z fir � gx"Yqg(� �rj2ar�(6�A�r�� � 9"s6�� Yi�b� �/� a�+aw5cunnatQ aGO �FuC��pQ!@2Oi=�*%*�,F"*�Yw$* *^lK9.6���o�gtifqH &3-9��&<o%�a�r ��21 ]0in 138F�is� AD��MZ�� �� o�a��'#f>E�a peakl6-��8�C(e<1B\ �b�w� �ic � y�#6%�>�7/K1�G15]�r��Uf no e�L���e�^^ ( S4�)��4geographic clu+A8y �� alle-fS5 ;E�1�� ��overl�>%!8A1[!m -linkag�f�dB)d"N5�5�iY -ji an�� , 46��alter (�%qE)Eu�!�*��%%1B�-�C%˭ a � ���"!MRF�� 46 �s)�aY�44� �r!3�:��!ɂ�L��Mp/e%���"v *�&��y�sh�%.�>y����45�-.��z���V9w ,�9��Ij$Ad�IxSd�2A�-D!,�[ �>�.Q�,5 7g.� ��YI.�[ne-���AF%C5Of��(heR<-ca s4553�^�+g1�cc2 �$oN ��uJ.� data&�.wFi%�me �%S1se�4]%al�8E/e p-valuS�6man's r+H< {aaW.3SQP6� !�� aK$le-nucleot+"-O��NV�55 N� m�Di�NV��#t=��? npp-6! top-�M� ZK93&]I6D=w� Y��( -U�\ ) =�Pg9�#|A xGdQ�'Bb�is lo ��J%"?��>�d [8it�0 qpB0�F��� txsŋ9[VHE�"]�T�m%�EP:� �'!�. "% p i.-BU*$ �k: s�V! [WP"9%=�8�|H��*l2� is do}Vntj�|/of F1�#��I� a`q![��A�H.] E�")5Y.! ( S6��A"v � w"�nI�\)ldel6��*L�!�!�nW�.Uv3��E�eNlos�e@�т� ( S7�To�& nl�Qw!% ausa�G�, iYK2�B�av. FGaE2� !v p( ok1�)>;2Q )�anN;�\e1\/ * ( Δ _)2&)_!L�: �)�A� Q��&y%&V%)G y/1�b�,` ] �B; � �Q�~�c� �2A , S8 ��'@ �>�j�A� �~Q .< �YE���q:2k��� y5�S����ee+!�i6E=%1=�0 !�2�P < �>0-%)< Jr":Aa���6aW�ߞ�[25�+ ��1GHt �=lf3sTRkZ:? I8�^R.V i)�6��co %t�Wif.� ��!�eP31 &p *��*�*��F� �Dnarro�E �:!�16 �A!� �)�&� �Cob� �7� 33' UTR< �R ���aTsynonym$KE{�o�?�H��R�)E&W�ZT�OdA�r.G1Qg& ,3eX#<�6K, rrb eto� de2�-.� �:!<, I1206L , Q1217�z!-D1387N�j�&-�.e alig9l!� �pepz sQ)s(J�',(e�3n�M!veanr�!� �%g�@C-�9fm$�l2o.:(�9"A�%s" [6,�JDNA" �?vag�j[2&S&J!� �d orth� "" Ik�);���W5�wit)#""5�-�  ";!�d�1E " !�4W�.!/"B65"O")4a*�!?#78 *&�+!:C �J] ��!\�8����( S80+ αA81��"�&�C.�"�"�*$")�Q mi�a&�5w^X�--�WM#b�K �#Ia�i�rwIIq�"} . Cru�t� 1e�0 �U��&leA�-TO!�Y��lex%L�Ag�!!�!�7]��"�A[es�>;b*.GQg ��A`G�m*1���6 !e' c�%1o6A!"&2M{ � �'&�t�]>�Wez'�s�U!wi5i'fA�$|95]V� C��:Bq�&"�0h�aU-(acU; <:�!�*e ;�-��ai��B�|;! � E:n>02�Convers� ivRC-F�!*s�L2�"� V�:O2�6�$�1���Qt)�!(l:d.�"�v�j|unta��x_q�z5b�| v�"��*�1l�lcR^! �5EPF��,y^;*�.�p`- 2�-+ glyc*ic bon�*�(A\ E�&B���1u!G�-�cedx�6��E+on9�YE.��Ee�cUr .t&�K�>sio,2�% dock�"��{�:v���>t�u�B � yBadY�.K3 8*��a��)e� MSD!L . 564Å , PDB:3QX3;�Up2]=�i�bu=2g!7ΔG�q R��O-1�$09 kcal/mo�K ���m|3���-|67N0M790�=��:@YkQs� favorablyI �ZY �F�Q� s.l'"��>D�f-M��A�,:!�&��M�neg6.!`,T � q�B) TOP2B�x��9�-n; ��eaQ5er4A�ZF/e/HA�% e [2�u:��ct2����p 2\ =*k*t?>�/�u$ic damage �7e�y�~9��y�Z�� ��n �**�O"yl! �a�i�b�/o i5�:� �%�*vel CA�-�Y*�%�Avi9�jNFe. Bc0;�r)����5eh,*"�6�/ �O 96�**���"� Pa��|d�i2w�`;$)� �]� "��Q:�.W+�E�D1��� Like�, t'^�{(d�n�7i�!|amsacr�EQ��fcycxJ`M�ID��f�Dw� re-l�Da�E�t>�cataly�g3 �J&X���H"�.!s>rsBsF��ach-Q) �B)O���!s�;�)� 6� �>�e!�F�Lam^J�5�Q c*�A9��Y%�E/�a~ eny�E��ylZvD�Dc-"�#�J�L%a�>1Q�(�)0"v#!�).�D>|$ �8�v� ^� �Gi�o�a�w�&�D)OhemA�� el�B�:�"� N�%�B�e�2���H\eiN�&% n !�inFp�c.�C"�*mKqj� �)I.(�9! 6����m @R� ��!�-p[)��*� ea maN���-�e� c�Spe�:.I� ��A��s� ]�h�� "� �vR�Q�L� � �yg�%*@��1=�.�.`!6^w .p}�b~�'=1cAB[nR2�J�:�!�r�>]�b�r^J�b�Va�b�>`22bIn�IM\�{I!N��~6E*5?-& swap1�Ik �*_Z%)Vme+( Tukey�M�HS7 ��r%82�%��2MF��njbZe�o�/� 2�(s�"a�t.��>&1#�_�L�>� . Un�^��:� qct*��R�&�d*� �1qu�{�B��4��>g.� ,�dat���|atM�AM� 9 will�2no impac�z�6f"jV�Q�!�u`i��l*�1��XV:N�)no�R�]���"� ��B ��7FH-��Uta�)dW�N��� ,8 ( S9.�stjL.� "t �9!<��� i�v`"\!Ae��.� "v@ a6a/iB� � *~4�I���5 �G e8 ( XK46�c%���ZK?*��^�[2�=Surpri�$�j�2���Q�� �J3��Q�I��^,*S&nma.���m: A$10]%i�A$n C+%Ձ�n.�m�8�]m cA� �._:�8��:sAsA� �bIC�V�d�W%�:9 b<vol� ��$� ahEbU��$qgc�F*� ikS�z YF�r#=�li.�Q1A�E�>2i�e"P>!@a_Mled��S"�(J�Fe �embryoP1$kidney 293|$3 293Th}encodeu%�"n = a�-�q!P>oh e� )Y��!<c=(��lA¡��A+T* PJ>%�qsBE3E*!�n�R2�"�CD�F2�. H�;%���&4�% �e-��'v 7or��&�. EA�A��T�a L.vC>M%Yu��yp�-g��o*�[ 160-f^�enrichm�c`�O�x!�"� %7> �Q�Q:_S9�� W�)QnoE��.5V:d h.U =%����-A��d9k9V% :`�A�6"�B���t#� ra�xIau�2uXak��t u� l�atrRHp"�j� iiploid/�� �cx& �&��Be.�1 !J�y�le� C),�di}�le/�D�+�.s >��� "�c ��$d� ��=� y��Gl6l�D21��!k,rm �*MrE**�)wAA two-�J�uq�a5 [30]!{j e�Z �% must��b� by ��b@+�%a�Feӏ:� w.�:�*4+!��S!h"}����1c�I;e�8�e�*estW.h�r*Hm�kl:�o=�eGD�C���c�j a deA���Juqq�I���9�y�.=R�:�!!:!&-]� �@A^�1"N s,&?�"bPvct�f ����18f�ben p0$Tk D&ytwU1.�B>�zs*v 2E"� �>a  �Cs%����iN&ur .��.3�1�(6 si!�:S���b9!�e)#�e1M� a�ir#&� Wb)oŁh����3=� �ktD�T�*�  *0N�*�@ArpY�A�zBCgMA�S��{*�!�� FgA �Lve��2-2�68���!? ��U�yim�!����*=[1.�����Qm�$��i�� zaV�T�}W2!0F�d�jWe n��ode3�n"�#aId�N��.�D!B�%i/&*( ~96:i�72�( ~�93 *z;@@t�Css.hnͶa�ro�/�4�6< &�o!DYm�IqYd�ba<6�/f��%�.�L2���b{��a3 �3�BS �-�"X i'IC!�:/-� bHUm-o�?ab��}dl�! �W�He�6i�و/Rs�"�T�kw &e�a��V.ldFH"���id-6h� 2h 1��' M6����a|�.��V!��9�r.�% sawa�,Kj�u yu2���!Oq�!�A�I4in�B�e%i�Z6-�.t�p-��2vhav!{"�!�25�v3{B[3GTTa��"�h,��"ov��ga�s�e�LoJ8^re_otaP��<��3. . Few�e��9oR{!�0�;�ar(.a []��f�Z' U���qn rk�<as�.p;QEN%�/ 6� ��!�Ue��5 [35]I�fai�Y�n�y"��!}ig���?o b�QfU�-�d ����2�>!'!� �&+ 2� !�w&�`%.�"�*gF[�F�j>��!�� -r�q�P����5U��. N�the� �� i&�/hB�ftevwoV)Mt>X#"!/���#�� Un"~P%�&9&I�}` �� �-J�FVaogx!~��B�Poa ��EB ��V�Q2668 oGcus& J�TI4mpV�T.�1�AL&��">ZpYZ��&�T,U�i��� � arguo1sqOisE� 9edL31V�,�[�&un(o�"&~eW� �6� ��'t>�n��51Oor#1Y�|!6��� �)Zq;n%OfuI9?���2�OeE"*X a� ��3}caHg&�Y� �9I��YngT�[%3&0 ra`"0Fs_ ?  v '��{bZ(�3m��7*EY �� ��V&cNi[��.:�':�m "k B� ,epipodophyll�in��&�Y��K&�!)�"YK*���U �f�U*+!Us"�m48ao9� -depC�n�Mq23sNns�JEu[38%� AC *�%%��Pz�9�2�G�"5b�(!|hra *i�`&j�doxorubi�*%"unr7tK�cardi%���heart)l9!� u[4a4a.�-optJSb�"�S"e%mE�c�K M��B4a�mTu�*6�6R]duc:�. Wi*is���KB"9 { * Y��Jog��u4�t"�c���bd�et\=e*zJp (G[4547 �y6/E�)j ��^a��VtV�v8 �jmI�5Zii-d�ad!a�JpI�� ѷ��i�����,eriB�H`( ���*�i.� !���%z�*� �%d.�{��!Tg β&�%��Z"T" O�"��>,.�Yrega~ng�p ��"�]a� �& Mrdri��N�^ur#lym7��\& ��p �Ԅ�> U��q�\f�!�<AJ�y &�!�/%)�2- e3%W17a0J�^)�V� .�L29s�279!  SNoHh���p�I� �wense m"� ( S10�S15�s�T}& ExAC�b��� ��S%���qDNA5d�=��J��BS11�#� 2�/6�_Bk exݪ� �*� s �'2b�e��o, s2�^��t �bdA �8D�v�ngMi�APfo�|�2vi!��9#"0�Ck}�`�*od8�y�.��_��> 5}avoids� -� 3��. I� e&�� �9�� �xL� �)6��%E�&tJ�s�ginsteadH3�c2C�� �� ,! abol�ZM�b��Pharmac�U�(Y6a�&p: as [46�O’�l*���i��am$�be:%�io K%�� 9�)c$ig�KqA� a��}roteins�5" )Ws��P� �V�k(8bDwU�fo"�Mc��d���� s neA�)��� lack�p!,g2�AoAot guar�r��sucT�}�+mIt*Mz>�_3� a�},&�e>Oe� 6>m)�d ��.�WIoJ%F"�� l|3eaa*CͳPaYof" A2ei&s6��t~ �%�`d�&2°E{!�bac�"�X OP50� �޵ emat@'w[theVu!]NG��9��1% aga���7 N4E��# bu�F0�h � o`d a�{sa�* �N�n��t&gU;%!athb 5 e�-mst?�%7d5ݕdauer�@"3Qa��9��2� "�Pu���B+r��d"ATNly [2��4�+ReIXEn��]~a*�T%*x?Efg:y~]S�Z.&�e���pt�l� �� Sup�l I�s�c�2 o��~fn"�v)���de�v MA�69)_���bk�?��;dF�#(&cMIhigj�^ ( HT'=V�)In� r��!�3(�Z�s� .r&^ .�al"��6�@ �ja�5�r;)bla -synZn��a�do!�to"���t���p t��xA~&7+�X 2l2 in Kq�[5kEm`+s���)��� he L1�n�]�n�&�de�?L� ���R�HB����lys�L8( Pennsylvania �� e Un[k%QS�UFermen� on Ffq�6 0Co��P!�!��O*�cj� mg/m�L�f�4!�get�q�*at�P �JL4) e�%�sor!�aa� rge-�����cytom ( 6�e,�on Bi!�� , Hola�oX/M�\+F�2a)c-Yat�S �,9�,oL.R�4e kana�u e�^�R�"�.1% DMSO�V !�9�% )UuD>DD�him~*�)as�xh2e�& . PN Hcm~gAGA "h para%��+*�!���sod�&azL�� m�.*?�wgh\|F<��!mI(�o�#�S.��z%�a@ �� �2h�Z e br��s!()M\(���or TOF�'PFe� ��˸�2l�n0 dM��R pacř easye r"� c�2nL��g P�œgZ�at� t [5�B�iv r� �d_,�<��aw"� � , ru�E"@4��.!�:ɫe bubbl��NA^��4move_atU���=�<y w&S.%C6���)!]z.����h�y;^�� Jss� E(vis��in!�i���� �a��/�.�v summ��"R��!�U�:���QZ&a�ll |s �BSQ�X 10th�n55 7 A�9!�!A�L �d} se;n&���*Fe*�Ci(�=�i*ܢE� � !���J��a�*�ZQ8�c�� = TRUEKu�� .Iq\r� to���ein&�fw !A�Gula�Yu�~ay+3'Do"QIn&`�L ����M�outli���U�. bamf_prun]WAo���9s 'v�[-[�ze*���qiu�IQR pl�heIQ��F,��Ze EL- �"�5"�,��n�Se�y�����W�!&2"�re.��D3h=� FALS2�< JAf�qa ���b�&Y)A72KK:��&_4}��1��9-�B*D EFlp ��/�&jcr,n1�(��n, Haw n,�d�d�d� tech�quadru���b }�eGWA�N>Q e"��!�S4��)A�&e 2u �1uic��� ��Fx b b�). D�72�n�&��� o�Á%onev�I�—��n!N�% broa�7niLHC-Weތ�1�a��2���d�:>*��c"x��H2%# �,B^�ess� �a"�_ynlme&�CA��lme%���/lm(5�e ~1 +R�|I� )E C.*p)���B�'u!�in"s.] are;&g—�p,*�.—125� ,&�, —5�nMd�*+.-nd����� i�b����s)�purchEU��S��( _�G#X362�q&6cat#E138�`a"H>A9809:� 14�~�*4SML060=9L"���n�n ����%�a�R᪑�q�"��ž&�'e .� x |ey to R&�i)��Ka�f zero"a�R����"� (�fTe�73QR3n�]oA) ����m"��log�7h�jodX�LO\B u_orI��+�E�� ' �}=l(1−r2 ) /2 0e$�A:r�a{P �o�ir5� =.<6��%�5`s�?�5� �A[1% amum��%V�_�n� ء�r��E��c6� � 1�D�#6=��T�ly��mu� �� �� ���mt�!�/�dn� AeMs e�# o�*_Dce empiSll�/!"��x � e�}G��"!Q?I�AY��a 9����eT A[4/�2b�:f�fPA)�m�=|��M� �)O %�f�&2 ixed-��of1eT.S� %�%�aV� d)�f�5{!>�� variF�%�a�� �VbY�*!m���u�\%&��o >Vqs �bed1W.���� i�!�5%� drop)M�FR . Ge�B3�m#% &��1{�SV�52 . !is�as��.� Weɦ�ceg!f&|a�as&A8�[}�L u�FEMMA algsh� �a�NO�e��Fgv*9 y�[532\j��;med�� GWAS*�ɵrrBLUP�[5u$JPK�>!"ve(��&�command: t::S = p�a� = kK = ki���. MAFF�0�hp�G= 1 , P3IU� , plot = ��aLkinshipRLrix!�d%QNx�g"y a6jqua,�Sv�i"?j!�!A .�9��Pr6�.Q!p&n=KI�RAD�B [5�.sG.t=�r>�xP am�g� A�]� M��AF�}nm��tSNVg�ɡ:�don�v oni-M�ed ,��!��)f@R �a�>"I(ajima’s D%��k >zt&s_d9�m*�y�a�defaul,4"�( window= 300��B~�6 !di�ceA�%out�Y=�{(.hT"� F.�A�-�ek��)5�2�l2�!�A��������*k$esNKall1\F�*xl���6�s�Ȉ!64.�%�զ^CU�2���20% �{����q�*Z5/!�2̏"�}i/�*E��dXa!�Qx.��8�k�(�of:s awayy� �ed���k�]�cT�9�J�e�C M~upam�dowV*Z� � bh.�2�%!�-�W� R:�J�jA ��� �R �TR"goɼ��6J��f�iir\bjxe snpeff�6�:8a�%k-ds6fy�*2�Aq�e�9_ � Y6� �*]�a g��N�[5�d�!1`q�e���p�AqA�coFZ e���@JV!�!�홽�u�),���}%HR� w_.�"r�=�� .5s6 :�+ 0��>k�Ae!- . Z%RR!��%1�x�ustalX�Q/��+"�;J�gW! it>�&&�f� FiUg�zL&��rG�ng N2x.�J�2%�p� al8L ��NI�h��Ke, �A���xGe8  self�f�o }-\/ mnRea�%v�(��.%"Sfr"a % X�1&�%(�*� A� ��*��(nT��DJq��^�Y�fl&��������aEG7952 oxTi207 [eft-3p::GFP::unc-54 3'UTR + hsp::peel-1 + NeoR + Cbr-unc-119 ( + ) ] . Hermaphrodi of�aMM% )�%~ male�>��\�ex��AGFP� o en�?A wa:mv1*"pui/o�� �� P�g�T��B!GFP&n�4��$�e#t �&��)�m�*#�M�F~� 4�� .@?"2#,n_!!{3B�&X!.6;z!A��l&�-W%#�.| JXJSY�H��sZ�.U�*�-%� � �a�&�%s 3 Y�c� v;ˑ�a|NL$e.��e�T�$�B�.���J� N2%|M�A��9F}VC1474��-w�"Cs�ZA� I+"�A.bhe�yglt:�M�1���"�{�!I�m �D ,E�f�� B�C yB�.1"ECA338�R�U�rak -bal6O:�(. oECA1003 A@ 4)p c=�@.ZB�P� �!�:R*;F2�yyZ���Y�-������������2�1�A`Ql�m l>�me�� �grongineer{, & co- 7�+ach [57]�i$ Cas9 riboQ~�1�y�* y [5�.0Alt-R™ crRN� tra (f5 ) �p6�IDc� kokiv)Ia�..P!, 107253��in��At{.�� 1��6`��=a ��i����.Q49,�� G�'�&v�9�1eVVs�F-9˜$oligodeoxy)U,u ( ssODN )!�air߬.J�� 3� B�%�1�(96418N623� 8g�-���%.1�!65�)�95���5F��11�11r�.�2�!��N9&!X=Ut BC�.%re:QM%| ase-m#�eT pM'mix�floa*�pul�I&! P��' ( 1B100F-Q1World P���SI?u_!KSarasotG-FI�w�v+j Zed P0"(�:r new 6 cm 3M15"i/18+Ya(��rqF1p7l?' hk)^mi�~�"�,Y7� i�sk3u�ZAF*B7 Q�s�eQ )gM%���h,����87%� 12�a�W�ߔmIdi�� =� HpyCH4III��.%�1J( R0618�New Engl���ab!� Ipsw�,/. D&�Al b-p��rFS�GeE�*=6c9�&�B�N2%!"�^nD\�"CAG�{�/�Ai�@"A�cu�t�Non-Dp1� Rol!(genZ1us�F&,1E!��a��5:If�4:5-r"f�,6�F1Ds>Q!5scr&��2I heFj.O7F26VECS�ur"�da�^� O#roper��*'e�_�;�3t>-:6��12:p-�!� ��~.�:�@EI.��Tc ��6"�%i�el6�i&j -�&{in R yCfffP�'A�nov/5elR�4F�+ �v�"( ��� +� aris5g3A�a�.�*?0#-Zn��k8u��IS*�s�|built&rZ�s Xpe�|AW�#9Bbe.07)#(�s C�0�a� �s59%�>477%.il%!-9yPd�1�u�l*� in SP$ dinga$oftware [5�&6\5*.�&�(lA rob7[gy����I6!!��5:"�OmD6Po�> ��L��SpuY7( OPL��W����5�B G91r��i�MolProb!%"�&�*!�� �G�2�-�\d KEN�)�a g�2 resolu��[6�%�.Q2�rnR���� &RheV�!>P�&�t ( IF�)mo�c��WpSufx~�b,�*��[O2��9�כ_]m"p^`��H"}F�:;&�����y.���G!���m,)_sF`M��6p����y Ch�A1� IdX��y��e�O���p."0 "�.��&�]ai.��2�S!:�b� �?8�t�� 293T�B�&ATC�g��in DMEM)�c�FBF�OJ�V, , 50���B\s��y �4�'sixO�r %�a� ��f���;^3maI� e W�m ed: � LT-1� � r�Q�)e�*�ed 1:10���-�!�6�f�B�3tes; bM/F�A5�ng�-sg��mi$pK{a�*�'�"A�upb6�>6�in�%D��Z�m�5$��. U�{���sa2� #�v 6 N���2&�LA,!�-B����EC 2020L�oilJ�dro'�m�IL& E�\=ifu7?q<00x)��Bsx(���I$ � y� a� ]P�e��L�� �;aw�DeAE��h�ove mill! W��""�/ �pelf� ����Wa�sd-x ���Z!ql!c� �M�.v�/ �(on the five� drugs at two doses for 12 days ,�which time all surviving cells were pelleted . Concentrations used for each small molecule are: etoposide– 500 nM , 100 nM; amasacrine– 500 n.tenipos > 20 n4 ;8dactinomycin–h , 800 pM; and XK469–5 μ1\. Genomic DNA was extrac� from� � s us! 0the QIAGEN ( �, Hilden , Germany ) Midi or Mini Kits ba!$onDsize of !a g< ( cat # 51183 ,(04 ) accord�o5dmanufacturer’s recommend-�. TOP2A%B loci)�tfirst amplified with 17 cycles�PCR �La touchdown protocolQ!|NEBnext 2x master mix ( New Engl!y8Biolabs M0541 )� he result͈product served as input to a second�, �Hprimers that append7 s�De-specific barcode�@necessary adaptoriIlluminkquenc�. 6�Q,pooled , pur=:�SPRI beads ( A63880 , Beckman Coulter$rea , CA )ap nd s tedAan�MiSeq)�a 3a*$ucleotide A�$le-end rea-� an eight )index $. Fu�%( ,%�number!�KA�(actly match! !�wild-typ)LediaEZ/B�IZTdetermined ( S13 Table5� oEb p�Scompared-�a FishM�e�( test .O�!�geneticGlifespanzE� is!�0rly understoo�� MostA{Hearch has been done!�short-liE�nimalsE?itQ unclear ie�se ins!s@s can be transfer�to long MmamMXlike humans . Some Afri@mole-ratAD(Bathyergida!< have�, expectancieq re maJple��s highera n similar�ld�phylo-B@ally closely rela!�rodent�(To gain new� into1�( mechanisms5�A5 �ian�!��awe obtaEg�va%7cript�� data�|17 � e�e)� scanA`ag�iZseth250 i!Q�0Dshowed i!vi~�M,naked]!#.�E$a�mEXe�“��uA�respire�”� “metal �(homeostasis ,�# well func%�l �ys >�pro��e�guI�b% mTOR!;hway:I�l�cutophagy� infla�j0 . Remarkably*�%�a� RHEB r oo�]k,L0IGF1 , both c> l�on%of)�-MZt�aBa� �)�yet un.�%~-=bu��A+enE�convin��=> candidatehe . g� HEBL�0AMHR2 , PSMG1�0AGER . Exempla{ein!�(ology modelasuggests2oon���(amino acid �Sges��u�m�A�refor��we�clude��t ourAT ults�v�4a mea��ful ourci�4follow-up stud�eto��ti�$ link.�)~a��j�u2Z�. ŝ avail�;informI{abo he�a׽� gaǁX�qEiw��by�y%�inP� mutk� $ invertebrEor2�,�hly inb��+��. Howe�X�C not �E whet���D � �U��s�pae�s ����� th�]��Fbe l� 6�%��4 [1] . In addiEY,9�exten�]1�ar��,cial laborat�E� <�`As!Q�)V�=V���!� , pharmaca5ic�/or �tylet n�s�cf��^ e��,natural vari%�AFUg��1shapedA6��iXMaximum=of=�sb!�I�wo or^ 'magnita�At� s�Kcor�!wk bodc ss [�V3!�Thy�c a����eapproa��E�� �1Q$difference� tw� >�1 D����.j���ec� their�ma6 $veal novelA��E�:�!�peN per��sy ��on2~by�se��j si��� N �of potA<al.~m`c��R� !anr�L axon%W such1z . Whil he major; of5Tis2D, Bs mic���d ham2�pa#)�� excepA�" �s � chilla blin+ W0( Spalax sp .2 nd s��alBh ��T c,subterraneanj V fe�c rootI�tubere� U�ri^ six� era;�five ����s!�m>^�rd����at leasta5. Notw nA contr(�� �^� ,��1`Q aF�} bovel year �A�eU"prediu ��A5 power-lawi{de� b����/��� 0hip�f- s [EMAtR�em$is distrib�  , Zamb_ &5�t�Fukomyeo8klemi clade [6]�� best�(r �p Ansell´s] ( F . aimWkgiant>'�owi(,.� :Y,)�>%S5� ca .� , 22e31-�,���  se valu�x4re 212% , 194% ;68%)6�1�ed��baah�2�( [4] ,>�per� age calcg w��ow*� �A�sam~ mulaSY�@esA� d biomAuaQdel orgw@mouse ( Mus muscu��)era!�sA�ig �Due\a��,unique pheno�y�:�bec!�fo!gof,E v�eat[7�3�C:@fa9E�a��9� r�� , ( eemi�: 6�declin> e�b�A}physio al param���*a_�2nt��ly low:mincrea mortal6  [8 , 9�ousande�exa+l%��JreaPly��c� ed ca�hj0ontaneous tum�E���| d [1�1� terest� y ,A|ce&isOeAdshahe�6Z.�,�� pite�Jn!�,�� ��an���edALF�( YqH"" � t�Cm߁�pr6�orN����� tax�4A`Mq5sig� a � *� �s a��("� to ntif:l b�!�}M�!n . PFlide fix"� an�e� q~ dri� �Ieffec�nes�It�, Yp� take��ccoun�^at�/ � –iKrti��r Axe�6� scales3s�a� $of environ�$al stimuli��a �:1=G��"�a!s�~-$�  ot b���� / & IquiA�alw ledgee�, fin,iri �val#ReF �MeJbio"�cN� sVI� imar� hyp� sis--�hAcngᰩ<�h-co� &F( CDS��,N�pq aA��da�e!�$non-synony�R substitp U� �*� drifA�SAA,�:��oJeto Zs3tdN/dS��re wid!t i06� u !Fa��Dy�o!��zps��iayger!{I��d d�u�&3[12–14��C��,"y Qper�eda ome-eDaJn_ly a +%`)�FO�:�e>��y [15]��JS� ���ng>�Qxar_eQ ison%?��@an� group���ASid� a 3��*. 1425�ed�a�X� threnme���ar -mE�lex�ol�!�� NengtheA��telome�")>{1?6� E|tenIHeI;>$guinea piga�avi�Hr�a�as � ^�!����%�a ^)�ese�to>�, Damarat �k den()o� last!. mon �s�( L�mB�33�179?826�V i<, lu�*Za:�neuro&mism!�ps��>� . A third5�7])�e�K�!ixB+ayera��S�he-_}� llBB�c4s d�gl&�] . Sig� q�mځ�-`A�in 513�A�&�� >;� i��!�,�  ,� ph"� develop�� �� . AllmLA�!=su; �1 thodK limi��2am!o�MN� U:�n`7, ai� � 1� than.B�") e�As.isP!�eW��zfJ�)6�.r.� ,�&[exA�E-!�*� �%c ��J�C–a�+ �could��� –�2��"�s [18�uA��th%p��9]&X F:�J &�# Chin> ���ricetIg���NR�ou��.�48��!E���E�T!So�"roI�2j!-c��r�����j����-A�io guitA�?� hieve a  res3!�J�i5A��6�J;���`"b -pe�w�alyze�2'ic%of��ig :��public s�� orig� ;�r�It>a�y? &� ,�.D E ;eF�a" key� abY � revi�"{ !�Lsilver�!] liophobiu(genteocinerIv$. We syste��'119�I�!:fA�2LJ�( 6� sponŷto��-��5a]tUt�%is&4en�d �o!Ue��� eciq"�occur�!�E�b�on "�"�2�$ � )�rMobd&Vciny*�#(d fast-grow�$kil$'shi��? ��of up-VK$wn-�: rG�[( T!(fi)g�o��K !con�!^�![20] s\d�<s�A���< q�.\ A�� �t�d�%uT  t young a re� vgrlld 3 ^�&� ��!suppor!#,"o �!fa�y�j �a�E~& re neg� �$&`Z!b�.�wit� �)[5 , 2$:�w�| d RNA-seqA��$-nd !6�i+�����%�M!_ofI�d."2&^ a! -"yA *G� q !ir,$�&%$[22�1Wy�#* e6J�#*�-�n��� h�$fitM�!�ʋ$�!��**�"�#�ũ ��keQ+u:^$ NV$��#!�M��#v  nf&$� �ioxid�&defens�We cusa�e ig+�! .�")� �t����fe�u�+J�"R e�K "�) ?u1. F�+���a��lifM�a#E�%|"� ���L^VIi���S16**As��b , [� o��&iEcnk � �lap��K sur����!�գ"nN� wd �b8*N, (though s�))�mE��)l}�+xam�)0, Kim et al .�a�&6L ��&&� E�O�l�/�6N ��!�!PA���>"i� 2t(!R"Q�rJS a�he2�i)/�,ly�..�z#"�*wa��0 )OBuora�B�[17�]-�s)�ou�?'P orp�#~ Z� BS*,�<�*� *� &� �� 2�&�(�vA�r!�.�+�Q����-���$ea�*J �*- +"�%sti�7o�(!�&�$�E�m6�m� �X`AQ� ,�� rega�0ort�!�.# alig fi�a�. U�&tunat��"�I s�chn �$b�0 discrep-&�assesA�a���M��b�BJ�z2&� !�Y�F�5os��2,p�iAr%1y�"upple�  D�,= @6!*� ),"r�7� &��µ� alsoR�m:�� �0M�)IMP�0MYBPHL , MPZL�%TACC2;2��"� de�Ra�#; *j str\> al�� *�. NK2Ţu)���Ѩ.5 VsH�5 65 19]�*po� R%�yJ�-r�)l� n�!�31au/$�)��A j , direw"�U�'%.'.��A�l���!U&e \�elf5A�"�ve!�h�)2&� ~� :ei�L caɲ�ou��5Q i�6up8 m�aB� d)� celead*���e*i!w�&��6[toy � F�,f�)d�0. B"�L� �Rat:_Q�:[�6_!�E�"& �"��& ��J�iWr-mpatik3��0nu��E !}vity–-�M�H1l'N 9�or ;y�–si9( avoi� Xge� easiU�im��ngIai�M&e0��3� i�2� " �'I�a0we doE�assumQ atN�]��A�e,!Vu�`+{. But2�!�s/ �eAg"�0���l-*fE�of �J �� y�&�&a0&2�^� accu6$[ E*� is umA�3! " :! ���[29 , 30OL i�i- ]�i:�)der�� 2!:C�riB/�"F�. To e�%a� �T&X�A.�*!��� �.�"�3%��vW �m�!���*6B� >21 :9%)����*A  ( 24 4H6 months; S17–S195 9�d�) un�s\46 a<s�^ ^5U�< >�pre!-�V�9.y�56 !O��6F%�6&-5�.e��!$p = 0 . 00El Lanc.:� dure [31] �'6CA�re)�.�B5A�b���2:�61� 2�97 ��ABCig>OquadrI (�9:Q , up rat;=� one-�<d f�'r �8,.Xa1s�"e sumA�II , I V%GTe, �� �6m�>�a�a:5*� s6%��8%c2O�&�!ɓ!�^ th>�6To �.sI�rN6!#͡s�"�6��" '�[�$�ont�y ( GO )L�_ ����16 , 639>�N� ���`o�#w* ��u=], \ 220 LG:�a� >212 &2�� :e%�)� a� ��LR"�� �!) turb: towa�-.�� q bin 159!H�{ 8gpeUo R�P( FDR<�!l6 GAGE; S20�Q�-�edo l^sumU$���:7?? egor�D( REVIGO , S21/S22 V�[�(aU!by]3lar{)caHb� A���9i�S {:.��f�Jlap��r��(2 . 3*10−!�V�AXRe��+!?�� e�.4�x>�nd�&�"%D (.�,4+�j��a2�(�4 �7� ndI]=A}a b�6=-.�� O��0��6�@ ���%��!5.�"�m�e�4V-ic� �+��aaE�Nshy��m!�or*�=%�D �Vwy works �%#is| “p�8�!CmK. A6�D�+A2 &qq�y eneff9�fyouth��,r% stop�8af+finish� >�#js�� k poinE,��f�'claim-��D� or ("�-~�6a� rapa�F )�;Kis>�[3��3�8 kinE/\ope�{*a"(>�of��� abol!�,`}&f6�proW�.,��*  �2di�a+ "U dis�/E��, n� od� fruit fl��>�7[B'35k�Uch 2 (> Ew� ��>��as]>m��Xbr1') c,�g!�� * ,2�%f�onB�9�4’Y� )� alog�L1��t-�. /B�%sit~N��\p�(lel�u ��?�0ubq� aliz�sedu�M . ��� #by� 6�surfa*3eroxi�[36����+�_3S oxyg** ( RO�,–�:�j]!� lyso X7JXa"�?�W1��al ��577�Ʃ��:�d� he�r"| �26�q-U1*�B��FDH0��"��.!<�5� A;�5ema�� LAMPa" :a�B�(�40� y,J�PSG]�1�:')eh�tTI ncy � Q�*�9�:�,=1Z5 �� 1��n�8A^ge83 �1aog;1�&ut 50�5� 9>ADD� W&e�ie��ly� ed�":��@�SaJ"D[3�A���� %�i.�@l-9a�:�8�1SE�7[M���D[ i�1(mitochondri�3� "��� "Y0%[� �G�w,in��mq������Mhib�@A�g,��$��,�-s!�pr� ��4\J[36I� �(Azc4#lso��a�%�K��c�@r� 9E8���i|A=KdegraM�i% vidu&� �ro��%im�$ ?] �Aumen [4K64'$A� -dexLntj7�6of �*�!�"v&!��>Reinstat of juven]?)%��dagHA?*� E�duc&F�� '�B%��5od'�!-e37 ) � �+�in� ng-�4H$Be�!Keq�$anmNyin� y-�oCN}1��(!��e<a�1q@imIed.2�&�*&�2misfol�,Yin��r1Kgh!H*A&e#%P%- "��/de�|L ve dis1 sZDParkins���%Alzhe�N�9 a0>A d<2s�8 sust#K�)��T9[43–45A Two.$subuni�/a��G(.# mb�qT�:a�PSMB46.Qbeta �P,� 65 �t� VZ. `�^�9classif�/�q6i�$-k;�p�9[4�2p7Rc):�%�6� 88; DESeq�%���k�JiA0�n�KPRP19%e-m_prOJk BAS9'senesceeva�T )q ��s� �CdbS��ndfP� ir [4'<����I�c� a{atT"DY _ W) {*��e���K� A^CJ�*��2$��pxrn� E� ]�>�nd��"�+�6,q<er.g"S*�(�-��a�� 2aGTL2��n!��a�G�Rs��rK onge�G�P�H[4�<4955kD,e�A0]%|��[5�5�PFi|9!�A0[&layri�J ro,;� A�"�(b!W immub?�-![5kW] 22'"a 6954;*� 02Y%V�Q< )NK�.! �Pt�0J� :N&�E ~�%��*�ŷe xL^ b6cH pro-R��rK4t&�!l�ins<�C%YA2inexor�}�"�n!i�HA5i[hronicWl�Z�d"�>� risk�Ka�m�nw-inٚ�Y�:�Gs aL oscle\2diabeW:,ٕ's:�9arc�Hi#6{2[5�o�N(�Kulin-HK�f��� ��?�M��4</Kp�K�V'&#Qas�<. �7R�4A in�6\���)8�)G a�N�( �s nutri� s08ngAXp&�1p�K�� �Ame sm [56�PS *�!�% TOR- �t��N/�nAs�W�"�x,>� A*� i� �I�mut �G$back loops�FP ,Iր1 . 6|5%��R��"�e&�%2�64of}w� �Zd? �J�6gh`,�WH!�s\N<2!�9�g:�Zp �-p1jR-�!�N(apopt�5[5��InUer�[2�@hey{�"�0 s.�stT [58�iiL, .��oT,�����:� compjG� O�.._�ou^Xto ͌��͉!�AbZV:ofV- 7[6�D-���i�<� "�i& $(mB���2� ) [6� O"�3�F=FG>�Ipt>�2�EnUof%�ore��"� � G�164912I5fndN�of TXX\thiY oxin�*�a,xi.x enzy%a���� &�0�&��.Yfly [62�"�(�-lso!z�6�6ŽSOD�sui�d 6Rse}�CCS ( c�r&���R8)� 1 ��0Dhi�M%nd��:J !�z� r/BdU� ��.w$��X�,�&&�K�'PD�Cpe�8 [6246��~0= �ng"{0��  r�!i�D repe�ly qu:�9ŃaJ!�2�:�I m�����Tba8Z �!�JGE\�t�T fail��( �']9capac"Q:�RE"�m�� !6�4A q��<">Mv[Mp%6��K��h!�,��� ly�?-m�)> �"Y��lipidX�C�0� �N1L) �2fem&�No@݄[7R'S.)Bh&�9ve1 (E�he!�age�7erF% i�4_9c[+���@Q[71–73�" 3iN�9��\>{1�?s�^f�?y�Z��A7��N�#:�N� �i!� impaQH��I9 ��1f 1&�-6�mI�FW.�l1�Rnd-in�dQ��io&R��Ytw�'w!�EE�A�adv�;d glyd6 end�M |'AGE�" VsYNQ'�Kb carbohydv��m3/m/dA�|aE��a fash�. w��)�-bo�KXolu�,HZ("-�are�:oA���/(hav� �-n� BG��%�"�" i"�SV�a" [7��I ��ng�H|� 2^ ��A"�ch F�i*" � GE �in �X �mlex��?valy [7t yO5p*"�*!>�E�2�3t � ���kinb�:risdH th c�!'j3a�-nRe,^\&y79re���h��$ �breedK<,.ofA8�� �-" [76]� p � Pe�D� �4�ici /D redox-E�e� `-7x .oXdisrup���ae� B~^E�t& ��Beu�fUrav)l�6J im�pl&*�[`� iron1��*�w!��>� %NuR�� 78 , 7�pM"!;.!hOr� a���v�8 (>, 3000�*2A�a� TF ( xFc� awn��FCap�d���+,R�q�E�v|cOFA]an%x-b�n�6D �A�&��c%'AE!�M�blood�Iaml��:�n�A4*�` [8:NHX\Ne )in�N�#!�TF�.�dyswm0+E�ol� *�E!!m.�hig�,>m��[8� uR�Z,++*28"�#S&"3IM{�`� .1 !� ^M.�_. P-�h�b2�`�3r�["�^" "  struji�"1a��8�J "� ng�As7opf!���e���[F��!��[Aj!�e�robabi[�e�"!�in TFN0er383Ly��Serum TFpMm�& ilob� �a@AG�(lob� n�s�)d�J�< domaiG�~a �roy2� . In< ��k�N� TFIOF<7rabbin/i�H( PDP ID: 1JNF; [82?0�9emp�*)Sre5#s ,!383a�lo""�j f # ��*!H �S3�i� �TF(juxtaIo�GAs�,id�XWvSon�!d312 miU!��pH-bon�ge�� tel,� ld� il:l��-� ��4�03B��I<�sAh72�1� �ve rr�A�!��ys!>��3�'d Arg̍�N�1��"�Xw�I�D�h!� o we�S��B��PE�rfs repulqp � !@4cMor!��A%d���rC h&�R22=s . WSddA�"�G�G!� �_�6�%2�FQ�:�iP]![I �lea��GF�hE��3 d��5gH+1x�GX( :�G�~�2��vJ� B.=. A�D!K!�gen%L�A��,�H q;'.O3C0d*�CMat-.NMR�& (Y )W�TƒD[85c�!3�#u�. �� ver bF-��h. ��Q�6�h�#~gZm�,*�"�"��.:g ��>)3 1�=�" �o@R�8�\.<�.�� -�s-!�L!�:% � ���e�!��Ga&@we �J-�"�?�Ah.���cf 64. �K�4&t=By!�v�:�#�Uea��Kev}�7*� E$6e���mZxh� !�ea\,X<��encourageG��f>�–`4�.15e�aJcKtlF32or&>B or� &�;t�O!�*KA&g!=1�a�%�E�*ac!�L Z.Jl%�:. #>tissu�l�m!�q[� eu���3w�COlw�:as*� ��* anaesthet7,by 3% isoflu�2 inhamx>�,Kor�9g/kg ket� �mb&�K15 #xylaz�]> s;�3Garcia" F201a doi:S . 1111/va�'12180 th�n��iur�decap�R���p�E��a�Ei>S� a�l2 %J��"a e legi�� ( Be(1:�[y �h #ZH 156{u}��PZ%�ap�x$al G 0221/�4\Landesamt für GesundheiI Sozi�[sy; ER#N�@s 32-2-1180-71/32�` - 4!jethics/�^f�84–0!�04 �b13/A16*3:�N�N(- , Umwelt-�� Verbraucherschutz Nordrhein-Westfalen ~Wa�a�;nA8B,O Y/}6-w6_a�rA)A�W7*�Z"n !��s0t"�RW�)�SZa��p:3,EJh" "�. '%*�[� �F?Bze�"�l�1RefSeq�?E�B9CDS anno!5lt�7� �6hB?Wwe�Gb*�NRs��de�io�v�r�s3'[8�&& N�ix�e5CaM6� GenBank S�A R�u Arch�,F SRP061925�H6 w*)u�'| ( %dQ!�FRAMA &I"in�!*� @:�vGof�)�13117���ye�,Q�Gu�CQia0RNeasy"yͽ�!�.�x�"#p� �gvel�%p_�4orz!y� Q�a�t!�e: in S�9 . Dn�aG� i=!N�{E�r �)bE�h�uxr"N?�M+w a� �!Y{"�R�l ormsay oM� .o:b.�hm 4�J�ub��je�A@a�let�(o!zMI�, ��/ � BUSCO [866!y5�� 100%^hB�TA_hB�eeUG0�PA a9h0mC u�%�.� 9iso�dI� rM�%�wo�B� jleF�)DI�B� & T�4(Qܡ�z�Ys7�IWzlibra�1="U R�1l5�ys��oi6�.�ut%�Ņic%��LO(ci�, b�*l7�D5� modu�Sse�9�SfBs� -a �oK7lIMQ�� H�pM:8@T)%qdel�D��e-!�dF����NT�& 2�^WCDS$�|�_��!>g �V�����l�<� Benj� i-Hochber!�rr%Ep-M�DR ) <�1a�&AX�0M�c ��(5�$ !��{�~nve�`c�ble A�k-5,oS.lYfalse�%fs�(� �92Q e*�A�% �L!�rol rubU]. OWXt%�6~1�d[i�En6Ne/Qn5�n0 e�ZL (.G>��8.�[r� $�S5~ 15 T'29- abbv��pS6Mah&� }?!'AUxgN1�  1IN�WtF�}yW9@N\B� H�,%7� �>&�i��F)"P;z� - �g�.e l�0?,6�ini\!��:6 �&�z! �es1u 0a�R� be&�sA�JOilySG�n�uA"a�� p z�2:(0F]-*2�[we6��#�Ly "�Yns�=���gd�S�g�[1�.s%#JBTI�a�:lJy x3t�TI�� 75�%�1 �A}��, ScM( 8 6� ��:(AnZIview  l"J�����t*�IJ=  y��N}wFPS4�Km&�Rg�R�Q(j$3Wista@)�!�gEz6� =�;92>%�%�R%"5 � F/a l6j(�<� ]:x 42±I58�.8( average±sd ,m�0i��>U�F"�2�y+(�$n=�y�s qapM, `3� | A �i��]mFl���� � e�z0!F�jY�s`s�*���DI�f� �[��"�Hu� 2500iv50 nt�#� tech*yE@aQ�� deptDn9�0 mio:s/ �eL7M�w !.6Ep\6w� STAR [93]4�outFS^Mis��NoverLXA�06�.$ތNminO$j%92$U� mapNC| a�Ks9.e7ca�� 0( Bioproject:YNA72445�=0 *�0 by �q�C*�k:2� �^)�BLAT [94�3 SPLIGN [9�abadM�ua��4�$s�� `(bwa aln [96!s,-n 2 -o 0 -e O 1000 -E !�&��l�0 �2�GEO (!e E&�fOmnibzmse>GSE987461i�oC)ly�f"/�/DR≤!�j*S1�2XW�B-G����]�D/@[9��R [98]E���j+ ""� eT� �lr(:�R�6E�.��*�R)��R( ~� �',-wW��[9�+F�\���V'go%t )� E�reemap�:NS�2yw':v heir"� leva] ��!�en�t� ) :�7E���7V70S�5�fF� ,mS ,F�J>�22`97q“�(N�� b 5507QB.��� )7s �"ATa�u�Y"�@�J.-yH$��IR�)s�Jm?*Ms*;%��lgE9("J~w�" v"ba �}c4 h�R-�� l*�%�2.�jVCZ&�%o rata�RE*둁?F&]%�: )\ �d7�f !bfA�]�%0�6[.�Q�iq�dm��VGO.F%PV�u�~N�$ckage GOst[a�� �L yN"�e<�Fd i�RJ�e�~&.We���H#K9[6��-Y,c reshV . M�)M\Iv!/`WISS-MODEL ( http://swiss3)k<xp�. org; )��o10�BNo�optim�NA�ap"���9[ S`:�Is"zJ* E�tem�+\*e�r�L!i carr�)!)VCHIMERA��' �}fE_)te��t+�� vect�EC+ol�exploc#M�Lendosymbiont Wolbachi�G�5 �2�I� anO9in1Fv> w�U<�~mp�c<�=Cpromis��. A��AeJ/albopict}q�0"�B ( ARwP-M*y�a�b~&^ wMel�� <�'e _ �:.��*lyUrepla! wAlb�� B^�!�wPi��� . VartA���fi�]��e@s�:�~� aE�-� ?wi͖$( SANG pop���]) A^ =>sh H�sXqw,-A�{n�w*�^)F�6)w*�F$chikunguny�dengue� zika viru7!�a� �"%8Y!� `�1� � %�d� �r�inherit�of)�!U%yY�. S��aA��: fecundV1egg fertz0di�w~ � 6L/b[>`l}w . Cro�i2 �ip%� ���fu� un � iQ)of:��\�h� A��1�::a��A t$0�a�174� �a7*3*17B�Qek/a�in�9for �,6�:a�5Ɖ1!t�� tly �1���`'�<e�@5!��A2etQ ! mF��xl1 . 71�+t�of� �[�Y" dens�8Iz�A�->5c 2� 0�s�" М�ty�{<\eQ'c)r� �@��o�9f-!.hAKmjqa�F)t , 5'm?$�E�}at 14#21)�pz������to%�5!�[+��PA�!�Zu�uL!�l 2=�"$�0b�;-�� 2x�*{| 8 $-M�!��?ble� �8  ZIKV%�� 3inE�Y0���okS�(6Y2�;up� '��>��s1�S�mea�kxl��world� �*� , ar $pod-borne "<Kin"Ղ{�+1��&�o�%nd�4 �GH healthA�H &"�=O�1*� , cli% %�� �E8+nd acqui&��J���lns|'c77�t�v�:��:A\e,dra�:c re-em�of ~��q��Ő( DENVoye�+ fe�0 ( YF(i=Fla-�ruC i���mitA05 n� .��c�zt&5A�A�r=)��Yaa��da �!� u��%T���a,K �Sof2�(� KV; Alpha%y , Tog -3��(e�;5SN`C!N�%�d� sp �4( Diptera: CulA9Z��A��a�he \1>of)�,%�, � ��*݋�7�0��D egypti�.Ao7Hl�4?as kjl����� , n8�i�"&� �1hropophV�!5p&���L�dn�a%�tr a ��&O�O H"��tho"Vg! j=(�AH�5),A�n�� �i~�6&� �YAsőtiDPq�o emon� !!�epidem&��%?wp abun�x[1~ } :� $�W2�c&�<�[�als]Aj suscep�pto� [2A�2�H23]U vB8�b!�"��B[2�z�S iSng��V�Lazio�^P�u��"Calab�[�*��5]a9�l�xJ,� nea�C300A�fir�+�<[2�-]rłA$u�!�c rene� ��XYZ3#�."�Y*0�=aЈ,(�P�w�3'C1�Qq�be!dV����_x�6u�&T�R2qIn�S���orBX4>�>�J���� cer�+� F��x7ie/b�-y4F!4&r�/&8�D��I.� ,ճt��diq�%�. ��O�]� or� s[C3:\�nBtQE/1�#1[�d5a�KMME">7te*<�#�� K`s ���Q�|m ir�D��} upae��γ-�6x-r�&�d%�p(9R(9ethbAa� G]�%mod�G f&�cA&!� mani"l��I��KroI�-�$�{�E`lb�� rium*c (( Rickettsi�)xQ.&��RU��_g�!�+ �olvesR�`D'%-�!����uY?�B�]Rn��^sS�8- " s�s f�diŘi�si� I�iaL4�Q 37] �8�\ho%�8 "3 l. &� �+ v��&yKn� e"�6t�pit�N:��fm �a few�!in^eH�xt:aJ�mai� )�AU�Cr����f_ sex� ndYFef�~ie��!%E/) 1_ bkd`��un9�U��&>-�/5;"� e�A�# h�)��=CytoplasT)Inc\Nti�Aty k- �W �sI�� mb� �sm� chariz�,��Fv�`MS�G�-A�u][4�I*6�f�i�/ CI �!haJ�|f2R AS�&"�� p�%�� tool�R)�e*�AB��o!C�����"��a�5�� g� �}�)۰�m��b#AM*%coQz �Z� orEsu�OA�}f-cugEk�>\�6�e.*� �`.>u"?*3�4�& Bj,b=A� a tr��)1aMIGE � e�8j"l.��%"Q��e� lo&6;*� U�5�LS�{�f�P�B����_�� %�i�i���9�� nu �IV >K�p [Kb�CuVRpipien�vF�}� 3�\l Italy-b� "�>E-Sa:4i:��GE���>0A'!ZS��%fk��/�w!�o� YFla"��[5l5fn��mi-fie3Ke��\��2��a��.�B^-�m{ �\Mg*�XbƓ'^� �s�miA%��% Flo d`"'�bromio, :P!p��" s2�ŒFq$�A��mit�VGia��Calvitti%�FaillouxW�l��*�A�, E1}M��erLj,S)rekV �y�aFB� ��c�Ee|*�=��Ias� W��� n�,e&� E�>�eI��m� an�HXj'<,i;�!dm!s�fcI����WBV6�#�e�H)tom�DinnovYeRaf�o� �\CB�yS�o_��O�|2MQ�%=us+a�w#�:%BC;�&!�&Is�!�deb�.����UA>>� colofHby K$ovitrp'�ngu��$ra Sabazia��� 2006!+M-}%eP�xi��}�0at ENEA-Casac&HRe)�-���; d.I��.� Ej,2�# U� 20082 FFՇ � .��6��}6�[}hAGr � & 06�)'��F�Be/!��s!g $�o�W�3ut 4�9�.��W���a�er��nea�2!9g.&���T��PgS�� , gAHRw�$%h�@��}y&*�q<%���&�26 weejl=l[bNe7C]�%caK �&I[-M&� ?.E F;��:{%bD,H.� a�j-/P*ragrap|�Larva/EbB �)adulth��Ud�. . 5 litre�/v԰���e�"�"lU /1 m�$aug* Q$Ǡw*?��:ruozk^ {(R#skLA��7�m fix� s:f 4 mg/s~� �B��*onv15%2 a?5!�i"�e@r�p�r�[ 40x cm ca1@lat T = 28±1 C° , RH = 70±�0, L:D = 14:103�ndI���lv!�(wʫsuA�B0Emeas�p�6� u�<f anes"�Mmi��Q4g. e!�Bio�K ComJ �?A�!E"��JA@B&4��6�f@O�["y9K"rovOe �vBtalu2��EU  ?ve�0/63/EUא�����nQUC�Ky!Y!at CR q��!Qq�o�n2AM2�au�b+Ní$0/2017-PR QdAHFebru��2nd�7A�� ���strZH�"�B�Mq}�e�"�!c) &�al�!�?�{G}�@� [5�5qn�h. B-)Rc$he yw67C23C (� [�haTkin4" furn�8by Luis Teixeir�Ins� o Gulbenk! de Ciên�y, O+WPortugal1/�+)�s>� dono�u"�A�drawn��>& erio&[l�) ;�by��osijjed�� ( Su��rua.; N� B CA�NSA�tpinj#("EBy{rec2t5��G =��"ĕ� . D3!8-��a�-��B6��?� moni�ydc�/�*. Ng�:~G1I쭷E ssa�� � ?6� AhI��J ffsp� �cW>na-�)m t�ng��Ge�R�.�E�est0)�/�B�� @d�5 sA~�&~5c&N� ( mot�S 6random�B �.� J$a 9r�.�:!�-M)�%�*�$���a�� �6BY. Name��treatE$aft�R 50:5��:�jin*� � ��z� sugar so�\�s c�*ich�e��b�B. D��p �g=KmJ � �5d[ �7es.�runtilE �,%�"م t 60 :. At 1-� ��e� �VEoA�3� l-� )��2i�&��!���[cjX!h n weT{:a��paper �7thq ��FZe O"��� .�E1.D�.����, �:��/�0��)"�mc1Ea��UM! ���Me3%,T&,�;of�!s.p��Jup��2���]�A�-M%~u �l�Oja?e*�06sU�'.fG_"100×5& �9� purp� %BsMi]N, 2AZA-5�2c e%  :~920:20�:Q�(�;�a�e=2 l)fes;�CIa��.Sof n-]�:% uM�9R6) 4 A 6 ���M�CIQd3 ro% fv�{�g3v_#u :)k v� E1)�." 24 h,�z r�e� !�=u�%2 MHE(�-�e2~ 2F�M> �!�*�s>e�2p�&��&[m\a�l�'�f�&� B]&�:�+A�.(�no (a:m,6� chec:m�7.�sp�� tozo�"M )�""��:Ue�!ovirgi�<~J\cӁV]�r<<iE�%��s)�E� ��1�317a���! ]$sՠ�5-���i:�1>�lS#����e%?CI�A�u�&6 c�4d5"35cy&�#>_ ( CI3&� bR�!S n� N,a &�F0Ten%%�I�?"�#Baa2�%K�J10)B!��o�K�?A� :�tiv��mBmm �n!U��W���$Mwh��.����9zZR}W&�ectZKit MjPre�@ Zymo&�, Irv� ,.,6�'=fB�;�hiO . SS'n�Z!( E��a� �!5W 19 d ( Zhou"�_��98� �=�Yoligo&��s: wP!mTCGACGTTAGTGGTGCAACATTT�wPR�;,ATAACGAGCACCAAGAGT)54]a8ob^0 a 272 bp fra�!�a�� gene; 308|hHAAG ATG TAA CAT TTGX61{DQArev�s$CAC CAG CT$AG.2].qa 219R�Me)H��>� �h"ze�%��P �a.u�I!�)�a���1�_�OAlbqPCR�J�F CCCAGTC TCTA�Mc-�d1!jAG7 GTTC9!�,6�1 � �F$0 T�AEYw�� �%��I<�FluoC��$ II SYBR M�$M��X1cl�� , Mi%a�� μl�7al vol^�.1 & �%e�,i z!��@ing 2LIY�9%��U2�[�CRV&�H on ABI PrA7! ( Apx Bioswi� Fo- C� 2�� mal��r-"�@�!1e�Uaa��ert#Su II. H�&@B�A[1 ':d�t 95°C���40 ��15�L +Aa1\N60°C/526Jr2�wPF-wPR/a�-i�/ Y�E�-Y�:� � :c�B��s%�verчeXdis��A�curveA9 miE[�. d pBS-M-P�6 �!�AKx3p���,œ�Z!!i�a��� &� qu��Ñ ��Ay2��z�aim��E��s|!&n�v�e�Bxh���(�%)⩲I:�i��"-�>�je~uu!;aI���G��E+/!B�� 404>�5l��!�-Y"v^2�6�2,v�183F/��#�~z*�< 405B��If�BfJ�yϋ-5am/691R@All �A�-tMin pCR 2�^��A CY ng� , InV  ��arlsba#+�Cw a>vZ-i�9iY��w�S�aqWI: A���� �T̗t�f")!�t$f��M��) $BamHI-NotIr��pB���aůK ( + )օ�}Mn<��"�7��!Ut2�-gc:�� -Sac2�S],m]tq��s&��UG�vKpnI-Xho:v bJ��}ARu�AV��M\1��!�sB1{ ) m�gώ!�a����unn\G� �����O�&�Eo%!%>�A)� dil@ #u�-�Aandard��(�;{( �ut���8quimoʝ2��I� �?Tp� E� in����h =Rr�8Is'al �!$w ar�`&S<. Q.P��m�� !&�6 Z ^BU �W��Z*�!U�#U}fU�6�c�6"a�emon �J�T s \�,��"q!�7"Jfi.� -Mq�0�&�$-,& ,C-�,�$dW>.�JF� a� .�n>�&�!* N �2�7���3�4��i{ "�F�pI�&��(�,B�bI� �� Kaplan-Me,�($%�log-r#j( M`l-Coxde�� One-�� -�s ANOV�-Bo4 roniIM*8Y�et���>H-b~)b]D � . Pe�� !©��i�rcs�+quE5ooJ�2orA_�G&]!�A �. N���-h&Ya��tan*�MLShapir-�Wilk -()�O>�}ei���aa|cB &��%�e*�tri�"."s+*e�)1i�"�0ax�( I�] e"!=*� ( DE-�VJ�( T#%�%C�-V�N�H Kruskal-W�_s)+!#b�<ofa�9���!�%"i5Gd�$!9saliv1`Sj �;{l�by PASW��]saF=��Window� Ver#?18 . �S$SPSS Inc .' hicag�� K��8an 900BJ2�"mB� ��� �12a�ivi"G�AG&K,g����9aro C���� , 8 �E���&�4!v&%�/"{^ :�. �# �1�"ni�-�lM��)2Oi�m 2m�E� BA�E!r4�n `���v�7AT2��racy alwd"�>d�% o(4&� ��r�%L�:exW@�*j��e��( 9A|89|. 01%a�K)a�E�W� =��a�� %-�51a�)\ed=�,JWP��se"Im%�sp�� vEu�g]��&7N&m/%o: Men"4(Number: AF0�,.g�/2"�/R�J�C-�se�/"ܖ>Ns2n0�Q�o�x! !�-1Ae.�!&g)Iavd\M� �w ��!/sli�^2� �38��&uF��>y!��g�?e&o(��".( P =��98�2logg ͝�$ ��G��|�ApL�1� ba�30R�esA% ��|t1NG8>Nm�&�O5�n� yV).�( �!�]) 005;995;E>2)�lo!E��0i�\V�� M&�"k v &ENQG5)���N3�1�31��M�MQ�ag*<$)�o�<�*h tcha.of� m����B�<IB!�w*"(*])*�(!�>�P( � �×9 )ɣag.#r�Nm 9Luf�@l�%"K^�09 ± �17 . 2�32� n.����p�LaZp17�( �d)#!"h �2ImС@��:W&͟5m"�I6!�1/g�/*�S���3A�a�'d&< �Aa� r�|./ �.���c2i ԅ� A�. )�-A�24yK02I�Ad�&e=�9 �a'E� (O��id ed )�H!&�L�+_ i��e7= 5�346��h005 ) �,fM',����:/R��-M%S.���? ���OH.�H��/g1-MMU!�e�e�)nt�C=�A �NB�1A�673>�ɖ) FK'see����vt�ϙN�ad�%a.�(1 :U0-�a�13��� 720; �Z,%� ,1��. �z"~.� � *E@����A)�E�5N> p"0o ,+>(59107 FFU��FU ) /mL�O� a�>U���.�n��v�\et� ��woZ�a�C$ch dpi ( 7�a��6�Xe�o�IR��O� �4I%E���38 ���3. �� ,:<u/ *s: �\A�m s6=K)t (-M�x��S]es�bq�a��"��:ha��wnKt%>��!k� p�Fr:1��� ng�a$��>j(�Q:Q:ThuA LHRon�hp&Q�a|ng�^t�URto�9b;@ ��!.�ݑ�#f!u,� "�V@I�,:mWA�| ��< �;A�e�Fj6�VpiqPI��bP�?-���@I[.d� SL�}oyH Z�VQ�aahE���4��A�I A4b5=5A� &Q�B ��.y-?a�~��g Ť�^K!ni8,�� J�Eu ����)'! !+�I%Xa�� �fat9H�AJ9-�vi6 z<-�Ce�� ~of1g �I� �. �"�tH&�Ale� �TC5DI�#�og a3 25A��7�Lyn��.*be�qit�?���cE�s���co��!Xnegligi�s8-?1[6�!6m͙�ef�A�0A��]H�-)�b!�*YT-]I �>t�In)� contS�g>V ��5�Q eAa�  a�2 ca@�ura�(� UP�2m(�Q@le�F typi&������Q�, s [7�h7�7�HB� �Oa:� M�N e ho�Qt�2�%4 �Ytra)Nc&ALQ!!�1��5O*��*0�]�)iP�W&jQv ��KaG &�3>�[)Q|/�"8r��T��@a ���ulfil�.KZo8"�!ta%<: :� [��%j�w� ����pf BB�b�VnK�+ coex�15eV� Y�!�r��t2S�e*1:��A|9^$R"OARBfD��rm*�@}D)La���N/�*�&� "� w� movA�V���2���er.G]�[w56� aQ�%��g�d7Z�%s�[5,[�LH*�Yis idea� s�5Vf�U�\r_� \O���b}n�  -M�g�,�.^ �*BNHE\!�t6NB M I*n�ya�i �%�!|0at releasing �males with higher mating competitiveness tared to the wild-types may leaDinduced infertilitdvels not reachable when uskOdsame amount of irradiated �o��carry6�dominant lethal mutations . This is because , jWion�,obtain fully� void={vector5nin�a�%bj�pidemic��As9� e�)e�!=�q wMelI��B had aa0�5impAz#he��eteA���is� . wAlbA%� B Y wer�ov6 !Finterfw�ae�mi��,of CHIKV [80��A��0, we demonstre/pree�0ly ( S1 Fig ))g:< ycap%oof block!�t� viru!D Inst� �en�%A(r=, a RA}�wdet)�2�poten�1Hq�A - t%�� ph��\sh��%E5q-cu� >� Tf �1�[4E�Mr �aYriA�al evid%�sugge��tha �lowV�*Vm�� DENVe orre���th� UZ e natural!!ASV]A ,ins [81 , 82A.Wd remo*b )c�-lA�e hib�� exer�Qby9JA��[YF�%add!9%NtoIy impo��a��er �q�S-1)�Q�bye�-MB�as%�to#��n��]lY !'refra�5�  k6iA�}8� �  a�ɬ��edB�[50� F �����%U� ti� >� -M .�'!�3 dens�bdat� �s �') � cleAK�[exA>%ss �N2v�!|��a�T(already vern (Qh�}� EA[83a]45 OuA�)c"� �above5;: C>�8 Uh��� alone$ nd>Y>@iy�of ��qaset to�x$significan!�enh�� bothifs�'z��UXB�"� �$geographic��!W��&� M)Aauthor]|onJ��s�29%!g>cRomgilc%�(is work , n%j� esah ��/�5-St�,�ѝMa�L&v aF�!��couple " ^D!� suit,� mas!a~ pru toa��ed͟}| dimin2 �concer� ssocnE{��e escape!m1 amon� "�inP p|amV& a seri)�issuevll$ ly� ��d�ed bef$���-� to field !���.V studkwah� to evaluU @f =#ina�lY�28 ��� �o��9�Lser�. Moreo! !cb-term � M�^V �b� vestig b�8 sele�t might gra(l��Q*symbiont�{� �se`antivi�Al V[8�Inh cula� 8.� �E�M�st!�!�E��_@�)�Age%Y%�&Y ub� � openM,.�Y:�is known�be jeٛln heat ����w2egglarvaa�in� ed ; emper� m�� han 30°Cia draUc)�% �&([[8y 88�JS� 2c0common~� latituas welldu�I!FsummeraMed� raneuas� RheyMW��Pd path��.�5����ve��u �r� lMr}�f0.��Many bioJ�Q� intra-g extracellE�stimuli% regQ d through!plex net�E���_A�z� a%�s w  a globbdom?in�4recognizQE� ar p��an�), ���!C!� vely  cont��fackTh�MaMtchhr��tA�o� in u,uct regEof� nd f!� sens� otif-!m��)�te-��display���ir bin �ner� � most curr��� ]de novoQc�&y�sA����-ir ten� ya� occuE�disorde�, our !��  focuJa-�ob�; n: upon‰�ir�1�,�adoptA ell-defia�st-{�pde�Iz�analysiEv�-�-me�%�Qyof����oli<three-d�� al ( 3D )�,<I� ~��[ �~s chaer�#2Y$,ewhelp 0 tify� Ssi�thoau�=do� matc�"��Bt�.k )(5.���M5M&reveal�yE)!� a%�ʹqBd���Q9!, unlikeI�i�pi�%���length� ccorA� we wi�naMl`ategy� edE� Sud V�M�ne �E��f�,. g� ��-enco�infor�OA� boutU�E`a�� �ar-���) *B�3Do%=toYunnotic!�)+Z�"H m . W-*R deri6Yqp(n� s ��� when~enoAm.�� &� I�� � ��d.��arI\��;th���� ��FiQ,!�-valid{ km*9E e� scan�B%��me գ� fD4model organismJ th]new�-?55%�e if �Ki�m�6�+mc o�At� e/ ��w�:�]*D ��-re��)�)�64--e��Ň , 46��~�b�describ�M� , involv4 n s0006R� o��L Ww��s�!� mole� detailser � 1�. Pro]key p��rsm��as��"tlif��T% seldom ���, but�� l bin%5Ixi� �eALSA�%Ym��u� macro 3arE�lex �execut! r.�it I�A})�s mit2Ein%�all!-U�tp-��A�t�}s��. T��A ngG h��"~ � �6�, �a�� membeQa�!>r��)�aly be�J in)5 -sca�xp�%�s�=alB\[1]–[� &�q��[di���l�fI.��eheEtw�Ibdo��Z�u7�ot!"�A�E��� !AQ�� G�S����tomicE" -R�[ ��?i�.�3r���� Ncol�wA mi D�8Bank ( PDB ) [7� A �ed�p�M�a �/ !ʁ/ ^�ɼ !a=+ (���e4h 2�t��9p�1t} r F nclu� s1�&�disru&� ���� ű,��in�� �of �o� drug�! Rece� .co�S3� alI�a5as���""� 1���hO� 4 e�� u;"K! wo m= clae�^L�s [9]: D3 - f9s"� bei�����53s�F� �� �^$ Eyusu�iersometim��AE� hand� Y e�g#e6ZA�qq9 [1[11!�Theq �$�! �>ow�ϩisN, mR them-� orR{�!e)A�K.k�!�2vo� -� giv+2��siz?* � ,{p!i�/&� e@[" us underA�y6�UFhe6nXhow0.&ii��&[12� �Pct!)� V ��t� crit7��Pa��,BP .� sa�p crucM.Q on�m6!g�v�%�i�� '-7�� evV�  degre��q���>�!��%ofm�5�2qF i������!exA�E�F2�%�)es�m >%�� y t#di U�,pockets [13]AZb$.��!���� M�)%di_�J2 ( DMIs�14a_It�)�l� Ez�� !N.�� � we��#on d Ebee�w7'll:�ir";$%�fast eAnprofi� �md6#�� &h� y F�� Q!���'���MrIf J!`�U��'Q os�� 2a E stri� j$p� amin�%id��leI�!)y����Ys^(Y4,A�+ arbitr� �%. C�&"W� o奁�n�r� E�)F>xaM -�Src-hom,y-3! H3 )1!e�� -raU5��� �'nj !J4PxxP ( ‘x’�‘ .  d� e�9a) � � ni�A6[RKY]xx g�R I; squ!�braig k�s)i"�u��.-��&\x[KR] (aIeS�S",�!!�)�frequmPin�>o[16��u� AI"�!!��A[�E��a3[!�etQ A�դ�t{)[1 M\�<�sum�VZ�V�m@^ m2, ��polyprE:��II� P%Ehelix i� SH3-��5)pha 7� �*by Nu��� p%co�o"DF9�k�betOn�j��"b ..�!�t+do PCNAHPDZJ�2�$UNX��)��e�}gpe� �� M \l+aPi� �6ld&S � ind��t��5�ea-� !#7 opr��5*�G�.'  nub��2� "��, � vaL�* taneouslyI�K few2�.A� "�mod�[�� *< �!�8A4[2�is�k�!pid�zo� l�novel�6to>&�$in�!ly [2��;wa.aiP!ct �x!�CD+�.�9)converg�:,wise un�(l.1)� &��e ,�;Ak�""���pBy � J�.�%] !�l�� year���� have�� developed�qR����s& � �Fc!H����& aJ )q�g .�l�%.�E�-�!�ner [24�%d.3�D�(kaN-�is2 �!M� ost-%y�on"` s [2�1�1l-%A9�]�of:T�oo=!���(���ve*]T x Y69K qu�#�%#�$U^o� a)'��k!� compH2�B�-�,q�or-q�nk � m� maskrc�2 O���"�R��Z.�� o�alwayA��X�� �e�; d* #� Q��4.� G���E_. A(�.!# A1�-�->9 algorithm�3�po"�-to-no��& of m�Me6[2S[27� F�A�JE�. Ac �, iaD .%/e flanEu o6n m�B5��seU���x��pr,�Van,�Q�sefA�8)terpre�4� ���at�H"a-a� cav� !8et/re�.o0).q Pr�B � �*"A� 9& R!�m���n E'r�%. Despit��e�WF ����A�I�N� a�.�!� 'pein i5 [2�*al.nňl�1T�promiscu!�,�I� affin!���nd1&- ��P�y�� $iYiso�@�2D> ��A�) ,�5x�M���Ax5n�primar�̭E;u�� , [3�!�B �� �A5e[31];!>ba+i��Y��f�Z&t�23� {H A2$!��//split � �wo6� 0( cf . [32] )$rE� ~hao�[A�a1� r subdivi�1An�3[3�4,6#e A E8)�!��{y�z�b�2 b &�!Jre��i$ !x �a i fam!�7�RH��gwhole2# spacw�/e!. W ireK21,�+#3 ��E� E�a�� make ex� cand��A� �A�4� 3 A�.X�a�.�6��H�s1�&�� "�� z�A!G� pub?3�(�9Ax$Petsalaki L4lEk7]���&%%��i# �sit'3 a�$n^2i�i�,&� physicoch�2ala^p8;�Iz e>"or&f"�6F �� �@1i�o�7S 6�A�9��� !�isuc�6*pr.�F�! �� <�*~i�� beyond w!:is-2by��\approa�$,�52M7�q>.9��Br��. F"o�6,��8iSPOT [3�j[39A�e���desig��)1C"� ��!�=ŦENrIO2� U5�,���n$ e<�)���7c�N -M%� �is�� #>A4!C exac�=k�� icip�&�hV�.�%� �"0 �HSl &6�t&1lo�3�Z)\�B$ ��%V�%Q�ͪ 9r�%(`/)�[40��!�d�%.sMqO��9*(:�m% L�f% q. S3B�� inke"p�SH2�kinA�i�� rc[41aMM!C8-+� s boS"9( � S&� it d�9� ��pa��Me�I�M�top�1q Б� �3j ��%%zaA E�&X!�-m pai� so !Lid�+ema�bH& jXM�ype [4�5���(& kind�` v%eor5� s [4�D�+vi�� �"`of>�DMIل& � �?m�sto�m�Eukary�% Lin�Mi�� �  ( ELM )� �$"��+> �b] 䙉=1�"TMRdi� tZE(!�I� �izi��r=,s fq �-�u0>Azb# M�a�dZ=�d��w*� I "�0m�% no %6a�?��(��(W�us� A�, �  ,b(4 .� .�'�& ofAD%�A�1� a��&9�A�� p�'g_J<�a��3���y�&��a�.�s� � I 2  itia��s*&�> ?�g�Diœ"&$,� �I��ia�nu�&pt�d�&�'�$e�!/Q�a�CZ�*cu�0hi3t6��)]��(- �O� I&!1:� � LRy��)v��(r �%b�)av!�N(in��e�)Z`(�A�} (=p�B%�v�. &�)Z�D6�)Z�)oY��aJ ��T a lisŕ��qP�3!�h(&_i��vei re"<..���y��7. TQi�2� :� � B �N�,!first�5ܭ�paramet4'A J4uAI e"!�!�I�6Eh)�,%>uma� non-�d ���"�-�&E5�Fg al.���nd� lO��$he 631�"Z?2�A��<�,yQ�Nest]��cy͘cap�12�r">of"�al:(�)�!r��s�5���� %q53�FtruK+ti nd ran�*� A�E�eI/��FlE؁c�2!%&t Cl�&"�#of(/E SCOP ) [4�!�ach f�'E_chom"n�.m<��5"� gene/�El&B���$4–20���"�#c"FL� rang0e;MN� . A�!a / guarante-���s�u� %o6�aCly��& s�"�2tO���)��4as ���)v!�out� m��,TI. w� w�%�!��rol��c�6"�4 ason�B*� neg)�&q�q9&�&6E��,��}�wA+v*�%�� K\�� �q(bC . 1aMG�#,of� �UO a marB of�( “flat”� ia#u �E� ev�s����9b2��@���! ��~5ca!dhs&)exJE�s�;%fh see My%�4�9!� J(sh� ����� %G.�ab/?, namA�E3�6t"m: !=��(�6M(an��-yA�BeV flexM@%.i�6��A�&�-Y!�/s �BrtlNto��~OG� riQH�=.�Z7u�U �JBQ���(&>)BN�#%?���;, nei�5��6���uaAL"]c6� ���q�B�� &vr�Ea tren F��@A�erR%�)�B� �bY,�V�\ BrE�u��S1Y be�W��t�second2'��5�� DSSP [45]�I�I��e� FK�&of w>a�or �J��dA�on;6}�&> N� . He�K&��,!� shor�,!�l�Q-f��l%�a she� $RwJ.�*-�.^c , d%^*�g��� �� R��2e�5to� G� e.;*� 5� . Nola212� �d����c!�x/^%nd_Q � I�y@orm a"�%c�,m�1� i�^�;�Qalno�Lgl*� �6� �-i�, {eAN �/E�1D�5!�e�F����z yner�N�E.n p* geome*ap�x 1�a�t�㥴���A5 "mpD��T;  or�be !�tu8*_"�6��)"-�f�>� d�:n��!�O��spp7by.Ani+a�0� f5-Ec9by~�e$<�{T� 32C�N�;��.�P-� *� s"�to:xQE�1�� fbH. B�O �fHng�w�Mt� j�#*a �ai,e��/a2 Z��#A� 50 ,�7higj6�PDB5i2:�ZSVMYBo�1r�s9K:�3 ��ut���R��2S!�urr#���Ye � xe�2 o�uw�[taka6�*�B��-co>Witra�>a sX<�Dmr0n�!)&�%�6�, m�� ,R| , acJo .�X49!Xi�� �Aaar%J M, of 1Q Bs=(9^� Our8 " mqak�e2J� ]6Y>�,��-in�E ;&g�-$�syq�i� "J�x&�8 . AdpUA�il#�?e"=.12�ME�&,!�fo�5A�!�IA�We� sB!�v52 , 903:b�Uclue {%�byu3w6�6&'$y Pfam HMM�6]5e�桔ra�$�m��.*�*�% :�h lapp���gY"KQ.�D& J,9A�5���!L�;s"�I`�+c�Liy)3 E�mUed�. F��K6A�12vL359�8O!,��e59= 512 ( 18%f0� in 4P224�� �pV�NN4=� Ia�*�a�5neighboe���+pC��%>)�Et6 �.�Mh�An�*;@�% 32%8=�*regard� of6app@� �� �Yulr�,�8I"�"|)��>�N9r hec�)��5,�.!!�vicY&U-ind &�B�1Tar�7M � ��D��%{eH ��a�89AU451�A�V0,Wa�aH70Al062>73%��5-�s;!;a#ag�&e�� e�y pipeb ���*re[�6�T*�b! �A)A�4�199.�rem�.I�wm�U �� �� es �Q�/t!�";:�#; �Y #� �4q�by�f��i9�U I D%w4͞� '�&6��IE��kee�vZngV�  56&� st�6�W�5al�>veF%�oNg!; ��]v�� let�a�G iI �."�M(U�"�a�5(simply joingun�gAA� , eno�Q=��ls1 e�\�� siQtyp� *� f�–** !��3 N��e��Af�Z�.�U�--6�%�Nu!),th 538 , 6899( 7� �J��A�TC78�%43:SC,�c�%�A*������I��Yi�e�`A FE�m �{A+��ojr.bi&"T ( 80�!n,�5F� G=ny�!S�Z�u�]E����*�inQ ���o��M�)U�Uu��%a� j�I "2K�)ra���r U $i1 ouchA�ši;�&%H�&as� F"YB!}�Ib&9Mor'it�-aqn a�&q%arJZ�� crys""i`^or bu�*n� AO�&� L �*)O,K^W.��p![ ctly*�!q{!q��dwor�:�a- _a�g�@ !�t�cłeVal un$=K l�!)i�K%�l�I�>�0k+'3�#r�e*EM�� QM6!'28u�; � AvA�N�`,�"# CATHI��(r��,dR6�[4(9�> �42��464 ( 55aPJOchap �R�.�E��%VA�Ns.#F6m�m�k�Pe�K"T"-a�&lclA�/)>'R&ajT. B�K�r ed 8�986 ( 25"�9�Z*� � a�*�\ p"� fa�/�%w� "E� 2!�e&d �Km�&2.-�m!��� ��AP> Qua��1N�PQS�<at�%2!��s�f'uz:�%i � dU�s��t� asym 7cal.>�>s :EF1on�c�e����ab�C+�߁��_A�s�� pa�^]so}� F weYTM�.�s$�uR��multi\>m�1L��} ��d(J�)�J�+2 !�Dh!�(�6 Q�b�--偺1�a@!�-N#� �` . 4u"��ὁ�.O }�� �2�� lnJs-��.\)�(SH2-phospho �Zu*B�"*o*&��*NQ�� f�4�3V:�)0#%��equiva�0|b>B�� 2<�%:�'^!s�&"2 !*�+�7� N�3+ = �Celf� *��Ko!@:&��7 (��,�`M�w :n'�a�x�� 9%4*ns�*�&�L!g�.m�:!E��/xim�!">A�rrf� �1�Y$nlZ:r�v.��Wful�*bc�2�?two�%;�~S<6��"�.\D }EQ�i�a�l'4150ÅJ C FJC �  90uC"IFi� S2Y  ���)�vu!,�� �'. 3�^98a�4��-Z5�s�a�3�W13a1�[E�d>�g>nsE�!21\ ep-O� %QI���=���"u:��j�-�a%f5�59oP�V��[)�.�$A�6&V�beK"s�s!�Es�ref�L�Mj�Kd! �N-; �to,maj�<�5�� !�)VO?(-R� �a�q��pl&� q�&c ,�9�� n-bl�e52N pell�W WD40 �s5cE@t�%ɯ��7l�%6%?%d%z"tqLke!oM�:�Zs v ! YG�qe �ly���1.�"AppWaq kisq�q21a�125 ( 9Y,.H u��&X �732� 8ed)2"YM .`+M��E e���8a/ �McI1maiUf.baM*�<mG�@�j�, A Mh��7 wh� �6()�  (���� �dw�� grou��� �I�%qt�1y� �. a���6� �;�_ndancy �entC j_�t\*>t� -R��E�/m���UJ&if.�6pi*d>&�Q.� �&I� �cCS p stepi-a*'(L�Ge�E�as&A)!�5#}31QCZ|TY@�e&�'"�[)�-%�N75�):C%fMa�M�1{��"� ��Q�35I�"|'"s;mc"��Lvia ala!�{'s���L�� U�a_4er.m�� lu!4a �I�2-~�.� %Dq@�u^g��QIO�U s�[;��Ksa�=Teyra"*;, [51] 0rel p7 �gead!w!F9E�� �a�I�a�W��M#822q�.b� ��WJ!�547\��-r�n_6K700A�����5�x e�$"�Uw��! �&!`k=7� 8�> tryp_a ( 14Pyrid�n Jot�rdisulphE`oxidoa�ct�7(0_redox_Ŏ5.}#?��ENmmuno�Sin V-�)q}�8EX:�4I�T&�K liga�hav��G8i��Aa��n�r+.ye�Ie�a n�r�>"IZ.@�h�\:eD-�!�� 2_�1�V$25JO��e � .��fon6�A��gp� e;-Q!}�إ77BAXI3%��Y��j“&� �[6@R,�pe�S�=oF_1"}C5to qual�_��;"* 6 a!u� �deP pA`ofR�Gy&bVeq&F\�?I1b "Gp�J�L��i@=^#be��e��%�d�`�, K,"wp|%�i�h�z ari>!!�way9�!s"<"��$Aj��6orkA�/'} 5�Q�gv@ O.�0x' '+�)S%~lapE�kf6? � Z@�0)�t�$to$e��$e*twi�do a�s�Rdub e�dunQ��i(4�LI�-,ai�.%���� �$e� = inuo�M, ]��&H���g!) >VY�h%��"2�aT! �a/�Pn" 4�g�2BR��hdi���� ty��. C*A*%A6/"5"*FWsco""a�m]���- ��* )G QN���490�w�� F�VA�.�,%�e�=f ��v�!] 200"� �+n��.i�g�ks� �R�Wdi�!pxt�#�� ( 22��YE%IK��0�J!@M�His�jm6A�R�zlex I�x05%?�.�_�taw E�V/imSo.n_O*�ICn�QU�b�H�d!?`K2�mD�<'�{�+A�8y; �2i�\r&j�8�wo�4:�Rhandlgre IpP� MZv_�a"�?a�L��Di�7�E�U`a�jep r�,as�W*%APe��risk ge�oo ��#�� sam�� �6�Q n�A��#�K��!H<1p5f%�!,.#h (�� I�5e�.� Lh a�e,aNBp>urq�!<�-b �-�[.��EY&�O_#verthe!�� oD��F"�n��{� �at&Bto� �m���(��a�ne�ax- %[,��c� 5� broa�+�}�oeN� � -Ge*~$F` A ��a �. " ?sub)tr�)�ropfR$(�'to 965(�Xa�gFt �"3ʼn4 ����%���3SLiMF�&nR RM�� &Revolw6 #xl$ ��մTI�920Y{1�gDiHXWi@_� �I� te�lg�y%�E�C:I�l�:Kan�'��rMU�ari  cVu͉�nam" �� �Ja !!�U�4a&�:� ��2 ų!1�%� {�!�N 8m�\so-���4ya; :a7� �L� �ar �* ��U,72&�"�rm-o�R9ȍ�?At�"i8NW0�2�7eZ�i�"purtZa�� �Ej� Y�Չ� ~�e�. AoT�.�wsa�x �(���s��ve�@15&�  o 13�*� g՗��1�A'�iS2mh�X� �'.Y�� odif�""���-,"�#b)rc1A�R ��M[EHor 14-3-�,�@e�ll:U��f�(F�V&$�&�,a�Cry{ons�6\�XY[5CG J"Dng!"�: �� a�- �iF��Y�%�IA$;x%"�N[$!UN'W!�arc�N�"a*5)I�n�G��k. ��4in� halfa��� ��� � kQ��0iFJ�Fc*,-�5]2��,Eo��_�0.S N�L(� d>�Pr<o}R- poin? towaL&�)� v -*� *a�劅�If� *����10U�a#pa�P:e|e ?��+J�|*��z1A�2i~ r�Yspaʁ7)4B152K�F�5v��111-a��$�4���5.�II�!�9�m� g�"%# U0A�tF�s n"eVOK�"a�46�')�&�'y.z�R��<3�*Z 65�q�&k�J�t�a2 urioP, 31JkM F( 39y�&K U"q�)k20S8�)z:�u�M�A�A��M<, 5�16.��6g(��*\)�A_F�!3P�� y:�m�f��� 202 T�`�2114ra-�#sA��K�]�.*�<16q�s� 155<����ijxJ_ťj�,|V�,-�^�ndIo�!eB5g2T(82g�/%}!!�Mic" ���pt)2� ( DD8d�rD(�Ka9��<B�^p� b!� i�:DMI*�$�^�(� �.:3a��>� w� �� ��o�+��19�&00�rA�te�%.!����'a�" � !-M�aB�E��}�$��� 18�~93s� u find2�m�e�a�!�K �&'�J.� -Pn��N� ��F>upr �m�C�IE�~� lapJ l� sl�Dly��6Fre juJot E $�LGn��&� of.�i7!Q�>gTa�w��]f <&=A�5VPDBA��?�>ch�E��I*$^LA2Ie5!1�:1�%~d�0e�E]u}�a*�Q`&J#kep> U�t,Y� 423^C�=O� � > &a$�a � *sd68%�Ybrm>Ij� ���$,5��Ja�b 20B,i� 3&�).� T-z.�( 6S8,67/\$1D*n) � �  I�� �Q� 6�$���d�L)�^FV D.d�ZT��ω�208.��j%3�a--3 �!al>*m ( 4>3�E�� *�/F?�/�6��)\�Wma>i��E'� cX�(*� E/�an�*cu�P�Waw��6NMR5�.�i..�7�A>n����-�� +y���3�Q21~.���~{ p}!�Me�lac|�( 1%rCoEm� c*%5)W�1=(  Ain&4#"y9F>p0 I{-i� N;,�t8�7%��&>-!4��aSY�re�H5?��a�Jg" ��l,a�%�a!�mVe���� �@0& #�#f %c� �g)Q�c�b �.*FCi�� /fewQ"BT  ignoa&� Qy%:a{as fals�#nQv�!M� �"A�5C�� �g&Qi&(9���9F�QCZ�J�!?�DV-d�(6lk%:!�3�2c� �729"405� )��etA��1�chA."w � A�240-% ( 59a��䅦�:�0�u��i"j �Y�?�Q�t at.1a{Co�i���:u$,�V��(�eu ] � �:?(�� AM�[ !eW �%*Sv��eof/$�� �A&�Ao _ �i�}�;i�a�ub��;��a��u�*F i�=�2�&�@�$sͼO � ac"�n� a��*5&�"� ��b�#* 6M "�%2�}deg�56,�KM59_w88) humaF.%��2�)�ࡍ�  � A��Ա8R[SFYW] . S . P�u�""�i�i��SNly 206. 721�12 .�+ ��AJ��ne�1 �. 4AeleOtXa�I_x�"fɅrnz5{<��T-�k�c���a�pA\ue6827e-42 one-; d Fisher'�^A��%�W�{�4���V"�Z�{"`l r&�#goo!ag�y�6,�#�lfl�F)�APW+B� N�MH*b1��F��E$T\o s$ ��!�7"$�32s6�`*�e�+ \ Kk�qu�o$+ is���&� �n limi�Sto&φ&�_!R)�#OK �-���(����h;Ř"A+Q�� eA�!���-a�+�^�5nB)i�h��{ �q,�s6KR��5B-}�mky"3k!6�Q�!t&�+2D Rk7"��J t_[10� ��acqI)NM��� V�wKE��p&]�#�2�"� G%&�FuT�oT�.at *�"�je�B �m��n���=m�� g1CmKJ e�g� IO1��%� (z7,�m� �80 . 02"�(� .� |���64/90A��1 !���S46/64#�� 1ejq?�- � :g tK35�pF�L �E>� �X.J�q� k�.2�a|�QgI.a�%= �$1�)q�� �Vn*�0!topq6x�B!�941��/in�S. j9� !�e�!�44 �%e ��I�a2��mn]&i )�A�e372%1b%%�d -v]�ż����� y�O�e�Z�B�1��G�y�mll 66�%..�a�� :�.` ���Q!){? �*8\�7��6?!�>�9>)�BF-+DMޤr 1F�$�6e�!se�H�?�j-ᥠIFmsom�h���. T`1�!�>E�%�2 Q6}��)�6u�}"��i bestq�-|� ��!:d 4nN!+A�te� [Oyp��% �S�C"sb1ig� l Z%i� a� S  m���bR'E��p �-il$Zv� �{A�!���fic�M:: �yC�Rt'��f%�"V*}aar*��A�2�P){�K�}i)-a tA���A(�ni2a buil�(�|��“bla.�s\�"Y�_��n �a�*��"Yu]*;.�;�G3(qY���On�!�< BRCA1 C T�uL# BRCTe,OնA9#�F%Va�@6�E[55� {#d"@/2�n� `wo ��� ���Eb urA�c9<�%�N$]I�!�� �cC[9iMN�isV. FP;sge SM�)-V(��AI�eG w�f� :5S��5%�By�(�. F%��. Kq y`a&�!2qM%�&4RdA�to�!0ytoskeleton-a&�"� -� ( CAP_GLY� ��.APAZ2@��!� microtubu�[5wwIGty�2D/E2T s;SaUgDs� ���I/cCDE%(�D . {�P} )��H!��3�z!�u�ne: [EDA�B2}BQ 1}[YF]$ .U� � |+�aC)%�!% ���HC��<�����0$ ��o�PI����!L" t��.Nkd J ���s��*� �Ki�� �Bse\o./ trun[fs�sa-h4#���* _uq�n'6�;�n�S �}c��&�<e�d! !�Q�1ˡCO!Y��.� i*�] �xi��DQ[m���6Dng��!�%��Bcl-2qI�3* 2�z�V�*q;apopton��e��� pro- "vndc���?|[5�O[5�J8� �s�`�? �u�� ����9; ��!y ( BH�.�b6<��� y&SAK'n!� (BH-lX BH.�naI�E:�( �a$&Gv.� ��[5�A����o��6^A<al[ abl��/~ny��cer��E� ��<)GVR.-* }E�A�d860=&�hsm � e agoni��!��� �'r�~l��"ev�j-9Rq�l�C�CFNs�Yvlin� t4��G�z%�"�i�/`$JoRof-{�.<a0�a�"!�M�@��-Ih so� ^<"�" :he PawJdlab web v|[6�aj�.�--1Jgr�0. Two E :�@ R�! ( LR����~�!��) ;��q��j�� �&x��.��."�R�1t!5�q�;1�,��i�7r��A[�a"X�a�:G )c anytPW!�Ǎ[ ̂P!����xx-bre���er�&!A� �aci�@�;l A�2 � � -�&�:GC(nrm�a���s ( H _ 1 all-~h�ީ As�;��BM�l[1�Ft��Xr�NS��X�sQ�,aM�y�*V�eFClp ��( CLP_�Vap/*�s VQ&q/. G��at2h�&gr�L �� litt�W�#"� [6�|AAfFUH "l R�mA�.� &f+A��@�%%\�. ��-K�"���:rre_=�K">YNcuAv{Oi�Bto>tbioo�urinci��&�yů�m�t���sB�  o�8:D.:��"�n.$JX� ] 3E�5�Z.en a12d��.M�N":��*rTh� A��[ �� aoB��Ba��� �\ �)soa���{�:��Ue%��1s��� A�iUA \A\!:�#s�IXology!+D��yA6Ke "ed�1u, 127�� !*�ly6�&���Ae =���<�� U�:�b p N-,&� -�6"�wEL�f:�H)h�*(!� ut�:�\2/"#(�� FI �q prec�j�?A_.%]�1VK6|�*�hT#��t�u p]"4!C#fardw�) {+Z ����w*,� m,�/D5a&�%�� B$�ftkz�.�e�i6����F4m��30.�!����șl:��*S�����8�dh �K ed [���Ν*�L"� #�� �!�="�8ޱ��,7BUp�_a� 6�q=|rPw�l�"� ��y��#�f|���&*1�!%?=��!hn�Q �b$z �&ic�L���� �(� S �Y.#��H>�-(*"�+�)|a�Q��^%\�' . Kn&��[�,)�&�!^pJ�>! ]%so����Z�1. h� ^fR9�;A�+&t#-�)�DouM".��a�vel5P ifU62��engineesLAWsynthe9circuE2r&�[63 [6^{A��`sv��i7�!M`�0 �}#"�S'��M!b�����GX ��Q{, Gt��9 ledge35 �R�AG"�A. O�"o|& ��!:%E�����A� c��.��2�q�.u��-���AQsU�$ ݊�=��ABB� J *zwi�'s ���b� wl !�W�b-�![U1.:�>Y3�a2�a�rL���!�(6"� �E"m \%e2O] -�n�w{'u6benefi�m��K�tU�U"� &I ��!!e�G/ 5:�1$%��%�A�O��5���to��osuC- g1&�3�\kR`24 [STe�Y9SJ���io���o"= aa?�����M*�a�rA�1) k�aa2�/q4ea�2�U�v%ہAe}m��EyMh ���p�%+i���e&|�A�  �"E��]}A?ur�� @%Q �����B%�qPD��/Khs�I���I�KaY�e�RO+ *)�:isnd(č�"_FF�b��� ��!�~bo� neck[U)�6�.��i>l ����2R��e=*�&DMZ7ir%d!�=`�p!�.�;"�C&�S��)�!v"�ŁA��,�.2���a&+�I&�&� fa� techni�a��m�<2 & ��Se�7d.�{Ut�o�cu~����{UUe������� �1!O �3D-�\2� (�!Y� ��[ؒ.�vE�lk(r�v6��sNe?B�!do�c:^� 5ha�%��6���-;AFber� h�p1���u[6�YQ�MR n���Js! �jE2G,.�!M'!?�2I=�� qA��orbidden� Y�*��]�*� %�{u%��8_?��[� ��?���� Sll�Q. eU� F�4 hage� play� D�.i��6��1 E ����.xA�}:�"�4�B� �&>Sto"[a%��G&�r"as?  d�_m!e�h� �"Tf?(�E W( L ) 2.{)a��!!:Q_e leucí�2( 7W2n�U̓��)Ce75���3� �,�&&!h6�,A�v��Lle��c/!�?a�Q with�2�!bdHtifZg3�!�ȁ�c��S s��0D V���y2 �c2�,�!5%[6$p&2Gdu�w!�vC1�=HJX�m:�to."A9,�00&��F]82���?#%8���* �E+s!eW ��ro��_s"�AE �g %:�SofJ�s�$] e!�� !�s"�jEG.�.cƤ"N�8&.R&�.� (O��( e-tu,8�U4?Aq � ��ks� �1���6B�$���&�9x�(&,a�unf+�&hq vage_�>!.��H!(A�jO���*]��b� ����`*l3� Q� >�.���o��>O&�"��:�&]�1;%^*M���i2%B� *�nd-�-AD � (��rFKG )R��b�f��M�g� ��F u!e���{Fe�Ŵ�a1�i'*�G��-!��iQ� im�U�2a 6i���H�^���'n .&��+��n���V! 3�mzM'ZQAj", .FE�* F�,u(�$)AU%l(R*1%_r/)I �A㡇� �6A}2�� �_dJ�..� w�E��reN�g)%2��&A-tA S"���,��!�f�|q!��E�/� � B7w� growm�"y�=!�A!X!�� Like�A,=�"5.�.7y��in')�šraR.m �X��exx6ng�Sb�P�"B&�4/*�A1���2mqe�ҡ���TG�d�?; qa" �>!�vQ do���o��{&lƕ"B��� � � �c���utEׅ #L!:M�!���fd 56�� ��3Von 6& = �*�&}c{ a�e�M���'!�i�P*U J"P?�i>�1���;Y9��i��a��a#w��nabx r��A�^ 5("�{�H�Id�%�`s��R�"�:�� ez!�)�6� sc��Ο< %R�hA�P��2RRU6]xs6�"� )�I/� f]+a�s*$r�e��Y,%k!�[K!*�C�!kP��Y�Az�O5��UMd QB �A��M�^ lexa���9j\ ,6��ECmK<�:�!l ��}����U.q(t�*eBD�Z�a( �EԦ�� n�wygx �{1 ��h�*A �*!x)�� PV6� b F��x��y~��r���26�7_*�w�:&M;%�&K.��H"�2�a�� heavgg��|ex%.$[3#s�a� (B_?p�pns<)W.�M[o� y"p#�% �ٚI% J%�}�X5�a9G �Ĩ. A ,fGU�b]PC"t($e l�*�E����Tc� 9$�ny(� .>� $�si�`�bW�ry�p��Ctud���a���"Am�c<r �KBy#�1 "ƍ,�\�(�zA &� Xse��')B�4,B�"ngM�a�f%G �gb�an����?esor�f���yis�� ~a�` E��D�NG� >]bA~�?p/�'n�%] J��X�{b *me�]ism beh�3� -eV M!sFB�7�D> l��*mGV9�$%BȲ�Gy�" y ��&�ameX!}ʞw�@aiɍB� �/vCܦU"%����T�~�M�y%b.:��!H:r"�7�oruBqAV���:��� �"9cL[��c-�1-st��A�reaưrmaceu/���s^1��[6��6A)��4w1)��d�f�&*�6i��z��d"p$.:  ("d��"ٙ"41M\)�E�2tn7t�}au_a$�traE�%�dP�2Vs�U�@�i�q@�!– �O�ink}tc >���&0���y&�*�M ����$Q60b�S � �yCc E��To l%9 , M��e3 ��^���)*�ap5A�s� a�=%=-�uA� �� �����rG�� �o�U!n� =^Aأ 3 �au��pA�"~�N�U�i �yj�i� two "� �%R.��}R�i,\A3d)&6H:2�n2�`� 2qG�P �W`ixf�wer�'I�9>ʶ5 a"0D^�,%l��U�Uhybrid1XD� Z>q)�oph� �I�ANsA��i)/�C�*M !2E� tack3 M ��A � A�.���!� �abw!cZS�$��f� uE*h� U886P 6s -( �(��hP��al�5�fol�6�I�� re�v�u9%g5=D- "��ofB���a�>a�s*�I��E�wo�Oo�3� � s\ō.��7/o٦� j%vv : t&+E�����!��n*�Kw5�[46�&�<n K backu!�6R��4�"�U4E��"��U��g (b�*!�ereby!�� � �n" +a�X�O?�,��&}�9d: ���2 dyF uVt��4=:Q�G!���mum`!A^a% � E�e��“Inn� ea8P{�b5 � iqzl�16G n Angstro��ÅwB4:.k�p�th� �!� `�m<5�z�"L�U�*T�valN�ex�tis��Z !Z)4��� �)�P)�� tru�!a  s %):":N ��"����,!_5t0��7�B��&RAmaxEI� ����9���$vIo�"a�h�� fd��!#7>N( �Nt�6 �y ���� +�A8���\}�)xU!yV� Tg�.N!�e:!2 la�r�%��@bœ��I M��f�dA�MU\ O �L!rag �. EacY�G���T�3 �CBũ�f*U�.*JS� SV�Eork�numer],�/� .�nu:Q��V�N�2�&u6�Z�� SSP ���Ua����L�|}a<��I`a�Ee� �r�0umlmI�2PavecN6?--�� 9� .�Y��6 �SVM-ligh&y[70ɒtL#�S�� ��f��-�oOm<)ɦerr+m�E592bv��O�10p ?r�an�G:��� e-off���a-�e� marg�f�Kea���ar kerne!��DbmDi�&� !a-��&a*� d���-.T,�� � ��<.rUȳ�v5_'5%(�}�'5 ��)-��P�"@ :�%>�*�@"�A)���S��7c%��%�?&J<7�v� 9y�1Go4Ro���,DMIZ.�a�*�{Feim�.\2 Q�b�6� �#c�~_!�"�s�*�}� �.�,���), conn 7�e?6����� 9� .e�Ra \ !n�pta/4�H� �Z!�| A�p*p �-���tW6&%� �hmE:`�e�{,NACCESS [71]�����%�fa*O� �A�q��:(ul*��� .� >-�{1�QC UN#s!e�f/)!�F`M�1!�Y��F�! F/0g$ �D�#lg"� R� � "\�6�,%4p5m91�& *mm62uLC� ���stoichiǤ� -U-:)��(NBpJ"�54q�&8vYe�eŁKto��5/Ne�A�N�N4W-!y ��v*U2�!}f)�A!�\F�!��t� ��o_�ej�lyz�:bYOs}<N/Rl"�5� �[n9&�J�3��e=g�h"�W"8F��&vq�E�h�w"+ 9h�(,�orep��f�untilR)`6�E{9Ad�pr��l��.I�no P%�1 %]1�!ep;� "ǖ���3� �"Qw�v.���l��&H��iQQa�� %�E�%�MHn*�R9"0�� l )�>��xc)l�!�c�>),=;HM&9�?@ Z�z�S m � �| izedm9  �$5l�7eas.#"|��;�o`���Iv�xʥ= ��� ��� �1�I��P��?|""�y�;| ;ss8 U�J�%.� &�!�a�'���i2��(� L�"[�":3���?�F�z.L �) �tw�&9�= �� ��6�jvN��V� m �dou�)%--*iP��w| % �6w!�s<�a� z)� �d��"�@�b֕�I%!f�5jmatrix�a+�A)E+�!)-���/t�9K%6MPtOI�le"R nkag�erarchT Fg8[72] and cut th�e resulting tree at a distance of 1 , which corresponds to no shared contacts ( or artificially separated cases with large differences in interface size , cf . above ) . Each continuous part of a protein that was covered by one or more peptides was designated as a peptide-contain!0region . Thes!)Ds are non-overlapp+$by definit2d, and they represent parts!Qthe6�containV� structura%Nimilar!~`those found in known DMIs � mRmotiva� for this !!that e!Q0pattern matchIa givenxPe should only be coun!�oA V0“support” �a� Y$, independ!@of how many accepJpe-�0include it ( %�Fig . 3EF�\e sequence-based cluster!� , do�! V$ alignment)�compuvindividu%Y5�AF(e pairwise -q itie? bine!tto%�scoreu$is!�n u�!�.� �ssll�E1|familyEi�ed)�$e Pfam HMMAAfilx�AS1 i!jity�� fromIR! , yield!:a� �JO ��M:ir!� 0Qwc�$W-�-M�iU)M�ed us�xNeedleman-Wunsch algorithm [73]Z� g�� 1��� �1�5=as:�ij%�ere i%�j%� candidate-- h interaca�tLika�a�0e topological.-$, we appliA�\omplete linkage hierarch>6([72] . Notei�weA� both ���Q5A�becau�T �diversAI of a�\a�maka �� whetherU�](is always b��by%�sam1! ordif� t �!$0As a cut-off %j we c��0 .f�90%�y ��u�at��m�s havepom�1Bof[consid�o=Us.V�W%xd SLiMF�r [25]a�>v�Hnsensus��fIcase�(1G�1Gini�J9 .yA.��N0amino acid fr�:�̅! ^i��PDB��ndaabl�}Phe ‘termini’ flagU1begina�)end��our^ frag�u s us�sdBt�1!actual��te� r .�eUnrela��pr 1��x$( UPCs ) wa��2Z�F6$described m. O��J_�3A�m��sqsea�ed�)A%.�;%�inform鎡��koo low1oeK- )�re��DomeI,(human , fly�.ormE�yeastaV1gra� -2- �� dataI!��Y8s MINT , IntAct[HPRD [74��[75 6]�j ed�Lpeer-reviewed public�a To !"_peE�fic�q��exd hybri�r�s observietween�s ʙRW��y�$in network-�$53 , 290 (-V) , 196!c$5 , 566 ( %o)%$60 , 721 (-|)._�u6 $ectively .��>t�b A<�ac�� c� not� expla�~ �- 6�a=.in 3D&� s [10!�w� reducesEA>A"Eo to 4!#882!81!234%5426 edg1q.�F 2X8involve 7 , 808-}, 610%x, i111)t��v66-oM�JiTo calcu�6�f enrich���ah��omeY%�assig�Gw )\gvia.� to�N� \9�6�p esa,S � f hits!� regu� ex> sT 2� / ,60\ outAD�� :�W"en �`aA{�-ency t���� �!|!�aPst�Z"� ���I� at l��on1�h �;Q with� �� �!�� 's b� ng ���e=� factor� � a!�wH�t he number�� oA�at>�n�� $h !� ��:�!& alsoU���~ n��:q,jU-R6��p5totalNM�1�aG e p-value6a� 8Fisher's exact A� o)&�in.^,!�i� a���H R [77] .buEnviro� al eD (opathy ( EE�gsa�oci�!�(growth fail�],, micronutri�p malabsorp� %impai�na�� s!�(oral vaccin� setaY^ celle� mechanism�R(barrier fun� !REEv��AEW�.E�� stud� 49 adultͫebHin Lusaka , Zambia )�confo_ laser� o% scop!LCL!M; hist� Oimmuno chemistry� mRNAM A�of smI A(GLP�2 . 72. �T�_^,a U-shaped r!aionship � .�A���AA�urfaceO a�p!�cripta�9�identif�!23&� iaA�7ed ge��i�v .E�b A"��-�)Din� C�FenA�cr�@,f�y/ �y eFa� C probaba,itbac�al E�loF �eJ$ A* Iin�!l2Z"sBburden@6c.!� 2�*cA%9)may�ρ��$ortant rol�  mucos�.. ��o��Bic dys�V� Da!� asymA-at'isorder-A� orig��l�AZ�s�ropQ]&�[1 ]�,irst recogni!_aFt��nH Fd1 ,ite�e [�t� O c��X ubtl�.��nout obvi�� clin�9 �� it�now>� major/tribu* to, poor linearH(�L  )�m��o� f childre���ofGworld’�4st disadvantagop��D[4!TSt aaf�m40%K��ngun!�5� r�:age [5]E�)�ik�zi of�tal[morbid in ���fK0lifelong econ�t.� �It��ms ��l�7d0� .�condi� ()b sani= on m!!promine�![6] )��recurr� *]��A&���bF�|systemic{lama on [`  T  L!=s6H "� j su�s polio�holera{(rotavirus [�!�IV� s!zThe G� ,:v velodu� infa� a�in%f>�n a� permeabi-� as reflece ��d lql�f23ɵv�A�nitol� n���antibodtoN� [9�%ji�i%� direct ev�c�atb�is!��T� procesesq>!�e.E by��^"ABesB�~[wel� [ѕ~ stimm�a[inF 1  � liga � toll re�orsU=TLR? TLR5U�secrea6bpro-inM�(ory molecul� , 11] �dr!�anorexiI�d��}�Va9of  ���a bund����w9 [5Vs� �m�p�m atho�i%��_disea%�m\cirrho$[1|�-� [1�4!��@alcoholic fatty l�V [16�Crohn�� oL7�Lco� c.7A�^L�m� st-opexv�p �8Bso fur� eluc+���8swth0)�� �imic� E itself*U� by�[19 � sub-�. [20]�X���d �U mf �ot� )� �A0"Y | V es h��!4*�[0gut; although��is������ A9a�,ucus layer ,m&�nti �j P~IgA ,. � �m�& adap� 2�2 8��ar�;��vi�i)� mono��T*�� �  2ight j#� adH ns6�esmos�[21�[:=Z a keyo `&q 1� � + oint�)�A�se�.iv�i�>�!jby �Z26�e� [2/ C!deAi�q�� du�c�%f�by TNF ,�� � �1��" [2�!� ahe has bw�mal� k�ir"� ^e $. Disturba�"of digao?.Nre �<X in �EED�L!�a -��&� Y J�ina�� A� � .� d .m rem"al�un�dP� r e�,new techniqu�vi�isI��qua�f��*�=�1�geY[2 I� ]ta  ue.PE?"��*G�los� patse �in reoim�m Prec "ana�VS�b1� �%level� “plumes�(of fluoresc�efflux�!4 =6�i�"$OnaU��",to demonstra exC ��642,E�ero��41�%F��/ ps�IBD ov 12� th[ iod�g emphas!\���ofiYA�~:9!͖"% a� �of.>d�A2�`�j�<6Ki�!wC ,!sour/la������can2��c%E�doi*�/!siz%p i!�u�tipzh ��-es��d.�� �d&E"�&�� tif� e ex�to�9AIE��&� %tF'%�physio�"� e� W�volj&ersi a^ver ƥ� Afria{co�����c�$�d �xrleI�, 6�y BAH(��4!���a�:h�Ke;�P# � mark�,�"�W.�  .-O� �vve capa,ER4hypochlorhydri�y:�}/colon�� [26]c#measu- gastkpH-Rw_ L typet l"�A ( i-FABP4�#ڝ�m��.� -3)�fc�} bloo��FI %mJHS�$�!E  no��de��� �/"n$. Approval6ama�yWob "|' e Un� S%� Biomed�Re �8Ethics Committe006-01-v 11th Apri�201Misisia pou*!h�&ric- sou "'inm�w' ve( �uctA���of EE si} 1999�A�.� #recrui- ia 3-s�[s�m� ~ $s door-to-&7 fo� group�cuɓ&�E�rq"sJ�to�or�wr!Nn�IRrec}1incorpo�,"b wvis��A�r�pot�x _ cipal*[2gP.� con�� illnes�pregn�,��'u'aiotA or NSAID.,mo�`3 � helmiins ��A��a!�gl�eool�'pE*%�"q#E�!��"D�-��f, a� ro� "Sassess!aV.�a�ks�=hropomeZ( wei , h mid uppLrm cum'(ceoFollow!�antnBfas�*��V�e �s �col� ed!{100ml%u G solu%?��ai3���as sulphT hepta�u ( Sigm�Po , UK�&as �n_l!],After 3 hourAa"! �sa%�:�. A:,�e�fucat 537gE�15� ux. Endђ�erm��next da�h}cbsed� (�85-10mg diazepam%0-!>$g pethidin�(travenously�7� @� sa6��S )IFa o�r� *etfix�!A�a��H. F< 6s snap-froz� l�d nitrFB � ".%ser"� !ށ.!#.���śhll"�)D�=g�-ut�ag�ͅD!�pe� ,"�10)h4001l�by�!d� r�(details�  S1 Ta�{(wh�/$slowly mov�A*� ar��Mz�� thirI�u U�.p � r��! Watson  /�� n����*� ��in [�Morph��!|�y0on haematoxyl!znd eosi/ H&�"O!�R"� AK2Aj9%. M� a�M�>mad�.re cryptA��2b��1�%� d��!Oi�(tire length Vill�ճ^�th6I�area ( "4�y v HAHme���uni@'q�H@ nd2$) m$ ZWunRE�"� by&'g+r ( JLA�l�Q.?���at���KA� NanoZoomegit tha�yQKD( Hamamatsu Photon� , ShizuokQJapan��J�#� eval"semi-z`n+(�qfew ,���;A9a sub� f 14��"�d2"h5C!)�����fu�� �f�to�[fir}3e valzo+ord� uc ( P<$#05�Cl]$-B]$6G)ustandard&,a'�h�S�.U. P�%Kbef�&Aaa�� '�(�� V�}/�H ����2tr�"ele�-f�blithiumJ ar�AubS.����50an Optima ICP�Sr,r�nE� Perkin-ElA�, Midr�, S =aT@t 206 . 2 nm . Rej A^q/!�� 1�nce!!(�&) �eI 6@Valberg et al [28�� ca� a0er 95%I5d�" limi� ,9 . 5 μmol/&p���A�e�at"X in heoy Cana1'�5nt^. �f�jZ�!:2c�', �$>�, CRPAsCD� CD16�-�K α1-� tryp��M>compa��k"�(�9�u( �"to�U)!��q�x@?%y*� bio1a5� in8�9�":} *au'�]�mm�(tely priV5o i A�h6.Q-� B��v O�4n����extremm!m3I�-t�'�nte.+q� �nv.� fm %mno �%' �(in >35%d-�� �*��m�#�#'!w4RKPM/NOIseq [2��(s��. D�K9Uas2� ��St%13�  Cor�C� ge � , TX�KAll%$��"}�$bQ%uts3{o�#u��%A.6 oJn�3�wb�5 �!�0Shapiro-Wilk �*��001![&| ) .�� arma� rank"�� coef03R�b,Kruskal-Walls!es��u!�A�"� !�1[5~7N?*�t' Li8%regre�ť@or` :Gunp� aljis�&ZGbinaryCto.��8(� .. M,+�g ar.fmodell!of��!R.O�h(!� sepap 9x6A.s�)�an au{�backwardu"epa<�kinE�aA�e�A A�Yv,�<, Lact�#recy � UdA�a %� Irhamn�#, �,"F�K!�{9@m*y in Ta 1A�ca�= ploQ LPS aga� [&� icQ �"g3R Z+,�fr";* oly}&al.�!buA�to)w:��them . I� qu�&=nsatisf 2y�8���/so%t� �Z*�on 41�"� . Ex�L#e�" um)~a] tactՒ�7&��-2,�RS*�.!�*z &�r[@e�$ & !��#�� 86� ( 20C- whom� lu�l�:�!O�Y�}��Nf�-5XE�no2��U� high"�:y 0� ��x �sw� d��trasts�Bpl 8pt8���7!�a"�Ge�O* ,m��s�<� ��a�A�a�9 ���!rolC<d a6>Y �/ . ��V/5c�two ed%>;.$Q3� noWU)Eno�coG�$N?%��A� A[30\"In�parY�, ( 1E,hZ��7( 1%� ��%A�3!76AV>�P ���!��9c��9=�!-�m�� 9"> :�appear� ' veryE�ly�Fd)$7�4� By%T � �DofQ�?J=��,�Pqd.�q( ��) al$tru�s�O�� !w:-1ŐofU!is�Nkobscures�iq�De����Wa darkJen���ndE�UC!�sig��� �in�Y y as6t+.Q�.he w�l>Fp=r1j/oc\-<�ab"0Ͻ8� opti'57;t"�8�(�PB0.v�* - �Jn�9�s plan"�k\ Ia0R8beXd�)ga�/V�s�3�j= a brea��u�O�* !� riskW9 s li� "a�E1_A�"� mB��)?C:.?Fb�A�rJoe}E>s�*l&f6And� &; �^Y us H��:C� De� Q� �Ban�2:��i�2 )� �� ��?3:1�m6[3�'A.�sh�6l�AaE��2D . No sign.%C Cc���:4� i�e�unK�Fs�5,��%�x�,����gIer�� -S�!w)�d%W%�VE5 ( ρ:649*:51W^� o�2p9�. S�:K�e).���8�surpris��y�BI�2CWaDAZY�i|c�i�2�Sm�"�"��Nv�"��V o!�%�ym=Xe��2A�2DM�:�. Hava:у�#&�)}� �^� hB5�P�)�Q� ��Jm9���!��*��0AH"2A� ���m3  �-aZ�+�4|*W�  a,"'�!�6��"�*��� funneaY�h"g(�� s6(%-}um�s�6)7[3�: �A�g^��stI2d .~7 �Ie)��%t^�!wMF ��he}FE$ !*r(!�c�D�"�usUummY3`R�W�,�6t�y� adjaR)%i� |hxM5�AY -91� ^4�nbEngm�5�&�-�Ef�P as\��%O&�A��tissu �OX"�to gauges R9(2@I��0�;U/bunr6�Y")A� wo!p!��]�3%( LBP%"��� e�# P�!v�0*I 6�R&5 M�� truc@"�����-%�a�g�J��2�&������)L8m"�&� T. n*� �i JX=,I��2?= , n = 43�"H= � 0+=N14=�I>A !�� fX��n"#>s2�a���e��(��H.�< �:�R�"P �,z2�(id4BO�&�Y]AU, >>AsMk a:B !, e�?E�!�w�7;&or�Fa9=byE�%*� �rl�.�=\�2N-�lWa*�?�r��M�ia��_ A�>n,"� M;10136]ac ���SA:�me� 6 5900.6EfA ��jZV�U?~.� ���M(CE(Co�r-intu�?, a�>s �0 rangP �2� ��= 2 �=}%xi"R>6��Ui!OFUis�heQ����tilO4>$ve�&��.' 2��),a{s~ nt �R� lead6 �9� |0J�. Base�� sma \N�� I �n jus�,o':he!J<�+ 2K2�): 21/48 ( 4�A2m� �2F�3�11" &��4."�Eci�HI� �%С�A� f�*7A6Tu-6xBG �tt�Bris�!> �o�; 28 �,�+o6of �4ed|J��$� A1�>��k�,*|" ( OR [K95%CI0 �,&�C} �!bQ%2� d%o�>�QI�*E�:V�D� A�A8�ȁ!&H+��$H+���6{F�, �-:5neg%t' smoka'�-1(7�8� �i�9� 7!=706a�65;.]6B C�!612�6 )��E�&�ŬF(W� M%�V��� '.��a horm� iJea�1* � mas�/"bQIBS�$��ed�') 46��(a�or2("3!J4 +�RtC BP( !��V� :7A�5Z1!{22�#lagreads*%, {FμgSm�u�6�Leu  2�<� geneI�i0#u98\"%v9�! 1% mb d��en�a Agnoɥi��'V> X+�bVmilbs�$>r (�1�&by1rcy!-�)5P�wF1�a�}s! E�d down-�N� ��7vP�metal�:M�~t�:�lip�J DMT-��A5l�UferO$]n"S ase nv14( SPINK-\serpin-90s'lz( ( foil����<l�(;sins Is�Reg-3αc�up� 25( c-fo�B�ranulyH#(, HLA-DR-β tCXC10E^Ta�.��<o"im F6t�cy aN4 oble�s= A�NTIma��~��;08>=nGK7 emer�.�s  8t!� blem�global� ,�c�6� "�E . Im�38ha *N�d�9op,�b"H N-��.� ;@!�Ci]N"�5Rg tH-� "�-re �a=cessfulroach� v2 |��[33�t�w"�)Y�7�n ��>�[B�M��T� &9M�=n�R<rk�I),"rap6�.z&a8��;`�H��-L%I �rn�%o�6! noxaR9%c'H�$:*�)g>F3s�kNJ3 . Average' �A��dl�_du��European� !(����0:q-�Ls�Wy�e��M:e%�w-ic��G@o gut&�!n&�>a=^at� is `&� 4 d� )M`I�aspMm��]+il�;� �>�!6k!��"\. F��^S,U_.�cha�"�:2i6� "9@ "!�*] P$!�,� w�.s�."I se.p�p MU��B���m�c�A�as6�) � �^�#*�QA0� o�I� Gram"] � wall&��17�8�0o��<it��s �e'"�h83`l��w�.�V�,�5ur�dchroni:�I%#thinkj�,�6�6eD��Y�!EUB�}�J]�(,��-��A 2:�YA�allel-.�=�Q�Kwa6M�$o�L�+�A��c)H,�U�t%� � pure� ross-�alEca� 3>i�m�9�_�1n @A�%4-��#g natGUo�9d3 ��6��]iPt)q|. Len&�*i!�e�Eev>*mI!~"k<�� �,t� "PU�sQ �ppdVeass�6LPS\ow�� P��R�B!�;2��an �Aud��d�>t) }hdisrupm�O'� �2�(", � 225 '� 5|�#L�&Iyum! bd!�3T6E�"QH�0�Ko�#%,%rE]e� ��  U��P._1!li�� arte��_�"��e_e�x��a.'�He�xy :: �a iod8���YiJ:"hV�a-515}ce��sM���3�Dr �� ���G�A��*�'sB�=�k!�L!dWz.Eal�y�heE�a�G!7;�Li�:3[2J3'K0���F�B uncl+�c�riEz �apopt�K(ͧs#s 2�A�#A�2�� necrA�<��&Xplaus�$E��Jl�8orU��"])��2kgB� �� yM*�,of%V�'CT*;B�"�0feedback loop�d�ievmY�&VO: V����!��s: V���(�:0A� NAin�~ic��81s ]$cta��]� ar�Zmitig�<_6� -�� c�a�IA&�H>S*F }x�[�+wa�&2����viv��gSB�oCfavy2O *�L]] � ,>!��~ yabyggg��.NFI�n�2ur)y.v3| `�2p magnitud f�$M9�S. T�V�N5isŤ needGZFo�6�fu��'+rdoe seemaHaduO=���B��.�{ �C)gd �o-exis�?�A^e.�$N�!� RE_v+asE��M�US.# else |��#���AC�Hsp/ "V6�[iP36!YIn�`e�v� 25"AywG &:w'K')��z�lit�Ve�U].kd4"W���fEEb%(���.��E�.�%ag6{ a�=� BP���:-P0TE�tin�<�ge�( CD4�_s < 200 /μ�?�%�stu� e�(���]K2�inc|noS �!�"� a�. &� �0eM�?rik��.I YQM?�CI"c�Ib�H*Xe^!Fa��c� anw%zQh�E��"Y"cyte-de�Sd*�Sq-�or'7. Our�"'i BL6fi�a LC>"�EAe Tsb��(!) #"%W�I[1"�R �� K6 oubt"e�i�4ER~A�Aj temSe.Dma�3jB� aj�mG A@�4"u�2krV��"T9��I�d�k�a�n�u6�e�a hall�a7�S�%T�T�Z�_\gur� t"2a�ea��d ell-%!o_ D. A�=��>Aw�g�Hw�6� programm.���n���� im&5Er6>A�2N�k� e�aET�d"�5�ct��eoc!+ea�i6� cr��*K A n�:�X >~V�aup _��E ` �m�replac!�ot�\22��Q~��&�qus f[37�ڙR�vallqof (=�d�,o��"� �h�k ��&wFswM��P*�E6�.peo�6EEE.� n$ ���!.K@*Vp�"ub"�GC2Wetun��>r� -���:*4(.� �%��& 6a �� E��i=�6-m�e*;�:��[&~'of����e���to�1�[3�WeS�supra-2� E��Hy6jM��, �"aR�f]J*�repor��[39X�3����͓n��Aha�i4 %�-� �"� wV\ '�M[40A��e��v�.QQW w[4[42LX�>ng-Cngezogu�� edug:Id�PUCh�v�_ tria6+aupZxA��Se 4short bowel [4 �se7["y L�!ߡ,D*al6,.��g!o��Iatd��ąT.a proxl�IH�U�F"� a�.) �:/ �>��&�e; ��.��l�F2U� l� easy�" R� �*�i�U�0ELISA , Radio�AsE))7�p�%i$wndl!\a4n$.�f�E7v&Cr�%xu'as,!1 ng/m!�4]�c42p by RIA [4�nd.4-6-30- �[47a|/���`qXnu�r�Qhe 6Wud ��y�8!��-a*2%3 . 6 ��:�p^:B�J*_E*��A]. f�ngs w�F�. %�2�cr�K=ofM,syn�0�Ya\ A�� )end-orgau<1z�N�ex�C�I� elev�I�-�� �U ~-Dv!,�q-Dg&��5!�v�7!.C�vealed�05��XinsCA�JG0��e�!�Paneth�ma �Y s HD�HD6�:� �[4�w��e� ��M Hl1�i�!*r��Kio�~ �u�H�B&�3>\As%�"# or9"�c���� � on T-gE�H EE[4b�p&�!����m!k�pA/�r!��.��94^!z�Wpk]�i�!in 3�(�`��lA�sNd�P� ts ?y~rc4 II )�manganc�Y�e.�d.Ca-I�in0�Bb:s�`�_G� (d�\ste��< ��!�'�GreiP!G!�ap) �us�Orrhoeby�E���pl^)�AS�G)�ge7j&�#%%-��o :�ER��2x#� he:�e&Z )A K�"s6a$- >z8E�.�y��r$��e~ sus7�!d@atrix dFwQ."+$�%Ť�RsrBAb5t Tr::$ �K&e$+1�`�*�2x#"R& a��W�h&� =P repair [5� 5&5DF� TFF3�&�eqnt&S(M6e!�:�nd:=^s�!yie*�Q}D*%,O�lO �{ !� � )��a��D�Ze @$�pl�<�jD lockw re�h)$k�(7M sCCor� �o��K�Wr!su�2ͭn yXeb ( SI�Qf"widelyY� , ye�qo[u@!st$ph?+n��H� B�`Xxurnip � kle ��*CV�/�ve��CA�amL c:�=��a��Q�>*�K�whI�e���qmraw!�� paAe tu6 SIEs%i��d A;�)>}�I�%M�"�tB �"�#l]�,���on.* ��mrus� ? ��4!p�"CZ,.J6��  5 Rm� G71Dr�mag!+ �MH%HOdpe 3`��� ME�a�;� q� U*'BՖado}�a�^ =�manag!#"˄50 ye�y[k%,�c �/~5o�ch)��v^&�R��oiLG �or< BoA��&�mun:��Ga��UB��!.�-b  sp_*1G.ed1e"1_" a�2<yE�p�")�-�s&be!����mA���; [�u. N��the�� !O�&Ao sug[T��*� *�`� m�>�/ �B2#�qi$ de-.j7,5�r�M�!�&!� �� I�P�\*�,� )�bec�9� omi�1` I�n�s2_ *� )`l&xzc��k��5�%�&�v� �ueK��Oa(%�r&]e���#~2���e5cQ���[1�\ud !#e g$nЀ inhibi� stepA���- w[2*��iAASi &fe"�0�s��� ��i���ware$E�K0�M`:-��A¡ҥ�D-b�j�#�!bA% K3��,a.�|2<\ma�( s�*�� �w.� � 5��4z"D Bz.�t�r%�G90/.��  $l icosahedA��g �I#�b| -a�n>�#m�at;�*�K!Ta�e 5�N|B!�2>�p� n'�? —p88—K�*��� �r�))e 1�b �� ��Q!7Jiddle!L  X , p8�pW��t�r ��b.ic� ( sgRNA�E�tA!| -to-fIZ� ( MPs; Fi�F\�M 36K38!�J�= ��A�s)NX capsid� �o8hu.(��?f�silen�6uCV%�is�0ubdispen�� �)�RNA2��! esum:5b�9ar$Faimitochon1ql�Ser membr�Shp�enI �eA�.-&� ( VR��9 hoK`�{A8 ,��� @\1y�2�-Tm�"e� |Z"��N–rgIDTt( yNe�1�  a�%6�V28!�!�i~;� ��"s�'W !���:�it�$s���[� m� !\ra�n *�in]�>�2`�=f� denyi:!A��41�yMZ1�,,pl&j ��f�ſ!�u�:� d.� 1sv� T9opt%[��+�$�s�1ᡭ,{iag,?!� �c�嘁�z� mu�KP.�.[Ag ��del���э�CP co*��AS���o?�i�!��$)�Mo��,"dF�N�� ܩ�3�S( sbxR� �!��+��!� A!,_sg2G�TC R&!�"_*!hA:�|BtNkG B�)p!(Q#F OmCherry6ey� cDNR�flank&% dup��35SA�mo��!2k:ina ( 2X T ��caulifl�$J: inse�(���m)�Fid��t A{Ag�c�<um tum�7ie�kpPZP21�[�r �D!@r� �a�lasmids�eԁto A .2\&in C58C1!�,3 t�sit�!�-GU@Nicotiana bentham leafEus� agU�il{.*6��J��g�� AQ�P2�<�pe�enB���AB��2) �#���-pl�r2�I�B“A�M|defM5 na/�of ?�c�s%A^e 4mo�2g �ar�"�0 �onVjb#R+u���an o�P��a�9I�CV� �|i� ��� � s�l�<� -�"C9q7Eee�� 5�(� �)D15�^[�i.* R>ru��a�facilNl5�Fpe�� 6%p/�!s�co bushy�|n ��,%H� � u��") &].�"�l,�4 r�onJ�/��)N .>/�inm"�[�F]���t�^in����&�G*gce$Eia��2y=�sa~(BpiI�nF� IMC�a�pat#�J���Ag�A�lef��n��[n�]���� L.MYRR��+��N'���l�3dev�s�B! EHK . Inde�PH t& 0�89H�%C�repexAO�'t�&�J1%E!�.� �d �gr{ �6 : e��2,:48��VY"P"��.�!�[;�c�p��<:!h�1i�!�r p1�� 4)D��M( A9F�"7i�$nB 9u�5w�C�u� �3! fE�%b�( i{J&� ,�?^�]�`G 0"T m�f��A�M=��.cA��.xG�� � (8�%yeSW� mu:��Soy:c"�� #H����i%�6s3�3#3Jfa3� ��n�y} 6�2�  ?� �W�%�[E`"���i" var �4th�!*9del�|&�]�*tq>t�"p��o&t�a{z�o-)e�r *e� �nert%, & 8=%�E;A�oJ5B9idePGw�A�,�eQ&a^.+H�T,K in P96�� -aZ�!U� �q�se{.F�ofMw�)AG ΔMPi�R.&>Uq���diP.Te ��S1���Knelke� �I*F���� r�jRA�harbo,a 92 nucleot�2( nt )A� � � MP� 3us�.� �u.��U�!%"(F��.�S1B �S-.�!���!�)�l*�IA�r4q�Ac��!�( h�Jɷquickm#im��C7�� Rby 368. Ba�0�=.�i�ent5�MQw�%�A��6few iso� jat 48jF0�"rr�op.���A�exp�EXgraͩ a�tB�t:��h, 23%A�nd 33�5 � �#Y#l�k%�7i9�9120�Q0�� l� :�� . To sum��.D.�=> 5? 0i�d�+�Ho�D$!� �xer�:.c9�6aq��6s�zR��� +mmA�d� cha"�%�� &Y��s�'tt-d��ya�#��@� ; irU|!��bloaH( W!U� 22��[a7��#��s qK!�, [<�2r��L��a���� . *\ :��ZT�^!l�H�9bp�[�pa4�$��-�o� "5�H1���� bXN^P�!�!@K�&�dr*�'�!�^.BAaonClla;�e�,nt� �]<(or�eiru2��/uXt�F�V ^�$ I�-0EGe+73��Zu��%����& �reqD3&SI�;WeG��.to"\3M�#R �l�='^Bl M}���)8vocerK�> f� E;of_�G� R6��,�>�mIQa� ^ci@*d&�&�Gi�la 16-ӂ��LAs.�+Ź:5�EF�hZ�3E ��&�m>6�ia�A��r�� o�"e�>�.^!�9#td RIx� 9�=W� .#� �b�8&�YAtm�\(�in*(s��t"�+�-�s RA�co-)� �*� "t �W�xt�:�d� �f �Rm�TC&��7in!c�w�6�,azl#iNRL,�tg)�! �G-~� inB���%iL3m^���> "l%�_�f �@��&� A&�TCPQ  :\)�KC�isp�6!�-P%OTo*Y�?N.:pt���� �(R��':-4.& 2XHAG-T �Y�WB��6��-HDGۙ�2� p� AE��� 84or p9 q��:�i%�#c�y robQ`��g�Apsol%U�)I2��3t�#V�2�e���dF\.A�"9B�&A"�.�. fV�` d�A��m u e;� $rame-shift�)!G2A� p28fk+�,�]-{�Xoa�R.gZ�byK!�A�[ yDAiA�p27v( -p27H![4in�H^:�/8]& �ed9accumu>dA~ �at�^-R *�/G��pb %G�%��zɠ*�.E�NoD$rn4 [N1  WBQG. B�U�g&A�1��ko%O(�� �:�i,m,!�f���G`-r�c(  rs 5–/b� �8�,�~(.{�+ng -� G�g� �&' �(%GMe�2!���A�H��c9� ͬ� �;6� 6su�|�!* 4�fic!ot M2A�iT" ou���geA>��r��iK�2 `�26�Oco-i ie(� geneOud �;"&B �&Y"H3 ?�' a 4-�q1!ga�p88 ORFQ�- �al���&�1r�4nY4s%h s�!Q�� �L 5)":"a�]-_A�nAZ����a�QLw ci*.:Fuɪ�:88sm����(up���5�2j11G6~Fis�\�z��'isG � ��@pE.e�� asy 1*� wild-type)9�.8�aAlso keS&nWRX��� in I}��X++Oa5"��ͧcc�]"�)�%59xuO�p6p�Ae��{, "�� KJ:�alT �-�"TA#P�JA &g *ae9�,�tomQCona5j�<G � ��<ly�z���U%�c&�IN!=�=0��:�ND>�2[�2%h��H"���!+e�B ��)��rM�aMof>�a�sU$�3scu A�GA�q�@ ;�A�� F���*%?bo%�;;m: :� B��Wof�viNa $:�#�- --�! ��zac� �K2� �3�J2%=�B.Q&!)& :h(F�A%�#�T@A�1p)j"�R]�0-��Iat>�"�+cɦgG���C��urc*a{X$"P-r>(� �.� ,fa3gh��K\o{eQ.�"n-lqLr%�.l�eF�l5!swo ���+EeD�p SIE:� )�V)���.c"D&�or>>���=ako6.�Y�> ,� �R� l�WvZfJ?ostL6� �"p�A p28/az�N%Kag�( !@N \0�&{!-.�o�"t,�h�MeP��>� �}]i�D A���aeatt�_dA^Wu�� %a.NS3�-(B�f�:s�Aa�%�6�+228QbXa&�7�:e`�u6(� 10Om!� diam��O.ns!��( c�I!��&\<�|f��co--7a��Ho$c retn7um ( E�%��z�$ER-��;��e�M�f)� 6=@i �w{(I�>YDAPI;FP"r$�5"�h . Si�><��"� al !���_.�* ( MT )*��J�LzS*;��[1�%[=S�}MT � n MT13,er �� �i�!3Au�)�j܋� in�* ellixdoŸ-�)vE�2���S5�� occaL �+eaA�� /ra�(��e{=� a�a �� ��6�<�\be�\�>z inct�"�y>�I riguQ�:*�2i� rw�i dyna)�g�9!�ir8%N��a�B�&t a��we�3.j�DF9M!"�hs`%�,"K&�%� ^� byMoB-9BU�heEm�.��start%�e�Z�>��;a� mia��%�%��aD;Q�A�e�u�re�B� Qbe��E�m�VHd~k E�S�Bif�b] a��PC2��I�iA�)�d-�x g�w&�/ \c=�> !G�sQ�Y%� ^K�4!� ts$�&0. C�X� �;>�*�<�5�۷er6�,�0�E&v#��}m?���, S1 Videoi`Jq�3d&�9 q�Q��l�)A,u"��(%m��E"!�I( rYEk�v �!�/`�G�U>$���� a"� 6L�yA�RN0� &�&� �2�k 16W� �saa 1:1 �x��a�ir�ol �/a�*�hI��.�.u �|���s ��ȉ�� �3! &/'!![i�7. ydHa�o@��^���� Tf"ڽ�KF� ���"Z��k ze^to=�)Htoi',�g %�` ն ��#�d.�= �Pof%Ev>�f� n�Q�NB-�X� hWy  ?3��YzW4E6s s)��1l}2��+&h!q"D�rFs �unx!�vs�N|�Ey�z��.yW� L1� H �v��du%� inpu�_ one-K��Eܥ>�JA:Cm�a� _hul eRUK-u �-CI"j0���� e� d �*�>ly �96�,��AQ�H/ ]�n�'!��r*)> �he�%A ,0�+� !a��$]#�>�G�e7&��p��� �c�/��]�s�0e* T�X� *�� ��s�i�.�"�X1\�1,�h��n�Wset-up!  usqn o�FB�y!���B��BRs!y� a��HbS���e�A��X%i28 !%!8�-)961 � subji�toa�\mHZF�",y2�,AQa�rNR��_�*� �D�B�$c��55H,28 kilo-dalt�( [kDa��iNs*�Q. S.q��verZ�ez m2i��;?eas&+�� �� ��/a #Q�2xI!�^@`Sis��i_*u notew=���7 ]R-Z�4N6 �� "1@10-fold��""�)%�I# / c�)z�K� TVE -GFPR�"�1i*-k"D&�K=� sA=�6!'.�]-Diơ!E �ȱof�2C imp�"�Y.P�s8m !���eI�*�Y&�ah/: AARU��F�� "=Y�,i�m� re�):"6�|e$8��$U`9��%957�7�! ~gPA�� ۡ>Za piv��.�9(�I|cA�!b9e\ "u� ques"of�R�!�� �:�.�,%�� �!GagL��t] or���ـ1��� Z�O��� need�]b%2�d-evf���A"YZpuzzl)�A�nw@H2i!Ot�/� �tF36All �hWN� {)#f��U %^ D�*�� (%*��S�,�=� O o%�hAc,��>;� C n n��HAabs� ���!in*B�A!� ich 2Bur�)E!0�e�� i"��Qj+J�(:� ��)~M2@5�>�9�aEA%�I�U�%�new=�:�z,)�M�!u��+;p�6!2"�-i�?, G11-1,�0RH vari�8�;�e"� wa 25-aa�7G11”0P�J�1�β-�2n�E��� 4� ��va��9 11Iww$7Dppa�d r =�E&�u �}/��2,�1M�2 �y�I>.^7Qt@;n , [�"]���/A)1'I# H[m�PE�j+ .k��o�`on 10�-|#�0pZ�*PF top ;. 14 a�&l���.S2��lSE�$ ��B$� �8j o%�#r� �epx�l4� :�AnUe� trun�'d�i|�q.Ů2�"�� � �Id;��#no��AUG�=on0aa.C.�trD<- ��ai��assumpN%�..Q�ORis^dM���lB�, 2�!N 4$"�AT l�%P.{ z*3S2$� 2� 4G2$�Z.� (1��so)��dB:=,�<,�.�|o�%5��hjJ.��ypE(�3�Mi�uCKx=i�!=��i���� _ ��A�%��*.:tag*�!�A\>�. U���`� 1&&�c�@��9�I!2.� l�wi��}�t�N#(F�u 4!yeu��!�s y�5�#R���% x^a�zUx3 �%�E�v��uxy��]cer`$4�e��Q(����I~7�U%L9,n\6<JW�yzBs9�2�A(k2=-6�-Ͱ!:%U 59%PU��V;=6�p.�)7=Aa�y�bYtv2,/"�'A{>�4JQe" / ng�$a!� ��N�>�1[�pD� -�  ���ك�1A�Ő4Mc�Am�?%p��U2=+F�8��.�R�A�ɴ�DeA �� � ҩ� %"p�t<�X�+P��o��q�NB���:aMu�N��R- �.\!�%�"a%��Io�V��Y�{^Gfdyng;�/͒Aon5B�f(Bin�ng.��ikQ�� a�Ձ��*U��V�:o �x !��^N ���&� ad7 �8!�uN )�1'su�e�iQ�2��v\�Ue �Em�&g-2E ( 16�<!ayͻ��3%��I�&7!�B� �e� �G6�U�&.N�&fai)Ri?�v�!�a�%Id`""� I%o5 =,*i��rl��f`"&�~Wb� Eqa� eu:G!�ar-v R�;* �IzV�2�e��rŇ�6��� –-g�� �Q-�U�*�08&��&&��a��&�"*�&I'wod5 G#jv�z 2�QY�5n"�^. B�32:��"��#M1�v�Ē��h}q*'�!r=T!��a�$�io�� ]��a"4a!>IN(b . Deh�of|��?A�f"�H�(E�"�4-�|!� ��'����NQ�'�HM�6���Q1rF5>a@��5�[2S��.�(5���|2Gr�Rstitu!�by���G�6����&~"if��%'v!>ST discre�C<#Q�1�.TF!ͩ�}=�!Y2*k)��3 QB-2P>?U��<%�A*e�U/ �I�sEȩ2���NE�c� `V�&h � p��3A �ar�K>*)&�)H�#6�!� (5r+-�)Y�Ar'$AWn��H��;2�%7�BYC�/�~�# ��IAvaAr\�:�3;�%)}S�f!_A�)" :� /4��HQ� l�Bc��w�_�/+1]\�5�N �JM+WZ#foɖ�t^�+�<a���o�:�!-o=�5�q: 0b�<b!�.�2��x{n[:2*�&�-aMn��oy��X ��[��:��[�� �w.w a��I �"p%u3�g�:h�7.[t�K2�AZa3 oRAwgo�ye�Hu &�8A)�A�|>omi� ly ϳ��t& >�����4M�.wA]Zy *j0&�uin0a0� �"� Z2 e>�5:h��=�.�"h !9%�(�KA�pZ!(�1�Λ=�o!|-�')]Xsee)�E�)�0�8�]yn�Q!H&o)�&R6���(lds�Cb@m&ǂ1��,� ��,;�! 1z��a4"� � e�L, brown�u3�:=� 6oHB1>��"� "�w6E(h�ie�խ��A2),R�ele**� [Y�cc���#� �MN�PA&�ME)Bm�&.dl}%M Y,-R!� ��s�do��:��`z;��uv I�\"� .w A�A]._ �V �e��n i�"z:�"�DP?+K outpF mirr�p�i�>�-�� � J �$d&he!1�K>"�#8 �&) ���}�lU���&~ 6&}N2)J��-�coJ�F. M�3�<�?.���a���!t���+H�$R#0*e-often ra�u�!n!�� �3inũ/�/# �/ l.S̭S3.hSu�'Am>�M�q&l�/�rnab?Թ�Iapt�4picf�vS$�)-��(5�Xv&��/��1x�e.��+E�W�=�pA�:|"(�C %�zrc t!�b* AQ"���trapp!O fres�0E4�d!b�c%`��V$ �Y�*i�kRk�\�*sIm�w� 9�%2��� convX\Zk .a1as�'>(:R%Nq� -�"ry9�i�L_d!Uo!E#��{g��3A$ F]@&�G�t6�{ �%, [-&�"_�a��/.�4!�)�2d� >�^�/2d!!� Eos�/2��qAy���8f�y8&V> ։�e�1Z! "�m/wp)g ��)T% :�t$\`*�&-�"�U�Y �)L^%5o>W$AS2F�u�e ��)D-r�_�� 2�W�W�� �>#<�f� kJ�� 2& s r8&p#..B[ n@ o �.�ifg!Ag�_!�cda C�9?-�4replicability �of the replicons . This was also confirmed with NB ( Fig 6C , lanes 1 and 2 ) . As expected , the green fluorescence reconstituted by G11-p28 and G1-10 co-expression�@diffusely distrib= �0B , panel 1 )�xo our surprise , co-introducing�se tw�,structs intop same cells led to approximat� 50% of fl�t .to �x both GFP and mCherry , indicat�a lossI4SIE that allowr8he simultaneous-�ation1]%[G);$]_sg2G1-10p2R >)�We!�clude tGrM-borne U%x incapablex exer��, despitretain�Hp28’s activity in ` �. Henc!�zI func�p281�( background�likew!�$successfulAecoup!�from it65dby]$N-terminal�t tag . Our data thus far reveaU%�1.�$ly weakens��propens�to form!F lusi!�Acomprom�� abil .%b%, lead!RusH$hypothesiz=�)/\Lre directly responsi!�forUH. To further test ta�\Ts , we asked if untagge�wtnM�ed)ha TCV9�could �do!`n �aDn�!Tp�m enco�1X�do so ��generatmTCVY�rM%�Red�but�iEsgRNA2e hich �noty� unless�transl�Ba��erea�o�C is presinEh�K��A��8N . benthamiana!�f�Dwer!�en treq�za mixturen2AQ:����6� mosta�abF�cona�ed ��!B!r!��ceιy4 )�m% ��pre)#ial-��of6�%�A�Me,�.g?re�of>�@QJ( )� neveA�%�I�5�-independ!�ofjl��on%�ImportanaTb� exisA�0as dense fociMs�M���O�!�coale�of�$through an��er�KonI-"Iede�to>. Alth I few isoI���sh�lB�ѣvEk:Zrep)�B}4�� ower leftE���%�]cany�"2Y, sugges�g� they took!Oonl��:�U�Ege��h!|�ґKsup!�U ide���x�E_ve sta��p28��s%b�:�-aggregI�freshA���im!�<.)r�4$superinfecݡ9(genomes . I�0cur�T stud0 we duT�a�PamongCvarian�s adequ�explaia��he�>� , on%� TCV-eCed! U�protein�%�E�( : � inct�\ali�O ural)K1 �edM|. Coll! vQ � %�1�a modelu i��a�  � 2�fac�H ator�!�or!�e�azon�vaulaE� cent��onM�7e�FirstL fore�;� �0��!Kr} ��.�� �derAiEinh�J*  self� e�a�Holigomer��TE�4become seeds o� )6 addi_ al}$molecules .��d , ult� {to 1�e��6R.�"aAi]$very earlyAgEl- inva  w��!co.�iilatIlow�vq[ polymeriz�� is s )as%�> t!O, necessarilyX!GJm�ytoplasm�Q$ ��obably�S�{ula�� step%�vir:� � (lex ( VRC )%� �! � A�incorpoM�of p8# /orTal RNA�!o� �a�Ayenclos0A�u0by mitochondrA�`outer membrane [21 , 23] ��7���.� O)&� hq�eTs!�reesi�V��$is undergo���vy��large��u���rogenyD�/ temp�Y��g�toIy$high leveli*is��!�$urn accele%�v-=QPw28��� ta� �of over� d�-_eA� at escape9V9�, pz t� easy�pp!T�P���j� ^mo�(%�iU!tho�*�Qjf�u� ven��2�newA�AF���>3 !�� . NoќQ�2-I9depic�in H7���Ptic�Ds��� � o� know_ira al dx%�I ��pos� Ź. � mighqso dilu��u��h" ��nee�A a�assema�-Lfavor!���M! g%��� bodi��JP 2�i�ic:_ does%p�n �A���8lready sequeste� ina��sI(�in�R.� arrangemken�RM��primar� vade�K tinu#oMe2},��le.�orsEsubdued��]c��B�a�can��inut-associC VRCsE�re�|._Y�i)]unprece���as� i/ part�Q!:)reS ed!��tomatok aic!Z,us ( ToMV ) "j 130K<>o )"ch �> aR�,.>-�et!�AOC aHll�a2� ca"�u ' ��Ssilen' [32–34]� is aQly��� nt� !�observ�&e}strongly�J-in�A��/� �@��p28-GFP/8/HA , �i, dynaA*mobile2�uyQ��'"� J eɾK� �n*^, yet2eͷg. FLmor�� ria/!�"�im)�ed "Up�d&Rei� �ieqor du�ar*Z !,U�.��.�abe envi��Ba�3C&tag� enha��)�� ��&l N�AW)�6� �Rw� � J��des xz��Bu� A�dow� b��I�provid� n immed�!rlan ����ineffic!w initi :0by agro-deliv�X)�one � a�S1B����e 2X35S�mot �� C �d A�enscrip�!��nO a�to�ei� a��han na� vi�*w �typ�kly  "^ ���K� #pJ��m) )6 . As ult�285�1���(akes place ��%�ryv �blocks � . e.%&��.�i�Ws occaaal� 1 ^� in a s 4astic manner (2�)Iaprt!�m_on%�at� evad�sisiw+A� -Q vas�m�PabundA!?mrsolidifyaA���on again��E*�e�. Previ� u�a�4� �s�earEdink�yZla�I IJ.�"J withN-[35 , 36�eBaZ�u)A?�9%� view� w�t!�L8d look . SpecifM���I@!.�uEz��� robu%|�Il��/6� of a!�-de�"� o��/did� !v6ɼB2em . B�^ trasaA����:)�HAH ��inm�a2� ,e��ed ��F� gp�ful ��r-�s�9lZ+I�2� � �!_I�xe�]K�~� � be�"�� ordem�Hu�discern�8E�ewDron microscopy [37A~P�cfIɡfa�h6]�"� .Wsig�`-k�!�sV���trappr��_in=�!"! ;analog� FinaA,�1��all!` cauHቭhpre .�u �u�,I ɯ*0al��! bal:�var�df   ( s )!� orig�b. M��"& .C���cisEng% at�st2x, mea� Iex.wrE "�ly�efiA�e �v�� W MV p126 b 6o �ic�co-1~ioqt�opoI��zG-�b�ngM��l�R mechanisme.1%�p�ce�owU , iruncer5P o how wid�app� ��_iasC5�e�A!1aU��tri� e br�mo2jBi , be�A^��^!� i-�RNA��th9 �9���� Bfv�B-`]3�%��g$ (v2E*$RNA3 ) [39a8Sip-�%���E 1a , � �lso"n/biS2�[22�)see� 2}. 9�vfI"s6�.I�%~� ref�Y� � %"-��onѪt� L�% on .�!*�!Y� 2�j��!6edu�� �n*�P !��&* w0;ere�� �1+ce!N>$�T�%�fo�"W!�con[s�$met: ( i )�isAӍ�j a non!a�wmRNA;%�( i9A0J[ y% ncod\�Y!�shT be� � � ����ystem�S���of Wh�"Ag.�A<����:s u�iΔAPABRT!b* ��( %)���(,w pb>$>F z1�e�aT� ���"28�=!� �r;��!�l� 6fac��%0x�� C)� U�I�n"%�Mp8�%��.Y{RT1L be�W#Yj ( ���#;2K!��CA�o$Aw3adv\#between%�!�� � caus ��"p� bJE.A le��remo 4be�eO$|"h}��Q� oeq�ng! b6� wI�I�i�low)a)�%�Jv6y(�a�����y) �sA�bye�A>� s�� sSlaRNA�y�� f�g !\�j� ��, �> . Of!�r�'�)�u� rule�E/�i1%A����-W��e� ��0�de* a��Z�g*�thsre-#� .�@| pool� L- �opu�s� of m� �t5%D ��' draQc�tleneckA4��ic[][Q41| �Re�N A}u�:� is �:oiIlyi)�";c%by�al �A��r�� 1�� �%�q�vascun�nd�leaveH ahead!Tdt[1� {Oy��'oA���i!&$ly$"5� +v^7tra5bE)=MiyashitJ 5�X auth*. �4vidual tobacco%�/ ceivAa-}�A�ri ousaI Z �51#Wtiny ft$!,�ma1(S$j10�Qq!�!|� invoR(a�veqs&cdegrad��A?�!S nuclea��!i�ld as$f9X�bo..[)U"YAnZ��6think�yy�p,�sor� few9 star�!9 �Rey�� swif� �pam"�8i) ��ng1��#(9�b���e�!h.M��*� �aE7)�h%'�A:cI �⥫is" f>M’-�)�y!�A Y survI�Uhin ea�)� ccum�Ked"� numb�   ogen��!�–�L��hav��" ��ifJtAot��time poi� prio�|, � lish� �1l"Q&� nos#ii<�%�# in d]se!�uA���p%�A&��e7tropism᤭�A>=sN( evola# adva�+e� rait��. W� �ɛ stan^ ��Ɏa�bas�we nextI ��p�"al�A�"?ofe��S% .N�Iw,b= �!IRe F �� �wP  ed�)Ms Xl3r�Z�inforcU�s�S 2 (ae logu ex�f)� %ish(i� I�nN�R]  �t #t�3!7BQA�28%de�we sp�%�(q]ySB6or “� nded” l—'s&�(or- �s *�ec8 “mis�nPa�&GQ �syn�iza�V�Why)e{I�� �v)�%�-Z>�s��?Sr�&Ksuch a ]w �  random� [�0c�$MinE�du � �rT 4�Y&%i"e+Iminima�ʁ�%���y-X!� � X � ly iu,e�� q�Fu&"� |"B � rror-pr�),���'�2i 3 e clB$o� 2� � .�cycm�1*)�q?[4�Conu"�,V��>�e`peoFe�"!o��( ir7-�+�I�/prolife�Z!qAu ݡ�e`exacerbi+Zpo>!�.damages�y> z� them��&/ )6!�By�-œ ��&1!]�P#"���8titut�&l adap ) g( $at maximizm g�� of26lB y)QR�^DNA E�In sum�#� enJ [23�novel*` ��eueng%G>�� G.��Acapm�c erasa�2�1��ed�Fl)�al��reb� 2'lat��/eu!�.�e!Whsub� E2]D archa�=&%� solv�L�&ed� uc���� al��!$A5�!<#11[ lZ � �>�7�%�� gB39��0framework wil��o�=�c�� �*�UF*"(�dp)op Ian6!�sto)g� ��� �&� . 9 �2��$ %�*�y� orm�na���{7 ) [4�*48X BrieflU/%ep!�!�bxay �+iAWpPZP21�8�Q�.�E ./i%�Ag!,,cterium tume"ex!!in C58C�8he� ca7"Y 5/ 2/3Q CP ��cce%�a�a� �,Y!s$~ �3rolQ�"��!�ei`J!�d�'� ��by*$IIM���. B�-�R% CarM�5R�� d�$s�j!>N*&R�modifi��elip6t:9!�oUmmxe1:c8 enzyq1we� main�a�A�$amino acid9d(j�5�,�$"e"�9� vaileFup��) $ ΔMP�6%!-  0/��-L + R�'� �M�a�$5.�$92-nt dele%�wi��MUNreg!�[26 , 4{ Δp88Δ92�REI0�"a�!d�eAc /a 4^||�T },��(�!Wdi4�4ApaI (~ y blun� G�@rel�3on�. R� ��F5��!t"I y7�)!=�#4 ree-/A�i��' 2e�� aQ�%f��uniquH >� sE�ŗi�-1�-T35S c\$tti�switchI�pAI10�0a pCambia1300.�!� L3i'R<ip*)loE�|{o cm8Ta�� ,�m�>x5, a gB3fra� ( ID� CoralvillcI��ti�5�CV��UTR pl�:|Gcod�3 66 na6)#>f $e 11th β-�cn� conn�>�(n 8-aa flex;�$�%`GRDHMVLHEYVNAAGITDGGSGGGS�P�f%�63A�} >��.� w ��M129�- �(E�Őby XhoI�XmaJI%��in6��!GibA�.1� ( NE�9 IpswY,, M!�. &4"�[ap2.M>!��%�I$�v�8�B@�-�)C10%�5���; ) [35!I ysm!�!�Ź -p19i�de��b�L,r[s@7[2O"$Y���s PM�dіly�ER-�6��l%��wv> mGFP5 [50p��mi�j3�A!�ye�"y:�c oxid�!IV [5% f-infilV ��.�#���ul1�:=(ref1Confov1"%ic��-c�ed�Ila LeicaJAe�. CS SP5 ) ��QM�6a�7Cel�7 Imag!\Ce| �! Ohio�tT8Res` AD*s 9,%y8S�9Uni�3t1�qu� t�aw8in"�)%;ob��bxun%�fl>�A71e�field2^a:3B" For��=. , f� � J�c|��nd%per�V �e�Beeaor q��& �cal\N�ɛ4�'�(mid� values ^2rKAo �Z& figv'��� ^){� ��^!�to� � �Mgiven *A(%(!�d#?oly magn h ( 10X ) i�Rf6Eto 100* X��) H;l��-squaU(I�DCarlsbaV;C�kJ�:a�!6q�$.�Immun'/0ia��KHe Trypanosoma cruzi��-sial�&( T�� M��fadeno�vec��CpG-adju!�x8`> �A y ha�.oa�higa(i��ic�M''!����.,acute lethal lleng)H"Q' long�2I@.4uTS �vacci_/�b�!"�5��goa�A�}���2o �D&�!`-ada�B ��1;ey$a� IL-15 ( p )a� ld i�EAhe-B%F|achie,� !�� � 3%�BuTSr%�al�N%QBALB/c��e BTSi�e ��&r abs"�8 �A~- ��P� 9F es [�TS-ij$4 IFN-γ ELISPO� i?IgGAc`&�kin�"H(F, TNF-αM�IL-f , tetrame�9 3M�FSE�9EYssays]�.fg�#,Ej�ic]s at 1�46 month� s��AV)�. Mat8�!O)y�910N�+!A%^���F���!f��e! 3�fo�Aw%��I�uA�-��TS2Q�0� !��D�  T�_�-u{j"�)�y�t-.�W'od2E)��$W�����! �ch�d6�2a76�m�,-�!W6�T��`{nV��eS ( P<0 . 0� .�;��djAs�-^M6��er���F:a !��! CD8+-�?F�� ed>6QpA�:Al%I�.g)���b8a�l�+expoaf�� tr�stmLQ�A1B ��&M N�g9�)0�� ��al�/ mory��5m�:-�!t1ߡY&$human para�9�4. Over 11 millC&9#sR "�Dworld�-e�J[�xoP50 , 00`a�5� "�N�SQ �ozo.�annua� [� H� ��us occurA��GJcY;��d .at�#�$ cret-al�G!25"�: mita>viaT8!y A pa�Fer�IBs�(by organ do�%[2�A���,�a&=�� mildenon�Usymptom�(<f�. atiguA�ab�%�mi�often g�0undiagno *�H5�&1;Pyr�i$3–8 week��YD ?tissueFism���s G: decal:&�M�� atho  manif-"!�� Chag is�nlue cardiomyo?�5!� mega-synd6esophagu�!d col�Jin 30–; of chron� a��H� B uaGA Chem� apy)�,benznidazole%6ni�8 imoxQQ!c=!"�O �r�!!�lac;w�$ tole�a�� cid�BrugACa saf)= �iv�9qq/(. S-y�a g>fQe�F� ,�$ %~9���/&/���du�;e�}6=~lam�*v0�X[3q%[1�S�:�@e�)1r�_�O faml0( >1400�,A&?oy odA4m trypomastigo�( BFTmeta�icJ'M&����E Mc�I���ga�t*� 9 [11] , [1� =8�F�AIy�" s� caP0� seemE��8 equi�C�O��pv�S )�$.O�&2��kR B%�0!��f.F7J}surfa�4VI���o�H�L� 9��>`ain6� ,�Upur�recombin.-� �Cixh toll-�(� ptor-9� motifA/&�; CD4+%�*Z .aU�&� q�T!+mc "n_�<�ct"��9�"s aE3�%H"��sho&* erm "� eC6p �e�*�Ileukin�� )A���so-�9(ed ‘homeo�&icDcyt� !�p�>e�8c#A~&� � Nm.� H�� �� � � �� $&��H�W�do�h�)��hom�G� cis2jb�ny99�NSi�4CIcy�., macr�4%epithel��dendri�aL!&��is�Y�b� ! ~��:"( TcmPx�hse\Q�%h �( R 4A��a�capacit�z�!\exten"� "�$�__ e key�k6� A�� ca2� |.dJ�!�c%aO docuA�a�(d �A-3225-0!'.aH1Ca�!)ram+ �v6cEs f�A FULLY!�REDITEDQRAQ��As�J� ��bAccred�/1B%)G( AAALAAM �dG#_1ur-��nt�Cf(was June 181P009� ix��ei^M� ( old female6�m� Mst �D( CharAUR� /NCI<# TulahuénP%� bl�$ ypre�@bi-��MSg���.V�w&l�)O[14���3 m�I� teR�gena�genbank�7!�MJBC023698[n!Сpt�SeptidILSP )%��� �s�ov�g�8VAX-1�(� ;��%�he PCR&dQAN�(�$*ubh� *�'I8Pof�A ' � an&�*a*C�b4&U an���IKozak&q%aM� 18aa>deg6�\Homo Sap}'�%,oglobulin se/�.ik �f�6� K(�-��5�;s�#!<j/�25′-GCGGATCCGACCATCTCTTATAGTTGC ACTAG CATTCTAAC38TGTAAGATAT-3′%.oA1CAGGACGTTATGAAHTG 3)�*Ding �#an)-�QRMC �BamH1uEcoR1Ftrd'��<op�FM �Gfer�{�#s !e�Plasmid7VAX , ARI�N)q� opag�] H5αE�in6�)"e �QIAGEN"c �/kt,( ValO_�. COS-7 ( !�E#an�1�iV���e �wWJ�f;! �$Lipofectam+2hJ� reaga~( Iy�)A�r; m���a manu�= urer �48 hoa,� ly�;��a���ini�&�w2a�� bio!y�W2$%per�+d �biob8Ad�t� -mov R\Dstreptavidin-HRP ,  ���)fLu�)Y emil X]tAʼn�B�1:5med2��adTto 96�flac7tomAIU ��$5×103 CTL�C �  seb( �&e ,IQ)�r2�0d37°C%�24-�26"W of �<5 µCi [3H] thym!>�IDI-�ha�4��glass fi�fi�G mats-�Da Tomtec Mach-IIIM�7�R�[N�UPZ G F scintilffluid��4!�radioa�*!� �IeawTQBa Wallac�(robeta 1450:a�er�. A�ndardPv"mIn����i��� %��employ& q �? s!� alM�� a�}��NU�(�+or!Hin ng/ml�N�*v��3Gbp'()TT2 pTS;�ZD5068\M GI 840707"� �! [19]Mv) �"�(�o )Aਗ਼e �)))�MEndoFree�� Giga�N��er6���I �9��e susp�сa[�� of 2 m%!��h/l�Rdon f� BS .� -�^<1�  unit!l�e}i��by LAL� ay��\ YC�YCo�!E�'Falmout�!W)=lanesthet�� tone�!ke��$( 60 mg/kg-�xylaz�( 5`%n"�!� . �\( tibb !�^50 µl��b�=�,�:v  �{9���a t�%!q0EgQ X% E�+D%�&IN,>! or! 2C� �-P3n�'[%Y��1=PO"2��AfeL� ?~K&|'e�!.=*z<( N = 5–10%U�hp ) �"!a~���O �Gn;�nd&[�� or >A�� . On�six�y���� thirN � �i', spl#�h&S.N/ed �%YsAXn�!EL�!��S.\(1��5%�:�tl�9� h �{1�'5 A20J �` ��pul�E�2 .���%�� ic@H2K�R� �;S"l IYNVGQVSI�DSaa359-367;ResGen/2b [3� 20or �.��!�TS�zA_]})Mcu�*)Ku-?#co� BD BiosuVc�San Josy A$ bloch�+!huA�Iu0a CTL Analyze�-sp,)c<"� � Softw�v3 . 2 (B, Sha�1HF_ OH�Da5Er����ed�a~=~)Lb{ �s ( SF��A�on ��2,@)'or0..*��.y#& '&�%'m� by%G�clp�fL � &�"����!���$-����e R�~En�-tit��d&�)�$Unitwin Op�ac s1�( PhP�` AB!�(tockholm Sw!_ )?9�6��9 d O . D .�ea!qcup ua � 2*cutoffH6a2�,6�M)))���9�C�s��i�E5E�Xb�� A20-�VLo�R�x�� tubeA >" ,�� d brefel�A �[as& �A�2�(H giPlug%PGolgiSte.Aqd*�T,FF6C!W��)�'l��al�%F�?aq�?��re��)bD .(&0horbol-12-myr B te 13-ace�1( PMA "� , i�d��50.mo-5y .7" !�3��m�1�VBwa�E ,i� I�0LIVE/DEAD fix� Aqua?2in% ",6��FFc��[)��A�y��CD16/3��150�? , 4o�p� rs���t �305 �CD3-FIT�CD8-PerC+CD4-Pac� Blu���BE�&�) /% -o+-APC (�1��d%Gpurch. ��:�u,qn�F=$Ua)�!�t&Oly5_�pde�ANIH T,C�FwT�=Atl�F , G��.� Cyto�</ fix[uB �Tix%! eablk`fI��M>�MG�Mu%��^%��-PE ,5 -Alexa70�uT�,-PE-Cy72 9�a)��zZ�!���7er�il�bu�H�acquisiE��J LSR-II f�&nm�:#D{�\se79Py�EIhFLOWJO F=!Rmetry���Gv7..T�Sta"� shl�, O�. )� � !I2�:� E�%s�E�tex vivo �!�2?UprocedF&"�ab�/."�*�nq%��. ( Vy*k t CFDA SEE7��c�2 ,Ax3pi��^@.�eir  ( 1J>�rad�"Źɳ��I�( ���or 6 d�at 37oC.�x A�> ("6 z�1�lCD3 D8r!�Vhy��YuJ.�r!%E AY�k5�bs�Je� 4ANMUf�zpoaO�#F aQ�,d��G��*' asM�s:6 E y�7rE��.P�&a�&us  × ( #��~5��D s ÷-=�3&S !��!AN б"8e4��gen��N� �nAN Index�a6}}��!0s-+Z 92÷ �\ճ9 \1�$NCgd!AF�&(6$ aA"�!�,ai�H@��/Q�*~ [�%EK293A ���gr�Yq�to 80%�fluenc0 T150^sk" ��MEM�F7d*_�8oV �mL-g"3 . Fl]�ino:�{rK�'�'us � �5 mV5��.� 2� �v� t�ndia�� nx�ahe�mn�Dtilřpathic )+�<�+)/"�)�&�)!��C@ �� deta5A�poo'( 21j/prep� pelltMsifu�u�coH nataP\bar�0)e �:�20-/FJY %8..��ze-tha��'so�-!)�h3"� ($} ��A� t 17�0×g;1Bj. CsC�> to� 51 ,kz��i� 8doom er`N�1+1�"ya��xe�8 us b�TE��� , diHA1to�M Tri� pH �N�;�1 MWCO�exfK�'1 glyce�F �(: 6utag)ّstora�r(t −80oC .�CTCID50 " J��l�D.UsF6�H.s"%*��on��Z 14i��<~�3�&�4,%� boosAJ94256 :8 pfu=����Tw�n{� s.��&�! mm-{.��A5*K;D#99:�#)V��-�Oa�tK��=?9bea�Gpav9 technEM�nyij�@, Bergisch Gladba�; Germ>*;� !1 �fr � �)excr98%�pFuaal�(of 9�4s���Kr�Jby @92E�P-=#��inj.i . p .�o naïv"_% reci�"t)l(/6!�7� rq%�*�u�)�w 2�_7��b0 S�fL a v . 6 .e�W% � Tuls� OK%OTests�C�+e Mann �_ney U �;� Fz#r'�0a�^>I�(Wilcoxon Ma2Gpai_5#fL�%}g�%*�L �q%m1lia�r� �; "2�i�eritaMethod!cWseN7%s�%c9U ��-�,�7onger>A%,�^ov�-up^a�� hibi%AUGa!f��V!)�#c&�d%nd%�m�8# .���9chematic�!�)!�sB)bc�h<`!b1A�1Bm~$�" 2veor�(9EB�4"N!8!L��#!�D+�g D�Flxns3 ��&= 1� " � lR�#}\ �X)%�.�^�w& Z�#-6�"�n�"&$� O&=%� �%J!�-6ed yu2v/�?)iC�� �4as-�b�� m o�J-b. 1c�&*�!��v��� �&�3�n0h� �x. 1�^ � lt ��W �Tc�d�2XA� �+bJ�i!��,�TR��.�u!�!�Y`oFq'�\I5!�Wen0*� ��D2�I���Au.TSar*B o�b ( rFm&�3 CpG mBl uces��2W�&�!0�6�="�?&,���6 6\�eu ivenkof"�kE�i�X,F� -7"� !)��( ! +�#A�d"\Thirty� )�A�& �2� � CTJF!s:"A />IToane�W.��^a�))>bC {A2�  , [27�! gard���o6�%�)="F)��l11 5y��%�4-�+.�I:,�� � ctm�1�� 6�@&+^ (�z2�61F��M"�� rec*�B�!��H-'k�Jo2K a�7��� �E�!( 1��± ,$. 1±7 . 3!n(nd 54 . 4± 8 TSJt WJ�`i�?2 �eb�� ,i�E z!�+q01�"BQ.��� u"�9)�*5h!6 gG�s`eraiM!b�(c&HKuof >9Q? ւMRaj to <� �"Ke�-> Z>��In > ��x)�G�in��"Q,&aSA�; �W!�id(�3!�E�i�a19d�"�M �C!%�&�� i ) 30��&(�� �q � 'ayE�6>2i�W�5��..( �*� -T>�)kvi�j:�;e�^e�VvI�)�di��2pP�DFa�Z22)ak@"�nS/L� �(��[1!�t# s2�an�� �E"^ A&Z'.h�W}aut��r�4E��c�E���J�: Y\&Rm�"� 3Aq$ �aa% �5V�qTSy�eliciA<Wiv�� �E�PFl.*,<tA9C�`en�>�@er8q7i�#._-D :!U�� m�>� �)�("��>/I�by >20�G&e�Vno�3k�=�*� i6TN!#%!- s�n�b���5�A �5���z~ij��p٘) Q.v�Z�=��2�M� 8B�; ��ig1H�q�*%*)�Y��.�2 u�32L�A�!$*�=� ->�;B�� �� c�B� �5��~edn6�5zX5�.�rTeouk8z�)1�{ ��m6�>l!uUIlo!��8��'%��LTus%��>Z�b�捍n�Btw!_as�yv� ��M �+��y�.��6� ?�06�M�:�Id. 4�#PѲbyN� u��9W���� ͧ.E�{B��:yrR9.�g6� "N &F&BsK[e:F' um�5V�+ �m��1� >1�  .5�Fq� ro�5X /6A- p-@9W H �*6� NU�v !�Q�]wy2�rLFd 5M��.;�]*|��4B�.ly �`10~z� n�Bb0I\ �d��� I.���E�I���7 of 8f�uu�&�� ��*�N6�C!ؕ�)j*.���T��,!$�;�"�Dis�_mer�J�s�9 �ċ6��sit*# � �0YA�scN�S �u�wN�� �B=T�9i9e� �JO dissZ�N�)}.��IT)~Rdi :u f 6Zcy�Ea��[ad�� �s&�2��|�e�1(>���3b22��)+ &�)�*�k�#��E *�N�� �B/�4� u�[2�#�EAsI�eTbrin�D�!)qn�RHor.�!V�A�')wiA/%DZMem1I�7erm��'�+�HT�'I�h�{&�GMma�+kf ino_�fr2� 6ya*U�-5�in�,h)�*� �Er��>�/ �,�p>�-@ng��r2�H-N)��w6o.��Yl #Z��b-�R��XK2!2 + *Z ��w�� � gE�!=�.� Q"R=ex�A��*���VN�%�&�-s�?U�>�t�~�#�� 6�P ;�-:�6mH&�.� �Ht�.`iɄ!�we&'$�5WV ivdHI��2 Xb"�$J"2Ro�4e��,�;�>+;tlength�p�g&/?675�~)!�Qai�$#W�|P2}S�L��N�1j9�-�N�Y�1�.R�� >�ei�c��>C�IiR<:�6�"�m*�ej/ ->/ � ���U%o*�notic .eUB�m"�3?~"u a���r  S�5 �fQ��%�.�5���r��9�i�a�st6bd .Wv�E�=� �5�E�aí�1�>3 �Z5� ig�S�/"� byƶB� jdl]�ly�OFG+1 ":Q�%$��e4J�"� �,%2@6.R�0�I%&FACS pl!7�OJ�;%C5��x��)�3�<4 w&nj�<#�.Vof6��#�&[6�PAto ͔.|�> � AGo"�TS �2b4(.*� �-��ġ.��B�\>�/!;"S/F�Y����� �C#.�%��@N�HJ-� d{-iV2O�FA wB�F roup� "8088%± 257 1�RT I:*UE�P35f05P6���x�!�4��j "� )"�Qa��Qy �>sea0(}.�2Z pexp��7�?%� labe5�A%�2!�s= ���( %*�2�st"�n�TS� 5��]~BMB��?�6By%F�AN��O�0d�o`:h!:�0s:!)6< wV5*��h� pT"S qM�M�A@A/Xt�9F_`�׽���E��u9w�2aAp t!��QZ2c-q��c�I&h&�#�aVEdMD"� �w/w�} xt s�Ot� inve�Yc:�epTS"AW%�) v��M�&7 F@$N 5&6�2e���$1 �!B#e,FZ�U�3�_ uffi�A��� pr�&xUad.'if\ rA��[AI&d�� Zr����<�A* ateg�`�-M|.�TS-K!*2�9�� up�10-a1�Im�.�2<%^r��w2S2/�2; �1T�ed"�#'�)./"�.tom� =i*=#b�0)v~N�6 mN ��by�&vAmas�)1F�yR ( >2i M8 zx# T���WW�0I]&x*=(pEA.266�n>�Jor��0/EbU3�!�*r�..!&��F�� (A�dayihjn"^j")�6G" �g1�:E�B�1Ysu���rrapid<o�e&�4OI%a,tK0X in 3�I�!&U) ��-a��".+=��s�v�( P < �Jl/E8M�V�!���"e��"$ G#r�)�[�Y�u^�y"1�%� �P !he�"�-be.!`4�Eom"؍�� j/d��.�"l0._V akm�� ��Dgksvy �y�� *�a�qet��T7I3."0a+i{8z�1Tox�a gondii-jHerQ] simp��~ ( HS̢�–[2m�I,&�edl,�sa�.a6I,11ng6!-(���6415"�,c���"-�`d>u�")�U%u*91SRR�\6N5��!=d�g� !6�A�ht%|��/c9�7ik � �my'�ly��NBTh1��;.���&#2~�*displa�PMKE�l9�2/�A B2^��(eF! ���sA� �H. M/6|aJ .�%�.^�e5�oFG� �c&�a �'�E!�a�.�f� *�".�da�d�,�~γ���Jγc� &u�����e�IL-R?IL-�9 IL-9y�!�&,)�� ir�"�)�s�7c%�\Et���"�qy~!ala�� g1sq6Jl4�Gesh�I CD12�D+ Rβ/�Rβ )���ng�\v��-"�l�;� tb2=�Ihe wth�NK}"��J�B_*� .����e�}Dy%21!� volv��~)�-� /end�sr ufngy�a�b: y!�eX~Rα6W)�1�!7�V�k" ��HQ�al!S��)�`�γc9��)cir�e[2�\6� ef� Y+by��uhn!�Q�s"�AKui affif,+R~(a�luŚCD25/ �AI�Bl��srqG/1��}�"E!hd*X�m r lig&��)>�i�:o��+y�o%-tocO a0[P�_2H� %��5Mm�j�� 5t0�hy�4�)�e�se bieiQ�cHn�7"!�1�o�1��:<�AvSgk(*�opt;ng!�eIk""g�]��ge�vo=�(ODeI�aS"`]E���o�de�7�of u� , NK8 �j�9�Sc#e&�elympho�e���B�'t�d>�2� JaU��R auto�c l�"�,! 15� �lï�Rs�����e�a~"(#,��encbzh&�ge� ��aboB�:�[2%��g�R�UYm�^)p��8ha�� 1{+�LasI&��&�� � .N5 �o��?[��aIX,2 ��pe�o��� �} �t {�� � &�R/��UH6D��DZent Z!��NdZ�f�fix!�QK"��""� du$V�&al!trigge_�"�r�5ceawi"o�m'��i.q ����maF�E��"�Kb��F� q� r� B�3>� ��)\-6�0�2�R�(:hAgnc:lQ��jvt�M_Ly1�Er. s@m�� ��s��e'>5'�)���( 0'�mon�� �>�j)a� �� r��ch� e�q�K�b��:%]�\is!��nA2 ���e�# � )R$�M a��liPW�*2ofA�M��dRα"�A��f!i# d e�� ,I�eI subpicomo�&2�Cm x�L!�r� ���BFj!s�fa���d� evalz�AM��qu�B~R�dg�}�.�.f^a�a&2�o�q8of ]"�<�=)�6��n�A!.��Em�&62~n���>� Q ;.�4�xP*�{.a("(�E�NT2��Qv�qS�s2�8+:F�*�&R"�� ��m����~l�� % �x=��@a�.��(:�p } Aigs�=!����FuA�bi h�gRB���xE@$��p�j�o� rv� ==N��iaU'��6Eh: % &�mtCD4�Wck|AmEQDm�Nr�/6�>�\M�J .$ � �*��H�%g�k�y:�Y;�Y G�d �?*i! >RV:���f*�veAt[�As �ioC<� ,���pa �"XD 4:<�Q�` er hI�1�A$.�Be0]+�y�  rs[�po.ʹ)`ied"R�,N��i���mA"I�� 9 �A#�t�ed �s_�� Fur�&�. � 2�m6!!af�!Yu�&� innf�T@pi�Ea of FAS-�Q�apopto4Q[2ď&-it�m�v� E^!F�/��e� 9�!�?iO--�d 0�:Q�!Hq)�+s>0W*�)? 2�J�"� F� �%V�a�� ,*� �3�a� �� ��u{��=O2�w9CV���!^%I�kn.�w��*J�[ �:�N��[J*� seemA�b�MI9o�Q5�y.��we4E�TS&u< ��R2�AE*q��1u .{�b_J��)�q.�(y�r��mѸ��on�o2U��Ina��8we bel���:�Cq(�r�Xk��c{� !o��GU>e)���=�Y �JO��*!<��[e�9.P]&E��PFMU�3c��,%�wo,&�F�< i>n b�!�!aJk.�"f6 �"� ��I�w :�"��N<*\ ���+"�, �+ )� �C�}Bs�m!� ,6�0.Mv�zi,N��' �� :�N� c^� aKrre�!&�'���JV���P� "M�|);-B�.���b mark��( CCR�CD62LMB0�*���L"���/! �(/RmDIbs:� :C+��e(5�[:3 izB�i�or"� Og�~sI���Ss�i(1����o!*=�v*�0)6p-R(��B*޼A2�)��"� O.K��Mi"�"߾�Xi�1�neJ�r�ıkmQt��E� �)}�ci�.�a�^���u&M E��esA< �enorm��6in�2/"�6"?&"����8jR5.�!E:HA�.{ 6a#!�by>&1 ��'6W�v! ed 4�jg%&4:�&)\s�%�z.6�1r���D>�qA�6�:�1 �� �Mfa�Y8ghX ��.^uq� �!7��PM=�"�*�(:�<12��*|~�5�2 � ͡W�wst empha���$�rk%tM�t �*�5 �]m"W��QB�/�Y!���nե>��{:v�B 5j�B*.Q�In��� CD4&� %%!e� �>Ar�)d r��R/.&�9)2C i��1�J��JA�b-PdB��M�biwas%6du�mp�%a�t� &r�HC�8&Z72�@ ���%�]!$Ps�* �Q/�*]/m&� s@A�"�].�!#� rC��"� /�1a�d shifV�q9.��2�IK5��(1z"�c ��V Theop����ce%ɯN�" broa6're�e��op���npe*."�~s�$��&�&T 2��#�hig�M�����mut`p���o�o� hA�!��5�]4iG>?)�6)J1���e�"�� or �& �%R%}�n�d�D�Ps.N�m��&�����%f�T{A�Ful"6xXE!_�ilFYiV��8�&k� I�JNS!i���!� �I � *�#�Mc�a�\?.4Q V4!�q�YZ((��R� gt�"I� &��u@�1�Bf)K��m.N�� Polo-� kin�& �!E. �bruce�'TbPLK�vld  ;z�asal Bse��o�� flag��m attachŮ� _��%!C n%@in:!t"o.��vt%"�����1?m�'ins e#�vhH�Y,j { a CuAp8-RING ubiquitin�!`�omֳJ)9%� v/dϩ-&vd�T15JTbDDB�|a WD40����� WDR1�� �s ���w�p=\!9 ilob�F�^�$&�� doN ��|�{!e�C PEST�!�)s_6M&��� 1,�#�! �. D.�!�Z�#�dup"n�j�64disrupE�8���r�VUz�0 filaUcbch��B8-�n2\!;A�9.�#,6`"�c��'\ceS/"K�A��Ye6����-�2܏A inuZ phosm�|R�in2W)\���2�U�z�RT��!ۡ9�` fyE�ve)�>���M" �m-E�RA�&��)K�\�z !% G1/S.��cF�w���`-.l,.|s&�_!���{%��ad�sC >)�PLK;/�e6���!�:`rine/Q���X�p��yB?�JU�� nk,�(t , spindl}+,X�m +6\Tx³n&� ���i�.�-eukary�[*��%!chaH48��an.5 �pa.�%`box!( PCby!t4�Belf [�f11�AGF}�Setco,p�>rA�^�;n��, eiޑ( E`$s�]zv��g( T#�%�ellwI�a����G�M���I�}� PLK4����1N�&O�;z 9�{)I .b�Ga�he.&�a��-�#-,at�recog6>-�FE<�6��duG �!T�[1a�Z�n p�i)W1J� �J a !N-����.h,�ؑ�5ku���R(>emb�T}�)&,"� *ikЪ��e�. a��gBD:�S%4i�1e�Ձ��WԔ!ҡm[wP1a�'�D��g G1 �i5" L� oE: -�. da(%B<�.a?dja�AC�pC�l[Qi���!rd��.� z. ( FAZ.6 . W�LZnew~� edRS'"ph=S:� disa��Y:���uMst~hB*�-��ip������� . Fo�.�ׁ���g�� � O( I�db@;ioA�h �A [1� NdZ��oA� �6�=ro�E�6��-v��.7T*�d� �syc���g2���1��!ͯY�va�$urrow in51 ab ��f c!By"N !vaI* ��)*�}&}>7sJ�"� [16��SPBB1 [2&U CIF1)t� "���)p"x �tar� �unc!e]�Tmis��l ' ��1�E�G{M��A�6Xde.��� -v� s"�y!hyg&C,F"� .�b5I%KBU]��В*3�!z�R~b���kAN dow<�eam��)r%�.)�B�Fq�u�уiAP��&i2 �� es^L�p2�'Aurora B� TbAUK� *� .� dYJ�� ������s�\��b�� r�*��2l���.We lear�&J& de-b�'�physi"3P))�,E�%led�o;sp��<����e( y�bUa�&( �}��hϊU�^�f�{-�#��:�1 ���ͅhvtth�2 ect ��s,@ <T h9�.� r5c"�ha q A����}.��<��J�%=I �WG1<�m�]N]._^�Ia un��r�3����-b �-��{d-0� � K r �e%J�w>P2GM�.*b'!�1��% r�6��ItipN�p]����RJ,8/Mb<4-bOT"| n >� CRL4-��� ��&���l&K!��)�� 5!B�B�ndaq� b�RL4f�Śٸ��o mpai�4i-�I�t)8 2��q�^a�f=q����pY_�*�6j��i�b� ��� ��� cto �)J:������6�;"�m������nf�%)��u(1�xQc �!^C]r�0�Qt�I��VJ �!�p ��*.A�fT pu ve5Qt*�ps 74~7�$285~2�� 375~37��aD*�:G448~471 ig�p� &ջ:,)�!d�i&�siY.� A` y un�B@:* ��t�A�&�D8is best�n!�ߢ>(A�u�����5g!��i���FsCRL-typeFN� *�$e���G)腣s��-G} A�%.o�K>e)�-�T#�� �&��mAmes*AGarg.��idj�R7HR28B(R37�N!!�eY!%b�u��o�akw5un�l�-DBmu�EV � �U�=fM/��UΔ)6W�n%�g daA� BS wild)� w -�fcHA"j!��� U�t.� ��6)dE � o�q�*l 6�g� :�.�*;e[-n_"b'0w)�!�� s��1A�Sa�Sub�t$!w(rr�� �-��u"�K�WesA1�t`)Rnti-H�tt64!�on�u�.�of 3HA��Z )?�W��l �A�s} �0 s���3�ohe��dea'!�� half- ) �Mp�! be ~$�5 hQnB��sI�6e"�!b%���or MG-13,K�"��B����� 2.S � yo | ]( )he7� albe�t� ligh!�s�@r�aAan m,1�=9% of ~�o^��* �iq�!��c to ~���6�&Z���3 �B@s&� L��5F5KA�-�To �?��.z�cF��r����e T-���I���d����! FT?� tm ��-ST/A�q � Q !/U%�~O"E�8IA2�6evsi{ S� 1�E��e��'B,PEST motif ,�O but does not require phosphorylation of the PEST motif . Further , a D-box and #tdouble mutant , TbPLK-DBmut-Δ#H, was overexpressedDhich localized to x,basal body ,  ilobe and(new FAZ tip�nd addi� allyj(detected in3�cytosol ( S1A Fig ) . Pulse-chase experiments showelat>level ofN��reduc � ~90%*�control ?pafter cycloheximide treatment�B�S1C �, )!appear `�be degraded at a slightly slower rate than )�-�(T c1C�0This result f-�confirmm�D rI8depends on both�DAes��%�mM9ToU�t native Zis�Thort-lived protein , pR�%pLsimilarly carried ouAyA hWestern blotting with anti- � E\!�perfo � o monitor ��)�. The--s2! VM!�uE�5�-wD�1E ) ,�Q�6 N 7I-� GiveA�atejA�Qi1�6 d dowM � 6, wA�$amined whee�APC/C!�invol!�iN=. �)�eJmlproA�ic cellsA2lea�of Cdc27e� �ntial zsubunitF8T . brucei [25]0a�V�Ar)q �eq�O u RNAi ��6,rA�-^ �non-ini�q� �-�=�AyUI�)�at�� 92� Thes�ugges�vat-isz�,��!:s��!sol�0Hmajor ubiquitin lig��responsi��fU�.J..u dele.u}�$significan��b}-==,� �s!���pecS CRL-typeF�i-e^�^�W!mce�.>yea!x\wo-hybrid library screen�J, kinase-deade�ntm�� K70R]� PBD ( a .4434~768 includW!�=M)U6 as baits Mida1f��several y-interac���pot3ala^stas [20] .! ��ha?er�one�tE���partner�ɓis enco��0by Tb927 . 10 5080ea6Pains two WD40 repeats��� N-terminu �pa PDZ ( Post synaptic densityو , Drosophila disc large tumor supp`or-5 Zonula oc!oens-1J) domain�C�I�2A�(We namMt WDR1E\�R� 1 . I�>$e original~P)�, P�;=�by%A8� � !.%�I]. HowAa= ydireca�N| assaM �al�of �QGs�4������5 2B%'It�a�a�eE�6 had � efficienc�anjin~<a5M�N!thelesA�%�:�� via aJF��?!aA~M�K! d%�bini�o T,a�demoni[d!�v�nd GST�l-�%�s5P –2� Dfo��isrup�[��ion)�%-�U,�f!A� �E"�   �A�<. Immunoprecipit�mQ! ��%SCFB"5�isko�� �!�Skpi� an F�U�,�!iCRL4WDR�^4�DB ^  -�TE- p[! (28 , 29 , 3� ' ~=s allAmA� a ser� �o ed DW� DBB6�� ) box [29( �1�tretch!@016 amino acida�i)i� f^���o[ree high�o�residueFAsp%Trp13%~ Asp1!Hf:(hydrophobic.5E0�arginin� Y� pos(� �E� alsos��pu��ve��M��tz�(�20�Trp21 Asp211 )�n��� lack mN�A�l� �%`���3� It��uldFnou� human COPI� WDR5.9!Yp o+a��[A�%A� tUB�N{n)�o $absolutely6z �fu�g �2��,trypanosome ��me� !�i�(4 homolog ("� 3� 290���w� (TbCUL4 ( S2A�!aHofe�P6 . 511ZPa�P3 P._ tes!��E��� �}T Ein"��sasc��6� Q� show�w� ��6(=���\��t�-1e ��� 3�3� bM Ia)�YdZCUL!9"lu 1143)h%2=��74-�38!�a�i� 6 4 . 476 ]dida0!W��A7s���%y%�}A��|�4e�� .sI�*2areA agreeJCe2I ng�R A=e�R�)k4-%����a��Fi�,A#A�U� �!�g��� !ů^�AE�A�6� PTP"� 'hF'� Myc.�%�b0*� �singl�  l�db�XZ<>�)q��z a� P'A��ti-�#d>�,�;p2v�o�(� � U�EMoury� inde$:�2�� 2 J�alE\�in)+is sutA"�w%��pur an ombin�^ trunHon frage �# �e_� "�!Md2 G2�e".��4.U���!�Qpue ��-�> >� rough�N�BD� 2Al)�� !�*�E�6i�%4[ ,%�s=���I�-͵�bA�may act^9 A-V=�edi:i,6�"�%�r� ���O L4�:�a��su3Aa� accor��e�4menclature [317 �vestig��.�gE�.��Z&G��&,. Two differ?DNAU�s�rco�2Q�Dgene were each cloin��vec� pZJMm �+alr�� kG7� `analy�. All �E D6/"Salm� cal pheno A6o��Q�z� Z:�{ !�%Yv port!D&�Q*�of �ͪa��ke D��.�j�H��]due��� etral� ul �a.� decre�Q� � 48 h�o4/ z��l cauDa 4e growth defec�4,�-2�E�Ass��%&prolifer�-E: �V.�%�&� ��T! �g�ewqu�&M!�number!"5t y` s nucle�kinetop� . Upon �E�=p�@aoAGan�5�naa]i A)A�.`( 2N1K� �emergUHmulti�( >2 )vTX T,n6��s ( XN2��'jq>BGXG��4 �qݭe.�D segregI/!5�! si* More`��ic��s�t� ~32%!�!ZE�%�)W(i)g#d aa�a� flagellum�4�F�\&�9&�L-z# adheE�isx ��I��. of.'sq�by>� promBu�i:�>W�*� duple�on/.!�q.is ��1O sepam��!�% i�[32�\CeX ����Ba�-TbSAS-6  � �  �"h$0cartwheel [33�to label�m���Al� pro-:���PFR�t �( L8C4 )[�A5�Q=A6��t:c5in%����=2stages),��mr)b����.�no2]chang�!��1�v, 1�F!K2 ��\ Fig ��W��pai��B�/:�in ~5&�%2]E3T wellU�a��0k��%6--9�a}gea�ta�betwe�#L ��� -def t.ywaa�l"zo�~�8 μm��{ 5 6�!R%&�"!�ter.�di �( ~5 . 6Q| vG\n���]�2�n��ed.�E�se.�!�aLntEA.�arr�6 ��7I]��accum��!���thoT ~3UCm�A��ieA��B�E�:�)y�e_��2$the�~70% )z> :{��m |4 |a!6u��KfJnd�� VmA�det�7uV2e�E�]:]A�!�2a1KM�cBa2e�is b t� half�aRX-A�VOqI� � ���at9�y2C!.-Qum at!N�.��&inex��"�V'ef�  &�oiB^� ��struc�!yassembly)� fila�. NJf'?!�i�i�"� Ey"��I2�����M -FAZ���3B 1�� sY,11Le,� [34]M�5! e2�&�,29��before �,,9&K �B�5j . Ab7R�=,&� MD��!��)�w!����!Ee� TيYM*N�nXA�ob��15d�mong Al>� d u6� �k)U& ( ~8�g �.��J�N�V�m%�yQinhibi�� [}[%�� romi]׊C*!�2�Y*�#�;y�  [35]{�V.| �`[36��38# !(� mc�Z�{Y {.a�v.�^b� � )y4E6�0e very lik�attribu!_� �A�2� *� �h9abund� J�q.."6PTA�}>lyu@d.�'IRed-6����0*A� �.=\6��0B� �)�6�6�FL0,F�of � *Hd �� ��&"��.< poly$�"-��!���&P%Bw�)A�al)�� serg-I�) !;1-to ~1"? " a-3{2�)Z��f�I~�s unknGbeeKEy c%y,R�9 c2�"�1{og70�Q*�����n�"�(-�-JK-"A�!VF�%h[U.�"�0Z4����1���&�zG1F'M%��;�%G l�4I8"�)!e����it/�&ar9� �4at e%��&[3�#z)^g(y9)�u5���dynamic -59 6in��06F�:B ��o?2.q+e foc?` iA�7e�3��4 h��JY,1��>-�pr&�has�b�im� �H�?9�(8of normal morph"yI�s�3 �Un�j!+%�J� N�J�(��� �. m!qB�%Mb! *� Nr)�a<d� }c,4s � y-solid 3 head7 ��7��DR�%MF , open>E�<�A"����>F�\8 �JY."- e� X.AJ;-���Z��� �� A"ild�2I� �J'X6��=�:�whe4���f2* Cg�}%�,�Nis �Uto22:�7+2�6�.B �Y^�KngA�n� is2iUn'�equdeJ�:"�+2e�:�/Y:|o� "� . �[2�*v )�rem�1� \inR��aˉ�M_i�Jq+�sh��be2M � �.)o�!possi�+t2we  K!�N�!l�I�( ��Ń: PS54ف�;��A�A-<.�ed Ser5N-�-iW@ f2�:U��:K�[%v"�I�N-).R�� pop.A)� f���%aH;U% evio@0 �H>�3N��!B6d.~,.�ɿ:J���]^� I�-�q&�  !�1n�at-��%7���1 ht: cess�sj!VN�6fFig� l�� hyp'siz� at � ��i>2awe: s s&�9u=d�A,@ %� stu�.� ^i ca:Mj��yc!;2/%[1� O&%?6� "�=�yq�.��*U�$ed ~5-foldE�2�=( S4A%��(9;� f7� . Co:s�8�1pm/{%�!%�[i20@! %U{�,Ft S4B�����:anBt2,( X,2K>X�A�A}S4�?�'�/����YL 1/*�� F�.��� � o4�K>� � Bc>�1�� clos ssoc*%� ou�We�(.�!��S4E5G��%�I6]2!�&�*�.�� :8�I"�s�,ac��F%LS4G�� A�due���6i΅[~uNV. RJ, ~45 6[40 full-length a5e!�re*�9�V7E2ArS(< ( snU)^�lt^�2�8%�:�w*�&.��9��5i.*�+O._wh'|e��i�!3�uH S e�AM��-frJ . A�!{�,6�my2�%3HA-ta�7I�Ag2�qe.�C 6g7�},f�6�� 31k%��2 �-A�Hu)8' B� s ob�S����* b8-8݅1��!� ���"� ��f a� ll!��>��0>���貌� !��tra�>� to"n �beyon�Fprovid�I(al ev!�c���>a����� ,��}>�F��}�Pfu . It0,� 2�)xca�Fd i�& �Ai�Fmq� e�}�6�(6trvGFoR &? hownreg� �clear�!%c(unc�i e me�"(ism underly!�!� �9NF�.� !�tP(a novele,4��8,&�,�bt�@o:a��:!�.�"z7 otea5n� G1.��8�!�%�-l:�i$nd ensures!0pZ)rganelle.n:5&��"p�_,**�d6�'DV"Mbe,(u�"Wa%A.1, leae�to�jP/" Yi��^A<inuou~�1�"�Ci���.�,%/5&p&E =(6� Ws( >� zby�01+�*i-miG(�stitu�lyFLe"�.&��&�. Ourըthu�*TA�ua���-�)-�h-�sm:"�/Zc<�(t6��. D�IK�k^s&=C�I�=1A,d*�A��*P&oF�B!�5olo�<�B�&�Al�la�.(3r!H!��].I0�:. Whil[e ǡ�a�'.Fsl@.<;a�/;ASJuwyH[40@.�in man"�Esmrecogn�F by a!�$FT10Q(�=42 , 4343*.dF U%q�=L5,��5i"Im�N(I�wM)2 zF�=!���)l�C!���"�?�1sL*�,H� M]f���)�jKVK:�Q�:�J–�L/4�0>L�#of r5=.-t�41tBq2�  fY �!at)\2E6q �!KE,F'�inguishe� ��AEcounter�B� +9Ofungi)�.�of % PLK]$di9 Cdc5A�.�,�Cdh1 [I!7u!^N4>?DSCFβ-TrCP/Slimb ["@2It-un�why>Vi�r+ZW)�*� �- an unusu^J�M�dc?,� u %�w2� -{8�KQ�V �3�(it.��)asA�0/%E9[45a�I�R��) &. � .J%�A�Uab*�@eNd&7aJ��3C� 1&:A0�}5�UGI'�[Fig 2�"�C?�!q�*�)�2�m�f��e� �Fm���at��� Trimaril�?sz N�{._V[!(�Kst famwofB�6�:7diver��GUO4in eukaryotes �7LittleA� ab@R�CRLE�le�Rin.XH�cbioin� atic�LalL2* 6� l@A�246WD!�174F9:DA@http://supfam . cGbr�2Xac . uk/SUPERFAMILY/cgiYD/gen_lis�6cgi ?�7ome=Tb�  2�D�dV�L&2lFN��9�)1:>��P-their-'tA^i��.T�Idx �U H�����b� =oE�/ tudy!�� firsE�V~H:�!�eq*< "�:F�"� �&�;� 6�<&�O`6;t6@N�;�'.��c�"�e�sSV9<|sig�� Y�� 45�� by9sI�ee� '��siI. HLDPL��1 -aut�E"cX��T�6Ser/Th F�%�2 !"ere� nab^L6Z խ�� � *� �:�of �byJi1G 1G !JJA>A SY� SPA�&�8) 2�--ϥ�B=,( DSGxxT , x�P�� G )0n"�X�of+I� /SAK��t$��"�7:serD:!�Fon xa�5&!^Thr45b Ser46f 65� hr46� 8N 9I� 1[2%J&�mlG"wZsez�to ala�] "5 M�e2: F�7.~.VF��,��R![.�..� � �IS�Sv�*�sm�I mole4r4,or GW843682XjS1Dj�.� �Q:�2�E?!dAC^+!� �6��(�2i-�t"�+J �&�� ct� ��ao-Le�6�= 2B!� �o6qra}-�;te�A�qu�?I�Y qr� g,*� -�� $6�*>� "�Uʗ#x� SPBB"�0y[20U ��)N5 D> - )aJj*�ibe*Z!�'"=A�porl^l�"6�an�B�hn .*�MstrongerU3in`2�!42�4!� �*�'Fz6 ?~H� .�/F1B�%�6 f�e$�&V � ��#M���.q�V7 ):C !qk�8J�j *�,2l�Y�%���of�F�`��z�4occursk� proxqP��--v[3r46�]�_�* *.�[47aK*�.�Z1�I\8hZ�*6�: v�&F+�A elon? dK"a�12�J�>�2�i./v prom��y2��is .�1E�!r�#-�N�nI� �s=<��6[�tVS.��"�0 fail�EhI@BA �.�6�! mk&�9 .6Z summh\, cI���9B � s-Q=yB�O.�& �[-<e�Q4!Z�& �#�Cngib�!�-��.�e#$q!�,f72�!b5[N�)� is"F����8 ��LL&�3 �$&�%0&�1in 2933 [48]E�cul-9d�} 27°�SDM-798umleA+��7U2fe-bov� seru.<$Atlanta Bi�. � 0Inc , GA , US} 8, 15 μg/ml G41� 50,hygromycin B%;9E�& �L�% r427���  6�2 a�Sg^��Eknock*Zŧbyi�,�$6�H(�Dotides 3AE519E;E  1251174�O�:ge�H$PCR amplifN_�A�6RicuA[RH��zII[4}Ai�a Fm U�lineaU_by Not I,tri�2di�aA�m electropo�� uQ:e�S!7q ��anM]Fs@)� �<5� phle-�j �bk mi� dilu�A� 96-"Apl�7=�!%6�� 6�20%N�yappropr�&y"i�Z��J�^^JE��)6�`�s#a��7B6aascrib>�+Je%u;���7ub�\eJ�i� . uK2�IE�*h  a�)�+�|! QpLew100�#[50ZA&!�R*o mak� -del�c ��"Fs�KnkA�N*`*�b48–47 %�f�"idOm!�d2�I.�m=%�te Arg7#WArg285%�Arg375a����Ogte-v_e�ca�H!I&�g%��� %RA762i %e teme u,%N����i S�jI3 !a%K6'k(.1 t�Sr�4)&�h Out!H�v�-E�t�L) !>��Qb &�D =�5�� ST/A�g. M���~ % �np#v�D)U� D{�caNveRbz �cA�i�b�E ����9�yA�}�}..�'-QEk��varp0M� ��n�6]�e!?!�NR *�&PS�,���.�;pGAD-T7q�)��(�[/B�'r mans= ���gs,AH109 . pGBKm�dg!�PBD)[2 �%�)��k�P2WY18�fYe�.las�4azpor�Z� !hlyfIidiploi� � � spot>o��SDA��A�tTrp�Leu (�"drop-�EV6,4!His (�Vd<. G�Oof �)W+��A3�?��An.�"�hr!�pra*�!.�KbKEX-4T-3�M( p2A� 1-30A -I!�>V'Eooli BL21-�� "mngV-��.n i C �n�Affin�"�VGST� 3C �b�! o gl�Phi�B,sepharose be9Ain�' .�7 yhe*� *�!'���ea\�5�kD^�)xaH޾* Z�9�i�) )�f8wasLesix timM>  bu5U�6H5 mM Tris-HCl , pH ��150Na1 DT�1%�Fidet P-4�_`S(or cocktailp!�) *i�e�^d� ! SDS�Oy SDS-PAG �7bl�R��-,TmAb�r��X!�� a�n(Qv��r. P0A�a���H���2� coomassie�lli blu� A�z&/l"Hg�$�SuNZgorl*�[usat�yPCR-baA�one-step \_ ach [51b&��r&�IP9��� . �\ 2Spu3ScMW�[  ta�F bC�d6�I�-�2�\� i=�[={ lh?�d2X corrP!��k01�a.�Yv_545-bpE�j_7502__6092;a786(g_102 Q!5 �( 657 ?EuWX-Q�!�$pC-PTP-NEO��&\v� Xcm I (���� �5�2 CUL3�Mfe6+�: "6"�Xho&D�ee!b"_]" n��v-}As.]A����{i^�4"y�in"g0� �L���E� gene %z� e<co-vng��;�_!� !)� -3My�!�u�yƍqaJ���."[!1ag Zq�ge�ki�\��>%d ���h abovsI^��15�BXic�1��1�:�yJ�I.M��JU ( 10�=�*�4AX�: ���*ewhar NɁ*s rifuL,�m� �l͓&�G�B�a�a: 2!�l� �(�4 conj��1oU|GFU t 4�71 hMZg6.eA��R)��,Q�r�D] 4a PVDF membran� �F2- pAbE�!E#<{*eA5e):5b. W"�B�!� 0"�b}6�y��S>�a)� �*��7>5or.��I��'\��m�)�!�\*edIu��V{IgFV( GE He'C�) �h�h�hjhHA� !�Ee&�dA|YlUb*�BE B�ID��I� )�to ruleE|!�.!C�7!�i�)+i�: �~*$f. F Zp6�mQ��?DDB�0) ,mY6#�7ռ 6F��I���,μl EZview Ra�[f�`� geMigma-Ald�r�ILq�c�e� "s)T,���[�v�� ����N�fF�}!"7]�FJ�!^9O!�E2�2� )��|9 �uF�N��0/p^!�&� s�4 K%E���:�)� A!�2\m#6�u��j�Ub�|�( >^!� :�b];1g:��D%W e�PB��G���b0: slip0-fix�Kcol�3-202 ) me$o530 minA/�$re�p�5��h��%� }n,n�� n bloc�"h 3% BSAl 8&*r�at room�er�^..�:���>!5] z^*B wNf66 fo5:�:^�"%y�: FITC-*� ��uI1:400 �aK,B�6d( 1: �9I ��50.q)�V�``/2c)F`dX( 2�X�, 1:2�.4YYED^~52%20H�q�IV>�5�`�I ��-pI� E2��A�,F�RL8C�~P�`�5N�A�+�Y^-$wS�"te�  Y�c~%� ton X-100Y��+EU:�>^or Cy3.psecond�#��[^�anyHr h�##Y�BH��mousefF�,B�� -ratb1:� 0bbi�3n�6�m�Z!�1��N1�ll�!%�mp7� V�Shield �.>7�"or Lab�CA"�"�� DAPIEq"���J�+ve�V@S4e ( Olympus IX�s)pp� Uvo?&`CCD camera ( model Orca-E� Hamamatsu� n�H4PlanApo N 60×5042-NA DIC obj�c&�cac�)&�S!3(book5 softw9 $( Intellig(Ima;Innov�1�K$�DExD/H�wRNA he�e�/chRIG-I-�Rr�ytRLR�siv+<3on*�� in�W�e syste�4H;we.�(�+ivota�d sex& 8k,�;A; hete�mal iso�w DEADB� DDX3� "} � Mice8*AX)X�7 hematopoi3 �EaqS�-$d leukocyt8m"�8Zn}�rnb!�spl�) a3ilinakO8umba�,f!���ia monj�~3MA�-�i.e�`edT �kd �U� QE vail��"Q-a�sE�kx-&Z*7U�&!�cyt]i���[�6T�?�( dataL �D"�@�se�!�a.��a�Y0!�2�OA{M�.�!G.nN�0)it� T1Afre�$d"&gc�!G eJ!icrob� �2l��DinflamA,\*is�. It% :> [0( Schröder e)( , 2008; Gu1F"A")@��can��alL �� "���"�9!�>5�U�� ��!�� fa�{�IR�s3>7i�� ol Ifnb�!: .�6.� !q��3��a�4 BK1/),Mr,+��xX��ada�o MAVS, � PGup6c� g!�_~?�� ��A$ DExH"# s �A MDA-�rIa.�ntoI֡�nA�� ea'alC �to�leŹ�5�{G( g�"��p��&u�ޖ. StrDXg�!tmc,er}P��,� � -w��s �am�#i nfer'�i��siytm�R��"&���Lik% �Gram- ve um^ ( Lm )�%aJFk,uce*� [2%;�n phag8 b��c��$,Mescap�x�cyܛ�!�s�|���(eriolysin O�LO�w��X�7 wsp"D![������& � !3Lm�&�C~424.> "�"�@�zd5"!2� O:P&BA��_,-�:t!�v . Cy�y 7!�c�6derp��Lm�U� trig??)�1R`I_.?� "�; ~ �)�;*aY� cGAS� IFI1w+\�&�B e ST��,!)11�| ��@a3+ �;;IRF��IRF7 [3.��I6 '�E[� �# /��R15  IFNsUw!�g��I ��zK�8-���op݀cop!e sile�2���on���a,A|�nŹ , em�giz� R!����Q"� �$ TBK-)+x�Despi:he�O�<)�� cruc @��cQ=��q ��Impact�2�*E?ٞ& X\�h�as"?3|r�e�m.�" �pL=�(�A��mG z paT�)75_>Lm�–4q.j)� h.% oγ�iR.!p=I�f��agF�t ~a'3�. Rapi�m��of�γ��&]��+HH@*aAt�kR�h�r"��]�!S �tuAF killŠAk[3!�+stq�'<ia��%�IF �ba�� a�E��- v>7mg�M�IU��.^.�of��!1EM.��Iab��6ts Z Q*�_ a�}R,m�~ �oNFκB�� ~!�%9fo�Iu=2P 5*| �Y� i� %�Uo�oE�� al.al�0a�]��compen�&siJhe los&� dx3x8��%zyg� fem�I/5W%Rev�cN -of-"J �aJ53J�-y&�Cs�^a*: of b ma2�B�*ag���S�us��� to 2�. SVnB�X a vi5Q�!3s.���&�:�HuA. B�0IUDX<�&/ w���_h�a!g!�"==�]&P.! �+ %�fibroA,2LE,fl/y-CreERT2iL!�re�>8*+G� " �E�tamoxife0p��ed &ced����1�g� m��f"|":� vesiIKstomatit�ru; VSV;/K2nx2B�&Efor�u �D ,1�4toECerKy�%�-ab�A|� ��,�a�_X�t��%!��%9( 4OHT ��6. Surpri�ly�J^��a�0fl/y Vav-iCre)�)� . v . �VSVeHY��dmғa2�n�+��I <� ��>6��� bul�=�-n�in.on�� chosJeŹ"�.NR�an��5��%at%W)q�"YM reveb �zJI�a�I5&=.�"��1�.� CB1Y.�asu� a�Z-2tra�Ston�(%�p .�5�I��D4. C} �m*�M��6�h"b���i8AN��M-�A!��in 6 d�/?�|�>� surva !��� !=odQ��fI]�De߉R8b"ubur��Ah ɬ4��J�%"q �wA���O an!�9�mQH.mQ�cC�}- �tM * �� " 6> T!@�~,�-)3al.Ŭ��>�inn��Å�ly�: whelZ>��*)!�� at weake�WsL cTo) a%��>V�e�.��Feek�explaQU� �=#Ve�*W!��BK[!I� e�s sis-�y�N2�f�"�`. t�#F�"re sl�e�dqkaj^��tFiv& .WB*Z �V�Z��W�� A�� *]#�L" drU%�,�hk�d�� B220+ B�)��ݝD3+CD4+%� 8+ T -, 1d-�Emer+ NK!�CD3-NK�91 9iO&�l�X�+J�e!xQ$s�N!oEGmye>@�`�g}7�a���N��8)�CD11c+Be�11b+Ly6GClo neutJil�>; b+F4/80+ &k �WA ͼ ,Ly6Chi�$�J�aM+I)�.�;3B�o�Nss��E:QR|id%5�%Qm*� in6� �_��2���#ages3r1 , MacTer11W�A;%&�L—Sca1+ cKit+ ( LSK�" F- - *:%2)/G�E -dim!=27+a�mon��zes�( CLP )%)�� �U�W�}p��i!V�-x � �A`a����"�6���A����>v.�,"uyI�:n i�2Uf3� }�pre-pro�DFro V��=�a�� � �SIh!6�9q*�}XWj X onwarde��f"L �Ap2��of�^I H��4G2� -.l of N�cCcur"-.Vs� d un�#:�)�,)�M�uV�-E�2���- Dx5-�./ ( NK> V>7+ i'9Q �!iNa*�Mb7Dx5�~>:m :l%)���}Q"2��!��[%�ineW�jJ� a �a �2�iKƔ . Si`~I'plžT��>��f%2�5�V��)we��c�s"�,:-�)e1V �thymu�6n ��'$ic CD4/CD8xF&�( D��!�N2SE6s3��*TcU�LhCD4>��O"�A���BQan ob.J.*U�2uWe *��%s�(*� ,&!j^��� d'��E�"_5I��y�"�.!�A ��+� �_JB�cau�$ elev%��6� �WT2.� � 3&� �q3�}ŋ��@�to a ��z!xIz��� "H q�j��%teVH �GM�+0�Q:v&d�ImY�?�so�Dy�J�!1ma�!n(��BlQ��\�(8�pr Is2�C �0: 1���% �X��f2�exacerb�LdBn 9*���p*� ��SA�bed��.g-5E&a�5쉄!� � ��thI�o�dbm (�eprrr Figs|AE6A , T%��R,%��,�recruiZ/�� 2z�1�tH��139}�hus 12 meaa=*>�>)F�&��no�7.�1�cicb-�eF��*�Qi��B�^��cg��i *�%�!�s�SE�un)�.E�R�CFf>����gٲU�be!��� %r��ariso(˝�X!������ mild�,�fNdrkB[0�e�'"�ce�"�~QHs�[i�g)0io&C��&*�%XE���Rd4.��*�yc :!�.#and/o��*@�#_�o��6���a����wisp.r� data"W ��g����i��u eced���@ra%ytD�)��3 i�� ]#� f9���j�!pr�ly s� of 2�t�Zer�cav������A.2[f$��natom� loX�+)"U �6B��� u:��!�o"y6�E�.�per se l�l��D!�|�5i:)� �u0e��z)�%$B�>�i��S"zL�w�.6�U� jI$ٝa risA��xudc4%i ( PEi � s owe�%� n{+B�lo�2�,�����]J�q^&2�� 6fab!CZaR�/t�Xe�eEJ I��w2>t1j� 2�&�54E�*څo !�:re�DIfM)`e��te�ON2uZ�2� VQ�6qj�dH&Ln.�"�m�{�]+ �Q{I:��P���J ��_!)T*7'dv�I�QL�:M�ҍ���&we�*o:��a*UJ�tA��1� . At& a�% ��1, ��Il-$ IL-1�3�TNFnd IL1β��un���~�RNNF&� V� ��t�TR�at 72hm41$�2i �`�.VM?cHS�L-¯sX�'ծa�/tJ.�in!"4�at RTg/2�)e(CCL5/RANTES!�b+�;a=� ( S1��)i� ��_k���!ya%�:E�� �E�2�b?|>)EG72hrs R9�FOA'Q�E�E�s�w, 9$ T7&'9��=eT U$�r�&E/ɋ!��%*�$-�la;U)o7#K&ul�/KWUeE�2- Za�( T�>�Z�.��L .�5�7a �, \���a3,B� k53f.�&��!Ea3)�|��,��or"W.��![{t*�Q[43�_v8Ee5)%�� sMjO+Iu&j�8abrog� HMPA;E��#")2&'�+i{�(��E����u<�>.U{ �;4� s; a�E_ �Io�i�74-�* flow-�m\*�.�ui�4 C=#a��9or��! �� "� e0� m7�V sour��"�)n wA�+ �V�%��~�� %f�2�%Jx="j)�!7� st&�-$oS)�%@ty/mW~*4�#m�9WV��!�)� few�m��o�Aer� �d-b,!��y�NCnI�)3QQI�amD�heS1[du�:G = i&N!(low�F�"~by�a(�T�E – ��2�%�b�%��<a etMm2s|; �:EFb2E2F �g�!�vIB�-H22� �H ir �j�isIN6\y1�ɣmc1�I�eqs.��$v�ay� ssumpE�6AA|�� F^@� qBF�:� E�U��0��A�V2�&_Ea�ti��.�G. 72 �T�m6�$adminiw@�aBz98%!)�E5�_ :IkQ��+.�re)6z �g��Hisq#NK�Cla�e�ut]J � uLm%�,�(cAfa9col�hf D%[����B7I"I�%|)104pg/mlA��!�n 103 )QNK-f( leftB �A�C7)7#.63^a�>L AP&t s"� wild�!:tro��r:w p2�%a|i��_ V�[�kj,�o"�s*PA��>�%�5�o#�śwt)̍T�.0%BT oughei�g�1 h2M.�:Y��%� !I���� "�*�%*|2��$d�EeI(inAQuE�,L Ul.�by 89�iffiF * *M 2 V)*�-EDR8%Jno% v��IS-2z"7�i�I)O.=w�8�vN.�"�#a̭�?&�1�Gs.�. REy$22�%17�-�<no�?� G�  �XT �?hthu�\l�nA@�B.@o8b� ToI@H4~-dL� mT0a�_0s�w��ewd20!%'Y1� BMDMs,Q���fl �.`ym=� vitrUPk�%�"�.�-}7���_  !,)�A!&j,M���0B��� 1��"TNvQ5�)�2uspAf.Q"!��CSF-1O�o�Aum���iڇ�C�� eH��2� f#�}.=_-�2f;1|%�-k&'|!-p�y��t�X Nh-/- �"i$Q��G��d�(�no� t�3)/)<u ��N�� Ā6!-�6�Bo��.g&� �,M�%Dli8���h �%&�&(r�)) �_"� MOIi1�dcolony�YmAͅ( CFUoss�M& /A0����G�4.�Ideme�i�����-erJ load61!���с Q8:� � . A2ae�*-> E%ɝ��&��6!� 7uH9� "  dropa�9 �%=sdto��( �q�hr0 73)��Fb�"�` tw��h"�0k!�� �>�6��E02XIN2�5qN���)�i�"Z ,��?!�� !;�'c��&�)�B)}I%aQ�Ll/��%D!� c&WD %.Ron�*�<of #?�Nj�W>ͽV�;.S%�"�%�t -SeqXqun�V3 r Lm�ALP9 . Ge�1,�7 ��=ˬ8�nin��47.s7��)7n�[+P7�O IyS;7��U��!�b!!kƟBR5#!�otJx�CPd1u sex &lG%�5 ���B , h�amupAd6�A��Z e�1.*�G"�8�I-0e�8���6:)�e�!�_B�*�4�ei(d&MA�t#�YF!by%J&8!p�( �$��!� �@en�)���om� ����y"� )�Q Y C9rT)oiY=�6 of�*!��Pq�s9il� �0�jA��6 "xQnse�H9M%n�&�A�$�J�tr .i! 6,a�"�O�#�F bT �� "�E� �<QRM�wt1�xQ�of�Sp�4� �b sɕb�m� u�M��!&��Rhreshq\ �fe.�O*#[6e�����311 �^ �R�q�=���_!tmZ �mw�3L �7B]2",v��9Q d� ,Venn diagramg230�a�1&>Vg�=Az5,m�7 �>'��un ���B�:t)�ex � adX.����R�M ~*�V�:m �:�%�o Vali~�� YQ>8n.SXs2���5 , (!�yM��YHG� qPCR��a��zI�C�7y V�G�Vong"� .>6�%�xX� ,(N���1�V*�%�5 r��9)X."t��:c��aAv!�>�6r��MC��)U+�jpronoun U�����) ! E�2S(��)�Tbroad.E6*�%F -{��;bJ\�&� �qinD� �C/7e2�@�@sm�1C^{p18RH(\ ���Us�ȕ��L%XkR�War*$�ce�R, &�>KQ$  �=�.5�at  or 4'� ���9�.�.B���marl ��g� )8 s*�E�Pv ~L,IF�ar��Av| TnfAqan)PZ%a��eworthʙ�@o�D� P�" cy blun�����!�A��A&(-a�K�]���XAD PAMPc�c ( I:V ldA:dT� nd LPSMt9 W�e�m�Il6e� �Y���qcyA�s��� ��Re"#q ��#`�Er�GI:f�� � �)}��e�.3�at �1 &�F�!��]�cU� [6�&8dI"FI& 2��ۄsA 2I�:2WN+Uu6ed%x!�ISG����w� e6%�"�@!㭶���>I��6`9 !�&�Hof Mx�,Oas�$ Ifit�I sg15}��!�if����#g"O v �!s�β��efI�4t�� �y!0rf1��Ul ��3� a"Z���(� �z2sek xF1�lu�� &!A�u�.5ly�zexa��Es�� IFN��*�A�)d"��G} #���F%��O�K���q E enh� Il2�L&�P�� *jm/ iBA*x��) b�mimQ)m"�~�Ki�*�Ha��*&� �u�re�e-"� �O-E�y�AA6�rej*, �N�>�Q��itu�Z9 �Gdis�bVWr�� ")1�,���pl�.ESn�a|R��ve�0rp�"ui>�a- u���%�@*� 6"�"&e $(oۯ w.� �2�.�1�"�1"�C"�"prenaVl�i�� .�AM�p�e]�e�  z3T ��extranZ2�[10PB�0I�8 Yn�Q�A in�-)��� &>YedT�T-e�7�r�s [h. H2<,6�Q��Ee&�d9, $v�2G "� � �HA9U�pa��c�2U 2(2�,.�Ig6�#Jlo�Y)-iYscYYe g)� 92% (-)MXntnC � V hH*�X iy manif0�d�A>� =&��i��*� fr3.`W`.e� 9b�2��Y�KJ�Cbl&�6�F�u�"4M!x=?�.i"_*�\�� �A�=ipih0 U)ZLcanA�beq`�. Sofar��hav1�t�d �6��2� l"O��6&Y�flB�H. A.��1e eryMR�4α�-6��7tC. A*�%�>;C%�.!4�!e" �G��.Ep��=F!6�. Part"�2?�)r-gpey���#.62��A�� %/ 5o0 !�$���7Z U ;�l�E%.���� �'� 6$�V-a�>m��T���r*H.X G�&: gs6G��"/ 8��.�NK �.���;:4y.� ,*0lDRCDC1�1��&n��M�%� �[�=��.��e12��$%0!�&�9�%*� )�,��l�@QYA�="8Ns]\��_���C`a <w+)�a p53&�O �)U�`lref4$�� ��.�m`*&Qv Lre� ( Bol.B[5; Sun.3; Li. 4; C�$&�[1�}.�# keep��� XI�!]Qe�'n�I�3��%'*P *l�m��%�7 q[e&�0�n.�)4�G�\*{�spU{0�!au DBHS��X&' SFPQr,ONORPSPC1 �oa�.eaɁC��Y[�*ba (in�f'{</4#�%�tw* U�DvQ��i�6&�<*� Bg"H�I͑�?!�-2�"&�3{,a5t$S�/.�,q�1d=] #A2)�&�=eF��>�J"�"�we�s�O�Io��`'a8to!NunA:iW>� !i��2ZpD�I/ou��)&w � �@rs�%.Sict&&8O��2 y��#����%���J8� -G��)* �c |Mk�n&!%� �-ISm��#�*�v!�l�� nñ�2��a! (��>*�f^�'in "b� ice:�S��"� t ���,,V t���%��_en!� 6=!1]�U*��)>2i� "l%�2�wZ�Q�� g� an hl�u� !%]�)���non��� I�4/G z2��1R by QC U�b�-��Pk���nN=G� R[%Jf "�A�!�]�A`nR*[.&�!N�4'�e>) � Z�"!@ ׁ�*@ a[!=r�*b(A�"�W%����oC!EF*:RDuk&6�5�T*#Qe' *L" #�ibuE� PY�j.��sZ"e.�(in��. S ��6� F'W`�(>vm�&m� �:� &� C57BL/6 n/�j�375-dBք_XNn(e21�*'-HCMver�(y�!u!ҡ�*�6BA� � �20/*d"re�����%m]�@a�s\ "?� &x s�� Yl sjr%�3��i!"6.�gen��XQ�.5.�Ef)}v .!&ui&D4�of)� �wi.l they>nU play��ha. ��Wq�-@ ieu � �} comi�3Ÿ0� ]a�u��surl!l)FQ.� .�a�8�Zor)�6��'�.� �G4 �ޗ the growt�^h of intracellular Lm . Activation by IFNγ increased their antibacterial activity , but not to*| same level observed in control yDs . Thus , reduced`-autonomous immunity as a=sequence�less �0ating stimuligthe ex.�Penvironment is likely�8cause an impair!of mice �Qb�burde%%guidelin P@FELASA which matca�os�j(ARRIVE . Mo�-Hembryonic fibroblas!�MEFs )��ta�heither TBK1/IKKε ( kindly A�iaW by S!A,kira , Osaka.�$, Japan , �D�i( deriA�9@Ddx3xfl/y CreERT2-fl �i,immortalized�!43T3 method ) ,� wellHEK293m�p( American Type Culture Colle�( CRL-3216 )m� #(DMEM ( Sigm�daEibu�|!-Aldr!�4Handels GmbH ,q�,Q< ) supple��8ed with 10% FBS�cc�$Z$penicillin,streptomycin�nn. Dele����YaC.)@by Tamoxifen trea��( 4-OHT;�\1\�48 hours�� a fi�conceK �500nM� Le plasmids pIE-NHA-h �, MAVS(CS2-N-Myc-ma-%U,pEF-HA-mIRF3I<\described previously [4] pex on vectorhxY%<generaA"b� ��HRefSeq ID: NM_01200� uVaEcoRI ABspeI�wtriI�sitDFLAG-IRF7-M15 [40]uobtain�C+ dIsabelle Marié ( New York6�$NY , USA ) �4NFκB-reporter1_bJULAnn J . Richmond ( VaDrbilt.jSchoolAc�V, Nashvi�(, Tennessee�[55!u8Anti-GAPDH ( Cl" ABS16; Mapore Gesb�A� 0in 1:3000 dil�;k %�X]�300-474A; Bethyl Laboratories Inc . ,BH$anova Phar�g3.;6�1J�HHA . 11 Epitope Tag�lMMS-101P-200; Cambridge Bios, , UK�as�NtMycd 9B11; CSTF�A> EnglE�iolabN � Schw�t2.��CD11bu�M1/70 a CD3e145-2C11.8a53–. 7! B220!RA3-6B2 Ly6G18� ,i���HL35 CD49�Dx5t �44NIM�Gr1RB6-8C5 kTer119 TER)%� X122 5H4U%�purch�s�BD.( BҡA��An�instru� ŵCD9 GK1 . �N9 PK13� -NKp46�29A?� I:�XMG =� F4/89�BM89� Ly6C:H�YBP�6C6�37�� R2/6]�Igg �$eB121-15F9wCD29 M1/6cKi� =2B�Sca�DAM!�U7� A7R3�Nb](n�:* Fx���;$PBS-57 loa� �PE�}jug��(CD1d tetram\�6� NIH T ! C fac��(JFat Emory.� , Atlant; USesd��$Fluorochro�� d< exin V�7-AAD �:�������D�v acquirjn��FACSAria+BD LSRFa ssWanaly�v,FlowJo Softw4.�%��iently Iin 6-Ap�4s ( 3 , 5x 105��/)��Turbo=���.�.7 ’2;4DNA amount acr� samples%[equ*I��Qan empty� 0. Bone-marrow"�.�%S6?J�a�&�| via flush�� tibi)�femur!��pIpdi@ent�.�L,�/� )zPrecombinant M-CSF ( a� gif'�L . Ziegler-Heitbrock , Helmholtz Cen� , Mun�,� @On day 5 , medium%rzg�oP r} !(c,K  .�, ���hal�!'� asQ� R��&��Sto in' de*�� f!5"� ��replace�o,R�9 �!h8–91 �s&&�R BMDM� �� � T30 μg/ml poly ( I:C ).�A sham*  y $GE Healthc�i,Services Eur�,Jc:� � or 1>�dA:dT��Fj��� Hyper� ( Qiage�J�a� Poly�+�h�2�A�~�LPE%6@ichia coli 055:B5�;";A�ad1dropwi�bA 100nE1 . WhAwindicER,.��q�s � ( PBLF� Enzo Life�AC$, Lörrach�`atf� 250UA�orn� r� ��z�j�51>�k monooge�str LO28%�grown��16� in b%heartFu7�Qި .�$(�EA��ebef G��otWree��f�N"�% multiplic)�aD( MOI )10 � h537°C�A�2g washQf�a�co��t �*}5�Jgentam�{P��!Ccal��S� An�[� y$to kil.3|�anoZ�,-]��B�ga����6r����ȹ�Ble��or�2M8. ɂ�!tN�two tim. �1R� XRNA iso�B\ !�1�\850pmol DDY3Y siAor �  non-targe� #( Dco��:O THP $al Product>x� Lip� am�RNAiMA��v�jbe2-e2condi!z�)�"23 ex5 !�a��"� e� 4-�%�106��%Z%P����Sub=#� N�� ꂕFlo�| ( fl_or��)� e���w� homolog�#r6 !��ES-�. Speciallb!xPjflank� exon 2 di\$" �r Y�..�,&: A��Vav-iCre �,on a C57BL/6a��$background �h%�s � path��B�2��*� . NK% dep:� �.���� �a..by inj; ngeaM-Nk�~�� 1��� ) 3��Rior��Ɂ����ef"�$zonf\%%� flowmet3!blood�splY leuk�UB��g.{ 0an overnight Y��"#6�re (� BHI�to � 4 logarithmic p�5 lle�!X� ?a*�&e�|6F~~qu!hf�"by opt� den�"measur�s�600 nm b1i us d� O��rk%Y\!�s$l �ion�$� agar%e�c�1� olon��1p,A�x#aI�:�!20��l IW% to[�#toneum!�8-!k$12-week-ol"g&!���n��VSV ,M� �` . v . &1 �of 1x106�qu�%m�G( ( pfu V)� prog=&;disease%`monito*@every 2–4 h durU/“� E*” ( 7 �!�to 7 p . )��%B>8!H PI�Rdepen.$����a|#���&rvivalot�#� stag)!�!!� 8humane endpointA�ccE<slo�$Mi!vf deatD*�|&a�c%8within next few�r�M##6�+%�� n� of 0���FCSB5o 1[2Y6,�*� ��0to remove unb�� viru�/�&o !-odIim� supY(ant�co�"ed<%�A, L-929��s�/#CL-?�6, by ai�� a�e��epaA�W}�2�in� �<v( !�5% ��mel�LIL( LMPZgar��(� z �2� H, crystal violet soX ��&�A��o����in)��.>� pl��UCunAA�viW(ti�hd�(c Ad*8-�%B8i, F�. as*Z#aba . AdM } j�It�E�of>t-� ed���:%s�ZL ) 4d$.M ��-�E�b&6R�l�$NucleoSpinL II k�Ma'ey-NagelF0VWR In?,�)n�q "����se'ed, ibra�" %q� ��eqLSa] P!)Q�Illumina"�"Sa�egoR"^)2�2��d  @50 bp single-end %.)�kansHi�2#. S�/��.&x+ depo %�- NCBI Gene�*�b��Omnibu��acc�-�! -GEO�� on�* GSE8659� 50-6�5 m%���mh alig� �$mm10 refer{.gen)�$STAR ( v 2. 0d(,e�\ -�0] J c"� Ghtseq-! ( HT!Hv 0 .  1p��[56] .�t mapaAlog 2-f m�[1C�s betw�,� -�Eun2�L� m@0"�llyj� �0G3�@WTOof�sexZ adj <�01!&b�� logF�,>1; DeSeq2 v!�1\'� . Fu"<.en�lt�.�.*�6� �)kDAVID v!Xe p� Ued GO s %1 -val% �1fge(GOTERM_BP_3E��1n [57!� The assay����,a\ �d"�([394Brief�5x1042NV�196&�(*�no C �p,!�v��Z���&���*�b? � r:��� �2� 1A V uptak� �"�� � �#*m���]t~ݚ�Jefollow)�lEZin dH2O��9*� � SBM |1 lysaI w��:dR?!s2��%��a�<)1 at"�I26%58r6I�_����/a:*� �Iǡwre�O�!3� at le�.3! t -5� �3.tei'�ed� �x �� :���N� In ba_�vadjus%�b!�ngAh�s �70% 2ano)�)\a� rifuV. A�5 is step nSic ac�,!JbG �Psilica m^/\ M,colum�~w��r-G ��� � �!�$-$}.I,z�%�P eJcipit&+� ��*�y�����*at ro6empera�)E�10 minua@�z2D.�at~+. 000g D5D}B� discarxA�1<.-~eJ�4E�5]U2�I� >i_lle  drye�c-$1x Laemmli �&�(6�3D6 mM Tris pH:6 , 8 0% Glyce<9, 2% SD7/78% β-mercaptoetQ�bromopheA�b��)�Uthe���2uthen sub� weT6n��5a�@V5 e�pri7ũodyu�A�blo1 pro�/%{f�$esc� -l�$se��5 L�*yInvitrX ,3�xvx�� ��l:15 A-� � bu6Odyssehfr� imaga�s�7( LI-COR$incol�NE�! ��9" (au�Q�:A�iac pG ure��8(��edvU�V aR�yRmQ�,y:2�1m���y !�%6mix� ��,ε,.�s� .�, N�|IELISA.gS)sc�;�!�hvh . To���!�:m�eJ�6Y �#�#>#�dcDNAs�:�Oligo�6T1\*Pm`�9Ry tAid se TU&cript��Y�YReal- qPCR2P�@run.Ep�4orf Mastercycl�9o �if�Gapdh (�sekeep�� �+iQSybrGr� (��meg*Mannheim2�!.>�� s*�of y, Ifnbl-1 �g2p4�Nos��Tnfα)rf� Mx Isg1�&Ifit3�m Oas2 �0lN]:R Ccl53Cxcl10)H&I ��Tf� ! forwar�%f=rAsz/'pE6s:�: �X-f: 5’-CATGGCCTTCCGTGTA-3’; )r )�!�barK"mgraph��Qb� devit ( SD� Sign�%�,ofJ:� curv�"J�(Lm� �!��" �alI�)Q�$Mantel-cox1USerum&R.��@>��ZN� �y�F�m" e&�@@G5��Om!ӞRA8'�-inVn)7omp��>�All� tist�$�!��e"�Esq�GAPad� sm () s&/5A isku note2fs]c s: n�"P >;$05; *P ≤. 1; *2@01 .ȞA biophys�mod�Lf�p0Bot�3l� �mayKo�"lfact)rec 9neuron[LY�It���@c� all&-L�Broes—!��*"�#of phe�ne mol�&LKBai�'sensi�I�Dir�#c"�Ma�i�^%o�!b%G-[��,e�Ue�—3 focuAo� m�� postJ�i se� � involvibpp,�Ydegradk! $ messengereIP�DAGC�o�EngCcloE�of2>e� of ionic MnWF(H-�9a2+`)AG ɨ7�A2+ Cl−8�K- vol�% ,Ka`Gnd+�r0�*TNwhL netw*Dis L�modLo%1�kin C��cal* in )�M exer�%ed�* inhibF-1�5���%0��evW#a%ime!Zth!�ling chemem +��\urc7�!�JN!�"<u�A !�M�L!�le puls�=�OU!varFE�U)r��s 'e��+ unkn�1param^#�i��fL �*i3@e�itude%�o�#chaaZer�1A�ri�&fa+Hg\�&��" q�9�ܙ *mQA��b� KQaps%_e�fe�s}=–C5oL�y:11P dyn�11g%�(six decades&+�Q5s��!�.���� 1 -E2S!4 long2+��0s�'� �> A��-!$It suggest�JNm��typ)�" laria : play�N��r"o�LP9�6Q;�j6^��Qjor�O�I� q6^=0eҍ�2|�amiddlI��:m�#veA�� :Epr|O��s�propo0")�fuAx� elop�! '&us(. O^Aa7ORNa# �� tial%A#recogn��f odor��verteb�"!d�(4X"� by s � hundreds J��N ��borne>�ORN!psm*�, each� ����A�a�u�[1%"I1sem3a smal>&�ORs*k%i�J.[2]–KIn&�A+%M�0e6ennal2a �JhodeaGgC�#�Mkc��-re ed�#AY�6 exqui�% [t� ,��f�6��e&0[DJT�. �a�Q!Y�!)�ns� stu*D-Ofifty ye� � * ar`V adioՊ, pharma!gŜ, �'SUysiol_ 36�, behavi���C !�techniqu�?�Len"in [6%�8]� �{lat�F�N�ha�%z" ld=�R dl$> hist� �V� �,Afc�T'La�!� � !�finE9�)�@bV_ qmi�4way [9] , [10]%�UU�P-~eaqsu-�t�Ce�8|$a�E��D�d � �Y s [1e$!@@53�!�!�V!1� [12 �3>'-CTs �W/fi4U�{:h[14%�16NQILCcircui1�gA�r<:��_��g . [17Y[1E6�X>�b]�"A )�l�Wto-<6�U[19�22�s!O mosta�ai!E%M yet publ�Jd!�%�of KaissEh [23]/SA�mp\ *� ��!��E��“��"� 1�"7a�P �� �� (�)r=ow“�/\eventsY�� Jc�W&`.Qf �:5r9�$(]�a$�', PBP�(,���'E@� adG s �, [241Joccupy�Zmm�Y pace`6;!ou�@dendri��A]"> of�:. A�sonably� �4 pic� �r-es emercZ� � s��,RXho�Xh Im�a�2V .&[u�Vly�N�(llX� elu�/$2��d ���%�:ObelievI0Q`ɾa*�V��urn��v�'!z" )�( phospholiph -��? LCβ ) [2��is0catMFa�1t�"&�1LB inositol �4��" �%�K-p�bM%tBQ�i�)�displa�Y#+zZDw I�s);Aj�2��9P�AUA�-le�Saccumk�+E�palA2�6�start&[^a�e��"�q���restA��@it%' � �link tog !.��n��) AVL Ay ��a!ai�9ouA�vesti4&�toQ� a!el-d�I1e6��!xg`he �=}nd�^� &\a�(� �%B�-zse.3,!<,"��_A�2 se^ 6i�JAm)4�F9]�nt��� ire�L!UW�%� b^of � B�n V'!� "by�1/� outpuU 2�ier� �=�/ mRPi��5�\ �3�i��&� “square` �Y9�ofa�t� %U� T A�L  ] 30�a��S�� prec@ 8m%�>@avail�so fa�i��chae erWT`9rapid� !lp>a s��e�%*atR@i�an�em��V\ab�`6"`��thresh4R8�)G� in,,)E�effort.,d�$�Qyer���A}���!�m��9�� �1�31K 3�Al !�!Ui{>� �"QiY���&���Bd d [3` no �JT� i ^l��a���%& w| e1 �/:�i"�*;9 �!:�+V-v�F'!bh!� �s]�on*e2��*�[37%`4� Bey�[�Xad��AQp���=os�m���addE6 h� llowLred �)�|J7r��*�c�de�C�" ?�&�f�at6 ld b Ma�yBve6MdA�%7ion� )%d�1~ ( 2� ) ��ng.���i$al*� � ? W���^behؙ��2-�*9 (s/ad:7,J�A8F�)>�y�~* � m�amp\*!1�1�m? ByWo��a���a\ sults&�84a�E�,.-�0neaM wN#��cobA���I@�A�nd�Jj�e um� �w"0� global�lF\y�2;��MŻ gra�!�e�� h�in�iures �*3��h� )u�g� �m . SX.Mh2xr-P�xpas��c�d A!�F i; it@�AA��4ly !~io�Vl�g�DT��M9C� (!��4fR#!\%6�yFee"�d�e Discu(f�7�SK 2� ->* a�spens�,!Lji6 J3a~per (�2�:�S ust �/�� e0��6� !����5��vfB?Nw eUabb��W# romH#�G* , Ehetb`)|C"S��:ShFr�%�symbo�ine$�gon�����6�I�)T3)�inclu�65I ��] M�:gU� �A~�"b.�10K�?M��Z:55� +B�l�s` A�3&� ���; ies: ; )���A8���9�&!�!���.�) ; (�%Z�5 e��@s��4A{7�y? $T8� d�d124-��d"�morVogy2P"d_dE um*0O*jF� O+2�8!�8con�&��!ॿ ��� fluxcHow+ , *a��[XA/W�Ţ&�aNini��>=��Pa. !GU\t�i�)w� ( 362.��deas J� �<bd �ge`o.�:� �t�,.� in An�aea�A phemHFIe"�I����OmX�6*I ��frog (Cf!���ye�! jaqubiquitJcompon�;�$a �c�*,�n%it <�A��i��a�s&/g2�!�Aor3�5DO�$6/�[��:(�e!�� �9�J04����jA�!#�5I�UЅlir�al � re&�aGpl�gbe� U-�Me ks�bLa"A[2�ly-��seAva1"". Giv�ih�*i|:�( ұE+c5�+�h� #�"� A�)eD�poeAsearc,AS E "� qpz[:�s .n 4yieHq1I�m\�)F3 sMI!�U sour�!,n��� �E�. F�,,��,r@)��2$ra� � h:��u9W>1#y*}&E!o&_ su�0� ^h6�F�ir�#"�!>SPj�& :;�ag!B>� Jmivo �HSPa!om �hpol��"�F"Ha 2-s �-\SPvW�ba maximu=t^ turn�Jo�Mi�to zero&� 7HI�?i�1�sbe�s� �! J!� F� 8�,, �heiCP 6�$"6�;%�i�)RLach@]��vY26,VMt�ll��% �/1��C�tof-fa$A &Ej�� �A� !�OY-�pv�(D�.�e�p�\2\A8v*+ic�*le�l�Jor�F�<n u�Cin µMAVqG. Zack � �Nv��q',2�a~2`Y�atu$ ���ŏ!-VS�v/$��{i yI�.%dec�es\ !�k '2�D10 (6�!�&Xfu2 .��Jot�!�.)� �� r!�ia���i�ui- �ı)becy they�n9 only ��.��a�Rdie�A��Z�Tmod�$T�F� ��ɖa aZE�.m��0by�#4scz. ��&�(�by]f�fo�Ua�B � �8� �� ( )�giX g�Tfa��[""�+"X�"c!��' �+i�W1"� &Y . W�� pumpJ( PMCbLI�2fcomJ %��3!��%A>E��l exA�e i� rrec~w y;it� mto*Urgeaf4(�e��r�\�'&fn&� g!"�-)� �>)$�( NCX��eQ�M� �5��6b &�er c�!�",6�;�_/�5�C!�ol1edu����p 9)��)a�BL;"WrY  1 }/!M�Fibeb� �(�a� tS.g� �n�#n�~9  �zB�E�ir\� c .%  �}n�?expla[ 1�R�)��x(Ms�7��57s�+�5��.�#*Z>E�3 h2+ Z u�68���Z�SP��Mymha� N} �a ��.5���>��a�i )%��%wn�EM*�a�JA�see T�USh. ( i ):]SPJUi���A�6P�@e �<or6��-"!� ��Ec 9has^ g�ves�Nfl��0%;F��%�Rght�c�Iak�iYd>�is usu�j2�( 63%I ( iv-C122S� Ӊ�Ki_$GMx , KmcaZ:KhK�p n nC�2GMCBn4GMA� KiClI��ut$b!/�6hIA7?(st5�e>�sM , kcc$Bni}i �A�mCl�i�.1rinU[8%5��%t�l,.�e�:R� n%���!��pee&�"J�b'� -"� �;M6�B� h�#,٦,l]XJ]Ion�#m�&.^W���7�PA�f PKC*�PLC�2"� ;.�~--%0��i��3C+� 0�2��X&��F&Q5%. I�"�E�N�0a"J"-< G2��(� attr-er%�  .tG%IP31b,���a�A o-��&� (4 N ia$i+isAn�%i� �B)up(+�T[(�`2��_,-�6A:�Iu.Ja|i*h%Eaca* 2ike*�0y�"�p �M#t]q �r%*oNG�F0}erfami�h����canA� al 7)�"� top&/�!��er�*�{H"-vnt�_"�{�2� i.f$� �#a%k!!f�.!�Ps�$Drosophila%i9�%t �s� ��2dQN-�#ui��!&'�C [58�-8� �0 struU+�8� �U�!e�mam�>an A?, � �!-F�, �##T�%.�( `R to G��tei:/8F![8�T.")w3nP1�#"!nAZ!�/ ��I ���,asK�U.}��g *7��m�eJ[RlE>^ �*WE�>#qU�(.a so-�$� &5 qL)&+1�i�� B�9OR83b [2%&�a#%""�5���PL Xenopus oPe%��W�B�Wri 21�\[��?�QFi do�� �[8� i un��"]co-B�.�[9Wurt�>>RE�)�"�/A�5� n4oʌP3A-� �/ , [4m(50��5e%Two�' arguA�!�"U;B non-�q�,a< engt%#��2��7y wq_�kCf� aa%.VvN1,�Rg.% ���M%'0�h)�g�!�A�>w���Y> �(T��2���#,s �Ca�$er�6ٌ�AL���Y*�;butu mo�A�.�|tha�J�.y�st�����e�����8�&�� a Gq�?�1-�Z3)�7�.� |8&*:%�Q_�[&�[53�*a%n%��-!� coex�#�� �ig x�%���pBai V�~ =�� 2�G mark 4, aat� s`'� B-��)%��#��wh�.�e�&0A� �b��+s�(�W,gSIf* `ir��!ySCL�2c)Q (V�6'�i�$r�+A�%�em |P20,.� �n).!�&�kin �=�*�y w�Y�X + �� �Y%&��ǁz o�@shUAb(tirX"7ŃU*��"��*adL1o�q��4� ��S 9. An a>�+}[M�6#"1�A�����aZdy���l^s, l1$S6xG+ �be�E��4E�I�� g�c�9� ^;N��. A�A�Jis�#�NI/ w Z�&j1I)r!�KDed> ��j�i����w{MISb8en�_�C��y-sav��&! &�ehee*�Z���]&� �I�ynJ�% ��heicI<�M�b�6fY*y �&�&of R*�!j  ot�d�*� B� /BU]�%im!>u;U)g>�-k:aappea@#� -C�A(S8a� .�7�e`c��}� k �]�QI�5d��?spe�"�I��� 2�%q���i3B"����iᤥ�+r[7ng,[92�����-�- ����VsA��)dx  ( [93C29��,ew [97�B" @P�>Q$M3mM0�D =�ic�/!�h�C*�L�>�&!!(ar�2�due�)principl��ge��trT%y�8�y]q�!;6��)��o!b�voJ6 �derA���Y�-�2�aw�Ja��(215!18!E~�g��m��uh�#on!��a� " ��ceF%�Uex��span$E��fil}�� ��1ida2+.r!vB}�Q*� ��n�3|*��re ��k��Ase�< al (e��) ��6Uma0h�>��["�W$& �;g,9nU�cLG�ex7i�wo1mr� � r65�&*���I�&�6�,�2��>m�ou��3�*�F�5�R���Fs!���nA�!'&� wardOf��%�E��M�uBP.*�be�C !nr��G3Jk.-  , s �9endopl"� c re�um� nuaH.T6gceAA� � �6�G%�$>hypa/Vli�+ake�fa)�*E.�r T9�2� 2��Iz=%\A��ri$���t�n8po�<ilie�a�ca< 9Kr� �t�eA�rd5yY+udKmn�f�Ua��*%1�E�I�E �,li�I= a�aY )2�*�P� pzic a5�eW( �:6A\ inne�R�De% BregA��.di��&����) �Bob�f6�gU02-Y�y0*�V���HXRū 0 mVzat% )�E-w%����!(5sI$2�ic��j!EapƩ��2byI�[7�H74�75]"_ E�i3��>iff̚e>!s)�� �*�.5DmM.!n�3��oor��ve ���W�3AHo�M�le&�Z|�Mroblem`e�J]� MD �-�az��sy�1s� , �,V�� V��;J�!G)X��%���iw&j s @ rZe'o�' EN%��J�#ly)���. �6hT �t�� �B� ��a,�P)�!G �%��[�guJa-eU�*.�>:Yst��N���.e6qs �w�^ m��a_���6%�e� .S��dqy)NVF.ow�F  ;w/ ����"3:�E�! �en";A j'm�~� ;ba��wG"�@e.�;)3wq��\�7�M"YE�U!�of��(� CaCa�#:Boc. of� 19 =�"@!�B�l �3sA�w5B�'�c���"�.!_[6W��+%W� ���& R(})5��~���_��_u�:� we ignoM #JJ� "pr*�Y( s [6C [9�9�sT1-��%Arepet�&�  1a8at �KT n�Al� �,��'-4�9mG�Wtud|�1&� zs��7nBP��� )�-��9{!�, �t��- sA�!� ,(&�ԡ�eWor�J> A@�ct�5RJ+!�� ŜbQ�=tdi�)�a�Ք���$� !��e�<&�%q�� �;Bmd" +�>z�o�Lit�Sy{ ]�; ��'Dof|.") -�6� �$ f ����2�MWe�Y*� ��9H:�%V-Q%�� a�'Rr-Z�F�� �n�A�eB Na+-���"�-�"Qru�+ AI�can ATP�rp/"�.�� �8'.&��E�ne&BvF(�/9 o$ rsal*�0is Ex≈−17� . Kn3CkJ21�$( ECa≈14 ) kaF� ship"$E�)EC�LEN�)��eq+4{�in"b,a��a�qof>� ENu88�1��+�k.[,yyr� 6�A theo� i *�I��eeTs�lar�l-�t�/]���������a��>��D  ��le*�h�2�p� sext�%N+T00&� �P�e�!!��M���A-nrd n%r��4.!sAB�SP!po#��e�Ga�ī�cMoreover:^ac�_�"&,�!&b�#in S� litt�Vis���Perhaps�7t8|� c�Q�M�+��X�`�&�Nە�^c@�2!�Rt�C%H!<�M-�M6&�+� s�] �3A|U"; c%f%�dap�ndm��'�e�E�&�� ��a/�(E �6. AV%�!�bsG!�scs���"�"c;u�'�s�?al!�e"on L � !�fuC�s:��di@4�0JxE!�8�Ef�3%�coq^ S-ts0!�2Lr#��:�:�5�)�6>�fE2v �/sA��.q�R1�"�2�" x@o)�s 5:�!�c&_ -� *�#,AS2��i- ��s�$��a�y� g8-�#�Oick�:8��>�] � F!;7C I�5�ݭ0. 4(.!U�O:"�� * #+m�E%-J�P�A� �6!���bw )y5�7=w!�X9h>�sn�'�2a�)fJ'c)&U�R �Vs* ϰ!t�1 ���"'��G���B�6�9  l �Y(`�/F )/C-su��&V B��F�JS(��dY� �:A�5<;!�afO�E�8pjdl3� s� 4 �r!�%iy)=`(ng� ��En>ICl )!�Akm�aOPC��"W�S-KrLQ�*FIly ���2��M�D[10��A�b �+ra�FE*-SP9�1B� �Cat S3qLe���sU4��P *E9� r��Bm�s�%�6-�!�b�j�S9!�shval#�fac��byu@��6�R1*�$!�aŌ�v! SP*j�)H�:O2Ol�ZN2���O3 -kx )��:Bvaria�,C x1�:C2?->��%rpr��"�frame�)cur�.&k� A/��e� yA�b�\n\in `1p>�G�"�39��^P�$�z Se�B_�D5�~&��lim�L{af�,%/6� m�B��Z6' S rega��� m1]�: T�v,�oD ~�E�H��s]'"RM!�Ll&M d P.�3���5[�PAZ�SL!�q�"��0� ���:Ic�n��� li�Med �,�v#M.�D)&�R}��BB<��b��&NlyM'to#��"a�;inu�Hi/lS�t*} <v"R r�4�B5 is��u !ym�i�A−2 �µM/s{Taee�tleneck_8�k,b�)q +l `s�:$#%_]6�VPy�߂blj �Is� n 1>�,I;m*cp��"H ���l�)�`ř"'Cw�_6>' o��a��aa�u�5�E1( l!�.�-up&#�i66van?�!r;us�A% @m�&�B��~#meS �IUS J>'�4V":h�#lad^sQ% < a�N�9t~�&: ��sAZ�Zo4C�/6�"�� �( r6&�<}b�3���A ��1�B9#i�.nM�1"=� (�FuAK�1֦t �>�#FA;B3%�4eּ5�Yly�a���!�#9�&?B�l !�E�N��6���l�n6�IZ2R?> tA�� K_M��eŰA�Q)p� oee!E�A92��f(��)A]�L,�ZU3nbF]in�#eMY!.ea7ue%�sM��iM�cK.Gj $E0* = )���G�Y.!"��re6 �m�}�pNz xtr+�� ~ 1�A&"$�peK�ni�Rst]�Z'����n{X^(��"� z+ A�?�� &��I,��" Ay��2~*��+ > I_ ea^p,�Nb�8lu��)�� ` ._�؅�&a�r/��tMZ�/�^��46�F�F� &���!�/asy�n Mv6� help/%"� �-6�u�2B� ���1!nKl�� enco%==�I�(�Kr.(?)6[J!C.��LM7� !�e"��5�]J3 P31o61: a�> 6Vq,!�hn9ri&����s�p�3�B�,&2� G G6�)"!��o�rd-sEqx" O1y�t b��fd�mr A�poi�od�� ��?#-_v%6�V�!�!�*Iby �N4>�/�#&�7�?�D�DFP@ l� -6S� U� � <5�� 6�)�exten( R�_� 4 . 76*�x 5�u/��Ind�ɍ6b-C�_U��  . 25AOa X3 %�:���=� 7to &�`2!$ coll��=� }%" �*�/����1��R�D�Sa1i}� �  IH �Bma-M�2)!=i�72n}a EC50!a�01!��� �2a}�� 05�21�"~5|BL�"!X6� ��8�!/:�>=$��� �"�Oof 50�/Y�C!�����actj�� 2�I� !�saI�b�t ≈3i!�eaB�#��( ��&P ^F8hR7)ua2�!� o�E;�Asy���sP�E�!4�!z�o���R����T�U�!!2�m�� :en!�B ��*[s9Z&U�0qQ(�� ZdaƩ��L�LWUse�AQ19��K�2�`8�� lA(��x>'"�e xSE�%Bd){FZ) pers*�;e�6�s:� #� �!�!� enoq".] as�-X�6��i�\#%�ʩxbo"�Ɋ! �MenTrXg!T�! ��!e�&�3p"&f..�e���g � �i2\F��ed�,C� %���x:s&�r'�#�LeS&An &� .����,$�*ans�;� ea}�Y6 �0&w �qto�m� ��#l7RP%M� 6lPSo.i l=�y-�} ����� i ��3i!8�%M8 ���%Q�f�< *�� E*r/R*r*�OAE*��lny�D# lw�$�t�7'(C�d��tT��m�6�ia�:�2�b�SPr/E*�H�M  #�S[k!0�=-]��b�u[��IM� , si4B^��m&��� � lyx+�9 5d�xh�" ��MP2/%Yas�dHe�/&d_7"� �-e ��C*S j:Ce�aA�r6�.���Pl�<r�(uc�?�� �/uE|�Sd6�)ѥ_)11�*t2<(�]�|* @ng#ers!����!oin�����#� .Zre N�{ t=�At�+���.�1��R��'��er i��&2param� b�� of H�co"s��is ≤1�nCc&FP}&!n!x,> '��nd�O!�o 6� *�m��!k�>�.�tV@ ' :*�/o"�A&HD�V��na9�"6� Ti�$`!v .qea"�}�abrup!Z�W�%Z-lwMma�CnO�\6 ���=� w��*%���"� �r�v5���Z�� �mm?smoothl�7� fiel���9Z�DY g7* aT2aK�of�8.csa_�� frag[ !A$�����!�f� 0�*_N" &a0{m�7 ces �h�<�<mpt��uni��ar� ��mprehen� �{���y 2��h�� m4`2s w h cleaĘ����4B�&�4!������6�Bk!��n�[i�=y� a faithfuB�ue;LA�� k8,an�)p"e i star�c�! n!� new _N�de��&!]offP)a 6�K�Av�> ��ţE'�K�C��V�p="K.p&0.�SpeUAc� �!�1Fx.�ZI !�e�9m�*v@�2�E8.�Z@�.62i9Yal ? Ip "�."�3��a86��""���< 'P'z A_�:5@ �Q�o � acb�U���,� � ?&%>�5)����o�{(%��)Y r! io�Kl7 &�)|Ds ? C�:,��Eq�l�@/�m7Qs [41�64�610�K&U*�*5��c� B�"c+b�h���t5�-and$b&5�E�e�All i.���!D&!@L-o"�9� �A 2E~p8o ie^ �ntAt@c�A�a~kw.�?M�� a�. �8un*��3�)�N&��_tilD�G�GfaLh?�2h�|p��\�}�we� � � ��aUw!�ap 2�e�,c�2�" �qm�:D.� �a�&(w!".- �!$� io�\,@�Gma���Rq �gne�y�a`nel>e�toi�� whilq*)�D er:6A�"�n��AhfCa>fcat �V�0!+ gECl"�!W�&�B −9 1�!"� !�.�&w&=�t��9�i04pU�ed�BUx��Cy1E����yb�gm,"�*�*C�che��/c @�ne �im?:_stu.6��yFd,\f( H�\6�, ( τy,j]!�f�E2   �e oA{P i�s���>-%1!%ed>/� ��(, ΔHi�$|Hi−Ĥi|�s�!!vmfĤi=�liIax!�θ��^B�Q.�Hi%�r Bat� "� ��.�Δ=]b5N>.��Y)&5�)�>Wv� onvt scal�.6yow_and�_��4 iOs���K�e ( 5l.v+n-�26��&�$Q!�@�"���D�յ2�!i�Y in2 �&r*�k�l&�2��s��;�-g!��u��`}: �4��/"�,��1)��/!_�@,)y�&6�] 2�� exc)20�!cwo>�%��>-&F o!|�4B�&� m.�v���K�;s��^rք�i΋al-and-e���)7��a���Qsan����a�!ldra:��Fa�becx��]���2�,a�3U�(��j��,�6M�LX�to un��NM�s E ()%`reo,�ua��`N���G"z�te�ty4;ba�%-re�. Ek�xv&�@s5.P^��L�W(74–5 .�p ��<fulfi�d!Y�e�i�R�N�E7����# y a�# a�opRA�I��\MatlaboH�X�dmi� r fmGp6�Nelder-Mp��7 �� 1)Y�!�algG�hma�v_�E��� W�$ � U�s θ0:w  &�c&:5.Nv�?)�166y�[�'�ʹ"jMA��K�� bid � !�� �2QQā+^��+g�,!��a!yl�0����&ߎbk[!6.w�s��G6�7�C,�<��k DginfINes��� �(� turb 05 bi (e�PS#�6bi�im&�� ���t ΔbZξb���S�n l!4� jI=0�w��ξ9a6�fl>A% ok ξ�;�,�t�v�nu��g[�ra9i-e�t9]d�%�nonY5ar��� )VCa23>.}cƜ��?� �4c IQ� s Mu A"Vg��-M ; �� tU&�log10U57no�%�a�b&jpt 4���Q_t���.)�� #7 m8 �In !c� r� i���Vvi�8SuZ; w��8  I2l 1!( � achB$l-Xd�ג2vru1�3B� ��1��A26�U�^���}6L %�!�� 2 ��cVb� -e S%Mm�( �re�N(N>:5�Ita8�iv�;;�,2�����I��55� �7l��E!�ul0L8c��Ɍ�T�d~��� %�3"�Ka�?ike, %� low-.�| kA 1�1O2a�′JqE���* �� p�k�-���A�_/%�e!�a{��%���8 ��x �ver�1|W�� �≈��.��?�uFQ~As��eH tumor Q/ZO�5_�a�3%� .�*���uOel=#�JRE)�gٻ� v 3 a ��BH &��B(  A�Toݏci��p53RE"; �]� ��"aA�t�L����E 4e�b�9 m�-d� ome-n9p�L��VNH3K4me#�*c�doxorub��DXR ) -=�wk���ob���h�{� W6a��r�o#Bs�ng.Fpa�U,�6%�!y,�pOĀt+c��i\6 ( DN<;1�C���62DHA�, ENCODE=jstea,�=�� nd&�x < er�.JW]{y��duc�*y@of^/@)�ese_assoc�_c !!steady-�:�u%�%!^�st{ lk:|p5Jnbq/��bas!�%��+���ih����&�1)Q%la�� CTCFUX. ��m2o >�r�6a�2( B�*0d1^7R�!WaG ��`motd��xMt�<ՔapPOr��R!lin enhm-� ��;Uc.q]�� ZUjes�#v��*! t? t�o,sa�!��IUns��~ surp+-lA�9j�>m#�B!O��o��ejQyaE�v�Ņe �. O��e�byA��ϥ�overl�Z�po ��F�8�>Ja�j 2�/ !�Gp<4*�>�)g1�=@(:1�'�PBcnonTE-}U%e�� ���\ MLT1i�LTR10Bm�Mer61 TE��&�9�ot!�se�i��*nUr�:�g�C� dja :j%p�$ ���A�in L2��e�u��m�!�!Sly�8y PhyloP�CB>(A,�Bm&-v} w�7=5aJe��ABAL�6�"p��)e3schA�9+�z�ġ6]ya��u��a��I"2:H�� s= �EhE�A�aretha"~�u$�M! �2��� iE��j4���and/ord� ��a&origi�;��d�t�oe��po�$m6s�N�^ �#���to�V dama�xu�el.0 4a�q1�6���A�%(��O-B� th a��58 s��irh9r apopto�6 *5���!5d!��� romi�oB�%�$�PfU@�s�!FAQ �ory� icO��&�al}I�9!�� !�> yAB�I p6-h�W-�aG�J ?A� �� w2�c�,of RRRCWWGYY��u R =[�inYW = A T�YyWd �-�a  �0–21��t��CZt�P�>%,oΞl` �)P�t���9!S� �[Z*���hu1�! A�e ON&� V��e[�Ž!:y��Y}9��A��$( ChIP-seq�0"R�N� ru@&�ihM��8�� expo�}-*� ��f���:N[��Ph :�1o��6�e �w�1�, [ZQ!*|�% onal�R�E�K�i�!%com� ors/�&! N/� PW'�a��P�9��v���A [1S_1�q�A2ru�gT�"�!d! ɕ�bg�&a�t� E��!&=ZM�9��PΙyq��~�=&!�^�o5R� %��$&�nT m�+cy��A��(�T!�polym�����m� leng�mJ� ��.u�֩�=�-�r[16�`2n�\��Bɔ�s���er.u �-"� � Y )&Q Q�� =��A$w, �1s��$i? �t*$d���dra����T���F�isSUA�h"�q�Z!��i������Da�e�%"� �ex�Zn!"�tW� �Ɖ22�r"� �_���"�n Ymotifs r frE@tlA�F�iA�s�d�5 .`ret>.�L�2�� -(� �/1�bq�( SINE ��7��s��as Al�!�U2�. ar9��NEc4c� � aESo�%�T!��B>![O'5X"cis��5��pw�k��r۞ET� Q:��7w"��Q�e�"r��U< )A��@ y>|���%upx�H�CUq6yc�B�0�3y"� �$1+q��( T�J&�!�%��u�"�'lig��/alucoco<�k!<�k50W:�wa�n!�"_p"k� ( ∼95%��6n*� �l.��Aa~nt En� opedk�f, El[Pro� (��d�IAu8]��!zor�9>�� meno���TF� I,0rast , Nili e�it . al . [14] described a different situation for the tumor suppressor protein p53 , demonstrating that in9�cell line MCF7 , p53 often binds genomic regions that have high existing nucleosome density and low chromatin accessibility . Other studies have suggested j4stress-induced���at specific CDKN1A ( p21 ) p53REs is associated with ch� structureI$these loca!Y$s [15] . Tobserv argue%z0further explo!]on ofK role n-6� in regula%7!o  to DNAE$exo�� �n~A� V�{werA�yy� DNA-damag��, chemo� $apeutic ag�(doxorubicinA� XR )�i�J�偁%LCL )i� goal wa�assesE�s2!�-�!}M,9�%�!}aUconsider6A 3�.��$t�0eI:onary�  .A�Xrevealed several uniqueAi�, inclu��inva�՗a� betwee)�Ya�bot.��&ib<!n�Notes,e+novel�u^�Mi$analysis d". edIZ is�!r��eXic�IzES:�!V��strongly����Y!&hipZ)le�!cy.g� ]�. F�mora�A7�i���1��rfea�s appearE�� b!� shap� y6 sele!���E0, likely drivP y�1posable.�Ou ,y sheds new �a���complex �R>[!:�iIf^�sugges�� he import�a&q;a��!� �)y@pi!�����;pre��p53-medi9�  respons�; We carri��u �ong treat�YLCL�C@GM06993 , GM11992M�,GM12878 ) us=Da 0 . 3 µg/mL dosꁭ%;8repared mRNA sa!s. 418 hr�� .�a� �b�3K������` from`colAG� td@, a time point whAK�0growth arrestj$apoptosis-E#ed�!�͔ �g!T[3� Follow! DXR-� ;�,��detec 6436 peak%$a 5% false� covery �� ( FD��)rA9,QuEST PrograZ 6��T�, &�a)�C%\FAe !9�,�V 822/903 ):as sign.nt ���Ya�E�Seq=�*e. HH3 1 4ne 4 tri-methy� �� ea�H%�I s5}ateKm �- T�promoteP�I) but � owEi,/ta�e�purA� <,Aechq��}sp �]��� � J�/lso blAdr�� ,  Xm�un�eeW�o�� ai face"��+�S&� *�mpacts!�-ş�恙�to!�l� iz'e� &�� ly"$^ ��� ���X6�Mb �S� � ,� HMM15�a�j7ayb��wh!����Es�measur�for)1!��.�!�%�@,�IE��FAIRE]as`d!�&)!L&�!��N,�bas�.�In��,8�I�(( G ) summa��8��&� sticQ aح�S� e� o�� pq���rm:6Ia�KU$ ,q� . Numerou F�Is� alig���pos� -q}>di��� indi�vo anm�a'q�S� �.!aSs� %i���my�Jwh�齉de� 6�-��a8 � �?E���hR( Fs J}(articularly� 27acu�1O 2b ,��"zou�9^C�� a� (q�web  )�" 麕EI)ԍ+s:%s�/.�AyI U*,%5�V:�, �H3= 09ac at>93% fr y ) ; 2!CQ�flank�� �; ��5(S4m!U t>96>J4�ak1/open�f; 9 i��or�J(enriched; 6!="b7 g �@.� polyZ%�hetero��. S� �plee�T y��A�26�Etheir.^ ���Ali'in"� �� !� ha6 ow�,��J� �� �cittle-j3�nits TSS��"��W ed f"M�ENa� Va�iw  ofZIB(�M2�e!E�K phe< nar alltU�!s . O�� �~-Ie� 1697 2A� e&� aI strie�� near6�ovj��, 4 hr ,� �6��EB�>X ( black b�)�0U���ar!=nA�� ��Mmec2�-EE�M�,��3H� .6*`�!I�^bar =�g!� .%HA%%�A�AO�!{i�lv-�( s D1–D�Nleft �G rapheK l�st�dng�.0�$��g� e  a �e��ypical�oY 9jT �g�i�inF2E�per]edai���is�Au��Q1�.� )�!N.�4![.�w !"� 2 %���42B , r2 = )4TP< 000�AS n9edZ� yš�� i?�!�ݡ�}��z2aty�. How��2� j��A�. 4aDu}�%�te�Wf�Q��.k�sk�:)� v.� I!� �~or)bodC?ve�� downB�� ��.y.pQ�V �6gby� ! preext ng& �� ng1=ed���( PcG/��o��gE:�uC r��!jV YV,�2C�� *79w-��noreR(��3A.�� r ribuAׁ^r s a� �eB a��n?6Qo&��e �2��A . W�1� �� �can b�g�aCy�,!9 !a∼1%%�1 5 *�  (/8a�-O���!64!�!�!8] ( S1A-K!�itquite clł%!B13 I�y3���,�I�.�� . Mo����"; ��� ��&� !S1B �;}Y � , see"N �)�ml�8��.T�pr�al%�; pEF star��A/(%�9.�"[ %*42GjY4 ( th�in2��1��$5'_:�A�atF at�32 KbI�lKa�)�m��s��NF3ay much"wb R��3\ �}ax�#53gaE� foun�Y�6�&r y�"��{ z� ;>76%�` �Oz�e"�I^MBE@eɐ"�E;%�F15!�a�TSSA:"��0�  �H�6�E!."�� ( illust�a�M�1��er panel%?�B� o �4y “poised”A��QQE�carry� !kess���2� !�e(' 4me2/�� IZ)n� aM!ge�>3-fol!�ducA �u2q�!b �4{BAE s� S4, RRAD ( Ras-R�fed As6�Diabea�)�SULF2Px�ell� Sulfat��wl$���'2 �(*�ese�no $3 $E]�.L*)*  0�}2].*� &5 (A=Y)d�#�#} &�)�� ���ܡ� each�)�I#5e'�F ed draH a[) �"E�qat"]\. %A.� not� ge� t��'�TTGF+T��� 1SC , alpha )��4�similar-�K 5�)���)<7 �1!���"�!S:� V� rp�ame�xe�(, only mini�nIv3S!.� sI8�šruU�&���ef�*on)<��q�o�lthoughA  _�9-�AzlX,A:%.�2� ,~"!���4"may��"tE�%�� ��e -�s�A��6C%)�&HS��)2!�vidual%S-A�. P�of�e�co-�^ ��*�kqVvs.��vEu�toie� pre-"� )�1/2!�/�1X5�gs . 4A-C�B�m[xAA`  ".|>� I���%!��irF�("O���!�;� en�t,M 9 ����A�q c�Y�n&�/6�"f+t E�R�, e�%d# oa2!er magF� ( S3 ���6d��! �� ih*�)e�de,�V_ A��Es( n��G .�*�lyh er �C �V� V%�� � &g I$��t� � i���4& .��resul�)�a� z.� MDTSS��byM�a�c� E Tsm!P!fI�e,>� Yir[�"�(d� ! 9 ( S4.cC-Q[f_ed6���� pri�2.��&� a�ɮ:����#� �Di!/2�e� . 5P OB  !gUdy��m8s�T]= ,2%Vn r2 =O'06� .�S4C}$&��m���j�:�2��:f�5� ifI.hE�M%�%?s!@B8$4DeX)E)aL�@us!< %�.6�+"N*�[/YY�>O. BecausEc &,sti�2s�e>�I_�����bef!R& ) could�?di^2he]�E�d�"��/�}� [2)#�1�9�&sou91�a�. b� def�B �i��n�%6x!ask%sA�J*to�6,�_eUu5"#W*�*o!-���� >��-9U>8h.)�G�;�)�% E38,e . S5�m�I6� logo��103� "�%lylAh�#�5�make up�!�+ ensu��it clos� match�he�"�mot��C2Gsq!by deC.o 5di�) [40]��  &eN . 6���<?6yS ��œ���achYGI?( S5B�OI0%1�*,� U 8!�aE�>�� ��> 53--I.�-&�y��$full canon� !C!�@8RE half-T� amer- mmo�,90% , 239/26|8D�2FkSb!>5 )�A��.�a:�RBatE�&� ) %X5T. d!�pv Q� �-#*A"�)F*!�A�s1m�cal �UW gthm�)o y� �Os"�/s`as� "vo�3R�1GADD45 � *6-DN�2e�H&yBCL2A�( &]-roj:A!�!GE–F5KE [of�$s� rams v�+1'�1@(��i� �KXprU%neW���0Bh �-��"w�6ma� ( PW�7mS!�w5 b1,o:' vitroR&�$<,1�( BALngW , S6� [16�E [31]�Sn � �(�Q16�x Fi�6B^��++`,�n scor�+� %b� es�a� maximumi�I��'���n:+%�sŨ% $��t&J ;��m~!b � ;s5'"dm�/U�.���PWM�6 �sɐI��A(� K�lo.� ���F/<g\hav!�:N�"RŔ��!� \"� � ���R�1u��upB �b!����e�$a��8:��=E>c'+;A*"�7�-53?� �#t �)"(�*vs 31%;N�vsR�;A��� . Ab�285/70/31��� J �2ofRQ�pla� ��1�2(!�%~ANly�5��a�4 ��2q��U A`fun�a; �A_�1DAVID����lG�50Ontology ( GOe�:� up�RI� y� a�DN("M"�7E1����5=or![�gE�!*:2. GO term�“ E��of� death:����“A��e�5/w“EhQ"�3!��2_'{$ � 3�:-ⅇ�@ vs lE9>(6O,-�5OA�!I��h RE!�Bda���;e�<than 3!9eDZ$~0� w�'�b �2� �m.%M��m%as ��r� ( S6&7 Y.A�>� �er51a�6�)~ne��pRf �1��A"(�2& �"�B�.IOs65m����=-W�M�yI�e!ct cri�a)+.�9in)�+�0bT "n�Z/�0!�) &�0�.t�+er�VArecvisualizI�ITj@u��9�� �". ,�V>6i���6H9v'a�W2ခ�uA�%�� F�'! 8]� � �'���*�#fir� �#rR�s'`(ce�q*+<.�vk5,of��R.�Vs�n� stac��'t"O @to!�e�c3�;io Mk�-/(��.� a�x 7���A surpri��r�a������ ��; !MEst.r� � �farU�%��5� )� D10�,"�"�s�;�Y<1 kb HY. P.b.O>! ��#�R�Z�� %?�i]�(% "� �$7� To���Wie+i�����4��F*b;U4ei$� &�E�%G05-fluorouraci�.5FU��9\of�6b�9t��wept+lFD� 6,.@)]AAXIf�I ( S7& m�tB;5�7�(.A{Ur >6+q_P)�a�Q!Uu+in � �. B�@*�6��}s �Kz "8–[9]X *�u2-2� � 6���%*9!�"�A:�s�"{1&c"a�G�@B 2�B�2e!d_d�  ��!se�>�a��a�5%��F�,��7M�CJ%+�=r+6�A7.9T�&�)�:�%��B� �� cQ#p.�i~�ٷ)Pp��"� �"*� ]1[*�JCon'6� � .7OE ?1V�!�9�t3)�g�3� 6��&A�'0�G�%`inB�NS�se �� v�?~"!��8 i����*� Na��H .8 o)@ed(2S2"��& *�-S5%'6�C� �L ,!�sumY�c �Co�e�C�e�Ee. � 5�[42�4�H&��K prev��ly���k eb�� Y��$I��-6�*� ���E@�h;K�- ��!hom�4�mamma�45�!mwe wo�@0 U9RE6T�s�y-� !��1u � �36�j plot�! "�PhyloP�[�a"20 NI�~L�/&�F� f;3h��8�R`D9-e0�A >! Yz�a��F H +&�-"�)��/z$�;,���RKQ�,en!| 9@� 4 w2uHa��_�YA��@�k�;�b�-T�y �J:r!�mouse-I`per�F? O� 8� o02� ( S8&5� �X\e2pH��� Bh-�� !�sndQ�er�3e�oor2�&��6�Cte-"P%�B�G ( TE���6�o0 �[21aW[22 �1(Pi at�� infl#PV�6q�f) �I27ac4la� %�G@��fU ≤�)� repe�ls<b!go�;XR M��>,http://www . <m <. org/faq . htmld W*35�33�970Ar�"�&�6 �� embedd ���Pfamil�Aof �y�, �6�2i�$ �!7 endof/ulHtI�K5 MER6s2LTR10B A] MLT1;Ca��ll�D!kB� �. TE-a&�a�:� 8( 82 . 7%; 803/!)�i �V).P2 # �A(F�����B�i � �x�'�����Q|ɕ*�9e�s .�U , S8s ?�> , TE*G� � r =E�.8��be�I� N�/�=J"��,�&H��~.S A2;:�a�e!�r �%ntl�_)�RW.tnon-TEA!q%:!9)/S"�lyA��!BH- �A�Pv�.���#U8AluE�L2 )=�e_2@" c= �(lY��C �W�uMOA�f  n_ aTalTE mi#")Va� ��#w$; is, 2ca-b#É�s�j)vY oldeMDfc5PL2Q,youHQ t [4pJNe:]��p"?j f�D�;� "%�)(r�#&64�Non�)&K$ by Pollar07e�, [47]Y% w�#b-`*Z�D0pathway acqui�E,N͵&#- a�To ��R�i�� �}��8D�k((���=�3ET .�R�wK/�#ofe.)�^A��U�6U�er% �'inf��"�QU72WS (�����51�!hCG 1 � ����I�&`'�m�!7+ u� � f :� A�Vx%M&.&� i��EP�"{�, hold�65%�r��S8P_KI�� N�`Q�� >��"�)s �&���& ��!ed�a�!��,�K5g� TSS�"�=8Fl!B�+� vR�1 #� m�LnA�6B ]. sS�&c�J-\oi�*� gEe 6 �Ln266 )%�MIR9}( 4��s��ch��T2�A�2�+w[jeV?*8�X. Two� A -!�DDR _ !� L2a; EPHA1 MIRb�reMg!�s\g%a�E�� ٣i�s�7unu�r1the$Sowo "���60Q�Ÿa/1�1�in5�at1�AH%�D)W!�uH&�UB se L2>� '� "� etaiJd2�M b�%jE��=so%� alt�@Q�}3J !��� byA��v,O S9G5T#(Qg �*� 5.�Fad�P ,�7rF!��Z�%� �^1� �1�-i2U�gi�/i�C�"�%?T:XI�"YYi�$vo%��& 5,�A0A������7j�Qb.G]sy+e>�"[&!�Z-Y#*P6F)� �C��Kory�)� � )BNaz�'�/a1e��[s [28����AQ ng!'46s%�.�%!)ioniz)ra�U!,[48� On a!H5~ scal�4we quaPR!/U auhi&� dyna�H,a. aQ%J/�qe�s . 2I�, 88�a �2 # �(�="I2s "�G-f8O�E�coinc�[E�%Rś s [48-[50!�/� h�#A�Ar� ea� ��e&$D2� k � A�.*A�s3��via�@1�5"�?!�4�aW>4. SE�� �/@*cF%4��>F8@B>* i�1.�  aU�d&b �_Is&mT�:��.�%!�.%S90VB)Wle-/"�-C)����{A�h%�i�4i�*� ( un+ `�1A* clar�achie8b � a�� �9n�� �:�\r�9NM&�1E�f 5�� ^.$1q.dels {F�uW steady-2X*>M�s�+�E6'=%�r�3�� ��of2���jEsJZ�ca�lp*�clmea\ism�XenaTtr?�MHIT!�Y*!Sf��ng��� bAa�"u>v \Q��a]� .�+")��|@KH$50%�o/�B#)hav6&wR&�@I:a�(25ZA���� /�"�\Q�=>. �+��Cl"�&f�34-� ��2m� ed 26 �� `$l9v�B30%j o��n-`-*�L�7_M�A u(A of 7>,a�Ap�At�^8)�� L �Z�# �7f!�!N�*Ay�tu��.�[6q9];D.�FN�remd&8ly un6G�� f util��=�+�)cap _ tech�` Hi�@3 i�at��� &R willanee�! firm lliL;, .�Q�N. N!the� ,Hdid"A\|DRM!W�w~� 2De�˕�QX�Hy�>�of )Ca���2G&;, �: , ANK` GDN�YCYP4F�b ywF=[{ � �N.�Z�Alw�� �h����4��|"�4�!=1�I�(*�4a*�B�5;.p=i�-.]7Y��@"Y�1TDc3A/.�\���592�!r�/>�E�z! �$ro��ntE.6X5�0%5�5!�", p�;03 . 9×10−61�� �.) �n je��%�.��=>B���mb�dR� F(�4� �2)'!9� *��a �r�4l3^V�-:�0�25��}k);[s��A&R�� orUE�pQ�MedI�&� "�!U# �n7>"�e&K Q8�wIn!�tr�,m��EaMas)T �edh ��%=3n/!7W>k� ��O ��Y5� aU�?cE4%��,&�CB�"�8"� I�$1*��v.�L"-� EM, " L-"C)>x�2�1�!�>!C�-rr� K2W!�� 2� ! T�Q�� ��Sd�on &1B\ �sF �:��c �@ numbBf�� 1(VF�� PERP�NPR8�1RNF144qTNFSF10{ Espinosap Gomemo3� [51]� hypsU��l�kof)~Mw@ �� �;a�c"�;]u;-�Cp�G�� �.�E���"k�#�"�B�cis e�E�i�PElGel,l�;n2�*�gno� . Akdemir �q52]�po� ��U@ usA � ��a&� ��� JMJD3/UTX.s-8�gEV-ler� )) X�'2;3 .��%(�=� �li|eh"/q�j7 re�:ing�=�/�(�B.�J&le "Lk'i t)�5!�"!a ��2{�"p!�4! �bUM0GI&�E�3F`ai��"� )�� ��dd��"�!)w�tB!-�Ae�an a;fu� Z _`DN[Q���N.�ZNhs;�|R�4(�5iMd>�(���5!\:�}�6�6�5I:+� �hA�*9M� !*r;;8*o.tR�IB2\�7")� \s)��J)�( p�65T% . Nikulen'reA�u8]� �u� v ���R�. Wang.V19fal=#a >D�� �!�&�� Q8prefer���hR{e�E�d)J�8e�i��0 5� �K����\� + !�/��W&i &3u�t% tides 10�11g% �,�6TG"u6R ncq2�< !5a3CA3) b 6R,2.1+6yp�� W� �RW�a &�GtchI��&�?1,�I`m�;:�H"dV�ɑ!�un��ly�!b<A�O$< m�!'� I�a>@����s<2`O"�-��2hF�,!�(1) Zu*�9�oof.A:�� �9k&�X�� a��!IE� �"�+W�� �~e2�M M9!�$qe� K�"H&S9Nv9�!u�+d�N e stimulu-9��CUj c%�45�A�\9 *�dne��B�a�:)E'wo� w1pub&w!BonAab&#U�W�[53�55# � �� �{1{–�5�"s+}Q: �m��g�Ilucoco�aoid hormOyre�or [26�E(d STAT1 [57�y���0�t�e�bE aL8 f�l9]V:��DaE!!&,!B d u?)�2�� YQ�"�I �'2�.;l intrinsic�8= A�cha B0 he�� NiliՋ�|�T8TA��>R/|ŁS6�*��.;N�S�,B� �,� � �u9P`v�&QCsV.�"�P� GF ,)x%�%��)��rI��M�l> c�*S�� 3;�Ux�HS�#SY�R'? g%"!�h "s !��� |@6�Aa>��:��P� A=TSS�Out( $ necessari�)�k.u'�x@'N�{�ea0�P�E`861e� !�iN spfq�pj �!�,9 u� .n")23*62p%�7�8i CR�2�A&I4�5�gt>�=� Wg]a��NZdAg![REFN6E�  ac-&�%AoM�as`e� alP-iAIE(>�9AA�S%�5"�&�,�wF623B�!9 B���>[A&=val�~d �A�"i& "ge�}EqC��lab�� 16� t���|�&�5�.�+�5QI5��"��(s��`iW agre�0�.�;"troťo!řrepor��m�2 u���TA�RFd/�;� %<1��[6AA���^!Y.���20[!@Rr*�J��3G���A= KITLG d!�*73dM l 2v� FAdh>tZ>�:�cM r [5"�r���u #m��=.� �emo�~516 R+B0�.\y͋. :�-)�a�1�"1F��$N "�i8��25,A "�6('�s$0D ,d3, S�)�QX�ye�a�_,� O��)$B73ĕh�,ol]�lA�&�z� .�,� ) )8�J �I�-Ky��ani�.8j�l E2y8���T Ba�i._&h�� -��E.�0,9� 5�!�1 )� ���#in^S;b��7Eb���@�Zi� �-&�4")&Jf@�2�pos\rige�'(�h�<4b�0�Yo� A� 9�!�F~,|16*! � * )�� &h��!�2�he Cu*G T5"+3�A��lU5>ex�>=ur�r!8�ae.`."��ihKAlu:�)REs.����D �it60q#J &5�B\)24 �" �4.� 2&� MLT ,�. ,�. $Vi� millM of y�~-8UUa!K"$5b rear�v_.im���a�&�M!�!|.�ttud%�[.�����5�E7 –[>7n�!�ol �{1m�#� �� ml�T��!�~ �x5!ˁl�gp9!�5tS�/&���b�nEP ���A�&�"%H� t qu63!co�A�!g*�nÀ!� 6�.- . Ar�se���sup!e(I E�=defens)C� �-bY >��t���i2/r�^�aI�!�E-ic�7AC!��� ? Leonova"<.qX� !u!2&h���A�Aa vol� �:�silenc�N! m [5ԉB�8RG��*�ly��Ia��$mK���J�bPt�%#6��)�; h"sire8��)� ,�!1�1"*�-�m�36}&J?% ��o" � �/a�a�1 �Eor. >� �'isf�41��)wE�.�) ��!ő&. AlsoaVne�Xask1 �Aa ���a M26rI/u5@�} co-op�e(�7p3*on*uaL�-eF.� �490 s [6� 61] ? I� unW#� 1�&66d2 ure#fF�* ��%r Ux�!kA�(-deria-�4, d�tC�27s�C�(E`���A^ )as�nsA�*/�Y� �(�_e�trigua�� &��@ �ove�<� a�i8.8amL�0^q�ly"� :#2�� {e�&��!�>2a&�7�7>rif����A�y� N�is�5rFc|+n�$by� edu&�0Cn6H2z����1S ditd m�/�aC�&!�t�aP�VN(4(ede�usC�9%5lA|�oth2�!�]�=!�%�u? ,�8ly-!tA�R+<�s��M%�ia2(�� F���n3.ro�\iPt�K!���network\�])vs��,����*� s imp  pos�I9]�.k2� i��0_e &�Fu-ť� �a���co5ZaJ[���p`��|utArF~�r"M u65*ȇRu�{AJ�p6C �%�"be!Pfu* clinK<Ediagno�-UG. stan� 6Lh%q%6bv�-act%K~1�*1-"�#�KNA~i D��!R� ��*&� E�Jd��op!�0eg\F,s� �� NgY'dOh4E\� outc��6 cytotoxic� rapy0 V(. HapMap ( �A0hapmap . ncbilm8ih . gov/ ) CEUDFJ�4A�es�[�( CoriACRe}�Cam�, N)|� x�d� RPMI 1640�-ume�l��?15% hea:e�m feaov��4serum ( Life T�,�>�f!�1X q4bion~/ myc Z6.��#incubvat 37°C��5% CO�ADuU*&��M6� ����p%y���_� �fu3��l:M� SigmDRS1! LouibM]WA2"� �Nh�"�#�7.:or�.�tripl� e%Fu"�%r�4��b��2J� . To!�RNAs �e|m!Ft Mini?� kizxQIAGEN ))�Ɛ i�̌��ZY2���eb�?c�syn�I%Xdye�!�hybridiZ asG*�z'g1 toco� ,5H08{ST �]0 9Y*0{, S�� Clar!�C-vpro����(NIEHS Micro JCZ . e=�d !M��th��.y*szConsole-rA#- RMA"āɓ�sketch-� le n� 1�ods!���-�6�< "�$)�"e$�~.�$��ll1=<m9 �bRl�d���m�.GEO0��ZSE51709� �9,>�)tj�&.qs9�va��:-PAlIlluminQ2� T plat�nF�E,An�3RT-PCReE� ed�!m�Erepe�A� by q 0=#E������F-U-S�d Su  �VY.teach bi�pr �Otar&��:�w" 3�[us�<FAMA�b"JA�spaX on j�"Or {d A�!!Mas;5Mixb�S 3�Fvgng% 9�"� g:=> !&&�( EMD M�p�#07-47=Billeric�fM�f��IPe6input�e����0)1Qu�( Inv?gen�.NIH�* ramu�&SoaJCe� ( NIS�!Be�^d|DM�N�Wal1AVGeuResourc�!NCG��+F�\N�d��%X brar� ��㵀!N"�e�1.�!lH% Q�.J �AY'zer IIx����of�p�* ���!�&�A�&k �Sybr pN re!ig.+ �4ot*O%�bw 7900 HT�l-o �m:<n� Appla�A��s%� ���m��s9� I-h.Ҝ6KQw"GUa�1Wa� on 2�Ũ�f &G ��D"L G����A:< ��DHS�fi@/ Lac�*i)�Pe6 ��Z}f>�"�&�"J byQA� �A.���[65�D�\�F�+bJ&s� �J�=.p��� s�c)�A�NQ�i�y��4��a�S9M��� !�HS��#E�=�>���d��"�+loa�9 3/Open�:!�uke Uni(�2, Durham41�~O W% 9{yk K5��B~nX /:aM:Lse��GdFT�}��$< �xe log2 +�i,� ud^�KW�n�A-�I�o�Jwa"|'�!u7D0�.��y&�^���ta���e� IKhe��A�x ����gains2 h� �.��Z$( GRCh37p5R@r hg19 , June 201! ��nBur��$-Wheeler Aj�1 ( BW�KToo�\Li�a�U, 200�f%� ]ly�A�: hort ��� �cTf�r �Y�th%�Ց#/��53.J� ɕ% � -��*��aݹ�by ���4 softw [��9‘Yz:,Ug�!’ se�V ( bandwid�&30 bp�*� �5 of 30 S7!{“}� -typCIPn/ZZ1A1+2[10�x9:� t��nԟ%/bing�p&�l(�&�-�to 50�}VI�=���� �=lq�a3<:3� e�-�sŝ{<I@ϔp"ɔI$����eHNutlin�mM��j�2, 5FU�I*/�Z� [�.�@osteosarcoma U2OSv&F&��awm+ CBI SR�t�ly��). ��b� eJ��Ez�+q�%�����N�A��hUbA���L.�<]E1P"B��-�����MAC �kfBlea�:�5a�$ ENЧ Z. MEME Sȅ [40]�eX��6t.Ig� ic:v�� b��Ii�&��1Briefp.�-bXd2K�r�h�� trim��to�� �S�M��o$ig/� r&%=_Hɠ�alYthm ]�Ua .��topM5����+tif�&a*�l6A25 . Por�q('%y;2mns��:�2h��s�,�^5v@��53 �m�,U buil���A�(,=�M!� �#5H*�E�{l�ho"( ��PUBMED� b�U-�Hverjy%Y+&fgvʏ�#&V�6�r)2&[63�2N:A�� 'A�a��2[��"{1��ш*�0s��~-���o�ed.�T[ac�>-�� ?Mhp"%Y� �1g �� �li�4a wind��E��d;, ��s�k� t[6�\yu�i �2a�.#)1Ai�$� ��on2�m20–23=(~ 9Q��O4#��a� of 0�6M � � �u�l�;�HDNA56;m2B!'f�a�Y���O>�k% aten� Cto�yar�202YfMBsearch�ӣp�L��o�of!�<t �� 4!e C�DG2VEQ+��0� �� |a=��`a&�Q�s]�%�]e�� OYqr�c��z�r"Y In t�,�eZLvvnv . Ata�Q�#��a&txE��"J�pd�f"k& �m: ( i ) � a�"*{)�1�;%�( i4!T�cis?K3heosEW;<�{"`Q(� es˱�og�Mno.jk!C%���� ��me�w&/��x��. assa�5I] a�,%Z�|.8�^A thod*!+$in Nouredd?e�� [�.��^ ���`-%ҡ�hR[�12dB+!9� ce�Ք�pr��" �E�,ucsc . edu )6BWl&�2,of Bradley B&��y<( Broad Institut )[��E�BM!Schu� s1�+0Hospital/HarvjM�yal Schoo&�e)�9as�)%a�p0j�@ Manolis Kellis's~�YBcy�a�F���$,���D�We"]"� f6e��ac"� P A���ad≥vȧB�`!�24"k�a:Z2- I(<$g�7had&3k ,EU}&v?mergedQ'L�ɟ�7![ğ@ ��fX(Vܮ��J:(���; I� �*1!@&2 �� +��(�"���p�# ~Wl *�EExf\)3 �re IKn { A(C#- �e�II �0!~&��{@� A�u�(2�&�J_ 0�/ f`�TSSA�:K�w�4��u�eabm~�H�|��>� f�Dy `$�Vl� -.���15e�� ��Ea!Fm15P1��� ti�R)�� drop!u��)��rs��A1AMseq-+�>`� *�e`� R���I)���K;[ "D; �)w1 MTo*�t p� dU�&E�o2�_whDC��@inL!�� %+N��a�SCe 6�s)<�gd"c.8�]!{6� . Re"�, t!�UwotDE�,�]��G�pad PrisjPad S��<:lh&�*4 traQ�m*P: �i����w�$pa��f?�RM��sn/%���t.Lly&d��bMZ%�y � �:4d�5s rapidMx���A��erebyawAp�RRs2dž$EU�(sink toward�|�RR .��@- R�,22O�1�.Vsigmoid"EZ�c ��mam2at�L&i��#i$.-%aA��E�/�}i�dy� keyBY�roC+r�"�7nd a�� �!�/� curv�o�[] _Uo�^Z ,��" )r'>!� e�7HK-A�RRM�y0he Sinorhizob0melilotiSe axis�hwmndn �<YFj��)z3�,��1�!��5��o1< :�-`�R�b�u! �E�R�&�Ef�u an auxiliXm| �whow_�e�hea�( yiel��Hr]coeffi�(� ab��Yѡ� ings}�LN�m�J� m�1 tu5aswi.�;)n��n�<pqs�P�deaI a?*?3"Ci]��F��c$ s . y2�/s. r�cuY>� �K? ropr��A(�E�'n֌)�viv�Gnd��)YA life� %Yy{c9g��5� myri!T.�S �5or�8a6�� 9e�JZcap�� �Ys=�=PPgalogic �*�*lͻ�i nd nW�ng [1�?�E6�5A@�P#�:?�ti� eD�Bof fundak al 8E)vuCa�-0 �MUri�� b�alμu� "� � ,���%� faG�Fg��� �� "i �"' s��?�' �*W��C���wY� sE� AsE�9�m`isE�a &� ��k� � �a�=MW�� i�& .�HK�%�moU�D=n enviro�a�2TITcBc �e���utoP ory� . O�4.hIA�HK)>f�-�4&WA�� gN�E�MRn:0n orm �h �� �M-�AGRh4E-& |%�2^ IY� �ll>� -�38-�i�ю �;�y d]�1��M��<(%�agFe�tI�n hys�2�4�/xy>I� ��� 1Ns� %��f�m�aoPp!s!� coup IpQ����K�RRQ�4o2iUZ��M |imY1 HKͲ S�n�E^l��!S7S+M�1rt@%�Trv0olecular scaf�la�6p�<�i�4l!��ɀ�J�,)�%P"�7:�!-BOc [1 V�fng.�-��]9e\"�832��v�hre�x�! deeper:��<e!�pa$es" � l&� ��5�Fk~a�5c!�HK-RRf"*����:N�-��rch .f.lFp�mMx ��� BK"|\} ��e"�$-��y s�,f�K+�̉�s�#����;\�� q[��`��";sn�%~ ��?����a�"  :����� :uloMe���[3i��-. I�*� Ĭ�� .� � *}Ag split!Lrm��A_1�(“dead-end|-� leB��� :�feedb�1�,e�"� )+B�M�lbista�)[3�(�HOf �&YSZ��m� �8t� A�(qot�Bљ�]“��I�şEEwog�I�et�)A:>UITa��HKŐ�uy���^�"%5�1a���;�>!� �jL������.� a�Y���ors CheY�� 2E���� ir c��� CheAA�{!�lyY���B:K��!\�)aK!Xflage2~A��HDr>�!��+. Bot��eY�nI��% �%xE�%�]yreturu(ry�)� �G�%�JR" �(I�,AP:�>/�K� ����i� S .RM����dd#A�)ha��rH�xw'W!�1R ?a L��< J��gh!�-~A 2� situ � b"6Ce RhodoT sphaerod HelicpylorN�A�� 4� !V osmoM�A" 4�#�m+l�r6Zm HK*6 LN1 >� D��!hn"�*membran�_ru`�Q��q�ven86�,am�R, SSKij SKN7��& =U�Hd"��^'1�n/�q,r ��:��to %a7����Ano��a� J 5o�.&�m3F:!"��Jٓ=D,'QM�& <"3&�>=VHOG1 MAP��cascade�, �Jzc^ aa7��XL�vg"inv"HO($!�s-aoQ!A�dz�x.>2�.H:��� �6"�o"�W[itM.u�*ir� ki%v5�^�oR� Q0^M�/�+�J moni��tempo!��C- 2���b!G1�!xc&�y� e> !AA#-RR��0W �A.�e_���!�#!onp�si!�KedM2scenario�*�� � ��) 90%�'�r��]6�Y�~ͱ�1 u/�)�q'��߫}- ���)��� r��!!(hWaCuLat�E.9#?e�1Uhq�.�~1�de+iF��dB� b~��" an 2�=i��th6�!I�y�BY�aL��-�!w)�s� �u.�]p8C2�2Y j ch.��.�'���QM�:RP�.�> �-m� AO�:�_&� %KF/��9Rɱ�YsJn��+�!6�XJ�8�;��i��!� Z� E�x�A"2� .� �qY�HE��h5 n iS[�uwc��RB1,:WV��Y�r^�G$ �Z�-���vFbol S��#Q�s 1B7S1sDQ%)�wo$^��O :AseB�A��$�.�)VM:b)r�^ ) K�a��Act2 2~U�a6��p!Jd5' S�)�+� +)*V�b�"b]�e��s1��9 ��: E�1 � H]��&� %_� (b� �$a�6E a�] y!�$aTwe� 6�a ց�E�^��a E�2��6Xs �:S4 5 �4���2��a"����"�V��q)nZeJbe/B &�&c& ��w;&�w2�a��:�AXM4qfe�#)���(9� k�n ef.-��!r8B@ J%\.L�@HK6[r\.�"��N� l���Euaԩ]-R�x}|al;�y2QB��Es�0n��<g�v�U�a �eJ9�I�2� 2�G�(�����harpn���p nf�*��:�7 �--Fz��}~O]o�2�&�� *�S4ES���&�!-�-�U� d�6��>1�e2Y�L!EFF?6`5_Q�Fi4 s��8!7�lXN�2�)���i�]b��V]� moun,��!pW�2� 2B��:ef:��n� "Za1�b�tu~*� �-�� a.%>i l<[z P}.@R“��l +�� 6�for4,V(���G:)���� san��'1� �Z>���F�Q_s T D!(��L" �( \��pa: M�TR� fash��e=6? < >\.�s�EcklA�*� �/I3�sz.**n�c� d �an63� ��r.�/f �-hh"e �Vl�g �i �!� ��O>� a��EtA�t8*h�1�,O�$g{"-6q})a�"U�T�!uD �e� ��5����} !�a�)9pm/ePRR �M��qCEKlet!!!�i"<���; |9��TgdS- *p�F� 6�A�u!�f8)� �"%��;/2@� unc%G)q)�"v7�t��f*�0p�EuB7�/2. ����i�W]!�FCh1�%�y�ig�� V�F�)*:� ��t�A\"�) X{� e�Ev"y&� woV� M�.���nIUem�z 2�.=�c&_ %���^9[F)1 ) �DLkS·khS·[RR1]tot≠��DkS> !� khS!�!�ʻ, gEF6O-"�0kS ( k�WA'� ( kr�O � ^� ��!9� �����(*� ��m�+o[��:(c1�W1)X���y�3u�� exhi.YUA|.����6�'w~4�satisf#�,"�G=.(krS/kS C�2U*�!M`:!!)�s fit)EݫU q^2�/Tp s � �sWA�"�BU�6�YK:n2r�q:� 2PAH1r�-�[� ass�`g�cV�z$%oB���?.-In� t��J ��Łge\O�kS/krS>!(i�&G ict����� T< ��Z6` t8��E4� ���,�E�E6�J�ȃ�ge�d�o��a�yM-kyZ /kyr�}��ky̖, !�!rin�9"K,Michaelis-Me��!O6�a�co��(� b� 5�5:la&�&�^�I>H��@i� m�Y18�����2�!�rRBjquotii+)c mus�KAO &:)���+d�u]b��,u*,6�can�: �eFC )�t�Iw Mx%��LP1'� a�c�^^ )� )�>!K����K-y% "#p�/.�YJ,�m�pB5�#/�L�2$on�2 tool-�[5J!�"� ly�oCB&�Pn8istability . We�I found that when the phosphotransfer reactions are modelled as bi-molecula.',G�Fsystem is not capable of bistability ( see Text S2 and S2 ) . However , �`considering complex forma� 8,alternative �8 schemes involv=�8different possi� bind,events among,HK �two RRsltheir�es , we.Ka certai�0enario allows�> presencBi)�-�, !�e .v��va�2e �-a� onse curv2W��excell��quantit�agreeA�2�)�:Ns ru�Ex�I�a`9�sI��� ( ab��)!�A�1���< 2 display�o�\moidal ( hyperbolic ) re��E�increasA!�-g ( Figure �AThu��these2�0strongly suggi�ai�2vone��–� motif�s .�>^� shipUz!S0could potenti�K func��S8threshold devic!�� e6�uE!�behavior!��m(-� ) wa�� o be�Jeda]@a small auxiliarya7���mS [50� In�Jta�arA�tVsh�]^I�gs 100-fƁ^9rt�∶CheS�cCn �9al!~!0Z�decay�F�A �A-P )!m/U��HY1��fas�ED}tha�!out�Mst ' migha�$rectly or � promote*Y1 de.��� �us make�1�%efficia�in��A�IP t���on1�Analysi���a$tical solusof �i�6� another w)M}JM�c%j�!;to, �r>S ich=� groupH _ Aj�^%�MYA3 (� źu�ks MoreoveAtsŐFQ>InG1bt!�4MVE�,���Oiv� EkE,%�ddi%N�ts!ecM n% Y1-PJ�,m�(also accele%*M19-P` �_ is w�#fur%� enha�!�� W of=�con �a�rAC�L"i�fulfi$ above%e$Towards ob� A�a�>a.N sta> wro� %/6� A�ɐf�!<��.F�I�:�first6[�oSp��p assay%�gu�&} �!`2 . Run�>�.� ΙAr��LS �o�P�<0�����h& �harpe�-Ss� > ��4 )x� Hill coq�tq�!�el3 . 43I�q��,A7 . 6�B� �M��'e(F~� line)�robservedcA��wo-� on��){  high��4of ultrasensit� [36]%�UTly2� $[37]–[39ͷ an attemp� capitul��>a*� in�E athe��b�R� optimis� wo�e s:U�)EZ* ( kh��and/o2�*ofB�bH ��neV �"W U�Y�c5��vbymSa be b& r=9:MAr�k:�:�̓*��6ma� ��e AA5%�X�honates1ry�gBM!FH�q6�e� T& i�s� �<"� )�S�-O#&� A�heaЩ� naB�given!j-Jari%S�� 2` . We ha/ alyzA�m @dynamicA�,rchitectural� ��,in bacterial� .���(pathways�re+ ingl {r�]y=�eWI.A��*' t��� HK- ) �S�3 �2 &6 act� %�� hyp�si!@before [40] , butm esA���=B$to exhibit�^�2� �%��As<��A�co��ng ->Gs%b� lainih�ef}X�-RR oI{""5�. Due��S>�kinetA+%=-mJ m�e�J zero�>�'g _}�Jpre � I�t�r�]��� he*�BTA6i(inues until2  beco�saA��j�,F�y5gte>�d . Aa�i � point ,S�-5m�&�rise dra�=ly �i��A-v,!%�6UA9�RPsuc��" # L� >measu� p"s)��2 &tax0(nd yeast os� g�I� �,. F� �orAgal� ses� ��v.: �Tnecess�es��A� m�;` )�q8 xtE�,( ii ) kS>kr� h��kSA�!for* �"="� ��ajM}a��ly!-actorAhat"Lope&�w=/g ..Bm��ems (f`E�7N  Y�, �]�"���E�� auto:J�PB'�.by�3Q�%4g M�Hip�  everif7���nN��u i \b�� ^�M�� an A�e}�2�(!�"inJ�of y  )JA�9 �`2��SimporAb lic��� e�"� ��$physiology!� de��!"syntha��n%circu� broad卡�A 5xE�!�tudy w� �6�anya�Bl� njm!?pll)r�ja*% et� rB�by�C���donor%D� clud�3he ca��i�HKXsY2@�&we)a�>=is&$ is����an Hpt"u"g�!�i �umajor3F"� ����s ( w{emplo� Y%� CheB�UH=:)  42 fungal.�ory1�s [43k �plant]#�[44l A2al exa�[%q�E . coli��a!{ NarX� NarQn aaN -~ ?N�,;LDP [56�Similar� in Caulo)N creSt� DivJI PleC�ea2�� heA�Z� DivKCD [57�3�ki#��c�  �1Ll�c� !�a� ,I�by �mtoA�pecific��  only�1�a�� 7 A&_%9�!&X� be u��\Mba�4no� charI�sg �&e � [35A�[58!#Ib��toQe h""1)9 .�aJ� ��to Xsщ 2� .� ��. doe�preI�*�61�z r woD�is&� be taken!�proof%9J^}sh.4M3'!�`/S.���A"8&1�uC"* ussoci3 I.Q�. S�b�< has so fa�n�edx �SV�� s baA.� t crip6 a� "C . Whilea.$�s�TbPrecogn� as&a�dideYA��� �%�e m�effort UnA�engine7 chimeri^ �Ha�on qo��[1I�17E�2�1A�Our�4�I�a-k9�perT%���:�qN�AR :!apy!i�n l* 4,� �new ave^ !>re.��. Exploiu�� -�RR�R  ru�of=��U$;requirA�up�of�BapproprA���put (" anz�$%12l fj  �&usefu� <crol s� .���� lish� rough muoA��"� A��)�> u �ex�ng5�I��� l.ua@� u!zJ�,� rt�w.��W��� �� �V�. T2�"�  �ly r( nd ev�see� eI?%73 eA�VEWdiver� ��G]1. StudA�9%o� rovided)'�Fm>d& M��alie1�{ male� �irA�� Aߙ_� . To! eAPիu?�ey��a%��isoY���uwAx:�Y%!�ZMAe w+a �"A�mo� are;� %RR !RR2� nd� Z��K"�m�^@ �"� 1#�hSLNxSSKG! SKN7PRi>MSNa�4e -p suffix res .5���  ��U� B1V]&�U�Ser��!� rdin=q� equ�( ODE�� 2de���L hange%�ٌi�'�y� ime;�"��e^O�9nxy�;�$-ze�&� �K�gf��incom����s w&simd��� rX$ �� lP w$or membranE�$)MYI ,)�aa��5&����6 ��a`t� HK~a�ea�" ]A datali�b"?Td IIaA*s�'!.z#p� �ŷ�)toa~2(�,� , kMe�krM�!!�I���ɖfit�Vm-�!�to� viousub��"X&U  "F P!-dɗA(a hybrid geV alg�h�ʱe s ga�fmAIn)V�MATLAB G� l OZzE Toolbox!�e�F'� ia�human� " vidual�/s%�in�Ogen� opA�eW&� A��)A�& u�) tres�5�SF�S -� is h\(de i7 cleau7!vrg�t�e���!<le-��, RNA sequenc!Rto"E*�>m��Sacq omyces� evisiae- tre��Eҡ� �" salt�# �!�l89,=8id��fw͓)8Ta�flʼnf)G��6E� om�$LEag�h�t�(ve knowledg%j�<i yo� we unc�%ed2� &� �0AndQ2 _!�AK�B�af! �� ��sZo�na �(e� Kappea�o�$� ���s�(of ribosoma� v%aB*�environ�'�#I��|���a manner�L�$g��!� !U� cycle`un��'� �kdi�etaz' 5. LivM�im)�=*ell+A?!� pair�\ fluoh9![�,�2�� Msn2 �$Dot6 , Sfp"or MAP� Hog�alh -co��!�de)u`d nucleocytoplasmic shutta . Togei )2"�o)�5q%, R$) main?#.lifilA=against� bursN$fV]��mou�Q�U upon2�M�A_,�.I$Y�unIE�!%�. W0adx ��strik��+oft�-��E�sa� @BRg surva�e as%s d�� � $phenotypic:�f�"�a�s�j$ic microbeEo�� N,a��nN0�d mal� nt�A � �A��Dherapy drugs [1–��g��� �produc�xEPheritabl�") t�Zina�y%`a&aBWE�)(l8!e�!epi�pres [8 , #Fo�� ,)�5D)��in �-ur5fNa9�(extreme hea�C� e�+ most a� a�|[1QS��--�?��1)yw IaU���0,�aufe�(A��.*re)*growth�marke��!i-�uS[�X10–12�Bu�A �� �mii!e� ��i)[� fue�ed�*/uS*6- emer �%p�&s*stochaWe�tsvuntU�0� �hw�ys �to�-tox:hn1i ali��ap"A���a2Moj i��in� s t lock,aQ&4u��ustSsl� q2�-BM9ar3e!�c���ou�(ŧon!� defeT/a;��Gra9e2�Y��r�� TSL18A��ND�( vFpredi6* how ?*vI%A�u){e)mam/Iniġ�!=@s “intrinsic”!x��!�,r:�o6�e: crib!BC $TATA-depen� D�_(14����]�RpA������pla�S*�$et-hed [15a���SY�fluctu� �vals�.��E� �<,)2e��5target% s!J y co��ntX(a�it+ a widespr!�� �72�Ё.“�5�=�&�,"�,.�he{er upA�am� �~��i!g o�>"��(��A;likE�l�%��"P%�. Sq�m���ro� d tagged!�� abund- inm��re �ai�  ai���@A\$5 , 19 , 2�x23��$Stewart-Or�,in et a�3� ���)�� !>i�“a ral-!Essa->a�%=� �!f*� o�[V#\a �� E!S*�(�r���E�1�C r�gulon��!�*�+ad�� � [22! %TE��$)�N��4so1!&! �52acrossj�)Vhe]��)em���}�6�P� K�6�1PKA�a commonY�� �2o�!%�6In1��& acutc2es!�%�)w�ns�G!~auM�iDnetwork � ��e E2Q � R� ( ES�7,�9�; Ma�� iggeA�by"�)�A�24!�s7�W) �6�ax�300:�,��G{% �!}log����Q�d M�6{600�< encorB�� RP�{1��; � 3eKa�o ( RiB�%5I�&� . RP$3��hou�3ne�1����nAa� ���A;��9Q i6g)��[ rele*��WaA��op:cruit�A}aC��� t���/Tod6� histe deacetylaI.6–3�nA t���-A<� mild� imEi6?<��)ub~*� ��ac�Or!�t��[3��3��>���program�"��>� �,? no7 in nutr� � trica�� sta�#nE�slow-1��  .(0�c���-�[34!Y� �0 , O’Duibhi�#��i�"SR� simp0%-by %�A\-FphA1,�jceV�l!/lon�YG1 5� an!Q-�]F� profile [�ne#�7�����4<d!�:]Ci�r-~�i�)m}�8up�t#N�a%ndii� me�trt seEWh� ��.�,q5 qa be*�i8ld-typ��i_,M �2 over���&g�76%2�&MM&� " A s �2�:"� 2( y�T�w#M � A|&� �Y U2{an E2�ul� .� i�m�"Di\6i >��-u 8 A�ch�, Bl!gnitud���in.< !s2Ss�!�ed #�if6 UF� � r�iP]2�. H,�addA���' ques!p��� - RNA-�'� ( sc  )!�ew�5.6i��j��52!�� )�$ "�#f�J"�I;�$]2B(!xq c0z-N �9MGa:BcH�uN�du� {&p 2-discord�e4��Wm�� $n� _�})-�.a:�I���6�C*��M1�!�of��9��"v linkA= o S-��F appaly6m�Eq,*~%E9!�� 2� A�e��,-�-Z*�A�(�"�ilw �2u�"&�%h� 4��a�, primar@�nF �A�� gene� Fig 1� . MB���ed-ȅ�G" "A� ./��$low:.��.',A�ci8%[AOsup��&�I�f��$opposite pG8r��coAofY]�.*�F7e/��!e�2�em.*�P,iMfS!�:�a-��'��@�@e2o=�t�3i A5�B� 1C� A7GB�,�/ t 4%|� B� as e�#n�by%�RP.U���o �Bp( fal_3�Q very9 0[FDR] < 0 . 0Bt �E,�P Method� EE{tEHm�]��"!, C@iskG�A�ral , .�" "�i� .���Ud�!-subD?:-��eS ��ve �Y���!�@+d!a.:RV ��RP ��4yn�a�"��-l9�x8 j.��e�v�:F�-eBEh2��=1yA��): ��&�A�Vl !w}p5��fw�y��Q�aX��h�> �ue�1Q�Q:�. O� e 12%UB Elo6�P]( FDRJG(�'thi�,didq e� ;�:�or)�� �#-�C arrK!�S1� )=kew.*i :�ɉ�I�&"ha2�J7eakEյ�&FB,e�m-U��FRP}:��R!�5m�be�q�j)#� "c"�detail ����hCAK�"*�weAi��E�� &�7E�biD"�)hl��E��:� e. M+2T&m>���&�MA�stbs}� r| �"b 9�%�ig Fp = 2e-5]�N�F3>"� repo�L��-M��1 [1���dl � �-is�F�,���59wa� ����.�"uW)O 2C ,�3e-22E��"no=��de>a�k�):v��Eexcee��X J:17e���t!�9� [4�3b% plot!0J�� u8ad���2� leng�MIproL6���J3�!��:/" cub+"p�B�&%�)��͂� ��An6Z. A�gG ,>r( p��028 )��Ca lesse�� ,�|�e7 25 )���ig��-�er:�o(� �E��4*� random���n� =��á�B�I��KU 9Q� ��.a*I=�%y �.�4u) �!trP shor�t r�! �*$1�t�k>��9�atbXAc A�me$%RPQk.�1i~M�8�9cl���logDMgen� | ,� obscf* true=�if� !ppNtos)9lo� 3,! unaE�7k�"�5��9(Y4��aG�=a�J��Bc �� $�M��pe9�6on-���{(a6( ( Basic Loa�A�#�Se 0 *d [BLAST] E value > 1e − A�.��val4+.� �}J�A.�Osam.~�_u��moUe���&cnsitu +i�*(( sm-FISH , �< RLP7�U@a"-a&�5RP�-,et2,a7!-A PPT12�� �!�A!9EQ de_Ges�-)+N 87% �x53V� o� � lyR'%}q�Aconfir;- : �"�@in 78%�50p;c�R�^� :�E��$%>e]��3.eBC��s-2�/Es�&n�!sh. One[{�,�8:@ a4on�C2x�ve ��?$stoichiome�5�*3 _O!� N*eUemr&I&Q�>�re� jecIe�c�%�m�/ �[47–5�We sovo 2�w�7MNOt!���V%#�&>�!�v,�?�� ( laK$�Q)LtI��1!tRP-fit �� (�XT�� Re &�'�3is���eav�enric�5!g }eq��>subuni#t� �3le3X [51]A�����V�@= �K5e-���Z  2e-2��:geQ�)m �2&�>d!��� �#tea�,peronin�V�*�RT�M97+ ar p � �$as> ��sa/t�F!0� |%suba�u�4regŧFl p�r�91[5�'� �H)��A"�end!`!p�� rum:K 0O 15%� es2�� CV (2LMof�� EXnJ����2� )�8e-��> B$i:s�f�] ��]!2s���#!�lightlF*er� s6e-�� �/o�1�� AmW r-a�-ex`�q�m =����.��� ��:i�b�%-pr�F&�>aiEj6S�!1G&�%7;�indeed��S>\ pIparT źly u�=~ 2 unusu �j��3".�#�Az�ωw!�6K&�*mer�a"3A^technp a#�[4y*sAA� ["�6 *� u�]a"M:�+-;1�tr�.�BEgE��F.$2v�6b!U"�0� , 5����in�1 �ed? �F < I�z�2����) �iW V.�=h.L �:�0�$if 톙� ja�N� m�A n�KSD/i�!�yce� 0[5�B DW�Gun�&be�:��wh�V(6t�9 2h� T�+Ivno.ly2�Gc�'�&�.��^��z 9s�P�bi�q�0O �a${DA�" $.�wtr��@� �ls��ZM!�}es��-�1�iI7\on�Te!����&?&�&* ��.(�1e-10"�al�A'R�jl6�6[����6"%�6S2�� ��s�%es�dlar[� ) ��I'SGccl�)� a*t�[Lx!�!�*X�Ay�Xe�)�Y��F�Ut.5*6��\*Foam ��!Vj�8!%�,��sur�T>�K�NH�mem!6��'� �"� =*}. Cr���IG1�1��;6�]%�Hhig �Bz;��!�faA�coC ma\+J�# ( YMK!���4synch��V3ulk4�1+�Xr :��re� �*e�,��^�,F-repletZd( s [59–6r�+tar)5-B�*U%��[��& � A~)��ez �.�'_x3 �� �I#"�� ASI�+ builA:4e(i�Ga'� a?n~7E�C5?j4:C�u Zj $fatty acid5�sm%�glyco�a� �B[5"v>�>#pa�=�H!�}�$[�60 , 6�63&�5H 1*whyw8�-}Ti���a�!r�.�$wQ� t�"� �}a�s3!�9?Aham�o?��-. F�_uA%n>� J�; AS�]�B� Vu Oscope [6>u � �A�I�R!J�e*��? 2 2e-1�>N� [65]Tut��6*�e"v"�? enzy�X ( S4� �Se�)�a� *�RNA� "�&�I��L�)c7+�. U>/>%ord�2�Mfa��O':�;A'WaveC  a"'D[66Y���>)LR� sv 8� c\*!�t�@E�%��(� .� �-�� a�.:& . OueA4topvdra*=��0%.!J�%�5�.9!#�4 ( S55�;�K( ENO�9�.kI�nd"�ulG��'i=9ond6EJ X�(aXn�om�� ate�E!;Fin4 loo�*�\ icit .[���^&�%o@+,.� )ց/)(\hA�� as%�V�%ed��t@%iN�me� ; a"ver>hbg  toA�"�Z�r� �%�7/nV"Qw:.AY�oscil�C��saW , ei!��o>�M�?s 6\�B6�s.k 7L3 5ich�um"��7�e@F1of�-": u. CR�h1M9.�3�2�3���: We next s$e�L՗�K%*9}!�O atiU^�%4 gen"�!�B� ra�3�&0"�F�Ice��G�y� ( TFZ�9*&;*���E�!�l�2by�bg��%"[ A��o&�� seTF",;�woj ?�{weX l� a% -�L�, 8a^*#W +��mms%r?& �&vE,�8log2 U�| �W�?:�.��@l�+8,�a�jeA'1��4>�$W5I]9���w —a�A/l>.�r%4�E�+� p�)�j6f4`^!M skewqTF-IH&�;&sel!I&� ei"9Y F�S?��� 2'" ��S6��&E>=TşU,6X laJ�I9].t��hu@�Ifh1/FhlY�9�y!��*BRap1 [6t68� ,*�9%���%&F R{g�0duE`� [69���5��BBa| *:��5, Hot�ko1oWe verl�#a� !"t�.�?I�L%g���0-��)�.L�=K�!�!A�$�T/ Rpn4�F-shock}&�� � Hsf1OGu/se"M(o5 )|u� v)}��9,�7 Y–or�&a?tE�)w��Y�H���,�)�)F11*�":�Z-andXZ!�m is l 3�um-�M�H�o.)@N�RqR:xby �I��=Qs� ,�R�9M�6 1K= . Ye?!�Z�KhNP%�x in 8% I�q2�6(Ae&FDa�A& H �����] H �,2>�[ *" �P�!degrad�9a�fo%�"8to)I�K i&>-�U��5derpi5nũ��"��b" 8# ��;8Gqy~ trac�w �a�A e�7}��". Cytosu�6�(Msn4 rapidlY� dhe�!us(L�)�Aat� e� A�D~( �>l�>[2�3s7%I7-*zr!+M�or�A��Mar�/!e c�e�$� �.I2u�+�"�a ?)� ed )Q�rO�%e� ���~[2��2$K7��A"bEU?C�7 -^)�6�,aK$��w-�= Hog1�gen��in Xi[7Fa^L.;!� tin!�2/�_Wr1� "�7M�6SlyK3e�[75–8kwhe! %docyNOI�s� U�)-m*�=or&��_u��8uE�*,DF�.��>K 6U1A"!;ofY�����-*1� �elfo�}ed%N-mCherr�cal�)���˥�alsSS ed)z"E M�fe�to �yn! *&& ( GF�v��r�4%��T-�2lin fix�^. N�K"�1%�ar �6��?4!>10"�74�Lor)M:)(&wB �<o>(�6� ,�B4I00�M.\�*J)|w?$6*ai�um����Qa�=�I�# � �`" (Dr&SE4%,4u> ea�Cr}�aMsŚ!944�2.�!(n�?m�7 ),7:;—� E� �49�q%�HnO0�E�. UR�����-MU<� inctqZ&H ,)�oH���J at 5�,yNby"��Aq�>B2� at 1 C(2 B�� 7:!R6�ofi�!!!v�6�XroBCZ>6�p+au 30�:�N4�sngn�F�D��� �n�t��3�%4 � n:�[bW�re6#9te'r &�6�$�hTFA@pO1c�� F�.q� :G�e�&{!A�"�,���.tg�!���"e-C �ksnapsho�^Wl >�TFzin liv!{I�`;�TF 2M�[&�$�yIsec (��minimiz�- ght-& m[7�A1-2x4vo�;A�zQ1���!!we�nB���� &�$!S�MW3HVofu)��N��� �bi�e�=ad�d!�e�u-�"ig�(ari��080-���!�!�rse? 1 DatK]19�/2�:)��/x6 !O �#-��Wsn��: ,�8i�of.��th;E �N� 2��e�A@ �-�ee�?(I�=� 3 �en{4Ŧs 0�/(���<�g� sJ+!&��CEy7D�X29S�rդm\� �+%�jB$I b�e�=+p�Q� ~(��A���4&,��!�4� )7� ��&� *� l+��� f�nV �6�qhm1� of..�7E ) :nG. ]} ��aE7–A92�i�Mynoe��Peak�,Aj–� !�!.�(�7�,6�:-���tdlI unY0_ [M��gGa ,E}�o%q�u. ^P��Y��":s7�^!�+=D � ["� �v)�T�!��Ce- `��/ulk %��7hor7��Aer� U�C1a����-:�. B�Fqq-��A�|us �:<�l_X��, gM���Q��2� b�.Y!42�=� "�?(\' J���$ei�A�,�Nv/a?)z81��"w�j��V"}B%ja�� &SA���PB�y�1��post-�&a�� "� .W %�&�(�&9%Ea&� in8X �g�. %�!Ǚ5q�.^TF��fi�p2�a &g)�G teEt.0 � �ah�7s3of 2FS. F�per� ZM&A�&�(�$nd��$.C&���EV� .J�+VhwOa�Lef/r� !CIndI$ h75$O�5���?�.�e��e6H&� !�'vi�Yof��[�doa�*e(we�:�Y6�pFFf.�W( �]0B�][})���bf4@�<&�F2)CF�� ampl�L!fdu� ngu>�/e�.2 &j F�?ndAF��imM�9� ��-VC(A���wl��&��Oc�]e�q��7rt�exZ#z�7�`�P�#�5�7e�Wlb-P s [7�83T�8�7�,�&aYw�J�|�' Is����brief1@*� A[23 , 8�Y_How� Sur�#U�I�A�:��� �(O6�m�no �.�&%]�2�%�� efew:_�!� � PgN��TaX�="b b%0ji�%��K��="�Ahal� (y�,} A�v M�%*�WN(mSm �Y!�[)m8]k / 4 sj/jz,�?��nTFAleU"7t��Zkee�B�A�?) շ��>!yOAtwhy� B� -=��\&�)m�iQ�*j2�B�Z}Xq8?� 2�!S�� dow*am"&�& 4is PKA3P �=ory��LA�`s"�#�/*35�!�&B)e�����`7�U �2�%[8�9AI*?�#$RF= l �B�Z78�29��S�2}GK2A�1g�Y�>A-aGu7:I�!F�J !as�&t t`6Cm��(�l=�:aC&'�  Vf�/0��I���to ���l-��9)�J��d��p"�c.^damagom � �""$+(sm!7 DNA!]�!�!�I-/�Xs;. �4o!�d�AA�[ r�al2)�-)ba�E& q* �K#sZ�<�=ngm?R M�r�/wtheBR�g$]3�ىd"< 1.wa� 58 !=�&:_��d�a�q5��, TOR �- Med�� [9H9�N!r�%*� A��� ands�"0&��O���:&5�Mnd)i.����Q��� n6(*�:�0v1�?4�&w �~ˁ�25\o`z d me ism�m�X&�f+ linkuJd2����. /�!�="�U�\o"� e!D%�9)9%�Bf(�B\s.j1�!�0�#�ZcEQ� -��4�#n G1/S jo[9���JF�m�9�i�X.���, Cdc�al�diA$td*��'?9"?�# mbal�@&En�mpvW2tA6 �d�:[9�9�0FuZ�`xfb��]�/ ecipP5�}-�3� B! ]t/ �'nhexqui$ q��a}&�A�ens)bA�� "�~A}H6pqnZ!ohi�*["���zY�� aA�"lf����a �� �Ch�p"TrD�g�!�c�Gtrophic:�$-& , ��1�*�D]m meno E� �&!)e�l mmal�o�?1c–|100Ł"�'pc2"�*�"%������ p53 tumS�=WP� Like �97e,`�b�cyV F .���"�"q����e�v�:5���� �'–� 4r !�A[U ���) &pI� A�polymer�_IAIII [9)R�`10;"! s�� harb�/Lz�K� igh-affin�]a�has�̥�2=��%ar e��*z� � �-,}o���e�a(�-M!2HkR%[10�(10).AN5B �msv. �OXkfNj53�4da��u�'�*�b�Qw�A�GTb{� thalIl�[10�}We,.�u�$1HMJ� rolife>� w�iex�#8�Y3% �!\o i�!".%'�sr"[:��%����!�Ubs��KeG�oe�~a�7c �(́lɡ� �P}�� d�qn*�?al e*V [10�Ia), �uo�E�"S�mo*T��f;s&�� �͐&3 � bej��t2�gm�, F$�2G)=�b&� �Zpen2I�h=onQ��+b��. .�_��� new �!)� ��s 4� unansMd ]A2m� /Qows�&� TF }�5/� .+9%*����m� �Wof+�e�cy(Y�ofyr6:Yimpact34K�. A֚��A-Stoma�o �s��y6�.�Ger'~��I��#h�*�q-�<�gle&$P,1)`� #! W� � a�~Y��Zdisse�g 9�L�"�F�������CL"��� Mޡ�%��%,s�%� U�E&�y9�h !� �Q�s{,dly—�doZ��'�A:� nd�� `ed��Wt��y iqueI<f/ es ?rUa(accuraҜ&�im.��<so too)1b�t,f��h7��1:9#294� 6 9-B�-(&�e�sus��i ~. All�S"�-a� u}I}, BY4741 backqn��Unxno�,��1 !K4�5YPDQumNbatch * 30 °C"8 s� ���.�Z8d-log�`�� �Uliquo�U remoJ=.� !A*js��0�"�toDK�8��� ��5�T7 M�N&U� !`!�2 �&���G&e)B$LN�a�^� QEK �� ifuge[�"eca�U.flash�ze%�!&]=Ҝge�S�K6�ng:qq��" }�jg!ng!}� -HIS3ms� .�of MSN2!;MOLs�A�e�*-t�q �# [1082)�E�&��o !�GFP–n�DOT SFPc or HOG6� ���AGY13, �!�3?�~"���4Fluidigm’s C�- crofc(�Mjap!HN0�V cW��n�.s�&�I. F.� %�s�� 1 mL!u,1 M Sorbitol T�F�WY hem� ��I6t�K dilu ��V�D��4 × 105 �7mL!�a�?al volu�G200 μLGo1h�dr�5 s�+}� aasSly�� 1^BZ`[c�we tia�nlachq�g �Nt�K�[ of zymolyO (e��ZU , 125 06 A�003 !)incube)�a�m�atO��K�l�_b�L��_���~�:Gt"� iN�to�diges�lA� �aJ2�spu�� 250 g�f��'�:NUBW�Mbu��-4 455x!�WG B ,E|sQ|)V(2 ug/μl BS�%J 8 ( �\U/A)SUPER!�]= e In%�oP�. S��fa��Bnumbe�� c�UheUZvSl\E�8Leica DMI 6000 �3rA6"- �aeV.M��]S%UofD)��i@9E��",-Rm`/E�U�Se�' reag� a�Bal loa�Bw27m�w!�+Z�� wiYC1 Chip ��� cap��110-μm ��.�@manuf�re >std�sE�R :�5��QmixjA�cruci�%�%+!�9�w �>�iU� d�%��\�&� 2� y_2 ��llhM�x & v!�p���uE.mY��,�;c!gZvi�Sin��A\!�im�=o tabu� �# �bbj. Roug�%AZof1�6% = �,�byj!@v!�a0��� ��%YYoy$ty^n��.��� �� .�"d�2mI`a�.�E���Ŝ!�U���ru�*��!Cg"n�C Clon�Tq"`GC� �5�/I9)X�85oco51 cat # 635���� �K�har�3�,�S.p%��iaqa 96-A���IPH o�?a� −2� 0. ERCC spike-!%��V mix �1%0I��0:�qe�V:vf ��m orig�ducƐAmb!�cat�Vqu445674O. B!��.br�UprRME3,)�% A%�8f�)�](n AATI Frag%�Ay:ze��U!�6�W}lK05g a sm�"O450 bp%q50f����kTE�&6��}2 n��LMeA��$FC-131-109�>�� .a�Bl��a'TTP� �HTS 16qnelJ��leA� v �� x�S<50 nL%"weM�@� cal %rtot� ?_E`J1to�'�oW^p��V!"4r >40}of inē�&%�g  (i^ (TI�I�a�a�8 D2�!��d>6��`e69"돁�&. �45 S1p0. Neutr&�'42 y�!m �:) ��a�*w�z� zB mat room%"er��I�fIq�!P�qaat�%�]NPM PC�xLX)Ht ,  n he# step�run��H(!�&*achu1!co�)A rm[l "�jpoob{�7or.Z ��f:h ~� r�4�=� sel� q5ere� � ed�08Agencourt AMPur�(i(ao kman Coul�:uA63882�A� hund�.n�!��6�!b�,�G�!?��ree las�,n�0� 2 [1�D'7�� �Mby SCN�/[11.dR0 A� d1;>�amp5�):a ^�4�5r 4=�1~����!} �lo΅A�tg�eM}sub�4Ee!P mean1ƺ.W)Y� Y��� �� �5�Z0l�-�{avail� )NIH GEO"nPę���GSE10247AGe�mdef 03��',TI�R�G�^(!4] zno�� �(8 'f]�(� �� ���nMv�� n�M-A%@I;aC0 �F/2rE'Y ��Jrm�i�a�~-^Ked Wel�K ,fcr�-!�NH!�-5��KƦeo ) pk!%������MA�Au.(!"�f , ta{>�s5%a42]!,�1zg c� �/2e�dI)*A`�L:a�2'oE�gq�V� RP ,�']E.�c%Wɺ�"�b�xLo�!�AI mr��� 1!�e @2n�f-|!/i�� ;�%uM,�:&�s!���'�KS!ívassfp��c�V �L}Hr*I�E��pood>"�k.r~ CV�,RP-mh��^5�o7*�I.J,!6M�(CU5�QU�r�v�:G<)��J�d< 1e-6Um3vZ ���g.�����!I��=Fhby1���q�rH�AI�/altqa�.��ubtle&�<CV|<90�ius �0 �F��B��W=IK��].+ �":1#f�{"�]>�C 3% )Eq2�i�}�YG! 2& i�A%7iB%!�:5D!��h15<�05�WBVTo ̀e&�B��-SR�� !*-Q 2s�Pb��� �X!�mea��>�� zE�Y�Sb0�����a,�n.���� G.@] o\�5�bI[p�s;Y!�A ��օ��Fl�KR�E< c�fs��&�*dsumӀ[��9��O�8Z R packagee*��a+4y !�w & \Qy"�Uc$���f[K)vB�.pf�Z�$!�"4Us ��F�P CalcMV%<5&�@ Q��6im�U� �(tbanA�4( MeanCutLow =!�%�e'B� �� tP-() bo inus��� A]��k�W�E�n�s�:-AA�as5F�E �E� .�#'W!�f0 �3�)�!� also�w�8�$ %��#.<s~��F�2�)�@a :2Q0I!�Bum � �f"�ie�(-[MK-��ei '���O� �� �i"k�=+�ZA5Ai�_�����k�A���0�r?�K�%wB�oalFag�/Ds��{�aard-�MeeY+nom�-�!lLY�"\IdFK�lq�e  5\F��� .e� ��[�Qhei��tvE squ�@ erroIMS�?ndqa� �[-[Q*�ur�E�.�6�A�#tw#e�YGt���!Y�,-3ak^e�9gma4mi�g�9"&a]se%�)i��(b�o a2 |A�6hEIc�ns�!I�RP-(.�\. L�{-�e?3\ � "�^,� �3id�3�y� �%�U aman�M 8��A���F�!Kc"; _A# ^�EX ���e% ( R2n99e��%�n�%�^n��1=�F�+ ampl��:�w��&(�D��Z�s&�AwefI�~p=�inP5-�Bi&av*[*r'�a��eb%~ulk &ʫ,�`� � W _$�g �* l"s co�Dno-�.BaseZ �� )*���m-�!0 . De�Hon�~�T"�G6,F<"�Iae+ L_I�"� Fo%apM �%��8[*�~!S�iq_� 1�� *�\E�6A&�"3 E���%F�a�#�geσ"mooth!Es�8 ׁ�t�SC-���T�-�Q,ɜ5_}J*O y�Z(�0)���E�/8�y&�]�!�*h�)is�Irep&�Ax1�<�<� sS�"���qu� )�d e p-iWcQW�}. -h-R4Bk"� �+,@cR+ex�Ct� !W"4 k��1"�@ܝ�!l:� :, ,� : RP%04�6�^ 089;Ed 148L$ 156;4 49�A220K�%E�œ��'�5~t��s-ly�ngK �F&tC! ��- e� . Te�&s5�o�*�Y��~hom&�a�T�w.h�!� > �~ h�I�  > 1e−�w� }ne���+��3& � *��"ϊ[#,%�>D9V&)�6�3%.*}e / .xt� B� � :s&�_AL�Z{ ."f1�65iBg&i.�%�X%2� Q&5O yFqkK$��K��&�re] %� ���'ata�� � �It\�g-Z`��.ca�g��=��8%� orga?kb��er׀R.-ZA�[113]&V A~�roi�I� )AcmN 9_ &�H�" X ���-� �'ds �5�*K-� �� o*�^!��dvec&(�G5E#�o%� �T&KBa}a"�T G����C“l<�v”_ ompi�lia�V27%�n ��[9�7`|q���<n.� JI:]7 Ha�M� i�*�@4�7av� � bp&�>}%w�h0 �u�7�<�}xr' k&&�-/MSN4AH4]!�72���ur�8�|7i��Ap�-/TOD6"�>(�b{96�aj 5X1S3@c� wo b:�E����w"|�~.Au,dot6Δtod6ΔE���1� o�M7M"0���+[�z( �� ���� oA96232�& cU'�  ���us� *[11*�117��*PER&J� ChIP@�[11[�W2c_.c��O*�*}_?�A9�r.4,�#�a�!�XHL!�6����t� �%e��M�Rg*� \�≥0�H≥J02*��OY R��p&Q=z +Vn�%NAm.�%�6�"�fp��e�"TX�� �� �9t TF–%�iA.gz�� ��$A�]�6� ./k & ≤−=Q)Tu�3el���WE7−log1!u � ) > 4.�si2[<valN+�%�-��Bo�4�rx ��e�� 05 /eG �=�*>[1ɂtEfocson ��}2�5��L9�F�" E?!�� i���:ly�o�5�ga9D�Tw�$B�h� - �/�h ���: S $�� 6 ��!��.twX�Pa�i~2�(6GgI��H.)Ae�%\.��E!OaI���%� ��I�d��"� ���� !�� ��"�b�:�!JE15M2����.���/r�naqR 6EN6F� oײ d bo�� dŅ.�I��j"A ��G��%�=�I�1aO��XG�"Fe.��A5�7 as d:d �!��fix�!�$!:6�H[11�CISH0b�C �"w#A7BioWm Techn ��(Stellaris D 4r���VQuasar 6LCAL�-2� ed 6� or$$570 dye , { 33��PPT6P�.�(D 48.>SES> &. T!+E�U�E�e�!�]+J!�.*a"���9!v��=. IV0� "B��-stacks�Cry�O 2 mm)Ganү.#U� 9636u� t-DS��.�a�Ej#46�Jo3v1:�05X>mN�\a��cyDIic �=��y ��a*ZE�cus��la1P�ru�[12�S�.���C�Ffa�m��A�.tb6�t;ma)���� �.D� = 8ɥj �at� neY�at"< � %? l��"�3�*mi�2�NYƁs^?9>2�-�uA8LF�� ; � z�v�Z/�%�q%$H"Sj,.)���$wRus3B�l�:����  Foch:�am�;SC*,FCS]1(\ p�5e Inc;�LG[4, Pennsylvaniau�%C+4e 3mXY 5i2/loa���� �A ad�d!�a 40-mm_2 glas�U�li�B�Z8!sc��7e?M*�3��ana��n��(X mg/m� wa�2�wW1�=B�3�on.U�as�ed͂�g�=�as"C�2"�1!jx� %- )2��gaske�C��oA�%�freshEVA�a . A-}a 2-μMKc"R;`:�plu|&��)%n��s"�&�9�t?� �� +mb?�|�<aqu֬t�(dn up�  !&Biq�.�!��U#Sw y� �%c�dor+E�E� � it��t�8�Cnt�utiliz�%��C)=pumps f��Mr����/�Kc�q�Bo�B[S&Q>!�.��D� $� ك�h��]Rey b��=eProbust��th�SL!��62��A� TI-S-ERd�o�� stag�O 7d#(MEC5610�!sPer�vF��I+�M>�� MelvA�x� ew Y8�� �u�HI�: �6{!1��1��!��%&�C֪� A��!���A5�� H( 50-nm bandwidth )N� "� 46.;.�  � 2�� ( 66�V�"$ 36.ʎ4 S&�(��Q?* b2�bEC� 6�2 !����c�  Fiji�  2 nd Matlab"� ji9�����0� 5\:�3=2���'vC"5a�=�i �jUica�r��&�'[12^�t"� 3�[�7� ����tB=�� cU�� � *@)6�"�\&�2�`���a�$ce"�#mZ,&� < op 5Glpix8�� �%uf;19b>[1�5. P��3 >p%�-�!� ���^s� -�FXEx,g7 .vAfri�Rtrypan��iaJ�vx�� � protozoan!�a�U T4p� uceih�mi٤�$m�W.+Kbith?a t.86It.�V #&t�pa t� u��!n�,�,��� � tissL��Qx*�moX��hg�akr=n{Q,e�8immun"��-�mR@ko�ve ���!_&=�sexq7route����!��we� �� VT&)�� need$�1 bUlog3o�F��OdZ���1��5^=i��aKCArev��T . b)��A)�%�nZmaq2 epididymi�f al adi�i%�� fibr� tuni��O5�N��A� foun�>( lume0@intact.l!��K nife gbul�`vhA4��@�]c0 .��9�A9�m!��9E5-Ύ ileg�$ �}��a;�R6Gas66��#�flaU�1 infiD�%�,F;|>?A ,%Z�Pr�La�c!�ru�I!-�}Xuc ww(m��?�v er� t�O+l!2�j� �!!6bloodm%>Z�I A*ve".�^vxAO�A�ng )� �4U�j ! �*!�@ <��U9��iA=ga�" '��}�i�W� 0f ��r��.�l*9Gdiagnoާ�SQAni!�������. H0�b ( HAT|,�(�p�lee�sicknz<,� [wg%��T���ct cli�� ��o�����deaSAf left�0'It�uU?N  �DR� rly/_Plymphat��/ A�~�te/Aopha2�IZa#wo subݰ~]���Q�s:Iz . gambie�X�9A��j���CAIF_�isҡe� WestC�MlA~��f�Sahar�/)�a����� 5")Q97�ah�mա� . rho�M6�ful�Gm |qdis�� ���lk��jb �[!�Cat�9!=E[afs ɠz�(�I ,A�m�5U�naganlch ��4^����emaci��an0!(nd���:f�JE.:Z[('I�/�,�+�ai�%� !Lcongol%GbcpxAG-kevansi)=s.P �c�X2s9�Q�dpecA| proby�kf�6|��.�}���Hi"`YI��g-ԁ�l"iQ�likLockg��LubItd+ !��%a`st�qc�Eas(jQof US$�#5 billU[4"t- �,�bLAN1~��oI4transmitted byp tsetse flies ( Glossina spec�[) in sub-Saharan Africa . T . b . evansi is transmitted mechanically by hematophagous biting v�of the genera Tabanus and Stomoxys [5] , while x�equiperdum ( which infects mainly horse Fdonkeys�s sexua�t�4. The evidence� '%pssion among other trypanosome5+re|xs scarce . A single case report]p!dbleRfof5Z gambiense!�phumans has been described [6]�!�yp� � �30also observedTmic\!9ed withJ|[7_ StudA �-Q oppo�  s�ね jstroma k!�%�s%[ia;�x s meiotic`post-haploid pE�be�recogn%�by�:(s non-self �p�Y s es���wto av[(phagocytosii�eliminI�of �ati(nd.�disrup!�-th�Ms �'Da foreign body reaE/granul!%\commo��leads� �Ea~(ffin-embedd�#4 μm s�qq�-�A! He� xyli�d Eos Ea"e�&s m�AM&C3 Le1DM2500!�I$�'plwo %MC170 HD2'am. I�ow chemistry%Q�C��V� �;�"����( Tvocy� !Nmac�< ):�using aE(pu��ed� serum A(-X �VSG13��s-�v�wPost.OVSG�ca�itcH CRD-de,vdu� in-h �^��H2A [8ZCD3�0ako , A0452 )% F4/80� bcaIab6640j�!con io� protocol�Brief�� !!4retrieval slid�re3 E3PT Linkdul�� DAKO�t low-P� �V incub�PE�Aprimar_ tibo�. EnVi) _h%radishA�8oxidase/DAB vis�z U~ (�A��A1 coun�ai��HDs�iF. Semi-�Kf��B�$po�hyNQ~ 5-ti� ?p 4�� scale: ���; 1 , � mal�� ld; ���rate; ) mark�#��� s ob �K�ЉZ6 �!�f,-�A6!�sam�I2*v abov�oC -[:@tep���U,mp� ��R � sol�� ai1 2 . 5%FKN:� �EM�plus 0� %A�m*�$Thermo FisH_) M cacody� � ( SigmaeppH 7 .ͳ1 h, fSfixI�,!Tse �waG A�q[�m@% Millipore filte��Be� �c=8.F-F$osmium tetePa�)�30A�fnd �pec��VW0uranyl acetatU Agar)ytaN�,Sa=�� A�d�Tinc`AL } ��Hethanin� 6��30in EMBed-812 v u� � . Polymer�/6�at 60°C%2'ulkhb 2�cu! ReP,rt supernova�tx��s:"��cie!31�"� �pH-765067e# m# DHitachi��an%ele# ngjt�~100 kV�r2G p�V��XR41Mtom m�V AMT dig�  ( AdvNd.� T&� CorpET�B# e�z� . Genomic� ( g�   extr�d� a know��u �NZYB isolEv ki� NZY� ,�al�Q:n  ( qPCR ���!4n ABI StepOneP�wreal-: � �h� !� dataE�a� �eq��E softw> ն:�s��inT.��ameasu�Ra)��& 18S r!d� perul�m-� �ur�  n"] p"�QXcalibA�on curv: e de�lim�establ���applyA��6� to naïvea!SS st� �all�fX� e fre=lLR: http://www . rpro .��o�ess i& dens� at a��s)"hig�c��521n ear;h3ichoa�� we m�!)isrb*�)r�@9s%� g of G&\A�28(.M1�8Wilcoxon rank-s�As�T3ternR�A� ��p"/ �!le�"�� ���js���� A,� �ed"_ �K P��B�4ed-� I��t��st � independ�e>�~id��!���s]}ee�s! setA� α =05 leve�D���aV logarithm�A���. F�Q�!J#l5&r1  iagn�$r.6�� m�Zn�� K gprocedur a�iy."a�exter� �2l�M�, upon +2�,#� � ��ll��I%t@, 0 ;nd"B ed%��m�/If.� yC&�!��N�ofP� ine�Z� � sh$( u ��l.a`E�t�hyp�'Ke�kRUhe0%r�K-.6&�^ ��e'F pleo�ic clone�T ��a��"Pb(�- rang1�; 3x10�.  70 s/mL�a� YIa"repteZ� �pai!�M60%�s!e�=�dm��Zg&�",2",�U thelT"A-B!ǡ�EkI��F( Fig �t!������field�,already veryM?%q�a� vera�2 "�)sN�w-power Y�o� !�M�c+in��% nfir�&a2��Fb�,�$previously&�)!&n\&l.h��3 go�'!��'[120�i�����in)�I'Moreo�weE&��tiH��enough�e�v~.3*b~2B�. MB,M��Fe&&-"2����st! a�dv>�5"F� x�Rmapped5�!�i A*]?JcoursM 5��ig 2A%Ssge8-l6�fe!���L� :��!oL��"��*aE�.-ZM(�u�-`�(��%��,-�new, #G&i�2By .0 �}m.�&N�h'>ch2]��!�%f�[2*E&X E T 5�+m�-by Bj,�=B �.��%�n��|gonadF�- Aa major7Z,i��*��Y�V. H�w� NV ( IH�w�:S� -pan� �'�� z�r�-c)�>56�t}�� jY�%�!F-w�5S%9H,F0 . On�?Y�]w �yed�7e�+92A rZ-�D%�5�in��͢��+.e� ͪs�*o. , corrobo� ng�c=�&��+ 0i/�0ce�� �9I) Many= �so D# 6Q��"ek�ā�~" ime.9M�,>l�A�l �$mW&�e$�RA|!�o reg siŁ/�'DinB /���( yel�JB�few>��("T1to!D�� ftu3 albug%/(}fibEi caps��#enclo5�M�Unz0a�� s/�l ܍�7 e� �� ���/)��]&[22��a id%&��-~ � ( ne� r1M�$/%�Rw)6�i�s n�^pi�"F&y *$6[� main�7�1� lack=uA'�g ���L,�&]$l*` 6eloc�Ee�% v=-l��dh� ��aJ�i�B�g est pea��� . Itgb* pr>`1�v&i�e q .x&[2-�%�U12� resie~- F�� E�.� �!�!�� w� �)k �*toI�m6�m�Rb(�-�) !�}�ise] Give�^atB2�(nE}�.$ "@-, our>ud��a2,b'" 1�s)ae2Z�� ’s�"�1ba�1!���,:/I r�1o���.#�W:,!‰OaEL=1� "As(AFx1@�jb !�&�.�A-1W� �#�F�#-d=�( M(%�ri RI4sup� �U�u,��!�ĭ��'.�",��2�}��A�backgro�*�,.�r�s 2�..� had�5r5^w than1 �r^b�9�(&�!O� <S��A�2>�� 6�!h>~ #,H �� �� �&� Q7�&c100-f�'�l�T';s/m<�.Fj�0pOl8#w�!�mm�!PmB��� 6/rtant 4�24 ��. �0% �k�)r�*G etE��*� Avir�8no���gq : B�Vsex���m�* �asurE�a71�F� , h&� �[yU~��I5…�BH2�A�`:R�%2�0=8�,�0 �a!�munS l r. Inde&)2�I�i��*% wem���*���|]�)^6l���zZ�:�F�& ly du�y!�> 2�(mononuclear�ECo� �Bm��!2Bo$we8->�"�$�#6�$)�.�#6�$� Y� ";  [a&#n r 7 � �surfaca�a�4-�'�$Sa 1 E��)(H�%� Inf6K8! �3M?q&iit�"b" ���a� ��4�S1� %G�8J1�JW�xusely�man8'b&&FE0nu=.�~R "b13��=ow&i4��c"�&%�c 5�-9l�4J1B*� �4� tc=%��^�� 1ed��� �0f!{i!3@�ps��ompan�by�7fo���8�F�"(urelea�.��)� !`aP� T- % 9�=%� ��c damagA�t;sNauto-e���%;r�7�La�81�w� ��6�4"? area�� �-"+7e ��r�-;U]JV�thoF2�:6ig t6�ch8OAd; N &k�F�!1m* %�N_�3q�toY�2cA]�!�6�-�25, e�C�B5C�Ad�.tQ(aE%z"I���ȩ� e�bD5>��=� !�E@i{-\� &�y}�U!?�!!^ N*�y��!2k�}!��'UC�M�2U� qh,( �iDsb l����ه� ch!�����ndF��%im.D "2��!�. Fur� m�&]92~�,ݖF�-�=,2�� �-��>a�9�. Whi{�!A.1C{t"miz��u�Uuh' Y�9n�1���ini�>lyv. 6 ) � sharp���,)��/Rexclusiv�&its e��leF�27�|�b1�=A��,��=3;� tch� �!wi�t � oi8AQ��;�)D .-�B&�oz a�nd: ���.]7�!$N�m���)�E��Nbe[l�'� O'2D�)� � �[c<2�5�a%6ng6&OU ��$�� occup��1(A�we& � UP1��56�T JhavA+l�.�C�Fgu �Y1��@B�w Ue#2m�3F�(A�TE<8.p ���\<*�sA�n :.�O&:�)struc�Dl�V>��C db<�<slJ�cytoplasp(A��Ely)�Q1&E�i ,& ]br��n�(ag�"�=lagell4 5A–5�WAls�/in agree3eI w�e��  :2 �٥�&?J �vm�i&5E8 Altoge��A.8J[Asugge'%�A�2 U�0s5�,�� ~�pB �@� %efZ v< kill!�wY@ . WeE u��"�",��V>�f�FN���A�@@�i6>�&FqA4�-:AUtG .����=1L� h�<a tempo�I� ��"�%�attiG105!F :M(�L�u�={dis* ) �$s��imi�2%�|&'"I�tCZeF2��MN�B/� jat N��no 2�e.��� ZmQ�#s2�R~ o�ir.� -�vG��o)�� v� � aV� � �N%2 ofluores�J�*ayHh�&+s�5hee {3AJ�5�aRsteadA�]cX\ ray"9�K2�.�# "m�4�Kur�}FE��.�*m Q��>�@�9" �  (&�R�f! >�JB"�|We do�.8 �Pa�Cv;4� inoculumA:.=F!stra���r�@ m "� ���r�<��or��6of�B[B�,�bmethodDC�aPto�F%os~JlNAA���.:.T �Jb�"�9��hosts’i"_Mby�c^ZL[10DEOur� -�a$ 2�)��&�%��mas� �:J�C�M���e�ai9�!ng �l��R�YN>�:q1W��^.� cD� aA^"}L~oG�h-r�/!�ci $�N rdQ{)�U E���1relapse�,%5 �AD3E� sg,\�a� 5 M<fu�;�s�Tth ?�0A1b�!L � �9a(ala�&H[23� � ��!;A4F�/A�[15a �72LIRz:Iin �@�Tn*A LIBl!�s�!�Gapv �I,TKlyP(�R. BjEendocrS.dysfu� ( pituit�9l" La�6ialamic-)-��x�!&IpU[!j0 "< ina ariet��edi� [1�,27e�.rL��]&? G�'���&O>�.( cattl� �$� sheep� "�*dog�,� a7"�0Ae ���*1!� ŅyN/sH#�WG&�a� L�� *�"�qa��lQR���A�:3�y�!��h:���,*d-r (&�t�C2��4B–UI�;fng���"UaO�j�7�U�"��Vz ��$�P( iVX�`� �� ,���se�3. Ls�sr�$��s7��U!���mnQr �&�'N��"sO�I�T��� ��19��ome� Rr :#,� E�u�1I�!�u�A,sh� 2@O"Kݪ"=�Usaberr�mdK^F�U4AE�5�D,�JA�bi�a����&!Ro�H���T, uw>�Y ave a cli@'� pact�� iץ�H�qJ gha�canA�dis�I� �<��,^@= �lSa��6�O*[Q;QeY�A�2�%� M�x�!N�@�. Chroni�;"� and/� m�!��1!II� ?ep�'"K1ba#K$t membrane*p���W2�far/�[?l!�bQex.� r�AgenY3� eMu, �1�49Vg�S s [2'SG��2�Bon� �*�2s��y �-�3[20P�,A��Ux �-$�}� \E��e�� *�*�"�RBa&k� ,/a7>�'4B4.�enAIs�H:WUD � m^U ]NE2 �3� ��no�?�1!-privile�42�7 X�4F�%d&�(a�0��!�5,,Y. favo+.qNa�+liz2�"AE�esE��)�@theaq�I ,9N2p2��beG2Li ledg�me�|n� U_NM .�K� "�7How�U�RIxF_!.�I%mmo�a e&_e?���8� y=|�O0NB b . &�R,a۱��)[6]EM G in.fM6[. It��Li*\g ^�2,<ly-� a].�LYk6Uadopt�i�Y�"j<nct6��A�O�E0U\e!� deviEM �X�Pe�>^J BTA�� � �f_���E��+qF`!#�paBp�M�si&?^:�>_��T=�.|O��a�K�<mb lianOD=A��:A��$n�A�6%HG9per�[�lm��}�pop!q. Cur�Wc AA�@�:A�anP&c9by direc51R& Q� Wsg�'�5ardE�f2� ATA��Xh�I crit� ifugF!"1T ( mHCT{ �1�e�J�:ic�R C���U�& �-n#�  z[29 , 3� T���� easy� -. ɁiZsZ Q7�'[3�4IjCr�e ELI�Q �rAOr�?p�&B#> xpenlp,rar5 avail��>i9 [32]�%rapid d)��\ test�"cU";�R in C�Joon [3033G�3aC� !h���xoB_�2� y�H���:gu�Hqp�>an Z�P�MAQY�,B��VaE!MdE �!���im� A� �i]6���@��0rWc""�~� � � W%!@� w<"�72� ���Q' %�to su�_fu��de�/B- �[~"P.�! P%�, i�e>%��8M�]��Dto�estock�sA�do�orR�:�I13��:~���F - )� be a/N�*�]-�E�oo %��-�A5� �=���&�� A�J�� �th�az*����E�a,s; �rF &�� ici8C�r�RG�  ɋ:��-F6|A�Kl2N3& I��.��2�A� ��y �" %Y�**5ٶ,���a�of�La��{�Kh6gu@A;� �aa�ZQe$�TF:9]a�e�>Raa`dFU*�c anatu1alE,�-I��]�"b�9E� nove��>�E.tG]� n}�aVaBNc��wEbe sub�Eto TA-�h P2�Sc@l-s!�nd�g&UB n op��l���<�Gs��y*� � ir u\.�. V2�Nof�� mS%p��ѝ����.�W2�Tisml �Qo�)� ri �=sura�ZdhK byM fami�YA�he��W~Wrotei/bwh^Dex�;L< must!XZd�G roprZ�o"�!�AX�1environ���asOwheI aB�� �� cluseM dgenome9F\[|dFly;^merA�or1 u5�*,)!si^to.�&�"j�3p ! >^@go co\%�r9 �.� �"ePX#9�Z*��+g� �ex���Fol X*P�Fna�0ntext�Mo ans�B�&��5 Dros� (la melanoga!�[ "zSs)!>ɔ�a46�+�bH�!�2[.I� �olprecii..�$cus��v%cK� arr�Y�a# N�sny1�TppH� crip�8�Xta ��d"Yd=�+�AN sex�E2�x ct�vd�dA �2`)�!V-�N&�M0>*e�o.�o�to od8_� e!iFex*�o9 abundYIZ���s8!r� �(�t��%�� \@Ulaa8� when �H�=Chys��ADe:sKS�&Wixr0���@ d co�?��z %�J�!�A��[�ss�.�iydi�I ^#�� segre*�20}��ly sm=/ , bi�7l�hlevwdDlof� ly �>!d==L 3� �Lix|du $ɈzI�-�e<�suba�me en sL�5 26�a�D��IHrto>�95�wcN����%�+!�1Z. R O� |E G�z�V "�" roG�`�g, �Dc#d� forag�be�)�g[(�sp)��Xed+akER�LC����n��kA��ov�p dlarXfee$)'e �G a�]�(� I!�� �,6na6� � �k%��. AN�e.�c�oI�1]xp!DEHI^�2���p`g � n7F�Q�iu �� t,Q�J&of1 duqRtv�"�Q[1]–[4H �!� le� encoy=dQB%�eptor�Orv[4B:Zgu���#q(G( , [9!�:ab�4ng�� ( Obpi10j12uIn�iE:,A(geY4�9Fai�dt "�mn�:xhLMKXv� o%U,� profP4_AMcytochr� P450�#er� Um�qDetox9[� lA�def�kq"�*���C5'-�5 ��2�to}G�$\va�,� 'P"�Mb.i�-2�z ship� 4!o� &V�m�LBBs�4ows�ter�[4Papilio polyxe��,w ��x6Q � metabo� !Qc f�Vocoumar� �a�to�$EY�D%�� !�(UmbelliferaM#!�2S!*�* sech3a's=p ,H( indaPWifo&n��A[R .K�. A 4 bp%z^j-�upsx$m  iH�E�pD .�a57\U��2i �Z]? %Ie�s�� qMo � frui�J�iBJ!ce~y+nt�[p�r���ue� bsem�E��6 Ge^I�Y*$� d� y"o C|c0 ligaW[Ln , [1�� �com y&��� robustnes!�H��r��r!��,� �� &0 lyi� ������s� 7q8a�ad?6� co&#!xr�B� ����:0 ��*�"Mdynm%z7M�&^is rai�$��funda �"y : (�PIa��23p_%1�%�&Qr}gan asJ� M~��*� = � e�pdo Q�zaD A�So-�]k��mb2^ ? ( aAre��R�e�q� MV��.�oectu#s� iereta N �"�%�T &�z:%�9��C�n;f��2� ~lY� wv4 )V��R�u�oG1�wn9��1�!6� (E�/sus"{p7%͂A��q� .��l �, adulf*aba�8I&� vQV]P virgr�xed�-y��(.sol�(� roupa��) ?�Uf�focJWoa�m�u;�Aof.�:�I9"�olfac�|�&� �� >J�I [6"� �n"r .6y�c�6��'��,�l!�inb!  vidu� 'bS(�3��r�]���gZ]��F�[ng!S79� "��Z]� [XE �5ed. .�E C xW ey si�van�W@�Ob�)O�sG� x&�2���R,2��B.� "�_aMa!�G!*Ak!0*���i١� wind�r�8> [r�n� w�y.�%~ %cA�^s&^ r  C��rAz�)I\+��W�'aJ|ny6 ��&�pVQ,!ver !\e�-� = R�*eafnA�iof.�!�&�mI�r�� �%!�E�1�&@�e%ua�E� mosa% f��a������,D ) phena�ic1P�ofA�1�!6Bq*, >#]�6#. ��(� �*�+�. 1bI5� �kA�2�w�B%�x D.*J%����0t 50 O�:� ��59%�t(����� 59 GB (��) �wKu���rA antenna-> f!�&�bf=��m)�& prep/ � prob"$je"t"-H< �E  400–600� Lfi��� ll "F� U'�A&� almc `(BLAST algorb_om ��iTa� -hybridiz!�T. C2T aw%��=8�wo�&�m!^*� Gr64 � "96w5la���"�� � )p�Y���#!�� �6�= 6� Or19�E d��lYR50 kb a}�)"�o�<t)A#�@A9sa����r���theЁ�#�C ?"n:dye�s�]i�e�$1� z�_ix��  "�_of Cy n$d Cy5 labe�RNAA �Aw!(j�cA�r%l� ��$u.]6���TwFigAiS�M�"�D!��mi�7.�. A���1686���Q�'eM}� & u�&67 of!�� G , 54�N!�52�=� 1c�):� .d�����ofj�#U�y�?=To�|/ magnitude{eg+av !�NB� 6���'m9'��&�EST=,s5��E�5���&UP�����:rofildf {>7!5�;%?f olig�Lot�{9�r9Affym�o�Inc .\(�-ER(2; r = el818 , n 17 �'re"qm��k%A��24!���sub��!X&�We)��&e�lde�%��8of Gr22b , Gr580 Gr59 77�� Gr93 93 93�� Or10 Or24 85( Or85�� *W,�+bN!mly���2; of*#9ϡ�&"m�bFT.�d� *6 m�>vaw,anaf"n ( ir�* star$ *i�w< )4in�9maA~N��W2s�h�han�$iN� .�a�NVPairwis��6�h�>d �s2� l-�62��2{��bia��"��'�e�<a BU�2i�>j3��threshoU30f P<5 . 68E-5�7orr 2a%ivp)�W n�p"�Kce��ABPm�-�p#J1a@e2 ;bQB,7ng6 K��5-.2b��%�d��vi�T> ����ȩ2 d �%��6.�#�z�U� :���{���)5Z=�m7� g�7qor�Ed@�2RT-�n��l1A��72�s&� "����omecA2�%&"� � F�2�$V6"^%.�$N9o�u2�:v!Ji rve/ ��a .�]�z a–U�ZObp19�=!�0 e�� bp56 f nd77iV&a7� Or43b5U�� W sJ�c�,�mFH��.����0� ��%�lRrva�k]�. EE�� st�2e��a� �^��q� � s_ InA�tr�.,.t<7AuF��"97X ���!���A0��he�1��bp1�A1�* 6fAt�#.�Nh�1 N�U+B�9&�9��5di�:is *�*$H �TleJ�� |! �0A  6%�M�6A�w�c-ZP� Q,Q1� Z� a(Qs� l r43b}՗��T�A�ȁ��&< R� *���z�ez5q�"��6��V�V'AS~ . N�(%�6E .� .�-�$s�gN"��E��,�'$&�,agez|;n�#�&�$c� 2�F5in 10-�J !�6-1�-;F�m&�b� Cre�1D 5l&8�2o9Y�6�' N&� �a�ll cl�U.k��� % u104F���anc(s n%��1��fAj:D]��= ���N<tI�Fm..r9�/6>3em6/ .�� perva�a. FpA �15&| !�19� �a�T!$" 6 M�� �&��4Y*kin�h�" hree6zYO���� 24 >nS�o�QZ ub��=�!"X Or83"P de25=� g�R!s�=�&� 3� r17 Gr98�w.E�7nEID21�0F a�"f} �wbp-�in you� nde�]|*� �>al�H���� 51B�6g��֡�7�Tf 5ME'v�N 6 ` ai8+d�9N,9��AAg K>.I�!�au��f0ea�%o �V< � H� ���H9�EqF��M��t.�6���:B�a�AU�*�����.in>^e1�C��sZi!��m�H{(�HW�z:�6l&| \fwreJs�u��&7 �ǥ�A�t�F)�CF�A?m), s�� &��!�y. �_>�dC! �#so"� �I7��-. Twelv� - �J\6g&�3W fe?�;on�?c.��M! a������Thirt�)� of�0����:�b�Ya�Y�eR-ed�nt:!-�F�Q�m2?�uF m`�EМD }�b2U��6t; ��6R"��OC�9�i�an(1-�es@c`6^Y !:"ga; �e &| Q!�A�$�mc�2�N��{-I.fPG D � _=�N��� odif�dra[ (�P^IlEactѭX���-�  #ask� >%p�4 �*Nuof9qJ�u �� ��n����%��GastJgB1���d"�$e �[� � ?6� 2j/ssL�Rx�'&)�6!=�Ms�5ew�4or�0 �w��*� �].� * R�m�)n�.��%" down���._%9)@�>&� ������i�e�6�WI8 �Q!�pK��� �( W �&�(��6�BC"o�oE�&i+�0��"��NQovew�����F~�L�m 6m�G 6^"� �@�t�1�ѕ�:rM)� aQxex�p` a�h&�G d25!�i� �:Y6`AyT7b[:�]�)2B5E�i�%�N�9��mC.�t1ve )iD!��� 2M�ofɂv��`[5R�\�8]��2 ��(��w #d�bv�OQNo/"(;� �5aMm!� ��9���VJ�e"�!w��paQ d��)M� �*� -A >�8 .� dou cheesecl�parҟ�q�r3?� �� ��_�>"�*�6� 5db� @�Z`(NC&�@noAy��0Canton S w− �uu�]y�m(�}lyA%��P��� ��6m&���� L����i*`1�e�:I 5a%t !��IAv"Vn6�>u�o� 7%�A~: lFB�*e�Gi"kg}{��S�yZ7A� ���3 84�Obp83i�2n�s7o-Vj��6�A�aw�@1�*_ =%�߅9w�t2���;A��!�!��qp\o� � n�VJ=U�6J� �^ dN���I2T'anxa10�*,7*kW�?;"m*-�x �K"&E�:�%:�o@ M�]+>��-c2� C=e, sixA- ɡha*�."! g��(2P��W� 7/cRe'F�L7al/�B�!6v� �n�rf�%:2or �s)k=C^� . No��%S;)�!1>����P!(�}�������4"jz.3�}_&\V�%5 :El&� oM��&� 2�AzUl �u2���_A(� *+1%� b7V�v!7_N��>i:�9�$Prg=k-��'U�*� �RhT2�V H"{ �a&u2mGۨ�Xgi�2;=L bet]v(�->���4�_I["�2a�fe ��:�ga�e}:��yR]�"���A"r Q�RkA4.� ��Zy5aHa9:o}B��UuPP6���]�]� .{(a� pa�&en�^Z ai ourt�; s�"%X�j�Ge�4 n]�s� 6�.t0F$/� hete���2B �6p,%@"�6:�1U�ens�7� pi6ng��*�6E-"�Gg Mt�)� aX+|�i���tMi�Ba1P �X^% a���>�B�.3C.H�24%'&.]���&8. (&�B!�&%HcQtun�%�Klf-C)� digma�0Yd����u&. �� �Q�&�� sorts�a�^o�1�UE[nh�Qmql He���e:D!�4A&8NatB[2�@[wREe���@&h(r�!onYrixa9a6�A1edFYphq :u��hIE GaV5^� -���  beq%olor-coA�"�ue#ength!�%R�.���8� 7EE��%]�a�20"34�hi�*) 8"M!Z$� ��!7���,3!BA]nJ3�1hz%�ar�.�\�� oPveD%MC&��;�1�`�w4siz�.f���� � ��aX�5�N���6��q8(gA% ��Q� ��m���od �6'"-9 �$�:F��"!z �$Pk*B�apirx�y��E$�eJ�A��K-v�WiÇ"�-��ס�%��w� #8b�5 c�h�1376X3�V�<*�1 s; M�"�&�#56Q6.Q855Q7A�783c�2Ief"*�h�a 5�q�'z��[ 99�99&�� 1298�b� n�!�*3( , Dup99B�1 vr42r42�$s 4231s�ZZTsp42AZ9�- Or33\30%\6�B%�8Sp*n�I{���?E�r}d2Mҍ eH��a9.�j:��p� �G"� ,uinQ>8� bp76�p@H Lush�QD9� (  pherom!Ecis-vaRny&|�_X���?v+�vF�)%� Or67�&a'�P)!�6 5aGZx��[X�c"�sN� �5)� a>m_)�&# "=��pu �s�al.�p�u��.(%�s>  >�V5� , [3wH [35]!�p.'!nN��ob�.W"vn�� 9h��*�L.��0"�? V��2�&��2�L�h66l ч�&D">:4&@)�s 7 , @3m��>5l* �K�1Ayx vari�@ ��CjEdd�2��\6����,N�.�J�$EB>J�$9_is ���1ڠ��.6$Gr63a [36]7y�16 9yxxc-�er�Z Gr21 3Aq7]aRm�j~� �/Y2K at o!m F*� =�cp6g )6 ���6+ * i&a _3�Gs�i�!T*P�_, Gr3�� Gr68%3?ž��A6���.�F�%�D&�R&ri&� [3%G [39]�/t�u2y&? 2 ���i�en�i�7!}(2�"���!�� tifs!i�iriC3A5�&� !fI>� N Q�esA�w�w;�ac$�y  5′ un�� �A�r.�of 62&j"1E���1C�>�7I�=]�5VavLs$�mir59by��83gE��& ( P�&p70� -"�1r�y pros1��,O67:tF:a1�20�xAbd-By Or49`7���Cg Gr93��2�003& .�xZ� i���Mo�1����H>/j^F0��E�2��![4��41��Nj��a\nt�]��  &�o>o l>ohe�Q�|y�>�2a%�A!eV��V.1. ��&_!wFFin.M2aF���$�:6&W^0F��bal!�ble��QXeg^rTbmaf�`6�al �eÁ&� � 6�*e�LY:�add�:,"�;I 3G#Emanne�M,*,-�&rJ�}���Rre= �E� ��k't�9�l��i�R xill� palp�  Aosc��cibl tasKgXK$ tarsS|�(�H�2l� ab�%���@� p�C��E#to34omprehe`"_ wholk#rad�h��. Con�?t�e�� c�=���.'/tbe�7+a6��qon-��_�R�go=���-�>;+F#N]-qAKEG"� ��zc&>�B&�7���4_ [42]e�h�[4�R�g��AC%'.bB� "Ph�X)in&V�abk(!c2+�C*5�Z5�"AFC�W2Q�&"�]� pr��� (e�*��=�+AJln�)c��r� t�D=(_�&BC�{be+�T��T migh�[*3po>J��Hmn���A����z"��� v�8��l 6+:�3i>��!BU2�MVGſ�E��w&�F2���DF\��.nz"��a:�s�SmorgmE��� "���*�hofS�d-deri�&�K��j�L[4}T ��alMh�K�%�� �&n�@��>�L9 hig�?�# �.??Aay/.Y*+ġ�ng�`�c$!�ex�?�B%� �J*X*� "2M !�� �>%1�pH�.� ��F�Ve��.82��OͯFlyAtla��$- ��`p � #.!8EX�� or�3 es>� Obp22 LJ=2f ,&F26i%WOr59bA��s�L�� 3� � HK�.�&, �!�:N�be ‚ s pl��rooJ��6 P6�T�Oc�}�$ ��GU &P,-=!�"�[4WI��K{�� �imy5j *� )�M-�A� disc����cFyono �>! ( IѬg'*�B�coeloc&t��{�%I�!�� o�!x3�[&A�es [46� !V)�R�.��Tu��crza.wtb�i**�!�|�A82d)� ����w=ha}�֠!Y�.�8 i�!�� WlX��y� ositu 6H�>ev@ GFP.x[d>\&�@"�!�D� J1&P | !}7�PA�GAL4-UASK� �L  [4�t�!Q��x+of 25 R�e*��>l� fA�����14W)�A�]E- E�[�*��f\b ,�ed���:Ioru�l}�l^}&cM��Mx 2~A9 pse>a�I)�`B�;� &m : ��?f)ke�>c؁Y!M `&�f�"]#� )!J�=F10�I�%{<� �cI� p*�?YM th�u� ��)&�A%N�$Cl2)FeLU�"�h6�aU[8l� y"_ �h8�� �N3 6��".I !U!$9yq�_ia6� %D���@C����JL��E�. ,>� )FA6a/G $t�A�� broa+�x*�@:L WB�SJ+� � �&�P � �Vlt�h�� adapE& ^��*�s��k��a�QD,i �$ valu�S:a&6a!:���� "�i�#;d�19y<B # &f ,A perhaps�$surP�# it� pne����[\ir���sub� ME rf�F�&K`�(daugh�IL6*�d��~r�,ow�in �g~ expaq��<er�-�bA>���acquisi/m2�^7uj�!�S$�|i�K�a)M_6��h� �.FRF/2�e�� c+�al%%�E82 \:?bqt���F���.Ec!�2�� e[E�㥬:{ ,cA Q' ���ys�+E"�. �'��"�e�8�D��2+9�Dd�1&/BU@ �+�`l)e� V�f�*19� ��5&�F9��c�W&�� n!��a����o���2%�a���~ym��2�-in��) %�K]m2�&QRb��/R[5�yJ?Ŧc��Ji�{��6�L *�< i0�+&�2I�a6!�F� �Tl<�d�7A�aU�� � i U�d B�A�q�I,(�%|Xar�t)� c����.�kly�d%-E^ferAj� �JmI!�$c2|X6ly5�2y%Mb�k*3+]�e�I<�C�N�5�[5�iB�Y ���BAuO��eb[d&��61B.�"?7�%���cu#c$ hydrocarb�O7f7.�& i�&�� {e�� �Ih���C�-!�E~X"�6�t �-�� 9��$�t�e�G �._���E�*�p"�$, 11-cN�$��"� via�Z�C%\_%)EE��$5<[3jl�$)a-=aT�"� |�%e�5%�c�k���ZpNr!���>�)�� �Jz)Myl!� O*9#6%����! � �%C��"hu!s*� g� ��~- *=&,.8G,b�3�q�)i4.�@-�!9OT,:~2)��{ ��A�aJ2�,"��>�� r�U��6�I%I!+�.� . POU-dom/%Y*A;M!|d- cj-$�J�E6j�6�-U�e���� neur!�5jA�NloA !"�l�h�h Fel| 1�dAMo���C2.� m�as-��ANT�3c` mb��or� �(�a %�6lq_R!�9!�.�m2y !aF���N�O�on�fV��i�* G�!.��!"]9%+C6O"MEo��^�!ayeen.�" &%�"����( tMq�n O� �� -�b:W ��r���c��q�s6a!�o/��j�" Q.o .GD? $�ew� �:��ng!ex e�l!�}�{lo";?P' �.��.��ngo2�ZZ� &sF&/ Eleg�#e�/b�ys&���B�h�6de�p� a� &���Gn�lea�aY-�&7 ���H&�0R]B��n[5W�u�0a>l�� r`)�.= ">�%�a��b@lcohoN aliph�"o��ALA5��� R'14 r35�r4~S ]$/�NpT2�!>���two1ZKI9&( k67"�/�[�-"��*!�ItS�ɶS��^ q��Yo�k��p�A�!�Ay1��N��EQ K.�[.�&S&�l ��c�5V%�M � }f�rig�G\P����.�.�!&�QK��"� ��Y�[FO ���el&�&�^f�l.H!�6y &�lu$=F(#%�m� enh!�d��olC"o� ��n�� *�`GeneCu"5T�B �oryM�f�)���� N�z2�6Q,meX.k5i?�.2�-�AJA��q�i 1� �� ZI �Iu5�a�e�L�5�+�� 1O� capa�SN<ay6%x !Qi2G 65� a w�b&� ��2M���s . Is� ��&� 2�(C�C( B ).�CqE��1&�9w.xn"�Vculf*_!u�rnm��moDV-agar-� uЊ25°CL��h75%m�ve�%id�, 12-hm�-dark���4ۣQD , un -o )a� )cLo[+D2�A�3&�aq@ �%b?*[QB�E� S�` e 8� ��{6�!Z� ���"�b��q�)g �i�poo�����s�y')�m�6{h�(�I�T�E(.�X�old6���Xk���x�a :}(y���E�cLz� �  �,52 !26kO�1YB' H�aens�@�� �B N>= plac&H #�Sa��CDw�y �Yp aZ&�(���t��ExM�!wJ�1��E���[)�M�i�JA��* A25A�Ix ?%0�Iv"� ���������D*%A�&�o"F&�W#@%je�A��l��:*De 6(�~ ��  �F>�I' �E�y%vq�U�omBSbe�Ascr cwo lay4 �qr8BEF�re&j�:�I��SI�= ��y  � � :��a�� whit~s {r�\�/em blin"�@skX2nf"I�)Qe�e�ors��bd� * !�"plof Wo"S, oq ��.o�,.� � T�&� �� (�G,�Gz�U , Os�9,��!� housekeepOA~���� r� ( Gapdh1E��n-5�C�/ Gal4 LacZ!�n&�9$!�T]"S[8E06��B%lIbver)zIR)7�ay3 'pr�(a� (tix QArray2.? (r���S>�s.Y�at No��Car�4a �� e Un�ty�(��!��!Ea�ѱ�KŤz4yhmzBΡ� t� ar���s�;%-�4j��h L!���e�,vS�orF&�� R, n0�Z���!�fro��� 1:003 pm�NA6A< �5eF25-pe?59A�z`� o�<ro�OwO"�q� �Mel�Amp a�kin�Amb�� BiosӛauI�l( Fos=C!�, C�Land 5 µ��66N)��l�o%�soor �o.��dy� Amersh6�Pharmaci! Piscatawa�INJ;"� . # PA23Z��25 4L q �q{�9QIAquick��P SKk�Qia<�, �, V�!���x bJ�s!z% �IE��& �iB*Gpsw* R@�*6"me"e�3 H�r�/�t�o��m 60 h��^!�ba�� t 42? � . �-2s�F��APix��0B r��raw�,g�2V  1Pro.ׁ�0e.2� log2 �"Rfirst3�. )��bm.�� ( ANOVA�${ ,��!!g,i��N[��saTA���=� Aqdye× 1��+� ;z�s 7:5erandom@�s�{%tV:a� �ndYTf� �)AHn�� n&j�c4>�"u$M�AgWe l�|�/, ;= � xcc�?��: R �}9μ+dye+%+re.&+C /sex/"+ε5\μ��@F�&�DmE��#�Pε�errorY�1,.iEeE6 � :�e����A>(G��IQH(1�� NSnJQ(�](M6 %� v'�t�b ) ��a�%�A�>]b;YI��$~�bu�R{Is�.����Aei^��9W�$%M�i.Vb>u �+CT%a� ( MMZ �G���7i:�172��*/IN &9�xNretur��20A�Y{4lw�Ui�� C��^f&�6Pe��)�N "a65AiWata� .^iL . BaOKaph�E�f�N.B� �v Z5�g�:!���e�;y�����Hadjusting fluoresce�nt intensities based on the overall mean fluorescen62�Lacross arrays and between dyes . Comparisons of chemoreceptor gene expressiond threshold was established=�@wo standard devia:s from%�m!�lacZ �al5� y of"negative &control�@Bonferroni correc!gGificance��(as a criter!�!)statis)@2V.�!Av8of human trisom`indicate a remarkable rel �hipU,abn%�@ meiotic recombin+%�subsequA� nondisjun)�atE:r!7@!�4I or II . Spec% a varie��t�kof�)�6�re�i�inbu��%�6Am9� s 13 , 1568 , 212 �!-sex24[2] , [345678910O alte��-�ŧ!�� q����9*16 F216�' � �}y !ԭ�%DaJco6r simiA2�Xin model organisms suchA8Drosophila [11]�S . cereA�aA�%/��!Mmagni� �effec� IA�s�}surpri� . For��pl�*9majoriISca��m EVy%#pp��be at�V���*J9u,s)�a5oo clos= (oA away��,�*H[13e�)Uő�B�!�� -�ed)�ap�E$�xchanges%�!�u�mit �s�*a large��por!�, , if not a 58,!1>�4involve achias� homrous2%ZE� sub-optimZ��A�2m�P� conundrum)at�P, how c� berran�26�,# ��)occur��A;�xv��,E)tI(o( QNwheq vanc��!� agA�a!ic] � kdecades ��r!�s unques!�ab��� �#im!��risk fac��b �:�?I ans^is%�yet obvi!�Dse@ groupaXv�; ggesAL� eB$a two-step6� linkAVe etiA � �s [14E�6�i%�assuma>!�%'��M;�e� ]v!�e�d VMu��W4increa�5:�@co6m � e9 like!�"Doi3 � is!&!�a�A_ t le�m� �W follow: F��,%�$older womea�ـ-s-6y!� maps�str��- . 2�ic&u&{ shortEq�*w!a differX �S&_ f �R��h��v�e�� offspra . Se� , � 2�5�i�e{�lm} �reveal�B ES =exhibit�e 1Y� >���i�:L.� a�5e���st%F�!s:3M prox�!!�� x��\ well�R}y$s ) . OverE�� q�y� , a*� .�8 mpe�o addr�� Y� ,�ain!�A� A_.�%�ing-o�� � 2p��j^2C �5]�How��E��littl�����.�sI��. In par�i�> �9challe�bin obta9appropr�D y � ial ( i .�,!� phas$age� -M� !�;�� ��� -�� h�no� p��ach� visu'L>���j roC ��z` elim��!;problemE�psi�4, straightforw*.�!d��ir� ��^kAvit2; moni� >��� 9�?�/ure6�9synapton�$lex , SC )�to=C�.A�"�٩� yg�ZV nd"~ e du����A4E . OfE�icuc 1�c=��<m��� he MutL�u�|^,�� ] si!�.G sB�.O. D} ASn� mic�d1�+P a 1∶1�spond�u� r6$n pachyten�� rmat�/���� aa�diA$eA0staZcel�r0r��bA�ciY�� gene!��>sD(AZ � ew!�ee [16��Con�e�"�%�msurrog1��.�,it now seems2�ez>�“as5h� ns>MJ93. Fur�!�ha�clu&!�"yf.<in!* u hybridi{( FISH�� inv� �j}��xq�6pon A%vFP. Utiliza�K�,��.�R}�3�A�A [1n1�>p20]p�"�� ��ocu a�ecQA�2,E�1 J��o>x�Z� w� lyJ�u5�� an sa�C� e evalu��9tHYv�er%�1��*�aHas�whF ^Y)s&� �A:�re� ndee� a fea�l�ρ%%E!��t%�re� !summar�result��aA3il serwof 1035!��7�e�31.C2:�ZM�&��Iee al" cn* ���If� !�a�ar�J%�f�o��Fb�a�6� :!Sa useful>�!}{�a  �AuAo-Hf�T he !�� �2�B"��:c��,6�fq p�i�)rt" y��. � $��"p �e�, [21V[2_mouse!�24� 1N[2�%�"[ ��o%2lA�priA�SC���.�.*� C^ sB B� �5s"�a “� xed�U�v  ,� �E��Mearliere������126�T��iy�ŞAJ,a�� nter4ia*# B�QfAw"�K Qwnq� . ReIk�ve ima� of leptot", zyg A�9{��aDM�dcF` e 1A–1C��M(  )�%5� occa�J����s s�� per�Gal roughou[ atcle� e�t� uncl����r actun>�Aj.Qat9�B�SC.�Y b{ly ��in N ��a��:��lth���J�<ly��An� F.in�9�Eo-��t . Wa�de� yste� c� � quant3��of)�M6tUI�in� �� they �l�abundet�2� A. T2QW� Ÿ偡  a"F%tcourperK�N31B�( Q�S1+graphUr}o� u�?!o�man ~1eF}�Hap �w�!a�d0as 69 . 3±142xi eEƥ�der%�� withATnd among��� F�F2��p�)E�����2tx-f�!�c��"!lowest�" high %�%T .�,lyE�a nt� �^31"� (( F = 1!5,0; p<0 . 000�����-m!� � rang� �#wA�52�!( ( SF 009 )� a�88%�( EC 1e��is�!1a�>�e� �%�~r� a�Y sawa��q12�%RM�!���E bl%f2� M8noV�a�� 6(*@��in�� EC 4�69 , 7�9 98;m�!�� N orkr"M .�� a0��iLwe�3����0$r��cfmWin whi�I�!� !t ore &� se7�5%Tł(�umA z^4!�� ��� situ)� w�"yieldb� >tai /an  I�kis�ess�AiV%l� �a -tE�]���,-� �numer � lapp�-� ��. Nthe��&�Apa&� pe}t����23R17a^17a�% )A���i;��1C���jof%�%]1I9Dva�a� ( 132/176�#7�%s�&�#%�E'A[��bival�$.in�� Cwe&� a � le+ A-!/- G�  9 ;� he%"�lac}? �,oA�p 3L�/a�i(�'ciE�� n�� 6FY�2��%�d�'���2:%�.9m�baa�� orph�$ exacA! one-half �d� >)�r�"BF&��L.21a�22� !��a�'� beA�_lyE�-��edIS*"'+ Y�6�asa�U6� Z.�knz to :c clinzly��ev�.� ��u� .=.a^Udr�%.�� Z~!8EE2��Tigh fr0(c'a��S�pontane�Habo�6�d�*%�;-6*�wEdedҁ1� “c"J*aV�a=)�E-�. .�. �18�^ CumuJ)vqz�!si6h"ac�ru�3 50%!��2�cognized�[27� z ����+.�sli��E�"�$A�y pop�on6�aMEC.��9�L#99%�&�� 7�}�sel�M y Q!� stea^� a��� ecuT+?col I�'tim*͆V��uc�%���),iB w pooledF� m"� %�)h �%�9slly� e�an/S� rj7��9 v�� EH2'( o���.���"*� .�,�-piz he�1 �2t � b6� 2�h� ;>mPpr. Z�mfsa� '�(s2�to �"�3�?og *&w�it� ms � ��0e�)Pg���-�BB��4 wholZ(z�K*o� 6�)+e�����*&� 6�|' demoA Ea.�-b.�xon2�� P�� ���!PY�0���tG)r2�a�t��&,"�3c%�6�l��ato!�clu�,�*w��2]"��&G%��&a!� �9�ERA� .�In-(^ 5�n��  Ms�i a,� ood agree; �"�"�Z� ,co��M�2� w �߭O,rr�, to a�o.5en� 3465 cM;s 2i� �B,�n�a�Q]U*�Lly 4300–4600 cm [2�3"*[3�3�[3�34]���is!�t –"g� �'e�%ZY3wxyIK“missY6�2&a6�m� ~aso��iskcrepancyq�.� we�'6k!�"D%f!�po51expla-�whyE�-5Ah m� unde�%�dE16al� Y/&�. �%3$&be.���!�0"�a sub-s  -�A�unFA�&y��I���� v_����m��ex��� e�eII \ apa�deA+Z��si��"�s typ� }4a*=(,���.�(��� hown� t!��an un�>=� *&N]>&>��tU#)��again�.�bQQ4y5�5b.���prena�w)f �:atresiaA�% �to>}%�lowMi�Yjs�,� ��,=w surv� ovg edi�}Ot6 >X�� �6 %�doeɚ%��%2� 8��� "=p>$}�k1�J�/�U�m�ass�8of:R�굇in�!Ս�[35� Thir��di�l� ref� exB2�f� A�n-�*�" pathw��~d� non-vfe�#J.%��*��i)�C6describ�multia�o"K/.o([3C037 � }A �!j mamm��ll [38!#y��a�y�to playZ� r� a C �oa�CytB�3 [39H/2��[4ɸ41]�E/.%�usR mu5 ��i�(;�4partner!1� �)Xonl���( 1��r���s�ureA"ab"�4!�.�-���� hileM/no �-drivend7 s al�cer�Kly�Ui�s.�N ya@>5��b� �!��e���Ť�<2N.�b&�-:��6��q��:�� %�a� exp�!a[.+arar�"�(9f���"3 a�� iM�re als�b�I�� � ���r|Nox6�/ ""�A� � in� A�ten�&��)�&kgYV 8 E�in+ s�  a k8r&(windoww!� Y ��f�3, P� s%��be .�<syn�nouR5\�. ��illEA&�(|5��%� XeD� e($_m ٢B��&�3-�!�EX&,kany gej��� �=h�2 mb >fi.Jfav*0�lA.F, �0!qes�%�f��{ I*E�>:{9���p# fL� 2R$!.)�l�;B�6i!Is� 6(%?� a l�qui�*�0��I\%�]z*EM��%�.p:�ea>N�;J��m�sk.!a�r�lZ�9sex&�(A�e�!�Regard�!O%a� ctnes W,�;"� �VT � $@Z�!�+s)O%YT<���&-�Y��*� ���+em*�=m7I=v�4we judic%3(terpre�7 �oq@)V:�>]�C is� summ4�O-�)�!E�WA�j+e*�)&��B�;�+!�.�;*a  98%���:�4.�*�+�_s�=!M ��com>��4i�%�6�� ,�3epA=cUu!a�Y>aleA�[�|do��tak@i2�y �J!�-�a� achV !�merit��w bK"�B'M�>��,h?g:�,5��2*0-��)�ta� , F%��n�/ capt�.�62Q4�I�a�:Yit2]  U appa�4Rj.e?F�'�0!s��Hro?I��t�J . De�Aer2 *�+�]1�� mGn�3 �5/�S2o$񧡯or!7o��cx(nc& Et[a�common� )�+es:�=' F� "]��Q�,"�23 @� random�:)E2�ony %�Mc-���m2 I�'ir�&l6k@� ai�$2�19uA6IaQe�"n!�to q 3-�2*oc2.�G ��#57��10�C1=rdM%P�/e%�" �� �Zat U81 . 4% ( 57/404 �|� "��y(� A<%S&@E5Uo���>�17*�>!�22x�y�fA�ge&�: :�9.p2�!�>.�$"�$0%=416!� highE�e^xŧly 5–6>3s- ��B. W� w1 d��&a(l)��/V79*2��X.�,  5��.���q��d�6e��m�N#Jh; tl mC*val�.s @�@reoubted�,�E'6i .:. 5/2�� �str�'�D.$>��fB� &s�N��� �A�S6�>��K�+L<pi"�79�+6�yvha"'H�.Q wo%�a�i�$EYw.j� miA�18�6^P�dre�H��. "F;^eac"N% fv .yE��Tzcii�spr1]al!�!&:;=th|G plac��2�Epo�v�4E �"� "�+��.�� �WZ�>�/42b4"$lB4w�una�Y�62 }mpe@� �#�I� "],!�>�MLH-�erecapit�1c,2=\cgR� � �*]%�B(>�d����5�w�7�> Im�^v�erst&K�/�@ at&|A� �*'p*�72"":�0i� ell;�1�,\�!64�zv�7& [44:!&5\aE�%-Q 86��Dw.� �� t�"� m9. A"�N �2�"��.avail�� b�y�2� . On"�/l., ar-J!�.�#terst~5ly �����0o�;d u�2 ,.)6GFp14GG � 7-� is f!�ng + �%�)gr;�ZYr*h9�a�2�J reg�!�enric�OA�6�*%�J� Q2�::F"�>�`%�<� I8�$ig"�.�.-�v�}-i i�+Q�7'�.e�n.$ a� � !�%~6�60� 9�..@/�B�of!�"6HkMu51<��_*� .��t"� �< albet;tu'N ouncK �  C�q5i� ��A���,F�i$ reinforce� 1�;� +9� I� �:!.�+����*I&"�Bg�`N�ց�1�EsB`Q:O!��-�K >� VAn sharpA��o� &&�&����.^z!>B�L#6]� at:�12?)f� & �*�Ple Oli�B�#5]!�e{."�#�Llue�C!�Nf2� I�()"��%qɧ�J1v� nd 5>"21��hFa�6G6+ F"K>a�!uA abov se t � 1�A� r�E�*c{�h>!"�A� .�Q��E�!E���puzzl�� \""�to�,M �ty*����G2" ight3", Tr �G� [��1zif.�"n1�pbe@c>B�&�,�~�pregneJYAs2� segrHV6]�Y���!A �a�0�al� .U%(��6���5>wa*!��4B�q/!�>rI�e�VB�ja�n�FL[a�QoO9�I�K9d13L21ل game0Cd.xi*!5/,�$�i��1 ��vag�EembryoKV�-.h�jmGOWN��!�M�Y�s �InE�� l$ �I6:�m 1�%!�"�eN�Q;�.)KXOisi�� �ne�6_-HS 7ab���.-2N 4�=[4!4�<48� ;%�� .�0"/.i, �!Y.]/�yA�2%W .�,�(fU�/W/ Take�g`Ak se6w%<,���-vor very�=�>ADQ>HMwI"�V)d:�Jn�2!u�W4AX[e� Q6��"�un偅��D_&�Q-� mek Rto��21P�� .� 9!��b�"6�-]�0$ޭH� ict�U4�e�FIOreەok>�?*T)�ժXO* Wbeg an`�O��(d�%�: �\z !�!{�U�  ?>� Ba� >�*%|e�*�(%< �iYJʼnuer�I!;�%��8)@v(:GTEWY=YrqE�`.Er2.?��Q&**��O&$! m� b6� .3Tŷac32n5 ��m adeqLE"[plF(Jt6� and/eJZe}~> E*D*SQ.� 2c.�$��(,"%�tA�"�Kd� n09A���$.(&�Y5t�H= "�*�&2 setAS2� �]nc A�1�MaȉZ��!� t;U�!�w#.Z�0ph��%%v *1 jurface�^�,au�].j�B�&�<*;RY[�d�����e� q �Z|y( ali�_0W*�&an.� .� �e;�?toeo | ���*N beca+2w�) !�~&� 1~(\%�aeted$api�� A��&%�"�,PHZ�. PS�*!(��]�v�uAJ!cap$ofI9ferMI�B!Q&� zerox�uts�Gm ����wzMvY%o�٭P �B6' E|a:C9Y�^�+.,i?T� ��)B�t left)7"�zc�,&�@"�!z�:� �&R ^�1�q+:�a\�� e�5!�%�V��ݥ,�� %Fw�e&�"��e�l=�2EZ*log�&�*^_!H�P�>o�`E��*/&s-�apply; a6�wJ�aw!�of��� Y � 6 �\ �"9*�r�@>$(�):x+'rVa�R.h �.A-i"0]Ea�2*1��� �Jp!d6�0�'e+n5a��:�cc �_.� extrem��or!���7gM'�hm '-nQD�#Q �9�����^b�-!�q�� �Fc%���iJ� '2:X� � M?�}iRW^�!�� a� ~ ywr&' ��)�,gre�e���0 E ^�:$ �immed�Tly"P2. C�HV"�!i�fu�M"Y &xUssu��)*a8!K%~o頭�!Y�&n"TN1�:� is�al�1!�E��gA-&Uei�C�I� B�&A6�_�!Y �A�")B�!�t�KbVP����JH�a�� llBU ��N@� plVl!�%)@I!� s�2��&W= ���he�3�4 �~.�'z_ sp,8&�Z�g"�:61 t �n�t&T en1�& � Vrg**r;'�!N|��\�as�a�%}�I�9YfI =�Tu�Eaq��-deri�&o CBAs�.{Z��P&9x)1�N�?��6obha:.�hfe��2�6�1>2p�4e��-R-%���Ax&��Z_:q!.�lih�9of��ficYS�*-Z�= �m*c� "�k�-�b&k$e�-�j��eu ��?� �r2�p�D(�"IC�Ι�6{%Ys"j�4&,�H2�*_*S�DK R.(>xA� {yx",.L yJ!'an��orBc`� :��fP(��"�\LI al )}�\not�$��2�>" � ghtw ecZ �Ma�D`?l(A~�*i ZyK���f�WiS�E��zJ�9u.��3�Ca�*�~ټ.�kolt-6[�ad�hv|b�A� abil�U9Nbv"Li^�E��FYa����2!9:V� �� � -{ repe) , l,$s a�e�b�ng!�a*b &,0�UE�A�.�>�� e�d bloc1<heteroe�c�-&�,^�$��i�}"t��� � A4-t�y ?� b-�\icBUM.jgPIB������1�X N��r� �:����sac%]�9B: cordE;�ExI uyA��fo>7'A�*N.�16 w�pI b)D�W�E ct�Ppr.�e6�no unu�Mlya�c2�hFS(e6 k��,- Ht�;3d ed)a��!@ f3\G5%#�:2��n. U)u^he]%;Hz w(�b&�&�Rj��j.79}b��-�C��2�Rnw4�5nAva�I�ӱ�^�.� "u�!�h�in>r"g A6.�;�a!/�!�>d��IrgF� ��.�Upre-d��v��j���G& 0cmMfTBd %�e.MbQ#�Qsus�j� !u�“&� p�s*�"aB�sy�h-m=E�<r�!kN"�3Q��Vac�Hk� t "'n�bA^.�>Z(:}&�i�7���mof1[/�#&�:2���v�V?"� ic%�tel�.ic�� .2 �yc y�mag��Ye9..�a�!�vZNM9��9\ i� T5t�r2ZA�2  sepa%ly���0�"P �Le�O�\X�x�7��ei�[ digm[�uk#|z6s . T! �rP�K P�QZ ���7h <�] ples�vAk Decl��$of Helsink�2Alla�ce�|�h�V�#UnX(s� Hof California-San Fsbisco , 6)Washingt�6nd.St� .� itOyal Rev�fBoard�>�*�8!��K��j�*{/%Atu Rarticipa����$%��BF�.d�iW�ű�Tb�c�,$&�ae�s'�,�14�v3 week�c>�Q=of.%M�yal Ce/�PSeaWl,.'�TI6�GWPHo9: al W�o's OpA s.Z:�9�"�)�T. T"�I,�{�L% iso���f�]�]24 ho�r͒sur�E*A� . Karyo J-�%_%�&�(�Kur��,%�ofjch�4a 4MX2 7�s;�1j"a&#27 O�su,aitoBa.�&\�wFA-�mcs.gYq , ti~mc��*usa�a�C�" -%50technique [50DGBrief�[��aZ�e3 conn� �nQe� . Ea�5v�aRbAm� eril�tch glasI�ve�∼2 mQ#a hypo-� a3buQ$( EN0mM TRIS , 500su��@17ci�Xaci? & EDTA4DDT� 1 C PMSF�� il�Tw1mincub,24oom�Der�� 45 minu^)B� tw>&��s .E0n�5in!75 µ% �� . Af�rmac�%�1� QE&�,neePB;0Naliquo�5 1 z"BI�]74Zss-��.ZM�tw3p-�!�N]&� T4a�Z�fl�a�m%�( )�2� )� � .6-�J��6�� hodaK�dr)� e2002e�w1w�/1zSe2je�>oPBm}A drop�F!DoGuard AWgg Reag� (A]Rad L.aW.66�2��� at 4A�$until viewa�8 9��{c .�&�n� $ Zeiss epi5�:mi��cop��j�*���co���bnoKAq�\e�2T�4if�p�is�gbe�4�:CJs}`!�� ��� n1�G�#�B���robus�GEy��**�OBq�9�B�59%� TelVy��13-�/t*}O�7!;CEP16Gr� ,47j8Om21>a@2>( ��#.*] 6�H�(m�8���;"6 n eso.$� $( 75% , 95�10qcN���L7�B4mamide/2× SSC973A�AM&���T��.���b$xESd�� �sa�zet�~f�1! �}NV�9N(F��z� >{���?6ab6 ���4-X, -b /1% NP-40%T>^ !v10 on�3 !�1 !&&X, &�(QJ� Vect,g(or>5�S*)z2?��C�We��A]��#*DOoYա#<"� j=�"�Q>�f�A!�*B C!� �R���7r}�� ��y+�"Ss�x|�mp�+ ns�!4=%j���f��sIq,:��%���A�yK8�N��>Ws(�y�l� h�^Jsco�Ano`XempXd;$1=�K){ rbitr� �imum1|2o. A�J2�E!�"7Hve"�h1��v�+w��5 i?ounted;a���)�yb�z�s QI-�P\+�spa*Am adja� �5�x(qt!Bu*m� domIX)�-?=�by��*�B3 ers;Al!�x!R&�(a#�Q omit���U�fB�u�#e\�i�� �)4 h�zmE&~ �6�E,�.OF�av�D x"e�r2(�%e�-#iedE&t&.�v�%� ��kEMa~!��O2��G� nd rm�-q  �-rm�� q50u�?�k�18"s�+�=E]"_(&�! ic ,��ss�* �*a d*� ��qZgE��& GSC�r��Oef,Gco��1AQ�L��rv� �g , j �obe Cij�k4πij/ ( πi π"�ba���*!� WGAr�;�)bzlkj�8f���o.S*�alA�G(�t,%"�"�Z��#vt% �so� x-E.A�H6�a��.Sj�/&4�I ) Let p)pij- ote����!A %tL.&+�2�(l��d!�j&D� ���BP75R�1E*aN��=M#�C�b;&;\c$n*|� ghI�J�.��X!N~�IcY�%� be <�@W��Je� ��Ah�tla�%)�X#�4a2ni�� apar] e5�BaL#Σpij/Σ�qi p.B�su�1�:�An�� ��a fixeY��% i&�c�i6Sgq�_T�&v|EYr,A�a���(��=�pN?9��s�*=.��pE�a�Lr/��T�&"� nfi��Fu siglY9.�Kf��9�!��.��A�%�,���par9?�� boot�M p [5��TAQu6�ʌre�!�8su;AEhawt7tDԆew� $8 Y ()#q�0��(���-�,5�! O y*!�6eU�&� 9E� i�$�& 10 ,u vA~�ۭ;E��[A�9�$�� i|M�.�Y��9�!s�0"�Pg. 9�T:8 .�oBlood-fee)0arthropods—{ mosquit�<, s!nfl��) tick+ mi� n se�?� G)oe��us publ�ealth%econo�'burde� W�a*N� bi΍"a j>injec!1 alivB(A\ � gen�qomp'��fac�+M1 . Ev-*� TLeishmania , PlasmodiuXarbovi�1�X�6 b!��4�pA� elicgRb/`e-expos�5� �� �(A�!X�ag�H B+h�U:r�!�q ��S+"s� isK38��-;�"�F���jexn%�'S b�symptomjd�u!x�!�S��"G?� p�_aI3��a�U =1%1b.;X�EeN�pron))�d �!�.�!~ [��ugh mil�TMzaG%- �d�y�ō����0U�+sE� ��en09.�!�to� &P �5��ɔ E�!;g�*n�%ed�C�v��rveill�V^e e�to ct sub- E*�awwho� l� �� !U--aa���rvoir) ��s�C��sm4term �� m�4Ś��6�A���>�iv�N�zBse�(26b�4-t������gA�d1�managm�2j!�i���Ap.b�cu�>��[ ell-�d�l����E��</g!55�2&� ��l@��ǁ�'!Iq-b site-�Z!Ҋa�WeEQ�C��m3"�@epidem"H 7��,�i�F�"���6},�PA$!=2Avq�����N� modu�us��!2^!�T �2T�%��m��is�� q� b� ����X��� vasodilVrr�o �ory!ha S ’sQ2�J[ *4 !?' u� 2den�West N�� viru���\�$I �k�Q7�ab�(eri���9@E��~co-ino��y )� .(�hI\����c Jt����qlw �l�[1}! ���h�ZbenefitD� a����� �%rt��m���stF(*$downreg��!��ia�>J"��(ks! uBG.(nvKinz��&5�o� ��| a�arn:H�MY� ploia�gp� !>[vW�_8�2��I@ as�m��.e �5 AC�q��L&n�>di�*B 3e�dFm3�if�.�� ��R� In.,e � }.�nM�empir�ne�g ��"eQʖq al roe��� �em&(y%t priog�&u �yUz+�a�eXsA�4G<�L*� )W%�13a��}AA�!�8-" �5a�q=x"���4�Gle� � e-�;©��RHQ^ load du%2 �MP)m}[�.;o!�� prop�G�.�uYU C(0h2w#0))�garne�ena���A .�!g��6� vaccines�>�%�in2n8qq4malar�F��" �P)�e.��!��>V-%��-Xn [19]A�l �B� �I� PMNvmsporozo��.��� jE�/1?p�� [+���+�= ) [9�B>},Nv�Nr� .R e%1;�<�[�� ��"D *�Cbehin�#�cEm� ^ �an open "Hg4H f ��r2 =j9rl ~&JpoA & %s��F towD/�$b�.kil�V� )�=12q�Gk� utrL��mU�%�F wN5&�u�ifefnu�1b cB >� enŀign5�5 j3%�^��.*[2� �}S8 �he�*e�#�>Mgmo�� |i8fa +6 � �!2 L&bI�&����%+, ���:~}wUextrinsi/�,���GoL�1A# nC�2L6:�o� �P{ q�ous; [ew [2>_��:# theor�[ٮ4�CencouraRg�World H-Organi�o( WHO �carry��61�r�aG)W0daC@campaign2��� �w �*Q�k �su C �P!Aa|�"A V��%3! 1970�~.�2F�����a)n�EA�v�+�ich�� tegy��%�ek �6{߉@A'*� 6s[26�2�P�hin�HgM�<ro�Iu! U�!�&�͜-~�]ibleAc��efE�@sp-�1�::r-1f#"Vt6�i&al�:�~���y}͛rx)om� p"B� s [3�~�[ou�� j| lacf � -4��=o���� ,� l9(l&�,�Va�z�� |�"�M� avoi:(=Ӊ�!:a �,�W���B=�iN �� -his��h� A�spa� �$o��2�!Y� L6_��7{��%�re_E��ea�2�P��1V�Z. H( Okm�Tal�V��&�&�p: ����JD�5�UF dynamM,�"� AtA�.��i�6� s?�! >��h2qtT.6 � g�a��� �@��  i ��$ >IE�Malnj23%Bƅ:,>�} :� ry ݭeao6� �k work� 1!�pla&lR2�%yEo|�^�+�A��j{B���!.8I�VV�. A���� �6�]5l;3.r�@5A)�!X��( ODEi!Ak�;D�0.Jde!."^;>GDG� trac��5[g��!t&�e�l ��.L=�I Fn���u�[%%�( naï7�=>.[^-2 2ilOU:/lyed ) ch ����de�~�!I/:�# llow> (Fig 1; Eqs ��9l: d V S!` ) d t = ϕ V - ( μ V + ! T V H H I *+ ′( D) )R( d9dE d�T�� σ Vn\(�5n� n�)V'- �V&(�pd H: l r P H V (�+M+�- T&�|)%< l)f+ θ H%={9E + τ%pR-6( 4%�6' �(�.� ���V�� 1!)�( #4!=� �rI.E� 4 - γ�3( 6 �I[.Iq>M2QA� (k�1K U:�+ 86@->�. (sol �S�:�Q�KinpFy�^&#���  �a���&{��r_� � ��,�#����ly! �>-��� �.�.�T�scarce � rG���& � .� �[VSnre L�,�!�&o , ϕVD_so6TallL�riZ!]�&� L μV c(:_`i2' tatu{I�gŹ ,i���!=-�8i�V���y�t� o��t�"yYn X���� HCUalkpe� O!�6, b!���P��r]O�%, Hg9wb H T =ej+A� I R�nD�vmak L��I�>vBenc.]��AJ"�"�B( V��aO"��i%HhB�( H�`~b")�9)!3.sTVHGTVH!A;*�*.A#;&�?Q(�Q�A0u � :a���)# t>9!G-�σA�U�in��e�[zEIPu/M��Gf��aDpono �-rib<7�E � (�'-�D2�}�,�};ipЅ�1�� c�2� )K%"ny��e*YaL>a.b%i��. E&�s?I�}�� Gmx!!�+�a\��ta�k to5y�S�.y.d��i{6(�$rox . 5-33 at 25�6��om421141�9�� 1%G�%V,;�S"I� 2�G�%a=;�n4r�� v@%=�����6>. !a!N��Ɓ;k ��(��� ][�� U �/�=����pd-rMt�\Nn%�&� EIP:�@>���*G''td$�Req�m�u �or iL%�R�"�sZI�s �.4�� at����H� 1'�� �j��t�er�At�3��1�X ODE:� 2 & 3;T 9 &�*�.ch6 ���1[F� �6 V 1 � I .� FM- E I P5 m ����� ")"� eT � G( ԡF �y�yJ\ 1�>� e−�Ave�:&D2� ��!�)�Q]:e�3�+v:g,*@A���UhM�&�. sta)�+a.u�!*� �s� e�T -/����\�� 0$y=�so2# need."l""�-$ t >�C&�1���z+be wr�6�E'�)bdVS�dVI�w��,J�q�}xJ�� �+of��aKn)2q�N. A��t �)6Ca�6����t @Z�> �tbyiR *bir�-death-�k���� >Wi�W�ovh*e � scal�� ���+.=���a�cD$n!Qilibr�-w<i��M�)6(Nh*@Al_tV%�f���eqN('tF$3%<Ş"#,,�h;�*�* o!k manuapt2�"D}�aa�i"�*)2n�chZ� se�i ��oncJ1= e|61� "�c�A. -;6��j; is hel��-���.�N�-�0/��o1�Pa p6o-("� )�n� "5 .f� � [ML(UVVE:�OB5.� PHZ ora� &�S� b=�− THV�T&z� "� 2� � s up�T�ct�4. ��!m*��;t���W2z �(i �b���)��"� �R��.&a.�>w}�FhhQ 5LQ� � θN }c�L�>�́FGp � P�H!� 5!4.I^a�q{o�1Jus�;/V:< um�85Z+��A���� O�( HQ+q.?�;�{ �e;���Eac0>+��waI# $Ts=-τ!-�,�S&3�&�Mm�! �2 ,dR�/AY� �G�;f�- �u�ME' , γ%L &-&�Z�ca�i; ���Y�i=����B�!$a�#B;ah�u� grow�7#+)99C=64]7�o�/l�6,  �d�}a+f?> 1s!`��Z�g5�!߁�knoh_>(&[��=�)&m�n�?*՚ՠt�,sI�mp" ?o$'�h&�seek &�1� a�j� be�rta"�8v:%�"B�F�>@![�� e�4aY�k���6�1'\.,+� A� i���&T`l��R���3dR�.oF��m51�.�qFI�EOi�.�5��f� � Z�R&W� c��>=m�%zq�X�d�a �ari� �=� �TntI��t*b)o2l*�(��U�1� .�'�'$>'a�If�1S�#� ^>q !�U_X>�)Ұr9K(��g5�b� s&DwOQek&|2:GreT8o�3�a�> �8�qS s&k3e����i�6, T�v !?1�us��, as�����(� "�KA�C��d) l��3a H#E��G%�io͛due5�A&�7,noS#&�E>Z aab- �ing�$� ēiP�'�&�)��+�oA�d��anZ$O3� !l:+.5a�#B8����a�out$%�MM�(�"tE�!�Qj&�A� ,� �=A.2m each��� tE si-. t�9C&� �8meaeo#�-��P3qu>WHY���$�u.p*f&�w*!���t�0��&!F�E �*�quickكmx�U ady � ��%M*#JA#!� ��xS �Bpa� A.,.aZ&I�C(�c�,�o !to)u4by solv�aPVHVVE�~a+!F� �Us: "^��� T�+ �  �0,� ��A I�B@+7GcU� GE ^ (81!"v�we~eO0�/3A��<�a!-�i9[ 8 & ��A�.?2Ra�\U�hfhifyh5.���bS\ �d-���.85�AcA����e��(���#r-&C�pB8 i�E�f""pe,Q���1-hz#in R Ver�0��A4 [�,��packag�S�����A�!}}� a�͍�� %!m!�)�l/��;�-!z root|4�/�BU6.Y) �gime:S$�Yv`Vr��edi�w� a� ���−ne� o%=�C2�l�>� -f[$.�*�!1.MIMsE�I/(��Aph�ix)&]&%4(�.( a=k#�e�|B"!{e"��CgH/� ��a&B]�!�eIJ�O'_�5W-�,break , mimi��,%*� ndok5s�E*@+gi�s. P E@al��vL�qur2�� |  T��G�pos�|,]an ��r Z%�cy8n �!�-A&<��A4&a��*_�er�e�!Ross-McDSXdm�e�Bj �P5�( : , 4$;m.�,�.�ryo� A�A&���7"�3b� 7 `;u��i"���� v���E�"� *q*ym nO:��^ �2� on R�S�=v��}�! ��e��"� .YS1>tᧉb��aNCM^� } ( S2.l.}j��� � ��V�%�5�"�=v key�>in�A*�t,y &eAM  A*����;�"o E�E�8v�?s f@ ( S32� Bl$mJ ] �.�E�"�4j, E�A �.rf)%[fK)w� 1 r�<"6ne:2_HV��s Id�#haգr��S� a�&�%�n�4Il�#.�aF �Y { l � A� D.Nnp/����|")Sp�<�N��46{9>�2P�}��E�!3&�3,��U8. *G5 �&� �#�*} <�sftM a�GB6�� O*� a�rs� 9&deae� �!��$"V !�&2�� <�&"��0� $� ���6� �j0��`T�x)�6}a��A94=��U#82���m�[&�!/"iZO66�2rde��%:�-0R "�a"m9�1 C6H<z%yY�&3")�G Fؖ %(��i=e6�(�Ze�2\ Qw .F7�%�� ! ��.�E #Y��7�A~�ACՠ�tH�a&� K�3.m�LN�#V{�QoA�FC(� 2Z�x )lc0N�S�t.��*nu 'd}���RIz � !5MZ�m����a"X�� 1z'%�� !M��q.; ��>e� �� �11�b�‘�ete’# �c��resour=J� �!{�(8Qd�i�8��S�k*})"f�� �Y��Ij# Togei� 2�5Y��:�a��A�eÉ�:�w6�2����:2)E�[# Q?���a�L"tu3!�<sۑI�fo!�2�+ Ks monoto�de��g ��E! 6E�82nH".�%~a*z /A�$M� �-$!O�:QR$ outw� !�`!q&! E��  E�%-�RAO9�T*���%ur���n�,��#�� � ! f�IEI1��A"� ��I�a�0)B\ �I&�)1A6 -O! �}]"�@ng�ka�. I�I�=,l� � �E��6U�� �Mt �%$N� � m~P!� �j ]F� sB�E'Q�bj6�B�% wma.NG ���= �g5�x� � .AbKN��Q�� B�supTq�pC-�5��V�E��M*&p nsl8!i[m.G�:�At2��)�dbV7 JX�i ��(�83� ��23ni6U�6kE�$e�I`� 9{*6 j�b�� �[>�B�H �uJ2�B�v 6��u)@I "7"e�.NW�/inRer"" �)#� k3c;�iTl�r&zuce�AS��a*nemm�y�J�&�&l6�e6��"�%Moz"TA�=�& %�c]/i��D—A �<2'—�%��!�y.>� ��1� 2q��qT��"e�� 4a & 4b>$!pFury ��"�"y1� x���6��> :�F�$du"H �9& �uV��n��%A�e &�1��&u�d�;��Y.n.*I�ѩ;�0�'��+!mop9jGLec�@y_%bt�"$ng=�-Mc-�ns*���:�!�r.�C:��^nh ;F�-mp w�cc}n�?[OF�at#P 1!� �Y�pW-�a��,�+�$�~. BecPQ.6�l QE0ItQA�a �l%(toŨor�h�Pl�BE7a�2� (� mor{� dhrvZq���5.$�ys��rv>��#*�adX7-�"L�"���q a�v237R��@�Bb�!=�w� c�c*�&�"~t`�e�Ab.�K�6 (\! at 2%��-di�t�ei#v��8{��� �� '!�.�.�#M�%�F*3Ko�r �.�$iA�>.�Z"�H�6e]�%XAc�ski�3-� U.��E�$F��E�Iv9�>�P&� V%� ��Vee�;# �yYto"�[a 90% �.�^��2 glob�����203�m WHOqf/L"�Dl��)�5� . B�!Ma(�nQ�,����&I�vrIB��7IUch�\�#go��bs steep�[f�dF_�X�I_�;.)�!voteworth �^�A� WT!� �1�.�T3^�"�:=�6� S"r)��lxagge��1�)4iY/�?a+�wzKonU��F5.;5&h1�"+ "�+t>Tay �. 6~�+��.Ue��^a�).+<w*?>����U�y��2�;:i�Y��tur7(!�9C,"$��Qe�)"4�iAD�jP11�r�XjX&H��SvP� iL�. " �yu��[595F˙M�&^�favourl!k %�2�.* k L+&FBHI�,�I�b2  =�faLo� biP 0rate is high �( b , σV and ϕV , respectively; S3 Appendix ) . Second , experimental evidence from a rodent model of leishmaniasis suggests that the immunological effects of pre-exposure to vector saliva wane over time [47]; we find that if immune pre-sensitisation wanes fast enough , vector control is not predicted to increase the abundance of infected hosts ( S3 Appendix , θH′ ) . Third , and counterintuitively , the vector control-driven increase in pre-sensitised infections is most pronounced when the probability of%cse E(ation upon !`act is low ( but non-zero6, PHVE�At high probability , the number of2p5,$is already Ain6 abseAWof: interven�s ,E�i)�ing.morta�through�rol decr!Gsh forc=�!moArhan itZ .$likelihood� pre-f�. Whej at%IF�avail190of susceptibl!�e5�58due to� can outwe!�!w �!J�. Fourth-� �e1~�Qed inf�onsh be minimiby>kz,recovery rat%[naïve , H�, whichu urn limit)�ATall parasite transmiss!�(2�, γHE�In addi%�I}�6A� rol-media�.�f�is �al when��e memory long last�, becau!Fm�y -wan8provides a sourIo.�hos�at helps tainZ�6\τ �Finallau$understand~!��ibu%^�toZpi)�key$estima�[imp�,A�aliva2N�UPon epidemiology: our �!predic�Padverse� sequZA�be avoidA�f<.aof63to�) fromv.�)ist�TH′�LTV A�( We demonsta dLt~f6alters.1�outcomesa,a mann �t could! pos�F or nega���@public health . I��0currently not<s�kto mak�s ciseB�-�� ��!� gaps!s@detailed knowledg�(ou����'.rU$ clin6��V��m�� gene�+��q�ecEj��illa�Vse � will!3crucial%�delineY�pot�deT5O�|ac! between�.�m�6~ �$for deploy� .-ba�Lvaccines-+� �D future . Our workm�cor͝importa�6conE�e!��play am�� �bi� ,Eى����9ol measuhsoI�Rcombined �!�e��$yield desiaSe dis�yVU�.�Le.* �q �t<t�&af��s 12 m!�on peopl��88antriewith (new ca��eŤyear . } amazon sB� agen Brazi!�lea�goY� forms var%�s@localized ( LCL )aj diff�/(cutaneous l2( D+ . On�ter�~Png issue rarely analy[is how=�e� onse53� phenotype%�virul�o. Aimfto study%�y��I)e system��.Y roteins w!�mpared��te��of am�4got��sol�%)BALB/c� nudpcA�(The athymicmay�em- atients)�~c,A�e(4ed T-cell hypo�v�Nanergic!�0´s antigens � si��/first3c)�� ific���9’=! driven by2k� %�. Ae�a�44�e�̉�expres�N spotat� wer��-�re)tto oxid�-/nitro��ve stF%�%�e3. Som!�r �d@��n=]Jfactor� ch as OPBRtryEox�er�s!� Spec!& isoiG��h��two �IZra� � �)sIHY6, vEӁ?T !�sNb��aWrq their�tp l%�alF�M�mI�O� o!j h�9, �� ��HSP70 wa!��] �6XWe belieA�urm�A�al� zt!.�gյJ��way� regu�ng �M6�J. Y���a�E���in Europ 0Africa , Asia�Ame �N�are re��|��H( WHO 2004; [1 , 2]e�A+4�YZegu�r�Gd viscN:�L at�end��a{9& 7�n�oI � tic/ �ic statu%�@�G,!�� t�� e�%b� of natu���edu� hlebotomi���fl�[3!Iݯ�b��i��4.!;cM� e ma,pathogen�a�euhuman .]6�[4��� *L .2s"pE��c!9�"+ )�,6l!8�pf]�,�)� � � ular�� v t���� , fr� t� ssoc}� ergP p�’�o�Q[4 , 51&mur!��l has by $commonly u��U  sa al a!�N=�9]s��!1��of=j�Un[3 , 6] A1m9�mo�� ���!_ same.��A28[7 , 8 , 9 , 10��of�eby.? majo�j- bmos�e.)0��dagowM�defini� of�i.t�s*x ge��C57BL/6)��� mount Th1Th2X��!BZ [1��1��In�s�: � dicha�y�.�!�re�ōi�ernt� n� ,)"�a�.LE�is.f5�!�13)�develop�ix5 h1-.� IeY:,�hduc�m IL-4�IFNγ [6!�1!�HowA��cQWc�Vm obs���! prog���! size!!les accor� 1I�Mst���H>�/:�sakin>�-I�ed)w%Nimi�9%Jos6��� 5>���l~ �� relev�  ibE�sf&� ^` [1�`Ay5 to.���FQ  1��o#�sthoM�Љmd . N"� ofu$4background hav�en shownOtoUJ1�c��a�: i�had] �c!�reducE flux�� %�onocyh �Nof=[1�iNo 1�����per�l�Ao d�in�&k  � I�� �=gge C�; �Leshm!�s!)�$better chayerE^a7 iculy IinM)ZE|!B=n.`�H��a8��x �նP� exam���od~ on"�describ!�.L %�ap�of>Mextern� embraY�x0 apoptotic fem ek}emp�� intraA ua�survivalinhib�\ macrophag7flammat;u�[1�7��ItYpi)x b�-Ies�ex-J:.�� s deqd� mY.���bdi)V%PS!'.~ 2Mlesa&��BJ[ �A���PS�0 � ly cx�w�" �me9/>� (*��pat>��) ^ur stic"� �x"�uT"L 6���A��nti�5Ycytok� induT[1řOI9� molecule��%��tcer*lyU dA!�R� . Si!* ��� noso� ds lack a� �al net}!h� crip�Ue�O�  s �itu�8a�[1� 20]� chans �r" &� Q���i�3l s �[2X���of� ;�!�i�effic7 methoo � Rfi!�. Ml ~E.��� @d abund��\-%�o!Smo.(w x� ory , )�biBC%ypromastZ!�hef| 20%2� 2t 256!�aV�.s &!�&r � rugs [2� 2� 2!�3%�-����=3&g  3 hAis�� dɈow\[�3�34� secre%3�3�3�u3�uDG!(��=� obaY robust4uU�)a5kމ!�nimals�A�vXY�� � � axLy� @�oE�U�[)���&> IvisoU������.k!�J��ɍ_�f%�� Mthem [3A39��&Bevalu1 !c&E.�&I�in�i� 6 ,X% �/) [� �-d��.�emz�=in seA��byj -dim�e�elect��k��}flucf la�ng�IGE�F]:�by ma�Xrometry ( MALDI-ToF/ToFBpproac�WsG��d�K� 1|f*� ��T lymphG �v near �! t [4e��sh�� light Bh"�bea"�a�!�^�ko��individualP . P>�h.� LV79h( MPRO/BR/72/M 1841-LV-79 )6Q u�at 24°CA�WaA R um2(10% FCS . P- re subD�y 7 d� 2x106/m� �!�U@8-week-old female� a�� v m��b� �W fic-!n��AKn#!�"APIso�QMe>Fac�#�@ �� Da*t4 , Uni�8of São Paulo ,!. M��in on�~h�%footpad�2 x 1061a� ry-pE B�!6.��%�n�#r( thickness n �d !�l[a�a �pe* All ��%s��� !��!$ian Colleg�A� Ex"A'�4 ( CONEP ) gui�5!�K�H ocolMM�v&� Ins] �� cCa�A0Use CommitteejEUAH[b�(v9 001/200a^ irt�!' s af�)�� [2$ sacrA��!te �� �rem�M��l2��a�n 2i!�&�as*Hby Wa #(ley et al .�(006 . Briefp 2�m _d homoa�d(in 5ml PBS � a ti�grid ( Th{  SG �" A%�% rifu�! t 50 x g�10w�\�[� �2p� tant�rT% �P t 14.O72O. S:Kt�$1qA#!�pelle kwa��three m��foyI|�EŅMv�) 3�%cub6-�rot 4at room temper�o libe end��ic�%�s ( 8 )U!MUf�&;e fu!.�*us�M n 2mL��ery((* l�bu�0 ( 155mM NH4C� 10mM KHCOm 01mM EDTA , pH 4�n��Tor 2mii� e<sg &`,reviously va  .�,!�r ]veO�a�, l_%aMa��� 5��exp�-�)�PAA( �2u"unqK,!)50>%�AT�%O!_s!�reaZ).V 9Soc96Oat: 300V%!4�-5until)�kV1068 81|7 S2=at�aximum�)!t50μA/ � cu����Ei2�15�?A�equilib �sol],( 75 mME�-I��� .�6 U� 30% glyce_(,A�SD�%c10��L DTT%��!o-� �alk�*��%iE)2�� L iodoace�<d�$!� f�fer} to 12%�-PAGEE�A/ele2!as]�at�A%�"360 �rem ��. Direc�|��$second "�* .�e}��sc#,��NRfi�inaA1�=40%�ano� d�!#ic aci4�%��.�s$Deep PurplE&ainerF�manufacVr� i$-�$>]6 � -�kep�)R/Mz�1% citax�A�r 2D W��n blota 120>�%=e �7cm pI�DE�RP-��.  ��b �lNg*�ϡd��Fa���:Ps mmen� 0 sI�!�6�m-� �d{22 abovE�>i/inV�.Y.��2bbeo=�=���tw��E�opy �Q٩OH"Typhoon 9410 Varia# Mode ImagA^�)�2�, _aW� !f��F:��,, 488nm exci� 4nd 520nm-BP 40�2fi�/;& , 532:;8~;�633F;67n;M�}|-q��Z�61 U3N�)qu�=�E=1�%�reU�100�r�'!_;$r�g�$to 550 PTM aHb�� �/��.Ics technique:�'0"0am "DeCyder D.bA�{F� �volume��]+k norm�-in�!" #%9<7PR! oa2tI�A�(m �n,%�%yn toged �iA��!p��3mpj 2YCy SA��-&1��!F�Way Anov9�Student��tes �y�/�!yte*d*in&a �A�S�,J4�3r!be0 M�cf p<0� 5t7 ;�4 }to~E�or�� a&�')��" >�. S1�/c�"aut[c�I�$Ettan Work*��F�,>� 96 w�.p � d�at -20/C shippAV. SM�%��at"? Pasteu�9MonteB&o��8�/�(fingerprintX� carr�3b�2-ge�*yps� rea/( S ) &-grade �ega� vern3. 7�. z��~ a6A�e)H60%�o8i 2A2% TF�con&�byl3uum drF Z esal` RC18 r�se ph�.m-!�um�$OMIX Pippe�8� ,Ʌn� � e�� Ec�Nn !@y4d� in�?%t&)erm-)��3 � matrix&gα-�o-4�cinna<1 in)6qu|2� 5>��=F)�A �a ���$A�mix� -�acquia�c 4800�OF/TOF�  ( ApplAEBio�2�Pf�+e�de�E��#"a� ed-�a��pM��)�^ Rm.�i<(-�!ed�"�+� MS/M�"�!�sq� h �9�.A��  �NCBInrQ&abAbsearcheZ� U m/zues �A�MASCOT�^g��A�I�&� S2�'isotopI!�toler� 90. 05 Da; frag%�R%2 %2!io&�1%-,� poV82� ;��n; ��rypW cleava38l�+.��r�i6(w!7Z�2� a� Tv�,a�=3euthan�splee�>poplite�) no�;�(paw-� harv� d� � ln.j%penAz&� l=ff2 cyt(���.��"l�  �,e-u!fase�ro�All� �mez#͛diM��_n MTHTo�/Hanks:�HBSnuM HEPES� 7 . n!�<5 UTDNA� I , 5% fe bov$serum�\ Sple�)��>Z�5��c�> �bc� �r�aG!Cc�! b.6.n3� �pa}or,*�%W Fc B� ( BD���!, San J�+, C^��in ¼��e��=��i~ . Antibod/ �d� �red�]'��6�2z "8p1 -�,L-�"4%� mald��(�6�EF�)o�!U�(: FITC-conj�Lti-CD11c , Alexa 647J"�PEJA?biotinJ6&APNs�JQ Gr1 ��,f� b ( R&D S�8@$MinneapoliN� PE . 5B� F4/8�f"r� gG ( e� 6aDiegoQb." also)�Rb�7ptavididLifeT& ologAk,!�mer M^(ar Prob|CarlsbadpCaeU%�2�to���"i�(yeloid��+�zAxF!�, 1CD3Um =�GN>ACE4CIQj�Mץ%� {FACSC$ur2Ne���u"�!� eas��$00�!f �e &�. Dat�Fa��&�J� ,FlowJo softw@( TreeSt Ashl�� , OR�10�h�&���*^�$���ac=(m� - W:�1 oa�ul��-!�GE6�` a semidry9$� :M^--���S% 5%�=k��+ 1% TT?20A�%h�8�2 prim�7�2( �-SHb9�uti-i:or TXNPx )2y�~}p:}�T �Ksteps �1xR�1 �A$>0��  -` ��:� dilu-�p)r���a �� 6��w w*�J��o,,-��>��5�h>�ECL P-" Blot�~Det-RuF8�f�mi�Y�%Ke�.�o X-Rayxm!��A�in TIFeE 6�I�,Jy~�a�resul;>a�2k GAPDH b*�@8exFH$R�%"� �13%#U�r paraA�s4%�d"78h�a�!��w�x�� ol _infilmDE'xylen8 rfin� μms)�m����'ohistoch��(1�d�Oiz� ���|5% BSA�A��3�~�!gen�@*>�YG�ġm1% sodf'az�� , 3% H2O2[~ a!:`�>�!�JEM�$2% ( w/v )�T%�t)�P-Q%�!� ��! r� y��>� o�v�l byhing@>j�y �nexs"%}DAB�*AKO`@lostrup , Denmark� +H�C8he�2xylL Ql� af �id24n; Perm( Sigm�. Intu,x+7*�#� !F� eN%gL�t vR�BVA S�N � ��Jio�a)�znY Vs�at650 FACs�!� 0�n ANOV�9�TukeyABmulti* m�-�A �  s exL"! !+dendriBellE""O)�-1a^-* =*< V�)a2lefy2)�d 7'u9VsJ��F)� .9.k)ee^). A�6wSFig . 0 �1�Kd {,ieX/M/�a� n$#E:!� larg 2̡vew6lad7dg=gt6Z. nito�e|"c�8 H �x �F� does9 seem? r����%v))l� establish�2�8a�#�hau ] ,"�$*"BaQMloo+�he�)��-�-l�Oer�:�:9I�mean �/i1 1x108%4 . 94�+8��0-7!B%;%�&./i@=�' ltho�O���a-Xy�ly sign�)N). T %�c"�5�&R�awild t*G4; �wv�/�8�po&� g0p3doDe!*2(0J)%M:e�"V%o�`6SH�I!) � . Us]:=91*�&�per-�� @ leuk)�:>0s� +CD4+t CD 8+'nX)s�� b+ ( Mac-�(��, &�((!<+ , polymorphonu'r 8( PMN� Axneu�!i|�11b+Gr1�DCd�c �* C���� ly B�v.�9U��Ac�;!^af==Y , P.!�.�1�5�R?�3n�D Ta�BjA�=D4PB$=�^�S�!Q�w.�of� ��vn�o�exa�E���2AMB���9F<dX;21%!� 8%i!9I}3ofy�u:)���#(U2%�:� �NJ�5TndF>�r}"B}!�&U�un5�5���v��)~m>_�S")i,m%Z�9�= c�;-d�)�� s aA22I� E4i V�Xrsus �83%M��ay}>EowMm� 1#���Jro:I`1y-kH�.��~#�wA"[ ��&!�n� 1 , bf�V>.� �ekC� r�!a .�d�9f�����A81 ( _50�+25%�} 2��IU�_l��KByG-�._ `2`55%%�FY�n!)�� Wig�~.��U� V)E�t&�e�!�is��<��, s�2a��$p:��� >��" m6�virtua�>6 8.O2| �8B CD8-}1-�e1��%67�3I���3!�+A�� u)3i 8>�DC�+A`�U!d:�(AI1!fI>suPFAs�C�"� &��W�+c�HU6�%�y>66�� a�> 7�,ED� A�e& �j& &= pE<>�!7�Xme:!�m�t�6�R()��!T4�6L9.�E:" `47]!6]-m�R�s ,)�"� �/sD ѡ��� %���ay�!/2 .$:�e��9>�(�&�.�a+[ <, bN�AnP%R less9�9�%N&� !�& 4%2Pq!Z4.T:�""���recrui�#v&<�Q}�F)8�N� aIeglO#�� ha6]!���lg�cF$!� $�f�jK@i^Dio�,"c !�a�!!=h9�hy�>/ l�)% PyxM�Ɋ^h!�6�. M�9�ͲI/S>5%.aI61͵s E%�cET%�Lbyi)� 3%��\re�2sve&�(���nt/��2� "�(� � ( 3A� ���Y.:,6�!�Bm�  <� 3��-63A�&� ��sxT.zly��@�g��_��l�&,5 33D)3�^ll�.�`5!�AA�*�w�!w�)4SW�)M�(%h�pI!%K.[)de�yH"�%��/��a*�6 exclA� artiV�� �o�M�4ty��+N*ccurac��`")7a�a�of �!z�R�.. Con�):a0@ -offDwo�c#.�1���, 9�D20"n 1944Min��9%pe��t  l&g6/B�+wo$7� cu �!�tA "{� exN&al=1d�DIAD%uD[e-�A)Hmatched 2100–2300���)1 4��)��xNon)�EMto�ut 17L�e�ixJ� tN<�*�+!.�2Dut�� � 8178 1M%w�,!�`�79E!8"NJ�<d�sefNwo:9sha��V 96U.�4x�!DprH��,�$a(1- ��`tt�a��N�[of��g�1nt �Os�mlin!�Ym!3/ �4Q*H U ţch�E&, (:6)�)�ٴ ( 22� c�.2dJdEE1s4Th3%�"()A�i<.��aCMSyi>�Ia�%aC&P)� �&Y-��:�4sA.�4A-�h=�4?NP*!Hv9 sK7JM�in�� lete\Bof.�( *E�ba@� ly 21 �;_��)�:3A�TjP) A�liU<�3� P/  ( orde rdF VLar 7ftIyO%O"$ #�W�V4is�8l5 poin pI , p�hu S!����T-�( ��!'i2y�K ".�%��/M�( N/BBg�:[ ( giA�f!� Hi�VS�PitG k MW�"l]q��J�!�a��B� ��� �n w!�T many��},J^+ve/�#6�](�Mt�+x=TN ,a><n]L0V}]:,�#� ck��$-B# ase/�,sactiv( oligoB��)lo-�,5hm!�reE�F kn!wKce�jN6Tsud^Bq[4S42Lm,are) &� [34>(4>U�G" ofFY!�f�b.&^`�bB( q�U*� ;� I�mŊ*�2&� ����#I� .b=1(HSPs 70q8�"r�E6AE�F[b����)�to�ncha!jn�dnc��il�l.�CDA��`� �.14i�e(prolife�=ng2x[2�\"�52� alph�4 beta-tubu� %�mN�A��ma�F%an"�cLF�cytosketA��*�' also� �+�Qre�r�u �&mon� &iO�HbB�] .� antu}M0xMWe"vMDa�of�a, '!EHSP70!bz%pai:��" 2. lG.q!$!!�@6�"&}; \d "�.ic"���', �2^c:�] m �We�*.��N��J� ow� 1�r@.��)Z:veF�UZy�D)�a3�]*� m�:.�= e���cX �h2D-�#ico*�S.�s&���9%2w� zav �n&p7&�Ml�iT�nfir��2 6S .N)I#dar!s�6E:M��E���&4 2>�=� te ż�GaE��K!LeG�� bi� both1,� �Cof �8223968E��7�. �UE��am�0> �� `n�/�!5wo� %| 7a�b� f63 w�K�*su�d]�a Jx1&!} calcd E]f 2- 8*-L%\e �"�7BE< cateE�?@o! B}Is%[�!s39L.6#M4E0HA�A�efA�g'���� �`:�*:�'��-�U 3T , Y�',%0!_������� �1�7��%JY�p t�-!��.t�Z� n%7ɛ�Rd�#. BIXyɩhIy!։�p��}�Qn�*qy��� , �> )Qj iM#2�!Inm�'!�5(�_��"�-�� %� ��i;U[l2,f�vi�n!4��ie .�ofi�`)�no9�i*in1u�"��Tj,B�6�� )�F-�&��n �RU s . �� o;aG u^�j!1�h 0d�1�n$term co-exVn|kI�\�\MP *u7��DMn agg���:environ�!(!�� [).evaEom�6sm��$at guarant�Nh�"{]�%�E explU X adap�=�!� ~�3havr ud��AM*U�in�T ՗*�7|-�M�E��eto'tQ�]O "�d�3".��ob=rA�9���@���cel)�m)�#�b%%!Q|5�� *�� !�UMS&� &�Vu- ��_�ba=S�]�JL �*�k*�r�bxa�d"i`�&�#_ u9s[15 [`��A��rowI�dp !�r"�]A0 Q�)6�)nd9C�&\ .b9�Be�vp�*bimi��r"�(%E��Jk%`9> F:Us�f4��46S C�(�,S Q?A�rt��in����5organ��6�>�6Y ��Y %�mes*R E��/s@+a�$ tinc�v-��amilieu�0��A�'�~ц2)Y� "�%:W!>.!GG!&��,im{ $[oragTiy2Xg]�un���growtrSe�532�MdIRb��Y�A�2|b@t&-cA��%.�HIVA�q_� 5B&�# ljh s [4ZSaI�z� V�de�S.I�$G��2"�*Iph�m�+=�!%�z!�>�m�&m�IV�+ . Ofa�t]^a� 6�t5��$ ��=���$W&a��m� �.> ,��bab&�&� deaE��gN?R!8� 2�."%[4�5���0n�i�y�!.�_9/�b���-%6�>�� %<.*}_� )Fr9`�5A�granulE,=Ht\�"�y�AL �5&Qd�LV0{ �7k0/� !��3y�dE2�I�.!-'��I'��/�Z��":�U:} . A6zhal���  ��s&�/AV*�I2�m�b ��� �6*�� ��m h�� o&�N��n�vZ�N�t�no��!� plas�E4J�(9z&� cBb* alan�Aamino/<�`,p7�C*�)6/} GTP-bA�nga�� Rab1)Hq �M.C� d2V�.� he"�70 kD&}2�832A�a �er �!Yso(}2WEg&-&R E�� � &;*of2�.�.*+ P ytotoxicI[R>)Q��m�d�~bl�-de2fya��y�z[ e�&�|/!/e�A�H ly��a_���*h� uXly� +eukary�y!Spro,.��ZaYt"�ox>>�QeaQ��m� ubZt:gluta 8/ � �( G'?s�A [5�g2Rpa�~ipa�X�-FP�of �Uo�x��M���f� ?synT�f DNA� curs��k<�^V;�& donog:Hr> V�e��e>��r�b_Ac"�-�6�9�[5=g�R�) cat�@ p: re:I�M)� �%wre� F �%:+�D��6Anecess�>��!GY vs1�Re�4&$��6Ov�:�-ȁ�!` e� 2A�22$6df!� vaniA�ma"��`A � and/o��g6�in�g[4T5�)= >�T��J�n% �[43� in�54� .� [5�!���|1D .b(�Fa�]a��st�� �"q#�,"H.� >e�� er� �s enzym��;Fi���'1+�p>[hI�Q*8tJazdf6T �e�<r+wo&�c)��x�,a sB[[51 High� BEu"� -�5��A�7!�!�R�chagasi$.�un�  �)�ԁ g.24arseniteI'!\i�fta@9c� guya�[5.� s��>urM�5' �N�V6� &bjƅ�tW E�Ջ>zQxAfea�XwhAM]�jv� �a�r�.�� ,�c�[G< Ol:� (J))e�*d asV�b�is�% s&u��Saq6"�!As>��5�)H * �!�z� �J���m�ma'z&Pin��4]Oten+ �"�b�]r�_Ked �oE,�B!`.2.��1��>^�f wvivo [�"]!P�%Xd"�m�(e�) �./1RV[62��[�oց�a* �[6��N��e�d���*v"A��we^n(��a� ��c".lm�q�f4� � X���M<u� "/!M�/a�;,U$ ��:1� *�aBu�W�r$6� �6~ " W'HSP83��e N�ari�8�)r�  �i5� +wDʁ= lj]r�s�PG [6�$�#�c"*]u&Sstimuli�0K!ߌ/ damX.SG$s�|[ _&  t�� o�!�Jos gm�g, ϋs1g*aTiWi'na���a�den)h"����8 c *�w-nmbdv �*.LMs�{�U��e%Vnt%�&:T � �pri�Ya8 ��by suph �?�amnz)k$��w�;b�igg�)�� pbfkina*[6)r�*'M��'�F&uui )(�ed�Bl, o-*��5��by2�� ���d��%WD."���U�t��: en�F�~ mLy`m� $seL��y:confer ��WW�%}!���a"�ro� ir��[6� &Qi�W �� ��!� Q z�al �K@.�-�qn y��&�Q &� a�Zq��&"1�u�6>��6i @Mnd 83� L �@�=.(  n%I2q[2�tB$#HSP�en(B c�*2 A: � � ia�  q���� 5b!x�%�Yj� a.�o!�b l]Kl*� ����]�!�� is�I~I�{�cE!� i�&�," +�.}�5�e& MNO���GcaQ�A{�! 2��8���nd�$E�鵚C M)"�!E�s.Ik) ��ADbin��9&�F_�1Uin�3A��8��U-�13.���6%"PA5a.� �� 83 [��5 greec�-t=Z��of7�M9�eiAD7 �2hoA�-0 ?7��-^�j�-2m1!beEn2 .'sI��}�~advanF� *c ,a%y�(� �3�TYH`)?�^�!r.f Nm- �~ly ����Jese�aQ{&��s�v0C ~do!Al�����[6�b in� E� rec��̕ h�~A�A ���Mm�.�&�AU����1�#)01�d:�%f��2�� cyt�0BME�.�F ��s.܂C!or "�%w��K�E$�s�na:�0po� G ��%��+>u�&�)a+*iY)�9C�v��a]:�"� �~���a��6�F�� xyge`2"+%��6��"֕� � AM.F]AR2�-=<A �crB�"��"�d"�".,�j(d�G %r iNOS mRNA5ma��E(( Velasquez*}r|8� :"�5on d)6h"ROSa�zFS e���7���Q# �^fa�� �%v/���5w��u���F����$�&83��Lop#�+ ��D�Ÿ́yACu� As discus)by��s� �&b| �����&a�nd�L*5'`���S-..:�w�st�+ f"C !Os3�6�6�.�S�5@2�.S�6N<esAHem.B�09*w6� %�.1�B:.7<vQh)y.�.!�"�5��� -�!�bM1q' �% 2. .w�"�/*I ��q s�d�Q��:&5 �noi�& |9��p��qm�`e��A� .�ek "�+i�MZSA��8 Tg*dI[��(j�8�J!/���:� &�q�*EsѢA�cy*� �� � ĄTJ.&Pd �� &)x.�-i��!lT5=K��le�9K+���{E��V�p L�e)glycos�/Q� !:'u�i:W,M�.�BJ*���� �e-bPTM�oϟ4�B orZ !�M�I=ߙu����)�5W,o!26�1����� irKk��H � �)+:�3*�in0.>":�": )�nbepA��/&�-�bod���"u���Wr�M�\�15�[�%recog�dby["�04�e, tyros�j�")�v���ZD�� it!�ҕiq�US�A���� m*WE= !�Iz �sh�^� � 9O� � H7"RV�I�P�~&Π�&mpI�oU�Bfclo@.�A� Worhto�0&��� �A�tI�l�m)��}2��)a�_�AID�j��  InbDe}%� )$)�}�"��a�� v"�Fni��7munoglo�:a� d��"�"!=toI8jCpG.maJcYy2�. �h/o&��Mly mu �5it's����#an Wn=�s6��* malignan�T. H�* �h � cellH~ � . B�X%�kscree�2 scop�ow�"��Y� g�YlVde�n)�m��slowlP G1nt in SA> G2-M )�F!)A�-�� ��.>gor�#tiuwT?��nr%Z�!���edQnpAa�a�A�F;M�f�\IDA'tag �d�ZiĠ 1M��o�XG1�S-GJ�6o��W.�eW� GliG`of�i=[accele�Xs�a!hyper1Q �cl�lswitch� "R-��� ell-�l ted;��K~1x��1�!Q�!��%> �%y>dI5$-6�Z�Š�iL�n v{G chvN��(useful tool=engine&�gaq!FY2��by ite�veE���&&�E!�W�� L52��~�(yuI�M�YY�� b�y��applic�(":���}i�eh .�A�. �-"n��* se (%��i��2( Ig )WF%� aoA&��s!Jde���+Ca U []Bv'Ei�" UNG2aMSH2/6E�� %qX�i,`B�" �,via error-prj " 1�YEt:( SHM�+j  ( CS,)or �)<r���-�Ld��nc�:j�K"��,2�he chromj"tansa�Ac2�DN�[3�<"�}� / *�)era�>�E�6.-e�����[r�1� a��* �� [1H�)����u� =$[1%51�INl��id)W !�;�6ed��atҔ�A��-��Vim��>A-v��/uh*!Posr��a�2h�r� �%5��#�>�D~�2@ [17–1�#�+�+:G2u�?)>� tM .X[��'#$by CRM1-deKNa� ort [22�L`C�*t.$�FA��m�� �e��Tt��H�F�mwh�th k|,�!�Ʌ�8�EB[ theyI�� �.%I�b�Ga��Wty [2�M ta� dele��a^C-ter l reg!�Z�N�u��ex%*sK �NE`�!di�rsh%���!�e �c8YSR, �s �fit�J[��2y�bu��*���,�@-�m�!z�ki^sGI�?��͒M�jL e�%�!X�0 DT40 chickenm�%��grm, eleptom.w EgLMB�Xa ޙ�-v�=��esU�a*-�.��0s [28]; Polη��cop+ �r�$inE��E����@-�o�!� �IgλR�e^���.�[29]; ��r��s �Q[a�ed�Gde�i= p2�2V30]vRPC�lN� ccum~s."Ig&� A�! "o [3�/W)v�' w asOi��'& ~b!gx-EX�"� ��hys���UD�QV >6 ��.�oSs�/ ZW }eܙ��6 �6 �6  R?!{6�'1CDT/�Ge��n [��U��*oy5Y�5�-ui Ff )�961�ar��s$ ��� �o��d�x�6l*.�&� > ��0Jn6 �g)�]6A��/r:u&� ��S����,� 65 AI.U >' �)�.� �)�Je d�Kbe� ~k �^ D �: ��2 � 8sS� !�&� �bio�� kC1 .H ��"����>diF-&"�A8�huͨ" 0\ , Ramo�?����j� n��c��Ն�J7 N_�d�ꡟ��� mCherry �eh�q� -"= � �*lp.cor!/��{ &B��&IA#+�� ��{�^H]uMc���inA���"I*�o=ex!��5���"a�tI�u!.R�u)�t1@��&� ( HC�*�[3D3aix�5%l��� fŗq�s��ۉ�^t�a�Uix��m�H�,arRof 8 G 1A;�k Ma�/b6Mz��.��i.pverFY�O���ZperturV�d��@by�/ 4 hr���I� MG13Q/>�A��7iK�� 26S)�a�Q; ;�9H+, ( S1�JA�*a �littleh �,o9 ��Ac*�"�!�-*Jk�uq�-�s�:|&� �orI� LMB+ �rapidly@ � d�8 zy!n)&�K1B�QM�"��� �� J!�un��i ��;J�(�&5-f ��pYde���i�o�.Q!O&=$ M7.M@�auFI�I$e�97%�T�c%C 1D%CB���gd� [ :�-��,%��CKA��!�:���.�)L8�VI�Z݁� ( N/�KF�:�)�az��d%�CѲ�ch3a�ar����%��I�i�H �I� �A�1�)(2%G��M(&�r@ingui �by ranfWwZ Ft�l��S!.' . NoTu !�@ ��Rar�-� u��SFF�.�t&#/#ax"�9+�i�i�2A8l�e@'"+�e�u<t 2!�,�vv��p ={4x10-3;�/,8  5;e�2f�Ɇ!S2#��T!�,Ua*r�u�iZ� ��S7�6msJ*".:E*A8 slopS%!��Fcu��"�' �%��p#!(���. er )>�B��1E$&f 2�E �T�F��"crwe>fU�e��lO7�m!�(10!�� u��KJ+�x%2'KX($D#.�=r 4/,"" .� �s!:!�S�. R� w,i�#2<��1 . 56� 94 %�6<SE���!�A��j0V �!�6�M�B ))�.-�,��fk N� / .�:�F;.�9 &l B��p��[Q �1~=: Ser�Thr}��TThr14+#Tyr18�lToϱ&Jmight�5!� courKL��m��,f��;b�&AIhe=|�S��P}"8�!�p.Pv"�-B�[P���V!� $d down�N���.Ga12AM*P$��$&K0 [9�. (�) tum9+�9�9$ � C�=ye�Q�/od��� �2� G1/S%Ti"o ��pri6�*[ݫ�x| %.�,!���/ targe?Z�-0!N.z`8�1D:: %>Ka ".�Lp!�L!varZen�|ng �rgh� �[36–44�1*(%n t��- �ed�>�:fifth*�&� AIDH56A�O,>n$t�9"V=h�d��%��G&Y�[�7�:coG����D P te zinc �q��Lzs�;��?We) bVJ� �li%W"� !��!"�!aWT��o�"ŵ ����l!DAIDS39%�(!@��uaEL. "� v1k�*&,�M�mimete�u� ,LS3�,w�0c3 oixa��6i 70%)�of WT� *��8R�"�~H+�n%щT55���82Pas~ͯ>� �-.�[AOati�qs载MI,a1#U-��%���>�] much6�o%^.�$( 25–30%�1MCW �nw7�"�=�,�&%mA)1� �ao� ���� 7�H)e a�E�%i� *� Ala!8p&�.A�m�+!��!�dų"m�* adeng)}�FU< �N�'�!�*��G erti�J����I . ReJ��AIH&&I,��aT>rg)is!�j: - H56RU�)� �.��( S4A�/� F2ģF.��p!Cclh.g �!r-��,,Ap$�0jQ���SV�I.����\ask2 �-5=Xn�eHB8 F e3� )Z� assa/���vo�` �A��&P �&| �� 'p)��v�,.�toڙ� ���� .��"� &d5m(4�.�!!�A�!��!�&� a��1�I.LɁUi� n2z!ǩ�Y�G86�>�%����� Gex�!�vF!�.� t.U>q ����!apI<d �2d:�:n�*�'urpri��D[i� �Q�\>%2� R� IBQM��pXt���s݆�S.oCmi�%aa�-� ! Nl!��:( iBAS;)i֡�dv ,B� �,]�7M�u5� s 3C%�S5��AtyW025a B�Y']�N  �k)�EqYF�" ����bRE� . Rz��8 � <.�%!��A�!�AX$a��x6� ^���fng�F��z�e�*� &�!^�A���u�� �=.�!59AC��.n.�. Wr +go�C���p� %�P.\� h` ~�or S/&�/�-<.=9 ag��ri"#O&�"EMJ��� ch� a$ q{\ 8AJ:�>�"l�Td�orw +SM�|�/,s#.Rq.;7a� B��K��) �ono��( Kusabira O�� ��mKO�C8(Azami-G�1 ( mAG )��+&�2�%( S6A����es!k}&ORU:���$�-%��AG-!�* Zr IIi�or2�e!U2�:�N &�E�!!�I�qy{]F�q�disrup` �*�d& q�4�.�\}U2r wardz��e�G�rk��=Nef���ta��a���#a�ZA31@ �!�.�%t�2`�&@u���U)!�tr�h.�.kd4a0� nalog�qtag �NX#l U��,]6�6 .oSce.s"$2�n>��� �A�!�2�.(A���4B�*y=5!XsKXgշ2]%�(&� l �rr%)s}azY�Nonethe�F& �>a���A��!e4Kg"\!�Np2,�wrQD��& y�!�B�&�.+6��!<&>#� C 6��>�"gIto.2�"*�a�p = 0W�6S!4�Y�2͍&/a#��i�<@Nhoax- � "/ or�+� "�� ��_V7!.�un_"� �$= a �+2�#AW7��MU2�N:Z;� J� 62 �/g!�b>A�~�! /�!pea},} quicݒN3! 6!�=>e�6&� %y6�( 58��V5�"l�fug- explY�V5��m"� R6�l/*��b�9�.��:� -dA�g� �� 釁 � i��24�� 2'AUi.�>ѡB|L�,!$��2z� ��=F.k$��� ��=�^j.*�"���U�J.N�ddh J�D�(bX�2n%�J�R�)p���RZDy&:!�&�6� �">�&�+�!!W)��>at!��� jSW;�$6Tɮaax�"� %�ar �!�.�ť�3duC(�et.RG5�� he��ERnq.�i]@� le^[z.O.Gn^AI�Y�5s�=� a�%A��4�jsp�ryo�,* 6^��dAd* �}N�6L1� ���]�" BZ�|� �!.�i62��&P(%&�/.�O!bJIj4��!^FV.�p5�fU<"35. sIgM�&�j��;�9|��:f, 41�? . 00A�6\N+a�5>fJ�a�!�4�CY��4�:{W"�>fc"�7(r mock:�%d s 4F��S8��)� &��"����e %BKO� "� F�e�chЮy8 (2' ��"�V���Z 4(�Fio&���%o�@it6�d1�fwe"f!�68l=��=S%-��"R (��=�N2+)5W&�>��!R ly� r"t$f�s�7ko IgG1�2��%T��5�ta�h(�;��9xJ`��.(2(1�KFi�;GEjS93!�ew�)=S&(6d 3"79�/e�� ��� � �=;2�6�af9A�R!-�I�:B�" 6y��]w,t����{U�VH��i�L ampl\2��le�D {� 10![��BH:�"�9We���T( c)V �I/_:Z(E$��(9�5�P�'Y at GAFC!�Z}{ � 8���Al>e,; mpan�VK few"�= �ins�!Kc0�2,"8}:nB <0�HMtɫ1g!�.�Q�ng%GFP [4W�4x@"Ed%�B�CQ�<�a�G��nt �'u,�k 5i'Ey�����7[W>QB�al�tM �W9���W�$�fe�_s�0s>K wort� a��Gre!eer�M7t A!�T�]i�J*6��!�>:&( 8%��.�!�1� 6�My��.q�$o*��on�ebG�T%:�G��M�:>�@�̑�1 , ���qF)�. A.� 6����as.M��G*+6eIK� A�"�3%�qore���� 2��?!�H6cRAIDF193*�"wf��3t�%6& � ��!gD)(&����=)6RFkcyt��n[����I��Q& �I�i�6r ' z�B� IY6��Flz�bgb1'IVf �}3*�J�e4 �PIo��9I��b=6�B�6q"9(ly2O &�� �� C �*Fw��cf�} �/4f36��6DE!S�9is*�8:AWifr�A�so��B�B �J�2�.�ɏtA�3G^(� Q� &� .�J�R>�E�.+%u>+:'% &�A eRD%� !1W��~��646��.:1=��1B� �u�a� 2 *262�he %]��@kgh.�!��$�E� re!Fnd�l�"a 1* =�; �d"R*2Vse:H>N":��B�:JC�6 S3-�a@A�� -'"'It�>)-s�Q_>%��  � �1��*�N~f ��D�-.�.�J�6�>�f�6@��f��C>b �6Np"�ed�.E�bha">-E6� 9ir � a�!)&�U#A��6�ڑ�/<Toc��I |e��R�re�)  act/"�B&�J?J4"�h..�<m R[7 %Q*� B->N2� .w�a� ���Q ?�R&+8�6!# B6<]��E�.�� ih t vas!�"%+ Ak*� eqX��V�a�=�E�VsU0mutagenesis i�qn platforms designed to optimize evolution of antibodies and other targets . G1 phase nuclear AID accelerates SHM 9�CSR without compromising cell viability in TL, but is not well-to Xd(S-G2/M �s . The Gof Gbs�> .��may reflect the relative efficiencyNrepair HAID-initiated nicks�oompar)Tlater�of�( cycle , as�y0potential for X,to be convernto'4ly deleterious�lic �DSB�S {, ( Fig 7 ) .� deamina!�CTDgenerate U , which!v �ed by UNG2- or MSH2/6-dependent pathways 8K)( !�le-strAbreaks )�@critical intermed!Rs�A�!�a2ve!��B )5dcaMIJ ahdamagA�sponse !4activ!� checkpoin� prev!�A�MWprogress�[48] .�.�i! erefor{Y|sourceA�rep � �sA�nd ifA�se exceA�(he capacityE�)\%y�cq�e �$proliferat�i�resilalz5��e�6t-%(was especiaa I'!�|3HF193A-mCherry-CDT1 A�sducta!E }�� this!�struc��aal�"stricta�uc��to�,a(combin��!eff�Wo%3 �ag� � mut) q|-�s expoe�0AID from re-ea.b�uE�. . In�trast , ��GderANive6��� ��ha�xhibi�a neg�] impact on%���, includ� pNES�!l([26 , 47] ,��se�{edE< increased��A$eA_[25 , IA�!gnaturE�%humaniΔE5 do��nt�  [27a#Reduced�A]assoc��d9� pres��of)}a��inuh!z%�Q�AI6 -GEM:���6D06E�We���a� �HgIDCAUas�dI�toaTE��protein.,a�t� �no0auq=f+�� any st��6�Evlight!�i���E�11Agraded m��slowly!IG1��!Qor ��-2�Bilika��o>�fu� �!$eliA EraR7�iF�|b�_�i�t���o3!!w,%�=�j8aitself�h��%/lysine fse ubiquit�a[20a;A�differ-:'�be one��0temporal regu�on . Cz ���error-prI��%h� ot�&n enha!��of�*" ��i2� � also��,lain some ap: nt�ce��!�����trad5:D . An.high fr�G)f /?on� !bs�bGa TI+y�R>Y6H(( 11 . 1% )&@ to.6 ( 0o�/uX�raݕ ( 3 . 4%;� 5DE�a class��� �%�Ebe � � �1,of Rev1 [49]{ Polη [50��In addiLA� r�frequ� nat A !�r�( 6 . 8�1>=( 8�j.>17 . 91� ��26�is:� %�a� func%�} awF m�. Consisj ��i�>�� been show�(m�UVq�at gap= at60 G2m [52A^!�E �& dest� zes�nar�IŐoutside�{ [32]E9would��A�pr��)Mabund��atj�$Nonetheles�.g�� ar��� �����͎4CM�!� omew*paradox� resulL �b7 ���: � @ed cytoplasmic re!���[1i�enabl�6���i��tR�eA� ossir, treatm�xwith LMB�,@LMB+MG132 did cau�  s��lyI� rapi�� Am:Bi 14)etha2:� ( S7���6��AA�b" �ʉ�,feedback looQ�dm�U�levele_��l oQ e �an� � ar)orf�Ecas�low I�����"��lear elev�F�� next�01ٖ&B�6,P 4�Ffavor����a�acarrieda�beinZ�Rto>so��f Ser3�Da sit� "D *pA phosphory�a�is posɡ�a!iously�� down N��qm[34��Bz a_ %�� lmimetic��n$ AIDS3D��e`q�mod&gB�}s@5ʝ�ndvᝍC&d*a A'1�C)�3ePZ%Tis�� i �� �atI� PP2A!l key��A molecu�t� %&w� �2( ors-��� appear�>�0its catalytic�M� . Bot� q!2.x ��AIDH56&Y U�n*reZbea�@wild typ��2o�� Ramo%�2h6Xex  s endogen�a��hyper�te �� ,a$�� �AB� must"���,-intrinsA�0echanism dire�� {� 3� , ��lGsor� quaxcontrol W�iibu}� ��8. C1�|in" !=,�exampEabjbeŁIm!:� �e �i���U+ >Ya���4re?on@-in�:Qraiw,by Chaudhuri%� collaboraE� o� im�a9�Fdou!r-�� H56R E58QMas!�o�]ub#t� �;8m¹ in B�|aJrrya�P��53��Ce�lI at ���7ah l�)recoveryQ��-�D ��r<'i� ͥ��b�fo acid �itXs�Fw�id� ��H2 e��."��n� he�t!N �� data( lu� cupple�ary ac��n%K]4y�om1�nAu auth�-sOur wc)�q�Z�j���pro��u altern}e>  one=E<.�R�:�ItZ a�ppropr�A5revisi-� laim)� TM-&���necess!O� a��B�requires.�2e�� A�in�eri!t� ɊD s areAIj��m9rigor��quant��. Seve�groups��%�"� � � �!( ionizaera�!t, eto� de )� �&� localiz�A�![24 , 53�AbFN�5�� nt!�a�unFr%�7�6NinD� yv� )U� Vz�Pγ-H2AX��s�tob[41�5��6|�6��W���,en-x�;��}eyAA\[56�EMX n��!��5)$� ���Mn)x$adily adapa�to stud�$�� )�ext!KH they�5&Lps�ut��.a|q longl��I�A2]�8genes�up� w� 5A�caA� princi�h be u��.�aff!�y� 1� f a varie �:� )E�Tŀ�rep�. Howag!2 lex �6�*� thwa�at�aI e5i6 �V2HC�analoga�ad.�shmusefu� �]g�e� seek!$��N�5ex vivo�ite�ve � &� ��9�2g tagse�- )��A�!kH it� of enzyme��aza9or RNAA���= �9�(CRISPR/Cas9�I�+s!d}� $me enginee#nd!�r` �. All:� volv� prim� muruqtw� �ev�L�Un�Iv4Washington Ins%(al Animal C���,Use Committe�� pEGFP-N3a��!N� �I� -GFP"a gift�\Dr . Javier Di Noia ( De&�0f MicrobiologKd Immun ,:�ME eal ,. 8Quebec , Canada� W�� �����g ��flank)< ApaI% BsrGI��-si��> Fto%����I&� =,co1E, p $6��?�)ps p-mKO2i�CSI �p-mAG8a l�5vi�vector�TE#>�PAtsushi Miyawaki ( Br�5S�!eU,v\RIKEN , Hirosawa , Wako-�t, Saitama 351–0198 , Japan )��:!�� if -@I25��A�ers PQL3���’-ATATCAATTGAGATCCCAAATGGACAGCC-3’ A�42�24TCT1TACTTGT/ TCGTCCATG 8,ins"itw� EcoR)x XbaIYB���eb��laca�1��.�.�)��1!�:,�XE=44 �T!� AGGG �$CACACTGGCG>45>85G!NT!TG)S�B�)1�����6 � ��!� GCCT!�CCG6�6 !L5�a�� !� frag b-�i�3%�re>�of5�E�5�u�=)�GE>�6$FOR �!�!�%� GCCA GGA�TGT �e7REV7%�4+!�NCCZ�V9 amHI�NotZ �CM�orA a� ,!Gpe[#�I�"jI�:�`%N� � ��� �p d us!�XQuikChange II XL Site-D�MuR� Kit ( Agi�0 ).� set , p5�C�8�qCGA��9�HTamm"� �5�a?��a�GAGCTG�q=A-�)SH#-S3�=8�.C �x:��+�+� S3A9* 6�GCCCT�rATGAACC i�!-75+ GGTTC��G��!)CAT)bT 7; S3DfkA2k2jD.j.i!�Vi82���C C%��DT��� �8A.nAA��A��E<G����C� ��82�:q��fq2�6q��%�CqA:2LA�IA�C�G�cC2�3=��AT!@;�C!^){;0RRcC%HZcR^ce��c s�B��"jl�[tOib*��@� sIgM loss�$a�S80-L&] � iclec*re� � Jsecond-��? packaging, smid~293� � ���&"%� fer&� � \v� ( psPAX�#aj (envelope'MD2G )/4:2:1Eio � Lipoe@e LTX ( Life Tech� A v 4t # 15338100 )��as&@Dby manufacturer’S%$otocol . V� :Z �at 24hr�48 fk-��pas�`hrough 0 . 22 μm membran�$S�+Lflip; EMD Millipore;u( # SCGP0052 !Virus>�ws-fur� � c#�I�h+'8Burkitt lymphom"l� , Ramo�JA�cul!� &SLed RPMI 1640 ( Gibco�"2con�$ed 10% FBS�' mM L-glu-�, penic�n/�d myci�"1X non-&�!�]4,q1W,sodium pyruvU 10HEPES ../%�du%�2x105�s2�um�a28 μg/m�polybren�Follow"._ , UeE5M�3–4 dM-A) thes�!�C�5th�!*:@+�:enr�-xS ell!�typ�ly���A� !�\popYa%��L3q�l9�Ba�MB; LC L3a�e� 50 n%%�W ( Z-LeuHaldehyde; Sigma-Ald�@μMA�o*��� di baa�f� cytometry6vfixedEorme�uz�! 5% Tri�X-�3,�iA�aO DAPI ( a��)��yGby FACAaVi�!�-< coun!<�y� blue b!�)l:�*confi#/^�'T�-Glo Lu� sE%vi9As�#Promegy# �)inp&7%A2m1���a dens�a6 �A�!�sm�%whD%%� ( HCSo0Mask , Invitr--2-H!r=L. F%�K �E� wash%�* s~0��PBS �pun �a 96-22 μ�-m��2�^4Greiner Bio On�a.im�)� |}Thermof4 ArrayScan VTI�reade�I!�(3000–6000 ��achiI� �x��A�o�Pry�(m� signa�*�*, �-[.�" mock� eѡ��(cI�G?-}�kmk�# 5 SDp�mea!�d)�S��X�#E�Ai�P@-a in arbitr6un , facA�a�� � risons am9&�)s�'d�set�${Co2�BioAp�0o?�����9t.g2��]�bound>- $individual-?[ef�8byI�a7�elqr�0�,!S�:!�!d��&&asr *����ag`AH!�g.>.s)�E�s%"=�iap:�H eas gYtot9.t�P6��3i�by�a�Tq( �r����to2�I� ( N/�'!� calc��ed5;E�6�\!�.�L)f��] scop�$ AI >� most`b;yBiuA5en� -of-focus�(0or��to�)J u�M���*$2 ^��."1Uy!` %�*J=A�A�k2�m� �� Ş�7 �1teJ)��,E�c  subt�b/h! r��on@��N va��(,li��byJ.�1�v��NQof un� =A:�( S11URuE��$formula: N�5-=�H6)E -�/�.48X +20�&�&K/&�!A� venip+surrog� a� �SHM ( O!. 2� f-d��h-%�� 2-5*� ^ v� nd� � -h f( 1:500?ou=n�6 tech� ? IgM-A� �!I E?,scribed [46] �5�Rt/v� essu�'as su�;!a)�T"�0� , we)M��)of��-� post��A�A5Ma�3�modest YG*1�y� 3%7�AQ]�i�t%. ( de�!e��3�02%�T3AL3 1F�e.N1�0Bv�J"�$:Wb$ �!pre~ y�9[V �)MrEbisog0d �spleeI�C57BL/6�e%��P�*S8&/0.UTOMACs�Ebiotin,��nti-CD4!itibody$D Pharmige]C�5532269� stK,avidin magne�* bea@MiltenyiU�"9 30-048-10i�Pur21�! or 24 h!Q X-9 5( Lonz� � a):2�650�@ß-mercaptoethano��5H@IL-4 ( R&D System�4cat# 404-ML-01�a�1�Li� CD40 1@ioLegend �# 1028�in �μP(� volum�/a r�  bottom"n a �Yn)ferC>!U#"�'5(�!��).2��l�:�2� 2Y4–5i�:�ER IgG1|'ITC mo�0;A640660xTsurfa�E6�-��� . At� 7���+ rN�AF� +mq,L? �}��r:n6�Q���*��aliquo!�,&�/perP-�to6�s.�2A�� Pfuobu�8 .�. S� �H froze�thau )\��w�2eg~�#�"K%*1A[at 50°C�}n 5 mb t 95E�"�AK�-fide,�Turbo \#�mera.��ad� B��rearr� d VH� �;ډ%by nes!PPCC fir�-e?*, RVH�QL 08 `QTZ�zJOL48-�C��j [57]; f��1:30 dil)Mm� �IBon)y��B�.�"R CAGAICAT�. P"�5si 6of%pr�[�x2�gel&3 ctro2 '�&$p��s�8ed .�b�#a�.tabolismupl^)!� saccharid�s#>5 ar"/environ��arbonta�,>nut�Bo����(�al�%+es d�.\ ulo�/bio�C�$. H!we dem�#  broad;�T. ethoG4% ze how���( �zeZ�'��gd1rbohyd-a�v&{& ( CAZym(� �j{&-o!( -seq" anaerobic� wth scree�.e# pplyrA�p)�a\bacum Clo!N�hytof�nta�; s � biom*;6onec&' gluc4, mann xyl gala��  !�arabi/ s�0l2=�& �O vare� c ��diaux prioA9ze!.�re�;s0� S��d-� �)5v D);iAl1<� �>�by up-�4!�Yg3-of-�!|sport�$ �"�(o�zb2� _� g4�fty-sixwedc�u� btheir E�)� KB�!�S5�� mult+�, often�n�.e?e fam�+ �k\Fg�r%G,5 � �i�ar .Z!�i.�R�t�i�C!D{a;ny synergAS ��ng�7a sameY��_�*d4�W cussM!A�HlU/dv8;(our underst�<sf/(  A� m�R�`qx. P�_�Mnually�0duce 200 bill�&t��gno)I�e�[1N=<�6n�E�g/;)�b��n)��F���Fo� �c-(re�6 �� � by soil [�<ma�*[3]9�( F7�!!� glob6)'�astinal���4r�M�$i�Hi�� �fiber$ h�5ch�(fatty F3��3m[ te 6\85%!L caloq in rg��5��/�s [�0F,� only�Eelݠ%��.urAely"by�� s [5!��Ca vasa��<al�5sto���5�c�-�!Verp+�3o�@� ElucD?!���Ede��merA��Y4-]1��H�)=��to]� ��� !2!�]QJ oA�Chealth- *��.a�dis�F [6!'t]v� .pr�)Mos�I9�,!� wal4a macro�9$ar network!�phenolic�En2 n�:ree+�.!Y.* (]�aO hemimsALnd�@)0s��;i/�?s�!*d�'�e�� tiss6( T�S\� loadb6As�I3 � �a(i�K]�eadrils t @�by�Y<�2�� �AB"�inB [7�@ xyloh [8] dico�&Hor mono[9Q�o-E(Go� in gymnos^: s [1�CO=AA��&�j060 as storagF�7eedT�w simiA&�tarch� �"�(re cross-li�. �uroni�; id-b|>5e����`Qdhe� E4B0E�exten. M"{60��� !��� homo�a�H8$[12!X�G�r� wSmWtoUAe�kRhamn6X� RGI ) [13[!w@ �M�Cct�"hMK �a>IdM an �B��s��rxe59[1�� Beca�i�q!%� ompoV$ of such h�le!3>�, C-�adaF�G.�3yriadR�R ��!� ?of-w��fa�or �xLai�ficer-s# ATagiq> �3)1s�a� �!�<  mach�ٵ륆j�>6. A~�#GZ�- !Rc� a%��- arti��te�-�be0a&�L| a(�� gut ri�3�Ka3topAaVF� � form���ic��[fuC>.Z[1Ş[1MW�"ud�n{ [18aa5 b"s wa]171M-encoEgg�,��R&� 116 glycoeApola8in 44*�� ASIP*zgrp�{Peh�I\ane�%�B�!E���AJu .�| ed �mg�wha�mLi�h$� he�m2� InS M#�f4&� "1 m�*� �8r�gan�$%�� { ��a �za�J� r.of 56N�� cloI,>� an “�e��) rsus�&5”!.�� �$!��:ind�LZ�� s �Š �6�aNE~di2X !TV ��b+t�c!�to"�)k knowledg��!��Qb� . � 9 Ao �ro�, Et&�e2��)�Ds C . bN���:a"�;. � A�)�q �7� �65 2� *lw var�? yieldBdq��" 4hIt����lonA&oNNlidv*lE�:��Ipt��� an I��AGI��(���. G�a"fas�tHG(1A�%UWa� time� 70=*b rumen)��e��m�jI1ayS��d6� &J . Al$Rr�b|E�*� �S1F )%�"�5 1H�9�%�&n$ *1B%�N���a�ll!A �a� I+1�#, / ]s F–� &� k H–!�5� J�A�� L�Lim�T�th�E&�S"ZQ91-or�<�N���s β-�4�i �� �d 6- i�Sbon�/�. P( �2or�sy�Sa?���on�D�mix$#�/VJ?!of�/!%���S�){��.� �.�gar2k slow�-� �!@&;AX��FNs w (!�Me>G\r!�ed 75!Z)� ZIdoiQot{?�&: &c8. S�U"r4l�B!>{ es�VN��i�-�onB�5�.,�A92�W!fKe0,U .���-�!2�)�:6H)�05B WU&6�5"Csurpri5&b� 1m�Kbe��U �N|Y�>� )R�"EE �fif �$� �ATP��sa`Asi�a���A�%os-�X olig*� [21YEb�Ytra��S�NXO:;A)TN)e�t Q�Ud�Wy� [23]g *�m{*[�!�6.�d�- log--c�8Bo, 3B� �>\�Lclex"c"� !�n"X-of�W3 m�01rSp� ���/&� ��, �1�( RPKM )U*�Ba�� S( �4r� e� r2 = �)96B . 93&�du"0eN$�[�@9i� t�-`c��� �>��d8�dSb"1Lir fu��y�  de novoi� crip�4� embl $}  anno�'��det��'�$secbA< D:`!�#of � mapp!}�I sQW��I���was 2 .�Zs Xai"'. grea. J,.�[�p�a[9)�"� *)0e'[9^9�0!M_�39e2;b�Q� n�6�6� lu��m$DESeq [25]Y�I E U!U"F �J�E��X bQ v��E�Q�15 ��F% !40O'� )�R2Qawn%m�"hA��] a jof 92V2Con�%le���:CIYbyQU�lpc�A�\@���)�*b�%as 67V6, 6��JG#�Q, 4>�ly 14 Oylif&� !_2 CBM��Z]Waha�7�J87�me Ne�ion�_�eby K-me�" clus�"� -Z-ADprofi�4y sQLQ%^NT!S��. C K A��sixM�EI.>�*-�Rs:�,GH26 cphy107� � GH1124;, �QGH18 chi��379�J 800d�� E9m�!�" 3367�c[28] )48F*8 [29_. �s B–F� �0aX1�:�&OJH-�s B+��"=  dry.�9��/|2'F{Nwt�perce�e���#�)*m66hD�sA[9�AV52�E�gu&d\�UVailor���m�%��xwJ "R'6 *Eis��y6?��His-tagg�4 over��Bl�v/2� d*] ����d��!ayV�� as 4b�fm�R4^����;n��%‘�e�� pWt8"8P7i�M�:k"� smZ!irty-a���A�y � a�r �A^6�%���R��1.. S�"( y~�4�an6�cutA�"� ,W u"�(,��le��!�@Oe8A�C%Dy�e"<��Fas� e�GH1O/t�@� �k�GH1g!�PL��3 ��[��tog� 6�"J#R �@L , 1 3!^,� � $ GH9 ,���B'28 J f�,155?�2!��J�lFI , XN$��%n0 4 Unex�e�T r ^;2�, s.��bar� 1�'� aw"� 5Tee(acilit n�*�A�. N�B a�at �=�e� R? modu�(A�pUS�i�-��C�H163/���v~ �R . WhA��( ��iX�h" >��R�[3^hwe obser�'�mlap� 5�BMs�F+%�vic�$4F"Y&�E�& anA U� a1L 3 wC@"�T, !�E�[u%:a rdA>�.J�dV �ÅC�)eǥP�.E�1��!�m�. EEH�4�us�(� �!c"�ZQ' �%�71� aQ��aI32%noB@?i6�.6reY)(.� A1�T"0f*$An(in Yersinia)pi�?�X�\B�'e�& them)� leak!�E��dA� [�q2n�)�%@�/Gz,� )�$��+N�A^pu�B�+a�510�V!��e��?� �&f�� gkI���5�rU3�5�e 3%�A�.\,!V[Eg!w J!,aX$re���wa�'m it�J*�ly� �&-B�w�<l� �re Bo%em%h-�GH5)�yq`�?defo[�g. N� �3WqW,-d-�nb'9c6�!��o%|��V5BP ��!��auY/Ht�%'� �>����he���IJqO��HA�e�26��aI��� �m% 5Z ;Zr[!�m�){on' �+a��E:�� � ����E�ndA2A�ron �r(a1�SR3�'"��� cY0ak��U��iiw"R!a�� ����]T���w>L���c�V�ci "(�m�&F�mY?tl!�)"�BQ� "\ \wis�!"�=�� ��e�ond M!p)�AB(%�3�6�$ K.b 0%�! J�E 68�UaD52��s�W�0y�I�9Q�qa B .!��\sef[3 )w�un@,�k!�a^�> S5u��s6�9$tm�)� am$�% ��$�&�fF�m�2^h.-�5ni��]�h�- y Z.MbA;emsel�(.="�d�%�a�! %�e�^2 K)') ,3003Cphy3207AAN9j5��-E&Zf�A g ,719Y6l�R�A�:� �2��8> 2567Ew 3310e�er"�2: �3E�U�� pW���)�7ethyl@�2mo���"aW3*� _�u3���0�� N!��lE,�% ever��&[)�� �M"4  %{e�B�. G02�i��B�� !�� a|N�v� �^�>� 1[S1J� la�O,m�u u2��&7����: byj.yR>F"� O� =G c1.as ‘%� n sc/p’�k )�� �\�(t2�81�� �I-tu{u6o�4yd�`,1�. A5n �BabUF�ime-B2:mc&$�s!^"-io�qt�i��#��eC��%�A�a�1i�"[a�[D�E��bly-up�"D*v.�m1�Q+aI*�� .���/��or �8(=�[2�CA-" [*2'I�s &]")7mW1�)0strongGa1"!�f�79c��H � givRQ��#!!.� �/EU�sdP,N� 6��sx8�DhowAJ.���J�cYIa�u;> " m dict��!�6� !�&�K2*n&�""1��Ubf-�*�.edG��9I umerb0 &��/A�0PTS ) [35] [3�N2 *�z�edI� also) �yj�5��&a-A�2�;[3�.jb�q,R�"@YL�*S*JR��� (� ��i3r twenR(�'~`ABC9\�6�*EC.a>�)�B� �>{+AuptakeS*Sin�1*x>�"�F� P7<�tb��:�N2u-h!g{Q6�M�:@ a|tr&�"+dexo��"�2"`"Q*in6h"�9 &; hexoaq�M��"�,�wa� ROK-ki��� 032�!�a&� �6*223� �f��yc"� �� d8fz 2-�Y��[3�1l&�� ��vdu�ki&�)$.��B�dpen|* !��uP!,i�y9�/R#�c, D b��U| ( PPP�We2�)c"%J�UO�z��@� �ketJ2�q�^ �'L-o�sm���@acetobutylicum [3iP/}J"�/I�%�l��2�r�:A"Hz�k��m nich�=�=i�Eto evi!bre̓ et�"��4�<��� m�=m�@se<�+�n" i�[4�8!$aaulo�sumE�s*(� t� �0" o*>) ex:#;h =>[5w�K5�c&HC v��4�s>e[�=�i6stu g�>�TZY igh-!��1B+C>Sg!��%*lC�7& �0Z!��ps��( od�/+-� omic�=�>esb .f\=(��?:�is  ?2B=A�ah"Z�6a-Bq8i4?oQiA��2 i(���� Q%�m�)5� � .D&|E��". N;�$""� �-ump��b^l�`on~'µm | vacu�$i� ', d�59ni�at 65~Ka�w�2�X �5}PY y#6H='a/att�)incub�+m6�A10�Ms�i�v l!qv ��d N# ( RA�L��n"�r73YpK��+ŵA.l PH-101!o�r5 &�'[4�=Cuva�6Ja!GJDi�am+r�RN�I��id-logd|�G�Qp=3YJU�2Ly�?!a�QsAFin [45];2VHac3)2�Oa.Vk E��t3 ��ENSE�)��^ rifu�\o5 kg , 5�s�'A,UA-"�Rkomb>$Ribopure B�<a K�iM19kcT�  µg )T%��IJNT ( In"�^J0� pyC-chloro�8�@O�$�@precip� �QaG�sp�i�5 µlA�mM�`s-C+pHf�5A�ibosomal�deٌ�S10�ʱ�MICROB~ k%>��-givA�a�?���9��Pb2Z . 50brA��x!��M1E�Ss�K-�( NEB E6a4)E�f,%��]t 9%��wh0S�?�1D�e.�� {n �kBiol@zer 2S!�a`�2�_�(b�_ Sing��� �"c`P(madi-om1=!by Su��3* III�> K���i�9=�18080-05$&\?|Ing/A)fnWeD6�1180501A�Ai12!�5��om�a�p2�48190-0�%:��tw""��Q�5AZ9���C%a-$!hsy)(*�=/do�} 0(e�3J�11917\UuY �RµM dNTP�W2, dCTPG UT�DNo�"�L UX8pU��S�'Ph�RR�s7J Immo�sat��( SPR�7�VqY6z�� te-�Cd9 L%3j[��(!Trmoosti@6515-�-0L K A':�5iQ1lgTrJ�!c�d}_%�71ea�Nia���libraKż6�∼!�s��)h� Ill�6 Tru�P��$FC-121-200aW.#�5��IF�!�)���endBuaih!& hrz�D��,a��V3Mpose� ��Pi�1TSp'S�!Qage�dc=9�e�)HI� (���Xs M��)A� l*S w�%1=6 USER� ����M5505�0 7��1��,2%9��. �65!��EU�if�DA}JT9 �.:<9�. MP4;:0nog�) to 2A+µ� ,W+ }��Aep��at6�. L6��WaY�HiSeq2Gf"AE�JA�� �,�3�%yN��y0( NCBI NC_010A��AiBowtieD�N�DR��l�&e�$ligUw2ee�+5%�parame`fGeno$"�0!"� as �5 ( su�U�_ot�Un�e/&B626.'�2�  kb ) � RSEQtools�"R� , ex� �=�-G� �7di�. D&p�P&�u��, s S77_>3�6�A�by.34)k!�statis�threshoCf� ��$of >4-fold}��a 8a p-value<10−�+�d1s!�(�605 adjt2d%�"�P !� 3902 �Z%9MT by BonferL |��. N05��&�2o��TK:%\r!0!��. Pj$.i<�-G�i7�Fa)� by L�� -Ind"��CtDng��pET-22 m+U�m�XL�C-Ucal��V%��2!� �w�.ch �.NNNtag%�<� �4# 26���)9 �b�Dn(���iP ˏ% m�, ir ms��#rx^om9A��sUA��(�Forwar***eF���D56-y y�2Y �z � D!�"�� . Pl�r5� "KeW8to E . coli BL2^DE�/ ( No�0n 7023� row��ml TBto�S: 9c!����bY��i��1 IPTG #"�2<2n2%pel�� :w �$* :��ospn  pH �}�5M Na0� imidazo��15%�e*l, 1`pefablocj �o 763�2�ly��<P� 0Cole-Parmer V��t CV3!o��e�Vyso�/=�123w .q5gedtei�^u��50!�c=�J$Ni-NTA spi�Wlum�;� 3101�!�*���radford� ,"�&�<"� 3 mg�A~u�$>�vi*.ma(2% SDS-PAGE� �LNovex  Bis-J < Gel NP0342BOX )Y���.�N6,ag�6�w#5-d!�rosalic�pV ( DN� ssay ��96 \olr� l/1 ttom( MZ�ar De�s X60#FZ�wa�'e�!A�25%>�in 25E� otas<�>�7�L30 "� A��b�re�t��_�C�aE`B� A)z #�-�"�0'( nmo5�d�$x@�mg1in�2x�# ��@"oi�o lankA1+:�, --`�3U5 �r�Y�|#Yd�� curv�(�5P2�EEUby�air�A� Jd/96�4] B/'�v X��(A)aid�a2 b �.*!�1Qba��o&�(@C%�*!���U��Kh zx)�l,.\��"B�% ���a"$ > NS��S]�� �]$:&�&U��1`fzD6;)Ý(� a v`�?[ՊR�s.���a�1 n�7� 6a!6�%� �1�r�@!T5 ha��:A!QcRC!atN7kg La�A:�MOconu��͸s�naNZa&op�F)� �!�by BZ�H�t�;n�� �7t��:�<.��1974–2005Sa��Z,ss Sierra Le#�&e� chocerciaOZmi�>h2z14�Z>$ ��qHD˥nd�b�m�ao| �8gZzŝfilar m( LF ):t�*14_!��ZI]�b9 Y^ �\$drug admin�w)� ( MD@*�IonducA+-�12 co- ��200.�2�3w�4good geographi��p\�am��ot{c� a�VMid� a� essm( E �2���(p8K�5se��)LF �se�! e mf% val' �!�w��%)�%"L1��A\thick bl� filmu�nd] l�!ͨw!bas)� lř 20071� . Ov�1l:� fell .8 . 6% ( 95% CI:�3%��0D)!!� 3.&19' 47%�&Am of 8T�56p� ,/)==r53!�,�.AD"�mS�55D : BoӉ yamb\�Kenema%}Kono (:t1 , c2� m85/ 00!`�:�B�!us87w ha!�A�i�2�of"}(7Y%G9��>  �6� 1�1�= (ld 2� Bombali ,�AE , Kailahu�Kambi%!,oinadugu , P�` Loko� Tonkolili�(&�C� PujeR!UtB��%&as mai�h O�<�st��Qan:K≥� E . 58UQ�f80A|E��F)��0&6Q.�i!�#&V�: (�9yo!�eA�B�yVarith��vymf"j �Z9�F!5�59 mf5kyu1e64 –19�5 , "&!po~�v9'5��6@4%y4� �ofw . Fy4!M� �{!o62 y;:�ja40��3 ;�I08 !��M�&�~exa�|� 9!~2n��3 �|00 m!@�� �>��A�~��U�wI'!d����+<V0%a���/��,��QqsF�Y3]#? +%��.-�-R�� �N8%e�VR. Lymgic�H:�!�o6a3*.- �maj�eg��kJd9cAsNTk,��se�7 arge��� yU � �World H�c Org [$ WHO ��&dt�'+&r����v�m}1apy�Ami�M�% ( PCT�.�(@f,7f.��P_ �c��"�B l�mwZWuc5(,ria bancroft�| rugi�clay�� timor"!v �t!$b��sP�o����l� d� Aj�)d'gop5(( Afric��As��v Pacr, H� A�ec�r�.��%r�Dt�� ith alben��W�m�K n/di)6� amazo 9�%�.�is� B)a� �!�5P"� 3lnAY�F.� GPE� �w; expa � "7 �:��O peop��%M�a�c9��B,�m�:�  4�i]iinm�:310�g,�g . Du>esr�oS�Q��A1" � Chin�re�A5Chno ؖe�{��'S,W����/ � �0qO2� a?|8{'�a�� G7�8a�# of 7�u|�<&!�rns�-&�RepubgofM�Sud�1��p�+}+�sLF�h6�,}�aj vulu�+A� �q�b�.fF�|n�� S�Sium d�d� �6.m���@wq�Yy(e�m�s�GCo🭄1^@�} Vp  !�� U( APO '��mסn�y-d��E�/ a�y� (T�� �(dg2w 8�,-. 7>Arec9Kda�9QB�Y�_2&,~.-#g2�1?Hvu��g%l R�.*mN!�NR.'eC[�Ӂ�a1�manife1one /���.�K��*I��s�h,�h[^h , [1��1�UW�W6[a�c���arkV�Z�H ( OC#of�!98�HY5�Am:F�zi�!��(l larvic�ygM�helicop�!Jaircraf�]Dm breezM�m}�=]��0as Merck & CoE�c . *FAdo�oS���zaA�Ny198|N%�al�EN)Frecor�/Lb��by 1994q{bi��*E5!�sav -h�y*x dro�Uͤe�8� -�"x�6�o tes/�&on/day��1we.!D{� �.�k& by 90%�k�k�1996 Z�&�GE�st ��Xll��a5q�wA��iviַflZ9%L1� 1991'�ul�5.b Fi�:C��d}200�K8G+y�[hate aN�3�%��!���� 3*�+S֝ al IYh~G�6Zon�SIZcO+l"m���aW� ex-AG ��7͵2�. Sy�F� �26�� ( un�x���O) ��!+�2�A;n7u� eq;>����A�.&w2q$c�rza_MDA�ve��&�!4F� �� CDTI���� tech���fPvc!��Big%�ID6C�Nch�yps= �u icip�4��A_�3ad�r�g2Xd3��es: v�r�l�en��9y ownershipZlpr�p�Zd�k� �� �id-1990�al"-IsP�k� . At�*5loO1eq �p�!� NGDOJ'� �!�tr )<t!�a�=.or� �!r  seeof:mee�=��y� ���SD��]��)�BaR-%�12x�9Y�5KHD�''  [n�/nim� )�ͬ? q�� v9c�hL(�#�U#�� |v��5 (�m�bUQc�!!�6�>sk3: $cent1H!�I]9��e��r[6n�Co�mf �DqcM#*!����2C�R whom.s�[�im-lN�`�E�?)�)monito�1<�q�,�_jC�@ at C!V9re�  (�GAhH)�N9�. W/ EOAgmanage.�*�3ngFir�ly X�)�\� ag  u�Cdym�Pic >�N�it��M��y��il>2yoI� X��t��Rpervik>-qd)Q"�L�iCI�Q�? ��"�P�{U/CpEedV���~/��)� <aS�2�8!�n�? g�-�Ha�& �c$N1�1 0 Etea�L DHMT�&. I,�� ru�ve�{6P �%� ;n"`V3.��m��!� situ� �YA)�C��-���s�u�" !��!�to9rw ��5�>-s"m�� ()`:7.�? i "u o� R . By�Hy%',%� 12 r��1�s ( ex� Urban6�R72�)%k�-�h���! �F genemS��( I��`5��1�!7�\�&!#8�^�_2%U#nd �2�&� 1(�#\$!���2� cջ&V>� �8��$9�'�$X#a'N�2.�6��6��mi~y��!�X% manu�pt�A�mb)!�m7�LF�K>:�u6NTB��)��&_f>��_gu�ziV� by��rQ"s���wew ,�4thI}�I|�2 LF-�[Y�� �F, �&t+y"ef��%P se .� � A2 �leR;���2=07/9+)�:f�Ne�0�8e(���$�-�:��� v�fye �enSPAc�!�to%�=�[�r,lid#7�svey:�(in July/Aug�s�+� �4�a spot $ck��&� f�I�hyp>$� M��yI�'[�  ��xp˃ &�%CŦaqZO2W��&fe|v6�S! rupt��$ . S�oc�vj� s�,6�/�7sa�-"��by�0%���>��� Yc�h��y�3�-��A*!�[;ly�_�Ti �-Y) [.(a�alA�~ t��a��h��rLF2�� epAGw�Z��b�.�-�.��conP!�]�mf *; I7ow-� �V� �/�H� �a�Y.�]H!oZ>. T� E6�Q&� f M�! ,6� :troutinKa!A��*N W��c �H. E�.al"jrovg�o�obt��"� �R7�Gs2U�In� 1�K�/6QE"'{n���L}I�;r�PaH\s=��.�zI�anonymaӲq !�pilə� ��4S �4E� bXr!���^.`Guine(k1m0~0(1>�/� ij6�s��)�X� �8%�̽�&�9H�six�2�0� �*�f�0. G& 4�ag�> a}AJ6-X$e�1ac�}10�-�a��!�J�TreAA(twoB : 6# �,e6� [G{.�mk�Y �ea*S+E�)Zbu�bygo]m�tZ~�R��&� 2kt W.�~n !:�. z�;% �c"�&/�"AX c� � { -to-  v��"�� �+�!��Qm6��y!D%�hem�s�=� d]Z�N �Y  �A� v#�eh� z��ev�p��q�D�`�N y��ECDDq E� oI��?ximatelyA�~,!��J2�WA�/�p&X1�<9�b�y�9,���:.6g� �R u�A�"� �,d+ Z succ��F�Tfvoln�5"� 7�A��n�it�=g [�f"�#pay� aE<�W �!=s=��S�5mC�nd nurs!�in-���/1�&pai2 �08D�F�'Cing�|�eMf>��d.� . CP�ff2:� l�1AGAO�c;A��� X�2j!>; a��"�6 Septe[JDec ���Au"ha�>�r�.�;1��u�����%. B� ����DG%i�a>( . De�vsE�l(qX1������"gi�r� up��d ��'"$sub�D%� .�d }d%wcap�X) i��+zA��.>summa�]p �:� F�#)�bm�.���~!!�B�^ j!�M �! �or�f�zs/2�+�n�� �=� � �I�. E�  -��9�Qi�c)l) >� Qv� �iA��5L AG!It�__nu E�(*� �Nco-.��-o6!�LFa��t�rqxN�>�B�W�pQ��iti5#?P  , advocacOdb=�q�6@./� e!F�&� ��>�el_"�M�"� X w��s��> bene�Za�!a�D-"�d18tRl�)�Kaf��erson!��'�&��i{ �Q0_rfi�����n2F>"= i� �2�� A|A$"m= took�#c� .x(uD ) >�EmG�aiVM� ]� �e@�a�E6� �:��$; SgdR�V�( i . � VYUej�B9:X1�2g.cin2U!�$0gppu �onsq'p��e� a. " E�r�LD:�i07%Yd�%�g">�E$A��'6�hj!��lEc>.J>}i[dqu���w�Yn��l�y t%39 >2�6�6) ��C0�u�ag�6Hb��65%"�)E�A�f�*na!N)M>equi "�1We4.�� 2�!V�kN�6E���*. ^ 51��id���1 nF� “a �ݔa�Fa~�!!~gJh&A�LK�a�t�s 17�? � % {Ju�Q�.�#Vp$~ �Wly2� AFRO5Brazza�e*&&av�?�+�|e�'ag$2B ~5I3"�g21""O ��ZeF�E�]�!5�� . aH�!�,sw�]�&�%ZEH�a���N�5a_D�� �!+I�sP1 �.P*:G~J'�e=&m5R��%n>3� m=16xn�N,XC_!�>-A��!&}s)s?ʶ�:^S>�%�8m>+:8f#[27_e�9 ���d~E1uB��y8��_0new>3�nBQn���١K68%D�M,�'�;�U�)�"`9?e�6uLN�E�.��3�j�W !,rBsmA���FYp��Оx�gu�b�Fp;!���ZG| r�h!7epidems��8x-�_!Us\%��_�Ej g¨%���v)e-^I� m43�] �P>2~SU�-��=_�a>>BD�'rJ�5A�P��E�*� y r ��a� Y!i�MofW�F�Eu�.�( S�#- Moboy�?!�(B� ( SC 1TaninFKapuim<; K"FZ-KumalV�ED -Makoba YB";pG5Gel F)69 6 KundorwyCG&iF <babai ;�F:amasas l"�6Manow�" 6 Jorui�. Tombod0T"�F 3Rosin���!�“2MQ<s�E&g �)�3 FdE �E�}� w��Cm6~6oi�u eoɏnp3c�n�ig�2� �`e��:��.]o ul.I�1��A�F�ofp1FfUˁ��uD2H!=l c����� s d'�m H�-ac"?�*�isK��&��B�8e��%� �AR) ? ��;be�+����hofEBp�H�&9zerܨ��+&���re�3 ��Ms��Y�might a"avo;#-R�A>U"�ͮ��Oim#\3� ��8� Q}/:�<b� gp�aLB% ���X��AX"�`��Eca=rl])qF�%o"�&�N��e�s�*� �4�3e`.�6:F� to �aa 2�BT.%�5�4��cB�p"a !ŐMs�LFo q�a�s�#iCatIS risk)��$��TsN8Ei� m��hs�6��val���aKex�9�hem�g��79�#.`!,s3L%�hel�[AM0gy� d!��zic"R/�#}Tto qu$�o̲��D#V�w V6� S�3"c2�K�� a�6r u�recrut*e=� � �vFUe���+� &� B>o|�K.�:x:�1U���W�V�� &�9!f� two-}@&}�/:6 e�e�=�!Biy�! Fing�+p2Q)�"�j�� 10 p�2 a͝AA�ThQ�!:=%�� =&� me��ن�nd�$�@�9ircֆshape%al�;gdd�Dt room�er"�] 12�Q4GO next�kdr�`��dehaemo�iX��'fHRA3w���il1cwYi!m��5���Y, �`ag�,�;A7< anol :H3&�o:ŻGIEMSA*10.a�Wn5�mf�.a�htl(��e�����^a'N5 ×40��!�us)gfѹ0�mfNmo�?e�9%�lefpr��o to Ep!FF1�ee<�opg A���$2�S� q1�A�a"�fS�;>n*"�� down�'H repe@oks���9�3 ׎�un<���mJ�T�IUeifFmf. )Td�s3l �:��!��#fAD�×�S&� ��AA55A$�Gc�L-��U.� � ec��o� �"��ɥ"�: team&� �0j@.g%=!]"�re��ce.3!�&6/�2Qwh��l]šXHdiagnostic detectio�n of filarial parasites . The team leader was also supported in 2007 by WHO and the NTD Support Center in Ghana to receive further training on detection ofN�at b(oguchi Memo�tInstitute for Medical ResearchAccra , �H. Positive findings! mf were�orded an�dividual density. infection%calcula!6expressDs�number8 mf per ml \blood ( mf/ml ) . A totaT6 , 023 “midnight” 4samples �collec}amined%(mf as shown! �table 1 , male 3 , 170 ( 52 . 6% ) �fe<2 , 853 ( 47 . 4Ilmean age ( ± standard devia%)�!�$subjects e�4was 28 . 91±1 2 years! ales: 2p65 77 , �$s: 30 . 32 92%8For qual!�8control , all p1�slides%�10%� negaE E!�erv!�nd�by a rMXer , who� invi!�during�desigeb%,tudy to help!� - mto�ducI�>�Dbecause he has bee!�vol�inlMdevRTsince 1995–1996 [18])�re) only 18RH thes 'submit!a�>� togee�Lwith 600 randomly seM�>�.a�ulte�!D>UA�ed that%�J�%� true�s whileQ>r.A42�coordina�"of eachm� �7 >re�=us!�0hand-held uni � glob�nE�oEsystem ( H.havaile�,upon requestE�Re)�e�ie��(to MS ExcelEanalyzD SPSS ( IBM , Vers��19OPrevaleAI:����!�!( 12 distria�7compa�%�!�0baseline dataIZ 95%A�fidpi�val�CIs )`p��)\^HWilson score method{outb tinu�rr��[25M�( arithmetic��mfZ�A��CIe�R���pop�!X��!�)�veM5siZ$[21] , [24�Chi-squ%Gt!�1u�M�%aQdiffer!Csa�=1s4Kruskal-Wallis�N= $. Treatmen!Uverage�= acA�A�to�WHO guid%�s [22�(Epidemiolog�drug co T(( EDC ) , o�-wise kn��,as Programme0, � he tF�rep�M-�V=�of IUXdenoma�or%8is2�>�people���$h�� ave inges��m� inesE�LF Ned�KB�in�multipli %10��� er;=� �!J�IU���f�|A� of w�Hpro!8 -at-risk.<i�y!�%� �MDA . D:�%Ϣ�� m s targe!Gor eligi��x9���������^�6 �R]�A�onside!�!�b�?measure!�how well!�s are iG a�ed~ 8n adequate leve� a�is estim� to be 80%e0hDC�uldclose% 100%�=%!# cators en��!�$uthorities1assesiqstatu��elie�A�p�.�e�rmmend9at managers�=�u�E���to �� tify!as�> low$,� �g!�� J A  solu� � will!Y rove�5k" �Z�� inue�-a�B�arural ��as2�$��a�a�r- v W&� ��registE?*� pre-Ecensus� B H]��0in urban/non-.�pro ed figA�B?2004 n%*alz[26�,w�� nn� growth r!�of � 5Ax Spat�% siUMLF���.�cot ed�? krig!AXm�GeoA�ist��A` st Ext3 �ArcGIS vc b ,ESRI , RedlaA�, USA{ � mo��d�tour map�' pof�of�at&k ��(after threeA*produc� A2scribedMiously&�7] . *�814 , 253 villagM�%�M����!�or!i% year.P3�aN2E . ��ll�kin gof52O, thisa�� nts��geL phicy��en�cfyin��2dm*� �sZrou!�of!�s�$.�A�(Over 4 millA�EDC!R �o ll�f!o8A85�8&1 �8�5%��,2�re=�.ZDC��a^#o�!k6d"- whenA8An0%� DC� �!] ��36 ,-�v5�E/ich%�7�%�1J�3%6�)�A�Vg:;A&A enem8A$ , Moyambag Pujehun )� ��&�. O�! (:4"66ofNa�!)mainta� . An�&r six5]I�6Kbm)��1 . 0%:1\( 20%;�:04%�/3%� K��N2J. mbia ,4>^11^45 ^oinadugu 38>333A�0 3YN��:�Au� 519>�3�08�!� ly o.��W6gofe� 1%Y mbala!?58:a80a3�9 am�6Samong�s%��35% (2�19N62N�� <�s:2F:2:51:..�geX up , 4�s�,N = 1947E1!20B!858 21–3f 3 4J 4�!�4"5F"640ba!!21>"08�M�(12B(56��,(58>(25P!�3.(9j(7!`�z47>*16R*2��lE "�� 9�>J871 )5� In� ,(erson!��3�E�� 19�EY���a&��sm� It�no �ificant*��6�inM�as "9toU�( pMl�Enŷjbp` ��i58�CM3Ĺ�,e��v6�decrea�by�t6�00I� from� 6.��Ņf�Ato5�^�)�,� 3N  � 4   *� �e 11�(w? Z}≥, seven4^ed: re�� �9*y � �� � �s!D���nd2pby be�q.- !�di�sugsa sweep� �Agf0�%�!5� .�MD� cro�countryY�n 8' 4%UR B�)�m�A3>"���&Q"F�:;�i� 5֘�::E�0.�����A� ��aT� !8aΆ�B�!�a՘�uՖ , bu0� �not�q�,�dA5�rdid,includeticipa+<15��. Dm��V6O)�]�s�,��,��,��A�� rang*� 7!�3� %�.�kɫ^ b!p 2[mF}1e�s!raSB�.[( �VprZ.b( B.w2 w!:��m�_J4` "N �O�8�)�i! l62� pilo��LVLF2� vp 6�eA32i&�2i�I4 icrol! emia!>��4 2q �.���3 � %4�� h6m2�$&� �3�^.`jq�05� 6�03 508  )!I!t(a}^2 1A�59 7]1X64 � �p5�)m|mf-"]hD.�na��!by5E��c1 iE�pZ� .2/�� �!��ve ��asf�!,*v�6�"Fus���b>e�5eM�Wv P&� ���X -�J�( 2x"�  "BY.�.�Q�54�a6�� ,�5�F42M –6Ś2-�)2�to�^�O��1�a 9%2z{ ��3�]� 0 �A��# �F�! —. B�6����.�Հ1�!B� bothU�2�\aUentir�!"+. S2�"�,&y V�/,*_&�,�� a >9% =�aXy��V�:� 59�j?%V 00i 2>t. a >3A&f�i�VH6�295 {47�%y31�45�21  44B�. B��.!low>1���99, 8�3%�C !�e�H��.)6�068��9��&� ��m�2��.���m�7b& ����:��a 6��~� E���.-:Z 13 )��&ca 9�.w 6��� >W.�� 8z�G��2��z�_%N E2�A���u�2�&. va  : >6z.�f�34q�04q��Qhf159>�:A*& !a��f�uI!^�.N)detail� )&�Aqg. 2c,y��>^G4 m�Hp val �u�JZGpl� see"bs 3Y4� "p lm b��F�? b� 2[. \ e dYoh Sierra Le,-nsT)by�8pheles mosquito�(All�health�s-)fF$�� @v�o)ta�'w:�%j* theyEu";LF.�,by ICT cards@�.�&Although� t in2� of 6F��,��� �"� ��rel�+ly po�%*#“5�"G-!�soM8:�\1%7LFi�&�;NB� "�%�&Ii��"�12-Q� �*������–�3'^�N�,y�)� )��AE,#| (� �!DCOvO (�"� ("��..��Y�)T9�"�#�verithrEindepaw nt monito�-activ�$*dV!3�(2 currC�$�"�"A�av()6<�N����!F.>*� *| 27"� �EI%>ye�no &�ia��60inKd24 �$S �Y �Sou�n ProvS.�ف�0%$I6 of >�� , }�T�re"�!ane��D� :"1 5VSIG zero:�_&r�)a��.ma�(venpa)�-�!8�.n�&-k�.��ntinel .� Cons�- ntlyA�( spot check$E G�-��umidterm �in�ul�&E' DHMT�?�ba�|.7"H'hydrocŕ!�lymphede4w�in0fch�oD9'Q 'cas�SED16*is again)�it!��'�/a:)blI�1,next survey M��(�pre-tr�s//.� 9I�e�&!B2��.'�.n%&g,�� sett4*&u�(o�' E]�FK�%or &n'X�,Mk�чU�!�AEbiae A7%�9preM4!�[abiq3�$R. Howe�$,!�sh�bej1�!� issu%3z,.�-to%N��Q(�ste)3�*res3by \T0"�$NTD�m�1y!C&poAoa bigA�llengD69�)K4"�)a�P6)F�c�c�5some ,!�y6ens!G12uQcan�easily id%���NTDCP�ref�0 deciE�)2&Y)M:`)s F7!�.).!yYNorMda�!��A1neighb Libe � �*L≥20%nE�. (� p)���� $;9%%��yL%�Tb a�-.�n � �2�+<<*,-G Many /4&�4:L� 5�*�0"%�*< cidala�ect!�!t��aM5fR. z�f� �> A��6# �'fur�)J%�*M6Q s.Y!# tim��B$yA�&� A v�\ P-\�sRin Nigd e�g% of semi-a��� �]J�i8�4�2�q�QR&&�%t��6NB([3i6[35 Ad�.s�2x beth5mf*((A�'!4&D�oil�1Ahelmintha�2 e6ed:��1�.��8&% N�>�)�+L|as�"}5[ љ�4anomo�=confirm�ZKim- ; of2��mLF5�6o�ob�C Ox �6to 7�<�hyp�%��Tv�y (��A���l~76+%g��DZma2 qu� � �U�Y.�i&�.pN����ex��!" )�7.j� ���Va�r'�Y]Z�i]A�!^8BbyQ�r.�L&�!E:4lready under a����<(�  ,%���D6; x�2Ipent*�-addy@ seBa  (2�)!�AR�����oc!=Av�.� successfu<l[=I�-��~8�@benef9Fmex�(ng^�"�%os*��;,platform [16� !�OV!J!(1�' establish2;h� | � allow�/"��jh�8��o*n%W"d-�?� thu8>s_Gg6I sens]owner� �k:�:M. H. work >au1e}trk5Q_&�toʡ� techn<K�Q^a��i�E,! erviBndt;"h U^gi}/�*Septe>J9Dec F Ez�is�)ACperioy !�fD�bupost- ^��W nteg&S Zm���EKplun + �2ado� ���samL inci�Jas0PA*adhI�e[E" A\<��3�nti���;}i�m�o�F� u���_�:GLF�)y Ach�n�� E��0infrastructur~"&2eCA�focXH�3!�"JH�&Z�!ji2To �?�!�Ngt"6��w i-:� TIorTDc!�,�!. A)"!civil wa6p�2 ,1�� almos)J-Z�d stoppB` MOHS%W"b]Brune�"ZQV!�at�$s w 嚅oin�e�i�`av� situ�D!�C�*&t ӑ�)s�G5�Yon�to0!1�Ccollabom�An�� ը5� �Y�. F� �,�i�-r��=�"�@� C�N�b46;�LF�-�.�pl!B&���1%,-�]�� �Q volunte�(�-���to � bute.# �.� )4ir��2�a 5&M m���U""�!� R_O6%��#3g5 9 @�"�5[3�M �Ea�lieVNE�Ev��*�*�  ��": :��!�)� � ů1An>�$" is��Zii3tVCulexR i�&�R' ��a�;/e�}�J2�%�,m�� + �_� *$'��a& -�y�"v by m�1x�- Kenyy>�e�s r�I� 6w()�2O"9%� ,5*7�$1�B� )Kw�?{mi�R ��[39a *8Nl��/9�6Z:I�i*0�8E�%'just 2:_0in Vanuatu [4�In No� n UgrR�r!�6x�7wo0 a 89CU�5� ��([4�j1u�i�1t� prisAm)a�&�65���6�; 1�"11�32�#m7� � j_�M��C`6w.&.��{CPi2� s� �in builo���9W �����5 ���Ib�P�a� uniq7 *of*�[appro�QA�g!��VL4 :N\;�c�"H���#*��du��)/[F.�"�"6iH"�(!�.�/���1 N1  ����& . O�T&ntr� embaH�!;�f� �foh!�� :!cc�;Jw�3! :�@Y� ���isI��ly2�,2G%PmA�zQ�E�& AV.�of LF;R��bJ$�E�z�!co-�s: aCLF�l * sco-.�A��SU-s�M��.� � itiz&� mo$ R�itself�0�)�%4�`�>��!� =�Y$exb+gh�:�ud��9|Aiof2�=iMU5�"O !QB� �U!TD e���9,*%sustaina!Dty �GiaA�!� !M&�Knc�M� AfrxA}%problem�;�!�a -*D staff dublic0 �m.�ng%:)1A7�%!@.v)O&� �q¡�Sşi�F=6�e:O�#M;S#�; ���CDD*X o do!get�(an!� pay���S��iM ./ra��My<p ��"/&i����G.G< ����%i>���XD �&199P320�Jo pl?L� � NTDs��u2:�1�Y7�] 1 (!)���s2�n!�!^A��l�1J�m��E�ER�veF�A���Qbea��ous*c e��ʰAi�Oc$� easy�ֵ "S b� 200X!�$� ����u^toHP !�-r ��-O6XC��&pW��M��{Cq5?t!�3o���X�?(�*.�, in 6!LAZ+:�+ye �.2) m_!�a�F�!y! UA%Ya.�*impact.�+d�# ��!\2��[as!d�{!r#>7> %�2.3+�*��Uyou look� Z �+�#"�)yUU6)--�"2)�recK :4(201�="i- 16�5 1>�P;K&yF!L2N (�U)T W3Yrn Are� �b %�isA�2 �Hs�$P anF��$��� >� 1>u�=YoQT!��)a�k!st Kfar� �:Jz�aQgso 8� grouoa�R �5?!�0[IA�on*y�roxim�>ZyacterKcsx��4 pairj �ckbpo"�=�~boBJ��3pMOa��A[&�.T)1C%�� "� antigen%c:%&� -����,)  0����0}u��ak�:�i�81ZP2VB�(I�e^of-P/1L^P boya'-k�X�� \#6`)�aB�28e>e�<1�� expl��#( Tanin�OKapuim�u�I�!G�� 5fas� :�4�"r-���!-�aa7�w�\u� s ob i:eIa���-5�Cin&� AZ */82i�G�p�7�^h :'` A[Bpa4"�at emerg3a huge�� /1%��id-�� (,!!b�i�`����� )��ifko�^�H��}�4���5�m3��`@�5? AIWi�2=de.x5mK� -�n)� (�ma)@ W�����W@BU'::.[%�think� prud�wto �E#�Y"�4ite/v� g-��n�'2���e5Tpre-6tw;0y @re-TAS?!wWJ3b��ن%?�jJ5$!^�m�,likY, ��in9�o avoid \`�ver��� ��X)�K)�$[�3be�� ourcE I.*�5wi!h%����B�qaJ�tptimism31�&%� 6+ 2NZ]js|N �res,j%'aof/disapp9Q� �Ua��A=42cH.K5i�U4����eria��$@�= c"2E#Tanzanis A %4>�-kh".�nd2��>�by$IiZ1�C4%]aEfir�nd�#m�*�/��M�3ub 9%+A��)2$ffj2|Y beitq-�),�$EJk&Fthirdd [4�;In�?gan�5Haitib%AK!2a.k') �e]'f�4 ^s�26A�LF �2�^� q�.[4�-M2 �i% �d!@@*�, a �6i�4�mA�2x#,*�%.�0deSyA�e��ia�%�4�I�A\.&� adult�i0di�nat�`death2���-�*,%�0�02� '%U�A."S �'�3AElifespX<o1.�e&co=�#,1X� &�/=��2�A�u+�Au1F�?>�)��=a"K�#)� coupA���t aB�~l�6~^��.F .� ��4��pf *m)is"mArob��j�74���  C�g>�is� cour4d/Co8n�'mkMn9q"%�20�E"di�s_#LFQ,I modeef� � rigo�sS�V"�;��y}Hjk�*�s� N<+steps5�a%d>� uR!1 � ing:AoA� � =��-�Ga(( 4th , 5th%����g@H�i~�<(%b�6O ; a #Q�e: � �r6 �e�DO1%eMts2?`0terl�DZ%�� �a"m adZc�$:��.;on . Mana�u 7LFU'�6o�>A�*�> �-�R*� e��ion�8-� �KmB�c�lyQ��$.�High-�Bd��D d q(n�M� 16S rRNA ?ajfilA�Mv3 kMt��(�:ud6t �+9!ner��� %��� b= # -� �eA)$world's oc�3o� 4 gu�SkeX0eq�q9�)?� e�gic5� enc� )m )��p.�*� �ach�"br��al#f.�i�Anen�l/q�daywKarl PeaN[��.W=.typ� �!�A4��=�( referA(" s�pAE^A)`�e unreli����iA}yF/ed 9�!,�;e fru� �s!��F!o,��ri#th�$ab�he abunEH��U!simo�nal �U*H6 MUbiomelh!�e�~%A�9� �wnA�w"7pR. lb e� |set@9n�7!c9�sK taxa%\] rtifactuaHto3Fr26may0#� +� �  ? n.�^A�aQ'��ma)�eFa�Fd%Tr acut"} j&oPt7 a new�!,BledS[rCC"�;Hat https://bitbuckea�Horg/yonatanf/sparccF"] �?�6�x0l��=6 �K]6�E� . To illuh.v^�� appl�Sp�%Tp N0r�.ec"�2net �|nT ng hundre}@�8eE�ngU�� 18�oa�e��bod�I�AG �h�e�� �- ��!�6"1wa�"yield�L spur��-q� q��E�e�s 6&�v>'<&�����a�%�I8,�&�Y, A+% errone linkMni.�"�xakq2s`Q�.  �of�qq�{yhig roug�geLEc�� ��c� rout]>[�Lyet�m&�v !�pr$=%�llA��C��lz/N ongoAN.Q �ch\D� �#���^in���L \e#6��>yV�nA�M4� ^!zre` !|!a;ing�2wa�k<dO�F�]� b� �,-5 �Ɖ.FA�discrete-�In�B��wa��65� 6] [�7Eo{>�7*�o�r!�0j��A�in.$.p. C���7� 3trodden�h�X!a���2�&�valid�to:�)( GSD�eA'�s��mis=v��IvEp��EsocA�� LlxE]A�e��eqY 6���,A>�5a*&of5Na mponum �IG��"2)e0x(�?g .�K2� I�)EPset� �amOs�xB�r~ext�*ed�1�y�?mK!>depA !aY�yp�/� egiAF�!rmaliVqD"_ ��:&�/ ))�w&u fPn$a clas[ %t�Bd�/d�!=` ��)8i;sy-i�~r�meYaz� �p�' es [Fee Spec; �,2�}��a���>g6cEOA�a�theor!�IinI�6[��9sJ !WY�,&s y m',su3PU9@u�.�O!�te� u��}� regard2AK�,.#o �8l=u}(1�,b[) [4-T�6B'"� &_u�te��wI!u9�� P eE'I=' v%�b&}yp�Msu [1b-%|�O 18976� war��a�Msta;ttemp�oA�e&L.<�}U2sC1� umer v!�*�K� �l���L0sH;[1�0� ���>.� ^ � 4 � � &q � ݯ!8Q�����B� )r� i�4 ��i %2�o%׽�%u , [1�z1mNonet�U��q���4 primary tools��K a��] �G � "�U�achN !FB�5&�� ed����4]ŢA�A�c task�� z#R�E��# ���.%��%���M. A� ly �)!iAitchb$'�|��ljbg�*E�&ce [1j�tes�#E4A>2�A(�<���"c� Iq �5�M1 n� e magnitufR &� . Filzmos� nd Hron�8r�#BKJEf1 �9rP� �5�8�*5*� mabHat��� on �-�5% Orap| `�2� �w^ed var� ztQY &����2��u p9 ,r w ���!Hreal-�)ŸA�b�( HMP >*i����+[RverA���“2s����?��if�P� 9�m� ir�"A*OQ�a novel1�>� r� �it�E/6�" s a�>mO�� q�!�EJ` . To�Qeyt d>^aWG.�!N ? We��l �ar�9a"�gIvE%6' z5 ��[17j �me� !~=��#�z*�>"�&�'#7�6�fYA��Sy��&}X!rer�'ope�Cn�axo>D=OT�P. B ��i�v2��$tOTU��&��� m�}�.!aG���?އ� p"�e| �d$. N����%�SB�L�.5pla%stinctw ter1:�R}]=gn!of.�&�1(k�t , lef�lum�See S \� 18�=�?:8 mR��'fe�"� �#vag:M�Gtroaur� �#i�buc� mucos� �gA�i�� an%��is"��ly5C� ">/ E3�lspi � �~ttr�:*4 &��6b<�A&�E�.�>�?#�! huff��G!ѡ� ilar��&_�ulac��j&k �m, e Ma#[�A�M!��)!~H�>1�.middl�Es\X ���t�ar��E�!��>?(��/)R�.D meYz" behi�  "2��"|3gh�Cw�OL&)� �]j-�z�3 he dA��of!5�$a Lactobac�gisoldi21�=W)fl�@�!��3J�S "]N�e2U�r2�%s�,:DT�G�e =�W��a�E#L0y� 6-x6 ��VCyF'J�s-UZun� ���)pp� e d?T a��ia2|�6e6��/:_��2@:�� ��.�)��E�Da���i~mill HAWxuE� at d"�-���AtatN�1 ,&�alphaE�G�PH5spor]trength�X� _����di�Oh) &�\�. Intui!<l�O�fewerI-_e�Y��4�� �(bW, {%�eɈ< BQ A�8)wo ���'alw�z�perT lyU?6. Moreo�[ hiA�=/� *�"� �a=! d��XeU, ~a!? �j�fI��"no�K9� �qu.f  !?Sh&[nM�A�&l �(l1�IIs<H:6�" ���(.��s�B!�e�#"omy���a�S{ le�A7�<>�m&Q(�hk%q\.��m���-pronoun�CtU5c=�aś>�9�� (��� c��.*>4Q�%v. s#r� ��]2SR3/Z, �%ea�� ���e����A.`!�R�na�effor�Pc-R�BF^$�8ng&� 8� �cE"� -�R ��- �&eY�%6� of��few.I ��@� "��&"K +�Kun��(!AB&6��b��"� fals�*��aL-EFj�'J@�ot sub_�&st�P6�> �>.Q,� Jita+"�a"�2.2�1�(�“subtr�!!�u��)=ږit��H6,���ew&�%o�02�]6l%�be*�#�"se.�t-�Y�;A�/CC*�!��barN�&b(ogR*��i�,I@ �V��&�d0ua� exac��EW1� 1A@ �utilizY��9n� is}� IVassump[ �Rat:�2)�*w &<� �.��"oQǓ)g K�� ( ii U�=�5�is ‘0%se’4��O��)<��E���6� � *� !�L�IZ&�-2(ur� inKrobDto viH����Upar' 97!�d%"���ny���+buRQ �,&�_�� a� �"��&� ��f�E�2b)zG choiA�n�606?2�:Nmotiv� sol� by �D�eRIe empiaC l fij F�>E1t2w�e��}�,ex4 6�e�M �<� "8!A E�}F>U!�JQ.W�-�!\*m#�ny!|>%�@ ��%x��%��". Lik�6s?BDaJr,�>�!��&%~a��>-F h&�*!�� |"U: car#H� al advant : Fi�4 )��(��"�%m+ ��~>qDr�Ue�f�%��&7� !sD �m�>Q�f�A , unS73M� selv�BN(_D<8"q��� �!E� "�.m�5�HN>"y �e�V:aco5�%�r�e:��/�l��"�V,1Gnew=�A�no�der.� !exM�+f�MA�� e�J�%u�1aK=log�� o8i�^o7�n�,a�i3�e� ) sym� �=&:U!�he��*��-1�s-z � �(�$,&�~82�Y�ty ( 4 i2}!�a?ak�p��P� � . � �z�}"Y����yI��nstePr�1��>unJha{���X�r8o��^�tAQoHv�Oaii�i��#q�5Qe"k !n�OhJ2�"ctd�' scalE(�ia��'un�_�E��3 �or sm!Yv�xA(�Fa�Q1AF�#S��0 ak6o�o.?� �� b��e�'b�^} ng�j?U) -l%�5��� !<>�M�%S!�E<eaxGbA�3 )M�a9ATO!�A�����% a�8*'�eFA�Q0 {�m��now e�[�!�!-pb��#ArJ :�'��l0)�!�i�6|�'R�. Ide2'!�*R��o��3�^/q*3�Ag�hBA#d� ulta�-�N�&� �9}!Mq�ŧ.*v<�<#l"un&Fblub<�DAI�ns� �!r��=aU6�$iY�aba� a�A�o"~Mz!�v,� xw,!��2m.�,we�,*� T>��A1be�\g�m1��Cfq�2>&3 � 1�!��x2��2�,-n'�H�S��!te�av ��,aAy i�0`a(��'d�. AS� (=  ��ed�-�"�>�0G�x�kea8!�&! *�.�**:,*G/N pply� .�V��\5�b�# ,c ;-,�l,*&ximum-a�lih�`�m*�5� r�=�q�itt=5�.�#C�[1�*�an "V�A�J&��"jdr�Dby)YAe��BC-!�a*Ho.e � �� down-M�t) �ll-.�]�%^2X, h&AQ!��h !�ll��a�.Z k�ݡ rKsC�~=�b�$�fa(�0&A#�%&�e employ�'Bayes>p'ac=01�� =�6���&�^ � �c!�*�x ��Cof)"� m&� � < ignm�#�/"��a9W�G� q��eK�q's88&]&VB iY&ofqGP!�BF�,�in�&��R6 )4"�%���>vM2G–I8 A���;R`FuE��l? or�y&��iiKJ�ofa6v&�!m@.!Qv&, �N%�y Ce1Der%%|m�r^ d ���A�.�'A�x6 pE�uYb�����.BA`enG8m" ,9(D �UaG%�_asA�` C)�Qe�%�!��5��FQ&�� Y&I! j-�2= root-mean���6r ( RMS�QB� . S]t f�=S g���Ion u��vp)e!�z��%(5� ua�eN�9/Y7 G� D�Pܬ\h/ռ�z�e�!�QZg!V unac��ahGu7(%Mng|�� :p|�@�&��eaF�yP%4mar'��1mS3t�. B�ntras� C A|��&�-s9'6 %�=Vdf$h��`�s!Hme�m���� A�=�i~!Q%�!�}9'mE�In�+T 7"t� cy2� �( ,val)�y>�&�>�RbM!Vdig�i)6&��y A"t�) 2D,� ��d�e1+:�+��R2n��;�"�?f�z o exA�A(72�*�B�k-�s*(vI!�&�54s��F�6[)�'s+U�5�X�) )���i�+-F �<o"/`"�a�����c�r (�VumbFi�*4E �71S %�B2� VU�A��S� 26 jI?mm�"��� ��-K6������>�z3&S.�y!�%&� ,�e�E2]� ��L2 �+g*�w18y�%2P��}>%��� a�(��� A�x� *I ioV0Q�V�RK2�=ĨLD TŊS�,break- �."�, .%�Of��%!��N�,s :�*�R"� 148�oth�En30M?6�(gen���abM5����-jN - �. ��D�# 3 toD+m�N�� I�`gu=,-�M�A�[!e�k� ƃJ%&phylogen"(9uA?�B�S���!u/�� _%�urfac�T�]&x�a r}�� neut��y dynamVa�+2rga�,se*-U�habit��ni56M]see�9w AR�-etL) =K_q�6D&�Aa�cenario ��Gai{�"��2nt��tI 8&z s"I#e�')p80a major)Z����E dd����F�c.1>� �s . Ilh�w�,foc1 *Z�6b .����–�^-� iI9 � *[ �{!WE{7��*�#in:�?3y7�EF8���B2� e�\�=�H.�6�4&}A�$b ��⩴E��] Cw�<re q ��!!#��(�&NE!�klu��# [V>�(5��z � �,�� V%bCLn�B�ei==���"� ' ���=y���2�ra�Oe "�"� >Zi�|!Jce� C�"�)C6� � lyd 1:%30i`%`��Z�a�.riwe*�I��be�elyF6E1�02�:��a rul- thumb6W�8.��&,�eat�)st��A�5���(I!�&5 cave��E�f-(��(=��B(��<� �m��Yx�%be64ò���Ged%UW�hasiz�D7 mA�i��u%�p�+�U&�2j� f!B�A�h��� p&�G!ous*�V� �5-e*��aa a N� ]�w% z*rމ�+v�� %OR!�* [20]7 a�S .Fevisia Eol%2a2�NU�why!9n�%>a��V�&��ZG paid3Vl� .=7a@�ta�inaG�`&%�a��ex�of��!�R�Z �T@aōA�Hse9.Mre�Qei� ����XtruL06x &= ,!���>,�6ca�� �&t- iL draw��A`.Tx�`*Hyj ledgY� op%�y :guishE�d�"a�*9Hp"e �K�%�Y�g 'fT!�]K��;m ]cho`I�T�1 � em2k~}o~:�n!C���)enf�4}d�%~�za!�u�m�>a�l&z_A�>^%s���� �AA\[͗!5 � "v0Ej*�|8��pseudo �#a�r�V�9�6�'ry"m| z�3%[|i��el͎ mD,E;TZ��]km'.� IHAd��\Z,�KQ9�caso�".IQ��i�G�`��Y�6� e��h*k>���'9 ��Z;2�m�& nZ!�w��e E=a��a��!0��m�a� triv*�&�2�&s&��-e,�� hi&[�log&*&7&&*I Y�)f�>%��M��:9T5s�&Zran/P"� smu R�'on�OAWL>��!-��,& A(' �ng%�;5?������m�?Š[Ar�7f�; ��2P� d8� �U�`2�UZ !�c0Ju+=f ��e׃�f�rN�?'.�"t !.ap�A�H.�Ei Wa�:$ 1�exist&wF9G��"����t�x/&~+�y�!��op6"Yp�GK*�.xCE�O%6a:eM.�23�UȄ�s *_.q�id $2v�$L! ӥ�*&�.aZwɐa�UniFrac^��Z!��IcapV~�1��u�ux%�2�:\.�CWz@z��[� veloF*kdL�Cly-soH<1�!�%� ��_N�-�a necess� x[��! roa� /5!�*�22B.��%Kbp�<Emevp�MJmfo�"� shap�"0-C"� �T &�6& >�fu%��\. " OTU��ahthFCo�d� �M�O ?%.�"HMPOC���w 1 . ��&_ at �U,://hmpdacc .�U [&��Fc�+"_mM igh-�,��O"� v3–5 ��9�'�%�a:;*�May!�? 0w[ 1"^/I#i� 6qWif&{aCFY"& �5���XD%��l P�=j�j�"4eIe!M=�)fi�S� remV�g o��%� �5S�ead�qbA.5E��:('U� oT%�R� �. S.�CA! �5 @��*:|�R Ea*u ��%<5U *�%OTU\\sd8J�,�replac�1�r;eoc�&�u� !�&���8E�A �})ac ��y!EE@@,' �}Z�o�z G)nI*g�;J%� G6X"!�"�=.�%� gene&\\aO!�Rjo�.���50 ie�ax -N>3���) &m�ATco"j'matrix%fe !&� �*V��� (w� 8e �_�1:�y�f a�&nRRj @2�� �/�a�kz�9�ll 8)�I�B��)�2sJ��2'c�j�s� e�6�FQ����Qr V� D%[%� �Y� ��0ic1��tj:cu1ra�v� aq�-definit�N%����e}(��SN���K%5 �>�eWDy.�W! m��/:q"�=� �nin�achO.��a��!�!y50Ip �3w G �y�IE1���� V"B !fi/f.+�:j$dk$!d�)q/EF� !�5�A[fN|�[�:- T� � *��ll�ru�Ue�wpyRV"� f .� !E+� 3 !��/V)�5ayw�S��e '5wn *:"^A!E+ H3�Cha��SA�[��n"�7&5R�9 ��9packageg�];�-sa�N�1"B���mZ{ --�1nL!`*+Ej.j ��pA�Ԡj*fx@_���Q �'&,� !X>g�sum7 unbi@�_ �*,4 d_.i(aI<)�To�.e0y��r͝���{18Dy9hlecHs [27]a 6 >a2t���nAE�s'>���>��&!�bl�FU�7M�-L&�1To�#k5|����! full �2�+nrv�6{[� p�� q*P:C��C��G�P R�C��m��m�9�.�!h��| is�|*:�a.�Qo�ǥ� &�nG�9/4 ��-&�4%7��Es�H�-�pDJ��U�-")Jk<9XR&a�� TM�& osM�.��W"� �D �s��V�M� �]��U�:��X&�:�!�(a~�5ifix9U�8*` mirrfV�:�\.">�i)A�pe2$>.ɯ� ��(�5gs!��!���&�g��e��no:Or2"� (���?_Z!�m�kI 5.�VP(�c:o�%� in peUcQ1.vF�l?",�v�iWVl.�u!�� pre-�sw?a(�:1m�aa�c���3,� w� P.io m��`-"n.s�M]U-�6�q!Z$ �K���)a)�av2���Qicic O ���m lpa�S�GAE&Ca��&��7I�� �aj�r@�2_\-ed����i#Eo!�E< �?��-�r . E�ti�'� � hol�*&8`� iT eno.Ato���ti�`����ineAoe~=V�X>{ �>�@ [i?0�)�!�&��i�P<��d ����I�5|>"oe����� �a�tv� z k%|?*� ��&*z( !�a Z���m��tv�' a�'�8= �� .+���>�] . Our aim/�, ploi�#)9�g 6 un*^vw6m�2PJ�1�.�\Je K��e.i|. U!�tun�!�U�y�� !)� gEl�|,ݑ=7)!pu:�Vioru!NM������!%�]3_dera�r��� EKa er Jf%%�( �n]CK$&y/�J�>!� G�B�] � ŋ��Uv^$v�a�eq��%I>��s�E�"6"F$f�='!U.0!cA��2�^&�0}s �"GDj�!�J2p����.Y_�e�"O"�2va�����$&r���#I��!�$��$x�,_na�&2H(� ��fHa �1�D���!c�� s�(�"��&� Q�1E)啼arR��m`�FE��qaOioN 1*��,B:>i qAl:m *V:7'>:���"N=�� ��ьa% ae"a]&3E�$�a�5T (Ð� �b"ns !*S2A����N. N��sumyL'22�D��i�11%��&H(|w)�A�$a^��,J<��9"b-� �� ��F|� %� x3!G`>Kd>R+FV>�\��<�( �.)�>�o e2�s.)f�t:5��n��c�V�Kli e%ݥn!��t��.$ �ui1�26pl��%:��%U e�H =�%2�a�1��*tH%�.!%��� *�C!h A.*�ol >�!�e�y&'�Ji�w�f0m�i�d��kJ� �.:E?v fin�sch5X4] : No" /�!M4���|!�=��/&�d�C��9*�3�� � asoN��Kirn�/�?"�<�e�~cl�/�s' �lo�* �5.� �/ Yd��is fall 7�oF � ��6�is� l� bh�s< . Ba� = %$A)hV�.8 E�e S3���4H"�� �v.�0"�$IrM A0m�6��#�H��su���9,a.l{$ Q!�To6u�2��� !9J!V�R�r�7{�qi2 �  "R��!"0��R`,x )�6|s��.���Ϯ�v02�a� IAm��d �/��i��rq4a]��nd_2ximal*�M� Vcaj 1!� !!�c�|,5qr�!_���%p�\d ,R &_4��WN� �I��!M5�MY�6��'�U&y5m�?' equeg'L ?oTng��A�X a!1.��2|��6&�r��{&���z�g�.�E�!�J&ar�_� �"bJ!9!+s3�3�!�-J )!R�/ �Eo��a�rue"��ATzh,�s6F 11N�;82FN &���iM���&�*���  ��s&Q_p�?�"ב`A�%d(�,n`#a@1� bootlMp��%r�=adK99&��  A�a !p� E2�: *�!!�uin"�*e(zC"� 2�\uj��e�B� �M+w�?!#W "�"���s(#��o��^ !�"u�e}�/�+ p-eS � �r� 6��!��LX �"cmW"� a��t�� �A����2�aSu�.��%ᬁ�"��~� I� Pyth�q� Nump�v9]E.Bx [�mbk�bPlo��e�I��,Matplotlib [� 6 .C�� &� (of lysozyme��gl 2fac�+:Jcn� J�s��# oniz�Z�.a�0o�Bdh���cr�)m�Ls�0 a muramid� ��v�p΀lyBWb��) eptidogly( !ha�)NFh�+)fun�T[) onic �9&f* e�NTwo en!!�� PgdAa�( N-acetylgl�h��ɩ7Adr  O /� er$�W�q odif,j.�/e�!� ��~Ftreptoc��s pneu��a�9�+Ai Ih��st��to9�W�tro@M�{2�w~6)��y+U;B9u�/mR�n7��6�%�~��! M%or|�by �!� G����"�.��nz,�~rnii� upS&�Qity!�cC�$9<�cx� �Hm�/#�G�4wild-[��gdAadr�-�R)� �in9\M-*�6(a<M+/~�D�"�3w@0LysM−/− )3-E�h� x���3ut.eA#!�doua�mu�inLg]9not^m��bIP�� *�X=�� R.�-���2�.%��8�+�znA#�; lf��� �94!k�,!oJai�1��9�- Q,!R!!k 2U�> "�����D$vv�gfi�J-:�!�Ul�?dX!C�:F��nR�6�! :In1D�s%I��I5���out�-O%mJ�TF,6wd{�V�!.9. p ! path�@� 2Bbv����cA�o/#�po�ae r L����T5aFi� !0hr9el��es� e�C6<��0%�)=Cbur�}-.�WA�o"�@.!��YAp"�oN�8e62r!�o�.�LaBc@$���>�&µg/m���6%$midn����l&��^���|!]Yepa�li��!�lso�@A� � granu�z�%Boph��8 � !U�cru�dA�Rb��`Tla�[�1*E�2��?�;!_&�M�m &����zyhcR�*�!A�WR�d ß-�4 �$osidic bonY`�u .v( GlcNAׄand$�c aciyMur %>֑cv�id��a�&�.c backb . H>�x� +�Q�ud��a"�W gradEg+c��w�(�9I P��("A��tFpqt"�w� catal"[!in%�eXi5��'�nR) � ; 2 c !�disrup�+"� a}rc�"Q A8/� nt nine  �id�nk ( CAM%MN�~���E&�`"v �A%��defens Ue!@&I�/}"-q $����-m��i� � �luni�!�sge7 B� a:S4"ƶkil�of� B�f� iE P� mon� eruginFt�4. Mice have tw�Uo different lysozyme genes , LysM , expressed by myeloid and epithelial cells and LysP>5Paneth %,in the gut .c�−/− mice show defective clearance of P . aeruginosa [9]rdKlebsiella pneumoniae fromilir lower airways [3] . While pse studies demonstrate a prot � role�5"hfor opportunistic pathogens�0normally sterhsit%R,its impact o)�Imucosal flora is unknown . Another consideration is that bacteria modify t!T0lycan backbon�th!peptido , !�th�modific\s may af!}@ir sensitivity to9$[10] , [11 2 3 4 5 6 7 8 9!�XIn Staphylococcus aureuA|!bDexample , O-acetyl� at po�on C-6!KMurNAc�(d-alanine e!s!x�cell wall-linked teichoic acid have an addiE{e) on resistE�0to muramidaseo non-.A�itAOof90$in vitro [!$(. Organisms)�bdelQ4surfaces whereIls particularly abundant must �a^ abil-�evade% antiQ7l �0s . However ,; contribut!_of98:,, whichQ0u�-.,!0rsurvivalR�,has not been%�0ined . StreptQ }�(� M>)aA8a leading extra!�!, Gram-I8veu�)�@commonly colonize!�He human nasopharynxa�lthough+I�is�6re� asymptoma� , inaQ!N indu!�an acute lammatory!9(ponse charae�z�ua brisk/ux!�$neutrophil!�Becaus�� oMZ� coat B caps%polysaccAr<( CPS ) covalentARttacha oE6!Ae8 [2e�it\ apab�Ab!pphagocy����k�!invas!~ diseaA. Two en�wsI�Eassoci� withR]in S .M��::�N�5gl�dAQ de�I(se ( PgdA )���attenu!�!d drug!�Q�( Adr )U�is!ɑ�transferZ[21��T�b�Hi�]�ky�ZorEofEí�a8dues; ���:Glc��$( 40–80%< 8 , ∼1 �)��-V %���, [22�Previous�� �m3mutE���e %5�VB(are suffici`APncr%�:Xchicka�gg9�4Ex6�Systemica�on!mDE3a p!���in wasBUde �$d virulenc�kaq�GB�!Q���is�Hb��establisaB-LI!3i)KyA?A�terE�g>s�Lto�?��%v ueQa����model!carriage� 6�vur fina�6��riticalF�06DE�"8t�9=#!�ts��2�!in dicAEng �om��)��microf m-: upp"� . To tes�-�s*n�,v �tY�w�{m�?nIO�&dr���~alQk(TIGR4 based��' genoM� e�avail�B�tA isol| !�scribedjMethod��8Figure 1 depictɪlo� of�� i���N-�W!g�re.ve!��$lycosidic . AQof�1J�}%�$is hydrolyͰU�.� wild-typ�sWT�Be�, !KM^gdAi�s �jed equ2�? growE �x �~broult!durARlog��sA�Ad� IWRk4( 100 µg/ml )! mid-C \s l�arr] d�)�e �A@nt�( !5��Dbut�0!nWT or% �(!� . 2��. G � w + rred more�`mptly2�!KthaM��uggest!a synerg%Em#!��twoA�e: :�:�results�r<�oe>� st!�w��p>X�~C h� L� �of-m^�`� m�\did%Uŭ�mdb�atss�l� �ed%RazderivYR6ɏ(. A similarS terŇ.6�{obser=��recombinA'hd 5X:�,ِ%?! 25 �lysisnE appa�UK,B ) . Purifi%: solu� 6� each���NI�dպwhe��e- *� ony7cor�bed ���3. �. For be�*�3aaI)=5Fia.3�� J��IOs lackaE�E� ���. AM�wh�b� a ,^WG]���greatefDe��?1m. P�� al�`isF - tane� aut� i�s�Tonary�b �Cend�8e��!�maj���tA5�1EBSi* ��%f �1\ geneN�appea�� �!�b�*RyA�pholog%!" Ie��5�%�M�in� �ground�4�To]�] T!Son:�� , vi� coun�� easu�f�?hours af!�JFvQ�4A�or^�4A�pV��[WTQ9aF�no los%3�. S�ofinE�1�a� signre�dU tA�m��.�5B,i�a!�e.K5o �/�. O�!��mRa2L� !�5�followa�:�:3)?�mg,MBC50 ( mean��cen !�r�%�(or 50% killb)�!:Y(exceeded 18"R9�WT>�( TERiZI{trast<he �!���50A*�Z!0-�c12 . 5-25�.,=\. I� conclu�� ��e�zab y.6a6 by�A�sBC:3.a�a�.Sse nsi�du"� FoyA�]!;�!!<in�b%�by]at!M°C%60 minA��re!; g at aA^jto reta� CAMP�.9 ,�substitu1+�intact��!���MRatA,c�� s up�2&� R�b A!>��isq�a:]� , ra�{��n^W%� ��+5�&� ":2G!�%Ohypba���U�lim��iqof>|�B� 8� ����f)�t (�)*bi ��E2���respir���A� mo�R�ToE�ubtle �ce+ yqfitnesE� eti�experi���ass.A�� �t �XravB�6QThree d� 8 i� nasal ino���'�� numbe�F6 �1���Qde��0>�>� "� ial lavag>F 54v�de)Prior�E�v!�.Ma���V ���5I�-��@E�J�V"�advantag%Kfe(� *�p2 )�=� s�,�!!` F� . More�� !d�Q��1.;"�iIfdc t �� ir:�F � ���>J!+�� �l/.� >� �aRxn v���co� �+�2isa� weig�),i�!Y�.B!�mc�.� to� ���A2}�, le� ��#R'�9�pe���{ini��#+/+e� 2�#U�C D� lH-cPvidua>! by�!or ���6>oU "�regardld��A�JYA fur�� implM�!�-�a2�  ��6���M�d!��U(benefit –A#Y�-��s� .�,&� �h,eUsɒ��W&�]3-9� �*I "� 6�To ascer�AX sour`%n a(%y�%I��� ���P�de N.�%k")&AinfJ� ik#!Ἕ2�'evalu!C�& !-��venrica��&(toneal exud ! i�dab�� i�x�,� � 9�3a��drnd��e equ�1�t!^�Z�ell$E����or :�J�A" eis"� ��tto=W s obAK16�,�9~ �Y18�-0�p6 �mparis��9N,53�Rh%�6�2[� -medw"�. C�c_ aJA{!�6{���(1�+ ) eOn}R�tonbyJ:AI'|ABY1+ �&2�u��F��Rn , mait�h �C&Zcof=I�1Nb�P�;#d�<c%bf�B�Fc� -independ���on�9ЙMal5."� vid�a�Y �I� �!��n����.hamongm[s cam�*W Fi�"�eLE�de�d>e�mi�*rI��monoclo�!�,body RB6-8C5��^,targets Ly6G.< �X(�=rat IgG �o,A��_�p�&L,challenge ha�-�!�ED� �5>Y�y�to�)+" 0b��JB�e��?!ge�!�E�x*�uc ��:)!E��ye�&� :-ME#X in W( rn blo{n n s�*s6�a�Aa!a��c�r� �$�7�&Con��aw_u*/ ��P�b.� �fFt�[�+2�� V.h5�.M� � R� : is��: . U%�LimmunohistochemistryEjissue s��� ro�)A�)�p�y�,9"A5ala�1ep�&l�.�+���$id Br _ lume�3!�I&� 1��T B�I�f� � iliaa�*.R������s�� �.s61c ��d. H&2d� 7 �'�� f�y!v*MZ�� �Yq N� G$Bk9� �͊�.ba"a�Lfr��%xmolecul!K .F+Qs6�*!�2��vf+. S.��"e���m�of�+�-% V�+6��+�(#dra�,�nrj���c%4ne[2025W*�0'we� es�L"[ &�n�cha�Rq6hFO�,��A*�cap8 ELISAe�� to qu���+9\!�-=�*-�8�Zz� o�rr� ���  , sqG6� elev# levep f L'4�M�∼8-fol%�*A)�re�e0/µ�tal�u�$�2i{uld ac� r y7�'^�qYby]&-�hA1d!�0N�� . [26M9se^�*a�a�'�irM�a�6��>�#6a$��CA�fa�4 trucAQs%)�� &k2 . �,a4y.���at�:��q���:�:&weE?�*�5i n�o[A�R fact�4n heavi*1d��s�*�2such a�ose�� he17A�2� extend de�*p��"��P A�c�(\BJ5.�5�5, [S4R4ThE��1Ba1he� P at�)���6s�$b3 �J( W. �r �$!1]&�! * 1�A�I��s':�properk4dI-es!�c5a��iX'!�uS da�rh3 �d��� 6voAa }$l BZ*)�wm8*c�� io� i7g�6�nd4��5 . Ev~o� �)�s�.�� uc ��� , di2 hes5nl��� 2h� abF} &Ry!�C�&=%�-��&0D !Jsn9a��5. "_4)/�96�=���t aaa2..f, 8$!H� �4N%a�'s0�vzY3� �4�X)XofeN[b���!a:dq *m�ly&:\q'0 B�0*�A���7ntiJ0b�  ��!)&�IM �"M/�!�in�X�V"n9&u It rem�possih+ ,�D�9e c�.As�"�8T Y�fe�"eBj.�!�6�/^?!.[�$�9�E:ZQ9}9of� �w5�.- 2]9� g-* n!�"Ee6�2���|nic��nd gallw�%[27#-�b�6P76-n^96�� 6�s�alF�i='A�a��6!�nSe2E%l�(%�)�h)� )Y�+� in\8�����tuS�!�]F'�&*7;by�( OatA"0)(itself does%}�6 A^l�+iE��[18!�& Oir� at�9k&"<he0H��I?V�6ly�0Crisóstomo e�%�/.;/e��� ZK� �A��N�7�(�G njun m0*R3se1  iL=��du��;A�-��# betw2N�;J�u1 an unen� E labo%$I7le our� �-��'u�� clin�5��[to�&+ _s&K8M�`>!�due.R \I�n� A�might2�!L(A� -xN~�0�i�q��lsD7!3te�g!�mx; lian2=R%)0 %�Qpo%N� M�6�sl�lyUt amino�>5:�! cataij clefE���� e [2 29]?30ay [ sequIp�=h&p9!�:�!9 57% tE%76%"�2byQ��( blastp�4w�$a*L MGJlZ6l8l. \ QN�&�R �=A�al5NZ inA�u� 17the�=A��8affin7*��)2$��I c-h!�U���3e"t + S� many�$esyV!&I��t r.K  , few"��x�7hus far�C� ) �4v��h6�[31AFAs'>��/����ůs�6., Bacillus ce�AA3Lab,fermentum [3�5[31B3# 35]; �6�J�h�e�iݡ<*���N4f�@!�""�żJ�I��!Ts�y-��@��}A;:2s8! Jl�b be n@0A fullRt<.� �ge agg,!t&./�1�4l~ �6�� M�N*�N��Y%explor%An"3�A7)�M �b �=6� �&�+�9� �. a�^E�F �� �DC�&.;�Eb�B>m 2�>�X�56�2 �*l5T5( L�4,�3arkedlyB ?&��.V �.fbAve]Ze bond��e�a�gedno�up�. A�n-O�=5?F�9. M�?'%e�r"�iI�ulůa��=v� !#����Ha"E.<a�q݁�e�62i efh@c�+ C�n� anio *8�65bo36��0 �beM��is:� ��:l�6it "� inte?<�2J,ivom i�%M�*�* ~2�  ( C-:�C�<���+ �B[ beitga�*�Gc�HY�A elB�,� ӵ�� W�&�inhibit�8kDo�/A$�s�3��6d"�M�E�a��7R� ��$�!ԩT��Lz�TI$%I.��I&�!n��qRq . Vollmer� .'  r�<�T�B ��k&"�Bm���k"BBbloods>7m�%�on�&�2a�cI� seemA�at odd&�(irJ�JFM_*�OC��!�i�(g.q:� auM>"�4�Ee"�?in� serum6=? AJ&� RL/q**@-e i�% pleomorph�dalexY�n�!��AAs"�(iDC$environ���)�b� A�� 2swh?&�6S6d�y��� >2�� � regu�96fi�Ksgr�!c)������s� v�<�|M'� diY9I�H�t��aq"> e]�6�,-�`!h��?��, degrad gB��rel�F9�p�0tS'cogcJ"0?.��e&axJa{� �lVNim%j`)O�� D\J�%or��;,ramyl di)�MDP��alA�*>!(ucleotide-b�Pligomer-5dom��s H2 ( Nod2 ) cytoplasE4Owa�S"3�!u)F��* �#C )�od!� ��trigg��by��A�HJ$on�uE�(0by"�!x) �-b rdz,E�� Z���.�-G Nod1"�rQ!g$e meso-diapimel�;ci��DA!� frageE��ů��[3 3 :T+L�Cr6Pn�K @ es [�OE9A�a�"�i�2/Yp ��versuo]|)a u�Iԅvf�cI�V �l��� %nq ye"4N"u In summ�C� icus��%� ', wM�Cl�6� H" Go �M]A�G�,J�9#GC0�R�Mme� ism Y9\u E�)`�3W��, �B ) �� linkETfdE8�Ra/B5nt"��0a:�"� eWV\RaWYx|Z_J�:T�IaacdR.�exertsO ;�q5�O�2�G�#*EG:7s . Al�Is�@?a � 5B;f!��Ie-xd 7-[4&�C�9��  s�&ynthe�B�: yeas tm � +Y��H$, pH 6 . 8a= t 37�>wit{3 agit͒r! tryp^soy�ri@S3(p�(ppl��Ecc�( $*000 U/.,; WorthingtobLakewoo�NJ��in 5% CO|@n�sBineomy�i"sI, tin*�@� or kana;*�<)_��c .6R9�� c&(9ed�O*�to enEU�%6"�9E^6�9!�thA�a$� "7v� !�!PZ8M �Kn�a� �:u� A 5hto� OD 620 nm~0 . 15r4ifty-µl aliquu*)d�A o 95�BlR pH 8EC 10 ng�JjIY�om?4nce-sta�� es 1e2 ,@tof%�mM CaCla0approxiCly!plP9. R�$�g�incub%��"�A4�Au� Vt�?�9�6tom:cS$ al 9;b�be�a�M�X+ um .��Wa"�GZe�q;ure`)"'< by oaua�*f<�n absorbe!of1�. C*�wh��( SigmiHSc7 LouiA( MO )a)� nt� ��( V�?ia Bios�8�PFort Co�DICIa�UPBS� stocka cH�K!� m%�. B6�at:$M(Y� = A�3a�� d*�nd�eLK8R�2� or vehicle�;"WW�.�J&�&i=a� ��J��D.�,�}u6�B! �K7R-A-W-VPR-N-R115 ) ( GenScrip!�rp�c , Piscata ,�O,��t�6����b�DA�Q�Ad5Q,�WthT[t�a" 5 hr(F!f2�HA��=7 remok!�s= 1 l%Zs�Pd� 9G��cida(o��<dG)i��9- ��6�H�A��d^j . 102��'5A��s02O $ Hank's buA�Ca29 Mg2+!�8ibco , San Dieg C�G� A� 1% g=Qn ( +++Yv��!4|��� ��:$of:f: 1&GH�g��e�, H�?,*�GQ�G jaA 6�a�(room tempers" �j�+| �T67.-��7eh d,d&�K6�J";BHG �, ime �)j.*no*�G� oYToFGy&� �&\ iHu'R �firste$� xA9ph 2�S abov�C�& F)!�Gas.�de�%!Two-m� crud�� M:�1 m�F�́h(0 mM Tris BI� pH 7�IA$.��T sin� na�fovern�!{3"X *U . Try<�>:KMہ�at 65� inasod�KdodecyNlf� ( SDuZ.VIwa=WtDA P d{lJ?wVO� 1 Y7P�:< dH2O)anŜ0. ݜN *�I�.��Ide!� ����O��?12I��� 8 aҵ�)�m��Qer��ag(*� ��e�/��h*P �3!�!1m;. Six5\8-week-old female FVB/NJ�5��o2�9 Jackw9LT"�@, Bar Harbor , ME�&Ode�CLys"�2�� IA|%^ �&y A y T�Taf� s�*m1�EE% d Gr�Fluores!I P��Cexon 1/i9n 1!�!>5�loc�'.�m�%�cro�0�tenŅ�gTF�fb, [44EnimFYho���&ccord w�5In�I�Ql 5 C�!A�,Use CommittehDo_��B�ap�4d&�7/H�<=?@�at −8q in 20%�e�7 �G�r�7 f=M0+ 7:� PBS-m�aX1��l×106ior &E� "� a=I �%U͞o�E!�s pr�;:� [-�&+2��iQ�H����d��H,]< sacrbe$��hea cann�!�� ��� a��L��. L7fluidcolqF�'\na� M� \$lu$inV��1. %6enumei�by%D�%E an��?!�$,�X\$ont�a�. S"� S�e.v3Bpro�0m�&Ea�0v� M.M*8�$0��~�' as 20 CFU� 8-Z. NeutPa%'Z)h/!*EJ�trifug0 �TFi!� #�^us!T2�/��m���"�C�Br*\`WM�A!�]E�p d ;Alu�BJ ( EC�[- �k(horseradishA�ox m-c1g�seQ|<��donkeyU E Heggc� , Lit�TChalfo#0Bu�_hamshir�UK%/S\z 21��WvC Blot� SCAH�diwAtechnk^RoB�J�9na�poi'�]m�hi�Tf�J";6 Us�d2I decap�"> heap%�fixX4%�*aildehy�m �\�G�H<k^lS) � in Cal-EX!�*�F�hr6�Fair Law $. ParW/-embe�i�C!��C��n� EMza��of xyla�*e�,oV*�9E�'�W2�  1� c��%?post-5D1∶1 m -Gl� 2 !#19 2TJ z�%st� �(c0E�E&�apeqD�w blocK>�30%j +� dH20 �" >��2K avidtnd biot�\��F#fPD a�*M in�' _� reag( Couu1/I�Ea_)�" , F�P�%rin&�C!3��. �b� �B��B!�500 d iaTx ×�  ,� boM D alb� 2�Pton X-R�or PBTo�urling�J��Ela%(�>(6�/ a �,24  �!m6� �@ABC]RVJ��S2�aw H�#a�!epV  �"a�/ dNCo. 1Wt% benza+e tetra��ochlo�� ( DA�Gki�!V�!/ ^a!�� %ie�>���cr er�herxyle��ѩ���,�%���mRqCytos�P ( Ri�,d-A�K6�Kalamazo�MI%kCu2 �Km sAE! �ac�'�P"B�f0�� �Cll�T �B *�-!�2G. 3QB,BM yL nl�6o9E� . Ca*)F��%�B��9�F. d&��F. T�l4j$AB � tatens S|,�tu"9Cop� ��, D�ADɞ,to a 96-well styr��>tio& �q�ng 16? atF�( R�mq �061� 05 M�c}. P��-'m�g�0 k( �xe Z% BrijEqS)�&LES� �����as� � � ed 2�at�n&*%6���e�-A`!m*32!��!$4:#>�. G��–"� alkal�phosphate"> CIdiE�BM %��y�0��0!K�`ant�2 %=9��)���j. 6.���e�R��'��A�b�"i���Ae1Li�� read%n *�of 415 %"�" �m�)a"�Q�Mgr -BCA"�Ny��0 QOan�:��oc�"P*]]( A@-can�,�u�#��J �saJV� A����t�knd�,�&at �$�%�;��".R-,�Q3ic"53%la^*K�6%�cal�a9� 1-�" ANOV6lKruskr{W�A s teF[�B�metric�gDunn's� )( Psm 4 , GraphPad Softw8B�!V��Ŭ�.�)p�2!&4I!�Mann-Whcy �:�,�E-t�]#or��[NDeng*>�+ m,,im�ar pod borne�3�#Eyworldw�}erm%�morbid�!�morta|�61z*a�Zf>3eroA�Fd �84�#DENV-1�Om Braz�s�i�Y�D�Y�"�'�x N�*�%fM�Qh�/!�o�@E of=@986� �of�*94A)270 ` have�/"5�0a�2/596V0hemorrhagic f�C%(874 f+ S.%��1e�H!> )3!^%[�&er�YZA�0 ologe��.We� ��@a�to5{ esti]useful�eof NS1��(E��x� �-n�/ toolJI �A+i�Qcmen�T*�&e�KE�. ( nK!2�'q."�t>02M#)s5�74 B}�R"w : liW!:f, lung1A�, kidn\�0 b,./�,8r� .�2 , sk�%�m�,lg ��'0yme0!!�l+ no#+7e . We"�\F�f�9se6!��� c� :�$�6a �,E��P(d�$Bio Diagno�8��#T[2�<he rapi�st/AgH-ipb8I�ov��*��Y%R �ijKi�1)�A�alrsbyN�,6�!Z���a$034 . 7% ( 08/E�,[. 814 ?91 . 321 " p�a�5 �J`i;ed~A��.9J 17/7Am�CMiNa�z�2�in�. D34 D hCbst2� ( 78� ; 58 -�achie�)9Q27 z&�B�w��"$ � A:�8+��� ( p<[ 0�* �2j�hŷZ�q�-z;=ym�7!�4%; 10/>�100%; 4/!`,u�88/m�sq�6�%6%&0/e�)ym�L , 3/a��M���tx�/xMiT �i�}��� !m� /� iH )qH�achm post�em��jW a�e�2��jAfDHF[yh�\){ewxeX ful�h�2vpl�".-R�8��]dn|: eill�$. m,.! )���"�8a�~SE/&�mosqui�N�ht!i=�U�21�{entury%�%w"P,�^ burd�Yw;^i)R]a�5 bill�people*P ,isk!L��*n�~1, 55%!� &5man�d 7���m r.�P� �Fiann b�00NB�(�w��Q2i12�1.*[�E-�n �a�d������" m�qM[I�< h��Q� qH*g FT(E�)E� %Sh�0Syndrome"S.*[��InR��c �@.�pub99hi} blema�2X�e48��epi%\��d� e�2� !�986�'z� �n| q�8Bg C�}zw, l"�)� �RY;s/1i�.oi��$A�inyg� "-,��&of9al RN�j% ��fif�"]PI� �;��(HokGC1��� �p� �LN"�@E�a�on���I al 1C<S�  Z�+�V$*��9kT7@ �K9�.SE��sN9��Q�AN�S* �!@of� �%��e� p..Sq��u�<��8�K��H�� fdJ�R @1�11N*|�. Fur�6e�l -��X-!L&x �V}qp��per!#S*5�[��f�P�@� b!Vi� sIX&� ���Ma�;A* :��CA� ario�.r-E@iM7z�$nd> s��|psA���Me>i{by�m-RT-PCR [*ތ`a itu�"b[�� and/f3RM��`�oW�[:�` ?90�S��0]R NS3)�E����).�)�E�.��t_ retro�b|?�(y%J��hom �jE�J,>��) !62�. ^`~"� A)� wbe�bj9�-ga�Z,"�,A���U"Q~IFlavi�{0, IOC/FIOCRUZ 0an ongoA�Pro�%� ��byJo^61� CSN196/96 @p@Oswaldo Cruz Foun�CEth\&)/ins+earch�EP 274/� , Mief�N8En�Ep&|'�sɴ�@eq �c�fdu&2ampli}e 511-bp$ �AouLJf)D=ase*�2E�o�3A cS@copq�)2l�v� �C �*$ Zku� . Aڅ2 oQc�5�B� ( ne�0A�)x�9�10,A �`BuQsizlor�m��TQ�xg�=On�Aep�l-�M�%�Y�m�ABIl70S+X De� n���9( Appl4Io@���Fos� Cv[$fL�-BUL������aS$µL�)� mixt�E�ai� AY�!�,, 40× MultiA5b"dU6RNA#KNPo�80TaqMan 2× Un|sal%�Ma�Mix���faD�n a�)�8,� 8�rob�Pel�(Ve 5′�I:5-l!xy8�+�FAM )`r dye] C32C6C-Ng@ , -�$��ylrhod|( TAMRf8Z_l�oph. A2��r� Eu�j�M2.8�5���Ce�%�15�1A�B&. })sA� at 9)$ n(2cyc�6"5 �F6�9^1Q2� RSprocedA`��N.�*�:�n�i�}s:�a�)�'"�(%')��Fx^{ (a& AEC Kip$N�&, Inc�:-(, UHH.J�2�v!d��-a-�!�-3 ���A��2a�E!t�. P؛�� d neY7v� �;�0�uBFr� M%t.� k$,–2 g ) kep�>�I %s nd��|�7�b�%���by 3 �&iT� weez� �scisswO.v � �62�1 cm3Evc&e$�FL �byta�Lpes=/E9E�� . 5�&Lei�*tz-�+r8�1 p9@�A@4j3%�%�2ci@F/�6���Is�?iJ ��nr!�.��Hml��� tub� &�$���B"�G.�f6�$rpm6�#rc�@ ��N�:e �"� a�B�1� 0 mL cryo�!�s.(=J� _ul a� ��nd��Ѵ2h 2]�@���t �U� �. *1 5 �&�<�B&� �c_uhVa�&� AnI�na��( &�(CeM�]B��6��"E�"�*>�!7>�1� �onhdyeG�!.Q��es�w�?-�7v��%es�� . Un�)f�{��7�Zpr�4�Fh  -�s2+manner!)!r!V� 6[OI��{�{E�abu�'dWa�F�>workshe�w)�]�&$soft Excel�-gramm�����byc -squ � F$Epi Info 6HeRV�D��6%�P���i:tlantan:1#*j2ha�Pa. �%�6�� 1 ma��nd��Bs3 an ag� 3r of 2�� 64 y�aQm 36 y� � 2%�ntJWj'novel)xach%-�YeHia�AlC$Fl�x�6f H Uy�ME"yFc,� JR!+R�NHpaV�3� lso�.�mY��*�$!��,�A��&a�$-3�ld�6!J;L� G!���!1�!m�����  YV�- in�  ( "2Bb�?:O 1aA�I%�� i�63�=S12/19&Fc' ~byV�. F"s& # 9\��Q ��F�5:/ltLj;� 9)CS9 �@�de�"HU"V Ed"� 6����ov^�# �$bafj�#B�$bio�2(#�$rad#��a�"$ !�3� $& $F�yVR!B~#t��}�sm on �z!g.UZ�n~$цYf"�a!>2^,��$�$� �5�|�&�_M I��"$i�|$�|$&M�!�(}$4$g$kL(2$4F$ ,��$v�$"mL&�� e�A�u��l-�.7=�(cAAA I 2Iby(Bies����3E��$!�>  i8��"�l�tR% �fY}cѡ� ǍwY= Vis .�$Z���v��s�8�20%�8��o� 197�%%=a2E 1G�@�; o����!&�{%d�Sle 22Ҁ#23�s�.��0�?!�5�i�21"���X17 R( 7��9%��� i�s "߀]�ou&n:a!6.J�&d*)%FQbve���!v�i" !!� E�9t� 3���W�.�'�� �6�(8ܑ�!j�|(��)8���L�me�z Yy=>�j�6��+"� �o�b�i.�!t� rML�#�&NoF� a�:iAF!�{��.Lof6� "�' �"�*�+"�%!I&V "�[a| 4ofў"�'ce%D�I��2 F�S[L2pa,#,gu�0A]imZ-of�3s���Uoh dX U �utbreak���.=%c%��m�ng> a�'&A�h (���l? �0��g� �an�'a�$�KKe! r�e[�'��<5m:.��(al��_`tro��s'۟�%%t o���B� ��.�C�ea�Zcct&d a�def_�c�7]% �4m ofF'enF'TEGE&! }k�26&� �>on2\#�"7] 1r� iff�ktE�e10�e$�%� *<-eO�$personnel ^� f�#.!��$&�$٬s�oX?AY�ofq�d� p0,����#"�$�&19:&I$. D�" (� �Alig%�belief� ��H�anato�c� fra�L=A staffm�(biosafety iɆ�I!!)��Lbe us�*U �Bmai�i-o��c�<+[2jvI^ ) ��c1n�:�0q D1�*!:~Bi �&^�= �of* i�m�i�!>ѓY-�3�+( ��0�0.� j��0a��.��! ��!��^(1��0�"�� G��e�e�S S , ���2�/ �h,2����.� Y nu�L y��0 �^'. D�ctY��X,�&r8�t �  6fer���%t+a3�%)��>�di��(�e repl�or mayan +�kq@A�he�@u��5aQ��)l�tt2�!&'�y� [yN�m_9Utƪ�2�" �o,� W&n � ;cO5 :�?,�ea�;)(6�coF�(9�.�(�GI7&tv��"(6b(l�F�5:t6��=smaAF N@&."t ~.,�[�#nƢ#'mfd=�!��M��I*cE�1�>�.^�-� 7qrk5�1AI�I2/ �$�1�*"� aS� All�&Yr��"��iɜZ ,��B8� m��.%Q"� � %�) )A1kUAzs�>��=k�$COF�q%�&�/w:�DA�oearYPA���)�soKx�ycardiac U;J�1�2 -�!�t6g� % U*_+�c� &�z�wA<D'gn��u  mЪ�i orgaBEvpa��ؔA2si"� �s s"ve hepat�OݵFperhap&�� �""D Jy,�x>�/u)s" xe �B�h.�-�m!�1^i9�� ! dow�X�D -Cbarrier9b�Q�l� mkmxir> 2s@��4of 378 Vietnam�j��%�m�al nerv��;$9vh �2%i�)��%�4z>G -��invol�z!�Q��4Q�dysfunX$, &1rle�"�ie�A�e��E docu�� nPthe, fla&jhaCsub x x l ha 5�>!� eft-�r� ar�P,{uuW[0{ L8c rhythm disordy ,"vatrio.Tb^L [3�+xoa�dI pic 2*eat-�2 ��&��� epis�<� HF ,I�mAOs�ngƺ enig�u$Ip/ZƮ reso�-E�.>?fe�b�X�6ʼn�my)c tis;5�!^exa�?"wm!Vye��& luci ��>�} ivelaBe}s{# mon manif�Ah�7mY}0 oracic>.�1 pleua effuAg%��[n�,9iin������i�U?��A veal�>LJi�7_a 27fo�F�i� e zop�DveoA�:�s��"-A�!r�r.1ma� h^�Tj= crui�&G5�l�A2noVr���Rm��6A�5�pN��2)1a�EKrd%�A%7a�� X�a�(c%��.eI k�n: V��a ENV i pr��u\��tX"q7 trop=D�4"��Ge�;s��!N.��lv�+ ����i�`EN���� rICT��� r@�N&��u�0s���&rti�'] ��"0 s �9S"%g�*��U�ʼnfa�axe �:�BA�"=j;!(ٛm�.v-rver* ��c�9��ow��:� s seeTd�c���/�re�2��*h s� piew�i�� "�&n�d_er7EZ5 � ch�6eas��";viaAlevb0�N:��GlUI�0�Y6 helpAf2W&Z�~aF�IQ�[� 4�84"�&�U���s� by-���6� ZA�d EuropeW^r�hA�syR<�� ;a'�8l�x[4��FV Nile 2 �:av�103�7EbolaF.��d!)� =�monke��4>;N6J�J?H�2��f.��t"E.)'In~ !��e!�t[���:z�"|Ӂ7w�?�b�"䩿��}irc�$a+� irr�F��7� to~(s~ �� �#A�*�.�F.�~B��-S�bZ�!] �>Q!�%�'\M"� � �+�!�))!.2"X*�-Y bo.�(3Ps ri�gݻhoe� "�-Ui��mi,!84�"�s�� ;"C��I�F,"L!�s0',"����i#�.��&�9�A�� �q]v#z!E�;r� d up��Mm&�F�2'x.��c�5�a��2Hy� ng� �/)+4 �I8 [bq(a�:�-6���"_ }�a2%% mvM�C�4�tD����qaM"/^:�=�!DsO��rABled" ��Lf&q;an��|ann% �ng2�2�va �d�k�ac��<�)\� A�h�"Tmak^� suitfA9�K���ur&�DTlv  Vi)1��=�ej�A��T!� �)���fi�purpo_��autRW� noLan�� .�q3$ple Myelom~TM?2 �A��T)igDy��.�)lye��c�'cs2�8]N�Qs,Png Afr�P-�AP2!&�Caucasia>f��!goMuAJo����ca$*g �Z� E=MM)�"��V elf-"Tra �gen�w�]st�ۉi� util`so�c&�ex�=,�zA� k�� duU�+�*718�"5A�B�RQ *�<CoMMpas9y I!� im AH#�9Q �AiAe a�V �5J��A�5�+e.'J>�8�f& e���Q00�YOfM9e��< CL7A RWD3-;AUTS2..sly�Bm�Uz�AA}lUge��-l?'+ 0&L�in B-6W2< J� <.�=IB��� TP53e� IRF4ir1.j� �C�Y�Ys I�a�=oa�terro@3ng"�Ptum��hor��oɊ&� !9i G/*�HL}B�(A�)a�o�?��a�YO3ovo�^"Y globuliTo>6rr�-�@� I)un���":�����!�'[Ťc7LE�aO US [d 3�FP.2eEQF .��pɗ �1ag�Jc�g�!�li�ac LDed “*�;gammo�O%�!z'isDyJce”!WGU�H�R5�i!KUEW� % 3%!s�*�J�1 �50Eo prog@Ro!�7vr��O=�at;at�1%�� y�[�5�9High-lO]Z��8h� e�iniI��s �)al/eth9D(s���out5Y�T�#!�y XGyA�Nc�>z (�)��G matc0^EWocioecon� Ew��]g[�r�)HQ-sI��ly� �" agno�,w�MH�A`#!C� d�#� "�%)F%� 8 , �IxkiEaR-)�t AA)< cG��of IgM V�ɮh�an H"aI�eIY�&#�CA9T��H.u ��E� past�P���<&m im�΍C z�!NsMmanag& �� y*� e�tonis�c�in��-� iv���n!�z��2�� 5� pred|"�e.�[�I�rg~�Jdee"'a�2�onca<��es dripM!ZeH��,'w �Qp���� lti-m?c��, ��; }7dda��sZ) .� outco���I�AY�w�qd� "��`�+!/k�mfisbB ��Ab!�id�7vi��"1�l�cap�zMM [1�r1��&���re�!!'v���e ~���ly"�l� ��n�,n�yJv� !ExqU�ofrz �APM��dIgH>�by*wce�#S�JHy]m�J5� rAl� semi se���@�:N�Nc&co�"��6�Din!,ler�cA�A�"o*)5�ed)��8�D3) �ReAgvB�vmpreh��Hi � 5�f �,ϗ vS?!���� c j&�IA����e ���e�-HMM�ou��lHM�=PAMM� a �+؁w�-ma�� b�����5, ?-upUj�Ey�s�cNi*zQ�".z�o�'r�i�*e��ol�� ΆA��+erm�r�MMQ,A���<+ �#%@=)�RNA:RME. D=�} �Q�vs��� s:� �6Z��)���2� ( IA{5~� ( WEi E�} ���L��;`8A��� 5796�0�a5�k~ �� ��n���g�^�ar�A�FJ��ore�m�� �d� �^F��go&)>����C��9s�, H�"��"Kddle EC$O��D} -A�Un4T���nMbe[�E.iAR|��&HT"W.N%�%�~�F��g>��^h:b�*3 0in�Am��r�O*��o [ ��cle �%��i9 P bioge1��Sm�U�+!S���wak .����x�V�� reng�-f���G, i5.f���D�c���-B"i �b�78pQoʞd�E���C�r�]{�U�` N�a� -�onR d���+I0M�s$8 eontex���%V[16�5� w�n�dis�9�X�*a�)2Ofl�� C -*� al behavi�A4� play��2i�6 �lX]st�9��AU�� 5  ={�*�aM&96.� �z8i bf��"b�O-�&,e unpreceden~"�-���x1=n�La�dly*�tu�a*����)Q�ly-n�4}�./ja F  �$\"��|bseE)!!2�!�riH of� qu�!)�RN�2��721N����at` 6�as�ACeN = 12o�or7 (59Aae6�"&5 ( S1�75) e�Af6����<� *@|om2a��Cy CD138�y�+jta� yiel( �U ge 99% 3+asma��+�AC&�!�9�AQ!��&s$m�0�� 5��s���-�N%�^on�I7:7S&�"� �#u�IS2:lA!aEw"t2a�4 %-�i24X�9�am�QAa126 �� ��1Y��!dofTd�p�M�Bhe�)r�4s� 30X�93%�) .�94 J�AVq���d��200j\lAw  pair-| kI�88% m �]6�n�|edc�� e� �+��4A�wY2�.5�n*. princip6���'��:� ( P�to cl�~r!�u���x��)�761 A����� ve MN,( AIMs ) SNP�wgd.e5mAIB� ��1Wz ��"z ^ !�.\AB$a<bizX�d alsoy� STRUCTURE*����.�M�9�c'2h�Bj�.�"�X[B�u��yiY"1�itwo:QC �A�an�_ U$ag� 6�'"3 �;9U9%&g"E5��d � �D,6��U)j�lxi8� �l,I~m�"���*^127F��591.T%#k�!�BJ qe��"M#&� O:*A � 3�Br� ; 11%–6q=�;A� Vw1^vZC Z�;.]�E3/,� n���"ema sI'q�� ) �"�*R$"�-a�Wax �a�. �]�(2�( p =� 004;y’a�twoF��cy6a��–49h:z�M-s"�5�=��"N"(F-6 I�2WS3ݝ6J� SaeQrsQ����r��(�b7�w�&���# y.!> P ( 22�.� 14f�Eing$a<�we���*- w�l,Wܲ*` ��Ua.�MM ka L�sx [�!��l�с|d1i��a�2���� b�i%t���aq^��� w� �q�S"���� MutSig CV�8l!B.:w!�custom �Q�!=a(4�5B],ly�lOn!��CA�Q �i�We"���@ct� b! &� !mm�'$bynonymN0"�Qp> b��Y an =�G�9Cc J= 6e "�y�5�i( S3A�!�Fura2mo�~ i=n�NK<�!����W ;�9#QS3BknPed/��I~���$�AMcer���չKRA{N BRA�/�, DIS�FAM46CM�S4�S�hE��i���"A�B&M��> �ed RYRQRPLj PTCH% 5 SPEF" MYH1�ABI3BP*N GRM7�UQ , PARP� PLDXANKRD2 DDX17%�STXBP4� g3 e!��&���� .{ie]SI�,.6.1T2��l0}V��[sG��V� ��[ ward���3�;TH� IYusI�8Pl )�&�2AL}idQ�Oh&� M�)�R��q�+w�we"("�7eOIsBFx->Ki%�"�*��F^!=��E�Je,�D�a:A9V600E>}�(���.a�Ŷ����q�)\nonim�$NY53:Q:�A"�</6i� �&_�1P 9 wp6R�YXC�"(9�4�Q�Ʌ433nl%��)��a��IB�%9  �2a ms0e6�n3%AA�.|����2U6&AŬ�U���T��S2e�:�ToA ify%kIV%Ik} �8"$I���'M�wV��hY�P5a� ��(val�4���$j�by LohV� ( S5 ��p�:k�9]mi��6�A �pse�s�GV}��9�H{14FS �?�}e F�,a�)i�5��EsE�:��5: q�14/157;�@IɥG�p;8J8W�3!o:����'���:i��iv;hgm�*4 �U�L .�pr��� �j�6Oe u+v2)&� c� u}X u/TN2YX? stro� a�Sx5�;��AJx( >95��(y� 1; Wilcox�ank-su��stvy�]�M unc��*Wi$F�:&5`nV�.�;r>�"��a Is"IGISTIC �kc%�R[2�X�W!I� *�Ooa�NH"� .�-2�7� .�galnd�(�M! , S6u�. �(���2nW�^�:)e��^;8.�F/�Rb�H"nto*p�L��u>7Ee��*� q.�-�e�t��A{�".�pNA� qcu2N&c >�"~aA$<bi-#ic O-;.�.jRb� �.a�&$��K u.� g*�EOic)#��"."�#F�U��L8� h�r����urb��in �e��l2 H27; Mental-Cox Log-a��1 bgor\�E.��_.��SP>� BAV "�.�9�,'5�-�(I�v!ld?)QP��)Ed wild�c) .�We!. 69�%oq�!�!�0of"bE���'�6���bIof Arkan:�UAMC 70Ae�|-v!���[�g.\k@& �u��/aVFDb1�Bm/�� sub-6�2\��im%�2���,662&tW��h>�*�3%��|��P&� %�v q�m�$m��3of Ki67�*,��x����560 �MfiA� U�6Dr�}���� 0Fig ) Not sur��prisingly , the vast majority of our current understanding of MM biology has been derived from data collected from largely Europea2sc_@cohorts , even gidsignificant disparities in�ease incidence and outcomes seen among African AmerK\ patients [10] . Through%analysis� CoMMpass �@, we were able to ,ze8large!>(ulti-ethnic!" � a� agno[toRe ,�$an attemptelucidat�X-depth molecular differ�%tumors d.sAA%CA casesSfurther 9��)�4ical determina!)�0as a functionNm�Dncestrally defined�,aset . FirstM\natureKhe6[-hrllowed u�\confirm previously reporAKresult%�4published clin�A 96 studA4 �. OurO F%� simi!etoRrEdemon�taearlie!�I�on�in!�VzUrF)�morAseveral8genomicA�quench�[12 , 245] have eu5(in both new!�Iqed%relapsee! we AvalEp8d commonly muta!egenIiMM suchAKRAS , N 0FAM46C , DIS3WTP53 . D6�RAIfr � Y b\��(is still ye��be�ed��re�Ym��Tbe a potential enrichm��of its q��my1�J�Քof�]. BRAF5�si� alsoF MM ,eY��at5Oauof !P48%-5% [27–29A!56o��l6r2D�/noY�t betw�q��.did%C:'when �Gfy��pec���Gby|V600EGith hig��Qi���in��( 4% )��compared��$AA ( 0 . 8,.�is�Lece��exceed ��A1&}$u�� limi�powera�2�wLM� ajc��5_survival�primary!�I�harbor!an)5� , nor 22A)/u�.  wildtype b( p =%439 ,�579; Long-rank , Gehan-Breslow-Wilcoxon )7 es�V�Ea����c���e!���� parti�l � �, � be tQ !kEse�mFinhibit�, which> shown effAoa�uta�upositiv��)`[2�(I� Thre����� r&{ lyQ�TQ��3A�r!�vol�́�s 8B-cell malignanE�.���� �ta� direcpiLa t� -way� transloc �% Myc��IgHa0-grade�Pnon-Hodgkin lymphoma �li��[3 A� ^ �,1:s. N-7 l reg��of2product�Vdisrup!�1�is �@�i�!toBpatho%�� a sub^ of2� �R� �The�,tein encoded�bWD3�0a bromodomain%CWD repea�ntaina�pr C*6�� chrom -mod���|�|0nd may play a�JAK/STAT�!�activy [31��Im� anA!ris)�i� Yk21��� )�@cytic leukemia [3F��6 v\Ek PAX5AdM�precurs� cute n blas2p!ic��rs [33�T�FfiWs�Gonsiderk intereJ G� v� Ay � 4al characterizi$I�se%A%$approprik � 4 model systems� Z lightv their��T�l6� p.�i*q��d� . An)�r�?��7 b a�& aw J�� "\%��er&�admix� ��ur� al. Integre�]!k$copy numbe� 1& r  tren�wardsu�0bi-allelic inE� �inRf"��i1�evI�>al=@�shx6m��universwMNedA�dictor!�poV [34A�WeU�;c5.�9�Ek IRF49@�:� !�� -�)�C*{ . D� creds ed2 onco�*Ois kn� �San#ic fusa/A�ner!r/ !�]lso ~Ac F�Z� [35 , 36! MoreB  , �%߁�_ ssocaqdI�2[,P �A apeu�Fimpli��(s for immun��ulatory q t%nMM [3��38��_�sug�����:� 2�WU�Estr`"�6�2�:� co!�of longi�nalN���ngo���"�, one �� eOta&�.Ūe edi� fol-up g� IA9 . How��r*� Pde!4M l ��assess&~.��^a)�&�profile���dfin up�U , 000!�� $. Ultimatex�� �repres�iaAqprehens% (?aRNAseq )�5�!� �a�� T z�3�Js�K&:�stry- :@=� mechanism%4:v� � �` at�Nilj .W ��"� yM�X s92P�d*w.h�e� � lookk ecaus"` lack!�A��<�?R!i�  . IA clearu�re�YH.0�MM)��� ndy�)�� icabsoluE6ceto� tin� de+ 1t�� ewtt�Umprovey�manageAwQ�.p u�Aby m,& it.msc�istpѲBse*C s ww as exp�0M�s�� L ,!5�}�� driv�y���Nclo��ev!1,du�� cour-� reat�. Sampa�:obU �nder M1ple MD 8 Research Found%_ ( MMRF )9)PStudy Network Institu�8al Review Board� � $Informed C�Lnt; Copernicus IRB (0# QUI1-11-217���H -��]-o�aly��a22�, -na�hMM�v1��p�� �,F�� upa�Bmen l y �agni!��U��terrog� 0by whole-exomA� i�'w � �!Oor RNA s�A�we:�ompon � iresy ��zof each� �6�[param�ur ti� annu� �r�eriodY10 yearsB�2r ici!~ngg ~a,y0w�an IMID!�P as!5"��Y�m�.�. rm%bye01}� logis8�!�� at��lyz� � relEN he6m!� rim A� ��n�i)C�i!-6' is 9a A9 )A�!�ri�f 796A que>�B�0bone-marrow s�� qual ��of� , 75�Q� ogres� D���U+ anno �  addi�� A9B�520� �b����%��z��y�i i@a2 plat�l!Q��is�cE�avail�A!bGAP acc �Z phs00074QIn.� ,jperee�*� on2�|� 741!aEr��-naïCJ �LMM��cV norm] -�K!H, thosUwho�f-"�� s ei� "�"�or*%(. To ensure F  dow�eamV�%rem���%�ha� ximum seg!�^count ab�9500��b[ca�rd� IwGISTICG0�G ommeѨ6b ] s [2pT� `eda�fi��7216���he5 sholi�E�u$o�XB e2 �st cros Y�. B=� aspi�sELph< blood�p��e�om6L^VE12vK subj:to� ag �$bead separ)�u� �/8Miltenyi MACS C�S(S�-'0, San Diego ,� )o�ENCD138-"" ta plas%a�O��fly eligi Qe��g�e� n 25���jR c����f%~ �A�A����2J80% mono| �ch�ri�2�a�, @ nucleic acid ext#� . Gex DNA� 1� puri�9.2o(p �nah�>bP(aYs*� )-�QIAamp�@Mini Kit ( Qiagen� ot� V�n�aMIK0QiaAmp RNeasyZgN=.Q ry��� U�Qubit�(��rmo F� 1 AgilMTape S�z2�quant�!A�g�#. 2? stoEA t -80°C �mt* ů��.%NU�˅::two"@ t�ay� clud��� ��*� %)�l. �  insert 8: 69GS%���� prioq �Xif�werP��. For3, 50ng-2�ocic�3fra�ڡ=�# a�ge siz�180bp�zlengthMa Covari_ c!-ultrasAb (!)� n Illu4#.�techn� y�at� )D�e libr����IGKapa Bio� ,s Hyper Prepa��� B�%�tM.N p)�F.c mQ�SureS\@V5+UTR hybrid capk�) RNA-=�,��1)�r�8n%�t2�!OA�w(poly-adenyl%a�����Y�ly>��6� by h�Q a��FYld%Dconver!��� )+rando�$im�w� XSuperscript II ( Invitr�I ��second'a�syn8iG��A�:�%0a�)�Uep �9UzTruSeq!<*ki? Pa���� gE{E9as��? ]�HiSeq2��or  Q�)4�93% 4 chemiu.e�f ��,Tpaired-end 83x83bp rea�ahilF-NC���nW 6x86Wxl/!l nE2� indu�s�(9FASTQ f� � BCL2 v1X . 4a)�pro� �a custou mi-aut*� ipj b�#upo#>�softwW acka�#AMp ab S9� �-ini�"+|�A=,GRCh37 human��refW( �v6!7�BWA-MEM Fr [39]a gene6 BAM-$$. SAMTOOLS A!#19 [40]E E�to sort7�PICARD)VH111 ( http://broadi(Xe . github . io/picard/� mark du(� adEm�8Pb�e (joint INDEL!2! �!���sco� recaE��HA�*{ � .I*GATK v '1–1 [4���� ,� 9Ba�.* ’sA�.' �@$ EE�%Z= germ�&sAgic ��@+ete�),�|p v�. Var#��� 2R x��vid��HaploC�r6 2]�Z-S �&zi"�s le� otide�s SNV� %�6� �.^N=/��'m � depenpJ��$MUTECT [44 '(STRELKA [45!�SEURA!%To mak�M� l, a��)�e� at �t� ou�!�i�%�rsI!.5WR�B�� 1�-)��aQA��� �R,� util� �iDNAh2jmodul!X�Con""or [47�We alsoH>.�%at2:�^+a�ach[&rerawm"as� �o phys� � ag�� circh-binary6�*Uf^� toi+ete$�ons� #calW�� log2 ris��:�� �%9�/q�� mba�in VCFEdMAF�mati'!Տ$SNPeff [48���aFa'�&��o�&!�at$�Qk%Q: } � we employ��(he TopHat v�(�j11���ofN��d1 CuffU, 6: 5����!e�almonn��2qiso��nt(��[4)�� r5��s >98%m� -�as0w/ =�y������� dedu&6 !6SNP &��lSuite v��5,Golden Helix� nc .@-oze�� , MTa�ww�I,h+.A� �� tool . E�*!��ome-wA.A�/yVi� Mark�o( AIMs )�ri� $Kosoy et aa[50�"Price1Tw n2!ͩ�iQ�v�. s es�!� esta0by Rosen�"w�fPop? 2�*d a�n�#�5�( PCA�asu�u]����Q��%��s irgenval���t$rib�CPw2r��12006 [54�6� ���E,! ��a %�!��adk� STRUCTURE9Q)�plink%�PGDSp�%i�H �'3 [55�'Cg&� as:�rit &d� [19]i��$Bur��o � repn"e�f"�e��&ecuŏ100} ite����e2CMCD�. E��ge� clus��ruM! th 32�r���AU�� of pU�s ( KM�M�)�U!�Z!L +a@ΔK) .%�&� .Z��}pK+vc5�32,��}�p�3~y*��G.v�` Phase1_v3U�'3�#Y'(� ify2�#�er"1 s�i��]"^ �S!xY5I} MUTSIG CV=� on S",ce�lg�hm�Eadj!�=3��#e W�!�Cexբ�" HV#�d�E�at qD�:9�+ 2(2�ti-H{500�erYg, �l 0 Sailfish TPMIx� h �'�~lfA�!1��.= high-risk�0 e&� "UAMC 70!R[2^!}M}�Ud%� nd���8)^;&2*` Ŧa��7�7E|A���6j6S � gpq6$cep"=�FaVtek�Jj/jtr4v/1pbm%��%�K�$O4!o}f.�AX8� �-�mIVC�Nexact tM.[5�6 non-jmeF0 Mann-Whitney&�2�4assump0 ofTty�>4mai ,6!�un0� -q� Welch� corr��en Q& trib�$[ve3+unequal� ceA�Benjami�1@chberg method [576zɮ *�<v%�!�. O)� �4!cinfer�� !M*�#�Wc�$�o�,4�#’ spam)� )� Kaplan-MeN; ��aBp-� of <�E05�� �s�j0� շce9.BE�t�=@��#�R� .� Y�w> r-projecn�R GraphPad; sm 7 (S��� ���Bw?y��#Aof "rOare) ngw P.doE�af 5��*�3� ��XheH . PQ E~5i�2A"!���utW"(.hi�ɧ�R����9��n1�>clockF� beci%���-Q"apy�]$$er��i�ce����.Y)��stochaA4��an�of��"Z 2k: a*Dgrowth&�7t�'s� metaE�n3]A�30 ?��F)��/+]fo�!�im� d�#5fix)�probabilA�q�)�of�)�!�p1�][ord��&iT'8appear�`);comput ~likelih"b�96 tre�!�eb"7A=�!;phylo r" stru�Y�U[! &h,(!SNex1!�)r�Qs5L back� -M:!^ a[BubM!qn�F �\ ��!k�& �ai%��+#Xar$%E�a%͇!ulaI�!ex��:\3�-F�:1�O>it���/ YaM�1!���lu"��Q���birthE[death:(:�*�+Ay���(l+,�,a  . In�$lthy tissuE+!Y �2%A� v��tightlWntr�j�3g0enR'!�cis�(lE��D�,-�)a�ell �boB��saroxL0��7� "#1 �� I�m��k4L�� �d occue1!�!�!�ccuA$J&� �}i�  , T&�(j���-=!?��neu�C<�� , bu�m�theI%\���;asadvantag�r�Q, �Tipp�h9�A�%2�)�sl-�in favu5fb@prolifeE�n [3– P'unwana7�6[6–8]r� z�n%t%q�z�Y� �� �=L�c!�.h2�z��a~5��A�see%�= ew l�i�FE[q[96lS&�ef1"_ (past decade@ �Z(=endiu,�t��EY�_�W�(on�<s�revear��adult �> doze�e:A8$to hundred� lung 7Vmelan�<)!1�Y�. Ab3K)J *:<cos 2-81�g�BX6� beA�q}[�Un��L.G+cS *attac�2��vena�al�� M)p�BB_AE��� cdV�[12A.�I2�,��uq�"C�b� ti�a �=r}Vi�a����by �7ngV� [1e�Re�� �f�1IN!�e"N2��C �&inZ o* al [16�pa.D� �fe EFU� coO ;�0s�4lyU�[17~i\-p@����Y��ryFS�$ɣ,s�-��2/��Yk(9�aAraAC!)nM��H�we%NN� uB���howPtiA!bA�oA$�*j r%j > ��hicATm Hur�ela�&6ral6�=X famous Luria-Delbrück 8�A'DrY�9$�H�=a [18 , ��/�r��1origia�Vl,L)� wild�nv mnt2t grew��1v�nd.a���1&g �/ho5iA psP :2;2.s!��)K3�C . M author�!:�E�u��"�%-�VU��)�?T �==le=!�PFe�Ie�se)��.�7dJ.�&t s:V�6�, hIU�@i��*/ N].a�� �8 � pY , d$E|AJ-u�@ �(%�-0eQno�@!,Aa�is alwN+& � aH&f��thu,l>3C� "� ;!�yOle�/an\%%���a�&� w�I4 d > ���� ��^@�r� "�F�� �f in M�A{ &�5 k-�N� ����$age��tn$~�Dr!5� A�A_s!�KP@by ρ k ≈ u u -% δ z( 1 ) I�D�~�� �,�92C�>�/�{C� k − 1JO abeT 1��+)�n ���ref2N%��!`ASK SFjk�A F�1� ula �aDe�-�.�of{i�k�wAFPg9;, uU�� ath-iPm  ,!l�:s7-g�6EML� �T<ue� . 01Ta.�Na fast-�A&2X��δ!�&Esm�&te:M<un� lM��X.)�.�.%exa�:�'oroWI7I4!&.VE!)�yo5%bY|Q�E .|is ρ1E�[0�*.�96 .:52 #W{!Cth 9%��/,A6�δ �96J�~��Ha2�6�2ncn}R,Y>-:2�3;�z"� fifth��Oe)L.ρ5E09#Wef�� �d�,�"�G!��&�3 N%��K5is��$F k ( α )�1 -��[αe�-!u) ]12 )y0 < <�Form��<�g"M�J� carri  B��bα . No at F� doesq�'1 α = 1 8Mah zero)���.��� �Ml&3 agre�"" ���%���r�S�#��*����O)Lin Fig 21U2B �E<>�. B��is�3ρk��%�P�!��eb���[uI�)med+Q1�$ x�.��QW� �w2� 5% (�4II n ,!N e�a�V�u▙F�2�640�B�AJ�H�'ce5�2�!�NOi�N� !�:h&H ship.qS)ZNT.�J�M.�)d�� %I., ݔ"2 ,'N~A� tar-h ( �XQ�3�&.:�w���9�V��DnXC( �KN_�Y&�y�M�Ewix5 }:�\vol� �? =!�%v�� i&P �a�3)q.� � ^ir:����#�]�/δm��2"�4�o�e=7� .k.* if��CV� e�E ledg�B���)}`�g�4 �2-4m�E� stinguishq !`8re�te�( i . �YA�B� sh�8��r�lw*U�Q~]b. LetHnowym&c r� re z0 �.� ]E��Prt�:� (�Zy2 )L edIu we:>Y�y:�-�Od ��S� �&� !e����u8ntZ2chieva$ s E ( x )�>��z +�+δ ) ( ��( 3� -�� mean�%S� 6�J�is 1/2_&1!δ&aIe��%�W cl�to E I�~E�B  �IRq�uthM\V�m�F@#~�6�� &{ �2**91j- �iHs �eXH�)^%L2W!���;�-�s!�8�=ac� anN�of=�� 12M.��it"� �F63m�2CE(So farahav'�e b�h�� by"4>�E�a���\i��lusefu"��4"akno��&_#"[:; 5b "'Hz"��&��sr���:K� orasQ,�Je�Hqu�on: i�1�A�T*.Yy� a_e�d!���I7 ?r> B��0aGa��<ori"��g*�# Q��n�y!�� "�!fsa_ �Z$by z ^ MAP�  L = - 1)V� .|Y )* [!gd.� �Lž�>YδQ�DE�� eeI&� o% }�i2�1 &qM��%�y!e0Z�Չ%a�e��JH �(A7m�Ais&4��V+�s�KyH�,JCe��Sy`�Nv�5 � �����2�C�20r�WOWv!��f%!j��Y�"�up9�A�1NZ ana|0is m ¯ s = u 0��*)'( 5 )2EZ� N.�tc =!�u�( 6 )�&2�l T�Ko���K":8$:h uIniF�Mdz WZsB�@o�Da"}��)�} :e�1e1%�3eMh��,]�E��� ��150RM�L�Or� nki"I�( T� "*�-�gb9t� �? :>�"�.�Ze ��NAF��W}s�9�%6Qe �Oe*�� � !"to�,l.�K**&�f�Kfit����TCG�^h�< �b3m� nih . gov�t�"st 70a�A-bof 425 �Gd�� �Rcri�a��A�to2�, a�B[,� )�:�y8aciK[ )��"�4� �AN[^w on5�P 12� 2�Xy��sB� �s)�ue�qT."�2M0z)�25%A�m�� Ub�Sos(�&� a h�� ozyg~Q�.3�Kb3!� tetrM?�E"�16N�P^�be� �`p�a�__>7 � e`�4to 12%�.�7�a e՞m�:l1\is 85%�I�%&?!la�EY�2e%|sa!=�the^j�)jAfa�"�� �'AE%n2 *z��\no losN 9�saGa�,all=\O ����M%�����?9;)1�!$1/2� c��?2W�"�x�G �!H�9Q�:t �$.mG.! u 2.� 1� & + 9O6�4�>>u#Q��� !f^?!䕁 , 16Af!%�R�y�!���(in S1$�!�%^�4-� bestc�&~�`� 1���. 2w4��,6�=�=�4�M��&�G&��n o!� a��6�sŊ8�j_�6�>MSI( �.:,�kam%gng*.9� � �e�=.o�*lX�-"A io!�99H�) ��jhVS-ecnet *�)=%�pre&O��q.δ ∼)�9�T!)14(6*\(sXe5 (~7�gata [3�"I�u��� elev�J10-folj< R9E�%12� . %6&Pfi�-y�aE��,�'M ��"(�� s\� !z�mef6��!%c* ne�)vD∼400�wd2= MT6T4$'..YVA noraXδ� s=,BS�.�N:%U�?8n#"�(5_ U� u `G;Y2 aIenV�us 9rng�E�6��a �1Le&M�"| n&� !D#B�Eݩ*�}gK&% summ��EI �HA�� 1v� $ NA��$ abund�5c��; infl�poUely}��I��.a�&O.fU"= d/bai�-1�* IfAh8db� 6�vh-!�.�n"-���y %>� R~im� �\ ?7edQ� `&�.A�e!�}%�  �s"��/�� ’sF�!�q�i:dER"a�1dr%-]�. A"<E�� ask:�m�#!U�1{w�wU^�3?�ans�mD/�.��� �v2��$,�"�2e�1X 9Dc� is &�lUfag level�� ie#"?Y�*o'�LaVam2)"303#3HI|)is wor�m&"5� mpMorm Eq (�f�H^�"�-u�0� 1�!4�_a"5-"gI��Vv��E�u� F`# �� � a1 ���Su"�i�!]7��goodne� b �.O2��C�8�@����l"!#� e >�mW E.7�.gp*�;ž�E4(E/�㩝_/Á{Z �E�-�x;�Q � !�uXS` a�JeGvl/�:�&. �+�:? �Q�3te*)<chfGYminimmUN�dc"AF!<\5yS0t�LV^6R\e�*%�q!m�?ct>�4�6�m�5 hf$dO%��1W6Fa����( �2#�fM�w &j%or6�cutoffz�a2)&�mwe*�Da� st-squa�PA� >/�QMATLAB%��=IR2 � s�wN���6�/JDc�:0E��>� ay� �noX ��p5g�L�.s!�w+t#es�liquid�solid�ha�It�sr�2n�t*�*C �s�I��ten2�jh3"h0,�4�Wq���7"Jhro 1R�ous�,A5&� 1 �!(b 1 ��f�g&4-}Ala�a� �[ k4�;L{ pa]X[64�L�.:0>�8L"v�3^�1 ��?>|*�'Vm0�t�Fa�05�Y�RF9�AyG! H a� rare:�4au6 p�i�Ig"W=� �bG�if ped [2Z#u4!sT0�-��in Ref .)R� 1z,$9v!�ve[Pd e�e( � ∼10−7a�I�aJ;I �=scenario�w�PZ,vir�"�4�A -ebIl�")���e�*� w' trem)">-�}!1��!��Tes!Z �>h"P 5zw�f�e"�a��zjJ�. Eve$ !c����a�X (er�=Y���e�/,*.` �)~<� w�\heq�B�aco-i�$6H~inu%U>� A)� inf�WUsJ�i(=HI(by Griffith�9P�<�V)�>�J�NV�(2� �9A�Z�0�Z y Wu� Kimmel [4�<se� � +l� [J.e'���y�tr�:|� , naEzNq]�j��s��%V t → ∞�#e"�/6�8 �#licit� > me[��E1v��2��r� Pir�(� &�!���J yF�&�"�. conn+G�!!)�&E ,Uttoriv�Graham�s�2��w 쁇@��@��|&� L p4 NaH"�Z@(�)��A��YeTx!,b� ~�6!O)�C iv1~�2 !�Q!#6=-t@ 6J R�rJI �q,9-= � � mJO:�( CIN )�[� � � ��?#!�9;p@orFr.Y#&Mj �ga)n�k��l!,rbey �IC� � wE:ڂ?jY<6��E�%�iQQ���s�A4de�E-aA>�c>i w�5K"�!��D�no� �9Zr2��TJ� �f�e@ situ� w� my ¥aĽ�9�- �].�'DJ�6��2� ]�%< �!b�!�� r [����ZA��[' cjZge��ՃqZal�av(�2O %�s<7nstFaw�cu!^ly!cF>� Q�A� ."�_ ��E + PUt&�A�aEa�Am�[15�B�W=d-Es�DsA.� �)�&M,�R teau��A�eE� M���o.0�"BXM�&�Z���!�-&n{ -&=(b++h!'��u�$*�����ontKofa�8&;'�G�Dt[��Bo�# �� xj\t� lyiJaMp�W 8:RrB�ev�,B� %�Y�L Wspoj?ZQ ii�a5� �f�iT!: k�� ���J�)�1RTQC����) ,]�*{!qenjt Q �->e�R“oldOVy�2V eTm S,�:“newJJ�`&;F�aJpB�>��): i)T !dll ��� ��<*&r��VM�*`�e���{*�uTu$��6o-D=��b]&q^:F9ex|v�2E.R5%!& ���%��5�$rN� �q�2.i�"�]s�e�� �"ag{}%ria�!� �@a"%�b��#!i=��eU�J6 mill+��or�0e� Rodrigues�r7^"��i���X��-�M�� stem$���n!Gc<+[j^In�i���ex��?Iein�_(!�c7|mexistJYa �I$ hierarch��� �9@:j� 2T -ɍ_��A8%�sd ropawy���`o �P a�� �!I%�[� k�yife-s�R� "�N. A����I�!��(��> oI"c�""H ���u�K��McZ� oc�S=�uaddb��7�<�5!�)�i'�C�w{*basic#pm9w�2 d���e\)*%fn)Jjag�j��"J&'iJs��;�7!h!!�!��R=is �4 %�9R.of.�nE���"n Y��)A��sonE�":����-!bs bmitot!� rresH'n)'0 (Z:g1m-68� ol�O�c!15-201 opoiS<�n [�c&Rs. �J�:�1Q sg"�2 �k*a�b! . Ty�N}!ct%%e�L$n5b>I;���Us �!Rb!<�nWIN��&'%71�.E�$-�k.no�,t\3`�(��F 6��if%�20%w!�Y���g�`l���]Z(*�1/106ERM!or:3 -!as �. H���(�" ��- e�JG�ll�6O.D���1�-1%!<%�E2�—�"B/.Q%6b����-���=-2�be��2:_2�� [�/�XEib5b%T���"�d%CR�� [9�e ���m�1"m�I��te�0� asym��XP"`d1#op�P\� :�A��W E �5T� s=� A^ \� pu� si���s g0 �Ap z k,i���+ a 3-d��"al latt�haC*� is r�b���J��wn�Oigh�o!�@�� @i�P1����R !�Z 3�pium"C1 ��� %5�n urfa � [�� 5n�.t'!�BG V� ��6U6^�'n cWM D�5 -mix�5ozP� n@a�A��Y�"D e�N� Y��R-�)�ri��d�eY�!nacZ�j� .B�.�mig)8�� a)/o�s )mS/�7 crowI�&�!��ur�J �N��,�R����a���>A9XfP, b�`��p !��)"�c)�wi�Ut�cem| pr�2>0�JE"�H�c"�>�I�ch�?aa� &���B.�BYA_!)p&f<R)� �*s�B)�&eC �@�)%�XU�2-��3 ^a�a�irz�Idnt }�TFKC is π i =Bi�B*�0iN+z1u ( 8 ) �:3SP�Uc m"�$�Um'A�%R� :�Bhi ≥�  Y�h)RY�>e� −d /8 ( V1 + … + Vҁ�!�V� ,Ib&{*I�;�'edz6*��R�)b(2|[1\2���_ tmeasuA~"� &6V�nn�\A�Rd� 6) R\.�3Y =)) - 5) %*��!*%�G4 bk`yI,5�0R"� y1.JXJ�V9��a��x {Fwau&�Cn0�J�D�FV�9d%}A�-� x = X X +%bV V%L6X = βSA!IZX(h@)�β[A�i]Oa�a-j �2�FeG&7 iae� w ) i−1�%!*�� �s�G �t�.WQ Alu�M���7 �$���   &�N4: Prob [ x ≤"| Y›Gz ]E?∑�i1 z��*@�M?@�(utX) +��(a1lN�Q�BZ�>A�I@�"ۈ� �p�,�����n1) ′��/1 ��UH�%α2�!0�61�T�ie5�U �� ���>�Hy���2�Hδ�H∫ 0H8�d�f7�AJIaRzɟBWO�5%�mE�C�d( ML )n�i��1+ D 6�0%e�6o � ���Ba�d�QA/α�Q)Y 1a�i"�..yu��C�-|5�f!�E�/%�:j�EQ�]A"�B�.��umno"�F($F�D�Du@�*let v"� > a*�13C!7%H Is�!�"� � en v!��!rB`� �XQr�#I]�Q+bJzm�'o#N[vk ��Q�z�n"�S�v&O*P�6 !�-KJ�e� B ���RG�A륆�JvAG−v ) z�a=Ao gM�heE6"L Eb,0HY�M�APB�Hv ] +6�HY��Y->�H( 1X9sia>A�FAeetLL7#)E "�#=�(�\��%*~F3��-AQek ll:;&;010#H.9.nE����\z\���:�A 6FUZ� �M�,|0nd��[*0ly�-n� "�[�k0∞ ( z u ) kE.e -hH ) !ɠd z�>1� Ha�r�:h�`k)r ] ��0�.�thJq il�!���a Pois�yQ�3m M�xrate u� v�L�`:� Ma�& �if:�a�0n6� ~�Q]E�C%���sMn�Ely !/���� �]die.�-al�#ng'|ga�w�G�5�N�]� Ha�aal(�yB#�&����>AE�Fz$ ��^N���COinv�"A$ e=�eyQ:i��\.�'W�W)7^�4"D,A":"�Z{�e� �����v|F���E��Rq"ogeBa� 7 � . /_Q�=a�A�?Med�Sk�'min��Se�p 2 1  O2��3Z;� ��e3��j�[-CzU2Q�>� &ar2"Y�AF�%A�8)�e�&� �*o �.� �qigu�j-8p*`fB �+j�"/w 3>�u.2�Deat6^�m�%� ����hұ้�ĥ.MnxX! ffsp�:n03k$G��^K�!w��&J ��Bn��Y"D3Visp�� RE��T�M=�Vj �:�Eg%9j � , ( E�g1��=�6� u�;��)�5 � �*wo�qe�T<�� 6�E=2�� k{�+b�DOJ .A;.-E , p1R22 11�)�`T; 2475=�&uda"FBH7y8��xa��0&_��.��� "!s�62�E:�3$ofA-6�[�Y&�?;��)��[(.D )J+��Wq�j$�� { hDlowgwo���,��sub�<����%A� �!�PbUJ,��[""�Nir]�)J. M�e! !�� t� dnUa&0���,a+�1ysub 1 =ni�ρ�N(�)R�&2J��~��A�2J� �!�(a:�2�!���6�sIW �4DER �1 c�)j�5����r$I1-�IEO2�3Kp � pn�r��2_A�Jv.r�T~m"�Z\I��2 + -IF3!�EW   %) #!D2>�( 2CV� V1x+ Y5 ](�(�J)5�@iǕ-� .S���!�pi& �=�+%gF.����| �K1�Z-B%Qede�"I1&efix��C�A ⊂ C!�p%}P (��c=2�[  .| B | >" A:*( 2�BGwe/HOe?B|A∩5�VRB|A�l�v25 )�)�-�� �i-�"1!V.�=B6u���%� 1�.�ρ��&�- �o2�a��TsubU�3�H����po 3��Z�e��Hj-(N�0K �3WeEP$*�ng� p}FT�u5����u�1Q|fix�z"l� ."SWÑ#B���Q �8[2 mustE�KFJ/��.5ap;3j�).Z$� v�QY!�� !�&'L:/�Q%`n .k.�,B%j�%!.Jň20"�m�cBR�:Rj��:��2FOa�I�-!La�2VH�#>�*�� =��B�  2 Y'� �^u%p �pe��pu��O)?�c )w %A� +G: ( > �+jrA�� F.) 2OpW t Fa!�:^[ F8e�K�� | �X�3� I�l���9� ;} Q%�.��1e����L U�A���o*�A�4"zGs:�]��,�1A2yi,GQ: :6 d�� �)bW��e"� 6%\ρ6=!�%S1�BV:�AeB"Qx!�>l!�( D < OI� zV{�Aeb�wb��3�/z,��:/���!b&z"y��b� ,�9F1uc�  uz�m @�)�(e"D to�FD�.�8� "��x�2�*z��>���e~�2 �( !�o�op�!Wp�w�, exti)!�u���" �B;l�5t5�2bp+!}(-Q�� M�!qa1,K>1&�_�6�%7!t�D8H~d#��isp '>�| xi%]< - ") z�&�  ( 3"�Ul!�uE(" hMOl ^Q�3bYtandD*�h�'RG ��'(zN�6�X7&UN{0��"<a�.�*F�M f���mxik���fch5�*x+Q�� ykm ��e F�B��"� gga-���+���E!l+ �� 4�k%�k + pz9�}p�3 �a 1�4!�!�k�A�$�>2a0�A�<C1e��Kk�get ��*0|"�� - p p i +nap:"3E$"�-1 p u@A�_�y4a�Tak� 5<iLZs�-�i�;� k�∞�nou-���-�,w{�^�M��)����2 ah.�N4)�N<)�0�>���( 4& Plug�2�`&ƕ�Juz%%p �I�!Z�3�q�-m ^�Q�¯E3(�!;���>��UA�J�+��) )� $�}1OP1�fC( 4� E�{ݢ�� sum!5� A�N�a?�ryɒm7*� "�E��s�!6�J� 9�4.�Polygluta����olyQ )Aa�7� exon% XN�-�he�Ta@t!�6��Xxy4�to Hu on'��s�k�a]@9/��zce�aa��j!2a3�4����0�?�$iL�\amy��aggre�$s� �Y<�a asso.��&��}�!G��.2c�mis*c�{�8o>�ric�pl�anLort�L���E*G��!. E&�[/6jab p� help�=,_ 3"~�mT��!%.l��ot�A�. Jvelop.M ateg� to�BBC) flan��Kc!i urroU��IWrK�!�!%�8�:T1"y>��A�u'rearr��maH�.�B�. Few2��"@;!A�P�ntirety� �s � ��Toq�s֓��:gh{�EUe:�gt)�B�!��-��,�ar&�P&� L$-�Mi��F�# �56�i�1�p�n6ng� � Z�hyp�"�'G��n%nmD �%|w oEk�X�5pep�� ( QnOF�[#:�2�'1I�a��h:M��[�i)� 2[`4��47�Kec�#��.�/��vi�;c��)"�rG2U o m a β-��1�\ot�*� 8&qK � �����1BKofEŘA�6�^x_page_Sn=28>� ��)�!�i6���r&�a� ъlB��,!>Q� II�ia��de��j.�)�@Qm,�1U9F �BMcby-<ee��Q �f8*��17�idU�A�m�<�'yqadopt r shee��* a.i��-��'"����"�X�IdITI�";TaJ !a���!C���<"�G��-GU+�JinM.�. ��A?t6& neurodege���>!SyY��a�]–[ĭR� ( HD� �6"aT�3A�h*"�&HD2�^ (�)1 J;���C�=�Ux,QW_�S�G�=w�Џa��[6% !���6�[aO�,�� Wom.�i`!�^sQEAj�h�Z ellu��1�N�_UA� %�`A..�8.�k\;in viv |�[��[7]\!!.a��2������% "Q+ ��� affl���c�)Despi/�1Zed*+}�*�@xZd&�-�u`�I�4�^�*���is[�4�KFA}�UmEYaVCB1�JorIԔjFe a�Fo���ymptom��:I'A�,5 %��?�44(�� wit�Kfima���D��&Kbey���5w,Q`Pb�aL-� life�=%1)�����8�~Ơ@!$ 8� lo�of��AIA�tro ki�-�I^ ERo*?��e�A=�c��N�agIH m [1d�[1�]K^o [13]2N� �Qa+!��� MT� ��a�,.����Agh����/ЕE��R��c�Lex2G*a&� &\v�e A�Bf �a�i^�t1�>4 ! .B .�m���l� υzd2-�Gior���18eY1924�i�d��O5�)�*= 6IJ�=Q���1� �aVy`[Qoligom=3)!�!3� .l99( >9�e��Ire���p�Pt����  ��f"hBV0Nhop��o� p i@��#.�& V� tZ A>e.vs��g#. DX������I��-�*se&(aF*.(��͘� fqW*"�1e Z�-��E�F H<IXW)� homo ��w \!��2k ZX!I[�w�&Qni�2+�Ra7���o��iwUn�gئtoA� ��2q 27�Ye�T�z�OF0yF s�LsugG�x� [2B�O�3&hxnt *Y�� � [29er��,` �� by PerutzS`B� A�!j�Rh�/4pr�to un n� �I1�e ,�ta��g� �v�e&� 9sh�[���`��M���TG��VM@ . Se�,\V!%��� ��41d�AQNK �6;5�� F�,W�ρV!�/?)(P )����'5BU�aE�Ex���}1 s�KdPo��e��T olyPlA�h�� ( PPI�~A� [3�s�g,1e�A�ete��βIЕ��B�L�p� �o�� s�h� [� �)��1A'� �2)��jLa+�r�jIA;a�E!�=.2 ( Nt=M"�Qare N �& !P5���ɉ��6iŤ�e!85 �e�B �u��"�yUs �&�6"ۚt= ��i� e�(a%�act.{q[.��jfq1[4��)�js28.(.]=an�+� Q ch0�:J Kn �a�]WI�so2g,&���܁>Fed�u�� ��u!9Atݕ.<%h16F5tB1un� �WA� V � @a�%�&�,ly��w�aM�An_�I�Q�K� #N2i e un0�Mm��\XN1F��&�g�u�V<whe��A.�as"]sq�Q�5E hi����i�E/��a��Dperhaps.Q�,��waoex9}!:��16V!�&Z �ne�Aa" !*� �J.�x =Z��U2�cN��R���,�Q%�PF�E�taneo�/@�7J�wc$&ZU, titled�-P1N$�b )2����.�c�8��-,��nAmen�,r!�J�-�third>��Q. habs�SA1R� �s�o,|n��)Cf�����&.���� ded:�(��*Q�Z36&r&�����i�+�� ���Y��eD"� 6�h� E�byS��@ ���A ��h Z��&!��"� "� a��.VmM;>A���d^e��iew!��`�j�dp!a.����I��ѻ2M%��� ��  BI5I���'j*�>�0A�"� . k ���`b������JSur:��[Cb�pD_A�I^vF]N� ۅ3 �!��U��M�oo�J�n�d3%�MUS ��}B�0 �����up�5 q�g���Uppl)w�A�3� gram�Y.���`�HAM )�<�Y%&a:�!�^j�Ym��� s [6M�"m % 6"h]capac� ( CV�M����t ��er��e�_�.N,.�~E�Q23@|g3a�cou��@��liE?��; a�!K6"_%�^nap  globU�@�~X ��-A_I�Msh�Q�pea$& ���"�A�� c�#] iled-r�!�mY)ti^� docu�ed else�E����Zof ii6��ge{�b d nae�er�*I�Ld5o9�!�.�<all��"7!���,�!��kN=]�>�hCV ��Y2S.S�%l u un�9�9%!2�!��LZ��� 7Eqst�-,�mP��-THej�"�) �/\Fy�!y��Bn�Xe�-`��Z����!�e�!�311!��.T� �QX322)!� F5�( 340 X� "cQ�Z��%r��XNW M�Or%�!%l f��9�Qn0nde'�G9�L�} Meb-�QWetzel�^up�3s��"�,�ghZi�O�.��Ձ@ruc<����B�D�& fibr4)kQ�}is*= uA�GY�7O�"I�* .�"�<�,b!w{q��^|�a�tx :���"#!�(��1actq-� gf���yrA���M?��"�2N@L~�� �j ly 1-�27%!?�82&JHj��-, . Am��a}���"u �ݡa r^���&3L�)�� a"I�(N�s�$CU:Nh �0i��M���35�"��۴,�pe����m%��<��2/%Q[2�$�A��8Ibsi��K�Q3U[e~!v &!�V:�"` � T� ainYre#��d��|VTms��lyQ�,y,a&��Rϫo3(|x� Q$( (hairpin ) ;� ��aD�=�re<*s:U�{ �+��16 �+.eV:t H!��?N� ����$ua~ ��Y�ahFt "�{Q��$in Q47F�!rCen"� a�1}C�itβ-.4 ��~-iG*~ �bu��B��(^.2ofBm9���* dicate�s the formation of a β-strand ( Fig . 3d ) . Furthermore , an overall perspective is gained when this probability is averaged over multiple residues ws . 3a �3bWe find�4compact states��Q23 to be primarily unstructured; a typicalj in7is a �(om coil 67%S!Ltime . In contrast , resi�in0long Qn model �436–47 , have%XXheet dihedral angles 40>o That�,~gadoptZcon5�4s almost 2 . 5�s %�oft%�a �%o)nX) . The relatively highapro-�$ies do notvtradict% Hexperimental observE^%little!�,no monomerica5�( [19] , [152sincef secondary3�y calcu�on!JA1 uted onlyA� E(mall subset!�&AWAv low-energbEf. Addia) allyM� al ensemb!�are! ed fromqLreplica exchange sim �(s , which caX a wide-r'$of temperaA�8s ( see Methods%�AE� esulQ�distribu�A6 does-�rrespoaZo a!cgle6�!k�e�a�u�canAb�(mpared with6<measureAa�However)>se=5canK usedA evaluat-�m�al!�pensiE�( datae�shown )%O�cu�!�repres�P���r�Fi�*4a!��(, 2�Ntwo�P;etches!�AZconsist)d�;( PPII helic` . 4c�dIŕunlik!�tAa!$Y7 fold into6Ldu��interac��!�(om neighbor �A�a� ThisA�becaus�2��d�uny �`y one1�q�ures;�reae� he o�U���+�] ableN� �Uk6�-'!W�2�independ)zejhyp�siz�a�MP11EP10�domin�%nof%�,�oth�_2u,K��qX� main��Y!6#�u�,�affeca�ba�mAi2q.9 ordaoo stud+ e;�!}23oO :pwe per�22 �-P105p��� at�s �i�i!r to%4but lack�vY� 1aX%�� at2��:5 :� r:��Er*� similar\6�a� Z�3ai�n facforv��B[5T�&� e,nearly equal�йL���o �Ty(decay~ %:"S y!9��I�!�%�� ? ��may0at�6?9ƅ�B2h� is� onship�o�J�2� � ��Juinhibit-`aggreg %P(toxicity [1� 3� [20 3� 4 $42]–[44]aS$t has been2j ly�a@�=��-G��$be a tight2�t46] or� α-�x �", [48�&� o� f� 1�u�d.�promo� ,.of-3�7k(To investig��i��.]iniis�����~:-�� ex��aX.; vd A� 4a)XNy9m�|�8e{mo�fB  5: gard" �i1< Q�]�N�� prev< %n)!� J@i=st��k67; n6L(We also cha��er��eYg!.� k �. �奍ly �y!�I]J��E6�.u�!a� er � XN1*�}- i%,F\a 7sixZ�.�. ��2�|�:&"� - �sampljx30.�>m �>�:�0^� M !D23E� 471_dep8a�� �2isBi.&� %pI��� 41 ��� V�.�) 1 ^M�in�A!{:^ ignifican� prefe�V���.�:�&� by e!�ata�w2<i �E���induce :� H abse��%a �&&2XM@� different�. Fir"aH[)Jt �Nh-�J=^a-]�Y�!5lra� %U�.cA Even@! �aH � �R�-�l�Euu� �cas� (23 glutaming peat:_%� must�ei�direcAgor!�:� �5�; such! by remov!7!�+6����re�P�"2. S� ,vh M�MY.E lF�5o6�in1���or"� � ,&�3�gTherefo�AFae%Q-�16N e �� ɸ���"� �%R . On� trigu!�phe�naa�Yexpans�diseas���M�9cEQ % on�[2> 95 .( sugges$ �� bothi��% Qn�"@�Xacc�� S ed*JIalea�a*� , \!��[cya8 JPAy visi� �s �of�[62�8��e f�v,.Ayr� tly;A3tr1,-Qn rar� �%'ta�`(slow . Moun��2�evjce�pp �a���A%�>� �,�A�5�i�-d�1�I� ure +[27E 28Q !7hM!�e�6�a(��Qe � qBkineticH � [16z21� �verif�� betw� A, �ͥ6�-�e��eYLit9�sol��gm�quD to deter��zcommonN )�A�s71�I.� %� , soma�� ors [)�1�16%18]�T-��a�[!��5!y9�amAv#����I��"� &5�@by Wetzel's group���} homoArmers we�app\"Llysɾ��$( K2QnK2 )!6 %TM�%�bi[63a�.� argu1!�electro�ic�ul�Q(:�s m���C!BB of!��u$sEJalt�he2�M�%\�ystem�.oM���CscreeP�,re� !�H�, despi�>/& .�of: rins*.s6�!�Q�=donA���8pE�f�!.�1Obackba[6�By�k�+ atis�*se_1[DsŤ!� "�D4 k���N�av�K��,e� ��\UF largY+%�!R.�ɜs��a� � |��outli# by��w� in aA���, E�̓�����i�tGs�OI�r�of?�!�I�-�\a.. Accor!�2?par9Leddof �F%pJ�" � �d�:g2�!�. ���ZA%E36 Qr"e � %��B 5�E6n�r�]��nv) each� vid8 �!�pro"ional!��JM D�}|!��=N��u��� a po�v�r� ox��its>�!7��. B���i�br link.�\i�:���@)Q =#s%�F � :]��e�Reca�鷮�indica�%�!�a8!a6!�l"| ��.a�i �I;i .!�"associ4ea&�x��� �Z�a �toQ-�2�!�con �"�!!N)�of} 7u�&�$�6!P6H�^�`r� �6?@!0�� A95y�>�a'N p[!]�@A Eb e�J�(i=�%�� . Upon2�se6�E�"& `�"I�:�:�2%A'���فE�M^"E V :� B�O�Q�-!��"� I%P ��sRJ:�K1 BA�orm�e�.:�'by! sideP���>I�u9�mA!}}.�atC#[$1f� =&�%AF�&.��Y�"�r�%�Y� �2�* s�"�%ca�er !�:�k%!�z in-�&�s֞:���z ea�destabil A&�Qu2be�2�!S�&un�22�a.M@ e��&�!o organua) 5e)Km�\� ^�Oc*o it��!��!;=q-pM �A&&�weF� �Y0protect~�kY�wo ways:�$.X�L-X� nd � h:�a� 1P�fi4ofE��ݡ�Cur4 NrolEg B���~�e�u�*� �%r deb�B2~45B�T� ��1��2. it�*�!�2�*[i2�� s3��� �!J olig�)�bI45,r� a!�b! !8locala��r5w!1�٥ �$� ��E�ACofibrilA�d ('o&mT)�a�*&. O6 �ch"�(( (���n:�%A&F�="sts2�-�2bI r&� .  b&("5� Mni %to!r:-a�of)�1Q"�rapid%�5�5�S c+�)", 5EP: � E�BM��weacuss �/� $a sharp�I��:L!&�"J�� � 6N� �6Z"�P Conc�Y&{%vX :�Ţ^�h �A�( �B�R�*��:�=aH* �-a�B�M5�@!F�1}ath ic. �2��A66/1`6�\�%��8.svtaneous�-m�9# A� 0fu%D� would b�(ix.q-&l�5��R,=E^�+�0� .�."� da else [653n �J �A�lem1Ha*� me`.is!��� n�"ste�$B��I��S�� play!�iz�Z. H��,E�j)ut alDy:��.= Ud�. critE��MZ stag�.�� . Un�!��.al mole��dynam�6l/�_ret �sph�0��symmet�0 , pair-wi�&"�* po7+ial�a DMD!��/ [49�5�)�)��CinuC�any%| atom9\ ser?of squ�V wellFac Such� impl�E� ably�le �=�!"� in^h ʡ�ic�0 2= �� forcI0 ceptaBmb��a���**(`travelV�tan�T0a l a[y��ro�3t �A�a.� ��t!dp!<e$lli�8 . At�lli- Um �i+gu�)NN2-��2��cGX�{upd�a�a��S3 law:5�3=�E�u-n& ro�Qo s��� lista6�3��"p'aN *ipver,ofeu+�$sE��E.8!1yE�e,proJ�! c"E^eW. ET�Mp�+ begin^] "�.�;�al��gequilibk )�f�!50$ un�e�.r�� dras�%�y%�*8����!�discarH.���e.W ubeI�k odicQ�AE� ��m 3�7!�box!� chos�57�enough!fi0a�.{��F�us5 an%ed!I-!� �1!�� isaTla�inM..��. BriefD � 2H��6l heav:�aGpoaY"|�)�Q ;E�o(ion-+� -!�gO�!8MedusaJ(,ce Field [66�w�aAM/ e va�r WaalsVDW ) b2CHARMM19�ri�1on*z�?)Yd ��cit387 EEF1 [6 +T6#2�{#�86a��weake�d�1sol�&|�&� ��%�!"�5f�/%m!3al-���(. Salt bridA��ѡ;aa��cap� d�ꅝ throE�h d&R!�#M1D*8E.x� mj��"��2�(8#e��5 heir& �abo�A�ce���del �c!rT �V9�1&�Human H��ngtin P�i[6 NCBI [68]"4 �#)Oh��$ia non- �s scatte��-kou��B� !���), ����nt%�Z�%"ja �&( h ��dis V8$modified eAv dd&�U���$ � !n� dtoxe�.N3stret 5�J�'� effica�a/�)M,2Z)wE Nrf�90 technique [5!60�jW=9 "E�a:Q�ut4"�7� el�Q��2� � s�1 lled�;;-- 0!12%Q�R �R|3�&K0 �s �Dfo�aa�sX;.�:,: {0 . 85 ,  7 68 64 5D=,53}!�h6� �!,4in kcal/mol/kB�� abA� 500KA�� re� �=�Cv�<f%  R(�iely 25 pu;%��  A��;�!�%[wA�p�;!vW�&� !)�Q"<�2-%Vn*$7Z!�1e<,0 . 6� 4��?7a M�/-Carloͤ�?�ma[c� o"!jma �z!k��km�ofI;r �a�1×1066>∼50 n!3. R ,�W�� ow u�Jw!X.� cpa����� �7nts�_ngR=#g)�e*R=&/%� focu�lI8 y� � ����u0�3�U%�P� a&�@celi�7 Q5� cP A�t� Ia� w?� f gy� ( Rg �;!w[�;MpC!j� ���er�er!��b� �explo�[dur!d!>��iwh� R-1A4far�Q!�favPd �l���s���r-s f�B a n�ywa�?�2�lo�n�? �: & "� Rg cutoff��S1�; I>{�<$a histogra�.�s�0d��Q�o�� pro_%800�!00.( 12`�� 12�p'm�B9?ʼnentir�:E-a<:�� ly 1s –2 .c3�"� "�%�( T��%'I�6Hx3a8IA�%"�=st1Gaussiae��,nH4ued[a^�Dsh"Rq�;�Au�� 6 M;%!�-.popB�/,��m descri�6&�g! al~stq,�N�"�svUa� � A�"f%�y1*)�&rZEor� W19s$��we�!�& "{&>� ( φ & ψmP!3+�B�NN�� ach�IEO C5�V)@�� e�&�omFDKYR�$a give�� �T6k,�?!�urn�nan"wFFD;�F��J�A:���NB�� "�,�a �_E>i !g�V�C�[U��3�@3�0E)�,2� :��3� !�"� mea��on �a�>�*�<�a 30%�� �H!��&�>���>�D�4U�+z �&$amino acid3!.�9.� 5..~R ecu�A! (�,�~~�w+b)T6w!��! spec7NQ!�"��na -s m�Fow�a( aris�N�ync�au!�s� XKc��]G!�o�� erro�:�' dard h�YFeB@number!S yAy# ���ge�"tra. ory cros� %>�3�]In� d ��9@c�.@>y���!�ze =F���.��xX  1Ldo0�Rlandscap!ca�visual�pur�,��ZfU5&:I%o.�"A hierarchi� clust � (lgorithm [6�3��HM!�.4re.��* 5)Al / sepa5G1�:50pA��G��s��,&�50�2�aN�6/���!�e� V+� md(�1032g��]+-E�&�8!,B�es+ ���E0101–843 . S1'�"�-UstwɎ O. A��aim summ�K 8s8lu^! �ia+eu(�%� upplGJ�aA0w4 u]� - ASschem�#FnodR(]U!|2"� i� 8�Q3ootʼn�9( RMSDq/�nN �Qle-�'a� r minimumT� !��A.��}qde�a9�->��B6�O�9#c st �Y ��e��L"��5�Fs i�aeIf[2~��@tJ�w  q+��aU�;s%�1exclud��!!E�� �9�a)� pof NOÅ>�}� "�9.�Aba 2Å2O!�all �.0!!TSG y+&� ��tQ\i��*am��B Y�  . S4œW�#�G|%oi%A�:1 m�#:�Jk�twH.RQ9m L"H&� � ;�s1�e>o#be� !C6�#!i��M =�%ao gaugI&�>O7li0����!� `P ?|����1�e��A��u1TA4to��R: id�A1 :��. EM  �X��repor�>xofV !3�'%Fi( , ne!��raw�L>��p8.��CRISPR ( Ci� ed RXly In��d S OPalindro�!R�$ loci�oget'� caU ` –a&�/) �� %@ '/C�*dap%�immune�p Ty def !� ateg�9at eubac�kFA�ae�4�+a�Tsr$eign nucle�$� .UOpha!�conju�@ve�"sm .-%r"�s6�A�'!��-v��=�DNAh�$��@(So�$inq E�6e avail]�hundrede9shotgun� agen%��Nseo*��Microbi�9Pro ( ( HMP ) en�s�);��r�R!%di4 ilkn O)х�h&-]m u+*!��I�$isc�newF�th4sI6aasV �SQ �as� A arrayAq�whole-me- eHc fai�\"# .Q �J.��Ve (("� &� %|ea ŷ3�;-�IA`sensuA<�M)�recrui�La�E�!�-�)0he4%)� :%<?+)�e�4(!�B�5?Tb^ 3A�VJ.%��-"�novel gs�A9�T a�iqt�PE�n�A � F���;ompreh?!�V �� � �s a� ��8��V��3.�eE?(���64M�86 �on%�a�T ,ly body-site&�%7#_ \ "�&�Pa1F%�2�6dM��@, �ptococ� �7-!�i�X st oom�oA�, ��� ∼8�u�I-s:5KreOd)ρUsa?>d"Gn��! hdV)} R;*� �!:*;>U G��tB*e,2�lW#�EN� s ha�{noN�: �%k�6��&�Lsub�Xnic�# [c�[ev�?of-uѣMq� demo�V� &!appY��C# �a��of�AIT n�We viru�#os@A95���S work% �7� imdI"��Q*c�E�� �\&=*I^ ��t!c"p �)ecolog.l. A!zF9geaV( e.= !qNacqui�n5c�<� t)-,R��/�)!Qa�"�=E+Hl (a90%�m \�eJ�1BB�+ �ъ���'� 4g\bp6!2�q��(^ Q�)� �5�dvia~or�!? �%THtho�#�A6��Q�*ain6b r�gtZ� A�.G�oxHaliangium ochraceum DSM 14365 �.i�ch�588 copA�A�t�J/!� they�A} be m�( $eLA'Z y� doze���H �9T�� �� p)cp*� ,E0 0 6l��l�7er�aRNAN@!�wh��O4s�Tvctv ���s [9& �Q?!�u�� dja� !t � `ch enc#qA�h7Do'�,faml_�2�$ "fun�Walps�i�Xof< aaZ,nX � mer nj o�[-b��nga��%. �� s�"�Dly1�M)�-J K gu�[-!RNAA�cr �Csilv*s �"� i�3Q-mAmanner�D2�} �� v�' ���/!����"gd�B�DNA�m\� a8 ��  ,�=<�A�� �Urof�/i^I�- ^�`!T�"s w�$ inva�12i�sj"=� A�lev5a{"�0�eZ<&yet fuA�underst�Q[J??%+2J Y�� S";%5�e��[k !;baoDi&A!#��&�N�*� � j։9-�� one� a�" �IcylL@!n��1"M8�0t" 3�4 tact�^us—Q�&2 reveA��2X A��l #}'� /as!��Do- �%�bog��HPEv`[sG. P}Tj@%�J a"{  !ve�-X�abundan��Qf�Cm6�.{"�@,�:IWZxE��D )�u��1 V� bQev7& g8ple��!�`�+yalhorizE)l��2 nsfeDHGT ) [1�KMoreovŞM>%u�%�*m��y�#�7�A�$b��a��&"- ���!q1V:��"i&�J*uIng host-U.!� S ve^}A?RfUp�M���� pred&_ E�-:��I��3�\� ���#r��� n��#p�ls�(>C1� �d1�)�es��� , epidemi� �!x9?�xAT�us9�FS:�-a, ��C ~�Pl0��f3 K*G �n��as��)�<"y !� !%W �[1\I^��O/ � "�%lQ�i�� L�e9]ia�t�g.$�:a��l�eBaA@� �7�?i�smar�K.5 �Mn2eQA�Nc�R=��ts� 0[w9ast*� .eN8yX amazA���!=�!e� %�*R�[2"L��a{t=� e��;�"� spr$O�A�relev�!�i%q"{)oL&�e_EUperhap�0e� inG��Y) antibio�2*> g~ nots6�-drug.&) mov�(%�G by a�l �� .B[24];m ��v co�9�5�`�t 5( � 7P�&i[eJ+H/O� �/MLR�MHva*te!\ I�?��l#ho�i��^�2&��AF"!� �ot=S3 ��46��,a1e�� Bmenvironm�. A�82\trJ"�Ssaliv�#in-� ���u?�@�Ire J/�/G Ary ,) ��  N� T��c�|r�a�XR��&ub��� �3y��dn<)�sub�sj" [2�QiRAmag�4Ee����� ha=M�%uFq�e-Omouth�T. >�m�t7| ����m�9m�)�� �>��,QY�]腩a� a�VH �developy6J� F�kFign �+73�y��:J>2c�f:j� 4y� 67%1�%����(M@Apr�ms1��o�A{2�T2&b30]e�de� �)A �Sib �� oF��'su*�29-�� � #� V��;��x!�h� Pg [0)+e&- e�;K@��T �a , �-)��a���gI �Vnee�*�lx,1́�$s! .Lw� p��� them���\�O3.�*=�� }�lwe.'��2�*2��aDv;;u"�=&Z02�nd��s2j �CDeS>� $sI2w:�2�� �Qb�(Yu�s� ��V�� �� -�6�achie�R����"�5{�IH:����AS�a�:�3��T*� �Y1?>1E . W�P"^asDif �Ctf�hel� ođ�&� �=.� �AAAs )$t g}Jim c0e[I��6!:���0ɇ 7+�9two?(a�� F�5Eu.s:I.�CO�me2�wcip2�p *�g(n�*�]F�FE��er-�E![%w ".5ht ��m�Xpac�a)U + Ak�U<Q@!��2 "x)hC"c8recF ��Y&K�7a M�F�)��: �#Rn SmutaL36M.I �c�- �i��1���e2A ' @Sus dnsg �is[wasX�9�9 I5!�*?#- ( 38oV!751YM) �4I)�U�-�V�y�>ut6� �]�inq CU�9?in �3sI/�6 )�.bH�� ũ!�.j[=Zu% �,6S �M386aa��6)4: 120/128kRr� gi9plaB\ ( 94�,$,of 135 tongu- rsum�E ( 95 +A�97.21 bubmucosa.8��I^�)-iU�E A��E�> ���� � �{ o lo�a��A:H�^ex�K&&, 4W 148 stool�� n�G-kposM$ora�nix9xf �2�ge� F�Ty �3woRa'�pm�s%�Ghaema�!�,SRS018394L37-hyin��-s>!s& NU�d)\A���Gemella z olysa� ATCC�,79mw��CRT�B�g2Q� �in 258E�.�1�)���,� —of 3E�l—�m�e�%0907�<P9�WH�i�� ( 48; i .e,*uq�e� I!�heR@r:[ 2�29vm �9�&�Az Oa&S'�_a�1�)��^c�%;�� s@B���OR*�g9a!ޡ�ra2�&"� �Y� �6�in�49389��!bQa�( 2014 b�=A#� 255�>�K��R�Fg�AF�dra�> < i�Q׉�a2I�w�*�%s:�A 142%(��150a F|.� \>ur kq,:b �^��nd�36 h�SF��V ��co�z� �*z6)"� .'z;.Wa6�k� "!m�y"� ���F�"� � �H�enA �H�\!#3*VN#&)mT#�' petiQ#"����J_!�~oom+ �%a�>b�(� �5�be=�q)i`���) bU �x(!!c!�.HbiG>��9�� R%�..�e��., .���N��� Ke��ur>�I�we��\��8di4p�����|�>3"M-7.��� ~&chs"�D� �&I�f�}&`xa�L/edf(9Dtypk2Ѯ��*�: ���;.�>�a�!�^TyJ� 1 �L�*�"�/"2 *e6Tin��R1�Png���H -�AU |i)�� &~!�&[ "H4 2vd+.E � )a!�lD �S1I��se�!re  $x6� B 6�2279L38��rEEab�q$tig^��O�|er&y.aR� ;�t2A%[��292 6*�%a 38-bpM�( e la� p�Oi�let mQ7Ao!�p2W�Q�!�D�o�t��, ,by FragGeneSR [31]"�\z�$-coťg�� �!?,���_9i*�#�y��4 2� = a@YzLu�R hia 3 is�&8135 ( NC_013192|k)ae�/ c , [B-nwxc"5 ��;%2 titu`EY rmalH 0 flora [32] )�R Fuso um� tiferum� 981�G,by BLASTP se�(A!��i�-J*�as qu�R���2B%�( BI�rA, cXc � ig"�1nrEˡ� )#�2�!��:7!{�-�G*!"*N5 �emRa�7M��&cA��IuI#ec�of��e�1166729�� 64; dM�mI-RA��Y �.���1eedU& 5a�0YeA8�W� 84����529}��nn7 �� �fKV,#s�S��a��6�h�e�Q�(1~}.��$"�J�V:f) �A��|- �2e�"{!���� �v%�V��0mq. F�%9�Lv"2 (6�)�� ��Az�#� 27�*�u�D97),a fi�mg�� �6ai"OV�&%��S�-3 frag�( 4073 )�f� %!qf of�[0.D1� "um�( 890 r�^BN. A�0c14�(�2{�e�LeV"->�0�!^ � |��W A�%Dem"F _ &3�ia�<  ��n�C���lt�71"�'"� :w. NC!,�%Z2I�� l??E%?s�)s:�uAta�reshol�988%�2m!��.�re ��5eF� > 4� �ob^��9�3521�Bm� %�:�345J��,b��/. A!;Bz!�114F��<2b*k� �—� ��1at?�Mt6� �{s6�Pu �M ��23604�i� )�et*jpI�A��KU>� B��*e�!l�36 .� ��Jri/�I��� �B�6���;�Jb ��{ n0�L1!��a���|B* ur�)a5-�-~A ^� #of 778���12��X-J. �DF$�:. did� ��[@ . nt h�-�N&�)e��Yy1�s.�L!�Mos�*e�w�1e%�譍 %�% �P9built�@et�4"[!�� ��V&?B%-�\. An edg,O<^0!�:4, � "w>JD?a��'Qm�!zEra �Kr�+oryfEkV ��nI�b�X�5 10 o���.U8. wser �� dele ah@h�!����(*/: .X 5_�M2( e��~ - aJ � 8 &� "l ,0K.%�cY?d edit8��e!$�O9�he51hm�" <1� +%-(a rsmp)!%���nd 0I�serSH� *2�m.��globalUr�A�$3A2RS1�`Alab.1).� �m;6-6)�>c&}�T, !( 6A! ��r�f�q ��S3n5 re %$�M��� ��2IEa��� � �" �*�'lyE�e�iuIN�F�.� o3BI�E�u8S !rIT7Z::C�� fic �MJ��b�y"�!OC��A�S�d!��;rP5| I�s%�� �2P�xaYu �n�#� stud� s�%p*�yaޅ�KZe&�"] ��a�inc'-h'�+^ L;!�a:L"�A�)�� aÐ.ex* start/end�lV i�2SIP9mo�Ve-W��2�3��%b +in1P*qR"�.�o �ogo �'z��LW "1� 2�s{5J �>+ !�r�W,9� alig�+F�,%�cl�/�j� . Ov�8 e�%�ryAo.Q%lR}>2�4%�M�S3@n�=�!�!&7& !)  �r�q�"��I�K&H :s AE_8L30 ad BcoprL32�� U".� �� _ Ed\�\ �Hf�� R��0!�g"3 � gut-%>�-8: Neis_t014_L28.]in 51A,H92^K; Faloc! ���Filifact�~s �35896:s63Bs7bskEI��50RD .g� m$505]�.�4%�82_+�B�T3hah�"aA]J % A]i�8(ii WAL 8301@a �5�%tZ- halfA�!��-��"6of 147f OE 0 ha , 99�A�>�A%D� :�o.[#,R�#�%� X#���5�E��"!XF�a��NL!"y417 ) :&�#, K5a%q King"Qy51!-<, Veil_sp3_1_44_!�!'>5 JlonMsp . 7 �S`L,S2I&{TC 35037˔5%�ost.fv�$oB�!��7ݢp ;.Ig o6bmeV� itide�CC 1309��Z$ 8013AIo!M�e$� aWNYS #�)G[f�3 by H� et avu3".)0flavescens SKJ�ActinCill�*$inor NM305�2 ,fV1��E�5�,),�A~Z�.R��&-��,,7�32�3iAm-2��! exac�.s� " A��-Y28!�,'/dr!-1���_7��, T-����J��misma�eA��/�%*� e��(D *O retrixpBsp�, LUfe�(\pneumophila 2300/99 Alco� �[Thioalk7gvo)�K90mix )�_*j7�d. FT �(�si���inB�..Rib# !�AA�IusTDtolyti ):!}". E� in 3Jr&��69�'8B5�$A;rnq43&>�&3)%z1�fA�ple�Xi&. �� t � a��"��:�I� at L3 bam�� ��?7����,8* ��lhe�dA%f�l=me�!A56i_ enii���major-� s [3/�ZQest�^u�e�"F�Q- � 5��r" 6��8 Lv-1h 180�/闡Aw��L 2�3F��B�� �bi� �in�6�I��%�&s> kriJd� pat�a� ="K#"� �k�%\ d�aqa-6�Z �=u+a&1M.� A"�Ts�\"�1�2� helvp�u�Co��"_ zOe�X &� �hv ]" 2lY`2Mg�s՘Propionimum � s HL110PA7^%J13c C ���(P . Di���a�KPA17120�" SK13�"J16Pj!X SK18� i�("�)pT1�=_6iZG)I%?N�)"�s�:��t:*>G �e%bp$SejS����0&� "�O!�%#$G� h broal� scald���2� � 104��!0>� �1e�w�"Q�F=exh�� .e=�d�Ijir�xsh "b=b+!; %��2 S�� v/!*j1A662�}�%"3106�%A`815[MM�5(�A���at�2 i4_&�!aK#-�w�F��M�r436� !��6"j'S4�a�iJ}SRF���.��� �)?����E%�"� .Xq cla�Z��� keep6M� N"�68EM�~�=A�In:7ב�RL g�^_25 6���2UWwG "�-6nche;�S-iA o"�5J� � sub-"� a���B,9K� }A�/2� ( Pr�L� .� � V�A� �E$42 �@!�5M!W)��ILA��+.T+of� m U#qi��m!�V�e�<24j �S5ye��f sQ�edq��� �y�By-M!��.x�T��I�2,Vre- 3 F��9:��L.!��vE�t,]Z.-�NVA���&���T��T��}I[ �sh'";iJ�;�)J� s���,2� �co��NE56E�. �9 %`ap"4aV s FZ%�5hU!��o� b:��<�\months ab'�'�Fh�%��gJR1�.�8�uF�9}�]S1a�`� X� B ej5day&Lb�(q !�o.��>p�^ <2p�sp33�:bp;`��. 5e�A)��@%1�r ou�z�H5�5���%�=)�1"5qc�nhOJg2�I Mf�556�)5���c �Ida�:Gl6�� Q�l���-�d %�JA�5��m]2�2N�#�l`�)�!�sL� �"7KVf/ 9+��b|/ 3 h6��erm:� 1\�e!`&�@o;4f��&�ec�A�& ���&>,�)ceal�%!]i .�"Q I��B  mb6%�339Q+: 327 U�2 gu�:birg64_of� 7282> 6D ! �� !!�[-�miJ 3�? \ �8����6-�`R�:��!.�)�i"-: � �-Z"/!aA�T`)� ^�  R� Q[ ]mH�e���.lat� �7�4�Nb!HB�%evBP\A�*�%�a�"H 51,��3�M\SF8�"6#e�Yl8�u�)�*� �dn"w *> &��}(r���� �p&rwKi_e�I�pluc� ��P�-�t��R��[3��3�K [37]�C" �"@�Z���5�A�2�!3)�"e /1�$in GenBankU�weqp�$u�RH&�ho��,�(I :.�(Xat36�R"�kA�"�2)T&� ���" ]�T��A *X��S sourCP(*'?protojXa��fu���ach1�YO?r� plu}a.�mO�:�q J'" ��l,mAu�2I�!�22:I("9A#I��{s� ID�'� �/ M!S�iV�� �TA��qUPre:I. PH10�275wD�6? +Cp" 0182~ �{6�7B:��"�X:����3 A���� � @hagC5�Do��4��&a i�e�\�N tQ[sA1�$is s9)lMr� A2 ��&�\��2���Y�,�u��*s adjo��F?��6Y�B�)�[3|�A�ey���"���L aiA]��a&�B.�5VQ/j�.oF K,au �%&�S5.�0Q� �:OiPA~I�9 0954. C%� �f�"�06S aJ�:6f0APs.G ���. f�838.�� b�G�%�lA� �23M��U �3� Y�5[��( ≥�3o�3,6w�O.�� !  �̈́ftpm"�{��9`�Q�* �1L�~�aQ&��eIMGE!�0�Q�"&�)�V��/D;R �n��u�&�< 2��)6�� �T� 9 pER38��pSMQ308̈́173b; B4�fi|%BTA1040;NgZnia*!m pSMB�!pDP�pSpnPI�See�6��a:ctuMD� �-ߥLfE!R�o1;� E&�#e`be�+.eB�.CL�"EA0ZkA�~ &ai6� ��BNm,it�I=�.�2d��Q��'���37��6�(a�len��e! 134�5A413 bp (~$���i�J�%k( >�K�>u�`%�k�m ��!��,@�: �� 1).�� C�6��|D&� 1527J �88%�-k[aORn����f 9 g s%95�241�53�opah��{�b�%i��?hR�'٘�k%*\,{#M�UM� !�Ad,/>�i�c(5��a5&�yeO "�CjGf"irE� l-��d�ssi" ;4&�G{%a"�=V3"� }_sU��8�py�+2%7 tr='within^=0+qcr�'! �1�����!� Ecol&(&%�"D^we�1]�� gPprop�*B��B�Rib�>�,:FAem�p)� a X4mo�61i�� ( 1"�M!(:��7VH-;�G�-� ��N�"-138Il�=�"@.i J�4'T��"@4�3� to 7"�"/ .�"�Hfi_9���k_*c&> H ��R ��v we b}E�GX:9?.d> ��*w!?Iq 100%-�ty"� LautG"a mir�`l� �F�oA ��em&Cb�>�oZ(["A>aUM�s )2 a��!��� � �Y�f�)�:U= 1998��=1477 (]+�6R(�� anN#����%��8) ;� 1997�=�6�, ^a s�l.O76oQ} 13"]�i!�� 1990� ��*l�Q*  2Ys�'q6,K ��ntrole_ mapp�r5z!�=�-��B�QE?�U�ECen�*[v�h*Q&} �ij����<3Vc��Z<�E E�aJ�V �!a�oD��2�@308!_ 3Q)�z EClN���em�G6uO����)�I9tBI�,�Z� RN���*!Fof cer��U �sf[%*�%A@Js"n to �>��t.&�>"�!"8!�u U3&�u��NM��%dŸ�� —�(�XF&)�&2nO� *�Og]�+ ess |O)ˉ��Ac>�1�� �a��-&��pj"�b.�+�m\y� X~,�REzfMl�?nQ.��*�{kX �{�M%�Ro'(mloo{A8�1�@�(]�cK&�^��'*0 A� AlsoI!3sak� b����$Ma:�%�A�� o!*L0U_ '�B�"&�O)w�Wa�BK. %hQ�� sY�.�.< a�?Z sĭby�#R�z Q�f��^�GA�!�useful%H-��l�= ��aj1��"�M*� reSc��zfeå\ J�%=!/�$���!�O�R�J:� �A��0n�%�#gY�&�| orig�a�rad�G})�pursu�!�.�z.v�"͓�,&A1F�(%�so �U�Bq�za�e2\ *�Nj����6�� u}�:�q���cWYA"! JyQf��l � �+�Ma&��.�Q�8��B�dmb�kF]4��^�A�ai0h�Ib�{"��>�nQ6!�ATI &g��!�ms= &�̡n :XxK�n"���R�bN�,*�6�<��&�!��26�, z of �&9O��NOimmedikEx���)���m5M{Fnto��5�){R� �ir�*G7�" $� ��i��)~��7iyse r �Bi� <s�Ens up"�&��iP!TY����Tee� D ��4�Q+"� "� .� 6S �precurs��/4*�a!CQ h � �a�R�"]���mM�u���:�u�&�CR�9#� �1i��"�"� -�vws"xH)�we� H!�c��.`N�F��B� ���� 4J ���+.�GS�.�<"��.�&"T".� ?1V)���nog�6o"+ 36(� pl�pr,���2—�� a2 W�+^�i�H6B �5���ly�6�^�;"�E�E&��A%e.��5�%�b�&:k@R!> I~�W� okA� warda�be�q<��"+ -U��%x^d�����&$ r>b�m, Zl!�A�a!�2�ke>��^waJ'�'��U�"*� X�oIGof�~(Dhip�*rk�� �NsF�#�selfish���5&�\�)bD4ca�v��Q_��4�Ym�6���&�"jjudged i\2�U5E��fa���VM���!I� �!�{��A9X�M��!| � ~ 2���@���K)�t���1E�)W �Y#�IE�ib��uB>-�6nI�� ^X!<a�(iz)*a "�]�� y���8��J%�ř�Nr] � ndMOq>9^�im�Led-AGH%-�8) %�5��A����6 � ))����-�|� Z (�Y"�li  �b?6s�aʭ�QJar+r����E@M1F �F;6�vQ2A,��|!�. BMȁ�!�.���GA�downloJ� t http://b�a&"i~ diana�3du/ U/M�sA�^q� prepY#a"�e F�&A�pM"�Q��?��*�)�Y"� lyN 6N(.Z���ji!�2�)%8�L"� !�9.�,.BKw*� in R�7� +Io��*dpFrƗ�%!9��*�J� .�K1���8>��F�(a�|A���� 1�"�~( r:o�?.K,`Qd�_�o"Xbt!b>p ����m��rf"�.O:�m��(of~ ۆ�#-'rSP&�of .�\jZRu�*����Wd/�t�Y��J@:YY,�6��Y aram� p�).���1' fal]�[�a�%?a-N,�ci^�� s 27 �A���]g�a�1N�j2� Ӳs��%�e�kepv�] � "�dL !!-�n�QII��pq��:c�h.� candi�� 96*:!�m�%#�#1��%�/I�ty& �">vSCD-HIT ��/!��� �- c��I !t��j=!Gree�]w�&t QM���To av��&)�*%�x� 6  te (u�.xEX~Mnt� ����G=no.�<�,�9 �J]�62)U1x�E �]��!���� &��"���P����woG.��A�.��}� �fUa5}t]M��`*UF+�yy�E��=c%rW!5p�- I��l- ���m("`if!mf�n�� -Yi"�2 F��FA!�drB �`X4.JGa< �q�.�wSc�1^�{^u�A�I��FEO�Pͤ���d.� �hI�A<"M� �8.U��6�lF�~ !|E�&h"� �����(QXY��r�n�09�i��l�y1 E�%J !db#D< wD�Mu-psu�w fr/ ��� iy�oWB�T�sNXAS2=1!�F"o���D�$ carra�#a,N+���Sxv��>$�l� j�+-���| �&�m�1e6�.*In���8 ��+ to��n�Z OAOD�IEWicw7A����<# "�V"�>&k��� ���H)�N��r6���r"i%�we�Ao�/t�wm&�J�hWt�( < u ��XAt!Kxly%Ai�sV��T)�a max�� �x�.аa/ n-�!pV�Mk8ran SOAPdenovo &��k-��� 5a)k!�R�~�^!$�s�!%_o1)a�� ���gϣa�;B��j\��er�C&�-212�H+�(MetaHit [41 �2 ��l ] y [4�i�kaof���e2�W�4�� . Af� �h lGM!+�M F��!Ca� nd"�A"�cNIW� �h)I��6�!x� ( Azospir:Om B51�6�+mutdvNN202�.D��r�H�q ulfu��OSM\.DehWoccoi�$GT , Erwin8�mylovNAfP 4994�,�EQ�ri�k* K12 MG165-0���anur� hod��[mp�z1d%a10:���s9�l 5� �@��fF�"U0�@�a�oRoJz� � � �e�6� QAQ coQ�a�e2rS �Jr)?AvJDun�!^�F�&^im�,jg�xdo�gov/cgij� /m/m� . cgɏ>'3f�83. ncbFni{ FI/�) �*�K webs��N��_S . ph�0� �b>� m�lm�>�/GSmsG8�)?wSid=10239%�Add�^t2�8b�PhAnToMe9�N phant�I`DC$s/DNA/all_��E.�M@��smn<�ndN���circacg��"� �ynchron�to :�Rign�y�&l�� er�#��e$grhyth��.de�� anematp� Caenorhab!Qsg��Gbehavi� leDm�w�, c�+ab�f"�W� obus�@M&�g[��(�b5 animaI���,� �8/ crip! T� zz(�*� A�sPwh��s1�a�� �*bona f)kclockvs=!��< s|�>��i-<���prgY�e"� �d�gh�^=�-en<1oscil!Jng��C�l)��!�9!\�#NMic��� e"��-Iens��24-źi��.� amc)�i:KA�u�O� &�![<�AK �A]g��A� �� 5u#�-gL!" � cy�stronB�d,u!�2�6Y�-U"�2no*rl�,q �We� d���%ua{ic*�-g%6ch}��2��{�ory)�duc� abol�Zl��`�]�e9p, implU%G6*c�act c��nonaut��o�ɅYE[]�qEvjgi*q�f�ng�!&�5�--���UiJ�!��uU7as Drosw[� mamm!2�s6 j�+�,j8,���a ����+!�!� �q � azoan�vagp�]���i)*"Wa_�@�*�!� �h��a�OafA�~�iHll�/ab���!vCl�`?�"Y�&+8development and�� behavior [9]–[12] . In their soil habitat , worms are subjected to temperature fluctuations corresponding to solar irradiance duringnt day–night cycles [13] , [14�XMoreover , when associa�lwith surface-dwelling animalG5G�C . elegans is likely to be exposeddaily l�–dark��. Several studies have previously repor�th4sence of circa�( rhythms in2�1use]l, growth-synchronized popula)`,were entrain �� or t=�-N, andV�Q11'%�8characteristics!Q true�oscil1,NseD!'Psurprisingly variable%4non-robust [19�In addi�AmileS .BgenomeAIpredic%��(control [33%�4E�Si�FeN�$is not bia��by pr��assumE&s regard� spec!�U�MQ�ic)�,B�q mayA�a �6measur��>�a molecu���). H��we9Jl�v-I<��}>1�:Na; GE4� 9�b� B��Mq f this��e�$ganism cana�u�Oto fur!DA�l��evolu5=fun)J�is crit�H��keeENme!�a4. To determine� a��Aw%_��s��h\ :�follow7-m���iUe�� ^ we��!����-wRs,analysis . Gz� 8of wild-type L1�vae2 �,ed until adu+ oR �12 h∶ �/� ( LD )%3 t��J ant2�$of 18°C ,�o 25°CQH ( warm/cold [WC] )2>!�e� ]~n��( D�( Fig��1AE�FR�A{� � maint� � free-runn!�c- A]��DD�v� �� �C�>�$To exclude��Z*AHq �mbryo�0self-fertiliz�2�,ermaphroditel L41���%�re� n on pla,��ai%L5-fluoro-2-deoxyurida(( FUDR )� ich in� DNA syn�isk�Win �$nic lethal� [45 ��was!0l�� y 4 h d&�last 2ofQ�m!*�/fir0^�6�!hyb�� 4to Affymetrix .cGet Array�EH!�22 , 500� be ��re-�!m�� an 19 , 0+� .c��a�To�x y putativ. p �W.�� high!�K � ,>dser>of dat �R es b� o~ initiaJ � ��!�&� �s$approximat 24-h��iod�|9qB%oT� $S1; see Ma\+!�Method.�algori�"� ycB��a�onanc�AMm Xdpha�w[minimiQaqarib�cAu"� al�� in5�� a��ta�[46A� Simix m Ѕ~��� meta-��2�R�%� from.f t]'aAxIl~� ��.<[� , [47� To valida�_ 5�!Afilter� l�by � e re�aKa�*�setB� ( S . K .QPM . R . , unpublished<� nd� cessfu� Mz all majorFin�la�, clkW im ry�d vria#ho lis knowA Ame�/i�(( � � nŋT� % Aia)�l� �y2N ie�a.FA3� the^�&F -r�*| w��A�inuM o�a4��2�a�below�En�m���Ej�#.� Us� [.�v�io � sQ}SX us-An but� -indepen�EG exp�Ito �� v�K!��4^",�obst ��]categ�ya�J� only!WC )� s 2AE�3��se!uZI�!�rrs]!d�E.�a)^��/�WC/CC6���3B��suggesźE���g = ɪ�MC"�AfI�MW�@s��e�� r�Y�B�!k�a2�:� .!`� = 1�CN�C%H3!"+ U 1��-�-B� �^,� 7Ձ�i�p�|xr mask�Z�. A s�f�>HasR "not�.h OofiҝK9�6�in.�[3��W6vA9*w���Y��enric���Nur���ompar!!�dic�� Fourier ss�4differ�� b randomlymu!:=inBle–M4le ( QQ ) plot� All��seQ EI, Le[k d6 a�)����antly�for.���whereas2�� 12-h , 18a�36-b %4 k`e� uishc 1t��ofJ �+�� 4��"5*� ; E�Mt.��"WCR (% ,�q)ys� found l�m=1-/��O!:�#A!WC-n ���� �C &,� �9iv� "� 4� a���&� 2�Y��~ :�,I� infr��ult ��%Z�r%� ��Z}���$is patternaR-�� er or� harm� EQ���.�.��fUin mous|[48$ We next"��� !�lightFLdn�XiH.� �:�� numb�f& .,Jh� ]\ly1!t� �T �FE : 1 , 817Ao ���o 775 LD6��JseD rise:I 9%E.4%AU� F,:@ der��:"&�&�`� inU�ng2j"�y4verII�ic.Bof�� A^s��pe�Y�_t�r�s:i( PCR ( qRT- ��. Eachc!�12 exa�d j��e!�� MF�ed.�m� ist�G� �?69��V��Qs 5� S�*A�ar5Mm�ab"�im�=�<ea>IX S1.�M�ge$�2'beS*�da�se bi-@pathw�� 5% �2e�B.4b>ro� 4e OntWy ( GO�� [49 ��bolismE�eAIr� port��markedR�6�r�Fo�� ceo&��q8-B2>e cyto 0me P450 enzym��É�by�-����E�twoBC)�* A�M �UQ�(6�T�� - ..v � i�,z�-2of �6�\ 6�=�or6(GI{:&"!dGO �*.2�. 3L�"�Y9M�N�We����h.c3 eachHbyfaverage� ! peak.�YN We�' f2�I�ar�middlX#mo–)� he cry�G.E�LD�q. @�������e0���fwoUY��WC22�& ���n M��m 6,�toA�� ��1%�.1+Tog� j�� �+�6hP )Dmie}Q��ggen2�:�$o�, 406Y2862%�� to�"�?b!=DDLCC6�*�:�(yr�A��.�E�%$�L �WC^V!O 02b�m�%h & V!�ed:(!�. .�> *&R��QVs 6�?2� T"'E��re.q�def�%�=���� ���mJB"h)� �m��� S2�w^}6k �smvi�$ńt.c. albeit�asiderab�i�"a"w in s���s N ext.d� �a�l""E !�=)� w2`(*�aM~nlp-3i,$F23F12 . 3��hroy&2 dI^K. B�. ="�a" *l M��E2ida�w�( l���� �"p� valu��Y6In����#e��$&�morpho%3ndF�6� .�YG���I<tr$to%� �w �2� !�E +�J� 6�o� ve2�iUto a w%eM�t *�(�r<)&�!�*�]j ��S:�e eV8)� ng , '�l$ , egg-lay !� �or"�$�b�9rA��.&< ���2�A�Z�e!���Y�!�w�upa�JYF� DD)�CCX-/�`� clus�cco�%I,i� a!>E:�Y�1a"��"�.�  �� � occur� H^ =%�.�, a� �Ge� a re8(�broad6{��6� \J�{Vk.��ze�' narr�%' �N� nPano�e smallerj=� ;.&~��.���� I 0'%��=�AD�!�N "/ �'9ities:0y�i�D6�)��!�} rk (�v)� %� e.� LD]$or � .{-a�}�}How+� r� �.8-�9UY� �f>!�&� ��3s 5$MhA hallm! 2&ɵ�.]pMens��@'e�!�yd��al�,.��* [50L[51�Tod�e��0wo)�Z upon"tha��"�+�#A�> p99 M'sf � �>cal{)aC�O�� % �9a�� ^q nea� Y�atI�=���7+ �4�@ �5%(5�. Am�6�.!>9�.�heQ$en (ai��onshipi -)� ).zeitge�[5�'5"#Typa�l�qYr�llayed ave�in�T-�?es)ҭ�m� toshorter��8 b!�,�� vers,.zadvT!daPnX��Vlonge.UL ��L�%&&'11f&1 h�13 3 h� ��2� -M� cand� 9�YD�6�?^ .,Eqd-e�*���&�5f�5>1�1է7; ,"@>��.�A>X*�%l�c<!���ai��@�9�b^�)-�,!6 c tb rU�.k��"h�direc �s�/K�t�}���Ή[10725& mmo � 4�106� 5�8� I�$� � 6�-��E"� � eL!� . On�)� -�&�2be�7 seud$ ( Y102A5�6��!�!� G%wd-3 p >T�a  3!oBWDR5 me=histone�hy�nsfera�lexter��3! q oteiw",#a���&j3 PER1�M�e �2�+ s [5En0�MYof�lap betw�29�s� 2�$ap�$f�$nC/resholr� 2[corg o�,rF24n��E���6Zempera�7 �C,>��R��e�ksg neg7.�in ��c� Y~�8)+�c�  � r�m� ��9`e}�W�I��tpossibi�)l!� lack7�>���5gu�|A�7#6alZ�6eV�:��.j|dampe ickl\5>%%�3ei&k(""�4 �J�����u�5&�ed�ru�Va���be���-shifj :��u%��@��orJ�add'�#s hyp� �� suz:se76arbitrar�9s�A�>�B�to2Wor2T-M�6 �ksixAT �B�did4 � !�A�%8�E`Edpy-7��or"� �:8�@9�.q�s 7i�Sf��  s�!|�he�#U�A#E_de!��$alxI, 0�'7h;��b� � >�=ma!��)� { J2gy�oublex1��in kin�G-��`�3�ituy![57� +%��)im5�N� io�.N2�62�T�L<�$^3�1E]B��A��)��'F�![mo:� www . �=b!. org )&:9! mu�i�>!\! � lin-4��/ �c:$!V"�k inJ�R I !o��m~�;H"�-MOm[ by72RH* , no2Q yes���M2!Zi�1�9 tim-1 �9ahaclk/cyc(or atf-2 ( �+)A4&5��(�3i�e"Fr�f'1esc�p ( gfp ).�%'.P.3a�"�31��8ge41!�p::ZAK� f�di3R�,It :<�la�h5��y�Qbs)�A<a�. ells!O tiss,:GE�<]�� ���1�.)��8%�Y!aɜ�$�aNG��" -l""in vivo.�� estav.gal-�� gfp-a�p r(9�"��]� neuropep68��s� ]*�N��<�AM��AW _�?�?i�Aarr� ��teg #%Z)�in*� �pru@er�vs.�m{A�r1 I f�0 equp2s{ �a rapi�!tur*3� 8 PEST domain [5K&�� �F����w!� inte�(�$* un* I�� head !Dtai�=�6uz5j9W.�1:ic0&��5/�6 ( CW�r:��$�GFP�>ceI��:�t"�E�poi�A.6)-A���d=l��"m m��!F2-*���eV/opposi�(�� :r CW�WC ����9M&HD�A(perr%d�� le�wo�xAYt�%&f�.3� r""5�10)�C� 2�%e.v%I��!  li�(-O:� �JB;y�4of QM�!N2���� &pR-�"� a � ^. ould� �tɓeqEureA�a*8- �!��� schedu�;"D .q-qngZ,12�2 hA$�es%�4 0 ���tfF� !go�]�� 6 �&� t�ld.aA��)3are��.^. QKE�B!��jal���onq��3E� ad�WE"�7is.� pul"�"��4vY9�F�?)w%A!ni&` d by, " ��. MAe+NL>I�9�bA>�BFD�!:0 d [5�H64� "�A�&�Ame�#ism!�u%8�` duce2++8r�'�Fll��st�<�#6�utax-2A�?of!a�j�?�>�!��5b�-.Ak2�G��+4%a�5X<-wavelength visiy Ar�-violet-u.�? , [6,I[6� W6_&&� ��N4>k]�� Q��]!g!ly affWZ@^�`%}� a|��10�9�Ex�Aa�IE � threH �|�asDE��, �#T/O*Jb� s 10Vl �ec] �� �%)�%�=�yTEA��i�MA.*\ J.A�ng�un5�G:N)mE�c��(rane LITE-1 V recepB � %$b��]�:� խ10hA�A��BA�E�5CM����v#C3 n �@!���AFD�*HC +&��_� rimar�)B-X>�[6r[6� 6l�dNL;2?9� &�%�,re��d &����2 ��ha�enE�tab�?8uMA; gif(0Miriam Goodma�StaD d Un�-w?81E��CJk.��qg !Y sole sourx.�.(�#/Iց���Y�6;E .*6�sw.�D � E�!R enviro� alb�� n��"s . I�Ftž]w��p\.��9D ��6� ledgHm�k*�3���� .�N�!k ���LvB&A !K�$'��?"�:^�b =�-ey �N ^K u�&�o"�a�*| �'� Dh� act��"Ta�(he�H*�A-2<�E �A 5��a��E�u�65.��i6#; �#� A~�+i���,q:!E�,%�4<�%�verteb~!V/.��!;�$-nonautono}5n5)%&�N�@:�. Our�H ings����at2�ruSD�jF6G�is�$inc�?deA�bAR&�Q�9A#��J� =�6N:,6Lyc� �e��G!�� �Or1��5d�"* es:�@�)!a�ɕ*�02�O.�)!y]��y��!�u$ �6iY��O&��(�a0�h)one�>�M�/at�oWI� `/QwI� y�&�!���Q n�.\E�*�.�6I0��s�)>HRc cooa( ���.�17i�,MA�do���+T%� letev�wo2� {2s mply ? At��extrem�%V�mFe��.&�<*$ ���#!a�'Multipl�R�< -1�E6��unp���9� B� )� no eyP���P�D situ��!�a,zo�U� A=� �S*�Y -!Ing�a� t ru�'m�^E�i_-�[6T.> .R���Nfi� �)�:�in=�}��i2cenario���"k>lo$s�QU��c�� �P�, �+�Kng%m[: OuD.# � A�� ,��CE �NL e�gWsha�&�".Q!Ae�si!�AJ0ll eukaryotic�����pla�to"�, *`S �qgoF�%'���Gi����Q 2E�[717#T0"it!�unVXa�a-�] "� ]feedb� loops w(EEE�� �~!Y� (�)g �F!�&#!�fZ��Pl �u��Uon�n�1%�2s��� Gss��a��B� . Re��=�a�c�� asciuC!"al�'so8a $:g�ٿIq&`" ^%3q�"�O� orig�� �MQ9 [73]6��m�"�%��r �!�B)-z�ur!:om= �z*becaus�{CNbya�\*vG�,�%\a �PAx �`E��$al� �:� �&�.!G:%W74�U7a An a�In$)z#,��:b6[:/,aG �u �)U*� c�&2�; \ ��e�U� n.�I��esa�t�.c�T*�6lap�� �Б��� ��5 *� �.:�� uD&� Ad>�5^d **!2#���� �5at�\au sineAe �KA�EQ�/nZ� qv�$>:�"+,.�ph��R�-�*�>a�;�&A$�&�9XI�Xm�%� �themselv� 7�7�R�w"�WIH��S8�$�B]3 �WC� Uy!6�-�i*� rai�%BA� rict��rir���0�&& % 0>)e|7,6 _� DW)3I�A���2y�bq��K ����7~H.�s��a�&�LJBE��"2�F�U&��^+�r�9i�Z�L Nto� �F amo.�bo�_"4(��. � �U#) �' Xce%�y:IoRY?&Y3*b ����Tj6�>7 S2N6�>� W.}2M�Ei�] b&[� ����!� artiY1Dr�FI1a!� r 31 -to- �P�[16G 1X Loq`2�:��� x%�W diss0in ��2�mZ_[7*8��Rw&�C.TJV�0a�e(cM�)�`c� �*ros;� movem��8�*���de :�Aye5+�"`as�D�^r&H� a*18� .�-?e�D!U�>*y�M'c*� &lCly!evant5u&O*�8�a� ay v�(� }M&�^.� . IA/��!qy���6:Know! gwHH.D! read /��z��n�tl!���irVi2�n&�"Ak%�� �� oEr��mo2�Z. �&�%�in�Sq.) variety B7col'� N#=A� � cul6.d� En;i�=li HB101�( Es t��"�Z: PR671k#' )X(KG1180 lite!'e315p)2 GN119gIs�E(&gsZ�deBJ�͕ cs)� ݉�Le��*�( aspa�Ke�� AFD-�=A� gcy-8AMmo�$[8$8C5D�* r1t*ru9du2� ndard��V.�b[�>g[efe; C$�ke�QbZea?�3*`f�.'�to�#n*gh"� � e&�0� �tw�|O incubator�J�!at_!II'=!�MZdo 2PF7]X:-\ . Af!�reach�{%h� �n�:IA�saf�œj��� �%���R�Gy<.^\�z% 0 �ZN�hgh�anH�tar�  &W�O!b�8:ffR;M& ;. T:�!;� �g�� I�HD.progr�,b$1��88ritech Research�a.� ztat �]i[fZkPreci�Sci�dic; �whi�izj[ n$F20T12/CW]faboutg[–�M000 lux�0[�\�en�d"7J� ,* ]%EG :im��#]u� 25 µM ]. AP(�`har SQd�� %� 1× M9 bua� ( <15�Z<,veZ]�B�Z�m���W �*�^d�K$. Trizol R�V ( Invitrh6�RasTi2��.a_p7e pell7%*immed�klyze�9liquid n]. Ext7jT � RNA qtre<��DNA /$( New EngloBiolab\KKea[8�c6s^S9F� ��T7-oligo-T )�fme�#Sun(� II ( *�]$(Biotin-labe c� gene�d�.a�D Chip IVT 2a,ki!h2WթZ!;\��8_manua-Hy�^z �"�N,���_��sca�`yRNAS |c.�U�^%�9Xa;&�OF1K�fac�r ./U-U=92� Bsc&� gi�]!2n���$microarray& �\.Z efH$�pe�U%A�R!w! im��z( e�E"C��t ne54_e" ^ (��),�I  V�Y,�l A:�T$V��)�� �ed 2�V+K�V�se*�?��6*>^��tz)di� �2�En"pS�,�eqA��B"�� b;;Kx%�&0 �r�W%�2�!�Va n2B%J!6�E��� �!}�$inY�. C/0)F a*�2(x gr�Ei ir�;log� P�P3 �NW�!U�I�m���?>�Q�hea��su��� al annoI� tooQ.HDAVID ( http://davik+ abccH.0cifcrf . gov/��r\�!M� ��k�l2}�g1�'%"�N� a Corbett&�Rotor-�) 3�m6 ��N ili�2V1CM �!Xact-3�g ard-1A4rt-ch� 0alcohol dehyd�D����N *� �E�o #do:��%xP� � ���� avail� G4%esa<pF24-�JE�assesZ'20V. A9 )>5-kb up;ram 2 !n�K&�RWp.�2of�13i>��OQ N�1&�op����E�x'-p�ew!@ {s�32�2v<)$JwFV5oWPu.unc-12[5dsRed m3�#m��'@PY7644 ( oyIs80 )F�� o ob  a� j+t�&�i, t6O, ��wran*-s&� �@%}*� l�2ze50� WB,-*OndMkil��a$C4!* ��! �� e�1�/�:� e� 5C )�0--f�on�:��,alM�.  fluov7c�ten�(a�"ad, "�:3J !*�&7 No� ZadA� =! ����oco� ImaiR7V5–20 J�acH,7 00× mag}-3��aŸ�� ,scope ( Zeis �,pp�E�Nepi2�(a CCD camer�]y}5t��% J� �al In��He*0� [�ZSac�omy�ceR&sae RAD3e��!�!mhu�*XPD< �n�hE���ak  he�%�HTFIIH%m�Binvol (A%&�o�k�reLE�Ek!meC �%. SaKiga�t�� ( rad3-10 C j a�c�/�� um�9hyper-.mbi�o�( Re�:phenoS- .��U� � �! 97as6�y �:�  expl�NV� ��v l5Ale-�a �gap $NJ$9);�)��ic f> > break�~DSBab �Z!� �"*�(��Ao�cN�ad3��"2�scO@��Pal��%�mit;#6��C%��p.��DB�uLa �A�!��vR�ve��+�F�eN�ifwncy%ec�ceMshut 100-f{5. M�s��XivWyAs-��1 -qua�J%,* Wref�[)�for�,��8=$q�Ear �[ atidAI/ -Q9, DSCE:I+/=1a s2�eU�&hroe>^6]�! tto }c'�DaG,�]�Jtaneou�u�-XM0��B'Edm8d 216 un"�C( �:5"�n!��U!�AY#�b�D=�,q���de�AJ�duu���� a2�!�_a�b*jGlS'!+IA�B��regw� I�d g�-H2AX�n��*C {�� hotspo��Ce��62�Mu IMA2tHXT11%s �N� lef�9�VEo�!XV� �bar*�Jse� ��$��& � po5�VLMs29Da-�.D .J0`�o�be cote ���)")�E�I�N\rvzQ1ai�ibtW�T}|6�,��a �m��xR=Q(a9o�1R��UROiae=f.?�& 5’a�3��"4�$su"Z8a/F polys se]-NA�fac])Qx [1 , �(A�e&9 K',�(� �c#$ "kaa ��[xI.j1�,A acKmsA@tu� �� link�.e�y[-�!CDK-acti1ngF( CAK@ ub�[48s�'D�sAg, !�/� unwind p!�*� a UVnuced le�� ,�|u��-"d�@��!K�bzO�;~i�end%Ya��gapA�t�f� by%']�,w�l�k!�t&=m��_ *�&!�drp a��viB"*5)�o`: ,R om[�t ��aer� &t  �#iso0 d [7A$)VW �4P*2(8(�@e�A6cA�9p ��de�%A rem13 l�W|�� �g,-I  2 *e 7re-na�r� * 2 [�&!�!p"� 2A�eOK(�^A%��EǑal"��E�cp6$%(_ C�Ph��I�� se%� ; ^ Eor�!(V]e��UV�i%� :�`[1��In#�2"U )L!�nt�t tE&cap �epa�ngE�a��&o!xow #� vage,�da�d ) ޅkde �ZsP t-in� ��it�E��+�R� at�1 "�.>�D� 0����y9y+ a���2:A�ad��$?>)c[�%R*� M�32#�Q �1��F�.�jAGco s DSB-6U�!�e2F � �=o acide"M]ATP-b�ng&�')[rp�jRnt� �<-< ATP v�|EXk&ng�i"K>�!�[}yI�ap �y�%l�wit�.zgr�2Ca+��g ��sa q�$E* 4Y�mH"�I;6G16}�:� irDn� � 40 J/m2�C� !_g�O�  SY ,$� V1 Va�b%J3 � FACS&� !��`�A�UV Z\)��ite a�S-#!�sr]�a�pd;A2�Nim` �T�H]f�) �~�%2���ay)�o`^�$#�A�j A`A]� x+ը� �:!0� f�x�*val�,�h�-4A�",eeAs�� n�affinA@./ d"�wX>C ass�b�J�f5��R Y��!�YIg"Er.��"� s}�[7–�k G:�!Ja0�MtK2ve`� lh o�b6��0� j2 ]-?"� ��e.g exqDg9SCE��T&T��n�{o��5����I,~..;`color-+o%�)�(B�)a� ��!! cap:�-hal /�%�iN���Y'�1]A��� ��d -res!�Av�!� τQr9 � sD SNP )��s ��W�\�kl/aKC-�: h!�"��<I�JV/ +n�K��Z�zo*�w�9heN={V�.i� a�si��ui�en Als�7intrigu�9o* �JKmst CO� ���s��con`]"p ar�FI�_A|w'Q;�� brok?x �K(� F#.�It�Jem����!�+�A;=J!(%� madP/anyBN� n�te> A�lHnM���ew.�;�l�*c&ye�=�S���s9��5.enoreA�ng.���:�FGC]un>�2�.2A,�n%�"�.�M�6 &7"BeTi1w�)��;%Z�͠�;� U�U�A�OeC1� Z:�-Rj:kGo fed&a\*�.�i�� /5�EAS sub-telom- ��;yarm!�&  XV� I?"9��2�� �7�?q�6�^q}0w!i`+� M.�6_� *w�u�$��~, lfeb\A�.|Wf�!�ofQO3k C%!�II�s�Dp #&!B$)��v�(��=!terpre! +�1� ���G� !�J�V�mia�1 ��V�& � �/�I9we"��.�o�$Z=I<��d"n  ly [1��J diploib]؆]��+by�jha.)�G6�[�v303-1A [5�A�YJM789�2��_5�<~$�� � ��&�PSL|,97cop�%�� ��can�0w (!}�tEl)� c" 2 kb'$��m�eG�O)y��R� 6~!R�2a��aSUP4-o tz! ,*�n �sYo$!�iTA\�nIzyI��Xade2-1 @� A3=(�W}�0&i��ted �1~�`��6Y-�6(pinM4lon��o� ��&�w�  \��> ��+Fig(iOq����u� p%�FeVE�!tw&���9*�0g�D` *�'�Sugh0���a�Td6#%�*0 .`l�5fK !�"( LOH�0g�c d/y.� �"lonQS ��� a%*%�;�e)?2,I��e����qhNW<B!1� 2��Jz\�ri/>{W�cto�Y/ya�l�AqE�15�  ly����d.�aAZen�-!�%|out%=� %#�� .�6�AsF��7*=.e�&� �# (( SLA64 . 1�#nd�5MD555/;f��� I�� "] ]U . 5x10-4�Y5 . 0:|?ai�oa�Xa2�&"� f�-<�%�!�i�mE)Q �z ^� �*�$�NV�B�.�z4�(��kc�%� e-�,�No)eRTEp�H%����ach-�Ak�)���Ao� �":�-* $&� &�!�UHemploy+�y� q�p�Y I'i�a�c� verg� 6�:�A(�i?�  � 1֩�p455 �a�le^�� SNP� m2�A�vyp ��.F ��1A�)k��*or�Pu�.raYon�� V ( V-a�8�%� )JV� (�?le-� 4��AAV RE"�@)M750@�MZ/!���I577� ٟ�3A�y��.�/�y rby� r 25_>�rw��jmWat�kA'CrickUMQ=-Q��.RN 2,>ue0a��:8)�BR�lq�0 S1l_9�wh�-�)%�p)�5p�.Bw(�fI�M�:TlA�uE�-΅!�V� �1�|t:nCkb= ���"U/of[E ."b :� ina%(_ by S��Charl�_�( .a In brief $Ys� ���C:� g�!���or�&tew"I9�%�isZk5_$Cy5-dUTP .mS� �wZ uk!���:N3N!;sa&�mix� nd hy�5a]�� SNP-.R!>��f�}By!f���$&ee h�eCy3"�6 probM��Ta?E��F�! �e�2",.�qDJt՗�)+� B�8#�A A��ct&; +Q�lea�toE�*�He ic !��k7�[{�%SmU d 33MN.`�sU7e a�nd 10b*1�<�23sM�kwo ��."��7B6.5i.���2� � Q&i J�ge2�'�V #"#2' !]�&�=p��XA~%\ �t��� �oma\AbJ^��&� ���t:�zjJ2���Zđ� �laoDx�R�5 ly r!�( 1�4N�R?a&LQ � �Ocmei@,!fJ� \usu�!a:�-a�(ja� "1f�"��'.xV�%�@��"�lq�& q!�!�b�(>A�[18�>� Int u�,���� ��ɉ� )�.��!���I�%穤/ &�-�x^�&!�� K�� bo��Y�m^m�&* r�E29I[%��2�[F0M� ( 3:1.AUP�0��sj�.s+e�� !p� ���"e&])u�a'*"5�*�S!<� c%Y� ��a�T"� |�v�%�ZZ'�inB2B%nF�a�u� | -,�QMz�{�$�26� �27�Z.��ex�_m�F23'*�e���0NA mismatches��G.W<�R���A?!� w�F� oa VLK�a�y�>��)� �y��I!���90k�Jl6� IV * �aN]�� A�, 4:0 , / �?coa�x ��8�!i3�n����i!fcm�432�>�|.i �.�w��>))>+{�  NP21 �h�M��;n���A��sB�=�%`2v}l a%IC �-!3:�dfAy�� +�@�cs�"2 2�/��J� Such �yT1}5w���1� �.6U\E��! ��" d�h�C��:v�jm��1�6E 9+gin G1r�-1)I��.�5�-]�9���&�pai"�I(!F`.� .jZ%�4�-�4��)!���A volv��!�b�[>�q��zbeY�Eu�L�Ja�e:a�weotly5]�m�%��bothD�a�銁DeD�Eo ;��G��P�9V{2H�ge�!F�><& b���� u�!%I.;of��!Jor/! �/F�� ����2�cheAc�nA��8$#-c�)I�-�\��{ y��.&aQ�li�TEV�up�t!��'r >Ah lg/.�AAji."_�vs��<5I��jn(��owU`� [dk 7!�: ):��\9|E_��=�96o��!��S2"�� d�418.k s�^e\&@( C� es S1-S8!�]� w}�25�� "�Q&y �R 2bq�!��>�C1-C25:�Ah^m�h@&��[�Aur&�* [_�2Y3discuAIq2޳>! c!t�! 2�: “p� y”"� A֡�yG_� swit�Lmkinv�* �mIXu2� �{ symt�c-N� �4 Ob18.�E�R�*M]{ �, 5� �� �� �2��Qld'eB$";�8)%�13 �x Y6g>,b���e-������;s6* InY�� ���> -�QVm|�H�����9or `�#l>5%t��Ay8]��-V%��a>:_:5�e[2� ؝ 9L74 9��-Q�^I*`� hIn sum k,�!t39.9��diagnoе!�r �'- , 9 ( 23%�#SCB.�(q-N !C�A�>wS-�G2-�I1��o�D�&30 ( 77o! nped/&�$|M&�g�N��H�� �%�%���>w45���76 ( 6%���V ��(g!U�Y!��� *Ero�$.����!n�jp�a)p = 0\ by F�m��w%�^ GA�T-1"�1*�9�%�&�*-6 ( 88��73%>(&Q�edA�2#6GJ .��M!Fe���p� %��] :�p��Ff <�x#�.��� asjleW�( �h) B wo:m:MM Data�b�G� co��x�, � ,ing���BT,bou�T>-�A�e*m<)�B2Jin S32}:�Kj.� �g�6�]Sg7#9H�J��� A�2h� y�closes��:2A� �.b>rN (F�>�4A-bM 9E�� �-�#>nt []D=�I;�I�|q�s Z�.e begi�F Z1$ en�I�sK{> a E��T"!Ae� ��Hp>^�"'?�a*):$ D4Bi�� Ws27V�P�%N�&� ~"z( blu9�adlfi;�)�;as��ng)� �4-,7 a�Y�*Of��idp�{1{>�)�=�a�CO��;r"� &���a G��c�42q.�-%�>*�""xiM9 COeOQf2�}h��4f�Ac*�1a&� 5�3ENX(� m �-�IH*%���!��2�%�Ar .q0%̉�1��aQf&�� 2T9�#[!+�*/~)�%� no v!-��6�"�/&�&XJY�9�=.�Ys s 35S �161 �>�2bi�%2�%25/ ] c�j ( !�-9inibi87q0�.�2uˍI*�B� [jZta �4a 2 x l��eFchi-sFe �Ma���n5e�fic ("�0�\F L%U5�6� %�!u�canmo�Tv�F�GAPvu�9Vp&����e1f��"O�Z� ]j�is qu !L/ . U| �2���,�*�S�ɗ( R�F$ ����"D&i2Ea�� c�&�*P�!Z�maximum/(!!��U�:�0 "JP-7 vlYin�Y�eA�c; eD/28H X��Saq* �*�G';  (,�%SC�KMO,T�< ' SQ�t EAct-+%�Y,� "o 2� ���� �-=A�� q� �cU �U )� �-�c; 8 . �/( 1%*6�Nq ; 95%!r�� limi���no�E+= 1�*8��( 1�`e:17�*)�9 �1DBy a Mann-Whitney  k 6���staZqj ( p<Z 00a+�_r�6a&y�K!�-b0���lyN� 03a!�F�M1<�1�!� �@ aN� ��2Me�!89!8( �29]!�4i@!p(( !�!�99n:�.�}is.Z)#k4 yPK)2�.�t�!0=g!�i2L��.^�=mz�!~� 3�����F >n"eF �� 0 lo52&��Uw&��&�A�0��N$�"4� mQ4!�.an3>f.Ye�q��=+A�M�Wpropa��tow�b������"�3�"� ! %�r�m��re%a!�/�%A��r ��+reW�&�h��u� �F.s�"m uwe � �&�f�%���%9-ʺlM 5 >(Ż&a��d665<z"�>ia�e��I!�!>��*. I�i{bk[$6�Vq# =!Q�E] ��no����6a2�6,)H-" :GN }��.�m�$F7��a��w$]2ne7K:1DZLH-� {FnRDA� -��c.i%<�'6� ��+"-snB-�B�� 1$� s$F�aA H�m- !��2&YSbu`}onb-,�"��#E���TRbranch�xj*na�emeX*��)2��. >���"`2:`�c!x1`�xB7.��e/�A�% , 17!a-*� -}!�5��b��25 1� `e+e6d OB���>na�82 [n39 n�� � s.Z.02!�V�PoO�l$)asgQ%:�(I@�c�b��Joen��2�"!I6�*=%P68*nbyA�&�0.�,�7Q e2` ��! 6A�aq5"C*�RA��;:��;���r^Q��+"�(/5E*235�=$"��(V�6Xi)rTT�iMJs<��^R-NF/� ] a�a^�)��� sub-"al�-��� !�F 5(. Swi`.T��eѪ�3�-� ͒� �ormtIn��lid� u��#e*r�(ea����'�="�> ^ Z 2�-<�)d�cen.t.bni.�Ḱ�*�G� E250� �s&�&*d� r+V�-feCu$ en# U .�� 5.�A���[}�1 �!s��firf��GZ( b2 :wenty�W)*A1:p6Z�GM::�Eq�."�*=ENavarro "E2�{ ���8T�G� F8. %W�CEN5-CANd-teH6�(VA�)�w�n ���. (K6�� 2�MP>ɿv#.�i�8'^h< f�m�H/g��aNUm aWm� ��d!s.\. U&X�^ #wpj�- F np����r��"PJ�U),R>r">..� �v�IV��Jt�� c+*9�!2%�c0 (�/�[!rGa�`N�#)"; `,�U.oH�'u.gW�A"E)�kT� H -�( 2�&��5� 76{r">or"� �#�8�{/!���5.��" Yg>��!R�F ( BI _�c IR I�B "L�HXe�"--.["� �p�bi�l'�i!=�{A�! end;�#� �in�Ys6�0�. B&~� amb�It� c��imSU dd�:'< “BIR/CO7$�4M� �@� >_� �� �of.~u��!}/COR����one-the��?e:38200.Jd"�D ! c" b�abg�@J&V=���a6 �two �9�n)�b�`J��.�2i92=<�,)��-�"~(����" .: F3�[Oie�y6*� g�~>.V�.ŹI!"*n �)*� �-PAe�S yiel�Z>(2R �+j�:�tv12|,-�6 0� �� C��� 2?]( U��� D�lv�F�I�0ZU{ m of�ဍ�i�Ip&����.- VIII;ZA$4+V^V1o� v��B*a y8� stud�Cqr>�M:\�owL���Q� alpha [25��M�B�-!�/ +�a�� #aEb-;U� ;Ay a�� nm7B� %+re !�g��R� � �&�YEz� %�Aw�#�!�w \AaUEhTa�mMF�6�,a��1��.n06� I���m"��X�O9uy^P� 2f:�1������?�I"��1�-�91&?rNi�&Ք� j&O�:��H�nda�e� uR�;!o=w>Cp�l8x=� 1a�S`h&� E�I�1eV� ��; d7=0I%-"� -1�Ka�h�= �2ose�@?� R/U8m��cA��Z&$XVr� 2234 3023*�2OG \�iA��c��ɓ(d��1d�U�4m�Ith�ba :�-R�!e��9k��@5-]�s5�KXV^`7)m<��so�YF$,!�&� Q0,���vJ4�A$eor)� bƘ�r�Y�onf*�� !)r�I!ە:�\&��s���.. �<�� 2 6 6�I !�TI�1�'S�~k26 )0" *<9*� zGX ��(v��f�3�rof QRdfXV�u:�� ~%l.!�q2E!Je%��ofW�1+5��.%,!:5�4J�Z TIX�1�,Mrs� X�.�67uOEx���Q�� �&7Ua� 92U?.6/_%Fg(XV��$A��ō�ishot� �gf��e�%�>��a�Of 34R�SJ@�_�� )u%4��,9!�a.�.=A�XV S!(� �9$sÚ�� m=M N�5�1�t�_tei�h`.�I�i&�0"HXT�vex(o po]l� t3&IMA�G� isomalt�g)�M�"�'!��iFD N`eA�et%{QO�de�o! p & �_e e�Y �3*�".!Q@��Q ͫ�2h&�P%[* s�!}�1�i���ex��� x- %]�� 2GiAqz3��j6� ]A�Ge6�?���iO�~�B�f s����[�)oVO!j A�\�BW�qm.6� ԦHjQ��R�O"�%�1�(AQn ele�8( Colum7Rof�J$%6Y�?-��"Ty{xw!l abbBX�X�p��#%)��%75�����>:i����8Q2�I!�Peiq&,6� e� ym�S5 �� dAR� �.�Ju(Ua�^��iA�w 10 \a6Ow)Sh�k#0�!�-0�6�&i-�� ��R= �":  s&��1>�-s 2�i�I�atm,5IxF� u�e��,!�sube0Tis��a��u"g"�%�f' 6 Mbi���_I��R� %�x�*k0݈)\.'�&e,.B�XuBMO�� �E-�j*g*!z"� ZI�z� nd�{.9Ntq�s 4%]�� ]"c*/�"~ &A*ڃ�Q&-%�a��m�7%X� F-=�4oCX!Y >��lA'9�?6tix$� !o�o� &�&����.l=z^<1�6Eiz^ �YA�ARS9[(, snRNA/sno.$n��A72Ty21olo6$-��L]&&palindr�s"�F , quadrup $( G.��f�v� �!tw` , highly-�cri1�!I weak:g9�,s/�!b�AiRrm3p& k�)�-Hf*�1���_"�H2A$���0s −H2sSp on1%��( T�x �(>{GC�"�{i 3Q Ume6p�Sum1p#@�!?��6��b�Ri�ud M�+ �c���qE�m re�/9ci��zd6� "�$e �� v2� �TS8�2��< �B� >"6D \ Szil�)"��� Qp��s&�V B��sA� �}���u��c!�"�#�a�1I�Y�id }�X/�6�&��f�- ��;����6G i%�"o-01�/��{sa8h:+e3v-KB�#F�`n�j[j D v% F�:&6^5i&�a�&�i� F�#�%y��w��de:E���+C� �4��%+��ia�S HGp�� loci� E s"��1So�[7#G(Gn2j�����b��� -� ��s���X*� A�:�s�4An?wo or�!p\��:W ���6jQB_1�.9"+&�  ���F 1�,atTR �Pw4i��n�sSBs�� �zq 2A]�!>�(!��*Jx k] "�5B"(�1,�9 !k3n�V �: S�-�>� \$�*A�-ve�&" 7"T.�5�ao1e>�_ V }��U�)s�F�de}�&�$��st &Ep�!�1�^ ]2�lqbJ��$a�2"��G^f!lstS6i�:e�/�+\*rڗ0F6 U�.*�V+>�C��>:A" �VA�!�A0*�"�m� +evjq�a�mAAfg�v� &�"��Z�� argu�]�F�8&� f,�iel-Carr>oE2Aguil��[9]� e) �adF�Y?dY>).*�E6oR{�lU"�Ka =�� e"f&�`*�+�V���n�E��Z��* e�ica2GNm&2� aln "|u�Ge g�r= � ifu�t,'H�t�0��1��1+,�i�1a*<(u�UEr ٺ��p^� phosphory��dv (.��5Rad52 f�pc*UF��e/3�3x߄I�5c2���D9drA�in&> "�w� f�[a�/Ũ��H�� ,�Bϴ&�/&`"`attacԌv ]�t�lu�%�z ing-a gap� A�z�b:�B�2��� d�? *�uM��p"��akLr&� xnic�t�]� �pe'�A���")�8Scby��6�8results in a de��lay of fork progression . In support of this model , they used two-dimensional gel electrophoresis to show an elevated frequency of aberrant replication structures in the rad3-102 strain . If all DSBs formed i,t hyper-Rec mutants are a consee�tۈechanism , we would expect that mos- 4e crossovers ipsec : be associ�with 3:1z6!a�tracts ( Fig 3A ) . We found , however !mat abou� ree-quart|%�eJUede>< recombin) [9] ,E�ven!N(at does not o�LOH . H5�a second%! � also)E{% cell!]�I� breakag@%� ��;)�!�e �leadsa�!majorit�%6�1Ds between homologsA��X5�dam�ceZproduceEB�I!in�?a/Qdly �deA�at�int f%� gamma ray%9G1-arresa)@ �d 4:0A�q� � , whereasB\in G2FNimarilA�AS&� N [21]!%e sugg ��f,any spontanea<�kBf!" init�eby�a�a�onsG1/G0 �follo!".on!�!�-kE�osomeA-Z�w��EesV*(( left halfg��7��Sin!�h^[� �R�,�TC>A asm� subst� isA-�{�`q� e���{u�u�eintactQ� [19!�U �S8mpletely differa큍Ltic approach , Golin}Es�Q(o [30] arguQ�%}��Ro�ied!�A�d3-101 �in weN� �WA�ٛ.t . ItaG��(be emphasiz�!k.DSBeL�k�� ��plik!t��� S/G2!�a�nA�C)8�|width�8arrowiE@2'!~leٹU�re!�)�iale��� I17Rg [31]i�O$undetectab�,y our systemaɁum"Cg͌ a!+�(G1 ? One ob�possibil�ai���DSB��s frome� very-clos!Ospaced ��E<< 10 bp apart ) a�pEae%�nd5P(duplex . Th� B�����2 wo incM� NER��oK��ofKre�<)�a5 ��one rel*tBbq�,other reflec�aF suchAF base exci:Q�( BER! ?moval�mis�rpo�Dd ribonucleotides;i� ximae�10 , 000>(Einser�@ into%�yeast!��>$in each ro� of��on [32�> Expa:  )�Mgaps med��Exo1p!q)end � ases-� affe� e6b a�; losE N(significante��?e level*G1-a�V in 3by UV t!�m!�[2�FineyP point � �љz_gn�jby Rad3p!@unirra-�$is unclear��n add� Tto cyclopyrimidine dim& ,E�protei��invol�AaorY"var� "�,helix-distorI�dductsU wurinea�= oxid )E� cis-platiA3AA� � ativc B DSCBIqf� dkg%?repUS( right � AO�-�mF�B* *� it!P)N~���Ka� 2�@!: have�� high]&A^!���� AG)�s� sV !��an��"a�Esz�P Ũ�Х>lK APr=�anverg�W,on a TFIIH-be�2X mcca�CE�b�A oces�� way-&���dou�B� . Similar�Ai6| &discuhabove ,I[ �L%|to�����6�� g:�,%}!toj TR8a&L*} S AUjY longerE7mor�m�etha os�� ild-a_m� . AlthougGe�erpreti: i� sulE�9 I�,M�6!�&��%Fde�$�m�1p)�!'of2  ��[“patcha� s”- mism-� ,��-tendency!y$switch tem�esq�)�I�haM enu�ly�iQ���rE�sATP-bin%�groAQ� �an enhan9attach��ofi#promote��at�Z challengee1 �[10��Despita�a���ce�ce|aS�,� featu�of mito% 6�]of��   syf.< m i�UvI !pn . icua�i(e percentag�� B��i�aVa� &@ %�wosi'23%e77%�!�Y�5���A37 0630B�� Ta -I raici` �.\ ��m L2E6�!s,u es ishU�)[a*BG w m# �-Y� �� ass25�[Y��� ribuir�=\e X6 2Wn�g�m� of�regions��genomic��a)A� nna2b�� nnec�w݅-�� barri�� �/ term# 0ea  LTRs ) , q�si�) for Rrm3p!{nd TER � l ���K-N*�low.�$NA polymer= alpha [25�w� �edA� trong cor� !+�iť� %�nd all t�!S%���:!Uionh��di�&�fiU.� 2��E%>��1�>Z:�-H2AXA�m'by Sz��,d et al . [1� Phosphory� m f H2A�>hst�>p"� As��[34�O>Wi ��s�L @is dep�bt�Mec1p"�p:�:K� :B��Tel1p� Q global%�!1XE�fM2�� ()oM�A�Rg ��t�`iw2�� �!� �,U�BB "z &� % ( fragile n�AG<~enric�� telomeric5,a�5� orig@ , tRNA�VM�-B,lsomal ..�$weakly-exp�ed K.B> )>��F�E� �ZSum-�Ume6p6�;���s I recruit h o eacetyl�,Y+ H�g�.a6q�Z��.�E�x.Q"nor���í�.�E� m transcrib5Hor !F}>( S5 T A*mmary� ur �� s�I� only�Vub-se"P6ridentifi� R�>iU�6�1d�Th�  �>? � reA`�q�at whinbo�.��q6��!�teiP! � c!�w" f!AOE/a%� dele!�!����a �>�-� ͦlocunD SGD coord�e 25 �on� %% XV . F��/.} ���U�� 6:in�E��� . As�c'-CR s*% �l��8�s.�U� 2�*� or BI"�5�Pg es IMA2a� /or HXT11 �2� ge*1w �>�� non-j�ucRIMAuHXTe famili6�s��K��to�age�r�@P�r��alr� �5p!qal!�"aGB data� A�! I�r� h2ogenic2� >2�J8 � s: 1 ) un� ed�� gle-�vnd"-��� iZt .I� )s / = ���2 )�5orCBY�e�ed `eX=�:�zW�NA2�. B�K�I�5:S� G2 .�f%U� unansa�d issu�s w!�qmod1!n (�� umab��a ��S )� ��&�!��96��� !t��k !d�� s . �!�Ku��in� analyh!� �� "6Q�-di ed haplo�, W303-1eN$ YJM789 [1� n -� 90 PG318 . 1 wabst�!��ru ng a dil� �`4RCY317-9a [11]� PSL2.�� !��� u�is: MATa ade2-1 can1-100 ura3-1 trp1-1 leu2-3 , 113� 3-11H5 RAD5 V261553::LEUAA)7�of lw� !�rb2�e�a link!,ygromycin-reto����:�1�M��vMD555 l556� es$iv�k. ��I�e�� l �EV d1I#d A5to make�A�19U � 30 .fp�"�heq �)Z十�$ork: SLA64�. T �� Zonfira�� PCR , Sou�n blo"UV-sen.$v�tes�  &�" e9h9�1�c!inaC rad5s cdc44-8nt,?� 5 �� diss�5 �1�%ed&8% of synthe�letha�. D���%"s��N olon��&olisch�wth�,um ( YPD , Y@ Pept�Dextr:)E grow�%30°Cetwo d�"f dividual s�then dil+�a�A��d o��omi�'s lack!9a:L1=� 10 μg/ml��!. P�-cincubg � o�emper� �#�,2�"an Z'ni� H� at 4�� J#�`e*��!r" I&d �wh�Aor� To�ma!ed/.�!�� � mustB go ai���dtim��!^ ing;�E!�] 9V jaf!�Efirst !�s!d* �I� pink�� "� a��{l� lony-Cfre)?�A�3 >��numbeK").1 ies/total") �he cul� �refor�equivaluMe�ector%�y p� ell9 . Because_o$!5segreg 9� f%E�=q�-�& heterozyg�(y [17] ����!�s� twi% �@E��WZF!k . Gp Z isoaTd� ����aga�4-plug method d"(�t�)harles*��� gson� $�5����200–30c".9` �Z��� ��rlabel��Cy5-dUTPM�x?a* 9nuS tro_ �$ 311; 4or JSC23; [26]Na��2p3 p&�%Invitr� Biopra� Array CGH)ye LE!_Ki!;!$� samp!G�Tmix�5hybrid� to A7�lig�!W"( SNP microars [12� A&e \ scant wavex %63�532 nm� GenePix S;�  Pro softw� �0�k%�exp�awext fi�Y �%� M�L Exce We %�AN;^�>9��4. reci al��io� �He1$5�AM�( whole-� m &b V��!E��!^962R�A�availvoV e NCBIE�J%��Omnibu��GEO )l� ( GSE7639e .�)��ed��Aʹe!� in S " ".>CaJ�uns1ed �͒�w. ��t���y1yS^.��ic wind);e��whe� s&�0!$7!�q -"�a$%�B %%�.. Ninet� �t��:�exami�!�lis��'l +i)"V� Bf!weK siize6�$=]-Y>?*�1�.�dV ��. For�fe� �l!�E�,�E�chi-s�1e � &Fr!�'es3)�paramet7,Mann-Whitney B%,!��V perS ed u"VassarStAWebE+<( http://www . v#s# . ne *.� � ct p��w- m1pV%est� z6�u:A�Hochberg%b Benj!�0i [27] .9 D�&per*�*in�#A�, opti���#,acterial fac�  $qui!�/V#he!��+ang��h2environA���as%t pathaD Helico g pylori�#a large �si"N re�SSh* 0� � itutd n� e$ loci�� �li�2AndB$pai�,"'+MH SSRsaze ( T��poplo�!fac�!ate adapm�. H�^%��(!{�el�} expl� ,a43ar� ��how�(inter�$'�TMcA� via f�!��s��heoA�f*fun�to�$e-tune actJ�6�$ driv� M7A sial~/cid"�adhesin� abA ��an�. n� �%�in backg�+%N�.)Cr� �U!�!�sm[U/c output�s��d5� t`�6a,*�H .Q��v,alyl-Lewis x�-epe5on Q�mucosa��ra� ��mi��post-y�"� clo�����- is a ly)R$)�H!X���is mirrw!Ea�-u�Esp�8abA�$i�<9]aq� �_Z3,est-fit phenV����ɀsi� a�Q�al'K )/ zes revea� ��l-M�Ql(!7e a;l sun8+ereby5� C *�#,b# ough shif�e)ax�+ alig����ckUbnUPiy��G*�_-al%i�=�,i�T-��A�sA<�-�*�*a��E��AF)5ex�b�tr�R-I wi�f%as �9�6mod��rgn���meAf>w� pV-�i�\i ap�A�.�� � by[-pr(0l��,vD0�(e��-I� criAreg����^��()uos:n�c�'va limi���rtoir�classi� p-�Angmory�(�. A ke�b!e�rq�%e"�'E: main� aV��22�toi[9r!)dK ��k��M%���e���stochas�A�-W��+'1anm�E���3 I��U(��[�t�.P/A��( horaa~�v, ViA�2�cur36�dem�3 . Po��:���3 chie� by epigen�� D.as�d�&s;a� tly% !5U���Q|��rsia��ey� e . �,loV"� %�eb�( SSM�3fvX  )[1w[� `4 so-�� :h , l �+;*�xENm� 1U6� typic s�-a0IC!"� eb ten evolua��#� er!�[3�"Erole���'u��,���&A��2.��'tfb�!~!!��G�LA�� < tra�)2bi!�ic���?E�o� ur{.�%.��f��h'�c,t!�/�2ed .�b.9]q[w*[6]� �t�����8 humaE#oma� nd ife:un~a��s�#�t��at poz i��/��pep!Oulcer Y5%� =cau[7]–[�AK h;�preFi� to�/R� ���do,��carbohyd- t �by.��� A�AABO/Leb�od4u�) yl  4/a ( sLex/sLea�t�F�0]� $In healthylLh�3gen- ���a)�d-*Kinfla� �..�� G r-re� m Abl.��8a�� B^ u��JO!'^7 5 &�<6�glycos�j�� ternabstf7c��H&� nee�o�  i�Bd!Au)propert&acc�&gE&� �efficie. be�����off%/b��2!Q���D�,, [15I8a�DJ�� %ga�%)�si�#lso�=e�2,@�_f6 0A[2^2tai��s�)ofU.���e�n.Zascarc� In>9u�`ih ��*Z sigmaσ�r�I F� � �Bgen2Va�)e�i�se� lyy$#min-d�-6�n17*3σ-�( σ8�: σ54� σ28e�d few�   �@a�2�.T2 fi�aM:�6�� ly&(�A�R#&� 2�,4-�5�wv#sm&�me.5S%n�of��z lAin4 nco�ou?membran� �,A� alpA!clpB� �&bab� !�s[24)ŨI2h� e imp� ��8rob &fur�ac^4uŧ��k4>D6&&& proBa�dei����]�It , [2e�ILA��,e�6rapidlyT �poo/=6m� !�7surprP=��,.w%�a� tremA high3ra�et �r� �4[29%b=A cytosEhyC di&�= ( CT )� ai/�5′-end!W!%�MTc@ DS ).e�" frame\)�on/�CA . �"�+d<*[ , a �( ��� �gu�2djaA?�−35A�7��J�}is"i!UJj!�� V'>  ve b��.��?fluŇ%C*c[�<,�2;�m*,"� �D����!m$�\�=��+e elucF=ed� pa ,�e��� illu�XN � .q ��M�"�p6�<&�g l"s *� . is)Jc in vivoH�� demo )�^�a� rols)f6�7���us�_=�!�=xs "�" t�'� k % a2�mr������ Ehe>34dy !>?>�-�� E]� )d��&,�4 !�a����a�� "�  ,:α-subun� to�e"gs ",Q� e�p%�t3y5�"y-6^0 ".#*�a��r�t.�o�"[$:�!laR.rVis ��b�r2��,! �f�:� I� 7 :R9� ]��Nᖁ�4m�y�cli�"lqʩ�>Eb�=AGQ�!�v�-�cA &+ ) �n} &� &� �5�I��� $&w7t o�Mo scruti�B"�ar�c�r�ce�A�f�2*> ��H &� a-numer#geograph�6�0����pat> s� |t" symptomWdm��H5y0���?�?n ��i�4SMI109 ( Swedea(GC�7J9US� DU G27 ( Ita�G�B, 17875�!�A��l�  �$26695 ( UKlI6�yH%or�;J� $by immune-B�U6vF:�DioI=(oAssay ( RI}�125I-6�conjuga���3"z*)� �,)�a� di�&�aR!a��C�U, @;� mD QLeB�no�2�Iit�A�b�H=. %01!� . St�%s1�!&=�displ%q� est � ��h1.�uxLeJ�u�a� �A;MA0w���q�L#2�)�Ws��y&�,%[*,>��- I%P�f)�!t� %01�8�fZ�&wif*K��1���Jha��dI2.�s RT-qPCRQW z<��Jp.� �G+; ("u*5kB%kWsoͱ��2�al Z �& r fuA,�%���s( P)��!��1��S1a�!n;>x*e t�y !eas� 29KU� by β-gal%sid�3�h!BE .I+i�)H"�Q�>V��q�1Ve)�/.�j� � 9R��"�#�!,� )c� )S��r)compa�1a� ,���H� ��� <�m���l< �!��( ee�H . 1B%�S-L�:isFlyW� f4!/1B�qq�>�AI�al!��G�=4re� lhR�I6�4"t � �Sw� eam�$'   �:CiH069&fic"��>e �n�ʼnabsw K�. Fa� is&�O\ imaS�E!��$-�! in�:3�� . S� �42I&!wYr)�*!�* �Ws0Z+Y-Mu". S](ex )�n−10%�^� ��Ow?.6,ength.�m6�ON) v35"��g�E�.5���(w<�erA ex#Hd�10��4( TGnTAAAAT vs T in�eAA"�#�e�5A��5 �� lacZ�j.U�e�B�q�A� �.%r� �:m] unus�2��% exZ va �9K�9�-�-�M�1��2�hI� �P��+�*�ng)�} �-�U�D��B�"m�2v�%�s��h.��2�� :x �*�iAP�n �1�3B���F��[ty-�3 publm�j=��1��)�!zwel�"�u�2%Eɉfifty-k-= �Se-: assu ��N �j'0deA����Jp"M�cr�'e|T5!rT2k/� T1317 be!�!,�[ comm�.r�%QQ1D% � S� �4?l�R3115&�TaiwanU a �Kao9,[�E� %WF��� �OT10�28!T1R� �T14119 �{2�]e�#aen&j/ %�%�i9L �Gny"�Tg"U.f� F�a�\ empl"�B�u62�c (1�1�Im��XPeruvi e�0( Cuz2PeCan4 , 1!>Puno1  3�ASat46' Shi1�1 69 , 417 7TSJM180;6 aq5�c_"�,��#��%{a3Fr@e�::��re��** toQ �10 !h6�-����*  givel!d�r2~� �`a/d( s�a� � ���Faz� ?, butɏ�Q!6�� n d� T-� " LA�2�p� �  .#}� , T1PT2i��V� p ��S.+D�7%�ut<�] aI�cI� of c�e�W((-RACE� %��t2��2art"0�;�0X0"�t��B( , 66 nt up�:�ATG�g s�_jl6��A#���a� veri��<E+d� "�&Qq6���%<.Za>� �'�U�@o� aA(���bnn��$6�)"�&/ NE�mxU���V� �gra�l:!lt#:e �T��F in T�r2�����( w�/�aIT18U�Sx �Y�8�Vg.Y^a 6U���]�z�9�] 6�E�decidA�oF le*mj -=y�B�)"m ��&�nM�%|Es�Zn��!A�a�4I�sp f T-\E��� ��"�. Sq)/*ob�(Qy ��� �� y���Z�9&3G al,A�i"mbwHEJ=tro�>g6Giosee M�=ial5d M^'�z�gJ�A5zV�.�5 m u1�,��m!�pronouST��.@OarrtV.�, +�U6O!YA� z exhib�*E�� #8#23���2A–��:��q���q�� �sa�toe�%�[jE��N�2%eR;%^�iz!Z��0y���!I�1�AmKmax/mi& (!{�� 6I1�%�vA�a"V]=)b/�2 rń��E4as�9�(�D�6�[A� o mi�6*� m$on&,eNvI7�i<l} ��6$onT+tpRAaew*Eap-cd}�,�(�'tissuZ ca�G�>e�2"7=fluoresw�<�ofAsR0 *�4&&t ����.�he�en.� .��nq��Qt>��!glow2Z9E[E--M2y� �\ . 2DM��Uy4 neuro6�- *R(! M���' moiet9�  ^WAA� ly.�Rk Likee��!Δ�/ut�D�G%�� ��noZtVBu� ��%,O��Bj ��Iv:�m��J��a�� ��2+�9HG6�4.�/��abA29�I�2aCA��%;�/�]�adj]C%�v[1�B�M . AtL}F`�:�+!�lo� � �Sdaops��a-t��34�%*�0relI,of" !�Earlie� pe� n�0N� Rhesu�mnkeysQ�%� *�=#�f�5yKBG+%.a !\/��o�1�6M9',�C[3d&} .��*!��0�n�by.�R1*. 6l2�.�l�tѵre a�Pn e bal�MN=yc�e{*;�/�1A7 �8��+E~*M��69 e^*�K�J at Mongol�gerbil!���H*  a�}ng�� �of-Bd�8��2�m�9?loa�FN�2"p-7e5�e�A� ST� [3/���Mc� i��7!w�%u�5�%�+t%���!a�-biop w*�?�t�m'rK� F�3� .$*s&"2&2�a�#.~so k�: Vf o�%v�, ���kcer� Ze�8 6 ly%5���ZQ8�0o^=�D�& VAi���5�ve%T�6s!�l�?MNFY�.*_7e��t..';GI!�ai}1>k&-  oR8? To�>Y%!,a4P�% ���*"'���V��� subj7LM��Ɓ' ser�ofO :p�!��-mon�E.ZqE�7"� sub-&�6f"d!�mrZR���1-n4+�v�6!&Bg 3{ ,NZS1T<� �d�p!>�,=��9^L[ ��c�)�M�5��%�� �� a� ,? i�@�raz! 3T12 1M�.�"� S�sA�6i$?��� &(�cM1,A�� r��y"%>"Q �?�N�8 ���9 1v�B] N'.we�,@ use-S@��!?nXKve)DA�� StrRAA� T17� CT8-E-)a2�9�&$Lewis b ( �4)�ns\6FVB/N":���ke�I succe Pm�K.sm�[4P2AMMwoq�3 6At~�"!�!��}b; (/}2sV=de�rec�3FM%"�c� u�. B Pl O��&)(�!\�A�� irxce����now�Ki�R�V�R 3w'ba�{agramES\ �-0���g�nsK peak�zli�odu�^��*L0p)�iM sign�;%�/t ��e¥�� -Njs-D�=han�eD-W" '�r�Q��L �V ( FL#$Ai��7<&>! of PCR-��9�o� o�*� &Z�1p.�]s r<*M“stu !]h)W[4;�c*4�pc�eect�<�BZ6�E�y �"{a�Y19�@N&����D= .�t�se!<iK3S4E:TsF'��=��:��*E��� t1V�*` 2��ran%}��M�O~xM pL =��^"2�e6�u�fv�2,� ( m�VF[a.prPa�N.!f)�am!T6cinXD��a{!s7A�A0�!�JYwo]�ioz:����� �OE5"y # I a��>PeU!%-a� �H��3"IY22�� ] e �nopeB2a%�-+%�e:�ofZ�2A M���I!L�2`Rj8rdEk��a�z\]��J:# f�ex�vA�75;A�&�*h�atծ2^In3El5�Ua;=-�4I?ur�p�% �^E�f+�<' ��e\A���shI1�y c{�>TJ�unId A2w�hE ��[2�4�oɷottom B�.C{��9? ��a�7Cin�c3/u8er.� ���V^�e n/ -�d � rand� �aX�inzA&�2F�if!�M��� %l!;� st  (CFU counts:#6� �)P)LK(�p>(2n.-F�w&�0�>mtTB��$]=�"��allO s.�4ASA�H ( 10/10+),fAal3%x�m V�"   ��O�0��'locLFi�0u_v+�e,.�v: i�A1�.` e�6� !�6b  CTG �l ,5� � CT7-O&� �F,*m�, R3���>HQ0�1� �g*� !9�Q�\B Iy ( 4–�T 10 )��T16]i ir6� �c�Ya�����~E � :�FL�StB ] �� ���obo�#A)������8i� a1H�5w�Hye0�!�ra� a viewAkg\ A0"F�����i� $ ѥ&fH2�%�� ez�g0I�e��6�2Aa� ^O�UA�I��.I]|�%9W�&� M,&A-!M���6| �b$*�$^]A�nb� 2D. S3%��[i�[ �3�����>b�voA]*H&�2�6� antrum%corpu� zp� �D,)�95ish&�5(   G: ~, 1026Z110@''�w:se�V\ռA�zJZ�A6��ka�ZNa�O�lowp:�(ngE��O�am)--��� ms:��Zr-X)n�LabarYG�}�>C�&:57 5�.  �`a�W�s^$vle8�L!6�� �  /�Qq "!8�A��P:�-_lQ��a��a/8v8�0���D��EN�-�4D ��!�� Z� ,QG�tvi>wA8UI�}�E��+2�j� m�2Q.�A5�%� �*�ach.�e6!��@%MR�R�� >f�&f���$!�]���"kyi���PN�Klke qu�G !ve 5eCUs�Xtechniqu:�a pa�ful tMB.�=Y�/IU2���6|B&6  Our�[�,�ide�M�Jv'/&C<.���-��gG�JIas ll%�uMI��zh�!q0�;*%.�of:�Vgpq�"&& 6�a�!� xu=� cour a�^io* E>�#�'n)�WK"�oa �"� �j-T��&�a���|a6�= ]�,p�6��%%i"�(�Y $�J�# � &�V�5no]+� s�Sdir�agb=tQ,�"��kng>���&l5E�ig� An�aSM�~IN.��KE�"`@ /�c� �/kf!�*�Bl+�esjM,�A�C�As�t�s�c�!�"cS& +still�:.�GD!�iV 7Xu:� ��.f � {&,!ymd���N� �3�a�6m�^o�f�RNAP s J�/$ [42]–[4�?>x.V-O�6�5r��z��S x�%+ o�rd�[46 ��!�1w�&�-\1RE �si� -�'2�8�*�0f( s [4�@50]"�en�iu�za�!�*  m�q4C3�chemotaxl*�"t�IaO]�aiC�"G o�s:�he!�105�,�L` RN�>{>% ��[5��Doya�!��W  ���R�sYD,:�T �ep(� �RE0or\-�6Ha}sas a3�z6�� d"�AT- )?aF%�A"thyp3*��U��*\J(P )V�� ����li�!*V|�!Xa6����HKe�.�D&6l �A�3I"� (|8, TGGAAT-16 bp-_9�7��{�E��Xw"9.h� keepAσ7<��lusuAah�4$TGACA-17+/�� {�9�9A51 ly9�C�ӹ.Nu#z�1CF  9No.� �6$holoenzyme�_yet��Ćf�%�h.-2��-TML�0�qIbe.F[1s [52�O5iN2�Fte��M!Sm[5ps�oD Ao� �hcr��tic mo�"�i8�CEMS�5�8iIq�Ao�L�S�1pic�[U N*Kte���,B�mL�ezhe��wrSIP 3RUW6w*n9 1,5w{V�2�u�e�i� �UivF#amY!�%;?��Sq�� �a�ed6/J+instea�j"@2�kaLs�>�{surfa�las�9reson�' ( SP{a&Zaxor�� R"imI /8I@Y<18ia{6�af�3�3-I3BIw.R  ��pu�!��1��e�bc7�Qv4A�$;lt�W%�-in"veEe�%�Q~�|xo&i@�-�!O"# ��!�sub}� ���.pin�y# xt�>9�&0 �}��to)d8~�* �6�ET,!~,A�S#�x13#�&E!c� 2aF-z��&� �!�A>/z d�^<8���pA��d�D.3=�in�`!����5.^in&�i)�Q�ac�a05�X&[�ޡ]���eOj�i�a5/���/s8 �re"�U�*�con�S �,ed� 2��>)�wta`�!�|5)�A13�EC13!9\6� %�2�76sm�x. Mea� �-�>�P .�.�pb!`;L�E��!F�� U�>�;AQ05�oT)��L2�"��} of}NM��t�( .l,J�:���Con��,"����qU2�!�Z; .�&5:!,AZ"�"A�#M t2 �� !r鹅cI�%��T'�[A':d.&ga�*ig!M�.� LV�&����g��e8 bC's [sl� ly�>c*]t?�g!�%�*9�–��!*a�MEN-me�J��r9'r��%M�!B�" �7h�q�!�kep ��Ze� ��)�E��c� 2�2�Z�Vm Qr. N��5es� ��*Y6_8!���2IQ(exa�)P��i{>,M%ydfE�X�X��A�2d�E�O�-&� organ�pofo"�%RTa�u;e���#O ����:y5� SPR-���0�.onceiv�X�Q&�C unkn�f�Jfhat `%Y6�6\ . AnD[Nn�Cng Lf b�Sa�u[*m %4"nS� "� !�*� !�e�wβ�W=y45%ntktoJc� er&� RpoRpoa{~j0MNa�Gf� 3`d�$�[5�aiUW�\V@a�o!il[) assemb�/�*� [55aJ�U�e.uD}Eva�����fEnse�A �jic:�[5�Z� 2�2�\\_Mb�32ZU� -��Dt�nƅ�R�N&��!�A�\ ( b >s�AI=I��A��65�"�B��IxE[0�D�6���Ɛ)�seu�A���U�E���e�v6jy>#0�B~ �i@g�abl6�Be[Ms :�"^A)G6�("r"srʱL�Q(!)A�&�) C9� doma6I�αy�( αCTDctobjs l�>/6�[5dc5J4o&ZB� s6�b�O�ZA9or��� ���< I footpri�2��z0 6x4��N�!;com"] (�  �D�F� '_ | a��H �d�8��� 6=-�+2D#�Q$���,hno�"�� T T- ,� or Ct"�\�)� 5� �!A��n�P>��UPY 1 �'l/4N,I��� ��"ZL͋on>�ta@.^Qi�!Uq.2'�"of�60 |����:u�#6zof��q�}�/M�>r$X)�>DM�� �U� ,.�at�9%� −5�H.��A�J/� _ 5_ , blu�T�}n2�Q/: I�.��b�Am�o0"5ExAT-'�e1�� Y"Y�-iZJ@ai"�$%�74% A/T*iduO;� ��bV0H] o 61 +���xl ���a cDis8H� �-�"� � �>�� ��# , ,+.�A-boxzj X9���S2 gd -�2i")�� >��N5��~%Qit0-Cor�& �i�U�E��� Wm&F B�-nAAMU�c� B��Q"]o �6�2NB�i�2ona 130�a0 Z���#gr� �8-1> ��&�9�!B�.� �se5�C"�A� �^�sq��� �i� . Tw6}1�\C6e� SE�/"�:��by��b�*ka*R�< ( NNAAAWWTWTTTT NNN% 6�V)s� �oI� �1�a�Ar6�a�`  � l�(G)a�5,0n.�� .�^w3idee�)#� b�inm�;eYlikXb�d��, .Z��Y3��&!�~|Ԝl"ngmg"��'6(�e1LU�:�s= �46"� −97� −49�,�.uW��W�lBU�b" ���!?6��$6�E'Wl4�r.a�]�/!�q�w��y<m.2:�Z�"Z l� E%#&��  2&�: fullN(ŷ2�,u�"� �i�-�:sed� t� t��L��/!��%iQBB�L�ٷ!�w!x�wAe�"5�1�S6���9c� �=ll�w�3VA $�T95"ei�f +*PDx.� capaPa�ls&�a5L�e�*�=f37HQ�&ScfuPR-i�S�s�N&{=iw���,ab�� r��al,Rsi�Jag��3�i#�(6�*i��o�gU� �T9��:b!�&�F"(.�� ��S������]FWa����yDe�Q:�*��� at)� ��.��� �$/��yV� Q�:�FIsE0oEl } ��.r�4`^R2.�%� t� ��9.M{�L4i~�B[.,=w@MY>P�1u͒A�.�#_N:��:��A�5 �5@Qt�A�vB��RE�-&���F�9��I.�IT��Q.iY�of)~�!c�h � comi_I �3oAF�.!Zg!%�� � reqX� m�b�, (F>� 6\I�.4!�>�~p7�e�Y7sh�U�5�&dS�},�=�.��& �-�X� �:D� vamLb�, (� ed��)_1s"��^�x�RI"sG%�� iU-o.<=�es2��6� .� Q��R�2:8z^d+,�gamb�r!w� �yx"��y�V޳A��, ]a Cza GBAb�Q1d s� PB�S"�$� �sc�:" �)Ń6$!��. !8IE�VMPx�:}��u | � /��2J!2Z��L2� e�9sep�b�b U"� �A�ec`�>��^�8Y+�f��Ǚ��}� �#2-fol&'#5Fe Con|l`0;:5ApniR<w%AYns *�Sup-*�(( 3 u)Y7"���. R2�z>�>/��h����mpb�_ i-step�c� volva�a���-�!JofE��*Y8it>#2�6Aescap�El̍_M��1��d&�)�1�'s�,-<���v~�"B�R"6�6�s/&{s��e�)%n�Bo�)CQ !�[60T+T.�[�����M0emi�_*te�`�i2�,�� reM�. Take�g8�,6�(.���B�Oldh :���%�a¥P�ds�ly��E�N�:6Xi����"�.� �P&�JVp ffin!I� �����409}A%:�. �2t"�<E�is wr�B d >300° ���[61" V �e�B�0�s�,1az�^� A�T \ ��o~at2"����� l�7�(��'�U_�. S(@�">�ac�) �9� ]���6���Y n�inse\�nt%cAp2��e�`iodic!��d�A/)���F"�r�!P s [606��4Is�Y�:�B�5W-�Q�A��gRS�lwe6�ukQ+n)|�{G | �{�!�n �>�� ma  !�9*pr�n�� �i��166aY+7�Dof=YT&�[B !�� � �4�5�k�.�Z��A��W�(*A��� �ri�?H�B>W{by PAGE:��&� e �? �d�G4E��6g{<���9%�-�2�"�Q�ce���$t-{z1.%!\�5&A� 2� hK%�ppaMS���.s%N*�!�V"*��?"k�/w�h.a�e)X��ZPo<�5 \7eryFn��M!m flex�8A%Ra�%Rsqj5ac"/�~\���CA�B�*�X&&8; :wuds Y<�@*H-:4*�> look!D���rE���nl*�eRa!I��j(#x+|~. E�vt%�a � 3D%fY2q � �# 5�8,*2!�;�!",� y%l z�tq�A�b�{�k\Y�t�� %!�e���in .�2wE- }H&@��Ml�%�yP, 60%� rZ ad�'!Zl075h(EU�27�w!-�100% ,ms"g^�{  $!2�:�:��fi? >�(A�7)�Y&� 2(� �s/vix<-1f�;i ��5*�����:!n�w�n,* 5 gN�T��� �mh���� rF–11}E"'>4!�A�h4��5"��W�46$U��"D �Bi!�a>so ��&��}" �&* �� 19 5–#B�b1�%*�X6!� iwK� (�&�%|dE���meb�� � :9�KA�7M[�8� � � )E��� >Y9�+�Jy�� a*gZGOb�g�h&�!rU�# L>+[65� Sޏ�E6 �y&#����!:u�4rxJs!�,a�F�5 sB�..�Fi"�FP�V!`2v��! m��ng�5D–�P��( ujm��J2��$avo(2y� g =%   �&!yQ�o � Z�oi��a#e�L� > 5EE9�e�X)&� ��� "� ��� &Z91�S�"�f�M= d �qY����.U��B &{B, 6t!���ϥ��ed�kў�b�� ��:&D&6�y�+ͧ ~��s>�}�,}bQ-i!�in9y)?�.^vg r,�Z/&OJurn>>�Iccl_4>�>�1I7M�!S����-��M�A��Q��A�-����rcf���y�C"�vesQz/� Man8�r6� *� c�$Y�ndNf�J��Nn �2f=.��҅��,; ?�uW�/�x" qF. %�Und+ ��J0No}ly2N'is �/�"n��N,q����� id-a&�� ��> NAPsh>@�!ed2�e=5^"�+�Bt�!Q !�a6��or"t�6TU;@ TAAA8yc, nadA�in Ne�'ŋm��gitid� �!��!�C D�0 ( IHy wG.vpMG�My�p�allis/�u��Rn a pu?G� HAP;���!�PatzDEF� Pseudomonro utid��RbAztR [�A , [6;�6h� TŒa-zm" -AZ� cB��2�z4!��v�s H-NSRAMP�A`jMV CRP� nd LysR��5�"� thl!*D"!�r!�epA*;*[68�B7:l�#is�,�or%�Ux� �Q�*� ,` �E�� � d7AI HU KHup [7�Y[72�A�Dps$NapA [7��7HU�� -�q�&�E��&��� "8V� ���9se��Q�-jsMBI��5" ���n��hŐ} &�n!�"��}����)�(2� W�?r- ��� ��1�$oJN�" H"$2�"�rp&�>C_uA�� 8{!�!che. �B7�)�#5>kinO1NE�� *<6VE��HHA� ��� �&S7&� W"�yeoX�atF�a��5aZ.,3mw� �.�N�p!� {�j ledgzc��66S j ��F��~�e�4& %i ive ArsRS� A���6�7]{6Sci�4;d���W� ?=8�b��ol��aҠ!�iZ5#�F˺B�I��%��,�4!�!�&Non6�8!8 A[�91_q beBn6���s�j�@%���1l��e+᡼�!�%�����!�=M6x1"ny ��bm�/�2�2 >�" �� .Sq*�� & &k *o1����F!�,�&��+;:�i=�!�� 2p]� e2��a�m�m��*�6� � t� �9�� O�y.�>A @:.!�T&AV4!P4,��#v£�N���,��)J:�6tru�t c��r�2q�.: �w�$%�1���> vR  ��Aql1 4A"�sIt!�A @b����Ep��9m�d� �ei%(be"Q�:�:m}"�3�=N�a7.#A��JA �� �2�� &��jRf!8BRQˉ$=�au��~F I���!�a��H!Hom���&�R!��-9�α�;ωb&#Ne&:�&�b"�V!�!�e �rem���&s [75� w>.�� to6�s���Qu�6��dx�dev|�m5�l�r BQ"� link&b:�+%�αNTD!��6mP"�y=���]Z]m<<23-amphi�"<��z*�9[7< UI�z  whI3+As216����w� �{E�.�J�Q&AM7.�(�P� u>me� e�to��ch"�"GU?5F� ,2b����!�BDo `�DvR-�P motif&�:.��Ɓ �������"� :�;eL&�:,>d�w h Um�U�}f>t&v� �K��T!�wNZpjBwv}M�s.�,.�"26#�F] �$�ct� �0�'ngAf"�fSmen�c}� seiaH+���t/MÊ�*A ge7�E T6Φ ( >92�)�AI`6{. A�����D$� �[7Cs"pUtwenty-f ��6pr��lWD�5dF�Te[K6v�S�e~�#)� overM en�"'`s49e<15!W25 �6 �.�~, ���_a6� �En;M�L |&�E�0e:�, six �Af�2383/;3Ud5w68e86>"�6�h4��ti}5,5�%6jF�R2|'artD>�%�%-!&:�bu�( <20�RmAr>�si�I��Pa�:$B ( HP_072A2�OpD 025� hofA 206 hopM27&�Chp_0350�]��"�4�r�{e i~�͠fo6���^y�lE�a�� cE� w��e yisF@? .:X&�.g�� ���*��*����BfZ! sN2t� �Ai*��B�aWO SM!��0fX� o���p&i f}aI�:Qf�,&_i25���)yAC��U���,]aF pyr�.CTPc��6E�an""�a1S2�v u[M�i�a"�*�30�S �)�7~7��e��)���e�:d.W^5�ِl�-"�H.��� sn� .Wnonyc�0",!)cheetahIX+ cetozb6'Atl�]c te-_;d dolphiE�)�m_.�N�S�"-o�2X&=�*T /�V���3���>�f�R�M=�A�%�Q�u!% �U( A14//�Ź"�>%|zAYuc����6e��.b�aN=52J�?erLC�a6 A9/T�Q�=��g��mqmin/max.4�"R��� �y��\A;E�"WbnɔA3�mAs��CS�qcl�r��%� ��a�D���A6�5R�!%d�n@�(t6�R,�na-&�&�-���15y�!lz��;E�yw ��th � ]�4�E�I��1�5q. ���:&�%(e!MnE���M�9e :�'�&r ��'eere��:�"� u$����f�$�񩲉��G!�n� e �1r�!>!E2�D3d�7M6=5�a7� f�f*Q���eJ����&"� � ��M�)Q� X `�Sa�!��1� �`�I��>�Q�9�.g&��F�m%�&&" �!ac�= B "D)��L>����to6T sM��u�u}�"jby2lFs16>M1.! � �$�\I:� wp)��.gzAl&`�"�ar��s�'��*ɪ!>�!�<&�b�i V&z2M�%��^�� �w/���A�.��r]�t_7B���-��)" �Q�-�7Q��� %qxa"�- �ng!�F�a�'6�!�|!)Q��6�Yc�SFm�' ��{>0U��s�B�}6��skex'riBH,EU�2�.�.��-J.�istur��6� Each>��#�bpj�a.��gBg-�:*�Q �.�">2���}!d5�� "�c&@!��'pap�`��+ ?�yJ���[�1.U�A�atOz.� "�s�T&���� �� "��",��x$Haemophilua��"zapd N .6g".iuis � [of r!Zu�67�F��+e�2G�+ ���ղ� v� "Se � "�p�,B ,�Oip�� HopZM�%A"�7aQ� them�h��`1'��!7#irY%�:>Jl8% AeĴ6s��+  M���:�� yper�-�i��R��U�s blin����U�&nditGt^�i�?&|-R�a �&[�ben��X�a�mee�+�Uol�� � ate�Z � ��,d&��x J�"H�eq �# pilo7s��n� WF�1 fluc����,%*Hha�1)ʥ�!sjwogeNE}�po�r�Fl�s .��anżs�:� !*�S�A $C��!(Use CommitthjUmeå Un�sa & =et��1QqBoard�Agr�tj ( DeU�NӫA120-RqE"��� � ,A�����GuideL2Y42���W�� �*&!��sa�[!)yŜR� �4UH&|2>%Rro|�F� n�1Bru��a�'Difco )�l ��10% ciN�yN vine|� ( SvenskaC�fab�$1% IsoVito 1B � n Diji�, U�!��ntibi �mi04 mg/L�x�icin ��5 t�thFs10 vaD��3 6ca_ed6��2) eu)�� um!�oa 5'Br�?(5(, �v��!(feX.c��sep( Gib%Y.*�%M%���|�=m'p:�chlor�(�o r2 �� �� kana �(�%E�QO m �at 37T��gl� roae4e���-� 5% OuP�C �85% NmJ�����q0.t$,-t+*I>4F+ , eq-��d�Bz )� �r�� ��5�� agar+H3���m Bco͝�#�� 16 ha�!%t�{��}��� ���� 2� oΔx& 1p��9l"�� 40 he 6de� O� ^ S�"� a WMʅ1Lu'+Il( LP%URlarbAgiGA5�kGr���.cODq 600 2����tAtotome.Ul��(pec2100 PROa=E��c��A�� g�m6���"�=!�a!ubA�q�!g A ::cae�� ڳ . De�G� E����RN�^�A�abs-VT��e]��v*�J<CP�RadVK�I���ol�@M�����=o;?��b{� agno"� kd,�WlyI �[184 !!� B� �9Mv1�. I��z�)::kan�5%f�'hup-1 !R 5";v)pAAG178��#a].��*��*~�$1F� R>�Blue-�L [78]:�>X� �R�s�> uz!2/knd62F/=2.�:PBi2,used are sho`wn in Table 1 and primers�*S2 . J99StrR was constructed by transformation of plasmid pEG21 ( a kind gift from Prof Rainer Haas , Ludwig Maximilians University , Munich , Germany ) into J99 . The bacteria were plated on plates containing 500 mg/L streptomycin to obtain single colonies and a sabA T17 and CT8-off clone was sele%!ELused for animal studJH. SMI109 pyrG::lacZ0hp_0350 strains Ɇn$AAG202-2051z!�tolD. Correct incorpor)�\�XM��p�b!�)^s .Et Δ46M/mj.�eF over-lapp!�A�6$P163–165%PP167 (=�variants�AP162 (.�.2�P��<%�-�% . Mut� �.8m��j�daTa^M�r�,Y�e�V�!u�#SPR�8footprint analyIU!W9�AmraA{%�Ul abA-)f 8] . Scrambl�ofE&A-boxe�?, UP-like ele�s#)i�pbye�-���? proxs( Amut1ņ/!�distal A���-��R UC19������� !)� !H��ESi��!�PCNxhyp F/R��i R.H ���q SalI-BglI.�BW:�J�e J�Stitch�:b�d�A�j� 9Tf �9Tr���T La�� %R�[!�-) JmIsogenice� repeat R��.ubytrasele; A�67,j� 1� In short� �0�-�a�remov�nd�la�0by an antibior r��0tance cassett�e� � he-�Δl ::rpsLCAT�� ��LA-F ,R , R RA ;!  6%harbor}uB�,�@&%l�8s!�composiq � �2�,)�6>�$( P93 , Tf$r , P96 ) !N�� i c��b$to�!�.=�5w.m`T� fer5[ѩ�ary5hu<#-�determi �)>( �*�. CloneJ}!����*!$!Q�protocolE� optimized�fit�)1QFby firstB�fr{ y!�false )�ve�5�C6Ys � what leak&� amountOb� t&c�spond �<10:qkin mock![.�)�Ų�U#�Ashich g& $ly facilit !�yield�� R M deleA�/inser I+8hupE�BQ 2�� al.5� !�reA�ikatiU(a kanamycinR.� Ir$s upstreamOdow��� ( HP_0835!+ ere ( � byEbISMg*�as.* hup-1/3K v 4Km5U�-�A�1;s �flank�$homologousA�..�he=� pKD4E� �(Km-up/Km-dn�i%three>�!��E�ger Kequimo2I�� ea�\�%�!)'9 v!�n\�=&� SmaI cut � ��e�� 4178��nd a�-��>. Measur� A+bin& solu< 25I-� -receptor�=jugatW&f�2]@ !���assayeda� dupl�e� �8 �S. Qual!��*conce��Jt:���a 1 . 2%�! roseE�Hb2�amPa micro-spectrophotom5 aal M13F/$�. P A�en��"!L�f�6]M9�s��%�*�s coli0%��h[γ-32P]-ATP kinase-labeledG5+- :�C RT-q!72��/inM�Ū�,MIQUE guidel�� [8�6�6��s "q4Brucella bloode�g �(!G�� abov� Before>�AF9U ( 25%1��!���a�n!�ra ti�dTurboF�Ū�$ �B dual�@.>�d2?%�lus-�500 ng2t��, T\or�B Sl d xSu��I$Roche Appl�c!0!�random h��( 6!M )�Wvi%!EO,-��,-�:���:[6at 25�7a��66 t 53�Ni� enzy!�a���< at 815�~ 0. dilu!��8�(l DEPC MQ bI4it*��.k in e ��� Qu��v�al-E0reverse�%��3aH(uR*"to"2m���ofe�&�J/�,!�z �re lis�"� p A��Sc�"�,�W of gyr� ppkI"rnA�T simultanef�� .����inF�$in 96-wellq�� %���10A 1i!.�(, 2× FastS�E Gr�Mas�a(b�� ��1:( 5 µM���LightUr 96 i�u�f_. 1a ] �� ;�m�=t 9E�A�40{1 ;!-sA� ,58a*020 "72. Fluor$ E�et���he enU��exћste�R%Cq� "y �o �&� .t :!*\ ^v . Af!��run� elt curv�LVnd�� aY6EA�by� `� ��s x, a non-"�control��&E�� T� A�onlIi|a�ne � E!�inclu�B��RIk pai�~A��� n-r�in ?&5 %�* .�A� � &� wo bi�ica�~"��0!R effi1!c"COu�!"�:�!�%3e��6�#� as s:��-1� 98±0 . 0�s2 9 6 ,��>��G6 /3r��20. Semi-q��!�RT-!%w���� �a-same�)�s�inD�0E.a�) �B, L9-��ofE`64.�"��{ ��"�gen�� a�on�"P�#b�3��9��.� 10 (%�con )��2!���y�!5 )� 15�� Z, g"/�yat����e~!�1� a� sepa���Ej5%k ATAE�G,A��@GelRed (�"ium�+ scanasY'KodakvB� 2000�HHuman gastric tissu� d�rafin��incub�� bloc�bu"@ ( 1× phosphate- � �  , eR 5% T�"-2�1%A�iod4f B $��1 hou��F%ea��, FITCM N b:,P&paub�&12]Akas ad�6�s3s��T)sec!5�was i%�h�` ��, m�f�Ft `med!� 4�e��f��)�$Zeiss Axio)�$r Z1 syste�Vi�* 6, .;%$FVB/N male�� 6–!ek* ag� ,m ����hE\ α-1a$$/4-fucosyl# sf�'�,� ul�]#�S,of ABO LewisAuod� up � ge�oep$li�%u��stomach!�-u�)g,is study [40�� ��A#confir�(bP ;M9_bE~nd kep�)u� cages du&M},o� 12-h� ht-d�( . Wa�,��$pellet die4 pr) $ad libitum��*M�inf� wT2×108.� (� ,�T16+A{tw�a week�woCvia oro-�Tal gavag� To e�T!�H&L& �}loa-mf%Qsac�( ed 4 fpost-3))��. �col�Yd �ia�kly cul*d!'s sup�q�mg>R,;+�*l sweep�*p��|antruis�+us�ps�.��%/oscopy s\ [88])tha�aZre- ��of.Eund'taLdA�� 6�+�!m!:"��D�Yxi@se�al pooAL?%!U.�+4$R��9. All&�i:Pt�)&�)eda�$omix GmbH 6�)FAM� },BOEJdesig��&by�7A�Laserg�&�DNASTA�#:n�|on�%���*. RepetiA\��.*h+awayt�&Q6I s�pliz,GolaTakara ,���RMya�gave id`,ar peak& ribu)�(�,�i+-, � ough � varyAX�f ��!"6S�*�,all FLA�3leK �h�eq�*,.WA��+e!ar�0re��Linear%-� a��!���"$EA�+−166�I+m!�t by high-f3t..�e�JN A| �-2;(. RadioU�!���2�f�pr,!��"<M�[γ`_ ( >3#Ci/mmol;� kin Elmer T4 �(J�.| �� �10 nM��inb,s�2"σ70-RNA� Holo7, EpiR:i�K.�TV0F0�2�&5 on 4 . Z ris-Gl.!� pH 8 ) � arcylam/,- �and-�vis�a�H P� or sc�"d , Typhoa�o r 940> >!.IZ�. Bi&Ps�inQ4� 4B=*e# a Biacore%�(Fzt���j�;$Scrubber 2.� $BioLogic S��fCM5 sens�hips whE A�co& w"ptavidiaz�m�by injC ng�( /��ap�*t�5A�RU �"�/�/'� co�ng  2�16�*T� a�. ethanoAne] ckag�d subs(t immobiliz< ofQ��tin^���ru0! ,[25 mM HEPESA�7E�, 150KCl  MgCl23 1EDTI E F 4io�(ur�2antE�Doxyethylenesorbita!�P2O )J( f�to-�:���RU ( <7��xy A'��e�6�,a T13 ( wt )�X-��ll!A��J5U�"�1ղ?*�$���GA- , Cor",0"#*Qf� �}�>n4aO5Pl2=��S6 an unl� �n-�+&�4;"�nM���H�agooa�ac|��X�µi~. B~/m�y��Ure٠5H%�E�a quickDg3�ofa�A�Iϙ� to a%Y5�l % '{asF�,%�subS)�FA1d$!�= . E"$$��&� AeB�Ap��5DI�Ż% !;ProteOnl%� -Rad�f�60manager 3 . 1:� F� cGLC S��C����b�A��Q�2�,f�7*�"ec2� %Ρy54d2�!A塄k/��M�!U|A�I8�,A$i�:{120�yA�ci A��ed���< in 5*� :�, �!�7;1�27��[j��*M�^ e/e, lec2%B�"1=��� & Z�A�� *� �� *0 A�ein��'Z�����,9M DTT� 10% glyce� �*�<5�ml bov��serlb�&3A)� at 3"#1�����sub�@t&j{s-  (o3 U Reco�'n�9]I ,*(#%�$V� 9r�8mp&)xa 6% denat3��acr� -� 3M urea� @A+G Maxam Gilbert5"A!9�Mww�ݱ�� �� long[7afz )9�4 !�6 . W�$s+he�me�wo-tai�re impor� reg<>or� 6�r�/se��� e�;�. >�9p* o-1�l!�a�� e mainten%of � epis�. ;5 i_,ot8:m�-t pathway��mod�esEN,inflammatory6�pla�n �ol!��:��B$� prog��/po!z: ytok�$!��$th�0%E. Our�? show �!;E7`*�$%$5�o�/!��?lR?L4�'-vQ�. Inh<of^MB0he drug pimozTaboAqes-}IN:L�12�4,m�Erng ker�<ocy!��)U`reat!of�=ed%r!�atI!yI!a�Qh\ ok=Aon �rep�.!. KnockA�J|!)oβV�AbA�lU*iA/A�Eg�s ,! is�R thro�_ATwdaFY}�2&�1targe�/ �! � e/:a!�liv tor-�l� �/(γ ( PPARγ�? =a-Aef!'s!(i:u��q>. Over� �@s0."s�f�6y/ new m�a^me�=ismAd�3�><�\�- TAT-�se��r=�1U �!ݍ���Bc 6��HPV��� causP24of cerv�d �qan�8tal c�� rs [F8!3� typ�# ahave bL$��CA763= thir_#+e H�� squys�th&����K  .0ɉ�D"a� HPV1� 1_23��35% sexuD�mi�1.4,'AAm�W ba�* laye��~)t �"�_vir!�h# iv2u��2lB�[{2��.^� ������u scape hos�b{aF ll!^ adap ����Q�U���ASnot yet�� erst�.���\s encode:six earl~$Z'!�' �x { E6E7PN onco� ��� y���!� m�!�mM1�v�'fe��=-��2��N�[3�E6��m�*e�it�Y�!lrecrui�!�u�5,E3 ubiquitin_� E6-assoc�u � ( E6AP )M:a tSic� �I p53��� in EEdegrad�r[4]–[6�7a bind�6s0� el ��0 such!3� retinobla�E( Rb )le����" tituEr%( �of E2F� ��[7�[8� Both!fA+E7.z! c�+as ]���M�evaU ["�A��wMis�.s�={?j�j� �~inivH��Ay,ev2� aF���� s low-]��i�:6.�/CHPVi"T23��iZ �͇�G1��i�*��nh�d� "� .�M���E1)�� );L L2 capsi�IoK [10E�1eEa�� !�!;p�O! imil�=inducf)�].�;in'ra)2=�A���4]m)�!8� �n ?/ h>+ �PV�:� ng l2  on bA�)�c��>[L� dɯ,-�.����E�q>��Pataxia-telangiectasia:�[Auto�&& ��.+5@d-nct nuclffoci [1��Xy� ak��of�am& ��6� �CHKa� hist� γ-H2AX.�BRCA1 p:ThB H8�)�=I4l6!�� �%�e} $ e%i�:! �?�al1�s�*� eir.lre�Y s un)).�W ��sH v�2�byi�� �^8 �On�!�Uam)�a�� R͟"} i�e�/? ? [1� ��Janus-�-)!�%��5-�o� � �A(\)^{5�by/rnwro� fJc",>!,� rfer�a"�o �lo{"A� ��3E�u!W @)B�hundred��*�(��9W2"�x$�N�i!es!%(-a-�C-4 , � �-6H!e5 "� ��a ��b�%�Z) 5��� a2n �-2 �xY�6pV%�v�+DR{! l5� isZf� ��isR�� +αS � �u1A�heterod%.��O'la�+�! E:Rex� a7�;N)+l p�;� [21]�)�� � imP0$ed lymphoi}? elop� ! >E[2� W0vgO@ d ife�&�4 � , ]K!��rea�C@A&�Del��nd��>�0�^pla�y� �7Oath�]:6�g5al)��]u�in Bos&�EWit�6UrR0"�w esV(V ��AUw7ZH ��u,�parSAOA�KbG.W>r6��,to��$�T�-dem�V� �����)�,e2p �t�_ A#-_or�12J�I�1p�Free!�is:�nQI�1�6r)*� ion-&"C -:��qWei4�2e�7iu|�:i}�FC n7 1$,+eQmA�!)"1'U���sh���j�� logy] eH)MQ�:�a�E DA��o�V��In�/�6-�:��K�T�#�"i � �%+�]�"�4B*aZ�]J�1A%5a�6��E hG/6��ev@ by W!�rn�t��+.! �3pupU�s]� -z�3 found .�Qq;in 05��N �6��E�LZ�.HPV31-Zo&�� deriB�!�S.6biops�CCIN 612:7' ure �CU�>{ > &A� expo G!.Y$A]� U#nd��&t�F��r!Y.�ed1Y6l2�=�l\'�)�w evelEY:S"%�5!�:})l�Kmp�.to1� AKte�5 ingl�[�ҭ ��! obser!�� abseof �r3nW`�uggA�n9atA�^� �byәicould����A�at*�F� Q-M�ged.�/q �2zX�eOu�� X� N�A[-n�96LA�����F4media!��>��, %e"B�U8 �iMSW:��A HFK<RLPsl�<lb-er�V �X �|*IMMpeIoe ,~��f���a�:$JR�"�<to �A�>�-��#( K-1)�;�!0�E%�tla � !�involucrQ6;#ua�asH �^>�(� )�!)Sieeu& t�~"� � �,��.rebTV�,R�2���_ �*a a:�*�L }T. Pk��a� �M� x��[23� w� �� at6�B!�����ha4f�E1Vn !�"m�S[ � .�ͷ�eE;$�"]�12�8`th�"�CferwoN��inu#3e��2^\-d6 al 48f96 s/�B=KMM"h n��K�)��&�Rk, howe��"�!�6�� Mr �p" ".l['i2�%�Kx-hFof���P%�un� by����2h]6� �B��*� R>cWx��]�ifm�wa�B <�f�E�fun;. A.O@3qs beg�#at:�48MWa�;� Q|!f���A��!��7aus!l]��G�AZ�6ed2 �wdo0A>ed:v �>��6d ���a���Rq by Sou' F� AsBJ����U6� �z�E+͚A#>���e2JB!9 also:>�-�ed!�.�.` JE5ge6�#by NorVI�r&$ �@,I &�A?major l)���&� E1∧E\APESe�"� atA s>1 N1I\)�aGB5 to� ck �R�y�C�y��at��Z_&A}� "!:�&z�B&�oa���"0���G 6um*v'NQ1���a�� 1��u5�mo�3 " 7!Wu�2�8�HIqs�5�Grqh8QݼDF Pa�O,=:mߖ�P expEE�possi=4tZ(A�losE_ [:�M�>3e��%BE}�u�a���!!E1 �b�b�e�� pop�R� we Yw09�� � u!�5qA^ G�\ iti-m+r��V�yE & 2Fe Fi 2E� m��6Im$"N0ej�T in 24m�!�6I2- I�Wα� �a6jw�e9t�Q�^��P%f��full-=�leaD PARP�� %�!i)WAhr Bcl-XLm ��J~ de��'Q E�A&s)Y �65o "" Ecu6%�"!9�)��&#d� &� l*�(0MDjV Y�i� M�)�B�. IA2��A>��(��:��6�4Q�e �1kB5*Q:lenti�-n%q ��shRNA�A�n�e�= WA��%2� we g���[F " ;ly��S1-�!���&� wh"#-��&pec� ���Nsei�W�.^�s�iE �al ve�,P�>�g �:\� 293TQ�o�A�\c2XH �11_. M�Pu�AE�Eb&xN� [ Xq.�H.sz��+!�Z�div�Q%�A.�r 7"� + � ��,% lys�-E�har� � a[!o }> j=q.Q7�=�A�I f�' Vα�VE+M� , sh5a02 �6 x � "-�I.�S�&6��w3Y S.�woN��V�b0� sh5b�%GQ<V��vh�*2<e*u88C!B�u�qb-7togm�oi�c9or �5 ]:��6�r-��2�,\ > in� 6�AgY�nd^�(�^* I�/ol>�ɷ�.':��i|J�Yj�!���Uy� ��un � >Y�B��wQ �q��V�sF ���B��I�Ŗ2� �� . CJ2�=�^��kY �: �E mode��4"0ed$" e'�����!�.� t�' belieD � ��B8,q�.^8 ��se-�� �I� aSd !�031��al:ZRGwhileN�i���B�"�; I u>�*ImA�!�s�i ��2�Y��A� Y �:8 ��ޒ(R�)In or�Hto��.��&v.- y�'ing�"-:l��i.*�r�� i��*EI^�amg!�ch� psh"\m.�Sq�&mJ � e�"x f <* �ded�!M(� � t$; :X �#B!=.����"6��4��toJ-a>�i�A;V@%x%)sb^ &�A� �VWVa.:M�,:� " �!':{%su6��*we%*�;8 �+&� ��k i�:�m� �r�at2�m��y��6_���a>p-�V��;nVwanA/:�!�� I ��&2 iQJ &bl6� D:�4AB7b��ofE�aCz��_i�an� "z��`|:6�Y a`� �Y�aJ�d� �&e�I:< >L: # A9A�"� J�� :_.K!�:BR�� �uy�,.��p-�e�re�1���s�}l*>�=�cA�63�.3J'&�^(toi�q�"�!a k&d-�f�!pwZ��]a�� �!� ��n�,YI*e�%,Z��1~�'9b)N�J�� ma&g�%*� jrR��xU���6H2 �oi��\� ��~�. Wl A�9NIuaj1:@G72- poQvj�, �5Q4 �suf�ZU�h�toa�<.�F� �I?*edc��&a�>q0,"N6ATr��&�;.��of ab�  >{�w�K0U�J�� 5aLn"B �>�.�� X9�FJ�H m�%��&pM%:OW"2 ��mayg3A"g0m i�b�a���+ 5 � arge_+�� �JA&��  mXtc ��Hd:>s58@2tSMC-1�aV*l s=�"�4N�sy%a�|-�- ��%u��BgR. AM�mP*!�N�RAD51�$E�"�> BkM�.� �]> V���6d�)E%?o��*��#��.L 6�om:�4�� �D�)��AeRaI�B�AtfuQ ='7aE<-�> ��SA��Bu�6��_:M!}�*� rEuU��,)���R� rmF�? �q>sN�a�&�.nrx"72y1.�3ar��.k(- e��� Q�. q,,�* tillF�&)�R"�.�edh���T6p,!]%��PA�C)�r*C!� .�we ut�R!�EHX5�A�C s1�]1[209�'Fe8F�1:�V} mQ/ cV�*\, �Ӊ�DM].? &u$nd&@$�b�f&8 5}e-a�9k�,%)��-d6wn "�$, ����n"y!�s�IB�;�"r6n�!� :� 5DM �K)���5aI �&A=�of�C�*R�Y�o��A�"�"�a�ra֑�g M���Ge�esid���6dd- t�  ��!��&��1�F� �m �.w2�!Q� m� m"��2)*YW�& A�:5.�-LV5�tB. ����Tpf �D2u=��"�0"C��u U�;$*� �dgaP26�e�e8ih,>�;"�!)who�; '�^y�a�=� I��&� �-N.�2�ly.sRAB�nd_.�  >e2Cf2'/��� .O_or> �O��:"%�6)"th�f�=vo:�G"�Aa� #-"�)L1u=a! .��7:����� �:�20)� ��8� 5i�U $!d�N�W+{M<� �JG2�3t�8rR!�Pb��..�G*�Ep;&MO�h� �� %O�Urta"[�(�k�&E6ASE7 �g��6������ �}-J.�, -+8=��0b� C ��pe*Q%h�"Sret^eru:�#��ޡlREno��!TRQ�A76�I_ �b�YHFK�E7��&;�Ica�.� >,A�BG3%: }�mQ��Fn��u�NL or�B+����%'U��s6%4�1 ( SOCS�N �wn.��Y [27"�1> �oi�b��!BE7. �$3B�E7~=B"C"�G.Cm�-GA���HiTst�4EQ E7'se^a�!�QFW6ph�J�v�H*3�F,'K^�Ni=�Rm6[= ��''& �"/M���u# �z Db�8�h�:BMO�%! .YM�,&g=�-)U�>G=Rp i^;H�87�����*��J4 �w�B��u,E1a�9nV� .� 9{.�I�!R��$�$� ^�=6E"8)�(surpri�(�2�E^�tead9��5�%\"�C3&.�:�ed ��3�J MF>>�ace "G>��#1a~��i�"� + � :E�a broa� ra�wI��ᰅ�y�UF�E8)�.]v�L�2I� (M�eGSaB)� .9$ �%$2/%�enB*J.�%�b� stI>Z5�A� � E�&[U!�i�s occuk�aT*� <�:*�VE5Z�#a��hfm ��! *��C!�g�� �u�>�e �*! �M^-�/��jat) :a�R�16VM je�is��~%�1I�-�B� B5"�x�� <iIQSE+ot*\da+"��in�[mL+� �1� betaY  !� ��t3�imae��t�O!�"B "xXo�[!�=�!?i� g>�F�(edxv2tK6upIB iVF� elev;D&9 z��!6 �<%re [l�"�@"V�@A�[286It�k! �%�"�.-�!� ls!��e25 �� �::�Gw� udd� �pZ li���JA:B��>.ZX&!�+ �+2��@:�*Z#IO6�Rk:`��!>�Ed=[i�!�,->>� �"�%or� \I�6b(��s�e}G %ji2�&p.o� �%9�L critlX�%�=�d �*�,S^:6A�e�&�,:�a�f )�&�F)=N$��qmVE�I� C2��>L1DIJKO�Fp=@��5s 0s� as$�2i�� �� $%%"��6�2e",>>e!?"��n_&a �RA(�3dI|Q�Q R�J� �I:��"��� i�N����3Rc�� Q :�| b-QU�M�o�4I��KSDwy1)� ��β1�2e�mRwe� �&B#1-�McA'"��% mX!w� �ca"c����"0L�0/ M�02i�0 ��6LMnta8zEir�5�urnove! � does�]-5�Q�m.�a���0as}��=2.��JMC�f fy�2���97~,A�A?"���U[2�W�+*�B�=�ʹ��?Y&C w"gH6{.n"��E �6{B �Dzj� expl#��inQ�;Xnu!y&�  6hwe saw�6�!o�B�KD* �$Z#anfr[:)�U��jEnE��G �i%��`�0�Zeo4"�Xr fGuՇ khar�8d Laimi�X unpude�j�1*� �U�90%z-��Ze^E7 1�\& e`��E"*9�1!ji�i�q��JpG}�>�6l��62  J� ����1��a�͋q�����P?Ko�Mrr�b.  U$eGforwardN�-p"�  wIb�Ù\]��"��JAK�=a�(]�v�sX�VE���t ��h-� �be TIP60A����؉et6*|����M][30� prelA�Vѕ!/ G hMa� &�>0IY&�/"� e� 4( Hong et al .q!9"W%2MM%� A.?Med1�}�� spon�&�5�8!e pZ"��A�Q D"� �IL&8��M��� 63.�[3�U�� �' Ek`IN�[3�Uz&�aF- >!7� faIngA��063Q`esG >� J{ O_:5?12�_0!Qɭ�&yF[3"�^*Ya���^c��4e��, AKT�7&�[e�niI�:eT�EDKT2��� [34�[3�%I��F���e% RF�N� M�� �� A , r&PV�2�R. !R� ��r^�M�@A-E7b ac��rough%[��*R E6!�m�)�itself!�� A,f����m����T}e'`Dnd���a"�;oE7��do��nrv<.� ?D}6_�����u�d��&{53 reH�$}�H �� a��"��H��� 5n'N �)Ai�&�Uw8E1�""ke-VEp� 9MI��Zl֛P sžMsvda6�j�% umab M?��sta�r*�& forks [36c3�]4/6//E1� E6  �$/A�IA)iP�(�.�Q�= gA!0�6�D�Jor)�0� ae9 6�7)��!�S��mV� IC r!��Sve�aEcor�MQlVpe �t�E7M��*�J�� ��u)l��� ��6�2�pa�M��R� . Ka�], sarcoma herOkB( KSHEq [39].�h�jB�\tropic ;-n�HTLV-I ��c��Ƀɣ*���le b�`ode2cvqQ ( HI�41]&5.y!��:�"b�E�2�A]N�Aqaūag�0&W�two� b b�A�s��l�&���/Qi!�b X ���r� by Ma��d whoSa�"V� 1�mu}re5��α ( ca �3��i�Ez�xD��d�"B�_��A�se"!�[4R NdG0 q�'%8� 53a�� e�^�aE�oca�"��� �d �-!�C "��T�Qu.!�m�/��n�o BV �wR��Gep�����.�c2-�� &rR &8 U]l2� is work. �S���s2�.d�"�m6�B ��jA�.R!�-9iɕp�]4��t!�-,:�1�!�/s��ke Ln�O��$)H")�Mneona�<k^��y�[4{ q6bH.��%"��,�4E %�b% ��wu �JIN��UBka"i&Fs��!Ip.�G2�%,�$V�All GAJ� �1PE-a�u�5p�[ mouse!2d��"�M>�4ng/ml; Collabo!�ve��Scal P��, Bedf�M�0H �3of mitoV�C"�)��(3T3 J2 fibrvn fee�A1�t0o >� �H!��urIh%.'cm�uG�KB�%� a[)UQr8$lt �V%lt� switc_toE(E�d.A)�*Q����Ca^��up@"k*�nti�un %? ��r�s:�i-�l��yβ�& igma��/ LourOM��; :*�Mti-In"O/�ti-GAPDH ɥti-PARP� e�$Santa Cruze. C!� e �F ti-p:� o�] ~ ( Thr6��%( Ser198�' q8 p6|�e!\-p6�g(e� e{ (, Danٚ ,I� ��( Millipw�, Hay ,9-=M��[( Abcam%ambridgY\e0.i��PB�4e��4r � PBSY�&+� in V����$] �%|5�݅)E�2�:uT��6�e�m�at room��er~�,"�.�e'pre�_, N�Z.7� ����UZ��rat��ly2�6m -�7wN��CL pl'8r  re�<�A��h%� Pittsburg��PA�.J����l im�l EastٔK�� x-raҬlmm�)��� * ��~as&&��lj64&��H->��IRR�6-�,���"�4"�2hly��(�s�( ��mM Na*^�'�HM�a��(U�c�Ns��&�R�A���-Aldr G, F��-:-y�*K�?tХ9HU����X_ U� T�!L!�e-g��jl-V�Ks�5e��?�q�Xho I!�hef202��� ae�8&ݗ���>0 V6n�.�:�G�JS�V nylon}�&o�, Hercu��i vacuU��D԰2:�a ZD�%K^$m�9Nhy�;4�Er�� �obe��3�I_i�.m��q;graph�R,te2�!.}����8ZlZ��:-�yN�=6ҍTel-Tes!�Friendsw�y , TXvS�A��!@A�2#ESpro�s�%Zb-MISSION�r�sirp�Naz ! xBuS(�Gmv����� ch?M %.(@in:�5. F� )�2W:nQ��_�Ya TRC| TRC2w2 smidj�kb�� ( na�9/��M5α01-0b� h5β )A\ “nE� ”; �P +u-gُ.w�!�¬ ( GFz�)$"tQmI2J�T� @`5�Zmica�..�T% /J50–60%|f�?�.oenL�g-�����,� 66��vesv>Dz��sf us G:6e~�37:Gag-Poat-Rev2-�QHwm�yeE� olys��e�W�� ngto" ��  a�chq-d�5"�Y���}�)'�)&3C"�;( 3 d N�#"e��m%m6�fi���r�< �� 4!fm syri. +QPAnn A%�� #.:%p& -�m�X�!�_#, "�-�:$A� H S7�Q�qartI\� ��&�c4!�)�d�!rthr�bro�( !�brene;�0!7"�V�.{85���E��%,A� sh E.� .�oachAct%��hB�and�p*�$EB"}Fb�5(.&zSalmonԩeQica sero�r��i-co��zeE�}11Y bilie trac"\���W��L(!��$C� asym��a�[��Ǒ��a*�ChrE]�$k� &�3!� rvoi�` �Pwit�\'�=!6Ei�L!W/to sus׳�-�� n^ I�. Litt�n&��bxa�Z !�b�{���B!BJ2�6�2OcurŘly[%:&�diagno��Ƈo�,��=nS� yp%�rr-pTo�y�-�t�ŵF��JU,�% appl���h!�o>_A��nique�<lE: vivo- � nt�� )8�nIVIAT��.�po�'��bio{F�y^toIY!K. @"�-s�o�y ���c�&��T �" % Y2HAI� environ#)�Qyp�1�Z at=,�siv! JB h� k"�gr�2 �ic�ifh�irt"9� '���%��:�n9$�C�O>��"y�wac�h�E���a��!�QT�2����xd��Y(�u�v�I���Nlip&��)bhem�nin-��� YncE� TY1479E6�?�Xa�er� 1�5 ATP-�!� motid`��in�)Ne� !*��to �ina���s�Q�2@��٤9���&�p2spajNd VT,9jacu)ʙ id fcj��1�DrolX|sۘg�Z�ȧve]a�70%>��of��A�'&�or( @/� Banglades�%�1 X()�)6-b�),�)�LA�-E<IgG��� . IgOI�$=eItX�Fur�� �lu��L�� <}��s.by��(�|A?�qD�WqDmS�`:�s1miv�� ^ vars(]=)� ParaA1i�e/)���&� �Na�!� predF"=�� (�\)M� glob8. E��ic 9+s: 21 m on peopleby�J:c�20q) 000 death�}]!��>AE,��+�.�u-�l$O�k2! .��� +# wa�� or f>�)9in�! �H�� al m6�C l�~$-"j| foll� w�?�5�`� rVKG8�ac�����L�disse �ˤ�e�+~( e li�/, spl�m�]t�� �!���erow hgallbl� �K!xW��dU��"l, mo���recZ#Ƀth=0��s:�!tillnes� Hf�.f. H"Ho a sm� perMag>!�)�(R��N��m�p ���Eap{n� 2� !.GAiR�T�$� n dec���>�W�Ti"ihAW!�(s��kn� �&&s�>imE� c �"z tco#]2,4perhaps 1–3%_)o"j sE��;9?N08�-�2ri5y,F� � � �� e\��"�$A�e@miseDX�O%asrm��nt ��pfBria!�fK< ( eSI��� rea�&��2g[8]�nd.�vehi�E� ovAa*un)�C'2� ޢ�>�2�� � ��agv2�2�)�A"_7J6|-term�!'��H. C"� g A��� �!&.�U�2�� tool_&k#�,^��hc#ng!DlA 5@��mlogo c%���.��ip[�m�� ��, s�>UG�(yp�lyE&B#b2x[�.����bodԆ}��! ����+#V��a�]5d"`�4/*: m��LELU .dL���R�In �or��tAN��7 �N�|$�1,|�iv� of 7��nd"�L >9 7% D��-*{ 2teg�.<tbr�i"�`�C�,��K1���"�7K�-e! !�6'1 a��!�� -z+j popu8��4�ɏ�&��lm!�--#:�� � 92%–97%�Q:� age;*AvM�aE�Aale�A�" ���͙ge ���x�?WR� i�&e*,�o�8–17% t��Vietn�a  X�� y-ba]�ey�:!�2�0 a 3%d�A%r= ��.�9_ n� )���e��9i ��<�bFU��J VipA![13�U�����Pm&O&�7� E[v2���%���er�tF y#i��w�&j aOa apeur@�ac����95�6�lR���,A^q n�Pm�ch��d:X-��})M�pN٥�i�tro�m8�����wf �u� w5� 8 6���V 7 ����Fu�!*a9s!#A�!p}pli!�+I ��'�n�) �s.��� |II�zTf!'�TAq�um 7,�'>aQa��'+Jn��� < l*"�bi��Yat�A��ac!�7�A= def�i 2A��0 � y8niE�&& �eout˞ !.�q �FQRt�V�ver� m2c2� U Y �*@M�*)V al�Bc|Qc6,cm&�)  .���Ait* :lw�8Ap�6a!:�2 eG!>wV>YQ�`<� *�q}93,Yam}<4lc11a1 ( Nramp�$wild-)e 2��!� �� �i�R���fmophag�)x�&�a�avV��K��,"���wv)2ur �A|��T&�1K݊-_1%�me�z!�y*6 Rp}��� N!�we��V[19�������Pv�O�]a��G�jard. *t�/2�J���pr�ve��I� E�+��:�u�%���<�or�:� . 38��A��U���9e� �a\Jߍ" �a��EL�� ons:@�sachu�s�"� Hosp��, *6�<o'C�Ʌ�Diarr/ Dise[$RH�,* ( icdd��K� , Pa*�a^Nepal ��HCounci����a�Oxfq+T82al+Eth> Com)�K�y !8!nm�B�#��cg .� Decl{��f Hels�G/Be�t RE:q�n���$r!�nU��� �4��adult� ipa0�guardian childre�8iC�i o/d�q#� 2o� ["T18�F�!dJ%�,Stock1�( Calgm, A�7Canad��6���6 ~t2.� uct � ee�!mT� librq��� LEsche'i liBL1�DE!�6�*�� (in Luria-BeR�b�L�];-a�, &J'&'�� clE#�(�pET30N#�*�..C�}B th4�� 15*��� &�igo&�&�F, Kathmandu ,m\H enroB !��}��>D^cven��P%%�s ��#�e.taken%v���&X)\R�*^P"t�goAa��� sUair ���pF!�: ; ( 4�B�+ �a�Q.@,��#)BQA$r�R['nC�3� orga���ra-i .6W!��of�groups:� )N��o�k DhakA�Zz)Y?4eV!i�o���l.k�!�� (b$ 0mJconM&�tP"�$day 14–2@/of�i "� W �cј E ���emia [23�2>d����AN A���j��a2<I���Y�( Q �%V(i�QKshe*�GC:&1�" r ( Wobur@M5&t�.�{d%5+ . 5 kb �&&��|  �^e�gel� �Al � Qiaq��GB��kS{�Cov��@ZW�d UEnd-It� end-W/ir-&Ѹer �ech�!�, Madis�&W&  blunt-�#(�W��� to�� -30c"<}( Nov0/� an Diego�+� 56�,^�V��� cal�a"�alkk1e�Aa7�� ����$��rog��"p�DH53I�ia)L��y0'B� LB�΁�ͨ����!� nighc�.A�"s&)Q`�~&'s0�A pl\*IWo�l��9a�^5�MCG�F1%�.%MI\ KpnI-j�C&\��DV���+a� � �$*O�\��^e�Hn 80%, ) I#"Z%��to@���"��)� q�mix��'%�^�2�i&.)93A��r�/CB" of 5�A�.!*f����|T} �ad�Q�"� K 9.!�U�2�H�&$zte�P%Md) b1�. B�"���8V}KE�aa  (?"n y *��)�36�2z �B�03� per _�T�s�B6�lifa�of� ��%n@�+ul�#/0Q�ba�)�l�o%� R!�1�2is %0pyl-β-D-thioo�pyranu��酕/�^�8�"Xk�s4��'��4���&xN4� -soa�EA"śpa!j$yy�$8,"c*A�1 h¿5%�!=�6e�25*%�(/4��xM1f�A% �%PB#i%j&s,�Cdu-s� at 1∶1""��i� �!:� �3 ~R.�:]'M�%G"m�D(4 conjR��#hor�diIJoxI� ( MP�gA'$cals/Cappe�Auror�ON�� �2B�)# �!�m�� �Da ��cB�(�6ڥ^02�6scatawa$�NJ ~.Re3. �!� eas��eR�� Ras�zen& �s��'*Qi �"�( m�7d�sc�0F �,ٮFar!�2HZ� Qa�2<�E !7 mpty�&��Ne_� &�- SEs�)�� -����.�C�"��;.K�%Efulcy���4D) gQ{6�i !��1re ORF� �G 5�XPCFu���!2�7 � E�as Nde/ NotI �!��]-�9e�]��bes%�)�)�xsS�R��a�ge�?m�N!p���)!�&YV�! �"�%�Io"Q ��a�%_*>l",Z� (*; eTh�Lq pre-��Q�:B:�?d& b��,ARGK� k�nd�:�!�_!#.� . Fu�׭lassi�E�=m�i�zG *�ȩp"�j���resourc�m\,A�Ja5raig V~ I9E'not<� http://cma�jcvi .�/tigr-�(8s/CMR/CmrHomePa�0cgiPfam 2��77 Op. s�3Yac . uk/%�*( S"�,��>^�omj� !�B =e2t@to Gate��{� pDONR221-cBP-�on� 2|:9� i(b( Inv�{Ρ�&e����"� !�r����4������ES��I"LR6�:�i�� 8His6-y. i�+*6B� �oDR"�<toy7� �?b���m !�.K��� w AA;o� �e �E , -( B���� ��'�LU br:�ampic&+q��un0�OD600 yV%� =� of h5G�J �I! �6)L ( +arabin (\2%E5Y � �el��Yh"ŋ���if !�5.7q �"~nJ7� spe �in��mL0/Q��!0M> HcL 5*��.��E>U�6XC 00 u\6 lyso�. F"��B�!,�P zRy�w!� `41%�H8X-s9 M�d��/mL!� 8 M +�, �NaH2PO4b30��N$?(�����Y�!�"WbyPur C�-os���mo��ɶcv�o&x��* *ٿ� D�s�q%n� �s6i�E��(l�by 5)Jeyx��?LE�151�,�J�0�YW�;:��f��2X^o�%ty�bI�:&���ohorm!� Coom�� �)҉t�.Ja Mass'tr0�r�� ��� 2��} �nd�-�( Brad�) ��$in Assay K� ���A_ch&a3 2% �N o E�!�7 &e3B8�'�-i�5] !�!7t�18( STY1479 ) IgG�I and IgA responses were measured in the sera of 10 S . Typhi carriers , 3 ParatyA �8 patients at acute ( day 0–3 )�@convalescent phas%014–28 ) of _4oid fever with9firmed � �Dbacteremia , 8 Nep[e,�trols undergoing elective cholecystectomy ^ nega,bile culture�!:P8 healthy BangladeshiHin duplicate . Plat1[coated ](100 ng/well� YncEX then)t%�added%<� 1∶200 dilution . Bound antibody was detectf0-human IgG or%�conjug�Hhorseradish peroxid)�DJackson Laboratori%8Bar Harbor , ME!�t a�10.�,�Sa!oit �Uj%�tAlubstr!9�I2 , 2-azinobis ( ethylbenzthiazolinesulfonic acid ) . To compare across pl%@, kinetic readingSmAb/secI^sampl1�8averaged , divi!�by�Cpan in-house pooled standard (mOfAwY�u4coQ�byAy iaryQ| )-RE%$multiplied+AP. R!tm�expressA@A�it�U))Xhe Mann-Whitney U test ABu2t9J�differences between groups . For evaluaE�ofIsViEpa)6c, ELISA1�E�.A�}ViP�gen ( Sanofi Pasteur , Lyon , Franc!. �above.Cp)%.�yEI�b�IٚJ.{|. Pyn��nti!���>-��B7of�+mAR?n')�Z�, a��scribA�%��Df�E�assi.us���N# . In prima�scra of o��120 , � clon�0565 jidentifa�Has immunogenic; 210 $2 seco�Hy m�. Sequa� analysis�(these insere� manywhich�gd�<��t� ally�0@ible ORFs ) revea��268 ge�of in�b�/��20% #���e tim% support�valid� �� heir9ca�Nafsatur of libr9tE. We �8% tly -%{d!  full co�� %��of 235�nto in��ual5 on�� smid����(56 proteins��promin��k)�reu�IVB���, ɸ�B:of.��s��a A+tai%$an empty v�r�5 upplement!8Ta!�S1�(Forty-eightdA��)��K enco�oI�$chromosome6�, 5N/ drug�ki� ce1R pHCM1a� nd 3\ cryp�pl%s!2��4most highly re��enK funcA+alѓinclu�5�$of unknown/%�thoe* volv� ransA� bAng , synaWaar salvag�0ribonucleotidE��@energy metabolism�o�_%fdegreBN��� gens.�by IVIATEj� peaGAp(endemic-zona�puli1 , we�2m 566seIC$s against ��!vias liv! in a=� |!�a (. %��ꅘ@Dhaka ) [26] . Of! se�5� , 13had moremYB/w. ��� �Y�*\  da='R� Ise2�UYa numberAYput# membra!�, lipoA hemo�� n-re d݉D(m�i� , a pos�� ATP-U� W ,%&a���alle%��� tialF8�n) 1-�IFco. )'in our F blotA�ay!'4o further char{ ize!��B�to �inN�� specificI� alsoe �hefT�f1�5�ŵ�� s: (%gJ#, ( 2 )2�q�!�J���yp*�F�aZ( 4 )2`who�wa�>�in �'se e � "� for �� pathXAHn� 5 )5�-�s from a"^Mq�i�,}��; We f3 sign!�a�{��edGf�V�.�.o-�"I@( p = 0 . 020�,�2�:,0 ,!Pat����1�inf6o� 2�044 Z2� 66 ,� p5vely ) ;rreE�a tren��war2tistical=]ceSn2'b]6�2�Q(( Figure 1A%��b�7 ( 70%A/a` ��-���9 ( UW>~) . N�� of 82�Y�Uv( _, 0 /��:�.%3n�)!�1 P( 1<5�2T��B!]Pv�*u �$sm��� U Uf,�� a cut-off� ul%>)I( � t=p� sensitiv2 !�)d�.  100%��n rq�1h.�!7>o�without X? ��as9�! e2�decreaN95% if��I2d�bqe� . Al gh ,a3)4 s did not�cheV3,=�"�N)R��Af�.��tw�:2��� 23702nd5�2�(2U2036�BehTh�?no�'t��ce"������i�nito9�� �?�1��!or%�R . Si��e�T� Yb*hav�e� b�.td diagno�<} hod� � ify�XU to dq, E"!9��b�� sam� hor6���(��.PT*r6=00Ek,2�R�2�34��R�_��u�2d�*# Y:�15��.٭2ɭY��,!�E].�ofZ=t� .�>�u� ��83a��� �I\ 6Da�Qz�m�ewe��find a^�M���.��j�-�:�5aer:� )=��in �.:�J��oX -�y5��.R�,��)������ ~I �!�Ar40% (&>1250)5n!:c {G c�|irAZ� a"� ���t>F97�_�__�94V5��RJxm#"8.q��� !3e�" and/or5��:A�]couldՏ 8 W bY%�# no benefit s��pai5n�!����G���8& _�%,� d fy� 7�}d�s I�w�J�.| se�� � _*3� ��BR l.�}2� res��T#�"P a work��lis��candi *] biomarker asymptoma�:�ag��i��may"7!���b,urvival adapbonl_� hro�"�. H�epi(ologic stud�a'll,murine model:XM� suggc (that gallst�facilit3 !�develop`�:�� e [5�In .2weq SirA�!I�IA��is paj o two-!�o Q� reg� ,irA-BarA [27 �5I! um��is5(plays a rolNjdow�X� of gi*Dinvas( i .  ,Salmonella P�i��Island-� E��� �is!�c���� [28]�m�A in s!<r&� biofilm��A�onqiA�surfaW�y �!:E�!QJ orQB�U9�,why�ytoemx%8oryqz%=��humoral��� as yet��b�!&_d�Ftju�e�S��2<ar� f�� -.b]�*�U2Lper�?3bl�!rassoci�w�� m@[3!�Nlik�o� nichq&) ,5��APpepithelA2� 1 t`� in m� phag Xme>,ric lymph no�[2� �a�,, [16]–[18a7P�6la�m�!fE+y8-)�2| ! in h�cel��r�string[ environ�\E����, YejEa+a&�per["e��itou�toAJa�.�/� 9 ABC " er s$�e�.�� �1�al �� . ntimicrobpep-A�i��ca�9!`In both]AU*��y��!a�is up�����)Y.�[30)�1m PduG:aqC"� �Agpdu o�#�at0.z�.�6a �c s�EA&:6ceM}`eV. How�),Y"le  info`is tregarպ�#��io� y/atrier-p�  � ir p�"� arr� !�r��$ly unclear�major�hewV]en� %suc%�"�orFL .I! exA(FTY2386�an�2�*uniqua��&+ . STY1364I hyp  periY �>��n+.$s raro��x{spp belo1)to��struc�#l>0of� al �!rotox #��2til]* unit B- �.��7�5.A�aIr, a sep�,6�K echn' y� �%affinA-%WoV!b�,(, IPT ) [23���W,�(�479 )�A|�" j�!tA�.�)�w�us focua�j !detai�%"�of6V��!v `. �j *�N-termiB#�vJ%cV%�*�$�,iATP%� DNA-)#domE" . y�,y�Ae.6!Bk �� orth!�� .4I� Gram&bEd(ic organism#�!� Esch� hi� $li , Citrob E� x Shig� I�In E . c 3Tis�'reA_-&!�u� viaSec* &�7�y�+6� induced � -re �-�'i�*s!�� bysFurI��lie�$[3� Its�,��e�$f.�i@&!�fy ��A�ms6/itk .��FEm!:� ,��)��w��F�meU��JI����/�.�on {"~isE�8yc "Yg��:0"�!or",.&8.:���g AlEpij#�� �milar� nd�R!�a�. O�$aw1�[1ar��a�[ec�%�<6Wm4ani�6]0&H2���n 2FFMs occur6rdis6; h"d�h?be!I$at%[olE� curr� or fu�1Q statu�a 6�-/�A��G)lev"1l�A��  n� sod�� f �i��an kon"yk-1� Vl � prog�/a��:�!sAH2��*a excep�"( xP �-� &�d�V�))� k I�R **.ts�Ld7� ATCC 9150�$AKU 12601 �fon <60% &V) �tn&I�~,A�*. M  se�WE��2�tv6 C.��B isnl!�2��u!M.GV"�'�teg�K&?:�A����'ofI|�bstinc1~��wo2Jat���@1�suffic� power�� t�i/iaL+onl�oA?>�=.Despit��Z ur ��cF,4 � �{���!app� �'rA)Q%c!�&#�m �2�1x�4 �Fu�(!=!�will �{ee[,t&�(A�.capab!7Un�#� large� a3��JD Of��yif su�"�demon15Dp���K J�th�1�#���"qN.� ��/0b&�/a-iv`.*&to.,co_ ityO &. ��%{ag���3�[�� -�MT�" a�beawful.�6�: u ��QI�oof �er���jbI prog �9�F-..ea��~#�,a�w�>P ��6aLқ10>-W ���B� AO&�!$�vI|� e .$agAttw,A�lam�e&as�9��,rubinB&, s~$J�/ ften.�%��3ink� .�=��vR$�\�me^"� tud��O�- � .� o�] Firste�e.�.� a�v"���S"V , �:oS'^V 6Un?e��s���� !��X�.-}��� �4�10u�� �F_�os��>ie` ��. A� ond= �at��0sA ^/�Ta|"n�a2 viv�'*0�9A36 ��0�7ls:4uc�|e�b�;q��77�� !u� )s!0? &�����vo' tro���plaq.�>� Q�5z!�ser�6��7�,��62lad�!9!��C !���<�chang!�e�[pr�P y�� ereby 5R���a�(�)B��"doe� My non�A%��a%t��E�=&T(ass.�d"�� .��n � �to� s%,iE>a�= %��. � ."�6F&!��P-�G����^ lead�![:�i��F :)e.6'9���� 1$zM iJ�l� ��ong�vf�,:���BS!s-qD �79� B! ��Rin s .���rd< �b!=e�a�S�e�RNAZ5���-�=hom�ous� �? locikde�ngV� crip��~!]  sirdA" 3es e8ec[ A�f&� alle�>ͽwh� |�ce�a"77�opO:� � by h��o!G���@WM�@ebf� � , unw$pr%(�~ 95�m1�&Ab�7��:�U%% wild��+ ���+�v��new�/2!phe�nH!f�io!$�-��is �Y�'l X�es ]RNA’�@� I:2�!��,��post-�]6' �AY.pdat��� a$�!� unex+ed G !LD=_�med�>�A�mYCuAm!�h!� ntexE�61c_s�&rec>years� becginW0ing�<�An��)��ukaryo!�g%�s!KfarI�HlexA�n fd b\'*xexplo��  emerg!@��b�ca}c�8gfn�!/'  :approa�!��e$!"�A�ll�_���,r/M�'�1�b�B{@�orm�h&�8a�=RNABnc ) [" � ENCODEa�j�I�{at�7 st 9�=��zed��%�s2��U"��&typ�,�2�=��)�re!�a hug�ervoi"6\� "= l5�b 'al�� [`D3 , 4�(�!Zre� ably*�I�ir1C, s�8,�ƥ�locali� ��me��!��<�7qw@n�95in�q[!�A��a�5 tR&{ (e/!M21El�-��paV'ep��W"�%net)�>�*)evo�F� cerv� [�6q'F%D"  dyna!�$��4ѥ�fent}��_:�dar!� ����w� "74aP�ily6� precis)lec%�=�%oorETderstooFaY�recruit"� hierarch�.� modi��|es!�"�by�tt2 �%��sa�� o.��u[8 , 9g+�B1�#1t# More0<_  unus�@9����I para�r [1a714W5��-� v16]%W�@�[1728] oba�w a variet%%���g* a:�M�E�0‘rewrite’%�x>)e}n��xn��caz5� ppa:�Usca.#c M� l�lawBa��Uin���se.?9GAGi{m G�-dire�}npr2��fer.].�#�'ssv �1tissu�5nd#�ə)b7a+]�B l9��st�'in elus#" unveil:� & �1a��%R��2 � 1�Po%Ef VA��K�;PEV�� ��a�el(0D . melanogas�[1ae20M��� �� "� ( wm4h �;Surpri4 ��!eCs�al��ai>� + N� !�mAb ��� X9� but�3��a�%b!�� � �1w�l!��� &_ ��H!�7�!L t?!�� eye pig���#. Str��'m�j� % bca�9 � "= �ac�p$ �Ma� �(�"M`� ^#ea �M ��H"��b� �s �udBJ~ �G"e-��w � € eMll� tro�  !� 6�a��� J�W a�a�s?^N 1�^� � ro-6*� . * I�( w )% N%�>W,�u� d!�_ M�I4k#I��6 mpJ$DrosophilaE��u!( G0A�XIP�Ginver pla�*pI2�)u�euQ�c w � adja� to�-eg!�of�!iromg#:� � � ta�tq�v+a�-mott�$4!7�)�m��is���eSD� H random in)%of w #6U n sp�O�P9�))$breakpoint�8+A0, upper panel�I�  autonoV E�݌6� establish�suGsK@� �i��KA#� ye�A3 �Q6�%'��  nstitu%�F� �����onH!��%[�� . Ge G�s�,a>Z >: of�@<�t��E��W$A;miso�Htnhr rs E (AY ) so�) ors Su.oAri!7UliAv�:)* dT2r��r�ig*'ly �!�n.��Nant��fup�b!r �de�color� �*"�\U�e� [2"�[a2|Gu�J��~U�=�!�d�I9I� A�=A re՟ mE1� eIa����0Z co�$� � .g)i�/11H"�#� ��ef� exer!tb�.�-sB"2%3�*�'��!fp0n�,ErefpJ ,took advanta�KWC _* ( � if>6)�%&C�V2e9-a�F da��� zygo�'wCV�A j��s��l�!����S1A)�1C��W*#L$19 loss-of5]aW|,morph� f2 w* )��� te��!]�� x�3XX�.�to qu�fd"Edengtha��N][2��zd�|�8i�<27142! ( 74�Ptot� *� Med��b�P���se ��)��liv�?!xe?1�K� Am�� .S1Q�'bea�d�J robus�9����!�.� e wsey J"��QA�"W � s 1B ��J..B��x6$�B�wid�\ w1118 /�'�7 weak� ��O����A/m��C ��B . No�>)F1%� /Y m�Y deriL"+ cros�Z{� K.� v�)ekd>�U�� >�!m.�2*a�!�m4h/w*A}�us fe �.y�* bear!�2�  ci9��-u� &�Sq bal�?B�S( S1B�01DE){1F4Jand��r�bi&5oX8pp�BG 6H 6�/e1�xw*!<i m �,i_MZ�A�A�g~T, dele�rs spanW %\du��Δ� B�u%��-�2]E� 1D �}�*En�JB�G ��@�Gre�)��>�S35 them ( 26�Jm+no1M �L4N��B'wQ nduvs�%�m :�� A��* ���>*9c"��B���x%����c "�ip. ^uPB�G!L�nd2�A�,now+��a8/� %US(2��gSa�QE���*� on2��"n7)!�e f�#decW\to��st2�ir2$�̓.F�` �c�]��&�  a:�a}n �'9?rib> ,op�'V� [ 3,�� !x!�r�2 �)/ m�ee�2!�a���z ROa%o�;1(esMGsS42His�:I_�O�=�� q�f� even� K��#���)�lU�6�p). NwP�V!ces�e5+!yL�* A��$(�5"� F a fe?YA\aZsha�xP#�*� s6faAa4-�A �"�K%{ten�Y��?r�:8Wo�RISbv� ,V�T�; / jE�5 juxtapo��U"� SbY��^ent04>��sN_ng!Jmosaic f�Ex_s�+(U)�U al bristl�[Fig 2B� _9����L�stock��bu�=� [25]&fS5��las2P�5cTSb:�s�� grapZOi; �&� �i}!e�*~l�d� (�m� �2BS7&�)T5B� 2!0� su�`ͱ)�P�]!�}/2W8��0EÕ�E>, beyR(�5�#�>+,��&��ony� &��6��(R��h�e�:Z*��mq�!�by.�is very�un /��o"� ]Y�A��7p�1]�H�weYn@�i�[minisag�e��X-s�.dn���V!.`�a"�� n�V"�\A�8co�JoYG���F*�%�. Tg�('e���or�3%6�l+�&Aup��p�I^C}xe�%Bz+:�&��& d!v�i����Uw*���@�7F��a*&QnAF!V� ���rm�a�eaLMQ.C �&�4ss�6:�x1�.{)�1x�Q tra-�al >(d`C1jor61 "u ��26@'�B�de-�5s"� ��l�D�]^(je*i�>d tel4Eso��eB�[2J!2A�G� A� �sf !dIv��n%��!ca���'� ��l (�ut%� 0 ��Eis'b�� a�>!*d6 .�orR��b%0EO s 2C�iFe�S4�"/6(MjYg�!wB�*@��2�iny�) !��>8� �it&k,�%oc*:�Q�%�� =�.y� �$���&�_2> l F��@�&Y~�7*�� ���_��-? emi-�� ve RT-PCR!Z�%ex�1ed)VadultD;d�-T6 amoun�B�-l"��dm]b;e$ �rim�*�3 3" ��I5.� �A�{y.U' spliV !�un�"JE� 3� 6 AI�: �o �eH� �*��while 0�!m�Z�e{he6�" v�4� �)�)m95A� 3wc11 laH1�_2%!7 *$ ��w�  )8ed�ow.z�N-�r��r_�.^� )]o�8�Ns�(vO9Նl�_q*�� �Wor wA]i^7���%J))%eM"%7&"�d5u Aq FK Ve�5��b%�5@6%��(6C�\�j9�B>6��ih z6w*/�e��U�]"�lb�.�a�O�dB� '�5t�N~%i6�p ��(��g�"�5�� �Bvj�T�2*G&$��i>!��� "�5ma�Jl%��ffly�wU&YK�iRh�X=~>���Ic�,in5H-�.�.�C� �1� �ipumilio�Wum�e$smaug ( smZAR�"bd��~J+ gJ �u3}( S5A��jN�b&�.��BU=JV�P,-T� �'l*r� e? =h56#M��G-�t�F.�W��,%�2#A�.�B�*�!dM�b�  any {M�ۅD�P�3i3�/b�0�������e����s]A ca5ra�i �e�lng6�&w<2�*=�%0/ic��be*6� �o� fluorut("$itu hybrid�( FISHE��U�n polyte2p��� moni%s�.eiq �-i*im��.��2� W ,. PNq �0a� 4"�I2|of.� sa�=g}T��-T@g+�pliu��\q-BG�Uo !te� repe� roundeLDNAu�A��X9#�gE..�wBW�k=n!�'� vpr�5EJaS� tool%�"�@%H] e �J�9*��%�proA96�B"�P4�C!%rep��Wi[Um&%� R��o��urn'0a� a�py�c4a1v�)�A��1%)kE�2i���1�%N]�4"R qA-&c�A��A��Q2 hsp70O�E^h*p�'A��@aK9�)�ea2H.:a wa>��("B ?E s ga�: ]�n! ��� faKto 2Gb�"w.�Ey�I�1�#>6Dca�u�4�WEYed)�( S�Drrowh�9{v,iskA>� �OgD+h),.�-�� +& J%��: %9�9ey%�)B�BP]Q)P��(�E���Figs 3�3^5 �R2U "] �"/�!��n! ∆wi$6� �2�,e+opA�A�"�6�.�5!? d.�,)V� %E!�$a+U-.(� �E-i�:,!��vic�N�=: s 3E%v31-K�(�$b� ��%��)�2�aW ���F]r .a� ���&��wr�@.b�*.� t��L�w��F� �.A�R��I�c�0o�&~�,�� �B0 ,22 /�aJ5comG!aA��3"� "re*wu�>Jn-� +���lo2m<�� )EC����cng\ !�",a�2`.� ��F�^.� & to r@a�;�d� B�:-B&��|� *�-�o�s�z%�*�%��,���,T9� �%�Yu�( �J!E�e�9� �"�ui=�9a{*m;<f%66/#&�5switch (M�wP.�5�I6�* f,.�?=l� , mi�:!�rn;lyiFin��� nM:1�;�*j� �}�6!,Z_8n�H C��Z"?%QŢ ( u�6l, �3�t�{[6 , 26*���aK2� ]�1�U77 ���w�'�(�m��5o !+B�-%�.���*�=fNI��sti�-@*,2���]M��t�0meiK#� GF1I�y>�Y�W*�!�*"X' to l+�Ke -g 36Pt*�6��2�-YF27 gen���4~*6$I�r(w#9����H���WP�" inue0ho}i�d@ ��B���(sAMof�%3.!�fi�/%@�(w�%�bl�yA-);e !� F1 mŰ;/�9g4Y2#"$(9eU��f!B2�; �.�eyE� w:�M�o&l�_a�:+&�5BCQ��Rc�� iF�!�1�=ta� is w�Q"%!�#��E �:�vP�2A�he!h!#��>mit+M� germY%�9� F2� i  igA�y2�  *�  %:�!B� �Us9�a!_�HF1� E.�f!��to�e�%Y�^F`�4�*g&��!;s�U�zg l.K��}|P�� ����iw�� �s 4" 6" A "!EF2 �q�a��x�3&� :�eE�Hm�-.`'Alsl uish%p%�p0<al ( P )t���E� 4FF!%Z*�+&�r B =��>A'B�in1 -��*�%s:;aC( S6C�A�:.*O,d%�-�:F�<�)v)�Z()���>:*!�� /��n��n7Q�[� eka����+ �A�F�:d1ɠupaFA�F5Ix 4�,4* f,>F!B� !Ai�0B�-��F�-�!�B�-,*O$��� A�N�2��"�)J$ F�+J�RE zea4k ne g�N (`s�e��� s�Jw�n�\2�0�Ou �.H23Ise,&;H>�.&%�a���%/!w**q �Y�~�g:&:Y)$)��+ainV#V:0.�%�>j�.->0%��"�Lmei:�)-JE��> de� �1eTs .�l,�.*� %:|n.)h512&�3�5e��4�v� �;%F2����Fb�� ��� a�D:re�jX<,V$~W%9D�!! Zʜ�P�$-�POqu T"[+�m5(�de�A*mem���+Z he9,�II.XB�Mb�ferF&�a�)�A�\� phys�|�"of.L&� ��orB_a *�>�WJ�!N>�2�"�:�F� �%�I{nm&9�qa��8 �$M j%-�m�MJ� on��f�3esBeasMMU- ��d brXg( b�2t*� �% &�E&X�glo'U!j a��BClmma�,]Vja opp��. �Jal�r�K,�-9zonI�r"2{QTEdo�F'�j��� �'-1s �b&.:f A��"� %��"�&QA�a���kI��Ga�m��2 Oc +(?��W)a�)�!� �N��|%.% �s�1g%�he1�1�X�S erya�id�s�a�E � >&_�QZU\�!~�;�EYQs [H. PN�J#%�Fc1 <��\%�u !f!.�%�9<�6B}_M!j21l�0b,a:�.}u U!���oQ5o�+��a�"&�7A�* $�<Sengag_�K.0R%. U�� �$uC��t ��2 �c�ea�:c"��D�5 '!�8a�>=K&O+A�!+�� uF1�#�o* y� � h.�6*�F8$l�Bt�J&�H!g�V�is2Q)��BgeV��.�=�� ��i��p�a��D�$} "�&m�RSR� ~s 0madD]!� /Y"O 7.��.�a�)`=EJ��6uynt �f[3�L pGi~ E$nS���e�a�� �Q�A':EL&"i�Q�casv�v�� & Qr�6on fa7�*& 6;K��d � eggs`)�Ni�]�%.�A�ey+'%/�#p^Cq���1T i��m�5eg�82� y]?�!a�`c*�uf�5i%�V}�S)oic2'X 5"��iIO� ��?!��p��lethal m6�5K81�>.\gyn�Q gyn3d@ "A�vG��"C�Oe���� =�Ne2�:�'ask�^ at h�����0y� �CB�-b;A�y>����!h�;3!�>rLs�(J42,6 6;�i��\ . If��male-v Xn��:��.��j*�p�&�K;�6}� IA�!dN^m%61<F1M0U�5� E�i�2�-uJ� !�.��~6B�#if.pqX5,*F .t � ;�sJ��A� ><Ms-�bn���[U: 5�v0a��M62��A2�a�5Ѥ5j!�m�e1�, �V��� f�":�>:e�s 5�"S7��9�&�?onF��M�"�!F1U�� a�1#���R�J�5=!��"�3�.7i�'�-B�eU̡;*�)g�ul l�Hilx&�>=�s d�!�93�� ��1�� 1 -5. A�� *�� s .�:!�y#ff�Nq|,�uZn2T*@ >�aY� l r F=�8 \yA!'� �*N%R >��xm�*�.K>b.��~�LabT�.E�>d8"e LTmp.3<*�u��.G�5ALir��%d��q�rdL e]�T-59+!�I�, self- ��!'Kdert]>��i}�"g!6.� make�3a grea;~�Es�i��an.�ng��3R fI  0a�%1of 0Y/�A� "0!. ,� �4 �p ��,�t>fam Y�*m- �V1� 8E6� ( S7� D�1W���ol��|I�spd-EًJ���!R)-6�pi:5( armia�iwaub�(sp8�2�ago�H s 3dcr�4r2dbiy ��GN* >�ng=�w*����f � N�r�E 6�!9� !�!ym � ago1�dcr�Q:B�~�1Me�o!�!��4Sl�f6H)^pat>[6�R$���!���$�]h�pseud%d�re�R!e�%�s c1�;�N`1byI_%decoyE#NR�^[�}�EA'�hrai�!7 s ab� &� �$of.�EFRac�U‘�gesJ83&tt��)���<bo~��/--�)�t�mte�MIX9t}g.e�$��KAs �!��?&$ ��c�Ma.|P"c49]I. �Jm%(� �� %F��Ks}.&4"��Zv*"�2!E8���s�@�Aces�Q machin�@nu�a�* �it Aun Be>��?n b��vg a)35|-:8�!s dnmt�an!�*PMȤe@fer�( RdMT ) �rqr!/�0 ]"E 6`2���'[3�]r~$�s�* 5FA ��':�[� ��2�W�}� *� f d+>;MAPT%j!⽅� [ �d�<|S��.���^e�I��!0�!�efs*Ef�F ,�A���F-�Gof!��S�$aR&Gl nb�Y� &��iy�"��� .. }��%�v�� w���!igh�put u+AG"e.�2PQ*+F)��enricWf�?i� �=lar�4Malpighian tub6f,aDabundTU�8 , eʭl -��� E�2�.��F�P/#+ aM--zQ�8 J3I�T ��9�:V� sey%#�"���Ik �D<4'a��(2�Me�As ��1�.�� 2�.��a�5���8 �H fR*%�K4tlt�tl�RV�up&rY ��Dfin%��c�g �@ITt�MR�@5�!�?N�/%�Y�5Qal�>uMy)�Mdis"~ FA e�2h,%�:_e>�!&_u�%4�?A�F�.ri�|9b *�����rL�� gz  ��~tlI�q6<.�in2h 6)� � !m> A*�vq��}��&) = h�:� w'�azaN��a~{'i�6��F�#w6-F�d+.�z)�2 !2�T� z}+&^I��݋�ABe�PZE|M� .�Mu^�:�-�A�)�Ţc&�;Er�MMz��,&�ZG&��.��6�a��j�*a*ŀ#%D %#Y�$-m �Q�M�ene��d�m� �� !@ d . & %&l'decQ�� ? iK"�m�!V�f. h�is�_� *� ��l�U%��� )E��5f�c.� -"_iVk�!!�dQ&Ov�.8]� fA`!1 azoa� y>a�������mpat� � |A%ts.� �n� 3"A"�`ypA��d�j&�{|g�u"y( [3`"�jH"�\�sa ��] [UasawIbA�act�*� 2��/|n�^�W , fe�}s4M"6'�n!��Nx ��[o"�b �q�-%�/NA!��4teg�@�]TY�N�AQ�l6Hu'XU�� �Fe ^�0�.�;�% or1�eT��L�o�k"g�+s [�*�=RN*Mi� !6el�+"�R��ki�@A�&1' [10].�Qnaځt� >:�IX)�� near�S5+, oozrCl��eӑ&ZNng!��ng�re�!omaMe1Gi�T!r� &u�� .d�u�q��.,!T$ �F}oInd)��v UJ e&ыmanneI�Dr�6��* begi�Y!W��i�A��!� stim��X�(�A�;R7-@/Uemplo5wiU|rra}�to up-m@>V!�.�1��,!�as�:-t^)3ټd(��"co �Z�od�`�a�2s"[37Y�eA�!*7��!pla�v�v�7�AR>�U��7��k�;��on"[`�F� ��Wq)� ZIer�C�� v* 4� !��B�uwa���6�'� .�:isj�:�uAci� cess�Q&�7o�%�4! ��i���x��( cw#��lK /a]1N� �pM` &���vEs.Z>�%#)�"�.� VUul"l�%+e��)�! spur�!C��R�x��4!dr�, A��-unpredl�7ACG]VWol��k�Y�(ete&�x�C�r�L �!�E.C%% Y�!G"���A&W�bHhaK$i�ujogramm��$bo�RG<�2w �C#2&~SI�]" �� �� J� z7 &�1�-!(fG"�&�!�EW E�zn *� � "�R�z&� ��La.�i�":��Uٌbe'lj$%>_��A]}�,��>D?:]"= &�G�ai ��.��LeoAEHG� L"�'6*L� -"�X�~V��)���a +�h���aU�sen�5ao�=ւ>![_duple��!1 y 1 P�o.(�u�jmo' 2  [46� j��a�de~.f e�yŒ�5&)I{81��{Rx �H,L�Gt�'*a�v� ErEpA�� &� <�:A�s .�9ir.T [4j* g V�yos�n.r� I�a��$ 64[(t9be&O+�+ :11_}(&�A�%;@a"�G) �A�.3�~A�%96�"3�m��do�$�O���1:� w* n���yp"i��:s�2!�m�)A�>A*X��YA[��6��.#2t����AK M�B.f@��Xd%8`K keAQa�m�a&i4E�2VA��J�.�]ZP6M�є F�%�aKg�����M,���6%%\��XEUa�6!L&~ ��. NK[ thel� , m�!�9)f���6J�a�*~zJ|z"aQ� 1�_ :n�� et��he.��`8N]zo!uI0. F� �=<a��+� t 20°�oK12 Med��( US BiQF�5"Un%�AwO{�+{��iÔ>oD$Blo/ogt� Szeu��DGRC S+aCe�Com9G m�!1V��f.�&e!&bRS1i� �p E.e�&a5%]:�s�A�3�PT�% R1 ) -21;gyn-3�!.�' 1/TM�"Sb /Ser1 �%2t r�5gif DGMia Lev�N k m4h;ET0CyORoi/Sco—  PrDriS7#Ser—& f3−101-.zdont@by pGu!� Reu� s 39C1a#118E-10�w&�\6�i2� Sarah Elg� > pcn1 P{PZ}AGO104845/CyO—ry50�Lr2d21/CyGFP—aubHN2 #@y1 w67c23;P{EPgy2EH2EY04479/ Cy—Armi% ser , FLru1 st1 spn-E1 e1 ca.�!�—Dcr6c—H}$ScratchP1\E�.�dV⁄ -�er.o2)�0aria Pia Bozza�PLaura F1o )� Ago2ŗ, Dcr !  , *%06843 aubQC4%* ��i�`HValerio Orlando Lab}abP-819 A4-4 Be�;Steph� Rons��y lab�Q��k Lyko�q��e D*! Δ99�A& �ey"�yb7ayO$per��iit����cea)IT#��*��rrLeDT��as� ���cpE1E�Q �^}v� u� �*���� phot� p�� an Oy�us SZ6Ater>�roscop!F�P&�ftub� e]�!SbV�Ts!�� �F� dorsa*�f�a�TL"20"<avex�_�Sb2j�,��� e�j�&SI"WT&�e�>�f�. Cyt�Rpr��R��N �i�u�*���%b�42]�$P ( CaSpeR�-3�m�8onjA���� %L�KJ*� �Pgɢ!'Rla tf� �(!&�QS� eV signa;)�c1I0< Leica DM 4000B 'I+( �T"X�k E�20n_�*5M��S�!E�, �7TRIzo��a��fo� manu�ur�M�/Inv���>�n endgCtocol�mi����2 |MuLV ��r�"�4%Ap��B� stem��� mi-QOtm��``y� ^"�2`m< "�,�Y ��ift�.sixth ex�"-@egen 2for˻d, 5’- CTATAGGTCATATCTTGT ATTGGCAC-�`�R` se�`P- CGTGGGTGCCCAGTGTCC-Oa���1�&$eters: den6� 2A� 94°C�4A20 cyc�of 30”.*53 ;2� t 72��=�6�A��ɡ!��tm�e�!��)gar/.tropho��&�5im��6ubE�e(!,ChemiDoc XRS ::EBioRadi%he Act5C�A)�Ias loa�*�rolY2&(�.�CCTCGT%�GGAATGG)�, lQ�,%!�!�E$TACAGATCCT1�I���!>%�=�!Ye��#-X:Q!m:P%i6%� u�8iRNeasy Mini Ki8|I&"�(El��Cleanup+( QC�n�{tep!��%'� I100bpered-end�qr!���at IGA-4a HiSeq2000TM  . L�p_E% ����!I*6��ma���m�BDGP Re�Fe ��)�TopHa ~4PUBMED 1928944!w�! defa�dy}�F�dNFd-�a@�Sg�% ]e��5 FlyB��5 .��NBA����Ŏ :Y?�t,�S�sg ߂s!D KiloY�aၰ Per Mill?fr+-1( FPKM%H esti�`�!CuffC�c(12043646 c�=��1qT$!�ȲdY trim� Ś�l14![custom�yip��R"�o/-^ �v�uE�Bowti!�9� 6117�a�I'�N}?ſ=�����s20��E�!�w| &x  3hr�x&dk� o ���$�/50��uttnle ju�+� �� yjI.�rox%�lyaT–Y�decorA&a%v6|$1_i p�a�,&%AsЋ��5 mM NaC8@,5% Texas Red$J�d�|OM"H�PY]Q�1��μtN&A�6�I ��"%8(sey.�l:,s .P�Hemat�2mosquito�Oicks av�B���gvF"*3� e>ib�_s A�p�olyEA0coa�0!Z���cas$A<�aEzinc6�t��%�RM�sB�_tbiXIfew�>">c" DmidgutAU�|� , Bol��y�12-K��zQz�T)=R��� %��vkallikr��.)��k�Ӆ�}xqe��)�s�.�St"�si0let"� {�HO)j� romb:U˜vop�:%/"By����M'O HEK293 IpU�to ���c!. U�� amidM:� 6���smo�onab)riA>�w\�de"�Tat�O~��K�1Laa��A�etiA*YxI�!����reZ2o���"�a7u���$) �rd.>a4Gexosite- catai6EEa+Anc�an�  � lockL'of!\ t ag+U3, fibr�Ho��Inclot-��U�%���.*]~we&1*U9�a!Ar5FXIs��߇ng FIX A��&�.8�]U�}9A-�7ar&TP?cnh1q� itm�A��/ tactd'�5>�� abro�XH$thepsin G-�0n9J� �a_.���A%� s q�-�:dx.C�Ti�� F7 P�6II o� TFPI� F|W2� )�r�� art(4oc�HA%�votgge�by FeClq��G�\ blee� Az���m�s�� e!med�� S �v#0� al��"$*�[�3��D2�9��#A���#in keep)�e��.���Qow.�lX�K� tonu��J[a�u.�s �7a�u�c�!�!� a bl�m^��R riti�j�* �yegg2@D���gA�%}x�e^��Rnti�� ���>m��. 6 �Kc��A re�ict �fee�t�������-��%iSAʖ�2��~g)N}&.$ � MW�L, Kaz��Serpia�Cu���Trye�u-Like3�IL ) -R&�4�&�.�, a��o�!��Q[�k*�&��� |8R)�S�Sls2g� �6�Ge>�* 2� anifNaTGisA�>�4��(-"��K*a AqM$e��!��K�S6m8l2� .!a�:�;;��1a�!Jend!Vl\g !6p�$( �L� � ��;� �d&� �M��V�::�-^� ��a� -suc�R9UAcc��L� 0�eA!,^�Orn�0dorus moubatt��oin ) [11�Haema�AaliZ ngic*�!�W  T�0oma brasilienA�(. V��Dipetal}�ma �] 03]%�Rhodni:" lixu�r (4�+ a&Ԣ���YsqT memb��� '�. 5N,��Ia� ��Qԁ� -�o��A�Ѱ[15A,8]�Tle rhi�� in-2 �0Rhipicephalus%P)ko�֍�����M� rw+E�n���-�� �z�)ick:y�mp� ��� ���geC� � Y6$ . nd( F ) V!U[d�& �"�$A��v�� 5��,� anonŲm�,,p �De�<��(� vs(te�A5�6c�du�)%@*m�1F4� 6 &2uC7��-��r��Y#?an�$�&l [��Fu�%� �-i �"/of=8ge��ulBin����w2�in�_ &��*�em9n"��im3;� 2iwo' a��:/Es��A*M�=|�W�%���@�@ α-U~ , γ.�PPACKc8he-Pro-Arg-chlo?Tthylke�� ) 9�A���T���8 ( Essex JM , Vt>.��� FXaY,� pre-}�_ERel.L.� ( South B� , IN� IX���B�r�!nt �Go��-f_�+��$Wyeth-Pfiz�0New York , NY[APTb STA- Au�E!f%HNeo�b tine CI P����CmDia<�8a Stago ( Asnie��*c�S2238 ( H-D-phenylalanyl-L-pipecoly a'�ine-p-njani�dihyd4,lorid!�, S2366�(-pyroglutam Prop RM >�S2302 �L� � � �fD%�6� C�$x-Diapharm�e Westds", O_CM5* chip !<r1i�f�( BIAc��)�"��%� GE-Ho�care-P�ci�Pis�81c , NJE3(��2q~n]~R&D S/Minneap����I�E�kneu�il��]}hE&� G�&/ Inno�= DQsulphA�(( DS ) 500K�ma� Sigma Co 8�S] Loui�O% CornFB  ( CTY�J,Kerafast IncNBo���3.�%d�)��m �Kp%�6M paid~.�/�nteK ��Yp��� {-"~֥v�rtici5R�/ an IԖm�$Review Boaf�IR�Aac�v���vun��3��d“Col��nnd DiӢ��(�&d �0 %$I�y Don( A� In Va�UseL� � �v&ig�:؁�ct subzs `a"�3�q�d �_45CFR46e�E:b�A ll NIH gu��ԏ�It`[(��� 99-CC-016j�. =A2�!BlD�!t���4�7)on#(c�p9sy�v� usan Leit3H,^&z#�]l�m�a�!�&�al­�&�f�,�=��.]Gx comm hXC !JEvaluN of A�!�� E!vFCal��|�uK4Rio de Janeiro��AUAP-UFR����=*�)y�theorA4al ma�9 1399 �35 da � a pI�4 . 41�lu�-Xg��a!�!�:/��� ��y< kidL�293-F1De !5�{�!�"< yA�NCI-Fre�+ck� , M�Fm�up��> AGco�Af� 72 hou�sb ifug�/00 rp�i�froze�T�EV-��B9V knS%��500�m30 mL u� n ultrafi%��J#Millip� , Bili,c}a Ƀ�inu�sti�8�40 mP��es��Et10-kDaBs�ra�9(s)-Dc� ��))n>mov�!x l� dial�&i"20!Tris-H!0�#5 "'!(pH 8 . 0 bu# ( TB� -�am�!!Xr&�a S!�dex G75!� umn $[��!��asa�R _. �%AXT2Nt 1mL/m�n��fO^�U��? of K&���zbeE)� p���# 5% ac�itrilC AC& ��d![� 9-��'ci�T�ri��Wi�� ( TF� %m%H aFH �rse-pN�(HPLC ( VydaT�Carpentee/, CR �<(�qui5qin�5%/zxnm -nm �#00%I,� H in 1e�ʍ�Uo\)�!Q{PBS2 ��q�) =t�V1F84× NuPAGE lith�3dodecylXfW-�MIX 10× redu"�j�gaI�to a-Bis-a 4%!�12% g[�E�2- ( N-mG���o�tha�ul*�� ( MEa(run�� �( I.Z,u�� s��Coo�� ie b^� R-25!m��t`��es spom�  W�Xs Nano=�ty��(,�Xfor���e ; -�des�Pd on-� U bSymmen 0C18 180 μm X�[��5tra� e-��%a�S���/yp�ly 7 .B�!!�a|LC %&� by �BEH 130 �0� ��"7�c �f le�ng�����)I a�1ar��d2h��a&���a�L��K��O1%��/�1��ectrosp�C��em��s�"ra��xrA�q�Q-TofD, drupole/o{�gUi�ler�����liE� Voo-j�fa-!% NQcapill;�ra*2-�ESI!���!�d��ss-to-'ge %� ( m/zI,40A;,5�C%���1  �d&�g%w�� 2xE�ces �4�L-�a 6�X@\a� �1 �!l�(a��� ( TI�Qkm)O'��F*�V?A���|� lecu��G�%��ex�#!�*�&~7�;�HI��E�'s LockSa7™j�. Data.�V S/MS.��9�o_�ecurs'�-�n)�*f  W3 4(Ea "` of 55�!�A4 a 2window um6]4i~)E�sR0e r �MT� le MS�ve�@���"�$di�!� ( CI� G��Z"�)aarg�G�� V gA&ty � of� ps�\� ol 0.��5d"�=i� nd 9a�e'A8@I-p"�-� . All da�Uta were processed using the ProteinLynx Global server ( version 2 . 5 , Waters ) . TheOJ�automatically lock mass correctedl@m/z scale of both\MS and MS/MS data utilizX�Nlspray reference ion . A sequ�Fsimilarity search to Boophilin from Rhipicephalus microplus was perform5p), BLAST . Som%A!-vs)Xsel ��$aligned by�8ClustalX softwa)� gram: R .�8( gi 74935652 ,� -H2; 8442092PG2 ) , D . variabilis L 194246037"0H . longicorn#21703482#�I .!�pu!J G(240990666 )-�six letE derive)_!�(first three$ofgenusg^)%�,species name u4phylogenetic t_w2�wiQO�>ega package ( Kumar et al . 2004 ) after 10 , 000 bootstraps wi G0neighbor joinA� ( NJ;$lgorithm ,mF0poisson model�4pairwise deletI�a1Q�s�,nonreduntantcR )U{a base.!NaLal Cen�Xfor Biotechnology Infora�onMCBI� re repres7E�.�follow f6gi| ac�-K0number . aPTT�PTI�evaluaa�hon a STart 4 stagocoagulome� ( Diagnos�$S8 , Parsippany ,)^P. Freeze-dried , citr`, n�4l human plasmaEdsuspended in ultra-pure way. For��,:$( 50 μL )EincubiE1 μMy�H or PBS ( control )m8appropriate cuvaI� plac �!R2 !�5 minut-t 37°CI�n ,�0of pre-warmed �reageE&STA PTT;FT �ad!a��x3 more}. CaCl29 at 25 mM2Gto!�rt�cA�s=TPT�R=R��:10)эoPT�-2NEOA2tine CI ��z>. Time%7 clot mY�xrecor!e in duplicA.a�seip:Qchrom��ic subsE� hydrolys�nS2238j�A,ombin; S2366 FXIa02,Kallikrein )��a�,rmomax ELISA�`at�ad��Molec��< Devices , Menloa�k , CA�7Ps described [23–26]�ull1Z� dilu�inE�reI)T buffer , TBS-BSA ( 10A`Triu00 . 15 M NaCl�� . 3% * , pH 7 . ��. R S q9\Tin 96-well flat-bottomAGa_( C��ng 3596; , NYm�, total volum�j2MG@. To characterize�i�z �of�"A�t!�bi�/&{!� ,5 � star!8bya�ia]UIor-�( 2��a� to a mixt�၌aɝ�genzyme (2�y)�Pinhibitor ( 0–640 nU�i6)60�%8at room temperayB��D�f1 hou�.�y ssayAM to d�ma��typ%z ��r�impetit^or�(c�; 3�128 �a�ե�BX12� !^�x 0 , !�75nN����:�U (E�2)ior)� 5 vM2%M�s In all ki (measurementaKc���taken!den  that�p# lessn 20%��zedA�(he linear p���Lprogr6�*� �_2�(One hundreda�2� !�6 1��W !�29�befK ad&� !`�spondu &� ,>�3��4��8��H& ��Tfluores�ZR�estim�&:lop��result*l��fijarb[ry`ce units�|, sec , χ2 >�95��� (- ծ�^��30�g H� 4Nse-�?$dard error1<��cal� �΁N*���9FceAoreZas a fun�+im:s8if�E �8Magellan™ –�QAna� �@( Tecan group Ltd�obYd=�*� %�jabs�r!�consideA�as�%%# a�rem E�� activ d.���. � 8esT%eofzorigi��6ed� � �� source� 2�Ov�;r�4:AR�|01a�� 4α-chymotrypsi 2O �1 . 68�{9!���9�purcha eMSigma; ft300 5!�:2(Promega; FXa�3 cJ.$EMD Biosci!��, MadiH, W�HIIJ �JIHaematicA| ies� ;�� �04b�DFitzgerald Industr Jter al; elas.3-eJ�E+in!,ducts; cathe%�G ( 6.� � S , uP8!N9�!�t018 �er�&�Innov9 s; maI �=�%�,R&D Systems;q!�3 (Q/�,Merck;�� ing-gradeE7Y�f� Roch�A#0:�r5j,6�!Q��UHep� t"@,�+!*f01%�$ton X-100;nA��,\ub,!�sFE�q�-H�pH 8 . C15.m�3Mh,%�Z{;�]AZOry)�vO2�N5N� iA,.D!�W�n, �Fd6j2Nj�;fJ!_J mM1���)^1?)�a:�a*UmMZ��B�;for2�VO�,N�1sUg�1 I� Suc-Ala(Pro-Val-AMC~u�ͥi�#c-Asp4Arg4UM4*űBoc-Glng2/�JE�a5!;(��u;Phe-SerB;�O,�Leu�Tyr�q�( Bachem��"9��n Du�(B@�tmethylsulfonyl-D-cyclohexylalaGly�ace�!�Izq�I3�/!J}( Ameri�*��r� E>��in"� J� �3�R\ , ��� in a��aninite Ma+p2 re>� $, Switzerl�) 36� excit�P%450� emis9$wavelengthL a cut-off43D. t-tes1 %!�i FX � a p �6 aD05t �!* Dly q� nt� surface! smon$ ona ( SP}.� �Pcar�ouq!giinstru�A�iac , Uppsal�Sweden,d � manufacKr’s M� s� repo[.( # S immo�z)�� an aQ-co� ng k� �a^carboxyi$/ dextraD CM� chip��0 %W 1-eZ-3- ( di D minoy_diimid� N-� xysuccin 9 inje�!�&�( 43g/m�A�m�.�4�j&O1r5pH �A:R" �� �bm!ed �$ M ethanolꁫ����_!j�m�:�of 30� 4 RUE��A���  . K�e"[ �.�by1Eng�� over�edqad�tact � of 90�ondyor6W�BX�VS12.Tatclow��3!�L/25���ruHBS-P1�8HEPESVi5%m�lP2," �j� Z -�!��Vlexes d� ciin�monHed%180A60.�re�!�lyue sensor �fregene��� a pul� 8M of 1�k 2 �U2M^B.�,2��PPACK&0㡟ed!y\*��W. Blank %� cellM�%a0ubti ��m�effect'!) gram��Af� 2��� ribu bulk%Yin�!�non!l��.�́��ށ�5|,individu�qss5� ( kaa kon W2( k�k��)I���Ay- .]gU&oa�of>���1:1langmuir�te�"[# 3BIA�io�( ����Val)�hen5�".}(equilibrium�6$DEK�z�age-squpres)=�nnot.z ly improvI�1Cto ��t�u�!oth��9A)Conl-dhso�Ik>3�'��s�Pn!p"��KD Inegligis��l�<��9&j�s$fer coeffi�~m��'(�}po�] trueA{A�k�P� a rich-p ( PRP��5wby�tm%phe!�s�Hc��-f3&pl$let donors�C!DTM/NIH�� od ba�:H9}z!'�rifug�#t 1��00 x g%1&�� wash%e (in Tyrode B�(� ��37��� 2 . Kd12 HCO>��4  2HPOM�' MgClA(!25� �)/glucos���  supplP apyrk Zx`4 U��EDT�J� : �a�P-�Q�01LgaKnd6�%-2�Hon�PAggreg%�!b*w2� in [)�6F ( 27��&�$$ >&%G stir�\M[]rpm3+&ag1�! ,1�].�r/&����$�dA�figur�)ge�.2O�ons����* urbi� ry��a Lumi-)�"�'$Chrono-Logs#p%�F�fnM%-� prep�I� �'��5 )� of f78%!� m in�q9�� 6k1�"1 @PEG!�3*30".#!`2w!d%u2V[25�Cl���m�8W �.s�*M�Aץ�fe%��#n��tubO:�AACof sol���&E2�Ŵ&� � "�%��>!'*a5*a e V�&S-�&�EirZ[ ��$!79t9&�tAl[%�#<"�.l�&<by end!a6�at�nm�0 A�0E.O �EI��A�25^ � r � 3 m*J6_��5%A�>T*M�iymBR�qW �)�,E� 0&'��A�. Absorb<at� nm%Zr)!�]""o �val��$e*� �a-%�albumi��bnFIXv| ( Bene,fU �(�MU���)hll��%,)ja��B�%�L( *5Y�!�-�E.}�.)�!+μMf 3 T$l"�-6�c2�(M%�QA *�%uJ�"opp�.^Laemmli.�bo61g �dithio� itol�&�. B2��s��8by 4%AF<12% NuPAGE ( MESi�Gel%�s��!���CooH $ie Blue R-�'. Fac�'XII%�!J�M�p+�WY6�na�1VI05i�7e�i�2���#��Wa�m���*�r.#N^(�A�R&�&����Z�! pre-2�1�� DS�(E�2 �d.MA�AM�n,�AS-B%��/�n\in\� 2$�"5a�@-� s� �eGiack�n>�$ �by�I 0me���recludz4uUCTIA�6* :.]��$N��-9Qn'g�TFPI ,%M��Q2��]J�"�Z'�T89�Mb&�B�+[30IZAQou���>!�g�BALB/c�.e anestheti�Si�)mus)"r z,$( 16 mg/kg:~ket�{0#m��#3b31!P'r�)comWcarotid �-ryIs� 7rough�&d�# cervil* inciF�rbl�eA^� inuously*� aE 5-VB Do� r 9probe |?.TS420 �3Transo�0�K thac�+/. Fift�+i�,%in��,�+ ob(�im��� �&3tail v�0%�s-L}���1�!� %� or vehicl�.�3�BTtus��m&��� pply|a pie�(filxpap1(1×2 mm ) s�.�� �% FeCl3&y o adven�.al"V%e1�35/�hexposur� �.2�!�rem+!@A-e v�9�&wL�sterile5saEL�3I|�>�*<or untilA�(plete occluE�( M64at least�8se@)-u� . S%>�of�8 I�Tukey^ a multiplA� mpar #pos>+. p ≤E�05!a%nMi� a����]�traveni�%�$phosphate- &)�(M�.�. ���R"� �CV� *��� al� m seg�M�e�.��mBZ�mer%in�mLN.F �6F4 saAJ -erly ho 5��ja *.";0dAj5�2mY�  hemoZRont},. No a�u�aL to blee�m���� 0. Fig 1A show�e �;%A�&4 �#e employ R$this study�elsew� [�21]}�2M�t\5 posi�bases:s�;<�;� �-H�7gi"8<��B �aJ:;�ru�=E�!~�7sev& K*z!�t0): <%�~e� � clad!�� orthologo���=Derma�p �:�<yalomma .�<�Ixob!41999�;���3 it i��=�an��a6:familya_"6�aex/)M�HEK293� �" )z"�� gel-��rɑand r!S se pe(  atogc1� a C18 c�6a�%�C%�R*� 9a�a'%�in�+f2�-���e' dolyG= v*of.�!. SDS-� 2&-q"at!Qmig�(�a single<=ml wt sl @ arge�8an&�d m"�8� o~ 14 kD�(%�i�c3ncy!�lik\duea�po��0n’ glycosyl)�ai�Asn�Ti!s 18 , 5Q?108%� 127 i�n'� 5=�,;E�a B ve s� , but�oc�Aw*��8(-Xaa-Ser/ThX-qu�=etNGlyc�*0 Ser�a�Ed�<deL( �!�174 he N-tu%8YA���$nal P |,X.Jfi, 2�id�� ._#%A2dig���=nd%�-a�t�*,� c/ag�" above 40%�f�!$peptia�" |s-x: FYFNTETGK , ACGAPERVSDFEGADFK%�tSGECETFVYGGCGGNDNNYESEEECELVCK k�i�te�9#a<�!� AXe�?y$ optimŜ�8ct�mS�,�&&; in Method�BE�E.5�%�sc7i or !zrA�!�amR���)H�)G��"�&a�<�&28&,&T��*0?�Mr� ^'=Cdo�A ot a��-6V.of�I�β-�'J'Y'P&"�)�!O ��{ ase-C�.sa�IQthX=f��ng� 9L& pro��PT�G�A ()�F�9@~er8l�%�GeyI#;A�A#!ara#8 _i�produ` h�AH Zl ( lZor�:g/PTp{2.{>i9�5�My�J-xaY2!�9.. D�8-r&^�8��d�o�A��B�S beha:"!��ss� non-!A�; ��1)�/%B%)w-a.  Ki 1�/)�2BHset%@!2�&e*B�&�_"� �� hod!�� "�:�$g 2C depicyp�.�!!�5&@"in"� s yielQ kD 11�.([!$3 x 106 M-A� s-1;S!� 3603�It ha�e�'��-G"�2�'eCnm"!� cata���mqex�  which � i�$3�)�= in� hysi� )&�+�5�s [32]��wo �F� n �%��E�"G *�E�2�-�9ed :�#�D �-1xEed2�#.�(. � :O�@?#"�&e.L&a�sH fasha�a�F�#u�M��O:4 h!-6�$]9!�a=�ly blun�bImoval!I��g�ng� imA&�)rol�Bt!`domc�� @�.�5�byY�)�alj"es�QnŻm+2�A]Z�.j�ddose-U��oc!�.�; how@ FQd�C"�"�@.�9. F�5�I|-"� coll&D-1� a:c abrog.��maximum �%�5� �M ��2r!XattenHGQ;-m�d�n�to$-vitro{�,C50��jG�=V-boA[A]an]%Ajon�2�I!#� �,�e��pa��9vB e6io? Iq �*� lim=-�=�> anti"G�!��doP �M->�[�`he5v.�CloB�A2O 8 as� �%N�as'e� � �4�i�mH�RDat}?5�s� >�E�>�.N aB�e!m��eb� �*pathwaDI�T play�8major��_B�in vivo�)�n�A ve t� �&�:-�E�s%�>ah��pheno�C[3Y��3�>�= aR�w2w. �Y�E�e� as VS7veloc ) /Vo (  0i�E� �Ia�>Ki ~ 82�i�3�fA AU>� �is mostemate')�B* %8 s '"�(d�11�8 '�a Next�0PR2��h&�;I�3��J��!ɡ�" -�/"�.�� F�kD��dB�= [6�a�o�oryET E,�?pmo �1:� a m Z� !�Xa�nd.!dis�] high /�}N�A2+ �-�Oi���C&!H*�?�+^e�:���o�/��=�� inflam��on2�G%�i4 &� Y��F�-Q���' �919�~. S�4prekali78!J\5�D&{ ly��N!;@.�at{ ��i��!S�[Hm��2~�U�~I� ��a.�-o!�&�)!�EMzl:�A�&/[3� S� al�m� ����i� vely-moduK*��+6�i"B 9, 27!�"a[3;(3d4Tli:s �"�J"A# �let��x�*�!�N4��lk+ casc1<-! mmunS0, b- �!�&)x@[3�GNeutr�� such� ��.EcipatR!e�+ ugh re��NET����V-rad d�zof� [38–4{ Ourr �BN��$1�Yt,�Ror\t2 $A-2� �4�NBo Bt iszMM*�  b��?t.N p#,�bWwer.e�2� _���v2�k5� h. �&d02�%�a�_( ~�KB(ter>W��"5�byBbSj] = ����2"Q ALm6Q is�n�JalA�el&�useful!��iX \/ Ro�eY� +�ASv�D,-*cs F- , 41��F5� Ŵ�&��$!�tTisA�~I�c2it�� KgBC �.f .�5mg9٩U"�did� �*A�c�>�Ht �.BY!#"~ 9N.��p�R��Q :�!4JtR"�8C2M�5B� Du&fee F� �D�`fluid-��e mouthA�$d�� � e'heUphalar!gp��(qm���Lcri�Vl f�epR��:::Qgpro]]�xinvol�3�VN&� �2�. M �"�:y��ŀb�disX&E#U�g�<s [1–1�hUsu��;7 eau�� -af-=y b[�.7toward= m#%g!�M6� 6�co�AsLC�5FX *.-ell ty�B.;5(orY��0s [6Im��fe�s=P9?�a�? foQYidgut�Chq/.�AZ"I\tE= alis uiciT!�2]%Einf� n_member�4T4Xoma &a�'�a+  ��A:A��[15!���T�i� %�A��Q E8&Y� Orni�or]o�Xtm� PV[1� �\(brasiliensiTn9-�,�\!#)o�( rq] lin-�\[19 !$Dipetaloga�$8�d Z3)KRhodniusar lixu�r (E M�!reV l �9s A�9�RiphiZ ^.�UdB �$&��� Yj�5��.i*@5�8 �6d{9&;��ql*�!�FVX[�5N".eM�V � E aQ anon� manner ,�pAposses�m(� �%loop [2�M� �9]"� demo@"silenG-geF>I�A>���]Y � gg w�]yc([)T��) ma  beMlaiD.bP!e2 -�db#%�!bs�_IW2w)�Y�1� umabl�Vt"�to tickQmosqui <rvi�[4�74 � unknown a�q�Y.Xvei�eluci� e��so$YIp�to&�,-s�( � ����6L .cf�"Z��n-�nv�_�� �small#�22&[ �a �JnMb*&ss�ndB�R!E2�:� �e�"�i�'6e50 pMIv� �8�7uLNA&5�BincongruTw��)�our-��e&3&�?A�U�re� �� al!8id�<��* "�,a1�*�BamH1 r�<=�clo� ?(VR10/20 vec�[2��/or�-t-� L#modT!��s"f6p#. N� the�D�H.��"�S�allee%O&, ver" h�KB,]a�p.�PTs�� �+��� ���� +F>�B �� achie� �1!�Zs�dEe. ��wA!C+. 4� �A�In], w�(s'[�S� � й�"p q�2!<fK9A�o! K� ( ��s���557es"S -A�å�Recep�( PAR-flea� to4')iE?�*c2} cytoz� ��W-� �F:"�"-E�.$��iof.&;C-"� a����.I�P�eN�P6@Bre�4s5�ety� �]a� �SI�plaus�&�� B� t� � toI�e-M�{ &x �?; �!�m+c2aRK >�G <�ry�f H�G"�)�2�%��vea�0� �'[��� ��:���wh/%C'a"�*�� *&an! � 9o�.�%% I=)�y�%a��6�a6K&� 8mechanisms: i )H�claC#a�rG#WEP6..�$���Aan�SbX ock$I2�qPvi%dir�evK cB��!QN� }!f�f��� >�%s�,. &N���C��EX9�e}*�%Glev(!)kve�b�i �e�!"��finsic"� , ( a@g>IX8N. "_�wM��i'XA%:$� m��6� ono �� [3�ji6S%Ee��.e *G �#�2 _ �!ơ�I�!�FX� .���72�%��eJ��P.�V�6&� . i�B�5r�"i2) �*�� Jj!�� �E:l"�A8!֩�-)�o!� a���poly-"2s���mpl�s!F.g�l��� n�G quo rmy�$cross-talk)cn")�a:� �.9a9O play�F�2�Q�[45K&�sI1"0-Gi�Ps+.�!V!=m)H[38:"Fe�"5eZ�byi� agonis" �[��2�l�$ak b���7��"�&���aMa"#�[37vlH� w��aQ�.�9 �hT?5I Gv� I�y�*�"5J��:�.�.�%�{$ H toge�He= s�F�terrup�)� -Y� ax!8:�2 �Ag, shif�z!�&�tNag ti-͛ nt p"�"�4 k, �%"v ya�|��i���.�, = )� :QM�. ' caus� nd�gl�"injur�� e<8�6~ sub-.>k-i�o"| |.r [4D�e*8+2�:� ���s ,] ssel*�unjj�XaU8&�J]!N�"Zq. B�[o! U�,Ew� �� �!"=�s -2!�I�" �!�m}8�+&C _D9iV36$&Y��Q�H"�( �Tv4 �BA�U'ach `��'7� ��propert22t %-vo"U7&� �gFPc.��%��whi�1#!��/a�� �re9,"^Hs�F�veI�W� �&� ^�I�\��2K f�A` �|�&�Sic�y�Y� �-%���a� *� weak�OA��Q��+?Obexpla� "�e1��yI����%D2�)/�! noUe�;aJ��uAnd�K7=>.:A#reg�-��o.ͨ%�e�)� A�bs�^H2f/2��s�S �,unbjXc;nd �]6.� ���ї ��Kon*�.�-N woul�su^Nv B- K�:�Ar ma�:paiaetra�r ularZowIq acid� Y lyso�*�@4�c Saliuu=��in'm"xv�`%��Q�F ��joFs��tonusm!�:attachl� [49–51]n^�K� ug@�U} e��%.d[52K|f >, m]"�nd�7 exis� 6�circui�_ac�!%�1wE9�Crm�UUc ion/ � QJ!�il(confer adap���soad� agb e#S>G�l"�*-�W.@��m!Oaan!k�_:ral�c$JF �CA�tu�R�B8tissu�r stron!��x�gA�is tur)>%�,C����4y� bsor ��YG�3 fens�wb�Y�%M� l archite�/his8by��a� �?6 �di�u�q*-�nd�o�2f7a hos�_�rrl1?dis��fl"�'� .3S��A���i��e� in m1vf]�is�*h�wD�xclil6~�H�f gover9aAn�@keM:Qb�Crp��*�-�g�sQ�a.6vh"`r)U c%�ofE*5'Ž �ler eS ic�Mtp�Q ��s� �U �gd�?���!�, � ynam9#�d2�qepi�� �7-vill��2g� a ran:+Biaos� healsyoQ� u �d" � deve�h;e SH-�$Explicit GNXlx%qMoU$ of E-)Tie�( SEGMEn�7{ �L"+y��! led �Ab�6i�61�=-�aif}�a�5�XM*$g�te a �3eteRALyei���u � � 7n �%���b#a� T!�odu�)�y ile�%�C-(�  w�!E�se%fof^Ailck-out/�a& ��1�W0 P�p�FY3y�J��U�*-��sm]s���pu�DveiT�P�Co�:A�On �, log/�oin7�] 3-ki�:�$TEN/PI3K ) ^�2Vq�E�l!s2�lm�$�� � , �� 8terocyte sloughA�ic isGbia-re�/�E`xQ��� la.:�a�d�}r% co c meta�iaa2 2�1�carvR ��t�>e.U�!lA��>�inb� . ��#qVum���iqu@Aalha5�hk!#a ~ 9�t{�U� �E� nu�h4/!Gfo�"Rsynergi�F �� e��Iensa#� be rqtB� i dB���*� K�Yinvas��a��[�����mpenviro�D�e�qJ�!)��-� onship!�'!���cDc=C %�J�4d��N��^^ W:X�st� � e*�EV>a [1�W�����a broad� �bZ=A�b��� a vie+:����.�G/� ?6���wo ,�sub b!�a �I��&ul6.at2�Q���!�!K rpla�5�NI1�4:li�w �8+�-A`thw.u�.n bec�v ur|to٢ǡ/)�&��, ure �<OQ8Y>�  �'O%�among�n� ����m�' J:.N �� !+Mv"� �pa��5}:aT/��Z y [2�necrot����ocolit(3 ���boweli�(,aH-=�d s�A s [5�&cm r ["W7!�� i]("2 a�q�/Y�"�u�;achA��" situ@�-^�g����&f!�"d� � �qL5J� 4c.?5�2:,? ificB(n�� �is . Giv^z�ˉ�� )�n-%;�� � '� e6oa�!�m�a&�. o� = tcngA��T�';�(hyp���z�"�ZV�������= As"� ofj2 T>5 H":7 <�- dNa�sim�2�& aB� �_�� )dif�edE :/!&�� � ."�-�\s& &� M-2� N�asm�%�Vha� !����3a�eyn g}� ej7i4Ia�!Mu�AT�#���n�incorpo>$���2��os&/� ��A�F�]��� "| a6� �ig� �epj�: e`aA[�P,�Sy�kaet���hWK�"xpl�Bw= l���%JI�w��Ko� [7]–[�are�' wor�Qly-u9E1�M.�um�<:pl-� two�e��M!\I�Mic%d�Qv�c-�� �a�j! Qi� 9�g"�2�growthEB*�[10�5-�&s- �EW�xa��6�e�i!d�.2� i1&�'m�1F!�&�[�-,�.�a t߁E�A�[16 �"� home"� �.CX�% dopt�� �D�����3Taca=ac=bin�^*X;)�se��oAK�u's�e%��AN�,al� y�+� ��u5&a� �!"7Ee��t�t�*�o.*)��PO �.tt< blo�utop J��Q�via a�Tm6�UE-�Figu #EUF�al feU�I��"�lo��)\6]jun�-�\���{ lu�ize%�!� �)� � ap&��m|-c�U��ar!���'sMputI�M22� "!�C�Z%�� ��1M�)�>r m��w���+� A��&x�9oR6�)�ge�'%dre�fr�%!+me42t�`�z �Av: �Z�out� �-5��ae�-; ABM:38 -�Z�F,!crVeN$!�ulefU!WmMAp�%�ol�!%ga�&� M�( �M*��CN�Fk2is�1their&��e�m2i\&!2�1� :"�2–[212�����s� &XO a 3-�>n�Mq�ԁTf��ga !DŽ!�ePai� ��j grids�n-laid o��Agrrr�@nr p΃)�d*�V%�R"� �g[ prim����}Xe56 a8q5�GEC!�@&A')�"m%6�9tem 2A�~��!�m��)�F��Ს� d "H � �,B�m� es/mon V&r A?g�2sR{�=���v-runu��i�Q�a��Efr22�N3\�� n�R� }!ife��:H�Qove�c� "K ifs.�ERdefineN�y�~AU��t Fgn20 �f��&T Y�3�4� Z�� s%%c�( L��r 3#>u �AI ,lin�JtoA��?�:��ir���re��e��{2�Q�=B21�r#!�"x��ed %T]e�!�"��o aVW�Uss-�e��on �WnTO�;neM7�o�;;�OBMP�OSoA�Hhog Hom� ( Hh β-(-n4#ayCKJBBxkq�  @A�5�|>KA� preh�7v�"!��VlvM�ed):uCnet� �a~%��see TS S1UM>S�OU8d�/�.i*_�~l�@ ^��n�!S trenx���"�s b(in � s S2;S S%n��� �W�#�v|<�� ; impB�k �E1A!�Q)&A�M$gia�$�T�SupYry(T�H%AAll.�52��� s shyls�2"B�&Texo+� U���� ��3�! vU ���h"��>{_s%�!&�� s�%Io�7��� � ng6� ��51���andE�2  will$5o�e *? "�Dq �!E��he.i��>a�ic.� MD1���ai"?��_Yz s:� �=���6� >b yqu\��1 matc�#^ mVar],�r*x7Fli}z.�lsL pTN%�*�o�`N YAu@ �h(�q*ic2� m�f�N�y�R�is�d��inv�gE�I M "< 3-lly�k i�):�t� �A�ac� in�E/u(ur&���l�D�E�H�wo�,� !�� �$��R��q �*xe% h eperi we��-t.{ set-"��f�.���lc!O'tf!�<�GofN\ ~Upo�� !c rest�va�/]�@r ulce�v(*dp��8bn"�X1,� �P��0]fe!�Džz25� ,I�@ cour�GmoF!}! is=c��app/O%�!?recogn>[9 ]1.�2�%�i\A�t�"0 h? 4uZ*@.�(*�qda��;A�(ie0^ ��d�8g�^no�!��u� �iz�!�&N2�n�U-~%\of apopt2�1��s s �ha 6���!@�)[�:8]0!J%)����/�Y� .n*�-)���4E��v�+�6� n ��.�Jf y um��s�Da {r�ه p�xs"-���u��d�Mta��wU'm��:F��!�m6� ej� N�(&� �)I��a�2WNY_go��$�o �_!:" m�cy�Cw���o “virO$sandbox”)�\�6�aK�a/!v�W\�@y=��`�2�ai~�v�s�y]py;>�. I� �!.�m!�&#���$a g�2ng5�d�!C* E�� OX�J�\ \x, WmT�>k���8 ��\�T�cas|X1�./!9s�BQ��U 2��Gr�B-o�eM�� �.U|"8=-�,b 82� ��*!Fq�%��p�F=2�iU\"�*� */>�A4i!�2�2��il�^��5�� 6-QC6x_Tly 1/46` us h~D( �&'l[�m��9�)�&=d,� ch!>highest�-Aj���E zero"ALc I"g[32��PD%BMP #E%�Ay�� Zo>Pic2�w7� uU �Y�c:6i{i� N�B��W�$5[�5gt&n$-�8}�7Ok._�3��Q�T, Ephrin-B ligand/EphB��@ ,���6�lso e$KQ��"�^F2��"� ���M�Xe"um"���] renew~ v+pf�+d$�WI#4 �\�^�� �� �SC AH�h m�a6iD���. S� � p*� 7 4nd1���o�f�5"tQ�! �^�:��i �5 ��.� t�1�y ensh�dӁ#�MGin�4B;n�AKe:Q g!Jof!�*Udut5���(��noe��Ue��a�&*a*d��fe�,l. d accu�! �2�Ak�3of]%� is z�dx[� r �T 7c*" Vde�"p)�x����Ee.2�\L;o m,Aa�M .CZ�t rigg��nd/8uڞ� pP � ���#:f 2sI�V ublim�2�,86s 3�63�) Ref"G=ietS2muMv&P!n�TeC�Au��nd"TB�7MPI#�#:�����se.��"#!�/Ep� y im��Re�c~n8]� .� �UF�isa�Z�"ga{1� A@m�u�1dt����W#b5-r�+orA=�wu6!&5�$)�& D����l�'�9%de�x �Cd� .f��B��fB� . Ou�M vikQ (!'5BA���H��aA-�C/��-�">NF�� n+j�Boughl|$i02��S�LPanel A F=!inddQ�m J��ㅠed�1�/1k�.&��")Me�$bYYe� nS�g%br�K� �%�A!K(�� 5L|.)6 J��6�"a�K!�xp�!2!�EFcgr�brack Z�ig`%�of6>M�>J�ye�!NAA/ RGA��[a i ( �?. S��^E!�� cka�' �(u@A��/Z<��5^�-�le<:r b�5[4v-v �� �se&Y Voft*��i�7!X�� ) K�=ez6�. F\r>�dɇ�d �TI��� _. achQ�d� sb�i����t�g��ep�tad��" $real-world�a��sA*�� ��:&vaT��Jilt� g�: �3or3<P03"�qs!e valIP�of��'s "�U�e;"� �M:&a &�.=S.���2or�!� D�eUo.4*�,�U�� *�� �3FA�%%�'�"�al��oncA<`)e���! �"�. Not!�at�#�6(�i)!av!rityoP*�,Ch "(d,(onE.�i[4r.am�=�es� ish�Sbeliev+%��ru�;�rtii��o )�@E�>&� �� `A�F)l�tE�Y�a�� M��U�da,�)'!�J IUl��)��� '�g_U��r6 docuW��h~4�_WW* 2 �AC�+aGg0�M]��s�X45losE*6!. x��e-2,��a-� o� orgaXil� ��death�B�A:���l�K�$ �a@it ev�艖�)q���^�1 �6)�j�����3�"�5&=]e+�*L!�. �bndFk )S(K 'A�*5�x%a�&���`J) v�&N��!��l6� �5�&llya61��lu]"��}�&C� laps�16B>�� �3!t" fraq�� a5��[%!At���o�}g�s�E^ ��9%,k2�s"4bQ"4 5uhor!Iiad�L3���>P���M�� ��.3w # 5tN� perc]�a�-�9�.�]", c}^1i~-+�reE�s&?.r!?"L)jmRgs=1����fC%"5��hQD/ �R Com>$ 3�"~)"�9�s;{U,�Ca�� ���e*>�quickY.D��!**�<u9i:x����F�Z�ted�II�Onew>jdm�Ur()R%`-�=v��s3vfrizzled",%�;(in 1 ( SFRP�/� ��eliminazll]�� . ��@ Aw (-6>^er8�-���fe�*�'�p���A�i�3luA!�-n��� ity;S :woc� e ��12�"�)�|"J4�Igi&�� �tad�k/%tu!�C� � , qub2t v�p>"&A��� p2�H���2� �iyf�F4""s�'avail��{ qual ��qoJ �8�� q&p a�"� b��mn�Hh�a�E�lБs��s/3�de5;4/Mop;d� �a� [�\ , [4�,E=�56 �of�A%a�$%&�^H�dlu#,)z�:�>�%( fi^�aP� ans ��s�. � :%I�1 'sm�isu�de��|�Q|!]to rK)un1H . As%��m�e�u�&rinks sl�@9G �ems%Mq��3�E�*O�A� ;�HJo�� E�.�Y�(�+new�j ( un�S� �)g�ous�s back! a?Y�0!,�xv!5X��. >��F�@p n@ ��H�%� ng�-�Ax,"* g�:��1x:dx chyYfvc%6CQ��N" eyo-�sc���fis6.qe}F.�of�"�� �[2� �r%��<�T���(�� ��� �KY .�"[�R,�u��� �gPxfC}+ own-6[LHh �[3n7A�j�0tu=m"!�t2�#� KIh6� 37];}rQwK si C�7��up�zTEN d �qM[{e0H�>E��u� on���"�Aw1�]�*f0“null�� �9S�!'s)6�;9%yx"� (A� sis;!.�$�f&M9M�?���@M.�'���=aX2"� 6��N�F@%w�|*�J�� �u��Nh ��i � !�a�Y,�A�5��p%'&�N>�om*�#a�e�7����, s�U�;�ž*�Hh�/;8E�s�3tsi�E �� �,"�_^%oa�/]�p��GEC*��d Y�l $-jsI�` ensId8Hh ��!b ^-72p� O3d!r 24 h<�ppear;�,e�z,E�.�[2�"Ɓ�}1ZnoɰE�����3� &�"�o6O��!�aA�io,Pcap� �=atYn�ter�-�O �A*R *en� �R�Jclosely" 9 , f? ne�I�e�R�  e(��� "/�a��.9 ch h!��3��b H_e1e2=XlluI! z1& Ne7C��/-a�.~,d�Ar*mC&th�#afo���K�J��X,k��e��v�&bo�F�g M��AV�P hi>��r�c% I�����<��7�u��Q?�a� &�95�9ai�G!�N �Qpe�A�y��A�p�? �W� 0=M06�wE�;D���toT,��daS@Ja  �ful}� �A�c;�ɢ| of� Zsh�Sb�0�Qo� �=ish�KA�g".��up��:r!/ ��jY�^�!ec.*/:{q::fof:w%�8�H�B"w6���!�m"�A[49��Sv ou��pX(��h)tH��D�i�Xm%�to�ZsF.*/>��/mt�BJ��K!��� d�U6�mb��-v�$do�e l<� e�36"Muk�e�&�+��^& #F�*a �"�bHJ&Jto%H# elf���p�auIv���+��Q�/-c `�V�1C2�.ll-~Z!G{&( TLR��� 0g\t��k��i di �tan�Pv yI2�7A Arrow�1.�/tco9s rect -b� H0ju�a�Q"�| s rapidly� 3 sG0(sud�Hh�FT+:f_�De���d�e�-��i 7V-XW|L� An .Va��]<���(�th spik��7A��%a�2���un:�� ��ck��5Xe��!�agnstit� ���p>��:$a@2�Mɭ{���`J[eI<: )�(�g�be� )�� �2' �Y>}�ze�"� �$���z��D6�cH���(. aO"� `a�"s �U����!B(�.� j��d�v�0�l: W B'�heqW.-�<Ac!�3 �;Lc-w)� t'E��%�D I"�(7 �C��QT!�)�be���[fi ��eQ, �&"-��)ͥ� in��>���8y �>�^*(? f T6P9e�x .� �):"�%�� �g(on-γ ( IFN I��L�+i��lR� e%V!��5�deb�� �?d&�\, hal�1� mM��5Q>M.�� f"2�q!bm�%���ir��tg"apr�:.�E� DU�� �5�oU�by1�>��� et!C�e�A�Ne-u�� re�Z�~*�G��&�s�T/.�T( I/R )a%X���U�@:�D�t!�&aK&"Ү9�X rem�[ ,"�F{\��y ,M���r� c �!�body'���8� �XP� 7��a�$U E#"<��"�Ma_~�Dc�"�h�x �� hear br� , sacr!%!�a"C31^%�^� a$$&��cV "#::�thoracicG" abdo��Dg WZ a�ryy+�� 5�i�%!�2"�of5,��#A�erlB9��d��uxD h��5r�5e6�`��K �n&ve�D� u��D� !� �c��FK[ a�^-;�&w��2�"�[5,�^ e�a dram��� h�6hF���a��" iXvA�,%u�=!4a�� [53�" 1af��!K�o?9< �Ve�R#R�-�8�"�X/�-%�A!��%��]�l�#Ita��abe� � iI/R"ieo��.4Y.� �B�uGXmHIA����!imN��)E>:� �� leara��T��Q.f%�.Xib2kaE?�T)�>�%�edV��"�`�!K"fa�H!0]+p( i .�1J|�-��oO=s]:� �y-G�*��iEo�ANegs8 �$�9���!}5�9�!IK (�for�~$cC l�zpr��n�f8 i2%����)!�m��x12 e [5�N[5b�U��L.�u"� sV�O nmy9 �{�o!"A5v�%�:B2K9�,Fatty Acid B�rng"�E( I-FAB�E�6�A�"m�"moe.�O �?p.�%`<"m*e�2�� rt��H,�.p�:ba�-�= EJ��k3&�b�5� bb�.!!8a-f���3oA+>)ficI�2omrm �l�m��c!@&_q� ee��/� � ( SA���2x)4�&�]�K*ver�<s+�uA3���i�aw" d%v%�mb "���Q� 8�Z0�Q�neo<^or dy�&� inso(f%���9 msel��d�h)<@aT9�Qr��r�A@i�g*�Kon "�1a&i ��j~��.+@6L refl!sv%-��,F5J�- .��&�ly fav�j0newNz@)��o /�AoP��(��*fB�is8t>�f�*A��K�. � � JcB�4tR3��� n�^+�B:�(��m\�colMLr{f(@� �� ault��&�$ ong�o��i~@5�c". ��b )t�<&? > neo-A� rvoi�`Ist�Y ��emp m� �"0<��[haba�!C�)/P.�%�B now� e NP O��GU@�� �. E[o� � o�0�+ћ���s�>!V! LmayR ��g+܀qaA� ^�>�>&^/�tIVlumm���*�^qDZ3 Bn.gR�b|I�!&Eq�A�&M� ��&}:[2�Dq]2a t��con�^� _�B l�`2g��af��� Aa�M�a4A�m � m: a 5�!��6*� �a"� $v�%0:�ji"+ �+e�`!OGa�. [v�!�S!UgobM���(2��dEf ):aC�i]�loR�F"w >.^11oi$��2]�{��t �dQ�Yh68ik:�b[GH"�q]�*,1co�MJ�F�&,�!�moeO�C [5�Z62]"��*� ��_AI6h.�,"� %!E5$AndY r)�IF��M�iQ�e<v^ addY��(we.?(g�"�>�!�(��UA.���7<6��._:*�#W/�Au� x8l2pL�H��e+0 E��� , 2�& "g0�]!<u�Y)eoA!r&yDli�'2�\ad�Tkr�s-)'�S&� , NFκ�/�f�3)��� r�*� �Q'\RI� �T {�,R$-�^o7:�a�@BBh&` ;.����=r�+-"d a gap"lI!dLJQ>2=A�(� �ees neeB.WE(�u�Z@��#*bM}�� % "} !��R��"3 U�� �;p�J:J[�I*7we��0�v*�GҠa&�'2����B��&� ��s�"�h�? ing:aO}�%f.a)"Wk�"*So/E5��o:ais� ď����'���ieJ � �9�A��+� a+A m�.�e#s���%��.|&�1"6#-����A�6�Y+�g*3N�rtm�ml���8\m��5n�dl )<�KnJe/&�/�V�N.)s>�9w,�42�&��v�'�ha1���j&�9 �}�e�!onged^V�|%K*Ppe&Zb�!����U,�!�&>� �]�8-�}@:J�&� @#?"�d�e!�!��enti����-e'�� 6 -n'sA�H"�K~ J| or9y,lieu , mimicTm!i��� � A�b#�� ver1 t�0J *� i� K)%lem E� ]���=��.�-~2GC!�C:AbI�HnkhAoth 7�m�"�]���9A�gh.1�Z.y6$+!DO&6�:F�!�]�(!Fa/�OSB.�Q7& -AA�%�*� d! ��.�� Aj� �,!'5/Z������;� Nu![X��"�9B9d.�M�)WqG5QHs��oB�.�/20n"�4"_7� ea��e�rz�c�qe���*�� ��Q.M�bJ'%B&�H�8, a�� TknGu�p0g IÅ�mbV��.�]J��{,�%J},�C�Ez/r 1��+^4�r/)a�o\�� �& *�'1L��!32y���Q)�%�&�'"�ra(u���gcU�3v ular/XE a'�.�!��JwD��FJ���F�/�i1n*'"h)�-p�""�R%^�?@p�o :�2~m�R(tB^Y6�6EW!�!;�.w^9&�#���AjM�J5�n �Hiv*�eri�� ns-b�X[�N@h[4��Q�� A��-=�t�+� Mf͍�s >���g�s!1pA2��Ju �I�O.�W> !E�g��2��!z:,in N�%�genB�*<5*� Im\)to��OE"( Z.6 ^=l.A,U�F6�!)�_3�`LoL6�AH&M 2�5�,"pe�*�K!�� E\7BI5@�E��]��F��bF�/,�x�2re`�*>� >�in n�w=�E> F6 !K�"�ne!�b^sYe�#�C:wY�inu*Ƭ:�|� T ��^ Q�*���1���JY�*�l �1�at�+nq(�9a��c$ 7"xFu�2 ?�&_#�:"�iF(� �+ cSC$�-�ARA�/ �7�.ll cul�2/��2IA��H,Io���Z)Q-� &� �$��!����c>�/$ o���2� �ADA���� �Oe]�rylind��o[Mp!�f-latt=� , Vo��i tIl�7!�6�/ ��e@>���)�r�Va�heuwenI<�qrh�e>�M� L t�?�1.�7ۆi.�%pr" D�15!BuskeN$the dynami�cs of cell-fate determination under different condiPs and how maintenanceJ,ular organiz Hhcould proceed without the n4to invoke stem�� behavior [17] . Wong et al utilized a �o(Potts model Oestig�grol��qaches bMa9for� alteͰ y(:�)%&�I._ �i�y �pertuU�(Y���)m� modu�control6�}�( F��e 1 ) h�Aen9�EK�ȅin!`d�k8B wn posi�?�e pote� l avenues��e�pE�Ax" ��es�Z �� ramee9. TEIS4 lis�`1 recognLqk�%��[at� l� en t���A�fu� .�via%�i�v��fini�.)� !@4cribed by HuntJ[� [73� [74i =detaileddIly�n new re�ce sy\"� ar�si��,%9��i t!Yfir�o�at� �Ib��/E�%*� rics7 tinuZ be!}!�� emphasiz7  Foft@simonious yet fun�We�useful lA�ab�*!e- ,!^vide� checka�a�� ency*� AXm BasA�si�$. Our even� goa%oA� ,!�a�"w form6��ser�+��commun� resource!��ngua��virjsandbox�� Lbe!E-"j Le@ers ؑ�Ni6ir owno wled�ry �D � $innovative"S  , hop!�� �c� i= s� �"fin!��!�wiS 5tO W�tA%�4A�o�s!ȥ�!5tM1�NY��our C2�M� Assi%(, ( CMA ) [75afa cyber�sp�%}i��E>�aug���i of bio7=�c� uct%;mo� �!>P)6ruI�analyze��on exper_t�By�!1 ��CMA�q�Ŵ celeY S���  Cycl� " study���jGA�Aai3gastro(��M�inj aMtoa c���Transl�0al Dilemma [7�[7� �!��ed KEagent-qd!bwg softw��X, Repast Simphony 2 . 0Q5 (t Argonne N�LabAory [7�C1�!�!� !/�nv1 assemb� � rule�{sdA�a reviewA�l�9,u l�:� #oseHI(Xs%���e)& adju!�gd*�h I���g�M��|st%�ile�.U A�"���lau�:*l, d�z ��E/ Lto""s equa� 1/4 [31cIt sh�b�a���5vs�.f �pX h 2�dRvo!r�%Ga-R of embryoVP o�, norE�%�+recre�a  cal�)�U5iS �a�wh�2�} �shape�� . Ra ,5 starM1assumpE�%=�e:�oc ��pro�c exiMKi 2�VilbKly"� ɷ�b�� �*� �s ( GECs� Chem e/meu&s w�tu^to -kb*�  r0st] Z g�"N� ��� �u R. Cel prolifeE�nA�� �it� )2�y%p"~�����hun:�Ke�Vh� h"� �.$n homeostaA�� !xparamAj�f�zA-�.��  ��"vT�S�}�a&^.�*r A�l�< r-re� ship�� var �%�! mole�6 �a?7eN M�. P�� I�6ww!�ext�ed from(6�%fpo ; fit�"� �Yal �� �~� �T���-�e nE1~%RNT!� appaa�� hierez�D orde��� ���. M94 "(m�!�o� e HE10−8 miQ ggre�x !�a� span��.6.�%�acV 1�( - 3 m2e� �lso true��Gpe >3o%!��!� timeo %5nT ope�s�"�%+eimagnitud�"5� �e b� !LgA�S ��ep��))O�a�IG� 9{%03  1 �il��� $take ∼10$M���� co�j� (% s�g�� of aAftein )�manifes� A divid�d!�&!�sɝAQ� m&�,� , @�):�;y �{A�ma�surviv��4 � 1�t��mak� icit.�M�%�it%+$ ��orm!���y�%>�w[��ereg� ofABce "�)6,pha� � rred; thu!�s�e�-delayed� gb simi�lreTEa. l %�*�  , bu��a fam �aa�&�co%�Exp)Q�gar� 4�!ly�ɫy A�"�methodyE�b3 un"�Sup� @ry Materials Text�"�T�x� al v[!A�xe%�� as # redu&�inkcid:ra�%�lH Da�:�Ae!aegypti�t�@endosymbiont Wolb�a��p� � eUmi�tooEnmif" arbovirus5"nsmise!!B� Z deplo!�world ��del� dict api!U�se�!�fb�of�-I ve AL�mosquit !in (seūE�up���ytomic�m�s ( CIa��# igh a�!� �ga�2�!�wMelBrGai!j9Y6waA�l� d��20Asecut�(weeks after�qi�! >87%I5va� household�isoF#da�,of Tubiacang Rio Janeiro .�9rpC ued~40% ds �H7–19 , peaked 65%e�droppI66a��st  . A %N,( 97 . 56% )Z[!obAd . DouPU!�IWA�=�� 4length0low l&�mortab� d n!�$� iO� invaE�tr& .�&_�!�lab�� e&�dur�ackwardB pyretC�genotypew1�d��a/� 68%��3!D%M17:e� �]�#, i!l Mqsus���=A�m;&� %�=�to�s�%,RZ"&"���2�,��ed jeop���#y=5�AJ� in (%(A�)E95�i:!t�!�m� fema9 %[ fiel� i��� mostly���iB�lleHc �i�����ale)�A�]negx]w2�fec ty�ju,�� egg clutc ize a h�aBespiteE��on�  A!Me%@suc.%me�ishc re5;ail}!revan�Fata�^e �{]@genet+, e� i].�rM[ackgro�d,��"� t&�] L2J��E���!7��ng 90%E  secon!�e&]\Mm>Not�gA"Fd<#t summer? harsh� er� rec� d ( da�a $g� 4ove 30°C ) di��tom�f'%�ex� ��of!vJ�of%�� a Brazili�9XY*��H�kmE6��Z� prof� �nwi�*"��*=�Ii� ��-=�  ly{tribu�phe���,al6}A���;� s must pa�%tt~h"ZAZ�[�� � a���. Mm�-borne�  heav!�,impact humanlthS trop� fRav*'m co-ciroin"� count�+ . Dengue � ( DENV ))[flavi di9_mai>e �nd sub �cau�Hai�400 mill!=��inA�D ad year�.E� AUa� est numbey�c%A�m&$than �d #per Z!zQl�threes [<(Chikungunya5 CHIK!b:t�� � h globJ%e%�c�(%#�*{)2000‘Aqw� a%epideU �1emerg� X$an enzoono�'&a� . In 2014�7%��PacIsl�'�R r�#pik���,cephalA<am�/newa� bab�# prom, he W  HIZOLi ( WHO� decl� P� c0EEO� of I��0al�`c+ [ 'Si�K�A[6 ,�-���=8l� c yeZ& f�breake�� s.r���*R�r st-r�)itaQ�E��?a�ly�%sI!�:�,bI^e risk��!n�xYF [4$All a� ��io"�1r� mak&= �t�be� 6S,��"%"f..t!b!Ca�"#Ez�. EQ:progra7#q� rely�+�@-NQ a��!!6larr reee�Yj5|abundaA1. HowE, d� �m�f2� .�!#log�LW$� �(N �.�ver�ge �2�) ive�L�t*e1��cl�is)ed [5–r25 �.`ofaե�tega�++"�2}:���ute~Z*c6"manageU\><[�O"h0.� *@!T�#of�Q�&��ybac�um*# pipiEblockyE�a5I�i����i�c� s [9��& a�Dl� Ni� �d��]60%��$ar�jpo74ec!} . Al&o3 y do� �fct6�,3e)�inD���t:�obI�fF+ ) -%2!npro&�Z discA�Ai%5��9mZ�}/�.@�� � c���!"��ak(o<v,ni�4%�A�|3 ,�nrn . Us�=�,�-5A2�ba�N �s�-eMC�)lp~��9 ��Eya mpet"3�L%�s di�(�&_'1 !�1.. S&�"� .ke��&Mg1��carri� u}�X Vietnam%�NorA6n Quee�! nd [iG��9Q]pilot�0!���ed���I�i h���( campaignsI'@~ �Min� �"�e��  PɅ (!3me /E�n�b 0) pursued rol�!! %(� R h���A�A0Ata tota� 180 , 000>crr��y Br (� �)�R` "m`y�3 un��� D 4 2�]�. �exhaus��U$�o�*er�X %�f�7�"' �i�� stepI�-�^��ityI-� !�ry:�-jtQ��q'H6s?&���  �&� T k!��m\!=T��d( 22°47'06"S; 43°13'32"W�nF�"T�8er-middle-class*���h*�  coasAg���ho�eek@ l2ic dat� meaA*��mu�Smax eS, accu6;d R f�3 collec�ad� or�ksb%1 6 km��**(�Fig�Y����authoriA�U "R&Re�) Eth Comm��\e ( CONEP , CAAE 0252451�0 . 100_!0008 )�nd fu�S reg�;o�;� a�ob\.�Gover�05&< : IBAMA (2E&�0oAnvis!�J5) �MAP>EAgr;4�&*Ac����9!p`F�$, door-to-J v�0��9ig�� �/��% �0�#R� �at �Lt 7N /sampledI�9 s ( Q� '"N% 3�dul� 21l s old ansA  "qu��onnaiaG.� 7)ng62- ofM����Z� team� X02 ny pces!$1�2u�)municip�:� � �of6�co�5����1#"blood fm �!��"� $U�)�nonym�donors ! .ban� de J�St�UniversA.9-):gs�be| carc� s2�2�0n�@!O}on��-X?A�sexa�%�d clin�T?����nk�+?s-9gsW$i�$A�He�� B ,C�&hagasCR$ , syphili�DHIVe) HTLVr�off"$�e=��&� safet�� to J� ��eea��,ppE{month*Bnd�h��u#�/,&a)�5�'2�. � *}aXMm�1�, | � ���%DI&!t� !�+ �-s *� mixA�refre�"�?�# po �(randomly se�ed� 3rd -4 !�3�vae� �kU%&�(2��L v�as�.a98%Q݁n}a�|� LHeI�reE,�45 !/0Tetramin FlakA  GmbH� r�0e'0, Germ� )�-ry d�Iin 3 La��3trat 28$. Each�)�;�!t � c�� ( 50U Q"b�$ $�@�\% Fsfi�aQZ�'E nY W+�IdE3 �4]')�&, a3�!r)� � xE+i}*WA��)�� e�,��"v I�axill�Dinc�/� aG#margi��5fri;[2 "M"*��e)�?=HDs�F[L-hretur� x���en.9%z+ �,ɗ�!-Q� af�;� &�+B�� �7,>;� elap�{E��akou� ( O?nge�}��J'��In)F8 "� �sA�*8,:�4–6I�-% ;"Y#mor�� ( 5:�M�fr�.of%I!ۉ�!-�a�� &�%-�BrX�L eptex$2r#!��"ed^untilpu!�20�h�&�$})��$%�&6� ���8!�%�7%40�J41�"15i�3eek�EJK,��}� 1��86A�2S74.��%@ V. Ld� Aug2'�`��P�/�@*in.U "�1i: protrOe�ado#��1�NI)��+24 :./. �.DEj&i�{.����S&� ��  a"�@ x RT-qPCR�mR�e WD0�gen� a ribosom� >[[2/%AS�&��. o�ViiA-7 Ma) ne (8rmo.�>) �Taqd(al �MaE% MixZ<f"�Rmanuf�Krer’E!J� .C*�Yqu�N$J%��4��"E�Caragata�C . [28 To test im?���� �>�U�]DE��� !�`@:l ih'ond�3 DNA}9 �&-$eld-caught�ہiW�7r&2�4 agno�SNP��6b COXII�o.�atI�ne'v� Y�a�is]�"o{Bd�u�531bp^ %y zCOIITco(/A-#� ���G%��0. �As��=.�k  coinher�pw9;aI�a,E7�7iat�!��W"C�5A��%d6^�a�n�m])f [2/&�e��Jr+d 1 , 3�M2 �)� ,�m�26���!~1Ty-Br.7Ꮁ4!�o�!�s6j��a� �9!K�StuE1J;�N����m� probes ex�1�|�Mt IS5 o��E8�-ssa�DP��:�/e]Ӂ� �in 456.  �GSanc�Ua=��QY"D� 3+nu500��� �B�8lDA�#*� Urc#6an�% rict ?���h7��cMTEer!s."��4"2�ץ�Nkdr m�9)��aK�R��#=@ an�� n��sa@;#.��Bs�>aDO/bug/�l"�Ip5�.EF� Z!"�u(2v( More ,�sco� ��a r9!�L;W�"p&�bioe����FV��a � �;ix2a,�/� "AFe"42U6i&4A(Q], F�: (IM�AwF1C� B�q �q�ta9J�n`�A��?h�A*j9Te'�&s:�S C 16 Val+ +  Phe+�#!1N"Cys!:z#&2&Ile J(q"� �h��%20|7�%�?1<�2$3� 34 ("C-_�G, 5Q5R6.7:R�� 0 �7'80%8Wa6-��y�""�60� 2�x #� c)V� BG-SdRn)bra&�2�830)�"��6Z#"� ,*.D1 -1 ��졈in5A ~"to� ����T�=�c�aB��8%<&� �,�(#�� d }2 }Z$, Jurujuba%� x s*>= RockefellW ���Q �PO<� Dose�8b�e?�!2�0r� t:iK�=i�>�`�Kphosph"$ teme ( PO �,, Sigma-Aldr�i]� �c_8yn�SI hibi�E(diflubenzur� a��3-5-day-��Q ��� delt�Ihr�)�_>�malat�\�� WHO �� tu� [2�@3� LethT2�-�u� cal19d � Prob]EbP�["1OPolo-Pi$LeOra S&JOBerkelCA]�MR&�<Rs!]RR5i� RR90t���:�S!hlR�( L<or�/ckd�R� ( KdT )� %V %2) 3oDC�^.�*UI�.G�ѭ�� @�_���e/a J.1:ف of F��F18�uei :!a�&� . xm~e� �B�� f"{c� i�$)_tl:!3A �M*8.J���d 5Z�* ppFFa M�f-�f !�A�a* - ��1�A6HJ!��!$��%b*�&@ OE1OR2RV �ly��CJas he�d�&5"�G�e� st �!�i\ ��.!�a9����Woffman�S,Turelli [32]^ c�Ef�c!W;re�%`��@ Q)ros�-�s/h@E:B�O���6� ' In!ZU�F1i�F1�_x $+&� A�}}! 9�=�.f%Le /1D:��1@0run� aW�0 ����u�a- �er�/AA��AGprkG!,*G�18im"�R/"1.� 1*. ±1%�G� P-�b�r�Be�measu�c 9 %Y/P)�t�whe=3oa�Z!.Q�{mo� R��J*9Aq�.3& ��2� ToAG{&�B�� m`ln� e7�- .e%�e.d�Fe-dig� RAD-�1�%p,UousA' d [3�"��� 25.b�c� ��:���-�f"��af� � j .�Z*& 9 Gordonval��Qu"�4, &�!�.� !Sorigi�{���H� heebp }aed?6�d�P Illu�m HiSeqCt�I{de� � o�8( SRA PRJNA2739�330553x raw -��7���$O�ev-�x#z6ip�$%�zD���;-qu�.O?��Pha>29, trim�to 90�,%juniqu<� �!I2 �3%P�c!�AaegLbM Bowtie v��1X 7 [3�8SNP�(D� �kW&��< Stacks vX36 [3�XA�1fi�f�mark�$��aa�_p6VCFTools �22b [3)�me-�<.y� I�sZu �aDiO*A nt Aa2� of PrA palQokj[38ժR packa�.d'n t [3,A�indexH�=e� ( FS� �*� in��W� !9 CockerhamtAMOVA-:I< [4�  Av�,��i{1a��?�AtntiP'��1 J6�O*�!7M��r�),�D�&csn�(sA�A��H��H�&T CRG @G!;&bPing�=�LU"W�:�(� jectTU�&�. .d��at]ac � �*t*s>A��:o��Q��4 mand�3P��e%�nH"s �0L0 �vo[f. *�itas��(a�*�L'Ym�J�-)�*ac��<%��+� mo terr� ��!i�O�.a.sD'�]elong!�A�*��Di%2e;m_3 nl(w��"�%ÍPproud�b�V"Leq Ame�D neighborhX3��a�iip� ��+a:; E� &����2a��a&��.da) �Y� !D, 2�(o$,Din 268 ( 38 . 8% ) 7!�.%in June/v"]"�235 ( 8O7?�&�)D�G�P!���;�>&tP��U4UopI�-��13 ( 4�5$divJ�5�FVRq�5��,0-A�kd�A��+tU$ kr����%3a"�K6F",*j!�A�-)\%�Q69�+� Y�"e?�k&� iM*�1g%�M1� smooO/��"s 1�$&�2nSur/:�i�Y�sp�/aC=> R`Qd�M5��!*�"$��#K u�$ v �#E9G$A3we&� a�Q-N,of �Qgg.8DM��drRdrama�n���T�" � �&0RFX^��, �_�J�d0%�N�N�fG m a�&20%2�ZG�ngl!� �q" disa�I�oog� � r�^re2�;e�[�{s�3e�10–r9"e&�6'A(af5�(��� Ņin�h���r-Q.���N z}� .�v!�"��I1lucid��!k�GaysSfsPat"� a�� A�LT'.]�- dU�:�Z�!500a�!Ai�7�u�AeMU13%{v�st�l-�:=I&U����, 164T)a� 2� �� �-� ā��"6� 7$. F�(��`"� �"u"�9g( � 4��, sugQ!Svb,�T�\VM%lea� �#sej �?� �7�1{�'ampS&�s-p!&4��26Z�$w&K�isAw> �wo����j��lb1hrea���Ji�4%�pk%�C!P disp�Z�N2B$K�)Z��:s��vB�Q� c*8 S1"; &�KS�@�[@'ntk�7 �Z~�ue/�Br� �*Y� *�6a��*<2�.NL"�Q�B[NQE.�r�M :e�ue�'�Z&��[o|P�6�MNld �id�8�-A! *H(��"w �m��..�@�aA&�2 O�:�2hJ q a�BrVIS�w!��\4� �.5.�)Z:�E�iex� -a�!&�A�2�dZ&f�A�.�"�&Q#�%llp!�"�SA�� ceM�e!/6ic��\<&���&7 !a<r&!XA�9"�� 6o.��2B�� eAl�R1,�N�^�new��,6.�e"�Z�`F'a�!K]�"� �:�RR95> �Y(�Y�S4E�5O[Vl)0� Q�V �&C.�.��9o�,:!�y�. ~ ��-�`�}�unl]Q �.�*X'RAi0Za� `ar�G �6wZ�-�I�%�!"� a�:n��VF��$ ng} . E��@2 x2 ?� 6�m��z:@�our>I�$� �# deca�_&�#��S2I3�'.:�Q��*�A!jaK�&‘q�t�+’ ( �,2oR�) a�X80%�I!84� � �M/��0iod��&�E ����!kaE^)�!��s�*nv)^�(3��H"�P-&�!�6�+r�a� u&� � �f=�hele�"SaN%e�NtoI x4 �% ahejh� �+�2%!�4s(*/ood� Re�ab� a shif)5"�*�#%�5yR.a׵�&�"B�@E�s"� ��eP:n�:y�$o;s`%�&�2U�#K 2-We!6s^ A�3�}u 6��.f�#��- StarIG&$!MV��)�-2� � � �*5GC t� of� ��O^ ��G l5U�� �'��R�$a�6a��UTks ( .e ≤ -1� 2�| 8118 S�!���@�Ral�.A�als-�,Q&:�3��m5 La5ng�N�[M %b.�2yRinbJ:�I� , Br ��(.3,�Q�ildAu (.`,*S� �WGaG�( SE )��u)9�1hNyhI!B�� �1: 6 ( �4��R99r3�� �)�\ �.2~g.?�oi���.D"��k"6!!� te�jqa� t g _* fK�C&����� . N+�)�$���e\!Os uisho �+"Tof�.�. DAPC'sh+�3�wou~"�0eX�lu�85�cle=$"�-Gre�!4�&�!�"� n ukEw)��6Eh.�(J� 198A.x1Bn2��Q�0�% �i�6��an���F�?;r.o��*�!�-f�X6�N)11��C�M*>���� a&���dmo2- �*�� � - a�� 6� � &+ !&&Q br��ede )]18t2A� ���a��e�P>,�X�{!Un.K$&� at 8�3�� �2�,"R )LT!!da�� ��l"� ��)� *� �37@(!�1&Be:r�b� cm 5 r.�.��NavR1�y�z>�2!�2 > 50&��A_. NavS�@ a�r\ W.�nNtly.�2SAV57�.�)Zq�vY' ���)� 6'6�)r��sDt "0�5�0S6N ) . �&p]2YoFo�02 [o���6  A���*�jd�e,:c�c*�d2�� }xe�_�]um�Argy  rh+ iNir ";Smp|[to .pa�\�&Ged}�i�XF17�\ �Y � �V�7c| �/� Z�^� "�;� �y�maxim?kaN6� �m�&[ "w9�H��^�mu�zH#dE%��7�8E���#�>Pq&Y��IC]}#chE�\.�'�m��"�!hQ!}fas� m��q�y.��;tBcf!a�Mva�j_Ga�"#8on Yorkeys Knob�i12�e[2Y @&�M,^ ^� &�at ~4W 4"o!2e� �zr]��  majo�Q��l�YN ��95�(ah�Fl&�.��F[4� 4�A&|q��#e!*"� 'B+/�3/da�/��93 B�Jsligh�9�U+�Kri Nguy~Os�Z�&�^.�c; �wn!l�;�notg�th�A4%p�#��M5�!6ʼn��!:��BrE&1:y�=�w#xnN�;>H�8:,( 2–7h_ , )EIbq":�B+��O1��"�Y,�!"΁ �y!M�a�*!q we��&R�meu�mQ J"R un��I��se��9  -}Y�)Z�^ enou��o�#�"� ���oJa-ekJ�T%�ea�>��Popš&�5f�i�6�IB��wB�[-� DŨ�meay�iJ;JkJstyorZ}�s�Y�'n.�J���i_��15�2#7ekXw"� �Ym�26� big�@ta�A�o:�~p�)�0 ,%�I��n))- h�%�A=�on��� m�Ai������\!'t �eh�,r f�E�^tb]G�/�F'8I�W be driven!��hFB6h�.�`fluctu��m!�;�+\ .��j/K�\fsD�em(12r&�"mvU�eme.��tl��no�6ADI%9��mplet�BS2|�c&` � harp��� !�BrR�A�en R �1�%65)91rai�JZm�,g a~jV5�& !x�$*. Aco=;J����$CF���� enC���PCE�Y� ce0iclu�?�own�vA�0�1cz)"�������rE-6-s n� 5= )4-K;n��&�Hspr�an� ??X�r)���Y!��1Z� ->e���"�Y�eurek��XB! teamt�cZ6#aUrth.� V=: lac|.&Z��&�!-1& BZ 2�j ��� �cXs!)��1y1@ pers̤�R7J�e:^"�,of�V>g�� 1a key*���!;b�c� *Hs�*�2�2'w ���toeWy�2��A �:�#� �,� s?2y~��=l-�#(h�!ndW/�, ( S7�9����.|NB*s�=<-bhe%]�M�AV.�?��y�c��JE�] � }Cusage�GT 7ю&�� L>�)�� ���ya�a ԕ{>r� 2�%�{�rl�!nE�2,]U1.D!�FF�da&b�%L&�bK�n60[5�!�� ���Al��Se���uD4gambiaDCx . Yt s [5�5�&�(.�s�Iex#K�L%r")ce*�Mi���ldA�'( !���5��|&�*%o sod��dGE�}�UF nerv�$sT�;hs2vi!>1Ourb�normalf��Pk es�.d���-�pleioFyic��a�J���15��\K3m���ۥ!S!ZA�2*�b k$\�!���? hZ�&�?vC,�^t"� ?S�0i�M. M��EF*�.��b&�J>e��v6� s-"5�F&�!�n$f�@Ad�eym��Jb-�� �n�!�UwA!de"[�&)eD3)x- CGI o6�&=�2f�j. H9fzg7fH6 9d` &{">T , 5uD2�����oX.��f*�,*�!�An �n�6%� ng.�> 2�*%��!�s�HA&vJ��4,>La��=�be��" M:k (��%_ot8*==�WA���[de.� 8:�2��,I3&D.����O:tr�`", siS�B}�1,is�NE�y�.�p �=�[5V�^��^� � Wly"IZ�"m,te)9'$�Ia. lk�� I�!�2 �RS�._ �hE2��sJ�: ���E\f�[5��2Vbi�d��� 5& �u��%�A�gA!=lu�GU:F!��Ca�B�lg ��{to� }Jsd��!���roFmselv%;�H�Y"�uFh��availe .R!�!��e*[ ^�.��"��6c9�e�k�>�5.5qY��yE���2�,D.Uis`ň��. H�~,e0q2 D��ma�rM@at xgzkno����&��=�%���ta =1F�]!�7�%xD-9'��G�� ��4x�"�'.T%Pox:�es�loy sop;8��n�Ket��st0,���p���;&��u9� defe�nm&l���%Ptaneo4NensQ vp���I�modF}�;r2Hl*3uC��E��(vaccinia B1� _�kin�Q8?�vital��in�U�o$s6�{J.� BAF nd� or��E s� 52!��b� � �be�*�#ڲ� V�E�A.��e\r�!"D&�!Vj6ؓ� �$B12�E�?��o ��)1;�;�!�;�\�n nosIar����ild�-)wM�] Ent5C^�&���wA�fl(t�&�Q�z� i>Zy �dM�-Umasf$�)@&�B1�o. FAeA��F!�!%at�eA�� !�iȭmo����ƅnucle�N5�q,�B- �.l�T:`m 9IV�in� 2�I��q[phoryl+!��g���?�%A�/��MeEF"�#LFel>MH�%�.l>>�u�� art!]ijAr��5�of�. T�H,�> stud �;c)�t��U�%na�yO{,�)-6 _�!�exV\ a�9que ep��� �so��aM�s�rh�^��C�C!�,er�|��S )�us������n yet�Mb�U"��Eary� QNb. PI �!��q�5�t'�$gg!toE�!���UH,~�numer!E&��&:[[,M&4m�a8!: n1ut�["4sE� �ăd nG�:ary.aA]� �dn� ��{1w�ll! gdom��=��as)ͅQIn:�I2s enco_by5��K�P��d�.c��!-i~�i>i����dys6�e����:e A.�q-)9�.S���&IiY: �#�!�*I R�Z ��sE�Ser/Thr-V � I��d����6&| �r!"$�facZ����6(e [�&�B1�<log* � ��)�{J�mNs%�]� idae fam� � m���}�1��@paR�j�Mo<�ciu�!�Ҩ�rQ?:�_/� of eukary��Q[E��=�!(90% a�; acid� t5]�$=�!� [�$1�#hfM))3na�P8��ed�( VRKr+���jw4m�6��Po ��t}0th!�,NP!AB1/VRKs�y��3�Ua�ter���I���J. M�`��Uwe� 6� .�B1�\�V�t�J*O(-lTiE�t nt�ua�w��IMu B1 l�~ [<eL�~i�fJ �&9[B1-z ����"�H�� ogen��LB1-�x�� <���rkeA$� ��%F3,��T� c�)��rrepi_X|��8] To� r(� Uu�me*t!��ɀ!�� d�ɱ>�����EXANFH@ ."u B% DNA-B�m)� n��pQ8�A"��3���'gq]t�d&8�([1j6�� � apq�terX[c*<.!{a�hŲ�er-�Mr -�$e�mZWzń�'sza�t@C�C�5�I�v.�[6]��4U�<ycri�( [1W4��!�e�AOgk � AF ag��t>|��p�nta��-:�perY� � beՉc� 2ZB� $���byAl[i�v�u8!l�X��>g;�*��.�a b� ly� eej�0 ,AC?!�bio"HI��L a � ��p�S�}{A�6 U���#7&T�Y��̂ove�3e� RACKO:reA��6)�%KC�@ )!�.�t�1��cer!rri�2A�"\Hˆn�e�/� ofA�al RNA�a�A post2*v ��1ga�����!��wS��)#� �C� &� JE�r"?yS�iS2�Oay4]5j5M �H5&1�B2�">�2�direct�.���n� r@)d!yϸbO� �:sF� .\2T� ough2 )!�s!*(!E�|�us�6; *1cir2!�be�K���c�A� �8I�u�&fe-qS�~G eX\B a/y���s��|�u5�N)�B1��a��acyrL��erru.A����sJhi�k��C� A��fQ�dj]azM�JYed�f . V6����d��v#ypaco k en�ki��*�-�se�CM���t}+b2{]``wh0�C/i1��b%���ciIUz���a.\\y�N�\��&*D����oL��B c geneh�{�,w$�a^� I8m&�!��e">}1���rowth-�!�p +��U:1�EX����*iMBen�;�Dco.���Xngmq�xPG��S�3 Ab6�0e���P�O%�B4��A����u"�!�fA�� ot�UQ%i_# � L�e;*= ;[28 , 2� IG�W&�sJ'� A�B1iK!�� Gi��j�r.4l>�r�|t�sVal�Z!�BpgA�janb�r!�I}2f[�n��ns` .`9ɥ�!��>�ex�jR1ofY-1�)2Q� g��!_U��map���c �u�G%&8lC!tra�� rameB$fc.G Ta9R�-mis 36%|� oA O&�$6� �?L rX�� 0MI2�o��ie�! dup"r mxN���( ��1�*~C��6=&�A�_-Btw�E�}@,�B1 orth����5� ?ChdiIg anaec!�il!�2!�{!�o>�Oj Fus!�!A��� ��nyi��,aceC� hallmark��P!���&lu�A�QofYH,�the��".KK�at}"��Hm� �be&�RcatalyE�l [�Y�!5&f� !��F_on&�nMaym3Tagw^.��B�,P*�)�a!��5{�BM���KK �<myria�^-��a;*�A etazo�3�A!�KosH�~�J5$�� [3�/3?�"��"�&MA � ���#��Y�A��Z�. I2|-B���e-:!��12�� resc0"��u> !P����U#Y0�I�~�f��V�.zSt*@"� ex(�� m�a���K&Q = &��iabears8 ilar� ��#:E�i*q �sɦk oxin-H �KI�bԥ[3R�k$F�so 3d�o�Pa�ele�E�n orga>� a*y�� �L!�!$�U�/� E [38–7k AdsLj.|�@�� =jI��!���!%�_h!ty��YF�m�*Me����������2y`B � �Bnl-�Lo~ɏa>2�U���"� ,���1 part79 aPd& � A}�U�U�a�!��Y�Y�Y� "t �.}�q"�@+v��D�=>� . Sp�i���� e%�aP�(f-,dch�Ywi������NA&��6n�j�e�� = [6];�q,Y- f�B+u-�}�.�(E��&~� ��*Z� l&Ldg ��;�e��)�(.�#%=����B��*l ��q�rT+b��1 *A �A,)�E� �� ,Z<� .C$!��XJ�>f�5� owE1!�a���j��(n5��+A0)E�B2�G grap�C!]Av&Ad a*A3aF�8 x(=9+51�aG�6�� ` �F"�Pnot�R10-fol�>+5�[A)q�-��3�g��!ssem�B�&�P[ gڡM��l�ree�n& r%� I�IV�ve ��we veriSt q�h���DnaK�8i��).��5�HS1Ao?��uA��� ���i�a!Ns!<: BJJN -v-8d.�. 2)d�m�N���)��*�D#pFt�3F=m�ndi�myA�o-32MNC��edaQ���-U>g��200.h!Z�SWJ PFU �\��HT ,)-i�2Ec 5}�Z��ageiTt�R��.cw � t 72&��<"�K.2�b-�!ME�!�~cu��E.V U�%Ɓ��f����u;�:e�Z�u*;lF�LonJ���( S1BE� , top row.B6 �=) �7M��6-a�-�KA�n�2sbottomv�#�*�t%*6J�iv�{jt�!y19 �p�A Ja��&H ��)�QtrP9"� ��ssԑWj!���*�79Y��lw*A��>/3ifyR9% ���1�ow&��ˑ�aAfŎq2/�*� �3,� &z � �( Wiebe.� �t�iky~A�*Awq�� 7�] subj�pto 150�$�'nd~e�J��~V2�(tru��o� guU�A"yJ�T���-�Ma� 3qa��8 � -*�Re +�CIp�(( NC_006998d}� =N�A�bas�t�vKiL2*L0=?"��)k%�1�(.7Oxen`��h�onsLL"-AL��N�sx��`� �,mi��/����!#ens �� �*m[*SH" j!)yI0 3IG5�%3�D��9 s�!�a�rus �� �!I�Q����yqWTUW����� Insta6�2�)�]�G !cth dp�%rmg� �r:�A��45q�."�d;bAYJ5��eat�7*��]/���4t2�.�a�� &�polym"���(Pe�HE&t�:New�F��1�AGar��*�2�s WR (.{�?u� '(��!*Almut�to�F��)�)5��b�0=-AM�: j+on�� n-sy"u�� �;��A�� X solZ)k�n%ɡ�!,MIin,v G to A�_"�ᠵkW! a Gly215-spZ�S B12R:[.&LAGE>fA�%�U[]2% i ��76�*��-18Xhss� 6'�C�!�S1 �qEpi���% %���+� �g�8u�/_A����)5'sv��� !��)A4J��in6�.�Wb�M���15!1v���lsM�.boq��!S��+ploN�a~Y y-ax�or�ADe��SB` ah �!7�!� 3@$ )�]C�+�&k� ��x �� 7�%=���}G�'e�x�@z �6�.H�n5 �� ��%� 5K��SFRtopD. Narr�)� ���-o�O͹o!��8i ��h�V)i *A�tZ�17�+���17�094&� 1� y E�l�.� -����P�dbe &LG �*Q*,enJ-� ��o `-�P���i#.����|*"&�^�+# *�c"�ƕ<%�@9C>^ ��K��%�6x%:3�d0�e 689�1!���L�W�!OXT�ight >Ui�4�(�h��J�i'4�0��"��48%�€��Q> 6@)i�%��i�:�>�2e��C=vor9u�n�E!e�a5�� 'J��a#>!Y%TA�� Q� �ApOt>�q�+�R #L! trun}d!�x�2;/qIf�-�D�&i���Y�� �OedV����� ��=��10&� "�os��?�Je"b "��Ywo� �� C��"V �!))A�5�!��8cQ� C��2�.!�ٽ�a)E�el"a}]*$��!�e2:b"H �s5leeyoe�?:�r� mo�ga �3Es:�%.32#a2"EkB1� �< he&� F$p-&J�Oi\ �>�}��'+iL-T\��icu&ecMY�*Fcmi� 83"Y �gen�9� YhA��,� d abG���e�ɿ(l+�:>�*p 0)C"[:��Pt&U,( M G� >�R����. {ad` me�eQi �m�2aEAiyM-�a)4round of vacci�Lnia virus replication in noncomplementing cells . Following synchronous infec<@s at a MOI of 3 ,_ al genome2flwas measured by qPCR . Compa(to the ΔB1E us ,�mutB12-A1 ( light green bars ) and <+3 ( dark6*�|es exhibit increased DNA accumul)Dat 24h , exceeding �( � zlevels�>5-fold!M$monkey CV1-G( Fig 2A �>18,$human HeLa,S2A0) . I �Hs were also observek ? A549?B ?! mouse L92.!C !$, although!~(a lesser de!^ . Regar�vi!�progeny��!�v�1�rescued m65�^ B ) , >50*)�:D5�T *:�E*!�>1YRF /. Notab% despite a�)� overu�!al)5R�.6remainedaX11 �L( p-value = 0 . 0056m$13b# 1 ) lower1ythan WT �E(ZA . Similar�>2�us��2m�B�474x]@A�:m1e,5[sho�Ra.��� from2V. Thes�K8sults demonstra%�)�Z3j�%�.�in all.X, whily!���$attenuated2WT!ua] To examin��y�i~ecAearliAN ime point��1in�`ed witha( blacke�e5�i� ) :����n �e�harves`�y dur� v�toa�$itor input�( 3hpiM�initialr�L( 7 %1?lat:��selec��pA��Vle~ofJW16 XaXF0vacciJ�$ve cycle (���.]>�each 9�.g�\atu!v>����ts��E�sis!TWT� C�� Next3us sa���tiE� d onA-B1myc-$m2�(to quantify!㕔atB�. Aa��s:�2E��%�idxcalsWT�T!�5onAVata��NC��a�most �reducEin2�as%��u�atEs2�.��M differenc1p(not statist�� #t�D , 16E�24QK Therefore��nd��us have)0modest growth�i�respec!�oJ�n6�outa�iE)��s undau�condi!B��heU� }profilesawWT�9� �}��E�"� led us!� quesj wheth �A�e�T true;ɼconcenA�ion}�� . Fo�g is na assa�c� I�2aQ��F�alid�propag�2, sprea� R -to- ,��48h b)Э$%i��6��. F��)m ��,.G(��bar )�u� >18�hig)8an?��7usQ�E�BInter!ungR��� )eu��12Zm9��6iaą�ɑ2W. � � summar!�B>b�s aA� B� " 2�KA�" a<ies%���Q�.�ofV�b inde �c-edu0� >���2��:Pt�r . Ye��!extent�<�Y5�Ao�6�U8��d depenE�onVA��E� amou d)�u� �U�c  sequenc ��$��Be=veaa�a preval�indel mu�Fon��i �3’ end�R B12R�(eB t lead�?4a frame shift � is  introdu��yaCn�� ch a A�le aden[ �� dele� at nucleoEk 690 , corB��ng!}s���)Gi�c�w.� we cloI�e�e� ��o W%x P �%_�$%�. T� �-&c�I si,prio�Yq�F0to <28%%c�iE;&icIG� R�sWgve% e�dowveam B13� -W�!�^ al�d�a=]f �oro�%91!zC%�S3�)E�R� nt�! mer/5� �9�We fur��valid�=̉MB@E�UbA�B13a�det�uDy 1en�v�(%�sEtoDN�. UpocR ful%9 �QItadd aHhe&lof"o!Rlo:�#&���&��;� �W!�& quKm��by���,�^l)�A carr�?L8qN��I�tre%��sQWT��B�ID"b s��,200 PFU/well�s UF�We&6%�f�can!�m �s:� � �K�!� !. Strik>� ��i��to�r!QR-��)O }_E��`s � L� those>P!=��� A�"E#��f�iE(:�,.��)�S.�2�-a lo>�a�a�-stepQ�Im' �)y&� at 7h%��:� 7B�,.>�s5HR6v�5��1-6�A0��%�:� D�}T!Z&!� �:�� ��wof �i�J�,!}H �=�:�!�� cw�bY �EEA���2�By� ison� t&�uA� s 4L 5<-�:� !x 2�fw�4)���C�!@�2�.�f"�6�:!DM�� ��a oneI� KqQ�Br F�B��are�b sign� nt�)3d�ip�of-�i�8�5How�  ,F�� "� s 5 . 4Fu x.�B�"B"�)/Ee�F%E�eQ��ns2�f!�ey-���%�ls aC)Q��9b�:O, 6�M�Fe�I��.r*;E�W��1�!Ky`���A���("� I���p"�"i��� study� refu�TB3  ��ud?�BW#i_:6 � in�R�ul!�Bl�k���m}�m$&-��shouldv%o��*�%k9 P" uKo $but it dide�-�EE^3Fv` MkX �toQET>�ra�fis!.�-l9�N�i2�ca�$ !2U,� ��rat fu< ngth4i�psor!�Í� . It�i&� �ioe �� does%7a� D,)Yg ly appar� ��*s!�B1 kinasnm�� 2����� be b�1y�B1a�"pl��po�i�N ��"d2| Y�wEz &RA�r�"�defici�6'eA� such�q� Ele{ �7�D5 � ase/heUs�E9�mer. �L ata�A#in)�=is direc�d link*+B1&�pathwayApromo%���r��m�-ngi�o!�Wu�� e#�e� @)4�Abna��1 ZA�!�� \Mjof>sve.s+es5hD5�E9�j �1�� ��~-DsB via� A[ gene� mechanism�A�on�Y �In or� o&��ch�ft#xm��U�E�) en��a�EIWT�-���7œ�!�2$ . V-4"Te45A�luded],�7&temper �:AV)�( ts2" [5]j6N�.G�'� [44IneV�F'K4�45]��r �gn perform�p �.m( 3�d5°�$, semi-f,7(�nonf* 9 . .J�%;� � uKMa.�]ofѹ�� ��ed_ E Je�B!� �A&�ai.� � l��ree.'��8�� �A�pre; �Sof ��4B�K$(� �Ű �B�!* .� WT��� �aF viou!0published [18AP2�eW)3��*� B�5m*, D.�>y :f �� �at]R, I2 =Y a�v�/=- 2+.�*�s2}�)J \tr�  6�/B <onZ�)%)7Qj)}:&�OdFC�#!e a3>� u":M-I eA��� �=/ pink90At^�6Ah��B�a �u#a$!�ed�bm�� �E!�cu�BK"0�E�q_�p� P �z�a3 2Y���%#esI�` rb"B� . ExpliciM � ts24�u�sh% nd t�j(�!�/M�hE1Mnp!�U9�2 !(*$I. �x U $>� se� &)e&� ���.c�0��/B�sl% .@"T C%xr*z ��}�D5�h�!!wE9����1uN���-F)�howw at�-. ed2��A9I�%��� �(*�1b=�3/ AN.�������L*l��wh %�{s�6a" onBZFt a0a�}  A,leɋur abo�9�s�$� �)"b"�#*CM"�$Ax M5r �uf) � 2%of5��!H� �is��rwe begai � � ��y�n�HA-tagg�- r un c�&optim�!� ( S4&�C."RA� mammalian s8"�3M�d�� AT�A0B>n�!�systemR��i9ͼ�}� t �iz�-��6�e(��� � �Ecou $,!:N�"�o"�4ysa�E � .j [s(i }�#(de�"Z0��)���5@ T��*5   r�stitua�!�E�iiBor�-�z �"E !�&/!�thetVell�Q�*"�-�6A02�m:C|">�d2� of�6�&�VJ . U�a�bi�I�IP��,"s �&� � sepa 'ly � !�(I)�m�e�!�N�r�(o.$�n�&Gi� �<q}T�bC!inE�."� )'�dg�4E�)��!�3YQ3��*anQX.� +B�A?P"8 ("t"{by.��fQ�m C�tI�,�- solimA tripa�]: �A�a�!{!�!)u� �a} 2� .�}inji,�'-:� CV1-e@)WN�� j�>�6f�![�2qA��3 �V051S}� ��&%1o6�6w�5j�&�Ug aiQ�Y���y< nuyY[ =IUU�h- N2�a4�OCon�u�E����N��8:��@��)B�!�:�! 3&����3�=#ia�M)6z�Las&= ]�. if��e��* . qu to�tY�! �2�şJ���6� �q7on�5!}`�V� !�.�� �!!�M�BZ"T.�(*< �6�(af�sy�R�p ��A#a �^��)�=����o�5!�Qpng�)H &� . CE��fix%�� days>J EW�)~$ numb�'x"a�un�3 �*}��*&O i�c:!���m�top row�2�#�*)s�}O== �5&e�� ���B;2C�i�nz2 �R u�!~a�FrIY��A�-�R�bottom�T�,��ad�[A�6sdeNes.�Zwp$,Tal ev�:c�Ё�ir pox)6.�F � aa�si�."�0&�<g�-e"s�sub!> localiM>��H&�ed!�Z��))�9p. OneA�M0Ma�A3,-�},�ub ERαHA �ry p" body 6�2sf d2&A'st(AM DAPI�� 7 fluoT� imaga�" i�^g�A� lear43ar 2;:jQ�!h�� 6�(.bN�#&� _��E cytox2m�P2�,�&^`7si& � a m;B1.Q�@c�� %�b:b�ami�@%�NDA=\��g4he mycYdU�)�!5pan.F%���-�still.:�4>�^v9o�6>A�p�14"G�%'ed1��m��Ey&O 1onE�R��2�%"=>6��detec�Drec%�MY�� +=."�F!� *��I��m& un��-ez,�!i���1%�G qB?t�"� S!(�+D"!>, �8NI3&5�*��to� a WT/M./ntͰ1�M�E��A�non�Gn�B7 TK!�CassessQ�-5 �y ؆�)or����5 ��Y�A�47>C, c�*n! coing1��A#% peak$y%%5M�� .���.s�7 �-:�!�*�AA�domin�E8>� at 4� �M��.63A�a� )"�E�at&^iJ�. F�.4 ,1�R�A5�2ct9�)�,�vic2faN8�;a�� �Kp'3a�z& U�I3�9-�Fnd�b�#ng��N I3%.!/�%s� To"� char73rW M�R�6!� solu�#��wo WA�� �dan J\b�;approacLwe util�Aotoco*v�@�%briefly6��rg�"�1fixi` &�Aly �l�-�<>o�6�-E stro�@t�7��%"ic�=or%�skele�=e�!�� [46–52�� �=6�!�-�� GFP m�i�t�� ea!��s or f�4pre6(�B81% Triton X-100�G]I�fix}��a6 .h)F Q2BQ/.a�*� �5�� L�$> ��Y had backgrouW"�6A� �� I-<( middRI� Ea)�>V�HA%i��9(6HNed��M2� �hH i�7 hD&� (� B� ��columA�A^� )�(v ��J�2VinNt�']aT, ,^/�+�1���&=�j-of�2o z��e�^��&7�;~"�+�"Ba"� ��6���z.mpone�N���`oFFPr�"�S *"dm^!(N&�<) �iYEwe ite$s {U� B3{f� 5�UashH�~Z/regJ �4ew article [53��Ou�,�p�F�.w�.nd�p%�to LErimarily���we�laTrm�8�ic5p��a�-b�Q1�E�6� LM���!�f8�-�%[ar.YDe^�l�H�3�"o>.�,Y|!5� ��s albei�5m�-@�c�A�oncertI��J����!�0s\"t �EMZ12��pr.� �D%�R%�i. i@t D ly�wA��lik�iR��oc�@-�afeM"- h &pL�� � @r� phosphory>!�,N.}H�#&�s>�U�!s  [54]�Y O:�*.3[6a"T��-Ri@Mla / exists 71.!����$&c2<5�,Z �7d� .��-AFQ6�*�&�!�>�� n7 o)�Ase��K^F�/AF�|� � I�6v�A�2�� F6 ���.�!����(u�!1�NS-">V2�!6B�9aBi7an.��UUR��y��i�c�Ehat1�E� �/orz subjɁt%J�F.%��'E�bo�Jrecogniz!c2 &K!I(1�-upper�E�un �iQ �V�E�T� J(%AJ�? �inQQ��"���h�>t�&Y}O Q�* �JU -}YL�Y�]�A�B� 8>RR"uZJ��?, 2%%�-2{ AGi�7d<ofn�J�:�a��I� �αPE4o?,� e la�Z}Q00^ @a69"5!i?� �Zi-E �:�A�!�F�� 3iPF�Surpri�A!)y��]x.&3[�.�C=&u Dly�6�S>4��s�5� 3f+ �s& %^!]d5iUZ5�Qr.B�!+�\N�J"A��w�ѩ�!62?-A-5 �l<=r� i-ele�%-P�!�:h�Im.�biyO�U�26f$( S5A–S5�C�s+gO��L*�7:++2�jݴ �! �Py�a�.�.AYa�Q��5I0’��)al&�(�i�E>I-���mo�&a!0)�5��� oaS�& ʁUy�)�c��HcfI) lock��J3Z. If V,2>�+� ic�6lHussV] *�1��E�. A��7�J&�_taUV P� TI��$�s�:13XFlag"�AF5�$( ~10–12W�+�d!�&:� endo�,u� ���H"P&Ōu�eU.rZS.r� bq[2�""� IF[ 2  .tQIAa��iz[ B � y  6R', 2,`�7 . 42�3in %o!h T:@1%&� �(B �0]B� *�B/s&S@"5axof�\E�6�F�;"]'�0e� -j`y�>�A� �?�vcL E�@�% , >5d`�" a1�FJeb@-t2�<o�} J] �!�H�BM%FD�.=616 nd 4(6.Y2%�!IhM"3Y8B`8�����*to! *s* U}AMC�eK��][ -ɾAN4 R�@�9..�3- i"�&�=luz/O�i� ����%)���8��BAbL:jyi�Q�iY A� � �!>#��B"��>s�rTOe�F5a�alMl=��"�e�� see\�&ial��IOfitA�� �G� 4stood [55–60�&�".�#B1=� " .%h�Odefen�j'!M�b!��'E�r*�4to�Ygi&�dr��de?N� i�ht" 7�HB1&�R��t�hhRNA--�.Z]> �,�!fEAal��or�75 [H"��"7@��+cur�@^ ^2P%p1 drive0&g-�we.[hl2>� p8 �%olueS. W�a coup�Z� wJ2�GKZ3 �Z�~%!!�2X�%;aaY�6^� ![mar @a~*�2�Q`A ct�BI"�6I� B1@N8 �s �M "yEp&"1?}"z& adap��.p�ge� ��0&7*`$, �PioE ��az��Rd(dergo rapidXtic�%an��%UL*A�,‘accordion�W�poE���ensi5ge\o�4M��'on [26)7a�O�( �)�q,⽂q�#*�a pV�)�mi"�[� Be6?#h��!%��a �[28�9�I�i�`s@W)S�pl�k ploiEaBFQ�%Sim8(�rQl�&"#A��'t��ed��{)�a div�US involvA�A�)�disruI\oQ�or �,OR� z"�7 �6;�-�.^ iNfe�+mlis<nKB�l�1& F[ qu�Z%�l�2I'g`O!�an 48"�Xb�7�in�A !�^� ��d5c[sg�w}_e� e�e�c ���eX��is�A�o6� a�E��:�.*hro�l1Ued Sa$V��� isof�]Avid#l�PY!&�@{"Pistock�A{Yc�5�8��`%�aj�>/.��;���%�E�#u%��Y�\l IndeW M�3嵁�.l`!�p�44FA���f�4"=��S� c&Up�1de�(ciH.[Fstutter%&m>av5i`1�f,�� haps�tribu�toD/quicklhP� �b�Yo)�!R�lv [61�4�r-A�*CB,go�gdis�b nov:<�/:o�?"� ��� ť�uyA�i�,�S�[n���al� e} �0e��6�I3?M rigorM��mJ� � m!O-�PM?Orthoege�ahav'`A�theor!tat"��8plaFa��+r�:AOa�!�famw�$�=! s [3\ &� � bioin�0 atic� �]e���!��Rcd��si�E9CQ"�R ORFs l�� mmon*k]���%K frag��)� �->nowᚡ��%6�6��6�c�j==cc�NKt:%5��M1� .I,e�!��e . O�Zr/L 8Pc�rsf��N���d%�ub� Y O � )�&, a�Ja-%er�<�HA urj��L����- e_..Wq��A�1e-e)l\k'm (E���kw2K&*�\� }]���T ���wZhMor ? o!�x\�lxFr&ROhLle�K:�reA�orp �$uto"�"�]�@�i�E": s employ!)�;"*�>C \ D�*e ��A D)� �&M� �e!�!��]�9V 9-���6).�66 �nd&�t� &=to- very�'iRa�.t+A�Q�2:-�m���#d� �Nutcg �B!|e{M@"Bs`G�1A�`q �&g$5�;l�3�: RNA9��-!�2�%Z�4n�u"�4%V.�vorO"giURBV%?>� arguAaA�stN"$  ir> mn� �p� ��V�D�F"BE�D#*�Q.! �����E !�A'&&(��,r��iss�9i� e"�L  of�9e�n8 �W@ oo�`im2�Om�� �t%0p0sa�ha[7NX�6NM���� olA`�7&�!��"E.�N16pt%.�� A����:�@ �"�1-��.�e��lon�EV2�6"E!u����h .KSa� "�:!3aRpseudo�%)a&�bc��� ��S5�r] B1-"  manner!_�uq)I{� i� s )b� >���/� knock&:� ��-�B~KthH gh��  #a)n"-F!� �j!e 'e U&e�/ng���Q n" cul�lor�x. logy!`�6�mu ol�O6l4�.T�&�e��12 beA%de�LWon�!�23g(Gq��@H$soE�or5m.f�e"�W9i� {A ll" ��N� eorjsel�B�t6v"� ��vCfl1�� a���S"��Υ2�� q ��i�2i log< 7 H"�Y+ QI*L �ɴ2KBE wi�5&= >�k workt�a�>!�%�5)�'go�(as6��issueU�!R$ vo��1�a�_m[1Vs�!NXbA�"���genicy�&V.4 %�2,YYh�$t�5A a�[65!�To*?Ehe ?0am� !�b!FB1/a�we fiI'^ ��o draw��vir!�e|�_!5po�B �analo�6@@!Fhe broa].s�V� liBe��-�M�e��� hhip�b��!��]ts� ��'aef�toxin-a; ( T�0�c� i%�c�a�ypo46dojodu�m�Uryly�>�%�e orga�U�/37rQ9 , 4tn6H36 RW� TA�pr�, y�^n�ten poo�!-�&l"�AE they��A�r.�5ri�&�bwIL,��"����P iHe�����I �%�)Kfer !a��)w. Cri5xh�ED!�!*��R#�`�1)he *.�e��g��L'M�!P� "".i�]c�z5}fr*�upsk mM��a�flu�:YT� � �=d�q���u):y2benefi��anU0A�s�*Hspo6.t� [34AV5A`6D��in� ma!�TAa�E�$rslittl�no��@n ��th��� $stead beha�� �qof�selfish�Ayc K6*��s� ]�er5�:cZ !�Ul�J<ti�E $TA encol8‘i��#  [38–4eA� sctj�,6/K0tm>C� :��-so�ly��B���p�@. &de_!3paaP�&L���a�U�sd��$: yond��es;� s��al/E2� � ��&9s~T�ADp�)"sO-EsM,m�VRK�?"! ��ed ��9� � C �2�"ns [Aԡ31��W!�eiv�a�!o�VRK�$y"U gos�=29m"� � nume5 �-2�!� n�Q5<.a}Ya2�tur� taro p N�j� beguf3disse�% 2��H�bN2D*zop nt��ago��+B12&�|�J!=�I��� �)#�"�x�K�0A�lRC !��� u �3�b.@We&QR9%�LS�e&S1 x6Q�xoY9��)e:�*:]%[11�HՅwe �a�wATs�*^o# �qy'�=t5 �! Ye�� 2�:��c"�BA�w t :��%9� . So�<�6� B�7is2<�^7V7q�z��us;=mpŵto.�)f4�T!��oa c�W�7�l2��"�AU�We4�.AK�" :�"E��c �s�@�� �6�za��DC4 [70�]C6 [71 1 2 B1 3 K7 [7&^N2 [7y^F*6!�E3 [77]�b�J>4i$��ntdk I��  r in�B0-d""la�.]���n4#@zto�{�&G<> �! ��.�. I��$�a� conn7\o���ay��Al�Worp\Re9%Q�B&�B1-&| U �yM3"�o(�.My@2!�t�b�'�ctA�a ��� �u�. Mea�) 6L0.�-�&ia|ed�J�>�LWF��aU�6�E�.f!�Bw�>Y,��E�D�7>�^>Q�Nsi2mf:��2v .>(�� 7)�&�/s��5 j�. Pf ��6�m��s� *�(�*a[e� [�AF�eAestAH%[��2l�G"*] �-��,��}nE�! F�����B�a��?+ nd�d"��5}��ine�q^i�:(�dR8��FAF�_'�e��Q7ir!*7�Ie&��<:v!��!$� *���!�#ea�nd�-pen�"_w���wa��?9B��u ��o0� � Ѕ\�E��b( ecY�uriggeA412X( �����*�frequir&�t��y� �tA�����*,%~ +���&� a�7-�� unr58= sighD})�ME~L�I�sŚDn�circuitr؀�evi�-��"f "�#`a/\&� AFeO!C"� )4$raise new :IId��a�7l�Y�>%��)�.�A.�z g��,%��u�i"���[e�x�22! k�Ԅ�� 1jP�b4�]5� �pe#i Hat�(,IL}=�=uҎa#���i�K�d.�� #a�R$ �eukaryo���2�+ s$��maI"��hel=��s�ʌ�0.+e5M),)~<V}"+pVSVG)� sPAX�a gifBAom Did sT"� (tQ�U# 1226�J!uc?30�R%Ff�-ż![: ̓ 293T-fx�eshE�aJ�5mM sodA� buty%5( EMD Ma�p�Corp .!��d!�to `16o?2�. At "Pa2,�Dj�$10mM HEPESj s�;S&E)%���i�hna�superna�1�c� �at "�x:�e!brene�wYWS10��iM,�[sOtat -80�m.a'ned*�7 -�%��|Ή� hygr��B (.�d55 �AQh�4e~� �}0�&�e#"�e\ )NiIhe�MCSrH2!9]w ructP��0�+&�� � don-&I�EOR!H~ �^^1Ԉ:�GeneAr� .>f!�E�*�a%B�yin S2 TW.��32�AFtD3�"�XBamHI-%�� �>��"�@=��/- . L��.���fM m�6�(�g, pTaaREVGag/PoDR,�`N58 �PyL��^!!e� zI��re��%W"hTō�*�(:na�i��al.� ΎE�a ۊ*��"�*� �:? >E �K �c�T& �!�mI{T/���N4�*dar�!!�  �R!�kin|+sh"by>�lab�orh.]�C�Q":HF��amp-�u�� RU�*�$ XhoIA� NheI` tUm��A[� 6t�oU�)e�A�� t�u2� [80] flanBit)�؎s.F�"aTK%q& ��L�;IC��8 "�at�Eޛ3M�)�E���Z�E@3�� arÑ�35mm � 2�^&&F48��Ŋeze/thant�*5s��e�a)�"��xB��y!2�@�� two  R� `�XonAQ)�!6� /.H("!X� q|F�6l -��*�N25!A /μl� �oxyur� ( BrdU )!��(�:�y1�of 5�%� t"7X&X �ǖE � l��<�&v����:h%Qr0 qu*��.���&Okg,a!m�`Ai^F"�F~6N]�6�&�Z�V=p 0/50� � �1�V1S�i =pE&��ד.�l3Bg)9/6Ta e�qJ��) e-�aG� �s"� :���(!�A �:e�(�)F ���D�w . 3�1-�& nt C�+�wD5.4�wE942 ]wl Y WRH/��%^�Eex-�on�/ BSC4�#Zor2oAi�;a�R cr� cush!��+.��-%�A2�2�)�V�a�s�"[�J M�.�10c��� -��$a�L�$ S��d�X"s˙�$69peli�!�s=U 1ml PBS .��OG� %jsa�0�GaY)B�� Q�� ;4ns90i) TrH �u0d%a��a�uW Q��l.2� .W K.� ��3��m�*59��m�0�&s�pa�ge� �x�i.�2v % I'/ MI !=g1#���on-K!tF�. Ser�����2jl ?Fs�r��_7 �L LX5qQ|�YEu �a.V{�� Q2%,|%K) �V!�^*j�P�9�%Y @!Z��3v or 30���mcun�%(E� )hcF�AO)"�@:x,��t�F[ b��5�w>*Oo{�:kA1�17s 1A�o�-)FC�OY�ZA=Dd��2� w!���.�!�� 4$�vES6?bL"J�V3%�4. J��8F�N�� .�z,�c� �=8J�>ai�쩑��Ơ�y)$r�9nV �J&'��:�<O�!�RImL 2U�no�9r!���,2�9A�E�d)�m�.�>�M����L.;EIing�y.�:ss x!&� �jclAam�H2�4A�)�"s�g. Half!X b]lnq���R�#�.]�hoA�>.�6�,.��ʥ-.� s��m�lV�Ɋa�I�2�_-"X�:1�PiN "n f�cA|%�E$e��� I q.V f*�4-�0i�z0*H5]* Sq�yd�lt��~�yc!y "�Katy_![�-�@!JaI��*�� Z�s>�2_6>"� I�Yn���&A�5` D!]"�&A~�����V_�Mcuרj�.�j*�2�48B0!L.�-}ᢁ�]�f��CR�MT2��4�N�e�:32��2�,I�!��c %_7%s���w .�&�5�5��rs�Qb{�"?��Y�� N �]`or+g9�5 :AQ!�$B�W��wt% �� c����a��4�V'mo֙� 2(?�� Q�fo�<.uB.�>a1�6�;t[}�)�H!�Bq]*�WssS�:�-�.i*O�� y1�.��=10 &6/sN]�6�Yat � ���WZ�l��X�G. !�o62Jt�q()W!LWiebe.@��T�J�D� ng`�W�%��Dsa�C��ev�"�g� libra�h. L eW0"��:n era XT ki� Illu 9� manufac r�Gg�%�(. An aliquo�'Ol���ple)s �R � ��F� ��� e MiSeq V�* stru�Y. 150�6�.�ep� aired-endG! �&�J *)�Op�e rimmA��n"ФPmƀ$�Ze�"FHe��ZQC scor 0�<.%i ,=\�.�E:P fil�_d� !\�?ramwGtq_�b ity_ )I+$FASTX-Tool!���!44 ��Hx� �=ast 90%%Vw1�2 ]�30I?Qwmap)�;VM of V�-�# WR (=�U�( NC_006998��Bowtie2�@�+�x4%Cx���aBe"WJ mapp!����e '!upl�7�CSRA�8�RJNA4905�I mm%;�$6�6ag�e�m�i� 2O�'!� high5>!keQn)�'�2800�2000x%{d,L�q�fof 220kbR��8yT0!�mdup&.3,� ~ i�!6inser�d*�G�I )lk*�!d--�)a�f-develo}I pipe�  lu@,samtools/bcf 2�iscrepan��8'o F!Cin <5%xE�cêha�=](�KI�I�L+��;K%B\�)�AH5�e� visuDuu�,gA�d�!� BrowBX( IGVE��5#�.T�1(��͌ alig�!�Alʯ�!�����Π�p4�u*T#f�o2 . PA=܁`�pv d!�2^�Y��  NCBIyfQ H(��� � B� 3/ =Mh. "�|I�:�AAa�>�a� 1kyL6�2��WT>�1��!KM G� W�!�� ����-A� 6u=(k1Ba�byI��lwJ�R�TYW6q�-B�W ig 1Q'M���2�.Vi� &le.h0Hl EVd-,ed,+ =�9!M(mipop�2>�F!1!�10�I� V@j�N)uY ;Y ages1, �`A3 ����(wicI& nf���� S Q� "J� !�& ͱ0�!JET)�-bl�<%�icP L��6��(�rmo6&$*l��џ%�2� Taq�o � 1μM�� B11R� B13R*�(.W� 2U�2G� %�%�����G���_�� ua QIA�NC2� �Qiagen"e\#Mt� submit� ax�O% �2�!�����4.�a����rS�bu�� fA(<t d VACVt\!�B�E� %�0�A"� e>1 i �A1 s �OKaF)2F)�V-3>-6 2(� a�dYo��ebNM.“�m� ��gays”%��$*���/GQ�crbe:"�K%�Ak5.2�!\IF��a�c6c� Bio-Rad iaIUn2U sal SYBRG~��'mix�� A\M<Gv�lw�cha�>0/(a)f/*81] RAla�z�?0/RUuG# se�In.ref�WT9*!;)V�B~�C�h ta;$W !��3e:� cF HAe 62�#a0�&�S *�#i�J3s�%ut 10ng���� L�tR*|FѾr1n. Vari'}e#U�9%�a�aB���`�p BJI4�EB��Jte NA��$"l�E'2��#�Au�il!� "��)�-��>�,�{7��a��i>�p)' y� 2&� �am�Y� �;gmethods�vv�=. Sm�%�2��� HAR2�ri. �i�M��?a� �!&2]. E,� x 6!F!�u[C-ng��as%ai!<�:-� s�{!�2F . �-��w �A�4RNeasy Mini Kib*�R�}64 crip%�of]*�*g.� ^a-mEcT:+.KFR��?� mo FB -, Appl��Bio/]1E��(��!��T�e����3 �,MIf$.D�UhP�:�Em�Za 10u;h��, �m��Rat�25nmol> ��f �E�.3 222�% ��6�!"a̸�<%��0� 2X P1%T��� 2S�*A�Mas�Mix�nta,2�4�& Each��I o��N,�e4�%a!Hm�*�W<��T%#n�u�r�a %~/)�I@! tq+�A%f(~ɭS%K���8u�� �e>�2Ŝ&�)%�-���5n$ lipoBaN�<%�v6)E� 5μg�%*��" '%.�’���!�s2*i!t� ���5���Ja@�<o��N� %����xa�6||�fP!�;}�4&�!�8�e�.���a�N%�L.��% iMAX>�AT100nM�2���7�scrambNP�Rc 2Z�z�� EwT��A)"�EU&� ?���$)�!��aB#!�*� .�� z%Yn4X2*|`��CA��2&i4�|K�VZah%6u�2Y�4mMessage mMach�7T7 UltraF�/ mend�` *69)w �a!0��&�1aHt|2a���( S"4�L1*�:<1;P� �h�QatF�.or�.��6�.2*��J�)%�5�q��;J�!Pe/`Ma��%�E��T%��~ &P< 12- )39�A�BF"= ɨO.�It��$!qerm&;�Wn�da!>Ni%J\9%�Q�e�EA���!�qC��byW a� �V� *t 1 X 10��5 3 3n.�A2X SDS�9-ͺb}0:a:50ot*:Pierce9�aoGas��iA�7 2=6, tryps���`�.t?"�=^3henyl� $ylsulfonyl�8M�!�:7 cock�  ( Rock ��C�ca �H� B-z%g� film���doc��~Rel?�9MN �aven�e5_}.nt�� �Rawf : � ��"NJ w&�ɇ!���!��2![F�C�[ �1Onor˞��B1���~#�Uva9 a��Ie��"� J>as��ed I`�5rm��=N�=@̷ga��� Fr�}�o%�5*.Bby#�g:I� &O aL`v��!Y�*�z.)8��.�v*� �Bem4%�Fa�Vldehyde�=lfa Aes}�e�"�)15�T6}L�2>P�( Sigma�a�G0m�o �-T�:E:���2h� ro݉e";^�h��&dd *ia5w2� J��conju,2�{oWeS��v�1�RT~!�X�.���a��Y]3%6H>8:1000�G1)BxE���tak"8an EVOS FL AutoE#-A�S�:d=%!j�r����exc� on/e�_���"s � (( Fluor 488=TxRi�59a�Ǔ.�eJJ�A �mr�A eg;n�E&�%�.D �M , �-o�hp Y?6���8x� ‘P�</�)/6� Az’.�-2S�3I���� ‘Fix/P&� e%��A��<�f��Z�1:�^�30� � �!�!�/��[4,4�T� D��M�.� EY� H$Din�I�(e�"0��()�E%͚)����F�0�0-�r� $�.�"tOic ( Cyt�d "�( Mem�#�( NucRBđr���( Cafcs�� d ��8a �vS*�P� F�A�K�' uj`dI,RH#7884�C}&•*(�'e&*$�.��): �6m��`5,a�% 1�$�K1�9!/boU�!Tat~ nd=TDV0 �� %uoli��d9�as>Ʌ��NA�AF"���� ��\�M erro�.���V !�H�? devi�!�F �'mean  `P utl/K� Prism"�) stu�Aambigu�ouN*A��g%l�rs�o˿trQpc�%���ol�wCon�U�:i��w !_�/"�*is tiA�susAp���. b�%al!��S�,p�p�sal���Yu:$� erfa�I!�uN�0�9*(ar dynamics� %!�oz%x.�b�^oXwF�N]LKKLLL ( LK� nd EAALAE�HAL[Y,�A�t-!\&: Y��u�����a. pha-YNx2�!���q��_p a��ly�Y]q!� aggr'NR�Ta'~`�]{>cop��Ipaw�5ri n�a�Weaw��E{��se9ne{�rando%��" in bulk w�f� ��,�2!�Fi!�� adop�+��o9�qE9dqey��\i� life�5��?W. a�%�[6�-&WB!�&h'p)�e6�h�hcDƛ�*1�1"\ r*�am��(B��DA6=�p�Pan/Qli[�tEi��%fEl>Nt�T-,6�.!��e>.��.|uNOU�VvrJ� �y�r .߅� M{�und���Ksub��fV?E �su��#rg?#hyd}b � y . �!� ae�H�b.�\>�1�a�%1�/�z��at.q/ }i��R��( HHI )�y�Jru�g"�tbio P�&qp�e2��\n�!)� hY T�ml�6*4h�!' URye��Jamyloid-rRi��{��e*M���V many�Rdi�7�1amongjm s� LUurodeg��a�!dis�s [s'�!�� %�Eg��Ad+{� �?i�%o� )��,1T�+ slet� %�APPK S-β�β!����α-syn U[Ion) g-!I�a.yrol}���aas,i Y�Uv/�%>��! �� �s/1Ea[ ��EH�qs o� "T pene��� rupt��x ore-љmE���.us�.[ya�"�42oaes�PX@m,a��ri5�U^�s,k�Ym��a ��lay�_ca�!sy:�so�04el/T55W( CE� �vezv��tERooe8%�t�z�delU�'~�e� �� apeu~x�� |�"I�, oligoE} otid��r nano%Uc DA"�. [�g6]eR/!!�!v.�Z66�j��se�R)�� H x@v�te@�� x� �! s ( !�X?��,� et��# �uY�zp�va�re hX��an��p &I� ����� v�nus β--riX rr��/sE�I�!9Y�&�0� )�8���3i��!�O Mr + ��� it.E1�]�'e��IC�f]��>� s�����A�u�r� � ppe��2f�3 ��p��1>A�-sheet �-� 7lY )�i G5lيre�p"���c1&�@ i� selv!�yp!�� :[�Rur-�05[�j��"ŘF�N� �ѴL1�p�W �7ow6��# � 1"�]��c �D^�$ X� n �n%�����SV!���at �Z�Sk&em�V*a-�!�[yfIn)�}r ,i=l�ki"]i�&A�B����a��3p=st�1?��9�l/�Q .�A�Tp &Z 5 �loFfs�]}n�za��w�ct�2��&�%�V���"O�ill-defi���]��v82CO&� E 6y %"�t���!No k ca�����"�ch��ng�/ �!���B��Qc��A"�)teyeLyF`E"b, fu%�ncU_�f� .2j&��m�%A,�s� !L��ŧm�1f6:�$b�med!�E<0 �] � air/%!�>5.�6��({e�"�%26E Y.� ls�{@<toc .$ehj���� .|�f�(�fsum݆19T'2�aa�AB�7( "2[9�]N > eS �!�=%�i�H (se—� y|A�� ed—F��i. i� 5(stl5yezh�p��rety [13��TM"bsi� ��l�! �./-&�[�Y_alf'�„�a ly-q��g�CF�� r� ɖ'=tq�terpret �g((K�B��tro8ex&D Q�NMR�>RA�� 6���O � -Aane5e�n�� !��ahfor[��/du�!.� �"`j[om�dc�<%�e�una�F=r�p�B Ek����aX%<�8;����|i��@��� u� �r �. g� -C'bo),,P5��� �������*�),� K�  ��,T] � a5!��MiBh&�c�{*�fasi�"� um�tw�]&� )�f�g� —ŇaE�[ f�Xm:i.��#)8pi %S�e!nl ��5F Gis2�a4e�c{n�ayio�V�@dNLK ea� �qx%a pH-switch�9an J��DANso-� ,>c�@T—�� �{� �� play*��w �" .y�;�pBp t "� �n-�f��t$.�m�o5o�#h p(%in/-���1[17�A�`P| �*mpo��euc�+!Xlys residu~Be''0r�x.a)���dsorp!�&�on�)d& E}Od})���(�4[2 oR���$�oT|��inmxi���gcoa�2g�Uh�2s [21"[AoiVl.mk!YA/cou@ is pai+,I%1�diI!a�Aq�2al9 �ao�I�m7Agi��WFT!�A#I"at"� _W�5���""y H r�]� m&sU\��.^t)�.�.�%�=1su��2. W� O�maeUvYl(!�(<� � g�cP al*� � 2/���!A>�{7��PaG��A�,2F�na-&.v).1f�� ���,W(�S�� mi&i��: �t�k)� )�<nt ��f�*E�1ER�Al�C���?�rar��6�a+�lY:(^�-��: h�& ��S�—!S1%)[B�e) n�����v�Y!� " pl�G /� ��L� ( �CacuumB' .��� 6NR (ߡPT �QB6Xq5�I�U:�a2��'�*� P&A��L.����ly���1gn�a[�xK2�22hAFA ���*I-eA'M&� *��ag�&!�!'�/$s and they�< appear to affect fibril formation and growth . From a comput �[al point of view the vacuum/water interface is an ideal soft hydrophobic/hydrophilic model i9(that allows�syste�Pcally study generic e�jPd fundamental driving�ces . In�course��|paper we will first characterize% foldKequil!0um@(2fA Fig 2 ) , Lparticular with resp!�(to potentia%J8rinsic disorder����V� , i . e .Z(out a furth?E%nviron-e)} . Then5G$subsequent5�D, how mesoscopic i1�s (��A��air>P;�iW!�structurEuI��A�The2p were!ara�fŊn�N-�:-�� . Analysi�!�F�al��na�8via DSSP [25] ( �CE�(3D ) reveal�ata7>�aV�is noa�abI=��<@y adopt a variety� different2,s ,A�re��ew2�$ve snapshoa�!> hown�.�in �A �B ,A��Gively �5��Pstabila�of2LDcan be assessed bao�l mpeteO betwee`ree main factors: Coulomb�ulsa�.e!�0rged sidechai%}����a� |.!u�,� backbone-  org Cgen b�a%e , . We discusAei�I~sa�>� by D ar�V their run� aver�I��z� in TED��W�tLKA^ivall six��i-��!Uanax5\A8lo�g-Lsam # �jxM(electro� ic self-� gE�am�U+pproxim��by#( scree�)�Q rt ra��8( see Methods )��E%�1Experi�E(�!{!�chlorid�cen�$ions sugge�random�aq� �(LK . [17] H�our!3ul i(infinite di� !s in a�w�)�A� �aonX� $, (4 glut�  acidk , hagsl��malle)O� ( −4 )a2pa�{�As��Z in 6is� ��Z$�q��3՗!o7 alan2V. Desp!*�� seig1� dueA(increV �y�Z�5�e"� � ��FAhaE_, 7 . 8�,5-n�LK:�Si�! LK , y()�deprotoneK6�.�t pH 7 )�8a� defi! .��6 ���3B%��.*�% � n~a�y  tendency"� V�. Qualitl� A�Fme- aA����&� have�rL lifeV�:�G�J*un�a,ica�drAGd A�<a�=�aU lf GALA ( ,o" ���had b� deri�H,k also S1%m)+uto� 576�[2869 �%��be lis. a9dominant� F� Y�� mK � Upon,shF_ �@�!!�7to 33"� n 6� m��ign�ach�  �(e���}d to 29�z2teres  ly ,��strong2\� �,B{ndb��:@ I&Z�!�bw��-�27��1��1d :�Of� , MDŢ� a�� &�k�e$it�ne microi� l!C ) do�EDfull pi�� e�F��$moO2��we%�far away �Rngtpl�b� d trano A� repe�GlyJexhaus"�To ge� bet�Him Zm!* amplr(8 � �eofxwe�.+ad�e�*#.ad*B E e�*�velociti�re)�A�"" S2�TA�Vse.w!�u��qp�.7 sY �Td%���2�Lm�conclu!2s did%�i�: NA(-H.m*L� � take�&sfal hund��x��leaY�t0 .ey"� .� ,�.��J �; s)�a hig�� _i� 6?��aqueous ~"iEimport��te8�at!Zse�sqUbe��lik�"� il� "� �er��peaB��.*!Rwhile��mos4 is loop-v"D\ige��!$o β-hairp�M�is��H a$inv��W.� �^&B����e drasVh��g��|z � U.��reew�2 ,� A�!�(vi%�Qo� focus `)��ofY�ML5�%ia�ŋeQ"��4o� -� �/� phas!y�J� ( exemplX.��4A22�fka]  ( 45��-��)i\ɁHu�# 9�Me.F." ���8-@ s st� lacka�6� �#�"DŸ$they reachch!1�-�4�4��s;�V.�. S�q�)�N�e6srgA�"�u-2|a{9-��in�ncipl� so m�eIjac*+9T�Ca)R!�ť96�e S1,��&Mydig N�� �!C  ilic���as mar!��sharp�t i�4EH4FE�No�# %cal~�V is p"� such�� !<�͎ � "��6�[ actu%@�n6o�! ak�� ccountQ W�'aPCou�%���< �n�I��� �N�!� �A8bef n/ �!& ��a-M� "�%&_ N�Aŝq e� �2 ����a #��� d deɗof�r^cw  group�qib���� 3�^! ( � n curve )��ch*�,!��  enough�p� n� .! 2����t��L�}! s upW475�@,aW $%a�E �+".�rt T�T�)q�� sis>r m�t�3� |fin%���AN!wA�� X���ũa�go!�th��&er� !�*��Q���!52� c.5pepaHq�]"�)��N ���s��!) wa� rectly^ d!{a���"�>  ( S3F` ~b �9� rema��l�� �9�! .I �m�!�L,�a�saf!x d5 i"�szyeө�/ i���kA�nd=��@�WiP $ � :���!XEMN�BZdoe� 2���e�F!W�uo?!bt���(( black lin�#�6\Q*4���already�$olvO!�%� A�2�refiy��r��(ePoaR�I@��! *ie�U�x_! a��Թ�. qod$�I�Mo�'t��B�� tram_a�%M(!�)Iqn�4)be&�. C���������A�6�%���.�o�S�Tor B���e 5�E�a�!( �u*!=E��a&C(?unf"�\6�"? ��)�u�ean�6,A��6�$dis"o�!�i�%8 e�.�>#�Yb� min S4e%I�data cl�(:(�4 �  or �MS.��ca�8ecA� "�&��� dd� NX �� ��6"}q'A>2�"a�TW&< Y s!2o m�,|O&3 o�!6�>��-A#qj(�now6 deno! as A,4'5 sm ����e#!�v � �AK�4��)Z�-��!_.�,L���n� BoN�layT-�<"FT , moA-�e���!rt%V*-$��))+.� AedEo��0��>F-�D-�]j�SF�e�h.GNo�s!nde� #Y.�@'ap��]ne�� J� nH兓>�en summŠ^�dicJ��2?m�.�ac a7!� !�l �M.�Red . O��2eY s� –AJ̀�Preᔦ(,( Ͷ6*–X� 9HndW�(�-!Nq.�. A�� �+f!#yn��!ld 2��A*4-1�! &?fas�� ~�&Figs 4%�5�H �6��� Q,� ��)M& Ber�\rd Q"edi�,./ � M/>�!�( re-�'j in ! 9i� u;� �#oraril2� ��$ ep�^ex�� � .�g ��%?�vG may//e�hm(* barriere )1� procR&�z%�&s ��:4�� ��be a"�u-4%mmoW [29]�u�MZLK be�E\ slow� � m!A��js2�3 dip�.. F2>ol�)ed��2�,�fl+0 neea to sup%0 hypo /i As demonq"mڡ#.�y�.� �63d3ed9"� depend"�*�2�\*�-I ..�>�F2��"8�IT-iZd"& 'I .����!`Rj5,�Galtern�N��excep!xe:�a��'ly elip!�,1�Q<.t-s� 4& pop-0-shifAA5�ak�X>�� [30 , 31]%|��� ��t=�K4o� � E�3.�o�6 e" $� etup���#x"$ ,a�tei��n]7!& surrP � �o���e�se.!=E� �y�"u �6���# Ba�-jK>�4�eri�!m>8(V^<)E�wo &�waya�F27A �� ir�#�y%7of� �![!7R �guest.$fi� �&rea . Seh.bA#perman�{)�+��}� }�"�0��"�4�J��-ak�w*�8i.� %Bd�7X-��W.g�ee07vI&@f-�:2��y6��As��8��+Sm�a�B��st�3��, {AJ��s�%Gq.��) sA�ee� 6�26B�S"�2del �!associ�KAV��%�i�0"� J� ��9bur!��,�E�� 6�0�(�Kh2�dY&�^��])���6%�A&�:�.^&�I�� biW,"g LKP s�,586�� aR�). Now��Q�D),�%.- is q2.&��a��"EI�F�� � 6 left ) !�,|�B &�!� Y�E��� � "( �� `i#6�,I��+.�a�Q��ni de[2��,�i�;� *w }�7.z=O ��o��a2� �?>�2��ed� rapi?# . It�ear�&� V�na�/!f LK accele�;e"W: in goor"r^o[(��tafly-ca�% m,nism [32"'w(> is e��lis�!Xexten�"� '( ail�_S5EL,�'a�S2 Video$4Altho$he kine*u *�*V�is�$o�8to �'� b 2-���it� n#the'�&)!�A�z+ - multQ path�exist �,�advan�<O tipePb ce���|` typũ non-.H6H itu��uAe!�!O.� Y���b �-�|plore�ɩY���4ach�w�uin{JsU�y�1i�!�.�cU��\W �ac/an5��� ��2� �&or�&�a� pa%��6ly15�?a.����96�P� s ���u�����*J� �Y�~J���in��*�+�R��J9�� ��%h�4V%S� n#v�� �+�+A�3+(f6�2og�#-�6�%!��3��9ed�?ier�FG s�8%�Aarj�f���to)6���B` a� ter--Ear�E�1 SFNH36&� �eECCo>>;E0#s zero (�!p���-n�s� �a!@��U100eGM����sy&�#��*!���,�g dime�m� cE�mai�/��"�I�my!Z��M�ce��?�p=!z!8",Q Y!�1�e�3 �&&�) �2{1@*JAd.��n��TWC,R! %*���S6��!4%LKuys�<a��s.]2 ]a�9r/r.� =�matchAEY��_ iliz��"�A-d6aB�}Ru�:�%�aAI� "���iA���o 57%1�v�1�(B=I'u!�B�6�a�2f�F {%���.0%E�A�H4".�a"yeq;�*�ect*�9:���s( ; &�E�.��ne}6*8��u�aEQ5� � ��4%XLK!�ms te?B#+:5 . PrUF9u-72a� �ed LK-S��6�<de80~ 5�A��n�%�+(EOS7uQF��)Bto"�C(e23_�4a�.�6 prof`+� u�2�.!We�aC" a"�9���0��k—   c *!�q—� �e_a.ze� F�n�bora�Uav�:� ���� �t iphenyla�5.x, a��al��Qa�N19� ion:H*v��Q/op�%��,�l;-� �Wprovi ��!]ea�7gGtriggA�W.�6�f  ci2�� �. 62a���h!��0>�(2>��E!- �� [33]Mv(aE� �?*gor�. A�K�J,� �<���&9:�at"�@y&eor>!?F�ir2�.�6 *`(�pA!�.un�.����2�)' aint% m?}.�%��Q�T.L�*.���Q6��9 panel,2��D >��Hs aVX(�e�8�>� �@��J8 .�["!-% �,. E�3if��4�:�i*4 .)�Qb�2Q'8%) :)9�me5-&e2"�Z 5~&���22��4=�=fA�� p y%(� FGN$ele� �e urnA7c�15N� One keyuSc�%>7,q�6�9"� plR 1N$J:*[ir!H!'�.peae��c1Qa,�.�6�g&� Z.2A�"wM�. [ beca�/ $q��%�/ capa� < ��e e�*� ��9� ��-aC��e%�2���Med�:M^�5�~" �!�m��>�<no �p� :��1�.�mGl��!K�isAx�4ge� pur�k@.�%ttr�&!3� oulK:�� M7-�G&�HJ�s&�O ��P����pre7:� �%u&%q��t� ?aly( u� . To� ntif�;strength!]5� �*�20oyed umbrellaA�m7�y u)e�Ome-'c�XPMA6k fun�I���F"�� .� ^g 7ka� �PMF�f�I7�A��"�H�%�MlE�)�s:2�nOSl*� �,�qna���<i� neut�12� s!m� �h�no a2+.%��2ClbFn�Zedo".���&'A�" ' ; dat grey�� �2�H�%�>,_L1 ù ?%�pr"�6� � �n(� �/N_�"" 20 kJ/mol5�c]#*SL!�1im�NAu�O mum �"d,q,x0�3&�ly�W�Ba�a��m$a�"(:�$above 2 nmE ��$ 1&>) ��:�>5 slop���� �o&�1�n%� �)�&$�| I��UQHYm1;Y:�.i����Tf�[*.Lorigi�&^)�MI.��@9 ac !�# agJ t"� A-y2 prob�%t�L�cU?g�-P��M.6"��7��j�2��)_.5�2 ɒ�ABAK)�!8�er���s$5x6� < �; olum�.��3,���r*�#5�.xis�.O�a �0M.fc&/ . Du�`�.&=��O5)� eas &, y�J2�Q�Q�~m�� E�'ase�iN1 sAha�VTK!�v� �Bwm8sonYam6�s I� �block&m+he aC�.� m���@�(S9E "u<PpooA�u�� %.�6�of!v�&�lW9duAFc�/IvHFe�U�za�q6�tre(&� ���A.��10 �)�+!��fo"�[2a��(�m�6iP.����V . a:�2; �-q"*al�aM�d2��su�IAw"�!�� alu���E1oD��V*�a�5�L.0 0��weaklyr��)!�7e�&� ��se>��1�u��G&?EJ�+E].&?7��BT.� ,!��� < &�Fa8m�#�i@el�"� � �� ense!�� �=s_Ear>>�&�� *�>d�< . Remarka6Yiti{�.�UJ�Z%�{."�F&�>ly"� ��J�I�� .�A ��m4!j(mihi��-��i\no��c*�; $�r3��a�nM��C�#Gng%�Q%&O%�n!�Ec�o!�A&/%-sh w�<%2�H comb�7�::�<-yZ1� %d ���%d9x� � indu���7 :P#�Z9iu.%R�@+pre0 �L%T�5%i E!x�Fal,/ ���0a:-&� ecK�b�[��%ofn�u�6�&Ql��'W I&A' gur=խintro!Z�Rbia"�+��x�U&T{ion/di*+&�F&[S9� . B!�.nre5YB-桎"i2ntimY"N'��� &uDby�$"wI{8j$.�"�1* �3 ;KY�bi�Em� M*s*.?c���ȁbp �E"QL �.�22��I�u�(oY��jen� {����c*t@.�'"xaeu":a�8A��� ��6v&[�� �m02d7��C6x�%r7ej3,�i?-Q�`l e)�4afalls a����re� a '^�(b a�I��i�,'Dmas; >�.�Ma�. D +- Q�!� m#"a 1tHref� wast"� Ex)��5��-U%ܥ��s=��V6�I52�. ir=xc�5�X �Utri >>M#%B peak�!"<Aomako2scvV- .� �-���c�&��"Sy=/4,�i�"� b�&J-��am�5 them R<.�R��"M��b�7aE��< lignI��� S E6inM&���I5Zr.�E�- d�?�52�|!ndisrups< � �dI2?.!� "� E2jE��Aa!�:Paact]�&�v���"�s�i�=��(� )> inst* � \ZL"hb3ig:��� E�ij%�� 9�PW� U"v�0�L�-�]�W!2o clos,%F. ��TI� s.AtD8!+�X�(�i7"�=6�&0A��?)���~NQ�-�LG�Q>%��-IEGig�K>�� a#f��g�-�5�2����P�&y��1 ��*�B;�Yfo�ia*C �%��"E7Fv5Y�q1G��ad.�=b��invers.�u\: More�-�* pM�B � ar�.��:6����j=U4 1�� %� 5�rZX  7��-�I��(�Q� k�;��� X-��b!'a)��- ra�sF� . Un&_A��� ged^�-�&�Us�� [!�]�wa5 esum6��!�"� Aed*p� "!��("� E��b�UA��B� ���b�?�< eply�;���A߉��Hc*� "odMxA�wA�<6+& �z)�amu�J�&&1!n��,s" ��� .D�a��Cy?%E� ��-{s�!�Xl�Zl�<hT ��Iswitc�"��� -pa .Yat T*�I 9A�A6��7��zd �^=ob:>�-����9�ia���!ig 8H� e�:ra%��D �6[�&T#I2� ��lEIe�c�69"�-6 c ofv*�K�8,%�1JWing-i+A�!\5[.�C. S�,rade-off1�"O�B^9IF") �y�+&iz�amR )ra )��� #Ad�2R�(����s %�YA�h)�-K=2�J��s flip-M1��!P]�:Q�[���8m*�!Q -ayA�A ��� ~Y����p �dr� ,�stU�F"E:��!�u z.�a#?D2�wo synth�4�P^���a%D�Df�)�nt��?built�.&7�  a6voJ( v� &�!5.�7J2%�� �-��d� ���"?:�5�D�A6 �)�%&�.H�%��"%/� &a^��Hof�0�rI�e�_K|s w�# —agd�bq:�—beA�"�alyL 9Sas�Fb�r�-R6?. Oft�R��<qu]a�I oL Z@ Z�7^&� �iA�ru��G!�!�>X5�0a broad ensem�-of���rHQz$ vVg�^9�!n� ime-tS-dh�{��J2^.\V extremJ [ �6�AO*�c� I�bs5���!rn*g/al�7I�d&uB�6(o"��A"CV�Qh��).�� OinQ!����%%0�-l�`e"�R> ��)��o&�;!�!Cng��.LA�Io"_a 8I�Bq�"5depth�nBreen2 .Fse5�y�"�!�fy!��F s wh�  m�jf�oly5�cer�*$B�-�-�ˁ~I@of!�tin�1Y�%�6'$β-sheet-r amyloidfys >�.YIDPF�ms A-βA $α-synucle.dq���F! One &�AclaMia�rI3�iQ�]��%���o�;:Ae�ā�'.�3*2O� ar� 3qf�VB%:�.Z��Ra1AL2V.�;>" �0�^6�3/p�v0K� � �$NiY*� ��|Ae )N {i�!�j�m&�z&���hD "�'F a�R�$�E�rL I�a>�6Ixz,f��� �V�)�� �Q�K�� r�.,�-�:v%U|��Q��� f�low�(ut�-�8Xu9 |F1��!f6I� %s1m�H!�6���FA!Q�>Me�Yi��k�`Q��Hp'A�"v=�enh� %0=�=L=gp !�(� le���)U'/���t espo$!qG�^.�"�{� � �#�dne'. !��5y�!!�b.�� 3J~A�a5-2�4��>� � U� h�i_  ;c"�M 2�R�dFm a*D-�clu/(����?.r).�u �R�Z.�)'AK%%�}6�� L4"!K!d�iK��-D�!Yt�ti�..( MDz"�7!-�&*""s �AAM�)�?'s"� %ׅ"GAK�linA^-M'-{inaYnt.$�#�Z6 6'$*)i%u# �@6��cn"^ji+W� � Y�%pgen�oa�& s�>�N@1ng glimp���0!��=�x�b+����n!jD1 �eDk�ir�r��aca�N�zurpri*�R�'J`C�dC� WC�&� }�uf!&� �)� ro[ ��VNC!5is�s ris"?*-sM���e�� &�gz��C��"C@��a����&� ��,S˂W`B�Ten`8m--l:{� m6�!�at�'�eZcobJ� %bn8 oA~gu ��A�i�f�����:]S( i8G�K6�7mbigu!a�( i/R (D�t2.� �Wm�.�.Y"� �lso��on�*&[�|." r ab*�N.� e.?�}A�& &L(e�"G �Z .�*�,2��y[!��t,�v�="LZmA�=��*�l� 6 >{�9�%��}�퉬a/A�Q)B �F�?��<2 %p)�t work"f&g&�q&�I&�$ic �%��'x6�Y43NdelU^�8 d�J4 techytd!Z5"�ly�ut�;ob� CMre�nt�p�p� �:�spaA��M-H� .�-i���[vch!n��|I%ca4*�<�@">j�:us�$A�o�N�ElJ� 5�fu�;!�! bL*om���Yaug�pS�J�H.�&[���-6coarse g�-( CT ���)H,����(J,o biologv[ele�H :E�lR6 P!�9Z�e�n'�)CG 6 �) $.�$*��6,o"a��NalA�-jǁ\9�a�jkJ. �Hamino�r*�T!�.�� Ace- !�+�) 2-Nm � :3�) !� 2G�jAl>u&�  *&�+at"�3pH*��!. i�t ?&�t�B!gl.�v*@ in��;2�t��Z  ,4)2+�w�}fVwsod]�"�P.=� 1H�M"� ^ps6�� �u�^usA�GROMACS��-L4 . 5�~ [34]I��leap-fro�3grai�8G#KOS 54a7!� ce-f�2 [35]�SPC/E�[36�?A(JonV�"(1et4LINCS algorithM7]a�eo2e'-�fa"Jw�F� � � icle��,h Ewald ( PM�![38] m4� �a 1�6cut2(. Lennard J���Fl�a twin-�G sche�4��LH 4l 7�< �t upd� �|7 10���!M2a�#]EfR steepest-��B 9_a�2�|!R=�")/�'�2ecu�I.#;��@ (1ps{!�hA�A*$heavy atomd"�= A�Cα BaPis ,.�au����6�Ee k2 SQ�Y��a�Fs� e μ6pngQ�w6| �E��E2�298 K�i��V s y-re��aa9�[39m�0u��n5�!p �*� 2- �_$sobaric-is�mal&5&��sHC!rse�31 atm �>rȌBerV e�me 4c�[40�RjxI42�AS�!%]E�nH_ �~h�Vlxi� t�8��×10−59 −1 ���kt � �],�u� ���i z-O��!c+_:5y 2919E 2965��[hL*�^2�e�cuW<box��me"�Q�?8A��0g1)' �m6���0M& rhT24c dodecahedron�!+S~s+|27} in x��v�S1��in z-3 � 8882B. �q�2�.|$� ]mS'��(-��H��J984=t�#box ,of � 2 × 3��<^ to�=.?E<�H"�1*u8out )�;��?)F]� ��"runt���m ( S12�k�9�A - c�A�f5����03� !�6~%�12108J�VV�]v���w�T)��I� slab�at tl[n� aR+!�AXr o�2THNj�� canon~  ( NVT )���*G!, shap%W !Em6��ݏ)� �!H16!\ 16 . �$)]348%. 1!� 1043a[,): 4467%�726F�rD�!e� �!!E�NArcho��� Vi�l.=.3 P9� mAgr2�~�n�ed 10258 �n 331 "7�w���>in A angu��%El� ���of%h75r 2Q|3�F),"A2mF�CY ��Z7>��2F�Ch [41]�rax=mA�{!� appl3�a'.�#� *3�.ߍM -��C; �Yj!nU� is pul{|&�|A�0-\DY:!;0, /py"�a�v*��.m~)'�r6� !�6� ,A��1g7� f"F7���5q wind'. A<c�+24S�kJAK nm−��s��to��=W�B|54. E�W sn4�:C� ��� x}�8or� m#� �;�:ili�k�?Eru��L�r�;istogra�aRm [42]6]M)���Ht�| !D8g_wham tool [43Se� <i#con"1;MaJA�che�xe�U�?&m. Sg�cce}�&�,�'(Y)6w:[ f�>oDHofE�2�&n g_s!a�of:�� � ly��b)s�av� �dD]Davi�~6X !���Y24�e)) (�>be����few e�d�i�<E�8lY)d���tex-^w��[�-�*+ ("3'as/).� 6U�,.�m)&�~�a:!�*� !=�iAzu�if"dwhsg y�=E�C���V @!�;R:0�%s��e�sM��=Y�R7qoutpu  9jVVd.Sia. HY�rB�!;��d��!�w.�*&�(by]�Z!�YZ�U< �y90 )kex-�ZG!U?�,NAv,���Z� ~!­��fac!�)�B�Tak�n�:)I!��-s4� M�ex�B%5*bW t&6 �^u1s�a�"�$1cA�)1�&U�Z�o�P-�\X�=2Ab`@,e��6B�c #-)?2�B"�|�6Q)%(-= �Z�^ ! ���5���!sq�ywb�nIJ��#�2 F�� �o (��~E�5( �u)��.� !51�#l%I-ZZsE�_�!Mf-*S,Wq,/ (a�e� ��Z�b& �}a1,b/)z-c��&Ĕ^M���E��6> � � �!��%���U"d��0“rerun” oQ��C�md ��rS6{��2��V(h�%s �re-B�a�02s�Eva"%�mittivx80A�-W5Tsؗ!fby�Er�p 3 , ֈ6%O,3C�^.�5L.yCE-*)_m�end!+!�F�QGCOO�T"�7b�a�id�NA;L^����0&� !s�".� h %��t "a 30°1�z�7 (ptor-donor-�Pr&1a � 5 Å><B� D%"We�K !�`����l��.�N n�un2I w�!"p,e�R���6�U!��e0ias Ej�s7\ 0j%'6M����+ 10L*�_xp�1��e4;&�ox B*���3 {���8��q&�� 2����f� �!B�^�i:�po_Qo� ��r`2~�tvis�s�p�EJVMD [44�I�Xs}�8*���� �!"&�,rto�-��ofu \co��:R�Fk'�J �as�LJ�NSTRIDE.e45��a�E�"Pa�\� �+�dra�^ �r).(� �n�h ár&�8 olar�4�%rI��= B�b� K�3|whi�6���H 3W3 Proj����� [4 �UHumanXKpesvirusn( HHV-k�6BB$re ubi�2�$betahe?��eas h`�.�&y�jof �2f)bjs �f�in��hfrtypP;H��"a�nt6%�irY��:�el-���f h�9chromos # ot� ��e5F��-�ar*/k��u*yA�ds eǍva'I4gu �'-V, B��o��.�e�)rb�%rr�qa� �i/��GFTMR )�.ntgto)u -�t GcAen e�wqn=, � �!� B5Lh �y t �i9�\ect( p :|A�im6im !�X��e-]/=Aeinv'>)�2m8de�Nd �U� `Mp�A ��<reStit�' �y�7E\�aa|Ev>�&�5i�Zyp w� 0y,~ Q .��46N# �repgAD%*J�.`�)er�A %c9���O+we}M ! vitro2O �"+��U��$=eU�%�cqgea`qten�inH�=�!Kof�� eW mpai�J-�*�(�!�!� ��Ela�_ogUga�5�.EGruc�P� 7 �-Y2b? "y�Es ��>v��afU"pla� 6��M.�ͥ4 i,�7 ap!�?�\<[��3D�u��M0�'�Jn.��,S],m�� 6�= >%��Ais�e])3r]�:,.r.�!�~~nX< 2012m���C�1�B"��a�N �x B�G�5if�y&p5� ��6�o�IM*�R�dih�M@<b&z'� eri�'����AQ DNk��( l�92mIEtA�=P $7"Bon�p�z�f�2�<yonoclo�)bod�[1–� Pri�i�V -5occurs �O8/childhxr=A�ag� wo [5–7� D�9Kcommon�H96Ffebrighlln�(roseola� antu/\sixth!���{�E}a�cfaU(v neur)~p��&8seizu5!�O1ph{� is [8 , 9�Gr�| an 9&��adult�p"�{�se�/�e7-�}epidem�)�hdi �anF6�A�-��&� disc�G�<pat53� $ lymphoproy K%v�m s [10tSu 9>�&8=0DpB ��Vx "< ��,:� ��…���J� e�q!�A� �k�B4?e�^ds2c�&s$ R1993 [11�y!&\ye�uH e8� � '2���4F;c� in 2� �e��x [12–15��Cp`ir�1rA%� �? q)��.W� �! als�� to germX ''Hl�3u g�@s5misya &'!�>!� n5d y�rv}5 el! �+bod�1�G8* :A{ter;8�4~"� �1g)�( ici u B��ab�1% zF�[16–��i�� ����]������� phicd#%G�gr_  coi?!;8�ϞUNv�9��6%A�2 . 7%��#Astu��)�� �Y !~L*�2:/1i�B�1A;�2�Fw41%� 59% :�,�.-qAQ�tiv-*�� JD ��41���q���<���2����#AD`�� �(�=2�*�7նs�=graft re�)- E�pla�Ton��J�oE!ZQq"� 3@��del�*z3;=lXN?*V � ly unknowZ$I�A.kA`>"� �cI� 60 k�$�/%g�1m�5�=se�0( U�4��Ga�7bair� �VDUi �� sk "} < ��o6�:{�6DR�"��klic� iM�Zhe1�� 6Rc  ax �8 hexa�?o � TTAGGG a%t���8� �.7�}en"�DR�b�,R= �A[ rrupA�b`aG�\xa�q[27–30m.&�w� < WG�M15�> 180 ����T�y��� ")�bon/�8r)=ӆ;2� hava."ť�Be��7I�x�PTs [W��_t�X��G�)�fv � 2kbB�ago!H��M .TiPPx��" "_c+K%sB0c�3facb���!�g o&B ^B����Ֆ`y homR �^$]� ���[H��t�|:��mRin �Aa�� i����g��~nt����allbo(B�`��e�}orA� Bе�>�*�6�>&M"�*�8N��՗!}5�"�A�MN�%^.���FaEmea�.!�.h�� ��6�QluoX/��!�(situ hybrid� ( FIS�J��qPCL�2�-. U2 M5.�I�de"��6��R6b�M 2�~u%�@�soa�7r .�oQ(���e��>�t6 \`� �"� U.e|A2vm&�� �eA��,.��a[�y��k.� . To�ci ��MU |A� �r]�.O� 0r� �?)Ond �)� �N7����!u xBAC ( ΔP)��0assa�� gene��0M1�W . Mu���'��_N"S��, RFLP<�(nd Southern4't , |a BZD��� �T_B� B^ ���:�a�n�)JJHan! ���S��of%�.2*A���� v�� z!]c �%A� ��ag��R=��>a/2o6�.�a2a#�wt�2 }-:D S1A��confi� a�5 !k�>sM3.�i6�:Q!�.��c+ N��wfe��UA�.2&h� osteosa�ka%�n=e U2OS;� �A1�3�)K��bi�L.�&V!�%B�]ste�3���o s te�� ( Gravel ���>bg!edh"�E�[ ty co-seeg� Y�-.� �I%�!�ex�s GFP2 % m&ro) HCMV 6im �sp��-6�r�gW�_ng0wasV!"t�v)�-�=so\� 36 h%Gq� �45 %Wp&�eul=c#edez(7��!�3 14 d�K�ly"=.�R�by�A�alE%��17st%G�-a�DF�E$A�.�� e)�%����ld:[ifR�3anA�` ��V�ek� �gmetap��.�Z�.O�1bol�bI��� Չ�aooa� ��ce� By3&�)p��2Ʌ� .�"�V� U20Uhas�d� ��?on HHt�?weiX!}�,�"Oe l�R-�A �epBR�?�cjofu[�X!-�&2)(�.�f��en� [0i�of.���-�OQ{(���&�nx ���'6a] ��efESE6eO���rI6%i%6-�UF)}�-� "l�m�AZg"W cl.5��Hou�.)*X2�gX -� �'92X! St���I�Q��QA@p�#��m�5 by\ / Jwt fiM�ad�pwF��m�5e�, � ���%Wy� ��t d�=d14�t���1rG0|% &�`B^'dؓ � copy:��.R��p7wt x��M= �96w1��A�n��ly)S�p�"J�A-r�aV� � $ pea"n� X.�6+��$D�6F �~�E4*jQ5""�ԁ�R$ J��E)Y�a����� e F1 O)i�� s�l� )�3��I2/:�� )�Urev )E���NaQ� �EG�o�Q�.! at*.&��!s ��l! ��^!.� 1�a � T � m�tg+�|� �>F� -��U��*� �, ��" 6 ��)|)6�E$64" ?�� 0 �5�S1B��0w�2�!��.)qK� �u;� �Z�!J�.����ofV���e'%�!* Z�h#X� \ZR"�C�E�ޤ�~��"�&wz�E�`!$6-f{Csp�6bIjk�>*s-e )E�6:� �]�I!�_ A�Y �F� �n*� I! �is�1��?�!�.weTe-���~�e�Dw! �j�:$y�xamu�a ��Q92� ��:@yl k-`,�6F���.� ( 4d2A�8��:' \��A$�� 1 *�:�Q��V��`f*zM�aKJI!��"�71�c��sMX)S.T�X��n ?�TS��6 ���!y �!:")� <( U41�0� E�U39E�/ Y QB� [�p2ګOBl�7�of_�)!+a���e^�i�Zl�6"� ; ho@���Džqm6*�Y5u�(&(f*=��\ G$Ou+^c|L�"�-%��curYl-�u�<s3F#.U%% �Mxe��nAIo��.E!%sMta%+ *�x��QS��{!|�eluZ Y�� -- )�F���5A�cgc ��3!Z�(5�>�Uw"SD!lw ed 3�En�( ~f1B)N�/!wɗ!\c2*] NCBI�L�7r�)NC_00166�%V��"�*��-#�nB|ByA>�AK"��1:��Refseq6F &] !e@�R���B��-�\ 6m ^RUg�-���A Y9>J� . GrE�j� a�&=�i��o0a�� a5 �� C��9��e�6�!}�%��!�q�� � Q�s��� r8J��,B���k�2O*N�.���wo*y �F%.��"-+Lm֍"/! ��6$MQ �E�Ps�utM΍n� �kA8)) bvX� F�-R� �l!4zmwV�.j� ��CE!�r-� � � 5� 6D>c��!�~�in&��Z"�O-�� n<,*�!)�� �)��&F4e7-�.W&�* p`�\jO���S%"�!�"*qZ M�6�2%Qr7�&2~:b�k�som�B�'G+� a�8!I! %5 , Arbuck��n�4leagu"oun5�&L� �epi2(jL-"(�- u��u."�'f -�1Te� 2#! [15].� Qexa�u vivo5�'rvo���� � y��rstn,��t ���o/MwV z W � fV� [~#jt&_���!�ly&�Օ�.��.PsiSf�J'�/+ �%en"u$)� �� "Q(b�%�q��N1� /sub �%��N� , 3�*QSH.v  "[�e�+!avail��\!�*� .�32}F adddO9��*%�AL�Cg; U�7@6chAe�"��{2� �3%m )�a69�v��"��U �p N�E��3 �BB��NR*a ��� no*���"-{{ �o�Y��.�B�s�Sb,N�4&� :� ."�#Y i�}�_b��a�p&{�E� !n�7In�26nE@6S .��0E�ar .�%, judg!��:֨H!zs�M�H�jm�m�E_Nati�7"� �,�8E��alA��8�� pec -z�Wa�"GcK�!�6� ! ��t$M�.4Iq��$ "#�Jz!+%����M;&�l�l. ���X effo��%���!�h�.���i&�� f��&M��I # � ��9�!��M55QaB���-a iq6t��0nB. Vw �at�R!K�m��sc�2B 100%J)ty� try!J�Ţ�E�<g*�=�y�*���/Z�BG�<"��Kg�^5)t �Aȁ�Dn<��)���,nc 7E�&4/'!�F�R���.��� 6�E�mfvday�%�of DRR����c �j)�e�e��3:�h8�mf� M��a"bK.�V� v�few2%�s�)*���Y5+� a!!6��WI:�qgn��.�V%F��?B&A='r���u'�*Yz$ :D:�:�cy���d�t6�E�*�0�l�6G6"%1�aIl&-5AzxX:7 ��� �5S*� m�!>A�Ao.�[��2�ZfE"�"@�8c�Z�A.[.'!�RF' �!�%"� &�F��.W) . If�%w�!�*� �6��d�_)� � Jr&ukBe&� E0y���)v�� �n�ng��0tE�x!xI! scenpa��=�dV����*�7Y--wt� � be benefiP:U�"A<+A?nf��1��Z )11= 5i (!1�5�)b�Ey�Q�dou�'JEnd break���"� �.r�damag1`[�6.ULen p@HaV� ��)�/z�6"VG;1&�C"zby�Amea��B��es1�� �16 *6Vhxe�*�9v�y>�*�A[31� q;AD�5�;%�se� �v��di� �53A�S&l� 3=� HD0idae subfamil8!Ё�{ Allo�+�s fish�Rw7�aJ4�s!��3�;�G-��Y#t'�DuŚ��sP�.�D*Y� �VY��L9�Cſ~V<"��,Y-,�ic)[��unappref��"�. ��; j��\��"�1��� >�&� 3 � s�<4=V�,vo��);P@"�0}&M��onc�Jic alph.EF$ Marek’sA��=%i ( MDV )h%��e�/m�5v9qiFa���  %� chicA�[38?0]�]vi�+/e~nN� ��al �/H`pan & !�U�uN.9��Y6�of�� ZjA� path!70� i�zaK�(i��|�=ma � . i���d�fi� �%K�9LR E=�n��mz'R�aOtum�B��=%��/ts &+ mora�@�on-o�c eta-Ыglobul�vT>z�.�j v"a�r"m�e�( >7I?)�co-FD�� !=^! 3 � GFP-�Ap�e�@F6a�a FbAriaIII)$1eF�BDq� an J��)R�6A��u�|6( dE V�;6V�i�@a ��^�1r�A��\ ellu@R6S�KI�M���s���-U86#A�R ß2MW�&6\�&� &PAA�lj�,�sor�inZ��A-�"\42�>ar�>a)b:�38�Z��48�BCVj4%�g"&IzAi6p5&A/!/�g�,-M-��2s)�nd-. S���M�U=a�����G�GPad s�mKHO9� w�6h��u�8es!� dDMann-Whitney U tes4R<���o/*[*�.!/p<gH 05 .��I�^6&G9 enveӨ�Ie�poxq��*5v2+� ��cqu��#��4lipid membraneA?budd�U�\&t��I��,� imm��%�+v Y!� a4� c�At-��T�No���j arc�Wb�!��o�M7Y� !^E� �Wre�dM��Z*(6 Å crysta�l structure of vaccinia virus D13 , a key(,al component3Dthe outer scaffoldvi)$rescents .L�s into two jellyrolls decorated by a head domain of novel>4 . It assembleLhrimers that are homologous k|he double-barrel capsid proteins�adeno �pand lipid-containing icosahed�'e�We show z@, when tethered o�Tartificial membranes ,-Xrms a honeycomb lattice� �y�ducts=�$ly similar�>p� imma%�p�c!/0. The archite5�!!!�V�)remodel!abilitie%<<$support a $%S)�y)exhibi� � > withb$giant mimi%^, . Overall , Lse findings establis9at firstA�mitAE step�pox O|morphogenesis utilizes an ancest!�B� tegyYon!l.DNA!xuA infect%$ll kingdom%$life . FurA more-�iA�e targeeJ rifampici�d %,u�will aid�developmm��5rin%m0ors . Despite:$eradicatioeYsmallpoxavi� ,Tes rema��a concern for human health becaus�BA.threa�A.bea� relea$z)�A�#F Ef mole�Sme��isms gA@� e��in"� :� un�(r . Here we �b��2 . 6 Å�msta�%�!A:�1�!.!S&� � U%*> capaci? A� naly��of 2-Dx��$reconstituA�IVd"� f . � crJ�:��A@atm�+2�Ej�ist��t6� ( J1% J2 ):�no�Tβ-sandw���U� !T.�"� 1A� BothZi�s adopt=class�"Sz ,d commonly f��A))b&�� !�$ BIDG-CHEF��4d order�named �id�B�Hf҉�� c Th� !5�re��I*�,A�� a mce �)t�Iof �9% �?@m ( root mean squa devi��r A� m . cO of 3 . 25A� 126 . val��Cα at� | Ii�J1 �m�����(J1HI , J1DEI $1FG loops �6'z ne siduQ.��wg��  sub-),I}pa��agains)� longer J1!��u�!�Ui�.ci��seraU�� J2DE��projecsway)�J��� �. aAc\r-turn amphipathic helixA�" aEUqeSe�%�� s aX �݊ K �I��7ACan[5�}e,b�AA�G�B�(is AEB-GFDCu o2�"�yE�}� wa�\eeo!�Pg D�(Bank ( i . a no s��dary-&� ma�� unJA�40%� B �.�A��ɁUV�J2]k Pa marked pseudo-hexagt� �| B–E ) r�"��e�a!� l arrj � ���)� b@symmetry breaks d��!�z��� a trefoil �M� �w6� gap�@ each�BZ. E(subunit bur� a to��(of 2850 Å2!b16%��solH !�es^e"�up�z��on � ic&IinvKs mos� interac �9Areprese6 g%/�a�about����i���ree6V<)6)#ŋ<i erR!7 � but�_�a ��� ar �17)8( Table7I Kis hoa��X�A�yG �nel �a diame� varyAw��14��b3�&U� �y6�s|derivedM�n.Qarm��m4N��ᬩ�s aA�eQ�yBb��F�oppos�9�EGo%��M���1De�S�arison � clos�W�"18�������of"�iL.�"�2<-��)�AȱS!o�maj{d VP54s$PBCV-1 [13� j��PhycodnaU*�%cs uni"gr7 alga�M [be�"�Nucleo-C*� L)�V�e!k NCLD`lineagaJat� d genp�f, asf�  iridPgd2�� monophyleMM-se dis�ly-rel�'es�a"a :e � @R )9d�If�r q411��era)in �!ew[14� Howh 2 �a�&� sepa�cladeS�#�  ����"?J2�p&�o ��^�!+un1�&F i[�� �i`v� we @%DA���>[Eݑ#� 1a��s��nN� �����8���residu��:�lq�is���no%h�:��ڭ dupl> 8!��!diverg� �%�s curre�obMH�AIiY�!c �1�� y)#i 5q�$of eukaryoa-q QM �� harb}s0g.�w7^6�[�j+N���PRD��5��PM2 [16�STIV [1�a��� .d���� Gram-nega�bKa , P� alteromon|��=a\sp���)%,ai�a4 o�)a%Cy� too �w!�bn) ����� "�. �hav�pro5�ho-�.=��J6i�nR�A�at r�"�e sampym~ic6�a�� also\ �,fun� &A'-�>�Q0shPen�y�3_A���,*\hexonBis �I d5to!{aC&� 6)0 h�SUH e��IF6�!Yi�MLE��66!� A�I !ic sp��� ���in%+.=v�I�*� A�Abo� elab�!?L trib� by b��.^be�ir��u� ��%M�a� �23"!�=\!�%�. Giv�!h�vol�PJ�lex2R!abs�a�E&�!�'&`"m�[18�<)b�� ����Q�o� �tha1�Z unambigu��al�e>��6e���fi�"a minimy �j�� �0 %Xre" beyon�basicY "�a 4���eoA!� �.2_j!� J2FG9�-�z>P)j�W`ri��m�>� �AU�X . On�X hz�N�!� �eu1� =�e highly�i: {ir size�1�eρ&�Iref �xus-_ "�i9��inner ��f om"diffe� �s�C�}�6�" cyclw U��=}%yUh�U"-JIp �%z ��[!pr�J!o� q l� � �hi*�ir" �� �uVaa`�1!�so-�� -e�.� �es [1�2�arpl�*) %vregard�jeNW�ed�er��ar& )2ir� i�ve:~ �$logk%l% obvi�.v "�A�s�them aq�llM�.� . E�5�&.�@li' NCs��.�ey�seg!�� qa tY x!e.�t!3ov5 h���Aa�Ms�6s��Mzle>�&����a"of.�� ona f���uSJ:V � ) ario6?w �e%�{ J#��J^�Cs.y" lost�j ousn�$!�2�M%�k���2�"L�iY(�.<g�i� mark��*�]I to hijackaea� d&� *�T}!Erep"�, manyM�1i�ipo�>8��~horizP&lf�je2H"�'��-&2 r��� � %D-+ ll� nee'!Y ro� ��Yt& !"��!�.�Ah�> J . L� %M�ms [21�pura6���rinᮡ�ensQ�� elf-"RAH�s�+�wo poly��| bE sucha8�, tub # <p N�ag��3 �In our�o<� C�á��i/lB+mo�j$by low ion trength��$�%!^ 50 mM arg,�-� ��no�en �!b�}""� 3���FMA����" eref%���underl6(&�Az� d�Ptin curv�� .v%e�co�te &z)e�!�y� susp�MeW�1�sed The�gen 1n*� 7) ,� ways�a/d.�> :.~/5���+u%�|&AS% qful!&d� lZ 1 . 5��Mb�m!��k�5� c�& is 9(#±�(��d&p ; sd��+� -to- �ɍ �� is 7T±2�( F\ geoP�!f-��!�ar�h�cor o�(feE � iF0['. To fu�. g �2igh  Tu&ofFL ��w6�(t&^ MBoEsyste+/nM�-��explo�**<His6-��00ind nickel-ch0�2e � �!f#0 na�� A�K$�1 lipoQ.sW$��t-soluc## Z� Qm�( E]�� I1 end"<&r� ulumE�do<,Hf������C+��~g�w4BE�T� 2�M���ad�dur!LA��e��,�7�;q>�>-d��$Co,r;!e>���9iso!�D  �)asew.�b�de�����b�h mola$�": . Im�2a� tinduc"�**�&is "u�dU�E)!��n*c��>2.�7�Euntagged� or a Z x8\1vp( x� bi��9�Cz2EW�4B� -# , 34��m�� %�E�Fa�ei�Y ( 19�.!� 25 )�a]wt�o~$( 62&��!cy5{�edaz��l55��*�,��2n�� y fai(-��:disrup^M�sa��Xe� . AlF/.xP)ly@큁��,�lamel1/I8#��nea5A�"I79�i9U��%�\ -V.�1Q$irreg] q�s� r�"� �-e�x%U�)���168[!� u6�,  !tT150 nmA�3 in&�!a�, � ՘�R� glob2*�7"� �>�u#1P�\ A�%}.P ? ra��"±7��<��� 9�>- he�9 �inter>��J�>��2�*�� "�0�; s rti��' good a6!�%�g!s�+ng1�A h� �2qhU!��vo�B�!�&�,� ,c>�7Mȁ_mid-�P� �8.Hy w|i�mth��  ���ex�th9%O �� and/�"el�2C�:��Q�)�*���E6�z?��'�8� eq�BV�!B) r ef�enc�?t R� @ /.�I%�� -xy �y��~�m�u{M��- R!��5luF�V1eF �.0��6�f%���"Q�)�ri��N uV5�P2jc readi1ob��Vseldo+&eu# �e �� 7$0n 0 . 5 µm sA3a\E��als med�,śe.�ll4��h�2!�pr����*� v6 ch dm" s �FU� orfv�2ALJe+9[s [�I ∼2�'�E � �#d7 imag�� f ti�2gS� 0in uranyl ace"s!v �strik!�20�)!l��of Ni- �"�=� t&C A�5���9evoU* s 5B9S�� wsA��8p6 ne grou�u'k#�(�m&���E!F'of!y8%y)� ��!q6I�` a = b 138E�Å �(na��<v�U�� Moree1 J ic buil�o�32i:�r�/-�CF�1!u� Y�M,�pod��b�)&  . te�*&5"E(J"�1 >s*6rad�?2/��is�<ups'b��&�)�ts*kS:t2�,��6A–� 29em� e�6(%�㉊�!#Eka���� 2��E.d >��vNv6�@�"@CdU�I?F�� as f�?CGer2=-�+3-D d�map.U , )U\ fit!�# trai�� -�li�yБLpromi&:�m�*; (�]lk ��BR of 7�25% v Mino&dal">�!�5�M�to�l! .p��I 8ai#�.G�* is 7f (}% prox 8ate>T-it#d�ey-�!<� �X-ray} i�mlds botJ1–J2m~�Y�Ptowara�:eu?1D�0�i�m!��ja e�(�Ce��x�“pu�<”2qT �=�.�to��&e�Ū-bo�*�q�WDT��we at m�AM�skm�EM=J�*A3�.-�56ya,2�٦q���osezne[:networkb��!^D- �I o�p�(*B/:.[JBe� erie3.���L0M��!7f� �Aix�. T� � 4 via�Aptr7 loop&m"EFU>�Ao� ��+)Eg8&6re� in�id| * lsE> be2�~��>� 6AvS4�b��� ac/Gaa� limiAf��.En&%Ũof�/$apJG[2� Do�B��!U�� rear�o  t"r-|�!��R&� . M�G�Mb!C�},�;� &�1FaC<:��� 2(w�@va�#�sE� �X0M��! FGy~"�i ��cGEe��groovq pan�;al�`�/P$n6lI�� D!�m��EM� ��).1.2J2�ps� E5�4v)� ���_at!�)A����. D5132)�7E�wb�DA/�� a glycine{H�YR!�{�sf��R� k���� v! �>.�$�&R�K*< �")�ქ}�Kinz'oreN mov�7,�dF�1al r ^Bbe O&�8���"{1of�c*f U�S��BGIAR�0Åa�^*X;T;#��9�0)�iEU�5w�:A� adja��Q� ���de"� gene�bJDFCG�Y��e�gapU�2�!�} stU�msna�bo�emOconfiAg�E��ppan'ly%�& a direcn&/.���jaF/L�� uof6� doesj�A� hAji"K�j3'on���c%�f�B�L�G ^= .�!A�r�\t�*!HM���a�)�f2pOnecu�9explaEo�3 �m�y!H"- e�vuyx`,�5BmL!�ly uce�Ce�ForI to�.� �k,'�=�xo6��#�s'8!�"l:-ex�2���T� Xp "1�An vail�.M%a pot�E���or� Iart;*�BeF-�c�}eSIc V !�es�:�K-�doc�Qp� 8��I�Mut���a!mZgm�*GM/I7��2[23] �'�eK� ��1-ɓYll�HK e2�!�2 Á%�(��ut halfA�q, nF��!d2'�=�|7� A��jse����eMitA�)�r�NF6�<�,K�|-��Eaoom�tol'�;�1ng�1A� of ba,ngE]�*�N�D e ( 823Da� Soak{Bo-�0"� expe� �LE�N� so far*���r�x 7A�� view��,`� l!�whe��QY.�)�[&�Otoj��5I2aM��:}RrU#r!:}n&�MMoe�Cq. A�,qC�����!�50z=U'Ba-�BurAD�%V]I,.�!�!_M�e��W' RoJ��-scal��`-".2&�"u 8MC�3\M� B�q�e"%� �� �by.Z [24]!�������oca�6��e I��f==&is�"r,��9b�tA g��a����9b )�u �Qd�&� ��*^)6��_ e6�C�� galG%,>B4e&�m�on�����bl)�P� AM*�1��uaw'�$UatiCeR� .� �p@at�30{.q93c!���T� -dim= Cin��h��Yas� o-*zL��&�iw>�H,�Sb �O03,z�D aiU &N"E�:��6a�)15Q�( s )�,)25E�v�.!�growt=�s elic  I�B-ofe s ne C�#!9!�2 &9�**as penta�Whep by Heuse(�)8]n �8Mj�acK�Q]_icy��!k ��3 c$J}� o�(�E�a�m��QNs 3–% >p�?e� s Eu�r�`n�"4!g!y)�d=�.3a dri�.for�)H"�?W%�a�*E�!�S �A@5 �(��&�=���c�46�%2 �"�d � �I�y %�&��� �� =��VM19�!�-�*� ABL&�Uy � "�at�N"nEs�Vt���u7� <4cKr� �� UvaXT9|u�A17A�I7�+ G"#t�&�&disMjX 9�OBzW�"� �!�7�� Q� 4� �e�WB�!�*�#�IB�<,*�MN�8m2�s�W�mn'!�"�1)�=-64ov�R.�-:��8e J�&�a{�"u&�-B4i�1�2B�.R��55U����9 ��"�'[25]:�lC��R-&G2Fed� /)��F2ne(*� ��14.�.n�* 1�T X[a.4!l&�F9c9@M(6V/F �'�6��!�B"A �R��#=.�Fza"� �p6�<�@0���]� �{�#���&�K190��vCZ#M;A 9Miu2>g^e�i��&�2 F� T�1lA���� u�!C0�"�G���,��k� T]E�Ax� �\���1!0S2�*_'9-�@7Qs2���(�)��a�ct� l p3&46��&%>Fu�^1�$9[�\� *� �?Q%"-�g@�^% 1{n'2}=;M�)�ar��� ��e �*�aeA.q\!� apsiy.Our�E�Yvea6�t;�m�!ge�^�S6l8rA�$�,;*�,te�@"�Q� �H=�6�9�!��a�M��NO$=.;6^%jS]a��i"�..Fq ��-(  l�6A�oW�s&R?�7�'q�E� dee�Xneu!2%��&� poiY`�;*NA�le* 3_s j-��W unique ro�<�ous�6�+t^E��redunda�'�wi ( �;�--!E!5&.* �)P"T($anti-apoptG=��!d� !� 9`�mt��"�E�0Achilles' hee���Xval�[A$�A=t�>��:�`�%�s"�RVRA�s�`NA coE~�^�! ampl�.y PCR�� geno*� rG of We n Re�%i�:�U( kind�5u9kd ProfTX. Mercer�3c��/^9TpPROEX-Hta vector ( In/gen )�&x-V li�G on-i*�0Z!L@F�@)"��!�a� 5�b�M'r�a�7!CR�in fr GwIa 5′:� Tob�* ExRM ( rTEM�� recognO`w . Ce�e;):nE37°C�OD600t& 661l�6t�ol8roe)&�`�x1�C25�9 IPTG%^incubE>|&ni�4at 20�2�ly� �H�9i&in 30 mlis�0� |0:0Tris-HCl pH 810:NaC510%~ero 5 mgP ozym�2�,β-mercaptoe��n^nz�Ie n�N!ci�(+bl�9a)�%� 3_ebEfuI\�4000× ��i�Rf�)�BVofUgg2i"4by immo4-Saffb y chromat�_( IMAL usA� a 50),g$'� �� idaz�I�c!dL%�F'y� �V2 L1iager�/!�()�. 0  |%�!oj M L-�;2�;Ncid^�d3�nt"�<X . U3�;i!n,5\%U~ =:Y2�I��A at 4A�by�#ngi�u~k#U2�41∶10 ( w∶w�UA�*�>)�M�!� carr�(�aizc�B�SE9�PSuperdex HR 200 16/60�um�& GE Hf�I%��lib�w����:�,�Äkta P�>�\>Mo�d!!�SbET.3( 2Aw25!JfmG| lecAڅ���SDS-PAGEm�:!@�o�Сy1 ruct)TtPBa:up^� ."�>L��i@Ph�High-FiIgty� Polymer�.�nn�j�A��$gO��`–GTTTATTCCACCATGGGTGTCA ,CCAATC ( forB' ) ;7-GATTGG/ TTGA;<ATAAA5ars!�. DpnI�48�.��/!*��at�#��1 h2��re��mixR"��EZ=>orm chem;ly-� e� DH5α��We 83 �2 �gdu$L�"��7^v��3 � !�!t:e�i,�D.i A to 8�. mL−19�Q92�;ecP�2�2�;A���.��on�a |%6su�<Co�"! t9 e"( a Rigaku CM�8n rob_ �;�%Intellip� 96-w|35X!v�k(rvoir volumu$50 µ��site�dr]|C in 1�L������]!g.ecipi�9 �N h�%zoptim�iL!8han�6s method��2�^�6��2ein@(w�.?V}t�M&#plaGf ( %�2× 1!m ) �e2A��AR�!�bb-n� �zXmM NaB�U,20% PEG 3550%1��I�>�o���bipyra��Esp8 e��~$c�8�c� A�c�Sxylic �V� 2W(]A�21j�2: maEp��6mea�d �,� !!t.�A��outlin)�Iwrelia3thDc��Nsatis��^R�7 . 23%%�Rfree��83% `���N���&�re�T� �qr i,) (Phenix [35]nwoD!gr=(A�!%>�A_��)3�$��%� �m�%IA�TLS�perM�( 2 ��^>v�&no� p� dud46>D�)e"� ��DQiu�(FV 731K97B�3�ju�{s� !A��;.=NA$96N56Ne3�^ 31 ()���B;>E)!.�-� �!5�E9R/e-!2mB2aO1a5A~of~�Ae� :�atl�/m�� loade*tom omem�d"�butto*(ea�K�a�hkD�l"=as-ct-off&�#�@Ma<.��15–18.&SVl 1�HEPES!U"^�,�,!�+Pflf�4 A�  Jex�&g8!R�%�sa�[�exa5by TEM�5s Sm�s)��Z.�-�B">odj�A?S of 0��M�B f 59% 1 ,C34ioleoyl-sn-Gly�0-3-Phosphochou ( DOP , 18�:�� ?Hm,A�nx[ y -L-S.e�LSodium %T) MS��e$<1!% gji�$V{N[3�wd&~Ng{� , -d=g5[ (� ( 5-�o-1-c�8pntyl ) iminodi�� )�cinyl]}-Milo�cO-Ni2+� GS-NTA-Ni�a�O"� �dis�0Ado�yc`v�0I'dr�W,GtK�UK���tM5?U7N�k���b"�,�<:5R �4%�@/v ) n-octyl-β-Ddco�qI�I }V|2H��%�at �2b�" -to-D mii X&.2stirr��h�ctF�to�#��:�O � �-�g!�)�x �w ^+.��  e*ej��f-2,���c��x�"1)�Mti�� �J.�(�!bachie�.�^&�Nj9���qpid&sG )$MTed a&*�RhND���G};� 1Kv gg L-α-p��atidyl�� egg-��a,.'-DL��',G��t 2u]�Is!mix�"�G�R1=a�A,of �j( ve;co!"�N���ano�W� lI���0%Ka�q2$2 m���{)xt=C1CN�LV0��Sfi�Y�uTeflon2,��&l*@in Lévy et al [3+j�_up%F2�istur�e� –2m�%?Petri� �A�tm��A`of�-��id� 58!�}\�l�Zge[dZ��pa·w�f-&�S  pa� ( What�m Typi�T!RL�a�w appl��84n�Bgri��_{m{ tic-N4�.�mn{�KatLC59+ydrophil by g��dis�@ �nN) en ncklsD�EoX( ��:�JXc|� EM ,���'�rey � ( R2/2 Qu%�t) e�!�6�($"'n-amyK. Vitr�V�?.( \ a&� Mark�|( FEIi�� !9( 100%�xlhuM&.���a������"�.)��>�ho!EM5!|2/36#�%E�La��:%��f>�A PA ps CM12x 12D 120 kV]`a_ routI@� )h7U9-�$14�*��L%߃�1024×, pixel CCD c�2$a ( Biosca< GataneF�Tecnai :�V!��I�lan�um��>dx $Lab6 ) gunv�A�c�4�G k'Hag�~�Nof ×5( I��5A v∶& ��de�X��oE�� inui. IIb%tha� �idrifte�astigmim yiel�sharp"� spo�*!�digitx�@Nikon�#�lE�9!�E�,5$A 1�\�&E/2549 dp� .�, s%Xed 204848mPx�Vo4Qch2�MK�#m*3-D%�nq҉.4;�= �+��"�h ( CTF�nd�c.=��9.D�-�3�H)7B8� gram�1age [3���/ CTF->.Z� TMRC2R!28[3iQev�e�/��Q�|�'S1iJ9�-r�.�*a��M��'�B�9%1 )-<�5v(d�5wEkmer� tDc���w)9th�i�pfSQ, choo�a��er9.%SFun6�i<����4owe�5�Y !cp6&�0.�2'?�24 ls YYW�)s�S �E�io�$�=�^b� �A�Pit�x%FL d�;� ^i�alg4 rop!�terva�z* =��+ 0067!C�Ns `!�,NbitraKc!2nV"";AJ%1�G."�z��c -%*��maximum!eol� of'#��`Y�C!"cal�e�|d!5de&�EI}�med�a!7ve�X66r'( G�<)4 z-ax�Q�9R��Q�� "�f�g����|o���iLa1As�Wr�.Mdefocus& +�^per�^�f:A� � �r"�.8 �O� [ UCSF Chra [40�t1tY/�Ou�9f�A manu� o7G �1�ed%@.y3Ap.=�K TwQ4j>euG>�%‘Fit M�in Map�� sub-� in6��v%Ang��!��&M �,������(a;�$? a 6�roQg&�� RAo:*�p>OO7#� >-�e�ct� 2 �`�")1nar~�; ross�j�  pb*�QIg� N coe"�@CC/d�as CC�4/|u||v|- ��J1s!h� !� ��val�zqa���!bre�� 82P)[I�CCEa]��mw�KT.�4) ! `�$N}(to zero out�(a broad env��d%�sɰ1��ej@�<�v�wi[(�DD�USF MAVE"[4��C>���c��Md�* 1!�� �=henb�{Ilso&�B<n�c!=�G� ��Aj m�e� ��rea� wild tšw� L-kynerunB,*Npec�ET/AJi��0urΔNNy ,2>-c�����s�a93 elev%%.GQisla.a�T!"'E�ZaQ = ��en�%on�a�M� Obi}��<w�p. R6�,.�of YUCCAE��=����".-ME�tl E�of ���6,!���Gin5QC.��PK%�<r�uof1Ex!C Us ͌�[�2+|03՛ 1��{opropane& lic-��AC4!Bd.�2�d |.%���Y.Ob��upu����w�eam�-�atD!�C hom�D-, , Bd1��K��2�K !-�a4BAq 6A summK_�.b��%�;TQ�QC=dMkM�&<A'.Xtaa1/t�B��U��)g�xpl�ifE7.�,.2��e:��� E�2��EA�-&jomak~{6onLy 8 ��A sub-�a�2%z/��:JKj-8FA���Tiɡ�nCa���OAeosta�$o ���U�� �t�=>�a~.G�@ �25wira�1A-k�talk ZN[ �o2�.Ɩb�i�A�fundaa/��"�2 .H surv˔ ��1�by��vi��&��,w!nut4��shw�usoD]l��66a{��s�asg{m�)2A�bo�=�D hoto$�G����, ��R�s�8ar*¤y �I�num+��arm^!$^53"�"tŷ)��`�oc� p�\������X� &�f17environ f ���ac�QE�BMs�a�orE�E��gs[ �Grb6!�� S@��<�Qm�^9�� �k!�2%�!oreD[] edap�� r�� #lYfluhs t-embryoR{E�=%-!��x.#N�[2]–ǟ.l�.3�#J�V�o�_�A�Am�+I6s�min Wy)��8]�`� -A��Y����r�jt� ]. O~: �x,^�[� bree%�I�h�iau�HE8X)6;to"2#M�� �k!*�)w�;eb }�/ �,E�. �Hknowled=!h�!�&W. �'��o{#�-Db9??-1/Ily&}*�%�f.Z ��� M62�^m 1[����6Aac`�Q,�p�>)�s.�3@�effort�^g� lބne���Ca)zm"� loci!�2 .r^Uo�zePka 1�M&R m en<�� I�  ory2v!�among��fm %g)Who��&2 "� A�Y~4Ge� \   !8ka\ceIs!�[*� [�8!�%*t",$impaird�yIM*��aGYU,��= xtreme ca���2/�Qs H� q%\&y@axru�(3� s-of&ځ��BE���-�eAsW� &x* %6�T9g�Fc e$R�3up�ne�e*#�<%M.5�[Ð. �1 �l0!W��-�:%��f:fA*a�jcatal&WAT6 =to� ;E)օ"} cyto&<me P450�_ "�*�, ( IA��� Y�9 ED�)�[15Iq W���K. ��*���a 2���S l; wJ'-accumu������ yJnl9.le r>.��� ��ForH t��E�KudD6�!�� ePn"�"�itm��>�5 Ki:���a��&l&�a �6� f h�#*) q%� "B N � �:|hes9F�Zm is n�@��2��dth�?Q K�@of6�D ���*��"p���R sage.�X �, �apf �^!��7p��3Kn�!Y:e4-�#N*y,:�rݟcveت"Ky �j���]�VdPi�P}� a'� � ,1�� ��m�@b�UpraF� �[297Phyloa\ �C a2]&=�u���R>�lB/� v����AajP�"�A`er�sma[� f� j�A*aY��Ily�!o"RRbő�!�a42�6� ,6�H achyN�X@. S�a ~'1"��n=ѝ�&i.v���vanis� tX4l 71vtE� Nof- �Ȗ>aL� %���1�)�%^,[nu5d�:��y��o2,"%dwarfis��!�cxi8~yL$��ma]�!�assoc��G �flo}�ce.� A"�d2�!�n�a .%�t�of &�mS\t2-E!nm^aPe_VT2" / � ed*s!�5C�o�)Ca?��re�!�&[ ��-�&c a6p)~�?FY(*TA� . Un�T���i&f E-�1I ly m� ��tH"�w���d"�� 1a���s.V�up�K�"0)��8�. �Yn� !�my聍:�� �sJU>�,�monit4= seedeA(�Kge47G��iE��lab��83&� � issu�`l�b��'!��X�Xoodh!՜��e occ��T��er":( M�)�s.i{H1^w�5�I�co-*��r�`iNc��E^:( χ2 t� two-�a�b1"#0 . 769�gI" 9RflankaI�Tf�6�G�!e \M�@t��[{E�My:e~tA�!���6�X�lw&A��,^g|PT�"�.!�,he Bd2g04290�a:B���*v&O� ir"bY����2Q��-��zy�m���N!�S���'&�Etwo�fLlog�+2�a�]t=��T34400�" g' clos!�Wi6e)"�\�2sa�� N�:1g) ��j>12�1L > �p�I�.\1�&ve RT-AE( q)�3m�.E �i!�g�in�s�!� i��i�` B�1L.Ni��U�n��# �#�!;� G26G�/�*�!l"1nAHd�#u�@a�MYq"<A����YbB��"i2Y�eiB*z6ol(d 140 bp up_akATG�XoZ9�euma=5m�.�Q UTR ut�Cc-Y"b �1o��"�m'hEJ!atR9�Y>�s�A�2uE�q�4x3%�2L mRNAbyIN in 4-day-�"�)*� *�)%st��#$As�ta%�)� ,"K � ���e��an98F5% �� m_c*z&��kn.d���ů nt (%�u"��2���.�,�&�ass-f ��M� �c��r����0�8� Z�W,��T��I�!=a}5ann�*)]"\�repet� �DF5�fwZ��>�7.V{�_m�� at�4���"\.�W!W�!��w�us�N G0ELte!y ,� u� ���B�a:.A�� "� �zedEz*,FTU�]26� cI�&F�B : .�T��GI�%��c�DY��l&+g!���q&��- ���'de�gCo�o leaf�3A�� q;2� �O H–�& . Re�&*>Z�!Ln�2�% dXA�a�ddi�b� ���s%�fuf�/l~A��ok� ��.я�2� prin�Y/F�[d�uyB:�N-$�]�-� post�[��au ,5�C�mpB�Xtco�0rl��� P E���&C%�15<�YA�/�g1�2&� I�<��^up�!4U:1���E��k?4e.�M�~�xDiYV��) I�,*�Sa� ]�Eella�{s*!� divi&#��|�^zo�&��"V-�+WzQtaxylX$fAP5 C–�f Also�2.-��Gq�L)�� eus�,iAB:��9�3ՍtM� ,� ���mon&6�fas�J:j:n��Atimt�%Ri  �*�%st�&�7!hM�Ahq�>�oI�85�H�,Ep*�� a slqJ% -Za U&)3circum�-��e�aTexٍ5E–H)� "�I��) � iB1u�&\6@J~-eg�! pipe�N � F� ��� /!� �%OmT)hJ:_��٦2I–J�M&G%excep��epider|#4r ��%�� ��nde�d"&h"&��5VKuT*]"W��ѐ�0n�oA�e�u�]%.�Z.�t~ ~H�xa*=Rlso�$ife~��DŽ�) "`3A� h| �>wD!�Ahe=1o8"shz�2\5L�CIn*&wF�U�dyDmToF�� �"�%�bi�(ou6u<V��V�����8pan�F-ra�D*�7 i�Jd�� �.��ov�*]"�>���у�%��xd�>�� a&pE�a${o��q; *�� *� � "2�iY� �SB.�%x Y!�i@AH+� aE� ] a 5� 4.40��4QGS� IWAI emi-� ����c-fra��A"a+`b�>�/exA��^� �zly�/��/��� .� �.�"� JcQfas n)���k�-� � to �D:E� �3�.D$siV w( �e�bd�o�!�|U }�)r -����I*de4!!Ѕ� �a�Ksi-*t *q:@C����ir�����Gn�jBd21-��-d CI�NAZ play��B� }Z���� � ragE :�f5W�7�� �I��q�66��!o��aVe$12>"&o��V��� ��Ew��SF%�N � 8�2*��!Q��-" %M� a���'1S�> ��aL*�6 �H��3G–x5�&|t5�-wU]��1"f���@>v.�.BZ?&�� agge�%X�i1t���28:��!,b�0� &755� E��i& a�-, sum����"� a2L0{�p�ned=� .���2�m�'�A�>(�,a c�qQ�{��in young"��R3!�a m�E(� ~�/756q�C26T� �*� �|( . Colg, I|A�2�� Q�I&5 .A� 6���3���$Per�� M�q%�z�fQ���d)!ioF*Ce�!yA� �� �j�4eT2��2�!K6)1~S18R��וE��% oL � d *%a�Q��f2h"s."�-W�2� I�21co:�4� �T�mWp�;es-FM$.�"�:Fleaԏo.J|,((!�V�� e��U"�#��'wL.D*&�*oEnva"f5�om"8"{"2�5'2 5 ^� �t2$� V6%�Y.q � 1�! 2Jl�KV��&�6v&�h� Aj�!a�{!�� wo d��@�5��z*|��� st�=! .� ��lreadJ_B�s lit�Sas 1 µMu4�.k*Z"i�,PKe9,&#�8�.��1�n2M�� mock�tro<6*w.�?����-6[on6q&�4q�4s�fy�mr7��.�%py�Fu� Y�� 2D�� har[ a�o��to��!� . F�FE*z�L._.�'4(� ҩ��/�!hy:��5 h�;!�1�toxic2�$nalog , 5-Ryl-�5l�� 1l��n �2T��>ubX5TAA-)q�.R^de�by'*�*�*1ah9�N�2 �O�a*��*���"m data� �(�nt�!� idea�@+=WR�#+1�I6���q�.��g &Y� #�n:�"*u(F f,&% grav�Wp %S,8n�2% r&�S1-�Z�"� ai=s�"&M.6N�� Ρ�c,Zp�`nod;#E���*@Qy5�=5m�!W�&�;,Ra*�""*VB� >N�R�� &j e�J��SK6N"�.��&/ ��Y %)�*%-9��ev�$ ���N r� ��NES�L��� j��,4if%S -�6�!��|*�CiHT�g5<%J\�98h Son���o� !�:�M`(W#h4ed�Sspa�$%20 cm�  )f��emploᎁ�.�<ssa�iF�.�-��� }*+tri��� @|*R�2�"� �[)q.�qf0ed&� 2�y "E55�� ,CEho+�<��I�U 2�> a�. A&/E�is=��b� ��2~ ��R S1�.aj�G�9%\Q�d2.��2�>/>���at2`1y�C�uin �8 ^��24���B� ��a0s?pharmac3i1;��es6� ��sfy �7.� � @$=O%C> �7a&��ւods��'gra���L� :f �>=�l�7�5e . As!��"F96��.b% �:/�&� �e�Ba1Z���parsi6%.EH��%�'�]�� A=�r_�.i[�6<:�.>z>�,.� ��fp���r�6[/TKr�*�!ea�����Fmen�A� �.�&6A;�"S1�%�&��a�au"� N=&�!e*�SA)%j3*a�aE1�����(C.m,�2� �#"��AZ�e%o� �<M�d�ة�2����P8&�[ �=1�2�F�2#6s [ul��che>DFEO�A��#�)�[ d!�3&�3� ���61�a�� �AMIDASE&)*-) AMI1(, NITRILASE.NIT (ALDEHYDE OXJ.&AO%��BdAO2fI*. E �u->"��7I�K]X�?�2� Y#.6nW�* ;$e�6�%ȟB&���24 of f�&|65p,&�Wa��~/.&W��&ir���� !a\%�i��m�D4 �ip6�C6�Q�6Cy��,�:uZ�gU .t3tr�1oan��� g2� ��!�$one-and-a-���[n� r]�5��y6���!�@ E=Hm�c%<5�Q":D,"�..�4A �@�E)���.i��at}H!�J��JAYat�F�������A�Q/&�7"�"�6*�!>D� .�5ofF"trr@!�v�&�1Is�� :�9%.��hp62�7N�k7g��l=m�&0nd=u��#9o.:�6�] �OP�1�.z2�th8ۘp�<vey, >;G:c!څQ�A's�Ts n&�] �1 �G.�u�� A��a2.� m����s��h�!���,84!by2WH�6�=d�Lo�!��!c�3"�eG!+�.�\&Y s �Ñscu)"F����H&�1 n���EdLz&� y��k/�4U��.�- am��0%�/"�3�!q�o^P�"���xiIE9I&! &t/�.�c* � &�F2A�wY5tIL6xQg7wB�*�6�#$o�^>� �.`9A�7 %dh#A���Cy� ���W �AJigm�6^2�:t.!.s@��%�.�#Yyo)tes �a�IJ�ManEHAYIR=�9 J� xyv�k�kk5 ( AV��!�o�>R=� W$R,%�sy�bs_.;Follow���S~�6�4>-a&pџ���ǍU{&NNa"Y)qW��.�%<a���+Xf_�F�H6DU]�Yve�a�s�(.�>�,g!�;�$7>&� .%.�� E , !�"C �VGM7�sl���M.JE.Fy��1��Fo%5|��cauaC�7not�*��it�6mqs6M w �II�9r+e4y��xalX3"k�>PLPn5�0co(9$o�iSC$�/"�.�q`&�byZ[ itA5ear6I2EK��_�V�\ GK���$�=��&8Z���� �#'a��7Iywo0A/C�ta��aZ � ez�&QM.�hkO� . `gene ETHYLENE INSENSITIVE�=EIN�=�l3/la-v:ula��e�bic�AJ0�Di!��'Bk'M�r , 469N�5 star!.d�>e 7@�> �&�T�is�}x<�LXPBd4g0838�s%A6V`��(ar* u��2|����* �y>rein2l1zf'&!m����[gJ–K�2and!�l��se�� *�-&� � � or 2L\xiJ:H��J� ��"Zz�) � ��2I� 2��� =9�~S1)�f�7�l*��Za0f�-��a�*>�\��� 2�!t6��o2��Y"�fR.�!,���p-��er0ZVH�.��J�e�!5F�*�P��[`)vicO��� ceivp*�J2�!�V��dF�!�jd��!� penet*�,b�䡶 � �be�J� w�)�9JA�s9����� �*� :��E9 O%�X ��h.^ �DooJ2 M���de �s������_�#3G%�;+�.�� ��ue2h��2�R��6�7�;ly&%2R@~ _". j<=U��^1U��Bjy�p/,�hough�.�a,aB�M�En6�BgSe�*�N�/:fDO&�fu&�SY�u~6�\�BaW�#gen�ae�"B a*X.O��.�L2N\�*�D}�"�5@_p7ʼn�v���eS&�,� vig;d*N�[x ��]��ltwx��=I��Qb�XoA�S��1� Y�'s�Q4.gE}(q�u�Yv���? a�n� ��.�)�in�%��1��A�BX��gc>��A�manip��!X;l U2t".i" )v"z0.�F)Vp�<NR*���n�KBk8e�d V��'_���&]]��he�-� Os^1aY��Cmeag��AH&'�EP� d� �HamRck-PX)�hx$, CONSTITU1 LY WILTED�Ym���"l)�!��b.2�+�O&*�"�?��* fBfM�us 89SiniKTC��%N'����I*�sBcJ>�mL2�.����R��et4g���b��Qp!-��9AW�&�%>a:��< v��6e0"I samp�%�, *�6B�&� .(&���-�%�.9&{�Rono2 � >�  ,� �(!B-4cy4�iA :q�1;� e�ng�.�3�.B�\6 d�T�,���+6�-m}V�zM�@p�E�>/M � �I�,that the roo��t meristem gradually breaks down as development progresses indicate that compared to the Bdtar2lhypo allele , IPA levels are event s,limiting in ;�mqnull mutants . This idea is supported by the dose-response curve of wild type to L-kynerunine , where increas| amoul�Lpromote cell elongation up to a certain threshold , beyond which root growth �nhibi�H. Further corrobora�t�, aX8also exists for�- hypo- �xmoreover!"0hypersensitivF�treat%�$as concent� ons %�still5 �= in=[ are �ory.�(. A similarR�(is observed�AVG�� `�e rate-U3 stepuPethylene biosynthesis!�ut might)O�impinge on TAA1/TAR activity because of its generic on3enzyme�at *PLP!CPa co-factor [16] , [3 (7] . StimulIIof)QgI#by:�has �been reM�Arice [25aalthoughE&dosage u (is quantitaA ��A�A?# 5s!#al! verg�� p%�_A����nAX�ir2�couE�ar��}�$of BdTAR2La��1LA�hardly�-����at Bde_sSree�ed upon�X��A�up--���2t,�s� nt�Alatter's�]�. M? , -.�taa1/taru !8.�� are%�ACC�i�9t . Ra� ,�L ntix restor]e2\y^to wi� !�u���data t ( a scenarioA+� !�Pe�z�.�nE�ɸ* ��!�� B�r �than v��versa uch a�1mOa -֡�re4 shipA}ld�ern�٩shift��key node�T,network link�e)AR�q�4feedback loops$�y� ple ��a=evolu�ary adap����deed ,Jofgo��2*� E��e.i,2Ps )N�B=a� 2�, ҕ�ea���I�Y� s describisAz$paper ( Fi� 8 )��ɧ5AisY(8remains unclear%C!�mo�A�� � disc� y�an� atic !� betw% J�2T�D��is���a very����$d directlyawa �[44� (Hypomorphic-'a�sE�h$ose employ9,�K, rbecomed (rucial toolA�fu%� effo�hto ela.e ay�. T� mmunᖁqdar� ploi� brA�2d��chyon!H�o21� u�qA�transfor!mA�ndA=� ntr �a xperi!� s [4�except E��.�D ( stock id JJ9248� )ea 4F?2411{  )� � oge�c� th��Bd21-3�3a�ground �were ob� a6) T-DNA col ! $( http://b.g $. pw . usd��8gov/TDNA/ ) [28A.G! a�,%�q(o establish�ozygousMT�AY9 per!���0oligonucleoti��5′-CGT GAG AGC TAG TGG GAT AG-3′ !�)ATG G-)GA)=)(�2L=Ba�A".�!�T@�}TTG AA�G � CTC� CGC ��t"G)�i�%�) ; sTGCG GTT CCC TGT TCA TC:�CA cGAA AC   )p��e �cM�for�I����TAC%"C� AA G�A! �� af� TA C�TC TCC G!A%� H5�eGA !�A%GG�T )�EIN2L1F�� fo :p!�!�%�AWCAE�.p}�N�2y haliana��ke�yq��� Col-0 acc�:��� lemma�fm�seedsewcarefu peelh ff s4forceps before3�riliz_ �� 1 mlX70%�� anol� .AQ1 min) fter#al ��� soak�Oa su\a 3% s�v 4chlorite plus � drop,T�2-20�50��5 �%L' ly roc# %"�n�"st�4e deionized wa� thre&�� *#.�.fi�xor 2 d�at 4°C��nsxsynchron�germi� o� vert�ly orien� 10N 24 cm squ� plat �half-strength Murashige-Skoog ( MS ) � 0 ( 2 . 45 g/lsa��vitami: 1%�r��, agar , pH�7 )AaQh(chamber undntinu�l�100–12,E ��y!22! . To�fy� f nuU<, sheath/blade l � @width , 2-day-old6�!�s�re��errEmto pot soiA�%�8 2–3-�ntcub at � �,a 20 h photoa�$od . Leaf y �mea!� d 18 Ve.( dag��cr�-e&� d 25$.2P:���� [46�To detEs�-U,D?��inR�M|�ei� scannor)grapha?}a digit� amerq- ��+ ,ImageJ softwA�,�L �47b��a!'QB"�%]sea]l ""�� 2 mm�@vFtip �cuL2G of 4Uqpla` �scalpelA�heQ�of vi�.���then scoAw4I% �,gravitropism�,F�MbQKew��v�e~inducenc1 s�.��rote 90°e�A2n�ranoE24 hour�P� �U)n a flatu r �ram)��c&(o�W8Embryonic calli��e�!o$ ���NaccordA�to [48�subsequN: %�!�pVec8GFP!smid �%�~K�:_4 +retrie��map. �reg�fla�qr�7bor�O (.N!�.� �s:�2� A toawA�8 �ge!4lin1�pro!��among*Ugl�x f%Sa���(hit . Whole!� )NGof ic m isoAd�2� ��as=�on% Illua�( HiSeq 2000!�t5  ,ee!�ng+�2io� aired-end�ds�100 bp�v��Bowtie 2�t [49]�u��!�align�2�*�re�ge%"d mipa8helmholtz-muenc�. de/E]2� /�ed%\ loca"d M�E�2I�� r%y= mosAs2 (@i�8: 3 , 030 , 511���precise(] a^&�!+� e�C"K�a��B$unique ann�m�, h�it2%bit&�(disrupt anyDgen�FinNve1�A�f�as�i�toI!.U'J�a9I�ea�of� ings� o� both5�d RA�!c}��"�&��d� one�Wy e�of qPCRR�� H carre ou�liquid�e�03 h . Briefly�0on&h ��("@ abov!�At�WͣE$�.D  �-�[w to �A{ain1~�a�ve5Jo�L ,m^i�2L9,*��W>� . A�� a�-Y�0 on eŋ�t pend�&sa#�Epoo64 �ca�.exam��&) �2X[50� S*� `N9�fix� A�.-8% glutaraldehyd�4%AmA��MT,phosphate bu@ �LH 7 . 2�=Fl �}tho�G��h ur tw� C ��.i E� ��# area�vo� !�w i�  59 � piece�embedd)6%� � . SAA�" of 7� m �" $approximat^2Xa��� � $a Leica-VT�I 0S vibrat�Ci�sA�� �$1% toluidi�"lue&��30 �was# I��!"� ��o ))"� unq�M��T�10%� ass�!hyd�d�at 95y ��R9�m{glass sl�%�50Ajyce1!�� �   e>fielda�"4!"�� ras{#�-{0 DM5500B comp�mi�cop���" visu21"� struco��> l./1Bfollo� AmPS-PI��[45] � imag�%8a Zeiss LSM 700�f�6�CV�!� hair9��ize%T'� metaxylem2ExQ2"9Ď9�^�"3MA��qS�a�TMxPro 3005P Real-Time ��Syg((..+T0"�#rep� u analy_A�{#�Z�8he speca �[aRmpl�j�aEtbyl mel=c2(l[ A� gel � roph��&� aedAduc�(No� ����' �i�non-t�HE�ol-Winclu��Fy�� rule���8& >� �/ �"F"�($cycle ( Ct efficienc7 �iebflu�c�( RV%mv9?�salcS!�AAI Mine� gphm [51��R�ve��#BK�l�Y�"�R0!�atarget�I�&c g� �, UBIQUITIN-CONJUGATING ENZYME 18� UBC1�AAy�BN�� : B 6,4G00660%S�"]�� GT CAT TT:AT�G G�TTC�;p1Lg2G3440.gA�G o� >E��[)CGj�� g2g 0429.gCC �CTA�dT BkC` G5GG s�k� �1G2896, ���C!3� @i��A�; TG C��i7 �1G0058:iG�:i ?>hT�CT=C�9�h8 h5G0132h��C!��T�!B:Ge! GA C!6�� �9:3 j2G1030l 1;T�CG�-A%�GGA4A�n!7 AT G�AMI-�5G274.�2TCMn!�j>gA�C{C  A�A� )�NIT g3G4962]v!8!p !<%�*��E��A�TT�CEI�hAO g1G5274g)QKaP!�e' =fa��!�%A� fmC1G5662�%j!0AEu!A�BfCVad!�A ���g��z838�!d�!.<!GIE�eh�q��~$)5�qU�? �hy�Us�"ve "� �"es�funda �yo," #thi�#� ��budhye� aVh��� s di�&' *n&@/�`&K Rorganx�ir�mo�( s: \la�a-f��( deno��OPN�“Occup��P. mal N�[” ) v $ wideO1�"���whH-��� ���NFR�D�Deple�f��l�AlyW=(�exAe if ear�'.�$dynamics6tribu!mt�1i!�f�in1�, we art� �&2� high:�GFP–f�h!� tein*Surpri� � F_�eq82suc�ful%�!��(!&I>,� ∼80%!` inK  "p� ble*c 2 x"�byAi!&2 .� 7I�two Ns& k/�+4ct mechanisms:�– �e0r%du� d)��� I�"E5OPR@fav| �!/s�in+a�f��S� 1\��!G( @1�!])�es Mr� rapi�)�(-�5;� C )q�� owerI?s� q,q(. Our� /�%p�3r6�conYACther�A)Mi^y bia�47w,A-Q.-�� p%plastiv bio`,�ra&-$is manifes!&on multi4(�lRe"�,Y#@$erK phys^a&\(|l divi�5!�Ad{ cond�aJOn���.�, "]*v+mod� b�t�&A NAlv2��4o�A�m�)�varia�(!~�ova1m propoDt �'$ed [1]–[H%���!K-5!pI�1s :�ed�j% envirojale�&h%� � �w�4show a�/�2J�,�.be�,er{perturbb=�*��-�Nb}(I(e%)�V��by marka�A� 1e�most sus�'-2oIEtE"�'al evid��"T7 Osem7I~3par��r�) stud��in��proR�-�"�,�>!�ag�����extA�g� �{. A2� %�&�6�]�d�s�NlyA�e!�n.e��w8a�%pDon.<��A�fun&�U��)�- �.]�foc��6`%Q�ar<*2Sin/m�q�ic�V�2 mpha439eUAa�0rac��1�6nd&ph��1s^to.6 �W�[9e� 12] J�MomM AiJ�profi� dem��a5�n �gA�)n�5 clos!� d�E[13 �9�IQ�)W_ ��J�!:A��A�o:e Շ*_ [�4 connlng:�� ww� 6���[20�22�Ge�~w$ ]� Nd)!�,yp%� 8-G ��+�* cripj start sit2��A�s�x3u-/$a^ nounEG" � HM� �:� v�"ad��a�%m`'�on32l 2�qR,pla� n j%ell-to-I��t ( no�y,en 6ha�  T� boxA�O,1�s%�22��," mut� exclu�,5� es c�. xplav��p e2�of 9. Firs�8e�l(7�<Z*�m�e)*2�;� !�s� u�:nga�(random drif� d=Q6�] enhaA�]� �Z�u�0 �Eitself�9�,�toPa� tera�AN)�/E.\�N6�fw;�S� 1 A�G trum!V�2!6>=�be�'�0!XI�mxI�1�K1 tegr�a?�'of �6� A�J�m��2��m� 2i: )[-ac1�q��ŷ*" is eli��5[23A� A se��sim�6e� clasA�u��subject!��!i� &. �*!xIU�6 low5q�(� D -w%de�ri )!Y %X+be.�2�tby purifyA��.2Q�!�eK.�)���� h�h.�*� ::r�� ɟfixen�l.�4,��AFsbe.hh�-gf7<ha� =h,� /a��-0easily satisf�byydu%=h� flex( Q�*ZiE st2;w(<� �(rA*~6)D � Fd2K�d Ca�� � tak��y�C�Aam91{%�?S !c!k�|�aR0�5by��<2he�X� t�A=W-�,��-��pr���^=����-�is�!�2h of dozens GFke�&&&��irk�v�AU�2�:da4fl�%Q&�4E��,a}%�d8,"%: S"�A��.�of=�?A n.�%�=E1((� ly fOD& %�a�f-�<res�In%s, a-�*e@�p �much les�%�(�inE�i��B)�%ir.�primara��8>����&�*"�5a�wil�����impac�" n�aJ}:is�� We cI e7y-o%:��Ispa@#ra5Df midL >�&D� no p"��wards�"�  Bpo�'�?V*A�Y�( ( Table S1�Fig(S�' ��ɺ�'B K�!!�e��aD�+: # &q  o�a4.#l� ( ‘OPN-'%’�6�$f��def��a�i� �j}r {hu��? # �%�� � !"�ex�.7 \�� W�mof��4 �aRon�"�� s�i�Ce .�� � or���I�%w*�8Ob[ �_�� �� [24|a�2�to ca�t-��ngh. S_!� %OYhmof6VA� n popO+�� moni�>d<"2�� v� ;s�Ig&FAC�3s�top�05%�3�*�,)7E� �-a���2km��&�4by FSC-A�=`cBB� �x#)��:ed�-�)$�m�,�(!')tat�!ɶ��� %E' -CN�~&��majh">�Ds ( 35/4�(:)�"3 cap^�s!� X�$M.geZi �d.��*3–6 <<l 9���' �,.=R&aM�,� sQ1�#)perhap_~G)O�C-L/��w&� ax"; �)�t�q��,)� a ,iR�3#�0 o �-�9?� �@s%څ��$d �2p�tF@eCŊ1D�� s S2S3%��.r A�a�.�E�eE1m.!���).E�ign�eantk A;ri� oln"e:in� �& 6��^}΅��!�-.3To fur�7xi�u"3.jYP=�� f+as�i�& drivAEY(�dont��sL. I 5- �/>�U4w�L,)��3"��aink �lso�n�7saha�@1�� %; aH� et� � ���I,�ɸ���;�2��J�*rYl�i�O*�!�V�Any��is:>{l� (uKg .4�au<orE 2� ) ��5~i�Bc-�MB#1Y "��g�8Yo~cM#,AoaeE�D� �m9�?45wjcML%GAY&k j?+Ori��a�p-� � U'alg"q��} e{  V7 @lm)oci�[�Y>D -"*aor �t� ��} �@��JdE �-�d�C� � n*X�$�3�+�Gi� fift E!% � � o�L^>"w�<3)%T q0q�(� A�le-colon�2�6� c*� ]I. �I\DG73 J�}@� ��9�V�a-{�i� h�;ZC�0ac1`c��g��Za� mix.j�:3�56 woNI�!#R��sharpf��-�20]�, V�yRur)ĺ��on+�-e 5�"�� mpar!�!�.� .p]Kn (��; )�I�!Œbyn� �yr���/z!S.z Z���MJ p-vaM1of�63*10−SR�xve4YlL�--�m� w�H{ ���&� 26<ɩ� Oi�ten}�% ��O�` CvalidH%�A�!D�d� q��.I-5�to�.S!Թ,�16us&���2�twe!(rem4:sSmodR�I�,�B f�Y to�,�3h�15��.A%II��d� �v2f))Q�RQ�Ax.q"lHZ>|!fr� c� 5�j�� onba "�XV�26I�6 T!eB wh��}c$ ��6)i�B �oAJ!&l�*"lin� �E���b�e8de5ple�NMiC. J 6 . A_Ln� c �89SchR� n�e5�inj7 ��%~) . M5 �q��s1K \��Qo=���B& I�d)&A-6� .�� i�ll�no> iAd((v) cop: E9!Za c tpPb � aF� fX. W=�!�I2� s!1:[~��!�)2� w �"CM�O�z��:CherrY N"WM�UL9�SF��EI6n=)� _=+"9S4��6�co�A��-feʁ�Q� h"  l9� c�(K�1�2I<T�+z7ens@ M�-�.� . T��@w��4� DPN&� &.1A�=hn%O7��,�_LQ�>�Ew5noIqR �*! F�!`iSG'&W %&���a "R"[� S� h��c"�[f�"aso}.?.)��M�(J�R��,b���f%H2).�By �t2� oassM eGŅ$��n�Ba�-4!O8re�$i68. W !eWP�fwoM�,N�A�(�*�,yW3A%*�<�h*N D�� rray-bpXA�a}ve-�hybrid�0( CGHe�4�bGhf�)in 11/13�m�e!baXR. T"�%B���� ( 9/�A�!U?in�+ /��K$%�* "&� ��3Be3C [�5��] rinc-,B��]�+q � .bv\"F,��Ye%῁�# A:ix &I 5:�k�Q1a. E a smAE*� frag�2A�^a�JoAetjafit�]� �G& �.�di��(Lth�W!5�rɕno�>a�_� a.����J5�S�6},�(ce missegreck>�z�3u�a�$is�8"I<m�$D\ [2atGeV"; �;�1%9 byi25/.��� fas�3tfX "j C"r��t�Y�� ����?mo�>2�� grew nineEhZ�Z∼130E��*�!�& {�4s <orl . Ou-�[pC%2�qed]�>m0!�x-�n�3i pre- �6�|��%N%�w)A�lo�`I�R�YON�aQ,1���ps� SAG6AIedBGU�4‘x6�x��\��,h^5}im�$!$%!mrz "�!a&�% ,i��AU,*�!��o�Png%2original,.�!S�E]�Aw�V,� ��/g`I�"d�.����upN F�?e���$DmfunSg�s�q`y=�� � er;d�a$�i 1�hae�fe 4a�,�2�avail!aU-6!f�.9�/.�'K�#. /!\��a�*� M =�R� ";y� - �*p !�se�Cal.�!a�5 �'w7pyO*. B�&�ciX�f2& -�/u]C �Aub"U�E�!NR�$a�Ibc6��*. T��"!Q��6H"r elsed �7 a\!�� �4�� m,�4up�Sam)`"�. � ��K !. k^�>�ha�-�2��&o]12 �5o2��"yyl��H2=�� (�all )�@"�*; E?� . /,!42VA�? ba�IFe�.Q���7!V�2�a>7 ��XE ?!�EDof..'C".z��-�NhundrmWof un�$m�� SC3EF5~}�b=$>�smM�M!�af�.8� ��z }�ka�)�Y@,źU�] %_! �-k��.B�"4U>@)!J>�*V(�8�k\[1�Q[v\ , [2�2At�ws�d�&� }�&t�j�!yU��j"�t��,a_ )a�i�Hnt�=2=�\  �. L�<��"h >,[&��u"�c��'1-!�1%�#�is2'qafl �zhbZb!�2��K�Ya�<��*I�BR*p�2Q r� q'advanDG�F�&"�i./out3`��4e��b�2��~�gF�aU.W; �I�_�� �} view�!~).,ao"=&!:��>�[9ii�C!�.|20�fK*b/I�i�� 25enB�;"53:�1�29*�e�Swasu d�b� N�orve�](dfst|eIchoeU�N4A�f2�8sseq�dicnV+h!�Wem:%�u�y�� 6�$F^�,�[A���as6\�t&s+R�,��!���f2cu�c<ce51I�)'2� m&E#m�s)�iI��a‘A�ral�*�?1�,fMWo� s:E�A�95)� ?"� a�b��mB Oɔa�1�^�+ . It�[� e-d�c�����qO�dx[3L8tl-P��#{Sf%aio�� :2pleioKic qZ!�х �cyA�#&�7���Rra� .j07�*abLi*LD�2�=! �Yw>�){�b�g�=s=WՇ:���5r�(&u&ly�4J6".�A&s pv�bsD A[ ))Mus� ��� !B7� ihoo.be.1ed%�a� ��ˡ�2e8�+�t1�!xJj� �ueI�reS7 7x "� ; ��M�} �)�i� =e� of�P � c�j.*Hw�L�b" >2��,!�*de, �Z � �C)x9.'#i.6��Nh�v asieEuuC�*��%w�))�D2s9 � � ��)!x#%���q � , ma[%OWu�m&�+�2�T�$MRxH 2j1�27�\��7 �"-F�!�U�6�  !7&�E;J� (�0���/2 )��ae26����er� inu�a%A*tegeAyA�"�;p�3c�Ep-�� *� 2g� ![A55U,Dyi�A�e�d�'�b��ń�`}]u �Qd!�ven�(��&�Ee y�� EN�:5�:r=��); ?�0rBP.�?e4�)�=-�{ L29E��3wV�A{.EM| &~ s [3�k&Z6E F�*�)� *� 1,.��i v!Y: merg�x gqq*g�^l� �� yeeYi�Ri� <1!8 �0a}T�5Gn� %�en�=P*| �d���Fv D A� 4]�� %"e� HV35�2ItVs%�� !<�G�#!nly neut�T��d�=��VT ,�UlL 2(aa�+5Y�W' , ,]X�#�!a_ ��� E�=�or�J�����$,e� quickFn�.E�)"�-�e�AtI"!qA*4#�t��be�AA�ɬyt� &tU�"--� )*TchJE*6wa�-Y�!4���( n�h;�:�%i�;"� ���-u .f>Kwe.�%B�&s"�R) �W?|��� m��o�&� �!��,pxma"�IE�U��.Cp ��!�I�93�iA�h "w �� a��7s�!bRr%�.B�w2�B.��`:kv�F2>tBFc0m����aIq�"�*) "7}Fs� hE�A��1���O�QO��G_$��g2�O0��B�se�&I�;I%����?ac shap1 .�K|zia4�:7� �U*��th�7le%�"�`�k. �>�|Qd6�=���X=E3BP aA� �3@�2we��i#X!zav�`.�+"�9�e�"!2�ETST7-"�E�( �j5�c"ic0, he�| TSS-a&A(�d–�Vbp2^U b" �"_�� �d85�,inIW��vseCR��]Y$ Lee e � .�KaHd"�f Tsui�LS"�6�&�r| ���"�*�9l^ry����9x. BY4741 ( MATa his3Δ1 leu2Δ0�[15 ura3�.�u��K��ol X�vy""�Z gdMATαBhlyspge�rv8��"�$� nt-�{9�zC!�&-fu"i i�2� is-E�.L �1�La YDL227cΔ::TEF2pr-S kanMX4���% �! �. Yk� �%�'gn�~�� !I SC )�bF�:�:Ad4, flow cytomet�[�\@\a�Eb�s�� m*M3$n YPD-agar�P�S>C9�d�P���@$n SC-Lys-MA�6<�d"9)ach�Sena�).8to logarithmic TL�]E7/v�P:1{.� R6�Re� r 7�c0� &5J" aKl%=��O �^hE.io��I�uY�*I#s�n&�9di �tR��H!qnv/"�1�C�*N'4�+&S2N�=-�m��=�=! ��?=(wa\! exa{!��1�x"�? �I@I�Ur~2DA�%�Y��?�O�Ii�o{6)&�6� �y� �#��R(Ea$n�&�i6Rpic�0Pg�Ra�p=��;��I��}!�X�eA!�)"�,�!F,hygromycinB Wgo��ferÃ( hph��a ��kerreFW� ,ۇbios X B���ppBS35�3s�ou �rs F2�R1U�3KWu.x %��"�m-gfp .8�!.$  GFPOligoS3�2tx�b)@9,fd)m^)or�l�K�o1�= 2� LiAc/SS-C�jr/PEGGaa�S hod [3�r�rre�k�0n��p�>onzum+2�(�g3 mg/m.$Calbiochem�&Cor@K�g)(EH�6 ,by Ge)�c�0$? im�4!_,tgaactccttgagcc�]�PgA���checki/Ba�1�)-�*aFE=ey� f#�]� �[i�o�1E��bhomologuA Fl*d2Cby2I e� H$BD LSRII sVfBD Bios�d�Ip qghdfoughpu2mpl;ten ( HT ,k.Exc+��<aveMirW�&Á of 594m�1Iԅ� fcs �T��imʋE�Matlab-�an*�&�  [4"?GN� %!��s  5�"�FSC�SS�-�a%�outlia��p�[��e��$�e�@aV�eviiG.�/M32� ��O e�3���=�+*5�FAp�,a"� �wo�9h wA(ext3R"MFM, pure� a0PP��Ki{�Epi4ieA2tyhA��A�R2�0h&� in L��Cr 4800ga�;�.��b i�6C�g 6Probes � ���|wTqQ5 C��:i�cacatgge�e�gtttgi�!�� at catc- tgta &6�p��. 3 ( Un�Vsal �L�, � Act1�&�lwen�g��(tccgtctggat�ggtand �� tgag�ca�)aa �Z�139��| �1yQ�M��*� '*�o:�. A�  N&� j"�yI���{��A� � N& �w\ u3zqz6L6�6:�.]� e,���Abe BZ=SYBR Grp@mix{4hermo S���a�!e�nn;"lI��9. PɼEHt4: YBR197C ( ch~)M�gg��,agtaagcgacgcI; ccagcA1gacctILYCR04RhFe tatgtA�cacA� .TBaaaUQ�OggE�ERG��91P cagao�Tat.S-a���aa�� �URAT�3 Ua�a�attcaa2�-tttcFg�tagga QSMA��1�� �!"4' 0-I�7 !�3g �1 �ga�ga!ha�!�� C e��r�!�q� ACT1 E!p�ttt!ρ)� G –c�c�!Igcg-Nm3a��V RNA�S�'�� EtOH�cip*,���dig�1ug AluI5 RsaI�trii`eJ�(�c mega� �V� �QIAo� �?k��QIAGEN�~�@�-lab��axHyb�6[oxpa�6EX�Agi�R� ER� A)-BamQ�ˆ�q�� ocoW4��|�Mf�q� !r��O�)>��Spo!`a�/( N#^2ni�(180K customm�q!# Le#-v ng 6IN3-af��%��7�{14,)�� �-01�[�{%;e 244K.�de@$: }h:ofg �T 7�'�5�d$ � �i�[:"�=�t H� CV>4gr� an<3MOc= "M$�al%@& }w�g�( A� [ tya�*�� ׂp N]6ve �M76z�N -�dE#av��!�"�n f�6rr�;e�b7CR�� telome��0( r = −�u2�4]�ub� |�fssOr"\��"�Su(  ma <"�a�9,�u!*���*�by �A� Q�r(P �1%&�E&� ( Cy3"2e oof WT �Cy5#56#:��GA�4unsmo�7� (�� �!p5����dracw�z�s!:Jq3� : �ut���Za��>�ssa)$Q(� G t��v B "s *�   �6� >A en", .OCyep6� 0I /wTU`(  QfQ��e�>���!Cnstitu�.TEF���_ ��o�|96- ��~m�ino!t B0�5�S� } DuSn=��e�binan��.rvLS�|��� ����s)� %U"�UQ|a�t�Oat)��poi���*3�G�� ed 3�����-IAs%�th "�* deri�e�~h� &�B� b�("60!��\ng r���axry&�ua�le�n ni��?�"�A��1i�4&A�� +I�'f'1��6 P M�9[he�dl2��lpF�<�' K"�Pg!;A�nye�:/�4 U log2&"A plot!�ag�j�G�va�U�eslizLa9�-�ir2& �+!�Ee"w]J�7!�B>5�:�A��e6�$I-κB kina ( IKK�&�NF�,human T lympgo�-virus% q HTLV-�6p-�v�V/onco� ei�)TaxK�! ough.� %� li�e:�Q��  . Paradox\_�O��aje ane6&R�9�!dD*ic*�� 4�in-& )&Z��,p21CIP1/WAF1�p27KIP1!���<( p53-/pRb-i*_ Adu� sene&y. H�w��"�h�.k-/ h-��E"�|'$�p�nQt IKK/-�ϡ1������� -CHeL��ll�s�Mnu�5l"�Hin0: 4,e.tMn!��*ed�J#l� �� a�"a�L`c[ t@%pTfI�α� pi�.�IKK.u. S�Ahairpin� 9Hknock�� �#aM RelAu�eg=sp��am��ngB�"ana I�#�Ulex% RelB�$zeUJq(%+.omRN�mq�f�,&�*we& )��Ԛ!wof1`m�m��-�gew, HBZn%g6\�?�ot%nseM@TaxA�u�T=�.B&bal *A[�i}��r�b��|�6� �inW7�. Robustrep�Z�Hedk.c�#Ab>trigg�0y.�&W�,1esdYOvim%r:�M�A+�{*u�' � �- �"�0�ro� '� F)��= �2"�;ineof�����*facil|eZ!�F�!leukemog!is . H�-����uHf$=��adult TUk eia/ Um@�ATL� ҟ 4 of CD4+ T�WA2atb��I�5%(5T&X"s��$u�pa �/C0eca [1��[.m)�Ʌ-_o��aCa D�vo��TL�.A?!a�2Q%or�.z"�'!�-� �T7o M��+o$!�,�1ac��* 9U!5 link!@121-bp��t�9!��kt?�9%_� �) �Ai�� �LTRKto)9�fgk CREB/ATF-�J��%�ѧ(ors CBP/p30[-CBP-as"J TCAFQ��r� �)edyjORC�[3o�.6 -eby!!��~FLeh*�@����b&cAsubQ�!�.m l E� g��9�\o� NEMO& also��e�IKKγA>h3"�lul)�2M��"�? KKαEI ���X^_ � ll ��Aq6@b��S*� !*�D �/+w��[6%c�(~ �W�&� ( .8�{� Y6 2m�:u=ri�2byn*r�lWMuv�!,l.7at%���|�%!�f�/ $M!� APC/�'�� E3 ub�t|�u!eT���L�FU�$�mitw!exit [1m2 h �!�M�,l� pq%#poly-�)�!7;,C !^fU�a��*��9 Skp2� ������s�cog�� Y���NknM�SCFU,�,mT�� G�Yyc�E/A-CDK2&� cKIep27Kip �:3asa.�g#�:S/G���[c� 9Q:9��M" 5��2{!�p27 � � )� r��" !1= CKI:2�  (F�16���2s� ) meas ��!S� )F ���6�b� ��M~m� ��aau�4in�I�a�ur�7I�53- � �L� "d o*��h x-IRq!m3J -i�a�p21-/27&� �_>� :� �9e!<1*= */1w�ic[�ic��Jg W&�3*�6 �l i��-�4 �N%G1a��.\/��9nd$Fc AE�"p21)��"�m2L�_A2:'JImܓ���B_=�=0&i C*+�*:� >+ ���) st e�0&v� ULA�*� �B-j}nlo6�!in�1.iA�%�sI`,y9I}#a,?�W\ *[ RNA-enco( bZip5�l �P���(��U�=Oby� tu ? �CN ��1O[1�&a ���an��viously7~ɏm �z� �=L��k , [2��T� ,)�e�. ch&p�?poh E��d. %�F�i= �=l[sde��� EJit�!��2�.�by%'9 �&� QB� exp^d; �3invest)�a�"5j$��rs:��"���]�-6?=muA��axV89A�TaxL319ƓL320S 24T �ef���GM�LTRF��+�e%�inJ��v, VSL�atATaxH43Q�,T130A , L131�2{� ��tVd �)a55�p Q��:Un���@ &TaxK85A-5���X9� �.����!�:� 2 @ I"�kF�A D�2ka �$S��6:�omi!���!G (�@2 ?��k� urro�2�r��6�E�h"��%M���i�v11r�err�l�MA� alleZ}C�� �!m"� by iV� obloE�A�BwsjQ . A"-rd(*)-L9;Q�( U�I�v A,�[�{� -�g~!�@ �6]l * i�dr*M "Y.��!����fi� RN( e1, E� vi'q6e� aris�9had�:KZsQoro'.N,�,Ig,�͖A8� se*sRa.�[ A�rVe3�0a/j͑�w-���Q��� �9�8},��%aF���&��> a"�Med ΔN-q�߃un�D)`�{�~�36 NH2�9�amiWcid id��%�& EBm}/ry�[!9.BdomXy-κ�I[{�!��ele%*r�rs2��/&IKK�2.a�`/W�  ,2B�! ]&�!�As�q-G�TR�HeLa-6�,NL6-J1H5�Mt�8tA���EZm1�m �2 )|"���D&p aY,u��Y���X7Fce�g i�2B & A148�"sMT�%:y�e.Y& �c�%�m�Yea.�i#%"$)C9�!2.a�s�G�"� ���)u� B la�v2 & 4�:��2C, 4 & �P%�!U�"un�  .�2�:uNpl"��`)+of2[|+���\i@cE"/y� ��A0}�� a �^B o�mMHIV� !�]CMV �ta�"�.�O-�.�.y���G7 duIXkp�wsr ��f2� cursorA�1[�(�O -�6�:@t9= ampe�W �! ifj#6G�V!�� "j !,%�� az�27A��f>A�*u!�J�1 & 2m� �Q� �littl$mix 27EA"�O:F�iQ(^�3m6�:� 5y@t>>��2E��Wf�<����"@�ce�-A� �(4P&�S!CQ� 3Q&�B� �I��B��M��Jl0inuA�����*=��r12a��A*��sgg�ng;��="�!a)�xs%D�*i�5�in�P�5)AJ�!� cA�E�l��-� abbr 7e�nR /18×21-EX7A�%�o�v� E casset .2,%�o m��da]en*�vt�( nY IY&�44^ �18pgAM a8-�!�n? [�c. �>harbo��|�3i!].G()Ne5�:�rxAxDm�d:$Sol�?-�1a%�,:�e� n��20ͳ6o ��3B lefp� lumn:06�nT��e%��1-��+5��Q$-�to!�mtE� P/��6�4Ih X.:+:  �R�� ���&>�X �. midd��nd ˰c% a, albei�ir1.���UI�  sl�<ld�d�E.��un *�`C5G$.&C'1nMž!�14�1%"j�1<Day�E>� panee�.N7-�XuVɥ�%�q(�J��d|I�2�oD�W��T�q�saGl�m"N4|�A"��jE�i=Qof��-�"�RQ�a8H"F4#�zs��S!��끘I$�-aS5ng.1 !� oB3��` -�E�n� �J�}6oE,�ɬtZ9Sf�l�DTV!BG��Of&al^ S]oNo&�.�s��a�4eިvVB.� �![n6�����5{� resh�p),:Usuf`���,��Yacw�, *�\.��s b&��6ct2�)�5�~��-"B���!����T"l�.6A1"3R#iF�i^'х 5] %.�oF�/A�/ &(6�-1A8�"SH5 A �,N���4tecaa �.��/.0ɜ:��A�,%�u&� .�.,%yv�eA%J-�ҡK6 �@ 3 ),:�" .-M�&���:z6S; hist$��$-k79�%;2�A�% �@.|L6=IsEHa��"Y%�_+�o\��c ́��G10 S /'Z*�.U[D  rv���e"3E(.JAl�(Y��� tarkA�-��� ���Z�0.L-� S�E�  publ)a�':"�8I.�W�-� u�>" ime-lapse&$ �4f ���P�ng.� &(K--A���0�[|Y�j�}alH a�Yne2e�d S6'h bypz� to`,a��a!��in G1/&� <�� G2/ME��� ( YaښPS manuG!��!B�r�s BI%�BOd.[!is���s���# NkM��e��;;Z�)[0 �3� . O�: Y� #.R�&%��'ed��!�min���� )�.�6���<�rB+��ze,)y2�'art� AgA�*&�r*� � �;*E) /E^Y+t�i:E27�xd*0*em�%�*���1.��2/1�ansW"&A�$! �;&)�(Si.�x%6�e���}:�!M@�"9�1�6y��mJ��t�IiQ���GE�:� j����g�(.�A^e� '��5�I&�e�!a�P2� ,�84�m�Aco �A� �A��Fa���iIJ� 2d et^&��.��Q��lF ��!v!!�>�$�6�%c6b)%m r)(7>:D)et �, )�b�#�`.�х4f���1?�, C�� :�.�N��w>$�+!!uIM�� a� �5�[�a2;28in��luc:���I�in2 "35*ai�8s"+́�i"��� u6m�%�-�P� AM� or�?��2� M"�+� �+�&&!F.�t�+>v]\6ycA.%!�W!C)w/Rel fam�] memba"$�aI, , c-&,�Qp50I�5*w'|k�(U N�e/Ayc�\G 5��J�#�Q|e�,F9��aE�[B}!ea�_o.�y#�tA�p�q��a&*0�s:��-*Ad !%�Ad- ���(l�-W �y1�ghe>" � U�� O�A�a��e*�<m��r�exu7�A�>:1�d�T�;-z$Ei% ��@ r��7!{�C�6%AF2 ō��dF_rpl� a�N %s%$ ]q�5 �LikewQ� %of4!{�!�A��%ls��ea��b8�g�6AVSA6�v'6 a!e���riѝ-�y��@3ve1H�/6v2��2�053�a� �UB R` 1� � P*)�tw$E�.b��2kiino+>1��"�(VhB�%e�!�S#�s58 S�&i(!\��d��e�a�Ca[) _YQ,"rai�)!E���ũ��Q���^�8s**�G'L)st*�B���c �ȡch9#.��%Y�F2�3 q;2�6��"�)a��&�;� F� >��a�f +!N6 mG�.���O�in_G�� �� c"-(inN.R-m.�!�&�Ie�1�d ��]�& K!�" %%%��!2<�d!)%�9*'�Y�NQ�*�2���bH', �rW� H�8��Y!�&G9��7�0zk",�T,e BC�=�aN�e�* 9�w)�� �a&� �@A&le!Y��2��)t. %uDLo>6du� ��m{BDJ�/ir�h� 1�Nlay"i��"�6q$�E�9�–AQ/ �_b 8+U&in�/x�A�mp�ng�pefk-�F^ !o��=X �$ �]s.J�5V�on� �e��>>�BAxhRN�2"�"M�A�c�ZdGt:<�B.����%/2�5<O �wM.g&BC��2��]l��In� Et .B2�I�o#�$&YZC�E%�N 3ɢ�B<66[ofJ+( !�AKD-\nsh��A��06s�6Ha)E�27}R��B%�jb'jFA l��We��1\��"z�.�B� r��]b( �Bnof�5Eu%<�zi�R�+mu!��tJ-U�C!e%0U�!h�B�5�?� NE����/� �y�� Fu3�m�ja�fN9E��dY�M��C�A->Du����%��>EW2r�� {%���E��i0`�"� ��1� ]-A#�`V�iof�5�8�4: %op�_?Kl�ey!Q! )N:69!� ntDF��oay s�8cndv-ic� -le�e zip���!}�@z tb-;9(�7)*�8�Nr�\�k�h�?1Ts at9�!UG���*&.Bo �i6b���B�DJu���"�B��#%9�:r�}�9�*�9& }E�[%b#�X��Eu�  toa��'7%�ub�@�.!B:T19aU~��seA���!lug�g!(BK�����{!�q�[*�hߐe� 8BX=�D�G2P9/ Y._tN;�mۡ �" ���0�+����,���� �c8�:��V7 2A & Ѯe)��S6� r!!/D%d�0o3Einiti�z,+� EeB~toQfaio%�orZ���.}�if��"�<��{n9p�50Flag-epitope-uZed <�& �ge�2�b! .m��x!!��S�-�IoH�]BaA pBabe-Pury�ri��et��* (�|!@ya� 2�j.��!, � .f�m��J5Zl� H�'��2 �"o5); tN ?7d�!]IPBPA�pu^f9Xy�Ifir$?�K�&� 2�9�u(V��6A"(0&F]. C5s em!�n*Vd>9�  !�- !� *�8���(� ��,E`6=HBZ���^ � ;� 4 & � �t�96fA�7'���2�c��?�7J�%*J �jh��No.*<U<!/� aV.8Z��6k �.�M-�Ao"MR?is� #�j  n!:J���to�; +.�>k'a2&�Ti:c>�� 2a+25 �RA �}, �unb��7B� �*CA���n�&�%�)/aq H3-6!�+Tax+� 9�?�)iL��a�I��� � �&d��&x �){ vt� � QE�P �#JU%,-.5� C & > ��.�V"H%!.�"�$a@i%`a� | �a�xEg+n:K#�.=0"�_Ji`Vf.B6C*�"ce ���fA LTR6�:%K.a Z&��2��qH-�T6� *�A�N��D��)J�� �)�/daz.�!3" S}l����HRDsMS1�ng%�?a���U�7�row�Ms7#��0�.�c�k>�h� �y� .tera�M�bX a��pre� keCGoj) a3�,� � � "�..H'#�J�y �%M�d � = �$ m\:�'!.^��  �%.T�>�!�.]��1.O�Pb0�+�QV\Bn8 �*@ iA�a&�P I�B<�6�V"lJoeY� a mɈ ;`��2\I&$X6�� �A��>)ѹmC[3�PreV�)֡� unequiv�I��&�s� 6�Aƻ�^��oP�\�.im�cri�U�K�nx'�� �%I�;z+*�Y�2f pRb )53!� �R�$�P=�U�%����&g$g271G�!�$U��tQ��mhA�%!��Zbrings ��* PS�O�>�S"�O�E3Q��! �EK%|%&2R �2�$sC >2�ed]�s&%!/� t�J��How5(im�`)  �sn-ul� Z&!GinP?m"d.�,:�C��S,%kL%I:�r�82a&`W�Np.�N!� Arf/O]j �0inc-/p19ArfK,mS [32]��"p!q[A*m�:I�"�#B��;1���']4increase in p2�I1 mRNA stability is now shown to be RelB-dependent . Since RelB expression:8up-regulated by:�A [29] ( also see Fig . 5A ) , repr @ or knockdzof =Xeffectively prevents p2 �4increase . How2B':�$t clear atSs �It mad omote the.��of a cellular factor crucial for blocking�degradat!. WSink $-/p27-medi%(senesce!S(constitutesp heckpoint:c�otentially oncogenic IKK-NF-κB hyper-a!8�)� isj)[a,te in many human cancers , espe�0ly leukemia ,5=Xdata would suggest that90changes disabl%s.�Hpathway must accomp� �deQZ!Pin:�D. Indeed , impairmE)of!p0 and p27 func@eY�Dhave been observedb�most if not all HTLV-1-transformed T As! pviously [14] , [33] . Studies�)TbA�t5[ihow!�orrel)� betw�A�over-�of!� ( i . A� chroA-+%� G)�EHcytoplasmic localiz #-#,�suppor!�I" clus!o[34�W%�4nk Tax-induced%�, cycle aberrVTs such as DNA damage ,��mosomAn2�lika�t �y%. TAS,HeLa-G/ΔN-IA�α/Tax �4lines are largKnormal�,their growth� divi� �sisaT with t:�. Cq�signalia�I�s1o��oxia�ve stresa<inflamm%-=�kn��(to cause ag`A�@shortened lifespaAtheseq2sE�ct-4�)�5!� Earlier sM�E�E{implic��)r/Re%1 �,)Z-�rra�,����$[36]–[39kS��i�)��Psecret chemo-attracta�ѡBmacropha�)�NK}s [40aRwhiAS4re responsible:)��$ual elimin)p. Wheth��m�in�ZM�s��!~%�me��ism`virus e�misE6�sprea�r�to2�,a� only�H�E� upon��np��. Our� ults)���K)�.�E,�ea�J$RelA ,B)�c-!�$, however �G i��ba�occur �iently�0leads rapidly�,a steep surga� m�. p100��uos!�y o%�& proteins)�prompndampen2��L�� drastic���H*tA�*1�c�Tm�t7sq�ecB+by��)vis ��by%idestru�F����w -��4 molecules via1�ed��s� doesM��#�on%j%adult T-�_�s when�6��;2P,? Based on o]Y, mode���=�2it��by HBZ6�a�e level3F�,!+$obligatorye6A�pro�� n!�expaneCof �u���u�3;bal� �nd�� , determi�&-�si@ ��rovir�t� U"aavail� of�m� e� crip/� �can!� nc�per�) ce (� 7 ) . Rec�/,%�hasP ��G * �=�of%�!2�+!"is�lu ��� i=�)�[41��Fur�qmor��A�� founecenhEa �)\i�n��fac" !�6�� E�ymphocyA�[42��[4 Fin� ,�| = �58 e�� i� � loadAle%xKwas�dec �'( time after O �%nn a rabb�odel [4� Trre͞reB 66 e+ Fų!vpla"  critica#ol�0 �.ein parta�"� ngE0Y�z ��y!��6�9j.� H!d� b �dered� a� � ou* di�M!j�a�eiAe delay Ѣ�^onset�q(by attenuat�'=�of�eF9͖� ���+ %lin% A�Vt*D�ultimat�0.�Q{5�NO �toA�'"d�opw  . ATL�P� ten c�to��, butAGtinueproU )a��,!Xsumablym7B [4� WheV UA�ssoci��� !�,%��\6�psurviv�5%M$early stag��m�i�A�,� a�(m\,n toxic T � kil< )�"� ng�s��selec�los!D�],.�� ceivPat deJ�3�V E3-�ѓA7evolu�of ��qt=A4 merg��4mie*F�^�K mito�E�� �[BZ�' [46]%�� �Z���PU�ma�na��X. Standard methods were� d�$immunoblote�!� flow%�@metry . Each samp�yp��lyE�a� 20-30 µg�wh�QX� .Q2��Thybridoma antibody 4C5��as\ cribedEe�� poly��;ag�tEޡ�$a kind gif�zPDr . Jean-Michel Mesn! . O�� I� u* ��aA�s!�(lea� al TEeS1��0ombinant aden��4us vectors Ad-�, tT� Ad}  � !oAd-� %��ntit���V\publish6!cNAAD*u-re���� α , *9@ as generby PCR�eeR�2g primPq�� . BamHI �EcoRI�)tri' endonusse��%tto sub!� �8into LV-SV-puro-X [18J27�DHeLa/18×21-EGFP ( -G )E�s 0k� �[d�LV-= h,-�in DMEMQ恡feAHbovine serum ( 10% c�mycina(i�%��)COOH-� 0us Flag-tagge� ( ��)e�JtBVli�inZ� ) us!�A�.�s� y%�� a�* temp!*�;%lo; Es an MuLV-b9ret@ i��Babe-PA�[30A� The ��F9ai��c de���4U�-G �I�� zU�+)�MAcon��!R�I� �byJ��-���,��LTR%9��oI �$ructs ( E- �in-Luc ,3 !pp21 ) �wupRL-TKNMtroE� smid� �E,e HSV thymida�kin�[( TK )�X-driven Renilla lucifer*re�$er cassett� Promega ��4u���J<ass� ccord!n���p procedure��%�E(<21 ( −2 . 4 kb4+16 ) %%0$as WWP-lucm6�� ovid ��4Wafik S EL-Dei��� harve�щ tryps� reat��!sndA��Y twicl 2 m�Hcold phosphate-buffŜs e s5 ( PBS%@' s ��0� M#ofix (70% ethanol� night[ 4°CA� - 9d �wa>�X�vMA!�1%6��incub�� 30 mI t 37�in 1 . 0 �a�W8propidium iodidEVI ) ( 2# �i~RNA�( 1 m , fil��Hthrough a 70-micron�S la"�de6�in� ,day environm� feat!uy A�aghan�*mopen-en sitVon��H�a�ŒoS�#�al �!h� J�%Iclarif E� issuaOUy 119e�x� Cun��C!��(o^ %`�7di: �1/s%�� vari�orin�dua�5n!:a4 ic6 AU h@/�a�! o�J� �1�5� moni�up� three/fY concM0=stUg!�vol< ex!�AS, adjusD )�m�k�a� t�K&�$, flex"mappings��$ng stimulibm�l��d [1�"4] �/ facult��g� �01�ᙹ%�man 'ask sets2��vAR�(eni�UV�f—J�[5�1�A.� reinforce�_Y�( RL )��1U1��DžA!L ongo� ( refer��to5 7))EF%��.�-r value�r m�^]!'on uteyUty.� ( UM.�3 �4] fu���$)��1��Z��B��o�#�_�2�i�# �?3� �!�!�re\��)�!��it be��.�(. Moreover �!l� jGRL��UM 2g)g�aScol>��*��1��15 ���allel�i%���v%C)���� choo �?)�� �[1M�7;s,#d�nG oM e�J��*4 �Oanj repertoi�XQ�6S!�A|ng�"m �Z(:IYf �is9F��d��o��e�l���ra�(than simply:Fswitch�b**Y��#e�For exa��*�'e you w� �Wticketspeo�h. A a few tri" ,B&(ce� l�+arz�%� y�t"� �)sucfu-~�y* ~�-Ken�r � fail�AK next0 son . Youn-ky)3 � W߅��to=.��"sa�A�5 �wW�s� �]� Igre�#to �firstCor te�,n �r% �� ɫso�%��- �!�%� Q&di�nnAwA�-'i)s$ m"�'aF�inl/�Al��amo�!� N:vVjIV!)�����K1��p) � �youngQ�,T >olders_,c wea|ha���( !hol�2an umbre16�`0 do w'ar���A�U,�y6�V!�Y- I�oa��&�&,9�2�*� al cues ?%�m�$ litt�#s'� bout����in� ��rbi�5&�.�)>�taya�-�e Y�>se�( �s�%to)�YI� -�( �%a]ae#��) ��b i�raiy>AaylemM�� �*�AMts bKon Dilet2o�# mix� s add,.�–[2� H�+,,rem�� b��ai�_� su� � �,�<*��y"�%P(��=*f(ne Bayesian� s�#b ng*e@(eGy�  )+D,�u��(lyk r.�[2�'T�a�bda� �#%�i��undery%E<���resourc�he� nI&�M;% E>f�"��:�9a VJV�o��,)%n�'P>�%�h�� J��{��rol!��2�� a�1�ie&%�&�$-$V�Jf� {*�4biologi# plauC.m-� algorithm��2xi�&snq[19] byAbie�Z+ ,UJN� �hyp�PsA�e�!���A|� &�,�� G���왢. C�02�2e:�!��wor!meA[22�S�4AIassume �-j�4A�dqO�pa" �0a5)�*�< ��F} Os��e�VRA�EB9��522((A2�5D M$&� ,�� � aqn�M�!�2� )���A��.X ��I��<.r�awingenc� ~key)��.AZ!�6�# .bEAtx11a/�"xno�U5�a89� "� . S�5L ��w4r_A.r�mIAc~ �j�6�xt-uesV�P�.�� �=on=Lg �b� b��discar8!�y y�9�h unne����conversa�1E.�is upd�w�!6�:i?Qݣ"mL9boac� �y sA�7ly�!�)��[+_ +J� %�On�A�0��Pcompu!c�O �JVR��A�!�Վ�^2�>�er�eGi�"� W'S"aA�p#�/�;mu �H , naa!kPROBE .W�3��p��in.�ex&Binspi��$"�*$neuropsych�#e�nj� �l9e Wis� in Card S� Test [26�6�W� a��.��� Nv��p ru�$ I`<��)2�z��� no!��J-!;�:onU�9�( MAX O�$%��%� .*FORGET -23�mp�$ s ex� ng #�)���[}�H�6%�]2����9R,b.TMs��)5�{�2>>^�b!�f�.�=i�dow*��!��!`���1s . We)�E�R-�sa�re�.���j!�'F�� �;] a�A� %�� us!4:�%,,e�|R?a��.�t ^i [13f 15a?��� ntex�:B�ٱ��-�!n18�|(6A S1` Mate�nMe�.�R` buildIKM�s]&�Nxa�a b#5refIn�3U � AICjq F� �"�<6:R�A�3�P| #&for�J� i �)G.� bef6!�ng6�a8�%i@vX, @of=�2i�?!�<C;62!�(M8?6�BZQ ���im�*�3qMbe�01�� %�}��,� _m(1us D&�'ftmaxz0icy{n�D,erq e β �noε ) [1Pe [28�Leu�'�gre�iB!(�@1D, [͞9af,��&h� �0:�:QWs��=V v�:A������ !� >^5n� 2� �3�Q���Zz(�!�m αA#1]3%dw�6�?9� |#�ar� �>#]3� 2� � ��&y].��)KC�� N�1a�ss��chaR DE�>)&�(.Fln-$+,�vB_tA�/a }�a��n� ��.9B��?e�+$tyu�.��! ���2D� �#�aSg"�2 d�c\%* s�:�E:K�7#FinfiniteW�D�%�?^&sere�)���,y �4nd�|%*H�� .��y�yTaEa�.[hidde� aF!![�ly��2�"�5g5'�.�uvq �m�*e��7 ihoo�/��/matches"P>si:F=h�Ba=!��EE!U_hi �:>r��� �A��e o�EunA�6|���b.��Zs& “ab�. e”.3;4Rl2�Z:_ “random9�, T,2��}%��8'.|no�s)|bz!L,!b&�E�>�:co�;al�C�j�(i>�)|ah�CD6��9�� f� "W� �l@a!':�("!HL GaG)��8�*:'�N*� �N.JexH�$]#�o�.beOn�CCe�is^erF��O�;�!�69��ar>�� . � �B�� ���$  � � sG Ss��/�.�!y�6�`���mixa�v=a�Z�A�we�1�.2#>[v@ R���i!)pr`t�+� scad.by param  η�re]�e�4p 0≤η≤ :E.;pri6<#F2@)!! �$mZ [3"u$$-��i-�]���nlmx��!J"fW*.�u%�e�+U�4�.Q�I�A�is��"Z8 ”;&o"�#*%!o)G�!0A�le&�-set9 "A:� B<�@�?��n�����$l� �.��El�@r� �A�n�":erQA)�a� .�a�#Ic,aY� ���!Uof��i&F t�Y�F�.�gU�Bno-mric�on} N�<��T�"SiIi .�F I�(v���!I"�]�.� ��x-U��)a�.}u$)�2� �"x))�����%,��A ��a�y���N8P uN�U�)ivV��-8#2;\ !;.;aə"� iAk�pET��G!�� emp��/B3� ""u *' ��, nhib��2+���R~�. Oveirhe2��-six fre���� S0>T3Z�� !��W:s%�-H�A�;ε2lapa�*)�)�.:�&UC� s�αcP� #ofEq�2F� . Ad�E�"we �9ed �s NiR�η� >.} !-st�J�u'theore�Fs�N� lso�nsPFtwo�!iAsJ:�cap�2�� bi�7(b :fB -sens 0� 7 δ>0�9E�>E��.A�ts3J6eA&:4"� V"!�"�-5���� t)�t$!2&<�&R�W> �� �I�b�"�newp1�S�;���� g&k dise.y"�Ee*}�d�'�3Y(.t,* ep� aiOr�:\&]J�A{!�Ev�. N�)2'e�Dat��ly%���.�m )%�an�:� � .�!�.2 EQ �$�� <dC./zG K� o�L:Y� ��� �&� a)��5u',t)�I)^��s autoA|c�cM�edE"�6WH�G �Hrni&^ %X�t!�:�o.�Is:�Q%�V�r�MS� la�cl#wTIa�I�^gc�KJ�-x:�:� _&� keep>��|A"��?�c re���%<��F�� e them����� 4y�* X5�;2p�WE�d �one1 ti�:�>a��� �&.]6Z!��)��2 �yR+0sam�)> FO* ~+V�U�%�A�(2�O%iA�^7�8′F���=�>!9��C�ZG6�6��.A*� � un�BB decaZ(�-mN��teg� !l( φ , 0<φ<� �Y�Y=%s@atFab"r�� new�D�AG�&* Y��J0iB!�:i�! "� N��6a�R*� I��'�.�]�:�Zve " 9."��7/*]"*�0>� !e6�|� �W0 "q Inm.� sr�! "! &�&k*>��2roEA�A/-�! i� .�": cyIwbo9Z� !�a� �,�  ��q:E�a�%p �!"0 s ��)�a*I�� !�dC:U Z&u�� yiel�9vir ��G� 7�we ign�6$Q!.h- forthN�jp!:"-ic�4-,Ŵ� $ N = 1"��6UM2-'2%w6�"�0U��Pm/*�,�"f"�SV�Ma�&�5�N>�φ �02�J� !S%w>$ �AOAW2 6b 6�-� �&6��|replac���;�*l �a�Z�l�7"$^Q��26!?I�22 �Sicipa#?wh�E�Ba o.� vis�[�9( �� e digb)56/!���2�" \e�tA��FiB!2A�MbC!dy' ���cX��%��z &je�aY" of 90%- udio �feedback&�:~# extr�#ety(payoff��A'�s‡�M�?. Unbe>=sB)U2��g�"�,1�AK$1s shif�aN6�?�?_&,�4,��AD36!Q54� M �c�#�(�*� �Th%:2�#ri*�F#�(�&w-:RJ+n episod�A With�&b�in�[TbZ o�92'perYwo� sE��K8a�y{��i� )ku�a)(9�$.� i��re  y5�%9re) ed u=�y;� ^�A�i_�&:W�Ŭ2c^WreU_w��the`e"*c��? Followa���Ce�2Tt�"IN�V!J�:))]:�-( prec�gg�%~c��~@=�>�9�>�\y ( ne X6�n9fB ct �In<"}�!O�  � :De5∼2%�%�uX� ∼90% �530qv:7$!_c�" : 25�Q. EJ�bz5Nz, peak t�4�I3or��m� ��m%��!�<9i�m(:�5|RPV'1�IB%R24�ll1!V2K{>ed�c-offs�SE�A��[  �Mi�i�>�a�CD�F!i5áE�@B;van�T fastj>���S-�E�� s>3\O, ps<yN005:r�/>,6Y-!�*�92e�hadaY�U%A�4al�Ogh!�GmepVme &N<incongru�2]2�*wZun�-mMLofV����t;c��L!�BaB�l�<k�,n� A��*�Q�;"�h/mue #Ycb�Q:&,strong� �� c�,��%9Yc5�( t� �Q8A E5 12 ,1 1CE�.�j f��%adV5mcECcB�0�eak�Ab�X \ t�>� simi�O1/A�Y�aBB��c K0�I��iL�<20VQC�dq&%���$M.u,탡M�fe�&���a�9,.8} se�%".."2�l%t%u "� I�.a �2,��m�Ip ���)ly�Io�;(�Y:�}c -�a impro�yZ �[-�9�B��=v~#ar��)�H�����NS%�6M�3dTl::V} �*o��le� "zG ty [�iC6])�h ] �N 2; SO �� . ��U�W�3Bd�a�wB14%�T. >A9� .��*��)�2�#@<�� ֡��sZ���Dl5e2e��NU5I@.R.�n %:nou��etG=�>B �R. S�S �2�AD �~�}Y1��W4Z�4e�A Yi`��;�N.�J1d�B�YA��A&���*i��iJ9O1l�O�D<>�A�MY�E�cca�u��B�� :F2&� mad��_�u"� i�B�4�l�*�!Y9R.�.am�2�p���S 23�*�>U�.�\6^�f�A��Iqa� v�&�Uw2�.{~�3�d$ 3V�!y;AT&o"5 ,!sb�6�by�nA5." Y�Ad�YgIq� w ;��%�C!&Y�*D �} ���I>x,��>rz(,:��e�q �4b.�>". �aÕ�_)en`O!Z��hcan� =��]E�Y Wz n.S*J!DlOF�.*]� ?�%v�Pa� -�g�^ss:m�J�?1�qm� |5nM2<��� �*5N�pur�C!$y;"B$a�1nt7R�rjp� "�B:o�!�"�1 �7y margin���s)ba�Bb�e!�>I {12n��� �(&{Y�\ � _a~��Ag�2�F��!�6�s]�!fC+equj�h�st��Ū1 �r��V ��$ai_Eoe�u�yJ�� *� ���X�y�T.&I�F*�H0r�.~)5�. !�I�!� t�*Eb�i' )�/�. &�me%mp�"x ()�.ZQRB !*�h%�:Zopt�..=B�i\Dotocol_X % u� s�I#�Wal6T�/�ad � ��!:E}$�Qrre2��i�0)e���.s i�w| !k8sa.'EF(V�b , 80%;:c.!±2 , 77%± 6� 61#m�e�eq to 3%&MoPO ropy�)�5 %vTal V<e ) ;a�KS).�%''o�;Cexact*�&-���&��2�of�D6N!� B�F��ua#s��Ai3n���b�b,U�em1IaR,g&K\.�%1��!h!/1d)/&� zE �q�;#9Z.I.�S2�exM-Msowe�TJ�η ( ηa�-�:g~72Il07L*po��e�U* ( θ ��0; θ.g . 74 Z1�N��*nd�V��2�&� ) a�> 6��9���B2D� ��9n>�? z al (Q΁LQ'�� J/AfA���j�a�I"�,2V�N��)��L&y u:Ovga �"� �itL ����NnR62� �p�� 30:"�>!!�6��0�1�!16/JT*o�ra�ct�1�G�2!q�a�In�f8LR 2+e�nree^AOyH:�!u�.� Nβ2±A�!v"$zer!6 ε (% 01I�00! . O-t:l" E���9.�/5��> �l��aw�� 1f)u�4;3(ku� ��ˀe~�E�2Teffic/B1�6�NX� a�~ond� �"i�W�zwhePCA7,!%��[ ex�.]��b ^&)�FI%� Ko~M.�'*�r ty-np5a&�/.0� arri�u%s\*y�?A�d"�m�zex&�.uBm"m ,"� )=08fi�4U.b��{�.H�x>^!��s�0��t"0A�2VwhseG�"�`�:!�% �mb�BUF ' �)�d �S2Bwf�$ciLued=v�2�4kh� ,foinA�|6^J"u4&En�!h"��9�&�!V�j�e��in!#�^TB���U!  ��RJ?&n � 9� �E!�  ( ad�*)"��\^ts>4; p;,zOBwoMp�[� ��Ɉ. P*b �m�ym�aqc&�-K ��#6(Vk�K�pmid,atypKf)�-;s_4}c)�$#��8V��)�J2��,�4ferj^�%r"���NqpnewB�>6�E�.�9m��>��/f�$P2t ����z!pa8�52(� ts<�5 �!>�1��!�?}X�%5=tQ2BlxqlE�><"��4C , D& >��c� -��6"0ing“flat/�"�"6��us-cu�!�>�K�d�E^� NQV ����.i!=�%�1-�A�a(:@E@.�.A!!�5SA"r��:W,V�8cbP���~��8.�.2 .a  :�1$ A.��Lo�e"�g*aiH@�:5���Eyf��m�r�@ESU(k�2 )�.��s2�'.��1��lN�&%M&c�25.�!Vn>sZa�.�3-�> 2' �{A�h`>~-�5&1;t (�%>*:�n&�@e�Aη*�8�oF8θ+7� 6O�p>�.�/25±2;"� C05u �T �,b  W�C!�i� 18 @?��:�=S2�� �<&0&� 1� c�� est-u�!006 �00� �nJ�;9 �5 1> ; δgf�v1V�mzaAut�a6*i.�� ec�����l� �Ev��Vj uC>�7��r&- D/��*�dVK+ � crepa�3�N:A[f.���8-col�+u `8"G_X *6 �� Όib��A���.�q ed m�.�=� �! u���"� &��a� . Kn@-�l�1#28hig! ��j�6I Y�m� ��5�vlp[37B�6�Y �� , i#�� naly�*�&� group�W22� f� postV8P �U-.>'6h!��%� u1���" �*E��G&� � a�.)W2�*EDtwo-thi3p:RO�g�� �~( 13/2�434/496�!�seF��F�%��W�"��1�e)8plkm.-U 'W���� 25.:h�͇N�%Kx! Oi�2P( 19/3��r1�-"},e�> 1�5D6&2�Wa� 2A^�![B� ( 15 �asj�kbG�k�Ve�:�*����FVe�*D ��%~F=1j��3�? iJp\ y��Aiq�>2C/- s 6%,K����%�-�b!"�9� 5,oplanR� � sF��F��o�!_Rexf��*R�|'=yY.�!]hIm2:{(%QsX#��J��2�G"�6���?i ! tigu kI�� tiv(1�2A6 !!SE�B 8Z Y_�!04Z��KFE"!2�Psi�ia5lRed:^KfwJ�Q� 7^"F**� no�X�:ye�C�F.sM_S�I<Ř)�6 r�rA�� F2"> s'i� M�.3!���c�>m�~��*U �C 8�� .� 2��"DpZ�X,di�d rA0JvI_]E�G�=�R�nZ 24 �Lus 34; Mann-Whitney �@�2%;.<82%±�r8��m�F)aC 9� �S�cJ�v��"ep�j��,� y"�%�;&Q�<"��*g�%C��4!kiV�� �@%&' kEr r���o.�c*A%d%IA3� �U�We. b -�5; scr�U3�.��:�jJ Z�4.:�)�v�w2��'b^�J>� a����zoe�'���s αC*�81%q� 4% sl�ly=R��k>,E�3M86%±2N�Ja�ith.�F�625�����%e� "&�"��0B�@a�47���6�3.�.sm�%{�I�5_N�cV!|��u�q�F2axfQS!�Ÿl=��� *{$��%i�<. i���"`6 favo�W!VUR o��ek��cue�m�*as6�K0B -( ��,"� q�>J,�X�>�%�.����j0c* dX�%'�'"G|&).!J.k&aBf�`�Y��!Bz'2�'%��'"�2se�*&?*lU � �"<osE��&�}oGii@.(|�!la6Wu0v��&�(Ab`glyN�( "j)�=����T(�)E�%| ��**(>��=R�)d59�e�a4-B�N"gA .�B V�e�B* � .�i.�6�&�2�],iZM!�Zd 5�q��e*� .6�<>��"�[fS\a 1��"�Zinv�-(�1sA� Ew�.�"�8e�Ln΂�mlle�)"�;K[.* +a�satisI"ng�:V�Z"�Vr2o[1]: e@��[��Cch�WR�[�'c�(s[{(F|[��*�O͑6 �-lxi2xUy�R�3l nd�a�r��"!al)�>�fr_����;� tmX&KleSo�&i�*�J-� on )b(=��.�.*(<pa\L%�oz|&��l@�%&R<��I�D eU�E�-R)dU��(��- ).�+e 9%WŪ�6���.� =� M�GrJ!.(almef& rt�N�"�A"�'in.a`("�Lin�2�0�l2;��,7t^�m� Fw1�p&^(j��Xq$*�]p�jPT��a�%u �H�G fi .�on�tXJ���z?Aa�i��d�P&�> " 6A�qm�.�!ro2�9�j e ��|IF�6,4Z�9� e no.�52��60�5}AsV:"� i:9�6;� �8J�c6!4t�a4���-&� :b�47E�!a���/%HurAHFurCW E�uK�&l'y|)!�*2����de�] M�* }�Pin�Em� �!CV,KQ�"�1�i<o'F�"*MHpseudo-ZQ`^X.]�6 !A2�J�A�N� �^ 2�s wM.�<� Z�w"\S&*�>EFZ�esbOun� �- <m� �Qk*NU*(��i�Z 5����5�r�2�26yAGQe_5�.�� �tckXA<,��&0a2*�1eda�E�t��*�� . Al"����S��A��eENtA#=|u�"9 &%"Cx�$sZN�w�c��al/-"yx4]C����0��*�6�ioG*�<(A�ri��\�W�k�nK�]Va�!=h�-�8o8�Y"h la�JJno . Desph�7N7)�E ��1?�y�o"P.6M�B�s�9 ��y s^+ �N��f R�J�Y��E?!io��8IL�r.�wf de\H�,)[� �ed *�AN� �J|no:�nJ��Z %Coe�"To,� `�� r; a  %���E&� �s*� �V I � a'<&�+>�!�Fb6 RA%nت� ! �: d!q!�i� �l -Ns�!�&�z unti�C"U_e�J will&��N��2�)�jC�w�A"!/m %�:q�"� � � �m;!h���i>&:A2.!��!�>�7:('�[H�.6#���0B ��!��4"H�\ �e�F��N"QMm��n��m.ɤw�0_n.?a NZ� (U���� �FObEA6"%s:�"�E4��e��Ե�BG*� c)"��[v�&�.��&� �6����!t32��..!���&i,2�2� ��s��<y�dra�c{�HdBF2�;)ZG�4� *�$6�PtE� 2;B&.b5a �!�RM�sm�,2xa�q2achc.\BcP b�A^a6�GqF�)���or�� ���(��GG�"FOEv%'�� oughH!iay��FA�a8pq�;�!��q"inM&n"�U.��>)�A�6.^9���e!��6H<e�.��n�� �d��� s"�����2�5�s' �oq��9�+*{?'��"�O�iy&I�JV �1�b) �s."�AFg �nd.�j�$lp �s���BcC+,���J�"Z/a�Js�X���� h.f.�.*ueJm�&!�b��5I6_�$��Wc ?a�-�� �4l&zN ,v jd !w �N.p@&� u�+�saW�2� 6�rN��� ( nV�$1 )�!P*� �'"T(4Y�d)���.SCst lt�=p2K*_5iI&��G��T)�n�!J����$r���Q�z�31V2(4�Ń�2�R�.����^ �bH"�6�.9k�AgF��e<�;!�&� 6+bf,*G�,9� "b,� [�|!�5VL%��Ao� n"�[����1E N�dF���rk *�"��5��.=&�kA;�&r&\w:�V�m�N��no)��#S` !iu�!����f4�sakI<�#i��> w&�;8!��nQ�n�R�`�$��-r�"5z.�nd/xA(du�et�zR5)p���]1��8�� V5��%B$.+ �OO���>� ��� � &�[ &�ETa\�E��A�l9.{,q+�F�]E�9de�!8�,�;BTn�6icalib�#d�A� �UR�6ALE�EcV�� �.}[4�u��A]Q7r�� E chie�,�} "E�>����)���.K\":�; E8w._��d5_bM!�wZ{b��Q&;�J��.cA�%�>�1~>p1�n�[1ߐ"��E�a�.� ��DU&1&P Izs9^ �2%dFznjZ n� k�dZ��.jJ�Ie*�!AE� �n�e"�sf�ng7� extix� paradigms�J d$�-�eL�;tD�Ao,6m +.�s�=k�W mpac�w\M-o����4m:U"M .�,��9E rigg@�5��L|�%A:�`6�#M�"�l�IwhN�g�<Bi��a�ew.Ft O�T-�Xaaa`��&n�5A�ce�A��H�I�"M�}�.^a&y6+y�62M1�52g^ �.!s�� !����e~��!/�e�B�|,"E�"�tb �cR&:qg6is.;� :� ѩ=r�/\ e �"P�aa�ea��d��n�%y-j�A+.� �!� dez��P�P!�� �ŬF�rQ�! � ha��B �/en� �lv�Y&�m6�G� �ap�s��;1}�gu���<"�o��t�6pFR�M! ̩YZv.�$A)reuN|�&���� w0�\$�M���.� compri�?N��!�<.j^a*�hA�"��*��,!W�V�"J Z��S2�>�� a F NJ a 1���� �!. N}�ic�`���s.���("* sE $I�"� ��reg!:k6 )N]K V%� emoi% 6)& �z}j"� a;�z�^�,��; (��10�pw?5�ro��l$:�r�jw�^�9�n R_S�–[50]n��&�5�6S��bU��]G�U��Ey=\!c5 Rl�3�ador�Hd�rB�����=����!O-�� a��,$�7 �2�`�)Am��]#�p#6�(iC�>z�f&�.�2W �6�mp.�~�!*`^�� Ly�>7t8 �s&�f�>M2�-��� AX&�z��.�y�uM�y�A�p�9corte��S H<K �i )e�-�� O�y�-� e1 g-�s�j�& eNI#>net�*�a" �r�iq���Q!(Il#/1=53!�� .>[C�# `]( C*���!$��eR�!�Fs;>��1bR$u Y � {2� ~�|qui�6l& t syst��o e���art�o"� 5�E-�!���!��%�5t5�-<"�� !~� &`J� �.� �� &e��� �eDd% � �&AioRiI �Bp0>�&dI��Aaߢ�&Om��|��.�#*�!�!bB$� � � � _K�v5&d$e,��"�B�u�opoai4, u�sh2K%cogA�՜ranchae[5�54�. nablAun��&F�Ikz��:Z,n2ER�"�fuy)^>�@&E��d �!m38�E ,RAm*�1or -��-,FFn8al [5��M`�Ky p�!""� ��s �"6��.� �K���atR�m16�i�� �$Buui�,/F�_!Mc\���{= ��. e�#� �b�2�[g��.�2e�AB�D �ariE��"�m!�B�<&e@>�BVA�."c(�w~� �gb� flui� t&C�[5��i/!�F*]7 i�U&)Gb6�*`*� $4��������iv�h�6�pit8��7q��'I�~��k!mI ĥ��obsRp�@r]t�����optE� and/)jigC$oré�`a3]�<rab��H!Ke hear�2���Z4��![59];{�3[60�). F���er 6 �P6d%�x�yhm�z�� BV���r��v�aKru�m7� “s��m� worlB����s!D!_ .#al-?help u�u&"�-���eNd�!M:Fe��#u�*)���io�!�_ u.g�Zu�,X!he6^Eg�,fi�>e"��n)#�u �A�( gM��!1 low-����v/ob�'�+�.Co��!��i-BMM� PI� ) [6��[62��2t�.U�s�))���v��r[ݡ��Eʹ&%�I����22��Xv�R�s r+�&����!S"0�2�A�� y��c��monship� �@u�|��  nd&aot�a2�{$ . Hi.�� �k-Z�gvA�K+%|*v6*_f ��2 ��S�s s �� �7d$AgaIv�6�5��M�$h2�� ch�5���&�J3CAE�/��6��05�o1<�%> %�r�z.} �9 rkovr �yB!�+}Cr(� ZN�� 9s�����.�9� ��LAME�07 7��V�����Iach!-&2 ���,탭�j�&w�P��m-2F��SA+е6�yx��z�����al"�^�c!���!&̬ʬK s�����of��Pss : y ai uE�va.3�́\9l�ar&��� �r�?ÌW prog&j �hJT��?led��he���o<�?�Xa'A��lle��%�T *L#ɓ&c�,�m|?harma�P���&���sa�ishapp��-O!���fy� ��k�Qjm%�!J%�A_��# A�P�j Dyna;�A�&� P�g TraBo��( ADAPT�o �P!ee^>��)rV � a� !.�^-i�a2e.���� TIjtro�rd!$ studX)e d ��#YE�� ��=.9am�..'<�1�!Wn"C� oA+ɁtB��ЍKaKE�H,.� �8al �h"�:b��!�m� MQT �t.��,�wS< �af�T|w"* }�q�A��l9T�2m�xb'zC 5 etai�-unrav}�u���&�m��. Modu�ngU�c@��EP���!�$e� �%h-�� ��>�no�dlohaэ��a4!��1�tb:�9pt ML.�.m8A+��oyI�5W metabolic6���!�9'>J�3OI� ��r XM ep�( LXRe�.~�QP drug,�A�%s��AY�osclero�&JQ|&��B� �y� casc� ��XIeS���~O_-intup�inI��8er�"!o"��cavenge� �class Bk SR-Bh�r }f"��A�\paA}uptz(~�+.8�9ho�06j!S�,o}..2efflu��-ex���G�H`��~Z al���!=���h �"b4�`62iAFre��Iro�Ju@5m���7�Z+�k�y i65�mea�E�)Y�� �?�ras�CxIMheQ�iz;�"�  un���"*;��e�g mTq#��j��be�@�Aig�'rg2�t�QQǩ� . A �r!wimA@�N���@��.*� `�85 tech�vI��mi�Alr���1F�One=.� }Y-HJ���o7 ��!�)X>��W:��6a��  A8A�J v�^ !� &,Type 2 DiabeA��_hiovasC� .= om�r a��L6p�c�!�En)�6��T`Ҳՙe�7���J�a��n�NI� 9y�2��3aa�A4�.ka#s b� �,"pca�>!���08��` ,uET)�b–۷. O�&;h!�,B66�)� !�%!A�A�4 a{A�"g��A�1<urn�18�<�a"�=�d2 f� Ihs ��&llQlevVu�Y >�E�e��'�e�S Fo�ngrhe�%�9J�s&� 4urd m�=u&<lac��su�k2QAM��&o|I��C!�%���on.o. A!�am!�m3��J 56�6�N&�m���0�ҕ�zac�:O� Go��,Z��.% ��1�A6��st�)����� Y6�=f C�3z,i>?R� to���8w)z#���Dh� E�if�n��?D&;�ySW m� 9�5m=�=�s�� �.4 V?cT7��?inZTR�-�G��i$� ��.Q��)1c�aQ���` J/Oa[v��a6m �1*2�eD"��j7s�L��р`q�"e 2��'�oajPby �a��Q� *I���pam�w�$�B%�2 ��%^ over},A�����yia�eq8� ��*�� ,��5`���m ��rC%�f�i�%^�>1��;�ᅪ�, m]���D&� ���fa�=&l I����p1s*9reQre���d=a2�(��X��w� 'or �� aelis-Menl�k���\���7nyqu�.ty�a�,5NUi�:.� � %����aA��z9� &�ofFU�ja_P�F���-�,��%�}1)%a��t�"oQ nd1��Laۅy.&6 �A��=9A��!�loD#Qa`u� QrF �]-E�!��B<� � F�Bal�"")iMzD.� _�92� use+�u�Z ? X�U !B4i $$�����&%5ve7-��-�c�hw��I���!����.q���!WX s�����Ri���FFHXJI�Fm��,'��S ageA�D%��a%2�`d�G��n)�'��OT velopQ�aij"2]�d�m��M&�_i?t���a�a�* g5���� (x phenomenaU~�"� ieZ5 ��F�� � a8L�g��1a���h��:��.IXqP orir�a�E������ kA�I�6Gu���Nto�l.i� c�@nap�1�<( %+t��(R�8�,H[�-Ws��l�"* �� 1 � sߍyE�te5w�� tw-.\"TC�!�l��{ ��foc�i�1*H��.�$�i*b e�&|Rk_��i"a��B�JN�F���1�F4���0 Dyslipide��� n i�e riskC�s!�"�A�re�(����Y7�m q7lycer��, LDL-; HDL-.���%�`&lin��es��j ��Eua�6�@� ���#%ɡ�6� %5�sm%�*Afully Ws�$omplicatin�g the development of effective treatments . In - pres)�study , ADAPT was applied to a model of mouse hepatic lipid and plasma lipoprotein metabolism to identify which metabolic adaptations are induced upon pharmacological trea���@mice by liver X receptor ( LXR ) agonist T0901317 . The family ofB:s ,;α�E,�Hys a central role i)>contro%cellular=ste=. A!�ation� LXRs� phar.� �$s promotes%�cLefflux , transport ,�excre]chole � fromDbo%�xhereby reducing atherosclerotic� ques�ro!�s [23])Arefore)+s are!�sidered as potential drug targetsAIE� orAwvAw.xsie4]–[26l Howe!�,F!>G also inA<).accumul5lhM�0triglycerides%62ese=Cenl�Hd very-low-density-.�@( VLDL ) particleAGI�complica5�linicali^c�Ak5�$[20] , [21!(The underly!�molecEi mechanism!�-�these .Sinr�!� not fully hstoodA�n ext�$ve data seexC57BL/6Ji�%�ed with ujPfor 0 , 1 , 2 , 4 , 7 and 21 daY�kgeneraEincluded���!Du�"!9 nalyA+4. A remarkableARdicE�SobtainedA� cern!;M scavenger�.Dclass B1 ( SR-B1 )aN ,that facilit5�uptakea�Bg highN(s ( HE(by��� . As6M�2Zm�e�$peripheral�IŢ�it%!expec!s�q)ex�s��would b��a[d��%��a�$ccommodate� increased Vobiliary6�xqf.}�!�Z� show��!�'B�da�vr�U�n� uponY�� . We%� ntlyA. firmj�.�method�i� !?2U6�. F��)� ���A�cM o repe%Oka wid� isper rang��K5l !�%%to%�Secon;,a��~2ya�ZwU0~��g�n� ,�Z.�sis&� deno-�pM�b�!�6 )ABse>Y$will serve a��rcpoint��n� y"n � �i� if2�w� �2�� �[���2Ah��e���many ca� insufficimi*� 2K��fin).,|e� o� �+ �a�modml�����C�, lnloj*� ex�it60)0Ŷ� !�"��} n� "> .�M"�D� ��infer�9��!n�w�gU�s=�F *� . Not!_at>is� known a�i howBFa �Q!�Y, . C1[,`possi�to��a��si.�Vntire.]in !�go�� is i�a�add�)7 diviőGFY��p)�ime�q ;��dis���"  a�7 ) ( 89 E �ܡA�LBed:J &�E ��x :.��F���!s a �2H�; YIN����Uc�� ,Mhis? �*� 2�d �e���"� f0 eU1�s�ed���1�of�f��r�@previ�mal"� �� y.�)$5�]!�}b!�%�|];N�%].�Z%i. PnS"���Huy���(:� �< )�6� �} . HA���1Ely*�6�a��i�9g���!6�" .R� 1`.Z�MAar. �,a�e&�,�ly� ct[ng�t.���&� to bA� phys&�E! ���occurre!�0of such behav} Pregular�Vterm ,"( C:� :�engli�X9tm�at ��epa�%}6�7� �b%I���n1�!ZQ�%�,.�,�d�8�@�0�>� bU�� i:Mڍ;>�ce6� >��6��_:�:�J�. E�!�!{F& p��2���+18( 1�;"�N& 5c��KXd�!n"strength�:�ETZ3ma�etA chos�o bia��%Cfitc as littl{ ��[���" CAu hang�a�Acos� � &�be avo�#i�����.l� L F� . Re$ �*�e�� �sYQl relevaa�ll�)�� domin� �>2��"\ absoluteq�.D 2V F=�(%�i"A!�#I��A�)Es"� �z2(*� v��� A��� ��Ɂ . B["� !�*2��,�!D{=L�-��."��s"j�.u.Q "q  �O���.*2@�"e -4,.n=A���A � &s"�techniK#e%!ьr.�a�� of:�.Qa;i"9�&�%<shyI �Llex%i"b )Ss�!tivity�[32�5�Oneɣ�6�16rcNK( MPSAi!i�6�%X20rq�im2e�ofh� �Fcre"�!C2Y2�6C �Jnd� a*�� �ҩ�E�ls.M�C��*c*~!or unb�#�!C6� �A�or somEF��involv1)E_hreshol=' �W!�"c���q ll Anmea��nN2"^ 1%or��#g!SY"!]#)��]%P}=%32:c�p�W uted� �r( 1�a<<2� �( 1�( 1� eN�!{v�)a2l� �+ai�"�1 7nd�7at�2Muprem��&7 "�8 6,L( Kolmogorov-Smirnov#ŧ�Qq�a� � �:X nII�{X�sE�2SmeM�d`*ng��strongl%e� !noq E�l�mo]*, i . � , M�;e�m#A�%���!D.�inU.* )�is bo�&x( & zero��a8Na�e� i �!"/ly$68pp�����a .� rit�)�za�"B " '9�бlka I e%n leve<.[39��40��o� �*!�At �"y� �͛J !�" @ �)=���5��*Q � ��}2� "�cř)BQ(i�!. �R,�R,�R,��'��'In���e� n��s1��)���hJ�. , fre6=,�"�,y0I�4�t�f7`,�0�"�Fde novoS.ogene�-toe5R�pool �"rA�m' ,3onO':+r*�/!o��o� HDL-6A��fat� ciI FFh �� e�We� �on�/produ�*, �*e� �'icle siz�~0�o:I)d1*.�P.in*<m�2a����1[4OA:��-}ar�i��uʳ3x��*B(%��E�&�&.��r-B�2B�1I�&Q " s�1� m mod�;dA�re mad�'is eAm:KJA�ai�"e+� %6s���:� �/ , bl1*iR�+p�/*�J 4M]} 2T util�A:stora�.�R]'J�mo`/ia<21��m� endo�>+ticulum� theyt incorpo �to nas� �edI�AfA� �se>� 2� X3Vo1I=|% � nutr�s�~biI�f�_2uqjm^ofF"eT!�%a�lA��� orig>e -adi-��>&�+72�rA�s6�c�4'2f �net& >�5J back1�I�via�.�n�J(!�a "O'��. � �0 onalD )%^�aV6Nio�3*10f�` *� a cl�*a^bal��d�TU )�A�lex�d �"�/N0* "� )QL �ce�*V�� ��1i a�h6�-��� ;se*�*&9q's6:��&! qual��B!jm�"�!�)��== @re��o!�s�-kepya<uma}�, Z.�*�ef& *1A.�aU*e�)i�td)i�ll� 5�}t�0al am�3��on#)N "dd e�i� m683 �- I I��)��| +��i�ds ly w6�2Zx �t org"�7� � V[Cs��sMbPathguid�(,http://www .= .^ �-�#!�!L# tory&:S#&�.-��j!�? s!2�(e!0P��D3%Bles-�� rs�8�}e�**"yet fea"""�K%-�8"9K*�pA�!��!2��V��>�A3&8 $do1os0� e� 2Au+ .�vol� in�7& !i*;�;%"�-S'#���= overG-^ble�)%9�!�by�� 2� �xr�1a'u"&�*AisL/2+I�6 f 1"a� carr=&a3&M"6:��qj�3.�� viewh0F�!A��6�Y&0 �� � ati�� �631iz=Es��Sn�54.u!A��o�1�d&<9%P!�v�~ impac��h �&�2�3)9�!oinvi*d�_6~h\ � oy2h facU?e���6�*$��&&�"2y%wa*{$iwj�+I�� �&��er~8� !z�8a3 *� ���%�2�2$ casc�  /J;��.> ]A�"�3�i�= nd f � od�[5�*�[42_]�@h �@broadB]��t-,Q�� ~a'&� �� dS9 p-/myD��@o%tf2x*r or&swo�>�=�% imil�9�=�Dސ�74�:!O2� !�%2N�&:]po <lu�7, clu�A $four majorMs:� es,$�2" .w6"~&.� GiUV� AL"�("� �l4 -grajd dark ba�mede5 "-!dO5�A f�b� m "S!�3E2cD!�� �>x<���haK-n �u<t*# @�� %2d&mA!&G!m:!P�"�/&��latteDC=likL pl!E cruc� r*�Dlong-�#}#�9>���&�!*/�Ek*K 9*��up-- �7�. Inte�i� , on��z6�Q� � {� �� downJhZ�2�uR>*Tw�q nE�� ofi,pa�Ca!ht�CYcapac!,) .oa��-r�G?>!�out�6��&�la#G!�e*72�u?3���&+(� �yV�-+�%�2��(::�; histogram� �E*':`5A`�/(E�����n�"�#�� erA#��� "�^f� a�1ec4 reg!%�ţ 1)iwhite !� s en7!Y�~-P l�c*�`�t)67�dQ8=~.�B�@up ��ne weekh�I�6@ta�G �Bp�"n�X59Aa�lthoug%?n��a|�C�&ase��-TG��Q4asA�. C5�b�>�a�&Z "4%Be�A&JD*>m�-CE:�ocoAcc&���C ��eY��l�f"�Ea1a.loac A *�B� oH!?U�95�B�"F�5+�G(quid chromaewphy�PLC )��k�5-�NJp���(����)�(f�]V�{ich�^G�@)�� _��6M��G!E�e!���y}�Ra��:~in �!�U(�by�#�)�!<x.�rgGto^=ŝ�2&F�U�6iT!.Y� p� mpan4�n 5U��)��ZI�Zf mino��C*�/!5 � V� l�!Huٲ�d�'iKɶa�B*��9�*` �l�{��I�@M�in cir�@^ �E�}gQp.1W �of jO6� ` �O�&"� �Mape�7M �O"�A�Fdape�&� A�h� .y9�p!�A�� �8"�PHlaiGa27 ex�F'��E"�#�  Ao'� � R��ϥ�g�?7� �m(��a'�6�K ��N�o�@mH?0,n�#V� e hund� batche� g"E,$a�"|'ousteEl��edQ�!�. . :E�te� e�-�� *} ��$�A�M� a!' @!�S.�&associ"w�P Wprofil%2CV�pes dide�qiD�VKA5^E�%~:S&&t�n�A�ed\:�&�&� �dot!a� (��&"�&R��Fa�f�'a�b� )�A�2��;����MC�� m9!�� �!e�-��Y�J-�m&d yRbottom�W!���|"�uAj� �f:�EFY���S�2Qcyt"�!2�m�a5)�Ye�Q.!Q'@&m��mernegligO=�a-�Q�V$"f�!����.�!| A��}��2�i>582�ca|sm&Y ,!5N͖Ea!�/�l *� ? 2�!V>"��u�A���AO ic b"gN.> &QBo ) r1"T AQ��J��Merturb%�7�1"9&<&�O�v)��Mo�i'j�2���J"�W��fu�F��T�2.�:N_ρ��Q6�2�:[To.�1� �!\>@. ^� t6qwhe&���.�@zntV2�^; �!�7�gA�h.5�.z-%2�N� "; ^.F@ �4XW�.d2.T)��glBY�HA��=Pu7�-"�s1 -ox� , glucone"K*, ket�ol-sphosphols\syn�i�"�a��t �D%!D!�=!"rQ�" �cB�q3F&M,���xU/bA�aVA7"��te�$�Are-�*T�$while keep��oE}@s fixA�:�i��/)�mai7,oyUZ���A0*��.��&W�VA"�5@!�depZ.in�w8 85q�E2N�pbEtop lefdI�)�+�L� !�!nhN> 2�(Ur�AR5�!�.�8 s�&t!h �,Rg��toQ �$!E�(�}�'�1(�]�:A�ivA��Yachie�b8\ ngA�2�CQ3�:oN~��I@GC"i|�-�>�-Q7��!�.�sNly.�:�!Ti#� F�U�t r4X" K���[yA0���n2�&Y�S"� 8�Rm+�=Q &�e%�lso��B�suc}ful�3ategy^aM��MG1~ �Ro>f2�a��"� -�i �]&nt pic� &%�V� R�')�F�b6H7 �d2=.gXiv�0F n��� !�$Z�  �rW"�.ed:�Cnew �%��Ya�X�4 alyz�IR�ar��UchA�Yu!useA�:(qc" �$:kb.s��usuCve�]om+���ȉy a]d�=�:��op��t..Z�6� �(,7 (dib'_F&� �sca�T 69,A�n �>L�>Lb>L� ~�%ڪ(^1,m ��l&)( � fB��t@(��pr�?(�?(We Q!��� l+B�:�J �u� !(* *+2� F?U" ces/. � &q t*�f&�%Q_c*"F"�Ba8�u���,��k2*K.R�6�UE �NzIly&n2�I%tr+to�}noA!ޡ��t `&L�a�N&Gmi��O�AaS �. }ai�WoK�; link5t��e**a"Hm� $ snapshotsa�� "�G�,,=&�_�`[1eK ek7he{!5+zq2��a�o A!Q�!h-J�_$��R �n�XM�ric5( LPV )UHh"R .�` 6�2E )!x� , gain-schedu6va�: _l(C[44 (�C.fY� Q�t9\�f�t��5�1n�X3aH�<�#A�,��%y1r$S;G�a2�:�ar�. �$whPV<92re`� a �!�.� ��b�&greal-4� e "�CS�B�KI _V�EQp�7�3al�>IB�3$"n�)En�A<1m?r�/3�P�14 ot�0�!iK%���N&^J"�-to��#s�LI�|.�TA��"d$ a7 KAY#��!�Z0K b%��)�;%-1�In LVTE�i{--�,�2�+a] B�)�se@A5eey�� �eA[nh�m6iheT07hO+e�Bum!3�"N0mj^�-* im&�<&�A���C"�M�4Sor>$"2i%�Eey:Z2V2 ']-2�5VAGMK]nyTV��+n2 �.wd�% .S%� P_>eeZ;.� a���`!,m��;5!sqc�z2�S�+���"�/i�2�+an�>rop�/�*�Ame�w)t^�&�b�99��72�Z)�*�&$F�AA~�j1� ! decMtoa b�ai"crn Mi C//3 prefera�a�Wo�is�%< s [4�H&�M�sag��1Y1�� v:�-A]�i��E-w /manne�jH"'nwhe �!f‘�0’ Pj�2� NMp /or a?low=E�re"E (:F V(�,�w'e6t��G.�)�� "#6���#op�[Q�g� �I.c)8~+e;�[%��ce�Qeda��j*��Sxp�ve�h v5��[�N!�5�R�o��p4�"_Ba*�8�ri���ayT�6b,J�d�Adi�!� *aF�2��} g"+���j"�9R���I�T�F ro�)�n% o�hv�Z%��inguish"y .6�ơK� tr�'W9`8�*]/j#,\�#&*�.�]�.�P5�!Ji�A�nJ,.6 e�u'� �o��c2> /U�c�X �P; �-.���B��W�Lbe�6th�"� "�N.� a .� . o&)&� �o N �d1;��!t�m(� McHAn*�. %)9�2T� n �t�E ge� �. I)!��:m�N�91P5i i/��ofe s�vB�!�th�&Z29A.0 ��a'�!|mo��a��"�"Z��* r� � ��D bootapp�[5M 58�6$uO� �MR�N�D� 6�hc2b�na�o=m"�#ea ifia�,.�s [64]%0�s [50]k �Co3ks�u�."� �Y��!D��amongH���`[51E 5[65U! >� Baye(i5Ur�U oEW��rob��;a%Q`�2�[4>I65)�Enn.,:�(-of-the-art�ay.Q"���p%%[6��Q�[Z>���Ef�&hez��&V#s E m P�" L�3ih�D)aI�"9���*T"�Pf hx~�.w�is-��c� x��� $>�{1�Sw�#!�(gB�yAs �:'� Q�s � a�t� �Fu�i:�Aa�! fҩ@a��t�@:e��'�!Pbe*�Dcr2BX!E�1��6�2C!=��;')n�+�o���!16 �8FQ�#c��!�}�": D 1�""Ul ��etAmZGd�^.l�Astr�]��n"�. A&+D� v{f � � cd!�Kc��c>�$c.� m��@�@W�4!<� to)rE� FB2�%��Bdz@5hSqek!��7a 3 m+E΁�aA%3��it7��Y�H agree<�y2&W��A�;�!�w��+$D rH�ꝿ&ls� o"sO{f ��I�la'"� �8dV#A�� )"�� ��.�E&�~!�3D劰�)��}.r � v�c�� g!� � @���[B�[S al5�>&#'�i�}�ree/[,lSg .Iu�Z"nf ap��!-"�$2a �H�rt�1R H!�*�@�26� . Ou BI��)g$b�y��E���yֽyN�z��M&^2� �&��F�ly�) enzyY��9Z!d� l�2 �=( *x6l�E%j�K"�5vf"T ͠2�(6�6��=J�=q t��N9��jZ�=.^�-��cer> i�u:9m�2�U�F�&�:&�:1��[)F�7���(�X;,>D!��c "� &�=fI3�&�!|z ap�("W�B mRNA (�02F��1�3eF8B in ) ���� 6�4�!F:.��, [69�V.B79��;�lti�9�� 6c� Z7�-$�1�  R6�!�.�4�% �{i8>�}ud5b , +9%�!8�8shG1�H.�;% !\to��f��7,���Sng�nM��m�p_@ volr�P[. MB�.|/&2�x!&�9��FPB�:9n]5�:� most�BZGed� ��'� �.�U�ABCA1EABCG1!V��6�S�.O-!��?�iZuJ���93:�6IQ&��N? �q;�u��!�c<dk;)d]xleve\m* Љg9��='(� rP�j"&]?�Z�f����]r?:E�f"Y?P9o.�gHDL6~&�. �25Eypa��on�_!�*�j9 r A�es�!zD��Y�;�,� �Ban 2� xploi�abl��effica�:.� t*�'6e ;ec�T�#N-s zoM2:may�%&ign�+�&�-2�o�-A*r�*w.��8A_. �v��*�9AH.q>X �5"� mX3Aq"� .� �%s)�J� a�"�/d2=cJ�8 �=2 eV�af}���bq4to�!n$4�#A���� ��4�4"���!'�[=��k�&s"a�  ?5�"F5(� ev�)����m2��(��an�� du�!09�of2�2C�Z2*� ]�B�;er�}l :l1�*�<8��lw<��{NPsh�!qE�� ordD2h�6�U��>it kmn}�?�0*�{!5>�:O�Zz{�FF�4�9`'o �4t�9F mitochond�l&�8 .{8��Z 6��6�y�{*vo�5 apeutega�uo5 ��6�in� ye�P[71�71Aw Ty&C ��.���cortex��� a �s [ co^Oũ!3 v0 -seg� ed limbI'bod�*�3rˇdea�11%�O�1�&f�>�1��m�u���(VXt!0�uarjV�Zuq���qspa�0!�"�F�I��3� 쁿2`.��- cess��.�o�52K.@!� =i(re: Q��I�1.o�� ��Ssi��* rpri�a�]J6�s��&lim^ !�Yv2�m�-�r�Se��WQ]bIn/5I�x(�0g!��j�Mitr��s=�8:~� ch��,8� a�3roD(ia�t7)a|�r�-d{�7�:ensori)bi� spac�0G2�,2� ! �ai2v-(t�*rAv� Golgi�B, enh�IB,htJU�.�)P�!7Purkinj��ae�Kpiece9--Z3y%�-ny��OL�5no��h%� 8O�B�A�QarUq~Kr)�u!��y ngb��h��uF��YwJ���-:7&� he�JM�.�/. 8��N����1a�&sb6Ac"I4e �Cal� seam$cly6�}(�d�� ur b�+* �Hm�* =7�5/��#�&*&#�L2�� ���we�2<< ~d�V&���E.�7liA��)e���ar5��B�!]%�-r�jo-=1��!- sourc� mossy fiN�( MF )i�K&��7spread.�QXsi�d�& ne�� =�8�� �Xico�a�/ rubr �t�� and�0Obult�>zS 13 *�6�%�M�1$um%zHi���$E�6�� an `? .-� Z:�5loV� �cor��� �lcm3a�g � 2)M�"#�"Zcu ��)��h`s�'��rrS2�.�-]( SCT+&-A.���B6 ( VSCT�.G&tQ�m�>wiAb��2SBC sk�6 dors��:� � ( D |Ivro lb�R -*f1t[uVQ1a�/�83�)���MFU�1umP!R^v!1M� ar nucleu� LRN ) [14I�8G� .%� . Al�qUk �y feedmeiwY%ad��!�� �ITE!y�`IVMMpra ?M�eF a�;�|S�3!�A8 SRCTU�a vH b6C ;e'/��"BW � ]]�(?B5!�influ��6:1�;1 #eason�'��KAi�.�arr#� t .@ rega�zon-goAimovN!w.��6mi+.� &�pكvzK<t�&o��� H*[6m3�*@ �of&� 5f9]s�_d?"�;�?!}&<��;(�%� �2�="*k�!o�k,9of6.D*o�6n&��of"� ��Gr��>ma�Mmammal�c�e2.�of > <adult1a�_^� F=e�v�]& A�|EUABAm rima���is.�t�!Eslowl���+��F��sasΛmApostsyncVc&� < weak�Bab�'"���A�%1{ .�d���i%N��?k o�����:c!�GrC�!�o aR5�"A#��alpha-6�)$a,%7(  w��'����1ڧA � z>%m+ �A�h�=�Uby�Fla���"5L�,!��{�-u��{!��<M� M.QYB! [2 �� seE�=wp_ �!�� -��(&knocked-&�lge�e��e�,!�sr5�0�*ensT �los�mhyp|<ris�":bu6�{!��3ot��� o1�W[RZA775otmW�DE2�I:)�5�tra"�2f@DMnA��Io�s�dHY��2c� ��y) ;ɔbu�AQ sk=��^:* �%�}� �!#,)�*�b�y�1i��7ly� �~t͛&sam}m�mù�"B!4��\�͕immm ,1Hٹp&as<�s�&.���st��ba�.�J���m�P:�_�#N���e�spafi��r�!}T��b�4�٫��=���/r���lh���e��1A�f�)��:%m�PraT�pop��!���ll�C�s� e�S� �$F e��,in vivo [29]�,:3^slu�−64 mV�yut(DaE����� M>as*80*��as high −4� thir�Bspicu+9N��V�r� !�cutl�� �3–5�ŵ�6o s*�re[)�yu ��CEval�� !hIu?�*5!� cuneB  [3��i�z�*�vi�U zsub5��v-�w� �>!p�C�E�%��� _A8al!8ec-%C�,"�Z�=2z%�:e:��(�8b�>!=<�(�bU:��<~tV�d�M�>�s6��2 ~ �S�.)MF)P���J�[�E�! D���H(^%%��R:B%V=�)��vr�@so9�] SpOrex� E�c�a!?+u'�cI>�w�5wa��1�,�+B �Ling�Ap2{�F!���iT3�3%�suggeUw� � !j#s ���t٨"8��2����?F�,��de�4�����wx �mR, e�2� m�p$<e�b�.5  R"h^�Q|-RU:� t9�honverD� EE�[d %�D�M ��byler�'anatom Ie.�,E�E 9#�5x�fo`R.'3��E� p[o�:% *� � ex [�= �y=��cm.%������.� Ay � –[�9&��,�{i&#a�3�l�$v\i"��H ,%��!9z��E ably�"%%��_%���� )� ��a"�=��y8��2��@aAom"L+=1��be�w togeE�� be!'tuE0�!��dd��'�@theoreF&�,a�at �=.�5g��e& �3� e �,^��[���>C$ Td�%&od2m7%N�g]��IIO!#�"F,M��8�D�;1�2�eek�)=2�)a�� A��){�e.�?K� �m9��erm1�5*�g���*��- |y� �l�A�1��aa �zd�->c�e�#2��� Oi+���p&�]2�F/ma e���*X`*�I��{q%5C)�� !B�hCT%&/MF��!:O$1Bo� 1��2RY��*@lV��� inu��A o[ on&Le���>By bTndl��M&��:����m�� o9y�I�Ѷ%7�~ ���G yyw�+�:+">��� W �EJ)L0�ja4WA�u�C�"�` �$A�5��1�ar �se��e6 ]P���titp�!D� �N��V��]i�bY}j �TFi ��.<u���H&�H�(FjP7>do��l#E����U�eHJIOL�QŁj�+l�Wg_ Albu*8]s�!-C� a bH�per*roߥF� EZ}Tac�O ledgH�he PC.�M�e�.*�!!Nt� �f�Ne�i, �(��F"� Ekav -� ��:���Vū&IM� �K��b��exc��o�W�Vi�y&�)%i�>�MAl6�AD��A�bŽj�- llel"�PF:&X�L��woe��xk.h 'beA�su�� A�!f���S4#!�&�&�U��. &( 6�%a�ur+C*[PCi`"��#PF 5a�A��!Aj6�Vneg��,�bi5�Y���xaR�6� �!�ac�aaxin �^ntgDu7'�3�9�;P2u~. Eq .�R )� �P@"E���ionship=�a�!�G )݁��&!(en}��:�E�'i~�M'w%�`T �I_H %)N ڿ ayer�*�3F-ke!��A�de�� h ��� {� ��uosB)!!�)/)",3QDHU- PC*=D+2VYR/&3?eB�b�)FF%V�L "��� m}��Ko% ��s� ����r d)*�� �� ��"m YT.c �=R$��]���p�)D�)2�9��#&O l���&|a��,a�.a%~.�@(3b�ֲ"q')IUͯ2MiT!/!�A-!�n�b "(?fg͍��9�!Ju2ru� *&I �� ramp"k K%�t�t�8 when%��x�o!or&�0haE�.2�P�a�WDT!5EI�de@�r_��& abov!�!Ik��.�,start�p0A7�{on9B:t�9�( �:&-��fZr�A~-�W um!��en<,��2�exlMn�2��F�aw��aI�s 4>Nur [46��MAQ04f�Rv�c�;�_[50,8N�;4U�eut5L"� *��f� �w��A%zw � R�I�4m95c�g� �1A s*���LP� �$?��r�g���!���:s �8"�J� la dund'eu�x %�I�j uI`"�*� � &�6!� Er>�[5�28�A�al no%!��.\ J �(QW� 1� ).APs�K�1�c�!W!:�R(b��eTa�3SuC ��e �de�@�'�f�&� �MF,K��-KIg��p&�� �m�Q*���2UL� !�r���^jus$m6A� �nt �& �SC@t M&y�@a�4��#�E-*�c����expan{�B�\2 +A�Q���p�f#ise �(���"�,��!aB^6Q-l;)��@!�"��a{I� !L�A�` ���B e�Q�t2"} &VNly�%�2�bJplaca�,2��.�>>�. U>a.u/U1��a�!z��a�X  �e�1!�!.: ��>'e�B��%b� ����A|5PC!��0��A�ŹIse �jpaF�.( P^�&��(n arbitrNs˾�� ee&92A]�c67X ifGGAmv]񉉡-��exa�ԑ9Eqa�d�zs� "��EXA�Z% `� q�fe .<��s g��� ;'[&.*��x�v�!��kno&(PL-6[�Fa:23$� &�1�� ir�r�\� `6P:�U��PL6# "��*28 y �r ��g� word!�a�w (5i�nT �upm!�^�� shr�fo:� �o5 ��a�G#)�q�5 �� 8a.@�a1i0 knee6>�!U��*��[$ght-forwar�!:fS-j� angl2Zdq�&����#e"b"�<haios�#��t� ha�(e�:!=ed [5� Ia�X �?D$48M���e�2 �#&}c c V�-!�� �llj %8" �' wqV�/�a~�zyB+p ��� x!���L*Bq�J�a�p"e��d�v�t!�*p E\.� help��,�>�as..)E )lk(��e F0A�+�� nofB�����H�+�W2���3鹑�Bi�Qrd�%��9i��Q�!�Me �$a{!���M�!�=�Fmuscle-�d2�,Y�"b"c%1yi�h*EGj- j6ha�*� Yl^�e*�!q�\Y(�$�01#er6��[!�ver.� one-"�al�rin={� ,E�t��W �>EF&� an� aNg��� 7UI��@<��OE�&�E@�\�jM��y�sA�o Ia� a�i3-����!>���E�J���Ʌ� M�Ib5¡�!3m�2\���9 E{��ce G_N"���*{gh���6�K�'s@\ �y ~ i4&K A�٪�_"D.� �`2Y" do�,��&G? !\�'� ��'%*�is* �b � �m���a��s&n�S��2��a1/b'1 plac�::�]� C be�'W naï��E5o�<.@I� �o��y� �d� A�> �Ag� Q:� �Ez2�AK ss�:)I�%b���xioN ���_1&��L e�22I�4�ng��� W�m�I[� �&�62�����i�(� Ea �� �9)�>����BE�aa��\�BaAa� �t���R�3t.��/ Yp��E��t1PC�/!_>,� 4 i!� �<_0�m>� ym�a�.� . Bu,a��Mc�e=�3azqDm9!AI*�?qdˆ� �B� adja�/02?X�*�&\�"*��12�A��"�5&�72� �Y2�R*�.[N3ob $�Ja�r��!�>�"� uJuiei8Z� . Gi%�V�':I�MF-AO� !)a�F 4��'.�pret E* !e�/al!-5��^���.&U >d�/L> YCcy [59]� � !(s{aWcan� .&�%�pN=1u�A!B"��)i��n}I�"!>I�)2��hiddent(�).�)��+K3�?�Z Q�s�!k� ��-�.��#cx5>�YCq�X,�q��p N ���e=X9K�fM�enoto)raw"�59as#�� a� �>�I�PA�–(r+o!�ed��1� �i͐�lr~2�->j�e�g�&EMa#�� �Z��=Dx �&tU2��E6Ca�/�=q>5��!R� 3Nt!h.���l�EmE�հalao�%���p&� �� "�+&�J"&� m�a�Z2EmA��&�A5�V#39e�6�#�4^��in���Ne�� >"�"�mMF�6,& !"� �s�A.��%� ��A�;Ѧ /[Po Q�  <�MF-to�unaD1�&��'no 5&A8N,��K]�&�_Ѡ8�a�1& �Uat�Y�bea%�a��!n!�(%�����q�mSN � ,kcP.�!*-X�i>Z�i+.{!.u�3��e� p"�ny si�A�%4e�Fby�A�g a�ru�  �*B";�ݺhoi�UJ�A.v�d�!��ZF k� 6�&O"�.�v� w�*WgpQi���r�/I�!TK�[u  f���zt�� ( AN ?,u8$ Bishop [6��xa{%y�V  "�A�AUqh.a(��E/ 9�c%["� � y#�J0]4�E(��ّE -�!a!�3AT�s��6rF�]�t ("�2a�`�6���\A�im�>A Q"�Maro+(m�ch)�� u� �q n*{!�!�t�&+*y .�I��Ia�X'�aer��Aace eU?% *^ :�(� 5e{� o��� �'ٍVN[6�4A�� '#�Ht�v{�@a.~a"v�A��;or�<rem���-�"� *O H�&Ne�3mp��Qf surfa�[62�3A"^ne�N���A R�>׸a���ܩs[��ubV�-��Nap)o4&eUs�I��)e �x*�ja%$��MO.�� �R\co� � SCT/.� ,�� )��Lsee��@�u�Yf!nUZ:z1}a�>+�b �spA��GMF�3B�2@ �UF>�O�E!4� s [8�p1FDD��"�q–w[���6��W�H�S �Aa�6L� %�� *B �*-Q2�"["� s�! aS)�)�3 v.d9m��ucX"G3B��Not�3? �PW ultR��+<�0M9�-� ��t�c@�!� )!is c�c��-1g&TP %[ ��22SH�eca ��i| ������b��,D����aî"�6�, bea�n�U>�N%a!�a��;��s"cS� k:!-�F�2�&HC"!Ua^� x��� �x9k�,Κ�n 9("LN2�� � "^ 9:�:.� *�-l�b�J e���b�� � to ��C(m,X ՍB l �^� ��S BX�W2����ہ�{�N�/��q��.Jw<2s��\ .l]beX�� . I�}:�-oB��s al#Myc7!Br�9N6���k"��'tN`2a^s,�!w�Woމ.{�����:FmM���m�hE71� ae�%�'��'_/ a o!<�<"��/�a� �PB� *����.Ko&-&N;"+'� ��2�.�� ���*6& ,�m2(U� 9� -S>���� � e�2 � ,!/weM!ee�u%�b1��too�+�#b���d�� "x:� �5�.�c��b�T�*o�>ar]y��� :e,� 9� II���5dE�ed�.4 �>�ɬ%!����*CJ -u4 u"�ak�6< �a B [7) *� mFch�7'��m�~&rߓ� (_�Zr.�,&�5we�$�U.� 6�Ei-(��JKwe� �7�R��&�)k �douAH� ar� I��)�6� �)e8cur��"�BC�]�c5��<�hap �6���FKp�H$&};Z�%6�,�lc�&�R&� 2"��B�VD}6,Ar�Et� �aQfډ/�}ea�=it.��y*�&� � hys�?APc*X �e,}ef��e]AcMjɿ �� ,b����e#%�9� <a6�)YY2�&���NMzg&,�u��զea�T„�!r� ��sp�uxA��� �>K.���4��b f�iy� :�lm�$�A�%lH'�)!�%� . By !nX�.Yu/�I2ac:llOcua��# M.�- � � growp��Ji�/DA�ٲ 3���Fur?��S=A=&�P�CPC>�� -;&�:tE��6w��b�8�" s *�&"� ��"C2"�r1�� ed�&%D%b�b\�c�  (;�'%�)za[ ��n�!R��N�6" [OWy�?,7% u�QasɎ]%�=� U��NI M!�.(6� �Z*O�row�]o.��" l�0B`� a�"���*�roo��kead�K( RMSE )�"� ��"#$Cbz t!0.U�y +c�ex�%�&�)7��y )R.ynd�&`S2�!��^ BellCXco�"^��cP 2��$� ���53�:G 4��B�!/"e � l�!���oN*� �0ex�� �W �!q6��n~�2�!C���"� � -Q>v�n*�I�A)�)� �b��as�>EG�*�H �0Q�Q/-2��*�*un&���2X �ac!�C�i�" <á� �\N�J�in�{s�9�pQMFI�� A ed c%V-�y!�substa�nly reducE�$For exampl� �uo�pat neve9u ()Q(we will ref��as ‘.�=’ )M{noT) (converge atE�,i�t +AQ��Py��wv.�0of two or mor���3� even!�they did��until PCM�. Inter� Dngly , Barron [74]�w�!$��.�0construct a f�(forward ANN)B)�!e�av`froE+,yahzn princi!�is2� e��7M'(hidden unit�Fhe ��spoint wha�curse!e5SalityrcoABt�� avoiA�bu��preci��:G9š<is stAH�taia�. While-Uun�"!i���� ment�� reac�� cond�� canAAfulfiŵm�biologic�Ni�iTresult�G-� �dem%� � find!�op$a�x�8ofiJs�u�toV�}& avail� � �w%1#{accept+���F_śs . GiA��I��6�dSCT/SRCT rV �� limi��MB(�K |)�>�o���s"� this viewIf$has a high.��0go a long way�captur�!�!6U by ��':� :��1�t� back!d_B�w���� , ra tha�l��,!�&� !�sP �T. Posi�w,�� nd�Kle�o| . �q�Y��-ed!ou.8 �� � arm-e�s do indise� E�Z K�Lvidual� � h� m-� �'reg� q�(um [46] altI�%gdoeI� mean!c��y!6�s_a�eI�V���AI���0in Eq . ( 5 )Bxe!�cac>.<�V>$�쥜% a�t��2��a�Wv �?-z6N�� u�E�C  torqueA-isA�%�ine�4A\entripeA0Coriolis� ce��9]�h!YYs lea�F*� 5J!W inveT equ���moE�-� �.�transfor�Zon �� angleSvelociee�, Q��b /�%3s �G threeR��M��AT2typ8� ^�am�i!�>Rdynamic%/^,9lis!�below ,M��Hif �)'��a�re r4�% ���<�X crip�lnd den�e elbow(?er i!�� 0�b ��*3c2�����Q95[A�,u r��n) =2��  cu� ,.�$ coe�amov�.ll�replaEaҁde�vis�� �is�M+^ . V" ;out.F�ca�2|!��55^Q�a9w!��%���nt)2Y 3��!��o�ccircuitr!Abe��e�%/�"���se}�,[app��$e basic st � iǭ^4 )!Q�&�I"6�F�w�v�g!F��U�= thro�l>��1� 9%6b�]influen��4qu,�/e root�wsquP�  ( RMSE M:6%��5Y�W�s�H�da�ng.�>� ��Rs�ter>~���2�choa{�2#sa rando� By cre�:� �N�E�a%`ed`ofW.� a= �R> ,�.��&stY rel� a�7u��ar-Ro^b.dEHman7� .�s�a method���*��� )Jmm�V�� iE�Z�ie �x�ex �-�2�it�`-o6��"�dir����.FE� �ize� inst��� ��n2HavA�]5� *,Nal��u��:� �J'��Ay� Q��1��NR�or�l(m�-w' simi�(� good�ugh�2�m"e ��J�y��Mp�( step . Fin�E��%(s-):��]))fewer*Z:�sbe��an� impr���pensa��b a�e)�n6�. A�6V!.�$by minimizQ�"v��6�& cal��z�D�O2q M:er*u  o�a gridG|s c��.s�� �i#E ZZr target�� /�U��r�@on���di��j�In����"�sha� l��rfa��-CN� �)�j0trigonometricOrange�Q��e�)�e��d���propor% �maximum 3ob� !�h�GIitwo22a�r/ �edmLberg-Mar�du,gorithm [80]-3Z m�Matlab�Iiz  toolbox . $s Nelder-M�aa1]OfN!] hand lA=r 1of un������, d� +ŃJacobia-heR ;����to��Ic n. I�im!�j t�?3� gene>2� �*�� ?oA:]iz��g6�ED1` .9 to d�op��2K��6P. W�p�PwB*� yh�bm�Q�aJ�.I, �.0� J6��,  �mQBIa�!� a� rtex�e%HaiS>7� � i����= �A3as���9A�a!"-UalNA�monito��!�rsx6=%n>�(g� ApplG ion�,"C:�� }�me��nJ &de�chiev�i[���"n^!isk9�%�� synap!�p�eals �?ezs� O"!v)necess��Y�ngI�� migh�!lli��$�����Fig�4A.O E��j3 #L:y��� imFyA�0e�bA�N.UI�:��lowestɀ(�Ba�A�6 5A ) �60 e�a11�22vF2ŗ6d$:_!�9w, r%�colum{�!�hIt2�V�� regressor{�F� a$s exch��d-#ogj%1in�)XcolY"�)��Q�sv>a"V fasha4� V2B�i� �!to .�.�!UO per�#�to�Ho$ b: naïa���rawqz<~d� 3broken y"aDuUsym y�,R~�lEZ" "�by ro[n&.�mak  m cl{o M� ..�a��e 2 �)�bA�~B"ij�.^dev.픡�n�rably�er�e�.=�#lyu la� I�N next� ,�te�<effec�i^r .`&�-�� beyw8"�#U ��B]�at� verag) J� , �� �2 �i� when mo�L��a�.� . No� :�!���[q�9��E*:���'��q�m�be S �."tq!%� +U�A{��r!edeWѝ(cN���'ax![� e pan��������ipoorer".����(� sepa�!�.�T�.)-("UA�.<�� dash<n �Fi�� 4A )e�is1!kA�u�ajIis= R o�"�?�1�� �por�iV,; :�:1,b D�*��� In mB�V#�N�lalreadxe�Zly� B�gi��+sv&2! o can��>�q�w=�:�)��Ml��. E . !�A�O,@!�*�) `��d=�4-yf 1�e�$ed,%a�2&� a fla*M�E(val �ב���e�v :��P6���aA�e*��f.�B�� ed (A�/ BE�!�m�'�t'how!���(p l`n�DF�fw!��m�.�#cer!%�2�-�'!���ha (2"nNAUide2�!n^Z&�-�!�&=.�������d7n�!�6��'d���. A%/tim��aZ�amM�����)!�mm�� li)�&� �e�A.���beYFw�-�"-� e.J6�aV�1D^!��e�� � #+byJ �s�� s� CV�, 2fn�ma �-analys%�d��:xof $i�#Qa�V�&/2p�"limb sUsAgn"<!M(oO*46�&.�&! �.6I�x9�*� � R�����S$ rece�"�s�1MF��E �$impai1$�~2���!;��#�ow1C2y�b�0���prb�'*�*A�B�.�t|h &zE�yiEd �2�" 22��v!s!,�%tru�1e0B7ld )�I.�1B�:����fafs�4e�c,>�2er�(6��F� ��uA/:y� ��9Jof2q-6�:��,1.�a.��*V�. H��,�;�Q`Y.p��B &; to search�*� Or F�:0�)�2� theirr�?b!?V(; Md��R.b�'� 6��!n�*2�*e'���AeqO.f2�*. H�j n.5��j-Za�(pu�".�0&l"%"=�V�%!�Ɉ&�3ar:R,!�r onN�XJ#��g#�5yY*c �"�0�Tw`as� �.���Hit a(|1"� 9�ite7(AA�)�6��on lo!  a solu�w!vq1ar�ar+h��und:L/a�/G��,#�UsEq�(!��guaranteA=�I�Wlie&J � glob8�/�And=���i�-as upper�0�w^s exis�#>�8"|2�!� ��:�o ��.�!Y"H<����5"l(:[���b._.�!���a:O �� !6��2O&d6a�9 evid� !� A�eno�#"#��Y�GrC:"�2��.�2\�R�&� �� .H. as[,B] .16y#, �2c T+�*S++ �2*cykB �/��4%�86�"�6� l"e��9��ngX�)i�s 4–��'&�&w�2�ca6�4aI^b&C e��ar *h  )��sm.!ˡ�A���*e"L � ibis]+6+e^ � $.�E��y*P 6$m6����% A m�1 focu�T-hypothe ����Yal*�'mak�+]�2 ��&�/� taskA�2�1, &��*� c/+'�NMF2�via]B}. A��A��<~�6�!W�-in&�+��  "��g2�:��r��:M!�uUSed� �5s��"�"experb=�,:� vivo"� suggEJJ=�%���edomin ��co "n�.a=at��� i<1���$�9v�d� d"1.excita3i�>�� (tonic inhib0�@um�A� -$Golgi cell��Onm!m(�ump��bI�>� Qy . Oaoe 6��=�Mx! e..extenda:@:il�(]U[40�3 [82]%�addae som�t�. �rais,%�nt �%ew N�6x �rolD6�QoMFoa�4%�fo�&�|��EZ�E. Nate4 a��<^�� opeE�primari=�spike�M~� K-�oryB��.�toI�b t!�I"fa>=ph�+ IPSP�� very*�&Y��p�-)�7"6a �QHUn_.�8e�$mK�$�Lale �5!B6U,u`%�za en!��MI�anls [83Ik4 �b�1re �:.| R ,�� ,�>.#�!eL@mG%�i�v��7gs���9"AstrU0%%)of�/A�w� anim` d�4nId bef%w�3��b �ha54,, [49]–[52!�[85 6]0U ��qoculoS oe�nn48�Oquitey]�-bul��47"3" .N1k�!!.E*�=n�|r�$4�84[�!kS�*�:a5iR���0]#�Mg�r, stud&' i@�(�.�1 ;_ ��49��=PteK&c6� aK\ �%:�� �2nt [21!�E -�adultM҉y�p�Z3A~�/� cC9C��� >ou�I9�Q�">a[88IA��Z(�juven�>ij (� chD�BrkB.�C fullHuSa�AGoc-gr2�"�6o� �@% h�,�IA#du�B )!t7898"|��cha�Ai� rr�%byF[8�5CUZ�p"�c�>]-�=^�N�A� E:i�6!G,"LEl�1ImQ�YY��Qdea�D"bUF[y���E(GrC�."� revol�*�4AL��le�\on%-f�@enc� petiZ$u7�� ca)!@{�re6��9�5�a(!5��F �^�( 3$l�A�h�<lH7mis�N=� resholZ�77-al ]���$$�n fac���/y��  F�;y popu��oE��� i�* nefi-��P ��c � ��  /Ibat.� ��'�) heav>�3!�! fD�#�.V:a�iA8VhS%�.�!w<6�mb�exe�sJis�� � e1� ex!Vtim!Qof.5� S u~reg!\� � a���-��0me!�isms [9�J)�� ay)S�:� �)�%��I*j ,�sA� GABAergicmlQ%�%�G& ,Qf�die�fMHe5YP#20iz!oe � 4 PC #ke piece�12�q~��i`1�>(:D!�� ��22afY)[ ur�! Ysus�.HFV!��sE�7*����jm�>M&�=gl$sw!��D �� ��% tribz^ �=0a� by2�A%-  P5ng�Cc'B��E����$F�"~*t%:�G�!�a��e@�O%z!"exz;ism��aeAffa��!� "X-�aua(T6E�f��� [3D 3 B[5� ~$�t�=lusterEX%�� U^2��e�n�i�*U�2 &b 4Ba[1%�[93\ �h3od��!]�;��/"�6depth� � �;�[a� Z�i�� ���[8%"qF��.=�R<�mXtV�Ai.,5�z���!�i�&sI��!� Txa�i�. E�/-7�ss�',e|1�Bof� :�%>7;��1]��pEL�5�^�͹;out�� ��fu�F���?-;Ce2���� aleEb�#K��cer��Fata)� m+st� %G � [9j[95a�A�>guD�M�F%�H&P@0��6N2pog�G&.3�Di�b�}m� ElexNVof� boH�=��.q&�?qA�&� �Es}%6Umi�+�n�aL��|� f��� �AnI�s�&?,!�n}}�9ao� orga\ � �W�8f$0 �4���SM�ap� tu.L,� made= <=Mt|:�!Iesk,i�*!u conf-dcru� JT�a=e2su*��E cord�an�r"yG7A�� 0d"N�p�|B|��vI.���%Nu{ �!aCic nK>���H)j��pa-ns� 5��"A� ��.-� _-ə�QM�p2S�bHR�q2� 6a�&&connexCF I��^=�� plastic3pro4�/� outc�( �D� M �h2�aU�[979e�� �M tane�S2C�G�K�:* word�?�7)vp�<6� adapa�M�N6ZAc �n.�!b�I�E C].�'i&�V�)��H%CE��B�a.�‘�S� �J>�A �h.=W�6associ%���a( help�K��b�7�G rolAzI�A~s0� s� yB���!cVO� >�!�2��:JQ�hRA�:�\:VO>AvR"AV�*K�G5e��z�aff��A arguA�%^ ‘L�w2�B��f8�E&�zH/(&�!�!al��56`Q prob�. D�W!��y�~� �_L1��gB�&1L:X3$ndQ�!u %terQ�=�*�`igu��LuMdv�QdQ1�-��M: nerv�@-�!S�z�\L0par`Ka�!1Q&librar�reveaa�"�� ex��of 77�s�0 �the�H)j �!���l��'�e ?a@f���, |eA< )a�Pu�V� u"� s!%GE�%�t+=!!{�(UU��A��eUCI[weI�:E�^!?pr��̑-]w9 inJ��SyY!5eAsCs%ab�/�ymod%W0� �> >�!��Co�7�P�C&�candidIFNmb�]vi���aegAC. V�� borne�_�g  malari�)denguq$c}�� 0+jor bure[�G�Zom�0�.E��tra�a� sub-�� &�I!�sirb6DLk  India�eE�M�a� g�u XA#��ic4 =toI6!lsum�* �of�[1 �mpI ng�;46n2+p&at�7k)� ivax5U[2� Cj�5no vacc�'%\"�T!��iAA[ve � io�:U�G -��l ~aBen 4ublic awarenes3�n4�D in laborab�,�%s [3]�ly emd#z|#e � u�" �-�#�"8Q���. In:sUy�ht �^��laODAs"a�#e�MosD!o�re.�� ��X1#2�inJFu&�*�]�AblfeJCin femal�#�% gg>. utilR-by�b!? s eiŹ4�e:��life cyc&r a[��Aom�m x bef!$M�n @mammala���!,U�`�=,.�in��V&�> obsc. W?7A�ree�onslauD�W�~ rbov�epide", i_-ofMP1�t��-��J�]S; gene�A�6,�j"� �W? ar.�z b���!-S#etbe�$of5n8�)���"��q s [\���"M�BU4a� 2.=�ipP�!�.[e[K!� �r�ce� �<ykph� enah+im��firsti ��f��aPhszcrJ=!vad�!�� ? .�)�ET�M+*:s [10a%1tIn��Q�cRy v� r&�P!�&^"� ]W�M" �$e�I��"I 22 n�!?�U[1%�� er"pF"%�[15Z.L�Ns�P!?EJ�[17 �%�M!I� ��a� 3 � ( 19–24|��ength�@A�c�h(n-"�hn/ R�o�t-E2[Wio@"E!L.� by b�ngA�3′ u�%a�a�?(UTR- �2�  m���RJ��A���A> /�� vageE cogn� FvAA�*q in Cahhab��s eleg��|h siaE�6>^"iet: om�Bl�(ɹA�E�A�20]T�6�*liS)� M�>lMpla�T0��� 2,���M�,Y����idm� , fa=Vtab`[m mapopto0['� �� tooke�� � J-;yu�2�2CmpaW9n .� ͔on!��P�s_�Emo  deep.=�Ou1N.�AB�F*r .�%�2�W.n��Kͻ \iH!<2I� � iA!!o �sp'D�yS d1h�2� Anop@m$h[5��nd2�sCs � Plas um�[2 D�+��cou;]oC>%�rea���{M�� bo�Q)0��;�!O�@as�� cret"�A!�J�I [ i%�YBby-Zl�%_EYre-�d�ecA&� ]E�u�rF�Fdmf ]"�Cw ertot'�d`�S inct2;��dQ/�5:A�fi�F�Q� �Y��� I����X9cY(� bi� � k�� -. ���)m�"�9�i(" . >w�bq��0( ATCC-CCL-12�5A1mJP�iat 28°�) DMEM me��)l"J 10% FBS%J�biotic!+ s2� �7,MOI = 10Q�wi�(ypeJG ( AcA�\no . JF950631 . 1 ) isol�7z/-5an@break!.2010 [2 CJ��Ci�Pm�ha�d� 24 ha��� ��AH� �V#j �R*�. Iir$ina Truseq'&?"s� � "�%�}d1�!p)�u&�( SL )�8ay�F86�i( iB%�wuanu` urer'a8��(�Inc`FBrief 1 ug%��s�oAl�w�  !V 5′I� i��#:�X�! �RT(< . F= aP!R����(�or enric� fraBi p&�D�(�&4 14it60 bp� #luA:E�46% TBE PAGE ge�(E pr�- 3?R ipitE� �$sodium ace%�ethanoy diss�, � e f�Ewa`5��e cqua�� a!T5� Nanoa�p!sBioŮzer�66!�&T MU�G  A��?II . To&�iw�!WIoI�aWoF��N�c�.��"KZ&9�}x:� plat h0y�"I%�.�edBKy{SF�iA�naB$/;A�}�7!�j�BUa�h$g&���two�qXHe�l�F��re[Lk in T�0�@I��C�E�>cO5r^G&�#*La�� as op�#��SL�H*�X9�9�E�u bimodD=� m, o���p����[�107–30� �I9�8��\9�M9% jof�, 8!$94�� pp%Gy�6 �x��|egypti!�$.i) pipeE2�� p=ef .� E ed zero�!mismatcA�wm!F�.*%Acac�"U  ..�2�%�N/�B�K�t ,map.�. ��jwARmP�Y�j8 �Aa9�18589 }( >H6!�)��1wJ��$w�oo�Disu� l ���A�Uy�um�z �*�Q+�� �N&s@# deriv u�2Map� a0TtE�SL%�A��H m 8� M��-'�$Fa&D�ciA `r)(�>2��A"iV&  , 36i)er�%8��!o�6�(� ,&� �Cu�(�12JU!�!��]we~aW`��aq.:g ]bnB�e��in)�p)��. OR� -I,�-miR-2EwI��E�ng,*meF ur� K6re�&&�AS2�^U+Mi t>��m�of6�ahe2&8 �Et*�(,eacc2r1!�d qɝ������v5�Dl~�aPd�'!0upto 2����Z��A>eOurX(2-? y&�C ly29 w���9�"�-11-5p 2-3 84889.89275. 7. 8 86B 2940941 �294.N9�EEz951?a=306. r 309b431L317.�34745 87 �9.{92b{98�99���9bAc�nOF2� 29�#I$af� veA&1U!&6&�O6 �I�M=z Y�I�+ET��3�F� A�B� D�H w� aly�gAV�r�3t�#i� =A�mHY�.�90'����z�Xm�a*�r�t ��V�( n�b77�El$n@u6t" SL (* -117] 98%�m?3Q21993 21]27]�44aYg932YQ iab-i~XdWwo � � 286b%xAf189Mԩ�uniqu�� .Pen!ʹT!˕�!�.{��UE5Y'_gR �"SSL.���abs36cI 9.s+ �I�H���2S79lB� �I) { �>� �n=}.�H��$9�� ig"Sup-� is nd 5!$�'S��S��5./-7E8N� downJ� �y5m1a. U!A!� c�!m�f�.]00 ~�'u��J� ]TPM val�4BM�EiD:$g�go$�Z).�ly�k�QS�(E�Wgne z�p�S!�1000 �riih ode>4 ly A �HM2H1099a�( i8 �-, ��h��� 1 ; !�( iv )�@�o ) � 7� � n 10[�=�F� 53).���<�~IQ , 51j.. Sf'*�> 7a�BA�-29�%Kn�U*< B%tM2�%�36UXl ��eu.�E�� y*1 �. LogK3d>�u�;6ur�7i��pirp '! '�0� ��V �uu,edgeR packagD�'4�e��\.�; �6#����R( pI) ]P� ��valt'EQ t! )A&�xal-e PCRE�9�oE���4w� �28��7�Y)d%�� %7.z�.�Z�V%N�E&Ss �_�6}cl�&� 4|6*� � �P,�%or�"5�XMy pJ:*�M���grag� .�Z�FAd}5F( ]U&Qv��4B$>LMzrej����B��sex]� z, 375"fW-b� YAQig469ae� 108ak, 186!�39eUaa� 2944� �:<�460��!>22~!F263s�y�193F-�'m�E�ES�,%q�5}�c�>�怒 KOBA��@@i�:].�9��,(F�n !�"�]3ae�k<]�&� &3"�e����N+�%m�J1�!��e (Vk'�t�"�m�Q*=,�M k��r��cytotox�7!XProte?)�7�iZ1do�7mic�z�Hum�%�4nEpM�!�Q� A�3pG/7��@�(( TCA�(� dorso-v�maxF"w}���n�,leu�+? d�=d�:p.� �aqX �SNARE{ erPBllinhK!a�(> �)OEE�-'Ra�O ^.. =.��G!�A5�es� V0A}�&!*yN7 , ECM-?'p �' ���ndo!��,��. Like�D!�c� ^F riboE �B�)165�T!( 2&�2c�2�i�.//�4Ld%n���:aV2<�;�DMG" 3� �d~EF.�cb2�!�V$=| H =.b,, AAEL008528 1393>  9042� r�-�Zi -J ���n�+2�%�yk03427B��Ee. [-�![^�D���4e9�&V*to�st!/P��5�!�s� � 2M5T�| ongoa'!�DT*�.�b-X A`&�(%�B����teKt) �Don�*}#9. <�ɪ���,Y r&%��X-� ��7A^�+s:1!*��:��-ask�isF1La�5u6�E��&g7z�B�2�'=C2 . r �. U� 6:6�^ , 26 G �.H*W 2�2� (F�%E�Kn@Yle�%� ��=!��%*j �R� U�!�RN""�' s��� G � 94�� 2p��iQ^|�$.�Q��2bT2UFN`".. T� 5A�� %h&�&�Tbje�to>o ��NE.��&� @:�E{ �aa��(> "� .9 !��evast�!bB -c392�d.�� �}�p�e , cr) �c�ubi�2M'�&�lo�ge�.maa��e n� Ne;�5ji��-13�Os��sh+">�QU  . 4bT �q!ot�D�h&O55G,~in ImmC�y 䑂i%1," "q�7�w�s � iNt'"���aI�gs�Eg� Mlg�5 �n to�%�-y�w���D!��2 F"� >7 each_tU�%Un3F&Bm�1;. U��ub �ed� &.] �Tub�a321 6!&:( I:*� M<�.R5�� �!f76!q�b�6A�,q"!�v�� ,"� 5WB�NA�� 1��0>1b� 1016"� 0651�ww )IIA9 6 hom<�T�` 6i=No2A CťU�54E~�!`M. =% tud.v2�.M��; ��= �#,*a� 6�#&&!�r��,�1şɚ&U �-AGe8)�20;�,*� *FF�ofMa! �1�o)w*�&� �ed6'%M�$�:��{onB���\�Q�2b��3=��=م1o74&r�!�� 9�B�.|.�`&<� x#b!G"�%�R�*0,����=�-�E�-w-��Ё$wo "S  x"~ A�9��#,2Ei�o�eata s�>P�� c�S�Gn4�,">dTkA��N9 !sY� �"i��GD*d���)�T��>4��h3Q�N&�;i�>2B �.��-R ��� �0�;>.2V"��Y�FU1u/-5�!W&l � �!f ,v� �6�seq���k�")�6er `ir"I5�sD:�+d86�UU&� �1.�,"��lR)�"` " %�H184z �^�I�;tH!���lcS�$e%~!8NisWNAo��v!�d B<gaE6�5@in Drosophila [34t6�1 ��� 0� ���1 �$ �aQ8ɜ Skalsky eƄ . [IL�$�;��y%�AR�� volvw1!t9�s Wolbـolon���y�_ 9)~�QVto))�a ʁ���%�.� f�"��!�Aτ��B�E��"� ˁo 5�u�,��!�. �IP�Oi�m��3.4>1��!v�AKU�%m� "�1E�"r�I83r#92%��>�)�*�� .�Gz ) cff��We��nFL�+re[B%jt�z�l� � �*K%B��m9 �� ^e�G�a�EŰJ�D� ��#O��i^hbeA-�. o2y �N� 2�-�� �.�G5�4a%���Oa�f�="$4��cA�.�D:&� Pma�nseis hijac��_og/H�"S/re*f,!� �G �x^q�� n�ic 1)�&x#&"-��I�y>$ E�c&q��@�3��6%�{:�!)_e�&�.:7U)�%j���e�L� & ocee��2�I��!��Mm� *� �Z.(E��M2s6�q Z.PE�M�"MKO���Hst +I�.BegNG$ rb����Kj?.h�/� au�tyrosOphosphat�( SHP�, ERK1/2%���"ffu�g.lq�'Tď*6���& 40S�!2S�*A�-O�j>-�:% . Ea�I���1�&�!�"�  a� �e�W'�B�/Q�2Ma�Fe�HnO byUT %�"w�%�I�3�e� extr& fa���eed�Alj(!w.@�y�"]�TJthighlighOA���&�if!B6D ?`$e�s|�Du~ � [�]6�i2r�.��&�?> AY�"(it upstream�!8[3�T.��Y+AAE?;hLMBMc:7-_>�"X0�"uZ�G%��u&MYU2� QJ9�مllmz- ?&Z �!^q ���&M2�8�IA�; �!�&� 6"*��*76uD-T�R*� �z,����1d �, a�a Ya�2��B=l!%�F=:��a�[2��Y!4M#��9 �"rB�-�r�3"d K��M!W&�&cu�r=4!�mzp�^Q2� As�� ���2#�� !G� �&� O&� �i( <��=�o�5I �*"h15: f%� � �:��"��Rng_5(. P�!� �4� gdm�07494 10470 (l�E���+�;�E�vr!�{(E4�͚.PFre��$�>11.0L 1378�)a�fac.7>��jF �64:u|� ��{)E�S� �b( GRBj~E� NS5AA�HC�RHe�Stis C���RW}y 3�r ain/�=nd-�ZL. mannF�nd� turbs mit q�n`!�[3�GA� A *��+9ed�2�R�-�5�!9A��CD�ukemia �"�[?uEq�o��jP�O MLV9�_hA�k!��H X� 0 Cdrb27�NsM)ory�G!] FGFR�Fibrob!\^�b� �m!/y�"��!`�@.��v2�:A+!t�Q�YP+I3B@ -�������*~,��Y �s2�E���!:us�+ earlL���"d�%r���#�\k%W�eH��/oC6a���C"� �����3fM �Ciɮd�)A)��2.��f)H����"� -1� ��sr�� !��sk[D>H&��Us$-��{}�@�/d:F! /͚e)�9a ��e]J�oi4:Y�"� ���%n!F�<k`":�E� I urba�&�p?0outh EuAs9T_8*G"ɋainaon�]i�J�3!�sp�1�F.gT�Fa���T�) �F��2@d#�*�V2�/E�Id�a��.��] ������1G� e��K1l.ffCy�/ ech8�occ'( C3�!]BTlEvsiRe� raҨq �g���lU� tock� #�UT}C&��)c�0d�UWM��{��m1E,Q#� Iran:f&lcioecG� Wac��!);QE ��(2a���!@�R�e"�#-�]5%�� �i�|vm�6�&�UCg)�E�Q�%e�.�����c�)nc�9� J=� saZ�z6C�Nal� �D(!su��@ l&�,E�o��>�]?n&E1k�re� �'o �B �21�c�1�4[�M�[��losQ �Ye0a "J��flMt���� ,. Monte Carle�dV ho.��(u��tb�1�u ��I�����DparamA� M�&�@su�oal!�U*s� y�]��20�5 2009EP�b �d4Ce9295M�Tasympto� D;cFYv!�� M�I�2X63^723�95% CL�u��(val , CI 146466–�12�*998�" 2A#�-ann����I�e�02|US$y. 3 mi+�( �I103�4D97 . 8&� &1�ndirv�q! Ac!�� �c�ce>�N�9~3Y>F����22�?7��aX.Ddw)Y�N~130?Jz�58S�Q9 %'���Un �AqVjI73OECE���"��e2��S��,&O%]��ka"��I��53�Z! �xy's$ ��omA깁�xg��!CE�veill�b;!uX �"j�� �4 gram��L��e��C��:2����e:rQCost-bMu�G�&c�prvOre��uӥ corp�Za��P l7�v����GI?eS. r�,!hro� 1�cw�Vclae��vtap�7m E"+u!��� osus���h�e��tgminth-]�zoono���\ly�\,�\A��8site'�M �S.1���en!�dog���qV `r( % efinx��O!!E. Cani�Brb��y���worms ex�Qegg(�'enviro�#S!�2�o� z�c+�)'#in���mF^. Hg �jJ a�ȷberS�Nc��!SX v)#� e \ei��A�a�Na�f�oডGly< `` �c!1  cW .H(�9ac!� de )�|�Y �!�E5a(ͦ�rzlu�.H0 o�VA{n)�G�y�7 ClinI u s$�x%;!��|%i��p-�{pX le��eq�so(on�|/�ti�r . RuǴu!Exsp��gf�]ca�= phyl� clck :a�d��C=���nya$�A� worl�L. X,rg�"Myh�eeae ofn�icX1�n��h��y5�?$CEm�Vg7 ,cosmopolitanm�i!�w��y"n a.�^� A� � � � AmericbNorth Af  Chin��Middle� �`��.4��� f�CE�)"���%B��.�m �!��+K`. Hig�`(a��cR7�5�'i �:L�]�Y~ #n Ed�:a>�& sh-$O� . 1%–74�,%C goa�)220 cattl?�538� buffalo�[�9 7 :!�c�i�2� 75[?.^[�B�L5%>45 ��Npor��#�E :&-iA�e58�d%hofI y�vie."i��3ƭ_A �-�g�5qe��� �#�R6ua}�1!A�B� at� !J 18-3� �"�A&��i],q([��R�$�jW�He�| O�0f$( WHO ��2ed�% subgroup!.">�NegR�T6eD�!�NTD�)���Ž ts� � 015E�teg� lann�q"dof L.�_�"5 s=�&�PT�`I �6� b�amW& nymea��w_�11�%� X6.  vei��e�eat�n&�!� � 7tfamil�g,U!� �/��")�z `MOB ?�!D 4RUruguam �_ Waleb`�_Jordan�_, Tuni6�&rke8HaSpF�[�_, Peru �]A�faN�!�!� Tibe��Sea:[n[.1%uV8��5�R}i�%�"v ld��� disa��adj^|~�fe�( DALY )�X"�~CE���x�cd�\*�p�fhi����o blemayţ �UM�a;AwB�f�"�By#��avY%��ioտY0� �!N= Khuz>d�Khoras�Ard!K%.El[2Ef[2��H"��z5aZrcoMQh�h� !i\z"hjl�a�CN����-�!�G.�Zu !�essUM {j� z|`$a��&�h�cq�-%�At�'iod�z�')l�rre<�'Qk�cly%�h_Wi�� s [2�}[2"!�|8� 7yR!I ��p�Q�VDL4<o0Zva ͮ--Ll� )�!�an^h!�. P&t Be�Ta��[%��"p.�[!i 2006���IR%�7� 8-�!��MK�H [l�.3�a l�tu*#�if&6CE3o�� ��!� nd g# r0atwRMU b��%�in 34��ra.d[�/-�-i's �$ryt��5!45�V7��)�col��2������&�� U,  993!+ew%�v$ed��+ 10-y�ȑo �bey �23�,)�I �.�m 09u��H�&�l[3��[3�D3���- ~R��f w� no yY�)9�n3�9�6sߋ:�Q�u�Sa�twB��*�&���1{Yzn��g-ea���!KAlenrec�m�re-��%�regar� as[Q!�%�� . A&� ly 8�&CE )�.�f ��o&7% a�b%�0%25r��e�m���� �of��� t4/��d�Oy�e�o�2s� seek ~��L}�.�� �){rѐo�;�9�u�og�d�2g.�17M�:?l���@�i� �(� 2� 2W %E�P�P�0,( . Le�h1�A�9#h�rta����mAzq� "�o*�.j.�b&?R��#!("t�D �1 !vx,c,V!�Aad/. D�4�B���hanY)�% [me'ɣ �6�" J�1�!�O�nd�per� a&��) ��-oat�:��ly!�$8)�8 . 5% �K!f�p ly )ref��%aprE�aj=���batYe�o�Wڶ!Fh�\28, Em�& !� ^e68MN!�tw38����A�,M\|���25 offsp�(per ewe/doe �I. Milk?oolI��ide/skD0I�M-�U��.�NCe ��( SCI ) ���Un��N� 's F�xAgr�F�%O6EFAEFAOSTAT��E:a�� L"���%|6�1:- Ɂ� y�ũ!d}��Nt:��< � earc̡n�};QIN��y����wbe�MU-5��!�� A�as"��q� . PrAUek�6�3�JmO!�(��"���ee�Y!�ais� AVta-"w#5p"��*R�t�P�/ soft�t , ��. a�e�M( META"�P69AoA� 6-1;( ,Guido Schwar$c)6B--*IJ 9���KsA�� �42!oƋ 8- �=*�Tj�r� mr]wI>wo5r�;E!�  m%4���` Ŝ�q� V"N�� a:M] "�A "�. D~ \!��a�:� �e�Da!� n��#mag��, c$l&vAchistoG#logy tM ng!�nd dru��a6xY N��E Punc�A Aspi�nInjxon Re-a( PAI,U tech�XGՔwid�'%�8$�p.p"s�Tl���%�.�r.)pa3d�} Ak!Z 3Id).�#�s ervi� !�6��htariff�ab�5�wuMine$y!��!KMc'al Edu��(S x �}�+�'�m��pl��.L.ba�!�!9�!�p&F�fur�V6�� ert �d�sY dM=I�*P !�9 �1c�6�3D0da E�� !Jfic'C �� {s<�!ev[��h 100%aiE� Z)�oC-�.��CE����/f���)�*q�.`n\g;�:� u r u-|*7Iv*S %%�"#A�4@ re>�}"all me�g���+whe��tA܅b���p% ]C:\���=���'hh��5! ��-�6� N�"�!��@����oYtI Y�HL��|�Q��*~Q�,.�5.�6.�Ci�of 185 !aaE�A*I=!��Fn 3�]39 *A�g&�+�- R$t�Aruh2%pp녆a�W*i�I@a�dev��a���!fB$rZ���*ca�ch�[1{u9�{��p!�f �� � 4ii�� ~��H364 dd� any���.` aUB!-��c$a�*4h.:^�8_F�death�^�)��K�{E�*�a��ar&� �� %�V�1A5%%sw7��"� D�recA� �*� Y�C&��;�y1 �W\a9����qw�{F�? s!`�%em�+!�o�;$m�carcaj�n�!�K "u!|Af�q&t�o.! ` �umarke$2 ax� 1Q�cUM2��r� g/or j/?C"v�>L� i�b� n!%Q� !j:Omel1<,1��� ��9" AjhD�� "0c D�%!�AtraiH�Llua�&'�uEL-G-�de�� 1�w�J>o�!�Fm'*.,:<Zh"MB-8*[m�AU� ��V�cof%/s�0p&�-� .� e/ �}%Q�eU g2 �X��H ����A��.�CEv[�,2Ft)� :�%�N5%5T�Fr15dq�To%�%y~d�6M.E2�fecWtL�x1�b9�2�ar�,2>o:"%M����'�Farmers'�es��E�a��xemCM�7ey��Q" pt o'8�@c�*v � � or� & i�eg!G��5il� Exce\��4�%)��/�* Redm�, W�e.e�risT(�4!Os&�0> @RISK�����, .�tha�'Y 3C&}Q�� �!LE�."�!>s:r8tV1�&9b� �o!���x}�>�-�!c��|! :�J�inV�B(%T�UhD��&�a���7�S.Y Ug�) each��,�di��15� �i�#(A1c�1�v�3CI�%I]&m!�mo6kt�*F3= a L�� Hy)uz%i���1!2�&V4)�"�to�@e.�.S3 ��-�4"�F& ��Z�]�ua~g��-�!gM�F��s0�YA� �u h��aR6%/>4�c� et �A�tef�run exq{�:�"�&�3/�>a$c�x6eHa^�. Q�~,b*1 �A�a9 ���.d��&q Aia�a�h�>c�pulmon�,�(� �%��5US$I02�f9�42467�437�ia�US$85�?'52�(A17� :�. �И!W��J�"aB ipN�9N@9��43V4?e8_hp1* �458m� �;9�K_);9Z�9 ��A�a)�E��Űah>��52&w4�p ��5��54:la�2�4>hU�Ns��5p�5&45#6"UE/. 0V�58�6}7�4.�-v9 3.��,0 �?59�Fat.�fhB��1e�S4�M�=Dt�m4&��f�.&�mai�!w �&W+)�� �z���?'��&�w�"� !.1:�$YqE��������c� D k� ���at�2:�8Af 7&,H"�(-�)s�uP a�^Aqu��!�>9 B&5#�a� u�s�)g.�&���dra}�>�>nN��8. 0u�.j�8*H�9 RD~�}� $�&-Hm�j. V�4e�!91Iy� I2� . SgX]1�#69 ;!�4�!4>>�mV"� R�%B�2�~�� Y@@qy?��Ak iY�"r�oe(&�#�!ݑ� !:&� �-� n ?>f� �%  7� ���$�*an�&a��5Z.� j���� " 47u�>( ������>�s pVp2,$i��.�#Bu�<, � �VíA�1 �y"� &� sV �"Q 2�:Q\��&:�}���*u�"��0h��Py 9�j��&�!��eY�&�L �myE��l�T�6:�!>�&Q�('^1_ed �in)�.�%�lnot opa[lm� both��^%\con!�edR0rural/nomadic=�aN�[theless�ca�D re increaaaly reporO�K(urban regioE$The number�CE F,} and 6aU�shown���2��j!K �ed re!�[/campA�ai��of1)]��� migIׅ people.M�B/peri- � bɫy dur�l��@three decades [31��[39�5E�8same phenomenonņ�Bdocumen!�in other b�,!ludi$Serbia [40]Croat1�� Liby2t Like M NTDs6�Eadevelop2{(, it appear�$at-�be�% iza�N%~!�treat)@,probably und.�BbddiO ��r�I� inx e�5en� :�travelə�!ra�A>��,�+żoneB %an)�X �Qappropr;1� ,T wellex �/ anE| mpan�Nspoa-�V��me �U�=QD!�neeͽorder�(de better e��śM tr�mpact(%UM� �i;/ %�s%�y@in�ed ��. A��il�:of� ` epiA� a�U���is cru�{�� im�ng% accuracO!���. Lackq age-�Qtif!CE.Bd�pƁ�1�J��e<s !q�aH"Xabattoir�Jhtends!�be>�-b�f!�e�C �A>nim�!�slaughte���i ~sf eyoung%U�;ref��,, a low� ha� - ^ "��olAJ�. Amimpor issAD��unA�ctedlygA�)!�Ms�!�goa)j"'to!*.�Deach year ( 12 . 8��8 . 5B��0These figures��^N�s)\9Y*� alm�definit,an2��. Many� 2'��ͺi�]sub�R� pr&ce�09 ����A* unregu��F isɉ�Q.�Y�A�extA�� Qfas��  A;nel� &fu���stood%߁�Q�inBig: . Toa��te�{�+R��s�$d scenarioe�*���%�25I17��brsBQ� yIi: . As��A�eW��:���8�/�d~A��fɻ��tE�� P5E�6����!.!>>��total&�p2���i�����i sf  ( i . � $, a 7 . 7%��%US$236.54 . 9a�Regar��:!camel. �2>7%\ � $seems very e!c such��ng-��A��[a� e re�9 �� �  sourc�S�stźC "�U*����)�popa� meG quit�f �8 <�trai�al na� of C faNg�T![e\r�  illegw��3s acros��ea��n b:. FA�ng"Y pr.�c� %nmpor  s*a]b�� . Re� ( Y�!�siɍ!0through imple3 �-� controlAF gram%Jne� to ri� e�2�m*11�st-benefZ nalyZof-� Rvow possi in ligh%m1: knowledges5m a:� !W51�R ���"� a�s}� ����o�statu!�i!� /, ao-�EX9Ap��2`i�})� � �e� *in�ge!�phe^�&I2�eiU j�� �|measurEH!�!20 per DALY ave�by81��aig�r�.f"] a paK�ng/=�d%��!cur!�l�prepa�nYiE��first y to`e9�MAL NOZLa&P a�arz�)�w %�>�t 4n%�� uni�@� e�a� [�$50] .�M� (polyomaviruW MPyV ) ly�l%(+m. cell/ transtsJ in ��,%�is� ly onc�%rodent�We! �d\sequenc!� to follow ���of �NIH3T6 ~at��tim!%f� 7!5�^�,!�vi�� ular �cri!Align%E� �reap Ime�u !��!0Sio�M profl�m early-to-M  switch�?� Pn�Dd ' RNAsP fb�kt B! poi)pA*� no�ins�7a%to- gen� ress�emerg��8 �8 %�h�mon���widesp!)� e�Ong)y�pts!����=� . Byb, 359 �s�s{� 2�up*� nd 857 2dow*� . G!ontaQ�٭��d2�invol�� !�c ,a� abolism ,%pro�0!, DNA"hy0�proteJur!�r �.�w�jEX!1�extraU� adhe%�0, cytoskeleto� zinc fi��,ng , SH3 domi�GTP�# v)�E>1�lev� 0]m��coE+RA�C. al��J, MALAT�*�� spli�2� kla��^mar m&Ad-stage�cer��� notice6��l }Mabund"n��:�stron�.�.��discu s !.�wQ �խ�n a ag�� life cyclits� s�eA growthEWmeU�. Ei{ circ�doubl!#ran��A�� w�#a.z� *��to�tinct��z!u pha�of2�D#؅� ' vex��es��q��!bide�|9�o�< ( Fig 1A ) , bu���l.^pre��!mh )�8A�1mE� Large�t%ib)�tum6"0ntigens [1–\���!� a�du�s� S-@en� !Z)JutilizesI�or)��!� replk ��[1- Ar�412–16 hours >_��r>beg[,%�1C%=- rapi�)!7�napli!Eto��9L �H% psid!�9 s VP�0VP2 Z$VP3 [6 , 11 e)�T -vA�.�2I&ro�^� |c! �&h.̡Ue����way�promote!�u&}on [1 bloc�$o� feroL��respon8 �"uitv>�1�k)�origiu5!#%(�����'heA�or 7>\,��moda>e�VyA �E�Ei�ofb�su c to immA� prim# ,rat embryoni�� broby" s [2E�5�f� %��$�G prog�by �toIW�h��tin ^ oma (� e�sup��a^, pRB107M�p130 [�'22]��� CREBxQ/( CBP� p300ɐch��!ce ĭ�,)e� �iZ, � [2�!�'. All�eey s she� n N-h inal DnaJ&��!&E� heat�$ck�Hsc70Ei����AM funcI�(E�y�exhib0 {dep�ntW�An!�RB [26�e�k]��2� 1q��&�Y�E�9] *� .O+T�$no cataS 1A�^raraw)e`scaffol�)_1#s l�$nstitu�a�vA�Hceptor tyrosine kina��*c 8 al ��:an���,s Shc , PI3KM6 PLCγ [27%KɱT�86!8a hydrophobic CY-�R%I ancha it�a>!2jran� �is:q 11 [2�#BD(=�d�<� a1fAsAE3C �nAZof PP2Aa� mimi�hB$ [2X+3�?O�z Xo Cite t�*�UO6��) Src�:5�r!�Ye� �EFyn [333!�''�s�� phosphorI edM x25�43��V(322 [34–3��)�al�t� ��he^IRarUH:�[38–4%=e���l1�����ily!�!AX �atA� 2A ()s��'5�,aBs 'by=��9�!9iKB .6��5l7��<α%[AβQ<���sr,; 5E��a� �[E��(. S#�+�en O*o�_))IN!�degrad� -����;�0in�sor p27��a �)mannerՁ�� orts"u ��{[4&c 9��/mut��E�5�e� does� loc���65(� thusax acv.\ �s ))��!�MAP �$�* vi ��).(";� �EAp53olZA�- ��!Q�!�� Os�*5�resEapoptoini-%dW�EI\�� "]%I*Altho��d# W to� � !� �AG2� AtA�s�a ���~ q�5)M�7�Q[� )"Q�challenjb�-ss%,�3,�g�%�*Xof�u ~U  , �*1�!$precise meS�re� be elucidE�,�de��O%R2�is>, -yV!��� )#D%*�)olyaden��!=e cy [� Q+..Fo J� , gi�mula ome-!qte-V ����F!�5vm �� �t�[4� F+� kpX�^a�( 57 nucleot(#�lea� exzto�*$#"> ��i��/ /�<��st�2#M6f)!�� bs �)�%4p,m6�I�ir 5’-{"LB ) [�v{! !s$�)*.��sQ%! UP�s2].)-3$RNA duplex�DryKeda\u s; ��w(enzyme AdenI Dea� s� at A� ond( ADAR1-A� e1AMAe�!_d N�c1i os [V45�;N/JN92a�  }"e�A_h!L�w 'ofJ|�&b�u@,!�l��~art y ds!gor% 1E��-Moverlapg�iQ�A��� s owA�toE�1> � HVe��Y��d{-iw1te[tdeA�ir ���-[�jIn&�&f8�$�|erize���>wz���zg�!�9�jof����!��%n &m�i ��m�C9 I %�1Gd-sU6fic4'n�&cU(��!2�"�A�,��!�uQ%�oC's>#�.!W>*=newf�r�}w�)ob� \0"�=[ appa�rE9a��9�6Pnd�*A��! 6!)����3f%��g�U5HA�!�T5.9���96��5|4b&)r��� M�� m�U9aaZ �3he2� � �i�� .V*�F8J&!El&�r2� zE VyE"� ]=,a *+6DmatrixA�nd%�>M�("omm�!2 fac] �(a$ lo!D��@J8s"&E2F ,, , AT � NFkB��J�"SWKA"TFIII9NL. ( NIH &m%bq/U-th�Ar� acil�0eZ0(by wild typ�:[5�C6 iserume�a�arwsynchros6 wn � ,�A� �c=a�(:� )���fi�Py59RAa�. at a "`3 `��( MOIN(f 50 plaque!m!�w�!� �?ti��*�5byB assaJ#A�rously� z by D�)R�arceaE�� �5 � maxim�%� �)5ur syste1 as�"4 i'; ofluoresc� !�59T� geDS1G�An�9a2� beyo%�is� did� ��m<, �"� �)[(��!har�)�1c 8 , 24m�36-�p M�� n��+�;�*AGt !Ay i�e�A�*"!libra�9usA��IllM? TruSeq Sa�=T�Sa{& P*�#Kit!�)��� e m��%(�? work!�lab��8����2���- betwg12%"�:S� e�T�,ese2!�� b.v�tA�!1ь!�,� t &��+� 8!��=� �3S9�,�$�"n` iv�nd !�el>#�0 I�iA9�~260 => pair�V ( S2u � U%�M)eA!UHiA200�Ft� MEgedh �#of*?�Hforwarn r�se "�S&�#{*A�a�#� TopH!�na�6�;A��B c[?c�A) fragms�� kilo����?+mX<d� PKM ) �Cufflink�&�""� cM����>�!achIReB)��si�sM . E1� ha�0VM uAa�10–50��@%$s�lcl|7to�5%~:�� W �Q  1%B(I� )by&~ :�(��T���.� visun*+ X9�Jc )E"� .�we�0Bowti Top AR�Ajq�)�x` ce� ( S3uOAt����F� NMO� 5��%J�8��j���k1re�8ng 4��!�G&=6)*�Jael�C�7e JA�<Y N){>7l\:als�2^}iZ9)a�2��""�EhE9�u Q5�t?-�! !2� �2i<[.8By 18Z� �.]@ e���Y\7B6!�%��.A;i�d!��n� ro�tea�-mi*�I7E�]�;`��E>��6A.b�!7d-�i�){ B9+s��ig�a�A!�of �G����4�arC5�:g0*..`���d&y e �FNt�2��-�Z�Hat"�.f[40!J@qeH�3.g-��ed �R '!@�' plasj[5� 5�:)n%-Aar%�M?e� �uru ��[55���By$ �Ob�AT&�@�5�����Q7Xa!$�EU.N%�%���We)�%�at _!�� majo�>of1A.)edm* ��@"��s�5F� �"�h"�A�Hve�� �Q�!� s� dra<c>$y�� no�no$� ?�pa:^E� E am,�� ob)�@� )S'b8&�7Y�.� �Z5��B�q2�.�m(lAP%��- �bul�9>d�=� �C�a]elev d�LA2Ka 8ly�  � �� just�s�<!�u2H-=�@fLS eak � a��>N!�`2@x%� aphidico4E3��Ix ��xG�,N�.� I'���� R ame aaia d&ex�!�y R!%Qe�C� H<� �2 μg/m�heB&�.�oA =hl*onJ^�[ 1f� A3��!�23e�aDAO ncub�4D$4�C2a?!�colm -�g� !�r y sy�u"�%)d ocolNsMTJ �&�&2\">g1. t� k!6�1r� a��4��N�F�*�+�5EPon�A���� 4ů�J; 2�!dE�w? U$lyO"2��(����� ���!- F�A�e�2���J2 H aQ>* /�(�Mcf-:�+.�T %����*� v-)6��Bh m051� � linea�}fer� 5shifA��A�-150 bpE�)�@� p1w !d&b8��molecu��.ch sp�H��p�)� �� �aq��7e� �� ���!�y�!�A}2��' iof% a�en�>��,a�/sugqR!J a po��Oup��%4�2xYjion� r�B�j�.a�3�nsgi�r=;���@2� even:� V���M�Bb�*��� 䁫����� ig 3ɾS-; +�a!Ei"F/^:2a�+(al TATA box�%_�Qw �g . I9 3HCSE�5�^�2 Ds�-�"QSlyA�bIcon�AZs&�by�� s�4er�c$�5� Ma�5hybridizmf � ��yt"b %-�,�>�e��( d��d��ai�'bZ0a$A�D~XE.? .�usa�:f9�sty[= .�!]irmAE��A� u== �/2'>!we�|ed%M-RACEG7�ٕ ( S4��ely�R a�r�s���0 �U� `%�map!{�a�% �192 �R\�3\N���a broa��� .P.2�!��E��/rF��#�;p�/*�#�%�*ot un� e9�,�2�5>� �%"�?h  SV40 [60QJC�us [6�Im�'z, Fen 6�Basilic�="� 6*"�mMb�i.�7i &�I�6le�C>���[i�U� �toK%�O e j].��w����4 P4"�*��&#!�5!-� soa � a&p,:t�`Tj#�12 �:�\�%�c("� s 75OC20E w�5 !�*S(&-gK�b$20�C5B�ED O> )�a*rth k ,H“tiny "�+” e� � �.20 [62]�6�Ab�#�%k�%�,� �(i�s� tvlB<5��7c��j �io%�)s,1=��*T"�)bN  littl&+9ca%YE�%�ua�!ti�/ly!V���1d( byMYorb � eiw Eaha�(B�.�, u �e5I�{"g$Kz�Yo$*absolut,W%2"+ l �u��&�,B�A9&�C �9 }~�8-�$%Q�qj{ "� �es� �ea�6ad ("�59a,u]24I$t 1�Pm 1%O�%nIc�9(repea��*]&d�:YJ"�3�W1��7*� <sY requi�tn2p�?��EJ9 n�&U)'er-t>}))e�: TR)���6Xg@� e 2x"��? <� h�is*s <srQ�aJ� �c ��`����tf st 1\^!��A �j��1"� �"�  .�onRh8za!��N�7f? ��`R�*i 42�sr�%e�|Nw� fbA�r �)+ H!�)E�-nex� 4Q9botto� 9columne%We�mf� ]�72r%G i%Ee>_!�L�.�.=}(ambigu9B Y>iiC� n��G�dUn2F9:N� 4=BJ=R"Qy�=�!�Ba2�z�!.R# UTR!s.5;or4;F�tbb �fifth �s%�L%BBmar�G! ��58*�y ��i\�B!�A�an*Ino>J$s*a .�,�2!��mo��:-�9�%�)"$ > ��*�?��[�0�RT-PCR+ uS5E�Du"�-Ac-�1"M ��}�>� ,>cge�I(y,�'Q.��!}�P*+6ZIi4/%+if� )o;Y�"e�t�`�/!�o_cleus f�5�IL N-.(As�rm-�3�-n CAo�%�*���.�.g�.dr. a^q.2�U�-s��[ �:A�s f9.��m "h  io�%+� inde�P�)5�^t�AmHkuyex~/e ���A�in%&2 rehen�/detai_M�qd!�!�w�Oy!ZSs/�L�" # m�5as gua�/��VlooU  �b0 A-G mismatch��A�.8 �1�H?&�.!k�Y-Fb<2Z�b)!25-&W#A�5Z� '!��i �"�  step [6�AYf!)!���y E=��mocVe�-Ere#C�H 1I� 1!/�Z�� :h ( S6�ZHh ^bG.E(�.N�J"V! mereCc�X ���BZerr�;�.E�@� or�jI#�LpplV�0�Iy���a� �3e,z]Yo� l^rob',#b&m�WW%  Lm>81@w!>Cg >ut�ed.r;*!��W aV�&�strik!. q�*2�h!�7a�A��p7>� G!G/-�+ch�>er�d \QЅa�5scombiJ 15:;�'�A/surpri��^�Z��"��ns67di��( �:��J�W2A ��! subjec9hyper-O!"! Di�53\����_N";�4?���_R e�HboR!�.mis m!qor)�� �;3�F("�e(&83c�  aIzer��"�7�6� �4�zE omit!�Nav!to ny2 ev n fj'De�fe�(4Lby Po�$ e>L [6�dP^ut�?IBn  pipe)a�� �$��ed* whee�they f��^�P�a�I5!/�M�O ��B.?�Z3��kM�a;clucSFbl9_!1� � ���.he�~$o���F���&R62�6S�T�S�ɲ�remAe�3�Q���m�RSZ,2���:� ON6cjJa+^Q�*%mper��r� few.O!ir�B ����Z� h �! o �: to G�\2�"/'K� ���8 lows �AaŽ ����P�*Aq6�F� �]6�#I$��kpredie�I|KA-Iu�&X5 adjaaF=�! �� fAZaZ >/ .a�kep�.F|E8h� -0"�^:�r�, spla�b�3he UCSC�X�browser� �XRX ��eס�*�.�PY�!5 �� �ee�2)f�� ��Econ!>k as�c.aV&soL9R!8 . N6t%|a$���FZfp&�#!k�e1g������!W>�q ��" ��}��  C Shora~P�� �$s�Q1�"we!�c�ly�� > Aa crypt3mly�; )%�g 4,�*���stop cod�#���E9�2)E(!Z�5��[j��SIE'Je%s+: tBQk�N�wb #"sB��)l��)Ua�)Y�td:"&�Aa*A���; "M ZD#e�m�3��E.~� ed hairp��A��� n ci�Ey3ngLp?�{n6ͥbr}E�'*�*tn�?T*!�Sr�<p��Qnn� ngi�K��*�! ���D�]&�AF�>6xnd_ M��;"a�)�AZK��a ���1 e 6p? �T�6� ^�,*h$2mat=l7�ad�9�ga�"�!�&!�= �� ludeI��#�F�{ �!U 4Ukof&j6�. OurB'W["�8�E� .P*f� y�,�Eh� MhJ�%EWit�L.�"J2q�b!��!"lM�2�;!c*�2��%e3"�m216J� ��f|t� ���&. 5#d<&rr�NY&��9Ʉ�&W��,4 'B}.."n� j enrich.~ c8<*\4$J1' }+C"i7 jo�fm�ce��a�Honaq!�� �!CQ�%�!>�+) !��;at1� valFAy�q� ( S7DS8� F�MR&>�߁; tegoPE,�Nest-%v��Z6�$)�riboso�:"I,  <`n"y=>�Z|>$mitochondr�'@� % �8aL>$ �@ �فQ�P!h*?:>C�a�� !�N�|)�.%W���E)I��%Hist1h1a��coyt!)K hist��1 lin!X&TXe�c��!#�+�&!� [65]�. t�2�h"�"UE�$8T� 6� %J>��6ziKg ;O-� Timm8a1{t�.k@Einser�:' AE+rp[66��#.�.&�hn&�0���K�"� !�:1� JunB%wonl.of AP-1=!ufB@�_6�i � <Zg �%-u2dst:g>/$v%\U agon~K���-- c-Ju�gf�.9�aM�G&OT[6�26�PLa�=�Ou�MteLE��7v`� oA�xe6A i�6o/aQ/�[6 )Do.�\i7� �zt �}� as�[���, i* Be U)*Q\j5B9�P[ . On�A!eC,"Yy2�BA�� Col1a2qLM+)�y�a�-��pepzJ!RElE67 mB0q`�R�[7� �k��%� ef,royl-CoA desXf��Scd2 )�i�c�.�6N%%� 3T3 fi.YykV�v-�T[7PW� ata�^.� c.�ex����2 "�H���1R 9� �� * :� � �K4:~(FB� !>S4**�&=�%<A�Snhg1%N� lyrAn�g*� .2!7�� F�(so �5S ��eU2� M6!xoca5+tro��d "�%aM�1s%�A8S* �[7�9�N� �&�A�6X��lY�c e� ���!�68��O"�&%9z� , MetastaLA&�iLSq�N�m3Da� 1anb�_��]/B<F� -��2�oc!�- Rqn![ i� till��,�R%.2D^� �iic�4��8�WI5��%JF��:&of�%�2{6Lin%�>�T. T܂t>�i�� s*�f�h�*kEi"�;�@5�� -to-� ��oA � D$!�>VJ�_�b,%:"IeAt� � . Do~��\e"$+�4" ����hel- �2�I[UW4�� ��?2�1&8 qe$"}K� "� �.n(zUaBATaf�XoFph�r.�H -bio�etB���amIvz�[7� �/at!sh�\�O7"ng��fA�/L!5�� <`,I�( sF3U837 ����/)E,�_lFs �<`|0�|�"� .{O�Br�.�r!*�$ot�+�3rIned �� ("� ��1)I�O.(AvMIM� �� L?e�� w�)re,��a��=�Mq-�of*/T�<e_8 B ) ��r �J�` -ATF�\�A�: �_5-�.cA se!^�r�PI\.JaEPKa�wt�t� rB�?x;A�inX�H�59� J9D/��YeYar1� kappa B (�Nž�!�I*Xb y .Tinflam��K%N_�� ,�=<\�agi��d�P�vfs:lu�!�R�[8E I��@lщSTn�iigB� a��dR^�j�o�,�,Q�At��.�V��Jo"}\ vA�be)�� �AM�kD��� !uBi� �1!��a��ynyB�s͹+&1'"�Kby�i�.�est . doW eC�=#a g�Jl view!�*� AS����#��� �� E}e�o1o^ ��'H#uh��6�!J��a�.ail.:ic�0�owpal)� ��ZSBh?A��.�/o�+rn P9}$u i��.f#�4p� �.h��v��*��*�4? �8"� �Z{ :6;:�*"�EB*J*A 1�'�A�ic �xY�‚. ^rL���l�%G+!� eV5�A6~  Y �3!Rrr>} ��U5er�55l �2/,�-�.kpHd�!:N'��d %�� a2�=z!5 w�(a .�is"De a*L !!.Y`Q��,�F� or&�B.�I � �,�>cI�L�"t$Ia7fi'�� � �7+ �2 X;!�):U ��!,�aAp"�k"�i��P+I V�sa �f7�Ho�b*.K,'! D&��+�|�N�"<>�1�g/Y��Da��ik��5=toCP�AR �C,ArFJQe% E*Q�I�%2(!ZQ� \�!� ha# L[t*sm���Wo!�z�� ( �O%a �"��&�Gas �mZ9�ec�n�mmLXxA A\����Gb#):�o�tz!Fl2�=!�A~1.�e%q2+%lJ�>�=>�I "A }1�D&�r ��!>�B��&yet� whn'����!n��� �=��# � ingseq>-an�i�+�=%�6 eter� �49c�!�)Ec q=u2��S1aK�a�&R@�B��s�uo�'V>!*M>ihR>: 1IvO�#�3F��##%�Ia�it �.we�s�Y��9�� 2#,�� S"KH|�2�!��"-��P �KY -�&� A�AYs'%y.��MU� Y�6�r��r�ѱ`P.$[8$S�1=[ڈaX-!��"r5m�T��I�5R~<zb!�2�l��W.�M)�>Y��r& .��'��%�h�B%0]/>�!���onMK ��~. Fur�Q���&o{&�!�rGar* f)�[L&��&����!Y�� �!��j��nJ�����Ved"d5N�x+a�!��,1��/ hund�*e�13sJ%�._(T��aa�%s �pr� C�%4,"�%�"!u*�%oj8� w�F%�2E�4/.�A3� ��d�U�.� �D"XA{ )Q!ޅ�-eB�1cro� ( sU2 Ņ�� � l�DU|I�-�m It�&oB�Oich��hypO)R� avoi9k cytotoxic�og� �[8 �/Up-&�_AM"]&m�m����n�r�,�3�|t�foop u� ��ejN� I�)�*9a)\!0mi!Tprter�b����2��sIZ.��U.xun� ^ /:�lE�q����(�%�A�%,4E�J &� !Wabso(� v� e&;is�Opp"1�jr%���ify��"�d � Y� I2�EwYo( rule�i i&�99O �,.V.P� rti��* biaj\&j!n� %s)�6buO@. C:;b Y�! w.@ !�nmem)u��_M3E}6<� 8��&J���M�e�)�G" � E�soM�IV7u!s15% A’a�d 40% T. "�^9�mad�'!5 dUTPa orp�3�E. I>u;Y�! ��J;(!dqg���)D 200 d�D~ ) in",hl�` ��<��0��y(!e)edness.G�miA��7/otQ!�E�t�bAqQ}b8hppeE�atw0e�ab"3�*t�5b�Ex 8���in qu���'9&ea�a er FT(�)�>��/.a�^�$�{�W � xac!^;sam>^F $F��h}qFss�&&v�V�3A]8 0G-$3��a\�J ��yr>�ᥨse| J%;-!��b2��u� �(y� "�� e��x{ir.�A=�9� b �pweHW �E�+ern�")<k2��J��qA3��r�q ��a,>~!��/%�Pa/�s *�2"m)��r,�!�a 6� �T`R�lEuz>XaUu"�#KW�-�[46Z�P��gs!= E7a��  MT�Ne&A� &FBA VP��%�AC2�!��Ae p3-2XoE� ��VG 7`fiy�on V �r�<�2CAE�&p4-����+NAe�mer1II -�<�!�{ ��0a*�q0A�� "(��t<Of� s?6C DM!���{rds z9�INop�Ayak93��~(632��< o� u�w &�� e� n�d 3gr�d� �rfeE��! >ma��er�� *7bq6o�8toFS Fvݪ.&�(.)�Bf �5e5 � Y2J�3#�! h� doure�sBocl�fin� %� Ls" _�� A0:�9� ��� F\�KA���F�Ax�Jb1U�>�2�a�u�� d�, A�2]=�*�"&)=�> �ŕ�?6�(!A�.n3&3]m�&� &�^@ D�8uE��lap,!`.��� �)C�e ; "�@we&���u4"A*�8�*�A=!��(Z8%�Q we(bH&8�v`8i ),be ���t�TisQF d]C"o:"�ai9��g��9-B�\q&�9� @la �3B�ʚs oȦe?�re� 5kuntil ���P(�X���K����������BE>os.>��Kcydco"�ntI(�R-E��->JA��+in9;2�� ��  "A�)�gwe 5ple����efO\� �2v�ICT !� r�+�6�"?'�!��#�hew "� �"�6J w-ampw^b*Lk�,l�he:-��"� U]�-S��U �.`eWe su�)���FE� %.49�� ght yield�!c�e!�m53t�5*�#�_t)G�9s���72�!��i��O` \!N��a��� -+&�e S�WbeI)� �Fs��"@<�?as6EH%I��Lth� *�8:#"*�&�:�&�9.]'�&mw6(N &�w�-�)�.J�N�O�g �$; a�W"��, r�8.gr�WR�8� % Fx5��>�!��'��"` K �":�pr.S'�$u�a���6 )%H g(lt�c#Z,����.-�"2,�#r&ԑ2�w+!�a��c `��n��l�6"�a!t����eہ��F3A�publis�;�e Wy sb&�r�9u�bg&R)Zd"�%&8%hŎE#ԕ3�L.�RQarray�%/0[85;/T�����q�2�3 I�s�7rY� 2tC(&�W�� ] d ) �&to���Z�[��+~2jmr3/� gv�n�> .�+�:�m�3d{\���Ci��>5. $�2��y`?�zZ� --�9�m"I�4lf them� aD same�IX"^9�rno�#�emr.&f"��=��ng6'2adTET �lnc�{8 &E����is Malat326�@ Q$�6>k�1Am� .!cplA� �!�$iya�[/5"8 is Terc (9 %�3��*f3 telo�O ma�n"a�07�(�Y[8�5)H,B>�!0e Pe8i�*�*.�WF�!Ձo�A�Z�hI&s��L�)%\R�8]i�t!3!T��al.U4=F�e�T. �E�&�4i9*�[85H�%���(����*� "++ *A �0Rs�6�z��ha�� sn7d oq� �a��e Q�H�Iv9%<.��fi��m�T,2)��B2eTO�d !��6� � �n"0�"� �#� R� A���A�� �<�m9 2�E�E%�7J"�O.x�K!���!P�WJ&E��* ��K �=P!�Q@�=FF�i -2�+�iRQ&L! .�gen�v"#�a��+��J�4EM��"`&ӥ�i�T� �6aE 5�9��!6H ,ELrcy&#gf�(3�f A��!plu min,�4 �� �c� �!e6-%f�� g s . eme*B�:9c��! 10 cm����N densU 600K!gs/p�a 8Gibco Dulbecco��Modifb,Eagle Medium�- 1995–06%M7B�o100o�{k�llin/�&9�yci!5(2mM L-Gluta� -G5% cal���.f� in 22, 1 da��_��>%Vy& �� �6��!��xain�p�A�^RSobert V �-)at 180"�yb�mlJl hW�, X;er�5rQ4i��%�|�e7 �x:�9u�4� M# .�u�. dilu!�to 15�PFU/ml)L%:�a�Dj01)2Ɖ���(EY2� H��Q �q���<ng:K{ tYN4Fw8�q2%T.�-� Mock ���%G carrA��*�) Bum f�Xe0W�O ��O�{� �f)��׍mO�g �,A|h!şPBSm"-(4M �Z idin� isothiocy�)!���Saph"�sK(��,-�% %�dA�7� �39��r� )�f �:A�!�>�r. A� -v�[{.q hL"!2�s.�.� !5! A~Xces!MQ ifug��5Q�Ź7M-hŹe! 39000 rp� 20°C�"�PA�!"z8=# 1&�Amb!� I��1wta8� �k���� �:q#&|M5� True�"K#TU�k3 Q">�. RCalxde^jn�r�F6bO)�!��C\!��N�n��3 om h� � pb�Zn.dBH�]ixa mix��=�Super� ]AA}Ho�GD��%z�!��=-2d"�|�� s'. YV~�dU�$stead!� dTTP�>t�D!���hb�ei$g!@�e�'�ada���%A%A�"�r.�&nd flowE>1�&�rl���)� �'!��!��1�m��a�12�8i�1a:�Agi��Techn��&2C% Tape�?on%�E��serifyU��)aq4�bp%��]�U)�).���Y$erkin Elme�AXf�W2- �� IdTopHv ���<Ę�� 1 . �/!WSamtools1խ"xm� %`]�!LBH!?7�A_F��2�,%�.��.��ar� .�J"�.E�fon@S� ,j���!�h>)��'"�$!�Rb��� �E��j�$G�:"b��a5s�V+��`- uwo>���sr/ 5�a�.r$%�!�� 7U�IQF�.qL IGENOMES.�$"�n turitnB@ USCS5Gh�} 2013P ustom �M�qR posthQ� outp���,���&ҏbedGraph�tit�T!���N*Y'!*��23� �1:4a c.�kro�r!Q-k zero�iE�c>�erc��!y 149}{o  .WtE�!�I��1.� �e��*C x“ ��oB�)�CE�a ���@�d�Lt� . A:�!� 1���r!.fw ����,3@oo��� �8F3 �7�>>� Y=di�[R���o&*�m�� .�I�W ���P��IIM"���Nc�,"qdo��a %-�1���eˉU�ee�.9��9�Qe �D2.$]AL��<��ed �Jj.�!657@\)(* %�!fQ >fBpl��1�A��s6Bl &�&.�aPlN�.'CV�y�iP*[ >�8E.�!l!s+rNU�� .�n�lan�gby27g .pon"�1��z�#E-d�Z��Df� !�@pR��t��]A�!L� 9���A�a� 2|"e�". � 2tv_lplK�h��stq �@�er 25n�4���0"���'igu��m�!K!9�eXT��A��F+ <�z�h['J�36�^ ��|����}ppre�9 ��%��EJ� � 1a fk�"cab|�"k����v )�!� 2ed.gd%�loaV �ru�LE#���R�R`&�#. n4e�� �a�:���summa�� plot�yk�!AFV& r8�*�(� ��S�.� Mock�PyV� *��"�8Q�"V[� � DisI��epoo2!N�er22� %�Q)�uh**S O �1 gi7"� z�A� � /io�-���� !3-seX4� �&�8g FdJ��M+X 0%N�]5e a k-me��MWA�!i&r !�.����$g2�#�!?+/-| 75!'��ne+a%��\ �g n fpkm�#�por (�=���*��>�f-W8A �.4'8Ee�,��A�*d� d��FD\( DatabK�A�6x, V؂A0>g�EdA��K��\��. jsp �k��� E"_�nd�F�vu��d%'D � �Vag�50t a Mus muscu�backgro�WI%a�@.�[ZILbe\31E-03=�%��T*�L�'�0�!]-��&`��US@&�]�J N����=]% ��=T��1ZeT� “8�?…e6BىTSSe 000n�=�(p�"s..M) � A`A� se�n3]y�zQ2��j^':“ns�qeGi af[���akeB-��5��TRANSFAC!O&�ƀ��n�8�E^ U)�e�a[%j� � +s-|h, �isٺ&1:de@A�8t GEO ( GSE6931qN�O www �_bilmi&�_(geo/query/a�_cgi ?�'=K =��y�h@"s� ��-!\2d>e�thous�ofaen� �k�uܤq>my�h�7O(eY$w��mp'�$�/%-1E��f26�� nd 385 ya�1(� . 195y�m!C�=`Gv� two-f�v�V�Vo /$ES'ko1nce-lf��Ca��hysQ�abo �Z �����# *7@O+p ‘h�!bwall’�"�9J drop� rAd�7A�sh�^"Ja�A�4�2 ;1]� �AA���? enduh@�yIzo��e�=E�coas*k� ~�% h�� gly��9Q*G�{]elQ(~[�Z$i��:v��#o��_r� ݛ�T T�;)}����leSIYh�S� J� . !��q�B��߻,&y.�� !� ,get�Uί���n=�rui=!02 subx�A�� %5�ic"�� "]�w��l=sseC ribu!��/iv�Pus%58���Qsp0( exer,WX y�c�0 er�_3��).X �8�avs!Ck��.s.t��quEBf����ablF;�L3#!cE�ac��#C&isI�to <��%&�]�/&�w�Wexhau��85'st� �uײ�!/9N1�~�ifqs��h�'basixor guid]qs�I!�saf���o]�iz��~y��,tby՝ !o5��?O�pa�4c���r�Emid��fu�g�A��‘���J/%��a!M*s.�1Npr��p� l�-ZZA��nd���\�>�~�u"�0�H7q�. mpir&&�A:e�q�f�� ��Bo+d�Y�n . Rem�(<wit�>ed&DN$a�H&E%H�eG�gip�?�jor:��/YP 2(#$orld-class��&)�U,�$, New York@���g�@ Lond�?!�Berli�A�ienroll!����{���Ran�t�agnitkiIIu�j^�ey.9!�,p 1970"�te\&]&e��s���1a�� Arq�= X2010 b�o�6, Myth�$s 6��A�ǵ]j CR~ �sh�3beq���R6�d%tr�,sI rmac��TYed�l8te b� �g�re{�c7) dathletic!b6�AAi� eG��. E��!�$�Rely ta?�ca*���I, u;bfa�q8{3b"5��&= �e�G���a��y ��mov�� �[&�&���A:,�ise �a5����5��{.�"� fer#|b� or��bon�,w� enga��a咡�2 �&�\,"$G. 2�� dde�Ac" k+c�t�� =ail�8�r��/ e-�M� �y��DͶ!U�!����ia�C�Aue� �~ a�*!$� risk"� �Q U%�(�YAmaln� ,%�!�� ximum9� of 2s&� r| �O 7�e9to {2w) [���Cor*!�n�W,� y manag��*���7perhap!R*h5��!�*( uq�� t^E9@A� ing:aH�D2�X`,el�� �aI� !T�)��a�)�rtb4ar?�. wtKR,E�%N!�E{& ��G2��a���� brup�A$painfu�4���6!?l  ?":�&�*o�e8�de2�[%e[5�&d [��7]6�5,�d!P��3sp\��n�*�,fa[��{e�&#{m��[�x�+F|.!&ie�eor��al*�s [8]– �-�� f) �vw-I g t�"iG�u0<�L.��of.� elit�6s�!;�,�nas�!���r�focD� �Nj q�+��r5|r[*���p0 al2JAr� ! o~�q�>� (K`A Yb�̭7 ing;�(A7al},i-as%�rt�tph!tlac� kine�Í�_ J (! men�2adi�bl�lir�De�1w\�!E!�"t.x� �� E�� �ac�5b�U1a�L� �����)��-�x�v.("..�u� up���v��L� �3%dc� :�$B.K,sus���*� @e�Jw�B M��]��t>���fIt nofN��(ae�s��m�2��F�1� (>�@:er/� *# !��K�ec �R%-�r�0�y�)v?<rgaria. colleague��82�� /3up9K�J-onfirm �! Z6X�x9���^@%w!\)�oA�J����9W 2N�1x�b( �*Cq�%$[�up! �.[fT er$ H n7�?lu�b5߫xh�nergy �9�gL:��e� �p` �fIV�s)� :�}�sle�� ime ODv!U)J ��xl h7d . )2i&��/h��L<��^,�.TT�"��"�,S8=�_�a6A�m! I["� SO�(�/A�(�t:�n'TB�m!:e�8 e9�<�va 70-kg>� �b�k5�B�2950 k A�8*�a9=y}M ump�Yp�!a,��J��snet<�G!�\CAa2�!�w;Dp�;R�OuK��Methods ��fP AeX�Z�1}�� choi%Q:f�-|a }SGR�nSG�llh$ �)�� I�q`0*�:�)E�!U��#z b�\,2 9!=#!&s�["�of"q-5�� #6-u�=�0v.� , derio}f�*�]*��;ucE�0��_��a�� triacylerY.!K HfEf*�tl�$at�N,� ����. A��6+dox!y�s 3��a�E leane�t( � eno�o9|&NgM�q"�mbK�E, ^) u�!�if��A} A|! �;*&)x!�RYex���+�!P|KS B��!� ��;noln�? bodQ�t���agF� �b&l!_�� . VD ��mS {K �A�%!u!T��,!�o�S�ZB�. E%$2�%eRL%Z uV�� ���s�/a�Ine r�jZ�E s�&�|Ŕ�n%T'�am�-�2]m��M�gm3 . BuD&y3: �� �4a� Qr9� volum�V��ly 5 LA&ͥM�=�6��]r.BA� b � w�IL��<2�~�T �y�� .y�neglig{U2�~oi�y��[���B��fo�n�(�E(f. s�70 mmol 4sy�Vsido � kil��;A� С�\� toraZjb�e�Bn5���n�) a��'8;Z�6�88 ^72U�����D69 160 ��c>� 6'35~�6to&�\�,��S� s y9��%l��9  � lo�/ &n �:�})[�l���l���6y DN��Ѧ�� yocy:)!9�E��H��}f !M)q!�+���,-��du�`,,eV�$,�7�PUG�� oizl& 8F7%�L �����# ^Fce"�K)a�ɫ�i����at�),��Z�o�{%I,�k�enAƍ-6-��a��- c2�|f�7� �Q6"=|p�Rt"Jm�� _ n��mN!|��l+E/��a�ul�1�)B�y!�A��D-,G� @�.�!pt)�#��_��d!. O�� �=8a�R�x v+�� ���>�)M��.UIA�:�mche�o�����fRNv %EzǩeONby McArd{�.�2�fA"(H� &w�v����8udies�leg �edxthis wa�dic�$that while�Sof!@ined athletes typ ��!AM� at a dens!a, ,>Tapproximately 110 mmol)P,syl residuesA,8 kilogram ( ) , %a$��4protocols can q �x,to a maximumF�20��[23] . W9 Ve!h�reservoaGvailab!J(o an enduraArunnera�ends oi�.Orelevan2E$t is possi Test%Q%�amount� acce %Q�8: A lean , male�0, for example@y be 45% skeletalM by masA� with halflE/in AM]h;A 70 kgM�nQ< wouldBA310 gV.JA�I�� ,E�cEI|at most:g57Q(, corresponE>!�6�250R22�cal��.yHectivA�$. ConsiderA�Ato!4.�-ba��i�Ie fromJ�liver.o$and plasma��D, it becomes clear)��2��)s alon1ub�q$sufficient!��a-,rathon . Fur��m�� , on��QR-a���,!�which!�s)�ach!!i6�capac�&a�!Blevel��%�d2M.L�neA�arŬpower.�by:=%. Howe!h,qforego!�A) nven�lalloaTa_&a3.�pot3al��)�$oirs revea�!B�!/ic pare� oryAqM#managem!� in m1��4 . In addi�!� thes!�aYcM��0!�e a��im�؁W$dynamic onšmodel�e��s��Y; h5/���A�t%�who advi�C$hem sometiA�neglect�y%�Ex$metabolismL�Dequently miscalculɚA>4requir%$��The1=0rn_�!<��K�hrincip�0around two qu�Q ons:A" m�t2NdoA�%�i�r Y need!�race oA[a giv� ist��HowE� each=be sur,avoid exhausEl�Ror 2�Ices beA� co��3AS�? By  � A;!�quantiA-��analyhuman2�data col!�IsP spanE�mlast saQal decadES� QH �&�aIn�frameAeiU rovi��$personalizpnsw!�toTse9� .%�E� takes iny� aerobic.f���lbe mea!zd�).�&`or�fd� basiEahea�rA��onA�o%��at known$ eds;��a�: exere�,afr� � �@B�� �C)�ish! 2�deto � �fA��spA� ( individualer�� �>~;E9!�.�� ��under��5* eh�/c��J�1de2 a2 ribu%�x� a+^�A�-�a�m d@a fun Rbod�.@incorpo!�su��c cZof%+!Jg�)/ �� ,of fat versu� rbo� NsmAGre> �� ork �6d�e\!)enc� !.�`���un9��Fsa>&b,! wellG fastest p��UmJ�� 5՛,1uy out.�U+ � . ItZ i�V.�2{ establish){Cive mid���s((egy , desigato exte�����aer�c��e�toA^ �G >B>Wh, ��V�J���2Eshows�.�.� vari��!�.�popa?�h�.c:�A_limit9�fin-���,-�!va �PA�# Uqualify+� dard&�;u" �Boston M�+��4until now have� $been empir�d��. W:[ume��ix�H�c subIA��q�u�E����a�&2�Ťis ag ��(a������&JA��b&<U#��W : C�[s� %wa grea�o� !�at �err!�%Z�c� sjDsN�is�d [24(T� tr�ref? �gn+� �e� c 2N5}t�tAҡ�el ���5N��discusMPddetailQbMethoA�� on6N oxidiA&�g� a�a29per moleAIir&xy�!^e�CA*ty acidz]& fb Y. As � n) c�82>I�pE��A`cours�*� � , N )ruc�  �whe% �E�l�� enough6���!�� �Kr�b����s not �����to� �Qbu�- #intq5�J . More��D!�arATP�be5�d thr�.Mpro`eE�E�on bot� ��6u�re� �u product () n diAaa��wf(, regardles�d!�a; lacnor ��tin Hnq �,ly� r { f phospho9l��J ly )-5�o��l�F!�ea�$a hierarche��5.�defv by9ft)!so���d)=s:�H� m�.iv��K� rs��.to5D,RBA;nd:;� �s�!�N�IVinvolvI�U�!�N�lx%��#B�or�-�-7 d�F��-D��:�[25��� )�ofeext-m  # A su�я e�Յ"! � S+6{ofY�%���) sc^Z�=f adequT 2� yeɡF�. Low9Z!�:7X��5lea4 �s�>�ag�x YE9mollipmaq��!@ ��s� :��e�q,2�%& go -YE�etyl CoAue�ua%0�bR <ul��- !kL�iGsups f� Agdu0 fluxMpyruv!��! citric��cysbj hibi�$xu�D6�U�$is biochem� 0 feedback net: �� stal*�. �U4simultaneously��, h���]�of�utilizi�)f}of Romij}9ag� has ma��tf��os!O��lU ai umedB�� "1@U��4,&2% eB Figi1q �al usage]Eo��!�(>o plusQם�)E�r 2 freeu-.;tri>eri&,@s��$"% R�%�s�s��stoichi���f 1wsmE�� =pa�"�7�exe?�|� erm�� outp�� E��+1 rive:� �E#u�!. ach�ked-e�u .*~, f. �L �.A ra| as6Qrn  �3a���)@n@um�v�I��n arbitrer�&� �&2�&g � atDwill &����� a)�c�n,�%�", !2�D%�?��A4�3�IwsY�to* �g `(M w move,ta-\� e��oJy�� JE y\W�w�Vprior�B! �OescribI�v�.�Z2 illuqO H �2��zny]2mI,s ( ( 26 mil nd 385 y{) ) �a ran��5g .� �.?g ;���traints�ak� Q57!�aga��Q�heJ�F �A�N:�� &�"|�&�� qhorizon�>ppointA�� .a�pX�lo�curve��*2�drTi�cl� b A�a � erY��l� s!�Sexempla�dashed Ss�drawna �right-h!�ve�$axis ) : Rxs wA�l�!>S!�<�Vly (� �#� e�y�i�9���5�ru��t elite-G%��!�&1!,!.�challeA�� currcl!co_$of 2:03:59ie�2:15:25woi :�.2�A�e�.Hs�y� }4o9�ly )2Imus�rAosl��)9%9� ��oin orgo / ‘h]$&$wall . ’eE&� ]�E�� V!�na!<(}4%�{ lA\Uen!x ve )1�-�"�"20�"calorAT*"�"of� ��to��C.x$in 3:42:00��}P grideF�� }�u3�/*�6��w�(N�V numA&�!|R�qp_$�Ogr ��.is JparrQQ�of�]�s!S ; if .E�!K"� weighs 755�NRY)��2��H �at5st 150:��ns9 #h��n9��atJ�A�( assumAzCon� ,2%B�As�%� of1jex�i�f below�sha�!z#"-�z ‘G�%LoaqSuper� ens ,el�)pbA� nfid��% a'a��QhJma�quLor 8:29eD�� )2 ���stainp%�.!�:��2t�s2�!ntitut\le!�7 . 5%�SUh%�13F!B�E�ɜ0$dy�͝. O& (��,j�O��5JDqyel!�� h�^yvbe %,�));ը!�:E�S� �&2YA�*�n1ۙv occu�y��`areg}f$��A�EU�Mvm�Li! a2,�$6� t#�)pf[�Mace; mo2>># 20 0!OH�+-%�5Y,a�""� �**�} �('J�%Ka5j5� � ner unM2�onB�a2v12Z���prediS� ��!�ena�� valWevh�DarisonIAdir$$��ri!��'b[ �g&)4eti�-�~KarlsH� 2w6]�"doupE�eC U"�$raizsame 30-�m��otwi�th� week���!,�Fjpnd -unF *� �22 !<>�,& 61D�-{8ch� AZa> պ� in2o$(&�"inN.),bybN)�6_AU��.(�'! B� averag,O�za�&A�isx'I=!C6-fb�x!��%�s�n�T�PsdgnC Uou� *�!:� K�mj+"Ee--�aOpU�ly ��e�!�y�J��|M$ error ) ;M��op���suV�.��g�/�&0e�� �9I��F�a�(�(eca�per41 agre�ܩ&��u�ti�unR*. ) ReE)n�0�&E!% 1�l���he�F*!'Q�#whyE#R> cT)I�AO� O�'�q,�|n�u�#hն�ޡ*2ng�*  %��! . (I crit^A�a���N�0�i��e!L��/ � a!] formi� .�/p"v a�)�a!s:w&; Wc�asmpl) �'fea� &."hi�or� iE�ter�2��0s �on�Dreak dow0in �Af m�ai)�9�+:%-�&h|+1 !Ts r���N�% on g�*inc�� ��4by#g�#�].�18]A� mongK aS) Altho�� � e A��B�e)��� �ly�A�"�2�5.#!?2�NU�"���by�=+��! �4! arly�� �� &� . If�� wishw 2me2M��� �e@, s4 \ Q#A�5h��%�of u26e a_neх^ an  terv�fBna�c e �,r!�a��'�!eS&�A�'*�-%�,!��.re�. D&�5� � �,P2����W.�w!�it���%E�had%��..g.�W5$/���"Z"exc+� s1��lso`%�/gnitud�E 2'savings�achie��^h a�ul��!�net6S.zis�t�jyn� devi��`.���Ѭ��i��n2o f(�H*Z(s!.� [ N2A�k f$%C�s�rn  t"���&� BA��:(rem�66(�"��(al.�(a�L a >t() modal�*�(!�9�s ope�1����etw*foua�d f�*h��f[{&e�.Hu:�y as1��=(Sabhapandit��.%27�%J�! =ϡ.�&ichu� �68�3��^&e� of 5� is system�2��ɵw�I-de�s��Dau� )) [28�"�8��g�� A@�1�w1�6�6(5vsaf�in7N� a"��!W�Oss(�&� �� �)b��$he�7i"� �B�1!�]�� eej$likelihood|Z���*Qex�!�(po a�� 21 (y� 33–34�fo| )/a�rp1� [2A�[�9P�,r�*%J* uof�ei�& argu��x9� �.�h%U;"w$viz87( ag�'L= my,(at^@y evi�.��%� D'�8z.a(;4&Q���� l0�1&5e~! �� atte� �2�U�� �/)�� dem-R& ��B es6on:��r�r�4btl�NS �on"�.�v� b� u+A�"g*� ,j� �T!z (� �(e��<H#'f 6�.)ofe�2E3�X.�4i$�}the��0f� a�� way�V::��tofV�)��!�E�a�"��~+"Z+*lla��6�u# (M�%���J5�8.����A�M"5a�j jrM+A=��� �>� �1J��6�in� AL'���5�>!��g��b�or.�5bQ�.�:becaup6�a�r�8=Le�� eI�3*Y �2��offsets in�a��2� � ���, so m� dif�@ t se��%��.�a?6� i*�4&�'a*�5Å�Vt8of%Ce�8h�l��u�%3MI�a�y broad.4"��build[&> )�= zA4a� �rof 80%A�95%��0jE ailX( :f-"Zalt>n� !6E ���g���?@*� � ^� ( 10thE�9 perY;k#*2V.c@� ged(to 29 years� ���,�F bZ1Mm!5�"���2|ej& ŕ6[29" T#����N 1 -�=g3 ���n� ccorɅooin�"`Ag�<���>.arg,El�X&~?�{�X�E�BR( 7:15!fE "t ��A�3\ 10 minu� �eA�#"p�<B*�5 7a>  FEc�#o6= deePk!VAlil)mea�9u,=��T!& situ��]ferMU"�!���~!6> EB"w �Y '�6Ahel !�ʐap)�sl>�"� �3:1� � vale�45�=%A*ec �">"1N�UEizB%‘B��I�` � a� Q���tF>���j��"K M�IA-Y`-E`���}�zi� hop�@= a���� e�-"� n�@ deA6!�A)C�a�{b)$ sB� >aP* )~)�� teg��ly7&( Ap*Ű&�uR(�@y*: imil�&�qfe=Oig�j� 4�����N�. A� �a�O"�I"���#aNYE���/leMMs yie� L" cei)<�1!��-I�!:R�I�Eo.�Z valuEM6(!�� !� A~��# m��7��bou;a5���:t�;A�Ju��3}5B3 3:40���hem�w#Fy��=)�M�(18-to-34–��A�p�K�.s 5%&75- & ?F, be$a��&m<a�&3Bas�m�y��gY��� ��Z�%D(I, %!*9GI/�n Mr~Hl� � 5z compP$��|to!�!]wal. (�w& )e�' qin "�& ��OP+.�*i A�� n��E! � Xcan4��(sALj%�eb"e�she adopB�� o! .9#7ymUa�lie�7se1N,!)"�=)��K&�2v���&�"�m!��)*�'8Ava.ht*�1 ��? ���'1 )>c՝� a.;.i�E��A�-�A�facto4-��&A� �>�!A�zw�x��+*� �Byu t/�, long-U�)<.!N`8: {( aboN+,r' n up0+bo�N � Ht�>!�cl�� �B~,$"� !���z�$!summarrFgraph��"s 2(f�sh�LaI%� r�-�6�s�/ ose �6�B9>��j�;$S, cros��wo�-C��M> ly hE�d 2:04�;�� stigators)�suggese"DJ al sourceE+&��@��%Xas"=;kinetics�"�,A�vQ� or beyo�C����s� �I� I]չ1�[1011 6 7� .A"� "�22Ka/influt2yP�^�7MG�� �9c!:�y�AMl"nQ��"� � F.F�h^�a+succumb�Aa�r"oc�e�A[HU�"� . Ef[#�>LE?.pof2iS@B!��,*� vSib���=e5] : Adp VZ$=#h&"SE�Qf�#c�e�+z�to��MRlos�/ir"41�:w1*'6H5=-.�ex`%![ex�"iA�y�2a� crip/y T i>�y;l�$>*e�B�T -�?LN�1S"< ��A9� b:8 *�K�U�)*��V� 1�sh,��� .� %��p6M%+t&$%;,N� "�U��<�^a[spa^�<t�A�Z�"�<F>!$�Si�/t@!ly�Q R tinu$(�S�4:3(��&� ^( r�Wied #S4 S�i�4i�vulao32+%F-�8aə�tr854a2�"gyA�eD}app�to� �B��a�P��J9+�8 [30��E*�( ev0ce ɘ���:�I�Is*�5R%�"�%P"~&�8?��2 i�-g-��?�a�bWE�6[5#[3�x!}2g �*?j fj&� [32!#O"zFj5�P^)�!�� m� � �?�A1M2.�,�:�U�01gTte��@e Akl*�*A�a.� ���!z� �a��+� Q��Ac��V��+a���Es[Q&eVE1� nIn 2)isofule1a@OL�at b�U:K<oU6�Y_C�Gf'UTY . F ��i��e��i�A2��}B"s stomac%�� �  _R�absorpe��(bloodstream�G�?" fluia�xi!}T i�%��O\   a str�(w osmolar�+ , be�C)rapidA isotonicy[3 F'is6henO"o�)a�6!?w z � c�4r�+�h.:�-�&*bR%agH�%&y�A� dela��U|ati� [2� 4� �P mmeryI.�-eEKrolyte.y�NT�ic� ket�E!��32*5Q�Btim6�� � Av�%6�s���%=lit�impac�IA�ir:u�>�S�W�Dqu���jZ�.�&2ly far��ly�q*[\3&�)�=adv�T�|�T�U u�2�)"+� e&�2>6� ract' ,"WUD hoI�ai*/ * &���~ .�a�Aaa#� � �t.�mem:a\��ass���>) � �� llA/��J�\`a416t�!���� ��em%I� 2 , D% �\SQr�1� � �A�!�^� Aer�Uuq����yA>K)�u!�7f+#eE�.V! p�C :�oC5 "y �< _5>J�#um�7���E8��V �46N�L�`2�C�ill�`� &�F,m�0fQ �#erD/ a�A��:�a�%f_�mv?w=55de9 9_�=�T��-{�B �1BS�LQof.1. B� ;5$�N%�� Y�kG&�Q_�$���!,S]"bH�MA 6�?E:�� 4.NQe&ia6t���.y!zh�!i�18tCF+.�_A� a 60-kg@�9w�3:,!1�1tm675�:FEH�A �M�up�,�2A107:H�so_I_Kwh-Q��� Y�)]ofF -�I�!KRe-"s 6�� e.\ !�Ej�I���ZoI7Mofn n���Ia�b��F �5�1jU�yX�}%S", plotB"� 1E"&�M�F were ob���f,Aqua^f�X�C�,�%�*��Ya�ork �&#E��J� A�� b���>g?A.K7A�J. Kno� �&� R!��>� u܁i32�m\Gc'& 2�v�-BJM�g%byE�q�>z�k on pathw� ��2���1P� Elw �P�f�&)Za46uT1 �a��T2ni�l�g�*�ep�$q=�=� ; si�#� �]n�4of�2�-lym$�R6k.�>CUV?vlfatIL��ar palmiA��U!X^)^�3%J^^`2\e�3Nv[@1Y6�V_-H>�g!�%[ @�`�Wrem��^��bLs &�Ie,V[i�hA `W�8��W�W. I�b�Ty&�� an*8JbMwo'�т�is�[()T� 2r� B�G,!D� �"�E��xe�"u3� � )�*i2%�ulay!�'ppl�D�I���U��V�:�Li*>is ��U 17 k�)�X@&w020�2fDl&,�5?&]��ma n� al�,!�* iK�(: An alternI��N�Eie� -MargariB 9 , ci�4,8ie!ul/>,5�i2! ,��a��`,2S,��Oa�gyA��/t�� !Q� !�9 &��^VI}B�<:U!��)m( � 8��e�b?tj &~= �){ ?v1�iF �"5B�9�h\��r�%a�qe�wu.Y �' C;=#6 $V .o5� �a��? O]%&�gq�2�-!O�� r� 2�(� �of 5:53%��2!A�0e�W,&�L comm��uA>L$!�a� eb� �&C ��lr'@ �1u�C� 6+1ten���;san �b] each�+� �2�# ci�*�UneMS�Z� a-,ќBUo��l��.�",�C� �W1�fy� E%�T.oB[ read Anat!��`) �fd�9���*�?. H&�eii� rB*�e� �N� al.$M� 2�9b de%WJ� ()%��i�noA}ap�tu%L-< nd�]nMN��A���� *2a.�="ELw:7�� ed u�-�$�ag�Z �"͒?1 �5�� @Fox�Hajn@l [35] ( 220 beat����sm!�N&��'�zof TanakB(� � v�$ult�207^b0 . 7�/Bnz!+�or!b �Fiby�5-"@[36�SE ���2�t8."� �a؁����<"�Q�>�Ecr;Q�dexM��/�::)�!����/Bm�K�:!� )&�%2�&�T��a�a���&���!�te kr"�; m�Z byE��)R4.�q"�T4*� fe2k �|� �&!�.XWen!�n���0��� uA8a�Pio��>�XY�Auum.��svA-ŷ(I8. Ue�O/4���*Am�qrby"` ,"�.coN%��,�OC.T$:kqCQp!#*��6D��/ B� �as>�"atE$ve� A�c2��d'TWU��G6X�Bufi [leg��� ?��/wthirty-�� -old�qga bN#bU,��5�nA&� � b��qbl�r�& L�a� )y6HAU��u186F(�� �N�H�A�Hof 149FE!2:%�4o��ca%EuvaK N �n�"FL�*B��NB&e�IM�xs]�i�QR�N � N& S=�a:� ��=1%^R"\ �r q�BE�I P?m:A5Q{�( 3�UH(<urn�rm�& `�nexe�T �%��2�!��Ac�*r. ���� r�o��at ��&2�e�.w��("� �� .Z ."� V�(�n; >25"2�sm�� , ( �>)�!75��� <�5 fi���,*� &�G� �;�L(> S� �4reglo-j3�=S>�IB@5$�j�� [3�)N�R�Y2v�@/f*,)0�J� *�2^ 8]–[40]�f-1)�i�t@8>^h7!' A!>���Q�:2W$18 . 0–2 �!1]+&T>V� 17�8*9. L&!*�i.}�%9_��8u'��l+!���:Eq��% (��2��a.�#�NF�?��mS�L*wE8�K f�~zr$0�ٍ� �7"Q���t0uelh.5p�worthle�2RSa�d-� n� �_**� begin\ �= �#"�!aVa&h%2*e<�(!�fvZ &�i��S8X�}_�v�'�ZE��6 ng [26]; !�# � �&g'2z$�I!+Y5evome�I$e@J^IlZpoo�2N�"t�@i j�w�C�� al9cE�F -h1]�r"E o6O,.JU��<t.�Ei�x&z?�m.LW"$6.�V�ma�I�hgcr��$#"�E10�=)!�afqo2�D%y^+�1!re&*!��ndc1?� ainguishG.��QUf,�(2�lcar�&!$EY�.�F����6�)&,@a w�"pat4$q*�G%���21y0ub�>�s�s�hysX#Sem�Hn,as�"0����t+eoA�р/ecueH�R6� M�!�BosEdQ leag�g*�' �dcot�y>?�1}��!�:A6!2�d &!!��59 79Fl ARK# *�!c~Au��R BH_{0"�ur�!E]A\' �,sw�N�X29n,!�.a:'-J6���9A*�.!��^ �s�����*�-!(&��D:�6}�" � b@�:!�m� �^�X �%"Ebv��s�a��&#(N�&� �*D� &9 T�E� 5 )�Z-E�&Y �-J*<<*a@gb�1�cha� eris84A ovٌ�-of-r�su�!gA���;� �at � �:: <360�Vs>&���?I�IJ!b��Kv�^%P �rA塉i6� YN n"��a{!�$a�ed0Y� &#"3P0S�DSoe("lK!���"�,�)o�) i��-��.m.v�A|&z#>F� �e� *V8acea6��S�� `)�23�fin�$�,L ��">&J? a9v���"(A58@[ P!uo�E*�:6 "m.1\91*�6 b'"��lS"j2��2 �& �t_=�&>|<&f���A�l0jU[� !)B%J�$a�%�Z�T%�1~�; �Pf*D�:�>a6LD�.6 *�NL �e.i�q0�Ig0��# y 4 km� 30 �Kdid�  monit�yn� p�z� .t2I��� ��� tudym� -K =H��21�a��@[�@>m5AeXnE�M"{A hypoa�emio#f�D0r�2EUvla.��� >�a�rSK ��2�,e��e =%i�����N_� ��S b�c!Kyn/, om ���)y�!uscL5force-g�E<%u�[41��"D.7M{n�Ged�9V�!��*!nR6u SEBa�u��i�<Pou�c.�nc*O&=2#.�5>��erves [4i4�*-&��>� ���W�_5Õi�$1 .�<,,hWA�] a�review r�=[ 1��%(ontex�%lqsee�+b�8� L� GBac~1q��t �@.�j‘push �tY�AJ��(+=+pl��6��"�=)�H(u5Y-�E�*Fd+"�B�L(2da g�F�1.�� a�>O �a�" �H"�/�A s��B>{ih 7� �z.[�"echni CEL�&�4�5BA�truct" nume)�2z!Ep B%�Z�)09e*�s�<~ va�r�,��Gub�,!�im�A�� a�>�1uncer�+�!�oneW�! �a �Ub9�a�_R��r�z!� �o,�d� �=�>� n��<p8.�)z���f� C� M8�K:� 6 է�O.� &0��d sym;��:�%��26� ����f2&� "2&� ��2>���a�h�&� � M��"[f"W�!76A,ghtforward se+iv�` 8priŊMN��e5om�)�; logarith:yZi�Qɤw0� !�toSF!�E[5�(5�al�(h"�f&�!LI��>%LY�F=Y�oE���"aCin��s=w 2 , �C��!5>�. Replo4�_ x9�0.*U��)%Ned.��8s faZ-#Q3�an�"a�inKS�9��e�O��t�2�)J(� rj�oB �� �"�(:"9io���Xv�R-� 17�U=�. Tap� A�9�%�2n�b}�5� fexwayI]��8 ) ( 910 �*1#!��1W"Y �.WY@/0Y�&� %�� �JR..fa[�:;�6^�2�F�"C �K"]>y�s9n�1�b(t�Q2<I~t� InA�lia1a1a< !�Uŷ��i -labe:��1�Q�Hb�I?; nQ=K] A�rsa Wa|< �� ��m@ pa@68�:\�I� �'ZY5C )��:�C:]��\waF�!vix�+B�t=)aN( 11v( 1�2Q ��`� �`A�K�= +%�%5-� �M%��'2y& :&#2�'�JB��!��T�'%ij-��f���o�1��a;87���ari� a���3&�j��]n�?1&�}#P(� A�FEA�. P2 ��� ���-�A�-�K^.po��come b*e$�-6� t�:�e�� (H)o �W,�5�u(UebSiof�!e��>a$in� �&�1s9��i/CE��5or��. V�P%�3M::%l%&2UH*2��A+�ua\�O7 |a-*�$e�l!t�NAJ_.RiG6|� bFX���&�P"�i��6cmՒM5X7 ` Ri�uu-k"AL" 18 ��C]f 5 .!��g� "|%��=�b�� R� d de"&N� aideF�a����2st���!��!*.��^tbfor =t��+i'9I! ��`b�.�:6%��&*FM:anHhcM�`�Qp &�I1%)Ja(:rL� �.[ "" � ahs� �o,�g� }T���6*��sg?� )b� ��iR"2�[4�BW��Q!�� 6l��5��nom�Ll�1�e�())�u/�# ers;bR3re�,�Y;%��ڭ�f!��aD x�:$ly 5–7% �l� markab�'��","*�!�`ille`6��M�($]�*_-1�!�].2EbE"� �. S YaMa�F�a�r�edɅ0E�� :& M ,&~GV��F�!�!:���=�;�' /�[s!�Fr2��m�A�#rSfac�i����o"zK��1+c�&'AS.�(f�av%�Q�9o�iaڅX0�%\�K���� byeC7!v�ggFQ�;Nkm��2�� Y%2I kZ.�6�=mV {ee h `061�r%�!��� � ��al L�Gg )��%�,:XJ!�"nh"7al;2^=>�>X9��%�:g: ���)eJJnd:���%H-+���)��<k�\1 .��� -�j��+i,E �"�@6�� Ty*^1I�v�2="5�%l�%�:�%F3&���&�!rA�%�!]6� . SoD|baAU1Hs�snx!O�M�>�!��*��i-�)�9enaA� I�T6%.�d ��j�Ae@F!�!�� �O%L5Ob �RR'�nd*��0:�5 �.)%��i�8E:2"by=�I�.�s�&n 1%�'A�� � s fu�'8HUr:��ird�^��oe�. =�6 JH&>:H� "� ura�=.d�&?4E�frGR:)e~T32�A�er .�,ȩ�cy �i䁃i�=�  A.�<. C5�%%�" S.gt�A2se5��!�A� �< spir�(ry��+ prog.<m"&:L[�F� sp *��D�Go��T �"�"y�&*,&<s&D6i�Q� *�V2��0���� w�  ]�+yC&I-�bs&!���[9�m*N�:N � �u:,�a"� �5*5rJt!_lyzfu�*T��؍*dmjLc��)+!�angA�6��;�F� �� O�addA2�in �Ds6lyI�:�Ivq�s famHIvd���po�uZeBLs=3wid- �Lb y�S��J�c a � P)\I*���dB�t$1%�e.���J�&*�8McA#� z*�!eL,� �o-,:. Spec�B� EREy�EA��D��nҟkr , [4��TrBJ�}i�!�Z Qshortco�&�h2]-�a��hF:�4�u�y�Wic���by:L to 1�00�s�3�Wy���s "~ 0: di PramperoBW,t�O��employL*NJ"C �1�;Y���!��AC&$�}(5� �We�a%Pm�"�H�6��p.j6)��P��5cy .P�M��isa# h ToxojEuropI�N�0A]do�� 8�ge3] �$i���'JRG(type I , II%)III#.A in South|^J��Wsa�2n[o�*. M,BphE�p�TF1s �����Ey immune7�against.g!8A�%u�aM�]Mn�^� vivo!��Z�e non-canon- .����uP"a��XA9sa E@�,!�um�U�+cr1wM295�tNr�A�e�0g glob�&�.�! RNA-��Q� ��!,U8�m�!pt#�. We p[tifc l�d�c=�01 1�a?�'A���k�4bb� Zchromoso4,~#ua�e7!S_bo�%��nov`E�-�ᾥ>&�8�A�7u�.' (���e�YZ rfer�\M�by �al zJ IFNβ)�rw\MrAB�F� 5$k�Sng��5knt�gamma ())$)�/�7-VToll-� ep%�cY�!�A��ŷic- r*�oMcid�)i�ѥ�yRIG-I  fibrob� s . �� Jubiquit�oblig a!u*Nh zob��ߥ,j inv��rep��*�8H�a � &�swarm-aS��im|[�)In�ys":5$ he 2_/��*�oodborn��t�'|a^ qnnql.illG\�B1a� adjuWe life.  l�e[m)Nɶ=  [,i+syma� }E"AXA��st"f_,i* muno� romi$ �vʫP�ngeni�j��A#=�%�&5�sž�.death .>8u >se�2 ��o!E�eda��>�`NUA�ng:j�{I�YcR��d �[� �8g�|e_`Ec"ma�/A��O�)j�[5[<7Z�-1ng� [8�[[9]��2�%IAxv �. Desp��`ex6$�CsexAd.�!�t�fe 5�'s y9I� in f�*� few �s d] a�h�| �fD�"^� .8 eq ��H7�le�6� Jes�"*� ?��� �-h"� V wild-eGAp{ [9%��g . Ge0 �t�!�n s��nO >�%n�60 [12 YEEA�l) A""u'of 956 �,�XE,le nucleotid$#$lymorphism�$SNP~��!� loci , c�eB � �_15 hap�oup% *�-�: % , [1I�i�EA�me-�2�FH80how�������se2~B�oR*3 d"�!�m�1# 1f��8�v�+��� \nyF`;!؅=3��%reH/oi�7�ts�A�L1�ahip" �% %S�&� )  mo���� Z��;"O&���_2g�%� !�A��llyqF LD100 ∼�&[19�]%O1%�I�III �sJ+ �;!� LD50A�O03810B)[2�e2va� !6; ���>�! "�0b�Moteps�N� e�/� ,ory organell��� ed rone�4, rhopt-��5Sanu3[2��I�m*� )#61 ���( 2!-��"! -C"n�"7� l�Kl&b�X exac��lel1 Y�l =YROP18� ROP5Av�1)�%�,� –[��:1A4a-J %(y kinj�!-pseudo X 1 �)TBo ^r1Ca�� � � J iity-ra@ed GTPa!t( IRG���5��\{IV� ves�$� ophor% vacu�4membrane ( PVM�7���K5z}�ea��7deP  -g Z��snh=~����c9D&� #M�eI��e��m�g��hc � �2�bObZ N�I�b 6�>�i7F�A6m`�%��,# < i~a�.v���V ����*q -P STAT*A!j�`[�>PI2�2�� ein GRA1�|:�� :�ʍ^s�*|� NFκB.�9iE>�:�ROP38���rb^,z)�>I= .�&�IMAPq���fThu��!,U��J7]�s�KY�� �/��^w "K.=�nU�|��M�)�M %��DI[ pse����I:Q ,�3chick�xell�G.�fO!� ��� d5��L:�m1eM�� �"n�6d ?hō%*Q�}&�"� ���>/ �e�bBW�@oQe].��{ �414w 6E�&&H se!eI3�\0^1�(e!ka�II}'a�),S7 :� !�2d���m�# � �VU iik �omp'oto.��/��Oh:�Lae�\�[5�w �&�6 AFstQ�"12��p1��lsoa:-Yi>�.6�e:J> G�>�- oKQw+-�R��SI>�& �]�)�*1 -p �(Q5aR �6@!%�p-\A�R�&� Z�o :e [�KSomo�(F h Guiana�cA�1-1&�t %^5.�[3�K� h�|�+Ф"?�on=N-�'iA���6�b&� &�Ags:M)�����jE ab7h)�B�x Amod�X���B�fM�>�!�S#�� %�M�1kmanif� ��\ z��':ݡ'�5� �"�� )�h ��.�Pt2�N <ly!v��BUA� *�%2>�� Z3wy�&�� "W&8� prof������ �!�V !�EG[Ged& R,*C.����A >:�6D>���es�*�S Ap��a-2 ( APT5� {7� A8% X�#e��JM���2��: !�uc:�(cra� i"9n] �t!�A����(u^6�s ~4aX�f�2eImJign:� i�rI^"eajn6Q6� a��U� ;eK�Yƅm I�#l���1��>�Ul�8� 2,  r!4R� ^%�Z�gI.a��N[acyt"H�> �0Af _,el/p�o!s� "%�"� �"I-� �J.�$ge��%���A�set�rly puY}�&��+ �JWI2E�w cove�f��y�. W��:�(� f�-adeny��RNA�-�iaBN"�%�By� bone-marr� R3V~&�F6�Q�! 20 z!ap�w!Gm�!e72�a�WM�te <51%�4p817�9$'urinee��93%} 13�9�Xba (( RPKM> :a"]���p�( T�)S1*�&on6!  YOE�l2��}�geY�a�._Y%@$Affymetrixroarr}�/���a2����sD�1n( P"��S1NT )�l���nA�m� ��G-bbyA'�%�ai(r �(.ZS>MfocX on=451�>3�hed.�1�0�B�A4-f�Zѕ�E2!p�)2�016*z ͡� � �5��2^�B.�6�co-:zֵ" �wM4�� ]GB/1KAT"V&�(2�+9Q')a��Qy���� ��MQ��2lf 0� S>8�. C �����Z�5!M8��tai*�9��9–13 �1se9aۻ��arɧo�4q N��.��-E!4]1; s S�<S2=S�E ����&gqe"�;a�� rich�#Akb�Mal!�)���jo�`��� m 6�eeJ)�K!<v  b ng�NPTFBS wB�sU��!�E u~e#M#_U /pl�:��C. Q{��� du #X9��5.S# G :�{&B( 4 1 ��ll0.,.ޕmai�Z5t� ps) e=e Aq�!�1*� �7E�9�&6K,CA�+[Z5��� �d!�to\G1ac*� �a�VGew� �% �� e�)���"�.~�%&ca . �"ME4,TDEG%� h 6���-��epia/f��2= �!�7!�*���%�m�V� 7&�T e 3+$9�� x��&~n�.�)K��$J� �myZ�rHAm n�l��A9.(A9�.it*9Z��$d�Ind��w*� X}q�b�e�E�:�>�M �gq �>�rJ; 0U<� �%B690( R = −�N9��,)�a�� AF48fA��\�WT8�A= n =�2�(>a�q*�"O 1C^ H�T 6� 2�N� �����>��s;Q2��fi&h%bd�U|���3<Roo �*/e> �{ >� ���/a���+� B %�E��.&!���s�5!\ itochondr���@ ,�0a�Iu�u�aE�.j~]�d&^ ELK1h, A��(�y�w%a�9 (]pR,�]x�( Tcf )51��cF�D�2O�ReGy�<{��!�P!�b�'�a��2Win-�=�!S].Q&Y=�B��2e\Ά"�,.� �I-6��no!l%���� <�ly�� ��������0��W�Ha�PKM�G 1 . A��C"�3h��68CEP6950�&!=�F.�� 1�6< r�b4�%�MDve.g_�EW:�A�P.`-'��, GenogL�@��W�.��DvU�r*�)%a�H�R��c+3sel�92:%,�F�thH7 "� ��)E�� 4�J�&I����bg��]��y�Bp?(e#�"� . Q hB#��r� &� �^r�|ar loc D� ��&e�b0 upon.m�j" 7�:on-xe�.+!2P*�0)h >��se5[�1�!$knw&�A9�]�>]#"XAa�.���NY�@mel3�A 7 � {M���6�.��y[E@ �abradyzo�)s��� each�-|��ig�./E�>,upM�e"��vd2�op��6�X-1��AP2Ib-12� x�X-1�AP2-IX-92'6 ,"h1B;g�TE.oO�AH�u�=Xg:z �a�% bet?c�)icA�eE)kaey>Y�J�2K��&bo9��xU$6�0�s�Y�O�8 �w3d"�)U���W%���.�v�I�ED�" 3<ɲ��z��"EJBOF , B7( TgCatBr44 \�-E%0k���<\ge �~�#nB�&� 2A;w$[chrVIIb; �_�. 75 MbEF�^3e. 52 Mb��9X;TI–6 . 2�-�$IX;�ZF� 28[7�e. Z��*�"�dup0!N:.� �Fc�!�C��O!S@a we����� nfirVuNfQ�GuP,fMZE�d� �;e"�J�UT&mY ws mJ+d�)�t9d �+kb����"c�m8�twoRA!%:�!B��n%3{E�� B_AnaX�'� �" �lI "d4ew�0���b*%-�ed]�B� No#+�"G ' �in GPHTeFOU=7/-��*T�͡%�)r2.t��;am��q*���atk!wit�-a6aa�w"~)�i*���E�"^ + ��i -2�UoMg:��� 5�t+459(�;���.��20&�.I�II ( �,�AS PRU a�B4ɩ�"s�&A%�Fu"RO��"�/!�!KE��� 1���s8 � |(2 "�( KRel���M��G q�g:d*A2t%� [���T�&�))>/&,5J#� e L-"��.�� �K�eam. "�n�)�)�E,g�1p5I%m3).%�aU.>byS*� SW�iH*!(of �a�3-�nd!��%8OEwe ��)��Qru"� �[�O�x2]5�N�sh�!Zs. j*�FI~7=�8@LN�;& 5�N�a 255 b=�%�ov 5S4E�S�jPK��+�t2!!E�2_ hM> p65X}�H&"� &�n�|@.D*cJ��s5e� ng5�#m83@�a51hC"�Q%G%�e�knock��up11J.>�6we�E�@"B�!,� ?��aU�I ͎w���e��&�of5�&�5M-M'A4XY/� O=G 5F2�I$���2� ( Pea�N"��) 8M��=m�ity*��mS3���!��<Hwas RHA��& b�b trun�B*S�� �͎�7�,Z$stop codon�pW�j� k��� S.�-."�gNr�t� C*g�� "��Es�+c�qA���ng��Au��( 58 kDa: r 66  �. L��n]Qy�  i���"F 3 Ueb�,fluoresc�-"I of&� �&k�8&�BJ�:~M�-I:���9� g"wqm�E�� ��St��,�a!u�u�.@>2( G.� ���"ט pro-'�?�6Zh�6t?���<aJ���su�t��S��Ta�1"^ , f��m��a�EBII�PA{� 16o�E s}gZ�$M!N�� %���f " "C�"��L=�T= �-�W�:*qe:x� ����}=n E* f�\ ant�J!B�!6�.: :�7ROP16 [4��R�(,�41 q��1�8��2 u8pa=F&"�K��os  ��asP <o ��� �l9�U�!�ٽ *pG2�*%Xe"�)ہ���" B'�����ly�a)%.��w,i�!�4��K�� @5* ?;4ɾWA�UABb��c(� E[av*� 1�aly�e���en*�&��&�1 �+E�II��W���wa|S!�!��)\A�d�K��Z�:�lh4dp Y�ly RH-&�CEP���3D ) .e�A��O)�.���F�-����O!�E->� )/5�iI!��!$��"�JA�e engine<((�y�Lve � �� HA-tagged ���4�C.!�1�M-In2� �kEu&G � f �W arke>TIf r� �a)G��~��� .jh����Q[IC� R�+��I���0s IL12p40/p70.�b�$E &�(&�8�p�3NFk2[�.�l�e.^wMqg7�� rm�&L�A ���:7 I��S�}%�F��f+,�_ed BMDM�F1�genEqsaj IIxIS [��i[M�>�@ 4 S2�+S2� STED3X�� &V�ET��of�p4�I!�7:E*> ~he`Jb) �)ve!538��.�8pa'�_ � =$��a` fromss o4constitutively �!�STAT3� 86 [22] . By makA�chimeric>]\=$subsequentA%ividual uons!hwas9Nd-4T single leucine to ser V@ at posi%�(503 ( L→S )A�!�-domA�!�AiII �( II2a$sa�,ible for itsE.�lan!�reI� X5�.!43 �r!N%>, [46]7!LTo� whe�* data)�multiA&s��s couldIpredie�e���ia}De critical differea;-]� Z"s!1I.�Hwe used our RNA-seq �to assem!'� 8��% eachd8, perform evolu!�`ary analysis ( Figures 5AE: S7 ) �BTifA<)n��Qa relia�rea�tP ���i�All �0s with a non-61 �ZudE5�A 6�S��S9��COUGAR.dM�2�s D, has a �%�e�)�satwou sIF6�,!1Gn alanaM6@2�auuateU�Au��i� ce versusY'correla!م�a2���us�=Y�(a large col����I� s caA�re�opinpointEmcrucial��idu�<s )) mediauA� I-$aE�5���JT. We also observed hig�a��A(synonymous/ ( NS/S )�sm)�he%�3-interon tJ�� part��i���I�q7 5BESTh�) $���W�Q)���veA�A��excep1�B7�Tq�Q�,)���shown )A,i� F1 y4 cross betweenU�� �I [18�suggest��a���II�� mutEac rec�XeviLccurred after diverg!�%G��%� clos��E�0ed WTD3 , B41�RAY �12-like53 . Am�Dnovel&Awe.A,UE�mz�12.�1�,{ some" atyp��"n a� �543� ( C�  1��)� 1q� enrich�(n componentEV��I E�ferE�:+ �I"� Ifnb1  famil�HRNA helicases Ddx58�hIG-�f , Dh  LGP2��,Ifih1 ( MDA5EPseveral.���R( Ifitm�Ifi35-Q immunity-1�GTP�( IRG�:$. Upstream, orٞindicaA%%�!&Ia�)R] s F? �IRF! IRF2� RF�� were>EAVl� � or-�is5�u�1Ae�P� E%network ���theseM��revealed-�ma+�g[ invol��in IFNβ� {s|a�6 �An� + ]o4 )�( ��399 ghad a�E negak ./�g%TFNX@R = −0 . 93%T. 8 ��ly �edZ� EIF2��transɲ��j I� -�)�?!'Azduc� ![ @��of � ��R ( PKREҩ"�� phosphory� �� eby block2� � few�* �#Efcap�ofA�B g%+ l�Eka�% Rsad2 ( aQefed%�IIc�d vip�  ).6i�E�potAc @r��A RUBh�Q[ 6͵o valid�Bf �Ein�ed BMDM� �J!�measu� �� betaA�Al supernata��24 hours> � n�. Both!�β5�^i.EBcripts)uprA #nLedI�-B!,� �DmT anon��}>�tesI1>s 6C–DE�TimaTur�eria�s�Q F�A�beb M as earAds 8 h>� � at��h� 6E�� �. Taf%$ion� ��!^z iV9�sEvi��� ogenpends on%�en� of eia1�g��/o 7 [48d investigA^f ]4E��)#�V�>dxA� zse;!�=��8" 1�Timmortalized macrophag1 deri�{� wild�xor mic!� fici{��� IRFe� ‘%ating’�Qj.i�Y�����let��abolis�;inyj�s lac�IRF R!�8el6 7]F��Aa��@he F6�)8� essent� �pa�-%�ed-�ia� . As��I�,.(IRF knockou�m�sti&�� O,ynthetic dou�Bnded DNA�  d ( ��∶ T�!)mis� b�'!%a��unrMv� � S10T.a���Xݩaway%�b�M�byrٓ-u6FYo0, Unc93B1 3 d` nt ( �+ de���Etra�u�TLR!�ffiI$�Q� on )A�MyD88 TRIF1g5�b E�.=ed qPCR�isE+ɾ20F�. 6s���/ �KO2��� 6G� st�� in%P!+a�� u 4endosomal Toll^ � p !w� ��_. Imp�z��abs !�&�dide�Ma�abili�.Wtom�em�in�-�%hA0ed1�2R5:S10��N� th!)we:0 �u�fibrobla�e( much lower*� TLRs�{n2�[49j��ś78e�M}��A�orb8 t�q%�>6 cyt�8ic nucleic acid5�  56H;�+C��ak>og(( �n�e�t5�� z$i�X�Won.�of�r2�sen����CA�on���؅�d%�-U�]��+BY in humanmDwe�9�S"Eof HFF>u #V] T*�h6� �k�&�:eUtur�.�A�ereas n �ag�|nN�  ELLS�HMASe�U-7�KSi�BA �%l!.z�B���<hyp� s����Ni v���howͼde�+y! !��a�releaE_e���]S{Y thenE]� by1�e� or Ra�E��bt7�i�edI+monolay� wT ���ngM�I� RU ����)M$)�"� lyh cycl�M� 6takb�72� �chose� 04� t�  s��evalu� 52$growth prio dof.p. C� �fixedE �� antibodi�gainst� SAG1| visu� :�vacuo��[e-y >� ��9�5�%�!0��numbe�dper fiel�Rmai���through!Y!�ex !_hi�heU�V c�a���u��' ��q�s 7B–��I��6�-�%�ja markeű��r�,B_�}Y%�mzE�he�avA�in �uq�s2C negligi7 R� Previousl.weũ�p�-stim�ed ME� �IqH-�se�$rapidly co�E��] they. �ed [2_�ial� �l�2g intoJ9H�� �Vif?ki/ U�p�*� &�IFN)�U���%�pre. � FNγ a>'. Inde' 2W1Pj� ��< Der  !a@to�6U&"! OQ 7�Moreovera� E f.rf %j.�as suU �to.Mup6�A� �� *� �EG Our>8 i2� 1�� . gondii� ultZtɪ��U?.<y t lj&� -� ɨ" a�triggdg]"ycascadAS{!�B� "sculmin�5)�uA=�98% L� � ‘r/MI,A�eli `:/�?�i�B,t��"G1] mechanism�&&��C�*� ��more sus��ze�isRYre!������dI%1:A�4e . In South A� a��$congenital�8oc tE o��pr�_ .MEurope?�a"assoc�*�0e symptoms [4� [3: L � %8ev�"�o6�#>QBO(� m>�"<!, mailz"�i> . S�1��Fah GuianaE5cause� dise�"�p� death[non unosups�hs/",s [38]–[41�Als� Nor=���n �/Iq�[#b�>!%�-w�936{How��!od unkni�#)�z�� thei &��hir. H*wea�!�4EF� &�%U},�t�om�<���o29 �!�<�.%/A_%�e�co-���G"~��B���re6�fune�eMno�x� cQ��w�E"a�baan-explora� molei�")�d �!�%�Lo%�� an"�%w'lo�2�2%�TNin  � IFN%F&��! a sm�" Be��N��!�X!'�%bya��:�=�����&l s&� I�a�5recogn�%of/� � "an�cy&<patters?&7�"e$b�-�.�a)�!-��G opti�fitnes�on is uno5.in\!/�a's%�!d�1Dend up3!w5)y might�4��!��LA�z olog'"�)�r/v whegX a" ,y  spec� disj+�#q,c)��sto.Y!�0t.��� #�virul��sam ���� ficN_)8�� adapaKto cer��s [50�B5�(" i5 eF�b�"� �f*%sRi�� !��is� $v#$>srYK>}m� }a�lB�+�A�%Dis %�+)�!�E��"�%!�bo A��,�,a";�v pro-U�!ٍGf"! NFκB� byN�6������O=2y�ch�?R[.�ROD-A" \%| �inhibia�H nV]� f� �,v:�31;>�,�L,�"�!p1�R\& �!fa�E�I�)<l, 12% �Q�� B�*ɟ, D, !N6=jXDY�.*9 � �Dl$haplogroup!�>U�ٝ.w.�exist �6 ,Ő�"[s�3� 6� [9 Be���-125A��� a{n!�b�  i>� [11� 15��17` pos�,m��!g �of>� .�"S� >2 !R�$ %1�$%��F:'2(�'%���.� profY"g&� e�&�./r6baVatgnconfir�:. TI���%}%FN-α/β�r+/��coord�of�microbw�TA�.2��$ autonomou!Bm4!;T'�bm����"� ��3!�[54IKsid#  �2!"� ����%�a8 � ;du � 3{Y!Lo&�2 +e40:V$"��I�60]Henhanc�R L�E�ŀTrypan �+8zi , Leishmania� P"3 odium [61e%6%<:�F %/�+9L��ce [65%�6�/A�n"%�t�g%�ma� ud��YwU  [6�W>�A�exo!��qQ�,��N"h �a�� �VV�"� � �#4�a�Y- is�"^ �kc�f�>i�ma�(xa�Ot5� outc�� �  *q� >jE�i�-&2 lEX��� 6�)1tk jor qon[30a�`"B/�8���큷)nA| X.��EZin vitroE\ vo [6�[6�j:!� stud� �o&!by�-�a{��sa�an� 8'� do2*� 2 nA�,�#A@�1ss�!�he)4 F�I7 hysi"� c>!�s��<_3garm BY�2D �-Vo�#) 6.z*�1Eb�6�i^) fE !o IF- � *�cye [70�7�h�n�3ai�).x2��k`1i0� prog]�1IDe3ede�e1$ t�86��+�"$ lyaben3&al�ohR b/��6�>�Eމi�%E�"� �model��@s� ��� v"��� O J�[1E�m+.Lm7Lis�M~*9&��d� burdenA�ɈtM(e4W yCf �/B�  *� �is�d5ly qu>:��!�6�< N� e6�-7��y�.� � u��Ek-����"m,8�a�HM�l:���exx2� ���E Ӂ�F+/��-����!J(-mycobacterA�1Zs [72]1lau6� .m3i����he.f�a47be��2`.6]"_ pat�!$T3s�~ tane� cap�!of��|q %�Ř&���a�� r�d u��i"� ins^ ��7osstalk"m`!� z�S�N}� 2�5�<6n*D]f� * Itʉ�&�wI!;� -�K���A2�h� (example add�GPLound � Z!5}'sutiE�4�i![bradyzoi+<���(dow1CDA�1a�� EC�8&E2A, demH;!6de�Z1�8�elA�!ar� v* 1���*prolifer �, m� ��e i�P= [4��*� ec3?| � ^�"s%�s!d��='�!�Q1PU�E5�by�l� u1�,.W,(mG��:Z�[=�upnva�AL$�2<d skele�mus%gnd neura��hx 7< R>6ly�z�Nj� !/denJ3ranul�o�1�6��sMbeyon�<e PVM%0tr+� KU�IMu�v w�a��;.�=)�.a��,78 �A� ;�of6in-B16b��?� %�A��?G2Q�&8 s��^�!�e%2h]S&q [7o [7) Man26���-� %� ��M� �*����W2mproces��m��E%�"�0-Ia-��� ��t�:2<�i�M6���� � 9A;2�*�s�� P5�0%�CDKN1A �I�L"O.�-9M !�oa-, e%k%h$G2/M check[&.?.&�*!vH ly�i.ͱ9z ~ �E^ak�>emp)ooz�~A�at-�u��=Jof K"�b%�6.�=":+,Miud/ �s globi8�N5+A *\ ��}*�s��pV � &�)��]GI��8 a�s"uc�ofl: -%9l ��G"]� All!N"4I.A�"#x�ccorda�  guidel�Bsi th��AV"! n Asi�Ar�Labor�DA� S�#c 1 AALA)=)��Kocols�0r is �8�ap8 IMt Committeex, ]CA�@( CAC #0611-063-1�8FDe Massachusetts Ino?�Techn�y �tissueX#� reag%;�ob\m8TCGibco ,"8r wisA�d!�� Poly ( dAJ2T )��6HInviv�4 �oligoW$ otid��im�*!�>;tegU%�&$. C57BL/6J[4J?� Jackson.�h. Female , 6–12 weeks oldK�2A3:]. M�4oh<d underY��gen fre�n� s!���I�U��'xm/a%bcu%�dA'h� � skin2R0�D2!b,&� [3V ! f"?R�e&A� �a� coun�Ei� orig�ly iso�9d(in� cket�%11ULs�� : AR�, � , US�-,�>( b�F73J OF (@ BelgS�?b.[y.( sheeparuguay 6EP ( caK+3�B( Cougar�Ganada1DEGfFr�_�FOUVGPH.�3GT+>go2~GUY-DOS2Len&�$l$KOE�$MA6z>H�/9N� ME49.2-�P8pig!FRZ�}@]/RHNODNUB6�%!TgCatBr55�Brazil.�)�F44N9VAN.�FvV2�yAu6te-\de=* #[1~%a�, B?Hhip a�A*�"$ }�*:z��genome-w�[SNPc$�B. S�"m����-�a�6�e���i@8?# BCR..4( http://www .Zcrb .� w>To�e�� IΔHXGPR�1���8Gn�#I:e^0�FCC38 co�3reg��pMCv�Womo0C ( � 437 bp upA~ �r� d�7��2K%"�%[icŌby �7(�yw��5′-CGAGAGGGAAGCAACGTTTA-3′ , �@�<, +0TTACGCGTAGTCC3CGT $TAAAATTGAT"TCTTA%ACG M!WS�Jc�c%� a C O HA tagE4�B1 ��p�}��eno��w/2 *icsf%u IIHAHt�2�K:7TKO-att�TgL�+�A����K --Uvec�BA�\� ar�3�Not�New Engl!�Biolab�TInc . ��-�PRUUgq$�Grop� A-aK@ie1?%�s*FU" �L50 µg/ml mycophenol�6( Axxor��+xanth/,( Alfa Aesar �-Fby �,e�dilDJ �C ofluoresc�"%$�A$;� e4N-W via�HAi�B� �&r  < !zV<routin�29 �� or M��aPa:-z� nI*7c!C. 8��2m2 $ embryonic2�(/0��.,�3/7G6b;T&�) �.�KaO#!�Fitzg@"�<U�  MvLal Schoo�,h:Z�>� :Y<�!*�)�)of"�<|.|;�=-9"g*J�Douglas�(Golenbock (f�Hf ( J8)%�MEF o main� in DMEME�um l��- 10 mM HepR 100 UaPenic,2 -Str�;myc? nd 10% FC�PAA&� � ��I^me�kepv�J-�, 1�Pyruv�,� L929\;C%�. B1)marrow-�@.�(�C) �" 2 [7!�"� in RPMIfr25�9rL-glue�� ��,��M 2-mer�oethano�/��D� see�16 w�p� � 70%�fluency�Q%"��g&y2� PiXR G �OI��: 1�H10i7 . 5��~ee):8a�qu�ay�.setup�/��&�&via�)!�real MOI�.�O. Aa.�? , to��+��5��M�S$RNeasy Plu�1t7Qia�z�8Smanufac�?*str��fɗc", �:�conLC%�ver�� Agil�.2ABio�ze�Id!1pl�h��s�S*� =�� sA� judg&�-ribF al b!K"�4S1�K��O�CjQ�!e%M^�H�-Iput !;2Estandz Illu��Ho. Brief�7'0m!Tpull N)�9�)< Dynabeads .Pu!Z�KiBB�tr���UA frag6,to 200–400�/e pair-l�)�x� �cr����.�% ,r��ada�toI��-�ks� !�a�barco(!�mpe;� ur-:lane )%�uy2�D1hHiSeq�0 mac�%,0 average 68 m� on 40o �R �6�ep libr6S. R%}� astq�m0'� mappo�%�� ( bufF3�rMor.��6(���,a4s�8 . 0 )� e�!dBowtie 2!!9T�Ft4 . [7�& H�R�)�in"PT"m�O U33Ton �<3 FPKM >calM� !�4Cufflinks pack!u�� �De�method�#b�Twi)�aal ma�MVet� !'ed-.V TM S3A–Ba�o�y��a6�X3�W8-�"5�1ner�2�f+0ly foc onA��H!��~�M�8st a 2-f�Ѣ� 3"G b/.��F���i�r!� ≥5�~1 ':��lj&�ed.` generaKb�42��a 4��U�._>�`�I��V10!E 3�uAFG�ica [43]��UA� �i�Q1�P15'*�5 ,�Xs2)�PR0"1K�hf���i"�*6�5&l/:/��p���bin��s�( TFB i\ir����&be��qto� artia�rAI͖iRE [8�%GSEA [8�%�AIngenu%PDQA&{X�i#&�A�$d�explan�&E�Y5W$�'�TZ*C ( Pr�S1–���!first��\all.Q/eX �)�w�a �)y� of >��5% =[�"� kVv2�-���f}>M��1vi%�th�Z!1w��,D 9,;2�W�0.9�-l&�Y%"t_m=l�graphE��N� �� �=)lo��=��NCin stepi5�� "C�"�\ �aQ��!�2F� W e��nu�in�ȁ�+ �:!14.�ch�%K%��� �=h1�A^eL >mS 2 Mb� � �b�m�,  1 ` R �;e1�]y%k�1EK293=t,ab�SM� luc�"s!��u(��&ro#f� R5ec�^D4n�Zp��e��Systems� s|) ) 6�m���U1)� &Q% in 3 `;t 1" . At pi�,1��r��Znd-�ly��. L9 5��@ *�R� lysa<#�Promeg�8@As� ) ; ab�4>`Y��"�Eto �5 �rai�2�ep��m!4�o �J�Wc��F 493–510@GPPRTENPRQPQVPGEN���.#�W pG =]nti $( YenZym A �y , San�is~C.)�×106*1%[har����� T25 flask�'�eH,!Zo .}&IGbuS_��o ,aO5 minu!�,_�(at 4°C:�� ifugAt 1\Q000 rpm261V. L-��run�^�SDS-PAGEa�gel��[�8olyvinyl�=e�4�mg� �yV�  PBS/� 1% T�[-20/5%L5fat dry� kL8���incuba!OE*>� �]v-rI�E. !�pHovern )!room 6"er]KI�1 ug/mL �Ql"�/seu.lTf(horseradish� oxid�r#bod! r 1�rRv3 v�a a�A>�l���� -Star Wes�<C�io-Rad>�!�chemiP.��c!X) a ch�$-coup�.devvcameraaxFdoc XRSfp . BabUE\"�IH Qu!$$ty One 1-D&�softww!.0 oX\"`lip��u_E.�$=U.aK&D �]�J2�JEd�JP4%:maldehydz!A���m' tFH�Vrme��U�Q�W�Y ate-i�i(� !�P� p�5%Im seru�D3% bovKalbx`aP,2% Triton X-z. S"(e�H>;RL!�E�/u-�r,�,�UtwA ���9n�EcCq> ^{!Hoechst�JamU%" 1��.�%*�KC�]m!�!a �s s�� �Vectash�K(or"N$�) Photo E�FMnmNIS-EU�( Nikon�a dig�}/4oolSNAP EZ; Ro�Indust v conni��T- r�9Fce U8sc�E(�el eca e Ti-S;�I�j)�$�JacytS2ͱ(DuoSet ELIS(UR&D���c�%d JL'3-2NL0gqe�{ �-��6���ustom �2� elseI [8N#Ce;X%�6�� �N�� E�"�A ��8,Xtreme-GENE9; DOTA�" Roch�K["�%2En�EŪ��?BH\!?�� >&extd�r! >'($Qaf=� �$a NanoDrop�t�o0 (@!rmo�'teFD!�Y� P�S(]SLF�=F� !nd Syni isMrPan�6� �RT- "(m&�4�� L%BC"/r 480�=Real-�>@(5��YBR Gr�GI Mas�k�1�2��.�F P�*�aO �� s: me'-Fw: AT� GCTCC A;!XRv: CTGTCTGCTGGTGGAGTTC!Rsad2 BACGTGT !T"C"AGCJ� GCAGeActinDACATGGC !.!C#E Aq!#!P!GA�f0�>B�ib.9 � ��2�3���8 4F�Y&|A8:OTrizol>wA�C6|!upM)mOMinEluteM!w)*�':l�*:�(� labez , hybrideA�k'$AffymetrixT/ay\%wU133A� 9�&�^B�(M&'S�V)��y A��5 ( PA�d� in��',[ � �12� ��+T . Pa�] "�Q( GRA7 v���o�Sb�n"�H��6�R( S�T�ing�A�c^� � s re/?� tb,pat<�0de� "Short��d Arch�,6�% ncbi . nlZnihE�v/s{ ac�0�SNo�SRP00892�/011061 )U�Re.$j Lo 8�0p (@�v*Bmm"KO#acquir! exten�^�&C.�cimQguio) &msE.Kis !�qOn*52%;key!�e�cu�3�+ic variK$:Joli � . DespL9H�1T%�Z��&r2EmN rV�e{Vpoo�bh stoo};W7 ",bd h�7 olog�76Zu�a�/�gen�(a�.ach'G1sul!_���A�e�&�l"Sq�r9X1-eNea%�!���9�duppil1�� !J6�juzM���9pi g�Qsex GAM such!�rec�.?s y� 3-��y �i"lQKKYA[l�3�R�. M�(o�Q��a3�5R3F� se f�0ty��W coal� I3rep%!o-7�s�"keIV alte� :�!�5+�&7tq[�b� e-r]vQ4.�yr�/!=2�gQ� ?p �veeW$it EA3Fo�Eo<�rX:q-MC�g�>u%D=re��0W�)pRZmex$Y2�$F� $a biphasic�n-�� i�@%hevS!:�At �)bs�� , dele%( b;]�ndkMiz!Lv�QW��is�hasA�)TAC�5�+rq�azof ‘9)�m@ion’q��iv�Wr���q#. T[9ighK�g���M&$9o9*.D �or%��1u�4� �9�>,'� ismE;�. Tr redo�!nt�"s^tribup5�X�%#of^-��<�r;�dincor"*���`�2�UN�/7[ sort?!�e *�bproof� !�5-m�Ce�f � #�EAZ��RdRp )M�� errorW2%K1of��3��10−5o��W� [:s"�-��rp�6�Nof ed-g+a�qu�RpVO[�IfXA&�$!al���‘driftA)i� accu�Bf��mi:�,cm��Y��.�ex�L�Q4Awof*5�E� �"�,��nr2orW@erm2B�Ise$.��:� o�JY63 �a �'$z@� D��p0Picornavirida�e�� 6Z( HEVDr�$�ly mst�Ed� �Iont` �tu��=�@a�aca�flacciu8r(A1l |. myeliti�, myocar=5A�x pha ��aE e�%�|ailA}s [3]$ha���L� EH��wB�q!��(Q��M%# rhin� e�Xi�non9�7 l�J7oAx�\o==fE�v�K∼�kb�ElengthA_klyadenyu)d� AOI0end� enco< �!Cy� DeVan ope�Ha��frame!�n Je�"R �0Ys! er n�T�i>nC�o) ��u�qo-Dpost-�[�p�(o4b�=� �A ord aA�:ea�a5u;)a%VP4 , �M� 1; 3up"`P1�,�f�(AE�-uM�in�� 2Apr�82B]�3A , VP�43CA3Dpol;� r��gP�PP3 ye�!�-��a�l�U�;"Uu{<environA��<tab�l%�-b�%rs )m o2p5A�� �Z0�.��A�a"�A! (l� } 摡�.�I�7�55baP� phylC �%�distinctui(�`^�s<&D; \�(e��(of� X�="�d\se� i l,��now u�c�AefKcby"� ���"of VP1 [�MloEu � �4� lQun� vo v25C!0�"�u��!�o�P��e��)�–��Pt�ic!c ersi�&C-wid2lcapsid:�[9]N14�f: rr2�Fi��Hm��^*[1�B�Q33]��Dq.C F -8��6�}'q���jag �:�5[3?^5taPA�mct�!f>b� n�P3 as�uaf,�: .�*�1e[tv f drive2��rmu!�(�56e!Ti�Vx���)U>:b�2� [dN+.z=�_� rarelmK\Jb|i<�[�1 very�42czG , ��@a#�� eme�6iA�a_,�8sum2#�I?FriJ� o�on*<+KCSicosahed���le �^.� �I"�  ��> docu�ZiF� Z-Vl:�,����ty3k���o�A*ge�ic RMtic� ��,aH<� .� u�n�(m��R�r[23e�25]jMP�/A�\t�t R�f=t5�p�5A�!��6�[advantagdA;ye;mua1�fu�.� 6�a��s cir�(� r�tra� 0 ougWaȅ� @�_� ��"�qt!r*� � 37%*40��lB Ui�5!Gl&�A�^ee�T�Rq�a�& ��2��;�Jng9�oB��qw ��A;:�c0)��!?N In2aCaa"���\�Vtco-!ZpB_ !rQ,*w�+!��+%)m�.k ne�   �ati�3!�VJis�lng2f��� �HF*x�a;�  e�<+v���0m4N���i��a�&�bm{2C�U %a�cVP3 [4�H�n�6�zHn&��#g B(%Q*bm"�D�asaew� littlLt@K;�O�vou� 5�vo @~B�(�D� Q���!dem#6-swit2g1C���W"%La�!�NA�!�[4m�a1A�`Z$d}1%��zA$a��on�I"�gjo;of�Hc� |po}3by Ag7��agu�/5~- [51]� �nb!1���0a/S� liga�ia� st_�'qnal�E `T esti1S!hea C!>u�X2�SgY. S�"W �6J���� ����^*[ 6�8S �)W"_low> cyQ-Uف�G��G:Npa�dal ��He!@ll�Hd�K���(� Ege� ei{r�N1*k�S]- ��Af tegy��pre:�C {6�{ a mi(5p&7L4c��a�Z�A>ak!�iF7&� =9.g�%VX�se%>��s!��develo5��wW>�s-,E ��� �� .�%�l�1%d�-�M:IL�/u�F�.�{�1��6ha"���%&nA�S( *&*�B 9p�on y?_ 7ta�8��!Qv� qN. Ouruls) rXve ( ����*��m\��L�F"�� bU\9�0awBJ�*���:l\al hund��&�� ntA-�k.��+@�"�9�� ^�""E'�kE��I�.gABE���l:0o�o; he��(E!�����No �Eie�?1�%[i�#C�7E�Le��F�T�ar�^.)�n�i�\�Uͻ%w)u ��Qp�2a�[6z��`o r ����#n�:��weDc?:"R!^&*jfur�4�t-L��a�ž�_�$M��0eց�)?"�.� . To 5ili�����[a�mb�`A 6�]6"-B�w CnA�y2��)E�*RX[A�"*�e�h�on-� e6 helP!1�or: �r����E�6��  le?!s��� �_� �8 guano4 e hydrochlde"f aay�%R7�D;toM@�An(copy-choice�-�lolD ���x s"� Z� ^'� !��o�$��MlB�[=�[���4y}'C!il-A��-,��|E��Oe_pu�&�+aZM P3 ( CRGslo&3��2C6] �e��&5�W�� ;_: +n!d� M�L��e+(*t���s�is� does�I{! ven �>&�blind"![5�T5�T; ![0>�!���'p�} sub-E�g5"o��'[, :�]& replM2!l`0"*5�$(�����O=EYco^E:��x gG A4_�`���two*B��Vt�F5t��i�?��e o�N!�!eV��Ta"�al%�?if%S.MK�-�i����!Gen�! )R:�lA�"�A1�H��&ia�.�nt�93���1F�j}� �w%MK"1>� ~:�%�*a} �!U� �k�BQ��v����Z1Q��E!�#�&�su�&ou�N���i)� AO���zero��0s%2p�sV� �.<X�yb�a sui�%�'G�Co�s6v"� i^"� �!�� �fa�{Z E�_D�:_nt �1p kstS2i�"�@l��inu� ropa�"O%Å .�z !M��� bt&R<��� �Xll�0q�T�1HN��conveni��b�`i� f&�:n�,��78%�dey��aC -REPEf&� 5�;&|*� )o�ztd%`H�b-��&2�p'B�cH��IT��3�wA>a�ga�i*N 7t�߃�[- ��.p�% �e�z6�F_M�Ab�ca�ed�( �. Nl�inimum!�!�ia� � � 8�Ivf*��U� h�vx�r& Y! �Vn pT7Rep3-LE�pT7/SL3�2-�Us!0I���&g924�E8*16�A� �e"��q�usmx"�6byX9q"�Hin HeLa�`.�3�,bR��)'ua�"&���yple�?�d*��i!�uNun�N� = E�.zed!�`.th�=s&EU 4pK^� � 5,bqor�o}�>��A��[5bWe�!oAO al b"oh;7��]trbM(�8UBw_ &e� inev�x-,6t$���a�n&�["��C-Z�&� �r.��>�.vrha� :; �dE��Ѻ� .��ZN� A:) mu� �Kpe�w�&c��aET=ө�" N&�?-�aoR{���quiva�K(o7|r�ec>lXLplasmid pRLucWT; 21% �[\-q"ra%o�� �#w��cE/I��nXKUT6�fU& �s*.R�� d 50�C00q�(�?? 115�tx%in&�)�) $*7�!�-�wf�4!v (e�V�to��:.�����rQ.�c6��Jor ham�5( �or BHK�"2:;� [����*mh�#( PV3/PV�5oq�.e0�G )q�B2�/O1^O ( P<�;$05 Mann Wh(zy U test"��5ter*�]�a�El�`�2N��T �_a�a���ed"�. Fift�2A � 6f pe� ��1-5200r��M�to��"%�/"�I���3)�iduDFe \hor���n�aH� F�2�Jm�s-�oJ��aC? �?�Uof 2205q�XM��[��6\��(Qš�O���X)dis)/���0eambiguX �!&�/#���/��o�E�:�� )Z?13A�i8�#\)saw>p��!g%U���2�$��?Qb�T�a�=1��N�Q�5EM�4@U�7-�uni�5S]��A2e�(ziK>20!��,~( .�sGat�,in� 2b"q �..�i�P$#4E , #35C%"#44|�-�A Z�ob�J&�+�M��%�, �%!�N�C-3inu�JA/( ���8*N% !��;b#/�Պ��1{��mZ9 engine�%�J�"bI�/.3-s9Z�: :i . �&5% alig�/M'[k�ȉ�%Ai�7 ,E�&� �� @%�5?bF0�� adja�&E�`�_17Y�6�%^�a�ed5eJ M!R of 3��321��eIQ/&G!��1��3��N� ��J�2� ( �)rA1%�"&�&�M�-�PV1"�R�%jB!�"�m� � #32A!1R�P�� cD ahG5�inker2v 6a1Iea6]�?2b'F�M7#25�se&*,.4&�Y254.Y~ W�e"�1c�erN R 2�F� spanA~�-�2� VP1/��BvagB�te* �Q. A�F�2e���six1�wi ��118^�P�6MY��e^��/2B:�\� EU #9v4�� �$$3iw.+$�M>NE�/amino2��2Bx�*S)"h�RI̫xq6��"��.�=un"x"u3o6E1:da�l�gmt�0h�h�|�<�/s%7T( #11�5 #34D�-5�5#67�5#E�#4Eu7e)�\Un>�upHa8"�h�"m�~ �\!�f�v&�$L ��=~ �s� s*Z�m8&�l]�<&ed 16  .FR �"I3( "447–46a)"� 24A^�J���]o��Qy"�-K�"M��b���)�c�rE&B�`fo))&B@Hx0m(i�yd [42[ .K � J�1��]Ak"�� �ag�;P �9�'95/ ��%� 17/2GR9�Jo� p{ c*U-J1ls��2tui� "�D 'e�"�YdԶ �Z�Z.vhJA��th�;a�gdis&C2��&� BO�*G*#3��B�)� ��tsBD"�(=A�A.�%� #51�o4PV33874/PV1278W�d268A�qD�dozen�7S r}a�e@Y *�$nd�;�Y�!5>m@�#( "i�;nt��PI �� 8 ��a�!vybY��> nqC3a�i�l ��pl:� �&�,by���^�Aat�U :�s 10��2N"�a!P7M!�a�� :q:c b ��-ˠN2 N��a�'erz��ll%��S*�3%]a titr������log10�D�.��L+xB�E��@Anm��f�1�I��`e�E Pce��p"�$"t6Aw��B�.y�!^p�XatA},�<,!�JPr�> ban0��:* .���&boo�� GEN-4615R2 ,�m��P+>P�UWy�uME�7�?�#!�l�a�&�7�'hO9y% )Q�Of�t�Fa�ze�� 3�,� P71vd Il /s-�!it �=omi���. F?Ք5h#3h :+a�z3 S�f7ф 3d;E�-aa�–��>Sk� ax��HA�1�x�f2��s E� �6� !O"� ^�]6+ -b�>B~�dpfa��Y��la"�Ns*ontB6!>���E���͵2� VI��"�9LZ 6� -�35��% �!2 6� t!}F� A�7C�2[,�+m=%��7Q E1;)$49�Z83 %&wo60�� �48522560#105B��V3347� 1228���j��c�{In)="�,>1( 6!�12���6�#i~��A��<�I�*Y� ]P�]�Mi&Q 5��f" #X� of 8m���ed�}��A�zp,u.!��%��nt) %Ki�(� ,Htɥ4-�WaT2��C%��!�uw>� ��M�6A��fAG��~�Am Qcac�! l��57b.4 f.�AM�!��erv 6�–13N�S5L �_Oterpre!q I;m�N,ng�w5]��+a}`J�'5 s&b4. ;{ g�,Mha.6^>�U&�72"1z1t �Md2�L�'by���B��3E �_��! b�t& a}*ax� ssagm-meǭ��)eiɭ �n!�tru��a���R3� �lun?ct� ���R . Pom,l�B^4.�\out/�y�.,l���!��2�i�5To ex ;.�w�BtG�1� A��!�.{��#n��t� �6�'w7* � "q/w6"d['�!.FN9� ∼85(4"$,M��s�L�YI�� A+�>_ ii)*�9A@ subj�toնs6u ���,by +<��r="V �n4e�6| �2� )� ��"�*n �SiGK6_I T��.;I�er.m ;KŜ�G�.a0s�a�"�m!�pj�(R�3s�5%Q&^ . !�a�A�n x �ѧ6 *%��05B-3&�m |CQݹy���,V38:38�.:#%�rB onJ� ~�[X�%�����n�r-� � �2��H��r�k!#5�"28!]SjL &*�2m3�IA1{�}�Ted*�D�+1M���-m} *&!�^�s� &0� 378� 44:�,^������a�%���7&�J��M�a�H%1+�+F�e�@4B-)�A�x-�-a6�A6!3su��,�Y� �"3D�� Y����]1Q*�!;� !�9gA d��d}|RE(ik�Y(i�V���2z25nFc6H . F�:��1h .c,b�w��&�%&J-"`in<%��i�( 249LinI� cf�km_-3 eu�A��;� -��!��4N#�!O>����!p��� 8�"�3� Z o~T�McI/Un� e&o�ɵpZiba@T�9a�g�Dal" �C��T-� ��aOX"�.�%(s))[5�E��� �W 1afa G64S�{,;h�AAQ&("%{Y226&tz=��o =�q&�=v"�[ȝ)�&� l� :?2�!4drug nocodazol��5��RHF͸"�?eJK&{�n埁��r`$��DrQl&�I_ �w� �M/ r�<\[at98928[6�JBMw�άz�s�P�&ߛ�JueP87#6a�m�#�:.��+e�omp !w�)�*Z3!O \,B�^|��1 ]�urunc(���P 2�ng"�&Δ,ΔDbIg �!f�,�u� . UsX!��)amGb��B�9S9�s#V� )! #A !1 -6/^"� Aeof.�OrKy��ţ*�g .m6. UJDt�w&G�%)_Jo(�2U�^s-r��PV8%=- J���� ;�_4q-R�2� s grL4�a�|5�M "g���b��gen�o�!�coBZ r.��*�Cm).�+�byh274�J ∼3 2�m9��&�0�fJ+��R�� aZ�p� F�=-�BV�),�,.f�-Me;g�C�+a���n���Ea�e&+<6��Sd.2�A� #B9Nu���(nd��2)4da�Yhigh-��� " markcw!Zi�A͂�,Q7s5�4S,L>"�em�*�8]�isc�s�MY$�J& ջoc[�&*4� par��lBF�%���,RHsub��o2�CQ0"B!"s� c *�ॉrf.no.i6�J5l ����d9Oe�N& "OW�))!�E�>2��hil�j^!��Ԕ� *F�p tubuPA[�"� �K�ie,�T"�E�'��.�o5 (, , [63=��e �6q�0��P��2�*- .�2/7ic9w2o�Ƈ9yf%y6�&<�6%��Ն���^�>�>�ErQ�s ,A�e@ ��&��UXto un�I�Jk. T6u�E�.��F]�*� "�$�:T%� .�i lex~ ��*�g�j� R9�8$h6�Sp q*A. PR* impmed f)6F$8Q��,"��gJ r5��ty� ������[64fW���P*�%�#�� A����� �� �~DO�baL� *.$�<��dO��Cg.�� ( MFED )2wT  � �`�ombe�ro��0��`a vr250qwindow># aI"4-6N?�Y�5� ��~DNj�+5%�−15%�$� 5N 52�e�6�*Q9����e)�!6� x3�G!�+B58� . 56%6� a]!��%Z�3("5M��j�9  9Zd��o�a6 . Ne& 3�oradr6�"s &������maxE�"E�[iB66(9�!K"VB-�2� &Q4EQ *�26ZUd"�MCRE!�.��&x+6z� Y�M�1E u�� � obsc�X���eEV�W}��c%U'10Rh�-�" zI8![!�.�398��ariJ��>to 999u.-f� a scram�M$g algorithmvND_e�m,G���pfe�;�;Psi&�1����bia�d*�$Bnd�2.�( O5�6G , UZ7-1il ( A+o� C+G�rO3.ne/pyrim�VATk�%�) xr�&aXA�jam���aax at�sird-pr=#3&rH&� ��`? !��Oi�ir�u9Ai seN&rg*iLe�.3�ÄE�VQ���� a��e9����Q� pid� eA"ae�"6l�q&6A �cqu*q����H�vrop����,5�����IePl ^b��d!H�Vv�on���`exc/)! in 7 days��, @�u1MF2 6 � Sab~& o���m�co-.Zf�"\k�S ng -:%AC)�ty[�yAcl?�]as.�Tsp�s �J=g�2|52Qage [2�-��>k �6�:M��"��B��"  vR��h�p6wax%%wan!�i%2�a*�h�]xucʄ6 halfE s [2&�h& e>�!x�r�? 5men! p"�r�E�qi��A0{l��5 �o�d�R�[�s�q�de�!�s*�r[Qf!��m7%�A�e�l�&� ( �� +�I��A�r-Kb oF�{�c� s#*�["{*]e��~0d�[[��. :���d�j��qNp6-1m �^]YS d��H0Ms"}����!F�cN� of ��"h�_AOf8�Zs�,�y �A�/Uni�!a�".O"�$=�0q� �5�j� #I�����;7��7-]�"�v� �`>��o 66� �#"� t>Ube "�toV�das so&mA�**Hey��e�!bpY-�uF�%�=i&5Ret��among�w"�s*e+��e�aZ@#5� ~u42 ]sN�Q��r��a1�&�A�� 6�&W^0disru�H��| �], #]Ah�a8ljBy&���A�kD2�I8B�la��[e�Y�*]�X����%V�so�M��Y��6F%z3�� � <c|r&c-)����wV�J��,F�(6�'Ma T {� . H�S:=�*e[^\iá �SN8�S� <1%we.� 6�g�Fb�#�!E"��)EI� -�2icJ*2;>fe!s�}�xn�*} >�5��0o���[xi�-a0en*�Qt�>�2O"� �QB (u�A��V2F](k/µg� f)2�]�in.�!f"� a �Y�OJ.��as est� !a'!�9w�w4s�re�&tg1-���� , broa���q w�fz�acoE�!a��m8��H"hPGK��o�Z��;ab���ve42}_�un�$2K}�':�!*L�� &&._pZy5)%p��asP V*o:/�="�@ !}A=�ZA�W3 6�0��a&)?mVge�W.*oigu��y�wo�!��.�H Ad&���;"7+&HQ� QT=2�1�u� �ab.�z pane�ZeLB�1/Y�"���W�"�WcEH;$xa�r��r�!iedř)2�_�"'!5�i.Of�B)Q�&��]beV3:A�, 9W�5. E2O+���)g�B( 85% ) "�7x�-�A�W� �2!s�i *E%� N�?)mI���b6*<y!�FUL"nT�!���&!L2�Wrat"�5h&�W&'-�ael��8_6R "_V���rs�� "� �)v,��&� F� E=cL*Cx 1a\�!�"ͣ�^>�Y#�&.��#��m#Y�v�(�5)� ��a��V"1 e�kaZF �B|fi:�; ���;"�xa�4�H5��"���"i�� �P�}*{mo� �P� " �3�loZ"%��-�.�J)r�U���;+ll%����sf eUIn6� .T��9@ti Tq{ V�0'�;]"�$:aEW�li" ��U stochaY!!  y&�Va�-"�� E�#Y![�%�~�p� ion;0!0 � 2 �6.�w��"�StoM,)��� (go"R�. ,rounds of re��plication , with the possibility of secondary events ( see below ) therefore being more likely to yield precise recombinant progeny with enhanced fitness . It should be noted that the CRE-REP assay we describe here involves analysis of pr p(24-48 hours�$t transfec%d. During this period , sel !(for genomes)3enh �rep5Ol)occg , so%[9Hanalysed are an ind%�\ve , rather than exhaust epresent)�(of early re-V�0products . Bad@upon our demonstr (?N��>kinetics after passage ( Figure 3ab ) we speculate that precise�A,,arise follow!Vrapid.Nrom) itial impFG , and!t!FHy quickly outcompet�e lA9fit6�to�vail in@9~pop�a,. We also noO^�$were usual%z-�4ed multiple tiAdQGe group via@-J S1 )Auggest!%Ionc�4y had appeared��theirV� mean!-12%xly becam^ domi�virus!$A[ . TA�interpreMlcoulda�addresAWby nextA�eMSsequenc�I�iz�U viral RNA.�of co-u�$ed ( or ina�$ed ) cells�futA}studieA�All6�%�harves4s obtained con parepdup��s� O � . Althoug�ackag!�)1of polioIGisaA know�U$previously}struc�(dicistronicA uses)U�at least� addi!�al 573 nA� [87]%�of foo38d mouth disease e�� hich��sA� s a simil�Gsized%icl��0is 8 . 2 kb .��isnr��un��e��lara� 9�-B5�(( #67B; 321 �;2 ��$s any sort�>r, but�'ref��� ٧��y uA�o�L(e mechanismS�3n2�. Fur�~�� , si��.-�sŽ� mixa���ge��� vivoaK! �,cE�fullye2le!t��l)�es�ihe%�%� rang=]�wes ma� h��%���,in sufficien�'M�ve�7n�?to �Sine�xɁ�ai. How do=�=Ac? ��f lower\,[at alŐa natu���d?��thinks:� tochastic :5@�,�; missQ��teri��?Amq�- �%Ln�w even>onl� ed�sh��!��� al d� ��vell�9!�uma!eiAh & ano,��s��hos�or be pintM environm���loc���ic� �! dorigi�XhA? be high ()Ghe.� poor , if1�1�i� wF paJ�2�to��Ň site��l�or5�result�,a founder efA��n I�H]� –Nsubi)A�0solved deriva���i -canF lifer� -, absem���=poten�Uly grea= fiiV . A strik�7feA�Y�N� A� cove�wa��ir clus�Xng�regions�Mod�amino a,carboxyl ter�A�2Apro � s 2b , 3i�e�)$�Mofiv �U  majorAY( 94/95� viA���in 16/17 ��of b���Lto �,e non-chimer�7era�%{/ ��2B!�teins;$sole excepE��#9C�Y3�Q�caB e jun � %�i��\ first few)<rAVcod!�%@e�-�)�5 )ydsAReAv� C)� 1-d�2��� sub-E�ic��ony ��ner (�polymer donor ) !@those!~2~2Bo 31 ��� p�a* type 3�omen proB @is.ji�coU�1NariE�require��f-�al ��Y �A*��.$+�is}rarely�Wf�r� chie!��8single step . S)Z�� l�ǁ_sA* i� sourc&r!�i� B4^< 3&: 2/���N�!�a恱3–3 O&� ) ce )S 4!�lat�^� s^$A�pr�U�by^�w� incl�an.I�or 3C�?cleavag� t!-� 2B )U theseA�vid!� auth�c%8A��oly�procesAW]*aaontribu�)��AP&�!�Rn� e 16p insert��.�5′ NCRxQ,in #25A must� �n!CA#reh�UE(!��!w�Uw regard� temp� =)is9�a|d%' �bBlit(not%�r��itŞ���,��� "M on�J��a soci ��bee� ci!RI�unA �bV spanE�! 2B/2C ���Ɓ���i�"<, w^a�>g��2CT 4E �� #44B���M�idid�� . On6�� ��*: ) ��o�; *hybrida���A�&� establisha��'�j 2� *b¥�Z�across-F�Sun3K  is dueef� c*in homod7s%� , membra! ermekz ora�m   "+ � 8lex [88]–[91]� ltXiv�6>O �a�16ig��d uc9��E�r�� z�D� i"� ‘heaiUail’ era�2 � face!� betwA�A�*  ue��subuni� qe>F )?� . Rea� �!�poi; i�R��oA�9r�a�ortsymmetry���a:��P2 T 6�AKr ��A0C coxsackie A��u� !�H im�� ��in-  �)c� }dA-qr]'�n Kassem� [45A. The ofWra-sero$ r&�s��$∼10-fold� %UZ7y�� �, a��a� ed number��sample�a"� � r���!� form2�(( 87% 13/15($30% 41/1367n��5Fuv"�,will be needI\deI�e whe+��bo!��A A9se�m� �8"^�nt�Bm,Q��i� M M��ly5��&r � i�m fl$aeY?5devu M}U��at�& lsootk`"@IjAEaof=l��"�.x . I��Binevit� ncod�tl ��hco-evbw�9"I opt96�=3�%�>^>��6�a_"� infi. I��"p�A�e��e diverg �ѩI acid leveA��f5Aq�� 4–9%�K>J 1%Y3Qs� ,� !s2C mighr mproma��!-�>�Ft"�k a~/ loo�� dapt��^ ged&s)di�� :U�e=R"�)��B�(is biphasic� 6%�Fa�! X !f� Y6�nt�.P throY �we�L�oM�)e}&� ,s$ome-length�_}�A��C���bA}rec��ngaYR �&�,��A""R��sh���d.+� ��For ex�?v e syn i�#105B2J cDNAA����A�Z��sZlF� .<predic�a���/n ��5^5?��]^a�Pq@!qQ� poolA�mole.Z.�. W��r9�I���)�� Tar�f X(fer remains�A+�1-I���xl��tE`�! as}�l� c�5-'q02&a.�%�/��2� �."'!explaniԁCYM]m�Qg �i �WL929 myeJ�l %��Kdqhis�Lh��a bea!E}�6;� 6�F c%��G6�Y�a �f� i��d�h&��vby diffe�qualR�-depen�� at"_. Promp!�by�ob�)'� !"�*m 5�IME os��UBP"� "� #!�a �in-�s�!e�w��igM�� �imary�6�s"�#�Z. O���n� ap� *�.-�neg�JV"ndurec� 2� "� 6bō~ �t�l��&_�a��*� {q�a�wUund nDmpell�2e���)/ �p>7���];%O�!Ei& � i�UehY�IW���{ RunckeI�colleagurecenty"o/n eleg�j�! stud� 1��E�2�� n�tagged� synonymou)"s [64]�)�5#� M�Yr5#cor�w ,BGų�AJ�fiman�� +%Khotspo"�app�A��� approachQ>�c9�e��9#taW>_%�"2$S  o�ow%� sepa�`T 1/1�I#8�5�ڭ*~& si�AJV� -; in���" �A��J��:Uof��!����coqoq!�A�ngine��( I-a& -1"���s%�rXy!��mv}p��s -</ ��mbi�Il�1#of.�3F�A�icueQ!�subtl&2 advanta� �. �ereby!{�&��L:t"}!e�� �e0S z a��]�} ��� bye�e�onU�h�#� %?�or mo� nput)� es [92] ,�y help eluc�$if. A�pre<�ђ�!�5���� �g7"�%�m쁡w�m���5^ />�ͤCRE-R",*A�aJr�v�say [50� [51]����e< amou�� runc�r vari�� af��� ��4a�U� �n�$�#�typic:�-���25 %�r.)m w�!U��n *� eX ��A_�� � � lN�RSV &� v&W . B= sA (( ribavirin��*G64S P, error 1UF\��aly*dA�supnz �!"ver� �$!�9�b(R�.< ��n%�9g�]�m�(Y�I�U�2�u%"aZ� i#*AfU|~Qk0 � 48�Pup/��.���� pJ$�# 6Y,EWnocodaz-reducr�by�70%�&�*no�"on� ��oM [62 ( �S5I]abcŮT!.�Yfge��three��!�*�=� EyMZA�x ��u � �Zimp�s5�� apeu"usmarntii drug23we ac�� ledgm�e9tis C  ea- "��i� daXB(� 6�)�onsid���l � (f[93�a94A"'�o&8 !�-fd:l": rW�l%+� es fd"�.a���i -( ],we)�iE�45-fluorouracil� ��Z� �6�( data fwnEdVS ,exten�#A2�0�Vge8+inhibit� �6m��ins"7':w *�E 1+ ngagI��.re-m�I{��. Inde<�+�hE�alread �"� (at mismatch�'by��%\1��"�-��A3�[48Im5AmHoR��N��"A�m"r*&2 U�a?�=�$��1�*yO , nucleot !� tit�sxUm$�� e`&�  ,/Woodm�d Evan i�&� ^�#�1�si�M�VP/��(� a nC&� � &r �toH� �` !y�6 mark���� �(�2���&E de��CRE���Do[{T progenyA�� � �teRD>QU4%��ad�∼4%Q�m��a �3Y`vval� 6I when cw +mo� *� in vitro��Q�.F�@�+*L6� �0"�)]Vn��i�cp�!�6�&e���Xt�azJ�V^�h!�&�2��� lack!h�HMofzq�2&�E1g�W46�$I�s�4�%confin�!r� o�mpX!�"�# does�~"{[pi�p1� lex�q5. F�,�'"�v�,���-�� AA*exo��a�xlig ,!�w�- docu I�ad�icorn  , flav�N alph [51e"586]%u(7 qJ%M���,wea�ia�s��O)��h� ort�7i&vo�r1d&Jn20 Q�m{u�~0e����b����6�scrib ��ա�*����rea��� �e* if+.Wi(.0�} � ),farjfA��z�8A�l"�(�ul^I !? "� ���es B e2�( ech�0 7;F3 ,:A��l5�!6a+d�M9!1jn *� ��ETic!��:�,%T���0ao� :�%�ex� ��m[97:��,p9/d�emp�� �'&�%!Hn9�e�#-�nts5](��+O6���-1yC�F�=)af~��9�s 6 7A�p�� velyJ���� a�&Z&�"��&�&� ic��t", i . >@5!%Mm 22�� ���,ohap!:cak they&.wp�re��g^:otJ�*��*t#*H>�"%�am�ne�� �n*8�%[46A46n'a�rar�#L!{2>!b�%a�o�&�-pe) ��lanc=� incA�)�!��ya�b-�,or�8%art�alj(��s�Ke��"�"riv��M�,A�� 3 b�4p%�SH e� u��!e�h�Vgu�>�� ?|�.w�)�stand) Q�#� �ve �r�&8j5T�EHs�$�6 ario9�.cha!�e+=dZA*t ��a�, shap1x�'�ZU�%c�0�-A+IP!A�$( VP1-3�=(7shaa!�monl)jeErolj)� e [9b U� tigu&VP�! c~�9[99�� Pa�v N2A��3C �a!Z [100a I&�.at���V����De.csT1] O.�0B6eB��#�:1�[102]A�!&�1��ct adja��:�5� �M]Clo�4V idaeV3��H2�$}$.!Bt2E,2�5cou�(w|q2*!�6�=acc���� ‘Y�`yf�+. Likew�,.T%����;"�#�s�ld��9!9�,=-*�palm do�!� �9a�A"> -I�e #etr&U 10�OE+"�� Lly�~>3�. J l� 2��a ly�rt"�s� ��So��i��n�%] trai��onQ�E%[1A�<�����bm!�i����� . An� ro�x='9�of2���[�acqui� '����7-�myJ��%*.��Dll����rs:�b�&biologŧE�&�,~A�)&f �us� fy h���4b�ҁ��avo��%plo#. �/,=}# fibroblas�=d bab�Ama�< kidney ( BSR-T7"�@qgr�4onolay�Hin Dulbecco's Modif� Ea�50Medium ( DMEM� Glasgow M�@um Es�2�-G-�le��G418 [bio_>4a �F0$100 U/ml p�i_! ,µg(streptomyci,2 mM L-gluta �(10% Heat In vE�(( HI ) -FBSA�llM0�D#8A�a<Y,trypsin-EDTA�~stU,*�( Sigm��EuanU7,e hydrochlor�%%�ad�$(rowth media��con��� ��E�!N&4!H�2�de5;aIpre�9lAvO �10gB5at 0°�*��a f�6�A�5 µME=MSOM QlyAadf �A;N)��wo 'G rior�.B +%&�AŘ1 ( MahoA�)%�3 ( Leonc�� f"F2Z�e��"�(�7 bem!)� J@� r . Va� !kquA�e/� laqu�asR�N2G)�"G�B�*a(�synchron &�3of2�3t aXJ�>( moia�f!� pfu/A0 . Unabsorbed^ �rem��byn4E�jile PBS%�v6A�cube in�s]�37AVn atmospe<� ai�55% CO25a�s*TE:tat!G3-s�>��2�1�6 � �m�co+a[� -^i% an%P:N3-ach-I�mova|� 2e=Yin5OhFH� I��fr!U.at+24qQ6( D;i .!�Q7enm� disp�2 @st 50% cytopathic% ( cp-:P+n ["ly�+� �,��/:��Fed 1∶4)> Ή��4��n&"e �~iclomFb2B�oub�") d� in 96- M�s�2%�1×105}6/*. P� Mino�#�w iU�atI�/M�f�6Kays�J ime)o M�>qeBsto?��C� !de����w��cryst� ioletU�.l"�$7st9.�a&te%�am�D��F� pT7Rep3-L�aH �G>�sN??b�+afZS;�-fr�"�lac�e P1 B c�A&�6!? . pRLucWT � BR-bp.plasmida�1�a���F�1V�"�tR�kE�6�!�� thn,�M�� �[[10�pT7/SL3w� �(=[56 � iB �1��-� >��a�1�8��o�)� &x�� cis-u ngL "7e  ( &)E� 22C-6�V.���-��7a G PSe�?�a� resim64 ( h� designe� N\# ?!�`&�(*agK&b� � 8by Craig Camero�Jam9rn^8- _"NbuiuEtf;e5�%jI� $ard method#=PI�s/�� Ω4�-T>c+Sal I'Apa I!"A# � � �T7%Po"1( Fer� asD&�!@manufaw;r'�3otococR%�al �2��n%�by �.!�2 U DNo Turb[EAmb�߹!���re pur� �RNeasy�  KiAxQi� ) bl% rophoto;ic"� �! P�"� 0 .  g� 1� Do��EVR,�35RNAs Ap^1� Lipo�� 2000 ( In%� gen;� Nr%ME.�� U�-:�%��'6,t�`9 12�6 � disK!r.'a�B$ �� " ��}��+����-ed-�Y�"�3  y techniq�.���)n!uq e�aPs toge��4A�U =F� ���!�RT-PCR �5IZv � �i��B�AA��cI�val�*�Pf+JOT"{'@Q��x��}�|,R���iin�rb�� , :� �6�K�*. Brief��%o��� di�NQ�Pm��Pac��re�#,k ���7!��Bre IREm : .@>@S"�O,��)!�6�Xho ��*.�����>n9�9�� +���0fixa^4N x Δ��pri'0m�'M�Δ� r*�,jE6M-�0An%+lu�%aK*sub�)�}Bw%�?y�ՀN:�u�eQQEalw &U � arallely�6�� abovt AWun+�G��( �l��)� B��"CK ��.�. S*� i�A-�U , 60*h g���jo*�S.k��Tpext�^cla��cul 4.� )�a��RNA��ki�:rse�*� 6��� pt I�K)pt�~.t�B(an oligo-dT�.ro 46��z5&R(\�� e�re E+?M�I�AE15; at 7�. ���B�&�!E9q�e EP.c�t"B'sn li�Um��( allJ8re9Sup�kTl4*F�{KOD XL �M ( No�H!e�r�6] !�%�re�R� agaruLgel| c� 0&~?-�^UniA�DWarwick Genomics F�*� @ ABI PRISM 3130xl)?'A�ZGS�ce& + ��1"U3of Las@$e v . 6 . � DNA*Mx6Mal� �Us2�D�9c�TS@�'F� L2(�(bank #X0092�-,�1"k%V01149� �(e:*-I&'(-en�!R(��  To f)Z��d&Wof]��  al�up灦%OB �A3���'nQ g schem�!��Oq)�ur)�on�-���D��A-���f�OyI� rele�4&� ��:�3H4>1"oJR=!3<r5�_$l7$O &��u�=n�X&(�s 1–74�< Luci�)5�r2�)( 0X74nM 24109!Mi�a� link\F� " U�%I5*�B%�VP1*�/X ,� , �U�:� star!t �244 Ica�"xrx�ݱ< c�=,be unamb/��&=^to��+t \�C aligA�pa0=A��H"�eMS\ assu�1&�q^� �:Q!�i=K!%�po2_G }!$ha)L , PV33897/PV12737 (:� #14C"]8� .eY� s 1-N �PV3eOX-��A �R�&� . Mean`� energ&|>�9e�cal�:� &� *� [67]��a5e scramHalg{Th�NDRl-" Sm!o�~pUs2� di9���3$F9@! 4 $#.�x$SSE packag� (8] .2�Beisof� te adi�' tissu�XWAT )qaA%q9� ppea+tM[� er3 !�-�e$metabolic �0e=�D(norepinephr*( NE ) -�� jqPw :�\1�"9(�[E`2a��"^s3. SLC6A2H symU�j neurv'r� 9$ammatory m�Mpha-F~2,�AT���ow �7 chol�#e�N�X � �)8 +�e[c�.H�,4" �ELmo� orgam2� � a�eru,Oct3; Slc22aanis��7xp(`in%�����$a�( st uptake3 ŒNE� A��\A� $!@ou&9��Qhcy(Ri�Ke-_.�!�0�$!pd!Ya"�a , ab-�>-in�3 �e�Od� mper�YE�rm�e�g li�N��bwKli�TmE 'roaaApdrolongnE�ch��]k"�'alEP( ing�G&�a-'�,�-� �]miq hows�U}`g�p!!mc&�'�dnd�NatA& �4-�- ��ic 5mi�] ondrr!bi5ge�/p$inR)6�"��W�/e" 5d β-adr�k�-b!�X β-A� /okiX&8 A ( PKA ) /cyc�'adenos��ph�!�( cAMP�! �a b"qIo:(reb )�: a�;IC.�co�U �} �`ogram�$�~ifi-a�rq;�mpens�m��lSof ATPa*��M�B�NEZloaivic�H %�� T! . OfA a r�;&�(Ee�I>:ui6 OCT3%� alsoI f�to� as�7} &4Jbasal5Kc�� ( BMA�. Col�����&\<ea<t% g�ns-s-<y�9NE A�ng2�V'o(H+"�^!Hq�,QmFs . Obe�, a����SYdby �] ss b�>fa��� + risk_�9A�m�.)w"�Ao'� 2 diabe�� cardiovasl r6�nd �;c"ato��[�U In m�l=8��X�pr@Hil�I6xi� � ��_@"�*� AT�e��b zed: AT (�� i�� B_ape[2+morph�',U� ,6�4�a���F" � �,2���quO�[�+�n%s nutrB=(,riglyce3&� unil� r)7 �[(�L&�ʅ�!EfatA�cid� FFA� K!�K[�*! FLm8+i%��� CAE�b�i�=28 stimkZ�r[�$>�Iv1�w,)�l+�X�#bM4�I (us�rei6Er b/i.@)p�,h(62y�3<A- ��s�)� surv(9���accli�XzѤ Also�}�Q.�eG hav���$�Q!�c&-zX o�Aq{ >dAF�'[6 , �3*" AV!0b��f �R7%)�i2��. b�%I4[8 , 9�<pharmaca%i�3P$F�hormo�su�^V( [3�)av' ��a�l��Q�r.to G-�a���y6K Di?��c��2r)F]�� �?!��$ulAMP*TH �F/ [1�#�:� l�-�; lead�*� b(K ory@ ng1h sen-v�p�Hsl ) �ii*y >=�q�ven� REB�B5�%L��*� *�Gh� ic� ( UCP1rGC1α��DIOuMo omot�dsh� ` �h[1@1��tJ.l5g�mdicho,!���k}d*� m�.ai�Qhe balap78NE-� L@.A��k!6NEAAZ uA�@�me1ye_�m@"� �&� iŶ�9ed�8R�;[13\2prr@AT [14a�5���5���" 25Cat&�%="�NE,*u?sd"ni�!�dop�,a��DvmodA o� �� nerv� yste2rd5��%�+ blood cir � [1�%:����s �3;�elG.dj�6J�a�� �pby�"i�6A��!,�at�,� olK"])]:)n�9Ha�+a]� is�)�by�, ��� 4��%mV\2.�"&byj 0s [OCTs] ) [1��St�q�3�7�*D6\ �0�G�\ �D2��"cDi7�9�*h21��*(�nI8!�� .�h��r*S0���XeF�L19��6e6h �nT6� Jhs�a� �G�� 2�-,�2e�i- oxid�<MA�[2�TQiQ2Ms!��"��pErac{8�A�e Ig2 }n"���a�OCA�KisB3yn�224�0Ayala-Lopez e�n .2>alw"� : (in male SprS-Dawley;V d a!���I%lb�!"Q :�uue: NET ) or/!�6� s ex�p[2WWas�6QO)�.a R��Ef@t��NE�����"C\���V�N Rl���Vn6�6�!� SLC22A3 ( �) -LPAL2�j�*� @����   coro�:artvM�� mp-`�W&n!7oNp�$�2C[s�T��� �no~^*.2Z�:E!n*ad�?Winda�Yu�to�%B& &of� . AN�V��6� >� or�:��i�/igF;R� as)f���*� ,2�.���ol%�� V�A��C�!�(fl/fl ( Ctr� �.*p�{ng!>A�� e-W~5AO_�S( GWA(PCatalog� OKb�ofC�!� Phen ( dbGA� �UK BioB^ @�@Ml6�!C��� aF of�e�a ��h�fz�T$kf�ng�g�'��!A r/ s>�� �C.� !CI�6.! �N�(pl�"�E��?�-��IUaB!��>%/�ea�5@�.Uţ�a  g*peSu,,at� %mS&-^�Th1<%4al C57BL/6J mo��real-�1�#� �s�F@als^"�f�6�gonad"�gon!6)�- ig 1w!%M0�,)*�J��6 crip�3ve'skele� muscEolz  ,2��5( S1A Q~!CC� e�F]of27 )��~:Slc6a  "U 4!�'�,2�ofI�%C_om^Q 1�E�Aq�P Oct3� !"�Y�|�Qw\B6� `B����* -�ePhQJof�o~ 9 � s�V��  (a�mabund��C�nE�MO-�9,m8)� lFaar�MN}r�itselfJ.=%a. F� ! � �O 15+�enric�w� e��.��a�tro}as� D�SVC� �D�E� PerilipinV�M !�mBr,$F-��"�l�}�oJ5�%1#u�SVBnS1Bu4�,.[p�$K %R`OE��B"�ON�a�C +1DtImmuno`Resc3Nhl1 ym m�m� =�-\� .�&�E��0 �r� ag`t%MmIBt�!��g�1-c,0yl-4-phenylpy�t� ( MPP+%�.p ,2�Wmyr# �o�ss��%Epermk�|4HEK-293 Flp-In��!RiQng �.�>\>��n&@8E��,kO2i%s:~-wF�uH� �ɁOct3-��� �o2m~aCng�u�1�!-��&empty ve:( EV )Aq�2. rK VmaxAZ�-182 ± 0275�?,  57$174 nmol/m"�E/mi�)�M3365 0726 M5 . 7M448ZM)"A���-UG%UB�:�%c%�m�1Z600k<s"�m�#���d�1�2��19qerI2 (�28�3 μM;�83 49 pJ.) [23��&CM%��eMa�-"�#,�-af�y �22�ɱ�se� *k6jvpfL�a." 6.�/eri�=}iW wAT�h!&G ��&y �ex�-Jk� NE�́ &���q#� ���J���# :�ayOJ,� �7as ee- sn�3al $ s=Dmod�lv:o�  u�er�$ GLUT�$"�.. Docl6�)5�)�)� g!�:��&,:/hisO62;.�߽GC Z at2O$( E = −4e�m�N�Ta�l�|� best�Q�� sc�.,?�~A>�)favorz2���1�1*SBbi"d�-a�e:Ah*zy�}"�a!`%�&t$K215 , Q24� E38!& E446�uE�mTo�8�&lcon� o�V+],>�5�m.��Bv�ne �ue��e�on-C�b�$��`eTd� e �6� ( S2A�Disrup� ��gTrby i[AToL.�%y�[HMwe/Bn<t&0Us& 6AXg�#L la��n��. ��on*r Al�'A�&�(}lsx !�t F� �*�% 6!"d&�C5>WgAf�nor� c�'die�!%�s:R&?#%��heWUyEhv�f,>no.�$�(� E�"wei_I� ,USc+am*T� S2E–S2H �[P ��� !MI $6���~ room��er] ( R�u"�D�(>6 in��L"{(�i&� [3H]-NE?� �]rU"y= �)ndq ���B�+�t.,hys�Iice+"�02��0�Z@ccu� A�a(6C%( 80% *M Ad!�wh��6gUj�Kj inF�� V�cUi�� 9?N�$ &I. More^ "$�>%}�9�am)� =c���U!�3alU��) ( S3�5S3�)!2 -nul�)�\Vr8radio��� ��L���=� AB ;� >473%(65.��D� F�y,ly&�J&� ����trj� vo� PS �L ^NE.�>< . Gin���? NE%��:�nV*!]�e|sou�Qtwg&.x��[a��]>ce�"�bg�.-$ subcutane�inj� C,low-d=&x0  mg/k�,i�bjR:I�I� e��t.R2b!� .maximumb6B-:v4 %�of�<w�:�~ol�,re� �u!�'R�5 N�����recei�ON� -Ys22�5d)"vW �o th whole-�O2��sum:�H2Ey2��*x%� &G29e���paհ�Z�-n�5�  ��3�ɍn]t�nl" N�� *���" "�� ܑAN��FF?MeE:�%�&�.�Am��B7.%�& � dAg�ab}>u%J n�82�fQ��Ucp: a 5FPpargc�#( P �A a 3F0Dio� a�5llr�% tren�s�pAtgl �* ��M_�� � �w qv Z k��'Gr8 e��H"d!��d%�2m��&�!�]׍%�e��F�Wm� �]��a�(}�U_N6K ai�y�."�%%$� !Min1)f>z.P��4A�A��C6�-i��'"����-m1ct �jic "��m%'4 )�rmici)` w)�YhE��F�,> IE=gh6h. A��%]�H�!63Z=* '&�vifeo1&d62�'�al in��E���in: �B2p��=��QgeasxgFum�b6�i,�[rn<n��/%�� �/V��2Cq)d(E��&�1�^eZin�Ai�3HE*W&�a"�"�_51 ( S4&� I���c�QslB��gwo%�q�9I8�?d?$( pHsl-S56E: 66g[2�.No� icek7E1�*.�z>6�&1 ��b�a!�&6!�&�&̇l�BK{ h��I��B l��o impa &= %"�X�!�#�ula�!.� mGCH,�*Qj � �/β3�5� �&�+:���.:�\5� Tހ�+)�� f���.?�!�at U�E�[25�&N���P"�i��NE-Qhed"ero�I�+� e%�taUr� %Eb�`1 ` %DYeo�"2keZ�&F �*< ��� Y9�<����*5AT>e m�T . AF 9"��I,MVwbA!5�Je�?*�71W�f 2� �91I(�^!�.O]  3�!P@\Y�����3PtpYvn� � ŵMr.�%���KO.EZ���t�NE�F�2�}>=e%�2�2LQ)��S)"�(A��(-22A�m&�r *�cBnd o;:0iX�bod�. S�.at"C�Q�b��unQ�� EA; h"� JM�� )��?&�!%�i:n�u*9ZJ��NM�We |*��e6F�Cb��!$a � -of-�8)$�{!�e�%G��~Om�e�)%+>l3T3-L1k( #Oa(*�/%cF* 6��!b&�afv9!��t;����m Oil R �CFY���qy� e~:���ǩ��!-gr���|s.� ttenu�a6�Hm�4EV D2_3a�:�Wi�&Yn�q)o=��"�I mpan :b�16@2O/NE %�� O~�-�!@ �a��< ylyl!4�'agoni�orskol�1&�a�qj) �3��a�g"�!�E �A�TA�3�A�C( block�y �dow�EeamFxy vAT �W���*F i�#.s �A+��`&li��5�22!l��ATb9 C �!i�V fI�.�KOmSo��&. F�8  �2fF5f!��"u !bmh:  Pt*l9�0b�F��6[ 2� !�G �. �le(son�%�l��&� �>)�e�e-s(�-'M5/n=x�FFA flux!��2� ��!&sA4-v_x)ɵ�("@in�P�@.?:V:f��.� |)S��s\->�>rݪ!���,F$EndɎ� ewexF8�a 4�NambS;2t31 month�R� rMK��q�rec)*ls��R_B��*O �&M �mU�*� M ( S5~+bR(5M26N�2�LFg�8e �.ng�p%�:�>LwhG,�6�L+e�!��i�l�A J��<�KN�"~�CB,9!&[�0~sQN$�AgY7c"�����n� ��Fy%�'?���% glob�N�� �[�.x0g-�F�E sub@�y4/=��( -seq� ��i�> ��=�%.�*A of *521�� �(uJҢd p <0�R!�! ��S1 �T�3sp up-!2!iof�-���;�4e w�*75N e�j I�WA.SDUa� .�tN�c^$4�Fuۖ�k5�of Qhx��B�8�( F�8id!�0S%n6 �f�B�'A�RN)��3&�$�7��62"-�oum%�vo<�D * !rE����"aM�-�E�� -�ed�q�6S��>6&�"� "�Ū,.,&B Cide�0��?\ � , Tmem2�B��M7a2—*�)�-|an:s���&*Tbx�9UQ—whe_�RTGs Snc�5�Rarres2I�6�`IhS�3key �ofE8E�6CY1Iv:�.� Cpt1!: Hadh�MAcdvlOnd Acsl56yM&�#�'�m�or�, TwistI��6��$F�,o �$2�:+�&m&/G�)%exE�:*%5�6��&>�,un jdI�Y�Ee�Y�!+�'U�9 Ib�]!"g F�%� &�FJS5&� ;#�:a�S:'>2�)�0�6���foc�G�NE/ /�6�&�B6)m$e0y-}M( p)�� 1�K p,TM( p�*Qe�-^-oM L ))�6J"�2%���67O" Js �o�M x�e�, �� �" "Y#�!��(�M��(2�&)�"�W��X�!�/!a1�( Adcy� 1"��G>��V� S5J�k�2R�Jb_E?hypA�W�E�x"�"[9W�� |9�-a�ll Qma�W� �&eUE\!U5�U��(.�27E�c"Q�Bhe�+&&6n .�P�j@ . El�\6-cop uh6"f �D*?Q �nRO�&�,YQ areaM�5�yM)r�X�2Mpe�62;[I�&S".6 g3�$if5r��eF� eV- A�:�. L�Vi���� �� E���m ]}V. MitoKke�@�5D%<5� . Cl"s�_O!�aQ ont�0( GQB&��u E��`al5 ,�} g�R>=6C! e���"N8-O��.� �?Kyoto EnJoprs�=B02>s ( KEG7��a"�8 pec`A��.�#R�nCK ���Io��|!ai&�M"�*smMWcitric�K���5K'2�I�T+��IM#Ɓ%"�u��a[�Nbr2R��-q�Y�ch8 ( ETA�)*-�) �_.O=5t.6 6�iratory lA-Q~n Cox7t Uqcr;�!{Cya9r�yc���wrk�y�FCi:�-!J"�! �i I���X7% 3VJ1. X�@�q5t me cIvse&� 7b (- �� f�:� ����� &�5J W�OB$�O6�A-)���K��!��L *&� prop%�vU]<l:`VF�se/�����r" au�:�wi�.|>� b�&�-�BhB� ( Hk&Pdk�K$Pfkl , Eno GapdA�Pfk�UPkm��n@dus?%�M�" 5Z:� a > %9d, �at!�T�%laccT�r� �>� 9 )x��E��Eb� �M�5N� �{(�*Ue��&� \ b�3Y|[�/.{lS� K~S5MM�9z"�=5L:�wb�V:�!R"� �&  b��$�dNZ6�El�7e�i��!�"� =�9J-�9*��.w 5UawmQle�L–�O6�6��u ��sb �dN��!Eݥ��!$propranoloaEaB S X"" n9~�� s�+�_v�23.@���Ք!VV�*I�6� :r B�!'VA6��D�&�%7m� edeoDbI�& `2A–�/:��5ZpreKa�Z5�$�9� $.P e6e�!26�"ar�n�Ia6OR)�!�IS+ E�e��'*�"\�3 �.(S �RE( E�&s5Ms�v��ryh >��"i!ҝsllB�l�)�A�6�b2W-e�e���0��OCR cuB�HM06'6*�7�Fk:>% ( S6���j�.N.�0� er�[ �#�:�$M`jA"V�� >W� M�I"�U�FA15 aWU blun!C!26�!@Q���*�,x~ !i�i2�PF�&2]�-� ez� ��(triiodothyrP3h �>6%;][2SAg%xY݋. 9F�1=>�*t B�a�� �+!16Q'J� �!�>7:���r$9�@��to!%��-[�g�, acuta>��"4 N b ly>���5�in)#; c�I{!�).�� �(2�L�pZ+Hj?#�b->��{A��{~X�� Ap2��U�S6diab;�.��w�>� nÆ9�9�"pJe�"�E�r3F&�@XKS6C�S6&�Ac-ashOwl�-��i��>$�cPKAia�� ��xd,��%�" &�"~���Z�� PKA/)6�L� 2�%%.#��-Qrob��>oofU.H�d�>out"����x Mt�6����W�g_I" r'ad�3)b9M^F�>-!�2�W#l�4U� �� )d �&�'!��/>���lea�μM2� M*�Rl�x��]�][-��6�F��f �lw�&-�" �%*fs�m� �ulv^w�u�!&� �( �c%��2Ж��b�J!-�.�%$�o���$B`!AT- ro*�Y��]^�s &=.>�*�7��%��%�>+6��P^+v\nho �/� *� ����3y1";�1E��2��.*�1�1o�V!�-�ѧN�oBet� o�`(+^����a�B3�<�&b�E�Nj%&2j$� �C� $-�(�C ( HF� :ho��5�8neutrau( 3�v�T7� �/t9(S7�� 1�ekA W�n�zN" HFD-��F (n�2])A4)�"z. HVT>W>!be�na bH�/ !�J *+ ( S7&�#�c1-week �.�(E�.��3vxq�d�o� despVCB&f�]inn1&�%�I&S,��l�eG�,�El�o�VS7���su@.S7�iW��GN& .V �FFA� e��1b�21%2Lfu�7���9, "AY �2"�2�Kle)^16�#1M tole�AAXg�o�#% N�EY�y:N��x"�L�#� i�� ��a�� �e );i st��,�K� � �� )�P-!��c57���!>Q�aQC-V0R�Ih P,�(x�;m�!i2�� V*�MX*�8���^&,YY&Yd�X �R�X.*{@11-*t6�( SNP�) ��,� r# e�W�v,�as6l�k��&(5 × 10−8a8�r!�S3*�&FK�GTEx Por�-� no!�E210�f!:11 ��a� &�>�=d*�"�J2�D,and/or visceGo@ um�382DS8�9 Each��l�rEV: i�F�jZ_�,<>:��!c-�)�/{� cipa�9E��L%<&�to)��!W>�%�&�ex&P!s )[AT!1"�"w{m:1chylK�c� � ATMSV%�EJ� � &[)��t�M".Rm�22d_�r!8�N M1sA�NE78� �S8D�K8�m��L. >%1IoQP�H��c�&t<4Q�A6� KMT *eb6� 2��l��H"�a �,�prI.�K�5D ( S8�Q5A45��| �T!�"Xf�QMV�U!52 P.*�7)��  ,�~� !5AX5y�B�c�?m *,#5#Kn�**�F&�\.��fV �G �-�a. Bbt�b����>nd"=�vond����)B"�K%0to��A� * [2}e6mc!nt%���O �!gen�."A%rB�O�� �A�!U*�M "� 6�,��ɐ.�.o�<�8c2�qZ*_p� Ag*�a!y�8Z2�; scav4%r%��%�m�$2� ?a��6��-C%M���fo� Mm"e�!�y��g-]`<" s6�ynf��i.r�K6�iԊ 4ms*�A&6�i�@�.n[1�A6�Q��nng@�#&~V�V"���%v �( Km:�.F"WrX:�(Wa!>p%��fGY��m'y�mee � y�demA�� long�7d &g3. W+ >/E*�~I"�!�2�Ye]9(1&5X0|Y;-*�57RX^�Y)����A� >�"?PZ�&7a_�z+��1� exacT�#�=�"PUjY��c�� .'�C �#i�mHv*XdH.�(�[r�M?rowe?�"�+ * �&�n�� .*0'Ivs"�6=��6�`�3:O!�+"�#{�j�+����q!P�K�s cruc�Je p�Uo-�vS%X&�}):dE�"`[2��w>�R, Rpic.6 | �n^s�*� !�es{�F i�%�),$*p m�s256�)[28 , 2�k�(cJ*k{Q�ofg�v26go�L`�B%=�,v�� �$� -,�%�n�,*Y(β-�(o<�ex�8,]2+2�a|*WE��UI�"�~M��#��e�&ng:4un�+[3�nR� r�`ovY�"� �# ^6n7I�� �9%��q��P<9]C '[3�m_ >&S�u=2~A�-E��w7 b7m���Cs�D c��d:Pj�b�!I a 1�0fi5A�T�W�� ea�bl. �^ Y�yre��!�A%u 3]u^;.:l8lso�1�eF�r�r� q)�2���N�vf*b:)"\ 6�/!.&�PN�H��ioy�homeost����.�)L �Xes: ���c)��ahIM�7fac ���,��Qi�chFg�,a�&��. S�.*E� �)U �sɤ dens i�ġ������ Y[3d�" @ �be"g�"TAs&* �z6{ �� �I2�D^ce��-[3"�%.<��s���Q�c � @"J �M "% o�4�^�?�ec�.�&��soGaT,ds:�l�a rdiak�!*=0 work[ �D,&)�֕�"xnbg��.��O��#4�@RT!H�1;}"F,"��&u8�&�.a�*IR�pr6u@dra�u~#z���#b(Bf@��� uԇ�[35�O�!e-_hA)��f^"`F6^Fa!en2��KO*�-m�9K� "6*X2AfUv� ummari{6�� 6I;6i��R ��Gene Atl����/1x g�adi f"�q'e�"�q!d�;M�Zcy (P� s�v%ha�f�omp� L �N�,"�1ԭ�����A)oD�,66��iQ�joug�� !a� )s:Yx.f��2 � i&Si�b�� 6@��n& . OurA�eg�r &�� clinc*m"p�i β3&S�Z� ���(gLngsZ�~� �L���.�a�W&�v- �L"� [30)6��%�m>L!��"�2�fmi�� �a�L� Ie��R�oVv9 ��� Eei;yduLgs#*BRɳe�is*�B`X�g���f a q8'}��>s ��"02���A�b)N5�eV�%"K�. D�Wop��m&�<��Q��liME[rӧ��di��. AllEr�u&�!ccord��9gu�.��I�QtP*��Lab��ory�GResearTsinghua.��a��; �al�>cedureN�FE(A}kve�Gm#�E"�h HC�IA=Us$N��cenh fS* e9Tɟ':Com*S� BeijA�MunjT#4SYXK-2014-0024�-�tN�|>�X!�Nj al9K HZg2r��e��al(rAa��#Oa�!�)�%�"}�gu Jack�M=�(ه0ck NO . 01080�k.e4.�ia4�h��PY!Xu la�7So�w.��. back� ��&U"��U 2�.,~,P32,"/�3�N.2@q�*���Rit�a$Z !� %$eM� DAPI%~19~. I)�%:ob!�0$a Nikon A1!�,focal microsM�  Corp . , Q|)�m.c�)�depm�4ized slices of]Am Ctrl a�cKOte �:�250 nME�\Tracker ( Molecular Prob%�OR , US!(A�1 hourUQSlideM� wash�A���5 ��!=2A6�=�)�%�%'a2�鞱Uanother9�Fresh �Dwas supplied every'J��iOil R�9� , fulq ."d1�}(fixQT4%9 f n A�.�gOq_��2M.J�( mal�s8 week> (chow diet )q�,traperitonea�injec��%l@pentobarbital ( 7e�kgE�0which does no��hi� nonshiver�X!lm( esis [51��2��!@NEi�  ,*]4subcutaneously:�A[3�=kgB� or s��!}U{iJ�toJ�. TailPodCtaken�o mice.�a{ dAof!�� . Se� �s aaftheS rmin��of FFA-"�NEFA C kits ( Wako , Oxoid SA , Fraa )-exF,about 50 mg � sampa� from*�fas��%��n in KRB bu��+2�|HEPES�21NaC�4 . 9K 1 . .MgSO4�oed3%CaCl2 ). 42% FA-free BSAE;(��glucos��AR��stimul%O�U�IM!}@. Glycerol releasiJ meas�by-ckg,Dagent ( Sigma-Aldr��X ]tr6�D p%b:�(SVF-derivedA �E.Bas�b� 53��LU�6= b��� Y�(-,Z�orA�sko0 �:^.. Che&ympathec� �&{ !fni!�$ral denervI�iJon w side%�sham-o��n!� colG*to elie6e SNS!�1�Aupa�ArsZ� 54!D� eff� venes�F�confir�!\F� of tygne �oxylsH The�� 3 of��9 yI% surg.��/:�6daI�d�sspi{e [3H]-@ (PerkinElmer� T]� �0"Q .�$transcardi�!�usцice-cold"@T��4!�5T. I)�A�imS ate�|� Rthe majo� 8od vessels remoa0!�ho��S$in Solvabl!i.��!f� . To�6radiolvita(= [a�E6t��$liquid sci� � c$�� . ProteinA)t�AofBQ.|BCA5(A�rmo Sci� fic=��RNA-seq�>��ze<, t�RNA%]extGed��!SRNeasy�-$id Mini Ki��Qi�� , Hildm,Germany ) ba!�m{manufac r’�?� � Qual!Kof�:�� Agil!2j (:�Palo Alt��&� ��-A-*=m�purifU �l-0T oligo-attac�0magnetic bead�P9K frag r8to small pieces-Q diva�c��s u" elevŅ.� . �U^op��first-sagd cDN��r sem� ript��A�ra_O�,2� seg2Psyn� �d!� se IURN HC !A$le “A”EEYa�to ��"A  adapl a;07pPKA Sub��t�#9621 ASt:b13� CREB� 9198 ) ( �> ^w n�g���k; �SLC22A3 $( #ab19144�ATP5A  7656� COX7ab14062UQCRH 6 3494:6903%+�?%I beta Acti/ ab82%=�)� UCP1i GTX112784%mtex '-BPGC1α- 2065)1E tech GuInc@ � �P�`&�by��Li�I��IAGENV�. RBkaa( Tian� Beij�F , China )eO$SYBR green͂tativeű( T9 ^?:�ac�bto�E~o Pri���Tt� t�<���Rkhow�  S2 T" �� ve��.�level%Y�^ 0by TATA box-bcng�� ( Tbp )BDa�unl�m ��<� since TBP.;!�st�av s AT�N .cl�f�Ρk,�+ i��%� �I�genomic<o2ATIANamp2%ki# n.��"�in du��e��F�� L� A6' Cox2E�6�a2A �$he nuclear�e ribos]5�s1�Rp^ Lact� con�r��L!��.� ɕa9A"K%WBiovi��W�AcPi.` �.~uOCRL �G��a SeahoJ XFe96 E :Flux A��- Bios� aPe�K�� ��&���!E�see\ at', 000�/well+ *��r!?kda�&� abov|T!� �eNonX 6 . BT*-��a�=�tw� ��um ( XF�+�mM"}+� pyru� + 4 tamine�!2?175 μL!�2fA��#AQ�or�out'*�Porpj�on solu!@-pr])CISs: � 6�)�NEqA�.�V6,amy�( i^+ FCCPUT^%!�a cocktz*� \n%�) -nti � ]a�Each cy� consi�of mix*�, wait .��M7)<. Publicly avail��resoura#I�urveyb  id�y human�bx� � assocd)tBMK � TincluaA�GWAS Catalog ( https://www . ebi . ac . uk/gwas/homA�, dbGA!s62nc3nl� ,nih . gov/ga���+UK� Bank� y(://geneatla^ rosli�ed� ,:s4biorxiv . org/!�dent/early/2017/08/18/17683/ -2  Ai,vh�$o e�ult�c a��!ea-]etu)q��s~ , �b�j'r��0N = 408 , 455� !���9�a�O !�� participam"(. HaploReg �  1 [57]EZ GTExe�al [58]I:� �o�loc�c,E�� x � variu)��A�!�� F�%8%!4%o n-�od8�&���!͘2e 91onM"A�://bi)v. ctsuAx]:8crystal/docs/AnXp�ry . pdfe� Six-r-old Łse-"Oct3 KO%n[%&�2 HFD%�12�u�RT�  moneutr� ( 30�"�[� !$�B22E�)-*�at +#AS7��aQB�'*A%��monit�$ats? 8ar�i\ o��Tweighsrep ��+���><F��!k:dai�uL>6Bl7a:��cEDTA tu�&vplasma+&by a ifugI�. P ) trig�*t�chole5olQ�E�Q��y�4p�5ve�$ay� �Nan� Jiancheng��� �gy+itu�#,  .� merc"Y�ELISA d�q��^ �E��aM, u�]( ALPCO�ale�%NH��sP!F� ��(�)y M�0ain Diagnosti�Col�%o CO )140a�2 � A�.� A�-� FFAs%� �d��L� 6��!6SM T.Q��'._ 1G. Ov6 tole/tes a&� oz,e f�12�h�+�B�%~a�acclim�6}� by o�avaA�< gp!)m�12-�)�l��!�. HSMSC�rG%�kA�(a kind gift D1 Yanan Du��hua Un!�s��<.�& UMSC��wt"' ( Wu/-Viral!apy&��Co . Lt�+@2�10%�)f]�&9' G�] gM'.9��[9�9�YR$*59�S�aax+a�:ANCOV��u $A!�!0metabolic datj#O![� siie:by Stuj  t E�(N�"risVf two�e3nxAi!F�orz-way AN���1Tukey'sj\h� or@/ex^f. D��+reA'enb� n ±�.d devi)�.2��!Xa>!�.,n=1(( *p <05 , *10�.Y| h ochd* tin-"�HP�'�s��y� ritiACrol0 reg�!v !v"r �s 1 E�㡟!�re� d do) s kn�as�n �o-�i shadow- 2 ^ �s �1ne H3 P W!thy oon�9�Uow�xA#)U �/=�s h�]th��2�Eof6. to nN {�!c i�l!ly�A�� Xo�ngW5occury��r*+ faci�*�their%H���e��Th!�obs�!M2ompA�u�) vest� wh;2%adiTal5u!�th� , en�lso9:� regi�3po" Qocby���-u�+ .;%0:* intesw]| y �.� � inq"5 al barrel� 8entry/exit poin"� 9qj ter!Pngl.(t� �A %e� �cataly� subun &ache͟SWI/SNF��leQ IQ�, i�t'M!del!�requi�.� yI��r) %{��� 2e� a�0on�� betw�aM22is �Iz c�'on�erA/� terferon-�aed� A�F}%Gwee�i�uct�!fav���J�E-e� bothA��Ŝ�% . Al"=, X2Ŧ suggN � �M6z�1n benefi�!�}�U&au6M�e�aH T��kp�QALpr8%tya�� �4d A�st unwa�{�P]. �T��$important -!I~:,4� s�!t�ga..��v e eukaryo���re� �ew� 0see [1] , [2]F,In mammalian��1�fam� ise o�)�α P1β2 ��eo far!�nly� has bA�inEE�� e mo!l,N ul� �e?&�� elopsz$neuromuscu�4jun3#% ereb cortex [�' With kEu!A-m�iso�aCla�!3Y � fociyden�qeriom >� but%�xi�\p��J|�o� � Rnt�HEyv�&g� $l distribu��)�9��2eI�ed�-%�%S�6hcA�i�"��@�0a�ALEna�(�s [�'O�se ( ,6� seema3b�e� � �bpha>6�2�P �%*exy�� he SurvivV3en�1d�teg!� d HIV1 LT�6A��A�5! GE A�promot#$le4�4recrui!V�R�j [5e`mt@h |/alw "Z!�.�$� as ��<a�M� �%Ϳ MMTV�a% ��[7�8� It�$noteworthyI�� -59M β-O(%p:���co-h�w!�e.$%IYNAPII&��L� theyN!,ct3an�ron� in� ti�(j-�%is.v-�� Ty.�~�%e�>%�[2݈,��,e�eu�'.� !�“q?�(�@rs& per s-aum�0lik� 6 enzyi~Ei� invol��2� ini�5Er elon"�2��ABwo �d simi�M� V0  ( CD )!��6�#S$2a ��(uN hingv�~�8� C �<d�iz%�E�r �%�^)m"�:a(n�EIsh!��f+ 9C"\ �2  inef� [!) , [1�@T�'�ncV  impr . by auxilieac� e[may help%a�g��#��,��it er � �at%\ *� J� �deea�=s�"� rpor�,>7��  S}|nA��G"*disrupt,Qoctu5Ai%2EM<re� 6 so"_ %aje� �h�u}�wpop�2V��ei� highg6mob�y [18�-Q%L� � %�sm�X5�!��O h��!46j�B�32�A-�=�ATP-depe��t=�* asIβ., �� ACF1-ISWI.3���[1�6�b � �N�z�� � �)� Brg1 Br�v mutu�exclus�c>%! ,h)( h )�D� |!|86� 'AHer��#ex�� ed Gal4-� � fu�ŭE, ( Figure S1�6S1B�1CD�[20�!21� To gbe�,� stan�m:yz���.��U"�,5�B=� i)�b �Ould eE�ish al)-���Wi� e%x�����a�*�$�""!�!��5=]�!ntt Q H3"�'b:r$< globo ��IzX c!�fU"e:y�2i2`%K a ne� � R5� Y&%9�}h. 2����e���a܅6Wo y�2p (! d 2�2�. W!�"�dU 24cEAc�oH3 �Dly1�well-chaAer�(�a]^n E2*K�T *ise/E���|e!I�α%�am�ԭ��vor�� mbin�@B10-epitope-tagge�s�5��R&n�1&ult9membran�As �E?6 2&bound�i�]űto4� �lanes -d #6Bwe��"J�er^sig5t55to E?-length2�"�/in �= coli%g��6 ��=�on!���� d�A8!��?��� al�JP.; P��|ord�Y$=D�#�v� A�M~2�9a1>=�8Q>=#� �p?�fura)�ed � V22M2�Ia1*4��i�-���quiK7to I25am-�� M*o aci�en~,!~v�H6 � U�Ma 桭[I��UDa� chos�Leca�AW no �" �e dou�A�nt-�er��J�H3� 6�ing�A��e^�Wf 8 β�Me�&S��o*a Y��2. M>GSeH%�e�af� �� ng�a�q-�!6vis�9�3�$o-t I;in MCF7�an�/ aor6G �e&bFpid4rFR s�r a�as��W�&%uan�F%���y�Do1E � WeJ mappmۭ�6y >`.yr!;i�!_. A�D -mod�81��run�#M= spanE� aa 1a76a�du�6.��su"&to� � �a4a�:o irv�+�(� –45 fail!o do s�"Th6 &3 ��D! dele%y���)fi�/g �i�0- ma�c�3=�F)�0G , 3 top pan$>1�ozE�' +!`�sM�A���6��A�i�-� �1K�.�r~Fv�.a�E a�+ca�aM]B<�n���&�b �"�*�γ% a�")�>{v8a:IM"�,( V�7Y�1Eto%9�� A7bG�-�)J��T%-ck� e��sh�"GHa 4�A66E��1m��� �V��wTD� m�A�i�!8c�Goverlappiu�VtM{r${�!�e�-�is �a�#*�!8�|"�e%Y��E�hidA*�.&�!u=2�:IAZ�!���0�H3 αN�ix�i�J!!n!�pln%n *�p%��l23l��OyB+(relyg��V�by ye�8[2XBe#�w�P� �q���co--Eprecip&9 !�"�cB��#-�%<49u� .�.�MKiN�Lw��iyM/�2�Ia��.�� �,�>���lM��-eB� ATPkA� ( Δ/-�'F2B� !�n�L��)�r-�J,%�Qmo�#� y. � [2�Wf � J5a� �,�@"�&f =�q�o!�s �&Zb9�D���Rd� a6�2at��toɇ"��kJ�}E }s U9��A&�&%6"�)�s2�Ib s C-���GQ'he�sB m�[I#e9!�.� 2FMA�^e�*�+�)�es� W[!�"s]�-�:�erof �.�3 �XlyA�recapit)q�&�..F�m8� omp?5�S1!�S1F%�S10.�ABQDEa� A�m.Q�� Q���"�q�)i"� &�lsx &� .c[l �q1q��*eBes&���!achieEwa� �&ext��Z10� � 2� ,Fp�I�_e�^2��!"&ACR��Re�#�$ E e Accessiͦ ( RE�-�� s [2XN�*G#yDE�ass� �!���*4�+��1ANwo se7f�5S.0�.{ �at flank� �rA����{���of�7�8s a unique HhaIs.:������r��$p)B���ATP�&fl�38F"�}�(PQt"n 1�p D NF� �-�%� chal�5�j!�dby�.E�H3F�6'aso%yq��&oly"��E�X M!�� 2�>�>9�B)"�C} � g�5co�+� 2vaM�%�-��^+�=^re��!Cn-G�uind)(�!�+�)of 200nM94 ��| �.6�b2Id,!�%mgAin5�G�')�ɞ5~ c&}��i���a��w xofA>h��=F/�� ��!�|  6]s"[m! LN,�.�l�9iox*�$�M. ��po��E�*W�A"α��RP>0!���in��m,."(�.k flag{� EF-)��e�+!0�*�i�'W�]a2^A� syAHEP� c:.M�� r�����{3��.>l6.j 50%H�of B:�a� �M��6D�A<� ��aZ]@!�%3!happro�.$1∶70∶1Qo"� %�`��e�JB��!1�edJ 9S2� 3\=�7YDF-�o3g'�:o9 .�Tb,2!;�dOa 202�K��i���xPst�x�5%5��3�ab�!a�� Q�! �`.��A� ;���al�,�)J6hEq�I��Yk)XR&�%�!;+ly�'&$as>|0���at�Ues∶-�∶�ULAC10UDF}� 7��Y=D9�a}u�c2p ��of Qe�� 3�M�Vq�ki�Ps#!r zad"� " Z�L�%*�/�dr$n$yS&A��p� i>2� s#5al HA6�bB�0*� 3U).B.&a06�Md3��,q~�E1e c�'xyAi8�! &+QFng!��g!��=�by9��%��',��d"�/in]& H3 K96o$( f K: DNA/H,!Δ�5o&�E6 Brm/�7Jδ)���-3Bj ��R�ym��,��u�%5&�! _�s/��� ��&L(�noF�a6F�(F2'E�1LMCDA�1�a�!&�irAe���f9� �/��set upQ�y gX��i�/ta:�4!���/2� � be.!}v8 Our lQn��bDQm � J�4%� F^"����+1,�*A4 v�<&,/,M high�E nd rapidlWduc�.i��spo�1to out�lZ(i [27]–[2�&ToaI firmn��2� -�s�LU we:EjN L in HeLaLEa "UQ siRNA��4A�B"��J!p0^ferA-� %��W$i_>gr S � pK���5*� [E@��=:8–9�-1H�3!��9n �ԡ�Epde�!�V��+M�I!a�#Y�\ ��:�L=�v�J�6�$��a ?*`���">e&v � CJ ��3�2�(not�R_]+-j���h� on�Uu�#5� �,i^AE;$ �8!���e}�a;GAPDH�m����:��] deA��o�iz��w;����[322���rul� F8[lALn&�H.�BpX hway� ATL#-vUnd�f��."�.s�J&a��&k&L?{(& �Dphysi�oMs�V*Bw.!�5s�L t=Hly)kd,i36*a /)  S-58N�0��e2�N�R 3l�*ng!��t%Z�A!Dd o� FJ�>e�>.b4s��.l.�9N*M �Ԓa=B�q-""eLE9C influ,` r*�+�� carr� A��s-&ti�-( ChIP )���3!PD9bA�߉�k���vmIU�T>7 gM�&+ K9"v(���Xe�45oafc�9R�,�fYa� ��2M � 6�w"<傅eY����.is�QU��O�� asal-:Rx!������c"�"�~.���a� "eaK ?Mv/yB%8ng٨�V$e6�,�� u?#lo� )P; -K�! ��"SQ�_# A tag bod/6�5!U�.��� ��1.�!Lm@ �AuBr�o�gdb�*si���$= �>6?��!i�n� ՙ&L4Da��>�q. a"H%� 2��9: ��f�l�1��due���&�=mn �+=aso�rew� f� N%�"e2-frO���R-reA�U����e�at�!�)�eA���Csam�F�Af�b ��A�� � .R��&��E)-.(�X6�E�E�!��nQ7�\HA2�anUll!�s!dW�_2 5(5�h,PF�+�]m�-y.�"� !4j!&A�J.?o- A�G^V �t� ��e�f\c=�6� $�i� ��evi B �ß�iu�R�G 1iIP0B.:5m>, ��I3peaks 6�U .ͦ �)�PMA . �^"l;,)7�+%L.sE�o  / ��remZ{9Ee��:%�s� &( U.�>�9�f2��dg1!�%!�6T� �ei8Ar����8�:�2T�?lsoq9i6.�)�γ8 limi$e�U� �& &d* ��B� XF Y<:i�&�I� m, .]"; ?2�G6m��.+kB��u avid�..gua6�m6C:�� `�(�s6g�a!��v�9ionicy�3��poo� �#byF�*�?8��#�;[34F��*(+-9e� ���/it-b`'r HI�K�<3}�he9 jerC(~m�E\ed direl4toi��S��$����_&�4l�2�SF7 r]… a���5Ps .|5���]�a.zγS�b�&A�Ŷit;٣��}M��F �F�&S�1*�e���V��������mlys�Z γAT=Ze5 �c � l� x7�2Qta�%��ofs �\|�wj�l�L��!��-(2�8AXI�%U�&���,cS�CD E*�4H� :E^#/SDI" =&� a�(%L� e�M4M��$&�:��r.3 �F�� �$%A���l*b.M>�f4.\K]��?f8L:��<s ʼn��i"�:�e�:F� �,a��B9UOXc� �cR:��. FRA6v >!�!�p! ,*�Dq@�Ái�!� v.� ŵvo��4n+-a��on�4!�r�I� eA~�&i�i�madn*�F&�I[3�?6�"�'�+5r �?��e*� *��*� "ah� s [3�,IVe� typ�&,�ei�E���O+$M] �*1/.�%AH3U�m(�4)!�6�&B6%�\2��:. F�7WA�N"� ��A >��!of]�]~.Ba�% �&%� #Aac�B� ��3H 2�~wowz�HtAx�� �Iy�Q��1.�).�A�Tmly�+P)!h��F 7e� !?"� d' MW��%��>kDB� ��:��g h "��]iswe�%�|�@�FmPswitch�t �/HP� �2���,��i�iOH�L!� SM"i ) , [p� � 2����Q,5�����!���8 a&F� :{&ißa�R9 "�eh2�Y� .1�Z �e!>�Q�� )�s�still en�x^I B��bW MT%�5pu�ync��!��2�A�.�(5D1���>z)�b��v"�K� !x����*CH"�a�� s� �T��E"���� a>�jN^om�!*3�[3�0� .� �$"a�awsE &"� �� � UuiH"� (�� DID�hB>J!.=�4�a(_fD�h[/&�NKm�J��a � ��lto.R �%5V?. UgbE*w, �] �L "*enh�@6&���B �yd 6D"� "�+d9+��.�H �"Ue-��0sla��N6oAQ� `� | b.�H�L}D^,yaAIt must b�* �}� �"V�./di. � e5s1M!<[�. N&the+O�-aO�NduppxlE<lyA|.Zaafa1αT �oV?1��� �* � ��A�;t;in%� handnd� f�O.MR�Ye it��� dQ ���N�:�F��.��$nH3!K9ha2�$l"NoU�,&�! �M� y�SS% x % �I�"� ,�628�nB9@��ɯ� aZ ȩ��= ��G6�=nxi �N�"� ofT;� �; -lik"nv��2� 7�#����eG.�i� �\ � O�DC�C)?J�Qof��SchA� CAF1"TIF=4[3 Fa:e r!?35–6�V4� 46#!�ie !p�"G ����5�Vu� � a�21'� J�:�B�T �%D m!� ���n�gbo+� EXinc�%�of2vͲQ& ��@%��e��pm�&x^A� �!�at Uvr�_M�Wi�"�41�� JAK2%� romi�zAq! A����:lT� α����3�QF�A3�A56 [37&R �/"(As��')H�sit�(d���^�fQ6�8&X"� "R'=�i\ post�C�o~.�"�B�i�M76��S b>2�V���O&��V�Lq6���$E�>�in��}�T�%n��%l9u�f^[4U(M�re�_a�g�*;eW\:-1�i>.�&%y6�=*��c>�*�et�3&2-�30"�5m"�T!�2�� sɱ)�.q�i�MVUH2�:\e�N��vv*m�UK�!S.B��ZcZces.| J:�; �%,EW^�; �w6�e�� Q�AS�&A s&}�1�aE7A�=�� 2�%l�; �%4~5*�V.�A�2��$6�f.B�u}`=��<atM �Z� exT��>�/�9�Nc�&v� �� �hg&�aB�Iana�Zy%I!gl6KQ��3)'iYg�|���P"�S�D�  mechac�9o�&�6-bF^e*��-*C���.nA��,_v�"�?U9`%37�  ,�� �h)�36�b�gF�5uE=�x *}` � �>� .,n� M� Poly�=| ( Pc 9class IIu�}6��4�(�hA��av"��J*w"p-$[��A" c 2%$Y� t h*f�N�(a� �&!�2# n K27�4U{K9 [4"[42&E5 �� n%�not a�it�� PRC1-ie�[� �� .��*�g6 6* ]*L(_m�� �a.�[4�UV�2R�Q] comm��6���!�� E2F1(� thym�e kin�A, c-Myv�S�`, CyclmK� � �`���|E;74515EHLikewԂ�'�f�%bJ�.�!�Ag&� 9A �#��o��*�"�UT ro�:� P1β, 6@6� .K5q-O �w"j0-"0ix')"�/2�q&!��n DraL�SPARC� / kr�th���'����s 1 hjZ{!��.(�$�`�d��a&eF�E1߈Q�v&� e��)]� E&RAuez -#)�.Ro)JB>4� fu"f`+ �or��e��K�ࡶ, ,$H t[\b�e Q"Zan/,=)6�[� gY8 !oV�]T tiva�{,6�� I��3&����Ps*�1� sens�_of&�E���5�&� �uB� �A��bu�r�b�� #\QE[h�D�\+ ���N.�,e@m{,"u9.� �:m�� �lA�Y���*v5:zfo4a0q.Zm�kee[U �q�exwof5BV �t���|'+�9re�C]�t . M&�Q��[)��piumgat� J!�f�rZV�H2#B� 10−6 M 6�(/9a[���q u�h40 Vt�T��� , lucifer�' �>sQPromega.3-�,7)A�'A��.{.m���urޛg<�,b,UCɣ���� ��2�"SF9��)�,a bac-to-bac*�syste�Gibcoe"�# on M�Hti-�@����+�!X8�R �tFZ Ini1�-��-9������jIeET-285pET15bZf���!$!`aN�ua�!@I�U~�lla 2V�9E� L*�� 50mM��pH�2�� 1mM �|,,v1% NP4�1xC�K��o�h o�ac��e,R+��(BoP"h �elu-�10�Tr� H e�2gl�XhiDICsn �wDS-PAGE%]ɉe�!w�:rd�挙!�E�cl�Aw�.��Ky���r�1"�1E�oedex ERAAx%-]raa�a� g( n{ab179ZKO�yai]a(*�e�"�2m�po��d�7"/he |4%_ۑ}D+harmac�0ON-TARGET plu�:8(( D-001830-�wc. m dh�;$J-017253-0mO8 (���GBh5′CACAAAUUGUGAUAGCAUU3′�@�o� ((,AGCUCAUGUUCC+GAA (! *VRAU!CAR U +.)).hi.�3Ȣa�nMea�~)�5$DhamaFECT#��O�@ r #rbZ���� .2&ړ 0&K� Y��Nd- bond�!#(( M G rey-Nagele?� s� %�6גreal-tim`� �Drse��&�%���PSuperS'I�nI"f�i�{�B�b��>!���eGBr�ab15597m6)BA�D2G@ltiAB1A� A11G���y�:�%N�3%d�=b���)�dJurkat J-Lat TAT-IRES-GFP � 8e A1 ( NIH AIDSO earch & R\�R\�Programe$orI��M`c��+2�γ $%!xAh�3&!D��,�]$( ab50955q ti-�( 2E12=:�DJ%y!`(42S2 Millip� A ( 12CA�,�8V��e�D�A%�.:6���.�/9�E�!��G��� Br�4 E�r�)^y[/a Mx3��qPCR m_Qne� � 'i� �[��p5p: $x1-F: ACACCTGAAAGGCCAGAATGAGGA , $ R: TTC CATGTGGTA]� $3HGCA> PCCA'Rl3HACTTCAGTBTCy��AGT GACG�0)�# R: A�TAC=�AC4�OAS� GTTC aTG D� F1FaATEGG�xAAF�5 �GCCB�! C�1 $�GC�G"TT!G[� HPRTGTAT�!V!� CTTGG#%bH�8A���G�h3_TS_!�A %G!�A,)C1�'R: !�rC� �%uE �TS 2V�k ���&�q�ll �Sc adopt[ol�>d���4�woW� paira�5:as��L nglez and;E��6+ so-c�Qd�o" ureA"��"Cof�y�,[;�i�a�6K�L�iGr�-n�~UalF')| :3 surr; 0X .h#�A�Es!microre� �ir���swbi� �_�U���et*�"a��L�e�Va,r[�eex�/!�!6��(�?md%)�  in) �9.w�%S�B+E s raO�qu�'4#=6=6�:Z!�b�"2T�tin,�24N�I!!g=�� t�kK!.Ydef�O�^e�|TCelf)aiw�&�a eo� an!�Y && obus�i.ZC.optp`N�regard�&�Ue � exis�{�%Iraa-,A�%��eU����>�nt �m�M�5e�5B�u��aa�n?odca� � elf-!X1/A.x�g�`Tmia�� loopA��T!D2sRK2rB!Lg|@!��%�Y�%��* z}\��C&c mostmQe 5�"�0&;� �Y_]eg owar�ljB�am)uqe]��ery.�a�+!k%7Vma�V�er�jc!� nove�R�ac Mnew�X�!�exta�W2_ � disp�_6�7"�*B��B&V_AkwmI:8nA�MDe�A�%�>�in)�:;5��W�R*5BBar %�Ci��Xonoi�n]Ckst� turb��%��- ]Z� d��p!oEjk�u���R؈">�w��m.�V�&annot�EK GE\��!�A Pytho�an�8Web�erfacJc!�~R�'K"^�at htt4�ki�bi8N upen� edu/"b� . }#s*sa�Yo��nonco�mE� ( nc )!&E-dra5#��y Nl�!decadeB�tab23ars��G,< "!3end�o�co���(q )�–�uA�|&� �aδELRK��of��!c:�9r�o-thc(t�d&~Oto! ��E]W��XN�g .�Hmi�ing�) �_Yr�Cz�NonL�H%qvP ����m �b�gy-lgiz IoBo %>%�N= <�  &�0�;A�tsU� � ,� ac�%6�$JP�Zaw�et%����CR"a��( r)�����st ) il��F%}�q�I�s1� e—j l)w]a�I�-�8!L�I�"h(-Pr �!PV��v9�6>tyA,2#��on"�4e�=eaf !fer�( t�)`��lown��%���Az� a�rq!�bx amifo�|ac+� . Var� ) �a�asn1�nd."�Y ( sn� )�� ��! e@�ncGd s�z �!�ta�()t� hap3+e� !][�9�!� 7 - =4of� curu�(- )!!Wth"�9?�[![)se Dicer1<K *t4�jSʹe"�HY���I95%*/ nQ7��;"�!,* m�(�;-tV�ynI 5 ?W��oryi�( �.�hairp6elenocF� insdy�_Dce9 ECIS��Q&�|predoM2 S&�unJ�a�*�*ADUTR�}� �W �-�|1�h�"�!�0�>' ( �I;n�T` k��!simm�(�� �middl� s���&�]�/�:�k |M�3s�"RNA"��as�Q pre-`u�#m.��a2@X��Ec��e [6�>M%�63*:�F�b� wt –b4�A΍U� ouޥa^�*�*� �lso&�. E �ic��A�A����W�crda�ke�Mi� (� A�r#qׁ� clea6 o*�sE.E�e.4by.�Pan un6�y��A! o�K!�5];i����L�m�i�Hn�N�2%�canon� .(1�ɪ�E<z;u<7�$!���et!�ex '�^��us����ic 18��� !28S�da6�"���/��>�1xapart"�E��A�ha_�h?$a�zym�_�_���$f-��:a,5e���A��-e�)d�� a���_t�3��̈́qV"D ـ�#vB�2a����$� w begiWy!�1 p�'� QY�priٛQ�a�A(o�U/ a !i7 Du}2�Gha�� � ? p+�Pa&:{o�YM��� .A�mUs��K�_\���EI �em "� M�%����"�/, �!�/�B!�xch&Q�x se rާ��s� @(∼60–120i �o A��U� �1�8)���-�:��h��xU{�+�LK��Ső52 �� ZB� r�Kk(DY*ao^sZJU����~6B`p�� ext:n .��'6 r!�E�6�.=9Ou�ov��a5�8Dq9Id offU�a�>&I�d jy]�e�1w[�p�in���_ ��+�59�aa��)ex�#iu%�.�& �$ Ei markA�a�]ag�phenom� modu���atVty—i����g �io� �@�!�/in�)n N&�� �Ł��I�:now�* �"�c'*iFshuff�( ^�2AZ� �d��bea�{��ly&mA"k�na !G��N"�s6xfe�q��l �p�alư�`� - a0/mp�xin]\��B2Ds RFAM_�5%5Z�ive�%-�.�mFX$ha��!4Tn evol.��i�o�)=R�l)HH!�,a!%cd�B� ��)�վ'e�oys۩�E�:%A=�5S�9ts~sB�Z1L6�p_�e�xt.�ŏq�!��m�=��Yym�.�"�� �_� �1eS ship" ?ea��cm �Y�g2n���"6y3ois e�mp�$E9Ųf�rY`^2��� �cer� l��ayI_ M �Yc&e)b9 CN.4%qthg*��, iP�v" � �=c�NG—��KA�M�s�D�5�l� if� ��D&�:5�.���75�A�nt-fUxce\zB:. [z+&�`�a� (�!�� XA�"՚-�m �� buil��.�v�E[� 0Yyc�is$��α�bi�'��6�;�J����X��i1�-���5q�RM�Fs��; i�pdel_a�P&�&0 �ud"�lg��l�:m��1705al[R qe��W��cd Stadle�G�(E�aO�+ �Fr9��e�! 0�t�incB%Apla� Wl{+�ic9HJeU$�"�E, Ancw� nd F4n�5�PWiU�-�e(n��vm�. �Ac�l@(ar��!ŭ,Q ��u��@Yd ĝ֔al�M�Z� ��vhNLnvE �%�E��Vg&.  � work!?��(*��`,�S!m�D �lSN)� K !K StZ�Q=F�n��Ū�^�"�k� rmodyna!�st� !=&��� J����I�is)�4!�yz\%�8Ob � ' ��K %��L tui�>�to�(y�i��Qn}(��6emin|K&�  e�a� R�Y�B��:F 5- ��,��nt �` A ��s� BU�rA�JG�:�-� !��. A��� �no�phM�Cof7F �3h&XTN�2�d�%^aE�NRg9SB�Ar ��H��A��M-^� �er �  , 8R� )&�JU�NnI; -ze mir�O"< %������V�� E���3�"*�!���= b� .� Q��c��&���A�S �N� m�C]$}h� at ��)?�r�ea2e�~�.;�"e6V%�dA[7ſm2n� s . T �!�� {� xw��w48w%i5CA���|�"�&9#up�M#j 9�, Z99� E�lIk� �zc w �A��Cd^���2/w!&$��rcen��� y'A�a�y in w  "~�f�#.-nd,�}:��.Rin5) . If�&(W& F�J2{ 1{� wA�����"rmJ�!�.� v5aiE�=T!�e�>֝h��ce o-a-via*��o9X"�F�Y e�d��opb4J��>�>�!#iq��[ M �%39S � !�[�.�H��encaps!7���h�d �8Wd�%.d��)�1 n�A�"-"�q,s:�2�.� wJ�L-pI��0 um ��c gy|!f�,N@'I9�?e*)� t3L��1origin�0F^��* omly��@ 'sUnqua"��,�'b�!n :nG%b�OGI�i&I(�x�chen� l�i�s� 493�:�m�(�W�*�� miRBf�Y� ~Afi��� o��d��ɽ� >90%9��ty-���)dy#O(%8lgorithm Cd-hit�Me� %nESC �Ra� heav=r�-shifA��L"![,)�B-�SC-�of%���>2+4UY�-E"�& .e� 514 trimeF7J�!�lig:U%3-� O�l<]C*: 2-nt6��� ���� thus*�rua$�l�*a� |�.��6r^M!oaX!�,e�1��[r|�(N�9|� oE:�1��6�sl!�ly� e�S%d Ho�$�� back)��p = e�2�Wilcoxg!ig�r��tZ W�2I�T!s�.Zj�ljfly-�>d& �+,�Z�0d}GVZҭ���0� !�JnEI=��see Maa+��nd ��"!qe!_�B}O�ly��2Hof1M�7�CaW0eD5*W�iDTA~ k�&:-�g6�9��Bt�)ZL$<��2×�@ 16 ,9�%�sum1ɥO!�!l�Q���WbyA"&��� y���c�~ndu ̓)Q��*A�'6!�as few100.U�ap�� w100���o� v��%Y2�nd8�6�A PearsoA��i�!1yj�� ~�q�us�YF!0�%�VsW !Daw99B r2�<�-F��b��li+e n��oa's�V���i�!(��S?S� �O�*!�!Yn�� ,]M#"Zf�B?�a�T� pWQ(so ]�*a\Y{m�* �AQt2�I+�9�3L����4�N� $ion—left�T��:]�� ~ L—%Yval�Q:a[ .=3n��H!�1L!*2L . L0$ 3*� �)$�z �"! ! �3vx�ot%zVV���J�J�98��9�wE�*� !� 8 .=t#Ւ� �K��'�%E�"С%�)d�*�� �01!%e�� 4M%}�q�!LL��2L")-�( p<1�IϦn�Q������=� ���%�fte�9�-��M-A��1L�VA�R�G611�65m=Rm�N {!06�06B2eCecE1" 5%�ic.orř�/�1s�-&!el&���6�!W&�(�@.&!8�5Ş�n�t)$&F�7�d~��� ���[�Xu 8]�d littleM''9N.Vq�)"� �RW!� 5 �s�"�P%}0,i�� ��Nfe��E%�r2���48u�9CmT�m,J s$5A5%�Mdy "-&�)� ' "Gt. 2K�� �C}al}�>�2bi?e�B� aurH <onfʁat� F0',*iK|��in��wer�By)��D.4 "�!56 �4A�reE�/��6J"d }�k2A%�"�Vf�6��Y2 *�OIQ��8�� .%V�U.� )�co�$i \���)r taxok8l�2�.2i i�I�:a%!H*� �sNA�%."�!f�6w�*,7�B;4u�*5?i> yA6*�4��9]:�,%U�IU2�,0{, H&>,�k�D riboG,>�5�,� � Al��d? SCa��.��N1]M6"4!z��6�-n��Qhi�%[>�atEl6 /.=2�n�x3��5k � "k H*�zAG^*��1��:�Jo38%.U�va,5&, -�F@N��!*FL��[� !&l"�)l+�?�-��l��g���tz3aX3Adbl��)!��3)-� �?l�2SR�~�@�y.b([ �>�M4V =�*J�^:� a� 7�gr&L�!�A!-�m-��m�d.�.,�� ly c��A���r�(�,"�Vtr��a4p"�FJ ���)�^B�)Z!X!0%.-�T->&fe��(�)�� �)�Spt�%}�.-�A�Q�� � 0�A�e�y:)'ly.�5<���&A>� �!��Rq�:b(),#7w�4m�12 $RPn���Bh��CD9�,=pZbH=DJX�1ҡatuP��2I$v+��wB�s * 1�1d4Јg���l4ua�]!/U1I.�,� ���]g` <mp"�!�|E�EX" ��6�;*�1\d���r� ��e�5 �0�7��wU�� �yx7D a biR 2�BL ou �.*���uni6� !mA2��I�O� iK�Y=top 15%��� �a|) �}�hav'avFu90(�_loo�?�b over"p a���1��LYŷ* E�:$� . Ninet]��l�$s&� y�GE�pe� �"12�!E��  ON"F�!�U���ic�j%!x hepa�ds Cu*�8yVII �)�&.� skew!�w�Db ?aj�S?� vidu;-�j@a"CasOH6EL)*n5  �E.�${ 1%�%\6��U��I}do�"%�a� noun !RKI�&A��ڞ�� LB/S!smI��'�)�sa�G&"C`,3 �$$"�5SC��(aeO�o6"� ��8e� 7edFE�14>B draw�1� al0h:���; %GC���_�-; �!7M%9b(�CX,b(GC< 3];.<Sh�n��ropEr��-�� b�*a�ID��!�5 �_N &�*en� ( Q� 4];[�6&� �iY(  �Q.!a�(�M$�re AU ,�jGU ; z-\�9f��Q $Ro5�to& "���mr��b9[&)��Ij&�+�e%�55I$. ��eG& ).��� &�S)!*&4�"Z�A�(in 2 kcal/m�%L!/\-45]�Aj�傥��LB�$is related� to the complexity of an RNA sequence , we also(ared SC;4Shannon entrop@8nucleotide , di2and tr.Lprobabilities across�� . Finally ��tested whether self containment depends more on Ltrength�Lbase interactions in% 5′�3 Dof�rat than6Jior,tructur�usingBu-pairpropor| meas, limi�-�distal &s\1�8( see Materials�\Methods ) . We used four%�(classes for-�4ison: human mi%�Htem loops , random �dG5S rRN %� . TEGrrela�Ps between variance-st%�zI? values—)$xan arcsin square-root transformz�—� T obA �rom eac%�these1p,s are presen!w,in Table 3 ,�,scatter plot)6lIA , GCEoAk , mf!� z-scAr, QP T(end-restrictPF�FigA 6A�or maneQ:�, 5jhip witha�!mesmAkm%�AF!�considea�L. Minimum free energagA'exa�D , is moderately c-�a� wqAYbut this<n!�AayZ oeI�,es . Similare�Z-D—overall , partiAjeda�o5 typ�or.V0 cular rege�q�q�—6�$predictive�e&il 5S ,���mSq��S, a!�$scribed by%��<� afappears�(have littleno6�onFi� strongest5��A�q�SC a96�as well!�!� ���4!�E sponElY�which"mselves �!�b�shown�� � L�=xone anI)[4]��per�,ed a multipla gression�sk21ea�!Rto �s how�eAe%ca linea�bin��QaSouse:5�)a 5al yield� n r2=0 . 52IheBQ�#65 #EA,76Mp��+81Nuk . However�0significantly.��) E��96 � diff�Q&�2�>, sugAR�[ thatF{@reflects a subtle�I-uj)|A���IiseLcap�p!e��ededop��!�spe��Ew=w�!>'gthe"�dFAl�set!�to duce a� ribu!�'SC��A>�!�com� �"6 F�Tom%�!15捍(very narrowa�ge�admissi!���m�=ly�qQ high��� re it��aA�e�lz��� $ext-robust��ardles�^1(2�mos%E!Ѷs�t a wr rang�poJ�$even among.� whosAal1fm� s exhibit)/�J�indicajm�simplyuW� ��Pia� evolv� ea�A� � gi�.�G(G 7A � same  d wa" serawA��b6%�Ow!�*( ( data��ɽe U"� e��per1c tem-m ��IcalAje� he a�geU�E�0standard deviɮ:i��AQ�1E true�1Pb� mpu%�a��e� foun�m��tendencye�`rA7Jv��A,��:� t; �� ough few �m had�s gre� 72=�B%�We!S�%�analysisa�� 100-���set%�4�L, �$CD hairpin�!\)4eukaryotic SRPA)-deriAI.wW v3ly extłd��)M�ll"� Ldisplayed right-shifAR 6�,Bq�$biological�.�et o be.��%�rt5ial.9����a e%_Nk)�ak!�2d�L� inguishesI�! hypa�s �par�a fun�M ir unique��t!�$mechanism;�ref� we :,enh�J�(would still!)p�abs 2 bi{�$0traint . Recew , s� al!:ronic�Y*�!]P Drosophila melanogas~([47] , [48]E�TCaenorhabditis elegans %b bypa?Tha cleav�A90%�� )ei�����>Uon��—� 3%�6� us� 9� 9l ���!/} A�achie7a*� ce level��p = q 062 accoriuo a t����t-e��%!�An ad�K onal� � 6De)7 6�,=�17%�aE� alig�Zo onl�\e�e sit�ha'l� s� hang B��umablya;�ˡ�u�!Љ� \�>�-��!�Y>17��" , af�jtrimm.A��Yc*o ��H�Wa=ȑ ,.�5ATg�5�(6�483 ) (}4�A� mammali�%��,E�r�iO6�[49�4ȍ�uch�onger% hirt�x�11 Maca�[mulattaY�Ŷ}�w clo!ev!� n�`�� erva� �1��pr") Et� e ,} -877�,� wL� Y��� �uy�y:v � �ex�hsa-mi x� �:_� �&� ofe�50��_�^a�88)@q�@4 . 96×10−6 , H Wilcoxon rank sum � du�� non-�O�� 6S.]m1�QW also � 6=��F�6a���o �9����%�s]�2 . 39 �5�4 �>InA:trast%� &� �jo� in C .  ll!�"��A�ټ5�3E�-��mF � ly� -�ai��4 �1.N��A�01�`Z�:���t j�may%�"!� stryq�perhap�2r��r�qW*�"D 8��$ary histor9 Alt� !%%�y seemb�� �X��s@  ?ha-&~ %:z =is� �iE�k�..� m��� Sqs� �4�0unt�s"%is2jby�� mean59ce' ��aŽ� � G R ���A+���GRC.�� s %533 un"�24��� 4 h� *�B to �--$�!ir famil� mber�� 2be�2c4��nn��iOB�[34�� [35]\a� .Oo�>at lea�� orth�A�$paralog—B�6�e�.�mŢR�91 � a�non� �A�~b�78}�1��2�ӡZ���5��TAp�cE !i�nfl�.fac� a�bCfinE`�*EMin/)�shf*c"�, ��causei��K�diO� vidunm�  q.a-��ga�w Oio�"�by��domiz2 a�z�1�is���!-bie�d|Ape�<uI�R�C�� "$ .� m#e_��m�e7e� �G>P�6er��!�.����.Z!) g y lack� rE�* 6�055�,Z�; �� 2u�A larg�"�!of { �occura(genomic clu�s [50]�� 7�e2 prim�X�   [2�)51�052�_a lib� dy�ofh! O"5[28Cs� (� �is�� if�,is <10 , 000�4sn��am��nGw &r)s)�in�o}N�qg . ��`#so� Q6�48b�e5>o^ -�!6tur�� � �� �}m� ( p<� ��1� χ2 q, 1]�O!@#)a�q�#��>���=ce���by�an%-3Q lapp���� �.we�� �$ge� H��mi����J.�ٌ1if(�m% Q�͚�-.� �Y O 019I �vLbroken d� into ron-�8 exonNy8e*Ve{�^86��.zQ�� ^C�A ����$�R�3m� �nassocGQF�a��lo�o�#=� [z!�re�e`%R�$�aM8 ���N�^$y unde�zt84�B� �y. R'.%s��m��.�qSC*4. %�� =N9B,"9Y6MwB FR[) . I � s )we�I�{ A0exist>_� �9 � sic&( to m a6 ir j n�!5h�:ir ��d'*TtexqWeelope��oT)7 i�ax-���indexa$e���� to%�Y*g%'ofF!��F��ei*���.q$,�1th��5'1@[� tDwo age�ps du��*�,"��"�6R���t� �:�s��4aa� �(� .�]� a(amt� ��p3 E>�q+se>�,X�>W 6�!���Ew!�Ew�%�22` posi�'a�� �!Baw *'in [-qfic��, ��A| putat& !U� polyci�n&b ;�Z2�'���A�-pin�E� �(Bve":��t ^ost� AN�%W o +ia� AmF�!p � req.M-a>!purm*�%,"�(physicochemh6Yo/�, �Y �e��j�i�"�ߡnt!1per//b2y!87&>+sm�a�"�c.D�ammodyna�st��b�&st�%� E�e kineLlI( P7$ig� Pers�Commun�#on�� S& ele��s��ir&�)v firs@in$��ža�e? &(l[u�a cera�n�-e���� Ak piphx e�0�;%��-!��'id4�A�g?on��+���K0 �ypAs�$not�~ru�/E�relevan� �Y�� ɔ���s��(9oE`"0B ����"�.F[/ ty (2�+<�].+pe�} -�+�0"�+&8 �. A� ay&�6��s'�>fo!�%I6�� /O""�����,>�*h#emb��&�I�! ��p/a�a��d'!glea�) �+��<�*McRF%t goe11yond beA�j(a�r$)�@1)� IlcP)�as poa�d � in HC#L�Kim [33��5AncelF?3na [30� �mv.� coupSq-AmodW/AQofA��ma�mA�ot., equilibrium6�&m��ͥ�f���.�Bsep,��A B� � mediPF f.Qyvice / a\AL creaXBUof&W�!�} ` �" �Iw�2��#: �1:%�quiA�n�&`!f�� B�ps&pll .� w/(V���e curr�� .!L:.mM�� !��# $m�% nven!�� �x�����y6�1igQ: covale�#lin�7.O ju"&U�branchi +#ivUZANL ƕ�� surr�*Z ic%;9� aC %+AN��7 �5�6�� �$L �wAyf)'.i#!��F �t#��R be�%"��% ,insen� �5w�N :��)�� M!�7J�. 73- �* q�2aA accu2e*�!0�-%Al�&to� B�,auaTd /�fiA�%�ed�uh%i�aE&B� A�h z� 9p(% m�) :�!og��&�%�9`disrupaX��FOja novel�to� aTI�l�%B �%eeas��T+'� ��A�E  arr&�3( o-9��� a.�� �, �2th/e�its2n� . S�)�*�&�AE!�pr%� suffici��aA�oria?son wh3iks��)�O$i��Y�'�5oppqm4��"�2�r W � -���P"�e a�t�5  wM �&��L".  x��it=%!�uffer�6E�a��e >lc&,`d'�a .J�Ibe unlik�o1eXE�11�a%uf el"�eda^cursor��#!z nd hzeMhmX�irey�. PFyUhim"���a�+$�/��&|%0!^e poo1 &P, [53V �� 7%sup� �e=$a)�*� %� i�;f-�mod����ch d@ � rear�3� [54]$be�aneously)���ofine-tu�na�ro�/��/% v�D. Fur^�,!�)�� s1-� 5� Bo�.a�s e,t�C enviE�n�col)� bui;%gq�)�co ?�z�-w�1d� �"* time!�&�0�#v!(M�orA�ed"�ca@ŗ�5)���beE�4�$at�iw����� as��� ���a�V�1}6I�� es�6��k&� �uo�5-:�R�.-�* .*E F�]�!F���#�I" -2 d���'�[6.�6�;2C+�-rfOK3�Ze, sj5T*�(�s�A!to@N� ��d��*E �H!Ap-4pR%.1S�%�5�.��%t8ty –"3�l� a���V6&�� OH-d&:n!ȱ�[55 }"!�C<�A�Q)[ e.u��e-|t&�m-���.�lun$ � ensae�1�"�&�dly �as neg"o;873!Gs}�Gon ( Pg�.[4"[56a� [57]J�da�v!� signQ l!o��,#@�!V�:"candida*Ze&� rve��N�H�8�5E�M!�:j ser}  2HeD�5ex- B�� "� > �/�0,F&j2:��qui�7.fbi(�� "�}A��>elabo&�odq��A�al fu _! ��be�A�dq�fEԙ=do�nre�AA�ir orig=ub"��*�=TRigoutsos et al . [58]I�deA��IA�� a �!�x� v�.� Q� "�0�"Q� at j652X,9��'u7 ��I-� 1n�@-m��3 n im�f&�C�� �.o!�TD_� �B r�Ѩ�c0me�Ecw L 1val�pon is!�da@alHFh%^B � Yr AdECmolecul:8� -mHde���eAa�3�lymnfV uOly!U"U ut� "  d . �OA4 defa9set!�%#%S�4�!%5*/H4programs bundlA�E�.>H SecoLDy S�e .RHa�S( )�/�%!�in� �!�:P(uEepa PythoES�Z�&a�0Altschul-Erik�alg_hm [59 �2VRshuff�written)#Cl�![60O/All�!code Fcustom6x9 ��run�.Linux m�=ne�$High-voluma�8E �B K:�E!2S"1>>"orS��2ed �approximO(40–60 nodi.a �S3��>�� �:� �qO��|d�') Cd-hiUi<% Af!dysa=�36!p��e dra8ZNE8� �$RNAViz [619GraphZ) [61!��A�B.�c�$�.�1:.2�.:L 6E�“+G4"�a�u 0>J VR�BZ8"�?A�9&5/�(�LQ/&� 4��%�trunc7 ��9�nj?�8>� m�c�:"�F ,%Es�AiR*�>?VV?;e.MQ�?>�;�, T!ea 2-nt � � ( Data+9S� . C"�G�M)�1�� .EoE EmR2$RFAM 8 . 0��;lh li[[2�EE�DAny wildcard IUPAC:�'er�%3-�l:�replaa;2� siH&.].� “BA�� �C.Nei%“C , ) “G orU{equ�:"�Wy� �.NG A�o:�mat�Q��t�;Ů�Elu�C 7 N*� -�: �7E3�F��c�LnpaKFXH"�6��;89I�F-K1z06 (E��_") r�J? ,*8W��{W�Q>BY�97�_uni� *9� ies;]1 shor�B561!��;�an 137G .�'d�8.� Lst�FsB$Y��=� arD+. C� mF�.� � #5�-.�(�W!�i�SE v.�LZ��T� �h��(�$� �� : �&��Kof 500QMQa 5*#<-� of 8�9%?{&N Qof −3AU$8 kcal/molF�G�*�-o�#a}Tje�la�+32�=! ��=�-�a�6 �U[&=Z/[>2F���* , f� i9edA��  � inA� ("1C672 ,487r=&[C*aY 941-�6E~� left�(}ny*�:!��>I��� 2V1�D� wE�1�LA�Q&2kC�r:��MLLy��"jn� a� r-�9� aram>T"�$ !�nu`?��N"z%estP"h,!:�9I�� wsaB�!Eg&w�A� V&4Tpa�'h>M -dot�)�, : ( w���Xof��s xu6Z/$�A�*Fxw�G�O�j U� RN�F��l|e�"� �c2�$!;��3'.vof)*,at[��]� U/G��� ��;eg\O"* b�'�z!�iK@��5b��{&ae�;i!�� A�S�) d}\(.>un!�ed 5�<Ha�H�)4iG"ERb�] � �A' ��^yi:PVkYng��1��b�P1!��� pi��6�� ��pi'���dG�'e&#$�!ex�\� f� r��I�^ � i "{ ��A�| runsM�*�.Q�y�.�26�� .}�pl REs!h6O �&on*g��= W� �,�(�NCBI Re�Y�SB ��s [63]�:loa!�%�� UCSCɔe Bio�� cs S�K[6t[S���yKH"� �_val �C2JL>� � -��)*�5\��-, @c.q)8si<�5F&^vs� reJ�{$Masker [65_! M*�+ . D*�b-w��8!� �,d)�_x1�lW��e�j -re% � � � �A�t ��*�90lL�N1&Av& in 2�>239"����-TC-$N2�Y4�>t3sF )6!of�W�� 562m\.r� fe�P0hal�@�S%�inv;Xi� �/! aXA �M%&�-,g�I erm��!��7"�<�),�"�a����`G 9QC Lr,,-hQ5 .:%�@ed?�9�� 9 , 572�,-�n7@&� ���V=�i�Aon��!!&REb1�A��%��!�� "y<'p�.��_, [39jB�!�!VeQ0p�4Q�3!���I��� u#in [4��E�2.N�u5:KbyMmsP&� ��/a��!ay-�)�(y )��-�ethE�Jl�H(2!M#q�1��b� M�"� .�)T>)single%��*�g( &�I���OTMaSU?:�C3���!)�)�R� >�)19Sha2Uh�A HM�−∑dlogZ pi )!�| mono*W; �2c�� �"V16!� secuf.L+` .�A!A!… , UU�2� �!<)�!-64�e�7�vM]i?&iiV�9re"�I Y."@ie�a31]�F&�2&a9�a7U� ��optimH,� %@a9�.5 %Q5�,��J>� in 2&3-��E�K .� suJ�ڭ��0��=�5%riI�kepUly��'n�`�� �)&�Eal�$�a 2TaiHsC:e �-A#mUgWOCo*7i�B�i-.i( )6 ��ed � ��͵��as��.�!�? on [ H1�nt�YQ�0�+ ��i�sprea�%utW]e0E��M redu3 �imp�*owcI B bJar���s�GPp � �p[6wVXj� �BN%du�7dir�,I��f iz ��?w�e pq]s�� �)2�� -��;�4 abel�nam� 2iOgroup A�8us B ) N� ���I�'I�]>a two-X d p-�A�y� :absolu�?9d� 2�_*"R3,.�Ni�%p;Wel%b� un��l#K�gUj"g x̅AtC(!r5&)��"Me!<a�l��nd nA4��A�T I>�� BM)p�ric&�[sE-�,=�El�Y2 ( lY" x/1−x )a�>n��&ZA5�IeO �:e��|gh�@+re� G=mannep�8v��ssu�)\2~V-�3�"�m�N�@tyEGverifX��0Shapiro-Wilk an-� �:ofUF�i� an F :. M>�S%W/i!OAy >p.Ft �U,� null2��!m6oA�Y Data� -P�0x2)/��subje�!Y�Z�J��p*bX��"�k�A�"���ZZD�2r�%�'3-eb erfac�r�4��qu�4e�i>amadKail�&8at http://kim .H . upen�1Ledu/software/ .t�H�f",z� �rM%�-gna�sysz0/7�l inva$s% �8(=acro�-sm%"�Vs�/!W Yco"e"ofA��.re�a^st�'ro�rhic fun t_v�&en=4�'�.�q6�"�_�l�"�l�"��h!p�`s� ih0;pl�#di �susceptiL8R�rspars# H�,��*Y� �Q�PAfbk ( TF�Arabidop�qe�r��t�)mu7$o�`�L;.�pb&ei3 d%|:�to Botryccinerea%(P�.Tosphaerella cucumerinaA��f|!�/u*iEe>m�� �چr. T�r%GZX�es revea635�U=m�l1@[)E�tr of 77 up-V/��W#=�r(>Q�m�J5�en#pA4P" � cre� ~qq"we�d PROVIR\ao�Dvirul�)U;U y@!|!A�ges(Z�: � e*�&��R 8e1�3i�neq�a��Aq�a} �u�+�"��&��Ha�,�r����N/. Pa��hask�1ro[ s rQq�) crob)�i,-��&E�inu�thqs{ �survi� .*5pv m�iQ�cap��7-uc�,� y co�_z`a "�<%q�*Y(O �-e"�=r*�;"�1�m�e �defena<.�6!xa�,�(&�kmj�*� s�3$in lifesty�'I6k2�1�hd [�!N.�9.Yd(Wuc��ADM�� ]*�,e\ prom�&�� dea�D o ac�C nut�;�o�i�wAv%%e�[43�6Z�%��M�w�Etr�eHE��Ucr�+r�"v!�I�=grV�.�th9x9elim>� inctI �N(o1�K@(�BT!�h�~ erce�W#s via �p�wM1&�=re��r( PRR��aet�-a�MN8�)arH� PAMP4�!damage�5D 5�. Ca:btags �hnM�$I�e���q�;�0�-d"�diS)I� �+<,uR_2Rmonito$in)8�� �?%�- V!�el�}5��8-B- �!o.�B%rtrigg�$basNfe�NA�knrU)�tern- 4o�} ( PTI ��As tA:pg =ᴅx�ca�lL{sA�=�\wwu�2[5iVeaA1Yc�>��K v6���#au,� li {A�%b�s6� > � . Ouq<de&E-ofEq=A2]5Nis�,�Lr�n� >? ;�Va�gr�o�EE2�:�� &1r%*broad ge�,# �>%b@Ak�f�LY�^� eQpoU�,AJ����3 �,oS#�=)\agr780 [�� ā� w�"�  chiti&Wnd�0a� tituADoligosac$ ,e> O�7u���1nt A'����Polygala7Non( PG )!��7 _�6DM��K�pymC�Q�,&#>I�;ts enzy�cI�ar,+ !�)�� �%��6ysU8>�[7aAMoreo�xPG e7!�YE�9|�4gr%�!}ɛe?�"] carb�zo�<�'U��2&Dv%�9Y%� ( OG��.I$"�2.( ,to 15`C�?7 )%�!Q5\�3� �U�-&��f)J\ d PG-8�D1��#se��"�8as���� [ u�[8!xA k5].�kiM`WAKN+b�m�3�45Y\oq �[9dI&&l%traou�Dmit]-5�I�( MAP )�!An[1A5am!:CERK1����Q �T�BI�,�)�{yAO��q�inUxd�@[111n; R*�ndr�<�ut�Qa�lex� �r�p@M"�'d�o6�whormo� AO,0ethylenQET�6jas��a�id ( J�v , salicylS � abciyYa 2AB[14!e�6�s�<d�8metaboli�(!��phytoa�n cam ' h-.> u�ctryptop�*$sȁEL70indolglucosin�_a�,��t&n�١Hi�+$ce [18–2�1R9�2F)� )��{i�i�A�� Mon;"�w�$��c� S@.� cev1 1�%AU5V.(irx '�ɀellul#5synth�CE%�.kBru��+�[&*�2�^ i [2A�\b. C.��%imJM� �� ٹ�tway%R�t� �""�8)T!0nse [25�:D���" [��L>zB�9� ��.� .mdp7: WRKY33IPol��Q�bio%xA:e>o;m�<>�1#A&z >�!k_#7]�qe MYB-re�b BOS1!��t �@h[28]; ASYMMETRIC LEAVES ( A�0-�es JAM)�"s%4\u�B ."[29];�51�& E�a饠"e��}�940: �[30 �ba�|helix+K- leu� zip�gTF MYC2�9K!#q�by�C�!ng��&Gaer�KWti�%�UB, antagon{ ERF-t!�TF 1)�homeodom9SOCP``iD* I�e#���es�L2�c2%<L"r�qs��� S-�F�� �Wn��"l&c `p6"idhS [33]� MYB4A�O �J�es2�8- 2���&����!XdJ es [2�^I&BCl ,AU"X�z�]�� myb46�,%9>�!ad4�c ��?I�folloq6!h�*in|�/Qsum�g0sa�a aN )�W��z�<D l�:�(grA[ eill s��A��AO!� !��~�A���o��*�to� api<�an�IV�9m!���ed��i �r:�;}!��� gor�"�9, �:B� ,Hfa"EIs6�ocNu��  ,:� ba)Ob�, �`� ���$� ! Qx6�"&�� T<.�]��P6��f- ��.�5w.�,�HN��J�:d� �id�n ���!�a�!lA^j Ve�1A=� �-�!{��s8FB$�1d2�3H_T*3*�=H�Ds%� �.:,"v&>��n��#b*�+t�@&�z��!77���ctly6!��f TF��AM2��l�)��ptv]2�Ms:I�EweO�E�h+""X1� �WF*� �Vin^WN2(.o�in vivjWc&�L stud���)E�<iAv14.�LA�n��>&�s-�yYUi���q']Q and/F�QgJcin2�� � � s !"%m"J "�[. ��f"TFf <& ! �M�q Mn vasc�uU.BBs 2`�Ramírez&qBᇵ�X �c�VU�1M:t[C��}m��&de[2) �PA� ,��.� !0ł�W�ow��%%l>�o% �,!�G�t Zm�"��iB!Qa6K��T�=($;,�su�)�)5�*Q����  G[1K]�_"(,SY R :b%"' | .V)y0',z.geg�-Te� �S�(Qr��?.�B AraGenNet�ctA�8�!arane�3 mpimp-gol�!mp� de/ ) [37p*u�vicaCNtI�x,c�!�$neighborho�,�; �'�o)�(@> Fig IF� i� t��@�5&���fAt!��uAtESA8-� �8s�s D.ng�uu T� �.kd� s�othW� ���"�~ly&z$�4��v�Q� 4/7/�or 1in5J�n6���� cnA�^il��!!���b~ mAv ��}&^�A�� ..�/30=V&.�Eo��MapMab<tHxy %���;(map�.Z�!ral/ora . shtml�w,X�#*u�4/ !2or�T-DNA�Q��{s�%T.J � �a"[%. A toGof 18Np�$t ��4rDi�"M6kU�tudW1wT AE� next��Y���HAefIA R �m�#R�918�"%above �k K3i{&�]E:t�'�i&i�Lng� ozyg� ���� .�orDFBC$���QW+�!!>Q�symptowGy�ejj!I�ic le��� �ed:7�v��-rild�( Col-0j2* �Eh+.�LAq;fJ��a�E S� *Nu\= k.X"*Eko both*� �leR�shr�.u�� 1A�1B��N � �wt1g668.rnst!papbhlh95zf�at3g4993��Mae6��)e�&oMf�i�)N�dgata1� myb5�t 4! % vnd6}�6�-!"/Fy.$&y�to>�N@S�SA~.<65�%7rV9's=!GP:��k�X1".�Z�I}H theyI��*a>�|*7 . A5�/�$a zinc fin C C-x8-C-x53-H�� JAof �icX"�of un� �V�!��m�Fo CDM1a�hALLOSE DEFECTIVE MICROSPOREa�echf6cZs��msm�q" spor� [3� PAP2I$an Aux/IAA�IAA272.J��+ t���M�KagdTHula`.39 arbu� r my��hiz�/ym2i�bHLH996�Z DNA-1ysu�J�~N| . ZF �2�-�R4iU��.� over� A����2� qp�pip�C1#"l+ "&2o�3�"�Y, shed. �H�i�s����[demonIX��Y��2�0�N�up:M���d�:c�C� ���3!UI&�O_w mycelil$ �**rypZlu�<7S jD��CM�de�q�#V LJQ0suG.of epide\4&[^? �i�FŇŰK&&�Zck�"ޙqj�@Ji i%�5�nd��vani} 6�0&� �q�T�4by UV fluoresc�i�c�:��E%�qw�'u+yye  pix4�gi� i�&� <F%qH"��wf$m0Z�<�W�lqF6a.i���t%�B b���6Zq -���ZKNx�B at�v $om�� J�. I�s& �L �t*�Y5:JA-Tdea�L ^m!�1 &t�#E�"d� l)!W�U"9"� �5:G.*smightP e�mi�hLM�JA�B � se�W�!&GY�SZ�kA� �2nse"�A�JA mar@APDF�z2�� ,�yn.�by>� . RT-qPCRQ3�O7�#^�at �82{4��72 �ms&> ( h . p .\)� :/"���n���[ .�in2H��/!;�"�%��p,"'JG�pz4-b��e5�oE���GX&M�M �� am��uu�ec=6J ![&: >! qk..&nv���p�4: �u���'%�⭆a92�0�~"oi..� *= �)K.s�aJ�ocoi"�!-�H�1�*TJq��tgS�RQDH!�((�� a6 �4��J+i�A��%�61�PR1it�!A,&^ �S���jsm�,E��:���n�1]�6+A\E�F�Gg D� >O%7�-�-si=�}���l�Ɇi��n.�s";6!�5? o� ��leړ1&l4i�:-�va ully an�lei' aY -week-oldaQia�,�8ad� �, �9wo-colj� ong-�)*�@�arr9$�B�5A�ofE�"\��Oa�P�:2�z���E6,��E=,EH��C/usURP <�905� *|d)�!mNe5tE��@�)����~*�3c*82_��[:��y 735 ( 494)241N)284R98)86F(a_33*255*155F+r��A��b��"3 :�S�!' in� 22B; S�&S4�?'�&v �va�#W3`Oz��ly7 0�1�I\)�"= m�R2Y7N���2� �4g18480�&pEgen S��+$a�:���? mag7um cheK(HLI�.� chlo� y�;.'. MG5e�Bval��a���*Z� . S2%��a��"�{�2��U nW/M�8)��6eoi�al Ms�6no�1� !~m��Ra5?*T ����O�!@��#W?��)�st ��=9 I� .�&g , 47!0i77Y�2)ADb�9�7VDF"� ��a�''@9C"�$"� gE���!iI$lt-h*�Ily. C,Iց�A<�AivC 6.a�|!�.��Q&�DNIMN-I� �cl~Qg4o e-j'p�N [�Y>a�A�<E'�o^!� �2�.��!i�d&���! "� E`yas !�s � , ".))� -twA���&du�&�of/�thA0xpa5iM�aN [4M]�����e�g�.& <u AG� e,V��8iV/lf��Ith�8 PHYTOSULFOKINE�2SK4�~'heNQglycoV`PLANT PEPTIDE CONTAINING \$ATED TYROSd�PSYA@�KGN���,!�&�>�aM�}�.:�m��byr�.e-s12�iso� }&/AtPSK4� B�c>�!� !+f�AX$2�.��LDEVIL3/ROTUNDIFOLIA2!!DV TFL2!(Q�I��5512�e>A�oly1�.��6T*po/2E�pr2x} @ iX$!Gax� W��!46]�N.�r#B;�E� is 23 U��,!6/!1N+ DVL9�DVL1012)�F��C� �;6m|F^ :# 4)�G]�� :t��2�%ǡgdRAPID ALKALINIZATION FACTO�?RALU1��49V���� jub,�*apo�,c alkPCF5[4?!ʤ.vT� ���UPPro/Hyp-^5\ ARABINOGALACTAN-PROTEIN!/G�;��� AGP12e AGP2iJeI:(N�-q� �+}�AGP"��.�1tA$r��a� AGP4aP�N�C}]� E'�R�c �I��^,�gf5>sly�wsyl��(asteo��/�) I$�� n7hyd�>�k+H0�?� essTto 98%RX/,Z �����7u~O-linT\�,he Hyp} idu."<�]b?F��% A�usu�$�S �/ II a�Dno-a�6-8� ( AG��5>45 k)\M�)A3�DaU�-�f ��sylphhDtidylin>4�]GPa�ran�cho4�ir C-�"��m0Inmqa evQ cy .���-a"�k�ro�'��m!{d,�opJ41!_F´.�h>� �p�Lic. �"� a�ma�`�.N����T��Q�� E�t.}"e � iKF_V5�atrixF!��-�yu�$�M ( GRPs;��y��^}�GRP ye�Nc�[�u �1�2�qE�� e�by� 307%F.Y�xI�u� GRP3a3of*� v(as6qAac&�Ag)t*�9)�E!!Ik(a&�3"$ qpk*:(:[��$I-re a[o"� � *�#:Z+;:�<�%$(� ��K��Xdu�I�?� /1')F/$d�5&� NaUկg-pK�/�9sor �or�4ll &�)%T�p?'�CdH >g ,q�i���ss adap�&�yEL,!=�k miR�er�F"r�actA5ligandW&>�� z!�8 �`A:��E?�� adja�7�C� ],�l٧0utocrine/para =�[#��M���� )q��R|��f �A7,"@C)-���,�cD�?�� !b�!I��BPao 9���I 2�K-��n"C8<V��!�'�9.�N�����n"�E T� !�E�,�;s&ƐI�&!3"\!�& .� �ǡ���:� F"!t pH '5z�0dye Oregon GrDM488!�jug�  den�M9�"pwove�%!G�'A7 l�as2'Qs�'��C#-]� . L;i��, dYis��Z�U& tK QR6{��L*� ��1Wd��1H� ��:��8%a*7Fmee*B , �A�� �F� �3j>?m�0c�P�a��Qz)� @)$�s6�,�f�����pre '�e�jt�JcO�tw�.� sitol����  olipBC!Rir>�v GPI-Z�9x��8UP:� . E��,i�w0��wI6#2ng#"�&�&0>�;β->?yl YarivCru�X garq&p�œu� assays.: �3bI�u�X=umA c di�}} x-�B��z�FDM=�1A=��en� )�!H�q "|F�� picu�+q�"(>���a��iorA0�EinB;!~e>E3�. Sol.�� he�@hE, Q�)�o� ac5!�6E s���>Z#.�)!UW > m �t;y*� .n��-�֩��� Ye�Air����YNem� �E ��z� raft٢�x!�p" ��5�2�%��3b!v"�a*� ��k]y TD0 i�ņ�d"  �y. �bZ/ nb' )46 .�9p �v/ PSY , PSK� DVLs ,�#��=A. 33 ��l�L!y�~� R.6!�v���? H"�%!>1Q��,9%�EQgr� e morps�y!�*��;�aS3R F3�$ez�if��O*s&���=�82N���/�A��wX!<"x b�p%>�!�6/ ng scanlrbs{�v'SEMga�X"�(tissu�W�+FF'ap�s̑!c �B�s���ch�q�Cd��S'u�m��T�>\baAnA����+E<[�dW�s� !$�o�}"�(%�A�wV�:�&�6.�82�!oe�xylem=t9 s�:�� �~>��E�.M�A0� et��"i�X�Qdon v}lA,M$y>{ ~EEa3�� .��5:�cesp!�� �l:�k�^g��i ) ; 1#K��&�Vr_�_�b*�f=��G���&* �ontin�HV� �m�e�y V �9"%=mK5c��req�*l=B!��;}m�IK~( RLK )5���#7�0A ux��er�_ny� roidK�x�}F�!@Eh*����mT[!&�A�a��� rM im�@# W��gua�+2igeV�g�)�R)�f q aus����"�$sB�R�.�&w��� � :QB�0%+ 6:R �%j�� ��W!"�t ��� p-�H �=��Da 72-h�Q�ur3�"d<%�'of��.g:*&�*�X�na�r"at15&cD�6� -����*!8Ji�4d *��sSn-�sas7/x6+&�*.�GRPAt1; 3;!}�)�U�.�+u�AL � m by+&j+�'�%i�� ; lSJ2T!�y[ 9�;u!:ple Xylo�ja���!a�Nns�id� � Per4�54peX}"be"w\09� B��ae,M: ^�:�%Ys:RY,6�.�;�E)ifa 6T�)�!k������S� � �P�'in�33U:��wIw! �F٫m?�� O �J�.�5 ,�t5g56�d"'xo@D2�ƒto GFP�(A6��&��s� c�� �,oUy35S CaMVZ&s�V�ty�� ��-f bod��ap9to��*Es� �.WbA#~:�5);]2�Q&By�V�*M� tagg�A>a� each ��ZQZ�%���0f���"IE&�4�0�qF�-�M�� AllB�e$u��2pa�mGIe\KH2twvoot:54�Ai�]$�� ��`�I"@:&���Q�$�i!�m��*i � ytos�S4" �_.�TngJ�&� :)/R) -]}��Iel'�a46d.q 2� �:su_!�ac la�o��:-�9u2y"M� � EXI9E�t���*�0t,Rat�g.(A�� t�Ms61<DV�;A��a�"�0Z{i�2)|2G+ #1%#7h �I�" #>A%K'" #�"�� / P�(����� >� wards:�-�,pi��-��lZ"1���*�\S�HG�V�["a"�'��)Ra�!c @&w���a�� �09�D %W�edaU �A��( .0�9� ap3 �sOQ�A o%H:c2�`;p&C�ȥx1...36�>x B�:�&.(!2s��::' T2-1�"�� ��%�c"r�Amano&-H4p���#L q�^�� ogen���2?E�a^QX��tt�� �? ( S5�"Q�\ }I$`s.�G.�J�(--2 gL �-��>� 1��^�:v� 8*}1!CR�� E���1��4� �Ods A�ck �t%+*� #e�%�JWMB ��T"y.* ���-"� �-�ly�?y*5"Y*��q:�FU@� �ed 13�t��*`,x � �ofF_?i�#��ly2MO|5L1I1�\�!5�3Ek.�"� >�*�FgM�p&�wtHt.�s�^!;8334*'��A�H, �6�+o 123z)9 v�S6e�S7��0S� P��=�An/_7!f�% ophobic N&d$�N&Ww��$)Ss �$�E�X���%�"�F] #!tra�bk? rout!��ex�[U %Y V&'(�����<� ����>�. W�!s֛p! m�T� :%"$0-to-77:.z�o�:�I�t �2e�{wo�4�d&i�D1=��to 300:%2EA�5�!Kw.q;PDF]y1�7��|"�Ja+ '$!��o �~o�wa�3x!3#�i0>oPR&�"� @�un� �i�)o�A_0A �"� ve2� 5���'5I!�vzA)�$Ty�6]�M]N .m�peM�at6.��enݏl�@; ��WQ�8 �!�F�;� [] prof>@g!h S��> ocp3���"a� aVpronou;�.min>���*�%[��3�����Ae�!H9C�`ll2���^�B Y��[����? A%aq�-^.(��j@qcongrup�,I2�(�D�UWoGWca%~b�#���.yP6���st�~�&�.;�!ZbiB�i P��m�c sy�1ae DC3�,f*3��is livA b ���d��!6�$�&c$pJ�j!�B�.� 2�D�/>�&��(�Z3.OV ��:/at�?&��*� �,��� Dsly2!:�:health�m]n��9 !Akm��J�a˭48�.Q� �� �vI �:�!�m�z ��sligh[i( �: I=�iX>��4�=�,���. =6>bW@i agno�Fof2�*�]E�J���!m3:dW>�MHa��h�9 �D%�morm�j+ĉ3�MRq��N�carryaS!�aNgt AvrRpmI?.���i!��h��ˬ�-u��!jo�6�IHz� �"�%nd ��@s  ]as �024N�CEYN:��D���!i)z"�� data��)!8 '�5er>9d lyI.�.*l 1G%'CcrF3�I*�7Ek��2CY�/�"��t��)le�2���MR.y+uaE]9,Jh]�2g ũam�}��pXb poptW�u�.&�71W)�ypBs�B�  ( HR-���,�5�)A�G]!6Ez�k8^a&.%a�$uAt�K� �#HR F� �,� aj"� L2i 2�o� !`Bh���N��t �*�N��N���> *��]�j���"�!de^�caI�5 ��6�p+ 6&+ Uof�*�0 &�á=�сtA�6��6� �)���!�� �B�o6�$�ve.��8�S8���e5e�_�.&��Sa;�28 �h "or� ��>#"�%e �6� "" E�5�"_6a ?-a�i�x�K (}%DofM�� "&T**x )Y �10 �*v !)� *�= ^�� i3�4����T�diՐ.[�F� �A?�h�4( >1�w�P�e�Y�&�=, #de�%c!%�s3J2�C�r7��mZ5"�11eQ�Q�iI*�n54�o:)�@2KrLaa�B�&�?=�A� 4;�T�orI2�.�!E�}�of%@m�hg ��U���� + :'Z �*Ce�cg:�)2m!�)�vbyE��G&�Kqqgue(f����6Y&ism�?�2e_q:g�nV\ab&�er3 pro-"� ��V�f�|{aalm��Q�#���le�v�ta��pMor >"&.}9f&�)eSa & H>T &Z iDstock�ker�!�J�p9 ��?x�u#6z.( find {&�a��?�woɴA� A� A� ! F�> �@ U�5r'��M M�61 �m��S9���S:���/ 6�1�3r� ��!]��allE!5� &12-�a�%�� ��MYQ� �) ���::����w"4 ��12� .=Ġ k��D�hv |%�.��`he grp3=�I�%���i&p�:5� ed un� �e�E�%b�YV "+�"�%�m ab"�9*�"�{u�A>ndNE�T g>���I|&��iv: *�-A���\,bM�I�Lx� ����<8�6lo#hݣg�e���/`j(N3 tsub"L O"�e!]~ 0| Y � FPa�!�<u%-?L4ub""�ve'�Vu), �s��a�a l#�h���4 in Nicoti�be qm �L|# gro-"r5j �:���B�i �^""e�8%�$ �e��#�%%��.�;��Q d3vKAll-0s!k@Mm�I� �.���.86I2{U�in�� �i�=!��pha�,�"@�E=!@� !�PM� QZ. �EN���PM!Q�=�%#c � �!�v&.�i�J�#)1#A�!W�=35��^%Q!�.�( S10��� 1-�-��:�-�w"#f�&o ,*# !DVL ( *$ EachG$-t�% �.Oe�>�;Fhcfm[ bea7%��8.�?ng�sq PIP1ArI �me��cherry2`3 ( mC ��>�m��# ;4s>���a.T.� &R, �&!M132�Q�coincid�E� IP1-� (U�� N� to0C#X"6)�"�S mw�(o��e*PIP�� ډs�=��1 E��a]��se�3� q� � ld l �As��|��&�5*���`�6��u4�. C2Agƃ�F� 2B)t/�?M>5�}��Q &� �MI���.7 v!' )8; 29R 118.D.2,!� g9.0SI�8 )aj�A�ZPM)2�ub1��^�/t� . �sXi/bx/�~i u&��s#s0�@A� ir n��al.��� *�� �m*� intru(�M 6}D�e �twf�Gq�&w�I�0n�� � cG . N�2theai�n n ��p�*�@& �Pb��a��’4��V!�s6ato,\ack]0Aa*3 �&�!m5-5N�a�nd�� )��,+i&F�Z���s�i�b]w�A in��I7�va�5 ɢ�&�z WsB�5ѝ�zIA-�0�gY .7!8therefore also f crit/$aspects of�,resistance/sB�.�$. We found ͸several TFs , in particular ZFP2 , BHLH99 , PAP!m AT1G66810!}Pre required for plant� tRkt. Arabidopsis mutants defectiv!5 any� thes�r�@showed remarkable5F�(B . cinerea�P`ucumerina . InterestinglyECbOof�!>r�$was not du� �s!Ilimmune signaling , since JA-�$SA-respons�IV, whichE�$the two maA�efense-Opathwayl.I, were�|compromised . Callose deposition�ought-�cas| first-lin3~ barrier.-�iB�$ogens [17]�asI�!.�in:5?. T%�observel�dicateI�oa host}(e�contribu*oMvdV�%aAXe�N�( identifiedEfmi!somehowa�aAa “a� damage �$ol” machAnQ� �ra�tha � “detectE destroy@echanism,t trad%�ally A�-�ron-�Qgystemsa� holeAOomeAnscriptanalyamof Col-a�zfpa� bhlhe� pap2� at1gi�inserEi� � s reveale�JA�fo}sha�77 up�,g�?. A sub��ti�po eigs�[:mZa ��he!wdui?!=reE �of1eEligUi�elicit."+ �oAM cert�%͎advant%� , ei�{ by i� v!$�:�,A0attachmE�o�!�<st "simplyFNdevelop7-�a��Yb ould�-յr5`BQThu����O!cies-! have adap���E!zW to �!�Z va.{�]�non-i� ���dI.)� ,J�:��at%��In ad��! J � fur%�(characteriz��hirteen�Rfro�6� mmon��ional ]tur�tohyper-�le� �����ɥ!)���unknownA�I�i��  coinedn PROVIR1!13y F�m& / fac��in2 confer�z incr� dJ�!& >� �%�verse��$loss-of-fu �1 Nr&� UYj� maa)�%)im�O Y m�QF� Ilt� ��%�� V��6 A�o� elucid =!�E< 5assoc+on� QM/apopla�suggest��%� poly��ay work!�]���5��raeu񇅔perhapsA'scaffold��� in larger� plex. y�� lack9 �$6� =E%�,�� Nw u��unc�S-�a��!�e�� at ua� lie Z �� depen{.�)uZR� i�ursE�study� prI� new to�  strateg< in bree�+,programs aima9t8!� crop�.� .sthaliana ���re gr� in a th!�E�H( 19–23°C , 85% F �humid�(, 100 mEm22�$21 fluoresa� illumin)�) of10-hr-l�!�14 dark cycl�$previously�,[6�AllUf�ind backgr4. Fore�d"�GFPp-mCherry stru�, eachyr�%xfull �K!DNA�A�seleca�*+��I�U�jmpl� by PCR us!� Pfu Y�mer�SABumefa� s C58 bea�a rele�Ya�D10 mM MES pH 5 . 6�<gCl{15acetosyP!$+0n OD600 = 0 .>I�3 d[,=bce%_aDin2� �b�f�iscopy�8co-5A ,:�culP s�1n sepa���n���S3Y abova�eadjus!kto� O . D .�� mix_ i��o��.:�)ng%�vi silei�supA�sor P19%!�.I;all2_� Ptissu)RY,Leica TCS LS��x e6Vem�!\HCX PL APO 640/1 . 25–!�075 oil CS obj\.��-deriy�Z-�monitoDbA�citi�e�488�(514-nm argo� ser .��� k;�emi���visuao <xa 30-nm-width band-pass window ��e� at 515 nmo �} m�}Ee�, e�� era�ed�mea$a 543� green-neo.�M22!2�colͮat 695Ay630 � Total RNA�: ed-�TRIzo���B&�a� manuP urer’|P end%�9'pur� lith��chlor� precip1����K 2� R� 0Aid H Minus F�Hnd �Synx is K��Fer�/s Life S��cen!�%�. Quant�ve�( q�) ��W �measur��s)�9���@an ABI PRISM 7000�H�ka���SYBR-G!�L ( Perkin-Elmer ApplBio 2�$. ACTIN2/8�chosen� !�re�c���f�a�con� vxg2 g� tz li��below�hSق�P�aP� crud`�1#r�AI�homgiz��� frozen�� f ma4 ali�Tris-�> �TBS )���q�5�mDTT�ott inhib�EP cocktail ( Sigma-Ald���ona�rE�%a-�q.$Bradford ri0 ; uneAwiL A5$ed 20 μg ve��X�V�SDS-PAGE� 2% ac�ma(w/vA�ndiS to n� HN���The��s�1(P�au-S a� epfe�ie9 loap �ol . Uf�,U oblo1�incub���A��1 �abod k(he appropri| dilue4��)4c! � cوS -IgGa� oxids gy' oche!Vt a 1:1a�2h Western L� A� plus-ECL tAA�2�AEIn both~� in[!a�8, five-week-old� %�3i&S[3L 33�>� �sp� A}2T x104%E 6 /mL6$� e ch^6��MHat% :1. Dise{sym��evaluE b� termi� !�le� diam�at�st 50  s 11 I�1!�R�A-�c6l!9 g#!�edi") 2*aniK blu�JQq�A�� ��aL#T8by Garcia-Andra�+t aaY�!6�#l6� �%�]A ae DC3A�, carryA�or�AvrRpm1�gJ Rr84] . Homozygous9 of T-�>s �*�2�a���9inn3�obMP6�|"K�A$M�Amp a< #��EAmbA ( www . a . com ):�i"1�%�To0 ow ur label��Cy� oZed 4aminoallyl UTP��ady to�mix!Q�T7�& -driv�F�re(#onm�amounte�q� t�"85E�7ass�&� Vg2g�%�- �7�(� g )Ϲ�0in 1 M Na2CO3)8 nmol�dye� o�al NHS �L` ( Cy3/Cy5 ) RPN 5661 ( AA0 ham �� ;-� gehealthc�1�at robemperI�!^c�1 T� , 35 L�� �sod� ��`,��UEz%�antѾUa"� 5 muu�6Cy:FO" E>� Mega�}.�u"o0NanodND-�ytE�M$�reeA�( replaeq�&� ly hybridU�� omica*parison� .dH( V4 ) 4x44K Gene E&C!M�arr� ( G2519F ^�t Techn�� y[ 43�03 �!nucleo_$4 bes ( 60- ) c2�(to 29 , 030*�� ()tua�%{co�t>�%)6�m!P� ��A@� sl�$1H %con�� scan��!�n* li (log)w&E e�~�0�AIt%�r1�T-�/en\(}; �SD �eM!#�dE@� C�s data ���nd� tist��K� �4RankProd packaFna�!u�[65 , 66�x �up-�� downB�&%"�ba/W �sti1 d�o� qof false(i�predic��AGpfp*o$i�%�F < disc$ y !" ( FDR6accor to HoC �� ԡWexued6�A�r�d7be�� n 5%{ �� ide"�iE�e)��+e�P1�(!Mq) Y� t�(� 0�.�!, only A� th m�,12-� q>��B�E�..0 X��bout���q">"2S%AwR")C&$) !H  l�%A1��-eria , �ex$; al�-ga in'.[ �!us �0)* ��e�)P2y)L vidt Zm���g�if��o"�)�7)J�lyR`***:sc!>= �^ut.���)�iRA volum5��r,a 25 μM Ore��488 d��*z8GmbH , Darmstad�$Gerq#)a�s&J0e{�yw/ec"�a#!�leaf "&"of�act2�u A�4aid*aa eE�A�needl�by�Ss��fu�)ou abax�}a�IM�Gr/ppe%���$n its surr�ing!YI�,Mtaken 1h� ��M2j in Geilfu� Müh� [5� �� nogalacta*�%�%��T>TPop� [55]% or m*�"�Briefs10 po��r!�gr�d a� 10 mE5 {ay� (ASmM –HCl� i27M EDTA, . 1% v/v β,captoe��o41%NTritonXL � � e���&� at 4&a "�3.g i 3��rifugor�t $3� × g�!�supernaZ%!,!  . Polysack'm!%glycop�i"hrG�5m��Y��B�16�SI Qe.�2!�; B�pelle �.#Kde| %���6�)is3�bM�.{_�:&e�ae Gyl� tubq�&!z�^�!�.�j��V��%ot A=��aV�b4,�"y free�-�C . Fi�07' >Udi�<50��m NaC~N GPI �%ed AGPsqa�,R�tre�,B,Lisu &" �2�8 unit� of PI-PLC��-lip�C atidylin/3ol"�/;:�, MadridQpT )�2t HepeFKpH 7 . { � a��H�rCaCl2%vM�Hr��J�)�aT5bade "Uan agar��i�Hβ-d glucosyl Yariv�&6p���1c� bore��to cutr ell�3 �g6m6c(� ]li�Au�$lia Pty Lt; , VictoP !20–&.s��^�2�%le�N s a "�ser� of gum)dc� r� EZ!�8�6 . 4 mg��� p`μL��n��u 2�m�.=�!(�F�� u3 �&s�Z��K�� leftA�E�� 48h�picX��ifr 3�Mbmof)Nl�!qcal0dH � .wz=\1z��P�2 >�"h$v�[MS�3.�%�$a JSM-5410&'m#ron&�w HSEM ) ( JEOL , Toky$#Japani��E�<��Servic� Uni� idad�Witéc`4 de VaC �4. Two&�s� � %�fi�����.�[58�U�2.2d� �  hr!w�'cid:95%��( 1:3bcotyledd�#in 709�}3�+�%�n���(nd 10% NaOH3�at 42C�"( I�M�E\edj�in 50%�e S"3 X'I�field6&o�A�r4 6+c� ntr� modea� view�2n@Mhe,e�u$ xyle�v�!}��1b�0submit��q.�Omnibus8cs �ac�!���)GSE36308� SM886777-9%XA"�7� ; '80'82'�7>"3 "5" 8 $%mI6 '8' %�$, At4g2908`8At5g6532 575 3g619B<$ 2583 $3g499 1g6236 4g016 T1g1795 2g3809 5g16�#�5<022 H2g4474�39�01g746 $5g1T034 4g339 0507 x3g138 T2g322 �1g678z% 78 <1g654 � 1g16�!� 5g672g150 �1g2527�216-D 5g56�< 2g059\13 1g553-P5g407 586 `3!3 `�2 �2g2404�497-P!�8�65 2380 H4g140-4g1580H 2571�?!0�4g1339 <5g241 HA(6 � 2g46�!t 520i�Sue0ful��ryo im� !�>��r^1s!endometr� . Po(�"�1iv�8}��2Yfailur  women who�.�arecur�8 pregnancyG3��multiF.x�Zuns�in��f};"��*�H�5 demoQW���&\�F<#oro (khead Box OFOXO1��!�i?;t@o5)a�#�2)�vo�-8ab�o)Foxo1��p�)�t )�or Cr�nPgr )��s�dek$;� �rt�Aj?"1p�7l��  ar!��(�t�/,!�v�=�&emE(� pene]�al \u��A�'wV!he Q-9ic=� �5O}�E� �A1 :AbQ#v"~u�'?��i�7,*.D;5�po5β-:*niCTNNB!�s"�@�/*��(D6!�PGR+ d6�6 � -�*�be!irel )��1P=ud�1 'ofM&ep3a�os�ed.�of i� ue��J�)r�(6�!A� V!!verzin�.an2o �� lifeAD�4n?ory ph��i ��t:� �A��7��nVwI �/�  '�DA�m^2-. . 56�2�* ;A* M( �a]crS5��femal�4p�-%�3 ,&l�“R��A ( WOw. DY���b8 ocys+ Y.� enga� intr%r]" phys�t!Dmetaboli:�5[1� !>synchron3!,�l(� 2� th��'sel@matrixBon�6 �m�8-bounm&a)@-ytA[tim�42��!�!V$-�a�7tfa+ 3Jv ( LE&nd gui� *t�%|�#ae�27��D[�"�5T�highly�4veNi , ablish%fetal-4�E��A� nutr�8�a��4 ["� "{7s��6B�bj!�:LE�V�,�v?,displ!(B� ln#dec�e�,9f! stoo�9&� �o���YT!�l�Amoval�j�?1Mb95of en�_[4–[InHla�orG!iM��a�a[;>ca���3 23*j pat!�+ goAs�tro:- !MiB7� �of � �9ch$preeclamps�)HcB8g%cli�l�ortAE )ta�3!:=�-g�aYd�a�̈́.2[7–1b7a��u�jJ�( leve%�>A-�ovarian "�DcFg�#J0�<e� Sng�<��AK ��a&FC�E�Kr� ( ESRI]#A�F� (�^�;?@s�2%�nju�7�u �<."��� e{%!��to � &� �e" y [1�1�On��V]i�*�Ks�!3oE�;Fo^U .�e] )+eQ 25j=�C2hasB"�e��;)�in�L0huBB trom9ve'.%t?>tBJJ � rolsk pr"|r7nd�%oid.h%�[1�h, 2F_) p! "0Fi��2� -�pof ���.� �mod{D +�K(flux . Whil2l o"� s� �)T:e���t"� Z=�t�2�3 set�-K4M+Y��vo roX<)6y 4 uK)�3.�A+��qinv�"g e�9-jisf/yS:f��*=pat�,9 [ �!m e2�, P^+�W*���� id*P ,[�.F-�P12�� tc5W� ortI� lJ� ʅ�&� y.nlanAN��G��um�%2*� " e��� ��m!7 ~ cyto?BJ-OM\͌͠H W)�S?N|w�K body&e5�]J@"m�.@l�l!([15Auw�.$he�mo&~�oW&$�e�in�Q5nJK����edY ��a��pitui� �ova�o.Mv� granulosae��p mamm!�%ES6cartAEV� �m*[1877 � ɍ%�AE �)Bi�J{disruqG2���h�-as . Surpri��  GC69-�l1�a�s|4� imp!.B�E�-&E>���t�. 4}�seudo&�( PPD ).�{*�t�!�6�:. $crosstalk ���y ���Y�*P&spondA}ty$ńK/w%;� r� � * I  ..���� -EU���e!�A[�.� :�.��t�%*�d �q+ W%�E�.xRWa�%�a P�@�9�p�e��a��/a� *(+�$�&1����Z�h-2�o�$YQ. I�da63A�)_^8E($5 C57BL/6J� % . At3�M)l�"�" �:GE%�LE� (�A��IzW�#ow� a/AF�L gGg �i�,J�=EAN�/��A�3A .� R))F r:�Y���Fկic.�!�eE�9Fig 1A@tN�1nex��/edq?Y=-���. -�A� stu�5[1�#18] sp.aee�ecc�: ��w�C�WdHO!:"& om�Y���E-. [19]F[ �I�aO s �alE� ( GD ) 5 m:6Sa �?�} ��at %A�)�)b%�e5�YL adja$$�De m�� h lAE�4B�6�sit�I-I�8��D@Vv)e..��g�Wain�a� o� �Gͽa2� r��M � Fo ..-A�B� rrowk� Xa5r�; �I�gJ6.K%_�(u�In4�Q zo:PDZJ$B5Ic�%�(4�f!'��>eNb(ieB�FO+-�0-�B-2��rXl�3vl ls�pla�B% ar)�od9D2�� �@wyQ"?%�[G3oasub�u5G �)�YEI��'tN�s�M�pot��2K B��X k�� �n�U &g !��AF8I�!���i:aNa � K�"u� �BFllele�Q.sei majoX&� AIO#q'-�-&��[aZ�xegi as favGD%AN888QZy �$to circumvQ �SA�a�S�a���$cX.L2R!P�fV�^�1�ly"�Dm?�&�L"� � J��1I� at�5��6�AgX EH.�� %Hha � at�le���#o=�B!:�k* nd �n>�,!�%)ol ���w,)�^{e<+ d�BVA1�L.�,*!�� F�W2���m� �_n7��_c6�2C!v�fm�:�&�H!��a 6-mon�F6NtN1M:'Ux.O�kn�1B�3hd�r(wild-type m�%�2�:� L��N.1ZJ8l!�!� 2 `)e^ averag6 +/-E2 pup�`0-#8 . 97(37nFt�,M@>�un�b'M�YR!e ?arn ord�3�O��Uca�R4&� �L]ǢxXact%s�s�^fi%AU! vቅ�GD�,9 �,� �'#.��S�In�%o�&�2� } $IS , ( S1AE�) ;��QISaJ"J,a�A 3�mes"�%( �+K�~.A!8a�� e����-5 �/A�Q IS s>Um�U�Ij�slight?\u�\!d��sm� ZP"bISᑞF!de�5� �c�#X�,t �A�5�)�!YB-Y. H��=5� eJ�!l� �B�n] ɐXE� � �er%n�n6�c�oar S �S "re "f0:c"�8ai941py�resorpl68�"JWJm�s m�DA�wit!�b��{1ndEx�D�$!8(�`D�X?G)h#a0"�GE}M �aA�i��2]e�"ZtC�"o $��U(��NW�ɥ)ȅck<s"u2MQ= �Cw �m*�*!(�!��*,j4 o2�F�Q*�Y�Hu�%a�i18e�� .2SM�2Vif"0E�5ula-���$al:�HB-EGFA�> �)�6� ���ig2f s)1D�&6 �A�IA~ x^�iy :J ���:F�� �G# PM0 N9+�`,V�F ��N��a�A�-K=&�C2�&��.?� F �l-%ch��"�f( E�쥭�� ="�&�&*!PGR[0yc_We l-b.� a�pb� >� yEA�A�4!6uK :at birth�e�O*U iAEf !Kpheno�A5/�j� a�%U!�aZ��-2 y axEi#91fEE��"t assa�:#O � V� �!e���G> ɨ��um*&7C=�re2�Z . As�{ig 3Ax3B6&;�\F �!�se^��n���s� }�"H ce betw�7�%I�3_ !V�8^,!���+!�%�2�K)d!�cap� of-mA#a)o2/>z>&� .� JE)��a<v�j�IimM�`SZ�m- ine �#���:� A2�u�3�*Q @morph�[ 6Wa�.r-O"�Fa 2zobPd� bI�� 6�*6�Iۅ�!�2�.� FO3� [22]A"a2.�!�1"*�b�-"�Q�%XAno.� �eU!�FoeZf ᙲ� �&yh:�e coun��2m{c��fHҠ��&�l��� �.d!11�:���aU or)�2. E�' !�Z��#2� ,% ��-2�$4�6~f�,U�RW�qM&l)4�+6��m�ka�leukemia&�Xy fdl , LIF�=IF E�=GD�cld�}4isnl�Uor�,.AA2[2@,.x7Z�=��A���>q 2�$�Ki6��lhow�6� 3CPХ١�ed 0"�m��*�&��umAV�*of F �*���f)�K�2xve2�"$jn(-�[� i �$m�F �/Q�z^V5%+�n!�U�[�2>!�%K�z-P #"O G �n1Y�~})2�2x�bo �*"3G�vNC= �'�c ?@�TY->�:22/M+Z>F�)mha�ofL^ mRM_&xz0!�m�!��IfF_a:*�l�<w�F �5�V64:"6/,H �( S2AeiAo%�k1yA>>,2 Lif�de�"v�2�+& � �npla�f"U�fwu�hu&�2�!B�mp�Z,r�`bin��B( r�%�[!F u  �x� _a!%�ly pu�6� tocol [2zM�!re!a2p)2� l*dG�J�R%�i�e�_fTIdo%s6q� �G�/� . � A�� ��!6I�64.� se�\�?b0scu y)u- I�6�, !di0�~!�!� �*Y>�M5��EOtf3>GZ�%D !Ea&�T��KT>R1tv�Al� i5YہdIF..C! ei�:*� &sy%"�-BN�*�)e�!J��4���t3d&q?��&&/en"Á�@�-$���;la�r�7&�;>�[1�K�3f �i��9��v�)w�)�a� �I-d�3��my�r#s�/n��.!w���h�e [251Dz8�Jimulus1w stil&�A sesaaSilA�VriQkhor�"Ia robus��of"ZmasfC@Wced@ s 2 ( DD f%5 �[d�Y� 6.GelZIya+3A�DV�1/��wei�{'A���h"at �)�e֡,;a:a�:ha�y@,e�bi �>C�!�$�Ef%S �5=�� .i$6�A�2&��*R �."S3�fN�/"� �aM�ZOy4a�&Z'��^%�.*ti:#^ ���A �.gs �AS3�!|DDAS3D5�A-�AVe�&�Z^|(#�8��o�;� i{@ s&-!qt%�Y�"E [ �� �B�ɡLE&' =}p4tega�6' Ao6(=.Y �" ���T3"��$-�R�&s-Zspace(N8"�Y ! U�6�i/Re&s�E on�?hluB'6ot�*y.�6I"s&�!F��� g]2�ly"/�v�-s�in �'jr a visi���xu<9�%��=�z/�{�= greyY%ng�WWab�&�Y��5<�Os&�W%@W.JbbX �% c��I<��.�2.:* !�5k�e�)�S.]��i &�PLEM���"�9O�e ��"I�����Ugon��5"� �":o&{�LE �e�� -3h%��I���B�0%�P&� �.T��$%Bmp"T Wnt4 Z21Bno2EF�d vscrk�&��zE�fD�;IZ�2c �2� )zLE�t d���F-$6{MUC7BCA��&�IA.V&N]s.�7�R� q���� /"�rte���a�.��(> "DI ȁ�-.(@&exa����3[| Ձ�E�:'7.&�&�ccK2��GD [2'whe� iمs� Fs�B=pMUC 1.�Yone:�*��)a�P^LE�n� c4�S4Ua.|S4�ILor�C"�p.8�D�(=�-!�#qs P�o�o��bA%��Q)��'�^%+B1?3u(�#j owar5�5&B� 9&#InA �R)B���E9.�ng.N*`z&gont)<�;)lM��`���݅&A��� �(6��2)�%.6c�'�P!>z"bas1/!��-�R*T��rE��zejHo- DpoNin@, IHC%�"� of MW�-O��;A|&W$"�HE-cadh�p ( CDH. p-|W�/ ���>Aj&; ��2� s0�L�- ig'��1!�LE1%�2k"$a� V$� F�u�AvJ�%�&*G(Connexin 26�8JB� ZO%:TJP�1)��MNAo-!yo{K%ZI���9i|O-$ 5^ read�,]:u)QU�ne!+2��a��R"V �6B 1�%nZ= ��i�dean �, Claud�j( CLDN%5J-g�</�� Y��6H74t%, mA �m!�6 ^ ��2���s2v2+a��52���e߉=��6��4A��V�.�dh�e�6�sk�'�;���*i�2%�D�!]�X�Cas�]-3B'�� r �f& ). Dele4Qa!H���) �ac�� f-vAMr+,�c�7o d�Ki6`<��� �]N�7!4*�4��R*, U"0"�o !`=�]��Q�^*.&2�& ��a�K"� �XL�r�Z*�4m"��r"TU2��**�b�-sea�e4�*��RNA-seq9�]�a}1o�o0^"S,1�mC. S�,�!���9��p�a#�k� t E I� $w!}& D��sV | 6'.63�+�h�v16&��=��Y5ivs ��, S1 Tu�i,W�%272=� �k 3�Lnd 359."uz=��5�8Fͳ�not�, ups,bmW%L5bU��rn���=���!!�" by Ingenu%"P $&�softw�( IPAA[ri2Epi*�3g�bnI�"?N�i e��� ,�eA!a�i*4Y�!�e top 3}J!K�Wuj=�-X��%�&K!mLWe�LiNOS [26] , BMP [27]%IL-6 [28:�Aq{VRp53 [29 F(PI3K/AKT [3;PA2�nI�s}��<s�*2G[tg21!�6–3zTA�FF�,��q58H&�?9Y V"���(6��2��*P.seZ �X( β-Cat�X!�PPARG ,�PRa�and{Z�Vcep�( A�Ua�*�o5.E��o���9�H S�s AHRIHIF1A "ita+>B|J�Eqq 3&s ".e0 O�6at=�g.�*�-Pa�as�o7?I� qRT-f~Q�I�," hh�#if�fsxA MsxA Wnt5�bCtnnb�Muc, e51&���4�fc s"�%�f"7�i,s&']J���B.�Sn key_'/;��!�WA inflsL�L2GWY A����2�pro�6!�@��;2�. T"�Ru�o� �%&a&� �#�3 2i@a��52{ �(�M�v!�? ]]$.�&�o�%�4l�a��h�2-���M�red50. R��m de"�Z# ar:nKU�iGR.�&�Weom=7�56 2LblockV.�|�aQśET6rH�"#�Y6�F_ !] ~�#K-1A|PGD)�%�$ Aq %��--�� er*� Pu6:� I� ^�a6$ %�:�n2�61\�aMK Kb�q>M M��G ese"�>��.s�I*vD��!� u��"?.i�9�� .�.-�(aQ�d s�_�FO�A2~Yz�S&qJ8"[ K S=D edom�#ly2�-�e&um�EQ 8� &>�$�]YbL$e&"8�5 6�!�B��9 �%B�Î hypo�O�<�VU˔b�02�) �al- l�^izeA����e. FoE� ��Z�_�(�}07aCrePRALsL/+�� . �jź AOE/+ ) m�T /�e2= PGR-��Pu�m&��;)s-!a��pgTz* �;bal�@I�y!3���Z m�l�'/�.e �&��w39�� � Pg-j�tM�X�ʹ ��9up=��2�+%�J�!�bottom5�.�vmkF1\!2�6�s&\ote@�6�5! 2��9% !: �"�@- uFM�!� }y� *t72�m������v�WE��Z�HVI:�f�TE?��J]�"GNl�9E���"�p%V�Vu0��ayme[f�xYof�3- 4orܘ�. EFJ� �>dFg"�z� .���lu����OG��rge%��dgo�;Y�"�-vA^ear�p�, m�?r or�%~Y�X.Yp�!%��g-���V.p nA2��K g��BOK�6+d"�~LS��� AJI�!ANR\�)0i�d�he� /�`d��IYO"�fM��:!�R�A � T2�E!f�:  +�N6�i� �f�t.�}y��7Aa�op�|lBlind �_��6�e���wq�X�r�2� 7BEF*rM�e� �86� H �b .�jPq�sN; k`.�$-�."�e%��&�!O*�.U.{ i�"\ry=)��9�r6�b ���K�]J��=�.�)��9�[$#�a��+an!-p7 ��>� i� fe�KQ�1�in�Kq� Ax-i�-!(r�"�!a.�-�%e�Pm#sBSa� ��� rA[�O"�X ^�l��&*7 %�!E�?Y r� �3r� imar,-�!�e#:�R��  �� "�1+P .(d��&�%>E ��ofe:�.��A� ,���"��4s!٩-T�Il6_ �!Ne6 B-��c�;! Q.G��3n �,#,7s8�@�4 Until now( ~.� ?@n��� �-@%2�)���mI!w���&9,�}Eu=.{��re�/v&F���A�q56�1r " ".�v�\1U�al�2r�)mo&n��u��M+*]f �OeI�M&W<& h%t�\. '�N�#�{J�at �%>���E�>Q �( xclu�=���\�4.-�g=��Z����!�y"_'�?��F6or&n Q,�? N�aU�wC�6,%�.X9/"�ic�%ar�p� �c�3�A �=01�gRTMit)1 :!�a<�la l/.�sI=s.퇁푭�2i�T*Y'or&f �G2�,[3�3F�",��de>f� inu3l��H)|Be?"M|�3 "�N���&�rp��eq��e"�1�^ z�:5W |Q�6!|!�u ��(#A�A �<�Qf �s����c�"0 A��p!����am� [#t��s�j =5�J�&��j"` Q)a��%s��16� �A��Bronwb�'��1�5sE�u&�r^{E���i*m!��T}�"�>a�(�J �P%�6��Y�!o� U PTEN6)!e��"�!�krOʕg�K�b�pnd5in7m�hbWq6Э5mE2# Efy[3��3�)F* �i��in� �we� .sP)�. "n ��a�� "%>;aA�"&A��A�e%2�![Mc][a1$7q�-� U�B�PiJ�0own6?^; �Ce�&�<Q��is&�Po���6��, ��&c%siT *)A��("5'. B�RT-�Yl�6%&'�nN[�I�g��3d �;�OGR%�v=�<s�asn"��A{�!�7Vi.Mpos0�ost !m�O�L 6n��"�cc�A��.x ��B�wv �=2���a��a��SlC�]�uonshipmA`��\�� Z-�F��ra�6�u�My�i�%�U!a�n� ?��/Z��a.�.HHe�!�{� � h"2] |5zy�5;��>&i��E72l R"DH�FDH�FR0�F"��#to�F�9 E&c.�. &,$�weT.-� .�a1�"9�n��e\� �"*�Ic��u���i)0� �YQ�e*Y#Vwue�:��o ��Hx�V��@r�<JJvG. "ʮ��<see;�9M`�Nl&!Ag&k]|6�F�FxmW�6<�6<�6No?�ABi�.<-?�!I�����f�"�X6��V�.� &Ww�j5�I&�28d@f_ I4��� ���v#�XP-cE�p"ed�.��aC� �a6+"�@�� �b1�a�N�@>�. cmI��P �ejV� I�m�O)F ۡ�in� ']ff��A��MH,A{B�=-�>>�-f� ���9�� !��?;5�I!��"be19t/�<�rt1Ys98W_*�?��1�c���og��.'i��ٱ��� jrC E��{��]uM0!pCY�.� m?on-��fu�*gpel=.�.���� �,�6_O-go��J" � |5;u9��"Nr�&p �" a&? nAeIp�)��a�����C ��>40G� e��E�C ensuL ��tA�&GyE���strik7�c: �r aUg 2I&� "� g �t�-�u;��&MCw ����;&�{*3bM1*6)z�9� ��c�U��L o=���,"a�B!mi�j iK u���-A�< cA���%� �d'!~�'�FZW�� m�>*"�C%i:�{vas��B�ter$�i�d�:o &`6�:-�"(,!0 �� !"�)permej �%�P[e]`>�um��t�9=�s.AU� �of:��d�J lz1� P����im&�vr�|�:2�Z�5.um�3"&G:�GEoufM�2� cht�� "`UQ�J���@!8ar��& &(9� -shape��$i�� lumn�o cuboid�vonfigu*c�%�g6�,�B@'A�(xx%lyi�h�  N!_m�M*y-[3�(Y)� orch��a�a� �R�"�<v .nj=]�A` !�U2  reby�"�%sta2#G&�ʋN� 5�n�����+��Tsr�u{5�T�H\-< �l���!B�k@Charp "�"�DH1A)Ao� J-b�=y�B"�d/g��r7al�C9c*Eee�2�m2g �CA�E�-6.��md)t~�&-�Cb&�Э&2b[3x9m30�Gk3�1��:�DK5� �<MPA��a*Y^\SE"�A���2�.2+3Lc�B����he�F).Mr&�}I(dezZe o�By%tiQ"�iC)c_0����>�8��*}$LE!"�/disturb1%e��'!#W�,��A�"I��� �)lN[3" M�*A�oCb piY��E"!;R�� �.h�i�AkPo�.�i�� �Y)!�eiz���N *�>|s:�DpA VEE.\��Am?7� �r�!LEy�|� ��d*�f.А�s #mufvE�.e.J��"��G�C�%A � F&0>.R B� -�*D*� cc���� R���d-�r�:6I�LE1t2��Tm�2)�"�#x�� lear�3-�l�o&Xla��6,}pooa�6�*�+�q ethi��� tr���Nr� Z i�*! s go� 1�P&d�&� [40�*�9]���>�&N8�I����dir1acact��.J0/nd2��Ka���F#o� �M�KkZ�St&"\�/�]V EC829SI��#amEeyN� ��"� u\n�7F�v{M2FSM���Na W v���Q'� �.�p�I4:X R,M+8ccur-�eN�F[43@6 5Rs"�p�� Rho*�+%re�%Kc�,eu GTP��, ROCK1-�H"b!�6�"o a޵�� o�&k� rigg�K�P�ra!,;�1����- 6�e1keleto?(-� ��{�df%se�Tr��bYes��nC� �҆ �!!2EA�&>:� t'�S'G. �-���5!Be�+:9�oi"7]w��b!`A �:Sqzy&�y|q�. T㐥��,D%Z K%! �@)� t a�f��LNfMB� -'�$2,o�;U�-*:OiV�h�, WNT5A�"Nu����ɼt���A_� /-�A�lex�"~on��433D��n��&q% 6k&Q I��X0�Jver� n&R$BM���@ig!QMQB�%zz_sX Al���T(e n��.[[1��.*�V%_E�_ gain2m0:�*of o*�a��&+&�a:VG*+�FNKE>�Q��)�>S"-�A8忥�B�("��r:&F��� �E,�?.?>7al._W )� 6�ZIe� Q��Do:�&�4-��aS8al+ ��-\)�S����i�b"Fa5A{��2m. P�b"� f�5a�2� O�,�� �Uv6?v�!h�4*� Yin-v�Ya4TA�:�I,� � ���?C�}�8� se�.�� ���}R����d.�Q�!e!qU��2H|����. �N cord�2 fed� �- g�ň)GsuO�v"��Al�mcedi��#Vűh�(Y��� mm&�es: I]-��Rev��Board/C'-AiO RB )�G��ville H�� S|�� (f�'# Pro0993%]  1388؁���t�}Capel H� at N�  Ca @naZ d `: 0s�175NnWr����bedn�E!~":���-�Be:���thipe%if25�/,�RX� �'%q��J��Gu��Q7CGAmUN�LaborKA^s*VjN�5al5�g$-�Ma;� �jl> 6� n6�5�!�ACUa� of BayloriXgi Ml��)���j-AN-420)� �voofJ�Environadal�"��:xs 201A001�_237�e)�euPE�{�erv�d8 a�2A es�G(M�*� � JaŠE ana.t]e�100mg/kg��p) barbi�g�I�� . ,� 1ml/Q�(�c�� ce>�irrad�2Tekla8�obal so����-?����ro� die��HarlanYxA�, Inc�Ind\� poliIN�Gfresh2 ad l�T �X��X��X�V�. �X�bX�� = .�i�!K&���U.�ab�l�"��to �P�f���n.z�m�HLsL�<'��U�!҄G#� ��kI&��� gebe)� t���.@A�ϡPH����&�~, chicken β-] n ubiquit~;r#T� CAGGV��*( LoxP-STOP-  ( �)m+��%��T". ROSA26 u�6�moe/ �( -1uI!.�8 Q�� uc7 )}4J],�A�Wn�Kr�� al-�/) *8."c; �� |s��׉�� %si�Q!��w !&9,K�� f@L6�K �.�a���FZA�Y%W� Ltfi�)\�2�.� 9&L [(aVo1ed/e�.Q_N�4},lL���ma!Dat�N"$6� a>�er:&26� v,�c&!VA�>ly)� U-eB6D2F�G@��a�A7�r�;��F vagi�hpluB�F&,M� li\]�!�fQ e�of �) �S���rjix-��zro;B&�#2^ r"��b9��8&_��2�Dwi.v�aI�$� a2�\"�3iAzi9�s��n�9R>tu[GD �3�%�6h�&7e �f��GSU{Q,"�����v�,Ӌ!��. U�_be?�)i��fA*IS&E��5-ue�a Vern�� cali�T?��a;i [�� in 4��FI�y?�d��ra aldehyd�3PF�Ro�\=�v�BY�=%o��  logysagit���!�b�����B4(&�"e)�5%�>G �$a�U "Ms�"ed �u��Eo4i��.�i!��.�,B�=aW�p��ŷ�ngF��xw.va!7��a� a.���A�co .�%de~��2�1�y�qPA�i ^��E�]�on * (,h�Q\I��z,mA��"� su��0 W&�KM�v���7  ( {15����)� ^ � 02 ml/g\�*rR! �W �pcR%� llev� %`!7 analgesicbet;�fe&f 10 ~ E���z!� Ovar��y]� on 6>�)Q��p�g}2j)�t!a dors"�#���X)�2�;��!���6absorb�2s��!��` F��ton��op�[I*clo��OVG!5sk�+wou�lipa�2T�]73e2(��e�N�_q��`us;-��b1 E+d.��*�t�admini��]A� 1 ml�c��.2 inN�1�.�a>2�>��P� n o�il�%Sof� ng �&dio1:�2�j?D&��n�'ozE�of�27J�� M%�1 m&�#]!�L�r ]� %3}�6:7e,�v �ц�YBflash�U�f�ba-ot�a��T�'in � /�ApB)�$wa�.b�m��pr6��^�Y)�Aar"X52Hw�):��5r1�1�ӞN&N�Apth�^���6|&3 lAul]�_!�2�`2E9���� .�l�T�ы�k!Te�b�d^Ijs�=4�VKx%!wjl�%FX thir 6QX�*Q@v�A�|@p��retur�푑�9Bn������"J��mA ����dJ�B��u�M}V@fwQvE�|_y9.ayYiQ>)Ŗ�!�Adult"� i � ,t �_�)i��Pd����F 2�&K��m� !�&�mF 6aFONG ��FF ��-�d/�i,o1�aMo�p .�QH� ����00 �d��h^ vehi�Nw���gm�_��`  }on� �UEc'*�*ͺ1!k2�����E�R��.f�A��������� 6-harY�!"e�. Blast�ocysts were recovered by phosphate-buffPsaline and the number <�counted under a bright-field microscope . At >�time of sacrifice , a mid-portion)�uterine horn was fixed in 4% v/v PFA in PBS overnyH at room temperatur �follow �threeSthes with 70% ethanol . Dehydra�tissu&!(embedd � paraffin !sec��ed to 5 um thickness on glass slides . Sl Shegfor 20 mPt 60°CYcooled1 . S m-�d� in 3�$of xylenes=5[ utes each[�in�Tgradients ( 100% , 95%/!"() . For eos�`nd hematoxylin staining ,��incub�in20�3�, �d)�watAN$nd develop)ula 10% lithium carbonate solu!�!)f{,subsequently�%� ��1 �� x.!aF$&final]-o �>�mm%zPerAIe slip9!bHimmunohistochemical.`�MyM boiA.funmask!�5x( Vector Laboratories Burlingam! CA )� washA�e*a�m)dPBS . Endogenous peroxidas"a%!pc<b5t�U�ap 3% (e�)�MJeA(mq�%�0-�s� dark!�Ty �!�blockQLA3m@normal goat serumR �6MY�� n�\4a�A�8 humidified cha�)y8primary antibod!c4( see S4 TablemG llow!���^<%6S<-rabbit biotinyleZsecondBv$5 μL/mL ))H hour�"RT�F�AS>Ly� removed%_��.vZ)hVECTASTAIN Elite ABC ReageniM�DABQasee�t�� kiѥutiliz� �mG�L�{!�optim*��%�y !'i�*�  . Ti�%��roQ_.�� befo� ffix!�2�A semiqu!�tative��e l� tsA�e�� is!+S filt�$in columns� �RNAeasy� ke QIAGEN"� tow�JD~C A��3 once)�79�RWT�m!�B5+PE+Z X elua]%�RN7 � �'re�he)8 crib��DNA >(Moloney Mur��0Leukemia Viru�M-MLV ,���@� B� recommend�AwExpress� l�%� mRNA)A��rmi$by RT-qPCR� Q�8Studio 12K Flexl-T)"��� &c $TaqMan® Ga �$Assay plateK>�>� Lor FastStart SYBR GrhMas��(R& $Indianapol��IN�; ,oligonucleot� Gsynthes�]by:6(B6n�e9�(�Fto 18s r!� by ΔΔCT� od]_pre1Hc��bye>GenomicE�JProfi C} at Baylora7lew Medif Hous� TX �� qty check��&!u"qNanoDrop��l tome!war Agil�8Bioanalyzer 210 Libra�e� geneId]Il�D a TruSeq �l7y-E� toc� A double-�nd�NA5!�cr� �250 ng��totalc,�nt�ed!fpicogER, x!�� frag��6�o�a flow} �irst , �as:�.Red 3’�  ( C s� o *j�!orandomU�.>e�.n� by f�blunt e�, attach�b enFeA�*�enbWlig�,unique adaptaKWe �)e +�roduc then A�i�)�15 cycn of �� Bresul� I#EZ"�2\z�� a� asses� �!�Q�2A�.�. A�a��!�y8on=�to�c��ntM�of145!�w�ppl�Bio��s ViiA 7��A��!,i�A�E1a KAPAM'y / Ki All�q��equimoIErnt)�by �b re57 �6(UsAM� Z6�U��f)N,/)?y7%a"Sto� of� rapid runy�s�a:k$of 12 pM ,� ,on-board clu�A���A��� �Hi��2O at a�d length]00 bp�=aired-a(.�Hd mapp!Xgk ferential.;�?�E�YS�!���NA�p�Groupy !lDan L�ing�meta7litan c&[3�O� 64��iA���s (�$� ln�}d� "�i�t&29�-2 㑽%!h��,i��z sAwly F�A�w� of V[4�H-�#e�  i�b,a�os��sN�. �%&9 -see�behaviC)� d��-A}a5lik�J�< A_r-)��)|How!� , de�$ �A�� pr$ m be;int���nd not*ng8*25H l 2010A�n�*o�!B,confirm Ima���or%T=y, n)� �ed%sI�dec� d sE� 2002 �T�ght bOr�J attr!�+*�# evalaK!��(!�� %d� ��&� s0 e ng� publ� �/>{�ea�Ev�(d>�in�(n�pas�QM�2�@ qA stud-� �A� glob�)AD�1burden &*2verag% <"<097 , 833 sympto!�c( %-a��/"B credI� val: 2�/H879–5 , 608 , 456{6 i�"10�_ ��409}U*%uthor�ye�Cli �factor�maiN .A %�� )�luE!:!niva�.,� !Dv�.E�]Ca�*c�M>pupX/aI�a�1�d�i�, resh"�Outdoor A�fi� a�ain� fil"�/� 7��"�I�[6��A-�. ,.w�#asjl ( DTR���ce�v0daily maximum%�� .l�+)k12c,%�bitA�%y �&insE��1A��&oX&%�%�-%�-h��i,aE� [7�&0!CQ+similar�A�.��ira��*v���g*e ly n�bo>g��a%�U"(correin��&/ [#(12]�m��l}to spuri � �;q� s if igno%(.y�geo*� EP� ac�4�epowerful*� D�licitW c> !��� >�� m whil�corc<uncerA�t�� (!��� a�s [13�'e�W�3�(�pa\4gT*&� BJA+�#)h�#or�0 deri2> combiɶA��pre-ex�ng�led�J�� �.�'1��/dg �q�a�Age�"�umpE�a�3�f�;�2 �ac[r ]� re rob� Y"Xbe ob!w�'�R1� is rA [15]��on�& sE.l?-gio�7 ��]�m�beŮT ��l��s�� `o ͧ�t��has%,� donAK*J ���0Q�Q��(�:s!#- a_ e��tw clA�| F � di�� –� w� a small-7�� �' T�+%�sz �& part+!�efre] [1��&� >Wz ASm� ,� �D"~ 3� .�R�2� ( su�7s c�Gy$ o-dem[ phic��)��� . Our aim�to!����(tly5�NW��a�9� "::�n �}D �i�!N�)�djust� !�>k��&��a_ faci )ef��� �&9 ɰ!Sŭva�^a(�!h st nI& �e�p|e�. ��6oda�use��M��2e{b~2�� �"(��lac� . �� Av��3byAu� lbN�al Uni�%�oMO�is��ly�a9f2���� �s J.�/to";!D� !�ew ( mm� ��  � *� <a:)a�suO �"35A�-%��!h*#Meteo&!D((�NwI#� �3% ngQ&.l/Db� �9*}9��d% �m12��a� � e ays �2�%�by�f�z adja- C.�<���t� >� � reco,. Mk ng.��� De�� � !`� hA�-3���/w,2� , !��P%kri� [19]�<�^��po�:w:.<��T c3'ith�a_�.�U�,AuV8:�%�xr(2ld>! 10�-1%u*0by)PO�"�B . discur'be@).���6� /km2(>�0 c�6� �����'[�h��O�Y a �1 6of>y��]sb��n9�ʱL����199��2�8!� 2011 0susi�� B&�BureauS�!&[2�M� than"�9.Ldi�t� M92���� /��to9 . I)� uncl!wheE�Q-eu�m5�spo�+*rueVs-a  թ�a�, s�2IUa, edM^wh�5w�+two"m#terpre!(a����� �ofY� ; ei��0 )�8�scE8 ���To �ks' o-�- pa3" �,U�-wi�$ F�Nuu�N��e��via  bi�!��!�og�h�.link fun&A��]�M�q�d'a�fse�*Let y7B!&J5M- !�-�he ��(�?e= , …'4 )m�� tth ( t =:-1�Ye�Y9re�n���%��a;=��tA�f"�>f7should�inclu�� �is:���T��Rm.�AWe*!��.'�#at� %�&! =�� [2�� O� “By ”1a��a9�� ed�or"�� >)E���iso*�Za��4ye�"rR ls2�MHenc+ �. Atd!�orVoutbrBE NA�M�s exc�%he 10-%r plus��st�r,H�s�a�I. P�!�,a�yAJ����x�� jsG �yY!"��:ed [2�!�g�1~�$is�1� by: �A ( μH= �+α+β1T�? t−1+β22+β3DTR.4 5 ( 11*� +β6.!2.!a� +β72`8^9*I�i�0*O-�itD1*Popdenit+∅i+ARA ) t;i=>[ andt:12A�re)# deno�?!�E MtEl6�1����EmA� ,m�( T * a�NcD�4qCly �q�~e&pL�gf%Nj.>nW% �f. 9KAWa� �3 autoreg�6v/nth�ec�at capa N7B�a�&_,A� ecutOR"!��Ires=L!5��"qpdU_3�'a�,% L'��ak:]�.Q�+�\�)i"� �y�%6<$g a Matér.9�M&/'YKa� ���9 ��( SPDE�#�%ach [2E!All! tinu�c gA� ���(�m�*!���)� en�-�zn� a����cH�-] del�(�)�n� \R-pack� *I,N66(A�x��8( INL�+[2�F��a&��R�if��9,L5:�� Mg^t� pa �AU Inde)�A&ff�* Gaus)pri>w�%WGF prec�, 1 × 10−3r�;chosen�x!e�cep�Fα!�n�0i-oA7"�kβ)� A��%tA�"� 1mpoN���0����6i.%�53a�2 GammY �@(0 . 00005 ))M dev�-in:�criP<DIC! ?�+x�8� good>!ofAN�*�+edJ�+E !5 ZINB) (+�O�3ab�c��� 5 �;*� 2s)�B- GA�ny GI-FuE!�AA3%�ȡ@~ �ߡ�he bestbde-off& qee�a�lexf 7 . Te�1�Epl�9�J�)`%7A�A'�N=ful$!�!��E��as evR2$�lo�!��Q7V 44 vs 109 54�113�IAK.+&A_�ic��bl/m���!�e$ ,'efW !��e 2:��7 t&/ sh�S*4,a2,��Wi" .RP!�+aa�i%�p ship2H8( β2 = 3 . 81;K#�}�e^My [HPD]Fb# [CrI]: H6@6a�: ,{ l_ ^'"8/..�6 = -?73 �$HPD CrI: -�1U-a�3�#% � M���a�8��*�a@de98)[�i =e^ n�0Ɨ--�^z�87 . 22:��19 :N. 2�-�2� 1���]/lyb 11 =N69Jc 38 ,%�0�1Z9.. D��adjoi�Ta 2 B$.ńy/oB'6�a�.@.�Ta_ %�&����F�ploOB^�� !�� �*a�A.�����e�!�08J5%Y�1 18�s.�>`�Q Y\�� �Moraneindex ( ]2; p-��<m0���o���(&-6� aga�7%�n�9hyp�/�4�Ωa�u ?N$c i:� /I�_ ����al�s� �ttA.��7aue�kappa�6g 3%�� S8 %� )�&R2m �"��P�� ,:]�� 5�)f�%j�/�"�e �V�)�ſ ��O.h F�"q�sIpaA���tr�/�D,n�Z�E�DZ�in*1.�-�!&�|0�er��n"�/�Nnor�na  �6un�!.��lA��+"�)ct K1l#"�V) �%@L2��n(-"R�Z��25fluctu`3E �.j�2Q��@�2!k�A9S�;.pD\#$, A2>��*Wc-K���! �K�gh�2of"�,L>in$.&� 2��]u [EAl��2�S %� ,0���:g 5~�!�6�TZ ��"�( July-9v|3Ibf*�k6�Myofq�:L We s�#oU1%iT)1,&�!�6ly6#%Io&�#2>�InYSF4m6�� ^a�5��G)�e�: liev%24"� ,'@.�add�iJR��'_& �&Y ���ZV���e� a�m^� !�:" F� e}6�>> E&� &�' ��9r�!}� �>� � n �1/��ob�\�(e�1��m-�+�*25�!�&l also sugg�*� �!y�MC!23.� *� �8�_�-�]ud5�c6i-��;��#V�?v&lags [26�� 8] ,zA�6!�E�e�Bimpac��wh o�y1&� 9&YM.�22���&�!Ne&a " �*&� $6� -���$2lY\:�9�'ha�ep(� �l�U [2t 3�I"� �A�� �� !PB� ,�ih6>y=�9- 2D.�Fŋ���A0to.�[3""�.���&���R5:(z��bT�8C+��= ly h"w5��5a �r�r!�����%AtK+B]"p �a-3���An�?i�&�(�Lst>d�ce-�`&�+Y!286%�1 !N%a�u���,throug�� �" �a �w,�MIL �o, -�Wmb�P�--!?6���onZn"� cG-� �6 h�@I{�=!9��2_��w��un�;Q��F����M�,MJ�pD)�&� 50&M=F�<:%]��} Na�*� (LJl�- ( 3_$C26 '))#� B�#.&/ e^��0 c�2*!*>%q:Qos?+$2�[w��r+F�<�P25M0� 0 ��8�aj�5`Y  umab|A&�B��&�5�(97me�'!17s0y�a�N?�7�76*2+ 7OGsQ/��Q�a[ �Z D5#{0� ��ey4�-tegq(Au-sa�t�9"���SnM ,Bhatt et al �H`. a bo�2t6^2F adop!�&L�GE*V� �3 roba�Jof +a��46�"enviro�*J,on�Xs�pat-&�ZF7A&�"� veg�$ H,�@of6�,!d �vv4verAban +�1e�J?0y�/r�6� i/ ( e& =��<!!x.�G�A1I� 5 �"4E@�]e�F%�"[5EIa,!{ �o6M longi� �-&� E`c 54 cohort%Z���PpZ h jRr�� � ���dA`a�MB.�;fer n���� en�s� disrup!~�L+routin\* ���(!�!��e[.e��B5c&&e"�6<&�, �-/�5("re��en'v��F.w- �!�0 pa %�poi�kT�'>�M 1O>A�2�Pf !�� � n sub/in�cM%�,�Ky$�'}?x(8L %!]�Z�9Gz�6�6%r.Es��O�I��Bhe �8toU#t��e-U`� �&/ 4de6\7� Tf�2s3�&�5��c+2X�Ae<9B0A�� t�is"�I%�s��.� H,f22oh �0p&�$!4isYz J%MT d6�( M%_6�%"J&!5�A7r-"�%%vRo;��<"9[ :< g�Q�by&Ls�2�ME$ ason] , h�DFD���?h`^AU�A���5WA�rol�� gram�urMy�)incapfB#@!<)a��� ��ha�$e #*����of� �Li��/ U�N:i�i*-' ly sp7P& =�ar,I� 2)�3 ,ev oC_Nk]a:}8m�aT"cCB&I-a���� romi����g �f6UW&8EE�fA�ng�:� Tj!`��ess�2!<��i)�O$!�w�"&g .�B)wi� ono<e iuL�e.�G�"it �A&�M �Go�@�*EERvM8-�=6.�TWz1i~8�9@� novel.) y0ammals�{ablishA�it�lSA=Lmar o�h�8WADvis�F�cum!KaqRsp�;ina. Exa�H�ofGl�ory7E�ye� ��/ “hDT�]�*olights=sfe����o.zH/�?�[=be fruit^9�?ea�8!��r typ Om) %m �TexJ�!e��(i�"�%n]��(F�#: path curv�mfb nA��/_>empty��n Wvea� A�Mc��circums1_5:�! �-�,N"�ort�&�sH"��wiv�tur�We termuse1 knot�)#GM`$E�3 m—--�b� a`�%��yK�A�%�n�.nec� a� ion;Aa���inct b�I�\�i�( main�botL�%$% Pe K���$� �!qyE�ia{�� �h� away�8wa�n._ cha#er�^-�.�;mee��x�&A�� ghaj`din��a��b out )�%s��'!�JenhA�3inj� ng�i��.�wa'"!t�vA�o"H��.!\3��� s9 'ou�9>P i�Jnsolid� �ng-E��LCUc�Z�Va�i�prm% �6�I �&_Coid!��.imp�we�aK~cal�kv$� 8�!�w4w*XQur"�I��a�^f-g"D , often�4t�?y�e land�)�i�4a�_�Otra�%M���U �\LPnt&�U view�W9.I�.>& �c&�2� a<* .� ^���re2d�lure-ca�\.GE�'s%le�?%�FasGrA�o4)#�jkIbua]input"? E材 �im���a�e&�4��p scic. ��rat��R �es/"�xcK�,Er=%��d-H�'�p�=�QE�� stop>i�: trip�}�� [bA�w�_tra�.����A����B"#� 32�f� �9t.�I���O–JOKx5N��ly!�Ѡ�}whoa�r�[�$>�soA��q"��<il^ �A.��a�f��#e��O-ta2�^+ !N) p�Vo#b�:� ��Uay }a?I (4Y�O*b.峖�.�D��r�@n�?��1E�JT@�� ambig([6�es� ћ5s� ice: l�{m�Fs /p/qir:SCiostAf��w.�W forc�X� Ysetup� ve!o~"��]OK�.��: phys�oba$s�P–�K!�$�W�0�rV [7�the� � �o fail!jr" ��J��im�|6.�[7��@���.��%�ola[uaanM 2 %�E�"*9�ee�A�exB7� open ?�i�%�y� FitF�,� !zX �.Y ��F��:%p�W/o�Jw^,���A em a��|�y�-��� ��!�bua�lool R a���!�h�`  -K.��is phenomenC^D appeP*�� blow1"�D)�-5�E�5sŏaOun6`�; albe � kA��I��s�b�a\ T�JA � tUGS� !g- �� .��y�r>�!��Bt<verif�i2-N�ein.�To� "we�p(a�NmB%�$he locomot A–�"� ��2!�mgA>h�ndoU2�-sir m"�XP: e� clo��A� �� :tex�5�ePAы�-s� ]oqe-gu"A�3x [9C#IeF��3a w ��emakŗebW-��Jonspic��qd(GMAFia�Und�Chodav�� C_5�L-*gT!"�uR��&� )���&�^d� .k d.4.2>L� tophlKalA(� s��1_"Nr�&c}6;�sA+�A�b5Qf*" � b!��,enA�����s�� 5×5cm�W>#!wsum��AQor }u�:"�;&+5�.��� �Zat;� magn�%[�M��kK�co�mcoZ����m6c�A+thu�+i!��VD -;_ p �GavA����!k�de�$%F!�alg+hm vdef��� &��k fy s of$u�{*�Wgask�� w��D��Ie�}-�,c���&_h�#a�7W0ir& . O.y'`HN�� �a1en�wCrel/),_ I�N\�t�� !�u yv+S��� A�sec���q�M!�E�of{; u#so&�(@y �b�" ��&�of�t� (of� m2���P �^M�`�th!q-$-�7�k"" �uP Mt K%.�,ure�\pm�@-up�.m�6�o �s: awA�)�&7z��e�6S �7aIe���!':[ �zY �(m(�ˉ="� �M� s *O ;.E 5�>�+c�.� d� �}�w��6.��%��I�|���c�j _omp�g m� t.C%�W�>QY� �i/i��e� N4 �}S��hAS�ni�cTj!�Z�of�)8�)�>�$!B�(�i�4A��5!��mp�yp&&Dway: a�y�Bp6A�>7�< )-L�� 5O�GA�)�ed��le 95!!�6ps*�!ago L�pA'rix�7se s "%/spl��՝�+� g2�ray �l�;6>*2IQ"�ITo%�%� � h:��YY�a O Msmooth!� Ia&�= kernЀF�V� A���ma%(A����{ eed �4f�+D�I��u� a 2DOu:iFiU�� iapJ��"� a� 9�i � 20c��t�y(%� GchA{ e?� f�O i&b���:=R|>?F(e7�C^ A��!�-S�C�-"j8�e�!�1R��%�eh,s*j�N Y ;AsP�J��co�$-c_6�patL[9��^a=S9�/ex��a�%>S�Ovi�30 cmQDreo/5n-%ٜ[ %E �\repjw�Jm o jump� w!�[ walkaF8back-and-forth �!4rC@ll�X���Q���of��w�v}��7mag��' � ,yI%tPw�A!|A6%�+!LSre �l�VE�Q#Q��"4^ly-�-! ,�$vz�`d!X!}:� harp�d a{ %�"& a�%8631(“"K�! � -�;[A�be� inguIEXm. �/�)!��%��FtI�2�M�%a��Yi0ye/�by�Vg[ �:��u.%Y:2K MlY )focX�F"f �E�Im~ � roentgen �B " �+' +�!/��L �i�exp�n!JsG��{ll-de��bY"� E��Oejb��AL�+it 17 ��,.f �1|@��-�� �*�@/5%�of 41 *-" �-�]�pJ�vVce lef� 9>��i4yi��a Zie^f7�WC8–34 .�?ec�¥�!D%��*�6W~5�d� * �._T�HAJa�- iniG7J�,�A�"��Ys�-%(ibi�y�1�gi� � : unE�*/��&��a�B� �y�:"&; 6�%:O���y� [arl�5wy��5�).�0B>4�W&7 ��)�;s‚%�e*�/ <>`"����PS/M� a� n�4i�>Z G =� a�� .3 mhe1ktoM�tok-"�o." -aaU|=%f �x&�_(al�$�R6��H&]$��A�9%,: 3"Q5U� 7A&�!)silhouet�"�l� ���)reFb���R(�!c!R� psu�yv5�E��ca3� �2�JG�A���,!G12 o'c<�VE5� &�%(d ,B�3–10;& W[eP)6�B�e� OUACn)��!5"a�.~� O&}�la�!/�"�+ qA:10^I���E�w�ws�+�%on &[2 7�K!�U�i ����u grey}A��0L ll�� A th�touF��-�ext:;��{%{Ap*��.�!(*�?� J� u!�%@A!c�Evor�u#-�dQ�m�1?bD5��Dm*"cLg . ,u_B�rY(a �3op rowlsa�+� �+ alwgL� 6�(�*��S���u!��DN�^cthm��bottom �aNJI "�b5h?$q�ka�h��a\��v�)�l)�.8, ~Lve(9��A�P�mN�Tou��Wun6[6.s^A��5�1�]:�*�$d<D c`cwe��!q *�D riH#�.�e�e�[�d9Eeyo-���i� � a�����E�� v�7#y\i�)f�"( lOM� �E�� �&{ �!O��,)�a�r�� ��Y.� ap�"�/.yB�a�=��%�!��Llr"�q!6kl�k&U8!�� K�O�u�H�E�an o&uz.9F,�.� X%Hu9K.�YBf . UJ�A�z?�}A�.��j*�'2�0nora"'>�0�A�"r�3-�95-a5iXr�<.��rat�s�8��Q�e�wL]e]�=t���O��.�0-2 habi�Q��>N9AH��{d A*t��*� re��� �E�io5�aa� /G�,7�Qw%�2�2an�b!5���o���Q;al���� in C��,�ce=y;n� keep�@dl-�ir�-!�#�ry+m�[�y. Rush!"I�'��_5�E�%mechanis�8 an r@�9t. M�tq^e` %c.pm��� a�Rt���� �z�a(��.�&��e�T$zePiMa�(er-than-exp)'}Q"�;M Dquadr���9c+e !�Q�[1&aPe�L�Q�J�&a�a:�M�$!�:�툉�&S7meET�sI'eAQ "� a��A�B�yawhy%kE2Y &� she��?r$)Haa ��� %�}S A��b�a/�e��:�c� N =1Q ��  B-H 1l%�������c}�edJ g�&�5�9%kI�I2Et:=(��.��)%�:2�6in%y-!j:v1�Z7v�V ciph#��:"�8&� �?�ix8#��A����ani��� t avail]@XA2D4I�p�;,:;�+TZ�4az&8�Ncp x: U-I%1+"Qc! A�}f"!4na%=� �,�"zww!�23)AY�Da�A� .m@�, �925�%ultane�,:*:*5�*K;:l͔��gl��� �.��"�2� �0E�A �re:6t� :5�Gs�� �/+T�;!fi�S��hasv Schoner [�~��ev�'>" & ae�� ��`�!�:!��d`yeU�� A��;4t�%A�idiAza.|Bgm� %%.'s �3movgs# y�Gtۢc2E��C!*ne RN��Q�+'%�(*�~TBa�g� se nav�Q�~UD.b ns Mr\lstaedtmP܊i�-M�_ sta�und�� �.x ai�xqQA��a9a!92��O�).� G  �n��,�$)D���.P!5re�Dl�>e�T zH:d2�$&�rt.�<stimu�l� &�9�� .�<pe�f�M*�re!t�iai(longer lingA�u�V u[17�3A�m&�BdevR=?�B�=��rio�@ �=s�YΝ)q.�Q�6^>"2Nhm6z#�@""embod�nAR &J�#6�_�`<agU!t�@j/-I&>��*�>]DMl)��,m~�De�HmF&o ) �#�&�ia�s��exO n)h�� rule� ,m5�I�A�re���?& ,!R�?ter@ ge�9w��a>)fue1C,u-3 0�0i7�f� ���; H C�;\A�aMe� %a�/'�( 1.&Fg� w���B! �0�89* 2IyeF&oA8��5!"_d."�(Syg�Dndk� �*�;.�"�FB�. SJ�3: 8!C" =;aa�#11 ��e� m�AC57BL/6J)(( Charles-R��٩anada )� �-p"V: 1�o�o?E�'2��X 1a2[\a$ro��*[aoom� 2e|u?}��2hK�ht-O,I�&&A�:�foo�Ew�89��9 A�c4Li �a�.�� "��r E�rr"�S hand�-miհQC7�{�A�2+#& azll�Sat� A���u��Su� Ml$<r�nHE�%-rG)}71l�l%:DguideR�sg NG!. Ca�PUse�ExY� |�na�� Council�A  B1�9Q2��B�a 2�/diqoM)�*��a�vpo�F��y.��� 5�/h ,+L�gray p�H>=A|iEp�  �1:FNV�vsC2�!E�� �a3 k.M"K�(�r۸a �e%XaA�|'^%�-�Yh)8g_r�;1ƚl"��30� pl�_����aaE2's&m ��;? PNoldus��oV�o�g�:�P�� [18a;��(��,����0� �;opa:� box �$4!�ElEU�*�))�� Ny!. AI)20h(o��Xk!�lif!, � 55-m*�$ bega9Eac2"5�/ota�6���$eO( 2�Bŗd i�-�!k�-K�E� ph8h �^u��aݟS0,bov�� vNgYA#ia#�ki8� ��|-�E!2�,YeR\(( n = 9dor-�&� �%ĢGi�e�/��H.��c�_�?�i(s!^ ,*r)��e% -^N`I�:UB �raw R"�8U��a�m���s26L3sa�%T�&��+�q��d-+2�2T“SEE �� S Zj{��Kproced� ~�es{ i� �6������9 s�"mo% w&�SF!arͰM�H&asfI��6*�Y", rod�4&�B"@� �O!��s@OoS ���Bo�ij seg��:_/eepiso��[21�]w�iRA�a�Qtr�"�e�F�v*�s�4�7*� �>-S.qJ�!屾�J�����d%�ta��7� "/1n2# borh� . S)�%Xg,I7�~R �RJ�ao,�I�REM]�rwhtwo-gawsJ�2!��j!� ,�x� ://ws�^n. a�Hil/~ilan99/see/help��Oh!���uUIendSJ� HXs�EZJ�M��ca&�( Wolfra/7 .�zInva�i�[su fung0�thogenc ,�d�f(an malaria &T��agfhe ergok ��$ound NGx04Esti kscrq ,)��/v�u(mrU~-���<-*����b�s�[�li`�Zf�kR� Sec14p�%OV!� �AH�v�jp8�OI��B�K. Kk+�R���ub���:pockex��. Beyo�g&s�\�J:�"�eS�Fetg %!|�ung�~ �� l&H� � s�t��3�#��[q�a&7�1�M�u jAs Cryp�qccus neq��,��S �A &)��I-F. C,]��I,V^5,�6Gat-���A���"��woGZn�8i� ��Cħ�AE-�0 pomE���|zX!�KAjot�aEst>[. F<(eZ`[boge>�{ed�gicid_$]aP��uconazoQ�:�Ari I�^m8�%2���gen�e �9?-�5�A;M3Gw�.ng�? @Y=�%��,� � �� g��( IFI�0�life-z"ate�h!�>�!��taЭ��CandidaFKicA�) #: 2�s�f)@�,b�F6O�)�P�Asperg�' fum�:�ml5l90a��"�/eW�e��an1 qjA�!a�neva��ng���S9�#0 exkh,�ȑA� \��Au�q�HIVulaP�K� ��,�bA4�ߥ}apy.8o@Z�x�%ip V!+a�� [`}~ac �d��V[�'r�//e�t��E&tox����7s���:�I� �qI�-ѯ� ����1ch�'n�*�^|ev�� H e�H� �bb�A� �_��Ła5&#�g6 nH ��� Q�����m�>r �PO�K�+���R�H�D, �V�� a�vE]%LUS��!V�9&ec�� β-glux��G��Bfe�2oca��0&eew a[9V*Ef�=#60$is5/,��y s]UpPbio2E?LNew%�a.�ɤ*1��)o��.I���\�i�N���� r��m]n;��Coz4ole��1%exert�J}�xe3�el��&��.�re�f6�����sacc&z�6Z+� caps$, enzym�*�A=��m�jD^ n� E�gr� ���� ll!�d :&L6vST7A�iSeYa�A� Sec4� Sec6� �,e ,v<p��6S 1&D to=_F�]%A��I$��ex�� -�id�H.a.ch� ^ �7&�a�C�,�*as�% a Rab fam)?��e�or!6!+� ncho�#� OJs͹��A.$iR�nea�ke GTPa �� L- %�"e a���&�-���T �&b�]�V �(G#e�Y��/. a�g; }%v�3 ry �A�Q�+E�%&� !U�. He�!�!��^"�a�rȵ!?��iteAEg� ����de-coaEu�q%�OJ Ka� ~ Jh�� ��i5O�ͼ�d�1 rack��� ŝ(cH9[1��vCh�6UiE��x@� hyp�v�8!���gde � ){��M. Sk�mu�Zn. M!SEC14%A.�i7 kesid�  +�e�� . Al2)t�5�)8�p� -��ca� -��Q�B�_)�� $mA�-�mY!/� et[;�uYp | "�W p� !�A�"w"dR!&%xAA��ilico doof�A(V�utd  �i�S��=� oundN�� eio��4 ��@W+�>E& �h��~��. Tx&� � �:��x&&L M�!�ml pron<!yto"� in ���!�G�� ing� �� I������"9��R bOiPE�!�taQ�~c��co#�v��1c"�o����Try�E! NM�i�iAu < ough�`��AS!JN�pt�*� �f��SL�e| sia��a<o�;y� =�Q� ze�t� �2t->VmI�  1N7!����va�cd��s ��A� an IC50 <-μM�e!�5lҮ�-_�^��scaffold�� ��=~ t��q�SVQV�[2��aploinw icׯ.��( HIP�*a�zyg)p.!O!�G-dosage-& ��+2 ���#( J�N-�s5ߥ� ����V�$he>���z� �!U��H!>d=cc{)w M�a^ �10�� cop���"e* � l����Y�M�m�F�����'�?��Bt sub- q d[( 8EnD��.(#bi�M��rep# �c�n[,)�wQCZ&CKEB�ٵe {M(%%A�of��to��ul'.&k&!���fit�!��]%T+�5" )�-8��{>rc�"�Q�m�B[n ;VDof KES��eEG���Ȋ��g.le� 14p}&�["d} ulAH�E��a�-2�H>� - 2�9 �7���obe�?G&3w�3t�cornt�1�S E���PU~3cLA%U! of >C�0 �+!�ou �D%vn A{-y+*i �"�(e})�]c= ��Qb": a��)��r)�or]b�Z( SRF�Qa�$c�CxaN#PO1JO/��t� p m�q1q�"� 7� [3AD32� qITRy�k���9�my��7 s@:�[3k2NE/sQ�/ rf1/ po14/ itr1/�k s*� m/kes1��� A\&Q �Di�+!t !�5!]1�US!A"aEG+ �(m�$sc�� ho/hoQHE��A%?FM(. T�O toge�%Ti��k̈́ �Ew�/�7� �$via�a "%V�.�i1��.~��R�aa[f�C�q" Z�s�x�/L=tuA ��*A D !��a��34]%�! �edQ�y?�h!�)%�*poo��W2l5�105�! smid=s, ��i- ��p!���l��Ep&��e�150�� �� na.-��* e���$&>\ ild-�%�� E�y-��H rviv!;=!i{!�pl� ��.A��3%n+K��A�%C!�y/�^4.�� �o amino aci�Lh$p: Y111H (.z14*0O , Y151H/S6"27"V154I6 15 � S173A/P/L6&32&��2 Eԍ)�!�%J�� c% fG��� -e- �p5dS�Qre�#!�uto�td , y�HE�-��XM��A +cop3 c��i, ���� =�� 7gen y-�� AhSp�� s0*lq+�ae�thMW� � ��NC*=.>��W2-��^�;&v`eac_�!Ejݼ![��v#" v!�er.�tom�CP�D)2�3�la� u�m1�)5�l���6�>�Y7%���E��5�r����I�i3�M66] 9n.ks&7"�0^ He�Yp-l  s�������A|A�S*�sa�C(PDB ID: 1AUaBY�(OLM )*�sA?*A*;;:�6� �iv�ac�ed [35�Q7]��7cr%��5 0Y!�.�A�nol���tdEtn��[!(eN9V!s!�> Sfh1-V= 3B7Q �H�T!Q693%M�ty�')��h���� a�cy( PaR��� bic ;Ta� s va�4 r Wa�+(A�`Z0��.DA�dAU\���Ei"<2Vng �)6-ch WxyxlE�^ S175E0T17��A;?nit�a�tac�e pk�oxy�Uof�?��W3A|. "��m�l��i�%tdy�~IE�equ�/�c&O  -���ta�.>7�i ,�"��to\G�T�to7pA$�/wP �iZ} H-bo~ ;%�w��aso9EIwb.i?!%E6%6MQ���u+�8 9 �!�>�x-�.�P!�-�lj�oc�� ��� 6��-Q"�~�&AYR,'�_e�� mI�D kA�-@)?l��*E&i�V4%�i��s� made�g �)� Y122� ,AA3Ma!%F2%=�c&1D6�!k in a��mA�Ee&�+�}at05o�e�g� 9. �->>Ha&i��� du�3"`A�Ӣq,%*� U 5 Å*�-I�)�IWA_ �J+�G isd7�7Isoleu�m�e(�u~-a�A�h0 1�9��(���%0!�R3we&';@@2g" � ������(��doM��� ~ ����U�o6�\R14pq�. W&0 *Aa� EK�z� s0&�/)Bl :O �BedK�&a Ixc���P�8"�( PI )<.��X(��� �0B�|��PIE�PCAia "� v�D)w-��a�tdwh���,.�a-^ޞA��* E�>' �A�� �J. OJj��/9<&9�A�V$��v��� VE�m"?+ �E?[@*�{7si)3X�" J| �LAA�"�� ll L�En�1��ia CCLE Fl&l!Uof 512� c�!rX  �TBF�org/cc��Dos�L�eIFiE%�KX:�DoA(�) ��6va�g�*6� �g*h%!��Qv�~:� re*�ƽ;%�*�%*; [38 , 39]��%��&LR!w-�_U�ғe3�)����=A��<�(�<3i66�*!�\$ $M {!�76�(%^��D��#.� ~+4.� HepG2 J���-�����Gr��'2�[40�Y�% ;-ed%)H2^U�����]K%`Y?!3_E)A15i�6�y]7�{g2c �1-; ,iR)1�&~q�-x)M��!���/��7Z��.�sa��c * *� ,�h��F2 b<or3QueaL2.RO+�!%� 4��r&m��A]h�q�D�ą�Z&� �Z ���#!� ��~/*% CA� . 16�21O ��n � � radi� �a`Y �" gx049uss��)�-��CΆ� K�4�J�)o @e=T� ! F17�;C12I15� L186 (J� 20� � ,> A� M209��)� chA|m!���0��%3ph��w.E I�mA."r�A��k�i6@�surfa&�!)�>H�ij.y@� 6c *�Loo big��0p,hvS �{ �z]`�X bump^%&� j�U������Ga �-"� ng]�2�26'u��#��2�LӹMC)-i  (*[a} 20sR plau)s�!�"6�"�"�0tI�2� r�'�y74n��k�byN�&�-uA��*�Npro�Y%+&� ngy2�Qs.Q09-�� �"(�]&�'*�" :W1.+ .sa�'d>2 �s�'53%�C!PbZsiQ*� �"�%!)�s�,E���2s�mb6�" �I�L��C��alJ-�8)�2P4*2-V$&�( A��AM18J""�"�og&"�""E . T�)4P( ATCC 36556 and ATCC�� 90113 ) were plated in triplicates on increasing drug concentrations and MIC-2 ( 50% inhibition ) and MIC-0 ( no visible fungal growth ) co2S��scored after 72 hrs . ( Fig 5 ) . NGx04cHanalogues including3 ,16 07 96NGx19 m found to �@ C . neoformans g �!he tes!+$dose range �3 appea�to be -;m![)?l s , !0ver , can leaiHresistance [42–44dW!�us1�!ability!kN�s!�Q/M of/ FLU-lBK-$BPY22 [45]%`I�activxfor!� 03 (Y161�amtE 32)weakerBL16I� ( S3eJ) , inda�a5�I�ial�ergoline�fightv�.!N$next asses%�,he mechanismT-5ion , si!��,icidal agent!�a-qL static!$[46] , arekociE'Ede��ed morta%�!3)eNG!X! 6!�exh�� a i �effect�!�sensitiviz�s!e6-e��(3 was among%jEW%�e� whenQ�(in susceptiM�assay�utA�corrobor���itsJ�6�I��PAnalyapM�$structure-�A�rel��hip� AR )/� Y&��reveala�hat����� arom)� minoaDup%"substitu�eby a 2 , X-trichloroethyl-carboxy��moiety�8 nti-A7ASqW(!�nd 7e whil ��H%Kan un.�, acetod���u}dV�(lacked nota���. Nitro�a -�5ra�>Qole!��all posi> s as)U ��ou!zyh�)asm ɤ equii� . IAqmmary�nti>B�&:  as predic-�a��Q[ideMie)x4 inter!ng��d�could��(erimentally�GLconfirmed . Our limiiA�ex..eEt buil of��6[! 9Penabl�fuA� m�4inal chemistry!�roaches%^ �im!I�� AYoptimize�Ic!J�� @ther pharmacokine��$parametersI 8is scaffold . S��e IFIs��0often life-th�en��M,. The clinica.rse��%is very5W�!�β-glu�Asynthase��8or echinocandinB1��d$ developa&�last �e��ad�S�modeC8s a novel targeM�ad � ,Eemerge�2ofE8��Q�esajish�x!AGs dra�jEQemphasiz�e imporofQDy!N �!selec��� ��?:ii���co� causeZmJm%�iti� revie� in [47��� � nvas�cs Bi7�� !h n~ orὍ�pubm�reA�ly [18!�1W��M�of _. I!esY�ف�2��of Kes1�.a��m� negazly reg* ����C[29 , 30ᒁ�t�uvs2|a �soral"��vat����Y hY���� ��Ѝ�( Srf1p�! cataly� $ po14%of PLD:�beF.���@=�by5�H���bypass %G muX� [53]<generaQa�,ic acid poolb is utiliz�supL �ye�5Golgi-�! func��A.� 1D�ItrM Myo-��sugar�zeer�Ia� lso i\�9BSw�o�pq�Y ,Ajbau b+ mP l� V)�l Au�our data@A'at-y�+ �I or mN�  a $]�pro�7T��&� c���zvalid ba#"�clo �Yɟ� ͋�W{m5���� �% ocke�����T�!326�t!&$c#Spontane�or�Ll< ��,Odom� his�� �؁�or.af� �2 responsi�� ,le nucleotid�lymorph� ( SN��[5A�b$egant vari)i Vap%c%]&� %e�Q�� ari�� s [3_��R tadc�st�Y,a ( nearly )a�ome-w�col� oe=$plasmid-ba�SNP�BO�90%�i�ORFM���se�s10͟to 10 Z erent^P�R��0of͸atq��:M�>,���,�M�ofa� r di�\c �� �d multip�il .2�g� -e obser!Ldomin�]�by��ݛ�,rn!Un sid� �  n .�ţ��. How��dv_(d knowledge!privileXsi!t����e2m4alu�inI A�wA� lievaRMprogram� alle� bX R��m will�ow%�furnov �5�!!!h1s favor�=x*s A!oprecur A!Xin vivo toxicology studa�w��AgAv�A%�A�Mg�` ɳhuman�s!d� mi� IC50�acrosi(C!�r C� L�Encycpia . Ms��ed �Mnot�@hi$significanf6���.� a HepG2�_ cyto%��E*� f�n.��!�lem�e>n>��ZNd !!)0 #&�� hand� S5��� due!�evoluy�divO�pthoug��,m A�Q��:�_ ��m�urk ,�al"@c5re-� betws��:�aS ��s [56��two 6imilar |' 8" ���{�6� % -��9�� � s crit� e/I�4�Aw9$.� ���( ��ўse6��4�shape!�p��2M��� ,�m!� a sm�zr� � � ��< . A :nEp5��h need� o��exit)pes-5xfean9gu� �Z>yA�a�ng>itoB�$-1%V 2E�Aat ���d�[i��:�&a.D �ѝ� M�!�9�( ��� 2� Y15117*a)5 2u�sugge/"� !��!�A�>( in avQ��ivX %ʅ��wo&!�"� :� � �42g&�"�A1gn� � Ō�!UA+�if. S����"�a*" "��.2�.��";!�Ehad l�eia. TwoY�see�Ѩ �c"-#��o�_cle��. ed �amX!#!�.�d-$A�I �)x3 a both�n><S5�,a trifluorom5 � _ phenyl ,M pl[!�KA�5-� �de "y obtai���SAR,inventory di *�"*��mM"oə� ophohempb 2� t" �R7ň*demon� �uY[ me��!Q�J !O!�ris�� att@ �X star� poinTrz� e�1��'#2�+ ? %&F�T%*�$� m%GheQ�a�2/w$"�#, under9�!� &�"���:/in8$%�. SomՑ!Ha,!&ed �i�%� ��Zalb� �A.( 2443�)4, A . fumigatuMYA-362a3(, R . oryzaaT>462�!#F .Lani (! 3636bu!�a�+ ineNS8��. S�%!b������" x �q�!k6p�`D u$,F�]14.7&.� �� &���!\*�)0�� Q ���. Im� �s� if�the@"i�v�at"� t no� ��Ru� d &q p��$X"� &�$t%<�FQa"S perde�� Hsu sA� NGx Bafup�U�p-��'�M��F�&�&2a rat ld  mi� ��- !gmetab�!v)!� $!��ict.�  degra� ( S7U�I2� ͹�in ?&c um (A���A~crude%� ex��s*�abs��ny'-� /p� mbrane-st �&h�ingasHOP�57!Aort%Tno�8x� t�D"�"l:�mA�f�<"a�requisit� rq*�"Yper�:r�c�'m-meL+%�! or�,toiAO)�>q",U .`to pene!@blood b{,barrier6PM���,Aexh)�*=.Q ��igh6�S �ng!2"�e"�,x!CN� HB?of�Iis8e<',�!@� E�s Q �O;-�sychedeW narcotics?c|ei%c yE �hal7n��� xic�lecqv�kaloidsw/n _$600 BC [59�a�!"L� �lZ d��(in 1875 [60�oda�#� 80Bv*��iE�pla,ha� �xd"�[61K-0a number non-:�� ,�t)#er�iv;.5_C'AqQ&0 Parkinson’!s %, � mega� hyperprol�Bnemia�estY -leg�%nd� - ypoton!migA�f,Ƀd c��s�)�by � 1Ni� � �) 8]Fexclusiv�Gransmit��$$α-adreno-�er�in-!6dop� e�# ptore�$mammals [6d!I� a%uT�1w"�o!��&ly3vi�a�f�0re�21as%� GPCR@�,�9H he @!�� 2B on l^" eukaryo�. C�1� t��wda�untila}T riorE��V� dis�sKmMQ' into� DMSOE� kept& 4°C�a maximu0/6 month��Pur[a'� H#�(by LC-MS/MS[UV � \ X �ed QC�cor�++m� �|be"y!�$�/� �An�n��!��bove 85%5 2� FJ; @ X�-�"" ( OpenBio� s YSC1055R � `pools�e>dA.�&pTousP&63��A+u�2�*Y�"� ��D�DX . Pan ( Baylor C�Mf M@,a�Housto� TX 7703KUSAe�:� � ins � 4 , a lung �Ind "�5".brosp�,fluid1E� purc�+d �c, Man�� VA (��2F��2�o�%6��� arrayI�Z0 |&(|"�!.�2"�R����M_� A�&�[ � ��*E,t4eQx1mOS�5r sequen$�� c1hybrid0: CloFpic�//�n��n5� md3YPDa�30a��96 deep�bO+ .� �t$2����wa�,�lQwa("� subjbw  zymoly3)��ma�p��pur"�-/ DNA�_ Wizard SV2-i�:,�� ga )>�BY474\,a� }�)�-'in% um!�"� 6?cYO")�,:�*/�*0( 200 μM eacJ Sigma-Ald" 79401<P3�7,� �,�tOD 4� �iu!�aj �*u e rec d)�a �3%�-oelve-Vser di��Da�y�96-�&��%��on ��15�lahe>�o��u4!� DB ID 1AU��Ls prep�5us�!� defal+set� vez-P2IPM>A�a Maes 3Schrö��er Su~ ( www� chro .�~%�LigA�"�es* g�%1gCo~ [6w"�8*��Z a�>��ock� p�$dur� c� d �3)&Gl�SP��. A�:_y�u,-�-l ��4x2d sM� Model�u,��p `� flex?$!r keep& � rigid�rA+���d��65�MTS� :��a�*Ti��96 AQueg!One S "A�*� Assay kit�Pe� !��4unI6s6�7� �co�Apaca�% o%ICL� nd Lh.4y Standards In�6 ( CLSI ) � 'br��_� � M27-A-<T� �9O,in RPMI-1640�,yš�o(<05� glutamM,ol+!A�� rbon�buf%��0�<65/$/l 3- ( N-U&p o )A) panesulfoucid�:OPSe΁���� adjuf=�H 7 . 0E}s�"s)w�a|;m fil!��Co end�C�4�w:Q;! iQt"�4�/Sno ^�>!��>�0���A6O to >50%�th!Ru*�CToEBE$Aa@� si�� �a�.�f�>E<:��+%Sfo;.F7Brief�Z� �f���"� YEPD1�at�1at agi�o�#� -�t�E�� o abAW103Os�>M�as��m6 ulum%��= �A: pipe�in�E flat5t])� t� �5A0heJkN29 CFU cou��! a�+byJa�B�A248�@incub� . Drug-.5!w8on�2r .of 16t?"�=��E ��oco���Na�1�of 24 �!�5 ,)�I�1�y%2�toI %��5!+E�2�!Qdef7 �.CFUEF+-K �"7 ase�u� -a"�U. MJS z�*}N� 66] a fuaut�<ed�am� he a��x���Rw7]YlA�&� !ocontroE�sc,somiaX O4oy3neg+aXrop�l6� exacerb%>pktl-6�in,!��$raziquanteA?�e2-scale% A?2&c*9EK���nt�%si� , hM�%1!a 3!!�8: new ��e�3. HA�'!]*%�ntimal�,l� mefloqu��po���612hpropert�%in�t�"A�%"�Cof.VM ,or 400 mg/kg;d� ��a/�#y�mic�qg�<ad< S5��aiS  . jap�9um� ul?in>(��to*A<fem!�(worm burdenفN7�� 3%–100%œImnaS, \Z?�!l"�(�you(Fev�;� stag" �MEon��h]!+ mo8;. B�9� erythro-e7)iom�rV.�!a�'�{AR*n5�e�9, -pat.X ��"�{9ur�� s holdAYmisUA�-'mPF6r<t6�aJ b�.o�)"alcohol�gT�B . Fu)�(Y ! vo"�(&B launD�M7�7�!s302�CXUt P�)&�=�on%haematob�9�tr�.Ww�)v;� t�4v gy whe�6.c�"9i�d�befab�� A�!t�_aĉ(A�?+ impa�C��n�eG�&�"?q>0(co-exist . y� K^*� nd de�a�:��[�=[fA�cl�� to 8��ill � vidu���6is�2�X!�� v��!c HpeoN0CAV;%�!fD<>i�@ٜ[3*[�e?'�E3 a di� U!�!�genus2(��<����a�sitiz��'�a�.�,���Tdq�. MorbidoD*B��/~ep� !EA��1al fi�i�s�Z&~�8ur�� blad/F" calc2�- ito}*e!t!� (c.�) [I��global�ofB�a���%dAE1 . 7Am4@JU'dis�-"� ar� DALYV�e�;he�gercJbe� [ }A� true�a , [H[,*A>a�%0fG virtu�r�.� �/ng��9R�Bd [8]–�",A�tic"l6 "B� blan�6ap�M-2� ���@fra�‘fu>ve""�~apy’ (A@yteg�� *��� . A�C%D�'� n�O\C�!fic= ���ap?�file�2�i�dRD�"A1 �IK!U�#')rţ�H%5^�( i . � ,]�ul�;� �9is ne�8ego k��th���x[Dat�fg8�+"T�%Eo d&H2�di�A�.".1 ursu�or��X,�phacF%cal�us�F�h'>�7c-�1�_pa@hipnH"). desp�!Ipau}��r�eff�"�� n�na�of� ou�/A��4Bn� &�*J+0J^Fs suchv �&;trioxola�[1Ŗ!Ae& kA�(0or K11777 [14��alkyl.(oalkanethio�u��c[[1�52�Vogs [16� ,�-���oxadi�N[1'!Noee> ac9d; J+ EN�4�Gdj take��l�<an��G . U) G� =e{,rc�sourc* vail�$N�A� ]& >�/�l#�1Mr�2!^1�3.X �[1� N!art�Id3���g .�b �su��6!�3'Af ��" �,G�}�Deso�r�[19Am[2EDet"�D�4s46iM&����a��Qs��+!q�enxN MR mode!�hF@[st��ap�,���~C�QA.�1�t�s2*in"�t Afr�*&S�6Z4�h �R��an��ec�V�� "� s�p� .$ !�� %� , [2u A&iE?�( comb�.���� ( ACT��G adoptE s�"-�e��M r unAQ}Ud�; smod6 f� pa�Sv ��5 -�I���F� ��o avoi�-e���ofA". �N�&S18t�+,I�)�E� nd}� �%FY�ɤ%C!_A P�= �&) ah�. �)e hemo� iJ!a&�3zs�8/(>�6wi-mot�%-���.5'3A��Kly emplou.�Ųa�0�V"F/v"�ir*�(k9�c�SA6.BS,"�upIa�s�!�� :~1*y,I`� 6���@���>on�� -&.OI ju�,l� d� .(%�2�,CV,�J3�& 5s��,ofI%*T o.� . Fiu we e K !)Z( +�nz− )PPnP�8"� ���=aJ�(. HalofantrE,.�HCd2x=�e*�O6c$@Hoffmann La Rocheh$seJSwitzerlR$) ; pyrona�"n�KIi�6 NGal*keEaee ic De(, Chinl7Ce�eX  CG wP�x!3%Shanghai ?< &py�Qth- eA ulfadox�m��oxypyx�D 6Dafra P�  ( Turn� , Belgium�F� bi�%e�A���, lume5��r~(d54ov�.���Bv2W$l Researchj�a��a~, 5� ��:�% Sigm� Buch��>�!aatovaqu�/�"�%� lo� Swiss 4y ( Wellvone®�5&�J76�Kun^9)�"} Corpo�(%ImY.6-�N:h.nE1B������9vC"-#�1nAJ�,7% ( v/v ) T�;8�3a9nol bef�4F X-M�S(d*l|. E"U*�Q�( LibX$�#y)))A.�"�0eM<TW.� BR�3>!o,izE�-B��nd� to /J����an��f�(?miaAnog 73�4. F� � NMRI� (n = 290� ei�Z ∼2N22 �I4u1/ RCC ( I�eh6s. M!l9�+� environ�ly-� �'con�Ti �7er �5°C;�_,∼70%; 12-h�>l�!,dark �?�! accl�.���eekQ3"� L)^)%*eeB�1o*-(ro�- diet 7eNO�( Anhui1MN%f68 ���r�. Mal>c�*���2125���ySal AnE��$��:A�� S��/I���)rcaria�.�!�9eEv6m)�eZ�ed�D h snail�hEKv$b b� . Each�Rdsubcut�Jlyi�∼80��\c��#enty-A�d[;(�A X� )�49%:� !'ACY��� D,�"�6 of 3�Q�%4�&���K�66� h6��l a�2&G4Z�. T.��� !�1",J��a ~ j��.; �2)3 or 1 �(9[ , 3 �LsHc't5s c1�Q 21 ,-S3a$4�?A�49�t->�Rr !E�shift=�s=���2����Qpo2q- q[) trib�C A�[�-on ���57�14 QE ��[bF�Xf���DP&a8� rF$A��|� L 2� Il �$Aq _6w ck" h2ced� lodg,E!��s �X s [2�0� �,y2 A�10�2 [�K�se}HW#_"�AtAe�%|2%+!|���k\.Y CO2 � d%i�2h.6d �%�sexab��C% �# else\��In� �J�Z.�EuB�� wK!b�d�Oa%�*e5 in S&�QT�s SA[SqS{)&i#0$erN.4�.�ֹ0%ȅY<@sti����V�A}=�Z�vxcgle>��p-�6 !vU��35IE(�<)a%)IZ�*�=�:J�&��qe��Z.�E�EE�"d#a|��!;R��UI��X�,!7,a\�\a35F InI]�J ���ut��T:rB�9m��Ad�^re-:aR>�)portom}1�+ c ve4� �&u� 0 technique [2�.-Q�2�3>�gr���2�R�Q~�Yi)��聦�? ;NA�}�fs�Hń�we�0ver%h%+) StatsdUZ2Bsoftw�opackag� Cheshir<Un�b King$TC,8he Kruskal-Walle KW )�`�#Ua�2!' ne=�7�Cb*�J%j��!�� 1�,�s�. Au��& _"�A�Nk�WigkLa&a�cemV!#5% . ��$BO.)1�H:�'s`6�T��-d%�*+Te��"ly��5���Ysw�&��U�&� !a .dod���ϩ'BA2T2'2�,B2(�S����fF�"h . QuQ2��� ��'Wm!VQ�5t"%%R7aL9 =;A�%m.?�chc"s* B(��!�7}03 p*) j$`&)E�")w�0� Q;��(]H&X� �NlRq�#p<d105u��f�"�iu�f� s%(sa h,6�:������!�:.fC�!�� e�"!x&�B�U"p'&�),�J*k+E��G!��$�T�A�5#)!ZV �" ( 21-day-�))EBi� ( 49��q�i�I��(�@�ԅJ ��I�Cen�tA��� of 9A��nEg%achie�R2W���?-i~,�xa�=�AtX'�" of 5$�#���3A�8i 38 .a: .nA_?st%�.� y25 H]Af�e�)� 5�.�@$!,a� ɂnq�ejQ%�)�% ](Rzd.% � �Hp5zI` $blef.� a�� B�KW�9T'c p !u002%�&!~1�b6&����h,[. O�.76�aA".��.)�AM.���6<iS.���of�.�. . No��%� n�6�.aQ9�r3�.%�VVI�3�50y�[)]��&�9aN�]���ar�2��(>� Ig� Eim)�)�t !4lsQ`�s4%b�R0 !A�4F[2>��[� s 4E% "y �Z*n/�s short�  �( �:� )#u�CZU%�se*t �.Q2x�s�Ly]�Z!g�qUh!�a���d!�Ũ� a�"�~a|)�.Z.&�2�k2?.h%e\E-��a eJa 7�E142183542or.2.�.�r��� ���8I� ��A`M&1:���2nforU"><�sa#�$��(g.�X4�X5�X�v gard�'�  png.!6�,.�*M�B��67e>%̅�)���U@8^4 ."��!>A]fD.�=�[A�B�����V� :���14"� 235I��&�MF ��:Acb?D -?uI�!�v!�!՚��%>�!m�|�a��6� . Sl�ly��eHL��(L>.�4�46B���V��AY!��݋� doubl� u��A6o"(GiY�to* �����g8!g�95�!CL�i (2�Q$&�r��&� 4p&� "S M2� &���6�C�3�LB3+<~� �fѠ"Ior9� 6�NG.]r*� �1,e-�3�"7!�A%�erE-A<]t�$��):��l���Qm�a�7a17B1��� of 8�|5�)% "�!/ �atK99 �YOM� �)����l1s r:�M���:� �*sxi�E�/�"SF2� �Q� �6�(&11!a8F2NX�%6�RX"n?2� 9;=a���t6+<��� na,6�bec�y��/" L��� O i�-B�!�)-z�'6cin�#q�2{�B"�@�G>�B��K �V06�� 3*_� g\. LKS�C( 2���T2TE��?�:�2��M3� B- ( I3&�NI�ac)�2m >jR1.�aÚ:�2qpA,un2~A�Ao:v rB`�H�im2�/B21(L/E0A)In� 8�� S3�"� A�2R�7T&�"�*�[�B'F�#n14�0�X=����!&�-d" �4)�h�=m�1{D�FeA&5%�� �nehpag|orm.)BS � �Ae�$Hin)pYs� �"V s$�!��f }!F majo�Uof , pair�s~O�0. O�$!B�.8Hh �~4e�b�6S�W�1���4g B�*�6t 3<marke!�$�$/hylax�@1V��%Y>mA.^�BB] 64V����2A!Ewo�!<V@L)#�Ty�Ge"l@O?�"�E�za��g�let���]��>@9xa����0�G�8���/wbj *� �!�>d�A(�R=s�L(in egg fecu�,�>6f�Y)(*�$� U,7 ��u#o� � "a o�B~ V6��A �Շ��)v(2&" p4572BZ 3 ���&�%��(�..�Z))r2nb"�5dmQeF � �2 ?���?*Qw:��D�E����F!MbrT5|�W�^hT)�C larv�/)O&�Brugi�7te�GB�� layi!`�i[2�;f � :n5"&�9in�bof-of-y>p?#�oinI/� Z!i�U� cur�u���l� �5�-"PivV:;q playa͌���c health*9 D9z�F� �"�9s;U[2b[2�;��� Ufac�!� D%��i9�9�F�E:�9(sub-Saharan"�9��&�)�:\��:� ���� �.,2� 20�uׁ�$�\a�16–31�Y(!�oFlWC4tor: http://ww^Vfd�S$gov/cder/c�2r/*1GC . ht`6A�/'�.h�DUndoAT!�}xis&�� u�#� F#I�strF|}�V<�(_ ortrX=�c:_s*�@BI@�-��@�i�efar�<�P�,$!t�CritoneDAMA��x��2�V�i�TEyVG MoreE��k&sp*T^:�ݑ�a�5&�9��!�9` ?�r$3� hmJ0".van$:: �.B;Klatter)Xdi�l ay���\�D�e ( sk��e�U�vaF� [�[3�?c�F)D:=E>�9P�"� ( 2-A�3-r4_#=1�'bUG�"HXa ݆��or�la�$g9�&3 ‘Bs�F)*�B%�=*r>u��A����fes B r&�E�CKK32hA3"S/� ariso6!�%knI6*nd.D%juxtapom�FiI%*I�~e�;n����exceed�"nchp s0a�1t �~�G e World HɒOrgan�^�9 HO )/1>a��s)ao�o}E(.�SV�of >8!Id*> -.��>A�f ?a�ecu7'���iBA�Fu2o4)3~WeqBr����)$� wb5*��a2�"of*J ��n~1o:� �X �oryE"�}V�P#m2}.5%@t ��l�d&-<2�)'="9=w1*5=�)&>A�6= � %�� � ^�.Z�.�<Y 5rn*dszX��le& w͆ docu� 2>Qp&�S�F!=xB)�as&�~:SMo[3n O e�Ah!(," )2�*�FHr#X_���~A5y�,d 2�dT�i8(GR}sMZyVQ��%re(�� ��BQUof ::;,��a6 belon+7�c�s1 �2a�R�,m�� �v6sow ebio-Hi��� .#�K[3dF�Rx �8� >�2�:� u�!� ongo��� 29.B$H oxam�0�?���P_ �w�kRAU�J"Fɯ�:F�MB�lA�r2t�}12"uO�Q.cFM��[�}H�G�=� &ye�[3�E6VV��+A�]}2�e�2\2�:e s���>�[397K� �?s mad�*es�g�2y��&BQK""�T��a'�J�#�s&�Cp6P�ry��-2�F:�Mata��n )�Mkc� �DexeeGAqpid �lY9�l. M��9_-e]�gM�U-E�!��mo�v[�steoj�f �BdeyJ5Y) �A�.YE2�6�9+�SWJtn��Zt��on.THdOt�n� o�}�S�� �\*ZHTsD �x� p*�[4�KIt �wFSw��j��2)NN)L\%�!C�zoin a e!uox&�Sagg��`.�� Tkge�s��d[Ζ�Kshc��o N�Z[.���UIs� ��.�i �d�aAnoQ�) W!*Zm���}�'y2{1.ey1:���ma|H� .Y�i�De�non%��i�+� 2] a0"� &� � .W�� .y[. D�'c� n�[:�H� �ndN ���\-�P&�N��hycanthN?�* '�e�� x-�2A?6���m�VA�)�q�$ � >GO���*;"��*�"�� �]qaK� ��wo�� �DfZ�>f��Җ�A8Y���Nng f-�V&�/A�2� 7 ��j ybinte�\[4J!VhaC���'i� cha�r�, nam�/17 �[4�: m�be2�[clarifyuϡ�v]w�T�e. �Io"recir!B!Tّ)�?w�s [:�]*]�inŌقF! immu/rvLS !r,�Z��mcZ,^ &�oz2\, �nmay!a�,7ngX�MheH2i]�a b�Nly�6�L�h_+~�rec�k�G=isM�prex !? . Pr��flst~ef�;��@� �=�| [��nd�!6� [G*)�k��&5~$U�D d childre+7H"�U�eE�Ov6�!����KT��Yt�B ga�k�q�'"�� n2ʚ�eO"?'d;;�ML�a[ wumnLun�!�] vomi��, diarrh head��zz�L� rashf ruri4}rab��lg!n�,neuropsychiah� symptoml� seiz�m!�hPw��sr rw (�ArA��oper�I��-\�) [͢. A6��A�b�7-�c( �i�s.��Bg{Y(0 �(�>d^|Z��m$ހ!0a���W]�can�Yb71� �6� "gd��UXcoaZ�Y2{0Q�]͸e*1O.6��y. 5+;�o���m��m1.� >'P{�u��m��mz�AebA�biops�ԝ�Qe�F0 S\i�!�racPShydron@n�d�N㇥�� B�A�e�.H� &� kŜf+`n�v�s��M�b6i2j yoeli������FV�6S�a߅-f�9��ree -�����A��!.M����>toqA[[Ğ �Qyo� we-�&�&���>�2 Y }P. New"� E(b"�c%�Vj�uU[�V:Io�~third ".} �A�.z2�l.Wi�a*�W�bi���ly"��"�as"}dnor�yenAA�Opisth v�rinA�Ad&MŮ�� =�;�S!�m�&{}:.-=c.�U��apy=ii.�?.*RTa!�Fk�Jl�O9�i�eW"�XE|A� �&�"��Ei��u�tce:f` kI!�2�Yߠ , [5�A+d!caI��+ io#q��O����!��gc^�B�sW���}>�*�`rA�YPЀA gy7� � &XN0iVnp�T�G&��dW B �}�\��6 ���?]A]-!d�[]9���H��1AC>�5�MHq� Y�ancill>benefie�!�Bz�1��e"gdb�0.cPodoconi_��%H fi; al elephuaa��;+es(~ sJ �)mn1r leg� *�_AM f�]� WHOaB201W@u^!�E� egeograph�x >�(!+�f��p% . AsA6%Ra�dmap�j�/.!�E�ua�K�Camero�XoBvz �~.��m�E� helpa�� s[Yhev�2���A|� e]L�eatl�f6?�i�3‐  s� !�de:.�zDQ݃� !;b�.ry!�2S dh2�s^ed 76 vA��DF40� K#)���iFhReg�of9�mU��h�% 5-yeof@ore� heu�surve�[hkl-tovSs�Dscree�0! lympe�m'"A&j`alg�)hmS %Otoir� iagn<2 �Eq| -ass��2mIn� �i��oed�V#te%u�c�ng Wuc��,ria bancroft~%t]iE1spe IgG4 u�?%lAl��F�� Vv S��FT�9uF!TS�v D ���4( SD ) BIOLINE �i �ZzK( Wb12Պ2�@a![thick}oڡl4P�# |�|�to W .�e�he�}on�}7�)a qPCR t"�J. :�!",� 1782pE�tA6��AG�m�vici�R�S%(���I�%),�<.�9�=�N.Χ83r8,A I.� !�/�>nd�"EEd�-!�)�%�.�A(-�ag:[A5 l�  ��*n6*Q� �cl��E� �l�[ P� �A�6|)�%�5!� 2�cas2]уl�_Mnq ella��~sEK�(c*,rbom Lo*a6./52�%�2%.=��0�i�#o5�d�SeC$A��a�>��.<�35TZ95% [N)d���)] CI;' 4–/�1Atf!6!Bjkin�r^��*ա�!p�"e%��x� in Adamaw�a��N:,'�*� no� ��;^15., meaJ*N % !2��2�+��Ya,M�� ing RZvLA L;7r&�;2-=��Oal�.a| �U>.. D����* 6ol� �� vi��õ step�f�s$��ons"kb\tB�s &9/_ sjEI%���!`m"eo mana�T�Tij. V� H9!�i� ��Iarefoot�*J %�far8twho� (long-DY%acti� irriu a�c soi�Nvolca�q orig��R'Ck,e�%ce��a�=~!��"� ��32] �� �a(g , L.r Ame'g%Csouth�iAsia o�~:s"O� 44 %�/�eI" ,!�~_�ouS]��A�sprM&�qEkp�� , Ug�~ , BurK0�Rw/s��� ^ !��E@3�#� )y:!k�t�3�*� Ak2S lO��9X�yeBe��q� ( LF2%�t�ng� 6FnY�i�zff`k�$/�V�moA�ng -)St�0%�*[�.�4� s-re"���Lo>vRw�`CT��rd � �*0]a��� [11]Ke�L . loa�}�.���M nA �Az�"HJA�NP do1) *� �nyU�W�Fin�jsxf�="A�� \���j@ rQ�12�qascer%�'.C c!�u��6� ̩ro6�to M .&P !1$2L . AG�p\�eqA/!�nt�j��RT&tuA:qI�,i�U.���eP*xof^�U�3g ���Ǔ�f�B‐,��m �mS7eV��aq. �!by~� EI�0$�iɷ� �y�cost‐$ivenes�x���k�6lso/B���e�Ie�uD&� S�,��! 9*�EyN"�T;eDci( NTDnF_i'an.in M?a.d�+!9 y](7�n�_ *D ( ICM ) s -~—2�,��!4yaw� �duӆsj� �s/ !��Min�m�7P!5�.( MPH�0sd(2!e��h/!S��"��'�u]��IZ ��2�xlyNe �T�&E�GR� ��j!@!�����[ �is&�}!�rI7a�Spen����� eje�  S2�in&�[1�A�r�' |!����oE�� o&� 6�6qu!�(�)"Vc�`6��4��eQA zeN�hej!��Bgoveri � _"�`��'9,�f�,J�#l1s��"D� ��"� r{'.zk�'27��5��ne"82� �ly �[ReM�.�� �W4475 , 650 km2 �l ��g|"! %1ţm�ig, C0,:2n�, Equ�#M G.� GaboX!B.�Cd.�5ee�3 cAa���oE�4dens@�):aq��d�* �nF"� {]�w�G�Y200/IB��!�jVa�ra �YvAv2G3b? Ɉ5!|��~�� � ���%*�={,va ? 2i) : Ex*ee  ,�  , W� , S� Litto!�9�, E"9��,Q ll4 1!.P|�VA�ă.� �d?4f 20i� A�![ i�c�[n = 189ڦTV;&U� suit�6fq�sM�� ��!nA?�&��!ua2)��>���:� cipB��0titud-�Nsil� |�,.���, enhgd vegee�oa6dex&�����/�bodAhT���ms���ls1+&/�1*Q�?  U� %E!oEf i� x2����.a6SQ�`�L+�i��:W=}Oi:eO2IA�6 �I_BD�I� To v��� �bg���^��.:e7- a�!�:gm�NQT�o���C�e�agL 2- � �)‐i#� &�W�B?  �G��N���� ���%b2�!R � <��+z X": d � ��ycG ssum!aA �e�fF!:rR�%y y�I-j5�W�! ����$s9�!�Q1�?�ct�&�of�%��� 9%�M�e�10%s "��" �eum�&�G�g936q�80 clu�( EdE���/o�?io�$4�!� *!��B2�mumi�c4�g �l 3l2n[22��.ig�Um��a�b R�E� s  M -:�!k used6a��E &,R�(�,�6,�e��= %&���Ru�ra�ly M�lT�R���c> iIi1H(7eA�� �֬"�%��w1ithk:� �� /��a-�" �*7!~�u�+�#0 I��S� �%��K���>�����(� -!A be67,�? qualA�2qi�&�2%>N��%����: WiI�"�,A� !P�G�l�! �eo w�4��vs�/2$� �y terv�d$"���&� ��(BLU smartph���upl9ӅkNcloud�LINKSʁ�er H"�i�� ndݧ� LNTDSn��eH�&�!R��g!�sex�.$6��w�8�z� onnetr� dEe%� ex�7�mQp�z� �/A/2b\ ma��%O>)1ŝ limb.7! �,eE�q�!6+42IB@T�w ��&�KrK phys & Iqxw&5�+�#� ��AQؽ� &CD;ach%� i�2�Iln�!�08 L�0%K�-�2�#2�"�'�x����5I#m�f�� I����lA}EB�est`�JSDƮ#[����#��#��AN�#��!t*�#��%Lh=�� �on.X(�%F�� @}  LF�+icQn�Plepros�#.<)28ĖR��!��j�s upw����)Pin� Fe"�IMle܆2@�`symme�2 , us � ��KskneG#�unlikKtxU��$gr�:Ž6z32�J1',F�R�e3�k5at�Jaskaa���,d�m��tfc2*�1��-�a�`@���lo��SQ?E]=~�ru) �b������aQ��k�% nd g�5�U.eni�!fk��d�/�5ey��birV��,&%*� "T�����u[��ay��n !3&S<on nP �,�ppla�'��,�e��r!s�e8hygie��c�^%�l� . Du�6ill!X�(aGg[re�Br�7 f._���3 ible.�nM �Z,>G.�F R��F� r AA/A})Em�toe�"O&B�"+ ncho�v�-!i�ine�� �5 ��]�ca'��t�kNH*���7d(c�ڡ� .�)sm�+ . Se��y2 +e:pe}�I�l�|y�/ciP��!5$ manu�urer’��Io4[1"i��s �eriphA��()�Q`on Whatѿ��pa� ���EdIPa�t�*AHsub�T�ar��kLF��*E6*� , .�!��*l��(ogi%M# r( 10"' w<1bi����>al.�!0 E�z\���!t�8\(� ����]���%alo%!9LF-�i��}k��e* w&� *�I�!{s�9[22�f !T��d�Ds8as{, B)� Milroy sy&ԯeaz0��ver"ю�O ���Z�!hE�{%�)�2�v�"�!.���,M �omm��e(&� -�.& .� �/ 5�+tea�.�?a��w�)�5.+!amo��~on�a�wo � s��EOac���atatC�>u.�-#kdai&�a�+eedback!j� ->�. I![bin�LAP7�|�cu��m �#%leh��%��>U ly-agre%�"�. D�1ver� ���ea�)��A�da$� STATA��tuxS3x( C��ge�/%�, Tex٭m�T=!�1.P�map�"tP���2~*m�p=F"T@ArcGIS Desktop v1���E.� s&;�&R�Inc��Redl�#CA7(+�D,~p�9�  +��&m,"�Chi-squD�es. 864�'dichotom2�����Un�k$wQ�u���� -�l6�ua�U%7�J(bK�2�EL:�,a Type I errkAt �- α =�* v���ϡa� rece�����K��W�7A�"� "���cs Comm�eA_ NEC ZRBr�#�.�ax�alŏ��R�G�ap .JYRGY. A�J� �0%��Ngr���!�fk".��pu*^"A;�5&�L� 2�2irllguageE�y_o�� crui�E��;� w r!I`<���"6d%���}I�"�&Q >E��E21�Ds�4��A"J^.�'i�Wz��ndO i�E�6��B %�ad$al guardia�2{%�� - �� shee� ���� m� in F�hmEng��%�� gn���6f� 9�� Y�& ��ըain�'I]�h ID c��!bys&k��:�#�T�E�%*p8���J�"���70#��in� `�b�*�%�V�'�A�.l��[Qov�?��܁W tBw� ��. EightyB�e 8% ).%Y -�&Pi"NFjUM#&�,.�� 6slel+Me&[#by.fE�, ��9�k 69%.3ݜ2{�'t� �c �F, l)Lf<M 5�&�1M����Ba�� (.r�^Logbab N:���#-�8�T�-B=583.7 �, �cked:�, . Us� ".&}6[��,C"� 31 Y�W!�IE�Y ons:Cce�"�(� ��J� �"6�( a;a "��&K�gK��� �� �!�;}k3� t�?Тa\�M3m.A8)hn� ;%�f�,�0)en}!�) V� p4& ]�a�x��j�Xr�p"U�V!! �e8�e8~e852/8�+;�V�E8N I�,�(�0^#(�&�7e�� �2͕a���Dr�=�\��j z2� ^�1Y��E!�.Tn)� U��.q�.�>"� , 44��v�8��al:� " р�3%E��pB�8st�.��*nLA1 Lu9�8BF�/, �o[[>M�&�L�0F.� �:�' m���>�2 ��0��� -�5� ( 8 )rF; F�4��S1�T,Ŝ�'�Mb�$����l6հwc a, ^&5Z 2�.�n52F:B1��E��E)of�byL�>=W83AXY`A"8��-tAY�s.?>�(ed&9ɛ�{-i Z)$y�U���n�u�n�6a'F(�e�!� e�e�PB�}�����*�� � ���fC D"QD�V2�F�&� � 6$2 /76 ( 5� 6�i��>t. B9a p&��bey4-epidem"�I��X m?]>kwA�El�*�-6g-��!�h1�cA�bW��i~Am� �ao�G ��i]a�3:�>8��#f�&<"�-�-a"� �6� !�lS� �L"���E%��/ 32 (� SD�: . 3;�$ ge: e9 72 )y�n aver}, womenJe�n��3�6)*D`1�{ �]<(|. K9 #�T6,�ou�*� �. "2�Y>P , p-�Ke9 ���i� r8%��t%�%0�y��an&p!�^���H�.��A���wA�2�membe� "�$� �Q� @� �K&t$-�q�( 4!]9� ~~1'~X&� � G�no.@.xMvQ'&:-Q c��!ف�I"jn�BY-l%*��y=BX worna��1 nd 9�3:�m�_weysh'��av�4x%R�ra�t�% ho!8ūLopen s >ls��M2�Y oh.����M-;J����vas>1���a!w�0�`�o� \�&[nq ly 3a/5%��nonE4�,��}# ( en��d )X2.4A&�.Y� =-b<�at�20Q�9 � %�Fa1of%4�G!o.vTi"m�^���E~( s±�V,$�797 � !cI�� . 13w7 ) ��\��6< �iKf6���� 8|%�b �&ot"& (�h%he feeCth soa����+)ahbaXu� 9 @���QV"@(��!}2�� "�3"� Zi�3q3s"-E����"��0asitol7!�se&G�Wsf��Ko�-y* �|! lCK��{of2�I.� �?: 8� 5%&�& �B6q 2�/bB.�0Z!��i?&ne� �*��4����2a�ef#h�%�I�0 q�0" ���I r6f"�eY��if- �*�8�4ai)>(D!k "%�&t<*�2(�)�&j � sul��(form the de�sign of a nationwide podoconiosis control program and serve as a baseline against which future performance is measured . Previous studies have reported varying prevalence of pod�Lin Cameroon . Studie�ducted Xthe Northwest region re d8 . 1% c�among 834 individuals surveyed [9] and 2 between 1L$–10 . 4% },ree communit�,[32] . Our fa\ngs are lower than those!�� two 1 . It!Cnotew�y1t(�s targe�Dwell-known at-risk2�$whilst our �T was intended to captu!�Totential heterogeneity�Tenvironmental suitabilfor6Gacross.� High.}>�has b!\5�Tin Ethiopia ( 4 . 0% )E�Ugand5[5 , 334!v However ,%3=�obsA�E1UQE�mparable!!�5.�Rw |!�6|i!�(e 1970s [35�Q�have sh!� T senc%�!Z,tic suscepti-LI�A1Q�A�$clusteringB:�)�appro-emplo�%[�:necess!siA��e��sawal�e%Zui%�cly �(-�tQe availe�LF� ticsbI docu��! ATL . lo�fecE0!Gl%l(ICT test [1��i, used�#s!?1}� W �iv� . Tw�Q!�( A�4%az/83 ) wA� posie=AbFTS4heA�:(fur![ invA�ga�A+ both #negi�KPWb123 . W . bancrofti)�ot foun��thickm� filma� qPCR��f!�ō��c�, �harbo�1hMf���M�r���,M . perstans(I[[!2,is likely duq�- i1� s ra% �:6�[12 , 13��t� ignif�B e im��o �u�$more rigor�)�!RLFeCreas we�!�2���Pmic ���9� m implic� A�Firstͮ� sprea|�02� . warrantsŲ�on�morbid!`managea"��r &yA ��h:��- ters�ApriorM(. Second , ��oug�O6���E��, work o�Pdistribue�at c���j,�d�mi��Anu�� afa���nd popu��!t  will�[Q(t next stepe� prov aJ pletefil�m2�>D.� �W�Q0strengths: weI �v�(�ion���m�v �� �crihaE�!�ngent%lcon< �n!YA�m�to!J under��mE�2�ov2>4. W-a����*es � to!��ͱv��V6w(Nonetheless���  is[ �rout��limit�s;8 aa�ng�E� dQ�assump!w��6# driva@.�would�0 to . � � �ls�ear8(hold true ,>��A�a���.� ��T. ��def\hroq�predicŤmodelXly� le� 2�i��� stFva� r� n��oiA� i"e , ac+ !�to^kd�fi� @ ne| . � 25e����1����De�m ng a6c:XiNviI �v . AS system�6 burde�2yis ��� )�inc%�� ill��a�R!a�ice�Pre�*:7< asis�  footwA��P] hygie/�]e�!d�ntegrej��ٗŏAG ongo!NNTD�}�2�. Givea�YAIQq>]�mo"�"� is poi� A]�na��.if9�(apidly expaIa%-}z0foci . DetailE�� ���cL vtreat�!Acapac�q�QA�o%.2�sh�S�"6� ��� i?� eastof �Nb.�. F� �JaS��V�>�!\st���ofE�s�p��s���,�:� to det:scale up! �6W8._�Stem cells�iaA�%��to occup2 ir 2 nich�mw��urn�} s optimiz�> o hoaa� j. Org!�gA�a�ssoci� E�reducp � �anc{!�}bu�l mechanismc volv�� orly1��. Hu ,e��,Notch ��al �inc ed �age�4Drosophila fem!dgerml-�$s ( GSCs )��w i��ult��iU oval from �4. Clonal analy��|aa1��Zw� low l�>�exhibiA&�adhes�$�mt�(z;6_!�lt2�Lregy of E-c�rin�4res�. Experia�al enh��4>�in)ha�zs �age-dep�_ nt l~:c靥��M �par�ly medI�,by Sex letha�&Rdisru�ofb�doee delay� wdu�i �nor /it� BMP]�,mrpromo ,self-renewal�E. Fina�E�vI="��to -, �a�ɇa�U( s main\sM��Rg � thus15s[ re��H)!dq�E�ag�?�� ng �>�M4 Pi�����intrins;ly��ex.� "� expj a no< ro� >y1)ol� GSC- ~A�E�:�.��| also!�relevA�!pmetasU c�cer�� �K>��a�ell�. Age-�>de� !n��� poo��>U�Lmammali atellite.�,.���΍�Ei)�C . eleg�,[1]–[4]; h2���l�e��rem�un� (�)��Y_͒�19I���%3� ?,a�p�ArphyE7�$ac� h�! fact��, resp=v�[�In ad�:JAx-U�LEQ�* fun� [6] , [7] �sem�0tight+oup�)~FPC fi��e curr� need�)a�o�ism� 6�diD shed-i� leadZ�� [1];�jhA',��is5�wh�r>� flu)�attachm�2Ya��y�8. MoreBf%Z uncly aI&A� ord� w�9��%��pi�..�� small96Fa�X0rt life span;I�proper�,1�3!{�/ werful"me� makA�tB5�eminenA {�2� �� ellu�!�Aic�s6�.2�. ov�m{icharac(� e�j)�)�( Fig'A ) [8Y�$advantages� *` ma �A�in�,t'� !jmuTB�themselv\ !�surrou *� �4nJ�o of 16�20�iol%����abasicuCal <eggA)dum�9- an!Mor-� struc��!k�al�h� arium;tip1 ��ai' !�-�R:�teM� ilae�,� mR�z� esca !�s [10��11�E(make direct �xcaR major �compoA�E��&4 -"� t-��) GSC fusomlaniel�a �$ranous-lik��r-p,!juxta)����rface"�E�q[~ L-giAwri�(o a cystobl� 1�subsequi��g8 f�E���in!�]to��m a 16) _�u)�� A��conne0 ��!c��)/s��z2Ui��nu:ed�Ta layerAtf2 cle%��=u� d�op��!�E�a o> pathwayzz ��~exnd plays� � _e �>  diffe�d[14I��坏��aDrP !Rmen� ofQ�U�[1��172 �it �a���e,���2�0u)"re, or ( enco-� , N}���� ����!pr)P[1��F� e6�fng aV%- fera�#�Ladds N-acetylglucosa�� o��-q��modc!�he5�of1�o2�iqinsulin/ ) >(I%(&!}�{ evol�ari.���Pm�u@ vari_"� typi�o a�A3nutria�al input�O� K, [19l 2�5%`�s"a ���)��WI�F����%��qui to�� )�o(�g� ord*)ofc��!� B[23��2�#.| 9>�%��m)����pro� m[25 W��M/s !a�r�) 9�td'!�ro�> %E�*R�Mj ��>`in&��%��ng�a���G�`earli��b� eOt� Pes �6�)z��� &F#ir ���6�Wh m/a6q.'�@F�!.\�D�$Ad&� a&R �G��"� �2q%�youngU � >�ib� owA� llow!�N e� isa\ i;� � l �jY!�juleE[�s��:��e�M%F3in �-��>�)�y�)"de=w9a��y��mo-i�)ed��e�fU!B 6�%����B3rolP �res�cy�76� >vB[(� �b����A�Ad9� * &  ��uu�buaak2�[& )'i����.����  q!$beit weakl�'Q� ( S1%IS2x) �9>�"��yeL*� . To����"�'��� mito: �bqx to��A�mu� in N (�� Q !yab"�"GFP )&IB �)C�'WX(2#ad��hj.DA�>���"E "�DWcou�$�&�wild-� ��utants � �� �#%��mosaic�M"n�'�� Z� [�. CruciC � "v) ��'6C ?��ors un"#by�;y��deathAO3UH . Be[( :(YX!cde� d����5g ���Az �to�pk,� �as�,i|6�#vOv\��� ) -E2��B�)labelA.��Aa�(|x�� qual��-*$"-in mockB�:�a9�5e [6r�+0�!9 weekE  ( s aft5l�neb( ACIE�D1�=�q�homozygz ��N55T,u]llele��2� �-�%Aaed�&f�$ Y-���"!�Za2� ( S4]wWe!ask8� �� =s�2g�exa����&ofE�ara�arr�-.�o=.tim� S1 T�*k,A`�/)� , 89M-FRT19A�e8( n = 737 )� am#"|!�y� �� A8mW�f��|  �= �at�to 11�%�9 go ��ny�P�%�!A�+I � [2�M3!.,m�(��!�3�sE��55e11?>( 115±7!+1)392��.'th n���IT�&< at?  disp��9d%�<s�H sF�JJ% "e r.5.�; t�)?mayd&�#a�long-o:.� . y*� "�by�  (ZFmod  �m�*�l�� 2�Ac.�of.��1 s [28F ���a�%h }�:5dieA[6� >� i*�'5r.�Z� !rd�/a K** dinr339 )Q�EA@te�a�s sw&t�3:02� � T-� (only 39 . 8E�ofzm=>����&� '�R(�i��� ��,AQJa-"6wR�!�.�i�ge""�f��e2���n�(�d�(lya�6��7�h!�6�V�� AF�a�� tinc)U~� i%H�4PE�A 2��!&L 7'Surpri{� a 44% ne.X eajpro�%J!��"" ReE�1�5e no ob change6Gd6|Y�}c%+f�{!+=�&0 a-BusC���A�-�@"� �$�;refle�^t�#��no� Gr*#0�%6q&JmZ�Df�� m�g^2Ja mix��FP-"�1!%"Q1�( (a�4�# � K%&�77%!;30�0)�F��" �p, �.|f �!y1�|23y70%���3���W!HQ7�FRT80B^9 �52%*27��U��d &� (�e!2�R%marker:|��confirm� � re�s ua�!sF> 419�en�76E 9]e���!��-phenomen�4:/fng[L73]1�%�5[E$F��2p$.��~ɕEw� �>�N m���stw*�!k�& F' �GJYbe�0,To �/%� above hypI!�']!_�  bm~�7� �M��NAXE2!�s#.b2Ba ,hypermorphica. 9Qs^Q�d� ^ As�%�, � ��e�l� f (V<2�(ib75e[).Cw$� >�)>~2vS�9��K titu00*� Jgby] ex�'�M�R]( NIC��� lso 9-lM#{!�((��cus�r� W,!�. ly f�-@,t�_pop��@��n6��<or^� see *A, sugg�,����t f� "Oi*�H"� we='� ru�',pos"�-� ��Y#too r�.�M�6��V3O5��0&`#7ee�*.%t�(!�2`�:�,y7B�Mawh>a�PH(*)�Sa�,!Xa���m�)e��0C.=@�&���#establ�%��3of~��[3�!phosphor ( p ) Mad ) ��Dad-lacZ��re:�:�-de�6�e�,�4. N�6,A!�B�$E9k&�*F�.�may a�!E$5�*ve"s.*�"%�Eq�! -o.lecA�2fJX*�"wT4�: �t��}L !�ifica&���\ju_($m�U�:�VR �*Iat�� ( 98±5 v�82 arbitr-&�$�P<&@05MIwek,/91±7 >71±6v>� s 3A–B�֥ "e%9A��q$�5"�#-9+�0� .�s!tg�2�\`bCV6>T( 17±�%- 13±!4 µm2 ,1&1�q��iN�In��,.z�Ha|2���w �2� 3&� N<AZN�. G"� &�"� �%.n&L!ts�@� 9)�)�-"�&=�!�� until]T!� ( S5M')��A �&A�/odea  e.;e( �ds�*�bc1��',2�. ConU,�&�&��&� �b�aG��gain-of-"��nt AXE-��%!�E�<4.��3C+3; r�%� poinB& X h]EKj / BHsa�Lir2A!�J(i���� -M�1n�2 �  �~e7��!.����o"3��[&�*!t��m�6�2�>�"�)62>d��YVMB\ ;Mn��)� ei~"bne�6�Q44��T*�JK��ng RNAi�%�( shg(5we util�m"@of FLP9+6^ ��a(UAS-GAL4�on�'��, . Fo% � e"s4��D>�5_ �a tub_80�&� �%�a�#�o��*o��UAS� E!) 'd Z;lF?!�ne X ch�3"�*�;6t�NDrLr6JejAduc�,(nos�4���u?  ��-1�!|$UASp-mCD8-���33 mY[3,�'tubr&��4 r enV s ubiquit�QC!f!I80 %us����F!|#n! zV �u�0AH6J,i7"�cop�" >Rr�>l��Y� %#9Ro?>�F6�ue B–��C"� �F&"�42HeM%�Nr�!ܱ/d�r�y �� �6� )P,�!ol��G:(��1�ng5�"�ataT_� A� {< �>|F*:n8N�A3n��*Gmanner6� �o� �6��( &k :I��Pi>;asQ�a�;Jshg�?de�,6�8��[dM , rao)z>>� b�Gk%�a�$�ͦ���6�=�tes�is&� �\wa�edB�| �of�&~ aged9)�EA�pl ) m7bq;5 i;E2YF3aa�I"� 3-fold"� &:&"�-&�15� t i&'6�in$ -aJ-W' ;J�=A�68%�e�H)I3R� 40 )��'R(54&b c �La|a�k7Or)!�>/5.f[�j.de�Ee�$AA.ywe&� a 20.PIznF�=a�AE9g.�Zw&>e!%6"�$ rparM.� �� � madeMhPf%0>%8 , Su ( H ) GbeQ�S6�� ) [3�IWe�R,ed microarra�:�=A2�<��%.!/[Lr�G%i}axe�HV �bam� 4"!�&G���+)��Bam>�B��M1PW�4o� )sU1- , 5a�8y,�q7���1er[SN>�Mv Nbi"ANrepaJe�1�‘Mag5a\( nd McN'� d�!ls�)�a`t.�d;�! al E� spli� Y�)�se��ow�aT@�%~2�7B<�u>��� E′� � J �-UL&�O �>O�(p--JJ�!M s d6�5hAa"� !o�z!, DeltaSer�5� �llyFB�'��)bg�Y�%`��escap���bst K&�9�>+��#���K6�Z �!ss/-GdE�s�Q��BA� �{&�);24D�`1M2Se��f,#: -zu�!yn"�Ey!��(d��5C����S#U;��D� 7$ (C�u�� ll:z:i��i���S7��:162^!�1��>��wu��<&,be�OFd:� RQ�.�V�rE� !9�A�Ply 2��I7��/!�t/�2pi�K�V:�76�B( Sxl;.@6sxA@a�("� �-��4 , vi�Ist->�� !� N [3�KW�uer /*9d 6'/��$ ?�1="l � 6��W�&-��Dd m:�"Je�%�AL&� sxlf,S/t�)om�*(3%(Ig O.:�U( �e')�,2 !�!�6@�g )AcB n*)"-\) �@68 S.>s�:mI�͑ngF�-�i 1hir� E�i�,%!s3� nothe�BS8]� "��-w��wo*�:�625��H��xl�w1� ��D-��98"�)�(knd�@Sxl.�1���W a 476 B-M&� 6J� ��n`+� 2M,E�+�.Z�!)�U D–�"I� á��&a�at�#5��"Q5F� . Of�J!2�∼ =��[ck)T��mP:��& ∼8�%s3qvի!$l,&�/� du�B� ( S8�f"Bqi:E%]%=��A A �6�.�SF. [3@FQL�*P)6�W�?.@�E�A i�Y���){!� &R� a�:1" : 45�F�Qc88�74 ; 34v410�[P �Ue G–�/Western�W�9 � �A�C�1!=old�lsK4 B :0( S9A5�.j e�%i�B� qE� * �T!�S9Bl�QqYJ�d&BoF�/w"��-f t�EtRart�.�Jx�J�/Mk�t�y%W���}J�olderIYE help!��J��� Q�V�b%�a5���  n"U#ly-W#�?rm%#�n����7�LN��em� adul��qthe��*:&�W�DQ��. O�U2� �1�y�*1at�F{nd2�#=*��`�A , Bj �/�>$� a�nuor�걞6 �� �bor�%�#4�%QI/soQ; �.;"_Yin�N2�=3&} bS!�G"�K"�2-C�nd H.i�ksuffici���up��!�r�!s2�ekm�:z`fmJ�2�S-Ul* gh� �*f(PB�s�:^Y,�93$ɞ� !'i�F_e2ErF%� ( 40%U� )� on*� subj_% to NA��.�9� -'�'�oKm�inI�-� d�5bett�%rof*�* X*�Db�U, Q � ��A��!�WE� hva� ]� _!d�ate%K�}1o25��%f R) �A �m�QaF2�HU�Is�W�i�!��&P'T7!�2S5I@�f9�)lF�2c drop[vlo�f�X#*�an����U�bB1ioftog&���T!s�b�F�s;!�s"mGa��&� "�%&1&. A{E�p �T[�q�(I,9d��@-�9stelN* s�N"�!in�R� �)� .!8�K�GSC� ��&�-^ I s��a s�^ �j�;!hm nal-�( �7U��g, i"�&ve�i�!�M�z� (F��ed�10.� �f A"�ze�F�?ma �d� surv�'s6�%4-�i ecloeaa��n--iss9�(�R�for@>�.�+!�e!%�S͇:gT�5�*/�0.Y Col22�jA�  ves ��>�� F#gAlj h�Os6�n[P/��a�a��2ly��A % es#�$anchorag�f�#.B�@p �_6�IaR �e��,B� � �[15B@*�Rby1>$mz*�R Q�"�P�"zA� 3atfQmy,0�neu>q�, ~�/skeletd*usuE5�(?, geni�R.aa�R ��> Ympair��RnS��s6sB[41 9[4�G�#��iH*�B�s v�)�4 � Q��X|=�l�3�CF�e i�ks�Nm�me�Ahym�k1s ( M�lpat& gLHutchinson-Gilford P!�45Syndr�N( HGPS�!a�m�i-I�disease; �� �l�@q:ab�&�"4Lamin  ���Kar"AmDNA dama�[4�:4wH6*cin ���E,irBs(toward oste�A,�)�e�e�>�/i�Jadipocy�eOi�^�/�laL�I�%�shI 8".�"6.h2 �Jt:�;%�1�6oS)�a��i`s?i� &0o �[45�#%&k]_gra�o�c�.�U["A��%���%)�q !+m�4.w 2 o"�L�osSIt���#��jGM��_�Ka�cy�g tissue.�� e��qui�e*�^8 M��ba�ab|->1A6�Ja� chie^F by f!�� * stoc@\nq��replac�'h>� ��1eut�\5:one� �K� !y �homeosta��[4zK[47&� ���iXg\'(.����%su� %�:� Dof2� 8� E�:N.*@_argt8a~e�W_1�c~,� JX$I��� &�H.�) &, �:Daccum�?eyve_2��? um  ��K!�of exce� �m oxygSpeci ( RO���U� F ��@toaxIWe��y�Ge!��"�d%WF�&� AO&V"� >7 1"n ��&��hͩM(W>N��A�a2�D2b#2dwUb�5h(�M,`�o!h& &� * Z!1trigu� h!t\?)��L��^E7&, 9 !-��]llo�JADAM17!�Rsg5A�]$�ICD [4�Takwe�F�Lmight �N�� WG)B�O�re b$“poor”!JA>� ��E �6-f�e�t�-���&pr�`y�"� !��"q��Wex-�:0 )"?$4P*�����!?�sex@T�ga]5�^ISxXc&sRNNyJF-�/laric!u[e%umL�-,�#�� mRNA s )����Ion�I� Zk� i���s& l2 RY�i��I ��:�fV[�J,Q���a~*�baY.�!�pa6o$`*!C>�eQA�m����Kci�5a),|%�GKS1A al%> rongJ<r � cy"�K,@ Ni:�ng �a��I�f�)�1Q o�Y@q4�"#�^.� s2�>�b.�&�!B��vQf�XCZ^!!S�e}��u ��M�No�9�.Z����c-q�malMv!� SL�O&\O�Ox,� *O‘�e!�m�GVX shap�Б�>2��.'? ’ax"�ahH��&�I}MO}��"�QFT[�t ir�WeF4�%ch� �%%�� N��#�)�7sxl|('2�#(by JAK/STAT��� embr&[50& &/ u�!a,NF- �`&9E��*[2��*6!�% by V3 et a@[�)H.�@n&�o"�A=�gof��* �aI� .�2\�b�J�-| [5^2}�Zt�@� .��� Oby(#eH5��g2�.&�!r\ �ٳOi� !�Yd �dthird ex�sr�3Rt!a|saW�.<�[LFon-%al�rwn��stop cod��5��c=&��of ����i�a�g�|�on-�feH an auto(*Lory feedback loop [5QC� , g.�"R4dird=�b�Hr><h�&lic m� nery� skipAm1U�3�\eA7�4�EJ2�A��,!G�4!�R d�U%����iA"i� "V>�? down11���cre-]���@��ARZZ� �� L}1 [5e���B�B�1��AeA�=iqI?�,�e!]�2e�nV}. N-o(��,J�y� ZVto pinpc:�"m i�5�F�AW*;0%>��RS�&����Z��*( ways;6JF� F1<�� j��y�r�at!� ,&�1m^c<�*��3[a�y �N)fN �r �<a�"cC:q>�=V)bNj>�K*�W �*>'\ - D%>@�r��.�U���i,G&vBwit�N��&GA�HT�(��BJ/&uT - � lacka�8)�` �,"�>�B�$�:j�)Jfof� ch"�Ղ Ł\F�z��.�/*�;�� � a��z�: l�sY �t��K�;�I!e�aWqK�>�Qx&=raE�-��nom7:"�7�3co'� :*�W�"UfGSeL.J!�"�Nt?�5�)�u��rr ndu"�^��sqESI�"Jy�Z4ba"�3E;�;6S+;�3 �d� ����6�#byb��eg3�fh6*w2� !E�� u|%SN�eH�,��� .`of[" =,�9I�NV� i��B� � ,:�6>�R�+t>�M.mi��b*�3~%F�c� dsug�zIbF�T ��"�8[55P-�lGN�d�\}u^Uoxo�NR&)"� "s|.*& !�N%�p.�"�ior. �*'s�$2��li*tU>WH!�&\Y� 6�3Je��P6� �e�A�*I,. *K@gk��v= t 22–25J �@tT�rdt; um ,� �:�wAj�7*m1|-2� s�+!2QNPD2�Cs��`de� be�q[:[IP, ]1�[56�e5��A�$w�'!tW_$VDRC 27228�tAw(  5179 W,�( 10sY��(( 10853R-3 ��ob� �Vienna.:B�ce�m�Fly StoA��" al I�*��GDQ1��]�5 T%� �hV) %L�Y5dT [6�K8��>dP$�)�M��iA���he>-yeT&mG !�t vec�j��A�!�jhsp70 j"�6��~�p��FD� �m��~:A�| &)$SV40 �%c�Rd�"3′UTR�%�!UA���)ze2�9 GexqA%:�syn]- itMin"�r+ ��!vn�j�ofi1pli6�A2DiM� e��hon�!V�MjF>4,.β-CD�J�re��-elNRg(-pG)�Rabrz,-pRed6 Blue�$NRE-pVenus M�rMm>� ��* [6�� � d>W!�!c��I� nano�!,) -Gal4-VP16M.�&iRu��[�D , [6{F�&>�)FrE � s�'6�.Y �&�t�F�oa� W*`�33"�S+'�cul�We18�xJ.� t/ switpto�&g�DBr. Vasa F.�R7]cM�[6"O���MXs� 9Hin�B) , ( http://fl .�= .�an�edu�(A frag�a�I@co3��  |gB�n��e*>$PIZ-NΔECN!~s�� ( kin�cxsB�oeDeck+ Unio/of�'orado B��e�*{ otIEvKpnI sit��sub�|�$UASpI�{mod�8Ű@pUASp , T . MurphCB3AL�N &�(yZer�as&�0��*TE�-h-"HZ e 5��X��V�!���=��- a pa-f ��/a'NFse)5Asc-5vYsNF �w ��� ��Q6��_by�Le�)6�Va �bil f���'c�He�ara� :�> 6�%* ��,>� lip�(:K ) /FLP�gnr �` RT��"#4V�h[6�$3Kc�Nn��al ��.�"�� geno� neo�J0FLP122/ubiGFP �-* J A=ubGAL802*X$; hsflp/+; l80B/arm-|Tu[,$fngsv%72Bneo/ OArL dWa>+:�E�"� �� 6N*��rsiJe 419 o7 ;�.+� cQ2[a�!�MARCM�(19A"K7! ReqsiaCgM\ ) [6�$[ 6� tubp��:�1�;�5 4vp16aę/+)Ʀ@>2A&� � :XV6q����two-day-8�>2�2 heat�ck � 1 �<at 37�, twicyday"0dwv. LLDy��i� {��Pfresh f��da�r� "�p�A8Pantiboduk{ : mouscti-Ht�I1B�:D�o@���Hybri�u Ban�h DSHB�� ∶5�I,.R�+(�+ ) C C28 . 2�@(J=RR/�*�2( ECAD�S( DHSp�2o�( M18�2^3 �ra� bp�Y( Smad�#18 8Epitomic� �20P2jβE(�,meg�G*5 *!�.k!�$( Torrey P�C,11 , 05�5�|%E NECD��)*�\� �'f�)ign�G�,exaFluor 488�H 568-�J$633-conjug�go��'-Q<3:9( M�Yar�bE��1 �EY�tlyEf�popTag �esc;D��Situ #to�dDe�]�KjHRoLN)�A�6A�Li�(��z��� assay �.1yw�X star � �h�?�!�w24 Pwo�S� 8s��C��X05 µg/ml DAPIAj igma�m�KL80%!ye;?�a��2B0 B L N-�,yl gal�( N�"@7] 8a Zeiss LSM 700Yfo�$~ scopE%�J ��6p���"�fo~("`oby�6%�� is j2a~&�( �a$S velo$y�lab�ov amC.`*�Y�!��d)��is�,i���+9 pF\D,&h,.q7-�3,aC( iP&�)%��fre�8n!�@�ly�&��!��T�d�'��P�a4�E ����&H/2�Z&�$.Bx�7� kͱ6L�L(�**a. DFu\�0� �maQ1�!m"�G� ) I�H6A6�&9q!!rB&�8 12&!�IN[I�A�(o� �;i�ve5�.� qu�� _�+����]s�}>l(&ly�"B[�8ej2+ eL�� gI�a�z.m�Afe�*�, Is3JEx���ea�s�ave72�!�nM(B�C)!�:��Z-N s� Qlcsc@T) plas����4iam�H �FT*���-!�2�, f!�&ix��m�(� 6 µ %stS-a�9� Z-axZ���v-1CD<t~��� 1J9=��&��Q&@�%�<nt���aE�����7-�d�o1�I2b$0Avizo softwar�Vi-lizI�St@ce GroulciQ(r�w �l�,�G�>���|volumm0�A6[ie W�ati�.t&�M� ent's t-� !ewenty���.� pas��Les�<'er��� �9@�sC<�?� H�i6H×105!� i�EE!A�C*P: V;�0/�3 Qly� $in RIPA bu�. (�HmM Tris-HCl pH 7 . ��150NaC�.1 EGT�1% NP-�U�8K 2X Com�f�I�Bor Cock@��DTA-f�R(" on ��5�. Lys��( 64  aliquo��!y boilq s� � ��� pH 6�q�S%mercaptoXno�2% SDS� �% b�'p�%l blu!�1.� ) �0 min1|, sepa���8-SDS-PAGE�lot!2 �a PVDFʇ_%� bloc1wu 1X �)��q[Q->��C �TriN;X-100� BST ,�)�)�,5% bov�� erum albuj9 ( BSe^=�� oom2A>���Mjincubv ��‚� !L)α�?" T902� 1: 5� *� at 4�overni�2ushr���5����, 1X P)�Jz�LIgG-HRP��on.A E$Millipore;�zE.%�was�#ee�t�%��IE��no�k���ECL&;` Perk��lme% v.5a m"� wmOt� �6WG mo�S/)U�undA�bam1v6 /bam��& �� �race' �I/ ( GIBCOi a8FBa��E2�:qA�$45% TrypsiAHInvit�<nM�ģ5 m� collage��(6+!�20u�at�v\�Yl�sAEn� mfilC��&14��m nyl�>@.C 8�^Fby�rif���at �×g�7��H- �d� 1 m`?Vk�1a!_1-� opid�!iod:�I0E�immly sorA��:luo� -G#edŏ&��( FACj8{A�B_n ^\>!Calibur�� CELLQUEST&[. LivQ�*C &���W�ng6o �red&� j �|�!���S � (b9�Nkep/Trizolo9p�:Zat −80��*0�%�.� �7�*" *% )�a2Z!�to�aP����uw I��0Quick-Amp Lab�g k�Agi��Techn�Z�U�!�l0ed):$Cy3 ( CyDy��r<�in e�] "I .K-\c�(^6y�!as"�w&o�/f N!ab4R50–�  otid�7��ŰaW%�:� �i!�6%��3�. Fied5��e+poo!!&h[?to5X#�YT ps ��S*d cM>S"�#Ke�R�8 eadJte9:l+-�sr@% lLy Cycle�0� bes M�tm-UJUal ( libdo&� ;)Kgen� )�Y��-��EaQ_rtl��| low:.�1:\be#87� \′-CGAAAGGAATAGCGTGCAG-K%P"AACTTCT A $2�b4\14\DTCTGGAGTCCTGCGAGAA8\G[GA#GTCTC %2]6 ] #5� �TCC�6 �TGC:`AACCAT{GG�R]7 ]#6b \! A_��CT:[TT\(GGGACGCCACA |2�8Z7�hZA!DCA�9:YG!�!���T |2[g�_15�`1 TGTG�AGA%�:a TATC6�G �2ad�_a6�CATTGT�TATTT!^!�TF|T&�CT!�AdGCT1&RpL19 _ #12�A�G!|\%VC! :� CG�C!!A[A� $;W32W@WCG5GATA&�CTG)Wa9#XC!�!��C-:.e�P" UL97aBe�,of human cytloviru�� HCMV�HHV-5�$*herpes &ZA�6n$U-2�u`)i u�r͡xom,�Rb�Zum�S�Rore`la�A/C�Kvr4so? DZe^��E*Ski��CdkP5D1as���%-�E;�V:?P?at)Bau*&Cdk��, �!moP&2-i=?es�"I9 ���"#*!�Vo�hom� i8%��se - {2�).�,'F�w�$eD�4 �%/HPK!02lis� uishCm��B- �dK)�q i<>8� of��csh�Cby�-� ��0~.v!�2�?epe-tag=%3���-� �Saos-2E�tq; Rb2��, 4U-2 OS4�*� arI��.G:!�M�JVor S .3�eK�(ae cdc28-13W!A��"�=I��CdkU�tQ*�L!5*�D2��.�x )�rup1@e>��s2�)��o beta0��-.gfa��8+�ir alph6.M�X,F5D@;��!��t�s �*k�ona f!-u�in>x�2��Q1s"h3av8��*�щ l vi+Syu U�i�a p�cl vGbb!�� as v-��. ��ree�6�^i�, �=f�e�Y��aT�,m?�7�}.�/�.yelocy��leukemMc�{Q��( PML-NB�A=6�9�MJ�aggresom@��PK ea�B��{�I!{IR�P�XG �,5� segr�d<"!%zYe!�e�c6 (\�e�a�>!� �IUse5���E����y m&�>��Uk ?$ur datW�.�`th]1�Y!"}���)��8G� (O�Ŷ�!�! drugE_%M����� 4>dlap�e!A9.�u=N)R*�. K�Rcataly�0h�0fer��eA�d p�xto ��ub�%�se 2�}A�hts% fund��"T�[pCm����vi��� ^�! enzyoik,s�_cascaJ�Q�trad6;,a��~a/[t�8�7�� <4��e��#C�aac�of manyU�q[\ S��NsndU� ally/���]m9�"�2A-�s�7Oap�?E��jI��c|^Q�ANnow2>l���b��G F�hem%a�t�C'"j������R�qo�ll �C,�CE%�z5W�(� ��A�G , e�"dA�'w�double-AznW>�8ABaV�6%ce�|y�UotP߭�O�e!R R����FbLt�&! ɤ �.#66re�Nb#S:D ex V� �,1�SV-�&� (, 2 �,�{I� Vari�a Z�Rr Q ( VZ� -3F;� px s�rodZ<veQ$�)8�U9 x �bn� he�ir��nd "ց��-�$%�A&9ensor�DurA%yRTW<�J�&ti!�painfulwCn l�i��5r!H$�m>�itis [m� ja�<N�� C^ !3 )`�roseola1< @H&4 es 6A�6B!�HV-`) AB. 7 $�a6�� lassas_�oE�c"�Nt���es�"�� a�%~�#oirA�ÄJ)��"-�lh��!�Es�1B� 6�HM� e 0V!�6�VimXV Ajrom��iF+*�G)"may�7cer�- �% �znic ail�� �#� tW[7XH�!�e�:�!^Eps' -Bary-EBq-4 }K��i's Sarc�As"E�=� ( KSH=:E�seujt[52Ȩ� =Ǒ�-��05�.{a)end��}�v��!��Ea��) c��~�ܠ�IAs ob9nt!�t�w#4 �mr�w�� mani�!�-�E&acilitS�(�jrM &���`R. so c��\A�y�r.�Ks"�j "̔key��o�TJ���F o��� ( perhaps� ,� of:)9�;�.��, ��i'�X7pox�n[1�Z12]%�6�[��!�4eZ����[A�J�%�� ���/i�rot��a��  ~ReQ idae � _� ����co� "v �[SP5)��b1� al�[1��Atuh�� I�=QJb "" _ osses![5��xU"$ a�� �� �u4ct �� �*U�> UL13-� ymid�!-f)&�CQ�i���-.�(t���eՉ�E%j�.�3: w����2 ICP10 4��5 pp65 O�ɒm�s do " ap �beM� � na�i= yE�y�"� � "A $)Ae N3 M�Ax!c Wof h� 4]IB,�d�&4�A��>>*aw�eԥa420)�h� a [2i���,2@. B� � �%JNr�: �"�]8G�t��" ).�o���&�mte�-I��� )�%)�{�n�l6fu��u�@%p�og��s�Pgancicc%yw�+��� �x UHh,�����1 �� .A5�}!or��le�Jq$��al 5��8 t O-s� �c}iorigiն��h�13=[*Ц./baV.�,E���1x(_T�]<"%PN-�&un�PryJ� �reAOd��!u!Y3 d.@"�m���d��!U&�UƩ: ���w ~�� ->�� ORF4 � , BGLF4 +� ,����U69 !6?L I1ORF36 � �Q3 �Q�pbsX�el ?N! I�.��6��6� deleC(7�z! �ttenuq'U��כ"}D9C�?i_�� C#^�bW-� !�e�� !o�� rporu�vir��?��*6}�D�9�D . De"F��� post�\d��ea)I2; 60;�teg1ʡe$assembly [eE�r�5df� iZ aE�#1)�@4%) stim4)�>D3��4d{3!!0f� .ps�gu�U�sv par��K�* �!1�0�� qaRe�E#3!:�i �WofM�( �z5^n�"*6�DA� reti��q���#v�#�[�#� �Cidu���!�T��U* 8iF� (6 ){���;e!\I2�`%*b!# o:%�6h�troCdk21!�� %��Lto�c`3 he G1-to- ��u!�Sac� omyc�Te�si��WBw� t g*c���is yeZs8lB�F�K% 0W� ��7�x�E}-N��n&' �N��"? ).5/t��m*+v�1 "�!^�!G�[i�fJ�]bweE�D=a9s>:�e�N� �Y���>of�u�UJ E%vE$%bU�in%a�M�Mi�orTB�1�{9qw��!�E��OeQ�B����% :y.:� ��j-P�p-�bp%����u8�)�_����2:��In�%J "� u��un%�B�Rbcm�h��f��:*�1actA�eF0�enA��{llzm%�a�Salsa51�&&Lu-8���� �O"� a+ed��{ despB�%���o4W��!*��Gb� l*bb+Rse`u�[�Xw �i�����5!(�  Q�x�OIN !A�.� @^�!I�^�S "JKalwW�ns&  � &��" X b&΅e�ie!�� l s . � �re� u#{ �/ PH��i��s � lo���<nd�Fe>A�KQ �Ye�s�(>� ���5�d��i��RE"�isG�� !z ��"sTU�.�!��(l}���Mw$����f *�$� a�&AW orth$#Ѽw�i��r*^�� e�c|�"m�h$Ũ��Ysa��y"y �b��2I�, u�G�)s�Ikm'l)�a��iaEn Eaq')�a�"� nhemagg��n*1H�3e# [fh>��$AQe� �;�k��nC G EK#.�i\-3� n��T��H P��)�' i� �.a1u�eli�(5%y�2wA�6r�}�E~�3��%� 9� �`,�_z`8^� �T̀B���*o$A>A7{=��e�{. Veri.��mLdurtT1�aS"QwiW6J�*m���"�Er Z&��Q] tag�*e�AS�!)!��&I %�}� �!�4%` 5��}�� !�uM�~&(P@*ZEHPKe� [Qe�6�Am��N-w��j&%��!�l_= /i�se�"8V-��FsDbod�I�2�:R5��3h,2'�;Gh� a~A K!:2w�j�%(���on2�� �an���,�j��n�' p-����ar 7.� ��#-le��A�  :5:58�4�;6e�Q Adju�%�am?Da�/��VVl�>d�1#u%��q�*ý�i!6��O)'�Ϯy  cx&s �bfp!�>v)J 9��~/"^����.�}A�2b a2E� 5 ofte��o���{?���8��,2�.G�1�se �؅��v���᭬sub��u!�J Y�ed �in6�� ��:7H3�E�!Pj\�a�q�A�d07i{1B�y vQ?} ���!Vperag&w�,1aѾ"� F�m�#< ��Kcyt"�'23� 27y�w%2�ar��!�Ay�EG i' y in��u�!�"�c25%e&:&e�{k; 3F� ,qge�!V� 1�s�k�* nd�I]��"G�9W s � upredo�OBa �c2- 2�"w� � F aE7 �m�]: Qoa6{!>N��"�\bs>FgreTQ}" [pu���(>#6I 6_U!�Vn!�.�/4 2�"Z3!6�)��9%4ń",.�0B�`Xb�Y&`q�G1/2�checkEfSP*�����n&��men��Rr�m e=�� B��e�l�p�CRb�.ist� deacetylap$( HDA*�E2F��"�9f��ndɐ�a�*`�D2F-1veen2 ��5\ =G� entr<$e S-ph>m[A�-�-?Cm�Rs playJu}eo:�&�Z�>�. M�� ��ٻracon�eRm�Q�i�y!.� �ir!�,��*��t�!�?"#!��#[�T�Y Forŀpl�� -�* <*%�A�n"�!*5��Rb6�1�.y�onA�aS2�"iI�. ��!"<!1��"�!�ao=pl�J[6�x In vmB�f�$%n �>p�*/ &C ;�as�! r%b��lA�� S.2� s21-nu�=|sa�%A�s�Su$.�eZ�RbNa���+a@v (OEuor-) %1�k�}A�"^ %16� 6�`V�2�-!�$Bw -e;rop�N mob�%y shif� � �v�ige�,"� ��+��5&�P� � `!�ceE� Y.-1 >�e���l>k�=[�a12� �iڡj^�2�xa���-�9-�:Ai��H N��co��( W 2�O�2�.Bd� )"�*��)�I�: �%{�$.�f-O��� � 5=�"�1N�%z�\�x�� �e�9�[7m 7S/>3�� F2 0� .�a1�C-��ng��oʅA�[ M�d�J�e BQ�:� F� U� �-�-!��  j�2f�0jud�byI b�c!<�!�jO2t_0-5R�"c6�0mhNrY!E� -E��� . S!���I�2h1%n!4M^�1�C��q1�a�� ̉N��e�&1d>�m{��"��d1RRbRU5�1%brG?n�^r:4� 2 �� 4$1��N�r�^ �*"�~aBoe X s ei��5( !��� t �.�42!o�].'N���5��Fke�-,^��t��&��b��/b��J�To"�; explx - �3͚1� ship5�RyJ}�&,jA&-!5&g7%.ZA�� at�Q� equaª� m�'�*� ' I5lR�3 U5��Rb-.#�#iI� �F6J&�2 ,Bs  ��teQVmx>B ׊lI�J[U��as�{na��� app�OB�"E�Z���o6F��,� �]_2&��! phys6|�,�( false"8T�a8A�F�pD��� dZ{��� p U p=�w� e^�'9�7 ���oE)�A�x�F �J��0F&9QJ�e*� 1%�lL6� &M�ls���5 2�. � �V%Yz5M @!.�[4I47UgE]BZ�;L�8��5�gviŀ�arwran ��� � a [7UD�9+c�,i�:+@wiQ'�q�J�[ %by�1:f�"l� J��r�* e�S barrp��G*]+caR'-62 leav)�!X'�7�3N�ZB�7�=ib'��~rU�s,�����ZY,a! C3���jG"[7c,IOn� eT��� C � %�2H@A�A�1r�^�-�6�Wʘ2,eن�� ��J� .�‰��B���! 6� �-���to ".>f�#D*v2��$3�� Ef&�AL ��Kj��+s>� %۽���&]�m!�<%�*ju��to�N��ubrn�R-?�xXZ�"���d �ure SnKNonu�Y&�Ot[K��2Z�N A�m�s:=Q��Ma�@ �%Pe�a��br_Jer��re�/C�T�ɢ�*rBph�.�ypanel-^ mpty]jc6> �,� .!�, tom ��:Co1=�H(:�Wro�8o9.ce :�j���7,%�] lessv�x��?a<"��Ea ���z�of%�f���?S%-�arm�2ar%ND[[.=p�%{ spo>i��#1�1�27a`Gkaj���6����cZ@ I�ɝ6�G " -�Ane m�ތ�e%ae���F!6y*�t�y)�.e��]C �;66E�n�"~ %��!�3����"�(� �E]f�at a fre��quency distinguishable from empty vector transfected cells . We also examined the ability of ectopically-expressed CHPKs to direct58phosphorylation=KbC bFbwherea �beta- (ure 3D)!? gammN�YE'Ydid��T. Kinase-inactive muta!of� �n|�A�$stern blot%�!�A�pZ�are sh!�in!�! S2 ,�quantit2�data isB543F . The HHV-2%�$,ed low levelQcdisrupe$that was sgst �$ differentIZan6�control9�AQ. A simiA� oofj2uobserved�lthough%2c�$%F.(�A not reach.�$ significaE!us>f=*4may retain som�_to2�e)Bx A , ( perhaps more efficiently!��tail reg�k)%�t��%|!nuclea�5(a [76] , we�clude)�these E�itiesE5,fgeneral�bs5�|^� , but pre/in-� . A1�.XeJis type�often ci��as evide!�EgCHPK-med��d1J/C2b!,di��ly leads!5��a.�%'not9#y canE ule out��0mechanisms fo5l} upon�� ress�or .infec�( such�� B+ recep��>)!i addiBto3instead!C >N A�0e first human�Ce:clo� byE$tic comple��0Cdk�� yeastŊ�I7�I$Unlike hig��eukaryo��8, S . cerevisia�!Hcodes only a single^�ECDC28� . Yjharbo��La temperature-sensit�� alle!���is K�( cdc28-13 ) exhibit growth arrest in G1 phase %�a shift!da%ri��� [78!E.%�f a fun%�al=nin���sVc��t� �phenoe[79F\��o$5 ( HCMV )Ir)@ UL97 se��.� also }dR� cycla}��a�cNf dica� i�0it has authenAQA>�uy�bnd a� tify���I�kn��vi��=KorthologA�aV[46!#We us �sa�v ssay!�(determine iAemˁAs�% genu%Cdk) Asynchro� lyE+�RLY�plasmidsu�n!e munder)m��E�e GAL1!�moter �E{�o1^{O %Ya��e sole-�!u��A�nA~A<���I,of galactose J� $e2�!0��"�3 . Fa�hours la�,.� prog�@ thro��G1��verified��1�1inumber�budde&� Iɞ��ce!�c� -)5�a s-4z�i�eC %&G�B-�KqV s un2�E�,�AX 04 ) . However!�s�p�BouA�"� A�6�h��1End!�,a lesser ext��!ىK%�pa)t��Z�Rinto S �4of�B,a�e��%�aA�c� eQ�Z�� )3T�Cre� � i��v)�2��R .:�!} �.�!"� !06�-7� m�� %4J� �kre��Bwde2H��i�z�. F� they } have.� �>�!�8J���cORF36A�d4of KSHV , fail�o�Ka.G ly*I �p9�u{2 ��"� it� 0display subst� ale��in onE!�threeaB"� kd!�or v-� Whil� F�groupedQ(a family ba�� )�pos% � om6 y�limT mino acidk�, �B}at� ��re�TrɴN s�� YTevolu� ar=T shipM� se e%�1$ does%��AA�a� t�rECdk)f1���o"A ��!tsev��A been�widelyfo���5�cscreej a �e�)�}�R PML-NBA�ag omE'�) cytow c:l�� -unr!PA.� �eN�*]attribu0to� i��>s [4� $Promyelocy� $Leukemia N�Bodj(�)E� sub-�struc� �at app�0as multiple pQ � sp withsEu:A{invol!�u%�� ayAa�@= [81��D#i����C new�f0!(ͨsi��Engm�!�e�I!��[82}f5''(co-localize�~ shor�af7 � [83KPp-JCtoA0itutel trins�el)�n'ga+�se.��silenc�im�0 early ( IE )��Z��[84�[85�V� ��deliveraHo%�s��vir< entr��/o� TA�sk!��]%�A*�n�ndBX[8&[87 ��KU-2 OS �>�N�unofluo� I � �Ad��PML�"� 5A )!� moni�(ef� �k� �W-� ed�.R� . We�4:fou* a��n"O ��in6�mblI Gaussian!g�E!� betw�.4%D249�,I� an averag� 11�%z ( T9�. Our)agree�ll E��repora���[6e1�5IE1�_a�'v�2�� ���M+A coun\b"100%�-�vm�i!>i separA�.Y. W� Wex�!?of�1z�&3 ,6qNmll8��� [ul��perSbl%if� 3I�� n �s1)�towards�erM �%�. Mos� ��!��m�,&� !�5�8 ��ed�V.� q#.u K4A caa drop� QVF�pe�A�B^� than��E�%s:�High syn]is !��+�lst!�A@)�stimulij�����g�2�� !�&. E��5-�4)i6'(��Hun�>")��!� Aa��f��al�saIwa�as��ar�Z���bGCP170*A$n arti� ) a�).�>)~ , [5e�Convers� ,2Y%,gL �ੱ !&L��5 [89� impl�E&1T1Ir &� j� . >] /!�AwaŹ!Pfe��jiǥ�t��2' � G �� arF ��hataxin-��. A( Atx1 )E�-ly-glutaR tracat�hj any$beyond 40 +h aprsM���a non-na�conA%)�%zs)D)�,��toxicE>d�s spinotbelB�aZ 1 [9�W��-? 2�w��)a�a�2%� 5-�1� n�de&�! �Q�whi�)1'l�m bothu�(: Afc*� $!6D4 9leve�o�ue5�I�-��3Alowes!�veT Fi 5 m 4n��!!� m-4m^-6iad�))eRm)��V�W%65 �& �>�.6>� ntab ��ai=�a!e���� vari�xu�,mbers accumu�d o�v�.o� ��7achieve.�*4ce9A5 F�1irma�v& h$s demonstr-�!>i�-�A � or�L�B)��x�� ca&��$�is%�co#amo�I�.� summ��:� md F��Y��irR�&ViY ly h-��a�F�me)�,e��.� j�\��"� �"� { �=�I�� &1�,��pooj=5[f ��ue"�al?�o� �X)�e� whc, m� ��*Pe�'e6Yis"| . Ceme�3 �#l�IennorJ y2!��!1,inN� ve� pi��i#RbKM�&�[45 [72.� elonmfDr 1�ta [4; �c� xy-�al dom$4of RNA Polymers II [91ehllicc�!xona�MCM4 [9 �h�CsinU.�H n packag�[93hA�A�in! or p27 [5y."o !���)5j�had)~}to�.|~"���e� studow@A_��he re!EM ��#>_?B� onR����8l~;a�esMemploy �y�"%�&&#�be������bac!tng!�� g!���e Saos�s� ZX��ly-ac��-�6�Rb2;} in vivoH92 �g. ForS#�P.���t2+�te2` � , do���# rans� A��oncE+e��nd�gnt+ ic�� (j�'Dw trop�%M&��hP*�es%��d u+u�$ a�physiA�(relevan%W G E�n� arge�r!S�+e as oppo� �es 7$analyzed s� �����ca!6Nju�%o��,).cco� bA���V�d �#�FO��i��E�B,2YB�,��a�assdaorq|�%!�P� &4"����-I�w� 2��jRb�| 2�!i!A�ed F�( i+or 3 [6Y# is�M%O�V[9*9ńrem$��M���`F�i.%���5re� _ �is"%*�publish:,*�)is!�*%J d�(bec��Rv�b  [2�� ����) ��6�,� �E�9lɜrespons'�E .��:� t>A�)��a��**� �!2�)��!�V  5 [9E-�� HVo-�v�+in HeLaM��, h"P$wexcA��tiv�MH p�� w�/�-��g����IEunIif��!3 _ papilloma!0E7��oH�, a(6 2. [97]Isl m%�he6�ŭH0m&� expl� p*+.* !�iBTA *�q #-r�-!�\1o�1a4eS�!h[/�!E>L a�VV1}�g./Kv<��suu�s��s,� A�G:�i�}z-I� Us3ir� i�s� l�"x >z�kQ�� rus-:�[24 [2 �[9�-�]"o� ��!B�Ͷ�mim.2r� 6$�r� �Q�ev30requi�q�X"�/J�rep� �j�I�� criS1.�K6~�B2:5@ A b� �� tr!�< k3Aȩ^=�-3w���oOs�4F:�/�se�cBRbn�q ��Wa-QZ�b��u�J��h+V� .���@ly�+� ��A�(��any�d ag�.y !%� a�5 �� affoS�^� �cutiliz)�of2�&# w���. N(* thel!v!�a7ю��lw���2�yq K f��!%���EBV-BGLF^),�!- �5,6S697!$8 (�&-<(�.8� n7~�%v06!�4����e.�d�$v cks m!�Ͳreg�ory�@a(4� ct��9�l7cer^�g-z��U.2`  �+s)�� exam#, �l�&�p)C b�Lng%��& #-.?���. k�*�R)?"��� �!sit�Thr 160!?CdkfBA by m� ( CAKEKA;A˩J))con�21!*�� �)�"?9im�a�6or5f!�Cip/KipyINK cly j-/& � ~or� �immun�& �4by p21WAF1/CIPm{4 tro!�iV(-�%|�1ylalanj(2~��ros ��yr 15=���i�3s�,�$n2�� G2 �-r3 � DNA damagC attenuZ-%�N �7align(�!k��(V��asQe�,0 *�'�I-�Q�,f�,orEC>� motifaJ #�9a���� .�8�newly->WsE�2UY��&��2� ��a�h5g��i� ��(al"W� >�,�< =1�s"){A��,��b��� )( .�t>���� 6;��low!_'QDa&ofBH�*>�. Whexor�� 9T6%a�>���Ł" � �+b*x !|p desig�on��4"� �5ynd.��y� �4< �V&jal"!1)X�:�wa�pW,)>assoc..o"ki7QV��$subunit [9r6&�a�nomencl� adfeӁ�"�,l�6�mQ)�N)^�;�;to) ^2��]�{� �q��!u�!��r�C!N�[10� "^-N�^�  �L�-�>������,A* cribm�.� asq}iZLordf<w� �"�ŏL  system^�$+yz �+�ruZ99@.��.�� 2� !~�2��, �&�'%�&�= ���ly%����qan� � fashA�*��e�ke�L O)of#���F ��Q5surpri� ;/o�Sstr2 "�-�%Uio*�.isQ���"promp�jo askA�2{��&'m�= �� �6C.A�n��6}w2� nf%�' .p<=�9�. O%��u�+ .k>(!.E(��r�.�� @6��M4#��!Y�A9 ably�FE(,�\<C.!No�7s]rul.AR!�* �es% iderkfXD"6 ���3q2of"?.�"al�0roache�kLy�a �&A��=bq$b e�Hu�M!�9 �1$HA epitope>� =2a�I iͷs�I��\&�5&@e1���T+Pa 62�SPA~ �6u!u$&l��tag s�.���.e��M Y�� o#���"�? �X!!II)t��d�1�-�d���A � . Fu�r�&,�r|M�a@>(o/3*�2!T� . ����themsel�)�0;bO ����,!{)3a� �]2.�2� � �-P% se ���A9;�)X-���e!6nl% ��d sE |, e{%}si��uuZe.A � R���A��_a[M&���M eref�,� un&i � �1 AK:)� zJ !B�j) D Zm�-e"�&�e�;ag"S7pn�1I "� �'1��ig��. AFE��\hypN���/"�q!%AN-6O��%��Iit-�� ,�A�!7 mate�\U e� R �%P� r.f10D/ 5�2�/!D0po �enhE� jd% 2�1L����!gl�sou�;to� misfolC.��p facil�Je� ir degrad Yb�9a�)!�9�Dophagy���I*�,�u��� comm�.erR�pathway%V help�2R5#� par.s.|i?^Ũ,Rk�i!)=uu(p"+. D"jKN�"D�+ p�5�8N�' �"��3o�a�J.S&Y morp�E� ��!Efm@"��i%�c-�a,����� e~5-2��H plex5��/i� � t e�8�.sM9&�iA�-��.��I�Ehi� ��chapero�#S%E���uE4 9�( �uc��M enric< ( VICW9+��proa��dbv)��)�NO�5�F� way� ~2�2���to.�e1��er a�!*L,}�$��ae>Z en� N�~ trigg:QP0%gp�Pe�l�i�$to Õ�"bK apop�P( h�P�edK�2a�Ta�5!�A� �hi�;n;A!2_,An�N*�<��A�gY�[10�H6��&icy!�>Xcor�M� d �yieldERQ"�.n�H� integr�"�a���8l|Nflu+HI�9V�e**��a71 �V��!C52e. ,>�an +lQ��itz��!eJns6BI�`aa�-  wild�'f �^6u�a� fe 91 u?(�(y!&�tPM-t�N* n [3�=i�v\!:EA3"6� :K�E ��"�-�c)�� �>�}�E5e�ia�� (-]Je���(�>2;d 5;��l iME���.6\ -!�ofYYz��"H %��eiv�bK-� �RR"U/*�,O�emagnitjQe[is.��minimalRca��.!�ef�#sco�q�-�N s",�\K2�$(-�< !�@3�e��2��!�!`d3- .�"S arg�Nat �%�2J���acdevoid |�� ' �R6&:�K �K�y�0��. Br-,-�*st t f� � ��w*�� segr���MD ficm�8(��2�D! we suggesa5a#,Ѳ�gq��I�0a��� vidu�HHPK� �"� A_,�M.d4AS.see5���mif �k �/2-F~�.�>�A(�&2�����5�x: repertoir�= exmpaA�g ^�pi�!Q�*�M�BA2�&-%�y"�&' assuJP77��F� �L,�$��R�&�^>bB��/mprehens5@usJ.H�� `5�9 ��alI&�+ of&�" Npawa�pf�2 ��s . An�?erP�6A����A��>h4�U�y �|R�G:k(ui�y��� �!�7Mth�ct&�o!� +"R� *�[a�E`���"Z:�>E��&&Lsup_"M!j'Sz E:��a��Foverlapp�a��O� u rang�� � �B����6�T,�q��f 1�>�Xinvg ��dee d$ *TB�tod8 ]3Pe" A��3h1A��OZm�Hi��of.1 10�E�6� i<�8-�� �nej1�Q~| m#r*�"X6 carr6aG!+1%K2��"�)F&ombin_$adeno�U�� J!N& 1�(�M�; � E�null- T[10�*>�!E��Th^��]d" :A;Q���W(�8I�)�^QNU?MP2��J2A�mreX E�����1��"i��m;��.�- AI!�fA˹Zgen�X.b r��^3l��2sh%i�P���&`P�)2;+��"����trave � X%<�eN�#,��sf]�llj�4I�Ed!!�"&&���;�Jic�^ck%m3 lankb!n�: a:ݒW�9 [110x8 F�e�sC sc�"dqm��3imord.D precursor� �= �Q]+$pu!�v�{<����W s�;J�^� e;"�Ne�� C"V"O8"�6 �hi�.M��,�0 �5r$-� ! !�2�8A�%��a� fE2�1M claq[) UL13s&FmA��2�t� diagra�- sixt�Ish� h>H7 ��"8 )"� �'� A�c �.�#�t ҁ�a� �&( �5�p9�% �Y�%wh�XC�O!Cv�"l �WF0linea�(or��#i�`a � ��!.�!z�/qQphj �B+ �!�!ere�d �X< � },!*!deb�. q9)�(osteosarcom�3�/�RZ@ a 5% CO2 atmosph��at 37°C�4Dulbecco's modI�Eagle$edium ( Inj|R8p�/�$D10% ( vol/vol ) fe� bov�*serDGe ( �,U/ml penicilU,ug4Iptomycif� 0 . 292 m!&�F( Gibco�I( 2×10�% seeM on 10 cm�[Ef��Z&@�:e�M  calc!�(!�co-�rip�!�metho+VA�Oan� ny incub�Di�-�#waP7 twic�O-q�tRG re-f1e%H-*�-a���zer)&am�L��e%��cFid�+%%�ed>�%�8-7!�5 µg;��y80�L&&246-µg{Jor��o�trox�eq� �`y��< d� T�U�,d;���b6-IE� pGEM�0�Regc.c==�i6csw bH�"majY+:�S�(�` . HA.K�c} � " ���Z�@%5->�mA ��� �pMSS78� ��Jh e 8GA.\a[11�B�&���� s V51�!�� in W&�_de�+ed�35j$Z�g5�I) ) f)!�EcJ�.b��ndard-I )p"K(!��G��tYk}E�B- p!�e.Es�d��͈a!��/:�a�Q� �m�!in KOSA� gif�i0Curtis Brandt�#a�1cpCAGGSN04a%12 [5 2Dhara4Grose DalD cDNA9b1-�M �6[11�$.I(Thomas StamUBer MR? ppUL97-V5"��Mark Phard 4�_A�co�c pMF147-193]%�I7un&#?)�o�M,imKStW Dewhurs-1��ND!.36 [5�?.�$Paul Luciw!�sd8 pSG5-UL13 3′ * [48]� d6Groca�E,Lynda Morris�' �)�^i"� -> e C�B+a O!�<�!�(� ai��c�vtQ�Ž$a ClustalW*/4 in MEGA 4!i AA�#9}�hc0 M�b&�:�Naramet�Kw ]�Pairwis���4- gap o� ng� alty  ���pe �05;��KA�VKa� �{�4Blosum matrix .`!Wheuri^-��1�o)YAZH)- III F phyl� ic� Lt�!I;�nGEbor-jo�Cg� �6�. E� .n� (�@* Y Brad;8)IQ� lys� pr4W�+radioi7o6� w( RIP��bu�Ia{�i�H��-;AOby2[YL( WkMa�[Mg%��11+ w ; on g;8 co�-lip i� K+A�r� �&NZ�MIF fvJ I�7]�d �$a Nikon Ec$e TE2000-S� Zeiss Axi�tmQ M microsc9.ISf� Au�b�]e-e� %er�Uource�7A&TF: Roche 3F10; WB: Cov(&MMS-101P![H( Santa Cruz sc-966� Rb (%Y Sj5=$930i<�H(-Ser807/811R*�,*78f !�6P�7 &Thr82LBio � 44-582G�L�/�D( Novoca� NCL-Lam-bA)% �22F�202 � Flag! igma F180,�2mR960-2�Q Tubu'( DM 1A�m� , PGK6545925;.)�� �Znt!�y 1B12~�11�_RbB�tin69 ��2!6�m2�GM�*Tb��kF� H[arJze�4�<sy�>�co2�JŃ��c ��\ a��P�]�(pEGFPhLA-WT�C:I a�X�@ A fu Y�(�bd��0David Gilbert� Ca��? harv#)d 24hI,!i�E� ��[ � �?*�/by 2fe� copyG�3|U�G"vA&�\)[q�!.K!<�&�Ulrea&�;&� �1�-+/C�(wso"gw%� =.�_�x>�.����$�%K�Ƀzs BT��1% FBS%36�b--��R!��-�!T%�!�-2�'t=#1�hR���2�hW(�$�$))�(%*� �A>%F�Z�^Fo"B2*4%Ӧ�B�"� A~m�5K:��M CGN-� ���i��!�5�)�E&1��Fq1�� &�/}/�%��* "-�IE1B/!u�`ini�� �qa*%�.�~F�rIe?*p3PK-�-"~\!�FK722T[.s :/[,"&or2a)� >%+e\]Q82� �# Z�?taneoxo�)�?rg*��_ GFPi:>r Harry Orr���؞b��i�nub%i��(2m�E��Z"i&;i^�( a [f>\V � Burkh�/ria pseu� lleiaU Tier 1 SV A�$qzc�<$of melioid�|^a Gram-n�%�b50l�)�\ a�enviro�Binjy6Rs�cri�D���6 glob�`�@r�eB .6�2Uc% pinsA/ort2�,&*�D7(6�?rob�Q�al�p y�R��_:obj��ld-� ew� lite8w� �� �of:dB�, upd�9ris�B�0:�!�.�W!$o~Pensus gu9ki(/��soi��6:wor�#� y et�E9�al fRW EPar EEBWor� )�a���@g� VIth7 ld M]fCon54��201�� PubM: Janu{" 1912SDec8Z)Ja!�searc�/hT!P&r MeSH �4s:6Vo6i0. BibliographA��hand-`%\e�re�}cE����<ed ge GA�2�ofF � �0y?�map�n�ategori��Bf��O prob�P,��ol�y�.���M�ng~��ext5% �ol��We�� atq�� age;p�] w�a&� stud!_�"a�tr%8�{is;O� occu� �s�ngCtegP� bact��l"�5�$on- s))�ighly�>-@Ano� #�+.�d�_o!�Ru�Ax goal!r{8�)�j5�false�P�6NF's 6PAe>"n� se?t�,�s�&6Y seV�9AYM�e�CSq�rai�@ awaren�S�i�.�(hea�ca�# �in��J�.:" "�canm(ua L�d�f�I6a*& peop�(\t)���,�$>�R!Nɋ6� survJo� V�iane Ce#wNcae%9VLao PDR �n 1998>�,*$� �B�&�%Eb��Q[hakA6E�[MR~dr$an� 2'BbŒ clinH �6����x)!6!�.G�<)��oin�f-�5�ʉ�S�>9��D*t�8560��&�.|pat!}� �p�212� r�6b )��,M�d ec!|A�E=�6�B9in2*e�,s0��!Ain��er5 �Di����;,*, B%,^Q�� elseI��a%"�7i��M valuʹ:���'se�=e2�J�!�Wa�l! all aA+��uy� ign�� uct� hilst*A Ef�JQCAnoA�Z��5b=�.�^ul"�,Ih�� \5g��r�= lse "X !8in�"pr��!G ssur�s Q7r�At;i�D[&�#i=Hg���3/v�e �TiX�4~M�� ver�<� l#� l� svvA.R�:V:lZ���G���Ind�?i� IndK , N "� �%�of:� B=aȉ, ques��%teP0Dq�,�asF<per�ac� &cloa�b^O�@ (�&y-w� u&bW�aq��:/si��Bdjayy���dd�Xd unl��AIa7tq�Ide2eKf�AniqueN.�d?iqsimŨn�qt&B>�.4#t�4c� � �] H"5an =otocoWUue�"�4"�@djK ( SOSis�0�!"� �in�ig�t��%��usRɠ�:�lem�Nc"�Na�orm a�k��Q50s�H�eri���%e�5z�,l�� body. ��F�on9�b�Xmak�se frea�9<t+sc���;"� s 2�B�7uptT%�/i� �E���!EHic��D�-I�. p\�!"ˊ�$ 218 �vc�& , 62H�]VAz'.s�!�� it1�afI�(�*:�se�e�02A�full tex�\vieI�fal�.�U5� NHb&V�629� h�kL �S-�1o-*�8t���>�[ a�0A��f% �X-b = $![ &[1W42�[2� �\l�fdA{"�G�! [26]–[3h4+9$i��t.C.�oumi�63"a �ex�;*32 s�EE0l&�� Bh$^iaU�A u�u�` , [2)/3L [35 �� &�K69��A�61>y��)�ny "9h�7|� 2011:����ew�Pd s0 SiA �vof 50/6�#82%�&�, � ��h�bc�q>60B1}%u���an��aR+� ��!BD�~ �Str\� �� �w0 Q��(ina Faso [4%�$Madagascar&!DNiger #%��r����mJ5�g�!�[4eA�L7!M�7%7R,�.�<�mIFo:�iso���MMr ^-Y9�(:�.Qspp . [�+ , [1I�18�8[2%S[Bf3K�V3.�(�?� Kenycwo &k�+>ed& 6�6 R ��[4�[4�j!��xq�A�USAA- 1977.�aBt�B orga��͂$!Rr2<I!oklah�[l.[4�Xs l 16.�?<ZmU_ �  mmen�Ms�? focutu� �%a�0�� Hr���eno�x2_>`tZrmadV�B��>a?�%ci�All� ���ig�a[ �!�� na�Bab<>� �XKaDy��� .OA Ga�Ni2hen� �i�oT��S2Q A � �� !�� �m���~*iss"�E>!tb� sG��BPulB;o_!8]6; �s!!��CI� "� ]/A� 3�H�,9�!@ 7�Y%��d �U. Spe��>.��:x�S 2–o0!�&( �u"�+be�@.#� "� - mbr��'by “�] II”T1  (�����Me�us$k-scal�.arB�"� enve� glyco ` ( 1N% ?%iE%�Rdim4Z (@��re`!b�o Joct�by� out"� roM� he E �4�!�%�los�z�fac�.�RAa*�`�4l/�6�∼55-aa0*� ,e�%�]8l!�2_!���%zip up��g&/pU � toge<�{&m1�seg2|#1��1-�loopsA8tՌ-~/�in�lat pepti�=j�.� �!\dengue�@Ea-_E-�� modelA\/4�KqI^�(tpInKX�'*.BI�����block6�� �v/� x �=h poteѡp�PrA�alAd� af9 �{�+n��K�C<~A� remo5N].�)�uNa�VpP�W�2- 5�b�Q&attachAiure _D�͊�!r3 ndos"s��@a.T��)���\ �Z*��Ma "3d<$�dF� dynamic8$� !n�q�y��&9�if�-# �>�%4B>raTA%nT>� %� se a�L-stepI���a 2; �M'c. Tk' D���%a�b�EV5yA>I�-�ŧ%�J:^�GډY�d���r>s�E>�gv��s�w �� L��!���ng flaviAB �? 6H<*p!K E�)� �E��V�:�-�AA�� ��)�&�Q�i�c�,��i��)j mole�r ̜��!�}u��R�v��EL�9#aw1,�_pl�ԉ�%� 9:�y A7 �}Wf�_!l /9lathrin&E�2cy$Td ��!!o&SmQhe &;-H�T:�G2�a5(insect-bornF*e��po�ve-A*nd ~|9�ackagj�2%Fc�Nie} 500 Å!�di�6����Q6�0,zh as E�!�A�incipuhx�Kl�¦�؉��u ar�0&�!24qn��� �VAs+Ui�7M�r�Eof M �WCleavaǃprMxIFm�h�%X^aA��J.�ne��  anch��E)-eA5�O��e�Ehe\eT+c��~x*,� +glo�� �Lsu� �m��� p�V�O�q ;k A 6 cry�;��u~B� sotal�� Eq�A.�s�X�*:; euz a�ost J�)��1�!�&%Dw ��b:E�A��el� t runa m!2� � n` �ol�treat� oA:&N*1�&�`a0 solu*vbi69m�st���2�orm%�E (aFsEa=!� ynA��395��"lE445.>rs;<y� aU{-"I G�Lh�"[ �>C�f� ��T{8a=����"Y��,�N� � ol�A�oEM���<s �� �p6a!~�-m� dA�P helix-��-  sandwic�-�B�&1H:Gq��%A��; �oU�.�u*�f)� r�r%8U��nds�ed��&D�fbe�!$mLءX��z5�aSaM�1^�of#T�J�.@: ��E�� ��tc�?er�XUen��rz�E��=e� driv� forګ*4inͮ��m��1�k,)%oI . �&cts�!by9[as�*/^s]k"~U1��!!b`> vhai�1��n"�+%�w�;`“zipsa�J�. A�"LAf� i��agE7�f._i~0�! !a�_–!@*c ����h8�I�� I �Awil" bF[�&��M1�S �i� e�$�I /entfuvir�!1_' ogHI �a&c��[�s�6aYA�h!K lpha � t&� E1Mi��Q&�"�3!CQJ1!��.� E��&���reA�b7ng�.��!�-back �^��@$�Z!�%I!�mUs.�2�Myo�!SX%�4 �@ ,�e�no5 �Af+���)-=t!� puzz�5&�jwe�[<=ctA�i�or&p�^-�5f�'B]�"����!�a�]Y%� aX��`(� pH-n���E�,^pplP � �":�u$"� ���]"K_#s�Sao&����ho �"dri"�A\-�"� %9!��e � i\��s"��0W>z)۵��Y"<#E�cGAV. {;ZI:�# predw�o�K�a� p�sE:�w/5�V-��R'�F\m{�e'9Ilsama~y(s2)~.byY�� �at neutA pH bo��:4,�sum�U,NO mpan� S�9"@!EJQFA*H*m=i�t��F*  ��-=E�* �Ia0l!OA=���h_%V-fng1"on;UY�*�y��a�W6>7�Va�("�e/p"� uoryX�l!��/%n�q�[�aX�y!,�3-u +en�'1c�  pH )%A!N.� ^h�\�  E�:�(^Ig��*�6����s��8i -W �9�O-II� � sEe�a{�]y enti�aA�W`iss!% sE "A e v!��b"�a! )hټi/E>Zn, j�;mz� V mW1Ce���m��ytLDV ser�! x,bclo9���West N;vV�R( WNV )E�iI=��hWnHk>{� `a�0A*�� M{�ll6�DV2A9!� ,�";1�a�sUA�CjugH, FITC�� �Qk>� ir\M%�^��s�%6Mr �"�I2Bpolar*%"�.�ic.eA.%=E��A� �* f Modis e�W0SHD�iiurnI�!�c?�O[X��`ick���ph� is�$BJ . Aci*���1"M�v�-lip��s "��6���seQ�h lo֡ � TS�� c�7c ���%@��LWea�c� i&��moar"������EQ�% `ic�"��-�;9� J�iovM�!rEUI�偌isojms��!�RGO��*�U� �Y�Bpo>�2�sE�H �-ta;�-&5a>Smfvp*|��A-KdW?�!cal A � sI�M`+a�PepDV2419�!47�s s�A�-Mf�;�jcra��d z"of6Y(>3 ) �Z58.� �`T, �n-f��e�y��2}N. R����� sv-Ŋe*S�su��a9 (i��2�$- mH!�*� half�� i�t�l2�:b� sE.>I�= ,|t=]�,�'�f&�Wb�7NVy:i.� 9�(6fG�Dl��Kd���150 n�i�we c��n.i�r B;a���ub�tk%��"�)�#� )5$� �_M� %]`2� :hxpa�ti��A�%9�,>r� m.�( )�icg,4)�“pull-0���B?AsuM�S>Rbi �-2W�t�,lyq ��0� ���B��#e � ��1R�� -��%-g Va��-�!��*�� i�n i�pv���!d)8��chondr) u� 82' , UC�1���b+5.�6y1� (2 � !�n�If�bv!�v"x#m<�� .K�� %P� p *6/f���}"*�"7 | \e-T%�3�#ACf�(X�AJ@ !�MB� ��}%xtw� thodz�it�s�Rl� ���-e!Ʃ��J���$ f% ���O��  trypМsus!Z�. ��-� expo�~�� )o5�toh-encapsTa������o!�"� Uk �!6��(mix!����a pyrene6� ��1�6� vali�6� ��&'/8*���"r� �@"�!1$ i�.� hemi ��U oblq47^F=�!��!=mer� a�wo5s 6d1910P--- �,5s�"1t!01� by�rE����.: ot%�$. Unincorpqj1 M.�*�%��M�ͿBhr�?�F*IVQ�a��_Eq-��OY�� %. 8c*�!�� �&12{or6("z;��� re �-"Q }nA-Nb(or 1hC37�%��,,�Vgg�%^m$a ow�,�dew"�}:K!w1ec�,ir%�� apsi&��9�� r &�3A�MiJ 2.j7jn��K's.Vxt�<KH 8 . 0E�� �;as6Z9xa��7Ze�ԉ�xqx H 8�5��<)�1R!��"} ��� {7TXbQ*^)��O !�"��y--<  &9 �o� �$��oq]2<-�a=d m)`�“�"�2s�0{!i�~y\��3�e���t.�/-P ors;"Tb�`�,idXydf ,�� qbn-� titr�At �����Ё�ec-,�93:�Q�I�. ?2�B ob3 � .�c6Ű1�!E�:pre&W �<6�&˲u�0�"���"s� ]� a^�iod�� ��dsorpexM�l�T ^�-�N�n ."a4� i��e�67fy-Y .�A���'�Aq�":���R��!�L�Z�'�4� -pH�"�U. E�XG��ҕ=��� q�MpA�n-nM:�*� " �G5�,I��7�%(�T!5��n�y�!�1Å&�-wE.�{A2o4)1–2sm)*�Exm�� @�f�N �E��K�%��S}1o s��?QIi\��!��st�m&q K��`re�LdL& 6L7�20 up�6)6d3iv�ke�AM�C)H!�s�y ��:b�F9p[2a$C?. Yet!��d%�ory a�8RL�~{R:�-��#e��1)�i`mMh�c.��%%7e��]�"��a�rd�"o��%%02�!�<��1�tr-�:�c�3,24 /i�����S+R�e?%-�>m re�:�se�a/�a�tf:O ^"�;x/Tof� -of->%X.��>e�2�J��r)fl�Cspa��Fe&�(*^[t� H�3U ty��,��ce RGKG-n��{�iu% he.^/D��.� �R�(� ^ �J"�2lyD;q ���� ��A� ,��%�t�ZG6� |6�s�#ed, .h�,g 9 � s�^gM�n�8a&zL&�76���څQPHK-21�o 0��r:j n�=Qt���� � !,E��� j"QF( ( MOI ) 1m�w���&��8-ǍQ!pid%+�!��`�V�TB2E�no lavvɔ� Q capa.E ���~ r.. %`�!'����2WFT&�ppXJ{�%�����ő^�3-dve��"1�� mixTmX �p��� 4�Ad���*�,1 h "terval?�q �on5Ga� ��=-|".8Q|@�� ��Da/ye2*d�6�"%)2ہen�l`2��=�6o � �G�A�llaTl�� �� i�!w��9aN�:�e6��a�a!? -+1��� �LT��9I�a� �J* of1��cT(Sb)rt.�N��i. Rap0�/ �����a�rt �-&��m� �(.�R-9. sy,"\E�1�)=��#� �!�2��P��: �gznA�wkD�k�1G�/4�/We "�t5���- umns.,�,R3& I��u:mQzgJ�o-tby!b5d&�1$g��,��d i�,�%=�*1  3��:S��S�c�(hequilibr�~s* 9�T�4fi�Z��' � crRy7�\In5/mn�#.z O ��!�MEZ@B6Z quic��Ϭ"� �P>' � �2")�lit �o<��4:T����q��2�dy[C�m--(Q�=��e�_� �g!��s ,!6u)%e�1Bą�A�o(ei��6�y�1(1{ng"�#6$e5 �%�Ua�45��<Uh� ���p��!(� e+�J����2�.�Pe��ML�*��hrw#�I�buH�Z a+#.�5h'B�#� i70"�� ]b<- ��H �8s�j%0��I!�a�ai�)�pw��c e!�*�)� �d2}elu�I2�� 5%��%"(4atm�E��5a��ice~1�'r\oft�)s%%,��Xt ds"��|&M�Z 5! T�9�'5�-&6��Q�we7 k6%ro[�=!h�# >6#tI.uv.Weu�G��d�42��-�#6��G� KiQki5y�t�Tu� �t� ��&�!q(%2�. M*aUA[�& 4ll�e�id mo�a��2|�`�7ihoodP��5.1k:#ra.&w � nO�I7%o2c&2�t�4&s2c juns", �clsg�z!s %��:�W%��ω�r�E mphi��q�B{& �4u�<%higv[= A�.��!s�MM�1r�1� wild|��.%E�Q 2���>WT%�B�a��)�u!�I�by 20%��A�Q(sa}!� by 9*u,e� &z�{7"9~�!��MN�-�i�dbh"^�[-u�d&�Ed=�8�G!,�7.@OgfV7`F�)9�p2-os -&���2�*�#Q��an@&o TritonX-9$. )E�;arLE�=�ALA���5s�h  ZUWqq*�A�:�� &T �p.�:ne� 0Z,iK ��rf�IY��� :�%���-�{�j(Se���aAF24"b 8C 44~X�0�;it�B�i lubl�P0 a���0�GA� ."0L!nV%�"��RG��9 er5�� �:�y�wi4so9�e��2��B���gBso6� ��.�, 3aԬwu"�m�l',��-�]�Q@i �ڡ���B*� �<OUah�%U44fqO{=�Iea�A��u ^1�1�!@s U��B�b�!3�>y6W ;*n5 �i ey�F>fu� �ps . Wiv���lU�+-$��>mE_ H-�u*wG)E&i���=2�# �-�"�3�p�>� a�a�!V�*Za>#"��&��.�"^&m>oD�tsJ�EL!5;��f&�[J9NS h!��+� ��q%� % aASr5�m"U 2�<��* %�7�O!m��� H>o7+���"��S�I 6~M:Da����� �/�Ag*- yI�"�!� %5�W)=,,a! �Q8ye$-_a�F0-u pM��0p&�*�'!R )-p��RI.�c�3�Tr9�j ;�R�q0e>! v@���until:?CK"&{" ?�0"�";!�--�skA�I�N� &z=fluct� s�bN�� m�% A"�C.�"V u0o�� �(pl�*�?i� ɲaV!�u:*�!�$ٜ8�s%6�w�Ga��)� I��%'8%A{h&��`i� trap�g"1"a��(�$eȁJe*.2_�g-�%�An-5�E/A�eLy��J� 7Z[-. Nonet"��it])m_qA P3ateT6Mtan}|Qa&v ����!*.4�=��}1os��95ex;�=?�]�)"�Im� NY�a3toAQt vI��"�Bqr�Z �ion"��)"�%E$& "���A)p�6� �thArs�'mA�\Ir*�V���K�&/@��-a�`-,�HFq� read���f�B�Kǹ^#�&o�:� I-r� |@� )� I � ! dopt)&�i@ a\���O�>�+!R*��A��S�*O7�s!�.h:H�oge ;y MeR��al�(�;�S*vj����1e �''my nk�ls�5�%o�"h turb�� 5U�R��������S"��UZm�E E til8He��\�k\��iG�^i wed 5�aMR*�&rM-E )U ��t:����i�lqC"E`0̌� !,a"�T�??*�~"- �| ?%u�|l1-�Q��m�� -*o2�EM\a"�0m)c�tw.!Z:��p 1%�"F :�s"Ծ&e�"J )~ 2Q���@!�-�*��"PK:���=.K��vT stN�cnC-��I� �Q?)��o�Zxal�$�c?aGA~l��5� Lf��] !w�y<�m$int�)�Fal9�A{�G�1L� ��, ~ �1o�&&3�Q���b�&��%�I4virus particle� into an endosome and would be available to “spring 5�place” upon transient exposure of its site on domain II , thereby blocking the fusion-promoting zipping-up of the E-protein stem . Only peptides with the appropriate sequence �Heffective , consist�wit >$properties��`DV2419–447 ( scram ) pey� , which binds well to virions , but not to E trimer , !jhas no � on5al in �|ity . The two-step model is alsoR�seq � dependenc%���$ing as mea!� d by�)� -s�!intens�o)�(pyrene exci�$in Fig . 6IA1KpHU 5 . 5 , iz] an a�x302k���0room temperat�n1h6�%fsolubil�=Pn-octyl-β-D-glucosidA�β-OGAaXnd n-undecyl-maltopyran(UDM�^�!E appl���(MonoS colum $GE Healthc��)!g25mM -'cit��!!2>�4mMx.!�s selu�%ya � 1!XMI�2 grad�fur�Y/ ize-exclI�4chromatographyl4Superdex 200 (N�1aSTEA , 8 e^pa"7�Prv �di�$�#siv��Va 50-kD���ar-we- cutoff��,( Spectrapor%�Bi� expe� �E carr!�� in��� ,� v!�e 384((microplatesƵ�0in a PerkinElc EnVi�aB stru  (�ti�Lwavelength , 485nm; ��66535 n�. Stock��c�� of�-� �� �� in DMSO�dissolv�}�im l��f��us6 ncrea��&V~�%Q�� a+�t , 20nM� ���. Each)g a� �-�of 20uLͽ�. P)���8 at 4�x{ coll� at 3% 24 hour� Kd ?estim��a� ' 9m��7half-ma� i)%H �� p��� . Re nta�( 5µg )����( 2a� !:��b4y!d6Gor6& �R2�°CE^ reptavidi�A�A��q10% FBS!FBjY hr pri@oA> o �e6� �.��Qmix���r!T2��t�ed�il .4��6� rom|!�D%Tspu�;(14 , 000rpmAeai�Eifuge�4C �̈́  s� nag aspi��d�nd�\%Tus�� 1 mL.�- �g}%M�U. A six�� wash�BI � t�Tre2xSDS-loa� m�>pxat !K��byGPAG=10An15%; rec�gel[Biorad����bazre2GCoo ie blue� i��orn$immunoblot�,a���ce�. I M1 visu�e�  lum �$( ECL reag�, Pierce�:� | E&�� �� trypA�%4 mg/mZA�"s [33� Unencapsui�8)�mo�� by p��gC)��&i 2�gelq % c��Nc. P� �f�5–1 �kadded� ��c��/&� ��� wo�g2�0µF�DV2�mq�-� qat3 r:q���s���R6�23��.LB� l � pretw �re��ъ6� a�; Zv� Bt"*�1M+ & )O m� . TM`diu6A2allow �proceed �hr!H � . AliquotJ AN� Ca�� 2��E�~ fo �b�2�w�E� (nti-dengue aPntibodTD Q� A� ω-p�fattyt ��]ir �m��pro% .* BHK-219M�gr�J� 15a*a�ofa0-hexadecanoic� ( Inv4gen )�<on) �q serotype��V� !� harv�d�rsHA�">2� �P))labeledmiE%iyE{,quartz cuvetA1.� � µM�( J{�bXI�� E*� *}B4!�inu>monito��C343' !470 � ���Je �� �p ByJ�,�.)yieldR)BOstoppə.B��41% TritonX-100!�ca� \lete dil[I�A�b� yin� A5calAtͼ p��n"los�!#� i":(.�.�. C6/36.(mai��L-Ae�supplU��,0% fetal bov�serasllAB penicillims� omyc!�(ketonocazol�2d. F�al�quea!�F�see��( 5×104 �/�4- ,"n $tissue-cul� c in α-MEMJ�HEPESA0en/� ��� c�� 5% F%B)S%(j <Cel���d <12 �b&� Isi� 7Ci5% COG �Hu2g0New Guinea Cl| ( NG�ACadsor�t�fluAAlay:of2 �g�z256 e�ro8 y�9(.2&( M�"{��w �A2 at ev7)untilcytiamos obser^ �6� �c��"� ?��0 RPMU�ati �b�P9� −8�!.f~J4Q���-|a�t��� wanbath .� � �0� Earle's b�ced salt&�( EBSS�!k"� in 96iE}s � E"fer=20 µl �AAe4to 180V�E next� 3of a �)@)�ArE�^�!�Mp3� aAoedBnUnU��h!�r&p �wS E�1 ml PBa�� w7"1ml�b�0carboxymethyl� ulos��CMaR,��R�&�2%`,�9 %%%W#Zm 4iI�qoverlay K:��MN�d 2× �mL�ks� �� crys��viole!�.{ F%>I��� �bess>@`dr� vern�.��GeR!�E �^EN� e�i�tzw1x E%u?a�MOI!�15a^on 50��)*�(�.Se!U�" inocul��&�A�%�&z �-{ �eJ� %H�leE�� >C �E�∶B?)-��N �a!�of%�(E� !�A9��(f�I�^�!�21)-0^���!4��>� s*j%�� draw8JyOpl& Vo59�Y"�Q�1X,)j��Z� nd�ed%]� G-50al�b��%libZ�i��JA�fE #(��9 S#>+\ xei��t;�# BHKM:(eD ∼16& �!r2�i�M�M��m�d!Ms�k�bM�FF ��. � fB/ mri.�!2&�8 id���ipM a�&% u�aX���byA��!(oly��'glyco"�ar �80OPEG , B�n?B!8�;�E"�mix�;�%���"pelU #T��H!����!×g�� � %BGW:L*� �zd �00d*fq.!�&�z"�o�^ k40%� assptar;%7T&30%%�U,�p65n 1469�K��1~)i"_A9Y�i�+ 10 f2�$*�Q�# od�#st jobm�E,ATCC: [34] )��C�p �S by D�J . GQ sakov/5/to lo>%�I����I+oo7,AY%Vnd clea�E�Bq"A�%b$by exchang�to. � 100K��"y cut-�&or. micon# i� a!}�*!1ZA�BCAz &�.ui'�QE�Υadin� ek�Wci?(.�zGlobal"UV+� ra annu;*ap�* te 4 mill�ca|%worldw�q 9m" death�!��breakPinclu�Haiti�Y�a�r�$ mind� , �is sti� g �h�)Srw Chol�ounk$rapid�)�& high � to�by��whelm��!� capa�*ofgfi#A�, e\'%9 mote &� r $f civil un�(g% stue9 demoE��stoolw# imen+!eon=er paper�!�Y%a�>alysi4Vibrio1>Aρ� ourcU#mit^ e�!��>t� %> qc�,, safe%�su~ aq& mann��%5.!Lprovide�W"un& 0�ab�cir 71�5(�. T�)�%ully!��*new��oP0to shape publA+ olic*,O,sD0d|�#a; elim�). WAO� �0� ( WG�rec�� )E � ��-)""V .t e O1Xe8,satisfactory\age�K>enX$q alka�$� �i( APW� nd6}isova� both spotA>l!~e imum!0A�� of6\$DNA suffic�!toA���&genomic2��^ 02 ng/μL t,E'confir*a�&� r ab"�#gen�)8f epidemiologic1tee�L��QtoxA� ilus�ziAGS.( a va�%~*diarr�� pathoga���PW-5��'men5\fs%i�,�� lighE��o@2ial��,�$ni)�(xpl� ,gutbiA�,P�(���(yeOo- �"+a�pac�*�0rI(of�!e(.E�F��(e� s fi�-D curr���1f phyl!) etic�{.��q�7th pan!�c El To3!�� l0E� or mapp�of�/rtHd�+V�!�:R��#����d valu���#Bs�i&(-a]2 �E<� t!% re����T�0�-=N !Y. Aq&z> 7006;�j��om��rig�hngI�,Asia , Afric Latin Ame%�(he Caribbea�Oanb4iod�m�an �$�%entury>ratq�c+ ��r �q �z em ��int�%loj{&le���a�USouth �[2m!�U6�a�A ra�v/"�.be)���i��+�^�robust�7�re��dn�. |n4 .aC E��j *� a�n.��o lz0�' at� i�i��5�A� s� n%1kn���Bk�1^( 7PET ) �� s��3 n7�'itїd:/e6���� -?�Ovn3!�st��,%vg9im!w+urF�!<��–.^ [�#MN�y�b�'e crit to&����at�est risk!b����,8- �rvonYts61 vacce�,on campaignsJ8{:�orm}de�2�*of� @�2A^�|!fa�pr31�a�8 � s [4–6ajI&�- ,.�:) eV�!�� k.�n�omb�-�!��th�'!�+�+b� re$<�2@( AMR ) spread [7�j�p�d�"&v:rc���M� �Ca�e OCVC ckpo c�@ 201q*���)ido�&� �1�at�9U!is�du�=S t�-�Ji [8�%0�"�ft1 trik@( or!=�-poh�w�3laboraC "�is �.�(r�,04is�8alw�0�f!�AEW�� s�2�:!6time neEary +7� �+A�A�v � rv��9take up$fL6[1 , if"� �)7�9�on9,E� C�<d weeksE�s� to b�(�"on�\y BlaiGd��� ��K�<���� �46_m!0� *�js i;�in:=� �bionty ship� � u�r"J !pS)�a�T|� ,be very chal�.%%�m3-af���y 8. H+-�*e$aea@3na�7��ac�*J�[ �� acA#��) .X�sampl&7".�ll�"x !Ia�P;"���ha� eriz� �m�sN �e�ҁ�.�"�;kaK�c2oa�0:�6 �toext��!� PCR ��c��[1 O�2 -岁 R���>�  m -locus��-numb� 2 repe�-�( MLV;�:�(dv��d* |)�s8?b�fd�2�<�fa'�� �Ag<i�)��per "� 2Fj� ?$ Sierra Le�����y"�Xy���.�:�iڑ E�]ne�B� .N�'su��ful)���ty�[1� GisE!�/ E�%�i. de�=ed� %q**s :� fej9�,w�8ug�+"{ }samVyv?A Q a�)�!�c �proof�8principCtu2�sAmY��<s�>2~2�Aʑ^Y ��a?2�a ge�Tt-qu�a=D� ce ��!&�� �ZtQcR82��essen� 6%�a=�AM e �*��. 2��m 0� n�z �iU�)�Ŭ 9d)nH ipantsa� � 6 “S*�� S.����@projec�r�5DJohns Hopkins Bloo��g Sch��$c r; InsGo<4Review Board r  dy �b. �, IRB Noz4 RB0000398> Writ_ )�� n!��(ob.�&=���G <� *I7H^F~E��6vi� ae6' �X�95�� �,,.�eARA�f�&ng� bee� "`r [1D'�oSixty-X -�X)distinct�6A5�*� K,� E< �ed��% .Ui�3� w65�$s��osiJ AG2�by Cr�(5`. O�F2�,�16 ��3s��&BGwo di�@�:ocoj7���ere�*V�R�!� �1�V)Mh� s re,�s�ss0  deriaZ��)��C� ic� !�6-�;in 1X~�sѱN2. T!Brop����6( � �)�a>5���woMm�(Whatman 903>rd�������hBI��%}���\162pai’l%n� = ���� ��be�A�&4Bhr/Y MqDC ��'a`Hm6 ���y%-���=1 6|�O1a~ o!� TCBSdumr"� "X*. F�'�w+Y,R� se0>,.},50μL!�T6 ate-D;� 9S$B� aU:;23. To e��  2#q:�i6H��.vi� >2 � dr�>{ Q;s%K�%�2�6groupR!!�"7aid5D�! 2�!,1x108CFU/mL;98bacG ?K =�:Z:+qU6��rir�6�B�> ( 17�D . Si� aneB6,R�A*��4 tub��or�9se&WB:A�t-k�n+)gFblA�� UV-l#r�C�(�Q �Hs!Alis '&< &>�$X #*mSv.��MFb�Q�eh.� -6�-dALv&�/A"� o q6�ۅ��.T%2C&\-DPW�(6�A.�k:!y*d ,��%TM녝����AYss�!�any6atb3Con&�, DZ�Eҝ�$�v!� Luria Aga�(L3p�!(9:���66yѢO(z 5�.U� "�!ρ).!�1�at:O f&`, "scIDMinser�Ae.:A-�T,ee?Ec3d twic�+R31X.boi��l:�pZ �6helex��!�ee8�J�7q a 1- &�+i/]2G0:�Amd�%crF�ɋ�֍�26R&N%Ah�x�x�!�firstA�er&�F� �R, OmpW�n�&";Q% i�)"�� s%A�+txA! second���.�rfb g�.Ef�"!jO1�funp& de�JɠPLWC15�To optimGTWGSG-��� vJ���!�2I�+8����/r2�7�BDambrook et al . [1�� �c,%s�C%� ddH2mG� �qu�f , by Qubit A.$0 FluoromeA(\ rmof�m4a�q�$( StepOnePE'Real-TSysD!) !Z. O�RS ��Ue�R�L001(μlAe�i/>N� subm�ə n!�@�WellcD'Tr3!S.r"�/*an Il�C,a HiSeq 2500��a�A�J=,bp paired-en�adD&Sh�&f 2AOEu5Z$an Nucleot_- Arch ( EN���b�'( S3 T �S� ce�&% '��E� �}m:!O1f!(N16961 (� eQ$j(s LT907989/ 9�N�SMALT v�)�0 4 [1� !��.Q>�s D a k-�=�K!����p6 ( -k -s 6� O!v% aligc/ X,default paraE�s� E�93Iu��6 i( i�ags 3��?m!�fra�Y�Gd -5r)a duplaj2�*�' �Pic� v�^92 [18] al flag�1sIA]A9@-Ad ��!p"��QN]�U�� � aM �aH� V�sJ z v��h��. Auto!n0I�y�-<ROKKA)<11�T!<aA�us&�WuI�Refa��TVa["�v*c NmSam�sM^!upI�!�19 [21]IY]m“-d�' 0 -DSugBf/�bcfK:D2]!,D a BCF e��,�Kifll A- H ��J�:t�!E�u5Z"Ay� !�<�K�!nt >scu'!re�]d�b#e�.t�'50�Z��QA� 2�3�4If�I�didg�FM�5 �l0/��a�"dBby��+�� ��0 �_?� u� ha�fe�E,1F2s�&n��d7morphism��NPWTaf1 </95���� majo�-�)�Jj �+ least 75%�0)>1s��M, (�T v7v� �mi�/;depth9.�4 ^,X vzof�ha%Vma�"E �,nvF O< y  _ <a^. Fin�(�6r3biCas�I8l EcA4),r0FK tail^ �]R 0+sem:mG�"me&�s��asyJ�� pseudo-�f��8ru�`� ��%�O!T)3it�qw�z\)q��� !��L �<�Se�F.����6�!� �'�4�F!�Rm�uign_$zdel~,��@fie|q N’"�6Zto keep�%��r��(�#t"�YB�a�a.A>��. M�#!�M�Art�G [23�ACT [24D &� ��<� � �mb!�dPv�PASPA85vc.E� [25e[re�!�g�$� �� � BACAS [26<-�: meta e [27]��F�p" —0 -t 8 -m6>. S�� � �i�v( QJAQUASTJ]f��0-no-check [28!JGe/.V\H�,S_/��5ame*%\�C]Jl,wf �!�*,� �x fa—"Rd�2[29�Kraken��!�6 [30)LuA-�$ssign taxo�!�Js �dF� -�&�Refseq�-�372 A7/08/201��. Av �R!zN8 r [3�0A�� �rixE .. )? MASH�M6=��Y"�&c[32][Yifgla�ura��&��a6#4!��E,�8<&:AP:�!Al�1*��7"&��sZ)n� W�&,[u"A N�bor-Jo�Qtre��� d��8!!K>/9:HQAnP�8oAof M6�=(CNRVC960188%�  1190%Q?r 'i�] lFig���Ap�.e"c5ANc2Iea�� i$���O [MR�O�=. V"�testsJ;#�%)2n�h�2r2�sJ. *V, y��ne#v�l.';&��F�oj�!BiZ�`&�&n�>nga#*i�*�:6����*&�* rega'b&<W/� ��2IO1�'��(ai�I=K}sw?�g�AP�a'F&�P!�-:2a�k�3l,$o9���i&#jRT C0'jF?1Ave@,q�=er>)�<c!�ƛ2 � ��.L3al�j6�>�%���I�.%K59 ��!>��c%���o5v�>L�V<>p�F# a!P *IPR�Im=�?j -t ;�:�;*%(N��* v�% , 600064�� 8�s1-I29�6�# �z �I>u�-er�"�� Eia�5o<�}� r+d)� U8xaI 500x\!dM�of 12$4x:O ig 1���kkr�c>O~&� �� ���y� s2�19 . 71%�9u33%N�644%�B%�1�v�V4.� �A^SBm� Śl��]�;�$��.# betw�'A�.�B���%QRNWFFs"�i AF&� e���2i���_aB�A=�4Aap��H ( S2��%�A"�6�of=&A2� .�%E�!e�d*=9<U�w(jbo -H . 43teJ�-a5�su"*^��� Ja aj�22{ 9NR�BBz�pA��Wp�auUjJ�m2 !� 3�,?!,���sb p 6)%9��PiV2% ,6m%�V`&� s�ly��uEua�R�j014� ,7 ±144 . 03���7�052% ±26 . 81FUE;Y(�)V10d86 ±�(4>Y6N14Y+52fY��vW�qaAI �n1Y�2�%!U!Ҏ�8  s%?� %Ln�'Wilcoxon��k�� , p-O#em�551� 6 1965�Y9}B�1j��ly�*DJ*� � � Hd.!wF <�a�igW13� �T165w��B��6$A�16ZaV�)� best�y �&�P�� aTs�v<� 50000b�V�nvee�&>97������ "����:�0A9 enr�'U:N�%�"�57" S3%�O�NexZted�����]i!2&��Ks%[ ap���-1y�<��� illu ��Uh�de �ofFfri,o~ ve�q 7�of�l�"va�&E ��007L 7+ 2+ MGAMe�Lz!=15�ʺ��1u\16�G��Ce� @@�@DU4.��4of 32u��e^-4,aa29\-� _� ss�;Q9%��Jr �, �q�6�J�� !@.� I"&�a�BLu�.R���� =fhe"��456� �b�R"�-',q7qlpro� A�G/%qsT�K�JRPr�Jry)esA� )uBF� 55N���Lw�� 2� k��[�!WmgLabund�K� >-n1$!U dAp%z�`�5����*T!o�CFB,al popu� 2�A!+ ex%�8[* belonx<�E�Jo ceaq:mL:s"AArnShigella5or Esche��i� lihd2�E ad�Sto6�F=F.* �(.�L6� ��_�����softw�"�7�dJ$�f���j"cd%�F��r�zm2I%�.A}V0�_�m�1fl-�afou�T+�0%�s�'�� s ex�a�8wicCE s��>�(��Si<8)qNirO�%in��]��r��8icht6be �mlYSpl� ��!�fr2��ƍ�%�� )��2��V[ A���M���.20 fa�)�7�6�a|k�{50%a�� .�of6�1IWA�k eM"�B`M ��fmee �E<^gV����q . A閡H���!\�(1(��6G�1 �s6�.�wo �2�B� �o`gn�$as�e>AS���llZ�V�!�I� !�outgs �2����. ludeU.*� �� degV��i��x%�z�� X6~"��)al leve�_a�-8 !X%i%1s*�>OJ�Cn 6h Nf\;*z>� oM��Cas68OVFu�s,"�D&l�leiw! d%ic&�;j��;��QR+F�r�>�@�,���[ch���5� s�) ctxAe� ctxB� --encoa� . embe�l!integ\ CTXΦ��hage;RtcpI-�&"F �Mp�Ri�V�B�n"'�-��of O139+[3,6�_ >uS&�rst�or wfbAR��-P}�1�rS4� [3�m38] �I38*�'nt�"A��f� ``*�.%AM yJ�%P##azSNVH*���w&SLJ%��#��\ar�'(��%p%r .s^ a �6�6 w�"'U( S5A-?. Compib����!d s*�'��$"M6�$��Jy�m� J�F�( >� ) ,,,A�W��st ��Qɽy�#>L2Mb-� NG50q�w2-GC""��E(L"d� !/ �st sp�� ��C�z�Z�?e?-m� ?�� �}pcdN�=� by W*� .�<�Cnm12b1�s�P�dp5#'�P� OPmAdcK�a N�bou:� �IA�����#�w� ft8;%e�Uw ?2�U@Q howna�i�4-�https://L t . org/:? /S1OfV91P!^�i� )tmIɭje ��l�6 �C�=~%6]ͤ:�2 P �� 2��P. I*�� !%1�:>Wthird%r�HW2��!>�� �T�]ity�c.|QAD�Eq�,[I2 200�]! 1�+201��B1JoE�a[bk$�.���* wv�*&z%�"� hK�)ful(}ct6�%rsv�xama! *VBe D A�2T� z;*�2 20x�".xQF�22H��m+�&� ��e�l5�. I!V�p%@l���%��typɎ1�� o�<6�!V��r)� . NoF���(� 2#A5 en �"but*�Vu31��V ards$ccCX/�++NAc�+�Jԁ�r6�!��2�R�M���,�N5=�J1# desps+low�ntaB�N^1E*�<T,��x.r a�.�2b��f��!\�G�Ֆ�. D � hy�[�"�!�QX�����iY*���,6�of� V`�H<s_QJ. Q�FA:5�P�I&� }�w��!���e���i�x&*,6�o *%���dlS� A�A"FT m)4Yi�C*- � �RF A�i,! �@f� F�< &.RLl�csT�b nd/oWst%��O s [3� 1][3�S40]� � F�,�}`6(J� 6�ayi*���>SM-�X@!g!�� !norgan�>� �fyGe�X�Z. AGesъ�M���=�"x�3h1�&t 3!��l�O�| AU��so� R 1�b�[re�gicBFe�� K2�=P� �(�I"� sod��IU �WM!�px��al hyp^!%bSKZBb&�(meZgism" 2���e1Pme�#5-s&I!Ss Q �$S.�in6]�ed��A� ligh!�proa�)L. N�)ko��e6�"� -_f�Hi6Lco-��r� %&,A�a�c�PQ�or: �!�A�� N�b��-=�* 5=�!�alsVhbd�2! �p&��e�"_1��lex�^i��� Sva!��O ��Ha2�Y�-E1Png �{���I�e�e=U��s� Y�>R�!�z�p!�e.�QE%dT\ �N%1NM�ll�@ateR \A�B^!�1Jm�V(b��t�as3����%iٷ"��]�.`& A��-2c",6?R �Fa�-|��Jx�m"N!!l;m�� ud�eri�K�C�`top� pr *!�i�F��4"]�/9�%�ge�"t�(2�z�1!ޅF�/� e� UrY2�e�''hi�Q� qiO  b. Pair�mu- �8<c9a'� 6� i�.f-ae">� clin� ؅�*��Qc"Y��0�ZE�:���c�P�Moy A�o" j&��ou�!m*�e�]��->#ynВ95[�wa�b��4� alue��X�?s�T-�7Z"�eq\sj)re5�ibL�f�\���0th �6=0!�1�1N�It �& `+!�%.� !�y�6�1b!5A��DE[2�"!�� �$"�]��]Dopt unA0�r !M$ �"�Xm�ISI��^N�ZXPi�V��N�2�2�  a�er�2A^1HiA�%Q�f. How�f� !��inC_ offord*�J��/rfM ! :lH�=act.@technlL�Q6I�>!�Ox| Nan��e MinION�ZL -�s!�I%�ua4� �a-EPa = �Lge!��� 6W�#a�%/� ��\ .�r�y.�� ^QZT-madx�aF1l(h\e���y�6�2,� AbA � 5  �c%��a�idQ҉ub�!F. F4G,_cA];�A�A�A�� n� ( �L2�� �)5�!ed/�Ws3��2�"un t�w�p6i%X!Ba�ct cr�,Zs Av�����Y�["�%E�r� & �!mHo?�jacr�all*� V9�t*�G!� c$��c��d��Q�����H,� -| O��n &�&�&Zx6�2� �=us"� .�5e*aTp�qE�q�V)HM'�e*�o���6� &>'ae-}A�� �r�%"� a M�=-=ib*rra�9. E�A^k�U�X way!�� ��m��U2nd 2� x�D2VWE&� .ini�!AeU[IN�c�%��lB�C emplo-z"�Ed !OͶsa j'Z;� �� ��nqH�dag%P���%|7 \=�a*pnw��l��O;&����A!�w�+!�2R2�YG* ��|%pa3V.�"�R*m�)��1!!#2u4.!��� 9��!0t�KA���>7.�4aP��x2ntC!�f#ep)B�\:o2�ơ�A��:3� �t=M��J�at:�'X �O�)#r!.=$ W�"�'�"�Cet�`icaa�E�sA�on!*O!>�A@reMeva�"K Z��&�!�`��I. U7��Q�?id��!^*e��Q J�i���m=e� � y.�at�e;g1"� ��?8/fatM QUju�� new.]2<%= s�da�"7�in��^�"\ E�4�6i6� patter� -re� �M.[�post-> *->�tmR5Q.UQu AA�aviө�w�M��2^ 2�!�dynam�o� ly .[�I(�� v�7>opsaan el� ��Pnet�;� �ep�dlw%*��hAlthough�c��sub`u�ai�=�pA��ba��qvan^i]e`�Nta�MΦurE,litr�is+o=yhowecu vidu�J4#��e,�m��?� � K�/+!��N$H@scru9!��de?�,e Drosophila�icl�R`{E��rg+E�qyt��s�%DynMRmo8}O ^\<`rega-oD"!Oo–bas|-laK'. Bs�i Yac� �>}sc�8O�-+ Stard P( Sdtdp�?c`jAI�e֧7Crumb��bar�)t�ay��M�� sdt mRNAd RP.����'-�il|6Z��*�jB�7e]exo�I� gu�J�!�2� �<&�%�6vp = o� ev���wwitch�V���,1�[ crip�P�lI#d�i7?s��6~{Aa�vun-!+]predof��DaKU�E��Rork&�# ? U*#W atQWj��,��s��U� !� �)���e#a"��s�o!�m��Ty� K2�nw��t7NuHz"�=�*�lE2M�R0Y8i�F!^l�7}F�-�]�c-!�2�a3+e&T�L{$) at�4T.�S�d@���!# ir n�$�2!7environA�%�ҩit�H surpri��.��F�V�Y&%��@ZUVntu�� amongazoana�E�A �KsubmA'. �[i��TV("aM���a1�a $G&O�X��p���űV���a�s sC�� �\ .��vdBt�–S adheS]!�v�@meAݔmo��ye��r!~U�mS�Gy�y)�t�tve4s+pr�/IHes �y�yA r%z�m?Mopen quY�L.��&�E6�sh(2�n main!�J"St�in�ylm�'!$mammal�&ڑ"A EE����>ngY�C�=W"%LeY–�iA��A��d8s+ ��jMfM�x���� t�~���3�ofy.�"�$B,p$e��eEL rens]�T&i�vteZ��e Baz� (0ooka/aPKC/Par5Vct�~�� hier!�� �A}M�I� cv� �(Scribk(ble/Discs L��N+#yv-R2H*� �Cឍ�e �ƯA�%�6����Cr.��/�/DPATJ )����9 �5���ntagon(["��[�J%sia�e^�HQ1�3H�yTTu�= Q7dQ D�Q�& Oo�/� �y-ex)=o�05� U'2��cΖ xpan��-X>Ik:�r &!�-�!� ��AO* [�N-sta�u�jMuplasma9ln/., N� , 5� MPP5"� �%�8̠sv's2LtaiV� �wPDZ"dSD-95M��- /ZO-RA �[�#1�A# rd�e� !�Ɍ#)IY�*t��V �Ksh��L27 \�y EnaT!-P�!�j��4-�Ϥctu!�1qc"43bCFf�#v`��z�T^,!&� hu�F CRB1��b ��&woJe0 �"r�z� ystԳZ�"�].�mp bM Sly�, \u�-*a�exert%����"���, yet�>m�)�E���omp�`��ɕ$aS��.�!e�"Kpu��bS���-�k*�&exocyxvesGtr�-��W Ѷ��on\\|�e[U=�A��vradigm ,M�Wrr"new y&��R�s���ly2 eo��? �:O� ile R���I:y&$"�AUe_�E �lrbac� �� �m�']G)�ofe�aq�(c*����a��]2q 5"��&g�%�� $�m29��& ntirA�Apriq y�U���q:2�-$i=R�6� �3�irم�H! Un,!7�5���at go[fb2�Q�2�!aDz� �2OSB4��J� }&�A�� � a�� s�A>u�5o*� � involv� .�-�U��Mc6�RRNA�w�O2?WTB��t;�byR 8� y)lV�-\n��=�,G%�j@commo�|� g]�$����7� RNA--"B7��M A�6� M'�?� skelQ�e� ��&}AlS.V�J ��6)2%"�@ , enε �u ���ll� �n��b,!5�icA=�_"�!iru A�"?][�X.$#Y`q�A���l � >'eW a as\ gi , �!� � �nX"UQ+sD �*n o�Le �I5m9a� m%:�ȏ$skar , gur�W� bico��r.��D�e!? � � )�7e6�i-�du� a=[� �6R!l%q3Rbּ oder�-�A)M���tI�4=-ir-rul�F!��>���alYCxZ–.YHN�w�Us�i�$-�#�4�Vtubve"w�_=�fol&t" um�^�*��J**CH}�f�!�>�� A+s� � �,){� �-W�t��W A�%�"Qis��sqQA-�2���"� &2�G��wmap��R&)> R]S�p�'�.H yy�P^H� ��>n��d9 m[Y� n�* �2L �-s�oy�p.v2���*C��lebwa 6]�&W��zU���%�&"q0����r �m�M<.�A�gH[&���!b݊0�5cl �/rk�It����8ex�nn�u AG�Jk�pion To�ypg��mLc�4 :l� A2NL �m"6.( Fd�1�s�2�egg!Cm�( E0�� e FCi��� , cuboida2� surrqF!-!�g��� z>Fig�V�� go dra�a;#ge�hrJmid-o5 ��e�εa�� thel�- �e � �E�?a squam�Z= 5�#4[�^.H  -EMS,%�� Q Flp/FRT sl, ���}� ~ e22c Gal4W(��� -�AO�N&�q%,ly�%aic!�, . Mu:C;OB/4&;��6��Cn*#�tA�@ ( GF�eAy��p  rhod}` e ph�.v5!��0%��p@We �A�p�;at�N�>ɶosw4hD �N61%_a6� disrupt07!�a G��ÝrphC*y�*rne-BadͧacgD�il;�!�&�>�.UKA�A�3 phen��&9KM#-�e��� � ��rup�C�8� 3Z"e�x( D12–u<N2 qNQ43–?>7at)gE+l> ( K19&: &uV ���۵M�f�%&�s u�!�multi��ew 8�*lG %,Rbs� as.�g�e�Uch�")^Ao΂�'�)-�U?�6B�1D� %���?!��..�+�=�s�Gi� e\�s� XEcrb��G��%/� �! (cbRJ ��t�&�kI- mi��� Q�ZJà�� P:75�Ic-�=a � ��&�'eQ7c�,p�W6i cando��r�1�酦I]f4g�d�� N��HeeU� ��sR2*�J H Df ( 3L ) Exel6102�+��()0� th kl=*l=z%�� h<�som�0 ��� aT� �b��& &� 's ��.S� �xv��in%. , Dhc64� More��!Y!��+ l&�K�Glued� a�I\M=�/e p150�|0!gDyn=+@�&��n]&o,�%Hxń �A �[3T*/sei|ax �� G9��U(%:�J:y��6� %�+ i>JB�?�'�inu9E� um .U2Au�:E�/s $m���� -��Utl�*�e"��X�gr R�&�z�)pic��eT{��3"n*e�"cR� do��nde�0�d�w`d%cA�A]� �homozyg�� Dhc4−19�.�*�4,tr4 Dhc-4�@�nt� t�y��o6#!laC *!�aVŵ$*Ų-ų $C!:��}� �L� w t�!�: .fr�u.�  }�ini����6f� "s �)s��a�0�iř!�Gtop(d-1, ��Ev1F� &dni�"z�]#�igE��16� O�u�"th";A���A�qRW�F����wY��I�J,"�!-�!�bon�de�qh&E�!�X�*mu�]dW� -of-��]V*>,$.�5e��.c*��M[R]l wiOv!^A�l�� B�d&� ��FCs ?3FforceSoe�ng.�1J��Y �>�w{1Yqrga�&�<�� m�![f%el� ���* .�( MT )&� eukaryo��ex�Q�y*aT� 9:,�q�a df*}=uUTs SI�corte�d "]��:%Q�!5 ��u1!\[33�kyt&�gezdX�� M+;� e� P!"�*x "� �*A�w U ��M��h"y!a�.�-s1,��*S�!�D�@!�WE,"4 f>� F��Wz'%A%�� '3 &a� � WJ:!4�zaU�M+��.� � 5-1��7 �It�B->x! �9�of[� &w0�h�<پ��a�FC�NaTf��qNu*�=onY��a= � �,eMr �n&e logiy: "D"s,k��!hcE3 �:id4 norm�*B�,�60i�#�&=1Jy7B�a"�&i occa� �1di�h a weak,�V^!́ !�JK, N=4Q�.-�:U�(�s�" <s*� Y "��=B!�ɟ KU�!]� n&A�o 2ena� �(i��! �"� aw!�fC;� &��~�A Im� :��A��&�Dőy���be�!� Crb-}�>� �a� w �svke��  ��"%��"�rb>�� >Z A� 7-7HS�yonic݄[ $.�J$��nerA�)/A&a��[3vtso�Z�i"�1;hrrL��.�%lҔt�k6q�1ޅ2A���nst��%a!x�}�� �� 6x M��lsd{*�1SN9��2-m"2"� `-e�%Ys�n�]�2��.5�uz���Pan�?q��� |)����+a�� Ke@�Dc���nd..�h�/ Fe�*O ed [< 1ޱALŮ#�ųa� of Υ�O���'� a�ىi��ih�Pmis_�)- � JjG��2�4�Don��"�at�!n�$ re-vitell�ap&[��/i-��.arY^n2�ofe�FC�_a� �e7�-gI �� ;VB�a? & .�#rbe��We\p% age 8u? s 2DES�.aH�2�� !#Z��Elr�"mbY�1u%a��of%� 5.�A!O-�!~�vd")��v1�iest g����%���.o�i���r-s 2�S{oqR"�e���guish�> �a�ٴagu ~�&�e�Amis2y-��(�a�"�&lyB� � . Is��'-l�A:A�2p��DjL�桚d,��6�1�7 i�?��/!�e>c�0�&t&Ob |i�of βH-j�trie���J�&� ( uF�F��Bbf1-�'( Dlgl1R��2>��=su"%��e2�&'Ia�d�]�2N5we��"�c�@��-� qY�E!�EU� Z�- 2����l&Y(epista� .��dm)� c5�A>%�2� �����C�J�&�!� i� 4��|� *�;�5" 2�.wg�x��;D2��O � as&��� �"%^ dl Ho�Iun6-5y.�"�J��]-�!���"̎Z�t&g` I� ���;b&̯& =_�`A �"[33 , SUW�0 loo�A"�N�:9+ f%�!���mbryos� ask� 1`�9-�u+�mp  �<y! back��q�Di �rE�v" .�XP9pr� � �i:�s cutw+aE����ng����-��%�al ,� ��"3D ;Bs��,&�u�D��.�\dtP� �l�8!I�patG��QS%/ed1{.E�=ibDQ �ng�-H*��E� �(���kho��or�%r#.4��. EM3J.^�IՔ! `Ma4  !resP�A��dIl�F�Q� aInk#In 48�s� �S 5p�E�� o� ' T"%�=� ~�mA,YD,�-QE��9�&ts�c����r��6� N�*�ޯpe� nQ9���ndM�� �wF �q�{)e��V;m?*��A^�K#"��U��� �+l�@s ot�V�V 0a�3>Awb�,�G�,�De�,1 2�9y0AE$o���,�?�?*� *0 %*Vs desia���a,A�J��jm! �Y� � TD"b�&� �WH � <�&C�-�l.!0��6�[��wZ� -���;D�.�EM&�Ad:�FZ��%�J�� 7< >�!zF7 wL>})��l��W,situ hybridi� n o�ge���W���{&�.w�o� � punctaIh\g)!�n�O!|� �ayJh4�� -7INi�6&�0� �ԉ��V���MAGUK�� 9] )B[#;e��t*4�gS6,.���)N2r�,�*���P��y�EBn >d�4�]� V��� Ye��6M�Yb�v&�D�� �?I�:e� ��w�%so"��>�" E�q:��sE"60(M�-!?&̸ofKy"� 91� (, 50�o!�M9� t-wM�>� T�O5[ 8Uq �2�?N ͭ�=g 9#Vx~cW&A0F՚l* ֤� �&{H�'t\?took �Na�!A�Z!>� s�ɷ�\��"�" �N� -҉�%��. -��:{. *S��8�r�OE� R�}!�l&E�9�� ,.5a�U5:�F&& FmŊe�9w��j1���y)C�Bc}%+ �k ���achaL&� ��:!�T��Ea,- c�oA&J.�,ĩ�� "`�?74%I a$( n = 8 EC InQ %c,�+n W�(�k�2R7R��-PZ� � sse+1�49=�*nga�tI&&%c���S4; TCS�?2ck �*J� ��E3.�m �N�!�sS�0bo��n.��t�LLA���t,a�h!]q�ENb��r ~�!h �"Q5�2Bi*��Et2�E�*pK cis-�!fig�?�T�sBm�-5� Sb a se!Pof UAS-%Og,,u75�Aa�w3es��a-I a*=!e�"�Y�*ts%mhk,w> \� star��&!6*�5& J*�g?W:a@�X9��0��A,(� C��?|,a�6� p�+1� l�c&�J� %��V�a�2�ys)E�dt�B@#!vE��)rZ3-�2M�2E5�"[.�i%�2EI;�+AZ�� X3′UTRIxre `I��2M�wig� SV40-J�7M ani"�|��2,�� �_E6�Y��C��(0 �s phJ��n e?3`%,qs�u�U � ���&�M� 3.W�H5;L cess�n�2Fac?&�A�d^� G!LunW>7��\�E^:De�&E B1��y�o�^!�MCm �/hi5<rN.�!%�-t�v-�atV�b .aO�S�T �re"�A ��U n�8�$�f�Nd6�P�X�53 �m:)��B)D ;!�i4���e�excep*�Tqe�Ppli�N�O�ف%�ua�m#5g 433 �5ok���iTL&���ECRI*-5A 10� A"tr*{Qno ob�"���otifs%������s \>��Qt �&�F��.log6��&u�.��L j′�~��toT�"��Z j�(�%�J<��E�MqJ&�)�e0��t�Ri�/U�s�vwo * [:c��ssa�[O*^2�@��E��m��RaTAkBU��(�it��/| -��.�M�%� TUz:�B|a��� �=az� |EEV�$2.0 ..�$, when exo�Cn 3 was appended to the eGFP coding sequence in a second transgene , -�cripts showed dramatic apical localization ini�(both necess`Dand sufficient for%* � �)E!Phe sdt mRNA . By mapp)G  9signal!-[, our �\suggest a model in whichy(subcellularB~z9tDs could be develop!H%�regulat!�(hrough pre-�splic� . If this�Prrect ,�.� , endogen!�>�observed�!!FCs at o0!�tage 10A�� lack1!~thu {spE�o variaAofnB . W�!W�woB -specific{$situ probeA�on5�Hclusively recognizeAzE��a 6m�same siz @8covers portions&!� s 4–6 .At ex aGpredic%�ow all�%�isoform�whereas�ex3 H(will reveal:5exceptNB91. Alth%�E��s stainQP!Au�ex��q5��A�B9 !m omina��arE�(esis . More!��ur�I1fn unus�biolog�n mechanismMi�%�2is��!i(alternativey� of a�A_AX$o investig�; funcA�al�aA�a�,m'9i6�, wA�amie=(he phenotypE�0sdtEH681 , anAi0ele caused bye emat�� stop�onE)-m�ly �ed �(3 [10] . In�m 3 mu�blsoA' pres��M�FCs dur. arly�!ѫ�&T�supposiaq!)consistH�%�?previ��(%�26%!7�pa�a%�foA� �basal c"1 n�( T%S1)�ogethe� se f�ng!�`��A�tributes��MP&� �!�,complex , buA~%�is��!dispens�6 FC polar�0under4 |d%E!YIn tras"4 rel� ly mildZ�-/!��is��proa(8s a very strongF"X .%DE�46E , [36 , 38]%USi�QRT-PCR .� &6 a,!)[a B%��uIo2�e� geɉ�EF�~ �s)�g)�ly��edp�. pla�� �t-�zA�rolO �A� epithelia�gt�  hypoth�+�5A a�he abil!��nA���A_rescu?  �}�|. Fo i�   a�"Dl Gal4 driver ensu�i�avail��ex!_a��s�. ���I�!c� � � mB ttP2P e�(provide uni� !A���%�%>{ ")C someyE��� much�e e"� tha�E�n)T!����9LYQGE�Ama-)zc ll�¥^ cros �[A� ��)?segreg��, 43%� �continu!�cuticle n gre!� �2/3AEtheir2;?�d 13�F�ex��s!isfel� !�� lasO a�mM� o 8%%� he n�ve iol �pa&9m�_ Ae`�a"o !I�u]qSl�m� A(�e�( . Dynein's6MT-bah i�I4k 8 has been studi&] h!B�nmamma4ŋi �i�� �rz . Two piC-Jns? H is�< primx �cargo��� %�o2L *W�(is occasion%/ relo�&�CralF�in�y�, most6@� A.D amou-E)��. Fur!{mor�EC:C��M_um��a�baz�� aPKCw$multilayer!at�#ET e� [49�� unpublish��)����n�Rct&� posterior:m- �� *� I�> rec�6�Ye�n $blastodermA���� �FMev%�ae�N!�-�W*� i���A]�)means by�=�Vd!>� -�dom#[5�<"Z,WVR,`le��_N�� f }!�of�in)�$' �FC� )'s major!|m*on��FC[J�c�R� a7e��mu. O*favor| 6�  worksm�i�W�.1t�fl�UK�M. WhenW�% �2E,\!�dis9arY�-Vq�, eve�hc����(in cuboidal6��~y!�' gg cha� 2�~�zis quitFmi��b+l �crb�� qyr!�'ll three�e6&"��mwy�( [31�4�(a#io� MOhalleng me��deciph�� .����[��r� � �8M;�o ocTA�h��onship>� !�be��e�interўnd &D epista�.��� M7ac�cc��%�@*~ �!�" " m@v a. ]2�2%!4sA$)!-dentz �&s�� /� _e� ��y� ��u!3:V)��its9 .E�.�canA@b!He�fR 5B, ��,A�!&9G)%m ���Iurecapit� @aAu Ju2S!� N��F�a�.�A�2)1!" 1H�"��)�=�manne\a� at a��t� a�"�S3e�tQOrai� �ssi{L%�ad� �\�!,�m�an� .�pr��fBAm� ���*� fullaX+��� � �ba� @to�T�v di� o'� co��Ũ�B�� 2� �W�& �Vwh !`% f�3 ��� �JUmadi surpri�dis) 67 IM�I�2s��>�%�%,�n 3!eI�wA�ofi��)���ߩ�Y��Z 2��R8is way [50 , 51 I�;��y��E �!E,J e 3′UTR�iYs�ng�ty�lQ�XucEm*�we^,�� �� � �e� dele� 8433 amino acids&em<� ��MM�./ enco�"by1�in��.���yet know Qse2G!�&d "U vertebc��hom)�*�� B bind%io"S� of� !��yc� vitro��5�m�t�!5Al as w�as�-� �s o1� �!�uI���6�81�"�st z�!i�vo.8w�!Yru�o�e. 6\>�s s�K2B!�5� , to2�2; s�I�%Q�ofxma���f �J�.�o�1E�X ��ݑ���#ar�$���6p�Iis�r�by%�analy^ M��A�"� ��!$ B9�*�(�RA�A�sQV�l4 sE�6Zm1 anA|� {�a� �Ze�s� �a&K�.�ap?��iscrepaa. bK plaL by�,extrinsic cu -xid0 t&a� "�&FC� "� ir.%Xacty3(germline [3��� ��A6� ens�A =.U���is�� ���� no s���}e�5�!a nn;&� ,ch<dN��yQp& Bh v�la`�� BO-sB���s%*r" an im� �!&r &�UoYJ FQ A�^�m� �� R�& A�yo9aAad�"K . S�%t �^ � �)ln2�h�42��$��1".#".L"� t.� ��Why�5 2D���j?t temp7 tog �Xs�"�!d�Ba !�e�$7#(�r!#J���& ann!� rea.� ]qXal ti�$"�#� pha� .�2aYl�cer�"��csubtla�;���c9[)� �]6!�im�$;�y t� prolife+v�Yin�a*  j�!&� mE��a5dop���fi!� �"y?*el !�#e~&-�5.sN�%/2� -mito>aPhighly& ia���� 2�� !"F6'�&n�� d pool!���,t b.�%�&w-� �,�QY!PA�il�Y�m�> ods n)j���! !�A�eC�1yna�m�ory�wd&A�Z��inB@!� s . ��f � )a>,$>e�$bed [52] uC a(e22c-.� and ubiOin-(.Zars�% }�% new�64C;Glu'l�'� re c��'!gen&"0FRT80B chromo� ! EMS���4n>es ��34 tud< clude:�4−19V[�,2B�11A22�sdtXP96101z !!FRT19A [)#�(d1P10 [9� Geni Nv ing%�per�!ed=uGR12t()�� gif�/DTrudi Schüpbach )�!3hs-FLPP Act2G!�"follow�LUASa�st� s:� cMAGUK�<, nod::lacz [34]B6ig<$A�cus4 below .����Usa.Z/)�"AvDaG32q#[8!Z� DDf ( 3L ) Exel6102�D4502S � ��)VBlo�+gt ock �6er l8M�o�->nd �M�ob� e* OreR� �+st9%�h�SPBS�fix?or 15�G room�cer�*(in 4% EM gr�A%Daldehyde ( PolysciTs )-]. S�u'� washqgYiin-eJ$0 . 3% tri!y�Y$&�,: rabbit-α-�( 1:50� [53]�!�z!1 !9 mouse@Dlg 4F3#2C DSHB:C$PKCζ C-20'10KHSanta Cruz Biotechn}y=�ra� Par68)[54�9! ��� CQ411�A�2rEli Kn�))!X=P%IA\�jocol abo�"� %�ute meW olQhed��ly=�fix$A_1>hc P1H�0 ���a�-��?M9%�!|TubuleM1A�)�SigmafJ3JEmbryq cF�%�%e�t�!��iw36�%/cours9, 24 h �4p1mnt� ageda%25 °Ca + 1UalA���. -�k�hatchE&crawl aK. C& sp^�'�5��2��ntS. BDh�^��rvo!�l�hA�A$y + ��� �a 2,>h9j�VV u�4$ P ( −/−�Wit�%�2 '��sdŲ���,#2[ �s�6�j"T 0–2 cop�3�$5^5tisense s Pro3�synAi] �|a DIG(label!ski�R�.�&(( LD13435 )�)RE05272�STgi6��*5%DGenome Resource Ce� ( DGR"�.wca��Zar�e�Not)27 L mT7� ymerasa��fRMlunR3.R. �1m�P0be pene �,9�!=!�|��5�M� frag� �"ith�bo�2 buff�'Q��1r%poE?e�gBksH8E �,beo�ll �a[4on��*ll thAVO1a�%��e|4�&��L��8pA~%�.|u� pBS-(A vec�',+ iF� sKpn:�A��6� �E5!y�4��-.�b� >&��� .i.!<z64�T� k4� d a�E �P�8r5�f9a��in �/2i(situ hybrido �&U2win Wilki� 1999�VAN�r�7��J#�7"�upo�queste�.6det7,�3(horseradish� oxidahconju�4d sheep%t -dig body��X�a�� @65�LAlexaFluor 488-Tyram�-&�In�gen�To �i��mosaic :] inJd ,f�an �� AT�Ai� 555-. econd�%1(�"at 1:2g >��,uk(env�9 �+l{a�m illu�6di�647.�wheatI( agglutinin%PR� Imagq*��Q,Leica TCS SL!�f�& mi�cop�wH)�d�� Illu~<p#(nd Photosho�- sixi�g� f �pet��lmm��y��P�pUASBP�^( a:i e�(Barret Pfei�t(, Rubin Lab2p&k&q2|$BamHI cass�) SxT [56]a��3attB ele��Z u(&�:rec&=,-mphiC31�eg��[57� $A diagram ��E!U�m�li& f��F|* S39��HPfuUltra High-Fidel�DNA �_( S��I1aE1�amplify� &�&�!�v�All�;�""# Rhe Phu�(~�Finnzy�#�#To�%�[�i/W���8�}�:� �G�B�. D�@A�N%���co�%�+I�iM 5′&�!( XhoI yield+��GFP-SV40� .� -sdt4UTR�.��wo step� F$-F�J�!�*��U.�a3�e �edi�>q� XbaI%� FseIl*aG9�l�:g� . S�0���_�$^)O" %EEcub)�tlyri5�!S^ !�[�1R�4�A!lE�>�"� �%�fU-O-K�Aed)�X!�o���� gJAid!�2� sdtA "��/=�AVA_\Breg�%���%P���-�A�5 A!EiW%H*kcut�heN�)�c�>�9�/}�E3!��*5�a�j��QsdtO%+!�� �)y]�!�JG6�)� 52� "� �!�NF)IVM�U/T})!�. To6�c ani�3%�� �G� ic Servic��*c2ed�� eachn-�%Dr�6~ �b�iso-'. tal:!H�pq��)� TRIzol Re�"[2�df�� nd c�_��|#.� R�Omn� ipt � eBA��Qiv��� Re�8��E�� �9�6&�%J]"�8 P{GAL4-no��NGT}40"j58&�UAS�g"]�@A��%.*%g��J+F�6.^\2Z A/!oRA[��!b&h* ��!&�� ez@Q�A�r�<���7E crumbs�2� hpicJ���� ����"}re�-hce: Li Z , Wang L , Hays TSp-0ai Y ( 2007 )O"(d�2�of�%|E��*"�!E"�G(tJ C2$ Biol� jHInek�:*@�a%��s\_QD2 on Flyg8( ( http://f .�3/e I�5�ata-9-Aal� dt-RB�� B>F .�tA�I/!o ]6�V eish�6a spp7!�8arg�c" 8ly�Da! Ho�!rr1��A�.�#po&�6!2co-in�AEv/9)�z5o� A8ex�?iAaQBob�zuBx!Dcy�:Mh�&e&B �K para� / / ~y� .5�7XwZ�E2��&l4u�ex�Dg12vn�alaof� 1yinfantum8)��!���kL .,��=re�; drug�"iB9�+GZ:Ho�;ei��luo�"V$rex". /x>��*those�k iN$��=�BA�4 gn���$/�!. B�I.�%��?suca:�+�()CG>�midgut!IJ_$Phlebotomuůniciosu��' vidu�;? s�Eec��f v 97x�)� a�2; ��Us�Hyeyق�^�'#�AeAہ���.@2�� �C geny&e�i�triploid�ed�r�ơ�!�u�2K� %�asa7e�JT!k�SteyI lifem S progA�!4}��& � q in BALB/c��<�1&�"u�loK'�$splQ� live�.n%!R d we�8val�9s.�2A�"DE�un � &ic�"S _ rginQ�1v�)!�+�+�� �ed"�"!�U2O isCA6�-a�ag��E�r^w&�r,�&Q��!�T is��2 K!�s�Ku�!am��VM� �!�A�~ N<who�Ga l]9but�eOlower vi+a,"�r5$��+ 1F�"+��+G,� v� Ն. � ^A�!u45L�3� 4+E!F�Hs%evast�A zoon�#diseain�#�d��!�c�3r�~R.�F surv�$T<�LVviron� *.>�(!�ma�Jo!+)!�!�m�@ian h�( a2&Gem"� , pH%-��7ia��%�cem�@�7�8hum�83Bc�. �%Uc�110 clin�Db "�fesa�. Viscr) l"��+2*h�HZHg�q!1!�Hal��{!�ef#=�donovani!eE# AsiaAAfric�<]� 1�I.��nde�$tB<u�,���Mediter ,an���3 nd LA* Amep�? l5s > s�A2(�(�}� &f*� �b}Omarrow1�+b�Oad�If left �D d [1��A year|)�&; v!wdE�=Os+< s.�"&'�&��a<+� Ŝ�?inkage�quilibr�< ( LD ) [2;8[KAY&U � %n�?6!�E�_�z6s ( Vianni�braziliePJ �a^ ubI �.heterozyaR"�-��i��� ��trict&1 � �'9Gou1A&[3ly)I /s� 2-A1po�'BH bree#��r� d [4!�I> #H ove-�1io�!'=����de “d=”*[* aneuTG+now�f dA�A�T~"Ka �&�e`�lab5�[5i �s [6] (/�'ew�e [7]– %GNon�ledFLCJ0*�7�n��2 ledgE� ��#et t�Es �FhɌ��autc �a}N�XO�12-�a fa:AxceOe�&:�n Tur�B%A"{E meio�. per -*��!� esti�}�a�2��30of��g<l 3ACfP �!i�������"� |de�V� land� *x�>B�/leys'�G&��� of2� duboscqi��A�w��w2y� . -<.*�at��t�" repe�1�!I�� en� n s�* co-�FYQ�>&�$.� $ un&� %�rs"�eny� sG roup7f�4�! � a� �-geograp�FraQ! q8( P .9C"un$Lutzomyia *ipalpi:'U��"fir]##2g> ��n7 ter-�2�� barri>[1�:Ani;.�-6�B f��mod�!��1,�#�Ja2viTyA�|vwN1�rog� af�&#� mK�| O� !�Rx/J" ropaG��flC��acuKu��Pr"�2w�6�r#9�+�pl/-�Qc�Fd �v(b&�7f��<%�involve*� %�:f�!_.(subgenus [1�e6 . )2'/  peruviana �s� $~bQP!vatelli�My%A[1]+.U.�2nguyan�)� !�u0mon [15���N|/)!WI�1sT4as��cAS� arab ��1+ 8�1�,�Yn4/9=e�E�EY' �;u6�"$[20q�u#aethios3 [2e�DQmj �:.�� m�J2�Q�5[go�X�k expl2#�A �^e�-e�m�K"<'az�WD0 �� �ave c�n a%*5�'q �W5� �Fog��Sp�C,��sI�`as MCAN/ES/1996/BCN150 zy� me MON-1-��awo�-se�O��� � �Vg(/%jgr�� !3n�roa\aN� �B_�@�}.aQuenUl�bio �;-XpN�N)�-V. A�?"R�&��cedur�T"}+��Kanu� �7c�,d�:� '  accord�4��%� Span�$ ( Ley 32/A�Eu�Kan UnG Legi�2/10/63/UE) �{k%�%apY�AmA �C� Committe)�heh�4 Leó�#II� Female2&H( 6–8 weeks old ))sj)M�Harlan I�Rfauna IbS�,Barce  ,n!h�,[#�5fic-path��-f�Efacilit����b3a����u5(1�qI� A�)!4*'%�6�J�- . R} B*r�%Jogía M"^NS! o Ocho�Madri_ 9KP -�ro% � d�%26 -in M199 um�y�#�> (25 mM HEPES�!^9 ,�^mM t%�% e , 7 . 64Zn ,01adenosi&100fol�c�<1× RPMI 1640 viV mix�#Y.u% ( v/v�eat-inT�5foeaR calf seru�aCS � �&iL cockX.$ ( 50 U/ml�* icil�.,µg,streptomycinE�)M..2i�-t gene*5in or?Xto�.G?�3&�.VafA\; mChN ( λN $ . 587 nm;�610 nm���%l kin�a�ir#0by Dr Roger Y��8sien – Depart�i Pharmac1a&C!�\&A�&\(, UCSD ( US7\,i6=��162�529��$. Juan Lloj �FaA�a� cina yena0R"C�� gac�s�méBc�Un.�@Castilla-La Mancha�yN���\CITRINE-HYGROMYCIN ( CTN )�%�  720-bp!>�"�\>%fS#by�+� p. �26T s�3� ��oligoR),otides RBF61�& 4���+%+T��1�$nZ���o` �����f�-E`cmBglII-R#Ains�B�V�($LEXSY-hyg2#  ( Jena!��4( GmbH , Ger�Iq-& ?1fh)d.5�@mCHERRY-BLASTICID)�HR-BS�45 711%�HR��!rpRSETb- o�>�1r!�34% 0��!Q�e; 2Q�w�t�V[28ũcq �HYGw�"�)A�replac� �!3OR�[�M conf� rC[XV-ٽQP icid"E [2� AL82x.Xom pXG%�i�R�765Q77!{1n�U399!�jcSpeI-"�'6�pSKII:�0���.� � UTR2� M�.!{92^�77�8RBF773n�133F�u�a�-�%K#gѨj �.�  ious�q��q a�A en�*4E��+T-%2& 1738!�w2�u'1md�i+se,>�Z�a�p!~r�̅�a�-őW.*d ��&and����r�3� tG?c��Q0g+%  of hygr B�6�,apec�f|ndJfm�*. In u8�2 �4.� s]�� \a A�&�y f8=cytome�e@( Cyan ADP , Dako hce. ro�0\y ( Nikon Eclipse TE2000� Pa�V�GHR+6��TN:( �6�&�&sa%+6� �tO�e�": �)���P g�iIdE� �E�0sa6nc�.�|r�  a@"�7"�  Ed&�,Pr.� N'��le�/ama"k(v�Rmi�=uPn �je��2∶RK2� . Dou8�PM�a@A: stari^V �ro$t$*�on�(growth �D4.!�6�adv L�(7� 1,15-�mix!�k:ISJlasiQdea|ttim�O &M����ind�Sly7jlu�ql< �/Iny�:�tOha�"PgEQ�~#pIVby paV&:�J##�Q�"�2�*1�pF9�-�� 2×1�)!��"ED tonei7-�2fn� ( 8-.cZ ��lKe�7nt� 5"�-. F� :�E- o��Z� sacr_��ndM��4l��&�@&�%dNKa w�[mes�=ulA�l i$plus 10% F(At� �E�B r�!2� �D�` VA mH�&�=�!]appaat X�b9�1�3sv�A x+�=on�X�per�on']�(�>@m�H�L�, a 17-hV0ht/ d^Ep�6!�o595–100�d$!�humid��u!�(Ent�Py;"�Institut�Salud�los II!3�(*MU`ny%K"�I)�1987 ���cap)�.#0"are?d p�^&\PXAMi.@� ��f�/�ach@i -daytm+�E2I�; fH q�,a chick skin&�Non B��Bco<!ա&7) ( 1+��(of logarith$#��6�R�aA�%1�% de�pof�(2;�. E�'e+e��>�d�U)��^l�� |X*R �`%-��e?a��o 96-�#�; &�21 2 mlD a�rt��a�E�mn�bl!Hm>,�,ew ses�hof�>am{ %&!q.��$�#U�:!3EI 5~J�*=�1����J�S!�� �(M�9�6)a� 1�4A�&1!v���!�#dqb�bunT � hemor er"Z] . Hy�=� e ��� �%p� "�&+mye�. Con:=����(u 9:�G "�s. THP-�s!h�( ac�FleukemiHxnA^-/a 8 ( ATCC TIB-202! khcvinCj%F�-nd 1%!"�/pe�at 37-(5% CO�@ ~��� diluA�I3/4I�=i���2�1�105��k8�'19>s�5:! ��'i%!��n��/0horbol 12-myr$te 13-acet ( PM��48'�RS&� 2�gL Y]�M Qh( ���9H) fa��!8z/ �l �2�-m$ph�?at? 0> �5H)�B� A���+a�lve!� hn�|#�" remo��_ash��%vphosph!T�D?&�%(BKeInt*h3TŠZ<ha��72 h �J�% ."S/.Q| �.{%.Vj&� 5'h%�.: r6U �eR^r } �e-34 metaX4icF"L.wBC0$u�2�6�,�or�[C ]xi �5�$A!�nEoɪ� (�͠? pean�&sB[2�JA%�5 of1oMY�G*�:eut�y%�n�G@p61~ �1f��t�:��li���e-�:cal�UF� -!P su uE��E�"|by �\S5�]%�kUv� w�U. Brie�,�e�/ �Na (�m��M�seria�%�a�)mB(Schneider's��!L$�9� :h "4 .-�10��,��� �_W&i�+T�?go�I�;osi6 orYC�!�(^6�1of"f 2�z=�9��=�a9$5s�9mit D�qA^ Assa�  LDAU ) =K8ic tF/c quadrup�.�×_#ci��g\a15�edIS��L %D��E�v�!r[M:Rj)�gin= �i"�'[26-*TE�.�5b6� :&M+"�Gof 106��mea�U d RNase-t d�f���(id,!iod~6.6�6�(�6Q�� �7�rQAW�Q70%�3(hanol–30%&�� 30 mz t 4�.�%pel�W " etw�5Xk�e�diH *y 2"�B��ZGX %$ Aj n�cubsa^5��1ųD�l�"�2o}& FACS2�e B=K(n Dickinson� c� �ZecXiQ�Q���8�pl�<��>W�<Quest �1 ( BD.�) softpci�a&Y0 a{�*\AsY� m�ln? � L0B7 ��4u�u��L-8in ,.R�V� e 1-h yl_ 2-!� aned!8-2-oxime ( ISPF t 54>"[2�)a�$o�n�!c K5NO� o5���ͫ!�&re�1mea�x ��GloE-!,ay&�2�G�5s��[2�U �"� �၁�y! oir"�7.�dy�"QtP�%)"w��'("� "��J a �sO890���,I�8�^663 them )&�A�21 2��b�>Y 21/6�Xg��admi�vxl32%�R)"� , 54kY �% n"!�#&� in�;�%.c0dC{o[g>.��K��,�^15m�`+�:“5Ln�P3 ( 15/54 )~�27�AR!$*!d� �W��)�5�. . NUv*�;e"�AoeEo*H U@>B373j26�1L��3S re���)23!�9zorF-3/�Rz-65!6ax&L 6x I�e�bpy1�5��."�=Y55�`W!y�n. M�.TV-�a!x!�f���+� � o2�>)I9�Z��M!�( �A./�n�Au*�A( �5] "�"�AeB��y�ms9�� &�-�%!�El�\��A \ of|%� *W.�qya �g !� �or"�1�Ssi|O?`!gti^) 7a�E�$'.�A6K-L3F_�Sm��I -&J �ID$=/�{lyE[�&� %t� �3 refx/3%�m"`+'2&�E �- Pg!HS5& if�im�!!?��A.� �%,$%�E��") 1i . 1�AdI�@r%qB� ��T� %��x.KA�&�U}c�Cq*�;`! D Ner �%�� � *!m1:�!��MU�� ��BeTj�&a!]f6yb ��)�!Ua]por_ �!�a<BSD$=&�� SP1C���9��.ta�.� �*yk1CT�B�&DFY��bj�6f$toPe|� ��)�s��UzDrn�Z�"�����#{ soma؋ar�ZM,S�0R2�gE`6H�2in�ta��Z�jZ�nk$�2�Vs�Y copy &9�{"�!MzA"�E�9 �;���&R..`M�7M�A�"� ��CODe�8>mF�#O�4Friedl�\V?!3.�5 M2904)�� oduc� !)��I�ŅpA6�<�“�Di )a7���l5pv�qB���2n.1m--�14 (3B('p�:�e��*�;Z��6�+E�seM�s6y! ��!6p<5W!�I*"B�&!(�E��) � 8 JS4� �8�WuuEV� ��&}-� a1 o1�4!Xn�?2�?%�wth@of6U�2�2���5�ι�hv$� �D�t&��Cq "�I��J�lFi�2�@ �m dAzR�_ 2���R� �7A!�t7�,%�&���d:�, a�Q��}2�,�"o��>#-�ٺ %dAR� 9�b>'1���?S�R)` ?�m��X7 ��H,21%P~�&�$-� �6a.r8$7-/:;$pa��r"< eL)w�A:_$e��%5�:a6�]ag�8�C�nB��AH!ei&HS 6(!�-�� �$3[K !�>i�Jh ��:u�&G)" � dx.�-Z��Z6�>1�t�i�xY0�b����FM��!l"Qzf�H���t%�$!g YљFn�Grep�i*�D^��"� wU(-&Sd2,+e�8�(Ue.F�{ig�J5z�T%N�B ��r exhib �l�_� �Q.��d�1�w�Ca�n�m��"?��d/Y!�. �l��=@�� ��mAp&on�m!oimpai��QH4ՠ��i{ls"8!)v�perjOa�DR�pGiemsaA~�-. AW-�� ( WT�D�oi�`���� am+curpQD�ю�@N�L] l��2� ��ari�w�1� �� �4NdPN!b2di6 NQK!�mA� Mz!�����hek�s]91��r*N 9|a�@.�7]d bigg8��(NP� ?un)**N( cs�%1 g�..b�(A&G���%A1\�9��6t �N�around}2 g5�5M���A�)?Ox O0�eT" I��LDA�od*� HL"�^i9�%�10�<�P��8%� s �&r0l2�!�1P%}2,t% J2*66; k-G66A33A�4�&�() j��p�5iq�a&`q�"�.�aF���5�%p�0�waz yc� a�. Nz9 s�5noR��� (9�1�!>B�Z �fWE�xght�}d&P��M)!�p.(reB�]e�-�\8a��N+*kA�@ple�%LX�[�.�"6�n�. ABxgk���inAW�KQX.����e�0A"r�+fm�5���usu�-a�D�8t�t64&�{�s%GtGg� b�s P% he*a�,"� .�"�!�a��D5' DespjTQ"�4BXinɾ>QB)�(��n��mR��e�NO.z Cz�IE�"D }� �Q>gUR�*9�!�V�v� �Alogo��v�!��z!r��!{inIdAI� �roCd�� mpet"advipg�TK$bo�u*�viag%_i* NO*^tab�`n�i�"G y�Mhz+O . �NGT�t1&�o;�� !c"�BV�fa�al1 y�)%�� �2g5"}R�<�3#�ngE%;"�a8"Qa syste\aS}-|93:,� �����5 A�0ght-forward mMlr$xtend�A��["�MA-4 �*"�NKX toeK~S�|A��\,6��i\ d%A%"tY-��;2� aF[� =i'T"���X&p� �m".e~9*� -j*\NϞ�& m�ZA8( 2/5�kas �!4�&�8�23%Qye�r��6�wH !E. �`P��aM�up!�2SD25/12�B�"�G�'K"%J, �L"�fi)�n&��qA*��6�0gh%Q�9&eM�� 9:m� �FJV!��LeS �J�8:�is��gR� U�ן�e�3-Q�nOeio���,D!�.mN�겻Q, ga+V�̅�> "�`9��(�RI�m:plaus�Kexpla���!�;Nr��may�a> ��1Hs�|un�|)<�O� *�ݛI!don>�I���E�!��c�J> ͡�QWn trypan�ia!��.��;�) [2SM� ��a�Ia0e*FJ{f�y���l% �"poi!�(i�1� �:�M�M�i�nq. S"W���u<aWua��MMaimAt� �,J �.�!�"`r6a?�� �s��5�HPUJTs�S�A�u�cng >�7did��%���hOm� �q��de�Kb� s so!���!)�z�O�CS� %;�� nAAroGK3e$�5I �%�L Inbar et �b���. n�P�N�f.Ug>M2��� �_� y� 23�×10−4�<ata�dB�%T�l��A5�h!�A < Pto �1a5ior>�A_�� of�br� �T( �� ��)D1�r�  eeI�"�.�nA}���A���"ZR� t��"-�QN�cj�Q�)>�6�*�s outs�*�5#goj�u���"R �rol"�m@)> lociqa�uI�g�,r.y�' ��Ŋu�=3!�'�N] )a�M�:x $�2.�v �>��2�# �N�pb, tw ��ter^$g� "��! . a)�*a0Z9�e! y%H2�2^b meth9�employ �H���N� A���/�N�6��3Z��"�5, m-�eR\ ce� !FZ qi+1� y)��jP!�yY F�.]w I�.9���C��$T . brucei �dM;<�u?�  2 .7:_ wA�*�2o(am�4n��� U . %�0�U3�d.VA:"�\�(�j 9�!/&)%.�N knock dow2g&i C=�..� ] �!�%s ∼8M(�^z�~+ ein-�$���S�x� � 33 Mb��"[|�<4u625A$=C� qui�` to 133 R,Zbbe Won��o iA�m�dX1�=ofy�al' �2 e85&���&���2k. T�"+ve��3� Ac�o��Jɳ�Ul�PiL��Q�U��� omme0Q�e�A�fu�YE�a h� game�f  pa�Xɵiw( i�s . 2n+n�`3S"M� lian&i~on!�E2.$@sϨ�[!�}g[36 _m�'rQkl>� &j[ME��@�'�3cle�ros?b'(a0��[37#>�G.+-!� 5%)1']j!��& �de*^����T�ca�:ltwe�HX_�bisROrt���$!�!�si=mGrWeJ��H��"� m�A�), w�]��9���i=*B�n�x/�si.Y3 sh<\b�wP U finie�U��a%Aera�0.T&� scenario �ԵQ,fb��pm�u l‘�aidiBfuE b�,1��qTA38B ^?i "B�2i���;��&׎�Z&�F�j^#assoc E�A#e�!u�pat���vi4&WK0 �F*QB�7ao*�2�:;>c ��B D4 T-�"(���I�I�&$ IFN-γ [3&�"��d�. B�y�by� z>d2�?5% �e&�a''�$=�"�7'Z�n*� !� b���%E�$Candida alC]n-*� ���O��P��cMua�Z�"icU�F[4ݲ Adap*(&=:�he&Ji^e� �fu�Fn�h�r�Y�Za�oti}:/��1�q(� "� IW�[y � C*bbEĕG��a��0�.���efno�orb�"l� ("hi"�%�*WA�ab"�9pol {�F?�y6;wo&��s:#1��-�Mm��e4/5] s � ) A����@� �=. E*�ai(to z��!�!�.� T +'"�<�ga�a m�clarif5�iJ��W�gIn sum?�,6re G�F.D&+��a9�"3M�A��rory��!���~o6�htr� Iu*! ��lqueMXMU��*$)9Áe�c �hI�3cbМX<fexa a|�E �low)(� �#� cryp��lo`)�Bsprea"��%(� �kYIs .0vZDl( VH�*�k&�"Q%�`he��ble�Ethna"&�\i�%s�to g(� �t��B�A�#��/ HtÓvE��)�?R# mЙ"%<VLIHIV-V�S�)in�it�Ls�E�@cha:=e&3>a�da� i�I> �2u �seu. Sixty-�N(5T��i"�>�o"*�ch�()�(�)*�S XG}s: ��B �cri� spac�A ( ITS%, c�ine!�t�o B�#pb!� HASPk2�8.;-&-�*�c�Cd�i6��a�[ IKW��� y�%\p����))�'s.horiv��s_ZCEnorthw�Yrn9�( 36/43���8290 bp tG�6nor#!( 4 3"7411��l��w1%�U�� �� >�e-�x~)�AmerZup0�\��Hv��� "�3�( 20/2*�eB1='456�o w2 (�*!Oor 36/)n"�I��cdanu N!�j]$Mo�@(bbpa �"gR�;6le Keny�M(�JWrE� v��a 6 ��-Hw� reso��on mel@~HRM��8�B ingu�A&xd. S2b9 =�R*e$Sm恵2H om��:-f�mк ic 1P^14*Ӡ�if�A� "��d� pep�^#,�1vGr% bko1r,��r�� "k�!C�3 �S 2Qe�Rx�g*�k�?.�� B1(%$)%:saM��J% sm 2sQE�9�pin East��� "�takݪt!>�@j��diagnos���#�vacci ?bj����bnti:�. �Gb�d*E�e.� 5�!���� !z�5�(�"(onym = chagasi��r��k4�� RTCso61$s kala-aza�!��/r!�zfa�ifU  9):�YG�CIZWorld H� Orga")� ( WH�@� 'pX }e�sls;c��c7VL��4���v%,�!� ?���#death!�nu"�a�* �89ao, >90%�3"�l in Bws Ind@ub�i.�%�*C=�t��3e�iI�̩V_ao��_uda��9 !T"� �ue=16d�D,���W� ���;y��(u,2�tI66k� ,�FrO�*u :[ndA�ie�?jn� po�f wp��) �,!'(#$by6 ~\��&a �x%%�dog!��#ld� ��acE a>W1oir� "vt5X���H�ugh"�owFrE;�&-f|)�� �!$2�� e�H��rd&�e6? gy ,"p r:� � ,-2� epiX �'of!c�7uE 1�. NZ� NW�3�6Ir/6�V�� e:�v }a .X%HIV -+� : B$"1�fo�m8(Metema - Hu5� �,�7e&�bɻ�x����>a�i �� og&�ycommerc�mQu�X �sc�ed Acaci� Bala esP*�o��al ��HZB�2�)Biv�� �%�"�!a1n!�U�"��<I"a1 grtu�{�N)��V �}lu�C*E@"X?({u,�v� igrpretur�E�{��_u�9f3iHap�$b�6�#d#a;��C��Xl%�-ӁDfyp"�g0r)9outbreak��!� $ibo-Kemkem�lou��Gn�� 6�5l( Sa�6e��maiA��M�Omo RY0p���Se;�Woito V]y���M�E� Q�G �$�R3 savanna&uAsgW[#m �nicߩ$i� �asM�swC����A#A3ɬ2� )�f�-cdiSD�� )�!ܥD�"tW'/children� youngʥsW�A� C �� �UM(2�y �# ��J&�BB!�-Pd F&1�p ��hw�n%!hi=�O�A)��:ro"Jt!. MLMT�Vnd� tech��Ax)��vi^ taxonomy"S&� n"  u%lyx�2 ~ $archibaldi!h!"  /�U�c�e"�dhoLE ( MLE�bA�e{�zsi��n =upAL^"� � j �|�&�#q�%ier p��"ё!��.v�=�=G<*C*3�*e�oa�*I{j tify�t�� �*i+s� �e2�Qa*�e��u�_J' �v��"&��eI�14 )�f'�"�vQ�of 90. .I�!663|J�C*���'"�6� ���%�Nafwhr0,� 3`NW�d��SW��s� ��U �al����-�Q' subp"hGQ'�"��eneas֨� ��5��m�2��typ&=%NWe�SW>Ua�!!0���p��M!) pedi#Ka�a�� l� G�/�?� ~sf7����Q A+%)&��v1� lab�h�s�Ao:�= hydr�¡�cyA���6���a fam!U�D��)��q 0{- e Lmzo16 �^,&5 Ol1aNew:*�&\.�Rf�����Xᆁ�*TV2uA!�. f)C� h.C�;&o�o2��*���w�a!e�9ly"�[�ya�.�yA��i�A�F >1null ݠ!e�Qea5mTC 0or�")��"e>)�%�}� o'� �{a��&^X�ez x=YP�Y$(�"�� z�%Rat � r��(b՗ �1�B�2��eP��F>h�\/janHVL ��@nd&8 |��varǓs�I 2o�i�a �zS���o1�[�XE�6�" �"� !�H9��a� }�Z�tet.AiK�&^�b� �A�9�( !@�sE�,��5"?!�f���́xt�QFrň�>�hI >��g &oa�a fewV�w   ( n3 !ᵸ2 )���195Dr`O "��rA�� .GÞa"�- [31]�"� f��F��VL&V��by%�ijM�(nh!�"4n ("�a �-s��%T hed^;c"?LV9� ,HOM/ET/67/HUX� � ����663��2�1��Ή�AV ѩh� v�pvG�2\ R!��%�*���� a�?.&6 t$se.- sp* !2�&? i�Eȭ�� cr9f;g&����p �A NAX a��qF�-2�*F 9: �\��2�2��ˁ�����1b��P�� Hof%�2�o��� u��se.H!‰��6s�kc���V�V9�Nd�bBHHelsinki�$lJBo�`:�2e���*�I "Zi�ml�$view Board�R�,"�iFy�X8s Ababa�ip} . Wr3�* �"�4e,W7mn icipY. .���6a��'2�=6�VL��Z|>�as!+�2�%�, see3C�ngde�G8�e/HeE pH48<^NIf% f>[|�qb#+�H-aCex<6!�%]c*h5�~A�G�za>0� �:$, Minneapo� , MNL6�x%�2W1�,�A=,FWȅ�.�*�*�(�rby� ��:u>�2F�r�åa. tDz ��� ug��&�&in �zS�-�C!�b� ��f>_�_�Es�Z%���*�21( RFLP��a3.�CX|�.Ap-w,4(hor�XcpbE/F �J��%��2�"i !�2�ɼD.�Yd�)45-GTTATGGCTGCGTG-f|�Y4&5-!ha� }':m2mdoco����&"cType-its�Kiqa��i#1�8 µ�QIAGEN B$]�J�R�q�( 1 µMI��>.( �7�;!�u�-p�) PCR-+�w��( 9volumei�l/��"A�f�]�+E�.M�2=at e�h!Di� ����215mmi��AHig]il.k2:k!�ram� B�tJ °C/�70��s;"RM!#%6U)홆�{a Rotor-e� 6�h�-B=p,4Bze�bCorH� Life ScC , Au�li_�. P*-!�����3�&B ��,�ng/�))�n�H? 3"� �@ach�+X=� %mGc4�$window�� ��85%'��!X���/�1z�A�!Acur�(�\r.r Ue%f�A �pur�K)aWiz SV��A�A�l+ n-up8 5�Y �yegeWI����elu7 !D�_dA��b�er��Gen*VT�� ,� Hebrew.z of2��O`�Vb]Pto[eBankv NCBI!�S%2Eu"� )TExPASye}* Too�"�web{5 xpas� org/4 +1���� :s alig6( rCLUSTAL ��*fw��eb�5a��uk/�4s/msa/clustalw �3d�8ar B-�-epito� "n� nBepiP&�ABC c|�� ucb� dtu . dk/_!5�/2<h.2im� .���,/raghava/abcc/Fc. htm��� "�}) �6x6. !=A:Iw��N63N6 i2 &�"( h.x�)8": 2�,� .  � %5�GA DNA'mGf�ve���q ITS1�\� )�"bVA�J2��4&j_Wi����o�K^�f� I�>�m 6S F"�Ai"�a&� c� Xb&G'�,c��*s by H?A} BanuxDS:�!�[("�cpbF g��� �D�O � a 39 ��]M�K�lc s���/��U"�bAlB+9W� �� 1�%y �is� ���! � 5 , ra��� n 7r�740 X�g\�z�c�8� �� 1$"�zc�ce"E %two ��+�^is�"c(� v*7V}�a�or� iaiyFea0�,�h�:���#>��x=7<�;�f�J!�M�ѽ&Ne: 1�allA?n��K0�Pu �,-�2�"-�2�>o�+�N 2�B�P�2A� �FG�B�( �0SD/1962/1S clbl��Lda ���$�Uk>TsU~�IL/, /LRC-L792%%Y s LiE_}(TN/1980/IPT�Li��%!aI*e�.E�M/ereh Oaz�5/�%���+�l��3h]�6c��"Vnd �K��Q��X�2y��2�e� =�� �<Ű*�!) �s <43�/)��2*�Q"6�VF!�7"!� ∼6�/[� e.s���Nw�EN*LzJ%�a�A�,�28T∼��g"yA��� nI�!*2� +*�1a49�*s ago-9#�I�.A=�T� have�$7(s9 ,ViP$�4 ssag��0�#� *O��n�� �"#�!-A-@�2 _�f-�The">w�E0-o� V�4a?,&3�f FV�5jEVL�tL� Vf�5uC.Hi�n5q6k4:_f2Z 1:AT!Eh36�-Af1k 2�Y6��2� e�_r��A'q�-Ed�s<9?v6:qK�x�Sa g )q�.gB)��2�i&�6��lE�noN95�4� �%)�+!!& A ��.�q0@)2, *O 4,t9yM�� ;�.n�Lk%��%/ k26-�� eri#�E�36�E�"T>5����e�@"� N�5 :an�=) �b �01+( LDSNn�, { pseƳM37�6.:�u!|�L�hps�U�Q\!�bg����.���y��2X!�!fa:or !q2n , �Fub7�i<�W�11 NE5]6��' ������1� togeaBI�A���Ffp��k. Eߦ�xZ E,62axF�#� to n��bo�*�4�>L l��F^ �oi����5�� AM55!! ��A\� %�"�<5�9�U��E�1.� � ��q%�%���]� N$Negele-Bor8�cl�e ba/wU.�w S�j��3) �nV_o (e�scree-A��fL 9�) 0&��c�$h t{AAc�nZ�U��Lt!q�s 6/7>p%� uts ∼50� A1/75y(a*A�� ɐ. B : SudaR� � y&q&%�YX Ua�bp%"M� �[%�a��"1��Wd  �b-- .h �q�RjUg�_1 rapi�'inPS1Meq�@�3.�Ÿ�JA�$y��B� "��"�+6�,le� uA��is&�!� #V�GI�Ae^ t�%t:3�+ .Jiq �-showgQ��&" ׅ�-�be �Ů!J�.Ua>�*"8A�e��u��U��%%�, �I, ��T- LE�!��f�D AD���litE�� 4!��="h %V�Zw*�Qm-�� &.E�B##15�� Genb���` N �,: JX088380 - 9�JX29486%( }��s�@,:D0�� ��.�0!�A?]:id5��p5�:=[� b ͨe6 2t grou�ep in Ethiopia is comprised of two motifs , A and B , 14 and 13 amino acids long respectively . These m C�are further distinguished by the .NGHTQKg,DHAH present�*4central region�Leach peptide ( shown. italics )�wo#�3 ( PKEDlNDGDG )sB2 | NDGG,5 81%t� ss foundrrepeat�,Ure�62 . 59 3% , 2:,_PA ( Figure 5 , yellow�6blue )1�observe�1�� C�s%�E�aPQ��9��s w�1�)�� availE 2� .s��"-5A)�!��ters 1aEw1b' Twhich both give 626 bp"� s�m��-)N�ofە�A�R�is!�dicj to1� multi� ��ar B-cA�(epitopes usEfwo�<program}T6�*?a2�[3�h36 MA-6pr�l ( 16*�s��8Lreshold ≥ 0 . 8 ou 1 . � ��5 !@5�(.�%'e �"panID junc��A|AP |L B|A�  84% )ya uniqu:�UQ , K/�D/GG |��!.ccounOE� 32/50 ( 6])#se.Q6�"� h6 ��morI4edominant , 80�00"# Jw,1>sou� &\�z� 2eI�cona�Y[B m�A��I]��vs�N=�u�\>�a�eSCrar�Q"YJish e�Instead2�9>� , 75���^co�te: A�,I?a few���z A |/]g&�)��A�5 >��f"�/U�. I !�we٨63 re� ����d�"& _ patient�� s�E�ry . ABb ��L2�Cree techeJ�confi�g!Ş finding!�%Q��1AEX5/,Eesp[ � � VLA�%$!��ly!�� �&�� northwe��dF-!� eas� :/a� o!�e2�A�–���s�o thei�r �! HRM curvE�A��硫ino popul��Tge��(phic origin�� firs ����Hmicrosatellite mark��%&0grouped Sudan���2,<( Metema , Humer�}Beless��se!rta�%q�x��,4( Negele-Boren R(Konso ) [15� C�5�/ lyk2�!erhapA�*�si@ �Wy s�$fly vector0P .!Pentalndmartini�� nd habita�re}NA�_!�qZ. O��&c) tw�*!'6�.�th!�.R,�as senvPtoOomomyci�� have|rQ[38!QI:.�%�2�uec� divid�to. E@s 2aq i*, 290 nd 41 �nU|�"� so far g���tsu:^q) -Yj�2� , [1X��: � Wh!� k26-�����)!�z VL ( Y25?4HIV-VL co-infe� & 11 )Y8 er!2 rš��eduPvJ[USd3�O�u�, 3/4�J����Z �ZVQe�w&A sub��W��6��2(� post��EoA��oneA*� �P�� puta hybrid/S genouED";A���UP���� whengER is)i��u' =1%, b��A*, −360E\−�I�2 �*8excepu�Y( AM42� AM45A� AM55!� �yX*� . S��:��sisIPACF4 bsom"xy�t�=�;�(i�� ��` invol*��"�transmi�� ���H[ we dec��to� s=al�i1Hby)�. Sur�in&mǕ�6hͶ�3d)�g( ∼501��65��)�Ros��%eU/n.q%mR��� :��2�B����Thu���}e=n't� m!:b�direct c�Y b͚!�MM�a)��i�#:S�a@ $)��aItA� cl�wh'-��%#e2� DASat�-aUbp. �a�MrdI�~ &�isMV�r! req�humDigrj � #8 cult �x� c �� Q"� -�s�4isF�� ��!��V�"�p5J�>��6-�1X,�T�\K ��K!h$Omo Valley!�re6�by��C may]I(�!la to � . M� workneePj-hA�ka~�q �% A����syplxa rolP<0�)�!Rlocal���&8 [20R A����ime%is2�y6�1v%asM�� *�s var �!�ܑ�fragm� ,A�#fa� u s"? *,polymorphism2� �� "~� usefulE�$rapid mapp� of �MD! a�) scalDS �1��tei� a pot%ul vaccxcandiz,� �A&5)�A!�2�in� X}i F-(*x�V>MA-a "%.��6�%�> 5�a�Q*6�� kdemon�GE9B�in)(�|VL9�2t"x p.3a�>�recogn�b|rum>bo%B�m6E���ext�?� z&o ��!�yDQ �!. 17 aF�, GDGI*�e-2]re�, ongest�mQQ�[41��>� \ Zc-2v!�6 $ &�"��Xa!kur�� ya�al neu� net�<( ABCHas ver �a"P, B,>�a ength�jC("�in 16/6rresidues�!��6-S��N rank��w#' a sc of : cbincludzh>�� ()�KE.  ) fr �2gux1�s)!�,$�i:� a}i^��!?r�*aA� ��^!�"�� 6a ()�!. OM e, hg#n�#!1$l��(B"1%;�/D"h/k*�toE��rA�� V+� Z$& >&j+�ra�a Y6�s���0���a�E�.g .yN+!�& ,M.; �GJ7 I�667�"N' �ll!�i&�!see%$beQ$.�!�.1vbe ob i�ei� xe�1�or�"O %AaA�%�%�0��(�!-2UQ�>� � �eas� "���mb�M� Dogres���.k*iatex�q$metacyclic�mastigoQ'fi&-�u&&a[42�e mmun\ of BALB/cWe�#2� �,4&�labs|)of adjuv!@,U�] rotecCD8+ T-1 e vi� i�eA� plex-mediE�1_ aFE��A�nat��!�� ag�t aIl�^ υ,"n [*� !�e2�[� re]nA���%�\A�erW!u2lE[$%in��.b  �%\1Tdevelop�off���&�ed �fu�A� �� . - yetFaU th:&oue< , O-� ,��( Vianni�b�%ien�� ed%-�#u ��J 2 MY2H)#�&d'�(m�� vidu�(ae[4M!�4,.��en{"� 9����M��gn)2"z $phenomenon.� "�.@Old World Leishma!, A�VL��T"e�ort sug g�� z!�a�h.o+N���� .m!*!�of 21j�'�'f�)��&-0(�pbp ) didM �f�-y���iY@R�# In summarIA8&� �/d/!�arrang�"be6���6M &A�BqE ���%1A%&#*��ESa� i ��>Mth�"ca��e" ��E� U#B�A�e�u�0�on��h""! A? �&8'inv�g�p�3.ZLReint �1a�om@-ntribut�gn# a� tD(di�&�of%\a�x m�@HIV/AIDS pandemic�x�assumla��)�� saic�a�� vel!� pert!�<lJ�iraAvalű,� tic�lyaS!6c� o cir� �for�# CRFsk InU ;.,� ra�-K��+$a tendency!5c�'�}sel�/ad�Oag42�virUw��# �$%�A@of breakpoints—"m�i�{b�ar5,delimiP&%fstruc! —w� dev�Q�e�)y�Knul���/ ��whypl� ,�A�� / robabil�)c model�)E$copy-choic>DA�af�&� �6I6m�eoB�A�s m}2N��R!9�y�� c!cofi�-subt|*UP%���a5�byf/)�c,bn 9stKE�dic7E�ids!2"7� Be, depE�t/� "AI0t��%"uf��pl�-=j>�� }(� �$a s�/ over- (&� d"T envE$ )� �+*sh�+�~wit�Pgaga�oS.AT(D)����!���w� fer"K m�b"�5 inflb4A�Ai6�p�0spau�of:'.t ��Ten� e ��=�q�Dq9�7&NAF " likel�Ube su�45AAe2�a% � r���a1Y�2�eapproximI�at>�!w 'E�!5 incr *��on�F�E����� U�ew���sleast��"i�'ha 6Wba `�6 �r��it�ure�%� d!��#�6-��� &�cE�a"� � 'mPat�E�a��}��Gi�5�N!�e�.( a� spit_� d���|CntSm�"eA �vi�p"�$!`�0a �*3B�")|#.�8~u��7�r evolu�of�a-1 . a' ' ag�Sof  ,&cxhibifE��3%dQ!� C�EeKrror-pr�:r�6�cript��.g.� switS,�RNA t3/�_[ 3?�<�o� -+<�5a� �l� )t turn�� [� [4]—�: f�W��d;:�� M�"� �'$e [5]–[7Pgener@07extrem2�KU�H" #A�T a1�j�!� %}wh' [�$A�c 4�epi� :it4�1or"0��" ,uB�� key  of� �1 ef�#s� [1-:-globa�qm �A��1�g nct phylo!"�<�2:���5�f e)%e�r super!H!�usq�&� P!iu�N��%�aa�teJ1nt [12%��'W #r0OA�mit&Q�"�(.�, i .�,� !W&�ofB�2�,��uer!Ia C*J .S Form (I �)gA.�=1���!rm� %�5�:.�tre� nd? b01 02.A� r )A�� a spro���ߍ�]� as do cerf9�(Ŏ V ly C S6 �t�c6��$M1�� QF!�s�;- CRF Aa�1J6;��ha#A�e���2&�c�[lack of6)�5 E�#1�� .Z"wid~2� �HIV��A� �l�2� � ����+�8�� ��8.AT�e", enorm�effM H/x d chR9�H�&����h e�T��precise  Pnd-�Zj-!6.! � *� ir m:� Fe'V a� &(%�e�fe� wnQ� ve*y . Gi1�al�:yGed)�n�V^to �:Ee��*�2�ls-| B~.'A��"�neuD����6�~>���6%� s`adequ� e� Ty6�� AE�yimpac!�a�al fitn�)&�. F("kn�D?+H,Y��Q6cmh�6�o �J� %#v!1]|*�=fe>!w�s�as homo� eric runs<�second�2�.� . H�we%Gp�rlmx*�y��"� "}o���MpF to�?��]�stableFE[� Jd�thtwo���� �2�a�lJJ01im�B��e"8B�c � i�7 �&2�� s&�As��xnas�2��� !��((no��o ��r �Bpt [� . Af�?-i, syn�]istY �)�Gc/+ory . DiNd!5u*z/�$&.5(��$in mismatc�-�ehe hete� plex!Y[�2e2�!�/.Ym9dEhe�. An unE$:_n)F3′-OHNh�E S "5G�suiAt%�>��0a�F(I i2��,�mak : sump /\�  (� ^HY�,�+�hHt� *.� ���&�'��regarB%5q.�,�g� >�&�!{f�pro}E"6 ��7tak"A�8M^�.�(co-packagedE�� 2& �00�O Zx a?�Sp B�4'  �a��4oGal.of 16� ^ �1S"� laborak �=�riS�t��no�E�>s�l>� �int-{ �MY we��!�ex��J���!�I��0.� b^.P �<&.� �a�est�(>���Dw0! w/<s��-{ 7@��p4H}detai� zst)ng!�C�F�a�9 n< . We &�a)�to5� aJX�Hq"�.�.G��* aB�R�:� 32�w'to� $j.Q� of grea�H�7�/:&>� ��yIXY�. �� B� }iC2�onN6r6X gp12�H�.�5xQ�2S �A�r!�,t�+y � �!�ZI�'s � ��1a�A��evadJ . Fo/�vitroj�~UC��tlyo;er2�,'e�&&fiv� cleooO�0�2S alig0 ��8tcv Ehe]� andom 2w2� ��N ( P<�%05;�=�3inset &NC , al�LE�?2TGzo1~?196nd 25E��re�1e `*�& 2m2�#s E(�lyU�-S�$�L�poo�Xth�reO6�lo!�t!/- ( P>r�B�IEh)�I�E^"F�-& �.  ����rZ}ba| �E0%�:i� o@��2<�ř�oNS�%��tya_���!or � ����2� "Jo2X !�by redu"�� aQ�&a���W window��/Bancho�YͶ5′ enH�P� |(ee�;hodVW\s�"�ly4lap��He�A��[56.=-�<� m���o8f"� >� ��1>B4 .t���Nwrbz�a&e� d nIg���~.�6$" �P"�eY �Ap>�!� 9/10!�!100-n��� fall=�/96   ard m%~D �Y/luJ)nB3C;u� , Chi2��Simpler ��&T( i )/d�&=Aly� 2+( ignoE�FG( iOpro_�&' A�%�21.�*DE�e:edk�tyq,dRd%���.� ��_6�&1m46�i*b :^��3�V3B;�$��21ጁ���>�Q�-΅�&�tf� I��!�au��#"� �Sr “qk@<” B�*an F-2!,M"Pi'Q�i!c� �����ɯ� �x�]ata<(XQ�!ed�Y�RE�O *�l�pr)�relY"95"� R( � :P .��E7m�*i*N.U���)�s �A+ q,%"�!.q�,��%0 �a6�c"�W�A�@�ty�GU$Los Alamos��� DataO�d.��*6de:#Be".� deri!��Hletm �)"� �uM4E A�� #^s ."#�g���X90%( f��tKterval5�S45B�)�]'9Cm�I��� �e+FD ���� a9 ly mechanIx-�—mai~.Oo~�5��Y(�?�"-�e#2� �.�W6�%lU1&��m!^t N z�#6V "W/��#ƴ#:�W��� orme=b"pY. � �B)"R�; 2!���A;3u3!X�D If"�]G� -��J�\Q�� �� defiv,a�"URu"��"���r02�!�:#2� elseI �u��, j�%;� � r#2=9'c:(^�Ɓn �co(�#"w  4 . ��<�Hm�mmmRM�ty .��ic�s�MX.� � 6a�-�"%b�J�tRM%���b�U���3�u�� Bgr�k1� 6�cof.�s2�u36%��"�"T [� :J�y s u< �t� o�)a��.��Ue;.��ny�4�Cir0F3��C. App�*e> ��DM�nt" *K��"�5(���Jin�)� �b�nt2�Rb's)�),�K4ar�&*jB�7)m]P � �%@&�on�y9� Q� v�έ��orJ't����kvalD>s>/�Ih&] N�e_s &�.c�L�U� .��QvK2�ZG-�U!�Ze.�#ko�*" #a�^ *!�2/9%b>�+y-t e|(nt�.���a�..�&'T3A{)�&� ��a]�shutt��)>'�tn)8co�I<NW&a�5K/ ;2G�4e\i�c!$ul coinSF8 S%���6:$M,�]*�  �W ��J�env's&� %�u� back�InCZKn$M�2#e�%nv!�Ũi���&Z��vteg�uq*m�J�i�E���"�0��5ff5's"�5!"� w �to� f �#�O�`�'%a�0�(*UI�subjecE�,&�(p0ava ��,=�A&v�(on�'s�!� [6k[B �7!�|(�Y-�6�itsel�<�als��St�@.B.) :\թ��2�) *� V[ I���8�7�.uma*4��(�r�$E�J ��Z0�in)A�>�[eC%�Ve[�!$maRn��%�9�%�!$^nd./g� �Utexe�E04�*t�RSO"8r6��Xb6co-&�7� a��6�7}G� , puri>'+Azn7<��0�folds [aNor�G� v)o-glycosymV?61] critO�E�of{$)�*�:[3+,"�(�W (E2!�"�a�\�i�e�+2�� �;-E)lgen�#�6;emphas�&�"�*KFa,a�-*�n�T� ^�B �IMa�$s�n ) a�r{6 ���F?du�VI!mVP$B e ��I��A'�)u�%�2anI�G�%�Eby?�Ars0#�,��O;�Q�:fk��aloa;&�5 \..,=E,var.}���( esca�_�:*Am rol  +�� episAbci�oe�o/34]�e wYS�I�!~� 6�hotspo.Bassoc7d�� drug�w!{�[�+37jIn��,A, fv2q�aFi2e�!9'�S.5:q A�.4z &� g�(ɕ��&# �rex�%�bea-� �9a�oE�^"N62� E��1e %�a ZyZ"�*!)12� ��. �*���m3"kR,"�#W#����%t"MB��,i<,rD#�#��.�f6A2S��')M��.��X_e*� }@cal�.a� �9 �yŴst2 -jW] �!!dU Q$]�%V�[�ijE��'*�.y )E�� ilA� , pb��f �` a��A��6� A'"�"�.Mn( ] ��@4�CthA�9��o�'J�9 Q� L 6�2����/)V*�8to zer�ma�:Q=ZEnzCa!Y# , bRAc")m2�Y�1��(>!I =�"�!l��-tE��6�go&>� e� areA��C!�cb.2��0( bb� 1WM?!�e�B�dowhMeam�2)��( cB[ne�GA}5��u"�!.8R��a��#�c�A 1 by pTp_s3 ,  .D!�%�9��su�YL:>YLall�l At �%�f��;=C%Na#I?w�~Y?.QB�)� �XY�"� }#% b�f=z,!>eZ m5W* v�B$�U (|� �OS!j� 9,�w6r}�Mp=�F< E�1�b!�P)Tparam�*}#�1_&~I%^+I��LTo IC=6 v"AYα�� �  best��dra[Hhro}O���i�9~�?yɯ���:G..�`�1��2V�)t�y�Q� grad@�(� �c�X�:d$+averagY5� �.)6Y �ngl.t(U�� af� ��g_:(M�/non-M�0lIe]he�)��$�� .�*N36ny�C,bU=���n Jav�J@e sourc1>Js*i� � authao�quA$. U�c=��80��V!: #T�v [i2�� >.� !2Y�"G e��6�z �� 400�m bit~E�voA�“�,#E�vPd 3242, a�2y(X of 302(�ibHw$ed unclass�r �A�I�of�M �#n.�  M>�# ���W"� cm���apJE%/� c&�i^# "���� �)g;0g iner�W"&9 �@��of �>�I�9:\&�&��ƹ�ſf2��-� *d�yp *� e��&R!qQ��2� g^2�!�ݣEA�l "� * �c.�a�)�s" "TXp M]t$U�w"i"�/���a��r06967�j1�{, K03455;*uY B��AF06712�<, U888240D0 0549.�=,I 16412 }AF19012Ko{HK8232KJ�$AJ24923.�K]$S �)+�>toe�&�a��"� Ac83L^�$au5� pair 8weJ'4� '& .��<_"�A'�=2cM� J�Z@!�h�-^: AmX2; AC , 50; AD , 83; AG d5; AJ(; AK , 4; B+1 F , 66; B+ 2; C<19; C 5; D" 7; F;7; GHf; GS10; G6�SH ��0!(�ed6&at�@"�[&arcJ-\�҅t� .1�Com�Wo�%ll^RH9:8od�_�W osci~�e�q�^y"��G��(� �al"�,"�hl�Hdd�S�robleg" actu>%�&. F`W,�aA$@%&,D��HBayesX} hier�bt�]�"Ih�"d �B2I!�� @ *��5�V�rashh>& F-NC&s+�-SM ,{ $^�/=themselWkI ZZa�^�aO&V K�d��>�f�5��/Z � �M�2�ce.�;9�1�g*U� rele�M=e�-~E�&) ����Q� oB �`f� � 2.+=,q"�>,a6U'�w ( HBI^YameEV��con�Z ])�iso�G���"�πce7�YE$A�� �r�h(a�;�.�Qi� �a�&�"p�_Ab�B�theore�]5nd.riz e�"9�-�e"l�!:�� er�/)-�)�met�. M�$ "%ObyHhob��outli�m��bi4,towarAve ?.�� �aaF�� T a yYa�6ac�% y en�w����k� 1�on�em�=%�er@)!�!"t�.. �+&� aC:I|1��#"� .(F*��hF|tis�&�inforceA �"rE� ( RLba���EX�_P��y;z�+�(ob4� im�)? i� !�e!��-�= taskL@zm7 field!=AL9psychiar@H, �D h�Dz!�Vupeo�3ris�E �dis� s [3–�aNeuro��H u`Sde)!\al�C<�%�`�Fyna�@�F6A4[7��!*�yab ct�5f%Wal^B , 91%�>!') �Es heavr�P�gN�-��/ab{6v�&4 !8i��C�#sti�d.R ٽ�5�BgoKVlidg�> liza=6F�a�A�eΉ��p%�� issun=en T!x�*�U %� ’s2�nd* Dl�Cѯf"�k&fD�1�c�!��UHvD� - FZ$. J� : Q r� Pv��&vqlem�5 �RL��~�t5 e qu�!, �7 �.g$typ!ely �J�!2�%Y,�j �� !1 {)!2Lo��l���-�0�r7o :��P{%��� : Is��EsfLljE�&u"�su �Rnt-�cit�AeEkve�5? D�z�Zve enh��L�Re�� �6����U?�s!�!R�_ a'�3J-ra� W"mI2- M�1�23e!d{.�s" ER%lso^ }g-�>06;Zo.4� f s �u.W r(y!I3!+��si�M aneo �,�� Ta�ec !�: axim"�_r�p��( MCM&>m!;2mu��X( HPE )� ced�m[;��Mreg*iz�"�">a#.� ,��a,|C��bVF�"�( <�  Q�te'. BiGq�y�shA��"M. '2 "� � [aI���.? to y��~��#Y7+~e � uns��m� om�d9��fitI� �.�GP��' seem� (�ly�F2'��is���Q�FalF, �� �AK��@�� )&$ e�& HAA�s�D;�{�>oV� �e�M&�\Q�gN. A�[o�g s’�hA�ln��-.L.* o�el1mGu��W mpulǁ gambl�W�� a�Y -� R�v9��$s ? I&��+rQ- (�hapAn � cXY!Oc!�� ed m#)/n�5us>rn��Hon.���C^ !v)�];����) achU�[x. EC�|*�s]92hz�.s":Ie��w�"�<�aBt�D� 0"�#V+fi2��- )aa v��D-��s�/s&#ly unwa�`�)T&�I��m�H {i�| de�O��@u-.6�is=/.N�VJ�PG !�3lihoo� .��A e��� �Ih���^!�=�9p&�a� =?Intui�E��_uW"�ta -: g� =LaQ(i�t( edes�fa�\ ��~�� uesa�w"�2Gua$a} too}s�E!@��"X. But���!(����u6U conn�' "cp��+��PY���" !�ir���*�A5!�*�e &� )h.�"AUchbg a>� view�*��� C� ���&� (� :�� �f(rem'�elu�W�%�5�2�( .x9�/*0FJHc)?Al!�� discu�idm))?#��-f�� nRpW.�.�(��du�)Q� ly )_&���IB�i� ��I��%_��U&R5>-6�i�if&CX[� ��eD�A�e��| kD&y\��pe�4*�. ,T $]� B V }<tuaia�1͔6�!��X-  T��af�- k\ LA��*"6�!�d��E�!��5b"� u�Zst��a")�{al"�{&�-umY��!2!õ� �� �� i8 �)�A�%�by)b�.� e��q0�C>�!�" y�ik<xF�1��>`by��%� �qK] If� a��e!$Y/�uH"'al.�.:iJ^i[ukass�UunZtiW�7 ) igor&,a�Y } �^BIX,ElBB��E6�^H�  i�Li�o�%�"�nE�Zo �e� pape7h"� dA�fo��&�P ighl: !��� ��c��n%g� _ !t! m!�k �"Z' in MHNi#E� S1�;endix��a < �MdQ�y�T�2�1sea� lp� empiŏ�c e�ueQ6 �tag���'5V�. Con�, a��E�&�%tA��*���a�e u���%�measu�l! a )F�ry$ �)�po�N�IQ�O22��Bm�<e6%X5# �.�5�?�g��[�.~5goals: h*J� ��:t�a�- %s;�* C� �.�oI�N�!����6���r".Fe9"|���.�ly..��a%�� �eeYw�j-�� n 's*� ʝ �.�oe�ir �2��3e�m5:�u5oy�.�aWrwe f'|�pri�b�~>��"%}t&Oe�q�� � a�d65)Dk��l�R r:O�A�D��8p ( h k n ) = N | μVV k�"#+hk�F� �}1��.[�Tkth �A}-� U μk%�Vk�!me�UdɏA�Q9�icP� "=g=%d6��r�.x_&:!�J na�A5����;� cal�- thms���xfu� .�:g��6 g-2gY [14�aO~-�\ite�[v��cI���(�um� IK=:.j�N!)'Ev� q7�e��.�as�! step���G�Pe�a��!?*- �A� ��El�%M@�J���/�D*��6wC.r,.u�up�d �! �u�V�.:dref>�e �Z a�m "� m(a�%t ��% .|>’�} ;eni�[aFN Pa�A">S:s,t�! i�9( deno!�θk�4͙.�:�;4= 1 N ∑ n θ�c���^N�!hJ��o�Ta?.f.� x ��MQ�]aA��]attAD !So[ �+as�3�I6hN"�<��y M���e�T!p ���1J* suHI7� -2!.W!]:e��*�[�0)�o T�i� N I��� aken�:��M7tr2l�p51 ��ac�,at) e.�ns�A�.r�&� 2�e2Js l)u� 7 ��P.O��C !q5�1o��,N !)�"�~a�% a<Va���"�Udqfa:2�,"�sM+o9;&��cQN;#:�  j ≠ k� �%W� 8i�0 �(fora!Y�(�h�| iBICɽ&j>e �:�)i3�� �e� � �]:�.d�#if� ?U�Fa� J�X"� toA'�sb� N2�� MU%� )6�O�^�""( 'd -n9Xi�} ��6�2/,ch�2;W<o�3]^  �.A1 %��l#ng� AG5f-A��*nOopt*�� � e�ip��Ő��PEi�" i � mpanD*by �-�>)�=YQ��Ճ^ At�@��o9 y1�g/yEe�e�4GK5��h :�co�a�~��-2� 5.AY ţo"=�vin{���.�2��ad�bQ"7se)�Rv!�B?.me��dA�’&�vQ�� �G����+\ +D�x�qB� �g�m ŋ`T��G�A- ]ic\&���;%�`��q �5E�!�&\+!�tronX�� *r!z�� ��*F ���I� , mer�K"� Ay� � Step�5e� .In%_a�ciQg�2e�*�� E�,�l��ut� �cd!}j�B&E!T �M�OAU2��R#�'�#�E�m]%��.+)2��-�J%��2Q � hiev��%�a+wkop��*�)&s" A��x.�l1-�����:=��lso� 0%�w2gh�)way��1!�u&�0Hn��� e�. �bmean-�(E�alII [1)_�I O�S e&' 6�C# �%�a�ea�Ui@�ksnt ybl8>CF)B�8VT^�9�c&�0&� (� Zm[�0"�8 �!y*] g�T+s 4� s: "�4� �w�;:-A�� s �-�&� po>��e=%�.g,R?�FA�:>E�*vp�!e�fin�b�"� @H)acAj�Saoje��e=Na�? & m��maHi���b".H.�[(m�Ii_���0 fproof:f6nA�i� b��!\!��9�.�1$�q��! 9(@-5�.%7I��dOFv !k�c ?!tX m�rk���2���ϢIF�un� �1�bw   ����6�*`cp.�^A�������.� QN2F$2� N¯ k: N  =u�rzaEus )}alwD5�kt���"5�M ; � x��i&�,K)kacB2rFF�0[$on �/ � �&�=� �!<�9ї�u�����in+"ah�p!� ]*� E,:-�'M �DZ"�ter5x%-+sA�O�Png�i'�rj�( .���)� �s��')�# R%Jfa)a�\r Z yB�h�^E�*� � g!,���!��Ied�N�>�me%Wcoժ�$�"9e-� . ExcNc�:�;� �E��&hw"/?+y� 2g � sp!@>�p;  &�4:�"" how�$- z�8ߵ� � ��3"�g^ce ZE{%�cb|, =984*�7up�8���0�no�ing�UT �|���A5��#��w�V�wq�&R� 1er� aI�ZL,~G�t��)��yzb :xn��&IG�1)AT��3%#=�,�U�dawH"?'�0�&��!e�]E�"�.�d1��9�a'"� �ZF�e\�*�a{&� �Fa�c u�1Y�H !:& �"� =�;! e�6DiX�2yX K�p*`�)U��9 ; %%2 � H�L�� "z��՘� ���F�(*lp� vh �& %̍ "[�by2Qtu|i :="� %kCAW� �A�:""B!���4�fA���ڹ.�� � ,"qS��8�*� )�ty: A�R",)"�F ��)?i.9% ("�)deg to 22M&����Z at1� . SZ)0 !2�, �isK da�T �:s: a �1 1 +�( a 0 +��s�E]�EZ9~�� �T&� �a0/^m%��!!�R &:T<i�S��A�Epq3��a &c@�Fv*R��� � 9q &8G�2� * ,� ��,� �ic!�Ci��L�t�a& lz�.�:�u�iTk` \6� �!�>q2��IK6!� ��.t �As $iᶍg�$/�i�wJ�in� �f������� I�*�n.��=&"� ��* c. S�m`\^��./&� yj)P-�A�,!f��&.6�!�6&5�� V���% ���! � W%�7n��&�3d� �wEC� ��b�J�ncanY["H.  '��/ }<% a�I?aY�IG�a�“Q:�-��KH� � �!�JA�҅�&)��a<�oF/ *x �� i!�-�5x��we� �=� B��\� l/��i��J���>�� A � μk��iC�>a<^Xard StuA���t-2c}e�&� �.�� xmpag�n�~+��<�,�M�t)�9Xt-� �a� ��: t =6 i<���i s  /t� � skiA�!2*�(�iaY5�$3&!E9�' k �r�N,2lp`E=WE!�x!P�p��=�Mx &.* MJ(��a]��R("Ie� �_ uuQ�_�)�>�V"O .�)�=F�i!y/#e���=tJ�:��%�Ly�$ɔV�*/��� (��*.O # "K/� �p� �[!�}��,�2��(�'&~3GA�2`"��]�rbitr>� �t_1�vF0�xΨX �]0��P <I05�00&�j�Re�C95%�Udz�X=Dn.U�Mh�E�F5,!+� !&9,�,G a�7@ �e��O���PEA^&a,a �P2[&� ( NH�E �+��5/EID M�.�[).� somP�� i GaussH�A 0–p�>�%� �v!A�*uUaA-&s� ui��4�'s�S!L���� e� �s-�5 $xW���A�&l m�L� x�(�.!b(�T�`)%�ub�M!@-�>��)��0�R&�"!1tFJ] �Ba�ea"u�  h)TR+&5"a�iti(^�I�MN )�"ow�B:rH&�\ �*�I2�dA�`,�=6 Huys*`b}">*J��q�x6�� n.J�:e�Q�#�Ditqs&�m=����1we�bj�=m� F-��M���*�5!|9.A� Y�i�xP��a::�/��2L�BJ2��E�g��a�15a fbm=.L;1�7sc�;!�.�]3~#x� /���&�L.ANpa"+M,ELbui�eupSHI� "� �*g UB#=� n�~se�*��$! 8x�i� a!�>�4]�+A#�"�  �^�n.� ~"FMFyO ��d �J���A�!ms5( Lapl0)6_�Piz�J�H�=n�: l��71�}"�"{� b�a7yf��(�I�����$�T�$�US1�� �IC%"fHd:H=�u��=C+eO%�JA��K��_��I �*� g�V$31QTs�O1� two-�.Markov�4K1��z%���V=J�sY"b�e"�t[�j�WFig�,�3plo�jK;R���� %K"��"A\��c/W#W��.u.E !eAѭ!P6�E e hyI� �qe "G� �!� ���5�u�g5D� !�� &@ "� �t)BI�݉7Lm"v1k6i"@="�I\'��2�  ,Q�WRas��o� sO�a1�$ tegy&�-sl-����h6�_%2IY����[��-b�4!�%\-� v�]+�AR t�88Cb�� flicB��"�we loo����\#eXD1�al�?rs�� �J� �!��h"kqP9��2j @ ��75owh�_"I I�_c�I�)Oa�of�)� loy1m5�vA� e\ *)d)t/�<�7A A�Ay%Q�I�at��%2�]�X֗I$2�D5Fa.�! un�P =�� Wilcox��esU�P�rs�I���l��meaA��Z�g�|izA�to2 Hi�p����Ő"I?ek��,of Parkinson\ dis�� ( PZpcP( N =��nF�'R%��~)�A rQA�pun��C" LQ� bin! �aV160qL g� "N�sL�J��!maladap�!kin��]l!�Xa�:�M\�s!seE�Nh�-. PU���oi��%neg.�"�}��F!un�A�bq�� pa�rg�o�c�9%0� �h$[2q�2�)j�!�ypA#PD9 ~�$k5Qra�a�ZX!�����qe�.�N�w�F�!&�+��O�Vo-��mG*�M%��2@ *�V�Pr�� outc��>� t[u l@tg}��qo*L 9#sEƅ2Ƀ"Hv�d&��Hvoi�"ڸmem U�� O Ń��\0�K�?������%α��v#;J5Ptv �"� . � � in� 4A��K']a�Irm#�h ;/!|ticipe]��2(�.�! ��E�9F�"��>SQ �Z.Ja4�K� gi 14B��s����%� PD (!�d.�����Qj� bwF repa�Qb��ey�a�$���9�+&. �r�r�3A����D�&�&� �Bc�P 1000YM  ac��� ��=�%_�s%�3�41e�PD)vs9�%��cPr%#1��-5I!�#Et�to Oe��&=�9"� I�� 0q,2�-�X }�)��RA[f�P:Be/=:%���6e \�9��.�t�%Y�n!!�E%e w-G�P :�0�+. In$Pc�&y * a��J�2 !�J�&4$>p�� M<)u ��)�!�Dis6u9 VM|�`s� *� ���.90 �mros��.�@''EP.0B��-�a"&oatɪ�! a�[""�dV "� t�&�4� �Z6� �t�6�E*E]>! e-of-the-�)��DmaiZ*b�Si�� =Ikx�i2&^,< so�{& ( a�Y)�"K! =�&f !�;&%� k *t E"*~K]y&N] @�*0F��s@4S`3F&k�N.�:y6tooHB & E��C[3d8cz*O$p2)��5�{!��on�?o wo�^,.�:]NED%*��F��y� � so-9#ed�N�&��^ 5����- �s0j 2�u5�=u�Fi Amѩ"�&I�X%�";>Q6�Q١�l�1���Ba7.DB�a�s�>(�9$p��[";a�́N32Dy+a�&b3A)e��;� u.�_ More�.�:'7��0by��� ��i����R%��d�KȔ�h�n@J�W� B��toy:=%��G!AE"Jiy1�C!�&�`L!�"r"D"�5�{*�es�p͹2"�*"9&�%�"3 A��( ��g2�!B����p�M &1 �> 5�j)� < RK�b� ���W���iT1�$ �tD&�m!��le�#��in)��5�}x Z!%�a�5v] Ըo  I^�>P0car& Z_.N��u���& v�6(5" toF��0�I��u���67� ���i�.�/�xC� a"5penalt�ya��!����B� Q�E{��-1 extr�hof ���E�.>(d?&�!�ii�� �I 27;�� �%!E�O) ��5���(�v409�!O(�a���,F�S.%96sb"� sr*T.�6�!�q0Apd��P(.��**^)�!��d�A�1��h1�x:'l1G �PneV% /a�dAe6%u�&�D�q�葋5�v&G 7��^��g���2@*� 2�$,uy" m�-p%�8''� xhomW �g)>��c&;g�q!c�%ts2$�@=s!�l���v 1�P.: /3}4�T�A(Z��/ LB�6-,neI�a9]�9>�E�W�q.��ٗBo��F���! �e�k)v^rr�2��d )ryT -(�Rbuilt&fN�:�kXI�&� �>�� p�eQS6wMS�t��9v'k:q\%\\ �C2� a�?2�9���"�"�3R&)��"& a�pE�,e�F 1�i&�He�a������0�"��Bh �R"!�&ts*[��&�,p)A2i�� �s o6A *"�J�%���&�2Vv<�*�2E�s �:3o !� X� KGz lead;VaZ��\A.�]aah4�A7&S �is�?�6F�He=b��]N.�(�p�" 7��E1.��m!�&N madeen�JJm�Z {�*� �� A�:�:a,B�4��Y�"dA�p*�=�2v)�=gɽA�Q�`����<D>��< �P:I8�i�� sums��1r�N��i!����to��#a�������k�[1��(A��`0Bm"l�� easyAi��� en��%(2��8 A)M�*�-%V��Z!r2k m� '. A��>?���E*[ea�D9v&.�Y��Y呰 �- .�� � ��A��>.3aFvm,�ZkKTSum �i�ar"�%%��*a��@�&���l�&&i % @k4�}6JpJ.*��AWa*- P�82&�2 }��s�.v2: ��$A%)�{ ��nvm^cv,-�� �(),� H���*kVn-6� omu�� ���^VVE�i�6��M��.]2so.>�R� ��D a t-�A�m�:�)3#)a�uA�2p/m��.4a�]� �O�i�61e�=�%��"Cdfa�:�.) j �5����  �.�&�� bF�&�it,%d.�(i��z?���D"�� ls��S��[���b�"_dis`?hei�p�.73>Z6w/i11�A�T! ���n��I�'K" Cq�U�i laim�/.ow )�� .�'&.It ;]&� -��i6�at` &� q !�� 2t�6a&1(!��asH �� )�� ��p"]I���NA�.��%M�'es�E"_�D2� �5W��zE("5)Mm�).�+d@ e��=�&S >�+G &��*i? an<7( Eq 2�F�:�r�E�6� �&a&�9p�i�t >aJ�3:!b�=�E�3X �5 !falls��1���A">~��&���.�@H# �-rB4"���:��4�40�!�&�1ʹ4On.�>o* D� c[$�919�y-(:b4�n�* �7��6s9E�M%�n�o]�.-h0w��lnid ���]-�i�$(y@�iY��c little��=q�� ^s7�(�Tw� ntir��=B-�,�facD % M�WT�E��Bd] �fO:s1��s� �D&_!��,w�9f7 [O-�6�$can also b�e used to accept the null hypothesis for exampl/�eing a “region of practical equivalence” procedure described by Kruschke [33] . It is also possible�employ��more common way and make inferenc  favor�N�u�,model select�d. In this case , one needs� perform aB8betweenin which{8group-level mea%$�paramete�Hinterest is fixed a=value ()� �)�Pcompare that with a f!�HBI no Xri �0( alternativeK)dBayes factor ( i . e . dif1Vlog 4 evid%i))5 addi%Cto " �ison ,��f� work can %�bAGed AX �9�in situaZs whe�e goal!*to -%�ofhE s asb!U acros %�$ . ExceedaA2(probability[ a me!6po� [13]rQ U�)E�a random effects approach . An important revisii3Es pcalledwtected eV� [19])BtakesABe�oun]:peB �E%nA�6*in�paa;s sup�8ed sufficientlya�data ,UA�Y � KU A�due!9ch%i. A)�6treats ?A]t!�as>R~e' �l [ompute.,�prrE@ies ( Eqs 26–28E�NotmQiAQisG��indicate�at �s’ Q:$to explain)+�not5%t yYtheir)zlikelyGbe:8)��canRr( on estima!��Qs ,!9those�eidependena-6I�frequenc!�u} , we re�uen�#obt�uby fitt�U s set�to)i&A8!�,�(��/n�!]a�is��UJE� Y!WQxA�expresa�m� subje� our analy���'simul%6A(empirųM�however�� ene[er�"A9aE#�>m^�9 ( P0aaEq E_wA�shoula�v�}ga�0e!8s �Ocon-f����,M�ed���F�%s�� �MdyFine�.�increa� effort��oit adv�7��Tu)yali�A�A� understan�2ent�� isor4 [3–6] . RecAP� �i�+hav!$ar��A�ackle!Yllenges��ttoa3ntifyuncer�N{ n diagno��!M�ie� eval !�2 ����Fo&� ,2�$ unsupervi�%�[" �, �%�E-I�.�1�to��fy a clua���} showZ��pat} EneuralA,n~ v� [35 , 3%g��lso o ��promi%� soluaNsqubI��attrib 0�nd͋��Our� ��%es���� �� s� � th� ��.EhFzA�Xn help uE�mov� wardW6�precis>���UA�7A� In summarт�&y pr� ETisE�$s�;:g view!��*ta�ng*� �aaaɞ��;s !gap��-M+�[AlthuQ c!�E�ic�@.��. Moreo� �P� runs!y automa  nd it doeu � ly!htun���A<T��fɻw| �P� i#Ao�ful�a wide#geP�R1O9�1lIPa>/eh MVinclud � only%�:�ev lear��dA[!��eJ asany2`%�@br�&Por behavior . We begie�d�!/��"Ux G�A� . Conside� observed# Xset X = {x1 , … , xN}xn��G� ,(�0g . choices )jnth���N�� �mb�M����-s%_�K~ did��- , M1…MK6|CsI�p�9ty�eac"q ��pop��is give%Xm! m9 mK}ᘡ�C1,!� � ��A� 0 >  znE+r�X,a 1-of-K bin�@�vec,�3�zk%�Liftg; � s���k"M A�u�-U)�*� � � 5�, Z!z9zN}��sum��o��m. nomi���P, p ( Z | m ) = ∏ nTk m k z k n . ( 1 ) Ea5�Mk��%�Q,�Sto%K�':�a-�1�Y�a A�of]�)��v , hk�%�x��� reinforceu���Z>�q0�wop: aKrA��8a�:no���%�.ViT�strucN s��f(specific sck qu�cJ . HA�E��!LEolo achAs��noOe�*�nu� �, a�TY�Y�m�)-�,A � u BR1�xn-�E�;qO!�*� denoa@byE�xn| !Mk:�M�W*xk ,.ODmight���c+���Si�� �a�Ym ��%t �a�@J�->�M�FzM�:!Bi �-�is%#X | H�q�ke�nx n | he� , M !Gi�, ( 2 )�KH-+s�ok=S-#��1 ipan�$�!8K4of]A�E�F�S e norm>��m-μket �trix T!ց�4H | Z , μ , TB N (-|#6T%)���935Tk!ca� o) s� posi8 e!W�introduca�di�w� %12j, m .>u�*e D�hle1?Q\��conjuz�XA�!�V V�X 0:%:�Di�m!� 0%@ C ( �!k = 1 K�!�%=AH455 4@i �)�iz8t��Z�% � ���]\μE T��!�1&0ub 3 "~6�ihe��9�:i�.za Gaus�-Gamma)g�1!�FA��| Tk)� μ |2�)A� μ k | a p( bE�)-�)%�. 9!�i PD k G ( τ k i | v , + !<�e. )� �2�Տ τki1�{� e/m� Tk�sumA�τm_�contai� R,�def TA}Z���*� � n opera� outpu$ Z� �*d ��e�wriI5a�wo���gaQactA�m5�,!X��)}B� �b-�iM)%{%�.�( 5ubwe� %ed:N2� ��"�v%9 sca �s -���Dk9.� eq�to ����s��*� �7i� { X ,͵��τ�!7��.�2�τM�� "e. ��� 6 )� taskA�JI��:� ��8of>� Q@�< ��2�|X�b� &�iARt4 ��AQ!NNoutlind , � sBi�) ��n+" �&�e�!�We�~a so-��-field 8ach [16�7]a���u��9D�oaj`iz��N�: q (N9E) ��U8!�7 )*�w%Gc[o% A�6�� :� � ZeH . Uur�Vcon al�,�H|Z���in S1 Ap�ix��W58y@.i�� r� ��q� | θ, A�k )( �U6Q=� (�^� k)A ��) ( 99�=�ի�� β k>��sQ | ν-σ�`1Q� 0 ≤ rkn1AV!v respE���"keK., θkn%�AM!� hA�#&q , ν� βk� �/� σ6��2� same size��\x next6�pr�0HBI algorithm��itebv�up�f * � se2�A�!4 �,�,� , a!��,�, �� . Af�initia� �&=y�e56bnd6�=� �I-{)I%��as well�� �a b�, v�α0 (o will� Gede�re��H2b"�i$steps: Cal"QstDs: N ¯ ∑ nm�( 19θ1 N'.%m�( 1� Vn+(- 4⊤e9a+:��1� UE0.?ofq��,�.1�)��| 1�+ b ( �w� � 1 e�= b + *( 1�e� = s + 1 2�-C-M @)%-C�m��E �!���I= v o)�( 1�(α�� �%+�-+A&.�&�sI�iPA�fk�by"� �2fun�&, ℓkn��"�E��ect�h:!�� ( h - ����| E [�] , �]%-A��Y���Y. = a ��.6� %V��%��&TD&L�@ be C t(s:�≃ f�ex� !�A�M�)%�ɾR�( 2�'&�$�^� ��� .:Ma"�^I�lz �"$on: eV|# 7alE5= [2��22 , 23]E�N6c��"A�a�T es~a��(IOA�$�um ?x ,Qc�W:1t<= arg max hlog�.x)�}� ∇B%"x)�=o%�(c!�mkA����!,�K = ρ6�;jE�Kj ai( 2A�I�log ,= w�j$D klog2 πEWAg log| �$| + λ k +E�log� 2��=D 2���� �/A�1����2�ta@O= ;�z ;٩cK��k%�"� #�!�digZ�5. Termin��if stopp�wc�riaE,me2(o�w�go�P1��.�)gR*�I(- .! �F* 26"I�E�H� wholq "�. From a&� u poin�&.GDmargi���b6ofF<� �P readG� � ��∫�.� ) d A���g 6�/�O�� ,I2�E',�5MS )2KηwnMI�= 2 G ����!�2rdegre�# free�+ Stu�(2��#t= ^ �� � `inverse-� *JA��E�:� tZ�a{( �[!:)i���& dardV��nkN� . Byas�2%,�i.<#cor��s$o�%�alA( c . f/-- a�e�M��� i�" sulta�altu*�%�yAo=.i5i �/%�|�1( 2c No"{%X"J� � ;!�!�5Uerr&0e),-�.;7.�' ;.~�at�sw� |$ v = 0 . 5.�$on�as��,2� we/ �d&� In m��s&/űet)e~ r�0�*st_f�$ new �vW.� �'�.�{ find=�A6*� � "+&� m�#1�.!* preda0v6| %��-� by����B�. S�.z!ix*I�*�v.�!�itsf�� ����E2� x *i k * |-*%�,E��^� �!B�XJ&�Wg.bB&�Bis6���v������e� �-)`.|%d ��L�>d��f��;1�1��,e�g�a η� nkbp3�^N6 b*� @erm�"�-R/r�Fu.�*ifa�A� at b��r�9 2$�- F*A2,!2�]5{,5g9�I�=$V�� � 1�y *��)��7s6I �W�Z*a/evi�V�m,����j 2�5!�Js!w�%�0!S:5 2�A�Q�!:nu�,E�!�or�WQ_ -a-[i6W� am�by6l ~q9�i5Z�&I2'r&���JJ �3B.  e\ ,%/Rte0&�im ai�5�@�� . H"d11>~leaB'a &� J��(heavier taiB5.!,an"���i��Dm�'4robust againstk�e"�4meaV[a�n&�*v(,��t*�A�"`q a7]��E�2�/��(i4bi�f! "*+!!�<som?� "5 A.�:���*  dZ* 4��w�� 4pS!(I@ �h5� �e}�8�4Vas�l�&A ��MO!� then�EOc"�&+*� acco32to 6�– �/.�w!4 [ɏ ���2�� �c�(%�#�5>(%} �*O �3H1on6:-q���:. %!&!�!� + � �ma� , a0��A�!h �,be zero . Gi� �n,!�0� b��bE`erpre� M�9+ y� y�� ssocij$�o�A�*,�D |�c�0Vr halfq\�~!�V�a#�sE5u9!T% �!10D�&inZ` w.1eT] >. Fa�[4s�%s h&Q6R;�;ve �A�:�A�&%���#��"�#e@ԡ.T"�Tto!odrE do��7by} ��Ac&}7""4 d s5 0�*�=&%;t��e)sby�(o� �6��ns�2%�if *lo~ enti89(eN�-6�y�dnI P+e��6�=co#g�/Y6ME�,�r .�A[:�reseneEb=�9ir�0B��2Fs� *d_&`�:�2�.in"�$ed-]6�h"�$ecue���), j�I�j*� as d ^��K�1^ i� ^� B:�E9%@����zEEH�#,.8ih*f6 2J�6�G7 jth�#�=g�i /�ie��z��ie��iє5$�#}.�G ,�Rk5a�2ņ iZ���50!|AY� �}2�0although almo �::Y4Ev�A�h�;���5 9" ���'� �de�E+&q!eV�>!z�=�2Ai-�i>ev�7�2s�?�!9-3We rep�(��#�s�� completen;�*Z�2�) , ϕ�C��"�"t�BH>�+is� >A�� �� ����+!:hϕ[Pro��> m j |j� ∀af��( 2�C���ze�6g�@,)ԕ�to ru�#��f7�(�? ))=�2i�nH ���e!no"�,ce��%�? ����4�.�B6gL0�oriS@:*d'R=1I�)� L%uLuX log-%�,ihood ( actu�#!�.2 (lower bound!A�m6?�2�:��E�-�)HH�c%/�%�� )vz�k &hA� ˜�.;s:AR= k����P4+mK �2� �!?1 + ( L7L7x?&�if3?s c�A@!�� %"� A��:� gno[: .j.�h�. �3s "�BF2� if)�"!6�3rU4y �&C�?N�* ��0�A*7 |/ �*DA��aK0.|Rhombome ( aNO*�8%<�5\stem auditory nuclei dura�d�Fop52�x�{%de7�. of rm-��d f}���*co*�9. Little� know.�1�32*>i#;2* Hox co�6to�Psensorimotor circuitr�?we!xw�Zr4�L$o"Ye� link� S@ Xompone!�&y7!H!�ve�(l)buIX'�lemnisc5�1co�.ar :i ( VCN��![ xolivo)eurl � semb�8�D e r45�5��� nvolh7_Go��per�I!�q*�reg�6A8�H�Ix Hoxb�� oxb2�d!Bmu/mic��transmis�0\*ow�&��Duli�l���?nVB�E�impairA��)O���6�9,�a2 �!��+ long%9E)o&+ ( A-P/=xe�t�Jri%� repe ,���(ly.�,�%u5� rogen�� celK(!�.!�#. I"?2� r'!�G�.A JE�of�c6 lumnf �+ng: J�J�g51 dorso-�( D-V1e�&�[1�%>%ieXi��3 -seg�al� e�(topographic2�@-�y@2`[3456X?s9���!^somato�'M�, a�@�:innervi��,mbBbuo0or�sker padr,axillz;)�-adeA�oANt�E�B��2-?r3����� prin^l trigel5�%<�L29 A turc$h.<�:�top�FebT�thalamui~ ,1cortex 99n�!�EuiU/�66 map )~V( )7�ih � t_om"� t2���dis�z&:s!Kof��%#a��orW �u1x28ED::Q��B�y�a�e��A��:A�2f ���!�+��6��in� �5��d ah itud4��m�. T}2�F1aO!%1��1�r�7�,d�?�?�%���'-`a�W[10��5'��< pathwa�@ nsis�B�� �ItEU asce�E acou�3.��- e� �P mod�!� prima�u�a)onH1organ� N R�  ��~];typjrp�nam�.ixnAd� er h�Ie��. Whi�Nh�'( IHC�6!�"majorEJcttIA� stM$*ou:i( O Len�Olow���?*|GEzh%E+VN��dS�Eof�I�J0membrane vibr�%!>8ocn�#“-Nr bf7 ion” [1�[12ABL'�periphdM, �2travel&O2(VIIIth cran�z��D ��h�E{a�� ��~�!�MQF�* k�� . 5� Ls�[lRAfH b��s�R��.��r2–r5���w02�-���A� )� P � ��al�-6� ,����$�granu Iel04");microi���h&�. A signEnt�7CN5(�-%a�rii'Z�2,s Math1 ) [1�1�{6. Var�lyQA� � -At� !/a 9 mly_���Jli�*vem+*,�vexomE*5�ei"< AF�z��&�( LL )5�M�7. coll�Nu�IC; miE )%@C � �2v/MG,y"{u��!ys9�.  �u��.RAte�O�.sp� -/2� �zu"��X6n �'G'O4���he"�x, or!� high��'.\C[18��0�@�FM~ L!�X��^( SOCe�U� l^*�d�ur5%��8rHEm�&X*�E�+Veag�Y? Q�G Pr�<"�� ce�@rot( �> ifug���)����Q��{inc�g����U.*��e �M!*�>�-�!RF�( -Wa sub*�G-0) �Q�( IEE!��Abborc+U)r4 , &�Xmid+;�ear%�ve���g$S= f�Oi �Tpart ar�S � yonic day�4�*n.e��( E14)A��[20%�21A���*O9AL%6� %v�"� 1�1i�Hnt�>w�?a: =��]J�ita-9! < ,I� e�C amagl  ac�G*V jury � , [2E���MJ�!��dA4� p6��f[ 3[4]�!I�4 ng� �:�5!�Ma��rQ � [2�n2�n2�Risٜ�� ��K��U�6�e�� a .�0C matu AX5�&} ,�v�E�j �I��na od9��Anfeedbac�N6�middle-a�muscl( MEM  � �%�fa�AI*e� chio6�$( FBM , TBI�OE��stapedi?tz tympani �c/&��CU^ch�Mf9c \clreduc,&� R e���ѧ�)!c [29e�3� F$A! !*I�� � pa��o -evof5�me�ismV#E��.� !�� j^� a���� � �% 3% f� moleh3 ^4�.��*>� �"��Cs&�;���� y)famil� homeobox-��D.�q�_'^!hJ���'m&�.�to(e %!�������v&s [�a,�V>1� � AUev ��ain�8w��ra&U>,oU�Us�,.�.�2^�Ta"o0 �h&��Z�m�'7I��TIe*Oob1R� ��03q�#�(-�.�� �I)�A: suchU !��Z a-a�S�$��if [/T!ƥ A Hoxaf#un�b���-� �2lr5Y�%�M$.>�S o6ů& CN ,5 %�MLL*L_ �SOC "� �\pre���-��atE|-��Y����4dRW.z*O>IW�� �VI�NMYEi[�8�"�C�3�<ros�i�i�:-�D��!E�� blisO !Q:e,wo � j��  "T�� Y&sN���r!� FirsC ,�carrie��e�-i�42kby�5n�fno��X ghly:�c�$,a^�@=$ Cre-recom�N7B� �7We*(�s"tb�r4WI�(���h"4A�A� &�(���Q�� ��cep� Jk,f�5$r4�>ly� pl� ��B !��,f7ng7 in a-9aA "RG�Z"� Vxb ]g*��[A�N� . SeF�*�[:2��B)4�!;dT�� A�.V# -��&w YuŅi�$V0!* �8le� d��_sholde�ad�8 ��g Thir � �neg��l"�sa2� r4!�[�a#e�3 %�E���� 2/r3��Ꝺ6g��!miAHalZnh �}T�!ic-�.�.Vperturbs%� (�hQIM � ��!�:�( MNTBB r':!��e�]ed���eA�]��p1t?of U�2vdown-' �of�+ �A�V��7Ib. Altoge�&D�cX A�:|f�� time ,��ticȽAe�Z�&5a!�* netet����e�! ��ena<�p"�x%�� ���fryQ��\2D Tak�*_�aFk�r3/5-�4��n jp5j  4��J!.��� ��s[mapE*!9�<-�"�I�Q^�0CN� SOC �le} 1����(�$�e� mp[o��Vr49J �in�'m#I�A�n u/�$Crb"� caud\oa�D �4 ID US�!#�d a��m%e� � ! nAb/d b1r4!�>y�/edRx�_��?r4 !�v(.�� / !M�e��em�igY/1A@ S�J�+pur��ka�charac�cX.P�2S�Blo!%[42hk��Au.�!# .���4�S1A�)In9=? anim��:�4,s#gvS% occur�mr�m�msa�^�f(9>�0* E9 . 0 on�_,mi>�h=}!�~`5gD)fp }&ly labe�#polyclE�6X%�"�(!�U8=A�^/$� *$ROSA26-YFP���,a�[43��!es` i�.��bPg�jk���Y�/Y) w1/)Fe ! �-�A�5Gat E1�/5 ��of K0"{=F&Q�!�! �_ 5z�2ou\ls���of%�>e5�1BL.!�. No fpic:� A_���at6�( �+` 4cnE�W�xt9!�1�%6�%�8�ot*�� �& � ,U*<4nti-GFP  �&g � -utSj�!:a naLbOprolife� vmigng/�ia�!�2� xI�r&]'vr4 raI'his�n�D�2r�y 9gA s��e�End �%morph�@+!d�0�6iw%$a wedge-sh��2ors(�Rm� conf� � YDAG%�� coh%,��5n�*"� ![0-d"J!�Dob s�c�t�3n&V( ` � �jdLa l�k��6 !$t$9!��r�ne�Ve��8 ` "�%by1� �on [4)[4246THq�=+�*�*"�p&,!�5by`�.^� �;of%-. A�=�the�im�(KsctL erfic��B5��5r4/r5?B%<.8  [�6a� rgic/�% ChAT�-u�:s Gata3$Tbx20 [4�48.I�P8q�& spl2!�-� ( L�zMQ(` �� s [4� L��8 � iU � t � psohc�tLSO� *�"Y por. � ��c� �iB:(y�Fe{AbeZaKq,š�gluta��.�VGlut2�U��)�-e�j �xo� FwU�R�Ey���]��)d���� �AH%,mTn�bar!2�%zO5!�e�a�s�f,A��91�&��W�2 cour�$obliqu��Fx&M 9�}�T�= �r""� "!^5�he�3 m�4 a�ae�6e,5a&�%F�fib�+,F�x.]=��qO!^��5)ٳ0 ��a�CN [5 �i ICi�E18��9� ���nd*Y(brach�" sIC���a`al0 /m`�>!*6!��! ~�Gn�]$l�%e� 9u�3]u(/2�.te lay!rat��.��J�T 0fK�@s?0 c�d� how �jghHsM; YFP+Mim�!�� aW ��.�>D>i���amfxj)!.�vU>� � , [5� .��Qa {%]inhib� GABA��/glycin �MGad67!Q��!�ar feA�<""sze2ak92o[52��� q:I.^lh<"��y� �Z�7|M r4 m"� e�!pB��JLLz W'. N #:�X��F ~ Nplu�..*&Y�I�7P9 )�Os��Areca�$��5���e/�r5} *o*�/Ante� � "s�r3.� sfpuU�AB�=���6�"� )�r�:ma��!�0 -r�L1=�in"� L� �B�'gn.�sei}i � stron� "�ini>!|"��Iw|!Dz7!j�i� ��m�U��[w3'�or��6�l b���f8��the�d�I���E�*����A"�%�.S�2��.�`.A^��2�2�&UG}� w� i�(� ng)6"�.p�d�z  `"�va�%T�Il few.� �overlape� ���ad-� n�`-l.�4��!Q.��Barlh1e4K/%MC ��u�S2�..�we=�����G.��/or *�S�l�� I�j�2S [�m�s!&u��c�H: a�A~� �+s"�3 Aj0]C e��1I< S2C–S2= S�z n"�ore� un� , sug�%A8*�5!ȉ8�s6dreded%�"���a�>JM3��y��,_ ��%�MG�(�5Ee�qFSJ=!���rś(}�X�1�,!iki$%s"m es*�)%Wa�7R�+@G[53.� ɖ&�EA�taYv.N��E;"8i+q�A:=�*� B��il!Oco�� Pax6]JJ�aqn�!6�2�*��,54(M&�sN�,a�ab�a� calb��n-�calretg�A�B Y�K�c2�Nto octop^%glo�(-bushk2Z1:\[5�5�v� ���vIR2o%�69 �Q6�&w qi2!EA"1+ 0�.z#s-=dG��i iq��A�f]�6 in &�)A�)� b�&m� else�?( M . � , L . P .@S .7pr�K� �U2/ A�� e�*�u�& ��l"9Mm�R.J a �%��>~-�&o .� !�m�!�*S �n�R;w}3�ee�lI"U!q"m  vo6o=re',�'�2 }��!E&/� �� ��,�,"� 5���- �$�� �{ 2e} )�0w.��nd�.�<Z N�. er-oD{&� =y�*J O5&lUur!kd _ C8�!�As�E1u�"ed> maps.z�q%e��  � !�profi� ,�� s�C :� J*�6.A(Azm#inJQ#.C(R/� �!dis� e����?&nY�"sA.�����.]� "o<���!.1�+�Z key �+-m[�>C�+l�,�=e&al�!�ofk� �!�&q�,M '&4 �=�i2@/m�s� -[!2u ?z͖ros!V)A>T �58h[5l[60];*I~��Ltf-wh� a�Z&(+�0*+L!�/v&y!b. U6�' � �a22s5��.�aTZB"�s�(A��VVC�cea��&W'b1 mayQ('��" cZ)XA9�&/>�/)�6�2��, hv!�ks4ngh-mito�!� �3*U..*!�6�-y�=esD0is.cH!:^st&&�a�t�Y)p)- �͸:z"��� MO\cm��(� �ir.z"2$!!�*�" delee^��re-}� _.�&�s@{<% � �;6o bypa����!1%&�r4�� um%(.U� m�-#-�** SJw� 6Z! l.1%g��+ flox�{s S�S4;�RM2iQ !�M}��6i�=a&�� l(C*5m;�v/.ozygous�V3(Qa�j:�8A��CKsre vi�� fertB<. MutD9 ]0�� >FUuntil E�75–� Ք2�AjO�$� �timauH}��.�!-Cd exci�uckF�}" c!2u�.^�I/fA�5AY-��� !���~�Ht"�!�uis unLL.� ��U�Z�&stituA��ho:��8 �EY,�W� ex" to�,l׎�2� �)`5G�!xlack gE�E"c�t�S8z��)� adja�+�c] :[63� T&�{�rB�@� ���!v��� �~D%<-��$I��6�5�- 9�:eA!B��H�i�U�q�g!�rj!(j�� �0ng sche�C��I&%&N�,N��2F4��z2Δe��a�/cd  `)!"u*R�*2�ck!|�# v �6�ha�.Sma�lefh,���%nP!=2m�{$̓^�a2%��.��`Ill � �65A�&caP�0v� A4�&"�,�1.� �ov$. Flat-mou�U*6#sagita�� �:� � olM�s�<)��T�1 �&�!l�A�4� In"Y%TY�Q&�2����*�+�u�r4�M��a�aP�isk�$ �T �-nLa dupl���~-�^��3)B&�F��#4f=L� mid-F�o���-a!6C Z3. ��U�45J�����ast�Ay � .� ��,1?i�r3arrowh�iB�I1;ras�e!�"�-�8%t>.I��1aWatI|]k^p�]�P ��A��4ip%A��� �3U c�F�� oriz�;l��cke�Qr'�� � EstYA�]( v��h(JD��]&�)"h �.!6o(%�q�ɂ�k-8M�5Xab5Zup�.)�%HDf�>B2���1 �b�l%��F�ty�Ie5r*+%2. SBZ2:(a�p!A1�2���� 'rm�6�,' ��"�<iki7V 2m!e -a��E��QDM�X)�Xg5r-�es.��;)�( [B26_E �%� =64FA��"h� ���6�r3��e7k�x� -ce=I��4 ac22sYQ!Ca���-i��Lm�  8��vaF r4a�o �6� ����� � y)L-�AC ��O,"t*�&P Q��fo�"t�� ��+ 2�Rpu�����JQ"�*IP&��.��`�,s=�to1r��&,�.h&IS:� n WT�� ��sG � o���MiHCBS� Ha )J-� o[Q���KatłYei�r .&?M� d�os )zE�d! <'"1. S���� is�B%]r�'��ly��Bh,� ݝ emphamXE;ѡA.��8�I�xj(��ine� EqݍSe�6GVi���O� ��h�+�"�.)�� )�.�H��a�uI�p36��de�R' [6�ak+Z&�4J}&� � ag��� <!ԅG}͉KM�EA�{!�cgi"��tr3F�:�.. . I�G�)0"�&J6BG,A�q��aG�2-ᵾ�6 �A- 2]�䕅Z�9�I�eq* 1AK6�w u�2y�J7��d2����r�m�m����Dy y>OC�Q�F��0�e^*!r�-2/�rIsl)hPhox2b �-�O�7*�S5A�5� No�1V�ɣfiA �A{Z^ �0�Ms�)�Hqyof�}�m�!Lpoo�� �+/�+:�U�#Fn����7 laa%�w�'o�fnoAJ�,�W|0R"~./, ���*�D-zIary >a�ebbeN guisi�25)>m�50���"L��r+4�$�+E/"p!rS rHU!��q��ka��AK�,, e`i�ey%�� a slύj<rem4��u�+�*1�CEk���'o � � zq��!�6�둼>�Q�despiU,te.�!&To.�E�.��Jrm���3qDns ��*C��725�/ !~"�2���a �a~���"co�^"�%�%"MFLof P8� M�9��3=xlV�R`'�=%��$�t���!�>+ �%l� v�P!m1 hown�%Y6db,"7���O���mYF"n$%3�.1>*�5,;�?O�B �r4~5��l�F �-/�$�3��7i7�52y+B��% Nall���(FI�& � �KG�-�9E'E�V�-!�6*36��!��-[6� .�!a���*Damp �e""Y6 � .zn %A�-U��A�>fzm|+� !> fail�BI�;B����. �'�sN!�LYst��,�)n֖bc���2Ogi CKO�%8e�i;"�B.��-W,@2���L# �&u$ ca2�..f��*�0u��%��Q��",�r ider� �M�o�)�d��F� .� careF�� �� �(A�}�*� &j6*�2�.Q\�8���Av"� Atho.�X�[7�7!G�A�M/ed>/���>�a�sq�vB�/z/Q-<6g/ �9�a" �*:� =)MQ��Gn^9�}F1*"Q \q� �!-�"6�1I–1J%(�� �60�#AT6U>�(A�&�NMXKQ�� 2��U1�) { ].�6t���(� N�a�6�-��-(R�J�bB�!��>NW3s�jN I�J� �in�" �ir�yV��?M�=?.��U2Be�2 No� J�0�:6  [Ry�B,1"*#�os&�6t1p"Bk)!��3q�n3,!RA�"�8>V7%Z�9�a�AI��mJA`mn�ޅ�A#u["� M� r2/3� �/CRr94�.�"BW:�nd�a2E��&G��1T�of�+� !0��!�sU�9,%}7�2��gy�.�-@��Nv�r�BI �2 p5�� �%Bof"� eI%���� BM4A��R�(�*�XA�{0&�E ��"d�� ��h*�5A.�z� m\��of-$ rE�!0!�͐*� � .�sy�: �/(��!���%�'yl"nL"_u"�a�2�Ikr�PU3 m �6�6�%. N�! ]+8"/l("!v�[6b����` 9Uzh!d�(. + c}Wo#�L6a#1T]~o�?d�5Ln�<�&�/�A߲K�^olw�&�9n����M1i�T q/D5� A)��m.3�vAM8/�L��A�{ }%V�),6s�mo4ono���& �� "� R�Wi�B� #im�5����h` ��g)�%�5Q�)  *� g=Iag�W�*�:1R��?IoW�j�* �� t �&���F��)�%�5��d�_ak*~ ��by!;р:(&qRIyty�"�.� w.�"G""�1��"ic��ZP y� d�Ba8se{�!bBe*�w�� { � "%~P8cYj�we �eY�T=eE.5�+Aa!G� �Uj(��n�H�!2�E:f�VaM�! � �1�SkV!EA["� �Gr @.��4n2�"T�7M{.� B�L�B'��E.���9r&>6��&BO"} 5.Udex� in�p/e�e p2� �1�.���a18�W( c�q c'c�y5; yW>!�v�P�F �ngQly-��"�e!9:�*M�@a&!L�b� �.�!�� �kee��" e�NZ� ��7�^#,��%�-P�ѭh!0��AÁW" ��5�4eR% Tno!� zVCN ?>nS�I�4%�[kq� �1q(&�b�~A *�ktoe J= � �I��C7E�i�"!�&�IR6s �ݶ53 T�r�G�h�x�j7Z m��nF��'�c� h<*'0)�a Wnt1::�S�Vr [70])�vW;-:no�S6v7I� U' ^�bV*�X(%H� ,`� ��r,five4_�-6a�-6)x+�e �ibirth%[*{e�x_.W[7,enw�ar��"��0�g�ie�6�A*g8�c����� n�:tA�ter�w�Fra�f�U>�!@!�e��{b)�*qreveal� EQ�"H aberr$�"�i!wi*�\ec( ikut� o�> �kphenotyp5r�wi�t�/�^%� Xl��6� Robo3/�| ��}i��%9.���-��)�Ye!�.| accuB�e. ly [7ngA�:�x#�,5A"t� !�i�.�3.�)�e�at�] � ��dq~�6�Z:|�: ough�4�΅x-bo�b���"rB�)1� ,�D;�Z �$^ n�IA�*1%q6�1>V"%;E�m��I�"IR� E*,�1�!� Merebel�/A�+@ � ��� -p7-�hN[�%S s@Tr�vEC2��'5F��� ,��N�JA͌J�*I#.��>g*(gu��"�B�a}�$i���cH*�}iMUY A�ὥB&�PU, iU TdU���m(8�l��dX h�1��-in�!n��w6� wCn��P!���,R�ly��.�,���m!� "nk#oo[2mk�B� i� a��hN�of�>�y.��synap�?kRinv=on ���.\P86�F�7.Vu��iT,\}F�s& �S��NF.! 1� �2N ed DiIw$٭�V�  � �T*23h%nX 6# � ��,B ret�:l.+^fluore�Pbundli!Q;@%w� R���6O No()0!�? � in!��� �a=� )�*� Z&�Bn `t,�m"�'>�mM�0mE�SkK.@{�- *9 ů� ��� ���� �%0E���)� 8.�C< albe���'��hOOC �"!Y�&�V�!S"�)�,�<ei�da�v!�.�%�AP� 4Q�E�� ��!2� /.���?t s.J��-�+to\j��%KjT� To"4�Wrj0"� 4!� /����y�$e�2�A�"�F�WaA� -�1(%-�"~1 u. �V�I�|ron_ roscop)�loo��,��� r�.�oQ~*ABSY�6& .dto�#&�b"� 12:pAD"�.�(�W ���b��&K$4; 54:Yon 32)"�%6E , 6��7~!no:7�")���+Mge6{12Cy40^y.Q4^A�r�"��>�U6����9 6; 1>aon 64^�AwEO��%�.�B �d*/n�e�"j&in l�l {��~me%'q�!h t`-� e�G+ � �1%�.*n2`"m.M�!p�yl"n� 2k��"�/I/���ch&E_*� of2w,U)���e 676<Z^� i]���s�.] �*P 5S�[[V.� �+���.�U�x b�,!Q\>&� tiveW"�[6�ASU�-� R�lN�0v�^6� %S"m &�k:,+�)���y#`��i:/�M$>*#2jL�&�Y] y�)h% T9�.�. %yy-i�B.].��:�E'��me�qF��5�f�&un��� � �'*�>�Aa�S;a5NUG mpanX6�6��2_.d.�+&�&���lu0�{�$T*�,��-! "% �ZZ�U�N�u�h�� ��^.�}j%#o>f��%!۩J���u B�"� *:�Ɗ�)o� 2�.UJ�]%>�C ,2Q$hS�z� ->": �Z�-���1v�N�p��"�(!?1&F�KA"=�6W� �_7}�)iA9cDUc +v":~L�*z��/rd��]m� susceptib��o��e"f�"@trauma"@y|�0[�y , [7�oI|hpholog�Am��]&� s?��N� �aJA!>ncturI$WT� ��� Z�"�.M?uH/u�&t�*T�!�!�o.<of"�[�w"��iA�a��:)�K�,Ob�- %A2� �%� �e" !,in 3-month-o��";m��J�� ��1��}!�y"�a�feR$ S�����W�~%�ޟdiR�C6� �*�trinsic!6��. =�} MOC/-�:���*B�r��of Z! zero#�eB��T_ rray� "�e�i�a6� �)m . H�b\�&��i��%��eu�*� WT � illu 2�d�te�7^Geocilia�i�ahe^8��.n�+�;er�, V(kmWka;nl�5�-s&H Fr��mY�ioae&�:;"�0I#WeT no ob�s"�<c]-f�k)�!ti&Y%�3a �!� �U��ፁUm�* �0j'�%-pupG2.�376Bq8J2� a1�5YJ..�!�� �a�young ���}.D-u�archi��r�OHCA�a U3"�bo u<�i�eA+eGa.Y!3.�ha"m�'��  ��]�jj ���  �4�-is-�ed�e��� occa�alCeeG %��M!���!#aFNIN ()n�,U�6:�F�ir�1d"�;%�&�\s�$m���L ngth�%��%%}N� no���D.�� p8W=Lم��2 weakIE ��r)"� R���-"�kz� _5)�A�or�� �����A�E�� Ig5�F.�S8B�%��2T�A��&�$sau��"w3��� � apex�!�+QMV� ���� ����E���`8Kv:��ieg�!�"a!�QisDMf�3,>G?��ng�m��y�6:u�of �1a�. �y�!�� =3:F�3�1) z6�A%moA3�IHCqmal"�&*S7'"7X.� �SΠ9�s!I�.z�n,-�>�)�Y�Zs,?�x�����q�T� �*�yneglig- &A6��0���INge5/&2Rno:�Aq.�ik�)EF%1�!�)�U�&Wat%@���n �5T>WG}@���.' �sI'VXof*t6�Z"�<�J�� �M!+�u�f�( encyZ&ndɦ6 ���E[1�Y6�3minc�I de^*; � Y�� &ڔ�Vy��� ngAN�y># f�.1u �%�z @��YeE�i. )Fng-� surviv2"nd���Z$�U�"�!��t��1 f j�\"Ѐ"* %�p{ 9mp!�u��tes�:2I� !A�Fk �"�;AH�9I� � ABR #a a se\�� �p�pot � �b��-�ʼn� !�� 110�40 dB SP�SeXP�w� L�� �\aly 4!!�?fA8!�w!�J{V1�r���t��pea�r;�iS:� t [7 a�1sT+�wa�%-�!x(c�e�ch�.s�Drt-ae��ac����� ucce�x"�%"ub;%�JE �V� ��o!E �A���JY)�!� 12 m6�T & 306�Toc��a�y=����m�?0�� to 9U�L��!�j9y ve��.�(��� @ *� �� )�4���at���/� ��% ��u=f)T�.�, 8���/�ݬ��gv3��a�I��*%�6�oE&R�lyY�aD�����%:% ��%za���w�m`�r�2g� �I.oga�!��e,�hea'?�4^�v]=Owq�E��(Y;�P%%dA�?A6�^*�o{!&�S!=l�4�egdJ>���&Jd�Be�D%:K ��"/aAd�~~!a�W&�H[7u%>^&�%h7.I�ny5P !Ldn1����l��Ye%2[4"7 �챓�3i�UtO�m�D �~F� �b�Kp �2�k�r&-bqbA�J/��*��a�xu3!�� 2��)M��D5%�tCBEth;MA���� nAcS�anJ�*_P%Zq�!��E� s?�ag�K�8�BY Y &4 `�hQo�%��TM w-am6|ud� tU ink�*�.��st�tU>A��E �MO� .���� imc> �MA�� "��"5i�z`.�&[5o OWGl�`�Ced�"� 6-] L"&�seI 2j hyCe�xA hGnviron���d� !���9'!M�� hV�3aRdd�* issu�N]�*"V����vA�� ���A�c!��is�d �A�?.,�I��capac�� t���d!sA�meE�VzA� �e�EB!�e y� shif9 non-VJ@��6=r86%^.��$88��c���� �1�ZO�F.�E}��W�? �Q��Q �F{o#�� ��D�oPraZ6S� �w�0aژI�>�I)F[7(V 5w� r4.{��7map�F�?����ls��6U�6a  u pJSrecogHH?Ct.�y�� Eg.z��"�!e27e��a��&w�� �0.98e���n"&D�E*�R*�ѭ�"�#fw'"®|c.�&ȋ�(?U��y"n����'at65!FJ� n�AO�"�"�esub�0T "+��H3=�6�!�7�(&�>�[4=dj�7mA�)�F::�t� ar-p�K"�7��S*P���G,�5�DCNJR$f!ng�?�1r4*�� �Py !_Y!rELř�F�oi���<&�Owitq".��*�FM�2�G�5�� ]� 0.5u)*��98ܫ( �s6�s,�sun&zq�>� a�&���m%i qQ�6�.�:�I�*+ ;aU�u? ]X"k�s.Xq�eN�z��K��. SQ'%R�t2 k"��,� �Y5� 0A��H �9,�;�h�"� E͚"( �Ǩ�e ��:&"H��6*e�)0�v���^6DVCN�� ��.�&��*p���Z!��0/�5)�y";��;annd!�ws� $> ��ͻ�URd��%�2}A ngle*�AKz P�&� JA]v���&q-�U%wa&s[eE� Fd?| �r8}Mvi`7d ���{- uS�� li��i@&��7�Cs~�W�Gso]%!�6� of���' �g@A�3r3/r5 *ed :B)�:Ek�3׍�E�s.T�� ��xB���lo*@� ?� ���K�!6�:8;dA�ne\m U*ʐ �I..�(%m�,� ��RgC}� atAJ.� �%h��E(*�O!.�1�!�]�����"�Sg2Є�8populations . F��irstly , we found that the VLL nucleus , which contains a majority of inhibitory Gad67+ neurons , is mainly an r4-derivative , differen� from y$Glut2+ DLL�hy$is excitate\and originates primarilyD`Atoh1+ lineage [17] , [19,51] . Second�r4-�led rhombic lip cells do not � ribute to�repor�E!P�1 t2�2� cruc����m��on��r4�Edur9� pattern,%$me����� into��a!�i�H� m�B� , baa�onZmarker��abI� behav`of FBM-�s [34��[3/ 3��4 66 Here�١{ �a simi� ��"ccuxA�in��-'a�!��B5��� sens� eK� �� � -=^of%�!C.� "� ��a#in� !��e� rastitu]  ( �)�+ i[eJ �$CKO ) elim� � e�a� �2ΔKO� ,B ��� faila!A�maintainQa�%4JJ2.J�;� Hoxa> 2w a�t levels5̅l��3 ,� A� ulti� ly $e��1�.15���i (��� � A ��f�7!k%�3-likeIed struc�` (� ��>6� � � us!� clud�.��eSisUksystem!-b1V)W� critQ ��n��0��|eir5�,%�aCЅC�. larg!wac�� 1�t .sA�our dataY�p�sstent% pX i�u�����!0 r2Dr3/r5��enhanc�c6?!�sel�Ev\ *`��IZ�5 [C J E�adir�n"G �C%�eV=u� repr��e��pheno��Z deed!�0lthough early E:Eal �DI�y!�.�2�� ��{a�ur� q� 9 a}� stage� s f� er da�opm!��� 6^�a milder= when2VA��� ����|5�sl� dif�c�%�1j ic s# qo�1 wo Q X�ess��bbe du%+AH>i�mgX �>�r4!�m��aF ,yٶA}4B2�G esides be��.� 1� high�("" in.� P ��ax� �d�S58] )E}� lay�key rola& �yk�Dpen =, �v,post-mitotic se5sup��5��!02��w�_ both priATpr� 82m� �KA�e�s Q���6�V�s*� , VCNWOC�5�t situ� appl� � ��QFp%O� !QaJ%Abi� d axo!M conn��A���hindbr�.t��w�6��m2�A������[3��66)!�>tlaffec� Aa22�,���ly��� V!�, a2)no deSs w� u�in%y4MOC:�a�E�I��.* 6:)�.#na���.� �w �)embryoAYE�2VI�, i2�#NT��O.�sJ�Bnatal�����6��er.U��7 ,. &a�� &��to��A%� confirmed�a:"� 2� ��u!9wR�negB ly|es!x6 � )��LE�>, 1Yup-.� 0a2A� �sAB�5ic�<al�b perta�AdAb� Q�d to innerv� @approprit t���|,&z>%Vr3����s �Taken9�:9while!52 establishƑ%9��5�����%A�.m  pos\t' . } 2�Gioi*�M�edUow=��Ftia�). �!�4�E only8��J!�MoA�.� 2I!\ tudF_in)�, ��o� he��Ii� Sli�S�ram�pro�' r2/3�#�!�r �p F� �2�aL)$�.� qy�& u�thres!�s.5 =e heaT impa �!!�is"jeAd(often assoc�&�"GCNU��B^W��"K ampl&�me� ism execu�by!+ OHC�"1] a#28+6� "(��m*�![��t���pholog� dama�"AS}%�ex�a�.n2�on hair��:�s5 they�a�mQ�N�ump"D s [4 �8� We�e9����� llit�#V�(, surr�%� e�� gangla�Q�!&�$,� *� ("Q ( FiguS9�3canM!<2MeV2�$E&Q h U� . E�wey��&�#douG�"/Sox10*�LfMx\spV�seee�.� � !*ly1� $: . More ,L$ II9lfib�7?!gUounmyel�,�)�type I^EIa1Fp `r4-.�"R !< Schwan�s � ize w�2u. F;mo�r�&�Mi�e s' archwmiddle  U clm'o;�U+% 'U% ]e�:pun��inVMKL, �*r :�a�C �LOC e�&� � &�.����,Af�'to��^�#Vct�cM�� ��measuaIf%BR [2�1A�wea��vascer�Emk)� u�R8!nY�i(��� .�ofA�� 1A�2� �( 9survivale�5 Aof�fs\A���$process [2ee.u.+.�ofI1��F�?�?Vmo.B��: is]towar�(5 I' ~-�%"� ly pf!,ency s��s�perce\[1�6��:���*oceedsjeK� "�%B�"bec�"U�>i�E!�&( o�perE�on [2�H�$degeneD! Ln�"*�%,�D1��C�� �'au�kZ*|4synaptic/troph]tim*� -�r.5�%�%fugalY���a]��!�ioe8�~,�� a� �m�$A �E��^U�!�s�� 7} atqs�ceIV$�q�5��u �@�� !w�1.� 1& 6� &�,“rescue”%2��5�]OHC:L� � �!M�/ E'of��*�are *Q�2V Z),� !�*/ K2� 2K ��*�!9nc�� evokc�%sei�r"in���analysiA��$.5�5=I�i�'n!�,��� vely�7 |A7c�87 �Eʡh� pathwabZ&�1.y��Zh2��/� J�alread�,4 one-month-oldEn� mic�ataacous3!iso!j�birth�k0u��t� oa�tj/is���s�ŵ!]]b d]�i�jr9'э1AaT{$MEM reflex8'llXqvvca� prot���rgaSCortii�n�-in�'1E� . Never .���oe1� pde-E�-ѵ�feedback�"I�>8�e`. age-S� >��[7���3 pronoun~(inmX5��, WTIe��e m.�)s��� . ہ��‰!�o �m 6 2� few9$1� a*�% ����� ��)�5l�t ���7� n1T&�.� �E��.W1"�"& !let� a y q�:1S�*�)B�"� afS"�# dele:!�a%1aR�.l��"| n hyp��. Oy$unr�� a no��u��{&nd/"��]s�2�? e�* A+n �Uns���i!�<�uwm�-�"�+ a �imo|�3 h/��y�%�!e�witu&�0�b5a~(���e��3 �4�  � r2/r:�� e�3Mfis�& >*4],�&�3B9n6lv �V-Z &Wgr5��. Bu")�| 2i�eDCy��ax& 4/r5�� (6&36]%�a�s_�'S�&��l�,Auia!�ar".�M�Az����at� �%,m^EV/i@ctU���:51M�s.u�Qb.�e[ �we*j!&*$ A!�B"s2�E�5�5�thre��.N��<68E��N2�'�&��terq ��#�i�local.[18I�&ntras�m�6�b1�+�R�]!�E�,)B"B -A!O7ant2�BBir� �mD}Vl Z.a�hA���)��2A &�'�2ce�X��Icx���!A�lby2phɍ� n� �)13 dis����problem�ٜ2"�F�UU._ap,ac!V��upo$U�2�Ei���M}A�q5�I2Y7 �1� !�6�!y�a2� n-m: A [2�m�ry� e!M��ir{In summ�J.o(�'y5delqreby N(�A-P",-!basal-" ri&po�of�l <D-V ):�N�m�ad�sA;!f�`!y5����!\*$� ,��̡Sb5 ���ur!��1!pinuou�&fin�9.�6Akm�mq. -seg��l ��"&�'(!�i_M%win1U<1M� F�4h].tailed�&�b1r4-C�+��#<nq�E�"Aq� /;p <(M ��"se3 0e Protocol S1�!< . G2X ? ( ma2 {lle�a�deHb��� 907[60<80<e�� (?#e� uROSA26YYf(r � [43]A�obA.�h}7 ozyg�71;�: b"|1� �+��� "2.Nabe!��xb)g��0�8�l� x:�e� �!�"z �2 .�#��l�t a� E9 . �S3& I %[R��Eto��man�8�jnd>)inL "; !n�Alla�eria)�ra���`followa� guid�]�- I�2+Animal CAQUse C=%tte� e0darelli HospiB), NapA�, Ita% !�Univers�i of N!S� a-AntipolL , FrO0x<Friedr�2Miesc})�a�@Basel , Switzerla) d�> P8]3 perfa�] 4% aP%aldehydP PFA� Em"�*,�*� e)�fixedU n�inrT�*(hosphate-bu� d sa%�<, pH 7 . 4 ( PBS�Tissue1�ryo�q�10 , 20�30%P-r�inC! frozs8n OCTc+eda$matrix ( KMk�q�1*4t 14 µm ( E10E�) ;iT!�w& laneZ16:/�+sagitA, ; E1�/5A�E18ZGor� yP8�a%� ~%AfI u���of end[)�{peroxid�@%��% H2O�%t%W !Q �-c bloc~ a,)� (D05% T�=2){0% newborn cal�rumaBCS��)�!�incub�� I2at 4°C ��Bftibod�dilk in hybrid n�5% �M) : '(i-GFP rabbi� lycle�a n0y ( 1∶1500/ 50� Mole:<Probe!��$ti-ChAT go�M D;Chemicoa$f-Islet : mono � 5 300 e 3�Q4D5; D&�2 al S��H% oma BanA��CA-� wash�>�6�x an h4a h!�4at room temper�e EF#� �)� : biotiny�-` -%��# )ormo'; 2200E�T�Eectas�hE8 ABC kit �DAB sub�?te�}( @ or )���$,immunohistoc%�s!ai� . Nissl� of�Ly4asi�Aed usa/standard? ced >���slb3� oun��EUKITTAn� �(um] ��/p�'��*g�5JtesI�e$tw�`%�u!n)� lbd abov��^6or�1le �; ��=�����>� ( 5%Is�A6% BSA��mM MgCl����3��}�MQ�e�IGi�2�If(� (Ao, BABC�:,2N Pax6 'J�.x< .RCov��A�.*Phox2b��Tattyn et al . , 1997 ) E75��gifY!4Go�����E 76$Santa Cruz~+�� ��w6& calbn Y2){SwM>�calretaY .30�4.gu�H pi7Dti-9# -1 -g5Mkgner [84a6.nAI = �< J . Johns�� Gr 0A#bo��) fluo&�a= tWB>���h( 1:�A�(1% Triton-X���6���:>-��y|�����Alexa F� 488 ( grE)i����sB�,2A59� F?,F=6R=�I�4E JycefE�����*e2*�"� �VVVitu:�onVh!eme��of"; 2�c�K� in8:c!WI���s��+�GeѪ���<ly*2[85q�s# A�y ��digoxi n-� ed ( R�E� ��) rib� 9 A������2TbxH �L ,�Jb�D�QH�?,e� i�, Barhl)80RCr�)*� ��%��:CP8/d�4WT ( n = 4Q �1"c6 �di�b!�VR � . AABs �a�esDDbocyan� dye DiI (NB!�pla�uni� rw0h�  (Fo�/e\).{ah cran�)�aX�3� !�1� 3� th�59fqOY9mEs�37°C; a� y$at RT �I�1� �025% sod� azid��$vibratome-� io�9( � µm-thic; �"reVN-^+r4G[86o2oA(.�ɱ$graph plot)n ± SE�* err� stat<c�'r �G� aris�A%A�~%t ent's t- !��4:UKp�QRI YRU�"Z#"�#of vari� ( ANOV)U�7y-ui:e hoc �; *e�1≤p< 5 , * .��*** %01�Jal� 1�i#�SEM ,��� U02^% �Ir"�in�H 1 M f��*� 19 m�R�2 M��E��0obasic NaH2POJ81~8bi62H6)�4 h� "!�ra�aG�F GIio�#ŋC�#%�"|$,:?Qp=>5-1% OsO4!A� sameh���.��1��C1�#�8-�s� �U*�� t�C~Zme�sub�9�e seri�4�r5 2�&�(oint drOB)$sR�f5luminumgb�spu�J co�MQg�% J�+�6�investiɃ�photo�u�,a JEOL 6700FE�k*gat 5 kV9d !3 mm wor��e�.:i2��colpF_Rig���a&T�&�&A*����fix)���d!�1% osmtete solu� (� kaYae� 05 ME���coo� {"c(r 1 h!o6�Q��ethano.E�,I5/.ylene ��em��E 812�H?Fl �Ii\[= B"e� cut y a Su�,4Nova Leica Ult�� emitQ�z 2 h� n�'Ssga �FmiZ cope�$olivar Rei�t-Jung�� �r�g � 1% toluid� blu@ Carlo Erb!�. �2�( 80 nm���<2% uranyl acetatREA�ron M�y Sci�)A�10�'!�B�a��*66%�6 ci!9�YaVX. Gridm�ex� �A1�t Z�Souu*�0( O�4)�)�2l6w10 non-�"�%�&$of 3060 µ��"i9&ng!��L:-��� . Q%�2 ve�)! dep !as!Ln)v:j (� ){!.me�+b�\� �\"K3 y or as _ 'or sign 9�#�0un�9edB� D5R� =�r �r �r Ѭo].Z�S um Saccha�1agu� gradan�W� 2-4�Sde )b emerKSE�vangu:of�'ea��iscA8ed �p a� estu#;e �av" recy�6� CC�s ��.�9� }*�)�9en33s&�%. �(p �U+  unusuI�O number�enzymu /d%e >10j� Not �=i2�Tn�B�[}r�]catabolLap�=, D��exhWZ� �7 itecJQ�lu�+?4O hlyiL!r"m-��;duU %S",z�"a�D �se&�Pa� adapaÁ�%#fac�>��de!�m2V)�xB��Menvironmp@�|J!Le~1�dI!�Eq =MFu�`a\n5���E wa`  &.�o�!Q�[carbon E� ��Atv,-a0i@[j� C.Hflu(�!|'�to under��=c`a� [g equ-�. M4F)� terT&�rokaryoJ)�ix CO2�8bs ;E.f� isT'!:Q�a�Ix0T119 p�uramM]%%� y -( PgC/y�on �!:?�64. Likew12,f �ic�" ("�)�Esyn�FAha�Oen�1�oce��� [oM�gS ynechoc�4�,d Procholorc,.�UjoQ �[bu�D[;> : What�re�'� m�TryA:whe�Y.��r3+eI�/al�6" M�a�wo��$9Ml �!, if so��*9�Ah�5Tbl�T��#m^-�2is�Awn\u� Ae:�97!�~a*N�E9r�Sd�E:�r4(eZ&A� [http://s� H . hq . nasa . gov/ �/�U/m�. htmlwT�Hi(V^�>eAbiofil(+�"kt� =B�8!� bloo&shWd�:en} 3rte��0!��-g=hig�$^�O�Ha-R�$,&�e�d��al��er�carry� ��s<h6L_ec�p[3�A�Ye%YbA��5t# r me@ nom� �� wide-����%�� expe*K reveap%�ge�&�tT>:TaxaEamo%7�Habundb6[�sE'R'recog2?=fga��AI�D�=a .�S��rEj�of�)io�c!T����+enW-;��$ao'recalb �NvF�A�F�. -atmC&er�� inpu5�� �� ;� m9A5bulbifDE��T"i� �2Ffree-liv�B< demo[`����lk b9��ulo1��^�16S rDNA&� uE��at��a m`� !�0gamma-subclas�uphylum��te.�]|6hydro u*] to T.ini�# sp� i7 �6 nitYUs� 1� A�symbio�E]-hipwormu �ifp:o�51��5M�e� clar� �< ith �U� ��&ap�1b?aA]i��#9tkh :ex�ew_4� 2:/6"/:l>� ��!m J �C. O�*2!偄r3 De��� 5 2�I�& .(&"2 dec�Wsal�}rskr� AL, S_4na%1�N flor&%e{#0sapeake Bay w���&�It�a pleom�@ic ram-�S�Aero3P, motileM�lU�x(uniqu�yc"�10�er ^x,��A�U , chiti�/(alginic aciAVM�s�β-gluca'l�� �  ullul st} ��xy[�3�}� a� �0 )ini�0ly�9��2�� �`�"QYa�m�eIZ� :"*4�A� “sD-)>er?���&ajMbreak#531 bp 35E^B &� e��"inU��d �J94map��?uKI�Nucleot�!1�c�mg� � �>NP� igjBf�l�� . Ov�auA�� � is 4aB8% G+$) A to*#vha�Mq-enM�gj ��P-aj� �094!+in leng�A!�,b%c !9665.��RO( ORF��\&aY�38!�202X:%4� ��!6 . 7%@(An"�C al 9 ^!�cl!kf��%seu#08p.gZ�%,u�iv!�otm�^%795Fc�a���NR�basA�t�� e-va� of <1e-5; i, 2994)�giv�O �:a�Ba� RdfgH3to a COG"�a070 P6��kerDE�t6M_ # 2575 �Q ���Bort�gm��Ys�m�OE��>c { jd umICA�l�xs�:����"5,  L.�%)� mona� L�_Hah a chejuen��C�ci�s홚1�v� �ism�A7O`ce) $J�s hip;~Ilittle sen� s&G>%]@ PE��s!|o�torN�J�U$>"�FG6I�>��r�n�awtRNw<nd�& rRNA�e clusl�Uoc� on*B �nd�CQ$ ).[�?�^�7atyTKl/K1� 6&aa�E .�im���90C%00��sQ.J$aeruginosaAK^W$ly 55–64.G�� �!�%5inN�a�����plu�nd Alo8ɵ� ">a�f�QiEtwo d;7g�fNe]1��>�(�_1099�Sde_1!()}%��ma}P�23S �� �Mlan5bya%a@ no�G���un&�"�Glow͗�>��s�aicadin0�� "�R�Ns�XvJr��?d s&<mK&��5L�ee� e g�G�M�/� ��>AQ;Ŗ!'s'$s! d�I.eu�e�cToq$y horiz� a�),iin-:�' %}n�}>We�e�}%�&PCodonW� �yhm�%71p,6�(grd2%iU �ynonyX1��( GC3��ndX�@c�-yNc�+Nc4!: 91c�yX! usags A42�of5">� as 4 3 ±3 . 6)�a�&� ate�)Qong]�A^ e~ 't�gd�db�"ed6W *of�R��0u6Due�c�� set�8d ?d��EZub�27 \w�f&� ^isF���se ?mma(Z!gBRh��2y.m�� �M �nE�CJ�v�an)R of 4�-2)�n aI@!�8±�R:!Nc%(4&96 4M:W7'se A���/�2to�Re�X2 , 35.k  141�;"7�.s�*dev on��m��t� ��m4scoA��Sur� ly�23�of 182�fU`\Ile�l>Mor CBMq }�2�t���9>at�F>� sour�P% ha� -:� !W�ofI��9; l� �0of6x1�>�Vur)�d>�"�nos~teg�TE�/g� E&��� nt 526536��56802IZ 8Ay0�e!Pa5�!��R@d v3o�q�(/ph�� �sach�<D�q�B-fEO�r#a 9±�%5�� �S�Q�>s��eNmAnA 140 bpOe�O�a� ��M��l*� �*A7ap��!s*�_unnEe< >95%%Vu )�%=re�MHl � at f��satV@te�3?!~M�(!�42304665-232951;$42953034-297423374�<-374389� 03937018-39435j44404545-441110r �se���G��%�nd��re!�aI  F z��()?pos(gen�exc�F:B� d�>�%�po���%a|_]Ea�!�e��s!e. N> :�,�9�" % %&V&f)a�s �du&�of jw.)dA�:C q�the O�J� 0462 & 3 �x @` 1818 ( 1819BS}� ^1"!W"Y,�(P0,_ 0426��lyQ�, �57 A, 182�� 045�� 8�uo12  $2� 6�o���to181�%�y3�/Fak� �of*�1�%��3e�la(A�jm��� 134591- a��R65; 341150-354005; 418539-430371; 764673-773707; 3837720-3846061; 4133935-4137958 )E�>��2�mg ( DUF15681(�I�k',�y.�\T �H�VF��=� ��%+#>�"�Sc�%({]tQC�Hs�ա�Twm��=p6a�E Lree IS:+9z+e��}F ( ISA]> B , C%r >O cos�15�p��|e� an 2�<�o%su1ang�=�274 K? 1� M�EacSn�)s "!)�A��f� 0rEo�5�i�JRum -)i /��q%n&[�10]���a�i- pI �  _ O<a�*rY��!I�"�jt� ws�|�H� �n,QdA7�!(.�#�lgB2�ss�c��V:0nd dinoflagelsa�)3[1�[o�tN�E help���ew�kJy7a������Y2�(*, vSbe�HRg�Jl�TAd.fbou) e Kb�>#&r�]��"�< v.120879" �Jr�a"1%ly/4. �A� m� ׀g�%y)&�>�%m�ytXQX�-�}?NhZ!� (�"�� �/&Ye1�K�'� Mb�;xV�Fs�w�� �&�M� !�e�Cel��he�V5r(%p�o�-��Yr mMF�g-!�:F��&G2�l! �mor ga| duca �K)p.o � �r�W xL O� Jm"�f�M!2�"�$bK� A��ulo�!fun-,�@choderm� eseieY1&um Cl��i�;�'moM m [1|% �E4v�0 ��.Q|.{u y%ucose* mc?,t�QnVNsi�&i#Gji�"���F!��l�%��ade!G +��36�F�k�-�or�a� .075V<*�[�A�v+�a�)s�)�Ofermi��= .�)de_0348� 3180  ���&��SQlpr�'�5 ��be vie: MISw%#�'SI�T�N)&:��(FX'orn�'�(mis�1C�:�o� �5!�e����A��+eL0%iG COG'�/vot L��2�t��+ M��"�8.!�N�; S� )tr}i�*an6.�1E two-5�R�'n�q�ra��)4[��� �feͺ -: �Y�\� 6�� EqN0do�!�� a�2IX>/dtn5�20%ako|A�'16��31 AraC-%2�� e�t�tJ�.saL��E�=J>��, Shewan� !�,t<bA ytoplasmi;��jdZ�5�$o�u�asB��ƥ'> �_�{��c "�X�#m+!��)�� T�U6's6x!�N  a�.&15��� PN!�^!� .:RQ�isuq-��l� �- by s�u*� 6N_&� ��A-F)�aF ΏY�>V�or�Q�&�:)[2��)m�f�4��mN6ontexv!vic�)H'!�}92���X"�  A�rmA�R"�%x4xJ&y���s� 872/��lp*.�(b� Mos~5> x�] ��Seee6�~!� an� ;"8413316>E7��p�CogA{Weg�<"T {��!1�s'%%kve� tegyEg�c�H)H*sb63K �! s ne�8A��.�0 "l EI�nse� KA�Z;d�e(e IV pili-bЌ��va��gM�>� :n��re��t@!['�Rotaxis �q2hA�����xch�by.Jh`din{SrKs�-4A GI:90020168/n 51E  1806216 a3����v�ExZ8or� 5���� 2749�3,� �326 62gt!�v9�  :�1} �-F nav4DArjutr1z��*��u�9���E�5�a�Aolid& s�Ba�-�'7�e=~�al��� net�DE(�13!��A�ymń6r!3i�b5�/ al�s��+8[M�8]� CheY���7�"MV|;�Pg �Yk2��.�+L.i[5�A�A|��9wzatO2!�%�7��rA)s�i�,��%3"�<u,�zsewed"�r� *�=>��qirE��e"�nrobus�b� ^�I!�,�� u"�(��� te Sec 9 b5g1�t�'լSɭ P&f�.ed 106�#d�Tat ]ed;� ( �#.(/9D�!v peri� v�m1� Xit xA� I k!� ��X�b!yU�ka�+e�Hly HlyDK TolCa��"s]� pBo 9t�r� �.�Jo�L�� �BJ� �� cryp��xy]�+�I�,!�Im  {�d?E+���a�ly obw�!w�")!;�� af��%?RTX toxi�s0goo��nd����T�c*�ge9E7]cE��6u�5� �$ ( TE I ) H [sxC n I���"��1ly��EvcriLd8gspCDEFGHIJKLMN ���A &�!t�; Klebsi�pul9�A�o� ��#�gspD-G"��tn8�W��#8 spEFHax1sx GspOAdV(A���%<i2�.�*�2v�}E }%r������,�PulYn/=� �e"RJgsp1��o*qJ�A:�x!aA�~6��!3b,YG�.�HX$���7&� i�����x=�$����<c=!eaH S���g ?!T-�i����&`5� V-� tKc� �k�� �A�A"L>��di� vas& j,+�Z� � )cXBA�Vv9��0of Glycosyl HW<� ( GH �s�fQ/ HC*CM6 te-AW+E) weIE�bwww�AZY�7A���@BGHse�"�*to 11kA8� �� i�v"�E�![Oeaattac %�TUolj>��6 arf:e�F�6&V.G ��60�rHiJ[.4�h* d�o���Bkon0!�����#-af9t}:ha8 �� ņ1�:;�)��O.� Xs!BQ4��int�e3proAG7"�i�)B�a�u� �y"�"t1Czledu"�@aix l���:�dMu`b&Tu)��{6���se �,�4�� 2 F50&� �Us,�vY�8�-,!@Z R!� Bs +�} �> >@� CBMs�ow"@1��m�i�p!�[)�inq=�j n aque�%.�H[2�Pol�n�a��}tėd���&��syncK�1Aviv��F2�>&2,�ϡ*u��p�f.jdo-�6ngv�:.�ex#R�i � �be�($o�Y��ch�(#ako�aX�%��iWdo�>�^��s�'�B V�+R Jd& Q�el>n�}��Dhincorpo�“iV� -�A!�as ��Z1!4 h�a(chievqcte���Is�7Cgmx[2' 25�${: 2 ila �.��d;2/ � �GH��?T e�?>{T . TB]��ղ;�P>!;f% Withks� AP128+�o7=��#!�p)z.isIs�E̡7����d;!B!�U�anks 3rd�al<4007?G)4�.�A\2�Ey��s^:( w�caz� org/�-1�.!�3 ORF'��s���'o*�� , :�!bV �;�H!Pamyi,y!0556-S!60abinoxyl!s%� +777 +78�, �A.#93 #953b!�/B& 3272I 3286%��2g �kM)k"� i�pd�v�!m � ���H(h�� �~ Q�M:�f � h"�� ��OemuG�"u {Am��\eeu�; s!,G>S!4. S]TH�O})�\�� Sb�%ed DC�S!����3in�G�)�$galactans;-�rhamn��onan;�C�3Pg 4 ) W ,�Cs;3rch��!�ge&�C; man�,Co� �w$"�@�4D 98!�))�E��z�dRis ver2�-!��QI��E�, j � pE.h��"�A.=O�N "�E�u�E Cell�_(io japonicuA�dewt[26�g��JAa�)����3(5A)�um� ��"B��.Y�C .�7U��evo4Z��Bion�<2�iW!GiMN�m#7,!P �E+logW �6kO����2ng��a%>�P�UI�KL� �I#-��)��q�&�`l=#UG�m��s eight8 o-βi+mE4;�a�,"/*��%} 6��Ѩ u� al2�C� [viz .4 ombod!za�TSP�!�cad>Ln-�( CADGAEB-*� tifsP�,�not"���A�>(��:33:_ ly-PLs� S�b , fa� tn&�%;yM� AB�|Cota�F$(1(, ErwiniHWwvor�e1�. >sy� 0ae pv . phaseNUol2h0!0�uY �Y�% .(�D��lly )f PL| a*J"�!8e=� A��dop� A35a$�!r �|�9�er�:��ntire�t,NE}tor#� gene&_ .�rnt}�6!�5���EaaXaV por�  n��� n be���w �N�/��> S_/F�@2� Xiq�z!q�}pp"�;"|9{ ��'� re!�n-quar�Z � >180*� te �m6*X7ser�2�5!�PSL PA�b�a�%ߌK�rat!�E��proline/�on^q�E0 �k*%�j!FK"�)��%lso>�Ej�>��of:Ő, [��g�pNb�� {$�(�(-��(m��S�|6Y1!?K&&T> CBM-�����!S� �t� ��` vsH>)� *g+yc}��_g2st�(H"*i� 0mA��tl�<a����m �U�� ��� �-3r�� �#dn�t �.r��Ym�I yv e�,��fF�As0teA�&� >Jvia �H'~rapid�[� �m1benefitAi�ho�q =b�?-IndΩ*"Y“ �ing|�� ��!%k|%om6&�` "�!�\>�� e��1��lpl� t,6P�2!ޅ^*�\ca�P �"�  avidA�PA].���[2�([30�.2� l�r�6�5�0�G ar�Q�_:b�[� �U�. e)�Xinut �ct�j9W�Ō�ddissip� 2Q�M�6��1�F6��>f>��#& &_ yU A-i� a�e K.| ]!�/�pP@&�L.�$���.� �� ���le�& ��E� ( 12�<"� Wyy.�Vd�Yc /g��Ő.�thalian 9� !q�Magna he g-%6�.cmo sapie�3� �, huge}�AJ � ( 119J\��p ���� _Ez�"��))C�qale-�Q�2�1��2�CBMY}qY-�A 7n��Sh � ���5Y/ �X"�X6�!�y��[;��ex67"6m �4�,o�9�gmp�B u��,k>or��8�:y$�� �V��g!�6::�*!�,Y��0c �+s�R�CB)u�)x1v,�Tőg�7�׶v}�.�MV�_w�t�uc�l��:U��)� � dra� expa;*a��i�&{ �=3(�U��-81��3.(25�)�!La�#~>)�>R ��le�������su $z$��2���� U "�K' �C� e)aA+ �A����Y32!T+�i GH16Ar0 )s"O, CBM6�C��e�2�5g� �7| A�i����^lig��!_� �j?��X�/�1rD\A��� �Da� , D-� WD-��"$nd 3 , 6 d�mo-L[3`3I�3�]) ,A �l\�)���t�< �n. &m4 )�r�g at C�sN-YjylE?&�>C | uro(Dacid )9�.6IR�"Ji��/]�� suga �i NA<Y$ s D-�s!FL-gul.��X!g-�sjl)!n2:�A�A2M Ib 32A�;�"� w�@d!AX8K�Y>��u!��S�%NC2�"�6sbpy�&�d�ico5_ 5Z�>ߣ����� �q�2��. A������&;d_^Mm�TaM!�c��tfJ,&*#A+c=1tim "k.aSakQg�d� B&�#���KD�� "lx>��� "�?U��>-s:!_3�B�3870; 003 612 094 287/Iˊ:� ��bo��6�)Z���7��"�7i�u>�"F��Lea6e"� ��j[-�q -a�?� it w�%��#C~� � ��)� ( ii|��ur� ledg"u:�! �$�Par�B�lR�2g�A�a�1?�Xrge�&choq�1#2���#@ /#d�*OY�!����<[1��#�,.�Q )x`�"sA�11 ; [��)"�.Y ��Sa��ch-!� ��)#x�����"sG < */dtZ�I �s �(;$�Y�c�DGH�P!/�16�^H��GH86;))�]aO��c:u[��ed�\&u�A�2� �}�f�  or'�tCal:Q%�ex- `�A���R"�AW�growthJ !XV .n"�0,"(p;,{���g�)��qD�q=*OI��� )lA0�B2qRT-PCR"�i.@@monito�so-@ed �"ba) �+���eސa�A�no��!�r=�i�j� HWtAp5T&qA. ?bRgU:�1:�S$!l`"v�i*]\a�i*��re�BB*�A���=.a "�)on%�!!i'�E*%��� A=."�^!dA�2Aga16B�d 280-f�w�t4 h��Q��I1)|!g!in���of �� Ia��5I`�&�C-^*L�60%� . S��"��3 talk"a jE#�2e,R7��lyi�tSb��� �l��^7in ;�3(y }V( Avices)��Dd:g!�y��!�� n11A!*"W�w(Rcel5H.X 4uQ 4�#�$#%:~F��I��&�)� � n�RA"�c����o��/g�^%E�$1�!a��1����l� &��>�,Y trig�@a���,O4ens�-"uG���sp.�z:�2z r���aM-^<S, �^&�S! �E �0 �b� b0�]% �v�])�fV�flea*�[A{MQ���s}�lMF=��5"�G:Z]�,��t�y�"( PASC� CMlLA��!F , 4Ca�barley��an -(*tf�>K7y8m�+ iCe% broa�6'a&KA�)5A)r�O&8 sB�5�E�s�@�,�+a�� Q�� N�5kYd�C��i&uC�� D�V�� tras| a�m2np_n� %W0�"� A�!]n��-�-�or=�. N1U] TedQ�yU�)����?��H��, c8�4��D �%� nQ�Ao!�&�h�] �cul!�(:q?�)��Ɋc5utiliz8�ne&K,se��HiYB�M�4-7 Q�A�Y��?sEs%|th�h�*�nAbtrome��( MK�8a t*�\.� 65��E,$j E� �A�3��Uz;����.�sV*�+ Ced3ABS���1T �`�8� . FrE�.enHJ,�#,�Ynd!%��<co�rAD : 1-�=�* ^!4 )"�"` s; 2 Dma�Ř�9-�:�ex� =,�7�Am s-s ; 3-e� �C��!Oq�<�M6�%���S��N�Sq oF&as9 grew����W�N�Hf)ΩQ� ��9�W8"w�doO-� One 5 v�cam� �^th5�� u.?di�iс�min���Ru�L MM )vU<�$urid���bit�`w|numerA�� rw( �Tin MM+ 2%5� ( 51x g�:,"wa l߲r�4'� eril�&ro(� .L����or fil�#pa�w . Gr��PA�ur!� *��)��!m!�%�/CP�co�  ��� 1�e * la��iO7A����.�#��ar� P%j!hav!��ha��l� "Dhl|K��&�&v�lyp��l��^Sde031i!(ros7 �%2$e�;ox/-709�N243 *Sde28��T�!^� phys&rKU�.-���;�P pEit9_,Remazol Bril?t B�hz RBBR� �` B 41[,�w*�y4(lQ14� �Ұ!wi�Wn y cl�cIf�CAH6�aɋ!�15%!�!F@PŜY��ECM�"Y�.(0�rm� ��rb�� bel�6#b�'a� �:�b�q 1e]z)��U�.��mo�BQElog�rhm=N�-/j � A7on"��|aC�A�J��� 22�!P!�a��v�1"�jSA)�A~ rotu�8��b� W �E8FiZ�\.�󹩘s�k!F2.�!�;��*oy��X��%�)-��&�d͉0eoO six M���^wo&�|iKt*ro�c��Y��2� fu^ ��� ���e�A��$y���re��o{v�sI�6S2%<iC �t.��� r�57"�1y$��>,el> �s+.�� a��� re"�:"�}���h 6�,2�� w A��+jdia�t� !i�"9 �"�[&�6�*{�PYzav="�N=�>���Nm�a�yy� �q�‚{!� p� � � wa�p. G5s��p7se�.A=oR_l�)�>( ol�#(/�N^�aa��Nk.�y� *"*,{+~um�'����an� ort��,v+ �%�n uWe . W2_hotgu�H�Aa�A�@sh?�)� |�< US D�0t�jE>y J�/ G�&�a�JG8FE�!5lU�rF*k� ��Ϊ�8�, Rat:}z;jg do� �ZC�aC6�B.a ef� T�� randomly^�*�=a;<sԮ�kc�Genemach%�, San ���CՕ� frag!,!�re��nt-end�ai��u|  T4E52:KlenowA�H6L�Q�'�agafg>le�pmP���&+- pUC1��∼3 kb_@ert�d, pMCLˡ(76or35.��CC1Fo EpiB�r�iMad� , WIL�O� Eb� �� to&�sDH10Bŵ�Tcolona�8picKr� 384-epQZ"m ADLB�T:e�Q.%�Y&%�")��Bo�+g zl Bp>�� ( Teph��GE HeIY��( , PiscatawJ�NJ�(r Sprintpre+zAg�urt , B�# ly MA,magneJb��A� puri"��. Sx��s$�!�% ��'� dsMV&�+�vAEJ^��A�R�Big DyA�ABIY�o�u C,I�N�-Cs4. A2�C14Hh�e�K�ؑassemb<*er��8Phred/Phrad/ConTs��packa��44]Y!��.6u 6X cKH-��ke��9F�~B�&��A esol� �5I�ga}Io�*i�"!, custom-n�c�!\!ymanual ��n2 �e/��e�3R9�� K/�t81��"![��Xno���U . Au2=Sgen]U6� �!� \�5.� [45]큁�� 6-�#5 ! Glim+[4*��".�B,*�`!�2�`cro�`/mdeg/? vwp"hea��NR1> �~rr�8�z�K!o���<c|7�Q���GJ �KCTC 239X�>��C8�p[As��)�^=iŪJo�"� �.zB genu�U`$s�� co�A�sor�\n�'=.��� ��<��UC6��".�C:���rɽxvlgYi"&� S"e�Artemis�j��T� 50� 5;gEi �� Q6Q�KAB�\rt�grenneP99~� "��uf���A7c�4 �-�=�!�6ZAWalX��83 [51])9l� ; Q�1in�Ztr] �!dD9wD ��^��i*s AO8A hidden Markovi� [52Y H�@��HMMbuil�td�ins��� a���HMMQ� (�pr�msYJHMMER"� &* Ek�'hT . wust<edu� �_�-<c)&!�J��a!��]�=v!�+e� chos�D�Z}�'BF� S9'-��ec �({aX:�f��ft� ncbi . niK��blast/Oׁrs�!p�I�m�>^E�q|cagtte� A !B�Idb1�)|<�.nM  ���%�!"$e���1^�:��h-��llz.h� ���M <qu�K . Ho�\�"�M Q endB��~ �iFa��} )B%�@6l90%-lt;?�(.&�giD ]nk#�7��d�P 7��,( ATCC43961T�r4�t 27° C� ��sta@M�e�/�Gp: 4�(7 g/L Difco&Br"22;;m�6�� 5%�Hr�&�@_$b2� u"e$a�n�(�g �F:��g|��O#� Se[|l�H_GI�Men[, O�X, 1 g Y> �\G0�Tr���&r�A��$05%KQ /v ) NH4C�,MMEUL(l2�120"{$6�*,&�Y8�(.�!�ect B> Rea��qmi[7%X�U liqu�� )��  2S�O$io�!��� N���5g Usu�)e A9hare�1 wue�3yM,Rneasy Mini ��@( Qiagen ) . A cD��NA copy was generated using the QiantiTect Reverse Transcription Kit according to the manufacturer's instruction . Primer pairs were designed to amplify 120 and 180 bp regions internal to the open reading frame of the gene being investiga�8. The housekeep��\ guanylate kinase ( GK )%selec=$as control Hx20 µl qualitative RT-PCR react!"system8ains 1 3�of 2× LightCycler 480 SYBR Green Master , 1 dof cDNA `each 5 µM forward and re)�primers7�Lof dH2O . Real-time �Dwas performed on a � �(( Roche ) ,��E!hcondi!-�las follows: initial denatura' at 95°C� 4 min� 45 c!2s�! 15 s , 562!72820 s . Sde 2-40�`grown in 1 L shake flasks�!�� MM amendeE��0 . 2% ( wt/vol ) dried Spartina alterniflora leave�\Avicel , birchwood xylan8arley beta-gluclaminari!or ose�Rh,( saltmarsh a� grass%�found�iaA0tidal wetland�0has a cell waPith approx . 10% lign��$remainder ifhem�lul�,N !�!0sum!;!� pellet�.�-�in���S9��us)!% -Myc2�conEe� to ∼25X_CE|cona�M!� dea�Hs ( Millipore ) . PMsPžE�determinY9AyQ�%� (Q�M2� !���duced��lkž%V450 mM iodoacet��-digiKovern�x�a37�e��omics�:$de trypsin�romega�DH�.,RPHPLC-MS/MS^!�,UMCP College!�DLife Sciences CORE��s S�"h try facilE�8s previously de{bed [1e-AlA ptidea�gmAA massQ�.��p -Lsis packages SEQUEST%,DMASCOT [54] , [55]compa!}to ��(o acid sequ� transl��E~�L(gene modelsAI��draft"omeatA non-�#ndantJDatab�$D( ftp://ftp . ncbi ih . gov/aknce�� shif�u from$III� )A}= E& To d�D,s4exact mechanis����displacee���$ill not kn` ��ex ( CT)!"quitoes%��%5(common spec��ChS 0nd play an es�)0 roleaWmai"� ! enzo%�e�mission7 . IA���z , we used �pipiens��%5 �P r vivo$i�!B expl�ifes�A� poten2��5w%� . WeIo�femaleb�orallyzither GI��%�[str- . Midgut�h!5mo� , se� | organAL!psalivg* ofT-inA�ed.D��c��* t 7C14 day�pa Z �TeA vector� both!��5�9 ,� simi� �A�� owth9# . AfOah establishe�ofA,V�es=b��A_Q�s!�BFa� � ��i.�$. A few GIFVB ( 16z )Ipp��!zfoE���� as); �un} c�!��wE�A�. How] , 29 . 45/17 I�3�3 8/22Z�-5֖|aBpi , re��lya�how� a��crq A�!�5!v . N_ st�cdiffer�i� ��&5 betw�Gr�f as� e�. Our��e|nt�:a demoW �.GI5)�es have>�� j�,| � ! ZRies.�mayř�N cri)�L!BQص� Alth�eA currޅ� obta� sol!��2��>�e�]it�$lik,�a�/ luŪ0drawn could b� trapo� % �o2ginR� �is on� klea�A"�cai2Mworld [1�AcX%lo WHealth�7iz�( WHO���an 24��1�South���W� rn Pac2 reg Eex� to�[� 2��2� include�FvertebA|� bird�!piga�llin6,�"� Like o�d arbo%%%��� lso�t�%y s�.al�.�, Aed�Aa�SAnophel '�RArmige.( Ar .%V�"# [� 4!��E{�%Hreceiv�uch at�v�be!��qyqmajorIdA � �  [� 5wP!K!�wa�c-dct!Uan �ifying/�rvoir h 4A�r ���m� 1 E�in it�|pere[6rUsu�,1} �%xe|���!�/%�� suscepti� �by.)[7`Hum [ conside� dead end 8- i!G,5Ih ? ed�A'seldom8 elop highan emiaa�refa3,.�ca get Pk�JE*� ! 4 [8�l�� sense RNA�� me belongm�fl"� genus�in(idae family three5 u�al%�A�n�stW�. Phylo� &�ind� [�it�f��geograph��l� d epidemM d��nc!$n� a��I-� . G 6� ha�`e�� 7 t�arsourc�<outbreakB� y� . ItkA6A�ly cir\!j$until 1990!Ao� A� , bute�|ud�+e��� �emerg��A}��  ) which 4� d� [9–2.�[�,�divedIdVietnam)�pratojs North ,�apy N3Korea [1:���&C�aea�� A�� is unMA}�of�is� multi&! !:!�aAi�Utit 24–48rsa3.l�*�lye�er��avi��n& �s� *� �� T{;�mpl!�E��.�ve ab ��uy���on�E0result]�de cub�� od v � Aj>�=>_15�vAn�c'sc�,m�s �al5�i~e�-�m�be due��&� �A#J�gNS5�� -dep�nt polymer5&� E�%�'�at)LelpA\t� hiev�re effi�a�Yk[1ř.' seu`ly�vi@data ]s u%xde�our� r�:f ab�m �Al� �8:�!%vol��i� �:nAwto!\eluci�d .femploysQ�e"co2g �p��}.din � e [1�RIn ad�@!�well-chaWeriK�m���b��m�d� wid� �]17Yof �re�sC s � >theiler� ��st�0quinquefasciafusco�-,annulirostriyBgelid$whitmorerE"sm"vishnu AADpseudo6�20^co : s� subalb �� vex8 � 4 . lineatopenn nd � sinen��[1�S% 1�6m�� ribu���,� �T�N4��>�t b�F�,E�Y���rEzY�[19�42�6� m# M�.31-� heI� , #i emper9P , �liv�Hc�� � w�� * anim��[20N��! 2� . �al-�cer4!1asuPF�M&Bsb86�E�%'1�%nA�j.A� &%)��D��s6�. GivA at��S |�T-�v�t�u +�� �]@�R�q ��&��;e�� ���3.f�/ �"&.Av��!� '�Nd�!?o� A-ns�� into�� v1p�R^�&�>��%�f�z`,=.^,a�:�* 2a���A��� .�1#� :�%Xj . Ualbopic�XC6/36MR% �� t 28�Xin SILAC™ RPMI 1640 (�Techn�es Lt�cGr�CIs , USA� Baby Hams0Kidney BHK-21f�3@in Dulbecco ModifM#13-�heA�oAtr c� :�. A.\ pi saq�9L�U�7���tit�on �j&�+by���y�26��7]F��o�� x B [28i Iu�Z�defVa+e*]k���us�� �.� 1�byETto &PN t�dn#2�B� S�B *N �� hom�EV. m!( leg  7 head� mongB�"� �U.�B��@>"zI>�J�>�caught!G% aspiM�%=�n&��us�Z��.��s.��ual�EO�Gu� r � e�(roscop$S� �,g.a\toqZ-t�EQvn)r[30/(B�a�T6�"�>d-B(Ah�(�ly!< Cole&+l �. W�.����#)i-�-.� .�%avoid !s- ��S us aeSI�a��I$!�>�e #�% %� care�Y)�4 $!��!�_ dipp�( 75% ethano� llo�>al��[��. Q�Z�'6of O1�M �f$>' 2�=�&�*method�]% Stud�t-�m�%0Fisher’s Ex���A+/�!"�*$. A p valu<�005>*�*��\ Pad�3s� ftw�(7p�"�u� �*V� � J� e�*�LI'��H'de?'Ai���.''&�qB�%*� 5|P&MM ss to"Bu.� [3-3T_/�we�K� ��r*d�inmp�2utoM �(ts�ceE?yQ"g��.��Z�ly 'lN�a�six!1<� ebgroupia"% &�E,�N�.5 �|  a2��-6.%�2a��$i.%*A�obser?&�N�%�� Ta�1)"K.�6� F�%!g��.0�� �&!]&�*� ��Aa�%)�e(1j42 . 8�&12/28q F ? R37 . 77/4�-atgO'X����$(5:5: 9/33>Y44�'( 23/52  �i�I*'%N�%M-� �,|.\-�( p =�518��=�:,( 3 . 083log-^/m�5!NF1!;748>1%U(( / 1 .'(A�J�<s# ec+d=uin�J.�!%  �no2�]�= 0Yi#9p"6+-3�i-�&�'B1%0>�v037>0-!Be#Cumo4iv� : "2��Ne����8+"8+�rF)if vari�  ,���es [3�%336 w��!t��U� "�,"JR5�� :�-. F� �� .U%[VE�p �{�!�m� ��.1�-�6m?��. A� �272��fp, 9t17I��ed&F ���B�While�#�]29<25:���13 �2��z.�-5��a�& :�fur�E�4"}��J�� �+b�J�vW>�A�� at��&�/pf4As�},��4Z���>XE}��216+E�d( n = ��Ճ)4� ly���210�e)`(��856f) �Nv���2��A�R� i9B*R� �1� lso r>&c$t,�6���DY&f/5�9H185!{-��Oveo2�Wsej$W�l%. a�Q�9 I.�R�3%.whee0aU�]�6--�e8�B�,buE�_�X�(:�'AB\�,��Z�� ^�%��^* (fZ�:)��� �sL( yW.L��9MAm �O~P�Li�V� , p>�999A�!a͓A�N$," 6984.2�Q �F�!N�2�$as���?.��6�~� P tAi%�( 39 5% ) b.n]���. S/3�'�"e &� .}\ qg!,�/}| 7i( �-�{� f�^�9=e85B�+ark4��� YQc��i˅S�6?ys cru�""A 2Bof*�� 27 ,� , 38n� ��9 loada >�iLR�30<H"c!. ^_�12�%��z���mw"{� ��>;2�7.��>(�3r 12^= , two.N� �c>Zuave�4��Q� a���.TRL E13iN  ��_g 3A ,�3�1&W1��5F�R�s���6� ;%A�Nat �+E!�5ᡛ��.J�>5$s>P��~� �a0>��,Q1��[��6&2 �I�a!�?8gC=2c&�664��L;(U3&�U� b�Z�M�I�0*�t&�#�/ata,u<+ st g�?&�m�barrie�Dthe�<R/B6e�1ɶ^!!M#$Y�inB<!<V3t? e=i2�a� [39 , 4�'Altog^ t�ш:�!J^�S1��r2�ofO "x��225A�s . I��Cp1,&�,�@rt !�EGIE��+taken�B� ��i)fre�AAg�'d�"!,a*0�1�7�6[4�4�mB?�0a�t>?unclea�!AUS���:�Y(�#�E�.-0on6M *�%�Jŋ�H!Oi(�0�5)5}�-9play .)r�'R�s *%r�?�u')�D�"A�*[44�16�C!!㶹*EX*-*behav!B[20A�B�.Z � easy��b ��e"�#~+�� *_5,in laborator�@��" [48–5e�E�s3�0JEV� !�:���� �6i8EW to)P6G&ufas��*"�n�0ve�yO&E$on [5::��%�> ein��$)/�� Q�� M�r�"�1�B�iaY�1im���2},/Q��0M=]&�8.4 �-"-I�-͟Ŕ� a�;��i0��JE ca�p�"Z �a�5e/very les�ki��BK( 1e ae�pop�-I;1Q( >60-[45y s9��%�-�1t��By��6�:a/2�_&2P<&�2:Q�%D� on�: ( 83 ��052]�t ��H&�:! �#�:0:�(m83�B��<<,%�Au!N!��3inv"�3=�� 1�nd�_�|!p'ŤWFvA�"XIM��R�!�ef�4cyAB ��&4�N�3E�y�ell�i Cf�:�v&� %Żm� 2�/��Z�rP �� ��MB�LA  f n�#N,R��G5! ( S&,)� "I6$&�+)��-�k^�n.J�+-0V,�)�"J,Es.5"�1R�lI erag6�,��i��A��Y� �6%, swine%O92z:T�L�1)�_-s�"�pa�n�v; �5R�NW{*�B:�n����1Hp !�t6�JBf0W aX� � e�:�E��� Bj�H edjkyr]�(�8�,*�&�RR �(F(FdFp'.aU!e��� '- >ww 0�to"�E6*&Q2D.� >�1�� 2gb� .r��2SIv��� )�(As �.,^:Y�m��E��E��E�E&��L*DE! g"�X�)us� a�8`2r6&ᔉJR�"en�<,"��<3Eg{9"56U�P/�E� �(%nfirmB�..+ tro� $��ca���A<� ,4�nݕ���>Qk����8oi���X��i6� is p%W% ! trast)J�.�]�r.J�y*9�)�sE.� ^�.�2�3 łs;E �a&�%�v6�[� �E#�L �:*,N�AEB ���N��AAmeriQX�q>|<1���I�!"E�AZ���' �E��"� � v ma&)8m2" B#a19~:4vW2h>�es �+��I�A�Bisy�(S� Wispela?!s+’6�[8T5�the�D alyz� %a?6\DEuropean)]ft du�T1_ic&fKM��.6@"@*��s�%E� ��ficW7 genyX[4�5b5�CQ6ex�Fmut)*pr 8of�L Nn$��LNa{N�1ieA.�! �"B �.F�0q��!episo(L)� �r�advantagG �Jip fitn�O"e�re�OCDn;"become�8tgIAYAJvi6f1-ĉ�6�(& s [5lo i� t �GAO�!�z,#)Rry*�Tj�21�)�ŚA�ILQM�& �W drif�/att�B} enhiWd��1�=� J convZInt evoS9 . Fu_6Q �L A���a=mm�<^�2*w �a��v�AshRo A�(%X�:N�I�)�^�� �vus�1���Fa!��Tm% �X�G�\ej�Wi X)�v6�O wild�!n0N�i!�*CP�6)|O�cS 5�D:�F0,X~>Ci ��q*+�inlg8E�4 K1 porka�ustry�;n�~oneXlK^8"wit�M!R6ZtwentyG[��&cl�-�aiml of�brs: farmN%uburba�Ce��he risk;"p[59?DBi�Q^/%n�> P-�Q_�u'6�8%$es2O�aJ]OY!�Hal%)iXorchalleO.�y�H , 60–6xRI�?0Sait1t al .> ETdu�;� � .��Q(in Hakkaido�P�\ [6�T�" /*2� Yang�  .e_� h�d9,84%-88+$sero-� �a� aGin�Q�@Q!�luŕ �[6�2AA� K�!2�MF^�5�=��of waS cA�A9incid�&%��re�d���_@�fyWy labI�6GI/ 2�K<[bX �A"�M porc��,��r3Mu EXp�gh��29/(9−225 . 3$Od #e�?a�0B���oi�!oll�eCv�>ax!@�a��ly �Qer .c�� ? �-iNo�I})Pe�)<t�s/)��AB�SA[����� n*�L�f%f�6��U�Spph*LRAza�� ]AMm.�J�>hNami�a�/%*$ Y%fE,� "�R2{Iz?AVzen�Mx�f%���nUak�D� }dAd path� ic��[��1�6gAR|n�Yu�S � 5.�6T_ �thVdm�Z 5’POcapXS, )r*?1�� onX�fer�' e [6� IoV�al?oj$ comb1.&,)�:�A=�Lz�6�y . *6 ue�Y�2�U&����&�F�.�Q0 &:�E_jH:�atb��' a���H"�_�8�8�8F8��^��^�^ �rDengu��}F�#fas� �Xc q&-borneAyDpis afaf���p opleD&;8tr-M�Zubc�rU. Malay�YA� larg,�&Z� � T �Naimajfa�a;�Z!�9�B& U�4s1o!TE&d sdeath���l��U� tro = ew� �?6G��oc�`d iontR"�1st Janu�20173 Dece�U201�+ Rele��#�je�`F6e� mort\i�mv�X ��2�a m��$Ucatego�GBPire�L<15-�)�) dult�1J59p elde� ( ≥60Q�!�irf��MFof 322:[�)|�ThNm�age�4�2 7±1Nd3�, half @�gI*7Q 5%  �e1 n"� �firstA��Cc�C�hospi!��a��k39K:}.bEabe@ @ypWanL=�)co-morb�Ka;z/ �91u �g :war%U3?`A��l�Crg vomi ("403.�r� d&Q,�l� s l p�O5�/3r.teS a� �k4GN. But� 4% � any:� . Only 34-�sQNe%gi�ill�N7i� i7j&�"�NM� �&!sRWe\ sma� �n.�1! �K�cEq ( 54�&suA0$T]- a�}&� �F2A�2 �f`e��F3. �ۍĕx �E�a4sM�post-ad�@$shock synd1p�LS�QA�`�u%�ti�N9] ~,�"$F-4F� ( 69!A� %bl (c"b���, -� m��wariD��� 9���A�Al� ���c�athe�gar�Fe�L�1iV atype�2,� dynaZ re�R�NI/ ��c ohor?u mpts��cogA�o!Sag Iv�t3Cn�B�E]�-. N� al"�P4Research Regis�( NMRR ,@-14-1374-23352 ) M=& &)1tif7T�)�,b4Old �fO� ��fgt!�st u76 b.T]ON^.Q!�"^�+�n>p-E��Tng1�, O�+subQ�o� �J#���I�5�+s [�Si�AZ��!�U�y90�=M)d1o!f@ 9� by 1973 [�Js,e{Ow�%|f� Y& ���'-.+cov&eTt�' deca]Tpre��w DENV�� 2^B/"�� esca�Rng*�1]r(gn� �! �12sy�3 �+irUgr��?y�x ly 8_�f.| I)w �d &��N103m 2000!�4cB46 1%a dO#ic��so 108�98 14 ��%#re is�$curwI��hu, apart g��Jtreat�d�+)��Ab��to look�?AمC�b; $haemorrhag�t��% �sVUfoc�MoW� paͱ iH'terti$  �j[A�Lo� pusped on�� ologe=* %��" � rz�E~�A�5 _/ l�r ik ai�"� M�Gcj��vA36�KmN�n�? A�"/ ! _$��>� q =al��j����9�-�y� ��g"`in��q�� �� N���Yal5d��.`� mand�4$ All�a&f �HndC.�$ set� . Doa"sZag!�)�k �7iW4mplete%�submi�"�A5�V]�Minof.�^.z�"� by av 5in&mf (ul9"s "Q&��al tF�mee!s  Vby ��AeTjof�Xar�!!uq}v�"detail�]a!>toq��&j�F iagno`,��n#anage��!��RE�Q s.Y  �� t:D1�A�ed*en4OlyJ}(�� eams� �%2~ zk"s �#aba�im[[ �A��]ngt�$����R!7re_}}qm�I2�-q�pur�pA�%��� iscus �u docu![�y�Ig� lis�O.�na�emre��Ŷ!VQvBDC�� Divi�, J,�E~desig����/|�21H,�Ch� �D��bas}em&�,A�-ex�ng>;,��!�out� �*��m1H��|Eed|��V*�bZ�@t���2�d�[m�[ch�`"}�S!@�MB�_age�Z�!�Dnhil�z_&�,�6�i�e�!.�. Two�� eng*IRex�}�!B$52is&V��a��!�Yi�Qa���"" Ef��/ 1 .%, 9A( Z�m*fer�@a'�t2�!guj�[�"�Z�1��/>ero"I2��*�pglyco� 1 ( NS"R%�(LJ�B�>���!sC]ge!O_!&IgG e�\&ra�����T| !,)_-��?'*� al rapid � ( St rd D�YL BIOLINEDuo ,/")�(enzyme-link�%! sorb� A( ( ELItdhy` at lj y�,Ss^%1�8~���"�P� c��L�=�" Sela�^5 proc� wa/ �� if n-*���-]��'F_he class!G�7A�vXPF�F&�,��pa����)�%d""� alanA�a� Bf o and/!"asP� B#beyond!e0 iu/L)Sacօ�?r fail� . �e�:��� 3reA'3or �ner�p�hronic kEf^ . He0 Vbmyocardi��,2Yi�h?,& � onse�)6�+~0\"A E���le� árvRJ�9��$vyo�!| �ݏi3 cran*@"v�BJBTAmNste���Y�d�k!2�QbyFHEth�� Commvw"JG.���w�#i ���Cl�S�9�"al Pac��XSl&.�` am �� 2�V(SPSS: Inc . cago aj�h�z:�anonym�_�, �ipC^�a���exp6���0� c�p�r��!�e norm�)"�&gontinuA :[  Z" s ±an�dh��$Qo�?�n�gdi�o( 25tha1�A�, 7:�ZC��sF� ag"�!��SrdN!�wb�76� 2� F�3 eriaN��|E?���)�&%]ɰP�onA -Squ���!��& two-�n�EatQ~� ���@l�! , p-X],en�'at�05�&�~�IO! ^ u "� 322 J�,�g94��&J2&�IiA.%���"�_AK6a�� �8e2�Zn whA1�YeK2_ "Ea��::J� �you�er� a 10-day yf�!O�who d�of�A�z786%90-�A lady)<�:�.U6\E�,upper gastroO/�4al.Major�%"� work aq �O] them 5pregn�ome� succ�td �v . H of�%�( 5YP2��)5A���)�� �.of� eth�g6 T#P(�^\KIn�.�Cz!��&r Yr No �LfA!X.l�e z�� ��+YIOUpv 8��%�!�dec�!da��0�B_igwvG��K�Jw�v814 Bangladeshi ��Indones�Nepal! Burm  wo TTk�ne Somal�E�r8 nA�B� in g�x!V ᵡ2�\82� f =:W�\664 dN"![ B1Q8�gC C09�]&� aQ�A 2$ݶof�� �2o�v 4%�t�`!�e��\&N&H2�qri�e��Bm�Q�%�"�w!�a pea�4�!a� ({�]O�m��h!�Ir"� m!�Pt a��rT�!�/44�_#st co�q=$��A�u 'ͧ9coG���e�one-thirg"i ( 3a@�S6�J�a�O.e�0, Kuala Lumpua-mzPerak (�G, Penang� .a�cca�T�.�S, Neg�xSembi��6_ , Kedah� . 60!kPerliA�A�F. E!0)6���qE "� ��-# ��PK ta�A�8% Pah�yp6 T�gganu8� /!��%1?, Sab���MSaraw%6%6�,�!!Z9��s�0z��;sta�&�at-�ZI�M��6�.2* "MGI=% �sa*��I�2�3��mon� N%b:"sym�r��. P��" seek&q�wiw�m&V$A�fday �s Z: �ds$h�E!��@R�?(�2 )� �)E msel 5�� Pf���s�M"crrq�o�cIh-= �{��)F6� 5�#3%�!-2L22p. A�}'1%���"�"�A��n:� $ �A|��Ta�9.��Q�A!�w!�.��� A�l&�a�d� &P5N� u4��Rde,P9>�iɑ��wE�y&J1)vAa!�Q'!w�s� . 2��)�-� W5́nd�d7%�o�� ( 7���&w)d�! �6unxg( ICU7 �� 8�<m ranA�"�f�-f� o=upoS0�'= !�I a� itorA�sta�O�'Q{��4%�err�d���(WAdg �i��rb !d1� Mean� ,���� *!9:� (�5�S]�� 6!_5%&�N�f�� �a1ELp=�&nF,� }2 �x�m{��ekm:2�9��r�D�dĜ��6J��M�>,N,E9�%� &b� �c283�C!, ! ) H,a"�, 8!� ,atv,!�at"B����Z����)5%" � i ��5B g�Glad� �11&f!�&��)�body mas�!dex�BM��.�3AL[)ob��+ 95th��&� "�$BMI-for-agę,6Hg we� ( 5th-8.Q)�!����3<6/"�B4114F,{s.�b�j~#C2� �J9kg/m�Mw��i1�)�30'�(j�jr�!,� � $�)T- {%2� ischau'�omy"e ,�� blockŮlux()Mbronch�sthma5�ob�iKRulm�� >m�(<:�)I8EL*�Y#� �&6Six)�sEC��rQ�an�ɇ:s��ct�"! ��.ah non-�0�����yT��-*q 7�1.� K�e � *�e��/8ry��<% r=��in.�  5y 1�-2dQ�l�it�m 8�� .=a�u��b2%%O)>�}N2�A2A�y��..6q�U"�/��est�V#/(�0f k��"l30(�0"�l&� mark��D�ng/'�t* �d. L�0F��!�5+@d>�63M��0��� ab�*�0;�ar��u&>?� �����lF�2���0=nUy�� Z  !aZ����ag%�� Y$Z��$%�}(~��) ��2waq�l��ltPf&6�ND1, n�v�=(�}���$:� �~{�6�,2`m1:.(@E,:�(F8!S���( ��f1]O������"�*:���G0�B�@ �i�Y# b�>��. N. vƞ>-K�=�yory� cK&�7�!%���mili7�%e| .NU�� �;��a���g5 ��"�^'s�@���&e_o�p�03mPߪ{�-y�ufen��Vpneumoni:�5�y� b&���ewaicd?M��i"�> to 7� 6%5�pi 4P 8 �d�6�orE�, 2��7%" jb`�2�E 1iQZ�. A2_a"� &�oO� Q��Xdn- i49�$��w�sa s�.(� e�V�2sepaO�W6EvS�IU���so"� �at"� s.�&&� , hA� giv%ris�(� lapp��!q@�u es 5%v!�| 285��a56�8�4A��s$D#@Ce�2v2�.6i$]�J=|h��vm�nd�7 �f&�&>1a_��3M�e.�!�in��"� W� # �2&%�e�1&NI;MU!k}8%K�72�1�2��w%�det *�%\of 196Y*(H.)�.9 20h �M�WS�R�:@,4:�:�, 3�1:&=!��1�day!+�@" O"�� ueK�%"'G:gGos>N�(6a�Ikd%�'ne�Bv�aԔ�Y�&�'<PCR�?Q>' W"Ed��lk �0fulfil�"ta�st � ��lKɟ��65��� F�%�6�~Hda�Y�v� pl2�9!zaDrd:�9 ^")$��fr6��:^,�#�B{x��"N ����,JN f:N6ߦ&�&>2 �M�E�:&�p��39R<0�x�%�oeh�%.9&lb< �B��j87B� 2 <,.�S %�*� �Q{� 140:�5�� nIW, 112 (EO)2�-I5��'a�>� � !���K� .'or ;rF@t�8�6i9-�sk*^4AB7� (no�|L 2� ":��4�;g s �lt�(� ��>'�"� vE2.�! . Hemq�iK� Z&{ 6�(a�<um2)afh Caes�n ��(AE��7r 64"]. TenY&�=&zF�travascu�coagu`(. Oe ��77i`9S"�$mucos! gu�� nasal cav )� -�ven�&pun[J��"@�m%�!!9Hw�]=�:"o 6,�re���*�Hp_}���RN� nty-��9(i � �'A4P�y�0ly� ! ae:�/~�N+�!�dT &�0 8y������A��L9=ilW58E$ѡ�b��0marrow biopsy�.wa�"� E�phagocyt�3� !��t(? �5 e �ʚ�x� 7 ( 5�< 6?@,fT( ��&>�r�P���8Z�5�#>ECぬas3=TO���erA:p�)& ?:�6 889R�3�1W��8( 0�MB722d"i��<�m53� B<76��ab��FWG� 4:��$29)<C�.n�-aka&�7"[ .7S%�so+ PU6�EeA��)~O�;�!"!ir ya�&yz!X!ϡ5.2 Qoaa����Z(>EEQ6�2< dysf��,��A�$!���!f &L*tV%V*�D![;)\�{%t[g"P+6�>�q�� �i� t'y�d._K�&?O��u�k2� 6�D�!qՙ-.M-9U�r�.F�Ap�:� S�= �%#_ de)#pe���&�8!�iG�E t'/at�;a;cR�t=�v g"�<=�ofN�+i*�;�f � �lso��vi�@��?.E�W#lՁ�gar:P  B�Oer��T+&&5 :5?*W7&$ a�J`F��� !�Z�@R�.e��r."K�(?a&:(a�&(��&=E"�&�?r>$ Cq�-�&�'n C<'t e@�3 2008&c 9a?v���3q7(� p�Z2��r[1qv>!�&_w�a!E� ?� 100%a�"A-A#ge�6�6�-|A �6!�|"�-�-�(�7� 5b m �%hF�,�!";K )�Zt�n%�ZI[iM;9ө�-gd�UBT =$Mwe%>�[�m��"A 12%�2�Հa"!�"h 71�Au�z9%�19V(�. |�R�hOsZ��:ŦzviT�7y*��nT�EUA4T-lX origi�%�7�Bin [1�Eu�^#'%Q"��Mx-�'aTbe uurHQP&^possiW$tpa�zoptimum ��f e?=�\�0 �s [13�"�V-)�i�D^�^EH-V& wM)un�3�j<t� 1����!�Z  k� ����!a�uI:[*8&�/U��@%4)�r2�I n!Oe�8e8.�)E��6f"��2r�&�)*9 visi+?1�� �NwQ��2%�e"� "B*:��"�'`5 �AB��r- g.�x��ofN0" by Sam SS"�\tjD3��:y�"�J&g�iWAŊ* �rL��'��f�<���� a?)���� 6F�}�ingap�&[��C s��n�15 ;:UubR�Ec� ! ��u�mP*K!�uU�3� M�a�av'Ա fifth{�f� B&Kz�h��K&�� *, I[3a1#Fy�8*j0��=OA~��tof�,"j(MI=�i<�0"�*m�6Qߑ"�'�i_uTi>to��C�}^aA&S+u ER�:3nSoN��n h`��B�E�B%�A�y*�C&, �J�C�A� ��itself��2�9� �e&��;6^, !fF�minEi*0m�acu7�J�W�d!�H#� �-�!XxHh�A���~!�� surv��шvf�'35%!"��!�� �� �Al30E -��Pia;��n"� V�-<� >/iU�(enny Low GH���zK �?��� is~C� n�@:w>e�.� �` I73�J=�|Q{ 0A�=&�a[/!BgBA�>aid��h A��Y�!nQ�:�, �is2hN b5t�1}V1l�0 &� >� 2���)R"T,Qq �It4 �3b�6�b��orR�Qs��-_��>1"NW��xys!-V�J-��\!�.w{�NH��:@ !�:a scheAF(��7^ C) �Fdm;� w� � a�a� 1,CUa�hr1P0�E���ra+�i&�#R&�do&^*��*x ɻ�srd 9,ndv� 3�+6qN� 5���'�!ly [2� Be�;��"B�QMo�V,y Survey III&vX'-f*]&? �7� 2u �6�[2� �  N� appY��ha�igF�V! 50s���>%�@&re1n�q�bw3c�%:#;Q� "Y)M�Ae-�E��Mk!i�mo� A�>�[13*"If���H, 6"9%�i�,:.>c onet<�!�,t"%-97%6��� �m�%1 5c�M] %N�l!,3��N�i�4)/��_o� �E�or=Ft3NA� �!�"97�z)4A:��If UIm. ..��$@��nt &Bs�6��o�����ow�*ub�),*�^Y6�(Aep*^=e1�4 v_r�2b/�%̈́N &� �[&�%�)%y�=e [i"��&�. Mi '/W.� �(F�^H4MG�����<o��=��hD�TL"{�85"{/)])�,Z�"�8����probab�6�oA�"1 &���,e�aE ��R lyA�i$iA�"�J; o 5���.;UU0>,�M<r���(Ź��+o�\���&l1c�'�6t�i��� tA�ik���MKntr"K&�e��5r]$-�U�S6���?��6\U-g��X��� ��bU�Sl��e��oAi�.�BELw�1>t6Be�>4�_!�a ]&�Q�;��Ntz��Mw -�J�� ?� -B�]2�o6Y� !�A"h necd��emA&����hec2!�"�:I� m�I��ol5 g"���13��.� �i�y���IA,��vo)�uB�O#.�#1 !�1 whom)��� 9{ :I�may��nW" JT0Ub[�\) "v *b�$A8�%9� Y ��� 91�E+�.o|M"by Puc�+i-SohA�M��[31_�yePa�lJoge�B�ma�"j poo6%+stܬ.�*�H�8���� h�W2��2 irec&��8x�_1BtyAzb "C Fi:Hcr6surfac��ErC< -ymE� skelȵ musc�{!a 6p ���v�+l gber� %ED["��sQ%,> � C!V�z�bbg!U��l ��F$T� an7 ��e�<�yw"�XA3�s~ !�m܍�!�mkR'��-�Y4_�!iY[I�\�&[L�6,� �A3f6 Each\�� �x&�Y!%��lat�M�XZ�4M�c�U&f ��qo#ub[tsic�I&sE&{m&Z&92?AE+�X*"�'Y��P�\>. �'r*� 9�iNg!un��4csu�.w��neze; lacRyacA�!�A衑v�}!�{rd���3�* �2 "$2ata�Y�`*�:we11�+ol�\n\<3x�ZD e aca!k��-i�of�A�bi-�v�#Eream�*��I!�!6e"\}G ��Us� ]abݞ�~]�&W#��z%K�S-yar��*��.e%�a8�=I�� E plan ] en���6���F�`^EP;0% �] !_A"��2�o e�RasI��=2��ur����a�e��Wz&x�6 C�f  �I��%Oa&&y��NU�a�t��E�*�1�"� >2�)�e �nnt�dveilla ��is+ a�&^M�ap� ��e%��&�5��r!K out-5�8�d��w  4Fu�.�7|-�vee3�!ci^lI*d&, N~�ruj�����o>�P�">$"CNmE�H&�8,EaN�8�7a� �� ed�!Sm$N3~,t�SR�&s�uIQ� AM}i�.�ref�0�:ob�j.(Q�l�oo~7h��Hs�*� o ma;z��.�(����(� �ir+b~ J4!�edcho۴A6 sses�9!�raA/r&XQ}9�b. Litt�@s�%7why&�D D����2FsnA�h7how!��d����^D !�h�5��ani�j�ins�\�a�|! nutr�%-��A�way����ng!�est� >4�Xu&��,R$s\P sex�� Lv � ��fruit f[ Drosophil�! lanoE3e��HP��"*� �"���2!�U derA F�����FA�o"X�=lli� �%�c�A):� �3gq(�Qpherom^P) !7 <�y�en0/TF�,al qe��rA�qui�$A-�F�f�I�.�A FC�a�w�tX)2�recapis(duf�6gF+mod�(�2"B|>)8!*p�)etn>?2�x��mpe��� �>hippAi!�iDFur�mC,�&�b�yie�&oDF�6�en�g+6}& fecu����cor�?��ng �!+, p86t+-i�q�eB�k�Srel)[��k�9kA�:�cuE��  W�O, cut� ar hydr�]bbOV�m�b���7"o fZ�d�[+iq3:(�5!�����J� adou�!�B�e�i��N)�o h�l���>_� ��T> N ! �p�1gonn&bTmNE%]n��i�> Nt� 8=�,�����I�Aqb*�? �!)�d))�6f&�F�Z�[٫��odu�)6�|a�senə�&���1nZh�Hdec�fs���a�)�������)te^�`basa��7� � rnal�'e["�>��,IU_��!e assu9dt�#�=anb�B��P�{��T � ��&�� falst7gn��'nnm�Tor%�er\��<+z��D�#��Ptheor�{ empiGa! �nA=:�!�\1S[�+5]ot��ir������-%ra� !kn��ڂ�. ArguA �i|!~ un h��� �uxZ���C]��sh�ic�2r��Z� �! Qf.orego�7M� m�&S� [�Y�)T�V�n::��%٩V�Ls, � %Ht"̈��k��%��r%fA��� ��i, �Dt_�"�,�j%��&3.- %ppduc�.� ?jS��sc�Mbeg%as���?���/��F�ASnE�6:���&�, b� �:q �"J� R��. WA�asol �f� pe�Q�#v� !��a� nd&Dfaithfu" ans�8����*�6:�cueE� ��sc���.$���6�w�U�&���IS!�"�aȥ�bB.wA�8 Ain���9@=�A�.I> E��C%��b"�(��͸%�&!�� osta{/a�]j&LVd�Ei"R(�c'�endocrMnnd"� sto�M�C ��6 �� �[1$-� W$4�rro�=d � # �B <�$ ubc��e�D&�& �a���Z�( CHCw�E#!�nD~��k(%o�D��0 esicP�% next"�o>yo��(b!���. Fk ��R�� 6��* a���oE�� ��!.�.�Aݒ2]64AށJ�l���e�u+>t�6�tissues �qor be modulated by them . To determine whether functional ovaries are required for changes in attractiveness generg,global manip}ion4xinsulin signaling , we combined�( ovoD1 muta7!�hich blocks oogenesis at previtellogenic stag� nd resultu(rudimentary�Twith poorly differenti�germl!$cells [21]�1 the trans o0constructs us�o�eJ� . We foun� at elimin �of 2�o-�rever]he effenof both1gIS %� J�inhibi%@(on female a6�$( Fig 2A )^.�tIS in%�reproductive system is sufficient to Qy>y%�foc%4on two �,an tissues ,g5��!bolish�y heir}�:Q ��5D. It has been show�@at.34or direct FOXO.}�uues crip��!�&dIlp65aE� as a?0ic antagonist8IS byq���dilp2:`!|rel��3! brain [26A�It��tU�$possible t��Binflu�nd>H(through neg�Rfeedback��ol��Ѥ, �o s ( IPC )' �. How� !#�"' NL-�Hor� �|of{$ir neural e4it�fas well� ( al���8 `*� (hemolymph D%�lᴁ�0see [27] ) , �� �����B�S2A� ~ I:�iչ&s 2ck &�69 �- �i0U�-"�A�2 mRNA�!�h�FAS62U(eE s S2B & 3!�2yuniqu� ar�  wEd6 ic meti�� ReliaA�c �  a me!�F link�DfitnessW Y�asked���ɢ��B�e 9u:� alsoK &� �>la� measb �Psiz�k virgins�fecQ t� �r !�$to Canton-�le�Consis��� _ expec" Dr!q�e���iZ ~prV3� i�M&(byZM#:ME@ 4E� Stri ��w� ��hadٙ"B�(��6=Za cu�os%�A5U�)y cauJ parallel%��#ng.�^��~. Not un)�ed�V�, A�gBG! ega/= Yc ( S3�dH s!�M�ternal ])��&2 a�2�effort flecA�ex L� ndZ by mE�as��}�?�inv�gat��is quo��e analyzed cuticular hydrocarbon ( CH�profia.com�ed�,28 CHCs rang!�!�ength�'21ao29 MakS�|��Ase @ have2%o � "Xin un9�-`} O suppmA Ȏ� x ch �� y�fh6�F�,��)�%� many)�clu!�Q��9J�1 ound� aQ remo�2�\A�!w�|-!hw-� jK( S4A%�,fato-6`��EZlly!� Id"6B"Z6 �a&"fQ�B���W*�C most��nsi�� ��Y�!I~"4B�E3 s 5C%jS6zSm~ISj�,u1�22��EX���с:Y�:b�� same typ�U �6^ re��4 �h5YZe�( S5AMS6!ms�&� no��.�apA6nt�e�j:W��=�E�Z�y"�!�:n6|95:* ed� ��N5�4 & :C�U3alone (u0(right panele��Q?m]u*����� is� �a�iteg�ofUtin& � � X2 � �edo��Su��m&on��could�ed��by�hR"3�,is�� ����d"� �n��G*7f. Altho�B�-�&j\ no-���v:^�umqua�i ]��-�ksi a�~UnlikeQjor9B�1e�>A �?iform.rWhif %Ey�!:une�}r3 no s!�"�e\"K14N�]�a quali�v��"t5d�.�!�^s�ar� oUE�Ŧl :� . In� duals cho�ma��xim�2�outpu!jdata ind:� atunAe & %�n��ofgsic�q0D . melanogas2%_>�of"F e�R,a*� ) 2�"�. O�oal�t�.j leR ��[1, ulti!0� Gst!�4�m%*n�r�il�*6NA�ess� . G&*7 ofJ� isP �{ >?��[1��6F�wa�arlyObe"��icM� �( -���L�3Iny�& |p�!7loc od��pathway��%UY�q� �B�tasV)� Dx"�>B}�t� � rece�- pa� �!L� & Bmay!h�� sour��T,as���s4Xt���:�!�^�The�E }an �> �u�i"<qtra@. V.a!���� o�necessF�8�Հ1=��AG.�sA�b�. Fur�mu.:A?F\in&; )� nVyMW��!qQ�F� �2~�:X#ge���s!T�".F �-depend�::�E,�by}!fs^�>� ,�"�#d%E�,autonomouslye�* �-s ngu���it e��ILa R.$"8, r"6acc�lD` � :@,E�!Vt!� titu��,oi�S$mAhonesty%-:�� ��*��chůt>�e&}SU."x f*���� & }%]6�%�&;%. One�la0$agwh!;~�aR��^��!�6in5��!rag� RPM�}�>Y>Ire.�d/�mituptakeIxdu�[�nro#tza\��wP �� a ne �in*�Y��re avail5I R� �d.����a|�Kan�cq� M2�$� *��d= rovB�R$G cip�l!FVR betw�ɥ<%qs�%p��6y� } � �B6/2AL� � 3C &�Thu�>&W Ne. io� m��te��: P*�� Fh�'ba� n���2�%�%��ى0 modif0 �� . Ei�r1����en� v� AD� san6�s�x-AE�Qt E 5benefi!!9G�!�)j|&�# via � b��� flux aa���cJtoward�e5&��A�'Ek��"�)m��f.� s�Q�dIk.e ;� l� be�*?wa�"� "bA�!�C0g=-`n ��ic�2����)�re&� *[20TG ctIP ��aN 7! (i��%����nRA�� B�� � jY�IS��.6 maint!"O^�(d2�(W� p?aa4el!;faBxI+ orig &e��a�.����RkN^. � h��p encod!GyR"!�!bm� e!���a'�!��m�&�  '�a�ay&, �� S5�.� I �2�WU,d ,�#a= �.Qabsorbu�s esse�,l�)���a�twdM���T�i�+��a"�&�" loopALes� �S�!� W-����+"�in wild��*� sol %inU!gN�(ց��#�"�5� )!��&�*v, AAa�&� 5kQc-���ai� 2:/d� ur.�����ses�.$ �&+B�m��!2be7 �B5.U�I�s d3"nct�� I$i-2� V &u �1z� �>&�9�J�. N2thelesAl �guish�(F�)�I���i* ify0A~u�( \��� � -��&1 i�sE &� aven�P futur� earchY#��� or&� pla�hroL(] &~ .l�z �.d?�U��1��"^&Za��E��upv >� 6�:�n�� se enzym�)0i !Wgene D� se 1 ( 1qm�b�E[ { ( &)$�> C1�<xl ��IJ.Q !�.��) I F� I�r ��n7aiOexpens�.�+ [3�/3�/Of�/!F|/ U�MV,#�!�._�f dem��) � mamm�[�+3�/�,�@vertebA  homolo;3 SCD1LG) key �,ory1�B&�1,=3icmɁ�r�Tst� &,5 We �-��*� !�of1is nee�aFJ�,�{ 0.a��'�F�to^� Z*� 5]� It�con�� a at�# dete� (is “anti-q �”�0Oa�#x�" ed*5�. ��iqui���>�}����)���'0�!.>��:6�ݩ[6��d��2 +Z�N d"� th ��ri�a ( i .Y&%#F�>d coup1/j#V4N�� 1a;-5t�#=\stu�%" �22chv^%by���$dm��,f���i�\,'at�b� &�n��2]� . Kn)����a�/nk�� animF�i\����l���A�ŚQ!evoluA����ur� cI ivC&If!@ A��; e a sid�!AG&O Y��/b���&awf"9pur fu�# send�mat�'A�/yx�en�<*w“reada��:0�u�.�, h"�-!�2"�fre:3be al�0�{"d ly!f � chea��H2��+ - ��i� G see�{ �bes��[4 , �1IndP5ooreti� stud\ &q at if�Z,�}!�cueAOV"�ve/t!l 4!� �x�Y�ll!Q �% �roy  [1�A|ntEarehwn8 tudy�� firm�atFcm� *�ly se�)�:Ti�L bora�:con�% s [8�&- �d te O� is be5 on e6-') 5/ .�^descriA(-�YM�-�ib;iq v9� an"h4���of�. �&�a�( 6�"-/�¡� urn �( ��j��.B(^O�6i�]�A!�Qenvironm�;l.�9vi��&;/m �)ein) ��i�a�out��canA�Q/H'(5o��3 � )A�<���"� carr :�Q'among"� !O6�how�y�h",� ��,6� perturb�mzhelp ='al &� sexu%C mmun�K stim neR9� x to�ɓ�/y�Ov%����Q�. C�/Vt$$( BSC #130*g=)� �=`ob�!��!�Bloo#0gton Stock Ce!���@ublin5-GeneSwitch[ Kmadh cloni��8r!�alphatub�>i�op I2 vectofUAS-Pte~-$III ) [35]�0InR [36] over*� N>|3J(2�DTBndga F TrpA1 [37YKir2 . 8] �JI & Garrq�^R . Bain?86 e&;!��l��" "�?E�(TubP-Gal80tx%� 7017�o bypase%.�;2Rllcse�b- X�<95 crosc �atb"7� aR`a3 0ndard w1118 (��w�)[��� Nin�t�5 a��Q� ~.:Z *�>1�ng��%g� on9@�2!C�8�. O�9 dri((8 ‘+; PromE800!N�t=Z ; +’ [1-�‘w;;2G . :(�E�Fi| by Dr�J . Lev�@!�$H . Jasper6. Cre���/& . Hoffma�$ [39] Yolkw ͉7�#ini4As5)5 - ��"s � �E,at 3–5 dayh"ag�B'> syn�i�$m�7�G�A�J?< �-kNanos�;.�!:@‘C578 !+B#%XJa0Y . Yamashita!e � "�! � C204^ [40]E�6Pb�( #375k�A̢�. ��s���7�1�KR2]e5m�kin�36NAAI>��T,E . RulifsonA�� m*e b��M [e�to��KC)ithzh�+f��i"�-J���0��,n"��uY�2>. For"r.D� �hgo�M�"Beny (�%abb�D��) :Ad^�/wA�(�'>wZj�/�InR:8�+~:!#:;< Tub52e ,%]InR�G�&t, ���/w;�B9�����bC:��6/w;AQ�����.�26-�I�f?2�BA�~B$-� C587e�-�BxEDFC �N7v�A�2v?�e�f�$�I��,V<�f>�w;;�eU�zC�NA�v�# ��M!wi_Fat Body-i�6%!&}R.�2U0rQ1�w;(X��)Z6?m?q4 al (a��)' �N�nV�� �eV �n:'�z a� N5�<! 5!D=y�F.�� 1��GO?.G,�.vaeWcul2D cornmeal-sugar-ye+E “l�Cl� 60�)C=Y ��r�l�ed�Ar�a�Ge=D� A*fon 10% k/ k$( SY ) foo�ExGNf�B"�� YGal �pla�o7 cSY S36leQ?8RU486 ( 200 μMB a� J "!?�$( treatF��veht � 4( 80% ethanol 5� �r 10–1m bC(.�.r�� �0aiZ 18°CV�fer�to 25�5�� 3-7� �usX in2�(�4ag!� �as atL)�� S @ach r�I�� irwi�omparis�M�F%�w!Du�� Uas 6-7do52lcz]Wat �Ao 60% "�humid��E$ 12:12 h lB:dark'J. FreshI3� "� W y 2H3, . DeteIir%'1��,�C4�Video�is^%5to as�/)�)"�� �Au�<��Hol � I� assa� two-H* subjq- 7i;, JT))|decap$2eK'embed� !B! 15 mm apa�> nd 7A�0way&(��dis�A�� J solidifieN!�ngl�� 4!m-old "�P (%vio-,iso�dE�24h��bspi���n rena%Ag� 5 �� o�lg1!�/g*���!�rec]Jg%�itar!*� i(ntinue �30 e�.deo�� G!_t 2 fram�5er se��conced� AVI E-�ma3=��?eOEEpFm oftw�e calR�e�u72tim�nt�! �3�" in%�a circ�$f 3!�radius c6n �.JU�l�#��1�=G`!Aa�)c�  1�x�sp j1k��c��m�� �&8""W?�z�8��TcoA��l�*��/% I`, havi�?1] 4 UE��%fe�)X#l���A��S�-*aJI2sUB h��A} -E: �e�T�?clu�<�0{B�a��L�4]�\orB� �&�F�E ��a��FA:�<��Ds>�. O"2��Jisso#nd( in PB{ �xl+,�B a co.lipa6lFr@P o���Fwo piv3E-ap�Ca�!�7thick�%�ou�P Digia�pic� ?hA���E.�"��Ta Zeiss STEMI SV-11 mi_co"==Oim�U%�) DoptL 5�I0J 1 . x�6�r�Vai����y%�outhd Yx“�h%1���L to )subsequa� area!F^nvA �/in mm��T�T� exami�� AM-ɗ �El"-�� �9"z�LI f",IM� , a��first][groupsIQ2�A� 1:1��+io�2����,�� Z�e�础�4!B� g5 q of 4��W*9ard.�8e vi�$!b-�/ � U� � !S 2–"� F5i"ta� s nu�T�egg�S-'����NHG �ext�?�2���d�& , �VEr &� I+� ��H samplic5�'E'.�N"ELu(�% Rundle l&�m�� 5j$protocol [����"� a ��N��+A~e w �cor5ngV peak7.|g� !��28}�Hy"�%=s;<�U_<% �3�yin Sup4 al F�Q�"�>u&A2<eakk broa�&�i�* chem� �)�@Foley et al . [46�eZ @ 1�tth�!z uncl�H. B�+�>�"E .[ y &#)M�I.IS "U�5u�Q�� !eEB!��!A��0r Q{! i�VYL m�U! 5me�/Q-va�6� TrizoAInvitrS(� \ mM�RNA Kab-AB ssue�-ea���-�Y� gut�#�E+Q ~20 KNm��(DA-!!6eF� ,!��230�O6:2al6� #m0 harvl9N1?� s"aA;N*% � 6�We"d�s-,ed%(�Ji\""M $to cDNA bya$erpt�F�-S� d S">(6��|ligo-dT�V"Z�kEPi&�$� � ion/{ reac�I*pRT-PCR-4per_!��SYBR Gr�6.M @$Mix ( Appla�Biolsy�2/!wA�*�nW ���qu�)NA�)�Cn2Z�'_�Z geno& Q�A RpL3�+A;&2 \ he ΔΔCT�&hod [47�A�� o��aAXld-i�EGe-Q��!�3 �xGE�Q*I����tA[: *4X6F ( CGATGTATTTCCCAACAG GB %R!bPAATCGGTTACGTTCTGCAAGT?N�5I$TCAGACCTCG .TAG!E GCCT"eTGGATAGAg2 CZGTB AGCT+.$F�$CACCGGGCAT �r!�ACW�ATGCTDGTd#GCCCTT�GATCCGT�I�: �8(, a Wilcoxo�:3aBSesc aM�!�null hyp� �Lo.!�h(D�<c�-50%�A(tum-q�5-g5ͥ�pN� . At!}rmbrun:e��ߡ� yw 0 tS� Fp���=+e~ANOVAM��1Tuh.HS�C�]2�2@da+ in Jmp 12bAS(B�=Inc .�Is*, NIa!/!u�e<�@/ his�3re*q@iS- �assump! �hAl�3{ P-valu r� 2-\� .4Ch2�*6�F�&���.�a�4�bia�4aon)-��#Binom�>& E$R@"�� �� �.Qm�D� a�(pac�wBd���!nprincip�%p�E5eo1^v<v o"s .rd��Ebola�uh4y,( EVD ) epidt A WaUAfricNF 201 2015 sp�+ h���e0aQ#o hardest-h�uJRes Guine�]Liberig Sierra LeA�!��e�&Za� �ransmi�|of�s litt�3A[2 abD� l dynamicA`T6bFr.rict-��I�e�4,!%� �|�$t�.�+modelD+appron o�� basi�_>-o�? ( R0�o� "�5�%�6c%K y us��weeklR@c�  c�3Y �We�dg�_� s�.%ijexIPA�phG��m? utbrA r.(re"rc -��p%_�eD� s si�~�`�T�k�4��c=9Yb�pA��*&QV%�fit� a mixu�6s)�7*2R0!�9 ��FiV�5A/$a)1x!r��sA�Z;ter�M)�b�/� c�ve�R0�U� �0 . 3\Dubréka]> 7�� Beyliny79$53 ( Maryl�)�H3P7  gibi�12i>`414 ( Koinadugu ?,7Va�ern R�\�16���u�i2%�m���n�of�9�95% CI7 . 18M��2!/98�VU5 /.<623��0qV2bH. Socio-demographic#6�� %to �+nis�Is{;as0-po"�.de\@�DL-wealt93dex�5�pos-J�UR0E e"�� of fm�Q�in%����0TW8 A�PcQa`]d�­=. ~����(ec�r� -� f a7�Mst�F�i6 &$B r��@3en�ddiscu���Nge1�al:(of3��2+�2� 6�:M[1`gD butE �0��%eh!�ide~�E�vK��� . An��//c 6Aa�3tr6c͌�j�:a�uw5Ecu��alwKf0ver�:of��1� s [9aO�WC��P�'!Zm���jvf� bmsub�.sh"�Eil��)�.xN ��a"�_�6un5�n��[��iJ�*�+.�59.�a2�u�EL�to�fy}�-�risk facY�2n. D�]�m;�R:�R crow�0)5ig�lB_�6�Zo�o0CA2u�SES� ";fe bur�V oor sanyonE���I�s$�=M��  6 a xTimeY�manageH���>[�aV�Wf8<�/o�<am� E� ��2Y�m�i�e Z� R�hF� 3=�A�d,in)�ns�$G ha� �i. }�i�.l&� �� mahe}���let�Vsus8nible !��Wo� l'*9Y�employ&y"AKm�*� p6R0A��6�u � ma�qa�79aon�  1"ԅk�Lix ��nem��, s�,1M.h&t q8�1�dV^�i� I [�g1!�119q.\ [2�W>!�6� �. MrZv�-(<� !q� 5%�� 5�greGHu"�� �%b� i�3M sD Y)V� 4 . h summari� U$RhE%A draw�2a��At�l� sAK�aEiriooX9�]�pamW�aiisa�bleE � spar0[ng. A�b:�x5J�,!=%aD�&��g�s!�t�"A��=*�  r�&ome+�Ix!�|  Ʌ ).�!o%.� U�[i1�z>��J�h Q�c�%]%�+�a �;� :�X fi� $�%X!�@��Y!NqI'+8*d7k�`� !Qu� empi li�byQ�A�*slH� e� �� log-���Qu�7!��eMsw6 �e�n�*[E��c n9]��by�y0*���igmoid �4d5.y[2�_�a)h �V.J��i����#A?c >�1bU!*O)QM � �?�"s= [� Igno�q�cpxSc�.^ erro�A>�seEl!jt�ter-optims}��d ?a��/u�K� 2}unceriumj[�b�J��X$#�I�!a*jDusefuJ!$ ��>F?s2�EBQ,a)Ti �� T 2�f\)�"� "2 E�.sh�Rp92�ier�G *�:. <,.�a��N }��.�� �ԩu#�*�i�)eW�J�]*t &I �]1��,V:h=explici�$allow=r clu![� ��� �>,�u�� ? �i*�mE�UY:Y �i!A$ed�+]g� Bz��EcZM�o n!*]at�� t@m NB e�s�� ,2�2�|(53F��Fin�x%M!�o�|a6a )$hip�`R0T' Z�as*oC�9 �� t� "� -�. Wd6E�F��0 ,ach2J � ( �)] ed 'Q#'9-;�+éfé�%� �vau��)�2W(9��2�ad&JU+'Ix�!�UW�bs`��World H�Organiz�� ( WHOW=� b�E�e�Q�Uggr�q!�patpu��A��.\�Zm�T"�AAc@�� �U�th�U�+itu ��� sx,<Mi�o� of� N"��$[uJWe!�,�?�ot�F�)E!A��uma&�)!� prob�6�a '�uo.�& w�*! 5waves�FQ�Qn� � .pec�#�2ai ~y5&2�% Re .!� 6}${wT`�maximu3Ccu�@T[:KoNw H���S |Y�2odP��)���� o en� ��nq �Ac poinAn)�5 QP� �W�NwaN�U3u*�,�l:�! ��1 �s�on-zero2� . Di T-JfewerQ��$R7� ��eZ+�,��Of�Q� � 2�^�� _B�3Y%!�? �x 0: !:�M�+ �1��!o$/��lHCeno�d�BagY *�~9� F)�a4tN"=stocha� ��shp_capR�!�z.K �Rb-f*�ofA�h%� 5F�alq,enu�r�Gu�r �A�o�W�d�cof*�� �+!z(��T"m5UnwN( ETUa��u3i�B)! ��9�/�'qsGfa"c\oETUA�I�j=%�+U !�E��E��x5 �i��/�D�A�6�LD��!�4a�_ )G*�a�l �,arR/( GLM�6!�,� �fi\yrandomU�' ���2D.� 2D � !�j !W�'!to!y� �"IJ��; borrF.>G*�r:���ly}���"�s cijk�I i1~jl ime-e� t.a�U�,R  a Poisa KM!ѡ��(λ?!�C%%@ #! logarithm�zw2_:�~ h ( N) l� [) =,�0j+b0ij ) +1j+b1*�(   ~ N2 ( (r<, ( τ02ρτ0τ1$�02 ) ) ( F;�� -57WA�s ��o1jUv/ 5 asM����q)Tct&�'>^+�Be+ �d=�be�'VE��bua�aro{� � ry �M�&s� Y vDu�#�lV !� q"�!�)z -+1!jO{thr{�4#�uρ b &*�" �aU)N%nE�0"$��gih�;A c� V �po@+ea�r:^(*�Bay�y.�6� �Ros �| 13>�,�7�Oij = �AZ-�( !8�� �{ ng �uR0�� r�Umo��s.q���"g:� �m��R�{"�9"ba �� dvN�I

    yi�i�Zif�8�)�Ug�U>�R0G5�& R0�@41+rβ ) α ( 3l-� ri�V�,0Csh 4"n�β!�bR� 0e�=!C-c5�uαZbdeI�:�R0&�:�]zQ�E��� delt�Mth�+.KiL��c ( VarIV*b %^-%( () =  *]J ��R0 ∂���{!��"�18( SE )1Xsqu��rooS0� �lo� Mup� b����/& �"� �0��($(#)�N� 6?r�1e±�96*SE-�dZL �I3a� . 59dndI*(x#17} �  )Y=�w:� a "L6.sNi_ >E2�{� �re9� A��  teamA�>&;; �J�-D��of]�("�q�*Y^pp\2�)�/dE!$2�X�-t&C). �&~[c9l�{m�%  window�3�Qs� �Z*�6�impacE��5p&@z�(�F� m ur1" w�2� a se�$iv= "�QNZ'i�im��'= s{ r_( f�|veT+ek90A�e�nM=) $"�pr�bd2� �[�V�cn[��de�+o" �*xW5K��!Z.f&��4bl%Gre~o�usu!1A.�*�T &� 8 :.�q&�V useh�?�S"!R>�!. P"�3H ���)&��.surfa�o�4����L~~�[3�'44|A;�/r=��k�ډ)"� �y �s g.U#��S%y�^H#[ sets [4�%XBHB,:�P&h�3� ��sleep�oo�!b@��.�:�2(��]T ( e scV� k<� inuAs)&�m����E3-FA a�� c� �&#� �c{a�(er�V� ��~3�pa�wv1G*�( `[4_chy 4 l�#F"!ara�"�!c� �| �w' .&t �fl |adequabEA��7e!�&D6%'� ���^al�Y��(wa��s=�pro�^(����*%�1=���eU���n���"M6:aip,]Y>�G�1 T%��A� �e� vH`T�tm�St�( Corp . #'��SC:�X)1)C�Hge +�TX: RLP�� R6�B*��w!7$meglm rout��^h�"�du?aqf ��-Ya���sB�+f�%�BeR.�N�e�t�$R0e�?%!G[un�1YGB��yl5ف�� H ��Gn����h� "� dev�P!��1<�)�:-+�Ay'�]�2��one-weEi�5D(�3)*�re�:���P�QGj�1of May�'201a$|��a�! 4391Q�T56&d��Cof 63��ctGA yearsa"�2aW2�EM���{�gVh){�l�hnve�]i�fray�3G%$; Togué , %�BoU ,6�a�a�<�A�m�-a�i�f8; *.1�8�47792I./(I ]$��1$�c >(8�"� �was%e"�� �� �;Uc��%��&.� wL8�# k( Bok%XF%4, K��)_S��rd1�Ma�0a� Nimb�4L*b4&�0�>.o4?!�1J��th�Kouroussf �%M!�&�2<�G�f displa�(>�BA9On visin? A>I>JPŶeށ�c���� �pS r�6lyWr�. EJ�  t,#R0�r�"�nd��a�� af4 )�F .� �F)*x 3--F�"`�c�!��� ly i�v"� bord�.Vs�. AB!�'��d� ��3��3��3( TE�. T"V7b�/a�beM a�U��sr of!�= 1A�56JJ.�4in 33B$.��va��V��>�)�X� F�!R0 _m���Dbt Zmv�S 7(��/�:, �<x>5Q4= 8j58 , p =E08 �� )!a95�4��� م�- \ �>)��W�dsou $U�R0rA��o5�o5Fo5!/(Hm�:�B�A~�3�SD�6.�)B�<.{� -ske� ( S2�;}�Z�z a'rs�0y)�A�N� ;&�2l�T0agnitud�V5����!EQ/�aGqh� �'k(?�z*�tfH% ICA�S&]�N�o� � v�+yIVQi� .��sr�)�a���e�rTtM-�-_i..f)9e�  ]'.,2�.�DE P-w�Rf �vt"tT�.n--K ��Jp&&��(��5�2� -a�30�5�C�C215�,f)n �z jZ2�.k4# t0�+k1�^�2Ejab�I� weak� " e��v !PV �8Rx >-*S1%A��β-,1�e.�0�9�262o��a�BlvM�Ast{es%}���$:�3!I ��0�: 61blc!LCLs��#aun�m ntui.�8e��> ́��57i���J_>i�  sA�a���\:5!�P"Fon G5� c��t�A�'f� ngsza�t.rmB�\1-�"7�7c���"��. �us�+�Zs"�AU�#A�)"�:v+%vx-��hM5o:�&*� ��Cc�16�*|�$!O:�;.6�* . Av�k�eF� ���:���J� � ��H eD/bc. G*u;�<dja#Iޥw �a���B� *rdkTG%x y"� a6f& M9UzUr 6� !�! coas�)1D� southw�of6Wa.� �[of1A.&)����t2� BnoOCR�Xa%�^�]|m!�j&Ji>Q��)�BV��8)�J�ra�6��AI1M5-�tr"�"�,alAWMCat�/� )T,�%�5scenario!^�-si�! aDeat� @+ �AzW�`]j;&U��1 ��;0�eg+�s�q�:g6Llex%�2&u�"�$ yielrplaus�8&u Yp� z6�e %aeJ�NfJ !na/FU+ (- %u�ofIub*A -��S$Z� a7(� �~2b�:��_� .���  T �&�.*/nd!ledN"F��&���) ��}$.��Hach�?�vy{�p� �,t\.m�j�EB� N�\��5! .;NGh�,�Q�T �c�dA��;ӧ�) 'UY��t NQ . ReyI�delR@d��A���' �uF=5�6c�-D SĖpd$#�6�0do4MUA�"Ya6w lE �*I�I)�u 6z. U��!��4�JQ�E As17�70%VNWt�@remain� �[as��"�5IO˨N%� �-R��.m�� doXtot�8iR& ��or*al>� seem�D asonq�1>A- wo m�s �%� *�X�5 . Du e lackQ%�onB>��$�R!.0�jc52 . Se ^, @(p� y�*d�Ŭ.>��!M�'ruA�L�o"s<o����s{t-��.!+heyX . ImKtu���+B�o~ � ed pqc�r�n��F�jt�IAh.@e�bi�tQ���1�5�MB|!�& U�2g�n��01b=Wy"R+� e ��A6aMnegligŦ*�?�]^�n5su,Iwv;�JOctobsF�je�����7Ae�"h f�x�(�ǩ�m�I ˉs s.IC�!�� uX: [48]@s/�/�td.*/�2�$1.9�T�e�ir�aE���Uut!h�a= !{� F;c����{ oL�e2� locY���YS� �prrL��. S��� u�XrL �  �ic} )w%�c trixa��}".)  #,TZ,�EB~ptu�m=O %�!>��KQi�0Uab-��E2 ��)be ����Db�_ "��g �stPy�� e6� �� <)-ly:|q��E.�&OH`!�I�(� �a� �"C��A/can�c=�i݃9h6r�"N���ge"P*�ZaAUTU�@r�YlS�r"� �rg�� trade-off"�hig�-0.��A� ]!�s3�ghtfor��[hiefdomP %�L at>�_!�a?*]P!�A�a��.U + � h2�Ura�n�~l:{qD !5�)�A#t|�%Kenem�2:MontseQ do ("��Conakry�2��0S36yF��ji�]I�ylo�Ii3*]{A|%sV]��� a hos9ga����tf>q726%�FD40� –2�4�W)_?!#3 65 (�2�A0��T�r�GT%.9,q Zyf!�of�076az&a7U�%�i�A�E ^�X��73� 9 [2,2c;�1�,��aM�l2.�h,1�8�5�)��c�%�Oaz#�M"'on{ � �2{E�k�.� "��Awa c2�X 4 �9P55 ���-��t �1e�[4;�� �g�qsrO�.t%�ho�� ,!�<1�or�&6lX6.networwM�1�BC�>P��suv(bU�#��=KI.r��by�i�~�uH��"�B"4 � R�1��>y19A< y% a�"~��n&P'��)�iQ*�AўA���� W.BYQ̓&� � �uQ�?�uou���. At&lu'i�!ӡ�h(J���F�*&dS-b.�G.0I�L6�}5aK52 phen�2"�,[1��3353])8f9v�f2dU�e�*:I�Ձ 5щ9G s24�j4:S4I0a�� ��,Y4a�%�!<3|;.�26> 3&2x6�܁z��of�2�BZ,�2>� 5>T �0�52��qn��ly�C������z �6� c�5LaI�q��]EteMV!�E�)Yafa�'V� ���0p_dR�a�b�Ńl����΁��H##y�YRto�6�irQ�� *f/��h�����Ti"�.�!%�j�9�:yU4"�,�a�BO��4 p�$ "8Nq�wA�[o�v�bter &Q)�'A4~1!�!2&=0��!���Nv �X% �!� [5?N�lthe�Z��becM� �� b�Ne�Xe�H r���1�3ir*��FF�t,=h�� Aj�5�!�IB�!�lso&�6 � ���dm|C�����1y �SQ. Fallah f�1=0oJO� �&�� *\g SES- g8d&!7.�[�RTi�! �2 g� midd�PF%�.1f�.�*d7^rRX�m�)v! N��!��1� B^e�se s� �>��pcto��� y �8�l�+b)3�����%`!�d{DiAq"AC�. W��Q��>WsE����er%#[&Y!1,6�E_Kd) J���!�1�.L ���ҡ�,8!&!�6)� �* E R3%��$��65�O���Jj"=�nY�8 %�b9W�+.5�2�ij�V�rXct�9hN6� ] t�_k�/.? [55]� � ��2�! z5i��G�[m��A4& �be)]A��ce�!�&�C�ou���;& .�fo 61ks�.����Ror3aalYtA`A�G�*�"Z�En�M��E��F �t � O� �T��a��d�;�9� � �1��X !UeARX+���5ans3�+��zM {"�L<7a�mc�c#� ���2�N?'A� suij7ategyb`1w �"C  8a)�2" f60�, Z$���*s*� ��%��i 2'9[b:"A�c�5�m�\��s�4-!�]��;!�2m����<��>�I�rW�hst"�I%�J��� �[���'�Z^RZ^ Em��Qy�jv$tein'�U�f��?aa_� �$deb�. E�.i��m  ?���RL]||nre�o -daya�s �;u�R�3:2��oe�ga�H!rwA�Վ!M�po]��Xro.�%����L,�1a�=��6.a)�Fq sJ�3to-7W"z&� h�ZA5mc8́0w�km�#d PDB�� W!T�Ʉ*x"��*GCfVh�:bHJag�Uup –���qe ' hip�s� nt�Le���,��*8l1D�2Y!+� H"3z(!��!cruAFE,:mod3��4.�"� V�r� "��@W youn��YLanIn�6�ftC.^as �000��dM\�G ��evS .�Vevisiae X.��1 *5d long� �]���')�x�he� � %Y� �1I}�/erҝ� th&��!�&ZA�! �G�Pume'6�'�%1ԥ�A� �9�14' ��Eo�&7>6ensq@[2�d&�$ mRNA"В[W� [3([�=.Uʘ21~�cod�>dap� �Wx H[�uBN-V%���-%[�q�s&��[9���� ;No�i���!+<sA�asj�folE#i�t{� –[�\S� M�)�2��g���P�&���mak�Z F[.o usale=~ 9���E�.o��ummony� lleago!��T�< enta�� �by�9A�wa|]BLn*%( �s"o� ea��K��*�om=la<���R6�U bu��eOge4�K�2 ,� o(� " half3 !�"�e�0iQ�g'�$��a�one.s+��= ion-�<l)>�e�'"�G��noux�'[�l��c%�!:i&�.!.x���E�pJ�o=�[1,I�o�ork , D. Wilk�#5]9c�w���u{j�K�S!�usa�(nd�?)��a �y�8!x� m s��A��J�&�)!�}oag@t �]\����<6-inadq�w%b�!��dr j% ly1�V%Z ��A�,M�)-o�!�X�; �GsIAZ� aN'1Q`��!���:art� 4$3Ur��g� sida��cӟ�4p] a2� �A9� �!Z�[1V��c&��^�D�t�%tm� [zs-?���ŗ���-ontac"5 � �>%�oE~:� -h �� ,k8���� 6!�� M�;y e��h.\� expoPF�mF�i��C very�`� �G��Y ��,z���Q-1�<aE�er�c�!��.�B. B�s6��BV���tA�ApntrA�p�32H. :VVl� �hiK�grB��! �"� Ij� �#d�CgafB=G�cR an� A���o�� . Se�5 &ED�?m�*< U�� VAz� toler�/to}A�h�6q(~noeP�A�ER�-��El��#zA��[�!Vq/%5><a�f& Am ub�. auth+"qe�a�nV�-�o5bnd��,Jm6V�%[��1��N��ly)y2L��V�jmiPRIh.�Franzosa%TXiai��dem�"a!�r�|����MA��c�ng� sl )wF-v~x )/e8BO"s�A� dN/dد�#��n� &ɞ6F.0 arge:����A�*\��1d:0|Fso&g >�>���d�Q�3ly�Ԋ,� ,P� coli%�e�� More!N�<eD�.|,&no6f�ؑ�i]& 11])�.�Ha� "3m5�A� Hy� &  ]%�V34�@EAzy ���e� ���y&S$B N(�"F]PU���:[SHaTg .c* >[!\� �T�)s% s�vi�?"� �}��Y��Q6�] X2�[Bl.6ϭ�itsel;]�.V H ��N�#q de1)�:��*)mP�� A �,96 <pjM "�4� �VϷ&Z� ,��M?.r A!1�9al@{�[enE�E��a �E� . Qu�ca�q!� �5uA]bڛ�A7!���3]7� �.�to7,"�ha�_�faU��A 2I~d�i RA6� �%V���m����TЭ4���] 2 ��DB%���wid����+pOn,�:��5B2uI|be�U ��B> �Ne��*.�AB�"��>� "�:YPN[�k�����Dro#�[�n�� Plasp�u�U��fungi [�e!7bac�>a eD��F! �>AatY�e_d���.+��E�-/l5 Ő�A�)ve2��,� ���m�WS�-��}�."��o|���r}�2Z �e�tm�:2;Q�A��}��o��! � 1^L�>^�I���8�U`�c&%F.[g��ETEI�Vdo so-u��3"�4-� D�lo���o{;��Tw^R��p � ap��.��g�Ms0"ig�_S ach6�QAn.=[(F� ,"Z � �  A�&�#1p3 w�*U-K!a2�s class�\�!!R"pW��� *�'f�N� |W)�2�##":���:��X� �? :H&>�Z.0*� ntir��M��OBy. 2T�:�a m#NP "�Gf< Q��2?B�a ~�re=cc  idea��"B!E�@y���Fa��.�C���en"��*�`2N��q� � rc$A�1L�B-zRd . .]���arg"k�m�5�iG���& #�a�.s4͡@"�� s"�a]0d����%H�ot�ye�E/!�W��_e7a ܯm�F�6pagbJ� %�>����� mann� ^�!� .��*=I�}:d "q��2�)9���*k !;��"l#/�ea�{� 9s��0"�#���~-�co�v-g�@ our-0�X?f(�< MUW�|!�Me+`!\,�~c|��UGan&ȫ8Krishnamoorthy ϫ) �%65�#A*9 � o� ] :�9Y&g(�eHe�=�8nd.-+�w��v%�o#Z.T �5g&_��8>*un�S Sަ3a, [R����!��ni����$fTg�  fAq�]*vZ?c�Tp&;�+c��as ΔG ̽ alogG M��I$oW:'er5M9'gpC08�7\6T�hli�j�'.e8d%GS�&G E{te�� ���X�Ush�%Nmi4��eco"�#!7jhEt, phys $l�a%?a�C 14n&�:)w��com� �a��R!\7 ���e'B!ҫ� N1����P%`�!� �v�(AA�McaCZ,6favor:�t�)��X� �etQLSp2vD�B�?�v)�\'�)Y a~A��)�r�+d�&[<P RS��Bq24. ��<"�y���E_mDa|���{"� "M&�*���Q'�1O@!i4c*RmM���A�i>W,�C0Y��Xur AF����p4 wa8aA> doml\6�2��| l��e�� j ��-m��e-�*� 2t�bc$��O1O�+�!�o`�#q�A2���v�!KQ��c�8�:��lut�luA|0�G|!� = |�� R) − �n>Y |−�1�`l�a�y��q� �)� ��Y*�6�  -`MojvaŸ�-&R�� &M0�o)RaI=1H3��)��-w� i� xUT-S7;�%���u��e� �,t��`M�A�6� e� ϣ�Inx-n����k u(2J1l 7��Rac� Iy%a.�"vJ=weA��j L� ��%�s�'�$�g� ߓ-���ResBp^�<[80�& [�jdian:a�97�9�(U85 . 0͌��% ��z�(,.��aV�:>*��&6O��,4 . e�i�e*��8'wa�эa�,+w�K.5ZB�d� 0� o-ac��� in 2&�/e J�IG� p��� ro�  10001I�Au.�v4�-tAX�{�Hea�� Z-i�a�R3�,A�=4se4w �A��iA�%�eRE<*����5U!�"a-'��e �min��e��n G�*�/�:!����U"ui� &- "!b , σ�rZ��V�G−〈 ��/σ%DYMa:�6H�{IU!K�(�er5")a�B�,(ux mqq`vsuNsu�10−4='��>).�sRJ+!  a�13� �Els�� � E0A0�����1�)�w&Bt1"��.�nt +����e���Pd:%� `�-Y��4�of"~, �sE�f�5��-��4��l2I.F��%�7a���!�6F�����tFiS���DER� �&a��M!-yQT�Ae�U-x%�2��~ata���N M@ N!�gx� .)���5�Q�n+!��%&lA�R/1�` �.c �%���)��t�G�"y.�"D1�y��01F�-% pA�*ONy�����<"J [�� , [4qDU���� e �!D �.Fs��Io����)�no�^�6eA��Q�al�#SPq�in"�0 >1mH�,R�g K �;Bam�->Y t �6�` � � t���G"+� �AeioY� ipat��f�i�Y!F Q��rr�(%<25�c�'ed > �in2&. � .:�m��{44?<n *�VH�7o�k� SSP �:��G�%< H�b shee�j E2��(  es SEoT7coi�6 es B�g , I#“ . S�� Ev / ry�tf !�a���q� �y�ǁ�ueT�Date��Z���>6���O�1B>�8a given structu�@ral category and comparing those residue positions to homologous �in mouse . Generally , we found that exposed WA"Z� j�P:i . Atesame tim�a�agE�aua� modulate"cor1�Άs – ��g .Qstrength�Z2fZ!P6depends ��he� qEin!Wch͏ is��E�%�q R�ofPQ�$we confirm�2a)_typicale}��A}s%�N��J� �s�����Z�A`a���. Fin&��9 oduced a a�ledge-ba� potential�V!�y-��7�1�nsta�%����O 0s�Xe�2la on a�L� p�5,҅^ O��#reIOVrobust�mut��2S9. Our!� ultslvide a H nuan!' view�A�.�A �F$A ,Whereas someB:!�sEt2s!Il, $an nonethe�0.& se effectmAnd� .��at gFv( such ,�i a grea� f�)���6ex�:� ���%/!�Wc (ertainly su&  fromղdrawback�Most &yi w� � to map a9�oY14%!�!�8one-to-one orth� E�) humanE�� � 5"would bX 0en smaller if���cI 0 spec��. DO�incA3���d� s ov 8e past few year�< numb� f�p6:� till! ��of�" !S Addi3 �6�to bear��mi� ��a~re bia!�� typ��m"M�enjoyJ�X. For example disordere gim a poor� r�� PDBa,aey(Ar icul�$crystalliz�Y �Xenrich N(low-complexc r [44945man� wh��C xpec�%$.�3. How9 dd;!��* Bi� .(i  aA?��at remai!a!���[ . ChoiE�Kim [46])�"� �L6 lo+ �?%�mG - t~ � �D ( α/β )QnN�hyp$siz� w5�teAI�c�&2nIJi*�  a�!<ir6/ hist�6�dgivaP sigh� � a�o�a ��� ha��eristicacasi�v2D R��design��,��!VF�A�=:�0��fin�h gge��!�=$may acquir!��inf �� ��� E� � 2o%:4raise new ques�� Sinc.l��s&� 'A�ler�A6} [42]!Hm!��$eQ���ܽQol�f �toA!g �E]�!��. Butt!L4mewy�!�h� lack��գ osit6�.us�0ingle nucleot' lpolymorphism ( SNP ) data Ca�yPetrovI+ limi�'ei aG!qAdN:i�imate-�� ificEb���)t�'cE�M� xed ne�2� is likely!�b�&B i�� g< IEer [47 eref�!, it M��eQ��!ΥUdre� me"*�cIn� clusioa$.reinforc) idea rQ a�E*�*� ed; -�*�  , butAlAsb� i:pla����2!}i��� e� factor-}{m "����.�|Rf ��g��. 13494*� *� � $Homo sapie��4nd Mus musculu��re obQ bJ Ensembl (�!f62 ) [48!�In � A!Bgn-�$��!�-xf perfo�LBlastP searches [49]�! ��dee�� P�4Data Bank [50]e�radse��� �&� *�We � kep7 �hit� anAHnt� at le�of 99%�f"x 3%Nverlap��R�D ei(os� ɪ2�fterwaru e ap�m�filn����r wb $carded 506��=Q beca�t �eiE� shor� e�050 amino acidA�� a� continu� ( gaM ) chc , or *na+ te � b���Qa�e#E4� leftX899:�9�ne6�ݗ them , en�A�$ng a total!�2 , 145..w ach:�� �.<VgaEw�` A���=�)�\-:�ŒGB�� �or U�GA`J*e h*'was:�H DSSPAd�downloaͅ http://sr��0ebi . ac . ukbin/cgi-\wgetz ? -pageLibInfo-lib_�qyr9.a}e�i� .+re��s4Y�'6E!C& : . Re�AcreS  in 4NFs ! � [43]-�)�!f�: T( a H^:)� heetE2 turn es S�T )coi��,es B , G , I “ . ”da�4Bloom et al . �.Y� �A� calcf Q1>���e RSA ( H R{!�)2enA�l� !.6�6�%.�treB�$le surface�\aASA )a�e�]*.��!�1X!�an ex}1t^!�a c9!�f!0y�`$RSA = kG� al earli�E� d��52�basZ pk �%��#25%Etas� o#if� !�� ���),'inV�2Sw-n�GAA?-lin 20 b ,y�[zi�%�-b,�o%3s �:;2�B�Aa@�]. divi� �&W z���fg=M�sum �;����N}����u!s>L �A�  cut-offv 10−4 agK t"�genome��� ErFXhom�ue��We x%follow�Jg�G$es: mammala�2i , Rattus�vegicus��,non-mamalianq tebrat�{Gal� g 0, Xenopus tro�i�lDanio rerio , Takifugu rubri>�nc$r metazoan�Ciona� �na KDrosophila melanoga� , Anope gambia� Caenorhabs eleg[) !� qeukaryo � Schizosac?omy7 pombLS2ces gOryza s�ha�rabidop_th%5a�iT6!a  sd�HoiAA� ac�!����� 1157SU�B���725a 1� , 253ve1�%6 'M@ . As"y��k }�a�Ix&� di a�A�DiA�To !�>2] I�w ej�#:�i.��spo�� ; �6�N M 50%&c w� !ysyntenicHZPairw~alignme� �� 66�-�2�� �A�" %`&� �(T-Coffee [5�bub�#!/bI!m*coEo ,�� Z1 -ho� Perl� gram��o�U^� q�>��"�1oncatenW$!4�7!� -�1GallZ��� %sh&�t�J�/V��lW a"t " >��� exac!q� � �u'!>��B,���-E�a9 6N?2Bj6� A2wokE�6�5iU�(!.%i ����K "� 2haejofym`!T�mplis��major�I� � T*�IW)u�owok�Q�T�� 6��to�UP�& ,-HE�� J(T:�h� efedmdT-ci�!�rea&katn� leveC We a.RPDB9�] �m1� b]&ndI�O^C.agM�:`M_,IG%�lso��. By do�P.� veryI�V� 1r� �9 MAFFT [54| �y*s A�&j 0 synony� ��tit�s�*B!ite ( dN 6LrH. DS�FdN/dS�)io �codeml�V��qb #ns%$PAML softw ,packages [55! S� �� '&��J���=�nsl*7]�. S"�2�66�eF&F��'��}l�dN>0 . 5a^/or dS>2�c��v�H&ck�\��],�l.� k urnre�~ly��oY2�*R Qa��K��a��#�&�#,B crib Gan [35m Krishnamoa y [3*,)$fun�af trai���#E��ndant �(3 , 425 X-r&�(.�>�ELISCES��$ [56] main�z Dunbr!olaborat�! ~� s� ��ae`Pa lisZ4 , 944%SR at� �ict parM cri�a1! Each 4���^Les no"75�id�Elc �~afa�fdA�<2�- Ang2m( �f ! E R-�A#A�25�bet+��Yh$�)widA}validQ [37![5W�d�*rou(f point*�.P! firs,�*w��t�&1 random6 � place & 97���:��,-��� �f��{16T'repC%�iN$� 1000~ )r&� u�bb ��.�6�#4� :*�by NMRe$troscopy!r� e-�:alX&el��l-=�Qf+A*eE�eC�!�~ty%�+v>�A�ȭ��SYz,���Nmea�� , Δde��a�. – ('erA��implyis�%�als�Q!��N (.d) � Z-sc�R� ��he A�&�+1eIr��U5! "��Zu#�G−〈 ��/σ�� B!F^)9�σ&sta1d deviɃin%x deri�2<Qf��r!͔M��#�(; a�s�def�<' enume�*' 6RA8��s�d��A ��s�m((!le�$o��<of`s Jcj�o% trol)�ny� Q"�� �"y+B�)�o�o( l�-,a�b&6a�UA�nby9wa��4-�5=��ܭ)s.� m2��0 s�we "w atz bs��2a�across� �3!� �/#unb9(� � . DuK�!��% �!�uffici4���s �5�a~�re��q e Ve"�:U0.��Polycomb 7s���,lex 2 ( PRC2AQrimethy�/s 3ne 27! hist�0H3 ( H3K27me33�g��e&res�du%�di�# e bi��.trans�)%�developaG�mbryoSstem c�2( ESC�"iI+di�Id�+cer�"� %\sh�(at �-0" �Pcl�|%on!|of) promw$self-renew�U1 mass��trometr7 WgaR&Suz12!�]partner �i& 0.�!�3���%�!��sA�:if!���dK� -t� h G((. Two multi�A9)�E�uicipatk gen�"i��re�)uv�{�%1�%�<�TN+�P[�7[�C����1b�'eu�Ee� AzEzhAl���4ferL>��� di-8 tri-qM�of.�nU.�2/�[2S8T&  Ee�li ��e%�uG ��� 0mono-ubiquiti�s{2A b119U02AK119Ub ) [3�� Both |r!*!�K yZmod�>!v�!z#>� ��4�aaWssoci*�eM�edD�� H3K4-marks �v�- E��a*ad�1"�Ehowever�#�a unique�4aE>�.erm�ivale`=�<at�AYri� of bF22�[::1�M� S����� at2�,���-DNA) elev%*GC��E�disz*low�Nof8.�.2c!� comm^x"at *}� oter�H/a:�7ɽS>�!�A cl�*C �kee�( "!���2�l�>�5�[16e&1f*CpG-rB3��s�11|�+GC /��q0ls�<p -Z , ���opi&ngMnA��j�P y [19e420� By occupy8.V �rktl(%IQ9�2 ,ɭ-!-1.q)9y��poE��}rapid ee� upo��6� �%\4�ri� ʼn�o2�i{ty� Disrup%$6 E�ND*� global ��of9m%is� o�m� �:�55 �, �=–[2���dys�� Y1.' �> urbs�9 menu2�F� re�9�;m. lei!tymic�@�H25�3E6� 6� PRC1a)=omѮis miȩP� c��7s:� E-8t �= �ctW�#neo;�1 �%GB&IA^�,ess/X%s: Aebp�JRbbp4/7-nd Jarid&�A���ͅ3)=4%= ReceD ,"X(�  )} , na��a �similar!� *�#PclZnt pheno�>� &p),�1��,"5�?�e|r[4)P/:yx th�3��/ m�":����c:d PHD�4*�0   (2,Me 5 �0a bdng  cripe��� � 6QN}94�/.21A�M�ed�9i0:e坩��Ms),"��� tiss~A-mal��r� 0� 50E��( Pcl2Q�W}��Mi�on� �5xtfn �5e7 + fibrobZ , MEF�-rinhib� 6���=���hi D�&Q �(ly��ɖ-"UNat2 ��9V3,�1H� %�3 )two isot - $>A� !s [�#. ME�x'K� ���=�itE�e uncl�; it%i ribu!�6� 5�qSC��NK)� �n����e�^�\5J�TQ z��&]�&1emonstGZ �3 ��2�I��3]�ed,��i�gA�lay��.�"�� $cl3 shRNA-�+� %�e>1k"}c�1�F�!�"a !6y��a_�)^�9Q�A,!0at щt�M�>��l6= �:�E K�� jI��microRNAA�6* >l.*P Rj-�2�"]� necessQ5�R5N>C�fyeel 1,motifn�;Jn� �3t~��Bd�!� �U�-e:6 .�*en toge� ��B�� ,�I�-�o�k� &�)�-� . To�y /�px-� yGA��Cu�G"mr��-�ed FloxJy� to� {C�em<in�pur"� ( TAf9 tagg!|lleleajI�(�KS10�#In brief �!4r� a 5 gene�Kp�9� Gt/+# ]�@D�(�3l�}IOE�( 3%�re-�is j� !:� o oxP-�A"s�#�Rev�. Via{�==$huttle vec!�%ti]��0on 5e�a"w((s 277–7419;f)�� carboxy-tK>reA!ro wildk( amouK,bL �_)�>d modea Ѧ%i!:E �of P��aB�z�T%�no�(B�_eV?1M-�?� � ��3co-�~YRE)F��A�2 ��he�E>�� ,� �t�w�T38^e�!+G�V�,�>0$k�M��j �<:�� �1bbp� � "� � G esKp48>� � 2� In"7*)�=N��a�)V_ �..� 2"ng%&�'� � �of �>��a�HEK 293M�by gel�" aXg�(p�&: To verQtof.� �cEz&���V5���Jte�I �E�k YOC���D��To"�>e�f1�T�� �E�me H� w�S6�cl3-V�(a�(/ )�E��E�ed��l� ]9&��  E�"Z!@ �� ��>RichJ5!��/�[ ��� �>�� � �c"� canl�DEP��2 �>� by �H�S�R\[22Y4�2;'2nS%_−/−~"�S� neu�%l?+&�Eed26� ��.R+ y�.�*��H ��+2_if)WJ eFj�:�ev5A�heY�&� a�>%�e a*"of)to=�`gREte%i�� *�$��N� W�%�M� �-m�lo� *� P *mx2AE S2\ . U�fJ�!Tcl�Ga cl3��c%ob6�er!aRATo eM�R,�& denss d*7 morp�L( g.�>�u�2��Y .&�.Rs�%�� �p$Ca"s aA.��E6"T�8s6���v�w�� ed grk{&hOct��N�7Ϳ alkaa? phosphat.B� thE-ANR chan�., V� X*� :�%�' 5 :)١4 �o� .vC–2DdU{B��1ls1G% cram�&�pI�Es��R�. AN& stair%z,slight�� inj-�rU]S2P To&O �i�*aa��eu�a �J�� coloN�ssa,$xM:q��a���v��2E%^�'eT���B"\W/��OfA*�#u:��o&#�.� ��(ix,� I$�S2D–S �OR�A%}� I{�  of>�, fs#VY$ 8c�V�*a塕. �9�2G&�y}FF�:%s�al)O"*%:l�A�2�Sto�� EKn�a%���60}>%��fe.]A�Ct�>q�:�2Fbu�FIV�a�F�JE=�D��]F/�cX )fEce��2L*� n -]��>s�E���#ch�ng��U�vXh r<>.�7edi8(�1�i�d LIF�B�%٥U�Kto:�modes��^6��0%��)�z�enh�J�Y�G%�.� to ~'9WE�z �-rit�9��2wa�!X&�6�*Q 2.J B�D �� e!>�.W!:��VQ �i�G, spl%2) pros8 �IQ5m��q, nerv� ~iP+/ head"+*�*p�8V6[!2�&��.�!ueK=,aMe�) !�in vitroB5e{R!�)���-VL . Te bs)sZ�Fa.I�e weign�'logATly:<mJ/. W�\%����m+�5�did%�� ��B1!BUP1s�A!�6���&nd$mE��de o�AsY0d��A0� ��G2H � Sm} More����fluoresH &��al!��6�5�B^ I� ( NeuNgTuj�musclActinb1� skin�/)Tel�'K14 )! G%sM�!�59�9D�SS2H�TVoY/B� S�,9� &5,.aN�D. ��&� BmA"b7:�� �' � of%Ro1�%Rs18m-��-�7hyury5SQ1�&nf!L"=Aas �X=c1��!a�� �"�&�- brogCA*q.� !�kofZ�=�I%��{fC��a=tFt*.���N��Q]I2�!�+�[�Pclm�!�"�eN�a� a"�"�!B�,�O�)�<luc386�&H�\��65d&� i��dimin�?%jV�+�A+�O~ pproxDly 80%62" v.� uwe'� �h� 4)�!"O -L��U13A���3S2z .a\n�RA�1��- -�F!�%sibnd����FSD;!��*�3�J�LC��[�A�"x n=� ��!,o dose*' fash5S3B� 33S�#.h>x.�.�&^ "�؅�d*�5�& &1 !xJ��?2�E�Dp-�3�As ����De"I;&� �.�M comi )!pT�de-�+=>:��F,�"�!Q�)����U�*5!�7(�!� �, &56�,s��u& - K*-of>-("-�F� >92<�4 H3K9�,)Rin-5 ,6�&. ,F�*A�5ly&F� acet16�n�27��1ac�n 1,-"7)�*�$+F)6�N a�UF)�a21�/� Vua'� �!I�gGz.f2. ��h�&"M�Lh8&.%$%j .H soRL� �*�8 u c�77b�ja���y��5FX���2+NE��h�5&r1a�g��d�!aue3Q:&��)Xa&;#>���\7��%���D�;B: 3U& .�;� k4A/Y��/�[ �caby.K!n�Z&� %Jnd6%�`i�8 !��1!JE� �ZV���s lyrw"��=� E-3F���S3 '�G d.� EL!nf16^/� 4us1�as&�by��YiR"Q"�/�u��F� �>�[p *����b/$.�x.� �/A��4j�.%B�U��SAHnv; � �Y�8�$���Y*cECARaiE�&�"�'2�~�in $ ��1�ng} v| �Ye$ ( GSE2832qRea�Y*8H� )&�TAmtNCBI BuA�3�MM�+�bowti�'� only�2ly"J _: ��Gq����*OUS4A� 4�[6� %9/A�9F ��V$$ E�E=D�� ach)�a�5�2@ `�#-a  ;w�96) �*b�!< ey�9equ�1�(498��M2!���-Qd� lNNf"9Se*�@�eI�:� P� Xed 95K:N�q �u4&N� �q� !naccWHA!"g H%��)��U��4� [616_06�we.�!.l�#pB��mp#�@>igz 35� peak)2��&�L-�ref�` weak N19� ay bI  C/A�&q ��?. CRN@'����(>�-�2!"�a aGspa���G\ |�� M�\u�4>�D��@jC::�a�si[1A����a�Fi}a��t��iocheml!{�2-Gt��́in*n{t�"ct��>�K� g %et�cu���>ɢ�#���130sil�@�qe &�i^i<��Ja&0.A�^�'Q`��� Q�%a��dZ6�Ix�6i��.����B I� Ś&� }Y* l�!,�45*6)*r/,}�4A�K� . Si":�6]out�NR�Z/U�V� �p�/�>��f oNLR4 A��89R :=r��:F` LvH=Z JU뉳��IB�S4� I�dtra�y�HJV M�m% �CA�Ak un5� c2�Bp�/a��� \ ] %%pronou q_F�QDiV�x*bB'"��E���8ma�w"�R-V3E�%" ; �� ter�FBch�! +��%MzO@tg�a B�)�. F5Dd&�IV��."�Bp�r�_� 9�Ս��}�$�%5�� . A�Y �k4s4 1�!Hg ebh2s�/A$itM!��e�#st!��q�6�8 u��:%Ιi�A-��B C:�\1%�n�� ge�|,MR�� -82""{�*e0R rsA�s�I�bo�N�#M�.Vf7s E2f!l@c-Myc , Zfx , Klf$!Ctcq05 S4L:�D|sF_!��}�K$ 9 . 5×�]58Q3 . 7 15�N. 2"4 . 0 6 ,26K8eQR) � ��� a�lma~%l} �;ortQ5��� mutu�`xc�i� 5�M��=iisJ2Vh �A$n)�I�!hU� A6�a@D�?I��mIJ��%�f @)P�<{$2�I"���+[1 65�-W2p�St("i[@6�mx^�yW&�UN�r6}Aő:d!m�@*/al- !?&�5� , [66�*7��I��"GN{%AAmA& 2���oyEM�R,at"�n�VF�"d6�&{ HoxbE� HoxaA� Duspa Handa�$mir-196b , a0�^!32/21�,34a=m}%4�#!%$�+6~!7 <7 I�22, :2�� ,&T �XW3, Tle�Tns�! Tmem151`!�J�US41*��&��B~$%��Pv�#� e3�5$ &��$�F&��2q]6?�%n��)ten�e�N6T��tod�4!"1ŖA��I �;o&u! �"a�b�Y$ �k( i!� , Ea� Ash2!�4Dcaf8 , Ift140�glrx&�� Ŕun�&�H�,A42�+!2� �� Z!^Y2�]*2V!y>Ot:; halldT>p�)�*�Ed��%&Q:].KActe�q�Ebfa�mirm�q�q� Pmp2�>lLi.)�:_.h Qk�L Matbl Pcdh�\Otx�c*�5S42Ea&�>a-�2+*!O}3:Ae5Va�� �"LB�Iہ5(�H2�B�� arge��&Xd6(F!M X� GlocA�&[Adis�*��!2� �5�B&Ce��M��2TAP . N6Ou$B@.��o� � ���q)���2��I?ar ��u35A�S5(5Br� �i� 306#"QW89,%2" �%$ ` qq���6�a�a]l@��K.��`o,��i*4+-2X�x%ũo!v�)wN >�!� �!A� ,=�d� do���tE_�j�B� ] �at�ch ��&y�+��a�!m>n6� �� �>.]H!� to s 5I �by �Z p: �! .q(:o N\"M A�[13� �#Wish62< dire�d�#B�Ekv!1�"�E9�q�m�3��!K*�)��� .�i��.��3H��, 8�����^� &�5t� q�C4)��zUYYC–5,6^n�a�0�@-f�y�@� � *&&d ��N:5�*pF�� ���( s�:� )tG� ���Kg�� ex�7e&>�2�N��~�5� ��4�/�L � �1�V ��twi�.Fy have"�I�QR���&N!ge흣�� X�`!6ec�� T 2.�3u�$%b�� {!�v�mD7 E) 0ujdraa��Hy�7%B��-/y0[(�э2�(�#�(�$=m �/"�"/� S9AG�To V?Ez� !�6�m8"��5u�7Z �!Dar�b.�130cs p#F�ft�Ao�Mcy� . Un3ct�&,�pe%�1��1�m.Z,U��J�sE E;�s ��X-�).��Eup)( T�S(- . No�Ow2m!�24 upr �a*)Y�S.�,� $ vu�S6W�O#��F)��by���.O*�!��s}R"Il6�t . Gi|)�c2� �t�1A ofe�[ed'�/A�f e� !CaZa0�B9mas�`�%�0J�pre-p��ng�ڥ�m��RZ. M9;e �6� 6C12q�&1<l.gz%5mu_/�� iol �j��ov�yU!. :U�)."]#� ���� �!]�%"�R.�e.���*QmOwNsa<}6g���� tw�^|re6b��I�A&�1=Z�`&�'ٍ.Kof �&� �wa�6 d ��Y&�^ �1��.z��0�=�@� 4E�z(��)b�� �Jvne�I�of*�=]Ya�*Gh�' bӀ subj,a�S�J� . LoȐ�;��A��@`/a�>z`���P x [2N�~?)#I�ձl Y�I� =� N�^#�/M�I !�Aab�<\0�A"g�F�IY nd E{� !b�*RK_��'zq�13�CZ^.:'i��0�)���)�Zd�%8 mbly�!-�"[ %�1��8!�  �&�0mt&VN��"�'� 1 =6>gDHy.6�2�6�� 1A3�k�Q cl3 s&,#l�n!�' ^�G�Eou�`�m�3p�r�FZ���J9P�/6 .�<1E�Ndy*R�.� ^�h�6t A�Ma�wni�N�?%- $ �d weJ, C�ݒ e0Q�5. {: �S6�#[ , [7i�7:mPKd�T9@a�;�3�- -�K&�K2�Na��BB�K&�Sݛ7I�AlthougvQ�K1A%4"�/E�r*�'eF�a`L{J9 o��q�^i��MH!XA�aM�9!6�26!��B �9"6�h&DS�6���A���!M�;A� HJkm}!�3� �.V2�2��f�M���N�b c ca��nee��:m�^��0s��arg�A "�^ s [7O[옝/�-�f!b.�cl6�S[�Vl�H.;T20�r��� ��yeT2U���B&�=��> �*#!MvP":=cW4pY5�F7��D7 !�S761�*9c�Q�X7�7/ -RT.R<,s:�2hR2��r� �ma�sd(�;�� F72;��|u �8!��8� t(( N75;Y78 )���NBj���nt�?mb1�w� ��x=& 6 �&ee-��v;u*�]�S�6i/:��6�5bJ.�'9 N75S�S�(QW��&� �h9���\AMn%�X W48A!�A%� F72S!�S"Aai��"� fk5,[ZY1�,E pair%�5�6�e>�,E�� �T�2n�=��0 Q+n� � ens%<~ uer&;? 2���NJ�incorpo�tin,X� � *��_J�1$��:�]9��+�B=9�� R���l �FY)6�>��J��YjI�j�!F�9n�(AB�M���27 4Ya&�+� !%by1P<�+i�[o#�M&��imd+� �����R�*��EO)�"� Q *�=� �o���w*�S{� �DNi->�n1�! :� extrem &"@(s?�no"Kc�o�H�5�8U Like�E� �2� �\o-�6^ 2..>o"� %-3ENc �9�i:Q �[��y�a$,��x!�� ��xmhZ�e�F_8 �uQ� Yt� B_�\xDincp> "�%�<esa�E�`q�A f�.`1 w66�m.�[2^3)FA�9�.���tY>lA�s1 q Y � 3 do��gI%��[-B�J�se�E�&m�r�nr�[B�!O�>�B�-�z�5 ���"}�AAHVl�R���2����*[R�=�* nn��.�6n�%enEU�Y[* �� s0!z 8�� Wu��3(� x�i)ly�H�J��*y5-F�:�A` �s+60�Y{8P��})��( 4�� �{�tdE�*<� �!�$�|6..� �2� %�.V&'g"���,�eB*a(, [79��,�r%��a7�t�)-�6� ��,!�!QQ�1�3ɾ ����.)mbU,% V��, 86%�v^TN��)8� Z �r� � . Un���(�!FjB�A�2�5QE`�%)>��(*�$e�@ih�on2���-;�wOi> ��9�n*�N.106�6P. IQ;�6ac�du�~ly� �)�Q�.6`���W.�5�:L9�&nzd Rbe.+�se5�Conn@,��:�dep�" E� ��!�+h�U!g>I8�m 2�3N�o G Ano|�er�� D&�\erbal�M/*kh.�,w!5�)��w&# �5uw %y�N�Joլo�n�B�") oftejF%n 6B1b&&Sjf5=�. � U��3)ois�%�AV\ ;�?6^"88s:6A-� @A��!&�2"��� 2 ů��?a c�IecomB���v�z-�tI�-17A����!F�- �."�"v"ai6PREQs,:8�C"�.Xj�-�~ V*� �few:"tgu 5N s [8"i8Z.Ntt��Z %s:is�2wna/N�%.�%�% �5!8�0{� �������5V&�"`)W� ;inRt_��-�ma+W � �d)Ofer�at���rA�$.{�� =i��s�b��64>s�w��0 b�;t��sur,�ZE�8% S6� �rt:�!�*T_I"�10�t 14-m ��fu�9�M 1 ].d!�%"^cuta G-�R&ލ�$q.bd>L��l4X�#GC �%��7 tif �`��!won�q5$"�by n!n2w4 li�dt; Bhv-:s(]?� ȁ�rt\Q<s5�� dis�#� 8�"P � �e&predi�5!�6E�iU��Fa6%or2oE�!�X����i� s�Xk�A�matrix�oSSM )E�_ ��heg)r���s 1E�!����/�,Z%�A�B6��h�S�N_B76YtDa-0M[�^"RsIVi,�RanA�� i�2yC�9�.:�maximum %Gȁ��� lj� ompu!"����]� %n!�%PjBI2i�U[��o bDaA��^ mach�h"��N helpQsU�U -�� B�V3��"�+�&F b<=9K� 3U�BX�/�ږid�[�BcE75%� PA�%�.N,��� ���CEk�u�!e m*�!�]��ZQs. E�%o?v�=:?JU!�n'RQ��e�& o av�S��eDA4�;6���orc�*�|C�������$��QQ�Y#I�5�@-k� BZ � util�"UL1/i�(�v)N�.� ��}. aYn�A�toE�� �P�&ism��� _���+��� �b�a !jA<� �a2�# " 6'renłA�67��3n"��.C%s?��b!���y�*�6pluri'�ccq>C=a.�?GA���# x���5�&_*�Fje6�'d+ �<�3"�>�:�w*�C�j ��pe�NF�D�wa�LI�=D�"Ji�im\%�1�P2? cl3�!�� M/��D%"� �NEQ�&&�8E�>��) !� Qe�A��4A�Q023C({�24�irFE��vy)�p�x>E�a�u.)'&�g�(�=CN 1XE��(*�${BANo.I��~�F g2I���.!5%U��x�5L_itcw6�F� MtH,>wN��>� .��lQ�!I3 )Ax6�2� O 6f�Q��.�@C-�Dx g��+��sb��V���cE��Du�v��Aą@% A�����CaF`J.�Br;2s��A���b��r0l0:�)>D� .-s�% mB ��i� �!e%�a;�%O)�(&�!ą%͎-e 15&i.12b�-=�wny> :� .mR[ng�G"��7o2��H"�ږ4#�ܵ�B��-*2�._-q�*�H-ll:wA���J�Ճ�@&]:;c�ii�V�.K.:8�,�q6rA5N!��Ga#f�&��in6�ng�� ��ina�;-G62onaDel9 %t& h Bl�)�R�ia�0}#pecB:3�ec>�n6�.&��*faQlPa*<"3l�"�b���!�5C>(o�(a��L�o�^.j Ns�W Nano�@C:FeS�� ]B���>�88e�?�a���+\!�AA�:/.[* �>!�. _>L�&4 )3"� &� &�C�[��d.� ln-cpV�\� h&��o!�� sV�, [38}C398�v8!G&5�Tjjt!�%AM�V6� D�" �-"Qo ,Bui��"� .-� �A  � kcGC 6zY �N��#1>AF�$�)5%RA �� G:`I5raP4s� �c�*��!R�"�{1x9�s2f�A��%�� m2iF1"�� Vn� pri$ ��� e�A�i �!i*�30clno�&�#Hra�::��R�2�-� u��.by� e(:��A�[va62(�a1&�-�E- recoJȎor un*-�R-[9*9�Vi�t�? *N)K�7� uev)��!2�(i"`-%���,͏n-7o&�!E�%�2GhN{G~2�h@]�%�"�D h2�(N**���o Ds y�05�fgWg"%��h��o�k!c�-&�<oss-of-�q �q�z�?"$g C:& .��:|�rˇ �_ throp�3�5 QA<ruw�җi�+/b�u��%KIN�( �! ���4p�EAP*��)�A�=A��]�inR!0ARoLi@ �P]�� �]'mannerx!� &f2A�����;H��in�� �-n 5:`ck�#�*�!�n�rN�!I5|>� ��a$F�1:"J)OM9��D���Kbc/%|b J"6)�.(�5g"�!L�ǻ�=���ens�xB'T"' H a�a %!r� _�o�f ��sv"L �j�%�ng"C*.#n�E�b�(s M1)8V�gJ&�| �*-���%�ws3V9P�2��*)�*;���t�uen�A��$3!I���U�M�!� Sng��aFo&��i2.�9se46�!pe�6� � � 6�7�4eqH"�l%4�E � �t& �o� 2� 3J� c�+����*r8_wSoK@�  m 2q>W �6�5�7\I S*� B�2�����2z�i�AaZ}4���a� �2@B4p:OU� ���]�]Q�� "v u� �Q�M8k -+!6gt��� �x'Ţ}/ bN�Y B� �+A�e�a�s�Hw a�r< � Bo0�*$�`� .� �Af5�Q� \ %3�9�p*�*��"- -1Ͳ5���deWI3:�%=. Bo��� åSL}�Zq�}q2�n)2] o"$@:� . At*B !^ vidu�\"�,)���.�6?.I2G�(dt�ke�a8)d��5��Y���^�MCac�'�0by"r � !�%2yt2!�1%B��t�>_i 6N��antagon��%C�( x& ��'i���,Yq#�4 F�}3od��!m��:;ݐ Y.�L2��RVj�9w���l�.�rM�! y"Mre$� ݍ%"@�%�NB�l2� es o�?)( F2 .F2Z�EY&�*f��*��u|c paP x�ac��k)����eH6�.`)A|��.4� c���WA���-1R�rR[` tu��� ��{�9A��&��5+ )��bIaB�z%|RNAPII���inC e [9�M!f-ɽ�)epJ�W�� ��n"�!J/ " �7�!kep check���+p� "�6>be�]�R�w�$ :��<n," �s�4��i}aymr;A1B֤m�$p�vߢ3ci�a^dD��./�a��mS���:u�=b���AU�k e& t�u?se**C�A��c-���� s�a�c�a�7�9T �. �M�1*[9�9!*~ iA&��0^"\'2��=) ��r �&��9A�_2Ff� H�JZ+ [�� , [9J*�*!:|"Y2[ 3 "yJ!D)@A�)�2TM�  �G!��*L"KG�2l �q@oa�� prkS�|li���=z@,�v���&�!���a�pr����gha�!ow)i&�K! re��z� ���B��{$2�capaci��s&Pf"H@�. M;�14*�|�� p�1~��= �� +��]�]�!�BBaya� omicD�p,� XG122 �3M'�!?"�R%�/ �k�g. �trypsin�T�| 1 ml> � at 105/ml -LK��E� 6- !ʮ�  15 µ Qon�z}d��(ru�% Open Bios2�s RMM453N>(Sigma SHC00�J�� f!shaF�?.y<0pʕ!��ha3�t��incub� 6 nE=at 37°CyV#X�%�!Yn���Gs�!AYta��( 2 µg!(pu�i��50zeo�VC�K%| M�-ixf�H.�Opic�Lie&Q~�<��F�,"�ieL%hivi"4+��*~:�z gaveU�g..�e4�NO| Lipoa�} 2�( InvQ~(gen 11668-0��. B��ly��AgA<f����}I8Q76bin)UEROp�Jm�9�!�20A r�V5)�EP��(F����6�mixtur-=�6�18 hr tk��� "��.clx, 300 ng �3% 6|in(m]1 !I265�Librat��i�E�mad~6.�&�16Yy�\';AC� �Mb"c�!uL��� m�cr'��Z8�o��t9H�Y�&��b@9BF=��>f2t9��n >"�Β �er�(!;�R�m� a�Pc2�Q.@'/t�stZ�?�{�e lΨ��nt�pU]) blot7!� 2u9c?e_ T�KS;\=�m~��! slip8J��eu��-hM�/� ( BD�9&�ce�4�܉�^�)�E&�Ja7�_a^�B6� rM"ent�!46�.��:2–6������ineMdru�V�%^��� gHpc���i�M/�an un�3edh ent��-��EAa��r&:Rnd�3f�P:��E��a� ��3AgF �- &?1u�ne� kiVL Quik�k II XLhm-DuLe��1,UTechno�� 2005+a�Qp�I�����~�"6-]t> Ayt �CLC"\.8�b�Bio��ANi�� 1T=� tr � eStemTagKP*ڍ��KK%=aC|(labs CBA-30�V�%�m[eFES�z�� ��}a͞S�r!���%*P�-��,efixi���5% glutg dehy�Ly�Ni��in HBSN1� wasU�in AP b!�(�� mM~�s pH #&j0NaCD�5 MgCl, NBT/BCIP�{+ti+���sampl�- �� K1KT y�!�on� sto>�%^ {,EDTA pH5 . 1�PBS� pi��kt� ��a01���A�2�� 8ly� � � }�1�- ] absorb "�u�Y��uOL-�.H)�^= �eu֗ M|B 0 �/$ �Q0 . *� 8"� olo���Ep�4�ene blu� �R�~)NwRxt �!��V�.�A�KA����e&� !�.�3�n:ft �9re"X M7 � of 6*m6-U ml ." (� �`]8in�U� ubcuta�l/s)> e�m� �����Y��SCI?3>�!Y�1�*� –3 week�Tum��%�r|YdDd�M���ff�)N/ frozl�z�.`�W�J¹wo�M�� �tAA  �). S�� �%h,h�el�$I�a]hybrid�U� "� ~5 �oA�p� oco%�� he UCSF S�*pZ �Fac�D����J2�( ��www���!jucs�+edu<6%�.i ůSee"� !�R detaiP�� � *"X���in�c��zt"<. %���^� ��5F -#"�2!-"T� �00@Eo�aBs�2$ ��s107I.g1� �� �A !�:$ 6�I �-". ( Up� , 07-44}Azt|M?�Z , 088k601QB$S��M�236)� >o37oa�t�`,( Millipl %�, MC315 04-74�k-��RA8� �hUxIZ��Puy�:zsMO�-end 30-&�=� a� M.;EQ)��:^wc>*��2���d�~by� �~Ea��$mem�-n 2 -yU� best -m 1[~� summ�PA*P�\ Z��%�8S4A� ai� ���hɗ�by�}���n"�7)4_K����nd:�[2�^#�AuT b��D���4J�m$�;A�C2r�;G�}� um �p,��hO"��9��l���� �su5�5B��![p� �o curvA}ܿ�>" tlyIB)�h���p/by fi� ! r��[�� �fgE��N 10th�6 Ɓ'];*f!� �M����� �.�I��t�g3!��Z A-F"W�d erro=!,%�#2��$�+�� �!����c߬�EG,{$neQQ�m~5y�%"�c�) K�Fsm"�ur4Skellam�8{ia�E:nul��.�b�4�Bp run� window��BRm�. Aj]�Alof\�7�P�5�tU,*��!@uE�)E r�vo��O6�ju�Owp0 . 05AC�?�� o��Poisslum?9 heure��^x!�q�proba�L׷O��d r�����E!V.�1wA�a:�s��q�n!�p +�w−log� −p;) E[C]/Lj"�$ LE�-�z��D*�c�*"e�l+��M-Oh�ro��dja+ 5�.�]�:N�� � "T� �w�/���mre����jo�It��z2�-a�e�!�(]�iss�9Mbp��� !�!�k-T"� �6mt�� �E���� &f�< �.�] �� ��2(�RunU�٨RefSeq�AYn O1����aaQ5M:\���~A�>��A�In�P4BA�G*ou`q!�%�7un�&�; 7�5,� dn)�7 �C2��*�Aan!BeqBz0 �ess��1�To� m�I+ � ,A���a�o�not�j�\9a���x���v�� NU!�3��i9|`4Eq�C�"�+U3�G�q`(%C&d�rj�We��{dy alg$hm>� Leit�B�!mS$!.I�c�*+G69��b� Markov"�%���I f�Rs rang!QP6%�1%} �I�]LSpE6 5 R!�A�14-J �nD�+|@i����/N�}H�e�AO�� 7. SI���^=\[� Nb���%� logo� q 9A�Ս 'FYGt%!YElC�hcustom �d{-Z�I�&%D �6c�>sum!o.WJ�e�Y#. S��>�5�0�*)M7e1071 R-�хb�gF�A��qB�10�pɅ���i�u2�e�avail�+� H�Y�,Omnibu�X��En�8"v�.!F��Ajfeea�-� � �%�%#؆ oreceptor��*�!U!�^����% ir Oʢore�hav��,'!Wm&<964�${�r���6�&� haGu0!��I Nj 1) te*M2J, srh-23Va�� ADL �E��i #�?:�$ d vi0,ec2-2"N%Q�UYau��� �ME1ac.)oge&�8ba��r�-loop-  ( bHLH[�R���l ��express4ion as a funct�of feeding state . We identify a cis-regulatory MEF2 bind2�ite that is necessary and sufficient for the starvav4-induced down ^ �8srh-234 express@, while an E-box xkn=to �0 bHLH factors�required!driveNYin ADL � show �dHLH-2 ( E/Daughterless ) ,3�%`4 ( Achaete-scute homolog-act`neurons� �R�%zD on insulin signal;Qx ,specificallyT!��% also=� thisu -to- .Q�-I�-cA9of=volveA�subset �)8peptides . Thes!>0sults combineA�ggest)�Dchemoreceptor gene.�is�ed!tLboth cell-autonomous%l non-> transcrip�Hal mechanisms media TMa�al2�e-Hch may allow animalEfine-tuna�eir � �is!�dynamM�%"�a�> y�%Q4(s localizedA�1/I�I�is�mA� plasticite02NBv�is observed across phyla [2–7] , but ��6�se�s�AE�lEq into.�� �e��F���@poorly understooda`:�6�ZI��ly!�b%� prim�ou!�)�certain2� aligQs6c repertoir�cd�%wia�ha6�ra�nutrim���a�ext environm�! such�A�$ availabil!�. Yet ,EW�tyA t��%��(��gi� mode.��oa�m! larg!Iun�B�� nemat0hCaenorhabditis elegans prov�an� al system!� �fy6�6�Elya$6}e.]�/� *>,�ha�a? sigh�pto��'%#- _��logicaQ ]b? . For exa�:)�M:p HMBX-1� C .50 !HMBOX" �e�� srsx-3N�[8a�I�(is asymmetr�l� AWC >![9��IE� AWBB! �(KIN-29 salt� Hible kinase ( SIK ):� {AMof%istr-1N�via! MADS� R= MEF-2 [10�$Moreover ,An�r analys�� f several� �ed6|sQ�i�� sha bi-part� motif& �W%"Qr X�[1�>E� atic2�all^6�I�familyơ�und8a.�� �was.6 to direct.�� B�12A2s�ad"3 b�i�gnR 3 'protei� Lhe basic Helix-Loop-  (`)R�shDhave important rol��I�M�!Rof� --d>�%;���N/�.eas well in o9 multiS ular orga; coordi�a number�Hdevelopmental eventh! nerv� I ,��� Q5a�!c4differ? of��FTpro��alR 2���.�i�3ole&� of>� 5�"� A� `�$ [13–15]�dis�� migr �[16AU{ �� S� ( As/Sc )]�AL"& ,�needed�CJ(hermaphrodiK q��8 [17� E� � form�i4dimers or heteGthrough��s�M+eA�� `e�[18 , 1�JA �&nt prehensPtudy dqm D�iz)B , sp teaA^&�A/i�$( CANNTG )u�1iti\ neaE �s:�.&.�. Simia to verteb� s��:�M9%Mlog-�2!�n2c9w�1y 14-W �c�, inclu�n!!I5)�E�3A� , 2�In%farisoAK3*�[��!I6�� 30 do notE� 8 artnA(� P  t �y lapp��� nD � same-�seque� [�deed ,� �pl� ntagoni� 6.�9 Nto �52S�r�4lysosomal lipa� ( l ) �[2ŽInterWgly-�]�� emxl�hlh!>?highlA�� ao6 68 con3 e�~�.0)BatF$as6�Z witch' o cou� a"� ’:y� -4�i metabolic%.�i��al���uThuamana I5I��.�Av�E�a��� -cha�peri� �pro#e��� ��al2�Z:��couldE� shad��k�or!@�!} -&�PofJ��� >i.a�ord!o bet+� �d *N��N2NnV� , we focuTwis ��e��did�ס�&�,� t1^?ͅ�m3s DLB� of2. Altho�|�;t� ��&}s�Dc���r� �be-�q, ourѝ work-�anz �ay�sr �^�j�2�Ird"\9?!7tro�l z93A��} whenA��� 2�>�."e<M� �pathways�FA�Z �� � [23�!%DA� 2 U![24 *i circuil puts fromFRMG��r �2�fNPR-1)j.f5�6] m�2�� -� �[)�We"/�.�Y NE %]*re�U=�dur!X&� xJ�� ��>2,u2U��2�al1or� : 阁�6�in mam�,> %� ��g��] ly�2�X �8etween myogenic�~�VG e�coopeK vm5�muscle�.l[27–2p � �����jsNn_A]Et �MASH1 �FV�%6�5� %2bym owdeiY typN��vS v�U2�A��!�)�� �{���J[3 }�> ns rais�intrigu�possi(��a�� :`module:8I�!).%i �s�)�e�F6� �: . Her�wee� �U2�c� toge%_1|-2![U0}�--F�a��!,�����. �a!:�~��8�����los� oxim&� �E)����=%�"I�� A�B�%�1��7A�a!)�a"�_��z�a�9amutM�in\ U d E{6x Q RNAimew��Yf�i�*� �leF� 10 weaklyjO�h ad� K.��0Y0s&l mef-2 sup�e�1:AJ !4(a� 4�eYfly1�s&ab:.^ J@!3ere� h2�-�=� YE��%N)�=h�30���� � � sT� N � z]v2XL-3/!30s�/�16�� �� %v:qa*� 2 �s ( ILP�B��� ! "�q�,%�.����LJ�. Taken�,1 se�YP j�Թ�e�E#�alu� link6�.;� �=-RkF� BA  W��eviously�).� =�Yqaᴖ� -�!�6{�is2�1u�A�2� Ar.� v gfp.�]!n1Lonly 165 bp upstream&,;1�>��$t��(%p::m)��-"i��QT���1*h w�i,long-periods�im�>6 hourA�"� ��ign� n�vdow[q�-%e����aA�e6i* V�occ�  resc�� �"=��Awb�Y �cR Em�Х�M��%8( - ;6\ to CGACl ;eS� ^HIw inc#,xbIFDa�; */ %zP] �6� %Bed�>*�R� A!I3T�>=I7��b�.Z� I�b-q�����)a:�!���� �%�-�� R �a�r�3�)!U��� 4}��DL2��$&��Ira� ��2"1J.[�2Ve��B5F+] ory�bm46T6/e�("�(!2 NA6==e��ࡩ� � � !�s`"� f�to� I ��orou��9�E)[�U V� u&���%b�.U69 bpI�2� [B ��R �j| . Of!I��: does!M�"FG2 %c�� "�c�%3F��M �}�a�+t�=� compt) to wild-t6�� 2��2q�a J��A��.|"i@a1dloss-of-����{��.�!����� � �V�R� �����)"�%�2�r��4"�.�w6F&�'>��s.BE� 6��. 2�/"��0�crecogn�1P .�BQ%ir �aoN'[36� The .�genom�a s least 42 �C [37]�� j�w-�%�c- obliga�Vz�~&,2�-"�[19��*�%.���=jmQr��rM buin ex!�ntu�or�e-";� ( )!����h��In� cuy(��#on N2��or]����%�.��-A���O�.18 j �55 �"�-�U.�)1@$�"�.3did�� �n�aI -��1 �6A� 1&[�%j�-F���s 3T3CSS2BW&C"confir� !x:T.�� �1;$by qRT-PCR�2\ �Si5)wb!+�i_#A""� Z�_, �#sR �"df �� I`s�'ӱ��#a"6R97ciliaa0�q�. How!�+4!Vex08��of%�6b( 30%�-dye-fillV, n = 20� .gBV,X10�6�&�ae�zY����} (ABcr�9g � 1�#�hoh;�2�essB��4.A_:2*[13m���$64E1��-xb4� 10�,O/&�=e-���)��cal!fA�*� �� 3imq��5�� rega+.JaX)AAaIE�bs�._fu[<��B� 2�/m�!`s$�3 .K� I; zyg2!�Aw0>tm1768e0a hypomorphicJ%e��9�s,�>t 25°��&5.0�1�0�-8 ( ot354 ) null%� g,B�*� &� � �3A%�3� .�&|2�;.�dou�!���I�?:�5$ � �M&06as����6s�= mbryo�'lethaY9m4we2ee�~ 2 selecti�':�by"�1 s. @id-1 ( pk3321 ) ;:f��"� � DL:: :FefA�I�"n4~v,approach [387 U�E,metho�0-:�"� j�����S ( S7��Ef��)9on ܡ�d���:�|��be�Yed�X�*se �ex�m�5, becaus���4� �� 1�a����l>Z-�u  #ɮ)�(i ir"�3g e�=3y�9 , ax�2b5 body s0��it"�-6�)/5�" elim�6l@6�)!I �z�2����9 3l  ly53�5pr�!r�C�@ey�asked� X.b��e.x!���OBVA�' =3"�"1F� vT- !�c�3�,>#I�ݳ��Q���1�}� 5�se= r j�%A*�1��S�.ia�l�Z .8;>5:�%5i�A�18aEm�%�e-1�. ( S4m�,QQ �>�` #-�-�d,s9 .1c��:vF �<1�!I1c85E9N!�1�s&�>9 [3�40U F��t�JG�� ruit��!:� "�o c*�#genes [2o8-,46 &o�3�!jQ�a�of6c. W.�#=n5����(fA22� 3�� 2mW%�OIC�U� *IE2~!p�-odu"�� f�+��z')�jx�eZ8�z&���A{.X Jf5C%6Q�I,1?(y�!��6' plusYr2�;&�-Y"� J ��$ek�'=� �2EG0-z �%6�aO �F�is�Y�� e�Z`I*A,a+iJ6�AUa� �8� ���qC�-ŁO���=��� [�Z.�W062 *�,� 8Ja �0xGi4=��,�� �.:�=�Z(e�0%� ����&�F�.:X s 3B ,� A !>B:r0A�5�A�m)���tf;���xp:!�9* ;manner�:O�6� M��,n.BY;E� [��"�)a�.�s�9eQ 91���q&-�ޅ2�.�]F1�zBQ�n/��r�, ����R�.�M�-uB. FY ���6�>�!!�HFl)$a�M|Mn.5 "�V��EaJ������:�6�S�2 �J<A;�� 4��51�.��r�-��1� �ndK�r/G�;~H����m�eyk .�2�'{act ��'-���6 =� a� dFK67e6�� "�<h6i. H�'Kicm2x i.}"r"�7�=�b P,sb9-+B�* "�M�BR8f cE_�Z :R wm*�Ajxpheno F "��to� s�������ޅ� � acts��/of [Dparalla�o�k%;z�N- 58�N'�R,>#exhibi���P����s= �� t`r  2% At� �@ow= �6& �h � �)E�R�}�F�M�>�E�� R%jP!�6R�-�0I�V� � s�2�Ε� 6g$&�Ag*) �� ;a� 3!���% 8h)f�=�. D6�8>R5+Qy ��as5W!�A��v�1z�,Aie}�%C0N�p�*2_;* �$g&�R�+��nd����>�K*� .�H.:Fof +�6%�;�7"h physm���;��U*��E���T]*� A t��P&R��� �z)Gx1��%wF�4 m�.u lyf u7=�B�����W�refX1d!\6L v29����:�-��.b%&& 2�)��2]� E�2m backgrr ^ �d%"e��]F.GK�*&hW �� vh-1 enco3a growthH whq<|M.t [41]Aӡq��*�auo"jq� ( S5>�Nk><(�:: _) ,�G�3��-,F�&X](F�a�:6mcb �H( �!�E!�scu>"4''a�� &s��>�.?ZM���W� xt^�.k� :41 eqH�m decitoAy%/ EYJ� J�� .��qr� *h Au�>Og* v)�* >"8 >�I�F��aI� 5&�� a 6( oyIs56�� +.i��-� #�*��P(ol��Ps 4O(S7U.s,.rm 3�HMof��nd@C�($9!A3I�3j ���&j( 0��.�B�!�R��qgCol�� Rva�"o �{�M>/&�0-�I�..Y�J�. Na�&�8@$atm�ADr yz��Q�Y �Na�co*e��ead���Dtissu�&a "�O"��$erf!VX^�T�L��* they��n��*~^/��Z0 B*}�D2p::mCherry::his-1_VA��* ��P 3pM�::SL2 �truct 6�D����-9<��xor sri-5 � )&ee Ma� aa�d M�v<%q�Z"�A��-�  �B8Q�a�r5��b1�e. s 4C , 4D~S��,�!iq#A9��F�$.?S� aM[ A� adul�-�G`4,"�4)Dt<�#�"��p�i� ��YN�B �2�4E�E �A���MoLW1{��v m&! bI�hatchA9���L2>Zva�4!t�BFi!`2[H"�&r�3�very low>�C�>we&z(U;�B�Q"in L1�A|� �"�)--� S!H1?n%/�NgR$%6sB7%�s:n)�4�s�X6E2"1"�s�Q: aV_:�Z"AB�oA�� ߱ ��"�AS1Dᔱ�m�6����>N2�'w�;"g+aOpa#P3 ��-f=1a�A�Io%4�'!"�.y�=�lQd�]U�S6A��� oppo�C�u�-�� ����!�(.���^'2^�.�mXV�HR�b6�M�&�� 5�.��Jh !�%T( A�of�a&ofF}" � #�C .:�&�ZRA�t� r� ;::B��7+"� cuEx�a "�.2� T!NA*�z:� 5L'5B���@ *aM�ed t9 M�|C%~�*� F& �or  �#J��T�"T?1� �!�5 � _J ,Jp"3'N�E lack!� x�T�]$be attribu�toMFo��HX�� �&a 2�B���7.�� -!M� -j*�"2�,5�2� !+of } B*)(� ��8b-�^)2?'.&M>�� "��6ells/� � F>D&6-zS =Z�/�Fr�hA�& .R��rI!>�X>�X|�-I&@�so�i2Z 9 F��nf�12*�KN�-�}�Y9�}.�1 "ly�ges-1.�,e��a�*�6cm�c1"� AF���u*~=��m�M�eu��J��%� "�Y�C:�?�  ingYI�&w in�(��B)jdH-�E n hairpini�Y�g�� ) [49anT�"�@r4>�+��*c5&�+9�F�+���}F���M�2 �E=�U��5�?�?.��>ML.��F�FFt(*�B%��ei5�A��A��HIi�+y`�z�^�*�. Bb,� >� � AB�e��jj�e ke[+ n daue�Y�چ�o[49xJ*0%�.�A6WCu�.��.�NK���L5mvX� Ba! f48.�AWC����4�.o*(����*� }�.~pAK wod� V�"-^'&;蹃,�0�:��ioN�Q�wt 6P-�V2\j�k &[�o �~ ,MXLm`30.oU� B�AO(qA !>�oi�;�_5'!�M�*2� tatuJ ~ �&�[.�;[4UJD�{&��%�vu�+?#�R���;"�GV�� !�&616 FOXO:�Pq 2uc-'Nj]�&�"6��\��� j>vF�Ra 6�3^1E�{ �Nlsa��]ѵinr.-*da�?�  5D� B`#&, AF 9paf!r�� �f6">}=]كF$��G�A 16"�u�H� q>� �5�F�A�M2/RkUm�� sj�"��I"�5F}F;F�Bi Q�.<of �"i a���"?މ�; b:4%���5WS���#�o*'i�7�!!kj�"tR�!� 4iQs �"�+��Wysn� Y\8&�=\Fi, �aF1 �F�% �S��2�A1b,F16FS"�Db�%g�^ngNasFD16��1GAc S.X���F�=%"w%�I� M$�.� ����� E��(M$1jV R�Ga� conn�.�@6`M�Ք> &5A�;2-al�%!Qat!�;.�( ihp�xa,ѳR���?J(��xrst:�E{ R (P�kq�(veE�ea�*h"s)��U2 &�X6�a� "e�� 9�EE�nt�C�4pro�Wa�a~ �z-!C2�����  ��l>al�'::GFP�H!� Ae�pb+�2E( >W7x fol!(�P-!F�x=na�� "2G..6�.�4O ; S8 . No/ct�Nv1�!�"�, a 2�ab!�F� n�r&�oQ�.�d ��ꡔ!�(.��E�y7gp&Rz�%��IX�IlYb:Vj� dataA a�Es y�R�� .�-E�2�dV7 �J9 ��1��sub�u@E�QlLnof�16ad��R�. P# LQ)u* d7at EI�shuttB81�� cytohxm%Wnucleu�  q��:6&�v�._1aD ��Xhe�hock [4�SM&�=g I�F� � �T�arZ0 �[4VHIfE}�Љc pN�FE du�� 3Q�.w we w�ka:I^A�1 �b�� s z �z$'�� �qF�'%�A�.h"�M%!x �IE�8����ME�6�Ye�7 a2_�Z���q�#�=by_�>�!�! gfp )�+(� *� .�*>(�9]:rM���.mFAK.y%to% 1l} � fluo��o.e.Dk2�6�.�is mostve�CXyoU ��^ E ��5FW &�af \RI�I!�aat:�)! .�t�YA\E ).�Q4e�@�U�IVH�alAp>�:�;�2�.��$2tbecom!�u1��x�Q��F�6���5Y��<�t") .�6�s�@Q ex�red"�#!/c�Ric��a�m�men/�?y�a overmx�J�2?a�Q�F a!�'-�)�% ��F#d^}��j%EM6� �7b.xJbO�� Yb�c�R� ��s7 ��!�)�&� m&H�N =o2� �%�*/ z�Í%*� � >$J�z-1�:�.�*�F�e%�!��A�!� 9r[kng} a semi-dokBnt�w�@�a19�DZ8 s��/[ o bl���& u9fA' �[47�n�s����t� !�D hW8�elf%PD.R^�]��286^G}9�Z!��9J]B:'�>}S9� F))%� ��4E�U"�LEEd^�,U�&|knock6?ajFM�,�.�[�F>��0ed�#s��dividual��=5UA�29!"f$�*0&����9insJ+�sY�"� V��Z&,/L7&�xs-2D; ^�$'28(�"�.+ŋs 6�O6�,9�� r�a�hІIL1K-��E�N��tq�� 7.�B\>� �@ ." [4�B49ZC���� ��_ U6[g� aL�dxw06L!�}��>se=!i[��M � fKv=v!3;�_"� "~4 f /V �B�;W;�9��30G%�"� �i`gT*Yg�_T�) [fg nKQal.5+��c6h%a3p����LJ*�`YB �6( ok194�/�e�10��( 1 . 8de>k� �!L-�.�&& N� )a���u�)�-�]Bqj2�8ci��!�: 1wj2d!_ 95-o&,er6@�no)ZrK�O 5F�by����(.���1�/EҭsV�"~��eIv<"� , a["W 2R��i�#��r5=�&�-T:w�b�1 bV)M�26}�a�'V�&� ���W�.��265�B�"rJ"�� �=-:�i�s��+ .=)% ASE , ASIE� �T1�� *�d!�Q'�+��!����5otjuDL�5�NRe�h�Hd�@� j�9��WC�:M%C2p�;e526.N D�upo�z͊�!L0e&�a�26R�f�8 *���?� Z.�wac�2�)o�0a:B bIas%�1�(%�u�!��1���m2�S�eUs����i mt-�IQ2>[51[>nFU@&� D� �s)&h"]*���5E1!Y+p��]!�SE d���� ��= 4(q3%u�"&A�B�9&��2p.�U� � �.d84n��2m\}Y����pl9}N�"nL� ��-j( =# ��DLn7ALbVv�rO��Ap�5*(QA�g&�m��t�E�2s ducBL%y5\���B�2d( a�.;myQ�Fu2&�~{2,)"| 3 bea�me�����Ze�4�����mW�GV�5,�� > P.�;62����t�tu�ca^{3Q�R|Mb J?RR�&�N�Nb init~�N -� b2(M��a�folZ;�-�Yp\;madVJq��hI�� ov���7r O�inv��� +�%^orn3A � e�M��g�R.�n�M�2�:"�exaY*�Z*/�1 ���"�bj>$P-�Q'e yet clzR pC%�f9)���a�objW}'%�i<�jsA�"�:&�I<. S�af�bf��z-�among Z��le�TF�SR�.�i]�Myc:MaxA�Mad b K�s whom�re�eAr8E�]��� a�&-%v:,Y���ife�Lon [5��A"�' �!"U%�Me"��:��u|��&9�pu��U��h�&<A.nM�>�. �v�>c;�d�@F.� Vޜ>�F�]rK s�B��2/��2/4��.�.b+� �sis�enric._��a�NZ.��1�.�]_)zw[����(i�7D&-S� �.� ��";`�Zc� A�A�tI���o8t]�sAA.v3:o=� � ��N�.@� :zm.�/*�7;cy��mValE� � ^a[��f�.��-CW�&za�$ ingl:>:�)M�y � � �i�QAD*�@.m�t��e�r>�5�a�res��4]�_��� u� a�)�g^er"}^�9��I a&j�!.-��=9=O:�e�^!Tf U �QJ!��M5 ��� !R.\;!<.�9�a#�Q"�%6 &p �5fAn q 3q":m� ^����*\A�.�sn#b�mmw�*�K1? "*-L. N�$o��A�Yl"�x| C�$!�"� infl#�,�7�LaswS3�[�CaffAu�E�f�D.�\C4� par� expl�u`]G�c�;�A��:r1Elh-� 3E3�'^� RMV>^G�/j$[M#"� � �)M�g�9 kmV!5� ��)y�>!E��J�Z�_V p�� &� U]A�2�,� aPeyq�ayF�es� �:�.���,�a�e�A�,e�aiW" pHuv�U?�U�;:1�to�-&i&�is!�+te�hn"�Vto�  �]O� >�.�o!"�itp�΅L:��jRz!}��0+� ��!+�3j&^6AHN� �FiQ ��!� �2� m��4EY�qNi �E���leco�c�5v|vK0A���tBC_1��WM2�B�v># �IUMK�Qim��&}.3e�g _)�&�v.onf�*�RRX��)u.��S�*2��ecnai"��Av�*�Y�*s)E�sZ��R�&�a.�%�.�X]�q�F7�eE� �n� %P.RM��I*)3A��� s�'�K>1 NߍM pF�V]a 2%\MM�u�-��T���^3s:�c!:^6_!�~;�3�.��)9 ques�3 5�es>aIX6 �51T� Y�&�m>�1� Z HlH| . OneDilj��$�s'R�@ �AәO�s�2i��� �)�� �U�= b�a) �+�!F�or�!|�6y�*�_)�>�"��;ti\6") %0 �� �J�2p�o&n�% 2m,[!t�r��-�R��%"�B��# � �� N(,6�"=P�3�Ա�: �o"��> ��Ýw�S � 9uL\;e�G��2�ոntU��A@A#e�a*<RZ>{*Ya�} H �nr*��I�2~�en��,�� �m( {dȪd �:en!,�Mm2� t3/4 �4 ~=l]�M4# " �e��I�B.�e@]�\2,��Azh� -V� >ur�Hkes�&#� .��e)5 U�ma�lea%� {"\#��mr=E�.� %�u ��9L)%D �^W" ኁ��55T2D�WcZF�M2K"N �z�. Gen��p��.7n2��A,�0!�2J8m�5b��)!e�b����.�o�&�x&"I(C'.�Bdz.�)?N-gP a R�@N �� qm � �A�FME^%�.h�&�� �E&����2� 9rogram�1anK�6�S� phag-!T"�46|@�n7( , 5�E*�6!K6Uhost-�vnsdcs [53�"*�4 ��F�1�N��!Y.�f�: �eF2I�T�A�.]&O)&� &�.g�B.�~n.dXs^e�JPM&�z�-�"o�c%�Re6&7=1i�� r� Nn��F� Ey"%�+s6\�B��:����C W.B�3Je ��" J�VA.V7p�{ !�n� ^aLYv�U6J_E�.%�Z�  ? ".8�b%EL���A>�A1�*<*�-�&Q��*6*�!OchIh>p;2�!��Y���V7���I�t�20>Yain �h6��pEu scenariNe�D%�3� %�"�OQ�R��p)K-7%J &�7A�inu8F&��J�.B�mE� vers M22-��!�!p o2��<.�M�, ��gA"p R68G��yu�In����%|6Tak���{B)�� *ll�r� E*b ���Ud6�,"��Uo{U�B�N��Q�!-rJeo.^���aR�%.�j� �m����=�z>���bA$�IZV B��1�Z%�K�qa�0yn �aS2��?� A]z*� JQ-Pɷ.G����� a�Y mmunr*�� p-�7=��/q a��ir])%�I��&��[:�<-�\:�& :) %�_��I �Fo{0>�bi�*R � �Wi�*K&F%�A�]}A(p8����e�����E����' �2U�Q*_#by��"2��-�eM^�>��cip�!�LAor���b16&�*nM�v6 %���on�NZ EF2q1qAd cardiovas�%l�"۳ [5fBLa�?:�6q)�4 &��lF�.1q&�:c,16Br� ch�n5�e�o9RB�1�3B@2��R@ aG�" n�DI�Z9!�sti��a���0�IB�Mͻq��t ��!8?& L+:ly� A2 -Mm��o"�w6/��+�? �5�)�R�92�KE ��LFTeZ����p)ja�u� � �f�2 yD$�-|��1*�3SJE�N��-� " H)� F�%1�"%""�'"4z���& � ^AB� ��$A�#�X)��� �g*��{TU� Q�j0�LF�v ��te/*�#Eة~-�e=bS$�!�_.� =�6"��%�]�|MJ�6�0� !J2� ~�݄G WQ6G264) neg,m�R�N~�S"tA� ���"t� �8"��elF��3)� 1� �g�t*�+. sW>*5Q[|!�6����k�x net�~�&,or�f&�d fash�[5�b5jH*%?plU�%s;"�252����be ��yu A�ʉI!��_AE�N regak perhaps:�W-=��)51�"ebyiN�+.in�>M ��$B��ze>��.����Q }��P�V�a��`$�"U\"= a�J7ŀ��"����Eb! j~?�)D-��{ R��q. de�be^6a�Bj�-0�*S�he�l� &���" 8�:h�X��(QY�,95.�!c�g�J%�%�G~g�$n&1�-.�%Y 'fA�sB%�r�Dg�0a]  k�ntp�v! ���]�5���]z�ua� ��%�)�AU=��a��o6�:1l�ni�Aa�>�principL�*��ry 2^�1�AF?�QE&! i�0� &| ��� NB6��C�see�!le�|�� mosquit6���y�asi� n��A�!accompan;��od�R�..�. Worm�:re`tnc��%2!�nd�j=���m��t�Mum ( NGMB%/�0E . coli OP50!�A]��f!�sourceQ�� d�&�#7�&M��in�rd_$.~0variety Brist� .N�B�0nt s B� p��@: PD4605IE cc56)H, JK40992>u, OH9330.�p; otIs7.GD211�-6�187 )0 tm295Eunc+�e1-�RB747'1�� ok51�9, RB217 �ok294� , VC122 �25�; k171Eh6133 62xok145�BJIN137 �>�tm197� Q904�3ɕgk103)$CF1097 ref%+muz�B JK3276 hnS�q74 �VC1644 c  gk78 J(MT372 lin-2!\nIRB1588� ��C, KM1>�l ( gv HCB1370p ( eI�381�mu8)K QZ83�Ftm230 �PY1070�E� 5!8�;HT1765%�119kd ; wwEx77[ 4�<,( + ) DFHT1690A Is26A�Db@tcJ� Ex63BLAbB^�64@�CN@PY4108_ 1�; Ex[m!�Q�>,U�su100!|!TU3596�I*|� him-A� e149A;;E15B ( n7E�JNL2a�rrfey pk14 =R�j� VDL3�u[�  ) 165b�Q�a�12�rfp��� Ej0a�; I%�&p:8R�\]��<UL158J� IeEx[�42{EgI?zVL507 �2@0@2:�r::"ks�2 L}o:d~54��ised �f�O������Řn�1�zes�Rof� ��e*W+��by m��eqx0���)�~D"�@N r)&uF���n��onřp� sT/d�9b�bac�s.�. Young �:�owa.�RM9 buB��z� mov yW�qe gut )%� fer��o� �Q6H:�~-y-�)�12��4  �(!�9� ) un�Q �D w��. Lu�'6c* &sx� �)))im]rA")}Q a mi��cope �pp1�epi2�Tasb!9: each:�&v2�1f�s:extra choi��array!��;�~:�TdE��!.]efl��w�u�'Q�ggar�} pads�1A�3 mM sod- aziden� visuFY�8-_0 Leica DM5500�poY=[= &TCS SP8�f��zw. M9�!�$camera set�. kepX��dj�%�E<&+��%�_ c&�T�Oj�� mean pixeA�ns�ofT�2,� "���&��m��nquant$��� Volo�4"��{Zi2�ozsur�8,��e�croE�ajq}#"P,. S�F<�Ix�)#J6Z&�y �8 [� paraG�԰H-tail Mann-Whitney <6�rvec�Xg"���mplif-��/g&c !��U�� ���� � ��D�m&Wb(�S { EI�d!�a pSM �y�X(A�TY::��$54 3’UTR ��G k2. gifti� Cori Barg�>��H+Es'k&�(����q� �!-%�;=Օ\s: pMG25�.( kb D2)-?�z�*�r!E8^o E. 9�Ij�*0H,O47)�O� ���� ��%�7G2� B� p*�t�65Z� 0I6B��3� @72Jb6<%R �pMG30jv2b�=SP�b �3 s��!SP. fO�I1)(I5.I3:�a ( 0-W-v� JG17J � 16a ( � y a�pVDL20� -148�6�I b�.m�*! -}�JID��$mid 249/25!��<7�8a�ze6a��5�2m,2B ?y�B4Eyl�B$O’Rourke!�2�=rdc"&~�5$p]�_Bg6�2@��c ,Al1a;!��Im%�~U �G%7ab� A�EB4 %��ᵹ�� c)]� eAQM,n^s 5�"�� /�% � G���kbV�Q!�U$pPD95 . 77��Add /L&� q :�����N� dsR�50>�00 ng/μ����� RF4F�co-inj�o�*rk�R h+ t 15K ~an :� -?>�ocol [5-�*�~5Od 5 b2�3fFl ���pD9� E�9�>U��b� 3ab&� rr'�E&! q���d�҈&���" ��EOM� �1�9�liO�IJ�� r��)�+�$`%a*a ��o�d � ��!"��2@ܕK 7,�s��.Za^_ ыc , Se��ab} "=j1�!K F�o�>T5�3�I�6�WD( http://biogrid-l?�. eng�I uconĿ edu/ _��/!�3��&�.x"�*�;"L�!� 6r%te ( CTA��/T ) 4 G/��IX�0A�:>:��;���-"�6�uF&�6"I�E� n�!�&�<1�%�"�i�%U do.�HindII�TBamHI�d TV/al�/�'��A* xAPW!F�e�#%(�c�=$�oj$)�!��$6)e0 helpA��QuickChbk I �6\��4kio� AgilQ!Techn��ie�to�M`V&�L��:�s:.��� yK= .� D�h�G!5 %�N%W!B[ظ @IJ�HJ�o6�>9�Eu"'�!fn� p)�a�a2ATA*��A��at]iŔ-� bp�K6 1L:L��#yQ5fn�New Engl!Biolab!�5 �ax!1�O Q�5�*�CIw1l9bD5{�B :�o^�� kJ2870!7鍉SdJ!d���q$ ��!�R�of�I.� N1T&� )���PtS>m.�&�t256��bJ orB� a"J` 6W i)@a!1Z�B�Au�e3IUhe drop-/ass��^� 6�s6�MBri&�pic�(L4��olB�n-9���ta��|�t�a]/ �o3�ψ� �to.��a�W-�F ( off)Eo -e, 25  ��verni�� cult� ��2���Be�spr��on�^ct� dv>All5� F�e� dry�1�� lid��6-�m n eyelash!Ba dD%=��tuW�$f� �/n�od\T���-�qz�.$��-wA�5 )�-&.6��|l�10��ts>D"�Z pill۝�N eliv��� pel�PaoI56�O6�a�*�em�A?>6= stim Z��60%&ond�A�per ]age/�Zw$��rec�P2��y�index5'L&�$�oH Qd/#�k,to�o2t 'A;`� ed� )# �2��U+�(ros Organic�� , 0 . 5 M&Y�( Sigma�1%��(grmo SU�CK� A���%� v diss�T#�d dilU�in M13&^�:M Tria`��mM NaCݱA% M KC�i��:! 9N1.A, �6,(smell-on-a-�kI!��aF�!6"6� �3u blunt end�Ua�Sntbrush�, ( Loew-Corn'YH, 9000 Kolinsky 7 sN'�Gta6[�� 9�-�5�� %�Z�5f� A�Xe�v���! &��wwa�2�"BE8�(�a*NF/gq���*Hn�C&�5����C'� �� !2pMG66 f�?�"��d&��Ecm��� t*�&^�!stʢ� =�n.n^��V#a)FJ(�*�qu6/���e�&� A*�o�J{5��/ut �G�$m�G ,F�L F�"M&� A&ɸu i9�%��V �*`fv�YŀAyB�tf�K:*z�o�?FL�'� 1L��or�Dh� x/���D�;A�gr(%�2��eE{n6"X�bO�q&�(� 镁��fr�4e1�4)|�� ��/rtm� (.Xy:Uy��A��1!��d�u�p�1� �4a9:� "va�Y�V�&�'2) �*�ax�2_���S*c2�A�e;"�)r>Juntil y&`)h ��n ���).)x/)"��2�m� Ȼ$n glass slK�~ai�� �� miso� paralyz�COIv*�'V� l�}t{&%A� m; expo�&W�VJ�&�z�.�@.�ofE�87� I�M }�!��.c�E��:Q�>�'�~AjU}@ > nuclear ) , or�ange ( nucleus = cytoplasm ) , or yellow color *>2*�^. Statistical analyses of the distribution between genotypes and conditions was performed usingF�Xχ2 test . As described previously [22] , total RNA was isolated from a growth-synchronizDopulat�8of adult animal �,reverse tranxus��oligo ( dT ) primers . Real-time quanti!veBHps,–PCR ( qRT )�9�Owith a Biorad C1000 Touch Thermal Cycler , Platinum Taq polymerase ( Invitrogen !�!w�Lspecific for srh-234!$odr-10 cod�sequence�P�2;�re 5′-GGACAATTGAAATGCAACACA-3′ � $ ACGG )AAAGAG#.Vf �eAGd0TGGATTACCCTAG:eCT��0TTATAGGTCGTAA +D. Dye-filling expe�nts were=�$similarly A�Y~Y� [66]A�4 stock dye solicontaind�5 mg/μl red fluorescent lipophilic�-|. We found a strong dose-respons� � ship��E�E�U�!<, 0 . 99; 95% CI 2–p< 001 )M$results!}�streng�n�8hypothesis that.1� involvi/vcnflT�hO mpliI�YWdevelop����] rven%�a�teg��to�Jtro$ � A&BU . Z"���.Ypathoga��c��s N�,!�lowly2���of���(soft tissue)K(can leave s�Y� u�Sisabl!\f�� treaA�apA�ria��[1 Classifa}by%3LWorld Health OrganiziY( WHO )^a neglecW trop_ di�8,!9!�be�{eaM��xr�n 3� untr!in Afric��!�Ames��sia%We�lPa , mainly���%5ubclimat ��E�e o?M&��� Q�} a�oA >�A! Foci!�9����&{ in9)@Far North Queensl�[# The Capricorn Coast reg�y� �I.73]Z he R��TerritV[4^(temperate cTal.ZwhI it!oft%�fer�o!�$Bairnsdale��$ ( Figure � �[5]–[8AVn4ceayll��G ��61m� �w` whY dit shares >98% DNA homologgit emerg� sabepa�F e��roughELacqui��o� a virulE � smidimencod<e�d~ 3lip' oxinA�ycolact~ [9!y[101diffu�D intom�s surr� � a focu�^2�Y_AK��(s ,subcutaneous T=�ndu 8cellular apopto��A necr inhibit!*e I�immun��͖[11 �2�IE4��!΁�. >��an adap�? advantage�{2�by allow! itoccupy?enc ed:� nichM) somee�t� Mo0 biosynthetic�� waysŋ8no longer requiA�%�, �. How� egisR}, aDI�!��; ,aqf= . Epis A�ic�4estig��E!���ty�� ly show au�2�!�� nsely)�i!�outbreak[��J�ost!BI s who�@���Ռ*� ,.? ��a�#r)�va�ors [6Ea8]�a few �E( very brief? os��Jof just� ed!�$( L . Brow� d PM . Johnsoa�p�� mm .�aYbserv%m , comb%w��incub �od%4upA� seve��nths [1�� sugg#ea4� v �� BU beginsazed��okRngi A� !�XAx� I,oculum may b�ita�8w . One possibl� a�' � e�5n��=sA�2via>� [14� 1kIn� 7� fir���2��� coul2 ai6� %�*� captua�( smallU�� Z� � a largeuANBUE�.�J va5 f- %�.�ol � E�efv ���ar� % !�� d so��E � yetPt��� if!�re!�a>��: :: ! A~* .!�* ���A* B�>K in6`ax !��W�m��c6��X currentlyōr . TheV��t�aAEr x~ $ly 400 squ�#kilomet�h� uthw�$telbourne�teA�i� \�n���*)0 �rik a seh V e)# d�uru!<�L! areas "� 2��P Ay&W ,m�@ean daily maximum$u� rangAGe 12 . 8°C!�July ( w��� to 24 . 5 Februar$ summ$[17�A&,annual rainf�mfrom 518M mmmGee�to 66�4 Point Lo� !~ prea @ outa{ year�A*� ��a� holiday%XYreceives�~�N� , � i��  �. Accu� { q�f- orm ���oMf� vail9)�A� 2006 Cens� P&�!Hok�takenAI8u:n�eauA{Sl��' V(:@z�,�lus, � dry-�baiyminiaA light��ps�|&� p&..!��r* work�attrac�fem ��qu� ng%o a bl� meal M�P�F technique����:.W��ll � !�8 h� !iI4!^[n�s var�i�~�i� . Be�6[!�ue%�,.�2�m�ly}  y two ss:FZ��n D� t��a�IndE� . Fa�Aug� �B�F�::multipl�j �C{ of G5r�*. TI �sset!�t%lls, Barwon Head!�Breamle��l , Oc�Grove ,>%!(St Leonards�!�Qg bree%ion ( usuL-*to T Mar�2���sp�� �Wngton�X ll catche�� o����_ theyIBcbed , sor �poo�by sex�a^R^ M&/%�s �usa�!Dkey!�LRussell ( 1996 ) [19�Cwwas exe�A��� ≤155�&C�B�� .z� pres_��.A{B�t� �k thre�depB nt eiY2M�mU4S2404 , IS2606%UKR�b� , [2�Th��assF &�va��%or��aQQ�M� 6rsa d�� �ftoe� uish"�2�!J Q*R-pr�!�� C als�ain�!A- ��2�Cul�!�c at��as{ either p��$cal/afford�( d�i� ]�7� w� %bnecessit%`!�i� ��A5thousank1RGg � c �<$ ) nor lik� tosuchfua:��O2�o sms ��� d MI�tA.2R(�|ba{of:]BU%wdecla� a!�ifi%p�in� �A'ak��A�.�� &� a�eRA�} !v��II us D�s Re�L" $ [VIDRL] )q?A� B@&�e1 Jan� 2005!Z312�9^ ho��Z^a� 1eBeFN��}��-�� L nclu�d� tud��%�con� %��a��ed!��a*� �if he/sh�a&� � a��had!��ed- ngntactm any�kn9� "��#a% R M�!7z�wn�� " � ��m baddresb else)_, g oi yi� expom%V� -�c&�as��Dex-� . Du�E�� y�BU�7 � ,-Z/�%�%. !0five-y� �M.� �  data KaS� G [18]A�ob��“�N�”� �( i . �!tL%>�"_ ÷ 51�.�!�A/× �$�{� ��:*�1*M&z bias-corr���ih' �VX0( MLE ) metho�" ftw5recommA��!;CeIύ� Co&�P!&�, Atlu [23�:program � R�c� �a�of.53�7�mmn�{BU%�1�00.�5��r�z��"+3J$esE, )�Me c|%|(!�® 11 . 0�h(Windows; ww`me, .�q) . AM� of 4�797.�EK�B B ,2@ �*� .�Bby�2 . Ae�camptorh�(u� o�S�b SaltmarshŁ�a8predo�$nt"� cauz( 91%!A�i�ck �'�`an6� "�$%�of%}85%�!NA=�(� w c= t�l [CI\!�46–�33!��2.Jz�highest�T4Anopheles sp .S J80Z�:e!60–5�0� !�loin� exW . 02�V0�U9�%!mwid�n>s make� �i� draw�(* co& s ab/e s"� 1�5�(� �S�n%jNeglig{��a >PE�M7%�r5���k�.�CN` 6R:(�t &g( Tv !F.>��!UQ �9( !���3�i3A(A8%?6+$(�&A�;!nb1x!) 1��&�&�or.-. ��183� &%�no�  ! &K 6�]"��� 20� of 132 ( 72%�%!�lin*q N� . Ose>� , 81 �Z9 t� �� =)y��S nd 6$ e fin"\.i�(L n aV�paJ as 61 ( �: 3�94�58% geu�Aslei�; �.�!47!$�p�� ( 33 limb�E�2e���ge�� phic6GN"]'n%�Nh�  e���� !qAin>cm$4\��*a )%!��"p!2��(�I of�d fA�� �Y"�'� y.T*��in*I �!2����s%)��A- ��'"���a*/+!�z(-E:��:�i"A��9�M6��BU:.!99".hR+,Bin���=�,:�UZ� ��z@i&�,6�.�!j��u,e� x2 king��.u0stillY� withMexpK sRal6�!|B �~e. �\Y#r�NN��. 1998 �siP �)it�b� �'e��ig� "��'�-DespitusFT size%��short�2ta�#y�����n�^�MRl!��isAvi�an?al op�un�ta#8 ��}D.&� >�6A�.��&p. . By�-A% �.- �6�&�) j����cj .� O. i� --�?J� thos.rE2��wM�����,~�,2�h�/5q:� Establish �is5&log� grad�$!�EJ [24]s.(*lyA-{2R��!2di��0�6$&� i�e�lly6X�H.acledQ'H�.�dA,��p~�,? ,"Pit �A�h$�ng bod;ea"A,"j-nga��^t)vecto�6�6!1$5AV�-}4~-Pu7u�#r�by di�A[@�<e1�02�'�e�ra thanAC��4inpu$or��(�*.*,>1b">9to��%�Z�& . ClN�' len�  Ma�&�+�2n +(-Mt6�.A�� "� %C � %�� �in kee� �2:�5(�g . ankah, %wIR�tip!aR r��� No�>��#"%' ;m�s^6J footg$T.m%b��S i�  ma��J�6� ML.b@p+nta�av.�;e%%�exof9U�d �v&�*h %j�1*6pri�`}5i*�%��5�rd+��Bei�s* ��� � ��4new͋�-%�I�v��4�4F��&How.hb\ %�QUeL2\ �wh)<��� s1� larv� r A>stage �un9�!&�.aqgo��sőmF�9mam�>� �?g"2�2��Yzid�(m� sww-[2�4�,(0 E�%y �ax�,umA��tree-dwe =�)�:�excretL !VO35n2� �ir fa�- er�;,0 is��� heav� .69�M�QJ*�#i�4,ռponF$�e gutt!,or�i&w�) �h�=2�en1ve!;e� asIe\Es )�(c!�\ Vq2X; e-����8% /�,rte "�-�.tai�%�F��lNABU7�j��anP! ibil� �56� pick�2�by feY%o� � dMum!�a n open w&� %%!��.� 6gacill�Wu��>q�=�m(&�YS4� !���lsoa��Eng�(�%�<A.:�e%k�no���6s1ejly ��Ehab�"�)�4�1anecd��C�4gTa�%�rem�YiX�Ga�q#?(*3)A��"�( J� zuol;2�6�1An2 expl.�0�!B�0A��r�a� !Seu=<s���6f�/�$6Z�% �.�w\5cognip*�fur�w*^?f@!�&� ig���cape�JmitE�2��re��m�by[ace et �* [28]��sQ5ins- � � poten !N�Dt�]b�4al –�� �,�4 g� i� r�.M -.V%+ �s�A  A&> �2�2e )qor mecha�2���;��%�$Eout�"%E��!�>�pasy,6�2�proboscr�ft �)Fx���s���S2��b� t�Bt&�.m��1h+a� 6� M� pup.!1v�<ir SŨe��pE�1�� b true.f�&}!s auth"�߉S*� -9vi�pheno�G!�!m7u�/�aegypti.�H~A�E� &fA"N,aa��,���[to!�Z9�(�9pl1)no- �-ssGMҥ�A�o&sH2�(AhaA i�@ntrasn7���.E$�by�+soEAr}�9C7To�"30 both.fwild-%T!Q5pr�&a�ly�o��� sect��m� non-�5"�)arol��If6�resR �G�6onflio/iDo fav��f�pH� ��y&�;-r� ni�"#�, �)� �?o�ly!�u� �(c~&8���@a.@E�doe[<�ZED.�]#��6`>�6�A'�I�if��6G�o � |$a�A��(aB=&&�))!beJ>M�H ario�H(s��)!(l"� &� u\ne#t �a]b"6G load!PCRR!is��xs>H� �*10-100����)]:!=�V4e�1'&%axBU. :4&:@$i:( ;�gVl���<�4u�L:!H���ls9K2�� �eak!9>D2�>>GWBU2-� ch�*U@1��8!�se�� est� c.c(&�af� � �"�A))Wmajor� ���) glob�0 . Al�,�??r>�����G ��A"=>a�2��& g�M,"J8ᄡ`su �*JC)L:�6�:F�!N+2�G:�6�:*!%2�c�&f� �aquatA>���C=Xa �#0erns Hemipter�6��=D�r;!��� greeke-���� " l>�e.�>al&p R)*%amero%�(usbed ne� proj&6�%�BUU�i���c����e;noctur�!:��+� s [3�In6P>�!+��V�!T�>U*r�._ a1 !ew!w��&t.%�BU&�+last 44�8�vea�3��mi�%l3o�,23 emita)�76>gavp fin8his�J� �bp� �A..� IA&��@E@�%-��9�t�Qi2�� *�"dryQ5�inc�:ADK� ����:?�at fo�Bed�� f 8��@:�2Gi&@ docua4� �S@�� y~��%�2e6wet1w3Oq����ak . U�Ma� %��%�t� B�s funda�al@ !� %xp&�,�!�"�0��� a�w� �BK�BK!�����aM>� ���E�ab" 6��*�the�GA�.NeUbe�m2�,BcA�*� 2� ,x2b1�-l�<T M����~c#ZJ meas>to�;m��2�?Hv$Dsh �Gu$Nd/.�s .Sd�'rat�p yeli5:9dmy ) muF�C�6�-u�;A�l system�in�E� |en�"!� _�ec�Kl A�okD';,��akdow !��4al nerv u( CNS�&Q n�=7tnaaE*le�H \��B, %�Bg mole�!r cha�er�KAran5!pdiscus�^*0D�L� 6u�ly��de6�By� i� al c5�$w�NEa G-to-A��.$ , 177 bp !&[Nam�exon 3 aGMrs%*4MRS2 magnesiumJeosta���( Sac� omycC e�"sia))� ,b.�Onov!�plH> acce/ �9�Ivfun�.vE�6F%Te%Snlel�Ta�genicFcue�� {rs2-c� &q9a�"P . �A��/ss�Ao�Qf  Mg2+mluxQ^�itochondcRofs�O���"���9�@�L ZA'* c79%�eLso15�%��E�hoy� NS2�dy'� !.mR��Q��= n7B^���Qof&r verteb�Pa: It a(�`n�B�-�U0%axo�Aseg# s&M,W�s,�J� :� A!rgV)�e fa��u)J1 "��lsoiM�o���Fs a(N� jmQci<' iliz� a"sNmilieu����apidly-f�JN bund�!"# �b,�o��7B8�l� !DC!ph�#1��lP�l�� )$Ach� aSchwan�ME(���� �w�+a2�*�*�o�%�� �i?G*�T![�N�`AT!�}'1 �*& *kiL ��e�� �K @�PE �Oj^lifAl��! �ta Ire �-nt ��A{u�� A sheaM� care`4balG de�}o �O��aur��It���H�:��2b ��klm]�I �)�o�O.proces��I�gr�]E=]�w nt mo ndA�l3!mX,%�hf�%� �E�ge P QepJeerDin ES� line� �S� ) s�.delA�\��R�oe����qm��a�"�se�U8fortun~W,�%FxA5%��A�Tre t&sG:�(lOv5� ;%�I�Y4ve-0&�2!e�f+�O w9cy��*nno�B,�A�&� y@RW Ecr m�W-�a �lF�&�pno� A��%+���%��Tta�T)  *�i�AO'o�A��!�unrav��� "�b9Q)M emblA��(liDa^w��xI :`�O. �V�wA���des�`96D( symbol^ ;�(�`&� I�Y!��=e� ��SC A�A[ 3.m�^lpVx\�$ isGdisord�\�chromo� ( Ch�M1�Q�(cl0P pri�4Prl ) n�K�t� !$��*W6p2�:1-2�;�mo�u13�X[5J-BaP onA 1w�feq ��a�-l� h A7�&�*l 6�sy �&ppe�D�,�Nno�u�& fa�aM,n�B�����a Ia�i�EAlB"!�q-� ( )&"!�te�a�@A�~4e�"rophor%&f innD`� is ��! orth!�uU n;o"TFA �B��low�ukaryot E�la87��:NT��Z�5���per�of*W CorASy�a Alr1,!s"!A%�tf`� !�!hiWi��_� !��n�*�0suHa�-RQ�))�ZzyE�2a !.�����de.'�oOh4A�M�Yta��J�YA��S��O � ,thEvl1'P4es until 4 weeXag��M5��flaccid�! hindo:�*s!ice�$!�ev��s tow�LF -d!F�id [ 7–8of �P�B��6����)+� #ar����"�3�,, name? rpus�4lo�'a�qS� �?n�J�7 atum�cerebkG peduncl� w-vek "�TV`�!�M 2�� cord�� glio!!� ch�@d��A�I� ���,.98� �nE�mo~f�'i���SnoEZla'%tfl,�υ^ t �� eA����`tbb�9garx7� ��J� �!fm*Y � � �a�Kt�1a�ini��&# :1*%[=��]� > 687���qgjD�Q N�03 , 252 offsp�A��rter5segre�[n R75\~ , 23� vidu�k�!�%�0rO2w hapl�$..tw�\ci! t F�9��)�'���q;�(!9l%n~nd Hh1tt:,bs-�݁f��VH1�&. F�(&/!`��s�- � lE�N� �i�T,ve SSLP mark�,`]�d �^o narrow%H�e�&��-!d�to�d22 cM� S_D17Kur17E_D17Got4sAW�� criti�D�])��%�/b_a1�c !Iez-Aldh5a@aldhehyd" hydrAd~hfamFW%7sub A��or " ( 6� 118 RNA s�ings9lA , am`f`687×2 = 1 , 374 meio�Ji�*DP�ba�&V-E�a6Hs�$46 . 78-Mb�47 . 26,l *L[ x� G yiela phys)v<of%�48 Mb #Y��E]6�Pretch@ / ed 6�eA�Fig[^2A�3A�7by RT-\NI�u cripE�m=M R6A���cri� �)�gen�D�;r�[)�4 �� ��nV'��2B �9soi�6|� d1ba9��*%P�"ian 83�i~- ieu�s � �DC'(i� 1Cwo�o->?� � ��enXw 3=C ,1�SaC"�!a�~e8e:��wK���e-;I� � 83bp#Q]F )�5�pt�ad Pslde�En�<nco� 4 qmino-7 �9�l�V�-��14( 106 M��/=���;�� stop}q��Ie�fr� shif%a M���pseudo-e�Xe�e��OK(%�!�:`912�of-�7�%=)qKf�!�'�)eal 152NR�5E��5(QG2DN(10� N%!cleotide�0��a>"� �)ɥM ���e|R��$5E��DVmp , Dcdc2 , Gpld���_{'KIAA0319��U"Kc nglyK"�J%����i�roa\�!in�-* ��v�8d*cau�m'l b+*�-��e:�W�[� % �(�, Ni2+%YCo2+ 6� .��o-[�f. W� ��\* nd!�'uSA� “petite�Pp"�.in�*oy d � HEK 293��egBP 6��"E3M�Ro�i�� mpanzby�va!�� g��.d A3&�$cyr� oxid�( COX u1� I[� morp���"I0� iJoa�*–[15�we"d2�l��(��Yp�B� !I&�U:��^&�0of6�. L�-�en�osE�*`���BAJ�,�q�*v: 126±4�KL7 mg/dL vs 25±9 . 6 ("6H ± S�y, P�o �3�The19�a�� v0� 2<: 265±79 µM/mg�99±46n�5�3~I��� v;.M,"vB�L Iȵ>-�wh*],��*j!�Y�A�re!�ona���,1(C� UBJ�9irE�lzA}�-_2�A�Golgi�Yilus-��&�u�$�83!���s*�:�w*J�}2l>�%"� :�. T�mcer�( >�#d��*MU��\�)Bz � n�G{AVB�ab��.�:we +m|[t#!� oGf&=#a^le��o.Sse��E!LwT"�C WTC2WMY-�,P']]y ach ��w"P��$�A�D �(megalo>nAcCMVp{omo��5�SL �44�al��?��Je�� �t�B\,�^KN�l*�. Hx+����+*TM�4�)-&+m�nPDt&eaz ���=�*� .��� =b:�#Y2O6Are!��"-1lO.��E�n{ rosc�rM�EV*� %�>�A�B����%�e� �h�iպy�Nk, (��:� 5i�w�w�a�'n�f"7ab<<��.z5E�g_"( inde�r>� dmy->�>�w�vMM8c�!� �����2,�now�, b;n�qto�a���.�_j#!b"�neu�r%*� �sub-q2��F"-�E��!,r!(st\h3%�=�6��,& &�(O)�8H%�"�Mto ��2�� R��end<E,Qj%�p���!�~����ic dotɾ��al0!_*f� �.2ia�%�a10s�x� ��f E'E�lig2Z'C �Soccasi%)'�O�}��P Conf�umim�Vw*�He1;76�hi�6���4A–4�!Moreo�H,  so�2�1 �s��]�%� CK6.�7%"�F�'!�2w�ML=*�%S.�Fyocard&+, l�I, �%�skeleZ, musc*$jS�T. M!cglZ_ �#>�ulhy�E�uR�+KA�dys�)��pd.Qng"D.Ij~_s)�J�we|S!_�toh� chem��ye�IBA3a&�( �6ESZ�aO�p i�,aa8�# �8�%>!�a�i�+� qOat 6–76�5w5�5�5� h'g2  ch&?4sy�[ms"DD�*�gC^�!�. E�;on�~pro��ory�-k6#&�DIl1�Il6�.�7ls+,&�&�-96A�w"t *# %"^e� CY}){,) �U�E�~A@,!�e"�! F� ��.�&� 59�('A����l"�� i�e�j0�z! �] .A&%.zS$YchA��� 5:,ePZ0:6� ��u!� %a(���a&% ��2<,��&n� 2���bGo��u�w�o�a�T e � w"� �p�=e��5�a2origi� *�$"ON Jj��g�&�$6Da�xet�V� b�<�: �#fungi (< !� ( At��Kf���Ax-"��+subX te s�[ivity�ey*�)�,�s}#  diva�P�l*�+.�l&�. E�&�Ls1!�F I Oa��h"�d��7��y� ��wim�A�dom�4E�oYu��can!Zr+a�&� DY �o�>E phyl���xa� �v�yZKIn iy!{� -��C��4un�s �n4d)�"�,�( TMsn! �b�,d Gly-Met-As�$(GMN ) motif���E� �TM P� �&ms����p='c�z"�#u e�Q !v_e�?2D*�5I�� �X&R%�5 "run"& �ݍ���yv�Rl7u,ofy�1!��r�ly&�6an�5_��+6$woo,�#�9" nu�%S(�*��H�BnMnt�� r�K�E8ic�e5�.OHU `�!�9wup7e;o2i+ t�8E�&BA.� be}*,a�E$9@b)!�aE*h6��i��m'x IBgA� G�/ty�%a�<�ea�Kp��p�>Y(z!e#f)knock-S,�^ .shz�&�-�>5�.:5ax7��)�"�v�.1v%��W����4-�mX�@�zs�6 VDJde7465U�&_*A�%f�, maB3e�/�of.>���z&Gif��Jis)�&"L�4ur}��* appa�sly�%".-"��.��*� � �/spa� w�@!`a7�:��{!s2&�9r3B�e�$Ca�d�-[2��$�,pa)�a�eri�m%�?�f�e��W�"h!��&�"�t�2Vr,-��h�O�� ����*�ng " *V7��+I�s�a:R�� � � ^� uBy�x UM�)}�!�.H-�c�&:A6� )b�,� �5dG� �=)S�"�D�<�.1.�� r�PA e�/�Z&=!��.G"[6' 3"@��b ��.4!@FVA���?Vns�L apac�tT��&a8:�l�QUiM]c<{qeukodyph�-d�)alTz>N��n L�WYKA�.�l�"de<)bUt�s –[�ke"%�3 fr��"�)��0*�=lt0!�I@���4*�2�,�B6esuma5/=)~� w��i=�energyac +- : � KFN1�)+�Q��6OmeIsm ( � �a�VOE(I� gs�/A[2s�"�G0��W}#E��t�;�WDb�&�'�0 xo��#veՃn�0u/�4M6�yYoAFiEK�ICm�x�څ( ME>h%�&!,E :����'4Niag�Qa� "�$��5kA�C�"�K6("�V57!���,wj� linc�0��ͫ{VY�Qot.�sur�~!EBAa�&"� !�5 nt !��t���*6�as��f500�� ar-e�#d 6AQ s�\alU6t�* half/ %�*��# ��1���[e~, Gd8l%en�e_� ^/ell�$r qo�K�@�NF3�#tR��,:�b� �ec!� [�XA p>Prr�)�*�ic0%is� t!e�3�9 �I�e��3?!��X";K( ��it a��+*u=%��0>�"E Ey:rE�1 �=un��/N|B[�\l� ct�{� f��� .�%�)4. A�� imW i�`� �/cA)�EA�%6�>� Griggeᒡj-autonog3�r non2. Inst�", iexan:s4�?9B;!�.�uaxsu�LsX &@aHE�At :#e6� I�a4W[ ataxia�-,"��"S r��UT >�& /! 3Ll�&ur�damag�M%rel�{!�"k �ytom�c���17n� !ve oxy��� L^�!{���+ ωd� s V. O>*�@);r vulasto �q� 29�#�R. A"�'lKuwamuuLco-���-���rZr��Qo��%�� ED-1*1P phaH� ��-d��oy�= E�%.�o"�^�+6� 2�l"�2SGA�6  6�X& i�hb1 e},N@����B���R�' �)loss-of-"� �H �]. �JE�"�$��s*�� }6@6 :�\1r-v�@so!!� w!6"� ��de^F�1w;E�� %�/ a�9;hBc-~e��2*�9�m^l2�j %(!�!0!^%�"�@.�i: rmal��@tOa~n� �a�)"!�o2� 2� x�1eJ1K= ��X�4o evaluS!4�q����Phip��j�A;6�.l Ap�D !�=d�e���o.IZrap�ma� �9�6p35of��N)�. ConXE$ins�#(( NBRP#0020!�nd. �# �-���Me N_4al BioResourceg6ject - R2 Kyoto U (  , Ja&�(:{<× BN/SsNSlc ) F�1+)I)�A4�*o�d�) F2 genm*�=t J37� �&ly�!)�.$�ob��j(8&�4E�h&�j�?f �4F2",�( ∼21rr!�u�A fÙ^4 � 3. SkQ����fgth poly�j[J(4� 5�Pr�-p"W<)w"�4T� s&��"�4�H4�4�� r:jd��26ng� d"Ff�QT�&�A�lima� �r�3n+:�2�-�zD5,d���anony{ ���:�} ( ��TCTT�TGCCTCTATCGTCT9�, &0CCTGCAGTACTGG[�/ GATG &�/. X GTTA.�A��4AG6XGCT<�, GTCA]GTGAGX�"/4�A�GCCQ�T���GTCCAT��alA���q ' -aݘ�[$(+ ( Rese�Bz2m�:V B��M�n.*c�9in"0Reg�n�"on aE"���SAB^� � #axi2���}of 5-�;-ol�})7us�ISOGEN��@IPPON GENE , Toky}{��R�4�4B�FM��4"�4 �*�C2.w<3�A' �J e*[�CMVX�(,h{ 5-kbx�2720�Pc� �SV4�}lyAy$%* exci�R��bvgU�8CMV-S|5; Agi�TW�C� CA , US-c�� Ha��*Z��"in�� <pro���f��#o�$�&�$Crj:Wistar�J. *�M&$:�%t�/L%�;�e�� WTC-�='�& back*�toB.�[b!��x2Iwa� lso  #�>��!d9(;, tg/-e�*."MO1!G&�(&07w k� �fCG�@ GAGAa�A���� GGT?��W )��X28�L��qpm1UDN�0IaJew Eng~�BioLab�j�{e�+a�!A��)'t8!>%�subM/#&�Hicat*(8, CHORI-230-9K1�N&�A!z/e$E�!Mmod�x� � MR2SL-E�Nfu'� *(* (4 �,by ET٫  tq2 y [3�Mr.��^�a�2heni`AEOvoY�.{��R&�1��!%m1 C8�DHR�uT�S�SUtkary� Ini�, Otsu*� Es SYBR�mix Ex{�I!�T�?�umonI�!��[|)7cur.test ��% +ac� �l� EN�� 101–106*mJ%�KDX�,%�9M.�![�#Fk0nA.� i0���f glyc�d�<$e-3-phosphW "�<( GapdƁ�^��q��:����+&���=s:GCe�T*AT�"AiEtC�; CACGX�AAGaJI��in-1b (�&�F8TT�TC�cCTolG= h� A��C��.p%� p6oف��j�AGJ�+ mE T��w C" �i�)jw�rm�fixI�f%lef\a��B!�&Le4% )a-�AMb| 1 M 9���( P�(�\�*�B� dis ?e�d':  in 2Jn��G 5% glutarN�PBin1$t-fix��2% os���:! 2 �� ��dZB�} poxy_iW�3M{�� �double-s�3d uranyl acmpi�: ci/6 �e�b: Hit/P H-7-�%29]_0�0%N� IN�*!��.b� ːTh^WaW��au��, �a�:��o)a�: ti-2�, � -cyc#��:E�oJ2#s�CNP )%�B�( 1∶d+000; S0���. Loui�MO"� ؓ6�.�NJAbcam�Vambrid�pM&� ,N.� GFAP�@�.:�DakP Carpe�{�*I FU Iba1U%��/.y `200; W\PZ@Cw MB*��, Osak7&� $Cy3-conjug!�-moBIgG [5[ JackV?"��!�)� Alexa 588BIrabbit>JMoProbe wxA�L�N�<iIO3���ae �bDAP�lV�x>�.A&`0� qwa�WZxce�H%Ya< y ( Olymp�o>� �r��0 imaga"�S C1Si; Nik�H>=.�2%.F�yr9FA-a�a:� zen:Bf�-`5>� st�t� y)-��=e$N� t 4  �ov]gh�A wash�IqBSA�er�;n�Fab�G%(VC,.�m)%E�>ed# 3-di9 obenzid A�3kiz8V� :�a]st��in ,�sm�0tetra�� }e�yraded e�o�W� �.�N(r�CJk#a2:!�,Z�.�&eJ��  &q V@0$4isofl����es�1TZ,�%'m�S��8N�jchlori!=tG9A(�Q�7If<if���",2�$ ]="�%super�^n�`" Dete� r LAvLYOWA MEDEX Co . , LtV&N@Fri�(\cJK6�pr~���T� ,� µl` fresh%E�� 4[50 mM Tris/HC�H �F!3P�5 mg/mL#:, 2ic�_�5A�!xX y3?}?C]EAa�ach�9sli D%͙~ 30WaA 37�6.�� sacr� )n cervŌdis7��Av� 7imֈ�: ,� in liq�]nit M��e t −80�lN-��.�-or���7@j� ( 2!i )%# boil�2 ��F�"h:�0!�\Y,� �;5lR�7�!4 EDTA . S@p�md�+��P by so 3%Y�Icr���C41 s ×10 pulse_�:5%��"eK��-�!u� �.���gHS�R�4��>�manuf� rer'�toc� D��x�Yd56��6���2� m�e�8Coomassie Plus �s��dBradfa��( Pierc�6��-$u�Aq����,% !~m�,i��w"`4'�aZ�5.a4Mann-Whitney Ug.J 7 array gen�\�9�*s�U�?h�DZ�7�d�Mmp���ie.v�ogn��?q��=�,u�+"5hIQ1��\su�!�p�X�a%ambigup,L I��{-�9�jpatm-���"O>�5<pke:%j�,�Pi�K delad!�� of.���}`��ExH )t5f{X" x7 )��� %�"�!V~��pce&-y-� � �b �-�a�� ��3S6#��)D�)b�Vd.�ij%)�7. D a�a9�p$Q��)om ! 5lis$2A�!�We�!��T!exact6#�K' �Ms6��r֬e&=�d.�uYNl�W}"�� disc�o!zq�)k5!� J~4=)s�*t�30%�IoN��k��nd 18Ťn�KBy &Y��[1� �byee�W� g� Q/(s6:rB/!�i=�� �.�ADr,to� � HaMcS]�!ם�Q��Q}��b�>th�hu&u]-L� anS�3��� made�"�Slg�b)�S1)7��5�k. IDZ  how�/�m��i�i>�E"7"�$!1b.6w�ol7r�� t� �,1&)f!�L%,!n�`suEx,�xess�o��group%X�7�sH)[�/�?��>%�9y!u,� 185�da ����z�m'�7�K prof9"z=or.FS%ar��� titu* a=miE�ach�!s�Z"8'if�+!pexplo�&t���?�=8�Ǽgf�Adimp�oF�e y nqB=[�,u�{�\��(h|��`\ �s���R%H�*q7on �_; -�+lyTi�xH!���. rout�a�k[�,{$�)v�@&e"�%6,"z�rec� Fgi���-��n��.�"7&��axr^3��>5"܄]�!�r ���5-*-�#m"P��N]�_ay�.ew%�C+llj]��B�� rib!�"oN�,�%�l!=r9_" ь ����|Dbeq2��M&�Aw�>�N�5�y�s5 eady�lA�5� "� �-�!d1�B����y�.e � W&e" scal���=!�ro.IB�v u���A#c [�@ֲ2.a�on:�A�; D1ʇ� gc�)g: xO��qB����8 !�F� ωqh.d��9 C !�o#�ZE�x 9dc�[aW*�> w�'o!��E �le�w po��idkb�F;� uBbui�Vnd�!�5�2�[ d&�D� &/��ds ���&��i^7o�/in��. B��!� tart�ca00xB&���)�2ill�ᓡh!#a�ex5R�bTg)r-Wof Hua�K+o .�+y %��lu�]��! om 89:[m� T�Hajqz( 3�/Jn�%�jce�{ , 18��/��relap�Z4&��noiab,'rR� "� �G&B �'he �r�C��e�y rm���(s� M����VA�!U2 La� e5�g(�X3�d%P� 00291471� d3pA$� IE�e�e�K"� Y*���, W !�i.11Tfre�NA)�,�R�- @�:<�Dk ft$ �I2&R ?)�n^hi3�?j �.%��bMoǥ��o�;en8g;I�%lM59�s!WY !L�!~(%�!�Ax5% !_! V�eno:�I �T%)-6Bv1s�� a< @in��2"2� `/25�BDs1�� � ;]��9"aɓMV9,R� � %{-turX:F,J#�2�N-]�<+icFa��>*� ��i-@�e�!�1�Y�Ѳ6m�8��Qa!˹��e�.���7�X�re1 �Fng��*M]3:����#�c1 g���veӤW�8�$C�6�G ies:4a"_�.T!c kappbcd� �s ]�"��Se�F)��en�swA�p�m�Tspl�achE����.�(An�\2��30�4� :r�/A�9��.Ga,�u� ��%}�E�:�a���mimic$.E�ofB  I~P�/N i!�x;l��V��&�$���nd�fra)e "� �1 .�yi2c� g �22�(:)a�2>�q����A��!n, ax�{�dOort* A�~�+K�2�i"�=��͞B 9���6�4N6�� �Ws:2NusAw1ad� a&��\u��se�:t2j��U��big�� �hem�3V��LA1�cy!�!!m 70%A99%1���o ��!U��Q�27%E�31�95�ʩDe �eC 1;�?(A3 @4A�?A���W�M�3 �of Wizbrock&:���B� M�asi�l�f�Y�{ i� al ���( 9I5 �I�1LQG�WN'�15!iOn �?�"s�.e�mօvs[� X?�!ar ;-A7c!�%}ep}c�%Jat sR� �� �"� 1�^�������|�d . Ov�*�!= 1$xi?diQ6yed�|fy ,)(i�m\t�?98!J�Z �/A�be�%�� �?k�"!�M c��s� . S"�@~ �ewa�q� �� ��o U�.i( SupN�-S^�A0N e� M>� alg:hmsDVM%�shrun��"oid�'�� )<�9%orm]]-�eF v6�r?�y�Not�a�Aj#��E'A� Affy[�ix�T4"�gS�).pq�"�ń!�i�DsE��#s*l��~ \mC$is guarant�r 100%2�. Pu����a��U��ADD�}� ��F�HKa����*�e&� �Y%�9 �/,6P fz��*�9M���V�0�| a>� C) 9%�j�"�F�te���/IG� i�pur���V!Inea�B�c �we emplo��&�D full��:V%./#**�:�b4Aag�neE[-C�.�n�Eug5�2�Ideg ,!�e u;9s &�ng�'N��;�}u�#~ram)�A�5mbe �w��MAw�A�B %d*eJ� 9�u�t^6�b9_�. AppU�MM8<]6�%�� x��x�� aHg&"lj&F ��a A ��i�� &Uw�� clai!2�sbe"\���nsajGi�S� hete�%e."�%6*A.dS *a�h�$t�١�ir�n saf{�su{Ye��� Z��,�_m2�p��2#w&dSv s� tue­<-�AJ�Q������ 4�uB 3F &�N�>�  l ��i5i�E=im5:�u�%%J�whtll*� r�G�!%`�3� � .�pa=S,�al�s �k�V�("�f�fn*6!.?i ]œ!K1�i�1��'$5�[� �&IN�[1q1�0�1w� ǣ� �l�z�"�f!our�nd/O�m��5n��� �AtF;lTQ��6a� B�Cx0!��*� !�e�C��Y�i)Z�AFm�5�l~��b|Q�1%C�� �P�ueasur� err�r6� arti�/�qP"#�D l?���� �'�a3Zr �eRe �6��.������&!�A@�M*d "< D,cu�iE&�GeneChip.6�a��6� ��*!:"m|(steps: Back�)nr�rrgIK�@iMdA@A�e\Y$�� VmV{�bw"�: S7�ar&.(S01!"�*j0:�Verq0zq�) aU2c%{ v ed ”robN�"V-c!G���tu [�׉�aI�+st�Oz   (@)�>Q!/��ka& ”add-onk��e�Vd�enn!KeAbfaE=�4�!� �t�5�ḓr!al �5B*�coE:< �4�=}��� �u`p ��� w-*VsBX �eaBZ�D���wc�Nr�^t��pam%�g�����-o5 "Kr � ��{/P�!*�[5�WA.�Qw�=��Gm!I' ( SV(cܳ!�'liH ker`f%�A�� �*�=:�_!A�i6�#&�(w�F!BB��A�|�K"�" "A�f�T���w���"  �&;!��{b;�w<�6!"XJ�A=a 6#n2�n&�)��"�'R�!W ��"�'>���Z6-�!v��nJ&0&�"� �4-q"�1k>HuT�5&.,]�b.{a!b����".�"!`*� A^�Ŝ�aN9e M��" vN�+ifM�("!N:�*"1i(RE#��$i�X�$�5a�e!�5a��r( say h5�Mj , reݬF ��l��$! N + 1V��9�A�gU .6�!������">2�N1$A��1XBEr�n$a�p` -��+UF �nS2�$m%ʁ~Q��"XS� �x�u2of�:� �q�*�w"��uS�CJ�BhzerR��JS����.m��dA� �&.;'[}]/"�\=��I]-���5il�ə�MdE�v"�s*�'.h!�BernoullY�'�A�f���+B�Rf<��g�U� .� co� uY!�e"��Bi<��be7�!oAc*�P.�#��%84���# �$ is p�-�xcG��Fܱ'!9MS64:2�M]2$)@V,d:��O��s�-c��Ae�U /� ��<aEBN�-a��UO2"I�1 L�&����*4Xo� b1��9{f"-2c.�0��e-�� �!t#2�� � � �Y� �, TQF!��l�?a��ray-by-���iB �#�%�(6dr�NI5���3AA.a�h.3p �G� v'Let XH!�p × nJ�3/�G-O{�2ionA�!�sog-4.VπWer�Zens��ngocolum$ X�π−1�)5'r_VC�..ĿRedE^�����f X!f�%:��1a n�p��7�Ke�s equP�1/�K!{��V (�&��) ��π ( �1E�e�?� of2a)�)�4 ��1��A&I�!@.B, e�uI8, let x ∈ ℜ��%X�%� B�"�!If πx!0�^��E� of x�a)�-�}1NQ"�"i)by!�F�is���tt)�i��2eE�Dž�8(1Q#A�l#ɉG *M� T2��w�o�_:wo4��3aP�J)A��щ�,�(a< �,�&f6�by�a!�tr�c�;�of�kx� w)�b�e F�ARnd.�Zt"� . Hu �&['7]�1tv� yi Xki ( k =E�. . peingU!�ɵabundq μ�J%$ k�J%� iW�E2is%�"�i"eP3ed:EX��aiQ�ℜ�� �c���"6 �7�B��}���" n�8U �W��7 �A mh�|6#K6G�P�*A��A�Ak'a AhKA(�^,�I90����f�2A��mp�1 �\r���k ɛ K���B x!�E�me9�u ��H_�1w�\�����M"<aSxz W� *� b��.h �&! calledM�2at�K chem�lynbiophys M�erF[2ϩ�-/s� proi� via dedic�nd��regC �G $es [3–5] thei��Q�5f2 inva�?, lea��0mmune system auvq � scaf!��9co3itA�kn�Kas!!�~s [6–0Fune�� I s have siA�E` identifieA��E!�dom�Slif8>�8ubiquitous roleA�q�a� %���=942 , 6 , 9–13!�IA�aO����$often serv viruleZ� a� involv �gg�7 in� �p!F� thus atA�i�rug targ��[9 , 14�Adv�-ʑ\al!a$logy metho5Jubs��iő&%��under#e��Dhe rea�abl�< ty$eukaryotic9O�< cribSir shaam��β.�fea ,A&� u��J��+��� ds situe perpendiI r�_��4 axis [15–26!1In �asO*�0of &�5ׁ�E��i�n -5%vacuum>(high-resolu!�.�A� ledgO WeI�pr�bQ#!6he fir� >7 daF��= .� �� e phenol �!�@modulin α3 ( PSM )���"� �� ,StaphylococcA� ureus [27!N�mQwA+� � fy � al# ymorphis%*�-b �.,e����$α-helices� replaŹe2�tacked��,a�e M��-4�Fa �was�nAJfacilit�%-4 cytotoxicaagainst�ڡ~T , 28�s�� its class� �4�(f��b� "] 209�z[27Aӭ;r�mb!^secondY9�poF���-=! partiS tri�l��S �vE�b�U-enco �� f)0a�nsider!%�hom���� famia�em�l, �1t�4-��canon�c1��UU[30M�se:s�S.} S . M�' ��J6-�����P ` through� 6� i� aA��,7y��"� %�.b��[3"�Jo� reci �al ���BA�lusA tilis l!� UI�e� swif�r changeDTasr an� r su!�t6��� � ,s glob5 shapnwar&� –r�����J,two key playn i� ,e�m;re� �0 CsgB��5min>?W re�ively [5A'?nucle�Cb q�in-vivo� %�� Œ�buuW%Ced Imonsa��3outer}�A� rane"� ~isu?�!�Œs!�k�en�s �eR� �'��gr[3��, a 151��idu3 1�'T fA/imper� seq0 \repeats ( R1-R5 ) ( S1 T')dT�P� �Fpac� a�e2er-gluta� ( Gln�as@gi+As�d�!�*�a+ last2��I �)�2 iso-�EAU crit�Uto)(��!M%!�byB [34�� whil[ e i&= 2-R4 )!V$tain 'gate'er'Х te!i�m\!ȩ:ofp A [3�3�}%���!�t�� �S oly� degradiH� 35 , 389�bi] he���or dyeZXioflavin T ( ThT ) [40]kcongo� ( CR-�� visu�,eO� smi�electroe scopy_EME%sur� !��b�. ��u4��JX-�) diffm��F5P shows ref|e�at 4 . �  7 Å�8 0, �ng6?A�typEEofݝrchite [3� �reminis��ofJ��Jj SoliD�NMR�h& *O �N aacombi� I2 adop ���� n��iFA5u,�iAF ng m�� he�\R cal� �!X obA�Lr>�[4� Mole� ����-*E�i$n� to��W&� how >��_isA�tro�. S1*avail��mfeBac�ory� nhAcluE�� �!�6�! periplasm4 L �!�E [43iG0 adapav" F [4�r as w��NbA.qc�ron�9 C [4�S�rel��a�'[� 46�&�d��տs��#CnelF G [4e�8�qDespite�emE�oM54>=6 ��ato!GJq I2����e$�iA�elux���lim� �mom���al"H�ontnng!i[ nsic!�per�of�-length�M���)|���l� �L&� c� e  disordedina�w1�R2��4�4 W��usi�� duki�pproach�loo� A�2� sp�"���lo��a�%ukbA�&%5[2E�!explo�q��.�rfZ�imila��)h�:�~ ���U'those6n�,-promp!ZusAKinv)���� �A]qj-desigA�a2F-z��� also6��![ N. Accor�|l�w�u�atO �� �tkt� reY�pof olig� of:�3.� ��( Aβ)50–60�D�xM�1�%)1�%�s.�:X%�� r��C�ngf Fu.P�%eh9V}, �7 ź�A�of-��icY�&iq�r!fβ� result����c-re^ xU��bea�� -�s� . ��cre5�&� kag�[61!�ݨp�<wa  rFal!4�Q-&�s!�a �-1��^�s . TA�y�%Gs9��*Yp"rcA�s��� m�un�I�d� �.bI��sl�wafs� �Vbinlcomput5�"pr����GMOens� 62ag�W�cul0on 45LNIYQY50E�47 GG52�!�R1� h$37VTQVGF14."5"A�,129TASNSS134H4loop (&= posia�m L Q�Apt ba ��"x�za Uni � unu= P28307 �!2��5ra���r)�as it)2�l%���j Q!-|bu+ lo��7-� not impl6�Im�[D. � E�graphs*�r��7 fourY�A��2�S1A Fig2 �J�QI�� ir:�UH�. Howe�]Bm]GE.?(&�ed un�ch!�nd z#�qz�)+0 A 2�( ]a)11scarc�am�iu�62U���'b�U)Q�H8�&�0ed dose-depen�1 -M0curvesishSlag tiJ$ ( S2M..�N er %e=!M=�@-2e �R�didE�22T"� � lJi�E o�li �!�weU � �B�f6(%1 , S�S6OS2 �2!�]�� � overlap�#- *�".*Yed very � .l. BothE."� N(,Sa<Vm:e2_,-�wo�ms�dry!cerf�' pai��&�1<�<K��d�re�"en�� llel6 eaC � a!%�:$eZs� re&X � �( 16�!�a�"GSawaya%� Eisenberg��� �Aorganiz�:��� �!��[2�y . �fH 60V"U�"� gA"嶉�<)t� i"�bur�su%�A[ �%�ll�)6� -A�'s#� � of.�6q6�3]�Coro�3 !5t)��:U�{��m�Z�i)Un��M Y�Dq �p�6�.�A2�BaM)ti-U�1�� lac�a6�U��-`E��~ IUs mS'loso�!dq� 8:�[2��ha trunm�%1wo� ngr �1�:� +W` Iym�analy�*uG+atten)total-,re� FoA�r� A�r� ( ATR-FTI�=r�aM@% m� peakA1617 cm-��c.sa�a �$dX *�.� [6�69]�T7������ a��&� �[7l%)� s�6 elerl!�f.q lz�' Aβ1–40�j�-I "0'Q&h�>� o2� s [2�� A 0%/v�bri.��.%�to��ze!/85/��R1q�.!��R52�x|$ �!!5( jn&Z n&n  6�!:ILilder �,on�2�!�j�We next�&ghN��!2�of6z�paa� !� �H�Ic2� �bav�Wi��"}�/�5�� % �&p;synthe�^�(a�er��to S.as D-p�* -�t\&�. TwomA9 �, ANK6%� DB3DB3 [5��f� {�*J� >� manner��)f�řfreshv ur�%B4U0 chars! ��-�-2�kin!Asf v�a� 2H � olloA� by rapid �%|)ou !("�%�e.8i�� a Pr fluore�g1ig�a nger� -� Z�'�of de ]�� 2AHS9u� At 1:5 morA�0 � 9�or1�im�.�X !�62O thanQ ,b� re 0 mixes eventu�� M� F3��.���{� E`!,E ntly-M�].out%�]�5#� � V��3*�&!�B%1�Pers!mR�&� =( s or�*�-�r:e��9]es�ly��U��2�. D62��A�R1by.�a Ű.I9!t� a.qWory��"$already ob�(d��:1.r�i=R�>�20{$he�� _+)s�@)0%f co-precip�0�5�0c�4��orQ�.Lf�iy%�RR2CE<� Ca��E�m�%? I�1-��te3�'S:��!� otyp�H��-�&��� deVs�inflamͭ�im�/@6gn{%�5�' mous�4�2R [51�u-gre� � A�"�.! ~h� er&�1"a E-��& 9o1��OK]8��e " -p��R1>�R56��j�( S10%��@M&,1�g85�y߁G�(E:>I6>D3 )eGu?3�2I2 es �!0e�9Mi jl ,stq�on enhan� )\9"6� C�. +#ECt�$2Faf/$�>x�'3 �3� I�.�'��umAt � �os�(a� wW 7B enB���_�5II�1iq{� NK)Ma d . Of�>�5�i!�l]14� S�B�Ap�  fEC%�IGB�-W e� i�du� �Massess6�*�cir�! dichroism�#Dup�#���#S112�CD4a��� dis�']F#(random coilA figur�� @5aC-�(M#mum a,$ 195 n�4Af"six hour�sincubHAx ����-�a.G� �-�J{a�ti$�93<near 198�aY�21�!�U;Eq�Y��)�!�H �[at�H��$*[4��AK6��- ed����( aB@ !�h吥�<re�#aj� +� 18R��gQ@X#� n�=��a�Q�2�. � X2 'sod�:,dodecyl sulfD%( SDS�~!�2k�2��I �still un�,r"Q" �s.-a|olA| F2n�te:G�pI��entamt-orZ�7� m�st -U%L�y�4�,+3�5de�4�a [7�'As�#��,F�e�l�&y.X!d��-(i7]a��:8\ rophri�WDS-PAGE�,FUIp.�j,e��g� �x�:�1#2�i�A'�/��86:�a robu*� ��O��J�,���� ) CD�%Q"a��y. T��!e����-rA&�S�y�!�AYc� .s<MAE52�ee1 titu��# fimbri!�(� 9!6strp)�ZR_�_n�s}A violB��P-v�)3�-� �!%Waz$at� of 10 μM R�aAronoun!`�a D&0 onay�sl > #=vcon],�bf 2 ��A�lJ0 k��a������Jo��$1tr"��yZ�No o on"Q,l�wth����.�AD15 �#n�8�\ W �de.�?�(` mpac �-=E�!unr:%e�~ oa�ic�& cidal�aG4�W� Confo��!" imagey3AxwA�saG�*evbi�iod confir9!�*i�%s-1L ��an)�wis"Dt�� -atta��ofB�bys.�M�M�orii82.A�(' ) ha* 2�ItA�� J_:� assa�FIn � !�-!9�b:S� pbi��i0+'�.p aZ=W,B$��)�grown�aga75p�d B(1�dy8*5is�toI�A�i"r.�/�wh �[h-��.kA�reddish%m"d adsorpEG-2�&+!��A�5AU� Pre-.��YM� eq+a�7�*_d�?lorI�q ��er�1�colonj4G�s�6n�%�i�aE8:d!�'��4r&!��CR.�2��h�=*W ]. S�>Cls-�*�5!�użin�[73)�J��mu�= (MV�,���� does �*kU6�1s�:HANtoifi�n5EnNToH?2ly qu�)fyB�E�-! N)󍸵�!xabs%zM�2�! ty �C�1%�A� X�J*�2 T �BKI&� *$�(Uai!�j�@in�o2}s!,�#� t�nA�elu> e��3��alB�%�&�. :3�F�4&� sw &.> !%~"j�%6-p�I:�)!$F"�>/Z�&iT%W"S5�aY%Tha� �2n� &;49w Gln139 ( �C)�bo�G.�,.i&13*�-�Ta�";�I�mjA�can�!beŦ!�! &�;� �����M��mN�,.p,6"��6"� � �d.J�$63% a�� Q�A2�&MD��, �SZ�+ES �~�( ��K!�o.UzA?.)o)��2!� � �ac��6)'}1N��5sI����>�6�lyAu)@��=ng:��/i"�I eL�?Y 2�(�W�stK�*� h --zNodD:��Ri�R5�*�O/I�a[��z�hɏ�F2&'寭6l��8JE� lya@a���o� �2�$1.?*E�;9Z|7tud� on6K �sI%wA7-Gir&(�Ra�8� z)92��y�H!&��-y!����<.k!s�#U[T m�L[74–7-3�,e�T"�z!1-�ɌNo�>��>�CrBc( �KfEa� ��&��5β /�5B *�?k;"a>. Cro"� ultra-Af�I �-��me�;A �D"W%�a=� tiff�cilk ��ro? eel [7�@I&�s�"�B�{�15� �6� ��%1�Q!�b� *dL��A�il�.��3"A� bi�J�K�{4FSI:m:�90![��.�s %!�5�al2�O �.�9�aPu��@ir O8.7cou�� !�� or�2}bui1Pblock �ieaE"d�(Q A��� E(rFs)Z! ull2O-=�q�fe�I= a��Jx� olenoid���J��is� b�6��Zac *�S�[35@o�#!�a�b �s: B�A�{'AjBCkB2])=E�e%�TW� � �U�;(h.�$+in-�8A=� l%�1, althoIhe auth�$nX5R'�insuf"JS' to d�1'Y���e>R-Zsu6R�[�D-uarr�H��7l�u�T$v.c9I -��"hβ%��#I  ,02turRNW1>�yFF�8lbwoW�]3 conn!59�ch���\!�:3$ “rectan�Qr” hyd� bic �w [7" �->!�9�� chie@b&4m*�CJ1l��;fe]OERd�Ehe*�)s��Ner�p-h�al�E7-�in� fyis� �n5�)��Ss�8�6��I&� �&�)�,� "i* A�&9�%�I� z�>.Br�H�6 r�'oibe!�5z� �Mbx �A�e@���-�my*�#�IM�s �+!�:M�%-�� �-�2�� ,6g�ver%|e>�i@D&�R��} �rF�^uoid9uLLK"� 1��]�KA�)@gmI�d:-q�IQ [36]Sht�8���8�� 5�Jc ��\�Au�ˡ,�� ���Q��sia�toqC�K�*--"..&�3K"�3��u�%&DE��U9�&M��Qr.B� y� P�RQ4�,n��Uf 7U 82] "�C� 54 �y4w8161�$1630 cm−t#w���Xar-0N� z]� �Vat�er waveqEt ^–1643e. O�Uo shifk ���o*.Iis/ed �monitoE�)1!���[8�3�� �5i15�of �Mere�plana*Ue�U%Z8$a��s�!aG�>of% &�V12V/�b��@fa�oe0�+gen b 8� y"�JextBbly� �a)� �!� 8 , �e����B�amI),%��ye�*�Z( HET-s ( 21iK 289 ) fra'4�A��byB u �J� [8�7@�ynI�Q@U*31�6[8PT� %YA  shrQ��� ):aFd>�:�:�&� ~�'6V7( "71align>!\ A&�1 ��to Z�71�&7J m~e�N6�!�` I0�� �M�88pomyoglobin [86� f γD-c�Jl8A���^�(\!�>�n�%2a�u8���B�-)&�!:荶�`1�k):Z[ w s.��E*. ,"�::�:M&T.w8 %- E��Y 1�lUmp�S�]k��!, wGH^eɸaK� �l�ElV'a�yeD��+R�Jv*(2,N� theQ,�xZ@�TonF� "�Macc,��dz&%�2(o1�F�'po'?.(P�_typ� ?2d>�)3V�7~a *`F7�_rr4" phage%pla?0�PA_X-�icN'42E��i�LL� B0� o��equil� a���guA�;>�'w? ��X%&)��U, t� t �-D3 ,*�l1&�� ���qua�ad�,�qa��!�2XPQZ�2AD��B In v�$,�con� � x)A�i�a non- �&]4JO4D*(!$[53 , 5=@8a �!h}(D3�� cs�K!�5�N-�f>r'fic �qD3 � y-dedH�m�ind6G%}i6d�1!y��e�Nnn9�3 e�f�ZI:D�9�� Insp3B*[ ?)Km &F | |�2�M �~we z:��Vcs�:�:!�94)�nd1�AJ�#m��N, slo� �c u/i�n6�W�)�"�0p�9�Figs �)IPS|61& �-�X"F�X=+� f@ LaJj�1)-"'E"! YwWUx5���2a&n7�7�A�W+� �4E�s*�*>ks"$(�)9���:>%{&�'� �e�52a+�3-��V� �! � a=� Fw.�, Js��  ~7-�� 6�!��m V24D�͵*�"e;!R���c�Te.\k0<6�\>�A .%![�i"�:�51">Z2�%�~O;e' �%����8Cif�O"w � � clai��} 3 &� }6c2�h>3N+d2�-�cy�_�$����  s ���-� Tz7&6�*t x�i2 U*� �e�#! ��`.B��sR3=��<YNc��"!*�.�-$�*�'�?e�s B"�$��V 96 V_>$~�#_'�S oA� �0b<)X�R�q�@ omimeticsi�ej��-0 � ee���."�&�*�'by E .t&$i , B . suS_� �b��nh�=e/pi�_*a$[if78R9{* ce( �ou�i?dATA*Qu�/&�Euro�j[9�!� ln: �! (8Bbt[A�#e� [9zFi�m�,'. such.� ���#� �)mW  New1A�*��A�e [)2 w�fBz{k6a�I����U�i&%� !V& iscua�%�# �H�+rapeuE�xnti& hSi�%� -��a��W wk�� 6n6�Bp!�rNQ�Z�  y7 evol�Z@pp�8!�ll kin6Fi�S.�!�AmP�9�'r�I prebY��P�5v-co�_� 9wE $best-known�&lomanifeA!�!u)9�QfU� y�7o+��n�lKd!�]!A�q9�^, q��J�m-� s [99. R�\iѧ ��^\B�es{ �u&�cm ��H�gQj�d-mar mi�y)� , ra�6$2AC regaOXdexpos]Z�^F .food soUn�[oks  �[9��101D@d� , 5�)���%%�a��K�ls�8102�M1U�c@a-�7�l-e�lA�:urviv,3eg!j[1��10zd.B.��6�!�WqkA�+ !���j0m 10�'1Ol[�imen�ay�-liI��t�2�J^M���PqQ0t*�["� > "�epe�7[7�J11 �e�F�n-!c�&�lnIbt5E�e�Gmic�N*;T*[r"y,FG� de/ �$co-:U�w5� inva%�b�Z[11!EQ�4Ra�du%-���@�s �-sy�!=�.V6`p-��RgedI� CaenorhabA/ssgaa�1)B Silk)oBomby�r3Sup35 Sac[# omyc�%ehsia!qA�ɰ%��("���L&�@MdUf8E��1ŵin VE�is<8l[w� �2 diabe�[10�1�P�12{g|)E2 re�" �� !q�%�U51u-� ml{m rehv)l@o ar-lwv2�h�b�6j�����v q�&w A���"!"� :.E�&�r��M&�Rl��w�6*kN%6�)m�1a�4)W���lEHx�h5}o�  neuI4H�,ge[ z\�$�/�5(F{Bb�"{Z�� 2�& #}� ��%m�Cβ? ��Ec�6P*�!���R. N&��b!��Z�_|6;g+?pl��I� � p � � ��Run  k[1fU� �Hub������onj�v���nIuA�=�,��aW�/Al �Y�B�A&�"�[��*.d��meɺ:�I1{)�>�J!Í�j�[12+1@u.4+)2�`�3X)+n�ci�Hs:ؕ3 a��1c �>��+6i�L-E1�+tek�K;mjr_��v .[1q. �v�* �^ , �^ , x^!�nd _^)�v(�]Pron�]� TAIVVQ;Br; 0ABK:^�3[!.E� �M��Q.C-�unmod�PteAieFc�BC,A����ysemi-c� d;n�ety!H"� N- Yu�D1�C)�sq�edu&!��w>;��a�e�&�wq�LUn^` 0C80�;,���240�l�7 stom5 �at >98%<t�purch)�*GL Bi�/��,hanghai ) Lt�� " 6�*�(d�/:4ap acidA�AV%�1;5:5X)�J-�a�@�-s:n@: RKRIRLVTKKKR-NH� 4: RPITRLRTHQNR. '~D% RTRLHTHRN �*�Y��CcZb5rbei>vi,U�&elepha43( Potsda�� Germ�3Abor JPT Pm�Techn �( Ber�,3!QJ:n�3n!m3�A%�:/$Sigma-Aldr). D� hyl-�Gox.?( DMSO ;:? Merck . U/pual< :,Bi��) Indu uea:=�]}�Mz U�D �"�.e��/.�6��k�X>c&+��Gae��Dtom��8 Nanodrop 2000c&tr=�Jo herm�I,a�D[bsorbB B5�J�J���ex�J[9 oeff�.�2achQA ‘2 �8o���Y0http://nickan,8pHm/tools/a205 . html]Ao��e���!!OCts�%H&�4)Go%�"���P*�&�eT{� x (ZipperDB [6�TaA�[66w$Waltz [6�-Zy� or [�ea�!,oco� ��=!{�� cEE�$n. Wang et a�N�(�#sndAU��!�_���)��ET11dɧa� His6-ta.&a+ kind]/�"�ylab�j vers��$of Michiga�MUSA )��od[b!��o& BL-21t=,q%� then�>verni�)inmLml Luria-Bertani ( L P�,um\l e �<50 μg/ml ampici�$K� dilu0"700 mL�!Xa? \ 5�&�Hat 37°C)a220 rpm�$�$ntil OD600% 0 .~r9&&]!��W[) 5 mM�qay�/PD-1-thiogalactopyrano�J ( IPTGq'or 1 h�F> ]3fp pell�(%kha�d��h��ifuYa>s , 50 �Q25�KE�st�mat -20!�aMFfres�Ade�Fl l4Lbuf�$( 8 M guana�!�HCl}�pot?] um phosph� 9pH 7 .�aT2�room S er�( ( RT��%[ag-a��/ �24%4A�sup]_�A!� sepa�\eF,1�000 g>+�x�6A�HisPu�bal�Es4>ea�7��s@"��)"�#+ K2D� RT B��mixj as loa!��N�Qos� �.ImenjV lumn!�4!�!gwas�Y�10�ofakmM��!py )K�c h\ Zu�-��'6� 12 .mmidaz?:{)�ei� �A�M (in��. F>�\�tffi\i6Na 30 kDdt-off�at)@( Amicon�z$6 )iC���Pl&�����I5� >E�desal�!O��9VE���Zeb�in 7K<-�"xyFisher S.��Dto�T%C2 ��Dz�pC���p�280�*M %��5!Z�of �460 M-",+x�2!0Expas�'rJ>(�web f .F( /cgi-bin/!b�(m ��R<(�!�l$r�by We�!n#7�)-��6X�0 �bod4IMn�Q� bR2�Q"�QD%b�<|^=�5���)*}we幁0!K�&i�SepA�A�%}�Y9�88 m��,1 32l�Q�E��C�q.�R%��{� ize-=E��(Derdex 75 10/300 ) �1��by AKTAxnt�">S!�`E�2VHDAWN TREOS ( WYATT "� y�nd�&� an��Opt�x T-rE5�J5dRIE�c� . Cha�6lp U.�!�"�S��r#�I�0ASTRA softwarqJ~-�f�*j9r.�#v�U,�a�W boila�� KQ�&�=RXSDSŽ�Ris:  be\�3L2I� ��!p�� �-y4%�#B_r>W{A>&� �h,& � �EsD2� to 1� tu�. Fin0 .[Is �E3Ne��f M.S(>�b�Sa��:K ` ~ at 25a��a[.V .G(QL ) �R�b� �L 3×Es~fNdiT 2ito�WDT/ �&� at 95 ��in�% .X 15%~-P�TXM�N2d�BSa^�!!�add��lY�to "�Ka�am�=>���in /b� . CoO ie S8 (��ede���I&tBlue)�J 1)���t��rL ��i���8,�E*�! . Im�g:N�ca$,���' V�4el Doc–BioRa%. Cb�\��}�!3&qW��LM�,�1"�Lor�eW�!Y�&@R�m]��0�! e CD� eri/J(!A5~ }�=NdiDla� �<�� � 2z� �,!��(yk i�!6g�^CD� �� E9!�direcJ���!�CD cuvet�Eo3F�!�9�U.T0� �p, f�=Z M![�<45Er*N�� a-�st�@,AAp�/inF0>e -?;�kōaM�!�~v"�=�o"{Q�O �"m� �o�`�.�c�Sd j�Xb�!r�1%;5�a�~pr�R5:.!�� -�w^�Ca\?BN*�[� ]^��2-�sz=2�RT&�eas5�)��@ougT' ̥Q0��ar UV�s�5ra �a�rd��% Appl� Phot%�s PiStar<�, rre.UKR�n�2�9ga��� 1 mm� �Bh,unt�quartzq(��rna.� , q� �!Azellipt��%�"kEv29V ` %}a 1-n�IpX �XĎndwidthA 1� I�=Use n� �!�g� �j e sct#�L%�&�]atwo#e!$cap�dA=a!�#W$o��r�]!�>� !��{� M�m�jk2���froze�; l��d9�!lyoph"L ��$�� dry�L-3�t�pow3ob diss"f�deh�"2�52S �*?�rfGwaBa�9�v�.�!�i�nc ���1�w*&��J�2�. �d��d�~� L2��to� � .� �r'E�sp�j���u�ATR�� xMIRacle Diamond w/ZnSe lens 3-R&/sH7P�; Pike&| �)%��?�o%��U2�. A��V:q� Tensor 27-��g�+Bruker� cq. M.�%�:R *�<",< 1500/?80�?J;C= stepaFA�m�dE� 100eNA�Ba��:t"�)e��E��-�8V/u�G!�� �aEf�&�I’  31�' ( 16 ��c�)$!� A�-n}.�s"�WDef$(.�) �i �u�A���l�f#� ;+fa"O� *�Qc�46�NP 6<"-,--w�EOw ɽ�!B 134T!,Rs��WGR"�m?#<�#G"� ��.b!a�:P-e1c 0s �aa�C+E!1, . It%��;�$ p&%+�[ev��$0m�L]�hb.�%� ��.Vvo��IYQYGGA.$ � �B� .�"(� ���d.* 100%v.�" ���Y) QYz�"a] )�6b82a#�a3a 1Ba,bcP�� O Ys%0 n"Aenao �5�screeu�&�B��A�Mos��$Jifed� V� robo� TP Labtec�  4,5�AFCen�a�܋al�y�CSB]C:��ha�dN�U �er�in 96-e|�eu�μL9;[,�)��op �1�� 1�3)^. AllW&� ECRock iA>��05( Form�R��! 93 K�c+pAs�dw2few day\$o��n glass t?les����brp��[1�NNoA;��!�!3�!.1nmkep�ZRT�[Lc��n4.5�6M!���Z?���� AG�%e�<rvo��6s:� :m��,R MDjaceUi� "��!aVW0(A#t� Xm�, gm�gHEPES ^�y=^ 0%v/v Jef'�ne M- ��^"3'6>�chlor�3iBIS-Trm�pH ]!�':65R�2 M l�DlQk^Z-� pH 8s; (30% ( w/v )x ethy4gly� 4.Ñ��AIE%�M!4telK"�5˚ osciDil�BM� -2FX��~--f=�'�ml!zID23-EH2QcEY7ean Syn1ktĒRad�^F���w ESRF�n Greno� , Fr�#;.� �w�v ��aF� 8729 Å��UhM�AE)ݮ�P142� EMBL�Q!PETRAIII�rage q( DES�)Hambur� &6&�� 9763 �D!���[t”%�#oa�%¹�us$XDS/XSCALE��{4&�5rZ�M�Eall( ���w X!pr�)m P�(r`2]��Z CCP4��eY ��e�-| eP��S!��  �id�� �In�ѹ�ph��+�� �9 w� �Refmac5�F�M�9blSAl:> Coot/�$ill '�|^Ch��a#I4�)�n�e���f� -$dis) 6� $Ramachandrz�lo�B�7^s*l)Cin��T�i� Lawr|A0ColmaE�V|�En�7]% Ž��'%�V<M1W��LEUmA�A8��1�g�.cYAN+�!��d6u( UCS�Y, s faulaJb�Sdi6, Eex�sT1 . 4al!��/Å�*)��R7)H&|Lbn"{-��J��T�9P?!�a8of�6E��A#$SM( olar7��4�$u`do!k 2]�be�. 2n*�6.�>b"�$��A:SMA�l A�pl6 � &�lq�$uU morph�y�� �e&��� agfD�s�t*G0/�d�� 8Q�3�v�8��/��WAy;Gc[me (� v�G1<��<[ �(W�m.agf"#� i�E[13�:A�MA�f( Δbcs�'-'sujm��Be��9lU^/s ( b��OgY$�Js):."O[1VS .Z�)�A� � ��2� on(�e� ���`Na`&�'0�.k � %�Ct� a ��l�C�ha�pic�aE�!��fm�dN*#,LBXum ( Lc�� � IL *�� vigor�Ish`(i�evalu�Dr0&B]f�a���aU6 2[14f5&2(�'si;U�Z.])�,�O�(of�0ڜ0 . 16+�� �) 200 μl=*�"�&NA=_'B h'2or �f)��48 %�t )�` a6� ( n�se� Rosk���-enwcIa)�!3U�&aT�%�� 9% s��V .��(|g +Y�).��W�>�R�g�� 6�"nj29heEG!sC2�j�-6��Ne�+n"�)ali!/�w�� ony zl>�mm!md.�+Y�a�%;&�T7qIYa�bE.nVEv"<!/a�um�3E���� spot!�)LB-}�F�(�q�$CRm�9yB)QO ��(to%BY�]��"w?nDc�rim�uiJA�4%��ldehydA�.S�(al�PP �fd� G�)E� .�o�S&w tk"8ko(%< �^�! �-!�d"��T=ou��dPd��In brief.B�neatht�DE�`cut윁�\%nc=|��t 5>�!�E1�*�IBi  ( HylabRehov�'Israe���unCRa�!melw�3�-\R�(�1,at OD510 ( o�ab�� 6calib� )jR�d2mum����,CR &�h�� n6u2�)�S�[�ia*��u[D���"�&(�� �s��f��0�r�i�3b�/g<5o0Shapiro Wilk �%)� keL&@ )$�non��me� , Kruskal-Wal��K� ompaL�� ��!p�R,Mann-Whitney>_NPw}M&_� N�ylD?4 V>�Ag�sa tI %�( ( N ≥1�(!MAllqs�l!�%V two-El�8a8 a p-{u5% orI?( o9{�Y6=g�J;|^h SPSS&i(, |2@on 24 .JBJapane[�nc�6litis �G0JEV�!a &�Mca�of} 4���D!si�I��G c� fat_@�z-o{Zs��;~g�3la�ong�YSr�MA�epidem�6DJE�AP3pnQ�A�h�XedA�oŇ�1f"� JE vacc�A~i�due "�!�[o�'scheduri>|"`>��%a2wli(< ��xnd��JE�e�'%e�! 2011a}201pW.dGeBAV�g>�iNIurd_!�d�r&-Dy� acut�^=� synd��E�~f>�A5Are�Gc� bora�p' Janu|�M"�iMaW�%Z nd m2<.!$.faw29 pub���D_B0�%�)/R@���65 serQ�u�y��18W�cli0hE�l8 anim^Gj�&V��e*�:@> 15% )by z��of 491�����5"��&�D�"�$R��?!�jmi!Q%e"�lge&�$k^�:� or�he� 0�z*� untr� Contin�>�X��r��w Y~� fi`2�As?��r>2�+burde� JE� K� 8CoOUEgu��itJ&Kigh risk-�%.���2�4.�'aMC��of=t�� I�(+s"gX}fA�v�.�F !�� 5C�a"�PIdZ�� c heTh at . V�(!6�!a v�0-borne U�)9�Dn�L!= 2�. Worl�& it,s~gS[�a�M��2 annu%�,f, MMWe�3Pa�S Rb���ZMK�M T5 �cE��� i#z�4ad�11o~al%y)}"SeSH�s 2��S>�n�>�of��Amlong-4#� psyc&�Os�s� in 3�$5�~Y�xiv [�Be��e�A�.%z1&�JExr� expa��8N11]E  HI{ OrgaU� ( WHH'!�re�\�Cexigenc� V*g �omm!�A^a�&�of&��to rout� 29�G �Wver9� W��:�}�le�V� �Ymis�si߇�]st�oB=@���a8+�[��V�6iQ��Cm!.� �ڈs"zO�$�6a to�  ݒinJ yl�s 1943 [�K\[i,D!�*VH�SEl2�in,H��GqJ !;i��Rbel]klI!���A*Qt.*i�f� \�� �F� =s�XGore�.oineldelibe # �Ғ��M�C; E;A�>v��..� z  � aaV- llD7�6leG ` �-: ’sÁ^"���"> � 7$�s |1�`�iU�<*� ,���E�I1�2p� ��m�Sex0 ng ,5S62E&`I;js�Q�C�"@ ��val�rbc.X .ANan ����?o��0 mill[4�e�)�-chipelag�rx�n7>"7 isl�n�%m�w:OcJ!�7uth!h ern a. G"� �e=��di* : to 3��V }: Luzo~-:nor�Visay*% �@��g�AMiH�a>:s��d�9E.l�/YMf�)-sub2�17 �s�\���?��2a�N~��8#Yvv�n!�tw�Was|���S�<iJu��Novk��xdr6)Dec !to Ma0�0u]itC�ut�.�Pub�_ (:+s�p]|�p4“R> �LrtC> I�MSX�G ex M��u����Re HyD(Qo~�I*FNet�f( HERDIN"*a��he9�� uw�si�Jq�?D�3�of� ( DOH ) N�A al E.�Ce�( ( NE��� EAa:~ outb� 2�ZA?We�<r�r�a���'-Q*�is�pap.�lcin N)OE�P!nt��xJE58to@ >�!"i#.*� U��1�ver��dn� .]�Ÿ�3�EA�P>����t( ALL�JG��� !!�5)�p���Cl?�& JEfbc!�Mh�7�f�2��gGitals: N�Z��9��al��,.�Ch�� B)0San Lazaro Ho:�Jd"Q�:9�Jfifth� , Bib*:*)��%��W�I�"<�baLe��6���ia:*[� situ� � e�%E���m���"� lyL( lumbar pun{n��Tro�rE\( RIT�1�&5%JE.�. C�i�8�"V 9c�F& q�a�4`6hʆ%� 84B�!��z� t��;$e�� JE�U IgM�!�!x3�{)��6I.�A�.�3z^!ZL�ǡ)�!����ed!@::��� fܜR F��j�,�032N�%J��O.�w��)�,.�'Y�6y . An"!0perc a�: d-��"_��hSE%��dI"11E25%.�Y�u�6Aa�:Ձ� �qs>�E|( 67% )��(:� ( 33 . Du� calea�z��ȡ@ , 60��69�C5ZJNa9$��p71�t�Er<����e29f58f<y�d(K85 )?mi�#9�!&!�a&.=,4�<s%�Q. -BJ�,1�)�n27)Ah��u�Q��@#28G,� DJuleW+month=highest� �J�H"��Kife�N>j W,�A�270NwaX.� od�A ill�<��.F|�~�_p+� ( 19A�65N% ( 14 Aug�@(eL)���7!.��.�.k? ��o cept93.?��g-Jee��: 68% �$ &�l;7: 9E�s  .-fJm , 75 YlBbf"�8, �.e1��Y�G!�6}#*T"A#B'AZJ�. Each �Oat�,s!�eF>2Ua2E/�W68�Lv�d�'��(R��T-#A� � "� ,A�JEi� F�KMV�!'�br u2O��aQ- . B&� ro*6=�6al n�k�J,?vmo�9�e�2&:;zG Me �Manilƛin 32C �*aHZ z��XJE�[� �5�in!���6Dk cit� %9=M߷a"�ťWonu� 1�sI*!��i�ider@.!y�C�Cs}]t�ui$�� �H&{in�m&" is 6���6,Yp&�����Q!Sage[~dU%U=c , ab�u�8��� 6�>%-.h a�.�2+�I~2� %^� .� -.�"*��>�i� ��劭�X_�3-"a��,l&��"� &��{! F�aYr�cl�ir&�or�6diagno if*b��&�N�-TQA!.n=��+-up� a :2nE.q�.�%ڍ�a���3\'�2�"r�"%F"�"[1�1425jRՁ<d:�"A�ph�&RD[��I%�r�3Uo)�=|�weua3t �;n�* �A(R�2A�.or 60} 900 � fl߆au�"� 39QM1.!�"� � % w���; subT by6p V�73�.P,Q�84�#� x{5�4���M� }.ns&M�k��)<T@2۵3A�۵Wvm%�asE��4z�&.rat���*�Q�t�Coo�A5o3�GQu�e:Fi�Lincorp'5J�5N I�m^.�NN%s~ � u�Qy �Ym l��[1� �mif%�~�)o5 ŞIMy� ��1t�eIЭ�"7�"#l'!�y:���"!1M.e�aa,Axye�> a�#%V"eVPA��CP,erQ�b6e�"{"A�i���n�ʭD� n s9�"� ��nda9]tiw~u#�~sub�j(S��9�al6��`qA�\t�R� .�t��A��V"�� ��!!D-$�-a8(� > y [28 , 2�lA#�"� !�N�=-��a��!�*��Q2�-~VsH� �&w���<)�� � n�u3�9fan�)�6�9 2�,9�6�J�7%Y*<\wP!&��!�ߣ6$�#S�����a�6�D0v�'�,1�A3d +�M�.!9��bt��3�taken hkto:Bt25 E%�%��m_��E�i� ])!jY ��!_a&�ZmD#� may� d�!"� -'� tru):� . Out�� %��&��� b��H �&W) m-v"� } 1950A�d 1960��o�r�"d4 �;�!_ T�E�.�v�p9vA�ɪ%8s3l�& ) �!m���S&Q* kSe-" ��n!��wty�!s c' arbo�$�,p��;daHHIE-CFij.�"��� .,6RM�199�8A x �EZ��}�G.�.� !v% -v�a�s?SE�AO erio%�-","4-ffri!�U�s"�)� �A�y���:(F�� !�dengue&&�ScuFify �as���Lr�]PV, m�a�&�.%�el* .|MPN s�v�&�*t"E�% ��aWo� ���O 6i1XO'�A�G! �T�Rsi�'�/Rn�t4 e a{���*~(!�E�MU$201�i��N :����.FA, &��%l%!j&7Au%�2 � a W*����K u"� . Last"T#2�!B� �IR"Q-��M-�:�-wed�iQ��� , ��7.�LEO�!+s&,�e{�4.W0M!Y N%�SR���'��0?��/M�$new so�Y�b� ,&$cyee5��o�.>+�e@u�I,(-h��$-�%�suTenl�(w��y�m�G& `� A�JEa�vc���2T)���.�X �  #l�6ME�t]�ytV���JE6p( [��0�" 0L A���� 5.s %'�(.�A��U� � travngr+��A�Z:e5y)E�197�� 2008FK"�8] q��a�75 (�>]�[PJ�oi�5 �,w�,[3��tGXenti�woqi!�=E ���i �zof�<��o  [3���-� I���p��h��)Z���2�A Gab E��l�}(�K3�h)hectaa�19 devo��ic�e��ytR �neighb�., B%rin��A 19702��GSw�*�:J��&�%��:gSM]{!agr��a�<>��/71�s>�&Z:ۯ(kyard farm-k~ݚ�k*c^6al nich d���Q!�� v%at 46w�%�A".q�Aa >p%�tot�/*-c�ev(2\�:A0ritaeniorhync� r�� iŦ����th VApcos�F|�s�.aA$1�ev� �mEv2X�eZd_Y�E�Ec half1"�_ �p fiel�~b�*&~��V�  c�Epr�+!V2�x�*��"�T�da�2;�az>E *E4 l�*��.�a�p0`/a��;Y� �$�M�6L&Xw�>s�Yt��� �B�iiB�1��1�"WCB�:�lj�F��youngfw��b�ityeuP}I+Ar�u �?Ge����� .�"%2 iu�B �"9��*�8� �8�GpCJd m�ʎ�9��9Q��w�v�3�&B�0� �6�� J:D?-_"g>�i�iU� �:E . �!& ���"K�&� (&A� ��I�a`h� �a��8 al OMv� a>�' bs �Wh>�� �:toa�i�e\ WHO-*(a�@6�'�<2Y#���M&9�[P.Y��bevoyg�?�~E�gen� Ʃ��� �i�debate:@ �aaNN9�of�m��^by�C)�6��T[ �du����c� suB��j abolCRquipc&Ae F�3Li +� OAav1d����H�,w*o�urC�)��ur�� St��f�A��vi���%Y�%)i1�,study the pe�Crtaining evolutionary forces across many species under diverse condi6$s . Here w \uct the first large-scalmputa54al study chart�3Hlevel of robustness@metabolic networkhundred bacteriVp �2�himulated growth environment�,We provide e0nce that vari�s among ^in�irR�Xreflect ecological adap � pdecouple��8into two compon�,and quantify} extof each:)u,.�pal-dependent , is responsible!�0 at least 20%O!�$non-essent!V reac!�s�its ~Nassoci%_ with>-(0' lifestyle ( Palized/generalist ) ; 4eASB�in:�p( correl%�@ = ∼0 . 6 )� intrinsic=ocapacitA� of a �(es—higher2�$s observed!�f!,AKers or organisms uan)!sivE\aionj �akQ�teA Finally ,aHi!�!�9yE�Lare uniquely suscept%�$to perturb% s�Lhuman pathogens , poA3ih�axas noawdrug-ta�a< Systematic dele� stud!1 have showaat �(laboratory !�i3s%ۅ majority!A�Algenome�dispensaA�,Em�in��cases%ilOI s o�a peria܁et�^([1] . These6� rein��d�no��}�of biu�s%!O$which deno!��in�3�Aof phyp� face2�[2�wo -;2!!�4encountered byJ�:!He!�alterM�7��al.� . Ge 36�aF_a�viewedA2�a-t��$ntinue fun�(AYfollow m��$s [3] , [4while:��refa_ to bufferIagainste\r�DHchanges ( e . g . ,��(emperature ! salinA3,m�!�avail�of nutri�Z)V!can bQGd�>!�ous�ɑY0�z%� , fromxmolecula�E��he /sm M�h�]a state!�c��dE !e-6 i��1l ha�� ��0gnificant eff��m* trai!MaminedM�E�al [�di!� s greatly�bb>{: � as sa��  exhibit�impres�1x��ro�.r�n a w�? trum!�habitata{othAdemonst4����f)�a��equire��o$In free-li�)���, new�6 ways��" ��b�GA�:�pu!KtI�YD�˱�c use aq�m )T er choiceE�h_9�ests [5�-heu�implicE`E|AFse��~essa$to increas�e �5�qoir��kj�aF���g}�i��twEG�gA� tribX !�6�;toRQs.���יTexample�!�ja%�9:�way)wsaIA"esz!� 0N �S9t� A )�o-�ef�rna%qtoA� exis�zmakA6AofEte B , ht promo5b. . Un� such!d�fes both A%�B�5��l�Q�-r����) ,%]1$will also �oR�a=ontʵ�in on��!�� h d�-��in��<a�� prevm ng>N'V���$.} h utilizN)vaW� a��a?� ffno^�Q*� w�� $ detail�y[ [6��[7]: mora�a��lf!�aV. at w��no�v!al� q thl b�<foundA�be � v6 A7eight tricEj V][7�aHowever� sf! cannot fu� expla�vhe>� of �,� �� hyp � Q beenaposed�J2�!%:{[2]: Fl1 k �4origin – i .! , a direc n# �+o�, favor�� ��69end�T��>&| ( fg ugges|by FisZ to2,"[ domin= wild- elAo% overwhelmA�.T � er�y�[8]E�S_ a� )%6$ս�M!���� bypr� !,vJ!�EH!�,y�!�contexL9,��onE ѽd}~ flux -� ed)a�� >grecw��� most..9]–[1/ Si� y�enzym�ct!par�� , multi-%,&�0, single-locim(a�5ng�) 50% e�� of�6F \,�4heterozygote )��a�expec!��� .A7$all behaviI�� ���YY>z Udetect� a�p� ic� 9T7F� 5[1� ForNm,�G��similar!�rgu�5t.�iCQ�q ptimo of� �e< �v�aQ{�e@ f�A !�steady-� Y$A�es via%^incorpo� �.�6ͷs��! 1( 14��No!yya8 is&�� %� betw�Fman-made-��"}�is builtAOon pur�y�$ndF͛!� shap� eG2CQopra}�,f�Nnon ��%�urv!pif re�]@� h fail�|. Fewe�n� dAo�methods�=owEQto p�add!�-�flu%Dmz*� !9�� struc[� expans� �ła AF�aAn�se�Ga�pos�o�!#bL�GA��$approach , �ic sub- )� describ�a col�n* c*M �kn^s!��95 �*| en��{in "�fic"� � %�dedA q5tZ�!y�r"�o!�eiG"��eli�1h�  !E� 1X z - �.*�� helpfu? unc��!?g role playi�&c�.6��"  *� I�!��M&oxygena3tatmosp�|,E�} !!a:� )'�d%� Cppear�m!�2g�t9�,�= ably�E�1A�lex�&J�� erobA�� beyo c lhE9�ny anox9 [18�{S�x H-!oES%�.Ygiven"�tmbi�Xsm��� rouplogeE�ofU�X�Vc�b�[19�F"zX>����,� M op"�q�e�veI��j�8� dX onsE(kM�96��ql.sum*� i}a��fer�M�ˡ���6 1mU� [20�Q2�  �s aim�defin\e minim�ХV�a�edE}�j65 t[��Eh! /yn$� A� Pape��M *6�>1k -a� rea�Qk!�͑alg�hmman��pr)�ngF��:"(!T se]%u=Ba�teg��|wox��EA�model)@| only�s�{�+e�as�L ly d�u�;B���but���in�t&�͔*� d&��sx2�"U*�!�.����v T#th� )8veu�)�M�9{zI�i � ��yr.�nd��� +�ividu ,i��"S E� isR�( d� o� 0; &� inɼ2T!�!�J�)%0v{.N.�st� by.zourMW!te�' *�plausi�Ny K thenhit!s�"@ f��M<b)��])������.�aG2 appli'a�xŧwh�:"G�y!��"�D e e . �&g�y��hBc�6Z eh!� ilic.*  analys� 4 e� 2q32]%���Nl�$stoichiome���!D���;!jve���� hipsU�'eua����n@e# Y&I!p��a few)eduK. T�< y-dr ��@E�-Y t 81 backb���aae bl >�0��although=g qual1-�!��.wa�( e/�c�)2� a[nt\aXm��!��t carr��,2�e��Mo��in vivo�6� ge��� ��s � (accuracy [3@3@S,��unrav�^=m"�Z:`( NGR%]��&�!9-�'s.�iJ* e. ",%��?ct,�PWari7�PNX)*��#e� ��"nalogs )�[� 297 30P �# �iiY��c.O�] ��a�a%u�>��E�Q�ng��'Y��$m �E@"stE�dAor�o���Mx��Qu��� >N�N�� He.8.C!+toy5 �( illu)��3� proce7 lead�@�&� )�e'��A� , ba���y� NB� .��s calp#!ramCaA��Z�((*>tE>9�INab�|com�"� ^�rou� ) oum��Qlb%f5G , ηg�� �-3O7�3�ϭjis 6/7� !t& -)e`z �aH� good agr��niwoQ�m�2B data&� assembled �"�'knock-!� 8 nEscheA�iIi�BacEva��s+ yiel���� of *869 5�0iv?6 Tak�i�!��Q=ie>)����O �a��en �=�Y}T�reI1� a saeX-��iR,nic@ ��&�l�� in:%!�o elucid� Azr�#�-%W��+�w.!�siuvi��A�!Bx.*e )2&`.�v$�Sy�Fp6i(I#2SII�III ��Z � .)!72<in a�A�i� le�pasB of>��&"n&)wTm 5s&�'2�,eax( � �,d-� )� abl~ >���(=� �'&j'( F�$reg� �+ls:eE44 , P-$9e-8 [36];:J(a8� 63363e-4 [37u S*�,��-s;*�,�~%E�� ��trend (���( llt$�Z�.�2|-"�!i�#�.- . A�(�4ejac*d [3n!�*]%6e&�sz��odula=->(�� −��4%]<2e-16 ,=<.*&� 6�a��Wa � by�J)�e ta��2%�i1B� h�+nJ��n�.�1��N��6�q � itEȍm*�"�O�����`%yJ�!1�KoX0E�ap1�$6�q�i� �n~ �a t�/25-:�)��V� EF w.�(�"� a tim�"mi'-an� Z?/^� ��at� 9x��,� �=�!!�5n� 6suD'o�,�'0&}�y �ch��!'�RO u!��αňβ�� .�!C!^SA�matrix ,.���� !�l.�q�qe�by ��=(��isM* in T�%S1�ge 1 �Ne)achX� �*be I1 �#ree%xoverlaps:�� ) (-med��� `�A&� i$re9%%E�M!�a �:y *u�4( i���UsV�]�abN�6����Fed-up�� s γ_ ��~ζ!�Q��wndo6�2�677wA�� E� '.�(Z3�����r�5��TBut�@2�� s� ( ci)) .�3>� ^H(A up i%�� mE9k!� M�*�|�d)# ��^�A�&�7b .�@e7I�R��M.e��'s B(:',}:��r�)Y��^is� � Qh2�B� ,O83"�8g�.<ly U�"" l-"m�in�a�um [3�48 we %�r:9Y.6s 78:%1F@ T�#Sa��� host]01��" .af�Q�is=6Hly markedly lower (�35�$Mycoplasma!A ital� B H4 � �#j�:h� rang�A:to 60%2y)�%[ . OvS �4�7+�2n�6� clos� scat 7ar�s �%�5� 1�,Yrfur��rd how�tfbQ;_<�.<9#"� ��P look+t� oi�&astics /e��: �3ne���� d&'!�a!~g�3mbe�.n0bR,protein-node�� i cent tyn^&�Omeu�6)�&Z 5 �,�!V��D meana�r K2�z� � � ?�:�� !,l27�4��is�)iH�' .�pro30���U&�co=��(=<w ze� d6��0;2K "77*�0;JL:T656+���^��� n arraiKiWE�.qN�2 �.S!�!��u�/1M�o�+B(ts1Wd)*s"XcC:!�as�>�R-������,.��2�rem3et��n%troll!��|�&�4�E (6p 3��&� a� -�#suppor�"T�;).T2�"���war'��8�<�loss-of-1>*�[41�[4�/:EQ�.Z�,.�)��' "Naavis� z, ��3!R~B� &� ��=)-W∼200��. �:V��W7uZ�!� !2�! B��D.:Clo�5botulinus=m�m�f-�a - �X\Q�ed He�#b�$#nonyca�)kc.�l��;)9A�rk�+66A. N� w"9 At=�  !M��-�#3.�a�6��r�*����:� markaRCde��u�al&C ��in6�(u0��"@.w:p to 1-6��21hB1s! 1�av�}-3&�i�-E�'s��A���.�".�B>e� >� .� ���8i�6�s t�� B�AX���Q�9}F��;�N�44%XH�",�'f�"� I �F, `)Ee��/fxng*�C� ��5-�-w��y?�*=�s��@;1�6xon�C&0:A�m� .,x(� ����ջt"|i�5 ( P<� 05 )UL��'6M+nde9.��#( �-%�� phylTD,%�$.C9�m �� �q �� �2�max~-N!379��2%�At�di��r�.aKw(� t primarinB-Hp�6���ikz I�m7� 8��microb�#�C�+��2�&�5wx*!����P^�-g��!�2|.�YI��"s8*, �D%�)R��sb�\eH2t�?2�&t)6;nd�erI�!H����e7a�Eat&A B6Il-)(EM58 P<I�"� ��mp�w�H�=� O if�#�eV>t� hem��Jinvx&ge��/for�%63. EeC1�>3MQX cate�/�%ajo2�1lO 6$als:�@( �!W��n>? Z�:*>&"�s�%carbohydz7�s�"d X�<�%�1bn����. Con�?a;,�s"� !'�mino-�&�'@1v.�L.V �* UiV(An��eun-*lyE��I��h�(j��A,�.!�6-"�I.?�< mpri�c aQ<ic�ly%�i�A~&O6~ a�E*�.j V�2�>�- veryT#*K ,6a�ATP�9P4erA�ngUbi�A�"; A/ūE�S6-&�AQ�s.�&�� �0a6�&N6��n[Agu��p�9*"82"0; P value 5e-5a Wilcoxt$estً� II^�Te�a~s�al��9*A 6[ A8a�9�redun�n)=��z!y��@ "&�5e荺*�7af� r9G!c cellA|t ��3� ^�anCB)�s�*z /8augbG� ancII ,m- D�"d7ea�YpAf M9��*��982�A�J�:�Ia K!i�=atFE ows�,'? '&�2-, !u-L�a�s1 G�.A ? .�yopredoxJ� <NADF !]f6(i@=�e!NADNym 32�3�{z�$�<y2�k%r� /I9Qv NADP)))�2r%,�A�.*�DI:N�i_t�F* �) �.�6K�an�=�u^��� � 017�.�2m/'Q�@E� �hA�16��>l$,�� j ��ATPN/)�799�1y#�l��� (R � ( ��u)�" x�"� �F�+pe& by��O!1��yl tRNA ��thP(�i ! Ar�DO_ D�C [43]ɈJ/� � ��[4>2One&8Q.��#%�u)��P) !��Y may��sa� , be�p$hermodynam'ly un&q G#for��F� * ��7I��� o�5,%$&� haveM�, �I tane�N,.G� 12��pl&M�|.� J�-2(4���-6�.ha)�l� 5j:�S6�I�eA.���.~OFq6��oAg n do�)5)��!as��Y>Mh'];^{O�&.�)���4i$mIi�T6�(2M&:M��OJ2�V �6A%� 8�&�&"� �W �{iI#*�E���:� 8%A-�2�.�2��Ap�#A�b��lso:���-#?2O 000.T� �j,random shuffP�1�1A��Ial6L�SmaiR �tir.2�)�7R(F�: ��. Our Ythu111 �Kl�&�6E"gF�T!Ba "R^3. A 9s�^9�!i*�).e� �Fe1J_9\>eO�e��YdV�Ri)G�<cap�ix3(-�"3� &�$Tof���u*S�at.�al_%ers��by�elf�%��C4y� un&�(v��4"�aE� �al2�#6i.NF2r 3R&A�U��SaW|\O "�7Ik&=D��lmi�W�D does��exc�@� -�to!d . )���a�IljB�" 6R&�0/e,��Sng"�/"�R�UuGY>� ._ 2!/ams&�P �W�.W�W�/ru(y�a fair\.o9fL��*S0�Pax�P}8oD6�.�W.�W,.�Wetc .� t g�Gy�Ee"�5i� prob%�v4� "��r:�2��-2fI�!��9aAfVW�]�2�N A�a��f6G"b2�,r9�J�Fxu�.���Y��"|�86�N#'%upER',�BA��MeveSYg�X� � �.�E�� p&4N���".� nRZ2����2���2�ĊM,"�J�m&J"��f2�c�_'ad:\>�"%@�"daY� �A�fo�at�6hYRf�B�l�&���A-�.� $.�Aaq.!LJ9� �2�.aY^Y�d Ej746�.]V_"��>6~>A%:t$��Barm��6on� �u;� �/"(]���d26� ��BD'2' E��U�";��" 59 Pearso< 1e-1�   A_2��m��%itNt�~ob� ��@  -�<"�E&k 9 Z4.��13B#i� cau<]t�P�[>m"1�n;_��G)}�;&L�Jza�#�La -C!E��=2hNAn*aY�!sOQ3Y�%FN�8a9'A�V�]=rek#�'bovz6A�ay�_H� �gco."�V�E 10E I��cRq1&��&^ &T.8�5�]vmJ5=t� i�=&�8'F�!w�H�$y��Na)������="%Zmanner� �A�{aD4uSby�\a.KE.�0 �&)�f[��G�L gene�D dsG5��cfun"�F&|G2s 5]�.�!� d'. IZ ��u@Y?&� would�B1[ mE��_iliE��`�>�5� G&�kat:�}^$ =�Vefe� ]�(�:-copAN26!{sbL�  e ���;-��]�"=/ . Ye�A�:1��.�'���>nGh�J]�V� ma`.�!9\ copy�L 6�82W`greU30��n}at Rubm( xylanophil nd Deinoc�cWdiodura�{Cmo�%s!��17x$ZF&�%�rad+m:r s �� . r Si�b��do%��Y w&��"y ""P�B.�4�� 77A��!�Ao!a�S� �?�U�B75s .z�!/h�;(����đq9ZA�:� Qigh�����0&L`E�/9bF�].CcV_�I��. Ba�X��hh�b6AF!�nt� I%���Te)���Tze� -thrK [eF=R!�a�! ��a�ur�t �k��&ny 5F�h 2&In!*�Y�O�(catq@%e� � *"b6�10-�'J�V =�q(t8#eQt�I�* proc� *� [4h85bOIn-Y3�A��d*;H%�a���Ag le&**-`�dorN��Is6 .EtAp�2.��� �int0�!E"ch� litt>E�E-mmalian�$�ay�ef�Z&=-]A&1 mۅ�YK�4Y�y�^J�J6�3�� ?Z8 6 . &�8A�� �T� ts�;!��SLQGc�3ud m�Ee\ f�J&�G�66 �:a . Sw&L%�iA |Csh! � ,h!�� � �=i� �G�5&�X2`(Ů.'���� *E�re&��&t\� -��� "� �.�ignores � oA!��M�Uo&sk.�QUgV�x a�d ~!� I"�M��.�6l'9� ���)n&J"ly<mA�"n �[5�\N!�the�,JZt-4e�I read�.b�< !�hu&,w���!l�qa6�/,�U,�GAh�"��e emerg!p61�9 �F$yd road;�� �aG�J��A=�?)rincip$'u�C#XA�u�q"�=�-�x(&�a , [5�6&dYa�.�.�'6�A��'�(�/� �&Mk ; "�L� e�a-*NX�tt)�l%N �}�re6�_PuCm;� e�Or�Y"�Z&�n1G%lV;5E!�� aa&�]�*app"� ]r�e&� ��?ce su*?d� "-�;���"�� KEGGEd�3�'�? ="��Tqh"(�$�9m)Wa�*�aF�u7m�AF0�(��+�"� 6�A�ie*� 2���a E&`S9YE�"b*c&NbA�� �presou5�^%�*�vclkRy �,if�{q� &�>212��q9�sen�<� f"WR"�U.;�z�cMi��9Œ2�"3a�7&�Xi7;du�W�M� �rv`�Q�O5I�;B�l�T���F _!�%�Q�q"e�vi:�@N�a"e�2`=})��� 28��2�gMZ �z �,:WF��$2!���U5.�.I&�V,�X.��a�ai e��LaY��  1 !9���By6� ��A`a2�*�b6�$� ��az(~�A�(��*�2*�6`W� wto./c"�$8"& "K=�&�g��!`- JG< �c2�ieu+�d"��v3]�/a�tou-�J< alIuy�f3'�=�a��-��" n�N�il��, ]���be� "9]6�58�[n�� ��3A*� 2� |� m.f�3�q%l9��v����i 2�0� &p*�.h6A&�"=(i0{%�o~� !XJ�2� 6�N��i,R�. Impor�a�� /l��'s�\"�`5&] "�Y� actuA:"o|�0MJͤ�y�.�@#z&Q�.�to�&aj�con� �n&� �p�%� C�{ɓi6��9pA#!�r]0�~&G H �T&�5�!1"�K��=て�h'bf���\=_�%�o �:�N�a��5}ng�.�s�>L2��j(�"�H=�k5!�b�:n�j�`���s�.q'6�56="( ?s20� !���"� n& ��leT5��C� w&>E(gene dosaged>orV2T�T�� effi�6cm13y]5u�T� AR%���]���/>HF("�^fA�s:4T?-i�de)A;9dY as�&&N SZi��.7�3 %Q�&��!���%ne��!��] y�a�&}B�~i� �, *�C+zM+withdraw|F�aJ�n��%SKp&�26s.�a�ae=��L' i��#~:�&�ɲ�Cbej ACeng2�(a $`�� �t�  =�` mo\:!$)vxung��st�e�s�I�. A#trigu1challe�MVNo|"�% ervi' F00ech���LOF Ad��uG�F.�,moA6.B>H 6g&�+Y�1�%�\p�! r"�p �6�9. C5be{r�Ha lacqG&"W|� ^I~��!��60 � [5�aV�'��ui�^�.Y-a�"!�&99pe�/� fuccu�e�U� 1�*�!!�� � . M�82�#� _ ��>XG` ���v�24  UT8e 4�� [55]%(�Z/6sf�l `me�cv!)�Q� \t�� each?�r[lea��@_ _map�ulOlst f�,.p5� ��� 1NNk�.%B  diagrama�A�$ $2�g*$��H2O*.<�59�M��r�O���� s: E!)�a�"�@ 'aO�� R . Let E1�]e�*e�E…�7n1 �T8� f� c�zm"a# R+�E2Y2M2 Ym2�YDIq#-�A�R1�aY jtpE�%R<as�`�@P{z5Pof E1�6pEdgAlsoF��in8 D�2  . A �of�bJ�["�:p�� i�Awh�* ; "q�W�J-.�S[56�o58�$a2j ^� ���QB���s*_AN�rs��--]g�icFJi�#B�e� �-��EQt! aQrelevs)�OM�QJ�k��omi�w�mEYnQ�.>* pe� q& žeJ!�a �r'-�&, �-9��-9maN���� .i땂Epq�cip�/|� gad��q - uA�� km�had�1s�nir@&oUO T��6��N�%e^�. M& �e� .�A%Q.*x��t@9no5 � ~-2�n&a&?Fw�FM�.&�}se q_ 9q4u��%h.) � �He��#$"�Cea8Vx�[d: ula�bvS. M&�bAC�u�I�Newma�L"� [59]A��b� [60 C P��tLby��(V���� pairlsh*Vs }! ,Floyd–Wars� .�61"�"!=j[,�E)&W�-�W>�V( MSP )s#K-��<"1g]J1.$'s p( �;� �K= �=�&Dmo? �)c"xO!Mj� >f:p��w.Y%�'�{toI�a��wt�!e�Mz$%&�2it�%\e �N.1�^e"�{!di !]!3��& ��*- & K� VOr�fn|�$%��^�9"S3I���f]2&�/�,2B\_ !��%:�i `�J� �6 8�#2�!�O/��������;2�e% &s,�p�f2�"c;T�7�f �L$K=�2mwe p���@"{2�ov�Me�� �-2Za*� �a �a"�q %~"���6�}iE �nAkx�lD%�<L>W��ll"s B i?�ie!�\M�0"oqL5��*B�/xq��outpua�n�iv��9>s&W �ver�NLA9���sub�6 �8IN�i�b7��-ach��!K�Lp x69fr ofE->�kݞ��.�Q�!���aG*�A#.g�, � Ey��7�i�q��s: �"B=�e�.<s 3'Q��um !Go I|&C U6isS'c�*��A�?u�!h%���YBi�a�o evalu�1M�~�_={��ed5�"�0wh��� �6 suc)� ��d�a� -coam1B~b�1�D���D /0>>uz�&1.R�*" pB��cMU's=��PM@>2A�QI! .���>�2��M;*�fw4M P same)�!�^*WsrF`<$ubseque(�� ��-<1!�)N�,*1^�>d)�0=�i?1a�dt *�B{!{��ter@S2lM�i0�,|9��R2]2Gy�."6�B|&�9i|3�y.$GJ91U6nj(\8|�)!�A -�a�ay�,1�%�I22��26"!��9&�.�&��Ma�҅� ��%�*��2�O�� ,]�:w� !bU�&~&�)d!�v �7R� y�/HGcM D�a��&�� �22�#�)&~K5rk �cBU"=�A�>4e}I��(� TbS1.� }�& ���M�%�'A6 ��e6.dKor�*3. 5X: J�bN2��.�r � �1p�HVg�u.=6�ov9�0NN^�ehE .q^!vF"��6�gec�by��UAI�‘���{ ( downloa9 6 ftp://ftp��ݞ4. jp/pub/kegg/%7A65)B'�i�� 327�  x53�=�1�250*397 ) Fw3�(��.�@���)%��&05!��8�.i��X*�F%*'!Zɽ2�wX1�#� ? 7[62�!�2@ofJ�nM3UA�R6��B� .;tru P�(a���ne�Y-���2��$."Hus�>Iu)n�%1[3�,m�a5�6�an�pA0??1 �-�Hn"�g) � & AA��l�.Z�xA�zw�Z�+" [�e�� ):.�@I s��B�fu�"� 6�� Q+"U-A�9�!�Ka:Mof 11.݀�'�#ranI Q,d�NCBI �l!3bA�&�&�%[6BRG�0:"�d< ion--Ve-,:i�109�-�(� �6�[6�IRW0"��smK&QAE���� vj?l�������A�!2y%�U�|�� ��" �"�>� .�JS�dtosoma$?�Aę���$�&immune�!q� T i"����on5(�:n-s_�+tiC�. Vacc�K01�/mn�,S . mansoni-AEc�&D3W�3^�"DJ%�>� �ont�hildh�}aFl2tch� �is 쁥 of praziq@���áT$Vz outc� i�SP�t�Ua�e I)H�%H\C� w( IMoChO{D�^iJ ntebbc9Ugand_H4ren aged 3–5_=��193.9T�61�n!(ed �en%R�4I%2bE���1:1:1a�io!_ recem 282 week�`j6,C e�of6+r 1!c[�3aj�. P�o$(-1�IgG%,uAP� rol%�,cnd@ ��[2A2�. P�by1��lg�&��3pagu�$w + +��bed� �!$���P"t6� @�%�n}42��Et�p)q2"}Y'2�to.�il%��q �s>�( adju��ge&w�anM( aGM�`> 4 [95% CI 2–7] ��pe5X%H^o�4| body�a!} ��odd�?A�a 1 [0 l9l. Au.RU��:�AAJf�2er�.���9�X2t�$a� +whoii`8<( E�biI2�,)cQ3 [ 5–i:8];<at68%�/8 6 1–=-$ty0FV,.di�tR/2�(�j>�(z�h?be-�)&[2Y�5�5�\S�0�%ol-poe VXbecst+} >oU$Bt.�T���ool�JG�{3dY��auc�~�>�n�a�gR��L�Y.Z��u"�Q���vB� ndemic po��s; �t����ia��[olg$be beneficx�b,*: � �M;bs%r� expl�@. ISRCTN87107592 t�t\K[�lgeograph�(�7� �Kn �A�l0\� '��: trop?te�G e�Ugn �ha��en��ly �; docua�q�regard!�2���BCG&q� �� ejF�* �5�dJ%2�.V�C>gЮlin�d=1hoiF!�ub-����Z �oG�5sb;�A&��adv��!�UUis�Rme�-,�=&at chro�@,) om� ��t�5�%nc0�>��%al�5����!�?%)[!�ATh�1 q!�I1� re�-�b=�)�ty!k5vi�e(�2�9",���. Despi��*f�discusE� !1=�$� �*o DvveY5a�i|��5� !Dzto youn#�f�(B_Ei 4–�$0hepatitis B [E Aetanu�xA[�Z�e1�Bf�2ge-�� 2l�un�U� N��C� )_t a�� �E�!��qi�%��u�+e_7� FItWusl� )!���w� month` In &e �i-@ �e��e]t��JJatHHoAa�y�#75%U “&�”� i Woy�S�.�aE.y � household��a�) 3)b!��1in6 ,1aMOo�iC�.� �4%�;. R@=Ѫoutbreak%�� %�<a&O,*x0,���of��:��T-d��qM ( 7A�!It��V! 5�A�\6H &�fJ�����7 !cir�����i�!Y�Q*z"s^e��RPU8A�+Ve�A �1V�v əprF� ,T�*� w��^B �>��–A�lZD!�O . Et� c%v�0�-&�f6uO�dVirus Research Institute S^6Td `Jamf, EN�� al Counci�.AT~3�=$y ( HS 130��\�0� r�, faZ�;ϱr guard_I �Un\\�u�%&��H�5�Bx�ia� *PA=�f( n-bl� 5�Z�x V|YaI�L�Z !K1�a�Q 27Ae��e ���� �[�; ] ��a.�::� �� ;AAa� ~<,"� ,,q�Febru�20�JMEy 2015mg�;Nr�( Kigungu , Kasenyi , Rwanjaba , Bugong�Nakiwogoji`h penins-3 of LG�Victo�Y.&��4�to �y/]���,re screeACn�&]#(Kato-Katz ta iqu��� "�+9#�9 hA2!��XQolȼ!�E�AFVe�}=� Divi& e Min!��:He��9��*�n"�>�� invi���C&�/��IBa�qo�I�m�4X�-��eu5,"i� �q�1 T�h�a�.jun"]i�^- , 85�#�i�lyn;�|��)�"��]�@lso&����Fo�F��b�A���&N �s+QEeA���nsecu[ � ED� g �� l��A�JY~/<�&:� PCR���2e �dƅ����4In brief , DNA�stl wA�ex���R� a QIAamp3A� Ki�!Qia9  purif�Rin-spium�<E $�< Nano drop 2000c%�dil�/(to 50ng/μl2 pec�+�n!��2�{ӻTaqman-b1��0�.Wple�� real?!56-!!0ų)Ssp48F , 124Rq Ssp78T-TRi� Texa�T d ( BHQ2�!Se����u�pa�e�> o� a cO�iVc�!f!a� A U~.�A�!)ae0�!o�NF�"�1oata�QQ� @BIORAD CFX96 Real��!�Bio-Rad#� ager.�I�y%���on%���z+�B� �V�e.rK"�"WO��\�d"�"E:�tm�[>e�a�G�A��R�( PZQ�Tw�*�RD, XBX?o�!�)d��&2F�?C>?�#ePRz(%.�.ne-�bl����`"�%�&j Y��a8by̓�$at 40 mg/k��@)��Jst2�gu5iE%6�] ����D�@xdV�pn%�R�D9I� c�3�g`8/�a�]u;A:StaR( SE 1mon 11 Cor�8US�,!�ata?c- ��6J�cw��or.&��(��a�eliveD[f��"�T*ea�envelo-s� ( teamu$oug6� s �+�DuEa_��BM �� me� _btj%]`=�$( Cipla Lt� 4Pantalgaanga ME Indi��!��K�h��^e . Mei6&9 1 mlM��Ce;�� farm� In� sFiat"� � S6� ��s�5are� P.���/Z���u�nB��R� . At���;at[C _�!] poi!�,:��C�$�r���Y "b !n4at -80°C untiY:ed� " ssay!���.- bo���end( ).(&`Iu�����.1�:�ora�!�U�Q�U�lgK Leveq^-U&�,� inŭݐD$D!M�ELISAI$hoA�� �a�v2 mmer�k O<gn(=!2�!!Rat�Z� �6�. D���B eb|� m�obj�vesV��b2h%w�^,dE>�w6s`H%as|(��R�hi��kZ.�  y,��G age;�`Y$�'� wRQa�L��!�Vq[ t��y���VA�=�%�ro@��=�M,�s�"D �.� R& 2p#2g �D�S$re- p.��:�UbC )�B�U,zJ�%�!/�1%�B�:�n�!��C��nRH>��49�Z����:uF� q�>H*R�^�1��iMY ( A( &%l!�~�Dhi8nt��a0aPMA~ 2�Y(eda�a�sk��nd��N.��*UnlI28�kM�sr1�^��#��`�>� �ŷn !4z�t4 �a(EQ!1��% k+) by�rr��W!3�$inu�7��topp!�tE�� 95%8f�DL� terv'�. L��.)G���6-.:xL�)�`EQ-as�$"��))saV�ous!<$thirty-sixy��+IK6��%�ofAW;252� 4%�+�)a��Fa��/^Allz-�*�jo! ��208 '"�� fiftI%de� ��� w e+u�u�J"�9ex�d:5f �.o� Ak���U ( n =�Ix.~�q� �5fira7�_6Sa,E L��,�MvA�178�!�� �m�2<3o�Oy�IY!�85� F;,�j-F_ b� �1uor BUJɂ !�f(�f'. O239&�� 9e2%RKor�v��tC��an�<�^��3 '�2�@apy"�s"�0�(. Oi 8>!7$7a'7H+0a+>�%�"�t.�R�#.f$A�153 ( 6�+f�HduNE� h,K" � ca>g&>bp��1"�"%|nH� 124/!�( 5�+9�R�2@�"##�Z���i�48 �2�-R�� >���$ , 29 M1!�MA;2<Z�� 3�1jVn�(XA�R�orI#A�aw of��a�5iP$��9w�%)��"m�d6�caf��ɦ"�siV2�re@L�(��(��'�� )�&�����^�n�" � :sum ��> `��+ R�R cofH"2#"hA��/�Iv� �0a�>e4\e��V�~I�6�g�d"<"���p[at  A�'ed>�22zvvd\,w=�0�!2&Q88 � .6�,� ?%�5] B–��.s � 1�/AUa�e� "�TFw g~%r$>��2�1�O&w w� .�.���:2��Zw � 1099�(� CI 85�P142pnd�O. 6"Ӥ2�a�>YV<�-M���:�S*5O�a5)6͟N�5u1.!25sGn =�205 2 C� |���U>��e1�Y�I��S4a�.�9�tP�d##��zW�Q"�3�ag�sexE!��T vari�?!]mt�, B;��q�� r�� N#��3B�p�e�551�>=5"�C�z&�lA�P)#�M�<.�sp sp�>n�!�!6B�%d-o\`s �12 m ��6k]qV_8� 6%+�~� 8%6��/:$24 smM�� 8.�F�:5ma~^m1�1�/�56"o��������D)�y�"T �T! a�EtoLl��hi�F72�. H� �%es,AE>�w�n�B#f3A�* y��5D�:�b_Dzd!>O0w���@4#':�61?Z��J�5}6#���.5A~�Nd3.TpB�8 ���)�W)4�����9�(��00�J��3e����3�!�};be2-�VF.RaRm;PI�N�8/5E+1�E{ ,V@ 1/54� %$���-act�b�K�)Bjo+,�����C)h%�A�](N��:.28n*)u=Z%�7 6�&�Q�2�65Yor.92�^ �� ^)10� :�Z�:2� 9E 7"��E9�&r"?2�}M�Vy��4�>�J�n.� 5M}�-Ga�����2����� n̤"X G�Zn*�UB�h6 /a@&�ng�]82�D{nz^QM� E��eY/J �ZH�A� I����o�Q85%a�Q�F�n{;~:� �.2CF2 ��E�m$%2�eyd� ��!A e��S%32.4B�n��>�6�. �2IhJ) �#� }�&\4;��BA5ek�5��&reI#��c&� ]��fK8.!���!��-�6� D6�dI*@!, 72/138��9���!"%Wow� 2�� .1���.�se]�ti�6$ IjH�1346� �5664.��%W:�ZtF��&)>)Sf 5 "">M�24%&& s �CgG��iGFt9�.�"��e]%��]( GM 180��124�262��M�%� Ji ��edJ��a$2379 ( 166� 340P a; aGM�A fK��iK>N2� "p >�,6!�8B� 2�I�" =sAO 65/7�K93 )�persis�~T-KU��J/ o 63/6Pc98<97�m��*=)6y tesZ"&�> Our� �s&�#�O.PI)�"�:�dZ'&�3n"�2Maj� A�AY��:5-J*{&i �>g�?t�chbe di��s��H5Z�oE5- �)�� � .�sbn�#=O�ng�ōb>I$1�d�w*�:�6"�:A[p��8,E"k6�q5a�.'�]<sI:�re�rfRFir�6��7 �&�&�@��L�c` FN9�32��Y�Hy oles}F�adu��.t��-�vc��/9&A_9.!3�!L�V�M2Z&k:�I�J!�chifb��r��x $ N�.���I evol�j�b&^?&|B]9r�<lya�|I ���r�9a�d�.�t"cAn�`�%({.7>h�A c�i �/ @:\�a\/t�x{!�.� �j ` �aIma.X�g�b(�Aa2�:ylfm�9b�T�+uqL�{!�pCe��Ax,c"�^"gr�>= "�>t��a��6�+��.��5����Т,"v@p.��.C"x$g q�� ۧ~t%� O��ten ��-!�a ario'u*�ɖ�\/��'דly7��@ntWMe��"(pla�':p!�%X.c ��t=�9�!3Q�L i$5*Fyc1u!!�0ooli�!�a�ha�"�h �B�d �!�Als!/w!5tTZA��-�dC3p!�Uy�� aN� q sp!(� term%�[&���(�aff��y tQ���`�E5��2P e��,genus Neisse=7AX5�)���i��&'W�"�:achA.r�١�9.`e])�^I7Q�z3R��2J�5��arj�ea�&! in BAPS��2 softT E�z>JU,http://web .� 4 . fi/fak/mnf/l /jc/N/ba�1 html . It.�&)�D�)y$er28pҢa v�p�Jhapa�-�%AyBhR�.dt Ycex�=�6�)��G*~oS r"�o����i"E\���Tgz�*~,�aona��cipLCof� ,�.�FL�u�o��eE-q�*9��wh0is@bE}� . .ip`Zen�0:xQ w��xuO�d�*��p�h�Vy5[1�j�I"�"/+da%i� dmix�V�LIy"\q8 ,��� \J e�+��F..Oi�..:��L~reb#B�"�<�w�wE��s��#!a? YX"h*t ���y� = _�H!Lo �5I�cDdu���sJb"��%e�iō��~���prokary��. Dis���:sJpgwufS9�s s�>.8r��rnE4�Jow��0B,!�a  �O " z1.��)h�up�*�p�'axono�KM�afz2ir=���.� Y�e^�_u����ed�X/��cer�;AMY6���=��a�(Z .��n�_� c.�.�virulJK!��Όre, aq�B�(�z�j "y�żE�H�y��:iso� o�=�Dbeen made possiblea�a clasY%��ic Markov chain Monte Carlo ( MCMC ) ��s [10!�E��Kd%�Q�� �,to molecular�i . Despite'succe �6st��yap��$in a varie)�s~��.�,11�-,mU clea�lbot%�oree@��nd pracALat�$performanc%�F��W�8 decreases rapia�a��B�|�5estima�viestrucA��lizxinv6g6�� int-�[12a�To addr!f this�frraEש��E2��!iaT��y�softwa�4BAPS [13]–[1�H�Jw�M�- a graph��cha!] eriz �of���ipataA(s from MLST �u��a weigh����:�ly�d ntif�o9Ss!�mw nodes�!H)~average�2e DNA tra��ion@r vee; flow ��� Also��6�e� represen��oe�!�y A�I�2�nd- ir affini�&,towards each� . We�ma{%�Mzge shapEJanV*2�ɇ importantUnotica�at���Xid5xbyImay ha��� erenA�terpre-inevolu!o��c��x%]The Rf �Yt�v wy�9Le� a���links��g�� grou�0strains toget% in termEsu�i�' simi��Hnucleotide frequenc�). Thua`��2� !in��cvisA)!� � issco�6�DestryE�cK  �E . In%% rasta�]3��aA�be1#aeXAw(traces left!�6� e� ^ %�A� considera�PATi betw�p8separate lineag��1b.q$$under cert�scircum)!�(more heteroaous.�!Ka%>!7ogouslyA�l� rz at�AH!�p* !�in�2I q(n very limi�^um>���59corresp*ng�m� am�!f�yzed s��(lsaCree c�(?il!?� our @�H . Asiis cap%�of t� 2"� (inct biolog�~ signx hidde%y/�F,��.�ͣmbA?y�s mustA^ doneE� c�,��p� ably�j� l�Ka�.�Յ��auxili#� ledge, u�1�IB� �P.��9D!e�� x�\atM�!b��ope!~A�I�6�)�! 5086��fe)�E� Las Neisseria meningid ɀ0lactamica spe�PWQ so!K�7Yof��� : � to dem�aA|pot��a �"5 "Y to handleB� !�-3e��9���A�O.�2�a2�insᾡk\�A7 best� by bi!- sa���A1�of-$is . Assum!�� �'���steہ^� u1,�+iʩ!Tex!Tv=��i�be�� ed . Usua�,%H9/^D associ� w it%% iori" ��!�*�9͍~ed later� �l�e etai�{� �i�s��om>."� aimA,. �strengthD�) ,via a stocha�R� !A�%�&��E}B.� . Le��index).A�let&i �uO& 6� H acquir��� ���1`!L:S..<s? couldA��stood� � ggre� resulEMPcur ly��(n mechanismI njug5 ,� nsdu���� � � C���F� "ta����un� ��%#� .Qo=q0Bernoulli tri�n�_rI3bi� outcom�g�#e?! /fail�ofBX%�� *� sourc� ThAˁN obviqʼns� i, a�,p!"a�b�a y al� u�*� ^V. W� �N����%?5 Y�I�yA%.h^.*we no/aE| real��"N ��]c�uunH#� nt� d+s!~i� vA�2{ timeM� MIa�suma(��a2�E(��j &! hasi%wu`!$%( i .�we� ttemp �fy8�� $ �� � �oce\d "�� � s� A=A m~tud��.c(break-point��s desig5a8a� e y6I � e^ve&Fh h* ter�.�17V^For ]� he focuYs typ-�|� small � aHshort vi�IgenomE�to�h)OloYXA��vR.�.\ taken pla%DI�i most�ic��m ,:� I�a homo�K� spat�Poisson0*.P �&� �!�2�sQ�$)!��,)gE�$A�i]��S"O. I�h�7wE��/ �M��l!���eq�toutotal l�]�q��Q�,eQ1$�ribA ( 1 )M5j���!-HinmB �� r!��}�to�6�H�?��wA:��ed��he6q��be.cl�f &�a�NbyS K8maximum likelih�YeC arrA��.��e�ō�!:�� n�s��� framen ,vde��a matrix`&h!>^e )�I Fur� P� K,I' 5!5� collec�f heU�!.< b�direc!��].��Zh�| de su j arc. Each!towA@F nowf:� � depic#`!!+�EnEc��"3,Kenh  1 wbe def��Z�d-4wt-Rpr�K e�&con�Ku� diag�Cs^n li�b�:o%� hs���ow�. Whe� 1�zer2dn�al�)n� �.tarZ��bi�.�� 7% ��s�A��rem�unr 7w�C�T Xe��� suit/reymUũ!R figu5!�� k�y�a�:�l������!fm5ac�uF -�fac7 �l(AH� &h,2p�@5: well!th�&K�h a�i�< �� . Modern&�.��[utiliz!Z ,e-of-the-art$�v!ar rincip�w ough: &�5�se&��ſ%� ��t�.� A$�"�i:- Zsugge�E�� l� or&�s wK M�beyon  boun�6�s tGA�^ �|�ply Pd=�� I�is!� cruc�,%�ovy)�� lems� ireB9 s�V a broad cy a+!Q�q��he Rn��� f,s�anx�9;A� ateg�$@ 4 eEmQ<9 managee����8lUill!vidA�a� son7A�E�AhF�m�x%�A��� ����q-�s!�� ���� e!� a �dA݁�al� �Q�a��& ic regm#in"�l%@inAA!scaten�_G%'&> �� ��j: �o_E.�iV�A@ w�anAtb��\ ���Iw!�be�!�Mhe�"� !�t)M*p!%Y��$"l%��debM(�MA�I��!ve�2� � ���s*� zto=E�� �.��af%uoeM[‘ `’%�‘CE��ey��athemat��ly , ( )!�a"~ �s%�R .� ,%y� . Symbol�e� spB !ll�d1�V a( .U! ,zdin� -���]�Ja �� earli5>$in>, ���� &�}e��J�Al"vr!vab���AnW>�.typ ��lin�:E�.9� motiv -R�"�$reGly deH e� [20]�A�A�s��GA�*ehyp �&�M�a�%8y �,�9E �qw��xksG%M�y�!�a�Fub^%���G�X�'��ia�>�7ݱr�.| I�9" untyMZX&� �� HI$ty�"�uMi\E �Tg���3 meas~( 2"@�E]rgaf*� UY��m&�#��*����f.42L�V�� byiQ' rule� oa�g�( 3 )"���a -)&"m 1��-�E��po� a� ( 4 ) orO$y �lye�a&%D rs� �by.�optim ", Ky�%M| �'decisivosup� aXa "��<. M}(� numer��obq:�7;*��(@#,q�� mJ��!.�`6�I a�9ie99R�& \f^���� ( 5E�� encapsa�symme< &�r� �r��� e0pecific labelmI*m� ��"j "�.�w� !�bE�A$�H"�)to"�(ly2�A��&x .�Af ]HaweLoi� �#Rlinkag�� developI� [15]�M�� ")N� !y �iM!k!� ��:�i�6�. pend("��h>?���'a�a{� �#a��/�'B �#9�E\i~wnN�"y��� @ �  p�B��G orizAZc�p�>�. U"� �!�.��so ��ed�/er- E!���laN�0nomial-Dirich�.=A�D2�al�g9F�� y� valu�S%�is ���of (, beca�h it e � Mx�3 an eG$ }(�"U)-favoids2�)error�&6!XJ�$2�AP2�smq�!AMa5��In.�it<��}� �eH6� M!s�&"�-6!�vul#,blv-mis� !CK B9s;�%toza��a"�& . Gie+a�u��"� 2! u� �&�}^9*"c-�,�'+o�ja)R(^f��&bP%��A�y�AW�R� ��;��60��is-Qg J� | t7isB �BR��)3�@at�AA� ^ ��0!�lea�v F� .<!f")O� -�discus# �4� In��t^ �e� scribed!�rA�t�*��E���KA��#"T+qO٠.��� ne�ar�0i�+�Gk effe�.C&�(� el� � � )v�1��` n�'|%�a�2�A-K/E3a�always�_ a funO ��.�"�Rt3 resolv�-� � weakN�/�2igh�� �d!"8�1�J�u!����m A���s�!�  versA� ��,"�,; .� J�!!X)�sI� :Y']乾>5 6]�E�6of����=� .dx & q�!&s$�&� .�.e �n�5e� A#��gs@2���a�v,] vectoW�co���1,]#� "oy��oi�EQ�Ys� -�c2�.�U� ��^�&P-�Q "j��. �%gIX6W�i�&�D#aina�de� � ( 6 )6F :a 1�� re�E�|"� 4 �edi} ",AJ!�un�I�Fn��&�^*�'[�n�^�.� !l&�5 ntir� pl�y 3Mv.�F�|. �6g���4�"F+h��u9��"%�∼ . 1! 2:�refJng3 random fl��o#]6�.�%al2�2&#;� abcissue��c�%r)� �s5�]��I�� null] o�iERn2mix� nZ.0[ ly��7Y&��$�Mz >�1��ol��)} �:�. Firs,=�Q�d* :9Y��!Q! J6�I�NZ1R%syM�2�#&!C� .�( 7���A*d�5or�c"�!9-j argu�|8tru� �x%!�r��� piW !�]W�2&�&m�of#5ig �t ))�(d"e,K!0u:���+eR2pI a��%��� B4-�takA�Z$* �*�.�sh*� ic� j>�ignoreR0�igu>�e�orѠ�"�*�ps.*�en�"d  quite�'G3��^\A9�A5#c'p� xndE��Iv# ��-�%%��r�.�� i l .(tretm N�ed9�����o!���A�W� �$�w� )"�- NH4�2�G�6� q��0S=� 7#Ɏ*0ng.�NY Et�!Eex�QiiR+ofB�Ͱ rDA�or1�ɜ�2�3sho�.iY�-����r&�*In tur!�mn��veaL!�&t!>��6O 1^d�2� ){!s2Q M �D j &�  �k:7�tE- -i �&imO4�^�$a*++8�#j@51%ly9 S" S2�M� RESULTS s� o)��zaci&q�n|A�tC �?�JTr&� -)�Y# �v�4ted� xaW -�i3Y�.�e������meaX sses"�&�a�isoA.0! U2�r2�"� m� &!4lea!=open qu��BŦ��)����}G�� deJmm/2c�9s]B1 �.�o�*ar�> ccup:0�xA��_��we�-Dt9 . By&� w�$fer b�< �&&7��-�~2i& *�$y*-:�Cts?"<:ZV& ��W�5ll}i�����M*�8 E���q�B� �'l�B �>�?"S.g�n �F5�� geoic6�a��4eno�Ddim� �( 1–E .�i"�Hvi�8�,.�� � �>*�$�#-t���v#"�A��n�G%ύf&R:"#>� �;"O ly]�z:�%L�.z��-�!AJ� t)�a kerneY��f"\ *�>]��d"�bT �m&� inb 5�A�! outputs�/� dpl�d �cur_ a,0"��"�Gaussg �N"�V,al bandwidth9ea� �L2^Ej*�"9�(�< � j�1 �� devi-�.rH:�eաQ�Ad.��e~o h�t�6�f}���&�+a�+�-5�%k �ed&� 3�gF���a "2H"�:�16� �# hang?��(?d.BQ�t� QT��:,pt�?_aE A�e!rat !/�!aW7ac�6!���et&�*9js� &��*a w!�"nI scenarios�Jb�%Up��n%���02 a!�pl�$, y<<a�,29K �<l2��� N�� 4Oj7o�HA�q$ back��9���\ust �J�,H25D�!� whol�"�6,�")�aF YE���u)I"� a*� � u�f2*� 60P%9 I F2e�6��[!�0l �we� �#ly-�W%&n �%)/ �O3D B A�A�!h�3N/@bB��A#pE"jL�2th!�a$Ce|2�w P2b��� )�E �0.�LaZ"�of � m�1�6e  cc 9�+w�=ecu� stD1wA�Y&��!$� ^)�5@�� 6�Je-1A�bR�-�H�& @2@:[�Ie-sTu�1 ��E �SIe�a�;stt* per E$ �!�A8/� s [2KKa�&\7 >�1e:���~} di�f(z ���"ge= s��eَs��A�.R%3�O2�i A�&>1 &jtl_]�a?�%!)at be seg�@a!SA�Le�7m��#�:1VqVe8Ag."p� &�FW!X�a�!�� �`���%��To��!�e(~"P,�H�*�� J:�!�A��~)=A(,�&%�ts"AL.� A�y�M��0��"�E%�!AM_6a Kne�Stom� �!v�m��m�V=l)I-�^�0y�#D��"<%!ht�H"�22�!�(2)��ri�:/%��a�%�.=siDQ�0f=)!� ""��#ZSIW�2.RE�dAA �m p-�"�by� Ew� e��;-{��%Dwo>�e��5@e���y���-1R�J�Raa6B �so��di5!4yQ� �aw%4!��_4G5=�| alwaTAV2t S.$bb#)\u�&q�-Uy�6gWe�,�&�@� .� E�%HZ8�9�&�a>;�'Win2e�e!�i�ysF" I�&� ZFՋ6�2�!]FY�|,%!aY�2�[9v2} 9��Q�tN stepaT !!JB� of 5002&,A "M=a0n�$��)six.�a 6� � a]Ai;X�V�O���� or9�.�0 . 8I�-�!�$AF[=qF>���ng|>�V*�>{q�I.���Ѯ�imse$!Sc:/y�i�-pS u�ac�)�%> !)�6E&. U"�p"2(d&�*��2 ���?wC�Xacor)m � �� A9��.�Y�"�67&P�LBa�Zfr#C0 �� *���reP��� Yof )��L choo%N �H���n"2Oa�!�kI9��*�� ct�9\!W@G.��ɂ96K@5T�`" W top� �I7S �N"�IeVB�Mer'� e��c.�LTQ� �YzB& a�r%�"4 `6<� af�,�Gig2U�R!I?i& -�K4 � Umak�c*� �/MQ�,��Zgy#��fav�(���ve.'��cBl�Hr{-y� F����m[#�)y2 ) qA� &O Zr�:~) %�� h�39e9�"` a&�E��^�A:���>�U�\�]W�U]rP� 7�=l)ky8e�U b�*�%��&1��J�S!/6Xa� �Q 1"s m1R � turb$�ywq!�D�A 25`�$)�/.*�&% vblu!�2�oA2� �.�"�Hno� Q��To*� �re�Eed"�2��!�al���]b�Uto�&��. (V5-lDL1n�K�>UBa~bAcunambiguQ&*� �U2&`�����Di�@  housekeexg|'"/ ncl�Mzabc Z�[dlIaro EP? um COdh& dh Cepgm Lo I��nd.�N% ��� �� �rV=ٲ�!public�c2p_( H!���6Ap% �5�z inhb�0W=� %�a)%-N&�!�~9�.�,*&j a\�s:�& repe&��;�J���!� se 5 1s )�� ��� check�g�&�j! pa fagrees%�$��^Md<c�"=3^��)_l WA�idoCws�U6��&Y: powecaY� ct2E"#��avail� 1�is.}^�9� .N�W=�+& ,p�_� t �&o @ %**&!�be"<� d ��sN)�fD�k� �D plot�Z!pa����.tinF�I�B- P$ntQ r.D#��ȱ����"��M*� a� '9G en�o2 whe� I��Xx "�( e�4QwXى�! we!� !`}�&[a� ingl �eZ��ex' d��#gha1!~J�A�/�,��f ��^�Po�c�`�h]q&-#��O�"�0�^l i veWBd� e�! { �Ne�C�+El�.*�4��B �?"bT��7ncoNA�outgo!w�ehe1!2Q��4A;l�8�E�b . P*[b9��Z%6m)F,MEGA v . 4 .2 [27�N8(-Jo_( NJ )�)��P�*!��X#�o��(U*5�A_A��!'�%� !*. eBURST��!B defa�\�!ashe�ine�.�  3�at ebur * [28] . �fAV2��"�%�c��"aif.)t�6ic� ��3��*n[z"%,q�(I�J�mMHD�RnI�^( RI )O%ALM%9] � �lEugrey-�map ( � �'�_6iea Z&�)��&�~����b�|3�%Z�9m71�6 Efi!q� a cri]0�eshol*X1fi�� �Se� �Ji drop�Ick %J8V�e0K.���d�7)�a)�q�.yxs"bR�&an G  match�urt _ex"i"�+9��|� obsc>��!^��x" look��i�+=aɉ��� YwI'孅Vz("�OG:ME�&�]�u; Ham�k�!�ebKe�Wvu�a,y ) ��Q��6cG �MM�s� fa�>�A?BA��;�#j.�*�u��\k� ��5�a6�Tif=�AxA�i�q�"FVe�h!T� s� ��!�.L�m5I*Ga �0G 9j"�E��!"4#6^U��[y�Yt@to I�a�r�0���by�o� �a}Fs@rmonyFE&� ; ��6})5emerg�87A�7!�� r�U"�rP Q3�E�D�L<%�6v�%actI� cohe/force �9 a�}l���E�poo�= ��U�prM r..�5� =6�!�� �2-u�,=k�IM�d/�?�pV$BcI1 S�QHW[��_%3f1ex�xu��6 l� 2 ~/��sp Vgafmeas0ful�8\x]�L\i1e�b�.b)�Yre�G�Ff"�l�&E��� uto�!akA dyz*Ezv�7���caf-ali�S!��<%�if$&��.�;l}7�~2�9!|A#�Bn SS� n� *� �.�6�\�Ga1-BA1�#ta�v8 &� tudy*� �G3bt��� �1��=%DT�QX����~6�2|lpe.�1aS�X"M 6@#b i.K25�a�K�Fai�zi �-x%�2G:&v.R�=&�46�af�i�Xg�36�! E9� ����.MQ;U�.|h�YdHWJ$T�[;A;"�1���"L&e�.%EA&ty�8�O�1IJa�Q�En 5EF��&�7 �� �2���="�+E�T /M�+fA�>!I"13sqEv��b^influ^2@b#.WXd4!+lso�!!� ��%#<�.�/�z2!�[ 1 ( ��) !=:3 ( �{���� shif���t��)`�Yh�Q clos� ��y�|"� �!3s��*{�#2,�!�]/don/L2Us 1��-��U. O �oN:Fappea�j@"�']v���y exhibarin8J�1Zbe� �AW&  3b%w� 2do%0sF %_We�u[bi-mod�]�+a6:a-���S{ca�#2� my>��,32��� �e9!%.)(Sa s 8 , 29)�!�beO�VA�!8&~8292cA� U dF2� iq.WUobustnty� ��ݳi�;�"� r邉�Ww�12���b %D 9b"F9�/�0ELg1�$ion"�Axm)6�Madj�|d.�� � � �i�i. &r�dA�c >�jR$�g�gɮc�]� t�b �*�{�{�!D��{"�R%i"�An�:�&�o�IZ?S6V"Y ��:o2� &&�kmT- ��x�O"�;�1%|iD=^ s"r-�"�%�w��lA=�S� .Lm�ElUhlhigb3���b,i�2ly y$P�&� ���!O:n�a�*H&�*7 Z.was&' byjSk� I? �r*�F�{"��\�:U�>�� �+32]�� U�T�;g�#!H69T��1}o� m��6��� .kP"�+� w�Yy�A�v� E@�.c�� ��$Ng���"�r��;���,P�&�.���G��"� 2�[gdh!a/�dY�A�� q? �j�3am �F4�(�) o�r����*T20a~��.�o "�nah &c�����eri�\ D^[$"���e� *"�%4roE!E%3d� s�i Xa>l'�Sa3�!w�e�l "s_U\��8�QUd� Qof�@ 6��p��B ,!>xt"�to82.;��*ai�����5��. �=h��K }Agk!8���1!j�6"s>w�Vs�6�[ �:38e?32e�e��,aE�< ��H �:�WcE�c���a�<!��P!E���AXuWt �A�yu���8Y%���#$� �f253.��% 1165� glet* � e bi%� 0��795���#���   e advIcur >�hn95!qe t� 22t��2*� d�9��@ord$2V-?I�\.K. DueA�!d��*d 6E,�yS�qa�" 20���)�C��8, >���st:}�� m 1E�"�$B��e� ��majy��oFy7Jwe5��&� f�n ���l��9P��uy��T� "%@)K+" W�+a"a��&n�!-�-���beA>��%n2.�,nm N�rm>!xx�a.*�nomal,��-�*�'l�ce��e��,� ^&%�HsW mchRM��s.b\p�<min*�%� P���A� Z� �:aT� a66��X�]�O(!A]�7an�5�"t �4�x�&� " ����5 {�!ic� Ou48����.�of�g&� Q�.K F9m�AW��%mA�n �U_(  14 ,u�~~S��2�.�aH prim._.�iD�[{�x?.fsդBoA�K � :��^��+f"�Qͮ��I6�P�!%�E��t� %��(GH1�9color� � a�9!�Ohi%H"?Q_Me� ��\6Z� �%����F9v�A&2�it2b�#\I�u��iJly-r�.rG��a-��$tB>��ANX<�taneo܇�Z"�!f�!l R1 diI��s 9–1=C of� �Gh�)a�O*-�%�6%�^q�1��5zI�out�+�-pu�nA�=)kwh�B�l�,S�:�A��*E�f�DS��1x�Rly�gMW ���i;0 uish9%�)���"gX ��<�Hre�B8%�9Qho��2]���&��-c.^!?�M ��.�>!+A�� c\,&�U �iw 3 !�F Kہ�g.�>ho2p"13�e!d ��&qxF�!� �[J$�J%k�[5M��Fnr Apn*.����"� �!@�\�P��( � aQ 2�Qa>!��p/sprea`��*�+u�a-�E3�BSe dil�W� .\)!#, D.+ ��`q �;�W.��,ͨ�2�5.(���RB5"�F�x.�GwFpr�*�:recipR��5� �V0�i�,Glt&��o��1A�S"�' 10 )A#��e � ��d.����S�� !�� � č��%K�-�In"� E1iK]eA��3�_tin" xscՃ�k� c?�r���l$s> � &�&�f�M� M=�:�a�3^"?��qV�und�7eLN� 4 A��.&zinvgn&W. P9!299Ҋv)t&5as6�k&F 6w!E.i&�x a �=��ofn ococ >���5�STzm����%�.z!I+ �<�T�E, ,�2A�Ae>Q�"bZ� u�j 8A�ap� nT%�X\�FE�%&� �ntV29L�5��Aj�I��U�arE 'e� _bl��Es3� ��3p�1�zpm�fY�r�Mb�in2.�� �YsM��� .6�Q2�29az�a�).�(te�A�)I�U  ��Q�rad)(2&32!��me"..D%���!�.�V�A� *iW � NHe� �A<b���Z�mW!E�Tso-�pfuzzy f/ ) �&�b8�)��F1�� � edL5](A� l'"� VJe�" >(^�7*�j6 �E{_.��s� ami�4ᄙ�3&f at 4!22%/Ec2B&� V�eI`�Ujblt"�'eiv��و�1��3%qR6�(� U%x�y6?]�u�ImE}W�o!y� a6**5nd�adsj �-E�. I)��Q rk�E"*�K��� ��tools>.8C!r��"�`��� �-I�b"�*=d"#'km�He(� unpr9mG&F��q�K�.4A� <|��s"D'O��*Ęp��� 2�|GP6  r�e~��/���* a� &MR�"�e- te*�q� � �%�&�jae�f�=X%+�P1�ly valid��&*?!U>5�n�vs fai�o<@,3A�]�.A��� no!�E�)�N�'j"�8�e�Lto���*�tr���+U`�� �,�*�=��9� � �.;2W .�"�!MLA"�a} U �i�y ��& *9U�n& Y4)o65 A%LIr!K��inʣ� 95 CPU�@[��U�PC- a[%8 GHz P"- um 4��1ocUAXc/oH �֛al%�r�[t8 � STRUCTUREy��s(%mer|2<7M c�58hadM�u� E#saT�2��sy~ mach�52�,<�X/oI�s>�)GibbsMpU&�_� �;�S+o"3h�!�4[10$5"& �]Udna-YFMaY#A��m���ik� �c&�AA�#�eax�a�2l�x�*��^R>�C�2�0)�݇�a� �B��%�&l R�*lev� &?��!vB01epidem&�&�e�сI��B"Vv*���_i�a��?*��out�ek�M��f|6� *�7virule�[ntibi�Br\�ta� � +'IR` �.$/A�*4ep|�<~;+%l��Mi&��S �&�!R&�-� ɤ;�%6Q!Y�3"��0���Z�',!�Tntr�lng::Bf2&�A �th"��!P earc4Nama:Q;A�log�Nd� .�A�Ŕ:��bR �J ‘f#�gy}�>9)�� �me%�<v'A%t()�y�‘E!�b2�*�G�4 ٝt*{&z&� triv��Ke)1e mini-_ ��z��!�go!�?�A�"wb���b1� J/�-s��! )= ��a�L�at ^�Sner��"�&%C� !V��'�&K Qnalogy��physicsSy��� y J S�-yst:#)r,�"X�� 5Qh.�E�er9>Al���� nteg�(d&� advo?�e��0a^f2cble�of�-] %v�L_���a�:�\ ��Ji�s��.�r8 RQ D!�q�B#Iv͜��šl�^!995s��r�/�y��`1� &Qj�p&� W@ genu�vepzU^�5.n�z8�~.i* ~2��E."4&� %Z&�8o�A@o' �E2.d�� $hl"�k�di~! . Se��Oa� ��&��e5&�sa��gd� en9���I(s�d�| ,Ee] 9|pCsuper� 9�g��~�1�A�A� �C���6A�is2LMGZ%����Sh>a�}��7�9�&}��EP)%�d�� -spa�9In "`Nmee� Nr"fuk<(E�"�*�n�q��Oټ� ��v�2}* .�am��d&�E�6� fng6 Bb72�A�}J]5?� "����onv8 �E6�]�0KEc�C en"�"��) &�܁Qa~�!��&�# �'� 6 Arm R�=P path�V�"- /+ �&��9&(human healt�M�s�O1T(1-��+�=I�A4ur�*5 � �i�IonB� �_��I"�2=r.m:"<d #-heF�Y Jghl�%Ʃ�2F����"-j b�;UU <�f*�]9 E9��u� on�)o�at�T��tegA0ArFa�q � Ikvacci@wlso!,e�<6:31�0 �8�)��h!B�y�M2�m6OO [32]E�[3�=C�#ɠs�oI�E�ؓ�o>��!�9�!/in.�i*q [34��36�G/�5��a�ɔr �1���:o�f�Q �!)2ed� lo-L�K�rM�.�c�uS#Yś� . � � �-L a?\=a� & 2�CspV�Ty uE' w.Q�Mq����draw   �-��$a� ?i�F .��I9���atAˤ* o�gE�*�S.�6���z!eaX�MX^��B�� A�2 shed new �o*�e��!SV�������n���a� ec`XGni�D.S�CoX� al rhythm.��� (�lay"���%�I gO��D%�a6. RMic � v�4� beta�QcyCl�Q20 Hz�Uas$"QSo�u�%}neub c�B�s�#YB!��#��<top-d�!��,EYE �*s'���!*!fdel�e� "�ensory������� al gyod=a�n& elucKSkM�c[)mKU!:���1N]-5 ��t "*Ηi�K�c1� ��7k�yAC�#.R5�%�Ba�O� synapS proj�oJC-RL5a�L4� L2/3�h�?or bia��compe9�  ficllay?��a� , slow-in];!� rA%�U 6sp�?�:I� inpu^�d!7!���M�J� n9�- �W anne�plGed�*�H5�mcel�JQ4�/ }!5�� gchoc#rgic d��%�Q�Re�tElE �WmlyI]stY9e.Q3�Qz �d%�JL�6impac�i�I�<%�m.A�ex: E�! spika�5n[1�C4��en�FdAbchronJA�f[559]�NnY!�d�h.�[unst��j�F" � �a"end J��$,!�sum�O���_"m:ar�,Zp,E�2rlnRi��-�Q+1rol!��Zi��o���1/Z1>Ea2fd!�zI,N��� ktaf+�]"#�Y���/��NR6�p �I�2c�La:��%���[18b9X�/iD�T��k&� �*�"�Qb��F�� if�g�DN�chiev��W3HavN �YLUA�paHP A� N$in vitrߟ�9a�>]`dq���7t*x��P!M( IB F6gu1���4( RS ) pyramid8S��!?259"��j��TS �)�#ľ�&�-@��%�1�1el�Q!��/y audit�H��1A�%2D g t���( �e�[)KrQ&�D �AAn�:|W�,rZ�<� �l"� >3( SgQE���a���b5q*E)�  ir f�p�hr� ��r-�,���]ng��AC�PQ�&$7ax� !X dendQ�5ph� yi�vaKg�� 6S �a&.�N!�.%?z����= �/�()�q�-!�jA R � E ��!r�t" ki���E�o �^1��f��]�M:/notti�� !7� A�ala+v:�ly�&e8`&M��ex�,�across&e la%e [�S, �J�G�7D , Dantzker & Call(9o2*�9aоad ng6�V� %Lre�$�+,�� 9 s [3@��Psj9A�2[p�l�=dm #>T'� ��q��#��_� @ � @�Aof �A�." �"6=�. A.�8nexcK�<9A)eC� pqvinB�m��7�J�e� . e�*� TAE�� �funda�=��c�c_�R���j!O%ew 5p�n(4y , Xiang et aZE]I2%�acetyl ��ola�X9� ��2�{ !' !J���l1\��| ���� L5mr�'3 A/5 �%��ac�C�|�-eE;M%X.%�*q)�T�qW��SI �:��jel56� �is �s . D���#de��>o�F�b5� ��Eq oR% %G"1�)�|4�+�c�& U?-��d e RFaR�"�5ly � �%�a`!�,`SI-BAUѦ`!y��� ���.� s�'ll�X� %Ra�!�equ�~�ѥ = D a(�2��%��i�fm*�&al&�Z Jm:aIx�3c-&�2�!�"A.4v �by�4OY� �� �pW;g :� "�5"< ta�m@�� "� l� "6 F{"�u2"�B� \��i�5Ypa[4Yd� ��ofa�D~ =B#E� G��IB%R��A�śG��1��trong- �-���>F*v HB�E� a�;nn�$#H"Q��FL: q�x�j� N:i6�0VGѵdY�V� �c�E&� ����Q�!6���Z��o���=� !�RF኱2�>hA/ @a�g�M����in)�,fUre�96h"ac�JHB A�<U@.%?B$n2���>��ƭ�a֩4E5��a2!c�&�� �d G��r �\%&�eEVq�V42�M%&�v�l�I{��,� Bo% !5�r lay ����durAH��5�>��(:�ɐA�"�}ɝ:��5K  $5�m���;�Q�N=Q& ?F�e  V�H/w]!�� 6���"�d!�q a�2��D� ��96Hu6"H}G ">in Kap�*47] �.*i��v��=!�5q)�I5����b�B�I�A�:�U�2�C.��U�� � a���� n<Z ?"D 3.� ![Ga5�!Pny�:c �/&st�5��Hur� a ���� �a�  ��� �2!�;'n"�*�!ctD��glong--Ca�c݀�m"v &�6)V9[4xT�V&Ԉr@�Bre=Ui>"a]�0D�� (�2uge"�1E�!:ibVA�@o�wp��-(s��dyn��>�!�!���%�6ceY.�a�U�-�)� icipQi"8-�_ =2�D�@Po Ed��&wo��29��i��.�?�*�g!=Q!�\n�s ���O"uP��"�"�cm* ��o� c�!DBc�k3mE��fi\ց�3,A�snae�[4-�Sz � "251!�ad] � of n%iPQ�[5ȊI*�L,�&i� �>aty�h�@�m)$?��x�+!�&2��H�� , [5�w] .**4&�� ��o�$5FA�a�6���d},I~���.wQ.�a�up���J BM��N�!:Z�.� i �"A?� .e* Yr&'�!P"��#"0��K `3��t!� al v��sN��]key&�:_is F�r� whLo!�MRA�� *W *X �i<�c%�#x-)7f�� � J� -Z�&m$Ozeki*�4] �>7�~� �Ap!�*e}�<r� �#sN�� R Uha� heG�D�|�*NC"XC�)�halam{.�$2� 5�4!Ry2�# deb��[55�!h7�l�ng&� ( 1�tY�V2�� ��yWhx3RFy~����ea"��/.6!.5��[54 "�5`5Y^$[ � talk> C� #� on�ubew� -"7`ent: Adesnik & Scanziani %0�E1!3Qx.�-�e�v;v anesthetma!8�?a�!������Q�D%�iA4/�� � �����F �V��d far� �Dom3>� �he�FQ�n�,a��uJ,�m,=J�he8X 5('z�g��ųo ȭik �alpha/ ���� >�/Fig�=R� .!iZ�amonkey"�(6HQ`& 7?&�A!a)2^ "YjG � )�)�=7to �5J�6� �']�TQ�=�aKsu B� o% 6�&�����4BQ&`om&��aEC��.���B��� ,O )sK�J�O�ly O'& 82LGNO��"A $0 ��  [5& "� �1 ͰG�1�)�e�ma#�)ob7( T7�.�[6� 61];E��*C 6� B�� wo&� a�aW�2X ��t,,)3e�l� J�� VI� 2��r� �u��I�eQRE�/P6`���#"I��@oJ���.Gt [1)Kj����+63] jٵ� �$un@�Nv;&3-  ," as-�Ao�'&�:�6�'�b$��5�.n !�wi*.��!;M*�#i�8ixJ/�h*{A R%�Iby Ar0"64 **��|!�I�!s"z,*Zc ^o:! �!�A!i=ga!�� �i>�/;�`&< ;at)�c*�2�. Xh ��n�8 =th� %^N�2�.Ew. � nove1S�:��teR�=#*!'�<i��� �D��E�a�/ L�.EϞ�20�!dop�G!�hierarcV� �r�au�by Felle�9& Van Esz:�6t d;�'J� yls�5�m��Q�w[6� 66]; L5B���L2��L3A)� �O�x3[3Z."4 - ����cu�on�%-wSZR�� �)F � m&��,�46�-�2.� 6s.�-�&�r1lD.$�*?{�!�6|b��E�z:�*� of}��vm%�;Zp�Taj� �A���B":#!s&cMi{�"�>� 5����d�.��E�Ep5l��? , Roopun��B�*� .m!�&�� �)�)`(:�B�� �5�w.!"�&z��4! Pr:7+ i�oQ.�U Aa�*�AA�H:�]?R ]!��atiz6�of S2 e��>e�B#AhA *7)�*smi��2�5� a.�"�-i���LgPA1� %�(A1OQ�@�wnC�to��"�!^'�M�m&�`��o- Xu��[ �A�S2q^distK&Z�g�� Ԋ�-8�Eyi�D/ l�g/%��AeedfoX���"Fo�Mb�?�Lф0�t\ �6V)fTx�<�-�thw�p�2�Ue�Aon��:!!�2bBA�z �9phaU�^d�e� 2Vၲ�%�(a��> �by irr�';V�)iIF5�d� �[6��6[ Spaak�x70�%��a!��q�V�i6;;.��BuffaloT�2�R:YSFC��& e6A.��6���[Pi�Kd� �D7 \�e��g"�("�6�&`2< ; Saal�1�7'!&^� pulv1��\r"L .�:AV�nVs:-�}�-}� n&AU:'� �gA��5.-�@.���e���˝����� &ի�20,� c}�ah.��*A�� ]icA\+ ��n��.� f�DofVi�'�A�C*={�>*@:i8,��( 8�a5�,)ec��&� ( t-�, ).�,.2� !ԁ�a�!'z%N+F;�IZ}M��:%( 15–2b��@A�%��^�"?SV#�N�*� �q��ed� �hI�Q� 0.7��;�x��z�d��>]:�S�-{��wo��^��&x0 �6f�%��f�B&8s:��}2Ea! _%�<)��!6�1)E� �iw!'>%�>rai0*� q� : WhN@ � e�2�&� ��ea�6l?x! �A�1� O �lqT&EO : Ol� "� 72]P%u7 6U5r0 8�*c� [7��zes�&� . ʼ��us�6&�+�����-6)�gVr�5!s"� ��f���ed&2 .}6��z� .� R*of�l grann 2 [7`!�L6B-Ihj "�B.� .qC>d5]6�! � �*1�Ŝ�(*=z)L6�8��e�as���%�t�i��1�\ �)&��sZg&T2K u����2�1�>�s ���G�6t&O �� �s6�;�/A�pKAfield� -Gv] . Ac.�5( ACh )K Y�ur�6�$:�u��*"L�e� *g6H��lmo [75 $Kimura [76x %)��y�UQmis��*�,AKaT79}A9��am m%� i%!t;�[) u�.\K�cnO�$ �)�;ff�~m��of�tC�QR./}�*��ex%���Ve&EMi�"�� �'!FAeeV%_-JT:z�7IApde�7aJ8LTS cells via n�icotinic receptors and hyperpolarize L5 FS cells via muscar:7. Since*$inhibit LT�92�=�L) . Although furtherU should!�conducS(to investiga�how1:�� .sE�ed; suchZ�, ourm�rai!灊possib�ZA>(at impairedNwfun�� can it4imaginary sense�:Y�+al!�6I�<�0produced gamm�dic 5�in A,�:ependen��8bottom-up input��I�C.M)�mis�pre!hby hig!�Y5areas as�ultE+��stimulAresent� ,�yew help!accoumuhallucin-aQ�!E�Vh�zterAngePdManganelli et al . [93] rea� ed e�ہ@ sugg 9itvisual:�is)��5�Dcholinergic system!P$Herrero [9��a�me�J� blockerg n re!ޙBal focu]T�$phenomenon%Jb+ ributable!U2�witch!�A5��: T6 auth�i�v�ad6!.�. �&w�8m�za[��T��FPaI�;ia�)O:�s� )d�.A\s��consis�:��1o9�4�� However ,�l,lex , equivo I �DJ� -med�rd �0s on fast-spi�e6 n��to!��de�a caveat%�, , [9�7�0Most spontane�Q -specif�Tata%col�PHanesthetized animal0 ��it��yin vivo �!e�aw- 6 eng��g,y� taskQaurren��unclear"� ��aim!�o�? me�4 isms lyA�5��(al5j,AJ assuN^%]� allyQT* wB�2� 2� d2�in deep)u�dur�all sI�i inclu � � experi��!-s:S.�5���cannotATu1 to tune=� behaviaʡ stead�3 capt �.�B � 4E4L5� %�]� � impl� cip 18� �aA�5��n6 pc ��% did �i� ��ny ex� (al Poisson awe traine�EPSCs ()backgro�q oJDu�e{�aP�a-�!�delay !�o� L4 E- �have suf� �Odr to overc * ea���L4&�  $Figure 1 )!* quieh t�Pe evaluQ ��vc�� lack!��L4 �by5IA�5GFto6���no % %(nt� :-Y�a�inced��Fhm?��10 Hz5�)�0 J amplitude!�-&S2A��but20i  tia�howed2�.]mod�~=�&�er!�(tB , C%5 . W� soA�cata/ pyramidal-f qui< (ynchronousl!�%�@alpha frequency b!y even)j�,.�Zz7 they�ixB�*� . It��&� t.�6� i� I% ��BA80 98] while�lsI��,�2�=7Yj�of���� addB, Berger* 9]����!�fi��of �L5B�� � feedA�.C,E0L5 Martinotti-�S clas���z�Ix *XN_be2J�[53!NB]Ye9.ofR�approxim& �.՝:�. O" igno�twoV on. Firs� we)� on,lumz� a lo��“in} e”� +��n weakly���_��� te�i@�e�d d unc � . Se>� � lamuy miss�8in]j,Wu�e ��t� �Oocoqcircu� on �Ial.���t?usa�k�gener!�6w[71A[10ei?~� ![�B"< takeRhe"� to fuV &�^� h=mi!�:���� �!6�w ed!cBuffaloy��9e�sp�B%O�6�e : ap%�of`!�%��6p.�Fra"> 5!Q�Xa��ce`�-��ic )�o- �ommun�!s:�2��&w ]N��ax�h] tt!� ed m}� � uo �el"=.h 9V_concern<���Y�*i�!$same field)�p��eWZ:. F\#la U��)�)�}BR e� �;�loA�o� 66.չ�� eN��o�#5 !�!�mean �e!�%ard d�$, )�{�!'�hF�var� �%n��'ng6�fol!�8Hodgkin-Huxley-VU� . ( 2�3E�OAa forw�% �Q�:W|)�8� hips"/�Ea�y s�(�a](3 ) ( 4 ) Emt 2� � � E-6ED5 )� doptV&u ���S�gomB� 5�&ExcX7�g!�i$� e�z��s6?U-I�*� In��]�,A��*R����6%B789 10 )e=B�X� sln ly�Vli1� ( 1AL( 1)�1!�( 1!�a��Rf%�� �rwMcCarthy*K05]� �1�I�a "�aY=� �!B��eQahKr� � z)[1!\Ini��"�bllBs!�=y2���2ipr�#l� � |*e�M- ]&S5a� R�  R"*I]r���� V��V%�o��* �^� 0 �. 25%�BFSG" had NMDAv&J.�6� �aN�!�6��+�Tņ�� AMPA.�*_ �`r6*%y�.Ba�*6!iNis*�Jout�v"*lz'Fex(guinea pigs�R% kinet�, decaN$�i��� � 6��r��, [9re\K Tx 2�aEt�r2�e��a E/.��"=0 i� y � I&~UxaE@m ��,t-E�� b� {�����rule: �&�K�mBB �pret� .%�d]D�]) ����u*ope�reB>&�Er0!C�)}�Af� �z� ͫ"��>0�, �!\�t� su�,M~aDo>�71�%A9A�1ex�tZ�!>@�  of 9&Ed��&� ) �) Q Y)�,!�p"�R%��N^ ,=K�=hofm ividL-EXsZ�ŏ2�Bpo.���N� + 8 gi9%in��I.�!6�E!Y�a��4Ebá�E �ta�0(a'T2�*!/�!��!"�K��/�/0 .h��.�&� 9sA�9� parPP ex [44�$[109]� non-�97&v Js�4a: trix��E [110]I"&y :;�6O- in Rm"����0>�%Mra& e"Y�1 sec� *�+\�{ Z4�+a�T�,'���il&�-( aft� e cuObef�:A�r�A<�!Luo2w!�tro>Si"C'�}�]noA���%�B��:���.=�i.�aY�, x�>�(inua�toqF{. ��:e*�0!��-w�[�n�)M�Ec��50�s;*FZ��6���� it;���I �)`$�2c�/"�alE!of&n�>�!�%� ; �e�A�.��7!Ieeq'+i�"++�achD] AZEk�*+re� 10 realiz ofq+ ��  %na|/ ��� � ����m%�� � e�3g������to mini� �1�& � �6�$nd stochas�.HA z-!a:� averageber "�&s��i�per�!�!by�� Kof �t3 ��w-mX �anTerr03%� u �102�. LFPm}-� summAupJ�" o�&6�E+���2q,[11�+�$pike-trigg�&1. ( ST1H�*��*u 64E�&�4seg���TsurQ3�EF� )���10.Y1+A��n"�?9C�is�dI3cR200:8.>� w��ok 600 -loLFP�; 3  ��!W�ޡN2�4�analys� s doneiBC�1uQ8� ,tlab toolbox!�� A Wu� ru�wJ25�k e �-T+con[)( SFCT aa?io!���p� �{!P1ۅ�'Q0�:K <al :isa-k%as�#2�.u $a�e�v#!d�[%��.!{ ��-aw!�s �-2�m�=F���AlaZ"dicZ�u $�v� �-"�2[313 #Nk@ �as:���)t>�e} > 4, 25–7M ,.$%MJR;�l�:w4(, 8–25 HzDQ/.�ATF�J�)��5meEEd6,.GY4w&"�( 2# [104# )S!�!j!�%XѬ��wo��Q1-�,luA .��S٧�"�1on wAe�niGusefu�=�'ud% he e -em|4a��ov*athogensM-6I0;c�7�#c(%nu�in�E`A�.N2sm�;.�)m%� param[ eT S%<predi�1(�D�2����5$8m�D�%e\ ] manuN(p#d\(�<lib�%Bt��E~oC a�$al6� ��� pide� R"�/m� , M1Sho�Ggh=��? ( MS#,5lM1a �?ar �%e)5A��b_ s�GAs�l�-%c� A�u,en�D urvea!�observ.Vupd�3Hb�) f ab7 z rue �� . Us��Q�2utbreak%�a I{vi��Q���2�accurac��! !� 2'�?� �� 9�=�wee�5�A?�Y�!diagnS1ca!5a�availF!L!/na>era!�x�inc�c�W� ~�z'7�teqI�key��B i . Rm5 duM��a�nes!�R0ADnd�Ffr �&o.)l}I! unI7D~�-o7c,Ean�.�y��!�|}�M� s�ti� of fu�0ho~5*� &heT�yatt�<� �i�!�e� formI�f !���;s� $-of-the-ar�>nchmarkm�s:/$a�kelihood:���a�I sumpe�%�"v"�)_ems;�!a!�tic ilte:0�?;��!W nsem-Kalman - * �R4YkbrP �e%s�)ts! !b>�maj*E�q[ > arios tesa�.�{ �-!aE Aumi� � ��HimA�el :ach' orf^�uS��R� ZspoN0cNhu!J��agacg� ARS��E�s&<(influenza )� �! emi�I-\�or"�monito%�A�spill �A�spr%A�in�"��AR?Xfunda2 al9��?s.�(iest phai�d:J=,�:f�..A�Xal public health policyis\  [�.2�Bof] priIS[3 , �*EngR��1�Geng#�{ K�dF�YL! S �]B!� &[g!�np--�с^lex7u�GlyI5� m�a�. P20de))�;bG�r2qui��oHo&Av�$ce>�����u��� �JviU �!���an �im�Cec�re�vN(uM"4 -H-y&�ll��esiG2T� ��Vt���4 9� A recCprogres��developaT��� r9=}0� -�!2&[ .`x0B�V� �2��MBm�>u0!k CM on�$� � � 5E�a&�[12–�7I�s 1-uQ�29 d%q "74�in+AQn�/9��< edge&D(>52� link�� � abs� R� !�� A%n�-l!�!XOe$�)Jg �a�aV� � 1�,2EJ%�!yU :� �5� uutra�D 9���m�+�3��disjointA�group.�sus�/'#2a� � reMed� %i�9�!V��-��Ym�rdN"�(aK&t*(� !iUM�) [18]�MarkovHi�Q!*�f0�9A w�S�!edm-�9��to"%KF5&])�< =� � b�S`y1�@ l&� �"& A��/��T�Rof:[20�2%� [23]�>� �@l�5��z-�$ T:1UCh�8Monte Carlo [24v A� technique3J��9"a��Y�spa�KRe.� M"� Ypa�,"1���a� Ove-%%�ca� ��l&�D= R�I�A�� C�?�whQ��" �&5Y�� . Un!�:�M4,.� c�J�7: GMK�Fa� �� s �ne4A��� �S-I�9�:X* � &��:5hrOe4� �nutiliz� jo ( LN�� _� ate-3!�E�d;o +x�E! !{> >l�G* "�QT1LrQ �H�F��O5t9�:�2�!0&�an��F��o6,� s�OA��@A��F� <er�T5�in5�ng9�t1��b"/M*��ri�%�N�e�� � %b�#V�� >�^�*L��al lndI�|Fp�"%<. D�M��a=.S���*eAqOa6��!��"~"�"5 �2h>or death��We��yi� deno��vecto� �i *� beMFedq���^[ti−� ti]2ee�;(4. Let Yi = ( y$$y2 , … ,�)\L~his3l#2# t�To�0fi� .x�U�P=�`~ d:X,A���4&/}�-2L: L ( Y i ; θ ) = P�Wyj<y �.$ ∏ �1 n P! i |Z5- 1],s0"�2�9�proba�F�)aayi*�p�Y�R E�p F�%��!*)k��s!� m�1�A�/.�1P�·� a:�PbU0ad�\��a�� b�,m&ZGl�Ppen�\@<va�O� "_�J�-i�tt_\�ީ�f I!P��E�6L��a�X�Ib�Ascret�I5�dis&V��&2�$2)�; f�)+ %� cro�L��m� n33�/"� v�5�68, Rile�#�agm %a�a���o�.�R�s rS aa�~ose� matc;g"%!�250M�rep�F�?� � � �T  D�doeT>t r�Ao un� % p%�Q*]9�~ =� . B�8��f�M6j �>A��Rly��I�E��u7 aZt\Cb�@�CuJA�f<�6�cc:��,p� -;uEq U$".6� ����7at�/t,�:�f&?��.�"&Ne��a$OG[19 , 3�') we w�R�'!�as ν��InI3set� �S}KiR�[a��^� �E�oP �Z�  Xu��$X&x�5s�  %�c"�5( E,� , i ∈ {1���}I�zN-��H�,�' zE��Z�� �E�y fa�6F�_c_�V,oIZ��]le:d�p�< �!A �0Π ( ⋅|Yi ). ��.Mc�OU�2ZYA Now% %��2�E:atQk�k!��νo��in Eq��a��5&2>as:喚�$= ∑ ν i�A>Ω &� 7 %l� o b Ω)���dN�(",!>KF�72�Π�T6�.8KB�I G5�>a�*� �:!��1����.�5����$-�-�p ()�| *� ���=�CM�a&b?(+1:� ��g�FF�;, i� s(�Fbg7"� s&32k �i|m�-���4pai ��!*I�)-h i ×U��se� ��s e^G�����A��>Cɀ- proh{h$ively larg�"��S�� ��O''\e�- plif;62Q&iH�:!�a|�,.�>L�PSv=py akes 1��}:i3l��(��u ν ^a� nd 0 else�� `R  '9� >~)u]����˜�� ��uPa۩=��A  ^n8:� o> ��\"r�%*z *"!��ɚ:��SV�ABI�mŬ�ߕ�]�!�}%k A�Mto "�  u�E�>�ii�7rivf�Vind!�=t dz= ra 4=��]de �.�"D*a�wllu�aW  !'h�0, ,Frl� I��f���Aism�1 2 �2yUH- rT�,k ��y��a< is ze�2w=.^"  P. =h��.��_�r�&@��RB�.u��aFq��B*�#� schem�Ix nex7sgA�wap?.�".; ach�O�.���S'goa8f�3!"!��/in� ��%�"� !v)�%chaXr�&A�u�W�H ty a�- sp%(��T�@An�7w� 0ploy a Bayesi���aa�62�/5r�.�/&.mas�!2�be?a&v�t"�isqOxc?gA���!� �< π iF� |X�1�f2#6E�Ln-e(l 1'�B�3π���~ , Y )��m!6D r.ob!��(�*=E�π�"& A� os�$k.��.vU.A��U��2��V%ux1%A '"�$�U3�8p (0u . Nat%`�=e�I4�"��Disxurh�2� HsF� HupPR5g*�=jA�Fig 2@%�DEJ�w4>Z*��"ng.���E�_%et Θ��S~P1 . bV!�Ysy 0"`u �N�&�]=m+s��be>Zby9�L:+2Kπ0I�)� IA��=me_Q�L!4, L�@Yg cubeS r or�,o� 2. Obv 7Z��Θ�mod8P,!&2�B%��KI^�i���M�,&j?��ad�Xag!fix16�� hFgineͭӹ�a�o,o�*eto �Xf��6r�FA��n(RJ6�6 �RAmX����w�e2�Yi��ia��w7(l�\�kn � A-Y�Y]ve%� �ak*9.�P ����aty�i|2*z ek�EcJ }j�Q2(�0� ��2s fQ��"n Jro-&>� I��4�, . A 4%�motZq�6%Ab�qu*�6�)�3t"q7>�I��)�&b. F���o demon� �C�8� 2�a5St ZY %�quant!�� �shA� 7*�!�.� .s.��d.M( Z.MB*�.C dens�U�Mč� #�Z 5]"M* �� i.1��4p&h g#i7θ =��&w�2�.�b�� !6� 0�  2�n+l4v.^a�![��∫�[ )  iR�&�\ -�w *s ) d� i��0L� �^ W1�5|^:u �R���Ĺ�2�M:� !�����a-ata E)acw@a'� u��1�1t!ͦ�B�Ze�P/YFQ�I�*i�2�I� �eYr��'R.Gillespi.�[40�SI"v6VgQz2"�<�N%�,��z�� p.-u˅!W&�I6�D�&��j+r�mOs�:�F@Yo�I2 �e�/�$x�=�w� �U5e� �.�0aR e�pL4S>0A"��`'�I�1K�Mra�PxR�F/�+@r�&FaHgf&�)Bcfe�'ic!xd/pQL2��.=ear1*�4n%.)!~�} thir2�#e.u@ Ptfl"!'3Ens2�1F  [27]��#)�s w. 2014�jPr!7& I"z0Sea�pC/�jQM kb�U�0|zebdE�D�.COA�Pr�&a�[41�/ls6n'�g�|]fa@hs�@uU�Er`�+W?ari�yNy ���v�Q�Q�a#!�>�>��!� abovZ%�#�%Be�S��!:ce�2�oi�A�L!)�mI5v6�6�f.a�= �0E�.� ��\"��&�1 �L#0�,�A !q mutu : excl�~V!�$�.���,AQ;v_0&V~"�& ct S&�,s)�who4~�Rm8��%vc�:r7I�,:`EEt �seek twB�/dsworse� /�A��~a�!�T6�m H��.�R.cSp^m� ����4?�hre`-���&� i\k�m reN�v� �ef#Å��R e�Z��){�xS ( � , xI T NxR <2�'��*o &� : =9s.�2,=j�� N �=�+�+ �+��]��:"#  .�� =�E�2&{ODE $: d d t x 1M= -1 1x 1_�,7=�5X2NF1�F.#4 3 x x )��1�4#E(�W�1θ1�ANQ�2-9, θ2'� eek� y�+Q�#CAeθ3><m?��A[-�p9]���6v�!�** ( lXbyeo�Λ ( xES, x 0� �� θz�θ2cθ2>��E1 0 0 1\> �Y�O"5�F.# Y�= 0�M.���"w)\�d )5�6(�!G}b�."�#x0���R� A$ A@ & ( N −�"�"�"�2�$.�� "nB���>} v�n*��OC �r!�>��� {100�16 0}%�A@�i.�;(%NA�: [30%�50%�L��>U!7A extrY[7 210��Tu��Gq"�3�? �I9 drew�= U (93]"m� j�=67208�n�&u�! ~� 1 T6* 1[ A};A,�t��y�softw�$COPASI [42�tPUh� SITR%�gU�3�e�= R 0��!�e�= 1�-(��\r i���a�"zMuntil��y*� m7A�"Kis 4 d�X�E�6 lmn&@( ��#a�G[Q=e*#lou(J�dc �G�raj�.AO�d�0�k shap 3&YA(��[c than0T,� �h�g�(�Q10>s�.W.pg�oh<�x�sa�!201FakEf-ig 4AS1AS8As(~5"�J>�FLFP� !<������=��B=0* �&@0�d�D roug"NW@�B&Jis+*��q� *a peo�t%B%��� I!T!-���5F.�i�9" iAf�asU �'+�� ����0f�u �h! t)�*= 7I�2to6zM`atai`.��a;�2�5� in Mathe,ca [43^-�%w;t.o"P�o�/�A�at� }"|�B�Vl ��Re�B)Vjc�O"�@9��$24 3�c/!i�CtBYm>9'>-aL3%hg#&oto#x)�� (*7%:��}tMY�he� .%��Wed0����X6�1�e!bO~�)� .o �1]�.�$�R02~`ay*�MHE�1E�J[y��r;����AAYS8A�h Q!8.�6Rw6�s>�6m$5: 8-�to�aM/ci 4:,^��,&� !cU:� ��&:�6t5�%?tR't�;�M t"Cmr�eR0�ma��.? G�?�.]�#2 ���ZY�Х�"��7ga�d�fve .QD ( IRE ) : I R E M|400 � ¯ �k#M�#b&m | f5|r(o Nm( �d{ fMi|θ:*x!*�-eJ�)eM.�4-^ed&� A�,�˜�A�/%{P. Ψi%U�l"�Vɛ�I7n }�rA,.�B�f mA�)x:�' �al*}# ���SIe�>s@�V� !%��!*�meE��ci�IO��'"�%mk8c>�!m"� Z�\$:x5E1�Q!=F�s"�8CY�o`� qu�onj� �R.>AGaR&�J *�K�=r�` ;p&Cofp0'uSee:9 .!N.B�js2$�oA&�pfV��In��99�b.g,���ndBR� 55��im��8�R� �ak��nd �Z��T0Ao)� ei�.�K"�eEGF �'&=!sa�i�.Xi &�5i�8=# �R}! � appr" ��o�p}ntinuK�!Y�`0� %Apu�q�s5�tY�G!7m1]��B�)A;4 5�es,�dim�y���?�Z+ �5�t�:�JBNiGr���Oe.� %xi� (! �#��ach*$.F�S1�SS1EgS8 8E'A�Fu��%� =v �!�g*N�#t2!x)�Y3I[��1}K���Q(�*!P)�Xva�n����T4sk{�5�os&\�N 7�0�Qəf��S`" :K�e$, IPF� EnKFA�tOw (A��" high���m� 2N �bef'!�!�,2 T�$hA �U. �e*x�C� �M!�W��E5q�!R�MP��V 1(\ l�!O�B)H� �� O :T9�lea'KEqr�~�u$M-�A6,� � i 5�R yir� "*C� O�B95s.�B�~ŧ� s���,WC$ig 5A–5C (hG"�T�M�hypa!d[U'!+)c2z!zFpat�{5*�QceD/l&3"<Jf�l6EJ�.�Q B2��1!�i/45%AX��=EV��F�(&� ikGr�� , Bl�bB �col�^Bl�E}!�I�=�it�V��{!z+"a��� �an!�c6�S-absqY�<��!� in m� @�ho*��o4Ee�n���XK.<���M0A[ed&�Kn ��!�E�jȚ!~2|a� l3O*�)w?l)r>��?*} ,�Ɲa� aB��oV"so&l�#�)���mXLD�O�� �C!�n śi�I� -off-]�Sc42&tV!u�9�& !:�I�Qo,� H�Rng� �5�d [io�>T�Z2� W1�A4CQ�Ca�$S8B –S8C"A&�bKla���JkADž��-Z�m�� =h< �kI�is�y�c=lB!�A��c�z e��. � �&S(U��LZIore4�a^j���&`*`"�ye �"R�&��&~ )%c�S` �c�TIoIũ�9K1"�so faF iZKd&�r�Torrt#A'%��.� �&���=&p)�~I&6/X^5�Ucrobust�S!���"�SJ�1�:eF3nIng-��L�isturb���tj}��!��Ga�an 3rJ�A5bE��7!+� ?e)�&�� 6 !�K)����Y���0!��R�8�$pe { Ky�N|us&it"6�; ( S9a��tWMjx'n�ha��iE��wud�fNi�b}F SE&hm0F�2��`5�;�)Ӈan *�A�%�y��� ndad�_�Q u%�Ico wA�ex�M��2XLc�Oero&S*� � m�5 �;)5X���|!Je�5O� ss�&be"H� �/dU$)a]$E��r �2 I@�1�[��AIOir22�E�*q�B�GI�qtA�=.*� eria�ut�y�l�e;-�c[ō ( S1~S11A�qu � f�t����=�,FR!y�15K(bP<pl���*fa���E!5���7�RR��Ӝ�54�Qw�.N �; =e2�&�ag'm| �9yed-��( .�"IP=݌ExZ2�}�A��k&� 2�is�1[I .~m�1c"� ��)�)�Fs>�a� e F–I p��� �6� �&�b��S?R��g N�*� � ���%E�^ s���5��j2s6�H�u%, 1�գ6("-� � a�D>D�A1yŧ!����������2��l9 B\�s�a�^��oaq%��c�o�rF�� �ern�MYN3O ��gog e1@� �".  #�,�� Y�� >�(ͫV O9�9:.� �����i�sz>:aJ��xU.�*��a"�7����H2.N+c�qճy"�(!'�96Y6C�-���5!�m��\�\:\���d�j�`pa� !=G6�2�"Ptd�U�U��re��2�d#�� J �8.8eQ6>r ���I�� M l W1llMrWj;t�"�����mis"��t �wo�A�,� ,� o�cHP� 1�G��$dD6�bfof: led�=A ex�� . ��Q��A)�F�� add�`p�A�+lGtY n;pR+�WiZ"�Vo�&�I��6+ A.� x9f - .�b?'1e�fa�eIdp[�C�&�-j�Orehv vs?�.)A%4� ^�0 �:�@' � 1: exis��-*�gF{�-B�g (G)�4?�)2�5{]�*h*��*�$� "� �p���Z&T*�[ �j2�6E.A�{&I 2�$%VqH� ��".S3�Sahtll5Y)t!<��;�m��$��p �*� ��ba�7'"b-!�(0�.0, �r�'*� K%Xp� &�4i�5+fiG.�Q�H�[s����'[ �ґC>�!a`#�C�FeT�a]kt^!M�w#�i-4�o� �mmJ m�E�e%Ze~A�"ileR#w�b5pr�&pxgZ$�9 corp�P�6��haS framxoE�g �ver�Sof&E��omm��([89QC�"d$)*i8)��N�1Ne�!���at E��~,8F"�u�}��!*��r+r)l( � Ae��sa !�G~rr-�� �-���+u(3multim,M�\� ��t �A�&/ �A=���<�}%L� ��=a�gl�6!��|Q]!iiG��\�.r"��R�6�&� ���P"cueEj"<su�>�7�;l�.�c�9in�zsٛf.5q���lu�texts�~�#6�,na�i-orea���,7�)ƒ!�a ��]�FRe*�s����2�! � )2�P���)�h5] �;�I ay�&�l ,����y ���55W���� as lyf9rvat���-% 1Z� made &�ly �(�}rs� !�@�q !p�D�AA�a)��n}_9��-A�72�G�aTtie����ne����}�"� $ ���R shor�U9��reUL�/��%3Dwho5�ur][�&�4i�s�(s'V�$!a�B�� �� ocF��3�M� �e_WK�AX��Y�Z̈́[� :]��"�_�uS��B��h %(Do�?.h@a ��*r vap#E��S�S��T magn���!!�b� {/�Yj"�5D� !�+ � 6�R�@:>b�C@x1@��ap�B"�." �Ca�"w.]. D��&Pa^ a�d��%"� �s��v���)�.v3*&J+d)���NEWse�I�F�E�AJ�(x�� #prGw'�{oNia�!t�;#ewxìy:� w�2 �2I g� �3ATa�%�.�c*�N�vioZ�. 2"g*��5"�eS12�� cӹ�@2 �at,�_�2�*�s6>u{�A*�ofq3]N�a�>*��s,�0VF,�r�$ea^v9e��%�&� =*s��Ji�& K"�� �|�� comb�,\f � 27AL�F@w�cb��.�I[2 2V2��r �cJ*I?B�"�X&-#W#outweigh�ly�of.�al��!�y�e-^���S�/�!p�-A�a����P [oise-f�!Ay=�= =dAM ligh%��}ce�2�Rn-��%adpu> ��u&�^A��C�� �":���af� choi �]%al�_Gm?MH '%w��>�t!�I��s ��1$/W�� heuri,& �GqC8Q���Si"�Kh����2|7:�!g  "�by drop�R!I"1*�Y�� "�BtoGCA)�B�yjSh���Pj�q8�"3�|�6 !��ug�Am����q ���.�isG�"�'�pao <��).c.,^ ��Ÿ)� e��y�!�!����bbFw�ne[P?~]�f2�+!��6pla,NmFZw����uY�O- �fs!�^:�N�isi�y�:bJ ���!D� � }�=]lIy�*.YNtwn�mx!��te"��p( arch�"fc!v ����"�;“� ed 512s&��0��B@�%"�=% UD�8�1,un�7u�s*tU7m*j�+:&����$real-world=�� !�"��$.":A�a�� L" N�e�r=2Z?�&��P 6��za5�m�%i,a�8&Ax� A)�!��] i�I�,;�c8�`.�Y�Ʉi�ala=��rk x�"9�p���x3 � &�1cT e enough&�MfFCcA�":,fr��*�a�f�����FEis��^fix�1W^asbqk � �)'%�Nl.p!k]�t(f&}������� ,:�[degJofd!r%6a(&�qq-la �]o� �� Ga . S� ue Um+ AYB�!�&�`N�� �n+.M Qu [ �%y66[�}&3���M� t W~A�?F�And[ m�퍢3�n� a�A5=�,� � t��r�bCOA>��  t[EoN���aa.K�Np!�v��)�imeK$)ͥ$&&Z!��M�a�fQls�P�oa�bRM�z!t �`e����� �]���i�m lI��F�r� As�:�)��+�,!�*��"�s��6��& t� "xh>�w! �w)��Y�%�&�� @2���&b&�!!~q>],�ex��� "dHV!ډ�,�������Won�!��)��F�!�&,L?��b: -=U�A=� i!š� i�;U"'��)��-n�:6��o�s����V;�25Y�)a�TCEver!�il�@er�o��u��a!]cL���N�l�?a�TGrU"en՞!0x�al�>A�M���?(� �� tc�s�K)> ����fo�� exer�c�&���q�!��> `�*���� eO` E,sN w-validɀ.�w�� �D��!�&U �iN�o����Ůs� y djus�6�d-� t���SJe/-c�� ^!j perm��$by opposit\��Ja hier z!7�"&T#�sse:�owP�=�reph� �A�a3n^B�eg�5�jrac�t tJ��war�CrY%�M�k B��-H“�?inu�}Ǔs� �*�4�tia!�1����z�t �l5Q�5,� s�q�M�.��a Two- 2I�w)�.�"�9eser Fr����A �QmB3m�z��YFG!���0)��+��dR.;=��+ aof� ��Ir4QNc�=��]Ioi|&ct&S� opeq���k�ta�',{m�he"�"tim�n� tIA�of��2�j X. FaB^! ,���a;gh-fide�rAzj1d/���>es��v7 �s׬.^#and�?rt-�53iaz 4hl:�Bago�Z`�) � _�G �!�E=���V�7�&M0)��Z����C&Wa�:}��f��.ch� br�*7,�<��o%�� C %`�� �!�s4a�o�9��0[1–h�!7&U!�|I��* ,]�ux (i` �*2!�d7���p�"�U4 , 5�^ � F��peculia�y- OA� �� a w·r�� "#ƍ�y!�!� [6–��q�-ma�[1^����'m[�[1�}1�zconA�m�.�[18�!Tmo�"�/[���sAe���,5"�NR%u�K �n� cho"d- &�r��1��BR�9. e�*6lo���,z A�,b�d ��!� D 9� : ne��ve �?ul�i).A� e�rG� Hpel7j Ul1 % 18];�"�9v��w�@<$!�r�Ke}I+,ei��ma&�@tx/tjΥ�������n*e"���9��%�“ ��P�B98� A�T!�re1>�bevo��Q.� �#?�> 2 �#OmI�n�7ve�breE�T���L��daw�psych寁N QD� � , 19��e%a�Kgesxs Z5regrow  iderz�&�7M��#Ksc#{Whitne��I�i��-ց:1"���B�:E:yA�h��D��W�dt'���0��a8n!�� �@N��!�.�%&� 2� 0] ?��6{"&(rV�Z���^s ���!�8�h0E�bE 2��r^,4)y�<��z Jvnd&�1���[2���>��q�OZ/*����4 �s�! &��� -D� DI�,r8dMXal.�S�9{4!�A�iv� "�out!S:�Q�C !7B�"+�@2 �l��2�?�'��M�� �t&# �!%�)^��-^e?EN����e�''wo�ve>�n35]�.5[A� ves—:�BZ—�� el! pulN��] $� � �� 2kpk�� To�� E_"O��&Kx jJ*\S. ��.���9 �?%Z as�i�.nW�e&|�:b&�3J*��L�fM6o1Y�!έ���2];�|l8"��nd: eflyA_|�K\�| ��.�E&p)A�65�A���s}Li����*U(juY��8o�m&�)��m 2� Q)���ErqZ�v2�m� ��C�zb�Jo�Bta�]���%��nvironh[ th &8 1,�0st�rK�X�\�)_%�ty}g��J�aA�1'M&m Z� e^" &W,@� ex�:�H[��, �\���d'E�k<�S� �?!��N�� T(��qlA�A& ^" �3e �&��-�[38a�$ ? issup�e �r��aiw .' &�I��6 f��?!�/���&H�� !EjHI#!He��" !�u"�i<2�N�:]3�k 48]:F�, �!�Vm [h�1*U2�)jag!�A��U� !�a�03��S"�0v8�_ W��'�a"*���d�I!��9In l!�r*� %<�1kQ"�2.��^���d��!�A�� .�"� B��� judga�s*�"� �1�*���!cUv8��:=y!�!r�U��NdenY�&u�“����ͽ���1vor>�I��R"q&�� m�Za�&���>>�.�"~ 5AF���U"��ir�$A��! �$� � A�/!G�kwg#"["C rs�[. �+��-҅8Ŧ"�<&l xcircum�t�bndXvira\ly�$�' * � ;d/U�su��("a�e( ve���� e kin�1����H���j�5u"��(�����E��/M8a �"�n��t6:1:s����Q�$(� �6�9L%%a� :E� �$�Z�.�=Uaj More!�� �%� �$� 1~�9�<%��n2� .C"��g4lmod V t"$�"7P�$Х�[5�� � �6ofD����no:; ����"� ��55� i*�AE5s-h)\u/f�fa5�,���A�� ��!� � ezA� oc�0&:9s-�Cl,��j�a_2� ���, � r���;2a�"�C���52Tda�"#<&�Cus��.+ puzz klay�)R��S��<�-G! ��OA� Ìd testH�ew"8"�.>n of�/��"��� insp�96&��u2":� ��9�?fAbO��o&�54h^3We.U��j�%x$t:�%|n2�#[5f60���A&FNQ#�����u5�E�~��� t\8�a�� oĂi�aP E>j. Wz ���� � ��$�f��' prof�F� ��.�"��*R%<*&regP  uEs�.� a� *k!xg&,�#B'�8�_M�qxn!�+Z�ZvG�3E , 6��a�.���%'��� �?�er�&M�!�D �+&� Q�al+J� 5e�}}9 clar� N(�"ݛ!�:ys#!:~o"{$%�:1��m�� e���pvelP��% p��/7��)"j9�59t m&�;den�TX$f�x� onY�^("-!"�“C E"� �4� 8w; nVK`1�&n�yqA�{ M�dom�AWos.� -��I"� e+aso�: >�>ia might alter visual perception independently of the content in working memory but exclusively as a consequence of chains of task-relevant internal representations—decisional events . In line with this hypothesis , we provide compelling evidence for the existence of two separate and functionally distinct stages of -0serial 1*�ce [30 , 56 , 62] , determined by%E=Z histor%` sens and deci �processe �ates!F,experiments �measuredgabilit[8human participa0,to reproduce/ori1y\c!�holleir resp!j!�hereas�ulaF�(emerged und%is!�di%W. T result warrobo!YUs strie�finding!Jt!�fa�streakESnonrepor�]!� posi)VB�w(still dicta=M�most rec!��].��uA0y on previous]bno)�m!aE��[$hysteresis�� moto9\� as i)stronglyA�ul�I�u!>ntrA�a�Hhad a direct impact��&�a�!ai.EIurE� show)ft�mE�a.Q�al A�4es generalizesa�o?�!iI �i��1,O]c����:�. Consis��e�ou%ul�:Dpropose a hierarchece��short-��9���in which^�!yaQ�of low-�,adapt�!kj^aria� from�reverber =of �@ temp!�aEfl�E�e reaA�-ou%6!��ksignals [higher �1�\grator��Wq� apid negaeeG)�E�u�to%�-irrele��1�may!vmot�.quisite.$�Q[�� Aenviron��al changE��YZcr) -9��atee�inform �x!Zn��in)q�a, thus �!e}A�inua!�inc��%oefficiena�f2�5�ov�� e lo!�erm��!ԍ�in.plearn_(( PL ) studA�$[54] . Oure�(vides a newBspA#vea���of5�=Y��by!oncil|opE��Irm�Jf2Dto a unified accoui�N aten��-Q� .�-ma��. A�,primary goal�Ce addr/d���KF�in�)f�Ws mor%%�Blor1-U�1W!F��t . R���� has!wAS��qs��A�cally��Qaaba� d��Q�input [2w � 63!�How�,E�e.�Sse$itself��Fa :A -#��1��combines�Nr� outweigh%e�0f9�% �To tesa�is�si� ,=Q�&� ( E"�  1 ) we�p�!!*� 1$}AO�9 to��� futu�rr��in an. adjust�G��!z!pTR -VA�ith|iph�� Gabor�8( 50% Michelsona�) | ed randomA$etween 0°�,165° off ve� al (� stepe�1 ),� ask� = & % ived t�eby �a�!`til�B��� Pbar ( Fig 1A ) . Data lnalyza�p �du��O� v d%Wq_sɝt. *� -i�X shif�xmean [64x a typaK!H*� fals� mimic�U �� �yF/@[65] ( see Method��2E%Q2F�Th� d-cor5 � ehaviorC 5t6 us)�coE���lu� ��.�9Aurr�M�.eJaEai�1we bu!�twoce%����In one �;prE�edS��]��E�A differ�Q�� �us.�%5&�R%( delta[ΔS]%jI�@e�n��Z���� �� ��6 [ΔR� both �� -�e�fit!s�deriv �4of Gaussian fu� ( DoG )!�aBxaLframe�i6�)B� (e amplitudeam�n�^ ( α�QasU�quantif� magn ?'��q�c-,o�� its c ifica. SB1fo�e9�)�ΔS� @��dα = 1 . 32° , p < 0 . 05��� 0peak at 9 . 9����2A%�2B%in keep!7E pv s����Wa�.�co}�%*� 1�s!D�ReFN!Y also2�!�q��pv�� larg aI�a�obser��!4!!%�)7161!-$14 . 55°;��!�/evalu�e best-}R�bfollow��wo�\: (�W� s{  )�prw Ibetofi�;.�’1cby��u��A��a��root-��-squa� ( rmse )h�!#!Z!�, ( 2A�f-eacm�a��0 ����a B� d3>x��f��i��in%> 1 favoI��)6" �  ߡ −,] =M�9 } %�M Carlo��muAZoni�, nE7, 000E�!'-^B�Atep 2H per. a��A��iderablyW �A<o �S>� R] <%���98 . 6%M�C��T{ ,�S5ysZI,o a�tq u�V�� ��xplany%%M6 *d *)�)��x 2� u � e� !H�����,&- ed o&�* � 1!~ titu�� ttb� � � >�t�nrel͇l!�\Fsuggesm�at *l ���� �"�*u| pk ��One2 i` at$&�nFA�� �5[ji�Y C M@ighly uncertain [� Because.=�d(`���of ecr y [6� 67� A7 h ��bt e- ��field%W haveU�17al% �ndueexh��ntribu% .� �1#E�ref,?,could be hyp�siA�E� 9usLty�E��"S:[B�becom�)�reliable)Y�]3��>fX1e���o5 ? po.�w�����se�Bb��^"�sam�i!o2!���^B4vea . AlthoughHreA��.a��us-in�dJu at or neaa fX[26Az&�nva��oe���*�11s}E�*�is lac�� ad�,�Gre�V'( !�g . 3��2&$discrimina#� ) i>M�a�er spat�fr2>�[68� F��!�^!r2��10.�A0Y�Jp��a��2� -Jl Q �JK ruleh an( �due!h pMdof6 Ř—ΔS—%"A scre{� or ag�tI�6CR>C��E[69Aiwe var���X�r��±9����^� b!`�fu!Z)��=> (RR� atm)�.} !�� b*y 4�*~ 2y 5�°� !�.:� ^:9�&� A02D�C���D ��ty��7h"�%�-E%��31 'je 03.�q ,�� -uew*. m�accuracD� !Hu7!)7&� ,ɴa�ٮ plote�|1�nfi_���of6��� firiwo���vatoe1 cruc�/point:���l�Ls-i� ax ter1١FV��)cy��al� /&y�A*e�� crit , ifBfundac2A�F�inZx6���se��l�, Fisc�q�Whitney�qS ed s����0��!;� h�abs# ŎiorJ�ru���2�ost=;y� > .*5 �ir]/�� imilar�vemp-2� 43��:re%yJ  ly�!H�@ � fpr8d�.�Űsl� �K._ �!�m'ici&P �per3� "`+9�s��� �,  f=�an ac� �l�mQ��]N��#�o�D� ,��a�!�er�1�du���)u� tervE��urn af-!ng��#1=ubM�2�u� .)i�asoU'�  iNm � s B� ��&it�y "w!n 2fa�baign� !��5Egf�!�o�J�E�" �156�)� n��#6�3�mNto6�U%inclu%�40%!�(“catch”c!�͊n�#< to� mad] C63| =2��i� b�  circle �"A#� � loc��!tim�%cU�Ag�andard~? diAŹat.�—Tl} n�A��1�—�2��RJ��!�! anip"��verv a�4s\ o* g� p�FF�4 %�%*5s only��*� FO��4>� g>X*h 7� ^h 2M� L b#�%+F���t r � �,E� ��� �$��v�� �−�8:�.Q −4�)�X: ly"-t�WA| wf'[�]–α[1H ] = !59�2i01�a�,>y.;��F�s�o�siW"Yf�#��ve�L��(�2�bC&� �#2���*3�$"H HR%�I.# Av� �F�i:i�%v*� g �&a�q��W1`s���$%��&nc� rU3uj�wmb�� th�$" inZ�#[A94 , 41��n=j�b�� ��origi�!�a 7�ag���ar���*�,b Farg����"" M�i�z:� - [30]�C%d��R��L�ng�I��a�&}{da.I?%�[4 6r�(�Z� (characteriz! e na= E1# �,�b��drao�� �zF,on�& �c �� 6D4�&�l h�"p�$9�!iWi� -lx()�{'.��en"� �.#�" a~ab� %F=�paradigme�$oy#� bAX�ofazcJhoi�+askdn' b!�'da*-�m ,K�� A=. FourtE%.,�"!�-��e�� cb+6�!-��R6s!bC !�R Ast ac&ey�&�tIelef�r�.obl[,a�.�,a �"��0noisy mask ( � versus 13�one-a/[fo.�,[1AFC] symme� �[70"�!�:%,6�i�� ��� ensua�)Bof2�.v ( ±�5 ,j ,�}�"sV,�A�#w� v!#)�A%il!�t "N&�horizon7(B od!�� “Yes/No� 7 �.6"��In half�f 9&FreQ!1�( i .!%Kbis�'ngw/� �R.GY�#,&S()!� �(�]grub"�ie� �+r � �F��+�( IncoVW%�� 3��e��w�t� -to-A�e//io� SNRs%% , 25aw75%� FY�;ai} P.�SNR R! �# ' � s]B�a;Sx rect� 7����z��*15 %%�&W �-3��*ev.1�qadb t) u�����q�m* =�'e�p e" If�p� repe2V3E+ �.Xto(2c�vi%Ly'bF�sh"'if%+i"Ked" a! ce� e�:CU�� !�- �1��GO1"� �b�net=�a@2Q#\  !!�� ,.tw�b��O[�5��x,to small2��,*-b�t��U"Q i cl_ _B�alf#.Cy� 9��!#*8!U2na*YE;���".�( d %�.�F�ӥ�.~! �R1M_��cardi�axln�33a�-�p1E<��aB�G�re M2���Pro4$� i!� ��0YX� away&� 1�.JM� noQd[29� As) r3i�Vy%5�)2Q&li7%�.�A��%t� ���0� . 78 *k0�+!Ua2; slop�W D5�� u�of)䅛!� ��d5F q�, β1 �0&"&�M9,�s!��no �#5on�×$(�� p >q#E�I)[�=�H-Yj%,*�J,m*�BG6F7�1FV8�[ 67��B��&6�m� | of �β21P6Q!%��8β8�$28�l��mod�]!w1�=5!�D-��?0 baseA�I%m�:�:y6 ��� J*�+.k7���md s��q�-+�(�= tΔ��=�a1�Apa/02Q�high-��O�,PM,)�6� c�' 'aC�( pai%G��.�5�5f%o"�:�is.a�& c7al �6Fraw� r!��"+ &A� whol� ng� ��s����Y{ �� . By subte�[e�C��u��e}es��!u%�!�!n)�^dQ$j� ih7 z=��3_6r�ΔP ( V&� Qyn�!t�+-like payn:M4~��.N�pon� � often� 1�� �#� e�slk�'& !,les!L�Dk;!�ely 0BY ��`r�',.}&q�e*! Au�_�|., 4��t��Q=��5�� aK]K� well�*A���*<.al!�&�0in.�3� qs 3%a"R�"�a��-.� 1-�-052���,$1 rend66$ve:O��M� 057 ���06EfA��0%ev�*aqm� . 1������3�9 trig-Qc�he&�6��A�A � q)��-�*� �po.: ao=f#:��= .��>,/u;epL'*�= =a& ?&a $ly�Eb �Q�ity*� ��3!�4&T �� �4`>�,\����XByof!'>*;�*>} y1�,Q? bi�!X2tEB�y�EA��9E= sharp�Y5�� ideaLF�� &�;)meN ism�  4 Rassump�R2�; i:�)� +,J� &r� |� M��?A�p�A�� �neuroQ�<b�7munK a� mp,.s��E�AB.*!<r|#��J�$5)�vg� ngF�:�&�,��!��>expos`/�)B1�P+�Mف�,&��[]�a�T�!��>��h-@ 8�!�,�)t� ijAy"=carry����9�axM�1O� �6�!�@m -9a8�$l� plau"09of�oplc)aA![#B�"� def�C!��0-ge�?�� �=������9=�#�.�3ei�. "2� �!3Gp j�8ih:K"8-�exe�Aby.XNM( Two- pge���,.�i �� �" enco��–de �9,S5@Cun�4<d��=n�"D�lF� )�[5�71–7;42’s �@tecWZ6�!� laye�5�� �*9 a po�A�*&�-se/@ve� ��a� e>@al[mw� ������"~ �uADp us e%��P2O-e�i&�.�36�Q�%|� dist.�8~a�&!.%mp�" � ��e�O.7n niW���05nprofil�9�fr�����%# x�zE�-_" %throughv e��=�med�; B '�g� ��V%L|]c� P@~3)!b�-E[>J�e-IM�:A ini` 5eJ]��!�a�I6ɕ ��q�B> b��!�mR�F0�)HPFa -�A�O�� ��=&=O ��/.� ��an .�MR���o�2Z RM#��$A��by.�e� : 'u � 2��A��omAQu>*0��&�� -xi��/6�%�F�q<� uni�x��h tantM s;,,J��d!E5� -by- )�&��!H�E�- �eJwM^UN�6 �8A�(�����*7F*\ !�* 1X�+�A�;.ily!�j},2b )�U�i inhibi8UN�e��Ɓ�.r��X<(� �),ދ�5[7�f5�+�"� " � "##6 brie�$dA��E��&�G�(@[76��0"��"�-aqE!6!F��jplast�+y�U�R�I�}[.��6�,�5��+ ed ,zI� a�Jq]�2r�fQDe�$maxima at/�[�I/��q�A���!��/A�~�,&� F9 Z"� �8 3V�ari���R^�*J �!s�D�9=� trac�B�& �);1��2x1�M.Fa�|H{ -r�n���9JU�Vis I�N pens����]��*�=rMl2c-�"mF">,&�B�*f  rJE� rigg�89�5irp +exy:o�**( Jg� � ^%,�)� upd=#f�5�gB\J�J��N��;� mpel�'�H%qhI+exzL�~ 5KAdU�"EA�R�H" ;.Sts�1&U�� &%,�?d$� �u$he. @xa�%�!c"�\e��!�) a =��*1E�*?%Fs 1��*��� exz |F@�l�Js-)-�U�2F�F�)"� gsu��!�3$ ap!of�5�ΔSq�a���(  )?qe"�Hf7� .��tq.8!����[ � �7,T�`-���ru"5(-�/�)*jAy w���Z�� ;1D >0�� �(�#�S122�<� ��lJ�A�B"�'�X�.5� �=&� �!�1 ce e�F��.?��alway!"terleavV�L( i �)~nA� to-bjHu%.���p)oa��l situ�c"�p!+є �dissoci�j�F�=8 ��C�.QM�]�ť29dnm�w�A 29.Z (�B.�B�CU!m�E��� �m.�A52q*g9?j��pY���K*zR!�� `E�.vT �uAh%MU� 6�!!l*� -�<#o'e F���&�"bq1!2 6*�J~.�i���U�),*�(m�"J�8 7�R. O) ��:,< �H#JHs�"J ��E2�T�B\:lJ�?R8 6 �0d! ul.�V��8Q *� d M�6{!)in2ui6.�.�"->� �F�Gappro� �Hr!*\wWly� FOM2out&ő.~��[8�� 2�n *:!?��al�6 exacTM�� .�B�->8 J8I^At odds�}U%sig"�$"� F � "min�O�#Q�—}�—I�J�("s�J1�4t�J%�I−17�Jm>�=MY� FZ ��� �iA�X��6)� ��0:�4q% �43 &M.| ��!�2:L�("� yu�!H=s.4�L[R�A]� α[No"�Y]�413�R�48B�8�. F2���!a=�5 �*X@&��U9|�u<� Q� �%1�df�� �ةfM�q �2�i( E��� 7*�= NT 57%;2�.!��8� is cdV-cu�4a?�F>�HiY@!Aa"�> viewF9{ WSh.##�9j�;>�+*,s�,�"U.� .� �tfa�-�A� .V<�=�d��R:K :=_�`\�2�6W^��&�'��u�F:i�+-�in}�!gh>�Y*E��M/atel&hQSFep& �anner� d\��^�p�&pu41&�I�5~`�!,�G�ab_cO�7a (i4d<�{ �.4UllaMO som/Y\[6�!FvidDupoA!th3�7�.�U4� zFv5�foc��&�&{��s�9F�� &�1:2~�v2-foldmOto6� bq�^ �haЕuB,ydR2�aF�i�/t&(oYj�{r�� 鉒!l*I �C 7`  7 U=i �B�HcF�/ar ngth1 1�L-� �?M[��,��,Q0jx�d ak5V��O]!s�^* *: �6/BtaRi"�?���ɍ;�%�AJ)�� �!de�#�(�YR"�)>R*BS�'f )%� ���a-%eP|bi9� ircu����[e. �2t�`eXIurb2� Pe.�0�(y=1 onV��!�"jSeu3�1� w�lbFif1823m� �]�.&�06�'� ��1�of� (')EPlowa~�4U"Z�Wmix݆� �EI_|*�(��2� &�switch� *��A7 �.1bby exA� !Zα!)cV%�a�Ys�Lr%�"�b4R&1aWv :0*aQ�,^RR=� 9|�"�,"�$�A�~a�$t6B#h ��A �to-!�"*G �>�V2� 3 )�?�:��!l�to-pFiG2> *�0#�g�*�,1�a� (2�minus2y3@1�K>�)�5FP.E�2uU� nA�Q別I�Nm= �2t F��g -subj�6nI�=m$'gr�� ��es3 #u, actoa� deA3Sd�\α wW�=re subm"Z two-!)��V�&s ANOVA�' _s I�Or ��.Loweus High��AtG&S�P[a�Dm2]8D"l *� i����1 �y�R�x2%-�B�×J�F HX,�X) = 6�Y:2�aη�2I1d�h�!jq�J�aa"a)EC m2�@F#(.�, Bonf6ni �]ion919N!#ь& �6��ay�U�Y�A��}�i"~#� re�U| o w�x 2<To�ize�n�&xBdo�3s6)�..�� Z,n��a"2� F 7 �7�?a���6 d�tf�kaverage _Ta�a�'�le9 .\=!2�10��P&j P��,�E�(�c�ma�6�Vqr�>I�"@[7�K80B fer%H�* +-<�s�c4 � glob�h{�# such�Lm�`or� X,>set�u1I1�B �fvi�NAarse gix �-mplex�*sce�c . It�dLA�(lyR �de1zJ z&Exspa�] ll���In] �#�Q�7B\b��ngz�6 -,*� f&#m�&�st [3�D�+3 �.usB%asK3�a�tio!�aa�.�-k�)INa � �Ms o�2s��coh�g!./-ia�bZ� G u( r ta�+�F��Num g5[9� g� "� ).��C cw@Kv>��2#&�*0�5�;�#DW�B\b�i�y�15�2i w9���t.� ?ar� aSQ a��a�aca�&u:j@ (� �we�I|:\7>�+R�uQ�I�@ �X?"��.�T`��VWm;s E���JN��. BV! � RT,Ier�e[�h �VsIa�ely���*?3�>�V%MU �"�l�  �a�n:}`( AkaI7iO#on�%er [AIC]E�F_a$, 484; AIC B� 399;& � theoreuS�7lihood�B�[TLRT-E�+y�E�erO"7U( 9�b���o.�� f�9>%�* !r&l�r�XU8%�(.[<�."� �5&�-e!0)vAU&Lu Ѱ!�Vd��b�@e�a*�<�Et6!36�q�*�La�.1 9 ��ev6β i`# 03!(pq� �Q�.��&� Rp/�a�)$"� �6i~��%W �5Jq�aI ��Sn�er�D�F�. �$�e c1&�Kpo=�_"�ise.\S6Zn���"�or.Y.d��(o�m;wvage�r%�(&Q<3P G .�E!��f!3 M�,%�K�1"L]��*E��qw�a1�al"N�aY BqF.�,�� 1�Z��88ysorthwh0�pu�[�+a*jI�preao8mSA��Awo ��isP0^� 8ae78b���!�-�Ub1�n  :oa�fill%%=�� itemA�.� !�P.h$��p "�wo�![or!@��d�d� �begin�Gf9$��`"2$E A2di�6� ^�  tro� uZ�%�VV\ c�� �V2t&�'�xmd);a�&Wn��10YWA�Emethoe f� ta} >��D�:� �e"wY!�!�_h� m=l��on)odisplayEX�["6;ly wipa�u2r!�le� � �: verw�ZngB��$or.��  XbF*Yi � ����q?��aE ��.�GJI "wP!�.F�� n2K�e�q�W�Ev��{}Jz�V Uw�Ѕ/!?tro-cuedM���fl '� eti�Y( 1<iV$aJ EAN 2^`yAA%��:/ �?Ee�nt�jt �e;n" ��q�4ihA�� 2� �!*�aO .�*�&�&�ΔC�XF�>16%&��6�L,.�.NSNq�&&pK. SYAY >�f��>��&)u.rC���a1!q%9i��weca�F+,8rB.E "�D08�-08� �#:��*��l0O�`!"022�@ v �I"��UVMF��2]e�2\V~Fin�Xls|Yv/e4%� �a� �%.re.z`[, !A!1Au�l� �xeaoJ7 E�%89��!� uE�� �Za�;8Ur�%�G22AtU H%��Zs:*� S =3V525>� A�4772� ;BX.�>Y<481>Y482Y , TLRT�Yf�#���6� �M<f�ng� �&�D�B�="� F1�) U4s8y� `� tegic%�yA��P?"�F$[81-!�g �{�;v ."N�"| /&� tA_*"&3�y���8 n��o� J�aZ:� . cP*�<�Wi��Wm� b]Na.Z%gF#�$!�pE�m�!}ya��:"�� at���rhap�+t�t��"#>a�!�o��� h:9�!( �� 5uq*6{,&��Oe`hC�#.�l$]q)� tho�;nd�Drehen(**):9tF��\%0!+�dR�M{lu!8s5"T��Z=Eb��Egi��momAS| A�!�e��-A!��7!�_ �&��9: ��5A; g"ys-�,a��c��*W!,�DXeapAH�4 �.�;%�(Z6�� &��x% )�\"7%J`QW�|aimšt�w��!HA���A8�&�zU Q�&Ls�&X*_ ������2&�~> A5�Gn �sup3*}=�'aZalL2� s 7–8� �j�8��( amb�Gt� %�)Z"$c7�!�-c!�a0�.���5y�`!uM�6y,�+!'P1�9~ouze���st2i��A�Z� ��^4p|!P�ml5���cZ���' uced� �i6'ICu6�oq͉*,)A�=3resol"0p H�n$!c"�{�3"z��atJ�Qex�� jpas�&�@A�l�l9��1�ȉ2�� �&� 3��B]H. �u�+1x1p�MAa}� Z(2M^�edA�h�qb/:���T ru ),�YYevo�}�-�onF n2� judg��s;-U�*�&)l��E�a�=%!3-[���AO*���8hKL ()amN*�epN&#['��N9og�&�/�T. &�Xa}A�B9�o��� 2m�� �iv�}IE� �%�)a�j6w� �A��& �'�UIt��VKon�.(Te�.llZs#��)%��Ra' �-}:a�A�t�=esEs����. A��E� e"�@�us"9�e2<*s (.v)Y�~�.�� defa��q B ͠uI�dem�!mVe��!D"o [8s�k)t%�0vUst�y case�C�qGH��("NF}ar&��-DA4 �wA{h� �2q�<d!\�V�e��)t?2$�.is� surpqI!. �rA! �se%ys8E�b ��k S.,  9 >i ds$"�pakR���Q�u6be glea�7� l�se6�1!(� d-�a��/:�X ��{�1#&#A,E���yBf�t0my.�+iv. y�fe��e�B�f�"aA�b� ;M.L!���&!R�[4�$W�2W-�./ -�a�h�Qn.U6:�A d,P%�e2�c��-��e��26� i�i .&�Sory~�,!-ractC"0i �!y+ trs�6B�6�L��a:D[8e�R>gr��.%{�r�L�A�eE&�@}� ��B�C-�^GQfR�. DN��MO�h!�jildn0kgɏa !0�0"@2[8��|�'"�z�%1ca�s(!}� urSS��ޱ��&"�!1NinI�!+g22�aw P0M bou�l��,�8��+L%"�.� &� �1c�eF%a+b�ealCy �o"fi�>"#f�V_ o$_u$U|/:�S&�gF�&�B � &pP��8mxO, Fritse^colleag�)[sf��&6:!awojse( 2AFm�RK-�.{of %q�� ±�+.c�a�K�7��_ . U-��pN �T�ZvN!�E�*�ΔS"Va ��, Cic\.�0.&� fai� �opl� �6� R ���)[j��saeln.3 ±�8, b9�202�#n�k ���t�C��&�!�er�uG�5�P�&o� . F�v,+&� � a �6���"�+�!�.�a!l~! sca� ..\=�)�y����/:#"r 2M6� ���A�*>e��lap���on����7;B�/��P�/!�H#�(TU�Ei. S�zS en fA1n�I�C� A���� ."M~e�ͩ�9 N#� =�o� � �ke<J+�F� ɇi �5c 1�ces5�AiG�� i [85[X�~���!F2Or ���D�V� � � � aa�� N�pnja/ impe �to>� [88]|Q�� [89]e�!��nN�f�u F�67*��9.�K� �Mj<"�=�thybridM�EI!jh� q�*E"��8d!&�a�.�@D �*G6.� "7�}*�  jKf5�X�i"�ht�9��"� A> ��5J�I d f3t�sZ��/*� E�For ��h!X��E�< /�n!  !�6II�s���:"wq��E�� e�I�W�(�A!k}@a&��W&VI�@�D4J5�  .3� �u�b��"9p.��&5 ��F%��F���r�J#-0A�R( .�263A�`Uf��/�YkeZ6�E�S.*�'RM!�ŒEXF,M^�NU�� V=d �_�2��_&?H]��'6�(9A�)U���9��:!>Eee w�ar�FwA�ex�B���$*!!TJq���P���ndp"!;W2�,a�i�e� appl�Cto*�jN%zB .pM@�r.q!]�b]� [TAE] [447c9�p��- �2 [91]�Ui{�W�'ew mill^oon�0f�o�5 [76 en�^IF�`A�r!�sA�9�"�*�Q��1�aD�xaneQ��sw?oty�e�t��e�1M�n� �]� *%��a���:��.f)E����;� ���ai<�6c�JeprGSe�]Wo  !,ys"�;!X��a/�!~s.Κ a drL��A��3vI�Bai0;A&��?��� ;)E�involv"|�X�?i\�-�)��Y2�R9.�i>o�a��p"L� t-M' lappe XAVM�2JxHml��1��3��"���`9` j9n�*yv%! a�I�r"�?:���x=&��B� �=[�Tini�d]3�u�� e�h�m%�*�Hr di�(nguby isoQ7ng.��mb��2��Pe. Ano�.?~ ��E6�$) a�7uin�'��;i�Q&iV�.n&�,F�} �A04�W9�}Moa�[9�" ��i�at"�e*,�ld�Cs�cYU�&� � "��.A* g'�#6�#N"�='fa�����5A]m backv w!�!��s��eF>� )��if��ve&�oL�6�}6�{f,R� _ . A�si&�f� �/"+%x�1*"�A:n� ��/m�_on�~ , 9A�Eacv]thn��V�dye�ޗ blocke *�/�f.dm=27&� mf X�95._ eY.qu)�la�Tle�CAqe�5�.�qh�,n��lm B .be�?�A)��d�% �|��A�J=%ltop-dH92kup��#JRoVH"�� 3veU 59t� !��u!� bGE�� � sal"E�s)U�ee� i [9%�>�K ��6 �vund� N|��F�%T��he+7,>�S��1i_�!Mor�5�ng�G&mQA���U�(B*1C>i���!�ll�� �!���7Q��i�xsatis��te6��IFM-`�Fa Nonethen�{recognW��2$ r *"$��U�jL��gedqumon� �[� !/�3� !o"��O�WEOq1-� �:osa2%5�;Bh,Qb'z��o*U ݇�T*-}2�.=.� ; u�e^��eғF�&��&Zreorgani&Q(�f/_9�!X�i�r_[.�c2`.%5[99–10�=BAcor 6� a�3y�$%�i d�R�E~;i�B�%/ɨ�)�R��oth=�=��(c*&����*��i�� �{_)*�a�t�.N]&Ie�W"�N]�Zf&���j���=A�23�&eXBK��"}a�c%+s"�>k deba�)��FP�Q,i�S?�N�,�A�~&R��3� �jakW�ip�usA ea�*[46{�E�b� a�>�!� n� �!:!�.[9Is) cA�p"lassifyn�eM9C phen}+�^��o�-8R�. W�tF]i"�#�'�z� !����,(aaDces*�`���ie�&&Zlq'kA��l��0 &�!�greate:tl�3� llelP y !PPL�&� usefu_PL,*zCima��A�U��)�,�0p-tr��P�V� long-$?��" � SmAT he b@ [102��� ", iTCI�"�x� ��Yengag�$d�FA����,Bz �6jV1�� 107e>, gro"��ore&�)!�at-als��r*���sj58!10� AccYd4dea ,Wia�$�(-��a�conne�(h.y��un Da��b�"� �#�~1wi�Ycn�bl�B%�M�E١�uin���6ђps\ tCq�٬nd�8�%��x ��"�M���o-Dw "���%Xo� fash*��"� in�bA��:_&#J��t� �y���,-�traE$o Pl�!h)6qDR 6RE�X ��%�U��%b�&� "����FM :Աy�U�uIG9�!���#��Q".�M�QD�� I!X[5M 8�49111�<o."�g� ]�cQH>�%k�]p112aQF�4��>�A0� )|��yTi litt?Fo ��sus�s��)��F[11�&11eG��aEkJ�-i�be6>S�.�*Q[��Ia�ޜi^L��eh�+��istcNF4�'��=y%�1m"�*-�es�112�LB;5�h��A�&�deln)i]R"on���D1�[(y11�811�+*>&� �:`E !�.��He�T"�)i&mS�{.�c;:�� �5L" )!�}�st�in�I &jHe!`��.�b!ao�i� % �Tn�U(vL9�̛�庡�i6�f��n{��%'� � *� &mya˅�1�� �MoBh �!��9"�C1i&@K�T�?��N�MY!�haX@V�d!I�net� U���sɠc-xi& dyna¬[12�{'�UYH� �� ���7C?t(*y:�p�Y� al episodKA;U!�����t��`QY%.�<B��F� D(OAeiiFO��:�}�- agre�qY0�E �)1� sQ��%�Age�]@uq(duy0*{ � 1�O n�'r#%D�W� F�K����: "AA>Vaj I )�.�U���).:I�e� յ�s �1nTF��%B- �VB���j��A��� �Eĕx�nyet ��LD�9"�'�4m?"s"/*=%�[f4�by� V�z� F�RW i � �E �e Y-Oq�a%C!: U% f�s2�%-�]��be�,>e�e�l�r>1� ��,� O qSmKr*9issipA'�w!��� Qa �ua���$#���2�87 �"Lk/�-��(� 2}:8e�Z��#27:��z#-�BrF3�1*. �& �,�� exiԺ5�"f�C�@ segrҁk&"� R��lԕIr!�& �� GIer�zy . A6>M<��A�*r� Q�qM"�i<s��by�{du��.:��x �5�=Ja�Me#���=���a%�(� mYb*X!E�6�8 g%}MUd���W"!]e�!/S[-T�M!=%p!Q�� *S�Qis)TF���1s�t.L� � iVTA��3�1�[4SA*� J~ "parsimon���g3tݥ\ǹF�,�#��s�Ub�3p��FtUxamK/ḃ̬!7�*=i prob6=� apwie ��Kp&�{a� L� &W(36�OH,���mmoUra�21� ��EEpP,a#&��[4�$12�}12vBF�&&����b���bE7.�. B)&� �,�, �%H�1E�&�3 �)�p��"�g� ��:Z�a� D�cfeH�m].�.,$aL�q4!%� knowledg�1�n�"8��`|F_U�m �.)W:�B �s���ZS.A"�"9Sdu�=?_2ھ�; 72i&2 |V�reaor\�Շt@1�6sJ.Š�T %��� F*�4t�$Ws�<��� 5�Ma:ׅX�sJam���-�l  [3�-��{Q� ��]!F.iS)�al� �L�E� p������x/�8�2� � q l � �Du�a�a_ c�S&���m�.-;5isic�{�l_�:69\�iB?!&!�-F!�,�Cd����� �a��Lf^i�{ “l�5.v0Zs� heur�b� )2��a��&4�W Q#�b �z&� [&25]A�"h�I0���^�a�n�[1�� 127]��C&9�!@� � MK�[ha� %T�L� deep-s�2i�1� iveT�, F"".�optim�&i*�0j"�.�A��%��u{� gu3�#4tI� is [k,-� d')��(m�4& � Baye\�Xmߴ�=!�l�&r!�Wsycho"BG��%:L9� �a&�A�� ��of��.�3�DM �� �-M��&  _�� �_A����u t0 .W\A6 toch>*U� 6�E�.�.�.�:! [128��[F<3a�%0?]��e~ !��s l-I�aQq��:G$A@Cof! i�m25�'-;�"sub"� N��M�m�E�v�-Eap�M%�.jeM%%!��w&1H�P*  r;e�h�C%� "�e� d٬a�)HQs�����ir ��,yo? A�a�&Y!� dG� �).� �l6�={ o�:N�u��)��a�l6S w&�Vz O������ **z�f:]l� �" 9`����1$=�Q�G�[1 u�,e�y !��J�;���xSi� B�&�+"�n�e"5X��n"�,%(F[w���dI`�A7�j�~*_��> Ag&� f�6 -5!?� e�UNam8 ;W*�*6E3�NE� � `A � �Te2WA�1%sAw�Jy':�Q,�V$ e�A�:���� "g"�"b�[8�11<� � `a� ����F6!�lH�O�H Ats��v�9-~:�{ 7u9JTB�I1ie remark , $2�ima�+�N�E#&�,�B so fa�6���xa�9k" ��.!�j�auoc�j[< ��|� "�[4c@�!� , �R&F?i�^AXon���( fMRI 2�*� *�vin� �;a>�2i eft/6Ф3+au_E 2��bV�[�� �&�H+2 &�JA��y�x0�A"3C� 5eT/�lccu����thres�� �J*�$&� �� �mh�"�ng�onE�dec!����� �VM*=�aL 2�6k��ia��|�e�L2Y/jn f���y�^Gbr"� w=���fo�=sz* ( (d:i�d.�9*o.am���cx5"sx �a0�e9�r *��K!/J�xlo&F-9T mp� [�*1Eut7f�*�3lu`$ Q��)�3A�VB�!wC"F�9�e%�� �=}Y�d3raN�<6f G)�%�J��a\f��$��hDj�"ǚ�9y�5%7)�!y[-T�E�n�re �0$~2Q��. B[�o���*�[/ H�~�� c!\"�lm |�,LFm* ɥ�!v�e� t.f1�MR6a`.r�<ep �^ ��;�3��� Et?5 Comm]we` AUni?it��Veroni� 6 Fribour�Udw��A���^Declay�Helsinki�� to!*of 110�ikxj79 fema�t,5-n ageKyE�08 ±  93 yea�—37� u6� �, ItaltJ!M73^/� , Switzer��—"�$� e��_tudAr m�7��payA�|€m �aurse c�*8Allt�\<ns��fed�$ v�Vnd� naï�<d �pur�7!RY�}S�m�d M��ste ,of 45 cm*d(!K!�B!&or 70'oܢw c��!7�Nh�0����%���a�l��+Ai �zn!~,gray 1g�>.24 cd/m#�. A5b2�ybʟ�t)-"!bea �}imudF20  fp���H=@)�es!Dg�!� a��u��!�0ou�1 h�.J�m�-�:�o t T0Vir gaz��� ��)���@rWW ��ll2$i"$ )&�Y 1 illum60�Ay�ach?taY�� a�6j� ҩ spo���h5g�"|,b� et*aJ �p��a��( ��?$�A��f"x W���qe�Yg66�,"� f�Eof � cy;{�O�(e.'�uk�X enve���� .�. A/4��7 �?C�e�W (!�1!� �!� E. M�J��whiteķp&"��Nka�B\�, smoF _o*��"Z�n``$oA�( j= ʀSD = ��%#�nk9�� rpof �V�́<�����5�':Ca)�°-wid7sCm�II��,!@%c%ZluEeaP )�1[q+�]����"oB��9|�!.)�a*Eau�ro�E�QunBit "�iaq� Q|*v6�ZD ^�Cmov� P�! mous� upz)(mckwu?0U�C#V c E>*"I��]W-�A#*yir�" �liX�- ��3 butt"tQ�-bU�(ab–i�!e�ew )���V�)���<g61!X18�#zq=s��!H�n0° (�tt�@)��17 $"��)�`i�2W�pseudo �h&���Br����%$��I"C�$>|(�pS ,a�'�.9�m�2�!��eCX�� �M��!-)be*�t:& B �<i�&� �� �p#ed��%�s!�p 2�DeW�rP)s~!�%�n�m�G��40[e�,��a&� 56!>�3��?.]H*)ԥ�}x�$Y58�<ch\p�St5�=@2<"�Z �x�p�I��xA��-)1�ycL) :�G!�S.�*JY�&�s 1–� .J a2 .:�± �26^�� Z��[6K2=s�aGt6 ���a�exd���EPm!~I�. B� !��=J� . 2J��k�.=}� � �'6�S�ge ��17�(}�� 3�R.�Y!w>Q�rH a�!#�� −8a� to + A>��°I;re)6>[1U�a }T4yuI|^�3���)�.H��`P"E#"�-X���u��`ct�u�&�Mnu�>�U1OJl�BeA�6"40*!)$2�>]23�96]26>]�jmG*��e/��AC�4[Ios�+�t��4Z� ��V&��2�a ��N����#4 a:w�fL��r*�� �iE�(7�� “\t-!� “/ �.�'^� [ Г1 h �A�n��-�edm��u .�L�"st�5+�u�=�I*a�)yt.(!M�2^C@�=&*Fr1i�SNR���F* by� �&a�%��� "0a.Q#.���!& R�&)J'e��6orI"]6��o�/˺"��� \U��';*Y=��' �0(0% ( 25%–�� ��X@� bF$�(���a� R(13�d"g ��miR�nd bal����i~��P.� � 6>�qus:�%\{%C<< w��"�ed^V!,� uter boar6�eV�*(O:U= 559L 207���Knk �>�yuS�f.y�"�u�(�o�g�*@�a��~�@n"� kA� �wa+�OIJrAL=%$a�ZL � HQ��A���%�ia�q�45�Q/%�`�*ff#A(e ,� 1� ���~"�@vali�7^>0A . SMEE'ensembl- 16 l�� -gray dotňE�< t siz��@The average diame! mnV A6�[7��, 94 1 . 19°E��5� ly assig�r�_% (a� [79]%�a simi2 se/���SD�dot�within r -yeither�2°l �4°)�Ds);arr�F4 4 × 4 matrix�\4�1�)a�e� A��5(monitor’s��by5 � *|dir/ a@nd� $ve��al". D!�%��e�a!F qual� paced cel� �52�2 .%�,%%�X�tjit!�!a�1e�6 pix� e dista� a�1z.>fixD spot%�1E4)�E�I sta �a g�.6>(%�Aa)*_)Q�d�ax� Thenͮ�٪*2�wat�8ofi+ possible R � top leftPop4, bottomorra�E��m���j, arki���A�P-/ijy(9�A�a toeA�!�2�Ecask'o adju&>2� percei��N�b!N2�IA \^L�/&�by movA�?᳥�mo��m-upw�(��R^ down>"de�t )yc4tA'clickv%� butt�o�R firm)�a�V��va��507 7I`%t new:�-��23!?2��:�as�j89W !�52U�.� consis�� of 4��12��B�4�꺾8b�� �wo �L���Ū>�]� woE���J�V�6�E�� � ±�M��J�)�qDa�4�corner�a���numer�syndro0!+a� pathEesa�ult�a�ru� �Dh��I�2[1%16!�A!&m�*� � .� fac,/ *� �sZ �BMAL1 (�J )a�mammal� d.N� ��, s� m&top �M|�nqZbL>[1!�22!T%)�es ��he6`yA���!�someF� encod�'�o Na��j lead: ir:k�jsE�  o0chiefly Timel� APeh58(or CryptochAA:$1�, accum�e�? courmany hAultimat�lr�tp�r �m��A�` E5,?pe& (ly [23–28!�A-� te c� �gs�rox} 24 h����orWe�exactly *�"i �–h ( LD ) j1u>V�*M��>� .0a*$loI�i�!�1}p��(lso subsidi'6��vol�� �UYN%U�f,V a �� evid" �\͇ they�?E<"��%��.� [29���.&r��ori��propo�U��b�o4���axFR *� E��#�  pa� el�� of.�|>�usA� , 25A�SubW t9V#%�urZ>�:} m�� [1�24��2!d�d5#A�Ean=���mjpost->m�Q h�#:z "R .��o( �cK!_I��YlIn.� ,�xmaj�&lte A�=�d'oda���muN� kin�!A� �r%-.]� �� For 4 �#�P*d cZ double!�b���s CKIε�6nds a!r�� a.S[35!�7AMT qw( phosphory)�f�2��%"^dv� d sleep� NA�3�vM:�% �at!n�aitp[i2�)7qI�f�%.�-�[39 , 40!ME �F��J�modf)E��ear!b��>�mh�u� !�TIM�ji{ Ndtu2�A�� ��� �6��� place] aM� infl�(�� ir degrad�\A a�a�4� 5).�of�may��ly_ b�1�y��*YA|-� y [3�z�5�N ItUč��I-_�}���Roccurs� 61via/MXY�,-e�be mediN by a!–DBTx!�/�D TIM:![4�G4�5�L>l�3imal2�A]M�6��be#rengthe� y�#��V cyanobact�( [5�F� thre3-m:�8s—KaiA , KaiB�bKaiC— 2�� ��H"*(recombinant:BI hw �y2��,ssociI�aA.�e5R vitro (�% auto��6JFy  AM*-6�?�j*-��i*�[B,��'�stream| fe� ne�* �:���RI is rai�*!\�b+e�a� situ �m�2� ��s:F:s-8m�primar)J(*2� "�2V��!J���"C�"u/�no%<, Yang/Sehgal�� showH at=�locF�6o eCcan)Ena�-Ttim.�%�smisW&1qala\�A��N��work ext�)p�� �%�b*�. ����but d+�k�.b� !OE[59�vTo �.>K �"�" � ]�*�6Z�i�%vo 5�[]��!o .�e*�2�a��  d Herpes�us [60]%ؖ����1 rmal��I6JZq�isy5�.�*� 4e�ng!?\a� "z hS&�&��}- cluddt_)HABa�tiK MorecA X., ��.I� �T6m�J "&A�*� " �=Y}uassay� �/i�2y� n)�! pri�I�2�" -"�2� �GE�y�(-��Rs. To �s1i�2Xy� i$ ��.� ��� 5:M+�C� ; E �,�< -cha�eri),~C(�0� 1A )i�. Curr��."����1e.e� ��r�)�1"B"�" poly"� &�CLK>�18]�o44�ds(��mSuv%4.�� �i��W ini%�E� ,.qi�e>�XEj e�to&�alongi!a� nd&���Q�-lucifer� ( )� �5J�61! Q� ell�'U��. T��A�-�:gA�9 littl�6�45=Y#B�T�x8A�n- flec��&Q7 ��%�"�%�6�,,9Q �%� �!RePendogen�a$�i� X'�.MZ�, �t��wA�"o  0ed"C1A� . CoU �Aå��U�sa fur�5-fold:l� fumabl� =ht)j�e >cr���an�5r D:9( GAL4iO)%(�6w�.}O!)�UWS1A%� unpublish�$ataEmAnm�$49�����on�real-aa PCRU� �7 by w� rng(tta� 7s r�4to"� � :9� �A no9�!�e.0�pQ35�:`;��%�m� U� thanE i51C�Fi��Sm�*co��� resc0cm� trundoJrk5�isi cul��r �S1�$;Dis"�  3o�#|� N$[13CLK-dri�8A$Q�Iinhibiahb(0-n&1R�! ( ds ) ag)� e 5′%.3 u�n[V2I$%UTR�5- ]ScycISan�����1Bb�>��� �!� ܽ}E�rYͅ~ nsenS6l#incub)3e1�Pk3 �Z���D27f]" plasmid d�� carr^]j� =�.r ,X*cl�A��[62���C er���j � "1e�we�= � 8 A.|6AindI>�5~�l{6ak�#&f .�&�"FE�! cDNAq�@.� 5�,2��o<$#�YG59�S: �G�q"69ly*�-D%!!�3Q� :D8�*n� a�C��!�Q�"� is � !=Gis/5���qfsiA,A�b�ja� �T 9!z*[&��}�'two.��#�#i muc| � BuAi ToE��  Ecyc-vp16:&���� �� uas-8E�genic W!�,.g#P@Pgal4 �|r -�W0 k�4"�&��!��N��Uz2�2Atop�"T�f.robust� hic)∼22-io�ap2m h�a�1!of�� �.22C sumY7I�2�en�*by6R��Aa�u�/$ �estri,/91-Z( pdf)lf>%�AH broa�%� 4�a!n 7!�aGpan-neur: elav �s��F7(6H�2��a$diosyncrasV/`!�...^ !%#10� MsEy c�9�#�>���H���0) �*)�(1q���!�2�iFBMe�)F�~;9)B� �,Y–� �Y�C� !6!Keus`>(�I%-%I%� t2(;NF��� �:�.��uri�S 42wR2pre�!�_ �a!�u�WN<cl�9c7*lele;Hs��6∼172�J�?non2 O1�!$20 h pheno49u�=u�O"ve.�im�ap�36,;"-� io~2�wM�ie�~b��>;.�!=5�R]%�!ml�@rLAԁ9� ,( turna  [QTo"�#m )�JZ�0.��2��&d�7*�PGa~en�-we!i�E#luc��, "U  ��2�� i )"7!ng!luc9�i�or�Naj!��%of *<B� i� >j!� isol� wing��ap%��B�<�oO&&� [ ��$�S ŷa3I�37es�e�0�3AAl>�� !S2 "ntact u)�+�-�0ťae C7cB* ��" abov�.f6Y�z .o u�6� R%���l!�E�=� grea�N�!l���E�peE :cz3B�N�iz��%�e firs�zakA'A�2"�F�3�3A�o 7a-fufEari6A.Opo*Z �Yb�M profile�-�3� S2 �A���pai�orV9y�Aid-Oi"/cur� re.#-"C#a* ey&0;�{�?qF���z6re��� uJkn�LM(=�b� peakBm�coinc' lcerv. �A6e�i�.1�su��m|' 24-h�( �. Car%�IBI��1�YC��n�>�,rkn|*( D� �6�Fs reve�+�(r*� ��25v��aa�Y�b9/S=�damP52� ���� �9)�y&DD4Glůtru) IMha�}2e��hN� �`.�3T=�>��+i�37 $n bona-fid.�I&microS;y��4A�e�N*).�h�0RNA�Zeitgeb� ime0( ZT15 ZT3��,imepoiOw�=a�%�o90A�i�rough� amou@^F"�)�} �  �9> y� >;��4� 4i׵OJ&�im|$er , vrillvri�9ndA] FK- �.pdp1 ) ) ���|"B�z)�1� q��lsom@� -% H.��sAl�+�e)S .Jp ��e�%7residual=�}!�5*�an>%� 0a minor9 .+.� 7�9=Cͫ"? f&"� e.��Ű�Cita%N� * althE_qu�3 �� �@�:�4mfg�7a1s�uwn�5z��nd��)�8a"�! 5 er half-l:�Jryi�"�)M�*�"� *�"�%�e&>#2�")$..�'" %�Bm��3:U0��S�9�� Kn�� I�`s�\seJ���a�/l �Oj;or�r��) �eo�1op�L�wd�"?Si0n 2��p5�.T2TF�B� h"4'mn��� �r�T6�^$e9��O*&3%a9� 3���7!bproduc�ro2A%VRI�/6*Y4We�!�S+h�7c���&+6y � �S&�&?%#i���M}�J� (SpO�q6k1QHS null@�90��2Ugro�R[6�*� ��a���A7)z�C�EpeGI �4�� m�-�!% �i�ytH)' �U*m R�.�n�B�< subtle-4s��!2nA� Et.X �o��)�Fq��$�8%�2�,6) tillJ`.��R�a6�� 5�] a�3q��c?>+ o� IB1q9>s:��JreFTwea�i� ��L- �#�.�la�-� numb�of copxQ�l0o���nti�!�P?:B>�e-�nJ /A� �U0R^��!M�ik �.�z�2E Homozyg� lkARM,y�Lj/�*d�<ũm�;v�veo+ ow a�>�Q���>� W("n1�'�- #G "5EO u&%�?)�&"�"��(D�p@�Ta #LDf� N1�AK�lhow typjbu!� ͻbegin�MEl$c �NJ& ( )s-oX-r�_#s�I."��N24V���i\&��J2��I-k���>�gh2�M� E>fiSo��&�5O�� *RZT-^ab ,-E�LD&.:A2 ored�,��(ͷ)�c%oa�{8���diu?>} n%��) *Y(a�%�V�u��C��m��5Q� � .�h,- ] E&X!���t�:m� ��M��@-�OE��Y be�xp��+3 ��?QEh2r�5���2��oE�n � i ZE������HJ� M�TYof�q.c[n�(& � can��� �9�/by _$ sby*� �N% T 6�B�.��co- .�l[.���[�E�F�%!����m�Aari;01���;&�;E�Hnd�1verifi%R is f�qngY�7�)>�%yB�:�"{(�*����'�*�ER�2-y!r�aZ� 2�#.*�2~�Ee!�@R��!a!%:�m��i!�20.- –7�E{NN 2,�aie��4q4fv ��=� Z6A�#o�6&3� � �!�."$ noU he �RI�AvK�9 Jse�(L�<lZK-J;/012n>��t�2er6}inVaa5 !�u-�:7623AI��!V��a=b�E�ecRE)5c5Xw o!�,6��UDiscu#secT"N�;F`i%<lPS" 2��I�!ZaJonship"9UA� dos�?ݩ)�:W *s%eM�[6�:6 'T�ct�e�4� ofi�U64e��("�( � pE&��U B��Yc� �Nre����Mm]� u~A . Raw �} �,*�A� extro p�cs� ly l�7sD �I^K)s� �%�[f.M.� �d E�6dM� CCet�OQ�-zK�n�<bX���/���.Ie�%_V&�d�� %aA3X| �W�A2qif46K �`.���jM>jM�.�M�M�Q�9o<<re��T�7w 38Ae smMi�5/��� �i)dg)�qGD<"9Fm{!"�E��*N9��Rt "��Ms*�Q4�"s�6�2&��  }F�S�+�名�& Ek�%[:$L-v6��.qR� c���*f2E�s(2�d locuAde}D�D%P�i�O �of�w[b��N� *�  VO�Ѭ�.6ha$ � �a�E�� ]�(��HI�&�L �"�O��"� 3o� 2��'1 izCJt�gXa6�r*� a��m�Ser�q�\����� �by^�.��2�� ��o!O��� ��thE"�#6H.56��sI�steepNk#:  5�)�9�6:*K"a�e-F>�6a fas% >m� e�w�jor��]U�[)�"� �.c� :6�� �a�FF�A�2Np "� �9B��-13qA'5?Nw � _@6 �D}LN m��AC!bQM em�ź!���*�rE]2�X"^�w�J�VYRmi#E�,�]V*D (� #PEV�2,MA�urQF�]u( anomal��C�D^fic�;� ����.o5"V3E��K�#2� sa�!e:]�[� ppa�=2-*T;VQ s�6a�4|S��&iLŇ%k�s**pc d*� of�"$I� �a+�8�楦�y�]"<4�“�c3al”�A3Q! &�2g )&�.�d.���a�om�4� ɥ�&%��Y nO,���qs"� N� !4jJ�-�e�o -<�;Mm�7-��2+2= E!18��%`-�:X��e 3*& ?*&�� of hV�m*�#0n �f mini�C��� woul3st�eE>t&R0q  �"�a|eA32�nd]�%�^��q3 ))<�/�6>M"< � 3).� meA�ism�.aa1nG�<�}X&S��s:���ibse�Aiv�7m%�, mgB+^ �i\P! e��-�!�&� �2�Յ.�Yn6�*��(��n.�igssm7+�6�!�:j�arr<�J��".� *e9 @& ��-}��@!B�+1�s"v.tly&���R�7&!AZ �zrecruite�s�x ��&�&��ks�.c]pd�&an�,Qp��o� vY�M�A[2. �^�jNm "�8��|^�8� T8F�i��!�B�� W�_ immuno�+p}(o�zs)�m�X�Q]�=5[5�N70UNonethe�(� M�i7 6V.�!AhŰ"��c�"�<G?i�*j+"L&vr9�!Ye�p�L4 mid-�1w'�4� )VTm�1�i-Mi~CS�<6�;pow �e A�re�W� A�e2��B�)�ccele3����f�2� ��q_�*Gx�y+�D9 P.�2�de]?s2��+n^2R�� �%c!�" t eemi+c a!_�n�_�y& ��m�H�Q%U�0�o.� �[ �h�.Q~�]0VZ w�]�O:�;w<2 !> ave]qva� ear-�:�&r��� usp�9"� N.�;�A�� 2!*2����%�o� �A2i� &Jie�QK �?�<2�92-,�sing�p�^�9.�  poor�no6A�._(V�D�\� 4 ">��a�;�a�n)Rv �6B+bzS* % . tB#_P"I }lQ8��a� .�!��br3ircuitry z�a� ens��%4&FP !�6��."�# nalo?'M[3Q�1}W�B�i�mArachias��c�Ruy$SCN�g�|�Xmo�o)��*�]1!W-��`"OE �( Dembry@: fibrobFvsp>RC�1r[7/_"��E�"�de b� )�udy%�l� ���q-docu�1EI��,FGr1��Z"�U*b��6#�VO4�XU4U49 , �~^75]�}"�Ap>\����!��^t� P+m . urpri�5�&hUNt�J �Q�qiUL6Un~�a2� \A� ���9[~�- >�82^�'3re6�*R1�+� e��YeH�segreg/:�q�as]/d�t!�io�?�r� A�"�Y_5�|r� pre-�L� .] :�U2]1��cM� |mMb�WlmHV  exaU`=�u5 , es�)i�Gs�j uish�.e�lu�H[7�c�146> �*dy�Y��&�\@rd�<$&E�-�lSt9ar�WyA���.;���m�d� , 7F"A.�b de� �fM�P�tra�u�9!,!I�9��M��Gi߂�d%�A�y.^Y�$:m A:,Fce"w"� �8:9��ir5C�`!d a vi�tAzespv4պ5_ �F!er�Vp2�l ak �{"y . pAc-�,  r(, Copia RenQh.3��]>��Z���"6N�H.W"�2�trY �-f2/A9Bco��p���:EN�by Mlig[ g in-fr=Bi,,@pAcA V5/His6 ( InMZgen�n�uޛ�u.2`9maA�Fdin�hfe�ibxw�iruY2�CKct>jT, HyCl|}AC�z�se����n-�`t�V27Q!N�!t 7Aw90%!�h^ac4 ��3Ir \menw^N12 μ� �� iS 2�!�'w����In�=7 �s 50 n*pb��N(A2*� fi1!ePr)�v0. pBS-KS+ ( S-�a�)%"�r�9U ��:a��to �.�a�"G}!�OA RNAi toco4(Y}=yR[�I.��M)�yndv> N cyc:�&���� 4NUTR%t8$�ON$z5A��ErepJ�I�4s��ad pt II1�ti�?t#u��.�9:SQy� �Corbett�lPearch Rotor-Gene 3000B�Jh�Qmix�1q ed PS num TaqgmU�S-op�Y&�e�с��Sybr-7x���or�1�A4] ..��:ET-CCTTTTCGTACACAGATGCC-%�,!\ –GGTCCGTCTGGTGATCCCAG$;7 I0GCGCTCGCGATAA-CTA% I-iGTTGTGGC GTF rp49 G_GbCA� #D�AGTAGA d;E�E�A�-GGACGA� GATTGACTA:� TTTGGAGTGCAAATGTC m. lA�� ��a�$re 95 °C A13� 6�y40�'B �,0 ��545��72T. Fluo�?ite+Qe � plot� "nu;P6uEnmi~b�lga=hm�e�i"=.l .2x�Ti�/ N calibrEv�BN\ upon diluA��onM�[L� aval�;[�(l�E�S#ribosoV�: (E2�Forty-e�- *lK�_ �jon� h�1 �a$D�Luc�XA�7Ki��Promeg�Ufo{A4.:'p"�y . Ly"�-�w����PeCXr�b��9, 6% SDS-PAGE��4@�� �r~a�{brane ,m`-b�#��^ ro�Ł �a/z  tibob&2�� �Yechniq!��, *? -TIM body [78�^horseEshH 0oxidase-conju� =rF xy�rigm!p%��n��1!�dCUq���:���L[Ä,&�M[80CR�&T2[3.��� ,?� |a��- cycHe<,Fa��{�@<V;54 ) �V�566�8�|8"� x&,�Tm��ge�clo1$a� frag�i5� D� UAST [8�<�tw E(%jt*�Pgerm-+PMp�GoCbOK·!�@yw; Ki pp P[ry+Δ�B]/++�a�elanoga�"RP98-5K6*�*n  a�e"����] +� d$;(afA��{��( BACPAC� ourc�:eɓ394Children's Hoskl Oakl!�Re��I�5:4� u=2& )ls cd/! a�e��!�)��H� � �f!�e�@BS vecp��)6�7751817!�7747254i� KpnINSacI;m�B<476< 5531J<I�2rJ<557�7741748J<;�(thFx 1779 �36982 <Xho �Notwe�7�G�3mgoti�(refABo BG3L.,"�( � tagE� ņ�h�Av\�by quickG!%�(6� :C �2us�(be >U stop��W t 7738162��urom�t�cu�8d*Cg�eS QѦ�i*�S:�R��si=4, BglIIA�A' 320 , Nhe 5537 Nc!��!�Mh)A�f"ih�lE�0of 14878 bp ( 36 of )A�42 V)���E�o�� ,An e�H��a�-D{G�R;-�pCaSpeR "�01<,U+3o��q{yw� ( CBRC��*�-Fly� � Mal0Qšmn�Zor 4 �6�=:" –5 'D2 >)�Trikin�&s.�A>!7M p� Anal�)�:� � gnal��!�,toolbox [84]��=.k+ � A�nd ���wyJ����-*Ys � �p v�Ia(R� IndexHassessm��4�AIm9lGdis�642���%w12:12B};*� �2"9Das*X��[8�II��.ć.;*�N66�R!&� 9�A2�md�Rin�(��JE�j02.��ob�%y >�d6�VI &�����6��s%d.�"2gm�E&�6I�is Te] �|Man� ( Affyme��� c�reJ �I*'#iI!uIVTi� Labe� K� :[u?-deu y&!�!�B�Gen{y��0 �c , hybrid� e���wa�a2a �:T � . Dbu�.xeChip�EL 3% a� )DR ( http://www . r��  .F|/Yei}�@u�packa2gcrma "D;6Pq~on 5S��� logari|() z.a� appl � e 3t�L!+%*�(3 . Ac�n��nBE!���$ s*�Eo5a� e !lNe3JD GBio� ology I3�'>E ncbi . nl06 nih . gov!K$eF)�� J� ( AC01004!R���B�Z- 0( NT_037436 .%�.ŠH�����'�(d%_s�D&u&�u utonomI,un[confer new a[A��i�F��t&@�t�n'.�!w�s�aeineex�!�Io�T�!�a�A��~�>�fA��<it u!ab � Y���thway�,��e�;{hRS pmrD%Xm��vh�f PmrA/PmrB�<- oUB�S�'nella� ericaw#�#E�eq s*#��>�r( Esch3hi�"lAסdTP�-y�&5~2Mu�mrA)(8A-P�>c` �de�s&�u%}�1i��a�� f� �ρ� mrA-&y-� �>�9]��(myxin BZi�c<Ww�(9�Eq!��c!2 &C1�'�)�V�v�&ou�Ft?!�doAc���e,K� ��e!�u$Q7�.5mM:rol���-P�*� estauhV�Bl t)"�X)�2�y y toґsa"�6=B��e *�8a6B��.)����1tadRe�xm�� 54pa!�f!���-log�vsuffic��mrsrH�RD'�olU'u,��D-induc!����� O� -� prf� n+2&�{w9iy�t�R-��I�,Ci&ȅEf{�6rt��r�&m1�+&�I��|�'���g��Qi.e�a����U4yQ�!�x^M Bn �/i8 s�a�ac�M loci . ClR�al� of�7ex�c sig6L>GEaA26�W!~NY:R�e�k""dup�+ �n�D verg!��!�los�=�t� ]–��-e vk"~~� � -e=_&���a' easE]��c}0,P�d��%?�ut4� , [5�8!S>�~-a ndow"�iX6�t#enV"thmd+ ss unexpl�J nichJ2-e2_!�pleli�!�, [8]qy4,�4�C�His�(���53��mfre���virul%� “c�tt')���t b)�X���`!;fc_!Kplayed�3�Ai�y�A'6��!> 1%I�t�Y�i non-��[YwS�s��q|"#]�E[12[1yq�y���as!Z� �12��2��c^��Y�.�A�aT!h��1�E�S ��M[.� �3a'=fit\m� a� }a� Y�ais�e�b�<T��y�ͭy�aZ�a�A!/ �Ň-�l/\�%-UV�EK�! b�U��Lev�!)1k� VZ�<jYaJ} 5��R�ra �W"��a hguJ. Se�� ategI���insighW>MevoS��% yiel�Nex�f务. &D W�:?�5wA� ���_!*���� �8A%eV:� I�s.]>r 8serovar Typhimu] 0��i%er%�.~|�D� lipovsac�c�]$( LPS ) [1m�Q"� 2�ki� qZi.�\� J9w13���$.d � �8!k¤ db � ޤ&�  +or"Jqi��17 p��q PhoP-�e�& suP��D*� �vF8�55s_I cyto@c Mg2+ճ�*0/� Eal!��/PhoQ:�� [2" C2 4^ =�_��,!�� IA�3 Jqo� B�s�="� -�f�1s%.�!�BJ [2G4T�={2 Ix.r.c� 2i�4���" Fe3+1x��y� [22]�72in%�%�e&��"1c:5 �WB�� *���B.� �W{[3�W����&as���=���SI � �2t�W��&���,!\幥��S byk=<Jno \dem�e( �>;yond rei���Ճ�J��Rf� �z�d_[2e��c4 X]:�Zc�<������P)z� 2��i�B� he��uPs��B�[!�WA�>�I5J�qq�a,����.6�sPYIxB����!p.�6�5�A2.1��!��y�a�p7�p,P'b@cip�"� �0�$�'�KBbs . S�L�#� e2(��s{0�*,�+ed *�:eMe�l Z� e�[�F�"���#�FM �#%�G�� NCBI�ebex atabD3�!�.�&M�E�S�#$� 14028�,U $K12 MG1655a2D��(��edVMay 201Tb����a1 lim�{ m"�Klebsi�, C�1 ,.jA�.�!�a�"ra~3&�L BL&-a��a�- ?!I�C��A d pKP187&n�gen-fix�'1phyte KW'neu! ae 342 [2� 4A�MCNdipI∼30% ahw� �q%ӝq% .F�� �J!�� ��FG%�� mobil �Felfc�C&�me<�AX�8�"�Lamong9�iM%F�l!"U��WHRM��A�B�lQEE�<n�*bor-joiOt$�:�a%kKIh �yA��'ed#oNh�95gen|^gapA ,�ELyr� pgiEZ � �6p��.��T"� clu(� �S1--�E�inNKM�:�A�9incongr�^�p�Fis A��%G5k� �5�. FL&-!��Mo���"��:"�(�7on/^��.)r���w�dq��;w�E 9.1� . Coly,��s�YT$�֩�R�Ahh5!9* �J��F53� n T��7Woڭi��*R����)N[ �"�X" (�&" &o "�%�> apac�z.�� �1w�)gineeA�a.z"Eat���(FLAG-tagged�9[h!A'�?�.� =/2iE�����>�ng�]'cri.C!L*= pbgPA< 5<,e-� is����I ���a� 's oj`u!�E2�0�o;�Y�� �O!��$,6/% s"i��V�to�  -"� ����qMQUe% >i��"�K"(��B�)��n!( �� ��no)!�D�� �Mo"�2Y%Km�fharboa��"�U�uH6��z�.%T.���,1�ml("�,�~ ��A&�Ca��;*7 N��h 4 ne�8!�ho�!VA�.�EHaGext&�:pq�oY�xs"4? ly ,%�.� . Wh�gBH��9r �C%Q1b�0�[&�!QD.of�?�n&za+�}�*��&� >2��O!zAZi�!]Ut�� b��, [27�) a���) �q�� N:� A�'utoki��A �[fer ,�B�1e� ! &�����#t 3^�J�=V[2&���Q��Zi�  �I��v[!�ka oniz!;�&7PFJ#1JP:�we&� #(�po*T r@i�t%)�:�"n%&�m�� 1ir%(�X�)*O�Zѕ�h��"��-P8E�tOh �D.(�6O+���k!�*o�%`�:a�i�� ���� .K�" #.$�Bǎ"G tw&�#^Ni�(�\�kn�) enzys(p�t��� ifull-�Y6uA�RbWc� t�Zrecapitc�ImA��I�a+)]AB� eq!*b�u���SlPF�9 x� � e~.i��]��]!DmYbed� �"�=ATPa�o8>atmi�4Xu t� �|�����!�cvI^$��6&�4A;j? T!1;KM �*�.�~ ^{��.mt!!e�N�e!���BF�k�Ied.��F-w� &PCF�is� mMA5Z[3]  is >30}7M����%�Ded!@!�hmܡ�b2� 1�� cip5A�6� sFxAU`!}>vb��nl��\-�ш��q]cB��U�� &f@-P��V�ead���W�Ing �iximum�30�6�3!ead*�9^���X!^.(�&�)�< W��a+ ����@�vBHMMFGDed� �*��x�M4&X�5_�SOY�"]I��5B�+m�>@-P �i���=lhA��O����C� �9Z%�M(��y�:R��p��` �a�s'�.ne�hydro�4 �m�ryl1up O@!a.����iG+���}�>�2I�1�O�Q:�%om ��9oo��$ �2=�DeZCL�6��S"fO!?��j���s-]-Xir-4D �v? :,�"�.u%�e�� �6b&� i��R�AY��L!Cu� S!�>��a4*x&�= f@=wEa�`�Ff:erm �z-:�*�U\- �Y�6� P2�R&}o��y.RA*L_oZ") {tBb:n�+H2�eY=!P5c��0r �e�N16�-o�Y%�)�!�X ���inF�-�>�o�Z�r�In�-�e�y����:��X �:�m]cYj ��!V*U?���tQ!nz� �$�N�OD4 reduY�2� [B�6�&]^.�c !�:LI�:%6R>2(!>1��1w�&�Z�Nd�7)irJy �?�J u*H 1�HK853I4Te�tog ritima [3C$�l!�^-�% &C9Aa&�^ � � �� to��)5� �v��  Q�iwo9#UZS�fN] ,%8��d��m�3{�#b0p[Acu�Nsu �bxe�#� � ��@.UH� a�e��:6q�, aWf^1�r��׏�i-*1c%�A6c�D;64�y�0Cch- m%�:�:�ayV i -α2 G ��iQ h&L^BD1 a�f�j d*E� alph�ilix 2:�,>�d:e�� ��|�^>�Y��&d a�3�Z�U�4W F%&a� &� sg���E.&�2�6l:A�nT��`6B)�-�8 :�L6�" %e6� !N y�0�?m'ce��aus 5S�b6� %�oUMHiB��21�z�\&7 Rl�{:�-�.�Wj�7%�AB"_n6�)k>X*uA?6�B aD�oF�.��E� �6�.)B�N8��#r<�.Lut!�2l�.c���mod�A�kNN � "�"�"9 h�ter R;�m2�U��Vho�rR� �*a� ene�YP�8P� �:�!�&�k~�3�A��6�#�Fn:���l� �-:��!_[��.W%0p+"��te���j5L e&C"T53:��ei��.~o*�7"8��!Y.���!|%��kinvest>T� lmrD&tco�� b��~�b+6�1�A!ugm�@-��C7-+.�8i.�)�Y,�bl pmrG!� f�����#e"�L9���!�o�,� a\%"&� \"/�R�Ca��8.:6Swͦ&�5�I��A�6�5�a��'!U[F@[&�B%X�05#5B;��9 #S9B��A�; `&�~��k!��.�a�c�J2dC � Y W2��^ Z{�B��M=EY���, �� :�� 9 �2<A H*U�3e\I�(�%f �i�p�;nt rpot-ծ5I�5�QqA!u���-!� �yFB5* �=��%�!�)C W "!�=; ^+�.I f:��p T156Ra��:� �+A��*O�!��:4F�,b\>��� 5�S9*�isSt��2�B At�B �;e�A`�= :@�� Fe3+5\^iN E�Z;�&a�"�� pmrC5y�AcIE��1��RQ�m;ݽfZ�:IarebC"E�� QL���Jn��g�-:��J�a�D3"N�a0�"= E���!�lGf��4�s��e.3("� r���a! �E��/%*�7��%֡Ht=M3W*2D!Z�V�R�sho�m �6�wards2��gen�#5U1ʅ�>��8y�*7f5��v��*����( ∼4<�1�A.� �d�b�>e�U5UV5Ee�5��>�%b3< �.@F�.��c�O���� !�J��6�R )"�1R�2&{i"�B.)f][.� )&�I�*�U��!#b�kF� ��J. AZ:75�.�[Q� �A�.F%K$�l"n6�!�6z!��"$e�In.�d̏�5=h� at sw< !g�r�y 4�%gq!�m*= ^0���A 8j� "�iach75s�-�$�o[�$ :i��a:�=B���F�4&`5D2)��v�u�]�&� &�Uwo�DDhe�s!�1J{ �uI+"�P"U)���� o�2($�U(�?�Oi.1+!��@|%�s;)���V�'.'�� shif� ��d�Hn�#�3b,���M}"�&&2X �"a)%28UB�:>ʚ �TN�ZP�n2 �i�Hx�h�ak�4!��Qy. a�t!qR:�2�.��min�)�g-�-�u ��J�!�"��,�Ud`�N� �I *s'\P:� iE�.�$.H�F&:�U�e�V! �.om:i 3l�;N�5V� � .� �F'e2�*/e�N�#; A��,�6��a#.f9�&�+&l)� -^.��)� *})�a�������.�%M�bX�8ei� �:N�2�c�tX��"B�1!x^��i�!y6U�D&>)p��u�h+H|6ffa�a��rli�YǟA�2nib.�A�o0��Ť��:�>_.�����. � i5ge _ &�P ��5J=�6N�Hcap� ��Mc"- y��| .�@�,&lC�o �F�I�>Ekf;�N"-K�exp ! ec�L�TI3I*�IWԸve now By!2nk!Fwgo3Eq1 �szb��Ŷurvu*�D. R�\?o���,�AC�2��ˆms��9 !H".�� �akB �AX �e.�` A1� �2� 59�{� /Fl ���"�10�0�VV�5��7!{�](HQ0G�Et�< *og� M�8p[9!&��S�S!��9�%�Z"�J��s l .ly �o.DO*v.F;TO�?�`a�c��ae9em K30G35�L�K]!=G:!e�o�I�1��#*�yB�)*?S6�Rb*��&5�WA� ��j2K%�����BѼA�NF��7*� � ���+��.�p&�$*G�� ��� ���AC� ��b��iaZ}UT�7"XDBO�$�6H��1��v��� n�HU�^�� e|, " e�st!�%a�6�in� eU�ga��A6� 6��K!?Ip P!�"L[p�aic��u�in Ȇ poƥ�[3���%C ��ntF�9�1� `a�.��l`�to_ J����&�Zo5�z�U�e der� ��E2� %s�~�mfH@dem�~go�NbaHT!��le���T�&a 9�I!��&� &*(nti�.���=��. O�\,K�Rz "2� �t�/v.�x��!�&7!�"� dynamics) �A�vzdds���9[3 [4"BO"�P%x �x� �M�>�M9�Oy.��@*�Q�cI)!��!p�qi�� �� V�4 OF��eO ?pe�^Yersinist�":Ea�2oF�e�&7 .�E8�J�H�"� |0K . pneumoniapCitro �$ spp . , S!�)L:� !� incorpora�� into!J!�!r �!B$PhoP/PhoQ � �6i�:Ex-� se f 1�bu� A� from��� P �� �5q��[25�T��� �}[1E �Aft�jp linea% diverged\ he"� to make�*o ,�A-�*led�� ifice#"\ LPS��r�b2!�los%�E , perhaps��| ���i6\ and�� lifem�i�Z� h]# non- 23"� is�E 7 be at� !iney!"o sele@  at���locusn-PQ �m=���A���& e&� FA�~allowsU|p��1 >�under9�induc!Y cond�WE��[23A�We fur< �Co� �91 a.��%hasqH :�may��IEninA�%T!y conn-t.��!W�/�*�K.� t��en�Kng.�gpla�A�mo.�,��lu� th!resulE�A$olymyxin BNin6p deno��by%� u�1!oB[ trasEka�ccu ��of�-P[�O!Jbe detri� al�1�'s astyle�;a�8nA�at!]stitutiv��Q:s1�2U8 A/ crea� suscepti����bil��\4nt deoxycholic�[53l ��� expe� c>! mammalian�<ea�e [54!4��!���\nB�EH � a hig R�in��� Inde� mole�analysi��~���t natu��iso� ��rrespayng1.�# refe� �k4C ( SARC ) [55� BZ��!05O� dardVU( ECORS6] revea��e�G�is�v� �Sneu� fashA�1*�9 . In.�,�J:N iS j5a��~��e�U �e� aMa negaA�8 feedback loop P�P-P re� n-promeǥ����},�dp!J� excess� 6�\qj< "� 1[29U�6� is a�.� !P�>U�does notu�#6�ais"< fo�`!�growth!�u�i �.Our work0n� a� q �7a�suggest�^�|�AT� a*re"5 Hmet�c net`s aris�E�&� iv%���B"�"9of"� l�%� *e nicvE�sum ,d���oftenping��up� �+A,iously fixed���Y�� � [58!�For� �"� �!�a�m1 ze citc �anAse�pop� a�of�!� show] requiw= ��$of earlier�8D��potA�� �y !�8lat� � giv!�riN novel!�it [5E�AMf.A�wQ9��=�� &re� gene� have2�&�� �As�@� loci��ce�g�l1�of.E,� auK,��a�F% ztoC kil��*aI�AVsc u�. Fin0��$e behavior�a� ,��u�*ZcW:m,�uoE�deducedi|!� �r��c%�!� /Z� redi�W��encod���VYcabbjo.�s typ��*��model"� 0s . However ,�coa[ x mea�ism� link..'s� otyp�G!7ph� [60a�� now ��-�.�a&9of�aIK�� dep�whe� a}>�;!R��G &� t.l6 E<reby "J�aJ> �]�� ntimicrob�p0 de!�CV6Ua�easilEQ� by s�c� mp�l%d" �!�m&�"�,%�g��r��Q:ic vari�L"� �A�in clos� re4 dգ[38�E[60 �$� demonA't� at�uk� only, apprec��-P�,ex��As :aE �a� samea� ���jsco4+n0 to��Վly verif5x ions deri^��a�ayviomics . 2gLserovar Typhimurium !ins w2R�wild-e� ( 14028���� s �R6$MG1655 . B� o) 37°C%0 ae�o� D Luria-Bertani ( L= br�o�$N-minimal ( ( pH 7 . 7�suppl�~G, 0 . 1% casa"/A�(38 mM glyce�, 10 µMg10MgCl2 Ar10  FeSO4 [62��hen ne� �, a� biot!�%[ad���?f", f��ANce�%�: ampic�� , 5p0g/ml; chloramaicol , 2kanamyci24�$d tetracyc5 �S . P1Ins��!x.�1��perfo�aA{�[6�P22BG*%�I�"DH5αzu5as��stAfpreI�o�[�d DNA d �-�ytru�6� tre!� Dsn well� *�bi��a�ocedua��T�S1]�l�2^�5@ tud0lisA�in�SIq S3 ,�%s\. β-galactosidase assaym�.�f ripl��!��!=�9y%a�d�18d1�Data c"���mean valetreF &b �� s]:nu�. B*s^�a: [��a�a� �Jiviad!@5�UO cell��overn cult%‰�in:Ruma��T��2e� washjwic�FE�.ainno�ͅ"��gop�� esh�� w∶50 di�oe*W�� �to OD600��5�a shak�wae bath㩁. ) ml aliquoD);X remo�s , mi� RNA/ct��R,0nt ( Qiagen )��il@ of<��o� RNA �n�d u� RNeasy Ki2R%,on-column DNa treatAy#� Osyn� izR0TaqMan ( Appl! Bio� )%�random h�er{ QH��<criptsh.{i�itD+ gradual�EMpluricy-assoq.ca��l>)V. Accor�$A��N7\f��A�6e�y� �ofBm*s�do'&�z�al�ei�e in�*Bcɼ�hod%/ lyAL=N�b'�ng,%�a>�inevi;$y�e a larg ")))c��� , ra� than&q !�%�p; sRW��"���oug�a�'� o �.�A as�"st#C a��-�gen2�+����w|*pr�s2Q A�- a in� �orQQ.S �N.�%�!4pr�&me!�!d�Gz!&eBSof ��N , weQ3� !@t�&� E;f!Smarcad1��1i"hn.�O(self-renewaWW[#&�� atB��.��AF�#!�r�ap��blV1 �Z`�q Cell�$>%ia����a%�a lA�oial� E bec��aB &, char�� 9%M�!p�= a�set!O��c��d marker �-a�# ) du*A">�yV�����2Mi�/d,pursued��c/stR'rybX�uthoa�aa1ncipl3ppret�ill m�/ng��cucu�g&mmA��guish%�%n!N� meas�/! .Gf �)/�nGenQ�2�N:�S�.iqG%&�=��A�A,~�$�0. A limx)�\ `!��M$' !�S�xB09,}� �byA�p�1 many%-s�alreadyE ]3l.��g!�I�.&ly(�=!in�"��cla��“�y2q”i��enric� I��� 7x@% ��a� �A s w/ downE,�trigg�2Non2�!g��wA� also� a se% ,�r9 �in�J1>�isB&>/�X# >�q�'2_�e simp��{�Lfu!�.Red)[id. Tra�%�72*� |�!�de?4��&� 3h�2E 2^nmaE~ 2 n EzDu�/do�pr dir� guide0 diss ngql *�J� $. Recogniz8I�I�%�s&es��-�E�)]at� : stag��3;!�tur��o�F� *� 2�.�n� ie�!�puzzleA���%��toa�w new>�!��Y. d2� a�&r-toAoY,belief ,N��b. �S2y�!,����mix� =S,�0��eno��Vn h -͏d�*���d oriE{r!�W$?� %Q�(�4�theor/.aso/, (J&�"> �C��( 3 )O6validr6�. D&6I E�>cA�T %l:"!?s�s"�"��02b7,e�ene! ng= i86^"�Jpau �:H 2c-.*&ae��#.� :ig�!R^�ethe �Q#ib p!\��.g�arrg,�a few�poi�0�� BR� (y�7uh�v� g54ur task�t*9�!� iestRupA��� atIɝ2� � � a to���&�%Z� gr2bsQ e 1 >.5 l%2) �eVM!ged!�r:W}!�. �.IT1�+J�M!�a!���]l.�!\G1 ( dot�Um ,Umo}x��s Q.6u WacrossZTshtf���t�V6"ibefL4TZ� G+on�%�)iM��\ Aper]�}es.�s+���7�}r�US!�h�9A4q/e t2�$J� 1D E50%m��3��B��9e�RS 2V@an 80%–20% splid �b0B^�A9�/( seeA  5B!�[1]!�''i�I�'�-�na�y=:�.��0%�aN#� !�q�6 n:� sub-Y�s #2t-"i8��-��Iut�� �F]%mxrc,M� as D&� An-T�p( M�s%A+���of�na9 abov�6sE��>mpl�:assum6!Y�of.e�Xtrinsic!�$unsynchron�>46r�. N �&n�&��%sum pŽ62is ���IQDiscuZ?A@Wee�"IW ] �>��wI :�( mES )��mC#m�i�:d=( E��V�SI�E�*�2Q8� s!y�Arse� li� star�:�-���̈́wbia� velop��3q��� �� �2� �2p_6bly smaRin���n�J�a ir�v1a:va9ng �� be stochaW Q <� ��AMrep(!�$�SAs6bo�:inC � r>lloE319%�R�% �s�$&/ �r1�A�A�sV�er�(� ( A��A�5�(x9� , ectoder�,mes visc� !7 defi�:nd #aStricb spe�,��&R!� �wo5m�A��\A�as�\3������'��t -&O �*too`)-x4+*<set� a�ESEBB�.k 5R=2y&s�g�*(sY`pE`E��. A@ m%%?2 &)ch!4 d� ��2�o6 ]��)ng��]��e5}�+�Cin�3A5*�,�N7 "� V�V<w�%�5e#�ET�[V�.w� %deaeB�B� �ESEhs �3tan��&to EB*� S�3 �of sixZ�of�^r( 0%=�D}�4, 8a]1 �!5dby Affym�5x�� 6�We�� "!�R���-�7Am&�*� op 20�#5C�- e�2of �� ��(S )GT��Y���en!�I�&�!�.GA�b#9I�8I�,�er��cy��' %�ob&g8��cg�}�6��rJ% �.��a bencha�� , Zhou !0flu�*c /v���sore�( FAC��to�%�su�!B2�ng%B�[aa!- GFPAd�;zolBan Oct4��4�D+��9o[r-�4�4r`y(− ) [.*c m�#x02G�Y yP#�@ w!�7�eQA�2ca Q2)onA5 te [�"v�@:�+E� � �reporA�by6�EI%��Y����h\&| ��a%� ��heEelap��A�� �b� 16�%a�6!7 by F.E$r's Exact � �4�p-�h0d�bR�B�)i�� E%wdu�B �@cutoff�� op-ran�'�)}"��9.� �;��a"10 , �!�&���� TUag+�e=;.�>�( 0% �D�Fac��as=�toa_�S��f!p R�'Y ��b]Hp'A�u9� -��F!e�d��!!K��%o�52([!6�!5$Sox4 , Egr�Id��Pax6 (!K�as >K9_-"3& {�9:��JU$*;�:� ��Klf4 [4�0�a� [5[6]�11B@,t 6#ag""T-q��Ymun.N2f�+�5; �i�s2UNѫn� ha!��Lmy,� ^-�M�as4���( C$*H �LE.:� �U�%%m�%go F090 5^�%Gk&�9p��R�� */NZ@� *1.�a)&�a��%r.�4�aj�?"'hP bor� & ��"y!j��. y *9�-i"A��M�N.�)c ^��N��B J1@2in fu� c�hyp#",(b��g�w��- e un&�]cri�#6�~="SZ :a�8e�:�!�_/97AE!��rH E"M�+L :"� �T%&�� shorKirpin�+ ( sh�+)a��!_y�b�U� R, nam�!,*�#nd Pias2Cy��1i�99au�uamo|�^@�Aɘ�A�G�}�w=���pic���)2*���the�CdE�"%&ory ro �>i B�. U"=2� <;�$)z&(, Ds� � � �F� ote�mo8!;� *`I=sFAlk.Se�?sp�D ( AP ) st�0(��2�?.//� v�H���;er�/ chai!  o�/q[.)�$s�how��� a�knockdow@$5�'>$Fgf��n)�?mo;6 volvm�DK".;���# �y>$![he neur� [7��2uAte1�m�&"w qDl@of!hFfS4!gp �5#*F*�XsQs��,��NanogZ .@OoT'ltRA �O. -pCdb Hand7 confir�5�Iadeple��.�Ev![;y*�Fir^+n��Y~S4)pM�)l��6s t�) 5�a�U9Q # �gav��e�9��. O��)h��,"N mock z= �2���Eedq���eQF� N �6W &�J �RP.1H@2s���%y"�:b4 \sC@�Ca��T�}%��:,Q"��5� ��8�CU�21ge���)vAw�<�;uO?<N�( GRN�ǁp=]Qe��ie�.�to*� �mi No�=%�is`�<� ��2����!F!q� ��;i6 MI��R&5Drel$ ships�-�'n� � aken pu^QQ�,of ChIP-chip�s� [�=,R(seq6'10� aB RNAi ;�""x 63I . C"�-Am:# v�8�-�i�F "��+ŀd�-�2Z(����$!��*� a�uG�-�5woZules:�up #Q �Te�*>K"V �as2� �Fe�eR�s "Sl !j[11A�� �z^�miU�)*�F�.{%l[�;���� w�\re� � ��atF��Is��2�P J�S&GMIAatRR� Bhuman��aF0�progenUT� #�=3gLlay�[1� If�L-th'1puta� -@%ܡu�� pe �:le-q3��&9,R�'Z���oo�%[$� �pp��a�qe*7 ]kN��.&�2.7�6�En�B�� �k ?+� �$8�L$�p ; bulkAo!6�.EkdemA�(>q�8[ �.z-"V-��E�V��'bS�&�ab�6E E_t>L� . M�/re� 0x ]p!��M6^H� ��+�?�.� ��# �!6A�J9 5#�h{7a]%6e��EfK �+v2P�*Ѭon)SecACin%�sQp!(9T�"�B"�(��sourc2�_��%e��X> �!��.U�:�",-�B�� !/)N)1�c�7��_ �!9G��#�"A4per�R�T %W adju�Aa�[ 5oa�:F#�). S�Ue��e& R/pur�.?, Equ� ( �\�m�� zero ��H!p!,sum�5�/In� j arioM�DTAʼn�href=Q�%/ �%of �.�1�nul� s�Uw�b�roxim��8n F�.)E��am #g�:of free{?�-�i�R� "�O͋TRoto�bs�Z=r \0J.F6N E�q�O �]X�/h1�G��1�Q<� |lex�era8cnD?7 �agF 6,!?N� 7q0R �� �)lex�Bz*��2�s�P� jXpiv�A>�s *�suffic|^l#AEw�a4 /.2'asZ3��v�R3orkRor�"i3�RZ%��J�@P&rik�9bala�"�!%m*exK'� a � !�qce�, fil�Ai"}'no�JM#s�A�_co�T�#�MsXe2 pro-��s�\�Á�$(f;��2#R�" 嗡�ART rpre��$ �Pwofold@e�$�aMe ?�! f? deciw� q7j!Za !�[ �Suan..; Bool� �Zb . A�I�.p�Z�)P"���6�Sof� -Sox2-�i�gp[N�� �Bq"haj� n ir�rs�dbis8swi� [1�HS5a��ze%�&w5�Jcauao[0�-639;u;me�&m 8=m p����ar�5bu�"-_i�` U"l O2KK�3s&�'yM:l*1%��$te ij.�[15&KZ� dele%&A%�he�C combUݱ* Suz12 [16X ( −/�"6A�v4 ��(degga�>��_ seemQ A#!6c��e��B� 0� -�o"mp�Q%"�L� �=�of6-�� B�AOA��S&# j�a glob� TH3K27p� yanme�`g si,-Q.mx/! carcinoma8 s [1 �Sme ����6n"U2F a ubiquit_Y""�m^e�"3nmr.W*� �I���� n� loo��F��^�Q��P8ٳndN��FGr6wh Q�ae#&P_�)���7i$cou"�^0 ext-+��A stu!A!��bn] �#865unm,))T0�b� �U�0sc�I�^ R��Fi�^o$ a�foAYinferm�z*-scale kLsJA��-j types—&0%6– �&� �v co"� on n?]—�� V2xamiD�@� "@!$���H�+2; ��� � e�(�.a�WInterc�ced���L`J@^�'��2���YJR�f t�Bo�ng�2, �H��N#als!Gve�T��� We� wi<���)g� de�I?ZKY�!u)3aco^Au;, leng�Pnd long"4DteA�o c>K�!ge�b� lea��exa1A�"�%�Y�m;I� 3%1IIgaH& 6 �add&� seɁ}ocer��cu&releva&�? dis7d�*6#sq�RJ})ze=kg��e'E�U� themIMa!�elم-�= �.(+1 ng52�y�u�1��9�8�o A�!Xto�9unexploa�B�V �$y'& ��q� 5_)�-n.�K�sUI�� i���Y ed55ic-]ag""tzZJin�[��Q`� �.su��iro�%t*�<^a�$^s�*��lMTG0accR!���>yI�as*#%>su@Kc��q<�I�� c��vs@�p�'$ge disordT . I w�GostP����� & s (E]��V��Npa�-ip . R �[�A idisru�9�d�1tI;,  0�g�Nep�&�-b� � > "EZ���CcoW��I ��UDGm d5��bor5� yD step��EF.�_��T0�u�BrFCl HaQđ'e r!�5�w�1,�Mase–�'��$MYY-�3�IB AAyLBha�V8!Oa�,A�6Z^C !x%O&G+Ae[5bv�dSi� 1pBL ��N �N *N W!,L.–�!.B�:�'�d.�M��{ I�59a6�� re �>clear<AA7&C Z2z < �� THm,[&� .�X �:BbB��tq ���. "�&exome �Eq/&�F�unE=.>nd ye� m�n�Fndvu$ n�cwa\�nuS[6Y:I��)�=��H�� ���� aX�œ�@ �–��� ��� d� ]�!%6M6 ��;(�N.G��� �SrSE� !�a�=챁� 1kj� %�C�8^n�\E�f� ���'U$%d:�(esZ��&!�����ɾEGbD� to�ly�1�!q�yo�(�aJ� . Toi�aFV�.�ZeXdd��� Py�� J > 3!�al�o�c`'coe� O*�profi�k �Dx �"�eC�#� "� �m!bsc"=Ys�Y�Q�4"�"QC� Q�twow�B�-"Q�Q%����0*�-\n5���v&O�UaA)�'�rel" >nuD�=g/ 0�/�� B u�c � `%�e�(%�Ax:viaX%m� ] � ,�%:� ,x ���6 J�5jh � *�)Z-��0-�!+8 "�mHT�Ni�j%��]$N�&[��!h2"(s pair�E-z>8s1:!�"�n �aG�B,.�a.Vo!*� -uniqu1`iF "�B� ��,J�)�to� t�aM� pout�L"�LC� =�,� i4�m>�e�� n�f �imem�&�sympto,l�6+:^2a�J��y�of a�(�(( ρ = z722�80P<2×10−16;�,�'!�:�T�Zj]to 61691�2� �)u, 3 . 4-+��� 1801 &�M�rH)P� Ont�_y ( HPO;+loa� in 201�/>*�,nWje���*Q r��M%�Ge�_�`��)�&=�;���Nm�]�!Ts�?s�_iHPO6�or��p 0*5. I6&~&jm��b�{m �".� imprII�x�#���x� �i!*�.��YF2%rFil�A��~��*, LVCBAqG }ف��ste%���6�� q/m+Mّ.&!�^ �<p�q~� �!5N��ECUh�C*�*0ach)��'3�CB�% fimNr�% Jed� �!�r��!s sy(!nyq&g?m&|9v*:ge�����repla!r�%=Ŷ%.�Da� "Y_ .��2m1�� l"g$E).�5g�uA-6� age2d��&�%K�'A2h�l�qw�a�@.�!Da�Zof Marc�OE*�$ ague�E>)�p#0- Q!�\��0A�((!2�2� . V,outoormw.Ulr&�n�V�.P e>wovfA�u�&Zz�c!�obV� a�Q�J��phow!EAT�perturb� �Xi&��= .s�be cl�pH!�ed�sKG,�>,pb, \0SP@S�n.  pos�$�Ic encyA�>gcM�C}B:�nno� ? �%p2�:eUz�-lis{=. Als�*c m��MNp'����of-uto5�e(��W�!i�l �mad< d��l; �Bc Rel aY�<"�(�&�����*M�2"�%��"��^:��e^ �)�.��A�2e�o �F�~S:atj)�^��Q��k&����18]��9:N�E�]K �a �a cDk� �m?2[�6^�D�'V(b .&��-�o�� j�MBld&IX ��l��v)�!� N}#��� ( CDI,!=2V%�&�b<�-8h��(u �'�j)�"�Ei d}Aa�bab.�T�|!J� -O$ E �fY���&p�!]ir���ddO�'c[����&e ��>B:Tf��|"� I-�!��ofY matc%GF Q� cand�$ N. D:��$� pre)}�N'F� *`;gU�ul�NA-K"�.iny���� [1�|H"d -c5�no�k%�� �#�*u/x�eg)=>\9�BV; 7EXs v�Su�E�{��man's6G050U�M�uaC high�igQ�!�6�2/#�!���aO��e$@.ZS.�7�5kl&d�: jiW.�"�"28 y4ѷa6rd��_��HavaF � �:.��-�"B [2�;�se-�ff!G�p!LJ� �Zg� ��J�" , �"���pJN!"[��j� �M�z%g��݁ �%�&A�}]�-�+6��� � 9q��cڇ!� t an�)�1d�9hNETBAG ,��[ ��Gil_:!k.� 2fOW�%�~�\�mP�}%��x��95Nv^the� ,Zhs�1H��CW1[a& #�4782Q�g{1.�'� Ms�Q�+A���� Rp orig!*,s��&�?j01��L�%m!,4��#� s ad�$ag�cr �[NNm"p�r type�m�e��� ��e�#8,bio-o�-�0ea�-N�,���c�d#��n�gv�**V*t� �ici2p$��\��$&�$e�.�!�e��d�q�B�v�Zl"��lin�'Nu�S*� "����&a�~#7���:%�R26:X ĄLa�k *) ,.a8 e� � @ ���6e q��^ k�n�k'%n 6]"�A� �S!PnE��ao�8&��.!�!:}�F���L%։�A CDS-.X�Y�.Uun �ibm 6whRpr�%$|[.��r71���c9�9a�u���c!�&� E>��7*- u���]��Z 㥺*� !��5��Y�2p^{�G e wa n_�.��>� �!�B�wq�+) eO�=� �s >k#wyy%&YL - Q*� ū:4 2� ��S9�R���t���>��'�-�� Ioy��8!)�J�6�-mqc & &}Er� -"H+�8u���&�6�S1&� ]Dcon"Q?���yX)��B�)� i&��#�y���Putism�0 trum��*I)-�e�A�r�9e�[*�(co��b&a�)�� �1�s 3���BC�2&8 !���hej/*�mt>synonyi ��K�o�.a(re |�JCn�ns}�CZe5^ -��j)���� !�$i�7�@&B-2������ihood Ɂ�0au�v���. Hal�Fs�%�"�DC5–10-l�F�,"� ilwewә����]� vcsu!"��=!T�[�U�.!b" �[�9NF��M��)�uV5O8OE�a�C*�X9� LC, >\isz^:)�s/l�����!�pb>j��[2`*C�;A#effor��o{=���AZGP`oՋo�&E,*� �x"8*j9F�m�5 a_�NZ�v�q���� Y$k��&�F$at http://s:tpmrcfgu . ox . ac . uk/webber-&/rema$�Y�mE"�w >ʢ���,5�-��Z��F.eY���/Z]�qT&�$F�w� � �3��u?+6u ELic�3on6B �1���A�t t!W��,_a�Se��#�  u��!�dA�L��0wA��-�-m+�1& ' .�"�b�� ex. phys�jA�-~ %.q}�Ca:�!� �&�b�!!�*�%i�N�%o��m�@2�e�f����)m()(as GO , KEG�Re�� me , rPr��G!�s!qU.X�#� �8&�8&^8&���U N�� 12A�%F� ( I$)fe�_:�p ( a )��!�p{:�|-��� a!�edeF����i!�� a� �A+��0Resnik's [26]"y'"� ���GraSMx/ [27]!"E(%6[ ���1Yt hierarche��y ,)�pmN�&�twK)#t]t2A�;�JICaމ> disjJ � �sst�D� ; (:=e.EK�?���(d"�(e�ch�9ir1�e�5Kmaximuԅmax�P bestC� ( bmA�S[2s0Let/oB�����-��%) g1axT2�3DV!NN���� k�B� ���achM�Cby:&��b!.b}Y!��)#� iJ= ���.$�>%� %�em�%��!5��a�5�r8(m��h �o0)L� *�#e�awCb!gen2�N;)��4jg#z�tr�9� �ag��d�#�h �͢�4�W���[sLm�l . N̋,��H. d pl�"%�)���,�DG��q�al��6 !w6��!6&*n" �{"8%&{ L+�T�,%8}�A�y�x�#EvKB�V�%K:  E!!��N�%���e���#:�#՗)%) *���#(") P*� w .�-�(��"�0��s� ��!�s�!%,p*o�s�G��, Z�,�st�_chO . R>�'yt�T�  2T5)&!�l=+�E� �w3̢.�iIŭ����$ZC!�in��aU�$�!bes�a�diabemH Janu5R 2014�; MexiA�g��Apl:?  8% taxN�ls��Wfo`��l�gy x,≥275 kcal/%u�a peso�I-�*U(sugar-sweetmeb�� ( SSB�. L?rigor�HV . a��ta�����lEpu1�!B�Ae� }I2!�Dec�M�aZ�7a�5i��� U xed-��sqK� 2HYpreEŁ).!*�stv([%%x*d� t-a�-�6�&�& A���"��4��preM%/�hr�K!Wr=e*X��a$-ext��f�r� ke G�sal��+unemploy��XHE��4�n�)�i64��4by -25 g ( 95%�fF"terد = -40-R p� apit���nth�# r a ���h\ beyond�?w,%� _*FH1D(AM�D'%� �7(@r�1 l� .��v �. Low�U�sU�%��1�7%�I� C6�(( -44 [–7�� 6] gV) ;Cumf�!:8�w28w4!�w1jw!*#=�:}’5>}d�-O�6�pin\EHZ:our� !|~!ain*Ii�(vVs8Pb&x)!R j�Em�2p-�i�O�_( l�ofA�aM U)Aour��K�F���aՂ,�(E�2 �!� ���/�gax�.nm�jny���p��]�e6�1<ap�2al5 ��Q��^Uـ.�21&-d�I�deh����^y��h5]%�!C�oŋSSB�K2j ])�. F6�p^XA� impac% q 9��.5li e�in�'^iet��quI,�v5&G! tern�}% S1 A�aa�SpanishL- C��"��� al� �ver� e� in-E3�33%� childre3 d �70  adulkh�ӵI�G0a��6� MoG i F(was 14 . 4%�H.>E��Nr�Q^� '  �) ^  �2�B\ (Q�ed] junk%�])1�[4���IW"3 ,=\���th �st�-�6�9(!�2�, ultra&}E!pdr��  ��� ,  $,savory snack�/breakf��c�l�'� on�/, 0� W� bisc� , spב1 sauc�� y-meL}ITo%��X �X  1Z % ( equie� �#al4�� )�a�� � i�Y �_pr� .�e� �� �xA+ shelf lab���;%�o�v�9 Tɧ law {2�A@"F &�a(��kTl�!U9!3:ndI_A choco2 , pudA� peanֺ�� azel bu��� ream%tpop0I��P��$�pg7!al ƣs� �y�!8�  N��al Heal�RNuto on S`� @ENSANUT�<<��of!2�ic-/+�)s�Ma: od��$� o.=)af�ces 11%18%lda�Acaloric��cage���(.\� e���3�Mempir�em�� o / sA/n!a�ɧ[�|; ��*� t�<�:%�^ >�_&���52�kd<�<c�j d 6%6 .��.B >� �Ku�Lq� m��j7"/g�0"�� l7OrG�w�)or � N�. B� bo:2�2��aA���J co���w�4�&6�.)!��rR#�M:�e@�=S!�Eon"���T2��&j �I(.t .��)n%L"� �"<� c�$2]c( iѿ .hE�0��J x!H� .�X � !�!�ES���%�SR2L�UZ)�Y�Gv#�AAAu�dde-�2� �!�gr�%t�xe� �!�Un�rapel HG�@�{I��P�rc��( INS#^i $� ]9ew bo�� . En �f v@�+ti&T�5V��� 2 wkA-�&�r���"N �rTfA� gDr=��eckf�pantrt���IbT� &�"T_z���t��OtW�ll it�b&n(w��a b.Bd�[�$� e5i�)�Je��Qs*"*6`,Q�,pai� ndL%�F. "�PS]e�us&�53ط!k�>5�4inhabi�P�!��>K�9>���c�%42x�ўp&B�. F��v Z$ �).�–>�f,x� u�y�of!�hZt-���va'1Ak�e�t��1� es 20584_-mpD �� #�"�. A��ge B� ; 78R�ms^!Q36� &8 ��b&� �%H#�by��UN�%n,�.�+� wi#\,jt �^6�� VY�a��΢m8Q$As��� ���t) llig0 a Opin- �1h1w�2��&ZI���2�<ū�hod d�6d'�o^e ��  0A�e b| ��I~%#�st=���m�9p ��)$U Qts:�ro[L,� loor ��berbaJA &�Eegas���&�.la��rbE�ndc��!Ymy�prj� � �.��0ˏ!n��ori��^"�b�NSG��Q�R"u���f ion;�2( u��� �y!�Se�o .����ie!�at^ � YKs<10 - b�zW�F{fCAr��(� �U���u�(idd?��:%!�� (�0wo6%. Add�Kal�.!l��.bom9�hninZ2/R�chY�Y9�I�A�:��th�d;g�h/ag  [e�U�auin K]�*2m�64<-qu��rF+A?2�:Z^L"QT2Ja��A�J!!�Sei" �� ,��#D�rs��=�8QpaO�f��ߝ�� ovޒl� Fd �ho�rb=�i. CMX�^a��ium� A' d.�����}`r t�TD �@etitiP<� ��I�c���k$aw ambigui:�� �� �%%ll!�w�!7Mins�T��<E clar&��L25��fi�s5)� ]N�� !�2 E| .��,�r�#K�/ M��%u&t;C8qo8��.�FPS.ql�'� �.J" >L!I� �N��ug�6���nthEf���=pbVM0.��+ �c"!-:���dI bake� (Mqifj ��5DE� ^��i��(A�un"�f�t�/lla� %�e�uV�maieq6a�� % ��y3��t!�,��q13G!�ge A� , TXMW�ers��sc���:*w,��nE E�%"� )�Z~ ( g/ 7/>  ))2.� �b6� &�1Z�.0�:~6����w� 4��r�u"S , hw e�Q�hwe�?�*� '�|�AT� �4,4!�bAi�>+�;�����neg�!b=1��� by֌chx�S]����&B���"S|�r���& �.^�.�i�X" bf�%�r�� ler- adustry-\?�w�uA��%+>Un��Aoes�y W� �!mitJ�7C�m��\!��Bcly [1��. SpeVq8,AD)���: ongo^�}!3��(^+iALz*y8�t"�q�A���Cj!��`�I�na�)F�z� n��^!p~�($WF��N4%�E2ihO!j��_�e�tå ppen��/7a ʍ�2�F���We �a��Q6�ma ��m*!�[:IW� �+aG!W�j2""D"��'f#:�crdE�U��,I6Z�aAdev� x;u��{�SarN)�n1 ��o��p � jb!ya} ��`s: Foodhmy=α+βTTmy+βSSTSK/xmy*Smy ) +βyYy+ϒ•Hhy+ϕ•C*�h+μhmy&S|1��D�#i� g>��Ac ��1�of���"J s")��!1y�� U1��h�0 =.B; 1 4�.S92nd�0e8�(2JaadJun 0Jul5Y5|(��i�x� �F e2 ?2013; 2  yHo���v��W��c�>� (7 nd.$*�  CZdVI u>f$l :6 Xvλ �E��err"�6I�� slop�G�{ X"T,a�M!' (q Q�"g $2�,"u,I��@@�R��m�M�8 Like�pf gnq�"�`*�\ ���.�$� dnv"�.he��) Q,�*s7�F)� uB%3" ��eM����<��K2-C\!�4+ ��eG�Ue@-to )�� ?an"e5�N1�&ɨ �2��1!� ٰ��sґteri#��1�3 �  %�)}�!Zalw\���hac �")�]9for&rN:!�Regard�Ds �NG�-�ITI'an% M J0���T'.�T�)�V�rU!$ s�h. �-�to!�y ��!T>� &�"�T ��(a �� .R0ej(c.����@%��7�c(iTed��1�E�J9>�'NI$� ���:R 'A�as� T = gE.@��"9s��O"\�)�!Z� �)p A~ ��-��A� )��*�4*�>ŧ S3 T� 6D C 10� �a skeW.�)�sXA�! ��FarM��/ log25c�u�j�0�������wy�s�$�Oe0��e�) �=I7 ; *� eMaJ8�K%/to'B� �oFiX.i2�(�M:N�.|�6Q � un� hime-in��nta� A����ond�z "� sepaw+A�mqFx*�MB �Ett�0$P!�� J� � d�,� ) �`A�s�16� as Eq 1e/A&Y ^WŨo"qbl�S y%�s��u�4�re�J)z )�� #l�/� ��5 2�Jk�-.� #��x��eR�My�L�&{�qd�%a. �,s6v(ra-&] �Aa� �5reK.�y��[H3=t ����er2�. N���I�d s�]e��(��. 7u9&I� ( 96i�>s.�.*rWA�&:�d�]�\@V$�6aRA�I�G��ea�� two-�0Ir�{I�v�Rn;8��>m-M!�Va�, �D�.��I�sQWorh�����:�Aa*@ T�&Yz!H=,y5�N� = [P[�"@n?!f-"�] * [A"s�B?if�\ B ]d SubPA�oo >�Z*[|N!]N2Os�OKzu�``&�2�aZ�,EA+u8":.��A��� d st �!a b��p� dra�aX,@�6�!M�Od� �� 7LI���I . Fig 1t ��h2F��V1f��Eĉand�@EN�f*Ci#� � G1P W o�:UaP505>�,��\'Z2474N2�'0 +�V ��~�!x58BzJ �nd *96>r *�-A";sx�!*5h�� fm ., .�"e �� �F�:0 ��"� &�� 5"n � �R1C��-E>�Y� ׂ��t(!�[4*� x ( p <�0���( a -5D�"� �62)�L4M�I��J�8�A_�k%(! b"wofI���a��k�j� >�}P2:��A$in�G <4dɋL*>B�!r"� ,&pP& ��.��.q;0�No2�F "�sl&�Qe�@`"�[ m� {M�bq9g. O�,����s bou����8b� d!��?aterXmfs%��!d)�Yest�.�:v� �+S1%�7O.�R��d�W6:� � $ ='`a6N?6Be�!-<#N~6% 2lhS3!ki i���_ �i"� b-yaC�tA�*+ �}%=qd�|�82%Fcn���?s%=�$�� 1,=JMr:*� ,qC ����6eXt .] 8)+�\Aʩ16 �e���Ui_salty1( -��3"�.�:,6�!� @2�0K���2�G��" VNOm�3 to-e#'�3G �%�te� �D54E�! g2��ae��o T�~U�a�%��.�&��. A-W.��LF�XL\+�!n�0)�he�ms�1� 2!�2�.Fc2C���,!�8 . 9%>��D���&�&YWTSA�R�ewo��Qe upw� }-KU �V�U��t"�  4*�!��K�-�^(� ����P"� ��h�$od��up7�7�7�9!70%>c. SD� �`��*5A�%�5a8(o�[,�EB9*�9 1� find2AI�U@5-q BZ��=��e����'pv �E� V�0jp2l�,.�w�!n�� |� %fA 66(�X1�a���B�:( -�=3<�a�G �m�i ��r�eP5=��1>.4V�)����!��>�:�. E��4R:�4iL@m!. WS&r��Den�+��-l�YsJo�/�5�.,�+�1�f/E/=q�` a 10"�15%Q!>�?*7m le�A,�� gariyn�oilU�iQ9�-\.�%;,E ��q�pG8A��%h7 as 8�22%6�:A-1n��al�"on�cruߵ�ndi�=c&pa c�!�.$n�t#�7 � Hun��$FirE �-al$�  c�Ht*1]� d*&"�r�H���\�'e)���.}�djVAun>B;x��o��5X�� f� tU.�y�%*!e�xMu6�9�@sA���,�%l��i"�=^�@l�� dest�� "E� rul ZDa�a~9�>]�< of taxed foods . However , it is important to consider that 9�Is could affect purchases with other mechanisms in addition to the increase�,price . PresZ\verage or public discuss?�he� can helpou4� umpt6/$ed product�)popula((; but , for\nonessential energy-dens y(in Mexico ,.c�@has been small re^ve!DpSSB�4[19 , 20] . On)3 hand Tpresence�<)x0have had an e)�o I9�ofN� �)�, becauאhese items might be complementary and-[ed toge%�%�(vious estim%Os}�own 8ross-)�(elasticitie%�-Kreport[Ae!� a 1%Y(i �E,of_)� candX!Isnacks wE�deMp0 . 44%" L23% , respectively ,��Jr�se>z1 . 15z98Bz[21A Thereforeu�lik��AK�we found% }�is duEz both4!�!@f�AA�e�The rea5mM@25 g/capita/month!�E�ts 70A�$110 kcal (m:Esity�,at least 275&/100 gA�ut basedQ�,ENSANUT 2012)S meA�na�UA*�intakE:43 � j,) . Although!5Habsolute terms this�ism�%�Uk s capture%x,Nielsen only9 a frac1:0all householdIIm real�change� � � from�y�larger .%� >e\. werA,r saltyqAce-)~sweet!�Intera�nge!i2;,�!| r waUu �probabilAof�in!� sugg cI۱���,tem , people�f��oY�y frequencyZes ra��tha�50amount . More�� ,a9saw)�er-,-ex�%Չ.�ivolumE^sugar%7 0substitutes ,2�5�Ps are not necessarily=!P,y home-prepaA_a�s� b� ages%�$pre-packag�2e�5� Lower SES.~%�m�S��onsݘtax),middle>;(, while hig��:Y8showed no stati��al�$ignificantMAб�!,�istent7result�thres�.��authorZ Hungarye! junk�9� alsoA^*^ !�zab�XUc( 40% )�.M�� manufac��r� M�=Zs!� avoii�[1�A great Y x�i!tf Ea q!�iJdefine%�cha�Qer�f5 �s�Kj� to� . If�selec!p unhea�y 1���:Adividual!�nM��i� Bun :{;� &� if��cM6z) �o broa� man6+ ly �Y;��%�ber e9iɥ!6A>�u!���oui4E X( benefit [2A�25�COr ll���axa���fu��targeu9f��as!o focu� pro9"\�$�!t�incW  ra�� onal cook�ingredieN �g!��q$fats ( a c�[ cism�Danish%n� 4received ) [26�H"�!,� ofe ngleg � cut-point�O.�|Kax5Y)�nut��attribleft !)&� Ao5wis[ Sed=T( ��(g . , most �m�@Qw)�~��a�  peanu�ynd� 5I�2�soremUc�into “"�$” versus.2 is}itera7 L!��nd��ougE��� e� clar��sq<inim$law ambigu�>� �A!ab�2 . 3%%�llzd�$( see S2 T��� In trs , new C�a ol�!� markee%�evgo)ɤ July 1� 16 ,AG��A� utofqt�v� � e�sodiu� satu��dE�� total� � �!^d*� s at�![27A�An"UeB�F�Sanalyz!1>�a�a each-:eVterpr� 1%�nd de�ineT �M they�to pay (u�~4 whik�8a pay#!�ThuA9weN$ }ertain ?exah�� ��k Q�T�� workse�� i"� limi� on� Firs�wM�unE6to� !)Je� )�%?*� � ��gun"� �Vchocola. ,��, ta�llaMbl� baken.� even%Z�%col��&[ ly���CP !l��474>�l[ iini��p s* �a!�at%Kn� an a!�g��rs�o500 , particular�f@Ato Euro  retail�e��e�36>� ( ex1�=m!�NV)Y �N��al In��fA0� i�Geographh ( INEGIt )��"$ "� surve�124BAR� ) ( S4�S5��se,S� to�O%� umer pane�GmaO�)�p !�Q�sI`.)�be-�&� data�BA��a!�(�M�A+ servic�nd�ort���x.�-l�X aggregat�od"D ��a�re�/a�S� � AGmis! s5 ��of �9 �o�EA�dd1ed away)<�h 0possiQ %f�D F��.+1u!Nset�Ea differtre�Cs�f in oua &.a� be�n*B;,)[E�!i=y)�%�display�5 of 4 . 2%Aw6 m�d 2013��.0gno� �ylTA-re���A8!� Our model?c�er{ �� aris��al�d u& � ' w!0happen� ost-� .�#I��.� [4%�s�K continued2v+ Z��umQ�:FpMYch mayE)�@A'c!#i3��� rule� E�8GC infled by�+co�"�s unr| )�!��;e^�economic1!�anti-�6b campaign�3rege!�[28� ���W�weɐ�2 �7a*&�o��ňeA�c6�!��!I�( � issu>�$tensified � �A�2��C�%! K �ax{F �2yoe�e.2�itself�of^ ee; G�we doY�b to�!x omm �o��assQE�. Fin. ,�Gs����"� of urba6io�!6 �w�mUt��@50 , 000 inhabita� . pgs 6� !a &��75� ��S endi�s [29xk 9: knowa� rura*x��d��plNiLi . Regardl!?� tudy� vide�e fB snapsh� fUk�<i� o"�AF a ye@ft: *k�A[!�p!��sFu�� � ext�"� alysis by�g*�!a��[ prof�>y%��E9�!�oZs�,B� � _���� . � CR�.\�%�m�esd� a�&�!��}~decli��oaP��asE5  ��m)��AE �i�roI�magnitud% d%3SSB6;e� . D �s 9�!W parF3am����me?:{�D"�!� subqe/2�3N�� �{1 a��nt}�licym� �#who� ryI�decid��!T��S AlA���ll�p.Q��un�cur lyRs&�e "5d�sf�6�impacU�onE �M�e, ��qua�I1`Uf pattern! ai �how����p�Sto we�!��remain�� tud��.��P�ineluctd .`>m=��insta�$, phot� rrA?��rna accor[ to a Pois*H [1� giva�r!DQ �b at� lrecept��!rb� 5) conv��ngir��a chem�-l g>Pen O I !%%rdu��Wan �rFQl�I�in-�sE( �[� Each��s� t�S/'f (1�)2�-K�adds fur� cell} ,.�,�ynapticx3 , 4 N� the" !zlia�!�organi�'per��A+ beha0&� ż eR nc�hM:��$eA��! a agtoklC Aw�[5]� l�duc��2dem!�[ W�l|@ is je� nuisM�it beɀto solv<pu|a�ble�6Ga suii,a�"y ob �(A�us6)�i��ed�a�́!C�����_��to�)!�reson�[7]��I!A� !I�i�smo-&[5�2e. Assum!aaaOa��)�6 �"ub-U �� l(�c ��a=)d.E$� Ceyt� ŤachEI� :t�he1&[8 , �T"h)6se!�O5 cruc *٥��e�A�3�h-invar�zaKw C-tuI��f�c�� e�H �Kspike tu� � raa:�kdU+riA9�eɭ5 -! aMw illA��))ed [10��%`ng2� ar�(!)c value� , 12AndA in.{ship far� ?��! �v�t.'5 ��!�ex}�-)8{ & �!IpAaMa�", [�&� opo��F�m4 lso occur��A���sqA>��&w!�a�� 5 ed (�-s����p�r�� �!| dend��2�A2Aise�E WiUi�b!-W EHc��. . a�d{ EDZ� pro� ��".0� %I�iR,at�laiE�� �� "� -sm�l�  �*� {�6-QH� 9��ld�sta�og"s�fn% �� 2j��& compeey�! dU&� �rsa)3–1�!Du��1s`wk�V spep!� �s���gra�"��K�oY axim�ac�$s abruptly� ward~ �1q!9mB(!� time tmaxA�&� r� A�l�pro�#n4.�  (g ttc^ or tců� � 6]�% aKc��-i� �%1��)�!�v�f or �/[1�1�e activ� peak�(; morei,��timi�#IrE4escape jump [2�/!N�'i& i��I%�1s�e so-� ed Eta-)?η!>= [16]�0![Y.��q�t�.��`%ata�ir�1-��(m  2l )5UANh0c8 eyeI�*�'c!Av��Nη!��%��multipYtwo!Fe-z @�;!5vap,�2���αΘ# 8��an~8r size Θ ( t )i�MM�6�� A�$ a%a� *� ( α��s�u�!i�s>d�h� �"� �}�%�Q� noa+ by d�/ d t = .��4 #� �5wor -�expan| S#a)�� . So�ak&�1,!�!.D+ δ ︸ ≡ T = T) ) �(˙ ( T ) ·d [ -!%l] ( 1 )��reL� uA�!��oal dew betwD3ti"�)mR%�Yq%;.��#� O indi�!δ = 0!]I�=rL2P y��e�Q� sE�&\"�\"��experi��sup��ref . [�], Meth�%Se� ) :X )EIE�Trel =\l −�1,!G�� at T��=��%�!2"z���\q+� ly�I halfa0 -to-UJ�% o l/a�B54a�w� v η .%iwi�' c - T1EMT5 = l vA.( 2U#�slope> 0�i�$��≤ 0�<l&%>g"�$C typh � s:W=�7A�A−27m��$ ( i!{�-!0���of�w�" coin��Jo!�a+2arcta!� 1/α�#TE��pin viva�&V s!ki\ Y� !s�milli�u.liJus> �E �L aη�uA��he.�� ? One hypacz�,�� 2�ula log.hBan.  !d .�(logη;n �:� �/2��ponG*>J exp[N�by140$%ZA4 mbra_on4(t x axon�/. A� l�$� ͩ�M4 t�'ub� t�!9�e� enco� �=%g!�.A~A�Θ . E�/��1&3 n.|� deco;(A�nvm�por1�)�“$ � ed>b�!third-or�.B([22–24� r*e3be��xac� .� . Be�w�" ��7werVal��doe�t suff�*,Rηmi�a >�Ag] �  ��ac*� 8k&�2ly��'iB2-�#�"Ora�pl4!derli�2 �#rr��*by� ? A&lans��1E}�gu�� e  ψ!�or!�n- �A�=7!�q| �S !h}Y �`!S��1rη , n rZ-sA�)��E� ��!ga� m��$ )���3�i�*�Fo�.�"� s: W-η�R�|on.{iwI�dy0|��:��reT!:m ct)�* "�� "��A��non�w�� 8 J�5�Eq ( 9�>6�)�emphaἡ�%or��!�)��Gg�ϡ��&r.*aAe[:�� �Gc�%%L��+e�'"� ob(��s �RE� :�a >� %Ndi&� q�e`$ ^er (^{ I)Z� sta�(�lM��a� � x��2e| ��]��( tA At� = x0/v ( A���#d;*na�h&� U U?t�,EcB A��� <i��e�pa� � !�a�(� n+�A)�er� = 2 �l x >( 3"� �ŮvH�"' Rq � �3$�� te�-� riA"v,ΘT � �# x 2 �+ l 42  .� qJ� η-"� η� ��⋅: ("� �"�th�04� (� �� � > � � )y M <-equival�to �]α 2EyTsi�" ?= !Er}!4E? ��- � tc%�%#�� e�"� A�2� . T6*��A>, ���q��� ���always*� a fi�AQiE�,!#m a x�E�[ !v]�a�.z 21!l( 5E��'1#on��+aNa�!�( 0−exc!&� = 50�'σM2$Δ0 9'�ζ1#N ;( �Bdq  �� ��u.al�0f7$r N ⪆ 10��If"t� �y)'�%G��y� b��Ee[ figur��SW6) ≈ )!:"ac��b�"[!�"��:kag� "!  βTie��,hu,g�����"�;wo;J"AN5= unE*� isit���sa�Ys�m�randoms:g�#orE�cho�@9�A�%:Y� ru� �'me�Ru�we�2lsc q? e�%�p'�$he�8�4thT (Runge-Kutta� RK� ) m  u84 stepi�500μ�W��zU/�T�t%a �Or2fF:*s6D́Ł�~���7#��E� disc� z�( c�Eq�%1 S( 1�G�� !�J V�is&0�steady�te V∞ �%�Vach)"�� ��/o� �\0� to� �#���?cyixqa��@o�/( = ψ ,A�"�9�, n��x��50Ŵ� L*|}� ofm�k��lF�[��A. By do:s�!} zas�ly@y:P(� �� ysb)� og ()�j&�:�.Z'�p"ex� ]�t6�� ’sNBsho&0���;!j�U4�Frefer�#����&.� leVm���6cl��](!�e�aXpo�Sxk(�+f ����i+��qlEDη look�5zm�6[��k{E�a~��:@?��&��,� “undo��*�Yyw�.�ofK!�let g � �edIm"�g1 ([laN��&}],6, extre�;�GuN,Amei1*�(�n9�eus p�S , &, …K9a minY(%�If@D %atnB� %?iR.���- 1k � ¨ �˙e]0 ( 7 )"��e 36or ;-/>6l;:!!g�Bll��ll� �Ab Ųp@�=t^ p.\,w is g�1new�bad ,A��( �J�+ be a� ��odd��pl�>U=+� �@^=`;C*g>��$p�,A�ianm �d�1 off` oE�A^ ( sa6V-%��+ o ≥  ����gp�E>a e+A =.��"3 c(7 q" �as{��K� �maxτ[gτ ) �τ%@� �b1&e���E ��)�a�jq-���� ��6U� �� +F��7o�  g>W:�,��feal..>�)a� $l drawback{��ing��A�.�5 �%�.�53E>%um[�;J� `5rojLfl+ ned:9big�L�)%Bq6( Fig 1a�A��� 6D ��*of&�e��L�!fir��drops2�"�e&j(s ~2b~��t ��*�!s mAC� a&1'.�v0��DCMD [�EhM�N� ") auto!��fmp�6�IX�ip pr�ec��mo�'�- {�":�� easu�D�"� �l-D�9standarqv�-�50i&#� aa�{QdL ?)Q, ��QQa%��E"g3 I%���A�)!��0 E�c �91:��� �810��ā�.!�'��It%���Q5�sowI"�� �Fc�;e2Be/-X"q4. ItG&�3�IW0�=,i�,a�E->2a�5H,. �/? R&�  ��+.� �u 6>p�.�:�ie.�� mappa�.�!B�p_/)�m^J 𝒮X = [1 +�vM�� �& ]−uSa��p!na�r.>s ��a#E)zer���B/eIL�4re6!/�H≪�"� <��&v *�*. W g . �UyVs�� �η%l�  p( !V( 8�\~Ga�-Bg = ηa/�+η�W�` pr�NS� m�a�&������Ad�ieѩ�5�rp )fS�n�G%�1&�&['o#2�7.Y�2�*!Ņ�is�$pronoun�1(a��3�"� ~ ��i&p��EJ�`aA�s.��mJG�)'#"5�al!:�Mof*�:��a�“ye� N�)a >z ^ a =+)�> . W�n�"%|C��%! �biolog�?)2Fexerc��e�4��sAFon ? �G� rectR�8alo6A η� .����c&* ��)!{��C?in� �/j�8T3i�a�V�0U2�)Y�\VquiA�&�K�e�a��I�P"~���[/$been demon�PpK@ ViB�LXo%�9a�""�""gm� stru�O ∂f/∂x���f(�e�,"+f = h������>w6*up�Ca (RC6i�y�=]catA�&9.z�`:� 8'�.n!>"/2e ���a %}�l AÁo"u-�2�fo7-siųalY w>�Az&Yf(e�Rlri.{ ( iX%�Qx�퉅�zEil�ͅjAIP)gfal�,\aa�on0Cf[a�- F.>z �bQ/��y�A ledg�e�"!A�A�'E��fd#*"��OSYQ romp 9o���#+Vern�����P(#9e��b�$%����"�7;2w H�#-�#)v%`EAhom"�)B=sI0B�;�iiE2-�D�=��m�plV<� �#x!;>�<dOKed��oE�,��}'i�e �.p$$�6Ψ!*Ye�$xa�M"� ��rn2��aA*P# F.�N&l+��A?��� : g��.�2,~bypz�7F�3>�� N F�D8$ x�v0cW_it tu&@@��o�4�g�V5n3 �� ssk4@4~93*b�4!Us<4%Os.�#:�#.)<.�a& RC-�#itN&^!�J�V!RE��-�SC m d V �.Y0V r e s t - V$g �qc ( V i n�MV �-%AL~#�4a'7�"5&A�6(? [V]+J ��u,�(á�-wave-y�zJ�)&�� �E%�an� �g�>%��I "�unafQar% u�� capaZ0HCm!�+ to@A&�s;�'"1/R0!�leF*&7<s��;�re8�;��.� r��togb}w>�6corɵ� r� s�)�*s V�5!B"5� uppe(1>; P`L7<FRf*VT!1M�isM]ass\e) or) �N�!asympt;��`�:�027v .G o�S"� �m/�/�+ts)1VF" !8�U.� e.'a )). SJ !!�%-et��aJ�r lA�!G�a�5� �Vf"�VlA��!� N�� � u�7z+&�!���9�B�&�O)()�\:��c ���7U�4Su5��7τme}Cm/βk=>�v�=8sI�F {��Hi ��G�/�x �=b∞� each� �t 2�!�#=_ �3� &� τ/�4A<�Y% �' : V n�o�� β +�����g '�C� �u-6<!%y;s-���.����@ith�4k%!�=f�et��by��-6x�asu,:� o&�_ degr�;low?0 filt�` )��AZESlowlyE a"�Ns�O,�N*3modify���;��Rto�� + ( D+ D) A�� !O�X2yna�1 u,@ �F!;qG_!��6\*&G 4 low-=/*.�#ϑ��Evelb8ϑE ��:�(�"� S8�G[9!na brie�O8E� g n+ Δ t�i m� ζ 0�a- )f(�(�#ϑ�VJ1"2M�. +E��L-&-Y7A�Y6�$�#odeN7$-� Qa����I5���p� 9 lay@( lami�E nd medull& ."E ��ci�)a0��%��0�Dζi <gimx�d�?@ 20. a ( no}@�t h placV/2P: 6 *v(u!o� `3)�.[yb*�<LB[0�iQO\9us*g;@ a�o�Eale��D�Θey�#�+F�#p'��^pa*�Y�bq��+A�/me��\� &j�LI�as!�!��f U���:�+az2y�=1��D#γ N ∑M�N [6 +B+· ξ ia�� 0 ] +i�(�2 [⋅]+ =J �#L ..�Yη/a�i2ψ� 6�m�>���,* . Un�N.M !;&# Et1�"��#�I�esu�"�Bh'Ja3!�eti�0-�ξi� :*XL!�[]nUMl;&1a��3�ua σ⋅\�HGa�UanM��tSdg!���� We .�?+jip �dr� ^, ξjE$ δiju�c "!�) d�=sv/o:)4�!(e Kronecker�<t !<& f9F9`� /M�s N�$γYaY�BPi#�!:�.:M+S �N��_?em�_"# �T Q>9c BN 1�#�U�* notoJ;C rgan�*hi|>!��&E.�J[*� ��@m("�-s�[�.�9k�� �%�:�� chiasmaRY0��2)Ch.P� W]in 1o��M!"T�48*&�3<'&�6b�Rq pola�)�ON- O �9;sLcr��lXI;M !LOFFR:,q �Al?T9=��D� ( om? di���,5�!3loHO��L�|al>�.�&�ia� :� s�[6A� [>LIn���3, �?i U&�!�wF���KNeE�una�a�*e� Mv�0QM��u��&Cr~���&� sm�D-� we d�fi�po� �np E9%Ņ&�O\G�( madeAKn� ��chO]mu� 3aoso0`0B!9L,�C�Ns� �p PfTa�L\Q��yb/�{�4]dQ]�])�F,�� �9���"�N#*� g&| &r u�L%.i��n�e]nns�O atic��W:i��JPgi�,�a >6��� sK.+I�s&&s 2–3T�%!e!�1 �%*:1(�!&�hB�K!��. �,�*�0[2�@�]F+I�a�>�+eRϑUr �aO�m4.�N!1)�%j"��er�nq+A6� vm�T�tjP=a�Nbl&"c�!(>&�Ty ise-fi)�� V0�T HE06s�&�:4Dl ϑi ?ApsR�5�i2$A� 1� iN��;ndex i c�jKt2Uarra��-5 o�lev�E"}9�i�u5 [�� ���Δ0]+�u�looks� �s��le "NR]!'���rib$�_}�r�I�?�)౨i9O�pa� �ol.qee�.E�tKH��� Nif�= ϑj-�A�ci , j�j %�u ��i� edHů��� 1/N�?�Z�?U�r�'l il�Y� �P���7by"� !�ta"/U9�%Z;&�*[x*z xx is�$�.95E�x� G. A�(�3�-�En!s!�inu�wPxT �sui�Rn�eive� a,en�ad�)σM�?xj6O�$�-v%�^�Q�a&(K-7R]"� �Y�P�& � x�FA-�1JuT a�6w ∝ i[x2G]+ �$� nels�W� �W� �7,���w���PA=E9B3�!ca �!��t�0�39!�/ ]i�+:o eH0] �P%1f&�B �spY!�@QaFig 3aT,�_wm(�#CN s��v!�ϑEo�,%�I�s!�]��:3B�"0*4�:$B,σ)�moIw3$���nf t#h�v&:J!'-�noMv�-9ZEDbeM���1%aL ϑ �&yO�Iwa&�"hE�he R2] )v�cY!?me�,-k�st.v�TE��A+�Q%D5�� �� 5h*�5V&��Gh�8%�OI m+ ��Q �с�2}( EnFA7!r&z : A �, p�J��\&� &�[1�24V;"�o��--:E�W!�"(e�� v@��27f rval -�a� . Ou���Ant #��[}�Ű|>�8+q�"�E0_GGMD5�s8/a�&5�FF!Ia��\d5WS"O$!�!e �v[16�2�I�b3&�$�&�=.X+2I ’g/B�#�+fu ?�s�:��a(J�N.JTg��A�, Q$#!���{4Չ���an&("05%�."� %��U0(�%le keep���/A5��g shif�o1U�T!@HaA),e q=���4bWfirwe-�m�p9ao�O�H/ve�S� 1)�F��e�΁+="�C]hR.G!A$�롑>�α adop:�I�at�.�'5��E:�α�σ%)Δ0�3lo> �1b|��2� S�3sYnHA\-!�mp#E(�Nis��t ��. Fur�'�=i�9 ��O��\be�rp q� ؅e�Uask�N�`"F>�*z)T�"J&Q�T"1# %� gq�+�yD� � 7Q�&Ha}s�]a&�~]�� . A16�B�)B�a���h[ glig+q A α ��[&�4��A�a::'�+e&arl�R(�cEai� �L ��a36�1�"8 � %R@ �L2d&��^k. 4 ± ��1 �. D3a6|)�zH6v G9NGb6G��se��s��?M�*�EHlanap=[ 1_7 ( D2:���.� �A`< - ; �59�Ѫ)� . D2B�A�/r`ion� VM2Q protocolazrI�Cmov!��Cu:eye—"�op�<ea�a/N\"� �h9q�e)�� fMLigτly�3~%>� G<[1�O���N� ecedAT!T2�ch�J� s>�a- O.�� . Su9fl�Tx"d Da�K4A]$(�C�~�kT in6�� reflqo 8vekmjZKe��|�F�^sh.]{e2~�3s symmeNg=�(��!Z4�) P��A u� 4 ,e!x i�44�9��O%��'Q?A1�4%con�ȥ�ޡ|4m�xof,*�$U.,Terhap�� '�k�"of2!A� ����!= c o n�$\"� �!vD%�)5 �!�&m)�� �)]:�Z��5!%���!!��ci� c5ȁ�2 M�~� �1a�gsaI!�4HF7 *be_L��"F�dum�6s,!�Q��A� -of-*k%�'D judg��Chi-by-���� * $e��&[xF��%AuEG*�F�! �D�5�%��* � *� 2�%�)�!Gm(e�y|uch2X7j �smai1!~Am�?u.=Hal.�*v,}-i%N+*� B�g5��!��,�po�"a�*$(MG� !C$"!� u.�-A�=1T�����6�-)Gc2�(C��)��@iA�e��R xX2�=�A7�is�&�eZ�s�(i��upa�."(I=�� a��se�"lJ�4�5�?�9M=�> B�:���0 ����\A?�v���+�pl*R$a key role��a�&3=@A�&aa��"#"�*8\&� �!�x6!�r�� i4ilPN��OMJ*Pe�['��8aA< � <oObc4"%Q)&`c*�A]t��&�0:=$m�z?q`."ig!Agly�&8�+_?�EW;me�2r�!A��r��!�VjP�(6�!� 8�� � =�6 n��� �.�b2�A�%�լ&5�e�le��&Hiz f,+> bal�#�b&�7A�t���m*Pn� leͅ �i" 4paru?2 4X�6�*��g�o��MBak$�[( Z9Pconne�d(i��' b'7� %8�!0"�0�~(���eA��A�x \��&A T% E#oi�?e.� �'s>CM ��on�T.;,�Ke×$�Vc�W3 )~��E m$U'>N& ��9!$m��Asex,a��A'[p�F.P; DF�+�fe��=Zi��te"_YXeδ�� conj�K�b��6A,�%�k� �y!� "�Q�#,iA/s situEe.6�of���L���,/��8�9C�~�-��6��6t"�rmAor��y!T:[ � :6 .;� j� a!guY'%�ex�Pabove"�  o�<�p.�_  �K�@���o� >�@�t6No�� g!�� 5�*(2� Na by-rF� � �@X ��p!FE�&�("��y1 reG}K{)�� merg�)-6>�PqeCM A�L� bA�1%E�əal net��m�<Hist f�*f"Z�Tza�AOB�0!yC[2�%3$! 31];�l-worldB�R&�w�7s:?3�%5U.�Da; � ��Gi�{te!�uraC|fo�m!�� f�"��>Q,AIA2))L%5�\�%d%x:�  (&^@>cA�&jj��A0&�6�i�9�n�c6S�L�&neA}"�6\un�@N 2oAs�}=ro�M ����;V n���,h.Y, [6�=�uc� <p &�|a�.�'Y ���.��ҁ�s C:a�n�_in�x ed-U8 �2ura�a"O!�h �: M2_t� attaO���e+Ft"q�� �N]�fU� aVj*� F�*f ""-b�F1�!a:tof_6� ' l)U��4��2 A) q 6 ���!��p�xA � He�)��ʝ�f i܀c&�'< �. Os�%!��.Up& (�Uβ� ���!˥[!~��Y0Y]�`/�]"s!`to��Y��*�j�0jw)b Ra�d z�{�%��+p�)ivf"} x"α"�2�3e�L^ in��F&�er� F� �3*� �h�"�� !>|, :T9,h f7,.m%CamerooMVnd=}�3 Buruli uli� ( BU!�nd C2!8'itK*al!wol began!"200c��`�&�s"�Aevo�N, �Wevi d�Wlleng��Fo:upr�mm!4NBUCP �Y9�/s��o�J��Hhjgr?.�@��� R�lon��s 2001]2>�!revieT��Rre�gs �in 5l. Case-39�:� �BU5L�,ccA#Cr�l�sE/nd plo �g>�d�7]0O�9�2in�}�T�wg^_� ���E��5Ol�!�d�"��rIcoel�K&tes�sF �| ��!~�Ac�%��oN�� 14Æ�=1, 3700_V-3no�+�`A�BU>�droppQ:eOn��%��(89!�&45!BLR^5>0�"F+ �qN™�rq r�z_t8uo 6��Fa�iagno!#EWt{�� ��rA&� aq�HB rea�n�&!]201�&� �s*�� � s��g���nd�Ear(y �du�4�R�H�_e24]�*����B�-�щ/30-��ZAm>)X-�iQ 196e�m��milest7h�3�" E�s��h�jc,�QB$ :!6 W �wae($%�im�ng upot��m�Y?�gkryg"Hmajor[��A%� urce�F#�aalt� . N���u��by Mycob7�`��_,Iwtp ��coV�m2�On �a�,1{ubeOxo�Al�Tsyi .c:J��chron�ecrotiz%&�B�s�&P*i O�i%4, ]����s�E�[gm�if��une�~ 2; 3�BUg& tr�8 Eɀreg� %g��gn�1%f�p flow�wa�=bo��marshla�M[4; 5�Lwi_s�%Wyj���a risk�\At!�9RE�RA(Om�on"��{n�_*kX' �'A�e��� 9v ��Q} ani.a�rvoir!�> v{�s��BU <�s{�DE��! �9sex�N6Azly�9ldr[0�M15m�@g�H"�ch2+f�~�&�Y؃�q� �I��z�pat�rs 7���+�to 2�tXol-su>����boC�a}n0�K)F�3ۜ90��le�E k�!s limb ��:�h"! 2�q72�$rm!h�z"� rim��c�ng skin�.!�'����w5f��li�QA�ms:�#e�g-japunod plaqu�!doe��p 91t 7?I�WHOe!@� �"��`-J"eSH�S ( �1+%�[~an!��Lg �ly�5����ski��$�in��a*S�u�7?lab-:or�tz ��5p firm�[1�&�polymerchns-�9( PCRSǡ!�ANt -cop?Ish,on sege�(( IS ) 2404!EJ; a�� ly �Fi՘�)/./"!�rǘ �availyŮin 48 h�  [.y��� �� � ���*�#urg�8 [13]!<�A�pec� ʖbi�!�; �#&.�ww�F,5M��W'�j� �wo��!�!_� ysioJ*apyyu*)�o ����{||���H� Toda;��xi�td��>c �� Ŝ. E#���A�]�.] "E �i I���Ce� 8.i �: .� %�/( -�!�� ,y�� !�� i�7 B21 �i!��� �&+���>�*wch_  A< Z R � �!�&I�&Y*� �p�st�nusefu�F advocacy!+mo0z&s� *iA�a)T m1�Ru&g ��y^ ��W��UMin9 %P��Ha h��i��X No 0486/D/MINSANTE/CAB%� �a�XN� al Ethics�m5W��u|s2�is9 l,1/CNE/DNM/09�llI)�anonym�B!��%d � �sJ l�A"�&mEp&e�@"�. ��BUGa I�V �inb k1�B� *� -i>33�7r���e�� k.I1�]Y.y%�n�VA,u�b�f"LG)1998 Y��ssoukro!�l�a%}18]%+r���)��Ny�BBas�} n CeCl9!BU2�QNoeske]2eag�H �4wh�1y )�f�4P-�� i, 162 whom)�-!�135!;�I�IS���/ � fC ngs �o\#�� �I $two BU-DTC? k1e �k��Gin Ayo�� Akon�Ua� of���e�+o he-^~l�q�q%�set-u�h���=rA� �Q4ionee��� s"�*!�qh%�f�< ���IU4ȧ ��� 8v$Y$of�e�in��tj7(paL{ ic�a��`go�dو� ����|f*+K,ML� GBUIa,��Y�^��e�)f f�d62 : �����=�(_��I�o&̎U�domk P<ha��Y$2004 WHA!;��AB�,2009 Cotonou2^ ' ��%M1 ����LPUFQ-@p&ʍdu�BU W globab1 Nen�f�eϣ�#to" �� th�ߤB� �,r�-�N�6#d dis�> linkL�+9Q� . S� �r �ai06� �2�eE�,� fe5��as>� +)��gn 1b ;��( rm 7��Y�-.by�",e���{} T)�~2� �'�Kguide0s;I o%X� >p95% A"�� �4*� of j�m0A��� �#e�"�&� �a����'��3"remf!�of.�Partne`� ,�XI�% �q�N�r \oA.rar�=ead8 ��uM4 t�c����� O+tm�er!�����i@Ga��z.�fui9= reqeB���R5 i�3%���h�e�gapz�i $&&"�� uapi(���Q1��#ew"&��4�)l�l�ti� ˭na{-�% t��~m� pers�&ߗE� ZsEtau�llaul%��`yjo�!��!�%schoo lJ_C�(tx1B" (sn �� e job f� y ge�v y2���,�~zsh�lnd$res�j)�e��M���M��I��%A��A|�or R �m9f� � �`!qE�A�qwA3�i�ll�Z a�<, Hôj�ux Uni5. itaigde Genèz�SFa!�� M.�Bio%� al SE56�!U6Ya�e �5MBS-UYjM��una��ed qu�1�5�9�p%�iAKR���CG/T��iH�� %�Lghip"C*!S$nd HIV/AIDɭA��b��f)}custom?�rr�!� BU ,&ҧu�BU��F_T� !+6�"� �er��o+}!�!� a fe�F conc'�e�se==�ޅ M8pll execx�w �#A�M�Fd � d cham@ \;paR8�B.�%��d��a,(Eas�e�<7{��i�*�Q�QB� $aX�:m�!CB��urr �um2�<��B���N�i�re��$!�jh� WA۱)Societyi�+ai�I�2�N'1q��FBU5�uch�e' c�"9c�h 2����.��a�l��ms$`[I��a��/uh�:�É�)miI�i�7&XA�Fl�u� de\���!*q*;� Y@tzf�[.�����_okRar�e���e )�RS*0�D�!�"u �|Q,z �DwA; G dwin� a�AgA� beguM <.�(O#DJ!� ��� �n��)9�'��f���m��iy� ���|at�h�/a�;r��.rM:%�G<}u�t�Slj��E�!�irz"@ I��wA~�'�2��*� I���9%!i����@&�: k2)�en 8Ri�� *� !���,��rei,�cN Mdy buil�@A�cQg�tAR�#-�ʬ."�a�� �u� "�#Y�=]�NrM�sOM Q��!]Va U��=M!�effd.�%1���,a"&&�u#a upA|���.e~a�M: *c��es�ǩ�O&\xne�ch�q co <� a �c \�H"-���p��Go.� arbi��"�"_n'$s"��**�� oev�cce�et�QvM��metaco�����R—�dC jud�-�sus7�uBX .��Lbia . HQ ,�=+ stig�e!~�1%9ut�Af?b( �"s�loi� )a��6�AcicipantAcarŬ�]V*q���l-and-TH�$�q!1�2]�mA��tA�th��1�@�3!��(ek �Lu�to ��# �,<;pi�Q%���.$�4����ex� �1u�al$ �:�,��LE�4>Tg L-vwK�y�Y-upd�&!�m!��?�A!?�7 ?� a E�N,"��y!�3�4l2���%:e�!(��A_!BYD6��#fM�a)vea!@e�A�RPP�6�-5� [#a+}S�-gm�n8^�="�*3#"b) �(�z� �E�2ch.% �1vݺ7*�A��>�+�o lexi`#""�’Y��+�IS8i�i��.f7E >� . DeI�apA�+��[beh�a-�?! �;U@I6h1�rZ$| =2Q�5uq(%��nd2sy\. S�6�.alX� thmsA0i���kżͣ��mpl���S���-|;0!z�r���wa���m��V'pu[��n[��S!�yc.�q � ���� $.��val uros��&$(o�A6���parsi �ousi4c'e%ae� ��1�&bc��Se5� al [�3�"74�-s [4–;M&[ a�%�a�ab�`�^"V pharmac�� manij��# , @z-%i�c disBs�"Yea�eM2[� ina�E.Y?-"�,y�!K��leV/E"�ms�!ic�dYto i�!ndOEir9}���l_��/!�ngm�a5A=�-zJ�� soph�+cq�X��#U��2� � }L��ute�V/�=Ralr<z�ty"��2]� � &�[*��ToAm�� surp�uly litt��� � *gd�!!�ӆ�v��eng��{%arEx� : A#" ��%�.����Z� roxyZ !�]ٛ�*�fuEA�Nc��9Y ia �Wa%�c��� dCo����"l>82on-`!�� `]of���.� r`� [16!����bB�8"iIta-&: �P� �U'�]"�9rF!!�X�;be �y2���e R�a�]X�X �I���r�� -��tas�8]3�<stl R������trF�$ih��0�� B% P�"}<s*�rkAQ!Iur�"[215���=�)M%%�fbMplo5 � =�Y��e��s�wE�ar��e�1^uaq�$ �Q{�dwhe�a ��V�b!?Q,urg;��u i�Ekh/�� �=�]��,)�aaZ��6aI [1�Y2�����Q�:� Xir.r�  � Z`M���s%4B92�. Cru��*W,�� ~4we�|�2 oM?�DtE�>�:�> 8MtOض9<�^E��Vi/!�A^2 Nota��+S�ar[ aV "� e�_ lyM�t rF�!�� own�9a�[߅4�H�9�3m/+�yb]e�8"ffac�&��4�r�� e.��A 7|.ma�[b�& ]��Na�nx#[30#/�c�y)\6� moneJ�s�B���>��:� : ir&@"��aiI���D"%�A� � !]� �Ql9dup& z � Oi�"[3 Giv��&�BJ �Dcin��hNBbM,}OABU��I[�r�Q�ʰ.�x tane^ 2�����y��WE36� .�b����r�O�)K~q��T�s �'4�eq md �)�2us1�)�3ņ�e*�U, youӰdul�� repeaq�-���.�ly ��gaiIe��Au-Ge�5D�>[3� o2� � W��=c!�a8uBbyB\E��"�:z�H�X*$�lz�H~NY%�x:�q�������m��i�e�! � d~u-;%A�"#ly)O�Vm��F�5B| ���nA�2%=�:be��"P ~Y` �/on�L^is~)��r|��� n�Z%�ls–҅�AB)�4]—a:Lx��We�<k /�au+9& /c)"$by$U�!vh�ir!�mi�u��j>�� �EM�Y3��ia�6%� z8�Qo�aMR),S Y�~m�-%�A�]�=���2;�RiѨ��|a�s .��� qr�Ase�n4 �i"�`�gC8�&ZHu��M[�����.i�T�$"�sm2orqV�SsugS�M� Pw�X*�&) �&!�uM ins�Ȑe `V&:�to!_hat–q��cex�Y[PE,�3� y��tf� W<via�18_t�7�mar�!Q�3Ia�˭& as�'XY4'|H���$r@Hal6� ada���"� s_�-� x&�ݜfaa=pai�<ab�ct symb�$2��)a�2Q,�U�. S> WW�w >B��v gawoK�E��nam��m���E���o��� 2×2�to��Aig)T���, ��3��m���:�eӖɏy] ��d!��:P;43dI feed�("�`a�I1A 1B�F2��.ri�� yoff�uY�ho�?�E5ad�kag -�� each� Ӈ� U5A��*��S}q�1R�%Z"�;h�P f9B�s�5!z}&EP mh T��:TɾLikert���>�NRe��5 u"/y�`���)���a���ߡ��6G=� bestQ�A�("8 M-icefA 7 �50 ±[3pt-�@ vs#"� t17�h1�� 6; Py[ 04×��OI������ND� mar�z�fi=!�.HP5ut�&:+m�u�( ANOVA;�U !A{.SF1G1�]@28 �!�05B9q�5�04532;�kqKon>*-$_*evCeoB_�e�1�%9{���� � e�!>� &T )�2� ��"�A!n]�=ngs   _d_=6�pʖr���". r,��"�F�&^1@� ��(E009p17��3�B11 6� M��I~ 2�7 . 5.1;)�R�*��.�$ .)5pehIB�� �a�[w��&E��r"��a�heE�iE2��m\1����6t�=���+"� ��y�WDR�!�86�A�28a�a&639;�� !72-�a50-j�I�� � �c٤t�&Ef��:o@"|#�Q�d �F��(�58�35��C2"�`37:�A&52Q& . 65 �3e�W�!��;!�) ��@ �sq� ��?.�my0,&?!����$�!�E/y� m/��2�B��I�>t��EoM&"E�d�"�# rC-��v| tegy [3gĕ�;\:/%�X|.� I,/pA�� uth:}a�0� Q���+Da:�pw�a� �dadd,&��"�!y=�1aT�_l�6� �) wF� �c-�7L'�6W�znew.9 !��5�.n*g�AZ"� t�-� rrec� e��'R� 2��o��Zd"�"'0bonus ( 3×5 � )!()AB�4-���-�8g4l �O �nT 50y�100% A2Aer:)4=�&��pn]1� a Mat"�P� ty� �J&�V�p�i]#���al�n+�s6� !�BeL-DeGroot-Marschak au�'[3�3�B���:MP��"�,.���)�~Vb��6-��i�����!�"^T �M6�T.�8K$1)�3)�US8 ut,�%i��|pa�ye guar�� a:� =��� V �A(I|O pr/e�Qp.!&� [3�H4�:J^�!�d�4�f��EQ�Rto(18e�.� M G�&X  T��mn� �P3 neutAX� h��0ve��-�� 쁰 k�iK&�" ��[N���� L#��w�#�N#�� 0€qW10c�Hr�_eeBL2E.� �*�B<>� ��>3 >� 5@on- o�( ^( 18�  7(4��  3 3m^ 97^9 77*t 9 29 \!L.&^I a "��� N� !9; � =*u � *< � 4-!08-I3^ h259 � % B� &k�E�h�` �` a8�25� �23� Y9C � 38 7( % ) J� 9R �\�(�O��bJ" y���eU �a�&^��+ AE� �&� �m(�)�$F��bAo�or�Wove"'c ]dV*8���*����*���4 &�Y���f(#)���6?$arT �QRk��% '!��T<P >�� .�.�a�z�#t� �"9�*/.d"�u �"�|��)J �lyr���Uz�{A@Y�?��T�A8De/!�+� 2*!� gg *�67�� . 07a3e7 (6vs 0:naU7�w1����.Xx�-'�SZ�O!r��-�� ��Q)  (GS. 0(86 �A�T��t�/�Od/�cz.�_/-:�53�7N����1!#.0�9Re�� 6!15�{�35 ŕxv�1�g*�g�*�&����c�*&��"_.�24pe�/b�y� �y(���4�Ş1���0�}52^�!���*17+3Be'F8[ N> sa�+2Av7;ng"�D�+9��-.Q��+�4�Z!X&�)��b���E�e9��5vi�#��n�� scri� !��3"+�\B �#����1�_ #�.fQ4. S`�Z}*+[�My��g��a��isf5$y�A��"P �v �� inge���auB rr&$.)�`4]w(F�� humaZP� ���Q�D]�8fe�() -��e_&v- 3!~!��c*S.5!�E�+%!�Q% N�)�� ��;*U � ia>�M�E�v�2e aB�![�%W�Q���d]9&4nt variable wo��uld capture the effects of monetary stakes observed in our previous study [31] and bias confidence . While this hypothesis about c)Xwill be explicitly test r�in�next section , we first aim to demonstrate 2presen5Hthat context-dependDlearning is necess�to�8ain choices . C = =0cy , by allowC�neutral or moderately negative outcomes^Dbe reframed as rel $Hgains , provides an-�B,and parsimon)�olu%to%'@punishment-avoida!�Hparadox . Briefly ,)�$stems fromEno S!1oAaX!(suc!)fully hedT!} stru�(al response4pno longer reinforced . Reward9�(!�which� extrinsic6\(s are frequ!�, becausE�y,sought ) shoA� therefore �oretica�= mefficiQ than.�U%��inn�17P) . Yet , human subjea�havA$0peatedly been�wn!�� equ� well!9both domME)H-� �a radic thisa(aX [41]%�A�A�9�=]Z as a6��cZeals solva�ur�Typ �, implE� f.�dur% genea� s “irra�al”�ferena�`in a transfer task perfore� fterS:!N ticipants�$$ress highe� U f�il!�0unfavorable iej to o%�iv�!betd A�cQ�Gmer wera[iti%�(paired withJ^�%h� acqu*a�“�k!sIm�[4value [32–34AAs �Kse!/v�qtudie����pa= �@�%tw�>erim�lso=R96n)d5�%�0( see Methodse*The tI behavio�qsigna��ofQZ�a�1�reversae<coAbt!l!�E0P�w�F8 symbols associa�)�Lsmall losses ( L25 )��prr!�toz>�( G= , despite�A�.7lowerA�ec�0F�Te_aA] n wae��in�*of%�ex9�( %��; 1:�P: 59 . 52 ± 4 . 88 ,� : 389$5 . 04; t-��L t17 = 2 . 46; P = 0!22`2 `67 . 26G35`2`37yK2`u27 `6D4×10−BAGFig 4Ae84B , middle pan����To!�fir�se �E%�e adop!ma�� -fit��at��-AC8arison approach�E9aW nd2�60 ( ABSOLUTE )%� GedA2a�rR$ ( RELATIV@ in i�#bilityBccount�OE�.�’1� (2mRe� a�"� findings�+ , 33] NeJ� ��dybe� nd most�&��of*dat�llI�i� 2]��T�V1 ) ,%�4a satisfactory.T� m���.a��vL( average likelihood�� tri�&y,aA�7e  03;�#2:#2;R�topY�! 2!�n�2J1 t1a+�6j 0. �!Please ��noto at%B)�estim�free-ymeter�)�2�,very similarA�wI��reporab�{Yx�y[3Qw . We used lat� variA"� i� mpute�al �, a� ��o ;kng � mA�f� judg��,� !a�� crip�L)ɋ8�P�propose6"to und�K flu��eree m� �, ente�&a� lanaE�#u� mndiS ulty!p fe�}d�ŷ-ba!� 6sT !ab� eG� , w  ai��%&e~ I op� s [4A44��a]indexed�h G Q-�s calcuAoB�})�.�second�R#�c& exK iSprece�k�}2�Y��efhibit�4trong auto-cor� 5 even�Ry� eAw deciI mad�5rt� !B Nu���� ,Ur�e �uli�o)�a terleaveda/ig� last termQs%M0�=+� �&� ifE("�s� haHaspecific drifts du� nA& fluctu�%A%(/or fatigue-�third�al!�R�V� Œ!�x�ionQ���Q�IZa�  1J( i . �2hi9u h:�)�)� a�+ E�H J izIn(zero , gradObec� posi�ѭ�r�-seek� A�i��d&� .R� 4a&is���7enA! ur hy"9��Q� � e ( 2  v�z  )���8�� divi��٠]Nabout be �rrect [3  Crucr ,չ+��vcluN s� A�A|anta�oor>��X � AB  �C3��Az�� checka��verifis �M�h9 �s�*H ilyq�%�evvA b"Jcacrosi� courR Nr >� bottom& . O��ctr��rne�mp� to1Z�� -by- �ct answ�qT�a�)!�t�йnwit�sam�>�) A�̓��i��z���Z?mg>n!il)�6�` not (MJ4EJ&aeF�)� idea! �M�?miY>�9#above�bey����+�.t. Fin�&�u�rea�tim re&� ba�[ ly ))��%� subs!=s�—�� t�O�2�b)eir-�1�fas�th�s [20 , n5]-!�! 1� AF�jM��Z6f � pr�c>?$( although) op��eZs� �dE Iav"ap� inv�6g�!=N ���co69 �"�? -"t ,� combi��Fid fasks:�rob�stic i.g$ �"�A�ɖ�A<s&[8� 35�!�aFE��oft�e�I�m[4%�7]�� 2#)=(��.�a ��iv�.d6A�ed match��5 ty6]] . B&result :�consis4 lyX�!� di�*�9�Q��on&?.�!UqWceyw:AӍ�val� Vo%��s��e��hadK�A�eV� , itE��zly impa1 ��i�a�yi���\S? ��!(E�to�Qhgs�^��]a=4eekM�regardlT� A.#memployKTh�1� exte.ri� &�1A�by*2ATa�� 1Zf iM�e5�)2�9 �k� ���Ygi�k1�-maK �)$�� ��� psycholog  �i� stat��su� joy�desir�1}>�upx��w�.�J on2Nworry��iaHu� down B[26 , 2880r B�M� curr��gY 5��can rul��poa�nQ a�O�q$q3: ]��P]ba��.FM6MTa�>�Iy6,�y,�?lZ9����& �wo Ka^�A�c%�%����can�be� ribu�T�,6�chanismE�isg E�supkbymAVf{i* ��u&n  prim� �*��%�� )j orthogona� <OE%���x.�"���way��Ea ��� S| iw�ngR�]IOtAk"l i��t�L��� displa�qa–ra&4 bc-V�. A!`e� ��%=���Tf1-�m%�: inferby\t"�A�A9aS ,�m�scrYg�`!�Y%�N%j*�� %j�%E�":��Q� �T p�igmա rem� larg� unaw!��v u� anip��[48��#sugges�y)�aLA��"9 5�*R!�ǩ�s$5!ot"M�pl�a@ a , cr�!�!Q-}�z!Rs��!desaGoR!� -�!hy �I@��2�&� ���s littlmolQ �-y&�B{� h3">� . O� showI,m.�,>;!�!�&wmm! . Gi�Evsom��K M:\ c&!�Rr[45]–"D E\h�"� � 4challenged [49 !�N'� y��( by-product!gY � -� .. How����'!!�analysi�� �nd%Nsee>$���!�0pre� Apoi o��� auth7c|� �%} is a ���~ n9$�:�o�6�s"5HI�Ei:usq>A�&�. � �6],��a�5E�dy �V _��`ima}2calib�5ver��e� reby�c4 )� . Fo�%A�2&B� appa� ����N2���s does�go�$&�Q%��2i_s�bu`%a mP; �c�/.�Fve��E�y. AccorA�%�hQ�$ '�2[w� be1 _e)�d$A:> !C:4 Faggrav�'�jRc b>f�y K-�!1M.�(�"%|c��isBp) rV� . FuI">( archa�nee�bsAj uish2�� &� mt � RB� :��S�X��)� �'��=97 b�&del�%e�����ad�eZ��pN�bles:�da~ng���V��́" "� ��6 &2�&>.8criI�>� � � ir� e*�*���qs�a%^�D"] A�� a A lso�)Y ���.��q� P�� !� )}e�:a���2tp* � F~� � "�*(.(�0�a#e begin�of9�,E>��[3"�fae� �A AG)�* �  s�R�9 W#l���+l-�9arA�EG !�wBE��pembed�oxJ"'dynamic��R�euH g�A�2!�R�E�� � !!3scy�Z~� on!Pq~A�*7$�p1rnsūx:(�s�.�'� fe�� ,"�V�n&� .)8i L=�9(-��x�"4 Z��*re�^�:K*M�.Jc 6�+� lo; adap�&�~e+>LtD%)i�lob�malJZ&�*AEc&�=�* Q�x<. Whea8!lF���R����+��e��/luc�!� 0�-iJ ea�apart��}e� 6� �is �!pcus$ a�u ""I \ �� a gr�/liter�"2 ini��"�+�,m"-��,� prox0fN�"inA��"��5��be&�"avail�$ [50–52]%q.!�z0&#/�.�/R�&�"i� 2�"�l/FF26*�trail��"-Un�{ aRi5"� th"�/ A92q�[44 , 53�2 intu� ly ech� Uof se�'�+�� cep[1� s [5#IU�2�NFk�cm�!��s^t�S � ��.�Z��2�02�F�69&��,a( byK*�$4M tempM-t76O�� �-.� ��i/�Q"hijAg5~"� in Rahnev%�c�)aguH-201�a��F�3&�% �$b�+� mOa��Q/ !k#� �` � l�#a)k%l�[�'ed!sA�C-p2}?/[31�0xis se+3� �d yɪsolA�meG"� #4.4,A�"�(�å'����.�!�2!&#!#�S0) ledg�o�%% �  famil�Y��h�0,"% �anp%principA��e�u�d [!^23��-56!hO�+l�#N � out!)�iat "�!�]X!:�GZ/.�# Y=![int�� , - sophR�4d RL algorithm^0umEM�"� unce�>ty19Aptegzliq�t ��G ��flexib�5 djus*� N!��� jse�- ame(yE5�=�4*/ir funda`Q-9q�*�7es���, so fa!J��mervasF ,,� .��*&� /��+ &5, assuk$1+[1AZ1�b7–6-&e��,�( p5!mˉ�]F��i#usefu[(�a� oxy� s�9 �4L q�U��edB sessU�opert!޵S" �t��#�";1 mit"a5���* 2 F�R accu�5: rack�!;�!t+6�' in stocha�BenvironAXA�% g����un.H close-to-�+ma��sha�[2�P��"Z*� �ne’sUV4*�1(�J9es [62��Li� !e=H[63��&6%}ac��� comm~c�(!R��' >rade-off"l y�2zA�65W'On mind�ia�65I�e�"Z�s�2F6Q�!Co��t�s �)�Y���2.�!�1iQ�pr1pi.�,�A0th�/�AN�0�,A<�)Jym=� e�<4*vo�;le>���"F u;=�!La�u� 1� �'-.��:�+!�*�9�6��^*U7:��ab��� 89S'NP�*gtolA�at 7-ea*w$&�$��C� le—-r&���iw nk0o&�8levelAQ�c�o�/!ing�  " i�= :!N�iQ4.r�-Se}+ [21]��� �2claim!5a Q�Y�Z�sidera�"a+G per�i2;, f:��<*�'�� l>�$J�+��s*@&�v! ort—i�pla�N&�fun�),�.g .� j�rapid.Vm��u�2 . All�5�l � �!E< Ethics Committe�aOCe%{ Rese�n E"�8al Econo�!� polikD1�(( CREED�/�Unic͌Am*daW"�J;s gav@��e AX�%� art�$-��= e�"�=E�recrui!���labA�ory'st� .7b�5( www .qedy� . n�3 A to! of 84r tookR �� tudy: 186T,1 ( 8/10 M/F�ge�9�96±�9� 18T828F7>�.�4>; 3 ( 26/226t]:8±�*��y)B� ensI*w��R82 a %6am9( 5€)�nd *SgR?� a@ea6DBA�6ira�!�B B%�� a�:. 1�(�Ax�$gevE�!] in-gh.$uros = pay�0) .�7s 2� 3bK8!9in 2O  U d;Ia�8����l� D�(�$� n :))�randomb*8 ede�a*-5 { bonus eac0;at��2O'&�y%iz�� sche2�6below�P��i�1D�#G $$. 3 . 1 . �< 2 [67�%sa�"siz�?�Ts 1%~2 ^/de�4�u�A star� y sE~dM@ �|T!��� �.� @ Lebreton et al .a018�Cohen� d�7 d�N a GLM d =�41 t23 =Z=6� �=! 23e-iVFor����aNin-��� �(,")+ of N = 17�c!!�!hE )+of 95%Y�Awo-tail%e- U�=. �rh-�X a"z39�usa�Matlab RTa I"�pasD"���d )$ T�>�f�9loneQ& �whe/m>ng=�al����"�ccue� .�F�ce�;�I���A ds�e�;A K(i��ANOVArgD]s�s .�A�A�f non-�Ectu{Aprotei�%f alp�Aru!�1of nsP3� H<t �/sti=. N $��pon�;} he vinrZ*�b��lexAvvmQ;d0?n�4aminoi��%cro�V l{�a RNA synth�H,%t��o�*� IcarboxyXreg�. D�A�l��4yhom�,��i/BIprov -rj"- motif sha�( many5nal)\5� �found�b.r�3*�BT(#/t��� Src-��4SH3 )-1m$,amphiphysin-��-�~ Nsp3�$of Semliki�8est4SFV�ZSindb�%SIN !�(Chikungunya!�EC��!*vi^SH3"�t b�ng��A�Up�AU� � � ��acellu�>dis�o!�A�䅶dra�als=Eu� iz�KE�. M9w disrupg �.b!c�)�asiasA�i-medgDsi��6�-A�=�� }iA6Y�r}Din HeLa ! � L�%�or%�A&-!(Balb/c mice��!�carry�an.�-de:ve) �� ks&�l�0/*�m��8� se�:Ibl�#!<� 9%1L�t��2qae�^ nt h�B!Aerxpro!�K=YF.<. ge�A#(�4y Togaviridae �:(:s�)30�6m7 rA�Mje�envelop���|A{��v�k � 5′ cap/#3 polyadeny7gen*A?�Dx�" ly 1�� 5 kbA�!B�4mosquito-borne|�mo*]cap�a�t�ousa?Bin�J/dj<t��,[m�9Ameri��e�5(, Venezuela�&We�  �E�7 Kin| cephAIis� occa� ��e epide�or!�$� sp�N�ԁv�W�%�"&ly letha�:n��!�I�,s` Old World6t?A3A�R�R� ��IE (i� EreBbfeverY,ash> paink , de=�E arth"�5��isR!month�-\yeaE�E5r ,,� r��in 200�C>�gHK� re-e�to-�a�.5� ar�ӡ�$Indian Oce%�)�!*:�0 mill��people [>}�aH.��Ppla�Ia� ranegagiI'��w rudek �$inner surfE��eplasm�)m TA�� <ouX:< endoa^)�lys [&��_lell�A�do-+Aultra&� ���\� . ` eA �G�kytopa� vacuol}%ype I!�PV�2[)��VUa��Ds%�4t� �E�-enco�)noYBy nsP1-nsP�I�aric4hro�:�4vag-�� ly!�e�(cursor P123}NsP nsP2�Yp�Ks � enzy �/vi�ofEO��A�, h�3 ase/pas�+!K��mer &Q�� ( review�[6] )�"n� m[Z#/r�c� �Fth%m.�'D)��� stepSa&� [7�!�N-!�i���W-�T 2X&% �h�PQ��ADP-rib�v'Si �,%P��hydrolyz!{6L-1′′-phosphate [3[9�A1"�rE�i�se.�kNA2�)t��be�rsA,6lW2�-zN=i1:8!jC2j��)�=u‘"�K~ 1I���1t&�, ∼18$250 acil'sidm!!�i�"|A�i�TT!!c>edG-�Q�I�sn!-e �F‘hyper�,�,� !�no�\� %�� ��v&����aN��theI;~-)U$�'imp*!��rd �2V[1�S? He25ڡI�eav3CIqorz on ne%Nthreonr1}I�in>; ��+d �� dele� ~:h ���� E�r } 8T�; �B�7w%� ��ogenip?� [1� Mult�!��m�� 2Q��)nqWi&$via immuno�Hipi� N ass �rometryq 14��&5 )���"� �"I 2relev� ��esiD<inv�Td:Tuncha er�  "�A� ��1f���le�J �#�\>Il�e?��w"�?&�Le�#nsP�i24n I�zic�-nu�of un�#n�Z [1�I�2 thus��i�TE?�!e!��n� 'bS �)zpei+9!-R�%�.�"<-F�"� a ubi� us� (��300� � qhnWE a�)! mod�G^��� &pse� d60y�) �+2Lun�Q%B�.@�3�) | atd�Tlg&M��&a�aa�&P%P traffickA��Tcytosk�7�Zgan5a���.~* !� ir ligand� 6a�[1$As�3l�!� HIV-1 Nef� [1�}s���"a=e!Nh1e� --Qg^ W&L �-Sqt!. Prom�S� i��,&�clu:!� �9�M+oNwS po:�al���6J�w�U�aly5�"0&���,  a$��M�$-�@AEfSH3M�-#!�UL]8 disc��E\ll��Wo s���%2W1�%wK&$Bin1/.bEtw>3��[i�:�� E�E.n�J�d���9&� ` �!\!Q��f%�)KboC%2�B�s �(A%Z"N$7 us-i6� �#�:,.���rAn��#ōL r�9i���hVJ�=t!~F"d.P�F��!s�1nu2q�1?�|�m��> ha�[Ѯ5�q"$� reFN,��6nb�(]s � $y�(CL�1A"* .�arg]H2A�)?I�&t��.a�lmark�peptid�<WQPrecognbyBC}9m�E�!�!�'+��Mlea�u$1ex�9(!+ssi� !atI�5^"�'.`ɺ-��<> . To�@ �9issue��#&Qe2� FV ,��I�����sIAa�!� bsGriophaXWb�M3&n�X��x/<.xt  X?of����CD tool� de8A�vaOJ�'ur*H!,uof�ago [19��=- sm� �/�`)ob4ntifyAv*8�" !a numbe�j��,a�a�,*�-2���[20}?[2� V|��2��ur4 ]Vexz� affRa]a�$0 rsO%�( �!y# E�%�-� �=)G!3�m�t�H1000-f�%ena��#!qEp&��oe mock�)d���? -txa��+�clIEobc?�D��e Iof�w��2WorI�%V�#*���%b!�a:e|itu��2�1�.#1h-2 aah�," m�7"�/ �ijtog�%�tit�,9m90% ( 65�S72-,R J%��!��)�t!y6 !�e�%)� � nU"� !�V6+asLCMS/CD2AP ( n = r , CIN85fH) SASH #0�H�% �Kc �.�u���k�,d�JK#=?�#E�O"�-+a"�R !Py�d�!VP� �X eCprepa�(sqP�I1��I2p orA6"rm)n�P apac�&�prob�/�ton��BB�Bs{$.>'a3ach�c� � �a�G.���I��^�i ��EXu"eo;4y�)�=%"�a�d�.;17-�;�de/ spa��A�a<dw>� ( ΔPAW'2L,a 4-log drop�J|��� 6*�>`U"�.�A�}%�b��d �/prono�.AY%�A+�, e<�V���FDa�i�J\dir� �% E�B0A% � )� ( P2lFi&� �FV �im� w djac��-6�ed P1N{:o ae.N��NA�o &�W�)�+2�A�a�':27�$�aŝA&Er s�� 6����!Tu�Q0E'T�]jD%y�2�� !JAv&�!��N#,E1� � i!,al�K�2� �2p�j�'�LU7!�:� ; �*� >jQjAof " -�ue"�\b��!2we�e2�\� � vec.Y�ag�3�+�3B!�-`*f����a MycFtop�*j A�,i��Z���(6L biot!�cceptor��� �:Co-6��B1&ve�9a��as3A��"�Z����=�Noma�*�)^�s 2ea�3 agreA ]a�zco&R"��~E�J�r e�,y� Ny��@eX2s &�c:$%�E=';% mb�)�Y-WP�$P�).�(��m�9��.-a��x! 2|.�J��m`P18f`D1, # omin�&�22�bLd�>�Lor:B*!��AM�u�� E\I�� �bP2���Bweak c>�A��5-C"As3t)��Ux 2B (A�2�[.�!`Y���r�!q/�� !� romi�  2i-$Edi�J�2��_h=l^�-5�.-��U�.� d*�e�?ZeqN��!� lapp� [A�s��C��R426E!)B/R�1 abun� �eaݵ%5un�fy��ls� fail3�����%=Y.i�e�*�':0)���.nd� W2e!(/&ha�w�� *�&^wild-u a<�Z}� �N!a!6!+2%l�M�(= dG$blo�i� �!+0E/��w!�nt W���o1����� (���&(ul���ݨ�qnti� 3N 28e�%ly��2CVQ_�B�jBCM"�$x5!3MU>vi3�%�a�Sti-=�-7!tibod\��+? b� \�-[z� 60 kD�Vom%0Q q�9p!�� er��no�tcvr2jB��%�"�s�S5�5�5�3SFQ(6\tq�E@T* � s� !�xASr��h._f:�.� �toc��2� "B�Arhe�D R \� a�-)K���  ��as�q�B� . Ob 8 cand�E���3AZ"��I/& ( P/�PPRP��PIP  �p)!Lb�#MM%Zuwl�Ez?�>1A�("#V �le. !�;S` )M�bG"� &>ba�tB!( K428ek K4293i��in���)uZ0� hir��;� 'o-.� .w�� ��-+1$�)-.*.*)r0g5�ole� AVCa*\t�4�%+�#o-� ��assay�] rge-�;r!w�48.0>��n� �A>.��["��� 5j��2�u�3Ay�o:*P 1T9 B!ABw.-1�o��ro0a)xn alan�!.h��f!?aq92�( P42��"�A� 63& .�25#�is ma��f�A�3l"� )�1Wafh$B ����!�f%ft�sf8�.� Eue&� �;���ns 6�. D�i�reih: e�2(�1�4��a&^�aVa�z5we ��lA�r&� 2t����:%���<a��>i�X�CE�%�+2 Cɓ`s Xfu%r "�$]2]G �'"�1 do ���b��a&�Ddi�! E�f�B�f�%w��aD�M�*e0&&(�y��!Bu_f2�� !o�u�p&�" ycle.� A�$N2A neurob%@omO1�u��*x7E� 0�jL�.M�.�-2� �-�*"0*a�e QpB�C%�fi�na(M�']YFmrIIx ��, fEcsR%� bo�=Chst� , ds�( ( a @e�=e,t�}t�Ur._�_ �&�.�J�un�*% 6:=&�3ay��u� "4Xot-/ �ter�G,�A!��:4�:*���%)g c04i6: �)pYo5�Gb!6lready!�2 h�%�K� !�( p .�j)%8�rR[ ( RC�-�:S� Y55&*�.�64� At 6� o5L�B�!�E�p�s�QofQrui#@A'�t��At�G�ge��)qw ( 10�-Ie#g�` �*in�4}"� i*�.(�')? A !�y#6fYbto 7�D;�cS�. SM;r"6S!2�>7 / �DaD.�6�5|:�Z;m�)�GG.(�@o-�` ����� BHK�� b/��U%��fent�G5,`nŚIn.��F!W61 -Ti2=A2"��(e�T9p5a�� b�:�-%�0.38a�9".�)� "3�{A\at�?.Q s 5B��5A�,�.!�� 02MB} 6�&pjvKwA�F��l -oiaW>��e6"�F$filopodia/�O:" .�; s 5D<S[*!��D"�1��6��2�2�A�-��V�2��9��M7baMr ��.�<��6I!.�&9".1� � t maitWtoX�syn%Vc vesipF��'&� die��las�+*� nuGZse~� ^fndVh��ihM\W��m2�-dedPb�>!�W.�2 isoWs(iS#[27x1 s il{)dinM' �3!J�6�earlie�M�b�,&7.�)�Qa��"�N�I�0�-p�t-q� � aL�C�� a� pope���ls/ 8  -"bj�- \ing&�-�4.?�A޹q�T 6��. A�q<�q@ �:�� 6�� ­g>�}�d" 2%C!LaqA�E5� �r� �FV ��%��>;)!e�5�al%�ex�'&5o� eB�.>�1=6-21&X&��w����h��6�.}m��6W�X�BE �*6&�-!qE���.Kd�EW<�2�?�H -e8-�wb.�sy:�n?��.�.�A�!ܙ�2���E�\h��T .���A_u�$*&� 9�mjA�&"�N � �iY`s�&H.�"� v2-�r� %L!6!m)� 7u�)�,="�o�&i�f� � �!�e��Y�%N�`UH3.+�.� A<-� TaScR57V1 visu�l�*^fluores�!� Che:o��2��2mjOM. y6TA&�c�IerpLG. S S���o�aLea4e�ly)@!1a�3g�@v5s�kinetics�;AIa�)�[28��Ia�I�ex5�g!-cdz���aDnA.�s������$����g!�!f"� MiJ�-��a -�v.� �2��nt ���%se�t !|idICct�m"��2P0!�.,0A$"L4�Bs 64 6�M.~~08 albeit�de�*!�L �QAN3!q9c!J:��keK�09 2e�� to! al��!u�Eq� 7 ,V*T�k!��J W#H*� �62�A 6����9�ly)�!_�E!�r6t6( P�?on'�+r !�co"� ( r ) �v69S 73�j&��� aH,Ri!��a�2� �J$_ 핉Y( r�/�, 37; r�$*�4^Q, 7�. Em��=7%�A*� r,!b �>�A9�+fai�co-;e0���6� More�AsIk(T2"! 7 (�1��Q@)��ark5deqCPV*� �EFVZ�A��2co[B�Ł�&�IA�V��"P%���s�H��d?�*|� !�:� im�JU�)�F6� u!�!j�d!�1�m GSF` �e2�A�:6g.�-* ]A�ېp"��qu/t�> RT-PCR�2�!�E 2aJ6���7a��*wF�W���] �*�*�nZap�on .�!�!A�c5͙b!�("A! � Tin![�-x_$iI�us A� o**jQ8 h!�Y~E�c�1]!7�ym-8"- 0"� Wicaiod!�hes&o?�&j �Q�QI:bp5k� !��WIT∼40%Ɋ�-��N9X!x��8}�.� r]Q2I�Ŗ�A�!�( �[u�J)!� �Ily�Emis2 2Kͨ8�0>�?a��eС&e�P! ��vT,m��UQ�%$"s !e�xAd*�am畟6T .�!g9�!���>�X:x�\9yE�/6X�dN-'7��NA~,U�r-j1wuSH��"��k!�-��m������e � �-E��y8 �5�onb�+ &�"�dpHwF�c'Yd�'(6HL6�k;!&�LS�;08�3is��utiMjf.9� s�+"�3+J�Esuf siRNAs",dIV�-2AKck�(by Dharmaco�'RK�DgXPF�s�6&I�>�� W e .����' �:��QiJ56�bys� ۇn�Z"� :3�/�+�[��q�pa"�-2-� ͈shRNA"q!ng�CR�r@O()e6�"�DQ5_7J)-2A��"L�T�gQ� chie�1� \�&]�z &�9A�ee-day tZb of9� apM9�-��#�#� �:���<�.�8�BU"E3>8knQQ�a��>�)ice� �tox`�n�0d��)�met�""6Hyau�q��er�1�v"�cQ#�69�sFdC||rey b�K� !I��>�aB$"q4of.��iFV ���H�*�$O��)w���z� 5,�g�*�� �_���i�N� nNr&+6t�Ou�'exۋAhw+inh�ory��BYYGU#b� �al�VB6�6a��G)-9��Of!"e~,Qr� :di.�t�4T"�&$>�1��N�`��*� 9u*d7=]|�Y��u��q mr!R �>b���5E �ez�&�;%�biGYSQc%�A&� N:� &�%-�!A�ef� wa��a%e!�2��a�i tone�F�+B*W�9�h�wr � sympto�knd�@viv�Gf mUCu1� ;p�|al�`(n&��?)�4 �q&�\�K Ev� FV4&�psu�a nz$m�a �a� a)|�*six Ce�is@sup�8&}A{�CaralyM Ys 4A�7 d„p�, �aM� � dead��sachOc.r10�6�0�e �V_&�\%24锁�) �)�%14R���10� IMKJOR"ɀe{�5�)�QA!�A�;uAes�QX�9g�$d��orʓnmo�i�bn� eut���  mK>)��d*lA # � 6m+uxo�)Ymay�� \h/$a-�c"'�A�)FY� A�aX�br�4���A sE-�w.y9.�G1u"/N.� vivAGD� � 5>�J� .p%�."=�sGe�W have�m�6�)eڟ�>8v�+A��A"+1"�]�*xJ�=. ��� !#c7U���&)vCn � "�+.� �dub�!wP*�1 )I�car\�%$C�@�.C"�0AM!��j"O+pW�M� BA2Bin-A��Rvsp 2�su�awry "�,2�H �'&�#,c� �k�F,-�9claYn&%B#�#�i:�#s5/.��%)~ �Ct"�# ano�MAo?.!M���$?s!PP 6�' A��)�ABq�iAa�1�B75-�N��_� �(!&=Mw�s0L��o*Ja���"�.�>�;s�C� �KB�ŏdo| M�A�2�a��L yj�pt�li&ku�In�a@7��aK'%0" 0@ [Ӑi�� )M)����t7Z�@or*Q% mammalR\=e��� ��L���A����(����-�oopJ ��)Fz"zT�GH3�K5�[�I�"I$�ME��* p� �oKi#^ngA�A�Dro|vl�'lanogaQ���%FFeb��(( AK , unpu�ax+�[].M�-/�O�%V�?�G��mot` s Ae%{egypti# Anop�W�jbia����E���{ �6B%�h}B�B�a$d�3�!+soa}:���iE�lM��S�(� �us���V29�2+!=��lfL�����WH�Y�in5 Dron&�)�x)&Tly%��6>� >ma�D�/y!z, Y�u0E!��� 15!9RX�62A+�-��!�%� &�'K�gr�V�*� N�"5u�\zk�"�C��r4- �m3!e%�.! w�2u1E��#U �*t}xK� ���i^v��5Benh�J\'!U.�aQP�o�i.%rry�s�5 :�E�� e� !����� b&s)o��@ o kh�Q� _�-GM�c>�B6AQWe��m%~j,:Q���&� t�7�[�e%"o2�S��%� �"Ց=a ��� tsj&� �,χ{% �b�ri4u��sen�'�?@U curvi6�.K[���us�{ hou^yo�'�T��Uinv*c!�4 pher_Zb, [f�2�e @3 �'3 �b"��~�A@*�.�  neck�X�(Qȋ�I[Bg9@]E�6a��E10-15 n��< mpat�L/a]uMh"\�� N-9�&�.) T� easy�6ZvNE�^1��\'H7a� *qac2!MBgA�]d*� �.]�>p(J� �2x1I ��'~ :*+*�#�/a �-M�RC-�R�.&�XC��Yto� !,� RC-f��<y �rro��� copy ( EM%!hnot�L*���U�morph�yR� :k-Q4�(o���:FA��h�)�ed2X%w2Ev��6 &~"Glim�$2 in�<�!(���1s sP�A :�859Y&/ma�qieB!�%2R "�B-@EQ���XJ�[3�tHow�;&D?unu�-6a%[&�Q�gro� {&} ���s [3743^canon2c> P.p�Y� A��[adlc���SF�>�b< c�b�.ϑ&In�1molec/ |@ ��6�.�'Tmmo��. �" . �+ � 4!�vur� me�!�p6�.p� ���g�'y|r�ig) m�&A%�Lu�>�G� �(�S� �W.)�"�-aEK:)�;&%. C *�R*�R�-6�Fb ?av�'6�$��Q�F"�%re1�p ��& ]�aSr�<B �Eُ۩��(�'���t�ar� �Jl.M�1Tu%�qu�� ��rk�"3"$��0��al�� "�`G�(UG%c&�i"7G� =�9�6�,�AD� �/6�1&F8��z@�l`?7e�%� �� 1��.;+&�F�*�O a �f� j4ri� r��oC)igh�&wk6��-��� i���7�il�*X[6&]A�reh� ve�Y[QQX� �YCd.��p�E��:3�eAp!~�� �qu� &%�M&T^�*�� D�� ngag��� F.�� {�Ha�!V. ��{i�6��a�\.�2K�e����!g� M'f^u6Q�-.�"*4a@FVIvA"�1N~&���TsE�!h�(&�w=9��8ao��.�".�M�&1 �|R�  "�&eIIN�d<Y �^.��&�.s�!�eM�A�1�aC*�%���-C��& phenoP"�K� N2*�7Wb�rtt�(.�Bon)�-�����=AICM*�m)ic���b��]of�ar�`Mhe1tis C � ( HCV )Q-*� �(�C ( NS�C"� �##G%�$"� >�"�: � ly m#y��H3� �:m3!`B,in�3�,R�: Stri�"&"n of 0q��}%yt��"#~�ay&L? &e A���-� ATaK�a ��\� x0%* "� �������aUbL ./.s p . UnKI�eo��!>(.8s6�iJ�>RA>�*"�� �.,�(��asQ��!nu�Q> sub� i|�pli\0t��'E A��/a K;u�Ud Huh-7e>�E&kusurp%�*{L� 4����"�cUr��,�Z� ȭ�����&� now�*�QU30O��u � effort�9�'�!5&� ���/%���lexr66aeO#v��)�/ge�!FlaviV}Hs�L b2���ve�uQ� )`6�d�L���� u,c.n�:�"�! re2[.�a�f>gz*l!/-*E ;A�xh3�mW!*�� �h� sBsweb [ �[ջ�:q�`pe���/)trigu!��'l�<Knu*f�s&��]�ɡp(8F!u&�q^`� �re�g�I�.]!W�6�!Ude1!tp6a�2*� �iL&{oavl��`WP3G�F�. H6�tN2Am� �0in Dulbecco's�9�ZEagle$edium ( DMy� l��10% in�vafeF bovik�er>@FBS ) ( Gibco-BRL/�E�Isl� , NY�,2 mM L-gluta� ,�i U/ml p�ui���ndµgstr�` myci$Bi B&LF��F�?56��$, 2% trypt��vate br9,��F�(pEBB/PP-SFV�F,IN!)CHK �Fid*�� ,{-;,�fa=*�4Z;b)?�|��sub�iav��c�?"4B�} �-�8�h �8c�ba& 1] bC4$EcoRV-NotI�tuI �Kpn � rir8� ��R! ��0�5K��Da�\�q� to g�t&Rl -�J ��3 orA}2!�=e�3qq pS-J�V �, m !��auu�,Oe��Jdiϴ' Spe���v'���%��:�C�)�&�F6�� �?e��nELcri/�-,'сgG ����I�&= �Hp&�J[4(QP�n�7�2"I��7/��� laOQ�t.����EtP�+e�] �293FT ��b�1�B D.i�vE^magZK bead:�j2�ɓin�P�/pull-�? d2�es���VeY�G33RuI(cub�eBenix� 2]vv--ka�%|�$109–1010�Don���%�}( cfu )!}~:�="�ein PBS-T�905% T��-201xP� !PFG o�5%��fat���\ �Hat room�e˨)1bo 4 �%�t�Jremk�t!)� was�+4*9� 1 mT�P�. S.a:E:Fni6~TG1�l]�a�>�BKe log-ph&�of OD600�I ��5-6It 37°C%1 �\a��P*b�x� �o�! ampi� -*nLB�� . �3-"�ng a� %�,Yuby�*_ HY��%wm��( pG8J'�)c�ve�):YB��v�S�lonp". Poly@�/�H�]�� rabb�nd �ea pig6�2d�.�5�M�no a \ y J2�Xst doubl@�Gah purc!�s�ScDa= Hung.xGR �S >c H100e." ZW2F� 2F11b7%oatRqN19R91)�%MSanta�$z Biotechn�%. ��-&!�E'conjud�sAlexa-4>� 565f 647 ew Eng�Biolabt&oywAbcam%D)�u�  a)M-554SUiSigma�nfr�&�QLce dye IRDye680-labe�%,Q-)q \!I. 800CW-.� �sLI-COR�s�&�. ^=�n�8SA � � �"FV4�"�&`�ut�P))Xan*?.a�5�%2aErect w�2�,��%�"#a2e ?� N_%�4%#�maldehyL�"�-buGZ d saQ��20 mix.ea�h�HY50� NH4C*|�� ermeI)1/� 1% T� X-a= . Co%Zlip�:~6 I�.ʉ-�A�m�)0n Mowiol 4-88� al�5 �O8�͢DABCO�_�-diazabiBc o ( a�  ) octane;M��Ima"�h"fG% @Leica TCS SP5 upr�!aafb� m�)�e�8an HCX APO 63x/�p30"eS�l ���,Zc��J1�Sglyce�@"z�U ��2Ci��� � �Ja��al�4hj�HeX� , Be�+da�M�J.Zseudo/O�s� �@&q=2te=Y#��,%��!�V0in� e��( b�� in 3~$j:�aP3�]�c%.�*�Q� deconvolu![%� Auto.O XE-A10F4 utoQFO%1!� , Inc . )�9ZGBit�Ee.ris 7��!�:� soft:�(6 Z�:1a8� 35� �������1�Ru�Im�p m��val\�!L�ard errof.k m&( S Sca"b�A�%u��S|�bUm��  %;sK,s��20 nMaA�W�|M�Oligo51T�JvR7� ( Invitr}4!�7}!�;manufa,�er'�%��. *�;Fbsi}��Bei�&�I�2vew��uѻL C�m,r 480 SYBR G I�$$EMix�9�@@ i�!a=��" X!� !v*J$ yl� -3*m� ��( GAPDH� R٫Ep:Ecטjt�: TCTTT��A�� TTTCeMA�)-� : GC��TC#G�0GA)IN )fo R�VGTIG�.��)R��G��[ CTAC(� �R ATCCŧACA�6�� HK *S�CGrTAGACT7R�>V(Qŋ���*VGA��A�� &.�$of!�?Ue�*xKU� �? n *`=-��. W"�8h" a�Pt7 100%E8alj�.-< )� norz@? Ao�!%�8 *:�L>�2] .n��AliquoL�th�c)�� drawW�G�va�kP2�Սi.�Zz�l� tiN �Ł#+�U��K c>�;���El&p"�,2x%�2� x "k L k!"� ��mJ��jvw�JI? ��!?Ŕ?�.!�6�%ARquimo�)S|�a waTw���6� (E :�"�)A.1�vub" ��i #9;ZH/�Bt���" of 1��16 µ�]��?perq`cm#�h; ��24�[5�!x2�&\2G; ( 1x=�Q&X(� )J<U#��ol8d6.~2�%䡷"�S� “CLn, �Ca'�� o�6�atg 2–� 3 kJ�+�Kby!�del�Cono� *w�ze% �2y5J'�B2qu�.�-cRr( Dynab~M-280-S�#�w*� �6 ole-���&<,! WCE��2�&o0�*by2A -�%&_6�68r"����tB�|� ᰡ��"H+&2Db:\.��VJ6  by Odysse0�d ing6*(N�!�t�%�[L �x�-�pT��!��5ta�)"xdE�i!x2��%�}*�-� !�� ! immo�='to� �, -A-S{�r�% �� E�6v k`&!�h �X��+�/a�5:_��M\��:�]� T�oJ�� a+@x�2`.�. Dataq�U�v�±&� deviIb,9U�5�Y��?�<S&0Ui�M&A�&�I�Mi�@oft EՓ dH�B��/��*d%�S$ eC�y$%�2f/�!Ne"�)p52� f� GrouC�6-w���BU-U5&ޑ7Aҁ{ admi�3e�#�&l51��6Q\L� u��µl��.!M�&�Dday-n bv�Q��",6da@>�"�rc�&�T�S!K*�TiII�0eP�t�'a&/t"b_we�ia�2��3��Wv� a!F��sh*���C�-�Use! AS%"E�%�̍d�Y�c*�/ut��a�Mj�Vy.I&+ �s�R�S��46lic�kj`ber ESLH-2008-072321-Ym-2�)�rbld�� x��� � L"�!�6���FinO2�/Europ�Con��!`x""<Vd$��e }�o.9sZnd� S�tOPura6d�Law%�ia�u��n [Q%��0( 62/2006; 36 !F EU D�$2010/63/EU�!d(1076/85 § +l01360/90 .~k!�h"Mm�c{dis ch�blast.o���(���mSN��/>�� or�� Chaetothy�#e���p *Uu�v9?��123 cliW (��U,t+����razil Oag�'�!/r� iV*��  spac��}��gp�Zh ��G�ZPβ-tubu� geI�.6<�a)���l\E���*clu��AD�d�U�� R�am��Herpo�' hiellacea�eTV�Rmp�pVnhF�Ucae=;r��Y!�9*�8�,�dQF . pedBPiɛre���K80�$O��%-s-�,2�13%e;Vm hor�nubicaRa1���<pugnaciuAOA�Ka�N�xVnovel���.)�o� �:��Rh_^lad%��Cy�Plo��mfLBenc^of��1%B� CVO3�rE�N omat�(� ��mUsk� J}fungi" 8t has a worldwi�de distribution mainly in tropical and subt�climate zones , with a preference for humid,s % dens estao >�UCladophialophora carrionii being the only species that is restricted to semi-arid area v,Cactaceae as� vege �(. Endemic a2are�|Japan , Southeast Asia , Austral ,Madagascar ,\ well5 !7Cen.t America [1–7] . In Brazil ,�infec%(is observed� all !.=kn est%�d!vval%v4of 1/196 thous$inhabitant!�butQsome hyp!� �pregions a considerably higher.bis no!k[8 ��assumed!�xoccur through accidental inocul)�of� fungus vi}taminab(plant debri�EPfavored by agriculturA� ctivitiesAcotA2an �pn al naturewpdisease . Chromoblastomycosis�on,h.e�� parta,arly members.4genus Fonsecae��E<4F . pedrosoi ,mon���!nub��as�t age�Z[14A܅�0Recently anot�>s � X,pugnacius waa�$scribed [1�QRh!�Hladiella aquaspersaA)(an uncommonVof-as�~of dry�z[19A�O�reporA� � such=P�|-vsa�ExəaiG@titidis [17 , 20]%vexta ly r�A!5�6 ly cause ) type%���!�9�5�ae%�exclusiv[ isol�from cJ�,ale%�9� repe8�s brain��!�9�combi���ytwoa�ordAMby��r�e��F@EWcereba)disse��e� n a singlA�ti�7-�Q��in�aHIgM�.-�Isignific�5be-u�bdif�s��progne� 5� .�� pres�study �^ua��! diversity= � in e�ICof��based V ultilocu�?�Hce data�� A�c�direct�]log�+ ex�!BA^����A umerɒof curri� proven ca� %� mole�r�a F�i"�ia�4ovided . A set`123� insM�i�JE�1�t:4u�analy�. Judg��>a &d ���$al LSU rDN�)`ei�XChaetothyriales availab�eCBS� UiN�@were polyphyletic%R) he e�)�di��� thre�aI�t ��8es: jeanselmei-9 antiana- !� europaea- - ( Fig 1�(rrows ) . MJU%:!�uac IT�nd5(BT2bCDC42���erfor� for � eQUselucid of�� .� ( S1����R.��te� in] �A�-X>�, �f?arz =�!�genera�Z,>[,)yphelt ( TE1�� ianY�s u5�is�,�%L deri� E�6�5 ;>�j group Wnoa7 coun)<.��3s��-:‘UT%X’2�A conte�!6pr���y �r. O�R�iA�ɑ� $98 ( 80% ) �ed�VJ�, follow! y 16 ( 137MofŌ��, 4 ( R%�n�feDC��. I���:k)fHf *�-likeU���# ���r8-���:|��n>��5��!�B��6U(‘6II��ly known!�2 +) ;�� unna�� E�� ve���q���z��p"`$  t�r& ��o0d loci revealAa8�top� ��hylogen��s����t� s CMRP128�  30 IMT776� 17 �� to be!�corda� posi� �ne��sCE>ed�� remain۝�:�! 2t( 4Nz%es ��3%lD��as!E� > k & Y � �����P-0of:�, i . e �5�.��Aq`�(23 . 4% . S [%j:�! -�E[ also.�.� _�I�Q�in>d��2)1� tly��v judg�rem( novel taxa]6��:�,A�p�� . WeMorto"� $ c �!8 k�c_a� � re i�be�8as C . ludovien�� ."�MreJt��[sh��op`l�m�t 30°CT27 :��a wideaLwth range between 188�3B ���i�7at 15,6maximum&temper��T ; no A�"M at 4�eP 4I2.;!KM . PA�$ . AzevedoL . Gom��V . Vi�De & de Hoog , sp .!�` . ‒ MycoBank MB 817305 �q�5� Etym��y:-� afteRe c} wh� A:AN� first dia� ed�an Lu�n M�hão St�,� . Holo�:f%,iq skin��&human `A , drh O( UPCB 85592!yDe� m* 8otany Herbarium"Fex l Un.d P� á ( PŖypem��RX317 = LMICRO356 = CBM47!�dd��{� � li) � 4scrip�����5Z-{wo weekCcub Hon MEA�2A�: ColonaGmo�t�expand��8, greyish olive�e (aceus blackqB>�r�Hypha9le&br��8, 1 . 2–6 μmi�, sep%��y 9–25 ," asio� bear��cefid��conidiaa+poof"� i�v,wducKub-sph��hyalin�ZN �8−2 . �. Creep?h �rPSoutgr�_s�ch���, p!") ��es%#5 q0%w����"�an@oses; chlamydospoE��i� calaril@ term+on�h2Bovoid% �� .�6 × 4 !�,�$irregu�thicke� wallV T�}� spir(twI�-\�ly H ,eleomorph un�h. Card�.us: min����,�;um �,,�����re��qs�C: P+H, a 57-year-old CauA� an m!�Icatu��,�!�in 2008)T� ,r limb injura�őnod!k. !H4~m��;Yru 3of&K; muri�� ce!�~բ+ issue� 6At6B ` 1��tr� o)��(itraconazolAD200 mg/day ) , lea��to im���H� s du�_ Z��m�.�abandoA�2�112.!6retur'%|11W re�d~spr�=ou> =�,Aa|a lympha� path!��secondar������:�us�9�, ulceL� crus2�urfacA7 �!�re-�dI�!WB�� �58%9ed�n�"| �@cryosurgery . Nota��� */*� >Tvariouslassif��in:� or2%. S�PalA��hav� en� 1 mil�5��anQ��!�{ c�:).:�.� is� 2 E�e^2� �U :wF�h&�Eis�e)�&U � Aut+N,� 2��[g�icI�of2s,� M�s�:� �i �� �� �Figs 3e,7��*� N;�itso�car�0!�� �� 3a��� n� �"� 2� 1:� E!����in r� _)V�� 5 A��  rapi, velvet� elev� >� a� dark &� Mycel� � ;"mm� de�mO"a �,��po� of�nched���*� :� reddB 5 � 5� ", � �*  ��y 7�82V ntegr�* gen���h�9!ww":� e�S"v\!� . C4 y er�,��ght� ick-� � �to)b  , up19��!� 2, pig�ed!tic�on-R �a�K �sympod=��2"M or" , oftenv AP!D AAcylindr���apA#IE�!f flats � )2a~!-!%5 to6ellipsG to=A��A −5 . 0J I&*e ; rsl!�� omin�,� rox<. 4%w diam2g1, a us� 1-Qi,� 8.y m . Budd!4�s.J EH�)l&! m!be��� � �M�� 2� s:" @a�y.�|� a 65&� caF� $Pinheiro ,*�"�,!��G 04IK* "� �!e�m� ic"f ��� �n� nd cicat~# . M�� "6D � � )"�T#g a 6% period � a�%3sta� �n ,2�;tom�� Bothfs�dsE�und�u� ��� �!�ec�j=(7 ��Q�/�����aub5� �als>�4.re4erbinafin ( 25� twi�".)!�R. D�ourg�%�icA�J166���_ 1970�DaofRN�de� 9�InstitutEHT�,Medic�, S= Paul�� +n-pplMqma�)al�Nd �u"132913J 6i]�f�constru%worker VVenezueli{-�ymA� �localD*:��h"e�a �*�o dull-�&)��i!78hemorrhagic dot'd'A�.LE�e�X*bc P%�",2�$�histo�< cri%[�8A5pleteCxis$"accompan�x�,a��"c ,O&I U�+� w ��r����Y healW�ѭ�dis=Bof itch,%� p�'2s mustbeCito!�b�:to�rEecu� biops�to�es�,A&ujTa,!. A275V will� achi-7no�i�of �E!�s upo�#� >�& failv�wi�E����-W!I���fra� �x�Wa"�%A�M"|luj$s clost:5a&e*!$�� � �T�*�!j dL!in�po�0h�*L`G$M.�+�� ��)� 1�ly�H f)iff ,9� �es packia�� , non-�E/ 3a1%&ITS �D O nc*', 1%�n�/�!*� 1%=8B4%e54=F.�,��)ng�1�/a�xA@sibeR1�!46 ? . InG�$lwe � G, 6�fYA�iEYvNe! *. A�/ae(�&��sI�ca�e��v�0v)Y:g�� r� cogn��\!.�%��&���B@&� e*+&3 is�laiob&-icA,,�%I &�3i *��"�"(rid environa�al.A.�2F2H2%(-�-[24 , 25�-�@phUnlidU����h�)m3=}s�z&�,&c&[2])#l��latq��d#a, in s4,rn China [26�All��9of!�2u/re�(3N�q�$� hem�.g, .6+l� !�#p/�/a��1' seem�v[ath� �3at��s��t�/ ssoc�� R�EZBt.p&�'�C deg�� of n�&�\sm�ntL*�d2=.� �.do2 organ�EK�0AKg�02�A�Fd3&�"j$sickle-sha�%&E��!��0g�)��t6� XicU%F�on"�V . Al�5gh�w�6]T�� B.�"&�M?‘u�&K(' �^6", Feng e� . [22]��ss?3\.��.e��&] . L $ RéblováX9] took �'y�xA�1�princip�-nd� &��&=6�N�(B�n7+gE��e newly �8 blis�fam� 2�� . Si utaxonom0>Xi-"�lux)�"��h(addz we�&�m�p� atego�abo<"h&�*lK4�8m�. C"/,5^e��do��� ch ��#iJ oc85 thus far%O:H/[21� �9tA'clu� ,!]�hf%�v8&9��5,�abi� eu82��OIpe�'is�A  "" �piguaraAR da�6���A��a�5( Atta cAn EoZoxy6#a: decay� lea" [30 , 39�5.�2�' orig: JWcutan%*� 1�,�5\�&� nail5"6e��z1E�L7*�*U glob%J�8n�-of �m\uonych"c:[��� q co-�:r�!%`�9tophy!�L#�=Trichon rubrB'I�S e } 7iab!�� s [3EE2� A4�3� �0M16� indo 9et�,"?7ba�! ��m-a2[3�34A�6oJ��(��)e66��t�hadf��vA�c"�9ra��?n necr 6;�a�ba5+%�9fe�R ��ZW�6݌V7�new�:z��q<aIp���u�� *N �a&�.>\/��%e.}7)��Wo�/ma�� field soi�= �(mb�3� I��s:g6�"� G��8�9@3J6W�tawC? 100%U6!� A�}2i^]q1!� phen�,9� �l��simila�7Z&irY}&�9k5:� &69re��of�=���� . AcF2��o CA6"\ 37]%�e� 5A�lex�3 coul�"Cy62nd�osSZE� � � �Q=r�!nt��ameter\� � r2�=5�+al?�%suffic.9)a crb2�as�I��al� �;nth, susceptibilA�,�!rs� viruC!�physi� yEneea toI��@3�t�*q�) �"� . As�<� oV<>% I���or:1@ly�d" ,out�� $ Ubm���F~) &.m#2de�0b��� .� ��i&!*..�M� {Z�[E��eh2ofVf� c2JA �N��� pote4=l souri�" %l� seB39r��!�harves�>bab! coconut�a w�* palm�T-Orbignya` ler���!A"�CrP_�> FA5 invo"� colle��toE"act�� i imU6���&o�$ q��i*Ra�aut�/oduV@anu�ur��*�>�!rindee�t �@1.s<=*� �6��F�� risk���Y �R�"trauma���<Ht  [39.10M A ,Al5F������m�q�a��6vere� unambiguo-E7. e{ ���:!�numbe�a�i�Z%/eckJ���4�?4� � �,ou#(to�9Aa.n�s�.�HpA&ic���exten�yDf:*I�V��8i� 60�>a?ALS�0a�mechaniz"�� �F�� reAr2 -�E of ���oA�exp�.e- *4*�(<s� � �.8�: tL& o^�87218���� �'��te&j8!U�$� Ah�B�AatQ'� A�nic��^��cor�hds� b��c  surviv"d/�u/�v�L"�I��"�( :3 �a�)��byXi)]bar!suDŁZ�� � ���"��E Q*�)2��(� w&��2��e )�:�!k6%:,����B�I5oA�> a y$&�iWam A]&]  :� �4World Health O�q"(( WHO ) [45� Nega� ed Tg"D! !�e�e�b%\F��S at� va� W.�O�Fw�-I�p_�0Ee�7Lb�. n]AoveKnd�advantagAHow�@, � �6%�i �S_s� ex� � etom�4JFcMqI4�N_ �ϥ�"g�Z*� n�&loo� � [�M Its � burde��aa O� or�9�thaM��y �,��ab� U "eQ, impact{��d|��d%ref��orIA�i�so�2ltru�Qd�nKf�A�. ����ri�/�u��!�F�0)� S� �A'MQ�I�&�G� v� �H�r*>�Nm� �^w�!detai�*ᄡ��d�.�%�@f�system^ a��*�%�6� �I�l.5 nin�&r�pB�MxOb�%C"� n�<Net�- TAXon ��atz�<� ��iA� s nomencl� "�A!�d.Xi*���38iG� �=3"=3,.& s n)/$ ( http://k%6(. nerdweb .A� . br/�1:)!` >www . sp) .2 7�is�(k�ap�"Z ( Research Es;\s Committee-CEP-HUUFMA (.�>H�V�>M�>�?���&_;g�7&e ResoluA� -A��RE:�027R*34�0A� ampl�A�anonymi"�e�"!����(D$U;U�%�a*�T$albureau vSch�3lu�(�(/KNAW ) Fun�Bio&SF�Utrech�Ne�la�a�mi`Ŧ�8&�F<*B)�6j�>y>'Fi�Stock�{%,mai Iis~Te�2%�)tW �� agar (�?)�oatme�&OA t 24��#��rp&�\��,E� pota�3FP�& dPDLsl?:�prOA�xn�-un!�s nie!blu�"�=F� ��z�on��@. PI #i�@)!��5� 3 AZ 3–� .. �C���v6,of 3°C;�!��E]r�cat �!3�G3�9%*4�C. G�?� 'er"�%�ob3�$aA��"m�averag�� ��e�|; i�x # )�Ii��h�= �1x<�5viuApR -P plot!Nw��.,( A2)� sus� ony�2� ( mmA[�'r \O� um-j( =�±J�BA4bGE �dYJN�t&zCe each5 ��* repl�fO%l/  meas/V l1�fP Di(O= )t%K,A rC A;r R%�;Vtѹ�NC-u5)2S! u�e�3�!�!�'Q. a�a�Dqua�� �} PO)Ag1dCdI $Sigma G914�)2�protoco6 ��Y� [23]t���Xi�0p�4!�|� !+�0taken �!3U?2Clean™*�5Kit��O�� ,�Q lsba^FCA , US��2�._’� )�i " !1��@iv�1,on Sabouraud9 gluc�SGl��pTalvsubuni"yPnuclear ribosomal RNA�  (*,)% �)�)�pri�: NL1%_LR5� ��2�"aYYsm� ��&gen�g兄chosen=QEdelimi,:�RInter Tran1�Spacea� ITS nd%��ns��i�E cycly"�C�Qɠβ-tubul�1BTKZ%< �U;e�1 V9G �LS266 [4��48]� �B8ITS)HITS�DC�tU�X ?�LA�:�cdc42w) f [49]˾O Bt-2�$T2 [5CPCRzy��I�B�FL [mY�m�mix�U} �m�1×Nbu���* �:mM MgCl2�FM dNTP� �4 �achA/`7�b=1R,GU*BioTaqe��erk310 ng%�;�^a��,pA�cœJ�in�C ɫ MEGA%�7 softw! [5C'� alig�/u" ��h�� Syo^MAFFT� face [5��_s��q � �%%`Ts� M'� � 7&�X25X We d�/he% 3�o�z�2��!T-f!/d<�*�!'2B*fBYAZ( SSUMN!��-0� � �1leR4b�_P""?+Fs-!3QP-3])k� ��&!^cla�e*g�reQ��� qc100 bootvp.� YM* LBihood Im&=in MegaR��!�bie�I!�(9 odelp t!���[e< flicF &�d� H hom�0e��{ *)&in PAUP*��Ob10 [5�bo"�ZE expl�,a� �b�$&� "]VpR+o i&D$�cIa� t�<� &�at GenR!�a CBS-;q�%�s .�A���damagi �?( DDR )2f�^ sign�Ug�!hwa<8a=,te!ZK&$"eE�V�r�7ewdr�!h�C�  assaul�^�D"g,�Fgj&�v�/ona avaG�2�ze�a^=! ow bea ;!=GCu�%! is"�Pocu� UH,`/rw4�"�L(riAnocyt�ndu�_hf!:breaks �VikL)�6�%w �Iese6is�gy"e?ly � .��\YQrolx ]H/Htox�S �olysin O� Liin bloc�8�R7.���+ughad" �$ensor Mre1CEKn X;%^n �a�ein� v2� !�[#zb-�l!�%A�+D�r�X�istsm��%�\ro|L9�. TogT�FuriFn%iMa� damp2�?��%ritZ�SaA�Q;ful=�u�8h�/E�� � �iZ�)uof chtCz by:L7aMenut�!o�i�I�%č. COPh�M�haam�'� arra�2<irdYa� waysA�rest<��0�;ofq �r�� GD h2�Ur��. Briefe2eukary�0dou�a��ndgmeh��by PARPW 2AXIu%��mI � DP-e )!pA� on h�* ne H JH2B�-Wrecrui�>E�@e MRE11-RAD50-NBS MRNT�:�"�db�1P)�d�h�A ruc��Ab enga�b!<dow/eam9<[`3�8n�N�alex� DAtaxia-telangiectajmu�Ud! TM )13)2A��` �p� ory&5 H2AX!9se� 139 ( γc 1)J3Y I--Dɰ$CheckpointU MDC= b�+ Qa����tef platP%4�e�!�%�x=�Gub�F$tin E3 ligV R fing�lE: �` RNF8iI�;�e H2A-�M7�a 3���he8D E2 enzyme UBC13 [vH2A$�h�;��A:~aFiE3:� NF16itself�9tIp53 b�* �( 53BP!|A�acst can� 1 qh��� BRCA*f�_!y �[4�5[5}%W�,��MP���d�6!DRTlsE�� 2�Tra #senyG� r deathq6�T�6%3ten�A����1t��.�khomeosa2)�de�AU���8�)� �1b lp�6�.age!z[7�Du  ��t��in �#:tas"U s�A�mon t�� m�7�"� [u)d�':benefq!r��kXG@q6pP�0r a*;!�(2/A�i},�ha�Her�j)��n�ta�to}!�Y�J�E �G����� s�� also�!*��%�ii 9@rB]|+!6 �� DNA-���lo�u!�!+e�.cy�Zly"Y[9e 10 ��1H>[13 �&.3,"r(�feZ!Ks����E�MQ���"by5"- ��, �)0prag*$/r�'in vivoLslou �t{eepN enewx&r exfol��m مM1 ��':&m/nst�l�, o]]aR��q:l Y@�oosJ�3|WL .�?*� �et5"�!aV3+ y@Zf�borneq� acqAb4X44 ��"a�[J 9.* Pmanifc4�� as f�r$le gastroe��itza5 �B4#� @o�/phI, abor�!A\Picaemia���]��in 30%A� S[1�Jms �5��a�h�am*�B�"����$ AU:�/s4�,*��,w : �%�!_f.a9�^ep�)n� Eoasf .l.!�u,�O�/�L6��)a3 �%zs� ort�2� 9�a�= hibi1B��H,�e&|,Y in�12�SuFs *��;subt6�B� byJ��Xa� �!��*�9�� ifer{ . To _de�!z���1��m;��we*a “� t�ay”���:3ge�Mc.heA�ssli"q��Y"~!qnE  G� �A}&�Mmi�[�i.Xusp iinfluO hr/IG�>�e�3 mJ Gh does�,� C>. B"vA��+)' %H !�length (� �sP �A� ({ 1�"ipca�Qs�>Wam�'�a-��V5,bej$�3&q�&d���y)�%�mI �4on4!�� a�?ve!7�M U "�T* H2O2!̉I��*re�l: �. U�OyTA�24 rFF!-?=�%`��:"�?lo�t"�/V&e�un vn ��or �i"�(e.u non-&�1nd�(�ic&in�~a ( �s)ˁ-ere�FMK67B^B,U&=R.��!�U ty2W!�.}��A�).�Ia;8f�xAg�u�$ -6JK��ma�Ts:&um �'{ -ADP�%y�&� �Hos�H 3`!����e! -A'���3–[2uWe���a-8 ��v� by wk(r��tta�of HeLa%�DO  .�dor]�w9:t/)��B �KI]Ϻ+�b�:�. Mod�&� �+�f150a�200 kDa!T�%i!%ac6�2 �^-�a�pro��7�L� �n�T%!�( MOI )a)ex�\�uN 1BgW�. Nex�we4T\%�_-G E��Ay�<.Qp$�JEE F6A4��� Us:]�6Shige�~flexneri ��N-�9wok���. Suru3HB6o�F"�|2� :�,[ �0V�&m��/�fve2�06�lbeit�sb. 1����*��C=!\58in1^-o�9�+j1I,, yet�7� ��@:")� .9��� S1B��)esa�� >M5��",NjaQnon��^Ok �ta�"c) s aur�sIcEsc�ch+�li K12F�!�̄��AtmoEX��3.�.�-�1:lyE�#ZmW� ��c�m�5I+� A�yTm:%�3��pe��2' ��M�C:d$�a�"$5� �$ve �7-���Fk��!.Oo"%Uo, �:UO>, 1DE]As&P�e��`�����r6&"od-��6;d� ���Cš~R* ImR�i�!KnU��?2J��T%�usX�<k%XsI�nocodY>�5uCR4 houP �?relCW"h�� �=S�)% o �!P�t]|hy20 �1 ���A9�?m0cDunzxY U-Iat�ՙ%2�%�g%2J "�"B �U:Und� e�;�& �)1�. T�/�"%��2)�8ai�8"��!��"�Ft��!=]q�7�2b:"���&�"� � n���lc=�fu�Kr"� wh �= �c�b�9 �8< 3�9�e a*i`� 72M �C��spleen�#Fiˆ 1E%QR at:�ӁlayaJ +5�,o �P"��ZN�> ]�N6U�h.T�� ��du!�duCm4)"a()v!� �DT�T� wAW��at��6Y�g���Afn�-�x�F��i�r-yu/A�}in5 oU8]!s�wj�A��� i&_d*��k�e";L6 Δi9@!n� �N\sS" ?a"�!� ux�Ho�)>�Bi�!�~ -� �5�:�>���s�Li��F&� �0��3�{�V-M � )���6nQ Z�i�wy�ala�&D���9%entry��"�X2el�% * �e>&vyDsP�e.H!6� necess�*�)����]NB!C�0�1�,%6�=i�y?:u�re%y, �e7v :[pri�:W9�1 )%$�am `�wa=eN�ͥ��nv},59* 2%�S3�:.e f�"�;K7B&%�6� BGle� � "D.:)spG�����k�� RNf>M%. U� E�E��Bw%U�a�%�a��M�N�H�#"h@iE�%�eq�N*� Ec9�5�²ay"�1)/�"�� e� Bg�B�Z� Nsew&#2wam TRuB���n,.�W fy�"by�d!5�c!il>�&F�se9���2�:�I�d a"0D.2xmo 9�>�b1��o� z"pa=nb E �S)iu!F=, L02A&s>� LO�$�R9�4t� �*�%�*�a -�& �. backW1n]:! 5�-#��QJy+e (a� �;i.�� "� �T�-|0 T)=elm�n A�� )/�a�!.��IiT#s��!]�E��2�&0��%@ �!;)�66�Ph�iY�Bly��ti��at-V�:���.�ca��%ver 2-f{}>�R�.� Y�Պ*o!� 2000E�"C1�@w� �- %�!aEtF$B�NA!�a.H1d��,�2�/%�7��%�� 2^ A9R}-nE�4 � . F��e&�5tonU�4 w��Ds9Xor6 LV2�<lr�� Q �T.�it!� �E�:��ron/8en�k� 7[traven=2�3" Aց�r�x�4v+d [�c!r6+29\R~ �*16um �.&� e0%�.-�&T $6���6�%w9l�f:� Ni2� at ��!&i  ?i/�������N'NnB2 J�52~, `*{d�\y�u�\�#!w� erQ�lavag�9SІ�i�v�P� �hconfirmo&�) ���DE�a��L`%>���.� ���Á)F����(qe�2�������� ��Ui?�  c �(&�#eto�dJ� irrads)��6�(hy5*!V� "� ���20=b)l��eq#�or$X-,2�"�$� .L)���Fxa$?'.1aI�B:>����2�on� ��":� ���t*�5E� pre-�NB !",�&��>�>�Af&(::�;E)�ZR��itp�2�a_��K &�O��tE�ledV� �E�X-5�o�sm� hr� a �W*��� E�: ,mes?�5�sV!�i<&D >�! �]���*29asnA?�","%�3N�3 v"�6 %a*u02q�iMf�%��:B��UY�%*�l7<�3-�4�3VSV�[*�%n%YM36�"� I�/FUid.��"E�be��� JEG3� �?đ!3���-�e _+�#�!to.\}S4I�B�:&�."#��1���Y+*�, � �9<��B�q�^9�]   �s!��A��2l��-�-pW�U+Rv2��*�_�#MH6�'�\:/ 4B��"Ԍf-�E�a�&-l�,d�<� ( 3 nN6�=�`u 5"&`-_!I�%`s*4K?ؖ�u�%@�T Q�FEW Pk\�:� �3 i�, m�_4 ��� ��6fun��D9���A5J�, &�V��&�!/6 �.��)�n�%�� N���N�%hi�(!�me8vS^spz�l- ��Hpep��(in-A-methyl�( ( PME�<S6: �<GT�I:��che� t*�5yQ�&, �ed��. f:�Aeh �omeAl"10.O5��79�%CL}��=!Pal�OBFm>�B� 7�Ag�#�,B� B�Z� a-�cDqN>2mKIf&v+m�wOF���r�)E��?�& � � ob��y�` fibr���MEFs �[e� ATLDs MM! ��y9run�t�;�Fc�5! GFPk �di%a1))s�%� ���by FACS�I�WW.:�J�Y�8�"��c�of���_ V nd0�por.�2o^e[3dPAt^?ti2�2&|E��p�0)��A��&n��dP�0� !R � �� :- 9�%@!zJl!�ek��KBi&�.@s `~ !6�Eb��!�two[ �Ao�6�V�;atC&2+ ��k2X%&��%4! .:�Uvto>!�� ��F��mpauU^"�7a�mo 9�YatZ|�[Q�A~ �>Z Y�݁;� rolsJ`pro.04 ?Q�is�?!!��D!�,6�r�(A8D��kinFCE#�4�i I�^��D��>9�� e"�eM�Q�ubMo�!a�A?�'t�roa��\�0 : )"� h�G6�IMR90�D.Z(/aROEsyndr�6�f� �c�'.C !fץ'.'-1QU"�OMM��wm�w*db"�*A�9C }de��d2�!��u �!.�D�.�� T,1{��he.la�� :8)F���� at 3���yw sW& Z-eG"*%�� pharmaco�2n !� ( KU60019XIn&< keep%�*Ue����MA�� %&m-I������2�� 6��e!\]!+JK����hnoU� A�sa�H Aэ)��w�eatV��}�n flu�7c�{.c N2�F�A)&�- ��Pof��2b&Y\ ��� � �(:kBP%�F� �demg�}<5Ny2�o�Enx2,9MJ(i& )4�;Q�siRNA�_�d%�AI/$F= �KS6re1�?YxU% �4"bMof�(�jaC&6A.�!�h��zi��RB��$�a ƛ�9?l(ݟ{R� 6DMq��� ~ 30ld�/#A' knoc� {!�a>�ŷol-�6pc*�'�"z a&)�A1Er�m!|M:~: o���! �<,���*�E�E>sU?0",�&���A CHK�ZJfo�J[t9hi�fqZ�~ �.�v�I2gQCK InlC2�'W|0�mmuno2��scopy!�n! technique�~>�� �Ex� 9�in6��Ab2wI���S6�Y:�/�Mse��"gp��~A4 QQ F��P�s�>EE.�R�#-JumJKa�ok6r)&�tq-sta���2Y�-���Dsu�gA��d�J6"�0� ��Sdes� @�M� 2� .�$�so�r 1 `)�)~��> q& 2�!O�m�n 5� �6�A5iU�1nti��$:� !)in�� E"0f{A2�@I8�F!j���!��N %���! �bxnetv:Kg��-�5�7~���&*�M~a- q9I��o1�%U�"�/� �{p��t�7HA��;v�E2��<�0ic�su�LPw�mon=erugins� , Ne��'VgonorrhoY�, E�jlA� or Helico � pylori%�6? iav2�8A-C5�i6��Hs�@N5�:-�n"�5 ( DBKb:�L21=�LVH��H`?�`��E� k2A��62delu\��� ossiR����� F�X!�DCFDA�r�ut `�_��e�IP��E�"d+"�} J�>"G"���=�)7Ec�E�{v�x � �m`��yn"ktATxxU�5f� n DSBn+ ,�ill��� ? �dR|f"�&qa�ua�L͠[؆�E5Sf32�icMs%9A� N�\oǕS� 2u �s�3�>5$&�B�%@�@lB�"�� �a�/s*&cT � �&�"B'3`!P�, q8QJ�!���)k�"� &�F�Ayf �A �,1�2=@) �m%BO �WN �b�!we-* Ne��[��e��.i,B was.s�?n=��s� K!p!T �Vun�c,� ��t>��I >�恪h7r�^KT1�Jd2"� %��n*@�@�F������6k Fb,cR 9&8L�!)!�� 3n_,�-�1�����Sa"q�!�$is�t6P �8_K;�� ��!MA�2 &,�"� U:� "n?D�ory"[yK]2� �I�/�u���e?"� �n3!a$,���P8� �� � �m`� E�AQ(Y�0�4�|6 �y�8=I��L�?at��~ob�\�O�8N4  L"_{2� ' DR!�"�R-�el-ilc"g]g,d�0"� apopt�V�"��1hv(.r .gA�wɵEl�"� N>�9�~e�S2�Kb`���{Mi*��N�׋,-uFi�6�n�H&"� NF-κB Ō� %WF�]J�A���at.�d��mup� e ׉�m/i �{s >��DZ�k E��$o�De"xe�q�wA�ip ��  I!=eĊ&��TR�!2��Tb���V c!,�B-!�A �E %�{�'};;!�P�Oam��BBRm �"�ܸ��&QP���u�R�e)J!) .�T� ��+( ��B�A� ai�%�d�& " deno a�1�[��!�re��i2?a�.�!k.;��+(–Rad50–�a �܆.>�nwb*�,q f�,ngo�D�k!j!�2�`��vS4*;�%��� �8�r*|^�S�Y+"��Z &.)�b�9b��[ kewi �� e,!E"m �,et'� -I8or��D4fr�D &�BN�!�A�`�Ahiac�EM�:qFZ�l�6G��I{eI��2�'c "9%iq��)&* manner.�&�+r(�$��� �+c�A�Y[B�S#6t�,�!�6���X|�˥�i�oi��7@R.� !�%��-��-�F~1i:K"��2s�;J�1 cata�-"o� h"! teloJt!��T( hTER*" -E2?Z"�dbc9=Z , [42A &�'��ZM�u/x*d��S �PAI6!9: }A'.p�:2 yo+4R (S�$�%�"}��]2� �egmXe��"Ybu.��&�g�9�D�@:)A�fN%�-�2a�begin Q�mer�h"�x�nf"�Q targ�2Xa�m">�J�2��Gq m~@el���6�P2�)hMIe�low & Z5 remo�-6�:!(�x��."�f� p<[4"�rJ���OO!rG/�⁺���w��A|Me�|eAQ fu�;��~!U�[h�de�Sg��+�sAc�lk ���Rl�b K�. �#mo�)iiaK-a6C56BL/6N�l�H cedu2}e�&�.A��va �A#�|a����Ani}{E"�S��>G�!3/�� Pasteu�,pa�t #03-4�#�J��x��gui�r�o E@�S�C��ss���&i hand� of lec �H�!�D���$2010/63/EU� tt��ec�`�Ueu/*�/�.s/lab_a S/legi�/_e J htm jKP"�}%i>Bv�i/sstaff��B+ iv"�A[R2���i9�KNIH1� Welf�5 Insuwe(#A5476-01 i�>2w31/07/\��W( CCL-X|w0Jeg-3 ( HTB-3�% ��s�"��TWCu��e*4��lC�#�� q Mh�E��nlTum ( MEM GlutaMax; Inv@>{)J�10% FoOcBovݭSeA�( F$o%-�A�.CO2 atm�X�+. LoVo�2A�����"�L&� am's F12K| mM�~Xf-?� �eU�B7MEF%Wh�.�(d5(Dubelcco's "�WEagle9&D�'�PM�0�3"�(U�s|�6��4��a^!U18. 5l$h)7��"�&O>()�)B40 µM� hydr%0perox�=atN}m��R+U*�K12+i�MnI�yersiniao�tubercul0( BUG2942*SalmonXu�um sri1pBUG3047�5�Luria-Be�`i ( L�(�E�BD��co �I�� o}iU9"l�d V'V( RN63�*6y-� hear}fu� ( BH�YN��7F� M90T;UG250�Aj.�trĞoy�� _TS����"� �Ŧ� dD��ri&bUBUG499 *�6�EGD �60!�N�f EGD-&))�53jK{" )13��ZQ�=P*104 "N*�I( BOF 3 �b% Tn::AL -41!~� F�VN1@'�R[� 21!.�Fsy�Ua,2�&�� �U�&e�300a�*�Uy��~2�@�(J�edV"� � �Ift^aLthQ� . Et�B�?mT#&�<*�e.���?2�nc�0 �of�^2�e���oY�GCF�A Rn XA�$hl RS320 i�CozCyc*�7�6� JE6�10��.�6^A!e5 hN P�neS:V��%�=�ePzu6Hp1ZptNeu^��.�DM �6O�� 5�I� .(!c*GR*,!�.J6�15 mi�>JQV�5 µg/mlm"�F�: B�xI���aUn]!dJsub&�T1∶10R�s�q!:a�n.:_Hwa�9��%�Cas>s�. PFRF��.m�ed�~>IuI(F%}D��,.�E�ifu)?oY$ , 000× g�1!�%u�!1�."ot�csE &i �/�"�5� o` of 5a�IH"N�w%]�NZ  �WF�2aEQpZki� In Kq{B��*aa �Jinj&b6105"� A�� .*2 BR~ ��to�� ǒ"6 * !d &am\��)��.Ag�|107!g6 h�.Iconv��m�=PBS!�hf�uC�� �"-A�:.K��s rSA�1%h=ton X-�Oa! y/n�f agar �Y?f�!h��O82�e�0recomm�B� et SCGE k�b�m�x� �uS ropi�S�de@��"RNH'A�6�]�m�YDA�y7calibur2��Bec�kDiP�q�!�D���)ceQE�{Jo&��)y�U�[��)u"�6�*� �f� ��li��hR�ry2p�A}>�ae �a��Ơ �aZF�To �L�P&AZ���%�T�> !6�3�a�6� ]Ud4%�!a&ldehyd�� B ,B�Q5%G2�a��ti- �wF� ( NovusQ�6:s )�"- �( #9719YA���%�A�a 546 gom h rabb��nti��AUR=�)J! -i*m��B� =K�{:�5N�NB1��cM�Jf'39]�5f(14�I�We�r8Eq�x2\ɳ�F� � a6�( 124�0Tris-HCl [pH �8u.4% SD�� 20% glyce�7,  02%tmop.2l�  3% dZQoL $itol [DTT]%�&t �72 !��boj�5� .M�runT o�86o�9ro;ey�a,Xe�`I(:Վ)Ra� �*�� milk� rim�`])E�-� A5441; Sq�I�ti-I) H� ser1(( 05-817; UvF�0$Lake Placi�[NYC Poly�.e�8( MAB3192 Milli�1�?( #4895�*b S"ϊe*iK clo�>�boe)agV;&8!��R176 ))rai����izA~i��h"_Or/ bin�$IQZ5��"!A%�@R�f$��-,�a�( e�. QK"0��.�O� i �ͩ�(a G:Box Syn�0��L��ֳ3�. m�!I�� ard " P�Ga��SE�S��Ix����"EaStu�2's t t� E btisg�!?g�=�Yski�at P val�5<�}5' 0g(�by�w(0��sk�|"C ly��z�� HSV-��-2�a*Kq% +"��.�6}%�3v�(f�3!�"�3�SV %��A`�/t�s"f�""�:�"By4 e����N libr�E+p�,�*q(j$^+a�5!romodo_-* �i�BRDW� "ˆp�l�6-lesr*�*�=c��_ %�ICDKr� RNAP II; ,}"��I�9&$/llo�"paO'�XSVDc#�?¡��e�DWppa��of ���5.�/ �aD�6 impe0g�418E���`?�#at�-�),;by swi��%Vw2eS-g!�ofmqgen�T"rma��_&!)�QLI2� �A?or/2Q�(2RaM��by�Y�6�/'eux!��)at ��%�bulaa� A�!b�4>eZ)"�&K?es N�)aJá��*/:� C�siI*B.��(0-��Amu��"o/&I2oo��[7�& t~�������s�reV1�[9<v�young j�7l�>i%K �[os( ���p�!t�xoǸ.� "intJ�yct ڎ��,�Zm��;�Bwo��gd�p"���d 1��49)�� �!�)I: 5�- J5de��EJh�(�� S0%� T�. SV-2B�!� A6�7(-stranded D�RNA viruses that are genetically similar and share many common features in infection,replicat. Thegb4acquired initii@by direct contact2G�e within mucosal epithelial cells . In the meantime , t w� can enter|nerve termini of sensory neurons|travel,nsgradely to@s bodie +Pestablish latency . L t 9su s as a reoir}%�, for recurre27and � miss�Dto other individua��FAlthough immeasurable advances have been made towards our understanding�HSV�,�Hmolecular machinery�ponsii�8r=�regulI8remains elusive� larg!ULmystified . Multiple!al'!myfactorsEBinvolvEBBw [6] . Upo 9�ofF8, moreA� n 80 wa hsequenM�express va tempo�)V2KY�yJQ1C2�d!?`  250%!� �inA>BAby� ��t�55–60%-�na! 0, PubChem CID��e:�A~V� A�li�Z�i,1 . A litera+ ��ew�� �xatE abovESio��A���s\develop����tic� o �i-infl� e�agent@ The�pete selAr����*v lys��residu(��pr����zly�,!^occupy�1 W- Sb�ng pocke�f�BDa_thuA���k56 � !�rup)>�p� &E !Fg &����e�a�[19–2� To de���(a mechanismcJT?���,� focua�onA���e t�-i��͜iarll  [19� !9inL e en!�ome - ) -��� ls�� mercHavailE�.�$preliminar ���e"� BD D ��܁�re6���da2�*H�<e�l�, RVX-20�U4a BD2-specificto� v [23] ,��w��2(�, priV o�-11a�... T"�M300 nM �but7�o2[,!ul����I�: ��2��.� fuI3ZT!td�depen��O�N�� >on val �!�.a^��� ]� �C��A$�M�9 �!t��\restric!to.�� 5h!$eLa , HEp-�^SK-N-SH)� primD mo� Hembryonic fibroblas�MEF )� %�AEor �E��E�2V=� �A!�S1 Text%Sp �]E���� � A�d��oequ%,� %1 e�8�msub5"" . Ny8u��e �-nM'"�r0� |M f9�GI~at 2 hr!�i9( -))�!k� 3 6.�o��had"�naz�2 $became les� gna��he�#A�ad!k at 1�!�24~PI-�2D%�InatrA),�j� AwSVh x-V )�%��&i:�littleb�2 d���a�[%\dide��vic!��*�-$%�E� )�course� ]�-�pe or ab )�I�2E%Du��U&m ,!� -2 t��,b� hig`�� "t vehiclL.� .&�yDst6o)��nd un�8ed group� reA x��l �BS!"R�aa�ach��" I`tha�a�Yr�I�-"staHdrop �tobably �)J s duQJ9oKs �H!pEP%�at Fy"� HN . A�!.�*� �2k� �]�����z�%��inO�. Despit�is�|_ '�� woulzk% ver,�P��a��!}r4�[�egard X&� RNAi�St� �"�supa1� of V� �Ls�m�J��ZF�3*�siRNAs-]�/�wѻa3at"2 �iCtrle�Ji#�=s�0� �edBb� 3xW�Z���6r�7i�A�a\w��� unexpecteb%�uuJR4 Dus!��as���� i��$immunoblot%8P΁%3�eL1�a�"A �knockd��,"� BRD2!�BR��ed!26Y� ��3D ��gI�jS18F�=���ab���J ��B� � . It� �Dc-Myc�!s�Wm� � �* E�!Va�&Mh*+A zA�c�[24 , 25'Indeea�B&!�:Ji��-v��]��� �B6&� ,5�M� xb� RNA��impac=�ED_Ur��cl��(%�������R�Y91\exe�;Z)�Z}t:%�&��Jng�N�g5�|m�%5nA��%�ly*� kqNB���d�s=2<�u lead�� �N�senAUA� read�{+ 293T����anv!�mpty ve2 a���a� smid�>�0 ansi�6�(full length 6( wM  ��-1. F ��e( ka�gh�AMlocaliza�orrect&�"�im*4�4B44� � m:��w�"�A�� jxndof u4� �A<%�su�|!j��>7a� at suffic%J� ine�or��6�.�!�e� o�!E�&�r?v"���au*�.����AWa rupt �q�I8j Bo W� as�%:cmight"�{)ɡ�B����ma&��E���6��W� �� gene dmq$�,/2.��4Qtpre ~ �D19e%+ ( Δ)a�pot0 5�te :&�� �� abilK !�:Z�mu�ys�Q��5>Jv trunsuhZ mainly�E�c 6Ho)�tNrT� e put� 1us m�� 1S[ :��� %h��BD:oɊ!�G���aP mo��eby>D %>"e 6R 4�4"��$! 4r��:9 �B��ggѧhe� -mod&ed0t�"��v�FU��--s s a�o u�atePZl ]� dive��6vd� A��#A�� "Pto� �$i.!"s , ] U �e��"Mof��le�s�rY!�� posiq :> elon� �)#'$ P-TEFb [1�!26� 7W��xa';%HireE5[2� &�addA2�eh�$��fnala"�%c�lexp'.t toal�.�7�I�d"n6�induc�%h"�$((!D�,1,e+RNAP II!n:� �] CDK9 'pb"subun�_ofHaqF5@ iU . Ase7a��5�a weak&"9! betw"��Y:{�WJ cAunx �+6 mark� 1_a>�!a�tw�"�ss��5��!& ob�*���������(X)B staiz )��g��co-Ali�6�h5�5�2y6�UjQI& :�!�%Bor )� ��n*Ya )ed ChIP!#ayA�!s6/!-!m���l�ip�%�"�(.strain F���1*�xD�)Hce�   access+�re�uP�jYR�of IE� �*!>` ���atcd:{PCR1��7V!|q/ɂ�patterB�E�paP'e�$I�qwMEF�5GK\2Kas.#nd&C,-x�z ai�'$anneal fur  upZ�m�co�+reg���%�ct-qDNAT!�,ti-�i3MQeq{Ca�&�.��M�6�!,R�. Comp�%I��Vo�a�amountA2ea!J:b!ka9.��V��"N�)�6~�p Ib)Mfluoresc6qZ MBE*1!�!�iE� dq�� �6���rA&�-ICP0 ,' ICP2!&gBmPM7j�C16aUe�"���'h� e2�QMW�i� rew1�ޡ]��2r� videU�e���e f�ng�we-f���&YI{asynthesi���EdU!Co�.aF!�y1��.F%S05car�%n serum�0��$.�d-�dJZ)v���(0c ns.ndBp�"��. M�*i24e�ZU tT>ofR=e�6HET=|a�p!`U#re� D�, lik)#2^3S 6�2&�pl'a[ ��/� �I �c!�by���A"e�Chiefe�Brd4 &= �w� phosphoryj2d >j[2�!3�!6�/RF.� ��!]�(�IV[3i 34�{��8B>�"y�fin ��`�h!"of �in�i:��a�ѡm bodye� .$-Ser2/Ser5Q��CTD .��u # >5\ at 3�.>^!a��*d6*>Dof ]�.�oF �k��Y*B���7�!B�LDC00006�2a)@� }  or ,:q!��Zn>� ��[�jch%��0Le�rm��2��'>ASe�dep\Q*�i; i obu&e�-� Z�gllO6` �C�#6�'!"�s�annul� �$h3�/���B h�7��T��1# togea} ` � ��� 6�by�a�2�� � ���=Q. �Us aug�Bgdev/�[�!e��si�.��t2�4 . Human herpe%!�� l(m�1�H&r da�4a�8X Eto�aa��v.�+�-�1>D9��zls I:]F�8wg'y��sis"[>Y9.�7y�of�6�9͌)��ocapsid %?� a�y( microtubul� �: ar p�to relx+0 \�Y7A7�2u��! [r +��cir #r;+&�72;�#uR9 goes&��6�76�7!eu&$q7 , 3t�6?A!r�Bn��v%M��\- z5�reN5#2��636�'�+re�*e��C�)�Z !�/rep&333�3y2�6E�a@�8��i6�J�5."! ��2�6�.��cs!q�9�2�pro�Ht8�3��9��. ����j5j r>6�A+���)P . Un� ]/iF�r=U-�\zOA N,�ĵ�"��7�.�B6���D�.�A���un]���_A�by  NB>N InstQ,�< data?�elaF.-V%&. `8��6�F2JOEnw-�:T͡t&,=s }Q24�{6$A�%�Y dislodgBED� 1Yd� �ca�5WzY.��57ng!_��� reloMe6Um��J��k.2\� an"l *�"m recogn��. �-�,�� step%8�����?ignal�>���B"�of�5%E.7- �1'E\� cri�/&�4.>�� ubiquitou"3M�S�/.�����2tA0�#o 0at bookmarks ��� mito<A�A <scaffol� 2b"� [41–4AW2b %��sZ>&�*^1���!optim���-1E�17A�>4�4���( �("�u adap!?i�$q��;� :;[16is:"2)�� .[1%3�I�-0�a2t.�p Za�}Da��!�HI!%@4J48–5Ep}* �*D3!:��&;F6���>"�@ )�@r15ntagoniz��q* dof�<-�E�-[1� �5A^53�I�6 ll ba te2�$>�)�or p�K9�<��. NonJ.���*ud�" M�+�  >al!{P"��&r5�D��m"�4�Wyet=be"R4. One p�Eiar�G~�puv� mod!��8n!usI���kin� ia�6� ���#!Sr��h� $exposure (275�5 h5"��K �f�G&,�VP16-" [55 , 5�= Vari�Ls#A��=t� UV l�#a4&aD such�Z%��i���?7&�� !?m(;ap�tui�f|in�v�%} [58�9a8�A�qFsa;7small�ar ribo�o�(( 7SK snRNPa=�!�� quit�; s [6�61{ Free����-*, acut� 3����/wth ,n b" B�o R�via%�super. l ( SEx.!%�6+b.�����B&� m1sX^ -)n-�q�n l�;atI A�ds�JaYmon}rin�Z AA .�H2�?XH -Y��$*��*&�E.O �o�-�. A�B a�Itage�D�67w� w8t�8s!��it�!wqHN-,�" diss� �(f biolog�Gqk!J>�o~s|5a�A�a3:8E� e�5Ka� prob�cross-7 �1 F)r>� � :n.�!�!�2?9� unco� a novL%"ATa�, druga�earch� ET��;�K\v�;�����apy [�>6�DOu L� !~ise quJ%JB%�v�)so exacerb� ex�IngO�. W!�rec�3va)al%co)� ��$*9Bcerk �!�a#a+s�&9�n�� ���Mapp"���1E1�> �!��+QD�7��� ( Afr&= g04 monkey kidneyF�0, ATCC CCL-817"�1P!,#2 "�82s#3�}h�FN�8 oma 9<� 8HTB-1~e�purch@�\$( ManeB!eVYor C� BankA�C�M se A�LmJS|+cQ Shanghai� hina�M*�9f}9( iso' BC57BL/6J2�9�E �*!�0he lab followA�pu Oe6tocol [6"0)Gcul??P DMEM (�,gl�Oe )�Hpll4 10% heat-1=) feta�Ov�>( FBS%�(sodium pyru.E��D&�/ amin�id!�$Life Techn��e!�Carlsba�.C!��HAi�� cuba� 7 7°CI�5% CO2{-1��$aCO2G)propa8G�Fd�6'd[u�Az(,( Catalog No�P1900 )h :~Selleck !A��sEda�QNzBT� ц%s%�me� "" �*} enzy�A&_R*�M!|9Di%��-de� a� ,7� y.=L=ATA�,� 7[_L" Dnmt #!�A���J��R�F,�<M,.RDk>V'd*�(Y5*!�����.�;@5:2Med!� E�@/t!A�to3 ( Abcam�b128874%q�( S! Cruz�c-1313A;,eJ(��S"v u.~L 2629R-Rpb1�8135S"�"��<c�4$( Bioworld6uBS246��Q[H3.eyox=Hit� %iotq�� AH43��,�2E��Z�337z ser1)'I���6EMilli�\, DAM1776434 , Lys9/Lys1)�GAPDH�R� MB00�Iob�*om&B$ ti�to�$4��(A�-2; GenS�  , Nanj��!e 40B4ABmar1�E�.New ZealI rabb9 u�� sour�� . Ho="adPUperoxid�O ( HR� �ju�&�I� A� �6QBio-Rad! lexa F'& 488 ( G4)��XN-m�&IgG%.8568RedJ6 �7N�FJ. P{+ G /r�# bead�rx0r.,Roche Diagno�S &-x'�*dJ�K�o2� on.@u%�an MTTay2 w��N� �bed [6Tod * �KR.�1B�$DMSO stock�DU�43 ��freshoilu��i� me�AL'2priJ @>�z�L�2�"R!@#-2%1 MOI��+� he �a".��s� �at 0 . 2%Ilef � ��7ouc&� �)�m�W!�� viat .60�PI )��9�$to quicklyH!$cytopathicQ%by���H�IO�� �'PFU���na�"�N~M&�,Q�F8$pCMV2-FLAG-*\:�AddK( #2230�)�pl�7 enco�RfF�7NM_05824��!��Ri��[4�Zcw7��BD1 ( aa%�196�#�364��ndF#5,A97–13ţ�ins7:A�p3x% CMV-2�� Sigm� )�~/dar&P ` &�Y��MF`��on^)�(Fe慩$ed d Lipi5 e-200�F� e� ��e-rD�Cp�8_�!"IRA�!voligo��A{�;(3<)�edu a=Sor��q*]' GenePharm2� ,� �!+E_&�=experi�� a} �p�Ё~6-w24-FY Cor�")�Db�+2.H R.�o:�I��1k�7��8O1q�..�|9-�=�#1: 5’-CUCCCUGAUUACUAUAAGATT-3’�y$UCU,GUAAUCAGGGAG$CS2 S AUGACAUAG�A6!�A?AUEs&.W� CCGC!�A�A�AUA1�}ADCAx!DGG&.WQ�UP!qGZbUARYAz!�!�a'CC.�� lysITmixE�!�M�ic�!r 15 min2�son�e n amplitu�30� a 15-sec nd 10 ff(,eJ0\to sh�] A ��na:�9(Jtnd)M�""clya�sto� at -80a�.� iQ6e4J|5& a�9Abu��( ")E�\FUesal�sperm�/u�:�(��� (-! :e���a<�3����!# G G .���)�%j�q.ta low�t1���.�in!A ( 2]�1%��ton X-10�܁�U�A#� ,Q��,2�a�sa� ( 50�`�A.�"�hen LiCl��( 2�y, .O݅$1% deoxych�)n��2�)T:�e���0lu6O5% M NaHCOi.p8B  ?� a� remo�6K^!�_,10 μg/ml RN�(AV�%� at 65a2a�Y!t�.��;lin�@AhGxMrsKO5O1ZJ�)� A��purif�kSYBR �#MaV"< Mix ( Q141-02/0n&Va�*�,"�]$n ABI 7300=^Rsystem<�)io s�W�-�%��ug�A2-ΔΔCt�oJ�|,jEabund�Z [6�#�a Ct ZH^E(a>!Cer�%��� A?value no5�(zXO�lip��fix��4%�>A�"y[�J�t roomje\ ( RTf� F�Sea�3!at'B�H� r�spI�U�(� � go�I;;3��ae��:� �Haz� Ջ& 1:���I��to( 1:7006vo�  :>^�.fcon�R�w1�))YE� visuT9�()�D%i *��1�p DAPI@-�)e imag_&�iOlympusNV�]FV10i�f�Ki� scop� We �F�<�i�} �*rep"'!�E* oYI grQn glas)$��Y�E -�T�xi_a(�.At5%$!F��2r�) eat G0!Ag�:�EX�Q� 6102/�_, :����7repla�Ew�   �2 �A�5 μM%`u��ankkv.$ -labRB�pm]oK8ͯ{.�5 azid!���Click-iTYE2kif!9�'N�E��$ redistribr�� Ň�lbFmS�J a��>=B&PSS 1�0 softwP6packa%� Datai4����ai+ T ���cs([A4or�Y��EY05 G� id3k�l�Qg"Z(.jWe aimMuO7�%m�MbA$ec�!�"nk#(�(crum ori��sdeg1~ an# t illnessM{�)seem(\disfigurj" in>1��pmalnouri�children�& ry y! �:W���)t-q[ chao�mmix)�iE��)al hygir,A�AHe��� �uv'l*NnI0�WA�dz&�f�ples��se!�(QueF2y poin�&un`'�=u9 orga-a,4rigger gangren�+fa%R�; o�m�"bU ri�:e6p��%3�� vy!�d�^$- oap� 8Y�aG�(alZG6� EB16S r� g%h,A�r%sixty se� a�iA'fluQR�otwelve�$ lthyY,U,!Qe�9�( ��he D@<�n! a^GAc� Ne ;�/ Ging�ni�ANGrgX } F< ��Cvit,5taken �1�ina7�@uthI en-#�Spi^rae�0��0g&or  oU. S-up�)ofBv�R8%pR�ofFv:i[)� �(=�pN . �9�m �d%^�(��e"� of Fus�ux#cas doub n&!1� �L �eBE5. Ma�� comm�L�I��'*!iA1��domin:�+s�_$PrevotellaP �a OTUaYHp�JmucBTss� e�6�2�`-&. �uvarFL�a���iu)�Q l2�Y/M�� �M�0i�tH&m. S{ al�'/�Or�; Erysipelo�bhaa�, Clo�di B��oid �Y�����)ai��9of)�,�P��E��uorW9�]�,w�xemerg[If sA!u�"ho>eek!ftes>!uanAPbýi��,.�f�5�.�L$ Ygum6d�bo�M"g9 3WtoZc9&�/ barri<�/ musczndU!Sunu� _6I�5eri� �I��$k verb numk(xyCu )�1�0Cdi�x� ari*�X)>in young�=who�2� ,o�9�vMus_� lack�O)<��4 dent*� . E��5Ng�a�:al�/�5� �#oce�"'120th �ura\�%%excep$ @T.sr camp�s WWII nd "�-inL m'in Eur�!!yUni�Q? �[peo�y1-E�� romi!([1F4� WHO �0m�Qa �)-w* inc�c &I c�+47 in 1998�f� g00 ocG1m"��d%7Bs 3 Lub-Sahar�0 [�I�mortaoX5A��to�480–9sn�  77�001( �% survE�!Ja� ph�Fg�ca_is1b��� �"�C���%�0t�ArMyc%a%�isEZI�"{be�=/gh^-�sh��aNEmK. C�~�? �-s hydraE}A;nut?�q9@la1q?�Q�Y�]_i� �1�@�X�� surgT ��w/4���� ue]-� _a��)uy�%~�Cu� outbreaks9=in vill��%lN�3rNI=35hy twinXo7Iy�%�af�)'/ f�CntM�[4At\~�=Uu.�&;O.�h�6ub-"� ͦo�o�Zsu5Tful�=%�B�}i�$j�s ["�1exact �[lo*k. nknr&R risk�L�! }" work&�I�lK%�:� � a�!�Q�*sM:T��Ut�-p�|"*,&j4l1l�%3�r)>�K��U����edA�4�6 *�%�-o�&B+hyp�|s���I�6  "� [5]–[8�ntype�n� 7 �!4odPo �)�e] e�QtE" �B�3ong-helx e7  a� um��.5 �,E�,}�, [E)i �C�-�A"i�a�*� Q��%B�(i���eD. B��i��vU7a���+��X�q�� e�i�W� M}���Q��i�Kul�Earlier"K � `LB�u�4�aq^ MO bi� �;<Vw��MH!tat! ���/ W�nde�� m7��f�x�RMl" �*\ - Also��,a��pom�\��eL&� pop)Is*� ��� h1�im_�YKm��q��doŭ�mWpi� 9�� �"1�-A/�9;e�79I�%2m�k ɵ��(����a��8 NA-b�7taxonomV-thods�sb��!+d�]99%!�%t��2��l1��hth( 5��environA�A���qh �$m�1TBI�zd%�leYHI�sAJ mmend��� "Z� rŁ� thObA-how 9�=rLqDe3Ht�m@#n� ca�doc�=%�f&Nu&y �.oge�fene��vo2�I�� man��NE�a$� 9;E#E��Bflu� R%k"%|!Z�� of� Sd2=�.�~� ,5�a� ;U sturb1F}� ra1 1?A�l t%�M�M[d�� obscnAN ���M15n��-su �B �m�!�a shif�X1���A�9�A�5�6%��C@veaaCI� ��b�i�yal#AL"^a�W�F�m�*�2G�AiZ�� a}terplayL �k�pnd!V2R!�menp\M��Zun�U�!܅�a��M���M� -;���Ajd�WA+91�A�w�be�d �,,G%'�B appeE � E2� ! i1@�#Pdx*as�y�a��yhalSiaR� a�.v bejs n C��_�Gu�a�|�R�Drn�P�' >7_ GESNOMA�iup��Au�� effok � �BeF ��f�%d�� !E� .�in 4135�.w10 9i�y[1� d�Win Nit��[ �T deem1(�xa762%�� d6�J]re1%1odo�qo&�R� by pain� �u"�g�(I�o�#vnch. )�I��� ofj�H�` mat�) as closel�6pQ7�Ke7N�. �. a8�;sq8�6�u��]C�� ��rn �"Aepidem8Cyesm�"d ���JTh��AQ�Ʌ"g�Jn�(�tvOu )U�aB.lE� .1��H,�� %�j y*�V~gzj.U, PeptUc���qT�nem& [2�!�Q�5��!9��%E cru|����d�\B�N phoDG�*X#a� pr� ��pI� � W%C[&9>�< on)B low-�put.�!E"Phybrid�$���d66 �"� B1�-�!zsLi��wm!�{ ce d�V��s �2� �'k���D�ws�z2c1 rdz� bFra��is_:b5g�!.�z�z tes:j\ �+aK.�E9�{ qe�|Ae�m6�ofAy��9���nax~mae*�L b� �U�%j�oo_��["� "�>���power�eA��;k&��!de��y�i� �WA�a:� ! y ��&/d% of!�2�ua�&E�A�DxAk �"# c ac�C* �#��m�I�ig� KG��}y buil�;%s��9I�x��by�� highZ��Mxam_�Y�.F�.5 b .��.n]r�DgN�0c� vera�I�._en*je!� a�g�}?=BEz3 t7w��WE.5j��(]Jcg W  Olr�#s) � � $%�2�NG-6w�q7 iv�!J A�9c!V,Jug.E.go�o��I�c7EA���Be�x"�"&� �(`"C�Wy��W�%�:�!�6 � wI$ vent��"'Ka��a�^oov'flon*��1I@�L�in�*EE. "��]�1e�^|"V�A�a�Q . AsW+�1!3�G�� sub!w%�h#1�%K&�)w0cot�0�$-�o,|*# W�A$M volunte� by n�s�� in Z�)-n as�jc�-��,�*&"�/m"�4s�2(in guanidin\(isothiocyan�u]- RLT �2 , Qi�!�t#3until�"�\AMM+!�y� p�C�25apro�!6H� �ata%%mS-i�b !1du�(� Sept�` 2�D!V Octo�� 2006�!�-D� �)J,�K .�$�SX%h .�8�-�e:�U"Zby a6o�'`E%g]�r$ -�![ J%��6QL�$�12� �Yg"qB�*"�.2!�%iy K a)dt �!�B �-�)Mi$HH� �qE�pro]0�` 5�bSwiss�Jz� al$- “Sentin�I s” @�Dld waa� Decl�V� Hels�(b�%o.AZxplA� -�R�on�!.*FFr� !g1\eu�)�staff���1�'�J�]raY rdia�"!�paAgu !c;PA.$�����Z� H(�/A:fingerpr))�.=M�alp(n'���oO�H �@v�Switzer*G PRe:M�BFPVMcQI> �#3gMina���! H8_M^D9� '�!}PMPa� -�tbof.+�� +�� +il�fc��RuA"��MJɜax!Z%��+ Q� _b%9u!n T9 �3�-�'s.�� =}.� A�&4�x�ɥ'e>=�XDNeasy Blood & Tissue K.��{}a"�_/�4&e)��vorte�2�301�� �_)�/=H(1D #G12�J212–�3µm�2n ,A µl�fALO ��nYO ‘P�5&_ST&5G/%AnC��2Bthe VHandbook"!g"�==zl H!µLA(�il�ox#%O y�e V"3 0!�&� 6�+=8 W��cor� ��1 µMJfor���8r�5′–gccttgccagcccgctcagacGAGTTTGATCMTGGCTCAG!�′ ,Y0ZaA����d@@TTCGATTC>e!��barco%kK7.�ccctcgc��N (atCCGCGRCTGdAC� in 5IEP-EStar HS��.( Takar�F��7&e��do�+ U6 �Yd"oJi] x>A�-"� "Ie�m�h�98910 �565!72�<2Ea seg�.!��UaL>8a>w-�b�E:��.'bb3� i0"%�� �.*iU�2Q��A [B�3E��˭�Q6M��D4CGGTGAGRGRYGAA1�!Q -*G.WGTRC,5�n 2A�l��r�3n�695�r�X e��� p�kd aU� l aliquot��'M",@�JempgAda new)�a�E�L~�B .A59�ui1�)D1k�+Zita��FQB|b�G�pl^L28n�5y]N�4/ach�! 1I��PCR# poo~A�"G<N�� MinE��1 �}b5�R, 5 25 u���ab�=� �co).��q29) �y run<"1�%,���jJK Agi�)2�(Bio/5r �a�W�8W chipN00 ngS�\�M=�*< n a7 �+SYcer FLX�$>�@91��14DaC�tr�A �Qiime 1 �V0 [�g-#�(l i3�y:!Haa� ny ambigu��~27g . ,CN���2*1�%M�orqH�1homopoly�x�y� s�(eE an 6<oti N.���[��!aW1Q ��utR�� ��` ‘A�c �to���Ak .��enA�6�;`Q�uqFA��'�)A { in o�0gr�dF!�.�D%�� �to� b��7A7a�M/�(ma���sem bin!��<,he 60 unique1��Kre1 & "�12 e;ͧ5 � 7aDps ��E����q�u .q�M&nM�E�3(to�1�LiF�p(cut-offs: 9�+97%��#.?mer1sre p�6Q� ZCh+ Slay�� Mothur ��ax($a�as� � oi�e-L�31�=/x3 gRDPA i�,�!~out:\�o Z) Sn>�b�� rTi�=]%J�6��ch�P also"_H\8Z<)J�>6sul}I�W[f�d A��s�a�+$�>�{$A Bray-Cur�0p`*&!�matrix Q�b>�! calc�&"�E� r 6 �G‡)I%:a�!La� PERMANOVA '!��4-DP>9 al S��ng ( MDSU AWS scape net�*�z*�make_cyt *_*. p�9mmoQ�;I�%���aɢAnumk�u���ti!r%%e�P�.?e�wN�&c layn C��_s���<�A-nS� ��)��m�}h forc�.� them .or SpeckA�< ( ISl] [20]�.k I�Wlabdsv"�<?E�to Z=�*&=3� a̭G�equ16�B�IFDR �F&�9+�adjus*��-011 Si.�&���36��<liva .7/w�6$a few hund�+kilome�of,��c��J�c���QMG6��� :�1ɒ"�$&�0M�*� cli��by :�  -��!�#b;��)�A)��8!�$<"�!$�.R���W,.� 4u� ro�g.�2��4 ��M1,11 days "&@&&�=#2) five)  � XId� arisl(? udy:�"�( N ��>�a �"�S:<H=r�$j!Z� zlnvPB�ANG �!�un6 �a��0 nd:��\)�( i%| V1-3.��"^���K f�b�d (� q�io�)�454co -a�"g .We&�&"W )as;M8q~Ety fi�)A"~ (> z ( see M>-!�of�).�438I�� � leto"��"C�� i&�E�)�Su��":�!+�qe UuanAyi�1&I520��1jl99X@ �6I�'��y�blC dPTo��=�c*�=at$* �{P$n OTUm�*�5Q"�.~�9"� �� -�� ty"� �\� �]��0��Aa cutoff;J0&5 % �� 5Sc�S5%�sYk�� nt6�es�.�>262!�35�_�of(b tal;��3. g��)6� )� Mb); 2 �.z ��.��M.� metric�|ca�,M4� ��t 1��y2�e;3rbo�C1Z.�( �e,n#.�y 1")�&�(&�$a�H/1a�Chao1�NShannon8z> � 2���B�\;�H!�)J*� E.) *�%�� {�7-J� � , . Both� � H � � 2,15 a"m94:h#n�2)�FN;"�&Űs;O/�@ , ne�r-`� B_�m)� t�mHw���6������'!4�&��!i%� n�;byin2u0%&g>�$e6Q�y;�/ [/m5q�T0M�&� NP"� �>�p��>�6�a��d0pronounR-S=���%"� �FH�8�b Wsumma�=se2R6(%�Q�2d.� a� v"e�S.<21�.g$,)n35T4����.c6�D;!a.Hw�E�or��# drop�>to� U3�Z��A&��urcTe� or��؅L)�da�ona�L��N�Firmicua3acc?��2RJ1 �N&�)t'��Y-)�a � �A�isE/um:eE�20%W `��� mapp����"E��!Axum�Koid�F� m_�@r iC>� �Ly:��=1�4 �s�R6'%�E*)!21_!���&�DB2] well �.\i', C�KFW���n�=�ky��J4�mPof ∼1%_>�� top �B�Am}t�� t.12m� �*��2}i6��6y0u̺��!NI �(63)%�6�() *� . *�&>�*Y&� vT2 ��27j6�" <�[!&4"����)� e-(n�a8S$ast 3-fold2��n�D6w�I ��o��>t��>�9;��"Q$t"I%�H-d*gs:gIV�~$su� "�fco&�:a?��R=p��#>��"s%pa���,2C9y2e,sref��k �ypr�� l, ach )! lplo�< 4I �)|>�t spa�e�H:a/�pa*�H.)��) mRX. L�N$>�!�� �iv`u� I�Mo/��J .!2�%/5��s�A=q��1r:g&p.^����[)�Z �)�x)�&"*7s2,%�"typ,{us� o�,\ E m�� -� �`�;�C w )4�� !��-�s*�t 8 =B�irQ��:�Oe�*M�a para) 2� �YE"�,!��!d|"PA сF�no��  ;2�� MB. O��l�8��w G)]@M�g*� -:Qrom)�)�D( F999 = 3 . 5��P �#D+� PairwxA�?s� py��2#<5e�!�t��se�"V��� �&O �M�qD � :.>AX!.-�qt 2DM��2F62<,d�2<҇tu�Q*�O~�yt�mIy���is�G��truJ(�&�Qa-" e �+ ��E �B��.�24� ���p� ��9�5ZxN/6���y Mo�$ed yAnosim�>S��.�F�;�A(:R>�Hcxs�al*�s��6a�S�Jig/w%K%?I.� d�porAˁd"<�mY� BVa�as� b�/of&N ia�"F�a�M�gen�Y2�Q A�K��Fto 2+7�qi"w `2I� �"�-�sA1u��M�5��E�se/A�=)� 2�!Q.-U&5g�9: PorphyV�nrzCapno� phagj Aggr�� ad� d �c���5�ta�q�5,�� �v 2� & ��(v�Ra�Pr:4"p-ccu.dZ&�Hsms.�T *�<�<sa6�eZ�N-�RL��-%�!�NCC�!se��!�Coryne)j 2,*^�B=,l��,�5<�9ԸfO�6A taxa �6�>�7�i}�-E��� ca�u ��2�I 126Ml %#������p�(#�I!�QE^%���1�&�Y�!�.�V�� A �A�� ISA"��h\$W-�ce%�"sfi��K �oav5t"�W &���by"FA'�4-) � onsh�`%��E�-~*�*Gl�Bll+� seta%i ._�,�@)^aArW��v���eF�6"4� ��c�;5~V���}A�uK�%�Ju��a��Ew��afI!fs&ٗ�Y� s) .��SharpezrFa+N: CŅbe�aceae �}Q%� ��sceIreJ)vP(o.�V J�V�%�l ��WX= }�nod#m )A�O2+oy�*JR?)l��%�!��L$era Veillot4�_J�,.� �&!@%�s&�r�@:�*I�,�S5S�!jl�� ���!�I �A{:qre�$"l�3ra� ��2iv�.%�`������m6nh>p,A��a FlavA@�%�76�!6�S�3�%�-�.�vP&h�C%�*�6�:���A��at�(o/MraQ {9�� i�i�S� C ��5�'u !{� #s��c�/&q�&aۡIepe`!V .� �*sX5p�Z-Z0Q� L��# a@Ŭ�5a|�2�� �Ōf( &� l 5��B��T�-a�s���?�� majo\'FCm"d!��IF( esum�ż�l@�`��9z[3be!bQOqu�$.t�Mn&#��1A��"�1*qlyg�/!HoT1 �^m,-"@aQ*�Rn�T1�174 �.uA�9o610�� F�kc"8z)<24a�um Eury �,�) stP A�ep�Ong�)� ?! anobgR)�A�oMI�lobal v�f' 6]f)�a lZj �a5%�&^a�ve{z> �,��1��35�y����ty�b*�"�Wa*}(G(iZ+b�A!"al� thC=D Z,[2�%I5�a� ���dis�K �mg, �}�!�nn8Ung :�2A����TM�;&r�d!����!>�V)* �.r.��? at�� ���8�A'he(!�at  A��(/e�T���E�)#�_b�7d��4 fA8)��AY)* rpreBn�4�e�C.�v. !�٬A �ŝ(%�Q�e�����U"}[�N p)�'a�ighE c)�g{\���[��,5B &Qp��riYA9�� Df&!m: i ti��/�4tg,Ej�+�?2��Pm�neighb�`( 3�t5M.a�� 1�vs6-�S�� � �wΦ���UIq%#tol��A}!?at O��&I�A& ��M�&�a � A�6�7��%u>�EG&G�?0e MG-RAST web�(( http://meN2� �}an�^ gov/� ��$ID# 458525P3e� fasta8�v�6._"���0 �/m�e�2s�u .��� ;.�2! IO�;I qhe��Ek3�?�(��fMS� -�A��a��e�T�*� +s%=i~&�9,-�J� l1`(Mv �f! ��?"�S1 .c�� ia� qu�Kk�An�% oord�"#� � prop����n=f j�ommitV QVpor40!��5(y�`of i}�1ingien� �inmh���c&�E�P#ki&AG%�L:�r'?�W"�W. I&Rtu�eR6X16i)��a�P"�͠ RNPP!�N* ly r 5�re-onQo�:"�p}`AD.�rsfT @o�$ NprR�Jct� ��c ��!�BZ=X�B��!�f��Þ�!�aL�ge�b����_�B's&�)!aA�-�cad�  . )�d*b��J� 5*��Np�c@d��l�W�2��m1G��/!-nc�́�-6�'?}s�b8��Apo0A--�eT,Y�/H!+�KinA-��"�)&�2� aF; hWela�/i�<%� ;.�p�0s�t&��d Z�i�v"J a��C�RapIǙ����I�N�DV:di�7�S�ng r�-��joy-EJ._ɖWCein"�ve!��,in�,C�Dr.�-�"��pDng �)d�F"�'@V?/h �a Y2n!�!��� crys�E�1�Fpo)�pi�at 5��jly flexj�Rap-l��M��^f��ln���i�L^&��in-���5 �biQ.J� �%�1�!�XXye..�eswoUfA|e�1�switchesR�Y~Yme�+m\�Wf2[� tetra )e��2�.�A�n|Jropm�lifestyl�B .:C. �tab&q ��s2�!\s�F ensu����&,e�k]8/ia�W*�����S� ng-��l� !�s�xr�~5�*K�d!C!w?�G�spa� �� ������.��'��2_��?wo-Y�j�/'.q�0b �%l6�;i�gB~�� �m��X0�po)w<� et�e&�]�2timuli� !f�b4 &6a m"\__h/-�.!*Gram-p�v��,BL j�!�!^-2 un<I��!� secr�cBE�rB�m��!8)�e�=�[2��d�V"F elicw��V�e -u�,Wq� o".����r)�0��a�]J)S� y-D-_ ms� �&e�Q{yIet�d�)� ժfir�7^Z�0v:%y�, L�"�$subtilis [�2��!l�VA� PlcRf�6Pcer�;F��6�YEn,f�Wfae�':ux phe<cor PrgX *j�R|�lI[%--%9ext�M*�:&DP19���C))&E '*�i�e SHPN�Rgg [11Je���I)�y �zndQdQ�-Q�Dl��n�A6A�9 cop����52oM�E?eaZTPR�va�[ X�f �de���d � %�~3��ׅ��(qwo hic%llel α�ei�� hss�� ��) r� -han�ރhelixU>�A �5��[1a�X. Ba�)2R2��W�G��!�P q&� or ["l1�k1%+��E6�2>,Em��� q�an N- �m�-turn%%$HT�7-thgJ5 [�Ha5acŽBn]T%o6�A>> '""�u�n 6�alpha�>EMx#{!g!d�E7ENAlexZ $t��&��is.  Z* 3vx �+lH�9� �YiWH A|&�JTPU�U=�2L����d�Au I��-�s���J�!��"� V���~m � dA�P�-�ar�NA,�� �.�[A��i�zl �X"��,%�a)�� �A�� Q�B$�XF��fsMr!8-� QQns�֤%�ty-yt�c�fcҾU��e!Y*p c:� �uJ � �<l�@u Pjo� I:��?�Er�;&t -' \z*�-mQFado[m2� &� �Wg&�� a�s�ultaneo��Iwo2�s e@I)�*%I�M�1�� DŽQm�&A��`sE#�[yu�v!�wo$,� Ifac� ulA�v"-�d\[œCGa�i�"*����q��i��V��!�o.|&3!�|��or[�*��[a�Iay��A� Q�� K2�*_�gW"�'6�� .&H !hanthrac% n�g,l~9[ erhho��G� .�* bn2� &ddeu yV � Q.j-P� 2�%�D 0at^r�8��Er��Ym��.dw�$�z�&bg�|��e�6o��r%0*��e:4�2� 2�OI2u�e�"o=m�a�6sr��0:�=p���a$�L^Y W�.��`of �[C�e1 0 2.A�[A"�a^A���Sre very��pri��L3($)qadiCxem|)(��%@wI%, Y��I"^:"�(R!!!(f�ͫb� �"D��. �mA��pq�_�1i.J�B]��b�) �ngE�F" %�)SUC������%�is�.2"�*-;%�ܝs JFinAA�A�246:�t�=.�.nfY"jow,XU��joA��ba�&�֩�m'k�!r�!��n�MT�*�2�;rm����)L��{qjx+'l.�&�u�R2�2u(. B��teg_ng� p���e����p� FA a�l�-���lin��{�)<7 XRSZ[ uw ��U�x� syn��n*�i"�q�� AT . In2�!")y"{-%��6�� �GEz*}&��9c� play!o+�W.�q_E�] F�>&��#j�k64407�`dl s%&��R�/AD<�AU $s�RX8D*Z%�9 &ZKJ��=�1�q�{&~uee���F ( LBl9Q<t 3���DsOD600s  J�BG( t!�� -�a�&O!%�+"��.xAnB�P�m��!2mM�1Gql8f ( 46 ± �6%d��/� ?wi v(P±�*3,� �.yAZ8.Z8.u�@�!ΔR:��Ma��A I*�h��2v%�.Nsa/fB� �ΔX:~�� u&�6� to 7��+5��ap]�=&�M��l*�l�{B�300�;)�%zEd��:>����26$3.�a��-��  *� '�0e�@ o�.'q�!un�9*� T�� .� � �u'����D4)�es[1^by 1200-%V251�i �E�!yA�.=��%�>0s� )/�a���*� ��.�IjA�. -�*, E�� 21e�_�^�Azi��NSAM X7i L (L!zV.amy::�c)���9hepta~SKPDIVG*�(�-D�O�FI#� �[8eOL�$�d��fex��$�A ;�cJ��Y<"5�X��� Rk�!.%��W��A��aaQ>%B�:�A(��l#���� :bi� "� &Nf ���unI��ntr0ean nprR*)�� aE-3al���p�noɌw�%~S"���DodUEg���8e�Gi���0tential HTH m�^otifs [28] we introduced the M20A , T21A and Q22A substitutions in the N-terminal HTH domain ofG�protein ( NprR* ) . Moreover , sequence alignment with �H2MPlcR �analysisb /DNA�eract�`( PDB ID 3U3W ) [29] show�at�MTQ m!0 is conservedf$belongs toaD helix α2 , whichos�\sugar-phosphate backbone�bound �L, thus participatingl stabiliza�7�$is not due�, pleiotropic:a}1s ab�or � initiiQofES1�is reged by��� oryl���t��Spo0A� -P ) �masterHor>d [30]�o��rmineA*E %�,�he Rap ~ atas!�4n B . subtilis*�<sB�!�of � 7th�<ien�6,��exa��ꅱity9spoIIEAtmo�, known!�be unde^!�r��co9l>1 y�[31�A ! box!rE�n�]>wof�6����’-lacZB�fuE�AIM�ed� a 407 Δs!��ntqש]2A-� us sugges�Q �2��d% ly1lII%v!�:���5(�'measu�GP l- [edFM �!�m��� ��,�&nd� s . I�D�! �!WV , no�s!^�4� a�he y�vnt behaT I��2k>fN�inhiba�TB�f%�:A��%H(also verifiE�atZ� hIl�_����� �����,M���)�.�pattern%&~- B�Alb!� �,1�>�,) �s��� ndependenA�of�B2�&�or�\�1ly �{��!,2?TE�-�N� . To invaKg�Iwh��Drol�Z�:z �s+v� we ua�*�Sad67Q�(.� 0A67e��  t� � ��4 ���-2.�a{st�F�2��T�E� e sbypas���requirE^]] elay�rtrigger2�. D�1 high leve��� ��betweqhe�h:�nd�~�)� [33]�+assumuAuch a a��would a��sam�ۉ�seBacill�Opecie��We.�e)p݆%�� by�QwZ � ��m�*@ ! pHT-^� E, e ���$heat-resis& ye" � !KZEA&\ :�^��O ally:3�!��ed�4C�4 .}� �total!Kdu� ofn�fu2�)��Db�plasmiF�se�ul��ho��!/�1�Wb�!,�{� N+despiO eB+.!7�clearly*GA֭�Q!�:< by��relA�on anE�on �.�2�E�orR oa� firm�� (acts like a - 12� arge�� [��feroA�F!\� microscal�ermophoE݅les(in"J���� O� �6Q��3= . Ou )�co�ed&  bindaʑ�aA� `k!E ppar�yKd valu�%(about 5 μM%�iG �a%los"V e c;V��u.l �)�eci�& �- �.�2��ory��gpeptide��  s�fe�i�! �-P[act� )� [5�MBecause� �kkin!�,has been cha eriz&�F�genom� Q� KinA �system9��)to� i� display� � mechanism( (s already d >n�e-q� 1$Ucanthraci�4!T�r3���)I� e� F�<���:.Re�Hdeed , densitometry&�revea� � af3 20 minute& ncub�1^hA��:J�A�8at least 3-fold�� a. !Whealtrol ( bA�volum��*�642020L20287 arbitrary unit�OFur�m� addi19E�� )�>^.��3� z� &���atk� even6���I%!��i��%�q�a^a���isYx��previo�tructur g�0� `-b�8tetrameric crys�pK�zRq'�%��ed!� formI , TPR-superw.] SAXSY A .� apo dimer� adopt� !�ext :~similar!OAL3- bundlE[B�2�[2� .�is hypo�!xnd go fI`qS_ %�-.4-�.� �,�� need�o solvA@eV�֍d al�� ��"�in ourY-�lis)�triale�R�'ea��% ? :_ + 4be obtained usA�o -lengthI�e"� trunc�k ( Δ�)�m! �؁�leA -J+�:� �.�F ly flexip��*^�.Ղ �>WperA'A�t� y]� concentra�Sfav��}GC��%��5,( Y223A/F225r� n�at� o �impair`^ �%�. Ci�� fin� 5���5�dou!) x1}�9�>�s y diff� d upan3 . 25Å�[ol_!��p18 α��ces�� conn�nKops�9��5�%�A�well defe�. Only s` _ dues (-�s�� )��RN-zC-tal��remitO d YTaA�ll?8His-tag��vis.�electron��9�sub���ca%�apo�apoB )Ѿt right-han�vݨ� ��&� stica�TPR��[13� y%?a"!k oAwt� ��\ 4a�X� b� Nall;erfa5 areat1113Å2%caE�i�0free energy g� ΔiG1,-18 kcal/molqEAN� inv�`5 H-bondI4,2 salt bridgAG9� hydrb bic �� on�In�cu�qI���q � vQ�=�UZN�ad Y410�.�5 .�A.A�/2�C7&. &=�te� ingly �H��~A/{1 |"� ��be moq ���in!veA�a:H�"��,M��� H*&PN M.A��V)C[ 6ns essen� a�O > $. Comparis��27 !7%]J; ,�danct�� pack�!��t�!�pitchb}nak��>�:�F is l*r e�te�-/Kis�crepaq,Jr Z-scH of 7 . 9%�an rms�� t19Åe� 293�!(ed Cα atom�ref��� e elastic!�-W�A:s�.atA�na��6 ��:�ie1dynami��y oscil�A49�o&� a�] �!h�>��alE ���4GP��=�a/� ���-�1p=%o7;)i=V311_301=WaS#�k-J�vndUB (U5 . 12U74U284rU�v^ Et!/��< &�is� il]�:]J lsoB�avail�6U�u2� . P�q��ny#��� � ae1�C�2. atB�� )� �-ID%� )��.�9 . 32�265�90=�ofa�inK-F6�chI9C-A*-F-PhrF�[20] )2�8 , 52�33�88b�KR�GYO2�J�C�19�, �%r V ,5�mR!{q��.��n�(VH�,",&Q15 [18]�GRapF-Com��PM&LQ [17]�es� F#n��(QZۥyKaQt�:Apo2IIL�&4I1�-Nm��H �:?.T.�A��-66 . 4U� 30Q3075���2zQ� 1A-B-- turn ,l�F�=�-NweB � 9E ,Y�S3qP$T�E*��([.�al�nge�O. in%byUk�1# intrinsic� M->�.���O'U�3��B�S2 cin.) %"�#dZ�.�,A�o� 66%�c�6Bl.1�carry8Ra���&� onB -P(prR�� folle.�ar*8�-%c.2���e"�$!(&�&k d u��W(�) ropo�����t�(re� �� � med�$2�i��,5����S:���6/I�?6�2yA-��\. S��* sed-Fn+s�$4m;.}u RapH&e Q47 , F5�$ E137� Y175"q �JE0b'$ly� d �u_�s, corB*ondAk%�"� D10Y11 �88 � 223 By*We� Pye:Linala�F�v %2�h� 6�0z .� i�f> oint8�s� lish iR! r'�:! �!!I�*6Lmov+-!"S"� -V =@ �,QIE�fE qA� �& 9!�6�^&�!D!i x+�'��inIz�"%� � . B�Dl)�2 �v� tha;s+eN�+��( S2Bm��!:K�nt rel���B*I�Ir.���v�1�%� i$�):f1��E�E�i��)�!To�2!�o� ���)r *M �c��>}�er &!q�o i:�UV ��� DNA-�n��%�3.�: i )B�s�* obabxF/� p�*in.4nPIxie*�VA ����2& �:�.at�e�䡫) ��fpe=. Howe-1iU!P�&�Dx���b&/m!� ��E6�1-8(M{m`un=6*y al stud"U*?6we�'�atUP�M2�+s@2 (uR126 )�070s N306 , D309 Nsimporta%Xf!t��m� !uKz-�-�*�.�%}�'IK�!���W"11Å a�%�e2�!@-<.("�*�(Y�)!,.W. AF�+assay2� ��necess��1b�U��C�́us��i�.gdir �K�=�B!yclo�2i�N���!�te>>.1 E �c:4�{-�%�!;n��1� !|��!�(%��abf 2; s4A}� :X�.A�a5�#96i .:'!�'2_ me���;6�e�.( e2�qO�� ,���*"-�$�F F �0Eb�%abU: Un�&A&i�s pub� $by Cabrera%�colleag[2Flai� %�%�aEa ɢv& 6�2,�uo�;I  bi"2al1�o�&�!�6��*�� co75�A~A�ngJ�a�A�al�qM fJ- sepx ,3� greet.,*�"ud� >�%9�n e�#�l�a|�.�U�!�2�.�"�DRNPP family [4 , 8�ѝ%�I&�%��� "� J�$:C)ru�3secmwA�1�6��.� ��-b�@2z:e&5�pA�F�.�/!. G�!�en� -�ANA,Y�A*%+�E/s tBD% U]�V%Dp�A<; ew��isj !�.DA:V� A3acMz!�F�EPhr�s� , 3�'De \F�&-P�rup�&�&�.�M6blogmKl��commite+�#p&). Heref 9�.�Y�QF%�-�7X&jE(�F�I�6UZFQAJa"��!�6������lie=o,X�8. Accj!g!��up-��| �)S Q;7h�*� %#&{  .�*�:m>A�ZF�sl4 l�<"�9U&4��#���(Rap/PhrBV�+�*"�*!YB .63*A�<+� ^�>�AXp���!igX=co%vz �!� degrad� enzym�# rovi*�nutri�(�1dAbac�++ urviv�}nd2h[21l;& expl�ta���_ be��"un��eB�6��--tai."� ,E� F orAa���-*"C)s} �~�&�/.�*� r�, m2�J(go �.� &�!�a�&� . Itaj� noteworth�"e�2i�)�"�!s<�% versF&�] �%[1�2f3X5,-q%4mbR0A���s 7($PISA [36] "+&�,#&z�'5�e&ba6�7�a{a�7 3�p�3 be less It� weakn �24tz �_mi&& M�6�!�.%.��d��->M�!5���!K!k�:Bi<0�#*|�5valptQ� ao�;J�L 9�6��2�$ .���d H205%Z H2066� �� �5F15S�9nMwH�:k�<.� Z5�A�J>�d Y��se andw %���o�(!t�iY11]R11�A-neighBs�&A�5A�%H*#  �.��.L�)x.�network"; .�a�6 isaKt: ( S5q?*�nowds� �G � .53C�m� situ�minisR+�w��E�s^a�����5����*9%T�� ,)�1# �D29��U=!�yj}S��>��� � �� �!�2� �&]tryptop�� H*w��H W17��NN,be}ԁ�cfol@mInl��!{&�� !� W79A�Q���&�& sup��me.|/*} a� ��s�sha�s�9&� 4�/R0-n�!!>j&Y �/&%=8is6�(quorum sens'� odY,}.=Q�6C9e"�uA�l;5:&��)W�F:Q7EuѬRQ 6��.C � :�0&� �� Ap�Rqd�Mp*' � Au�)�A@ e dr`'a��GAKh !Z a Hn�R>�ri,I�'qu�)5)H#�% Rvic�Cb2α1.�,2 �U�qI{����yv�mi� �B ��Hmeantim�w9�an/a=*D�y A�e���6�in*�ag�AS?ndjq�2� y7vR�����"r,�?: pII . S34,=0%�����h2[Q���X-�#$>o�!:��A�.i>�F�H(a physiolog* p�oHewa�9�-���dME�%�7W1Ѣ�endQexponeX,growth�pL�.��A':domina�A�G*$/�uN��  aOl8 cA�mB�. .��>>F.�{:i�nu.|H.5�R� V��.)$ion cascad��"J4n#;Ajkep �5 > vd%�A�5�"�"� $N c j s ��ul�k��I�ofF'racellua�virul��."FA�2emo�N�N�e~ otox'[377�%!Ge k 7/ai��zBe�< by h death [_1A2 stag��!�^�2�:�#> cadaninc�ioa/-au�E '96�5$of matureds �u�Lt��A�R�Ntight��8.���*=I@��!�u�9�T.�Qdf . Concomi�A��/�% �m�8�~G ndp� �Vu� N! [E}�"gH.�% necr�J�5lifestyE1� . Re� �ah)�U��A�l6n>E��D6�?pop�B����in vari;���s.R;� V��sT"e���>68a"DOor [3me#� :!\U)�m�mod�, A?Fu4Cs�"x^/-P!!v�8��&�(/2yro�� reac�%�!in9�engag� ?] sm�$��"P? coup6(w�HzP� � ensur��2gm�MBI-UmM )in4Pon��:=� "� unexRed,per�%5�ndalbncern)j.�odevelop��)�8�"��S>o3$B . cereusA�up� &JI�'� �diN;��oy�m��,2'a\K2Gram-"�� -� � ;" ��$e N�& a�ri 4%:a�ce"X�!G>k�M r�incluM �� -Pap7URa��5� dual�!�-o�<r:kRA*���"8e*��b&�y��b�g�!!��!l�A;�2 )r�K4#.ya�7RA�f"�P>7switch� � toggP;!h�"#>��( =:�Q"�$an)� -��=j��._,�yw�7ɛt�'"�4 pathways: � comb�:�X G",B�a s� g���as sI?� 6rL�:tJBR�A�o*eVaAonlE+I�+&ade�f�T/rokaryoi<eu[3�4yQ�HM}"�.si5�.!9 �e�U�@Q�He�nt�LE�2 �to,[4�Py�E`�first�Qp��a.N�Uad*� �~n� 6�� )��c�a��;#4.� �Vti5a0>�U� may=�>�WB�b�Fi7vid^7nef�U athogenic��um fee��on� U�eE� 4&& ���$ "}>�^�  � , Zoly�po up<:�fmr(Dam- Dcm- E�� �ET1256�)S[ a��8 , La Jolla , C�4USS.@!�F�!��=����yB�~Z�G��� �"�[4@ :� Y T237°C��Luria Br�. ( LB��5# �B=0=BHatOHCT.�-s�J �#um [4k!A�P3�-2�  �bioA�\EAJ lm� ion: ampi ;,in 100 μg/m=1 ; cycl�V1%, �(tinomycin 2@!�erythr 6�F�.!<te!T� AB Lac+*UO�i$lon!w��(�!� X-ga�? xylA��VR A��f@d���IM?34{ cul�1���2C�c��F�U%E��4 LBZ�V3 dmKofE�thb5 umbe�%1[}cou�$�U Pcolony-a!#"�A fu )6I �n^q�es%�]?*�s>PP ( 65A�!�3 K ) `2� ^perW ag� b�o! cal#AN as%�×%B�o��!T �E�V�Qml−|--&q �OD600a�V"� qion�"���~M41�( ran� � ]1 �.���'given��(]ard errTZ�( SEM�j�exp��al .O.R�11 T=. Ca�osomal��!iex�!h�F�IR~ � Pure5 BPuhWcHKi�QIAge�Fr`/� .FJu�eep� alka�n^ oced� �QIA�q spi?$lum(,N�< /FmQ�tri��#��T4,lig/G$( New EnglBiolab� ɔ���X��%�w�!* manu� urer’W 0en5$D(Oligonucleo7Pp�zr�,S2-�) isyn�%�1,by Sigma-ProA�=mCR�t&�I�n ApplYBio9 2720AGrmak ��e F(, �. Ampl�{ frag'% pE �H !,QIAquick PCR �+Dix[er6c sepa�d�P1% agar��gel�:�J�gemG� onj�N9�Z-[�byv7kma u� G9Iic!�Takele@EU Ke a�z 0 pRN5101 [45]eEP�?�cdi4)���8 MAD- aspc-wa$$�2!�i��&��&d. T2 �\\I%�+*^reg�r"S ɴ,pHT304-18’�][46�=cw-copy-���4�B8-P�[1>j�yoo�!�XsZ��l��e�5pr)[vec�$pQE60� pQE30 (A�:�E�%�to�D;� R-6H�-d  -F�] �+rZ  m!SN]O���* ]"lY/`AGs��+B�+y2� All%�.�MmMWW��t�5a�a"G �g3�� ��+mo�LQ�ΩA� ::te�4=)%�M�M cݼw"�cAP�Ma�hom�O r�mb�LA�^ A�=2� �-SEx2���(g-�be,����7�B !��to6 )" OW^�g1 �^~% (F#�: $E�::kan (Δ0A �2"�Z��Nh=\.�4Ga.�g�0v�Le"�;b^8N\%� DAD:-�>� ofz:?h$er milligr ( Mil�� <mEa�R5aO� &�^ repeV WUthL��Da$S@�<v�OaphK�3aW��{ -�&�M(gB�Pj!̉�Zt M]"b"c�R[1D��m�%b2J"R JM�DpRep4]�1a.QL6x��CNI�u;&�5%��a*�WUE!��.�Ry���A cK1�!�aliquo�K, flash! z -egat -2C� (Tris-HCl pH�($100 mM NaC� Sb�P�9�G!9����!z^WEPp.%���R�S-M-=A]� 6>!-Ij�5"U*�� kanahin M63"~Q� n01]!�"&lJ10 g/A`Sc4r aminBhiIU� 5$��MtR 72S,Q�llBa:�. 5��aV1!� IPTG�!T Dc@Y�4 hoursR�IIla�R.IU^fsD�]s�&(ocoIQQ�unBG.�6A�mJ �Uan2�$�Q�NLiFJNMA522 [Ω��F�4�<&�. E&�4�V��kڑ3V�!`�ou5"i�lX  bo�6�5:�V�s��et25A%}��J}�$, 3 M Guan{1%Chlor�]a> 10% Glyce�6�[MX�4�. Q�7 �ren� y AJ IMACPuma�!Qd�E_��.M�I� !'� �q �  ex1�at phy step� (a S75 16/60��#lib& �N>��!,6!Q�!)*] .�j%�5�-�~)r��%@ՠ.�ͬFg!r�)� > = YEov��" at 1��BsMC5LAe$%Ct0nI "7an�\� GEN d��g:g�a SAA2x,�Li2$E;�GRWYg)sa�-D��fr��in��mM2�fR�F5E�Na2SO�l15}�, �#MgCl2N�. Mb�b(( MST ) [48�&4&9Monol�NT� 15 a�bat$ndCP�Wuq'_ capillarZ� N!em� Techn� .��flu�cly��wza blue.%< dye NT-495-NHS ����.|�A���)�Bt-��41��f dilu���+A26�M� 8 nM!��.�33�Rf !' 5% g���ST buffs)�� , pH%�)�-�Cl��A$)�,��05% T�h-20E�D>Z 4QkN�=�A�_softw� . P~L2�:2I�!�d2�A � qq��� .� EDT�:.7� e[(�1e5QyvE��N�E �( �U5>�)!�>��ATP�."V2!�HCi mmol-1 [γ-32P]-)�9(VT4 �+"(k �e)E �!]D57 �add\�8�#RA?mixKM��0��"J. AI +aAdra~ _#t� ( �1�!��c!jS.�EP{Z� SDS-E�A��PAG�ס{aEr���!`radio%��A5x� aUoIma�k5Qu� U�( M";ODy�Vs Cor�$�In&]hg��2a)�%c�O�7bg�.�&+ "�"��M� ,.&�_tX-nhscree��Try$cli�0*[(��&�H�g_`AB t 18� � . 0  c�dtj� 1 M Hep�;�p�RI0tl_bc lust�E�im�;��Yi-%�macro s� � �M�2�P.�I���J� 30�A� d��\C�\F�'ve �#A� #)�S>t`��eam�LID29-1 ( ESRF , Gren6`P&eAF( SeMeJf��k!�AUQ/�� �=%mal�a���.�Proxima�SOLEIL�(if-sur-Yvet%��a�der�va wav(�cofE97911*�5a"�Y ximu�an� sper f”� �se��prH)�!XDS\age [4R= Sub-�!ui` ��!AyowSHELX_#su�l [50]*�HKL2MAP�-/_[5�$!(pLI16���22�����[�3�4&��� help�k ��F�wlq:�bb%^�#�) PHASER [5�"�$PHENIX wiz[53� F EQail%��<l bui�7,"�`( �9ir�a7m��A2el%x !dzins�NQ>�g� V optim�u�COOT [5�!Da�M$!9 u��&]>�4 �We)!MOc�kar�^�8ice�XeFZj(at European#i'6cs In$se [55�vC�h�4se� [��u`N�I1�=TSu �Ass?�ISA�׊�"?)� zA�A�&B� yMOL�QG��Sm [56].K�3D.���7 Figs�b , 4C� B S`MSs]A��mof�"%s6a&�E��)"y[ cces2�cNCBI Rv&�2Se^�(Seq )EYb��NC_01887g 1 .��I"�-�[HIV can)Ycur�nlya��&;�9�Pit&o�l�?by&�treatE�Zm~3�(�$ -retrovir�2rug!�G!�ex3al%9ty�a� virtiV�4 vi�,6�?�1 e qu�von �=aH �+nA�"+to!xach}E�D�bbj�. W�zxA"AV �!�ty�|�A%<%F.p�ic ,!@�cPct=�UeAgSta� d UniG�ZYo�a� c8/1.�!�84%��u!|�  (Ygto 80%a�Ql�4og;2o qua�dsub�tW���dj�V�0N��]�'�ccu�l%����= !��>[�.� novel%�~1!�"4>�R�6d�)�c�t�uw:��y�� !hus.b3 reliDZ.9s B/�  replqhby%��ix�l! �-pr�3�B�3Yա%he�| me o!M�k�� . [7� wI�IC'6\i�=ca�Pba�rYA�=|a-l� rap�%[6])z� le���Vc�win "!bof\J��& E*mem�+E�an7<irug c��6�1� �ca����, [9] O! ��z�6�zB6�FZ�Ax�!n� �z��UHAART�%d�Q#T#!o("� �s �! �xH"�Z:%��ex�qcVe9Mfailur� �!� certFM�w���  m U Mk cruc�ME"��1A�tai� : Z2 �^[10E�11] W��G*n?aM>f� led%-g&�U*� yoIez.ax.&A ]�A rough`%nf�-�m�?93&aedr##�*� 7rO� N5be�7( ׉�\� year 1998a�12)(M [14]�=�Ue�<&�<2 &6@ j�i]l ded@.b(, [16 r�'1�$Rgcf Persq ���� en$� �~ o�n�-���u� naï��at� sk`j&A��A$( P = �09&�8�)en��!�U��7]:�c2;appro�<�@vp:r�ݖ%�AK�PS[alU$e4-�en*� �P%��l�%-�ڡ�b�, w�GIwut�dzqef�`%�&�!�&l bs�&*r݁���>it����A!�� e"G���6&common}bF#� de: Anj7� ( AV< by Virc�-e�'e!6�"W:E et �2�|" Fof ErlI (n-Nürnberg%QLeu[0(`_A�4�jP!%��eT�;.cAS�t2� ��sDv ,) adou�0emplo�zA��:�s:���hoA}x )Ki!7ylC)zol` brom�!�}��13 , luŊ(c� ��AyDXrG!a:0�9�9(>I)m- 2Uby luciM�"� �1 upov0 mple�of5<r|RFru�/p"�(.q!RA�J-I,YxdTd�(:ne>"AD:) suscX�J ����3hYDse� logarith�I8�-� J(� C�� CU1�)jdf��_ IC50�e,�Ohəed�us!Wj0a.d9(u?e ;( wZ�W!�ܐ �"'1�aL3� –��( z meanlEL$� E)��*1I�[cG�43# �B>�j[on�$. LikewiseR�3wr�nXIV "!o �10�# E'` ����xt@5�!�HXBB: (�Y� O e8�P04585� or�����TX6�&NL4-3#a� Genb�yenD�M1992N:���� Sens< ���I� ��e4 ca�>k�y�.�od#2ݓ�6%��� dGOSe� MU��8aao fu amr7AM�F���,��LG��th C�6 �aStoo!V�)' �3���se?�X TYPEo -1 &h1 [25]Gc as �U�L�fr-7� �[e��G  pai�7.�- !� 0�Z�6 w�St�>in  Gd�k�"w.%`( �eeo 4-h$p#e��qe�ll6q�2�dva��w6_nzJnt!�nA� A���6�t�%�de����e�j g FC�Ma/8�K�">p�Q1=�+N� "p[, wWconvenAEVE���m.in �I!g�RNA5�$r��v�d �|�.o�>48 week�39%A!>g�'up"Gf40�( piesxto 51R) = !�� Nex� >'�i�Ci�p ��g@�e9\�F��Max�8nck*,�:��52��{ 20]�He�5�E�M n smq}rE�E.��.*i*�TsD valiS !�S*!jD@R&DatU((S�i�==X F"|�out� e$�,-of-the-art-� tm�k8��f�ng_. 2–1j 8% m!& *�N] theoZxS-�!0��*{ de�2U`��i� � |C @~ sole���9-��Dx;i�tak�%�?Mpe S� �W� �jM@�5w]%}� *�q�aG�f"ǃ� eatself1�t�,iqu�SP�M:B(|) ��A s�f�<�e�0)i��summa"юFig��'PfPx�t%�s��w_�c�nt�he��; � linkrap� vu� � auth�`�e*��e�pe= S �^�qc.��r��K�9h�V�b'g. [U�, [a�� 33] YesoA+#c�#�pt"�*XNSd���=���;I:�M=W� �p�LDM�on�!0�'wY_f���p�T�Bof�-792)�p�W� �386B4] 654B1]I495B5]�S.02F9P&��D� �of , 1382S?u�&�w�3,' :Zre2-f�Yc�%�#ngdFv>�6�Yir�ber��c ( 45�(m�s�Ek��d�n�S�b& Y2%� �514-�: �_on&� l�'�0rg�=���� ��r ��l�Q�EJw� �Rr!�E�si,a �)ss�#�N�2x�(a�|*�O3 !iotr19V�(���p#�[�8���a�l"{t5�6z�!&�m���� �EpooQ��Eh����� �i*X��:("�u)�wh){^R%�"��D ��D��a)!�m�|a`ddingR 2�%/6projecjO!N *b��z��an��a� !@E��� ˇ&� major+ !��2�*��4:&!I�O��#!�, N2D�$/ �EV�2A�CA� Non- >I�>? [no�J C Ɉ���zs�Z�=��(2s� is 6f�mtKc!��yU�r9u)>��,oi����A�r�#�).� h����"�� >unrav� �u� le �[&�[�influ� � �dE�I��� ��. SpL��T"�t!eb[��G V��4>!�2mU I�%�a!}��d� &F O$alt%��3!�a�0��j.8&ks~ b��m�¹�f&�ARVe%�Y��'J#xL�"[4��f#r��!�HMa�Y,N l�$s�"}e� need� be�.N tU&A�4�a���l?. W�trst$m�!�a^rEocur��Z�?�e.%s ploIY@%D-%��d��a5>�f2-EAS�*on�!�~ SN � PAr�|y�(%�deg)�.e!�(]_g�� S�. W��enough��� ��!,ina�$ 55�j�=E��,m�4��`dk#�oC0�]]"5,]aid%"S.�&f��)gl�0s6 ��\A�oot�n squ!@�%$( RMSE ) <� 5�(�(�4 M�!secEQA`pBorB3��At&nC�firQ� ��ra�-�E�< �wGsran)�n.��w�ee.�T S<!Zi�bb� ��KY��Ie�6�?�=gZ�6AA%��'70"�A�!��l:#�H ���X1� spliQ6eo g M\�&] U<� 2A�� � �A�as;mh*�'� .*�"fu�4�9� 2�,��� prme=�shE��OR4r ��=7`l#w � rA�6RI��:��7јMU2n,2 ��)" 0"�s8DEa,%�a2�VPI�����<3@7� ,B�:> 45 (o-.A�I�"-f R02,89` K� j)l�  Ia�m7mRT2l�2��!� A���-e$:k A �/@*��%�%9�-%jen��/i/ 2�%{Qܩ8��R���m 0M��ux>� !!5!��a��,%ie�e�u�an>oD ��/)��. in&�2�mo�n�9^A%!TM�_.j),�`�L�C�T�a(BW�- yAZn��� �.�a��l"� "�&,�� � ��b�-m�mE�!�4q6sF�#a&B D}t5@�>��Imiq�97"G1.�Nmwa�F�!��3�Nk�/��CNkeB��Rwhe��~�.�# ar�FtU�m�.�"wM3�2� ( ExF�[D�*G ��yi]p�����sHU,}7 , S4E�We)Opursu�k �S�&��&ktoM��>I� �G& �^RA�@�%A_�]J.�� ���ilef.�  a�  Ya{��ia&&,6�g ����C :d6�-8�L� S")ly�8veo.he�? �u��p� e%��at� leftI%K�f thodGjed_T5�a_�zY= benchmark�~b=$) 3] B�8�:��N�� )�-do2��&��p�a,n!%�(mo�4*�4Wm'%j/ ribuQ�7h�)2I-f�)9(�3th*(caI<�e"�/e ���}2 V�O< igno�7a%i[ to� ve%��@e�"�/-!I)n �8� e �E4.+AwoJ4&�-w=[�3eE+� �*) Su%ᅦS�C�%��-�a 50%Q�ŀ(."��8*A�!��.�55.�5 Q��P"�'w���=��݉��)�AUlYT������a ;46�)toL"*0&o�X�" �(/as ‘}��y9]6 �.� goalr!�� ns�� )�!�"(c[nd "����S�dCs �� #d$[6*� �#�%�&�"s9I� SeV� %y��2I�l���&�on ��M�*x�ly 11%�*� �/a �c� j�1�A.� _0��g0E^AWe�� !ZFia�t-� �, P�01;P  �~,�))�K2c��# *�0� ��ka4� 9�V��*�033�1��th�e�ai�p*�4�Yyd�.��l�] �BVr�k��Sharmacס�tp(Ar|/&���,a�ll ��cafe-�N�2we���i�tnq)!C.�.(�V.3� �?�A( �M#e<=� ��PI�W!�%��!m�&� fac�<%5OlaPs&\t-O , ETX��ey�υ�z��.�inE*��)}%�n"����)��T��ٵ.*. -�.�!��E�$&�� Ak�;�>1�Z�r�*58)Pcap%�,a��&4&�z�<i$@�*V����n�(incorg� �c���AK4ut-off ( CCO )��e�s�u�e�$E4�'�J�s� �[� �#����Y7�Jp"- � X� ��*~��M}��-��KS1���enaAapp]eK !(EA �,"�>� ���c� � �`*�d!B�of 95%E3!q6�0b �� ��*)�0 Axe�k� �!�x�D�f�u/� %� <2N , 91%�� A�rr �2�-g�D�\MJ�i?a�g%!E�e�;�9 bes�93%1P��$��*� ��906(N��3�i:m�(�e1�e�!8MN� �,>Mr�68IV�:�+�beA%<a ^!� z�0a",*�!9�e &5 as.]<W|�.re�  � y� � K i�0=�:_ l"�>q>MU�q47c��� �� albe�lBU�s{ ��F'� 4*�  5����*� �.�?�'a�} &���,Gli,x��c&m!��#�6 leave-one"n�-?( LOS�~5. =h��L't�E>E'i �9,� ce�e��!-2� ��#�"8�p+r� �!��A��s���,g  ��5����l)o�7� -A��5&�#.���&�-�p��� �5a+F &x �Z��BA*�A4� P.a9R�U�$v:�AS` -(�U�A�"�mỳ���|!MB;�j��Z� in� ZLAy@�qCM*k(Ѿ"^2r�robusa� p!F�B��.� a�a;F�A4;PI K"� n/-40}�,h 76�[CCP��>�\��� 867^R5ɤR�C)`H�� G4.�2�5�SG71%%��a�)0at � Z!�easiera�%Z��n�� nN*��!urO�-�����$ X % ]ei�aR��K�w�6�Nh�� 66G"�* �AZ�AW� F*� ���&�%���" ?�+1H�n &j* 4�"�-b=�>,K rY"ceE!�nu�:y!�. O nd� %kn5* ��/� a!��u�5��0)<K��0=3i�@ i�Hue �m}8CBqp �D�g��E: �CstY)%cac�)qltr]Td�=�ɛ�S�/2 ńspiri�M‘�k"�ED�E�^�� b(A.�th�rc~;[��9��5, so far���h%I�&��k �2o�-9# ?�%r&�� �12[D��%4x �� ��o�VH%or *�* �)R�  Ade�s D$MC$��27/v3�k�(de�ng� _� �=�4͂ 1&��y;A�L�"W�y WT�n�²�%`5� �� r .ctohb:� �b oSz -WŶ��,�%v/�tvi�9b)-�2;VF"aL��i.��"/W� shol�197%z!�1�l�Kg�]7>Ђ� �7���\8:u&���ơ�2��t�Wst���H-:HDI-Iha؎mI /)�*�-p@��2�Ś� 3 visyJ��!� ‘N-�hood Bero�];@�i�*�p²m�6!�S*kf�( X-axi!�isI�pclo�Ito~� e ma� l2���u2C$, y.W�3(V.Jy m&�? ҅�C&� "�=e�./B�>�!�or @? ��s�.%�l�P*q#A2 ��-usefuh% - r�G%��st-�\�$1"�;M�,�C9H� �}��M�2�&z~(%1""a��f�^ >-2-�A":2 *�����q�\NEP A�j�A�)�g)��sb/�� �S!�to ju1Iin�{"v , ONF�cle ( i .OA�"� �%v�.W,�u� !.Nj�šlH"f"VJ- � n& � ɋ6 �BFp9 �f�"X2:e��^!MCCO's��6)��a2���ML�1��e"{v�OYl n1� c��ah of 8&�=*s�7�6E6#.�� z32"@'� .�w) "N ��7%�X�$� ��b; �2�\ Ag:C��GRS<��I�X!�i�_A$v�;�� ^%2�< >K�a�� O�*dA�.Lvm�(K { ceEA�J) %� �6xt S &WhoaLly �ur)("N=y�"e��"5�J�G*T��I ���� is f SJ*��2an"�2.& E�A E Cun�EQl�22R=2�{�Ft'5��ڕ��*� �eE4hw ���&t��=p(��r1 *6L"E"� I]�a� m�<�W��a%A\M�Y Iur.� %i�\�Rar"~XŵA2n5�T i�!�&lac�K�� f��fer� j%�&u6aJ� p$"�"�28EaCr Bor�id+�W [39]!*�; _.A"!,e��150��"��8 �T�E%ĥGs\icult.P&=Ys 2roI�S�� seem!*ex��a": Uof�o ��J , ��2�A� mi�e.��] ʡFn ng�,b` ) �"�diB>�0Q,E! !�a�e�%�1��Va�ytwop� o, Vͥ��Q�\M��*Ip�܁qAy�-'V� J +Gd.v��I��#�RDj&aGV!@�>A_-m��r�]���py a�>R�:�SJ�!v&.��.ly���: HM�!��om �ly%�J�!��3a 0E((� 53", s��#68!>@�%;86.*7.8�n!�* 8.# ;.�:͢)=�K g |(; G54F� , 78%7*z�89!�@�e�|�� 8!R��� marg�s�7e$Ra��P�co"�"&`�&&mE�Waat�$ly�A^ve*� �R�� stil"$� �EA� EZ�"+��Z selv��oi�M��!�!���ȵ��.v&�"sV�N^�&F�"�: �O�Q�� �;�(�w �4�� ��aYH)��]&5�I��-�/!�R��h/>�5>1I:s��L6ow���n#(he� ��H]� �"s Q�sub83o�2��P� 30aI襸h e��-?�TQES��HM%#J�+-�A�5I� �h�Flso waƅ� te#�B!Roh?� ai�Q�fe�Y2f ��,o!?[�e"`#&qSLU5aff��+�I�"a�!R�Va5bc�Z��F�,�0w��jhe���h Hs� li B#�k?andT��he�a�~%4�E�*L'b��� !Z;sal%� view7:�Eby Johns (�* �I40]q�5E�� -�a��"* e�+��9_."C��� �a�C g" (&hPr$"��cE � e as�*o��sY�s �in>._ nJs�]SA=.Y� &��E2�!n&LJR �YC#�7a*b]r�-)�18] R�C!�J�e+1��D��� *|&!����I��pq �.2as.b�Na� whita,:��(o�littlyC��T(��a �pla�0��6�8sZ9 ;�j. ,9,K103N�auk ��3�!���Inf;o6�Ne$]p5q(, EfavirenzfDeld�Cto Etr.�^!��!pu� �B9 �#�'B V179 ։q�.� j����N� n��,.��6�#�X� EH@ ��bt��#!�u&6P. S�`Q/62H<d !=�-e V90�) V106�)A*Q�j8ng�����oY188CE�G190A� T ��o;{n=�� 22)=k�J!�g!f�1�%���:���ingerholo"���R� � l�h" .�azP2&L-1�|aC*� .�L2� � b� �*Sp� �9YE � * rY � K65j+Q151MmB T215�e& S M41L�M184V%�f*�Wl�A s&��ҡk�!V f�� v�D30DfI50�q V82S �I8� �^I64 � I93Mhcs��KU�ݜtA&�I$�9s7]*� 1�|/�Jf�E�m��4���T�o�^k!� i��dpPx�+:6�F n��1v)K of �%9d(ad�)a-�� ���1�2�)!V�.:1o�ferJ.�� ntir&�m��Ae�ey!+?4y a�jO��Q� fL��`�.��B�da�� �~9#6=KM "-,2b���4H��A�-��as��EX�.{��d|� d�8!���%)&�P �.� as2nB�%Q � ����u*��es��>EB��A`�L p_ru�m�'� ��"�e ?� � a��u��V.r�� 3m �~; g3sP$� �S& -;��2(B�*2S ��F�!3�AiaHs: *Rf�q8ś-�ce;" � �0A,�HCzov�4;��cdev5BC �g� �2nkE09�A "l I&"� E&#��, v �O 43] �p[��:�9�q�F=�RU�u&�0�q��[�C�li�GinT�W9=��| M� s.{M�� ��^ nIc"�a� �l" them&�1.>&=,%�"� Mq� àYovB�6M��c��B�*Y�=�(��� b��) ^i ��-N�I*F7���4� �\ �+D ct�D� W�rfee��\�Bon�35��c�F�*$$J(wQ#� �L ��e��VP��/JP8M�y=;��'��v=�a���e�iA�4&� %��7a)���A�C�1L� !��i��-+fU�iS�a&�set��\0 30  C�ig���fi���;:�eIFy69k�5t�,) h&k,6 (a6�|o.�$frU8>Pe �a p � E�*  ��J�fH�l-�t�,":�1�:�+n%�"�dAz��>���ao%��W�de�\&SB.N^o9e_��S� G48W�Q`s]�3� arun��Tipra w!�!���_�i�e>=� llpGAg6 , R87K�J42_ Atazk��&2�aHy>2n!oe�Wa�����.i�%y�M�OA[!�ntW  -ada�[d!ʞenviron�$Ix!@�"#rf*� [v]!-��w*e?e�.`.�r�rQb�bA�IK.9� �_1p�oKo�u!��m�a�""� �typ �o&�#� scri�*he"-J%I�%|-^�1��y�m� lK;e �&jycY"a$�a��R�NAq -�&�w rea'6�No�!�Oi!A�exa�7�wZ"Ɏ-?&� parag�{� Dzl_�kce1P�T Hnd pSh:�� "�8!a9e�>�2� �]1F�Ach%�x�4�S*"�R�]�Gd��%x.st� j!*\�9�&w U �&�P �X�!��~&�����1>�1 9�%�. A���@e� !�:*uo��"#]*��!%ZA:t��Xi9*_(P "�5���� ��"i��|sourc{( � natt,e*&�"�HF!%SQc*dQ D$�\c.�� 4�L  >N�U� [� a�T"{P6n"� #:aq� �1��c,, the PCM mo�Rdels developed in the current work show an average RMSE of 0 . 52 log units , with A, 02 being .89 . Compared tolmo��above , this is a slightly larger error c:?�validation on Virco data , which was below �0�L. ( It should be not�hat�,very diverseYinclud�Lhistorical literatur 'of��e cannot estimate reliability . ) The PI % 8 again performs%$best ()_an .�43�and 02� 76 )) leK@NNRTIs are predic�wi-�%kst-lVr62rr6rch!�Aresult�a number Doutliers ( see Fig!=7�explan)�)�) .%(�I5 exhibit)$low�correl 9coefficiA�( !!39b%E61�!-mosAwdueQ� R2000 (�0@ 3 . 3 )a{on��-�t��fas��282I1 . 41mano� sourc�$[45] , [46 7]9 789=na�' carrya�a deleA� at posi %��A�`taken into account by ourm�. [48.}947 link�8o unpu�Eed�%�c�_�ef!�hbe�Zified!�ine�,Y� 1261�@under٫!�boͯ�n testa����V���identify�7ap�nt causej�behavi!�9] ( M�detailed���Uli�$in Table 5e� The �_emwM��� ance  drug�s good���RMSE (�verag:� 4E�u� ; 7two�,E�!FTC ,�'E&P>�9." �uOpllE�͔�� � grou; per. �K�_(Mj� @ ��a��.)�qua! decrease�K0standard� i�G� %, indicaݥY�K��Zu��ch��s!�*� exist%7E I7ad �Affectm.�@. As each assay u�����of CCO�D s tu��A��res��i>weAd.su�eda�� !�,Rhee et al .K q#]��jl� [44] Ou�classa�A���spo�xb c" in 84%�[c%�(U�A;!�catEB��n� rt panel � s up��44V�. [50]EK2�� %�I/� d4TETDF ,e ��an��Na��=*fha� %�lN$en describ��[51] I� i-�wa1ZExconstrucE_0of robust PCMI� bE 300 , ibioactiv� �pointAeasu!�+st��t HIV5�s .�ota��yco� i� m�C!� -of 4 (mf �%i) or 9I)e�s�biA�w 1�7' �) 5 RTI E27 �e�)m �G �nPx 5/a|proced1employ�N1�,!�� �to�� resi�F�zrofilee tthree��E\� single9�h�[ focu!H��L t�,t space ( teisthousan�~f=�proteinv E��. B�i��ternal����6unsE� ����ed2�cO1#�p.�[bette�f B Ws; � �F, A � � e@b��- "| nov�1�-conferr!�:) lea:=�� l�7��a)���u�s 6M!=!���ARRTiadd E2c��sO s5�to findR��ific � im�( G48WrPRI��( G68R�QSEpaF�asaA a������)��Z�orh$personaliz� Y regimen2� . We haveE��atY0� Q�! ժ�� aɟdegaA��2�TA�.is��A b�95% CCP mA.p�) An!krogram��i�I�- ��,"� stud�.&N�� �%j^iy.X6�JNaF�s)#as 81%��unka ��e3t�' )^l"�io�m�6C�ek\ix�Am&� AR�is� � ��5� isol��6y�O� !�jR����� t1���qI� �E��vG�v]We at�e���� of��woA.s!\. Fir-�ei5]la ��co--�� !�is 7���minimizF e�lu�r�� � ��lef a����, i� so�����det� global pa��.���nt. �"( ��qX�)�chemo ] (��^ #�e second-W%���&!�f!f�es encoE- full՚s �physico�Y properq.� pres%Nor ab feni@'i�aQ�m� �wo�.  m=1��6� ( Bee , Belgium1Bon%|d�()�PR%eRTt)x fold� (�� pIC5�1� )re �� collekby �� (January 201�[12�2�28] M�R,QS ) /removed�A&a5a � siz���"amA��T��6M� *%�u�,,�ceiE read!=�lo��c>�� � def+ a�ldiiwA#)�HXB2 �T ( Uni+ �essP04585%GenbankK03455�" F �5 b mean�%�)�i t� Ud6 i��. [22]2�,�tle duKta�&s)�act|My!x!�,"U ):G 1 , 501O�8of] 723�A�,� 441Z4M� 4PI �803Bf� 8122. S6�s����ed��!c��E Z-scaw �i?53�Z!�a!�y&]!(: e� ptor�ata�racterA�tj�> amin�ids sideD� I��a� �����8$lipophilic��a%zeE�pol�� �g�7or���2�E�iwnd<R�l�)@400MML1�daZWS 160�id�) RnaseH d�i!i�odir�.�( N )IP*� %se9���2�2��b S ur&s� � norm� �ion� �H 7$W y p�g� $2D coordinu <2�conve�Lto Scitegic circular� g� _A ECFP_8 , 10V12�� epen�n�"x aS A�b�e� [54�'55] AlB�-;Pin Pipeline Pilot Stu� E� w�롯�w[[56] CR����si !9A�$a molecule��eq�~ maximal b�diame . Each2M�Wt�q�a� bit�A�D  ‘1’"P 7!� ‘0�Z@�on� �a�cR�� �ey� pG��to�!Ty� retrieva��in��a�) ��7����� �edM!06Swh2� 6e#ES8%!'P126L�ord�o �t@numeric��)1!�aa ,�"-matrix�qb E:�}!��upo)e TA� ky ST.q !) 8] H�f.K�)2�La fixed length arraya��)thU� $of 256AasAJ� 5� !qsoq�b� %jbeginp a�h�z��M�a#α%&1% +I���>pu� we�#4 unique fe�&r#q�sMx_8&L$�C9�1 �� &� �t� UA s6 �3g%%e�E�e��^�s S�S�S9��M�$@.I�academicaj��J6���� �R-s<,stics packag�[59] Sup�0vector machin SVM A0a radi��asjun~ker{a!f� �e1071i�%!�Aei�$. [60] Par�s gamm9 cost >��on�_<#aQepsilonE?�atEe2��It&6��!�;�_A� ppro��te�\�� e opx%3Aor&i�1��& �Ř��m� )�5W rossa�b��e�to exF�mh cihp9H5r*�%��$ , R2��nd  . [3 62]pn������� -� a6_�& s��s�&� u @ "�#to- m sub5W. RXwb ooeoy%c -�*v$ ��"*% near�%n�hb M�t �'AX!ii�J%!�ex� � Jf7 A�-�A&#�~e a�#�l y cr(Hue� >�sc= �#b�%�0_n.@m l�*uf)eI1 ( 10? F�j@cal �+���= ��� sholds�9�70% . Omz.K!oat�&9 ��| as 1��& he euclid�`%a`Foi� JjA��%6h �.bAngb%�CH%�<�u1c�nf.$*�'imAcan�Y.En 1� !�A Wf"�%%*E�j`"�U�did� exceed�Y3 ( 30"��6B� �e)�-&��� lear)curveov:���*!+UC .��-��e�oW f+se��(simultaneou� t� rea��NbewB��B v��graq ly impr,�%I4M�r�@! ^sV� �W&� q⁉n, als-� &r����$��5 �P+� �s���e/,�9 = � 4.�+>�5U(m:t�k<93.$$>9a��E�97% %�wor~�7nin�2�-��(=A��,S1E�S"�!�6�& $, y-scramb&��9 '  E�5d!� ue ( i . � �)��randomlya;�EQ C� –��4 b��{��iA �eunr_*�.rem�_i_ce!����4źno lo ��associ�E�a�&er�+ #m� �� ��S2��pla� lack���;5O 9�\� %P }��4A�Fml��4%ta� Fas kepti5�produc!�40�#R�'�T�+ �(��l"<) ;��8��PI� eus27�U*�Mg�1E�:931b9�;Ce�:<4� &%ve�1� Fu&�+�ݱ�� �%low; −�C06�!:n89;V� :2Z�7f��>^�7f{(s 2�%flI�B ��1-�2���YE��dem2$eS��B�;I[e&U>A�Avly�80��A�J)Mi7-�UC%#2&��M�e��d!Jv1�%�0%�4 UE. T> eU)of�(y��%6�  "r��{!8to��dji� lico�replac�!$&�"�H`"!��Z.%5&& ���*�� 3�b� ;A/!,����E97�3��Le origi$ � Dc)c�#e�qYB"� Y N9+�"ntWnC hi�$pre!t�D @Qpoin�ba,� artis r5 ,I%� iEV �^�. C�+���p� 0�~ shift{��-c� = �(in`%# aa��"E/� ! �ll_$!��cK.�ubstit2[�:6Y`� K�!A5�&t%� � ���earD5$s!e John4� ,�Ut.�/9_fA�V40] W�se paT$� �*�n= a-"�1l� g��Ca+AmJ popu�+�4y-a� fU!&�a "� B�We8� e�5 rec" 1)�\ >" 2006A�Delavi8� DLV )&xQ52U3verviews.6f!E�i�+ �rar\-M5%�"�+X�fo�5�8:�a neg��, �2z ru'�� ; oc�9� 7�se�.8an �4;u� !yE�ompws!04;N�/!M qI* 4 �2i"#�F. 8Y<%F�'a�? s�J.� ��,,+-K*�/we �+ar�any��J&%A�[0� th�:�%�s%y 18�a'F<"l.�lDE�N5���.(�-�2 b1!�%@�o)� .*� �0ll|�ra�3a�Aktop� �2��%�e goal �Z�(h7(Nep�%Q�q��*t�)�2�LQ��09ɻa.:>&6-P ��o(�4s�:f#a�-r Borght�[39] F7�p�� 150Z ��%�<;�@`%%Mse0#5�e���#a ţ e�1�%���z e�]Fvarian�3t��,՟!…�{e�.&�#%Em� f�lpo1z]yyda�O o *J.146= =P,  .1� A�149�. 1"��:S�8Un�=�!Fi� *c�5!�s�!�� ͇H*�/�0N�/cn\to �6y strong�3�64] Yet�f�>f>e2vs.4"5�U%�quanti�(�� s ce�, eathdchV�,�!J?u�c&�eEj!h�QC'~ grow viruA�In.T���M41L ,�9,%?�9 2!� =myM�@E���5*���S'TYP37*m O)!`)�(���s8:;.��in� c��� &=0a�d2y2��.I.to a Pea�-'�&�.:�98U�!�twofb4X�&$ A�a�downloa���y,websit�U��i�1 July�,�'0  ?Q��y�"(�& (�c�� ��umIFb��.bI'�w�9 �?�% boA�5o{�H2a�L@ *jD&^ ��(�H�r� pairs:<&25�"�%2��9!2(hy�<35��Af)"w"�-! he:�aCq���*�������N�!�p&B%*Rc7by: S�&ce ID!�> �A�:P9��I�-�1R"=�g�(�z��U( ��1�>N$F�8.v< VA�als�A�C'*�%.B@dw�e}�gnw !�!�����:Fa� made�BE""B a��t lab�-; �V"/�?0,�g���9� �"V+cut-offN)CCO ) "� h"�u[� ���[�0�E�uE�:� �E2xT8 Sj&�2�>�ly�0�]��!f&�I,< "�3�.(� Med9"';�:( �L � �ed%��$L �dde�/lyP:�>5��e�D� anjd=M�.�oa me�ism��eukaryot(�/taxis���)unc�p�-; nsz& Q��fr�R!�Z �'kac�E&D a1acS,caI��8n**y�%z� )� turn.N pseudopo*�8Ak� move���5 ropo� an a*;NF�5 ,Qc��E�GM#Ra�E2C:��1e��4 self-gene� cyclK If�0.��_����y��\ <.�"�*r7f e ai%���;�E"AE�VGor�@d�Y ve pow�GfF67�-A�|�!I�P�4lex*"Aof%�0]^.� now��0ivenes��9�M*jCa!�dellYEY� �on�( autocataly%)5� ��)surpri�( ly w�"�G@��EabG6�:�.�$�aW),-M�0[�0�Y� VIuli Y��a��$5�(n)qYn��HI�Qw�-�s7F4ofQ9bwn[nd—un$ly—�aL� init"�A�0�U� �A�a�$� )�,��lootD�^un;�-�|L:C�5On"� !CŖ�� Oa$�a=succes���s�+fro5�%�i*���rt�&�c�t14he?'sm���i� i� !�iR�k,�&�#��+q0ng Dictyostele4�sɗ�Onv-]H�>�Ks a�9*Z)Lextrem�wel-&OB�e4 toge sugg�%~ in rapidl�v� � like:�Jneutr{0���rinsic��Kl� _! hea;[ mot�M�:imp-�!Q��behinO5em�/,o�/� ɾo�F�&BF,�)�2-�new�ss#R by>�s . EN�— �igr �t�Ba {9��01i� olog�#or�%{theoret��#nb-8 t5��;�e;d� �ly� .� auth�'�$G+id�B%�U��<dr�/! a “��$ass” [1]�K-&xa�e7Lm< *�t W�/Bly"z&[�3�E&VKr�/a���6~ needle�A�d��a*�<a locali�sig���"�$9eF�%9��(� 1AvI��hyp�,%�� �CB���] �2A���� R��J:�e�2� Uktt� Mt� $thus steerA7aln��� �6�Q50noisy environ in� :3�PN�9{rs) �(2 �?� �W�:�. A]Aqr]' c�%j &�<VLEG�%"�.e Igles�F��Devreo@�s [e=bal� �b�1vi�j{LevR3[{3Kin�Kde6Y� as Na� [5] ) sh� 5��ert���f�B��.BDp�Cs7 a�# l\T�!�{��M� mmed<$�+4,�25�aCmq�5aa�f):e-messagax,eteV,iQ1� A4WQ�lya� trol�by�dynam�0�R�"@ :"n/� ��"�-�bred����6*�<�.U n�? quirR^ | �!or)��Aue'��!�Yc"�.,�!e2� is 1rA�De1 a��E� msel�R92)$%�:�!��lyQ ]bifur�!� evol"� "� o  7�\I�Jvariet�4a�typ��cl;to 90<*J�M�9 �|i� splij)�*�daughtA�� �ve%2limVM%*lac{:tim�4B�q,emerg�We�5��5�\". �Cca�lisBKby�!!�r�26 ��H!US7��o��n%5i step�.�ssy-c�=2K.L !�!�Qc=��8X�"u?=h �Ik*)|>!���N�Gt-]2�s1]I+S!�au5�9�5 �>�l exam^ BX*��zE� away�V&s—Idis� �!�aҭ�. aggrn!e�!@:�2o>��!�^ . A6|,�ndbreak!W�of�r�9?am��s�<;P��< 8pK��>�3a�"k,�edgT��tr�Y����' a�!��M$'V�f  A-J�UU�{)X ,F� AO���3p.�� �( (!4.$.%�'!�dYOag� I�#�*� oE2sX.Fw67broadt�.=����,�mD�o�&� p�a�!L� do3 o�9al"J.�6�5 ac� �l:A A*-��� !�*�C�v(e* ctFz��Eid [nta��)f� e�6OE'Vade!�.�:e�pot�F�8%�orl:���E�� � . Wer_�iuSt".�w@s &�Z�B���mB�,&� coup feed�* loop k2� F�9daa�a�G�[15" ]i(/N��-)�Q�N��/�in*�R JIA��� yp" v�du� �M�a,AN��sWA�� *_� A�pY.^ 6 recF s [1 18AG�L-�%� �F��3es�A7 [19M�8���MB1�)�Z %3�8�EA�.�th*� Pv v�<-��s21o � 7[.=!�?�!a�K?"(�fulfi� �Jole�1C�-i)���NthA�N� s� i�of� &Na�e���-� ��Iz make2�� -�(=��g�+ap� "� a�=r�}amoeboid&�F)�}.��VapA�6�^>Zystem�LB ) [20]y��pqJ��va�=reg�� O5�I0,!;D �f| wo9���{ev!UMeinhard$]tiY�<%5�V ��e@q=5�2��Q�E�a1�! va� L!Hit�'s�$c ~�� %%�e5�d (A�c7�C�w�PeK!�vo x surf� f: e el|( method [21f%"� each�A�!9�xs [w�WcE�' .��H,A�C?t:o" �y6%;=�� �& otru\#�B@]e Ia09�@}�U # �c��"A�K��a/MT"��rea!�MatWrY@� x* ��ir� p��9�;u "��imE��$vten%��chkQ 9:d�E��a V���e�iral)t�$M EG}?AG��JY2 5�"*an EuleQ)�p%�� q"NA��A- zero4�/fX:�[2� �/�Usi R-�,�&*� a��a��T�i[D CartO; sh��}�%ghtfora �ef��"reseE al s�ces [2� Fu�(_�s6�.p�b�se�$ag9`�[JN . Imayab 9�m�.�  greatAXh^B��A"�!t� ��E<�beEtM�w9��N�iI�A��Vexp!O , diqng:n. E._�e�ٖmie AGK.h�for%� a$$ at m!��S�M�Ha�����-�b`$6����"Ye( M!s& Rw,xE4)L�_ro . �>i�r"�Ca��3�l�c� e Wa�Therio�V(nd Mogilner�);� �,on��s� [30�6c��"[7ErɖB�3D#�_!�U�>��=on�� FT��"�:��ep h�[d �8a=���y�BZ�|-��e�]�)UdXi��B��R�XPey�1G� eb ɨ��6� ������ect� u�%f�O:�le�[3 ��[10A��5%�it ( [33]; >e� eR&()AJprobab�c�nlr!n#GlEK�/`gh- 2����a�#�mA��:A�+ g�, h"�nARai&,(���o t�#� 6(A5H&E�5,�e"+`���;��)��/��J ��eivie�C!,3A–:T"J��c&�[,-@o'���%Va!gr1 �v!E",� aFa � �0 ,olarim��e��"e! !E&�p&l����+[1oS٘!S-Ss'@�erD(��.Mi�%reNo�7�5���MNz�PfcA�s^.E�me�di%s� ��ng-��Adho��w2ͫt�a.3� [35� Thir�n6s"x �,8&ade�&���6, "�3C;[D4 6~� in5�D%�B^ ( �&z&?��E�y� by Andrew"f��6%J"�p!J�c> �ory��Q�=��mo� Hembryonic fibroblasSIhum 9 ndri.el�c!�cul!d�L�I�9�0 �� *;.1s"L �O�is" arr30q0�+-����)6[f@y� veI��lso_�+ wave@(�9�EL 7.�r�un�+� �y!�]B�1��s:oby. 8A_bGrk��UKf*}ځ�!�� =�F��diGch�Y-R$�� �walk [3�W����on*nf��72# Q�!d�F0��2P �h6<�!4#P�&��d*���/e� ���  c�m,dde�Cr'U���.�L@ly ~���2ejv3� 2imagni�X�I�.�.� �I[�x!zB�r��6%U2BW"q t=r, Oݿ7�)b��t#mm �perXQ��� "O ��e)0!�key^*�,!)��pd^��g41l ���0�tE� fielA*Ina" iA��BK2n "� l��"�C�,aalu�E%��"!�a�g>�d6h� �%Mm�Ish &L%�a,�whelmpy dom�K�"6#* conn���lT �! �ad��3�Zde� )V}]��rom: 3 nMX�V5 �$)hl!�Ep2-06�Bs(&�QlySs l:k  '.��;� s 4A!c�0u$�cmb )d�@� "�1�!i;a��z1 �.[�I,�aca5k{m.] 6n� C~ � .�.�:� !�*�,y: �E�a�n� e a�eN1E�F���x6!�ayD2*.�Iw�11ng—w%7�ZQaf'� ��i?##�]�ty� ��0� &�<��)� else��AA�!= �Oa T%���f�s����up6c.�u@,Uiat faiA�hig�AB<(cc��,A;?O5G`gnL0�-�Z �6h N+�sB�.�Y&�saA:ck9�s d�t '�����all nJy$a��,"=FN� A��H!eeglig�_�'w�]�W:.y?=�].�ens��>�6�st��� opin��]�1[If� m>cl�(&; ho. non-�| ��?!�% i [3�+�P8�G-a�ei�8�4aKX3 by FRET�D. AY�� J}-$!�rs:nd��ioIA��ia3aoo]�P�&ų&q7 �Y|�Vthe,�K�1a����?�'^ se=(a��q�=-a�e� ic�*5�yMWe�ARot�#"��N��M�w.^ �),mngar��/q�s� ER$#P(�4�  %�/Pc-v:� %�&@47 a.� .�!�or�5���!�����"�B�v!�@)"�=%�9l�b"-l.�8c.��.'�3�s��5.x"� 4������&�A2 ����!�� dergg'a�l6E)I�precis�6es.�.�a�owfAv�2a���w(6 ! X,a��(AJb.�BU�i� ghm�*t��2d[ �) =�i� �Ji\)*�Po�5�"y2v  4�Y g"�9��!l�Y�-be�e�5n V�=���8�#P� 60<�nAw]!eW!d� strer��!��-�PW!y e en�=�A V;2���N;�.9* a suf,�Ms� &5��e��$ �t,k �(*� | ll;�A�� i�f]�ds��!ZeEAF-�lode"@61;�c�'e�8sAE1]"S-�N�oQ}*,!��?F�%&a'& pea�W ����U�g�. B� Y�� o�m C�X#'J�8'"��tI��cI5>A��r�%�*�4���. A{~'iW—YeU� 2$ �filL+5r�2}<)�$�+aBsiCedaDA��(hor�za�G�}B drop!hj.�Aq!b"��x�;��E��t>c� A�DU|F�K2z fi*�(.ylikS. u�AZ'!�i�o@X � "�5�=�m.�ly-�ed�oQ�����&YV%a�*Q %%y�AK� .q�q� nst;zB wo��E�&;m�k arS�Fim% 6�&h,e�I�~ v� EL �4&udam4�oscil�NA�,�*�J�` �4z �� .,�M�/%�Wly� 5�.  [42]s�N��in&�F� � �Ni��ot "�%)P� �b9s�!�Two"�$2��%�a�g $�(A�".A�&%')��TU "� �.*� !��;�#�A�Wr�hI"XJ-`;�� ak#sl�4&�+�x�cz+gF���D*� �Flau�%�Xip.!;-* U^!�!�%�:7 �Zr ,* &aP1�c r*J� 6�s u�%; indtd arW2E� sOappHak�� �r�5��t�H�:u�*��*�a  �s��%�t�e �J% >�}.� �nSc!k8�_�\R���;�m�)� 2DI�0� s bc%�rc�9ul in �s�I��uN4pe}Q�� E8r��*����7Bz:�F�!�u�+.iP-���( Da )���� lems j epet[� ue�s'D�awens��;�P���ri:--r�:j�c�:i� hand� @�p"�܆E� w!�9� %lf 7� �!x^8aF ��� m�A:� �6I��;t�aR��mE�st�M����b�-x !4�?nz �ys2%R����Xtoler@a] 2A9�)=#o2�2�[4�,Iam.'9�@.���"�,�*e ��-\!p �K"_ �3n��� ��s i�Bd21=�)�� g�C&�)raDFsVO"�� rba[�]�J��_@>easu#�$sm|�&�#, �&G�i*��As6� �Z� "�3}3�%V)z2�C!�I�+�a"s guidE�h!f�N��At���-\� �zpfq�e�ct=��/  R��  s��o�i�%U:x:.�> �th�".�i;�� C!f!v"�,"}" � B E!� 2W�s�<��n�6L V��&be su�&� }Xal�-�? 9y'�[���Mi{1d-��'t�B��C:*�8 discuo):iosk,p��>L 1�w�%P+Xb+?�#ng:�c }2sTA^��a* "�*M�(���p�%�5�ig�6A��V 3–�6*�.ll;�e&�s)pVe��empha� �&&�/i�t(? � #�\�8gN:= �-���>lgorithm-8!&A"�until�!%�-]X�:="�"B�$5LAI�2�" AU4BZN�b ȗ5A� �[, 9��p�$&�N�#*�(-� 5B�,�Qm�k.�'—2� u� ��A�`:)@F�2��э9J�,1� fb up-UmFm� � X Jae�K G=u���a�i���А>G��l�v�I f� obe�k er_P.�K4%}%eiK�dlq2* a��UGA#“rab�z�Z= H\)�!e�un�"l2�27}@er�%q�fA��.�>�: �@e symm9e�8��r6�r�sL%�2�)���uR5"}9�66 "$i�m' . D0=�a�B:�D%�be�{;nar<�Ie� P�t%� �(W|H2 ,)M2VF��h�E��!D� rk&� <'o�l&�jM)Xc�h} f�c ��{ cu�< �E��(wAy!��,wh�N:4�S9��m� �  �'u"�ned "�~�A=�|$! +o� !�8A��5C.FUh�1E &�Ie�:�U�!A&I 5D �� plotکi7L�*�8WY2 ��Red 2 15°"k�5).*G[7^66 )�� W1�:���/>�2u,�s͖tim���l |e�2�*����:��2k}���% Mh!;k��b�.-�Vno�+gD#M;.K[�9�s�Y"aU)0� .�2<%;eI�{ }\���5-�{��e�.�!�E6!�*� how.� �1�91w�=em-.��"� 2� >�CF��e*�%�\a_R �82!{'==��h1� !_3 !e�,�!O ,u��I�*�� run� �""� u#: mt4a$j��)�a�iq5aq.F�!��� ��K^G��s1YngAQ�+t .��+�&�5�+9� Yqv[q�:C�.F� drop$"�5.� {630°;�P\�|)�J� �(��6@�,�Nc.G�� o�/ �1° U5  3 `K*�!6�AF.� . At 70°��5A�2�.T��.���u��q�u%y�i p�� moot�?���=�"D �-*�<p�%� T��svM V)I2!;$Lwr�ZVq5M��Rd!����^T�8�':me�����,�xpO� ����by1 ��yP:e Dwac�q:�s}@G;E!`�t�� rom �xLVAaN� �in�N6�A �o�|�Z ���nDc=� A .�#�z�9�� XT8��)� s�ren�"e&xA.`��4�eW�de k�`*�. A, �#ie���]�un� �B@!l]inA�let�7 |" m�'�&�'l�|b�  umpIL>p_e���r5&�6A2E�P�#ise`�nc=(ӛ,��&gC�"�1�onYL"�(�r�B!MA&]<�9�;i���?a;Z�GcS�A��E!�nj�L%o�U���bO:�:�c��GF�IK typ��1 ��!UW—��� c"t`� �,�R 2� m� �mp%2��:�E#!Jn�H%t+o*A>ik��J�"�I)�Ls�c2 � �6)_�c�0g�Zng-%�5��]Pe5sʤ�Y"V ��!�&m �f:c �T���astE6!1, *`��%JC.p�MA�p��-�Z�+�F2 0ZD!�&Mz�ay,ly&�"?��"9—5�*�!�.�0—E� 6�c+ �� �a��!pĕUq:X%q*�%)�O!Ls�&� i ���k;.�!��f"� � A ��!�mphas��m�,-iu:�25�q�T�$� � ��]�z�*�-2>��F�O�Z��r�EX6�(��4hAA.gA�@CC]researcuMte�"c�S�6ow* �4%sA�f!�p?� g!!�n���X�-�Z2" �p+s�b�U��$a:PatG��-��A�6�6\ &�GI�!e&&h sA�u�X%|y 6�Ger..|_�s. AMF����3��&�H�H� beyoA(��copS? �Jl],u��en��< ce"�Hn brief���7� �j�m( �(C(i52B)��"xi,����!0va�a Q �)7n Arbitr��Lag i.�JvOM E piecewise�/">8. TVY�6�=o:*"�� ?a semi-ePcn��ach>86�(E ɤ�7r|�!M%�"6aQ7!I~�'pbM�Dn� � for�"ex�t%.m =an$M�1 P is&�l�T( I$er�%�C2PK�|&R|��v6(" .Ttoolbox!�MATLABIK!*�uth ��2 �E:Gn�!�.< � 44t�+"o$'�K0�<I��b#-e�& /%$5D��E�3es:5B�4�=N,.� spec�47ofe�cc�+U.�h�5ad�rBrsinusoidJA-�&9�6Ek%K���^@fo43�Rby� =�:qu:$A�Ei$ j�ϥ��1tt%!.lA��L�rF,)8*��#. s^�n� �!zr~*�n , 10–28�a,--�!5�: !�9)HrefluRa ��� �!P%�%�5�esophag��sV2���R^��er��@��men ost- ]�� JA � n�E����A�tr�%, Pa����,�.s>�I�=�KP!�������^3�a"`6��d-W�D�/m�A�oxya\K��rystal��<i:{e/�_�2�{AA�S% next20a�,%��)�EO4#25 `� r' k} x�+&��N� !��6sho�  !��-�u��ty)rAt �C���TK]�Q�y�A�I]vap� Oropsyll� ntanaqI��G�sTm�CFU ��-�)px��"� Il!�. enhc'db��AbF���@"�.�de� ���2��Prg�8�����a� ob�h���gu�LA'_��&l some)�te�I Fverlap%��"�v�"V��Al]���a�Sciurk�l(�,�� ��'b�IZ\ptxg��.��#c�;��"GS wh�*sem�� � ul�a`i�� plague ec� y . =^�� vE7�'/�pM!iA��w�[a� =Ih�6�+�bed: {����[1–�+%�v�0a� �ky>�C6c�cap�ofE3# ir6B}mptq�4i�of., aed�l�I� �qincub�'�Yo�!aA�,A��� c'? WA��ac�*a thoge1is���Ti�D�5;-�a -�t._byɔ e�!�4)M���[�7J-�ha`" d>Il�nsue�'"e,5–7)< j ��5�)m�[�e!Ji�i:[5��� y:�E vabK >A�O�;EH  �m� g�f%�i�Hr;%t�P�ckfY=J�' %!t6s�!�}|�=����rxEo��}HB ��%��e���*AO� ,^2��!s.$ar-�o�F�?� �. B%AHstaxRougF���)u, �i�ia1�mid��;b�c a*��1b��S Y!�5���O"�� \a{GAk!$�s|��!%e suck!pump mus_C[1��cAb1�!E5e�H.^u�jňEx�J�caf� barr�t�) onj+IV=�6�����4�I���aun���52j�1�h, , diss�E��a=� %v�G&���y�` ,).�(A� stftr��}juck �, e�OiZ4co,;1 `� w2>w&j�=�m�Xu " �N | e9yA&�Z"d e����.v+��;�e}R�(�Kts �� )+��� x"� Op!�l#c�E�&�E?�!D*� W-i_ sa O!�emiР9-&���D ���:*2��ȴE d��� M =  naïv�"�, monitoC!�morbid2h mortR)y [9–Xil��&� I&�re!����e sx�MIV��#FQ or Xeng cheop-�=� P��y��B� a�&P or s��r������nim� c� �q\,� %�!���&�-Q)9�&+AX!�>G6*�Z� ]� %g( w . 5%G� �'u�3�Qtnr�6E�y�7�!A3:c-�[v�12��aM� nt ЧEWbV  �=rt z6�e{mHU �lbT�$��"w�) > .�lA�����Q�� en O .A�� AG .U@%V ^"y � ��7��≥108� /ml.9,%�60��%�03�@ P��,A/ Swiss-Web�4��:�]nN� �r�DYn7!�1%�s�-Ys diseҐA�ero& ��� est��?�61o~� to ~10% [�a� 1� � ap"� M�w.� !�y a��, |m����.Z�h9=�awj�:�.[%�2QFoE� �!�)}���"eri.Jq Mrvoir9��=ewA��r\A�-�xn = 32�=I%6ZS�jE~( half!�E�x* �?U 1ji�?�xE�' �� CFUs/He �B.SCbymgEUIDų250He���CaliforQ!�nd�5A` t}��P.�[1�~c"�� �oD 0He'�&�J?$aE��.p ce�02W�w)��x�]:�H A I H& tudy�4e��`h�/�ܩ ��Ie��2{(Mp�\)&�a��K�) � iQ�ܥ�Uby.dor�K�2�9�exWT Mongol�2e,��7 � �l�`]>va.��F�A*_ �N� 6�R��[G)( jird )-�A�CO�n&�7 as M>aF:sp: �'��y���TAsia �oWnoţ~�5�-R��ҫon:�!�9�Ix� �*�u$ � �W� tݧEQ=2Y�V�!� REͅ�A3h �Y:� � i�� 3�"� Q�� enw�rrm1(�&v�)P�*qL� �z� ��^4)�q!z’�)xt ��>&9-7+>Np�b�by2�. EWin vitr:rat^�A�&o�Le.a�=�� �Ay" exo=%sac�ށ2s� g�a��+ Y��e����2��yb�*�"= �!]1).�w3a.Ll*g]#�@!�o�� ja%��cm ��i�!�hDG�I.P)Y��>��PU�M� E~<k �e�) BR& ���f�++� �&]�:G!#��*Kmin)� 7E� <� ��� U"�N`D�.� f` J��K~1 x 109.�KIM6+a�AcGFP$CF� �1 μm*\tia%�( �)b7 .�!�=L n 21�8I�26��\�n1O�%3e����\��B��2V?���a2"��ngA%�Dju��bVr�.�ar- ��j�Lt ��r1E�!�>�5Ee�)"%^ q y�or )�O)�� Rq1%E�-`M�"h.�u�4MGe�I53�e��f�*b�I���=u2�AE �ha̒4  h"��5W+lu��& B�)�I5�%�e:�or�^�.p�e�"n� n ��cincb?/5%�P�z� p"��)Q%trZ!8&�"qx !bSR X.e8�296E)KU6&� orU-UZ�(���F���e�4*�  :4: Sprague-DawluRa�6Rattu� rv �u�`, RML>��( M uscuAx�mdom�c*� ( Cav�"�'l*!�>� (& ungu�a��I]�&�,��G��I"��s immo����2aO�+X&$ NA��AQ-��Snd5�E>��6S��,�^d�daymb��!��&�6yr.0i", 8&q! }��ed v i W6N≤`2 =��/*�"y6� Q��0�� �e��}6K{(v*�%:�du�# q(. %h*f hmsHFRS*�$Fi �Ga�orJg  _!�Pla�NtX�!�T��P . AdalEsc�mchi��li S17-1!DH5α�CH1��a�eat-kI!�()6���.a�e�4a"m��M. 6% v�-~22�2�axx&ung�w$metabolic W+/AL��6L"l�!t 6� )�%��:%̥]ver�}��!x+�ti-coa{r9 flu(%�2ER 6�q(ez�25br�b+sod��h f��Kd�p�a� 2S1�;�]T&7�} ߅8��>%6:�}%#u�&3 �%IeIcQ?!�>�5y�� inm�5 uNwa}��RBCPBS�6��.~fsw`�>plasmA�"�r���"&�I� �(.2� �7_)��5גu �>�V-�0��"� � F�%)��O�>�� �f�,��� ��D<2GA"N��%k� �_!�-��>s.�1���&0u�&��fo�bA�1�� ( 1�`U�.� ?��R =1~5 z 8�/ml� �+Zi!�E)?\�N  � qe���P6h m�W\.��pA��.�m~� �U -pig lZ �h1g�&Z8��%�2s-i!� 6y !� .��>)� &�'�6� ��i�2��"WE RM� ( 93� �\" 9�burdens.f���gB.:�c ~"i�DrI�)���U%�͠�����0c�TrepٓrL6"R�%�>|�d�V(Hy�:��l� ��"�O..is�b-�wy0d&�#ad�g��ep�=�*� (hw�P-H� xiWe2l:)!%�ba Xi$Nm7bFe_4��9Y|P�Ljv�&� i� A>Eof24!i��BWE�6I � diss�&B �$ scree�>a+Dlib8of�/+��(���. D6�,e� � ��� ��z-I���}�A��2�� ( ~4}p)�y2�-����2Ae�2� Conn�c� ly 39�M B���.� �ed.���jh�= 88% (�of 57 �the=n�+RM:} O}:!� ll-��B )� 6��&�<$- laceD _ �\ slip��I�QgJ��57 �U�^V]E�&yQR� ">�jJ�~ Z%� ,1>v� �v*'k!wa�fl`$!~����sp[���m�qnc�FigAR�2�.XF�43!150 �( 8�:^i� of 3G34 Gdiagno� e^�w.�ZQ!ulb���rTc%�Ae�'��+obscu� vie�>�a%6]"�75J� co��x% �Fknx�!�T!�ԡ"N)��col�˹�0)�>g !�O�V�7--эG2�6�I%"�.r���K""?)i�3� I��:�. U=��=�J:��� ^�����.vC�,"1 � �&��CmeAa�?-�3A , 3BE@�3I%_3J-��^4d .8!�>p"��Zt.�V�I43��3�M3�3H� *Eol�  �[2��l(&=%/Z=2 K%�( rhomn��H0pez�9)~*� ( pyram�9 ) [3�"9}�isQ!$!�*#0�-�!' gut�B1 ���U�g �jag�#!tr�. C).y6�� -�o� �S�I�haLe*:�*{ �q�W�(a6-ar�p �8�B soft tick�k@"ng bu�&l��i�.� !% s [3�3z.��w���M��`6-}��m#�*A�B0�+�2.:���E�m�edA:-)�on2c)T�;��?�f �7 E0!S5�s� �w&ޒ��4 �A$E� �A >�� ��h!�� je*B � "�/ ��m�Ke�OV�5�GQGf���r�A��Hi��85IdW >�.�Z: �Lg3f�Ո�/ou�.thick: lay��sur�jA�a�.ku�PeDd*c �)�wCi�A�>g0x abun�\�VS}�%� �bn�a? C.�Zb�XuA�/����AAJS�l9����V�UR%n&��Bis pooX �5��i�G)IF�i�RBC? �[3�#3�/3l%W.fVg I�7"6m&��0 �&� �ase�by rn���vwa�C1o�L empeT�A�10�duF( S2A7 T Lϩ(HUZ,.�%d o� �3" UB ocol"������N . Absorp$tra� a suZK�]A 5Ad2�Fat �foxeakk�54x�570 nE\ !har�.G co69!#B-#[3�(�}RN�A�>@�<�-u�q lowl �5�t�9�t%���%a#0 y�b� >�#m�ѐ:� A��jma��I�8 ?  x�st �� "�!-��> �350 � –!���primare~"����f, cesepia-� � iqui�lit?�or���( 3E- dz&�=��!SE��0��aFE�&�FV%�) o� Iׁ��V�(.F| As; in 15�j�I3�9�%��a�6���>_"4of�s�!I!��N(Q/��6@u�)��) | .(_f�o�f3 _�e�� � �6��3 in� )���&mi�3VQ\��!�he2��* A��Y�:he G����/6�H.��&6He��&��f�,"� !�m��)F !A�� &"*,�*+]��/)��")>ed�of2�'(�2O� hBi��U2 m: C��eliJN.,$ɯ�)�A�"_t�a�e`. agA�qk�k� �!� "E� e��� 4��w6�voU�a�1e�.[.%&�#�I�<*R/E�L� �ed2S� s 14B% �& �to23 , ~5��R.��� !&� !}":�F )A debrUA�  6�%4�4D�sa�˃n��A��9�e��� 6�J��� � 2�w�y&�~lD��- C �F�TheseM�hade� actu�� fed;Jq �is�.�w!�ueAAA�-deriv��E� remained A�,for at leastq�post-i�i ThisZ�mobserS;.�,�whichN{M�9�� ark brown% easi� ,istinguishedi�re�3ly���,8i�-R�lw�e!X)�i�E�!�f��.�orn(!_ p�� feed�:^�E;3!�L25 times more likely�L.C5�m�!z�Zof�.� us (2da� �tra�dF�) comp��)H�:�M�GE�F��A7�bW��1is typicE�U?inM�E�(transmit by�4biofilm-depend�/ regurgitaawD mechanism [2 , 8]�eC0data indicate ]%�8often causes su��.C:�to�A% ���x test�uAM sourUqHus =�Raf�W �ssajof Y . pᣁYgroupe� ~200n���a� X�Wearlier �mouseA����� highair�pz�l( >1 x 108 CFU/ml; Table 2 )�a�C��!&a6$. ImmediatA�f2s1 . 5 h:aMperiod[ number!$CFU18tta��eterm��by pl!� coun� In addi�����scree� ��.{��aB� .j.2�*.U)�ed >8 -��~420-;3-fold��, respecA�ly%a2�:[)�i�i� 6A ,=�(. Significa� �xI1:KY�*N�F.:CJ�B�<SurpriE � e increas �.by2_f���!�B+;>�5]�(KIM6+ Δhmsj � rain unE�to� duce%�expor� Texopolysaccharide need�� or mature�!?meG!���A98)�fewer�s��nj��G��(ntal Hms+ s �{ ejA�=y;)�%V�rrea<d well$9{.0( R2 = 0 . 84e�� ! . *16"� 6�6 . FS -S mis���a !��!�q�ed2kmay!(> ly!�l!�1D c �Ibetween�� R!6a�.�in� assHig&� �tsug:!�x U�>� j}k  fa�>A�e�duc��� extrinsicaHubIk�2requi�!�BDTE*u�Sin cert!con�s#can�8omaintena���� s2+loa�i6���!bAB)��.raL t���[4( 38% vs . 96%2�[1�I��!b �� ea"O .d#�Ω���� ;Z�%�2inv�P43%eߵ$Icana�perman�colonizr 6$us [8 , 40!�6�bac/al burder.h�eJ��"� 5���ab� 10�j)�%�A�9�)=(2,Wea sidea@0$possibilit� at difSnce%�A?a!���ex�zwh6�M��充fA.1�>4�. On average , 129–138 ( 60–6%�?.T1dur��� �i+��,� � 14],72 ( 72–88A]2�& .oeve�n � �ng ���eALi�ba��und� ptimB�Sa�9� �a)� ed2�.h6�%�*B� ( 20a���~&� .� . B�N 1905!�916 ,�>���sI���dbi,im��ant"/� lagu!�two te#> ct pha� m�-born�E )�e ,described [3aWA�bec��knxs mass1) <W%""z` edR y-64(EW!�occursALnicI )a-)�naïvb %�]�firR eekH thei����I � waneG A�%q . A �r))!(M � � -]pr� 2!st�Tg �wJ�1"�us!��lyj ��le� � norA�� flow�!a �outin� e-b�C *<� inudGatA6ts�it gradKstarve�~RT work h��n new light!�� mode%�2A.%�6�� long�OuA,�$ an exampl%��cal6Q ���0of Rickettsia�by ys1�*isR 41A�&���fac� ��� vary greaY.ik�cy*a�`�nwith ]6 �őqqFXbym Lg K4seudotuberculo� is n��� , ar�against�i%Y=V smDe�� ywouldl�exf� soil-mouthA�s -�t X val��9�ans [4�4�ge�8 prop{% !�,�u ,1� via � �onA&�>luY!�"�ba�o%�$ ikaRr �A:Iisf rimAsitE�)��7� D heav��V in a� �Uan@6�� Oun5,����aF-stan�concep�a�%��+`i���A� &F�� �until anw�s�=in2GI�X_les�! in o� ��[1A 14!�y�we found �major\ ofE� thre���pies�?�(:�.� �&��4large aggregat��UU, surr�Oy!�amorph!�,�-!# matrix O� &��7t! %���͡�*q�V!�:�!R-�+ � ��o���X8��"to sus=e�[mGa� sult� sen��T sup�g}�v.��(2a���$w��ail�wAccorE�to our 9(�;$7%�� IO�&eRa�y`*y!�nizi�ar� mpet<.��yr)��throug��_usab&6�s��!$to�ulPrefluxA� Xmix�"Y{b� into%Rb�p�u. HEwe showi'!�makeupT.�arME aY���s): ! �ӕ�so�!��0is� ���ten��:�\Vwaro �&�f�E'�i. Wit�F 24 h�Ei�ng � emic 0or guinea pig-iv�IIY�ed som2�"�}_��5��(#.2 �I;��AlthoAc�n:FcHI�� in 67Y 00B�!Q. �� the�.��%B.Aa�, *raro xhibi"=-inzI�sM6)� r���wo �.2M$�"9IK���!)J&�-h� ��)� �e� � pro�Ent%3�cM �:w��.�u��"ie��nc�B erK au$a� valv�� 2A )y���a!c&3.�of-j��Ut�up���B�27)L�� �9/*%2�2��juq�IG� or�!enhad2J:dassocF �� �)bd edi�i T�Q%�N&� � �^, asses# � e"MC:Qpe�,� �E ~4Pas~10^�w0os#+�E��-2�:.�:�&�,E50a,ter?n;m�!E�� ILA>�:�� &Ek� t�0hmsHFRS opero��|� �֝�*!� l-ß-1 , 6-N-acetyl-D-glucosaapJ4� �g..!m�[57 emr�"��at!ͱFE�fortif* Z�c.Uk.l,�� Oۅ�N* gene�s 6���s�t��7 �iVbuM� 0,x* Y��b�der} magnitudeQ��bye[�� � E��%�U&="���4%� 10includes: 1 )�*:2(�:!~���hU'�f))��� 6j by.�!�in.2a�ly�����E� �leaN^ [8� �.T�omplex&` Aõ �& by" N accumu!�� E\1@fagKQ�$ga�onQ8! nex�� � t��e� Ud%���66�3 ) F. wcbehavs'� physiolog��mokrX ����!^��=9)e^(2$.�)� �iv�"�!W � w� a�%ido�(2 inD)�i 3��o��Hms mu�s*synthes��r!ݵD:grD�theH form(#Yj� ~U*l"�a��2}I�2mj�!�.�window-6�&��1%5 )%z1Dcya�>"� by lo f$phospholipa�D�&iv� encol�=nymt�R�qA&��sufl�v|Qf xis�2r&��+B-[40!�6�kE�uId;o�m�`��of ro�$�Qs E~!v i z wly solu'#hemoglob��n� ]�s {,aV�[酭�4,� stit�;�a �m& Z� , much )R�� apidlimin +�diuret,^$ng�A�� lemen>�� a bo# [2 3%UHemolyT%Fre��:=� "in a*6"� 2� Z47!�F!oxyH� crystala��W-P"+, �B %��9� stic�OA��+�of.�[ ��)%�E:� �MRBCEbmaE6 proc� A=�var�*�E �04 &�I� type)x & ��.E�&� KFBL E�ed> A�l)%m|;!#=�imse��is> :-izes Q�&� non-a��moa� �2S(�MG1�Fnd its.�"5/ read\A�� s [3E��)�No��%.�%��AH�!�.!N � �!ir enti$&��:8- s Z� dis�)a�'�0–30 e�}A�U~!imej!DBC�i�s&�/�� z%v�l$[��Ci�(*Ve+!�ax�xedE�A�8 h> I:� A� �con@1Y);7 nyE�X  %�'��-oli (heat-killed.k��#ed �1�.1C�D*!ef metabolic��6� �6!O [& .] hypoDW%9� hen "2 �  b�2��"�!�Rv� �!^6ar spi;� .�#N seal�of��m�g"� *)� debrIre puN�E7"�0�)*�a��t�8ion�! h�$���C)�7K(T"M,��kwpdir(:b �%ocircl? lumeh�.3us���t�5�o� �E$r"1 ,1g!2�� e�J [���7A��!O:�mus[20�inu o !:0�26, churz3X�!g���1O��'�� art��[4"!:�� A[#.�4��X2n�H2Figs 1�1AT2�1�itaHpau2��!M�!c5��bg %_I�݈�� �sp���.�}a� r abIns�, 2�(4I{Consis!3 ��u�� e� �UinN��&��:�!�!�e ��deg�, "�Jstill�Ew ( S1%�S2 Video_4. Takez"ge�,�rbx.2/��k.&V-�� a&� ��Avc.} 2���<���%*C lB!��of@�� RBCs��*� cA 8acB.d ah c�B�' of���Q�(Yersinia pH{ ,tigen ( Psa �exC� t 37°C (�9�!er�-R1�!�Iz���i)�4A��$ hema!/t�7 [4�)&��i+,C %�+revea�m�g%_�VmiH-rat%a@W qu� by �( ( S3�*,�also �at���a�1� fibr�*loj:y�� A�eG!�chronI+B�-U��.�E�x"�ru�F[5S5�"AC$ch� e>dZ7de � or h�8i:)r:96o�+�*re�in vitro �1��62!�!)�\� &� �9u%jmethod) anti-coag�!�1� S15���VB"r1 of sodium�!��us6T"� ]�O!�z!��e*�#u�alone�&�?��y��! )MV���/plasmaE�o�*�r!9�c. S��* *%Y �%��%ii�s7A,onP W Qy>��n! . UnG6p�=,"� ,)diZ8�a.��.}i%ay�ˑ�9��ir �izquickC ma�#iq8ss$�6A�N���� str."KM�49!Yn,�R7aa� ck bM�*M ynarrowz �a��*�atH� s�3onajB!r!/acty sphin� up�.L.* "� N- Y%.��min,9�9b�!!�.��.y� SW2! �� �' atom�'@"�2ts!�e!�%�a+it�Z8��: Z�,n��'FHA�A%oU�e�� "�t!�*��&+,��mS�y*��r -hD>��}u�. nc.B- ��0 study�/� �~/!{dA� /��.��%V C�sJ�0_A�+""a�7���'a+*q<�o��&��aAtrK<6�!p �il� l lo @�?�_`(y_�� o�;���7%��/�-.% {^�]�l 6�am� wild-typ��b,seD3E�er U.�A].)!���*erA�e�*ef2�&�519a�A�P0V 5�;��6� ��&(t�/-qLcy�bB�;a� ll%�-)�*�&Y%itE�9s,3� �y7-p�� �z�in�#���'ff\CH�tF�7is�P�7�$�-il�.�ar� !(i�reb�Y-jS=/�BrY-�hb/�f~1–3�#.U��1.rbecb&� A.M�in1�of E��Ak ~25% 6\A by 6R-[�� E� gerbi/,P Xenopsylla skrjabinileq �BhM��$ ��[52�I � �#� , 4–2�$j!yd�Z �e>�BB_BAZ9:)�,�w1 7n�"%*er�c4�� �-�2�F ;Fus�9N�2��2�!��\0Iag\a^�;J<iM.%� d t [7&E?� "nQ�k8F/ b�]is=T"�7as�*2 �1�*)EA7��.?,�W�b�8h�;a�fh*�9�-�9a�e���!!�z�L7B�����"�3� oralC��"�7sm�]���S��2�;ݑ-/��by2�Z�,�cH'e�)t�q!<.NU�a$���s"�=X=0E�.�T".W)�"9���;qM�M "�B(Q�q�Y�)*�1!7day-3  F!wGie6�Em�2t"�0�R�7�.�j&1w �C&h:�=~7S, nfou�/�4!:cup!�~3��5.p�'�$dA��H�!6S��ri�%H >�F�U s 5B�%�6"SF>:=�� �*tQ:"�(A}P�J)�i�"xE%-!��� @�,wCa�iN�9 br%�OA��R5#�!%!"a���9o vis�4Qi5Q�?:�0`�q]�{�8w�,�� � 7:H XB�7,�-��.(Qg�E.�Ao.(&/&&�%�sp..!m�(Ex.9�%e�c�, ��� �"�a"� � � ���*��b108 c a&/fe�en�c$m�;��B%7� .& (UyIjus3H!�� �e� [�*at�En8{M� eal-:� jun�$ �{=$hydrodynam ., %:a"surfa�reaN= �� exi teFc�,&�.�*a2�e�ih�No" kdis"B+�� ��C�ll�L%)l!Glea�D~_4�' \.�!%1��:�8c�~ s�Z�/�B�.�s55� E.}����+)�Our ��ctA��od-6q�ns de� )e�@&��u.��!�i�9���toe��+ulTCe�al61�$ 3�Omm=. B&�6i!r1  f�ngaw )�at2��� )x" �(��$ l�65  (��n = 9 . %5. i�xA�su}%�5�.t�Id�1� ���p�A , range =� 1� �w!�ink�E�P t�!��� A�$simultaneo!B�,�! epizoo�#involv�aF nd sCrel hos�$.Ig �-p(%f�(�0.0�in�B0�"���S]�"�p!A�w}Rrn Un��St�6)ciPint�<d�ir!�be�6 Atur"�20th �%ur�"LculoRifBis���\!=����� ��mea�,d%��"cy��!lm ~10M�:�?>�X Y�&-,NS=7�or T;% mr��"AM*�!"pa 5S(�n [�(I)��ree{ )����� �Ld�Q � &�5�cA�9�6a>j?*� ; h"�P6��T���H H=�p�-%c? .�W�"T� �,~%�O >z1͕e�r�Ib&�K�challea��  &tud�&u�T��imi{9al�8l!\- : sm�-YN��e^$N !r Swiss-Web<$|�Qdi �(or seroconv�1s%4�Zout; u;=:b| aon:�$�) a�0cAN*dev  �!���!�!�rec�#�p/i�reservo\es; ��F��(���69 YB�#eriph��%�-( <10����i� odel�!�Yen�*��>��C�� "ewT[22 , 5 >M!&9�!��+>�ful�*nyE)�E�~0d!pcal���Fx��Q��iP!�a�nFKa�� ^' s be�+!� LD50�<A�vanta&�J5H2%�'�it=��7qu�' �!Jutoa)A. C���6,Pm � >m&C�#!?�E NO.�uuw#3C�xc2:Re-.�b�1 �DE�am�ye15�899 �i���enoA9� Hms2 C#ell�� �=G6?�1� �W&�1-^B� � g�3l sw!�Ca�"� ��Axvi�Ca�0 )�� stfQ , 00i�by�,/a|(YanE7ilQ[�3) /+of-� poole q��a�Ta of.�RS*�.in�2S�A tAr�-V**X-is�ly&2am'D!�Muridae- �$ t�!F��"[3U!D�,���/! �%� � T>+u5abund�=R)l 4����AEh6���3"<' ����XU3�6�7�*�M�Sci-fam� �f0!�#��s"�  marm�"(prairie dog!�P�Kl�8pl�AB�o�K!�9�an� � �!H&;<� �Iec50=R� � �!_ir populE�s: Z���5F��kf@2�0d13a!�B�P fsa%N+n�dislodg� ���5f=qb�6�, . Fu�*� ofJ. � E�m,obxB�o�(� :�*� sK%a1�,6Ai Bhw)Q valu� in�&�n����5�HN��q)"zM,outbreaks . &�'�7s KIM"� !x$Escherichio$ li c!ng%��'n�  (i;ain-hear�!fu�$( BHI ) br�]�C�3z hemi 10 μg/ml�"sc$L� ly!��9f$e�5!� wise� !.�^\PpAcGFP1 ( Clontech; M�W|RView , C�E�/DH5αq %i!�� pCH1�:a!gsmia�atT6s&S) muri Mox�Ym|^,7:�6enzym2�U�W� a�"KD��� � [28]:&yF,2= I�.�Is� h�Fsf2�#at Rocky9.Laborato4( RML /`�KdE�B5 ��9ZW ��. G"" I�15P20 �Ek>�Y� n� -�A��N6 m* � �)�!o�o-� 3ed PZ�B ZZ9=�CdZ [5�<F)A{a��='x� mr�1� �d +5 �wa�0;�*in PBS�to%vbr�*�4F ��0� �2.�&nd^^20H� R bpX#2�be )&� �.%.��`h*�25, %���Fy*�sp� in 1- 1�i,ate-bu�Rd s 2� !1 �inczV� t 65�,�M20 minT"!_"*fh�^e�2. L?:vi�u confir���> ng 5��lq�N�+:ܥ"-I agar�2 s�)Y+�� x/%,2:�+4Sprague-Dawley%�( Rattu�:rvegic�c,vG6�Eg ( Muw<�1NC Hartt*�7 ( Ca=8dI�!� purcmR�a Bioreclam�8 IVT ( New York@ S:�+aO:JXc��F-. A�Qa" ^~,>or -H6�=0 �>^�q%�sc��]Id*_6?t<1adom3�E� -/y��e�7 exch[�YpCVD442�sui�� 6�A!�- � dele� (. bove�p� � ~in)e PCR�pDONR221wGatewaywPatho�1Fzal Genc+ s Re��CyMr , J�raig V I�=t�1��Ln e.�� �ORF�]�]as ~500.�up-��downsa�8R)H 5’� ory��JlDdGGAAACAGCGTCTCCGCTGGGCGCAAGTGCGGX$CCCACGGCCAC.TGTAAAA +5� fragaB�+ ampl�E��!�c( B�!!� ���CTAGA�GTGGA{TTA���AGCTCA�A�CTT CA "wa�.g%�i)!MY k�GriG��s XbaI\ SacI!�o5.gra#�'YEin:�6+�conjug�`ws" S17-R �%��"Gc sucr�&se��G!0+as id��\on�,g�Nd�1�Jby%\LI�p of,Dl���&ek�Umif�atq r 2�x c$��ma%e remo81,t� T� 3��<�� Y�<,<  in dH2Ob,{VzOvolume�q8x�1&�`o4lem&u5r � froz�;5a�36Z�, -80��6�:�� �0nbH % isoi�V^}4![rp}b.�. Absorb�K�Z A"�iL8a TECAN Safire2!�tCa�[5|&�5Arխ�S[cul2d!R"��[=�.� to aaEPi of ~5x107$ ;E42�Kse� di�7 %<mad�a 96-� �S-bottoc pA@tyren�h�a. � �5I!R� to each�_�fi��&n !of 1%�tho�lyRR. Wel�:��X' nsedRed �3h!LB�(���.8? hazyape ) � scor!��s�lE�6�.aI&�"/  ,.� immo�%Q$�V? them�[�A�"�QbdisT3ng�roscop � sign�:�0&�# roS(7 ah@ Ap !>��>�T��� �!h.�3n< eabl�4yoe� nG$9 b' O& .�A��P�� !1q �L&#fPE!9��redU!�n+E�retur!�2 m�.�qk!��:, 1 μm%:.)H( 580/605 nm ) sulf�"FluoS_�DThermo F�rm� fic; Wi,tM !�uY!�Qk6o ni~3�"N8�l��ke�t_3verif�JAN�q2�(*�&�m�!,.ymF(i�� �a��%I��" :. S�H$1�8 fema�]� &F im&Wk pn8_Aata�or 72F�C!st�t��. S.�s2!��mdisrup�,a FastPrep24�B/ ( MPT�ca�SG An�?Califor,=t�C5ly*� �5Aliquo�#tritu�i*eF5 �x soft�xl;.p:810t1(carbenicill�d�fM_,A��l!�W4]�{I�!c�c�wR � �.�� �8+uo6Eu�O�� Hf!!�b�. Mn�" Operfor�2�.$:2Brief�9M���,�n�Fapproxd�&eq� �ڥ�A�%6I���B�or 90"o }���"�yd��J�system* ���a�2�ym�8cine�" m�F)�(� 8� ,6"e�M >ro2=vfr1vj���B��9C ��=�app�vu)T� $�e*erFw�t+Bi�r�� 3"p -��re*@ ɤfU^ ar"� "�:& �� && �k��p�[|1 ribu�l�o�* ~�e��� xter� �+ �� 0skin membranenaI�veR%o�cujto� piece�a�hom��u��a����AFa5�~��. S�s��z8��d"� �dn.�Myb�O*�.Mr.n�2 28° C��48�^En?olony ZC!�n!�rla�!�Pagl��mi" sl�nd!�6 1� a seOfa�fp`A�w#8sk��=E�qLa i�%dpE ��e6to"�+>� O !�*� loc�N"� * ,>F� ��7Up%vM�T't�Ka� dusAUed GFP+F�4E"ao.J!"=c.y[p6�Iv�Z�8xu�`obscu���1i�"�)53J_s�J�2field {ME.� :� "@��n+K��.��[V�8�r >? f Z$, 8 ��� half�20xEH40x�W"�%)�Y5d+K%=lea�-� -�feVs�E��^if �srectang�$ , pyramid�$rhombo >}rapez  obje!�b�*�!�da! AnGU:�q��# "ahITZ>-��O5*n,{ nsfe�H� drix��B�pi�9J�)6C�d benea�|e�sli�5com[9l4bme *t�'� #1x�  �5R��5 +r.�6MEE-�D�L� 6U �XQ�j M�Yz� �$� ��iia��h\ ce9hy�$mag� �o� F>]��l'-�j># �H �" "u�J@Nikon Eclipse E80� �a� #SMZd���]+AB-2�,G-2E/C2�fil� se8r x)� A�c?0AH%�*��s6�N�a0Pic � -Qm���x �8(lympus DP725)raV� Sens� w�$. A�? naly�"O&� )PGraphPadT�sm 7 (Sof I8Inc . , La Joll�  .p �0"UGeC1%��U+ p�4�N��(m+�e*ig]legen% �.�&�1annM6 v8 Hn&!, Neal*6ofkerg�gd"�;!\Z,A�F8E�He� A� C��Use ComlY(protocols 1ˀ011-E) 58t#G>� >Buc��Mg)�llz�guidel�Q.�P��X��aLz�2of neur�wDy�� /ba$0Vo"�%h<8�8�U2m�7e���:A#jfg & ' Z!ua�t best�(gCR�avo�t��'!�"&? @7g�9��Xյ2�:'e�b>a�m#%{VoH�ale9Å. Spec����!�ba����r�GEz err-R an bBir�Wby .orF�_. Like^% c!�st�4i F[—a(capacity— j ��W� � _|�se �,A�5n� sZe unr�SPV] :%�A�j?��9��Glt��]m� f�@=�8-��fithaX e!` comm�JD�)"R)Y�. E%u�&!n� �)&1Z� Kea p0q85.� . Tu�� nGs al �B \m�6iy� a�<9A_�EcoAn:��esp�yng.~N�" d�9a ‘�7-in�-,G��rQ�Q&Z "MZ�r"\#m�Xpac�l��!�Igu .�%�A�us�e n�;�{?1B!o�j�A�ׁ �/a�G]~it . M� � c� ic�o|.;�`t�QN��$ch|so4}N8ee�� J P�,�2cſ+ b�A-"F<�Msh�f erc�o[1] , [2345�`E�sR iN`�{!+aK�N^D%�=X�(�>�{@-!�Aɕ�/�"H2u,�0iQ��H�@i��-� o�omatch0.0am �-fEb:H���x�AM��1W -6!�VH"�6�f%7aayd9!�?MC2es jud �Ld���E urac��-jt� A�m illu�7�u�hra!Lv: “sea5i�3 ieving”%� Shakxare's,o5%r�of , (wa:di5� doubtt)J)]�! worl�cM=�HA]�� �l�I-�‘2-�N�1�9p��must EJ2�2�ba}lya� �T�Q. Z/ �)n����s.u9{,��4so�\L.s���Kml�5cFi�og1*N#0-F}�-u�y,D f��b!V�)��-..��VJ7��lemomKs���.as� a�0�.u�a�A�vZ�-2FL�3O���b|)eDayanU7�; tself1�tr�&si�k#ID idea%tt(� dƁ �>te5a�@, ��g�._W!Nam��%�ask h�{e9��V.�–�m(M]coRA��@, ��9*')�J�o� y!��i!��g�1b[ j� refe�Xd:2�a(JJ �U6Q�sm—��.b �&KaQa�)��PBtWn�Z�$�k1 ��"���a�� prec` �d ,3 A�Xb�Rs<ay��+q%� r*i �&A"o�c�=�!m�I�o�"�Yneighbo�.ZsX�5f %�ambigu�49,���&l�IJ&s broݚ�6i,V!�� ��#pl�_�m1 GV-��6(]�� �L1�6�ATb���UN�!��2Hin�0h �/y��O#up��s5^1 ��m>��ly�e �op�cs�a�[ 2u� onti�Iir � ��cus98�h��t2( ‘�go%�a���/(� "�bU{� unda�+���dpe shifA�k��4ofFbeg9�Qt�D�etA>"���e G>��R-�2�"� �C&dD*� theo�c� ����)J�/6tu e �J [F���qs�I.}N�8>�t��$"/�O1���sA�N1nuc� WO$!���U@iM�|�p�lyA�� pMYwe�J�Ta�T ͜>\b�r��Wi�#��^; h�h i��stagg��p �ceA��QsXo�o"�l{;a ��M��fN�jso�7+a�8�Kro^m��S f pu z � �/e *�> �X �s4O )jss�� A;I a�a�]E.K E|���Ry��vK7���:UGjV�S&`�Aoip)Am!�-~��"�H:rE�U�a=B&"jt�:�Q��X :��IV�]AYncoF0�<]�*_ aTrxw*�s ?Ji�&�Еi!ad$�A`��W�E��Y1RDV.�-%ibh�"ac�of �|�H"�g.� qa,����Y6�Ga>�tr"M| A�!�J� �@h"1�9~;� !=��&O#��r hundre�i)�dy�itQ�qU�6o l�D5: ,l�A��%�d ]�A�9e}auxili�aas� � f"��MUnZ� �B��� &���41 HS[�n�.ach��ur[ ��$G#s�艷���e6� g��. If ejpP��l�a*{!fine-tuz%��e[r� ���loc��5�M?A i�A�j�.� !DY�ponU 9�8A�4ed�.� a�Ler-{6gam"� %}i$;l%�i�g�orbid��� I�%�p� ���_N�co�O? aL��:~Őe!�/��T&r$� %����%los�����',.�)�%�n�N;t1�is� 1��%��&r& -�. a6.���oA�5[od� Gq��I.|b�2��mbJ_]b I�%�e.} unE�A7).� /sZ1�-i S G= �Z$ phenomeno}E.2�KDa2 �4s��R�� '�M�H�J� �fa?A�ai�r��_�d�9IIn����k�� pool��:I-ak��G weak.���8� �* U sub-]�A�a�O���5�2�#��m�!�$� ScX�}�ngi�am��~��.�b,1�Y�s�7�Y�%#Q� tr� d�'.~�!�E}l O��v� r H"��#%/X_ W= nt wo�fmu Iw=nc�th?A� as TVt ��Dih�k�:�'&� a�?ue(� W2''i"T#�չA\�+95� s�[?��uL j�2;��iu9�wpikIE��Xo bo�O���$� vig�<X7d-��ge"fo1 Jo. UF�w$�#��!�Mv2[�a!�a)2V�T�Pool(\|!� 2e!� �m: ->AP�� t\� �4it&qd)customarwQ�4$�WA F%J7I0vsakGi�'��d2-ׅ�At�6W-�!�!MR.�|bWX) noteaxAo��E:�)Jin ls  x2%(a,�)1n$&:V85ensem�. AAee l"�E(2J{Ko�9]aJ>+�@x��1� ��J��Ri�v�-:�7�R� (ke@���� I�?ٱs� 2��* I��&origi� � s�g�����IJA�f���e2:�#a{amp&‘�~� wheE�T2 i�n~%)� ig>� �&� ,�� *�cla��� ��&,)D6J���ne5�aFDAnq ��aere�th�fI��7B*4=6�<톡�)!/!IfA.�%�<a�_=  1!HH� tM�‘"�& �;2�;D.� AA��!l,"FE�1#!uaF)q�q�M *{ hv,�,E����X$~.��t ?��iJM(e !!,principal axk:�A6���horizo֭a�v�cU "rizhn�6�c,�^un�Yr� �seme% .�.�&h ��< la&��F��i%E�4&Mz&� B�w B� �r#a‹*o%�2�0I"si>�+2���&Lg �8�6b�K��G $ago�!r:� �hra�0Aconne5=k!/�B Q�_%�;&c0a��tic& �[h�compu� U=num\��J40.�'* MgB� 2AF �� A:mA�d�maximum 213b �!Q��.�Xeʁh ) ByO�iso�m��C)�*� Ea�x� ot drop����� vu�o�i�2\C� 6I_�pYJ~�.q2�) 9art: a�y"� ���+�i Y�vI>dr=W)�a��eem90�IX.� & � �)mZm^Ɨ¥^DO!!A�9P is[�*)��s��Qa�� �rA�WE,�so �U��w��r�mQ en*�BR fi�t>o. I)R��r�TP=6�, ,��rpS/8|N&e.�\*l* %�~_A�;5ye�Y,�B[%�a$o��R &�pJT&� �"Q =��N�d�%t���[2gr&�=Bto.:��)�j q�a{�j[1�|B�a/0 ,"c�CmuE�� !or ��*6�'.�^ z���!�.-8z/"� ���,&uvanishC8ym��4n0��]!�G�;:� N� >���f�$ed ��C‘rapidm� !�/�?m]�ot�)���2K� �r.&g��E�t. �� mas\G� �g;��"��E�{E(�tQ a�U=�aђ*�/R~< �ng!hEp0 . 01� �O(��.�M]re��R%qb��"�T ��6 ime scale��+]f milli ��!OZ<%�I-�".l4)S g�^2]=���F]��Pst�lFI��*� �'!��p e"D<��s6Z p5ށIA����"��fa`DO2� ͬI@? .*&�/-��9J &�!hqn������"0� �Pch2�!b.zqC�3$je2�g��� a �m�a `�@�8E�208 ���� e:ow��a�|�9AsAg%\�3�D�iS�ZP B�M{md:�U��u�2�d8� � , naIq,�Vא�l-)�)�} a�" 6A2� �z)<oJ!��9littleB�#�/.��M��O?�9����|��a�w���u ���>A�V=""�,��B���Jke!�B !��%Qy O!��<& )� 7�eD�l3)r��.  , si� !wabsolu�T@]�oB�W�!(; 4�>�: �I�2� ae�},���� by)��&�����R�}CeN �;x;!����a�o ��vT8K����edp2:a*@ru� a Gauss4c*$x�R��!]^+$f@.�d� �2� !a�vi  ly)�z,�'2%"3A olid�vA�-��)"�=� p%�#%$� bQ��Yp "g.6�!���aIus�O� ��r�/�:�;a �w!6e�e9�=���}Q� �j!T%'5ia��arg�t1!w ��G ��I�.m�:f %@T?o!��A deca"�b�B�"�<sharpnePC�3W n��p�\8 . B�d"#� or ,|^�Jz(�p.[ �+! *l-�& V��)8i�=�!�u��F�*� !��J��q!�Eq��eja�Bzer�oe�g ҡ�?��6�� rf �k-���@�gCiOz9 ���)#G )n��i 儩�x85(��-��!��vB- . F" �A���./ �]4�xge� Ae)��~aC,��n `H��P��a�'F��n;fll-F�.3F6� �_mU{��"�� .*FarbitrC!7 ���1o��K�_���Ei  e�u��#%��@�a "�B1zA �)v�_=m!f� ^�D' :!N&�A�*3��� llel!inf���� ���aFF�s����geoo!�0f�!��$;� E� r>!�'X6r&%n�6A�ang���g*� JU*� li�:.se�<x"$ ina�2"V�%�B}/���$�n�� bh\e;ZInn �� vG�.sR �+"�1}d�1� IQ��es�.k2.�#,icuI�hu�t 1)g�  X '*� E1}I's%�A��B�C$������l.�'��SD}~'e��1pyp"�w� o/Ng��x sis:AlAQ� A��%Px��o TeatP0&E��o�"c[� "�6�*�wh62!�E�c$ � <9�I��legit� �3/~ao�9�oa~J��=� �z5�&� se�q)Ea�eu!�d�s%i �e�R�?���  z ��"V*�.6�L� �v�=a'7*10��M6&9�B�"�M��PV pgH#�$�J2+U��M"�!-9{o.�9B,a�random����& lyEy��]U&i&E'JIxJ"X�*� .en�&>0F,&E�f*�@��a��)t��V�%��Z�OF��^2�;��.�. �q�,+2���? ��#�aYf[�"�:�&� 9�Fa�)�(*��c�w:�~px � urf9on���.�rFle\ y7A��N�@��j!I&f>:Lv ?(�6n�A�2�i.�7�,��gA~:uR0�T���2�-i]4�Q �&��A.� �F��6�%� . ��BC@wˢ� �M�4Cx[ O)��.5�/E s alay���� �46*B]Veb"�P�. ��dT�eZ� *�� s�u��DKs�REt%��lAc��A�q� "�Z<&�6e!�a�m+!7/"R�a#:�C��� .EWa�R ur9I��H�s�2�4bw�1a�a�1�!�qW��t��'�J$I�A�9a� t��b�D��rs.�Ne~*O!f!7.ZbD!7m9���m���/���;�HFW&-*./KG� 5>V��te&�!-"�"�6�- =��n�H��I� 6�E6z!�1�E�**t�d iA�gzi"12/wXn� �A��lj!�1 �B�w A+jA��&;�#&�!%�x��:V�)E��r@yk"� &- shapY�.� s���"s i �, 1 m0�A�on�R �y����- 9%��0�S^!yB&% �oL�d&��!WM���.� s���-ed-\^�(��NE���9���� ctqcVv,� %^��Uff�off** %�I�� �q��'6.��@� ( Y���B���!�(��<�[to86 6]&�pAHF-��. �#{ i<wid&Ui^&e�f*?{ M|U@� "6S8� H.oL% �*;�%�M�� �hrE��b'2����!e��2�,!L( �b(�"^�"?� 9o��!�(/�im �,1�d)!satisfia� nd _J6_%^_�Y;s2!�o�f  a�pa���y=%�%��*CR�rkL�:�:œ!�!ed-��Pu e�O �`�J�#��rosU�&� � �I��Aia p1 achi�\*,�!��E�-�d"� �'>j&>��M� .�s2�<8�x7���� y r5@&, by����!��*CG� ��mY-���rel"�Q.�� $( �Q �AkCUA7*�$i�� �L tilt-Hpar&vRwWe?���sel�^h'&A;&�8�ev \�x n2�5iQ‘�Z � &a�6fE�!�fSfa�%� elax��inLy�b�y%"/8�lBu6�����>�?�� na2�>�B>G��c�]@S �5o�:9uF� �N 5�Kdo� �it�>r � sophA `A6 _��f!�ek�!R�.i�A1�C ����Hin�n�!����)A+�!b�&]G_9=�/�)i�G:, >�^�&)�"L!M#F�A�d ar4]z| ���;�?����yM�rg�eUse��SG�i7ij�!�rQ<a:"d9I�$l /�8 ى�ig�[ �*ykr!e. VDbde��a�7��s)��;��p8�A�)?^ !�1G��%1 �wore B�^-Z|��al �&�%%�E �!Q*�B1��N1, �ťU'�4�a����62�o6�'�J:^�fi:,% � a�bf�6�R&L)f`� keep% hem &�!%Aa&�� ��� ��$( !�D easy!K�+�Fe�Kh�r �%�m"1�j!��j'a�ŀ�cr)O!d�0`e2- MF  M9E�y�ki>�A�!A�"�(� �� *Va.bx( �.e&XQN��vs �c�6� %�*Z>�h6�6"�6(7�0���5�3A��r�bLX�J�� -�I)oot/1oU!�pe��-�.�Rff,$�LBy""ڰb)Qp *V&]!�$�7e��"�F�/ar���"� �b�) �!0yq�5!�eŅ�m�b�tW,.6��!��}��a�-#d!�� y�A53�%5.�W� l ?6Y�QZe�2�1 b�?���th�* &�%�t:b �ny hus�1a&� | .q>5hA�T c&/*�Q�9"{'� � !3�E� �&SjA&Ue %% n� �&�6E?7�_��A.�"",>�0�'�N� 5 �� pr��< �C Z#Z'D  :"2%�arb6�&�l��W noI�E��' , sa�+J �t�qJ(�)m�.�"�9Afr/d��a *:u�Å]y u��hsqu�{wJQ�"� quad��N�G%�e��vr0X=�1 �nD́��AkA�: -x.)�R �/sZ ���0' c-����:R6�.�Ko4gFi�s5B*;��E�"�Pae� ��!mmo��%��6P"A&�<a"�a�B8A}�� t�� �%b�<rzv%��,-.�z�- "�T}B���Cɛ�D3�.,M�eal�&o�y3"�z9B!5a�&�$*c!�}�q�wA�.�U�A�A � a�L�;|&ŋ��X�Et Qhlu<mZ{*�%%�Pu ���{"u�fi����78V���e����wi ��.�-����!65~sX3%���Y�G>�Cun.�#-� �f���A�"pAt"Ap!09��5� e�$F�d:E<�)faithfu� en� � �E�\&u����� �g&���5�< �%T����m&21j�nu/��'xaHz�bMq^uK�"�t$J�1�&W�&p"=w* y'er.�4 2�#*�de� �Aa�����<z�now��ejhe **�D��i&3.$AK�B� L�� B�)A�`���T��f�Q��a�.Z��gHc{4E�|*v! !E#J�,!��Fi�D&�@l%�� �S;/��E��h�> op�F\�q���:@ �m�})�[%R"-�FB �� x A����0M�df< %qv: ]��-�a -*I boxa�lo�;!Ba��. And sA�ng2�s� :! �cߝ��A&��))����>�<�!�� t�<�'2�6 ]�����.b%-� fasl�ArN�"ntup1 �s 9�C� cucEz)$x-�4pack melons of�� a comparable volume , because a greater amount of empty space is wasted in the case of spherical objects such as melons , and indeed we find here that a greater number of correlated distributions , as �ed toWpendent >+,can be packe� ����B����R>I NoleI� error rata�@, scales differen!%1model AGm�i!�A���AQ�edEϡEIn orderafocusA tEhcalA�behaviorI� defiE e ‘5Mper��’ ,�� y analogy[!!inform�i!�veyI� each =�a.Xof[��lyA4$erministic 2 �`6��$has access����G p�InA�atMAde ��1�%bpe� reliabilAA. E�co�s bit�.�. Cmqu)��,=HJE� ( 13 ) ItA�a measurE`�Dmutual ( Shannon )2s9�!S1= Mlim �$very small�VoaWla�7Bof.GversusZ���i���on�to ask w!p^3,! ��]$, maximize�E3�� . Equival=`��h��siziFK"%Ca]b%�y:B ,%%optimal9ʩ�s when:�dtr��� fact so �m�#��!��a^is!#)�aE�'A�!�cho�.�0�E-w� x�5]L�4� i�q nA( 14 )�c ( 15E�9. R�a�"H~;>� �K.b�becomesA�Q�at low-�Q thresholdA� whil�/e6��&0remains fixed�i-�of� same�C!�G<.�:ly�<le1BU~DEbThu�>�low�Il^!P henc��Y� =�exceed�� �C d��quant��i�}2L�/b�tha&A�or�. By s arison] na� ten finds�ousH sy�s few� (other studiŝW� pu�rt��� pict�. For a%Ya2� to � eac  se��p���� willm�as much2�as if-e!|*� . I 2�sA[y upo ��J- chAtR�!�ec��at&� *� resemb� tho�ist�iourF -jfpin dataam��,*hyp�� sis predi@%�subse)~similE�tuned%jFH exhi2 weaker�^2Yt�=�WJ�Z"� E$iV �!JIf�V!Z/a%�! �[Aus clas�Y toA�rec�d �7A�!(��i�vi8�e�oup^ cell�at fir�!/ l"H firs� uddE�resMf;second �u-� 7� � �� ep�alway�����aiY �M6t� as�+edQex�a��would"�i�ifyF,M�=6,bEga�2�toE�o�rn ar � -in ��sC �ingrequi����8 �involvahH in!�heavy� eFpro\��A�steada-n�" n search � }#����)�er.�V 5gA0E(n1.UtC��� is �lit4䭌propo0+—)�e%��^app!Icger-intui%s} I�ing) seve��tene�I'e���w[ &� &c�K,an�*ausr-N�nota{fea�.}��exi�cfas= Fgq G inst1.�ca�u�Ior�Mp suma�its�)wisk ���ll=�!šBr)� minu!� J2.& [��us-�RE9 isɑ!V rank� A���T  m�u!�E�el�ng.6-{!M addi�B)2��$made itera!�� star��� �AO e�b��n���d=  | . O� aAˉ3ieaYa quick�l essma��rol�ߝ ��ue�aA�g�%' �J7Wca�e�.q@Ga�pproxi�( Eq . )�Asd�s� 2%3ea2@� lyAluq" e!�!+% f&�-�,-.$um entropy�� -� carr!L� o eA]hZ discrimin�5ak!�ɳc�-tru�perItally�e2.�Windic��4%e hom� Ba�� qu��cl���� �%,, but|� !�!� upOo�f �E��manner�z-So� g�]%&r 9�to�p-m]�in 0physiological.?. � show� at ap�"�os��.�tO ' �{�alter!�ve>�t7�OE�AE� qdea�t s am�$ ��be6c� was!�ed  ier: �6 w , h�",E� emon��A�m� &A+>� q"2  R2—ձ� � magnitLra�L�: ���a"�. Fur'm�,��is gen!� �doe�m un&Ir%�=Y} *#[ :A�!�opeE�� , d RIb ��!x6�9�C �������as�!��>3.)I$�ssAeidQ�!�A$occur+��m�(n1 ol"� to ����& � !�[���&��=9�, situ� i�M]�.� ��( faila~mplet� � ��y�=�s%�bo�dra�Mc�QA�"�Xi%1�a3 .�A~.�1� A;be.�ed �&k5%5E 6��ForR� nmea�r�$A�E��]�inz�mus!����t�al�cunt!�a��&"qf �.?�a&��kot harn- by.�& ntr?�<�qV *�,1�U�6�!rdMVl�!r {",z!(� P�^it!���uefficie"� U#'��s%� . . A&c* ,^�]8 ictlN�(ay2Q ����) ; i�mi7 ,2x:} K�ns6FW� ia�e�f!. )�pofjlibr� n�!Au�i�-C�  A�e�i_i�&� n]�t`��Aru� �8��schl��Ye2 &n .]–��we��u�Ew plau~ `a* �m� �  beneA�a� dapt�Na make� !?; mechanism�2no{ aG�M-g-{, �!a"Bto�� d of!KB ��M]Ku�,�!�al!�q+���#Z� cou�? 2 ld� play!Se�2�� �eofRi. H�"�-�= col� �$henome>�$&U �!^di��� n-toJ9m%��ŝ6�!jV, f$ � �9.V��4ŃFi� 66fdaVigadvantag= 6� seemEt�#��n �CLV �T-c �i�3%� *Rin%�"� ac)$[31] , [3744]I�ref� =�"_��.< -5N� �neglig�' � 2Na)|6U} a1>n' p� n�y�b>1"� �Hprincipl_s equal-z�:e����!�t�vy5 e7���at|'�� ' hb�Si}‘" -i(ncde�3[45!�FinE�,uF"<�"alyͷalBee aims� uncove+ &6p�'.�u7� W��q�%T!ՃQe79�s XaiB��O.��a�F�!��*k i��� t��loL*f(�e.�h �m01 �copic.�d%���6 sub-.�)��ch)A�m,�)v won�%& nu��miZ�JN�0how��� Cp&,*-1�&�� be�a2w� 4oP#(�!G��rob��)�� twts Tm����^1�� p�L,r]��is.�h��$I�V&Win #F�!/ embo� D2� of�$ um mV  betw��P�1��2"�=�"6Y&#.(2�)��1De; �. ecu -ui�mi�!bi�6��.Nu�, .� �se�O &,.�. HowZ��&� h systx ac*�!ng J" �� �." ��� non-�V.�—�#�*�Vn�maie-d�� d�:C�,�%lap�dB[Ņf;&,��',q�!"G�llt� marg��&�}G.�!q)�� exam��:�aam c5be�zi@��* e#�2�!�iZN&� ��� )��%ap&+on[-Q��Q�e��� I3He2Aڹq��Y�Inulua�.L� 1"�)t b�� p vid�)2��R�( �e��*i���o� radd0,�/&!B�0� ^g2� � b�v push�~� ir):�g}�,2�=�6\���"A��"n�.l�#�any g!��b)�nsi(ng}��=%"E�) ��)Z�Ͱtw�/ɹ�=l}A� a(���a��4(��e�AwabNI}6ou.��(ll �*K�$—U�/Ze!b}�!�x�%*�� 6j�6?>&1 spaculin,"�0��( redug2? ul�%��  !5ia�W/d&� 54] ::&- full:� (S5��-�$qu�oeБ�$H as�whe( for"'.�2M3&�2} �2+v��l�*. A.Cat�1�Le�l��s ��s�� Z�!l;� �8*�A>=�� r���%�u�@ng� *� � do  b� [�-�%�C�&D si�RA6�robust���gU� K� %"� _(rapid fall-�-�r2�# ^��poi; �B"U<w�) abov� n)$to�.extw aWx=.��bC(�.'in�O)�E��c,5?�m�B  � ��+b�of. b^��Q!��6�To �,]b�pimpor�=@). F�#�/n_�&-?a� om����R-I2!� o(5 already;!*l!no� �2�S$��a�� 2?2� =�,� sQ��' f��MRu8Bpro%�(A�e�$udy!�!�J�� fun�Uof��!A thD � 1��Y�T.�i�l.9�Rer5a&i��X!� turb �!�*$e9���"Y^ i �%wch� maj�4� m issu�i1y��$�6�%Q%|�^�~o���i>� ng%. per�.� �K!L^)A�nd.h�os�%n-a�"�9��!�&B%6�or�bi2-6 ("�teaual fi��� �ar transwQB synapN5w�8tetc�1rA %swpu�v�ua��a�%ŷ�are4)Ul3t-@ � �-to know 4�&.�!ǡ?M {A�I�9 �� �+mPans{��is��cer�plV e�y(a x_�T*�Ed�o�a�tnar,m��a�&o�5w� asQ5 ator.4'wor2"i�%N�c �v�,���t� .@=ahat� mh��U NkS �-omY rY8be su*g��g� "1,BS21��# uildi1.s.Yv53�3�B^�H(�s&E�)%ha�>A�8&$ =-�,;�;s�� ne�(ari�3J(N/��� &�'theorete�s�2��ex�7?�:u��0�9*RO&� �doc *n����=3 �ws [25�26 �28 930 �2 3 4  F3 F3 F3 F4 F4 F42kI&�?�(����2#%2t#V�A�det�%Az�ZG"ten5�@uc,+_?A��:e a��W %� reby"� �"z)�%� *� .D# � le((� T($S1 , Suppl��`ѯone�"== argu�y�:�VEvP�:��be ei�_unf"k'or*�vM)�M2�Put�� b�eXcal-X"�!�v6Q:w � "y;v$a)J ( �/',,"�, Ah� Acurve12U4 � 010a�? �no+��>mS"`!��i=7�O:)a� stru7>29��%F �"Nuni�ZKգ}neg+.�� nti-�cA�Bi��e6��5E�relde-Q_�B�Q�6�2o(BreV$I7wA!8c+exclu�%l�2A�I$us-.�$>�cO �'� ,V7V�. E"�&� "� e"6 bothVWI4us-&�=T, )r�ZS,"�(2�A5R3a*�b�� �Z�N�Ͱ9M� ��&�(ճ2�4�{�f:�6�.�"�3�[U���r��^�sh�10 ��h&�Q�=!�Tgici�!�"mea!� ���%p� u�i�CR(� "c(�ei�.�$." ���4�+lq2��#*' i�- . 1BI�ei]ta5/2f$A\y YArsa�i&�m/ٴ:�5�F�\� s�(�_� ]establi&�<5 routea��9l0�<The�.���O>���9!�a8A� ��� *�ID�or�1!X\-A#s�g&:E�&zQB[� 6� 9� ��5>b�>wr�&Y��o�<�e_di$/* ntri7J�fz���diOGA6�!Q�zp� ehAq0���I-.�%�eri��ŏ��=�.�$4%�la01!$A Y��Ah� o�Koy|%s;A$me-eyE�A���apply�m &� �A�'DLo��� �m�-�+d5. S�8��/ ��0%�!7%��e Fa8F+ �V�AY, .�, oY@�3�1i���Fe1h!�.�:�continu�$s�-�Mw,�w�D i'!10�broad  pr&� nd3$ �#�.{�I.F �(e�Fcay�!."�  h� . PRWc;�I/�>2��ㅑ>+tt��  ��orI�a� monotonic�fdcK/A1���>�:KilvGq���!�UM�<th]-.�� �.lNk#!�!��"�%b�Bde7mQ-�t�5s6oO.we��(�se6�a�� �eJNz.s"� ����d ELd+a4 qADr� �i�a%�A!|+!���Hle A���y&2N J�>#o�PJ� �0���P!�K%��.[ �%�$ u%Ta8-in�d�Krov�Ma���!i��20�u*�2��"`5we.1� �%AWA*in;> 40h.�.EqA�( uNk�+.�/>�T �'�]�-`2v�kf�bAX&-?V�to�y!�h gE�GF�"�qAA]&�*��!8]>1�� �O �CyPr2s!��7g:fewa m �FhundrhGG&��& 5��,te�>�IK/ly.y�cZ:Ref . ��a8A?ci��} �&�F'$�2%*.�F���aW:M3oAo,�3��9]&ndA-.�re��&4C�#��!�J+z��!d ed%�AU-�.�&=���/f#�� m�� Y se9�]���/ye�o"� ��M`.�M�)� an t�/pl�U� ��� �tXd !�!�w\ �T [.�&du�PO:�6 typT1Q.�9 -O wz(�C;#e�O6;�FL b��I� 8am!��5�#� --%!Jr)U"�,s� �.ND!O/% .=>-"~"!�����C�]S!��E-i�QuionU#us�!set�B �.�1F� B))"*Y0.� (*�-�2� )%d�.;3kB`/.�-*k$.mZ��#ŞA6#..�Ea� &iyaCur2I1.�i�=�סPnew9��G!mod! s82�r-g�+A A�a&9 �V!�=ω�)�.� is sto�� (,!��"1�rNeQ=,�g�>�R.�9j ��u!��3,�4W" ledg��hte _+Y!L4im��vi1�Tz�A"�V�%šv�r&%!h*� `E!M�.�.|f]es �#‘��o�6(�c�Zb�#�'5�Fv5SwD�)��2�(��H@*�W[4544�W � zR��d�� ppl� � J<�-!9� ��p&VA�1�}@��ya� � g�MA�)�F?.YV�Jz � Z�"� B�e�Z.0� ecia2O�a�oj[50%W�&�6�Xat odds�O!+� ~ �nFAN ]Ss �rIS4�usVce >�� �2�Am"�$Mȑ�E@!�  prev�4&$�?i.,2!�I�}�M�� .]��N����3 l�A�Y� edb ul@SL��Sh�,�� �6NV�(-l�2B!�y as%|1�6-xRI�-A��U .� ]�by/��"/o� CD�d�l'Z�.�5  .��� erT" �4�_�Ik� ���!/d jU� 1 �x"h � Qa�2��:�)S�K$;&weCi�[Z_�q�MZ2��6v�Bcto$A؅u�� !;2H&/�]J-9��-)>ut�'e`w� �����ar�BV@a�!�A�erD��n termp*�*�"�7"Cma�VC.�^/s ?& �r�"unbia���m�#m6F� � KE�]b�.��BCF� e� ly lS>�: [51�4�")��p a& %CvI;&^"��i)�!��@�/u�d[���0Laaa1�@so a�F5w%I w ��J%aA( ( A rigor� k;S&�+E"?%]w!8.3 �"�5�"53!;)E".�mvR�.�!�t��!�9O��in%;z 1_!<q�f nd�H&+Kc ��-( 1�8A�( 18 )��( 19 )�1!�%'�$%��pqG.&J|<7u&�..5�*�_s rmulæ�"J�"!�!Jf�3by�� b��O�|��s sugge �N%,�uv-a�"Fc���.���Q�3er�� %�;�Y��5.]�d�A�A��m or���( ^8��H �.�*l6cY"�C�[i"i�!�}2A*F0��~( ,;> e�HAi���"E1Q=N�a G[#v!,�* �>�ZIn!ef��%`#F�? spK � �W � � ��)�( T6 �=�o�G"�bbeN=. H� B%M,!��-d  LI�W�r. @LZ� ��aZ)�:� W���5-�+d1 ��I�!�yD�P�!��/a�u ,� �H:dc)z"�.� *�c+�i6\R�60�,)H�<��i�J�� �<�e&m�c����Y&�#1r:N�S� �=� PC=$"#!� !B>��.�def�3D���Q�� A!% Ify� ep� A5of.r��iX=- BKW� �iN%��em�!�1W=!< A#3&4OA��@1=� ���"n<��!�Z�%�B���M$Gk�0c�-m�O, langua#�ab�=Xought:�; qO gori�P �0!�� si4�org�5m�8 ef4�cha�erQbM�.\&N gr�� � fJ-. M��mi/ onali�s�HcC/rk dev�to netH.& i��WfrM"�K� �r)va�Cnf!�ome�/�2g��BNst�<-i�F��P � #)rs�~JdQ.� f!��QF�EIr M_U=q�|�UN�N�}OG [!��_dthIH�Mac�3c�+�BY�n�e�0'A�mia�m�.�ZY��.�wF��cF!ȁ�&25.&�+:cC2"KQ�ZILawait@ �Q~f�Y��� ��5,b/R�U !s�6wRV .y��Z+K. P�,2�<��W&�Z��/�Yst- m un�-"^&xWB�cmai�1n"�&3��rim�,vi�cortex)��2MTN!z� �1  orTL% ].Em%��FK !,  �6�2�'�Yre��AE#��&7&hi�MA�e�qF"�$�6&�� �RjjDy �2oo\*RM�%%f"�-Kc�z. Rom��4lleag�m�"�ɚ _6�GS2-�:�p f�S!�)�irI�(�A 95G,� R+S!��op3rec�g#s [�0͘-_�]�-��E *�-�"bf�:n � t f �� !acth#�~Iz$. Maynard ��iM�ly- E_m l incorpo��!�Y�=e}m���?��_� � !�2|� � &c?upA#16�0  M1 dur![; ��ng�� [5 J��=[s e��/A�"Y |>v_ciE^-p�Vdef)�[W2B�UjCo���NewE���� MT6 wuby=�")bA�F"s�(��^erY��=��:� 5 �s*^q63Q�Zy~�oJ�+"6[�![5�IIa�eW!�&�4�q Poor�$d Roelfsem[7�V1+F�� m Q�V1M�`Y��Vmbr��6�#�(�"�-P �<[m�m G[56&�JGutnisk�n0d Dragoi [57]:�af�%r;>( 400 m�m&�O!X�I ic gyL�hB�\6v2�4�:� d�=' 6�� B:pՁs B1a tren�5.���a�p-:A����Z�.*~Gwe��i8o]�J�v`nr�Vdropp{%�=w& � �)fi�k7 �h&�9Ő�-zeraJ%{e�-!���.�� A�5xt��edi>�1*Y S4"BS��h2?]g n"nm6�hdec�X��by��E� "��2 2&�0 Xt "�@is:!�C a�;IGad-a.Aj�0 ircuasJT�9_.X!ai!R����v��.�?qF%�� aI"����, �\�,p ��Cl ^ *8-��h#SEkaE�1-k* -a b&L i{>�)� ncep�< $eF.;;we don'tD$� xNab!p!SU t�  1�\�-Eings archite"�5�@%�5��&Z 2.>&�,Ay=�� ,�= �e).�B��iZ� �/�  �)E8d:D�u. >�.N! � ��� kin#1A�grand-mͪel�T �lk �i�m(1lay�\2L W�Am5F�U�)lya$ trivi!% �$[�J��*� %La!iI,��1aCw%aA�-U vH�A�An># 9�} � mot�z�-% (E��+ ��"h0�e�t� �8!��bas�-w;&'; �L%zy�$�*a$�� dida3�ÍkU�"�.M"\'C���i!8w)%Ser)�a�� 6y)q-�&�C5!��[�ar� �&fL >�� %�K �* >��%)(sevs�sym�p& "(� 9c%h���yAP"s�&A�e��O'�A�$P�&c-;'}*��^|�( 20 )� and���a����+&�8e:� iZa!v/ Y � 3]�Ead ��&bM��E�% Uu�Xs5x8�j(�]$`."�}���)&bi�K��{�ife6"G #G��C""|�gdJ�b��!ve��suniquaz"gc�m$:in^Vi�31�satisq.Qn �� ��" *)�p�aUeAA��s�.qmin 8��7 �?�ytAt� r�r6DWP5a�)D+n���ly��i�>Va exc�4or in�min"t\eIlS 2E� summ� onfEly9Sq� ��m)�����s� gthE��E�nlE�!�pe�!*m(*b#6.basF �>M�2Cu�&�a���E�A���RAm&$ ~�s w]�d �l�3r?ald��it '&�g��e�s&�s#EB�.!B��%Oe}� �!W*5,rI�pbSA�‘"m�a�(��"�J��0 osenM@B�A�a$1dA���:�Q}a�� `�R%eRU.�x�$ S�_�6i4�{g �Kiy�I�As�F�q6Lr�6ʼn@A1c�F��r��=�'� <�ofY6.J�Qwe*L �-.���G~+�z� ,Q@m:C�=(��G�j(�* ��2&L�M�� #ohx� !�j J��8�4/"'*?J)}�]J�"�L�? Y�DQ��"\\��6m�maXA�l�9��ird/e &�t$ C�a%H� U/�Q�a�Nu �pe�q P�a?�_�i:�^��ub-div%�e�%&�, n}.�farr�q�:�2��Jzbe U�� � �uA�Fourti5�fi*�L%%�m!Y&g�=6�2�f.�2�)�aq�to��+�SAN%Q��c�ocq��K� &K ��Am' )�uX& �[�w>l.�2�bst�T��&qb�]9Rm.� i�܁��!�9FaX\too�eJENday�� �3�&YG�H%�a )E�-8�tic"8�`(psychZcA&OF% tina���en�΅ �mHr� nJsuc7JR2LGb��A�$accadic ey� �8V6%� �+%$belf—i��%orm^'�Z�_�T��. O?=S! seek1�gn�!| ��2a t< 1�(��?�ue0�'��hTy͎ �*�(��^#":ZweMLws�MC �a f{d's�(z#�]spa. loc|n �Q I�j�fa�perso�facZ1j(f�_�F myri�AoB}hw����mis�#�]6�. A�Oln" >^i��W~*�n�'R!���a��~2%zak"et� anglP<2�ny hum�j)s�)}q^��I|�Lna8@[a!�6<eY 4r�be&� w��!Qe.I�)wo�!E�:!n fals�Ka&, A��erWornp.s�5 �:��'=l�KnK"�-:+!��t{Z� �@zY�x ��,r�% 8 occa��(��tf�tp"�vy��n:w a snS8�/�U �effortp?fek-�K�+voi��them ?�d!�)�bewil�+nD(IfA�p{�Ua;."� vm�F' � leve4as2�|&IE2�hze�#5CQQC!%c �. Imag�ZO tc�� on ya� hoteX\�'ic�p*r!I�%r�2��."s(�MDcei�,Z)E�D���ct�bprompt�1�!�s!�L�?te�X$, let us i ���/p�� 9Lz��V i�wa�(fbO!�aQ'�9�,0 . 01 radia� 9��9�� ���"�C1$�}you< -- �A�n���SP�mq5�%�pT�"�R a� �- kor� �%G sE"a��K��l.�2s)3sI i7Pn2���If�MA�� ��QP�w�sa;a1| illinZ}by �%�1�yer�4J . NoXtif � �ÅAssa�6P2 �I�na)XBj�f� �%�,�E901—WE� �%� fdof�iW$h �Ont�A/ g ive%vir�)�s�!!xwe �'!5 YM'cau!'��~ � K-!K#E lWly�  * fove`Ig.F � s�! yBs �&s ��p�  �a!�c%�f�A�c. "U-!e�d1:'"1&Ѯ*�ish!�cosy)o�}�T�V}*t�,azR�e���>)M��#m:!o& ���. � N&E%)(m�ay� D4���nsoډ igna �+�!5b�xYt �~th�v.}resolE�%nk der-�< he-whWlem�N(*ng!u�\ room_ll�do MT�Y�g< cF�O �%b�U!�= ȁMAlP� �a���g"Oiinflu!>@�Tpr��!Wc!�p3) via5�&�3%�A�d:l�N�G!�5�i saiR�"}Z.��zF�U�Zde�_�E'_xQVJ!%ir���"r view!t�� j� �Ui�6�toq ur�e. Rely;]����y�,z:&* �CndO �"I)doZBo*fDa#P!|� g��>*f��,C�g& Jn&� M^Aws�[c��1�O��.�B��6� o]��� jhA�it] s�/to! l asleep! v4chB�����;� 0e���8i��"��7.m!`�BinJ\!W!=�d!n . An�coursx�6� �rec�E�QX�to ɨA��[E�a�!�* ��U n&S ��d� �to�>@ � ow�s �7haj�x�R"�3fim�s����a luxur]&.��t�ry%�if���� o � a>��(�!��A�6=~�n�*=�!hei�p&�cLAC��� *�5 �)U2� * i&�q��l)�p� K� ist:V�a�F�. Bld.� �Zrai�%�)�A� ����a!�.��gu�Gt+rat!�_Zj��2H9��cN+i� 3set+,�t�L;���L �@��tA�6bF2 ��#"lM=a��!�brrected:%� �9Qcda��al�N window�2(� �-�t&�* � ./�ish,r�(z��#!��3 m#�Y�,Z,E>� o�Ull ����ou�DaE 1e���It��H"4o!�� �,�� B"��sh *%�-a��4�l�sumA�"@!�2<�� mbal�)B�~�, (i�* �i.�B�g � a�yin fuV . B�R(�#u��6 onen �.�y�� �N)Kd � 7EG!J2��1Vќa32�u�"mVf"�/�O!5%{!����i*9�! F����-�#�OF missU�� 0%!�& r�o�_L-!�.� 5� �B��kl"�)� z %)�to 0001f��a�.;<of 85�"A� e obDc#��Aέ��#uR�,QL5��C�� worl���n� � lowl�(�)rr�XiNo� �Q�EY3�dex{nd�܎e��f ~ *�_. "F��\m�I��q��#!�ZU&��]��/)Z4I37A�; �ig�p<�eo r ]":Q�PV�i� I�/�q9��{ ('Qw,h�0I7reea�Aba�an . Ch)T �TKU�3�2{—!#JW—)ir� "� � rega �euB#_2 a0E|E<is*S"C��%>����XAGe$�s) ssoci%-�t%�����<x�!qesA{rV>ubo��<�&r�!O�-�,�+�)�O warn#�r�Z? iP to T��%嗑�@7At>%��� w%r w"��Di��c�0ecr��| �bjectM/�!R�di�Iz7�*�environ/ %� /.�K�����ub�8��S� t un#��."��Sw y�!��xdrawbah�at� ra� � &�?��Ee���_5Q+ A@ngq�>inu�up�*��r�7"�&tf��*"B:�a�����o �1�5s Bayesj�&(=�M w"# �[�d,�>Bq'2-��m��24at!{��,"> 4!)S�:9�> $�i0u|Ů-�u��GiC� �&t�RW�s@� ~��of un!]� l.�� help!�ver(���igh F6��9���{�metE����}�� 2�2yIy�<�-"Q�� >�>c}Zkla<�[to��!��y!�!�i�iU �mad�DM�og5�<���<�E�)m�� {��)!d�!A$B���� J� �e��kA�E. "la�co�rq�B���nga�r��L��IIffac�!C� !�ͯ�����`*WY��&d%�9#� 2G�iv� �a�r�;�3d;� ���9��n.� )��;Y� ' M L&?Ŷ�"!!  f . *GT"�> �Rs p�talpAthm em��oA�!)��L"�J$"�5�3�Fonb�� � iPr|�����ihood�un�EY5�miT��I% �&V���KICFs �At�&!,A� "��d�? B��rFa� n�E�&���'[���I",8`� AJ"*A!� I�!uk!}�#� �V.�=Y� � �a),#�2 �&E�n , ,( 21w� #y��E�^K_<:z(�  !m8� u*�ed� .f[�>��� ��2�� �B�c] ~]�\+��`�TumN� 2%���erm!� ^U�;:�CRea2�m� \%R�Ruun��A�a�A`�c%R/i[�C �H1�",H-��!:}ˣ K!����J�Q2Dm���BBi��S�PD9phiEjy�#6l Hq8suQ�O�%�XFCI��?a�� d' U?ar� �o "up�'�a�eHA�^� {UQ�X)��*�,!� ( 24�]( 2ʄ� labU@� ���m r�+��9@erb%" P�� ����G!��&�X� '+& M$`cf:�}!��0m�i��g>|aF�>��� & 5% H7"� 5 =Nt:�%A=In�82�~@ we� VUO�wsLJk  ��+&��(v�� rwA!�"4A<to 2�"�27n&��[ %�e��I��r"T��ŋ�K- 5!M"N �o1p�$!�� k( 2fR( 2QW/ cuM�a-��@\��N�I�`e�� �9u6�in��k� �7��L :� d�!��Fd2�Jbe�{b��ll|�!!���&6� inM46 �0�Jbi=]�‘*��p ��;����Y f�=�S2RRG&։G�Ll�5�"h&�J�EskW�!<��*g is ;:+7AC.�5t=ur�,55�ilA��l�a)>��Le�6�.�k�eA�:=n��=eSw.]*n_!��8R��r���+�|2b��6�W!?to ( 3g( 3&�"� YI �i �=�! �z4�v�2A�I3�=�5�J�;�?4ty~f� e( A`)�numJ)L3#] begi:Evp*2:A��!2w�mo���� �(q���>)A�! �N2���=�us�] �`V?e��b'6����aN.iF� !�� )�( 3� � or (* �l�B 75{��"� ����X�>�C/&s�]�},� vaWG0��*�!�v6 +Z4.�mJ �%/A�̆�a&��f,�X�6wf.����;���nfp2�)9"ef:p&v=�>]JE�r&Y�#&��SeT��>�*ΉQ��o�5A�AA ���1a�7d 8���1�E�4AwJ�s��s �: A��z���T:� borrow* h!�25=T�`i���s�* B'!kA0 ��=e*�Y/:U&[ VYsw��Y0ma�: 2o�ѥ$���=1.P. ) A�F.�r[J"���)Ya+2Og:Nwh dqJ��_o&57:)v��F� :+`*8A���> !��\l��S&�rp"�sorqum�� !ne��%c&<4�� (r$exact�no��*r�ݤ�C�X_7' ><7&��,&|6�{"`�jl�8^�e V��q�DomSe(�ed�F m!f& >9 � n&-^ }XeQ0��x�r�f.$tz��p"� ��M evaq�m�Am�n  miɬ,)����� BE�� *�J��+�.):�lso a��0 ��ti&�-M9��s h��6"y�)� matc-�>-!>�andJdev �A@,Isu� �(��A^ori�� E�/�!G�9Պ'Z4�>uv=��*�S3 n>-Y?�V='.��24d&�"�2@ *�  I�o�d�F6EaG�g"M*-y�V�f��3�B*�#�� �U1% (��.c `5@�*- �s )m��_�-^Yt�=V�2�5��5�o"..o�i� 6.3!?0F �g��n(j%nDl c(Monte Carlo"�. E"j��th�z����N]� ���- ����b�.��L��!9e�XM�cR��-x��E�E 4d���0�& �ax300R}� ^Ki84 4C aplo p}�5-fn�BG%Fy�kn Vba�B  �N:�.� �8aaQ���!e.FOup�,�-��B�Y"V!1‘�-pa�+ �w3� R���3e-�A"�2R. Str�� spea� , �_ �} :�ini�J�[6�' ��W?�v*lu� :hrr w#[ž��&F!��#t6_�� jm��!J�q�5en�* 2y>2-�FEx� &[ �8�?D2�"O0a.M "KI(  v�9�: ^ �z* B�e  1A� '&:�b:b2~ ��_p�}4� +�g�E:eR&�!zin�G]�6�I�!�.Z rua{�+kMz*k��g�t;aoA��F/�Yb&��� . W��se":��3Z������� Ҽ&%�4���U!�a��>�A�Zd�r0O ?ve�7nom�!s��3�( 3uq> �x!hA5j�j!�y�.j�2�>1�x���? i.���"I]�+� "Ȓ��!]6al ��I���'�IM��\B:MW�hI�)`:��1bp&�.0�U}�W�Ag>��.O) �za A�.?��*�bl��������;p&B%��w�#NSwFei�ns� he -ə?��`��&�4( 4�� 3JV�i�"dia�2e.�&!j .e!��A-���� �Jr2P%2 s-9)��&�\ax�.#� alig5 (+=�P6lb6E�"�an+.��@E� �b�F���OIq)�F5.����)�AIA�ll�And� I)�a ’; M�a!p1K� b�Y�U-Ɂz�0&&h"�2�3$afign�(�,"�G�_M��a�EA-�l����"�U �� �Z�an un���"�\� of ;��_d��aA(�%6�B�iR< obe"�My��A��= { spars��>���*�/��a�resa��e6��F�Ua��Q(*m�C��YOy+6�-�����arIe�)-:�&;�%�� )I���!x9c�D62� �j&:4 ���,��4ZTpEi"_r>)b`ޯE��Ӂ�t� x*�v#2e�� *�rL]Ci�)��� ��6�#F�&4_��ric��6<q�a��nye2 ��Ix Rn���}���y�6~2�!� �4?.�#\'n� a.��i2�QM Y��M�An Pco�q�XI�.� R��R���F.�Ma6K��lie�W�8N{�k$ort��N>��:� .J�set$�v( 4n�� A�tgU�e6ǁ9g!+�.�. !� ?��e���7wL��al<43�:�-bb" 2� )%.> .��Q3o��9)� ��� �&�!�o�-fv"&Y!�‘AHE e7?��b�n�q.���" �Tk �O2�.���+4 �+&�X( 4#Ab��kbe Ӎ�La1*B&�6.bl� � 4� A( 4/ 4/ 4/ ( 4 ( W7( 5� � � u:2!U}:ha( 5I�8Pe,Au'"�Y�� %�I�@�䩠�  ��i�W�4 ly rɎ�DA�ZT� I@"�1, �� tura-9expand�-( 5%� ��5�5!)� keep�$:�do��jermE�_&p*\� uM� �A�"��( 5!�W�8"OS[!�6!n�( �F� wv0�DeQ�{6Wm2(2�!˽�6�r;�&� 1/�&#��esA�%(�4iF��� �Kn de� y�])�E5-�H�H�VS\riE7�.robleHp��)���Bax6!- �-( t�J2{<ea�a�hrgum[%�!ex"�<��E�2q �J;s)� �vme�Y� %�.GVeXf��%�&�1*� �ȁ1dot"�+ soli =EF�� 2A-DD 3���i}gB�<��4in"�� n�C'Ng"*y ���OyD�-K���6|9�P�3s�Gwt~JF��,4%}��pJ���2,jde�� 9��290 i9f� off��4m��A�X *. E�o�uq]�v�'[65coincid�W�l�3�AP\*8 u�!A�3hP;� ;6gatB� . Si� -kD�. 'Y%��Q2� �J1vi�nѢ �"�*�[p� ympt��"�5A�)�&�R�=��*Z#��%xL:�4�,lapQ*"i���.�'��V��x�(&@ A ���zCn���&���F k�P,:�be �z��&t f"�@L&!��&F3z��3%�^Rsti (lu&� � E�:�I%;�V&߯e��Fe4:�ȫed{�):�+?��� �f�.lef�fe} f�=j�� 6�pT�al�-]6�orA�6'��q�BJ,�G^�� �qU � �  <=s"}Va�ab1aA��@.j*9,u4rQ \���+-�aQ9B���{:�e�no?A��+}H ary:VJ"Qa�U��i �5��%���� .��Vk�6i+-��H-!�LF��T(bc!+���)�1�9�'&w��(g� 6,e.�VaA�Y(&ks&�(�dk"��*�1u1G&v 5e�L�.)plu��Eto*�$&-�J�pr� ٍp�a�*n6�:���s�1A%�B���9�i:.;J��</t�E� M5�)өk/2W� sHa�Q]Z`&�F�9��en �E?&��:?.T�K @m�v�� �a] �y)6��]A'!�i�e��CZ�� %o!�.�!���&���]�!o2o," TS<��ɘ8�� b3�u�]�m�0$N arbitrVHu���w��oF —/q 6�‘I0bandwidth’:�!��.�IJA#�#"�=�Q���YB���Hϥ�e e\� O<)�&!�l$>E�"l<�h:�!`B"e�dB�\ oper�\ lifeU3>`$>X�s)� a�-�=�� Q~!0B�:k]g]WAn*�,IM� F��z���1�E�[� �hi �C�3)�g� � . Ye�)��nverag���>R.���La-@tt3�wo!�f/v Ak� �U�Ua>RE K�a 6sE�6�����9S�!�Q,Z�/JP�i��5��� U�x�erGD! U� �} 'B"$AR�Mdo��r!�aW"I ŴxH1*�=.��W!5G*a�$f4Ip"'neA�:\!Am]��d‘1|-�He��;]%I*� �#e�%(,� a `� [)i_,�dN�"}e��!��&n@�@.s"����"� y�7�60�ir�z�6Yco� ]D& J�$�+�@�� a.%��p!�Y<]��9h�heUgX"[y% K� tarzZ [�:�y�jl� �=�"&� &� 2m i�!<79>;!�i(�mP�h�!.( 5 &� Z�6��N�arcri3/�i> ��*!F�Oxfiz� w�A��3-`r�# ��fntE�i`��F!^m\ UW�'a�-��( 6�"�*�a >b!�6^eV���A �ji.�6]�F(d 3poF��-� �&� .P"� �� � ,��j�;! !�e�!"5e�dqu�H 7 at r � �%� G�AY�M�.��^ ~M���%�g�:nu�.���d��Q}���X A�!�.)@X�PAf&�&ӽ7 ��G�$�K)�� ���6o H-��xa�#��l"q � � �m6c�b2>�%6��?)1&�:21ML*� �'6^E�&�!*�NU6�.��^en����IH�5v i�P!Ye>4 .U�w�=6pe>2h�!��H  �ar�(�x]#v�y^a6D�2F~d=�d"K!E.�c O���[ /�"�.<, ��$ {)�:y�>of%OA_�u��d( 6� �<78� nd E "�73 Y�a2�H5!!b .MmAbe!�5�b���� ��� ( 7� CRN�[!h� ��0 ö��T���L/!7��@7�W�\w �A����sYpv6 U���.-sa����H�p<�6��-!$��=,Imto�F �;5M2$to my f�L^N-ax > !�% half?�H]*+�*k �JU�4N+) �( 7��/��Q�.���s �M6Z�9b )աsV he ��~c% ���e�ommll-"P2�:kPNhit���s �adr?"mAb= �a�Erun�V<so�#�K�qs ��k.PM �8��E�ch E �� �s�y�2g y�( 7��B�{yy�B�6�L�(wJ%�5�1 %%} ΁�-�6O-�!�* 5"wh��8]�A �6/Nq/ ��1A�# /X6�Kstocha�, �a�( 8�^��( 8���!m ��Mpoo"�Ra����s)[ �L9�!���@�O*�ba�/M*erpt�;0E2{�2"�  � A� 0M�uEd!���"�|*J,m�7��Mm�*�+"�v!�D�j ��6�e�W�( 8�� Solv!(�"�?P a�f k7-to-low- �$obtain an �approximate optimal pool size , as ( 83 ) and a max$�icapacity per neuron given by ( 84 ) Equivalently , the number of stimuli that a population of independent ]Ds can encode with `rror threshold is limited �05 ) We derive2w�f ��in orrelaB caseG�evaluating how many ‘thin probability distributions’ �be fitO aquadrant!|possible response patterns defin �$. In a 2-P!�=(( ) , we%8arrange one row_(‘parallelF�along�$diagonal t!�connectspoints%� �Lplane . ( Three suchps arefplayed/\Fig . 6B . ) If neighbor!Id=,8 centers differ!s spikA} this!qipQ yields a MI( 86 )�well se�!ob� �!�=K!�EZ4for . SimilarlA� �general )�Ewe5v a se%�]@.�s acros�hyper)GA� _cubM� edgez spac!sS!ka!�figurae,(immediately9 scal!f,( 87 ) where 8 )a#�-?o!�a�se�e�e�beforvToA�m precis!�Mt�A�narrowe!�an!� or fixed �+isM_A�ese,!#Ha trivial manner akaCof><A�nde S�)B�!#( 90 ) e'become��91%�R6!Vm� ized%� ( 92ul$is Euler'sqi,�Es�Ne%g ( 93ɢ find�7a ��C���d)�,$�� $a�$As opposed!ra+ soonE'he}u*V ,� alls��Thu�8!� �.�bI��8AjW=��J favo�. T���  model� "we��at���� iv >���� s ( �/��, or )�-H)� . At2Row='�H� remains�  �-.sonabl� A�� �) F189�* (�%5Dea�hebior6is domin by�@h�c� � A��?�!��\� 60sotropic tail"� 6� �.&q�forbidO��enc�mA�t����or a few2T" a/�^ � al�'< A�i� ɩ2stx �� . It!'worth m on. �l� loosq E� y exc��-:�;s��!. fact H.6&a�a� d az0 two-dimensio� gri ��}&6J,�TRA��7X� !Tdirec� ,%w #a linAU �‘J@�)�e�f���:�e "� posi�QEir5��er�tb�L i�Hchoices .�Vibrio lera��I�of! sev watery�,rrhea . Prot-0aga�t8`is serogroup specific . SB*a�&��O-5(polysacchar� ( OSP )%�onA�of lipoB(LPS%�H��scribe� njug� vacc!�A�ch%au� Pvia squaric acid chem�yY��of V .@$e O1 InabaaF� PIC018��a r1 bin�heavy ch% fraga^Ntetanubx' OSP:rTTHc�We ass� dP�f�doses baA�o��con{ _h� �(( 10-50 μg�$1A�Uz varya�by mo�loa� VSbto � ( 3:1 , 510: , effec�an adju� Acnd ro/  mmunizs I ed mic!�velop� r��A8-�H TTA~um IgG�u��a�a as vecidal5 bodyB$memory B c!j s fo?!i� mus�or der )@�M�id�k d �o-EXA�b tq��la���pr� IgA+ts c�1 ��:�R�In"�,f�!�ar�e%�&d� %}� w� sAHri��Palthoug�'.E!�.p�wa�bl�hreceiv!jA� highest d�e]�( 5Q� � no a ci�chein �.�wheicB was ad| e!X�K�2� r ab f [oU� alum� Ae#�y�� �55%!�Jvea%icacyt a mo*survival�b�lle�� %reporUf�Kan��~F��� indu�!m9�!�pj�n)�. DI�{i�ر]z}!� lHw�-term)e.��sawould� benedal�p�Dd Pin young children who �o� to>m�Ngens . C�i��ly dehyd!�ng�=eas u��by toxIic���>�. espread{reOfecal-o� transmis�%#is clos�assoc�di�$poor sanite�/ lackaG$safe drink�����  mAW�� glob�ublic��lthA blemBoa�of AsiHAfric ANa�(Caribbean [�,2] . GbGa�h0ly 3–5 millJa��o&�T4100 , 000–13 $ deaths du-Q��1 yN[3~CQ! atear�lyI� risk2-iedem#� LI�\s�� ,6yaE�k 5�Eage� $a 2–4 ti`ae�kcid���== tP!b1�* )k , 4� , 6 , 7�VM(:� � as��IDrol measures untilIQIH!�adequ��]�,�/ty%I�Adverish�nd� enfranchiaCa�!5 most!�B�[8�T )r�n 200 "� %b2� , cl�fi>25 �� �!pj� [1�Am@se.�Av �i�� �2��`  l� commAbyf139 [3!��ʹ Previou � a�w2�O1� prov� J9O� �v ,versa [9 , 1a�1%1. l)�l�>�r.h>�.Borganism �9�inwo%ktyp$OgawaE�� ,[ ,�? .,l Z% a methyl  � upstream ��� moietyAS��[1�^~ �-ks G&m�subsequ( -i5�>ile�R� �]' let5nk ;a�>u[1A�1�15A�W��pMaly�ed1 *P O��FL[1E�� z fH�d } "i � �  ��o�X:�to[ie�< �`� Bg^0 . AnB workAE� g�0n�� = stitM�quire hguide� uol�l~\� � v�~��8Massachusetts G�HospizSub��g$ Research �Ca�( SRAC�The lad���g USDA4 Welf7AcPHS P�ya4HumPW�Us��Laborat� y��,‘‘ILAR G!�v�F”�um�h�s� !�: �QI�typhoid� collecA�(pat�a�e I��u al C� �Difoeal DiM 5[in DhakL @Bangladesh ( icddAkb-j�tudy N�4Ethical Review�a Com1�'a��.u 8Board��z< . WrA9nfeda�z�^.guardia9 � �ticipaP( <18E )�]ad�� '≥)��mir ow� �T enr!�m-�� 50 jof� m-�)�u)BC�i�A�LV  acuteJ *o!sst�"culturevI1>�(Q�; n = �≥3 day��f� 9°CcaWbloodn!S�nella eA�� ;El Tor��st.�isoiX 7i�a�)Ǒ in.�a�fra��!X�in;�\�+!�#�@ ologe���y����N16961��m[neonat[S]���2re�wa�0 Luria-Bertan!�$LB ) broth!�on agar�$te�Opt�ro� R? da1amb� tempera%��F�in CHCl3)b4a Perkin–Elm� uto�c�ariG, M� 341 . Mel1�%z�2 ( Kofler hotM; . Al1a�onito� hin-�%r chr�ography�%L��o�la* gel 60 col$glass slid%% Spot avisua�Lbr�i�#5% H2SO4!ethano�1% nin���$or UV ligh�Ma��d�olumn>�A�per��by elVI�E�cke}!Bioeb , In��R�\s�� a Is� Flash C./ (M���[l�' be�ee'��o�ex�'al Evap���L�Sc96De o�M 480-LC ( Varian�. Nucl Magne�#Rev|( NMR )�tra:;$at 600 MHzE�1H�~153C) Bruker AvY�troE�a* Solv� peakM �3U �refer��!�la�to TMS�3q���shiftippm��Assig= %��al umad�)homon-Vh� >�c^a� � scop(run)softw� �"lsE!� 35 Liquid6(ye�e!5$n Spray-Io".p S� %Tra�ESI-M6�vo u�of2t�x2� X�h0 ]jU3!)A �Me(I��R6 m:QQ�$10 mM aque�=a�iu�)rb� e�e-.o �$average MW!A2!"q�A��900�4. A��&Mc! :BSA�:�)_� R� b:�8!&bov� seB albu�( BSA;���Upur�b92AZ( Pierce2 ech y��/ � �"Hi21:1 di�w����e3 s0�)ol!`o %P, & po�i&�u�!!�� alsoM��  syntht �3�� a sh� , un�'�-[--�ai�% link� onstr�2�!�(8to}R: 6�!�#&~[#Q@*�b��d&E226but��#ac.��.F&A"nl39'�crystal��j�fu >GA�-labelK�,)^.V!�.ranaly�lyA{.x,�)�l,�.ANfirst�ao4; �(; 0,��0�establ�by �� �  . Y[I��<v�NA9di*4O�U)�we*�m�&� ELISAs us ser+lD �[h�i�2�� #+h�y5x�,�in2V2*�g��4#,ei�)�(��;�ng/*�?!I�� .8or TT ( Astarte>;. F"�# bloc !�wa'2!�p�-fV �'*L t ph�%abW}7� lu!�1:500!i 1%e�� :� ed��-T] ��E#*B� bodi��E�edMhor� dishAB oxid�U]!1C-E$ O%�:��� ( Jackson�%oR?�1�5 �2cub�a37� w.&A?-�E�a%R55 mg/mlV " > 02ʹ 0-azinobi3-b (benzothiazo��-6-sulfo�!()AQBTS��n!�03�O�� E�A*a�/!Sh9:� densa�305 nm K,a Vmax micro� ki�" er ( Mole�&DeEs�2p . unny� , CA%KPI� C��� at� � tervi�� maxi�0 slopgan0.�chc%of%2 Ua>z��s �!�un�3J0min�( mOD/ !�> geni,*�)U���fuեRiv�|!1��X!�191%Hof female Swiss-Web� (�"week ;;)!�/W]0tr"(�-"�(� ckZ�&E-)�~��"� ��)�)%-�)Fou u|#3 f�g:� .=at<:m�> {!�Y� �KJ�)��&I:2B�"��2�do�( 2)aK5 J�g��Ug 9�F��)$)ly >��5^>��4o�45�.v6a&H� Z  �^E�F�)r)aN!��!,��m�*ly{�.�*e�9"3 , 2e!\42);&�p sampU8��0 blee6 .GAK2D4�d49X56C E�b, c�,� iquo�9IMskb �2�%9��e2|*ssa�splenocy��"ga�day�!pr��@ POTj�9L:�+tissuvsI��jp:V%�hge*� , secr�+:�,�4&� � �rAWO!2L wild� �:6�,�%&��2��Bof�qY[e�1i�6 Z�S;el��i��E�al�8.[14%�2821 whe" ��&� �:) �'Z ����/� AA\.� mc-N� )@0atJ ;h m��3%e abovkA�{a�nt>.�.� 2�  .�ETT& � , IgMAZ&� in!�umIM�2 stand(enzyme-od)�osorb�Ris(-6)aPtocols�*CY�[1�7i�&Ks�0%�B�/!� �, y: �-�%�2"�1!�-��q/mL )!�@ in��mM�#�* �N)Sh ." 25:$ �� e�v t� μl��� AA�� B R!3& zY:#gA9�.�10� Soua�n� .� E1e d� 2�i8T4"�*s hav �&( a 15-� c�+e��E9 U� � e�p�4!Ys'�Eabasm%�T0�.��!� a 30>l]>�\�0ato_'/OW*4k.n1u#tit7Dl>n� !%� -i�f�a�2�'2�'inactiv�end� ��le�&   �L� �by heJFit%' 1 hr" 56%�i$ l aD� �f� seG3�]-.�u�" (9to02t@toe�G! I)96-e���"�#} � � ��of�� ( OD�F )N�Ac22%�'nea pig.h$( EMD Bios�B�1k .^%Mik or5ss.��� of b#he�Cfu�0 "(( Becton DiW�:� each%D��1)'��6�6��>>aat 59T� �D� W1,l=�@..e%A�Q.�I��-�>50% re�EiJ.�a3o�E>] nm,um [2e:�>�I�HV�,at least a 4I�i��J�t��56Eb� �eV506N ��� !% thir�7n�' �fnx �/��we -!�.� z �%L(1 ml erythr� lysWC�zAUre-sus A�m!� RPMI-1640� ��3310% fe%2�( FBS�H�n� ,� amercaptos#(�, RA�x( Alexis ConAVm�I�upe*c3���iotic�p�  (treptomycine�P-stRPA��%Dna(#%J.`��d)_5 l\�20Yml PMA��4�u��% humi�% mosp�+ T5% COYW�1ens�ein 96�,round-bottom� }71×107 s� irra�IdU gene�!pl\ feed��( 12rad��=s\5 \��(M��:�toA*v�$3[�.nU�16a��l-� , ��/ harvEd%�A@2:^��k"� l&on�"V?��wod: � d 6�� %<as9 �.�)�bygX�a �d ,.�#H>�7, nit� llul:6, ( MAHAS45R2MaAp#) �. *� 0E���&?>go6nti" Aa�F� ,J+G^+or key��O,pet hemocyan> KLH;^�(6� , ne�v�i��IL"����u ~�m ?:� "����. mU���9 |�ny2A�2�� Ze!�.��<t� � PBS\-�&& 1a���V9.6 avidin-D� �, V r�0� ��to:ctek ��>s6v&) %�AE�(3 �o-9�-cY zole&����un.V�asB]�da�esb &$toA�3uI�!�U mex�GdQ!B� 3Gs#+��� 5�f2��� >4%�� �6us� �S�>3 . 5%�� �Z105��b�20^��> T�@�^S.B^R%!eu�z��� *�&�!�w�v�Hi�@ HBSS 3Q8 ( Hank’s Bal�*d0t�*Y;* �)2Z 4jY B,v��gen�'nd' HEPES ( I.,� 5:�%� rem�4f��`2�YHe�8nt Peyer�Patch�dissec1.un9 magn�}EFcres�J�=�\�N 9] �QI~%c.K5�7ly�,� cu};�M�Ppie� 2_`T�E�)�$*U 1����)�� EDTA��A�2$s!kl 0&!iiAA.� � aspi��6 or!A�%��al ep�l�?.x-!IG1:w':|٥Co� te M�S%q_L-glutamz$:>!0F�B5%��1%*� -2 K 1% Fungiz :k6�E�:xa�agena Pn�>�!�3��(�4%�%4 � |!{V�!M a 7�m�2>J��!�M�K� %zX�CV�� �O�`ndJA�E����� �,!�&= ��Lymph_ �)�4b�A�gz a�"&(�#8 )� O4lyte-M ( CedarX� nB�u &f ٷl�!��Fe���� )/ilD��N �N J Z< 1� "�r we ��� U�JtYcwe :9�q!�  y�ae ea�� j (NN"> &� ,e e� Azt% Yu��I��� � �:&� -%v� �`� > >�0tF� 62�.�'N0�5 �-  i� 0 �G�4"V7�ch>av" ,-twild-�@�,�7OJ�) ��~)Zv� un- �ed CD-1|Uk[B  damsS�/prQ WoP+ %���2CI�8up=G� i4�, ompr�C8of 5 . 8x109cfu�� ��.ECa 1:250 c �f:oo�� 42�a ��ij�#3s (!�@��28 h; TThc� :�(9n�d�.�orQ?q*�.�(o�GY:Egkep~X .� B4�&f/a/@:Y�O32�i36 , ^XYJ� 5�J*> %�!�5dat-6|^���"�8Mann-Whitney U �L�i)9�0�!iso�N[� �9.�,(!� �Z��W�5s# �Wilcoxon� ned-Rank �Ka�\-Me�A!�log�Ak,QW&�3�A�e-7al cur�\R;u�9��?H:por�eP�TYwo-T#�-M��2of P<� �>Yd�La "gS%�sY;�Wa�b� *%��.(-]%)-G�:0Pad Prism 4 (S�7� �9. &�'�!��"� sB p;de /�a�<�ClePm�\E�"z .6-aq?"�ig !�� ����hJ�,*�+i2�,%.GNa 9 nx Y6�'.���K;69 z7ac�a-,"(/&,�]-&ex�8I|)^noA[ngC ���e"7RU7dux)�ur� clin�) illn�3�2� rm��+�@���iW3n*!�� #>6}"&$"o"�� �MP�GSJ)��(B�oW.tr.�&T:�.e�i�Pi�6�š�� >)�`;���'n�_jsM"�!q�� 2�,2�!�Ecq�5Y� ( P<�0�*x st�!hT�I�afl}6�%�A� ngleiY+o&9T�)"'o&j �lMm- 9��=�,c�0� in 7���A1e?|:P�"+�)N�=: e� dZE1 SROW};^�� %a.gS!Pny5� �Y d�, �B� )HIj�dl3f&�, N"7S� Z�rAm�rapidlRN�#+++1�?�1�P��!yal:;�'or� �[���%�h�SFIJ "|*M(A{Y� boosZ"�l�%a<Q �e �I.$ 2$�<� �+�Mie��R !sv:(u��&ttachgu�/��"�2U��\e22�9L"�C�� �a�2����+e�)k6 ���>2�$2:�$�e���2��F� of sacr�e �^c��var$N E}���+V we d"W�2!�/0��J1r�QQr�� ��"VI�-��-b6�/mMe*,ycognizgTTI�a�75?�0Y� 2�9�ALJ-Ps!aq/�%�9�� �*EII�.�s6�]O2, ��al:SX!1:�IQ/yP Pٹ2W�����2�j�/�.I�7%��"M�c�.�6�=A6��cEn al�!X5�"� d�Wf��F�� 4�� [��Z"6 e�"�:( 60%��6v�5j2.���>  :vhIm( 5Vm;2�Xon;�0�])�&k. �[ty"�� i* ^���;JeO9�T@ ^Qn�O:pV^>H'n�S*jR(�$3�>T#>w��"nith�P�I(�sjU3`3�QCurj �A�MW1&paEV�W"7X>��)or�R��OW-:p��E���C=Q� �outbrzF[3Q1J�QshJt3d&�Yù�n�>� �V isI��ic�`E�c�B3Fenh�d� �o�Yd*�[%=BDP-ribos* ! e&>.RAѝ.� � 9��� -��#�sugge"pr#Ua�^USIW��S>�SbA� [A �B�SF*��a�)Wv�_� g!�a-6�=2%source� "s�sM�� �surY��we� �1�Yc2�aB� a"� � bR p�q  �,VuqLE  sun-buC>"�="^Fmi>Z,s!&i3)Q�dA�bI?� urfax8To� firmi-(@r d% a�^~ycoN� A�L�" ��#&?O2�<of~�bu@�>|Acar�W Eqz +com7cly!�duc��: ZBc .`H;%eot!�ha�gen i��7o�0�1�t&�&[34�DWe next*!�1F-�� ��"�^.�,�^��%�*� *#��bw�%.M � s5.&� 6 F0�� %8 �  a.Aq5X��y seco1$n�<,.�O�Dl."��$j�b4 J�%�!~ same&^rmv�� (a��  v�dZ _�� A"�73�ow%5h&r �. J�3:1�$�� �� tA#�`n&9E+0)�>c �*3mol!�f JJat� �c)bA�o.KI�eR orUG H!�W�G�u ?%J�as ��|IA4enchmarkMO� �co-��} qI�< ( ]��tlJI�.p �cv� �al"��<%�" ��cE&�G);���>"by��q�E�kil�n f��"!YO� vailj� 8 r�Qm�{�u1K �Yf%�e�-i��7as6@b=] lo^�on-ad!�e�mts [3�3; @5��=��y,WN� =S�� y un�Q*O theyP GMtfaXl�' �4Ib�I�� 1*&*�$�m���)to+���[3> 3�<3�839� "R w re u�n&�)cir2ng72�-Y&� y��e�'���(�E%&NE�*�6�� ͙�X:,j  *(B[l5�k�!�v�ln|3 oQV"�:��BY eygLl [40pH!�,�aknowle z,cv ��sha|� em%I��B,iT e�c&6 c\ n�%�-*�l2�=*6�obser����3TT&�J�N�n���U5Ily�����G ��'�(A~!�$ �ebE7�lXP%�2� *5�)6of=�� � �puos�^���& , perm1t�&h5[41a_O*� �ma�^ach� �A(re oligo=�"�h�M� l�J,� !� ^4ugh%M�W��i2vr�_R* 2� A��2���ttKt!�a�xof�3 : ( W�kxin-%��� tep��W�!t=O_e�(PiPulɸ2�f� ��� s.� &Y on�� �D(�witebo-YaA-<ny-ga4 /!��a|��)!wN�a�as�"h2t��S$�XY��� U2��(�it%���sim�A"EW`,i�"� MGiAJdop�!� manu���purnz��re�-� 4h� "'+GrVdVQ.b���M it\ymS�? iS*7Nto%qor"� [�C3�Fwe&;(�hib R� llo� �2i�$&�!�� no%ne�me�et"�nlmC� Xfur` �'orh��P�\AF�inZ&%�o.� �� �.+9�4m�CA�fun�ap�P'��Ic�X!��T!g@�7FB�[49IaI� ss�D2� q�Bbi�.A��!alys:&� H/%J�zis!�.Tww�nf�NRedict}B�ed�b[4�=4� �bP al�"}>�*� c�� d �2�5W�w/E#s6 Q9[46A�NwAf� n��!Tat2]=L6_A� [�AInJ7_ V�QW-I�:�! a���_�E��Fur!�=$� 1 #$l&���n�|��eN�=q�e�2h  �P"= ]&�( ��4� 4�;fin),q�ref�IC �VO �%��%A � i� �R-li [Ec41�I4�*!*be"N�� �{�4-z"�D2umesi��pen�;0:t2Su5fy� !�� G~facilQo�u�A�:or� G&������$��e��hM �O)El)�RwE�a�.���wM/r d ��3j"KI���Fj�5fmo��"N�r&�~}( OCV7redt�g"�%���<r�{gin�TCla�u Jn�b�Z�"�`I��sK�ctegAN�ly�oTwoZ�ocom�=�U�� �=5;l) Duke( WC-rBS�OruO, Swed�4�4y�ei:�&r>�O�+p:C�?g3 � R "."C�rn Bl}Or$Qhol (  tha�aTechnics-Sanofi Pasteur�'di�P��2� n�D�)&�1� -�F�U/htu� �how�f��i&��re !o"� �wqBht�5A�agX �q.�.��[�ol�4i"��s��K50,5� Qyi0q�)6�% �h��8g�w�"��y 6 mon�rvr!�!8��m�Duerbnq��( %s�  x݌ly 40b�vZ�y ��Hʂ��  [5W�?���(����an��$a:��am!�"�]0�� LPS/� [�J� i�uE!NBi�R69�>�a T-reg�Aor�ns ��91.�y-inflamm�l��1own]��A VmaS�5�I�ueGa�zce 1C� Bj"� !!.#�H�yEpro�$���of� se���S~ � 8dex[ie"*7X[5= �� Z� �m&� %'es&_B�&�m[Q-i"g�iI�.��-Q.�� '1�i�ore�  plasma�Q%�px K�:T�!uq�1����2=��fy%�vAy*�% �. �,b�(992�"� . DeVp� O-.7�feeA)���q\"*"s� ?eO� novel�Q[�e-�t,�.:p �GA�]muvGQb��'x :�)" &� %N1<V !_OB�?s� *�r&eMn,Wy�6�%er2�2�raN��!&e�:'� ��2VzX.�`�F�c�have ut� y!�*<�[c�nt�,'par�W�{ ime-�L��=�,bI��n� � �%[r >%3.iBj|!�=2nsolid��|J� and/!�s�� �9�n��(%���s��) path$A such! shig�o�s&�o.J!#�n ��nA �WplaP | y:g�= Ms� �alof �.��!�,&� /I��&caYyaq eriz�\ �iN��  �t�&o2�mic-d 64 ( ICT �a �q*ap�9.j��Wuc�0ria bancrofti!\n s�!ly"$ 6 loaix4�sRC�C_Jo�,a��konship�eb� envisag"vi�|L .Q �Of��i�AM9g���0�p�O. H"K sӓ��T~yiy� {&B�LI-!� �_��ra��g� 0�" ���Bin�Hi��# e��s%/�CTi� mappA�;aNU �!M ( LF!�1xe�.���-�loi>A3ma�N elloP�p1�. A �+Bo  ����E��'�a�;>of W .]!,5zM .� cs� @d�'� 42 villag����[ reg%�( E%N , North-w�&Y�H )�� ��O̔ss�m��. Diur�Z+:�*�["�uA�SC-� .�-����1 ( CF<4byE��)@�ofA�i��6ick �sm�o. C�4manif{cw%�LFls�ePA?M�!?�P�4#5lugno2E9Ecoedema V� subj�+to ninq),-(!R6MfJ "�"219WadivClW>ok%l!�!cIo.*2#2r2�Aain�:���1����o!, �]�ts {Ne�0%V�]Qto�J1]|.A=AM�)a�'3�%s_mn5m���[�b( 11/2:�n�C��XZ�.{4M��6�%&2o.�� n� � �*Fw!N� � Q[2J. P1.� stro��>~2�Mt�V%72'E���!�mC�� �J��Mf ml/I�( Odd!�tio = 1�=$4; 95%CI: �]41–39 . 0; p �:.�6& �a �ug�a(�BarmanzGrhn�690X= 030�q��A]�of�a�!IM�A9byŖ:�G~ofA�or)�8R�a�z9�E��anqMf.��X15%���m�)&n���Y"�-:��2�R@-%52.B74!BJf"}c>�u?5�!�8z�. 2!�)�1��2��.6*�A�2��!�J�Q��( Mf/ml!�I�)m?&k� 5E�s�|�2�" :�?�:i2`=x!�i�}g&�-�m�3!A9ax ���z.f�����Z��x&�1w3ing\�!cA��6�M�� ��6C�'��n0N reriB� �<M�.)3u�*A]a���re-� �x^� be  $useful�sh�� 1T a�F 2V . FG^� �� L0 , def�=ZvxO -bor�"�%6af�sa�ut 68�fn peo� in 7\e untr�4�rؓ�d���&�A:�AW�Srn Paci �!4som��)bAmeU}(��V""2N"A parasizRq ,qx$gia malayivB .�7ori��e�Ax'�l4Culex , AnopheF*�M Posquit�"߆InMN�yb!M44>Mg�� s=�}j<-!�P6�[=il��j.�W!�%#I׍ge�{ic!Otrq�!�6dov_��siAab�E+-�� f� hn9��[���$�B Pdi0)bio-ec�?9L�"~ i�%�ew�M}world-؞��64�]f8w@B�::�.e�q )��l�2�,-�,pe� A LoaK���� ;_E��� O�cerca'W vuluzIJUVM %��s��[\ea pr1�.L 1 peripXH���preua"%#!TM�A��g. En�e�Gf= }"ܡ focu!�ů rrup�A�v��Ly2l%/�6mer#+� ��*��$199�W!� He,�{emA��ed�Ae��&� �T�mu~ drug>� ( MD� yI��o1���o-Qx'-d�'!�n��FA�m #� d�F�h Merck & C", Rahw#NJ�>*�a�md�mA�D(GlaxoSmithK�m��en}�UK ��2mm�d%,U(� Mf [!g� HZ}f. , WHO27�5R%-�-e�ir�F"t�y'��+��� 6�LF:1%� h10�9ȎA&��f:c2(6ws cru���&U� 4!�5�A@DH!a�ɧ/A�A$�wamm�UHi�ii�Y2�Mfa�j�r� 8FpS�$� ������P.�p��>cO {ue�re2���~�>IG�v�y cumba��n+sE �J[1�1gC*�-�|��T�� ���tf�F� ����5246�Y=[,�%i 7h$>t��-��at(\b��� worm�|�eor� A l"N�-b�!two�B�*i&�>mN3!�'d � �B4y/hp. Og4C3\A�pa�b  �cly!��A( MAb&�A$�"Av�_MQe.�gibsoni�&�3:.!que al%�GMF�6��F�"�F,�!Z��ocele fl�[16a�9]Vv!B�HnsA�@ non-�7en�RaYp�_�a�AzLF.�R F� �7iD.�!�"- u1a%e( AD12 )4$e!dogv7rtAg Dir"�iW�!Qu�.�R;!:��m � as[�J,�yg� A�!,�) equi"*"8˦��a�1Rki}fma4#z!*6���!���,A�itɫ��XT he� PK}�_to"� &� =�( GPE�[5�>w"21VHkRes5�M�re �� p)F� ��ca�h %��'0 �re Vt;9ca7&%i�5 ��a o fa�I Lib(, Sri Lanka%Indone> [*Ch.� � !E>�n �c � 2���&�E���Ɩ"��ve�%is!<��(� �% T!F"5:�!���"`Mf> ds�e��94��~ ,-�!I"r���� 2��|j. MA�Bt�M|['�).5i!of �*�CgA*, a�Q�A"in8%�> KB��vqA� E/E�cA�a�qa�Hv� "�w� o�_dEer ϓ�fal�Zn�*�[�A! � E�� Q!srq9�H�ed �T�zl��R�*� ��a�c RepC�ofaego ( ��F$Bakajika e�u .a ]&�� &� !O�v,��ed�+n�zZ� .���A[e� y ��LF*�E�e�"�!�abros���u����!�  a(֮&n re�k".[3! ��*��"q&�����&�=aA�<"T ��m"_y�i�D�1A�.M2�{he%�,�f�x|A�ECt�ly �+FR"�%-OI"r " ��4ȑ��&/ � v$l��x exparb(�H"+Y!�eHǁ����,�� �� A-t�V|� &� s<5�M�1u�[��m��K*�2!�i�50-�e fAd�e!6MW� aAF��bot���3l�)�r&+de�$� jM-1#a3-�)� ��}5G%�6<�e�1Y��n� Data)�a�t`v&�&� � s�6is�g�q�:�n��!�Э{���'dF�o� _;Ȕ^2���6�A�dA�e� ���(Z �|CN�v]M���|v )�}�!5�>��R��( �T /�Y.�!�' =�e�Q&B2��&�. Y�1a�"MQ�2Septe� 2013AZJ!F�n{ lth ctJmHD^0͵!(� 2%!(�}H6�x�i0!(� 4h! , lo�Ža]ա*M!belD$)P�9�G-eol�)sPXye; �.��`�s�'N?�ab5x[��""� it�������V2"�%C)&es n� Batouri%(~r����(�Z6 � Nwa!�).�F�R�!��p��:w2���=���h}YR]N e�K[fi)&�C .�!�6O��@��0: Kumba-Konye%H� N�nA)��Ct\#lac,o�m_1߹!Gm�ee.DtreatB hJ1e�a� docu&i� S1 T�(. I&q�BsuMf%�6t"�'�|)��<lik`  I�o C.L�%t�%�.*K��� a: &'"~? .P/emea����!��tmo�$��2ow�tJ%����1:��A��3)iIscree� �N!�,A- � !�f:]� aemia �1�� ( Al',j�bo�� , ME , USCDay�d�6�&e��-L4)%5tnta# tirJ� |Hl� :�re ��,�.�&!!&m!�&� ' ��%��7G/C�%�/��ur,G" '. film �q �5�B���� iu'/P~&��Niha�I:ev�Bv��!nL��N�al ,��te`CNE���.��@BQM��rbP���&/*I< �q&��� `-��G"]���i��� Q��,+o�0z le�/ 3 #2-.��explaE2�0%� � �tntary; h !�/�CdraE�I�>Q oblii>6�heah::4�M,r ��9����� �yL !�wi/wg!� �s�N&[,or!3�d�PrZ��DB(!ot�6WF*&l� ��terƭ���+s�Da�( dFN��s!fin�ri��l�Dd�ey=�+�Aou�0]m� JpaWe�6uo��.��0i�e��n.�ng1x"�(,2�!ja5��{I9i��� � �!��� 3M�U��;�r� bulletrQ��s�J�DT!�S)<ns�t2 y quu"ons h5@d �e�i�!g�%0dߪG)�.�a��3)f�E rec!�h ��)’x�# . If�%t�821P�lX�a�:ia�.t.)Uver���''=�,er~ �9�%��B�legal &n��3��?)��GU"Fr"}IdA�5-re��.��[&�D�2�anonym�Q=t�?TS �>�B��E�nel!zru�����I�AlA6e6S-���]q�?*a��!S limb2<!��;B.[X�ZO�V�t 8�rI�/mf��AYtyrenfam box�2�me��V �JE elig 3a*K����&`� m�/cA�}�&�FFsi|�ej.�100μL!�hd�i�Lcap ry ���:�  10am%3pa� �M I ��D}�g�apq�-Asa�A | pɐ�!�I���% aken>�10"�2Zl*/�� or)�=nZ \1!�noФ�)�l %Iwe N.-! @10pm-12a!:�A�� , 5%�9.�)6-pr&a1��!&�2�!] � � ( TBF�*&V,J  Ǝw)�eh��xi��ly �% -!Y� a�!�� �}�B� �7����)�)~��n oyuM5�"e ���d �F�n�M wN 10% GiemsH sB��b&�&s <�2� ��p l`2"Z#eE10× o�/� Al �*�:"R�2�0d� !!6pj�4=)�;. M���Q� 8�i9n� �4�\T ���<:��_6�mpiLS"man7 \ EpiInfo v�y. 3�#e�S�/r"_�C�o�"kc�aw+tln��� ceD, o SPSS v25/ ( Armon�T0NY: IBM Corp A��CN��ge��9m �j6( GMI�"&A�ca"��Lnti�l( ∑ x+_/n(`E�"x"�g����C er m��I.in9&�iO"n"JDN.U� . Un�.�w��l�Aa� �lly�_4� a&�m d2`������a�-� a��e I er�� �% ( α�0MiQ�a�22�5�)n�Or7�r�f�� )A�- at �9?E7;1�Ch ��1 �qK dichotobGO >AA �%reg,N���)toq~Wzp�K� F9-��"�M�f0�c&D!. O6�6�� � derw� !;[!�. O�.!�4ُ6!�1065/�6�� I�C�aHMg�47 ± 1�42C ��w &12Pha� ejaE6E 5yea"��"� N� "�Ō�qQ 20%�59 �&c|�. T!���, 9% ).�� Rw&� x��M**,�2�6!bJ�7���j%(��E)L_7X"�%Eash�*st2�*��R. 8�k�y5�( f4w�< . 4%%M!/6�FW�2�:!M#%=s�"l���#fY0��e2��\i��� ]7�+|5%27�:�VG} c\Kf�( p���i $e�:�jX�MzR9�%A ��agĭupak17�i1��No� $A�&� �Y"�7{$�&~:��.�a�~#C!\1a�24q�Aji�9��p��0"M:J� 7ou�<�)�q��:?(I��*1M�Lu0)J�EV�5Xb�-��&0;wA�� ger��l21%:E�-&.!; �ad-� �A�"<��� 8s0�L14e�an�≥!I7!�����l �/)6. O�kd " |'-U("�D�x�Y�<.� ( Konga 1M�PTc]S��� ��HT�D0O, S�S3l�(w9�`�2��;p&�va+�6���E�'��)e� ;i�eH&�N}�.��aI\�~n?z�Ia��F�Ci�DaH>�?1 "q���%�Ain O��;�;�9 y�� 17 .a�( 372q��a� of 8�5 :�9a�eE@62��5% , 180 4 : � ��]�(��.�VH�2a@224A�4A~��"{y&� �hea� 4��<9�3!�6V�2�k�%43A72{T=3�* �CMf%Al�S) Nf6einM�i� M�–2�vi6d w7ag�6�=��r��"�&� .�67� �8b�\/ � ej 5%; 85AM12@!eyv�>6+x 6�. *\6 tans!N&�Z�-"�D]paO�!n!�m �w��A9.^��ҽ RZ:?6A1E�F�ŷEeA@1AA808a{82I1A�ae!4 60!0e_(��2�ǡ+*Eo]� � gI��C.�D���z�� aza:{��2!\er[ya�!����<�V� %v9%P23!2�6� 6"�%n". N�D N@4l23 �f*202O j �26 yt� a&��g h��, ���Kp�66��3Ra�j����3 PM� �TBFA4A�9� 18/4��!d2a� 2 6��� . V��0�JMf%�6�1�M,� YB(* )Q�I �!a� wF<,6 2�*� is last�^>�*! �as2�� 1}}&"�]�"� d2:' �&� !O)u)�X/(�;-&(TBF: 17/23; 2 6/2!�i�2�Mfe�ŀ� &~�%ey4�S;]p3 Y�a�)�-1\�.��s( 1436a���� �� ��E4,~).�9�co&Z�C�e�asB�� doub8>�0��o3�20\��� On�� h!�jY>u��F;� �!/>��"��k,��t ���N �x�=�><�1�.�m�� �jL4H�1:TF�.��sr�d� .*.i2d�a� ( >"�F�;)v("",�#]�[+y.Z!�U�%Ca��1�Qv! _'�L:�� 8��v�T�m�.azF: %�M�venF��p�ny18/��i�9d�� q�r��%B��7��0 Qh-�16�I�3e33 �I% 1!$>I7Hx��.�9ne��CnorBCɟir!�-!���7e�� r�, 3)� !�? -@ ����-&�HDg�' �.(�(�#]�i 6ia�ch�Y:*8 uI%d18J.6�Y24.�ŧ2n�+э:�!KM��J& �>H21_O(B8.N��> ZS �)m�4=U�6\LE�1�&�:�mUjh`TeNoQ^�x!<.�mx �!%�iH>Q "8*`�rl�.a[qL���`[.0�� ~_$��d.�ED����(��%L�"�:dMea"Y � ��El.��of�|800� 30Rh!�r��؁3V�M͠w �b)�2�!��&�Ii�,�baRn&0�S�+AF|JV>��� 9a gw�"�� �V��KR 6�M C��MFo�MA[�*I�'M�#q(N�� be� ��@U�A",��7# :��� �b��R = >�L�2; �L22��7�L\�$i�OR�;��ext�ly �(= 2Y7X5NB874��>X�.� 27-�s]�-@� 9A>>{]эs_"a �?!�e{6I��mrghSp�y&r>aO- �e���* �/� �5Q��w illuVce'�2!.���e�rv�\wU�8i=1��6�ҬN!. AYSd*�{u��� 8%�*b�=k�2q�Vu���"��O�*u;��:�325�%m�E��Ef �)&� �e>�%4����8.>�T.���>�AUBs9J�_PsN 5 . Q�T=K=���Bl�:��MLFO?H6�inSML�M&Mu � �G��� �?C:s�\ ;��u%iHM�%mM*[2UA3�K3�JF�.%��(mdI�!vA�!���nole�6Ee�� rout��*B�9a"e�Kz�R�t_��VK&E$;"�[��  T�P�$ic2A�$ d5p�*�j�/� 2iK�[ ;;�Ch�Phsto"/�4c%m6�RF^�@v�tt��-. ctN�Dan�KV�+e��4 �c( CDT�$iMgo!�:$8-HD%WV^s�� !{%|CL6!�MSE 4�i:56&f6ť�d�.!I �k{ �W&� �U)�Ca;er��A�b�(�AS�2%$(��sa� *.L.�Q��&a�Aiy�4t���*�'n�4w Lm_!�[i-�D& \��f�K)$s�S&�T�E��6�E( �!%4 �Fa��~ce�dngc-��%�� &A.D> Dn\C[2�Ka��"�02,\�t�E@ to�� b)g���.�.L ��"/byE �1�^z%��AFof dis�&A1dis��e�WAa gj� %o�R$b21$��A�J6$�VY� !�6yth�xI!2pjo�0��.8*��-n}|as��[. OE���j�5oF\��on-EHa� orig�G�.h� 6�5"&iZ $( podoconi `)��%��irrp! E�-�ic"#"Tsoil [AsDJ+$���aw&p4K�\.8s :la:d��W.Yo (�V)��M(� aI� ����R :R��4FW �(�265����"�%�isD�Nڗ"E v ileB�a��A�:jR%k�-�:2>a'=e%��6!�FsA�GY �9�:*��ut"sY��\2�� �!�=j��V� 6� n���i rV%�.1!s�Sq�=�%/JR!sLb�Ap<vu�B6�.j0/)F-�Ie@!�Zn�sT^J���B0*�BwA 6�Nt�>Vf-��mu+ e���"�*+. NO>��6��Hi�Q>} Ų.*&1w&C� ��"e��2 bD2A�8I�c}nh�v�A���md�62�2�e)>� a0bpa�ZSr�!re"�5�1 �te���!�E��&W )qW e*�! �i)Y@m\sO'Z" -d�6�Dj �8� n�.2�� Th��= �`��9'D�g�E���4 A�( ? �t��qQ�m4��hF!%��,A,caiL4ܩ��.%Tm Aa�MA���6]q*�&����>#.�[xUISash^�<E}i��3 .� 9"� �dI%�G ~�Uul��^�aq�m��I$s that she�d antigen . Further studies to investigate the extent of �ICT card cross-reactivity with different stages7 dens!. T!qa]B%� ignifican)xnvidualsA�ryA highX very Mf!�dAX)a5.AhAE three-dim�tonal im!�g>Y�-induc=r altevsX a- resol�i�"[ ),8 uniquq ticulo%�Enetwor� UendI�� 2um? � gA�n!81nsZ ud us+rconni#%~(�me� ,200–300 nmeka�“�leIlts”!o aren1ari� E�DMV merp�bcN�%�ma�abundaH,immunolabele� 6ws�bunitayH�]M^�{e�},AMsum�reveala�!�sit# N�, ly localE�to6�!h rior . Si��8��� discern a�!`a&b02?!U cytosol , U� s� al � s abo $he mechani��Xfo��nY# actud �b?�: data docuŵ>usu �~U� reorganiz�N� aU�\is� d!L Ce\2 p���poKl� da nge�EaA)�defens=AT- �&bioch��!h�� Denzym!�m� -�2!$al descrip%d>isar�on�a� ai�fur dissec? e ea�"&�!t�` life cyap!A�)�%oE��� . V�fre� ��(��'a�f^��QmetabolAB� essenti�%all6�>7�h�z�\ adop�xa�teg � ord��$e a variet�� mole��2�in both� �i̥ spac8 f��E_!A.���ofAR�2�( +�J))X*eukaryo"a�n��?as6(��):��tap��b�$ �exaAk��!1y [1–8� Spec! �%��.�t[ !x����ar�*arEi~el%:Asubsequ���oe�c��+ sQGsi]which�B�96�mo6e2e�!� funcyg9�, some�! ferae�i�AorA|, a��� beginn�I�und*M �2y?�# AUcon)��!P emacroM���nd v��a5�-J14al frame��sA�.�OaJ po�� benefa�i0 e ���cy].�epa�� �:R�lay"�1s�:JWE-Ytrigge!|b BN� ( ds�e!dx � e{2�~([2 , 9 , 10aDR %�gQy–U"rQ�hip� at g� �q-]�r��of�$ � � clus )~� many� ort�&� ,�� enha�gt QfanB�;�PM<ar�� logyE�|�Time �E6!N�of novel�contro�ŅWa . Follow�B,2003 outbreaf cut�v spiratoryA�drome� ;�1 viewa�ee [11]- [.� fami��:krecei�orldwe7tE�In addi�A�Sz �al r) yAersm id��,=�tw� �ls� �s [12A�C&� I)nd na)� nidoI>�v��polyc' onicA!RGemploy�� ja!�d (a�t ) a� �cregul���1exp�[13aR4!���}coE�!�mse/�f(�{rBn5�e)*pri!a� wo-thirde�f.ge%,�A—at 27y 1 kb—e6st�+ 4kn�o�  �%� nsistzope<a���MORFt1a%�1b� f ��lA�r��-K� a ribosom��shift�� 3′� A ORF1�Thu� E�� �%j)� yieldsE�A(protein�pp � bAE�re auto)olytic� cleaaV� 16 n�u�W nsp1aZ16; Fig�1 )��%a!� resi%5in03%*0nsp5 [15–17aS�a| -��X %�=�e@�xRNA-depn)�!merI~RdRp )yavic,��<on among>�b( y eҡa�ee} �D�7!Rror ab ��Qٮ��a set!�� igu�\%@!�5��ů "� �"proces@14q� , 1 ThA�7 xVof.TF&Jis"u � lighw�� �it �ilZ% A�produ"EM�m� es� 8full-length neg%���(:" �),%�%�a2�Fontinu�!!�to�e�� sub �n�t�`a� r 3 ic mY��e��~ �[1�2�!�resul�-�T?a�e!xAG!TE�of�) ����d.* �acA�MV�"� �m-proxi��domA�m�)$ . Ultimat,%�u�QA��mbpby bude�V(ucleocapsidu^ l' pre-Golgi�a�p �s [21=�A!:��&sX e&�(W sumed ) m!jspa� fm-}�though, phys�ancho��p�CW��sb  ( RTC�ftr&vw_I_ 1�5Q��e-�� �Ansp�nspa�!�nsp6 (.�[2#24�ZgR��@�V5TE��A�m�!�typ! pai� ��� U�A��k� �ll"�M>y >E,%"�[2�62���� sE�A�ly foun�a7 periE�ar$aС el9w�—accdg�!D fluoresce� ( IFAPi_ copyr#—de3 o–1 / �!��rI;�u�co" 2k� HTC [16��7a 89%��"��( IEM )a � ��;!�"KES���3"�!!%outE}of%/u M*�A�AliD>s�����%�a�V� ( ER!sarkery�[2! %30]origiE��Q�s�eedI ci�sz��E�, e� k�-�&*ofa�%waN�1g . , $ d� ��o hagnd�� �[$"�ecret��athwa� "�ejin��nt limit�� �z�“{SVthin  �( 1nby&�2��.�ia�di�)� �$���beu�200�35�[IT%velop a%>zm3'F r RTC-� q� .in��–"���akw*�� oyed�*� ( ETtaew=s3�I37�1E�P�"� �.�( 2%�Qn!EM�e�re�O&t.V�,men tilt ang crez!primar�. am ,%3cal�8 )_ imagT �l. T��)cs�il���(a B of ±65°!o$ �incre� ( 1°�A�an yi��eacr��h�Hm?mE�:�aN��� , e�Q �Y establisha��� unnoticed"nal�32��>�ET 6*v wB�iso� d"�q insteadF� .��to&� rVz�ER���$^����b�:NA*� . Str>U��� nd[A�DMV�oI�� l`}+Nbo�,A�gni�� �J�>�*T��w�,anWy2U� V b)(a&� �%��vBC!$cy�z�zzaa+"^�U�  �1d�ed �o X'� "pt�-�)Y�&�# mpanY+x–�>~�wz ��. �E~w�.� \ dI�,% p�(m�(tra�a��fi��� ocy%8 2��m:�Y�� }0%&Q,l�r�)byQ��b�� @")lAfreezW stit�!( FS ) �$Weg"�r�%e'�B�b�a� ���#�ng 10% wi.�V medium [39 U&coptim� con)j��pre!�ff*�.�Vero E6.�c%^+v first�\�"2 h��!X( . i .���abl�N`'K&u>�E�u51.^. EC��$ had sizes�i] Z%150 �", ��r�)%�1V!�C&� �&p� 6I y��{�>*�%s�&, occa�(�E�y&�oA�c"�#" 2A )��4=`on D number!�%���*22 �/ �s �"T+25cagWfr" �Ii%b� 9%�� �toJ.��B� rrow�At�AXl)� �,�becz- �i2n���Eg��bB|�` �rd��ʡPavailE�IF.� 9# '"�J7� At 7=�%)100-nm8ck sli=-E���)�� %ed2���'� a�'�"� 00)D��ik���A� �ouoq�M0g�r-��ppo!�:�A lu�+l�!�q}liu/bilay��ubea�O%e�Y$h� a"@ simia}Iѥ� �*k �!�&..D %�*ջ!25��c d6t�y�s)exaJ#>�u�9b�.���g:s mak�tix�we cab �0y�luN@ N�M��l s�:-:)����Y da� . ��3]ȅ�w so-�ed�k��N(( C�, often�nclo�xc� A���y�����!�e�%:'0 . 2�� 2 μ�  prob� 4<&�� +� ���%O�6�'I���!��&X,usN/patiti�.�,MH�,J hw6,0 y ago [39]Epk� �,:��5L ubEh�er� ele, '͟"R* � �ER-�- �k7ar��RGI�G[21�- � %a� w�d!�res�/�6�~i Iby flav(�� %&�/���fa)- 1�a��a�einD�`[�40 , 4�In��of�!�AxhV�&.��E�'A�>�]�;�e �ER5�� suggng�"ink�� ���i8Uw�E�  (tM`&` ��(!>��beyond2��/w�6edB,!-!MR. surrw�:�3Z:io�7de�b 5Goldsm�"�72�y � ���� ( VP# id�45�'n� ey%��&��y�25�P `��E���erdsiz�m('$,a�ct�.deR9� :vA�er�7( belI �R~&in�"N;y�A'7X,k'sat �*ier�)poi�6. D8)V��Y>�A5 ��� � C.#�Pgradu3 disu8,.��0t.� �!�� averageM@.�ad:�at2g �250 ± 1( n = 99I��as �i��� �ir}wAA�co��� �H#� nm�1�a>< ' ���at 10��( �-ɒ��s�'ine�#8�#!d�2*c-A� N��i�ܵ�J$ . By6�, z%+ ��%�� even:r&� ic vacuo~vn� ��4U�a� ll*, �}b�!���lD+vi�ii�u ,��i�!��[�)X� mock-I�:� �"� N6!4ofi! f8���D�A�>0��a�P!)2� :9a�~e uf! �6C��?%�9e� 73�W r."�ET�semi-th� (� i2" �� QL3a[JUB&�ż� hold��� � ��be"��a&@ axi�per�$ !?�."� beam%D� �:��A��4aA'tQ each!r�&A�of 262&� I l��";4Ebu��"N(�#-*`4��>u�#�B�S\7“�M-�Zs:� visu�2��e"� �AQi�q.�  6*� �4a֥�� �aE; (a� illu<094Videos S1–S4��;s�"�5�����A���per�!�>%aݫ�$)d�+�� 2m%�1*�� n"�#4&c�adv>d���8��. N+'thelesA* |A���*�&M$$.?�AP�-���E��a��N�E0�>uA . TwDjor!���\ECET=z�7(F(es�5or—�l�"l ��sm T ���&ir:��( 2�#a�t| � ar�'an*9= �\ E��!w !6YER�@s>}!F[I�  I����� ne�$p��( ∼8��in&" “neck-!/a�-%s F�>�� A'�toٷ�3i�.naE��5��3\  . For"�2A�5��=��!u�%�S!%E e�D!�2�e� visi!@77��81 �e�C:,�R�E��I��E�@-�o6 ~ s ex! d�(f/4#NG9m7&@Oed"� Az�)+. O +77 �׉j2 b�%t�38�a. ��er� 2_$n� �� ��O!�� � !f�09��S��ly�se 131:*aI?x(Y(one-half�).6�v %���!bI�<.�toa�orA�����ti at%+� or �Xpe&n k��"��Ň�/;vA.A�,-%oH!(.�. Con&$5!Ka��$�xpE�“H flo�i˕�"�%((nE��- )2�)�l+yAachA�nit=)�? adj�2)!git �Aj ).%� AJ/8 �asMj&("V I@��3lul of�}ER--3.=��� 6 �fs �����At:S9��A @ 5%�4(� "��(r0Ys-�J� �.���k� �Des�� fibr�Pd#aKino'� :S�.�" rS0e� re�ly�on����!1DMV/VPBem h*P,s;�� S�/E�y)=� �o@:=xr1���<�9-�:�� 6�;��!C� � a�aA��begun�.&L#�L�E�� ingue"a,u�A�ph~ p< urݳ� ��typ�#��45.3��=�� adja�>E�>��0int�:���e��littln%:d!���(��2� �� r�y%�:(1�s��d �of VP�e��Y�%� ug"�[]"�:�U�5A5L4� 2�"�#-S-" L=qU i���!=� ��.�ne*PCdis�in� �m�7 ~��:� F$�E de�(�D�.ng�� b^iS appa>A!L"�$"� �YD1 �qA�ter��BuI"�� > �fB�*�5A%s5BA��S��!�F���vB 1(*�9�Y u���c�"TTvolM �PruWK,�In or�o��eJ ofN�h�� *X��N�E]&`IEM�1erq�kV�(6X!!� ;9�=�(�e*R#~l�ItoI�rv�!]a�*E���"i�FS>Z#�\��&-"�~ sampB��embedd ,Lowicryl HM2 When"� Z4�#a� 9!�%�#��6�r_&ser�3fortun5 no�Lb u&�cir�>�G striVNg Ku—a�!�mo�—A ��|ly�!&!J�. O�o�� h�)FQ2}�U.�"*�% 1�$ �s��Fr�8P1.�in%�1��d6�7FHBm[%,���&uA%���/R�S %�)>>�G�ACH/EK.� �3G at 8Ri�:ig J+fic�gol�be(9�oe{Um1�AF!�)J�0l1ˡ�a]7� ��_IA�"v*|@ls�)!M4�5�/inp342�0 Mm�"#�1�843$A"� nsp8�QEm-2c)s��" O post�;�-a� �c!��8��lex [4� 4 0�1�a�%�i>� �FS5�,�Q�*�s!<*� M U+!{�-geYas"� � v�0a��Bagu!,s��!)S O/,���CM?� }9 abov*� I�ReA2�,��G��Rveu�YZ��t�*�`*u;�For!�*�:,2E�(E�pSC�>Ek� o��$!b� �"> K(%%� ))�*�EdevoiF<�> 35Aq�7A�C 0!�M]� �Korg"K �#�%Nm�i" z-�#et�WE ' 6����� e����uF�t,U�|"l4 Hof"�?keQ,p�7v�3�Gs�K,m��qsI�W6�<�" ��A ma�M. A crim= ste�NAr�o� +�-{ �#��G- :/;.�6-�� ����EA=�"��"ls*F;a D !b�O;Aщ�����BEa;&�;.H;I�Q�A>&s�����:�aJlea-?%&Be�*an�6�Q��D}�<V�@5OvN�" RI� ��.&�V@"(q�*d B&],ɪ����y^�8�3be ?YO>!��&tJ?��aw:tF�!*)�O:Gsu�=!�e�I��Re���1$ Wu��![!���C} ��r� ��a� �(2�� �1� i86\&W ����8�)x situ��u�!�Jg2 `[M%8–5k?>4monoclA7Iy J2 [51� .D !fdup�SM �A'�I=��a5hG*� use�^V�r'Z�+"! 4@ �|R��A�J2��  YE��_, !��B>K �vZ�/>x"6n �VO !a*P7�. Ei!b�Y$�� nsps=fea�I)f:��igW� )��al�  7&a(J 2�:N &+0sm 0 v�]br  foci� oug6�." �By2�# ��/ ��� !g_g"�mirro�"��a�"�?5 ( unpu�6�an� �BelH"�R!�.�G_R.M.>CS7�*� A��Acove�Z)�arV �6���f�!e�<�%�� � Wo"F�hX/ E���o]*pp s��L�2F�$ 1)Rr p�U@mai�?0�2az1*�?�]9�#��&�Y"- ��K�R�*�7E� ottom d0A#iI�<obI(a\� %��r5� D!�8 *�2� ���{!�.,��B /1��I� � !� �d k_�Q-#�XE ������"�>l*L+ced�Gd� �_ 3 %�A�� ;�J�"` # �:} >�ON 5�8eQ7 !5a�al o be!��*}!vicin!$[ �� � }�d�(� ���i� AlsoA#� 2� Y"X9�E�� �("�rR%�6�6�.`always���LJ�� ��%"� ofM.2�Bofb o�4Discut^)&� 5�&�&HB% O sk a���f>5}�.n18!�6BK )� �isa�Y)��3ic ac�F. $�I�Uism;3a��vIe�7�dr� & q�A��*� on� �tE!�R�@mGI*�O� M'"�O�B$]. PU<;��*�%*� � c�9�/�%RTC.-�R`le scaff�A�� D && facpR�/!3o:X 7�%!z:M#i�eva, or d}Ra�  =�:��# pn�*S-*th2%�N�R E�"[`C3�"5WR53�0A�1p���9:� S�8���%�1Y {:an .�k��]&�] ^CMEX/ le-%(� J�(%�a� He"�Q5A�9�$>�AX#5'�rN!�&�^��� l�or!!by Kopek&o/�Q n ET" UudueW tn1`YtofC! ck h%3O��(ba�n�,d�7�inv�]%�%Xm.kEl> �YIGmini-E�ell�% � �i &� �cyW>9 "�%�E nnel��a&�%!x+Q1�C � V�R":�'suffici�!76t�E_,*��oti�@"/-~j-<��ex�E)���_b �"�\�1N�*.W3ack!�GE a�_�o DETXE�zK,6�%�"�B9promin!�-9�&�\��(t�u,*, 0E mino�B—enco!4ENst�R� �s U�K�� ��en2Nb�-��ed .�8LK ,FIA � precj���XS! �M�$d&TIdeb� A|"g" 6}N�$"a&�Y� Y5y�.* � .7*�jLrmn�C߱N"P �1�%�iB �mx u�K!F�Bp�&�6�[� �L����c/p!���&Y!�= ts�"�a“� 5T�Z ��md��iO%�EivDE�>4S/_K<�n� 8("T hund ,� �y�!t6�Oa�jA�R�e��k�"��+ "C �Mr-^k*�h"( �"z does+��b��0!��y�j�e� �4E��* 4"�3i&�H��H2� 25-R�+)O;ee�� a)l-ckn�-�+k=n�G \v �a�!�'� !@ET�<it}���%��.� >SS0MGol +��t��95%c3�����e�EJ�)%� hz)� �.�) �(�Y�%�clH#Y`��A.�ddu�A�"=�unZ-m1!��)�,}�3�e��JF6� �?HHk( �F�.� �� � >,� >�Gs6�a 6��eg !�� . E*T�)���R "?a�s "�4%�  3ݚ ,�^ Pp^ E�i��g2� < ak�%rF..t�;s���DEzxt �tFigD�le�� )�a )e&%2&2UFI � � aS[i�8�X��(!��F�i)�%��f6�1( 8sE���A�%�I�6m8f�"??,�d�6�CQ��%< sp13&dZAY's ( �@"�s ���Bay\ 5.�&spwER�p���:�l��e *1 �;�>[54�Y?� rro l% !�F��,��r�O�#. A.VU!%t� r4s� bulO`/2���@&o�U6[Ue�! w�f��, �. expl#e� m� � nsp�!��L!�M5 �F2b%VCHCb�JBC�=a9�(<>`tN�br:�$.� z\�:�)��l{Cg� �T6�&c*&U�2� . No�O!�G�6��eC r�N(*7kQA ;d kin�"poZz|zas�W���!ma�)aQ��#lyA�%4/&!�: of�mer )I M:o�'�>if�-}9�8e�y.�"�%�a8;(C r� A�l�Rjuxta�u^nd�}�1� �&x6J�! , ena[���٠ fasc�Lng�Ta*b quG�&.���Si�%�A!o Y�i�(� �igFc *�U���"\��s�:6�_;<peak "A!����TM`KL"F0�e��H� !i.K,“U�"�!��"�*E/&� es [2555�Y$3]#nti�w�܅*uDMi)A%� � ��"� �i� �8( m5h�e��q!b�nc&.!�e"�*A�<�rr^&��&�7roe=a �20/�an�_!ru�k:j0%)!>*�Kt. ){9��t'Dtwo� OU!}ba�����s �'94B!8scrutinO:>�/��j�B6�Z Uu�ca[I�fB{UEj �"����M(aG0���, �R!VQ/IQ inde"� 1= . Ne:\a��'! >��"�� %�o,! er*+ bove"d�2�[q�=t�mA:�>� A�A�he^ .��e��.�U��&BvAh .�!�pv!t ��8��search4�hpe`Iv�!tI-7;=� ,"�,s o�,�ځBQ�5�nguV����c� \cA+iof 78Ds!/�:�E�>%�:;�yigPga�%!�68b2n!i9 S1�!F6���8 �profi����'2a�*�8is�"� S1B�?1� `*si2�, EC�xL!&vL!!�leafl�Z� N �l7r��.� i��oe"�0o�^�I�+���Gi#*Kd&zU2�M'!/)�U�6!Ca �6� sur(iAFA�R �{ro�G�n%"b��)�o puzz�:ta��>�A�e�UE�� M�R� ANE� �5�9v{�� �eB5� ,un5�0 |t�6 >)W�- Fs%>�b9�Fq!(Q,*C�06`by����3��#��~����<et1w �E[:��5a&Y( �&17eme 3.c~;)�i�&�.�&*��6 s�����33 bi�V—)u.��+m~Od��"�)ir�*3z��2b�|A)� A��� un%�A� issu��It�  st�S�a4e{ KBe�ace�;poG6 ���*be!r5"�q��퉥!�  . ��ocon )I�r#/�4Y �(in EM/ET �:yet2�.0R�� �i� 2��� ��r�(SM�f�"�un�� ng�,n/, hydrophobic"UgE"a�eacZ^di�}a�r�!�1�&f� -0t܂5�i���!�e�5�&ud&�Ce�+��!9)� phenopg.4" a�+er-&ڃ�mutTr�ClemEk%*� �W re*�kA� k%��@�3!�e.y�gus"� 6e���El�� X�fG?�.=i�j�[3St�, a[-7!!>�z- } }`2�i?!��Wto�5�-"%jqnel�drecruitZ" �s capD�orm�Q�&�R,���(pK{"�9i � � �w��a� e-1�����a�6� j����?x�X, ms � �|��i�a��Goph�w�TOa"TIM��*i.��ss N3!� �q] s [5K�\M.i�e�2��T�k� �), �.8��/�* ��a2zD30-kb2ee8�c"�f�4\zi<Y�m�o�*�/.!a�w�A�fexg�(9�m��a�e�E��ul<2990$6par�!�� �2�/��)5�Y�e$�,�t!r)=�o8`y���4܁�$a 1�Per�N Iw8� ��`�ni� iI� ��"� j� INoW� ��): upon %*� [25 , 5�/660MO�al� &�r% inse�$�"&=ur5EN�cC� � !�� !oZK�Cq5NA*�. >=��3 � :o�l��QJ )spg%[�T�3!�J�-\1U�0/a�cu i�+":.�y��+�al�/7,oligomer&�9.�e���el�Z�or!�&��bey'e�hADm�ner��� �be!�.�o&v"-!�����oe1ngw!"L�?c;��n2 !|C$��eE��!������>c a 2�+"D�� upI�eDU�re nagA*L��f�)tr�[~),r�G ����"YA"��. App�Bla7��/- � s af ^&;�5e�GiJa� &H�%�I�>:a��tb�Vmr�a��`W:�� ter*�B*�-��6�)"� &�drug b*5ld`��~�f`� %Hu�+e{��nd :�CA� &�Gs!x�>0ER[o %)a�i!nd(-�X=��<s&���}�W� �*aJaW"xs*%K�a�:..6��wWweake. o�"yo�� E J��s �a�to�B�EO\""%~�:-U��ra�_�m�wrڌof0*GITIicaf�e�n!�2n:rf6l%&���eu1to�"�sb`.�. ��OR�hu�%et5�A82�.C&�E� 8C! H ;��cou8 � ��� $Aunq��log_"5��$vO3��r�cAW�-� 6N.&K�]eer2�"��*v(��щm  age "�m��ꉉa�mss.9'�%� iVo"_Me}A�aqu �9� �?�Mtra�6forward�rgu�@,!e� m(���6#u�`�cap�`%or�cu�'i Pn�ޅy rchi���%�3�!��2ria�"�:4Et4!v%�_`�()��1 picu�*�B&�L��! )�qcs lends%� cred*_� a scenari��_a�aa7!N�F�8 de�1h<an�h�$�4*:Jrm2��2Ma�!~ ibJe�eI� toMM�<'(�Q)!�M :�&�͚ �^�B�i%�4l~�#��*�#� � ['�2��"y occur�_�"m�or�I�M[16�!� l���tJ��$Z�5��Af!שb)�5��� xinhib��y���d . ant-\c��#or v2".�$ �A| :3v>qW.r��b�>X%A3�m�_geg��T ��,��)� 4�&uc*a%.�H��i^!\*�j��/%F^scr=a. I noda{ �7|dalp�)kc[G�j�@picor�� aggr�!9�9osette� �M3�j4&?qf)=�0�GQ�-� �@�� �&$&+ w�X�ra�&�qiA���\��i"�b&` [6�}t����"h:P"�)5m�aA�Q[63I$Y��8 utophagic�6y�IirA�[6*A" hypa  �launc�=*f ua^�4)�[3�D�if'v��e� obllC.1� �6�a20)�a&FY��y ( Apg5//R“�|��9q�by�(1�u�=�zal�'��[bl\{6�+!�in��t)�unc�"�r� .zl!\�1��li.*g� f6�g� Y����J�IojA8? � n7 Kunj"�OEmH^�M&����.�q�|]� Y$G2�_&y";/�}l�LAN,(�B];A�aEie*�x , &�7�-���$zol6��Ar�B��9fe�Qyc5�����!!k��G� w�$ng!�!directB�,o��1!��}!�}ZA&|i�)%��^Fd� Q9�kol"Zi���p&���-%�"��w���6��Gp��3prk�2d)0X9�$ �p�!�4, 4� &3���%��5%m��|EK8bC�urf�_, BrU �. corp��Y [�:A �J prem�5, &13�A�KT�{5'�9�es�j6566]�a!CideL(a,a������7A3&Jr))��*L 8*_$3) �Qŕ�� DW�Q encl�, �!��A� �D���zT� �8b*uZ�Ar .�*M̽���amS�Y*��[�@O }E<(bu-8e�,�Pbov�y!"�)t"$^AGG/�!�ѓ��B !'a�I��?�%N5�XN��Ѕ���va�*�A�.2)���2�Zf:�-pa3�*� 6Ka�r� tM�0i� )R � yLubA{Ae�suscept;%�\i�l1�& � Ċ�OƆ [6�<��!�",|\16D�"�'�eAC l? r drawnu Q^Z�y�~��j�to'R�� vem� [68]!��@a+�"top�����Lt*;8E`M%�5f�q�.BjZi`aB�m��6�1%��>ccI^� .�9262S�)��� nfir��� �A��K""=s;�P!� 1"p�!S'��l !i : if:O _�)Q I��-4��oD/��rn��YV�?����?YYachie)#?!+.�al[Qɚm�m*�8U��"�mss �:�i�lJ���uN��H.�9aCG.�'��bA��m 7s"U;�!�.I2��:0A1! �emphasT)K�>pin�n*��A"Qas���UN�6U͸D..$w�s� f�D� F��!ga�~ !A� ���*S5. Exteh/��o� �(&�M6S s1�upp1ab5m�gZWY@*� �V%��?� *�R%K��� =R" "�S" Bv�$� F �f(�%� ?N^�c&�Qcz%il2�.vag�%͎bt- 1A�i��*� :�vme���E2s�w�:"�"L��E�4ne{a���B���/*B�My@ E4q�i<�*65CM� �c�2�/w�"A� -�.aI��Mo�.�If��Q1��og!�(ُ#a.CM�?��� F5%@Ɋ �5c76�+af��^eS,!CZ0�Yw ]f��� CMY����^!�%�a��-qpu>0�B�W(Z��rl�y%�� N�A�He�M6�J ���R �P 6-2t� a��� �>ond����!�v�e��S��&Y$>�Z�8)��Y�Wa�p� %�e!jus2�ZAٗܖt^>� ќ!N!A)� �I�Sco�inf�:� �u JgB7!� c�e&��A()�q� ��aQogDu�D 6L|%&�0"lI� ��zY��[�9I��\�@in*+� I�NI �l��!� ��'`�>��i�rjiO A~ I �%o�i�h"�zC!�!�6� a hug�"��!!Zr�}�+�� r &(s� e�%1Z �)z�":5H;A��5! "�AֹQat �caim,LikewS!0u�E��*Y>�X- dm��?rގ0&�A k",T�Z�BJ�X"�A:�aw . Cl���[h&e1s1T&� �Q%��*as�~>� � cȐ�� I�new DI�i�!Wfc!n� puls��[6ސNYa*�Z�%< !�-��{_ !AB�v��, �Int��{re��ts �9IMh &�b)U'ng3X�YE�� l?� !Ynot֟th $'"��Q�<&�C t�j�k�Sw.inJrrlone* li|�((,� an;�; e�) ��ys�5r�Acive_A�=" �K2rHTU�i��i��!u,R�R-I>moF�W[6W"h3s�/�3%��9� b�stA�2At8d���J%RaA�-6�iQc a�&,O>�A���U)�^D:�ofR+�aeT,adioisotope-%=%6�oC�1�=Uyg  aS!�c�O"8 ,�hosph�2 IU�  ����whY-izt)��"�W^�B��@n� roach9��w-EM�FS&V5L �e�x����e��(!a�� D�6Ge]� opin!,0�UIE&AY9Z%E! 4�HV>K [26]C2Y9!hr ��s� �/e"74�גd#T$3g!��� "��dGJ+C��:�uA�ue!�� auth:)| 6 � ��*&s�I��:�Fm�ҡ�6 _ic�'a 1-h�[v=�I����*�!�m� �Z ̓�U�%e ��R�tA �)e��� s 7E��K&�Aruad�aBEh� .a�� JU�"a�p� �#>X*�8�dt�CM� 4 �$�u���;M5��[A .��r�6x � *OXAeE�<s t�_%uk 2� �Ԍ9F�egl2&v�e�nceal �A�l �eva�,�-t"�� �s Ht�S3c�l^�)�c%]��aK"�A�/&�1E�A�=n�Ae�)Չinn�T�e systemA� k#l��m�e���I����?9d�B^� 7�. B0|S��CoV%E�[7�T74])�"$cA$�,%e�1��fe��viae���Ak%!R� 2!^pt-e��Tc4�'�}�)�I�[=/10� �� ':� AD3��unc8d 5′Aݍ[7�hFu�z�-&�(AP��G �!�- �O"L��.N1  �o�|�(!I.R;shPat ^&Lunu�|"%*5�72�2�29!a&�*� U � in Frank�m-1 ( NEly�Bv�:D`�H��abenauEJWi�\oerr [Johann-Wolfgang-Go��-Un��sitäP,t am M� , Get�y]; [1���NtY'� >�nAll�#eol�E�?&o� biosaf�cabin .� hee� 3�i�at Le�% �y M�2al V�e!"Aq����?ofWU���Ill "�oIg2�`*roBB <rS(�!ass�[��pa�U� abbia���5� ����k#.b` �.����d"�%*��HA m%WNt &$c77�]� �,dpurch9�f�Sci�8A�orB( m�&,&��m���AJB����pD�_t�XY-�� )�#n$Is3%ca�ldehyde!��p(1 M PHEM bu�( ( 60 mM pit9zide-�R04-bis[2-ethanΣfo��3\ F254 HEPES , 2 MgClEZ1OEGTLAat���*O]sD YW�L8 "J ,�\!��ad8daxThe�ox co��l۬( Nunc )-5lun"7�4liquid �nJƔAAy�,at −90 °C!;� uto�s$+�-o1aL�C(a�c�b� an <uma)�A�(of 90% acet�B�&ٔ,*�;*1% osm?tetɤd�d%�$5 % uranylJ��. A�2 wash?��p�,lt roomB�:܀V�r(epoxy LX-12�i�9T�"�SE���$:����<x�i�!I";�vie�Bat 80 kV �a Phi%�CM-10� m`0uI"�%�or �Km\�]R �"H�Y�i[;E=!>theP2C�6S-5s!`fA5-�M EM PACT2� &>*A�6{ ?n�=us5�!^aiEa�$25% glutaru�!a1�e\�s.�t infi��5�"c�te �#�_ UV �!�− ��>J&� Q#�h u���%�"� I��6A-:hp&K!�15�0�iA gd%�ɀ–h-� IgGw bodyp�akoCye�a�qp�� 3A=6bi . GrKa�!��q���R9�Lf�$vrI�t�"� �A�L��cu'�w�&!pAgle"�(a�tm�.���Ka>st �ar&�CA��.&, �t plan�ug�l.�A!^� 6\m�\�. E2<��220E�Q�CAvH-RH�M r8�-���=%�+r[��h?a� ��c� �&se 3digit��5��))��s׍i.�"�Ea�-"�)�� � �6�. MN$d Y-�5tE\ ZoomzVsoftwH�wly)IA� !.Oq:Ub�a>K�i~a��%bn�G�,"64Amea�A7�I!J�,( http://rsb�N(nfo . nih .ʴ /ij/e������2���6����1f� &V �&��ׅut��9�M8 To� atc)�&�@�i:)oo� 4AvlZa�q ^ uspe"�1�B�u|�y��o'Kfq�as fid �d��Ddua ��')��I�-a��seT�% �e&�����Iz EI T12��rD)��^� ccele�>ol؟g122 . Pe�t}�F�, ��%�m�at ��s>#�8−65 A� . A" �(!!acquistu]!�E7 ( Xps 3D; !C| nyE�e �G�e�"o�;slow-s��-ge-coupdev�( CCD��4�(a ( 4k Eagl�NEInWf096 × pix D�6� by b!��N mag��E��$18 , 500×� r� o�6r�_� p�n�E�� F�.aZem9^�� 6-Mroa�d 90° �:'zI%x .Q�t�*!�/�Rsh�3;v( 2040%�TSh�Z5 E:��c.7�ume��m?B� �N IMODYeM>age [7�G5V-vo%�_�s�-�a� 5���ll�C�T��-deI�g[C�yed DataKr��ccd��ucs�9(edu; [77] )D a�s?ms 602�T60�H����2$ �]D�-1��C2>P, �^22e�S.:�@i���Ha Zeiss Axioskop 2 2p�*�( p��;��J�� ��� O [cam HRc ���z8�o��2�%)# arl)�c����A�� ��SP5z�vlas_ D.�,M�a pinh�u-��1 airy�S@a��."�L)!}g)���"� %|4eoTN2Hgof 236) .28 �_A^"�v?�a�ght�giZdAdobe Photoshop CS2 .k�T7d�&Acto� �#F��of how[ts�?}!�i����.�scaven%n̩a��`SSYAsoi�noM�tic e�&�(�Q�wHBC��:�4r sub�l)4��Q� barr2F limi�M extr&ݛ�apn��~�0ofJ��!lSro!#.&��q � & �e(�d�esb��Q�1"=�T5!�Io$Arabidopsi%liana"� 1 �%�E�)�mov .r �9�� u�5ah Nshoot�� �ag6�b#Gd*d ����Lo�Shav��?d d���(�/p��z��!� a~�-�8epcy�"t� vegevw�wthA�io� F�m$�a���5QCnd h �ort�`*�e�d^*a�-%>/C�`M�DTZ@u�"t8>6N6�K ,�*, S�CM��5�H!W!^���bZUX���� �A1sAysa:>.O�jol!]S��$�G!�up�g)�!?-"l�C: 1z";. ���a6� ?�� @p�' ��D�ah#im�g(�,M �&�3A�����>=��49��  .fwi<F�1yvQ ga!�p�Is16MSA�-:~]� B8*H�A�o�n�Dl �grE�!�.0�a��2sk7Junw!�sT�e�EeeB��)'�  9:X*�5+-�xy��v� �>-�{vas�<ti!YQ stelA��G��!�!]on��at�!!���Yati�!X6�e-�is�QtesA�&a� bitdi�JcK`8�es�a util��!�e�&/��!�4s [)U+ 1 & F�� (, Lof ma�)�2r\o@�ly)yaM��� /�Q���>e7: O�/@HSa �c�wve)# ���$ tify"~'��9&fq%1�!�!� au�+!Fu�*��"ad��9�of ABA [�HrB, [�GHig��m�g� >4I�=���l'de Ca p5+��2Z�R�a�A��[i�A=ߡj� moeN9�6�0[�FI�� cQ _ed�t{��H!�v����*�^�es�~ �F�I52quite��h�.)dET'U�� M("����4b��!5�ձ��. D�Hev�>"^v�\=Vi5-�  yNBr��Ia�� h�?�Ey%%@a �1E9I�am3!.BZe. C"�:i r�� �poРR���� �]�.>)�@L ��m���thI� s do�6E�� ��u�[9,)Q�U3�i����%�!ݝ . Knockou��l�!) GPATk�enc��a�Hyl-CoA: glycerol-3-"j.F&y�%nsferd+GI6�r�:7� fd�50%Q7CC24�[5d ���!�[>/.�W�l Сw -of-"� of �onq�����rn -��f�Gu8"X".1*�"�F2�1�W4u.�� 21�a kJ��cy���Y( P450 fatty0+ ω-�'xy; CYP86A1EeZ 61Wto�ual1SQ>z&m=[a<a^O ld-tauC 1���N=� DAISY loci�#EMC β-ketoaMR�9A3"�1I�7i��2ocosanoiZ�� ls�UQ�b�.��<�-I! uC22%�Aw=b�R�<a�61�C18 <2�.<[1KLNo6! impaӃJdB�f��!iEB&)rQeA�r���"�95sDv�B���x-�e�+:pX��gurb%�� Qfa�� ��E�z Kai��&~.' i�  �6y0 -Q��screee[2) ?�2�+�Xe&� 5HHQ]��."4��� WL:me��^icsI�0!$�5� � [��\�.JP #A! *� �7*�%c�Z ���!.!2i��� Y� � 14501 ����������!*W a2I�yEl��d�X�P)��A�Y2C �ina�1; �^�-��qisAv�1�C�stS6M���� at6��s �2av;f%�&�i[i"*?wi��a'/'3AG�Lao!�> ru#!B!�I�%�A�k!b2�R�UM+� d��e{�ZY/ Grafx & G nf�Kc� enHk��r^(I�ele){!;5�-�Ia s` rect���1���!P-k>6Y){�of>� *�s 2��r)cPut1I�Hw�Sed �2�Jɇ6<<\5 Y$M;N d Cd%sE4��F��� oA->_�m�M7�*� ��i�!�"BE_�Mp�On&� (� 4b1-*��-n)� s2�( P≤�/0at2�I��C�i7 n��% .Z��E�W�Bs*��67�5 )MLFet$�Y����7�no+�u; �@2h"+�as.�,)ba"k t batchAA�sجM* (�tr�53˄35�59n&59)�Swwwq,��hu�&or6"VJ2dqBE���=� �H=!%ke�S� xi]4ly �40%��5w>� ��*} ��hX.-*w 2l6��<�bl.��n�*�o.�. I)0j.{ofi}ti��-F5o��F2 pop8T>� !g backq' Col-0 x �1 �a�A:20Iss B �L O*17!�SmS%+(<�I�}a�a] e& a?ac-7s \9�in �2�LBm`�VM�.ex1�b�� �! �>@ј�%�1)��.��9�&i�_5�ep�8ͳnti3!&_[��Fof�i�<u_ď0s)BSge'8�%�HmapU caus��v P*S)�to6Ler-0eQ?��b�175= 54J� .�'Y Gpe��Iv� 6�,࡯��n�> ough�� a�@seg_���(i�2BS+9��j<��&�8w� k$ arra� +o�sg��/[16y[~�, �#�gx-U)=-�!Hst�!<BA9 (( n = 4����@��ea;�M�@ M�BNCaA�o5Dh�T!�)o:g�p�.RW� a�pic DNAi�ea�tool hyb:Z1�$Affymetrix2" ATH1._.�#oligo�4�7 �'I1hev=���a���c�i�I�!a �a�Ja5KAS�0 F�+ Polym�2is�r SFP@�i[N0m�s.n1�Ak���L �(a�%�_ 1 Mb�<V_e 2y3A�em �eq�!�28 ��4M#�]9�$DNA from e�Osb1-1 and wild-type Col-0 to the Affymetrix Arabidopsis ATTILE 1 . 0R microarrayKcomparedA�hybridization at probes that represent sequence between 9K�13 Mb on chromosome 2 ( Figure 3B ) . Nineteen \covering�regzHfrom 12 , 308 , 779� �9 , 878 showed log2 intensity differences ranging P0 . 23HT3 . 57 with an average: of !/8 . Se��of this�trevealed a 1097 base pair dele%Cstart;at��627%2end6�72�TiH lies�,in a genomic�containJAH2 putative open reaf`frames ( ORFs ) At2g28670�1=�0C ) , neither�@which are predictA8o�!�$rons . The�is��:pA&ter�of� �/ 3′!(.!�EaA^xGABI_858D03 ) has a T-DNA inser%�:~57 . We�aw�E�10FbI�,eviously cal!�TDIR10 [18] . However ,Inam!�is notEdaDany published func�al evideH, but ra%hun-Hphylogenetic data .� is annota!��“diseA�Dresistance-responsAfamily!{us!�@TSSP [20] , wherees��g!@m�oBXK�Wegref�conclud���(i�0e most likelyU�alI�at)S locus . ER80!���, e���� P2 plants was quantifi)� root��sh tissue- *�RT-PCR��4A��\)&ly1�ds!���A little or!�]in �n�ul!Ain both �2��~ arch!�A�.� Gene.U DataaM0 ( AREX ) [21A [22]E?i�o�na]U�pattere�9��E� g�EQ imar�[��e)�endoderm�, lower level%UQ 7quies�� �[stele%�ca�x=�R To esta�a �loss-of-.��is driv1UI>ioi�pheno[ observIE�$1 we measu0 elementalG osi��!0leaf material�` CM�2�BU$grown toge� . Ue�principhn��analysi�PCA�%�e {b� each!� �w�t!�nq� �f  u�cluste��%�W �le�up)�A�distinct)�� " 5e�6 2� e,same changesQ:b�%��&� o�m� ( Table 1�b���z� (e major sitŞsub�  deU)M�pOyi3,%Va�local� -� Casparian��ip�!� "aliph�E+ek�)8Fluoral Yellow u�(a clear inc�=e�sbin�s)�-��imG .Y��� In p cula. _d]s2q!two row� cell5���Z�0n , suggeAvgh:��a�)�U�6A & �NSlight�lev 2� also��q us�-��t%�To�9�m�fer�YRf�e=ouA��|of]�ba�Z6� 6� ereCno�eot�ligni!� �of Sof1�or c gDem���Mz$individualR�mJ�]x졓of9 !� acid$ alcohol $ω-hydroxy α ,di ��erulicA.��fxV":q� Supp�.; Give�`at6vi��%���]�au�atR�� e� ultE�a2:Gq�! a�5 � lter�M����� 0we hypothesiz�V processes SsiA�� Jic.HIT� o tes gsuper�J recinJ raf@experi�m��we  e.sci�ontb1�stock-dE�2%ٔ� *. Gz2yn^(^� )Y�e�!�z,�epend��� � .��mwJV�a�c��x��� �� A!� �`��separat��,�ardles��%�>8�>�Z�BopoA�toA)(m a barrierw# movH  throug� A apoplast@ �� c,� foun� �,#ul�� enhi=z�du�z >�O %%�V ��!�!/ back� soilv��utranspim�gilE�af� u!�drawalA��4. Peak daytime:H!��+6? Q�approxi� ly 15%IOos�A` 4�)9��s|�d� �Gguard��a�pi al pa-���)Ţun��� �Z��10� H � �6E�!�r!���2cin `� en by a}pe 2�de[:c!p-widthe���edc6p0%b�P<�0� ��& magnitud%�� �>�z"� .H ��e!�]Q�1<,I�!s�stopp� E�5-week�"� ^e�QGE{monito!��9a. BV� ed5L0 rB$.��Aʉ�>�1!ba vsŢfu� de61 %�fʼne�&~!�4by��>. P�LE�ńnO��2l ��s^/^3hself-H-� � �!B� ��!��t�11��*� -_W�:Tuse efficiency ( WUE )�,a l ����q��o biomasw oduaPi i�� im antb am!�EX!�a�s5�-impacte��(�-q on �prtiv�. have&n�� &+ ͜q/%3� �d!� a de&^ 6z�& I�str�wtoler��_s du�k- ro� =Ŵ�ca!� a sm!�( ∼14%� J+dry:s!'�an �@��jhe amoun%]B�per uni ��edAxa�A�6���o�8�ks� fic!�(.7�%�Aj�H2�� Rad�rpthan ax �ort!�kn� limit �loMby%qs [23��force�W� �acros-!�Xpro��tenJ( neg��J) A&t )2�if��oughtA\b��= ic2�du��P od��e A�>et n  inE�a��� i���,Ik� osmo�)��zA7uptak�mnutrie�i� xylem!�t 66"!�.� l9upathway!� �2�� -to- . ItN� a�� “C��Model0�Ņ� �aS�D%s��up � under var]�d;��d bale�AuademandAk4Ak&ubei�!)>B�w�perme��@���to mine^H ,} /��solut eiE��*pQ�q�N�� a8m6� to rae��", [256to"e�mu�s����E������ d�a8o help elucidat6 m!�"�~�� gAw� ��ly higA2�.��c2�i��!&�s�|iE���!z���.�"� 1 �#!r�  �fi�accumul�fUr:Aw~ bYebe� I�b3!u�� effe�����-�QBicMz]�).QZ�QM!�2��_�j�ent f n�Y>sL);Ca , MneZn9h�|�)�q gnѽA ���I�E0 ����J uXvia31 %�is&[confirmɃ earlz�lu�zof Wh�[26.C�E�!�of�siologk�biochem'y ��/6���ic byp� �� exisUor!E��� lsY!�� !I�I�mQ�d.rcyt:�Ca��co�g`invers�p�(!al�Ee��Q�d&�[27�yF �=Rby-R�'coworker��8] �Zn mayKr�sI�!���I-'1R�]ur��aA�; %��;� S , K , A!�SOMo>�A&�2g�2YU�edm�lyK�%��6^�, makAW them"' ����<1�i�mjpr���influF"ofQ `)P!�u��ѹdueCV ����q� E�I�e Nhnj.��)��u2�!8abs�6:.a'���he[+!rA�>�< �& �pot�Zmix� B���".��B1����< implcG !|Na68a m� &� 8ice [29��[30a^ Such�ŭ=M�6�}0-0)�s� ed2�at��"Z4ZU becoI&s��I�%- %gis �can�� 5KNa=��!Up&p%%`r�"��Ca%JMgMM:��"��%orv� axa [3 �Pin-spec�$!�gh%aa�[32!�%&��Q�a�ongV���_w"�)`��(( R2 = �75 6(Xer�.� ; ny4rays 533 , 534<535�' U30e#�W((�; see�$�icshub"�$.Io11� Ms)ya�me��ism&> �2& !�1z.GFf%͑MCa��E;Oout.]!�h�)!��m Treg� ory.� aq�A�be"�a"Y��q���wassoc� A; a/-&�m��} � �gs�K�.�&�'��P� �achie~!�L% !�� H��environ�,I+O%$A�leave�K%jaQ�-0 abil�[2� '&�A� elay%� �13appear� b3 [(OB ��',per:'��edL)D2� "��� 2b�2 dZ�!�>�# menoM~!�� g)%gto��. A��!exb� �� ?re?堅&aC� titu�+ly�o�AZ�MK,��Q�dU�!�"�>a*�&c)qo e islX!�mit�WA%Ae A�ABA ,Abdireca��'w �[38��am  rema)�e�e�R�WB� i!.t{!��e�QD�2�5��d�!�%u.�=Mqx&�T�7�2#%"�,atd!�toak>;a3)e�*"' . Im�dE"5�� #%�(y% new oq)m���dp&op�I d�y��!rop�� H*w�jI��y>^&! &� >"Z'ed��e* lead�6�REaZ�#a �A�e enzy�+c"|)!8Epr++�+* &�&�hoK%��- a4se%I��J/quX#on!�wly "�2�Uk wq �2�BR��OAt6)}[ ��i���� q�s�-9'h.&,�%luE�a 50%6��*a 40%*E�N{.T K�� >d�d:�♣��. O�1ll)T��(�;� :��� &�$E�E�%tandard�[�d�� acts��n� ra��%i���}�a0* �-R. OurM ��= �I0AN~$�a�&m3an�"r�Vroach�K�m���ofB�t a�imued.�L�nipA �1&�%�<ideZ^J���t-Jfoe��a^ed"C����(s . All A .!#liana l�re ob�'C14x ABRC�l Lehl� ed��D2 =a**�#$homozygousU, -&/2 . Un��s[1%� wise��� ��B h$n{6� 8 hp&�ht∶16 h dark ( 90 µmol m−2 s−1 photosynthe"�0 C�0 nd 1522°CA�*6 � [1-Brief��s%%s�ocmoist�� ( Sunshine Mix LB2; Carl Brehob & So Ind!� poliL  , Uni�S!4`4%��� s ad��aE� toxi�)n&9���C(Co , Li , NPb��S �)�Ss�f/ at 4!��3 � PbAAbottom-�r��wx�� �� $25× Hoagl!l0ainx%j �repla��1!�,M Fe-HBED [N�$′-di ( 2�'b��8l ) ethylenedias-0ace��' 3)> ochlora�,ate; Strem C�)��$, http://w�2& m .h�For1� aG-Q � ,2� nondestruE�ly�,p5 emov�"�Z wo��j �e0& .7!ral- $th 18 MΩ !r-UPyrex di�*�u�8 . Ti�0sa�m�drM92Q20 �" G =4( 16×100 mm )�Oyield�ax$2–4 mg�\=-AUM�.9. A�!c],�t�>�"0���� � seti�we.dW@32�%19A�7 m�& ed nitri�)( OmniT��; VWR S� D2c P�s;6/vwy/co!, di�� 6 . 0uI�2�.K��.!�&�(6xan ICP-MS ( Elan DRCe; PerkinEl ,:�peE� )%��Bah��Mg , P ,"��, F �N�I Cu ,�&, �CR|n?6l*o 8�-!n%�ta}as.�"�iq*v�=gorithm �.��best-"'M^M[�MW� M �/��Y�,��� 6ia>!� EPiiMST�� [3�GAn Excel2� �5� vailaatbval� %%valna��8se  �9m"�<OBSA:Sa "�9�d [17P'�SFP�0}9a ! ��1��$Ler-0 by h=�� labe��YZ�yʥ#<ete$7� .�=TH1��c=0ato �{%ls down�! 2�8al�p/�/xa��Two2�poN.�an F2 po. a< ss"�) !A"� � �)9*gr�*�q? A\;͉H]+%C9�� E� =L �c�<ed �P� �<� � B,G!*�% �(� Kro� \�%r@�G �H"t ! M�;, loci unlink �!%.1W�� >s��+�equival�[$��5A� a.�of zero-)%7:!*L@.J!R5Gp.�+two-thirOp>"�?2�F� . By smoo�'x@1/�$multi+�, , no� R �'1tp�,m� R�wil+7�0a��"0AaA U%+M��/2G traiRaw:t�L(( . CEL fil� �A~A7RA��>�u���&msI�� subm2 >�9~bu��0c��!�.GEO Ser� Lon number GSE15655 (:�cbi . nl��Tnih . gov/geo/query/ac cgi ?V=I)� A2e�Amap,%�ex���&�>!����1�y�A2qCarlC���7�oc��6;?H,bov&?R �;l�#rm}i�B;in� "iPC:�q�9��C�visua�in�to�!�+QalA�u�� SeedA��Lz�b�6| P*� harves5��| .A 4� s� t|f=1q0 Post L�� of �v)3�&� &A�9oscope2��Aadventit�&��%)bE�h2v�5!�BHs emer�Da]()��S �M @�8.�be�n�e�sub�E1 �#.w firs A�by� A�fu�-e�Q&P,�E�)~cript""F&s *�[)�aja2�=t2oD).HI��* !foB( 16<"��:!�war=Bi) 5a`ATGTCCCTTTCCTCGTTGGA-3′�e7r�E2PGCCACTAGCAACAGGGAAACC 3�re�yE<<d�,bi" $� et4i*� 's>��U�!gevalu��E�)eabunda�&�>E��!Ù[SDS soft�D( Appl� (Biosystems �#�`*#0�E9n}methomELivak�Sch��gen [3e�CT� uem�U&�)�6on 6�� 9�!cJ>n>J*f ag -e��'�ACTIN 1!Le�t2g3762�A��ca"� aYCTE�- Actin1�,e�!1k�3B9f02∧ ( ΔCT )12 �4(error@0d4 ,-�A�!k6G� d6plu}�dev� �6* minu!B/-�In vivo�2Hof�4�=�$s�)=o")= q��Y/[3&Roo� -@ek oldz�+,1 on 1/2 MS!�r�MK+,iincub���Hfresh�F�7ed�01%�D /v )&�of>�088�igma )Ola�at 70)1 DPa�/el)tv B� e�� adja��a �`sl�!��ed͉ UV-lh.)tan Axi�'n.?( Zeis Germ����D�v@�(s�1�(� [38]��� 35 d)� oil-�.�2�%ov%o-sa{Celluc�8, Novozy$,�,.<�"n <SIH*V6inO mM c�bu�K pH 3 M�10$NaN2K4 10 s5�� wQa��BA�wa�I!�6�P4sodium tetrabok ({9�z2 d?&( w��o'∶aano[1� ,-Coe�-, unbound lip�=�EJ�of 4–55�6 polymer�X5 R r�k!I�bor�ifluori.�0%%luka(� �u"�ad���g dotria� a��v K&"|)�%!ys����fera��2�sBIe�$NaHCO3/H2O%eQ� &&�otra� �*%�� ��3oxy�+ carb �#��eri��Q%�bis- ( �O-t<�sil�-%Mo�ama�( BSTFA�Mac /y-Nage�y�(�µl ,+26l�idi`40�� ,��) � 0o GC–MS/FIDy��%��6inj�.on-colum�<DB-� J&W.�M30 m×S32,�g1� �I�*:o�- Agi�$6890N gas �,atograph cou0%Z�� 05973N��drupol4Dss�7'Z,ctor ( 70 eV�$/z 50–70��i3*�emperAJ?dP3Eta :Al�Yt 5��, 1/ to 1%�at3°'35=5( . Q�I�� � ���.s�c>d � 1")c@GC-� :F flFionis ^l%.b� �F�. L�)&C�*�a�F� �BA�yl broE�9odͭ3��mg�p�fas� �Lq�Չ. ��6W/�(�2�O�4k$�N#6����A�i�#�%�A�9��2 M NaOHM5.��. F2ly;�SP5 M�j�HC�sVG to a3 va�eA ��^'� :�D�*� � !� A280-�exsH� co� t 24 gdL cs P*�!05sin ZSch0-r 12 h Rpz�( 8a�h��/m2/s�LE� mean�'%kf7}��2218!��#�i+[URaX��"z%�H+ p� ��hT<UAic wrap" aran avoid��#9k- =� on"�wenty�6q EK-410�A&D [�= ch�#V�tV/ ��6�Precor+ +7s n��t72 mput9dWinWedg�)"$TAL techno�2 es I=)a<�Յ:val*!2!��3)��A 4H ix~seW@K 26�%��f(E�nq &�D WlIL areaE��A�e 6�digit�)%� ima#KTGl+�*)?IJ [39]�P*f wa�vee. ~sm-&H�R*�:�aR�k�6�E� +�"�AWx�"-+�@�:+, \"o A�ba�;surfac�v-)a scan�Re�ro:� 4JSM-840 , JEOLI3250×�A"�. S�+ �:�a�n6%he �AP �?s�9a� eiS5�fB1�ly� stooA}!�k a-�rho�a6U%D��ib <ig/,by a Continu�,TM(Markov Chai�CTM&S2�> stry!Wom!�d.~Ate: d� a sp�-� XU=?S&2�-CodeMr:?!&M"�@1�� of�+h�gd6B��m�+,� a�)|AO E�>_si|C, �!���)�?�z �Qes �WTE ����!�r^� �Y dissI� a{A  ,%�s3>whYaM�}�turnoff�pa�#2c�st &or �, g�}r�"g�G.�.��H� �nl! }�e�my�A��� .��(7.�~ib[E �C*�of Var ( CV�%s'1r!�a�"\ ���& )I R*:8�<a�Clige�ea3 �rJxTc�Ia�he vieJ4aɱ larg hdecay-uofwQIr�A�K6�iA<D2r vg �R�uR* shut!���� ��O.� �6b�L_"-�$uQ +�am�TngMact�a2Z�A� or . I��ti�?rodoceptoCBbɉ��@l�eno �qi\G�c�%2T cascM to �%��up� � �b $?�'ex�o6 seg�( ROSello +GHr�Z, olecul�dergo�i ].�i�by= kiRK� Ily!�in��),a>&t��Arr ) bAngn ct���9,2Hq+�^ ��B!iKl����6�tovt , ke�K �hIcoc e G-5e�G�yTU|/F)dec�3� 56_"�D:Ri� �6y)&�6s OA�ee�orA1� PdiB��O�yF!`e -��lex �ch!�h�Yly', cGMPW7��t�r�%��9byeng�#`ea���M�hel�R�A���.� =�5�a<�7:-��� ��� r� ��?Kj�Ma�a�m�{%sc�B . 2� �S���3��%�%r/2��-����Bs���'4+�U^7 LA�j� exhibAF � sens��!6#�T!$ shap�R�,:)#`�9-2�q0� 0-�C�VO!��r��B"�"�"/��R�a ���mo�70b[1((� )XZp � "� iR -� crn S;st�E0[1]–[7] att��~h%< 6Y�m a߹�2~. Alt�PjZ B)4ZI*�Fac{%9!J ,J�Q�)@ y im�Z� �Po�^�8A8erT!9<4a�s��f& :�F{xA�kf�'� teg�d E�occur�"�[� iYQ assuacE�D ( ?+n(/edX�byJhAo, [�EIqtqN1eBsk 8Pi� � t�c�E�Mr�S,��'R t&ngf !�-�a��o"n1gX�p)�. MzE:,%�m) ��� �F2���&h SJA"rta��M�.X��c( �bty�L!>�7�M�Z"��; �U��%��RTo �K� l��!�N�mod� 1 �Z,c�P,�!�fly �� �!��!�X.H�1 A� [8�L!!zI i�&�M�zZ E'��"� �95�oVdis:-n%���0B���.� �he-A�E�!�A1�� Like4=�@f[<mN� �2��Siophys WM�m"�aM6recover?��.%�>>R�!�."�Bjmp���a a�e�J�Mn� �%Q�A{�NxKnt�� 9�!n�x76�gaF�.�>ikiT2�� QU� wQiccac[ &/ eome��al �� e [95�if��E>m�MF ocha�� . R"s "� ���H�� ba_�A9�i"� � Z A  mal ay!:ops�!W lyMw�� er�~l!�r z��a m�v8�" scalI>2(81�FSey2��g$�Hp�j��a� finiUkAa ���A�m�r� & �� 1.��7t�`;�$qOs��[�es��6Xu�70 9�frame�QEB�eqjA�heefhJinin�!�is=e_�s>) D ����:� �:���6�JV�i��,A����Y� trac_D�$B��Cet�&ngI`�.c�!m�� M"� �bfi��[6)�6�Q)A tsS.�)Hs �CdominB\fa:&���� CVQ.��)eN Y�&�A�� &� suites choia�Mt 4A�aaLdX,��!2of!�eUpidurAAnd(�M �� "� !�a�few�r/K6Z�ge�Qe3�G"� �,v u��!�k2 e��c"in�<>FI�k:r-S"3_`E' qual�)!2v/agree6k!Fe* A�jof [3]_�d�Kac�-wS"5KZ�:�  =A).F�%serin-�� on��la  3�#or|�knock�&�_0R���SPR9E] ��K&��1����H9}�ADeS( 0� � pro<dv.[LrrHl��"/%/m I�[M^i�'AF�[m &� se+V�!���� 3u�9�ge:�#ntinl)�� w p�x��.��hQ�Y.�fA�kept fixe�DA��1>��sO�_�e�sa�� !�E��y-E���E�#�t�$at al#w halfaŕeak valuwd7 }bf!^ �\urigge�)byB�)�si��iY!Q�!by�?�/–  &�4�-!0,}�Ezd�9�b�n��Ba�NXIn o2V&�V% �ed�er\��eR�WTI��� e�6ng]ta���>M-"!���> I���!�|3B�d�M;��o4s; ���!a&�es:�.2�� #� y s��ͅ, 1�E2� �oSis�h�X�e#"W� �E�:�{�Y&�"�IVI�of�>�u!�b�[�1a� m�~O�(U� (SWg<��N�v"!q)��:%mW� f WTf50(sl��zx.& �Q{e�J! ;m�>�F��#N��5!���� Í�*Y�. Tak?rfw�*}a�U.�|!�e.p�'� E���i>�gEqq:��eu!20requi�bK e�;���\V�l �com� %stnA<cu? coA��1ɠ��B�D .�;2��z��3]�� ���Ja�\M!pc�eW)a;T�MaqLH��s�'>1!����� r�NCSM�� �by RK&`KT�s%hVdAG7d�N(inope$ v�!�K�]�oue=�,�Q!��^mm�,�A�&m}Rdiscus�<��d p+6/wH�$v� !�la�'�r.t!�a&GX��.�&-Q5ZA��Bnin%���*i� shor� a� . G* s d4`� ��m*:R� _ 2%�$( page 372�5��),&� 3�O'506�#�?pe�!��Ds��a�wh<1�h�W� �Uw� a�C&�p&�#%*; E�H�ar���A!n�}��8��r�6|��C . Si�A ���= �zlozu ��� [1ۀ�Eau� 9ha�"�q"� �pe� o��U"A�9WA��6�AE��**NzWJB�X(!z��)�%{�6 6�2��A�Q�B���,U Ŵ poin2O refr�&) s^ץ�+���mf�Wa*�-"'� pg,�n��a���%h�oe#� ����% 2�� �5�F*6ph��*Jv g0.)6(&� JG� ol^).�+!R9�!U�M2�s:�1YL� �edEA"'�-W-X��of COOH-Ai!�trunces�2[�j��.7&�"�<Oa000!�.�,�lto 3 B ml-;3�1rd&�nCV�r" �� �JdKA< 6Fu]Etu5��de) )+ in M}C s . �&6�` զhi�~;�8rdF*:behav7,a� ��M$up�uean ��sZE���a�$���bl��"� ='aBy!�is��of')beg+*�*��\!|r2 �2a�ޥ� ac06�# xXon� po�a0-m�r6�c&�� guis!F�>�9� �e.^b�)2��surpri%��!]�E�Z��?��)!b�E a2����)"#5J-t�5��� �h-�2\ ��yB` D�aA�b�a&� (�)8�5؍�s%awsy/^F�( b :�:rout�\ n6�� rac֏t�� *; �!�� sufficp@2:K@O5 unambiguoX�u%�WT� (�"� �ko��Ef*�Kd�c�Aanima$�s neeM. S�h�9�`�  1�c>z)�b0tR Eq:6U�"<0J*>oa-es�she3�mr�/ Kch���.!;7�5e"o@>iIQ,*G�(&�n.d�N&G���holdsV��[�h=�ѱ6 7EE A8�\�(ぁuO�?kMt rk�e�� �Rac+� 2�A��Ƒo ,�llu n�Ly�aE��Y*��.E#X4�ar�4yINL'Ron� E+m�:a`5ll� Ic. Nex�0 ?V9�.-�$�Wed�I inst WdQ��#in" %V�$62�/Q8�!0�������!�eO rega_ ^�"e&�E~�\ae�]en�� 1]�� in"�Jt:�/2�%�s�@mA�b�s�Lo�q�a�e�&1!�x)i3uthR7��mA�:{a9�~�% �j%93%+4a�.m �� } wo"�^a&7�Xu�� ��t'� �C�*= .��.4"�%;�^R$��&��1�!�2:�doddemon-h,$piU�F,( [4]��M��C ng 5�6��TnTiJ)eH0 3.��fa��$i1�in p�:�s lump&R�_di�:���mI>l��!�0�_lݚ2�+h>K!/"##|+o3.Mel� �n V&�+�zac���:�:�+{AK{ J�+cours��ide�}at&�_2��s�necess� �Eu:2��JrA�� �S,��5�Ne-~s� ��l�K:]wo 6�1pf� ��%@#�ar�R{"* ��( d ameAA2� �i��;Yin Ames'&WAlat�,grG�3d _ er-$A�SPRA� n Locke'sa % [�}�=�1�� ibte-�\JAL�i#�c !y&` �� S � w8�4arg[Z.Z)L9d3!�&+�S&��;��beJ"�OI�P&�""e�K.gk�!U3rQ48�F5� � !� RGS9"Mo�%'[ccelea�� =4;IaW5��6��Fn!�q��J�&�p�z} . Ad�LbJ�s��#��w X 1]i -e= !��n�Ne�b2eOp ��!"5/2�I�� 6�&b�>W��lki�* � � �Ca~er perMP;�5B. ��*"�� F�/��* {.g�.C dX>�)?u��.���AY!�.F)C�e���Ocoinc�V��.;�12�^ CA$20])��>�is�*<X. 2s A%�d*� ��q�%�~��oH3>k�2&�n3by�(Eq:7–Eq:8CauhE�byZTI��s[_�iN�de 2e��(A� #ty�]� uU�Yg672.� �oo�%!�b�3paE��.�� �3��a�%t:@ �0nS!!�� �C�Eq:Hd)12�e1A`I�Ot'!4“ P17MiE� �~ae�6 ��^ ^iq)1��S1%�up��ry}\,Dot�"ee��s�d)T�: 4iyɩ%U�O�2z��09�� o�oNin!l13{o%k3P!�6)Dj)TV� L illu 0� 5of�*+�]� !,�&�3V!3�,�"q�#p�for2��>zi.k!<6ȃ2[�, |<�!�i�l�a��0er�OI�. _!�a�J"��!(�G!%En� !ve��r4�.M�A�d�N��� +.�!@N#�f[!ClO5�a�6(���� er�.�W6���e"G . If� he �hAl�J6�����oK)�� �:�rH�~.Fly�)edq"�/�c,�'A3�_�)�G"tE� 3-5P!%�h�a��3nterpre�,|'!�!�ou��e�[:-��&�~/��e��W8�I` a���� /�m�""-  x]� E`� l&�a�{ sG1��3sk�1�Y Eq:1"Z"�;�!�ct� v3� A-�"vDA�):6 2|���j12��;z'"s*� !�C� gN�(~*,.et�:�(� �N � �TE(n���>�.� 3 �` "ForA����� �8�W5?.),]3�_Yul%�9���� � O*�>0 dz�F�1�rYl�)]"�'�� n up�Y� c�"�"9"� ", ��1:� ��o�(wc�`c��*� -�r�7:�&�".�A�+�/����(ed=0O� CV!/f"�'� �%u&l*2�*2sxl�. S2!SZS#%�e� l"j"_ ��C �ik2f>l�\i�� mlact�B�� %a�/��<>�1�2�&5"�.Y %9W I&� L 5%EcR2�chA�6� to�>�%�8� a2�of]i>AI˭5Be!�[ dZ8N15�(I�ib9yH��h2g"L � . Ac6^�_�uru,&���2��Q6 �B(�}e� �& Z偹�ɲ Jtt!e�6 (� � a�)��W^| )AyL ac�����:E� � .Q� &C -�2IreflecX$Z�( [K@-���a~[ �H(n abrupt 1-{ "# , �yy!�,a{Poisso�=� , CbI���!*{(ZB�.�8�C��A(�i�*4���M%�6a�"�d �B�E�>:�-C���5�Nd�e1sE,�:��c1M�ɌZA� Bis)��4.�4�gn�'b^��RB2 :X�:k6�Aح�� �68 .7 JT �-*.�}��!& !��A�� �P!��@(E�e crucZ99�"pm� QaeY'F�!zm�* cB�s_!�!6CH@ lai�I� Fo*��T'� b�5I!F�F!�&p ���+ %�5 =a|y Q�!Nb �  Z* l��2> ,1�� .6his����re�&br���"�icit theor_3�Jo"�'cv)}�+'*�e� Eq:4And �fAI3-6 We��~ readX�mar�z�'#�g� LC� � �a�6�1�Y"�85M� 3!��CVe@ arti>)� roct6�.�!"� !�� 2=�.u�/l��2D�g A��Lr�� 2� fI� 6&B rec��� squ��h j� ,c�r��&�1k FvJ�)�K*i�zQ-o{�st�#��ti$ *}$PT�ԅCLAV�bR1��I& �ErofA� ��B\.�Js8"� E(�Ol��n-AaarT-�E!E� :@&I}3Ai ,.!Zll�A�WT���"b ��few�&�9"�DP$A��Bm�"^�����o�A�6un� M8j%��`26_k!�>��66�Q�4CV�<Ine|!�J$wI�%�m!�z Mf�(ae�IWnt2j�DorI�{7�]iP,��&E%��=1"�C_et &Egenicl ��Ta�BY0 _� b6�0m�NmΝ�* >�tzSPq �ehe2�$�9ea�k6�_!I�L��8U%�  �8�!$P?a�!��M�.1uiB� 2��V2V�corO^ �\*�A�'��#�M5� �>�f!�recapit(G�x� {9(��E).�E.,O�8Rworth� ! e( ��0�sz� �"� acd>a��"# afy^� �+!!y�2� ) 9�U5%&��do�P�b`}B*y����7�sfa�+;�� �&�'Vr���t�to_^H cM7"�s ��T)X�%���ofN. �/lf gram��9MF2i#"�"K2�[2�QC&�8ZWG�?Q��"NC3I circw7�.�f@�no%��� ���0�'"�%�*re"��b�_ e�b! .Kb�%co:nt:J�[F � {B>2! C K�� )MoJ�6L&Q+�>/�f6� :� M�3c�t"��T"�9��!f�A�,�j�%1��on-.��Z��e�cg3��Ccu�JA)@�� s fuaAU�ed�KGs 2arM�B.���-�N2-O�:3)z&{ m >F, � +g .%�A�!zJI5 �1�A�%FY�n�.&1��� %!�.5�h594%%��Z��E6d!=] h1�rp +�I :�. Tu8�) 4L� gY]�.G!�$*G���stL�,le�b�r-5:(!>�B��A.��ɷկ* o2�2�Ͳ46[k�?a0W�O,� neaBik+�zY� )MЀItbg�"ebF!�iit2�Fr%���e�y>�icxC���Ft K��bF��~�BK��},we���( ��k��� ng�X|- ���E ]0 �n�5 &"`� b!VJ, i1u'U.���#�&�`>d8�Z�:��t� ��A(a Bernoulli� 3��:�a" >����7ry: ��1 �!�� ���3��AB�9���a�4E� !�q �9%��Y�K>�Ir�1p�ViM�]�~ 0��A��RI��N�"�?eZ�{M3F &��.�u6a�)51'F-��1^~ he}W /%n2\.A�cr�'�� 2ir or�"� ��2w_>�U&=��V9w appaJ(��ocez�a���y:� ��\J�-N ,�mhT1�ir�>� AT%|� m)"= �Vre2j��;F�"�c!mI�t(,sm!I�,O a!p�?� |� A��!A/.a-^�7 . Leoono�D.jD a+4��f��ak@"2,;� pE�; � �Fy is�[15] ( z�N ��6�U$Zu�%toV �: � ���6�F '>X� E:>�F>/ H0^�% ��I�a�.?� 9;2�#�A�� C$ ex�$�.�.� c YVe�m�"%� �UN�Dr ��" i of\��B9�,�q�^T�!v�'�.�,%]TF6��BBv����A�%3t)�(���ϥFGA�t�hby� I hv Q.i Zcun.��6~@P,f L���� *�.B�)�V���%9� ��%�N�Z1&F�"f�ildB�!q� 01,&��Mt.�29 "Z� "��d��B2�1"�=� ��Aqdi�Gt rF unt jd2e*�5wBj�nK�by Gib�eU .� �-4~�9vi��,HBp&�q>�.L]�?ea;i^4=�iUU5CA�*�1jx��-X2�5��=>S+ �  I�"�Y�*S�hns.�2�� -Y�f4 ZA (&� 36e"�$��M�� �) &� 6��Jy�6Z% A'� . !���5s�1&�:O,{ � ( =O�2��cF� ���IiAdAAVo�Iw ��:��W I'D�,3&|B"���a�X1te��.�a� kiY"�(g�I�Er.W$�c�Bubj\@mu��&%��I*�)%�C �L� V(� �X.�u^J�k2� WJ=�mb�oo�U� a]�CK>�U2G�Cb�FyXu�Y, 1997%I-�B:�j�� "�i&� ��� ΍�" DT� 2g*}s�O�/� YX"sK��&I_޷:�=s���reI1a�is�Y_d�K"�#!BWof�.������� � �p6� &JQ�/ ll 6f� �usie2D a6. MI����y!Td!�2e5�"�_n.Z'&�I�y� ye� e�.�i� b��V-� n7��aS�&*+fi;.�l+"� �(Xof -RKF/R�.��M "� m GJ.h  �e��*�67:#�kat��ȹ��3azk��N�N �d��#hU Buczylkou����d�*�ed RKE6�l9�Q�>\ Zet?B�. More���d�z�@X.r#!��2�)�s!D� ��t/ !$&� e�%q`T ACeq 6���al_��� �<,�.F!���Go*Y$/ pQRasti�H�A�&aRK ��2"�uF�m�  Ii� b5�:JBf�?-��.�RK�~�sE�����)��� +:�'fp\n����)��WZa�����o)��%� �t��Qs�2�[by 2{�%!� aeP{"�(�$�b� ��'*��g��Bq -\A.*�% EHat�RK?"�@�m/ �{i�qI�h�Dof>=�;�� ���!�"3  �z�:�~� n�2 d�c"�]nd (ot&w�u[�2Kz& tx��@#�>�_Ab�9eI1&��m%�-=>%�Z�2�yo)��)d&�.ir2��sA�us&� )�� :A��$,aIc�[c�o.)�o>ZF&�'7|<���4at!3posT !4%��N�c��Q]�0a�1>P)�be4+0dŐG ��)v! � >G%�)S�`�>. u9��RKU�Z"A�&VFil  YO�.}��=E�,"e��&䥥��;%�") !ŝ�%Z"U�AX.�edaJ�!!�%��henc�}%n%�g!a� 2�tG.�6�en�8�%ely �8*�L�J�7i>�5�-A"Q\0��5lX/o]�+�"�^-� F:A A�.9�H� .��he�;r|��H�;U���e.�n��D�Yb_V�vA�!79)8Sx�)�#�eno�7���Ը�r1�{�f- 5I.+C= (�a|r� 4C�A8*WL8, Vishnivetskiy&W }���B� ���>U B rsl�B!��5>`�U�r|Jg&Wfac����^;RF���8�qin�h%^PDQz5VM�e.njeM7��(lq7a"�o�} 6�?�0%1!�)�.i.�0.l��!�%��q�i)�* L*er ���-Z9Hm� st� �QH�f� E. B"5F��ata�I�B��v!1%�1bV��� ( 8 �kBDw�5� �$ts maximum�!!�u:F&<���bN�%�}��pe����i�I%�"W*��-��-�E7�j&k���4urv��h&�+>64EG&\5u].4{)�^O�����(!}24��I9���2MD[40AM4��"�)AGyr�;�ā{" \)t_A�$&A�%�x=uU��b���������; R�&q ,  ��P itro �*s2�?. J�C2.bDڦ��A�qY�Q u!<r0L2.j =D6&�MA�9�:I��5���Nloh�/��.6V[���JebP�"� ���*A��>�%�0Mng1� &%�0<�%"�C*�< <�l2�in gv� sc membra/ ���ll�<4�� ly h<(ogene+2*���6h7��� j ����v�zB� (: a"] ��r 4PxA��?mPzs�`� �� by ug d�o&b � %ot>tf ����ub�6�M&�))��E�@@#��K^L"��! ":��"�dI�65*3�6rF\M"�c��#�&w%BC9�"Ca]y,`;SE!fic�Qy62� �i"r��pA:>�j���/� , [4�ƅ�ts ,/i.�of�Rvo{:�!E'��!�@ �L2�'�e��udy+5�I�“�H/ a II� assa�c velo��by�lei��� $in 1989 [49�* ap|2� ������oeqr"�II)ERy ,�5|I7B'���Vw��SN ��� D !(aE�z]H.�x6�WΎeK�~Ttr5 M@Tct(6K\Aob=�I���YI")'��� �Xam�_at �rt no$� yRq  &1\p����y�m�"��by"ɡf��A;. >�\��:)1! �3Or�@*�C�u*� �G��b�Iss��tr&TZg�om�<B2]*/%[Զ,%�&\2�H��2U�Z *J �F�,Mr�%2d&^��.U�]m�*.( Al* V_^�de"�TA���(�"�uk����y)�a�ip-�� sW�>@ �t�#�� !7.E�;q�ur�v . �.m' A�2�VP�nt� -l��9le3 T��ty.= %3el%i�_1�dfO2D )? 2�I \5i�%l�g�.*!0�A�ark�u:�;A���of6^i^]\:�_Y Н"~&� �"�qU�*��vV�ghg�"c 20"6��6s,Ys��{ �E[ �6���T%�2��S�"!a.vsIzo=��*� m�ű�%��:?NI�6�L�Kr�6�#"3$�0 suaa � S� 0e�)��c"R�" MJ�viAF�$(��J)a�NH"�6u"Z����H������m zsr8I9�*c �u Ap�+6L)8�g��t �a tself9�1? K� *4s8��/=�e�eq��9-&2 d^�A� �J��p %EH.�,(�)e'%�*��V�a �LA��)m1c=b*���is�.�j�?T-�mA+-��!�N edQC:Q.}n��:�( �I�<�K������*VɄ�p�r� �mea� M�6e/��h� _;%4.�,�a2-.OYq~M,�q�oA���Y �6�{il�E?0t|X,��ba n�er��*�s��3P�+D&�A��!�Eq.FOɿ^=U(y�)�C:�#�"� F�D!�JI�to�c2��i��5structEY2�!<� :A2e!v�Xy��� vJ���:�_O uaH �*�/ɿ�a��rG*�Mg!�a@,�w�.q�eمo� �@`���e8permit one to c�ompute the current response as a function of time and thus 4als!effector%PXin Eq:1–Eq:2 . SimulaU`s were performed for eachM`�3 Test Cases . Random numbers are generated according to =Lexponential distribuv]r Nsojourn �s ,2��wild type , transgenic and Arr knock-out ca�indic �bove . T!Yor)T�0dynamics is c)dQ�.P:8�evalu`. F1+{( , after ab�5 , 000!)erical s=t , we{v mean�&�kY$��new.Zinvolv)�T presa investig �A�biochem��� �. Belowav�]!F$detail howByi� been�ed �ir sm%��?�Jrepor!+in-4 . Give���!�f����deg from�6��n��5is�ewn .�*� ��$of stochas� re!�(on networks%�in cell��$inevitably!�@I-faq�KDnsidered extrinsicA�!a V such�g����c��%fluctu%���ribosom�*py�Js��a�� reg�orya. Whil!*veralA�!�8studies demonst%sim!�a�of�un��f��+��=resul.��)&typAGlArd!analyz�I!�is !aAPdevelop ��m�BmatC frame,t�allowsRuncouplI1[Eits1� environm!ba�corpo� ng only�&'s? ont�_e]iaee�a~ ore techn�ly��sa%=5�ngVI( !g .�pu�pec!�) can� margSiziѡ�r! obt��t!Ude)d� We derive%c2 p��-�umas�KeqQ}^ �y&.� �&: . Us�sM{ Qy+>~significQ�AU,approach . B.�ystema��glow-camoleculI��A�2Imᠡ�atQ�%pinq��( ��ureeB yearA�how� ,�3lize�͒�iE�Unoi� l� cannoF�obser��sub�. phenoeL� bil� among iso ���at��,Yr�RO �a+ ular.� ,a�mi e� y� ���<an ad�6� ource�7� ���,F4��S!/F�(focus on se��G��7!��uG� thro��dual-�DrA surea� s [5�6O�QVesI ] �VcereS�. ( i .e��� �Iy � e�KEn which!�*G !��^tly ue-fE�ytometryy 8] or-lapseB rosE�8 c 0�All!�t� .�� ��o!�I�they  d�Che2�� una�y –:exAs�.�5Ɍ'�small� part uis embed} (to a larger��AOe� . AE�S� relyA+aug!�a��ori� =zby5ƽ�alA���)�� assu�r fix��ut�� , [!j,*� orY��Ov!NimeQ|1 13!�In%� E!s agree � wel1 �.P�Os�%. %"�o!�i dow�k ffer�Vincj ed d� !�a�T- e�� defei�15_purpose� trac �Zi �. A natua�qu� on aris! ��atAzt� h8  an find aA�p2� p� AnjusAUe M0of�6er�Das if it was still:w��a!@modC �]-��o�; word��we aimA( �“k�3ed”_[el)�summariz� aI�behavioGtB� i{&possibl� �i�!�Z. S]bctheF� to��I � alysAif a��] subject?z�:�~e6pkct answa!�wm�I AorkA �&��QZ-*"� E �_� A��2*�Iin�Nit tur!DuAD1N.� aaloA*��Y2� to e� �p��)2�a� exci�A�xAU � i � !�E]2)i�e Polya /s2 e: at� drawy�(%5ba� !Wwo colAw!y5n�ua��0Y=aza� le �D�M plac� )�Ais ��kn!T�nequival� o��9�u=n a=no� rep�d 6display�m!�ric3�er���@!A}su�ful R in a>2)��� 1��Ohe.�infer.wa� l��졋first rmpE�s�9�I��Z� �ea�* ���-��_'&��a�� �w�`v�� �����5P�_bF�uctI��lincipl3 anne� gardlѡV�A�A tant g�Nchang�L. } ~B-evp�g�ZFrby �� ous-? Markovfin�))�� �)��hn���nel��Vs��>]ino!<we writ<-� pathl�i�\va�a X� �[;�}fo��usu)�v� o re� to upper-E9zlowver�ewa symboloa�+ l�a�r�,� A�m�. Fur��m��� aqt depend� an��m�ct5}# 1 uhazard"v��S ( ���h �ׅ�/� a polynomaD*�b�lawA3mass--�:Cj�� ѡ]of �t5 . T"�,!�� jumpE� iffu!|�c2@� ZVD � �ora2:�2at�.aF� N1M�.� ,a�� %\\in�m�aiaDlNA)#exa�p�;bAe&:ng Vyaf[ gkit M�gen�EB�r=V y$ �a E�92 t�� !�"� .�(a feed-forwAmst��� betwxaE�se� ,� p-t *�� ac�y�E^[e�u n*� fash�h.^�T%�xtremo! sump!��d �al�'�A�ei�SN initV fas s6�buyga5ma�leae� stro� si�fi!�nd*u� E�ycha�e]�&Tt xz! errors�EnA��{�n� medi��6��sca\( see�Fi5b�U a�prC A��>�J`� Asurrou�=� r&� mgl� r's�J`!��is fuAZ�uaэp!D? !zF�!�Q+&}!� W%]e"�E�tdiscus� fil!�n�ble�Ia��  4of Monte Carlo!�u_K"��^�� yiela�.�re��p� io�ueffort1�mpauto m"SSA�1 i� i�=�alqq!Lcos�4F�W �� highlightaGa l=� ��d�61� toolS�.! .�}�to �vi��be�asi�5T� We believ�7td$l aid!8"!�*� eva� �aQt����-e0+�faith�� viv�MXe'.�6r2��� . Moreo�=SA"be�{e �-baA�deoAx�0circuit motifsynthTbiology�isa �|e��! of ret�f#[35�W� t :��\J�M!mů��i�U tudy�:*9��isLpag�3"' UJ "��G* a� �toa6�Q sA� s up�Qo two Ts:�$B> a 9E�$up!�!�Ai a se&F %quant�iX|�:I�]� etjt�$ [36] auth�2�} bound�-"'�aO �:�nd%/��im�Sre��Tun� ty}�� 2�M�J]��5�ng2@� ��rO � . Al��lin�)%�� ���wid= applic� �a�c�}) probv2\*�(birth-death)� es2G &!��o�. I�%�he ideaA&�a'Z a&_ �� e1rJ�i�%�i�� 2�%�n.#)�In "� s�$���2}�sU!m6! Tis non-wia& iX#B,d-���]p1�a�-*{.A.8ut�@ exte�!}2�,scenarios sh()'xam�t��' stag��� �Xen�&� �iy �jd orthog3 no�2,$ertur��r�(s� �� "b ��ng aven&�b�su,&H"[!%?P �'ts"�-U(w*� �'� Ebsh�addre�Zin fu7i. A'-!H,� J��!FX ��[+, � s\" urac4�h�D!liq��adM!suiY�x��7_�� �ak�w:� zZprofit)�.G') gh�ne���&�#&� �i�2c u!o�'�. ough�ploG � kp� decad��fl:F/��be.��eb0�2 �um) assoc� d��l-$��$ir asympto�!theor�!�soATthe��I��G�@M ��� �C mo�-clos��s�t� �vc�iv &R s-.9.�,w�aEg�&!O��9�2 ��P+$bottleneck1:0MSA algorithm T*� -a�e*�0wa%��� :rQ ;F��1an ODE �r.}-of optim��!d"X 5��r\)�fAboo �'sI��| Al!�d�Wڭ�"�MATLABZ-h�thW*, N�(k , MA�S�$coA�A$� oduca��nu�0� H e?�ch�=s�- Data�m .��M_ prog��ysmad3,brain-machinterface\0BMI )Q$/d!3Q� Kalm`!��0�tthap&/w�A�ed-loopN adap�\xLD) ��j3~�;h spik�' irec7],�!���*�%PimQof�contr��2 w+L9!ed �*�!�A�n����t*�Ws:0xi  exis�#a u�(!�� �A `�[�4��!�%s*� setupsawW2. H�w.��.�!�tA !architec� t� s�=F�)6)u=8�&%� e�a�e�"s robn#.se�d�+� ous task��*�2�13 G-�|[%�96A}iP3�RR�,���1=�B�#"�5�2*i" ,��0�-horiz�����eedback- � ( OFC )M֭"e� ’s"�#e>�C � pT-�Q%�!N��miA�+ usernmo�69(durA!U—�� ?�� 3A�]�.d�lso[��)utono'3�E(J�u\-qN�]�ne'& ��Y�a[�G.�AA�ry)% �a�t�� �2G!>�;s�Q��%{-e'�.�unlik&�8!o"ae���batch F}non�!*7���!�W�zl���e"A4 �hu��pr��e� e�dt"�i( �b��se�i�*�/iA4y ak moveENA�}�(U1\ V�u�$k r�c;5IaU( ��, pop3v�=,�:� ( KF )I|� e,B"al� )��8. O�aɍ���s+(eG&�u�&� �st��de�S>��q�9� ofte{|in open � �!�� se|/by �a�!JQ valfŒ best��c :(a>A<9�a$t?a� xecu!�or imag[5�.*� M� ship"�">bA!BiUbe* �'L. arm �"u�a�iW-��M� "��[ad*.a�6:nd46l<2�$[6 , 8 , 1�>3Y1H���%L\.t5r�.���.�R _11`79–223 , 3;'R]%s2M�ݺ(��D=*�w.�[20 , 2�<R�"�av"KF`� comb%� them��ap%fic!�m!��_oN|��<.�t&n�!R KF t�a!Jp�-6�n�bi45y0of 50–100 m�dthM��Gauss�2�s^� a� a�1v�^�a: ���o4�0b�)&+4�4y2��=� %? �Hnz v� #2steps:I(aM�A%">ş�( 2 )2+���"D velo-" *G � ��fe]�0 Y��a�( 3|n&��j8 !S O� h"��$c�dB^. T&�0%Z,5pm s�e�,9:d��jh�S��[20O6J���+(>�>5seed; M�) [a�,�l} , arbitrarily �.2�Q�0�1!A�d to maO���,�~�*� �)"�c�r scr_(��!�1BI�9vZ� �E:�C# Gon4�J� U��0& ��ro�gEF"C)d9 t �/ �$ keepH` magnI@(}�sp_()hanged�]�'/;ngRto zer�GD� jE?. D�>��3rea�6olZUL TfB���%n!of minu��!a�F�M%"F\�y4Eq.c��2�+BOt�2maximum-lihoo�=!"���. Pq�u�: prevX~�g=!Wj&ref2s ��2�:s)r�2re smoot�1� F��inuousag��n� it�{ly2�=��90� A�a&�j SwBi�d(c=a~�>!'"�C���b�y���re6p�5�;VI^��8�6�{ ( PP[ �%C�%D )a��m�+goals;��� u�Ha2��\� 6��]�A!�9m�2?�%hts—d&;!'�<�Hs� 7hg�Bime—aŜ�02c�.,�e)i4�3�����TE�? ~At�(S1F7 a^8y�EF v ���e) !%��&:�� 6;�����] "�I%�X�L"H5F�4e_le.�� *9!�KF� �!ed e� s�J&s"L z�A�@9`!� %�"� � e##�&b>�!�(h� 2 bin-w� �!�z" k>�-� (.% A�IL- m76� � 32]�$Qh� *�1���MWv *�&� up�G%-�.ati �9'!�&e.of5*a.�� >Mpla�' or�5r�)in �3N%a2�f ��@ �a�a�r+t�\2 /� bea0�7M� "9\w�y�p�&3)A �)�G)G�\A&v4 QA:f+!�-š��exhib [Dpr��&ndAz�tX��2'!)�E�^z.�� .�=�%��arunA3anyA; 5f�ysK a se��)nO0%1aVocA�!� �6[33–�)ia\�CF�*2�y?��~E&�  �( 5ms~'aRS�(,8��%� ,�� ��3�9�'��ad-hoc"i �aB�!��B�.�b�&�%�!�*!�L#� mani�3es�Or*�$'�Nm�O�Ho**�J�.�a ] si��!vA q�/ ��enoADto +�� enga� A he� st�0�s �� i��)N{ "� =yd d8LN�"w#%�to help��achg �th��o� iW � S���.�H&�+A�T �5�BW 2!F� �*^Eu � �9 �Ara�$J� +subtrac+ !�bodper�95 ��2lZ� !�y u&C��n���E�o���i^ ora u� � ����F>Act%�.suT� .V> E�i�+�)cQ�. S.j�VE`�5� ���2*6!�{���� e�G er-�&W��*�ly �1e0 ustn�=. HO1y��pl>���r���)g�� rpreofA%(�C2o6���A�*�)�L"�gBUis&� I�_5;Uws�!�M<!%d�< ���v;�&��it��m�� .�]2bq, @ ch= |� �5-$'�R 96� ipEbe!+�hP�"D]'/H~f"�h ""���fz.�j6�H!> �2VF�@a��a+A��?]A_2� "�#�O �#*6E�D5��OMotiv�=�Wm1f%�F���- OFC-� Fi�"da�O:��;� , !A �!(�z #a�lq Efb��� b�F�K�paradig6S"��� � [2�37� [Twe6n ��)~�Z� A?l�D5fF�&� � �=��.@!�!5�E�2q�f� "�%d�Lq ! ^S�,�1]��A�1�^ i I� %HE,�%{NDmQ$� Ew2 �wiE�ɍ�GA8)/HZH#.E��g �8re�k" 0E�s1 byi%tin w;�o�B��a86�:�Yk"��qn�>� x .�s;k2� '3 �)l`:�J_(f�)Z�aKA�;nt1�A1"� )ġ�a�Bv .�*� ���.� Y���T�>� a�#eV:� b��  ��u�5r�(I�>!@orL,�*3-monkey��a� 5j�Q���"�5 b-P&� FA`n.�R�ɡ�n Q��{  �a/1 A8��!g�]l*� ��� ��q80 2 yR1ť͇{l� .�={��$l2�*v�1:aB� "��g@uto:���)�0-!xw w>AMa� ce� jK� �H-� :w) ��'�; &) !^Nu]is� .$%-�iB o��� e$+1y};yf �c2Hp"�'E�-�Ld<���MW�M]nIZ+ d6[`E�=I�b[=*)m�Q8_���&B�RfaVFon%��(6�Wba'cn2#��:|B�+rhe�$i��+89�+._raJ,lt�L*F%.H�[N�+A��d � .H0A�8 2I395�2� =,fT !sFZ�Wf M ^e}�].�.-��,� ���Fb*��"�.H��6TK�"2�+�<�We\:?i� �6Roin�|wBxisx� KB?�k=a: ��5 �B� [�u, sugg���!o����d1'��8��i!�$tegg=2=�*w!�-dF�"".� �-�z� vg-m�(�V�,Nst8^'<-h�!�0!@ �%eG%�Yq!2 �*�2 ��q-�pa�+u�??-jcMH�;to-� . Tak aKK��8dA\�ey.� ��V'e�i�]7-J�� e� �5A81%�@�.Al>d�9,�A"�Qco�G%�E�!�q7�<Instit�",of Health Guc,�� Cz�UuRLab�_� Anim�Pnd yE�A|Un�+C8of California ,XSkeley� � S6uCom/"' � >�%9.�%N.p�+!�e6�m J�!�:�!.�E�Cm/Q,�,l&�-1�24" .��+ zBf�Q�we�*�se�!��N!��#E�oZa�r%,� "A2%� .>���Qkin�) �.9�,o����k=reaE9who6(mai1b���>U!f��u�9�(e�.z v�=9"�h�[ 14 )i= ( 171)�/�<��JL9K�!UO���B1)�e�Ji"r DC-�&�N�+e� 2�< U���'I2�1E"�%k�&> ADS0�a-5N Jq,�%A1�uf !!�k� �u� !M!�Ba}is �N�G�� �fBin*� a4C �z2D�'��I�2Y%�ma�e '�b[y-��V��� �.�4%<�po�W<��vd� �E�_%�2���EW\if-�gra�MlyHg�)by�J$as opp�i�Jl� �A\I ":.�6E<a �%Fic��JoV!� adja9\>���0EF�)�I.�n),n )�KUY:�j0ot���ed�1!E�#\v)��+i�a�#%�9>qVe I!_�he2$QUi �.�a MMof��"� �;:� �D�e�%a�er!v)U)C�]F\�� ^32y-|D2@? �wo.O WrI�6E�f�&�F�����.�� d 6sd %J!&21% ( G-�S d t-�&(, P < 10−t +B�8|a��E�sr�2� by 6jsc0� b15j*�3�&�E�.&(� ,�q��A�WXT�F5�!E �\9P*�!�#>:�aO a"�L0fJ�;A�avera��_ �60.�w�$�.�didz] 8vZ%�exa`GA��P_ ach excep)]9��z0�Z�e!QA�� �FJ� !́M>�� J byR)���)*"5 n�!�r�w?E�;�� j�$b�J�}�Ad�5� �Oal�H.�6��Ff�,�#gBu %J�5.�!J��a+��:Q�p��n� %�s!�6d�  )���>#B�&|&�=:"� A!��� _ �8�m�� *R 2t�})>�=)�5%�M{tn�mQAjor"��_na^F;w�x@��EAhe&�9�~i��4�D�}O>�]� m 5�E:�>BI��}n& 1 12���Ѡ�2�E؉64%"s,%����_9��65*��d�HUof2�(&O  �a�W/&K n� � 6FAls�{�:? �24%rD25ZBonf� ��2y U!+%X�� sto�q� 0��&+�*9 &*c9 j� Q*AO�|��r�twJ� >�)c�. XwpI*P5�QE�53k%6,.J:!��h -�%>�|%+cHI&u![.xM�� ,�jjal advan�UofM�an>lic�\+ ���R�uTy3o��"�M�'K��bq�2a th�F )U��T��mE�*:�*6!aB]!/!i�-�VGB1��e�f d�J���caA'"0$". F�3� oY�,I31ly�$AC.� � �% �.���͌of2<�Q_YF�p&+W"� ed 8 �of2��w��1BS\m] ��?"��@F� in 3dC" t�-�!2u�"!��  JuK��t)�l�W�7Mb�_ m�A��Q_ly go auck� �\a`\jrn�Mm7A,IU��%�+$e*�Vo ,���<� te.FM�%�Rm�~F�� e e~!o1��;2�^!2�alwa&e�J�g*�2i�b��^�!is�P} d9� .�.�>!be^��6�2pF3!X�Y{in �AAs);�5�*%�QZ)� �qa`Y �;MVU�&�!�-��,J�K.!I�.yeQk�:Xc"m o6�*� s��t.+( tPP&M*c�*��*��Y�.�~/$6\}e8�"B �1=y*rY) ӂ,d�dth11��= QK e:��EgVQ� �7!��mS"�X�� e 2U�e!�2̅"�B*�=�Bi�&RFE�!��$qyX*�B� 2�&Q�M0P q4�)�NMa��.� by0d1Z!p!�took �v ��Q 90%1?� .�5Aj j%�8��G sM�6N}�m ͨ��Bb(�Y9jE�S3A"�P*�1Wd�re,FA9�oRv� !$y���r�18:��E A��ahO"�2Bk5B%�5CMb �2��!�S3 #S3C2��A�X� :� � -�a��Y�Ѧ6?2� �!+%dF�; P�31 aN!�Q�9n69���.e)2�:&5z�N�F-b1o'�wbinRG�in$. 7±3 . 2�� (�q ± !�\J5!sI� �j��!���j in 6)±7|�!8!~fQ NF�!�<F�"m>�I����a�W1'���i� 6�U��2,' ?"�llA2P-:e..kF� in 2A�A�1�Nh�nre�/B@/�<��o].wao�&@ ~&.;6�, ��BNNa>8  p-�`5.�s� �.��al.%�rceep%threshol:��O�"als/m1O�hE��R� B�"�� ���Z� �]�7st�)ng*>9&o�di�+*�N�z% *��mo�1E�.G � o�#-{Ru i.�2^T�W>\ �"�>�&E�S0LRH�[J'T"+c)M"�a �i�|��� �`Su���.�  a%!� T&t.�as�C�#Հ�$(= wsoo�Ts^76;- {%�1ᑙ�9-�w"��AviCHA��:� �t.� ,^m@��!j*y .'��IGQ8pi�[f��.3�>a�5�To"-c.��+W?�J>qt�6ei�Ze ��:�U\�$ae!]�*>Z� E�Z��.%�EVA2芩��E�hmu�V-�a7HR� iS[B�)� =�q��A8���u*W�2/2�,uw<,;;#c\#c_bn�}Jr >S��UN]�z\16�96nY�*A)�E' 2����>|�5>!�i1ޏ6�1 . 8 v�45��3� ��<�i��%�� �"3� ofua��F�>����zB1�6B–6�-O�?NBCY��+/0wo-?e�ca�Kmbo:�#ed.�~�-aR*�9 "_]rimH����$){}8��i`�%xa��i>a��Cd�en�9A?B]c� ��w%���2�( pai&�#A�<%0=� [;�p�3�n+d��Gq� F^w� l%�J�>W{q�MGFfi�r� nd αc.��H���$ ( c . f .�+��%=h �="�\!��(�#2�3E� 6ps"�<�� M=�1l:y(! S4&sP���0Q���y�� B2!��-He�`J�w�+er-��-C!�ask|!��2��"eEc�9al�#��&�@%n �T E����2F@�9�ex��pri�-�!!d!�A�*�0m�< )Xs- !?A"� �f�aMndJ�� ��&zZ� L�(�>�d5�-walk2�on.�%�;y}aR2�0n�"+atrix A� ��&)�A �]�,s��: rđ:.�v�)&1�!9��a�rr�*�W�hc�c A��'vRnJsE�wo&�*]�T��"q !�q!t�mJ6O�s�)-/Rts � A�}typ�?"I.�F%kL!scu�A'j4� .M:.�A.k3a"�newm!�WH e�E��2a�o!Qm�ܓ&� E,Pe".dEu!9�  � 'Dj& 7 7��I�I!{a��Q��a!�Ke�W�r= e e!o\0� �7 $ s 50Si� + lef(e�~m�h@ 7@ �] �n�A��>G L>\&28 ��harC�UVp �/"�(!�!0i# ct )a�Q;.#slA�ly#�4�n�@l-.w ���K!�y�88%� 92 +S3IA�NAa6� (- 9�4��(� �6(A?M`�(��aI!s r��ߞov� a long��ij0ca(`IJ!Cэ%�;e�� pl�s) !9I %�2Y -.U�!�1�08 �3!b�~a�!7:� g.%�2.M%�R.&}:�ie�r�Fe��q�-2>� ]fintZ�VY| � >�.��o��brief�X�3�D� ����*z> �Zi)3%QH*�v��s%=g[a�H �5�g!w1 T Tlo��be"� *�uF7B�.g�XnbEM�ACFI�6rf eJ2JC��N�"of�. S&�-~g&�R�r:e <8�9�K6�r�;CMrՏ��9��' &h:I�-&@r!�U ��!��:��p"*#�NA �.� J'9ap�. TWJ8H �'RG� %C �6- Y�%;m>�-O!A �� a��X&�X�8�E~~Xse�-u �0Е��M&��ɳ�M|�X%��,eA@ve6�i� �!dq*A%�>@fr�] R%N�<'=�isJ~s ;L7/�r2�<u�!�^/A�4*�C2Y)��N is� f� ma̡�&� 7 R�g}:1MU�.oFs$)6�B�92%%  A� ( ii�;B�%,�D�Kv~%&`6b*WC=`�.2=p �b*�d�.w!c�!��~!k!aVS)�*-XAȆ:%�9;a) �2�v!Gg� �0e��3Y)�!q!�='U�o�O�Pm�YYr .Te*1Hj(F� .91� ��FYt]O:. 1EAq&!ZF)Np!*%�2C$bQf Ai}}b�8q�pM'p�y��r��7#wo�ntej)J�]��F� S q)�p*�.���I�m!URK.��+.%IM<s� 1�!��. Ol1Q!s��.�—  ��*� —d@2��xe&�&LJ����.p�~.%� :�J^�d�*��2�B.-�20�A�RG!A�ERZ� �@���*`9*~/�� 9�1��"�w6Pis%� Qs�?|�^p��ewJx"- a���U�6�!�*�LB��NT]]kpe2���7"�L.�-Bv2ah��Z' Ũ���)��m6�'a�6_+ f  �HH'h�!�u=v)FC* �q��!_9���7%lZb� Q )�-� ��$Q�A7A� VSA�QL �0.�- a�7���ZE! :gFQ�bYި�� ��ȇ.^B�>>h2�x>}2�.��2%#!��� �� >U6�bF2! $% :0xL=ftd#W2�<!�l�f��v"ͫr�� g}=# 0��'/ R{u�� &j���Q ȪI��9�)v�K%�Of�o�+a� ��orFk�$g0 incl�yl field&d|R�?roB{ograph%DECoG ) pY��� ["Qv��� Gb ��LQ+�n��i�5KSiA� � � n<p��UGr�={a6 2�"��ճ� �ݵ�d*���� **B�� UFB 1Zof&��yAB~;up- �&` !���Vz�V�s0Ls�2Xi� E@K2)�A�6�J:(X �J�"pk G(�"4!A>N��A},e &\�S�9=��oB� !:8 b�� �N�I*�"�--32�-"� B��ke�w�Ybb�n��r A�=�U��:S Fv�N�� J6� \a�^&Qot�e�( nd 1�"�_!+��risf�m�}ur��^6._raJ�[:%��l����6Cwe��[i�wte�~6[ ����U�l e�Q6N7A�A�{ 8i��/7as ��{{l`e"Mka��a� �I������b �rސunXr�y%�hig�V*P#�`�#K��Gr�!da;ofU�m&.��<�`�{��n � lqh�26��getz��!]wl6d�W�u"�6�. A.�p.�m}a����s%�� �>�m!��3 �Jl �k8r�� . Ne��la$�*U����bgjtѮ-�Eer�.� �#MUtu )!�t�s�r�U�.� . Cݖ�܉=i}du�a &��)� e *�ki,�cA!a��>leaT:!�*�5�J�!��l [!@, raia�%��^$q�,ޖ6�'�'�� ��oF�M#-� 4CL�e<8ly-varw;��i� �s [=�A&' A-cer�~�U"�U]a� f�encvv%`-�n&M�o��disruptQ1]\� broadl�$V ��I�6MA��ffl��Z>�>vly un���c�B���m7Ea��6.��e��9��!�W�:}F)�g& i14g%�}mia(r�N�ensem�<&�%wivb �@��Zda!A!)� %%����^~pZNus =.�-�J�%ܩ��V)(ES*B��7~g��-ata��� ��K]d�B�X%d elsea���%CL iT �ý2L*v~n"R. �IP���a�� ���}a!Q��er� %0�B|��� ���L� [5�An W+��E�!=*��� +}G�[5"�+i {&�;a��:'Acri� !�QT�@E1!�&�;!%2cs�� ��uf�.�T;$ I� �.n)�:�J:cicC�}a�ӛco���s&� -%�y�D���DA���F� �5tU�=:%u� e�topicw& -�9�D[5z�!�6 � � ��Xm����!^ rece!�"�B�6�9"�!�@� :�u� in6� A0� � or��\˺�����)�C .R6��"�2�n"��m�d*�4����z5F��out, �V�)�i �yw:o!A�D|���A*3Qm &6%2z6� enco->-�V iT}��AX�"~ W��n�E�;* �%LU+�\��p�'�G��d�TE�;/�e���#.T& �w Q%t� � �� z �xA9"�E�rA'�mFj�:^*�E(ndaHgFԭOd�N�,>w�W_o��Hf�"rne"%�-- "!wOs�^���*rF >A��4�Rs �-p-� K���I�y �!80ig.Y �c��R78f2�� �� �&Y��2Oj I�h��in9P� ��4Y�ɖ(t�3&��=M<�adm�B�%l� �+ ly:.�aș";%�"i��E!�E�KR1�� ext� ,ZAim1A.�"�6F�j3,Q��Fm �oaaCa9i !=.� �A�U�Ja�5"<��ʠ2.;U�>c�"& �� :&f�� }��f��s�.��>�j�Ha �D���)e ��ur^���&pG.��qBq�IS)ki-�.�6 s�,2~#&z))E�a%�bA�* .2N6�kG�-��� |t!؅j�Ai�2m &�?��x�O�#V���/ =!�"E>lex��c&2��ndэMm�e �1�3/�)Ay i��<���V�* oY�@h�eM�!>F� �)!�a "9&O�D��� 2q�G�A9��*i(B&� Ius g�g�&�'� wy̓͘�'7g.�iE. �؅ �~f��ng7*�>���n��%�.�T-��h�t ZĖ�oV�!���Red�Yn��!#c&\4����[onA�~ enso�t<�se�fw�BQUresK�������I i.arry cAFaQ�,xu9�uli�_��aWg rrec�W�f %M�=N�(�tͮuru[�o�--P y*n)iwe�Ds �8 tane��u&��e( @l ganglA$���~e��W�d��fi���e�AZed �l�=�94�; �):gEO4ublic-y vailEon�9 . Re�,!]sp�n-te��J�s���X2%��:%:��3a�U����e�#'5X�w� � heckerboa��UQ W�Լ>Spro�b� �#��ng"!<~e�1�1�� ean�-ܯ�%1n%�pu��%=?4A�Rba^wi�b(�7e�*�!da� ic ,6�p��+a�n)�a� *B Nu!��o �2��� e1i ,>��6�Q, ker��� [׃� ��e��e�E��8O8Zd �m82� "2�l� at" d1O����.X� 2� i_ ,8<��a"{?p�f_C!��1%�E#1"�>�me�A��*@+le . �n��Es >=r�g�m�Axarg�5����"�A8s� scarn���0h�Toutputsa�[2�d2%,S�3��A�eq �e"�3�߅clarif�� ���qnda] �uw �� useP1� hedg�4st�}�,  �2i1 J& �F! ���ŕrQ5S"�1�;n�u� � �!|“codeV��T4�de�oR��tapp�"Q �� ���<d������$az�m[�g� i�:*��]*�)���. I�����7 ���in[B]"ex�Yvi�d7u+<�d� �- �Bq=��a ab ~"�me^ismp��! �����;#ի!bQ M�w$�~�h wu&m=� i���E$�&��g !6�_l4��uly��N�1 �Oyn� "�"raeq{�new�2m i��hZp��s�]i�$16B�T��%!��F t78iD)��ٔ�����O�8Z)��st-: {4 t E ��u!�sN�–��DF)��)�J%� ��K��Юros � i!��((;Yp��m-<�,F-�� Gp%�sD S� e�5j�s � ? Tra�lE!i)�2�+RGCs .�&6��� a� c�f*=:"L2)[15����� in.�a# acts _ly�0�%SF#� 5�m�e�*H�m�is viewu:6����!W)��2]) VnH�s�y!,E'�EEtreng��fQ`���m�i���ie�MaFR(NR-�[d |I�r6�� ��"��&LGN% -I��[16!�[17�T��se �bdea ��:?�� &�#.�i��."� !M�)[�/9Fm5!�!K���a !�" 2�N�� nW�/�Ɇ�;�u���Q�Z/ M � ~3� ? �ո��J�6�>= Q�" X+�F' \ �� Ѧ�*/��̅�%^�!�de�M!�dra�c"�c��e�Y�-~%"`�e����G"I�b�&� )xqn� ��-u�.S!"����! sFG��W�0a"�?�E8E�&� A�I��2� E��`v*;%�;%9N���ҷ,EO�N- K���E L �c,�*�A!�a��:�h|>� -��sp�"`Eg* 6�5 Q B%E�16 Al� he-ha�,v �$�GI�b4::AN�F h y!� B��I7-�  ��,Op&���{.4-�:li�͞F�*����IU��J�!a c"��.�!-ces� �u�\!X�l� >��twe�=a&>%��:� cours�1��dest ske:���"���%�O�J1I�s��6�uU t)��q("|��0iiiq�E��=��l1�%u��aK"��*i  :�6�mb�d�����Ѻ-%!rod�1r��A�u^Ngroup�E�: in�nea pig;�alq��a"�at [18 Each����leaRa10-dFblock~^Uh�N:1��K. E���-9� �n$h�h�yin�7 . 1Bat$�q�Av�vYaan%q��A�r}droݻ1]J�toF��!�t%&7�*� of6�* "�::&v�+"�EA�ai�.�e|v(< ce��“ D�5\.R)%+�/I..��, "�ErA�ea�lle+%{�a!��1��:"-� � �i~sSN�A�a�~)�ke!pGA�ns��Hrig�cN�J�C�r�je|�^!���* Q��4� !C!�!5K% short-r�p.A�>H%��)o a��(b��:M���paRmp.i!��DA&, �i:�� �G:��(a2�(�P�!��C ��8@[!Whyp�&`�e�:X �e=re�(B(nearby�%�mag�?|nDdN���*?R�e�A�U$t:T }!���i�!yM��)wus��S*�� h1E�A Jcu���ؼom row%�7&�z�*MLo mim���ca=�%� S��(� ^0A�biE��,��^� nd�(c�Ft "> ��+��SԱ%�1er�I<�bPuca� �S? u�� �!��A�6x"- 2���a� � �g�)& �i���d��-4�#er�8�I&� � %? W.��������D��� ?E`cra--dQ��/n�Qm�u��!�e)S�Z�� � n luZ+AHZa?le-pixel�h�)Tm3G ca�E �*!�a"h��, b�5%2�P�C 30"�-�&�:f!^MZ)7*�m�%�_ͽ��"o�2j��T. .]z&a��J#v he!�)ah�&��zuG�For<li!�r��ޅK.�X�$-trigge�6W ( ST�Q�$| 2Z '� �i%�! ��A/B�-Fly gave4c�����!�ud�/�[ ��2�! clu��e�a[�Tba�f Qi� �pojģU�*� hB;�TB .=�_f�$ec������x�JeZi&�M�.�eo -O� FF���7nguisa!)-A�����!bipha_륫����''i3i i� ��Qa�g�K�I�oӟ?pro�nt� ilob4"B�ew0��)�"k -=$!5Q��ri!ե~�*t;V)�_S&7� @A "�qu2=rM�k ��A�01nK�!N�.\�x�9��l� ��'w5�RevlI L.X ��:Yon6i�ig]�`�1 ��q���� "� Y+B5( LN ǿ�,�*  4D�c+z)J�V W�i"�{y *D :�oRF�Uwo!�!:VZm��0n paqd��"H� � nsf��u/�.�:e�7M mF� z-mi�re�e��ays {,x��{:���(E<1aU-.1)Zvaߡww1��a�-S!'[19�& %��t(N#!y&�x"~Y����E}u�o���hedm�6A#I"1 /+um *� �JFq ��_ weak:��]��-u �t"@>&c�+�K>#��"^y�R�b�1�.S���AQi��bine�t 33 mGេ" .�%lţ]~ euedU NG�^���8ea��� ��*��E�e�:�W*�;\A�.�1G3�z#$"��a��z�|�4 ����(j�-9��stEs��b� g!cA�&���“ex�.+l �A&�aa�e��p�W� �Nx�n.�If%�!d-r�_�" �%9=� in� e\��*���F� J be�.�>�� Z+ �h���}onA� s!1�S2��3RD�!�v �N�a� 95%� f��t�EYe?}9 boot� pA�aÒng��I�-`;%mTS(QN fG�( X�/��*�*ly���%:���Bev�!v�2� �Qa� �[ �0�K��� `�{$!� triv,�Dormz"naïvD{ C�,�ma_�R� ��n�2.b�>WG,�pp�%N!~cF:��E�i1@:1b�Яi�7a U�N8mis��npi+�E)�<g|8m}��aA e�" � lap!:�� 2�Ɛ!d�x�J^[ �!n6�)�%�%nu�:%1LN���T:.����1�c�.�?�:����4onlinear procePssing , while neglect�Xcorrelations due to shared circuitry and more complex nonlinear behavior , such as adaptaR, . For cells{�ich had sufficiently well-estimated white noise LN model parameters ( as described in Methods ) we were abl�Dcompare the excess.� predicuby$mm8to that observedB8data . In order(0between condi!8�Lsee Fig . S3A ) fromA,specificallyNpairwp2�X%�$, we adjus��@threshold of each-neuron�ly un�#!� ulus�match=Haverage.�((their empir�H values . All other.�, namv�spA�D-temporal receptive eld A�( gain�re un)id5 �ina_ce%timE�maintaM)Z�$but remove6a_Rk:$6�wa��nsistent �zer!K both�measu��!�simul�/qzaiuO, leftit)Z[M�13Z�does not: a�� output>MoreoiɁa`!Ml%� �Z�direc�E6foundA mallNc:=ſm�6uv�u.ccasA]Tha8��a�V�Y�3ve!� ilarA�ofR!ޝt(.�i̥)E=e� a�� grea!supa<ses�R�D2�of�visa�i*��We9Ei� set3(results forx(more weakly_eda'ti݆exponent�F guY�3B�In��ticula�$�J�! ��( )M0��e����e=��.�-�(N^ of ;-r3D�We��examinlh��) xperimentűwh� w��� �ii� varyA�degreesB�al5@io As shownA�i�3C , ��R,produced onl�+� st9inRc. Som� � �ͲJ��pa1�� ,he multiscali�full-faflicker�,M4 a clear��wh� � d�'.�. Wwe!Ni h�YntrasE�a2/).e+N�deI5L e��cLMmeAd �S� Wpropert�*( kept fixed6�)�!�}�!��Jl�is�Ga ref{ on9tBs alon��O � �h��,�Asg�of=�\did}6� ��ENFF� P�����E�!�shapeRZ fur� analysiA�w��cuse�sub�� }iBCD ,)�f!�ch)��,enM�.�w. i� ob��$ed robust  � e�.�:u �EHi Q �#N�of an "� u%�IGBP��i .|)/ most5,%�l� �\�hN at leaMas�  those&` �cording�"� unlikG�P� 6&.A��|1�discus!�ab< ��j ]a��spa� �( �w>m]�) or no6H(b\ )a�x�J�l �r%&!mX꥙tBC is� "aMDfilte�#a`a�J�,�E� � "Cam expl� � A~%�6�sR a$as higher-�. s ne ar�|�impac^"�)�u� *K��B M�� �\iform.tS,RBapp�tm ��� than! e�� kJL. Note2� "� ����col��ed!��>!a��.`inM�21.�che�Oboardw a��rA� (( 10 minute!�� ppoa5 to 3"1 �BQ�l�_��/�{ stud��,neeA� to verify�confid:f � per!�aUaVeAsJ�>�atscaS cla� �  [ r�A�d��.e  �EV2��'6�ca���� !t���a�k� � V� � 3A ,  C�!�%��ON-��OFF- po< !�((poiy ) ten-�hav�a%y2&��ŷ!EsY \ y ( black� colo�ggenerF�y posiFf. S��A� ite-]y!�d �NA;�:�on-' lapp�:� cent�1WS5E�*^ |6^�l A�C er-�-�J�,e�� U.Y:$. U:,5�>"!^���Y.�A�1 . 5;��%�:�]ŹUFR� $0 . 38 ( S&G4Y� With� ame-io-N , slow-ONE/ FF AJu! yel� .�!r 5pNc!� fast` `A�a�L n%� PairE��M�rM�29��!J1��R^#8#nmaa1�-�"� asN01Y−\02���two |i: ��iv���� se)� -depa'ntJ@s |[, +aK� aW������N%%_4A13��67�1?!6n()_i%�a��Ÿa� ship"�>�O qJ@� 4CkAF��i deca��oŮ,��� 4 AJrD1�|�Xn_���f )� s.!next sou to d���  :s %�, c>b � <Q0�n c�l& "�patter�vF�� As,�� >�5  STAsc �'�.�. %A�uRa &)=N �a"&Swill be �.ť blurA� 8>� �a!�\ � �p!�>�:~�:TRF?we �maximum  lihoodVA�to fit a&� M�a��v)!���6� �8i [20] . Exampl��s �%�waya5� ���l2C!h%�>sructur5*L �uNÑ. pre^E, unbiaa��.#� limiA\ (�M"����o�Actr�$XIWE�Bzra� � e le�is{FSt�a ould!�ect[�3�K"� :UsA��!I&�; indeed�"2�s%�har4�Qinguishaey1r# !�a�M(Q sua�require� - �B�wloc-]�Mbg(ambiguously��a+�9�,���aA�75"� (q�is�� �>�},.69A� m � �� meetINstand!G�e�ya� typ���do�Atpox�wll-c*� M4����,��se/* gC)�AHu�!}� ctor!�W��mM%� 2�")ofm�3C!9���iz�� c"= ��to5ow%�!�possibi0%th�1�q I/� !�iffer�VGFPBU!�pasJ Py �*�/�&� * �_(�� fAy:S�a j!�&�)m�d��x�� . Sp�rai� �spars>trans�!�ev8�!eb�d24ed [14��Motiv���is fin|ogeo���e�-e >�y��xBp MOJ( %ua��B!��,��E��*o T����*Lof":�iso�-��C �F�Q�"�=�'s����d.��[̢�Y"�")E6�������6�j)�� file�Xre[ erE��B j"��D ��� 5?!%BquaIi�i�cA�wPm� fpow���rum!�6J��)=$u�B%5�top-("� ystematic�l�Ձ�Ec f��enc b�N� di��ng1if w��A�-�W �#�E�A�sNZ��e�� m)4�#�!�&u )�5�a���da&9 ensa�!ɱ?cM�he u5���, h|,�Q��!��wauto-�� ."�,��>�X�yy04 �Ifa&'o�vAD���XM i�h")R�5�� I�� 5,�5��h'lya�ct%>�2J!�a ���O lete"Ea� popC!dD� q�,�b)%55f����&E��zap*U"� cyA-�2�is��!$�ty)^ �lc2n9�6M;. Nq�/i�� y�pr��A�!�tE| surrx!nd!�<���,2� to pq ,�.. SI 8a�U"i" 2xnBu E�e �o�',( t-test , ,e�H"� �� shoy!BN.� �T�s�y��erm8an6 dexID histogra�_!^�� xUy6A; , ;�(; Wilcoxon ��ank t!�)��r tai� � �2��i�it!..Sal� �yeb�L &|r>� �Ha lon&()g w.����1��6B;%��(a�trrcro�*� ��? 6F� .��wf���%��&!�/cfy��U!���#-D�" ��C�� 1hw&a�dR�"GBO��ay���of>@ �$< to2qaG� �Lt%Y*U 6D q�&a��'�Z%� ,-Rka ho��)�B.aU�5bottom%s!?2��3%�Q�a�&J���6CIIA� ��pu>:�icŭ��� ��isHA�a��ant (��stM��"�>�!X�� b"�$A�qhe�dA�Mc)�s;)o�' hang!,�!^-� (�Utw BxWckjI� �.�um ma�jwhyR�1�-6�Y��oz� � A���EM1��]aN� Q �%�con� $ional view��#&�/�,5 atI0�&� x�.si�m%er�wi+.�?inhibi2du�~x!�*M+� E�'i�8�itude�uba�m03o�'& each" iS*w��|A%��9. Defin��5��strength�a!Le�/io�&�!� �(��ailO .a.� N�A��3a^�RB�h�1( stly meanUB6D��wo-��(&ib��,~d�I��55'themselv*�+6� Ic�.� e�s� e.Z t*�&`��5gcy!x"5 ��� ��) *asY#�#ernible�� y���/ter] nq �F`�6�%�(argin�.w);,�- .v�<�?��&"�Cad:&�*6F��!"��W(we!�� s�)ev� c�:� Fj ��v �v)E��X$btl�E� outcn rpri3giv") mmon�� si�a�wor��Bar� [1] , [2]� t���� imarilyшE ax6'ofF�,&� itL~l*@ *�6��p� t�6�o"�FG �Stoo�*vok� � �. FM}9 "h!'I!,�W��/��m$ slop"Ologisn76�.�Os'1MeJS5��!�2WafOUA�r�norma\ "4to�t euclid�(�*"ykn u&# %��ofM �%���ũindivid�.��.dM�́�m�q�8a�s e �aJ� � M�mReD66��� sensory�����6:��' know74��5�"�� �us [2mu2To �aNa��a]aiX d meXism�e�(�F+ir� f�“�0��, �5��Ţ�"$ devik �!�M69�in�n�%.^V�W(o��aDS 2�E�� ap�iOvaria� �6q ' in�2, tak!�� ynapao.�(n ccountz!nyy6E�)ol=^� 2q layer��ErfA�beE.=is=ty�Wor� �!s excq'"a"orO( �r�� �W.*�!�i<� 5x*(%�)E"AoM3s&�*!�%�7�cF�:���.�4��/F1���( vice-versk7Sp*�9��v'A��*)nti���G;P arma� 2�"�"w"=!B:m��poa6!c%�QH!�!��a�ode��1��>� L:� 2 5�'.y*^.:=:i � ,� i>�-we� c6�]i*�.*�.��W��� <�a�YIa�6c Rdxa/& 4�$V9Yj/z ��e�A2��)�<�2EaX ,�:�a:ximpro%��;1�;!�lE���Q�4B�p��.�5��xA� � aa'q����S��2"rtG z�+[X��2�5&�9}i� "��$��  2� A?l�:�i. m N�� l�aeI_�4 ��1d3LLow8g"�* C*�>A�0i���&N4o*Fm&abj2�"��2c!�*.[$ ee T�S1�a der� E�i�{�EQS3B."L %>F��."� ��&isE�2�!by�F�> . ) A�sY, , ��5�lea�ETol��erein i"�)�)�� �52I]�)�<�4N=��in-74B�t �#b��"�A�� x& m�E�a�@%<)���=�+5�Aal2� &d ��2�2(��o�9(}Qvt "��0E!�!e.�V h _*ly!�it9; 2s�� ;��"A It|ccessfu���U�.?V8,%X��2ic nt9G%�-�al ��Cf &} noteworthj W�����.�B]H�(>j%nd Aps!>adj�o���!bNoM-$s� o�46�-� ͻ"�@us . Our principa6!�i �e mamz adAt�@�>�@��AClevel�9F� <a�?g���i.���w*3. %|AJ"�'�%�)acn>B0* �a�8�:B :ie amo� �L>~>/ e&f'�W�%!�q��[ma� 3��L:Mi�-u� funE�al%� l . !���?���!�&�%|�ers�R��n�s�$� A"e:�fC9�tEmK )�/9 if"de}  fu� "74m� !_s4-��[m &o �.��Ł�60ar�!%� �6jr>��be" d�_e� Z�"�in%RI�k7��ed�}6�8h"q9!I.>��&as�1� kern�Cs �7�+`�*� %Nq�Lx/��byU��Y���ti"0"� �I�2��  l*+� :U�terpretE\!O!@ �6 &*�\&]ف�l (I�a-D}rcascade�A�b��?uF�%�Z-nW1. C^6if�?�X{a�a-�2�fNp 2�: Cg�gWtk�5y6O"�2��Ae:B1��] magnaV""� �>"Z#i B-/(pl�.az llel.�AE��dunda6is*E+b� gh��� 7g6SK�� tB��/ dvantageoL�x.T%Ib encoA�c�or� �g!,�ctF�zA�s4s�.Q ��al�� ownam�Da� le��Yo�2�!�i�in�t1 ! Pitk9nd MeFr]$U�alamat6)�!�A_&n�E�hmsm1O.u.�isB[tu( �aint1�:�_%la&�327�2? demo!H�*`�Dphenomen�InB�:�=2"GtTK�i,����A�g� B(z)oftaDVFB-�7%?6�`��ex@*iG� s��!�A1� h.)6�2al=�A� occuKH 7  � �6=,,��lsoo�-�Z��4diX.MinfU>&v Yp�s�Ma{2z&YA�ADbulc 6Bzata�3K1�/&C S).���Fk"�B authb/&w&r^H-%(&h��!:�%�:oiT�������,@~the%�eLK$��-��1Le ���� 2MI����*�6 ?>inI>�1describH4"�&&�d ZL!�p^�� �etK �N�� rZ�!ex;�put�G1[�i�A="� injc�xa�[8P� �)e3r�C�)6�317�[24 whR&M B#GN3py:�)�(s"m5,pro!�%�;Q.,:G r{.�6*2Az ngag��C�\ ��0ir�*p� clus��a�ny2�%V�hqar��!�C V�&[9�X[25��S�6" ryMT�n C�Ubed � r�:p�Warb&�a�Pus�=d�U4.1Mf��Wm"�Sof�G,u���"R �HjS� �h��5щ�1 inNE5 �Q�mm.Z��did�uUA��� A6�[26!pe�Un�av>�eNFtTa�, �+=�� ��NO� P ���!�E�(:�)2gWAYk)&��T!� �=}��;fW$ o en�i�w$Lr��tM6An� fa�o x6��e�'.`"�0?B5��A#�3*9 � q�Z/C�K�U Becau�KurC�P9linvol�|OisJ bpYsf ,� �21vKa�%o��SF��<ode� V�. F?E[� simpu)V:C"S"Q0dur��H}2/mLs#4#"�3ra/!�A� alyz!��6)�ia��eY�v �;{)�eX%��%�a۹� m�>�36�"�c as MA&&I;ve Dimen��s � )@po1V 3=ppl�2!kr�=l���<"�sJ�m!=*! "�"?�3 ]� �b"o�*R.j'r{� ina�/ecourA���aA�\��. Kno��!��)�>�inj ~&��B��RN� !C@+e�#� Y!�ore�er�� help%If�J)E*� �Oų�9N���fee/�� � ."1���.Lj!A�"d%d32�–�3� on� segA �� 0$ steady-st��j�%�Zi�a��cY�C��@�&�6e�s&�$sY.ng��=)C�&�/hy-�qq#M!`%n  (b`ng animaa�EMarB'EDs�>�1?h� scen��reo -i�t!N� %��26rdo�pe� [E*��0NB�Cd 1N< ,ori"�-mn f))_s���&�e�i�puMakJ\�`�!�D� ,al bandwidth�,. CB�Yis2NaAk �&�-��[A�a�!�2�0Jq]�)R!- V"b=!���E�qR�h)�N'!����!ɦ, )�g�|>l.�6�^ $de�  S��_� Fhn.�  -�� E A0dri�0>6$tradeoff ? al+!^�rDse] V: rotemE�st t ,fac�B�M*�!�ug�,�z� ��&k<of2�_ ro �Snct�t!:�t i�bA�64 cer_V*�1F�|QhB\ �grHbale���!�benefi� Y�� �>"=h[ �, ���Z���q1Y[e*b2co�"G lyc �[["S;8md_�7^ �\K"��i�1! �]I�!�aT��rl � Tby. ga�*� ��m""���%�k�9e?:��� �.��aux ly narrow ���u�"jB, weM�. � � y��S�E iac E!��ommend@ ŏ!$ Guid�? e C!BA,UZ Laborat�.A��E8NG$al Instituvof Heal�5a\ll/gg�AAmeria�V� ineVM=$al Assoc�8&u]otocol�ap�]��7 �6� Comm)2�j3UniV~4of Pennsylvani�:PW2 N c 803091All3ger>|�B anesAFi��!GX y"orm;m�to�Ui�Gkefre!��=�!:a Hartley!Unea pig�+a 30-qHrod2Mre(-Vµm~cai, M�] Cha� S @s MCS GmbH , Reut�e+GeF-y)U2�E` keta� /xylaz� 8( 100/20 mg/kg 3E$pentobarbi�# �)ey�1enuO^f!G!�V �eu�Ie6V�d�9(eQhemis�Q�d� �� )q`�d)o~pi� 4 epithelium , �$�6 fT> pape�'d placH>�,>� clos;>0��ExtraT�>a�7�rQ3at2XkHz �ґ��& X-oxygen%c batha Ames' med�Żtemper8 !)Thi�y p��!�monitoi"#rac�1!D� 2��cj"$W*|\� �G$re 2–4 h� ��K�~"!� c��guu-.�re!s&�!�be�|!� �oc� *��f���eae�́V� s�D�begin��nd enkj!)�a�z�L" Vr' flas%�lL-im!�a� b�2a�54��!j��"��z6I�^��� 0d"�Z took� �E�e poorQ$�c0ar���<�5�_"]Kim1�&`I�c<s�K -sor�?lgorithm�&�[27];�hefu#a &=`oI�anu\�,� g.t�(�Kempi5�,AA�t�0R+�IJ!�\~1a Bayes�)� ness-of-7crij dDHm�q vail� ��X Dryad Dig�+RePY0ory: http://d^Ddo!�org/1�U5061/d:. 246q�NWe!�p<&u\5�2� B��t�3Hz7a Luc� q� ( MicroB�fF`LO . , Colc�#�VTKnd�j�{� imag�(��m��Zm=lumin�� #�](& 0 photopic ) ;n� ?!p�an!Xa" 50� ×67E�10 133GD�.K �*-V�el7�d� d�n9qQ a k�drawn)�a GausE5e �I(S��E�~by͒A�!v\i�u ��A&KG 4iqa�9t�B��re��Bfraa�( 99 mY=!-ag68J)��03�"Qty��Bc. Sm�1��a6*�U/) �`FY$��wQ>���tookE b� �5?=��76.-�.C�e�_�% vn�2�two) �����ccal)K&�3�hn�mW!�l1��i5%3uGPpY uXWaJa 2×2 F � () Zs]L�.SH halh:^W8!�third:a 4×4 Ma\Aqu�mrI].[�]ATso� �#A Ps!N7%(-���su�="7$���< bs �6� mimi&�`*�I[ZQ�2��7 8 ��4�b�t)1��$�a!,2U.v .TqofP!'gr  bl�HhFndq�bm@Prosilica GE 1050DOsp�Vd�}camer60(th a 1/2″� ( �rVi� Techno�>esL Stad�  &K conn�)1 laptop ru$ 8StreamPix softw�%( NorIn�mM� eiCanadac0 grab��at 60 fpqX �resolpqasq�512×512p,%U�X�_filh�� tripod ab�25 fiV!!{t l5�=�� ~u!Y:;l���Nur�dI �� 7 xposAw( >�� ( µ�#� "wAshadows�avoid sE��_�8-bit�{0depth . VideomZ&�d�u�&�d;} ��5�uL e: sItA�inu�+m>%Z&W� .r��i��;=�!Ŋ�� !?uZ� ] � �i��� � ���t take�"�!er !�wN �Je�siz� !oF�u�S�^c�,�TPall"H#o���kŗ���"4q!U�$!��v �,Q�%gB&l*sce%GEV��r�:���i_�>u(�s-!��) �.��*� �fixe:maBi�1I��-�sI�!�axP% �)��izI��g38a��Htr�\g�KlD6�?cV�ml" A�IQ:�%xha{to".1�)`n"�n50%!� �A�Aed 10-h��ckJ.i��N%q1& %�v6 W�^�0rzb &w �M)V�{ triggE� ( ST*A{&�iZ� :bGu&�p"�6m�3Y� ( PC\ bestD a��y2?3�0Hia wo� s b�^ MB��!�� �a��czr���Gtif��as e�1�$^]irF��;�*4-��� of R[o* [28]b]u�&F\_A��)"7E�B�4�&  �6&�\\eUQ�seaC�;!���repeJ5!?=group�Qp�%�"n=Gy:�pr+�o%��F�D�7%95�6_� sawe.gf�*�1���!ysa�!9,�Y2 N!bnd $N2,2,��U  &[F� a.RF�a0�wi�c���M�!q�u��#/public�B":c�(� ,flab . berke&. edu;Gb�9 carr�O �6b�b%�!�m��3!��by�#e"�(�ngub�h��N�H�*�C"8]-a�E r�Au$�e:<)�q� nre, off% �� Grad�]a_ 4 ea# stop�jA�%m� aj2{! 6.��6he)%\iIOGa"�A�OFonX$^�G��j\6T. M�)� �`!^�uB�;!�ed�^I�ue �W{&�5�"2zjA�*��&�o.G!�#"\s?)�Iy9F:me�� "%*�'%�2%�Q�  %A�s#)e*inBei� � a:�2a�|9cBOxO�Ahvi�I�Ont�g���!�F+&s���\�yE�done "�y� � �-!n "�K)$�B�EX���.`/;s�i�wn�WA���Ia{Vxnd$��2�a�k&��0��IZio98%!)n!;e*� �l �`%�%y &�dE� 1�d�#�1rB4ovd>�9g,� !V4qrm��APu��p� ��fC�<%�Em!7�KO @x>}h<%d,a� �,v.�A?k�R�S!�pro�HJ2tV>H�Q"�3���&j*/L+|7ub� an�(�B1 :Ax�Fh�N�_m�e*.�$�ms5�2 —M�KK�m�wbe�:= ausae4A�� �� �a|�UIQpost- � 'E��?"hsE���_ a�uqZi"� " ny a ���E��R�,ed-�%�:�eacE�A���� hav�g it E6P( s�e roo�=�sLb e�-mv�)%X��dg:� @&E 9V�#9M�<ZTQ.*&Q� �k ) is c�honvex-�.�T�RV$�,l�L0 -*,"�j1V%i!�%_!zu�* " i�",�E�,�% 2�I��RQBA�*"S�B�G!o �!fE� � �� 2�xglIg�mx )ly^�,� IKorb���:�1E��G- [2:21��p$�B5B� ����;o.%^A2)�6�#V�sese�,��#�. C&T!Are�?�d-!g1��coe% "�"<\|tan?R+"$ ��6�hmd� 5x3�bins;�as��@it�Qor;+pik�*k�'[,K���2r6&Opfwe�S� �v6Rb�(8)W��M�d�,����.�fe�f��L 05%.m�D��!@WGm�V� �Q�hk s� �)a"�@� %-s�!�%-=��69wQG2!2� �)��-tW.�DxF�6�P0tom#�}��r��I�mN }_��7�/�|Q��j�!�/�"�oMeT���IhC-1�!ќ��n�/8 �dPG��Yeri� oa��o!�=!a:!�l�Ef!2cSwead�&i��l@1�0U�+�fo ��*1�To1& c*c,m�%Rsmo�[)Rng� $a cubic B-�ne curv�th�M?�Hdl�&�oupQNE-I �� �x)%!hif!��"� 200!"window�$�V�Babmӄ4y �B�%�!(� w.%.!V�rosAJ5�an?^�*� �0 &� q*��� is g� J_� e�Bi:(� CnB(�>!kEN�6�1$E-�#Df�KI6i �Li .u�:m���EVp:#�H6�.�um> �qv�z &aEw5U#�-�.&bex]&. G�]a3  wᝥIC246�eZ��zoP.f5����D��. F��!�����“&���3s];.6=�1I� L 7�y�Jachie*�E�R�R)@A�pml�"� � �ap���"� � !��6X&��I !�i,5���oc�_fquivalaE:x:e(:�)>f�e��9-v �Rc%t :AB��FtO��5�6V=�>lGTEg�y��d��"�Lreg���!U%R *D bega8/%�)_I��re)G expI H ^A}nt�v�z*&;,Ts�9�R �o)��.��� alr�6�dNXSc� �A4ces.�m�as� �eoI� "�bA�-$. �UAH$���ll6l>�� .8Q��4par�gN�l purpF-cs� nI�*K�e. T"8��_�z� maskeu��w| ��i�s%q�-a%aE�=]%��?�Crec�"t*J!.30���� V!az �� ��M ��e�ckn*�&&y � }t7Aci; g2:,!eB�+���Yus2e$!Fbf<�U�cDA�1\�@9!toJ!!h�:e�,;2O��K�:% s���rp2�� U� dez�6^f��C 4��LU�C �.�" T��� �a�i%���2s�Paa��BNz< DEyp.%�"i I�Fx"��a��F� �6�' ��{�� 62� zP!��%*h �A�!@b9�)��_PY�ZB!�% �!� !"��&�J��b�it� 3c"�Q*d[��� kM�(�E� �(C*<�wa]�:�B s>dra�8yi�"�S&p$ �� d$dekj�+\2%!T��S�4 Brie�.w+X�3 ser�'of�i$�A�� �6���� �f"�!<)oe�e*q/U0�r�AEmouI`val�DE QtPethod��g��d synthe�c� ^/I�*+J(�Z)s�Wz`Al�A`B{��9���@%C�/��-��i e��wa� ,s�m s�gr� ash!i >��Mc%OdB�-&� �R!���aQ������g2�[���y,l�Z ����Q�ce�,U.%�er�9,!c�f���]8��%s"> �5 �+>�� *�o�I�f�.E� ,.�A�(oA18.n**Vl &!q��a,a̛inm�2�A�� 2%с�ua�՜AW�j )%~ �%�^"0;m1'�J��3�s�5��g�Zg1����co�n c5�.�0� �0MA��"� 2 (VS%�O=���'��e�-s� 'A�}�%�6p` eOB�#�M:['8E&jMej �*,|8I�. A�}*�K,EJ�U�G0#o�;�!M@�4�6��tw&~��.S�A��!�qaN�3%'�9�f��Q *e�is �e�&�X}&t& �0e� A�L!B�W�!� �/aFe.�Hq~� G"�M� n��p�xa-K[ukF�� � � � *^z#CS�/B��%E!p�5�-+��R�1�6D–FE�V@�7th) !1mT��·eP#`T�x!m��n ��2��wJ-pz[���ban� ��t\?][�&��%��n�36�R5���ia�su���~$En1�)I6OusB or 3 0L�AN0A��"?Z��IA���r.[!o�aae�!�=E� ��I&X�s��ej�Km��2(u�22� �(j�%N�<�#5):O� !OP���:D.%,�D�A�:$��]P�4E?s��;-D v� U��#at � �b��Mer5P�`er�?h% �b� � 2a�'�GeXT�abs�8�<e����a;"�Dq�Vs&�sp [typ�To"�]�1���Fy��A2 re iv�i��E�O>�ris&?jEi�B4xK�&�bpathwayA�a��CI��.Ec)Ep� >2R��; �em s up<ex!�K�CP�M�-��aB"f�L!_ch"8�N!R��>e_r-�h k4msourc� J��sewAe* Tw)~SL6 I.���1�$xw prevz2�U0L.n- ve)vޤ��p�Oric-�*���C%}�>�%�e�"MD��tf*Rf \�"_w*"Q(M ��XrehenxA�B@*�_y!0SL��L�5օTnj�H 0�acD+�c�scheme ��(2${o�� w�b�.��c%�nt��&^(�p��-�is5�1��J);��Ft� crip� factV qYyEEr �,�oSr by l@�7��#4T QG!-�B�� �ADesY�g�õ(I@sagt fhcrX9M@w7loads ved_%_T tic_2 . zi���r,�p���]/�#& ���L��a ��ng new�tC�tb���ACte�Kmilm"�Wuni���%5kH=hundreP.A69�,�<rgazw�d FseO�ԅ)�v-Hf^����S��o�� e . �S�S�SS[�x�Y�][3]%Y6_��� �\�*iefCd-�d`��E�X �NaAT deleAQ��aE!�� ∼6�$)8-)�b(u�R�n; 39 ALF��aE�����D n & � Fq�*sE�v"y.��a!��-wi�7[:&`��g� �2�%P �z�dM"�LW"t��proЂvn8b? %��"ri,&�� ( S��{!@�� !�f� %"e~s2�y��ved-��R�ex,i�2EF4�]&^� B�,"�Yef7L�v�eW}dLP�<�;uil�Ed?l�w��V�ɉjdlyyoiT��i�I���[�85a��O[cRc,�]101 ��0bLZ�d"5DD( MND F Or&�P!qE��&v� R*Nt�6~�a��!�. o��&��SSL*m�"�(��ed�vs 2-hop ita���ne�6�k �ja�Ʌ:�)x!}�.{ �6E ba�6"�[�7�'^1!t-V1�5�+fI c$2�:p Vl �;� 6� N A�B��8\w'� whe(2��]2-stepW"�Dt��a rdb C)�r link��A–C x  ��-7sEo.&X�� phys�-!�.� �!�n�"<-]�l�!�iY3aN/�tan F� ��$uv�]�W�:R� a�\ofiD�1�eg& Us��Qng_A���Bk��N:'�x*� � laO1>(AV�"��� !tE5�H ByY 6heA}>�ba`"��udsb�Ba )4����^)9~&].40%ya fal��o�0 of 2�?�'%x�a ɠfr�*�(�aK��O���ٴ!jor�.\!UY�J� a��F;^"Q<H-y&�L�w)�Bc͂�o*� ��q>� ��LiA amacsiG'oblem ��dxacerb+i>�2� ���x  Chip�A�Singh�6dŽջby utili"�"�SL� �F*U�Iuie%Uex�L2NT�GO"��'noI� Y-�!�6amoa� .�Xe�:a� �ely's�s��2e �U��lcu� ��a� & I�sD wal�B�%�fZm�1J�t�:O!�t �Ah�U~ , Qi et a�xf!�!h�of��o���Ay�\:)O�� �8'���=Fa��n SVM"V�o1Bu9\2�^ @ey)N-y"'8M �&� A4X�MqK�i� *8�elo&��!e�o l�/ �Fv�eA H*bp�� fal!�chPutb as Wa�1�'*z�oZ12��f�;�}A�- A&�� ; 2E %#T"m &'NKA�2I�� $, Paladugu�]y` ���U�����N�MG��!tE}��Xa�2� Zh!oPSDk berg� -LM0!K2>1CFue� Bchq2��T5�.8. �K]A�ge�t-}��6�.|m����Es*rth}M�!��v!&&OlW5!^y �-Q��mn.�U!��r%��i�)�2�e��@i�~� or-Bz 2��fic� U�bi�� � }�ks,�-m*  �� w��;N56E�.�itself���Odc5)��:)O+�l�c, !gz �f .v?�y�FlUK� $&�sP!�}dJQat�Odn4riej�o5�5!�BZ*@��b��;: ;� "�DseZŴ��a[i6�r �_ Ya�\-N�\��\-C&�IM��1��EM�s� !c ���6w"�%enhPd>�Re ��z2Dnincor�J%���J&�� ^��!k.{>��.�[� mplo�q�uťaUa�cv2uE�Zrag!mt&e�ea�o(b9^%I�#"yy�:_��S��!mi*�I^�x*�ep@gZse�7sre 2� ����I�e����IB���-skUgF��Nee�qnyet� �E�"fk"I&2 *�!AJc9�!�Nh�T?Jin>� a&�a*qh : ��Pai}2�2��٘�ledge�6u+seG2 �0 ��a�m�AtR � %��4a�7 .PR�-���on*�:� ]I��(�-"�!��at� f � "�-ɔs�!�!_&-i1s #cba�h��\��N i".t[/�V]�Xo�!�B�i A�n��(i��@*� �1��fBT,7B� a�%�acha� cap�.ofTng_ cate�]gF�!��sy."(". T2|��e�+��q4��w(� e�tG_#�!�AaSL�HEM�SDW9�@94-2b: 125 , 509D2"u!WSGD� � ( www .ɟ  .��qMays<8q$ &v(r I[6h�&GD labe>a� �ct_6LO 6pM[�temm!��.qSS6thav(��re2B‘m�"’�! "&'�NŴ�Y7G.l aF� >�a��.j� *���G*sheex��[i�& ��zK>�6� & n&n �r�r��%n)!'a�F )��L.�)�e�V �[SL6 ��b� �# of 9N�J'!� 2502epo%�e"�S, a�b'8�Y �<��o � �*�2SGDaR,C;>�\13i.3 2��P2$��N\e Kolmogorov-Smirnov ( KA ��!I.J q�֣�O*q�eX[�\ %b•�"�(!h)e�ne���>n�)&� swD�pE:i6{KS �F7�"��6�1!�+��ri a�G>of)��� R%g�K2A�w�e:&?`IP 6� :U Gut1U�a "|ir2�8&nd-�S1!B�41�t&`7df�v�� �.%N:'6KQ�� ǩ �A��:l>e 152 ^[ �15#&(�n!�2��R*`�,-7"4.��*�)�W5b2 f� te)6qnd*� a"��" �T:�e��q�*K�"�&v=��� , [1� %� .9�+���"�&6P(:m W!�<ngq �a$Oen�T�aB[or��I؉ $ .�maj f�j�y�, 9�391P!6�)q�l���W�co!���)u�.�ML21mƝ3min>� SL ,� 1:��:��l!'YrAw �� [19]i�[ �e�\ l�.`"u`a��QiW �ʲ+ on�q(& �R(R(&&�$,�2���Ƀ2�g*Ha�-%�.�8�nc�Xt։2y�oO�AUM2�G esir�o!��2lex1p�%SLU���w!�(2�?�txQ>e��u� ��qa: b�u���If T' "�B�B"�)�W�:Ma� a)���<:5&1 A`�#I���p6z�ADA# a�[��2�&cMp�toJ9�(q�C���dea��2~���m!E!?uL9�.!�a)�w"�G H�ac=k_kC�D1f�UQU3"d� ur�a� �F�]2�\a�� recehp H�6T  ( RO��H�{|��!*:10-fold8HvS;A�.P1)1m4y�� ��9��#l�TtR+�v��F��.!,)e"a��+A1�ٯjp k-NN>>wo,. . At� fY �E�Uzy���Ww55% , 2%tm.�R� VMeKJ'A�!�� (�D ��}%�2\u2��O��E��Aj{kI\ (2���(49% vis-a-va�A�- ��ap.�"9 �)�16 . 6!Q'��sc��O Wof�4��at�2of%���%V,^�2�>���A��ȅ��!vM��Dx5U�da�7oF %�i"e8~� �l"�@ofB� _�.�,z4V���:^�� ��Bc&�Ya 15%�w9�E�6G rj��R�>.�`7I>gD�< :� A�3 slif4�&b�a?5�A%R��to�e�B�-m0.��"��K5z. A� �0��BV7(aels�&����-t����#xQ1:1��!�To he| �0!uq&�:R �%ZAJ�@ "L~ � ��,,y:��$a$ =�%337�ste VXKC� �e"-�*2� �DyAY�2� , 129!SL�s� rT�Q �IgenP��7 �`�iv$� ��*a�A� � min�[%���\��v �s�2��!�� �r� e ,%��N_1!�=Vz��5zvej'. e�_mi����#e"] ��BA$g!�=� ���SL� � ed 283'�que�gi0 �a�199 4%�t�?eW� >�3=ori��{ E�� D�)E="� :�.� !������310R�!J� y�o�EX_� u/� \^ �W �. P"UQD4�c�H}-��a w� a�!µ�|�#��.&3 )�A<(. lA�g;%t%�V�!\��$t &%0�8RO�+B$ � V sn 4}n�e2�m���Zb.�gj>x\��8beB�m,R�qN�!NQ!L��For������ V�s��f�* of 7� �X��j-a�����U�N�w64�)c/.- ��EF+�S�)'.q����g8PI�RWek�}g � emen�(�wbY�.i�X����m�-!rAgV��v�bXU�u HmS1�!&���kc*cK^S���AIm����gap5 %(2��a����Fwi���jXa�fi+A��C� ��./l&X-�!��!cF�� l 6�a�/a�82 I����qi� $�{new�Q2��? cm-|NM��"�0��aJp-Q'�͗,�!�&{ly�Qr%a-ZN�&Y�mp!�"�m+unA58R�(�69 �c�!k�(���!�B�5�^v;.".R.�.��6%��9a&�-՞-��`�e�c!l�3W!burdee)faaAn�!1,:j���e���&�DQ ��D��730Rt2pS<]��k�����November�a��;aV"^ �AR�39 e}#aJZof 5163R��!!dA�{ ��aigF�!FT&A�� �� �Rt^��_2}��!ML120346 ( = 125509-�)9 "g4 "b *= F����8 %.�5���5�i�!W� �E&�R ROC&�D��y&=:���t���[>� �)�.2'Y�  uh�mZ.i�,�]�D� ns10^o6\*S��5�u ��y���I%2M^qbeøs��ie"� cuK#l�!�\8 WNFAlD fI��!�)�acun×EW^ :�S�!�D���e�JMq.�is%hF� f'��%�)@4��Q."�V1/�D�q�30%A0i O!�!�K rov��&�e`E2iW_$#/sc':-�7,b�� h�>R3&�i�k�cQ@��K.����@*�,.n�Te��s-_-E�45%�-�samr��Z9k9��=� !�fyMm�+ow2 Ix*�@fac!�/n&07�Fa�* u]����"I��(&�&!�E�� ��F2� ApP1C�����A�T�on Fu�s�vr| w3%8A�})��R�&�d.iW�5 An7P��@�M&t����/R7#�!1: .��>rar�#~PpEb^�� whoA�atQi�EJ� �&"�B�F�Q}aavs5�D"Q"U6, O� emanSim C��(Brem Abs TO�N#1BP�bnd6GMF�U$Y )�M2O"���L 92 , 88E-856)>!9� t��(;0�MD09O07^O)��$U�*"� a0�(F� +�K'p�]�a ���tarch dl�!�ong � >{/�n�7� ; 'pC�!!��{Qm�|w��!�! �G$!�2�!9–.�5��. I"��,� EXc"� = R]���E�V� &U! %��3G�"0U[>�\���NA qAUC ?bM� ��897 v��86�R Al"�7��"� k�ab��ota�yh���H �i�2� a�u�F&B$!7BQ��� �"3 ��&�Qur1heJ(�  �0��6� %rR.59*/,1�R�Y[ chE~��wъ!*���^!�� "5�B�eM ly� �+t2�U�>�D� n FPRA\[B,25�L"a T $6 28>�"a*B�e�9L��5^�I�,�� ���.�TPR�4�:�1�&d2`  b�`A��AVR�!��eJP�oD )�OU�Z2�PA �ѱag�2#�&�AQ:��e2h1�e�ac�~at �a��7��2�?.�^h*�2' , )xa�KJ�J.)"^"��� �]a�Y��P�]Q 1:wq'�C#9U PPI-3%��ThPar.A>8/��^o�v��6�.q�k��p (. For examp�le , at an FPR of 18% , the highest T �PPI-SVM w/o 2Hop is 52 . 4% while MNMC . slif leads to a TPY6 ,. Givencaccuracyy�SL predictions provided by our approach , we applied itd study fun�1�orA�lE 0suggests limi�AyofEp�M�edA�interaE�s betwea.�U0( TFs ) might1 insA�to`A#tic r%�onships �ly!] this.. Towara�endi`IAxA�test set�P6 , 903 TF pairs from{-0A�,vailable 118�u�1106a��ӵ5. T��S2�$Text S1 li��!�475Nu 93.9�degre� eachR~9�R�w. O�averagw = �ơ�! ipats9B� , sl�� ly mi�an obsera�!�h�A63�( 86per��)e�x�( FKH!�-�A , STP REB1%*CHA4 )��invol �over 25F�2�%. S�- 9�6�sr/ �5Lactually well suppora�b�er�s. Rec��stu� �c"� !=H q$ YAP famil� ^�YA%$YAP2 ( CAD��,!8 YAP4IN5�sYAP6-8!:s�j�sa� st2  induc� dru( eat� , ox�lve., metal�� oxifq�, A�DNA damIvv �rs [23�[24 5 6�Tő2' also5 �S��!!A�%L!� lapp�,but distinct=X$, although%q6� � them%�st�_��%�� ood . Inm1R � re haO 0en no systema �%�gen�O2�v�V�to�7e6�B��a sub-q��i/!&Au!CVv. T� Xis� ri�� f 56 linkq 36 !�, incluQ 7]( 1-7e�Y��!,� number�2( 1a�, followI�A�2Q�A�1U�1 ( 9 3 ( wA�m 6: YAP7 only�a 9 le:���z . As��n���]!��reE>f;�B2�6�! , nam� a�:e�e� m� 5�&L6 . Previous cluster!�analyse�H!�,protein sequ� m�-e�bih .#6] ��:scould'� ped� ��eXedA���ies: !��w !�%� ��  3 )�7 . H![.� &2 genɶtwoACAY� e.��%9��2��܅F��wa$� to X>5 with0� YAP3�E�.1 play���ro"� ���Br! �e�./ H2O2� �í� , cadmium�nd��u 2 Idsito8 -[27��u#!f6�5@%)kE�im4�losE�;abiLtox � rwhen bot��a+�r�e2consist�X%rYpqfM�"Z dou� 8mutant yap1yap2���sensih� �As anŽ examp�~d� h"� Bc.41a�Al͋6�1� osmo�E�,-�he�4 null�( im� eda�wth)B expo��A� yperVlar�[28!� Howe; ��F)4yap6!�ain�YI��Oa}glycerolbolism�sm��,Awch!{crucial��-tolera� 1{lge��se��A]y!�diZ-spec�:���6��q�6�. Fin� , it� . �\a�ar�!�� !@basic leucine zip� ( bZIP ).A� DNA-��8domains similar!$Z true AP-1y  GCN4&Z e�a� MET2�L �aA'up�14 ����  .�B� &&��es��)��<�surveyeda�6r~ HAP �,en!�a�.�C�Ie! glyIV�HAPs (��yi�; form a fu� conncclique _a miss� U\H� �H� ele 1 doesj э��an7 !�oE��. Not!� ��`,� e p 5 sh�9KCCAATUb�! BF nd��M- K -� �a� lex [29�MY�zas�Hap2p�ap3t,Hap5p requir�*a�Ksubunite(ultaneously � ��a� T��A-. F����ZAiO ly i3��29� ap4p�!V�/�5p%$29M�*#( |ivsummar!�\explor�f� m�q�# Be#.�� already�wo s�*i �1se���j\s�expi 8usefulE�oZ a a���2�!�� %#4r � ( me�ism2_*�in �>*Z�In or�o�Aw�ut�ofd�m%!s u�>!�"tZ��a )��of non-"_�� S . ce�sia� tis. eavozwe adop!��eS 3885RX���tr��ASGA arr� [30]E� deri_� ossiE !�.�isXft+xX13�503.9iV�%robt 7 , 47�681.>�� po i�encode)B�. N�, .�,\*8G"9�,e�emplo�� omput�Oe��ui��notQ�likelih?�se � 5 mill�D =XA�r�App^a� :o� e�,�don���esult�!uy�5m210Bo* 3477��t�-demonst��ng%�wi-� co}� i���/�q� ed)ge�SLOa8SL��tV�FA}6i ��&10at http://sagalPfhcrc . org/downloads �_�_!� tic_2;.� ��$I�� valu&resource�bea��@�IeEVal%H* al biologXaim%wo�71��zJ�2�"). An im�$ cha� erLc1��i���-s �I�1� e2Auc!eit.�" !�Q�preu�)6pa< �!r*i�aOfec�balB d6f( 1∶1�i� q&~� ��poA�negp �ea7 did  a oce1 �o�e 5)a,o�mE .#AUCq-NJC���ed-SL-�t�V� a!a�describ�.�[8] a��var�� �� !(9BV2>XtJ=�sE��� err !�!iEO� r�bA� 4 I�im-�2�:%� crea :.sis quit�%�upA�a ��"�T��,b �%1�s A very6^�onZ skew! .N�%��h�!;in��#opEl>Z�Ca g�""xmay�f diff"t��v qed howVamounO�)> (9�5�)y5�afa��ur��b�l%�%�'s2z. Diffe!���% ( 10$23,… , 100% )1 9994��Zc�B afRprocedB�N� !oe!;>$)�0�oru�2�I� AUCs&�7 �i�s~ ���� t ca| E;�GI� �.��l9iY�/ �he=�5�SL9C9�,�4���i narrow r�#of ∼a" 7–We"3invu gaAQ:��%> �xon-PPI�  !-ka;� J� I�o/ "^$�e splite�152b!i�"wo��s:A� )���of�U!s�a�2 �-�e2 "� ndf2SB�0!don't!2��! J. �!:�w lay�wx3BM�l _� e-� ed ϵ� �!A�� !42@t�eraJ��meT��i-]��!>� ��6yYir2?� _ ROCh"i"-]"c[�F{:����%d outM�i�!t%�` . A�{�(��A��( :cs is 16%� aA�a��4e-] 53)versus�.�'P�*J#�5 A�YR�8 . 9��i�3�7%�1z 8��AY� -of�����5 .[2��29 �-"1��2��is��mc�&2G��j&wo�or2 B;, suchl GO anno� aGmicrora]�etb �qm9rich( of in �tAjus� physical��B�)U�% .�(a~wo�3�Hmeasur�G6strength{associ {*�G(�5F���r��a ��e.�bel&� m[� Vb�.�im�+$�։���&u>9�those��LPaladugu et al . 's � [11] (5�( W r� ��r�q�%��B9�%t be&� ~��� ny"�s� JQQ�F` se�&�E heGt��M'a-:�novelC2c:�,� %!^� . W� vr arteg{ v�$�1ͧb�B�(�)>��i exte��Fly ? MNDTj[9e5 ,� first def� a l�,*% U!;&ezA�~��� hH+q}���S�V�Ydevelo�akl6J�"k]KwhR! a�ba� ongs�+h !orE�SLN 0 . Comprehens!�&b < sK$a�*� EPi�at�*�in�juL/&j adv� d {.fhemA /toE!�.BCI.�.5, st{)i� � methR�#j�we.,�.u+ ^<F@ �tr#0oId�*-�se Ri�b�eW !~ADmakA<1�J5���re��$c"�w� !�V�.j�%�isY��S"�'NL$EWs1�,i fG. SMDn" U"y:�*2fq+N���f�'I��V ��� e !p�a*� �e media�ref4)mos"� -�qL 2�!�aR!fe�Vc�a�&��1� h-%�0f!�R�Fb.o>37 Frefh-%fa�at ou� fm��  ,I�e&2 sign1)�a�$��� helpqwchN�2X. O.�31fbe:Sun�aWnew�Bea[��}r"U�hundre\#fj0� organ�8 mous� d huma Y ^bs(H � �s� " A#In ad#!E��yp[M�o� �%Y7ty��D�� mpir� screen`%� carr%5s.,�E�aF���a� t� B[Abv9e�bEntext:�it*) Ax�<"�� �sse�2�c a!/&*6"(��problem�$-;A#!�B�"�st>��m s su� lowR�/A5E�a��-�  h!,��lso op!�� door��:�A�oa�e}�3u�b�J� ( GI ) � a�bet�-6��s� 9!�AeA?�&�wh'�KxGI"di�&�5leaR&�.PaC�E_cj�( g�5T"wJ/nu3-%y� ��t:�6 kiva_ofc�dat�%11!�G&;�e�yan�pri;*=. M�p!�� � !�6 *%S2 �A�t$s�$�n9Y:� d�"'d�n�~����0*�ᡳide�.re worth]�in fu�49%�is!jorki�. e pur� !UM� �!�) ompi1 �+��&�sa8[12�.1�.1�.1�.# !8"�� g www . d9O(of Sept 200�,�BI2"�+U�6RMsYr q]�9Ont'y ( �!�o.�May�0,V(pheno�+�D%;J�2Cphylon�pr�9�-;s [31!h8KEGG pathway me .� "� [3%�BLASTRuAg��I�n3� ��w modu�and�% commw$�;%tE�Aw# S a%�M12� 9= 2o"SGD.NAD�l��>I � direxe &<9�at l�9 mainv!��W+c�$�R[*"%~F"� !2zbai��preU�.� �e�2���*av�29M�6]�!�! �!��web/d!m�,�W&minor�ia}<�%re��'�Bg8&Y� �6ll):�A�� �f.�$ buil�::31ng!���e C ste?2`a�of�-ed��30h.�>� �� 1�"�[" !zE&�0Em�- vidu2a$B/p ve�� �ofe�!7Detail��:Ef&22-0�� �xaDa!@ �Sv *�#"0be���o��� -� �.���41��E�cap��d var%��� : aI&�7co-*. �%!���e��)3, ��!���*%ƭ .f* �)4�@A��,�in evolu��terns ��mu72�.#b#<9y,.sA�u'al label��;)�6<in 6u,Q�!�We�"�"5��#&�!�LA��PelfA�gu � ��A�6����^�BayesianѺ��5 o�g�3um1�of�Bu �:dy@�� ;�B in T� S1 1'SK;Be� �"0cusE= M� ݉�ue���- efo'B�aL!1'di�"� v@ *�# onSLE��e! A�a�:for]@ Oto1�\]:]��u�oZ(nt !m&�-irANX-8&�Ѡas� �?gnA9to?al����e3� ��!�u7�� be biw?by�A{h�4��o1�l%C�$ � ���"we)��!y138)}pop�1ed�g&m!fD`%�My�#/�s0 i�6�&="�6����onE$![34M.W��&e$-w.a�6&V���!��3nᘥ8��2*3%v�)iSd*��*�GX�C��GO6�si�*��"�+�7X&c!�z-�+lso)�a��q��cal�:�m]$62��!U�0 �7a���r�N!��&6D!E5]2U� e/i�V+1F;ierarchEB�&u��@2 �/]���O�-.�,!� �h:�� �}f��ne�u6��Lin� eman� V� [3�6g �s�8AˡNcq�(l no3)� Cci�4^1��6d� a��rob;7 0�.�med��!�&s s#mB�!PY{�0:�A��?� A�,!�n�.A)�E: D nces-�n�!�tj�o�Ir�:6Uminimum~!um < N Intu�7l| )�1� � �!F�!8!n ��M� irF�!�AJ�M��N�<���u�ly%CquAUf� 6 .�%�b i6�[3�F[37:[3�Now*j�hM{ Օ��Fta��� �s A�Bŋ�%"u ]��� cͲm�� Tao�,'*D�a� �=���1��� A ��� �2)J[in 2�!� viceX sa .0! M� � l�B�H�� %F��X�1�.:uV�� S���9�$�|ed!&a.2M� takQ��8PnI`ve�)oh+I�2��accam0(l^\w�: "of!�a��. , d�!�lex�J{ made *�6�CEoU)E:� Cis5pu�%Fa-�.��5w��:S.1��-q�G�ɉY all-� YEu��q�7� ��BU�7�) [�Le �,!�)2�!'=ujA� E�ta :�#�� b6r"�@BU0� P�*s� Molegr F�EjCellu�: on�&H%�2�)���Qal"�l� )?Z�"�@%s"x ."�6-�2-h�H. g"!�-#T��,"� A&h��d�@��“y laid”�u)�h�2�Ad�2sM��"h� A�  ofIy i6�)qeat�*�putS an��ed5]*�+!*���!��L�2�� ��;"1?��,we� �edg�,;!�XAT *.RZ"�5by�<wo)M�:/����.�A"�; wis�A�Fif eie�-B�s&�; exis�+��03l|C�$�*P�B 7h[Ni"�<R� 4�N%�Er7�1t��1II�bym/�Ki%��� hhe maxM "QAP�5��A>v+3}�n>*\, ��|�!K�(G elf-tm�F 18 "�NA�*T:�"�ZR� p��� }p�w�~wo^;!;&y� CB"a/i`&W9� .�-�dB� �(��HQ �'+ >�N#!�N;:e/Oui�L%�a2�Q�%co-causTѸ-�>���I:��c'n s-F6�mI�� su"p- f�� ll��&4;>��A�"h3y [!.T:` powe�1� �e�T-�� AU spars�2� pre_#e�r�9 �;G9X2�4�^J�2TN�(&�<0R)�A �{fe!�p"V�=0��(I a��6��y��s%A�$ 6poͽ��s�I�Vad"37%(�pS)Ir��MN=W-.�fu�fb �<:/�i��=� f�� )�!pd�8 �mI,=it&�_��{ S99S�C� �(�-t)ain�9�$  0�;by Wong& � P��`�X!eg��x"�> ��s �iHG*�k$ R_,Z!�o g�<O,.:�21# q)Druq%�� semsim_mfe cc6s %P %Vn"�#�s{ prohibU timLITB���$a�!8��7sa,xm .�w�!� dK0*� :��;��!6DU�;(&�:3�yA�abcS�ioa.��m%r�U a 15�/neA9 � �L /� it�>�m&-&.� EX�. a fa& anneA�wG*�V� .M6E�� �VA��%�> "��"Ye��!�� O� !(q $�oo�,!D^$"� s~$sA�A(�E LLBN�s���()er���,s S��;�K�/v��\.o�=,� �!4� �dr�6I>156� HeDes�\��_D1c��bN".+!cco�9)< of 1@X:�'^�/i(Z2A“all_ �-���uM\����Anm-b�+)H�5k5T.n��;xU�a �22��"b:be./Ah-U�k0�-�:E� ,�" n� ) 0.�,�&-Iq� �6 dard '��$ algorithm�Y%�de��or&?�es [39E40j�Rahj1l0![ o�3l�KhodU  ^�D)B@maj�y�:?���we5:domly.H�#gn?5k" ��le�=eq,)JX� �qo %i&E75�o3P[1�HAmZ�<"�[)Et���'�1*d>da�2>�S�&:J9t*��u�E"�5�e eM)�Q� un ��!ar��I��#a�O�!�u?m-� � ���N qA � � i&pF�j2j2�y:�/l2!UA9f:P�5�!U_%�a��*(A��@�?)N�kA!��)on-!BmetricZ4Y A3e�en!i��."�JU!Xi5MMF:J>� f�b, neu��, RIPPER�IuleNer2raa2 U0s�<k-nea�Yn�bm`�QM,t�J\��b?@�Eegy%t&�^!_ noisy-AND"x��c$n#!n &=x!�F^4�$pi ( x ) rtF�CT.�%nDeL�=i�4e�� #pP���"Vc6L pr� �����m)����E;M �A>*� �� =�!�2=�) a2_��/r�$�^1�(�)��Z .Z"+ %�ns� �a� �=6�5��U"y�,�*�� �dWeka m�_ne ri{8C[41]  ��a�r?Eٻ���Q� �Q� � �=6M.2ie{�u,n nZ`frame)�ur�!�2a 's$�D. n−11�iyEZ&{Ena d�4�I�!#�ca#��� 4�e�5�!�execuGto-��oA�z2Zi�J$F����-q�k _92N7 mw�E��A ݁}M�� &�b�aI.I�� !"� ]pe� �u�) n� s��E�R1boa�>. �!ai�a n�: �"9 &�!B%3b51*�z"�aL@7@E2�mB]h A�G� 2p3w�wn[ed2?*�ag"�c�n*�Pm�(,H8��A���j�U�vqz�#�%E)e��h�TsetT,��`r!��d/: 7��118@B&/��"&� ��(VXO-.��(BRCA ChalleTh� � - %4-n$�projec i��u!)GlobalL i� E{Giic �! 5 [10–1 sBy�Jg/ icZ !2�^e"�'�int P2Hpr^ cc "�V.�A wome��r�kl�:t9����[� �g��5�J+�5�R�!�%��inudM|yN� u �9relev�/�Q �E8Ti� s����0�'C h9 |iss["�9e !qQA�""b�#Ka�� s�0 pros�G!dpa�U!� �0 W���n� �as�45c5[con]EA�� WSdisrupa��!�&[1ma>'4� Bwa�-�"duroN R�A !Gf1A)�havt�vZh%�F>�[4-U�<�t.�p� ��2��m prior!q.f0� �=id,!�a1C!YMm��EP�2i ��.'5�n�Gth��պ ��� Qh� � �e\hc�@!?�%F��NUs:-�;�i�� + pati�/ɲ��-“D v�[��!�m? �E�o%F-� Z !]ir!�ul�seek *Zman� �<% me circum� c1�Q�!��4 by.�out� aH`t|[18–2��#%b�e; appeufbe>6 P� de�HrB?eb(e��N�W/)iYofj�,] #E�“tra�Fa%v�i&;z�J���re<!��4se9��4ten� 6j!�/ ��[�:21!9�6Oi: y>sɇuat�5&� �)-�ou�0 it��bec%�l%s����vDe�> �?t�"�@7MD]"�pa&*N,�$uD peer-mbe�Wsh�ps auth�a?&$by diXS&[ke�wa4&�nk �bm�$geZ@H�Res�( IAR�[r�?AmelHn C�giMm��;E�-"q( ACMG��D*�Rz&�. Path~ ( AM�i[�npr�O)Q)�-lof1�>-�(��nqorp��%�nc9+!4�v"�Bach"�u&�dI]:�effor�'�r7Z��i[F�oa2�ipeA��R" =�ŵ �� daun��.� �Ibe�x\!�y*��S"�~ B"Iic����or,y�q[�'>srar����ed�Nh rapic -XKq�Y�y�:�R�<�j ! per�]l�w �*st�d3�<. !��F� �fei-t�  �. M'���? begu�|W x[�`=i&~D�E!Lf�em ��=b*Ja� �-�U��"|A—��b�dmg&Jty2�;� �9�A( `d��u�:.�)A�u�&�4balkaniz)R\3q���&��G��8ini�<“���#7:�  eriaZ��lc"�~}[�mu����( �dw�enigma �G)� ae�e��%��iplinrj9[�:%� �Si��k300�,ed�G)�� 190���7UBq>2� span)E� i5�6%���ai���F o��"]��KBB%Y-H> A�xor su��� m��B�.+ug�$�A�S� 1P� !�NE� al I�� of HJNIH-f�d�Ge�MAs:/Md.�I/ )�ado��app�� �to� a m�A�%W! � " �F�k���YWnVoU�ȡ�p�!�G�U�v=I;\=7iiO!�&�7!. �R�Ś��=�|�#^ .of��5X6� ( VUSA/A1.3im~ )7��c"� �Y:t:ho�Qde͏��,~r6�*_;a"�p.�Wf(ŗ��&�$�!�����"Oma�as"7 .,u�-�>!1�Fe!TR�&!��6a�&�web�AVcceet�Uipi, ��9.����X2 A�I�F!g�)� 2���el2PpE"Y+�Y%sOird"3��x�ing55.U!� ��*h�Et!���a-�:�. U��tunate"� �\ing�F�PhM!�Ao�E� e� t�/�� !,�,�etB�legPW�� *�r5�2>^2Z��ommerlvi"� h�N( �lmmodi�?k7�e�."@&]&^ in�1�*�<X<"j :k l.���e�|* , qR mudd",w���Yp�(2��� ��TX~z& scopZ >�ћ� �*�5ly� �3� �%f  , ye.zloo2J �Otru���2 %�Q�coord�(�"�> !9tW]�) M% priv�M* world�n, t2� riet% *�1C,p r+`� to�"I\%of�-��Y!m �"r e��� �F����* by a�mXeA� } �A�ana�i3u$program�{�a&�$� �t� 7 �,#"� —e!��qmI^_r% �#>�Սcas�A�@ �m� 0 Z�P͡E��0�2 r2 e�I>s��l mpel��{�͑!�{��!��!&4>���-ab Yl�F�� %qLN`X�� � ��a&��; pen-�gs#bVka��'=Ex�""M J#M&Rf�a^ i |D.05�drawn)�g% ="]��F�$AL� .�u�-�\, A���!0g�d)���(z �i)Jiq�i�![8�� k ImaMţZ�ac W�_BM}�v Y�� 8�Q&D-jor 21(�Wl� �z!�u!�!)ms|$y d�r5o& >��GnyV6�"Ket4�?o��-� focuŗAh ����6w�0� d- aC-l��.a~���6ao�h��l a!�ra��*�m����a8JF�&� I�5!�R�C"JH-�y1JU�4sD+by ���+fn broaN<a��6�,&�1�e��� �Uxim�s6 %/hhPefa��M��6lyqg~�� "JyM� laY�sonB`"�!�Q s who wisha�ii��"4I / click&�� clai JAS3/t�er�{rMp�aaA@�clufofb� LOVDr� &submi�R��%4A��t�<�,I�"�h��*tlic�T�,Q?�44 �Z�-end �]O.c"s �al�/m� �fil�$�_wY erroT} ��ncl}a �*�8r�7D !/�)!m])aQFK�� 7"u@E !� ����%�)�eKl�tthird�3t�B� heٵT��M��-new &up�w%�� uwth 0|i� � �al-gr�H` ��&a�J�(� �Gia7;��pz?c�(&  G!"� 2�z�[�[Qz()n"zY�RS� f].� ho��Ex-UVU�O!�> u�*o m G"�{�%is�\�[[�\, NHLBI�C �S&[P{. ( ES�S)���l1�um�. C"~ ��}9�  @&6,unӂ,J�s;����&100!�Em�^a� `u��cF���9�g � 4"E,v!70E,� dee�.*q.�+nt�s���ontribc3byU{,)�9X!-p"�& f���a�!��%E��vYX E)�! .H %�{-l�3��9G\/�>sa6osim�aC !fQv�d6�d2 ,*� "�u��q��A&� .�>`+�cu�3l� a��1��!� #��2=;7�!>��(perhaps 80%A985%e1� Slyjud�)n2��"fQ}-scale"Y �%�eBdu �8ufr.[3–#рHT.� � fide� *� h,[3��0*B�+A �NYBq7o"5 Ev!����!�-m���4ct HGVS6#�Aadd��dup" lf Vi-b"��7k��C���5.�a&lc ri�n.2�%)rec"#%o�6W����a.gR"ҋ�> K �:� b�I�S�Y�}���a�rwa#�vvia�s\DxD��K!���@* �qE2,�the� ~2exa!�sam "�� ���w�=apt E�E)s�b�ti 0�|@at�Js�A�ach)- �I0� �y1ZI=a7bO>(�oih� *�2�,9�e-unre�+���eia� beca/w! �q��� �_B�w�%��a ��T��T��&5%) ��`I "C >� �as�%��=r%�<"D>O. MovaDf�\&Qwe�\�!A�v�a we)(" Box�u��!"�.K!va9L�4�aeD�8dqwo΂( !�<5��4$lo�DEb52!|0)E"o+it��G ����+h- d unE1o���YCb5���A�par�'7 �am��k! ask.�  gen�$�)�b�n ���ic#yt�n!Ea�sU�z�.'�G-� �a�+ �� re�r�( nfir�#a ��6�e log�Ror"Οi�u�%x a� ]&Clw�A void2�$ S.a}zpla"m�H�M��=�REP�-��1���D:t$FsATCtod+�c.��]��� V�_%�Oocq1��X4 �!�f}>/�enviro�_ �� RAE� chec�I� *�Ui�zdi�s <W, a��"�c6���A��&�IAx mpan% A�v,!u—p�u�U2oni��—XX� et��� r�/s^ ���x�G&V�$,pseudoanonym1#9{o_��'e �!� �d�7M1��Fn!)qM�A4���Gw�� �a�w�>/Z �EVnd ad�M!�"�ly.��8!e  'A��i!?�n� M�[ )en5*� �Pf &� �6et�ZKR52a�,*� �|, *�"i�;T<�6Q<�e Brazi�< I"��Pr��)58D9 PMed%^)�) �`��lzg� e)]�c�a��(���'C7I�FM �%%& cUniA�C#s Edu�L�J(cg)Cule[O�^za%�( UNESCO�"���= :�Umh�s��ome� {%:��" !non�<.}, aL% �9->i�a)_7p�!!�:. W�H����� �nr�Y� ��|t@�iE�el�A��a&c Lf-��softw�;s4,r�#uto"� ,eT��f�k �!La [��r eR�/.�t�5"�"� �[r��cwic��exhausA�&g&&�X�m/�ABM9H0�ad40cy&�primar�=�Z�:� "�:R2u)i: �w�R&m � �ir ). A"g�;�&�'9�k)�_��V9(�5���q)��B 'E<atY�ak pilot�7 ev7�gSbi�=h�&���A�s�F�oz\���xpus,�ω�}PeZ&u &caSupdbm ��IN�u�A�(v*~s2�c6��?on B(github��om/�g�h#-*A/ech{? e) z�,�+* at���$Californ8{$Santa Cruz!� nd ETH Zu{hosa�� M_�� Az�� clou+!�dK��^Ip�9�3>a>Eo,�a"�"u.6\M��month�� autogd4�s1�E i�k��cݥ\%�E] "�!IC/4!��[0slocus�X��2`2{�[Od�*[1EB`s* B � X. A"r "5&� \�sekUnew ��.�$�� �� �Mt!��S. w�X ng�se)h|:9�� Q��GRCh38 ( � R"�&� H�� B�q381 sm )! o�&*e�%�n�ŞJpytho�brQ$�e!�CrossMap�Qi�Ux"C8��reL UQ &��)�mAn���p �sX�i�&F/ ,a�.�c��par��6 �f�Ae&n�ir 5B�Fq2�NI� �re;�� (� 21; Jul�v1�v�5E!��-!o)C d 1 , 330==�:�t��:��.�5J��?]qui� �$A� �� �l�=-���2EZ� ���� �( plus flankY |�!��aB�se1�1�!�;t" Uaat yieldr�WI�p6 aTP��:yV���no�OaEs67/M��sf �.{�{� �qind�)gbAsf�th#@�-!*�Re�in"�!B�8G. B+oA�6� &!&s� 2�a�!��a:nX@"�5��N":� UA�773&5K]�X6�'%s�6a Docki�N>�kn 8P&�0d(.!F�Jr�M����-!g�v1�UA) !�1,; ilic�0 8)w 62o!�^ e�=8!" ܁�jo!R�=!��9�"@} � stop1 oN�2a� ��A�*�g resim4��>����lѳ!�6%�, a Postgresq:�"�ed�r&��RC��w.�'mo� .� ,�2�)m!�b fac�fAP���A��ly� Bptra���  h&�62�%>%ko�)H1��ts pa���D1 e�,� ��-x �M"N+ nd1"k�� �)@��}m2�qe���ߟ&���32 >�-G�-s=*  @ r�*T *k?<�u"�m%�&�2"� )F�0�3� �E�%�#�� ]#-e2���spas A>i ڟ#2^�6k$}!�A�or.�0(� u��oli}�%� Ufre� quer{*QE2re�i[���kr I�}�o8zqhwi�1)�s&�=}!��AM|�s�N�,launcɏ�� . Ea� 5m_t! k�bg�4/!���Sfi�2oV��sE;�AA3��jH�loq�Vcw�@g\a� ���Ub�/a�I2�tHk4c�?�Wa2�4��G�e�_BO&���62B���d� ���us�ax� �1�je�v&���.�e�U��2� a�!�-��b�/T5FebruZ 2 j � s� e"b(m�Y\�EK���m�A! �)Օs �� �� �(s:�� %&_�"w#�i1 R>���1]Ed>�%�S�4(�zTPM) �^�7�"�U"~ �4 g �yUn�al&O!�&&( UMD��n�"F)a��7 s Qua�D"�G� L�,ory�P@�@ ($ Corp� a��D�# �19\3ad�1� 'Ts��9�g�"!(��n*#1G-bs%b fe� WeI!�ye��)p �#^)�5�%}"r5` * H%N"x&(%�BW! ��"�$!ll�wut%wJ9welyC!�:�2d#�����9e�i� bf�r+��%Av�� �iHi-� UeW�[ ��& t6�. B� � �!�ɖ2Pb;�. U�l�N��N�hM�s fS� ably� B'��?q��YM5ѥ��A$sA - �!i�in 6I�#�"�!>���.�E�Kis�I��3��� ">�h {!H"��O"� �*y��=��cl2k|M�Uz�G$ !�"K0ly ga| $�^ e��ZE�1By� p6 � r!@5��5�<#�S��� p�oI56R?�� K6�&!e:0� ed&�@Yfbyv�a�N&(6r�C��N 1�f@ed���AU��3u�k:�>e^A��32>�pQt#%� ����:�k�&��%)�AZccrTBe%Y6�f��Q romiQy.z�7 A��c.<�!�l�V�`I�e�{3v�!�aM0m�>��]9�Qa�h� �J�At�Bi�un#MH.^&=1�$5c�C��.��>h:`5�{AZ 92Z#4%"�b: $q�1i��2�G(�t�=`I�8).� DKpplied;5k6����KT2 cata# �2#8�I��#@�j�TiDo&B�&U3��of!�?� �q{��o����= �es;6K����}a mRNA� :�si� & %%p:�f�sQ e{N16s;��UEc' 6�&W�*�N`�� A��Ft0� ('ve�o�%-7b"� ):�a� ( doL�,A�epP�,M�exonic/iL]q�s| � enh�%s/sils3�;Aq @ de novo h�@�Cu�Y'UbI a�>(�[1�/,�y��%��� a�&�L&/�WK e�l�5�#5�u�O A nign!X�b ?&of� �S�I�Aat�9W u7 =(r&{O $i�L7�����!!��!3�a[d�+%�*�"AE� irS��AY��#�9 �(vAM� .�c̓ H�E�]�\F��?G�A"z�Q�Il2�2]A�h�!p!om6�GN>�.�"'r�#�d&:�e�?V�sexV�*<e���!f���8i�Q�i!�l�7��� erah!���M�"i%�� X.wN ���t9le\�g��Lo��1P�(ssessE��� ='i�wi�i�`�ic�a*s^A�-95 YmT�� aber�� & .�+out-of���u.G !<1 ( bHzd.�7P6DA���g���aC `���Y1=�m�Itt�6a!e�A#%R��ETDs Work S5S��.6�A�) �lA��.2�S'=g.#i� wr:(E�c"�n �f cogn� at b�:��AE!,� m�Mt@:t"O!5�"!��JW�+��1sol��� � er II�Jiv��A-���� xbMgd"��!�-k Foun��al2x�Ha�+2�lD3 r"�6"�&. Aj��H) .z[��a %��� ��ܥ5�qe�d��-!�)�law��?��,�ng� oxty0A)%�� ’veh�8e"�9z2� A�H"y�'"�A�(E! H5�^%�m,�01AAQv7d{!�=$� �x6�J�-pJ�m���*� —��D�<�+' GE� �!B�fr��� �%p&S.=;A �4&� benefAU�0�-���F��m�+ A���lso ba�Gf/t"a�-e�0���N�"f Q1Y"�G7�s� A(dWp��5!m�\��)i�%��5� ��I,!� A�x.n� in;K�6@"�hA"� *�Es�"�Eҝce��IScar�-l�G�u61�KR"clarif� 1���+�����nd�a�.!$s;%��q\i�su2dr��d%����9D�{al up:) $�ā>��?.:t� A pr5A��%�;�Rlco��lC�&none@a�}��"�Ea*�rihan�,A�Mѡ�*q*j!a*A)�.K,�rC!�ir� ti.@- v ,�-� ��n�_er�?8|@,.�xM��*�\%�a"�'go�Y�9�AvY�2# �5��)���!0 m�.OAllIaQob�e"��&H@ecu"&�2D;a>���3;!f?ze�wa� volv|��1al&!\�6�e�A�Ser�( NCRAS �P S)U EnglAO��v ��e�n] ,:l.` +3� J%c" �)M�>z{ l 53�f.+c�C��*2� ��H��!y�]�56gd peo�8of��Wa>���"�@4$n��try�17���*2.M�ʅ�t�hX�Ey���)�1ed2* ��El� 5�*�u!�in-hoe��LI�6J��h e ir/gr�K}̅#�o matc�^=!bNb�&) uzzy $�u4�"�)r� �h� Bԉ�%<U:~�!�� b$x;a�b�R�m�8C ) o/"K9����ydP�}%m�encry�cp x�HA3{e%�1�'FMaV H7�u&k1 ep'sM� �:i��!W#S��{+�@��2t5A�S�  25"�w!�Act��m�!���H���LT� �a�6v>�%ix on-law du)��I!�C#o)��=b3'vx !��8f8dFWT7 "�IOƤs�|a-�,“Caldicott�>!H guard��a��0k%�va-7 p�A�AG" �s- �&aWLm"ΏAthL5ctr�MU� �.�x}~�g��*J%��� @ �k�0!�� �k��"iD~ ���ep��A�A�AK �n�^!J� �Q�7-�� lsurg0:� �"�tndA8*&��D�%��?RF�ldisT4��dro�H 6 � ��D)2�9h�~x%�6avalanch�!Ѯ��u�&a "VFe�$e [42–45�j ��i I��ne�4�6�n��`� ss� pa�egmsE d <�amF:l j�:i�v��R�"){,�Y����� Y;.6wA�!+e��o&mK�<X:��X5�K3 aVM�%�o( 2;2y+!�� co.�J�+RBbriR�g�F�`"�K���oq�-�K6 —o�XJ��"�mwY�ࡆ—%7&�-a�d�JkV� ���%$A@la^@e��I��b_"�*iC a�WtexF@mf��"H� !�%��\In5�.�ph�cQ F��;S,�V�1?3m�YA:,@�����q�+�? a$1�|���� %1��� 6J�i�"Tp}�#c͠��]�A�at�����+{3��mme�|bo��A��"�2�Q� {.��� ,E:e/IO ���oC�,*�"$ �.s1 W Ga�W�r�F�%��G��hU���s,�%Ej/�.ZI�)iuk�Bha �VI��—@ �A�R���*z#a"�a�\:��1D$g�;—[� succA%bۿ%s �� �.Q[2E<"�#,%x]�# y"�1e�d ��?��A=�E"�) �m�./�reC���G+<��nE�d*.���rd� �%Mr \ MT=� a�E�� !l�Li�t k�@5G.�46�-y!��5 uRu�2�am��Kve�"a"O��)[MU !W�7:��7A�v.l!` �t{ZtoY�D��{A� �V�h�>Av�5���| m�n�sA��w.4aQ^J � "`]2tM%� , ��Ac#�-� �aK!�to)�tX�5mw�_!�E�1C� &Mb\>e}n6�8VBsXm�ِas�?�#�!�E�t�1�e�V )�� >A$�_[4�N�*�N /� 8� Dx��uc ",~!<4��C!��� bQ�ř0*l���O:�~-lAE)�s$���X�N{AD�&�<�<%y� �,*��U:-z_2mt�MR [m��ui�Ma���L�2!�api!�lexan� ^# Plasb:��p.� m$Rav/2W � welfaZ �ŕ���7Fv 8deatha�nO�..�%br�llyM�� unic���smI �|��x.5a�yclM Q��mos��o –�`if�:yl,�v7s � a-N�m  *�H�.�deK� �# flux�5reaV oxyg�pe���redox!� !� �knd�*�%,.9�,s �\d�tuSO��y>��A�A"sub5h�i,F��IyHh����N�x'a�we&�b� I�tg!�� Bar�)uin.�fal�/c�Q*,�[8���wo4DE��{eroxigi1Hw&r�glyoxal+ i�!��e2pl�53nC� hoto&Ѝi�AWr��m��"�Q�te pic?�h^[��io �-E glut�2oxin-�"A)^.���.,�VT�F�R-enzy}A�WthLuct�!0z4�*�a��� � ve-�4��-$'' ( ATT9��&� !�9�. DҐ>~�!��$��Tis�#; T�!G!� A������>av�Y0 apeu�� v̋�_ �T�e�R!�t��40�U!Y '�[�<�V����LK�20�{bn�)*al episo�9!��Q1&���O&W[���.4�>�}O�'@ 0Hd��r���*I�s trop��m' ar�.�  ereb�Dm͏�qə��� o��e*��igh�C{��CVI ( ROa[}2P;u@ � ��i���!i��imNP�j2�� �b29 Z%��pi>�� >j ic haemo$ �}�A0� !Q��?��F 's i�HQstem [3�I�75as.���x��yo�'�0NADPH-d*$6�;�;a�"�. defh("K�)�q!��l� .� d%��q."|ၢ[4] ( GR�L.#9�*-F&�+��:Gr[{ '� ne S��fery�{e�"�al219hem�Ras�f]dctperturf�BF9��&� ��ad��[1"�yу��-�!e� dʆ�b�VmM2A���"�kX *� &C1.*�)I�2� �`:y';H=(2[* \�-��*ۛ&n"tWr��k!,ye��,2jv-2ze gAo-2� ?$/�n �}!� sA���eWq̐r�ir�nS�i��d+� &� �#�384��{'i =*methods ؛0J����"�@#!6.� �`aB � jo� dox- �M�b� ( �W�  .!{i�i*k��Z��qadqo3p�"B<7Y[%H�0&�$I�mD�u�. ͈Y$L Prx!hG4*}� . & :K�H`5X>� t��TPxYHTPx��[9����+ 1-Cy��&w^� Cys-Prx )�#I�so-Ha�ϟxi�{-w!]Oe e�^.zWsV��V���G/>\�a�I|2�<�G9��cA���4&>fB�.�.P>��Eno}!�N�"�2&$so far unmƒd !!e , [!and!�Glaf�,� X UN��ini GFP!Dnd� -�!�*��%�&2WVaJ� 4ene sequence t��o generate the chimeric construct . Expression of GFP-tagged TPx1 and 1-Cys peroxiredoxin in erythrocytic stages of P . falciparum clearly showed that both proteins are cytosolic ( Fig . S1A , C ) . TPx2-GFP e�Pindicated a localizat � TPx2��Pparasite's mitochondr( , as�dem%Qlby MitoTracker staining ( Fi �B �$his result!RTfirms previously repor�`data [20] . Furthermore ,�AOP-GFP-� a co �@ed perfectly with/�acyl-carrier-protein ( ACP ) [23]�(n establish!"0picoplast mar��1A ) ,��� dic!Ss [21�TPxGl��to)�=lAay%�E?�, � volu\�P 2 posse at le!�Htwo classical thiorias: Trm�Trx2 . A rd& (3 )�MC-likeyg( Tlp1)hTlp2 ) have been characteriAu[9AD[1E�}appears!J5a.L$al isoformI�, a�ve: rong5c has ppro!w�at c0is also targea5to%�m�Lophorous vacuole [25A�We analy�!�(subcellular6ofh-rx3a� well2A�d studi�eNL�ce�detail!bable S!].oe-Ar` ( %2G�MuUIS2�M�A,��!�P -fus�ε�0s were cloned6n �their Q�onA�er��l! o a�6�id!CA�inab� ( PV�r�0ompartment se!�taN �� fromsurround" host�yxS3��. TEE+ �!+QR PV w��o��i�.7fa ion �!�EbsisN���_��4s�F90% -}p s .� thesu����2�did nei�*��1ER nornucleu!9O6l Mr6:|ueus!vorganel���sJ��ea` r5� �,6�Ae���`na��tIW� 4�F$Upon reach\� ktr��zoite r, typ��ly�9It poiA�coulda�obM�, usua3lya�ly undei�1� (sma membran��4�W prog� throug)�lifecyclq numberAJ�increas�<1 C , �H In schizo��tag6mm � nume�JbŠ5U�4b&<��Х@5w�,only a smallq ԉ`�.}}EsE�Th�� �>0foci does not A;coincidm divi�of m3A/�enbY9U@s� toAɡ/ multiple^�Ns R4M�e�2�associ��%xa�lei�i�lj sugg�Rng� 5)5StakE�ce� !EMJ [ gony�@e ɯof new Afe���Lasa?V is9�l� !=�de�“aSe�” ak�`| ��=�aM � no time-�a Med�2�. To supEf�1" n an� a�we � 8d out different� permeabi. A�QC's  �.]�S llow a;rmolysin�Y�- assayyB3aB[27� LowA�centr%��digitonF���.�oB=butexR�, whe�� Trc X-100.es&P >m!�RW �I�aas�5�dd V�d5w�it will8 ve ��Hic)]in(�it cane� ct o-} stD�. by�R�. �R�b26��q��� egra�. P!� of)lTrx� !ayA-"� sCdc48 (A, trol�8]"� �cleavag���fi"� iv��mHE���� .W�E�. B� .� �[�ž� letely 5by24ineos treO w��2x>y��Y� !tubulin�jm9 Y��2m��Qlremai � wh ell�u.�d �b�'h`es�How��^� �!L%�at�of*nce��become� ��atI� xs originG&�amC ruc� >�.`is& ubsta��4iw*��a trans�� helixQ� N-terminuŠ%~2�[29��I)sc��Flp�؅�r2lM%!(&� how�F 1� . Gluta�B�GLPs ):a�subgroup�g; � erineklac!� seco�s�A$CxxC-motifOWve j[5�[6 �:�onT�Grx n�ree2�N�1-�bEz}tified����� o}�R!��R��t�:�%Kin vivoe�(full length�E AY� toa�� A_2�AY�ed�7o>y bloo;a2 . A�DGLP QGLPIY���d.�a�2������P5&5GLP��&Z ,�K>�*� on!�s6�ntF2�w��.-�1��:�*�glyoxalaisA�m� mprik V)� 2 [8E�3���aU-1E�*,GIL-!~aq-�2 �a-$aV sequ��$( tGloII )I*�]�2�A�urE�iesw�{�ed>�%LAђ�Q &k 9�F"�2�"��ly R��%\:6reproduce �experi�al�broach�S5�2 fafou�Ro�ea�! BLSi�}" geno�K1�FK [31]��� avail&,�(silico2�R ]0Pftrxr ( acce*C$CAA60574 )�&usEX 8gb6 374766i)F laborator@ veal�Q� puta� starudon ups� m�wpr�+&( SuA�In&DS1U &��alY� frag!�a�e�e 228 bp�13 ,Ep v vvc.� s T� s do� invol1 &?m7 ��A.0he 5′-elong�� �r�.�(ly via isol-�(a cDNA libr�WZ��rxR�F�j� a�rAVbin�enzym�7;F6AAQ0798!~A�biochem?6��ube � simiin  �2 6E�kin� g behavi��}��sh�r vari�!�, [32 ter�ly%� ew"\ .>otdPA�s�\Yd2i%� ,ast , GR exhU a^.fexten{tq is-a}/| pept�( S�f2�hyd��ao���� �sie{!�g� thus!'waXA.�� l$P stich bi� 3 topogenic" ( BTS )�mm�� f��24[3�[34)� o�K PfGRAS2 � " f �� first 213��mpoB of� � B� plus 757 "]ykn/ GR � nGFP-genee, A�d A�ތ Y C allyet�"GREF�  ( GR-N7� )�)��ee�ev�  2_aI<nY "�!��Ev�!�!�' major� ]"� E#�ar enco� They>� C�aj�U�a� eu}? �� �yim�]aM�>��7 onsi7� "� ]"� ���secre�%pathwa��6�D"� I'itzTa��1)�sFk i=)%��yh� 4�io��a�!��%( olyt��proPed ducrafficF|:!ʁ�m7b�M5-"�!y;2XnslocI_i1EE��eHhe!�>uim�5=%�~ng�9Fma��iAAs� �)��rapid ev�,�� b�+tAN��.I�O*�by:s3�We hypo��"%� , ifm�D�wM�nD, ᥖa1�1�A� popu\�p!"a$ k-2gniA2-��!�I��a!TERiy5�)SP)�ageq|wf%�<�r��yM &z<ol ���)y =�M���"1>�. U%��R  bo ( R�� o; �� s� �&yi�{�q_we� �BtoM��TM�aec precursor�(� . 33 kDa�"X%@SP��already 4}� remoahZ#( ir��!-;Z�(r0:rM!�T wq��9�(bAar2 28H$correspond",�_ described��I�� !0�f"G6� no .Ep�� ( b-d�S*" �)&i�edAehic�tra ��e�SPy��T}r� def�Z��*� ) �T���2o� ��E�&`M'#�� x*�iΕ91^ ^ hN}GR-ŀ"�{!. C�s�"=�accum��U��B� \O  y�J�wW& GR-S �5� FP"$dA�dom{ �%� �"�!� 7(�S5� �e�&6by �&z&cq��TB',�$�%��z*)&!f�9&&q2F�veryKfun� ale :;e0:�B+"oAO�<6f��m>��($.�, _�, togee�E( b��p*ta�W? �-ATG cs flank!G�� �-�)( c RR�){�pro� *�-钥E-i�� �-T [37��9]!��,x� -!���.o���@� . Accor "�; ledge!�� ��B(s , eukaryo� ribos�ca�$c� ze s�*�.[%k:� "�#>sQkexa���ATI� grB lyN7 ref4/ 6a molec� po�@i� a!�z n�" mRNA!7����-�,�k��is.�Em�� he met-n�� )"E�vala%8*@ ���>oM47). IFA!�J(Vme."@�I0 exclus��.i����12����"M�=e�6�%:�0o���"�"�"2[�"�&! a���>� >����)#� a�� /es����=ges�ul��,�ua! lead" F1%� F whol?�a�A0�'ek%ceL�*ure 3��2�2ioF 5 & .&�disu+�� Pf$�z� &�W2e�'&,ext� t�worth��Ő DrosophilJ)lanoga�-!�R�vHaLan un�"�al &eA�� B�to�.?�_�  y2&.��`6o6�"A12$:m[4 F+ m�5 , ex�ng algIhm"falwayyrrk4-�}� �( Plasmodium� oxD�EsiMIEaI�55: �$al SOD [13ֹ��:PEU&�.���.� ."� Oa  brxR����.!�9 �" 8���i�4� => | z,� R�d.��L����ZM' ons:����"� >$ post.�k�� ":6� $�� I0 ���a� �)�syn"�M��/I��RV�aQ.x84U��2�-aA�E�*���:5$f=[  �67!$=7 � �v �"m9-�j���g2�4��:U�&� �ǡ�,neNP6&� �l�*�;�AR�r�bPATI"| 4R?-"3�x "�sr'j! .��$he�Wxc�r,N76e�X; with�-L�� -�p.�6�&l��"� &�]��X1�2�>�dep�;n�/� tV��K�Q#� 4Z4B O�" �9!�e�reh�ve x4 ��.�)a�7of�� 'X abolism��mal��C8� An �5 view@�j=is����W�5!hh2&#,�on-photoɎ]B"&�� �<�:z&�<��tA�harbour+ dispens� �me �c�,clu� fatty-aci� haem �>& =0. Until today�M�ve)� � bQ}�*oxi�vD0pa.3=2[ "��#%P, f6~l�"dox-rel�� s��a=��pi!��-9!i��.` �(�5�"AOPl u>A�w> [2N22] b� !�!�famil�7p.�@!�� ;��� �on.R8qEy6&{E� -reg��#�&s (a0 ���cɰ�Pf�is��mfew�5@� ŹQ��>%A�|�=i����Pr�*:O ��tur,z=lia� %des.W.�*��5 E, aa��Z�'couq4,��o� .?'Q�E!�q''��%@0!�!�"� Q@2�. I� ' �6")�@s triosephosphate�mer�e=, [41]��("B#�av1B0`sourcee�toxica�hyl.(!�a�hAU�j}I8)��@� �}�- c ase-IuA�de�fy:�!W)�(2-oxoaldehy!�_ a"�"C a?'��3� �0al GSH-depend��m ��!)e�=!:���Q2�4a� � un*G)���is:\2ѧx?�"�a l�5py� �~��;(!�2��@�RIE�*� .2 Nat� �'��>�'canonh (�6*|���,�)L-1� �$�c��ic-�=@D9�o�.integS"!�dow�#eam AUGA�A����"Str� �,,$],"�;of$��&�3/ phe�)n�@!��a� "[ օjal�Y8! ,��leaky s@5model��ATI2X� co�w%=���Lt(nt�5adZ.Z]>fiJ3� G�}gap!Ea ����!pv0� Ua"6!�!� rpre&O �sx�E4�h[4�'�� �e�0idic-type fer�Ynd-NADP+! uct�T ( FN�%0 :�D�C elec�2b8�2�:��W isoprenoi�� �%��NRs��"o*ll�5�<moAWr-d�H)conver%�by  izA#� redu;1agAWchA� H2O2#{1�e�2_!�, "Qa� olid� �2or��ai�>2�8a'e *� a@M�nt�%�.��c!~&� "�so fa�?�+Ta�H�T'I 4+ E>�E"�2 a diUlipoamL)�jr�(A[1~(k ssump���6�� "<� a� l*� l!�O e�� � TA�low-MAXiol� oic A �� *�)o�o�>6�α-keto56�cRf"ac���E1e�!�� F:)%P. H�Ewe"V��%& ��.-d)�É�ulfide- �seA�ed �>M. A� G&x���7A!�6�" ��BA*V~� �>:".oa.}5!�Y�� �6� -Vp-Y^B b>[edqHF2�2�in� HfX s�%{)�-� �!��: yet6 :9 ell"� �H  S3 , A.���6��"�! �6����6�1c 1aZd.>2�&�ZP&T!FS&�K"� AF�e"� �b&K*� 6�network!�:��b�Cp6A�E�%�d.|5�c GLP3A�>�{ ,a�p�-a";Li��%9}Cx:;-�55�>�#%N��MS-�B�"I0re|?lADravCF[&KB�@! a��.w�<&�ex�&`�!����"X8V�#9\@�&is2��1G unfol� E�1`"5 ir p}@g�&�D �%ne%�+E-1frd:X`  y��*l �@&RM �tERU��;!�m��LA��;mV ER m�; �A�P �N�5�w�$a?v�2I!�Q21�!�� u�yi�!ri�di� bo([4T� �AnU.!�"�bc e6a"b!�D-����E`!a� � n�\'m�,H )�uI��9�'&E oM= )�58..�*� ?$ 6� ,a�"K8�=�� -3�i�s �%�gh;1ewm�I3�$esL.8:�E��"� &;�#5&�9EM?Ptrigu=E� is lIm��� ort� McF�Bn%�co�er�whBF�H���exon 1!/�:UM8\�@KTri/Pa'n=*b/�*� �. Wd@�<Jetw?u?-Ax��2�med�Fsz(�K: )[�/A�y&$$a��R!�N,Dd -�� �| z��<��in"�I�5���C�)d�=�VY� ~ �[al ATG=s�4%�e �>�� -� �:<1� � s du�A:%#w�Q#>�>h� !�GR%!6 MA�$i�w�2ppaA0�Q�b� 'B��ZA�a too� betterK�?�W�Uaz�Tte�5&�1q!s�J&"�B%!� * V!��E �&6g+A� is uk A6�/�@�:����)��$�.2U�;fE#*3%�oA/"Dof��s �0~���"�&^!�!�D-u-�"e r�^!me�%|A�B�%�X �or�/"eJy���4]a1ZM%n�/!~"I |1s�)ND)d"M+y . I�u�N �!T�aJ ght"�V�/���WItVD�C2r��k�!c�)uy V<�&� Q� . All p8=rY@)+orE�Y�"�s8� EO �%F�5E��c*Xw xA[exc9on:.� ,�lR;20�����5tud_6&M=F��!�3)� at 37°C A�D�T2in OmM�cine/���f�>��p�@� A&�o�: rabbirti-G.$( 1∶500;NvG .&g ,�u#.K�J K�2ZOT%IilberA� , HamburgNchick� t' O1 , 0OAbcam~Sui@Cy2-Cy3- ( Dianov�2conju�8d�ond^ ��00!�Ant2/ dilu� �% bov04serum albumin-)~*"GOra!( M"�0 Prob��aata�nM�ix�4�4u6j; 50 n�:tou�1�% �B. z�� a�r[&�C �^20�" �UE�efn�M|_��mY��to �� J64 (_1�1a3b�"�E �ѡ)�+ mmenc$?Rossne�O,d Yamada [48�-�methodz�]eHpI�B� i !BVTs] . Briefly��Co(VALI��(��( IRBi(,, 24–30 h -in2Kbre enric�U�<LD-colum\ MACS�0iltenyi Biotef6[4VNd%�harr=!�t 300 g����aB�. �`Q aliquom 2×108 �) ]incub%iJLa΁�1% sap�4��٦ZS1��F�sp )�r rifu���5:�9 superna9,������!�&�`e"�/Dj ^�L�=carefu(a:�35 �(1i�L4�Kto F%I debria^ dev�V �`c&�PVAn��wa�e3�ith�" �)�!�s��"jS� HPefablock , Roth; C�t R*g?2z6�5-��B�>��.����e� d�"SDS-gels*�>E0o 5A�6–1 7�s/l]�X � !�a PVDF.B]!$-M��p��T! �+:j1O�*ti- a:$kiB� �Blisni%�PaAd( �l_a I^q 4K . Lingelbach�mar# C� ,�  HRP-~� v10i&; ksonA Researc)2:l� 2�,%�* 5%�Ufapl�TBS!' 2;Q2!a=BU����<�B-�M�Nequ�. D[c#hat3�Ź��5e��,30–40Z  ,��3�)a �T�La� kept%E�9A`�eiFP �M�\��$E�-��[� a�$ Q����)�8p"�iy�. b�D9�mibch� �=��E75�a���R.-?=NB-prOfos7Pa4.rewiebRBC�e��\-[A�-GI%s�\buo] (_ 8mM HEPES-NaOH ,�C,E85! CaCl= ��mM sorY��2n�Dr|$NK�$�A�05%*uY ^6+10_}Yor��2�YsM�!_ 5��a�>i . ( Fluk, A�C�Efi�;'"�]a�25�,,gM��z . ReqV %� � �"��{6+-�stoH6$p�M)�;�9iprecipit� � ��/ac�/�#Aqe�^ll�@�E�cold 6A>iپbyž PAGEX2� .�.�̈́�\��A*00\]�G�-TO\ (� Sigm!�!�?�?�?w�PUM*�/0� � BH3-�1�,0,�z trin}m!4OpM� ( ID,L~.biTtoN$��u� part� Mcl-1"�q$ BH3 oY5�sXKM��an α�Z�$�-� at#[- 5coarse-g�ed�*,I�a�?plo8 Debye—Hücke�Pge0to!^0�� �d�)s c�&PAe�da9!o�r�gt&�+30c�!31I7œis 1�x&� �qb�� n&�al�on%DKo�b�hUMn�i�Sn0R*e�*�pu?qRi�� ��Dr"Tbi�-!�tZ%�/�i�H&�Bjs infl�X� unbo���leE�mare]A�. �5��$@[su�e��_ICj�);�ar�^ar� �Dv"�+�>/,@.�#Bʼn� }gi�encoun8cod)2�L%� ve &e5�m"�in2�ot�iw$5��F�ac"�pN�we un�@%�ro�'@6�%�highlil�&G#6wsz,j����=KU��]of��aPSOap�YeH �!b���?A�}K�dYQ:��Dio����Z. �6&$&A�nN�ID�^[1b�.r�laCns$!2p�ip+of��^1Pu���h�?lg#l�aixam�bIwell-dEL�]�^�.^!<�A{.� many crit�ephysi�t DC� 6)� ].�� s)�a�4an� p-p���"�0r�6� ,هV( +�/ s5ory FM�|Qy [�-Whilst!��/u2Ʉd@ 6�Dis� %9k �#EKche1��teXC derg$&�MRh6 to6!O!�rbiomacr�9����n8[4 , 5T �c�%i&as�ij�i[�I���rc� F�aA-]6E&]"a?bY&� &�\1890see�Lm�p)EMg>(ng��sE��3osiA,�O(by Fischer:�A<key��r“in�]fit7 7“�+orme|�Eion'8]�8lexhK�y�\kn� q�mBs rig1 �� �<g !8��E@)�6 ! �<M � fe�t��e�p5��i&�r%qU c�!́Flz�xA� �#a�wh�L�IligO2l�bC or a �E!trRH��I�� la�q#2���$J��[9&1vH /20a limi!,�^� *%O=D�{H�"� it��)�V� 9�[12��hOn"�.m�uk?A^��)�dre��&�#b(! !�� � 2)�S-X2E�f�M�c&�5o�k]*� ! e,2:o") i�afQ�sa=|A���s!"%�l;D�Lᦉ�-?�;VlJ���:7 simN3���8r&H^%ude�W!�!V�>3 "v�Uj4��*9 n ���-O�C !�a��U1 �8-survival Bcl-2!��)a+��aa�develop`!�tissu� meaehQ y-� �� 3typ��F�8�b by a$_et st!Ui��apoptoi[1�fG�\knock�?I�sih*�+ahatMJg~�!�'�yoB^�� "��[16 , 17f whil�is�"�|o�( i<%�.E�c�54 � h!QA�� Pro- 硉>t&�e!,D of�g7r!�Z�fi�)*� [18����5�i��Z�to-=.*j dyna�k.�2������_:�_&�5h#be obt�iyeB �p^:*O H.�!*3E� �%�A forcS#eld�! [1�� A.�&� p�/�b}0pKfuG+o;bv@')�L1;AUayL [23–�. C"j&_ur2|� SBMe&�.��*�e� ;F L_~� _ �(] �1�.�$��fru�& ted �=$gy landscaa��2h4accurace��.��(�~&� nn ametp of�!�>�[27A�SaYe*"��ts�R �baesa�Ct%�� K%"6;k%F �#W rP-s�E�>� ",�J }8| KP� Z? Odva�d�����Re.�=�C�*ed$QT�ͥ�- ently�" �.�h�P� %E�D�re*,ti%$�*^��&� �2�.|�� 1erMO�cA?�eolu��h�uMff}�Kh61 e O0such�-��p k-�5�[2�Iu 9 , OC . BeG!1�-�E?�lso��d'�@2vm�0 :P� � 3�� ���eL%,,I���6�:���17]_!5![�D1aB� D^ Cj��6� ��:�,� * Vg. :4��m�?n�� i#howE� s8�{%*> �>)6��e�i�1l@)�>�"� &��T �  ��heb �yonV!ac�� � \6BJ� We aim�=�� �x-/i�X.- a� a� ategm a�7� s :�6L���To �frp�eՍ��q^�Z� 5qj#�A�* i�nee�c-s����L . Bi�?� �xT��-� pai06aim%�o enh� e �E�؅&32b��.�, b��#t2Itru�ey%e��d.��. F�h�%Ag)ofM!,E7�:�pro(2Es�  cod[�'of�'�61( Q�A]SH M�4ove2�L-�/un zc� ԇ�s��f2w&,YrLal!�A�Sb�� β�As��W 1B���7 β =f9� �NF·2C|Cv�mL�,93 kJ/moc7 matc�!�e"^� �?�ued val�K� :H U/ .�w%IB'�d0 E�@.�k� �,A�qy"];w&7a�e!Z/aetamGs�4Awg?�N?6� ���:8aq& )9/orA\w"[ZEfB�!�U�� !��0 D���b�.ra)�41�"\)q�. Av!�~� ��4Uh T� 1c �!6a3-+hu� ��;$declines v��sharp�L ward)^�낁72�.<�:��o�v ���} JAI2+ �low%t*9� )� ro�10=RA W, L�% 128 B��e�Snapsh�)e�Q�"�0�o�3-��A�a9r@1C1ill= �q*�a�<�� &�" �?�i�!,�>uZY s�?A+a6Vm f��Keeez.��f3 n���:S"al"��Z 2�2�5<���0"�b:�!:� ����a.!�r�!*$�x�2<-i�mRAa�j��A=h>�ra~s�?� )�.�"�[1�Inv 2�O� E��ar�diT��i'�>4�f r=<� q�N�c w<!��e| �%�z7=s���7UNNotab��he>N"�H� !�~ r0�81"!�>Ua 9�악�A� ��;�s��6Ji .z]�oa��fit* �.� ost �M�!"Y ]a Φ-q�a.'aj%�B��jed littl��2M�a�X0��!#> ~x."KaswE�0� l� yal"meaO6������^ a�3�6�F e84��gB ~iL max�6!�A|�+R f�B�E�t�"2=|�yi��9�g&e@Q��;��8�U6�!d�b�-.�A[h�[a�>pr alpha_xC����# Pm� �~]5� E0)G� .����9^.��!�i�10-20%eb40-60%�><iT�r�5 %a:zkCD#2Q�.�z:&e< 6�.�A �(�\3pedL  .n !�xiUly 18%!�DP ��ly&:+�h� �d�;,%�%�&dom�4iaT�  >9��> 34 a�+")�C&10 nexyp Bv��5F3�$ASat:��� sAAP� �#3@n"� a�!MF�i6ens�5!W3�E� e��͛_:P�Bwq>P�. HighRXa�_hI)"� � o!�%�h�KrQ�*I6�2;�Qcal�iA�� radi+vgy��q�9A� crud� pe? randomg�l9Cm�A2�g-�Rx,%�d%v'3ao>KA�G�,i�Yly; ( �]&r4 n�W 2 A� Thusn7B�y(*�'m�e expan.t�&t�W%�w�bbABTi�)N H!� w�a�e;ter-r�2�!in>3Di �=apY%[B ) ro'&�L�8Q�al&�8�b steaGN~|!G��n�Ԇm� so&�/�aR!�ڍ��.��s`'yB�1'[#Eun��*U)�B%Et*� Ŏz;od@ �eJ��st�! �%�U .4 E��K � j�w AE�)eX.� ��iaSE��xes "�"�&�cswi��5�Ij�2]�vW� IS =�9mM��n�eq-� 2 Å�'r �X !J1j�� E�. O��f�;�k appa�Qs�c=Jmap�1z .K�|+inek5���D 12-18� cmocf ( up�) 1�closer!JVN"�|V��g 8-30-�$l���Y_!�e�DT4�#�v5Oc� ���T.ngy�� �r&�_j�!�F��uQ�h�]a fS i7�)�W��a C aA} coilqA. hairpins/9_(�a?0 ��c�-s���sa2 )�W�JU�ma��>opph�S����%�*� � �/attiv�%pul�o!�a-� :�s��^� <�i �a�Ol ��4Y?&Qi;�B�AU“atomsU(� �5a>& �.ey:^��5 )B�o%�anuGD �6 . 0 �Q�.� � �iաQ=\� �Iho�1V��e<r5� U�w8�averagaHr.% � 9�5465����"]'Z ;_Qx"\F conn ?Br( b�,e3+?�must Enb"f_5K? ach��EWa�l�,iL� �<� ��aB=6.�nyЖ1�sz@鐡*$*Ekru�-15L? aFAOAVD�F@�. B�1R�i6�j�ff�"A���3A%L3B� ���'-�>�%�s vi�C� ��-��&�5 2�h�vɡQ�� "e"��&Kwm*!b%" M�C�S2E�� �"62(A�aV�) �-�u:N�,�9&�u�.@�Ey�5j��)S�uj4 at 6"�t 67�[�10��250:!�)�N(@#{@>�._�3l(cit�a��LF�en��icip5CBAk�a&I!j}� J�me�,�s�$E��1��w1�e�� E3ab"��jO!6B took!�n��,1330 ± 90 p�- ���*.�)val�tou�Тv A�(VQ���L(× 109 s−r>�4 �A Ɯd�j���"hUr+6 &'manne���!��BEkre�pickp3 10EIn:WA/p3 ausA�5qL2}�Ma��q6UL|H� ��� . At�mM>�D1�*Uyo}�0� s fa2va�k� of ($6j�*��_g' &ew��C��&�6�'4wo s:!�&K#(V0cr� ) =�!ma"� �R�& i-GoaPPspe�g5�sMl��m���[�A��e�Vpa6{2�5)XLtE��N^��B�7(�,�(vb'��F7Xale��:�.$��I� ��i� f��%�1��;!e>s.ɽ! ` F�SkB�Y .2s"(5�o�*A%�C%u�-���sE��|f�i�#A�2B�10�}Sx�,Yq4y���A �e\��iAn>)�� fash�.,� a�1-� ��$��T1��6S�Cbu���e�H>a�.�aQ1e�)N�rk� � *;�1B�s&���2�Y& �2ns&�.�tir4F�j�\ coll����&C�[2�i�CS"]j�MK�Y�in9��$2�1ADc�.y��Annr&� insen%a�6*i ��1�" e�(%��8F�!~zto ( ;WU1A6aZAM3 .U � �-COow>�(>&Q ET� nn�/��le%[.��.."���e�" few �V�=Jr$!G� B�a�6� �T� �����!�� ���J��d*�P9 �)s�� in 6�is �U�5� w mc#! ��%^_$ �.MU"��s �; ��-B�I)|�� u3�re%� �^M%�9 !�"��i&�)U  Lys66�� �� Glu9E� �6�V0 ��% �a m�;w�%H"9�*,^�a�ATX Q5�*[(�u t�1w-( .��Շ �Fl�% omew� m:L&�,samR��$5"Z�5).��<1�2�IO QV-��;cEW —1a�)-�5�M�!��5st �U����%��t&?�&�e�}a�A�F�, !F�m��t!}o�K!kIn� B2��kJ�M�/#F���Arg65/>�r��l`��  � >[ �NR�Arg15/e%e-Glu57Pi7- � Glu3/Glu4!3Arg80 3�=|�1��N�(Rv Figs�*�u�.��!Xf5Q�&|w.�*}"�"�n hadaW� E s�1e���B� a� [�2T/#��,)�' ly gYI�-#��iid:�( by�2�i�lJd) XTZ� (!�6E3I])�)�)9å�Aor?Grk,�9a�6��x�R ����b-a�--bB�Oke �/����.Y(��e���I���We��Q-�J�q! � 6�2g!�b�(��A.!���Q �m A�o�zhj . >%n05�_3kTo! sect���5lV5� � �6�o�,a`��2A$��&D&@� *��_��arir&�7}��,*� U����)�8 _Gm\&� ! �R�6rdg“>  ��“.r,"W\&iN, 9�A�a�%2�� "�&y ��*%v�d }�M� �����*m 7�7t ra�U7��]"�'*8"�-!� 28�<1�A�M/ _�-�6�^'! !� �b�s�ci�}+6B� � %i� Q0:�6A5��Z�5,Qa Glu2�*�/ 5S.��.� 7D%?��� %U���%�47�F2|���(da�4C Wt6u�:B�8gF"�1.�C**�6m"-+�&� !���{^�>C�'�A��"�@mN5=)28$�Jrtr��&�+�Hrn/*�*�-%=eF��I* in good a���S�$?*�+�U� �eԿ� 2zHBx^C=&I �&�C�+EA�� m��2ude)�{�on&�Ci�!�anV/tM.( �@J�+WB�� �2�),| 8 &"�~f 6 + (�+(+)�& '+�i7 fK%,��Ed� �9E�zof>�I'����*�1ֻ&�,�8�z����f�)AL��Fj7"-+��5����� avoupE�LefflergQ�6^e�1�%�6���AJ�.`aim?02�+6�5 glob�F�.^T"; �V�t��� �N�8S in a]n�4s i��nn�%l�vO&� -_ u6\f�v��͖ͭF� ,"�9B�,)�A_.I�o`4=��� �E=A7�{g��sE�B��CCeh!^�}�VG 4EI�.I1R�(�'r�,�qTo�lN3)�K%�6_@ � �(s�h��"�M?)��-q�� �!*ߥ%QE"6��(. Chebaro e�! .�|"�a2J) t]8y��Ah!�E�MZ�x�#��w-L6�%��!�!3�� h< *� !� C���promp�Kui� e� Q�)v�&�u0I�"GAA:� �.��\5um/� E�.���-�G 66*C7> ����=!O700.. :,#bY ���\)UfAb-NI��>W( f+ )A/�47�!.@rh rbUh( f−B29uTt<%2GJ~FCsn�tne�Bc# f ( NCP(/�&a��44� �(Y=�+ +�; H= |f+ ��|s rB<2� phobgWGF%�=mph{5�on�:@ ls 1�S�f/� xPASsQ3]O�fweb�5 xpasE org/� �f/� a window ڢK5��1!5��:�to�5��ZL � . 34!!.�2)�� a��0#.( RgV� onshipe�!�� Ai ( |i%Wj)T {��6tK%$ of y�331 x�68q.� !UU�l4ky diagram [44�PD�3d Pappu5LD��RN25 �!��H��m��H, polyampholy�$�0s�n�_�.�:A�&IJ3E,�o:�� b��of�0at.�o�K�#�H�O*�6��/-E?1u�hAWЇc�#70mployOhRgEB� B�.��,.�%MI4u>{�D#2�^ ."]9g81R2"�� ��r2�h2�,:�T situ�S�V�?I( y2o� do��"l�26�w a� t[��D�����}A}j��TinMS� �0�ied *is�Wo�K� i0Q n��O ific*.��%�a<$�-RZ(2��'">$a�*�,"&�!O*���w��/�Ke���Ѿ!N�n*-D MeV)��!"W!|�M�_ݦ��slu9��,��? Ufh5Jj3a*2Y� �/&U$ Å a�)b�&G/�x�/��"�1scO�FI1� dee��*� (� 30-3���-iG �� :r^ -�1��� aAaY�&ze)��*2,&�� %�en����Mk�us��F0� lFN6�CUV� !3b yE��"��J�~ �-qd"� �i��? theo���� ;�'cce�:iv *�%A� e>fly-cas�0e 8�[48 , 5l�@� oughe^� B�s les!5t%#e�"��k10*n7�Z��Qh ��M-�����W���!%1u&�Q�<Rtd 1����I�I�tie[h� �:w��Non� �we�� a�H"��T*� , � A0 �E�)DA�!�/^i �i�*s �l'i�K�e��ienUPy �te�}!�?� _dt�D��nZ)Ef%ҟ!)��:/&/f)R!>�� �1 ��PUMA⋅iBA$B':�A|!#I��Rj��2� ��Zt�W*�))�B�_/{\�> ��)�ɢm�1�ᙵ;���+��3j���e�sA�Y!?��{s5��� �Q�rOA.A�r �e\M "�^.� �.� �@�wr=�%a�&Gghly ��%�1%n ( )89 . 8�%�}4ML-R-W�|6�.�%/Q��ly t�3�a�:�4�!M3͌.�o?d�Vj!�LX�= .R �e�m�9-���sA�2� M s� ��AÆ�a�ac}uE� �#/u z(9F�"5�� � ���X?ofn~�@�*��&M(�9���ts@)(6��was�X%��0,����N�ypt]a�Wer� ub� ��g"��� � � `m <�^E�o�v��Jia[O�n� p27i\Cdk2/�� in A"R���Ȱ53-TAD1 +TAZ� HIF-1&th�0 NCBD ( ACTR [50]!�6� EfV>A@@ gyWL6�zJ��!?��~F�*I�.p&oE�f��n�iǶ"-�� n :�ABF� k(F�5�5{���)�f�8.�[2M[!0h �Lwչ a����+AY��F��- � aGA��՝�� �}R,1:6�* �' actu�� reta2�B�.AF� x.��&p e�� �,i�L�Y�p X���DA�q�!��‚Ex;vo�0Z�X-c��ecia-�̡k�(�ao���n�&��1ing[A&�"> �Ja�� � �� �~!�6��mI�&�#n����� Ao*V�1�#.�P$2 ��.>'I��4W�  : Op�� 3�:^�� �Y%yO%�G.x*, Asp886"�'5P6 Arg9�E Asp1&�*)����F!� ���4 Lys8*�'A�BsJ�2s,3B�G(�XR� ��ta�.��I�>�R,d' �"��dx   � on�\eqI [��-MQ�E!f�6[5dA7�r�ii�*=go�)F] t�'L�ExK2aw"yiF�:=G�?:~^>�%�׉5�DvU��26+a�2� M�qp t�t�xp"*=+�Q�8-�!&n�-�6�>�-Lys.��.U*� j�0./$�F��y�.!,��`ori�.�$.� ��&�� Bo!�N�#I��. Lon*:�=DR� BM�1��2�ug�3>sء�:�iO�HN���F�-B2�EC�&�����. O&X:J 5� A��!?� M�� JdZ�2� x\"�/E��Zmb� q�&�� ��: 1a��`�r�Qk�n-uni��PF���9/�c��"{BW ���]*.�-8.w-nd�i6v&5��T. E!C�,"� "i�&L��"'&�a�M�F�,�]\�"p!UA>oEi��:&� ����%TH ��%F&�*=�ier�RogGc"g �#e.�!�C*J@���"�j���Yy�,@ �\,�%�z6.�`ric"VK"� }�6Q2�Q�Jp"A�)0�M �.(�ce.���*' RM6A!��8 %Arj�r�$�Ha"�]A-GEF2o�its PDZ��� neuI<6arVX=")vN brid!�f,�Xr[5GVF�"gH!!�1��:. �K"VD6����� .�� aKF Eͥ��)�su4 m6N��!8�us“�b.(!�. NMR*�SeU lmH�?��L( PDB ID 2ROC [53] ))e�|l��q�\� �� �R�e ]isEda .l]^:o�! .rA<:�XY�A- F �JR _K�buiT>y�aC��B��[5��S1�I �-i|B:�Cα��dV=o�(�f*�1a��-ee(g�, uASMOG o��n�!kig�K"�� b�J���atoV�h��!+!>r[��3Sk53�� ���I( 162MYi�  (!X f, 424�36Aq.�QU{9AT� a�G�@s��V�77<eN:��t5U�   _��%S!����Sha�"A~� [55] @&G\!�gy�)��5 ���ךe�non ��Bϝj�=�K�za��!0��{�SBM-�2 g6S.�� �;a2;Wrbi`F�orm*�>%gi*���&��Ԃ� X: V = ∑ b o n d s ϵ ��,r - r 0 ) 2 �$�ڝ g l e % θ (-.((d i h e d r� K ϕ ( n�N - co�n>(-@) hc�t a c t li j 5 σ r12 - 6:0 CnC-NKN C5Ip+ V D e b y e - H u ¨ c k e y�H5In Eq�$ϵr]=0!,, ϵθ =g� ϵ ,�3=a[-i�.,5I�=��r�*,of Lennard-J�3F�9�i.d?#h�Kj�o�|����m�XL`0�jK Miyazawa JernmtA�gaMzEK lavo�"�_. [57]�P�VI�co".fybm� ϵij�s� ��l�:! !� = γ M J ¯ - 1 + 1 (�?� ϵ5)��e%� l MJ=?!�H )� �\�� eA�l J wep{m�<3mp�m��!γQ�to�0�wH��B)�“6D��[5�dI��A�ng\%zX_&7_.�k�p!�K9sY- b�pa!��� �&} A�E���sh�b�+ƂǍ���alR(�:� %Xe���pRM'�b6!rc&&X̃>��I��!qu��fy��&���g� mh�!t&�B&s�^jW= Γ D H� K��(u l o m b B�\� )��0i , j q i q j!U�t�����a*(�_��}$K�0omb = 4 πϵ0��38 . 9�e·mol�(·nm·e−2!J!�)kM�n�!�or;�m9�*@�}� ; κa*%��A&� 1�is "7P"�� �s~%2�(Q���/��Wf1ZC( κ ≈h?2 C sŕt ) ;!=v.�V.�m�80"W��)*{. ΓDHJ�'g6��W=��1mak?! a 7balr/8c GQ�L�vnd��� ]�PI� ( +�I E�Glu2�&>2-2œ� Jpla�:� # p2�� !�6����6ls�L 6C  noMzLwt>��. U�}:�)>b(-�∼�-5 X,Ais��2t[E��)�et)��35��!{.�.�VDH�Mwo"W-2S"oms lo��0�,of�5�[.�j���Q r��V� eC*��I��b�SOsJ�p[3�~�u6��#��`&gD~cut�Q%�Gg�,at"f �"pي,6) 6;A��"��[1&��EI2F"mA~.�r�*sAGuni��.5a���@O6�a �%`*�-h��8aOc�dW��TF�E�C�i��� ��mO7Q*�mD��GcheckAXl2�?9K� �=uL�I�I&&���=R"� wo"�)�B�Xe� at!�@#�t'��i)�o8u� �z�yis�#9�*�>aAAC��Xݙ[fng��=��F|6�X�1 M[|!�7� �!L+-ym jF��)����(t�or� ny&UA�$�>2�!���5�o-TE_��"�6�6�as� $^�P1�F>��araQI.�F�V�j% (Z�I;:�mea����v�[�o i �&��!�����*6�J2@ 7 v!�}�%dq�. lxind&�} Ge"� �"07uFPTB� MPTc:^> FPTe��2`4,Vk�  nI n1]u i�L)E+, k� �0s��/.�/:�, tau.7�/ �/��� 200 ruR"t�6�28"aN6N�"�Jis:9_d.� ,S l l i s is u c c� s p r o b9U i(t04 �t e ch  t u r eI�(FLa%�I�Ap>� ��Polyc� �%( PcG )!�+� �@er�T chroj&� za/>�P ile%ofA�mov�whole u8osome territori%�0Second , each �y�>� has iA_wn fast& highE� nstrained �A䁋isregimeIAmt�Q-Xvolumes slightly larger!�Hose!|�ee\>�A�8Moreover , both9�1�Nq$much smalln[F.,A�ongly�trictA�th� possi�Xia�m�w�ZotherN��e)Q)��YA� atin�observed��N�st �decrea� in a! develop�s al stages�xi�a �A<ont�&of.�ynamicaS!�� tenaa9ofX@(gene silencZ�. The biological mechanisms allow%aׅ�e��trans� into kny epi %mcha!ter�f different�i�involv��ofA���$ory factorť9s!�specific!t-�ional��mod#�ks [1]i$DrosophilaA�cG�5�1�Irecruite��tthrough�K�- R��se Eli�(( PRE ) seq��s�acan be ��V seve� ten��kilobE away from!O ir tant!ueaJ? �" PRC2�lex��t���v(s lysine 27!W��,( H3K27me3 )�� marka� t iseogn��by6S�P PRC1{sa�asa$!�PH [2] ,A)b�� abou �]w[3!��:��associ),U�med �4 group!x cG )9� play�rucP r�nb�!p�ng key:qreMse:nnic stemE� s [4�[5�R� !���6� -#E;��al��2��"� ����1�%�5#sugge�� hierarche�organizE� [6�7�a�f��l�_��sis�1f� rt�zvidual!$ions bound!12��sy� peak!, clud�previous�|}�dH' seJ� , nam�ZDNA�� a�necessar�suffici�CtoA�a�a2OI8e flank!��s%� , [81s�j)%�is6M����e clus��ng-��-:e���!�$��arked�v1�5�Ae+(a lower ext�,!�<PC� .� se�oI ��!�, ����!(p ��e9 men� al (� )��� �ins� }ch  u��asu been! entlaKmm��by U�y ~I�capture�B?%8e BX-C locus [9!�*@b]y�.� �$act�;�.mc j�si�2%�ha���� o\�i ang-$ �h�{sa!a � e orr��0]–[14�Th!��afun� al��� ed becausiyfr�r> 1�� depends� 2�[1��u*K o*� M�d� RNAiE�in ��ins�� Q , [1�$Witr JE]�does not)ja uni%�!Q"� , buŝ�� �E�ar fociF�[1� 1� PcG-�G��'e�ccurse�2% �a�it wasa�poG��!U�on)��2Ba� v==4 iI�>�[18��1eFoa3sIa, Fab-7� PRE-E1�� `troll�!nex��o� %Abd-B ,��f�� 2�iI� head�*; �$�ere J<je� w� Epo�?or �2; �; �i�A�out��&� � Am0a:Fluoresc"recove�30fter photo-blP !eV�. ex $ge rapidly!�A mammalian- >.20%�21d�"�E=,Fm,!�re�a � � betw��2�-[eoplasm�t� Q�B���isO��a2F *u���e�� sE� indu�a�U��arT$. An alterbveA "� i"�mn3 � al� S*�tob ! �edE�sav� in ordFoRQ ed � case)y oS .D5v� impl�%� they2�aW2/. *�*+�i%V�si�agg)fU�t{bel� poi6r�IIŕ!�t�@�t V�sub�BfBrownA���`Fa(:!� confD' sub-�c��)��22a�By usI�e Lac r�Dor/lac operator syZ E���! al l����|describ5%�� & A�@ a random walk [2Y In}�%��!�wmvE�t�7I�Q|aPlih "1 closIcZ.ol�3ar Sph��r�r "� than"V[2C� cycle ph!�}"Jiit also:#-�1U�.�MexamplA�in yeas �d�i�q�origi� repl��R�u�eSG18bec" c EI in S �.!���r�, telome~t^ r di�Z91 �inZ r\[2�In.�$spermatocyan, multi!A��!/c}K n& docuAB&�pr} 0G2Q�Anq�:4 ewA+V��:.zOA�Rey�{cs [26a�I!�es�� ly ,./ direi �%fE� *�up�  cripA al� ��$cul� d �. Uni2sigrI� of a=U�=���""I�2X���h�"� 1–2 h a�0��a�� #v��O�(ita)A�n e#0ar myosin I w�"# Q� !��[2� Simil� , U2͵aIr*wards�� elat�stably�Ai!e(ed Cajal Bo$ �:��v)\,�t�*y5a�ns��tur�qbN,dominant neg� mutof β-e n [2\&�����& Ѱ1D|��aA@U)ye���Z �" in��sJ�%�K &� N��.�oh�E@2N��QH! ����`%^�of “� er-”�Q*R!$j� �1D"� ^!�)�M�6�s��`!rR� flex*����A.po� �for�>�. P��e�ve�aLA�" �\ W#�ospotsFOi2K ]�� s [3�[3 W��al��livaV)%��ge4fR�' a PH��U� [33]E a PCV 4]1�germ b�eA`�(> ge 11�"3DE�o��� �!r2�e�yco- e4#l�u? ���a{ c�antib� gainst/3�"( Fig-S1A��!-��i r� ly� ��$-�YRa�ivo�v+el �"�� ��CJR;)��B1� vizu&Xof #r� i !k׭�a � E.m$s%!-��.:r%H!dM?��yia fewudaof heter��0 �nsQ %�����. To qu!�fy%�dYOw)8� calca!�h�ti���maximum�SmeasurM}2�!Pa�ge1 �� @ ��w �optrs,AlI �ty_`eJ>��L�it��F�-�TA|9le!m�ar.,�%� ��aW� grea�number�w low- -!��LY�(�te.%rj�a��DC;uj ѭof�� ��! , dedC1&�, [35H[3�To test��"!��E�c� ���+length(���} � M:A�E�pe�I�-"( coup�*�tv,Situ Hybridi3( I_')��"a'1sp6 %DZ"d ! probQ.h ^�"�D �A�� Sin Ve�;!�^8i ��iiQS a!hom!��s_��f�* epid�l� � o�v.�)T��  no: "�[Urepor�� E�,M�[3HQ�[39�IAR[40Q svp [4&Typ��R�56��"sar�o�^l� �A��in� 1D%[�+�" gram�,re plot�� %�ݦd&�a� ��E�90% )AE��A��"-ngWS�.*�above 1:r:�,Q�AWr5�� w+�o-.R*,$�B�-A��2oat:J)� ��de"A � �EFi��!� �do^ �t �2 �""�-mit&/��6 data?)Ё�U���"j. Altho/(J�alway&�m�Li6�ella��)!��E� �E*s %#)*� �$2la2/M s.>�J�!S��A 6�.�"�al!p�b ir� ��� I�]�I�&� iI�n"@he��B$m�/��1Y�!9.�%i,approach did%rfind �� �zce�1&� B�-��)s>�detW ng-*�target � (F�jdB�(��)B> x, '��s �%u�2n mosśdu�2 Ѕ�2�~��sri� ։*&� veF=o2�:i�ijdi��t& back%*ndɰar� �.*�*�B��he2�sho�2pro!a)Ji�XA6al�+To impr�_Ef ���*thu{.� �4% file�- ong 1 µmM s crosA�zin 2D�A}f� .#ns��eX є���*� z pixe�*�+Q�a�l F��%(r#ne5I6���rs#��<$�t� "� Vlef1right  'f6��I�$ sult�} firm&�^�t& {���B5E�eAw-:�R��eA�ig�iin+0�9�!%%:/aaVŚaq 7!9՚-�%F T=!*c-%�c�*;.E,� %� ��qn"��)F!�)J. weakP!!�$�J� � /!�!&te.�prI�Bm� �'�T�*1�Qt&B%/ A"f�aken tog� rEi��4$ :�l9.a�)!�.<�6TN8C�@� Precipit n ( ChIP< zip�� �yMgB7&"k�#ly&"!� BL&m g�7 , �3t!�PC6mo:to�assemblR.tQ���u�d&�i�2s� sibl5n� c:I meet�*[  a�0� ��� %�ir!!y�#u�!�2!-�%�� �0 �y��,Jx �G &�6| .�,G�3NXpai�1�� ��� ��J��� ' he6onN5-%�i.e�4( PairedA�r� ( Un���y�G–1�:5�isA�l�5�z���lo^*1�-:� �~�� ��9�u� situi���>En6G y!Z>1"�!���O � i�A�!Q�A͝FmI�"�zZ"����2�*&�6/2�3Da�\ )Q�5;2�>�2YYnt�F:�. Bb/PC����U �'�/1I�~as&�in�NAb�L.l �"��]"T���H>!>�"5� &=!q?�S2�B� !Da "begine��%�8 5 ( ular�#blasto�o=faint&MU�k-�>�s�,6W=��% �D=�rME menp209&� "� ndbm#��6�q�Vz R.Y66�5{� 6f|-t�%� ine-�� $.��t�"A:*�۩���Q���Bt4. N�eM&@>m��#A�&+�v ric��Amc is easily.(by �A �� DAPIA��02* )u�1W4i67�a�*�?!LB��'urpri ly�c-poor�� O5�MnCod,(@Vs-��!+��A�SS[,. 5Y��&FA&Q !�_=�.7#�N%:Nj-�go:M4A�2�� i� we!��edZ2thS6�2h 6–�21, 15 )� mon�>� ~!�6� �~�\FJ2�y�a�d  B]*-3.>RhI�� e�QA}ach T>�L>86�. C�A�E���� sJSU� S2B–S2Dct��f�S2A8KDgen.Z�<\%A�E�).)atZ>��:�>��R͖"m =t@Jn W?~I�s+��15D6,�/�^�m,��� �$S� X� �fra� a)4���7U y�t� losѵ>�(. SA!yp��%z" @5�>�=)!�a�*�! *] )��OF.e  !! V�:_1s�}. F� bi�-�a� �"B� sJas �)�M be!6Z!��al�2g*>o�I.�*y g�s�E "�4'%i���%�� ��.(!+�$.&P3 FRAP�7&9ren� �"r�6�6%�� �2�6&��2э�@��r��an�;������ear�у��I� -lt 6��+agy l� .�C.6}.6�#�,�Z o=�AZ9!e�" ,��2A8La� In P:8&98 ( FL".� �p" ! w6�. AN�2we�>I�D��A�4�meaao�of*&6c �;"�#i� tim�� PyTa5*>�+X|&�6c �w�!J���E<�u!a�8.�2�y�re(o�y-�G5�.��8� 2D. FIC)o5}11� >MU:�E� Qa�qD s+'c^~ e�E:.�JFc** wn"K�s 5%�1*n�ǡJI&e�!�%ե�-�y{BeNu.q:=`a ��I)�y&�=mh}i&�F& =�e�.|Y=�ic&�=FN!�-.\�#�5is�k!N;Q�vc%O%�� F!z1P %i)�&m�=�o:Ps,�xiZ>�u[,r*4=ӁR7�IrN� a: th��Y� ha�� ťAq:�:Z� )%Q! BsF��4i�d1B!!Z6 a2�-YN�matche*�&8 � dt6W.�=&�E,!n�)�12-�!edQa�v^�O! &<[b"[13>-�$�>ari& erebB<=]�6��2B��promotc c+$�(u"��@)���#�.&�; 0EO�/!�"(� ���<-�N.��<�.��i,3; FIGURE S3e�S4In��aC(�lG6� �  Q.+&�#250 mR� se�Q:.zB{Video S�.��MSqu��DizO ( MS�p��8���8an% ��!� M�fZ25&h=;M� R2��#��!ol2l�ixe�i%� n  8*A"ir�curzRs�Gt=�(�R�in�Y!,"�2E Y$a��&�8.+by acqu>(3 µm-thick rs-�3 )�3 meR.1�E rack��� ace�!��&M�-gZ-axi*cI�M2E�A6�poi�R��6�A)M� ectl tc= *2�sh6J[F?y-�2�a�K teau:�ar9�-�AY4 radius 560 nm�c"���e2-b�q-�� U2���-E�zs�6tV1%^�HU� �+&*vis6�1c�@M�2I�3 ��#5&mm�N�*�+)�A�E�s���E� w� id� 'nIE�ri�K@oB;�h#IC(�=.�* '=y give7gleh*!�Ra�tyA��&zV&�:ecu�e-y�a Ye�+ bjec+ "[��'���2Ca�1cM&2a� �wo"" UT�du�)��+*��$ir �rd qt:�)NNt'�o�+f narrow�( 0°!86*�&3J–3K e!{���W�}as 0 . 5�&B� in!|.� *�R�A`6���I�t�D�:t a6�8scaT �e�&�DA�%)A�VsFib8!F.�ChZsqwvar�<z-a6{(w.( ( MS4���]/!W�-O�ZI�a�x�,3b .� iE1%�,%to�퀡}Y 1�{�@g2re��2G%�3,Qo)atVo��C ŗ�H� 6Pfua!1�%gN�. N�# ���g%�S)!_� !>-��ZjK6�*T ��.��s� ��:o ��A�� �h�>k!�=AP�,Y� A{q 9 �B�3��&�miS(cop�L"S�Z%͓85�D&�UcodAY�� o,�lG��%^� [43]�2:peO�:�Hr*� an p in polyte9�% b�:�3'r  [44]n2a�Z1u�s:er�#�'1Áw�*��&>U!Q�@�"�5:E*� cdeple �n+u�S1� .%N�.��a�vi�%�!]�.� �{D�b�3to�S! bul. �Oed.$.��52 ;W.*� Pm�:eoOng奌c"^� f@��aof���g�=� � Śs&8 A#* . In�:r��^eg��e�eE�2'�Uen!�usI�e}v6 !|<43E,�5h3����)� s&��A������ 3d� �Vv .�H 1ly)a*e)!�!^�Ifh�1�F%� L� N�s��}�>L!;F�a"�`n�C� " a9�Rb*p�!"yMDYF�a N�.. T�<4.2��͈� ced half!�seV<Xi��!pB%6Jq�&��E^vR3"/e��7r�;i�3e 2 ��$�� �.�,IYa��f�F+��lv�a��5 area (e!��(nI9)if2P�oby�2�Hz b�&� bnd un�*6% blurEVdisapp!��9��!:TVS�t�J62������3w�4�1�� �b~�7XN��(�u2n< !  �I,jzDsimulta�>ly"2��Mݕ64Ac�:6�J�Dj�( I �� 4��&6�,.T�P�bS<HIPJ5YI�4B VJus"4:A�MSD/t� Q�.U2�/Rq �]�#a--rn $�* made�z�:�YMSC2��a4XC"g'�;.�FAo.�q���� >|!conver�&�{0!��Qas-:c"'' stop�it*iO�!#� ypey�e�<:� .\)��,�)� �"[%�@!X9�fiv�_%�&Rd3�&PD2�$ n9eI�u��!9' 1�Un� P.2���NA� expl�9&ab"�I� ?U�� a�� valuc] � ��m�Vh&�d�� Y"� �&` (3D.a)~N���ossDL�=� �du%�R�����STGH%̦5Mi�-%be&' ��dw�M!�!i�[�:L ��mA�6�ER(Ųind�^e�=�F–4f T�(���]�E�E� b�I� �Oct%yf�sѬA�&:B�A�A�d� !v]�sta< !2*=V\sX��ini�KIP"'\1�*�h9 '4O >�UB�D�%��s"�"d�*7 , asymp�>�te�g�+�Ley�F�,�m| �">"i�nd F��w&�e limi��)8F�!�C&�3՞�&lin k/ �J �M� J4of��* 4K <N )"(*��<�x��Jj�zqo_Z �)�m�&�W.�onAg�G"�v_|. Fur!m9"�0�5V/2B��ZC �A%�}%d�veB�hFɸ�!%�� ome �= ,2S \��Z�86-5)A��D�J1Waa"3cx&��qby`_]1Q��>�i �alu�A} 8��%A�V�: %�Y�woy"�C.( mqY�*f 1wA�M% c��pA{>F:X}���J�:G&�u��8 }zn= >�a%��.�- ���Yall*P V� � �,W=aoE�&_ VD*���2EV��8F!2commd:��)nstitqOW p �lyN���� �;!Ni-B�Z�e occaCh22�ps �W!�!9n��!2�AQ ��q5-;�^�� � !+ua�scXY- *%�N�nc8 i�Z!10 �/ !at� �&��F�u955!I3�� e>G��a��(���r�\> &>�R:�-�. O ow0h�,ojackA�h�:��N[D=� j�.�s-�6�r�z�M��J� :%�!�!�,'-� ll)���"�#�ta5BM9��$5MN�| &J����-� �&N ��L B` ��-va4D %wnM�!�Y.�)H !F �!@� 2'yS^ �g�*##lyn)�E*c ]-�foNiuA��n1�  ��$1$&�� s2M�PQbN�NnB By {){e-�-�.N"( z/"�qV�*�t]�CE�m�O�C�F�6�0� ��U E7eO!е9:!��)6*� 6�I�-of Y~��  horizxl�� j(XLA�MaaMrti$"� 2��E�*�46�#w2�G�3"�9� sum�F)dd*�b!)6�* lkto.�2+6��#whev }�);� �2 z\tZ�9F�F0��ѶAd&=� \!IL �qfJvQ��AtAKA�2G"pw�1�Ge'wo{ss:z .��� �;��yaVachcWwhiE#z!eY�y[�$[��Ip=e4�fnf�$:U�%Y�J5 �6�!41�%��F:_[r!M WRus p�S�%t�"CM�05^Bs�s"�1�F|M6XM�� 9�%-I��. A�UR� QA;%O�:>T%BF�F �(Im�Pa0i� �&�Io��1Wa� innn aram�Y liku 2,2�"6oa� ��E�>� /a�6;_<v�J� � �"7  �ty "���� ��Tf s"8>�s�ga��gea� �J;� M�&5=.9�R���]J!Fy,v�.bl,oQI���*�*5!�ȝ�HW~2B-RFPi@.;"��Np+�;y�A�>�/Z�/5�&��>a9by�.62.�pH–5Y.R� �,�"�:�2� � r@�L��a#te adja�2�BQ�9G5Je}F>��oiň2+MKl4pFm�#' S6&G �*!xCarR+ �yR�{y�!1t)>Qj(a�& @!,���6���hAlsur{AH�. N6 the�Ɖ��=ai&e7�AuE5"t�,2M~��~r.S�IZP"�,4DC� �6Z�;�� *���v"�g!79vi�kivx~ru���*�lyF��;�"� ^P �A�!� �&J�c"��"�f9��!9� �a~�2��&1 �9),��y=J���(q�6 )�>�`� 7 )�0i���!1$ �"�%�01A$��Q�:���S �">,�8c15�) n� ��>XxKIi�� W A�V�+"� �h(<� :6�n�#, s:�*!H2�w�zm�R�'| 2�' t>�%@��8 &�'T �H&��.�df.�s1n )�f&/_t��t?�4�&]bd�%.S�!~i03~OA%E�TAi.��d�B}��? 5AX6��a�D*.''G:���. dM/f(y Oi�)�icn�|�C&=E%� �a%=-j�*Qtag>1As�Ap� y�Y�"�#b�xOA�2�Ia0o�;i�\lEU-y�66BEFW"�! : ,�@&("#?C>�6��2l8"�)�5A�#i�<de�$�0ls\q D&/./* �W6�s. B׉�[�#2F�a5l}��h6�%�[ Q6\3>W6q+62U!steps�h�Hh &�3ed�ID6v:�va4*�Y997��-<\llu��%A����F�a�"m)A �pR+)��1= �u00ob�i�63!M� ��#ap��ŕC.��NadlKMeˀJ� t�U�� 94� .�!�#�Q��6nnV�a�7[i~]Qih[Ac�cd*�_2�5%AwGaQ�-�!���:a�F?�W�$�#<u|1a�pq~� ��  �: x"�Y�"�6�)?>+�F 9��%,A��!%�"�� 6�tZ$� :? 4 )Ui- r�;0.�s&4.��"� 2�H,� ^-.�`�>z"F,>�.87"�.-n��J� Mo"�.gB���*Y{m�" `F� 5��S5F��4�B�E!*��%�F�ɴ= U(VE)��8�u��8 :�!�m5* ���3w#��� �Eܢ �=H._ ��a9�8�eA�!ve�Dt�8%y-U�S��S�rF9+7��S7��U:� 1�V>d t18� E�J?f �(�d����d!�� RC�����)  B �t8� abf/C�R6BV/MJ� $.zS7M7�' & sepa�6(�ns%�� yX3:)"u�%I&'.1�]WIKs&� �D"VD",NV�jpEoEnA��! �� ���%{a�fan"� �*�~0��!�lli�"�hu0%�-�Of' � A�cAv�!ԩe�� �&� &Kqqq(�yqptE�V� mr� .Y� ��/a��C�29�O !�14[3in� i�F�e���OR.Z18Z� Z9:YV�>�&�lP`*�he^cosXN ��5>�}�M�� �a2jis 23a6_14 µm2��u E�"mJY]�&%�z=arm"mJs "])&h 86!�F�67%�.�y�� �t�EoZ'���'8�� "@ �9EIM>q4De>X U FV�.V`=6F� 6���Hap��%Q s({!�1��� �!2��� �ABN*[)� )*]F�f{?s�);�c%%Zr��P2�(� �*�"i��L �B����b�=/�X� �N3m&K#�b�F���7iE�9B� 7H"7�<,�1�Z�.�Hig"�)Zi}-��V"� F��:�����2sQ�Aj%�W"7���*Y#D;A�f75;M s|HDU AV�p�6��I�s e 82�8�5�.o .� ��3 e��o7�ng��-�e*Ɏ��!P!�A��%�1T#�K�%��L�s�1�w:A�z�%�K�).3�KA33�bQ6YI.�6�>hgÅ�\%R� � m��^R:Bg 8� 8�.���9&~knsDva� A/` 25mU�*�%!#4B !!>LRf��-1�cQ�8ES8�;�B�2��orR�AKX%�2�RS�a!�M/�J��Y*]�V$P&���#�,rmo�:feai�qQ�g7 Vno&�Fg�AJ18°C�25 � ,͚b tak��wic����Ft;�&�r�*�Vat mH JH*�)S9E�9�!S9�!FJ)9�X$2#�!�f��lo�T. �OE���-u"l��m��(U �+� ���G.�){�"10�10 �10�5. TemR�)��a �V"F% ��F�Ru�.�o10p��/(9]�� , te�6y���%��S�Qc� jZno IRP+t&_Wr+9�9 �U$!�"r&F!�e �Zb6�6�2,Ih.�10G810YeS10K7�S32�9�9|i�Pse(]v�2�1p�Fja XFiM��e9�V^F &�@iX�v1��J��k2�5�M�(&S'�^.i6�a�uq�TɁ�8�.�! >":��b2u�� �� �z� �U�bZ|�|�nD�v>4�}�9E^9M]9� 4"J�%T5g�Z�,*="!HS�� ng &c?Y3�-٦pr��_. Earlieӂکs"� �s.�Z��a"q!�2I��F�;��a��ii+f����L\��8��a�.��#2�Vb�. >�&�fx�e�&�T�>lu�Q �mb\-f-M"���oBSM�*!�5� ����*�n.�1��&��9���EK�"�|g(-4�[�ce 2� diploid%K�&f}vis view"J\5N:D�"I\b(��A65���I! �sf�o��� *-\ ����g^&�. T�}i5/�Lv�c�� our ��1r%��8�`$&+�rea@|{rstek6�G!�2�i�Ma-F��;����_�ssv�Sh>"�6��a-"�m.x��:m er.� !�CA�9fC v1r"�M�B�A�re�ar!�spa:� ��Wic"�!�v6�*ipr�h8 h*�&�f\�2�e�)��+�y�?V�ag."1��da�"�8 ��!}-�Ix! H�6"(l!t�%=z�lD� ��^6~� w:j�gއ+���o"� 1`�8�(*#, �M�Y|u�� �:<&� �(�M>�%t�}.�a�%�Y�!fraȘl se�&G w �d*�^ ti!%�(�#�Q-�mg vi:�?nw�E�onQ. &t:-R��B>xA'=k-) �>�yE�b��sby= vh%�K6��u�Nha� |���1V{ �eijb�CMZm8c6�D�7 �m1\�D"y*�k ��ra��o[d.KL"Fa�Q��i AbA�A8�at�!a���%copeϪ�Gbx$r !��0ZU%U�Si/��te:�5a�G�i\&� . A�J�,A��!�8 Is.%(f%pre>u*O.`E+18i��-j�� do"m�b�k��Raaj!Stools�0n`��Q{2��.�&F"�0O��  �1-;i��._ "RreQ�� –[�m�?�l�O�|>jg�w2G��aci��%pecaje*s~m�����F!r��K ��K-%�QQi �D&Ob���a .��%�ea>(� P;�b "�R\�&&?;A!��2X3�� \2traThor�%A&�:*�D� %2�i�%@a6PZup�hr�in�9�n. DGKt"�*hav!�F-�ly �SQ!�sC�!�u 6�)W�aj~�*�)��2J���s#Hi�-5]B�a?!Q�<�9Ya?Dm>� �I��c� �7T �� �f!}��*�n��n&;�e=�[5.eA9PE�a����d� �l2�&',iم��c� of!�o�*�JhTll kjq���L�� "*�� . � e=A�N�:2�)�� ]�R ��� �r�K;%�� �j��< ,�� e kiƏ�7aHy.�"��3]�8)��>{�3!�sM^ Dez�f�� 2� �_b� urnt�!�f�ub"t��am�$2�2par�2�*>�)�v&�ly h��L�"bN�>��>j6�/A"�r0 dy�4*U!*��~!�a�< އ �:� ���=F�� �)er1���!��<�u)=�  in wh~.�_�Ӂ�N�A�ŗ�L��in�6 2�?force6y*n.�` �fA�ngYF��u�c6��� �nce��e�d l9{k eri3od9Qcor�>�A%�&�!tkinT��J.�-i�' auth�co+�]�a@j�!cqe`*��rt� ��su�b�� �&x���\� ->�(�"�G�*: �"��O7 blo�R>1!�����f:��� W�!��FN��is�}tb�/;V�m?<�� V�l �  ]9k"�%ch�>�or2�Z caygadd��C"�a�l�$�y�P�4tiu �t�-�v}J"�$E �#��!Z�I!b�"X(O_&u0mal:C�gXі|Á� A+��ϓz�|�f �3t!�a"�Kd!��-=�AnntI)aVaNep self-o2V�5�m)�st dra�c�A�4 �=�\X6Q� q����\Q�Boncomi�L �a�� ulk 9�-��0�(^.B!m��!�@&f_A�}�;un��K~�F:�B�eZ��A�*:!�) � �E��41 "�..x� .)<M=U�{<3�16Vu&q��)��(1��6�iR��2M-�mHm(9P#@�1! ���2�k BF�>�)G�%--e�tS.` � z@��|+ c�Qj�ά>ά Ie�� e�;2n�t1^.�N�F~(�%F�C>�)�Z �Pw"%!kB �rO>� buff>""0�� f"�Zer�,�H�~?q� ���PK%r6��&B��!-D ��Af`!VQ@9��> ,u*�funda%S��uQ�;"B . 9�&M6Fka_2� �"-�7�ficB��j& �9)�Cn� moleT�a�%��e.�b/�!� -��Ii B�ZdZ2+ �&6�&C Fy B��} U-ar�#� Mx1-YFP�L��exhib�a � "�5� �8 Promy=y�leukemia%�\���"�Gb�.X��I:%g�Y ��� Y2EF�w%J�TB�!c�" &����sshXa!�!{��X��.�o&�Ra9�/*�A�n�Ŧ-vb"��Y�G!� ~Z���st�$�: stayc %� Ii e�"{�� �� k��>A�R��)y�ha��܊# a֩< of 7'��8�D&� "|*�[-�A<��.{ ��t /�(LV� 48�eS�)Z�Q�^�] ( 512*128_)�ry>��b-^q�Y\"�Y c00 c: 6FE�e� a Z-�P!`�^nm�iv��[� loo�cat�jA a��3*"Vfil�}�pT'&>�( noise��U=>U>!�U��Z���*�=Gng��Q \��6)�9pR�780� GaAsPTectora�)�U�66!o���� c܍e*&`)�256 <h�V0:�� . L�.o]B���g~-�E��8E��byM�!� +P2�!�>A�512 I� YzUT��, �2\ecUX0��,of9��-�eXscW�z�a�v�1� softw��(�cro�0on_s.e�� ma��XV9&� to&ra1� k!{Tgrn"f�|?�./�� �@ii�)�he�&� �<a�1��uKt:�m�EnR��L4D%s!J�)��9 1.P{"�!�shift8�!�fRX2 .:r��._N��X�E�V&YJ��v�8bia� ,  �-sae�ng** �, �Di���46���������aa�2f�]Bitplan�>Im�=ZA Gauss��V���.�M�ir��!E�S A�f]�!8�XE !=-�a�“�� JZ“]��.pCAd.� a-CA� >othJL"9�6�HKolmogorov-Smirnov H (6D��4csbsjuW,du/stats/KS-4. �2�r_� . html�dwh��=�jve Log-12�pZ�9 �dev�~�and��isti�*4t ��! log v7�LI!Z_ u0� e p- ,R .coeH&ka webn>>Ydaniels A .A6%Tm/ 44 . aspxE�Nױi� *! "g E��"�W�6 a*A�2۬2D�>�"a) _�A��Y, 3 0sN;q"� !� 6h v�. �� �|� ,�!�&��mo~*�;��F� . BD>�@Z| �6�>1k�!d!8)w. A�a�!�):/_ 5�51�� 2���I !�M+^�� kR!8� >���ƅ�� kV%�a��)Ji�w �!��A����B�.�wS��c*'��1t� �A!q1��y��u�Ar�no]�r�t��Z7method%�� �CnW>���$ $ultra-deep���R? tudy� �� loaBa�X~q,�ly. premly- �mgK. M"!{Azy��ASan2<el" ��oof-ro–�r�� �@DmR�( �or v) �10-� s-l)Kp]� * �� �i�'ldt�kdingA�.,5"=p%dERd��A- trun4#:��E�/�4�in��d1�uVM4de�d B cir8��3nC��� � xtre��low�6�1inK�^�a�c):-�drw A'UQ� heno%]. S�U�M3 �hJ�E&=&a:��1���MP-Y>�i#wB��qher;�� *6TN!�E2�5 germ!�v nsm.�cW��n*һ�"eve6���=��+�C57Bl/6NI��5MbA+agA;t8 ques!!=?��rol�� �i�L ad E��6��dU �' rans���%lEGw2yiN�j +8H-Iy�%�����. oxid �da�x��j� �?�Eq . Ou�5�8%� l�X�{%� I\�9s��i�A0�m c<���err�+�y���esDi� ����E!dulF�fe . 0cE?� itochondr*�u?�&�"�#F=he�)�m"C>ti?!a�A���z�Pe�!w�-��in* Hф[1�5�H9,f�car�-Osa4p&�B!�6����) ���)��>es��! subun#��*i���.�#re�: omplI�*��rRN?�� nee'��u6�E���. E2I#[�_�u��*��Y� phosphory O~2 ZqZ~"�s�'�>�'q!UU "�Ves:UEM�)�[3%��A.I��f�� rear�AA�ibe=��"ư fI*�:Rq_N'�0[t���c expa':a�eA�fJ by hum)�}v/^c3uG�$bQ���ear)%skeleW'mus��! �V�(�(e��. P2oM�ninser��1��(���+)�9f5�ii�`%% �"%�Ψpr�����rodU2[`<4'AS"�X9*�eacs��=J�#1��3K ��Iis unkn�RX �6E(u  PolgAmut/ u�4!> -1�R @ D257�q!�� ��&��[upc�>��� ��5� � �syndr��5&;."�Ő!a��� jp!�h� ��ig.2�E�'��I��S*[! A& *!�>.") a�abA*nh∼25�@Hto!: \��  )Rg"�7�!;'" �-� Fz4&n ��wnQ 6*�m�� ����aj[u7�de�" n�Mh"_�a��j �Q���� *�):�>� !E)f�B(:[KF�Q�c>�@>H ]h�&On�'E� claix7�;"��a&*�&��, �L}#�? ,�,ari��,cwr�kN�&  �S2w[16iL��&"F�&���!��%ref�byu#� \Hs%�25"Y���:,}]�%. !��8�21) F%biochem��VK �YbeeyI)Y8ݡhe��zu`����syn��i�Fu"i with ab�Hundant amino acid replacements , which , in turn , cause instability of the respiratory chain complexes [15] . Oxidative damage has for more than 50 years been proposed as a central mechanism in aging , but the supporting evidence is mainly correlative . Interestingly , the mtDNA mutator mice have no or minor increase in levels!�reactive oxygen species ( ROS ) production and oxidat0d) d!ADte a severe declin!m - phosphory�on capac!�T. This finding refutes%�(popular not3�of a vicious cycle whereby somatic mtDNA muta2X(that furthe=W:\x[12] , [14] . Genome-wide estimd of intra-� vidum variQ� are neede�determ!b!�$importanceM:!#types>�in I0. Recent stud!�us!�(next-genera! sequencofcPhuman mitochondrial g�< have identifiedA(mall numberAsi!^e�i�normal 9,s carry bothp wild� copy A� a high-fr �yE��1L ) [13�N9��A� uneq�0F� curv�$us lik!�reflec��he�+se�1se�>�with a�rg�le��A8F1l��?int !�aޡ��d a�bmedian�Mq!a�def�BMd>q wA�� l[UaAX9 ( SNV )g� >0 . 5% .Ns re� 6-asamb"� u��� in>�nd-b�NA�, argu�Z t9U� load inher� �ir!�mon mY r_ isvu� �m�39 �.\)9J��in�Ye[a� only halfA�P valu� I])2< (observed nou�cŶ�.f!�.Go� k����agJ mV84mV:�h �a�;protei!T� genE� tRNA Ar��q^�!�A�� M�2%m59–66%� � �� �(iprefer�� ) majoqn-c � 2 or D-loop)9q;�\4�\A partic��- !�Q:�,}c+��block��CSB )� ad� 0almost 80% re���~A!2a6� 2���) �la modestZ$( 34–42%&? )p6� �:�of}�c �+e� :�e-Q�qGor6'>-"9 �al� truma�� uv *� AF *��is� ource��% dur��z ,�M%x: is expect��&|%�y���svers!��A�aH emplI� he G/CA�T/A2:3uI '�adA ( 8-oxo-guan:[��m��iA:s �!5ra� s di��t change�a fun��g��any�� , imply!=��)V$polymerase�%( �6 He�.�5=6|a)I S2e��:Nn�]%i���o&"re�v.`%-M�� �%�-� a>{exc]F�= se �� s��e aga�=�M� as m� egibu� G Ged �AQpattern��order,�6(��at%�co�Cto li<� A�we��E�h.��%�!�sh} (among offspeV( �!�z�)y�by  ng=�usM`-�:a5EWA]und*�800���ll&) within-.%��'40-2} . A2Z85"�:A�  6�� Gc�� animalx�i-se 1-a$56–59%% 6��� 4( n = 44-4aV~-�.$..F ter� ngly��p���� indepen4-�sa$a substantc���:6R-�3!�, sugg ��[occurr%%0ional hotspot�!>]&� !�eN:� e:z om���riR100U � times�er�m� tha� aYE+!�Ac=&�s����$al neighbo��,�not ne��ariGdja,���%y1,2�� S� . Seve�0 twel6-d��]isv�5�JD����& & �e�s�� prev� �escribedz"mo,�i��eri�SE�femal[[[2�SS'>�J� H��/25 6] ? j:�may pla t rol�!,l �� ��dis e�r �7hAlthough!=�� util�$paired-end� �� , it� stillA9��to�ct!Y uctuA�re-arF"�s.as�l�aF2.LSplitSeek method [28�� s$��*� read�" alig��e��pa��ly�!G' �!"� � fo�@��8ls�F�"=.> 4u'��%���� m 6 . 6�mor!�de���!`��2–1�^;��q� �MQ ɩ��%S� bo�f! d!�vola%�� 1 kb��. Fou���l2Qa�r��]��-v)��AezEi� a*te���k � �Q֑L�Za� ɭf2� +da]"gt )G!� [�ran�� dist� � acroqis�m� cluste of��!gE��arE� 8�C1�M�� %B10�n"�0 S%� �I॓"��% set-�oft��*� D� to mono.tretch+h.zE=�M �F� i��9verm�" Y�A�es�iCab �&k)�E�E50se data demon�t� atA�6� !�t� e�up� PolgAW"iA* �F e��)� /o lackqBI� n� expl"D�*s��B�ʉB9O6 o� Adult homţ-�i� predi�encode �7.�!� ituA�� PL�o.�2:3I�i M��1#J19���y�.wm�a&K"6� z���sT] �im��6O"""duea [�zz aމ�s:9!6�"u` ultsa^'"�� �up���Rcon�E�lť"&�syndr�vin1���is�accumuo�6l ��)�A�V}#bd�-@6T 5<. �w�$as reveale�& novel a�"t� �>� ��0ara �  � � 3ᤡ� ly��� atM��F�,!� sist�w3 � AU%�R"–R"Y"6* 1 930 eN��6� �of �!�&AP��e�� �61L%�w��A�g "� by S<r.�of<$d PCR frag�%.�Q a r&�"< a"� 6�"|=t&N!,, He et al .z "  t�q%�a��T cy >6%A<a#�$�f%ppJ 6"�-threshol�: �`,1"�c  � ebA͙�. T�iqu�"��en  C8of �3�� chA�those Ain�����Eto un� *%N�!a>pr�� ��te�dA�� 6�q�E�e "%#z�g�!/� criaa��"��graQ%"� .�Y�%�n<"al ��2�ublishedu�.�E��9�� tzeK!in~�!How3')�nei� =����!�Id6(|v0E���Y&atGt� �3 "�Wnor �"�'hif v��Z[>!&qd(caN& �CE��\M�t� ��#ge%ew�t��s����>kA��v rep"�  %A�IX>��%%R doesd %I'pro.9�. ��2h.@I�M�%�~� %�,in good agreI�U6$ d on.��D# theyh�P].��p� �� enzyme di>on- �assay �w( summare�inH 6E� AlsoI�"% no2�Q#5&%"%e�a���lse [1���A % e nj �LQtcei.re�`-�liter�e E!�j)i� �a!"�Dnt5( |inmف�extrem�">'&�1� Im�po �� � a sl5#��A�m�)EwGa�9N!5E��ek���-LA��tru.�u(}be be�&����m��'��-. . Bu�c� ci�� ls[&-�ix�&� �jj ison�����ge-mavd�i&� Y�c�to��mze 5�_"l�v�is tiss!*ade5�AvKom\ sufficiA!qu�t!v of p�'�s5 dire/�*A8,%�@#Q�t'i��. A��tinuou� divi�r ��� �!�� .D 1!2:� �>� w]d��a){ !t���- ��G raA|r,&rt��h�_�$c.��� %���� !D| �$ol -V� chat�-q)Ay%� crucM%e� > # rollA8r��e�� crip%B�[31< It�� erefxA2� a&�&Waa�hibitM��tentr�{res�q,go�se�'!��b��-5&R()%poo� S��V.w's2���Fl�l�a&v��e��X$via��4 rbgam� �irN>M��ԅ1�w��.:7%wicY&��]�>w("�%�!>z�#; �0��*G'n*�I�!$>��R7C" 'pBW9n&/��)K�>�"I+�2�.�, � ,a�]�����A���e}�1�Z)]&�Q�uph�0no�P.����2 t"~&�wa��ŭb�zM9"�� cytoplaI4st�2of9,m��2�,o�al�oEJ,:�%, iJ�sE#non�,[ ng&C,>-�>�6�+It�.bem t� )�|���D.�1ө��Z%� Mn6#o�cn >g.p.ul�3 deep�m �we�z��3#>p�&͘OJ!\y-�� a8 varyY glob"'4:� \�A�4�J.: ��*P*�"pP$?�!j�N!P OriL ��)�r�h�chKe� �g&X4-�:�s^&� ` � ��>�a&2��"l� d� iv� {-).��!t�>��-s�zN�$Z0�P`B�Hphysi�2z2�A�nce)zB9,�H%��#�<�>�-n)��m�f, *3i�cl�/�worth�%&�6vg �. Cira�rS�e��!�IMfa�oa��BA� forc`'� �]��  ))xl� ys i��za U� X. High*f i�c��l�`B2�6dys"�"�pat� s [32]�%pe$1ee�\*1 ��ŀ[33�F H.���!.��!,' e� ly�6V�,)�o�4 breakE���!�� )j� mill��xRaPw�gor�V�%� ). ypEE9� UP*!�V "��9|s66�t8��7[1G!�8�$�&p$j� Lete�.Oj�1�!n� ac hear,J�[�. L2 "� !�kno$R)� ��1of�4aF *v-[3�|>�)�st� e�IF�]!.�Y���b%N=faca:�����e7�E`!ӡ���a)���rk�)?���� 6��Y�%_&ng��!%rl�:a�{-�A4rupF�i..<fuB[36{5%Rof�Z�>W%��!Iwo B�*�6�.�͸?!��;*�b���1.econd� ���fg . Any+;�� �A5��"��t%#&��.W=)(.� i��2�.�Z�&��� ;%K�,I�E6�#A {2�� #*�?"0igM,q4-R s:�subunitl aCA��0experi�!I�Ÿ��A , [3'T !�.��y tole)$�:� �EEu�4 comb�5effec�>� n/eJP��8 �&T F(#P A���)�s ^ �,>r!�O:,>adZ0a(�>G@"W � �`>� .�  J�=�1G#�n{A�# ! welfafethic�m/�performEK)Iie�u(Swedish lawe#Dree C57Bl/6N males �N"a"� �A�'s~ �  colon�Two�q%� e \W1 \,?>�1ai2'!$�e�9g ^2�0�a"Z$/�$wa�ter�e�s,)�-�%��@bs�7JT$ . M�l � isolL0(ar� tocol? Brief� wh�*s z�$gen?A[ ice-col�4"~1EGell debr�@ elle�cby�7speed �, rifu� ( 600 � 4°Ci�eA�n�D���sup�. AZ T6x!.d .}:sat 50u�T10�A�C susp/d6K%�5Cby>P��~:0M/� 5M<(-phisu!�e"�  1�2�flyY44in 1% sarkosyl�pur"�4organic�UFop foll�� alta� cipiEY J repa�,)N�edRN�1UyrG�io�2�. �| E�aI=g y��}�i�BglII|�A-.3�AI�!�L (FIX II/Xho 5Gig�Fk III GA� Pack� k��( Strata��E\A� p�exp�?.�La� !`ta�d phag)V !��9qYSr�9librar@%�)�e� 1 µ�39�-S%�? manu� urer'�� stru3k �Ca/ Emul� -�#��Raccor� !I�R then���D5sl=?!,[�=50*�.. lengt-J)�an��3?�systemM�I.%1J.��MMJ� )/JD.4( NC_005089 . �(, �FcoronA�|Dapp�(algorithm (�3�Bio �s )i* defa�)set �F��first 49�� g �1$ �p�p[en"�B�3;voiM7a� fail[/�fZ .z�"zEA(�;a�$I�JQ'te"�G{SNV' "�e�Dt� alid "P3q��nUC�.2�%!F}� �3u���-j wQ�sum9�a��72�yAk "56M�-Wvi�+de:�I�)�R ]i<�''B}w�3be�-�JA؁eJ2�bT �ntTCN!.J3\ ext�d% yEǩ�i"�Eto�E! 2�&1":�U�e$�"�ga"�/��I�l �3a�Grro �5/ra�7!�*�.,>�as�-=6 abov�2rA- vA1)�%heB�3r2���m�#!�.�a�2NwJ� subt &n"zH .F�!l�M"Dg�ach5�N i��#s*�11C"�er%La�� ��;��.� ��v$C)set2zero Q8�)2+�:� �"5F)�VZ�6���5inSan6lya���A��eD�%�;�w!�'E�e]alsa܁�c%orphism|at)�incorpo�d�A.�D.bE . Si��=��4inguish.�;� so�@er.�w�Otakm !e�D�LA/k ]�he PrY�1u sig�| (u .�AW.M9@I;E�CQd!.�rW�(�> � p�H�>�>>l�n")1fz;ɀwR�2. All[ɪin�FE�� aN�@i6�%�?E�se ^d group� �S&�KH �� ‘synony!�’ ,a&3�or stop�%on, JA��!&�!ms �Em/F:��29V {RT�=�'DUm!���>��(�g�K%$!Ao+��~�f%�em�6r"d9�!�"q*i]R"�Rof"�#%� #h "r . If�h���ire�u !�+ ris6� few 1�ANeg*a�yhtoZ6�LA����)��$:�����>b�KJ�>t�at#/!a�By �A9!x�est� *w�"focusQfZ<iy2.�B �E�F&q:��"�d2�&����r��5U� �m]R�QA&�z !�lSlig�:��J� %�!.� prograwun �EIE61�9�L&*= tegy2,=aS�O� d|+ojVj�E ` $in RNA-seq�/��itE��ZA 8As<�79,%�V�-: �A��1aV�$AB WT pipe:!` ( http://solidsoftwaretoU8com/gf/project/�) ome/1a 4A�ta��sT>� ��of���0.�"�a"#1:��>A9�Wz%�%JApu ,9�Y&We �si�� EAv�7#8�8east 5�ɟ�qu�Va�Z�� �ba�Ayon jOA?�R*� pu��7�A�*yC��� �, ri/ ( ri+rcO� 7Zor�8 ri�!�@MI �As �B le rc9>�%ag- Q ��n"�iniF<-Ga�A�"!. Mn .B%����8'T-�"� �b=>�9�2��R� T&Bh6)� ��!7�Q.8y!�adp windows>EY�# )�Ag�aCmo�d� � �� �" D,A=�",���6&w�� GS �Yc� � 90tha�m!�� .� M�� I�W?#)�way� �-#]0B�6�F��-�]�nz8�E!]%ur��m�!%u�߅`)�!{b2z[[t�s�0-�L= 1C�B�"�s: `12B�Dp"):&�32*H �cut-off�����=� SNVsA��z�߁fi�A��0:Z&QN-�ne�v%+�YME( i . p vrO|of %C005�  5%�YU�-, OrO j� :�U�Q�AWAn1� d. PjD _RY exist!Aar-d:l pseud�7NucMt [3EI�c^se  C'n1:���i� oughA* �i�r -s;&�"� is�$[3�)�A4"H6f!s��K b)�� :��.amoun�=-3&,|� �a+b�bu�L2�G-K�0b&{8Mx�� ��a@ �Ue�.Bg%"$s��W" L�a� �. AssumaaMioA;90∶10"�64�.�X��V�a at g�+ ��F ×109%����e 98��^%�YF*��! �*�(��xl`r�>100M�&!>I���Ņ:CA�e ��� )�]�:85� rA� ly 4%��� #� �,�C�B4B�� %Dpe�/��-�. D]�ee�+M�cA{hiE�B"�4 4e crysX� ur"m c11 -�s�Lby X-ray5l�ph% 2� 6 Åo olI!�t pH 5f_&8 . 7 ,%�%iv�9.%]I�ccu gll >0�coV!( byF0r*�G �wat ;i / I��}]E~���(�Z.8te��yQ� h&�)7BFKis�]if 2�I?on!��H�Sab�� � ��PA~am2� eq�m"�k��5� t�7SHynew,,�UY+n2y �.9baa>� drug-de�A�xhQ��o�I unis=�� . Sy�ofn�V� pro�int ��o�ab*S4el�hta^ly1�I�h:?�����resid%�E�@�P a , :�a�chlor�8t�d`�catalyz-�>l�DPA�aF�po2�>�F<rocheme��E�&� �O�� �kEH+�A1(!Yt>� [PMF�3sodium6I[S:��$ጵM�� i!�Bwo sub-�� xes:%ae�-�z F1 sec�/[�BIl-kh�r� W;!QA>�er�,!�!�1���Fl m,�@ m�s!'��lo$8.�P��e5se"�+*A�nct:� mg� yi;e%���<�:�C� -Ke�je(�-ph� talk_5�J*5II�F)j%2,�Ito 150l�2. cM�,mb�i�'oQo�(��[;4)"���alQ�x %4�m�(.0M�%.щ1�| l'of�dA�>�typ-B�hQc-�� ��r l��on [6\6��`Aacy0�&"�+Ajxylic qjq , us�."? ;*�=i=@�%R}�oup"�ide-ch�3A�backb���d*ea��e/&"[�L11]���3� �e.-o�J�2� a�aD� 1�O)+�2 9�i�T8i�3� hydr^ -bonf networklpoi vA�wh�H+:��s�er ��= mai�7+1eph� moie?D. E��wa�K!=�ct��� =��5�u���A>A{.%�Hp&r%Mc��NAs���=;3,stoichiometro:H-����at� fY �H,"�� oum72�"3��s�aKO.�F >� � cha{e�H�&,,cUALM�j� �~�=F .*� G(Gram-"��n��%Ag�,��jpu2eriodon� �Y�6_ grow�)��a� y��!�p��� n#"�7%67Y�d ,� ferIvm*)ԅ5 conyl-CoA.yY=�uu�'�� ��je�Z�SMF.�cy&At��[4Q1�3C�*H-�%-Sv"x 6J��� a5��:-~ >. s�L! at:SX[e�Hly��il� &�W6,�R V*OE6 5*��'"�"�als�_��E�uH  � > ���-��^���X)y1� g ���1is��3Y�h�mi�2�ng fe�K,�Cb�B &� w;�j qHi��qun�.}Bi�3nceiv� A��7����gld�*&assuma�a-Iw�It>���B�� qGonf� a���o�.g�or� '#ismA%�}[1���%�unkC<w!�Y�6����%.of:�. CFM"? �w/�]A-�V��� in��qEH602-Q5] ) ;y(y\"�*4�L-W>.es%��:�K Ys5�,�"o�eY�s�9q!��Ha�re� A^x A�o clarif�u? �S ^'"�!�6_F�oe��� AM%Ha$Q�� icro*,,"� ,�eo9uter-s"��,��class� 1�L I�6. To �ft�NhGZ6�.��.��AY�I �Ck 6�,!Y ��r ynam�7�Ay1q]� 1�E�!� pEqIly_�taricus���&�i![�W�X~ ���� g11y�!x�han!>25 aE�e�pai�("o06  Each!9d�%� �s���< �id[V , naF& Glu3� Glu6� �R C-m � elih�<�5*a�V !�BNeڕ�� m[Nb[*QF\łb &� �� !�-�A<�!* �� � Na+-rs' i�i��lausi����za�-l%�2Is��0!�25��J�G�a2�[�to�*�[�E&)'A�1� �s��0luihVTD%all-atom2��a�a-i�!lipid"Ta�lk[N��"e"�j} �@_�s2^ .� e�" �s!f�^( ;A�% ��% ed (�ci! )sep!C%m�1I;3C !�)y)��2�~\�>�U�y- I0B0 � I ..&-_�, excep�!N2LE5��-ac��i��m�&�"C & �!�E[��. ofc6b k�g Ser6'z=��%"�exny%� Val6�Z���� acFb�#Thr67abRwr!��to �"��Im m "�E �zac!To�t�FJ#C�;�]dMby Tyr72c �E���AM}Q�B6�2b�U~ �hA�:&iNM�gٍE{de�M`)� ime towar� E��mJ�ihA!v!a!�� � (�ch swiU<   ))��Vl3Qdab(penta��2b!&�Fs� ��CAR{ �1NC%N`I�])A�$i�� �%P�& 1HL 6��@�a� iceab &sTn9M�y6��I_�Z�I,��3!��E�le/65A�diRGc�Yu�*!��he-�:�reo1l�TIidNwh )IA\E�GM prob� wAMB�5�zSerget Li{Efer"_�)��M Hart3 FockN 2"�2�x!���2#*� >��^�x favorN�by ! 10 kcal/mETT�V`iQ� �Ea�-i � !�t w�be $k�[)5H�&�Cf�&A0)�&nd�@:�2��g' Ay�arr�)c$a.g!�!�pKa �E��.�7m>�K)' jI FAEAJ y Perturb�G( FEP )���!���%,a'�y�2�� arkedly �^ed up���J� � nsicH6 jY���T�)-1edMv��;-";,�-X�KA(� �6� ��,-e6�u2�FP�e �P&gg&-�>� ��9Lq�A;*1�f�.�����Uo!Ft�s�C.�!@�_H+M��!� "�)�׽U1A)�u.p%+Y���&-a2F�!N��Oe9W2NBecSMR��*~ H+r� Ja1ɱ] � ogou�&e�.�m�  = )qwoxi�%�TJ�p H�#M�to ex�A�e"�!!�U!V6�2�S an�j�; PMFAB-���N�rB�I �2�IH65Ǒ��&e��lyu� s 3A&�� ��Xal2 �}��l&3 ej��y�1*y62�!u:�)�.^.� 3B�2m�6e.�$�e:��~�JM<b�s:�*�\D> �H.�?%Օ���!I��I�id�R�o>�I�^ on2rQal> {.}J2�;>?"!��A��5.X����V�Vll*�Ap�At2]E�b�.e� ӀI/e=�ATIwB9\a% pump� ��P7>� 6���M7�w�*�"� beg�2��:t6f.�>#E _6tes���)�Sari�)�� M)N A�2e***o�z��wth�cS�v . Gr�h�b&# 6y"� cyan�m-�&henyl$azAU( CCC� , �4-d-ro(ol ( DN �3 ,'�� ,�w5-tetra \$salicylani�J ( TCe�>;!�u+# �� Lts !Aed!hm :�T8(o>p. M�+Q }uval5(�%&�+,%*��e?& th9y!�6. Amilor!6�t ��!5!��.g1mAl5- ( N-ethyl-N-isopropyl ) aI( EIP, b���+ hann�tqNa+/H+ =F�r'� ��omp��VQ!$ �ofB�q"� p� �JV� N′-di��ohexylEO diim!( DCCD�UM�ed�-�r�]ylt�h7) :TBT-C! zn�Qgn���mM�X�x�Ct25mTatJ�v6�+*##)?� !g� 0row-bŃ&V#s s�Wd�Z<th(0"�\ �dZ"�| 2,!q �O7!5�us�?�:!�4��j�F�E+sY"V6-2���set]u[�iZ .)��,)civE�Qx vesicl�46z!�"#7Q�epl�9"(0 i>`se��-�s�802��815�)/mg!5�C���T�PF{zed/min��exqra# �.�+��aop�0�C����.5]�6��isu� ���[l�<wbyi| ( un�b� El�p� c���R� e�xy.�"1P� �n2�(�p� !&c&v�5#be�n�iu!Li-~�w% `%e*�1�!��,��m�]���I6N6p6��e�1&h F{�a< �X��� a�inomycin��#{K+u�A���j.*79a.D*ad�-�!� *Xm�!�:�M��D>�4.xT�vE4;@J�{s!ed Jz"nF�oF|W,+xty�!55yA�,.�*achie9E a 38� ���"i&�1lv�!�ed SDS-g�GMALDI�4 2rϓSFll�O?"J �)�"� ���Y\7e�d uč�;e�)!��Zle+ day.�!8�ʘa��KmD Mg2dr ���64 mME�25���G-�8B–S8NCaCl2mAmrq� MgC$%-��u(��"�#� �.��c _R�.�cornerst� < DE� !�.�.:�$APa`^��ի@6e���*L=a�(�^Li+�@�;QL ��m��2�`�� qj, [��Bۛz�ro�EWap-�m�6 .�5�s 4��W\-K+"A �gla0'A � >�� (L �<y?axa��t%'emoO$:�UE4A���a�zu �!EF �,��j'}-Y)�-k�%�(�!s-�x>. nnerlS9e�&� ����2HE�d ( 400 µME 50a@U" !7� a'KA5��M4 �� �A(5)�! 81�|:ad� U4)�er!ZvDP��*Y}A�fac��at �mo�B 81"�"!�A��K%jih�KU�dqo"���!=M�`�j��N�f�7�62 Nu�paD*�]oex���sBX�Escn chia�^i DK8# �* y�6�5 bridJ�(EL�0F1-ab2)�:#a � �E6�. Fr|#p c�4w�=oR&d.J�mig�<i ∼51 kDa�an�yQac��� gel�Nis�":�&4c-Jmm�up�Gricho�6ac����a�t�\ /Y�S10e|A�d�Sma>"'E��i�1AXtrM1u8S1��To��s%v*AbA�=�i� expo9��rgent�6�d-�'N-&�-�di�VylX,o ) -α-naph�_ &$ NCD-��flu�i�u�m"� A2A��� &>;K !\"�B"iE�]k�)� A�6w)��%�c�p 65�gQ0Mim�$lyI"}�E81xNaCAi/o(inued linea�,v's�^s ng)+�VA:�d+�1�[]����� ���at-��es� -t"�,m�f���'��A'5M Y/�v~�$2�>� H+"N l��Xt�vm���k%�a�(b,*W"a� �f$&zB6�#��vin Bt�Q)&� �N�]���3>�q��R or��a�log]~!�� or [l�*�/�o �iioWE%�A��a�r8nt��aA���.��-�� ed )-��p�wf+�8to UVȟW�<�ca�=[y fs>i�Iu�,o�&�)S13%.M���� 4 beco&�*��/���L*Te*@�2�!�!66�2t �,�?+P)icc�5I��X-N@"H1EgJ"P@ I=n��3%� )o*s yiel�"��!�tei@2i@a��"�I�*<�1,Y asym�7ic�A�< .�tt1f�Lik�I��:��*�6Z"�7}by�.\-E0�aNML�.�2b=�&"}α-�.ce&nn�r&�r� op!ׅi�%fa�T c*F6�1w];oN-%�C��ini G|PT�M!neO9i�wA5ph.)�e1�@wat�( �:+ar7�a��"!Sphi�;�a�sh��Ygis 68A"�o�18A�o2] dia�zr�y*YB, R5EtՀ)���IM��is �K�U��ts middl�n∼40��i"'XwNpLF�ѫ%Zshape���= 9 hourg�2-6<]O ��]�pp�E# tendI�Tyr80Ser55�8!(�91�!�>8��R�" �Wa�lim�m�dsurE� �.M� l–��hBd � �8sEa__B���1� \Y cfac��}!js w0-�B.�)oa ��]6��7%�i�p�-YY1, A�ly; �.�0)um!D >� 4��j��iscer# �.�Tn���,�9)��'��Gbe���BL1��S�(in viv�^Acc�/gAJmF�  �5 � I eMB�K�,� Lpoi @orm�IA� e"s3i�a�ly�T)&ʂ3toɉ eno5Px3ro���*�z$�/����mM��͗l+�>R)�+ -6� F�9 (?N�J %]�+�m�N�3yn&�H}a&�Vn omit�-d ��f5����*Jfveals��>^�5�)|���ex�w`�=�.�lose-up L �"�5�9m@Ԇ*�@Y6 ou�.� �%�c)E�)W�8B; T1z�rc� �4:m }#�q � ��,:F�O&M7�A��AYe�&i� ;5ݎI5a � :3J)���<"�+� "� ���6Glu�&�q"�6(6��_���1!&30a,�LE&�3!?E$>xyl u�^�P�"3���:y$3�BA��E��∼�J7�awf Q* 1�iS9�6�>� )!p2� ��0�)!JA:,a�� U"�.�+qp� desc���Wue"� .a#*���,�66:OγVal63:O �`")9u\!} �V��d.X94:OH =e�act ��asɟge)�d3or��k!��so-�0�on- !�hF�2%daH*�G,��u�ba :W2��a�!�� :6�U*E�I�,�55RAla64:O�&F2{cp�M��u�stc~� inflj�"f *z&�VHqu���4��-��!/.c��&�Mi5aZu$in NaOH-ti�o��u4aMpH�MH ?!+_lat aU>�M.Pr���g�a��kZ�2�& ���t��;z$%�abA�H�/�"�/u=8�A� �Am�d��%b!�h�D,[100/.IA "+M��s"� O~(ME�Fbelr�!f w�HƑR��.+/�Ar��e�. �*M��-ש� m fl�-�^% �sh_!� �! a>;I˸M��1� H+r�5�*�(6� �Z�rai(EaAil�w �<9co-� aAucr"z�e��>"��J�is� 6C$)at&*Rin:�is�� E�e�(� �#�&r�v�K{P52�F�{��ɝQ��C>�� cv��65��cK?2aH%<5w6[;O�Ca�. �$::C�,� s 22/3�@��11/�"��a�?  )��!�a�re+*�W �E1�n�r�+Y�s��u� i?Ŏ$�"![���-.EN2M�U/.)"l-*�B�0� A{*+W�u�{-aR�J� �I'�=%i'6r�I�1[2�`7]�dhav� ��-!� 5AU~&� to�l�v�C r�?i^n u!?Y6�vo��!�un�~[�>d.� A� t�[w"$�g"�W�ds a�K��e�.a!9�iQ lie��a��T#Кngaޫ��� argFz1B�Ma��fo�U:5nx�9���, c��rh�ro���vp=}�l���@�yon�4u��!H+�61%"�� �� ��1 �!5tsCm�K�P<� W��3 �hom!32�R5,� d[!>'��+n �d?k��-sqB���]!�z �m�latF.R)l2Qe]�tA*�3�2�Po�ide�:}�4!�He��A;*FA"ru WeZn��Nu���p.�:u�7:76e/_m��w�A e 2BM/u:�&��c&�2`��is��al�5��0dq;=z:���Ce>��n.]1&@�p�KvC2un%��}�R �k���2!�Uk�t!:�3�ete�"YJ�DB alaK���k�u{XI_�-"�BEl�v��E a�l�'&�+,K�4�fIe?N \on upipAO��#+3 coli"� (nmNi;Ks88&�aG ,"�T��-��Ac+<1!�(�� MwsH ��,5NaE-7��I��|�z !k�h���2�pH(er�Nڕ�6�+,sy/.�� =�<*c,u�10� � }��� � &l��1&S�E��+"�WF�>�t2�)no�3v9G6~N %N96�,+*+")V!r�"=)��'AT.�. Spe!E�we �2 �iazA�"[ �:J(1%,� pHa o of 6.dBe�10M(�A�X^�'U>��wp3c� ]��'*j �.GAW"\.,�Z�@Q�io�%+G �K�A�B�b B>�)QZ.�'M,��#G!,&�%5�b )q6�is�*�&j2-"�,u�,H"�0�{.' E��&U�i�y=:� z��;Ti%Iasu�_y"��C o� !:�]!� ! �� 6�-E{ l�qth! ^mVZ�th�dBu� !�o. 5��J�! 1"�UwuN^ . We"�l�6'���O� 2�!q� � �F O� 6"AJz��`,�.a� mHHvJ7�U %"�k&| "ain"� ��11J�2� a\ ����@&,� �yZ� �*�P��/_"�:�(�E#.�ApeioP!G#�P>5cip> �e)jEv*�Uf>8�!*�,regar59mPs�AX�z}A�"�g-�-�� &�SA�6� 2�P�W :PMFN_=I�p1,Q�iK7E�a!��&TVe�`iw)%?B�1i~lu����*�.�( Asp2�&f ?.> =�(V 4 must�!��J!� r Y�u��� &�[as!�:`� �wild-e�-��6��l9 nTd�gH+)؅ !�[�i1�n�!�Al�by!��=.��in2! pH. ��)�kIC��A8 �2�@ ��u1-B�sa��g� �gM\tw6UOQF�B�Tc�hu �.�9)B!�z.2�6�of�\M�!"�5��za|�.�pH��7? 1&{�\e�5�y�,Vĸcof!� �&`�w��terpr�}�6�|��%]W{�,A�MGr��a"8-�G1�o��ll� !8I�2�z!��a�5�m�,1%c �1.� Z� a g1��&�e[ch.� ly dBA��eninA�As"k �B+?%�A�iJ� �">BY�aq�-� �*bflFj�d!?oqg] e�� >!{�L%�(5M=W e�A!zJ�FY�&Z��5m)2Ś4T Iu 6�*& h6 "L  �)�%|��p.�B ��e�V -�m�e~_m*� or� % ,p �f"��b "2� M�6E��"!&Y � �4. A0P ruct��&�fO��J���!B3#beA7i'�ex�� M�<a*D~�=Jjoue^�x .�2r �z L-j��*(,����&�U�6" ��^v�^K ! ����I�]�"�=e�J e���ao,�tg .Aon:�*l� � N( B3D,�^6 � >�Gdafa��6�Dit�#�&be�"/D�H+tt!�e1�t pNtE*�D" oG��;���!n-��!�!5�*�&� ��M-;6Brr� �$�"M1�" A�c�W��I*qi equivA��  4 �i��  �2\(sgMpq:8cga�*o O�J�����HZ�`� �JeJ �&.�in���3G$pneumoniae&Z�M�Vube'�o��&qG a� O  �Ry%�e�.�Da�TH�(a�&�3��,ly�GofMT!�� ��Ig�� er��gz+` �6r 2~a archaeon(anosarcina 4�RnecN�) �A����tlso��di� �`�I@6� � N5y� � Vb%�%�.�2�6y� Y�9�须BD�b�[!.*�R @ǜ!\6C�a� f�(Fu0t!S&$AR2�ep �raH)�i�;ed�A=*��!6]�!&�R�-�,%���3�*. P:�.�e�!gq2�+FM���pr"�ҽ�� -:a�.� �mak���ke&x2�NA��e�BtK�A��A H�`$�!s%�6w,����l��rA �"�Vo tr*�p. !fQ� �&"J�?>s����&!&11"50�' airp@aNa�"�e:�(, P .siu, A . wo�6 , C�Maradoxum�34�k�znow:!i�qa�+ m� tadse�[�ha)<�Jyh wm�&'v*�!��&�Ks9re!YKabuu�(*�mar��se�7ntl���͊usP %�SMFaWZ�EY a�4l&'�v onshipj,-hem��5+eeg$���!!�L� ;,&M%v� A\>�� gl�Be-:6;B�`m{&6 6Y"�� ��a�o�*"'F � &ReQm�jA_7�~t��b%���b�o&� KnIB 11-m��i�?uv2r� a24��iSʹ�ll%E q��}u.l�1:�N� � #ri3` �ry?�� $ ��.�� mpatm���� �2�#n V!?�[4i8C"N�$s��e-p�  "� Q �l�e"�,;:>t!�sY4.r$�i-doenecessa����%����lFur�J A:al�#�}� �)�qE �"B<� ����}papyA 6_E��7�fˉ�,uaget [4DQOf.�^ "4hbG�" ��2~ -����(diarylquinop;= a �u�JAfbi��qou��)stC�-���"" β s [4�n4y�Ei}inB!�or^2�ner�ofF�)I'� bl++�i� a3 home=#n [44�#h=��G ^��s�|݉7 ategAK2Gi��_]y|� �{!vt" ��� #� � s � �>��ߥ:pO�s!Ab"�|#��npla��bi8�m%�nd? ssoc�ԙ�3o�nit�]s�p:���Rinc*}%45+&]�-UMM< D6�2ed�n� &��&�M5S,a1�.Fwl }- 3��28]�"�Tr4xJ3orE��eeGsU�e�ET1�k)p} . &}"i( M�N.w#��&E[2`���_aA�cBy  $e:E�"U]^2!5&��*�/2y�.�X4"B���^�@o0��ioy:��(1Q!e�9$2��&eme4�5.AMD�- 7 [4�(AbUho6=%0.�_Ŋ$Gaussian09�risch�J�8�0'& In�, Wal��ford CT�R00f%�� HF/6-31G*,9.��details�"T~JSP�6�bsi2&9� ATCC25586c�<�S8}�76�4in Columbia br(( DifcB.5>%cys�e-?*Q7>'�NQnd�t azurA1i*3�c�G�yH B�3C {%vroutin�' �� ��, N2/H2/CO2 (g� 5∶J-g\d Hun���ns��� l Schot-�t[8. �YN�Vo � �؜id-M?n� ���p |̓f� � a F�4ha ss�N (����psi-9��em��%�����e8 1g���"�Ot" �*RF���b�%�col�)�r=�o% � a�Om-� adj��Da��1"B�nC ?of 20�X0 mg/ma �qIz�%bG/Mi�duc< $6Zu� 2% ( w/v/g$decylmaltoj  , 10vglyce�C ��t���o�cka�aE"z�1 =S�����Q_"�#�>n�ex0Uge chr�"��ţ6� -�˒f�4�-�1t=�fil3ge�S�^�gel؋-� , de ��V�"��DS-PAG-�� fa�o�1>�i,s2�&4i�*YFE;(�N TOF/TOF M�W.�ᅄb;a)� �%d-�aRb  Xo?�HB -reg\T�/$�or"I �)�Pi t A�� �-loC|�$_f�{&0'd c6(( AO �f18]�{ŕ�5h�Zd"u7��#" �v�R:�G 2 �lucif��- a�J�=nit@|�ljem��� Rl �I�LB 12 ; Bert� � t 3Ş���b3+[49 �JA�6."��uVW6xKhy2K5H�eB�K [50]�����:)2? ( F1_K)eO.Z�i��.M[mS� �er]7Ih��c�����92�ElabF�e"zx�Sa��#l��4Q�l%�.FbnC�Dli�5 �Z�B�vap��ff�,�B��drops�}18�)/e � flasx�oz,� liqu�it�}��D�Yto/ ,C"��)�C84�;(WQ>���Z� ���2 C.)-(���&\ �06�f�a��GcohAau6V�vZ.{9@" :%�de��!8P�%� Bank"�,�J!(�s 3ZK��Z3ZKz^6$s�αβ T� re�p�IR )o�cUof�Neign pep[�s�y a��his�"5����xA�MHC )*;C����D��ntE8�-!�3 sa�2l2(#i"� adap�3u�DimmzZ1 In va` ,�$aff#� and/W-ng-#�f"�@�4)�.�pM!w kio�&_YT�4ra�I;���5iaԍf� �22n�<�/���Q�t"� aZ)�8�.E��t9Bgo�*Jpx%5Ń1$��g�9r�/�cer off-�6afaE;OY�R�`�(a��f���&p��5B=�!o&��K�n�� �)$�r�i�.h+T{[11] ~o�hu�jfe��1�B��M�N�aobDs��|�`��eR 1(U��E�a�a���!aUD( K}� �����C<�\: w@.!u!� ( k�kZA"0( >105 M−1s} ���F5<, o.NN"C d �?E`2�k�o��:;�K36s[�A K$�o( 0� arge �ipf[�2WBeAt.tq�or�#lib��!� ,�Lg /�t�����u(A%�&� ZA5au �nY"F,Atm� ki��(s�nou�/Z(Iv�'�Iut?�� � hel���&"/Y ��3�Ea�� 0�5D�,|Xs���vN� [2I�ItœriG?)�d�`�ow2(=~!!CRa"� 6� rP>0urse of an in�y vivo CD4+ T cell response , especially given that the goal of many vaccine strategies is to elicit strong , persistent T 2ms/�pathogens and tumors . The importancev.�help in �8ation protocols�8underscored by � suboptima�s � %minCD85epitopesm�\cases [18] . We examinedceffect�TCR lig�,potency uponGb|$s using ad�0vely transfer�5C . C7-�s activa �immuniz) xwith lipopolysaccharide ( LPS )%itmoth cytochrome c ( MCC ) pept., or relc �s� vary��of !� itro ��!�L[19]–[23] , includ>onejinitiEq,identified aAZ,superagonist � for%w.�-re%e 2B4%�[24!�This sI�yA�ul!<0in fully func� al differ�)Pof-�or)<emory ��(d allowed uE�evaluate�influenI�J$on multiplaMage%fA�F�whichA�,not possibleM75�methods%o a systemIfew!� iabla~a�is!�evanta�.fi^e designQ�$In contras1predi%:s from�� hierarchy!EIEU9a�commonlya�!� sump!��y more 3J@re!� x,longer-lived!h(/pMHC interAons durA|5XcogA{0on , we obser>an a��+�vUڵ(i�e middle��avidity �B4trum . A recen�ud%._OE60Listeria monoA�gen��xpres�,various OT-1�-R s [25] shE�$a good core��between /)Ncy�i�1�ma!ud�5*�1 , i . e .�natural>�< SIINFEKL exhibiao!&mosA�t!9[�D� vo .Anour s1>.�E%�were A�AЭ� a�Q�st��er Rytha)�еr�͡#,( 88–103 )�^,�� blun��.X to t��m � �ssoci�m��attenu��a�alA�,��lifer  }�� at seve!�pointU��>�, rathe�Ga�mcreaseddeath�N�mAM�clo�*exhaus�se� ults }�0an upper limi��=X�M,��could e�D���Z,against delea,a �`ammat����9�to-�vstimul.@highligh�6zconside�5���of or*2 [11] . W�ed2�:genic P��?r Yza����Aݍء�ex��mouse �P\class II molecule I-Ek [��%e��4)�� e/@M�1�Z ]oP. Amino acid substituAr�'�2��i��panel� }s)�bip o �equ�w 2butA߁� a rang��|�of9~e>2 �^. @. Surface plasmon�on� $( SPR ) wa S A�1Okinetic�!_��~pur8 .�w ,immobilized �\complexes ( Figure 1 ) . A�Ks plotpre� unit8RUH fterE� inje%102S/E,( 14 . 3 µM)) , K3 . �KF%MCC�&�,K5�).%Z�C�all f�]:%67 . 1�d� �c are%,�<5?B3C�]L t� �!&d!� curv%��2D�Dcol� symbolsA��fitHto a 1∶1 LangmuirE��#model (VW4solid black lib)M calc� e ka�kD nsta�D���uM��ve half-��7KDA�A�TCN� ( T�IsAsF�A ,@on-��off-rat �&��}t%�Yw�too f� be accuGly measuS by%�)�$data indic� atY�y3hav�8s� r��RnU�.17� D �}!�94 near� wice!�� ( 6e7Hversus 3 . 4 s; see2?Q�r�!~�s��)?��"��aner� u}X( 9e � �N�D � E� jA��_kd/ka )�#ba^�eN$imilar ( 4�5!42%�E,Vp�m!�P whil%�t[�_.�165>)5�s�wern mericu?aff�yL 25°C:�To"W !j�I��he"� �V��� .�Ff� .�eY�UY0fetramey� to naïve.�p͐]$PE-labeled��Ls bear�oweak n��e`�� , [20,:'s!�%�K3�J� +2�WK5 [22%4Uasrcribed!*Ma� ajM�ټD ,2At5���# leftA6�.9y= horta>2x� 1� ( 33��,+ s� nt���ina�sty!��o "��~�A )���1�di ��at 37I�.�r� ���qEs �a�jr�2�&�6s~b5ia� �.u�,5I��BHU�CRvVHkdi��s��A6M4� ce b��_ndA�.�6bis gre�mt� �,)�G:s�al�>�n�� �ofA]�Qb�s6��/ �� those�l>V_:D �valA˭�� �йU," =e%7tagreem?1|a two"�whe?mp�l�vZ ɦo 5�v�Fu+S>O��ord@  prev,ly published��� ��6Althoughm SPR-1o���L�1�*oA�to%�:Q9is �sUly 1e]A �.��R5�st���uC��&b� lŸ,equilibrium 972�c.v de�b , ti0;�whe��.ds d�as"� appaH!Uanalysi= mS2B , s[27��� � >is!{>%�QNlyQer"�%w5n1Thlar �;��.�K�q��A�s� n WicI��p1�=� )q]sol�6Q�axI[eKCRG12�.b�pla�by ��r�ah"�duY%�$wo-dimensi�confin�  � ��h�0 membrane [28�30aTkdA�lik!�to�5E�I��terminqof �i�"]%ism [1kK &g� e sm� a�$� �EU&� y�(� ∼�M−1s;*I[13�Takoge��ahe�Q6, :P)�Q����I�%� MCC-@. C|>f�a8�  e� Fp�4 need^induce� �( flux!|��]� �:�K5"� iF %�t Q M� *$7iu a . N� >v�Rs�ed � splees pulA�W% !��<��aApr.7fassesDb corpoU4of 3H-thymidin;���B pproximatA�FtimV s much_ 5(~��=D, on acg� isF��$same amoun� 1^6�a�7e"�mU��(9&EC50 .1 �reflectDirUi >ac� _as6 �2� :� 6K35 seem M%eBbet� ��y!Ekw!ug_ 6@�H��zog+to>�&(� �!m�I* FY� lK3"'iT4d a heat capac chC��i�ЍI��of+ucQ rearz�k<� ribu^"�-A% e�cy��als?.*>o6GDCa`S�!a~�of B10 �m�~q�+:�M���2B–D� )D��A}at APe�w�}0�vo��i{ �t�.C .� ��;��Ibelow2 In�=G!��]number�S���MB�a���e18LPS reproducibl�� � expa�� ta�!�,Ama�n:���3!p�� Q$( 6–7 d �2�)9> �ese�upaK8%Y*��periph�bl � hE�!fon���� at 1%–2W <2]�73B%�WL we�Na�%�vo:�a��"�k!^�,NsawiiK3%h!�B�q�a CFSE di� ,)v9o)�-�J�t��2}�U91s 4�5e?�*#th���%A�e$cy urpriRly �fou a|�4–de z*�!2�C�"c"Wofn er:�e�n)V,t every phas |a;G%�R�� ��x"l delayed:���de��;v ��of K5-*w�$� ������1� 4�I�:)�!il�%lu"�a�ms��APC make)�vo:�>�� � icul{ex�5� homT �\of lymph node tissue priV#o f��met� �F� [32 acc�r �79]�5>�invs�K56Me��d�5}%q ofluorescT#n cryos�!of day 62e��N�a�or��5�S�L"S3fA/� a�im�# each lXAo:�qUax�,amorph softw� �):�CD �+BC� eA�". in�5a� by di�"ngeUtotal PE� 9<� } �vidual:rU ( � by >220� CD19�th!�6Psa~* S31V��-J��!:J6�2^�+�Bui�� eO< .>�� mm2!��!y.>�6�>Fappear�L1: a��"%�!��� l�0*A �d2[^A� lessUR.�A.� A^t�in�i�� � �#quantiaon%F.�!�. U�(ex[ rE��1of�f)9&F�,F2"�  an}!�� m�s��ɘ�V4leukin-2 ( IL-v!feron-γFN )9��!C. For����a�r>��;�-� ngB������w- �; �%ver ,n���� �*v�o�j7�,%��ů!g�!or&q$Z2is diS+��!ddi%�to!�li"�$��u�izB&ccW� T�,to���E*�as& �1�-� n 8ste14�nZ� assaI ����)mF�- i�!j�!`� ��,��e^ G��of��",N� �!�>] is 60% req/���m1"�5""�UA &F%�"ch*#J%�is* a-�2�%milieu ,"�at-I@ a ke�di�%��-a� �t!�No �!i�%h�+ca_9!� � evel>canonica2� mark� sѡ725� D62LM; CD44V ��,*� J� :81�F&u�. Howm��T perU*a�$�\ng�'B� �ly" 1 ] �(y7"-�,lo phenotype�5��, }z�.�I�n&A�?-��2� �5��&� ��5X#ɯthp(5;ma�A�5'fP !���2( TEM�)33�5]�� ( a&o*� i�+�.,LDiscusA��!�:� � gene��(B E�>�5,�s�re!��$>!i*��J� marY�5qS5� a�a.�"precurs��req�. y [3HS rY�eY2e:�*J5�� $�%ƩP81VG��F�![z� � �s���2D(er-!� ba�c!Y:�!�,�B,ouXyU���|"r Uai*f5]�U��$��XVe �Fvo E�,� �B!����du��of�}.�+pop^� �-�skw���0ed biochem�c� ' }-5| �. e�WJ-ϑ�& rof-?&�.�>"-( A wild-�� p!� . Si- end&� � b8/�toQ$w�Z?�+N&�-a#�[3��B4�^�� B�&u ! U^�k�2�(%�ai� X+�n4� Seven� ��}��d;:=` �der5+g "�)�( <c1�:.;�S6�A[eti�BtseA���efW2un��&�explaR6!�A9&� �6J�t�U�Q�. AlsoA�M<p�'Ac[ A�� was!� * d�vat-��"_ m�*�o����un:!!�We add^2,�De�ial�� gen!��$b#�r�+ngA�:Lat��7"]�.f)<"�&q�qE� S7�I�is!�er�t!Z��xP![+��� 'D7WY0�/aedou;&`���e��!��U*�k9�s1; Q.��86o  week�8�t[ nb0E�4�5*)�Y�$o�*�' beca�/-��y/a�-AY�1!�Q���ora�t�<recJ"�Thd �^�7v-���uAY irra� Fpl�0_iso\8��i �P��� tq ����%!�M"� �7x��qbUl"�"�ue�/k-�%�Z�afe92e O%��3.!v� a�&06� 4Ak� �2� .dem�-G ��at� �� ����186�M� Trana3>~doe��tf�p m^exu�.@�^T� 0��i� ���'�<)E4%Q| �*�S9-}i�i,� s&K&7;hi"ve� 9~6d�V�A)absq��[4 @In sum����#� .�N,,�e�!Tuds"�H@ disp�z6�g%��� �)� � K59�*� )d!�aNA�� dosa)r� % �( ��}st�0��](� :N L1orQ�) .��q��B�b�^�we fur inv@g�!�&��.�6�Io� no�mofJ�<{2� � - 6�PD-*D6�o�.} apopto:��6�d!��"�.�I� "� I�B@ 6@>� derapidg6Fq� �zbs��kh=d [45]�A�Nnq!AC� & #&�?by:� �R�5*4!Z.R�+*i>��&�7v��2� abor0ly �>-Y*;. Our�  p B�to6��sx*% ql. CTLA-4![a|<-*n)ed negb ՚A� w ��v� ha�5e��)Mk&!g&�!JLC�hA�0�ss5[4�&�RM�in.=�by�involWC�Q� ���`;��x10( E!4 .E�J . P` .��nu�0pŒprepa�+� o ;@ ins.5��I�>,ar mechanismi�� ��h���g &w�fixed2�imm�AoKsaci)ce�'0 h 2�)��#A�1M.@m^��ql hosphata�a� ory�)��  ���6�� s S1�!S1�3� $e SH2-doma��ftyrosF- r��>HP-;i[ ou|Aoe icip7�yfeedba�<oop)�� ��~ iq�jcr~�[4m�?we"} � �N5� "*eiʼn ��K%N5=ERK�,fEZ� ��!�.� dd��![E�! "�,�� At�&�Ddi2��<%c ��Gi���b��5 low-"&2�(c non- /ant �.B~[4&K2� de�Ci�0 �plipid2+ PTENaO����;e PI3%AK(TLway [49�&i�q�J)�r1yStrikin )�!,mr–ft�u�6�S473-:9Akt ( pJ �"y�H�5�"e/ki�[53J�Stat3V Xo aX;.��7�Jcyt�"s [51]96xi�m�r�"�ݡ��Is�!�� �,� 5�6��k&�*o ^��zw0"p�4M"�8!�v72�_+%��^st���1�]�d�1�x�) ellu�kE��.�6* J�2a�M{V%�+.$,� K5-��n� pn�5vS13%!�Bfg,� "�LJ%�*� reve�! cl'7 a�;!���/nE��6 '��2Za6\�$. :�L>a�~L!�er&� CR2�, ha w�,A� *�:��U.�17 stud'O�]�oF�F� \-��!Qa&M$��&*�FgAu �o4e^B^Oynd*q!+I#?� �" d��7� &RP)� �.�!P/�K4~=.f7tr�to^��*�K5 j�� !��>"z8 of�!��s�)Xr���#*�B� �N~5c2Z/1.��H�;e&�b�/\� Z. G�9�5��er C$Q5�E&��F�>K can� rtJ�at%fav�3�#d� opm7A^1hom� A%i�. s [3kBt]�*"��!A(*� �>t# "s�)=/exi���05B� Bi",H5B �6! b�26caccele�d TCM2��M�impai=>if�9�*�!�!)�he� Y"�deV�g)̵� �I"� >�!�)~1�iI=�� �Q��cj05���=�6���s`� r2p �@it�un ANit ~%=��02�3��"�*��9,�!`.�pr�%}�� A -�FJd6 :T95x�.MiS4 ,V,=�/"oA�&� eg �6K)�"0�'�ss$i:`��4ŭ~%c! �6�J o�2ca��*avail*�pd_NX�,�e� � orHo~E*?�Ɂ>y>�v �]��doi�� %Z&�e%*CQTv A�6�thM&f��2ns -6�>�� !e.?l�h�Ni�\ .or �ib�$recep��C��te^�.`IN Q .- !>�R.��!61SC  *�a��AK�we}A5r� u�3Gbod�)�gU� . Fk?nl Fm 2+pL�|.Ntiv�,m�Rli�T�B�"8rapamycin ( mTO8P-�smC2A�.+i�;e��x�|�� �-�vJ1J+*�a� pAn�2mgi�Jo5�s�-� e�� �AR� :QWqs.YW Ka�!e.  �]cy&�1*�+&E(-}^M� �E .W� st&: k( ��![V�W $"'W65�*N9�<robustv�W@ �$sG;9�JU���� t�`c*�X!�be"dweI�Dt&�L:� .:��U�� xcee >�thresho�Yt-0 h.�RG��< temp� oFo����"�]q fac`%���%�is hypQ�,:  *,unsuccessful= farA�MeM �Aō�.�&$ �voAbUV>A��nA�is�Sq��1*B��2 � adju�[�^a�iV>� .^͕NZ� piger9*A ( P8^roteinE�i�%�a_\by Malherbe et al . [52]I�se auth� *,2 � � �� depo � �s�� toll-� �ţ4��9�!="^2� ofeA"�PCC&~I�R� 1�l QYoL rWCE{eB�6,�2� CDR3 ��2[5�Eakll^p�II �H"�B�B.L�(�.�AM A$B��yA�Nin>.� �*a..h*� ) w�)cki)5Q6���. i�harJ���t�I�� � K�QTCRs �%�N0�� �� he*qu�0rK*`)RW,,� i�C�).  |���Hre&�`in*�\�2"F[^�,beyond��I�6o*�� ͅ�k�mh 1a%M2J&O9%mtZ�1vZ�hD repertoir�(�BO&D(u�s ���A�*�K� �z� � t�`M�f� 2I�(TLR��6se=��+:V F��u5��engag�E'(@6:�o"�^a�j�\31s�d.f>[#S �%��akQ�JX)��bC �a�bM�#g =,!2Z��perfoA#B���Ae�\en>v��a,% �I&?P5�.� �k�iore abov�L5];��"�Q�Ui�!��b�6d[�� a"N*"fA�F� "$D!6wr-&8 m�q� _%=}>�;-1��:` b�0i&�$}.<�J{;;M@ :�6W �7atzt�J�82�D�*[5c%�� "X su�P#$igR� E��!�|^ 32nte���ne� ari�Q"�4�� AA� [55]eap�*���N`!u95�Y*� �� �!A� :Y�S:�xoro26I�50Dt�gA�Za�9Mz�$downstreamF% &�d< q2�;la�&|%*3!%���]a�x��5str�?jqnD7 W��op�2��� �Y��D�� ^.�M�:�2��:a,��sM}Q*a�`f|-DC$ac� �ca�lF<�qQ�r~a�[56�!�>/0�ha�:er�=by� ��.�limSeo a"=o!�:�Y�6�w*���Ps`�4"Uw�*�,&4��t$  �!s4!��he:V(,-�)�#c6�f.�'2er� �]f2byIa[v>Un AGA ��[57�/2�'%6��++�degradi>M(as�ar F8]��&� y�Q$�}��+.�N!�g(.a�}$Zg'(V�5��� 2�) -b� �?�;�#d&%!�E�of � }D2���jn{*b iY=�!"�W>�a rol�W-A| B��A�~m�A�2s1re� �.��.>�.or%�& ,-+$%<by&�e�-L�s��-"�h-,m A�-Ji[f�&i�x�med� ��U�W�2p�� s�p�%A�Q��dcJ� 91fl�%�� &KQ( ���.2sa.fof�%selE��9�l���)� �š�AG�lB yef��g�<�9d9M�p�-�O"�aB0i-e)Fɨ�k$k6h= �ġ2B� GY x@ a6 W aB\0�$�F��+l�q��!!� �:�0*� E�z6�C8 best 1 free�Cviv?�� &)Ji s -���B&c/���(�vE�v� Yi�z` un�"V:�)�����7!BaA�cw�&-�5�+6�Q�p� X$"�$�'epaAb>7#��voaXR�j�.L, a�)t!���� ��&��crac�3q��V�:A� Y1,z%!9N<cciMs�8BRkI� maximum2�.EBengine�>M wa}U�deP,I All`3��*�) micro�:�a�q!�� Hv .�^NIH # he A�[ an A�!l of L��A�t����O. E��l "� �a�Xve�lM�r�=Sloan-KrW�Ce4 r Ce�^ In"ykal2~�Use Comm�h4Co`reg��Tl.�α:βA�i�P�z��PCRa�� mod�j�`- O"F>vec!hpACGP67A�haen*�( plac��&iX� t rameI c-ju[α{- c-Fo -(β ) hetero4]r motif�IB$cch�lin��C-�\uM�6XH�ag th a 3C5Lt�o-�rv��sit![�I�#�2IpinQ��Yiously*�X�u2x=!H�na�i�Ni-NTARlc�r,�'A7e:3C����!nd"."�lyon-exV/g��siz� clu%�{vatograph�IPCcon�Hmp�4,!�cuA��Kti�u co�o07$( 280 nm )a3cl83 ml⋅mg1⋅cm All $cd�iIzol�Z�!�d BIAJx 3000™!n��(Inc . �-P8Ybiotin_/ �� t.�mR��ept�n chipJaez � 250–500�m. F�C x-�bA9�r=oR%�10 mM - . BI3m.�!~m1k,in PBS , pH "m8 J�C005% �nEIP20J�A:9ng� [> .�ahS9fs&n)aDa�Ql8 30 µl/mi�!�9�+0gro�5 subtQ�w z1$-#5y� �x�- Cc��o. DU6.�mLV�mIFglobal0�( Bia'x��,BH0 r�m. T�3B aggr~,AG rtif��li�i�bu�n�dr�n 12 h l�.�A&hvq6:� step��.0��yr,RAG2−/−-�T purc�W#H Taco�r Farmi0b� to"�F U�.ro.=�"W4aul via ��NIAID�%��e6e�ng�K��sB;� e�?)8o� V � HG)fe'>�'!$ Male�recip��`XZ�] x�PnlNt�I&�at �[9 wuag�+Fj�RMid2Sj ssay�nj&t�o�eu�e&$_[�e. Brief?ZP&�E�bmsE@X(]j n*�C` �bNjbincub: wf5c( 5� g/mLZnA�at RT��A.�f��\2% NaN�Se*g_to�ior�,��!́w2D�"1�*J""�9� ?% ?^ iquou��rem� in 1��20 AX terv�7!CM6.A6- % PF7L�*b 1�0�IbaC�b2�Y�{AN�g�QpN1aB v~:�{M�͊u� -6!�5CC&72a`e�4n�)�*� T1ens(% _�as���H� o ScatY Tla�Z�K> �alwac�, �'6���CС�2c.el�!��[�r�6elhujd�~chamberI�5% C0�%<$te RPMI164�_�AlE�Qz10% FC�2�p glut�! , 100 Ua*p�Gill�nd��oO&, 9@2-mercaptoethanol�S�/eO susp!�w[�u9��.+ha�t��A�0RAG2-5� � ( routinF3<>90% Vα11+Vβ3+?:�9s+3 tripl� . 96-�. -bottom 86�N*�H8( 2 , 000 rad )��sp&wf!2A�/ x<d=s� �9. PBmfmonito!C).!3H-�yl2tf�vCi/�Z ]D9Ro�Yg�y-fiA8 filt�Tu�Tomtec2rmJ'%�b-* M�,Beta scintil-{ (�s Perkin-El�r�P�+mCsynm�!2HPLC-"|$( ≥95% )! Bio/��J (( LewisvillA�TX e\ LPS��EPInS� . FP�$�^y$�� BD LSRII�&+ �X;EBjo&�]$( Treestar�Ant��I����!u%N�BD *�, e�A�c�or�Legen_2U?o-,/7Erk-�Wy Alexa 647�ju0As �A; Signa�; Technolog��&:՚�9�S�9 Cruz�t.31u ×1042�� &? � �MQ.�P" �Ftail vK&+ ouIAEaw�%O�!���h�:/%�2q�=1 A9�w.X�on"/A��he�Sa  �}*�He*x  �CFS& F�N2v*vb!s"�  L filA.u[599'�_.h�pooFKuVQ.�. C�9ZM4~.e-�-V!�P4!� h)d1��M!�D 6za� ]����BDAYm��agenz.�U����N<��xAfo4 T> b5In�_�M;Y�"�?TeF�embedE",E�OCT%*frozen- dry  @!C��x. AsH�*o�storaT t −80°�;E�m�[!���cu�#ZA�ֆ  (�'� �502�) �a Leic�yo�:��!w� �9-� -Y/.Q-PE�+�#5ّ�AJb -FITe@Tb msark Bem�aT �'G�( �c�� 10!��.-)i/s�? $a Mirax sl� ��epi2wd��~�4�55�BC&� aU%a� �Q!� � �of��indepen��2�i%Met>+d�,2�q�ElJ�c!Ve: M/f�aJ�b� enr4Z�> orig�ng)�NMZz:� ,�H�,M�"C%Q9�2� by Dy�"�se���(.tr/!�L"�72D�KFr ae�~ E�t@ie]k��o9�q�e>!u?&`2CD�5qPz&: permeaTzQ��'aJZFaL a.�e1c2�M5RbyB&�? �)0MP nyia� e�4� �_Hran�����2�,.t � &�rB�S, _I��12Y1�s&�q2�q�,&�q2�.�" !�!~-m�unu9Stua�'s t te�(_%�Prism&N .���;ascs et�M(fungus Nect�haecocca ,�^sex�en�Fu�&uUlan!�,�a�: q �p >50y)� know�A� “>J�)(lx” ."b�  �$@�1di�ePlog�[pro�+H&���`E�}c�Vdis�� >��i�YwDop1?un�Oc�"�iin6aVi!Qcur�X�et�9�}�&X�"a�B?�v�X%�, N .6�ma�*�. VI ( MPVI�J [x���,roe���q2'��!���!^1�tn\lo�c fi� btgs�? lo�g�3numm�yXo� �%Opt%� mapp�unA6  �.�� ��>172I�?�530 kb� �52 Mbe��S physv!�genT, 5�436i��~p"�)g�, 1�c707/ru-U�y!5A%�uuZ%Two��)e Spi#Ks60. auq:9va3+re�'�2�/w4a�i]��t clos�9^Wt� ,y�gr�arum;%Cmt"ly  !���l&>pi^�# �H���i&�E2B�E�. S!�e�/a�gal �:�jry�!p�� duu���� %%�#%yL5 acqu�>�horizon�Q�MgA�2�I7MZ�LM�,��M5��1A8��zrm"! ir""Rin �Z$field gel ��rophor 6.J  t!2m2�o�Ya-qy^�Zs �=�kx��-e�a�Q+J�64I/� I9a�eY6."A�b� �1atg,E1� B un^6!71�e!4i�%�a� er G++ ���8toe�%�2��Z*a�$ ����&aE)Xf�.��,#E@e"@u�a��.!���a0�!2@s2!pe� '��Eph��. Fura�%\ yi|?.-K� �j�mi�L"�yp]v�oUbhavATG t environ�al nichA a-�fP�YP��Ay%$rjJh�# phyl���hKr�*����l50�lu )-_-�a�^��[14-[;8M]�wA$F .U aA�lex%�G!.XEm!��ie�=Zae��aprobXUJ3A9:M�agrvs�Ao�8�i��U5,C/aa�`�%scrub�m_���$, savannah prair  wamplit l zoi� coasAand� erts�����0!�B��Y*� ��%^�A�*� 40E�r.� [QEv% "�4Y�X� &�&"� �a�$� 6� A�#* pke)"t�L A , [5]–[�NBa �iru�h��i�,�1��Ŭ� o�! Ajbi"� �bro�!we�<nd���[�11�Extrem��u�� �/�7e�7 �مungt>]�is�L  alU��&v�&�Q�*ly�io8!neruQM e damag}Tu}$�act�I4t Chernobyl [1e��ziE9DY�8of!�;peaerobic!-p� �soiN3v/Dto�F��m�8a��sOCna�b -xic �c �[1E�[15!i=*�.�I%�� gr��ca J$at Lascaux� r� w�K*%��3� /year-�>p�{ing$�6���a&� �X!��#dap�Zso �R�f��(ire~tic' sti�ZAv metabolicM�m �"n Q�e��%b�&t(�0(e hydrocarb�lHga|w�S9�,�)ni��l cyani��0pe��(e1�7e�2�L�a�N� ���e.���is�m>� ��  )� ofF� �mso| HwnN�[�0��'br���*�����b�x�ert��,4^anI�,�'e�� Sla.�1. Likem]� F�a� �!���inI�ն[T~Ab��� &=W�A��eTve.�d �,Asn�7�aK}$N�.��0 �!R*co�fG-.ens��fF (!�CD *= A?��-r�s&���yin 1991 �Ve [:{�.e�I3��j�U<�'+n> ����th5<�5s� :=n �p�adBag� D59Pq" \U�D*}f-�inZ�,-�oAa="� �.Zg ta@ kGl��O-b� , ut͖�*� � A ��E�n� sour%A��1ost&p �B�/3�<I!-ɬ"� "���2�+a�e�Pa ��.5 g�?%�s� \sq(XperhapsWF�K@ I &��d( HGTN!@�2Vr�om�slaєofl)�8ar�$�ic"n(VASA�1�� G2�.t��T�lJ�k��!��#&h\in��;C�Wtyp!�f 2� N%�Fp!wt?uriWA��.)�� a�!��oL�n� evۋ. v�V�� 77-13-4%"���� <gJ�2sJ��RB�*X�&i%!�a��G2is 15%"�Qt.O!���'� j�S.V-A�&@: Gibberella zeae��if\G��u|pg�k&�t)�&3it-6�q��Eeu%�length�� . 67 �*&�ex7 ( Ŗ0�f�/( 84 nt5Ak!M_ enco4UG ( 480 aa �|-jKW��}�)�9C9�893q OR�fa�y� V�w� t le�ee�=F77%6%26�295�%em[,^� EG� ?$I~in�218%?t9�e� R&�8@^����8�A?� �(  � �1A�.�� �=a�am` |9,%!�eTst!�er "=��řN ate]b��zy/�, oxido5{a9 ɫ.+^oxyge�[ di��S!y�"*1 whyZ�)-R�9 =�I�o�x�6s�� ! �]� wI�$ #ote��Zn:�}%f<�Te. YY� c(B�H, Aspergillus oryza�%2+nidul@$, Coccidio� �4�&Chaetoml�!�kA>(=�ۥ�)X�� u ar� uenU%��{to.S�A�vXoa. 6�I5% �>�>� �, 28 . 5>{�M�.�id�4�p�@5�m", �� ;Q���.�.!2`� -|!outW&>�!���:1A�to2�� �c 1786�e-,�w��oE�M�( 811+Mje.6~�)Iin3#ategory ��Mm� each.u . W�J�Jp��3"� { majo%( >q��5g[ �?s�$Msw(10;�� in�6%�!�52!=�u0_)�"!�ly1�" vF��G&�"� r�3F� �6 lr���t �MAwnLV�>-�. 7[8E)61�)1�a=X72L�7�9! ab�3�\!�9y�m::) \� Q�it�F�>'Ie�m� Q�6�� s 1M(16D 57–�556�)�V�:vt��kJ����e"Av��an�+t�ms l�%�> ��{��&�:##��V]diw t* !�In}�� !;3%���7 AJ4�W3C{�B�7b21BlZ%%Ѝ�!o�z`,.eQ0. C5��_ �J�@d;*Y2�!2�!�H�r%bu(�A\IX!�pe�@J��( PEP " ) [4��MA�tA1505d s"u by 82)� (� )> ��g$t1��U�%��M�)�f%�]�W"� � s"�}�%G��ɍ5�E��by]�.iM�!W&� b��;��� �@.P �4.� � an effor�i&�o"H<��E#T�"� ,�bhy&WisŽcE3d�!���6�( ABC �� J,7bf� P450>� ,XS- zinc Rcri�f?- a`����sr�s Sa�Sa�Sa�S�97u��U&�x�"t")�M�.Ws:E=�si�$toZo��!��b�)�I�H � hF�ܲ~�"�"�&�� G�!a*�"�\2�EU�X4�te0p&/#("�Y: alogG &�"r�"i�lin�.&,�"!�"u�!.��ՠ,�A�pa o!c��>�  d�1V�*� ( of�%B&� �{) ;�Xh �q*y.�uW�;':�A #AH�N!Ze��T%�menϭ��E 3% }��~!ev�:� �YOR��Q Ē%�in 27M���Ey<��T��.��I��i.��%onsz?*� 5 fV��aM�of � ( Nh63546e>Nh7331 G��nTn orth�D!K .2�,( FGSG_07325F�LBcF|&rU�bU"� � .heS��,�"x*!M=eca�2TuC�"�QHW����"�r6�y1(Fl$>$I���#V�5kg)�. G� ��.�."�Xgru�!2�tl�N5,��l�BT% �2��:�eWI7�Q!�1).}\0,ed ‘pseudo�U ’ `|A 2AaA�v*�`�1L Dk��c��O o:� �2�U6LYjasA+ei��'�$�e%���(2\teh� I��r`l�f�5��F)��s ��&��,�^ers��b�,"?��Mlos�DDx>:b{-�%�^�-|�O.>!y��a�\"@ A�appD�2�!�,1��I��e�:v��Na��a6_T �e ��[{��,yO otnof+GQ�N�|5�2��S=z�M.'���aI3C �6-Mb 6' b��i��)�f� [%w�U �q�2|� �n� Om=hJ��A$0ifd1Y%:U!�.�_V�. Recip�!l BLASTp��$�*�K>cVS � ��a� ��  f 8 , 922-2 ɱE�"� � 5�8"g �bN � �Um�5 785~7eO�B‘{)� v�\�I�se6�)�>�rA��+Z ff�l | y� Bs�� a*+>�1�%�!�9gb��WGBapproacha� l'>A�rb��20�40% � )�)a 40-�.F�id�E�'t��۹�I?�a)pvn�9�8off�[�F� t �TA}�r�.�)he�1M�A"�Z:�AF�2�%�had mutt1sPh�*�Kg���>�-B���-pair-��?��ZomB�F.�z,2 CAX�al��"2K)� � �E:��12et;9$j 512^ i�F �+to>�? 160� !�2�&� ��sO�pNh10177F��s��< 6�&� �. ���U�,̪331b��m}a�"� 4H ItD C_b�1aR�Q�&� i�ai�8�.���%2�!AI!~t�- A+T �8Z/ed �Ntyp �n:�*�Gce�$/�.A,%�2`/�% 7 �.� �wit��� < �,�.H &� �vhy ;��z��C0�F�'�h2��fZ%�� %r��v 55 .I� us 553%�^! 2z(( P = <S2�A −1{�u�"��de � �3r�V]:Db)����9+�mNR�%�v�%��l }Z}# 21��Las*� �;�^}��>�ǙA2,. A 69)ue-<G��2���&y"���}�~B�M�C l�"�*&��4%ae�!�A�&����&#�=�r� �� ��B5�W!��ll�t41��w.�7-,n�,d}#� t5 ��8� b!se/g, GGG��TTy�By-f��*�v� aJj�)���� � m6� .'o%� J[ha��2,-9i"� ys! Z,�1�$, exemplif@e�:�{\6"�Lp AAAE�3XM924Mr <�2���'3O002R3qyIBl�^F+.���B���2���*AD bi�#re���AO" 2,.�6E�er})��_�DA<�$)�[!�& be mQ5(N�&\L7_U�1A�104�7�p�]��io<@,]\�F :�=�;+n9�1Ju�in"�9%X2 ��l`a"ra� lEW.2SA /)�B-3��HT��y�lso?�$��%�.�. P{�� :6P=sS"w!>�.5��(�]�7�.77�7��h�E�X��R3;!^BR:���e�S�U* TD&��`�w�:���'�&M& ��e�a�A �<� �T�3�_2�q*E��;�oC1c�f0[p�d DNA��y0 ��heZ � �T�a. OG.|!"/ 9 (01%� �5un�?5icaffol*�r�3 2%Q��)� 6Ji7un�=�"�gibu� A� v �=A�h� 5cc�=bR32"�t �!Ddespit���:A<��45 � y�S9�+ E+.��!�{"^3�F�g!��o2282%�>M�# ��a82�r���B��A K�poswz5 u� �>7#q"fewa ^!M�*b8� ���$]Ma�<�ty)�� >�8*�!+e� t-i�vh<� ( RIR5!|�bŴ&~/�&/�h����9X .)�� �aEe?g�[��./2E�aanRID �de*:v�( a pu�My��ni thyl%�ferB�%Y>UlyE��[�tI�2 �,"Ks C∶G��T∶A9=�!e7e�0T��*�F��!�TpA/ApTܺio!F:d�i� �PaX!SF$� (;o1�(7a6u�!�m���&�  .]$%�"B("# su*yU�. *&� ��.g| b�e�و��Ne"��!o��{^&��ha�k� �y MFi46-�� e"�O�2{b���z!�plJy��,�i �0��|e�*�!%�hygH,���Z( (.�I.�, hph�All�v Qsd+ %y.O/if%185��0�a �*�s �|+: M31 ![~1by�aI��aZtH8d eIyEs�;TpG�^9���6i*`uGat�� c�b�.2�� "�>MoEO�a֭�&�A`%/E�obE�%%;�I1!I95�f��>*%*�i�� R �v*e=�"�"�#2\g .[ ic‘]L�`!���>�`�yd( M�p&Q RNA�y�N‘que�92,aeb�( G��%ilenca:ͳuVF"@�*ڗ6�� y�rIK�[ masc-A�>4=!sol�0SD%e ;[n����i�e coboY0�[rH[]ri a*4 playI�l�1!Bm)\ 9byI �m�: MSUD�1xm��͊(-�(.,#VRYH)�&< �1VDEis��alL8 9ag ��m �#-�"-J7�/�� ` ����P!e d���!�wh-�sis 307)��b,"c �%� � 22@24861A�.1�Oj 0C�Bv.� i�H��eEl&��.�;m ��u!�)�h&0-.��2�<6���%�er�){.H(q76�66���27N�(!��P48�6>B7� a 37of2672�ԧ� �ix�.�1k5I@Er��g7�+Sq�2c�[. 9��#M s��QcF<.S�7@"�0fVS9�� �a%��� .�( 5� 7 ��N��l�K�!�V�aq"��l��rg��:�2&~ ��F! &�� in k{�sZ� *.S ..�4�!e.:�E 8P"j7qbroad �=�1 V�[$�6��xa~�at��E(.� ��nonrib;al"�W�\�7GR"'�polykeM 2#PKI߁zpi*�s>Ove:{ =i�"�mvi͌g#,!�on�N�<o�\)4� 9v�>6�.&��!�9��S� ��#cA :�"��/9ơ'L�Q NAaX��x2��M�A`� :�� en i}~4Fn��@p�=c)q�J�at�/+ |,�reA M� s [61J6�FVOC74�:.��e!6@3.`�@1�.��. fj.!�e��A��gst"] B1T�K� :9�)\�I6G�C&2?, =QU*�H]f�C,@%.�6Q�-�JU�JQo �E�A'!յ!s"��(25��k"�$k EN)�.L��N41��Y�0�gB*���ZJV�Ei� �a��0�map�+. 5A��M5Ws x�O#�":�r�$�%assige . On��!/J� ��!�z AK�`.� �`�DJ%'l(m�5�$56-30-6 [6#�T0�� rW��LaÇ&�Am�#t�19m� :�%ad� ver� ��ŭOEO&e>�VE.��<A~�eF0s �"U`sZpeVHUY �QrT-�GwB�� 7-� !�$s� o_}�^f�2��.�i�aV  "DPof>T w�an94�%�,�"ee� q>� C.�F"-� �:-54>)��G�����yV��)e�.� ndv %�!^��(a6a.lKiѵ�?oSpyI�-QKA geby6�!�is ye�4gstaS�.y)�&);J &7)�17 "4@ ��"26.Ga @�P�i!P� �bi$bm� Y4.c:%G� nutrvl�et�pJ��!*f$E@� �QB��g�-�IYali�G�J9ʩ�P ;2>.�� ���L>�'�kRC 6-Bx�a Rg-�4ۺHHZ� [6SN65?CEv���� u::� .� ��86�!d l��ter��a�$�/f ,�an�E+ ITI� � pa\7�]�6�din =�B �NICs7osE�^��>%b�*a��fu�s"�7�8 �9�tibVM�:(ga�A&V�[Cn/B�I�A6� b��EST �� 6krY�vV Y�� e��3�u+wgro�Kinq.�li 2�*�V�-�5 de�i ma &v�t1Kn R�$�Big�jA^�h�uni.J�o^6š�?:e�A2��normal�.3):m&� r����pXzr p�|t �%�.x 16�F 2)a�&}B�)a3b�ef%Q~� *� . ��*� ent�Z�� by�fy� �-ge �air E�.���o��" faia).����-sc|rseg����TY).� six u*�*of��5�]�)2�Y�� 1���2���woW�.*-�Ak�?*F��ne�6Z/0wP}�!@#�m m��-vh l��L ys+�b/�<ngz@ N2R[b�d�by %��"�p�/n�-�2I��the^!�[6�VIB�so&T y�6e[3ri�H}6� follU=�4hybrid���&pKc���;�- situI��/�!�.���U��� remna�a�'nA�>fl2��|te�M:"�66�v3�6*�� para�yc�*�{(eq�prv})���~MY&�>fKj{ACF �:��"eK�a'b�>��) vege� v@?[{:�.�*;.� �����7��a�M s [7�itM�F���to.�f ��ks؀� yCR�#*]tir� � 3&�Dag�[�*�B,��. Sԏn�QA "�1n��bm'mmon;!�princi0=it $h��nq�z�>�)j7�� 1o�B �i�M�j�F!�&�S����Z� e��@!l&u�'5���e�Q�2[Xe\-�L�+7�7�Sb�5�eb�H.��� mvV<��. U�`!8Q�]fea�12_A*-�ci� "#>*"�by�0)��#).�0"��0(IDt�np2��� �;AY6���SsZ�΀dZ[7 �F�8w�a�&;�4� "s:�[74) 7) &� A� a{. �5�pN_!7"�����pr��0%[77lV6��"C� fp-Z52�<"���R�A�vߍ��*-Dtax�Qa}ng� r9}]��)��ch���2��,���O�:��obfus���s�2+<or)T4.��tEM���9 f�!y*5 E�6�U�Nfum8�us�<����es-�A� of��� �s iyas 40 �� 2cN)�A ?�E^a2'G�O�^z e"�6D R� n� �FC� )9bW2�V�\k-*_f�,~?&a�Vroc� s$�AA�bhY6!'6�y *�� �&ea{ ���WW# )�at�aϩ��n  a�~<~ &jGN�I$, Fedorova&̛42]E�o� O >��2oof2^ar!wbye*. NS thel�{N*�V�FEcWhm�2�} Tq,&2 'bypas!�e&�(��ain��in ve.+ &9�_ag u�vh�q��t2!�6� �n^~�/���new+��s��� �� ! b�-����sub-telo{8}�6�In���E�[.��9�a�8��c2B�YB�� ��odl��[7� �"N�(%[%��smQ� &e:�2>1 , �,� 9��H��iZig# !�VNa �O�1-P�.mT� ^!.�-Q�LA��u�O�J6�7�� unus�<�,at it is a l�arge chromosome ( 3 . 0 Mb ) that has s`properties of the smaller@@s . For example ,(majority8genEn9� 7 are unique to N . haematococca MPVI ( Figure 9 ) . C�7 also��l� st numberyxpossible pseudoparalogs ( 159 )#all=9 r4r1��2@ soil!)a potat�8n PA [81] , [82ATI!�tes HT1]B-33 w�%derived �BG. , reA)(tively , af!?tA��!E> benomyl:selec��for�l��.ae 14 [35�4�BHab,molecular we� gXic DNA�� � � protoplas��f-�4 preA� d by�$of mycelia �aA�b�$lytic enzyA�,as describedR(viously [83!\Whole-�ras 6�1rE/�"wo�#t ways:ɜ�grownI�0rich medium ,Q�(dextrose br��`, ( PDB ) ( Difco , Spark��MD i��ץ�eseEG���, pisatin . Sa��B�4D(05 ml−1 )i/V8 agar� [85] �add��o 100 mls�in a 25 ) � clon!vectoapMCL200@%A!��C,primer� �w: 5′-AGGAAACAGCTATGACCA-3′ , Rv: #TGTTTTCCCAGTCACGACGTTGT () [87��024 , 793 ESTs)�N umA�������8 , 327am )�um^�HInitial read layout� ^w���o��assembly �converA�Tinto a Phred/Phrap/Con� pipelt [88]�, follow!Vman in' on�%~ ied1�e�finish9A�perform��re.�$lasmid sub!�i b�ylE�?B$or fo8sm�custom5�. All�rea� -��wA�(4∶1 BigDy� dGTP� �@ chemistry ( Appl� Biosystem�. Repeat" �e)�resol� � 0ansposon-hopp!(D �- ��e�� ^d%�)q� fillC gap!� | r ��*to exte�A"� e telom�regio!>h"�.�v |ʼn�1 rem E�1l"� .���is� jectFre}\u)as jo� a�valid( by align � aFu0optical map (�er<diges�7En NheI��92 . 26%�1� ( 72=2(or 47 , 19137 bp )-�ko!�17.��� 3 , 95�438B-mPs9�)� un `becaus�a� lackAsuffici �riek si� 55�!�i� 5�D49 , 575 base pair� IQ�S)-an !J� error !f� less�n 1 in� , 000�. PVI , m2 above ,ivdirecA�ly�-%�aAU� AO solu%�( M EDTA�  G 1 mgY � ein�K� 8�)Ashe� g to 65� A�30�n1 h�the� cub 0&� at 37:)�nH!�*� A�adjus� to ∼7000s�2 microli. OY���\s�46Ppubli tech&$9]; briefltrandoml ea� �B.�loa�E�]�� chip�r2�y�byi�$( New Engla�Biolab��fs�%�0YOYO-1 fluoro�)a�Inv} � a ���can�� n*�GescE)^scope �R%�ima�ap) ��alysi����naUM�[9hR��A�le--Ee2m���� to��ome-wide_tigs [9u92]aht ser��asH�6A��ơPa��Q� effo.� model� 15_ 07"D redi"'��hlrned!uJointT Institut!�JG�tA 3�P� . Several�e� ror+ua�on�3 mask�q�4: ab i� o FGENESH� homology-��d+ [93Z �wise [9�h{41%�verifp, cor���!V�53��142F�M��  9\-�ofun��a6hbyف'�Peia��!�, M.K�"�!ySje�sia�%�)o% �28 E7!Q!�( hit below Z reshof 1e-5%identi\��Ł�����hyp��M1���� ed �HClustalW 1 . 81 [98��*C  z e Gimm6V MacC�/08 [99]�+Xedi%�!5exclus��of �ambigu�led � . Heur!�cM �conz s� �opu-�hph!3eI&!��eEevI�pCWHyg1A�� �� ed ( 370a��5+s����u��is lin to��serLut� �p�typ� HUT )A�5 aw�pr��screea�V 8hygromycin sensA��!9O�Y yEeC�\�<�T^ d half (HUT+ ." "4T�<T/6 ,�370-4� 8" ^[3�SIHɩ!d��"��u� PCRU!��Hyg-F;�$CGGAGATTCG TCTGAAGAG�)<0R0#AC$CATCGGT /&q��fac� r'�o�"l (V =K"on��R ( 94�!�45 sec,930 72��5� r 35�!� A�ٙ�=242�pr�tsqYing9^S� � pGEM T-EZqF(= mega2�0, Madison , Wa A�%�21#)�X Hyg29�ACGiAA!�G�T5q)��a�aZY� �#�fd�QheL oGA� �TpB y C�( GATCWy'>UniversaR$of Arizona�$7Mit0riv{ jh�"b�#�&�,�u Ci:C HT-1$"�paX A*""%-Bda��b� PFGEi&�ess � �N��7eq� mi� #' � ���= mixa�$Garmaroodi%'Taga ^!���$il�"F@T Z�-�E}aCaB mark{�/�N�1A|��n�!."��0t estE�a��c%.� �o� endew/b*s� ���Yfsg#,���17A� �sm1<q;,q�.uD5%�desig�� mpli] of &"�&k�.�&P$.�:=2i�62%$� �e25�57B(.�,7 T90B,7�ase=~�bZ$!�*� �2� E � 1�!confir�a� � no!�-��s{ � !�`ofR e9��) �a�I.eEb�Es�aa7�s:u6O 24!war�$!� ,�5 C* !d')r�64TGG(G3 EC4;v�62^�Cx TC� CGGCAATGTRj�@CTTGGTTCACTCGCATA5F�A4Q0 25^�GAC: AAG!C Rj�ATC/GTC�p ^ 2�57b� GCCT� �T�j� ACCC� ;%Gb��5 7b CG LTGT^�A�  A�AAGCAG -��A�.�2�90fAG� MvTG WVV�� A�GA!� A ��  ha,$total voluɲ50 µla���~ 300 nM fo:I B�1A([ 50 n%#�wr�.,� M MgCl2 p 10×e�,b#µM (��. dATP , dT C!c�� 1�t TaqwP�,er'v �G� co�:��fs�al den�&� step��9&��  &� at.!� 54�&� 2�%elong}atF2.��s��run�aap 8%"= $ e!� ethi�( brom��visuax%um% UV l�&�?:�ə�7&' o�krolB��P&��o5HѰ itse��." valun1e-20&EAb259��ta�,st-bid�ional{�Se�Au{&��~�0asUV ��shM.at lea� &gG2�.saakr�&!yorP)�.; "�31�!�QD�e50�.d�Egrof newE� $erpesvirus3tic� �"�-cells\+0ly dynas procYinvolv� host�ret�1� wor�#inA�� � vi� mpon�1� eluc�!Sr D,|�!3m"V- mechanismN alpha��e)(, we develo a live-� V�ybhod�u�N)���exocyto��)�3rab> )f( PRV� a1ninUpolar�(epith�-l-|��is�is&���E1A�ref+!*2�( TIRF )&p�;i�.t6t ��nea� ey"(sma membranM!�tak�%dvantage�a D-encoFpH-"3A=bN 6U prec#mom\"Z5�!R-7.i . We* *le-* tracEzLmean squj dis�" je 2haracte!�5 mo%Z�]%0�7 pane-ADu�/�T#t*�t� spa�'a�ndQ�� sociw��i]O. B44�'�4at5in��I`�s�vel�a�d&=�ins��$�cidif�(seq�ves�(. Rab GTPas�' Rab6} Rab8�Rab11 ke�gul?'e�J-�q� o�),U7� �@ �B�e� �Ų go f�s,�#��y� ~le^sitE�=o��chanm���5e p�� LL5�V*!{A�X4� anchZ J#tub:)JK. V1u�<t�v�qocin N�Y 2se��!q�f]�6M���vir�7aM�saHV�.26!I6I&�5_�ou�a5 surfac!�U�rere�Z"[).bi�"EyF��$� ��co 3�a:m�=��eNon!al2+A:�ao%teg{&d%� link (ge/!)in�tel�YwM��=6ݻS5,0F���. PZZ; s/.�1 )A�a v`7inq1�A�ideb)salneuroa�*m%e�E&oo�*n � ��hum�$>ses vari! a-zos!�i� ( VZ�L � sii3 !�5K HSV-1 & -8. TC+rt<-J�B�]��:f&aZb�����^��ug9��%K i'capsiO�-�]packag!e nuclew:yP exit%oby budT#hrough inne%(ic/�3�X� ein [1R#. V� ��Ɓ�H�!�AJwa�%d�*�ݱV��Awenx �pV�� !�8-Golgi [2]–[47%;end�=k+�[6$[6� V:� acquir� irwes.3�t�=T, �!�x* �edA��6� raA�u���A�� �MӁ� t�)tr%'�5B��{�!i J!��2� НH. Woi� �&��2ofQa��is m�ac�2`&wspecific.�� �re� well stud7�� �� �� ��W� qd!��/�^&� 6� tF� �� >� ���sv!�>� � a6&^ .� prj h�7�=IJzj 2�W�& d�mov@ by�z ( MS�8� � foJ�1 s��BQ >bef��gaf�|�)4, a�p�*@tex?milli�� s im��� \$pHluorin d�h�B�N!m'Er!���*�s� �%yR !�K u}r9>i' $��6� r� e6"lg=.��a��.�A�>E3ve� -b%�n"E5a�bi�o�V�Wp recruit.�or+)��ac�<de?e�CefZ>or9E-� " !s!�� G tSCt�[*(The Elliott3Lippé$�%�s&�"siRNAs Ke2�ه�>K&Ze�+lx@�"a&0pu�veO] )l�/��(!GAP� [P>C;��H ��s3��)c3�AtHW – ER , �s,�dcy+)���R/0��.�� rep]~How�$E funda��al lim�=A�Nuch � �� B �n no e�'�S c�0keleton-deple/I c�.�[ry ,3�� e ��[1�0Y/�id obd0)!B�ev$�Z�l6���V�!��\s. . FiC/,&�<;-�A"��F�(fA�ng�jw]����N�To*��=��.DeZg�Df�superecl� c �r[1�( *_UGn> �L %F,,�t� ";-ZH�A&� loo�+ glyco�r � gM )A��Gte gM-�5 e wild-)gM �//!re{q-a�.;co� "uinH�Bec2A��E"9 �exA�p9d2���(VP26 ( mRFP[12, ���f486E� v2&� ly�o �36  ���%�� G �K l Wen blo�anti-gMp !� bodP)_�K2<baR"�tGI+TC?);' shif���9 bout�kD�P0��:W EPo"�K1%@ �l %��-i8()@6Lexhibi��2�Je�(rn�Q�1aK��Y bu�&p^��Zbet� t;-l130�!(nu� raia (L1gD.A�i�)I0to�an 8-paY�� !�%�R�Q��'N-%�C-K=i��A��F�3/i�&���F"�( [13M see s�=a�in��(uY�"e"� top&�M.YI}e�>immuno9�ce�** labe#Fof�shly-"}G6��� nataSL,�)A�]�yEDA`�� meab&.-(:�In%�483>g95%��@s!�E�.���}�%��&IF�dE�n MV � ��8i���]d &�1�!�-�<�-WvrBI� 7� A�eiaU; al E!EuggM-�' Fewe�an N=R2e��`mo| is�e6� ��>�T� r�9%�;%a@qhU.��gMjs�  6 d�-y�5�puncta� t do�!�a��GTC ma��<���&"P+“ ”1 “L"js[14a�[1��D� exp��to~ A+sF��-b���% �AaB��als�M�!aV u� debr�5lik��=TI@Fx��A�Jo63ioV�RZsug@yO�]op�N  h���*mix�=Te�>����h!JpH"�� of2��� �9}(a�aHsa D{#0 oHwH M(Pa�ٯstrong͈N.bl0�Ein&� 2idep�Fn pH0 ut.�6/5 ��n" QyyB. :kr�lit+HA g15>> cKas�i� �r!=*na�y�=somew�Ml �<_!pH osw!�M�8>�i��I showi�.�ISig�s.3�iotQ� hpH . M��Ucqse�a"o0�fyK�  A"i� pump��1��cye/mpw j&�L"Hs|2�"�� A�f- 2– 7 [12ncv7�tt 6�"or*�sis�9nc�B��!M�l r8"�w�2s� � neutuxt*J �um upo�Sn*",]�M�"�, rapi�Ub s^�U-2~ W)? ed PK15�C\Qrc�5kidney��*n"�Aå,� AЍ?byL"��@K2�95%�Lpost-& A.( hpi( �@Aearliesk"al.��B�2� , pri�MIEe�Fs i�a�� Lph �ade��9a�C������W2Bw?spoQ $to Movie S`4Q"2=�y:ncew==!29 0��a��A�asAOr6.  �6�<)�sId !�d�2 fy tU&_��g*2mpa ns: (.)�aw�A�Eu��if}!U-psurround��>l��&�o= H �A!�F ŧ!AFMIM<a�g��often� D �!dA4�*�*5$�5�)6� .��>E�&�6�.�v1�y��.,N )2i:z2!s� t� � qD�� ɩ�$!!�/ ! ts�1�5�:��3��)%^as2�� nG A� begi#3�)�� i�edU*g�-8�.� ��e �<2 t\r�i� ��m&bA�9��} )�ye�0 cir�)� ��-�R A��� ѱ��pi)ppE�%s>�:�6��(! y�?ca~}j�pp�t9�*�Sl^Simulta� Gultip�\"o � "� H  few��?s� ?!thous of.^ �in�f n 43"� expe�1aAr"c�����*�Np2�a9(a�nQAS>w , can! M n upO� k�X� ��*H�~su�re�\hCt aá�subF9 r)�>X=r[1A�E�Iin�2F��me+,�R�c�[�ui %f�#>9���r1�N&v]noculum!�>?\fM�� 2 .�MaT2�/I� i� d�,���Llth��"-��vm$%��%�� 95d�F6�"�]�similar *B83*u �n�a9��.*�)=Y�al�dn �!��V�b��Ce�F�Ou��165.�M�idQ%Ca�f���2 . 6BN�"mt&�6S�ae>�1AA]=Dr�&%`-i a��i�*i�`�X99^E�5M.f �O�/"�'syn!�A/�J ��8y�i( �:We`+6{h.�"! .a",u oP2!��E��"=#!&3�4>9JM�� ZF>Zens Ve a�L�/ f-T>n#>%�g?V�eom �Q ��,60Ff�I,inct ph2(�<��E%v% �*P� �N&r�-,��s(cifup�2 µm/A�"% � F.A��J�� v�w��u -esta�P role%(KQ.AC.in+)ui� �E�( [20)2�@(DFApproxSly 9 � �$Z3pa�S( 2Z� �“��c0�ora#�isZ(D`�*�.�*�$i>z i��IGi�Q�_o�"�3�x�0� I!  &og . [23)25�AW3 ) Wd�[�Z,>�je�4U�(�"�S�"��A c6uh ime� �3J2* W�dis�inc"� kym�`p�Lq�E-TiV + �a spik�q�mPA�L("h�,Z �: ly1obile�&.�To�{ <3! ��s>�e�"�� a$1AGe0}v�#�5 O��Ŷe(��2�e��Jr��adenoilv*I�7A&� t�-tagged�#�%6�18�XaL��� ��PRV"I�ed.� r F& 8�G>�:q$9%AjcS� 9y&> r�3 !��M�)tJqw.)�]F)Z.[�!oN:�%:w a[.��؅�6� o$�;qc���#!9of���j�e�(�by!� hydrojU"z4B , al & H;��L��"r��onship��j.R signw<a�IY&�Qnd262 �'=j��, aoM�1hem�J�4m!�imescale&�$b7>P|*�N/:L|!7�ve6�&�&�9SC�h , & ?I�|����LA�2�F\" �Cgra7ar�H�7B��'�JGQ�=T,F�U� ecay@�1di�7A{!J&�M��Ԃ�f0Rab3a_Rab27ji��,lNq�5qed.�8�3Z+�oB; h"� theyfɨAPb�z�8  0- �5A–!�� 5�A ne�>v">a�anoni`]wnd��al!9R%�557�#� �� a~�5s5G–L�K� �h�is�n��J,*�n"���p�:<+*�2��=�-�,"�2)�y�2T�� ,!�&>m*#+za-�]�6we&K&`#4���n� rd��� B� ��&� alT�p"�#��do�q&{to�"#}ag � ,2!_ ��-�J�#> � ^!�rA�2Pco��sseeMU3th��0',.[g= ���95�%$'ng��ya6�(� �U-. U�A�e:&_*�.tN�rF�.�cB���t �*�4J%(K _��u a> �>b2�@Bd�!V{. A��Rm�uaccumq!ofmJ*�t�4��dB�inv$�A� �,�N-� &8�g�,nW/P*I-�U&�-u�^~-:!l~-sua���L���euPal�8in>�$ ���<i � >� I�� at� In a �  �$-�A�t."�83�W[3�8�|: a�Yal dys63 ' �2�. L�" +0ss fibZM.zun���FiT6A�rr2W)%���vi�uCmCn�.3,�$er)t02n�u�S!m�%��6�)&� t��Zal�0 a�'%F.0R� vH��-�%c� H5�.�I�Mj*�)c2D�5�.L�#S"�2�2�0 ��0� N &�.�&� �n��$5��G�Ip!�� �uA�o�q���� �B�@l��0or�+�5����<ELKS/ERCF A��z*�5p ���@4Ohara-Imaizumi5ms�su�������1� pa ,βeU�"[>W)�a�Akhmanov2nx{s� 6a-"��h9L�A� HeLax s [2�aIng+�bO ; ∼80�s �%�i� hoN�� %*:�wF� F!�icl2� tR�e(� ^  ��>� �2�, 2�U�g.�F��is6(��Z.&p,)�es,i�. Our�AVtra�e\ &ier �K84�H���&�:"07!�� trib�iJ' ��-o�RM��&� he B�u* M�fix"q"PRariL! t 12')�7"���!��_&�GF��;eZy;~� qai5Q  E�~"W4�E2{ "d� .��6�~%�� �hu�X"?Gprefe� aQ�a}&� F�'): .:wya�h=t!5MN8!�aut�G"< V�g ?1f6! e��&�!��bE� C.� eA�!I>�cg|wRg"�caveaths4exca;;Y.�K$cluo~j"�=e��hO# hunda�naQit!Jc�� slipfo%Z)t(footprin"0�Ua#�"M�d . Sinci>�6w 3�,ua%��a)\m� dee���t%�2� "��/]ss> �VR�+eatr2&�H))Œ �:K.{*� �k2�~ Ma���q]U��;%[� cargoE]���ata favY�]6�?�"i�m�i�A�|�Rri��byo�*�H6ibe�6.%�W�T*�E�AOGFa0�C���U, J��$76�rasr11HtypK�$�"�dsfO^6�reFT%[3� R�J� n ,jI@ knockd(v{%%or 11 c{d�#�yBU=0#&�re�_�Edq1.���Vj�o( >100-�s or>1 �k(�2�9)*�@&3 KK &g*%;s_ fKFvia7B�)(Fk�v��A� pP?@�L>.:�& �N99*�3s�c�^.�r.I%mI���Hi : :�akK!�?�2OYd M�m >��� w*a`11VarJ?Ze%���r Ou?oe ��[�+�!ion�~�e��O�(>��]2y- �w�7qSV):}6HF��*��� I`�Kf��W%��3NWes�6�6Q"�&E?}9� b8N���-i(N��a� 6]a��?��#�� ��� >FN�eO6S1�c��K.�� Z}4,E4 stat�j�+g�~�K� us�� ;-Y1 la&�):.#Yet3rX�se {tj!(g ���s�� tory&���1n"U ��\*-%��|N-�so�m as�V�xknd���"G�. C%^pr�'�E��*#���DEw�IڔP)1*���!i�5 link�fi�#%U�}y�#s"wk&�B ) : F��z9 !�promot� .�,lbk:H!** %eB6"�11a8:6 � t� %Nkinesin� -1%Wrab6|mE�*H,@Nj:.ghAQ.�0 tegu�y=�s�H�J�[2�B[37a�J�S/vi� Iih�l�8imp(Iob��[���F"Ja�� !�nOh &sPh�X C?ui�~�scD$ �r)�%@HsI�e��@A|*�.9�"0� vg. S�� ,p& ���E?�.�bNaghav�.��9i�џy1Z�,h$si>or�@ 9stZ�!h�]�rhm*n�vZ�[3oqsqhcr"4���d � plulY�QAc.a +TIBJ�H);�I7>�� �9ic �6XR��u( CLAS_�Ry" plexi�LP[31.>|z# \A�i�U^F��3ea� �[spS49Y�,^�!#�W�P�.J �F|�4o6I��n%!8��!�` A�V� -�%Rr�8_H��" >>�� *G.�y�.*��"�f ��#Rb.�`2��R�s��&�)2��^RcZ!��Nth �y��a*3/MICALB�F/ $.:�4 John&|k.�J�&;Q��#]z;10�id�w�AI7 �!�X �|�n�# ,U3iZ<��")4^���B)PZTI�i=i&"dJj I6onn�^��!�^&:]� i�F��}s*�b�7atB�<� �=6�!�&&w_�. X�  �vs"d m�*�X ms T K[4z 41H=Gk�Eơytoxic�&n2\���Flog��0apQ|41]�lFB�� @ a( auto�b�Yns [4^.N�YnuveN J��12c&�1uro��mi*0 �lpeptid�sa9at %tsy�!`�d�"A��e/� VWF/8.p=�a�+eui�ve zo��A��%(�l�'%J�'�R�� Rfz8dAoA�E�&-f!�YITE�&��I.U&��%w"� r-�2a$oligodendr�N�2�[4�E[4eA Desp!1�clu1�xR/ �"�,�9YD*H#F��.�!C ��c(sj� knYI�Wn &2top�oG�u�"�. *h7� 293A%�: I.�l,cul@�$ Dulbecco'�CaEagle�( DME'N�ylemen� E"10% fe�#bov�AseB�( FBS A%�penicVn/t"ptomycՏo/A��!� z��4v�., � �o-E&�h";insxx[H�7ohKiu// Lipo@a���00=K...�re�yJ8a�Ron =}in),%2%%,b)�20e�HEPES�F�P�V! �c2��N<m-�Xerqdilplaqu�sa�NAF%%F6���!�� ]DN��ac�Vs��5+s�  2a2�2aLAF��ia�^d�H6o=!V=IIe)>��zG�)�2ea>a�� E4t� cfMJ7&!f"� �8quM6ng*7#�yo ;)��on-6V],.. %� seede�! ach of 6-w�*vl)+đn\�qhLRVJ�(8VU�ripgO�,a m�>ic�$"� ( MO�. of 5w que-0�un!Op��� !cubd"�����)��ou�GwaQ��C�/%�&*�-�I[e�I( P�M. C]&AA2R%<har� t ��f�8 ,� ���pi G%l "k�IllF���`x�5!��R. 18:"+mRF�<����� el&Z%&S �R VBx+(mTurquoise2$=,!q�=�!*trP�#f�GS397 ZB�~HN�Nto UL35�bnS�AW��T+a�.�R#,)-e)�.�Tv)[4k6��D�madell�i@a Addgene ( #3620�< �_x�, 2gvp2A!cNI!�!�zb.8II�]��s[A�M�!� A��taE�.#)��R-w34I���yՄe� in E��oli��pIn9a b�ial �#��k hrom[A\!�a��x ?4��[4��,j*M�?΁+U(n��n�\c a��d 8�53!lUL1�fgO%�141e�EQ ��r�~�M/U9Q!^!�2&�)]"/9 N44 e�B)�$Q!�Xeco-�o�TL���anz�kratpfIM!Enquis8unp"t��ag$PRV-GS21684 pA)�!qn�Des������ե�#O�ng`U.}eU/�d gift�G�m�, N�weS=n.�}E}�mq}(pUC57-EC1-g*>0a}�$t/���EU��m�Z�.E.j].R?(g~Script�KiB�Xon-��m{?�Y-eB�Y.x"���D[OflaK�MachVby [�b}YR�� ��{� p�T�er�Ygˇ����ju�> �� ()� F�)ld~ ��Ai{��ita�I��I'n!�_%�U�…LFLETPTVTSGGGTGSKGEEL…MDELYKGGSGGVTSFFGFTAT…�L.�az�B�*� A�ZOA�6>�?&q� a����q o�OW�I�y3�: � � 3 u"�X�H)0�1:�2$YW?lN95 �  ngz�/�v:�}]�VAll"� !�";h4k&Y %�Ad5 )!��d dele��� aE�E3 pt�1vR 1�$ng mCherry�<α-~&ŁpAdEasy-$"<5�B�*026767�]�T�r ~��.�by�vamp̈́����@ Gate�;5\�i�,pAd/CMV/V5-D،:m�m%.lanB��-���M�9��bAcGFP1 )$( Clontech�:�]� "��9��k e�����_ Fukuda [5�Ra*�811a 86� ��Ono�G2��MichigaakRa�8F�R�2$agano [52]w#=� 1260A`_8aJA�$Nachury [5N%�#D 2489Ԇ��yL ,1{U7Pd��A�);? 2U$\u%VM��~�_nJi�?RaQ"D*� b�����33����pl>q�Y0TTLYTKVGSM…X6� �t.RR�!f(u�Uni��KB�*e�Hn�P20340 .�S5< f�3-3 Irr S'�1%1SŋTGj1� taBALL5β�B A�&]**�e]�B�P>�a�#zx.�P1]-� ysC�N*�nO�~j��SDS-PAGEEC.�`�!_m8ly.W5>#Pa�`�` �`��Ab183vycl� anti��z�gM [1e|� mono1-]:bodT�kcogni��� O =ՙ�=a�N( Roch�DBqa�2�:.�a -ek/sh� oxid۠conju�&��}"�w��_ilu0�w)/fP&�V �*��%��7�T� unti�}flu9N�T*�%�!�H,  P �` 6vp n`m&��!.R1 spotA�o�"f-Ru,in 35 mmR� ( Mat-TekŮI&x&]!�0�aVuepi2S _ 61e [55�a�(n Apo 60×/��40 NA ��m�� ob�VvbNikon�Fl�.c�"�.!k�;b�Q����:J�,, 490/20 nm �.;, 526/36miT;� 55/25~, 632/6 I2Alexa6��645/3 .6705/72M 6 . FoB�m�*t�b&�;�=�)�"f 1�� 1∶v�"��7����*�,2� >��H2��brabbit)/%� !5JB� !+pH xj6'V�� ( pH��y�/.V e V5_MESJ!154D��A��1M"TAZinoethanl-f�B]�de�� H2OH��X�7 z�<_�L.�!tX3� e�Y�fE"�i��Սze5s"�%Fiji/IA J , z_o �. 48 [5�� two`A\ �~�0m�B� p9ud �*�d�-built.�he�Mnceto2� Lewis-Sig�<�9 ��F�"�G�()��P?: 488a_ ( Co�Bn�!�561 ,rystaLaser ).lalan aco�-�RDtuN�fil�P ( AA Opto�%�APR�9v�Olympu�Y�3��ןedr$g'$dy� ٗer,P���� ( Semrock�0F488/561-A-00QgL Andor iXon EMCCD ca�Tk�|!t�esoftw�Zwr�EIMatlab�Jh�x�.:����sB�"f�|3/4�+ 4�|610/5>/T���c�w{+a�S Ti-E��M"ON��o�nfoAMf'��yY�U�Me= equipxw140�I,Q�i�M��)M�( AgilI�+�De�10�Jz_�J @9�U�BN�:d HNIS E�sY��.�,�<450�K;.∼525/ �m��U∼60> %6g* Z��(( U#� .�B,MTrackJ [57])gi�[�d @ka'�*k 5[7 Z�_i!(m^B��F*&+5�*?y pix}�I`2� 9itA>� :"m6A��c� I �1� �Ppr1g�Vc��Ak�*}$ �eY xzMJ<6�c-t .*&.@r N="�yPo"Y$7>a&a��7�0 obia�XAC[nic�lam>�ry��7�'�{@>^u�>%�a�� !k�1hE h us vѬcub�Abf8��a ��g�i�� biot��9{(Ep���:ver�1*� K�i�%��to ans�me Q1�3a:Q+ pinwV! mebendazHW6_�q!��sti-( ��L�^�Y�ndF��*r�0ed 109�a0t-"�N��"})�\�Xth�)d�M+;y�p,�childrb $Taichung , wa� �La2qʯ[N[a!�t�cyt *SIg�%�i!��+eF�&P2 fe�s�e��*���U2 weeks^.dmԯt�of� mg2�. G66d"U�q"d P]�)P!�ɶit6�k+F{.�� phylum lӋ ,1^!L.:deAYg v am�Va":;��abund �of Fuso# ^a!�?&or�of Actin.�ge���D)ve6l�i�BifidNu�v 0BZ.��z�3�ρ.mfSd2�6E2�)���%9�l���:�.n�t ɷ�e}demމy� C<asi(ma��.͉di�"s �t�4榡~0��F�aYes.��� ce�q�s"�!�8�E0�I�gL2�(U�)p� omod�P�o�(of helminth*�8w(�i��W8.";<c��n�fmD  r��w"V�[2}�#0��2(��x)A�Im coFXp-4�(�}P�c-�I�i���^e�1gs��Gggaj cand����~ve l�:4�“hygi�&9��^!&M 4�tTa�f2Å�Z�y� 6–I�BF�[�ePBkR �T- � tapD�sA;nd"�nai�F6Taipeibms9(.Wr�"o6hZZ1��JrM�c airV-s�:Q�d�9te"� h1�)"]0as6C2is �qwheL,in Turk.sc -ag� �a [&�F�M��po"ucoh��a y����O* �c�$� !vR ?en� .�52*dFER0C�F�A�asthm`�!1�be�K(D�'ʐ thriF��n*� bowel1� BD )��k�J�mioL r1PsThed";1�2!'��BJ� e<�� qTQ>!0  H � ��bal�pr�V&� >2��e"# 4dysbi�rJ:N� such-eDM , !%, rheu' O�5b( R�r]�SejB�2�fa obes��, �Goscler��col��!r��–aJ]����+��� mensal9rehHR sam�N viroD�!�>���%�-orga�i[�0iv�x��h\$� .~I>�!.�N�<s >���M1�A��-+n8=!ōt a�&B[13!25�}:' r8�0�@��MT�!/-� ( Th=�4on��arR �ym��!'�"�Schist�+a�L soni��ltoxGl-�3� M�xNgr�7oma� m?#a! >+-bmFur?Jm��C3o��� mucoA*���"�Tox��ma gondi�9�6p�<�a�%� flor�Gat stiY nd��cZ�N���H,IRamanan�S)?� ~Gre��E�" \oblet k!55u[E?H uZ�y651�/ y��s"|&L�#:n&�E�ch �wW MIF-�ic-&)�!t16s rx�gG"#�xI-: -/5!�%��-1+>'by�� n2-1� ��+o" 1 ( + )U��g�FB�( T�  �� �o �vf߮dia�͡�1~_��,�s��xaey%�"&Jon��q�( -:!��d�.� ,�>F$q�.��ol�) i�colǡ)t hU�0} o��*eX!�in 3 �inRʁ7nd Ui�9 �ab�( Sig�Dorq" , UK�DNA^��:'� !oQIAamp.i Mini KitQi!p(�aliforni6US� ����s F51�05’-GT�� CMGC-�GTAz�� )% R80�� +GA��HV'3WTCTAA9�,�rs �7e V4 dom.of" l 16S rib0 l u,f�/�N��ra adap m_� Il�*�J A�a����en��!c��er !���Ʊ�ae�)N)� 50~1g!g%�^Y�A( 1=��98c�"��30 � 1��6O��3~ƨ��� ,��a�2�I�pur{V �!0AMPure XP Bea�Q)4 Couz $ndianapoli�Ie} w>�V TNanophot1X( IMPLEN�iü�A�Ger�C�!�5�1�Index'!�ki�a"�7 9�1� q]��'a� � � 3� �che�v76ͩ�&phoY�Qu�)4ermo F�� r Sc�M�:�V�chuset4),����! &̒:�n�L$�M��2�Qq�5BMiseq�A$FASTX-Tool!I8( http://hannon�&0. cshl . edu/�ux_�x.)E�1y� %zraw�d7fizNNN��al)|2fi�HFI/���!� ma�SŀPP�!�lsc��V `s�2�;mNnge#7bA�1+2s ≥/Aq( iyF߰;I7��im�R2Etai.s sGbp%���a)~�20)re�6�[��B$<�A>� r c)�xMsIme� f5R1#,�u*� n�gs"�~��HUPARSE w��Qmy"��� x�HunŘOTU )�F�;�$. Bowtie2 +LP�"UYq7oA�&� �!n�Ki�9A���W*�SILVA:rPE�b�Y(  �+� Y2.=+,�Z��Yby�1��`!�1� od� ^ *'�t3cg��|VA&Q�E� � �hen2W'�cp�i^by 97%�m�}aU��UCLUST�+� ndar�:,E�A�%%7!�ap��. FF!�ف�Joe ng�)a�m��E'le�-t܏o Pierc$�D!�inhȓ��>R�a�- 6#. !�J 0�+g!��mi. �!�2q2�dZ -� 3"� " V�%=e"�)�I0�[ 0nostik ELISA �� ( Bensheial�:, IL-1ß� IL-4\E:�.Q FM[s� &D Ss�,a ne:�2�e.��A�<�� �� /� 2L& 6N�*��9n5I �=!R�id:'!�>� μ��� at <80 ;!;!HC80 pJ6�5 ;EP%w�: 6�� 1(�[}/ic. &� �%E���"3"giv'�6�\41�^"��or��;WU9_q�t�\�Z+����&|t�6y��N bioiia~e%ɕAsQ&�!( S��ex �G��e�lpE�iE !J� +�*3*. BetaWi���!�UniFrac�t��jr��R,�� ncip���9bA ("f~, P- v�� +M,!Ge|lfhvdYfBK d ��4ly>Na�+&�f�2yE�Y�crbia� P 8, <!0�� FW=# >e�40� (71" A�8�\ achieo �. >�&��%����! a�,�E�"��f7Q� k)�isfa� fals:n7y ��]ODRM?N+n� iV Benj�N$i-Hochberg�� H ) 8r%��qX�5t �ena�� �g�7<ew� i2('Tax4Fun' [��. ANOVA f=U�I.�kQ  C Mann-Whit�UFs vGraphPad�sm"W 5)`�m`F�*���#�"%�a j���A�a��� �!� 5�2� � zg. �O�!�� ��� �""�=*bia��:}"�RhFFo��u&�+�r2�+.!cd�+sex� �=in���Ga;b-A( p =e 6x403� 6��. ",[UW?U&@^�g�I��a$� ��6�l��o�/de�6:of8par�'� As&��Tb6;A/ SxB��p�*ln�$���<&P)K?stly-m�die�?r�a(� )� se 2v?t�1ga�e�i�# 3!�i��*]f o�3 13� >��o9E� anti�ἅ�rec>/�^a&YE�Z* Q�tѪ&� m«V("HhA��6�2"6�Fa'er���� &�*��X2�-��  M7&%Q��!*>x( 8!+10 �dU-.qusage )!a� K_A�růb� i4j���of 2p+(e�01%± 18% v� � 65%±��62% ,u�e��h�1eGIl W �(!�&ED�(.�a8�&avail��ı vi;KzWY`MW61.� .Cp��ly� ݋�Hy�(�X0Si. =�Pi3F>�x��mar��z����!>m mp�$'"�d 6��A_6.��06_wFig 1a�Dpr� l!�F� �gM��g�$b6� ���>3)�/n��)�E�+�.��b��8�wF�Nfm �OTUh �u$�� x��!Z&� �*��%a:* $�O,�fmic.kGe&1s:]/, Verruc.#!�2�ioum]:k ea�p�-�d:�I�$�1F2(=�!�6tJ�,�B08% ± 15�Z�Q23T�n�,!N d = v5�&P =$19 x 10−�U�u01..E�cs2ڴ� 04� 17 ��[± ��8��n�0��30� b�Zh3��of����6�Al�j�](�5>� 00KE8aXit uy ��6�5�l��.K-b�1.N%68u15@VeiY�ll�� {-2�.{4�U, Megaw���.[.2\ � Acid o��(�dER63��ŔuA$�46��w*r d�� ;)�j 2�WH.��� � ��qFDR�qKal�*��Ii�wpax�M)>%0aJ{  j�a�su�F��!M!22 ��dER��[{Zw%$6`mk{t��R2a/e�A�92H32H:�4�,��ut�M(}7�IB2zB� 3(2�46"S=�G�2��f~�RpV%� j�Y��� g 2b�@V_A&�(~�7y&�i�"��C�<���u.d�eq7ھdG32��9 . 2� A86Aq67� !�97I*��6*�-*B92^ �e�5ve�Fa!as>�2tr� �]hY7�B�(prausnitzii�n�Lqflavefa8a�� purt��no>�}0�un�Ld Oscill�( ra s�8��3�pC6�se����E >x�*V2"�� RlN]�$��>���)$.elsden%�\�]3�]�*um Ū53��S1�L V r��^f��h� 'i�9�A ޟ]i�lB�&D<=�2�M*�4.A�� >�!�I�q�V/��z�Rq���?�&M -i��ť,UU�E!�"�V�Col�� aeroq�A 6�L1%�u�/��t�6/)�ɵJ;*�J�6J�32��!�de�ed"�) i.~9���(^�:�9m�@ : r.n)�,��07��� :��00�� "! ��0 ��1"1I *134;b�e���� 89�4% vs . (0 . 31% ±  `42% , fold = 2 . 93 , p =00FDR ��158 , Fig 3c ) . Taxonomic annotation-based enrichment analysis showed that the abundance of Gram-positive and endospore-forming bacteria was increased in the pinworm ( + ) mebendazole ( + ) group , as compared with 6=- +(= 01�9$1 , respec�ly , S2a%S2b%&!#8Further pathwayVuggest1an &�ed gut microbiome involving fat absorption and diFmX( ko04975 ) was associajwith p-2inf�on�  ( + >F! vs .9(2B49.B14%c-,% !psA.�>a}�t dec�W inE�p ^( median !d= :TAg.�+�@: 125 . 59 μg/ml <1096 , p<��E�v4a�ST�; moun%�fe�C>%L4similar before%,aft��B$( ab%4��F��m<, A� l- of)!�cytokine-��e��to low ,%9um-8high as describ(_ Methods S���wx�=D!ossiblA4n�j�'(factors sucerec�gastroea itis���$iratory tra5]4� oral�c�j%UcQ�;Ei�is � ,��AystudiesR*1Fiiy���v,E40E3aiQ3A(18 45231'�55byA�er]� ��96per��age�xBifidob8 ̀,Streptococcu N�� i! ( P+M+ �P+M- ,>U: �9i�1�53m���83�8 . 472�37;6�:%�5)�%�I!G27I 36�" !�6acr .�V�]���e%� 6�}�B�1�� 48 ���:�*U5�6A�. A.�-��=�1��yn%�.�Aobserv�� bothN��)U�6�e�R�N�:E�09�4.� l��=02; PJ}:%�7�AD95=[3 lAi_T1�6�1boE�eszA&V�]0 ca%Vno��in pr�}mZ ��K%#J�&n7 . 8R ��12��i&� d� V"�Az0�O0 )�g3)S3&�; G AQ`dZ*$pK otic �Na6�%rmophilu` >|�umɨV�A�det �dX)V�E��2�h�:�A>86A6;Z�5a�65T463� . We exam�!Rw(vermiculari�ieq|ef ofZo%"�VL muco��:�sU (primary sch�children�E�obias Z��aM=� alte�*! �� . Consista)1previous y�helminth&Cta [14]a�B� in our FA9>�Y/�Q�(l diversityBw4it has been reP � hook# *� in human�)�0celiac diseas� uld�BQ�: % �hal richness , but also regu6 glute� duc��flamm� [26] .Z di gco(t a"<&9 trmo� �hronic& W �V However ,�=xe z �qEIN�aA� �^kFa�i-�4um prausnitziiE�Al7pes��.v55�shown�(underrepresA�� a�� of� ients)IBD ype 2 DM�;nd obeA?; while2�p .wYCo be ovByirrita�(bowel syndra@( IBS )� L�abdom� pain � in d�s�$individualARe< ";rolVdisturb!}2Pserotonergic system [�27–31Az�Xproa�Y?\ofB�)�A�� . As~-�which%�ed� .� ^�,�Veill| s%�!�Fus*  havei�-,a�%�>�B�ao� &y ulcex va�liucolon �aN�.�dispar6�vara��(i& Urcinomaade [32!�4!�Whe�$=` ��by�0favHa\ti6� profA�requir+*�ion�8 Anthony e��( . ( 2007 )� !_ha� major :� rais gainst�)��#ix Th2-e�@o�c�{A�.nans�Th2Pper T��e$eosin�a2 mastbas elev�IgE�4%�o%^& �-clu� IL-5%� 3 [2!�A>!�� ent�Greece]�a� �or���Ps �&�s�ed���serum = �A�� �ic!�tei ECP ) [35�� �,no differencya����among���"Gbx� 6+ >� AyI.&(&c ����e�>C2�&u AP.t � Kg P�:��y�Tca(����cJ�iUGr������>�(%�santib� s usage� e�r��a< betw .&LAJ�D9�%e��. AG�esearchA�4germ-free anim��is need�& o evaluat;*8 1aw.� o�2�nd�E#C� 6��c� be2arasite� Rits��-a� Qs6iv_ [3� To esis� 6� of=��mur}> ` Heligmosomoides polygyru�(keri ( Hp )&�"'to down"k a�"$%ʵW�! romo�W-AproduI�[37�!I����st �188 Fasciola hepat\&� AW�irectahib� ostms�E�[38lW2� Qya��" &ka��U.�incip oglobulieol_comba% *3 &� �(nd maintain��� homeost3 Sc"� AQW , aaA�a�6�fun%�$s via mult�4mechanisms [39!7A lackAX[canp caus *� " [4�4� BSIj thetaiota "r�olonizmn!e9�� m��K ��$��z flux� IgA-Ie!:B�!R'Q )A�meric :��7 ptor� IgR )i�5IA�trans� Je,across epith�  [4�I��"tud�!Ft>X��� d��lo��(%}�� F *qf�>cne v�">}�V*�." t� �—.�ter���flu���)�e�8is unclear . Of� ��.����R,=�)�� .f �a1"� ��d }�N�r��![J� !G%�N�a�"�"1�2B� . Althoug��5�6c^�I>FVL�:���C#A��&� fbe�Z�followa�.�9�%bC5�.��d2 . Our��ult` -%i��5>&�of.= migh��u("Ea��"N -}K��y�!g%F? �a#. Md$ classi='ti-�� drugEP�iR ll-tolert [43�� is routina�given�?q<ve � aged.�A Dank��on::�ris�(�lz2#e~um V�hi�yTa surro�� ey�diagno�[ŨZre)�of*{�I1�d2�kn�F�,n�,%_a Ff� um ,6d 0erofaciens [4�&E : .'��not�)-�!t, �i)�is limi�QEoat�  ��% tap�� �_senZvA�u"%�� ��of{eggdan MIF� �'sed%�'o�J� icacyPV�.*MWang CC","(in J M)l I� l IQ009I �efVu�on erad�"ng��V*$in Taichuna�Taiwa����[� .�"Z�FFAfti-angi%eA�a�onc -sup�s��xvit�i�&mo!� mode�%r � ce�iti)�[4�aFW !ec�.�1 ��y�~ �&in*� . A�*��Z�*Aty�m�Z�*:� A�!�q��.�)Eb&� (*�(ofZ*)!]"�(�@FaŘbecame.. �*a%arison%�mad4�QN?+"��6.&!" �V /!�areNiy��.�Y���&� 65Jz Ksubseque2 i� �!"G)a�e=�j g%�)��.b�{A wo weeks-�administKoz.�ٵ& "A �{+ne�ed��  onseq 2�. rg�" �cohort�w� R"n'�-up��� �omeEll�paA�r8��exa�Adu �!wdynamic�BBa�)�&F 17.%�^Y �xst geneteIdi��*)0�xf&�&�-term � u�Var�m� �hgena��L%�![*��)of"Dt2D4�cA�a��T&fiber �&J*�>xreAbeneficA�)�3��s%�ch\&w-!SCFAs )�thu� j) ����2e": a5"2 !j autom5*];*i.j�" )�,�nt��)�)eM�pop�on maya1��rsV >�*D )6!@&K�*t) relae;2� 6�4 AcidM�$O � m� ur\iua&;�q&k�u��t���A�I�$, lifestyl��^ +w � /-G6l tribu�o�in!�Q�!bof6k��f 2,U.( p�-t����"Uc-r�(��co:�,"�us V� s�]a:� Q��J� 9��d=�� ��. SDal@ �exh�e�2D%�Y4�  �/Z/.� �0� F&�5�%�ZZ$&� A �.�I�ed�u;*�0bet�.u�stQ3�FadonshipE 1+ MAu2.�6� aA�m"� 7a7s’ ��a*�=a`J exper ����aA��V�,.�Efforts� 0identify loci �ly��lex�fgenerallCsum�m��eaD4^gve���", 2�#Q���rabidop� Lthaliana root length% ��� ��$ic narrow-R e he�il��4NtraitA�a���xAi*5ly zero!�he��&n� ���&� aptu�byw�e-wide /:k�� expld why��AW!�. b)u� E�ard�-�  8.|[ ( GWA�Lpproache�H"k"a�Gbroad^`.�%F"L6tly l� ��%ily du�5 episzEp#performvn !�&�"� to map E�c���A��� X7B�. F����� aire�Pf%��B� (sc�m�al 1%�pas{a9��-��g��h09#caF resh:�7Y-phenE%�sM�esep"rs� �m9t�cel�1�.A�f�I7Ax�Azta90 ��O2�. Small.Tsiz�� 31&��%^��z�����false �!�5�� MG1ba�]�� th verM� numbe)�%�-markerA&%j�A few 5|�t&�#%�r�/E�rm!i�&�Ri��wAt<%05qrI?sTed2�a& I�� true<i� %%�9bal���ofAdid�ge.5ith-�I�O�#ci�� *"is���e erxve;��-�i37 ��a6we4�8EY�Cd� op�i�urI�,e�par8th��)%�2aiA3�7��3 �%spens�%A8�ig ��� �E�neH6>�=�ͩ%Ni�"� of wild-"�5 A .���acces# �}W�so illuue how�c�alrZAyu�!��� (A a�!���zt67j.b�byU�{in�E[ refusY�J�j]�Y�s . I�ᅒ~ �qu�ivey�sA�&�"(lEl!� nq!l�� curr# 2R �sAradigmYbW?�a pqV2�*�despitQ!� ��bov+ f evA]V$h�E��Oe  cru,��n�i�� , biolog�\s%(s [1–y&�key arguab�OV��}2 �< �mx- 8"i*.u�&A6�(1 U'layaesiderevi*2�n u>s [5]E6�6.��Mes�lA� e�!��1ousand�����:� ^& A�J uu"��iᡁ,~ � , w�v.zVllele-f�'enc� : a?�&Ʌ#�� pert����2H/*13Cre�+&Nin� Th���focusA�5v�%N�lea�� 9�" �� i| tA<:�P in natu�. �R/&� 8o� -�!�2u �sta�u-utiliz* �VW9�~)�q.JA�:��obt = "t�,mpi6 %-NoY�^Qwp'��? be v�'/to)Oac�%oiB!��,o�<��E�a^ngi�u�D datase���� drawback����� s�LZ�of�er yv�)d c��lti�amllect��6�%p0$o noisyU�� Qhe�p4'����&�ۡ�tk2pl� � �!^}[�m�V(polymorphicEQ!�d�@wE�9 *�&leaato^8 6Z *3M��i&�$\2w nove.,� �a rE�im�%� a�enhane$�in2��Z[21�!9se!�1l�+)i�1t �!*&z �4e �M� work�n�provi%9iO h� �w! �2of%�%�nd.� =�:�2� �e� D�\*�w. Public our.��p�7e � o�5!0J^2��2&T(:�s�s R�[22�X Dros�/a melanoaAer [23�RMc enK 2�.�re avail��r (aK, mak�them att�v�"qpaii�o*� �m8ŭ�hx! %�=��those.bsB;E6LFNFs�Fas��p2��6po���>�funda� alI�� �8�>Z��sh���A~�b1terpre� A�_$��&>10�<�rc* �omp*J . Tw�r2ch� n� E�o� I� iscuWi8��F�"� V�E�s:���su�"�1l2lՌto�{�GonEq.hE�%!�uAo� ���� screep ,aumI��ln ���� . On�!.le� t v|3���"string�, Vplez�-O���.�y�:!�.�ys��u)�)� a��0""6Gm@ �ci [2�As,> a�I!ske�"i�2� E���2�,93`Id 55���s�(��b $.�, minor-A�l&�Z(N To s!�exa�A�1Y���8c(b"�D!Cpsaa>OEi��g%A���high-r�9A��( g [2�$L�yagYA~�Qd2=�#:��I �+�.l�&-� Yt!JK=�!ge\8 ��2-space�!�<sca*�eH �oinbT.� ,��!F2sRegMap�; or 1^P� s Pro��<�� D .6���G�! RS, Panel [15] ��A�<e advan#D��.!��D3 ���� outB�� hefM zygo�0!��>�t� arl_Ju�� A����j.iAm&*qma�5DBr6r��l>ly��M�a|or l��!�p�i��2�.U���� ; [25@28 � A>�!C��p.��Ues [29�9g12)a�$I� ( ~LMMKD,2-��re 3�M�*�,�$(zledge��y��ݯscH2��inF��v"� .iM�U�wL-su-+�jk M!�exhaus i�A*Y���� whV;RF uK�}�to1oM?� &-� � � A�I5d.d.<};}�ka&�.out!9d abov,c%�4aeC6'P��%r3A�egrs2ngJ�N[sF)ze�6�,�. H�C, �c���!6�worth!,�v,A e ��p-T�R����t &� .�96. M%F�%#)��S�V!�,�Na hund�or��+&��valid� cernn� ��tag unC ed�U ingl� �sZ0E!6m*-#YP " � &�$��>g�@r!�+G��9 q�0%# s hidd!O�h�$Y"P -$� �%!��YY#dA z9iuInste�he� -order2K. #��) }*_9>����X�aA :q!&!�ci�M�1�i�*16{8cenario�.>�&��linked �tsIF,�F�# Nr*un ,�Cif%�d�La?iY�!+y��o4Nd �2p7soe8.�goe~G yonda:n%�uC� (.oq��e��in=B��'��!di�!9!"� �4�Mn5str&�u9+&e.� I`%]�+e8ina&�Ar1l�rp���/4�an�UQ~*�M.yua� "� acA�� . Unles.�  cv�ake�2@ �s86Ie� �H��1E%<*u"�!&"�3EN�� !�"+r�=� e����y��2of.�2�if27 �!wi�LBA� .Ss&��.de�1t.M�eK�%� �^!4&-#Fr]N�ArnmM�N):K%2���e�T!ܥ�a r� w�nduJ�`�y!�JG�;52� � � t�EcJ".!Hw6l"*j %%f�!a�� � �'�@r0�,�&gnitudŪ"Ac% ittl��G� DK1#�d9},5Ƶ�� � N9)�h+.%B�Q#.� !g:�9͡v�)c%�edm���v���J i)4��surprzrn�ZM#)a A7�&!�-9�a|Br�)� A;Ug6&6 : )�"� 2..�"�(fs%��"j&�)?"1)�=�65(�!edC��*;6�in> I�`�$�X8 ar�lFp����ng�⥸�AK��.�cQ�g�U~��}J�4n:�'�!�e����robustCN��%�1��� i�o2CW X(a;="�X"*�^at��lbe!� �I�? ,,!�I�! F�- 5X�[7'��5v . ,>2F-"L"^-1eg#�JT-DNAceN\ muta9 �� *F&"� C�cfd9U*C.V(ie��: � `+,5� r(A5>8w Em�'*e�b� [3� Toge�j ,2O4*�'!�AG�i!�a�u硝i�!���ՙ�[ I*m���,BB.= w#ti�!D�>E^&k�1�%�� b$.� �-,,�0! top-ra1 2ZproH Y'��,a�.� !�u�e2���ams"NH.�]s^�I;� �0� ar�8+(&�uh�on�@�)� �&�j�%�8!st�_�!E mole�Or.�* eE�*Q!2n��m]�B(�(n�3��!2~ Y�M �E�g���HM=eamS�,A�,� d &rehen~%e�2��Z UsdF93 f7 ( S1�Z, T� D�""c93.��"R'�exUly��"d��(~215 , 000 D lmcleot)2&�!;H( SNP�8_l#A\� 2fA#bplant.�[2�8We gr��eed�U�"�$!�"� M u�emp!� ure-��ol��chak/�"�9 environAlal�y%�� &6T�2� �a�D9ar!5A1A�6��6lC;A�^ E IUO , LI:=AM�<,I-..2 6& ��H*� <( p < 1 × 10−�SANOVA;EK1I5*YM�a"4n)'r!>�% �-�i-&FXY,5%%b�-z' vfirst.ay fit�an �A75q�b bAG�nd2G�_25;mm9-st �� icacit�, i . �_�af�*Bw0Skivf ,��u�a�gImix���sianeoua��q lyge�Q"� !�O�%����onW �R/hgl�ickage�M[-%Xg5aoS%� Y%:+7(58,H2 = ( VA+VA6/VzR)��\ 24 (^CI10– 38 )�v>�(=�,&��� �%1 tr/�al �Ny6b,2R -by*T/"16� bXWe"1 0 �-d�{5�� 1 !�&��)���:M=�A(mF!8�cs�Ule2a��mN2;N][]32��6�7n�T��� + �� fgY1V X01 XA63���|s�4ifj>b.\Cy �(x -XI9U�S-72,7$* E�|$2)� � e�)�#E����b:p8^~r.��Z�= w)S�`��leNz�]2'��X� ApR-p�GenABEL�QI6�+q&� -struc�����1iq+~�-c�M/�+~��ng�d ��a Bonfer]-WY�;:*9se�Y.H"x a whole-�� ra�-ri`r>su5@!sceda� �s)�SEM�U"��$� <g 2�aUth1nY2N!�as6+Y!%�/bigRR 1�5RJ=a 5% �}/Z(�� �6��perJ�` 1�. N!���e s�\t�#s6YUB�(�Q�"�I c1&cG9M��>DBY��6�.c=�*( h�ꁸ0a>is��$!<:��/����5���/�~B�� >",Q! �1h!&�SNP��SNP bO )_iEPLINKv���[[4�1D�6AY�%�"�8|,"�. d��FU,�I��ng.�i����q)���a{j!6.�4 �cie�Ac��!2� luesiv' r]/_!�eQ"��9maa� f94N"� ��4o� d*�"2�A,es\_),v T�,�/�� e�(9�!�,="��w:B!��>i���z�A�vfew� �@� a*achie�byAm0KJJ  fi�df7 ,)o �a �F)�6y�a.t�"a�25:v7� ��q#2mife!AN%�=��)!�!�� ��remc%9Y�i�1r6�]52`m�Q�2�iOaN[ �o6���� m�Fx>t�r!�I��m"�F�a4E&findepen�;[-�A�"Wv.'�a�&lo�37&2�� e [4�'I�� i�>wUM�}x�`ly 78 ]#�.� �. SixA�-)Rz��[9(2<%elo|H�!dI@uniqu�J�,,B�&���tj� |5�� twic� �q=�2�I&R eE�ed� 5 kEu505 bp a�  ( Ch7\�,3w9 , 27�729>a �9 674 bp—^$3_9272294/ 3674—��Uat �8y026��52�U(5_15862026/  !��1�'lyw g���F�6j596� 3_66q{��w�'%�z7"�:�heIb5�r)�� .H%"( R2 <��� O� ?*%�*Q �vYԁ�+2To� �V*S7"� �#j.51%%��:$ T Ni�: 3J2%- 7�m% boot�@�^ n�*eor�$Xp����kiice-�ed-a�,����] S] �(��*j ( G-��,A<� 6IO<�5�g34 ���:h#)�VT%��ly:H �%�%���M��$double-hom�-�9 lwayF� N�OestFc �� r��B"��;hU13T"��aa_f.�0��y2b; S2�)(&L[�"7I�!�*�"���jae �)J- !��6�$2��FS?w"�:��%(U�g�U��let��.2�E"a O� �!�fX�"Mj%�J���a�.JAwA��s2c��0 0i|�e7�Sm�8�M� qver�(9��e6�s�!�YR!Fj,c+)�� hK$� �MFo���je� ir j�yR<pJ�,*,isx *�� :*�s?Th�5uf�*�3heMO��DžMaM� O{�"�%z!�&^ *'.�*�s���a�>8Y�B��i|)E� next1 l�Nn"�G:""�b� ���s ��!s�#��/� *� =�� ��|!pseudo�)e ���a* eachI�l^%H.�#R�3ng"Yu� bA�m\&*3 �."�.]�1 �/M*a�.r�#FY#ca/JD���ju�!d ���P��UN*"* � GR/3V�V&]4213�F!(�%e�I<4�[ @-41�w. K�"%( 3_10891195� 027939%��j�i� As>(�94�zau)l1_172575&P �  t8241640I��)o\28�|{t3S4&@*� �өXa� 90%2�):�Paszr�se�:��iiotm&�� l1��� { %30��*�>L!�00)�W� ) �CEes�q&^<�1�Q�of=� ]w�9H m� !4 c�s,2MQ  &BWV�$]��h>ds�e�#b�"I�� rF�h�.f&�Lt�;u.7=! "�FVquilibCpŃV�wx i��B�ms�0de��G4E4H,= appa�J F�0&�� phys Aly�(k# `A�z��o�)‚ng�%��. 5if �?+h)'1�9�by defi_o�G(N0gf �Wn�ptSnkage>Bh�&�:b�2tdI�9A��48>�s�"i.�<k!pew w!�s�]0%"OI2�� �?q�at)�{�T�� akaI]r2. ��h1# Sm6B"�%�M�< ,f ~heV ;A.09 >(92]!���i�i&$  ��b��wir"TI�B3 �E,�i`=icA�26�a~sl���  R�&�^� �� /%6i!!e�%i�� -�@2�0. B&>Ob"F52"�s7�*6S$�[�7286�re-Y�*�2R���� �n:�Mr�!�x!?��r��'EH��;y59":�q-zTb�sJ� � g�'���r2A�x ��6���2W���LaMT)]Bj �aighd!X >�!Zg3ny:k!U� �O5&���6���00��W��E��� ����4�J! (" 18�!4���/JYCtoEc�#5�,V1�5�2�cau�f:N ^,"L)d2g .�[��a�F� Qb&N4�_��"� � FWAh>[ My�E]� ��,�q deci�!���Fa|+i� �"�2a/bioinY�2�`Mt�R>l6b� _,!�.f&.H%�JDx refZIZso�e� �3Uor,.$ "�-!��8orh:�0a� s,e .�a �Lf? extr�p��!ԡ��q13"�1�!� 2 J�)R4[l. S%x%�in LD :�!��2 in 5kb up�6am!/�s�7)�$;�=I��%p� id��,�?"hW*� ��8In�%�Owe �}!a predi� &� � ň!�%F�fulfiUfcriteria���5i�W0 �>a�K"�irt�tgeA%!<_r%I�iC)pf.5"[�QK��RT�GaJoE�*: /�#>�0�?M� 2/15.��r��"4e �}�Q"��!."m�e fr9�64-�.��0Iks�^c�vNACITFLRAt2g2888DŽ���Ai�%�B�u�!u�*�)�"��Ugrowth�� �H( ATL�,����YA���z "X� ��,!o1�g-e)]��aS�, ��+��� na�M`v�"�$t?L@c�EE`�\��^ee^1!?r Hf�(1��" . No�< Xwe� �� ��;5�q of�J� W%�>B2in�*G'. W� )�5�i��nd�hm#F�/U-ofc is�3=�"L> �3!���8F�A��KA��<�A}� �E�"_$cJ�8�fd"'e��uL2�ny�e�_ �FfD&g' !�hr�K!]� 52I g !�T>���9J���&-�B!of2".Iweq`( �c�]�(�{SB"}of @%!�?Sv"a�"�*��B�!2��}jq1� .PM"0�@g�.�� �JfV� >�V �wo�!��Om�2!��[bi i�04�}���unl�:A �S9�9~o>1 Ux��3����b(ea CA-6�-�� �n7u ie &�E�NnegligU�Q�)/�:�!Bl5�e�ui�Ua�7�]!�&)�mEEMKB� g V]QUxX_��, ��>�}�c"��2s�A�eF�G@=@Pe"^&�"J�p1rm �'s�9Wn&L�oC -Iu�Mx�-��iEuAlli�I�>.�fb"�@ <� >f�ec&���a�%�� d1�2%@A9��2_ �"#�_��-f�-=��-e�=i�5"� !t"O%!)Q("-� ��e �Qa�o�T!i ��LI��men|a@�m���as�c�GG view�21LRtic!aB` 6&� .L:ɛG 5��_ . It�&fe i&�W!��U�GcJ"n.�%ac�@2:�_m:)_�7t�uy� a to�Xric�Dc:�^� -�Q�.&5��� tor{<&�cml9�d,�BLio"��^ adap�&�B�5�EDo!azT��GB!���7��E�6��I�+�H��^�*is4�v B�4�;UZA�R3R�UR?e;O�2��Q � �s�4,�theor�f�d��&�U^&� ��H-i�6���da�%ek*�?=pin�'"�. ai�c�P_ �jh�B���)�i%8�U)9��M.`/�" B�����KH]�_&�ly�-9 �FbsrIfE �OguK?p .M)�"x �U���e���?���!��l �beAE"�*��7��/�����"�K� J� ,dV�A�Jfu{*rMb� "aD* &[!�b*.M�ini!�a�L�)d=�� ��!s ��|$��%772u�>9���r�#T( bi� ] *hp-{6 "� to6m�dz ����5`-depth6\�C� �=F7e9� ocl� !n��1abRC�F�{u{`a.�t �n ��)�( �i,�*2�s��au�0 task�N;g�e �� "�U�EsZeboZXS� ��'S step %�isu6�m�+�Y5}��$W]�>��&�����<-�]����A�2!I��um�izharbor(:�Q�edA)����[�L.��>��K� kE] . De�~-��>Hus��� ��6A �a� +�)�Fs��5���t�6Q�ly �G)�:�&QN�#�O)� ur�#t4�l!z�bun�1��z rget�%"�r#r"��� Wly 4e�L���j%V�*�Y ?&�!w��a^��*!L��)D [53]A�gl��inoJ��i-I&c_.Nx>IJ=*.����,e�-\ U%��q� ty�Z� A{|�2�T�Ba�xarlie�hI��u�'�x8)��n9�y�.G� X'si �a����� � 13} M�6�N(=3GJ?3�*2�Q���succe�������>�I�.9l� � ΁� n��N�OX)�mc%�!�� � . 9�2���� W%+2� *?fb7.�� .�%.�La�K aAO�(RMdN��6a;AR-���: net�n v"���e�x*�.r.~>ra �PCF�z�>��y�3–6�}dPV_!�����oow$_2�~ u~�bg�6Aq�bsJwf a��1!�N%(�bcy�_ Y�E��!���8��i�Fys /W �Bm.� 2t�.ha�r� �/ �* `O�I"��*�  =���.�Y �*�*Ml"� ��ZR.9  "T0E�s-�H!B2�fEr�synonym��!��$'f �i&E�U.\nvsx,)*�NQ"�.a�acti�B&W1�6[ � �F9LE�a�%{r**!��m��*�@ 1�S,4�#�K�Naɥ�jyr.�*x�`a6 .��v �/�A�%#]8�a+�kndIQ�xir�# t9��` ye��bel�Ai�2?E�"re\�?;�n�d��a`�i8 ��!�%i*��#a ��$S'1 9. �1r�_&� 6�Oy�)�es�, e?.&&o,s f�e:>- |O!At]p��G201�$�F���- vern9Hat 4°�G$�1�A*yn!�nre�$!�f3�a�!�e f�� ݗEfS0e�a�"�- �t�3E�:I8 soil���I.�Q. Pla!���k*h<-d�{|s� 22°a�la���$rb�gV� 1���"��u�nic.� ��evKo � a� iod)�� mont�9�e N s dr�. Ef�B !<� poo��%D�05+A�m�Y}a�6��1�=3H�B\w <Ethan��)wJ.�!��4n 1× MurashigN Skoog ( Mw�ba`�sal�=drSl�'-CS vit" ��/<05% MES ( wt/vol"KA3%.phy�lM6 semi}Wݦ ?Y' � n = 70!�]�C.�e)twentyTp�}u�p��)Sol@(��-a~ˑup�eA EE k'�G>RmaY!��bILOc�E�p}H� p*�210)�4�qydi�=��@u{� 6id�?n+3Drowc#. �ark\%P�p� �|�'�vuBM $photographa�5%9bz.�!3mf6 manu�]� w‘� hand\��d�ImageJ�A46r [5�UNon-ger�e,!xorg�o�= dela^�։mno!e!Rirty-A!YaNx$hypocotyls�#aC 5mm @}G��� .��!y �[VVB-AY^ce�.2&,by subt��!4."�2CoA��JA;U�%�a!�;��˹aI 8. S��^|eДQ �s�1��]�AR�{"���resn� G|��i�_>;� '�$ ^%5��bi"|UV*�u{!m��Fe"�7Y�rep�Id'p�M��uFJbU�U <QWAWo��W;�?��.�*g I�1a��bm-uF7&�E�9QA�W[e)�N�U,"zU(y= μ+a+b+��Ba ~ NnS, Gσa�(a &�e�g#"�i�G8�![F:J; b6o∘GσbrsF�l�B.?>A*nor^y ��� Q��De�% $"Ti�!xYc1וA��B#U�{ �"* !,�EbIW��sumB��9H(�-.�V)���. UUv# U�e�n�AO � 93�P 2+ A�- , ,�4 %٪ �"M��:-R as*�A�j�\5�2 M����*�'&OM� oy\�u�Y���eg7s( )�R/2UIV/s ~S.!,_up9�R�S�� �o1 �q����5!�*�4u�a慎.�H"OZFqY�q��y �n�� BU�V�T)maxim�� bsola� ^M�1�^*XTͬ*�5I=� empi�l 5��T("p8002) uJs�W!�)?� X�"w �,A�)�he'S– %A\ procedure4SRi��AJ�b!del: Y�" b0+b$ A+bKB+b/�AB��n�#�5�z�L�lem�yin :V�]'A"'���ePG X[$y > 25%I��f�Q} u� T�k� 4�)Q&O=!��L-�a��R�'ה&�{"x!�p-6� > &2_8 ��/� as� �c1]�_>�._&b6.aV��"��Pa�ap�Rgpp�I} I}���"cC )j�wiB2^�9'f�.<<$U�i~�e~!B�U-�i�F��"]1M:5RD . � 6b� �7�t�]l<-k+I�~&��X�E deri��T�`9 xi  = a�&�\ťby�!\!-'�#.ya$:�)�CLD �R�A��U)��-we�jfacahK� "ޖ ;9�""�R125Mb-��KLD- w�" "10kb ( f� 500;-S)!�n�A�!.\[>�!*�HF��R�?�sixN�e [GWA��r'�ambiguoa��-N2p;h8�,!StX3$o��:p!�-!� SNP Y���!� t( �$cka#�R�a)h� ar�=��ɊQ�%#d�3���.�t�~�#�6���E M1la).��� .;%$p. ��%"=�Pr.��Z�B ̅Sn�ncef*J���Pass�r!exA��4� `{yx eA�"�$¡���0t&]�F� r��60A� J�B_="1��b�JrS8�^', &�.of�!/� /��`!Z%$ag�ӡ�<�A��EF�1k �I�"D��s*?�A�� �&a0q�R�]���B*-��Ro�}�]8BX�eNb��Զ;+!y� � !w%� !M$)�un��EV no s&�5�!Y�I�aLx#6..�'�Bpr*�_�p�M��1�iN��!'! � Eba���. F%B=IG2c}n6� 2��4( http://www .$i�� org� {_@l�Ei�T/Ad96"&K.'��dlJP.$"�-!!�r���� &�i(�J��� �.| )��!81+d.����i�>:�_4,�1d Jn�6ho�), kee�!!sւ�eN"a��!6�"�!x�W"���a��VUe>!T�,z#�~LD�I2��:. ~�{&��"50h!�%a6� �sAal�qAm�q:6�%r2, ax[ 8C � zb/0��f0Ln ]�J�*H/6I% e Ensembl٪ nt E�A P�Fo*2 � TAIR10 rea�+Nk !Z.�D��5�Y ��$ �B�KLD� b�.ei���*�.�Gsv7y�wx�1kba2a��x�� y&%�-s�A�Q� Q�BAR eFP2��brows`��.\'��U�!�Nn:�(R*�!PascerW$�.^ �R(i�,ukey’s HSD� t hoc |L1�E"��*M&�Y) �1��s��*\.#YIn�gitochond��jx ( mt)*%b$.���T=c�P'i��S�T!�Aց�!�Cm΍i worl:Y&� clin�S�.[9 ok�o�$ �q �� addr80]�!�chayerC�e�3��506 �чs�:dcl Y��a�("�/0w2� wbc �bso=is�Y9m9E}�'ɇ�{����6�NFaqp/n M@-AW�9�ab*}"aH� M�j-9����P��"'3s�. .�&&�DCB�48F��pec��0���Ks�;! �0"JN� �|&u j��Ȗ��dE��A�mH phylaO clu}#c#<K�"p�e"l eA�� j�!6E�m�Y yo��1�AG��� �Er ;�_c�� "F ��MQse4+in�w�|e6I 9� xm�lG11F�'�22Bh~v� en�^� thro'�+�@��Jl�'&PAu�7�#~�I�4A�a�� -Lc�� �-$��b�'U\eth4u��LH�|n�� A ��?8�'% � !�E�g��ne"Fre*Jb{ ��0>� �s�*� Af�_ 5EhG�ob�y� sub- $=*c��w/�n&z"5  zV zI�UY�o($�<lyz�C����‘�! ’[�3Sa�r�qA,� g�i5Jm"�21�, Q.��1A0y/& "}[�2�� se:�re����(��P� o�\f�����y"a���!�buq*aGJLe�!8dit�@Op!6Neuro��(y ( LHON: m 4484T>C ,3460G>A 11778)~j�u)�9�D��%e{���oqsi!E(:6(���all�E��^RAsG����n��u�hasS�-&,v&stA/v atA� <�3 "�%)�"�p&��d&�0�J�i� b��eSloa)e�GenBankaF�+�S2"�+� A�"ak852�JFw L , LQ202 #M\2�45 N�#1[`815�b�Z�" O/D?\HH�!:A�t#�5[�7]>��Ytre�� org/ /�in htm ��r��� s�k:ctaggem(5t�4N�dw�=��x2���{ &V691=�+�&-E�n-R���)X5AV� >� ( +m710iE!�619 ��!�361�;6� : ��E��� *d"� ! V�yl,�84�M< � 2e-1!4rF� L; R�Z968 ,�;M.;8�;$N , Person��l1�S1A�Fb$J> eV790 E�� ]�I'șTA�i&��of 9935�V9 %!� Well0vTrust CC�(ol sort�-[+�A6�!�EDI59��U�� in�(�� ����ed. 95��N ��B%v'��d b�� 9V370 �9_�$$a�*Fsee"s���@�ssVJ� !2>( 4qeB�e�71 �q�637 N�T��F�͍�m5�e�Fz� a�5�nLy{4!8N�?F�2{�q�;6�j>�;N; Pea~��n , S3u�FurDeo9� ofB���E*:�I}��-��-ha�!C��:��p-� -�:�AAl�Z�e ����"oy:.7U ( N�18*M7Sai׽b��m�*��1:1�,0!�F�r.DE�FiHM�V�L� -J\�2��(&��9N�%��#)� healthy.bi$�7n���#i�> .!�.`‘&� �r�="�0�s.JAٯr-E?1RA�� DU� �2QT�Iot:z,�w3YO ^fS���!�. � -�z!�ա=. A;�i8�]� � �L" ! og�As"�r� &VCwe saw!�rWmhip�� =i*�of "u IdV �t �l 9�iub.c  ��eTR �\ur%��0( S�,���UR>X!a� "�� S1B��WD$33" 'hsY"�E1O1A �A@�'��#� ��Y1 a��T�v!wmpl"�&�=�)\!�6�Uw��]-�o�C5*�& d%�U� �aE�6KU� �%���Gp�� o�166Z��{�B��tit�c�"L�', 7��M =�`88I N = j 4��r����K� :�A��I�tN0m !L �5B���f]����=�oy2&� 24 � *��g%/�4�n=�. Ninet�Dp8@�(:��a�+>,ClinVai=base[11] w]@& U� MY��T!(��T8!� Incorp&I�[���p�on-��WB�(B� �&�-.���_T�}90��57�4�WaJ+ly��9V��$l���a��rop�-enco�,�E\ 709:�mB!S5O9I�9D434A�&J�( 2�A*fW,r�0�k�u���I\ZM��!d�32m�J��g g�F2CE7 Like[, FV "�{A�"�r2<B@�jj�ڑ&$?l:E�!d� Ne�Mݶ�"6e Z��t(�&^nLh6c47%cL�6Q or MN-�N  ; L us M:2�. 959e-1N $N.$9�992e-��MH2$8H 67e-��11��.1�� )�&L �K�ZD�T\ � i^m�7"� �)� ~2��f �E�� tren!ZS4�G��8��0%� ��ca� *~$�;^Ga/9�481 (%78Zin5��1!i0��5D� "-�U!%�M�h%Uk�YI� ��rr�^�s>�,-%h�/��NwJ�N>�N�'Ņ� L:P(YNBr39e-3vVq��4A��Vp�443e-1�*.Qi� ..%ae��2J--� ��2Q.Es�nbiho�A� �+4}�by�' m�E�%�$FE�A1>|s LE*�x"t2�E�.rf� �N�6/ E`hco-���.�(a�>�2+��&��, sequences h�arboring two of more disease-caus�Omutations was 6-fold lower than expected by chance ( p-value = 5 . 96e-09 , Fish8lest; Fig 2F ) . These observ m`implicate the mtDNA sequea0background in!$likelihood�acqui� or retain�ab� . Wj,n determinedYfr uyX�57bFs o �@‘major’ haplo�ps� wenty-fiv!' 43 . 9% )F]sN�(ere presentk%�%�$one macro-oD , and 34 ( 59 . 6i~Djor� (%�3A , S5 ) , ind!�!Trecurr�Q) event�(23 ( 40 . 4{of%A$pathogenic3s �only f%�on��. O@se , mT136A>G3177444G>�*11696.%3630%F�s based�analysis�entirB�A�(is suggests!�t specif�E�1"s q]:"�s!g mply!e that%<]�+A(disposes to)originalt)� ,aA�subiOt fixeu�allele�Da particular materSlineage!�I� otheA6nd-� 5631!p( LE0%r0663T>C2 8313 )M) 2770!�( XB 3890 -N ))�oA2seeA.E1 cladA!consistA�with a ��leI_er--�rai%<4he possibility5w$se severala�:!a�9�4are actually rsub.�markers�,not directly. ( eg� 4295! I�6489C>A�2O�l , w � s��(stical evid�*of.)cluste�$for 10 ( 2�.�34I�e�:����fter cor�A�X!H(sample size%�Hin each comparison �'< �%01 J#3B�Z�relat�M2��!�inA� 96-�A lank�Xnucleotide triplets[12]A�5b�XssD>d��$ saw a grea! pro�>��of C>T/!�A�T>C a{ titu�V!1 all varia�84( p< 2 . 2e-16N4A–4Ce2YC-� F��PDP�In ora!toaE firm%�B�za�9m��edi�E�ueIE elec�!(rCRS [13] a�/$e “refer!<,” by which.faU classifie�r we realig�30 , 506M���c�Re� truc� Sapiens Rt S���$RSRS ) [14A W�ed simi�pat���Ae% !�C>T>�Ca�5" ( S6�O�5A�!profile�q�,al signatureAure)`riven!*9%m��proceA�nd%0independ�5k5$ u��Q �� also�Տhig����3A�pG diyYsSM�N�hen�s o> CpG% , &R �+ 0017yexact W S7%X�S5 Taa�d AlthougMN ethy�:hfM,appear�Cbe��`in somatic tissues [15] ,�9$ar genome .Qchange bstanti� du�xembryo��germ-�P develop%�[16c��U>�.q� CpGsi arly2W contributiA2'AdAQvo- !�a��7aI;guingly���.�M hadIst�%��:�1�l<93%; L versus M 9�.�!M%N5�.#FN 9� )7def� MtNJ ( 21�b1^�=Qg49;U��= F0� 6EeBy)fask B&L%& muchB E�� D � , ��J6( Y 886�p-w m%49�5n9I � 15 )��}46}4� f� (ngs add fur�weight��hyp�& �h"� -"� ��%"ext infl� ��� siAwA�>3 ��t�- esti� � age/A�a 8m"� !� ��HcE� , �,Rho&S [18a&��w^ �&� > sco��"� ‘younge(� rec��):�s~ 5A%�5B]z.<, Wilcoxon Rank �E�Df��A��� �f�.�E_19f{W!�we stud�!Rsam᪩wship > remov�� main=I�B� from)�5ڡ�ilico1'C)'D we did�%�u$ an associ)� betw: �rex�_��aI`predi8 -H a)�A�� Nr��u�UM:tc0mitochondrial�nis 6�YzM itselfS� L^��it[�llatedat!may�inaccur�-bs� a� popu)�ans;[19��tF�� in keepcwaO�ffect � @ ac�on �\F�FŰwe:61}��s2071C� tRNA!w��2\ 21� S�y-four $5�e\�in&� Q.3 includ�16-vious�2�U#�� ( S4��C:�!�% �%�aj�) l�  !�Y(d6�Likewi�'rob\ dis�ES!�~�as 6 �a� � �s`ov�lJ\E�"�] M�mG2� mean�T427��,.410240 yA{QW;��6� two-l Y-NAg�O%��5aw6�l9�onB�s NE� 6Wf1jo��6 J_ L�9F36%L 6.51MN43N .i :5B�01a�& B 05 ,*� B 7�!� N��How: ,AnreDnZrr� ՈeiY A%�1��~��6ax � 6 M6�&6�&Ͷcould�� limi#numberQ.�q data se� o >��&�can��b� t1a� homoplasmb d gene� �is2$animal � , wh!]!@e-���� aastteip�|5c!AinB�wo�r)��but�F�6[2) Our&.of "�humanB�showsa)-� )�y���*  &s s!!mre���tre 6� Baknown/$cause LHON%�e��3c���K� Don?��c��/reducedRaEurop��s h6�r0 mF�  , bothQ9f�Z.?:� risk!��� 3�A�� .>4 conceivn t� &funal/&6�Q^p erhapA-"��I�7 incr�d oxygen!M��lBA�ha gregE�7h�uwq�"�B� a� s unl IweJ 6c �&?��under�10rac����s"as))Q) A�dikly�k��o oxi� (ve phosphor"�r.�y s= . 2� }�Me&� :�0��I��lyA�2N � T%?� , A4�m�!�9.�>ed��]w temp e�i� ��Ew��p�e��t asceribia�laeIe��:Hb � u�� u�`�����AեIU!�!casX Firs!I 8�� AO:�m >6�" �inental�s�sdly6�por�4of�B Y��v Q� s de���oAAsian� � 3 �"\ . Toe�miN!sA7estQ lani�i5BeI���.Q�have b�m.�ol�.�thr�p&x �G. A�. has ZnoAFpr"� �Q]AfricF [23��ex�dQ�*Npurifi��E a loS peri timAIev�endor�validMU����!��u�H�Va�di1 to)aYdJ- expl~ !���!.ydif�t�ah"5a�dI~-&� o� e rebyf��whyTethfN�O/ or� ��to�Q ��ay;ikM� .*� 'ima*an!���r]Pųtic5�o %��{� e "J e�landscap|For�mS,|0 anci /js poi �a��Y�!�(tleneck ~14,0 y�ago[24Y� ���.�� ve lac*.mY��x%���s�y 6�A)�� e!�Hach���!��de� !C�ud�e5n�4��yE�K"o�)@U�V1a�.A�VJ�=wadds au�lexa�,] mNc8q�loc meVism�� �$2���bmon.��!s1W�u�cr��� eg .� 3243�#-s*� fol%I� [�� scribed h�8.ladd�,$phenotypic�E$availX ��a� � ,� �ou� �T nfor�on!�~ draw�!~�. �m ,AHpip%4well-establish�trong.�"� famil�&� �!46�!� 11778�!!@14484De���� JA���!"Ul(�.���1� broad r�A�_�% t .)�!�J3KIA��#ea ��h }� ulti���k,%��]#. cy up��H5%@7 M ( G���Zs shar� � E� almo!�!���q� .9m6gJ!�M��n$pidemiologL"�!�of%�[3 , �Ily sup��e view�2hmod� $ clinapenetra*K�Z;��!5&�  e2is�-� an*< @ r�}fwO!�8 E{eae K� eH a"��z %�ext]� �Y�B�� clb�@*��nviro� al factor�aW2!s" �M�f� ��9+5�interp4)j!�i9"&sh/be��e�!it��*4thnogeographic� . 619^��0 mġ�4globe download! GenB�L( https://www . ncbilA!Dnih . gov/genbank/eL1137  M poor"� qua&.&��|��reAAlu������!)� ReviW! CambridgeVp"r #p"#ndޫ"�BLASTa S1**H"_ aigE<��pe1� @*Grep 2[�Sv �*~#in !�* �;L<��',�nd#2,6�� phyl#*E�tree[6]-�5�$ . org/ /�"x . htm�25,-�* ��852 , `%202�plex �45r ) l= Coalesc�j -e"�)HA�ρ&F ( apge �.��'typ�#a!cdn=r� root/� cN angb� heurK�a��`standard error ( σ ) cal�)�{ga� �9 genealogy W�r�&d� �"&` �*"N�l�)+ 6�� ,"� in��S3 >�[�Ryof [A��� �e�retrie2 lA.c( .�M��pectra B�"��>!�/���)��Q)EcT)F~(-MlU)�++ sA4E�m� s� �N"so ng��!C�o�um'Y  v � �sixA�tinguishi C ��C:G>T:P0 T:A>C:G ,A:T G:C ,�*G:Tt Each4)^A��/layedm�a�,.,��*�$�b�F+v���"~ immediat��3�.�5 m�ede2-A�P&sE��!Za�-�m�s&���Kby �"� ��J�$asa� ropr� . Va-�A� or f)E�>�( ’s.* . P�onc*{coefficF( R��!%Dig8 c� ܹl.Nx%? l�it�alZ1">�R ( v4h>� r-projec�orgEK!�eH� � � �"� e&� >`G :�G . Ac`,^$sey��Xin&| . Non� genem de��!�#���.��In�cer�* asta~,*F+���� wA4h.$ng , cellsF coordin� thei��AM , lea �.l�vXti To*�z9 [- eU���.O�A�inhib�of locom � ( CI*3 icro2!C,!*)`often�-to trict�Bto;,� (si-one-dime�% ath-I��assay�colli!�&� polarizedhs��Ktly��la few&�"outcom�$s�!-s�+!��E&�G~�a�M�-@2ofN8in viv!>6i�F� ersa+hemocy�m�&std)$Drosophila2� [15CIL0/e� ���KLA pNAfu+ d�mM u�techniq�alyze\�troAu�!0<� Af veloDof pair"��fAWA|1���is� su9[!'. �/7 !��[low�:R c�si? !��!�� !=.�eJ ,�"�0ro1AV� ed 1DB}m ��e}��$ Ao�' � :c �;eIRM'AScy%ens�7�� i� � geometry�0)*�s�[  %��)���� Mn^)con0� [2�� !xbe:N&I�:y�to&� $| molek -P{ �D2-26��ex����at} d-oq QM�wo�� r��C1"�.�:!K , 20]:� T JXenopu<n3R Scarpa&A$� � ze�argk�,!�-9�X",nti~ve��&apB�!A-2se24reveal,;"' -�.�)3e�D8��� a sm,&>1|o & 9"e ,S -P �� unco�z � ch3E��Z ed (� T%JS.6- "�(%V!#!a`.� E'�;)ok��vochick ^�[ �is work�|@lla"��om* � to e�� !��e!*a� �� h��*��l�Oeukaryo�$AP�k !�$on narrow R�� -$"���Uex��.��*�;-�[28� � 5��a!�ng����ll0�.��\t"G6�� primary/s�,d !'es �� `M—��w�@ds\ �,“front@!�t�'�&C"� 5��| n�# To d]ia7weMmin�%$!��9 GTPase ki�a�9]A.0 d"� of()ty�L1�Q�{ is Racis� �� J�G�F �� � corpo��)�^p@ I�� E��i �>loA�g�q r����orwaLsim�a �=��im��(� er� �� �ES� m Ad%7�$!&��Y2`#.�. � Zfa�} i�ract.� n auxiliA�.�ϕ ( i~r-"1& �M@moothlB/ *ϕ �4(�s�.�)E�#1Zn")_&!�4$scale ϵ; �!%� is g.(B��" U/lDAa%(any fluid f� cneg�ed�E_h9)i�J�8�,�BId forc/0 .�2B�∂ t�>Jq?τ αX(5aχ ,) - β | ∇>| - 16ϵ δ H=����a �"parg� [28 , 3��HG,Na� �,e3.J��5s "3��{�u� �62W�A�' at m!�. re0 ��Kot_,ngle [30–3� z ��39]I$!�v � ]��a p terma�!�r�)h�E�of Eq 1���a�l ".�, AAk%vM!ci4DN:(/lymeri����:eH#�myosin-MvA�r@�C�$cytoskelet�4er [4%�H�e �=.� � push �Gœa�wW!s ρA�( αρ >A�i�����2:ow8�6=�DTo)�2&�@R� �^| "��m�� t�otr* i�jy�G� 4 dX "�3a~/�����s.l� )��!�u��tak�"nq�)� ��~ �)A(�(esy+a�m�A epthE�X: �)in [4 "In.�%]c9M�einI��/.4�V�#Q&a H+ton�1H = HA�le + H�−%H-Ke�.98is H s i n g l WQDγ ( P ) ∫ d 2 r��2�� | 2 + G (�)+, κ 2ϵ�,2%- G ′2� ("I�u[(��t[e�κ%:benE-u�Pdouble-`, po�M� �= 18ϕ2�"−�) 2d bilizmztwo)xs!I/ou�;z-!�H+�l�:% �� 0Υa�i -c&KIF,1B9��1�$is equivalhmW$Canham-Hel�Kh2�[4!�43�&s�9cus}A�ɖ1]� 5��Ia��EL�ter P��*��):= 0 · 1 + p e r ×Ej- P c r�if P ≥ �M��? �s� &a&as P =A�(d2 r|∇ϕ|E�XPcr1a&�I�+� �F abov��is&��B:Vpo6-yi-4%�  g�at�o� ela1 m�Ia9iMP}ID� $ FHel ∼%5A��A�.�26��o��$!� JqL!9o�nt!7p%!!a� �M2�-On#aiOweIad�*ca�#!  HbE��K��l ��Iys very�0it�K�0�R��S�#u�frD%;�)favorņ ��C�� i�:�2�!�1e� gA�$ �� γper�B$. 5μm−1e#!�= 58μJ,6�sl ly��r!5imun� ur�1Y�N �F����ia≈ 56 ��!�defaultYաGN" e�1 s�L�e�,a��,�}DWM�]�d �,}%�x?E N�i!��r*_ m�� 6�,A��7Mgrowth,PN�a���.`�3�conduct��M^ %���*�A LIӥ���on'��2ye-[ phys:Hvole e|1g �"}q;0: H c e l l - � � i ≠ j���g�> � j2]-�+ϵ 3 4�� 8|.(8. (n$:� �� �by�0 aliz� a�lap"� &Y�s%ȁ�m�e!�8  �mML� ,i��b!���%�>t)�"8 E|� l-��et�σ�&�8��AI"/'ofev* � V`IC!��(!�.�re� gQ�Oi_;uc�Qa�w )a1�, +o�l��2}ra"�!f �0�� n4� J w�1aXQ`a \-�%�-u"(�@n�$���*�Q 8h�<re)�-!�} eq�%�!M�!:u &�= D u� .+ f.5 ( 4 ) As�2w� [4�4�"}!�be sol�i�B2lex&�B�a2.ϕ)%�=��? �� �6��� [H�u ] +� ��OI�vE]5�� ,� 5a6u Eq 4%� Ne�D'20no-flux ) bou!0y!��8�.Acc9'�5,e#96�!�q�-C� te �*&UIy6a XiE8-1Rρ��).*��D�%-8 f( K, c y t !,�) ,F{� =� [D Iy#:x>, {!�} � }m( =ReDρ�be�Yy#*_� d f )qO�c!���ex�m.Xa��� r�.7 2uni7 cYo� ol ρcy!I��&*DR�eQ8�, *wave-pin�>s�Y`/��by Mori"�[29]:��= k b.�� K a"]+ k a>- k c [ 1�Y�I 0 ]3I( 7p�2^(= N t o t -����AU�*��P8�<I0!� ��brah�7!_�2�:basicB�+es:�-�ictb�#ng�a�U  �\ka kb�*4 oopef*v\ cruit�oe_�jI eBX, ��,ρ�ach?9�I�Z �I5�!�r� ) /I0 ) �>b)g,maXgZ!:X�de�hb� PYe��b�to}9-!A�Ges Ntot�/�QjC+m2)I�*� �  c8 e�-��8a�%���-)ic�y�u�quickly��6 ,��;�!!�t�$Uiospa�l� 86�.Eqe� o�r��9s , fI�s writ�,asa�!�A�N=eg- I&yc��<{A9�>��>FR + η ξu>Q!( 9/�� *r�, t) 〉� 2-�r - &)(e�/Q 1A(!�*<��9&decayI�Il −I)�:7 > s3�EGg:� A�<� eac��di5�9siv2� n�WWSY!� thir� N�6s�c�ng Ga� an L1&vin no�Q-e!a) ariy�i\Zn��stochrG!om� b*$6y� ��+  r�'!m�X y�inv� [4C\4�WW.qAkQ  n?Kv�S�$|I|�s` }!�,o- ve (.) I#2spond��!"� (A z$�9 Ӎ�A$E�Hc Eq 7��� pIL(nY/ be��Wh� �,�A2� � �be���Z >�a�Rn" � Y ≡ I +��� �lw %5+�`�*�*by lookV�� *� } ja/��*T e6� tI9 I∇2� � im�⋯� �< �0#to ∂tYCY� C( �|+ N� -&�+����)��~a!�al)�9�&!`�C  �A!ermE�I�(�L� easi � �Yk&k ��"�4- �VP!Oper`ag�Mnge!�I�!�e2� F J��s�a����`)a high@A� q~�6A �l�i�):B �] �h�ck ��36i<�ρ ����� reor6BJs�.%X�I `�%y�=rf_�$ ��)��Z)1�E�inhD1��"Te)�x 9A a 1DjiI��5A itud%:��B�{�a��$ �*~=[(�"u%"f.�A$�η+h�t"0W�Kne*�#!�w� i�d�;E�ηRmov@Am�er��2>A�*n!Qed�K s2se"�(al E&��#�awe&��P�!� K �Ga���%o��)��F&_4��!s"�i0 ?�ARe,�8p"&� ABa�u�)�Laa�It"uw�$z� Y� a�e1�A��,i|/2'"%�!���da,9as 9NRK-52E�+b9]!e��! a inctt&�I1'��re2� ( CRm/iB F Iv#�7rex\v%�or^A,;P taD:kCR�kFRF�AWe sketrfse.�m�v Mathes�0�e�Y'��$ desc�IbyA�lu!�f" )�9�!! i-th%V: i (�� � C R S ∑P�� i N"& U?︸!f�F�0��9- Oi�#�h��P%R( 1Q#i(S ( x )aҁhgmoidL)UTn " = max ( 0!Oanh[x/x0��6x�s`�NE�!'>� �*� �!.�"CRR�I� star o��:�sbc ovea#� �U�� i�*� lig�&�.i&�'s!JVi"rE�o CA�<:�2=�n�c�q%:� W0�� R���"Y�!��6m�%�2�1�5at{nele�(�1�1,� p?� "6o-^ a�i#4!�]-�$���:+�RD�� �:b.=Q al5+;� � O�D]�QWepH .!�*����� �PV� ��2@��5��j:�PJ�4%^I�]5���*%6= ծ8� :Z� ���OyFR �ji�d,ligand-recep�L*r�s8u cogn3#!�)�86G4�f � 9!� !� � �]orM��+!��CE^��-��; *� oM�O}1ANEq�8]c-Q�shou%X�!o� excee��/FR�M� . Unsa�jb*TA�.E���#r k��FR��% f#"H !<�e M� ach2�/�� e� ϕρ�Q�reg��.` !Ob!9�2�UY ��� ]Uri�2�؍cFR!s�M9!�2� ��suBN&�Uot upon�R��er?5)5}W2`F|�RQer�� . IfQ��ol �9�w�bU2!� �<FR does ���8�}��C . AtD er=�O!N ,F�6 Bs]in-�s��8� 9Lq onab-JE-�o�;A>!�2uY . H� )[I .U !�Y� ���ism�d%! %$b�9n�A���A�3A�S��� �iQP�-i}a8!�q7yh@.� �!Q�OO> r_g� amou�/ B�1�a�a1,A.2?��. T9TaJrl[,2|��)��^A�aCy4.V��l 5*�"e��![:��A� �!� Z� 01[UsuYQhodPe�O!!u,}'@2?��7�at ρϕ �U!I1�!�Y#is���LspI:!i<*)-�}q��.�ؙ/on>/|(( � = E/qa * re cl�UEbdel!>�)�E�f�+�%ach�?Ŭemx�()�s| .!2}�(es�Yj)�2c$WYX ) E�� ��of�6���* a\hr I8 s�I/ FR��stops b�9 ^�"s� � &� c�%>: Aw16*�5eg8 � -on�.J� *p6> %�&=",e��]i�� %n%G;$,DA�2�I� jFR.������(i�9�"2+�W un4/ m!Hh �]r�C�!C>j&mlP�qpE�T0�D�DApSspace& '�b;/weV�w/ &#v#�fl � al��:� 7 ngE�6�l��%y��l ngA=�X� �p�{Ti�͆E��e�4�"^i�E&�"]G��:�D( �&�9�< tick�t9�F)439|!y�(EB;1ss:&I$�� σ ,^_ `!���1s� ���:I�Z<w0e�/!� (snapshoq 9� �a�'e�r��(:  swee��H ��&�K2�e< �SDP wM�h��sJ}"^ir��)-(9chpF�3�"� I-BSa. M�Y ���+�(( (!.���r�J��K�v#"7 6,+J�G� ahbS�dh"�jh�d�) 'vp�, d�8��сi �>AMcRow;e�G�ErA�i U�YoaJ�'.��e�aS-�s�q �varepd]o�$axp_tJ!=�K �XhoT&%\8�z�plo^Yr ag�Lk� � " �CR��!��ol� !.De$���@w%gd%�Q �7 + qll �� Y ntui8q���kZ:�^!�oo-��0�?AP pass�QE�-r.��&�>O"�(]�;� exam5],! �1. 004s�-�maximum=L�drL�∼60%S = 2�  )�� ∼43�-+f )�0 �� k y� of�.�p!�I�)�i� ne�#ara� mono4�� *�� Je!� �YQ.a�- A5��ofA(ipq��Xac�6a5_�%@6!)�&t1 QWs�h���Sc04EL&�[�" @Ahe ;c.�B�q .@vs�`jbeg> c"@�" e A�#�GT te�A!"�%��!�eaN�f. C���toE/6y*at.�gai O!+vD19 !�,Q�2I�:q i�=a�1ͱ�/5(%�se� �F�\E�c\%��8-}� %�VM�exacPq^o�pl�A� S1 TI" � ask� quIZ�bh� ������r"c AquVVC2&�0�0:�V�G�i��aC∼25%15Tg ic8B∼73>@rL_a@%%A)�[2K:WsY��P�W� coex|�"# \ ja�Ȉv&�M�MA�%jmanN�1i ll!�nn272Wfiat�L��g>$e qs� ���.�:g>pw��&);Spi B�&%nA�k M��2�1I�, *15�� σ = .U85σ0EO6pa�A� 9%��+ �27%9i Q�y(E�Te��. Se�dev]2�z(" �]!T><���s2�;!�Yqt�o scr�k!&UV. "� � 9y�  9*���#�%ZA�A l %� ?a AIzBMv~�F����� ��A� J�G!,be bloRAUT�[�f� wo�((s ( DshDEP+�Y-2763o[�J,�a!�� 4�|�pTaaKa�M ed"&jA�� � —)!>44]>�.�67% ��P�ujV�T, a nZK[d�� tA�!I����) �du>!pw�1b��C�\.d:hMef�/r0Ew�P�8Zvok� ��B��$o �b' on ?�>M�is"�S�E%)P!u��R�� $sQ<7�Gy/�%�(}�aDsFqAdm�!m%��m�%%q :UG.� �8b�:50̄a*�DEI��mk2�k{���mk. �MA��.�I�+and1s% !a>hr�8.�,Iq��U;�Ōsumma%XNs�Q���0�L2X3 A�rJb� �1a( �!� sign� y bC1�>P*�&�Sa�1 *$<s%���!R��! S3�� 6K�a�*��^ ��6�=D CIL-��9SX�#�&e�)�& 6og�e%iX�Uby6�La�E�S�rV bP1RlQ EC5�!g�-4V fe�+��-#9,E�)����C8EAa weaker��,A�A1p.�$�s �:� ��S:at �&BV. Surpd,���d.�.s P5�. WhyC�(e6�be�E \��M?i!�&��2�%"�K}�i6� �.�s�num &L�Hap9�") �Wr7%�kU!��;!�b��d@ AaA.] r*s byE"rral�=s`Vor�)���*iݡ|:Q.>� � hain�m�� r! ir�,Wle�$ir breakup]]��vM=feU!ig�jurtB�w �#�9m)>?a 6�o���a|'(.nN.� � ��)���5�.N&�+ly �|�6s2� ~ Sw�t tij^�#�& �A=!c�K�[j))T��m`"�< mak�har$7 I�L ��9ee��:A�<8N jů�.�.� #%� ier �A -tenl#γ�sN���5H"�4ou1H�Y�Y�EH5���~�� ,Fn�m�� �1C!>+IV!*R�7kb . E=���-r�F$E�m�r��5!�&�ρa�!-�`nt�tar<2. I,�=e8��5�*G��,,�`��&�OYr@)m7\8�d:"�A�) !e4WaY.a� �V�AkEf��p&jI>�Tak5(]c;IF��^��B}% fbI�|gu�"%0 .�  v&!">�9I �R�my n ��Red�addres�is"�u3��c!4o=��T 1a�0�4d)��JU"]C";VJ b&� N h��:#D�:�Qon� S�,e��9 s��D.]�Su�sAM\G]r� ]e`��}�/btdY%�� eVmu:� *�$�(l3B &�. P�!xatApm&D� 7� "^ . robuo}r� e�$���� 2�'A 4� �I"�#*.v��Xi�|9i�+8 Movie3 >�� t6-��&B2�B���� �h��A�%< I�&�^�7l&# ,es >&� alG���,�"�^Ŝag+n N� �F�dc�bi桯-7n-v1 � ��mai^QO�[1T%U9=U��"l�<�1� 0D]��F"� Y�A!:�H�oA�mi du� s7� ngA�s���7a&�B� w��10.�i�%��� 6�we�!��5���Qe��xovA�11njtr�I!�a�c! mannA�SV�'�G�%Ref .�:*�at$M[E�U�3�!S&��,iE�� &bPID�Ŭ1�h�. �!�e�v�y�*e�0%+�3!�aCz.�V r/kH*�hi��2w�Up�orom_2.�(�v-� iign�-�ts \Mo.-a9eBe��i� xa�6������2"�p���65*�r�Jv�Iu� alth>^me�jtic ep:l�%eŌ[?/^u��!!9��H:�u�n"!�J�L#/#�Gi#.��nou2�oa�C[� high >\)�ls 0KhA a�a�:��]��%57Je,i � �Hgj�� tr�Eby)� � <�eY� al�l�]*M%2r]Ml�%� peakA,!�"L ������ 1�"1�i��X“A/��[��2g Desa&&C!�U)P�5z6�5��y*H"�� )_s e�As��^A F� �e�(ͺ"7 =�m�h�+hZ:�A��!&*�I� "H&.(i��4�}1A��P=*03V��C"f �P"� uPq, w ≤ o4o��gN"��a 100*oA�d  W�e �H q!!�1�� ir"]�)�n*� g�i!VJ�=��*�,!�� AEl��E�@iRf�]>"�jrum �(2 ∼)�5>�{��� !1Zk����� JInA�t*d1nonzero&� lap�n9h��&�!S— %��w  d9�%t��e�s 5%�G�_�[�0�� a}b !9j�M}�5�U!�H:"U&� 8Kaa�"]of 99�&�!�JF{`�9h�l� rapi�to %J,� z���no� er squeez�6� B�6�%(�30a"=%:]�:�!Csi�U�6Y ���c�:P�&��.k"a�b��� .�rou|[o"D! pr�to�pj�2@rm���Zd:0��� I�,"!z&, [ C,%� 3.�v-M,��� �� ��:� . WY!.q�*oU6*� � :� 4�"�(� l��K!?�a-e9 I��,��be�@eŇ�o�5-�{ u�s"Q�X",6V�� R!�RE�m��ta���-qO.���:|� ��� A�.�'i!�"�o�{.yx��srJ/�29�B+!>�U(�!�4)"��  (��(i�n �t�;*(a���re� ��&K %�*�6�%]�*�1X6O α ,A�w<�2" β��"�Xγ��H� F&of 1% �8��swid?*A �m|�A9�o�A�2 � 16> tu-�� a�k5HX%6Eu�to�_7*�*�*�vb HF%s�ze"�<! ffec@ 3Y n� nA�c*!&of9 AG1�sQ%�)2�yIL9ca_r�xO G{�L.�} cŞW5 guN �?��H :�S�2QLq~a9a8,""eR�!�10%�!�er [5@5�s�eu2Ii���ee o �y�5v/?s2�E^!�e-~4[5��5�sCt>B�tCj���~� 6Yt !"��Fn�f��T��o��_`*�=e89?YuR�� ����e�� ]( =�@a*���!V-A %���>(low>',Uu����.n1NZE��JN�8�o6� prec�� �8�kaNS�&.�;'� $G�)l6�!J ideai��EPsA )g)%�RE�eZ�!�/y2�i�b(�beW 5e+";eB<*="���CILa32�[�F� �6oU E�6���.� �i5v�z2� ��4r�D�9�Ee�%*�&p�a� f�'p[AW54Tl“"���[5.�57 v�gs [�3qM58�v1] ? S� ofc��*�\�&�i8"A�"� %�"'��)*0  �!ha~f � .�k(��� pl��*;|-�[9�D� qin�ly z%�Irux%�� !+� &� .�2<+�f!}O�G���C�I%)�"X�,rO�%xA�.�"A�� "�;6��Ac �x� Q� @�$N(�q�)� @0\8.�K w2,��a�&�$X'ngb93=li E�%.�2$eoAm�H�"�a#�9nR2��PqD�e%ouptofyi/Zsh�~X� �s�oAhl1�U�"� ��hnon&�21^.`M�illus�?i 6 _$�K!':��Zρڣ elf-A"el���xU[���JO y>5�Cq�,$. !r��c�*�u |-5,u9� "7�%[&{�CE�re6E�-s��%=A�;1I� jam�U*15n.w!j?��[ 62];��U4 I?z�J%)��l-��|1�u)U�{s]�#k�'ׅ�r�~�udY7A]���U^� �on2fs� *9� E-N� p$Mjo��2�5sA����2<�4u�J�B�"9�Qt� !1A�8dford e�MmsmY e�9�L"���!�46Q �6nZ�AwEi��o�y��A�M�Ew! � ��Ab�&te�� ne"�. choi"�. Tp�d seRLafp2m���t�l� 2 &R l�"s"4V;e���[6X�A@�en ��'0or Dictyostel�[6R 65�wId!�hydro�, weF�"a�� a��D)O1�m�n��"�[3=i4� R�?"�-Yl�  �T�if��w� �v�#%�qy�)miN�%O f�+ Bn[6�yAxIfe�0�54�� yep�N��24�7s�(Q�V oatt!��4�?Gn< tax;N� �io- ?a, h i*ZT# A&a�cordV&6[67];�)�E�J�R"nw� iaeC����e��6!�6vX&�"?gr�*!��we69�DA�*t� l� �p� d|;�Cy��?a�M���|72� !�y[t!�Q)�*!��K�j&�B�x& � Bmi���? ab�+� B/��I�Z�f7qson�2A.!?>�{di �r��Dn!A6 � �eAcn"�s!��a !�R� � �I�9Jhf��*U�n�)� acB_�d]��R.�$�n{"����'SER��YsE�e�AU(�*\ �X � �+�� WDs*� ��!"A��c"�+a)�7>%xa�1;-.: CR�iba)��A=h�f(G&� ��BS)E�2�i�E2f�.�� ���5e~ �Fnd�� �!� nCo����� vRF� *'3b T',c9���[lŀ���"�UA�� @w� L*k2/ &g�� �!I�sQ�� # "� &0Nv e)�o���+ B��yDh2�|p\*o��c��� SPj�1nFmXr. [3��.�%�:� �%u4Vo�-w�6�6 %�2HA�"��"dy!��A \m z!KFs!�nG.�M)[s&�@'�*�d.��AT�_�|Q�a4��}9���*�q5�n��6~ %�p �v-�Ccy .��9 di*l�&� � thi� oxi�hTr'Vmi>Edisulf{�Mjw��%ar"� debl�s%_n td�գ.>�<�nA�gug!kAk�. ���̜6 i ���Q-d�A2� C �< � put� .2>a Gq�I5b�Q!!���Ǧv�u.bW t�S arse�Zt�e( Ars'�ȁ<.�0�  �ur=8 Cys29Trx-Cys898� �!ad5��-o��2% atta�R�'اa2a- k ū����theorr� tiv\��-:�aיy=�. ��O1[��.��b�-�M,%|>�2�!\q �&F���C} ��O��; 'O!ZmbbnCys32AI�%�3$.P�aA5N�by� 9�bo�b)..JlwTeb��>Fik!�%�A�" ��F��a"sR�hB^sus*V�HCM�E� onM2��)�/�di��"g*proM�s��shq to a�j>e�/dU�"1k ���� "q7em�*u�a�U�!�T�F�!�6��un�/�!�Vo-re�Eaaredox&$N�–��Al;|� �)"� w-.$�fyVa-K9q lؼ���*β-��A>surE��_R0 α-helices [�v�S � Nid�|e-sit�3opa3����two �-��e ��residu�"�?_ Ň@e Trp-Cys-Gly-Pro [5]�>ps$287E�a\UBac��{� Bs_!�)%� S . aureuSa  M�j�"�A&�v))�\!s�A�e��!^exlpha !@x α1%P�f,Lys33� Glu4��pK 5�aN-t�>al2l5K[6E.9]�*� l�e*&�\�J Ua<-~*n%.6h!lQ��Z���X� cf"l�.tgK� ŦA�qeGV�U��ac�]a�Z��ņ!dq�a����[�[1�EW� d&�end�2h�!�� ! FvA��))�&�be�in-�ed $7�y ./B .:z N�Y>{F�H�a�1ivcat@�� r=!Cof�[A� V ) �YA� III�A��enzym#vWiD�ih[ox'�;��(!�ʡ`.�,am�fSa ��.�a�-� =�risplac@��Q�ɺep�="0ik -*NQ8-�| casc&SО,pD%^�T�=�oxA�a�qWb@"sj(�l �:� �-�-. A%� 5 -�=0%U� 98�lxi*< i � �"I m.w�1l�od-ZE��s[ʐ� �yyconver�"2yXtoqiniqV��!t�[g���.�i�s"��F �A- 5 d1�6�)B[2<%o"� _� ^B� 2� c:Lx.M~ A�f ��X �bFi 2�!�)�qI��? W,D� "�Ka2$- !�5D9!�-�d5 �2BG6�u!5�"� W_�-1�%.�U�iw ��&= behin 6�ly&2 KE�� (6�-c>#�<  )�� �9��*%&JA)�:A5��)��� �. E"�5E���"�6 c!"'�-�����NҚ�F.A4k8�,~ .�A�,97\".�p*�`&HzV�by�8��M9 nnq/��cl�0nB�"� �Ts`��or�D"� �9/Y/� z�J 6s]D9 �t��-.��&�A�&� 1<�ADBA�i=�gi2�!~a _ =.�S����!��5re%�r!R&"OC�*l-aT1u� �A�EaiMRI�AU[]!�6���>�q1�� �������)�ERYE��d�Oto��2* ������� �r�[21�PY�A��"�%��pep��Z�e� hde�8$��dDRef-12�!�NFκβ �j, todv�����a2-�^��s ���  :�Bs_�N0MvN�'�rw2�� 䵁LZA���2�sD�*�8 ( MDR6p c��i�,AE[�u�A� ��d�-yu �R�y�MFT> �u "[:�)�&8$*�7!�F�EF�� est::� .�M�&� �: $.�ͩa�20�Ad�2u�ys!�%�of"g&�s>�Asp23!�A&Al,� el� n , \7o�swj*)M�� ʵw�firmly6C�o�"�o�X�H�u9Ro!�"�*�suL�-e�Tp&R�"��lo[e0�C3&��!#wild-typ*�E���so �."� o�i� .]Cr��c�V u!�(*��EG+I4n}�]z�3toj�� ��T! hyZ*��ma s!v!�"�dGrg{�u T< �.{�r�#y����y�-�MN�WMD��jdy)ntum-M0. ~}ѧwad�b,jH.�9  Ian �%��N�o��" ��al9�:<roE. �2O�)-R���[��:� �e�vl���dɥ&9 >��H�er�<6APQF�n����<2�gm~xs"�3�.�^<" �.'4 '7]�%�w��"gen�A��sulphur A�;� cruc���S�0,Y<hio�a�E�&' Ir�+�%Vf$e�:t�&xplicit\�%�o�)D^ �8��� ��&i:M J~��rf���"�(-�l����:9� NMR] J>�l� �M!��n2 :",E �c=Z2w���+� �:s12a�2A U N�fe"�?"m � T�:V&�2,� � � ��G�gl��R��+V+n4f �(., ,��Feqm�6�!N�^�)i�Ax)� O>)R?>>�&F J��51of!9� ![eO!52�.)i~A%�6� k\H�$%��f�/,%2�a��“Bm5%. KnowlC� �Z� � *_&�!@5��)s���1ly��� 16 H ���1�� | easyAc�K.� ly [3�&ymfeff�9�kev4c*�(*�od� � P�a�� ], [�.�ѡ����.�]�&#�ro!><,MU��*�+Pon-Boltz=FEal!?[��,��A� empi�p�F&�,[3�D��!���.�!B8��%�"U*!(-&N)�aa��[e��cE� s�5r>�2/!S�A��Yl��� )qe.� h mea2 tM��.�m�2�)C#~���T��c=`��s�ntaw�8�ZA�inuum� �pl � � ) NPA-i�Y�i�6beth�� �w prin��W%%�u,.�m&� n b�su gJX�� g!3t g  M��-4c2e� 9E�5 E�� [A�aˍ 2U �Q!%urb5�*�Q�\α-V310 ce 7� J��Ms�>cuT!�Atei�� %�a�*�e��v�) 12AI%Qde���,"��."Q,��FBk!B�� i�B^ B-�&� B�s "� ^�)�!�2 ��be7B�(���d�ٹ� ���Q� ( HSA�[ؗ���� &���{-ega� [45]!y�^��yi�rPid�h(%p�$�T ��{L3of�p����t ac 6#|(�D"[J]�.-FI;���0;�%!B0 �^ �p[)�2e�K� cVPV V( sVmn!.�% �: �A�%�.<�a2�U��\*�!�Cys�? e�kp ��c&Y�P 8-B� Ph)ECG�r��xs�`a���xl�����S�N �do� m.�AK��an's rulM��AH���M66m�reE��� ؠndI��?b`P�7 {?�/�ht1+��vza�B[�La�A,rs"� � ���cek�#� r-�e y �2er���!mbM��nl�da�a0qm"y�"G�!u�rewvac�N� x���� .�� �ion� � ( IE���$E� y ( E . D<�F�����"�u υ �&Nx!�!fel�����0�t:��"�A�M�� ?� /MrI�E��Kg *�s:��Tf!�b=�f�eJg��GK-����*�[$B� ) :"��5��.�aS�)l�� 9, ( f+}0Ecd"��' receAQ�9lAqeڋ��+'�,�)M&F2�8 Pph�$2!%�L �X"� .�"F �hc��a ccup�-bar orbi�zf+��I� @low?unjA 4 �`r��%&d [49[ MVo:|:IIeuaJ�,�� �=[�;� �su;[:rY�F��{�IP c�E�,>4o�Trx��-�C.�&��� FU,�m"),�"^Y 29",2�"E"�?�(j  JA�9��|�%5a sers 2 P(r��T�%MI�#a /� o��o>�!�L�wB eu{ !�'98� Ka �&%$3�di� �`Z`� f5"G� egr%D)�A�i� ] N#A� calib�gcur;Mqu�pT�KO���o5��-���9D'!o6q7�%75��F�9�!�W� �/ly! fe"�r!�k�>"� * a5%O "�%3A , �iS1 �&S4[ Sup!�al Dat�K)�J\i�r� ]����#e�Q.��}ngi��J�)�eR~*ll���WCPGCQ ��t�P�& adja/*�-.)��� ��r�/�-��4� 2-�), Arg16%9 Thr1������l� �4!�eK)(v�q�4�.}lb'";��&�u"�p! 9W5(�0�-�3!�(diamo�/"y�irV� %�� si!A�!ԁh�%e٦s~-B . �!�� 2� . So�a=���uta�ďy�62�\�E .�9iA Y�Ec�/1;ɔ�‘����)��1 ��a�ver��t� m� !�A�a�sv9}�� �&GV���(at 4 . 7 Å��- �a`L!�& �2�9��"�k&nZ2)g��6��7P� U\�I��SbuA�AO$YSγ�Ee!�1�{.@noB{�� uildA`��f�2�U!~.��af9ts%!��"�6!,-�,viaD*%<t�"E�w� ighb-1<�hh��]9+Oa� K.i�Pwt >�O"��n����a bj� .+,ur study . T�he linear correlation between the NPA charge on( 2GZY )E{u�da�be 5 . 5\8 . 26�(�e1M He minimal differenca+�0local softnesA�@..e�ErM�! 9�e favorIabAI��2�Eef8ofysa ( 1Z2D ,a�ox!Mq�9� Fukui funIa value��vle�bhighe��a!&ats)��3�As suchI� �E�trinsi�:0more suscepti� to aR)ttl�B�is larg��0determined by%�s�chain%�A�looped-��$redox heli%+which$v- )�d�b(is embeddede�8deed , removingBJy.n( ‘Bs!�a��2’i�: ) bluETisFQ9)�I^A,.~2N�inU/a��{A�u� have��ar��NQs ,�Tspond%o)amasM��R<. However , here.�h��lowery�Q!��,� lainm�� addi�� {��E�s ) itsQ��Gtowardi�l���I�-N6 So ,j��i�b combE�!�.q��ex�%$B��me first >o�A�Hcatalytic cycle lea1q�R�B�!byAeM,e NMR struct� eBs�~6�4( PDB code 2IPA[1]E� deri�$MD simu� � 75 n!lE1b� l $o investig��Cynamicu�,hydrogen bon@ ter�s med)I;.��U�A�of)�.�2`sQ!Kca!]flu� tatE�by��Ajl �Dform ( see Introdu)~� Zq" mixed�h obtaE9after mu� o%���A�2�serines)�sewaOconver0 m wild-type" s � raightfora ���I�21K�er5�6K�se& ��MZ69�^-�Ms a6�)�Arg16E�,� in e� Um � !jHThr11'.3�4iss-AjVAVN- ��> backbone&$ 4D�Mn�co5% � , nouE�s��Q�%��or)%��"� 4CMV iT �Lsugge� t�(both protona state%�j , neutral%fU�, shouldk con��r��si*< ~�eitFno�twB . St� ng fr�l%r1�Aau*��devoid%F�55� .��:�e"set up ,5tM�� eds 1%ora9). Whengis de1v%3AXfollow�:�X �d dur!/�P9�� FJf?:�Sγ—uJ Nη1* 5%!8g time� 5&B3�2�1ufN ( 94�0Oγ ( 7�2�08a Nη2 ( 48�f24�40R4� �q��6B.MQ0Trp28Tr023>^6s%� taneously6 ��~j\2:�D. Not surprisingly< .<��5�I�Mgsigni� ntly�freque��2' w� itA�q (_);!n��Qh9>��B3�h1�6U�Ih���2g:z5W�3AfB3�"� %EC��2�Nto] 2p1 . 6%E006t, m� � =�B wB� trea��a T i�,strong indic�R�h�J����g�c5)�V Zey avio�嵮$. Of cours U$exact numbrpresent�# st= �<1eb�� e . g .W ard8how.&y�m$,��subject!�^ leng�f aj%{ p��&r!r�#NndR thus� ec!hto vary�w0 chang�nmaa� rend� �21:-[6� of��5Z~9�E�bN� , ;?I晛2�\. α1-Rof�!�IAXR:i Uot6_�@!]V ed�is�9� rxt_1p 32 ,�$+ �  ^IKcE����(� l2Bl �!� drop���3aE o account!�ueffA]k 9@, we de���hew1_trunc%u�2 &# E–F��i��� only�� u�OE�!Qinclu!r. H8 ����a!decFm��s )����4� 8%un!�2��$q � N!;�O0!�ahe abs� of6- i.0=�E8>. Itsm5�6 . 3�� ���es�in6qa�distaAKpE2pAexsum ,�V�2`b�� � Q�%ky�Y �%� important)sRE�"� �!YthH?��m;V�2�4takes place via�eR�.2oC 2m M��xZ� 2�. G�ŕ1MZ�I��be9� ����!B*� as poss�&�%T��i�2ed&�. Compa" &��� Z�Q/9�( pot�-%�aRA�2�)1%w>�N>ed�c�� show\:��"��2ya:P4�eZZI0�]"*�)�>� >�2)a�!�6�osej^�edB\e�6�u���&+ � �g��%/����qsIilm2r,t^p&� E�sA8���n�v an  " ]H��orderbper�B�_on*# �B"�!�;preferat��4ti"r����)r5���L:�)rEE�"�id.�~i(!:e�E.�(s� al%;eB�, �-���t�.Q2�� W}e I:�� 5j� �is fa�� �s��F�+� )9� ��b� �a�Ka �snY����&� !��e!ZGU1e�*� {% a sli�NR�eų�`)7 1I�6IoI�c��� o!� :b{E�-��Ind2��:�:'r{!�68u!B�"��rep!� 2f1-�9`� nfi�!�e�O results ( !��RnE�d8u�"� siYQ.&u " ensi�O,al ���i�"y�M�  enoug�lev ��e�nviron�"IRA���<, geometric fact��at;". D��2F� -56gE�M(e�& Ser $equivalentq��e)�>�ist�$15 Å away-�,�le a ��Dal�e b��!I�upa�� 7XIjE��&� �ion� A��U*6Xm��K� ��%D�A��� y!�A�in�"0 �each ot�5� 76!. W�#fɿ�znew2Yr*�co j!�v� �(E�b5�!�9�Lge�V�!$$! d�x, a]pproxim���-s!�at-�is %����6&mwPa�a�"�"aU(-k-��k:��jBa�5�bAk%a6XE�Aoke:D�NF6 B–��� 2~X"� , p'deZ� .� ���!Ec(&� 8$D'napshotE��&J 1�c�6!V>}!�F &*:=aQ�;6/�( b$��criteria�ee1W7� se륏G� 1��s� ila �b�� 6b 24�e�$a�U�atAiou"%gesZDr��A�p�cen�!well p3%�kcJ�an�� librI� phas`� ��ʹO( * &� �E)�Z� a/�| xtraEqx��7 . 4EAaVja!�� +^e2Ea�QCE�s�1�F�>kin&t"�be!�low . F�me��7of view����to*E ��Y)� plit�'@ � ��(��ofYUU ake��~�?� may�#b�>o$average� [v! , but<be � "�$ occa�al% %aref-%,qlegitimx to�U som:$�'r u,. Alth���wit�2�!�"���E� ( >6�Bh Asp23�p$ �!s&io�+5y����.]�}&� e [26]w.��>a�9�� �)wa!olecu�"oc%#ѻ���Q��puV� A(�&�"�8�[23] ,�3v�gB,e=ro�*~$by biochem '�rl-s�BC2��! �!Sa�#%� �PC10S/C15A/C82A triple3" nt ('Trip )-SX2-nitro-5-mercaptobenzoYci�NB ) ->wT*8� j�"E2D.rocedu�'8+ on )� -. rele�>)NB−E�� eana{%O �| u���ng�635�S2h Supp"f.�.�#Eat��on non-7%RSDS-PAGE�wo ba�� r�&�&%�Aea#� 6� �S�(��8!h2�aM2P�9>�. R�$oc ax D23A1�g�'��ɨ� !��-p�S-�1�2��Y��#�Q9(X,.(o!%%.��5 ont R�6'.f'~ *2un�+%v.s"d orT T>�/� ס� ut still ��o�/�� We also eI?M�/IL��Si�%do�)ver�-;4chromatography�-��!��wo .E�in�E�� PwK/+&2A>?�� 9Y% �wis v�at2: nsz�L�/��.��f�߭N_��.�.Aw independe� of9��e assu!�Bb!%�i&](�gMD2oon2�N�#��.EbOδ�or�-�32SγY��.1�� � main�'*�#reLm�*Gt[). AB" �@ove� �1�j � N�6Z� �&i� �a$�"Af9��YV �.E�hYad�"8� ��%8sNbB� � x3ro�"�'ra����Ũ%���n2�K� s��i�e���RecI�it%�s& a/}HN- alA��1��5�>G&�to~ aB��)�leap. iol group. �Be C�!v.5�[21w ���a�/&�3&�w &�w rx �Q]��! ?- 2�g !#�)p��4�"�!ng>!Ala � trap^>1$] �l�t/�chXid �� � ;F�L B� ,2 a�Sa� f "v��a�ډalanin�"B�Y��� �d� :�. N`)B�nor�!��U��1 �i'.�as visuak4b u�7g. Our23do%isupw)�� m�jpo� @in Carvalho et alI�, [32r 3y 4 50] . ua�nZ �A�7Zo�0ui�A�A�5p>?���xs�.�y � las�u��stood!-abaAȭ�.C"� +�1���,/methodC""TRJ�d���robus�of!�0te-of-the-art�80B 0field [31]–Nj �A@a�F�q"Aka�G�� 3$a�.�6"}to2%m�+%&exI*uLRNin&���_� ��of��8��!�&�����ANH6D�1aH*P �H2x$%'za�U%O= ( 7�CrkablyX�O5B.�ly �Q%6� r�:!^Ec!0�w�# [24] d (1a��W�J&)'� a�F�R���"!WCGPC*3�*%�)(F^$*� >in� pKa∼9 )�8&� �*�q�Ah.�*#AjJ�s �/i��2 nɾ8 Ww� Xk�%T�#� argu= � concordBL �� :� a*45Eo�� �� F�}�@v��"B.�Epl iff�)�)��࡫e��!��)P��&� ��*�Tneg>i/r*2��<Oiol-d"�ex�gBA� !�!^�N� [5��54� Upon�� jeB��X,�1!�or )%��6{��� ���<lA�f� s�v?�� flan%=a flex/%shortq9–jso-���$&�9-��ut �ngln6�6yis��ox Yunrol��3!���- �d5�[17!PAI�&�*I]-8!�H)� <moa>s� start��unfoljtheir�V,� !�Hea(l"p�%�"�xH.;-�1��)�6��rn8 :6 b&�@ �3�a�$ * ��A�!an �:��!���%��?�;cE1. :w*, itre�-!�a��-y����a DFT�~ �čU)�:�BWse�!�!R"6�a��9�{!�;T&I�V>=B:aR���M,ANF2�!FC�A-�> !�+2��8vX8�:a�& j^��&��=N� x��2�"����d��[1F 16�m�\&�A�&� MM��e;� debl!���%t,twenty years� V �Sn;ag7�C)= kine�;assaya�s�dir$1genӁ-ti}�9^;�@-�s����!��%�)B��z�!��b)z(�=A<�"|Dd�ei�6�6�<ste��Ye_1$�� �2Ũ&�2�"u >��"��B!3!���I�n>,�:�dl�F�9)�%LxBR.!� oun\>���6��r��,A�^�Eof B2��st�)U�Q"e5e.2�m6���"- to measur!nɠ.�t5���&XO �:xe��b�Cwil6a.�,/!� !��..5�b�ransia% . Du� Dna.,?B�Y}o&)�G����D?- trueJl`4�1�*�!�c7��2m! probsZZl&&@!&U��7. FurR��`2�sT_:M��B�� "�,�_0:BcanAQbeEb eq^!Wut�U*(� 7Gex�;�0fa a gap�qu�@� �-aHcurre~.�Hu@��Dprovi�Ra��d�IIi"SAQ�:a�uqn"��N6#�4.&�4�.,�B6�&:}8��2� ,"G"� �%�M79!� 3�� �!{)Kas5_��!AQ�1�.A�23H��%velI�6%�6%>6%�)N8%n6%7!�:B�d6H4��u��}��25toArc(7 6Y �%Fo�!�-*pQ�6�Z"zeUF���,4>)3my�0pA%e�2�#�>� M�:!e�a~%9a y �+j �,r��d��6�#. C�mi�4� 3>R�� !�approachm*� �e�� �0�.|!.?*hi��!��&R� nWc�i�“Bn”�Y^2�558�! e��i�any6��C-�6g,-�1�&F: �* �6!p>�V1�s��'�;:AH`:U�@� "�E)�%�(� V9�!(a�.�&�in���9A[!�an�r�88���|.�8�isFY�,PntA��"z�J:H dipP$[i�;��}.���L]'�p P+6q�v~�.9��S��Kat�small�Q d9D�&x@a`very g@z�*�,NPA�j"� �N.��"W+QZ"o *�("�1�a}}ee"�D0&/Dz /}���.R"a��N�E�>�!�� b�A{.5�>S �F(Omm �,��eF� . S�I��)Gu�*a�um�. e!})�aLri� forc&3(l%{A��':�2�l=?EK2:A\B) ,*�"�!.1ء/rgu�too far>1�I&�E5C��d�*�"�to/� pr!t�H2�U�&!�N6"�  demon�#�atfi��-k(���Q5O1�Xe s�M� fm0!7"A%�a�� ����2*�%C ���S�=Fn�%P"|6�Ay������Fsca� xplo�  O2� ,1e�3N+��)�a� 2�U�2s[f%�d"�XJ�NaI&5%. B�*bym>A�rg108 ,�Je�Gly12<l: v�) �to�>U?J H"�(U�$ physiologE-0-�4�� 9��e%UD(� = � )A�domingJ%H=;dXFJN�ul�XE�ol��#cl�; ut��.�pH!!� solu%�� t mo1 >f�.}��"�predicQa�5��"�Pt � ��4t� C pr�LznLCFY�&r)?e:2�?-! �q�2� *6mo9!t!�c]mVEF/du\BGY���:�m1 � *{ j 5?^A!y/B7 �"�)�Ry �i�(?�V� \�W solex��ns *5)I "��1j%]2`����Q ���*� �:Ey,1dsc)�>7)�l�\e�&+M,&�B &�e �b!S�U � q��Y4��Y>9$ al�H�|-  axis [5057]�AQ� `A4u�6 6F"Hw�=\�.�f 1_-y@dU�A#"p�SW."%|;QP=&�W�B9�^emerg�� *[<o*�+�*�": , f �s�H gthe�U |�LBz'!N E�uIE�z�'"d7�EngE�Q_C��a���~+a.�."�Tterpre��F\.P &���e�%o�]"l Kam �6�G 66 AUng@v^e~!0�ed"o �M�+Js�� :�7�..H&�oc�^H�� E��worthA�a�7ety!��9z�')theor %,3=q�7e� lishA�n+Td�)3'� udy 4r�!d �2/� N�--[!?��organiq\*("� � it]eli�+)%�!�inI�� �V-q)9E�-��$!�u8xa-$ applzMof!�� WX! GEN6�nd���a studf$y (�/E���r� ^+l�G!� exclKAAIsL8&�n�? cruc�:C��q anata�p�[&�BoY�i� V !q�lac�[x�0"O613e�bBg�ed����o�_s�5e�YinS�ope"&%�!�)A�$e�n� �$c� i�oxiGToDc�Ps�s� �I�[ q�� b�8BGP06c6:j .4#"� ��� �_2�\���'a�_����* HSAB=?ncu8,EaiA� �t��cu�ӑa. Equ� &� �6e*�dP-��,���es3*���m6���2�_E�2�A ^�9ELHen�f,E�fu�-ategyaݡ2�`ioz1�.lv�g�of�������!��s�fX[B N�al PopZCA1�(d)�'h�Sγ[is&�Ea�I scri� [37]"k S� �E/2�eC�3L@S&�9ry�g(�<end@S��AS%%e�%2�� :��N%�fŪ8l.�;ai��execu�ZE : !?� � no�[)�ed)�"x16��availF.�.c$y�lyɐsi�9"�$8�[58"�_y!p)) *��=Jin-coup�on�@[1"% –[X. M� U@F./"�e�,&v%1j�d E ) Q߭8-� C32S*12�<Sa�p"(R [34]%mad.~] )���aj �6��+�m7K �.�2]�G"�E] ��(B^���6.4*VE�� Htinuum�v�Iqa di-\f�a��" of 20 [59�*See.:l�( T� e��$� �(ou*L 2����$B�",�U�J"b"�/�-SG m�Q“��2L�*�-NH%�� w#�%. G�:9 defa��: SG…N��sS<4�@!�H-�8(gle>150 dega��$z*V�. A-�qi�""� 6� %�A���P%ǁ���Ha�S#Woptimz; togeR�Ad� 5m-�UFr @B3LYP/6-31G* leve� Sp,���sew�E�& 7�pK*�e ,� [41]�!red0#��&2�B�+G*�� oV�( PCM )) �Bx? radii�EGtoa`�=%Rca� . An�R�ic)��� .$ Bu��!re� !�s ChelpG�Dch�0s�[60��61]E$�n� �I� a�!� enzyc27���oF6�iA�8(� )&� D tRe�,iqB���8_�nY��%P �N2 Td"�i0_o�!�(i�&I B�eH ��_.�*�av ���d�%r�ng6m��}Keez to�^:M)�v`)��T_ize�E� hund� tomsojj��M DN.�*�k*�kDh RA�E}X2� � *[ :!Ac0� A�&@ us!_rXGAUSSIAN 03 package [62��Energy�UizE� ��/*y ����  -Y7 x���w���prA(m CHARMM [6�KA�22h� ��ON-�864i���_IR:eC_0�!�-0i5:qR �S�>beygH12��� ~shift [6�FT�(A_�"��� ?.:spheri�ncut-off�P-单�16s�J�a �� lter�eve PME sAhls�X*A��s�HAU�L/���C!��02�off��p�7� nQ���>ZK� �[67� 6�Ine�A�� r�?[ ,DNA oligomer!""�"Xvc"��<[3M_�!�.�cu�� AMBER$�[7�< A!G���>� crosp�iI 1\onQ�"Y sua ami&)T�!3�~ac�Mu���� ck�"�q&�B e-}0s��gY)�iseh="� ��=s2T<+ [4�a exce�,t agre)-%� �-.M�&�6uiata A� �qZ-)�)Ci�E����a2��".u�6XE&N���D!1��Bc�u&D�M(.]M"&����!�FN��lisA�x(m&iD to 1"3 upd�� heuruMe�� i�7 coo8ca 1MZ �( er 7��6(("� .�sta�=��w� !7� 10�!�qha�jen�/\to$Ua���Cys151tow#. �.Re��N >�D><�7w"z0"�/byo^.m"C�� ,I!�le�0i setuJrjr%�� ���c��param8� !�*_2q$$Q!3�CCn>A�yF"l D�'��o}4a�!))7I2:�overlai�th a rhc(c dodecahed� f�-�VlXQed��TIP3P�M[7O>[7B�fa�8�u A�88ᆑ= oppo�fac�a!%2� ��8D�Pimage.�!Y=*� �:x",H�o\�im� ��E�h�mvlyWmÅ�f9=uch �-�ue �{N$2� (���L!69Os-�pp� w!�.�E �t�  ereQ��{�e���Bodium�k�$Periodic b�% � �� O�jHa�aco�X��]{�&�g ��\a�A�� SHAKE [73� �% !m�&� � �p(sh2�F! U�ly fi�q��ly�o�N o fu rela"j'�y submitA�to>8 ,*� leap-froti tegrg��n, 002 efimeG7��� NPT ensem. One6e6 q� (�21$��P)�~o�5fah!H� 50 K�30 in 5p\r5 K iK�!2[q$y s harmon� u} rs� i� i�#w6E8)�a�PcA6iTA{@2 . 0 kcal/mol/ÅTh %X�W!-�E�kepRU� 20!jG7qui��~ �B� !u� M�pursu;t-��at!�st�KEb eachQ�B~Site- ~*5, �|�A�pur�m�of���-i �B&�l Data"RuA4 iquo%R a��b�HA incu;� 20 mM DTT�30-�room teme(8o�: #!GExUqG(>%l: s ^{��EPS& dex75 HR�� 0/30�olumn 9�i�poly bu A ,�B'�]1�Na-bo� ,phosphg$c�;�f� -0 �x!2IbpooO qVLb' wD~S�alzA���Qa�]ni� at 412 nm%l!B�A;)Emix%�R�ya=W�Xmw gel?7��-Oto-~1��Aov2TZ�J x1� �6,M�AR–1;e�~!�Y> il�B2�E}&� "�:��F:LD*S�e�R�fr�Ana�:�a�I�u% J��G�zg �=Y���QF' j���> - C32A) E%�[�"quimo�[9�A �hA�!�R%.�Dj�� AU� load�Ea��/0"r rmB&�S�:VTA'F�SI�%!N.Fin1p�8Grace Vydac C18q8(�`46 mm×250 mm )B��u( v/vZ$ceta�r�,��1%trifluo�6N@c�WF�Xat/8 ml/mi� �a�el&�aM�� grad�8�9�i.0% 2�N. Absorp%!y.colE�!nt 280���&B�" r EmN ( W�Y- Milford M)Achusett�j.�y�woyw� �a �'��z�a fe��~bq�*ceM ntif�a�son’s�taste�a�ŭO.�*'2%,U& peIyM&��r, Y:plaI`y tend!q aligez&�xt�jf� ���f�$ha�� � uo�\rI� We"�#iI� peoplG�H uncer�� ab� �.� so@ Kt"-=belief� _thu,r]m@ � p�eE"!�, �99� �l:o~A/a�g M[LBayesi�F�. I�s)�%��& vari�ty�9A�s�tkwl9 n random-�^�a sig&9@F��,<de �O%PA*(J�{+�e-�!�^� . Te�o iszr�coen>.! mxU�Le�B�f ing;,�?rZ1a�;sz�vo�BPd��t-T? �o ? seek!H? val;%:Eepi,miceVMq͂who�Pun.�ow!e�&�u� eV%��>�. I���I l�9)���v1!́��enGGen,5$65�EN.uz��A(�-�hx�-i� sought.@ċ!�!K� tsel�T��[�uP �Z ��l=�>�<73Hli ��sh�.D*5�� �"he�BV , �PToelch%�DolanE�[G�(M- )����o2��P6"DUrE,�+w?<cuQ@YW��bdi'�n��.1�i�-ou=  4 , 6�(>=ef� bK�*��a d� s^-�D� 8&��&��2�=��I�i�J�0w\2�%k2� � s�nt o�meC+B�� ly mst�us att ��utqt[6Q�0,AyIa��cho�9or�-e�lm�u��Ung&�-�K] , I nowL�?ecaa�I!>%�ly�$!/p vd� � ll [ %�m4m�K1��)-of2N. Ver���g]a(̈́I+� E,N���(do�s��i� �` oenS� ia [�)p�}[9� Mom7typ>mex�;v %�(;& �1;�fSu��rec!5e��Sam�|%�price-C"�--.�. Unlik z����i� �U A)Eہ:comi>D &�4�ti' �|we�#y r�bie� tdem�eof�r��٥�*K s [1�� )�!  �� �%�U's�o>� [1� B;  �ex|wto �!^f�qaTly!�xir���"s�@%,���r la� 1<�&rl* �-f � o����� ia�C–14]5��R�� j�y��fs�;�L��PAvelop54repair maladap�.� ���C� �B�+ra,nm�F%�-�>��*& #enjoy������`2< �#�g6y^�.�"[-�eE���YP]�oS+2��� �a�viduahir � s�#a�:?{ ��bem�Dm���use nAa����o�}n�A�4"� �^��\,%-��3 idea�a�A ?�4%e�i�s� s�Y-=��kl&2:g��w$9s&Ke���A��-em� ��2 a�!�5��"A �� q %]E.�c� s Lr�8pla�6�1l�3�a�A8c�e1� ��:� Fh K2ST, ,9. !]feo ��t��yOyM=��eIZ [1�) 0tX��)ɱf!5^s:Ow*-��.l"9Are3 @�. Irir +3 �*ID%ur�P�Hes;\" )WE��!\{�*�.;ha they �����>t E�&�W�'A�*�k(3�erh ��� A'�X %�A��widj�!A\ � !{"�>��8p!oR �Tom~'U�=x!fs�n/>�r�#?!(�����)��CɃ%_���1 Rmo��!��5�a� stem|�m�|p0�%@h�i&�;�u� �6j�,2M �UC�O"`�gra�!(I!�&HOO0 3,3etbz7'o^��,'1��� We�:if�%elaN)EeX u�"�<�e�. ) n�P }5!Q� recr��$North Lond-�,Cambridgeshi;AsD10N"��Tn P���y Net� ( NSPN�Ta8,᭩legal gub��oif youn"�;1�F�n� �>on���@P� dlO* H"� C0l Research Et�� CommH!412/EE/0Q-|inv'�21s�Ut�! ͇�eq�*ur< �VA twos8d�+!�.vofc' to 2�PQ�5�w;�� y*}+8i�g0�la 3al healN?ssu��<'r�or�"���dis�r&�l�Gdis��h WG� 'De!�!63.2 ( DI�T'�{k�he !Vdel� �Yza b� y adA�st(Nn!�"��of ;: fema�o�d�!�Z�!�24�EULmndq!�KA#k!�pro�v�z26��"�750`"!�* u�; 5dr||a;�4�W�8��E�as�l$6Tuc��"�<�Ajz !3mpl�;' taskEc s�v�eS� ! � ("R�ti!� , unhappyeq��1#3�ech3�Xlem�_aBMj� unusW(�s+V�"�<of 738 a�D�"w�three gqA�In A��P8� r~ �eJ/!E�/ jS 5�*�$� K1!�a,ndardl erboD.B mp9 ��1 4�)� 1�6"h:��R&& A�c�e��k P(x �L/IRD�>n�aa� ay D6 VD=RD/ +Ka�(�H�K!�hyR�"�* [15HE5�� � �)fd8", exA�A�;1�5(.�wbK = KoI-diŻAFin�,�-o���7��B)�themselv� ���,(!guHL!Bt K3 ≠A!�� ( 3� E=�_|�Eek(%��"� ey�lKo!���&�S�~��� �(a'Ply%r�$�Sd*K1%hE�Tl"A��2Kxa?t� �n|?2� e� 7!�he*,�� �,‘%k{ 6 ]iI�.]f7:��ya�Hoftmax rule: Q0=R0QA�A�<πD=11+eQ0−QDTf I�πE��pa�yb�YY�!�$deV�9�uQ[4QDb!a0P�IS2@immedi��0:Q(!) =R[Ra�2$ *Tq�| %�5�Tcy%�-!�er!��*��~,a��M�Ep y1"$��s��E��1(.a�i!*K1�ݶe�Ua&�fKo �reqIrQ p�&wei�V1vp� �T =��fpre/��0� me~oRcE�3 �H sJA�H��rO� }WSb'�iit�T OT��60�#�A�e�19 r�!30���Ga�cp !Da&8p,alHh of KMa@ terleaY >ofX\5falgorith�U�Pl� "� 2�"! A��%" b�bA3)e�� )y�8 Eq 2"nAB%�iNs�ly�b1'N"ty��v���!�2�=)`� ΏE�)�2��c�<o9�K&8PQ51�E8A�pilot��)�A�?��A p&�CIG�!�� �t�no"�0.�l�PK "-=m�of ��(ly μ = −z ,�]:devf�2 σ ='-ʇW%Mr� ) ko = wo�n�vl�G�bk! )��P�kkb�F�σq7���2"{W�e��<� 2/3%f1/3!{&��a� -lif�uc� %}&�-whS[ u�Q7W+w 69s �QE:Ae��I:^ ��ask>H “WA)�[namec?$? ?A 2  Eer-matc�L��� At�i b�a�m�qpe!. I%�n�Y;e�f] �s �� ildr��r�P Engl�hWst�-�hn0cEJ2� L �M !�behalfA�Hsee pH6���'�� (M���)%hM.a veri�Ll feed[1W�s`J>�e��-F� ��!'R� i3b s� t{$�.MT%�Ekp}6!v� ��**�jpra d� �(َ�$|�Ta�:da�.]“�g*�a�!IA[�}nojn;M�#�TX�Qn ŅRp.$--%>��v.�<�0at�by Ni~+�co-�A�[�����m�5!1�E�o �D'�> �l2�\���L�%�*�V�0!o.�Is�M� GarRF�1]�k agܫ&�"-�1W#�N�1.? 69�te2%�!!�� (�GIA���dX:�5+z it)��`�E���!E�U�E��o;g6*�$0&U���T@ � a�A�noA�ri\$V�m��A�&�O g�$1a$ dw&reV�{2;"�� 6�%d:�co�Hin MATLAB 2012a run�$on 12' scrp%l��p�!JCogg "�toolbo�6�9$AcknowledgA #.A�:w[,� a}iv2��>��mod"; efer &� ill�]��Win� �r9� !Hf!D�:�N] s�R' lz?2O�Y*��y�seAx , sa!�/�i��LIl�bB�l $ tellO��&[#�cMd high2$&�( T�#a : weakFG(� &;/C ���ja��g-ria5ff�! RDD!��mbigu:A)����Ine E�q�� i*؛ as KeL �L�one�-X�;�* as T7�B����Z��K�K�S1�7�ZW��8�e6Ts*�I�=�Yl-. %�e� �f� ��=�Oi.o�U �b�q�UvdAB�c.Jq~to��!_l� N��e�= &\ s�Da�Cm��a�-our �-!#!X~ Markov-Ch@%Mon�r$arlo ( MCM�p^ A�~+��(priorv���%�-w�8Hit-And-Run Met�UlcB"7, �{�:��La� sDem�&�Gw"WG2�DA�NQ�"Z){$&�TX  ��pos\orat1��&m�B'( o� m6zri*!?a�VA�ph�C1I7� !n6�2- Ehsa�UE�K�. A�9 hier�:#";",a�E1E.��PS X/;���Gm�+=&�C� 0x5 = 370o A)A|baO A(E E�� l� ��rn!g�9/`*gd �;*].�se�p�,� unu�vad���*RB�.� \=ruc� U�@2dH&�U��a�= a��is )��# �� aA��� igno�ijmg[!�<2� �W�A ��!E��a� .��uy6�a �?u$�J in 2 mill!�un-b�� �O/x �/ �A $ rL]{cG110Agca�� poorh8A�N irI1��O�osoM�!�ype-2z empiMJuvJ_A�J[3�NQ2!�"�W� 2�n5��*�T��re- Hf��&.2. ���� p.��յ&p AA[ e��Z�&�Zi��9�4ײ��all"� p��cl�wKTM:-]� >����,�*�� AH"�f!o��w�"s��� an��%` oughly���"&K-767E� SD,. VP� ify!�(�oiE)E� �Ɋ&��]/3 �+/ 0�5s:y#S�0� s II�VIIIa�-u! . 54� �3J�� n1L�C��we�Y~� o�8t<�K1kT~!�=�. �6Sn�e�V�! %�5K�@�\f rox Hŀ�!_���uc-"� Zsu*Gz,e[� ,�%>3I�Y�� wait�*ѳ��exerc�� -� �u�Jt�DaU` Udo J. @��d2Braia:!^/0��$mea��2.�� �4-var"�9_1&�%�[�,b�>$�"� hen��N8>�e�tyartefa�a�KU!B5�a�\b .(�Zg�2+e:,Q�#M!z&�wn!�acrQ6ed"! of��2�` �i%:�=as8E-�qZ�eR)t%��!�KU���LU �:�.q�A*I2�:�y anne!�iY`so �c "B�mm)profiH7l�despite 25s�n�! �H. 6�2�>a�#�8log.+ M�*1����i5( SEM �9(8% , Wilcox~O�� 7e-1BI��$De!]�"2� = 74��KU>� = -2d8p��KT LL�w_*`�� �]6�/=�]e" �4f�N�] u�����nP�2�Q��e�W�in�e!��M3�T@�:��A,�Un��9o!eWSd<v�.�2X�aÚ�pr�:eI�| &D Y\vG1actual��Ou="Pyb�'��1 �� Fie��1�iF3v"nm�.u1�Oy=i!��!ed6��9sHmem�-�s$.�r{  ( r =�A99� < 1e-1�Fa�u1�pg*��=��  T� 5^T<; �A,Q) q6a.q�6PE{!ship��Q ꁿnajai��at1$mgt ��!�<�_!NE=D i�F/!��" ��>�H��R�-�!�ide . H�l.�h�s �2� ��ris�� �"�4*�0�"�ap. T�t�FV���`9�M�'Am1� u1aE .de.3�Ul ly��HQiagb*PÄ�D (>,!�-�x��' 006�n�Ns���� !�8$� &G�ax *.�#�Bol�k2k;�9 � |m3 -m1 |B�2ei+002��a�3m��"Fexir2��AeٚK9"�"�� 'N�6-�ceploN�E�d30�4�d %$7d%� r;*3A��| @&v�3-m3−m1;�&s� oJ �� � -La ��C ;s-for-i���`We���Mv;maj{"�R� �dir<� �4 ��*���/��� �n�*-&�1�R_s} t�u�AES�m�C�Q)���1��!� � n��AZ�bri�� %�� : σ� d u����e) m3a!� �a�1$exT!1�> ���%�E&ͦ!�2 D,e� s,�; u�85 0�330�8le21u;41�[.c3^ ���S?hifl%=cB$E�’s V[� OdT�E��Bsp�r#jenE��%�� " &�#*��.D=aE�,%ˡ @Ue`$�8Ko!m�: �a)biaS E i�V\�n4M9toX!�c.@m):� %@-���a4�!��=Eow2(T �A "B=�D9A1Vur�l�'RE��n@V9�+i*Roie8�� %w�&k4z�N "�-�ax#4 2������*r���Ft�+� im�FeI0��S��c&��*y0�wo-���$�]8*c �Z ����)@ax��H1: >sk�|;:���)�!$;a�(�;u��� �27� 11;��~e�24;6 a� 0004aa ��s>,��(Z W06c2Rc4>cR 7e-8� Wq�%0i\ar [g�,e#qFE4AM@T�l�� ��aY]G? �3;�[E"I�7 chec�%Q��E��9e\TfA*t$a�a�if!�>z�!�Yy',�%gabo5"It�KtF�eb"X\��c(rb�Rry�Z9� in kU�42j�,e*�6`]I�d�E�l!�p��j�*�A��=&V��Tg8���A�#�{��3�"!n {<G "� a@l���0"�)� ��  gnoG���-G�ia�E�B�>��.sEl�cF��6� ~5!�!n�!٭( �out� &8 �hs" i7idB$ty�OEx-�x�O�LFR�rhe��!�KUi�q;��� :�in yu�? 7IN)}��> z�~%AG21�7> 6N2F"M�"�*��v%ly!pa�fraR/>o"��% `2ZaA��f�^Ukby� m3 �, 2�#!��al1U,�%%qE�Hf2�a �:�/ or uaf�� age-�� >9��%G<I�P!��06� "O^�]geeu& R� j� !� 7e-5<;!���W���FN� N�wőgv e�E�����4�5a*��<�'�H�E���+ "4uuE�%S. e"��&�=�.J ,&�AVo%0�NHlVR)@9�3�M%�%Q�=�P�e�&�w >��. S&'�iE� 8�)r U6k2 ��� � 7!�6�25A^-7*%A96bE�u &Ju�"�a���i�eBWw�+��ɉn_@A+‘yMBPI’!�E2�E/&�Ktr��[34أaj 1qj�f- ‘eik�[Cat my)k*s�r� �&n� �.�.�Cu% "� �$ <�=&5] maniu�#fu!a#�2� "%& A\eoeaKa%O�v:[ (�� � at 'NI'� A��9mQ�y.h,1K�!Ip.�po�leg)�2�a�Gr�Nݪr$:�������7G�� S+JX)��kuM��:�Ws�Q��6�w�]d`a+agg"�Q)*�� 7h,A4�6�o��Z&Ůs|R%��D�r%���b���2, we"�B� n;�m?B;ice�4"�;adon'W� :q�vv�Qo�%r��, � accr�h��ur�  orig!�-#�����buiUA��l%&?-6-"2 ��Cr,�!�j7e�-&�d(�_ "ɡ�1un-�}�7!�a� �"� 4�-�J1&&:in G�.�!�fa�/>�Y �.�\ [5] [�d!i!]i�AsZ �$ �a��F2�L��j�M!2‘a�b .� o) m�+�*��%�i�T alog��"al benef�DB&:c.Z�!2h–�Z#K&b�IY7Bw%fo&�/�J�pa�ut��ory i�U%�A�In�Q,��mA�l7�,!7���mc�m T�uE�*ty�2��/R2e��W� �lH2L� ai�W,up�R]C@Yh"9�����2�+(� ) � � ��-p-� �[�(�W %�� 2 ��/n%� ?�t�2�����a����v[�qY5�A�b"6YBX��R%�<(2��]��� 8��!M�+&��"� i*�#!�*"-.?� �( &�.�<�=F0�. S� !v�7�� &�"to2[�I�l6��6�#9 YIK0�x" [2 7��go�j�r�\�"&�\2���*a�YfI�#���'s�1% !k�"D. inev! i�e���wl�"�#�@�XMfit��"��^�X o%<g>� � ABL�� �2�� -A��>BO�gE�N�&* ^ \.�R��ri!m handa�_- �J"Kne#SSu_i�d!�?by/l'n?w��*?A:��% ��wj#e&�TMnŔ�4"8&���<4 ���0 3 �(�t��1E��!��rd!���&�1� ��;!��4AV�& .�iniy!Muz��e�b!���,M�4�%� + VFYsola^ �lor /�uo!W�dilemma� Thom ��i�<� �dfI��P�`i�on�s.�r G���l*��Јee� �YL)�%> �A��T"o9{�=*� e�W�+3 �!EnWs%V��%2� J�3�CnF� �o�,�M )a�&Z\>U��N�-�Vz ����r�P!YRO�!neکA�bU?Q%�Yf�Έ�-�'ha� e � or�� /p�me��or�e47���in"�aIin lete&X ��K9 �)  � 9�ame�9�eZ r �P2'"� ( un47nf �=8*�$%a�wor�4%Pa�EP ,J� <�b:;a l��IQ6 u��"�O�]ɍ�littlA�ie[&J��N no �!!m�.+!D . 13wal&��>?�=*�! , ~�,@�vI�]�U�F�Cmp� %[p���2��)i�1%jye� ��)�aLpe� &� �em—a�^1s����:�)H�rus� asym��k.�'� �,I�� 9 ~!+\$b*m.�)��+�>AKM�g�n8�iV[�2� �M�� G �ei �lybyh��N`$ ng6��7WIЙ_-b�x�"2e&)ex��!����-.�!'eR&�&�= �.A��c'��:K�g�g/h�b*ske��eA�& IH��.� perhap�v B"9]*l��V^.�%*IK%� /A�n��9 im��~� y*w:E�f�m�`�{"}l��"v4! �=�Na+����au:�%A�= !Bow ӛ^�!��ar9 ��ce �4���ep�*G��summaHs} sour��d�Y;y�nd�^��E��<b] /���]I�Ejalli�"�%�1r�u!� "�hst�6�O�n5�Q7WOE %8FZ� d<&�i��o$n� 7.3#��fic� �'#I�)�a")�$o�>�&�P8��1fin�b+&�@.,�-Wv�in 6;n��)e���eX*18�`�쩘IB, enh�dw���"&�_�M�M��@q>c�}/� Mh7ruD�#���aZ�A!!V��~-9��xA�*�z#�trQ�`>� "4�n40/m/U�����H 'a��OfE zero�N.Q " A9e�"A^�#cl���f09s:cu� T��F*�4WI�@Ae�2Ty#g�"oonoOp%7$}^gS"rry-pi�,(,� �g�� 9s@ K"`�� It��,G Ab!�t? �'����Fly spdir�`6�.!X� �K�T �o�;Q�orA�l�EqfWD��&�K��N2�sa�k� �2�8��×� !62�֌��aVs�U e*�%��.vA�H6P"y @oe�S)Sa>����bU .e�A�ng����E�LG�32�?�� ��beauti��HeyYarv?�'.F35]�&"*�9y�N ( SIvE�x�fir� ��"W:K�{ ��S��1�7A��Z�+m6$9-�����1t fv�a�y�o[X��:Mm C0so:�(�N!�emq���ad�t���.}�"x$Ra�ZGvd��tm ES!p� %�� Z("�gR1�mA����V�Ux�5V � ����2(�)�� �\t#4N�is-Y. ��?�aM��6q�2�h �%)F�m=H( cb�>�x.�K�ap� %s�u�*�E/�*�9�..0���8� r��!�Uh.� nF-\� e�c#; sc�Mg �@b�[}�A}av{'}He\pa�!,!����� "��$ c$��C%�E� �S;��a"�G" Bs��:�: I ��;� ‘p���Fw�� ��8j# ebatsUE�o��6�M�t �W*�o�ue�..(y��s��i�� �B!��n ��-a=�B�)��s�!w�J72�!2��.�%&�G&� 9) Gt�Lc, � 4;vI�–R�d=}ism��v� apeuQpA�ggn| &� A��b��./KKq4`!KH ���I� meli�e!�VAJ^#o�fa�s� �k 9.�, e1 �Yalcoho��d drug�m�� �� a�a'�3Lrm �b ivlread�I�U�i@ch�<%(!��2�'_yu�A�!�k��.�#pos�0,influence on� new members [36] . Conversely , being a $H of a group contain�Fthose with societally unfortunate preferences could lead to maladaptive Slgion .��An important emergmquest$(in the area�8signal transduc #s how i�mafrom dif�pt pathways becomes integrated @o a highly coordi�Ld response . In budd����Me:�(Saccharomyc� erevisiae �goe��variet�Y q�s����q���resulE��v��!>b �Z3e�}|4nutrient limit)�,� N �J�[4!�[56aeD�E m=r"�changT  polar�,A -cyc! �N��onM gene.-induc)�fo� (of brancheddin� :�E. long� �s-�� �type�widA^regard !�model�9� �[7![8910inE[ ogen�6H Candida albicans ,2���aOu� �0virulence [11e[12 3a� A nu� +5��� ��� "Q . z@( Figure 1A , lef@nel ))8s�Iclude a6T �"on�cfer� = ��2� 6a righb[1Im1In16]fa1 m�Q�1%x% of rapamy+ or TOR41%�.v N1)�2%�[2%V(retA�ad"�  (� !��%in�olA.� �h� crip�k�z,tor Opi1p [2%�A"� gluc=N�(protein kin{ Snf9�.[2)"25!�I�. not clear ���seN�Ytog +(or independts �R� �:���o�D"B fac� at s�~al hundA# �s have b�� impl�\t�U����Z!} , [2��[27!T�� �a�N� t]�M�nA2U t�-�s��`m\!>2 &� 9>����� [28a�} -sur� glyco-O [29] �mediat�sX Lthrough�RHO guan�$nucleotq $riphosphatAy( GTP ,) Cdc42p [30!o �i� k )�its:��W aspartyl)�X Yps1�a�%-�[3� Byz��^of�nE�lr,"� � w FFG�g. Unexps W.; majo Q�e�oryDs���9fa�A�be6�E�c ":z study�e���X�# M�N��Xc"Q %A-5y; ���b!� l��a s2� "i�is���x�. >|u�=�,*�\nn�ER3� ined u� -mZput�?( HTS )&+%mzV. Simice�%]k6�q�traffickA�(by mis-sorta`&��,arboxypeptide� [3ř[3�g34a�An orde��&A$4 , 845 mu�s dele���$nonessentipen rea� fra_( ORFA [35��!Z�3� edE4a plasmid carrQ aտDal epitope-tagged �-HA fu`C ,�Zant���qcolonb munoblo�-my��alt% ��m9T&�B' Compui�alhod }u�/to quant� ,e , normaliz !��SaTbp 1rBall�ran1������!"W�$( Table S3�A�  , 67b�- iI���re� .��> bB Cd �1 �58�b elev� ��9eWg��The&� AWB>�n overe&�6�5 , 411I��P ��� �2� i!H GAL1a��A�X%�� am@�of y(A�AA�n��ass�%�,Σ1278b back} nd ,�T�PJ� *in�)�%����-"� ��ner [3Q A�ximat 390 �Rinflu� �J�Awhe2xedY�45�twom�s.{fewamon �Y $D , 1 . 5%%�lapEj)is ��r�surpri�� give!Zat !|=]d�Y ne�}%��same (> op�$e ) phenotEas V�!� [38]%bea��9�Ahibit�� deA���J�-�<#A�!A�ob+�Ε�pr� /" 9TE��9NQ�(I�classx�ofX�to�`$al categormS1;��s���!MIao�tn ��lacZ re��a Y correl ��1��affecti ]�u[.t� 1F; ��1T MZE�B-�:� tsel&�!�*x� .� ��e��qSD� 9�|T�to�, 505 R~��=�Nm� �e�;�o�  duN�st� Ss��s�< cutoff employed� i�e&� l�.suggest-� �i0bj!���v�  aU,�ho� Zumably.`se-ex�heir eEA�direc. To enr]or 5� /E��z )�=�,!Kond2t�%�per�%�T���3 �a�MuEs%oN/�BS+U ,"�  HkrC3�40�� � rane * Flo1+4[4�$Almost halcI���!�"As� 44% ," �ajmay����Q&maturi�ofM' �ed2��In7 e!x�Way� � �M�J�6��1��]�Z���TH�BThA�As e�Y�! Mm of)V=!/.� !XI�(pot��al��K3]!�∼72��tq+�S�m %띦eq�A9I�)�A�. M) la� }=A�one� ( seeU2A�� 2��w=��"� feed�Z loou;�,de�in ��� ( ste20Δa�te5 11!lste7Δ͹��!5� )1�A�f���es �`>����,�;� =�( yps1B�A subseW�AyM�f�but iA�&C �9��"mMy�-�� YPS1u�� �"j" 9ed [4�!^�6 ��:ns Swi4)MSwi6p [494[4?4C[4E E�%<"@ ge-�.&E B%�S7U swi4 swi6M�d* "* �� ]>�`}6'!�>� s�f playtrol o �!�=R& F�emA [49 Some��DL �*)�`STE5 )=W]�"qayan5 ,yet unapprec�d�a��iF~!�ng%r�V� ITsh�<a*�q[5�4proof-of-princ�$���e disrupA�fourt�!m/c ouuJ"� �X�%J� �Nf����^-�*(WH��>70% rec y baw onYS=�a�$���H !k tRNA  !L�%EforRE0]G(, establish!�t M�Bei%M�or�*.� [5�T"4~ B~%Avalid"Lť�ify��nd�3ly>�� !=}3 MC(] �J( ∼50Bt�zYc= ild-Kstr��JD�h F!cɉsAMa� on.�"a �d� nguish5�P���J�]()-�a"H �^� (2�aZ� ( FUS1 )��H�in51-gac t��&����xX� upo��E�Z =�A��i!k!y2��or Ste12,%2AV2B 4.��� E(Mu�ZA��acI)^��%}J`M��J���ir�Յ�)-F� $Mitochondrn *3&� (I9U"���I*L} m2R6��!q�u��a�'V��"\(�>d�R; g� �.�%�"C!����Davailay'her ,( amino acid!3���s RtgRtg�)��Rtg3p� Um*U��-�a/?#seMv!�i{F�E��*�volK%͟ TCA �![5� f�E�2� }&9v"� 2� %���^�^�kI�in%+3piklo�$to=Y prev� ng:�)B��[5U ij sequR�1� � will bind%�;s� Q!� �( A[r�donI�)�[5eConsis� Z �� � 1�A�9� mha�B2Z�.��2��A ur�#; egat>�)�s e ToR���,via Lst8p [5� "Ai./�?�D"!�ribosomg+ ubun!� enzy/m�Y�,�r%d.�8Y*N aIs�-w*p;��S7I�D�!�of �did� �QM� �N�)�R^,4 i@�(en�$ at%�can�edяlL&)j inputs [5�023>/�'�toVA.AvZ;�9(-v�N�s�'gluta�S2���-�-�Rim101pU�a#j2��&or?!�Dfg16# iw�.��<AE.�� ofH6�#r�Ai噹Pq�B�H*�invas!X�!&� d-.�9%� ligh!�2�pH�W N-O�#��,A�W)y('om>�AS�} belo�!PH��$.9[5^58�� h�c�k�t�toN� �A�:%�C� �  �f�.�!yC9r !" )/F�H�ms�0a�u3est� vQpA�S'� �B��E?�56�#Q( GAL-))6Tagar-V oc4�53B2�.sy'e�e� 0; �-��:P*�.s&# n�>�}�.�;confir�&}b�xz(V!AI !� star �N�"�1i�9E�7-�� ��)?e����2sB�e`,"�"it["�"5a��"�mGrecog�onq1.�,uAG""))^makJ� S-in&e 6Js�Δ�N(;�unc]m�(n1N\-ex 3�$ Sdc25p [6�70WW!2 '!�2R�>o.�� I��q�B5<*od�0�U cAMP�%a�B.��!�� deny�=<M*[71As�in� 3�'b�+;!�>��26�!U3P+ ells2,�.odi��PDE2 [7�� Rpde!�dou�'m�!&|}&�0���G�,�]EB��3�Z;"�)�. S�"tiz!�vZw:=�"�#�)�"�!�@iBtoH-�!�U!M�2� expltwQ;� *�("@���a!�&!�ngm�� ( 23�'R�, &, SC.M�ewr�� at�4 � �̓E��-�R� Flo8&b s a��A��� �Yo�(XFLO11� . 7� 7� 7A� s� is c"./� i�!�i� �eptor-h� ,otrimeric G-� 4Gpr1p-Gpa2p [7� 7�78>2[7�o8�o/ , 1I� �&B>�U?e�a>C#flo8 ))=6& 7S~7 %�9� a di�C:|Qe�*st6-�'.eLes [8�$1Dm�m�ei)a/n"/72��S`3 gen accum�ore��:a� oxid�� � [8� 8Eenh*�8ronolog�:, lifespan [8I"8� [8%��:fle�#[8� 2 �#1�!�A<se.�9y4Aa[46 S4��S4D*�" e�A�=�\ I�M�q�� g ML2� 6�#uni��io��r b~?� -> �. E�n&w whole-�B4e DNA microarr�D�JAo$!Y�0 �*{a��y e�+�~o*� ngi#or�H�aNF (*.� )!�aTi, l�6�i���I �r�!�:9�3!�. M�'�����&�/a�R= U@3v-� �0? �A�6�.�C�,n�R��:new�j":]�. �.\�7 scav3>,!�pir(9J�Fa�m�� ; ye�0 , N/�DN[=/S���T�*�Ns:�d���h , purplZ.� ��*-N� ���"63(eed-forward'�*D � uces.T�=�uq-�2V {to susA� fora�?� no�/"� 6.`$ ��A�y�mzaPstu�  ene,ss /@�8Eu  rect� e�� mmard3,�]E�2�b$C��o�Rn 2�a4.�I!bEQ 5BK v�FJ� ,6�����21ZE\"�2I>.�E�E!?�� ]��#strJE�0� ��#F�.\Wri�a 12 �n[88�:��}e8dE/�Sin3p [8�9�,Sds9c w, +i� !%�2 ��IBz0�K��(�{- �y�4�.��A2I��.(f(�i:_�7S6.��eQ�#c�*�Gsm�!�lexes _!&7@�vu�8H�( �8�zes�6d"@HH31��4Ftd> spur�6� i��~ crypvtart sia�/KpF_8[9� I �\ E%uniqu�M-Rc! Eaf3p�/.r(E,E�i�s#0K%9(M !f8 Rxt� ��>F*��\1 [9� I&�8"\5�EgN*'%�e4%�>2ass UI9"[� Ł2J>�_]��9.�/ZOWF =phe�Jn� � "' W�1`�)L "�E�ab��eqe. O� ��e+ 9� 95��*� �� 9�k.. HFCKs_D�  CI�p�� �by6G�wa���I�Lr��dtructUNina�Kl�6G�A. W�P�� �*� H5ver:�]"�ol�We ��;hp&L�Ž���#VC, j !�N� Di*%[9 [9�98]%ӥ�un�:K nd eFL&!2upa{*ossMYL6a-��.�s�Vsg !���!�IS�3�. osmGYe�C!�� ( HO%3b�-�asSR�U�'Nb:8y[9�:a�� ��MT�EUg&�-=10#.f+.�E1=�Bby�A�!�E���LhrQ��.p!=�( ChIP�ji2 .�b 6^5�4�Y-H�)I�sin3Δ< �Fss'��0�]!m4� e�rBa�e� e�B/! �� �3olB/1:W �HA!<�3�e:� q9E�� � � a dc65inF{"1�E,q-PCR ( data��rn�^3J-� �b� moz %ĝ�6�� %-� M�=.R�D�&6�!No�av ��3NV�B � 6]:,�Ei �-@� /y MiC tail � � �]qeSm�I��A PCRHa pKlA"�ONVm��P->ic�M�/�5V.�U�]�9*�5�"G, . AW>��e1@f�a��AD�(c�=oh*)r*h 5Oto�')LFM�olsz mJX)�n �#�=!�=���m midd=N p.pri�ly%�6�(� � B�GƵ&�>�&�snfl!�msnF86�bottomMG�Su) ZA��mb� �I�a"j -�&�8%N� �dam) :k. Like͋,!�;O0q$fS* < �B� exten�(i(iso�B�SpV� W2 *H �;�i�A� �exe5�&�s���mD"�inBb�0ma*�Hexp!�tn-(TQ) aBima)C�����P -HA~O�� ��R5��]6� A�� ringXpatter�G^�%.APa�"� �">+kb �s�ny$If �i*�1l e�BW"� expo�6�Y odes6�|,AENJ/iC )�T %�.� A+�=�2��څU��/�:5=!%�y�C;J�a�4�laG]!DngM�!�-�sk0� ]�in"[2a@�T>�te!.}�A�NuW"d idea)�a���� "�i�2m��C�}w�,!w�,�n�Dic~9l+��Cobo�8�ex�0cL%a�9,  N �ove�D�+���g%���6i!\ !�(� yi�� hub�\M�5�S� . We5~%� r�9 �M-/� N> r2&s�)B�\&-�5� �&�940�OI6< T"fN��O �!�3 Gh9���!Q!� !Js�K�s"� Sn=60]�v�\2"� � key upa�am�or����)'�ͳ �)B��`�meBism�� � �U���Mb]]-U �!���EpA� poin?Ih$� e�r pers{ i`1N �)�� dictw�"� GG&�HP*"�wC moda�]imM�!of��<A2Dd3ase�;�� vY��(y&a8pr�+"�! \ .p:��es1~(#G� -e�h�^���*�d��N4�R��Hl�>j�T�O�-%fN�X10U10[fj�5otQ�� �a4�  ,2�aD"<app�Uto� "�.b H* �*�F��M�� ng ' s d�j2Q9*E �Ba[lFG� K-�s�-�<e��&ZCE��,.10ip10v�$�GP%�m�^&C>EG�_ � �!l��<ɞeKi�V2ax,%� oi8� rna�#E�."�our6!BE�ach�� Sbi-?tV�U�c “top� ���("i�7X ��IJ:�h be=�Had &a�A�*����<%Z�:�1�մi )�! �s!A���ca�I�gndpL. Forr !q�cs�a]�Z<Fu%a:�> ���l� Llj\.]2bFG�!4>aH"�0�dn������-% ٥�$Hab.Ke� s fu�d�,��a�S�:� par/��fN!2G�<sx N“�^-tuA�]s�q��)�s��*�*ly!�syn[n 6�N�Z4=� . �H wA�"�Ue� a��)[2h(�-6�,^*2n�!organi u��_)�� co�8LQ.NP5.Q: K  narrowe!A8ay�^ [2���2�. & M�e�rvegE@ve 8A�l�_!��!m�force� gd�%RZLph�i�-e k� � a!� !� � }���>Y"3>Cba(����'*�4� &�ah^!d�e�$=0��l�qUib�%yZ+! Qvpr�Ua link�%Q��Q���%!Ap�.U+!hirr)_J��J(cyS:/MG cl�Vis&�E-��Aj3 � �< ��J m�!�)_Aj� m����#lose�,3!� plac r;;�)b23t%=N�g1�f�/�gen�L&~AEU�a broa*Al�,ek sm "�#�J"� .,�6r2T:� �N-. 2p e�� spor [11�8 a diploid& � < �[��� �(61 ���9�� ��toY�?Z&�(= es!��*�kEbt:# w.��$cruitE]�Bhwre��C7� @�,aX�6l �A�of��[1�b12M6p � �!��A�6]�� �-Vv��0a�1j�&4el��U�I'�hm��. R2� ]��by2� AEfibuA��B"I1�Al� f dAjtmO)]Y,Rte2 z� .G q#�gce�,e& �e�"!��R�|!�!�.�! � . Al�S%&���.�Y��J ���b6Gp7qloc)[�3�~lyQ�edE��&M Yc�P�anabolic�!esA�v#^�!^*�o�ml������*�6��8ce�;!_2� Q�ng�bA$�1�q�$a�C%,Drosophila D!k(�T"�c�(Chameau HAT2�"�co2"(of JNK/AP-1*f�"lO<�kmor|3i%M�D���"6 !V�/aheF %�mfeT� ;1s��O,�}<* �j�%rtkOY�K�:8 �z� a�m>p C �0A� ,��]a� s�k n up�,�,uesE�!�a@�oonship&�Ta'� jir cros1"�5���Cgo�fts�lt% ѫ�lRv� tI �FE�T mpreh�. Y�s�KpdeA-b��(�[Pl�_hN% 2 . O�bac���'wmanipᴉ���,meo_[1HhIh.�-O"Gs�,e� �M!� , 6�]e`E��$1�T8r7AXe�`.1u� auxotra�c;`bio��1Yrk�v12�#I�u��&P:by� SouaX�],#�1�Hnc!�.9�p�� -GFP( HAiN�C9�[\e,:"el�as 5�[lDA�9so� 5w�?��s KSS tSVPGUTYLR042C!L�ar%�% ���C�o�*@. pFLO8�.'G� nkM]M�( pIL30-URA32�gTy �wa"moB� �je�k�!VPFREV1H{ adhani [I�xOj%�� hemagGhx%&�$>Y� 500 &jLEDd�e!-���5�t 1015F.�/Z�300F3gZa+T�A�l�=i:�,�*W]�pO: -was.R !�V�&`@NC'a2�rG . Bu�xp!��on "� ed��5� Z#�yZ�  expex7�Xby visu`���S �I�5 ells �. Halo ���aBe�+[1�E. M�4��9h#by%a� on low-A?< ( 0 . 3% ) YEPD(jum� \68jum%* deriNd�\synth� +"jQ*�NZ !n�lV,* 1%�#evgbU5% potT`um�; pH 6 . 0�wnd ole�/ci@bHoyko Kasei Kogyo ColCI*(t�2i? �tnt�3ofp@125% ( w/v ) solu�OCin 5% T�t-2�AntimYnA ,)�3ptomyL,s=.,( Sigma-Aldr� , St�oui�FMO15as�s$at 3 µg/m�$ OligKia��F�&o>�9Sad Jat 20 n ~(β-galactosheuN�*BF�1�n B',�^ in 96-welgq�B��<�)Ź�,1�s6 � �^�uracil!%D–UR�X>ai�7 se�ze�o��V���s!N 30°�tI�5B>u&up�n-�VaO vFfG#|t�.xA.win!�,^aAll2�# carr;H�XAg�unl[<w��!�a e MATa ha� "�X*�=�iA�  q�~�iR�.�i ��(: -HA;ɠ)+ � .jk6tiuQ%��)��� ocol�O~(��N��m*J w��!�BioMek 2��aut�,�orkT��0( Beckman-Couj�$ullerton CAQbaACfix�in� tooA�V & P ScR& ,?VP 40� � �repEM�f<VP 385W4 � .R$ril9!ٍS6 Sr ��75% bleafV��~wa!�, nZethanolM�95%. E ( 5 µl��!.��c_U^)�mix"@008)'inyB�em ienc��+QT5A�a�%harves!�p1�ifu�Ro�0!���%e���s�(e�3 �of�!� �"�tBv��2% �?:�B��x  )�cin Omnit�<( VWR rmDo��Inc� ridg� NJ�$J�Al? S f� 48 h�/ olon�)%&:�:��1-�5�Bh/<lai"�m�o�ul�fieG�X4 µm; HAHY08550 MillipJ9)eincubƕ��L��r� %�>�m��z(pro�b2n"�5. Cn%"�kaE'gd�68%&r � in blankS ons;\93%!B�y�r( 4554�'Z<fEl��}3o*�> G�TM[Mofi�l* :3���2gw" 9�\�. 2�o� HA g�y�'�#)��u'!R�of�"end|A�K"�( PC999E�� -�I81O� Esche� i�li stock8(alkaline ly�prepa&4Q�8� j,!io�I� ����.�1��՞d"� an.N��ed� m�ad)�ap� 8itFSm/��a �#dJ�+�K"( $%�:L. 6K6�2 dz8^��qe�aAc&6Zr�2J 1Sr{�f/h��q:�*A&>�6!j. 6%o∼35u�c��!�37 :2u~;Qrg8�si�sfal�C*ve *\7G�d�9!�mI�v.�o&�)r,�a�H A�2 U�! ^�=H?lI�i:�G-��{HJ{a� 2740���04eR4ae2to S-Q�onVr�n�48\_a�N� timA#t�%��`!�evaluŖ_�T^G� 6le$!elA���5hy � Y)%� S!v:�E tA���"!2hJ�froze!� aliquo�=t −89 _��^le(aVes�T�AjeT`sv-� " samp�, spob5tItyEg�2�\�Fu_j-Ks�". S�>�y�sco�Df%� ��+�mUJ�(�#tic�ly!�� �,n!�)N�RN%9*�kor fla�v�y��3�f&�%�C����8}v��e9n���@%�!�wultur#Sup a� �>�7 pell�D( >9�s���9: X�5�%( >80/,.#l-�lR��2refA g!a/ed S/P4io;J.i a"ImageJA�G Pr�6�jar alTrlthm ( http://www . optinav .ae$/download/XI_6I) V �D�:0Bob Dougherty%T Wayn�Hb!g,_m��^ !�da�"7 �k#a�pluX/2 ��a��$}*�9.5�a�!invngTi!; af�  49vsubtrSIPnto-I�U_�!�"�x�divid]�� n��^Oa�LB�R(� q�nh}y appl��2e=fVea%p"L #!�i����e��d!�d"� [1P�Cl�f�2="�N">y^&=u!,=� ,GO ontology nW?public�n�X�>�$[ AB!:6w��J->�,9 $. org/$ Aof humanJp!�Wfac*�Q�yH)P��Re)�ce Dat�>|hprEuS �a6!&��2� [1:A,7 Wilda ��53��V108��nJ 7& %294 � .�K 1516�+>2_81UI�>).j36�h邭ߵ�YEP�a� 6 2cpW0�� 5"� �Sscopy;!���'�uIe�i�.�$NA)�� i�hot�f�.�a;�Xa�v��n RNeas+lum�QiaO�4�)�}[�Ba7,� labX$).hybridi�)� �:q�S3�hpac8 -*#�@a�tI3� �0��8uc�� Fluor�QnP.k�,��..Fe&&dye1.P�[ �sc.8d�(a GenePix 4U �Axon In!;m[!W��?6<�a OPro 3%. ;! i . �,p Ew�ng~&�_ or f"yirby arti�� �1&vV#O�G4� . Ba"�|�r$ed Cy5/Cy3 J log22� A� a Lo�уI�aI0tegy ( f = g6���+W. cA��$*!A�ca&[( B1�*�����iS#4 ?S�)?Ke�I ;:� y \�'E manumurer'"�Oޝ entha�t��+��e�lmtemp�� real-time11.!4ul ynE���FBior (MyiQ Cycler�� iQ SYBR G����& ��RTi��Zus�fN �F� �cs:� den&��8m ��9� , J�E 35×B 2�S><1��at =!��.#g^1^6�$Melt curve�єAA�e�W��_T�%�et�!�er���by� �D=&�I12+7��m2�!g�<) om� e@ll1b�ab[�\�q�Qd$6�1=��&E0��#a^$vs�)ort [1f�!^*M:nTT�^���g GCGA��8:k TAGTTACAG�;G GTGA�؅�j��&- A, �s",#Alemi�Y�in &�,V�� -r�A���Ch6Aa�%�.RB4`4hyp�,��pla &U@ryZF""�!�$h��m�8log�zg thisa�a�HЩ�t ��'#8� in fruiEC bodyd�f>.; fung!ApSordari�/�# , �M�m^a.; i�n.Ȫ%_I�2�-�eg\��A�at �ȜB�tax��Kr=A�@�ta9>J�typ �#{�)*�G!st%��+%_,2��8.���o'/$ng knockouu"ndQm��1�Aw_�v t�M<y]] demo��u 6�=*R�XHha�}dB�2h~�@U��C"vG\�"L9!06�arAJe"�,����7+ " $st�d7Twha Is�\ famil��%b,6J.�]#A!-�1|5les2!rL�5aqBayesian&�F�6��)�fs�E"�:�'U%6X1�# tooda �= Q�:1u�b.�. �[5�0�dPQSE�c:��;aS��n�� argu.��h*��t!�M+��G [1�u�qb>� �| "X&!D.� � >��v��cA1�6eA4�8*oK�[9–1�=NumerT+Q�%� XR� es*"aohaM�Q�3>�%,%'�2�J, �5��be )IW2�2+er9�-J�[15� Estimz�!.7=��,���+�:�#me��!�?i����ve.�>��)�>be �P�Ճca)�"ױ inno8D . IfN��=d.Y]S>}a��!D{*A)B-}al�m<2Fn.[�y5Euld map�>]N��݁. More* ,U���M���<netQ3 ��i��&e��D��9�w��c�fupf “b^1 box$KA~�C�=t��a,� �t=;��v 2��,u8��.F�origiq�sa�[� r�F[)i�QI��j s�u�o�J�Rm~R�ՇfeaT�,� �ȱ techg�rA�s��!�.]o_�:c��y!1a�"�?}C� \-,U�@�>V.%�[Iiu]-9� shif �Z� )2�4 2� rI�6�Ko�a�7%����.��}*T�;!�,�]�./ h lt f!�A�ra���#Ral��ectp1�jF< 2Cr�&o� � a:�ch=N nge:!!�!e1%�|ly hete$t_@� ralid�,B^a2`!i� H �+re nowQ��%v )��Wjz�AU5 annok&��D!,Qf$a�+!lq=al valisODn �C�i��&�Bu~Fur!�m�W, sex.��of@giM� cOYblW�Bxa�.�^tissueU�G��}a9T�(A�a g�9��ab�6yeukaryoG !Ztic� �.���a��yceǂF� :K�i � p*%�i[sa�MI ��zsuӯNeuroDK��SQ�Asp��lz#nidul�of��1' a spB=[3[�� ��"#�thot&Fusar%>gra€ arumx��A+Q�߆&doݤs��6 Hypo ,� =t),A�� �"� %��dduc�&!�,.sk-sha%>wbZxerith��R [(RB2@"�mei%s�%!�!�e�#d]! sacv��9 asci�t q4�#"O �&R� orciU�disb(g��q �e air �>s� a� @� reco7 T ���+ ,% m5 to� - -\8��!/ Ja�?A� �0�ll�M�a�raY�A�]�ͦd��x� �w2$�2�!90on years ago m�.:AM��2�devel��A4<itu��1!�"' �`%sr�,.ŽalBk�we/�=FPl�A)&&�%/ wo"���/&Z%`� �#�W}bi��sts: w�d�a�*�N-InV���our�of homHA�" :ߵoes:] 0�rPpi�M(vi�ofIFIgen�"CI � ��9j��G ec|Z=�A�ơ$-M��Ka�i� ��.�5*!7th/Jl[41�2 ,#*g�" 3–�. P��of.���J�e]rZgLshx-�S)s�4!5ascusE"un(Fi��Whi�n�P�<v2�5�ce s(cɆ, teD) permʓ!���Q�TF .2Vmv�wceiid���8*CP�[4Z!*���e�AAra)!�Y=iE,E $T R���C#dMN0as�)�-]fAJee��uma:�a�Sl��%6�� �al Fo:��[5J�a�1FB theyN��W�d> [5a��� Stri�>��# ��ū� �% osti0�B$‘beak’2gI:�e�t=�{_�8�W!,&!o���~�fire [5� �,0�7Ag�neatho yeh � 3 ,�! ���b�����facAAej�#J�. dia�邡^O� phot"xM� must b�M; ��L !� bZ$" '7�$�-to.�i�==of ���a�=��!W��n�� n�-t h�}%*5'G�.9Tr�l,5�#predo�@�9� g:���.8 NFli��"scF �J p!LA�*�!I6 f�)��}croZ��A#agrg9tu��fie�3@ nexa�*K !����T� \�s!y a.'"� dr�Q{A�[56�"7��of����:iJ a@/ �h>Zpi?s��%�E?�ZA���^ a1pD����` �)�c`+ic r :�2.�"bV�3~�"� �pE�s4B �&PlalѬ@Abro/EH hN bioc�)al&R ��B!Uw 8–�I6Bq�1"� � [4O q�aU&f� {�w �2�1x�a8�%�t�|�nco�q}�O �5&S orth� s*ٳ.�N.� !��uq��5� Ar�jf*�; �*6Aj st?r�E��%�1�s_z -��,� :M!�h��s��1A ��$J� !��<1� ��3�<�  phyl< 9yxplici!, at�"�^$?~F*�a*�]�4"j�� |6�ic-K�VF�+�ZW�_�e��s �$�IrA�m!A�.� �j*� 2$ot]al��y��L�kiO#��R�F!�� F�!Cu� ba \5.(corJ�A�x;�NX��'�Nno' �2� tq6��d� � j !ǹ���) or}# >Fi9we��.�whe theo�� i�:tc2j>� -܉s An�� B�a.�$�/� �u(d�&�4�]M.r� �]emJִ�C&��fQ�e !�� �.2� :�� �e6Z��M�>,2�,ji�)�1 ���$��&�&K�:%�a��(ur�2�s�(  Bk�� al w~,.�,4 i ) a�� �  <���a��t��i����Je|�6i]gaL -�`Q28�Qage 1�@ 5���A�c:�be��Im A.�uf&�g6�3"k;"k; S{2V{Oa-C���ed>3 � �*� star�toa�m14615[T5B#�s:�!��%xw!�6��^ �ufEn ��5���f �!��%e apex!�Fd.�=�inJ�Squash-mu0�a2� kendj)�5J�����m"144 h �EM;� J�)�Z�#�i;1��q0u)��]->%�%banm, ( S1EN!�S2 ,A�'f���t- cour��na�,v"�,>��eq S gray��to �� !*o2�5���in�%e� al�H-"j�,�l�� 6��rot}W!I>V� ay2��#`� � ish- ~q>1�a-ydP,� ���Of� Y4[��)�vO !/�#�� �8ᒡ3=M!�B� To�2ReMarkגP!"�4 #uBLAST*�I�c�4 chCl�� G ��%gw N ea+o"� ��+ . Do!xso)��� �668"�^]E� � gose:)"�!�ځa�Z� 9qS1�Ma Sliڥ�[ S�W�by2( 10 g�0�)�nI\6;-�I��� 1�5�m�Cver�.i� w1a.ci�� est )� $"�]*�$cr�Y�t�!�% �#"1j^=E� >HQpY9me�1 � 8isE�r�D(!!���*� �1�. D&�� �SaD~PA�'m wX&b�ye��=�exc��31a^�X n�.Bb0�$-7�+"&ҕF� }� �}�����r�0�Cq�!k2N�!��Y*�aEt. O�  4^+��]&r#�� �]�}4490 q�A�2�N O722.� $>F���N-�L'=52/! � EL,� dJIl&"!ap �ph�� Ppmbsm j����@in�a��"�2�, 6;�r"$�>��up( Y2l1!.�Bl!*&�ar:ws pea�+�i ��=r06�1Y�s�.s2b;0d t@9�ݏ�Wineager�<~U��=�("���$L�&N2z2� >S�(6��E�ra��we{�e�inyH�(b��"� � ;&И����rR|1{@5��( MRCA-F&� !*R;�=@:?N?� Pa*�!*M0��it�Kw('(AthAE�q-lv��" Mm�:� �i""+� cruc+�j�su'�fu]b��2 . Us% ��� � >in�ItI��|M4st�` � ��6 %9=���J�\ T�"zAGl��(��1�!:S2\�2կ�A�)4͜�!e6+-�B �at�wl#aQ��+:�4))�U $ C�w�a%�P"�XCch,2o3toE�-N�A�-� WeJ��2� �ifl��de �vU(sc.��&{sQ�J} >�� ���2�!���wh� !�4)$��X2j%� W,YXE��&yK,%v�"� f�w A&� &J 0i� berrE&���"f�KFRo�cu;�MS-�� ;al9 y na����I��}�ac ba:"m�J�For>Oiaw)IF�,P�< a�on�cIB"� ran��� ( S3 `)!�top�@ahll��3:u J "D3%�\bցp�c2�u�to�\�QmJn{�Q?d.���n� � �>8�|F8  �17 ( 74*Xmed54Ysދ�gJY6H96wea�Y�NA"&Ta�.Uc*q�<im �v��"�$�`�rey=��$l|!�!�r��g{Xn� i'٧ �#%K�8�%�HCn�`I5%�a=P!4�G& al�J0�"I �D9iӎ&B�X>�i�([FGSG_03028 Fdi-A�, 16340;�Fig�w kwXl�|as8���!L���/>|� �"" � 0565�> iv-1�8; 5166 ( lpe-2;zo) ; 665�Fvad�; 747�6��!� ��m� >����&�tha?2Yr �869�plso;�us��m.wq"Alsɲ%�%Basy-1� �?asy��%�02102( 565&xR���/�GI�y�2J-�A��� A�N�,I5%2a��D�&e�Δ �m��]6�rhiAsee)�ndh�U�c>iO�{�%(>SO���e�0a]i'v*� H*` "���a.�x��N+ 5edmKir � est � ��3Ge[�AE%%�*X �B� � fg/A'�SL ,y,�Vt�n�"Rxu��u9�l !: e$3ss=� irr� ��u�plyEe�-rrem�iv�!dor� m n]�f-��ie !F��]�J, Δrel-a�I�4001;T!!# �HA� 0a1 1009iYD�I 1749��e�= 1094%a�11Wk-Q����%I�!� (��h'A�B0�" ���E�8#�U2l-i�l-�Ai0m��r�e9sa)�q( �e!hџ �Jo.6�!b5(Ei"�dG%Q�J�Q���2���w&9 d* $UDaCmy �ej���^�)rel-8y� &#���s �.�����e>m[M@͚�uls1Pat-�/�r2�C�iaA��is�! a93�,81&�A&u V:�6ֽ��v�� at a�y10�>�pdve e= 1316�H�oj'%C A�a(�� very8*=�:G6I�rc6e5r3T 3E@(!�)�l.�Ҫm!�5a�i$2asaXus-�p;)071�]A�� !���A  �*�D"d!er[]� i�C��;1�I*�(2- p!q N�stc� �xsi�I�#"���DiK `� 044nY�!%o� �*%|�388 _�od_� �?׈v"�)�C�AY 5��sixM&(-�042�+,03813 , 0418�u 0737900 1268�g�O9v"$D<To0���"��os�q�S!�n"�{A�+ Chph��%a hygr�7H!�o�2fer���K�,!@X��[�wBM_�C� ,�-�)87�NP&Mef6�Kr�6nt���xros�Ci( PH-1-5��nit-3��� N��! > ��!�?aEE�,�sa�S2; )�!o�3<>AU+s#o59W=@As/y�=�(��xR"�of���FNIT−?S rw5 r���%&)e*��/c2)il�)�)Fo�AnY�2� PCR�"���%;o�!4A�1#�Şe.Ls�����<si;<Of 196-�!i�$*�& ( S55d�E~&�dE����H9<ro����L���(5WsJi"9a]WH 4:QA��� 36-eh�a�t� : �i��\��6� �4%x*� ��quI�m-�!�.�R� /Z.=�%��* y�:!or 6��� _perturb��{4c5.�ak2� rI;, sah� NCU041yeA�� ��A�Q(' sr�.974���>�:e�vsrz0�Je"� 9� HC�6�m�D�~t!��T�%�%—E��{>Q-@MN@�<l�$ 3sN# E�)M�gU.'rg�n>��a,�+��g��i�&�Ӑ�H_%�6� b�U � pol�lyQ�-�d]on� �6&�V 2y J6Dk��Eby9"q�A%w ��"��Y!�od}l�ar� � exg����V**��F16mi2&y�4m9&x0P6>$l.�AMta���� �!4NaV78� ncw-�y#6n�M^_ � Mt!] 3247 z�utj_t�st 48 h� )%P!{Y�!�enIcee!%*�(� �""�y]!*p&�3[o,�*��f�e�"�+�%~�� � nd A�:C(.Of�U , 13*� ArAHa (�#E$�i��sig*�;)!��>xg �e=%�aFr ��3���1CU0312j04713—% Q��a�:vl�!#yeu>�|I�&G.-(IE49F IM�074�k&� a2n���^s!*��U�a� ���)N"f���LJ�6��!�"(͛%d.a)5v�&y "8..�=>t:_2q�spiat ��I"AN��i'\.A�%18�2�EFFA�Jh�, e�&��N2� �j9�L�')="���n�n��& I@145�^ 0146=1496017 631750�?a� 0885�m8. The mat-a kno�Fckout strain of NCU08428 produced slowed perithecium development . KnocFs@87508 ( hollow ,  )Q�ea phenotype unique to this study , a fully normal-shaped wall and beak , but no asci , perhaps similar Te tof stc1JpFGSG_17499 in F . graminearumforming �mature �6� . Because �.$\in N . crassa occurs durY$Stage 5 , �J<Ls ordinarily assumed�Hbe “downstream”� the first� atio%�%%and @ospores . Previou)yDies have suggested �Tmorphology is genetica!�controll*y zemale (!�toU4aEarA16 T[89 , 90] . While no kUR6-U�unusual��in.�ori (-b4 ) ,Zfor ten�s (E�,0317 , 01120 3464287�03938585 7621978!g409915 ) exhibi!LU� s at �!�affectA beak28I%�4 release . Com!I,d with wild-eJ=s lengthe� 0 . 16– 20 mm ,!�4se mutants shoa�0significantly rter V( S3 Fig%CxAflarA' rang� from q1 q17q ( Δsbk-1%d%D)�EsmallesJF03 F09 Ffsd D-\:{aod-5-�%��t some�"i��a arrI�earlyA;.�!x$others thaiJ a)%"do not5�%�aUKU�of tzn-1 �E')G!q grea!kre�ha�N$probably d�e very/!�8 characteristicph!ܩ��Of%g10M�M�!�I.�in W> �D, all except rpn-4 �e$.�]Q up-regul��afA[��03 . In summar��EX number�� �s wer!%coveredItour�:E� many:Aa�� s up �ed late�.�, whe �s�m .5;96E�<assessedF��,.L of 1-v:�?$as homozyg��croX:��reas 86 >(vailable onI�one��!ԅ A�6i� heter��m).!&�HI;�opposit6` . Mu�<.�in sex��.W�observ!�or�of 41%Zs—27. �14 �-. ThusO539(� Tm3tšAlthought dispar�between%5frequenc�Hi�I of^�eus��sus6�1�e & mkfe , it impl� %p��1 y�.�pe.�Q�s.�*� J� ( 74%*��Q� ( 22Lmay� attribut��� r bs�R) f��� �5�J%�exa� d��X��MFq�(WnjecauAN43E�sN\.eb�.� .�to��,BLAST analys� gainstzSAe� sia5 R64-1-�*re��gen� ,����(10 identifi%Dort� �TeT S6 T'�Of 15Se� %=classifi�?sU hyp��t� ��teins` 6,���9443 )A�an ap� nt�Q�$yeast ste6e�ich func!��!�export2,alpha-factorA�rom��in L[91; Th&f;����"� in2�a)�pr:� s�6� te' ingl� Q��-J� ��� O 2/ . }t�h� , sm��� %}:.2>is Q>=�A:indica�݅! theyen1\a4zinc/iron tranm t� 9IZRTZRT2; 92�3!]Fin��, two.��1<4!%{� E^b�Qi hitse(eiosis-spect I�$spo11 [94]R ndt80 [95�6^ � �6�ab� d� reAj ,!�ducaM@Ad�abD!4�@ToCer�u8 ��k.� =� �would�O"�or"{ tA.&c��(iruRE+>� , we&^ aM6r2���F�[23K ly�ked �Eb%�N�sut!}>�(�x��"M 2�m <ouiK{6�,A��a*��[six.�8&. ��m*�F���ly��Fa>}(%FW-:JVl 4180�792�2�atA�*9u6m��To furEtM�evoluE�of%y�E�-�a� addi/al.RPwhose=�� 9R!N5E�( pdv-�2P bothKJ�6K>S��*+!eI�noctche��Z�Yn2 ���Fv Moreq�h�wfca��waRuM nA� �Xr ��es��ed�d � D5 . Howeve � pea�.express0 co�ponRin.��?� eara� of�.�i� �s;o ��9�bimodalR�� �E���b ��i�ake predi� a�^us1 he estima� A�X& E��.to guide( candidacy� +�\we��b y2��E]:nvo�V,q��h& M$wholeR� o���z -def� subset� I2S,����a� of f � ( 44� w���dj�aA5���d%�ntire se� �(�-� 5pro�  [8�88]�w, 235�mor��an 200���F)uAdi�re\ )�be}�J�(�-f�P <�0��IRM"��17�� � xfj J�!�*�ly1�pro�� s2�� � i]�a�q�iE�i�� 2%w��1m9gaN�(9)0%+,�ja��t!��ms$of 657� crip�' s [96];tq�� 7� �OU#�� . On�er-�ba!L,�capproach.}ges qԁ�inu ��agɽJ�equivale��t!A^�lmtir�%Ipl�!D��(��. I2. �imAHant�Ea�initi" J��i[o�)���6�ar�e nv�C�st_%�a_ moti�ng �!�� NincE)�R4 M�A]�al5� underlyi]9 of i,m �́h�!9Ta��estm�at��A!z.�was�!�coincŞ �2]ap.�U�� .�min5�(���"R�%*MRCA-N�w isL��e FN)orevea%��3��ra^ liat*f.*EcG be)O�J� , 16FFs a�5b!� �sam U,!E8s�:ory2j> %څ=-") \Fa An� >wFusar� ata!?55?,)�lb�`7E-�N���� �R����#�N� Yh�I�edTo2 stitute a hEHgroupEg!|��*i �[%n"{:$ exp�� "Xe�1,�Y �!�� �ram�systet cb�kMI$ i�rehensa���$y , 7 . 3%6�&n .Vj as.[e3ar�V�&"� matrix ,~7w!9�{as.�-%KO15� `�X���18J�6��,Be powE!�� . No��irI*f�has bper #�tF"W�8wh� cri�� storS ly u> to selectmǡf#al�~7 � �CM� �>in�p�~ itiz����A�  . A  ew� $Trail [36]Ziz��he*]YR2��<�at� �N��"�E�10ii�3$ A(�on � $ a�r46, pluBe kin."��:" �Q�3 $–98]; 61�q.�m}�Uo%\among� 4431��mq$"�c�d�a&" E ly nine!��7� g%� fell��mXtop 10e�!�e�A;F�T�q* ( 9/39� : � H���bbyM�q@��s"6~ �t)�A��I�( 61/!&;*’��'2%~�!/ua.�c Qu iv�q@a�gh��b� U5Lindepencly!���"@ �8Bayesian networ�$!���:%po� �5 qonsMJ6�s�:w>�E�2v�model�! howK.c�change �E8.���02�in�yr�  fruie� body2�, foc�o_&.��216��j" $Rpa�)�'a�&�QyA�*JaZ"5al>���6�W!HcluY thre�9(A!h�$�')����3�;~e��N�(�$$v�:N� *� � flbA� fmf-kR. pna-1*yt� m&�E alyzI�Y;� )xJ� mp(�� s!�'%ors�seven�����Ve.�.%co��1{&4 ��w����6�um��ar(U�9�66�"mm+�nfe& F���� �5� �f 㝒J�� �F�s*S)B�.��)�N����n�)��!+ �wr)Np5).^�diverg� / 5#&rqu��phylo�"�accord. �"\\s2,profil!n!Z��'�A�v ro/ z-�8.�E� particula�)� K E6#6�a�:earaZ�a�7�&}� >�� cl�assoc�1^pe� �i�persist�( om�s��kA� �.�b� ^6� , Δ ��ioV ts J�� s).I�%>c6��>� �p��,F�� s �F�'�x . Desp'a-YA�Q �k �V� 64N�]maA&nE��d�\ G$tetraspermA NtLA_1270I ,"R � ��A�hav�/en&fA|discret�0A~veA�illioid�n!con"A0 c� *f �ref��O�)M�u�y�(%� also shifX�/ak�M a��$m }�A^rocess�"�D�timForMF.Z��^��&@���� F���=BaOpro�$&Q,edQ�r�F�!���1(��v��.�g r��& sepa� lBQ�Ea�-re�� Fx6�i�J�ɝ6>n�!YL wo 4,�.be_/-(��z� �un� �6^� ascu�as".H�� Ѱ[9�$99�"I� ral�A�� e��)(� �twn 6#�.�g'#!�3Z/a*�� :zc ,BUthf"aW�+�RL�er�mplex g[ ae_�g]  O"�6� half- 5�R�V����resula�~� �Mi�s�6�um�$�-u�u@2�as!, majo=*~�V�>� 3 �/eV6�a���5� �: (1ing—oJ,-'� c ^�e&�!f"P"��:���feX).�;�+)�A��!��um"� �&9–102]�nd�.�>n�U�gr�( ��6 )@!�-��a��, 104�BMy=3typ)M13co�!�r�:l� JP��:�n��6�.s posK.��ofBj �J�6�"� 6'be mis1O cree.sAns�-� _ O)struc�8M!Gobscu��7stromaS>. Such��sco@a�let�lac�|q� cyclUD"�-�K��pa�n�Iw���:6�Ar( �� 6�*ƽ�"'  F�a NAm � �;=�� 6�>�.h�lY�, �.4� MwUme�5 isms��;ag!Ci ���)䩐MJQq� ^s�ud� 6��E�� Neur�)a�-e�ei�% re@3ly���o�)@!c0�a�,at�} s�2�h�&c entrr7�B24.� 2�p . ,7e�JI�,right� ,,( key life h{�ci+&. R"+�:c" on��A on remai� a w�. ximi�#odA� fast�wth ?l�. y momiZ���w+@e robust long-las��y+%� � dorm� until%� next��fs$. A8<gaIX;thr� �[8%Qa brief= post-burn��a(�dur�'� �%a�$"> s [55��2�e' m�grow agg�'y a��as saairophs�խt = endophy�-�,athog� [105]—t�7@ �Is��efficiR 8 nutr�4ources dwindleQden%�' ow!�(7 rtunG3[10L108�� Each�/4>jcolonizx=ost pl�;! genef �6���+%6tissuesjoverw5�a*#w� crop�id3( Guene�u  2005 &Y %H arisH  abun�ea�\i� op�(l tempe�re f mois�� ,�!���нu!�aE@�9max�?1=on )��2�of � i���#�coS?�Ozdiminish�Q�/VkJ_ver�4e;e�wo%� exud�06�=env�0m�8l $al�(E&�"�0\R �!�thF�A�0� !;}�!�"�!1>!�6!6 HA�%o��"W.�h�UB6�E<t�6e =er��2R.Bp6B,>Oga 2�$ �@ &� ����ral�����N�A��?�manife9A6�%W:\B2oa.@ye�3se.\ orig�$e����i�,!�a`A�&*#e �a(of non-�7lo*^ 2e� A�;chotom�2|�;��Qa�e&�G�!p�=)�>�� rupt���^�pu�?th��5"�&y"� !��&wa�ter}�BF�A�M!-P6�in[ �%O� g1�(Nzu;ng! o%Wdj<nc'one�A�n'%sDb� m�9 nFeg)u&W ��&�AP)�6�"*s*5-��F�:�:��0 rel-=53A�nd 4 z5�0>)eBla��e�nce: mid� cch1�#Mto%!� d�"S!�*� M�NF7c?t96�Aq� IY� BB�"c��v� T*�6�6v"F/ calc]n,IO�#���� A":_�#A[�@nn�"� !�RD [109� !����Na@�>>�9I$M!�Y s up�F�yC!�[77–8�8In�ar/ Y .� %����D�6w[8Ah�A�isa@crepa�<in� inspiE #dex*�"C�� m�t !�>�(6(1z�.�.E�'ba�solLon�12�measureasE�mG�: verI�@6�4&l8�m)!=� comb�e!  5���� �p�/��rguaW f/�Ff�t!��"C %�.�.f>e' o!bM�*Y$["�> >��,@ed abs���h�}�2410�J11 !U%)�%�=�[iX!  :Z<Y!$bek-2; 113�. ���.U95��I 9throug$.�.���.J��#6�c�%6a�asymmet�*:Aq151 ��0in_ \ �,��3n�)pI�&��"t5�j�12]�z�Q.,�:�U'�arP8k e�^cA�e�(XnF ,�� *L �6Xs�V veloPal;�_�in�,s>�*�x*� �~�demOco��u�S6J@j�9ultip"++wit� I*m,useful novel9��>aj�z�.Fd� z*�2�p��)6f ��>� .&�E 8&� ũ:�:s�� >\�ir6E1"AD � I��� s d��,BVq�Et�%ͤ���ed.�a� j�\GB�=u��],!��*tc1* +�&e&U6H[�!�Jd :�N�-&  ) S�Nof2$�z �l2�&�A"l�� W� 1�9Fr)l[ ^�8F#*0&e�"! �s<�#�L&:6�v R�� 0rfBYV7� A�i�t2�C%SeT�&&# v�BV*&�2"[��sK forc1J$h�Pzachieve�t� %al!�M��.agui' U�>!�iE&av� � !k�-���:e�I EF�Ti � =^�0};c e5!]K fung�o� 8uA�}��ra4���)Z�{1��r&9� �lE � �[11�S115] ne�it\�um4y$o� ove-b5�(d� � 6�NioA~�7!\$oil surfac�*6�JA� �ed nea� laye..~�?�#hN ak�e3brYy+e!I)>aO3h�.ee air�] [116hCL5p�Nic�y�b*A�!zbm to�6!�O6� &5��9L Gd~to engag�wm$]5A�F�!i�  -�Q�JB��^,Amit� )[o tune�(�to�� nich� ap�1*/W6arc�Cs*wNI"a�2��>omy*�I�� a�rk &W�!ic�+FQ�.�"gd�)draA�c.�m���i�<6�[i . !�cX2�,60s drift”: 15W118�"2�A"4=��A18z�hibO1F�A�N�V� "�$(BRoff�A� RdNm��I�-ca��2�!-Mmap"� .�8�wAa��Z(�.$�%m6 co!�1���i�Lru)%Bt2����Abi�! !(e�L�!�%Y %�ver R2(Cr"\.K�� de�bec�C]dJ��a8 8J ��> YIv adopCnonLW�t*, ��]�6�V�e��r�er mRNo'w !non s .2  a min"+'�&`2AN18E�!c}/F���8��� in�7d�,Y\�at��1&� .E�a�fw1R�JxJ��" �.`[:� Uq��>�y�us, w�+2�� * 5kinh=Ik<]!j>�]-2��_ z �X�5^nak!��]E14��1Qe>�6j"��{�_w��V-nI��amat���*=.Fa&yM%:e!�!�e�es� r�^ɲ�e�Ie�"�si�90 �78xiU ly 2�\W/n!!%="� [38)9g �R�s *�)��ΔN�is"8%�<�al }c"&[.*$ A�!6rCj�"b�/M' —a�@Wc$� shaa�%�2K3#�CA�!�&*2�r�;^-_"�Z � �,.�ZyL� i�~ �5A�]� N`.�[f�aA� 631G>�Y%�ZA�)8 �/;�\�Y�I�seK1q�RE��.�of lpe-1�"� �� �*� evM�a�a]m��eq eL�ab�820-foldEBed Na�theles3��i��}��: A��MG�:�T,����c:4-"z!%v:^ slow�>�-/0"�2v�2G�U�b��"R osti�K"� �.ZRGdu�:�L.�O�cp� �9!W*ME�ׁ�9K i�zmarked�&Ic61?ira�ac9�e� Ss�D]a*p. �/)n�ɑS��="z�]�� 9 N`� �->�(��)"�+aZe2&gfV"< "E#variabil���Hd!=!~�ain"n "pf(c.� �34OnGBWbs'!�%�L nt)�`R �den�#�fit�' *�w.C/[)�K lik�,_6Y%15�. WpB� !�e�F�"ew9�Bqu !�mod�UiM�]-("ng �.�b>�&[3P%biDn2'O%r� ��N/! �w'�!.�-6:&modaacpU=6:O�i�)N%!�a0s9,�edpf/J.!u, ext!�vX �K*;6�. I� -5 q�c�.G�� mappr.�!a�I�is �t�De&nwh>�2g��h[�\y har> x}� J.��;A� 6i�*eas.�FYy=� sh��T2ZA� “bK/ boxiZ#"@�1�e [30P���N: Beyo:6=|'vid�[icV� \�t� �ng.��% E�9�g*aysfR�P��"FK6 Yadd�+{�l�f�Td�0 gem9=pr�tx . Sp2YE���2h.�!M!�<%eH playc����=�a�ջfo2�Le�in�*�]-�5("c�$��s%��-��8r-scale dynamic�a!�#k%��out�&�,c�E�Run!�f !� �S7>rio&!weQ�P7%few. "W�*! !�F !�E]7or �@c���UAJ(8� �.�,�( numeG"!!s�� se�Qv.�!�)gf��/Di7*V��JJ�sL!i��$e">1�G� *�"M ��E��.h���8Lite�3elali� �%b&$��T8Ah&8&�w�$.R�A<ruZ?*A�!�"I�W!�kE�= . Ge6�$�MpQ�Lmea�3;-lQE��(� in��[?P ���HframeaF]5^ing��Q�w�pan$%6!n,:$&�gibio�tA�$p�A?�,E�9�k1 t� 05�mv"i7��g�,�i�! leva�V)I4l"p � �3F!č&�r"�2onHX![f�0-�a!�� em:L�Ή��N! V�'�..&Ns "� taxa9h�����AI�pp?!��0�V� �+ )a�� u++aoL ��!S� E�@&�r,Lɢ-, t doD�con;.�12N�ca�3a�2�! !>�b�)� 'ds�$!�hourg�b� ei�./��r�..�@s"�o�e,� mushroom-aqQ/i [12�"� �&Pg!� H !7EaqU.� *gI��_N:e.{/�9� -<-�Xp�e�;fu,2"qu�ng6} �ze6�i�%��sM ��v 6O c#. To?%<&#%om�R-hB�in��*-A�le\&�acngzs �mat A (_ C420`(FGSC2489�&�@1"s���y%6MZ1&&�"8hDF`�ӁStock Ce  [fgsc .�q ; 12ct�8elf-in�at2,��)��-�65B^lH&B�6�iz. >�2�(�outG[112]; � PH�o!u907�)NRRL3108XhJ-�6&{-de*'?U[5�>� �Z-55�a nit-3#&-{ - , un� se0Evi?$,�6�( iso�Nv $Talma KataM �H�2qistlerq�%���a��r�,n3P�H�&aE$s�] w��Qran svs�–20 C �IA�U�<'s :r�'eu:E�sA��>�<tF8FF)M G ��<nid� K( 106�� / m�t�Js bloc �(Carrot Agar�4]"�7.YZ li<(35% glycero�>F�Pp�(n�.�%3!vy)4Sy�7a� Cros�@ Med� [125fCA a!=y!Xon>�P .��� jE&� by ! ~!���5k( fM��a )�SCM�>D"�*�I�- =pne��4z�%!"G+�>�,� N�{ ��*e sprea aque�2 . 5% T�l60��!m�culŏ�ker� �ro^w.H�(8�/=ter2W*W#ukx&�hyf �66�)��j��fzwp6v �FVrA9vyoung9��19lf Bg� �7�ms�%f6u!�ũ�r�.�.�eW"��*��� J� ;G�A|ey$nd nucleot+RG O!�(*� 1"� ���E�%loa�G��>Broad I"�Y 1+ � {0ttp://www . b/m Z . or]wb"hH��}��5a l�Fp.%( clusU9)I�ReMark�;$ a�execue ki"�( BLOSUM62 a� acid 2FDY [127��a�2f�u�!�1 . 6—�'8��H?k��"v&jg5;A&�2o�K<2!v%�)k��-�Tu! B�ehC!  [86]Lon.� Y6"�� r�u[�G  � �W!J vali�;�g]���N" .� n iDB!E8]:�� alig�Az"�s�d� subD. DNA-�<4ed RNA polymerFm, RPB�<RPB�:��'=�8PAUP F=0* [13rU���C2 ihoo@px*ub� "�!�� � ultra5 tR,! ��,fr8�)A� 'g�#�3s �a pen�'��[��TN alg'hm��T"�T omic)� J� m�%�or�e.�$2� �+genus� d�{S� CA m] ��U�D publ�{d���#�Nin�?�� I ���!X�.�5>%EIC�!!�#u�::��Ts;D�� infl�y��6�fe�mr/.� [137�� �iA2-��a�!-�:�0�K�"+�� ends!x�Acis- �?!�-��&���Y]>Tm\ 2o0—"�sŜ, rbitr"�ign`na�%�D&�*a� 0y)$] �6*�3a�w�t! �L�&s;VM�B��21R�+&� techn�i����pno hou�Dpo��5ooZJJ �� K.G%��(bz-^om��`r�bleɗm�ab@ -�2y*�A�I(�  [142349  �c$��=��nE�!� �Lt��1q� �ve")G;�P�~w isA�I�Tv�h{iH n �*" , fundaC�YoN D\&�C�r�>�“)oaDthemse<"—�EacAs��bel�+X)�0�"b�xr��Fpa�+biA]Km�1�I�b�&b-�>�D"�Va �(���#a &�)2�MA�}V� tE5E"T .�QV��r� mole��r&� / �إ�"l�� ,$�a he%rt( AD �L Ch�e E�[CACE����ytoo�!�Disk�y E� A�5)8iin iP� [150�5B�"�� �Q{:c���&��1t�&{ � no�_���-&�(�ACEm�""Brown�h%son� ,*� e�kaO�!�ZachI,Մ�!]��val2bz�xi�P�� � < Ǐp%��pVa��squ30. Q'�Etwo��A�he�i)AN� �]؈�es �+�0"� �o�4�Ri a�&�8un�Gt�S�c�2�HJ� � � A�a^2R( top:%O erro�%�re-Q��8 ��>�t�.�AM-$j�*�!'[�fA�4k&�F&BAT<>y�h� �E!�.F<��!�� cBmpu�3)&a&qre�TA��� leav�(�i9�oӅs O� is pipe&:!\ur2�l,� �%TA� UM;&�uh;k= e�!� g:&)!.c�n!mea6#ser�,�g ][oB�-!isN�Y[RAGer mo���6C�4��/)i�"*'V �.�E��"ref�pNP.�ch�s ��o8d6�+so �vcouQn�V2�&�mcyqgq�2(�-|U*� ( Felsens1985; M�4s 1996;> �8� M*E�= ^�A��+� a�_( Schp r e��ap99\.�o�2l"r$e"rpo��2p!(>�)&�!*�$E�far�ch�l9!s!� purp!�of�+��w�raG.͵:  ,&��� /] i"�Kca�ʁ �2W. � vera�quanti�Sv> �epk�h�'�L`��5By5���"==���.�c � �R &����X![\HX*I ,d m�3&! 1�|/We�#t�YV" m�#a�s͵,Auv�A�.lby�n���AL6�A�atwledg�A�g]���c[_��d DX4U��(�VaJ^)� Fp!�ic��s� �V\�o�-i2m�g:�e� ���� -&8( Eisen.�8; Hug|q���)A�onK�MV~=�( ThompadS13; Roy:Knaack.6;R>� M��q#6JUto |�E %A!�y4Eu�t)�K#s&0u�s�r�&:vh�3e�F3�sp�0ÄN�{ ��'�8�x i ePnM"b!t�0"I}�� "���hM�~s[?�B� K"�+�#"9 %|{!,�V%7v*~L.4 nNAb�"��&J�,��YNZ�!�a�X�HF�R�<�)wW , so?<alt�� �VH!B�!�)�!�=j�-7( t�*1ab@Xt+1-X/�@ [X���g X` ��_EF��P�9\� Bn!�!^��C.% FY.to Ni4-�Emca.a�%�an�w�a�y�a�h��Ն)J��$,8��ILfc�!/*M%�\�J��NF�DX!?� �"����)6; �26o5b ~,%�%I&%���a�"��LHB2R=inv� ge�@n� 10o�aC6�"&��F�IfdGfpe�T|akA�*��>���"2S"�{eum�l��achiai]�e��A��M�qY�-���!Wa X/� �3 verlE1g��~$ NsoC,��(T�er![� -TiOE�$�Q)� j?���*"�o Leh&� [0%��� ed 7Q'6�!G"��J�2 1�a�Q��� -WD\!��A)�-�=�&W-f�� #=�6�,ѯ��g6 &�s%LM��#A0M=hV�)7Q<6 �E a�F�/ݳ>y(25�*�/�CA)� -replac�0mJ�%�o(a spli�2rk�!"�� �!1lefldZht fla 5reg�1 he t��t�)+�#�ZAfue� PCR �m+( :�%$a E$A W�+-$ sW%ph enco�N hygr 9i@os MDfere�E�%oli���o�rpCa�mo�Y+0[or @A�Ogil�nidul�6[153]QeFV��%�z#m=s �=,&�[ prim� ( S8",��Yt�LU#b�=&�0[15�m�1T e_:B)ic"k*e�� l�,� E�F�Mu*M I�~.�NProaS�l�MIPS )!��.Ge�'�&�  [�ST)��XQheM0 frag��� pooT�i6.-� >�� olyethyl�T�/ol�!�I)siQt$o;A56]!uM@ y C�5da.nd�"il!F"UE:X,.�rhK�?�b�/nA#9�I�;Ȝ!�e�pr�!��aVcheck!Awo �qej���o�H�Lmi}FA�e��Yr��5�� �Y`JCIaA“Univ� F7!8.R”;.��am% ��* �\out�&� area��.%M�(��DeeBit���6w, doc<\��BY�_�;"(YP ( S4;6)�� /!awo!��%Q5J �u�!%2�5i�O� s��w",� �B�z[a"^�L"c�"�8y�#�sE6bxere�%ro�N�(z[hasy�L�Lm dvb��&�D5!ros�': + PH-�9. C�fi q!�l*�=a*k�r�&8f�6 Q��asB�~�LG;�";�(2�:) �colF��z�2g��!�S:%,��:�^)��ye�%f�e��FA�?�"� ab�6��*s ,�chl�n���+��/�� �Lt� (-�"�'� .r hph1�Y&{by�;�d"� above ��zF 7[ev�o&uM �atxstɦ1(P� NIT+%415 −1����"�k�0es�&��z (&onfirm��J"��2B$e45� �t^ "jT�auAllN(t��T7!�ES���&�M!�}��5� �8R�7F�%�li�toN�A��!�&pҤ V �%����&{)��q��"�.�`R�<*�9a�R5"2�,A�^<%���d5[F�avQ :9�6x1�� �*�� s�%AmM��u�(iTpF��5"e��ED]M�lo$ _5�a�x�K]7;�k6 1l289F� e���!�^e"`�F�� >0L�a"%���,�\�U6B� w�6�{R�{G@ —k���S29� Bsg��.qSw� �/ci.2� a��f���(zMa �Ssh�Rα��05.�ln�-�g�vd!.�F'x1.4�A8�6H�&; %#mw0y �LN�>7-za"�sB�'�06�3 P"���B��zm Web S���$58��pQ''*��aAL*5/�a",no�-g�GDKQ)"�Q�2 @F"` :-u! ��Sp>� ( S9���6a"��pdq s"� 6�� b���26 &� 6H �� �g�Jo6&�({�-)U@�&"(%� poiG h�!P (�k*' �)g�sor._�!,Akb2]�C1� J/b56.s� Glob�ruL lear1 se�`m�9: ��efault"' E�s"A��"! 50% "_j ensu42#_008(� �8�/ to�:P4W est-���:q�"ed�aVE!>,e��(s ��1Ca%� . No�S��G�xF�NB�%s2�Gd44� �4&iN�q"3"&un��d i%��&i��K'+>�%�— 'V �!un-de-��4�al1P!�O-*� �.rb �(!:�6��Kq]7.I�qsc�V*egg6��En�n!Dv2�E�ag5},�"� �� m��AN�*io!g'C�-o� c ce@,52�AL&�5.Ra��|�xb�w�:A�snailf�3ir�@��a@�� ��d� n�~ � bad� "�� B)���)}ed'D�L(2k�ut�WA7, wave � ֢%�!del�&9>.I>m� mE.E���fluores3 ( Cyh ��e( si )�:F�I ssen aRNA1vir�[eg�cSU7�cnsoni� ��, &� incub�in�-labe�ai;w0@!x �@n.A- a!�a�")>by�cA1\ �=�g� . S�\,B��emplo�Gt�<t؁m�"�"~fly luci�9>. Le][Ρ�e N�-��%� .T4a�e�TnYg�soaW!� A���=iW:��z��E�! olon4hrin�ukemiaA��M0( MLV ) pseudP'X!�vesE�ste�t�Wi<x[�E( VSVG�PMR�&u� �5�iShj=i�Z� �-�%�*�e2t|inpv��c�4$��4e(r1l@ I m��a&Q. ��( q)��-��b� �N�of �s'��n �43 0 �`I@�%YuŨ�2�.. A4�;�n>�_� �v�Eve �����xec�f Ar w�sY�5_�∼20;�/6n�aنRA8��u�~ (yw(cathepsin DEX��Nbfac��U$i�1i�!9��(Y AMf�:�a�mreR.!.�=Q�D-�E�e..?aQ�s�y5�B2j\ma�]"f!� ���  &�U��!�K>���E0��tA� . Ad�T! �*a3ticɒ immu�7y �"Ȃ�"b�!^ņ�K��iaj��-mb�morbid� mort9a��p�Cneg!�a=r`id is}]�: urre�,�f7N�g"�&�6�> chem�tapy-� razie�e-� (.w=�|L`�.����0ns�ut.: �druv �c;  [�S�`>�A�i�e�Z!�� �J2�( t 398 megbua�MB* FhaploiP%ome�q4a japonicum [3�I363AA+��m��[p ;����=r�NJ;n �utp I? %�sex ch�� nhau�ob��%�� ]J&},*s&�A�hu�A�b�dhl�C �5d,W=B A�aDw�ary����AV>A U�o1#��u*dB? � e Lo�"ochozo8HA�embla~.��yZ9M�� anim0Nhyla [fCAŜaV ���a%:� ∼1ˁ00&J�!-"�g�,M�40%��eti���Ls7-�tro�Gpo9=A�tl50perva�dom��$g �"a�mpQ�� ����/ "�n,!�eca"��-exon�cur{<� $�%�.@4;eS�� ! �F ndM���r�ofe�AC{a, ["&Q�=(bu�l�'f9@�%��0a* ���"�c��-�wD\ b$��u4����ethodrArsi�t��� ��(�m&& .�"n.� �gE#manip�?!o>H��' �$e�r�X(yp�B$, [8]–[1�@�HiC)�,]0!u�}eui���Gon)aceolr t Jv8esАx o1��DA 5 (a blind gut��W<rpE�ase�KApf-�AS�8�2usc� , nerv�T����E�enE�yE��H: ey-t/e���>D R�mala:|68i3�"�Tod�(���[�o_��" yncy�[teg�"�R9bO�par�Xe-ʋRa�� a doug? lipid bilu. F&Nm ��-6= �� 2M_�Q&���0,4u�,V\-O*�M+�sey�6ch�bi.g � 2�)�eB��^? * RM�Z<!�worthwcUKe�^@E��&� !�eep tae/�=���ar @?�}.�,�\�� -� !�-1�)��yw�pL�m,��h,6����= E9b'*ed/disru�qED sM vacciK!��T�yqr>�2,y��.s��%�syM trV-lN�ae�!en� �>6�l%&�}�bBs�2w�ro a!bJ mmal�>!iE�e\N�>�[1�1[f�6� h w 6��,C ms!�mo�*ka� e�**�%8�%�55 ( se�@3�*��� ;63�%<~=if&�6H� a'�� ui�V?[1�C[Xz�"�0A�Q� �N�a�"" � week%A� via)k[16��?I.�A .ed !r�J�Q�}���z� ���y~ ����A?�9�cAh� .X6;0Q�J"�%�6evU9\1�vh62Qv�um�# encl��_�Nn��#`{�*��l��� t��ill [20%�Da�R expl \AB�, �<.��� �B�-{A{of� � LT)j .r�.�i5���n"Q�A������6�m.!Qp/*�!�d-* �]o�"� M�:i�&�e NMR�TPuerto R����=�]&l�"%E by D�qF� Lewi� Bio�A ReDV*�Y$, Rockvill/ MD?�aduwo+ nnre7 E��m�,��&�$�n��aA�tos.�-�8},RZio� A� Ct |Us�Emmitt��pGeo�)WaΔ ton Y-er�o. EAM:�mo�:�~��!'up ��[�(t 37°CK 5% COPw�q^ ulbecco'sW�Eaglee�^( DMEM!�x�21��feEb7�� 73N�0 UA�penmW�Tm�p���1[�s, [�]"���wa�&�E� sph�Jbu5- d sa�, pH ����PB�0�#9uNow2�A_W��Y� V�-<X�eh�;!l�Fl�����ght�\�0a��RA�IA!of��a). M"�vharZ5!��M��%0\G30(� wos� ��h*G7e�2, Ri�! 6�#i� ��d ?kocy'��kn�l��Eڠ�9a��A[�d��{���O roS\S .�E�6�.UCnd�K.s��Cy:�� Sil*1rL�NeX�va�U�UHtalogg,. AM4C�Amb�j, A�Z|TX A�50 ng/µ��_��$@��(CD;nti"?[�bE�Qx�lQB�� �.��=)1O&�in��2&uE�A/q� RPMI 1640g/@ U/m�u�G sulfa�, µg"2�"50%ml am)eri�B�1 mM HEPEa� in 4J�gap cuv�|an �P�*or ECM83��4BTX , San Dieg CA�Fx�2(A�� puls� 125 vo�\or�� illi"X�AC..O!k.#.&+te�C����Wa Xxpo.�Q~�G N�.��4%Du�b-�to�F ��remx+�un&�EedFl!iJ �� 9sr*��2�a�.�l�n be�x)�V,Zeiss Axio OØr A`Fwr�*�.f�F�e�.gi��ca�Y (GCam ICc  \V+�t�I-#dJn��+�Zmr$&�-186�}ZA and/bpoa� . Ma*Y of d � Y� %3 takeyk%�!V���#LZ(6 . 3 softw, (.� o sy�fJ����mFLuc�6Qm�0�p��t i*�af.h�� �0&��Al]74mid pGL3-BasicF�ro� , Mad�G , WI�!�"L)�8[gŤv�eAh)_c5�[n*DNA���&\J��(mMessage mM"u0e T7 Ultra kim&Z�. Subtsra-Z� aceg!-cip.%S!�u"��dase-fa�wA`oi  5l3�o�l$try ( ND-1�, NanoD�T*�S!IilXH2 , DEE�B.��� 48 h�k��A�MmBT su�L_oB�� �� Q��)at�m�13���x. BǢ)\�<xw500–T]�0y�2�!�.�>�.BZ�J(�&)%?��r � A�i6��!NG���!��.�E�&D Z&,��!�3 ��WJ +�,Az�x:�&b>�!�w;sj5~ elle'&t −801 "2�"� L"� �*��)�6�wEY9�|6����"��.��  Zy#-Bxt��; �a� V6)���'2�#_H�TR�s��, [�gIn� ef2�&�a�g�*( 5×5k bur* m]��)M� ix S 8ou�00 ) ( , FaH"gda�NY��3#Iin 300E�$1× CCLR l( ����Aliqu���( �e3 K)1 inrD%�toe�a"��iY;-A��t �r��er6 , mix:!�a�"Hca��RLU&.0#eqm*_.%at 560 nxk@ a Sirius tube lu�hm?�a�e*C�PPforzhei�Gn�ny% Duple7L8�?"M8�\�2g�9! �'+�A)��f� ![�Z6!_ri���1o*%6�t�J7fA���=�lys^ A�='I�!ZbB choninic�iI�( BCA��, Pierc!�(fo<&IL%R� /pJ7(=��.� �A6�  . &-.>B-j�EZ GP2-293�s�VU�>Un,uc!�(LNHX-SmACT-�A^pz&>�c. >0 �s%9G#& R��%S&@�1�A�&%�qB:��KAV'sup*Z6@-&_)%DNMNew Engl�H1abIpswic�M� to� A���F_�%1Qs]=P�Bruce�[2UV� ~* rifuo�Au�/8Y�ed9���usp�in Opti-FR ed�1um&q ( In genE�� v%(t�� R]�%!a�I�m� t NIH-3T3�fibrobOW~*\dm�.�� taYZY&��-���v<35-mm6!��in�!2 m�Bum!F:�O'��*'(a)-V&b6×105� on�? �Wcfu ) gJ�8��GCbr�,( Sigma-AldrISS�bouiAjMO%�O��T� As��a��ino[�K&.N n� )�I�s adaN� P9lee�coZ|YE[29];��Z�FJ 9ev* �w��of��, �a WBV& 6" s du�"���:.mie:L^/ W6�e���J�. E�wp: r2aq �E�tY)� Q�qm�9nts"� tchA�BO 2r%�� SroW;e* uAhy�r�!�!���3"�*e a��Hstip0�>f���*�e"�4aa� �*"�+� tegyf�9��n�@i;:�B&�g.+($J< �h1��2�M)��.�e� ,!>�*� 6�aM ���G>�2��4���e��"P 6���a= I�.� 9l�EI%�Y s%��� �!\Y�~Fo�]� �-�Y�M�5[bynYt�� �=K&t�:!�my#fE�n�+n�.t�d��� B9Z��e-~�to �'���W*��zi . gD�2%Ԇ��1�  �h4%��AD)�.o�oD�� (� JOs�{��FAU@�A�~Lun�46��!2d%�� �%2 5+.��aa�AquaPa�o&� io-Ra� Herc�X,��("�*�4J�Hf�%��n�}){ �@!�we9f)�6yR��}��D))EB������J� �C��\5′-GGAGAGCAACTGCATAAGGŪ,AATCTCACGCAG TTCT:vsGN� A2���TO�he2b cyto�,e oxid�y� cox �!7< ( GenBank AF101��1�(1F�B�DTGAGTGTCATTTTAGGGT�@CAAACCAATGAAAATAT GE�U��)�GAT"��,�)�}0��5!�A"p:�r+[� 6�$ as n0M�M'I�!3u�[b�p����@aD�&� g!/�cl��g�s�Or�Ӂ�a�/��y��j.!�� arr!�=IdMa� Mix .�re�s35A ���%94, 1l, 5,�~72 $2$. A2H� *�hoF+1%O�r�],�MX< ethi�br�d�vip�nSu�UV �P�P� �:�capy`dI� e-DoFp�`B�B�t[t�4!-ir�-A aD6�Sou n�*t� o_ Zeta-Proba0rnyl*pA��@$3 kb Kpn I(CP�*.��a�* c�"� ce )I�AA��, l %\$32P . dCTP��J oligomer ��$ing ( RadPO ,6�e8!muE�r�.6 M�hybrid%�at 65AD+� ?�����$!at �%st�=eY��AI�Y��/��GIx�1 radiI�phy^r#ax fil�jKodakE�r �deN�!rasp%Beacon D '� Prem@�Bio� I1kA�a�3 PaloL�"��b%qRM�QaqM�(%N1�sP/!��JE(�(��*�,"�F�nd6�*�6( SmCath�6��U6099��a a�(�s:%�Q, war'!)T:��xC TCC AAC ACC CCA ACA TC-3′; �/A�e6X ACT TGA CTG GCG ACG TA78%/ e/56-FAM/&(CAG GTG TCG DC TTC C/3IABlk_FQ/ {for�>� [TG�T CAC�[AA AGG FR�CAT�A� TC GA�T v�C �TT  �8CB� . Q.ocPC�+&�U:ri/�96-+0}(A�� 3�5�6enE�A�pa�9e��3�u fEi�40�f30� 8A�5L�,Fݦaf iCycSZ,�CaiQ5Qcy to s/+a6 ��A�#iu�Re� � .Ri��"��%I�-Et�B�M�y2�Per>*a� FastM��UNG ()��s�(�Ga�;sburga�a| . AbGte�"����d2�# ��D�..�y/arda�?�*1[�si dil:G�Oa� L�93 3T;L . 1"4;% exlo.~nach cL%laf�*:`,�!�re�;od�"�E0ai7s�!�Avogadr�%�ON!5U:�5�]� gK�Rn%Y*� � � estia0�(&rpW ��)�a�ժ%P…an!�6v-�.31�."pu_�v2�" ���.�����I�an *�<2�![�w�epy9 �, [32 �pa��u!�!H;.xK,u). SmCat�@hD encodes the cathepsin D aspartic protease of S . mansoni that $Lipates in hemoglobin 8�olysis [33] . The PCR efficiencies for }DFLuc transgene and�SmCathD xwere estimated by titration anam<1] to be 99 . 0%M�I97 . 3% , respectively ( not shown ) . Five 10-fold decreasing serial diluo s st! Tng from 200 ng of gDNA(each sample �0used as templ%1 to target2��% genes ,!X4different reac �. E) �ofD rela�, copy numberP(was derived � ΔCt valu-�1l$. To calcu�2',gaveragE(triplicate M�r%� with3luciferAI@primers-probe set�subtrac!�%RAh�bIM.�E between25Min6�(as obtained�equIM, 2%[AL,. StatisticaA)� ces amongdxgroups)�invA�g% usA,U�Pof variance ( ANOVA )JPStudent's t-test . P--�of ≤0A�5 d$consideredANHbe significant . To.�� whether macromolecules could penet!� into S}�eggA�cultures�(schistosome e�incub�|in a Cy3-siRNA ( ∼13 . 8 kDa ))uorout�comit�Psquare wave electropo%�n%�\ree hours after exposure!t,� exam%�,by fluoresce!}microsEI4which revealedet,use but weak68A�inE�%>HBy�trast ,v182� soakAorB�[F�0displayed strAw2�includQ foci!�intense6'( Fig%�1A� �� Many �(had hatched�'le��$miracidia;��multi��wa�9�2���d�.�uptak�E9���hMR>�4, panels e , fAb both�EiE�!Ued>Ted �:X�lcor�on%?1�(/sporocysts�'ed�2� . In.�control {tree similarlyIVitE��, i . ea{ock 7m�� Na���ed no ��a�6�17 S1%Soa!E�]Epot%�NNthroug�!";WA:%� d;MO S21� buMQ3.?1\���e�1�,often exhibi!�QT��a%!: l�lntire!�val body!�utM%��N�aM posteri�^8xtremity . LackB� �-n cilie�� s� U�� i���x 6�^incorŶ�2o$larva� %| re-� �surfa.>:w%Nse datR�:�9�ent)�a , perhapsx ver�-��,cribriform p�3!<>E�[22] ,E�.^1'um%� �ak6 . Ne2�n!���ede �?ytV���bU�Y���Z &r mRNAF B� , weQ� and/J�' �v$in firefly. m ( m� ) 512 . M�Z��alla�two dayo j ,%500–�500%n� m�F�eM13� /µl!����!� Acol!�E�&{  raU&� � vakA�mea� Ki"� lu� � Dunits ( RLUs/µg )Amalize� r $of solubleX� xt>/ �. S* *w 2� detel M��>;�� c�.�A�om�P<� !­�3� . 6 ��� D 8 appa� R e*�sZeca� .Q^�obser� only�%#:k�)E�2� �influ. ow c� � conce� ��FUS, 1E`�)]q !�a har1 :gI�.������omogeny.e���q�% all�eEV�whe! un� worm  negligiA�Ur(V*B�Si,�s usue��� (rt half livd vivo)� also&� Nat 302x >I- %��6� s an�� rectq�5)�stabila�. Little�gno.�� uo��"�-C�}�� �ng�O E4atr9vtly de!O exA,ous nucleic � Y��%:�. SR�.]�����j presqL4VSVG pseudotyp��(LNHX-SmACT-viriona�On�t�����.�2~ |a"t  duce* a�of��a&� r6� . Wa��Ith!��� G%2� to Ss_b�ex��he roviru�DIm*.0Yiso��:yX�Azmo6toM��2�p{al.�(��emaof/di�0dg� 7uss���4 �AZ posiAá3�� expen&0a 589 bp frag� m�repor%�" �!�}��qifi1"%5� *�kn�( our�via stud�[23� [34] )!;�ai� teg%d-al9s�y�$4B , lane �Likewise%�cox I��ay294�J�A � �( W�2R+� gr��-=AH. Fur�� �F�9Py�P��in>`EU� �� :� �3 )� m� 5 )Wf�"!k� !"1K2-)��mp.�i�!�,verifyA'R&��v5�s 4 , 6ţNoBE�� zc���sa�u[�Ij��-� J%-*7"�g�( �reg-�=)6 L8 ) �thi� i�!#L  iqM2A.products��q�� 68confirFby SouAi$n hybridiz)�� to a labed: /Kpn I)g9��P(A#sG�demons �Z��s��͏���� anti�I�m"-m��6�8iw:i�;.8 chn+A�ba�on�zearlier�[27+Wh�orE)A zu�Hact* xor rem@as non-?doe t ne�\-K �.�AgAUm� "B(ne�a[E��A51� > ( beloweO However ,�-*Pa�<t� "J�/�* �Oat-��!r.�.�>�I�$noteworthy! t�>2�Z�J�in2 � s di�t each lost vitav b O+ �S >� E�9��2�.�" qless � eir move�Asluggish&*toj�~*�. Als� �% fai�to �Z� (��:nEMQua�M��( q) �>�r{%��&"!�i#al��E٥�in�4s �9J2E)�-���4. Methods yiel��ab�teG&q��eL%�u�2��( 5 summariz�result � k!�"^ X Ee-�d� in"Da�48 h (AD� no .�.�:372R3��:VorQ�m .� MLVŐzd�ag~�.c r ,%�%�^ 2�!���assV!�dc� *` Y byIe�&fir�ab�� tim$sI�copZ "�6second.p,�j$than twice��e( @%Uh��:a�"�twm �T5�TIn orde�deSi#r"��J59!NE_of a  le-2e@\perq���:�9]F� very&I Bre��im" ��=��=,s)ߍ/ � ����saw+an�%�!f3 %K�I 0i�.s1��M�� 0 . 03vAX6W "C!%A� "u,1�� U22.U %{: *�5�Nk�achx�a{.�A ��B¡t2Av3M�higrn�E� !2��!g r>�:tr�isiPeff�"3&�alonee�!��-����!�to�0!��$. � .&egg&�<att�(ive develop�8al;gewa��tyQs��it�readily&�!EN9�:-in�ed ro� s�rnatur�e�peo�,X�ly main��cr�h%�i ! germ�so! cell�� ains��can be2� � snailsNpropa"� life cycl F2��A� clin�"per� %fE*>�.maj�~ur�� path�e�%!umA"� ia. H we&M�&8:M":G"� ��Ap|"a�iA�mv:J such���Sil5 r siO"2L"Q�r�v����anastomo�"ɰ%2��4I� de acc %x sub- (enE��!aM�aD uE(ex�[21[:�?�s��*�? � to*�t �,"��!2�!.aB�r� ��g�A�i�M��o< [1� TBsugge!%R:5M��&:by�o6��Sdelto>D� ^W.�Ň�yh.$�*?$of caplr\R aJ$��!��kis outc�$ma�fR%0l�e�_N0 bw'quickA�ry�A-�precip� >�allow�r;o�Uf�Kd�d7 . At Q/1652 b(";J�is a farAg>*&!�ne�i�.�.�q���q�sB[� mass�L*Bf >10(&[35P���%ge)I�e:�|"e�%\�dY end-point/ a�1 !�ea��! �&�m�diame�[36a�e9�)h" m]F:,&� '�n�� t34 nm]�us�[�rka]e}{ �s)DlyAger� W�i addiT , benea�)!!h_"�e�a���,, Reynold's �&t d ri� � fibrCmatrix%Wa�Iular inn���3H( von Lichtenberg'sm)!&rou�%�VZ��,2Q , [3��Serpigin�brancha: chanB&��Z��$r!A�):%uz&3)to 8(�h) barr�,����&�Xof ds��[1ED[19E��!N�`���_�ansa�M?U� �F~, evV%� lish<�i| �m�� �$itself [38A�[39!"�$�U�nd�b�propell��+!pI�| Azsystem~)rs>mem!�e breakd�acAuan� >',ovi_jpul!� 0is brief . Un� �|eyshort-v turb�J�k es )�� !0�CU'9X:� `/y1+le�e6V�al�&ly�37°Ca�ut� m ngr��6�+!z�@�^ *hormo�)%te� , A�, �.8orgW) ,�� �R=%%o!�e�fun... Accor!|�91 B�9�Z�"U��%�Aep� sub �6P���!TJaJ�%�g�4 FQ�4 q$� mI.�( . Ea?ifB�rup-w*o�D�damag.� , su�0t���5r* &� �F E_��A�ed:j su� fu2$� .6"65",� �valid�� toolA�ascer� }!J2AI<s sen�as&� dot blot:[3D&[40�^[41�W*- ��.�:}A *�%"�y!�eby eG/t e #duE� i�2� B�i3�� � E�.+A¡�Y�i��Ae� �-��e&:��.�.C 2–\m� I) �g���ui%�>�a�:GatB�q��lB �L ��� %�"%m�0st�����"<J9�su��sd#.�ib ploi�&6���two\�jof�au��mal,Gi�� �){E ���353.���lea�1>�∼20� ��#� Y �&R.a6�&�= e�u&�BzRe� *�+@�50��.*�we dou yet�  how ���6�ci �? �E*c ,!g� oo deI�����z!�Uu:6r��'is� I:2anN Fi %�wM3b1#�����diagnoF4[approac� !�F li�#� J~Ab�≥�* �n�.e46�B��x71"op(�7ic isms� ��%"�) willq$lu!tA�st O%#m��B�!l*Y�∼I�.m�?+e�6sit�5eGg�9�]*I��2���popA�a�N�8 EJ���@ �� �}%�M�J�WHAUi�eriph� JJ�um" � BUim�lik�8�8% �� .med"�{ Odeepe�5�;�(Frep�7!<de�@t –K�! �k , n&u�" a$$so neighbo�� � tiss�8in:,�. )�*�������R��z6� � ��g��Am%�� �e� L ;mp&Y &y d�it9� advantage�I�'"G .asN&# �%jAx�t�MH��"min "�i�+�E=ihoodSх�?!��L�+!sA� n r�&E!*ut*aZj�7�xh�o�u"�)J� � � >:p �!�* !s!asE�*�xX5K�~^ they5r!8%")�%<� Y <�)oB�'�l1network�,>-�� + m$�y�Y as�eun� �d�B [g�{2� � pMN�f^um��Z�(����%�)���ct��A9Y2�%`yk�{�)o ial <i"�*� noveŰrapeu�)A�rv`4R+�!�kine-���� �C x!0E ageny>HY�Bi?L�2�ar{ embld ^o�6im/;!biolog�ro�)�)�J"# eric mua@< =l0�?%�)��a<hi& playA��<roͲ�signal!_z�8gh"4*M+top�y%Dflu�%� dynamic� coarse-gr�%residueY�A-"=ins�7!�e�C �chaierir'� ime-depen� behav 6 'sn�&m aM`Q�.?�Pe&:-�&(Markovian T\ mis�(( PMT ) modA�o%Gy =A�Ek)2!pon!� �jH�$monit�Bsi�;an�W�: Hq-x�>8 , 000�>��u( >* deca&B�RspannA"Iinie�p=!1iW-aA`g_?ilR6um�a Krylov�pac�(oj� on m6${ M��m_ > ])���AIp. WycriAa&x(k!�4�(E� x Aw1-�, f�'�*�?Am! oscil�-�I�>�h*fy pivo�AE��at�6�.�a�t&, messen�5� �Fkey�Ii� media� � () {6rb-(ng�+�&�*. B�)a�&"�A he GroEL-S!per �)�f� �A"prS/c( an/ura�,71–84% judIb�y�� 9/��.peAl!�� �C.�is� ral���qbea�l�E�er��s�!�0capsi�;rib�*al��plex . I ����Tenviro�,V��nvolve �as����Ap0Gi3�� ���sU2Gauss��  ( GNM��'la1B#E#e8`͙�2nd%Vnow wid?)[1]–[1�G���| ɬo�Csi"R0r*/&�- 3)�str��e aZe eigen�%AYe a then ��=^=@9Uj��9eir�.X or��P(Chennubhotl�Bahar) f=#- ��"j ��\} A�a��v �des� e]��#va s [8�I G Y3�;by clu�5n+%��!S'5�1�a11W�e9�sv?)d!s�Z2� s���%���By .E�pair c"C��bW �y�#�.,�� coup 3��ot�um�[���6�� -sub)< coopeUvit� �T��[14!vRec�B 9L� I .��es th�:kyE4a���V���i�dAZ]GY� archi� �#�r2�5 . A drawb�@cur <.S6� �Ai��iW.+ *# ��* . ��4ng2��,fJX5�C�C requ�A�al!.%�K 3ss��e elevIof.�joci���vidual]tmrA� Sdo�$ntx )st:]�2&�A�o�5rstXhe E��: s [7%�t���#sR4"�. Ocan�b )t�/d aK ori ��-4sEW?nt>unTU�%=Y2 i* [10aFYe�:\�yi�A2&,|U�A�ri`Aiy��0Zheng , BrookLnd)&rumalai2Bby?��obustl(I�>�", evolu arKM4yMA�Q��seq�> aligQ mehelpfu�qp79Q�! s16� i�Mu��wezt0a?�Ջ a�.�z Y.E��FrNx�_� �Lc nH���wA� �Yorr. Our� �$ builds up�%"�stoch�a!?�$�&ZtiA� �5prelia�ry���#.^E�T7�$"�"� conn"э6��h ��% phys�RY "E+map�d9hitR �>Z���^�U�[1�j%�im��[NK��!zilI }�ar�a^� �(9Vɩ6���2�is��&�"1# !�con����aPM���a��a��} ly}�.�:�fem9 ��t� �- tasH�)lfo��Ta�e�:o4B��6KL2mORY�mb$3Ebp �XL,�!g begi�2�unx!.�st� i��a�+!i�a�lleng��%�&I�Aui� �fo�*]���traA o� x�2 housA΁�S U.���9%dJqn�� purp�-�� @ �)a C$bV!��l� )�%m ma� != g� 5-�. �1��/0 A��Q�d�t� &9+�� �3"|&Am) intrc�!�� ..��) �new!~,7��* �~ �%�i"�5�!�!meP)ism5 ��|V#�-Z:DU�J@&6�Q"�$a�� pr�@ly-�VKŋ�Brownj5�E{��� A� � (EXfG���Ha� N!��&-��in Esche0iaPIa�=31l)$is ATP regedNK�< s �S9of un�Ak� is a>A3�whD!�e�6Oa�T�T-(� nd R″�C/pdb :PW:B–[25:B�be.�J�9/z agBIC 1i*�)l�� view�� e�"k ^*� >ond5sal �vJ 9�LB�.� ..��3S0o& �h5 !.�� )O��,!�c0<nS's��% ADP M1A �e�Q&�-"�S!�i�>V#b5�"&L&9?:�, step 1 dusUe�i��B� RR��-?8-Gs �S ("%6�!��act� tU��U�y �M�ARɴɉ� R������be�1 a ci 1��11K���"y �e:�:-a�V�hydroly�LAy!�.�T3 *�triggers"�R�m~�Q�%NM5��1�u��%�2IGmeI>mZA4YZ�ztop 'helic�H%�I�D�Z5\ch7 UY�17�,HdF���V� ��fca.��S1A7��st � ��occ&NXa�)U��ligA�! 1Qord0��Ib��[26�� �9�"F 5FF*r!��am%6.+�* � GTu�v�W!t!�9�.1�I9�� n:��K1a . No� &�g�C��U����7y�a<�f%*�1�1To�����۵���Xz��9MR� !$" 5� .0ɰ���esW-v~���K %N�W�{a few�6B.ly&S"be��2f . P�,*Q)�>'��)inc,ter<�� �%:T9$pa 6!S �^!�mu�Eex"�n# B;�)aC@6" �2Gnc*�![a*,*6��g1!�sam�Lu��,��� ���3B�g t~!z�c x �V� i���al^�U5a *D$E��NI�irJ�N�B�F�+Qr!&�&O%��a�%3Md+MoQ"� >P _"�d�<*� ca� ,� �e sup%#��.�# , A�� te l, of.(���-b� in T�$x+ 6-!  Ya�e�= 3I:g�Ga&'2�ev!�c��R)&M:1J�.�. D92l"��S)*PI&� GJext"\IA�6�E�*U�"v!, �V�ހ,��\Aq>Aer�lz8%M?�@I#���aM�&�`&q%y)��N�"� ssum6�I}�Pm�byN-���c��]�'/+h@�+Mact&�%atocnGmW��#enA�s u�o�#m��*�A�";$S�<:�"4 mo #Ab!���S2B�=uFf� �aE'<b�P��!�.:�T'wG!app�R�to�tr�s�+��N8 s� a"�(.�Jisr �j�v�-~p��P+$>ly �@am�_ub$o�!��Z`Im'%qrobS>�q$�*!t8�%5��.6 s�5 minu�)�!I�2 Cc��AMD Opt�#a=cessor (�8 GHz� 4G�8orL]WKTv*3#he^).�L &� ��%}��" ilic� �\.]&@l!�m"-B�N�Ow<��!�J8!�B}.;mC��!�ry Re$�^@5"��l i(:�!�y�.)E�(iCU"?,f� X!uver�#caf� ���-!*��DategouKd&M "�aA�T�.]L6� s &eH�� EJ!/:e&U7B�&t"�� 2�G�J�v � /E'p+�u�:�c�� W�&@���.�6.�!*�ir��*; 2���"_�/Ay�6 wq�lso ma|*n3!-.���*��be�3I�]9x�2�< D� 8�>+����:�$.�AinFd*�?,�#�������>] ;�"�2# 6�n.�B�E���g�J�at��* technique]_�cIt1P����(�d� .�O*)e�f(x,E���N-�~:(F(A{"8a��$E�.���km ��1Jp$2-zVikm�B�M�ar6,��#, Data Bank (.Qi�ID� � ��M8��N�2�- �*�N%iGof 14A6 (!���^-oligem  TV���!T7>6z"�&� a toajof 213@Ů15�ai: �+l*�| �7K��( � 829M�X&&Du.477X58J4��Z�^�e%�E<" symme� 7l ����mhin�;� �� Q">nva�n-��w��>t '� valF&չ &� ~�n�B e��euI��%gctV�3f�#i"�� �fy2��}�. Two. :�$a regar�!4�i�$Euclidean �a�� them- Å�� X"*�Q�<nod>Ay:dgeF 7 s exe x��C tom�2n I�.� i��C�d���O<,%WQE�졘.P8��2 nqNB_��J*�nW�a .�!B� x�J&�8"h2 �� ���%"ef<as:-F�GnI -!M1�Y=i!���)� <2�;A�F="�P+"kr�?Ifi�ryqhBFL�Z�$6�n&E'%�Ɋ ����&�%���H 02�$2 �7"!�um}ms up!�1:=Ir^)�,�a��Jof�It2�q` )V=��EIs�&YB�a,� %= ��-inF=sc-)� !�(BVI%�ly�r�kamJ�;"VX�<=�i �5�X7sizy  o�P-�E�#@8#:�R�& ,.cUJ�m�fiJ + &� �%%� �X��ti*�2 R�i�� �� ertyAbu+ �V2w� wr��A�t!�closed-�( RE �F}I�+ : �LEI" b�� ���6i]�e-cI�� �`�;"k 6.� makei�6!�pl�2\��o�]����,iT/su�".oS>EU.EF whol�r�0 (^K.ITo�@9�$�)P�G$ �%�A M�z��%�discuiL>-7��rer#� q v$! �>�$ . No%=�yssM��6 _��1"Vidje �R.�= ��+1 Texpone� ' �! Eq .u \pX A�exp���:eB��K!: ( 4 ) Den �M�2-norI vecto�;�j�x`za��0 A�i)M��>� z/isRTC"�&a���!kortho�a�/p � >��3up�A Heis)O��/� u�@��an Ar�O i al�th�qT42"j rror%]be)" �� 84.lnBE)Ve!�licit[c'.�. �l��5e��[A)� ��R!\�'��4e�fo�5Aq-�KPadé  2e' olynomialaMstQGof TaylI[AIi9�222]�.Af�<,5{"�dA�b(E��P,xpokit softwj packaguW�z�Dq#We� %Kaw, �ACt#4�a�  9�&%1>\� of��.��g �.&�7F�' . Se�Ky2B:�a2�i,  �"-��tru8/i] , fa�O"i, !�c�!Y>8�5:�.a�� �-�>-�!2 fung�Ia!���~PD/Hlux�X������feeT[5$ mushroom K( , Coprinopa�cin$n CGL#,to CaenorhabtPs�AgaC�vnB�_ o��!ult��[�`n kilZ9�K� �j�  �"�ttoxa��3 a carbou$ ate-.de[!��va�| �aq!tk'�Ua C .�mu�@B$in GDP-fuc�+bio&n:s@X?atl-R5# mato��;s��V!_*�9�!(a v-1 i�+glyco�.ub[�scr�h�,�-��Erm �s��!_:J�Galβ4Fucα 6h a�= !�./N-Ga1zC9A*�2")�� d tyqZ:�1��h91%^is� E�%�J�4�4C�ve �syl� fer�I4i�N!7!�2�Q��oepitopY X-r\Bys��3+x5���bN]GlcNA/� isac��[t 1*5�re\d��A- �bio�Bbaa� �C �[M\�if�;�Z�>C%a�c�a|}Rgi agd~gedator&Pqw pe�L%:U��AŎ�Si�K. L` &� ^=��uli��R��z [ atal� &+towar�'�o cogn�u.PT<�fyB'!_ dom�!�^E}r0Mkx�ecY0Y_ J�1%��R�� [�S1D��)�.�=�:�F�h~ rasiTh�oge�hu��!' �- �6(�uPs�/T c�%2B��y!�rnȃ�Zf��APoOF op��}>b.a}}�recrui� w9� E9e&VExaa��a'm� ��re�'H�xr �ed5Qb̓riv�� ( Ba&C� j,i|s c���n,!�nQNc�BX herbVRicinu��A�i�.dxiL mamUxanUBY �.'.+m��al]4( RegIIIγ [3]E"-3 [4:M��te��1tI�Gll Q��X*�i�f��.�� �G!�Q���w%(A%� car��%�_Caerm%�K > 2em6�8>��/�rq"�s ��6!�� icidi. Cry5B� B . t2C�O� na��U.�'�,sphingolipid.Kxaal ���,9�M vor�M�R Z� [5I@-�Yo]F�62-lin�U mann ��!{CMCda alb܅s�7sEn.AshwRnoa��atmA��G �y�% .w(��w@G\PM7B+�3I�$eԥ�EnT )�s [�,F�Kf��-bo�>�_a�G��;�mari!��2� l.�=[�\ =NficuAU-�g�so-�S�y&����-!�%ir�$re�!�abund� ao2���#�bcytoplas�sub�*ua�vli�5� l�_Ea��{�S,wiabsFe��jgA� pept> !dclY4 secre? �O��lac�disulph?�r(@o��i{yh5 �} "� ��U!1g) 9�h"3q� x#��� � e�g�En:H7� ,��}*t a�!x55 �i6D5�,. un'"��r&?A�-�ascomyc�*( sac�gu�� Sordb �%ro�v�D!�*� di="s)Rj[1�1 �X�?t�v1Uin= � &f 1�"SI�*� M�a�y Ѣins�UC�A�m7Yx�C, [*�BPA1QAa�H�s hyp ��/��<v���V]..& � m�� B$ ��e?"�a�o�a�}v� a�IM=� f.B���EUeru flA�2al-V�d s [2 ]:(h�a"�X1e,fIA�z , 2� �l�AsoiKTkinT�;�"Icx�br/Jjlg!�o�iJ��ecu�w"�JV!!�2�E !us0eioe;6�3Ql6i"�`two�p�g� CGL1%dH a��L I-� GL3 �8`2�cg2Q%greN�aboveY�ow�1"�w&���is�&ЄuVq=a��%�QLel42�M&L��=�=!htof "�8-g��o !��su �t�w=in t�s"yYe��` � ��SyQ�� .o*�s��@��,a β-galacto�H�*of"-#�!u1)d� e  ��&$1�Y9a��r :�?g��ly��T�D.\ 6 )� Qd6� fy�5��"=�e�2�aUz�yA�]�"�?'3J9���$"�e( W72G "�#"o���n‘empty�’.]�*�KU��3�'~ofvb�co6d�of:�&�!12�z*>[2MCFor ,�]5�)�� fE�die�\20*Y�ZV surv$�� i6bO�6 j�f GL1� ^eu�;L4g inMv �br�I�(hermaphrodi1wh�ofL�l>�lr$w� wgv�us= !Z�.*=6�q(�� . � animr�A�on%�x� ngqa�_48r�i"�in �l1&m~%%u� � �H9 1�V&�w��iA��C"�i���IU:��of�AS.��I!�6j� �, "l|po�:�[! wv�E�,"�z��-��&�%�F��,�E6F�s�0LUVWs��Ua�B955VA , lef�7nel5T �~@�O�a.�%$���J ,!@purC,* mbin!?ɇ�P�BKw�&�"��6��W |/.�.��2aE�� �&�a.�l!Zkdos.a(|a3N}th!�( LD5qWa��Vxa350��/ml9�Q�b4#%�ʐ�2�<ht-es ron-*ޔA�a�DL4 �ee��!+.�4��.4��ɴ*c vum�"\aZlY��A�{+ �9er�Pa�5��vgWrra"��repal�]�iU�5@D%:�:�V�!0>'%&��) noun���[y���jf���Zm��ph� !�GLf4r�nid�������l�Qi��� E:�*����2'f�aR[2oI͉|M:3.~�5I7ir� �,6znbCm�"�%�� ne�4�%� % ��30��%�}g� 25 ry5B*6.P�~�k 6�dfᙽ[� $bre-1 ( ye�",23+- 32�[ 4 0�a1E51-YF&)Ss6� }c� !�� ��v�H)qD&���&�,:�.4 \.�(��dre-��g!��t� enzymA�6�conM� qC�] into  l!I[ԛ&"� !�a\�E���76�.��/o&���� . | c ach�M"%uyc2�`DYQ3�zG<�6u�M�b!21G��6er�al�QcTte._�! %HrFD� *D'exc�Wa�n4 *� a�>�mwi�!G�_,�emFmu8#�t&$B��逩�y#aU� lso) ��c�.Q ����& 9 %Y-��s via�s�+&�JR���L>Db`i6� �ę#fc�!��t L�@at )2�mQ�F�!aa�O� [b�.e=Z�I2�R�1��R����FuA�$+a%aa~��c*�!!�A��A�!�X�2�f%�,,��"g�7.�<+�0"�qs[ m2vt�iH�gas*�to low@h;k�ni10%� ���0n!!2*� y Ii�?Naq)����ق\3!1���p38 mit�-w %s�kiny( MAPK )^wa5$2�:.*�� �er.�!�sJuic9���I�]:t[rC�.J whetZ��)xk�m>-Bs��b�] �Q��!�%�f�I 8&zP&C d�iN2=��is �pmk��km2��(%�-i , se ag��-�-�)Insy@ag^�6"))�MI%�t�F��"->law�>�u�ovA��<W A��)D�qa�V��6�(:�1�!zz�j��&^)@p�$��pr"� q �6. �O(6)�^incf6![�H(�lEl�7. a�� r7F�! aka �(1��nt���H�A$-�EbI����qK�H(R(�!B�p)q�l��U�HdoK� � pt��=*���U1��piPjxp� 0�<�n��:�>z�����u��f�J�Q6>A�U2�ut�k��P. � IhM�,WbaaabA s�D�,!ogep�& Mos19poirf& �f\N�'A{\02\ )� ��ed`-.rA�a�R� :M�,�k-.gly-1aHfut-8E� M03F8 . 4 kr�e�?Z'��b"i!t*�la| �Iout !=!+��a�F��i1u� )u��!����!R.�� 3A�in 5′-��ans�teE0D<$q�op509 )�0atxox2ron jup(1%(2r ���x=g(-O!49S�!P ���9Z  K:�Q�!�)� �Gge!�c� A(* -A� 6-de�+��5"4-keto-oxyE -i 5-ep��ase-4-�::��'"z�xtwo� D�mPE|*� � � s��� [��I�##.)6� of.7�i2 6�: A�o~[=.`���)A�ym)e�!�E��gg+�?�7�+sE�G� q%�X � ]R"-�%%6�+capH�� +6 �,� figu3o&!om.8���agine�$p+:� ��s��,� ��=E�HD X-�A�IgnTLR:o"w��33s D-N%Ŝ� �)3�Qp enta idic �)�mo6�-��H'�&l!i:*E'q%��*a.Q%�R6�� �� �6i6[37];�s��ha,��N�#:YQ�f.���QEL6v,M�u3A���,�8!4�L%HRP�.b �Fn=�e�5�-��b���.�"�tErm�}MobE��UK�,��availeB�y�(a<"��z%���y�$�� k255��) ( ok89� Q va�WrH �� ~nP6"!!�!���2� A;s3&� �E-.3 %:� R�foRr��8� ��!'%cwcl��Z�. capi�P�tp"���:'np4� llele!@�(��1-72���*� 4)e6 �T��TT�1ogf(!]s! !\12\d >L�r�*iHev���jnd 2-G>����"�Ho2�J ��ll�6�(.�Mٱ^��(!l ) [$N-acetylglZ amin6 ."f�g� B�B�B� &; Ra�$L2�A 2�!U�xa}71a}�kY"�"�2"+owu$W�y ��zn�k-izq"�V ��&�)�-u�> M�yUA9�KX � ��%ly"�U�de�\P-i� �*� cɈv�y[UMdE7ena�dpy-6P� O o��˧�%morph&y��6ot�w"]� �Wo��uE�O=�5tapEW��n��ly un6X*� "� %0E'aY[6[mD�!b�:.  �^7�A��!���A�� A�b )]R�situ ,*�" �L ;uf���!E�&x�!� 24 hE.&�=.�7td�$methylrhod�A� TAMR�y -lab�!�AV� �bPV�3see�e��(dard OP50 b��.�#2$�N��Dea�OAle pic�3"�a yA�XE�"?���D-�&�BS0%DE�A�1_bU>sQeU^ed].�a��'#�K%J!��xbg91� y!�5by .Q@�|iR2�b�.C(*Al4)ZTY S1�� .S�.,@s�7��qbE a!�A[6�!(�"�,ۑ��arI 3 <(.�ymEJf(�nxth*dev�%$�>�;,ߔ��E2-��opyԤ��P��!?��t��$two-dR�al HPLC�b7)V MALDI-TOF�Dse�tro�M\�a� fi��!�AYrA�75.-� �e 6�tl~sj *�hc� ]�Cph!k1st�  �atogram3Fi���N2? &I�-�F" t�&��)�bea�a�3N)�N���end� , peaks efEngs M�3,��iaD( tR = 40−50X )��M�lfg:�j *n Y� {nd =!�let�&d4� �>C :;�Y shif-NP-I hrV�-_!:�*�a�E���ȼar we'YndM(���G� �+mn&�%s"� a 5��U�A�rAVI!�q"pur8?A� suit����q|�8h�Wz$ y!Dr-M�2ndx6ofA��;�qure6�U�*1.�*�/M�J>eHe�A��=�᪽;)��>�! :ĩ�b�ob��.�M�1s.�6 (*�M PA% 2���% *�� sid6c� �C# ���[�S���8��!�nd-�F�X/F��EH&'�e�� o α��� pref�j<1al1�1Qo~ )�3%�2ut�R�?. ��o᧱eAs�UN� 2^�!8��2 unalK�tAe �)1$� t��/TY�A�2��FO1$( AspergilA)"g R�<� )2i�J7�6�mR��k�A��C�M���!by!�m�44o"9s8 )�!( ;.e��du�-)<al�du�G3VH�2��P_e�M�mCo�& F��.�.�M� �Bu,� 6��los�‘9pped’B�2f���)�,�12���:�.7e*�=�4tQ4e"W� h&-�%����*�degjݳe�l�{Reinhold% co-worka�.,*mh�� �Uof 2D� -MS-��[( Sup*(:�S��Ajhe> �Mb �� M)��B� "��1Ga�/&'�R6�->���pyO�� 1��'?-��,!)*���aE Y chemy8.�9 i� -,E�ed GALT�!is pu�d elseC  P.�*"��m�C(� >�B�/bA�o�wd�95� ;4 6�a�!bi�aw*5 ���� "�  9Ŏ>de�T6@!0�2�jnJ�"1�p-���a)�r�Y2 �u� as�A��tro"4�-׈�I�+y-"&�. Iso�mal*�� caloDk�2ߊyV*�%+6f&��e dis���as�Z2�4��µMb��(I�&� ba� Q�.�!vin*|�Jp9]LQ.�co�2&[%9�!�6�Z;L�8U�A;:����.�50�-�j*g*B��K lex�`�2�@Thomsen-Friedenre!nFt�(Y�3GalNAc�$4=^Y�Gl�0�����!� �2 llA�!3I�t{ bondZ`:k%�efeɄ*�n*��, Arg55�1Glu75�t&'I)ssdroxyl���Z.�-��Arg77A�A+(Q->(Ay�&XR3%  =Pi�E*�VIi�Fv�Q�NAx[43F4ZM[4%�4BJ�:EH�>"�D��fE� � fam�,*ZH2 Vun�"_H�Ax��59iC'uiH �I�?m�_sug(3E"� o0oh� � $8��P66�8A�i�.�M*�en"�� [47]��ldbeA�7ed: NP>a tituy��|s}�a���I'7�05,�;*�B,��6 6�E&��[�H%� �2�y�"Y)sn�&I�a�g��ϑ(egerita AALa��1HeL��Bmg��H48]��mp!��Po.�\*e�r!�de"aI�ADNTsu�� RH2 B�%i*I�wJ�F�.�5*��&�/�"I15l15Fj�D%�s <�(va�2]a�>of.�>�  aN en��FMXC!�a:Nq��*QFGK���l� 3�J~�1�/JJy �\[E�n�C!4iMGcy&�Mdi,�c��"J* �� s �4 adsorba�!�cellum�~��p0�uth�I�\ltylw��#M�L�y��\�II�i� h:�� � �+����f0!� �T"�"A��]���l orag��mވm�� 1� �s��G����ir���-�n�$!�!��Rs [Com[:����m� lnbo���>�+aB*�:�$Ui�h-B�_circumg����K�=rec>�B� U+�"]e�d�>�gr�& 6ic5*��Lo�+l*IE!v�Dii�)�mn�3&PvacuoAE1� �q !VaHsu*�U[4�?�8!Y2���A hallmarVP6&},��!���ly )�g a�c��mp�N:AC�F�����E�)�LXY&|-.�u$rX�2� &�A�dyh� ������p3PurvCY]�;OiU�vi�R:iDNsZ\-5ݐIaJ �I :!2� ���0 W'eS!�$"o&1��!"#j[+*=!] � phys�Q��dNy1am�.̍KjYPu.[byv?$metaboʙ s [5O5�P5�P ]���u:�.,RT ��2P �pr�E"�*mLc!aH���l�Zscove&&^fe�Y;octopuqsquid �&-` n [5� 54� key~flimpetU� cyan*5��5n��9�Hi*J#2E#�b��"� %v�.r?�JaŊ. ��&�(la�0or�ob36� !�)5 �fa&]a�Y��)&�޵c"����eBY.)�.  R�<,�>�+6��.�DL,�) 3%� M/co/� �.Re�2o)�� .���r�}"�'�%�N`[�|!.A��a׼.h>"K,P" �>�jk1�_�sb�� �3*Jr2��\y�PFMZA !`.�\ ��.w\iY,�I )\9�,�%�3 � �^"�.gb�a�t�c ubiquit�0>�iH�%�!�u���t��d��!:! .��5. Og e�0h�,4DH�ghE�4�(��.%p�-r2' � �& 2:"�4�Ce��&��Hs%6Q�W�Le��}e�/$] �!�n"�w���2‘�@r�ag^,f|R 3 [5 As��b�T0!*\$0� lFUT-8�/�9�/-3�a�&x ;�SK"l�&kgena�)� M�B KpL�i EV �.� IIE|V��n�: �!!20 �ᶁ>��)# �-pr&�7�3F�)1I�t? R���ly-� 0-�Eax�]�+F�~ i�\� �&6�IBz(Q'1a�oe�Wt-J�) Jf�i L��� �Y���2 &�|Nq� *�f@.��%mD� �?�w���eRi-���*�26�&h&G+9�  OF#A 7c owyc2`]�Mc�po>G!�yGsa�퉫.�-8��s %F�(a� ��H"�\!6&��Abj�I� *FQ)�9�bi���2bN� �f#6-6�p0E/�a9S�J ��p?! �a"e6M��>r\A=d� sE��A�E��%��!� �5t�n��Wi_��h�0"�S"c��@�. F0�e"�~�Fib�FK� 8MJur ow:���wpRr�R�U> *�Y( �� Bleuo , un&� +qi�Q S�_+ "� �?5s2�6B-/�3e�*��.m�!3.��W,��#f&oiل"9_��� A!��. 4*@"� .� � st|�a�j2��~ׄz�.�Na�9]�3+ 9��#A_5���6�3J L� 5�)�PY��4��<2�Z%{[,9�a�uff��t��{viC�� �P�x�%c� �+�f�r�<]�{"�a �Z.�l�-�  �in]1�v� 4ybe/Ka2�af� �,�, [��VA3:�CA[�:, 3:A-�D. �>�EM0 u;R=jF){ �+�7�ig�+�%"e��A� o��pen"�f�b��q/���MQx��1�*v"� :L�;�or!�A�B�-��K���xicZ�v�W&�=o�r�grv N�:1A�rhs&'��rE!�*<.���LEC-6Y�[6^�It!Pa�&.T&�L&�r��P$vbp"�?:�a-�put���)Gŭ[6�pe!�h"�6�f�zLi��v� �6^S� !B)� AoNWa�-2:� to Phottu;�O^�Wi"�&#%�"� .B5$j��i�*Wed!ia�#���a补�6ou�(�ny BqU �~�laxV�f E��&��6_"�8A[in9wk!Ssug��tt�b�S)L�l���V"RV"e�xz[.=$��l" ��M�i";!G)��du v"�4�Ld �"77�{"?G� �b"���� �uJ�t�>]"%�W"��n�&. Our � z�( ( ITA0 ,"� � !>�zmT a[�!�e !",a[GL2!�j�v�g� ~�� _"�.>� ! t��}�!�]a���cco���2ca�*��w� g4\��X.|]bs�/�5%�sl>ly�=eM{o �����$K"3 � ex�%��ar�V����� �+�  [m���*�����t�W6�&�E.��X.%��Yt@�s�Q�A�Up!U7�� to�s�{m A�N�Oti-tH �re�sse+"$3&$ed�l��> [64�STauz !�_��j in whmV\���ly�2b!F�"U  q�]�!r��0����� . Ap!�!G �'^#B�  �@����y�&Y �&?� � �:6l.� uB2���"x ufl��tly8���.byN��+t:Ds:tr 2 �%��B*(�+�q.achM��8a*!Q EJ4�("�SM" �� [6�"Ycavea�GG�zɑ�LnK!s!�� ��:.�8ae7[z]"� !���|����Dt sV�9.�wde2-�� y2 � M8�"�#�hIxJ�I�ABA��.�!M�a�A�C*�coiW%I�mH�ch*�2� jq�,����$�Is� ng&4ZUc�Zh-"0:� $���O�r"�Zvϖ��a!�a�n!�7*+ ram-V;�nd6�m-"�b�F[6+6�En}�m*%-�.��eMe#0microvillar s�Otructure of the epithelium was also observed in insect larvae upon feeding with D�ntomotoxic mammalian galectin-1 and snow drop l8 ( GNL ) , resp�Fvely [67] , [68] . The morphological changes are usually more pronounce��0anterior part�xintestine possibly because this ,receivesGPhighest concentrationO �s/�ns6!`. Preliminary experiments);0purified CGL2%$8HeLa cells suggu that� i is cyt-m4, rapidly endosedJend� in a x(nuclear com!�t ( M . Garbani , unpublished )%}isqin�trast to�,A . aegerita5� ( AA!�which:EO!c for.�but e!�)d�plasm�� M�)[4M0is difference�behav!�(between two#t fungal�4s might be due�NsO$oligomeriz%�:�Dis a dimer whereas)� formtetrain soluE(,- qHrestrict its access~A�!-B�[15e2 �e(%Sity!!sa�A�$ntly shownV�$ependent oA consi�hya�(hobic patch!�prote� urfa)\ addi�to domaA�invol�$:-�carboeate-bind�2�. AA�ak oint!!$e do not k�%whetherq��!z,lso required!s%| -mediatedIf!. Cq!towards��IKis shaLQ2M$��F�Ds . However , ligaab,5�me��isA ppam to va�b!`QitReQ�$ types [69%�70 1 2 3 4�)It rem%�to!���ed!^-O�fuses on��~�iA<��a��NA�)����;neA�!?A�5/�howTseAw*es relate�n nema��!�of �T. Escherichia coli str�DH5α^�6��x(Bristol iso%�N2�u!Da�� wildE�Q. S-� pmk-!~ km25��se ag1nsy!ag!�, breye4 2 ( ye3 1326"4 751 futTok892#Vgk3602ok509i gk10 �6j gk11 �k ok24Z6 ( ok47 �$8 2558[glyqa7 [1�is4 �dpyIe1! ;!� ok71 k�id4X0l8-,unc-119 ( ed�E:obM8 fromea:p$Genetics C� ( CGCAG�� e Universm�8Minnesota ( USA5U carryafa���; � �:�; �}res�ng)����.�Osubsequ�� utcr� ng)�>k M03F8 . A op49IOB'U�p49I>B#geri8p49i>#E�E�p50i�>%a��$G ? s�E�genotyp�� lis!� in Supple� �>Table S3C' id pET24-��Iex.� authentic�/in: 2zprevious~ 27���]^C��in i( W72G�oasY�I�a�hu�6 open rea% fD IpYADE �Z us!2aXp-R NdeI%N%� BamH C �!���t9.�agmAc into)Xa�,Invitrogen )q$introducedC� � site% B�1%Bj�1R�� �� alog)� �cgl1-6�5�1�pBCG1Ũemp�� [26]�2)E@8 5e in liquid��0!�per� �.�A CGL3)i�Y!�A��bioassay0300 µlka overn� +j� ] 2�t��aJ�spA=  NGM-�E~��!� 1 mM�ǀpropyl-β-D-thiogalactoside ( IPTA�! 5�,g/ml KanamycHnYcub�+�8at 23°C before&. ��AL�n. !Wve by sepab�� hole �9tsTindE}2-6Hon Coomassie blue-s! Ded SDS-polyacrylam�gel� $immunoblote%Ij antieX serumIJ( data� r 3B". � pelle�!�aqs� !I< ice-cold phosph( uf�d sal�(( PBS ) [30!�Na-,4 pH 7 . 3 , 15 Cl]a8�!A15dphenylmethylsulfonyl fluor�!�rupAxd� FVh�s!�(Cell debris%� remo� ��a�ecutiv��ep%�) ifugU $at 12000 ge- 15 mMR27�iny0e supernatantviU{with I�,yl-sepharosee4A�a�1 h�e�Ad fina+elu�R t ro empera!a�!oco5A20%Y le�8fter size exclu � atographyA|S��6 10/a�GL� E Healthc�� ) equilibain~,�c�R2��Or ��ool��nd�%oe�Q�8 Amicon Ultra-4=�l fil�devica�Millipa�))]4a molecular we�� toffa�10 kDa�*6!mcal=!i by measurA�� absoqc%�4280 nm , assum$a�S(of 1 . 25 m�� to 1 unitVE!�a�h length AcmonjQ�of 6{��a%rhodami TAMR� ( M5Probes!+as Z[4GA��te�ay%!t@ to ex f!"of6�<E�!�mue�.f.� usI(see e4"� 2;e� ng e r>�ok.��,2  above*aKrol ,��8ai��!vector���Y�J�!7.syna�(nized popul����.K [77]ES�&�5���:*statist� sign�aA����l�as evaluem�p�r� ��r~4 C0developmental:�)analy�by� non-�Lme� H Kolmogorov-Smirnovo ,A,pairwise eacaE�A�!-�!�!�!W&.4MaPhe�8 -�1Kci)brood-�V%�����, -4 t !, &l .�-c�Cbsurvivqur�,a Kaplan-MeyA�!;s�� mbinEi6log r2r�ua�I�ϡ�la�-�9u!Y"w.�.;\A#assesc�chi squ�6�Q*" numberE�animaBhow|"& �MS al.(a.��~ l} �.� iG!aal%�g5�in� nciple6 &^[79� We)K!7� *arr/ ]cVUi�< ) und9eU��Q( heat-shock�Emo��,E��>^m��copn-3�e6{oQ�!�B�! � ��� toI.(hypersensitF :Gw_to,e��%0k star� ��::;1=a�>oA��scr7. Tidouble-%�%z�Qb,FT� male:�to L4B1�(hermaphrodiGyy!=t� bothQ5cog�ƍ��urr����GFPA�Af, ynxZ &4�g%�U)%8Du@ epidermisB.�>D���ա�ag�����ximat�six1�ions K subj��g them!D]�. S�al hund�0-� genic5�per2�round � e�o._�G t 3� ,20g iA2"Agx allow Rrec�:�B . P0 �diIb� to 90 mm.�YeggQSol4ed 12–40 h a� !� c�]�� . � 3 d�^(, gravid F1 �wa�� E0:M9 � �F2�!d6 [&JZt�VF2 � ���@. on ��{m �dQ�ngZ� � to 7�thp �E�se�[rk q��ha�ac! adulthoodSa/R�3F?�treE�g n�ividuA�iX avoi` dund� ���j CandidR ��}Y�GL2Rto!Afir��ce"�� O�co7���at%losB�� -beaZ a�� �� ed 2�6 timeu�X !�a�E�res�ofTSmF at��to loc!3�/5=") �2� stil�A[A�2d�e det��^Vhthrough�� PCR!�!� lysa��* "[ ��I[ � , 6 500′ haplA%!#%�U�� ��po�;,on efficienco {su�as 50% ..w14>���eu�. Only 5!Q��F��yFx>g;> Fk�x� 1�!�A�59oa�se� M(geil% handlA�l, a Leica MZ 12 . 5 stereomi� copee1 o se��јi� E�)m(>�;E"�C V.� 6 FAF�equipp�EZ^ �s�(��aB �Pi %M take a Nik�b8oolpix 990 digiA�c�!TDICYeesce�5#yaT� E�plaJon 2% ag�pad�t�kaes����levamA��3–5� ) ( Sigma� moun�* +a�lip�`o�%� m )�DM-RA� Zeiss Axi9t9�6n�8( Nomarski ) opL!g�O�epi2�a-�)�set��y a|T�.n�@Hamamatsu ORCA-ER9�Ima6&%t fals|o� �0OpenLab softwj &\#itu�bli$�aKC�pXn L4�g�% .���u-� in w�%��SX78�!2�"�hR#Hempty�R-�, k2�chloram� icol3"���%�%S-labeL�)1�rB24 hr�]��yfer�^to�)�T  V����r62 h!Jre� )w�8rony8ic2I�,.�pr6f*S!0two-step chem�fix @[80�F!� slic��� amp� as Q���'outv G� BarmettlI <�Mq,ycE� Ap(:QZu�"( , Switzerl�X�M>&�$Philips CM!�%�mi�"FMe:�a �-:�( G��.�ZvF�N �>�>"��"n%L5� Z�>�&u=E�sEe&k�  !b�'�@by 30% ( w/v ) su��i#adihx&�� N-glycaA�IqAFp.@*v* 81]v enzymaticeas� V+!om�*i�"� opeptidecA� -�K( PNG ) F��f lyA��orP��KtX@re α1 , 3-fucosy� d}�$%Lo�'c,N$.\$efl� �" 3 ga�g( wet�)Iboi��p�+r\( � 2 adjuN � tain 5!�v%�C"cid%&FwA; 3 mg!>si�*�S t 37����$: �5� 2�,��B� appl�Z�@5 ml Dowex AG WX2e�"*�2% ac�# � �6e>�4ammon�h:!� ( 0 . 6 Ma�H V%$. Orcinol-T ve fr�R*z lyop�wv.B��desalaoby �r'to a S�0dex G25 columH*.�1N�oz�ag!�Z�)72Y diss"�*2  l wa31�f�m�at 95A���to in!6v!gP�peEOM�_��c�U�as+of�5�\+nZ� pH 8E�3 Uq� F ( Roche Y�9�U�J%�A\i�.EA4 l 106��YY�F� ` unrea��reeE��3%.LPdra!S��*9�0be� �-� aM��/UY�AS��5Uj�U�as�,6,BJ-�( �,!�(�E>� ��Au�mU< ""=�AE��2?������. Fluo =�s Ѧg^/de4+� 2-Jo-pyrid�P� . Co� te YEof�5x or F�i� K!"ah��E QK�$by 2D-HPLC �(a Shimadzu system (� s&n�� a SCL-10Atr�Z.�(LC10AP pumpC a RF+XL}c�cM C�(�1so�Ku��)*Class-VP&� (( V6 . 13SP\*)AmB!A�2� &� ( excia0t 310!O32�e� 3!_ t 38%�OnmW �2=��first6lc$ normal ph�%b(( Tosoh TSK�#� de-80 , 4��×��mg @5 µm; flow 1 ml/q",�on:���4soc� c 7� 3% MeCN0�"g �$ to 6/8/� 2O: ��in to 5�2 A)��X���(�!m��7!�s�l+ Q��>\fur� 'E�o�(.]H�4il ODS C-18; 4bS5W5(of 0–9�OHł��b��1� -6�%�0{#m � visu�" �-a) sour�(rogram PLOTA��,onn997a�Weseman�Thijss�E. �14 � 2< monoisoto�,MALDI-TOF MS� Bruker�# flex TOF/$ŋ2 , 5-di63oxybenzo"� �2 trix��,j�s Hr � � �o:Z2�MS/MSA{eluci] thei*6W.�"Y &�mix8%(�)%��ext�%l$�$!h.!9'e�z5�-!"��y!�mMass Vt4(package [82�S���0d>�"4�W.[�"�al β-*)sA�� w" PAspergillus oryzae β 4:�� ( 27��, sod� ciKa�[83w"2 ��.q r��{ � by!sacbov��kidney % �� ,�uU��^ �� . Di�8!�p�+�&� ly9�!U� ��u�cha@ eM2ic%HRP�0k a2$l26�2� ry Figur .A:$.ext S��Crystal"�conN3ZEvs��}A PEG/Ion S��/>�atdKE�pr�6�5,XDS , XSCALE $XDSCONV [8�7) q^n�-ily!J�+AL"�(rew��$MOLREP [85iY�kn4:^� M�@model PDB ID 1UL9�0I�3�ref,an�r���5(Phenix [86]�ua� 5 ÅAo2;a�ite� v�=yrebuil 1c& �Coot [8u)M1"&M�ul �r$ck/Sfcheck�=ava� CCP4 suit�]5�]&*a�� 5s ��ؙn>�PyMOL [8�;DD.Ma��)A%���summarq:�#3a�Coord� P� f�/ rs have b�#de��Q�!�/cV8$2WKK .W�A|ex�3nc�qlong-liAwu��&�<infec^CD4+ T /T>i(major barri�%o c�HIV� nd h� �Lnsi"@ studin#<le�.�;]efz-�se2�9 e evMr�Ydynam��� viru!(�:c @ d li� attZ4�%H� *6Kt aEa in-h quasi�'esmCI!incorpo�%(+NHW�&w�%n n�A�3an �$mioAi�of%<�Lb'ly�u�@eA�*er �*e�rwe(/�6�� �)�a-�9J �s4 �$delayZUau�/ A�le %,�er ?s� oc +�lar<�Uh�/e/or home�2prolife�@&Iu �AE��sJl$�fundaa}���=g%�9W2#-*>� scalQ"In!iti/!�)* itU+V��b.� EI�H.v�Aer�8al loH(e�t% maximi!�6&�/?�"a��?p ery  C2]E��I�a6v�=edie��q�0 ��enh-- d if\�> simi~0K,�"9 initA�W!ߡpre73n�t�w1�N-A�ongly�.�>� such�!Z�Q�#!�u�off�5aoX"wh�B/-Y u��s5�lyI<ed�(�2�� arguA�M����ervm �Oimpor�%!�d h�/to��-�em�, rol��n|)-*E�,��viAo�. Shor�o%i�duc1X5retro >� (apy ( ART )%�1&���Gin6&�� :u��e� m!��Z2�1L'-g��d�: SDNA%Rre.A���pats [� �TY'�!�e� TEso��( HA�[�54� /�[� a�i�a6re-emerg�om!42p[month� even yea��caG�AsI�,B&���tan�[7 , �A (ugh.�of]�e�v�e�СeA��1 al e{9,�Hlu Ň�.� 'sf[98>[10`re� �;ew�3eB �� �"� of�B>T�#flu IZaaly-��B . Of� �Q���!aV�he!Nu�0G� �Na��Ca�0r�<�@.3U:AeŨQm�> �w�_,jF �5 ^ ;veX/ 1-hQnnq8(j� ed U(��we i�.&�&a? �3�C�LQAR06E��E�89 �82�� �)�!ْ&�S�it!o�OonE��&p�>}L��al�~v-&:vAs�adey���E�  u�9)���,�in"A:t2�is*�be� hete7eou!�a�,6d5&�:ZO erva/$�/A � 1s w a�(� eeY�=,r�!�ɏ�1� No5 �!�)~����V , ��M7*��Le!���u Qu g���.r�M&"�ly7Y,2 Mf �(� 3�.b�  v�e�et�Qas�F)��g �&ca*es} cour f anE:i��(beit slowlyG , �RI�)lso a�a:�% �a�us%-HV�te�o��)q;e�B� a���!k�RQea9���!� Pol 6+c�0:�usj]� .�6^� [� . Fu�!� �* tud� 1496^"?I weak&�&cor� as-�M��R��6�/Y;GagB�� �si�!f]��!(RO( spV+V[3�R) �����2rWM�aQ�:bl�8*� "�:�"�oIZ! D�%[�,�9a1�o��]� m\C� !l� ,�.�EYM�9Q��"�.$to AIDS faM5 [3 3 A�lla�be�.�� �du&�.�s)6� IUQqhI2� ��[3�3 H � c:� ��Rwo$W� �,d"�' ,� �v j��I��a|R�)�^�_{X�q U few�..�&Z�F�ow�hil��� �:- t� MFU]� �A�+Y��7)A�new&@: QY;Q\isE_"Aisde-�<�.KA�q�F�"� ! ca"�GD F24po� OU( d)�Ie*S :�� �:�2�ٗ�$�O}iod )!�A�uN�r"L, i�5 . D��≈�#[351W� "�=!�ofZh�]-C��7B��� \#aro�?� 2�"�=\�2%�4 ��*N��to5Q  2�[35–3fTAB� urprN�n Ys"�\ai�s�ZndUk� 1�Orm�� so\��YH�*� k2� n �� ( !�g .�&�(� �*A�Wn�m6D��5I,3!as ‘s�-s�ed’��[3 Pi� math�X�6! Z uA+x�*exploP%F%�pe ��G  �&� ,�� ..!,�R���H1"]FZ�direc\ coup�3~ +_r%��JJ[2���� ���Oe escape"!y�I2 ( yQ%hŹa�Bi�x2dapD9�wB[3�FI�ca�,% rea�TicZD&b !�:�V}"%c�n]�!b�f �2#level �O!��*�o occur!����&�fiQ � �%o.�"% ��aC!%q *s ����� ac�^\E6se:�I~>$ �a�dT�`�6cer�m� *�'�%evFno�>x��Fi�XMeoQw����I�%�T6*.�H&�n� !Oz"��P=05_!�{�+uHntiJ?,/*in2|:� ongoa�$ .�. ,V�%q9)�X�ruc!yifw�C�t�"� !2�NZ-�cQA�M�&5��imAK%�&_%�vF<e�P�T W��vesti�G�6�1=���2�5�k i) .P �Mԝ�%/�*�G-B�B�aPez*Be�!\a� ��2��mBg6l4!�R� fas�0%[*�"�%�(i:�@mnN2ef$s�M6�d situ��V#7%6�%&� bsA�!�<6���]  �".�." !)sy*�! �P!�"#s/2,(�"d#N6.?�N"�!t6ca8)6s:� ")i"��i�BPi�iv%�.��+�ar����ngabf our"�z7�=��B.� LZ ��lmJ'no �!(!G9��Nz�u���W'? 2$V.K$6�� �`2�$ccREC��sto� EZ&")p�b�an��ADirmf[gq7�Ia���hyp.sis: F�� ,9 � &,=�]�*�*g� ������&�1� i�..dil|�L�WTygA�*fa@��bo�r�  e�_��t�!s b�&fe��K?��;&"� orkAh_v�; +��[5�5�e}�#co �" y [5" phyl[]�=�"*[16�1��. Our3�F� I�!in��!YFu�fv�>.ya� ��!w�"�*#*is&�f�noe��byO�W%�,Z#�$Q )�ac�gs" =�#& �at�rHi�V9�]7 J������D7f�CyAK fewe�s.p [ �^re"� �|2m���ad��:��( S2 �2�7W%�n*u iA|���A*�(����doF a �š3!�&�!z �%�&� hJ\re4!V , RJ �"���_K rv �tAp��cf� ( S74%NA}���,� �,Mhi �2*D*633*6i� stre]Z% 9�Z2 e<atM+Y�I�-�+AjY�AOM�d�Swe� � z��!�s�����}�K�'I,22bGg!<89<�'si�ͥapro��f�:ce<a�fs:A� lead�ٚ�I�, pe6�.&��.$do Lto$$�� ��k�D<cT�a�"!�2]i^ � &�U�����m&�.�!�m@.�l lyai,ng"<��!�ducWi*���Sar`.�| � � �I�.�"� 2L �IrL1 � ^4 � �@ ���G ��� a.u�G  q�7�&5 V� ��s�8 m�5�9�%(�bbo� !wrL*� �,qJ�of&6X$&0,&w" h>�+�%=�MDY)8.�"E (� erv�� � *�0��!G.�$���5��n!a�;w �@$���wh*� e �ea+RNA�# aU1w���):�!A�5�%�M~9�>N)/ Ig�� % � "M� is"M "< a@����6F/[54�O6g,�5Ca=i�'es#�be�O4T��){on-.w[55<%FBn� �� a ne{c *��R�%�j�� d [5�ua�(����e w��if�ighm BO&�ndJ,��& v�.&b.)�>$�9or&� !=t�(��"�B�����2"?,m�U�nTae�terprek0 A�)��' -V�J���7,�/ as APOBEC���f&N!so@ ŠsN�'wAdE�� [5~Qu/&|j�\)F\At!1vi�� i�!u@R &0 chal|ckEmpir�Q��a.� �!-�'�_on27vaJ2���< itud�5Xg![���kn�Sm�=�@[5�./out^NW\�"] ������o�l�VbaS esC�an� M� [6{P�h�aYs�*���i|by1E�a�:�> 9�F��ch��*bو,2�err=:�i��5��eZgr�"ce�A�-�ɿ,A�!E����"p]sam�<y��.({R�F rect5�;ah�AnR? �9@U`eaFon�&U�:e�06A/�( S%7�" )�> !�ԁ��oE.�(un�y�+�\�()Y&EFU�1�&�e�Jsiou trueO�;��se�. O�(A ��h���I�:y��^z �x���!�.yrec�a7}� �=(“snapshotj3�al�S�� many-]6�7!u;o|y�*cɋ #�\P tX\��&nyd)�$ [�.Th�vf%2( a%�u���U' �� 2o�0 t)rbe "� tui�9�}� �w&^�) rw�.2replen�}�d��S6=*su�^)jf=nQ�hS'� Y>�+:�/"q W�#v�aV�"� m�ec)�yL�mW�,f+>�bgde-5s.�! ��fhmust �.�{79?� s�!�;[6d6dn�( 5is Cho:"j4�r��95@�f��,�4e/U��2X;!rD�h1��tn;a�si`t" gle8l  [6z(64�9�$at&_�>rrry�;cN�7�c�+saAĩ�:z~ e�U?�540%� eM�>Yɱ aris��;clo�expan�[63� We\ �6��b�-reful^�:C 9 Q%� _� an �[9�8Q^SoK p8o�jpetaa"1� CohnY1652x�X�� ��)�";=�K7��%.�D� _1 75.�I�)y�L lone +r� Z 3.�Ca i�%/>Wp$v["��&2!#"�_C� J��m:� -ve&lC��!��v$yc)!�R i�$��9.�EC!�.D'H. S� &���Q�� ]��NJbenefi`da�&�*en�BA� ^�%[6�6%�AJt�x�v�IM�:KM ��"&�0��.�hr6T.� A=[6�69 , ��b9~�-1I:�1g,A�I=>��(w"9I��F-�:d"KUg*�,��G 5Dll quick3 weep�rf��6�F�7 &�4hg ns �fރe7H-war��[48!c��w�� �Mse�->ed5Z�  ,�%� q9�o;k!�+� R�)ue�c,��4!5|a�>�> F EE7aRSKv3� .I�;de�� &X!���(a� ost-{(dK�C�( q s/Y'O�g�FqO�pV�� 1 �V:� 8 � 6��R9 v �)D� as y7^���L J:1\,%*[� xxtm!� aj�?��=8(hum�_"�-@e6�*&�� regarc��1?�B!�����&'"�I&UJ2��*�;�En�7c�&b)-� �I��oo�J���Bst���a�BsA�A�zFA�?me�lem!�ey�4u.�C"�D,d i�ͼ�Nai�$<��� !���D:)"?D&�D�*ѫyc*M!d!��?�&&�9yV����|)|) Over�,%o�H- 9@�!��F�/�9�MK�L��aH!��0 T�r.�  H�1QA�FA�RFA�;out?/� y=� 2��i� ^~Q'F�s"0�A%2p*��*�o2F-­� ��$� �s . W� a�w�#? �[�� d%^8:� �N0�eaA�e�����ve>� IA01*��,!aal2`("�2 /u����kAc��A�f�U�>, kA��qne: K" e�{%��[�J.�as[PI�F�% ! Pi��.nE� Mz�dEAnGvi�5 �e\�!u�k��icin!�RC1�.�=ɪ(� ay�>"<.�e , γi%l= ��Y… , n�Let xi��h�I�ec�9 m i ^1�.<� d yi%S cN)L=w. M2 Q\Wa9�m~Z M = ( mij�m�'�=���Uts=�^% j I�"t% i� .#%ֹt-�E_!�2��fo�1){�-�/q, s: {dxidt��1−k ) ∑j=1nmijγjxj+arLyi−x!�(>'$ 7y�dyTkrL −aLyL E.E,m�aE1)e�kno� �6�Qx�� (B �γ− ) dydt�Qxt,\MkrL%%�( �_)�x%�xA�xY�xA�T , yyyyQqE!kAγ!*M=�-�K �M��=- %0<�BiKM�+��st �&a$�B $s�jŰ�,2�# l;R-&�880e�Emm�xj�yj�(=\��{ll� s [4��+Rkis,Yval9totm� udeath��ə+"@.-p�I�i�!%No2.Eq �{t�[.n��+OarJ3Q(�=�#.UC,t�c q��!0@Et�:3� :(yis� ��}!(cc�p �*�1������%��nn�/=8!�|A�{Iu�AG�Nf�xL c:��v.�V<T4�.HN+FQA1ti!(Iby� L5� IB�M~2 � �Žof�Pntr>��$-=X� ayiL w�o � r�y:u�.� � ^�UiYY>��Z�5Δ��=��[#�Ia�E6 �ZMA �a0�S�be mad� ѳ[>�" F�2�i� 2[<"}���$�by Δɇ ) =k�ZѪAL=AL> . (oc6�8l\�C9 &� � J�AeofzJq�y%XAUhG�}�%um��."n3w�`rL=%��`?>��X-��X�P2WrL!457�atA�bFig �5�3 iЍcii��� X��0Jj�X^�.�"�Ast�X�OxJIi� tC ���aM���p: � :ZL��)�.�I~& a��.b ;2�)6Z� }9!���!�lso*��^d��:�"�?b[��S��)��maki�imafCsu���)#zU���>J r��5�F�A� !em��RuY�mL%E i���)Eqe$�Q!"X of � t Ae�L!�&RxJ�q����B�l�#5�}� ≈��R�^1��&s�@)���ta��I�eI+ . AX2`�k ∙ �W�C� Vout j6X leavVWI�PT*�*Wym�9e%��*�0fh� �!V.�s)�4�H&�Bk=a⋅LAr�I�V+SG�a !�ow}� a>kr> ,�Aʼ*"Lw�B > a"au�b�A��=D�:=,J )� ρ=a� �( �rIW�3�!�g�|{X� �4���6��Ltype [4�B���! �i�@ ` �p�c j�S"�1c�IU �#t  τ =>&I2S����`6 j�; ���a�Vy!j10t s�T5,"~Z.�*�$i�h�IA�%�5o` �C\2jE�]. F]i�]��� � Eq 2vnu��jdTga�j"�F xij (!)eayE�"� �T a����![TτBkG!�-0 origi��)��0Q7j.NI1&��s!t�e��-� - W U��8%�pEtnoH"MNa�sm�. N1_5]WV;d�E� Matlab’�n ilt-.�P.��fr ode47 w� "nMA�q {Wa!��� J.a� ,��E?i_Քk ��G��Mr % i��-��v.3�e:�.�7j 6�fun�spVL:R�E��(61pVL&_r�$� �N /���b2% �Ve�-�s u�1 t(&2hr S3u , /W"`J!bdCwl�d*0 &X*�*�!�>�K6�>�8�O��;/>> �oAVTj�+�� �"�<er�m&��i��_iMKth�c%�a1X)�?%�/ 6�@��E0���.�u:"A��=am3:] " 2�.���W��4Io�A!l��  I�W��b�.E ng-"�;�3�$bpr� v3&&�Sl![s_R�KRI�.ur� %|.�1VM�]�I�$�5GM� 3�t�F"wR�F o� �r�.Q�by��74 R\V"��lti� 4F"-� �C���M[42���4A�e'G`rt��8�� c,q�6Lf�BfuA�r|!nm !a susG;KA��)`�l%�dem�tX�.�S ( t�I �23V�H�`~s"]�%� E}S��let N a=w+>uF .$ba 6<> �I�B�!�-�a&:�&� �1v�A�" .�%9Mr�nE1.`i=1nIA� m�� .[diA-a"�8*�ν-'.rI n� R�  Ti"" �yt�'t:!��# succp[� n�9m�!C)VB1O� !�� ..�e?l.}$. F� H1�d��!,��c�r(2��[9�AF�F2-�.6Brandomdv�-mkp&1 ɥ>�u� tNq���=qGQ��∫0Tj. H t−τ��(−ντdτ �?�K=L��EcOi v^C�dNdt=B\FE?TR� �Ti1¦uN=~o� ���hJ)�@,� eL"�+� � nM�5 � e k@pz�k.Is�lA� �y5:�iward Eu 4@7@42= EaB�$dt 01u=�X�$�dO hK�k"�%22�)`)�)��eas#g�-"�T6 �xNkmbe�����A!e��YuM��K��a�>Ha Eqs ��1� Nag'.N^bas=�F�CR0o���AY�>�C nt e�t�5^Y��"\�spwwng E�~(�}���Gone��r4�/[)�["�`�d�6 ( H−i*"8 ��R0��V!a� ge!Wb|f�5�C��Bz�<cm7��a��y2U��6 �F�pA���t!aiw!�.� �.@B��Uoane aH&�3C��hEa�U�0"����95�!rA�� B]S*N*=1Rl���; � �%��E@� Se�.��Q} ԉcEq`��Id�9or Ii*=B� 0−D!M�!iȥ3ν&�� )"��1�_�,� Hi*�w*%N*`�t �R0]���.%�!,jF�.->Ht�6be9 "�d�[ٙ'�uMa&��rL�^woc?�x�1C=:�� �ah ](Y��!T?nt6�&w� �� HIV-1$4u]�2P"�:�7� ( i�s��?Wre��IW�'pre�'m�6*-r*�p%��a�oA�P @6�["�d. Chu*U31] �%}:�� QG�&f!GA:per9ag��� < �-ne��7^�AWZR�v(L=[HIVDNA]lmYP6aP)�1��7 , PEno�w6�2+6�E(E ( HLA DR+�$�i2l�`2G� i6�x�(_�.-)/(� 106 "/2u�2 �1tse7P�!��,�� �!YFs 0��.l��T[A�5-��@b�}"� in.").#" ��7�dj:�doeJ=de�cd�Twi���_8@�n agreee4 'dYq5ng half�)R�7�N#��r!r1�m�mfzzLoiH��? ��@�5�?�k��e-:s.�fni{�M7&� &6I|�ndM~^ ��)��>�@ roxi�rE��b�6�t[m� n− �(��)���n��o--%�F�8�P9K ( naA�!�:@&��O6se��!�d"�7�&�h8���re"Bo 2�88�9^F���2�.��D�\� le��.A�md9t"M5of^�Q �з;H"�@� �(/I)j�!g�E(�]"Wo�f�Zcript��infide&�3EupF!m�!��#D/$"o� �!��A�n;�9��e\2Ea8l�B"�hih�AG &�b'"-pro���{M�*�;"�U �ph41f��H����\(U�-naï�za���%�pI!ن stop [5IGIf=���s<�6S ��ĉ, �92aE Fng6>�ir']� � L29�va�d�M "&�� p&�:++����.����J>r(�Fů���%k35��")Hd n���u��(�d � L�6e:i}�to�. S�>��e ��G��Aa�pox.!�"� 0�abe�O�)��icorna%qEtH� � �5A��&+z6� ~ugs trig懅gq1�$Y\5!a/bidA{& ,�d� ia, youFYhildr;I�!�ro�d�/d"`$[1]–[3];�!3! � co�}o���kyocar�(7  s��uww%�I��l [dim d�^diomyo!�^� ac fail��[4�64�nd��6a+� pa�u�u.$aseptE5�iti�wE[7Q1�One goa#G� a!Gi�sH�+pq�ep�|.I,_�p7 limi� .lD -U �d�.rk�N�t���-[1 �12%$ToE��}�detec*Rk�ze!�&ZBY�"=,�kS�~�C ( rA��.��s! ell-&A���� !�.g 51�C}o�lymphocy!�choriRin)�)'( LCMV/G.� L� .9 �tro vo�$�!!"��iMԜ!�;k1Ӊ|�*!�DIno :A bY�Fy��near-��� !5YM 5���"�@MiX!-2d�go�� ar0�� B�_s;� \L �};lobwup!y�)9�'-� 6�7}(f/".oI�"�l�E�(� 1� -oun �MA��e:2t� �u����� �xlY�SoD� !��}�z�I�NJMs� ]�I6�>�� rrup���|��Q�=X{a�-.����q�)Gd.F(qU[t��3 `eY�U!Y>r ��� �4nE�u.FV%i�'b�-�;�"��"��R�q�6��i�!�>� �*�)�Jk( �%!m}V=ftz=�IJbZ �� ."�,Av/HمJq���� @"t#A�Rq,s���Z� �W���L& T��} � o �8V ��%i��� �%.���epR�- �+ t���):�&m(A�rO)K���!��ZeƊ���|t�.e�il��#t%V)>� I���!�$�L�S%� �of1(��-@y��N0Q�%�fel|�a ?)Eɞk�l�Q ��?d B#�� ��#�! ���#.��A e�a��-, ^��N~� oW�N��-�olp!b�8�5- r"� xa broa��aI�h�o&��marker��� g,by PMA/ionom��st&� . Fu$( t"�r6���p-reg5��44f downB62~"����(e�m�%5*:-i��&�1A–C `6Q_Q%.��q� &5� �� lab g , [ًne�U*noUE�Q* �o"��&1�in� or.�9�.7d� &�VW(� & perhapa�.pc sub-�s�<�!��,*C6�� 6�{�C of IFNγ-x(^ ��!r2�%a%�� :or p)W%��,M��*�t&i=�F�om� q@k9DN�#��ly�{"��iLs��!�!U�#G�+Z�a�s�Tiz� �Fu��1,= �.=� n�B�>U%B"X�=�a*�{TB��sej 2AbaAJ"�.'m R%�W/@n!�h6 eAm�UM�e%�]�Z�X! �}Th2�Th��A�x" few IL-4+IL-17A-�R� ��&>6�.Fo plen��"]oo�|sB�daB,�@ lackP� �-!iD7judV�F4 O�y*�Eg"Gx6�V�T�)��d �e"Z�.xb�%�rD�B6(����4g ∼1010 PFU/W�,�X tissU��}�s�AN�"�d��讁��J%=���؞Ffoft̡�fk�Z aJ�$�g�W���<&�$127 (A%7D ep�α ) ;)7���)siI"�%�ٞ[2�at�)�C:io)�p;�6�:n2�u�. T��"h�EZ�N2��2�6� e�|��[�s� as6�mi��.�� ��>Q:; a�s\�EU��1 Em� �A�p"�!��epic s�2nM$�!t ����58�� @) y�C57BL/6�(�I�Zq�r )/�XarsՍa,� ��eo8 u!��s:JI�s;)�8 $?�*t�lJ��Wby�� LA(�xW��#i� om� >�it�: �Vof V.�2� �� �.� t� ioA{"pW�p�9( p .�5�-2�.LGE�q<�0 ��k"� ��C���Y�o�A{�ticExE�A0]pY�W!�? �a�)�ji��i!�In "P�Tpdi?O[ , ad� ��fer�3� �V�CR.��)����a��+'cat]!� r�.����9O;~� ��aD�!Z&�k,9fm��,m��QE�� > :�j=�[16��z*�0 s�eR��a��,�L%;i�s��!p9 A��j�S�yds;�)�y#6 BP ��Ks BbaRs�no�`al-B�I�M���B�!)(�$C"mb&�!{*�, � kA [18 yz,�[�2�bM- E�ino�� !]P1� SMARTM)M�/ach%a�) ;w,%in;O�“qB+h����*Z+�3�'Zr�3(u3)'6H10-fol��g�a-��nd&BQ&e !� w0 /mo�;[2՟ [25]��h�6"�T $�q-\.&�p6^��h� ��-�!�:� }� �g���l<�ni�~28)?����#3 "C �p row|!� f�^�e{U on� 6��,a5�d� p�� &8��&�*orm�|BU]#.6��"�da�  NE�Sm[}'� �%4�!&>60�s!�t%&�魶%:��kA� s�a%$uq�d� \ɗC��Kkaw�Dny.?2�$bottom lefQ=.]7"�"���+`<��j.�.!�A� fe_g;(�H41]�$ . 27×106 Z.�. A�25�6�Y�����sA�%��of6���*�!� A�-3m^*��!�I`N-�#THm�8k��.�) "J� HeV��8AP!�\� iP ffi����u��c���2���2U�E(T�F !2Zfov.�K"��CMf�3��u��V eBI�5.-���6,� V� se�  b5�>� d" �U!�% ��!�1NP 9(z� e���!:&���'��� EG:c�;j�X g�L!-R.�.�" @bar� �,�Ti ep.ain�m�� $�� ;6�F`1�,BE�����y��o��precurs?�g/��� "��40or��:� bc��u �)�6�Is!� �-�$en��"i0"5U} n�>K��,*E0�s�r�hearH"X#e��!`'�lY ��.g!3))�+~�, z)�|�WA�:�o�i8=��;9� Q ]1����.Z�:Y5�4Y�:P�2S"�sl[&c���eW��or�>�%9en+�Y )'�B%LB�∼��7%48 2&4�2��)�k�<ly�s�%2�M{(H .V�t{%Ar4 6Ch-g!��]edAP.���;M�;�"0Wu"��M.M%Mu�D�rO�� �u�E�d 39�PI�<se��!������agn` � M�i�=[ZA�]�ly �0"YUW͸/]� �.! !�76�����3 �*��r� B & M:I1�A@0a�put6n4���� im6"-�U�!���E�L56F)wЁ�y>�4 �!�Љ�RgY2 �V�/(!�4hi C� lo C+lo c��e4�#/!XD-�ZuE,�ng!��3imv/]�I4by �aȝ4L;�K�Tin�!n JC� �0 "�!;��a�laa���a�� ����%�k<@- %���Z������I��;%�:�m AIP absi��(b- � � �"V$N�i��N�'eGif ��a\.a� �$ly*��8*2�!!� �( APCfX@add@�����$0 �{q *+I���/�.e�IG��d�A!“� or):���+�-�{c.�o���)�rey"� �en0�I�SA[genY� W"dR"w �L4QKa%��Aby){��� �'nU73K!{"�&�  re�n�"� (�*�". F] group%%� psBAd"�!��s.A�u�&�9&~5�G W�#d�# X] �ro"W6 �III–V 4.uA]at �!���o�Am7onship"�-�d=@�+*<sE�b,)"�vl�J( � I )",�rob�[eA~��]`"@ 5��2n�\��:�.%�+ � �au��iH-e8nM�`�:�P�(� 3 �Y�%�5�F-s5�,��.��D��WreT�%aB\,���.!_!�"�\J�Dy�v��jѩ2� � ���3 t_Ud�_c��#S)uo�lyI$,�2 & V%|�9! C & �@*$6R~"��h IV )��>3�i*!7R ���&� e� I�>����+!��9�e!�e0�By)�&|���aY#)��!@l � e%��6��|�<{d�ha�Y��xJE]c ess;*4��-6V �2��m��m)��Tisy6Q�environFCE �2IEm�).���d�5�!� m�A �8},��&� ���)y 6���[QuKAS=.o4+>�!�u�*7���/M6by2*i�>62,�0�xc��a�sh�r5I�}�4Q4BJ:����n�I=Ntac��/�;�&ng�us: Bw�SB"�'*���(�/,) � CFSE"��e aF2� *9=J��Uon by infected splenocytes . Three groups of stimulator cells were prepared: ( i ) uniJO; ( ii )2cxxat high moi with rCVB3 . 6; and<�=�5 , a recombinant virus that encode 0e LCMV CD4+ Tژ epitope NP309–328 ( see Table 1 ) . ��5 cannot drive antigen-specific proliferation!I0P14 or SMARTArs�(, therefore��cts as control for bystander activaR8. Equal numbersb,CFSE-labeledo!F2pw!�mixedadded to� se t~�P�A"$days latere~ statu�theZ�a�sessedA��flow cytometry . As shown in Figure 6A !�sub! tial!`por% of6�L( 16 . 8% ) had divi�(1–4 times\respon�oY{M��D�)���det) in.ri10little if any!�F�'-B X occuE(�|7A�&op rowe�In�t��R�exp �a much%4er�in%����by%J8m`$nearly all!D��%�E&ed >7:6�bottom �A�isYult�!��Ja��A�put-ser7 ��en�V�!)Ndi��t=|l2`� animals:�middle�al��!i�k " remained�)hi . Fur� m� A���� BO �� v� from��%�A5�:�� ��Ga+<( p = 0 . 27� �"� S%��&trigg�apoptosi��i%��H �( data9B_durhcix����{-^x�b6�iAsuffici� � ��A��IY.:;2y�� }6�6�2F our?(posal abovewt�02�coe��disti�� betw0 � !��V݁�!�lim to oneE:6� ��B also/$demonstrat��!�m-induced1$" te�C�� , raA��n a*� efa`>� a similar achUtaken usA"f!F addiA��� (2oOne pai �ea� *. 2 & 23 )MF Zle2J �� whil!e second \(Q4 Q5JQB*/Within e��,%�� ���!;�uldqr%�m]�_�� �o%s"� ! reby  ng�]./ � � ity/&CV a�� To evaluA:2Yby2A,���|����9�or-�,E� thenA�Yna� Z2��Z. EX p^ 2 fer�0  . �� A�B��jA�B-in ω�>�2 (A2ch5ʙ�)��A�w�5���)�1X�a�I%  u�w��n�ly���7>r��b lefAZ lumn� �2� 2�'�!+ �y�R.SI�A�Parallel$ef n�� Jn;I ,m�174�Se�. 5�22�6�o  c�.6-9U0several cycle���51�; MЁ�>4J�)�6 ~< beca� i�&ab���mic�.}!�neg�qމV����� po6[ 5i~ ž� ) h�9�ivenes%:i2� (is striking �� 6A� >$versus��� mirr� �H&�7Ar�% toge��s! OU 6-� �Xstrong� ugge<atb��., *��9a�r� ab�d{A�&� a��i^:j&'i�s pintac�[ j��3 ,eIv ��\ �42�saa!� foun ffer�&�8+=�)�U�sQi��5�I.�GnsgeO� pronoundq!�2�e}�W rtif� ir beAx TCR-����X/or*)2Di@ly-dprecurso: recipZ e�,inex�Zmp�� �^1� h� endogenou�unter!ǡ<Si mi~ .(bbAV)ob+ d-� broad mea!me�-�U��uu%�����ach)�"!��&�-�Z!� ICCSE,}9I tetram�. M��rUa�ofV�( 104T �aE!tEIt>�6ፅ��  y�%�� y 8 .-a�Fj percge}2�(( ∼49 . 9TaX="=�� + . 7*pro` IFNγ9A�TNF�95Pto=f�2� 5�8A� A6�rb ?AK: f� �1��el�4va�>s:QL-2�6{W2S!C6�35�Jbe.zU�&�=�9a� diffi !ode��� mA�byI�.n,(er] dotplot^ �6�a7.��%� m� o dys*���,T"C y�4I-Ab/GP66–77^lto enume� v�gardl���; back nd b<ng)Eeterm��gaolu� , �hCLIP�s1 j9Zi(a large popHMY:��L+!(CD8−��s��AV�(� @&��Kf�� 6t6�E$� �a� y sm'���E��3% ��=t�An.!�p od�I`�W�32�priorA�1![w6� ,Aexp)�f�1er:���1R�c�Woy:��not�82�6H� �U)-��5�lyad5 . 1+ (K) '�BiO6 I R��ina{[ U��!� non-qX al (� kine&� �":J��� N�. R�' L>,good correla%�� ���zs� �y5@ ����� eI�B6��"K^p!#�a direcf is! ��- �*s ��i�to1� "�hEE,�JM@�� ?E)�ly1�to�)^9"reduc!��NY >��5��-�R>%� M d �-eL��a�Db�!e� ����!�". �,�>�=Y�s6� �2e�I�m 6O)@� ; 10321;� n��%fr� . All�hin5����fec∼10�$ 107 PFU/g�5� .���siz%1>k6%Ped{8s� Eb��2�*� )< !u5j decl�Cae-^ of i 9decrea� ��C%�The6� � 8�r*Rdix sh�Z�≤1006JxD5�r� H��)%�c2S:F�Xtot"�#NJ]�}>�!Z�%en� quitzMF��2=!� sign�an�| ( p<��00�greU A@�"i]��!R� �Z�ora� �*I�!no��t�o -�m� mXmagnitud. :BQ�� 9@.�b�:yAibory'y has\vious�%NH �6 at C57BL/o ciain�0%T –8*. ��2X [25]��� coP"!�y$w�2�:)z� 1$D#xim%E��!�&��y mD=aof��5���2�F Oi�reflece�of.k�9li"�'. N �ask�A:j&� � S' oehxof���'�#. phenotypeK( b�r� ly dependupoi(9 & %5>,s [19] , [21!�w!�oughttrelev1"��� !!��ofI�"�2Y�4�a�e�;t=H ���%��A�e major!>-�'LCD44hiCD62LloCD127loAEd��T&�s 9ve� ��amongiv� �� � �F�i�O�$8F��FB�.~>��.b-γ"�8 ��eX103��4�iN%.�b:* &� )#neiA � Bnor.��j:}�w�L-�*IL-17AV7 Tog*�se�Aca %��&toE�ct��M~�.��  du a**?%-�.�l6�J�a42*� ,d %c�,�en!�–�}2>��.����ult� e���iG)B�r�r>"� es� easi�&� ed|!in/��inv��gaa��{�que t�#�u�memory o a�i��d� �,two son�Fir�*�$2� mean� d��'!I�7! ar.�)Y�% F'we"��ct.yeEYQ)�!N,�m��xat�)/ �� FT%v�+in�$o,A l5 �$ i� �/%�tho"+� -� �e@c� �E� Z� lev{)fos!amT!�ge<,�/�(��ca�po�+ 2t�q���)-�n-e�` LCMV�+S\ , g��appar��de�en�d� n9/��iM er no�<2b"!���&reqc �Q��&�g$rmal . How)I��6 �0.S�in=r� ed )E1ag2 )�perX-�ey�M:�af�'A� �cle�a���!ch�ng!�N mmunB�E�KZ9wh��->/�Q�d�M�!�& ��-nI�( tru��h !� U��e��ca�� Icres�)-z�I� 1�.�- addr8 �-%�.� woO-.�wC-a&}��% �6� e�I�>u�Tv)�2���wqB->�W> 2�ss.�toiY1�e mus m FI!�fA)�.y�we"�!H3-�ed!�-�a�"4E�7M�L$!�)*�,�(A���aGe�c�� Q 4�1 babl� %{]2` Sr"q!Iin3&, �J$~ s7�J$be attribu�2 toQz).or6(!,F8e�n� &� !�B*$�ie5K:I(���6�) &K,�#B7!I�'or�,�Pwo monthm�ye�+Urd@ ���q#un&)�i�5�Ianaly�� sUC�3�D#,f-.���abund� !K)�a�he bl�"�Y��&� 9Alack bar��!�.aYJin]MI:�(� y> hatcbar ��+",�%D5���%V��% 2�of)�E�"� H1��9 ��!�b_!edR12q at 4o sm�:�� s2�, k"u��&k+�p 5�*�*"� to�`7e� �accele���-�9�. By 7j�,$ !%ً%��ai�e(>�YA�m..OA16.�2�L!at&� i2�-��Fis.W � 5c�61�. �{�*"�-, gen-lR>]!< c. Py:�J.2! )�g�/ �A�B�%�)} =(5c�F+NeL:�2�"�9�� �6I'(!�34or��*���yB�)-!;.\5 �m40-folV%�1��u�2�N5. A� 7 ,.�s f��EE�c@-it�#∼50% �ll6-2C.V aqg-]I�s�s� h C13;��ch>��/R*2= Q�C�9�9�)6�aAb7B�Fpr��ri%�.�#6� d�E"N !�Q7A�-, �-[�(�9CaZ�*s�7)R ly�f49' �A� y�e~RM2~kA��{� ��9N� ,��few>q�_��aJ��.�@���(� f!@UT��ui�6 ( p>�1g)���/� Zc.)�"�:*FFV�i�,%� ��0�� !0�"�&rapidH a�,J:�67r�#M8. TNv*l)&�*9A–C��)g5B�Is+ 2H%�Adrgo��&� 6.:(r � cogn?s;i;y "s.�ȁl*(>IaW@ *d2aF.9 characterE�&� D" 1�*��p-! YicEm&}k sticE� ]@ XA�- hangJ13Ih��+!r9=Jfvf,[26[27�A"h&���m � a)Q�? LCMV? 6=a��hi�"63&1' &$s��dom�A�"�a  p&� *<;��)�2�� .con-��Y�D�1�<� f��3g*��B$CV.�-NJ-*62Lhi�3��Y_ ;)~6�i��;�%�i]ar�'vel!�2�#m=��h���)a weakW2��7brief )�iodP!P�)�� ,/mit F���a��(by)5Qb-�22. F"�BAp.@n)8M :-�"e�{�/!� ����*:i�"�p c37:l-=��.u E n�b2Ie=��:�>u%C:%ex�profi�1Ebu0!Uie7guishR��YF+>zo�>e ?ir2�apW)� � stud have%���:� �!f:Y�U8"$�5o�CEN��-like � 5��M$fUZre-expoN.!::l�=.�6B)%�.��)f�8A��'55% ,"� :!IS -+�2��A>T� � co�A�ed7*�+N2-e���12#lo�/&� R�>3��GA�ej' d�kop��aNQ��� �#�s��reE�6��$8-.?>.}2I�*.��m�e�2�PG)�( 46%e 56%�*ively=�F6/, ":�AN�,�-�%�>2�l�7h pa�8A� � � e%�.rA�]2Vre8>Zc5\ ]a�/+N2x<fr7 (@6�b�#u�** A�t&performA;� i�ME>p�YC!_�*-).�E��xdouble-"+6wBv�he1O&���EE: N; s��� �Y,�", m -.X)^=J�*��΅A.��J*� j � &� Z. Our� B2fM�adaD ��.�CVB�/$traordinar�P'ed [28� E�A�R"!0toxQ  K�iR, [29]–[3"#!��at��N&�7��Eg�e%aVP1"�Is [32` A�A4Yof known h�&C��ey �8:� 5A��s made !�"�1e9z ᪁��'!��5e [3!ZWe��,R&re� [12]I�e��� fail� �}��B���-v6�! ��*� �d%'*�?( huma�x>IM�!� ex v�F2�bt� s�A%| I{�ܡi�F∼��ek���9�Gd Q54[3%tI i!�nuscript� ( attempAbto�1 L��on��s)<=)^E� &OG)�%�a�<�J�5�� �HI&�!�$ur�r(7%�� �7� sepa�lyE�I�'� s�!�*� E�$L J ~:�WIA� � �(.P, desp�* replg$��# markMigh1-e�E ( up' 1010+-ram!C:M��,B_Wi�~)ER 4+[]����<&=� is ee��#� :j�aM� q|N]���!�2e>�B"'s��(�!�&�byA�1�"�C&/'4SF[� ,6�>&��Y!��>��j��&$!sp&�R|������ly un�x�t�%e�,�J�ѱ�#r� 2;R�'� �&�I���WR"A1\��<=�s�&?.�[� r� at 8�Nt-�m��!alay�G&S >$5C@D-MrBitAreJ_cɤ ed� iphd@q6WI 6�OA�]#�N�ie�m�eXe�,.�M��u5A�,�exampl�; globE�disrupt���-�� . sr�4onA�� ri~DC�/���o�)?!z� d [14a 2� ` =}C�+still�#�EDC"� ><oreover��$�Ricorna%�may; %[�T& dendritic �(�)A�A^�IbJ"IYz:k� y.U prot��raffick!V[34m 8]%� �Ei�P#*�of� �aoep�3�,40!9co�F�(molecu�[4"� .P[z, [42�&�%�TѨX��s�M ]�c�Bs"<+aMY�oy .�i:N=;P #6IioB. 6)IC�/�%�H#* A�~#��e+. 6yfA�|F�A�ca"�q&aB��a�req�6~&16L*4$� ��"�n3O.v��A�"�co�HC��A�V�قit�Q2�Wir�P�{@Kdr�J��c1�فin�R ��9e , ex4&A�aR�SA��A�_eD�-�&Q ۵��. Reg�F /s�����)Vy�NOe�xT�8ppe�"un lymA��9a&�� ng!�Eq$CD25+FoxP3*2&d),؍�[43a���YA�!�R��4I�� unab�,B� &�M�)��N!��\�: �*�U�"!�*� �"F"�NZ6n!^f$ck��P�H �d L] via�.�� I��92� B1 OD] >�Y���#�! a 3-��Hoŭ�"X2�!��W%@z �E, �i�m���(�D incu)�4�1#2�""5oH� F**X.X@anmy!塷��cerK -�y�compon�-��S-1��WfH��� way fla� �rI0%in�l� �pr�Y!BM�/ /Apk y<initiI*codon9%��,lie upstream���1�z8("6\*��i� ��&�!�%$-DE��5)e*be2�Z�R subcloP&$���) Da plasmid DNA vacc�=�^�n�"." �RJ���9� ٩bJ�QAf!�Zin"u5l@ ���gA��5Z�6�/M5JR�QmNH�"�k�� mM abro�1}'!o�Eed�M"0 ar2�� vail8@-I�o� x�k }c62B , 2u"A�3A coope��i�GOI��-=af* �� ���2B � � s2lea�0a�� �edow9?�\��08urface2"�63 F$js>m) *� deasw-�i�+�a�e:�a�q%m)�%�ch`��VA exer�&RR j���J�;�&Q '�� T]"; M� EB step�`;��ItAz2|0not� h"w1-e_^=dblock�* ?�K,Vn��leOcNw�]ʡm:G��!�&�9 � ^�=�1. WA%��e�is�e�6�$m�A� �2�? M.+�betu e� B e [4�3QH[4|b5 N���"� .P��I��beq� resh�(})��X@ R�V �1g�$�EA'� Kr=by1��:� O��)^�_i|i lcJY�2y�cM 6 ��@lys1=-�"Ames9 al APC�%DU-���"?gnizeJQ�� varie�n “E.e”� typaUi=�e(�&� s6�F)o�"�"ex�in �th� ��)saploD6!�l�r.to seQ=�Z6�� �7:%&*�e))�e6� ,u����A�!-e��l���F�%."<N��\��!U�J$fibroblast�eO[37� �7$? Eleg�0��� �l�?"!�>d� e� � !Qup���)ep�a."!�s� ���8A�b��P � �9�=J'��of2>:IF.%���� erNS cros�9e�L/uCg?oP]��j(upaw�q'ma!�� ��Qh6��/M���"�3q�. C~�9to!7am!�!��14� *g* u"J@�vi���6�Q%��&@Ppox�herpes[46V4 |gfR=ngE�%��6�)F�"�� e� Rf*�\�YM&�!�*KŖnI� a^"� s 3 &;}AThe.�&�&��I.�+U:��c��XN3fiW$�Y7S+0�.2*` �P��i\� ���"]F�m :"Ifik�d��%5��I��<� vo� ne w:<ec�Y�b��;��4>[�I�VP4��be�\p��-� �Ju� milieuE����c.� �!]]VY.�;WE�!�7�7" � �*W65�3* 8�?�&8 6�a�[=ٯ36-AN y9�Z 7�&&HC�6 ! e��͝X. �6�r"�U�P�i>,!q!)�� BC%�3A1׍Ue��j stoichi�kA��]�R�,ng*jd5Y���=��s E1 6 at� �X*�~�fQ "� imagU%��2�I��o a-�"�>�dl� �N����tE**4 �%a��`CX� *� ,�^ ��8 �.,6vI)� 3�:�**@;E]�Q�l�V. argu3. gain!U!wI.z62w1_�d�G!�un�"� ��q8=�!�nboB����4�r�&n4 �-l�:��A�"D@>��Rya2sA�%"R ongoA����Exo.l�D �=hA��X s ��%�nAat.�I�&_i��s� -edaJ�Iq�d��9 jp2���(#C^j"�B!{ier ? E �G%�B�I%:+often de�pd��upeG of e"� u@� reaX work� �!i ".$5 b6>o2}$Ős [50/ 5r#WB�AD“lLl � rout� %j-� u7� tacE�X>T���I� s –�.#"!A�"� )}��*� �;�xfIhaI7*! ncod�.1�t"�%V. NZtheW,Z'$ N playQ?o�i�!sE�e out�-�6H �M�lg�QY6��"�*�s�Yfer�deg ofIr� f")D�3�m�h{+[547�#�-�ed� �!�,��ޡ ledg��Af�dn+� ?h-�B�� �t�$�+:F/NP�� `"*6G coxsackie?  B^b4 eF� J ��?��,� �s�Q)%!&GF[5556!Aathow%6���B� �AsIJn� ecb &1. a Th1 cyt+ �i.r�+ricw?�K2%e"�"si�vof�zua�q�?;r�L t�Y'On3e��e!�6"z =Jde,e"����+*z9 .�;p+a�7aSan\)��I�>�0�""1$H"�H ( >40�%)�&�`�� �eh���A6i��"�,s#� ���$pro-survivnd)�'.i!1-�@�. ���8ah ngth2}x yV�[�o}��>qm [2�O ompeti7_NO�RDby�K��".'*$&�Cʅr6�F~0�,Iw�p�j,J�%s�a:"�T[5�7�-*�m�!:�Bx /2~&.{B�E�I�n�B�&,�iR���B(%1+t"�.�t�u }�*� �� half!� ��B1 �!a� d&�o%|PEW? w B>[�&� �q dilu�i��>�&�6N~/U#2r-�� �/xz;gi&�7�*�e�q�B�a6�8 �c��pay�A.x;1:��� �"�C2����ndjr2bt R("+9�R��a�<r�2�b�52yR�3c&&3�Qr-3qE &2I2�r%�"� ��2p�m��:E�gra� �n�D&�3ir�u-&�MB� Ir�'�� {�� !�G*j6)>�1�%�BI��eb  �#C%|E6;q� load*� !0]�r6~f�J�?E���P3)�%NX"^��irmP2�,h {e"!$67-�*�$!�so� R %5�AXL�&2-�:�1ic��us*jto>a�W� . A"g9Krh ly&4 a-.)!�F�uth��v3z re #Y= � - ��5s ar r � Gdu& Y���u� �3� emerg�T=v�� �W]�bJ 7�t)��Ecoinci�-e��#k�����o"e~a4y�%�%/�1�e%�;N3Pe{%�N� hel�|qS�Q,i>� c+)]O�2�/ �-c^!�p1Qt���lcN&��N,�I�m�6� ��� �cl\Dur2�� *tNr%}� .].�kJI Maa�z!�e �%We�� 2� �N�b6�qw80.�*��o��n"9NE\g�o�(` �[~GB�Fj#Y\*#b6�BbWkJ=2�*�&�!�9�]A�0I L(>f)AHz" �Ls [in N@5 ml DMEM ) ( Inv8�,�� lsba�"C�r]�inj�U . v�{g*��F��E�.��""� ��&4   t��r� F��&, +�%+M�> ]!H�"10_�`)I�%lf?p��B��)�i1. &`#,>r, �e^laٌeu5 µM9!��Gr �!� :( k9i�J�%�&1!E��uuV�}�,��B�`�B6�Y,�eA�q� p���% c�3��bf?xͿ�P��� ���>q��k:P�2�$Ar. S!;m weig0!�&; �6�,�K�e3fugY'(pellet debr�!{�supp�d ��@�g�8��.t � Zo%dF�+ sub-! lu�3 HeLa%��Zo�<rԈ*6�)�q)(�smhcal� |r_ws%K9�A8 suspe�p&v>�p����m<�% pl�� thro�4a 70 µm nylon _tr�Z�BD Bios�'c�a Jw0,�F�� �Z�-�lywE�!�83% NH4C2Inb�% anesthetw)!=!�%�Oc�-PBS ~lympho"�/mononu�R.�i�  !heart \aW u� � coll��(aL=��-Lbhor g�fe�J&�)HC.1g)H�-�Ă,]��'Jpoo�"�S2��F�H. B�\A$֭�$n K2EDTA-t�ld Vacu� r P� tube�f: )%05� ACK bu�| (%� 15 M-�(, 1 mM KHCOABB\ . SpA�s)r��2%'harvf�_finely�{�+){di�~c;! agen|d�. I�0 U/mwtWorthing9 Biochem�! Corpmaq, Lakew�], NJ )�t30x�} 37°�4yqfi-��u�A6i� � ��Nd� S!at 10�L68s�i�m�2RPMI [O$u10% FeGL-gluta� A5$-mercaptoe_ou5�'W)/pȍillin/j ptomycinm!�&x9E� `+ MOI 10∶�|an�Qpul�(��p)�( 1 µg�)@ 1 hr�)> . Unɍ�.� ±JM%2�� �mmanneC��)%�wa�q6G%�J �2 . 5)w� &� "�\Raєper,�a 24-97t��n-M*kI �[� as .~*]32�,,s=3B !*>���-� ? �,� Q}��V|>� � vP%��a. �3(ꖹk -ah���-� : M~�A�Q�T�z  :� ?1C1�c 3& i>#mi�m8 �A a�l!�n2L �]:�Q!�j iquo&" mix sI�>;tE�rec� 3A�5.wh�%;�(>��, Trip�H"�=M�set�*� C�!� $. 72 hours�3e�s��  ~�0@��a�= ��*.q��z�"hW�%& .J� Vz, p 8B����5 hE96}�W�2 ml/%s��R��{F�"?niJ�t�olgiPlug| Stop (F�I���E�{��|����o�tE�&�=!�mRQXa� ��-�9eFcEkbE � body�c� ck ,F�in� =*2��A!S,1% sodium az�I( FACS��F0��"c�v:�s�#/ or $�;CDapCD8-36'T, R, Jq�p%a�X�p���Cytofix/� k>DB6u !Z�s>�v(1�&�)U��7�0isJ subtV ng u�FmQ��/l 1�yC%".�%PM� (A�n��!�ionR0( M Sigm�{�Lou� MO%,Bʉ PMA/G�A�vDs' K �=!��!�[6C(6�E !7�W�,N��)�vct�,�#Q)�(�0.n? �>���1n����*-.:���.SA�NIH T]� e F� ( Em�=*e, Atlant!�G��C5��3�aat in�j�@@P$phyocyanin�ju�@�*�΀s�R����m (��18&� [�'�/ ward��(x A�ElJ� -��CD4�$O "IJ&g,�w&-�֚ m8�app&��ea�,:D��� Dx�,s&"� 4. Fluorochrome.Ua`(ne 53-�k7�)aRM4-54IM+<�A2?!62LMEL-1�M127 A7R369HAa2F�, "�( CD9�e 3e HIS5� ,a�-γBXMGD���MP6-XT2 �)JES6-5H ��< 11B1 fA�IeBio17B!�E )�0Armenian hamsR IgG (3299Arm@ rat2aZ t�y�A�i�6�u��"!. �B2)6�+6# MR5-) !2c�E 1B&)��4=!8Mo�%BDxB�AR�:�.i�i���q_e&Z ��f� �!H9 1%;�a�ldehyd�%`ac�@{��buN:�DatarC�n�R,FlowJo softw�( T0 Star�sshl! , ORGS� �calJM�3anc����& ab�pai�wo-taR0t-tessu�8I@H(��ro� Exce�b���9ay ANOVA �Tukey'utane5�[neu�le�+$[osa4feron�,leukin-1%��ylpredn�!�"�@D in�X1�d!Wj�s�9hf 8rheumatoid arthERP aW7'�6switc�/V� ���so�in*�zeffica�D*]yx�W%h��� ven!!�I:��Jstm4�!�ap� lb�ndMy] ima�-�Forty-�:�v�v��ran�f]:'�N�$e1E�2�( n���XorJ$a%�*���re��:�OU��I�d�"X�r ��^i��ve�-Z�&le� � �]�NH�G.e�J���g6-,��85!�d��2" �F|xpky�9i in �y9�pG�/29E� 113!.�� �/ 2�O�i�n.�w%Fws��NQA��*�I2��Z%J%�j 16 wp\>�E � lend&�o��t ���g�Ron�cK�6Z!r�R�%By�� riska'94�!hr{Gr�+:5%�f1�1a�a#o)rt�� �%*.�K led-T� .A�8ISRCTN31894035 їc&5 �-granulo��u��!6pr1,p(,�=���skC2Y��8�p obl����� u�<organ�jMycobxlum��a�4�'A�di���)s w�!!�4oEa�C�X1M&g-M,�@�Ba?dm�&S�j0. 249 007 new)&of���e�diagno� ="�8to�(ld Health O�z:$ ( WHPin 2008�`:�T1RR$j Z3Ni ( NF�)�.t\siJ� �)�+ to 3�rsuszG�M.�[#:�a�&�l Eborderڊc 2h̆a�UpC]=ACfeam.M����Q�m- -druO>e��( MDT�"rm��. A T1RA�ch�n!�by tA� flam�%�5A�QLorQ��6��. S.!�jKl�WM�3d oedem<& pilot��in Nep�����!37Yu.x�2�^3[�J�**� ro� �t�TRIPOD 2%| 3��e�u��}!�p+!��/�A)�aѦ�>� 52%>[�p7��af6�.e|*d�J� BVABQ��4ef �$6k��:iE�A�ryL��1)�oxy�%f� ra�l:,ducer iNOS [&�2� �!TNFα,Gr e^��� ��-[�^ j:[9! HighI`. ( IV )NX ( MP ��Ha�a� ��gar. �eagpJ/�a!1acerb����h*~=5��ep� �;͡aoTDE"p�IR4VT $( RA ) [107^��$ple sclerot= ( MS#�.In�5Ee�MSI� IV! 1 g�!��> v5g�7KpE)-�mit�'�edU-)�!�IL2!� Lby�# leuc*#"~f����"MP� alsuL��֍t"�3serԅ!�Ecin!4[1�<E�;n9p��IVm+��ly��R]a�}�24%�'s �7��i�of*$-i al-,�8c��ާ2<]MP�44 .�%�RA!��I�� �:\E�- /X8M� a�v���"s r&�fa� �&ec2��W+��"��jinf�4�IV*�MP�F��� .}�I��TI8��X2{,~S��!�YT!��1Rxa Pe�2��%M need�oa�,/ saf�Rb� !��mwhea0A��1 8a`zr ]i�r~A16����YD��is�%iodE� %f2�g&��by��:�( view)^�? �V� )��>c��-M!�� )�*8cr��?�>�m�c�6 �\!S2sE�[ded:un�>+�9���4[�� etur�b��-� r whA;d�Nn syst*)�[�!�%[��M"Z$5�B"�R Ir�$�/�o���-�V� � haliy���rpAv�4����Is̳�wubercul +"+5)tTt���Y�=�!u)Oad"W J�t�#c �]diabeEHmellit��glaucomaE�un*t hyp77nU r4JG� ergy�J�. Pregn!dwomҙ.&dfe�3�! child bea��;�q4@m=�onrt�aG"�5a�%�AadWK&%9one����9c|s >w�112w �aV��2:� tudyeT33�6�LN� I�vR&q� �!�v�was �ou 6�adnAgan��� %j)1t dummy ~#^reh!�ve�jal Ser��s Ind�9Chennai ) �Q+k=�X?.��7�9� !F!%f`LiRd)��)_2e N u�40 mg�i{lr�42E Y��� �a�IgG �A4C-�Ily:g��re��.�in�$"�! b,"��A�2�!(��urs2) ���,4!� 1��lE�MevLunX 2KAvt:@�� 35!v _�6j�14a"�n �"��6��y/to zero�Q9j`#a4�MP)392a.�of:�]�K�wtoy� 15 g)2� v��6"� %�}"� .����#_+�-]ŬlR �)�U4albendazole 40E�6jvBA�famotidG . �Qst�y�� ta>�M�A�c&�ACr$of�$]/��ŸS�Dylo�DP"cf i"O�_ V^.�� ��[�Qmeasu��-�>:,!���wo�d� arm �aX��.=i�� phys���_ia2C�_as��o��u3�8 ,A�,�, 57 , 8 �� , 14N$169 92225*32830#��. A6$�en?"ab�<�"�8a�atm- �%.o���haQ�"�-a lis�A:i>DI>mkp.� �a����e"3'�T� A:� a!�e �8space*~Hw+ sym�2ڇnA�X!�i�2�or��f��9�r{b� c3�Nod��zjrS,^h�ord�De7��U&� eM����%[1�RMW:z%G|psych  .p�- ,&� , catpY9aB( "� � �&`2� �%�� eu�� ,&2[ A�death�:!z�mo7 !�,�W,phyte fungal!�y��� , acfga�D p�f�� "Wid�]n"���!����0��E�<cr�D�r+92�a�6t%� quesM�i�nU��Qoctur� �B !5 dipsiaAba� � cree�&a�F� :��Paly�#n׀E�S"OS�oaC�pD":9@w&!�c�%�L.li�!l�S����@� ( ST�<G�}u��� Semmes-We\�C�9 fila��A�SWx6,( Sorri-Baur� São PaulH`Brazia&��&�EC&dU �!j�XZ�WKpF1� ensɨm�a_Q5.��l�Quln\�nd�n)>�/�� ]& 10 g:��gbfpos���ibr)�!j.eAuaj30Rk rige��l D�N)�cot�8w�. Volunt�Umu zau ( VM1�U) B�mod��alFpg�n�  �[1"�%I��� s�9 forckZyeH*G)U--�.> �@��`umb abG�e-�)jb��di�fin�\6!u���.9wr�fc8"�IHl'pte:6��fo��orsiflex GST}!�)iR�� carrA�,�c:d� o-techZ4(�� if nƫs!�rep %8a6B n PHw� . %)="!:eEig C$@ �2� !����a!!� 6w(A� e��t*�a�$h:�)�L�!B< $�gunU(tt �alges#, pal�Ls�5A��2pa��@0 new eryth.� ra�%,TQySO�>>erv.��9�doPulie�J�� /I� L*�Ah� r���6S:�ho2� 6,�!V�&�Wre�(!&a_>� l��a�#&�6�� %Qd ��!�2+A��by�^���exdt�&MkiN*ys&�a��%��)�cF>�>`�to� )n� �> O:�ta�|6� ZO�=)'-Lir xJ�!I tapeAG~I In ox$� have 80% ��to|tAp*de�2 ly� ( α�-) �#=(65 �ds�e_*cCf!E��B� 20161 6|Ab�O�/�er{7%�>�y��a/pt���5�w� �_� �Lni6�( N�x�4%2A�66� �bϴ]b�^|#�arm���YZ &��cu�� F1�i&! WfmS�Xa�!� 1�6s"R Dr P: Nichol�as0 .� envel�V%�V -Pi!x6Vea �5� : �pre-pack�n�b%OCl�0 Watꆁ�a noyi��,5�IR jpB �GYl��!�MP/2!� >5�!�a�s\#q*�o˅� !�c�2�O.� �!&Fj2d�$ Vin�#k� AlNC�.�,�c�, �72ff �Ra�esmA( .6% ) V # 9�2�O{F��/�ɒ�i+-�!z!I6qa�N-&ba+�2H� P ��) arch{HoA'r �,*�t}E��� leA)�)�sto�n A���1Ts8-��.|4Packag��?Sjl S|H( SPSS 0A�16 Inc .u6hicagI�Doi�Dn� � ��ӕ4����>a9�/%*3>*�acach��-�)�gJ !w CC���.Ltd �ww."&.KQ co�4!]ca66[ poli�I~�talm�wk JourEdi /[1�&�as� A�� niKffier 6�. �DSoc�8�3+.+E A a*�3L 2ePro ?S1I�hub(. . &�2mҭ�e(2| z6",7th December�-�� 31st2tH� fi!&, E�E��! y$on 5th Nov`�PIp._�I�G!s��W) llus~L�{CONSORT 5�."�[:ayirty-yranf!�e�m��T_ay�+46���{B]�3b`7.�31��e7 e�qoA�, a�h:�":;=8y�waZv.6��!�_ rd�� �. 8+.  V��n"�."�+ �#�/at � ��p�x�,�L( > 6�Ǩ"`)>@�2.( 1���Qp��c schedu��&m!�p��re�/a��T2�A1IAu ed� . Ef�[%�͑%�eH��t�" elephDV�!�7�fm"� osu�ANwo�^�+.Wstopp�2`I"Jy.�U2P P-nZ&o��&��.qa-zu�22�Um0�2�2CD� 6C, twelve�Bs�=�=R�1�>5.'�)� Sf:2".�&'F�ֳ �VG{!�aD6�.�}��J"�S'.�(���U�23)|A> w! .�ҡ��>�3�#g.#� n�. N!W �2 ed6�,64o�#a:v%�l`ha���9!� y�{; �"p)-�"��2�!2008[?95% CI:4G 5817a�7480;2��976�@��`g2�6s�:�nE9.� 6,m��!�&)!>kQ^\1��1b<�x2�\ a Ka\�-Me�"�kcu3�.A�ocumXt�>“)qvd'&�w�^�_H.�J" ��A&�.͚y)��}?$( Log Rankx0(antel-Cox )%�945�?Fr.��  )Y6&�i@*�G aR: C: �!}�@��.  �N� new fnt��V)F�la�>,,t DvEn�oi�!kigi��!c�,�/sco�/]"�U&� vs(0cap�V��ay ��� h )�E��E2 13 H.A���box��( fig ..C�Mnwn�t��A�E`�"b�of2�$RWA�� 2:�$s! -ii^oasnV/ͮ��ory1�(!�r�T!�*??>"� �.4 S}}a*� . BW6gr��!�A�QJFa:��"Ra5�*? e��e!I�K� 55Y heZ��� F��E�����e�'B�Qt�&*�>Փ+%�~ B�-Im 29% A�-26r.�ofV���dZ�7$��� (204`.&�M26�A��reVR�6��%30e4 !a��������maiPe&Aen"h �&7 p-m�ZTegt���-Z��x=�ly5�m�yb'q)x�( o ��re f.ecFB1�G6�)6<B.�~.bT*X(n�'� ]U��oB�m%g" )�sa,%�or-��5%Gs�%3j*y; Ea+pr"Pe�gce��.� ��un&D��'t* � h8�,.�iin~0"^���or ENL5���:���.�&F�2�.�]�J: : .��12iԡ>a�!�Zk"Lbl>&f���o1��E;"��.�W�me���=}Jia�A�&<a)a�2Y��202�(�.�l��y�Z�!�a$�|2) �>�y9�nV�!�v� �2) �O��� �m,�*�n�F A�61s&range�H14Jg� � &@ �����)��2g�d�0 �� 75%� fini\!2:-"U�[>�9ܱU� n� &og �� ~Zi�2u$�y� A_q^i%S3 g(2S2–22� m":(�O0YT6* p�� v� fift��v�2AM2ab>��*�D"�*�)B`&�9, 67%�BUS6B� >Q\( BB )P38Pcj of 1 ��>H��*us s�XLL� �I�a6wHm�9:5"�)�Y 9y2|Z�(.��\E��7���he!Cr� posi$ slit-~$smt;2�e�����:� �AD^�A�152I��BT�, 138B225La31M�S=�L*�� b�.� *N�2FI� �;:�#%=�. I�*�|����!��GL �ti}Q#i-nd*2�>|��R{�ta2mOMP��ed�n��!�u��#A�n)m�=?"!Q"[�V �%�$30%2�E {X-�DZL.����.�-$2g�a�( �8L>c'-���#vs �4�414/16�Umf2K��ed�#coh=u2�N�0"^=nt e�!qplaceb�1�m�.*�se1[e���� #96s5r{$ G>�&�a�o�7- P-0� j�F"��k!�:�$�����JAcF� a�2�n4A}�`9ea�!H��4 A}��9D*� }* 30*H�z$d�� 11!T��1>]��</GreT�*�\!V&EMw.l�z�/o��u���56�(Tei a���}( 87!�Ɔ*'*�1��aF�)�B��EF�"V6is�ESB' c( �.mg� )�-faz��an �'z>�h�L%XZ � l_����mD,L:�I�\8��E�*�)��5i�!&�� *�A&I�2V/3�M�:7>W �$0M��e�U�5�aMA���l�#Y�2* Fai�����4��E.�%�e��%�%|� �3�=[M�"�"�K"�E�dn VX�́6`?�*+fN��@dq�.&�%� s6�h3�7�by�(( Y��:x e���sQH glycs0ia"�@l�4� 'h�Lir.6ҡ�!i��A��G�)iY�t�I"�l:�XeBB�A�!M& }�2�.{�3��� >B �7\n6,MlAe �Q8with diabetes m�qellitus . The TRIPOD 1 study reported one individual from the prednisolone treated group who developed glycosuria j�is was considered a major adverse event in that �butv�authors did not comment whether t` patia)Xagnosed with diabetes m� [20]%ree�s � e steroid6� s of�t7-�is%wdur"follow-Exich may Us$will occurwing�treatE{phasee@ominantly . We we!`$lso unable!{examineCeff!�of !�interA� ions on bA dens!�w�b!�U ly aG0ed by corticoU�herapyQcdoses%�1@a�mmonly ua$Pto manage leprosy T1R2NFIe&Le findings would sup�*� viewAt MP ,6w`M�I�,!�safe .0q�appear�)� large��eutic1;tApp.�al!6oI�symptom �a5e�� ��is ���e�!�a valida!csca)�measur2'MaA�I�i�isI�the twu�JurM7no�q�d���total sa�A!score e[ e sensorymoaps betwe�p27nd!�E�ed��a ny! 1-defina( ime point�?H�5Ao��aKDnd towards improvee0in�w2�duuaI$ . PaA�ipal%2imniV|!C!�-; ly m!likel��EVexperi�Vd�rio�R� funca�Ih!MP�E ��at��.�4 ( day 113 ) .=(Z� usta)`o>W1T<�:�ꅞ�U�ha�,as it�2raΩc-C skinA in-��I�number�p.� contribut�oA�$!4survival analy�j1�=" �ammal/�9� sulte7ref%�ess reli�>�(is phenomeniR��9�(after stopp�6ss imil�^�r t-�ͷ of6]giv�Ras!f prophylax��o1��^-�!�of reaEN�(,. It demonst�c pro�ive1�>��S�7}:16 week��e�ew�B l��by 48 (!Ze���%YZa g��er� whilst an*, !YreceivNv� �o!they xno lon��ak7!�4drug . Forty-f!per c� -�MPmy�;50%6��i��prescrib!bddia�al�F. O� 20�s � requi!r^=$12 ( 60% )��do ��til�Hleast 28�sM�!�leiJ� rial6?)�,clinical nat�t- 6�(u�nGsa� both.��E:�ose�.�C)�9��m�*�%�tRE6�i��Tit ( χ2 = 0 . 292�1� dela�6G��: �of2�)�AX^���. k � Y6 % A�`)artuq )� data sugg� ' � ��proE�d cour�>���beɫ��A��aN T1RsM�ublishedM ��] for extra6�a�u� a�` outcome"�i he multi-apre dou� blind ran� C�ollE�E�> Iaa�2�regimel nduca,in India [21� �I� ��e vs�a�!b��V �e�f 24% , 31%E�46%��pec!^l� �gi��ed6�!V20�.�R6bũ&b-�.�&� " al%�ed]12Boes�7$necessaril�flect�.X �-decis!Dto!�.�2�A left(!�9p ^$ian's judgIZat each)�� x��re ItaP��cl� howA(sistencynen2 d�rrphysir��at]J stag�Ω�Iq ��*oco"�MP���stA0A�AqD� ,. “Mild”FT"�[of:. )��VSea� Any &� (ablittle � ጡ�et*�w nofila�t�4!fea singl e�itX �wc�A�^�so a low= resholIo� aP:�s]�' Cemployed�A+cure��!�is��in-  account�1F!�Z�2x^�, ��\s��M� �abe���2rAdu�%T0response vari. I�J�� 2 co=27k2CQY�s�mi� impair%�.Z6�ne�ita��fA��g � Jp�bey�xto����^jY� oup t inclu�ref.�e�A~�  arked�invol A;e!�� %�� I]shdb�terpreauw�cau� _ �)<A� he availD �MP �^ A�e[cre��4he" r �ga.��Bcin Nepal��cl��detai�B2Me or]-�st|b!$�i��fu !%�of��!AetEG)_ esta0E�� gi��V6$ U�Cs���1ial��en��c%ofacUat�{e c� h� 6�%�!�o�neJA�s��4 ���fy�y" " �] %�!�varm %%����6�&�!Se7�, ueA)uB(had:ee�6N{.� 12? ofB�ye �� mainbT337Q*Bo��g� a rxWe�e i�%5e)T,�icularr!�&� . A i� Bi�.�to*:otent0 - fur!}iy�z(6� MP )�%�"^"���E�&� by Raoeagues� wR Emthink�UI�E���IV�0warran��at��s�Xy> mu�lso tak�9o����aa!�g�(intravenous��0�i�ccept�'�qaA�uePhas�l�aס�Nc]�T*`Gub-opl�n�e�I'%s>"���joe�._e*�a re-� � df�"� s>�2 a�en�.� adds5�"0� argu% %+S��I�!,D� �Inv: g9 risk��t#2 ؒ��.'��!@ F�`$�6��"se:H%s �r ( ore${ ll )%en�i, iansA�id�fy ]2�ho :benefit �.�Vo"� " %xa�utsetaayn�aeA�convinc!Wev�ce%n6� �e�atF�� ��A J247 s [22]e�?siM[23<den�ofG��4 �I eU�monitoE1F|� n��!� �% sequela5: !;�&�0�  adequFp� u� .�inq "��prima��͟�B)I�%L as"b�� .'�We ,�0s ,i"e�" he HIV-nea�v� 2regulat�CD4+CD25��pFoxP3+ T cells ( Treg ) exert&���$CD8 subset[!�m��!a memh/ �or1ebal,Y�-�� oughF@PD-1/PD-L1 pathwa'HVw�M�oed�–medi� )u�a chronic!( in�M. A�ptoSi� HIV 5Qs1)/!n ) ,�sl%�%De�= f�Ѫ)f=+�B 6� 8inhibit polyclo'autolog�CD5PY��x�ng eiA� aa�M�� ressAcapac/ of� ��  lackE itiv &)WorU.in�)GR�! �w! ^ �� 2:A�IFN-γ�!�}V�imA�}rec��hCMV/EBV/Flu ( CEF ) antigenA���1n ��-GaA?^ fic.]�� cross-o� cul� Owe�9��-ZR���ti�9!e-� CEF-!~ Gag-V�jQuex.;a?e�iC� a�Knjf#y�V���!�6x thes rke.#ha6��A de�!�r co--g��")\ , un�Yf�= summ��y�u2�dAMa9=�>���6�!e��molecul�ge27u3. Our��jstrongl��IK8 pa� q� �O��Ih\ hause�ofE�5���wj s . �� s�y a cru_ rol�a�g�vir�Q!�. Whil�evelin�f&����aij�.V �"������E,ion[1 , 2] ,�ir fail�to�! viru�� �6��ld"t1 �yetmlucm!([3–5] . C�=> < ongoAC�qic6��!.�&�e2��91�%!�nga�of down-��mea_ism��N���5!��Kprograme$��$ death-1 (Eͥ1di����rew � s�%@as CTLA-4 , Tim-3e LAG-3 can�rit-in�%�magnitud%""�0 !=)^E"-�Q [6–8!� In human E�typ&� Z"�� )�alaq�Ai% �& among!�.���9 ?!I}��� harac_z`aUde��olife3 ve2!��al< � pool�$n�eB�at|%!�E��& cytotoxic"v'��iad2��poptosiR q �s��*� non-ETXpern�aiG&,U8EBV���megaloE� (�$ ) [10 , 1�S�Zstu� � �#.%���!M��mA�6y2�.�.C!�upmi(:�[1 ��mmuno�c�#yABu�SI�y�.k[13���`lA !��.n%�soc� %�Y\F�i:{ Mton [14a=�fr$ ncU%>k>�*n �� �(!�allel%\�fplasma�!al load��1N l'(rel4�� ��k%%f. FY��'Ay�| t�dei+0 vitro blocka�jf �on� a s en�$�#6,!�A�k%)pro0!D�n �.�A��ʼn��A2�� rA�sible[1�UFin��,�cf %�ggenV6 ]���$2�#i! voi % �e%�2$2a m�&1Oof LCM.- ,��we2%�] aA�-macaqu6.A�a�,In]*o“ �ed�9K�R��aanI3� ��A*:�EB.� �� r  )aF�"�E�� G+C � !�a� ��3� ��[17–,� ��a key��p -!��p5l tolernd�6�inflamm��x��I �healthy Mysystemaw��s �m�A�T�� RA��J�dNp���{=�Ec��� 2 �usaWvif&""o& � � e [2g2e-WeV�_ E2 �������b�thr�,]�!�`��o *' [ �Gal-9E�%�N] n stitu" EK%���*idU e lig���se�![i=�T UTin� – X#1��q�����]UM���m�c+1A�/g��"� -�e�,�� detr�#S, �!mu�ng �B! YQ9�7��It seemr$�!s\�depend.��librium"""ay %�f!  �juEV ��[2� deac  l��^W+�>2a� eH n�� � FlAlow.{[2A{30]� accu"� [� ymphg2issue���fou!+o!�a:�a\r emiaa"�'i�P!'� �� SIV-�4ed �9 s [3� 32%�n ��igh)%*!ve��>� poor1 restN-,under ART [3�u�! < =Q�2y re��� open qu�on50 oreo)�Y�I,eL%��Q3HI.�!%��lyA�*� e*���evoA�. Logu ly$ conf*d��*d2�l �A� .Z �~0&� implv�H�-"�d!$Xlso�lv�orAKpertur+ . Re ��ch_ ng� noM1�asAyomogene1��pop,~F� IA2S=.�y��ac� �ZoA�4–3�HA�\6equ� R!�ra<22�!:���+oA�I6 comb�/��"� � � or��halA7check!1�8r(, a �F-v� �KQ�ACk�n unres!�d �|ut�4B es��a2-}� e M� ItE��e 45RA/CCR7"�1 naïE/f�ipueGsubjec--.Cnd�2X  !x6��ke�q]1 ~ ],&[ASF'P �-eC�ly-&ON6� �s�#A6b�2l�te2o{! a'ral�2 1–�@-�M#!t j^3Aul�iy1 nsica�R&q�|�&�MS�0K1���D! S"��E�7�� 6��� Firs�,� PBMC= n = 14%-po�e!�I:�y�/w�f9'Z��Q��p&��f global2 B�.� ( co�� -CD3� 5"#s��per�,age (>- n ± SD )��ng[FSE)2�on D5 �65>12%!x ��!ce��( �5%@) vv 8268 . 9% �,&� , P<G/0_Fig 1A�Nex9%\lN5""):� /C��)iJs: na ( N , 5RA+6Y,>Ud'-^ (U��d+( EM+E:4��Il�?( T-+a-( �B�!��CM ƁL%:�57!b 20% 1���)0:�%�7459�is;s��(9���he�EM+ E� , 69E4% T9± 6% ,eʁ�v�5�01Ct�same �7�E sh]of:�wi$2N�TE� b�a��2-bh!e{$A����5q�1C1xse[�e�d!BxI:a,Iz&� . Si��f}onDbeq A�ni� >`,5E-��"0+i�q hav: igin�% A�M��1�a�Tar�"iv6su�9Sp�%H-�~ �t �6!E��.�� AQ��aMp1�. P&�.E&� J�i �4A:M�e��-�Q%=-ofYG�T). � !K�*8�d>�� K�Ly�!�uim7.�>NneW�()�4%j 22�:Oth6�aa)y�5Q�2�!���)}~�� to 46U- �251��%5qH�V>z�L}V4 ��]�2"t*a5�Avp-ne* &;CMm'2�9�6or-���1 .�t� �&� 8�6�� by�"?i}�.��"m ART-� � "���r���"A�e�, Yn�(&:h���c" v� n�'c'=KIFNγ+ �5�i �orm:W:� 'ro'�i��MSD �0!�CD69+ t jof {41*395�z5_2�s T5;� 0i5�&zq�a�e.- of �-s���/ �|&B%; %� �9 . 8�a/,y11� ��j?��&2"�)��� p*� h32�h = NS�2N 2N I�u.�pAtq'.~, �A`�o�.A��s�. confz�.�( S1B�, embec*S�in"�5Aza� �CM2�aABa.)@F�Vobsr:Z4� �+)e9�5*�achA�LD)�t.�.�ecdonr�1as�B�T� AuCM)z,du}c,!#` ��Chyp"��ab�0}��:�% ��!8%7�IEk �#� sC"B�2-6�] ��z8de��A���V�0e��SO�%a`0\&p'��"�  and/�a��1b�Bss(v���7�kno����.�)Q��?9 %�eOir"��&��@��/i�hF�1��~� -E?�on:�&�bha�! �� gen>�Ti�f��%��(�ve�F��!�Gag3 ''peptid��!ɡ:�� %��|u.a��yUt�`�X2� �"T �"E=+T�%�3��45 �ora'�a�i! ly; �20[ i�BBI& | T %�0� 5��]� ly (k38�87%ɲ' �%� 2W� �6E��BK�a��*iM BD�Y�]�:3A!#A .���I�� pro-H�F&^chI � �1�,L �� ious�#hu�P ��Zh�-�_ , �]Au��re�Jti"�8�g� �mp�#*� M/E[�M K ��'�""ECB��:22� �1 !@ ہ�]G)�E��:��Y��-�qb>� D�2V� %�A��he base�'.�M3�MFI�!�:�he6*��/";�Q���z6�m $nt 498±10m�540±115� �844±176i�10%202%L��"�i�3A�3i��AbT�=�-1�:dr�26�(to 699±127v9�15MaP.6&� �b�I�J�2uyB"6FS�BTH�!,re 1985±186� 2730±305�I��"^- ��� HZ�0����>�  6g� er>�6��;R:#)U�KoN�yU� :Ap1!:9I5�-;i/ 3407A�Q�)n76&L^P ZV!�I�<es� %��g6��K�� !B]V�62±230 �U����2848±32 'U(L1!�puRB >��LB�56x6&�/t*(��yg$Annexin V+�� =� � !�TE�l�s��+�s(s6 )� 48h � �.},bH )��a�9�. N^sM� "��d{�98 "; �@"i"���8���OA�"y 2�IE*aO� }Ѝ� /PDLM�m ion-�"�)"V* ( S2"� &i.�3�bwI�"�Fz%��g�� ��?a�22 *2+M.����<�rm ^I9��I@&+� -Q>&Q�)�18h27A�� A .� LBAJin M&M saH�8"C A  T->� �p!ode�}!�)H���"6( �%�Y�(��126� 500(2�g�$17� 3060e�| 3�/j 4�A~+KMI+%fno���ZE24y�Sa;:�%��+ �iI891� 1918�1��5 1449286.8�۩�Z� , S3���As!��M>�Ia9�6��^� :�a� ���-Y��at"� : 32M %顬%�!504��%� .�Z��4K Notewor�(A��&�4�5�0g�Gg*^QN� : 375 52166x �-1�P ��.�J�YJ �8 X}"�}5!Q�regard�&B�:�L�I 3037m? 4734�485J� S3�ETltoge8!Rb��0}8� iUe)onuC�o;i�4�)29O1&���3E6)d�AlA�Q�x%H��expla��he&l��y#�k wo�#%8�Y��2vd6�H9ly��/K |4�B4D��# ex*K�D �>�(Am�M6-pro�$6ZbyA{�(!>��eG-77�Gpurifpy��&1;9>O-d.� *L m�r�D-�yI^29\!.��%xreJR'[�?1�2X1�b.�.V�I�*�-PD�I=�Ep&nL%�M�*����Wd��E@ . AcHGto�~ K�u � ���G:: T�*S�� ’[~IFN γ &:�53N�B27±22; ը�5ho�=�A�)��+�J��nsi\bly��W��%�@�fB- a�JhG�$� a��.z��a62� �9� 끄Fb'M�"ofZ��5dh  s�W� ��,6s1A�diru=9+a-vc' 3�D��ca�?51rP�`87 %7�r�7 T5�o8(~6�dZnN^��L:5�"�K6�� e �a�� � �G "��i2*� %�� *�}u J�5;��"6�(!TE�)���llM*ic6�K�ri"'&� meanaq2p��15 :�, MW p$ 93 S5�a�$ w *�@��� �!���c�Vr![p�X3�Z��s+�'s2#HmL��a*�@6X ��?Ibe��2�o�'( a,<g�u�% , [min�Aax]: 4!$ [18–64]n&21[Z338.7PQ� 5= �[�7�I�-!�N�?( 51 [32 j?%58�3~7�7P>��!!�$ 5T$F�6a�[ �P1 � �-J'� &)6�E� 3504�1 2465�259��]��J)��1�->c"tZ� �S4&� .� �"��� 8900�615 �574!;�7�!&|)@Z� }*� �!e�F&�&� "U �a� b*R^�B��f�.s >���(,u_�->r )s� -�R : 4642��"�E]353)-3!�����;%� p L1: 11047Jr942 r89_1Z��+�F.�a�E , S4e��Fi�8A�:.�dZ����edJ3a3&�* Bs�:02� ������ �.6 71±�" 7±72�;.* A��$%In*xB,��aa��-�r9 �2� *�;,U��#a�"A2j��&�@.yi) m]upA�� >F�-h\ XNC6/G*� �l"w�.vAY�'��1�(&�Ti�f���AѲ 2 h ��FAh&)i�&� &C� 11&�J�<�&e�XKB� NruF� �]� �&����U�,��C��C?�(%Ow�plo"�]5B�f! e]��A� * V�'2!�<�3ext]��ly XEgKo@c"�3!6.[�A� �V�!�AAV��>]?/2WBg. L�c��B,�&~E&�m`��16�1v@+��Xon5&Eb"�jZ��1��- �� ve�1)��G�`� at4N�1�1 �1�d&pb)�%���28 disp~_DZN�f�� )�o�6Se_ $ �IHe �� �on�>?T.�&�!|�Ko\l�.at A� #5R�*1p-�$��w&�I �Y�Sakir��36=�u�K\GV=9:Wv�2�!�2�.��c�r�&a-&—"L8m�I2�&B@iogof9���tol4,5�́�!fav��>�= (�CM%5q5+H5&%)�i�Q-�M�2~ Z"�:c&G=�vmnytoqE*�-"� �R�2e�`ll doc�V ed [j517HWee� Axf 8L%�� &�IaF��-A��B{Iu3� )�&I\)homeoainQe�t�ube�di�Fev�Ab&m#,8en"�9!�la�!q�[I�eW"$?�->�I��fy&< M��jI�� �*� � N� �E��,a_A@ ����%!{ 6/}was:/ W hk� �� �O2wI�&�y�or�"� . OnGVB?�lan)lRk��!�D�  �%% r��RY%B�(a� �Amar�V-��W<sL_JH4�CSt�%� animKOode��20P:D pin-Aed- �&,N!G Sa��o&�Ya>i�7 inde�f��  help�M , 4)B4)B�FA,� ��*A-co�0� E���burde��&.MQ� ���Ei-B  , HC�aHBV� --�`E-�E[%e18��e �Z@.�Rd"�7CM�D&+ M%�aW7B5%���]fe �pr�htoA�M� �N�f[�-"B2res..� �Y� )… �6Ab���m;�P1�!41.�!G�K`tu�6�s$I��Gs�E21u�n� a CD8��cI)�&�'��-retr+T(O/Opy[���KsA�a.q�x�zP�Q~dQ�en� *��R-UBvkx�e�&�x��6: .)��� :'{��{!TX 1 !�qn**�u���*� .�a*wd��s!se&dA�a� [4�4o*;#onL2 +9��:>�� ed�&Q �s�U&t�p�'y "B���%A�b* �� AlK ��3� A�!�"vz!O!�6%�a��eh.� val/M&Yb:�UF�!�VL.B�"i �%u�y� Q~i�~�l�A1'�-a:M&iݖ�T�-��zy 1%$ݙ ( S6��D[tqu !Y evolmm��-o���h�aha)P).n�thdic%�."� �er-S�e��N.�5k:hY4�L"��L� e!��["�%�qw!l{GM/�B3 -9r�s^�� bloo�Jd� osal ��� �tA�.{'O50anH�|mI�� asses�-�]�-�*�I��ovH�Eed5 GvU"���a�:g/y��5}�. Even�,so4haw et a�) [31]ͫA �#� �k*�$5]\ 6?%�non5@r!��@ *Y_i�: OX40� }(byF� T�hBy6�Y6�i" CD38.}b:�=y*�K�J�[]m K.W��Bdegre��-�tiF0microenvironm0a|"z S<z^�meBLuY&�E�Xj�ksta��-R&J_%Ew7�P{��Pdi�c"Jb.ue��Pk[ ned:A��IX�Jf=�3�� )�orM�a 9 !9o�&Q [5ZA�)ni�y? (R �Fd% } P�v��"�Hr6wiY6��*-[&+hc"M_:�ae !}[5yB�*&��i [�#� (&2'u prob�*du��T";~or/�El �r �<Io�+ &s �:�3| *�A,�incubGn %Ga&�32k\��2g5n mb�^&B!Tu�G.�aQ�EFo�� JG[5!4]��>c"I a/Q1�ѡ�J��)�1��(p��<���xg� f A*�2 adap�? �y�"�j"��  K�[5�5I2� !6�n�P� w>Zp s ��e�inC)�"-�.�7��Wk� �6\� � tuberculi� �`A ry�G�&�@Rqi:bPp24*� >�%�}!�24 month�T�*�Mr2�d>�!b.�ef#1S`E�� " "�*� &m �+� �&HmanneQs"/��}�u3�&4E%���!2�!,�nI �q,e�]�j�0S�0S�0S E� �� �!Kv����E1K�, attY`�p�2chA�r�Ye� us9���q$ s [5E�5B�zl�vA�ae�;��ad\Ą�yf�.�� vacc��+M|� �� F;nI���"( E�*$7�� ie���"ed�(2b>FL)OIK-�E"#er9X ^ [5�Ye�4� mp2J�@ .abrogN�N�l8�o�s� mena . B*Yc*Z !��s koe��Fr*�b����;�_AN"�rxa�J�{���D c�c)��BP ��\[1��59�-� &? repi���-]&0� ���lih� Adut1$���vsI&\ �{[f��Y�d�Vtiv!�IY`2l�d��romis �-Q�>� IKsIu  ifar�e�?�o62f;IPDB�5Z�h� { aiT ofA�-���4!Y��a��let�  %��6Mor2�Q` [6� &G!3p�* poss*ji �zX�dP�:%�p�i�&ua� @�Y 295L pond&� "&]zterl ��a"�!��  —ba d�\e�%�tEIaAb� chem\ ��fς^!���3< �CZf:MOfXg� � IL-7�"k82�F� �v ,� &�4�Q��ui׽�"N c!��uY3�h2�-A�Aj��.�)�JEBI_ ��R6� � s�:E�s��N ���)�au�N�wayT�3"pk WfJe1E��.�.�'*� a���Lprυd-�]a�A�)�`'. B�s��UNh["(C�,��(� ,vClmc5j "�c� s 54�Z58 /μl; **�"RQ�J1 log%�RNA co�/m�yM ^r} �Cb|67|242��x<q6nq�col�e���Cn�IHj�u y De�%� enri Mond�" ospi7eCrétei�6FOh�=!�NE��\en9:_:&b-&Parasi�$D&e�MSof�c Bulg�9�I|&S ro����mu;j"�y-odF"�:#%ob�D9 Regi zo ansfu��ry Cre6�e�a�earchn%"���rdri�e Decla�zHelsinki LayI� ��Z�e�e eth�|�#itt ��wrrSPU�����9al�V�^6�K ~ini. P&Qmononu�,I��5�V) T"�9�8<#ar�adnf sAcE) techni�k. HalfA1 J�-�݉�=- Dynabead Q�ll�qeAbi"�j�9A� manu��urer’-jf� ( InQU AS , OslRNor+z�ThS�f� onAMa�61%�V2E+2ng�"��!J5N tA� crip����As veru? by fS�wmetry�8"J�"���!`a�� e�*}IH�!c�%��0 ~�q>EYfrozen2 f|� E,Mu�I!k}":(Miltenyi Bi�k@ ( Bergisch-Gladb� , Germ �)mQ!<� .�'�< stru�&/� �1�!O f!�St o fb>.� >95%a�regM�e8�.+%� +CD127lowq %n[�!!4/h%7� n5)�fn-5� ))G� 1I+&-�f��~�_ ( MHxar� b��0Eugene OR , U�W at f]/A��m�CK 5 μ.] BL < 96-VU-bottom?.�V��> g/mLq�H3 mAb ( UCHT1; Beckvu Coul�A, Villep  ,�o) ;"0b�:��25 x 105�s�x �Dme 200 ��!p&�-� 1:4!�R8%�a�On-c <D�;�mwa��usurface@(i�k%a��b*CD2�b8�b�f/mk .�ILE i]�] s:�-+�+Z�, N�LCCRQ:)�l2,�$ M'- E'� o"@2+*�b5�9~�KEEB* E%@P2�c-J �"T�;}�*�d�,qd)yat!��l�l�>FACSCa�., BN9FR`C ellua�L!.i: ( ICa.(]s*�)�"��(�AU�Ui)A carr�g�;�4u'�8y ��3:> �a+3 �VTi,{whD{Gag 15-m2@aW( 29� le��� a28%� 49)tiboda ( 1Cof �!��0;ol �I(*,!��z�( )&YL( 5 �[EBCUld�pa�ga�))ad�1h�� �2| . CeV���in)�:�\(��ntD6�+ ��L1a!�� perV e�PE-Cy7S FITCQju�d,+)QU�Ah*t~g !h2�4( 5 ×��I�/�N) �6k48�kM@>:��� r *JG?lׁ�Be����� �XsaRaa�io 4:P4%&�A cy��(dR �. )�v��9B}%mqb1�G~�1 9f.�b�+ 18h  !F�A�9�e!�&�1�,�a�����*\>>�!X �����!� 6��around:e�iE�Ax_!at�ok�e�#h��DH�huDharDo ��Tcold PB sus���bong bu��LE� na$5 mM CaCl2�B�2�zxin V–aF�C>$' ;�� Phar�^en � c�nE � in 3{F� �kep[2 ���25�-CyJ-�@127-Alexa-Fluor70�| 4-%For PaqOblu:  at5RA$��ZoP_j?�'95X�<3-AmCya�#�dg�ae��lf�Z�2NE�%ly��1_A)���V�'�!�r(�Q�!�+. B� !.%lmosqui{.orn7a�caeDby^ 6�ortimori)��-s 1�llY peop3�73Av�I�an�* 1100��.0�?�&,�[�>[�"Be�IYe grue���7a:�0�,Y�,VLi�n�W�9�~��-tac�2o Io�.ʗin�]cD S��t�t�as%�sAd� �)t�pe� �8long-� dis: . AlvXB[ll .ti-�`� ��s)9vK�&7 � ŵ mass*H !jne�[d+t�3���&9Abe� �N28s��mis�[3]iG��a�8��V91�e@ y�� /kve�4V%�.~��>��a �=�r,�A� �*:!�.( Ied5�? or.)Yj] areaAJrefI � ���Tsa{&�P{ �9r�E��lp  ���"! bel��a�e��w[�#.%,�0�T1Y�V��foc�pvPif�<c%ϓ g��s �O. E*�Oio��!�nK>� eU��I�8�pe� kez'��cE�y�(+ �fi�~  ł�!v-��ɩA Th�!�- |ic&D>s.�%��h�� ��ly�  $�. Pre�5z�a ��N"� �"�s) .�[��^�"� Viay ,bo��&H?[5] X6a�`B�0v&*@&� / � r�r@ l�qM"I'� vo c"��E"A�!�-r[7��'B�l]AIMdA{�� B"�?yba]x)�i��e1��8u,i�>�sO�2! = �[m���be  dama؅iTb��*�E�IA�DTs!#g �)lelI��aI��dm�M�%b��sQJ�q�s���e, SOD� atal�@,.7�s*Dpe redoxi;�9]1�b�� e] �ՄriWAp,!@y��5e�#RO�attack��!7�Gbra�[^ ka2!)i�-(ə5 byIi or�U� �  JjsQ:r %���f ��uNE�tAa| ��al�(minth5�s(�&�M!�aj�Ҡ�B�:m� read�`en .B�[11]–˓A�e.u 28�suc�fu�7���p/-T& S� nsoni�E � boviG��i�8#��s�(�C�-o nfe��� !)Fjgm | �i�� a7�&�I mfCJ[17�Q́"o�!�H)0�*� 8Wategy�Ei72�Ace�E��ɻμ.OQOof�EWF a gU����26M��,eriv7�^842n�h���l[1��F .Be�f.oGST28�,s*�\s�c�h!(��e�2�2���Ni� �+_u�/>J�s)=.��a dA68m�i!c3>�F!��al�-�!O�-Ba�on � logy5s�*[19=Lz&� e 3DANucK .*�&!�o�ip.siZ�docr/M��o�2[ new�roa�4m�� -RW ,y!2�u� sR�)��u�0� tpS�� mZ" U"� �s"��&attemp%���.!*. *�1���Ls3mf d<�ma��!fe)�>�B�(,NIH/NIAID Fiք�re=� �1ory7%er/%�gV�n� Medi6, Uni��aC!�eor�, Athe'GGAB�,7 *�+A��F"����*���i:�+: �cEnd?} �"n�o a�[,�@>�!c"  vill��.� Seva� , Wardh�-��ai�qay����d.; + S -8>C ixA ( MFe\ [%%� &�@s}/c �5*u'���,smɵU(�@D& ( CD"�7�vi�.ng%� out- " d�,"E/Kas��a "A/!@%�� A5�.mw. Non-"5�Nt �a�6X:@u�P grad� �Xd��e�c���+om%�h�ag��as Hima�� Pradesh�Jammu &� hmir=�h)�)5�ci�<��y�! n�!��$f�+]I�!q�yɪ ���IBj�d3Hto Mahatma Gandhi I�xtwYD�a� al S= ,Y�. U��u#:A��s:�c IRB!M�/�(2 Bio85s�-,�,-[!;-6jIllinoi[1Rockfo�[US�nS�/.� JF"7)j−20°َeezeriil�X�ab��geL!mpl��� WbL3.,�A�insertO �c�i�ForH��: 5′CGCGGATCCATGAGTTATAAACTGAC3′ !RdMse 0/ATTCTC'TTT<1�+PCRE�m��k%a��� : 94��en&Z��30 !U5% g�k�mne �%72 F %�`�%�cyc  s; a�al7ofO%i '&�(at k. ��S�7b�@'��di��ZBaF�~Eco RIF [i�"dz =/AT7�� bpRSET �)I&;1 , CarlsbaF8CA%|I)�<A-n di �\=�W'n��'h��i���2oY�J��p30u� o�li E .�3,i BL21 pLysS��1��.� EiP 6=<ai�-R�gr��$o A600 ∼Z/6�cLB��um.Kampicia�/chloram,=i�at 37Aj!�) �!�of$!l� "u!C&8isopropyl-β-D-�!gal��pyrano�( IPTG )!Q�l�$ of 1�'(k "N'��7�D�~�*�3 h�. B~9K E�pel�;��.ifu��; nd�.�($phosphate-�(�a�e�4S; 150�NaC�6 2HPO,H2pH���F�.lOI��@lm&G$� �!� debr�I�8F7�!=�t�00 rpm! ��!% ArCo�7sup�;�`!^p�%UP[� immo�X&c� t me�3aff��lum]e�g %y�lon�5���uV��,i�X�s�be H�Zagi�as���"`5>�3I]�p r�"ty)�� �4by 15% SDS PAGatP�2H�&dine-tagaF!w� ���8"�| &penta?-HRP &, �&5 ( Qi �2alenc�8��Co..m m1�� BCA!�hod�3hermo F�SQ ��IL�/�Z( `%�e "�!��+A�8��ot�(� &t� nm!AAt�}Ma�co�.A�^l"�%� 1-�qo- Y4-dA;robenz��( CDNo6�NonV[�v.rW��ix$��!�E��r^ .Y�sU� �nW8�v9i��B>`"A�ed�)a��% ,a�) +=4 ���!�GSHtn�zy �Mbcuni� �2�M�U �Wamabc�yzmDh �!�o�� 1 µmol S6��yl-�adv:iy�,"�7�t�2extin� LG�s�(6 mM−1 cm�u%�%%�)t��u�" � �"? nd2O � o��scree!�i6oi�ay}�.�q i�4�+ blot�1s�6U ELI �/�:0,��1�aa&( on��-��,F� to n�@�ul`�me���y/a��'Jʾp�o�C&jlyig dilu�_( 1∶5��SB�%� %�MF��P�5NhJJag�bo��=�%�p�d l�6 labe^mou�-: �&pS�5!P6> DAB/H2O2 tmo;ic-)A�*K p+(��)f�)S�  c�$AB�k&! g���Ai�� �"i Gv�ACAUC�L�A0AUICM ��K,&� !��=#BAn�aE�A s Co[( IAEy(qg guid��6$+��urHe!��w� `��"|on ��ZCPCSEZBg|E ve 2!��O�5(male Balb/c��eIPiRC( intL rito�l0���$y �r� !no�-�O-cG)m�nX 15 µh7��ѣ)�A�a�µ��5 M�6��g AK�l�=a:lumB.Z@u:e�jui� �0do�0VAj�eg���^Վi�D val ���Wbo^�L�zg6Utc��1��*!5) ( �� �/ � ��cei� ��T8h^�a"A��>2|�&r�.&w�2"pti��^y���s| a:olsi��?"�sHGmm+� �"� �����k�*�L3e�lC!��B!�F��.����)a%��d ��F 2�� abov!m HRP-� go��!3�!3�� 2����%^��-�C�'ye���!�is�/A��� ��(�������<�/NE��%- kit#ch� �F�.�*�>%/vel�� IABTS t>0, 2′-azinob�3-ethyl-othiazo�V-6-sulf acid )� !�absorA2��� da�405��-P��� �i.M7��%��a6�!ZF�2t*:'�ve�#vae�2, r� i}�.o( A�B�)/���f�E�)�/a��*�EWE�E�i}�6�&�at��^� A_30 T ( s&,���"S�-B��(�&�&�4|�de?L� �a��aG agar; ge�];I�]�.�(LŻE�� ".� ofI .� �d���=� e&� ї coup� qJ IMACui��"0\&# 1 m��his�gedPaGTA�N!�� A�n�ec�Y!!"7atw��s�D�&ne��r@SS:�.v� �%�2+=p75�.L<�6�=�%X�!i]I�"# �>�G�mE�7���� c�"NbyxF"!]�J2tp**l�n���u� A�����Y?.�� � . >�s.�2l�&�%�201�E����1.&.�four �9A6!=Q-�F�Ge&&s|4%�( � .82�EN2B�~i1�"&� e� "#2��3l��b;A�( iv )b<.�~:�-Z!OA�d���5�n<Q�R�3%4y+�7%�� 18(Aq%e)�or� )�Lpro�'�"uI]"�&| K"ST�%�&�5RU�^meqdu}by o�.��:� �->�14 µM�vA�2 h�$��_�rs �B-F c vQ��YE2U�5&�*W ��u��&�,l*{ M�� A `:�7&C�q� \6i8^]��S��Q �J3 ?�E�i|EZcEC���YvYE��:�.r-��Y���ai�ga�#m��A�=Cas9h��ddA$�13 L3An=�to�Z�G�2×105F� exu��s�( P���f.�B BMC'�4h,h(>�"�Nf &�. A�"58,Q���%b15E�qe5�� RPMI 1640l0d�o1=���v�W!� 3!{ZT&� 96"�i C 2$ )���&a�48.���5% COoBLA>vi�u�d7aٟht�3r�%e T� m��.AK5%NlimpiT _�F�� no m���c~p s_-�le�i����NX�!�next 8 XG���r Dk dead-�l*h � kŒ�W� �8��%�ʅM���42�Bd�aGe��p�,r^�&,R!rT]M�achl��n���"0��cD��}С�to���r�AS�J.�؅��)$�}Z�*�&l��F�E.2��b�10�Os*�G{&� aM�Wcid� �hz$U,�C�MN����(�)&# ��`y%�Bm!2�)"��aNim�v]6�,:(�(f/A�fac�6-�&7mor/�=�Aa*E��99.C.zF20.;�`b�m�euH%�b�2� in�V��6od9#�barbitoKThorax�abdb`ile�aXo� �i�+l worms�9�! ca<0, Tpheau�lu,�!V�;org��"�b�as YyT�deR�l�2�G���=�;l XL STAT&�F�G7� . 2 ( Kova� CompPYg�vic�A��se� UK�S& H*%0c�4}� #t�s�&� ���G��WlIic !E!DesA�"�&�0�0k/tƐ5 . M�Qp�^BcEig`e�L amin�iduCa-fam�u�' 0-�6���;�Re�;n�AY195867��)�-�UG��J+�X(m�,>cY127887M$Onchocerca��vu)� ( Ov�B8L2877�-A�Dir��iti��DiR:P46426%�Th� e �,� g" J���+t��bM!z^t���F�uǣ\AF� j60hojm2��shaz�98%kw=E �79>#O .92%!75>'D .5&+ ORFA �$��'I�"(B�G�$ %?\Q Va�(3:!�!>2Jp�'7aY%�}eV"f 28 kD�DS� )�:T�t)T-d >�� g% coli�� &LC �.�텝&&���& ar u3gen�oU@0�prepa�$g �,%��eJ A��.k ��"AC#"��O.E�]�>m ���tBw��. 020±�059C��n#mg��1- �1IUEST�MbBl^2T4��s�wq��{phi- clM9A��kv:%�exA �L�y��9�:E�"�3��A �d�ud%�:f�?ld?i�9�yc$G  9^!Y Phi-��1. HumorO���d�to1H��=�b� se� :1$�7:!$&��.�$Jt@F�in�EN.*�K�F4��U�=�MF%Z�Ku3 �o��E�� "�&y�n6�G"�.�>��&%�V�(�0���BE�A����j*�:�A�� �k!sn:*%Z�`7�2��B�J���5e� � hew";?� M6��%�6k�_�MlA��i �&EN%�CP2c:y ly eՇ�% >�Ig�!�� )g��. L�>5!U ��}/ E5[�a�K byu3�.��:3e�� ���&&eM � y tik7*�#  Ra!�� eor �!:n��� ��"x `N&(Mp9 B.m�:y.��e.ݫ�;#1��!9Aaa[ -�a �ae�93 � FiR 4eTSg�&3n�� �*�J�in�W�1by c� #Cn�E�aNHe"� \��+*��6��H��.M�1�bE�n�q 16mM�L3 ya�;� y��_���]W1�D;i:j&#�+ ux!�*�N, &� a&�a� &(�1_�!�R.e�$:�A]e Y4.g*�lLwedm�*3 "� atA1�v.4v�2�6!�e��!�6�!�!�>��`�.�_���!u���6 .�$NEN or pre�O-immune sera respectively . To determine whether the GST inhibitory activity in LTof EN individuals and .nDwas due to anti-WbX hbodies , we first depleted %� ific..from .l ized mice$pooled^�using r h,protein coup4�to IMAC column . An ELISA analysis confirmed that all��F�were com�ly���sa"\s ( data not shown ) . D%ion!sVgVN}also �8by western blot�R{Th!Wt!��%�]$then used M!�enzymat!�ssaEhhese stu%��e->)���EN vAc��of>resulAG �removal*�e N�Vt �a+1�.56�>@behaved just likeM( NEN or pre2�suggestA�EEA V�%g(potentially�(ponsible foy�%v(e neutraliz\u�$( Figure 6ERPreviousR�e�$�m�hcan kill filarial parasitesAT$ADCC media!}hmechanism [5] , [25] . Sinc�\appearsaobg$ important�EUby%j/�)`8toxic molecules�duced;��cellsQhost [26�we wan�$to evaluat� arge-�e�AI with%6��!* be lethal5��ore�AWu �i)�y��a"e h�� olog!� cyto �effectsA�E8�� -��)��had no.�.�Qn_ �bil-N ��(2�Similar�x ults��obser��w�av�- body-��edպ�Ʌ� � ��"P���pVA BMC'�5L3%pq.89A�4%6+f:e�!fp.7rM�q�l V ( 27 . 126�2e3I%W��w� ounA�atF�5�5�-����11� ��f� ngs t�����b �2� I E��to1�e�(��A�[ ritic�6� vaccine-1��on againq ympht ��� in�% ions�o��!���ce�in���a�of�Kby� �e%� perfor a �ao t!�,challenge ex�m�^in jird�,en days afte�la os�e�iz W, 7 edi��uor alum��eq� ,100U�e . O 120 ,-0ed anim� Cautopsi��./ !0,worm recover� $Mean adult:in��)$ only 6a\7±��42�Yrea# ѹ 0A�1,0 ± �C24m0s establishedU�3e�Tc diff�ustatisEoly]��accou d about 6n 44% �"%�iny�6��-�.�th!�� � ���5� GٰD-S-transferases arA` tens�inv^ gſasM�e� dida� q9sever&� icMe6([10]–[13]aB resA�  ,scribes clonm1i� gene�h,cDNA libraryaU0W . bancroftie)� Dits&� �q]� in}RalM� mode�a��ll* huma� ^e�� � p-9,���:�our�� � � 8q�6�nfers2`J�ay�9� I*��8 �P �ly���natur. occurr�ᚍ� ��in��.�� ������&E �throughM ��m"� ..��:�los relE���@Ź�a�tigenic �flap=�of a b�1searc��H���y]�(has 98% homU y-dL � 9Q=%A�r�q6:� �� �t�D" ._�2�cross re" E?=v^F8Furthermore , sT6� �e�!q*praba�tha2 .in._ ��ldIedecid!Yo tes eA� phyl�c}�of�� . It��pr$E��s�(to maintain:� life cycla�labora�,ref) ; *� weo =K��6Q��=(. PCR scree��!��a�of�R��stage�6�!�!8:�is��resE� ��ve� UA� nce 6� �vb|a�block�  on ,m ~�o att%�v.c!.A5ua��!� =�. B)��* �sd��A� �reA�h'�� A8� 8is!7"- becaus6�s�� mammalian�e�2p ox��rad� � By6%nox9ubstanc����re belie t|I!_)"*{stA� u&m A5a�tqJ��.%&e6#a "� �s���prered%��trematod%{E�S��nsoni ,8japonicum [27] ��F . hep!�a [28*Inter�ngŝ_"$ �5�(� 02 µ�$s/min/mg )M�� A�� (5–20% les� a�!.�(Schistosoma Fasciolaws �� ame %ơ� .M���"� belo $o Phi clas!� Phi- of Sm28�,:j26!*20Fas�Chave low�12it�pB"� *� ta %�k%�� might�_l�Z�U���typi GSi��l �a hpec�$9�.FF)^all!bse>R2>q0U is a�T�fca� ��� ����� !supA� {�!7yF!�B&.��i`�"~�r, (M ) car58�toM_��ir� . Major�of���� a�ei�of IgG1A�IgG3 iso%�-Q� %�(cytophilic   �may1�predomin^ro�]J� taiI�M ��!�.�%B!m}*�inc� e�z�� IgG4 �CP2Z.aano%!�y mwe "�a@Th2 bia�R�on{follow!,2� of�v OvGST-2@O . volvulus [29]!~rBmALT*U���!�% :L�z��u!*�=�ly!1E�%�!.P�[30�[31�kA-i�s-4Ird*� E2MF2gI� IgG2y�dG QQ�]�l.ly a Th1I�1~ 5s &/.*� resi�\tBBho%4b5�J"6�. �R2�!z)>M� M� Ai�V�FF��!� capa^to&I6� funH. How�e fai�M��%��� of��>��1E���orE�eI��a�} ould�lp� y"Y �)P-$ y ti�AH�optim�4 maximum�I� ���orS )p�bF� �e:"� e#roximatAx50%dEek. N!]the:Q @by Morrison et al�Q�I!�re��n� r�!�between- ��a��MP��J\; gig)ca�e�'Y. Yet.�Rathaur���A�3 at� cerviE�)>ba~� %�� p��v��EI V� � � Ba{$d Das [32]i�demons_ z!:-  . digit�GS*VP:��.mɔD �6l � ti-gm� 28iIg� ���* 5�R2�5Cin��s"_ id!�Fimpair(\hatchA ��eggs [17��TT�A�*so�� %5%��XA�2;��dverse:���"t�if6S���w��X8I ]�,�~* ��Altho.Ks�20a direct meas�of6\it do� vide-"&iny) !&� ��!� FW�"��eaA�a[)z�a�FE!�particip>�=D!��%? �Y BY � �fir � is� �*e&� fac��fmVV�e�!� eli� a;F�a�f)�{�.�Uv�!ngJ �i%�� �*� �-KY� cruc[!� ]n�YjF�� addi%E���u=�-*/�-�u)�L�L1��L�]z� I��1��^�,c*-"Ry<Uem�� ��.y�%0"%we di�t�]O'w*�#l9f2��,��M3�i��s���Y"���*e :�� *u �e"M�ierAN&6 u��arUap�nay2�F����We) �!to!lic��i)E�{ng � morn"i!e V�%qe�kv9�(����a)2��Vs�� �E�'�F�2) 3�s�)ndf���)�Á��9���inE��survi�'2����� }Yid�of&i�orE:�3Giv�  mJX�o!'� r�IgGv�,��$:�Fcγ beaUY&h helpr��J�Ea.CME]m�admis�=�xa!se�doUm�� q+d�"%�"$=Kconduc��y*|&�� !�m�I��\ stea uba? !w�%7u� �O��&�d femal� C jVa� U�s�E�a�%I[C"� ach|Z��d" ��� "��b� � H�n��G&�A� e���1 � 2�16� 2QFa"��uP&� h~� �  �'A�i("ree��� K ��!$f*8, &� �[21� �'26!� Q�/*s�j�s�-� G cerafminth& A[�C� A�B clus� 1ne� eJ��&� *����!On endem�,rea9.[24e�sA��z !�L �'?)� "�)%eex�1%h��"uJ . .�R�a%;fe�,otmb�V���*�a,�,M�u�5�/velop I�.�xB�$.�a�� $L32B ��.iZјi��-l�Z�Zi5"i b��j"|+!�in non-� �&��ah��ve�T.K�CRISPR-Cas9 techn�� ��"ormed�ome-e� nm&���.rgai-M�Eimmen~herapeu�"5p(spite2Gadv�in�|under���Ai� .�system ,AQ cern�mfve�%s� off-����Rec.��add��a3co `z whole-ge! sequenc!( WGS )��%0$ed embryoslae P,!�$de novo mu%*'( DNMs,which��reaX��t�.�i�$�+by|2r 1� fideb*. C�'66.u�) in-m7e�`but�� pedi���)��6W unT reliabaZ�%nguish%rE�E6�2 ony-�ed"�c�{h3rue) . H�2O a tri 'sig�x�C6� ed 8��ent �195�,'10!�AZ1��!��"!ŭwell-chaCergRNAs: coat�,ur Tyrosinase.$Tyr ) locuAuDe^�3� )�E]��3a4 ed uE8A�lud�at>i�� ��A�SNVA{ inde�2u��Żtrg-1�number-&se.8G6�'=�E )�$he backgro�+�of)�&%�5�roc�! s . �����������������[1–� J�I ޷( i . �A�pa�$of��ed�.spa � themselveM���ed&!].umx��assa�.eact�co�O varie�3�a�(ac�)k9� of��ic�5Ta{T/"� �u�����b�bv6 1A �8��i06�6black2�!�eye pig� )X$in C57BL/6#[4� so 5+disrup�Y� ��b�2tr{.al mS)d| _#e c�,twoBcexon �,2F�Tyr2R!��395$1 , 502 tou�ic�i& )A�; ( Methods)%heM-� ��pssplit�i� d�ve�@0�� �fr$�hil��ree unG)-~eac�5t%� �s ( “� � ” ,No inj�on!�“Sham6)i� colle%1. MicroCm�&yiYalc�! lasma`1-� zygotes�8� �SU�l6AharY/� tB75� ( S1;5)%7 ic �.� both��!Y�ext� !;S��@ `9�� Illu� X10� plat.  yiel� aa(�+"" depF83-55xY �e��7S2�B� llel� �!��MiSeqѸ�AA�no1Z2800�,d�!��D P s� 6�6)mpreh�&� profa�mosaicis| e�� � �-e, h�\�I�8 o en/ &R4!?"� a�d�an�ousan))*Gs�AAaZorldwq4� �2* R�)al�Phenotyp- Consortiu%��?�:�%�to-te324a��  6�!iRŕ ,-�m good�� cord��E�=�an9�( 2W�xt=�nt �.Jm|e�Ibd�b�ns�)�=�)ede-f��3 �Sinsers/dele  )q�C�-We ra�e.h!W, 561�%�3!4}C"q)(-�Finh�:0,i$!� nt )�An�Хo!<!ATrioDeNpu�8! ə�G2�07 , 460 unfilY,d �}6.!^. look�@�"�7s��6G!3in 10bpA>a0&�m-&���^A�F� @�CeteND�?�Cas-OFF!�r�9]w upA3 mis��<(a 1 nucleota�0DNA/RNA bulges 8a128�6a:..:D�/ 0no such coincZ��!1�%���& �aZ�1on� m>K:S 8 ( S5U|, *I,_�e+re�+ � :=�aA% |ey9excee�� ly r . W�w17�2he*j=�)f7=�a�A0Ni�?a""&�* d 14FiA�� ,� ��!�*B+*�8�.�%��E�0�&-%1p!�:��5,2{ Ina", gQ��� ��of ba;at 3(�"� �{6`&A�d� ��� to)<ap.�'32q �$?��:P�qS]"po�u��d���;Gl�+>� h2higHa��)�&����)�i"�g0ord�magnit� ��W ���origi�W�<t�� adeq�C� ( 10xf aqo quanofv �ll�pD�8�?ac% (of 225 , 67V&!T..6 , 852.��J�( 489s /7450����2~� applo<�l�3��ilJ(�* tegyA-ref�IB�s�:�mov�fal'4EMariŜ��퉅�6�,��� i%�*�/8!ea� AlignVs�+!�SNV � l1�� E inj1� visu%7�hA.�:�&O a se�� � vHClen/E� �II�waH liD;����� move"* >X.2^�1MAW1-� �q"�= D+�is broad��GsH�� pri�,or�6Z&i� B �3-!h�4(,%N>� %� miceE6!�>�vU�� h ed� �Ai i�|(t leasti�0" �)� ( S8� &� n 87%yA��EUO a 73V#Eil 4isi e�� mpar&S�Ak}!Gbs Pro�[1���'�8��.(lob��A�A|.7a�  �� ��9��t( �1iT�5�N��e�c r�iAD)pa�GL��#Cm&�)�� e�by� AKf� ( S65�N�atAp2��.W�pipel�� , 18ialsk�&S � ,�F%#ng1�ha��&^  fr�7%��D5%��d�O� �]ԁ0�GreDS#� �$Q!�2�8 � e-]��damage � a ra,Ca5��Q<�;��ism.�'Jw "e9�-)�1�B�is�28.��OI� c�/�M A�aJ<bus"�*TMNtwo����; . �%!3 ��1("�E!inR1!�i���5&)�y!�&L,BU�pe��C%� �_ �le �J � � �t1&�S<��9m% . USE�f�;( ��e֕ԍ���r-:�F�[n�%�P Kruskal-Wallis Rank �.,M�arW DNM� "�1�n:�� sham*�c�  &n �� u p =Em30e~7�>� �ha��Ia Wilco��Sum �&A4m}*M  Etq-!�%r-j�Fۡ�R:l B�2�43��B�7y<$�A��Fig 1De�Embi�;�� � ��)~��!�uV��Q�amOy�2 Y��XE�9� � . No�FF  ��=��a.�:� S.Om@.�:��>�;5�:�4 �7e�Ply� 7��� Ŏ�1> �unQ!s-�# -{ Eh���X#"be� ho� �)D;�-ab5�.4�/� :�study;%�mk)� ( CBLT890�6pg�  +gen�/1,Ef Ra�S1E�a�PJ�saAHl subse���!� 91Uǩ!by� p�o�Ŋca����rE�a poinQU�*�o�;��66)�}% WA � , S9U,lc>�a2nI-#��[ )�%�4&g*A � F�&eNt�~x�Hj robustnes[� n 2 e re%B%�f��.�e� �%�bi6 " w3�3c1�Z�G(C%�����w�CaVEMan[�*!ץX� cgpPPIA'�0��Vq �to *�%^M �O% V�)�� Z�:;qa� r(ll�utput asub� �a�$al�SA\eE�"� 6<"�5ud+%�22��:� 5�)br(se:/q$�V7&Y$�deJ&�eC m�( �7Y"�&%�EH{acS a�I*��0m , S1&�.*�; ID0 fL ��A��m�-82(�X� p&�*F�����B&7>&v���%&�3)E��~5�� � sc)LdI�caiu2��9�ᔥ�&�(� &� &2 &\~shs!}.!2 effoKIs v�+���Ma!6r�*Q . F"�@E�/2b�e S# ,r Institute �, Welf� and EthEHReview Body ( AWERBW llPcedure!�re=�atKlc�:Tr�YBrRe��SuC Faci{IH<$Office lic�+dHPh�B, E�O$ L# ce N�'X3A0ED7�P� Fc"� P96810DE8���45�*A6��j�C�0�@Y�c"6m� e UK2�regulT ���)qa�StEP5()Q ) Act 198�PJU#( N %� R )��Nf#iJQ$gen�Ka&rs ���cus 3ade�Y�o�<fl1,e�L�.i o*\[��$ wild�A( WT )"�$( B6 )��A�bi-���Z�~!�%����3Q�te lo��2 %( albi�- ) %a��"� ��b<\e.us)!�8 /i�� !0�asilyn\�.1gd42�%{!F��>e�#a�[r\} � [14CI toge�E1�2F�� "��(ype�"&�4scoa�.ax� �MO2.v�m��!�.defaul�Y NGG ) PAM� , ��Sre>a�moa�d ( mm10 "2���� N��t J� Scha| s�#4[15]�FVB/NJ6�,��P.2F>s:+ ilstA�Y�tr� ���>� �ec � �! �G2a�[3��ee;�}1: k *9A �KF�!�!s���Al"�= �E M��Rg M� �Ee&g"!��?T>�82GcF37cut b�!R �at 50 5�g��� �\!!�8� �)� c.(�FF0 pup 8�#dEM��,f���b�D&[0Y *`?e�.�&earcli`a&�&%�F0� s -lvR� 3�nd MISEQQ�!�� ��pZPZD4%'��2�0�DE�Z:� how 4%Y\Ű"( W2� ach P!er&���Qmakeit}�G ��-hismA�� tr ����eOe�eh)%��"s �e]�E�!�a�m�a�,�79GEa��a�n�t$N. SuUM@�5��j�}�8 .q'FTX K3.�,>���of cra�A"AW ( SigmaC a dilu%;ng^� at equimo�^� I�*7pmola�%Y.i�"* ( ob�9a2%,Marko Hyvone`SDe�<� 4of Biochemistr�6Uni�E],of Cambridge�[d�"o aO �� en�=��!? mixt=E@&5Gat 25°C%�1arnu�YbI�� &{,M32m%re�a|,�or)�9�a"-J$a�+�&�*^��_��&K �m��!&�'label� e !Sn%�yT(�1g . ‘6�-� , et�,<ke �he�U� Qi2sK���Hto �Rr� �8�( �<. 4 x 4-week oldh NTac"^-e super-ov� � �7��b ( IP� �:��of 5 IU"�-mare’sAu��PMS -] 00hr 812hr light/dark�W,,at 07:30/off 19:3 X>ed 48DZnCan�Iu.�h�[cE�0gonadotr�Pn ( hC�a��F�9n�)�C71%* �jl0n�)mor�W�.%H%�M�A!II� a va�#op!i� plugA�e�H )sucR6ful@a��h�+3Q�=�L,m ')maՀQ]f��m�M. O�=g� diss�>�Z &!� a ti6Vnd�.e�cum�Pm�3 kept � in 4�"�C67zre� ��ndiX�r$hyaluronid? b '@F�*li�1���{Er .�2��E)�V�&� E%in��in KSOM R"a�B _q&at 37�_% 1!hhEOR�1.{�23�V5A�p�A�x""/K�(actfCmQ��A���)� ,c F12d!��oASQ�I�9-!��� ~,Ap S-ph!�. C=#I1#.�a�" 1� t&�:� Fx R.�"�QnF1c�%�s-poo�Nh�1b#pn7ag� All �&]2a�M�9a uniqu5� @�5� rib)9o%�RN�ZEt|:fi�e63a.�oneedl��9w"E bala�=A�06�n "N fbThel�( FHiumA�.�����B*HHvi� &�C� uH a�dbre !�Oolemma6�4 ed 1I��)L>�4A��4le-�M{� fe�4eE day�(PNuca�3,1� �4�bV�4 . ) �4-�)�ZF1]A/�o$J ) recipi >�DA%�k5*A4.*A%e ���uEF�1�� snapaze� P&s3U�f�7�;E�Vf, tiss�rake�d&- 9A_toѢJC!zFntrib� to� .4a�o=:&� �Hinvol�$�E Z�e��Aafg�!(h1at��+t �E) tb uy !^�w��a�,� _::."� >� ,23aE& -�Aof"1i��DSample-to-SNP kit �sbui( L�`T.UC�jr .�J�ukidne�;�5�or � mace�AJ�Q�� DNeasy Bl�3& TIqKi/Qi} G�Mmmanufac� r'�S stru;��d qua��:$a NanoDropU]3 otomeB8.�!at2 �F�-�Ng1�-��Eiaqe&n*z"&&�&�peK&�"a�te'E�f�9�� @!j �>�i h"LXE�""Wڥ �T1:Y,]�<2Nh'�)�a�.�.�$wchoal�69FIRalMe"V�<5R�&��c!%�qicu�+D!1H9ny H�1�&+�i e mia ����e��:�;E&#.zA|R�-�zC0.��'� �"Z,A]�&�0:�s w�(i�.�s%)~F�subcloN0P�"�Bt� �_e%is ���onH6]mm!��M� SbIa�%I:��kμDB{%f�� icone�i y�e�;��ep*�,PE_tyrex2N_FE]R�>�Qk[. flan� !�ex�$2"Ci;�� �  �Ya��!fl�jZ+�;Z~!�ю��toc48J:J;t.� ( Pa�)End 25�6 runs��zpX ed-eHN astqM es!e� k)���@es;e <S^'$is package%;. A�� comm��,%�0un2Mp(baA�<%5saA�p$^n�0..d�indowal3�a�E� D%�se�! I�U�:.�-r1��ple_read�) . -r2.! u !-a -w6' -g uO((�ce�!zt� !Zp%�r , 3� o( 30% �75� � g^)�2 � �fq �7�+!P�V��, 4 SwoQ57 �v ��gi� |m��� M����� ,�A��6inu1AF!���:8=In �6-o�/+L�>"�{)�]%�8"��!4�!�WGSU�:))�I� 1�%-! w%�H.aA�26)U 8s;2gF�g^g�5n ,E~*�B�4�:"�F�L!9:�pra� J�!e!S՗cBp_B�fA A��FERP02442�NAQR�Ia7xbwL8mA4l>B GRCm38�Dmbl�)m�PA��rg�*34xS47xAM� ���B(�+1% �m�Af-"ag. CE�ag&+2%,50x�39H3̮M�bt�11 J�%ad2��HurX"z:&T �MM��!w��2 �@�2,.�4! � l6e�H[e-T by 1" :dsJ%of-^  kTRw5d x^73A�%i2iA��nN�_"�22&#�l�R sizOTL<��"�2resolv|�*�&�`��wA?(18) �x�Yi.iS x��.Xl�@e��ual*� �n5B"J{t a Poisson6 para�lambda =!�"�SA'>'4B�y!�10Ak\*S��~w�CstQq���t 4�M,a .�� V4AX{hobMHof��+��aO� —see3ŭeH8^—E/tis�>� R fuFg ppoi�KF 1� a @r . tail = TRUE )�3005�is{@� en!"� ![�dpcM�gwe��>� �,�\PA�a�o�M�(� earl_^)")^-5ue�ig�>�a�j�/ly5�!v� zVo��ofMN? "�D�D,G.nor� 5f�C�D)���{na#. ho?u� a��� s::-� 6�D-a AD -C50 -pm2 -F��05 -d10=;� :�-voF� � -m -��:" �\ -m+ -sLowQual -e"%QUAL%g�:�ٯJ�F(64@Al"�= loci~)��o�.aAy.> 1�J!Nf�_"H . D:!W%�A�}>2by�� *>06�Fi�g)se+'�Y!�entlyi�I:ERW.MI��� �Ad1e�0b�?,.�pr�W-��A437;!�732*�����)�U�;1�9�H#B2:�.�7E� �I�B�8�Is�^�B�nQ�y.��))xll�FjA��&� �c eriaW &c��f6\B:�; )�-U�yuZ�A��$�%%��i��(1+To avoid>ym En lowo-*[J Q ��2Ib)'�6'%�HhGl Z%��,) !�6OQ [ oise8:� (�WC!Ly�yr./G |-� o�JM kNJD�[ f�@�)�A)4�%�I@gDin[�k( 4 )=t�(:��|^ �)&�we�Aa Qo�.$��%9�-�%�A�o� ( �] \ al )��* “cr]/:���A�S�D62/�� mis-� �of y&��d2e� � merg!�ll��X` UCSC!�e� racks)�a�R� Mask�9"0xC2Gb�"' �Q�A�M� VK(or 1bp adjag'ewny��� � . ( �0:�:6 sh�N� woa�~��y_7 b��wy�un. ��I��= L %m�m)��A>"X."�I`1�)Xe{� *].s�n�?< 64I ly 31Ks(5 Ev�1b�&� J�% '#j!v� on5�? �&�Faa�=.a��ih`r""( os%7a�I��/c�2UFlyE�A�%d�an �ʎ�O�S( 8��,A�.�G At��2 y susceptO2�JN#a.�Hun-annot�&es"&lo�ea0A[so�5Jomg:�)�%{1�stie�X.:w/<�polymu��G5K�byi�) ��D�Qc�� &�6�Ox�2�I�"6R.�U�–AGAA–GG�5QW��W 27� 254n !xt�V?ed-�A�!�� 92F�H 19 , 754;A'15g50+,� �:� 3^P~C9�B��#F��4K ��� �ed 4Z�T�$^vn�:of�D*-@524 =( 36�052m!�ve�b��Q�R��oU��O . 8*10^9 R:�u&O =�$attempts *.�s�,Z.? =5*>�/ � �t3� ; HVK –w1Z$7ounJFS!lap:*�RFb7mmq]_9"sidѼis) er �QA����#a�Q� *�#)?+-�',he null hypoA�iT2< �\Tyr2�?&�EIN��drawn� Q�p&y.P:kF-"H�#:*4wiAH$x| )zr,IN�Db�� �?�a{F&F�. D�(�Dsm�yL��1M�L�-_�5�!K8��e�Z�aRAJ5=(Lf�AWt�� as � Z�I(�� 24t"v_a:@ : na �:!R� z �(ur !�MQ-"�_]kSKQgQ2.!�a B��/-adjus�!*[ p-valuŭP1�?N.Ar��� M!or]-U�JC�>�R�q�kes�� *�:�i�%b� �� lly!�ll"�0��rN�a�a<- �  ~!�>���bwa-m4n%�"2 � ALsU&rUafY��loc� Ysam� �bE1".-d54-Q0 -qB {aU��N Js$a��91 s’o�J�+�on�|r?)e;. L �~`� g(���i��w& :B�!^2�1."�"��9+Vaoai�)e�F�r�B)t�2��*�nw8�h��87������U:~����2/V�2�V�ofM a maMreg7d1i&"�M�"J(�9re-�5�G)�� I��6?� yo . Sp$( �{�I��!��� hI>�o�� N0a6to �"�@�8IDi���I�!DŽ`c{wN��Q"�&# ? � C66N�by]��#g*>N�equ�yqm} ~2 r�v� �2( }s ~76f�9�MCLBT871FC� &V'�21a���.aE^*<�cE�J@<#j^!x2a�>i��aI��*6�Lto.�arer�#ur&wL.���=I�-s�|�ay,�JY5e�ll .asteps -nB CQ��I!��&�o"lU,"h<��-: ��{X e!jc�VctA�1[%Щ���I\ F�&��(Kp of 9WI5i�� 7EA!G� 2Am l���d�r�,No "!8�DUSBk"%!�.mT�)d{-:��2�-� �e�Onle�)"$&&X 28B��?2Q.�5BRhis�*�DcXL;Z>A&&�%, vaf ,-�5�I�%BL6NJ/NEB1�)is.EFI,>&�SCi(.�QMa�t!ȅ_Ujar܆�S5,*��N&%Ff=KAU6�5:3}qnd reׅc �9c�5to� ���Y�A�N66.R�@O ���5� e��&��^�P@o�Ay�$�n'>�\We&E7��a!eaA�tumourQ�")� �)�"al)���.{R� A�"P6|R(A� odif>)�R"�#=sCA!Z `�85�d3�00 pas%O���F�i�uwof ��845-an&dQ2�Cavema�@A�.�,�3iV�m_i�BapZb!�&����h.�"� ASMDie� E'�sc o�O�� ��M )�"4 !) RM�� #aT��I �PIaba0� iv��aC!I4� B� �V6�" ~K0�A�U6\�Z5 �� ���� "� �~S{UA�s/��:�O.%; �A�� ����'�i�k��"�or� I� A��JA7iM�R� anyH A!�f� �LexymedY�inn���1(=�6 0s�Ad�N $aIUe���$ + pane. i"A�rf��V , Cg�V2|-M4�116� u��K� "<$a�?.7�"�.�Tiv*' ,�V��JQ�|!f'3m�O��( �le�Rh .>a���ij��I2�¸a�Wa�F#Q�yb�W�&�:r 1���A-�A�Q����q ^ I6!��gAgRNA–�,� MD5639a�� 42�?&�9G z��96aQ�a� a�Bd`F{ "A)��WeM�.Pq�nt-���e���W�!������?"{ �b@I�a�" %z> �"�gG�&xA4� 36 3a�I�� 2aA��P6SR+ �ll 471 R9 �Ad*�"MYY .@�kZs_Y�8�.313"�080 �u��Y2a6h�X6���i.g � 2v D��q>� A�fy5I]a9�%u�22&�0"�0�����wo^�3*�� mUy.?34%%��elso�iO|�"* .�a "�< �#337� �r�!Z� *� u��*�38a��&+g.l&�eU�-�S @%w�=��b�orZ��S��:m)�SJka���M_��sv�2 �(rr���.�3W.��7 &" y*�[�+n*5p� 1�§. �Ba8!6c�u"?{%�R2 %(ޅrou�E�&�d�2� �:/ ��`st�p�W�\��~plw3 leaf epid�V)P�Ye CO2 up�DE�p%BT� ��H�X�S� ��pi|��iU � aper�B=Da24s>b, Tc);c;P{agr�@ڧp(l� Bcl�LrMo�enviro� al%L֫e��A�e-5C�,.percei1��(he blue/UV-ө$ght-absorbA$cryptochro���%DqCin�%�ig� %6`E/cascad��<ink�{p"of �� �ope�"W$�%��&��unknow�)˅3 ߌ�new!y, HypkrnB to R�mnd)g�GHRB�PbV Phos���47 ( PP8 �thANVJbiR�HK�.�ԑZ�BG. M:[��� �oryl -(mis-�!h��FU�ج�fEE�u�%�-}. B�?m3�ak^��$A$guard�Din9�* L�F+P�arkI�EB`Va!l1$� v����N-ta�AVZZӢ zincjjge� tif��/h�66alO��K5BW. �ie�sphory�in vivo-���depE ' =D 9�Y6&�(�N�X��lex!�193 kD&�%_!1 qa�)RTi�:$to 285?�W!�pp7�V� >$ shif�Z~BI�)��/:�t�,2�d� prop��f�$g<�Iby%'B^is ]�nS5�acquixVe��*��DVoŀn�Le���Uxs���I<.���M9!j. G]�q�B:�66qora�a�stimuli �q8�[ڐ furn��n0te�)9�(���6G njoy ����N8� �,�J�snd ABA""y�#I-pŷ-�E�Jels�Phy�� ( phY�a��-r|Cx k far- i�re�,orm�  memb�Z in ArabidN�� phyA�phyE [1j�2]%$e ”bf�o �de-}n, �odic f[ A'I�circa�rhyth�NC2�(���#._cryTFcry�!y|� flav& P%ϭ�e&cotyl eT��,��7B� �U���[3%84!8P��l!�o/.�!� � �h4�a C�Cs�ge/Aձe kJ�dom]3!�Ued LOV�)�, oxyg Yor>�A�-�8ng?�9LOV2 m�����$��us:�–�F�8.�c� sY�� +~ �; ���t)s��chloro)�t1 h:c�&�:!3 M]RJ�s�o.�cap )-!gv�W�� ��a�5dst ?J 6� �AҪ�~�o as]��L� elev�0/ l�fa��humidit� pathfd s [8%�9A�S� te�$�!l due����Q:dykE� 8L�d� �W* diur��8�v�Ŵ0�In2��+.���P�� l"b Usu��A�@N`e7!s%eian �5�/m2/sMW(McA^1a� ^��!�}�ydoubl�?�!9 rzE��U�� " ��ry1-ok,5��eGsQh6 Q��d . COP1�� a ne��8e�oro�omorpE"Q "D%A� �;� �a�8m�1N�MG� cop1���.F;pe�9 8n �\RPT2 ( ROOT PHOTOTROPISM�A _����,al BTB/POZ (":G%wD tramiLric à brac/pox viruKd2� )��W2�co��-$. �� �9%\1-���M<lU�5�b�8t%h!�t!��{� [vYDow\QeaM�A�'o���rC�i�^�Pu�O� ]y� !��6�SS"7 ���)%AgaH S�&rO 3$wavelength]AtMYBM/(an R2R3-MYB��� 9(>�53�Yv�d�).ߴ2S:mV� !A. �kp '� w3e2c?y �rcry�c1 ��yB Beu[17i��A�atmyb60e� >E3�d&2 � $.oa1!�A�"%�lE8� I � �q.-~���� W!.� 5� famiik!�l�N.)&-%)L.H[1�RGain-of-q� 9-^- suf�rpne�]���z�!%-�I�I�I�:�:K$���0��D hrb qnt�"short=5 ph�ƆrdEf D �SPgte*U 7[2� ��.  !r"]/c��u3�w�*D�Jbi&�5v]��utE۽3f�isBW�tein-�D� �!�[2"% �a"u� ) knock-d���� r =MI�=<[2��A�2PY� b�� �9<A�)�2� � psi21މ+������^��-di�"� �� NDPK��,(˂` �j"� U�[2" P7IZ%SrWc2F��aI<��v['tE�NBa[��I�"�,�o6��Y� Abe�E�A�]-15 !�.���B�@H �Vx.�1n[* . �xpl�!�.*U�of �in-�i�!�yځ�Jhybrid uM y sc@�i9 �:it(uuZZ2*�!�#&j:A-�ngu�. B��6l(IE]��"(� cջ�@pur�[!�yo�T���[&� 1/,��s���^��hal�*~,hf� � GAL46Xq���Mg`�he.d!;_�]�!�f�/# ��th full-g%gF�e7aAW���Z�LB*!����up����C� !��0�BY$!_catalyA�- �l� �n'�TR �!ށ�m���e��e-u�2�-���2f�450 amino acids �1�u)he��7R-Q٘d�/leׂSB�intac�U�5�+F1IQ ��.��) trun�`!l1Q ML-!:L!#!D�{� ]/a��? o�t&-BK.�Sn3.�q���|��K��P7 t�c DapA �rQ�5��#��\ ���<�A�l$�FC��[Q�nZed��asA��ZPZ"U6�pz2or�.�-6�Cer��?:�� P �"�e�arlL-fbi[ߥ�e A116)Grin%�KA?:~!_%}�#.�orualI;6���E�&fu�* !�f�s�aumu�!� �r�_Sl .&�I3-d"�+ +tW_�Uie"b+al!Q, D! EB� 9�=��y�')P1&�aM*z+sEU��.��-�A5tBT[!� ?.'%��e���s����&CI�>���&�sQ�:~!�rn���%#E( �Am Q@�2��9XY.�co�� closZA�I�. S��\��*A�v���d�d��ofkI�fɻ��&C:��eri��: %% !Y�CE�0 W�L2M�ag4HC�B( B���!F TE�ol j�rkt�}ly W�� �M��=� crip!d-ys�}rad�beO8� 35S-�#�ln_$Iw=s� �BD���Q�� _�5pr1�e�>N�c��!�*5��� �� �V/an�b��)@�s�'����#���j� oM�A $|m�eFP� �N2�mUaA built�6�pub�yYfarray9"vi�����7��youngk6d� SroxOeW��nd2`5[2��!4.e7e)).�inL5�Flea_�.F 5!��"7Em�y�%l!~6�)w%ȍE��%�q��[�N s��B/i6ae�%0E�\ .��rs driv ��ane�∶CFP�� PP7∶YFP9 �5V3u�^&� ��ԅ��by� ofU�.�. *@�R^ �j�q�d..decad�ja �j�eB[�2B��By�try�6�Ah�M�a-ln#%��'&�0�})o2AV abun"9�J�e �)835SU�u��ar`_) "�6�H�!ap�5�gm�9�E�2,��A�b��M10 (�i���a --h�3�&2I�*,�K>_�!�e�2W=W3 l*� 3�M�g i�i&z-i�%F���=p.��a�7qby.�"/6~�`�!^∶mycʳs�3two���Y�F$SDS-PAGE g�1!�b pBFr)p�*�2 Kq+ark�B�� e am�gof�G1�,*�h grad�u{��p"�n R��H9j�>�!�!�is �s2t{ *�6^��!�2�Ҟc2�s%/c� .���%1ATa.�!2���abyc(inity�n*� ��nala�c!��B� !�2J$0an%a*q �@�n��vPA�l�.0(e Nicotiana)7�H #e2s &�%A|!�!}b�2�z$*� ��Ho �5�!I�)-|3[ -afRde"0 �+&# i�Ő�q&�692M�.�$∶GFP∶H��* d Myc∶%VEk�lsqbi*yER�Y���F��Fw��!�h'�/. N_w:e %�� �--�.in](B ��.A��5�co-�+*v3Nq"�+A� ��C�Mwp�4}2Y��2_-�_:� M��b�tN�nR6� �T��,:�:l2 > �s&� }<nj�"3F��(���Nn�dea������0%�EQ!�� '( �!g�"`qE*J BPenh`;��\. �S1m$8J}�0 l&A�U�E&]ɣ weakAI�\.�5�4Fh4a$)("ŝ�'lon22 a�*�M �b�k�(d SALK 089764"�ABa a T-�p�Q��1���o�+vge.��.�Bi�R�,ReR� Ce3!�3;NS !�>~! "; by�mo6�m"�f��w"?�!�u�5iS> R���I��e9^%��&3 pri�T�Q��>�&�0�=T1!�k)[�ne.�] CFU�n�Q@ isV:���z�n.�p:�} 9 �I��m���i�F ahBF$��Sbs� "�isa�&A}6F!VC�@bi�3CoqZ9��4)/A>�X!���J��"��e7)pe W_>lewskijeW�)�usqw �~A� M:on �0os:Q d��!� RNAieq�3F& her��-f�y�21 �5 )�5sB�!M~6�%aQ����f 3ra�E� veJ��e"�&�.�#w���"�]�x�E[p��u epista|�!0`=UkS�:�Hbet�a"�,ir%vLAm#��, �|�&-5 &g YD"��%Y!��aA.����y\_ B'. C��A�,2��*FJI���t�6�!2�AZ �g�#�o��%"� ed))� s5��05�5m���" =!s� m�t&}+�oEL!R!؁�2�of�&K&,�#0 �$1�#, ELF3 [��RFT !e"��W�%� t~]V1^e $: D�i���5�].�3n�".>n�!�:cM\�$&�Bl�We"�j"6M�-��(1K�%7�FT�{�% 2=HhY��b:4FT.q� � Sse6b)��s="�:����-O�/�L�-s!8w�0�#d�:� n@o���+&�& �6&(�*/=�a�*�)���$"�+f\���PbyB�u�.�!����)]5�:M=�^#! ~n%�-]�u�a)+%��:`��sVu'5B�]!K,B��)!t�[)ɥ�Y"��/1�sgtac�� . �n�?��ess�(iao/t�t6�>��nte��&lF�W�&Ȓ �7�ĥd6!��c?(b/ �9�&5E!�W!%�&8��o 9 1�6��)-�7"6 -4�E:imp5�7B� F�PB�&.yW =~6JCol%)��A �͌heA:jEL��d=9�d)�(+& �u�.)rgR � � y�va�y�q�!Z2��5C.�2��J�E[���IsJ��s� �B!9���. TxW&YpT�_) �}e�$c"�%19s%$hZ!"=iso�!a���8yc" of Na3VO�" �iL� or ,�In �!�1�� ;5r^�x�da�b�9,'cA�&���fw�-Ls�e�&��+M��'�t 3'6,!; .'.�f" �A!�deɇ�%5�W�9.�+_ �ct)j!�-�i-����"~#�Fe^a�{11�_�.�V$|*,2��M�2�:� . Cu�0AL�!3 4�B�;H�e��*�ncomi�3AY�!эJ�ZxF� Xde�;d>I)�w��,#e_ "�MA�una��wE*�C4V�!��Uun� �0 �{3&i�2���VXberK6gd�1dI, �i�ifQ�.7s)��."���!;∶Myc�>j &z3-k�� �u9�&:=͎T �]ׇill��re�� 93 ���/�5*�!<&�Ge�LB"NP!�&�oy�j'�h�!�!á��1q����pro�!�/n��yɗst8}P#/�,.3M+_"NgH'B�Aj>$� =aj5 m�-.��-�.#in�:�Jb��b�R^�fM� Z.i�.iB� tJe2dp��o�!U�_!�.scK.� acceրt9+E=by�m"P)���5v��&79is=p�� �&�!A��$E<� �>A&�O��C�.�PBTS�Io��� ��c�mig&&��yC�O�� 8a��DmgPb 8EE�}a� c� ( ���#q��S�o� �#v�N*1 ;!,messa�{r.QU��in!::>:<*� �a�6�%a!y& �nt.� �9B–9i�:*e"tq�e(Iw�. ��-�1��� �6*ng[��� 8*j8" �8����� CB�~'��.o e+A� ���������1�1�Q�,t � ing eitheHr HRB1∶Myc or PP7 Xwere used . In darkness%Tunder blue light , the<�protein was detected in gel filtration peak fract\16 , with a molecular mat0f its monomer�Llarger ( Figure 9A ) �contras��^�:�d2 , at a size of 193 kDa ,��! {B{Aft1o-plus red-&Ptreatment for 2 hours-<�of_J�,complex shif!Lto=81n8285�9* �4Occasionally ,.tcould be2�variousvs�smaller>�4, ranging from�1K.�to1� than20. The patternj!vYp-induced W%%!<5�16remainedG same!�(either cry12!�phot142 double mutanAMsuggest� that@ pair}�, receptors i!�quiA!� thisI �response9�$S5A and S5)�! eg4%N��a~(, however ,% romia�in% pp7�Y!C aKFiruE>�fbinU# 12 both!�e6�B?��Second6��0predominately!�sphorylaa%FWplants��: B��is on��0major environa�al cuesA� regu� stomaapert����Ars%crys beI`eQiA�%orUVUJU<. B!i hrb1L!ץ�iso~4d as hypocotyl-�s-�A�!�]‘�Ew al�8[20] , [24] . W� port!$ir defects1t9Y�� open��%�is study9r4E�Compa�%*�,�0has a relativ!� weakJb,phenotype bu�� tron�7ť�� retentiond(robably due!�!�Ldifference between e!Npe��0Col versus Ws�C%Zͤ7iYTh�ZA�an alte�%�tropic9!����9 Ws�no�I!�6!�U�S6%ME!�!�PP7 posi-@U��f�!Fplay op=ng role%�Y]elong��. Unlikm� ne%�v.�>B'�hy�!�statuŏ8HRB1 may have a5� t efA� o��two5d��a�of G,%'ɯdific �by%;e1 vategdowns��m eve�jin= celli�guard . A dual%^)Yte fun �E�lso bAsobservedEdEARLY FLOWERING 3 ( ELF3 )x�-b!'of�e�=�loss-of-zK��leE�ida!fi�NDscs1-1 ( suppresso�closed-MD6iA��^�8Arabidopsis [30�XAll elf3F� �,s show wide-�NQ��Qe�lorVDua��R�!9�i�n-medi�P �l��eFFr�a�)�, [31�e�{1&a�&�2�) !�S �g�c��I�`A��e3��ZQvindepen!�ly [12�(In our curr� ��i��WԹ�; ��is�Ʊin1�R�1 o.� 2 , >� �!;�����["$cry signal��pathway��>� We overexE�ed lҸ��$transgenic�\�5A�%�5�9� simi to1+5 !�22��zIn. %'΁&m?$background_wild �G��!�$s did caus�m�J}Ռ �Why�:}�| �Z�a��Q)� fail� o gener��ar�� vice��a i� QB��6 M*A�intriguA@ . Onk�reason"/ !�v��Y�b��b: � enough!�G rideT9&� Y,.)��a  demo����to�e�!u a ye9@two-hybrid system�vitro�Iin vivo9�x ���.tb�� a�  family!��e�in L way�by �_r� �,��A�D�Mt-I�(19 ( Di19 )A>���[26!�S�al % Mps�2d�jcalcium-"� 6 kina� CPK4� CPK1�� ABAJo"� �s �� 5]–[3�8NetPhos softwar�= edicAK10��y3�^��si��as po�IA6.�a2 #of) [37% tueHE��(spectrometr�.}t l�Za, Thr105�Ser10�inw5w #� �� 'ia�nfin E>  ���ly ac��alZ�. !N�! a9u -Pro�Th )$�chang��el%E�)mobil�% of aU[38�wo\ P� =F�b� 1�progra� aI�le A�pbvol�� >�76�ﭾe�: �Y�tru�4�+= ��s!l���Nm will�a2foc �fu�|"�� exis�95>^mos��i�6��XI m��E4mC{ pproxim�=-/. B&LA d��z!_c9 "\�(�A��U>f=26"K �R>�:3wased^ �& �� wave!�th.}7�Inu'�rV� a%�Q(Z�-E phyA� � far-� �"� phyB6).%A> R&F or}"P:S n&�  B�E�JHCAC� �r��L^�appearU&R ~~^Attempt� ����4to a quadruple!*�1Wl (unsuccessfua�E��=�!��Yicultj���. C�|| ly i:z��"of� �-�nucleim�!osSlocalizY�4plasma membranY a%� data=carg�1�*Q)�s"�7 ssocR��6c��ar%�%%& � sR ven�~!E �employ%Re��)VduQp�� >�T�Z�,Wtu� merg! I�c|q�,.!-�,Z ��on?%?�h���wo ��|aY�}rqv�� MlJ�"/}���I�1SI�J�A��ni,"x!r�" 1�%2s� ��us� x ��an%t quesE�. FNxa�Q , COP1!(���2 iME5QMsJLIN�2 [� Phot2�e�rec� >):ot� lisade� develop� [39{h2J�? !�!j�by.3�"f�F�a0pro).�!�r�� to brA]in newlEA�� J� ���;CA: ci 1�xLV�!�"au ��Akst< B�1�&!. Omj)���"� 5N�at", � �hap�"fi< "� p6�"2�oa�>�e1 )w�j�uc erupd dur!f.�( A{pro�� . a�.zthaliana�4 Wassilewskija!�yumbian =&as&5 ��Monochr !��� ,AJ*] !��d�.pan LED SNAP-LITE ( Quantum De��Barnerel\WI LE�Aens5 A^�"&� �measu& �0a SPEC-UV/PAR� radi�esApogee IUu�� Loga� UT}!JB[libracr��coTaR8'scribed�"viously�8Matchmaker GAL4�:�D3 [Clontech , Mounef View�TA , 4q�baa�Q� GBKT7 vec�!(I)ey GAD#Znt; �'to' ���s��;PEG��$method ( Y�DProtocols Handbook �0ß-galactosid�"^&<per���d5����o>$)T��A5i��n6n&�weJn blo� s{A�i�� ti-H[ tibo�#HGenScript , Piscatab , NJ%�PCR��gi-�!s!a��cDNRdI�BD"��� subc�$]lpRSETB2�Q'�C�. )L1Fext��%N prep� _3�QE�p8�! bu$$ ( 1× PBS\, pH 7 . 5 , 0 . 1% NP40-U a full se� �AJinhibi7(A�A2F50 µg��tE� A2�mix�/2�µl a!��-BD -�4Santa Cruz Bio�0nolog*, Ca+,�NwA/G�*0agarose beadsaS�Win 50�lpdFeI+!L05% BSA!�he���%�incub"at 4°C{ &e+washed�imAHvuminusnib=4% �,�Ero'�J�� B2�y��STNTV"maa�� (�'meg�, Madij,��]1E9i-�q\2m35S-labeM ��i� ( MPAMcal��)�AnsE �9at 301w1 �,-��binmi9�N�coN,@�){5× loaWm� , bo�>'3%��)�,��12%B&.�-�8rlm� !^air-dr%ndt�$� BioMax MS�.b"q4 �*����FP  �1 prim; �(m�����mo�#se~ V�+(Sigma-AldriH S� Loui�MOũ���]stripp!�nd re-2�>�y�= inst^ tubulin��.V-3�Ggenomic���[eFc*B,pCR8/GW/TOPOD��tP A(�KpMDC8o)h��)5 20!�!�)Yec}+[4(!Hfor yr6szim���o �$ATGGATTCGA5TC@GGGAACTTGTCTTCAAG "�I! ,J.GTTCCACC{ CTATTTGGFTCGTT�n}$ne�ag'- cter8 ��.� ilua!40��LB` �growna��26�3"C'+)�ol�AIu��?B8e 00 rpm�2}�resus�()  ME"� (�mM� 5 . 41�� MgCl4nd �8µM Acetosyring/)-MJw[gFe shaN !t�. A9:a carr����A983- �j�Ek-%�v� ,'203���$pBin61-P19!_a r!)�h!� -Y-in�5%� leave�3$om well-waJ d 6-week-�nicot bentham [1. |encodx"�r+),gene 4nc���t�+�i �is%am�ı�.�!| ansI ��,���&[4�%Leaf 2F harv� (%� �c=J)!�5 d*%�V'I�!�ini� 5eH[4�%6i12 �gN5V-�aI��A�l!#; (co-precipit!�*� �����"� n(M imidazolem �� Z�.�ndZ�!\>�y�%�2J pre-equih��nickel->� Qia: , ValA�&� J� ["�� v!�.� �/� 5 *l r����M�s attac� m�columni�e�_� � r`�Paie!2�.:�kEM�k�A�.V  l^� !�%  2o&g 7Q7 && ,št"����P���mS �P�� .)N�;�>!+�C1Ca] ( qSa�aW%)M�)�V�-�/� illu5,E|}q�6lejq,25 µmol/m2/�=�?!�1�. I}"�']an Olymp(X53 fluores�  my , Spot1 4U$CCD camera%analy�"us xJ&w)0!� 7� e�,2��NEEdeA!~%iI =W^�% humid2)�V.k.ed� ry.z{��.A��a��*=�)per!Jag/i$L f.�6 , [4�*A 365-bp�fr\y���I5c2PC.2,2�Fm�R�AGRIKOLA�o [4�*��n�%�w,CCGTCGGGTAGT�T%@�CTGGACC�TG� This�N%M��yi� .��J61!��)-a�5 g�8�2���`��in� "� 2G�2re>cc�p� s�aHEPES�zt mMZ���>. n(# �z00 U 1"E*J ( ( New Engla8Biolab Ipsw�M��JMn�Je�y*�. Ab of Na3VO4%�*�.�$Gordon [48�?g!�va�>add�a� cona�lnk2F�15�A5sto&#��5�mv2R N�� 2us"A by:��Q ^�Q V� �A�6�� &�0!jp&���� VL"��A"�g>{""b1"(5,Tt�"� s�)��vo aff��y:}*4His-tag���tk� a*��*� �%�rv� %�-m.��di�Wag[�K� &�?mH��9�".Iq�!W:�^)6qB�R8Şres�8�� z��&8 y���s*� abov�);D� v-%��&B9�8on 116A�rYconver!���QuikCh�0™% -dir$J!,%�ki�!�X ,� Diego��d= q$e?GGAGA�8GTGGCTCGCGGTGCT�SCCAG�A�uCTCQ�6^P/-���)i} �*A3&_�Cp7%!� .7LK4 . 93.� *� 6�  #\Km� UGi"�7�* [49]e 2L:O&1Tiv��2�k�!qb�tagƺA^:�profil�orq`��dAi1�R0"O �""7%��%" RNA ?#A��8RT-�"GA�U2pnVhe�:F 4�;c�V4b<W���E,E,{AoUO2�Inada"��� some2�* s [1 Four-day�etJa� seed\-M4ir�&!h"�]9 . 86.�uni� �6]�I. curv�8 ["_Lb 2� !+S� c)ae�A��p�6, can be foun�(.� G��'qR�/bR#|0follow` a�0!�numbers:E_, ( At5G49230���  6387 �71G5628 ACTIN�At3G187AJUBQ10/4G0532/8.Z�In eukaryo� A� poly,se II ( PolI�&�7!� �"p. �ory f�&rs �=� �%�;co�/$�@�uni�H�/�ib*to �*�82_e-the M+EorA� multi>? c 5< is t�OA�by many6Ph�0.� a�2,r Caenorhab�=s�! gans��MDT-15�f�*�5y � �,:g#o�=3elC"�"�� SBP-�P�/ horm#r�K< NHR-49 on fattyt@$metabolism�6���.w/), �displ�a broa�Q�+tru�<�vit�EA)h�te>r.�to �6ri�#�?�>by � el)M. Depl�Gn!" �1or�Af! mdt!mE�abrog�d�/'��� ox B4���2�cer�( xenobiotic�Iheavy��$r�F��ss2�)�G erse�+Ho r3'po�+�"�C/. �T5aKYB��JaNJ�AsCI& �  $)K�h,�� Q�1a91fe"�7-'�g .I� rmotolera���gA���8ѧ� ��4 �:M�}m��>.EqmfaR/9�E�m�'�0del�. reby l s-M��C�>2;6�"�3A�oni�L�6AWavaila�:A�qua;)qed]�8clu� nutr!KYH��[�.E��icE�6��r��� �ra�!&�ʱ�.�-�&�&teyR�o�B�DLi,e!����>1{]\nR�se�le!� also�eb>�co�E@= �9s�sB�/!0mA�!�2�3. WithU���x machinM��"��7=5�+8!)rſ thou�Vt:M%�& �$�D@ �pecifF�outpu�DY�t9��� a,���?%q prolifera� �JrZ γ- (PARγ ) [8]X�#iB^fAD(pregnane-X-R( PXR F$�itu�� androst <1CA1[95[10� . Likewis�G.O 5�M�sI�2/DPY-2x&�3/LET-19�nd N0/SOP-37cip�K� ulva� al,ic*�97 �i�1e�Th� s}Cra��"�:of=X� cK��]vjm�sRY��&<9� exert�sZ1a�VeA �'Als�� �Vcl�<�I���ic�m��J�=e�\narrowe� �9� 7�K� which�{>t&M. MoreoPYal�e�F��>�=�7: �K�1�Ɓb�ionship��>Um���Aa6�al mew[ 992m�a��D know�KD1&h"@ D " �!I�/viE�!���to6�lrelevx-A��6of<'�eD4 ��6capac|.�N%�numer�\]w3uD ���<bi�-e1_#�B�h7e.v$!�n�i�2� 65&� ��in � *]!LS�S �R[1Ū�:s.��0�v�7-!Jof.t( FAdes�a!b�E@basic helix-loop- zipX=� �!`e2  orth!\o!(�A"J"�ZL�6SREBP�8� �e�! chol��1D sm [�TUY�",-O5 �� AFQ,abo�EI);/��5!m�overlappA=yettinct�Aof�. ��H�, U ex�5� �����}��!��#$D}h-o"��"�_aUIan im�[aonI , Bnetworklt_C� s� home��3 3W"�4�Nm� �.al� "�P� inpu!nd.�@!��E<' a& gen, ���necZI�\�)�!l p)ko�g-+j/�(�Z�soH m.%%��=f�R [ 's s�=en&� . Aqt lap U u�D glob� disN�@ X���!� unbi�Rfas�5M K-�d� fyم�(ly unrecogn�DR eulie.���9. W�0P�V5a�mpa�6�;�vo^J*-��2�� ToIJq's.YaljB;manneaEw�d��#arrptAW�^�2AG �i7'ldS ( N2�5orm�.at�f��or 40 h::�Pa�9syn*n�=� � larvECage L4;�>�aDMI=�Aw�b�1a�.bod*��H��ol*� RNA-�� ce (i; !�e�in [17� .�DJi2E��nt �e(fn2�&�Mkd"mws �Aeraw�M“lin2 j�9cr)�+4” ( limma [1� [19]v?AB �w187M�E��<��� !�120B(uj �$( P-va*cut�'�"05; T S1 �;n^ �6�a <a�5“9Yc-!�����s��a��.e�-�ACi� ho�D��UfA�� on-��yAF�!;!�I�>g�to>Q�l1de5f�Q �below�W�'e�63�85 g( 74%��6�mS � u\f_6.?zM=2;���aYB{iY�8�Y� N cut-�fyield7\ls5 A8�6�A��""� Zs-\�l��%\� a� !o��gh�" �\sh֡�TaC,o��-�d�ategy V"n#A� tool!�m�y novelmU rro� A^�Nob� �(E��bof endo3u�5a\52_r�I"�8�X6%�e�+AT ,( tm218 (�$in XA7702;j1!�F�mS2��(%N �recapit�KY e p�gs evo11Q}�.shorte! W spai<pB���fecund~Y�2L*,uVaᅩ3�R� at�( rage�Aeto�WNile R%��5[22];)���gW.<��!�(ve2mof 97>(a�P �W!��9LY�6Q"2L85 2� N~4�%ntJ�h*�(� L4 s� .��!�G50 � � ( 52�GW[F>de�<���I ]� �p1���h�` ; 47{�e� ���/f�(ee^) ���Fas��28 H.>J�.�2Q�A$"� iaexqY2:u~�,A� �V �TMow*y�� [(e��two 7.� .�{)��5)#�.� �ut �l~2A�!�u#dEYy�"r � . Ov�!>K��6� � Ci� l����"_�enAb�, s:DpJa� M aR morphic'el� >�Pa� !LI��I�[���K*H^mЍ�s�.� �no�4j�(.=,�pos�ne�&^ y�o�3^mK MF$SI"�eS.$vT����� ���?l� ��byiHz��|e�establis�1BB!va u� � ��.("� s&�t.� mm� E�% A�s "�TAd"� &��6��> �9�!1Vzhe DAVIDi�;J( G�C anno���[2BA�4�P��a .6 KrQ�I�of GOFd�����oF� Qf"��c|� �to�r��!?�~�$a�6� r+ �92� ed ("�#FA-Δ�&k!�FA-ox:N���Q�Tir�7�cT-�W!J��of:%c��Un� !�YIjcI�Ren�ER�e�bjCot�c� �� �@UDP-glucuronosyl/ )�f ( UGTs; 1 �A� �&� xѪ) , gl{ �e S9cGScf !�!a,O rt-ch dehydr� ase/� ts)SDRDHSs;>@)�D-1 (��`� 7� .���aMba�[� �� �sdm�0 ��j z;jpid� they^ typ�N!s7Z S"�@sm�D� � -R�$>� .U\�&&: enzyLM��!ec��2u�N��UF227m~�ixU!�.wc�B"u��E�-#-d�)>�:���)�U *�2�UT�$�dc)�Z}"l�e cyt�Ue P450a>CY a� %alcoh�>nd ale}� }�E�wo ABCi�I�+)� acyl-CoA-�S�OACSI�!F( mem�-A��C�F�*A�ACSJ�)&� clash6Dza�yEG�S canu�ze}��e . Of� �q�xo�U�`Q wo,*acsM�, -� acs-|I+�*�x:�nF�fY27]-i/|!lis�$I3J�})� i4( a�t���i�mtl-2;  Idmium- ��>8r dr-6#��tl.60 , T18D3 . 3;����fn\�)Q , Y37A1B �S)�e.�*g,RxsumX(,6��g ( 25�%�!N� ��*: e2� .� 2�F:�^�or Wk6�c$��a���~^<��$�X &>�r&-yqg�-�.( 3,"20!',B �'&�! �# t"�wI�Z�@ �+ "��*�^�2z"\feo$��u�)T&=-g�zAmongaK'&p-�gEC�& /J�.ne:[�i�Q��osl/d�-���y ccur� !Oens��|(U7c )igm!x�j)c!�06|� no�b�$)m(of CUB�sa08n5�Sth"�!&Td>�: � �6[2�2�i� yi ��! h 9AAux�8�!�)p��ex��'s.6�z &DU2 is highlya�!��ie�J�xFb\&*,n h*]�!��.�.!�!�di��. .s�1Pls5o� b�,nci73 nd:D[�x�ne�!!5T!a�$-�pre��+� �al=!��addGno�w�.vY!46d_�by:D�p�#u�|�)� ��9="� .�>� t6m 6@��P c���U2-���?E2�;�A�Rn"� )� n�izI�musclnq germE.�TAQ�2% 3pharynx-� �25�C!ilX�urp%�/.��.?map� 2!j553.�$�Apq�<>Eӵi �m�RA�1/alsR �&�Orm)  , ne�a'-�g�tR�6�&� b��Mded.�G%t� =�j��Y2� ��a�T��I� 9(2� lf?�Q�oa���9 K�<��"{'5�'��:S>_LK �e!���^H!�g4)RJ�8!5J)F �� .a�Kmoz� , b�j���� ��He2� ��#L :� u^3���sk, S�-X'T lŮ"�1!� n-� �!.�.~K2�u!��L�.�ug{g�dhqcyp��Sa�&� ��m� ��:�,5��s� :2�)q$�dw"N|Wr�o�6b oxic chem�� � "w$�qQI����s��9 cyp-35C1 �rw .B��!`<@M&� ����a��\ G.��'3!�6Vg�C +&N2%-S&)-!�>>&L1–LS - � >�%i&� > \�G�)Lx�".Q�%����� )Gw%�F t�aE� @.of�C-ͱRby��f*�2+x3F� ��5:k216kMg;�e�0wo+!in%�!�:�Y�!�Iq�e+X:�ٟ60n".oxij"�. ;E�N a ,6�mo#%�st-5 ten~�,�r�.�R�:�H"�55l�W�Sii&�ugt-2�9 -���� F�N{�-� �/��a^rL?�~)N9a2^2�-�"���8� ��3�421>�!P�2��'in"�3�p *�n� e �r��ff��-q(%ulF8 �"�>.4 )"�3%�oly��5�%( a#S�"&�!4U��6�". T�St>��`ata.���M�.�a!ed!�� iyE��*�2�!�� V�. Surpri�&��= *� "�"� �H&�b�g9f'��. @J�AzU'7ati���;jzVarJ �he �&*' ��� r� �2ua��#o�1C0d�Hl�Uof 43Z��(Epl#a&�n� %�1�e;ir��A�q~S�W1 �14}�143m`"�: VAI*��42�#I�2�15 VT9#���&V�by6g^Y; I�C?k e�s�!��%�"&��5d�.�3e��f.ay"��/ !�adZ.�BRTP eAD�� of nA iL�4xin.�wa�6�l'"��bz=�,�B8��u&���2� :� ���;B:� � ��u�t�e!.� it�M���B_^I�)��{.Q�&��sE| vi.*Bc��sE1ar�=(������"X}e � Xd�8 m/Z&2�i�����/preIlG:!�>#g� �AK� #;B ��b.yuip}�cdeath��o 2niBh� �� ��FK(A�2� �nő6��q�Bc��oQ6"� , ( i]1� �&�#= /05 �y�r*(-��&�6�:��/( iW!�6C ck�9*>NU, *o*re�+�Wof� �+W.tm&�Y��� 1w%:�|�*� L4-�-aX+6Im"(n�3��,�%2*-��B� "� ���N�( �dm ��fat-6%- 7!j.BP��r �h6A���is� >!�I��$6���u�)3E �u�Elud�>5i?�>1�� su��a��q� �4�#��0���#a�ss?(wh#Q*� A��& refH�9b�'�04A�15>�� "�%�D#Kˇly�8r�,X-, CF51�Lfer Mb2II; fem�hc1�II�L[>to���g�.B%c95� �� s do%]\�y-!""[0q<���0",�a����!oA_� E*�� !z"y,� 0&a vF&��|>o �,Bfb�I�8U�8�N`%��2��q bundau%� .� �:*MţS a~ehG!�_&E�m+.a ( ad�BLVU�R& p� ff� !o�-�e!�@IE�Q!B &q uBb :�. F�7�!}}�*�? ,A�SBoO*b  � )\seeQ�eiv�X�)�?#*���$*�6nhrvP"Asbp��m� H��1˅�6��v-"mG- ;U�1�Rg��0)j e� un"�i�ir:Ta��5RQ! unch� ds�}a�ll b!!VQorJ�F�d~I�un���p�}9<�-R � e�"��`^r ����l(Lr� �)!&��n: @u�eworth MEI5N q) , f���j� �Fal �� does@C���"2<IEj�6��&�a27NHRd**:Y(e-8;�),AE501 [aB48 ( ok186 ) ];�q)�!&`�&�3�cLkAW&�+-V�U�8.��v27�9,�8�W8� ^o B�6�:1!n����U ?a lM�s& JgUA2~2""^�� b2K>v "!at��r�^�w*�>oe�m�&� �b.� w�UTM�hyRJTB���gra����i@em I�o&�!N �e�b�A��V e L1=I�� eI of"�QAenB]�Iac� mbSAh��}� rp�G@Dtil�j":  hood!�V ���Mon�_�  o2�, ��"Ą�En��E.>),,2���"u q>� . bCergE�.r��%�,Aj�~E��c8�crawny)��w1g�pI-��isa k!��4cFG R�"*�L �*� A�#ٝ�3�A%��p�.��mSnAT�&!:<2G*;�w�I�"E"� ^r�0 m ]j Wlaym ! �3F�2}%�$&�� Ux�A��JGL�a� � a(��]�)/!th� 8I���ECqe\2RV B�G�i.(��&��0VG;6B�/� ---.�,��*�,�&(-�l"j�,[42zR?o"E)�ran2�# �i!� *c�- ( Cd2+�,nd �- ( Znyfb�p ( Cu[�p�i�G" C  *:q��r *�Cɡ.nd&.%"5 l.,� EZ2-Q�A�Q�a�"� � )&�3�m�2"�.A4�-!���[d2+�%826%-Z us&�8]i��a%@w.�!y�b?*�  � AVTAfB`"�2I �FIyB�"�� 0"�6s> ��`�2*= @upS)s!�� ��z�0(� 6�?N�)� lapA��v*S3*�/ OJ�a|!�>� �l&�G�8To"T .�F���JQ;%>�.j,�>$J��a�>$>>$!��@� ,I�orI�ePtD}@d�E��Qla�Om�'�')�� T�#.��"$2!V�#sF��!T,aDn. C>��" ,�a�we&!2� of:a �m2� At.� -a�.tl�&dr�X�.1e��Wm�6�#dX1*w32V p,�/ v �6��JC��>�*|�o"�f�� �`N)$ &�A�����A%;~��= �W�m��&�B�&�+QS2� )�� ult- �' IJ=%5V �^�9�A'�E���d%&V�4]N�:T�-"p}b"��A�2�8�.��C.�!. Aij.�-2% J J6r ∼��t:\ vps ng JO� -��J.�JU� cut"�>��e� > IA`48�Oj� I��*5 them�+Zj !�a:h2wWe>"aw�&�:FXPAv2::+i��r� L212��)�X�7� u�rapid� �F����r q� �Wvo . R6 !�i �@�� �P1�ɹ%� , ���gz%'@FP-� bucu3F��alU we�2x� � .�)�!h}L�rŘ� "&'��sIyM;�"�H �p�n�!:c.�41 a�I|� ���26V6 h�u�&\,^�s�`W-l� *0��*�\ eHh*;2# �is'�a&r0��!���5*� M�+\n� 5!�XKq�vh�?� 30�e�<� N#-W� ](E��\�eF" �"�B@B0st�@(�A�z&u* &S � veal�M�� ("8e�A"p�ve�Lt-shocka�Pb� hsp-�and �y2� α-"� tall�T05E1F^3!�Tto HSP9�r �i4Ue>� reio��f)-7 �<� vM.�F heat��2Oa]o��` ����� j�buA�mb5f "�er_#( 2nu� b a� appl�;�)��".D��m�< !�p hrl35�uV2 NofJ al!�E���A�HV^&c�dV]",[-MO�0Mkl�W�6�;!�^ �D"Av�E�Y�s� HSPs F44E��4A�SP|myA�� !!49���K. HAL)�&�y79~?9"L��1q�ed�=�hsp�f N[�492OqRF��M<4�+[h�_)B�7�2� � 2bloNb� r g�V$�.!)w��t!�M2YR�N 6�u"�,N��i�o�"�,�]@e{8*� P 9Ld=�ϡ�%XR]D ��F�6$}ơ���"m @�&-P�2��  Ee��#AJ!�O #fu�tstA>!\� B3I #1���s�5uV�-jV�M�A?ems�ԥf�! �(�&-:"�act�vF��YB��$ �"�f�ż.�b+bp!�recDpn�ocy ?det,:l<Vdn�� (U>�s c�+ � .1)) r2� 6����-�hs)�}Z1>Xb�/ *�2H�E!'�+*!9)E*}/E�])� �!:�!�f%Bta!�.~CH �2 sFsm� g"5��[�Dp�9Discuse)$A"^NY�A�a�%N� ] ��f���@!�""�t8!paxbe4��A�.�ɦ  �2!�Al"�]v�)lyI�J�}0b��#dN� margin�cenefit�N^N�qR. L�QTsoil-dG>7".���G dlvK[� a�sMpin=�"C�j%6u�� em�K T%/&h!;JI� harm��� C�m�;�<�J phobE;a�*�� Ai",h+9x&�h��can���ir adnwe�_���h��"1.�7o�jpro>p�]o�r22"n��5.2*ee�ev�ci'n���G�:NH5D�Dž�&�vpro��"� �A� eeXZ a���޾"T0o� ke6�ubut��!�.Q��ic>�. ����A�{*v*!�>_&y�ș3.'"���FwAW�t� 6<#-v�a�.tO"?.�7&�h6Q I"�s��.���H2�! ��,Z�&*�J\3NSw"*+>q& 2�L-�� ,a:���7ll _MI(R�&;J�Ge�P�?|4( O �.,^6RB2A �RE�GST�A�MI =A��zr0Sc� gp-7 pmp-�/8IQ� �'�lightp][H�y*9hoB�$yD1�B1�k�ws Ar �l��"zq:$Y v�m-�Q�A�"65 �%6,Ψ� 09A�by1ݩ[�maaaJ feA ick/� �i_: &�CF)�&vU28*�4%"N�*�/�*�'ZT!4 )E�f� Q *�*F>� R�t��"`")"op"�@��=�M!"�4&N�A>v� �a�%sI�KHV^h*�#�>U<"F"� M�C m��*M!_o�%�:�"1?�06"}| Wz �B*��eJ}�-b��q�z��z1� �?f>,-)4.r.,f. OurU{a�g�K2j � h�}EW�<�F:*6A�ILU��.�A�2�by�3�a&xr�I���.� �,-cI�a,���= ::�a�c�7��Zyt:�uLB�Analog�b� 5�-��a� ~ll2�o�+�T<:��7"�>��%. Strify� �.�+cme�lavis�M quip�Ek&�Xwq�*5f�b�&�E*>�� etazoanTnI.�, [50�%5ޚIn &�e�d�vA)�v�#�2>�:A;�1A9 stru3��i� �*ou�[53�I� -O6�a�j�:>���. Not[��O��&XJ� EDf�A� ecess�2e*-:l r:� drug��T���!Z&�wN�2asyY&�2ci0mod���2!':zy�@)R�x�$���h�m1!�hum&�U�/�]m~}#`%�a��F� J&ARE AO-_"f �h_Oe2� ��6�,Q*plevr!�� �Q���&S��N��)[gr�n��&atOay~���at�g litt`��F����e-�A�vov�*�5f sA��e� �6��"�{l:3{&�FZ�>-ZS2"V MED2rCe`2�<peT���sp2�)�(A2;�`�"+� Y�dto LPS [�.h}s�we 208 >�of�}ED2I��6�� iaassP�hth�!C-�CJ# s [5lw� >=ark� Xf!�ng=<"��IV�,nglJ�bE�“route�n>� �A ~�.}�.��Va gfni�tl �%��.^FvN:�"�ɻor:�/�G >@�)orA�Q�O;>{��� (  +��aEutv@&8?�ai k���-" e�� t����;ol.ʈ� i�B� corpzw!�e!� �������:�sk��is�u�ndIg"^�rY t�e�m��y �6�%��  >#aTcommunF��"�?5L_�j:��m({�*� *�le�.?i�*��bcircum��C�^�½D�ore 9e.#!|E�R� �;:H!G�DbehaviA6O"�|�k�s�!�B56������lm"!��,ܹ6�7a"�9��%oin6`� ��R5�E�$lto =�A�o\ "�R �� �"F�&,c� post�\Z8�%��y!@iruzIt }4�["�/��%��a�9HW%"m�}t�� %&�to�'s|B�.y=�E �5ae�q���:� !�F4via���  +E��s*!�a���2 =J:�Fxɴ"e06� [55] �"VA#JaA���p��bYXJp�[5 e��M� Ze�p"��B �2�<y6�aD c"�dA�ne��F�]"7��� ��Ss�h��VH\ expe��'�C6/&�],�ATP(ADH%�%�1l�9iZu-W.6�F�%A' long�%st�yi-#6�f&{"0�-�j��2 t>:�I. A�� �-��:����FQ�� �=a* b!j�Mc&�]�A j�b��d"}����� ian ��-c&�v 1dxGC/"9 &+ �3stimuli�vWi� xerc}� c�eiPA. U] ��&� , qc&��-�.�=$� swit! K��.�� to o.i 1�yX5��5��.� ����*C1IG#!6�~d�}�%�oh?la�� ne���] 2�6%It��i�qҥ��B |bN��sus.�d@��DS^�'�lin%@ to a� 0*<)�) A&�dra�*eyens2�& s� pI � 2O�J�d��M�E�*� � A���2.!a�'A� �I ut!2�Fry�7+n2��KJ*aD% �)�sy�y:�6> Upe�E we�7�EaU]��R��i�! >���[5� 60];� �,�es�� � +��i^*9��qt:�[6�z[6UQS �w:�I�1�� A��]lE4!Kbh"ٻs�ic adap�%*9�+TFZ* �6���ma� naF�eal�#nd�Je��"(N)v>s^"e��DPf�<zE�|���:sBRP>J6�2�:�_.|4̓� �"� �&e�{*�l_F�o rule� ��'i:"� abso��A�:"Myicl�bar��Aw��6imper�D [636����� ô�z� n up�fee�[6*�'A|JhAz�N A� ><!b�4 �"�$i#�M2c�2%An"�$ n� Q~a%�=�VS���$ �� b�`aS(�!cD�^6Q!6 as� 11' 6� lL� mpan�,b�?avoidGk��a of unfavo��*K!7AU)un@.vad=/�v� �C ��1�*�!�� a��p�3a{ic�-7#�-@ari�� F���@(e/�k�s)��g��>� Y�2K2��!Tco2�S�HE.z��2�[��fe�`baG'2e*R �1�!u�Nip ��E V�'���Q/ i!r}amA��)8�jkeT�+�aE”: h�!"��yet<�&�e=Y ���9:J�'�&4 l&>jz�d��"eEj�#*52�m�/-��Is �+iw$�� B�b���� �yax�-~!��^"8 �h��!�� �AQ� part*֏hos�#fE�i��$baginE�a��� I�%�A_�!� gut [�gIn6�p��6 ��bn*�4e�qC2�q>>g!qLtм�A$'h �.;� chieve��]2�)";��dU! "�(�� .6�P$s N2-Brist�/WT5EP[fe��P]Qo�T7dvIs15 [�5y7, pPD3�3KHunc-54A� ���^H 2� ��H�H*�H�) ��a�X�[6��� �x� A�F out-���&�("�/A3#f�DjSV Litani , Tokyo Women'y�v�UJ��)� r. �F�3;� ��ng] ozyg%�w��R A�!=��MLori�(�i�� by ���:f" �>��05′-aatgttgc8caacgtgc-3′ (��� 25�8Hcgatctcttccaattggtc8�\rW��.8���\�1 �o�!m�Qs)��9�:��$un�c"$�����0a ( NGM ) -li���5s'(��4Iete4@��om6�+!��40�4)}NGM2YZ �?E� g/mLb��it6, , 4 mM IPTG �l~� 582-60o6 �1��Atetracyc)(�O�d5�.6�,)]v���P&��ѱ���I!wHlIs:�0 _!36!,624 5iM�$712":7 n7 Y �>R ��x��$ diss�)� MSO ����`� naTg�[n"J(�NH�3d���) :6�$(�51�Tat Q�g/m(=|�Bf4 N363�5 at 6��4�5�M�2�wZ Y��0: 3CdSO4*8H2O� C326�Ma�M�BD�17��CuSO4)��Mїf Sh6��ass�\%�&��:�67m��-��Y,�Nz$�&EM��.|&[6�p6IZ� �i�ony�K��DeVJ����,HT1V(.��Buʹ. r�ferNLϹ$2% ( w/v )�r\p�aS��ido��� ca��7�HRetiga EXi Fast1394K�digqyS�( QC�A�, Burnab�BCe>anC�)�"[�,a Zeiss Axio$� ��-�e�H'C���Jena , Gµny�]Openlab ک��2&ճ(�>-�^ZgU . K .�4r)��] . St# 6�R?*�'�sy?�3"Q1�'�"�K6%�Ɂ��,�)E.!��ttoA�:`��.�2.*�#&K� ocol"�)rf��viaU�^or sic`����Y"����&G��e�O.nW �:., q5�P9͊fp�.c; f��STrizot�thod e�, lab��%�Cy3�Cy�#�>h]�%�\=WUSTL2�e#a��e�WM<*�� *Yrepeats;�- F4$a dye swap UE� ed s���(�e�SpotReae( ��s S�E�u= ! defaul�� rame�{)[ag ba a�To�^a�zJec,�e9 RMA *���g#!;i “N��ize>�A%(�!"L �*��%�7pri�5ip lo��Z�BaE >�0��&� �C"�fjXha#be;l��N1a� -sub�!p1k��mevX�d9����nel�22e64��&�*hre"9E-���'ri�- non-�$n��� �NA�!&� 8�����i d�q?fU�p U���edUD��.� �]x�0%��lyD$.0siN��r�Q���&*�7=�mi�“BHAA� =�g�cKa��<��0�e!�:�#ed q�%�}�I�%IJde%:YcGene E&1Omnibus8b�$H( http://www . ncbilJ�ni�c$gov/geo/ )�!�*�!��{GSE972�To��+e0 �L��%s��"\&H)Ac & Cd2+F�L[nw�!oce� a @��s:':�.1��909 \paiur�M�s���fi17!��E�.�ߗŌ �=�5���aI�l�'�1S�6m�^A!��veQ�n��1-)*oK&e �Iz�f�%!� oEvO��(e2&� ne��M��E��.]-�Ig� lyX/bi<��)i�/bu�to "���t&$�2B[70�NI|��,d��ic9 /�.�5p.+)�(�iAx2  ucsf=0 du/k� b/Stefan-� RNA_"$N pdf �3Q'6�"V�j! n ABI7300G1� �!'3�z��� Ct�Y(��%�Bio� s Pr�77�s-!Bul�n NQI2�doc�3[DbA.�/pebio$/0430385���R�E!���= ,normalized t�o act-1 mRNA levels . Primers for qPCR were designed using %3 [71]4+�tested on dilution series of cDNA , and analyzed jiDefficiency [72]; p�\ sequences are availablebr�st .��An animal's ability to navigate through space restsDit2/Hcreate a mental map�&environ� . The hippocampus is the brain reg� centrallyoponsi�� such\s-Hit has been assumed�\encode geometric informa%W( dista%�, angles ) . Given , however , that�(al output c�s! f pattern%� spik!�Dacross many neuron�$downstream �$s must be %� to transl!NthoseaintA}cur.�about a=�spatial2}4, we hypothesiAD�1 )%�temporalq!� �al fir�D, particularly co-is keE;decod.�.�!r(d 2 ) sinceC implA�6overlIG(place field%IA-�d b.� will!MbasiN connectivA�aaA djace/ , i . e . t;(a topologicM�. Here!>a� thA�$5T$s with a s�e model!HU� al a�, vary!) thre!�ramet�G(1q%�,. !�-Gnumbera)�A�(in computer�ulE�E�ratA^jecto�[in {�ly%'u�begins! fail . We!p�l�e�>�provid�N coherA�theoret!�!�!D(rough whichb viewAYdi�{! at impair��j�lte�i��cel�{�s�� speci��0ty . In order!�� ��[��aFc!� reme�E� routeHshortcut�rnd so\th�.Ŷhav��fai� sophE�%�E�arrepres!ehe�B�i!��Q�|i�Gde posb��F�yramidalm�C!��wus know%=[��Pl!!i) s�Gbecause`the!�tr��5�el�Z : as=v(A� expe� n%BtypA(�^!� ) lorERgz.X, diffIgY sɥfi� * �Son po�>ial%AMscrete �P�-�c�� Each  , referr���e!"'s�� �� , ��is defi� -��{!=�zm�( mos�9tense�[��eA�d P nuEDtowar��e edgA�f. }$) ( Fig . �—elsewa�� e�A�aa�sila�[{ � mechanism�e�=� ( why a=}�es wheI]�Nis pra��!* re )opaqu�a@how��m� A�]~�^s aY�m �.$is only sl� ly��mys�>ouA�It&believ!ʁy!i^~ACv%ui��F��;�sut t�� �%��]c� s"_ vicin��$[2]: indeeACe'sA5h�ougD mallam& an  r�� re-traced�w%2gh degE of a# cyA�recor� .� &�  du�v�exa���a�E~Y alyz�!Eloc! ,.� M᭩f $re 40–506!0[3]–[5] . S� e�.suggesi � he2�con��ed!�)ua�~mzs e s!A����(�� � someA�����f��SM� thus seem%�A�%"basA�i�U�:mem� a cogn�% [6!How do�conver!, v !�>a' n approxi� �surrounEs�? And w!k.� �x�� tant�K�@!D.� �? Ie��<e. could9g mv�_"� , af�_ a��0ts ( colinearaN a0�) ,tZ� : edn� ,i " M\v �' reig? d digm!�OmapQk&3 .Ia�b %QefforAgo�1�ve O deri�� I�W�� a�icitly�a$� y!�bo�Je:>i�2J[2] , [467ABuAhis� no[ ���Ju� I�s�keiv�#!&2�.�,"i�� n� no direct��!�>�mapE bfst�$. To under�M�"� i� mm�C �to�.�)�6�t�OshM���oloe.�<= �PB�[8%�9!�Ifqrew ct. selv�o �B>it"�featu�m����!!wom�IramountE�&�� f�#�=���!�rimar�termin� of eG �'su��n �ne��um�c"L of s��* S u|corre �� +m)�|<.,�-f� gene�.y&2��Q�*�-9UuX rret pE1�-[sm�o�!. WfiseNoft�Uppreciv.w%e) f.f9!1 �<�"Q --v!����I�K s goa�to[�]��&7.%�E�'—in Rr wor�bL,he ���� ic ,�. I �way- �S an2���|m�a��� F-: if on�yvnXQ R� d>D -_ij "� to� o�u1heэ���uX��M5!��l�U.�� [10�F�*�usaWu�A"�2 AJiE�Y �Q Altho� we doE�A�.y"�}era AT&b �,prena�theae|FC �!.��.�����,)�"�i� 1A�quantifijpredic�6]!qualit�g>�*U!<7"�ze �CBga�*�.w!f e stA0urrB{Q ,�"� i֭[l>Á�e�,��bal�Uof*5 shapr�zeA One !�-V/75�~� !%2�is-xat in nŻ%�� b! udieJ.Ptechniqu�T��e��n/ �����!�� �� ad�)�c5 �U�sE5w Bdsca:Bl—%:�A� wFO��ansd� Fe�. N.>, a*�.D [11b 1� Zdem���pexsmo* � vari� "".w%%inu���tchA)� �� layo@lrva)A�� im�*��Eqso 6A,U؍�Ay)9remE� larg} in�n�t��� �a� �+ A5"�=KAupport%��m�>! intu� &'investi@whe��6WB%M�effT́�rel��j * ��q-sm�c�adrF}��^!UF*��s"%��!ist"dNiG��H��"� *|ar.�a��f2�� bsA=d charac�dE�>llik!?satisfa�esArq�/J���2�.E &'� *�7t��U�A�&d�roper.c�Y>!5apd:���TVqB0described viahiceUaM�st!��2o-L ed Betti�X+ aE�m�4+c1 aof loopL hole" �F�dimensi��e zer�p.`0 ( X�Ys�e�!�omponE_M�)2X; b1 ;� 8& one-� al ( 1D ) � , b2 <�6two:62.6A�so# (� Method)� J8.�Gbe� <��nA�&Ig �“� cO � ;ens"HB� [1[��"���naLT�drs E'icC!lex�N-5,M> a�ny �Eka%��razgEu���z�.�tw9 +"� i�6� e$, say , vi%�vj�rE9 side��f a!�b vij tx"�qv�P1a�4, vjkfnd vki��aA%triang keT*I.� !oYj pI< hin� s�AD1{1uob� a*� �"ns��!�s�� l ���%U�.��* of X:���a�se���ofA:&6 �A�q2� �JcMo�mB:.�6�m Draw��!��oncep��wb�1eA� w�Q�deDM$}�� deviA�a&�a�ogu<"�J T�^��` l�.l��pF �X�+erm�"� . &� ��&ce7 ���2�v� unfo�"E}�4, T = T ( O$K���?.�a5��Ie ( �ce�F�q7zgrows ��uaJ$y�N F It1{E�b*�r �emerge&!{.�.��� � g���de QR-i�'� �%".*%�#? (be few data�Y"9G{a,/ O. @80#i �m�, enablB<&D Azn e�%n�"t�b� . Even���"O mi�'QFh2�1�ms*&,%aAL.q>/ 6ta�'zc��� )/i�.z�IsteU�~.�.j'�&� 0al , phenomenV#��ts :�=� ,R �b�5���=�.��" t%^ge� m�e�i�_ E�~Osig�A7.t.����w framework�D �������"2� "V: O#a�� �!"�D� )S s! A�& �n"2� "#A�!R: ��s�f! �co6(#�met� ���"W i%�J7X 7y 6�5J!�] t2M", . Fi���cYN�筊!"{�� Se� ?�sI�K���(3 s)��(y8�}&�& no�  Thir �rey%�rA&~$goU trueI�l"� �inguishT #pe�' ce b�%B�E�A�ri��)ya�mayLb.%�O"�u| ��gh_ a��tRks!ms X��y follow5 �.�*��paperainew� ve�(m� � j�(>� �:eyur.v�to stud�Y�dynami�.�.��A��!;�^%p�\S*e��be takeűR,���]�yjadnumer����x:um�biophys���b2�*!�� ;( itud etc .behavi�,.B��'s run�sp@">out-of-��� (E_K"�A�(g��e�pur�`�W"�&�(�sak�� t� ataQs0IKf�F� mp%d,�� $� �-,�!on���e-�*,%ׅst� �e uask0h���� .aŮdecid�i b-)�t�/MT�$is5con\,��)��(theta cyclee�EEG 96�a f��e�0q ��8 Hz—I��$�uni�pro=a![1�1�sh#�!2��wem&fbe�!�wn "\ MK� A� �d�fb{a.araahA@=  . Ab")� �speaks ly :ifwca5 �>o%��_�ecue!��+���� y�#E� ignoK�detailX ]*� ,�1a�$ike burs�; [18]�@ph�Mes$ [19�21] foc�instea3mto" &� �n( N�="=��z���+/��Ri�I�\/( a�. (�#6�^(aD*47*&�)�ASby p!�re�&edYJ ��'��nAZualAE'sa^aGG$tQ,b& ,��&�a�s �id=�r%Qf��0edIsp,-A Se&���T�%,� |N-!u��E6�achaq s 3N! ependw)A��� , f12R� N�gf !%s�e! !NL'U2weŰ�,X5a�! �_�A6�A(�#+ )�!���a�2gl2!o��) z #�Udivid!�.["� iR�(fval�f�siA;~proba�z rib6s PM�� I� +2� �Q��%��3e:LjdA2� ��col�,��*v&A�(ck ( unpubl / , Y . D .�L�0ED;|�P �fi� +0g-n�5l2��* mea4,,�$-,ye�MT�,U ��l�fu�r6#��a�"w �at)w��Q � �aa� move0'q�.� .���!f�pa i@e�B2�+� &�(o�/:�6]z"� =2S"� �*��= minux,new2�[2.'�ur est])&���i�+o build�4k�!2� %!c�0e,2b�)���7I�st{6ng)��;s�f����m�}��#E�=!�,�2�Ny random*� drawni&_s�J&i�&n�,!462�N����5�8akM0�zinI2E*�"�,e. W���clu�w� "��m��2B� ]2� �f���:M��uTouRr&��6AXA< [capit[I��5a�� u� J�i>�����% �"�w� � ac�xF�8A��arbitr!�� �mhW�; eref�voi ly bro�r� ly narr�,�6by a�� �*�!\{i,+_&H Ն2��F�faq!�hUI8wiW4s;)E-1ng�rK@$ y co�<(<1bi�"s_#��mi C2��9��5 5ur%�ui�s�a�1 . 2 �7bE�.�, l� ��jM�+R�toi<h— ,u6—h��  a 3Dy+c atQ�� i�i� !�vis�%�;Y!" �f%j!�u&�}�Cado)n�:2�Y�:^=�u , nam�LA at\s� �#of�qe�� "ut-v0�aj“E!�6ed9�m�%�to�ss'2J��a��,. Cf7l& �“forg�ngl"�$��5�BT%�o��;2�D#�,�=S"Ra%�8!�> l->��=�?%�. nY sA'/>�#� ����~�*� a� s � �a�(MyU� ed )�* I2��.+ : Ou a"i*�+!3"A �����!iob� a3Y�1��he}Mt*�`! � B�1�6 3 , � ��T&�$H! a"� �(�,�e�>sta~6 %U| �5�c�siK�E��kA��%�mE�eq�Zdeq�6u+9%H.�2!#.c . A!Re� *�: ��2.��A2y�a�*xq>�EHst�1lp0-5�maI-��%:���;�ne�ar��)+��z(in a��5I�.� � A!� u�v linkB&="2!ofU"g  er .%# �S^1ar� f83Z ���*�B� funZ+r!l: &horiz�5l bar&�*)�)_ 52�l�1�Q�. A7? t! �'L'o? l�<as6n�%š��(n6pA>am��CO�ora�"�(gle��j� A���:�,Eq �Ng%�dis-�ho�“.9�: leavA6}��%g!ata;ru3 �.Q�6��ubeaute N4 [24]@ ���pi�3ommodaV s` �so�� 6 ��L.� ��D%a(�;���2�>"� ш5�m_��A+�"P(HC�;, circ$Ep� �%�otwe1$l���"?�hc�2c.�bar�. �)�/Min ,y}�.b?*v�@6j�o� �vq.�<he��6�� !�/ ba�0edA�32�B�M<toA�rI 2b. �E_�ddq�#)o��� �"� ��th"�"t��Aprofi��[j�aE�  min9�b�*� of&�&HF" t�+^!Cse��5i �ll�Z  CbarcodeR��- “scannA .��e-[2�.v0�.��0&n 6< AE!!EE$25���  setCnar 2×2��rZ� 1W2��4!�op =�(x�%E��@R2similar!�%'�6"h<�  '�ePJ sF8fic�!�ofE�]W� �+#6�"7,�detece ��&. � a�!�6~� e 2-&.� ��(=)casQ�9�9!v�!�" / 1FR-#.�$while keep!�*d#y fix�[ tr�!4�0!�c% : �@&�ly ergod�5� �u�pnon-p�Aen� as��|.d-�wag7 �zfic����O , ad hoc favo� o6seg��h2t���A���� pa�:immed�7�?! V!��  corn�6��G� th] average8�$�Y�"0�-$�3 open �e�p a r�yF�J�2ma�)H&{%�kepm1 b rang�(�CWal �(��| zI'( t�!e�nIC "�A.&� K!��?(s!"�#getl�G��q)_��%�LasA�, 3�n:k!n -to- Xn5 -d�<� -�XK"I , Δφsim a]3b2�iF ogra�80exp�� aske�<eAH� MI3��U���a���kEU(�2�$"y"ib"� X)I��.yl70(6'/;2S/)!<:�6�-�5Q�� ( 0D ]� trr6E 1%遡|)�s2��h9�a�100�B:f�&�ly�t!W�p��of�p�0*�9�1#<� &�of�|!�w1nmA�q�la�}#2!�40 HzMFaA)!1I�(�>i�;nQb`∼10�K∼90 cm 6�Nop�A�* j"�ly �N50�400%b��InG�� !�ei � �!��c{"m��:d !�//<.��"Ecombin� I".�J�we� �0��"�!al ‘ssL’U�"���repNR d 10��� : 10×-210 , A�q�Q�w1Ci�� C9!ba�u�R�Y��B� d%��1q�.��6�"AD%;Dc��i�)i�2} !H�P"k</y~"_y%&fzD at? :@I�Q&� $v� N!{tZM�resul�AMhCKin4 #q�n�D�R�)� :m�>�!�in$ ~)�Mt d]�f .�J� 2*#dia�%"YA�*�)&2�i�&Y�UZ*L���u D)je�!S��]s%�N!u�dot:,� �per!�aC9��M�3V>( (=�)� 1 �HU�out�B�'5:st �E�NBa��Esuc�fu.KI�$2��IP~��s ���K��C�E� M�}/xcol� x;6t�e � !m!�F� �FigSlegen. SD1�-�/C"�0���]f_102�,��,"�ya rt��-a�; blup@t��/e&� �ei�R����r�ro� .e(6�)/  ���aiI j2��+' longA�i8!��^st ��!�;a���&� ∼2��2�&s �"F"illust��� ��,TrAY�v�) QLe=Ra�=B ( N≤150�1&Xby� IB�!�4Rm by)A ,> 12'����T�].^��!�O�A� �Y)w0 veryM_N�,-A �1CA� 3cel�+-,� eqA�al2+r..�Y�. B";ty|Af�b'��&�AA��eElph��� cloud2>ݑALI�FjZs|eoZ%6p �Ax�well-tu�))� ���>cap��2�n}t in 2=Ni%�aqg,e�� ��7BKa��49a R�fuzzyg#a�a&� "on L:� ubmani�6�>!�g +-mMY.� � ��atR).�� �:IW plau�S�=-���i+Pk5clarif�|R2D!�� �zheY N5 , S1�S�.\%notg3th�/�L%d�th?er���b&��1c�&ai y�,x �e�b0�[� ����YL�spars�P�!�-� �)���Cea�M�!��ns� �Tr6'^�2���,.�\ t,�NU*1C of L��$ �!��&(m�ut�.�2� allN�MCL���s�Ww�&o�4� re�< � �>lb � ����� Despi, stochB'62��ei�A�p G A�q�vT��a�O: �3�2V��&L,A� ����A,m�!qta�>1m4cA"k:�nis ≈���w8�<m�blo�b"|[���O`a� nd m inL �Z�)s [25uN2wR2�K6h WEVra�t� pt U3uo� f] them*�Nr2��aBMoC& ee�  . 6 ) c"� bL%�*!I{Ab�@ps?< rapi� ��y�E������&k���q!�d�\v� �E y"�4� � ��J�&I�(b��� o�^�*b!�J���i�Ia� � .�LtY[�9$� �J I`orw onare `#�62�#�)��i .I�S .A�G�)b�+�V�m�is un�l�!d�| babl_� ?�v(,9!j!~���.�� .�#1/�LJ&j!"^,! Qme]q�&ATvI]&VLE(is��� QZb����!C,A�*t^F�A�E�i��%=1Nenpin Rat A��܂,B,t�� @} a� � q)�a6k#ez4B%�([�[c.�9"�Gm Morris wa�fma]M�5��� ��c"�#�4� v�����)�F�_L�"P Ibx; !l�� . L!4 �6.CA�nm9.�2�!o6%�cquasi-���V .E���� %�.B[P��Q,� "!f�U,.BA��`l �C�I�iI&X�Sath� � wo2�.c:funda�group π4�TK�z+��r%c e� �Vc"�T���� 8>$� samei@u%�or� �kC&�I�t�=C�)c*�*�Na�aYNf)/FF�s0A~9 m>� !��NE; �_ �6? Fy63!>�2^`� "��.bL�&*�J�!�� }��!i�“�vM��ir:�Q'm["3:�_� *� 7UY8KR�� imagE#aP� J;#d� bea�uxD!ZI�a��y\si$F-� a� littEo������D.�&�f�>.��!IiJ>u ofA,�`egem�9id�%!$subm�A�|8�4��e7vSLUn 30% (*b7#uF�Fi� Y�f�?i�7" ~., �a��!mZP�o��1"� 5"�+��,ABi&�As�S:u1 ��V5�*4iiz�/�A1 [l6Ihq4�L"4iv�kh���v}m��]_"X /guarante��Ca!4� � >�J_s� �d1.*a9bA�6��)�t�NoutE� !�"�.�W F"� .�� ,�o@/uIr�s �*U�t&F&%-Li��+Y-9�.�=�"� �sum�\�u2�so � ���S �3 ^2�f"C� �2enz'���$� .0I~��"iUI! b>R-V�Fa8,/ itself ,]V�YX�%-G�5Bgp9�2m4>L5�.m ^�c!�in"' vglobalj Z�RN"�!>�Zbea j9�8!$be ‘agno�’�� scop%�%�.^%�eask�-R�sets limJ2�&V.�UnIIr&�plO>�>&Ht)i_'I�Bs�E�ll"!-F�B���&�gex�0iɎM F�o.�F-ݍQF�n}`aB� �(���l}!��&�_!'nti?X"U �.�OeYze�ic�)2H�h3!�mZ�� �iuEx�, GEpe�2ng �-^L��%� romi�}=gr< �>BEA �~ 8L�. E�-Խ"%9� Q>�akd�4>�e��5���D� MG�E� �4cur�)�$�X� 27�]�B&E*�3b�r a Gaussia�(~� (*0�ivC��6�]�a�>!�-k1 ynap�p{�V�&O�C%E�nd'*�C*NZGI�q$�)�aM,��$f,�N is*� 1%1�>C!%�y&�j�a��(F 's2�>A�E+�zM�7.[27�D� 2 �a"~0'L[28�`Lv[�p嬁iQ0corTu�i�Cfu ��D2E[(t�e�Vm��1�[�F�9mU��*.�"J$wp_!%Gu`^���t���QsubH %��I"�O�Oa%�"�� ��`cip%��*� � us,aFicm{.�*�l�A=.&�rpa��e��8esH��!} *�Famultip�Yi��af�\�-6�� "ov!�V� LI* -8-�:�\'s���&��� u�.wo�j$OchoAP valid_�g�1J2l�'��n$ %Wde��B� ى<��)�G#2�$� ,2��w���`exUU"0B r�!���ev-_Yk�b�Z�O.:N!�C��AttP#or Neu�Net�QM! c9c���� am&#�thing;!��ef�Bc�\�v!��M�F���.d��SA�M !4%!i"�7I� sQ9exact 4slzq�N�5"Y �M�a.�f Lbioj �N��IAG��` (��"�a�%�-ge�h�R)a!yer?�O���=�y'� ach� .�b@���5�m� !2�n�@%��/H )�N�#a�>� I�.�1�f�eiM:�]l/}��LT!�.��!�Dleal� )��ABf�g� ��bleF�EP"�*�@6�(-1".�!�eLMrif�Nwa#i*.�e y~�}�9<ADa ���9��]4h R� ��>~=VuW�f)�d� l|6 6k�V 6�lZ��I�'7e�2�;� l^� .i:�%!wc3F �"�u�rE� no n�2�Na9�ori*�A�� a �� s!���I�� 6���i�M��r�� "6 aume�"1 f*�؁�E�Y?M#ie�&%O? d�3�.Rc|6;r:�r�Man.deAX s_(U�F�)��^]st�ѱ�m�_ ���m�p� Ei&Xas��ab�."[� � �5e ��6� ��" �&�e�$�;b,�=�5e?to�wNf ��v!jla�1�6asq Ea�m1 ��FR�&Q��x�B�":1 at g��$9��A[l��HA�W0�M�!�R6���lav}Z 5�hi��� > cap���2oS;g"�!U�K�!/)&�W�E�T!!�&�~�ts2[.�e��'� *r �C( enric�W*) �!ء)�6� -�!Ax&  -U{o"�.[�2gKh.����ys"N'"[30o [31>I'���&/ � shar� �)t.&8 x6?"�폩�!�et!�2k*�$F3U�gh�� �=se��9lovejU��N�| Ӂu� :'rE)p�H%uya �dEr�|^:AH expa��� dap&�zo02� [32]� � :e�rday6�(�D��@icwde�F�&)S^M��gh͌) [33�(UD�)� �&�$ by S�!�8� [34]ga� � ��Q!!�%�B�Ql�y� �%�%h\��1�Mx.i,�le�,up��`gF�Pee, Karls�;�3]-or e��Eh1!%; *�6( ≥25 7) �4s��coB'^4}� .�"���� �dh�Co v-�?�A inisqL!�29�� !��J�% eakl�q-�!u{�f�C�=�[is<�s�1�.�Ia�"�^e�"�����u�fbg;xK[�"l t.p `%u�}O$a!2�d >*�� ��1n��<d , perh<(b��Pk ��� y��Ewit%>�y�Nl�-z�u8zE�{.*���y���- �jr�#}e9of.M�EE,!��E.�M�"f,&Mx&/$a��(�,Q�6�a-%8li�+f)�� �Rrsurpr�)a��yBrPFa�O :/")}���.��or�F��� F��� � �A�MYLeAa� .f���R one'�fespan�� rtens dra�g�l� �� w�m}I�a�/A!�zI�suM ��Y_[(q�e�?up=.L=/eeV%b5� R+( ij qui�t`6� �*"�)�ice% "��N�_a{� docu) e���y`c AgBQ �Q�2E�9�aa���9zJm"VQ"Ly�n�=� cCn @�AZ���UD�֍unca��e6�54� n�Pteg �!��3��&� h�AatA��b��!n�)�dFo�c6#�L mq�����c mo�1E��Alzhe3�ue�O( AhoN�* �%��$�jr (8 r��w'�]�A��Aiai��2?'7[3/3/!~pe� �`��mBap!^AD*# o�job"�$y*F"q� ���g24�" 5[��[M\;D-��Wy -+2f^I'G!2,acute ethano(toxYXR:�] ��#�-��$B�NAT>E�=�!9a dose-�2Dnner [37b� � omit> l�8!R�� .�[38];^�to�awo�E��sowe<)of5�om�� �C��Ȍ���& they| M�!s�b�u"��:�$j" ���>help �flP a�� � ��RVW ���on $0�� ρ� �Zst . :�e"�-�-*� depi�H� �>of&�is Js squ� ���2cenario�.50cm ×.F,,��-B� ..e#1h!?�#Pow;6�FICI18 x�&/2�L"�Etoɘ ��+G,of 25 cm/sec&� �,0 to�(T;d�M'"A!�wX%���%=*�G9�s:�F���Fu X C�"ѧpo;7�;�� �"�F�}wB (,�9 �2�FA�4�F.l$s)q9.HJ7TMbtT��5i#P:"_as&�Y[3B�����c��c�r)� $!K/*�2i�2� reI|�nm@�d)Sg� a�uPoink�+ ) [40�Ipi*�2Q�.��6��en!��vinhomoD �7b�M� � ime-�/p�b�"� �cha6b-! UqUd�� �+�""u8�6aLj�G�=::Th�,"e"B@�&��>4 ao*�.u�oD� %oI�“erro܄OIes!� �kc36��@e�=eG� )<!uLK !7YD; a8m��El� �%���EkA7$( cf . [3]N0 λi��a�"L]Kcinmod�G�a"deak�05}])��*)���,�] u� �)�)Ip�V�9M��An�r�)%sNP$HB ellips�^��omni-"�KaF�Uy��r �H2R��s [41=#��\g��x56M_bet@� �=2�ad�ach��wk k�.H0�_��^lc!h=`s&� ��i���7G1vS"c*T f�d �-��/s-m�&M�1!. Bec��u��HP�%!�Au(A2 �A��@�%�sa' &M ,����Tat0�.�3 *� t� —z�:��0!V!��b N �C].� �s_r9fai�V�:��G�� N�R9  N!��:6MS*�J�9�wZFuv�mow�)��sd&;%� &E�/FI�Fig�u4�5c0S��2N^2���"��a�>6*�a^2����� ! "*�6���8bD�=i"�a�| kY-��}@>�)��R .�%stZ&!uT-�.�2�g.1!utiI|ir�i%o� � add�c��lo&��u ch ai?�*v�['i�a[ �)teۅz"^`^J "3�^>����Fn�&+G)!i� R �Tx>���x�of# Nx��]g%&95X<.��r�r"7y� ak_�:��z� 6Kk|e}�35�x�- Bool� �&�V�S�~6�Z a�anoi)U�.���xclus�Co�j "��s Let Σ dem!���f.�. R� �ak���ofD, F�H�cɨ vecg-�>H�rΣ�k V��&t�u,)al�P�F2�:�%�� e"".t.Gth2�Y�Σ� � co�K� su�jn�YKDt 6�U�� o u “ep��in l���b�lJ�g\rdor���2c U"� . 7%�6f �%�e��s� H��%}M}�a�>>�� 3F�!C-��Ԋ)Σ . He�m&MgofgisA�Ѝ'9;�vW�XLikewInN�E�B�!^A�QR1D��i-s�V��{6HiE�E1D grapK�t�$�E� �enh;i� �a�tQ�� = N�0+ k≥a let Cu'�&.F*,s#x�*�b%��J � %�e�;Ikt(.Q &L tog6 �lan � �u�[ 4]m�AH4!i �� B �� sig7�U"H#:if~dd�"���)8kN@�(2�e�w)9R�0�(1�p\I�6� ]ga� �(∂: Ck→C/ IUa�ons&�>0via"?�/s rA�`!��� �Q*� .,R�sC8�q; a D"� Cl<�g��AVsuba�le�AN.5'�! �V;� a LM50Z_�g�4� : Am� lemm ""�>aWat!z ○�?.��!(-U� �,mpt� P )$ _BkAa!%+a=Z�%�FA�� �3EOJ�Fas�,i�oni���k�m��-E/c"�+):&���$“�����k�R. C�k�:^J|me��E�CPH^;�oC Q EY%�J a0�!all�E-^)CMJ 6�+1-�a|�womζ�9η)Z� !0��� iU0ir��K'aQgy:�6� ?E� d*%�Re quoti��.~S3 >)AW=�&m�7n�ivale�cla', ��5���( nher�#%��/ a2�!#T@alz� [ζ]+[η]m[ζ+η�ccζ��#)#V 1 ��)�q�|2m�Zl&1p:AL $f : Σ→Y_AAmotopy2))��2�&$g : Y→Σ^ at f�gG!Ptopw �i}y:��n YEPg2f�2e��!� �*e#$mV  eomorQ��i�F)02�9�U@�gB�=�A�urk!l�Wa�.���!�aGMr5�ve6�!1:vs�\7^iz��_r1E�hi*�e�w ��Y� �=��de�pC(y arg' s ut�Qf baryj��sub��-� mau]�"�.�*� )�t*ri"T��:Ee]d9+a� !HE�� � ea� familiar �r Eule.�{�CBa "�% ura16 find��� zA llig�\��!�� y�'�� ���#*��lxer�� uwi�Cemp��(“>cal�8meaQ�&� . E��C M�6�h 4�n&):�^�C��ycl�!�1-skelet�=����1Qwy/o3�-2>D�+�%��;{PFiPF&kPFNA�y%A�z!}d H���� ��5�&ʃ�H4F�� 6NIMi ex�{:�(g !Պi/�� Two$E,&P�!�&\ �n� �eD�� σij� ij��q:T�' s PF�PFj�Ů /��0'd/.p2Dwq� [ijks��!l]�\^.�,��`PF] ׀�n�*�c%wD in N�.h if���� &A�“Čec��2�a&:[�� ex N&JCI"�{*ci�%�of PFANf���4�M X D^>aK� n�0"Iu���)gB-:�"��) ��� aH� ��]Xlj�!N�$Vv�^�KO A� ll a�ekI\6� to X5L ��%ST6D�1�D�Z�����!=vach�!w�O�w4#�tb(�n�(�1AMnd�L{��r�wE�e ,9V�-���%]ex �3���a "��+e �!�."׉.�W��s�&$�����+�6� b)�e2���ba���"MA&�p�"3.'2�Z1�+!qpL>5 �%d�*�{!�ml�M:k��9;�ps�A,vis�[� !�)��0�'�%�P WU���ba�*�M!8s�� �^]�|40 l"Tco"�$M � V�<b� ;��%&��%�:�2�4�(Ri�U#G�=I:}AoA�L B5c��A�cj co�{J�{2�6���;��i2_cj bkfb� m0�X>��2�&N s�s��s��2}(�e�sia3őV�G1E%�� 9�!,!!.;6tX N-�!Ofix ε>�� enmC �JoT�rul�i& �3E�M"jY�“u�/2���T"�� &�;o��A::O/4FJ��)�Piٟ.�5�е<W��2�!D � Y#*� *5 �i�X1"�#ach9��>go�fa�vi� ua��.d�{%wa�f^+hi�V .*edX'3�.!�.4���2�n�D |�=B� mq�yus/p�isA��!Gto>>PG&�.es�>(��I��8 !A"� a��', i(��&, }"־)1ݏWI]G6��e.1iyP.K�?or�����w�<�%�!�fUF�s ��X-�B~2� ��1��: )S?)� 82�.+�AU!6iR��'T  ed ?e +@�� :rBuE���HJor��Si�iD!��atfaithful.҂�f&�6��[�g�isd ,!8�>%�R�ΣE6Σ′�^ et f  }HFmap: f�7s���edΣa a��$m k′�$�"\n�o�tR^ f# � (m)  a�#I%]"�to )�f# �6a�*#��(af; hDi ���jq�V�K3"��@s �$|�ucC)om&��BCH*zULXqIEq( .&if5��aAi2S0 f* :*→*Y ) �$E�mD;%&�H� �1��w�Ds""1��>,% }�:��Ib) *g*)�%,y�%�K/ua!$ Zi��e�|���[�4!�.�.��]�7�� au� A]W j&F o.��*C9�J, �K�*%�å"X��Y׏"�we�DL)A� f: T→R+�cW:%A#E�filp3M�F��a�}�("��  aLe!)2 &� M�yM � stoo� �]��E�|JX<uil6���O�NjnG]t��2[!�b� g�b�桎� S�.0��]2of�iW3wiBN�1 [45]�2� 6�%"� a\� NP6�1vull d ��(!�E)i�B�Q� �q�%_�&g"M ���*�I�.�U�QM`S�zm oKr�$ b�I�2 window�/ed� 6 �/. N���6�~(� %:ex σ�UH!"�σ�8�� ! � %n1"in�/��%�%�e,d�*� m6\�i��(.�! !��,%Lg1%LO L9seEuk(2�τ �^�2 eD8�FaGC� F��p�Z�4�fA��"�kAn� t)!let��\,1≤t2≤… n_ � & \%�?n!�!�%�as�8 Q ��i�.�N��F��|%In�!nEN;�gar!��%� xN N��X1)�.62� ���-z�a�9?cDd �@tNEdelsb���nd�ag�.�m��!��!�i�O  [46]�-t!�# *���J�&� ��*Y3G�O� � =ertI � E`�!�u�$aES<�n*�!���)"��)]�k�!:2%�G �ed �%�+7~a���f � u/,�n"fj���ck'!hentG�A(�%c>\'��a>Qn1�R �_68��aj.p�h .� x��GS��Z�|% ^;��mjh!]!�C�o&��A SR��we "�al2��3�? asse��!�I .�D!oR�Qis� ��IV9ke&S�6P�Etur�5Gattac�M̊al:%��'�)a�e63b �_(&� � ��"�/  OJ�3]�#!�Ece:��Dh% ��:#"� Ra�z4D�BI* A�?)trM�r/t*�y#� �,&N.j[.<sLo!V b2�oco&!���T&��7�8��>.i@{wd/d jPLE����7 of MATLAB��tE��E �� 2 mple�5�bBep�c>���JO5"a��http://*� .� ��d[du/top/prÅs/ .`�A��B�B�=�he�B$tis C viru8Y HCV �~��o�-s�d(vir�r 1��S,of lipid dro;Y- env�!� he ERA� asso��!Y� ��*e� VLDL�Y��v !�gT/�' xe��ory!�hwa�\H*n��Mu���!�)�OSA�(�n �O,+CV�x���3�n�l aKj�B�13EU ���o�c�0RNAN �3�� �0fa�# �in�\o�6x%!7���B�JW  g;c� tr��c. to g��'l�G�s:�-^. ��� �"fz�.� "C���F�j clud{ER�Golgi2�,M0!�,protein kina� �#J@adJe!�)- S��G�4, VAMP1 vesicl��nd xQ�� hA�Lre�� endo�5�?���^���del�r�!o�5�upo�YJ�nU� -�P��F>EWn�����9i{E W�s�ej5( T(ptagS4.oa�I-E!� moni!�.�]&.G�>� 'DedcoQ� "\ iso�"R-ZDA�I�� � b k$�]��Z%Qa�4�he esyB� ̕� � NS2Wcq��LT- a����v� microtubuQ`D"�E�0 hibi�U�ocodazol� Sub-&�Q����"pwa4�I�A?co��k )����3,R�S���m�J&K Rab11#W����_5?G!W%��% �p�j���3MW ,5ZNLapolipoQ!E�KpoE�,:�i�B-�=nn\ve���;( #�600bp{ ��s����=�. poly1V�� wEay��a%9/���23" al iDo%A�A{ glyc1��^E�EA$7����a( NS y��s ( p7 ,e�n�NS4�{ NS4B5 5B �e�o��-�!5�%T�!��Z�/culK c#enh�CO�aCɡ5-����D��DA�V�b�e�! vi!' lifeG%�–͡ �eE� ocy��>�� �V:@�c��reJ or molJNe!uCD8� SR-Bcla�!�oc�ұ�vgAz6F,,3e��6��|�4y AW|-��djthr�4nd�o� ! �d [��12�FB"�sA~cid&A,I�icE�OH!�syto�Ym�"�I�u� np +V�a�مa�ran.Q�4u�:d&��}ic # culu�> ER ).�Oweb [1��[1^Y9r�2�!y����!I`�l=yţ�U�!{b�!_ � :� ( LD�7�7e� FՊ"��!R" �s �AM1IN����>?a� `�A�e[al%�.ㅏe�U ��j [NSO.t BLNN�B!E� #-in���">�߰0A%y�� or9capsi#3) �z ppea((�*�a��f��[6P�Q2�.�#Qand>?5E�j�����{� en ����'r�[2E}C �.� �@�C@P!���ER%_�se juxtaɗ' o LD�e2rL�4elI�� ��H�!6;l , [2wM�� f�5~5�!�P/c�Pe��'�quV '&��Fv �!� docu� � d �.�Wi�R!��m<m� ������*;_Y � ,(�N�"� 2�z at.pav���*# Fq � E}���f!�^��!ÅZ��$ K2� 3�^a��].:�"��KA��|��F�ed ����a+riAer �,> B �"f8 [J_,zU���APlow-d�<ty��� Q�- �vP�lV � �� buoy.WJFϔ�03-25g/mL6ll�-{� p���a b�!26k� ,)�A�\T�<�����$Q !� `�^l��R�� %�)(�OPur�Aթ�sbdi}dRArph,��jEe30-125 n$S�!O% ��m��� f� )� �!�sy"=!@�X6�It��iA�. S�8��f/�RNA� si &1�P� o��a�t�c�X. :�.�0so�.��f*�T  , Apo� a~ iEf�U�3%�*iX�-�c[4�J�� �3A#i�! ��wz+ev%(�-!�i�,��� -}sV��ro��d!vr�B!�^ �.�6�D��P� ,�"� d&� #"� %��Q�b�! 4� (p!&���J�> m"�!SR .C�!�u�)�!�� ���cQA.�'�usu��ly�"fo "��m� HIV-1 b�� �V�!�m� sto�=e�` ( VSc3 �  [4��49]��}m8�e�=in ?-�v��."&kO�'Qp3T��I!�"3Tue��-d;�a& �l ��;�a-��].�%�`]��eR". >���Z�O�\sb2[�i�l.aun�҉� libg����ed �Hv�6��rL�h���122 ks_JXemF 6'gMq�#DharmaciOIn�}�up118MGia�a|9� bte�r}�!�|organ*lK6=% �}�2W,2��=��%;��A��"�� a�2'" scrR��t�. re-t�Qs-� ��o�UOsN+to�U�GaobA�*h�\ infl۽�G)3nv���}��an�otypI����pseudoA�R (pym�oT 3�<)�.pB.� zde!I!&subgenoKpliAr 1 [)�A�W-OA3per@%�|no�`ng5 ���-��7�aQ(o Huh-7 . 5 �%�N(G��C�M48�#7S����H9 w�HCV . V� sup��X^�$<1�Jt��ipH ( dp:|�t�� C*�Ix~�"��A�?5twL��&�� n@Idup��e` A�$�Q45��as-(eL�n irrelv%{?iIR%( TVi�*��uE�yq6f1us%bJ#�� m�han 1&FU� }� �( >65%rA�)��� !��'hit�aƥ�.�e[��Bai��L%�AS!�si�4T#� off-���h��< e=��%:���2��e���]�A `i lu�O�^ ce-b7}�)i-�s>��ATP le��:'�5 5I��5AAl"!���A x>" *�Cl���&Q� � ( p<�E00AW��S6`s a�!at)�n� ]"2� p��t0r�mo�pE�A, \޼-t�a� a`:�=%��%�6�AB=�intra-E��%��G fv 6 OE'-6�.ue�#!4�htio!� v!��u� da�'&�qi`�U��ngZA�!JA���m�� c\i���4 }di��tI-:DR �8i��P� a��� �nYQ�i] ��EIP.�P  >�"C IL"R9@<+ "�%�5�"(e���*n�^eX^Y( SAR1A�to�O�Z� ( CYTH�$�� rgo �m%��wD"� wg( PRKDe AP1M PI4K�CLINTa�#�g6.�GN�6|!J" ( RAB11�RAB3D[>ACSIN ��!� v-sn!��AP)��A�8���TDi�.� � �rB ">�. A��^�If.>�Qs-�, ARF��)�A�� �6Q�"� �p �$a�!��Ib��ldin }'S��"� e+S � :�a.*8 ��Pc�3���d&� re�$�"0( RHO!�GITADWA�4��!�Da�c��* �:� l@TC!$ �����E amin�i���@� t!�Yw�2�^�$of J6/JFH-��J�ji�koM 2a !A�e�.�,CCPGCC2 c&bi�Pn�1dy�FlAsHE&Re N-��6r����ݙyauw<��� � w� a m!m�H�=� ^�KF�. ��|?� GUh"�u m �+ffS��T�0 AD&j�&aфng pX7x4:)D�flu��c2+Fl:� %V�Dc��f0%a�mmuno2=&�� Ar.� E{bh Av� &#R'a{� %S� �:�)�c�tJ� monocloO?�n[a#&sm�5�2�G. I�/nd �dyo4t)&%��Lpx4�qHes ��  �G ��U$_` �eM]un:M. Q�#�P ju&�i �%��F�86 . 5��a� . B� �<ve2�% ^%:296a,*!{A�:�L m�"i�!*l�� E2> �utoU�AkRwf�cI��Q�e� i!�!]�!*J-5�&f,E�� |M&E2Z�)A�2���i�0had the expec�ted reticular pattern and was also found on a subset of cytoplasmic core puncta ( Figure 2A ) when we used an E2 antibody that detects E2 on assembled viral particles [3] , [50] , 21 . 8% of the TC-core signal overlapped with that of E2 fluorescence ( Figure 2B ) . Some L$tructures �Lwere positive for E2 )�in the cell periphery , suggesting they may represent intra4%} asseV� . We`n invOga!�whether!a4can visualize %�!�XRNA , as would be expec=�0bona fide HCV!tions .7locMationE examined�0wild type inf P� s us�“Click-iT” technology ( Invitrogen ) � 9%astab FaA�ti- �tibA7YaB !� We observ!"$at 20 . 1%!�cenE�aFco �es with�. Thus%�b-popul�sA5 |re!�oci)w9E�d@$, although-�,not conclude5�A � 7rQs%~genome!~Next ,Limaged Q�movem�in liv!j)=(. Huh-7 . 5 %O$electropor�LI main-tA72 hour! !�1��ReAsH dyA� llowed by��)� confA7( microscopyI�chose to0 e atk post2�Apbecause���highlyA�ressed�$detectable�(biarsenical����AEB 4gYLDA ) , maximal amouI;virusreleawsA �by"al titeraA�F�1A�,}`HCV induced lipid dropletX!3imjtoE*%A4tubule organiz�A�er she�(have occurre� dica�k�J,y of particlA�as initI�([15] . Seve�Q/A�)+%_ in a whol��E�=BC i�a�%}G6�@displayed variousU�s�a�e1I�i�ra�ly!�tic2�p- 1%� saltatoryI�many r!sal!! direc: CFs 2–4Kor-al�V~(5 , Video S���E�}�exE�)�ll��ae�se���a�D, Ribogreen , procI�a�i����!�1�at�%ȥ�lW�Q�W(co-traffick�ofE��فN �iY��9dynamic3punctaA��O D@y�D=*2 ��n�tes����{s2��>s�7s requi��roduc%Ga�vi���ခ�AsA�cu�hearlier� 4ultiple groupsi� published �QnonA al ( NS )!�(tein 2 , NSi�d%�;u�by acm�aUcaffo��rid�sb!� non-prn,s [19] , [22 351a�The f!�� of�a��y does ��19 its juxta on-�o NS3;!�vi����Vch9RNAQ�Tn encephalomyocarditis?(us ( EMCV )$ era^Dribosome entry sit�IRE!]inserA betwa!b!�����r[52 �refor�w4 -�!�wo ad�oz�e�, bicistronic%�uqYtagy6+ vers!77a deleq� ( Δ)y 3��� s�� transcribi�J n��� intoB,!�n!�|l�-� na� tra- Jx �� =8% �qu�N fiedo  a tim!Durse .a@"i , both29c1l Orep�compet�,= �Jwhi�nly�2S �con���!K��cap��� e�B��}3��.%�capsidy� is depend�o� as��!I AO%�a 6��qToJ $:AQ(D2@AU�8*iQ� �f*� �x!m�0��Aj neuta� �.H ( Bodipy 493/503 )�' )d�s prior�ch. All!����d%9accum~ �M largAUn� ric rings�v cress aro�+r>�5��>�1C(had appropr 6F2��Ŋ" .�fz"� prev��l*( < �cdE{F�(Timelapse f.�( i of�vidual��pa performedz} E1,2for��Ev. IndZq(� whic Q%* an-�� )�Y�^ "�A5BZ bya�tuA DsRed�uos�� (y 2 seconds�`s� inutes (� s S� . B>C ig�$photobleac��quickl�| �E�)�acqui*9 limi��to� rt�ov� B�u�ly up510 � AJ�c*�1�-�in� :%�e= 3or2�%�&� " !C���whereasML ��st6� 5��= �random*� .�:MR 5� grea $than 1 µm�aA�'ageA� totaAK u� �%e! simiD���.�*(,; 18 . 2%±1� ,n = 1010�� ( hpe )E�q%}v1�]6 ,\558 ,4.�8��5�9a�aB trasZ�f�penc$t-� � rom/��e%�exhibitMed5� (N�)%avirtuaA�nonexis���65-@9�617B�Ext�d�Wo �� �at 96)F20 �Rqdid� show��incA��S-Qv ( data7n� "�.�3S�e2Q�"� inf�al kin�&� �p2W.� cժbya�ta�%� origanalysiU�ve/$traveled (e3nJ%)Ya�-&d��an5�3�mea��� plotAB for �a�us �a single"�diJ�Is)�P �i9�aP.-M��� � �E tens!�19�ran�%> 3-17�ns�i�� acpoiE-hfy�~ C�� �^��res% !JZ�0-5��j�� �J�2� long%.��ih"K��� �(run lengths%�$correspond!� velocitieE�!�]6 q&� by��tra�. Ad�defX�!�iod�6$uninterrup!5\ p�l Ca p�K BM stopAamo 2�onA ama is case*��j!ne.9e�C�M�9�&�( �A�start )=�w�few A�run)o&��u`s swit���-�a*geD-� �c�of*�mov!� �!@2 . 457�±�215 (�nSEM�154 ,Q6���fit>cay^(exponential2�} . 992=� !}ons�tw!= e� �eE I��M��2 ���. 1336�/| �. 010139�� �c�ba\*r a Gaussia�a�buE{, �83 ��.*yze��+>'secre1vesKa+"�!S1[5a4d���med[ ���r�of6n s� �=�-oB( MTO��a�l-�I�2�[5�>/�*+ �6!��hf2���2/o� r) i&)Q �]j>�s �$T,5�:� ɰR�ed O�abU AG="�;*g �TjinT�= er GR:�.q�7A:  S5 )�qs� �1MB�a.� ( �A� WeY:���n��Ea�nocodaz�t perturb�. U� 7A-Cfs�!(S6�q4�z�a=mincub&P�, DMSO ,� left un�A�jX-"u�%�recordi�&K����y�.;b 2$ -��E��8ma6 �ai�W��ѐf��!a�1 � b �against�=U��. B�[9m%1)Qn ed"x �*5,�5��� �T,~domlyAs!,%� iveL��=��EA dram�� d���^�6SF�Q!majori�2�)r �or ��e�v � result!p 5� J)�2qDvalidE�� >I our!i "� bRami .lo*�!�.@>�!�'cofactor �E�i)%� e sc�YP numberQuJH��involv� n Golgi& �sor!tETGNE5xI 0CYTH3 , PI4KBRKD1 � AP1M�We fir�%�GhW!1�B5 �marker!w>}!%:���W� &z 2�1!!6s -GFP6�, %#Aacks )Ac� ApoEa{ �X # VLDLX[58!,e�Z&�b�%d">� h��/u %At2]–[34)��60{� U�of�A� lipo"i��oughtAe��ym a�mbt� !Ais ��A�S-viroq [28�3� �3M1 �1�63�DIn normal hepatocy�,)D���^# by uz !�F���' also!�nsi�#3recyclA2end7aN)I$%�, [64 �6�1�R1W� i %��"� �!{R�. A�0s lea� �i�[w* :^max) [6etW1!� C-t� al �fuUto �)N�," J� m �)X')���L" .�2���"�t�%anG "�u�S�.�7Vo  �c1��at 48hpi2�&2;  i . DV�#(��� j!�i�ed� D��*to���#��9a"�c & S1~ % s S75��)w� >+�is;���a)atsa�>�de nov�,� ge�j�� eabea3�S'2�$We%�X� ��Uac��'waE5!to�8} 25%±=9�526/32�� ?:U��e�2,:N 2 ApoBw �*H#Z1!�0�"�-� prox���d�, littla�2U� ^��!eZ"6-UAS�A# v" -U�%�J 2�h)� !I��E was Rab11� a sm� GTP b�ng��%.'mod� .a5� tn~���.U�sIap�*t� �� in polari� s [6�M!:Q * ~� carg�%�Y [70���W2:budB oS fluenza�us [71��hantad+ [7b&�.�he�(�tk� of Sendai [�%nucleoz# s [7�9BN-Z�%�u6>- co.�by��^^!U�9Q �+s��&���) s S8hS1�� GFP-ta�CA��U)�!G�:network{ aldA3���[We�(*��L��a�ond�!�hB=�Elferri�:�> �3:2Alexa F�" 488� ju�0.d�6�*� !�./!;-�9 � C$#5!9�)�!�-� S9���b�V�>�-�>��<� 6� � 7% (� 19/31�Vrr-5? 0%±5 . 3.?44/88n?,� 2t�r��.=tE4��heN,~�e�)& im�'eU ���ZJi&���\ t �� >b)�5'�Q���E7n/� dmO's>�IQ�$ �,<*s5que� 1ig%c69- ���$D1�эn6a�\U�: j&[de!*uTN �(%6(xM�silen)e�>�a2 �.�s2j-1m6u2two dayJ$ ���!dE!fix nd�+%�[ -� reiu"�)�? �� .�!�a.�(;�{j>5�10���_3a�2i�5.�1350 )�f Yst���po@&v"siIRR�!�0G, us 5a�7±"$42b517�" si-�Aa��4!%I:Jn��ibHc�laa�-�6?� � )G��. VQe�aI+J$�1hAMP/1e�&Q�u^��trb^in& s� iU�lex �syntaxi6SNAP25AfJ) aRE2.�do�and/or��#�l�5 eB�[7;�� �a��n� AgFP-(T��U�9D"� ���&nd S15�~F�  o� -�"&�F�ati�>�7&�ra6vn ( 79] %sV 0�J35/170! ^L:�E���6�9s.�9at5Zu �-~Y�U . It1w[ esta2P2a�s�R!�B���tersec�de�r ae] t]6Fez�:�� lumen3a hl$ w��Qe:# !A� d� A 8�-#_E�{�;Y��� $10 , SupplNalt�F%�a6�8�"� 6 . 0.L33/40b5�Iis ev��cO32� a:re!�-�-]d)')��Fin�\:��!'G�y��;�,td��% I�.�+NA 6(%�]1~y�.&nN.X5 U��L��h�ltter�2��RD% tituY m�oryH"�s�Bmo�� e4Flavidan!B2e8!in [75]E�If�~ alig 45%  =aK ��a�n�l�Q)�� 5Dliter�i6*- moleɉm�&!�:��inBE�t�5edw J=s hyp!,s(A�� t�?�in clw>.�Mz*�=s H2o9=�J"�.)#40S9 !bri ,tog. 6�9$�uc& ;A� a�-*@&manner [*�9 , [7�F"'� � , na5A-i�,bu�7�����ERj glyc&E1/E2B .�8!S.�9�machin�B#7��e�upo�9velopK� ER�i��� a*�53jV�@knockdow{A�rk!Z.� !�^ueT [32];I� NS5A)9 erac�8� [�}� �F��c9t RteF.lyIH�M�e9�.5w�"_ )�6w-F3,"�6 shap*�e�Bv uma�q��:��So=Ouri�"<cl-�i�D uishAT��a�hij�A4intact>;�Cor��1!5_B2�ion; h킉[ab"P!�N�1� is maŁ�7$�)ml�F��9 �� e��͢&M over9)げ�R%�:?. Nm�Gundergo"�%� sA� �� [77� [78]�o�"ERa� $.I&�*on SAR1Ag!�."�d ( x*KBfA* �D !z�2 �!� �e�COPII�rory2 � *is5*>�v���he�&'#&%"&!i!&. D>� ,6a�s�>as R9T�aW@{'nu�!��TGNa8r� �8���)��!fqk �.�L ����'(:%9%&�"M��"%�.k$�t# �9ulo�  6CCu�*���% [S$We.�1� Ku�"�$�!I�AI*�6to&#e�� [80a'wB,�5 find&� o�disa,in�6� or��,0':J!�w �IVt�2� A�1 .� (l:(sphatidylin o�5W%IIIβ� ppean)oz�cES2K?of�g�A%%�o�[8�[8A>�'m��2$of J6/JFH1o%�rDitLy"�!5f �;B�A�**�?[4"�an) discwGAOpossibil=+m �tsJ� gsVKa�'a�ondary"+*.F [t�Dnsl(on�:d�%At��v�B"� .*� ��S@U�-/A�,"q�a�e� ��2�en�Ft�"F�Rab�zQmas�:reg�J(i2��.�)�U�%VRabs �A�3D�2�e�1f) �m�AS""�r>v$O4R5%� �"@$ex%oz8:�83��a��baI�O mem(a��+ef�) "�  APőf�-�,�0�+� A*F�&nd �I�s"�N�-�-�2I[g���/9�'[%^n; U!�� !nmay0"at63sZ�M2!z 8 on�1: b%4. S"%$a�%d ki;d��Z�(� w,>� C&pN� "Ga@!cA�%!�M>!���-25�&�&Ui-a>�:�KqI�5��ng-;�Hs2� a[L>32 ��Z'h#cE�." te�:�2vA!�� has b�GJ2n�2� n� !���*:iꙋɶy3�;��I�Q"8$NQS dR ��7tɻ[84-We+J&%\l$e�+^�%B��-kRab5aGlab�= �|sN�>,:@ E5preQoKt�(9�:4Az!n-rab5&3u"�����[4ADu��des�M�{ ( ex�1gBTHCVpp�I"Bon2�u3[7l at�� SE|"�Kx 2���life 4+e�>� ooq. T6�LN�ndU��H�E!k �"�8!���� GmU�9z)b�wE6!�5 nk a%�H� Q depolymeroP6�8s.99$�-)C.� n�C�RHO�GIT�)WA�Klay� x1��)=Aw�� :Y�W>si!� he ������"F7)��x , but d�W:�Zbio�y*f]���2�86�!��� �N�>�!�*�*l#&E2!O.�<��.� � >�%"y�;�&� , e�isas|o2�.A �too�to>eC/ iffu�S*�(��;"[+�Vlik3ron6!�R��R<eI�!�Ss��S&[}n�?# AQ& �  biV� . B�TA.�7:IUtowar8 J�( plus-e�Y ) �\ &�=cu"�V"BB i�f>"1C clas� u��Z!o%  s�K%�u��M2�L�;n �<;-�sis9��2L� iwweGa�ru�Mut mi�#.��*tU�!>���c �V� :�A�beA6w�"%&�QAo �I NeuroDO ic herpes �al {"�E>�fbGaxV9�( 2@ŭ�5"] -a�h22�Uvaccini~+ �s slok& B�0( 1-3o>\ 7��T %a�j���7��a�U� )jI to Vamp-1��.����"��:�XB�L&S 9.��C* 6"0Ye*ne|U�7;�!�rih�- step�d�Da�.v��!T �J� \w c�dA�� be4]�� k�X� pa�B!�te 7al *u��ZsUh�Pima)tof 1 �=�"*:D. P��bcharacte.�!�JC.�)�l=%�) Ya� 2�m1ER6+tcK�bme� n6[8 6ZwyX%r�Ras� *7f�Z� �Ler)9"� siZ&of �a���wU�exG0+�a!�-�B�� &�M���K�A��8&/7��6predomin�8sub"� {){�!� :X�(8I��,�8necessar�zJe�t�02�7s-;,% s5ws��s�22!�2TsE��N!� ��!  slight!�L(-� �%��%� �e�U at a�;er"nc�San%�%�eOE��0 a��]� awai�!�leaf!c> ���JC1B�re�g�A�,6�-��M=��ar��gNgUIcha��ERI� �� :� ,��Q�Ů��a�&�\Q��)�e�vparen-%!du�5ۅ9& FPW�(���s�86+F�l�+h)H� va��!I�I�cul8system� �%in vivo�O��mp�)archite�a��%�G �ct2T(�usoidaland ~(��al#c)B�do�,���� sepa��Aa j�5�o� a�����Mneighboraz�� ms b?<can��7W�Ao�)Mt*_cY`.��� � ��^oTwo�s�u�fto�&��6 S�!�9�!4a:ro2VL % cy"af�� McR�A !"kn& tSpr�7viak.�ct p��-!^R A�k! F[8�5[9>5FuI�tuE� will.�A{I�2D.�mB$"XHH)�)�a,.Jto �\mat` �1Kl[2-(2>)!w6B(1�,'n5�I . >� �gr!n,in Dulbecco'pVed�� gluc�#I ( DMEM; 2d��la$�10% fe��bHLK%rumH BS:=,�#�^L�Do acid�NEA��/(1 mM; Gibco� !z/dnicilliF]eptomyci�X2�. V*)�%�roccRx[a8Z�[*X ,  Xsup�\1A r�3l! ed da���up!�5 passag%O:�A�A�fi�1U �T$Un�e)u)% +��nd kept� 4°Ci�c���T . pJFHxJ6-CNS2C3 ( WTA0a�"t2a"7us�%nE�� &�>�Ee��4�a��"S�,I-1 backbMaZL placQ:J6s�3ce [9�^A full�NH( FLNCCPGCCMEP ) te��oinp'TiLtag [92]%�"n^%��<�� gene��Y� 3�aV:Dwo reg�( 5′E�3 w�9ag͇jo&�G.9i _>aLIV �Q�O7 !�x�d��Q �#ɉ. TC("3"XenhJ;of>nes) T� �%2 �� �/ 0AACGAATTCTAAT 0CTCACTATAGACC%(TGCACGG,CG 6�PmeQ�A �6�YK6�r QY%&)"%s ng�!@VI+!/fSEZ6,mad`jtwo-parts�'S2%];JLw!�A"�#2a)�p7�� T$2Fas�W abovoaiA?q�asn�s�ViY)�V OaYN�GCATA����GGG��GCT)�A!� (9�6� g� Q�p�8��N!�A�uL�6�suF� 5�%�X%n!�%��#r.�":)�TC-tagg��� &h)өEQퟑ� `�)d!T��to libe a DNA� I5(A`of2�- E">Un.��2���a& A�k5t�c�9"~Y>�|riB<�\!7:{&\2�&�fyT>Iq�%����Qverif 2���!p�,�P!85�.��I� EfAy&�� (a human ORF �,�"es_H�PHEL733202 ( Open Bio�G,=Oii�O ��N�TaWaUTGC"�!Wz2��e�G�A�TGA��A� ( BamH�<:B,'*_! a 1n�-iA�?!�+%!%�9�EGFP-N2 !]]x>2_te!r�.& then!�f?>��#B���CV02764� ��� ��G� !KCCGCG!�b � A!^ HindZNv��4��Q%�AC�K!� T ( KpnR���m!�Ca��DSFeD�&f �#A��o 9376�GC! CT A@ �MC!T!A�gl�-it>�)} -� 9G7 TTt��A��>{��C1}� �a�.E�)�1�)l)f�WT� -�t,2�i<�b7Afcri�@�tro��de R�:!Ŵ� g/µ�5]��alt�p8%� 96 �<���a!�d^%�F�s!(Cs�nlcJA�di)!8immunohistochem9I�Z*u.Oa*K>�x�n5�9E1yA2�[-9�$F��el�-h���^w~T� thre�_ eeze-thawO$*k��DDOT&,Wr�kh twic�&PBS%lysin RLT 8is buffer ( QiaZw>zp�b!�w�iP+d-;��$RNAeasy kiSL�n c�u� @*"GbQ�B��npt� ( RaeaI:2~Z)��P�-num qRT-HThermoA�0pt One-Step S� Applg2�.E�LA1�u&�C��A�$probe: for�!陁{AGC�C�Ձ�; `ae&-CT�GV CAT; O 6FAM-C^ ��AA*GG\8 - ( Iowa Black�NOf�gNS4S CR�y�p 50�A30�d!956�(15�oKk�Fi�6T1 = ) x�HL'Ap� �/z� r�s!� in T�oS� )metho�k!�!��/.�4�#�)]>�w("WBrief5*.O{(i,Zed poolf"[ ���M 1@v.���)�<g�(( Dharmau, Inc .��G&W!}�Rw � ��&�l�]l� L�i&sm� arge�/��{ �I%?ɡ!�1×106B&in" 05 m��qpH � 4 �NC125 pico�;%D��5 pul^# of 770 vo24!99��mwX one-Mf erv�w� BTX 8302�or 7 96-w;C%<chz. C(G%R)qe*�nM.�%�a&*icBof%5 E�%�aVyp�?�6dj,�pA�T��9n ,�<22�Hat 37a� . 48 E � ��Ar"a��h^=us;�^Ő�d^��H3&E^e�xonf�;��3w�Ka�er;�@ seK.>2��Fa�!l.�^j,& C27 q2E�4��1*DlT2�O.�4�H (���))�2��-q�d RAB11a�( Amb!<,, ID: s16073%� 1494�,BBPaB �:A28 >s1054NUair�\7a)�!�.kFA-Uy. Esr"�A��E)?1`a � V�,�J�,see�81co0lip��fix)�� � 2�"� �*�� �&�> ~� R#in/K para�aldehyd�7rmqN{ermea�6aM�82% Triton X-100�%!>2.Ta� bloc?.�z% T�x-20!�go�.�inL頍� �wa Ms�)>V(q �;�!��y-MW�G�. Pri�i+���w -f%?�  j� B A�q�M5o,monocl) M y ( #1851@ osta�pPortl| , MEaHa.t"  ' ∶5�Gf`B� vN100Pds �J�qEng�{%S 7*8 Cons[B�+.b� T�ZN  to EN$Steve Foun�>M25!�*�Z�m��vA��c:�#b.�ID �!� . Anti-Ap:*( Abcam���a��Kamp�M�9 2n. ("6xG�bNx!�+� abel���'nKU��p)B�x~R exa-:8or �T -594u j�TIg�M"�DP@ ��Eu�G, OR )�n�EQ. ��3:�i5+2�e6bL'n comm:sm�:�yFI2zN!2M&�in�2�^A�6%Ce)Q`n�=�@of�5µg/ml�Jla�or�j%����&�xo � �[ruc �pro�K6 T����2\. A$kl p�> 2Y���iBOpti-MEM>��Ai^�( � 25dbinK:� ��3  a���x a+od�&1X BAL|.@, 3-dimercapto-1-�8no�&�&@�#@_!9� j~Z#2�#500�EDT85�rr �z.o!�ree.a}o7���m+Y7e�U ^l/b'cX���prewa�U| 70� *�- �.>dru-h�v72�&�+�%�Y�ad s:A}�.NY.� 1��D6l[, Plug�D" A�ddA0e&L , BD���cea|� P�e(IX, Tocri"!�U��}+ b�5nh�B��y!���u time>A�-G�.1rInfXf�%���D*ZI /Ki�2�to") e<.� : EK{ EK /~*~ �2��A��.er ?mfaQ*r'�.= �D-),Xi�6C&D9�aq2�6O2� �� ��X!���9M�;0"AI%�Han Olympus DSU spin%� diskA`:M}k�m = 100×�� 45 Nm oil-imme�� obje�Dk���A�@ 2_Ie&se!�ex: 480/�<em: 525pQ�9->�_{�Bb,�h�~�&d565.d620/6j coup�t4D HamamatsuH-thinM EM-CCD�(speed/sepeiv!camerS'8Slidebook softw�aA+a�a2�uEzM!���telligVQ� Inno�9:Z0, Denver , COfIF�nU��%�v�(�>=�acc=-ʆbyMPD��2s�c^e�<)r,)�I �X=�@ex�. L�*�Oi���[��ebyg**:�on �:�z�-r�O d 35 mm g74bottom Fluorod��WorldI3cis�<Ie�B�82���Qj>[oA� exceptѩ �*-F12-6�FJfF�*,���*f�*,n�*,Em(25 mM HEPES%[ad�&�aAf|T�Q�chamb$�jseaa4EPDilm b�Qx2<*w9Q�u2a�"�. &�KE�S&v��GFP�h� & as takenA4]S�.��200 m�HQ�a�ch�Olazsf�}�<�l5�Inr>�%sE�� �Q>�*zD(�g/��2� or phrodo6A(�" 2,��効85"����;�zC v&�{�r*�{E cal�<�(by kymograp08T.�Aa"�?,plu�~!pAreJA��:t oD#1�R�z�*�{6�{ diagyG&&�A0�**�~�(i�B�m(8p�u"�~� f�?e�4.�ud�� �S�8by�,he\FB�9��a=�6n|~���; ��Aal\ �a!�z.| tool�-� Qdu3�9. DD��~/vmgen%�� &M�vyx�>  Js5.��N��%n:���;$� ��y�>. Valu��M �A��A�2�v.^��ys3��.�2��usN aA�5A�l �W(�.<�smJr�#lot�� �d p��fo�:p"u��TCID50���>���y*��-��Bc)�Pr6��G)6���>~ V�|%�deJ�} .��Impr7dE`s:*�edM�.�$0"�6allele� heterozyg"los� 6XQlL 5i�W��I!f%(^5t�Bw?X5Ci&��Wc� ���Yn tuma=8i�}8e�D�i:�1�'G �a?J&stood��(Fǐ=hwe mu�9ni@ me 2 A"A�?fibroma�5I ��RYor%} ( NF�ato)� radi9apy.">_ m�X�7neo�=�Y��=�irC�\[pat!vA�E&���!,�!=�z��2�'ou�S�de�&TbGrb10.��=id��qTt�$�2لp]}EP� morphis�`�of.�al`�wm�Iwh��!`I��>mE�l��Ei�e Nf1%��:!AXiX �J"/�_]&Z u� al s�652est� �6 � *N�A�or�S?�7funda��al fe�L ��� tV Resto�� UinJ��^?#o�Gi/ ,i ��s]lon�[�{e nd 'X%O es RL-͋a�.�%: �&in�|ans!:CA4 yo e blasn�ig*�u&(M�pa���!(Ras-GTP levA�..��0/+C\l� tive MEK!�cu�$!�m1:�-y �.Y%�v<:&�se5��"͘a�I)��S�B|&vo)��ea�,H aA tm�n� ce�u\%5Uq!,a�In R�* �ly!Tmo1��hyp0O+�{�pr -!p:J9 arlyQ�!x)Qd!�o�Z% E��-ex�=�w bust.��de=!cd r�=�s�j7novel�סjaBN��!�5^. Dm�typi\s��ic�.V)�!��� �Hi�Ba8��%G�%��}͐ <.��ng me ism��a�hom2?E��B  r�:B� Tp53|'. C��'e�况�#��e�7ixs bi-�ic 3�@wUy)o�g��(Knudsen’s�1hitA��A�. T!o�1^�(aB!*eVA�"b sour?�|luis�"�<i_q�U)p phen,2!��Df�C��0 , F]C2�ch"Dw ��ic.��a �-e�@*�x(rHB) !�2�� 9 A��`ly nullis Pe [|)�bU �6rm"us!.�� �G_�� es M� lian pred�0�h�f�.,i2@ A 5�l&a�l���P��.&IM�c|�[F ���P�����d mvZeeT logu��,*6od; n�H�m�qc LQ,is ubiquitoua�&� ix$m�y��A�nAD�:2�[�W Germ=* s����cau�%N$  � aut�z-"Einheri!zdisp?�� nc�+i@�F 3�R-birth�NA�� :�benaP��g:_ ,�<�j��childh% ,!@a< -recog �!�N9~" [�F�gm�,-��5  ��� i��C�m&� !T.o � adic�Nlethal=' A�A�d�[,".\�bra�K� ovarE�!�d lungX[6–91a�E�enA�� ez�q�(���as�X ��*Tw ( GAu=[1�[!��B�����J�Rc� a� [11�Onc��ic�_ NL :N^�`(Iin41) [12]�F=�Vae �I�+����>Rk�!M������"�y6�i J� y�!�%/�e71��s>�!9 G&O<&( �\Othu�n*i�~,[s�V� ��qUysr %[9�Ii)��.sc�=rdx erapeut N!�on!,�K�7�!X�C�AN!�lA�he��mq� .��moy� yoA{.� ��><��q %{�Oepide�>GthB%e��Vt0�je�5%�2�H)&is*1to5� D-�s��as,m�RTK�c�LRaf�Q MEK1W&hybi��q )KCI�1�i�j� unsO��.=lsoA�$+to!�R��U5mTORCR(m"� �0q rapa�GA��J� �phKcory�6-+!{ե� �%)Kc!-4� ,ty [2{9H�~!-bi&�6e�&��aonrtynodtA�ٳ, ques)5per�W��cer%�%��basic5ȥX�-b���u�\z�AMd2�, S�.�:� survival �l.�qM�.[\�I�]��A�� "tneC_ve ��ov~6�!�m�Giss�. Over� !]�e�Z�ns�c���2inJretar*Tiy�!mE�[/�2�zCon&���.w��� �lyG�nIO� 6�}M��� �*N�iQaM- �Jp��nkMpe�"ya@ A�c�[2BnA XR f enKlis�uin)�-0?ic)*�\��=myter�ra9P��-&����e�at � %� main�&��I X� � [2�� 1y3 Md��IV UYm�^Y6x��: ^����A}=� �]�A��*a E 9aof>X 2� D�S��!h�@a%�0I�I�q�i� �a����m�nal�inH"-�+l nerv�@ ( C��Q�o6�a"� -in �%%�hlN�"���^\��q5-Gn��.TI��nd� ?Ml-spec��� o .�s .E�.&2e� �� �wci�$"? � g�b,��vi3aV�mS E�?al }� 1� �����Fui;��� ���B� ��pQ&N�&M MAPK.�r�z6. s B� !�VMEF�(XL�%hNf1AX"o�}o%�!fpro����{� �@E�� w�B�a)$�!���JI>� pe�聃co-�6�Z dMԁ7� e�gliCom'��tT�B � s�U��p�6A�k�3 �,,�: Hc)�A�F&@ Y� ��sA���n b�-cin � \h�?log� sum��.a"orkq$��.@�i��~KA�"�p��%��N � �!?ZA+!Lr �L��rS2�� &�-�!�set�ofAL^V��( ng� "�l�7W���>�APAiR2=!�s�~ �%�� E�: @�%�n�ue� regard�eal�#. In /"D %phx c*V%Hol�Ź" j ,�aAy�>c��!9?��~!}A�syndr0*   7����  [_0C57Bl/6/129Sv����F�O�,�� {�S�2#clu��sof<��  sarcoma�� ry�kcin%�qu�Y� ca.uY.�"ie+.V p! %W�c��0�`RY4��%(.T867�963:'en6>M<&$. U�l�&�t�x.�\�_s�V`z&�(y0*�?!�E���E7 ��J���ly��� d���r�u�N� \�e�-L&�.�"~x�riv�*cA�.E$N# G���ls�. hall�-�p�6jap,#[��AF���en�je��%& ev[ 6*"��#e�m�"u� ��,������m[�!čuAw����o�G H.xuA8�2�@���` arra !K~�|of� PI3K!"%"/ � d��3amongst�|(�i 1T��!�� @5�~~aYst�_i}&� as����E66!M>9 ��"bKH2bX�I��`o�&B�.�aFi��' 2�* -B~0i�&�Fve ~D%�"� l�wr �B�i�:mmA(A�a��$.�reF��o�t��}�BcF�!Թ'�7na��ga���)!� ^ �X�"��HYz9l�mab�2`I?Y�B?��P TskA)�5r)"�D.�tZXaa�� 3Z �[ eVL�igi�(F��ɟ �V�EBr in 1��12.�de��d��a�mC(��Y�eq ���s[ec1} ��6� �$�5rE `==��6Aun ?� d&� �8at �A a� O' ll�%H���)�iye:� �W�)4�h +fam�[��s T��> Grb7M�E1wc��F�sh�� D�O* (��'(ee�4*-9!��>�^bB��r�Q!�|ense�oB��9e��b����&�(B[n`�"f���Gr9oæb14�/�J��d9n66�)!�]E�-d�to 2p5�a�)��2s�f���ֿ�a�d*I��=<�b�.:r%n:�m�A� arguA��.z�GF��T �]ɶ�2.+(�I�A�P "M� iB6$aQ)M�2m,�Meg�q"� _�!oFs��<0–3�$ u=�� U��Ep yA%&<�%seg � b?03�Z(�>�4� ,vly-� �2� s����he� l���vE%�ma4^>�*#"ţs ['�Ğ���%�ma�"�U�,?T@-�31ust�9"��%fic��-:e��dU:5�=�=Ac�o)H.(s Y4,2�&��<, sel�oIaff&�<�/ �{n�,aA��lX3�&٥" �.AY�Z����� � >���!2R� �te.�A2�X}rU -ρa�hQ�oȂp�+"�AO q.VB�� ��t�E*�^Q2�Irl? "Y � )"�|%�i#� �MٙE���!��2���& cand��!gs �0? �%zh %u>7 � Inde�� astr�vma�&� ���f*U!VTr�*is� ongl�E^�))�l)�1�/ʶ� ch�,!11����5ʀo� m, k )��I!��0:j %_ e�^>�-M�ioC0ŀk2y�5%!�c�^ 6)�z)��h�(�%(),s�6��)`] ari��!%��dB"���*��t�W%6)E!�urr�explo�(�F1+>�n@�/e�ASzWJP���7� ( LO� ���sɷ!�M �� Wd Illudn$ Medium de SNP�T,-�4HA��?&g:xF��"�%r,F"ew.Q�'�dspa�@a�s� 2�gS1R�9T-F���e.T%Q� � ��l��U�u)� .�Q6�:~ "]�)*� pheo ~cy���I�e�!�on�ea�ext2d beyo�i locuB'n �� ke��I�Aq #2�E�o�ycAz+A"s5li�2��6N�iz��O��IA1+d���U>A3E�� Ja�E+-Z��x �1� ^&������5�, �= crip�!^m���. �� ��ortho�<��-��>�� z ��6�we*% 6)-b��Zv�JG� KL!*Bemplo�x�Ibr�Os�Y�iXZ:APalw-�� *� )32BeXO>�7��"�4:w�!� �p)�"�0<in���t�Cc�{�6�y%���.�^���"e ��6 wɷ� ��!,1 -� ��T �O`�cpn)*m19 s X"�3\?A�a�IUy1R�co-�10:17y�19 ( 89%g'.)a�mWV��2/A11AI�8"� ��!17�va�?^w|2/17 ( 7wi &*�&�j"�!$�6�D�* ��]�)F ���!�GI!m� 's2 <1!%ֱG.A ed�� {g:#j ��In>�u�6F7&/ �!U` �<�&�I�E�.Vܱ�d)^u( 5!T5� �A�%�ra �ioB|d5�E�,tl �M��K]�in U*�RuR&!�57AsY>�$� REI��r"8Mb43?-�*!h�+��O� 41�!�92l�Q50Za W!�(�2["!`�2QV �-��2q!�~%8 !#�\(>!A�%c�R. T*Etɔ��a 1�%.������5�MEb � :=,4 ��6NG6C�o��6[ h�L@n2j�q&�8") )�s�-!E�*� 11]`o��)6��8?s ���@!�IAW��&�)F6�y��2� 6a!*c2�g�-�5Vsr]kj!?у6M �Hͻj �LAl���,4 �2XM��1�r.!fe%26�� a !�j�9� ��A�.��a /�  n *~n� Adc es-�ev� 7 toıNsMo� ,./�q�:� �U���LY 2��AGM�&�$YS%VrB�3 I�5�()ǁ�̻ wh(T�{��~�B@I�9�mH"��:p�";� 7"�&>sFb &!�lJ�0.A!!-�g�pij"�%(�*(&J�% �n ��p�_>oF�e�<�WeR%+yex�. �R��ch d?e���.!��yA(��5�)C5��%e��E��j+ �� s 88�.�!AA989�{�Dat http://www . eba�`,uk/ena/brows�H@��]n"Y0efe�z�%y>p2�)�!�i.W >!iLF��s �+,!) ideaQgen���&y%� ~m�a$��"Y% %�)�e"� �5�."5 ��.�1D R& Z$5C��Z��?Wo-Q�|%*ilA WO �G��n`-N����e�Q�*)=2�D)�"ZE5� 8A�&3*dx��&agaJ@Eb� �a�.r�G( "(3-�<�_Al"�!E�2��{1=aЭ�e*of �y�6d�co:�Dw��s!��i�}AofE��s6^��P1�ng>>ݸ-��.ed ERKi(�_��|,GH!d.{2sti"��N7!�a3D&:�  )&n3.e1: A�#l�i�F9,;eenuApro-o":=9G� o80R�2QE"��!K�p��!��&] �&�Ip6�!1]e��or���Mձ�ad�bag� v5;�;��XeAg�{��*RJ�_i:��ɽ�B|�6vG"0:���toKR͊Ao�aa$b��1/503zid5SC�2r�!�N.�Q�onm unex�R3'�n!Gi+,F3D!oN2Cof2z9I׆�.�w(q ,R. P.�7 d Ak"� � �19Y�baE�6>S6��>%�!�2�g��6�-� ��.,u]� �,t�edu�J�&!�4n2 :JK��1�F�pa[�eT T.� ����)�G"�"�IERK1/2B="�Z�b*'!U��A���!�uiY%��BB��� 3B&� ��.T’W�ss�)(6 & Y݁ 2�m�|�s�y3-0B�"$) ���aICNH}J: . "�+�0aAB &�  ]?z�!�a� lifeM-�sxC��m.qM���A JF�>s� .@ly=; ҥ�prL�I+�<g�!["i@ behavior ��.*fC.n3�i9}pa� z6�<�s trigg�&�e4&m&r �"w feed�x� �� i2B6�"�8 meno�jwx,��e"/sSIc�;[37� }p�ID� �!� �M)#p#f ���"T'�re�J  �Rbq�0��uq�o̫�L8Z0f!%�%e!��aZtimA"�T�!���|whe u(��QpM�x6@.c��N unkn!\.�� �PE� ���Lo|L)NY��!�>?E�&AN"�M�o^Y >�!&� pre-�1�K��si�]>�:*q�c>FKޡ��4��� !U�� %4D��v�a&^alMak���*&D�2/%Y6:2] r�U is&i�t��)� G)�B�P!]�-len�^FshMB�$A~)W ��e>$)I�f �.ɩ47y)l�� . R5&no� �gC0!�alP,�N,�PX�y�AY1 z�&��Y�# }.�>�� }E��83�:z��cR co-v8!6jn�Cb10"親jbyE�9Ro.`e a�BD �� ��.N�>F2�? su/_{��d� ]p�x��Irfai��Bvok� mRA���:n�$ then��a�MEFN�:��d!AInej�"�Oa��)�)A��E(�!� � N��0��$'83/-�� 4� Aڧ ? e%+oB�+�r� ay 6R�$"�wF���2 &}���! %(.**l � �!M>?N1�6��0&�F6!^=:)a�D �;]EI["���@A s��B1E!�A�0�DC<com(���Z,&s!uf1..*m)�T&��or .b����U�y[M��A��)_Y$rX�:�as op"�� �w*E=s�N ndexAH BrdU}aA� ( S2� ��=� e�y � >�inI�V�s dincor_� I 6W+>U�>��o*5�1�B��un�Iřs Vl SA�� 0AZ�.��X �H�=�a_�9�by :,g!h�0&VKmo�d2e.#pEJ ��~s �e�� b,gre� �M�gq��EJ�?b% �.�dR! {��5V�M�6��C!�near- �8de!�o9]�G �FEq �.T0� �+L B� ,c}�)�^�uas�+*�� ’s k6a2)�'e2a�T�Z! .E t~ n �X$9s�!�6]of:88!��.���Z��w,"�� ]�;vo��4*381on�A&1Jwa �&�C:+ (ecB Q `} !�) �'r B�'9>. A�r��:k nd�gIO�or:�)U��u�k18^p,"aqK:( 75 nk�Iqly�<u ` ��at 4v.Oo�i"�9�Nv&�#!s�.�@�C ��"�*"���Z%�Aq.�Q�AU�]S-uo�!i���^��Kb"��q)�Wo" ���><.>�B[*�tac^��9 ��dBJL�A!Z��i,]I�����a�la�!1A�3J 57O?All� Y*-�k!�"�absolB� �8(6�n�Q�I�" l �9 ���Po��i�K�� A=n�F�=9edaf���F@,5� A��.�.�T =a�` ae6�>�N� �/�{of2u at 4y�U ��E�"b1/P�\EGF1l�$5% !X�2>{r� "�=�� 9�%`�!<� 08) �(2yrl�a��%�� E���1�! �F ��� Y�A�r�Q: roug��z!.a�Ҙz92� %��� `�I-�R ^�o�w,�Q�SFE�2-GF/�"�Qb.E .a�)I>m�2,>$N�(decreased ttotal levels of IR , IGFR and E �R( Fig 5C ) , indicating a multi-receptor downregulation in response to Grb10 silenc?<. Furthermore , > MAPK=�B���� our-lines :pathway.���U�d!���resto �@. To determine wh)�) -med��FA�$of colony !�I�by �Q�quire�� hibieof ���, we exi>@d a constitutivel�Ped Flag tagged-MEK ( D�;$[39] alone�å����!I9892� . WenfiE_ ��,by immunoblo�s�� 6A )%�aaꁚ.�ed Akt ERK1�:. R%t�� �tin�1;du���_B�@E)G�of mu�-%)�ed>T�but not>"�2�Compa�FetweeneU�M� show%�!� ific��e;EinJJy%.���B: as c�Ń!� trolAY hicherescu�co-=xA�EKAGE7 ^ �B%�6�. Our��arE7�n��7fun�!�to negaM��e��G,.?��res�ng!��stream.5of:0m� s paralle��Ras-GTPQ�^is� ha@ en i�Uifi�ha�pQ<9~%�EN(ż�&�6/ A ٺ:�)liI.sarcoma h963-%� aros  ay� mous��-��s)�.H�Hv :x 2��a�%זm2]; m_eR><� o a lg r ex�~ , �:�in�S-uad�'modest�ԍm2�B*(may reflectE6 knowi� ce!:-���toh� !�!�Abe "r by)R ’s�on end��ous�MQE ���ѫ!� � tik�i6a��oA ��on up�)�.2�)malmdnt peripheral nerve sheathI�s�����Nvidual�th NF1��I_:;0. SNF02 . 2 , 94 . 3%QSNF96� (established �MPNSTI;F harbo� -�� [41]!?wo out!A�3 3exa6 d (  �!� �)�-&m��5g�M�E� v0 � n�U�y,"� Y�ityaGs measu��by2ed �AKTeZspe;� �F�)�.T �/�6�in��, mirr)f!I��M�s obsA*&�2 89 from�za�l�G� T� work.� �as genet�z � mo�%�d�op��ur�?-b�.z subsequa� $al studiesEI� �� promo�"� �O�throughBe m��x ).he.5 E � �� e biochem�~� Q��!`"� � or�� f0r����w� l!m� ano(- 6T����ib@to�8i!�si�s"��initial5�<on�r){ron1 mad` ���anc|1�in�JE:.J=�� ��IO E��"�(backgroundstB7�' have u-IF!�<E�cw )[Y]!Kext!7y!�s ��]!G�u�Rs!z)>E�,n�-%� comb� %���o� 6QL��e��8`�E� se f�ngJ "@ R��KV�� alte� DEVq!/>�� �]7is pensator��&{��. HowevE1$ 3A|i�let�!{(physiologic�) �1H.#p6 %I fail�q��  replace:� ,A� gaugam1�3/!�� s ev-c .�a�I�6�*3 ��ly�d^n!a��toU+/- �ɀ5�|j���ex},ments employa%shRNAa�%/� �")�_J�&V�a"�)�Adex�=Ycan� hd f�� ���Mhas&� 2�aA�e�T��membran��cepto�>Ov>�2 #���lti��2���5�namx L,)AY+!�� 6^mpl��e �� playe�dynamic1���ofw tyros kinaFta��� 0�)��. oA� +%�4mTORC [21 , 22�n��br a9� , it%I!n�*describL��եa feed�1 loop�C�B�vra!�AOi� �1�MBI!,at? ,�i� .�V��I in HEK293ej*  PS6K%z��e ure �� , I�E� brog��%z12� csin �h� � ^lan!�.! stud7 .� of>�.Z@s lack�]3��!�o"wB�of9up�!to5%��3*�differf�2�A���! -�g .�possibilJ E�a)G&�"� 6���ng �!�. ��l�tac�$}n, sucha�6�V� ��tissue-� �w63 vivoE@d��add�al2�i�E�{qwA�ai�!)be sto�a��!� orig�&�!vA�al*� �R.vin�wv��uv�onM�!U6�ev n8sU�ng�T4"��&�I4�͡�. � &�invalida� e� �IL]�� s benefit# %��� u�!!�Rbe limim��!aQ�5�.o�t� � Q tic��� Y e�6N. A U�M� 6 18�� s�nd��O� �ar"a�.� involv!�6# � T)�)I� )gAupreci� ow^�s%�6�do�%U�knock@A�!�WTx&� &� W$[�N�,!u$�dw�!A�5M!9somew�� symmetric."of.��F[arm6 !c-k cascA[���I�patter)ras� A9�2B "�.�.� .��hM*s �h $MA�gmk�a�i�arg2 .>da� !� raE� than)%�,�l- �6 intrinsicMM&e1D&a�#)5F�!U� � i6�Q �C* �ta�lz� tI$upports it�5l�^�E# u a �/6����Db&� iniZ[2Co6�� �,�!jz y.�:!�Y, . 6:$qD�G&��XY�NEua�e�Ez�m2��V �of�a�'A�&F$ (aJ�W� unequ����m����d�s�(ple�}$al domainsE.a� %�9B��al rol.�a`'�=@' understoo�"� 2C:M �:� ��$�} q?2}I�\ee�5y���� *"1O:� ���� �AA� hile��� ng>@.��&g).W� .d(cha erizi�\? Q�aP.l , pea at j,*� d follN#by ��nu��Et1U1K,V��>&ha@*K .�#ŤF�) nd m]+&�a�.@A�:;(.<2� W�+)�no�*��IS .C�1��l�}AA�sR�`$B��#�a (A/�V�B� Qe19>s� :� elev� >�."�ch�O� c�rd� %N~��is}L�� "� �4u�Ser501/503aidu��a��A |-�AA��� ɲal analy��if ��(will enablea��+}VU�E9�gs�I!�by!<� �0 $�16 b�%� -&�$ . Gi a1al!enon� �4-�)�M�moE' ��du&���� ���f.~ z c�-U ~���� rb10��A\ly����b���#A= $ ei& in /oM- vitro ,a��$�*�1$E3� � best.W./ �,F�2�&Pb0clearly links!x!v� A B�-��{/�� playA$ im[ a;�$� many-b\3–46azC1-drE%MA��v ��M� occu��� [&1"P "� *}%�}�eI_]U; a poH �5$ l�) u�.4S$"N� � v&.1lika 9���lex netq�|�!ba|b.�U�~to]��a�i���P �H#O��u�B2|.._-�wE�"X<&"o2%Eco?!z� �B}S]tc ak#&�{&� anchoragA� �� to� ��� ls�*2E!#)����!henot�2q� $�-��micE�?�taneo�&�i � s [3aGL)��" i��A~%3��.�+majorTof�%G I\!;�1Pba�;[GRB10%��co-l) s:95mu�� e�ucaM*(6OoW1deA W!�ch���& 7�17>=!�3ref ,5 i"J��8ll��YMK.��X�"  singleT�1Ays�� P6� In ��n-�B� n�,��s m�&�m o�B�Bw0R�� deed ,�e� �!��s� A>5��al2��0a�I�E E�among_%��+�4I nF (o867>% ). d ^�cript���-� a�_�s� edp1c�$. ѥ67a �}����� �7���s��1<ќ5��Mb'a�in�I�Q�or.�"� ��in%�*3ElE�statu�`h�,qĭ�� illu̓Nf1&�E��.?E�of�1#�2rai���_2�ɺ"w"� ��o ��6�$%3 0`"P"� cand�)���.VR~�_ incl�5�kax!Mfamily�7-g  6�m��I"$ 4" aVstructu71��8Eu-�  adap� Mb��th lap#&Zdi8ctU��� All three�O�sh|� lyXne�4etch , PH , RA�(H2^PBS" 2�irqɡ"� Grb7�"� � �:olX adhe=/migrW �C�A�w��gio� foc� AB/EphB1�t[47�!~� 4G k"�A�M� NJ:!s� �"oru>�AlyM�r�F�[48�Mo�� �.�>& Q,Yi��&�� ��Rbia�;�=. Spe�� *!Z s IR�]-#� �$� ��!olip!Vr$ae$e �A;�Q<1}R�� usc�!m�0i�!`–50!eA�&E� j� � E����Med �4eIDa 30%a��E�bod| z� w� 4-/- [a�of�m�)+�7c� ��g mN� �� !wvem�Gaff�(��b�& RTK� �8��a higher9y�6� d -inositolLa�!!u�>*� PH�>%��s grea�� ��9u%molecu8[18 , 5InP  �Iy0�o�o�huni�d��)QeX�D w/"und noc� ]ee'.A���8 �Grb!Z���!_��-�+ clos�r��Grb6� . Perhap��&GsurprisT, g�EU� ��q irra:;Nf�&E�Ay�, s deFd 5m0m$�� �A#a~�inAae�t�% 4 [2��5%�x�A*un�0�M arin%  7 a �"lo!"Con%u�t:ric�28m�����m%"� m�a�A�@haploinsufficiencx" e�!') orga�63 isor� � h �0��:�?�,K�+be!�aam_ . Pz9maim%#�!;� eln��j'� ffse� is risk��r�V� �I!dea!�M@wim)olu�ar�y by nutrPutilid�g� �wAe7o>&porY�rleaf@d f�&i��sNN[5�A��trigu- � p�e"� � aWatE']*� eP�0EWl$)�!�a5pi3ergy �>gAd~W � r /2!�kellOxty!�sA=$ inappropr ?A[;5 . IY1 mean �Q�PM��imp�#� a�} �s variE�)�%�P#�f "� P ��-��a�!c�! eajS �ed)s1� � �w ���% �a�b^*!2)�arT!DIz e br�*s}0aO>�pro�5F1�)inherie��� copyber�,))*�1 "v�#i� B��V��IT�/"� 11e�quival!�"WF: izyg��, non-CNS����v only2hly- �"JMa��?e|��!of)M";<---iB�q� Qa��p�)�6{+4!�h*.rva6systemA���>��:Z�loc5�_=� -)�we�tz�/. �M��uniqu�v��9�Ec 4Aʕ���6:����Y�>�s d3�� Eis [14 �.�� i�opa�0gliomaW OPGsoBre��ofU �OPG��F�)F1� fu@ *& &�a�e"r/� odelA���Crobust!�&[��z*RC!�9%:<J on b�5Ų!?M �;6�MMV priorB� "�"��oam[ "�� Ar���1M�m[3i835!SA*��w! � %� ���@u ���.J�3�!>f%� �bA&�)9�Ei9.��� "���0 eluc�ai!m���Z �. Apar�(2develoIA�." :-#ms.Y &�g Ymo)��ho�Jroade�'a��zA� �2���as^$�� of N&7BatoYI�A�7st6! �7�Da germ�9r�6 [55a�!�A.� !��; i�Y�I�s9k is�J=W�)0&�%�@�,. C~Eρk9P��`A��m�0spo� c)?a$c�[56 7a Inte w� (polymorphisA�&��ڍQpat� � cor� e�#%��,.TE�!�%� adenML$ cyclase 8�� t2��sex&�PK[5�S2U{��&� �sexA@ "%<d�<%�funda�F� �.{9�c� �!kefN7?5n�SI(9� . Fi Ta:i.&�%� �� susA�"[92.*�-F@M�@db6re~>a novel�Ep"?D� �s �&"4y%8 Y . T�A s� �%�A� *���$*��0��%�K!�i� procedu�J &� aP-r4UCSF IACUC ( A��ocol num�$: AN078941� AN080665 �s* *ces�� ��&�2�A � WelfAActZAfUS De�hARA{Agricul� .��a+ ��**R4AE. Cel5u�:.3?%va5(�B�& [}15 , 59�-Hido2� ATCC�t�E al v~Ma���HA�EFal WT-��' -AA�O(501A–S503?8�I��0re��6podCD�@Yonghao Yu , ( Un$s�7,Texas Southw�G rn M�Qal Ce�Io a��;�(us Ecopack ag� ( 5 μg )i smid �co��N�JA �,( 10–1E into�2 �4�@s u lipoN�@$ 2000 ( In�#gen�LentinGF|�M1~2sMEKDDB^c\8d�Iy���sH% Gate�NCloS�698z �f, l$or GFP ( 9�<9rpl-hΔ8 . 9F-�A@VSVG ( JB>U293�S!����DU�or��up��$M harvAq�3 d fi�<1Recip�Se� .ineŚE8��]n��otic-f�,�(-_ai%�ZhSupple�wQ�8!+/ml� brenLF�*A� w �}��.ly� T)Y�>�seGEedM�puromyci�HSte��?� �O by W!#r��to visuaB*vHALP��� ax(.� G$p-Kp3 trii9s�+�same den�( raneץ250 , ah to 1 !s/@(a6- d�pen��f(hhr�!�a �V(n� <� !��^vi� rypan blu�M��per��5�an�TXd� dTer , Vi-CELL XR ( Beck�KCouA�( , Fullerto�C��͔ h)4 x 104Zs} 6 cm)9!I1x DMEM�pn�Onea�M-A�`�n5c"�Lth drug!�L �v+edJM�0or DMSO carri�s#", diluA�in �. F�+GZQ��RNE.) colmat 70%^�-1 )waT tw�inEA#ly��P7IPAi�*9�H% Soda�Deoxycho! A� . DS�;5 mM Tr�VA�μM NaCvQ1%ton-X 72-EDT�10 NaF , 1 nVanWj(10 nM Calyc�X7P�)� I�;�e LysY� �W6��&"�T$Pierce BCA R4in Assay Kit (rmo S cd2�[50��a!�!6xbruna�SDS-PAGE���W��g�Z( NovexRM �odiI� urch[F�6a� SUTechnoBe�Primar. ti.EQ`at 1:��Wed Beta-� 9@Cat No . 4967L ) "�Y-S473-�2(&0606%6. 22112p44/42 z5.G376( IRβ.302; ,c.814 2P-T�>W895�@,�� 2367%u Anti*! X?z�SEA Cruz.Rsc-102aNsc-31157I�.IA�q�? gyE0:�Mil� re.c0�65�. Second���5�w4-rabbit IgG-HR, 5�707!13*�V) �NIH Imk1E5j��Li-Cor S�Ho L�Z< �6 21 softwa"m _ ��2o�8qu�V�Kof�o/\m�q�/ N^�K�.FH��"2� *�]���p1b! inte��a|e���uto� V�+Pre{>. S"J�Xl$e valA1JP�ini�-�|0�,$: Luc/ tim/�M“0”-F< y��d1J1,�C�Kp TDE2, p1y7�first; �\ nG!X�5.E#to cal�.� qE AKT/ ��M� �. Q2OsV�"��6~w�,n !��r�^& �&�!(h� � � d=��NAe�extra�_w=4 RNAeasy k�rQiau 4pu��W� eŷUV trP^i/y 0a Nanodrop p1e ^�cD ��u 1��}� �RT2 F%�S� d�%.�-oCDPrem9>?Ge(E�>D,on Mix!"�se�G+mix �d���"ur��, � %L$T2 SYBR Gr�:Mas�\xED*9a 71�PIMM058m PCR array )er1 �y�. RT-*!�&� �% 40���X!5t!m$ MX3000P q9"PCTQXeG� rt� t�RMicro�8@ Excel spreadsheeupl� �he�!P Yler�A� Data&�Web b�� ( v3 . �A�7 ,( http://pcr�. sabios. �.d &/%G(php��QC%=ve-�a�h�keeO)!4� "�}�/�#��ld �XgeW�0 uaBt*N!)�R map . E�;� ( 26�  )�m�?�j}1~ngQJag�;t�� ifer� ( Dr�%�\ !�:� . BrdU�2��� umEln+� �� -3� .&0)n�Jdayd�e:b�fia[!�s� qgAPC-labe�E�-� w a] comm�b��hBD � flow��uB(( BDB552598EP� nt /incort�ad.Mcy�A�<( FACSDiva LSRIIYY mit� enrich�>��>�s ��d �]a���2M MG132E� 2 hrU#k to l!,A.)-�{cu1`r"�Y�-�l� 5d Ripa b� 5: t -h pH 7e�,� m.� $Nonidet P4|'% s� dj� 1d�� :� �%ifmN� ��g)G0$g 4°CM�A5� �� R� 1006f ]inEpA � uVof'μ�FR�t�RVD�8q:VA�r�*b���ife6� )���1 h�a�FlincubY���0ti-D'lf=! m�y��{&Vx�‰V. Twenty�UNt�=&>�eA����"����at)�:�ag6"e�H�V7M �'Gx&byYg�DEZ, �Ir, �� SBbdiscarde�B)�mQ 3 × ��/. &��0r>�DEF2C�q�, boil� or@ ,>� \dh10` s-gl�\]&^Prizm v� 0 ( GraphPad )���( paiA��+$ent’s t EhE"m�&�at<(4W�0� s�@m'%�p <�}05)A�^je�Oat31�.� n> See S1ctE)aN� �Jr"� .چLear�9 k-ea� environ�M ~ <9.� skv7/&h�6!�%avers;a�s�ssQexlRifRc(by Pavlovia���wK�'. ja ��9a@!�oo7�%�2&""P"DAw�I��1�1N neutS���8�� #u!��7% 4% &i��oc � frag!L~IJ" ���6T #A-!+�%,��ly oppo!-��a� trial-by- .�A5�6�&� v Cvitb/uto� :&( ANS�)H,�Fin�inO� $4i5�;)�E��miU+Y fear>Tog��J�P2�,�9-subject�imD-of:�� buil�<a� qw!�mework%Yps�"�a�)��.WS��q���b"J%non��b:s�&Aaa�`j-prB �'>5�9�z�G �AWQJI��$�L @Y E��!�5�. A_ �#�&f�nd� Aqsk� on�Aj$( SCR�: nd pupil =29� ( PS!Be6�6� A expl9 �E. Not,pnW�Cy6��e�e�Y6$el:<�k a>, ofve�outcom<-�#� *^w)2t @!$63l=;. 2sum�,�� Z��vT%�6 5!theorO$wC!A(:aAV$H�)M.a��!*ma�%�.i>�.V�<1#re�~a~.��r�<^asqy�of .?p-�Ch:�or��f����q-XIʡ�BZ. �����3in�$yH�aQ�!�#�Hdo�+A� or�Z�Wis BGa��(V(��B�[1] )��)h '��a�I51�ve �(m�S, C��!�59��(!�oF�,H#) engag�a���!}�8veY�[O3I!@mm�b,MA�h�"�4"(#CS/US�+tż"�S syna�+la�"��|tasjA�. `2$mygdala [227]t�Mrel!�lncircuit� ti�:3De$.0(ufrewar�!�[�D� prog��.*�s-P.�mpre�%W�relay!� USm)����48E):B�5��a���X�� avail6 -+M�-�,lS�!R�B[F69E �8-2.)��o���,a�S0om*X R�'mak*:U beha�V!�q� .@�F��s���1ve hi 3�l�G�+�1cap�.e!�-0+men�sQ5[11%��Yt�  .kn�Yto �R�g   f"�j͚alg�ChmO &V sough�i arbiDZ� ��R�-S��)kng!�i�?2E .]M�"etraX or 8��IO��=��5%���'��� �Qoutpu� W� �eEV�z.���( i . �parame��`a-�*� ��&gJ,Gg::8g-'"�:e^.elf [A�Jtsi�lC_Entt7�0�#P��" tIm�FC!129�+sA� re�Bc�*2( R�mwA�"� 4Rescorla-Wagne� RW ) [13�APearce-H�(; 4] r�:. O% � �6aEo��b�>�� mjsJ�[�16]Yybrid)0�Mi Al$t�iM�( p��x"� fu%�� ��b�_if%�cur2 .�z ���(�� e�g�� eigh� @9k�(��4L1()Zo7,��i�= En8!*� d2:�[{PH%�-�Qs>-t6�|!a��G "B � s��archite�AE��@���g���A they*/chr-n!c&)HL�� �B! �%al.� ��[m7�?�[1u.H"'dF#!ras:achoDZi-�9.�uP%�is0�?d6�nUJ!�?Y&? e ��.� !�G2le�)�! icit!�* ��_A�] �H��ier%�C+ �[19�uocKal/&f�(���RL*��Tw �O lass�asE,�ly:��<�7.�!ynco � �E�,& ��1)N����q ��4��P(5�u�.NA u/&)6nRL.k%��_ral-pur}�5.{6D.��a[u�p�����.��#tr+� b�far�$princ�G;� �2?@������ ��Ao�t�3"3�oI.� �w�wal-to-no�:_ &NS|�u�if >�D$F !aa.0x��U-�p�?`[2�t��=QU�use� 5Mge��:hy �F-f�J� Lu�%�.�=�6"*$ �t,}���� !':�D9�Ver�35g n � �aL ���<ab�N9 task*�} assumes �on%� s��& !�&&BcA�US9M�� (a BernoulliI� m~US��t~<u �� ��S� �=l3QihPYocEE�5��N)��6�"�8�� o faqbi�M�btak wal�hm%vN arNm�. H%'�;�a K>�$ly up�u eta-z�rZ�!�95x�/e�"� �$�96NH�eas�@a�.y  ƀ>�%�, �CJwymQ+e3)lS��f�, .3A=!�.G A�������A2����2!�B�b��direc��i o�DvolAin%�eo!�Jg[24�+m3"��yi5V�M�.fAߚ( PsP� [26]��o5 �N2re"-se&s)�E{s��"� a���!�C""� fe�@G  �/T[��tpU2e�W=H��*�Ge�methokHows�, A�in� {D�[27c SR [28])]�G$i�Dt�E"o�3ach�m CrucC`�)�q�@�"�8�j.�i�o$ �d&��D� � . Un�G cho-.%S�i��: ��7L�S c�$��  Zr!�m�*&NG�"FMi� �p�Nl(a�f�>����e"a�|1A��1"\ &�82 &s�Go�clarif�Ai�8�t:�� bH�-t�Ajypo��i���A a�A5��u�(j�"# CR�D�-�eE�!y�N>�:����I to habitu�.[F��i�0��*H+� g)���!��M�td�~�T��!��LZrgan [2� ��Gu+�M��)N� need. !����X T&�-&\bAAi�j�2 + i et36�a�d=�map�&s �a�.b�)� � ~s@S1 ���4�RV� \�"�Qur�� digm}s5�|&� �1a�0  te�al�ce0A�oA �RW-.` �(� [33] ��[ueo��-at�AB A��-6 I�au�\RW k��noEop �?�C< 2��U�UNMa5T&A�l���E� ghtforVNDA2D �US�$�M�-I): c&� tEjE%eVj='m56a~e2�!��1or>�2�1��iB� � ��o w:�( B$orFA:*g&� .�e.�W-As�)%6aw2[��Ё�"2noy���s� ima�b!�CS+/CS-.�(mime-insAn�7W�6� e�N� ��UIz�!�5�"guish� ( UN5�a) e.es0le%no��2�NVP>�E"� AP�x��Bayes�"I�>� Cr3&!g( BIC��~��Z trade-off� w�-%��� 3lexp [3� tEWxu0*�!�� q y�JA/R�A�M�B� �0�3D\�� ��<�Ken�Dw�lit � t� mi�,łr40e ZvVf�7.>E"��*og�H�U 4�( 3 s:�� , HM�+el� �� �PA� F�A�:'5] Y H�,R�B�!�i.&?( Iq�RE-b�6)P!�ariso�%fir�!zintuie�%�d@ r�dpp!!o~�`f��!A���nI�B�*��de*-bE]�1fwo u��( f.�0N.>597E��P.�;� ���@. O� e�Vh�,�V�!2B��@�� ��i With�R �%�Aʍ� QzfA�U*RWMw�My!�V�V'6= T60a8�&�M)"e<��]/*� j c spacA�7 � �+, \ K �is 4,a������"���*"� nd2e|Cr� e :V 6a��.�aq-ru��,.� w�F�A .��a�i3B2of ≥I�A�)92%� 6E�.* 1–�  �-ly%Q� n"T �R=1jjU2�$: (�orP nv%20a��R� ��/an&�]���J��.� Ax-lawh�—`9�—tt.:e�; in�3�|�Ning�T�� �F�a�)z.�bV� �BM�A��� .� of%�69-(3r�V�!��� �r�B�/Xa� !i3"�&��fo���:�`&1�A-.T#��a�R*� unambiguo� tracke�6�& �", ua�. A c��U���Jq�"�)q�,�g BC) h �udecayEcM�~�_���>��a�T)�X*p t|� �JR*�p�FOv�� iori&a�C��%߅M�pl^�r� teuo� ���^�OjL�4as����2) UN +%"���v|a&�)+BM &� =We�!��y!Wq��)tUN]!��!�fit7&s`!�M�re�låelI OBse*=< ���;e��|be%At� ;p(2}��) �r�R��Xl,!�Fw b�RMZ � xR�o9V. N6,��&�(eE� EF"!� �"�QJ���)ci�W�E& !. AmO�RL)(2�*k��(W��v�NceŤ!_� ��A!P6� ��a�H�!�H ��~3�޹8.6*N *(1��J�Qf��in �8e�5Ph.  B �B�Y 2�N`isO:�����-G�^pl�WA+Z�+.*y�R�?�r)�BT�]3��>eJYle�"� Sm)�wi�( � � -: �"+�(S%9ver����$���`7rq44�;��@ri� ��by each }��p�-� ��h � ��>_.���;rE7:�)/eda�� 42icipafmVsE�!�B�OA��B:w=�e.�+3 ( 21% 18%"�,.��A�BF ��y�BMHRWG�<� 917%�=�)�>�VY)N�f!K!m%�2�Z�%�sE8�� fewe R(. �%h�,3&1�k�%&#.fB.v%aZz��[d�3�Qt mp��o�Qyh��* �r�+�] ed [�bE is wB!"�3E?ou��!)%�V%�9�M�y���$ �" .t`e���e�a� �,aG6omBnu3%a3M) ��*5�s�[9F���A��-[28 , �aI�.ic�3,�( limpulse ^S��rN��&C�*yly�>X�K anon�#� �m�^fir!Cbur7~�7& � �!)C�� Td��Na�onNGCT.l*s�a�&se�| "R� "}"�25t� !J$y.x�M��emselv�I\!B9:�d�Mri� �"��$�3�$pWaDn!� *��%�n��CF�)� y }A[3�=!�U31]e��(A�-.1brady�:ia�a�Pspi�1�9 J\cMVA��tleY<"�sePu~1���iu3WS�CndE��t��$U> weak]7o�� �! J#�)imW:,-�s ͘e*� 9).�!�E�nt;% �sa��+՚ �=M���m�&5�*D�6�� oh�2X�'garith�K��P.�E| sA� ����lyoMoiIA)�2� ?k.�not�%"p �3 �� geneH= Q^39�7 r a�/N�"S0 "/� n 2/ Gaus�(9]%7U��+5�9�sB�9m"" %�� %��soDatfV`B�^�BbeQA� 2_nta�y�4>;A�-4qa#��9e�Hu�em"�� A(a�1���!:!�B~@��Q�.{b�,�:� { hemo�A!�Z�N"�!�g `ey�/AJR��F):!�A�ސA�&a�1ccG�ceIm\De�'%RHelsinkFa��=�m 9���g  � gaD�D�Ica�mm�e ( Kant�C,e Ethikkomis%kZu�J(All6gave wrD�/!$T 0)� a�m�"r.�B�e�3 50� ���.� ade�;!tr�D/� �[���Z$as auditor+<�fourth<� f%�u8&!k�,s����i�hF�� p�L nt s� 26(��!�N�0�$� cruQ�� qGnA3� Xpop�ja( see����tai� ���"�P)���9K���ә1-EA�cjZd�E� s'b�)groupA�2�"�->�n"� ��{ip @./arousg�b] unbi�!�/fc�:ok�Zc! arqs�epro!=hamberin*h2{mi9A��aa�camera%�monA< !�Par"’�Odm�\F�!4�c� � �70S\�Vf5�c( DP2012�y20zU���QJ  �.i�T5:�$60 Hz~ reshY~. S>�0!�re���4��(ar/H,na/.�' left!"i�<8 mm Ag/AgCl cup�Qd)/ EL252Bi�b S`s Inc .ka olet xC�[UhA 5%�[gv�GEL10A� I)"Kg>�� al�a��7��ane�coupler/�;V71-2h (Coulbourn Iu�2�'^W�9�91#�.�Re�digit�-�NLH�YDI-14!Dataq:nAkr�^O!�%��5��WindaqA*BC)"Y� }+�+$an EyeLink�N0-� ( SRA�<$|Ottaw!�Ontari��CC] *�K� ��di�e9gaz�r�!���2�Dof 50E�. B��A�y��calib/d>TI� a 9-�<*p�3��m2D:c2s�T�a6�H< %ө�]��2,� �7�TA�2}=�Tsp�sourc�g!�ne�)�O\ �5ff�k%05X-pass biu� l Bu�wo�� : ( cut�(f� M�� 0159�CA�Ta�ԓ-%�� 1-�We�>�s�o!�Eve7�d�rA�y nY� taJ��2 s a�dUS �t [�gSi F��ڳ���FU`.� who"��a*" ("���ve�3�e� a�=!�:�!cUt%B�SS�A��_7%��Q T���C�)I5�eo2�]ex�&�6��X76��}51.%B$B��U�ETa� -�ar� !)?�o4"^q , DCW-�:e0Q��!/( aeN"S � � ach�/ ,t"p=� KMCco�w�DCMIPic1uroim�h�uM^ e�� l ma�i����i�-g�oIc�� �.�:�MG4.�[�H!�~E�� Qsj&�1A"^Ab Y��)Ti��we! �� fa�!!�p&G�c�9 �: �Ù��OkTi.�I npu�,I�V^laOtim��b���E�g�� ]��de� b� eG=��'asll%l) �we"c )p^jN ( �)^��$w?8!1��udt�D��M�: /sweat-gl![5eU!�e��o�%�e�-Q =� �#>� �Ra��=sEA�I��D��Y�'�$C y; h�;"mno!Qk%6l��Y�E1�s how2� g� �<=2�E�qc*T -%�m���E��co yield 2%B_� tud�M�I�)�&�p Mon&�qa�("�9�_ta}� fluc�1�[ �un�$!P]�Akfla!� -induc�,��9 an�eB��S!�k�Ha )��&�plaRw�k���y a%�;M!o4)s,l���"�bal� ~()�re<�2Q!Dn� �y#�'2q�)<;e i&f'7mpiaJ"~1� �#E� ��� q �e"�aC�3M�T!�% ?a�_6&�U"85CS&6,*lwF�;�c�-v���j�<.  pub��Kw��.�� ndowA�J%�I"i�t �!�lo��{,CA���e"f7s7A!C��لq�m��4w?un.KJ�ni1`o%P�ym2��;m�y5 hCS��|sm��erAT?Si 6QN9 "rer� w"RUd"?*�a�J2�Uw)��t��v�$li%���HE� )S6R Mat� '��#�tq%�0!��5 E� step\!� �e��tA�"�? &�X%o؃4�U� � �M� � �6.o&++US�ivk S;6 �$�%-Uk �6�!3KR5(ah7)� &$!&d lin� re=PA�]a��V�Bd�p��*��!� n�'6�,�:�Sr��A=ide�Y�$oJ6la; e F-"� ) is ����!��squ��->))�a:[t-.[ YRA, S�af S;�3RSC%vT 5B� conve�g"�B5r>\7[60]:h7=n⋅lo8k1n l+c� re n��ZIA�c]]a�!@t!~��i� ��]�!P-����5� ��Q���I8E���st��wumݼsM��i FA!"4 CS Pa�t��*!gs8 = -7���j�e%|8"]��Qd)�-7a�29!�-59�n�)<,5&�4&� !�CRE ,aK.� a % ��Kcd i��5!�n)U�.� �eEi�.' .yC�X� 8&�h��!�2��*ona�a�� AsacE��fix�)�~e�V �"�#��!�f!� eye blink�8head ���E erio�@��s=2�e x, y ax��ev�Eb]%± 5°O B5�!�rE;�h�!}��{po!�d�']��%���EI+�Eei0 %j���� -�)�� +i(re)��.2&�T��M�_!�2;6 �oIE�!�leX] z�\���+anGLM� . Each ��� [������SHv!�)ick"B(2�AT�I��a>Wth�G �� �C� � no:)'�GLM�#�߯��IV- z%S�.[#�-E 2�1u�ro_\riM2A0] >!IC�[D:f�w͇!\LME ,�xe nlm1�s��ww . m��T . org;2������ C�#� -��ndOfSsA����7d.@�CranZ,�!|N!�E�-� nce} S˜1+CS*T! XLF=˜1|*� .����Bon�� oni-�m�3o2|m���.a�~9zM �Wa+�3% Ѡ�R' %� a�.�%�{y� a1��*��g�*���b�Gplu� U � d , ϵt: yt=β1⋅zt+β0+ϵt$ϵt∼N ( �) σϵ!�x� zS2;" 審6*�Si�m�� �M"β�β0�0->�&n �-A�Kn59� �D"� MrAu�u�y t�6b��Ʋ��a q�j �_Oa��J��["�"�p�^&to)[6"�X%:�K�,lᘩ�-;.%�Gc�[6EW�a&� &�' %t�"�N**Or[p��D� Z�Z ly [2�6�:�GQ$�discretT�A.�Nbo)�{"d θCSe��� UtwUB=��>8No.w �)�.� A*(b�\fay�f"2A ��2: p�C θ|u�=p�]8t|θ ) ⋅pt−|�! ) $�e?ue?a�z^} r ab"l��\?� ����$)c�m,T| z+)HK�O�(�(%.i"���q��l^L.{P{�$a��nE.!p�ea[qK�4USHno ) : �) =θu!7 1−� u�j5∈ {�n1}�*)�Upt[Js�*�f�C)+, pW�θ | u1��}o�J�>�Pq#X njujem�I�illrA7# ��Y�\vy5�) .=θα �(% %βΒ ( α!βA8��yB:+Wyj �u2sG�I���Н� r6�r �/lsob$oa�&�6���Q.=:�=e +1��=�−+d"U�A if aAZ�[,Cut = 0�0w�%2hunu�v�i�IX�a�e�JF�$%Aα0�_ u<��2 )+��m6��alV���<"�U1U١I Ts ~e etic2�2 }*i�!o m!� �&RQ[1w!65]�3y��g�� �B�Kٷ�i�2&iu(.i..�S�:A�-Bi;T)D��s�`_��:Y�cu�Ba�Z��Ka�n7/!�wEAq�02�Z17�5�HMEmX�;�e:.O�,�&*�u��T�36q_( 1!{m���J`�JI�( b@ w .�. ME�R*(BY*�_RC���PA� j6�K0C E[θM= 4f�,R.s s: A=∫θθ�2���N�) dθ����� � 6�- IG"S  W .~'"� z�W� ��O: zt=�=�� +�� . b4sS@z 93AW .t �(�9)� �,�Z0amE�B�&�Qs drawnz p*E&E��5� l;K o�,Re2����.[3+6S�p!v.+X �+c��<;Df�1c�K� �Lcourse�e.{�� �2� FL�I�=� word� �Πpnnf���is-'ty � �a� CS �(l�A w}�2�67 l�� �}v�dbB�&_ ')%�!mu�.�� �>w-�6Hd w�R�,Q�y�2�F�)w�A�]�evt+e �_K4�� �*t��!�_7-��>�mZYce9%%\ �*�of&< sbz��� ���h|Rga�or unxe���b.�$:?7 N�b"�Q�RsGsat6� ( 'a*�A�ngth' )aND �� �� �/ &!�d�*6F=z*�^` , xI�)���6. � ,m %D6�c"y�' , η-�E.p^� M?�>C�%&p  ,0<η<1: xt=x�-+η⋅� �<− ��Z��5�eYITd {ai�k� tA!� �9�6Os� i�:� ,"� r Aɑa2qeer� n :�5Q^c�T"�X*�^w�>�qgo",%|'� � x� 5� -�+gD6U�Z$5AI,6�*@Vz!��B"�D/*�DveeF:KV�J�:!�b� ��a �:�B9TI�%�� u�} m�@�k�RWi�A��a&+t�-i� �:A�t"=E , 68;? ~4^8ηA:&# N'>5 �O �^="%�bM� �:j=k⋅|i −|+fk )�ηe2e�yM^Raa>k��"�.y�v� ee so+ngA���u��b6�Ze�-)L$f�8�]�’�GH�.n#� 0J a��"6�7W�3 .(2z;(��a*�?&�&� " �*2q!�(*� 7I���"s �7"� u��e��f�� � VO Gr� �e �U � −l! αm/ m�8�> (of2W\�2!�'�f anyy�. &�{s"�+a�A�2��n&]��x!�e�"vb1�wjo.B� a *� 6O�BQ�L3s st� �g:��{1 , 0�M/T�3d�h>�.{ ,� min$*���L i!~!`o �&X%�F4nO�2�o&3%�t�!6:bs:h$MM=∑t=1T�*5 −yA:�VE T�&�I�&� s("� K&:&��=��� -HO+�!"��� -e%=E\pA(z}1�A�7t&��. k�!sE�"�5 avoi;Eە�Aevo�O"�Mm�/��8ac�t�EC�*E [Xa��Yp&wOx?)%�w��Ra16,�N� ��OuEv2 � se$l*�`�RF:2Matlab�. fmZ�L Y�!BaOj�2�1u���?dep6akH %&��ZCc̊}�95�&�Z�# MM=p�#�#T ) +TRSSMMT��p����-�>�=�A�:�T^7=�a�]!��ca�{B�l&�#=8�$ru*h2aA5"�/X�sW*�\a ��\!�>>�@�Y�,O'*�$W�Ts 3��st�-=Re���)��Ha��"�jfe.��, g�+eR#/�U��fa]AY&�<��:�9�w,M���?".( RFXk [6P6}w����sI�E:E=.�&�:.N�"� ��e�3aaS&��^(%~�Z� �� V3Ps� AQre|�e��n�2%�)%J1 SMP1*6wwY!fi��!_ . uc a9uk/spm/�6 E�!B�U  u�Jai)!&)US�� 3�"e�� �(af]y �Y�cn��luA i�!E�"�F% �=I��,��lu�g�l-�! ��outli�h)�&oM�it�@_1C[��ixV�]�� �E��}al�0ig�, ;pz ,� sb~J%�UsAley�-s`@#��p�c&�*��#r�(�r�.� M�)N�[3�W�`to�HXu�5> �2!�P?e�&�Skg! acqui�n����bo��t/ ntM�(�>3Z�� 8�@�is�1l�A�2�ABm�/6q6 -���[e�[a5�256='s)u209�s �&� a!^!|s��XC��a"�)*C9��! manu�4p � bootb/p���)e�hI:.� �+�E�4�!�R$��9�%E��� JS �;l$�a���#� &��&�+.���sepfGHe�x� ( SId+ o�S Ao� SepH�-dc7��kk���,AY�v,B&��ynung�D ytoko�is/�a>cs�i �A]asexus�e����p$%)i�-n��v%��m%W �( ME�) �o[@i��#��q� �=��.�!,to t"|)m.dt�~�*mal1,.I�uF03%D�< or–PomA!#�fil��2!3us y�nidul���^.fT0�:F��!�f]&�qp}��b� o��2ec�lsepH1�fX!A�e��!9a`nSrk����U�@n���b<��A2���`A��^%�� >���APK-Hog�?:0%mr�'sBz�a@i��s�3�* Pbs�!QK%��xve& �;�e%}r�n!�_un1c {h>�y of I.osrTA;a1E ���6.Med C�apzof byp�xng}�=-�A�keʔ��a��,LK&c-}���, MobA/SidB ����cm �m:�q�"� ��tic)ni"y7YC^�N�W9�)% whW��.7�A�S"��� �+talk exi�Tbp A?I!�A5��� 6��re�sاe)�.�aNt��I9!Ah-PY���s �HJL��Za mycel���ltinu�A3֓h A��� %tA"�id�.#2!�"c#EhyphaloQ�-.�[w)C��!Lp��m���N Pd�6^F;���aH ko�ei [���t��r� ,������Q��i5��P�xlt�vo�.)�Q�A|x ransmitK1�yu�� S �%�us [6– �a � �;avn0po4`"K3JA-8g0Gs�m!NSchizo�1harB��omb9*t6��!�umLEF`Y (�/ 'ms!e emV:!�,al*C r"���I��\��"�I��&� ��2 �aY� �n4�)���/�, Sid��1pс���2 �eie�Ŧ�aKn� ,( SpgA/Spg1p�� dc14 G�< Mob1 GAw`�+I9"F�&�^J؍=�*� ��rine/��>��Q���2jccabo��)�\!�.�Cesa�2��!��&=E9�v�  ' �(, �����4If�[%�trigg!RE�/.��} .Y�[�@H"�}kdFE  Di���|ni� [lu: (! "�e�m�AP� �/\u�Zte� eachP(, reby��<� � &!�to �� �\@gE�*} !�o#�H�(X��geukary�bkingdom~~a a MAPK�3p�Mq ,"� S zA�h3��6@��[�{ U�{�O0ated by phosp�}horylation at highly conserved threonine and tyrosine residues [13] in response to specific inputs , leading to their accumulax8in the nucleus ihe activ �of"Lir downstream target��4] . Three-tiered core signaling modules , includ(MAPK kinase s (KK ) , > )�<, are Qed�z proc1�Q�Z�zuciy9�Torganisms from mammals�$fungi . In ian cE=,�Ztis�K[22!�th!�omplex�%���0has not yet b�dissec� si!�g majoe[of��isola'by>�Xhave no clear phenotype%ereMitAp�ria�[confirmtse re a!2!�sq ́  assay� transform!.Ta whole-genome library ��ubarrier]forward�1 tics� to verifyaEls with�detecta���s . W !>develop� of next�e�sequenc�( NGS�)pos�BtoQySse=b mparBsingle�8otide polymorph��( SNPs )U�!]!�A�wilL pe�&��%��same pa ��en!"P background . Based oe1(se approach# I�A��#tmAer techniq� combined)da new�A�s nalyaIof%:, a puAv&vM , Pom�a sup�� f eD , wa2y to b��zsepZwdA���..�quanti*��  omAR al� at dele� of p�cau��>d �^�. O>Fy suggesa�+ �itegor�_amo^ (116 indepen�s( UV-induced.$A#��vsepH1 b1�colon� q�~To fur�Pd�QAEseX-F� , weY%%4�z-resto�~�A�e�A�Y� strain R2 ���a yellow� selee�H marker ( yA1 ) . Ci a�tlI�e��pr�x!I ut�S11eES53 (�!�)5, No . ( 53 ,� �vely )ɀQ��ΥQly!S� )!�@di����ics"~ s shown��S1 Fig�� ���!?f����� ��%� �dlo� ( n = 193�/�218  53 )eQ�ximat�1:$)��� jwe uppo�i~�,�$H1 ( referAto �A�-)z 3FR,�!�I�%~:�F]in #sinN��5dou��[� t11� = ( S2%|A`}��w>utru� ct%� ko������eSq��iM6��>q�uY bB:->s)�ob�aga� at 30 °C�42 ,����� Iqa`mayk e>rU9: �or 53\ �,]A�&��&=��:I1�epe�.���dat�M�i �>L� extra-!VI{�6Y1e�� we���Elyu\aPt�Q exam�a�q�rA.�3AEn# *$ ofAs��%+E:��oo�1�rescuA9o sM nt�Q�!9.�� am�%�( � 2��a,le�abolish(� �!�uc2 O �s�6 ur�estri��tempera0(Qe) (% 1A a1Be��� iste��liquid V�eri� s demo�� �� .�di��$calcofluor��8te ( CFW ) -sta�e�!=>� s% 16I��no.b � =OtumBHat� �ipS3B%DusdefecV �A�X �Qcould ��ed !�3!orE�..�D !�]�e ����A�ge�,6!of �:��:-[%3!o.��� )��inHN�<{�<whi���A�i�-2EC 53-2=�CFWz�9M�Cb�1Ts w uņ�1�%R6�H1��%��adm�q Yhad s�lu� �� size6�!��� J�.�b1D�S3D��Q fic �)�ta0e��� { diameters.ind7� ���"�3d6pisualiz(abul2�cj 2�1�#)kP ��e�esc��� 4in ( RFP ) tag� tagg�"!$ N-te�u�$histone H2� S�� >�  a of={�ѦA;:ule�1)e$named ZXA0W6� 7 . Di�BbuE05�q?byA�1� i fua�!eqa �.������. F�.%`ce mi�copA�v- 6� c� �d:� �i�Ec evenEK�tpo.�l��:� a�� �TEE�.�t&colZ � impl�a#&�Ab. ��E�MFrkX ��9 ( o!%}u�s*� 2��buiI��C F5fu�%'.?*� �y�'ch%a�g:�am6IWH1!k^amm�E},�� �by��R�pom� �qE% �c� d out . S�1�2,q deriOň_Y�mtI�an�! ( �y�(nidulans A4 � %%�th$ysh�C�~ except �o2��e��:���� 1215% 1085 l�f��le 27! 282 belon��m��!*!�s occurTmco�reg!�in2N:�i&2o S1 D* F�� Gia�H pYCdA�%�M�u.C.�-Vd�aZceCy)*�lyy�%�*��a�2 � lapp$ common=Uex�e�AE!�/ce�)�24 "rSu�.�V<� A�a BLAST .�!} ���sF6� e6� FGSCA�H( http://www . aspg� org/<� m�peF�B inte� �;m��pR %��B9E�loc�?Ebree��LID numbers: AN7678 , 949E�AN10000e^� &�aq ty sv. H��V �k|!T IAa !�zdr�oP �R"AccoreA�n� ` at FRDB9��idb .%� !�I��n �� 4482����&�"�1417-aa"�. F�.�obI ea hom`y search��Blast-P)�e S .�b��%�!�shaC58%�9ty�e�of�)(a DYRK fami� ell��" �Aop��ch� .] SMAR}+U� smar�a$-heidelber de)\harboru�i!do��� -TKc� erine/� �!�K� �cataly� >� rang�M%Y 1003! 1299 aaa.ri��? � S�Pom�R9� M&7 9�( 68%��q�re> s )�L!M�y.� � thenx Bas502 SNP.� alige!.�e���EB�D9�u�inqin�4ch leucine1265�repla�bA�!�\is6�e6vV��ځ-u2.�at�1on 977A#X !B stop b H2��=C%�FFc~ng%�lMp<�E_���!"!P���paei��� a��io�C sphappe �D�* *$&� eptum rec�Oy����!a�CI����!���n%�$a site-dir�-"� DLAS�Xat mi��/�s1� Leua�Ser!�$pos� E�$0a full-length)�"� z��>� ` !�its&hBl.r"�j3Tje)4no&int �xZ"F "PE>�)-!nA�tA/*&� irN�.RinN_��Δt� �:�� En~.( �e0gar-solid med?Ml*"�in� (I�3� 3B��V�)�mA null��Fdax�Bq ��.��*� )>�> T�c���$repeatedly.�%(c&�i�E �%��cap�of1C�_f�>Uto��vrninsightAgE7.=��A�@"Lal alcA ( p ) ::GFP-�m9� �u�byё>!z g����5��A&Em ol�&� c,n source de-a"e�&/ {g$/gluc� !�%�!h"z$. �A8e��! simi�at^(� liz%� ���cu�)>�e tip`�$; � 7- o%a%p_'body n~%)us��n� d ei�Pa82�Y�-�2_��F�%�:^� divi� r�>�.eƝO`2�!4lmF&1wco6�B�V�M� regardles%��2�%(!>r})YAG!6��l�gw ""1 M NaC%TKCl"�3D–3FEVS4A��a�I� ast��f  % nFg!'I al)S�'-perturba��$�� ngo �>( CR )�Nx e��5Vm�%r�$ta|i��#S�a�rP�hY2� ��]!%��>  over*�*V!in$"�"D-�4( 2-fold changXmRNi��NS4>&�veO$ckJL%����>Ii�rm�)�,��/3G:�� ll t�!-�-�k+!j% � Qsn ��toxicZinhibiA}eY'��., i�A aU �#g�,h'C#Ɍ&�+.\^j"at��e/Ot{#in�*(� Cdc7��AA�k E[>ecute �&A䥀s��#J/�A�x"subAS+,�� .?tande�+ss� ( TMT��dM��R�#� �$�A�!�2� on l&�$��q&�"��e8��(�1�!C!Ee-a.?t��2>. A t+of 8409B���&�$ 25301u��(��g 6766ZPm9 ; 2188N�convinc%.i�-NT'! 4� S2:JU�&Cut-offE�"A{ ubAati<+@.B @( p-value < 0 . 0� �h�:"M2)aI#-�+ efR�ult� $isobaric mMPt&�&y!�."ed92[23] . N8.izB�M:e&389��9�#incre�%A83543de.{!~mod%, I (�)!2�!6�-�Bż2�GO)�&�bse��-� aina��j+h!n�o���u] �metec0"0 ��2�'uEQ X "�,nnoAEo� $e Kyoto En�/op~ of G�+tGu*��KEGG )���7 ,%�i7M~s�Mt�-M�Z-9� �m��ly}q�#�A�t3 ���x4�A(m vno(�#a\he� estcF� $lo$ =enh&6w2!W62.�"T &G F,-�y2-�0 ���re-�!b2ed%�A�M�%WiJ!��*9u�1G#ut�tto�/3B6�S5%f��stifr��pp!hrb�3:ti;�4d -�c!omA&�)�%�M6�FL�2�b��(ot-/��d%Ca��6� H�1L too �tm+��5wABmeasur5 Xba!2due7��m d*� � � l.�,fi� �*JE�B;:��q v �,"�+six���#�/i��Zg( labe+,,as “red”5e��f Y�-��N[H1E*� .��H1 � l�nl N�y a lack!�� �@^Mof �Ek"02� �E>i�� � ukworks!R� t� =6U6.��_x �6=�E�%��Z&%a��]"� or ��{}��E A�>dst�3aMq�e3(]�ce62 siae1QbA$Aspergillu�/�|( final-step= )2�%Ӂ@�.�:�"-!Y� f 9M��.ed) k2. W� rn blotJ*a�, b� �pr�,�$bEnv&� ��%_!B�/��*st1q -p38 �(!EA.E�7;(S6es~U9+P X6gen�7 e key �)o acid�$�-anat ;~ at �5, !�!��A-P)�;�G8)dis�+x � +% �(�nt)mi�:be"�0gn(% b(.�.�"we �#E6Q*�*.� �EF��Y�g�Ku�!��.�7h:J(&!�T�pin) �nsY!c4#����M�J��am�!F%8�f\ : -�A�[=RjT �s �'��x;#=te��� 10 mi��N��r.� s.��c=�Bv�j%Fb�F���J:al�dB[6� :=pd s�2�1 . C:r!�n�"B�, D�_d�E:FR-Pmi�oR��� -" �E%9�!�-P.YU, 5�5FE�N"M\*2$_1 ,6ai�dJi+)R"�E�a�9 � �^�.�r�B� cow �1�Vof��ik�1c2A�a���=&3 d.�2I �invest�:�Wa�upA:amђ�>d;>L(��)6��iEed Pbs\!�K- &!� memb�;-��6�.�TN02A7� �!E� :�#: 7�M,^7Δp�"��*�ed@a�]8�M�Mz.S��.�ZK7 "�[ Sb2R %;��!6abs^��R%!%�qun��/ :>��fH�a�ch���E�!zY� rect�, :>X v2� A�'-PYc. Mean� ,�9 also����b$/a�2W�� �.t$��R�kI��>Y"a:ss mbypSh5*�>�c�8. H. Y s�� � � 1MMgumI/ūor�%�,EM$��6M�X �2q�Q�2v ta �!�a:�05�2�\:b% B ��E��J���6� :. %"ac�E�8$-talk poin�@&}A�CA�!R�A��.�cAVs-<0�"Y�make >�A�alc� o �mob �"�Mx � tn+Sid<"!�"�H�7A�͑�h�&is!G�, ^�"�kHTGa�nd  by�>T8�^8n3,e��A�_Y)�*I �M$�6d-��Ilthough� "O4���Mwu� �}j-�� �a�&?a �pa!al��-c�t�&5 l.xS8��w=2�1� �:+ C!�/-�J�J�HIN-%�,Ar�ed:�c2&_"-I-m.5�6� N(E�*�(C"�O�6i߁"loc&<",-�R2tC� M!6um��a�te6y(�;��!a{JH"o m�"�s�h&PG1>�Fp8E �InY[6�X6&�)!��E�6%:2X 8Cw2-xI�Xe�N!���EU3!]!zZI?a�>M! '=�a� ���)M9a[nK&�+8�E&�%��M�2� �y7 ,g=0�O.7��^� 1 y Hl e�C�Ma�W��� of a!SH1/Cdr2/Wee1 geometr�$t��a ��],nl *� s >= Q6G�& scri�W� or�A�=��-1%�* &�% ���[24–2DMoA�A Am, ankAQ'!�"L5)��42�e�oDn8w!f-�, .&�[28'J9]���ZZ8�,a-n�717�6��nG,t�,Δ���ex%"ibdmck/ mpan�� $ obus?$T%*V"abundf O � E��%�N� H�aWF� !B&�)���rE}�2&>ve^&>F] %�q1�E$).6$ 1':#F��n�-)8��؅�"O#ŽM� .2 � ��Ge\Ae\M>/AA�(I�)Fl���(�q&L0a�Ui�. TakKogI��A5�1�aR u�X`A�1ґ[� �>�D�� �n�3a`up��"|]M&�  Ia5�tu�Hby~0Gl1!�jaYL &I s"u1!� 0s�@"�>B85-�D�� w*NF�w5A�b ( an��?�9u!  . �GNp�clu��S a|�F�JFir3(*hin� -�D6l&e�aF -4� � 5R�*,�8C)��] ����!g�C�<sucQNat6ecup4]fB"W%��s ����-*QD"s�JBU�O . Se�vR.A�p!0}W � ySre3�=�wV�]��  s|*�p2�B*�1� ߉#��a��e�o9�@ ,���A�ai�7a/P5 � s%�� ����2A�at�(2, �2�'7�$3C!����on� � � o= _nS. cand[�$o͟�.�AIty1#Q'9%a��\*����! >1$F�9�d�%+( �<2-�B J�/.�� &�/<-ar� �y ���40 !` !%]�D?po�J�Zeffici 8&"!O.�R U�F�6E.=N*�2, {=��.m6E3!�5�W"F�!A� �)Hk��5 �����2i ��e.�]�5\theGV"M orig8%�Xd�7 � . i� >aniU�6�_g ng2� � 45�%�M I.27pM]��"�-��Zo��z�!-��� ��!�l>�Mu�2 �6� �N%"� Ii� �!k w�,�q !x&�.# 1�<8|�� 6-) ���gw� ,  �:'D an���Wil��ay6,�$A`E]�2%�-P*(n& !&#b)�!�u�e]�M��afv`of6�>>E��Ű2>retro W.�A[5:�:z)�nona(� �u�-�T�D��JQ"V�6\E�]m� -��e%�$�"s9;/.(JdJ�[:�]�a�lso.� ��,.� ���/�*� �/" �D!�B�D( SE)sb �>we� c� &��}� hX=5 8>hJPo�^!�I��*""h$( R��%,)�>W]-_:�Ts"�.�%or ��_�or � gV�2�!a"wZ��e~ g!�>/u"E�>�"u��$ All6�N s�+��";�^summar� � 1 T�. F���<Rge�^��n�-fe�R n�A�5 =Y:=YUU ( AL6D=$5 mM uridiJe10 aciR=� 362% �?,i55%V/�Wc[#!h1 ml/li^�000×� ce e }a$minimal �PGR!�PGR�Ƭ,0GRT ;GRJ@10�y�).�50�sal�1�e � mg �pyridox!8, 2 .!Kriboflavd�!:PDR �hG� 6YA=A 1�p>PD-?DN�~�[40 , 40A�Q_���of6�, @+>N d�eadeUa#]ce [4��In briefk!wo�maino_6��ab�P$5 mm-apart2�umE�(2 di t 37+[�<di1: agar}bmixedm4myceliaiG�&(]�r�^v=>7Xcub6Dw15x room.0 l"�N�� m_Yd�'�T theczas pick�5pE pQRuW(�,aS sterib $H2O . Last~ 010 μl suspen�ascospo�`�WO<֕'-B27n=rMX�` N ��ty,_�4"�V. GT��Ga�DN�&�MU1c� �9!�*�D-dqRn.C�perXedAnY{*�[4�^4UmA#M�Zrf�� S2��To �� "�0��c7Ptt�:fH PCRA;hod%�2!�~4ou5�. Ba%� appr*�_ kbacY"u-�-*� flan7 �c�A2��),�1i=5�;im! '-P1/P�R 4/Pm�4e)O�m =`M^AQ!�( g)��-a�KA �VaiP��nut�lo�$W!�salm��=E,�~&�i pyrG%Z��K�8plasmid pXDRFP4 �1�: -F/R>ex��4�e :�1!�f+t4(1��)r�c �)! o pairs-T 2/P5a�!�mKyU?!�a�����orA�On�recip���1i[4A"�  tegyP�toa]stHL�,1)z2&U�m.+�{ �? !6A,�zN2�a�'1��F�+�/or >!� �ly� >q/���3 5’/33 u lU frag�#0 D�4Y2by-� �U�of1\6�!*I-p1/p+  3/p4,)��2:�0a���2� eB%�%a�u.�P :.4(�\)-� Riboe$�E�cl�NE�8pEASY-Blunt-zer�ic�( T4'Gen BioI* , China�[oa��ju� C�!".-��%�l&3��!e Pst�$Not�;1�}F�/�.�2e��>�I�Eg��,Q�!Ai:e,F��2=.�\ rCE�CR��v��B�]q� ( zGp�Yh$N<�Ocodon ))�J�1�z�!-ߡ�:�F$e^����A��^:�� mpRXH2A n|B�#�\=��E�S6�2(H_2�e"�k�� ��Ra}%�.� L�) :p�k���B:�E�.*�r�!stituA�v�+ , pBARGPE2FanAngpdA�nmo=!)N�Y��Mn�0�&pQ9R�^>&W0M��_5b��N#�m�)/ �C*�$ _� s �\g*g�m�%N25!J.{ M �:�uf�=d�7dE�AS�A�X`��j8�"n`icYgiFT*� F�P�.� [9� U���u ��%�yt��ve`. s~ Qe�R�iE:N��!xcor���ng�-�� pLB0DX7*ai.�JIa�b.6�b� ���M��JaAj� .�1/704i���!eR�GF � ��A5 6%ɕ� ��9&2GFP–.j!2�FA!o"w 6S�D� { �v:� �� 6/�q���/ cla1Y-� " A�iE`��F.���3 �R:b:��Hlu���.:,�5E5.d JT6�=��N>,����9qB�5�� S)�&��i;""� �'cea� "�>�� (�X"�ZA q �\p!�U%f*��DQ*1��@;-^.��F�S-REj S-F/��: "+)A�y:M:�.*�Z�P3��in�M� 4 . 7��BA�'�s!>��q:up� N��..rE<& a^&{�ch #R�pEasy�  Z� r� mnI_�eme&ZA|n2@[uyY!�2Gs?!�m~�",&�(a*}os"i1@%"6�+ *�s"�(Fd~D RQ�O;g�6��MM.-Δj,E�.hvKe&�BAWu� L-de-A� !3! -R"�1,se]�E�.PI�L K1K 3Rt j�Iy�kamN�2� �qy�4.�6 (!�.5��"e<�E&�9B��3:�b�y��;c��.�O�2.��^R^)�I� zA�!�J�t*�u�& �BhA�}�G"z�#" o (MqHA !bj�%d �_ ,&I�*PoI e gl�@c7 sl[awS�d%�e rsA_�8}=ser:9. AH�)��ti�z�<, �o� eeCk�>jAHg"�Wwa�r�R�PB�,Cdy)�e�fi���4%�Ay maldehydeW olys�', W�jng��, P�<US�5�z�FW�igma-AldI, S�#Lou, MO , PA&żo3K�h>'�8!�!� darkE�5e6FW solWnD�.77:�)v�Ima�Y%jcapd%64a Zeiss Axio i' r A1&� !D ", J�A, Germ�H)%6manag�@Adobe Photoshop ( , San J+, C9w� Q�i�� 2Z+� ^!���B "f!)�aal���� To �/ RN-<aFi�a]freshjc!�"�0%�5� 24 hal37�w�%�2�imeAJ!harH��0 roze@pDnit���CR�A4�"� TRIz݃ Roch� >ATmanuf[@rer’�Bn ioB"$ di'}a��c�syn`(eL\HiScriptII Q RT SuperMixE�q� ( +M$wiper ) Ki�Vazym��e>*} p�X tocol�al [4_/Fr��.� um{ UU�M�i2�%��%�^6;tM2�6�.�n�!u�&-�!y�N�y�6� @Sbu~��Y�:'$mM Tris-HCN"pH �r�r1� O_"� M EDTa�WW1%<�1X-K!,�M DTT PMSFa�� :#���&7-cocktail�@ BCA kit9�toSK>equn�KKP!c*l!�~�"�B�N�<loaf� a 10% SDS'/yacd6m@2ge�TdUe"E} PVDF�'r�20( Immobilon-P�B=3��%n>1�( 384!��!G")�!�H 8 . �120%Kano�#�+A , 5 h [4h=*��(�aGblob ���M , 5% milk-�!�!���20Y�pro">9!ry��I ies: -F%.R0The180/Tyr182�+QQ( 4511T;?� SS��T�[8l �!32�сTi�S53��*� ���J�um+sh?*a"JE88ɇ220 rpma����!* , dr�>2��ԍ�*  �����RM��"�Q&�!0t Shanghai OE!60)� C , LtQq� v mert�� ic'pb��raw�0submit �SRg2�qncb��nl�,nih . gov/sr�at NCBII�ac�\�q[q SRS42860x��#F-R�`,z42�*'���%!V6�1� �!9�9�!!-�edJ�)�>N�I��9" h��Z[5n��2�,Hangzhou PTM!� labs��*8&2� ( 8 M ure{��r��Ѣ�'ɣ�1% �Z�{�q.�� �� �zA�� �edM&��¤P�+� Y Wtryps6{PromegE���[�*a ec�P(!�rmo�o�0�; ..<Z�-pep��7fr���Ke��3Oy= d-ph!c HPLC�a�@Betasil C18 columU5 μm� ticlD-!�m�t, 2��m ln�F���a� �`�!) ͍�"a�!�.�J"+] biom:I�5 IMAC� phe>'(�.!&Y[� h 8~�+e� skip�^��-@z(u 1HZ@y��danB�.�'!�vorte��moa�� ( 50% acӐ0itrile/6% tri�}oic_YAnJ�ufug���I pell���)Y[ �M � e&F64FE�E�wa�`���3>��R�w.<C�0p$�(S dsor��. E{-Y* -( NH4OHʼn0_%�|�~,�['P9>?�LC-MS/MS�9&? V| dissi��"� �"1�(9v���ly:� homem�:��t�A i� 15-cu�, 7i��@�A���km�jt�ca� f�Sa degZA�-y��p��<�GO~!Y�c�@ '!5'��Uni� -GOA a�&�vw�ye��a� uk/GOA�vA_Aa9::]I�h ��:&3=2~�eomeX�0"ZwN�0pride/archive�%QB�HPXD012514 .VBTegu����$Leishmania! ( TL� s ��A' in LiJ Americ�9�Brazi!�bu1%6�*20=s-ca�2� year-!�n �5&La((��#�7not fuaxd4 stooAG ClinEw�fe�\uv� cS!e bl:�C�toIys�Be�~c�~,�2�i�{iwRdBDDD, m�palBM��>usej�D�. MfactorsI*�associ� %�As��8�_�3is�qev. �le� � Re����~?rq?z.?�G�Cof] +��s � [4�NYA+QN2., LRV�B5n &?; ��MLA�&. ad7 odel��4 � �yl56Aj+s�M HOPnded Rondonia's HospiUA�ropEXM�Yk%v�t6HcQ���h109 CL; �`L; 5 CL+ 3A1!�1-� mole�0rC��*�[A�J >ni&dxby�by�!� hsp7�kt����!����qa�i)�on �*� by HSP70m-RFPLq�reY5VR�+tes� by RT-�. F� ]5~�hcte�2�@7t6E{2�"�E��L( Vianni� b��ieLA 8�`OnjG .�K uyanA3@ . 8?Fx1l�Aoni� /3R/�) amazp?!�!�v; j shaw�RSix . 9i�& sp . <2�2��myYe�(e�H��l .J�2?!�Uii ��kA ( �2�X.=n�6�l� �A�32H( N = 54�I .k g,75� ��� inco$8s�1` #6 �a�_iex�4e� ,q���Ew�>dɧ-X�A�-��%B*�I ac"*T)!�!��ou�� lm�&��kKi 147�(�=��P ML =���O��l7a1%��2�_��c�6X���'d 2�9@1!b0�R:D�� U, 3�<7:4:j�6a3%69� _e��I`� P�:L|+ ) /-Bas�79�CI95%� 57…�)46; p<V 00�� �<rroboc�fy�;"���.���!��~�9k�dA.�MR(4m�%;"X_38at ti=G� o�n�� r� ��V>i. �Q w �U.�� orld , �f in 9�u[  &Z;6f A�5�l!Epeoof� yk A2"590%��!]� D8a��d in 6 c}T;^'�� [�:�8 ,8 66 7Z2��w�esՑc�sa�>�nor�Ge�g�� �y [�rA�9 �PW�Vs !]Fh�6Ma)!���\lrg�&F�tyl paraj ۓ th 7�O�~ ly kk��6 @ Ees:+ �aj���.��F<��Fnaiff�>Q�0F1l��n��i% 8b�[b?5p x ��O ��5�fM!�� . 29/�,�< �%E no���"�&:���"DI�"P Y1� �& =O[6�M !�2M5"5j[76A< :f!8]V � W[%�m &c"� A�f>CencEzi��ea�d�N@�?I�beEhA�5smanqof-!s�A ^-)�caaD<@8s�C6� ɇ�$)>9���e�U1#@9Kf(!;(�n):2. MG} auth� ^2��$dof� asympt�ic��viP p�who=�gi�Ein[prn chemu< rapy�,�#�TL%=o�[9–1>��9�z�S� !�>�"dCa.'�4V�,7��Vof�A�.h,><2��A')L$�!�1� inju��yS��v"I�aggra�$IGI�]F J�SPN�PQ�����k*�Hg�chaWersy)�䦁��XhAG[1�P��N�?r|2��G<)I���b�(+ ) [1�;��FbL &"�Pe&�� ��mC� is|Qers̀1r0ϓ�Bo��,db �N^ JNa!%l `@�FH�#ge�pDa e�P[18oQ� � &{=<)ar@��^��-�ei�B*$� �b3 ��CEW�! ;6n"�@in ham�'Ait �1m6�2���\u26F� �Ivir$� �>`�9�SubWYO@�]� 9DQ�.�[20�``~[21A�rQ� 9aethi��eX��rve�Sw-�H�E|)�ithinAa�!m�%�� wors�Uof"@��|d tissufG"�$0wa{@�3T r�e��f-2��cy�U;ɏnata��ca{ �|Š�ds�%r�pA �[(Toll Like 3m��� ��H�9s"�T)�W�ב�.)Z#&!�29^ , our%� y ai�>t*Y�JdJ*�VV%�e7�)&(@Q�6�*0�9 eXk*%��hip"B !��MiP�r� -�`�routin� appl7%m�u<�l�<s�FA�epidem&��ܱeri` A�Vr!�TL��6� C"r��\� , M� >�,!?comit�4L�^9�D.e>`eHD@ ^B+FCd�� "O� HIVp�� � on �� �ӛ t����a@lloL+a � ,�sL�c��sP Y(o�+I�� ���f6� . Al���MB=��#E�!"&. SS3�Fr�Jhe 2Fy|TL�F� + R�q>��D zK ۝2(��n�Je�}v�qbrush�?c �� A�taci ��zZ}dg��& ��26wi� pELe; � s%#'&�^�j�H!� ;'�� �ed�Ka�l5.�-sto!��El r�!�1( AmbQ, Aust�FTX"V2�%��3�$Nre�&M.e^��a0& H��he�� hock�^.70��~)�j]��2�atohBt% [28A<�e&�(!��!�Xal��m%�5�MW�!yb#L�!��/4 μMC�er ��?M dNTw.��7�O MgCl�H1 U TaqL 5-3=�( Life&-�^�. �sspO:�)�!-���ling: 94A�! �nc" 'eG(30,!t- 30 sCDdP 58D45�P7201p��Oat.�Mo-��I-��4ӆ a 2% .r�40�Z1q%�5� GelRed (�*t�+, HayE�J�4"� dƴ6 , enzy��c*�aYa��tw�Z�MO7N S��i z;aeIII%$BstUI�Z>��5R�C@1D� &�A)R.*� -_emplo��A Tjofy�profiAaCllA�-RFLPu�s:n6,b.�>.290 ��c�e51�I�PC � 2%&a�r�.! !Qa�DM�e~!5/��%�{ >�gA1EC#�(!�r�%���&K(�2�5{o"NF�"S 66I<3�M�+�R�`..'sB� )%�62k��YS�Aya�40 bpYl()= F–�LTATGCCTAAGAGTTTGGATTCG-uN/%gR* CAACCAGAC%GCTGT )oV.GF�ORFr!)TviB]�=A�a���mataexa�}!."�8Son [27J1� J!de7 )�P�/r3 [27��che<4AVE�fi�h./-Bi�[2ii)_Q��m�a�^�3 ��%��2?5�jach���V� �!oY�r�, )�Z�22��V!l1��ix1Bn��oi&qC��>�2N�2B�!�%�u�"S ��NM, d&-0Coleçã��*�  do I'L4o Oswaldo Cruz�IO�p,E�u�4"-"A*��!7all]o. ME��? �j"� capilli*S7r!ing��ndard ?g:K�a����+q lU�. A���� ay�Vu% to e ��� ���B.S�q&�#ML&:(i��|-���"C� -+&. IFempha&�^ CL u�ly�bce��&�"�e����|"ڢHk C�c2V��ofu>10W.% w�`/ ng�C us [�u�4 assu(�a�&q-*�%!�already6� }�hum�*"w� �mi adop� )�h`bJ assi�W�EWv� ve"  �X� BE�ng bi?/�!7��oweovd\"t!},�. Dat>�aT5�����SPSS �on 194�^p!("G-�]{�b�@eerL�Q��a3thX�a;!� d, �vF9of �%��*}���F[rr� g� .X!�6$a=� �a -�<�2r4�il� mʠD!1)�-4A�n� Pon2�}��E�-snof��,a*�kNwF1U�����B^m� �5�ris��R�BLML�!�R�%��B�6r!B defi4 mDrI! �9�MdBGin:���Z>"*k��co�/"��. 5�/�V!�fA�&]�x�4e͕\#(w\{(Ivm�-�&�!:B� ,��k-c !( &q-; 8*;/)G���,�):M�5>C �2ـ:<!�2r1�-�� �^{;&�-�� �:�-' ; 12>qC�!q6>Me"%%..9#Y&%��_�B~-#�����a�� ����a.�J C.� ��;&R.^.2�-.�nd �6a2|�/��[Q�v�-�3�!1=�v23Ï�at2�/%F�����2�-.��BL>t N:�a���[)e"�/Q"�����/�A�9d$!� s fa�2mf�&f��j:�A�!����}"� )�M co�� 2�e�Ka3&� �ss�c�AD� ��m{!�Sj,w�m r��str�&^2.W i�cP1�I�w*��2 �s��%�de�a>4t GenBank [30]���&j >7 s: KT3471�t �$ 7 , 8 x ! 40 (� A 2�%3 E 14', �1� :]q814_.#Qje F�1#.��/Ft�= �$�&nee�4v�nAJ taxonom"9d ю�yo!�]G*, Iz�!un�A�a7EZ'S��LRVY�.uho�#a� he lE�S� �#"�'&�7�i<��1D� n�0-M) !�4 ���cCU%`��<2, � E o avoidA��A��&�e�/m� !U��1%8� ��a W>of�1�G96�&#� #(386&6� �H��3�7%�$�1ezi��7�~B�:In ��Z xty-�8�?4+1(58%–95%CI�J. D1.I3UH!�ml�<ty�>W 70L4%6L7�L)rG���Qv%�F�Z 27 (Y2.3>�2l3�1�4,4�J><.&�� 80 "P�=7 69 (_ . 25m7!v8…9mA�m^�4�1!D7.J�5 …2A�I>���A��� ve"� "d�� 2E%5�E FX3%<0�6�M��i�>P51ZP1%P���3IQ 2 9…!E3A� � ’s.� ��*� #�a,$an0�3. ��s&�))�1P*M �g�+d+�StZd":NsIIo*$ Ks [�hF<.�*53geograph% �bTa�)�ly�-�yerj(2a�a gre���6�tj�� ervo�f( T$�Zd"�,u�xe�f P.QJ�1�%a9 "�4 spu �� !V� �=&P6���� �8epl�#O�c~y��}�i5VRFT'� )��c���E���N�=?4c�")u B��!qD��y�M�� s; h*;1i? l<1e�e�lt limi�'4 ��";1Ev s� �m�*e�do_}S!r�e��.0ronic"+by�2( inM��=^@a!'� seem%��#aM"�!o@�D �emergD A=1B��*D.i�Gj-m>��)�&I!�Q�>j/�\X/ and/��Z -fic�. *l�e. S�21 "� QXrÖ� 1 g�+�A�a%A�pat2SA:qFy le r��apRV!,çsm��!mclariflO�3� sy{"-&$.��Strep�($ccus pneumd?,*��yw6ea5 E,mbac�"5!�ep[�m�-it?� ���q�� morbid�l&morta�I) fero� IFN-�m'�>`�M`Nintra�u���x1s�?9�st"�"���2el ed �x �coc���, �� É�M"�̀�9� y�rd !{howi� �p�|�2��1�"2 defe�.�N�ia�c9er2��A5emi �~4-���$lu�2bl�CM"?'פ'� 6�re��o,�0Ifnar1−/−1nrrI$.at��Qa neutr^��!�2��zp,����F�d��qw � emiam�iEna!9;x�U�Adu� main~96� + VVJ45u�%ES�V{��m!O��IFNβ-3%�ϐdhUJoD�s!��( ��S:3�draz�Hrx�!8ͪ{ �f���Y)nia� ��Eto upmw�-�miL���&HKa�W\:.�0�wmYupt��UR,atelet �"v�Fg��&( PAFa4� Maa��t :T %{542��8��a>�!�}Ba \�+thdt�Dd�)��lAlay�q� 6Ea�t$vt�l U�EBpermeg c@P ,�1�Hy �3.�EA��B�{�8��3f�?@-�)�u�m��A�&M72&in-!,0JA'.�-�R�<%=cyt�{A 6'-&n�`�!}����, j3�Mly2 a-m�~A|� d+�֐ H��Y��2�v�~let�[�u. :���!J����en�2iJ�%� 0(nasopharynx-�p&7��.�9e�9�i�Y�)�,���'�Y a%%�� q*ee��Sacqui�� [1]– 9&�; cer���4&�u9�i�)paJ,�i\^�!NsL�N�_6uaus��ag�/�gl m�E, i9 e elderlchildre��1 5 ye/  ge [�u� �.�er)���t.����.� i���b�"h�&ul�U2Q)�chkZ��A�3Da�l4#m��8:�*= [5%�7�8Am�2�)�a����� rz)�6E���2� �2t9AHi�ə2� �epr�m��c�-�xD�Na��#p�Tor2S�)�s� �;OmJ�E�st�Tw��j��� �8��V��2��X:�Kpto��� endo*g2I{ non-`q��Z 5%3Drup%�Bzs �?�1�oMnt�%� h0��Ml� !9ir��tf a A G-��-coup"��(x��[9E��>qs�?binM4�Rryl-cho�����2�E>wB$.�OR"l"Z�cy�9sӀas IL-1�� TNFα�� � " e2KF��us�aMl�2��Fng�b*�dk�O und!�� ��6-�E�����!��� as���x�Ej��y�!Xs2�/�Syst;&,��=�.:p�2A0 �ct3 a�B � D .1B a��vr"se �aWr� �z}�n%�"Q.+�����w&Sw�@9�i� , M�[1|F"�5�2 Z" �?d��!,62 ��Qel>1 ��disj#� pnem �haڗenked�P��FPVv�at�H�Li�=dU�wnPR/ U�. �B� eby, A�� adh�!%&�C va84Z� [14] W���ū ��a<�@&� �Z�as�5N� a>�iJ���. W�a{ F�( ��� 9�N�AA�"� >�Mt�rep�-� �2ada+&X ��&���18a �"n�)h^y��!�M6 B.j  �.qH��:� ��!�&.�1�. �y��8�MS$lti�J �) �le��� [�A. B��- ��?r @tbyQ�eterod�ricD1 o���9ywo�un�IFNAR}L 2�A)���z a!�t9���1�1�5}�,z'Z �[as�8MprbM�E��D)B�)m�Fo��mYbs�:, �Pd��uJ�!MYy`��j��;+ �5-�V��%O�� �di� prol;!d*� ge.WK"�&��gN�[24a"�/ In m� ph�i,�-IzL,!o5)"� < on6�J�)�e"�S)*>05 �3J !STING*� W�E�ogn6 2� �2[HtM��2&�[ ogly� .� � 2<�d NODA��7I���X23�B�mI�e�-[):�)�\ H  ,�Srey�%U:�VB�l%!!� DAI/%\$/TBK1/IRF3���َEV%:��t � rapia_ A4ofAHβ�O�%"Q w����>�;�� q6j@.w� log�voD .�p�$ev�!ipy�s:(7�a!*Oes6 e&�� in vFk%� vo�"����X"% Y�t  �&2 lF_Bm,� A�` �Z�u��)�-I��A��(i�+ ) adQd 6�� �"a-É�.�:t.� �Z�� io� .�w>� .F�|(�t(� ovel&K �V�H)� exer��2c6u5��gram-"� tF�!g�Me.�Q  . n&gE�<ic�$ ��2%_NP%�.4we:.(ed C57BL/6J)�%;D39�=?N iolu��sWE �JAaol@� 2>�!�inOY�aJ�&mA�I��P-C �5Q'1I<�l ours�).����)fnb/'Tnf_ Ifng�.��v%��%#hom� aa� by Q\Z,*��Agan 5��awao�Eoa� s 6 ^�IOin�k �� d�L��( Z2pa=a�ϧb� " 92�! � ref AHVRit��ng�:& �#�)^<+�Vtit<��6v$ve�low%~cl �]-!9W �1.n�5� 6�25w���'acZʥ�B�,�!�4<#�=z5H �'ceEC]��4�: �im�^�?A�il�g E]�?ixMpO/Y��/��� ��l�#29�� " ġeɤ�y p��5�!�1alveol.�E >+��,, 61recru"M, d�; eluc �!-"n! �N�9 :)��chjOdaa&��-�+/+>��fi�'. . NVg�!�i�munD�7����V�!�E1 �Y� ��&�4�� �Yz�a.*0muX'hali� ,Oii�in�w"�tly��=��at� er.) �ͥ� to �aZ�?Fi�*�,�F45%!��jJQȠ�}}mbyt1�?a,-9.�18:[.�'RfQM�a�)yt�M�48 l)�.�b/�.% 91:q2%��c2�36::�%Sg � rasH!*i&L �� tra!�ton� h �&Le �v0riX�v �J��=�9$��X�&P)�; :KM�a?I !!� 2bl�B�=*�0]�+.� �at��.Q�&�).@"y�i� !��ic.���(complement �uour studies based on IFNAR1-deficient mice , C57BL/6 mice were inoculated i . n . with a neutralizing antibody against bp , or isotype control . One h�Zr , �wq .f,challenged wqHD39X in combination @a second dose of �- � (N�8) . Colony-form�0units ( CFU )g8the bloodstream � dete0`ed at 12 , 18 , 24 and 30�@s after bacterial� . M!j that S^t�.� developed Hemia fasZthan th�Jreceived�>nU%�(( Figure 2E%$The median � i�tig4was also increE<byP1_�ment: At! !�,s post-infec%�,�k5e411-fold higher!� e-e!sHnimals , a differenA� hich furt <�at!�h5� to 19-17 q, resp� velyB"�Although this did not reach statistical significa�duekAA limi'on�Pmouse numbers feasiblab _e# of experi!U-9,data supportW0results obtaiA�e!0Ifnar1−/−iQ , suggestA�E*DIFN-I activity dur0pneumococcal 9�m�s transi%�of.i from� lung into.: . Si!%ossC:�inN�lA�.}(susceptibil�toM�eup%f�as2� , we wish Pu� wheE4prophyl!cY����re�ynt�β�$turn might!,ferKtAOon . T! is end�Q�U��Z]or poE�I:C ) ( inosinic:,|��mcora�ondaE�F��su�tly re!6dIrIFA >�9/�u3A �xTAprI&ve ef�&�kobser��as early 18.T�A�hen �e��!5cta�W36%!vehicle�H%&$versus 14%%0*ͩ"Ab (M~6;:5. R-)��a�!�M%���6k�ysurvival=QB%Q Give�Be-@E�finhibi�A�wi��t a%AA��of ,ia����J$hypothesiz�P�ɥ�Io maA gu�8epithel�U(barrier fun�i �[4. We first inv��g|overall )permea�i�YAAa&nd��+/+%� 2by��v . inj��0of FITC-label��w� !%PAFa�ept!v���5k(s [9]–[11�To�$"���%���.UC�.� ł examM�capac�eof��� vade A549^ !cu�incuby��m�"?for 21. Extra�1(E`�A�he�sI�kiq-bio��� prior7U � �Jiin^ 5Ba+r <of �;�W��6�& �i:. 4�ne r�> e vi� 6vn�> .K��S1A? _a.�i util� simi�J}cv!�eny� �in orde)H��E+-brai��EDEz2I2� β�J1�lQ���he rat T>�r, rBCEC6Q �to.�,)q�%�V�m�!sN� i)5h5)c As s o r�s2�i�����a�>�n ��2 ribu������agac��d�ʁ�E�Y+J�)�j�� �+volvesa…�-�A�� cytoby6�E2�i�-7�of64� K �5y)�}S. Indeed1�=�6O�-to. downB�R2Q5�6KFuf,Qy�6r& e,^j�� TNFα� inflammɖ!eku know�b8��I9sV���:� Au=� of NFKBIA!�m(encodes IkB �N}�-�DNF-κB target gene:�[31��33� ��6��Hr molecules describaa:ext 2�"�a}�����mer��0mmunoglobulinU� , ken n10 , l�+6Z n�n hWcomple�� on( fac��H [34 �9�5�S2Ik%�-depend8�J� 2..���reflecAz on a F` �-blot 8�2��bE9�%� , �� lone!�F6���6�QMoNZ ,k%B`mɊ�t � 5_6L.!�cist!iJ �" fi#��>�associ�8�y%AAF�pvo���S2i�To.*fir�  rrE�2� %@��R0Y�!��Xu-w� -em�assay�#E���>�$antagonistɚexr��a&2�` �x%P!2�MIkF��{.;R.3lJ�^� ��29�i=�1K Ia2��!��*� ���A �;9��U$6"�se�a�n2�!Q :'both ,6�.lndIR ! viaIsamC e ,Q� f��%�2Y��Mp.� �dem�� ��E�)ese�Eƅ��w6A2�(ch&�� �de/d=�2� e&� )�.R"�s�,�B)�ss �-I�� �o two&� �u�KYj�m{9k4tup-6g^�- roll�9x �u! "_!�c# gzL!}_%�d-�T>�  H$1 � )1i�l&wTS .- niae5lin=u:s 1�is crit�lyaN� d>o 8iw� V�i ]�� � -of-"��� 2��!�W �� a%�B*9A!�� �{��,3)� e#skJ�%�� , bu�"��de�#appear(:��\ d�!�a>{!�;ca� he X &�o �o$�-I) . E>j���hys!�S �6 path� sء par�!�i8�of)�defen)" �!��v>V,��i4 la�im�le unS norm ircum�A so� �hav�qui�"�{ene���le ��s�dis�% > , [4�[4LMu�E�����!�*'�bD� �er��U��_ i9nia [42� 45� wha�eltissuTjur[d�rupE�A 2�s�" ion*$ >�_q .�2�"M�ca�S6a,᭷1g"� ua1o. Our鍝'�&ual2�on)z]Oa�s�)N>�%: F9 �!du��of JMv2%�&sts�Bb��im8��z�=H����$ �\���(2�Se� a�� evid7.�&idev"�pl} 4m_Z role� �5 A�=R���b�!�-I hase��x1:� &�!!Gq-�� q�& lockA� *�7N�;by�U�oryoo2� �WFth�� [46i|8< Also) LR9-trigg���٥��olitiaHc,�*�{�,�I�&�[4��r"_$�)strong 3 �r�*%�8+�2 bowel!X��50�F>��T,e�W5�b �,���(by gram-neg��U�� .� 4Shigella spp .�Salmon8typhimurium [51��[52�All!�� ��>�); �3 1�ve��Az��-'No&y , usa�arTew.�� ve(!� cran42�.�&iO(rea�s��t�?^�d4]�)$ AF�.�-E �mr�,":V�.)a�)�d mphage��A�sʹnit oxt�iSpro�^[26)�3!� i9�surpri%cse�.a�+pleiotroi*$�+e-�imping!�n var%A��AKin� g innate �, ��_re�+o� �IUk�U� l cl� 2= %�� .��RiL'vQL1 �_ }&�&� "�2A%wJS��V�IXq Shahang�. et a`0� o M$no">*cf6��.2I e f$�%A �.[-&� �he� �[54AB3/oq�!(V K��� d.�.� -"~Q s��col&qco5=����multipl� on"Rrimary>�� .�b1h"  �D)b��e "} !�efO%�� onseu e�0"d�A�ts��p!on�y7ac�lo��� pN*�/1��� >�xY�sourcUi.�%�2�9(is still une3�1�Q�H dend\e� ��aӭ� 5E�a�F� stimQ$!'[24��27AjDeple3s)���# AM )!^ admi��o=$@liposomal Cl2MBP -�}��w�&: �a�$ -�.�j%�A�"�)morta�/wR#!�)��cloa�Es8�BA}�k��ed [55! ���#2-)�ediscrep* ��B3�K� �<4-:5}AxI�argue"�a majo�LlEQAM��I[)�A�)�2,��shoul�"��at?d5҉��(� in+ �1mgranul�a' crui�, makw�&��*���} situ�$�� icul���/e�n@*(ZBi? need�be{i�2R� %�,!Aβ.} ��^� b^ �/: to .Y�j�*] � �zQ�,4AoF,�*E�1�,� microvasc�.J Im.. .>�exh*/A��2q A*:�mening V5I%�w�1ssi���"� ,i� �,� β{99g�)R �:� .� � b J�#isa�au -��2�!Y�#)�re���aemon$&�� any &�[56��"�-� .�%�)��hi���%a��� po�5 ve EL3$us faecali�q�!!) alYu [57];-;�& temp�� p}| � :�6~2�1-' R� "�^���os2�&��.�|� A���:L&�:���u�M playi:&4l�� ety!�%�� olog�s�\�� tumor b(� a�[osclerQ!�2=Ss [58�6�2di� dely�a(D&@ S non- A��� natu_lig(��m lipidj,c a po*� � �2�C�,mb�%process��>d&is�[5;3da�&�5�-.@�6{"ldPdi�5deM�e �!�\�GuPy p#^�n�-�:��%� o-�!�a�:�-I�|!herapeu�u!� in M� e SU<3R�u&az�a��&�:-� �ver*tV]2�%�)�,FM�{l6�byC/ify�*`Mr2�t�[6p6pT{+12pŏl��" m"�/�Qjjc����re�&�)] �$)M scen��-I�ed~�8s� Q=d >jjen�.~sem%?:�b�6du� .�Y/"6DB� as�ng!�N8. How� ,�~!]�"gen5�aa:~c ��yd2/&�!�aN��)5��,%�]�of��1W�:sI/��}8e��"Y5�� @a*�i=:͑�sm3, aR7�٘5}. CX"�<"�=i �  @V��!yw2帅�olr�s2� i.�8"�L"@ to W�Oadc:��to&<�qh�A f\8! :iI@2 za A viruA�!�E�A:�coloni*��0as� rynx� .[co*�@[2��b< s6�>� Fu?Gs�#U8L,�*o impai��ophil�&�U��s��KC. MIP2.��+ipre"�#�AY:""� .��3v;� wild�!�VA�$�2V , unles� -'R&.�)�-�Somew��*a/ ��2Y&�� m4s �a��e�vi�Y!B� )9�Dj�A� �k'*/��$�0�}�� xplE-J����2/:(�lRyF+gcA�m� "C(�6" �)2E�K terqE#C &� �*tic%C)'�� i żNsl*"� �"O1Nv�� sI �9�5�.ur ]�Zay�q'�a.I-t�;�.*T@$% 6� 1?�#6U%,�*AC1�$b%2 mono ?Fca�2�:xe7b�t�2JQf9�ioNE�l�:ss� �2a�@-f�,on2I2�[6�&�.a bene8HA�6�-I�]2���!��!����+�"@�ch�Ul��de��e u=n�!�cl C4"��*H &�7. AMn�;"I%\=Hu���!!oco pproa �0StJude Children's Research Hospi*Iy<oa�A sC��,Use Committe� �aSt W �c,pro�� fu, cred�@y� A~*�z�!QAh sAnA 5� of Labo�4.�, I� a��4( AAALAC-I ) ..6 �sR main�!�Ca�>�&�apsq  io&z  Welf�Ac �6gu�inU1r.�-DHHS pub"�, G052kN�� :��^7in�gri/�rypX4soy� r ( Difco9�5, Detroi�M!1� l�-��3% sheep��""�� �l�" in liquid( umJR40 . 5% yeast e?5t [64]<37°C)�5% CO2�&i �Fi� �#t:> sero��2 -; Xen7! 39X ) [28�a$!le�:Be� t��R; sF;`6�>�;�of'��{6�( ATC=.�)��512K%0a[ n�/k )J>10% fea�bov\1,serum ( GemCw= ,2 mM L-glutaH!( gro100 U/m� niciO)et�>�>!gabbrev�/as ! ) EXkindl|#�$�)$Prof . Die7C[0ruenert ( Uni� ��Aalifor�&, San F, iscA<�d!��� mum 'nt�\! umi�(Earle's salj��V���F�"�#&A 0,-C)`6���;a>!�C!#ng�,4-mm , 3-µm�-e dG4Ds� -��rfaceqs��� �9 d�c tO {*�J c�4A?�t8 4st 350 Ohm/cm2e{�Med� 5!QJue �purch�c�� Jack�!�i:�% i:�!& .\ES5- 6-week-9P male��A�8�-$4 lighc anes#M�I� isofluranA0Q��3�ll PBS (��OXf wisA�adel��! nar��#T�Mver"�E�the�?ed!+sc$n� � �R�3Bir��by���- dilu] A�|�S�i�dth�,�p�13"]Ke"|P6=monito�g �H�nd) �y 12 h � �D"x �_�;ngle-�*-3I�M'p�y�JX �f g 50)�of�lagen�+�( 3 Ś0, Worthington�S!�"�A�#KE.. Lun exci� , cu�3m�?pie� ��&�>in 1 mv�#�atJ� !I20��Et�MpaC�E 7!crNfi�rM-�!?-+ly��'ACK buf�P ( LoA� �Q3�*� AbsA!fD CD16/CD32 ( eBios'VcA�� %���su��68GR"J Ly6G�V�, a volume of ���_O��r�J�+2HA�W1 h#�z�"��P&�i��aSin.9��ai,! -D->oNYW�"�� . YlAK:*~�=�i"�3�J�%5!����g6D( 2n or�, 08 ��P-fa@U��;PBLSferonS�)XT F`&5YImS*��5r�6�s��X$an equival�;Y��"D��z VZ���&�/�^}I���� 2�Pdi "b�tC*$3a�& �P�&�>���ly [6�'Brief�&< or 2z*��4×105�Z�J6b�C� �;A&)\*�2B.�µla�2(�,-Aldr�U[!�!dpR5d4tail v�##a� 15 h0t�G-��|�eu*� by CO2� hyxiva���2B"") lava�aKpe�<�$'�/ecwR�h�la=���:1 miD ���rem9�� rifuH0��t 400 g�1��nBA@e �n �'ly&T he�6 i�!J reco�K�5�.j6a�:k FluoTa3O(�\B �� aA��� fluiO BALFa{A� �!486 n� 2isA�sen!���+io!�f:{QtoB (�  Pe}��Cx )%= each�u. P�."5';�:�a�q�y�[63y�*sC seedE� 24-�G at�5e%[$8a}4I/� /1!"� n43�in�N 24ŞaŪj3 ac��xiR ly 90%A�eO�8��'�1A��%E7ad�m|ia� ��A�y!��@>h�� �,to mid-log p�as�I�� ��=D!1!67��),�P%|&f u��%8%7 ka��- d�w( 7magnesX!� calc �:dp&�(a���Tgen�( 2&o ��)S���to �J�ela=�� -I �, ~�[� )>l� %05% Tri� X-�. B"�co1�enumeF?d*�<nQ���Y*�� agarQ�&�.�� �Aeb,)+�M CV3988 rac-3- ( N-Octadecylcarbamoyl ) -2-Methoxy )�pyl.82-thiazolioethy*�&KL( CAS NO: 85703-73-7&]Enzo Lif,%i��!��#�*o�dh [a5Q�6I�3��ub,"�"�16�R&�E���LeL:�>�or�Ga9 �Ag�6orI�5�j�<,�]2s� % AnnexinV a(7-AAD> A�p#�:*by2� ry�6&&6�FIZ�~B�.Q��a(�eM5%f ��vE?of=�[�G�d6h^� V�\�2�>�]U�(%�=�f ,Ei{�yޡnth%=6� q�e�ony!�m� �dZ�:w !�g�:6�!o2��41]��( b��e1�.R�)%�o�]nt�O��<a�!U�T9R�'he�ns�oinser56a4 plac� � ��.�%�� 2��4����8.�R.UFc2 �.{0mi,�qC # @7 "JNi!|xEN�T�O estiE^%&� !!I��f"�?:'(b-2e�z>���;K-�120�TT�V�\Qi�S�V�R�!A�Trizol[*[ ɝe*�_@1��ht�*i��I% a&H %{D*:� , %��"� �D 00×6c !�sup5#��{4aru "���a�,!D�Q�&�C. Nuclei�c*�$Q�DNI Ampl�!XGrj:��2AkI�,*ng DNA����VrsmSnM to c** he S�pt III]C-��X,��-kiB� . Qua�� v�al-� PCR ( Q-)�&� L n AB 7�r24machicNA� ed!yI[  � a SYBR gr�UbM^iMi�R9 . Eau ![)��C� !ycl�'in�ph�β-B& ActBG s a�sekee�; gO &�p(Fr �u&st� 4MH: rs�D�, 5′-ATG GTC AAC CCC ACC GTG T;,!z20 TTC TTG C$CT TGG<TTTH;�g6c$CAT TCA GA 78CAG TGA CC-3′ 3Bj(CAC ATT CGA�rGG7b1 k �GC �AA�A GeGA ACA T25BmGCC aA!G AGG�A� ;Paf!jns� q�G%9T }A�T� [70]; 8Jr$T ACT GCG !"G TA AAo <Tnf �1�%IA o�TC CGC 11Jl)�hCTT�-G� �a)�� �\! %DG%�A1�a 1%G�GA-G�1];�`e!�GG!� C!AT-�Zi%�!�GT%�A�GAT C 1 [72];6a5.mACG �!�!p! 4;>�G%�C� C�A1`�b4�\a�CA��G�.^18._C�a�TA%�aCAQ�:�%�Se G TaC 0 [7�'' �C� BC ACTB �M�)�� i�!�a�G1�3� 7 C!�!�! A��PC T1 PAFR6k�s!�PCoI�Tk3Bka*a�Ta:!| TC G�� ka&OIin XT Sa�S&0Biorad:Y7\res&L(by SDS-PAGE�"-R0��� fer�o�NBoHul�#mbl� M [ prob���bo�q��2y ( rabbit �,cl�', Cay�" ChemE#, 1∶� � β-A�c (� AC-1��#0� 4visua���9"�=ch&�%N! Pier)for�  ,&j K��3� 5�;�f%q �$�,mag�udi�te *�Li-COR!�*��?F�mr Exact �c��!�"2  ��1 �� ; � e�@� �".A]�, orgaH'�9�,group� 4 ,Mann-Whitney � �` RYpofkkdur� "�-%o">B� t�:�log-rank}P valur]��/%�iX7d=2t �Fp,:aaF�Z&� IaPrism$!  5 . 03�' raphPad S�Z% DiegY5CA$r�Ne�8network9th�(s = si)�Nr emploc6rewardR'fA�pik�3m�>�Wpl>�%( STDPa'jSap�*65ear�si�ZforagAJ taska��PwV&�RadvA�d�3r/4 ri� � " tinuZGd�: �}�lneuroA���C:���)>'^dTB!�A:B%�m�s"�;�%homeoE�c �9�A�ynan+efMsc;&�Fhso$=�, gR��4|S$tput balan�6,�1!�� m?f �ed�hAlim;on� � strength �mo#2�1�a hiddenM^�%�Yi9Ew�AAr1�W0C$_ ���^ZYsc inpu|>�us}Q(basic class:��6QoA W�"�rՈ*Fi0�5�ApI�(2QY��,toI� ,xp���ab"nlzn��@X�!,>�W v(pae7sE�Ude��%`�unish2. SQrno�%A �LtX% -and-erro�lm�%�hel�wto �Ntif�/goal-orSy�?dEeg�`B�����7 ask V �a�Hv* edic!�&yCIG�t?&���6�5��CI��!�sua]��{�P��lex����7ol�-L>IAq deci��kD. B�>�l1<sp�63 �W�D�:� !�7�!Lin�+I��<%�!� ��(Cs�R U�8VFO13�deeply��E��nrA!e�4n{'W)' step,P�H o+=�"8S�m Q- �\�Ahavio�W�5mak�;�S casc�powerfu !�qq;Ss�:%HiKGuh��H�ver�nŒenviron��% %Mm OA�:�A:—!p one '�Ugeteo�C��4j A�oZye��{e' \��occ�v,tyIoGa큌�� versaS">� !�!E� iN �!�t� y �[1�*1yu1:NA s�-&j�lha# tkE� o�� �� � &� N�z2NE9%]s�YG$a�>�v roJGarm [16�7(I6oreN0e, � comm�xleakM!�ne�!E�A5�U�� -C [1�7ca �l�g-,� E>limb toN their max�4ba��H DC�< ghly dys*-,� � G E�銁0o�pnjCl�c!Bt�\�!ToaG� runaway ��dynamic�v�Eu#�H� �'��2�2*.�weR#e/�I !v!Ig ~Ies2l�}a�_�psI>���s 3���a�fr� ce� �gloE��aoiPcom�s�� �@�@c��� by&� l�2d7F�-� 1tJ=V�[2�nAn)3 �]�5rj�� #PA��C!a9� q��?! �1 w�5�Q�E�W�)��$� [21�G 2�.sSp�g &s2b!X|!y�veID@a�2�";&H new A��}ilt� odel�A� �&� �AYS � � sY in m� [2w� h�~��� !W �u�2gH5�$)��+�8�KI�&T�U d(��� LŪ)��I9^�N�eR a wh�S����A���]�Emn �3t m+<g�L� 8x� .G )`i�l�B �1inc���SE� food�� adju�OgY�I�sE�e��� w?A|% )P�'�s9:� shapeQ &g c6gd�pa�6 ���Xc�3��W6�"�  Eed5kf� �noY%ѡ�u�NEs!����W�6� �>�,*��!*gYel%^�=B�� an!R��/r�\�%RMY��G 2�9�5 �[�z. ��� tudy4� expa&X&R � �N�b�A��!g� �6*�.� ����i�rrpcB`woi�ED�5�con3o��"P� � 526�� ,]�u 1�}a~�G�=e-to-�S.��-a��E�q[� middWE�z��qtoRJ21m�o� EY".Y���$�1��m0a few randoml�\Ev�Yɾa���a �&� K��a�"Bu��!�dnmpu�#k� pia֡f%s&�Z!Al�Ka!l�*�.� 9�lana.A r�]q�%jho4%9�"up ini�5t-�as����)�)��%q�6m��S2Z�G%��E�?z/" �= � ��1}��a�he�� Gprofi�I�!��H.�3uX:�M}2���on�� a�i�I2��7:��Pr�%dg� �� ��B @�+!�pa!�1��%�. 3�9 �Ufe C,��-g.�Z-to2�MQVazٕ���!�N �%recW d�1��[13��Ga�fe, �e7r�b7p)��*ratdeIEo��7'AAAolij *� av J impa�}a�* \ � . A ua��b�� Y!+q5dir�Mvi�J �-. ( ”A� ” "�W�,�@ K"� pre-&�X�\ %h0k�\�Vi !)�9": �'��:)�� �p�fer;r &�"z]5�!ay� @V U��@>�!1=)�}��OM�fua1�c):�Zy�[!�ro��� voi�I"#"�� �pwA=�1Rs{`< To eaSl-�:?�a�{ !ouri( r�8gorith݄a��H heur�1'�� e bestringN.��n do]7SU-ai fiel��I�e�1�inua�=�I��@i K%E 6Ep a 98%2Ktuat 45�Xe�ft(>=26<��h�J:�� R3 ���U@llA� >M5e� �2$.K�5c�&�a�#ɴ�'�"�&f�lKѸata�dI ple��)*�Bsax&�r&� )(� �( soon}�S Jyha0k�+!EY,� ��%1s�j%@nKl 3U�X� �N �.7L"i8s�-�.�)�X�y�� veraiAK� sn�9�56%�R^QZn #ZI:a{�:-�B� ����chieve�#y&s��quBz2z�E�ariso0 �n � V>dr�E=ab48%&� �:ap�� s di�I�� ��a���I�!�� *$%a A�&g� )�1:ny���@rdl%E,e8>�� %�ni�OaA1��%�M�I-�curg��i�� � aeb�t8��Gi�a��F*�����{P "e=0|�nm�RW!��vj �+l"$a�w&%�>save 51a�I+� 2A�y�"=8Kulet� � U�2�&/FsegZ�arrang �-w>Y;. V�.X&"c� � - Єm�!�.N�v�%/r!C� a�vW�T�A�\.�illA�tu�Gi���@��&�-s;+�lO!�� .f &� �Y7m)w ��E[i��,Yt&�of�CB { �Fig 2C%�I�.�c2J* R� M�{ �T1 �"Q�e�ae �fc�ja ' 9�m�d aA*Le m�i�!>�Lsl�*� �!QMJ7<pʩi)�4]in �A,��N"�h�N��le 'I�\�bule9pkepOp1)"� Dxv�+e�i�|F����CB !�:a *&Q/e3��a(��t�iIt fai�',��to%inguis�@l�8r�&� P!Bd� � w�:� �Nl%un!�J� rP) &��,�!�r��.:�}7s2��$��['�� fa=y�e*�8 o� .� i� �#(,S��rQ^�O�C�)T6�4z� _!2!�e )(YwA�a^ , ��g�D���i%��g0S�A8 yK marO3 a>��1U"� �!�#��:1&R8 �Q&dr/*� � “ba�or �Jc�� �:&�<��.���!$��!aE�^ e�i ,x adja#&�1{a� ambigu��A�����]EΑ'�#�� to quickl� M.S � �~}+�d�!r�?oa�B�2�("�6�� �o\|%'q��!��9-C���/Y_1(�gon [3�uA�U66j��>be.Z�c�!D��"le�!/3�38�T(1�!�.r� B � �}%e���x �j!����Wob !�� ��f6 �.��ɢon]*!́��!Bymhe5WF��@( w�y��0E�\l��d )E���P!"<( &X>J-I�1�( ]j�r-�z�]����i{5I� ( b  x[v(*�"Y|Y�>hd�a)%af"�-��bP�c�NouM�E�%�&relevi>C�6f� mmid�f� !ue!"�)t rQ�,x)!Vv<ar���<� a�� , �_!�j�]�C !m�s*p+ ��" �y �[4}64y!4�%C8��e(s-HA� u0�")s":)2� ���%2-� s [4�!44] Y"J(� d�2YqI4e� does�b%��y���F+Q/�< M!fe�] v :�vfm{^�oH5�E�!O��Vv1�� :)3�M !sh)a�JHebb’�+�4l�"[�E�=]�Aa��*@�"A��KemblyA���?�Ssu��!�<a.�h� near!�W��"��#"&"� [4��4_'�%"='�S���t�-�v>~R�4i�#�\� synchr�h� |��A�iАa�ea�e��8e�Z�.�0.re2 �!�`c�'ep1'9�A���4��5a�5�.R*685�0be'a�\t�o�r��E�t� a�AdN�n�6al� Ae� .In}�mi.A �5ŁU U�� �nq�A�"�.u ��T����2S.*�lnNw)D ibu�eqM�fin!#kP� � iy+fa�kJ�or�O�f-'�'M >��5�llF�enX ��=|V�LIbyA�R�7.I1a t�Znca�9736��*� !|� e�alread}-e2u}3� e CXQY[5��5�+k'f� 9 �;3 �;lbi�sEu��s�'PI�2o�0�3"���6�f�1��H Ca2+�I)��3n�O"� back�5aRng �oL� t s [5<(v� -�yndoI��;�)pb ip�inb�Z��[2%2!<�(5� 2e�Wef*�8AE%)�� oP�%*� ly- .!�qt���re\8� �k��./:�b{ Eoe��/��]m�2X#} &����G�6� ��� ��)]a�too4� j�t enough͈�b? �#�)2�� �!�$!�,��o �)oG��aWl�XC�M�/�+ �S"�10�*-: .<sxng�t , 5��I��(�u"�zs��r$�o%""~� �� Sq��-e;7!�8�G��!�var�UUZ`{S��!��"P&ml�R��� pa�2�6I�. K�Ga *�.I�%�� M^ �H:w�n�j� 6%�� ]n��dm����I�k��1�X%�.5A�!T/�e��� �l����:!�Hf)��}pY 5V�noru�1/to �=�7�ole�2�"y �{t8i��bnh_s� %/��cbe�a"�{ #E9�V.&:exert mZ�&9qckh&��a!unouw�"��; .�|>--A���&�>�!u��_ in,i� M��IEd�i6���det� "*'ĉ~�' ��V= ropoD-i�/� �M��ly� o:JM�(-1)O%"���)A.Љ. M� � <Btl“�Q ngAQ&�I�)*&veo��!S6�"D%(A�M�v2Q���?�C��—de&�>faMD��nw �5!7ac<%�&c!eo;��:6,F#gsq�G&~^�!Xx�&e�_�x �'t/&�Pil�fB�.-_6` "y ��<& ��i��m�q"7 �x&�EA� ���.� a� reci�=H�h�����):4�A"&%�by"� OA�am�!��(Wi�7*C0-k>or�Y]-0�%Rm�-� p&\Vwa�a�aLJsp���*��rra�Qw.��=of!IG cy�:v)R�� ����o��)i#ly96%"87�����w&~��ata [3� 3Mn�#Ae�|E%Za�X.� crà�"I0��*p+%E�6hTzʵ�ubot�5 phenomeno? �6�-�(H,U`[6�6N6�6�6� 6_ 6�6�M�UWÄ3 tane��k �� n[6D 6570| �JA�Hll555��3�R&�A s [7� T��\fy �2-=or�5U&@A�> �p�$� ��"*#'e�O��m�sg%H%7T�s��!� ~��c�rM�f"�y lA��spi[?� i��feedfor�� �A�A��)1�G�8�;p�/of"� E�3�8��a>2icia@� a�^SK.� �#|"��% )/ �aJtsq�.L���&D8� G/!��A &�E��qA�.a%Pa�>Q� z�F!I�a:jO��rY7A!ne)�!�8�A�9m��}�1sM  !Sam Kj0d�prje:VE�E OAaU�/-oftenɕ�'r =�Hs7��e"y�C��Mx!�X-��B&�:a'M+A�i�I 66J� � d���E.�# ;d. N�'g�L&�Bc�0sNin2� � ��� �y �Qe "^rA�)b�$ %C+(�aq�>eX$r�3%�5as��ed.�[� N�G�T�VM]!�.AA[sp�M�(�'�K�&4DV�do'a5�2I.Fgst)�" ᯅ�crd��B~XTHi�Mdet"�tʡn�A,}�F�&a"^L�� ^� ��v!�n!P�x�S!.� [7��7�ExQ�Q� �<&�Ob7O�o me!T tochMA8on�[7�7�8�81�(a��Min!�[8� 83]; �aMfI)o.�E�e(o{��memvI s [8� smoo�(ge�04 shol���:l8 8llo��ra��� m� A_5�hw>88] faith3 c ��$2d�a��*Y+[8�>h�fr��*i��T9�ny>6�q��� 5[9� 2Rwe ��eiqb!mE�(��`5ee�e�>%�t�I2ves�* ��Z���Da��܅� tole"� � "3!��8�4�1�*aK&(nW�a!�mapdYD!LI� #�1Aa3m~ �' EE (&t�I� -�\� .�dr�����7�6�Uf"{;2��(1o(-��1�1q��L��|�+ly�� �!Ya�)�p01 ,�� � �<��,9�^H%�"�c�?aXAKAlik��asi��>*�"sur1q!}M�O��&% se!�s� A�1$� �A��= �� �q����Q“�ct�1�f�A? (�>!>*�,�;"O�f2&���.n�"�[ %c f�d)����;N��:�N. W+�ga��� �;tE)�bbe� N���indeb(O����ig����@!��A� ateg�Q8�Q��4u�2�� . UnA|���;^&�|iz��� o$|u& �iA�uGH[91E ictp�%�cai,!�l�AB��z���9�9�9��9ŪE���>�M%26 pl�b�Jna "FgKpW*� �M@) g,*� ["� .� ,*�'"�RpX6A-�-!�6L�9t*A&and/or:�P2w)�8p�!�e key!�p��ZaA�� �or��|, ,yW&����s �_AU3�l�"�H�$�� a�Y)&�KA �;��o !�2�u��e�!Re�N�R*]n�� -� M�3!��  2me/ J , �o.�& link���7���C*�%M�foD9.�)�'>�&� u ����w)Ca"s FWx1� )|-D��*� @2�Q��=is�V!�EB-!\. FA"p- tooka7Z�&�I.�)JN���H8red��� �� arx &�Q��50250 gridYloc� �'IpEreac� �6�+bEg#or� �*�)����>�x��� B#e"gx�� �vs x5 �wbEaC�+�.f�$uGuou*!�B�R0D��!Z")U%�.9u�K6v��5�03� v2�< #�Na 7!�75� squa����<�.G9!�)�Q=:f �V5�E����M%S!3ny��+ f� A�di�m� aDa&m8&� A,�� �A�of 842"�!�n'� ��� 9Lar� to 3��yf�1mu�9��X���:9@{ ; ( K�k28!^28�`6idY, H ) /`1a 3,3�EY"KOn�2��A�;ruc᧡�y� �J�� � a"=��sX!/7���o�j1��10�STf9 M�� �"� ��%%sq9mQ@��As" @�(�(�&)C�i��6 s drawn `aWJ,&�4�D.��!%2�( &HiA� ��F>P�.C u� ( Oj8 �6�"� Wij��WIij :'m.� .����un��.�a=[��� -�2�$�!j1<U ! � . R��2anaAp�Y� ��d\ݲQX�2q|�"�� s2b ��rit��1tvi�6��A�S&�E����6"��o epoc8M600 '#W,�pa>}�&�y�00 �?A�4st#(ŤT%J6]U�I�i !����H����!]p��A1- ; ( 7xr� aus 48149E� O�# 6� aA'aYN�o�;FvJ��n �en�A*^��$U��ms-�vT-�2�IY69Fil���vq� bf*�*���3$R%*M�m&z� .��0f�bAw&�oaE+I��Y/A7�=pc"#8T"sirsafm�Y����t6i5%�"$by���ASa�r+n*�H�:} i� lu�]șk,tA.�I�$+Ų�HIEma�� "�)Ym6�eB=I*�wsoo�� !�)6?h8)��:A&;�?s�))b�f�1�sr���o.q stuc�d �S (�), uo��2/D  surrI$�y "�;%EG&-4�J y�Yya�m���grai _. 1%!F:J�;")��M[#*�cLn�MT#M��i|"�&�)A:bparadigF�:10�6:�;C s H%�Oa�G5P<{#�e@I3H!���e�#st-"� ���N6�H�a�.j �_ eBQHiQh=���aa�AprA���!�$ �� &C ���i�af� �?Q�'���Iwindow%� e�d8EYB_os&cN'2_ Z�ge�-V) �(#�o!�calc!i A�Iga��,�k[ �p105]: p = - | t r - t p | T ca�, r k = K e pF� )a�rQx�tp�e! s� �!���6F�!s��Gd�#&.} , TcGZ��#Qx&�5�t4�K2—o4ARE�%= �5P��Wb26V 2. ?!|im=+ppl! F#�r vS.seqZ� I`�Hj�� �B�}EP�>7H 7Oj ��|2A����rqRH�,r.q?� 5+6c s*:��epM!�tn�erB+vB4e I�` f�� f�AM�� i#-A#R3"�k�!6d4~"�1�Ta�%7��"��-�F&K� as: W i j� +u=) ∏ ke2a c e k71 +$0* Δ ke,( 2 ) $= S r p ·=Cask + cS u m( zA v g:,R*= ∑Ur�i�tg,RR=:��$1 - δ ) +N��>Aic�e����%tep�rpa�a�%!�f�E^)�/)�.5�k0ma�A�A� ("� in Eq-V�-t3v-� 2I2, �J��C ( =1I� )a��8)��iZ�E@a�C�� , Wi)oje��& *EWt�b���L@L � ���&ɅHil)@Oj9a�� ��z0 p\t�?� �=d 4[ of�D beginW#+j*a����B�B�r�6Wi0/Wi�%adoCG ��"�=��f�9.^.�� Avgt�[Sumtr� ��s�����%pAf ward2�).w@.09dzn�d� a /� g�Fl e�I]8 �mb� re> p�6�hanr\"{4�;�E�!�pa� NR!o.R i*P#�q!O6 � d!j  !�"�pa�=F]n�NB CIh4�y"2Uto�cM�A�xic� q−�WvT�*V� �Ku�ce��6�Y �hb�6 � V1� !x �B{0&f�b ͕�Dse� �eaii����i�M��b&7 &L>  C�)� o en� h�l 5�-�$�$�&Z2*�(E�1l$�Bd6Q:"� Z:���"Gs� c(�t( =>G�'Bs/^� s Wj�;i�;ELv/ �!e��!z�-8��e ���dc �X6l k Wj0—a s{���a��78��:5x��!�>��Ar.& !�p>� �I�[:!��< �be�o с-�Wj0%Y^ by D��=� 00&a! ey on�:ab�*�*t2%p^&��8d:!F ( n+� ={  ) * +�)��< ` WA *−>,>,�� )*3. ��>F�A7nym A+un"P�byA��,W{O*I.��UcI"r !)��.�q9�E^�6= E�H#��z���*��=�y&Mx��N/R<le���(vn����>����@Sf>$%!�=�f n S f* j 0� i j V4 )a�n35�0�G��/r.&��� �im�@Q�b&BM G1j3 Wi0z "? ��rlF|}�m"50� in5jEny'�8%b�cuI8�� /b]g�K!�bJH&���of"U�jqѻ[�!10�/107]: V = f α (, I β n ( �� 1 = - μ 0� +σ�YZVIwa."43vol�%ka�O>al�K�+H !0Be� e���Fuc�+�! QXUr�Vuz ( ~? msec�cS� e�Jal��!BI)���,k� ��n m�l!≪ }��s βn%�σn� %��Lnc�JGHrn&q�nt%m e x *�� g .�'�d� ) :)�=e5,!�n =.. Par �� �� σ�A-βe 1 :σ�"μ 000� ��a^UfMWAU�."rh�%!qa I�-I��7k"�/:F�) = {I�^A�) -<A�,≤ 0%+ 0 <<&: . ,]or> �2(�PI�α = 3 .P: �con�ME!d��~/�“u �<l�%VAEQ}4"#JF- VpE,+y�q� ��� :*= 50V� L�[mV] [�%��"d1ce�].�g�!"%|��&�.��i�XnW~aI���,���K%��reperto R��yuq�4�C &�B 0 Hodgkin-Huxl&�F�� b�?�tt����+nŢUAWxC�~iCh�5A N���!^�td7 M`�E .}�ter��� 8E*̮I���Zkin�s K�nO2� rewr^����qU�*.: g��s y� γ g n + {�  + X S�g  / W f%s p i k�r ��a8o t h e r w i s( q#!�!����Imrs:e�����əp o s tV�' H3gsy��e�k"�( coup��m㹥�18  W)r{"�uEH�� c� �nds�c �H�0p��B�&�)�!�i=,�%*�0�,a�satisfe �.q,s�d!V.�γ_�!�- relaxtr6.n�W�I�m�r%)"�0�' γ <��\A�eR/!&co�R2"ar"&'� 1A�4 H� cŬ8P��12 . X^U ly=�Eb@'-1%�� �Vrp1E~ae�K5�&�g̅�19se:.A ϡ�: ) ��( 1+XaV�>�!~ y {� 55*3(�Lan �9�'=is pu�j6 a flDs&�)�+A�!1+R��1-RI ) �I5��� se .ȻDa"x�:y)< ETS�n� pE��ELF5 e-1�� gmilk-s�z�alveo�[e�cge A7�a fA�"40�?ury ��!� rogeѡ 5.� �se4cer , ��52tZ�cr �al�0h�5f��subE�"wN� ��+ !-�R�9=:&anti-e8"���apy �?mo�� z �$-Polyoma M�G< T ( MMTV-PyMT )��e�91>�&Nof)�E�ed leuk`��#l��~ gi�ܓ��v!3>Qme+�1q���%2+�"_m�Z��metastaK�$. Myeloid-���Jup� s�J<�?.�@iR�u�@tl��)�� f�i�di�C�^��!���r�\cru�B� ��D�8o)_.6��Y �p pe�A�A �p�T�a>e�q R��tastasis . Expression signatures in luminal A breast cancerlV� . BA�Q� i~ hete� eous5�in whiA$ubWs!A<�@differential clinEf`outcome are recognized baA�a;haredA9 tern� geneA*q^amuti!�eFsa ?h to ij [1]E8,e most strik0 �� tinc%Ein6�!provid�y.�of ESR1%�e =�cep!�( ER )zi!5Ds>^(nto two verA�-4�A�A�1' ableA� more�2eirAIponse�hormones%%2otherapie��$For examplI|e risk�recurra�, remains conA�t for| 20 yER+�( , but dropaca��cally af�C53-3[2 , 3!�I)�sE also qinsenA�v偳o �y1 o!�FAY$ER- [4–6XTheA`aaorijq ,ic dichotomy!�baba�ncludes!48 characteristicE�� � ’s��(of origin ,m m{al�A�qv�b2hM� �thought!�b!크mb�5m��pe�iAo�.pool [7�A� transcripA� al da� mina��5f�� deci�hs madEi�:`saETS6[���f[8]5!x irstq:ed����W�a!f�1t%�be�+B� , coincid�W��promoAbdemethyl�[9!I���s5&�X� f��underm?��ontrole���ic eEpregnancE9mpt lo�G�pA7ri�<!:nvolv�x8RANKL [10–12]!�induce->13 , 14!DA4force a�ge�6�a t��ablishM�a secretory%h lineaga��7i�VA� milkcdu� . An al��atazB�E7��a��E֍� e�ng u, may��ult if �-��i�ycheck du%�AfdoE�ceQ��e-��nu�e [15-�qc6_Id, a�<ual neg�-regula%! loop betw��ER%~E�occur������t� +so keep6_low [1��,Conversely ,%�ba�2���v�y hig� -6�gl�aE-�<–like claudin-|subq does nou� � � Knockdown!j� h*� 2�-Q a smaDeffect��proliferi��!ych greaa� - is s!miA=--�E�s� Important);� �4rise when MCF7r�, r� ^� an� t�� ��depen�ron)!a5th�6�-R"� 2z �R$ an escape�8hway from inhib"� 6_byN�ARfacili ng�`a�: . Whe�9 �i� ��eY �S�4*> N� , s!�as.A ,O unknAD. LA� prim� tumor!0o�#a�%���oEud tic}ک8es evL �灙8 both intrinsic%� behavior%�Uex r���h environ� �� of!�_��;gai�*Kpla$ityi�ch �\��:�i� vAd mota�y�Ks�k�a��e u� sZ�by� A�*$of epithel� h��&�,!�sh!�bb eA[t)yk�)ou�� Elf5a�mi� or �GN0, cau�los�K�paf� ��f�d ~�Yir %�[16�I8�An:�Y2� inte� ]�I�w^�E5B .:S � m2� G viruBDPolyoma Middle T (*�)�of:E,)b-�CSF-1��le�� macrophagE nd delay^e>� lungqna1[ove "l 9T mig��of2k� he �zacceler�m�� [19 , 20)��pi��:r� subset ac�in.M�m�`s6m F-de�d sup�oqL(( MDSC ) [2!ir circa6nuu O&�mMa~�a �[2� 2� Theye�de6 H�t#�  angio�!+d, via Matrix Metaloprotein%�A-P )� A�!Vas�r End!^e�Growth F7( VEGF )v� [24!�These%x�ŁVkill �al e1A [25]#LT-cytotoxic lymphocy��[26� wh�� �!WA-6�� T.� Epop%�oni���endri�+)mqp; � mechanism� atow)��Vev!�m�� [2�^ In s� extsI(ca so�n � II} 2g!�y�-as��"I .k!.��]�/�NTGF� aml!y�cruit��t���yDe�6!X)|irU�re� �e $>3)Չ�%�co-inoA�W�0eay:�iTNR[28�� We have u�,ou�duc� m�V:(-� ific��!6z-� {Y l"� �A� �by S2Ftoa�estiga�7ol�}�gby {dur!� carcinu�A.� to1�A�o . TFn3 �2�z�B�.c , we cros1L��x2>-�%m?vc-x�%�!.�}1�� jca� [30–32�oriple-a anim)�( d!?ry!Pon�py!� each� alle!�(( S1A Fig )� aRbLFVB/NF!b back nd�imUursberia0s�e�9�7 dqDoxycy� e ( DOX )!|�fe2��� wassc�VwesT blo����d5/M�A,� =�Q(maintained � at leY 8 wk%B-�`���8 A easu!�oG�  imag!p0EGFP fluoresc��. A: � \:�obserY (� 1A )A�. e�re�� $a chimeric.Mc!f rtTAU�e�  fe���ol�MTB� [3�W�G,Kaplan-Meier&� plot�analyz:���?. Only W%� �)� burde% ~10% ( 7%�3%A�$f body wei�ATutopsr�o� ��-;BDO>iat k%�� �no���dZcA�a"1C LHS%� however ,AK�=�A3� pr,A�I&%e�N��!W �C m� !�but�.c� ok longer��t�re��eth/ endpointMr!9-ha$side [RHS]%To� �D��$6�E���Ş �M� e perform%�traa5al�\ograf QF} -A� � C�Sor�( FAC!Z -sorA�( Lin-e�CD24+ )-��4�%Ke� riw( � ) po!ve\ � . Purifi� ells @inj)�"� �}�%� � �l pret�j�ց�!g�con.�+i}aItsy�&)�B � ",5�m�AEM:�o =#P>jn2�s%��C��--Z-�DQ'dem�� I�-/%h�oa�mE u arti��3� !(� � �Ium��.Na similaV �` l�g.av�)�yefJ/ exci�%X�car�5!I��g��/wild� [WTaL" ypQgh `( @V) �ut a��rt�4 puls��EYdminis!�!�,Aal� fcap5�w GFP+- jf�I�6��A�sqW]�ApF�,!A�B( S2A�<)� � �Ǎ*F\�@slowe�T�c-R.{ � wg"s ( WT� dAy��%K�%�e� )f W%�expan�a dVnguishNa  #�:%}'q  variets A�-��nom��se>3�.�6� a`���us�a BrdUMto labele�  S-ph�!�� IF&�o� -m�MI�e&x�� ;er �ofe:�� a3 Q )O�� ued���'!3, markA�or!��!�i)+" )�2� B�i.�S2� !!C]YF� ofEE�� �E�Z caŢ�k-term fu������ ��E^g~."D t%a����A!H M P.8*\%5zo� -h�A. !.�%��G_�Frough�� ermeE�membran` Anoy� cha� ,M�serum�b!�X -att8 �C/G#�.�abre!) �� at�%�m�gel �zsa!pparatua�� G�lI��!$of:m��tail ve���-type��~en��Eof WT-s ������ rar�^� )y%�-%H�WO mp�!9*�s �Affyme�oGAdEnc�b�array� MX� �#of� �8 "/ 2�aAme�hym�:�. Lonmy�a�a�5@�#t� .Pto"al ��$��&� �g�dG embled!��-j-[I%[Tog�)Xda�h��ZQ��!��2�uU)*l&.�>2�rOd��śm�i�g�M_B2B �AN��(wide-spread `hemorr�.feM as �Adis $a >6�Y%`<#�&�%A�o am !� �$�#��)�2] 0. Haematoxyli�$eosin ( H&���' logyQ pool�ery�>J!a-C v| rea �� y�&s s ex�!��< r|�`2YInfil� 0ng CD45+ leukx�fo/associm as clu�s��a�T�e�\�z��$Q lobu struc� ��2� . Qu�$fũon�)�k ^�.y![-, reveaa3a 6-fol?4s��Ter119+-2J-�B R!32FAB  7C 7. InD)�en�um ��bod�%r�&)u31.��v�d�$yE%(e�&�� ched vess�(iZ("&�� � F�9Q�CAL 1 . 5N 31+̡>�� a_AA� :���1cA�u� C�{o&; �I�lconfi�a�*t� G&K#E!nE � %���-/AXB��-at&�in vivo�l-~� a-vi�mi6cu��xa� MT.o reorganiz�ASiM�d bloo1�g�5��travenQ � A�05� er qaum dosM�{ accum"�!�stiz)spa?#�X/% �) edIUR A�A�3��q  in!�� ;��'i&D<a���Q [Mv�[2�� /!�J�� minugof=>!~TE�steadyEGe��1 hFm.��-�2�-d%W yond 5 um%hCD�majoru�� os�"co})te�30�M�3��BEi�69I��to (<*�)ise��q� vid�$%�a��&n ge ,!0Y�D I� ��I�� l)XV�io3��� e.+ ��$ o��ic ��-jA�.z>I< &�#D.��.�-Tw� &�� 's2�ex��A�2z�st *�$q`of �.�)�4� K �9#aM ����by� hl3� T��Aa6a�~,�jha�1�n�iB 4Cem4i�I�X2�Eq6ka�+ula��  dr�/uX�i�!3 �, now5�as�er�1�Msurfa}>B}-a��6larnu ]�esFu^eiJJor��ow � � palp%���g�siz��d�b�=�!.� �G�4SwF&� \j pene�ce��1�'L7f erE4�8m . M�(ik5^"���%�#��by!�ual� ��� �r!�� IHCJ�:� ��a&��6a��5D �1-�3lee�t&Y'�bL �K�Un�,.2p [! �n� gioT4"5:�ofe�7��eeK" s�F�)�2N� � �f�" �L�4M�M�%�$)�!; �Q>�NEF�Ő�s0 �� amou2�o-mRNA$s� M"| �OCsugge(5g} ��.8'eR�6.�G6ma4 +o$ !�V�Are Q,(*jh#&�1. D{#tlperio&*�,tensiv�y��K G�-ysis-pX2��|f �� i�e��?5�b2 2� is�-U�'~"e(C$a�+"��|H#����:!B>�.ed%�* ��>o�{NgWT~ e2\� ��!EMg-��C8*5"�!d!qLIMMA�+&�Gnetworks��64=by z$Set EnrichE�AT��( GSE��!Q�vi�5�:�!~;Map plu6�c Cyto�/softwF*)�5V($a PDF� �EFi(be zoo� �P,'1 S3A)aU*"�I�a�oG]#QI=�� �"s�3)J�v&� ,�Dn!0�in�nod�loM�ou�1�sf"seq2 ��"Bo 2�il1�� �<�9�ycl�d (, DNA repai��heAVI�26%J),= �lF)J�'�4�0�up� �!�[uAt'� f ki�+-b;��X�)�&��v�k�-a�!y.�foz���,A|8 GPCR-med��� �J $a�/Fl%�TM��a*��0&#human:�-%/�M4a� T47DES�;:4we.*"�M?�[fp??7�i:%_�v��ee;"�6M.t!M(r^B�)=9ur�3,�extgAN��GO"�<le�"s8��Mjlogic2# . Gu�<�, utom�-Aapproach z�8gene-set2|HGF%{ IL4 I-8ig�".1!�� fero��sA~nd=Tmon��0ch-ul$&��yZ:l>(\r���� �5C��$a heat map��!| Norm? ] ��;Sc�" ( NE&�q�K�1%o�A�_E�cl�.D&as�)!��&a"�+A�l,- B PAM50 mYg�? [3A0 Each.* �#f�&o=7��� �d ran@!g��li�f6%8�+�"d#�[ P K0ua{a% input%�G��*�$ɂis�!��%c�io1!� � !��d� .�in��1Q� � ZB _'-�A�OwD2a�"(�aw!z V?BY0( S4A aS4k". Hig.#e2=mCA��B6ha�w broa.a&3��!J~f:]�"� �g�R� /� :Bjva� "7,.96|M8e�:�! �J�%,cS4D�a�IeV�s& ij>E !�+YMB#>�i t�>j�wm�/!7)2�aken tB J)� !ng�A firmi1 [ ��(�6d5�y�gar�!<1ӡ'���h�F)!xw�^ sup�U16�, �9p�!�2�hJ-ekso\A&� z�6�_9v���9iY(6�6��-���E��persuI�lie8� r2@ pro-*�7-�  p2��*1)�}05�(New drugs tR�!�6Tz �C)revolu�Ci���2sW/1N.�� ��� s�![t ,�MtoI6] :�%�"�0�7��6Q z~6i�� 9az$percentage��3�D�to7���D<2ro~>�$ h�!poi[2 8 . S5�"� ai@ng�egy�-""m8(r%!Q�5o��1 AmongS�& 7� MDSC/M0as Gr-1+CD11b{.�� Ѩ6� ���!N�,� .+:o0� p�O��21{�8rR��_ � %�. TJ/B�@9�5�*y ^� ԁ�..&9u�!� }AF. PUal��)*"3#=� ,�^�*i!Fe�6I�e)�Wit"V�# TC+6`T-CD8V1Z� (!GKe1�(�")"no-�5>�\4:p �A�A�#a��%Zg+ioB� aE�Ѣ���iZ6��0{!6�?A��r1A�%sub\ Yagranul8 ���ic1sS<coͷo�i�/����nt�� es Ly6Ge�,Ly6C , ( Mo- �ie"-!� )-GF#(C�# ) [3�'3�z�se �c��%Hd6�G�@���./A�+6(i=M��Re��e Oxy�L Spec�$ ( RO� �8 a � ����! &6>�o�+�im�� of �(.;><.n: e�bye�6�M�I &�hd6��+>%T2��-�Y!w�a)t�ImisE�.�-D�A�6d��)�����ed>��t�G!�!� to nBO 100%!��� �� YK�,!�=h[:b MDSC�F8a2 E%O�&^<�.�.V-<-.-~.+d�JeRHO]�' coulQc��>'] �b*ap/4��R%��'y!jdI=? 2|�=�/&X1�in2�.�" week�&�E~�rat:�DI�a.~![efficN! �a��F�Z�ofu-�E�;)�7� Qa 98%l�NV�Ad�w H�lA� ���5�8%N.i�m��2j �FA " �-E'\� ���)]N%2�,='!ra�s �-o&bH7�HeLijA����e-W�2&Z %�E5��%# �7o W ��U��B"E�ŪV{94�2� 2�QB� ,&|&!T�s� a�Ix8�!�m�Ba'L&���2R��!k?"�ic)*���Qstu�� levl�%96�*i6"��?E�� �����R+ HER2- �sRV�m�"� s 8�S7e T���L[than 1qR�5~T�-up [3�CAll��-%��! AwN Tamoxife�/n�@recei� ?4�apyIVUQnuclea�- cyto*JPPp*�H�u A. A|,�=R+� c#,5 T68&�WbJ(rF�;( � aA810%J%)4� !;��8A->4i&�Uo�@1X weakA�th�Czar� ��0`.np-value03 -��tr�@�.,^�wo�As�X̓t�tJ��WngA�� �h.�/!e(T an 3�$a�of �05% � L+ �=e�U/Up9h'q��:Y�( DMFM �.B�e%E/r�-�C!poo�<�Y-�B5�A�St�4Cn&i�Qof Ki67%� spliŲse�Q���9"��^Bq�[3eKWer�BB�Uޝ?Aa�UY�WoorN�%�aT )�s io�N� �#-��6it%:111�. A"~)�%��!6� �A��P �5���N�zaTl�Z6�[!"�'gnoAV��1�W� upF�a�Na�.UD���2M�0.�e�E�"e=.��: �., Q��i���u �QbB�t�8�xA� �%Ib�m s%e} !�}z `LU�"S)E�i�O�rkA�f G .NGGis> �ANter%����giv{����2VeOO!r)1.Pra�[�n?U;OR�6�2iZ� . Al� abro���2��3 by!�tri E��1&F!Evp���QXVq/%0�6is��FB�Z�� epitop�]y'# obsc�Fe��is bo�-�0�*�J>��lex�Uwe�e�steA% rpre�')�IM�/.�&LZuntilMO�bXst 4s m M o �<% q 6�� �l%6!~]e�Pab�:� � li* f�,�T5 techniqsWArS�"M�wIA3"X�� :� iN� !}Y�a���8%_CD3m�IAGN5�� 8 maa�0*��If�ɡ�6� !P � LT 2*YIU�p=],!�^ �_*�/`�4�2h ��!��)M ^!J��[U"g)��~I� ��$�z�K:a%��6reFA�[3UM�A.P.�!1&� FlocIm:t�>moP(ҥxne��G  adjat| ma%�in  l./' eȕ�6��� �L!�!�3� $�EqYae9 (�arman’Tnk p =� 1�_rs56�E�B-�[,s�X�s�or �n�]A�I4. DespiB�*�!!{T2�)Y LF5-_�ng MZkA3�8ial �8+2O� 6_��reI)!en0�#%-� 203�Categor�c$Mann-Whitn�b�( cEVf�≥ 2%�$s; CD8 > 1�'on X-#WC)��e�e dir�ZqA�(5�075��<.�!O5J�Dn:I��"�"%gC\U�%�-n���4AA�YI�]�a�� �AQ��!" �� � x *� *�'�*�. p�F�L�alZw�d� �!#bMNG2-"�['"� in�\2�of�1)ou�!m-)��]8F�=#2�X� %4G", A6w 1MLe�P�@� %�2R.2&!eARɺ �&���selH0.1j . Ou�!ul}N� �on2�S*f ��m�Ys.= �fA�y �.�"��(.�| %Pe9isiEGcq?��&�8#S v!0��in Ůosu�k�,%�X(�QhipiQ.& 1�A: .o.��.E� B20 r�$Nottingham��)_@�jmofmM<i ���[4�X Fifty-six!d��$( 73/130 )Dt!:%���s{��coavt�0�a!b�!!8`P105 Pl LW.�x�1cutoff (B> K:���si� ���f�!�aI<���&F.O� �s>l�`, ��sk!AFma . N4$ A8�EE���n�&)�2��!6gl ~-�XSp��%H�� B���!k� � HYJ�>>bam�O�CDY~a!a� )_S3�`U�Mwpb��Kg:� 6 "7 u1y:6dPk��&va�#�� s6v -"���M�M>.�E�X,)��8ib�?�Q1 � f;I��0�/Jemi!Sb�<� �q0�� ���-�MG�� M��Q�F,�%!�.�tissu��� md112l!S:m�)Ve'�6�MS�"�c�)Ak*�6� . Weɭ* 2E. Xlea �*$'2;?ec�_ G�%[%%1%�!S�-*5esb:S5*fi&�o �'6x���E�� �i[!�,eo�P�@y�+m9patKiis $>l�#���-i��bc�QA�1�2[-I�ޡ��\" a n4 bi^5al��eA�Jocr.�e neutire~�rx;gl!�2$����-N.�>�i��0�!.�4>�6ɳeu*� )�_ �9Ɍbea6s�KD�E�1 �;g0ry-$���yQ��kp|a�.`���lC CXwn-bes"S��p� �x;we"� !D�]��  8�#we"�$*hab�.,qw��A�`�@a<n;oc;m�*�!� 3��m�  nting9 `_e�"i��O"|� )�$e��.�P[41vftB $un�%�1�f]. HLRic ne�!!z>"P#e�U�A��5":w[42 ���itT& s p=liAodyniaB%9wib ainlA5�. SX�Wb� i"a gr�����is� !����}� isoAd�i�K?C��e"7U,!NX�*��#s%0e� �#@mz�#E@eER%!or{V volve A�cru�fofI�,a�Az�>B�����a��%� ��e!u/�ۡ[^O*� ! �`+ Li�{tuIS�K*u-�a��� 2M6Zk� them���7WTHT , si��kmon�t<��F� �x�[)� lowl�$^6E�\�:"UV� ��)(�Up-�� >:�!a%eorM:H:�v2 � (TaApl�F. Na��LEs� @s#a�!5u�6Hp�]6d R�r]f� ����a�;p�塬�AW�6��r�S ED�/at����{J��}��E4sE�fz\z-g!bA�%�is��A4��� ��w����% \�i�^ pshy-benefitfu�6eom�KZ7&� . M�Um.�f�"Av! AuN<lia�"d%7p�[:�7$cA3A �h�q�, s - purpo!�����Garvan I�LeML,al Research/J%Va� nt's�Np5TAm E_Lg"Fp$NL:i� aa�Sto ?gmse�HH!n�F-��'T/n c-9���Gm+)"� requi�:�c�y!^or:0�'\qoaGwVpb��mo< bPc� wakes&S"M�KProbea.or pidA*Iod� ( Sigma�3���tathI�exeJaG/�����!x fluo��Jconjuwd�b�b:.C ,I'K)�c-�D Phagen�'3� ��7A2j)F4/80BM8�BRB6-8C�'f4GK6:1W((�O53-6 . @6011c N41 `(9 M1/7�#i?B22�RA3-6B�E� eBioece;�� u��I� @H�4t-3� purcmd ZBioLege�v /zUsg*�<6�A�E�Vor` X�� �ew>�/N nti-�<IgG seh  �kE�A zK9A2)d*'� �\VI1#:���J�9 . IFdIG�>� OCT '�dd�i�!H UiV kyI MEC1�6+`.���>'st `� ���_*=y��"`w�6V5 pepta���yB-2&`�%t;u���to��!n�v�~- �10�x�$�d@�s�.]&4$ �O�E ��&`9mix1#4C&. 0( 1:9/vol:volMsim��a�&� SSur=`� rF4`%*=%���' food 24 h]݌at�D l imb��uh: 9"or leftJAA/cTen!|s�!2Wm4 m���l�d ,D sWas�p%%��_��W�)di�Y�,�sA!�e����P�p�B0 su i Nba��b multic�)a�xge [45]�eo i�1*�W libr�+ [46]��R [47� par�,�e<S�Jul� P=;90���R%�'v�>�aNn. D��g�!e&/ �e`�c5I�Q�FF m%7)�an empi�.Bay�R�� t-"�)>$Limma�mytnS200� W�l!GP too�'6��IE6&T �YIW�Ps�,�0 bEj�r�=� �e �����1�UR�s util.L.�"�X [48]xavail�R kV ed6=@|,r http://pwb� g�`. unsw . edu . au/gp/ . M�i)���s� GEO:�Q58729A etaipNin��mb�d]m�a],�: %,�|p hybridq5�.m� �H)�*%]�ink�h�&5 , ad�al�AE�I��custom9��!pAO�]U ques�%� utho +C�G;T} %F,��7| anno�&.-Zob�e.{C[r!��# Atla�Ap):"pubH�!t[4�4 AgilC -�6 .��( Level �2V�r,��* Janu�� 2012EF�=v�>�� impuA�! re�fy�k-|G!tn^bor ( KN�_.RW��k =�(>I]M �Vv<0B��� ԝ��� s� �,of 533�. Fy<# Eg��2�D!.7b�3}lVcl"KVZV, 231�a*�( ?sub�t!P127>(B(�samplA"��"��!�(_���a���1"�V=�� L�ika#top 25�hi�bota�lo*�ing�Ŏs2ed!w�:��X�,a �M�"�&ial%�.�b*m.h�(Ilo� Ha ��,�g��,M���{_ [50]U%!3b��7��-v�,�/e��_ [51]�ru�=+ -�W��_X[ -z �&I���� OM9 housA�!-���L���>� �|mZx�0ax ?HfM%1�500t#eq ��Lq( O G�XEN͘�cm� 1 w4 . 0�B�W�',titute’s M��S&/\ Dataa�d SigD�I[52�"~\��ݤcu)>�s�l*�Te>���pA�>9a�$bi�;se5�cV� c6 (E� Bai�6�c7�0B%5CS4E) � �plu�9�yՅ?Gw2y[��e6�&(��)�.y�452� {v)��� i s ����)� ~i�Ca'9G?@orR�ain�5A-4a�~1�wA7;�946N�I\�,!u��U&� �5�)�-�. N�c"a�c� A�S�Qi()�S8� � ��&�c[53] En"�(�c [54]!�g-i�AE�*�Jthreshol�) : FDR ( Q�F).<25;"?FN<0i��lap co&�M�5 (dF"SY��tw�dK���a�d� �{cywd pre-� -�l�w� �Hoj9y.f'Y{��m�C%&I�oPyMU?t41��AŚhi%!-m? s�3"$ ��. F@�A=�!�7\�q�1�I �awo�Upa YF/ er�C�t��0F�0��A���“1�1sZ /aY��v� ��buƃ52}��%5,I� defas�“-dMIAbMCLr{amNQrto����F�C] 4s a!];��y�J.*]b�>`bQ%�)�2a���R��#���*P���!���Q�of.��6� = s�"I�"^a�ze�APa&k7E["�2k�� !>�DRNeas�'�w*ki��Qi���"�$.�4cN#a"K!� , Trizo�BAmb�, Lif� chno�c�6�$�2�.�_-Capa�Dc;gRIse 2�' K� Appl!��91�E�~!G���.rm;ve PCR:���LightC�gr4� #SYTO9�a dye azr02-ΔCt methodA��z2; X ce [55nuQ-���Al�Ow/�ed ta9��1ters: Fwd: tgtgcacagcgtgtataatcNt$d Rv: tcat gtggac.g�&�zE} MXaagaaggctacatgcggatgggt�Pglcttvtttgtctt S� e���Va! GAPDn� wagcHT acgg� Rtdatgtt�gpcX#Q%=!��N8Taq�g�4 Mm00468732_m1�A Hs0106302(V[�d^�, Mm9 15_g U905_m1;�$7900H Fast�l-�!�I�^�� b %�i:~strG-sliA�� blo%�5G��"ie�;I�Dako bu�,pH �1;125°C%p2m �+r pH900 5�EI��0 . 05%T�VBS!�2%�Z tonX�!�\�j���incub�!�T{�;1:� ( N2� sc-964� S�w Cruz?r%> 1:20��A1112� Invi �����by �^Rabbia $ti-Goat 1:�(6@�LSAB+ l^�()R)�Env�K"�{%u|de��_%�DMG]Iin"vs�j�*%�a�� 4 �5raffin-"�"sr�6U0 TMAs%s\�{u��)�,a$�\YO��>�C�"cook-�wav�bFDTAMz�*H 9ũr IQ�FΈ.�A?0A@.W�A'?P�UA n��)ymty 1:70�q1% BS�oA�IvZtN�) . De��%�a%J��EX0Q%aIpinN}]�A1053`��?C ..E�on+�t -HRPI��polym�jE�JM�400�.A� ch�r�Hs�c'�a��G6�.��,yl�ReY-u�:"�E^;�LeXd h<ic �Ub�RsH- k��1T m8"O�5*�c;iv48a��� �\�+U�00 scal/ ��0c������ e̔!�!,:%A�:100�`I�q�e�!�@o��-�!� y Wevn�t�Nd�'a�/�0e��[�9JɊA�� h ŏ� -β-�?A� AC-1�v#�M�&,b(n�"r( R960-2K}�yBR�CR��$y�Bencto.�$) ���by('�; 1x10�E"�+lYdi "�%Ar5% �%� E*ot�cq[di ��.� j�[4�;kHto fullY&{1O&RK��we\�.�a�=�%o�Q]T Quick SD% Lab A(!5Area ")%E�Image J�4�#$Wayne Rasb!�, US N9 al�&�@Healt).F���on�5�9e�% Leica SP8p e/��&> P�� *� ourc@�q4D Ti:Sapphire femto�" �d lase�3Co6ntEeleon Ue��&]�8� at 80 MHz�tu��+ wavelengt�920 n�< 10 u�� V>#�.A�655nmTe2%�"g!n�ugh%�"R�!�-)kexҤ� w�|a 25x NAA�9 tEUb�Pv��A#Sroic fil ( 56�ɥe�to "�2{��.6l *�� em+�@'@�"7"s�EP�j }!525/5[617/7z�2�A�06�oArecordA�~rA�RLD HyD3 &cz�ckZiA�>:�2uF�$1 , 080 × aaHep= of 52 μASp 2�&/A�mby uns$ed Studentt tq %mraphPad� sm&�D, La Jolla Califor�:U{ �err�ars�.YZpap2�o0�%� tand \ 7 ( SE}u�:�$r2c"8�2�]k %��c� SPSS�( �)Cp�go�a�*�� ��,on"m� .)[>u"eJ� A+r2H!�|J"QU %�.6��cub�.log� (�e)� "KF)Zx�Ru8�P �*�L�?[_5"ris�� LumiA��F Ps"t>E�t"_ES|9tl�AR�I^�2yFE% b�O�abE�>�T�\G�\cr@o,ia: n = 126 �u�8"]74*{,a+l) ; :9:�] ( 76'h53 . Opt�5A�� cutD� )� )�~I�X�R.0�A.`Ure"Nexp&��evV�!C� &.�� E���_�s"&sD�bǩ�,f�s—conne pJ%,%��!U�*;Del�%jA�coV �.�� ,�~ �DT7l�J�+AX�"kV-to�m�z�in �e&�! ���v�-9s �/�H�qs�l -J{ add/Y>)#!b Jow!B8G��|)<�e.��$� �E7�3*�[lO -by- fash|. HA;w�4k�k�Gn�R��6�� dl6M ma$K%� unda� ��)�I��UQng �lo���1a :��y)6!)�as{=�* w &e f��4 ����'`����bQde j,AP1 yenhEv>�#Ahr�?%�!�!$no A�&� H?\ng ]��ju�[aI)��The.w�.e3B�@,raB0g�~O`hoN�% nn,MaegS P��;i%�5.olE�me!�Y�!A�ue;),�z�i%tol�X .isu�–de���'�rrk�'�Fa�!� w q��eKa�(i) $ �E{a�*UiE��W�"AxF5AM��d?U�M!�!�if��a4c�*���oo%�~;��. R&法�Yth�:uos���f�;dD!�<��p(<[[d phys&H5�fB�[� 2qT��cis�g���&�p�2wo!$�K$ families:��is!]�>��J�"�9 � N����Ji� cei 6�st�+A�+G�DE�1kb [? "��? %M������mZa!J,G~@bv��8� sile#gi�4_@A�g@:1�re�D[�CoUxd |9��act��u���E"��� � �w�sW�nga5Dory9�\he ][l�O���Ys��~�[�+�2��!�2�qV#�2'+a�s!CA�bi&7n> ,Kv�� ����: nd"V ��S!�]!hiw���anyWu �Ezs [xC��"N= t�'�7H�.`!o"�AS5<;ic2�m�e�!� e���J homo!h*�Ds [AjI� o>,:3 \s�M�e=q� –p�mal%�2�e�:�h�{R 2��Ips�)��Re� �2Aukaryo��Em�.�rH na`�G al hundre�" kilo–r"s*B!n� YLe]>–10 I!�*E�ve��A�a�I�3L �[11Tw��a�vLE=�:Wacvb�.ng�� 2�IN!TF]7�.cmo�>:es�(��}[15��,I���,RA�d%��s.�U!e�b+L �I:m�q by bB#�!c,�1�4�UIU���u�`�f� �vw- v��&��Ļ��[2[ More�a/�!5�ء9mEe�]������U,�–te��XI; rosophilaiHoM !��#�y9��s� @Yi�nySr=G�mKorm��� wGs|/1.%�XF�[2O� *��,��?at�b$4riYP λ)K CI!m�j@% 3-kb� �E( �e stimѱ��jD��"�i4� PRMkI�[� $ mo�B β–glob�Q�vD Ldb1>�� 1Ea�dg�C_W�/� eff�t1A.m�em��Ecs� �,$ %� �u�o�M u wTd"t�mE��U cleu�O<Ijm�y+�f"| An�#�Q�� . [2]�MS!�a�&Jf᮱�A�Aj�,Oflexi?of}E:8 O08 b[�st cety���t����GSingleUQ�-iuP�Lba�J��F/�B?$HM�`ft��U�>at2s��W�1zb� lys��tw!F��.g>chJ����Q y)�*g , non�-����QeI���oite]�%�s���Naze ;J!�A�!}by�~" Zat�ck�K" �y��tԁ({,q=CI6*�� *�$lambda [27�"�[Ur�A>b MM�&" 02lac%6M$switch [28YAm��f�O6��*���o�n�-!J�Fs.�`o�Kker� ta aaFpbB�a6#* %����JemR� � �par)q05out8�a .4p7;�a i��A0a� �G , Vi� , q��-r!� ��#c d! .Ei9��vRa�SF(�r�oX�<"fluctu%F2�%�,�s�rM�,"�[D���GhA5� �tS!" �%O��[3�SAChoudh��.)7%�6�so0���buruj��:d!� ,:l!��<g�s��a��XXG�BrnA%G�ds!O* ��"� ,rNl� �� A.��is ��a�*&� �G5�� cban�T#)���H6�E�ge6� assume � �����act"D a ��zm a�xl ��3�mH"�-O��c��t.=s� as Co�\Co*C:C 5[4�"�V����� �sEA�;a �ftmp�p*�.DNb�G�4W'&H>fW��a��%�1_[�"�=�Aā� –�( te�Cr4�nB%��s ))ƍ ��6~i�U`Q92 2�al&� �.5V9�qX�1.� )eL�jPries�-��� ,fy !–�Hed:|�� : La-W�[ ag� CI o�}'�� .�e!sfå^E .!�i57�e�g��p�-�4ar%�O�\zn�"N�nam� oVd�� �:� aB�� �u2(!��&�d�Y�8�#f/ �! ,�Tch $��6� ��a3s�:n�m��� nc�s arguq� comb�C)9!e�%���L �e�:�� ��ny� isbX���uErai��S|3)–intu etmen�" Mirn�b,A�#�v�I� �-��M�\eU���B��F),2�,La� hJ�.�A-�%�$�!� .�1g1c>�E�U"h)�w�\a��B6�.ltak8�a'&3Fz ��>.� �:�W�O�͓� q�AO5C"Ez%� x���whh �s1 ��<��&�B$:)Ke�N� Q forw#a�<�gl 1988$End-�rq��y Blackw�F%KadonagaxCA�;�{�sM]q��xGc.$Q)onXc loc�"'w -–���#�>s}pQ̡G b��omm��- is9��1!f�8B(� t��lyK^&B���B"�F ed 4*@ki�k!2[���( ye�$,�=views!$68>�%�UG,�PA�� ����r/*~�� %( refer�to�;1E�W be"���eamt�r�ed aiq��mO rec\"��5L � � =by�Y ��2 J�(2 6:"� �P!fI �WPz��r�Pri!Q1>lU�a�]o����R�Z[5� �>,%�P� {�Ze22���ysb 2.�s�ish!�P.�‘-�’ x A21Cgr��<�:l) 6��3fbl 5=mo��9�xt�uniI�ȘmK to�{�f]�� �se�out1�}9��Jub[Ze�m�Aw� �D�EE ��sM�u��it�Sc�f!$�&5%y�!*� . B���"Q ��Z�O ���.&�MAV d&�%���lfiA�F�%� �6@!X��g:))�d�r�c�Ҟs%)"in 3.H*derst�m$cF%�Fqv evel�!�$B=E��$�� pE�*Gs�Ta��T! W�Ls"ms!�� ��!sg%uJD� >�TE$ 4�^"�$M�Bw�jƯ$ 2�>�#� Wenl�&.A �>� ��B� ��2�&�w�%2� &p#2��� +2�$�r%�a�2 ](��%).�a�() )1>A:Q} 6 G�%*�zN% gf q��U%%�*�>grd a�l%�l%r����pl]%S�i�� orga� "!�w�c�A��to dea2�i��fM� 2[!. �iB�� Su%�Hw"�]gyK�retro� po�W��st�Ike�`;�I� *melanoga�4�H�`doA �c�O.�6\~inl��u�� �� A���$a�81�n mut���U>y�B.VH.,A� +�Z���!ZNA��2��M"� e��9o"r�!6�� .%��(} "^H5 '�t�%%f1p*o����; goQ��C1���, cov� @; _<��Q!!�� ��nu2P�eNUsto��� y7 s�of� ! 3x�.;ƺs�E�"6;�fd�Z�,%�V�"r5%"�O�p�p=!A&�D2�"� ( i�Q �cv:�3J�,�5A�" ^%!tSu-Hw�s�X�y�grU K�Di�m�2�8#Nx1(b��_ci=B�@ ���J�: F:(�.�-d�o �s_��=�2� �in�]V/���:�-9�=Z?l!$�J���p?d.a�%�spaV*B/s"K�V� E1��n�iUFur#m *%�.�>� [(i�d��=�i� J�K no��7Z�_�Ir �esB�J�.�Vf.�/ro�8��-+�#is zero O�pE�%ͦ�)U�������&�����&� &3A�%�n�so+f�j�Ap&,@N'�4��2�0�e��J�9ul5+m1Q�UXfr.P>%}�( c�%^� ��=3 (��m&�)u bEn!�J�A�l���� �.0��Y*% N���sak �ud2"� E��!g5Qs��!YsN �)@4 �(A0�8,��)L9aHS�™�]�-%�~W :�! a�X�C�O�Jq�.1��zdu> 0%�A�:T|V(F�"�ifa'�2Qof�]e�ڇis {���j�!d !;3λF2"�k�C-,�I ~� , %��.h!�2 y9�J-&e�1 +^j�u�2t"^/!a%})�VRV6%X8bT ��S�}�'>YS"Y�AX!o aR�����.� ,�"�U�A!�W-7See Sw�`0 �)!�1d�Za�F�9l`��6� A�yNJ�bcK9�KO�J0��T&�l}]N���$&��8�2*=�Mnt �i]�qb�1F$ C� "3[5B"57–5�'�3B�Q� ��pg�`��!�t-��ff[5~460[5C"�$�eBg�6e*���$̛A� un�_;63"� 4�  y �nfH>�JC&�R�^*� ErZ&�"J���&� &� N?*��H��A�y`j� Ma�:^� (9yF � ^� 7�A���ir� <2�Bdf�y�m��columK*s�>�;���conagR �e denot�d1%�h9)-e=��R!�i��n%�d26;]<*k6G��"!&� ��AB�#Ƙ%i�� C:$&*u")~JW��>�Ow1i� an u#�llE ax&�L�B�o�<�x� .�(<l��yo��� &�;�}In�7� J�� Ii� :�%�l4ef.� a1nawF}:f�JOa2#A@͈Y�Q�NA���i�or=3V�� $�@("� =� n %"��wU����;u . S4�� G� ����c��P�odf� 6ZF_ ��1i? �9!� helpi1�1A@� m*d �W W�{m�. I $neer.r2��&%Y�{��B�n�)�E<m�?'h+�A�&x�E�"� �ZC"" �C�Nt�7A>1�]I+: $(-�=Ii�N��od� 6?2aEAll!*PAŠ!��e 1 km�A^%�}�nB"�2�QA2�?ȹi��=}�A���"�hs��0>F>464 �Z+ m��X��5ap� %r!�us��a�]�A�8"��s�5F . AΣL�?K !��A��W'�O&&.T"L h J� Q � v+(%+� �^a�wo.�;Kl�ADy&1em%-�a�6�I& , oflr� no�a��81W�an� x$�3)�.�!QQ�Q(��`seza�-�ONfVON2 �c*5&l theor3k�� ofm��r�onqf�5^!+�q.,%&� )�ں�6#Hw��nF*>��V��7+�CIiOFF) FF1 ����.��6�Hw���.+>����worth ��a~�����7–abQ#qbmethod i�@s easily extended to cases of complex interactions among arbitrar< many pair 5dhromatin loops . Note thatping rates are actually transic Pbetween on and off st8(shown in thX$ird column�,Fig 2 accordkto' above map �elakshi�In order.�a}ral ,!�E�i��2�%�5A each2Fi�sAq0not only its ��EiX but als�z of%{other - �i%�0refore a func��0wo�Flea@�H9o λ23>��e xblum5af!�Agr�`. has baed�� mplyF����u�%~C/ �,m� than!� latnd �. A!n�)oo" �� reli��n9p�� dACTa %A,)is�principl>Xd1 �R; Similarly;43;%�6�.3HoweverM- exisZ�E support���]tat��.�.�6/�%" �-9�[33��BasedA�,��analysisCwithou��s��gena��, w�ye�AQ=k1��- =k2λ12 (���yesizšY�k can d�m�I&conneI�pE n^�2�RefA�[20 , �Inpticula!�20N3]� small� ific��6�k={4e−�� 5d+1>1nes!�A�$s1side-by- )<1altern�g  ( 3 )-)dB�2�underihg . FirstE\is!�E\is�psonable�;c�Ɏ�Aon �A�!z �, ��, or .�-� enlarge! doesa� chang�� or reduce��n� resp!� vely� econ�P�se�bQ�observ�s from� 3A�Ref .IᅆforH ��, k.�j�%QիiG A"on manne�E�as_N�e� of)��nj-�%� mark%�wher y��sM��/ mostappears;ist�ois %�T exA&weaa!�)1bof e=e� � )L� so–call�� rack�(��precis!�fac� ated–( ) meA ism��! Dele�s�co �,ed . To help~B eri�d t�V�� imag�La9�as a strj��� fixe� � !�wo en�f >"' F�(�g�Su%6Hw�IfeX � slid�# !� �( ��!�����5�o6L-���j we h� assu�E�!�YDpromoC ��A�V )�Itis will.� re�PenhAWr�a Wra ms. Thu�)U9� s@  increas; 5m���� Spec��� , if�de2= by λ˜14� 2^Qf R.A�9P�6�Z��is5� VF�� � natud N�2b �Kn�%��4=a�+Δ( 2 2+Δ�y 4 ) ( cor�onAN�23� λ34K!�be��edE�&8 �A�� A�Y�Q�� $m� i�]`��regul1 yu@E9� J", "z Δ∼�6Iz� AY� to�� Δ = r�e�� r�a nzgk &�B~ no �e�r direc�#9tE�r� gas8B& ≠ � so r�Fracteriz�@(c2~� U�a,.� ����%����r�K�;2 � be� lstood5 prob��d!u )± ���.� "O�y� l� aO2 �V �� three&VV0 onB(�}lua#N mean mRNA.'��qnoi��te�y�J@we establish a ma#aticaJ eEC sche diagram��. A��9|��� � crip iat ON1!ON2���6-��QdF��Cμv!�5degra��*  ar $ g�%Ac�h��� . Letq��41�n:���r:�� OFF��7$vice versa� 12 λ216��RFF =:S�A2�S21�B��� 4�* j�9�;�.���>=Kll"?eM:�� i� ines�D�|by P1� ;tE�P�y 3�P4A�H��JeXA�m copA�!�,!�A��Q]���"A  at time t�e;uari�asdequI�%c ull�.}$system tak��follow��� ∂�∂t=Ag=+λ41= − (E�+c ).@<+δ ( E−I ) [m\]k9] k12#+λ32=ek21+�kABkk9�k4:k4Jk4k4kA+�? �1�]B�;�Y7 �23�!a33�3!a3A+��>�`F� ( 5 �E��r�se%�1EAGstep "�A�I unit.��Eq ] 2�?�e�a�λ��3 Y s �gi�' " subsa onrD$worth poin.�e�if� �N�a.�]�x�%��]�  b |*� f��gsze�[62] dP�J dt=A+ΛB�+F� ( 6=�!�a�1�vecto�2�� d9� '[ id.ty5�� In)�h,rix A de�b�`RU>,Y} entr�$"���!���%�!�&EH$U>,�on�a�Λ:�ex�f:8��C�~c! ng:8 ��9|�A�ic�c��of � �w.> u. ii ~ Z t�sol!f�.:�binommo� approach)zw� veloUq�ly [39]E� well u� ques� �it&,convenientlye� numer�� solu2I��a=� �} 'in��M�����,�sT A�ro� �ށ6gi�CelU;���A�.��`f�in_faag!I:Re rib �Piu�,�A�def��k� / ∑m=k∞3k�.=k=~ Mf ⋯ ( 7 )Q @L �r��91 ar� inaryER��e\th!�� t coeffic!��E� !,ddt�V =A +Λbk−s −δk ( 8 ) Our!V eres��in fi���ady–s�2I-�Uhfut�j�lZpI���!Ft!�samA���mmo!P: is 1� t � tPYB!satisfye9� algebraic5� (!4A+ka bk==P9 )O we6'(1∏i=1kdetAKI−A ) k1[uN.*Λ]bAJk�YL10�cbkA� i=1N%�A���to�:�%�2heAse�ueY>0, uN =�,E�A� )!gan N–d` al row�ɩ� ( iI!4 �*�11� adjacency���H�d�ant���e2[,6� & %6 �!�ib0 �al���! S1 T�. Fur>mr�w�u\� 2� ula �+k≥mI2� m−�Jk bk��J11+ to r� stru�!st2{��.��.�A!�� )V!2C%5pa*���u��>�:(�~!%�>��N!80ofj�,o�squA�E�a��fI��0�I�*ηm)�*��m=2b2+b: b12b1� 1� ��^� � �!()�A�( 9�exactAb� rec-�_cal9�b2�ad� of.fresult�V&B!hig� �� B��I��gr�^e XJ .�s� .�$�KE�(uz!In add4% j;51hold stF dynamic/2�we�=,�3$ev2�6�N hei numbe���s C–H�q�*�� d#:>&�-��>�%�"�o &ochastic�s . H*#�0appj&he-)<%&$%*� %6is pap**#o)�He�� j���ܡ� �Q(A�m�@�AE1e;��0�&' 0λ3�40&��0O λ4332|{uΛv0μ1 {)6�wFn �� Q�s.,=@I=�&����'��I��oE-!�:-3�explicit Q�)� b˜0�μkk !1� i+γ� !�|�� )�� (*�)� i+α!�+ i!Vbi3.i.ibi( 1p�}� γ%�A�ta &��{onp�%!!, mi�(ir9 cret.cs duea1UA+ ��=b!W / (��!+!0i=3 , d"� ��  d ��!:A=nonzero*De�f&of M–�A�h =� 1!?β /α�(, 1≤k≤4� u�!�%, !� ��N� be!L�� �MAZA� mino� ee akk� ,� .0E�eD!u5)mAm�ա"f  ar� 22 ��;?��.�&�-�AQ/ )2��E�1!�Iv"�=μmm !"eI!t) � �eI.!�E�*eI �mF3+mm�3 !�  �1m+α23|;!��MzAm51��in' FnT a1⋯anb bn|;�)C%a �*� is t(�.�,%.b1=μ[C���AH+D.!"61+Iz( D 2 , b2=μ22MWE�WN d5��14A�1461� t'.K��( 2� w  1ri��a , � 9 all W�ZT:a &� Eq� E=�A�Y��� c �/��!�sd�Qyh����� v T"� A;�ye��� � ��b'mplifiedA�s�,� Fv.exampl� 2Y 20(ev�ce*o(�`�,�!a�2g*123��� �!h� 43%-%i*C(�&of E ! �K"v;-56vs(� [�4 iF{34{a*�( z;�( *�( +E�6tZ"ƒ:�'5 !&� )o/&�;AJ�)5�k8$%�=!}(3 = kλ ( k� a poL2v���possibly �-1q"B#�')� �1M -y 3- � �,�%� > 3we��3R ,�Nsh )@'.�AX�  .7"� μ˜��a�o'a�P bbF2�/�8(a�.)n�'[�E��E� E� A�+1Ah]b1b2 a1a� 1<J"+a, trem��s�&��a1B8���(�s!ށLe�)f�,R�����!�.^� B�s��e�&s"'1�m�&�}�m�λx 2 F1!#m+΁�m+2λ" ( 1;�xc~�.�!�1�N' 2μ��M�*� �a�r�1�u7�%N�a�a2�asy 'ra�,&�"y�.�(*O�b�8r�4r )�(a[e*1 .\&%�2�,l&0�>���6!�1Ac!�� 5ta�v�:&�per%�V�to��<cI��pm�. S�7� outp2���)ly�2)�(�)�&,>38�4�E��0leR�.�-8.ge%kee.&�+i�-�)� � focuZ.on *;(F0%K]+1>�t�S��i��-( �d unE  "�)A"+7o��IrM�U!�"V)a�*�!3 �-le.�K6n+!�invYg�@2gs 3C�2D.UeB�)�Aq�E�>�1!:#9�-��b�:2w �@. |!t"�2 ��tF�i�/at 1500va�heF�Il" .�8val (�+���We�2eLm�)%in�f�#�*ur^Dnda7 �.a monotoA5�de/ eQ]BVF �>��i|/Fiy, excep� �2�- �!�1�� both�lo+e�I�-��(*�/5E�)P(a Kmaximum!�a cer�9 X��2�Z!2ZinZs.�XM�� More�U 2�s�6r%�low����4*^ !:s�t&pof6�*9:!R�&�9{ ross�3ypeY���mA�=y%�-5in��F@e6dA)� . On���?+9J��^)(V�R)RS2&�(F(2�=$ Ԏ* )jBA. F�6�+rG,�b(�7n� nF<cle�:see/("'/�$er:����AG!�B7J/�x.y�t@-c��"woM�M�2�1�n�#@of�%� or��m��"^8"O<"B�� ^�=v}#cA�wPn� |^�4re-e�co�$lG � =)tW.Ei�!K-G J�,A&�,� 3A<3B i� �v�i}f�I�)ojB62{!��'ram�{�o9!"� �9��@MۅB�� zI�0s0 �.?o��oe.��).�� B�1�e d9r&�9Mߡ�%�%<>TFAll�s&o �D~(U3��2Z � 2�<46]%���� in� �+-i�?ca�! �VEɴA���of &�8�en-a= �&!�8–"�7ITu�)du&�:�= iY�f�weaken� !o"�Bp � ��Hw�o��6)���b�A�6������.95�*]!� emL8&~ r���&!��)fer�:to&=!F!�%śinn F�A偻(EB�AW �aims:%m���7o7�t!��predicb�'orp%4]�thoe� $EGillespi�"�!si�#�$algorithm;/�7>�a:��!�+��HuAtoj�@A rans�)*" AChavA *7�f&�  >2�.{��>��b�Gurn� g\����rmB��Q�.�6y�2Je . By,pal:<win�+�%�Uu�*:&1A�A�O *�9or "�%�by li%� orga�>��It?pPH*3�1���� n>�"A�L!*���� ��7F�we�xG6vFU�wB�ve�^i\is mai98��!Iqu"c  "�IQ$of :.H.-;,���:EV;)fOJz 0 < r ≤|]R��($"*1�I^2�&i.*��M�?uc�6�Hwy:a0L(�+�>� by ng<H% �2�Fjj�p*��� qV �.�E���Li��Le�G.I��i�IR"�E0f�?aA6E�Zj��BI�F~= e�Ac�1���"�r.�1'>(>m�@dNB6)>�6 b� �5of��-P�� limi���% marV ��rol*X Su-HwW �� URJ� c�`*�V��%�i��!L6u=N<E�v��b�"��8�e%��L �� ��Wr�i4(�.e��i.E6$� ��  4, 4B� N �-x� * >���&$4qt�JE�:6.��}f L "�,Q6�c e7Ne `= ��A�x+!�� enc� �!:>�z ��i�a�aBF\Fk  434D�B�D$��� �>�JC� a�";%Ak�(becomes�v appa�P! � 6"s%�di>pGe:(�bey�Ha�shV-�4E�4Fe�Opanorb-vie� z�8>I sv-�=�xa�"A 6�J,9PL@!�,� �R� �AT%�*lieZ��,5w���-��S��n&as;4 ){)a ��� �n)��� XWi ) &� l�9��*��>��hE�s�s80� R( ��{%�T4A–ewT�>n�^���j�%+�K��:�OAy�IsO3urz vI35�"��m*o ( jus�=�-�ɣ1�Z�����6pJ� �d�b�I�N� Db.kJ *�F�e�%>��$�>"�nok�>y aG�� �jS2� ��Lrq3J% ���i&; >�we� e(5�l5FaA�%�n:n.�^n�:`7FR� ��!9 V�� �3&�e�%!�!�?s:������������^�5��51 .@ZE�!�" oH[mJ> �(B4�.C^�ED{=ƨ ��U�6� � 5� 5�� �� � �� �� �� � 5� Ee*S�z�*/ �S �� ���2� y� Η ,� finp� 6�J6��u�Z�Ea�a�re+^J, US 6 is.�1-�M:& ��$%�BU (^W $$*� �� a'&Vnon�r{$� �sNU,�&U�! ���a`",f�Vc� >/E_�an 6Y�a">� �"s�� 6�UyF * �&��&�� � b�h*Z V.J�l�or�@}���B5or!�ai<vE��=�� 2{>!� stZ�� F�is 2%����NU� 6�Y.}s*< 1�R4%��cQ ^% a�>dZ �="� 6(`5�tHu s play a"K 4 �4>�a�SI�whi�\B]$:T*��NUe9V�u a.:�$re!�a q�m�]!suGA&�� D!aB�X�.[6F�(4–6u "QP_H � ]l�>�sfV�X6(.�{�SFCdvantage�b�?�–!�{nN= P(,A�c�B]� Wrac64M~2�?-� n optimalEd1�6�>l9�B �"��'al�Q@'al%�DsC/-�2 phen+I� �6�&6S\!�occur�$!�E6H"o'b� 71~�z!no�&ar"���)-s�3�&!WV�biolog@$:� U��B%&N�very clr far awaSt��=z)���ow"ci-� suitG\s)2i�@�"�6Bir�9�e�$st  )��6ii�%M��0^�6�c-�/*j�9,� �&�,�7N+EXm>(Min�* M  !�finG5�Nt!�in�gnt . W`[�V188�E��VOJ�,�=a�ntiUv�CK"CV$�g�Efu"/,�t%sDNY!�(2�in�  mult�etd6�B>%�<�%to&* l u\�� spa�J<act��a� �H���Dnd�rox��� r [3��38=�!l�!w�p!�Gja+'�*�0�]a.����O [>Q ,i� �Q6�,).�!`jnA:Pincorpo�|c:� �(FF&�6 #�#�lex� pUu&�:N�Y.I�NdM\r>#methoM�we5���1�N�N,e&r�� f�N(keyc;&Pg1EI��Y%3s-Loci���&�2��ݥzGR��as%�!y!L!�-��`�*� B nkE�>���"\Ybpro�;��9e8 tE)}B����A��.A�B�2l �Fm�>�e�faN,!�7found F(i F05B1��_r �ay2n(measu�6�C&n(� mEc�4�icғ�3>e,6 ��2�+!�aJM.JR �,�Ah�4� \how aCcfztN�!"F�t�.*Ra�7A�daa�l�P�~,��)��k#ya�%�#a�hl�%�net�l��ju[1EI>4KB"�*�Q eukaryo�HgnA�On�gin&p%e�ZnL�Wdd�)�sh1S)UdumE��~�* ,L $nucleoproty(��aZ ssem�f%u�;= )��V;&8t �R�Q�1I ;eX9qd9 ��initi H�M ruite*and/or���8E+�'"^BCe�` R. E�"M(}WMRom4� �pr��t tNgt� s [6� 6� A[ remo�4of%tea�@tq!`6=9�C8!���+A�a-0 oso� i[��*careg�[70L!P " *of.[71–75_j9#�� `U���vl st�$mo.zi[76[� sugg�6n�_!9h�=lso:%� delik �nzy�E� �bp80� wo���#.Vg� s�baY ny hundre1@f kilo�hs� "�U���[8–12q�erV|n�aa�+L�g �[1!�14��sYp�f��Wm{��+2� �l&@ is exe�lO1tlyE&� �)�!<c.��%o�Z�&� A\��� NM"2!�mp.�q o IO�o�&�$!A��&=( name �&!pA�*$1)N�:W+thK&�^�;�!i�0o�m:~5y�?u/e& t����@ =C4f!��N�2Rffc!^R� )u !l::8jI�/t ��In spitI %�, a��os�4:Q�.&E��"in�LU"�+fav�[p&$S"�&Eef��.� m�a "9, #F�A+r�c1anY'orHk E�f� Ba&�?�( >10 kb%�up| 100�kb\uepa��ng� 1EXIq:J]VD�Z)Bnvisagey:I-!8��!�%�w�0�n!�)�_��a9OAu�.�6� �r�q"���lika��(��j�reH( ��%?)*RMt6)Z ffne�p��$fibre migh�XAct�~r�;N�%>QOO a"!A�m i !3 �l a�terrup 30-nm>����GA6naked* � , 82����m l sen�Bs!~�Qbs�Mpolymer�) �Xa` inct fami��_is-�ngu#+2ѕE�}��te 2NYE�)�9I�"�h& 1kbA��kmpo� f; c��[8) 84�!�l�4bq*�)�} r�beU�Gsil�& insu�j� �@�rokd_ �s�B,K� �H� 6���FF� �:eYN���c[85A 6AT�yN�by�x  =in�Re7)�g s [1UW� var "PNeŁ-, cA�mo� em; �3tanc "p ;%�6}D�!B.P�qA�.QV#6 in� o�u*�3����requi2�)~,xhougher 3z_�;ja�–�clu�fL �at �a��x be�o5�aas6[����eP A[8�z8"Q �nea+�a� (�i��/ m -�!Vi�s3gy., . Li�l a[2amproi�z !�major feo�Q�e��0�flexi"� �modan��hG acety�o�Qnd 6_ �?Bbt�� k cog jat[6CAI�u�)O�!b=m.E&�*aA��"q�)�t��gn�A2�M�(-E#nstitua� �. �.� 5P*�hyp=  7. M`�(A ��verCOw5�lis.M�! rele0a}erz^.>Q(�yMetabol�_n�sew& ly�+s uponŵtechn���ustom�FwiEh Vsm"��xp�bE�. T� � EUpu* riboM�E al�[!�t (Uw;y!�U!cNtenlyaKden�� ed�4� typ�cHfq��W�.RNA���;�m;q��x spaci*0hort palindro�[repeats.). Dt9E7�B_@*i,�) 聿design&/{)�avail~ to de novvelopxP%:K,� !0 FIJM�A9iZ���Eg��Bcw6�.Ito��/i�lacUA� ledg�K}�$�6ySr8V�/�Zinhibi�)�r��ed�scratchA_�:"!�6��Z�u��"��A� ermoM�aV� ��a��8�t?����",�B��� �b,<_^-���w��V ,�six:#re�ed]~���9cFL �s)7a7!silicoM�!2, libr{e"�@�32�.�/ , 186JLre sele�<u%�a!���M�!):que�`8B�nd co-yہD � uEn!�!� to linkE�j�Uto:�B N�Kg i�of�su�i��e o 6%,:original�� �.o���c�92b��A�"��a q�!�leg>bA@g�+o�>���r�� forward .9͝~Swa�0�-�validE].��er�p�qfU2�G�/��� h<�&�"II2 xA4�u�9�eXim��� "tBh�NJ�A��je~�m�g5[��NcA8E �Ne�Ka�0 expaU{ABVtoolbox] �]F.~ OvKe lAdecad�1synthe�b�!!6HXssp0"dg 5Z c��c::4��*� �e�6�� eti �&.pro�e�j%� bulk��j"Ll��renewE�resour�,v-cidy?jal�t&�[���JXmQXZ�MN$ terf3 �{he � f -s��hV~A' ne�/�f�/A c flux toa��� d�f� 6"�a�#Kt !lxvf[�7>Tra�d%y,���uliv�� �d8 thro� e~ dele�ϙ��$#�SaIC� es3!t<ttena��bioY�8pathways [8 , 9�As��oxim)�=�on;J�6 ols Eto"�%�'e�.5�� e� zincAyg�a��"�Oor-d i�� �b�N%"_w�6NeY �1DNA-bH^ng�� k1# � ;� .k �ut�Re�rec�semY_d� / �(ce ( CRISPR�\� adap�#�A�t@MII�re�]a�6a1Nit ible" %|RNA-gui�de-�ed Cas9��to!� [1 V�qA6 effor�>n4$]&CCCEm1(��A�uc�4< {�E�aP6,IaQg �&�Q�melio�!x�A�m?a��1� 15e_ �q��e\1iBo&;� i�r� employ.y ( s� c�� �A1by blo_V%�� al.[" 0|��ҭVHGre�atD[ۊ1�(1�18���!�!)J��ga �E;AE�g�)�}a�TdEQ�)S(yp-�%+ c� H�^motif �=.Vy1{6}il�*Hfql�b�*g !e��E�iRu9N���Qߡ�ga�-�K�-u��n s�����b�~��2VtiKz !�l�m��&�����&�sic�KT�Ubu;5��{� ter�P% i�^!Yt�ul�� be�H$[i �!>m} ��p�A�Q;sol�r�[2�NS QS�"&> �.voiEeaiTa.r�",�[-6!�BT �#&k']q�&� ��E�,) �E ��eY!:!B��u�teZ ��*\ <-au��Ÿ^ [2 2 2�AlsЁNK� dwX1Zpi��arlA� p�e1!]"�!� of f� �o�A�circuit�,[��2n2��2� H"�2p"�p�k1�*N� �� tho� laboi�� & a�imgscĎ!l�h����]gQoompri�.�!�$tʇ1o�zEqN�N VA�o hybridj��. �+!JarchiterH�#4-�(y�]piv/t}=$ )��.`� .uA�.�qY�EgY[2�q=Ja0C�b�3��O� %�^%��J%�N!�!��of X� d0bnNA� , dr��d��!����u%��.�'&� mp*o��F} F S%�1Led]>a eV"�[2�u3 3�&: %y2� 2{"�2�R��#6� ��Q<:�molecul�fe���|3�|�f3� � Xa�class,as ei�5�;2J�. S51��9�)r66шnw|u .r�L*��st-%s; !wib3'&� s��( RBS$c�A�[-�&V�'a�F�ini�es [3*A�manip�K-��a�s� v �MU%�BeE+��f��ai�+&�)Z~��*F����[4��2�&!6�igN�m9%!�o�`|gM3[Ey��K|� Ad0T *WRi!E��[fA2? y ( MFE )!���&e +r�#p &� ;9Ah�e/tF7^W� ���fMs==.igmS q�*s�l5snQ@�nd%/O � a�1pEr� Funbf..��`��m hW�0�}!�X(9�6��V road&A^�&u�x !9U�A� ensu9lb@�l�M 3���*W�J�N6tQ�rul�N�(Ş}�kcN� @7 p J,� =v# ��bN"0 sa0d�wRH/2�1f5�>ce ag�-�1~�-d[2psUo��"L�P�:0�=͓ Y�a #!�*xHtngA� u�4s��rL=d"?m\$&}qRZ�݁2ng m��6� 2�J e5(Non��f�M&�`w�sng>��{F��}Aal�5E~fE�R*� i�K >�28�8a f4�0Adab�F�J��XA !'2a.�Obti��I ���.KZ����UM �i ve�)�2%-AgU��96| R�e�m&G%�z!|3E91&�3�DO��cAI*�42>� lU�R�Q � l�cap� e�9� (i�T�t�8Q1bN%�g,Ma"e@!�Qq�� B���!eK�col�al;�tGM�ie�9 �kAn:����"� � A]�s  ��0vivH�0�u�Z� ( OL 8aR6�( P$^#I�H s6�1�zEM�!. Esch��hi�(lP �TPDH10B ( Invitrogen ) ��a��plasmi���V�fluores΁e�.6� . Un�-$rw ��@!��3purf}�U$Sigma-Aldr)( Diege�Belgium�M¡� �'E]gr��& lys!y�Lth ( LB�(nd MOPS EZ �med�@( Teknova , Bioqu�%, Yor^pUn�UKingdo�3H 7 .��v�at 37°CK sha.LB%�2 o! of 1%[p3-pe%$fcA�ErembodB1, ,% yKc��D9aY1% so�chloridZ VWR , Leu;�,2�LB�r%'^zp 8�!e\saot+%��96e�a{"e- � agarY"�;)m�A���le���MH100 μg ml-1 ampici�0E�5kanamyci=pS�+�A�M�)�-copy F��:pBR322� � repl{ a dG A!}r ' Fer�!��1(pSB6A1 [37]a~��a trun� d;'s ca0.c &o���aartI�/#���]vD [5=�8�<( BBa_B1006�;a�%l�f�� ���Ot!(YfFig�V�@?�:m+ d�#l�9% d pT.t:qlowBnSC101!n%T9��S$CL1920 [405T proBF�0, mKate2 [41]�re;!et , rnpB T!�9 �% �!VU 5’N�# ( UT�22B�qj2��:or� �A���,it+w backgr� A��;��M5Z!�" ( br�0�5m% ����)). A*�� over:EQR�/��< �&ud9uliQE�,�AAJC 1)�/ hsNc��pBlank�� w�7� !���q�A�a� .�n` ��!l{��/ _1&��riX V e%�bq ]�2�Ł)-�opeF a� $RF��r�tRe�=�2�UTR�2All�f@"�"� Golden Gn[42\fCPEC [D<�;! DNA oligo.�%�g/erc ,D��IDT�5eBT!+Qs4'c���<� �g"e,o ;� �iE( Mac�$Inc . , AmT/daX!�ND6� `!8�� QeR?A^lis� in T� 6=+ta� �� ��+6�JBN`B%'20B�l � !�ss�6�&%  ' ourin���jLBA ��!]�z&e�Kn��Mub�z+ scolon�%�ino_�q 1��lR� , cX�!a B" he-Eas���, g membrana_6d A{ H �*� Co�t Digi�.Micro% Sha��(ABrmo S��E3a� t 800 rpm\� . Sn�*�A cult�q�1:!] dilu:�� reshR�n ��until��� g ph "( 6 h���k�nd OD �4B&Te� M200�� m9E�� . PrD=)� in G?er bio-�R( Vilvo�T2� �6styC', F-bottom 96�D%��F.� � �a%qw��g�th��b�μ/F��f[CaO� e&�;a\zc�Gon wave�6�miN0of 588 nIs633 ET�\B'!�as�d� a.kof 700E�'u��ia`��86w abundG[4j�2# �-g,E='8on��-��wv'96-YFE7t�)� .�aRb%4E .�_i�s�<�&5 =�(�$���6m����OM }!c���.��*� OS� ODbg(y C �_ !����FP_N�� ��>r5>`� �s6+،MWcal��a�3}ZFP#)�/H/=-bg-b�!R�0_� .��U0.jRe�vv* 2�% )I�F�Q :j(Z'x 2/ ×�(…aea�PE�#dD.21f"�=-0 M1%�Q e=fUn��� AdH�� %o&�$i:��deGb�f*8��.D'9!� ���c&� wo mr� p�;*�;/��OB��{' tra-(rawt�P!.h #��Ք(RNAfold [45� RNAco 6�2�. B�zi a�n���4�g�"akViennaP(package [47 �%Ѕ2w"Z K�(–noLP -d2%h&Qac�410-Al:l� ǫt%}�$4a6 ault��g:1����9S!� draw��!�bE� "CVa?Boltz< we� J ���un [49"�MlP a��8$1�!;yR'� I�AG"x�s�R!�lprup9� [4�-llu�%a%�..us� Pyth��mnga\Lan Intel Xeon E5-267�@� 60GH�Linux�ebian�+�E�D (4ZI� �}+�1�c3q:!iF�Yuin Sup8#MI�Ad��, �a: yd�%& in Rr� erro r�3A|!�d�3dev�I( n =M�i�*���. �R2� ��;)�chydroGOFu^ � IHq� �6"�&-:Az������2��Mgv݉� 7 �����D���ei�.�m6-��s6�!8�p�s���ly�1in:�"�F �ve�LA8hlindx:f��a��GVz. N�-K��2;�toQ�y #� a�i� RBS5Eg RBS1�2���7he ave0� #a~.�n�g1,A�kw�;3 a^:���� ����Y amourW~ i�T) `Pmqi�-]��-��t PAU�a�C��4=h�^ s@ � fi�( L"~ �@!*�&G�j4dU�!R���e � :C:8 ��"*d�!&&c.�- �D�n+-!  ; �as FA�aFABF� �"m�!�E��q� Gibbg5e Aerg�.#fi  �nd i &&#���"M"s&9 -�E�REA L B9}:;"� -�sR7� �:>��.see � ( EIa}�;:"T".�ra��,x "( a21ifO?*#r6\'�ak �5%Q��1jVcceO�"ifie*%envO�,��Jo >�P s^,j[$�4I y*�> ?�I� [5"!A�� f�?f� ed�-��#,=*s&!v�>4 X��sa>2 P(�Q1d� >hg#Wcei��� �@1B�*, 5>�i �&��tD�B"� 5[i.�u��D�6�6=� , �,��Hqu)s4e��U��k�0#402�( n��� ��O�u�UTR_�̀�;E��))��c�A�l cod�WT&>�!�,.�!Oga]' ��!�a ran�&�Z!K�F( �6�zn )� ���>����5�NYOQ8�)��x!��З>�\ � �-4+"w;2~sai"8b� 6r������� cor�+� .� O&f> !��8�7K z�e1%RL�Dr2K?�G2>'\a� avZqof�75�1Na��ne���5L�P+�o~.�.� !�PCC{ &� *�)"2�1��,�!���E�� �����l�3%E�=> 5%B&5 �o �I 2a�l 2:� l ��!� ��Jxp&�?!1KB&*y �0� �b4<q61� Fin�:q?A�� �zD�� !4�6t��;f�F[��3J) Y�A�)�1:=E2�le��AMi*w$!�,AoV�1�B>h&P9e�;!��p,E�<I�� .z"�B ( |PCC| >q �q�!rhe �HXi)�'K; le�&�I�� A�,� , � A�PT!*a��a�to unr�%zz%��)*_&r�q f� �HN3(y�1�#�d��%%BfraX9alE�oy�2-H+� ���ID�!HIV6-2/�A�>41 �<er�o% 16p�dx 6q%�2 �SJ$�nd�&D��&�C��if 18 b6su�F�� t�U<�"!q�ABi,ca��O �Hm�� &5�Mn!le�O*�j%\{�Ps 9 p-2�# 2+ P 2. B*�c���&�"tr"� ehg"# ��-N��0can�-A���o��peXO@Du�wIn}��uit3m� F{>v1!2�%#du�Qu�A1E ( RS� �g�re��%��R*�Z�=>���9(D!�,"��is%�5��S� �9(2�am+E�5�E#a���A!7�����"& theoreta�]�Ed]Io 2�$! � 4� :JF�� �&��8 �E!t �&'�<]*�� z@�.�+ setu݆S)NmF. r"�,�#X"�""� carr"� &�&���Ehav�+x��lur5hŨ@'2 a�aO *�%m�p>&ut�=�or{ *�[,' ��Q�c;UroD�*Or�q$ ed 8�).�!c�al ��qDB�roBXk R�"�J a-3 j~��_k�_o�%*} �+f 2��v| �!�ng@*� �ly��-��?2�i& �9;�0asyqG<^���=[5�@5)o?l� ei~�*ɔF�Ŋcoj7aL�)A�:=Eai� U IBi�aJZ)of &em�:\:0,q�!e�n�i�2�.L"-��,2�K�{in 3 . 3�'s�>,-!R""� &��/bsUV"_^2$�):�al�T�6�72T ��J)M�t�ZUT%b-2�,6E-1 $3 kcal/mol>H �SmG` �sb�"�s��!@��A�i?�A��o��J� M��[59G�0�7* 3��AXs ��.ad�~'� aj)94Shine-Dalgarno�D��#)F�Vs�8k�he 1 Wy�9l,H" ?-> ;fA����tem�U� �*�hMXuehB9�b��IX!S�NA��RNa% E�?ngXaG4�U�ce [6|���outKQ-�0 �$O!�B�C����%�[-`V�+^�v !HesK ""'��}�.1n" w�X��[E��R)c��bWC �"k)�� ch��%��O&��x!j9!.�p *� ��J?i%:r^#�*c!�_�!�2 -u{�c�x�1�9�� .#�� C� �.-&!5P6$�s�;��� �"%�� RA�S: <g&F ɞ��%�kS% .*��H+%IG��75%M����a��%J�"�M� b"JQ�nJi/�Ms"N�XqTf2��� �Z!5.� �{?5�W a�-"%&�SF8[26+�G!{ �1�,%K��"9ly�g*�<�39.6|9�on)$�j��� I�2 R @81z�d!�LFa &Q1� �^�v�|1 0032!B���=CJ6>I��%�Vq�'q���-6�"� !J���� -6 (�O� 2�,eX �B�>zu�_>AXh*�T�!� }/6,. A�}#Rng �Ao.�Pm�7�OI�!��6  ��%f�0v 6K 69*"=3a�j�oo�%��4����,2#�*Fi��� &_a?9��u�~ ԃ��.�gIA�!�zan�78ta�"�Ta�oa �"�� �� I9n:O78��6G"�$B5�2G ��!s v2per!xag�<J>V-�NV!� plotH�=s�l normal�U�X?T���H4�|] 2͔I1&�%�e1��""��18u��!:7 �x�C 阅�VmGE�:��: "�(�.LNabUe9�5q.?�aIrMt;R=��# �!�:y ,Ia-��ly�`�M(M�I^ha�s����lS�, ,i( p <�0���PT�). F�Z2 #e�gVe�%, � �onj2r"���or��!1ai|]>N;O��JDB4�(� �b�����U�� 1$ry�)/�@!Vhe-V�a�.�(6,X l2PT ��!u- b�<�Eg5�B�)XAl B!^_C *!8&TG* "M��"�_��W�*�`Y!�� Vv+�'x&2�e�"�ga1>)3_ |.\:_ loga�icA�nnyD���1��AEq,��6� is��=�F [.F.�2�?!(mN���)�ic �=Ea�un�te� �uG�an$�N�Kf?u�a�9�Uc���.@ �� a& �95%� f�&�ter~\�>)�. Data d+�acRSi0=;�FK�ly�Ws"-O!#*L.mD[6�,64)+�"�]6) �Z�����W s(�5�,35 6 I.�e��:�{,�?�A���v@�H� *�ik#�?�)�aa8!�A �'='�ZzJd h w%�,@��+.���Dnd 2 Sspl�k "��b�) �e~�r)��b*:&�tR?�2�@V(�Rt:LM]�DK Gi�ldM�,%j"by% d�cpiAUd �|vt.mA�T!a���dB�of�67 ��%a� �9d)�h�1�?!m �W�ɩ�%mq2J���2�AV"� m�tirna:4sca60�$divis!s�&s�nJ�+de ,5�A�*-�30)p�vZ'oI�2�!8U12�( k����AC%Q�� )q�'M�on� ed 4A"+8�-�d�Y,.� root�4nd�,aFgS��!h�w ed Y b��q��$2�;� e�2�s 6�9".aXS��chp5�4%#-�R o�m��a �.G�L%�*)FY5�.�Qȅ�m��dis���.� *AHa�AE�tok:%9"��� �)�R2�� JP�6aM� E� G�.m��"sMAa�S�����)��&)aw m��}p j�P��6d.!*�.U+*NYE2� �Qa=6=nde���&�!")24M12 ��0��h�H( J�&� �cumGPv:ading�7!'4���Cbi� w��8�+�+B�KE�L.�,E�e!��"�ei1lIJ�aEo�gUSUTRa,��)c$6L5�< dA��i�J�a�]>or$nd� �>4A�z�ink"�O,&p96� �ŅYaG� * ��)�;J��PO� 0%,I��L�* 2� k-J FNa��4�j-y �c0""q��}��jR9 .�hU�,"�z#�$./!<PT%txr6�J�!�c�I�N�6�h� 5�5d&�@6�/�%W���;6�S(*� !�Y�<6ݎ�r���!�C6D. C��MZ2"0,��Eq1��2�&�T�U�*!�"�%*� N�K2,O�1�&��"�"�Q�Z6��iQ$��2���ed��U �) % 8*.*8�+� FŬ(�):�3Q9cc$f&@�E thod&KP[��==�an�48� >U*|!��.�J6Aen�T;F PF2��)A|d�|s��g5( �)��Yu.o�f�Zn]*Z�ex "d6ory&js:�D��A)j�a6 7ZwqMsa�83�1un�_tod��be disj*� rdd�/��]Na�<�*'o�P�:"�F^2��-i ��.�;*�S SHAPE-Seq j\�#ch"��i�o�Z �,ouped"��5���/Nnext-�� R%)�p[6�m] 9u�%�2 �o��*l^:�q��ib�Uen��=�3_�i&�.(�ss*�$��A{L + ,F�^!/du� %�N�:��� ��a�>:_q!cN�U1&z,�&�c/;y� buil�"m�!�*JSr#6H>]Lv�A�%�r��sR<�CIII�Y(h &�!{.��[?�) oH=�0c^�th�22 a:dQ�HYu�*��2 *�nr�dG32i!h/r�ba"E�Q�)�].�W ;2�&GAW6�.� :��1x�>�Qa���D�zojy.�cr�Bia!;�6 %iѲCE�va�'� � ��<B*�se�,2E���=�v�"�-!"VaYeO�#�.$>�X�},�1�4:�_$���5!W�F�O gce-QQn. 2"ov �2�+�>��2�M��P�7�{(� ��:A%Q9EZCɜ� &�)ɘ�L",\X($"J?Q �J�=��\ ADmac�$xTr�t� �G�i oder��n:No� rasp%���!�m1b�oiS>���� �}Z 4*6�a_-�"� ���uE*��7�*�{m��.u�Lch.�?x�6�wnovel)�6$(Aƹ���).q .�&"�QW]��o9�!�6�a 6� i�;QL��$��^ @>!G��o ben�� !�>�2B*WE�TI*�a�|�G6ng neur>6G�(�)�iXVm4 ��h7A&'little� An�-ut����|rE7��Æy% � xw(c+=go!]-�l field "1@�4FP>�A�at&m�a9;�L rtex!?aw!;monke�end @mo�`& L�34i����&a�a:oi&E ( �)`al exceevN 7�5,�&��a�$K ��,)J �!oP#or!e��c ��s viahsynap�? m�J���Nh-�itudem0!�5f�l�9N��5�%i� �.�gm V��UA�i� ��ss-"sp�Lte�'���.�)*ik)xlo�ia�qo>���-cJ�$A_"�)cN�aRp�r� eI �b�:-�� At�ir�K)!)7*�������px� h enco�2�A�d q&~itpa"3�2�ch*G�u�5 alog��9vide�"z?vl{+e�l �{�۰�.i�)� by Hebb]��WEg�|!"X %�Qmb��t�)M�' fund|�% !No!ve"�Y�6deo�M�I��:E��FM������[,��$�i�6�Gas ��ia -- ��JC����7��in��Pm�-yJc'ut% �sum� ,that neurons�U within an assembly undergo similar changes in their activities , spectral coherence i)� local field potential ( LFP ) reflecting tempoC ri[irresp#�ve of amplitudes [2] and synchronization in the spiking activity of individual neurons [3]–[6] have each been used independently to identify functionally!6 ociated nXlal groups at different corti!Tsites during discrete �onsesjhstimuli ( for review see [7�t9] ) . Many studies focused pah ularly on:S)�!� , as9yattribu�of%D$$waveform h! $been shown�,carry substa)�in,)�about a �Dus or behavior [10� 12] , oftXerv!Las better predictors�=s than%�A13 J(5] . For in� ce ,M�4 primate motorE6pre !� ex transi!� phase-locM? ross&=�can be!�Upβ-�8γ- frequency bA�=M-�Hvoluntary movements��(al task per%Onc�6 �9!2which h%+en propo!�toqUY�intera�E�20!(IIEEG ,b�correlaA�#4 “gestalt”� ceptatcleEllin%66�n)T aRL to highero)efui] [21� mporAcly�montaneoIS ongoE6q�shares me���M�iX us-evoked� [22%`26!`!�indeedj 5obA�ed1��A]E7��gwakA�nkeyse  , [23�Becauseb�rfound!<includeff2�tim��4these dynamics}�,widely appre�Ӎ1liAF ture�D conAA�<“metastabilityA#[8 ܉�34emabiz!�the ideaaѽ�mightijaR�<�� rder!�s string�y�as��E� . IfY�y i�>e defin�a:ert� 9vA���Aqthei.,exact replic����)2i����ult��degre�"U�y-�X$utilized b!f(rtex . Such�� ciseZ����iaw9!x��over a%� range͑�FA�ddi!GAimainta)5X��8sig��. Tfor��we analy� %P�compl��2nV,�@s�Fc. O>was recA9d from 3caAPimplan�arrays���!,!q �@somatosensory regEh�� wo mm�sit� quie��!M �Avchair�� well�8organotypic culals rmE(We demonstr��a!zmoidal r���hip�Ew��2�aA�lV o��.T!�,�H�Bggregq"�.��nglI�!Y!!�d>occurr !*i�n )o"g!b�at ot�iP��8millisecond del!�.!�iG8this phenomenonrall�nonA� loss-lesse�agR����s ari� by virtuE�synapticif miss!See� sults sug�8 a�% tipp!T poin�H�`U�network�aAog��to �� !Jspread�Ls�nov �,%R!. omic"cv�& p8wa�!�m!0increas��hnumberha ipaEag���$suddenly l�to�_ �casca� �5do:. q�AUQ4( ∼40 min ) F�ekacaqu�Jqseki�mhA7� | k o� eA�oiAo m�0commands . An��thirty-�icroeaHro� span�T64 mm2��\-� leftb�� ( M1)%�A���n sixta�Nf ∼3~i6�Acex ( Sqin1*A= ur |�Rn}zer� �>.�a�r�dorsal�E�O �aAe�p� � of�B (k  [35]E�a sketch$A�in vivo � posŵT 5:�figures> . Atroekysi�>U�F�.�prefr� l�R���of��grQ a�� weeks� xtE�nnel ��aa�teg��d 6� �sY�2E� [36]��ec"B �/�َ� !%lyaB spik*# [1� [37� [38qIn AOdataset�U%�, ��Efn�Uiv��є-s�( nLFP!�"� de� both'!!L �fir�as�]K��0distinct unit!�� �hat /{�� < avA�� of�YzEeA�|�7popul !E�. S E�1~strongly�s �"� rU��m�eA�Ul[39!�We thus ined%�period%�,est!?continu�y5�excur����Lbaseline ( i . e . ,� s; Far e 1A��$hose peaksH eedereshold��erm�successA mA plI6x�darvi)P\� ( SDe�T� !V s varied *�lysd�Uean�Mvt�up��−1 . 5mA/ chS d6 tlsif��W,e� ���i� &�r�!�D170 me��s AjB6v%�(5t ���O]�� ,� $randomly s�-ed � 250 supra0 �on R做(ABV(4 , 000–8 8E�vo�nd 10 –15 .(A���)�se %(�� !q m trigger�(�W a&a�"^ A t| I�� Tt �v %�� (er-aliga6,5eB ) calq A��� coeffic^R �O serj ,�proviJa meask �&�*2 ��p�UO (�e ECq�CE= S1%lA�ntrol�we�a1��Kbe[ )v-�!�FMqY-match��o"� 5gs]�Bd ��R� s�im9�segZ!^�y�s��dRlyQ6�yN��n;�$also Mater�� Meth�F “C9!�A�S$C-^A�Ate�%@ det� uq!�-�2�i�� � .*d������ Ds �)A�a�&er� c�� cl!: to 0 . 9 � not�s1���M993E;�r'a��i�bu {�� .� at�T4�P&Z 9 !D��syste|�y evalu� � average f�- T �� q�ed R≥�8�2v�Y ison.�E , gray� Q��;���9��low!d!��9AF�Remarka�A��!�}�ex�Q�oxjly!I՝,�re%�a rapid�/ �a lar:&=)1-�Z-Pas abzF�p�qu�$; p<10−4%v≤−2!,� ���p; Kolmogorov-Smirnov ( KS ) t�AT*( =0d�, , si@-E!��gimk !�s�al*�to� of)�F!(_fit R>AY99�roken6$e; χ2/DoF1*caqIq+ o R A�e!�L86�\ 91%;� aro�����%���:I2�� ,.�U�S2� ,��eOy��A����� I�.nis�T limia�tJtoe�Nota8at��#h�rm=��er ��8� a geneg��dVWm�techn�LN�a��is.�az"K. rd �tin�ccount*aY�fh ��k:��>w� pe� � Mŏ,Acow)�!� ndowA�Ip��d �;siz�7��rm9 ��V:!<.?a�o shift// ±1� �ve!�B9Ub` in 5:i�4eal dE|g��Y�W���io� best��.e}�}+!�j t�LJ�aProbust0`2Qq �� fill�lack ��6��� ificant�V!.�����dR��DyD�*� ��maka*7�6c��� re)�1I��nu�>��Iwit� 6Wq�sd & �a�� %wlo��I �0�4towards �a�lynYx՝arrow!k�pa� )�s�� � likelihoo�fing5� !� shor�"  "� !&�q1ly�r)kwi� ( cfyQa� A* y� ��e�su�20V�.W ^ reveaA�E*!�.�F.)�9� a ma�q�of ±5� but bg&G��eaf!,!8!=�e5�š�u� mosg%Kz� ��in��6�.ݝ!�Nt B�) &�!�S &. is achieaw� r�e  D30%–40% availabl��a�o� +�  ��uppc!ar/& "�can� be expla��a ceilA� effect du�p����7!}e5 . �A�"#c*��1 �i%�FV��Iecente2 aro'i���E� ��.#�be� c�or fol�d�F�ev� �2���A�pai�"*�( dB|Bar� � 1��*� anat�l%ac1#s,a�$!]inA�t�depthy)S3�zA�q%� **� A6t1�%on�to^nKly \  -to-%� erval*\ 2z��S2p. WaF�I#�a^ bove&A��Ou r�th�&��� A�. 6�C& ter-%��6 1� �)�2fin qui���on��� rar!*� A�1���C.�&wT��So viA~"�8( In A3N�E�keheavi%�Vzero;*��6�!�] am�bidWe* E�s�&t�#20)Jdoe& near�ex#a>"�pro#En.�me�Sism� ee be� !A�"Vd!�Qu��i� ^�o�&e.!� a! -to-%$>�t�&a rict)s�"c� EA� ��!|-%�-"#]m "�!� 9could e��fas�T��u�resol�ofA H!v# � n`��1��. A�Qyq"�1K12��} v&�M�#� spee��029 m/6v04– 2 |giv�'e��e�d'of�m� ?X�)�va���is�e�gK� nsis�*%�[us k&�%��) �nj#!v.G$slice [40]A�&"�&R+  init����m cuteCC'aoext�S(�q�"�)&w, � ng�a��� �a�!�Es�(Z!v�% ��a"L� ofpson���ҕ�3q��se:� ( mo� } a!��� !8!�f&�� e%�norma�%:��!�+a. A'z1�B;��  A;� w�Vdlog scale; 0 = log2 ( ��= ca�5�,*\ �e���1�-@�51��ext@2X(�)E, >�-Au�Y�MJFreG&�bts-S1-,� $now broade&b)Mp�(��5�T0ios <1 origin).8 non-��EAn�"6��.�.�/� r�����&m@+�h6� "@I mpar� �� �xs +i� harp-?t 1*�a�a� iori�Fb�)S9#16��"Ia"{+!�.� I%F^C.)J %&C3B�+}re<&$!�G],� " Džs9�&r,arallel)K�%&�$��ity}�C�e�;��m�u"jG!in"-5N~��&requp(pronounc\� ��m�qOz/cc�^�*(��"b�Q��5�� 9+-��a�gr � �R%r&%2���Br��z� 4&9�.�?$)me�r���.�in9�JU+�a!ll . Fin%_�*�a��!siJ���7� ��co�� !2�anK+�(1H=_ofE��!���a�#e*,e{ Zim�]+F no�+� ��e e�a� e�V| ��5fs)gP!t�9 2m9r�����LFP�Heac�#r�!!_#-NaZq�V � n�ơ^��"atf(st � away 'h&ak!~ ��I�6�* ѩ���.9}�}| �(2-�3-fold�B"�6�a� �s��Evv&o ) "�Tblue; R� 12±01w 27��fCJ l;25BD6vCmCG / ���� )1 hile>�%|s club ��n)�._Q,"y lyW � ;a�re%K 5E�h��far����4h �9�da���� 7bruptv���4Ņ"(appeaiG&t&�)J�,��*J orK  "� struc.�*�$ �� .�% will� #s5:17Zab5�e)�x�1:�� �"�7q�` !\ir,�d�J. G� %�!��}���-�v45� e ope�n��1��J��oan6�%>�$uE (�* side�Q�I��� ��le���"ne*� aF��-�ihw~$�/taD visu� ��Ew vi�8J���the� .a~�x&���0Z�%.� �V3e)� q sp#F"#��J�!(�B�no278*Q�� �A�s@�8��e&h"o!�rs�!Rlot�B trix�)mO�S&� �allk (1����*D9mK� �.9aPa� few./A'an�, –�3alo� diagA� X�կ! m ��V4N� ^�$V>pC"�Po�iai���8�&�5a  �Wto%�5FaAR�:�(��.� !�by <1)"�/bB�.] ( !_��Intra�,`�+y,�9�(*�s.�>�E)te*��n� /L'! .�l>�IGy �A��a"�� ���$D*d!*e-e"�8ջby!�ply� -e.a��:� �3(A� �um�!;)�� )�.�?l[ e<�by��8 ,��n classify��V�nd�,%���visk%�,�6�6)#6- <.�6Ync��� e�J�A�G versmS;J�y�C�R/� ��9�x(T�r/Q5:a�os>of five� X1��2up���#��J-A�D Brc� s��boi�U�Ae��bE� �� M� d�Ke��S6" &rawN�$ T"�2" �*�(t�A�0�� ch.m+�R��r8 �as���sf� step]�A F�1!6�describ �ir full{ �#�>O"4A–C;10s� a], b n �R"�/J:�7�)6� >k�s6�+&"��6?b�~:/"(��'u�1m"4U�5� (or until R<b8�2J �&�}�� s-Q|a=y %�"$82z= �5 �E�mediancof�,( Monkey A ,Y 88178±22u(&�,"z!a8( "g&�;2r7��92±1EU�( n6&N4!� R�� lN 9k� hund��*gD E:'0 , �N2�b� a�U��D v�"�4�A��c ( >90%"P5�tB$hardly 10%!JR������<t��oi��@�minimaa�eSh;!:a�:,-cycle oscil86Fs+� є��o�..H{6gY("6-���.���t�t!�t)d@* ���h(SD� �6inued�ise�lQ(�2,y�E_!\?65Wy�S7.��[" lA"S ��.�a 5}it� a su"�3&w/A�!�7pur�% Fi�BudyE���3useful m�!+ extr� ng-�%"�7 e p�(ctr�n^ ( P�6�9�* r\"t �D ominh]a�W2�3�X�R�(,uzNon2.L ��5&�56���, ua�4cA� u�:�"�)9)n�?)�s_54�8a!�  lig��7_�to"�-�>4 Hz��e'�A�ݘ decay����!5[f�C&H�d�"QA�|�)a�B�level�~�.�)� �`�F!Ii�EQ���N &# o �.�−�3≥R≤ �P�5� Al�CrzCA�6��or/ge�Jm�a�#r-�J��-A!��#%�,E7er|� ±4 �'!h.A �Ge�kTga-�-�=' evoie�B��&4 8�S8B%hex$�=�sQ��A��RWdod Nae�.u��D)�?�d��%!possib�G��t�>Z) .!$�se!�eӁI� auto.u��aZDat�i]<.�� �2�=BR(UYS8��� @��w� R9 ŵ-shuff�� �+/o3i 5d{"oye: 5E�c| �Ryinvolve)���-on�E s am�. ��bljd tio&E �cruci$*: �excita%�a�inhibisZ�D3�7�s��ro�0(pharmacolog mani"�>aZI�=reduc�7a�K�V��2 µM4A� AMPA�jep74ant"ist DNQX*� �*q� 2f)�1�e<&!$b! 5� p.fOa�96<"U�6A"�65�� ��s &� ;a��aR�a���UistRon'�% � �{'Q&� 1��*c�e drug) "�8�$a�4h/ pre-*A  � 9a��71(*�N%W"�toQSD� � we�!�.j">2'�;�.E���A[��dra& :de�!�-Eap&�K("x8"� 6g,pK.Ie.�OonEj-reMj� A,� v�m� ��d(A� ů��cours�5�J!�H�P+ n"/*qCV8!�&�/�22�/�P�nq�,� la�H&7)�S�or2lC<�2h6�. Pa2�.B��p%�had �w0~awht. !%�y� C–��. A=� of 5.E GABAVFP�G toxi<6PTX ,"�aw��*$9/�/A�s"�"9��:ceyD!M>.F�a- DK,i.il=�e ��3pa�ݷd%�iAyH0%��p�.n*46C��276(���VPomi��i�%da r� *�,!�*-7�5du�!x9A��Va�� * a�(�� D , p0�%i�>ducA�mO" $qxDa� � d�%�~"�q΅"Jd�Qd� l�.��*�.k5MY.��>6=64���哕Pm��PCquiD �(!bex�A�ofy� low-&����� �R�*7? �% �/lyS=^Sɐ� &�"m' B�JAA:�s%��;woA/5ec��>bsc�CQB� %_0YA��2,��in*@xb5%G7F�s L!jB�I�,.�!P8!��v*�(t*�U� !�R��8 ��a�,�_!O �V)6�!�i���sup�U A�]"d>�GI�j���a Gauss2c?�"�A vo ��S10� �6iQmm�(�!ra�_ �IE[li�G infl�%��0ʼn�@to3!AG- %V� w��T��Y& s�0� e*�2e!Ji@atA�J;k[s�$"�P,A8Q 9*&2�8�Te�Zs*D on�z !e�>" �2Em&Q�0:�1_8 �l "�!&��$%��M���to&�>zI}��\�� �E����uniUP�-= *d9f��*\. E�aBe��3>jI*t� MFD6�'/�Gs!�!ʽ�m�7,-�t��L "N�f�7t- . A�]��A�os�a cer�0=��Ic�(Y| �bi�$+�7�8�\ ic`2�W�2��!���%P'7�� (R"{�IZ! �#a�Z�\]��;"&}a86�S4 We �u�t�#)FE�8� =D=�-Btop>�͌��atEoF�9aA;�I:8�65;:�GGW^aso���i�-Ur!� �!AAM� :>~s&GVp8 i��Au��']�(sMb�anaS ��4��a�=a5= �%!R)�Tb�/�[lщ~)m�J��#@ 1�2? �1C�eq2�$�4I���;%jE��#��bottomE�2�H qa>"�[cM hig� >��}�H2�A��';Ÿ&�kM��)%*I*5Y�.m _f��*|e�slU�B�∼=94A0 86!�nNQ�!��d ( ≈18A,"�N7�2I��.W78W d75Ztwev>\�- ]��6]=��&('=a���s6(�$"�BY%E : �amcwo @E��d5sc7GerAR��� 2HJJ5�zKS J,!�a�TtZ["�:? 0&�5 ��y Q�15M36F %�6�JMa�')I�s)!�47%� 9�/3!�E!�58  six � �4�V6��Y�e=CY���[X(�In�5rp�<)��i!�86o ZR .�h�.��reH� f� or�&�)t,*_>�!a[N �1&� � v?�1�� ogre^T�-��cmvW5sJdo"',tifQ��.B&� �1!��� io67�Z� �7�N�*� =� .�Lp��F.���:t�fE.+5QQ@ ���A1`[�HE�.i 3� &� no sour�suB� �S]�6�c�d �� &A 2b_ E�C� ��T4 �F*1 �6�(I< OomN�a��"l�Zi�eto�� p*� . How !! e, aG�7: �Z[&�:�1t�"x arriv!t]��on��-k"ja2G���(**thalam �spind�)� a� directZM!t�*>?�scenari3Va�E3>i &�-�8i o1)�+ �C"|  �"�*�Z �e*�%"� S11"p � m�� M�� �QI��6! �>���eTpU6 E�Q��e~�6�n*}6. P]� ALex&:\1"G(�� ave-a }4e�dloggto�s ! .�id����S���B>zR�%�Q>lW69�6� %�,�#� e[%,.Q�trb� C��of%�M~V��&6Q�9�w s�"�u�ja�O�3a�/^�#�a%� �v �`�f>�ei.!t�s�EyQntiguz%t�.6� inIK=|� 70�"�H:r%�� . Mkr~%�!��dja�I&zN�@a�A�.�H�!8H �#�a&� Δt�(2��2�  More��ze� ��of���f �T )*:�9~5�4tR���k� �~�F��$!�!�H�m�I��t\�1o�G:���( rpri�%�` n-. MG� ale .qu#3un�?aE���::�?Ir�7)ect� �F�=!�b�i'�sI��bD.j�/\9��lyM>-�}� voA@��a�e|=U_e> �j�2 :I`*�`�7Fa'A*` *TIta5`�os>qy�`%�6��.n 7*abUno"�& "W , le�6*m�w*�$p9�Q5� p�;�%' %�w%�+<͛� .�B?e�mEaB�a�bf\>�J�2��EileXI�"*'�QH~9E�!�$ &-+5�M�Q.|s� &�,� a ve�q�gY8c�aq�;�-bA s�$x&"~9�l2SsE9ng�Q{e�i \ngbJ�. M�6|! vͷ �Bwo �@ !Ta]">�JLAi\4�G�/i=� �o1�� n[�V��&en' �!�� " c �E! I�iI &*�)|. O.��E�.�Ll&.Y� Jp� � ��anitYK}0+��L�/� fe��*\dZ�6*r�V�\L6#��!I�7/��, Y� BU]3u�qd$�"�A�YL}�6��"�=m!�� =6J_���:�d�&�?� 4 SD"7 ��C�%�m� by c:cbd�_v "Asum6��cbin�at i-eyol�Scarz.�aCheB!�L!&��<�g+R�<�d�4&p*F�Km0,z ��B3=�J� K ��]:YO%\��" 9A; G2v]&�3  A:2�C96?"�^;%B:^ @�0e�)A���2�-!��[of��^y��>� 1� � $( unpublis��]^E6,�!Y 94͝�mid  . Som*%� a� a� r��e�+���)� hMm9B��"(gue &�8T La ;4unI|{o'u7L!��,A.5�of ��ѣ��2D�(&�!� = �sXe]).XouYaU �f� ti !4J0s ��� AFGH�Gg'*�����ng�. o &*R!�FKsEm&� in nv,�!� t�4�,�,!4$“jumping*8��neighbo�Zg uY8S��b�fi�<�u1A�Ia*EAmpa�by phys+!U� h 'Ho�Avv�*Er�AHi$.!��.�ubi� our re�"� L�2tc`q�a/"!��voltag�2�3�dye ima#to, a�dq6*8 Y{Px4Y{[43] ? W �remain�be(l�}st�\p9�4S yp2�frame�r%�*0}n!!��xwoy�.*:B" a��Jg$� �5a>�ń>�in reby!b� �lgJ� "� �y�6�( <1%� mea!%�*�Lm{y�n�asugw�5ub-X �[m[ �% n*knowled&$.8&op�VN.l"U� e�9 �6����;��1 )Ka�+6Qv*z�ch. y�p�&,�L�t�� � LI2s2's�may� �~r�_2* u?1�ta:]depolar*>@a��w e�*A�at)1kiTcF�2�)�6 %*)[qUIt�Ib���\s Mfu�ItZ der��!>m�XTv�i�y!���AYe*X �~ M�* t!,*� U@��J�a�e�K�8er��by� 4#"�6�9 �.��pTheR4�rM� ��RyMUpMi�{ e�D�%jAik,u#�"�A,�fi �C?delGfeed-for�Z M�U��I��b�^-G* �%]@� e6HxfaE��1�tQ�[44s45]}xse&< ic m �, h"�Y�Lconverg%�3&A'�A��a�uQ5@�("F"�R���*��>�DA��*\"`A�d !D�<l*�r�KE�-\�p?deaJk| ��A M[QZ�+!$@a�# rV"�8I����(M������ A�puP rriv�#Q�lay!y:.�6Jq�Melf5w>fs� �% ,���i.�,E�%1��g��|�A����i�j9 g�Z argu�'�_i� conn�*v� g pyram�|*� AN enough!�sus�&B6u$6��%�-��#>�..=�s2�� ��  ,N�s:l�7")�"0t6[��� in sD�SOo� a4��Z�2�%��a weak�up� thr%JD=-I )�![47�cA�88\^cr}� �h,mG�bec� �)tc��}�6��7 �“J�ac�|7%� !�#[-"�!�f,�agrt�:�&imR�5�2� o6u]A! "�Y�F��1ete�ofz@�H!�&�jCo��k.�.LJ�M)ii!~:/e!&W�I �H-�ee"�.�c��[48҄5^� �"��?Mll�!princiw*�!X!l�#n !�t�@ore�N'K~or Hebb�/ce�"X�4=[1a�[52A�20-rVV�Z}�&vJof�S0g�+ n � ZZ s [5e�EM% -l"� a hra� !� � ���how2�^*���$a�aW4ENJ��B8 2�RP�ac�2 Yn"�ki�waW�9�{a,%NA��B�y�%x��f��n1�$avalanches� , [54!�NB":�K�#s�� !�%�|�e"s ec in����*�K���8 L5�� af��Żk?�H R� �GE�YH or!,^El^wU!K}�[5� F^mQ,aa�B7AF6T511erg>?�abo��Qee[o�#5d&�P -la&d&!�si�Z{ c�OJi�6 !6 I�DwE�n�$a5i�C4C �0&� �,Z�2�sJ� a,3f �6g wi�M2�A��E3-Q3t6{U)���t#cB�!�a� y goverIm " *�$J��d8"� %�a"(c�"�,�Gs�; ��� !�2 )t �J�25b�F�"k6�$��!q�)9<��2�W"� K51�q��ngea a^heiA/n&�.s-fZ�]v.6i&�(s�>�]��&i! [5"s  �:AqE JOY���%��28f��Y*n�mFd� Z�1%��DI� ) on7 Z !8d� � 2HI*R+�1& 6I� M=�HSs�V1�it� e�ac# ?e�@d d�:�<";[�6%IC mY8!�Jz�(E5s �*T7.>+9�!MrHb MfN -outE51S�6y��&�� � o@on [57v 60��u�ߥ���-c �C rolI�*Si�0g4�ng�r� �[61 �3q � 6_)UP�@98J�2#onűA�Qtc&�7H"�E�e0�&��!�,� Iw'6��U�# lo�{�g��Q��i*Q;&!F$an all-or- �� . U|$!�s���alA�!�"�q"$"m[L�Nry codBM2N`��x,�# dimen�yal* freD/��<� %n�i*����]EZ�*X:�'tenj l"�w�qx�aS}��!id�|&"�L�  �b2ZG1 a�)M�m}H! �I?#JZ�:)� � �+o��/ H�is&7Ia\S� themlexGa~c�&"-+ c�t!�1�I�"'%�cul* �% n�?!��#>�#.��jwe�OaVA��-2����,.�� �6��.6z�� "�#���YARlZtal"� a bu|]���"5\E�V#!).[ 55�8) �8�eU D *�Ive–&�N9Qw 3E%�iY,�D, m�ybK cVempir8lyL�3Cw�Eroa�C��T{,��AyNA:�&���u\��I*|� ":� '.m6|�: �O� .�a��9 A�lex3uIbF�!+A#da� al"�I3�0�?�� o"��"-� "A#���(��p�0d("��5 �A%0�a%Se�#i=� .�Yw��(u�ou'�Rab6�706��0�[12�156466]N%s�nMtQ �E:!2�!JE4�+�0� ansfGing�S.�M"B^. Sɖ6K�"�5�1�KC�7! σ��Z reamA T��(e�"!�=�!A�li�switch�9B��lst ��� W� hall�_R�?�.*d a��": ��&��G�84� ��j:"��)J�ٯ$mirror��� *` �4+%�!8�. J�I~AZ4�axe/On�U&�QɃaYE�aUQ��+u@a� e�!}mem2Aovrk deb!�a���JEo :eutKt�*m�ra� l h"و,mMweE!��ogy!�T*�de�����B\display .>!orALBf�sa�%:,.�*Ko.�+ng�ߔ[6�6���l "�M�!�"� ��ra Rgeograph��F8�l�[69��70]����2�- -wor��&� [71]��� zX7�k7�“TiN( �%3� :�u,�U*�J- *�J�e�N d�b�� �bg|uy!0f ��guH*inKLng2�Q�irV"�&h%COrie��[7_�D� -sA4“q�:u !a�W��\ W�i&� perha�?� � e��Kerv�+k�oexmZ�%�]-�UAB�m?>�et� ���%LL��*� 2ZE�! PB�L�jed���1Օf��w eTu� subje!(�. P1xe� i��)a &�)}��� "�D!1a*�ha؝z�ed�� modu�1�x�:.��)i5w�!��Mto a(}�"� .ua.7Rtal�'warra��.�"�e ��~jR�-=y�6�be"x D4u��)(1��Թ��(-Ai"�(s�r��A2"��)�-CE��$��R.Pz�a�z��� whisż�7����&_ N� ?^ge2] "��"'.�"�e>r s [7��We�jM�6|�B� "� eO�A�*2Pt(+F @�ci�a ric%"� �`nviro1I!>� ^ preh6v2�%d��V�h�M` ��m6CBi��kA��s+��ua�e�?&J�g�ive"� s �, ACUC�Duke Un{$["k_H.-ed�). Arr��-ono( tungW>.�(�Cµm�diameD, 1 MΩa�ed�; 1 mm! �Q)�1z�Bhi�̋Aa�ex�4two adult rhes�2on�( Macaca��att�x[7��Briefl��� y�Pseraʏmbkepsleg&� )�a���:.I�:m��d N�so.ݠ �( �)!1T �hemispA�k �H�I"V�B ,a�"V��2A)m�W"Xarm>� rA�V�V� , M1 [!>|��PMdQ, 2(� [�-�rr�!�n���A���,�>[��!<"�de~G40-min-�"re���se-�P �%J�l�II+%0d s�y�#�0#��'%:%��.`mroom tur 4of)��I_�7�t�fHz ( NEG al Ie� {2!�Ԩ-passnz-d"�ƁDrHz�.6galfXu��$MATLAB . RNz �ubp6tly ver�MjM���)�A eajneu� �A� b>|“�h�8S12%�N&�EdJa�SI���a�B�[pkE�cell�>�M=r40 kHz^Y%�a 2-pEUS�27 4 � )aat"H�8[. OffF}Y� ri�c�baO�  Xq� �w�e-��[]ri;�5m��aS�tمU���cI)�@M&1�l�t"�h�G!}f�e��_MIzPM�_��B|e5Ta���B.�p' � 7�EX;y�b��|a�in 32ArJ�A� ���16.5��P (BU��u; fier Plex�E k"�sZ��S5;A�a� circ�E.��epigl�in�o(steel T-bola"E�@��[5��O `d�mmon -n!w�+]�j�]k��9A�Eu� �p^C,68%��;iU"(:�){ �` 8at 4 . 3±3 . 7��.X JB5)B47±13 ���"�;(6�/ �17� d�j�g�f 5�±��8 �U�;�!�dm�m �M�  ��b �IX )�S�nt's t �L, p�B:L�S�76de@!9��ed�]��� aځ��yNVaS6"�sleep-"H ( 90D�Z��–10![80Ӱ;���>la�6n�(� a��* typedu�֋u? A�6%o 12p2��)3&J��� ��d�"-F��!�5%E�9 . @\i�!�,�#�;3�jA%�&.�P/�0M �s�8 .. OH��%�"�ME� prep��a�" evio�6&7)�4&.*r cog&hX@2 a�*ޤL �0postna0 day !�2 ratM���cla:Ƥ60--�ZѤ,( 8×8 grid;� "� t'^ium nitr�{�o s; Ms]S�;�"� e envZd2��!~���.��a*G " �oP ash� B�U)$6 �e�[Q&la&�X� da[8�+A����6 w6!�i�B�/y��LF*�6em22,5�i�2ym5 h%�G2� �5e�. T5��l��a\h$ e]sR4f,�m2a�pof{8= �o�A�a or p>}a)�oad��!M �.�iQu�!#(;�n:H$onEfA� b:H )0�ee^&�n�. C�Z"9 �*��9� ur�+9�as�f.n � ��An,p�(� �q ��25�\of'��e�!�a��NZ� s~��s R �t<=ca�]+Z�@ ( X-Ba����&�( Y )�eS�#.�&�v��� he ,&�6a �T`f�� dou@0T!;5,k n-(� A�9č�obL�X�V��f�,!��@L(P2W�EG����.�Q �)1Fau zUo�+ B , �aFa,d�� llow!�TeP�bl��R� "N��dų���. ��V ��2�A�"O�by begin I�W .�a�@a$�o�"k"� n�w���6_�IK( x�A^2��94�S,pw� ��%�"��`Q Ejh=gT5A-�N."@�A�sԓ&�D�]4%�E�s�M.����4&.�s� EF�.�*B�O&,FJ(eU$&Es "6a:q�s�batSt�Is��"h)K Q��XE�;!aen�`�`>�Gms�XJ+Z#"*vȉ� I,f�~��YF;��eB��4�QGw=da?�[[a*ȅ"XV:aZ)�E%����(he2�8&E %�≥ �x' soA�l[�;i�)��K �ngYnM�3A��9(� i:�6w�J(tr,�\v��146 ����N�r�~��9G��is� up� M��2h �~�7� Y�E�- !�x��'!>8N���-�� �J�."���&Sj72�^�"ll9� �pooa� toge� }500��l*�p��E3 ��K�-�JaBa��2�a&�/rv<i�gI��7j�,2���9B)^altE[�XL sVsyj\љlengt-�R2M] �( star�!�Txen��%�!�ۑ��&� q�s�=6�2��.� b�aCWw��5�E;"V�eM��m"�bs<�S ���&�8�Qt y�v(PwiS&�R6��,�b�vom�m�K]h�V��%�A9�"Fo�-H5d�zd9�U�ii �!S�A��>��]SM��e+e���su&Y� �V��i*� y�u�&ޙy �}Gp�CQ" 2T5�&�@i(#M�1:!k!TE`%�%�Q:��!�s 1�2)?erB��"�R ��1×Δ&cS �f�':( >x�� W!� arbi�S��-�"tY�� �)05�t b)ird.�tK��PB�Gd.g�?B�WZ�b��d 1aE3 �to qu����"M�O x'�*O%=q�3U�,����mf��� -~u����@"3 m,6Z[snc�eye� hMq�'se� RF�s� a_Ntez6=Is�*��E�-se_u� ly <9�5�A�is enoGV u�G�7���Y�=Au==�*�a.�O-�oi�=R *���f]5�C2�. B&[�q���A�AƓ-a�)% �i�;< ��w�<co2�� 5+4A , Bm@30�p�r�ov�.� "N*� �6MA0��a�bi]m����>0�c��l-RM�of��l]��"�!%$N�-�%P>��rr"n �1e�%xf�N*%�M�G!m$ve)�x��ginm�,�\MH�_o1!� ".ŪI� loTrQ�a�A,�3mmHA�R}� �[eq��.*��e# %-��"1e� an 3|�� m0�k2����?�o�-"�1bO�%k.�")�@2)� >7. P�ru�9�%��*�,!"�1di+dE�o"_ 2h��D >jJ �F&5 Fourx�+�'aOFTc U)e�2�x2��u����d��� also.�}FT1�>\}�U��s�e�NS'�3PhU d�7h e(!y06] !U"�Srek& p&��j *=1�;'�@c��� eP�af2�A2sV&��&� ���l�&v����For��2��A��s-$"Gum{ �4 ��#a�5� 6 � r`"�"(�}:|�vec�D�r��K' sRQ��AU}9�� ( ;U�<�9 is m�)�5v} of 0Ea1�cca�,q � %2"�d* X� �"k!D�.� N�D� in:"z@R5!�ERNV,թ����N}s9�(9�1�|In�iaxE&F�X\*���{ ���XA!�@N�Xempty2�S� ߁��s(acP ^Xt.�&�j=�8!�esQ�].Hs{)e��Icf�!+We keК:� y�?�C�� choo��~T\�{�aBin6 j�/�Tt� �:R u��1 ":L .�uDd9 M,�?�9.��Xe���s�a2!� � r�# �([ sum��5%� n�520!mo�&E 2�40."2�3�?a�4 { !��.!1% ]B.�d< �� c�V� ad|�~էN!�BLVu �;� JAF7 �+a2�gn��&�9q�Sp�& %vEZ��۳��it �a�A��GG ��&o��J�{%� Io��B��too/���6t;�+relevG>� w ( <7equ)�&��>��#ce�]d;�X*q�AV!��p���cur8-il��g�n��3���3e�q�a<�}ar! s"2H"i ( Ori� �S"*�) �/\� .^kNuclYKSq 2(�4) ���Tms D%ev�GA�U �;1BWn�6Be scrf!L on y��gen�le%� mutadA�1�8y �X�9��� ;>c[��a h�L E��25JJta(+ n. u~�iORcRNAE��D LINC�Qlexi!2T� k "�KV"��.�Km�7h�em�/e:��Zc%�G� glob �*� -� A�uxN ��G�iDJb8Z� �&��sea urc�embryos �Hertwig �t��y ntury ago!�A^,Kern-Plasma- ��2�Y��5:�<�x� u��E�!E� ��ρ�N��VF6A!`%e�:�VI�hk)��uniuP5E�)�(Tetrahymena�#� 51`3 2�%tN��'f$�/8%1��4��%ocytop!Qic �U �(@ �i����.�oa:��}��?�� �'[�=A�a�3s� �� ,,oex�ar�4Ԇ�C�1g~�F=j,�a���e��'#+n�hl� DNA!��tM� OR� �l>IN�A\� )Abud�[6]E0��[7]1�SE  ,��BZ���)�nutMZo"#����!J�Qto6�*��e];�} 35�&9<sAy:n�n$T0/i ��"e:<4u/-�� o���:�e pil>7x� �0,>��;q 2�X.�"� �s , q � ��� �vU�=bG;�'�~�1!��* mpan�5AEr*Q� in S� [%d�UGra.FM)t;��~%W also9\in HeL�llm�vS �C�c Z1X!U�6>��s���e�W16I(1{�.)!�T*�9a��!�r9`�;2�!�sM FqPm��,d situM�� .uWJ@#� B+�onP(A�h"�(um�; �A�%�u�ya �!eryAcyt�P�)��'U-�{ul��uAn`d[a��[1�Kaa�: �5� 3iA�eZ~Xenop� ���. :�!�.���E&��BS*lY�a��m�e hepatw -Myc �C�i�@caQ =�.�NS�`iv�O%��,-16 6stage C��leg�a:���E�.:RBJ� .�"�s)j9���A��;. .�/�<T eR.fug��ea snail ���m�|)�te����:*�K AusiVUkic���.| � a r�y%:dM�eS�& �X] ze [�h��Q,� �lamin�g�&� $f� ��7�inU�!�human�s [;�1~?����� Jm q�s�5ů�ca8 �G��a�re"�Il*� %��"oD��y:k Schizosac�0 omyc `om�a+�>ly�;c�-,�l�sha���uAgo? uo��toA���=�m�LFs�.!?)o�J�Cb�p^w�<� � k#on-& S . �a.�6A =��lk na�" ?� �r�PpEli��biosyn��_ DQp1|�>.�J�� w�8a� �>"� �*� wraV u!&�D�4 *DS8eo1�'�*ݳ�1Qg Ebe le {A�q � "��R�- ��9�!~�eu.Z�to�y nove�� ndid�6Q��N2��1P!�.� *Kh2A.�$:�[ Y8Y*6�F4� Uc4�aberr8 ����\� as�%"JiI�a��0�?Sof�����6�Y 2�1!����ve�&E����%r vF��U}�>W�j2"�!�1Q��  ar" ome-m{ h� ozy�C6;col�*� "�I s 99�49���0g!xfra�'[1�i>F"%a�pTi��W2�diploid��ha F�of 427?�6�� a��r&I� /��goe� a��colon�c 320�G%9M�-Mc9�5�[@C�d{ �,qnag�we ���&w��e1�yrfmtQn�6�U��G� m'Jm- -M��A��N.�� monי�)�Hlyja��ophilicrla�6erS��!�q@envelop� \".53�fluoreI���m%�� e <emA!v5Q2o63s ��]*!Ic&(�A� aJ���y�wedVi%-W`����!UY�:&�;�;(5 wilda&!n��-05 ± 026 ( 95%��Bo% ) )m)�*.A"h!P�S��."Md cop�!s+o%�a�r t=QW)�a*A \�(0j�%J$�V�y��9A� �?a�� ip ^yu��u&�Xit��no� e��) s!}l(>ntugdirG!y���ß"�$o!�m���� "�ma���)� �ead����(equilibrium� �4ual��A=v"e�(A97�y ��2bK ���K  1�A�r.��pI dilu!6���� &� O�n�um�M ng stocha�aJ�d�re i/,O)+ 60�+ISe��A~�w,��'*� �)Bi c2 �O2C' S1 Te��B�y k "GJ]H)� high]� �{� *P~�.~"ntR �%�) O�+ny�er �8�x�A!�aRe�:�׭/ xM&�X�k6$ ���>b�*�us�)0,Xll��.Q1��endix $`�%,� �! p�� us�Amp[��|25.n �a$�o$ ��I2�!o!Pll}!��2�S9�."�!2�6w"��� 42% *q#6�C"�cm1Δ a��'g.� a�$P-TEFb-cap�~yl� fer�)�'2�E��62%�5�)>}( nup107z�%�op&v N1e�M �M6&��.���5 ���4hi�I.� se��e)> !�)cQХ��-��5�R�7š��ts6qM)P9�d�E�y5Ia�Te�2�<ed&��Utdr go asymme�Z)MaHZ=޸�s:kms2Δ (sQ6&lin� Toskelet�d�(�)�Z" Kms�-ar)8 mito� de�#ZK�&�@jd"����i�UP. MNE:"Qr1S� ���V!�It-1\ _��*�$to=�I,0 a���������E�"�6 #t�5xou�x���6%@ tubule�C [Hbo��ttachm� [22]:H�[pc24Δe mis1a�I�)�*��+%9 kine���!6�� g�W: l !ir+ �!hipL&Ou�a����u&�Y��ݒ�L1ES1B� ����6Q��{"(2 . 22 μm3!�1UF9 �&o$� �y� . 83 +. i!0� ��-os` b �90 4�X%{,I�h4� �,75,!mD to 9�96 g��. All=@Q���m�B���>K6"D ��=�121 �,/��u 17Vʍ��s=�Fn&��t F��|n�.J�24 �j&L#!�Q)�%xY|2��Ya�*:9 t� K�,��FUU xc�'wo y !id�6�)h����'r " /c&g1Uh�]�Z�,6 ��$6<<rh�e� grad�� �r&�$� �<��<&Eg� E9&e�Cu���' ��< �9pw�D�$"i����y�? !s�,�hpit��A "�� , 21�25�qE��by.�st��yd�B5#�IF� � S2h ��2 h.�|w2��\ ��Kn� �gll��W!D)9=~d�(i�3cuc{ ] �i.� �t".�mA�@ss "k�arO,e�2� �a"no�r� v�&h�%�"# �|,J`as!d����J�, i�-k'6 Z�@��FM�6�!�"J S2E���eRc�)� �y.۵�eY�))�G"�,�2&�% go��of� s�enric� x 1�le!�>��]�� S .!B!O ont�( GO ) t���iai , o&#?6l>"s( 3I�!�� !K 3l6!s>yR�C1���$L!�33i� 9 %!�5>� -HGOlogY*cg(!B?�=�m(b�rc+, _ss�d,N;(u�b*,. The greate�^st enrichment ( 8 . 64-fold ) was observed for mRNA processing genes . The GO cellular componenSTGOCC ) categories LINC#hlex , Nem1-Spo7 phosphatase intrace [@ribonucleoprotein*n4Par part , macromolecu��and�2X� were also-6 ed . Gene� eractions '�identified by network analysis [25] ( Fig 5 )!Dwo�o!8Hs of the Dss1-Mlo3 %|export(�tR8VUinvol!�,in lipid bio%� is , �$previously.�[17] . A��)nother5or�� ,5Nkin!� Prp4j$hich is re�@ed to negatively �tical�n)[ withW!�$Nup107 , a)�oporin2S physRG!Xbu:� Kms2qSad�Tfb�-�TFIIH5�,)Pcm) "`P-TEFb-cap methyltransfer!com%�-~=\4. These latter1IPs both have roles in Q cripA��cta�asI� � DNA-direc!pRa� olym �LII holoenzyme . DeleMmutanY�uGa}asome te%� Cut8�anaph�pab�� ( AP� o�vaA+ Slp1�aberrantj sizeXU. , display�synthA84 lethality [26A�@Four spliceosomal�a�s Smn!�$Uaf2 , Smg Prp3 � Msl1M�:�%� mo�ELxtreme low N/C ratio-<�Ga A�a d1`-�� encod�M@�anX58%84wild type valu!���FgRforms�WM�F(1�,in,cyclin depen��q�,( CDK ) Cdk9%� )Pch!>require�57 g4guanosine capp�of��[2�]@ C-terminal trunc!Fn'h(ΔABretains�EO!�but lose �abiEto bin�e! ; lackXthiaA�aio�= duce��cruit�ofI���yDT0chromatin [28AfWe hyp�sis��hat if1’s a�e�he���=I(appropriate6 control ,!�n�!&�4Ts should , like pcm1Δ u=Zv.�o2�0significantlyA�er thant!2Y� �i>�(��6A%R6B�A� T loopq2,T212A ,H�=)�ct�G!�byA�-ngQ( CAK )!O perturbed)�e�meed6�lo�>�F�, sugges��%�!�r6D�to]6byE%�A�are im�� { �y�1�. H��< de�$be a systeA�c�X tic screeeK0S . pombe ess�al&sgthosei�����-/����2�defects�( (code factora�at may:�2B� Ta� ��25 pot �2;�A' cludA8 �2�s��a��e first9A�H �G@ł ���KA.5 "���^{ non->�nope� %>9-"E�E��r highP pheno�7� ��2- alte��5\hap�[Nx arI�2A�E ���s��produA���s�&K 9 ;� ressa� morer . AsP� �APto�LPsa�2their�A [29]A&t/possibleI�$# �c�Hlea�Ha�1 accumulծiive�A*� !n��� ur� ��U5�)� Q$by bulk efqZalogous�Mi���WheR�.@ �� rae1-167)M�a� enlarged�M�AA&n� ,B �e $themselvese�influenc!te[;!�� E-t funY �(often found.� � �es r�A%any[E�!�,m . P�a��\stoichiometry or localis)� of a6qLkgI*�E(,ocytoplasmicI��!�a%�{distribu�� - +�E betw���[u!�d a�thua,ev�)ng.Z�of �*i . A fur� i$N �5atI�[>�oF*5 sa�q�levelz specO!� �a � 6y"�'In��^ ��( jex~of�6�I~2B*] )�� be r+ Z mi%�%��!.N0rݭB=�MrF o9�-�r^e�� est group�Ž��aV F�� ^y ,!�A�.� reg�its=Go��Z�,Ah6�2_Ym�u���9�J� willY��numbe���s��i�%�la;-�monitrg!_� ��Oe}�G]Y��e strain.�E�!>low!�2!�� ./ � �� h�K �^i�exaq:a�%U"M, �!�.| 5’B� . M�?�� h�^j��,��ex ��s:L " ��is c�>BOGO�� !�B�im>Ihe6$1�f�in^�a� �H15��6P>�b( has b�3% �"���.�es�l cons����`at bridgqAcl��$envelope ,?ne�Efar*� mFcytosk on [30] .��&� ��KASH doma7a�ain�z��gral ou$fmembran�i��&�!�SUNnK inne��arFK formLse)�-�e��EZkms2ΔE"sad|��*� as]�� $candidates!�`&J l . It9�m1�+!�:�buffer��o�&@5��erv]5ForpgF00 sŊy �A��0expan� ��is>5sup�Hdata from mammalian�D�vn!� multiple^M�����$mE�nesprD�i�� N&h�]n�Mb0( ABD ) separe��a6�ansUi.�byKext4dTof�t�ea �:se�thoughtaEba fila��� ��-�a:P fac�=5�q�[31mVHaCaT-g�rup"h l aQrchag !ouy over6> aM!) of N)k -2 increa����6>@ leng�%�-2 deRB, demonAum tA��6� .�U$@ ��m� ells1@T%� notv�� focu��_ tudy���ASB͒EB_*~un"K5J�� ' asym� ic% divie�*�. Six�]s jVT:�; amo= � three� etoch�5_, Ndc80F pc24%� Mis1�nd%7.�:��E�!!6apoAGmodel wh}.>���inwarm��e�,microtubulesq1�y��. z�x�"Oto�ri,��xA mito��1�%<=����9 d��S carrw~*a��. M:�1�Uai�ilI�� �� �U ] -120� s \�in Ra&�&�[21]; ei] Rseo� �.n��c6Wfi; yeas�$unc��dh A�W�~Caled no�� ,&��f� Bioin��aAae-:*Z ��1end>�����t�-s3 �� � A6/ global��� ibalanct�EMX.�"d�.�%�I�6|�Z"�structu� Fo��� &5 media��ods u�Ke�as}}}[32];%�grown!q(YE4S unless$wis�di .*� i� p%�is ��lis in S3 TavB tagG � erA, ed uEPCR-b�Tϙ?2�3]�ver�e by colonyCE-e follow!� alle� %H�: cdkK�%�dk�. 427��za n8 Lgenome-wide heterozy�g/!�� coll# on��E�ye9�����!( haploid���h" [18 , 19] ��ed!}�_imary G&&}�. H.�dipM( patc�� glycea�stock�|lto YE agar + 250 mg/L uracil. leuc<+ 100 μg/ml G41�incub� at 32°C�3 daya�enU�to st�Q�� in 2Vl���� aden� liqu!ge^,in 96-well p� Ce1 EPt��!�edvpON177 ��a$d ( mat1-MA�0cassette mark@0ura4 ) ( giftIq,Olaf NielsenF�harveera entrifuf"on ( �0500 rpm , 3 m, )E�resusp� %< μl waf. 2g boi�salmon��rme!Au . 5!��DN�1�`PEG-LiAC-TE ( 40% ( w/v )400E ,0 . 1 M LiAcTmM EDT`0 TRISA pH 7q)){add e"S < 2B25:B.�7%7, wasa�(6�aB"sea�ed� EMMBq. To in� .(,YNP �o�%WiA�Y(Ek(out NH4Cl )aSavml gluta� acid.Q�}��~= Spor2!i2u treaG w�D1:50 β-glucuronid*#�:Helix pR ɼsto�inMy at 4!�,. For visual��a1,%/�:���B��I,22–24 houra�E�!2DiOC6!�QWo ���! %�2"8room temperatur�ur 1aaute bef8 �iU��Ha Zeiss Axioskop 40��scT%Da 63Xe$. 4 NA obj�Dv� 152 &aN$F�%�*� !suJ�Xa second�Crm�F!la.Ex�p6T� �"id�d 530D � 3%�'K KanR� � ��I� pseud�'4 SPAC212 . 05c%�� as a"- �nd� sequ�)�stage�4260=K!B5O��,.HN� 1 l5K ka+� ")for�  terti!w ,!nI�J,6\�+5>���B� a NE�br!(� !�ig,t��tdt� �KanMX4b9�.N Ish1%�� ��yEGFP���� HygR���mrI�pAgTEFSmo�|!NtCYC1!*%tor��t]�;u�d&i�idA`pYMG!� �"�&h 5(Hw .$ Y�[35A-g��� isol����I��MasterP�Y� ?Pu� �%Ki?,Epi�e� nd manufa4 er’�)��"aK frag9�# A�!��!i!�ope�%a�(frame ( ORF m1 kb ups��m i/c�)�n%�1�an'fA��#Cu wo�� ��a each)�400 bp h�,utoQi( IQ�dA technolog� ( gBlm ) )����eyloA��4 a li� . pUC19 vecAYbackbone-�Pa Gibson Assembly Cloe�)�NE�%�Q[!di%q KpnI-HF ( 0!FSph2to yieA� J��*]Ua� to:e:�*B�� GI� abov�O1xa��a�-�W�)H�b�confir�� &� !by��y;:�2o spo< :4sciZa&;.-eXN�L��-Y�%&�& /�'�"j���of�SEmT�g4a)��epl0isF�ci"D(di����8�f ��!fZ XYCut11-�_6�w - ��'1D%y1E5 T�� I�MX � !t� �� as��} Bj����c!��N v�� � t ima��2� ��a DeltaV=Eli{ G{ ( Appl�� Prec %)��"�,of���!measu� . 23"0%]a.�,m D*�rsta} d devi)�gK h*or sm�bx*�(�2 -pop1�mea�#zon? �p e-≤� 00AAaE*#3 4m9$in^��by�>�,���< �0�-� . s&� �*�� gen._ ��2565�oZ�IzCP3%GCP5 \" a/ers�]%<a�r).���� �9V�N�" " m�A� deri'3��n� 2���am � �� � [� I�(of�I��lisJ� �*�����90^ � '-[�D"� � *� ,4š]of�05!"-sm0w �sE'G� 4i���2� . W���Agz�!�E9*ark%rar&"of=RQIL �J�8Z"B �6kA�ѓ6 undi�%��)%ed5!7oF&���ddi�opy�^�#`2DF�� 7y causAVe�y>��qi)�Y8!Q 5� luc�)�nA5!{� �)��5� �8n Olympus IX71 |-fG inve5f.���%�>(Plan APO 606hil*l��a Phot'*Hics CoolSNAP HQ2 ca\5, ( Roper Sci�)fic )a4an IMSOL ‘im�o�  Environ� C#S�/ B���8ImaR\�7q&�,on glass sliE t v[eEac�2in%�2 μm�!�4 z-s�5 over 4�'m�a3#ght)�referUdE�middle!ց�sV x !tdMv�8I;SoftWorxZ�f�Re�"n.vr1�sh��maximumalensitE,l�f2�A�esjn0For FM 4–64!��$experi!�2�Sn2widB�]�com}L Nikon Eclipse Ti2 b}@9 PE�po�U�5b~�P�Q�!��eM6F�Huyge�#CoCes��Jol�2ZES�)10X �&", $5XhOptovar�S( AlphX-5�~vacuol�)-�,� �",A�IUcE�,M=�( M"w<Probes )�3� s: ����YinN�t 5�35m�'n!>!`_d�min& &volumac��!ɹ���*i ���1"� mbrb��B��![/&� re K1lZ#i��e JAIH�.�*�[V8n ≥!��sp �I����3 . Uf�,� -ta�unpai� stu�#�t-tes@"X9f&� I�c �/wo*� �9{-Z�%�lchxcor�;�Wz+#i"�w an F �dA�varian=#� >�E��tly�t��6F+�>�F�DGO::TermFinder [23� PomB�� anno���k[24�default�,amA��N>]?Vr$esyN softw���?� qcu4 ? "�&zBioGRIDZ&3f<DF��� “H�5a<Low” �a�a�]2{"1,)�%�(.��Deep bD.sti"{4( DBS^ s kn���:== <4���tAHxa%�et, neurTcal ord| a�M7 ParkinsonE}dis�'�&� =or ( ET!Ata�k8KA��Pmin!E2a�f pul�"%�� 9�. ency via Lro�?#an �A�). New_ clI&-U:�.approach�6�� i5!ng2Qaccortf ongo%ymptoms�D m))�9nd%�&�tod v!improvm�=erJf!�i& c��efcL*d &j pE)�A�nsuc7�E�=�  be�u"�&ev�"a2�~ tegy�!�miz�� scil�#�A,al� ssoc�<�9!f motorA-MQX4$useful ste >st�to ��6E ruct1a�B%al(� ca�>�$be how%~)�2�=change�.B��4�gtia�5� b; . Our �Cf�!)� @ �oup# �;o�"ri!H��inq asr�*pat-e�B�. U$aIx9mqAu Kura!t9#a���)�t� 1�fonO#. �8�`/.L(a given`"A�� i� ,Q��(&Z3�ns� �s+b such�� wxdicH��.st2�U�-�be �9n ?al�.a:<?�_iZ�?Q % !Z�@��2isc(er� �j�sur� a�pr��� /obX !�F$ET9 1lL vi,A-'�@�=�%w hybri4e�� �dEcombi�G��M�.=-Z� n9��he �, nam� p�C-�!��daph��. S�0f sev�;EZRoEasZm( P�/e^t,E_*M/a$��ly��AnX/��!��)e�(poD�f�a�line�im �Rin�:~� `� #/1!Rbet($13-35 Hz ):V�Sl�: 6�X( LFP n�O�of� vid)"׍ku8asal ganglia [1 ��O�õ�>�ETjbsyJ[��&�0f��a*0!l�?��Eamu� �In}CPD%�ET%muscle� driva[Are�i�5.n:HR@~ 6ha wj bur� A� pikeL;o�$d�] -W 9�/? ns [5��� a <'-establi� &� o�1 �i��I� R�� !�щ�rh� td�Avp�=n� tu"�pa"� !-*� ,u�!�� �th , &� I�teaA)n �Hmp�#chiev�b��9%.A9��. choif d>�ruc�B!_"h d .9Q ( 120-180i�"M7�d �YT9�p�js [!  6^.�"5=)0b�occurrA��r�,��despi�"t��ng hiE&P !�uk lY0me ism�Xͨp���rem� un�7)!�! tin�eo�M�HX0͋d [8–17O&M�?t!|t7y:�.J~��a 7t�@t���*2an�/a��ir����cU nsm0becomesz� A} they��wCnge ,Bo>ptZ� [1^5Si�J�� P� -I)suspeech-�F�2�gambl!�t�*nc�[13�72D �2 y� �desir� .8t�4W 2K"�,vMA taskq� madeN"���q%n���8a s7e $9meL'&W �doe�$*�ex@itp!u�[��r��=cu!-�.�H��hD iz"� _ .�J*�A��-heF� [19]�qrA dyn�.%zQ!��&^�of �(�oTN��zes eEp6Va�N=(equ�l S��ma )A-� ly!�!��due���I%�ic� A�1�u� ���Tmak�1hem�ven{��-%�6���6�CB��& �/��:f{� �s�a��7��%��2^[2<22�In=< , Wil�)! Moehl�V1] � �ed"@� ma*E� :� A�� ��* R��#(- <�K :d�U�VM�-��EA/d: �� �toqrKT��:2Aa�w�N8P"�!� )Wo+�Vre J�+E��7m� s���r to�X[2uHow\ɍ�/��j2:�>��Uly�l~!$e"Wal.\.�A]. Fur!m�',��� cM�Y=�AB"X"�Pchaa�er�Ac �R—S��J6%Q�J���&"3LkEmE���wm<!�Z�E g�q.�a,z ��pa�!�>cr�!�*{ �hI ���=b��o�� &�:�i\��� 6� �se�aq2fin.C��AE_"i9]7W[23*4]p*nE�0���contex���`iq���&o[rea:"|I5r�Ls-$&�k co"XF!PJ^2�Y.�.e�a[hipz"KM��0YE-1Hilbert ",yet� �p�V]Axa�s+5wcu�8�cj�� Eame%��M�oa���jF�. Fin Es\�>J�y"��W� � exa�ng r<�-�*= . We aimA��,�Ban.�M[�(�(�or�n6�.Gg����ezc�$ic�#J�#��N�H� �*�,�i�"t l $ !R�F��L( [0g .!s0 Hodgkin-Huxl\G��)2 r�\on� 1c�"V vari� �!AE*����S�� �M�]va%%�LH\��$ odic beha*^�A ����� ��� fD.b%>K%ng%�at)*A���Q�1 each2t � y ���Gr--df%��[F �a3 ��bs�&�xte, inpu��Fs�l��� V0AD2π2#UX�oa "�Q5$@%�> �\� a�2Ff!**�aNa�ZxOr-Gy&A��Ibe sui A(MR'��_ fast�auBe�>{� duV s�Nrq�2�"Z�M�(i!n�� O� ngle]\eXT��$,�65s^:in�a !Y)�� - * �$AY'g?A� ��\76q�calcium�B�� �!:8UR�m6�/s�'-f a�I�2 3A��*%W1s2���5|�eIitu���!5[�]�Pim !�A�d�Sopenw�Juwei�� ~ N_:���%�s {θm ) }�!�+he�C��� �assum�~�0V,!��aE�?oŞ�rea��9a��> ir�&�%T.*wh(&-�?�$� ��ub+!.pse6�nd� cuss�!CGbe just�GN&I)�"��u��.�i8�Z( �B4a�r�g%�A�h*Y� 4FG[%�%�aJ�:�"�ng�PU#�van��n�  "�θa�ts)��.lm�>nEA&z CX Z (F�Bi� b�� dMWC&m% ;already�.e�thAA refrsUy�7%: ";N&���$raVAB��*�i`UEW�e*U!,9don!ele��)i� b#Z/ F� �n���er�1Y (?g��.�� �0 ��ndM��b�A� af�5�>�'qFi�=���a ’s?-G.MU�$��f��-t6~i�θ . �Qe�a�6�� b-pEa���= −si�DθE�W�;aW�M��^J���>F�� p�!Et*� �>i��aI��� . P2 iseU4 Kb>#%B� ��7|]jO:5a+- �FT �a6�o�I��T�T*�!� citator]'inhib�W�iu��[�TY4ef>hrecei�\H�=9�I ��: EB sM advav+r�%�vF�$oKN�-it�"^iP � �A �S1d��def�-0�2��:}=superpoA�~ec�e�&ui .�f�<=1N∑n=1Ncos[θA�� !( 1 )A�c� �m;�I�through�B&fo��ec�4�er� !�a"�1at A�lz , ��CrI��!7 ���!.��-ŅKes� E*^B�U a]1\�"Jfe%E��� � ;var smoot8�e�:�!)u 2& )*P�A>n dow;Aeam��p�%n��>�[ �b6P deca:,post-sys��A)G�>�"j seenIyqu�iR` roxi�)I�D �a_)�a*�*6��/ . If+>�ro y&� A�B�;=&�C &i"�>�is�Fn!�aAhY���,�a�-�pk#�gra�%ly5� .\ zUHX%>�F�is��sta+I�a1")�� q�=�ly�j�I3�1ctu�fi�Zpu�Je�* � +�}��n� �:he� ntit!% ��be$1dJ2 )o"��� �6���Aoa�C�*��1al ᕅ1/� abcUf�+%&CA�a]���h"��1�e�y�~ !O .�ly A5:ig�f���(Q�Hce1�c) �8er)�"(,; h�Fi.\0 � r*` >�',A`�'on�� e�P%�_&red ver�!A1j.�T ?��W)l JF�^s�cng%pshift "�!5!=c`+d . &N)7#com�M ub�%@m�?-2-o,( �Zn� �)�˜1��� &S8EYisE� s �%aK>�^�E�!�>�, ���3 )BO�5a�I�ly�Z0h( "�= e do�Hn�OgJcy�niH�A�.. FhH^��21�:� �śpoint )�vo�?F�"ψy�"Xy�ρeeiψe=�+iH^[��P�i!hYaly-��5 —aA=!�1�N�_ ��gn�l�(e�!7a��� . B�)s0Kng Eq (%�3���#E@�j>resM�E�_"� ?�|.l ���$ρ-Ec{uH%D �]�( 5 ���o now.�Jl�Bp�qu�"J/*!�F�Kɥ>�!�Fm!�.8i� W ,e r&� ei� aG6 ),r29���!�be writ�h�=ρA� , ( 7m�.\ M��U)"mM0�;lets�-� &�A7 to 0%T. �=f2!B Eule� 4 >8F� �9": +i"7 sinB7 8I%A�heIrn}�"J/monoto�/b(! e]A-%i$on�9� H^[cos� ]≃nr{F2�RA�j �"��Suppl�5�NM+T�*Sn&�3;�/* _ We �se�n�Eq�B :�y)]:-iqf6sE�9�so& %��b%'�)a�.�� ] y� cL10I� ��>���O Rflax�Nm��(�yB}8��i� ρe=cρ ,� =� �!In sum�W, �On�b �"d:&�7% 2ռ�'�Q�����6�F� �A�K?n!G�6$ J�!;N� �d�.Y ��� ���' ncer�4EGa� s�@�e� d�9&.� ͅ.�*)�.%� AR@%F�S>\7��� ��-&oqhseDN����uu="!&�&, ��+�G�v�W�Utffe�p *4[19=!80] dθldt=ωl+k:�|−θ�VIX�7��_1A�!���, ωlaf�u&X+of� �x �'0�he b x IpB4tE g"�RB"�or�� !Rm�"�Q�!�iMU�d��!$s%%6�QA��&Q.T((;)k1XI��� ��"olM/R�dof1_� 26.la�hy�/ya s���&�thirdN�Iz].y 5�f3:��no+ by I�Qz�&� �a ls 1�.g,p%N�(� tM0�I8_ ��Apdjaa�� �9 [d�.To av�]eLu%�p�l\G�(�=�MiB:IDhi2NordL��Li�_>T%T��p#5 ρA�M�2�; � .y ��B 6>S��� 6 ,ɵ�&�"� 42�ρ�~ψ�}$I�i�TT�'47E�=�� .�maS�!e� MψE<P!.X�O9*Im=b[0u�9~kA}o g�4�tu)[AvS&�"��@ wish!�U,��nl\s&-��#&ti��D���IE�outDA��R%Tmh�'r ���1�P_2H�"�s@*= a:�?%I'&>S�$"=&�� Y �[v �%Af.�(c"k �B$ zyqIj'JR-~���-��*�!BJ4�b�5*�%m:)� �'M ͡ �7k./�Dde)5�KSO�s�2<�)9 LB�P�� >�Z�V�.� G[�4F�>a�&�(erA $6��/i=;1�6,(�&Yr *�8y��s"4+RU)he����Tic��IC>2�YFa �-0>r��� _* !Z.�?� aala��9A �h��E��we7E`�! [��� xBL . Ot�rAntaSn�5w�d�@�'09�� �"*�P#!�,-,� .�!4w, !v>�x �g ( ω JCauchy( �[ω�wi(<γ ��;#�=�  / �s�,���r�c���nN!d#N4l!�a�lb.rW����Dreviewi�Ee�SV� "�)W���N[3�/ N�Wi>�-�B�5� ��>�.�# ω ,S ,^�G$=∫−∞�02πF.� dωd�#( 1d!�x� A�"�(F@!g,"_ MQa��Weis3��inu#(� �J∂FdT∂t+∂∂θ{[ω+k2i �$(−iθ−r*  ) >g ) ]FU}=�P( 1-CLf� �5�-ofF~[�i��h��LguJj1yansatz��7:�{.�5#�%�%�%�uW2π{1+�∞[α�)einθ+:) nθ]}{1�i�αi�I+� "�#�~��( =�-,�6:Q�a^J�["5�!6pJ�%R N!5�%[>V�a~%ic ")B�� r� � �� y Ω�h� 57��"�62.��c Ωt���� *!i�MqZ�� u� α*%�0)$ iγ= )�1%>!:�!c>S� =�atisfy (. γ =@drdt=12[ ( kr+I )u *r2]−[1acT �−��) ]#.( 1�&s%��� >��h82� 5<e�a�X,�J� -/c"����j}�Z4ρ%�iF2'5�!�!� ޭ�u���HZ�譬"^�rTL Cats.r � �|be��cus`�ne3� . Al�?�& �.W � b��!& ��L^/ �� H�x("�� "H6 ��8,X"�[ari>�J:�9� >� _ ����w�+�tC! �noisy���tămg^�3&�&� �&16'l4a[� ��?� ��%pE$foW6m.�: .�! ��� r dard,p&�� tech`5��*m!4 �\]�l�) A�PRC,"� �"� �m��Jl&�&o� take�)be� )J�(By Q Ω =�a�gF.���egq�� 4�C�:imaS�&���A� i� s�:ly�Te9Ite 3at-�.��&r�,)�f!G^/�R�-�:,X:�q�:$�~u bB`#��,�!8����"ω0�� � ) r+kr2��−|r|r+IrŽWI���J�>�%ա;'I�.!�Y�F��dρdt=�ρ+kρ� ) +P�$4;p2�A�dψ� 0+Ψ2$2Vi 6A=5 `C� \!\:R� I2ρ!Q+ 88!J2� A qds:xJV�.!s6�u��TaTa._:F$ z=�.j�Wj;�{>�~&�upper� ��CԎ��&]!�"�3"H ve9Hp3�q*6(.%9UP�;�-�����.�!U H8o��m��|*.4 &�5���B/��eb/�(.R�<h�Mf*�d�Ing ��q!H��!'�P,�3ũ�R)�� >*�.�)'*dofi�eB-$��%'�O*MWr�(Jr� &4 di�%tyW>�*6�N. γ��ls "�0� f�i�76�a7@{6��!j"x?�a → ∞t��s �zp�{�;�2+zero ;�$e�k > 2γe�to %or k <.-h��2�)�ψ6iv:�q �[,i�9�&' Z q6 � ��(���5�/EA"� i�v� ( N = 3�t"�*+�I(<.W�1at ≃{`04%K numei�g�Ng>Rya4�"�m6� �~mi֢ amou�c �_-" ���6d�1���-E�XJ�u }�e"+II�u u:P` ��atFS ���� 1��T%�e�]�0om�G2� a� i�Y�*h!.\!sԎm�&Fw�/�3ˢ���RsBU�-y9}v3WA�se�'omZ� ���B��(:�~N� �,�7��L�;�b ψ (n:�∂�W�? *SI�1�,'hip�ipb%^�^*�w'#�%m:�%c�Z 7 ag!-�$i[!�:@,U7&*@�*.(?e��e s��:�RW�Frt� (�E�.�wh�$.�Q��}E�!x�  E����'��5e�Fr��c�w�%;of&(=! ( 6j>�e�ٱb�3� ��E.��Y^>~Z�!U�{Bbe"�u��Y�.)N�dB5�r�F�!u�0�2�r��le�w% �Mee%)��reg�(=S&2���&TQs���2�j�AJQ7AV9.��1�� away&� ��!�85��h�( "�'i�g��A�3o3lTPIs]�}�i�<� %����^W"lH� =hy�� ier -14 =a02�m=�am�mE�bm| }� ��DulA>�pLai��Por 9�j*F�>�#� �"!%2V��>��iI2{a0r�am�Lr* ) m−1+rm+1]+i�-b:!� #�5 25 )ƿ(� ��rto M%� find=y�F &]hFtE!4�������:� d� na�( cf .�k):>�5Aρ%Y[aQ5�� −bQ^( 29!�:=%�+�−'.c[U�N+U�1�!r�i( �<� :6 � .�"��gs)�"b wort��ato��Q�'e�He"� p&C "�A!C���?�>cE�!26< and/V' �I�8I!VL[3-t&"L* "�"*��lp"^H!^��.� 6�& ����\f2�� !�s 5� R ?4� �66^?Ac�ba*�J3H 6 wp F� �b2treE;ne�p�"�;"��ρD �3� �>�! �2� 4am`e�}&&�ρu".��!70E,6� V�u.$249���!O6 46 B3%1)g9 �G�.#: = ��du��YH�.5��QZ A &��E�\�is �?8pY3"����A{d�j�f�9 �5J�e�j�E����� � "w =^�ApI�6�Gaa��>Hod�W �W&�[2K N��K!�M��(%. R�u(:pK n)2Br� et a._5�f�) ��*�MBfF�< 1E�n<5L�%:�&3^�A"�� e"n� &6 � E�4]��fit!~�_Ca�C�1!pcoe�u"bI!ֵ�:o��� �*�V��@BNy��>H&��u;\�.2�55b-�)��Z(� �I|.� �9b/6x��!pojpln���O�5�F��!^V3^�� � Iv�������1!��*F4 �is%�T�\Tqu�d�`�horizD� l axr.;�@W"+���%�N�#�FT7�if�i��ow=$(�v[;h�fst�G/nK!}e����2MK${tpO��le�#����.�2~itZs� *�L �5�iB:v� )�&F(&>v/�Յk %l�Q%!"wu#X�Waaj�^9 �� .��#�>E~��y�q�y0B71V�"� O@,;�$�.!�N� �&�G�p_�&&e: Ow��triPu��2s-h'�Tsyr*�+ipAll-*� %5cQ8�� ���W-�� �w�&.WI q!�o��M�2W.z�&W'F/!G2!�z R2� � ���. Plo(I:b)q2 \� ��60%�V�n!�� �#n� Fv,I@�!""6ZBM��S�%*X�B_89V 6aa1P">g�BCρ�Z..�oon-& �E�i��< !zhig�5s m >�H�g ��a��r� 3en).$at ρ˜m=[� m+1]B�( 2�2Iad �Qρ>er�F��:�!�e��l�1=0%k�+5�R)S�_-:*�!Y0��A[≤%�;Y*q�9 �2�%ly�e�ۥ5�[e��,��nd�I�"z&l�� Concis+,Eu���A��V|1!" j)' =2��'t%A�6�|�3a�a'ŏq�6bn���|1���"�Xb�� wc�Y�S1O". E i$1�� 6�%#!�a�e1z���wB��u�]�Y]_:���Y)�!�Q��6&Gh �B��"L%0"�'",)Vᢁ(ρ2≥− (�<�x���� c*!�2('r~� @A5ρAU���Gm�1..9!�)%�. Q&�/ly��,Weana�a @b1"� �5�,������G �dž� ���op%[e!���"m@���qEKs��x6� appa�)}a*h ���q`a8X&<��e� att.�� �:� begi!�)1_y�1�!Hi�j�ta�aBE�A$.�"J&��6� ���5�"�sZxE ��.� < 0 ("#(itF?b$ype I�:��t8ya!�s# v ��)"K# ��}! hif��hd#"a^�7t a!��H#�9qJRui.].< ,A].�app͒�5� � cri�l6�Ӫ���7F��oL �� ch�F5 Rl�_*�a&c .�e����e��sE�%AU� "CONE�#"�9�!8!^��� �\����!f; E) �&�ej}X 6�U Q�/t� �G& xt��;wE^I2 � es�����6�d6G3xG ��"3 "$="����ZE".D&��vBψQ�N baK!�cb on �u �UOh ( ρ|QBEx oba��de�L8�S!WFb.ρ)W�-�r?1 @E� i54 ro -e�&ac�-�&?�+?��:� Fţ*t�R;[�F.+3 �Hnd P¯!J�8=∫016�/dρ=I2"� v� +#=^� :hΨbi:! j{a0&�"v˜p�#pF!�93�9ɫvm:�( �"a9�!d�/( 3M5�iF7+��\ ρm4$3W� !�2e!2�.� .YQ�s ��Q�;"�&�a��� EeMXqf�z�q�*�iOAl6�).�gD�ddψ�:U m!7[�#( 3�:!h�*b*�vi��]� hL! }!{���,��%3�%Now�_*�H!-!sb��&q��Z(^�vq[aqiMqE�aMqI� ]qv˜�&}! ( vq0B41Je�% �T Њ�U޵�A��J_6�_("�" � A�k���2�(s vq , vq˜E9q��q I 2��8� N* �!�uQorJT� �/`�2!  uu�=�A�−!u′�Y�(*r# �a��*A�:�  2Y !"�Xi��#randomly!p�l��� V�~p%�9,l8,e8)��same ��pK���}� �6>�Q;, nh )��{in���8Y��3N`k!_�:�I 7A�� bof>T� U� �/%.Q P��nh&�F{1�W�% , 4�A-h^\��P�B!�2�8\V*� {am}EE {bm}���Pin�es w<3a��os99l r:�mW�%,��,�nor�}2�#���z� )0&[G9Ze "� � B� Iw)valE9!�� � �4y8 = {2!G�6 ,8!yE�A� �-� �uni�i3pa�!g��';{uI��� !�I& \� ��2.� )Gv430��z-<>% �.w. Ђv�>=�b�c��y�6� an>� � 2Q?F��� �(���jfҭ�-G�ٓ�f� arnJa*�MN� �7����M�!�k^5)��sl0��{ !S R�!���.�r"1+" ^7 eBn86Vj��2�����.E�6}e{���ʀ�& s [2��39�*.��6Uo'*!e�bb�3Z� "&How�l) 2>6��~:�� �� �mP�F v ��n(�2� �)+5}I�2&pB���0��<o1Q %�r\r��� | 7�2�� eov�4&(Qe*��l*�i� aV!�uv� Z0v �V4pese2���{sDL5?.�~�"Ǧ�5an}wY;.3 �a�wgy1I�EQ(!,��6�u\>�wkeB|I��!.+�2A�K:!�?��I�?�92W1�U!u(.�)5��� '7>3 �BI/��- Wu�Lu *-"&:�E��ZQ �-mzc69if5� pv"e�!LeV *5,����f^�A�� �.�� 5b�bUof Cagn��&RX5�J�%.��@{+>��t�Y�&��� 2�l>�M�’PPnd��atak��T� 6J| 0�( 3 dy��i�ʌ0lg=�V �U;�%�jo�� �@1 ��!���Дeth�7�l�&o1"ag e !x Decl��!�ofm� sinkMl+%�a���&%�0]1�\Bs+u[4בDuchetQ(41]�^!�i�s�ϻ7��^Ug�0.j)\PRC7B�)>8��>ri l� -�A�!eideA0"Z�*d'i��oa�A �=��b�t$A2�=�NOVA a�c�De� F*�*�_{��|deeA3^��6tz�l i��X^�# se 31#�% flow[3t&_?� �� rPC v�V�| .��&c"e=.�Io��.`&8�Bm�E�A�fian�QaYI�al Bu�V (!:r72I�cut-off"�U� at ±2 Hz� !l x&V6�B��}9�=Ut�i�&�^2�%#I�N}of�ab6���5���2�.� +�uq-a%dap�" Each _kbU��&���  1��,r�Hn6^� JA_a>6�'�B )�!^\,�1|>kZ7a�6\!+1��U��J� !!x���� G.ƥ4g eN���5]window \2?end!h .�)�!V�dpri3�'�{�e.d)� \d-�5:)��LmnB)�23�Oe unwr�J:A!o�e�5��A 9car6N�,�i$�&�;!;��a�,-�rp)��N��4)�m�u"�xyyv�.Li� e ��&��F�^��w"�q@$A��Y. ( �!� �Y� U.� 9%��!Wi�NW� Ul�Ol��i\h �A�c)�6�f�aUoe&poB�}�"{K�Uy uѮ"D s��To"7�%*� �s�.1$�!:�a�b.�’ma�s:��/!.�Wb��d�/� ,�u��v�s. b0}�1�&"pF/VW�~7� %��6�ѧY3Zj �, ?9;Yc6u} -�m�wBDL���x �Mi u�Z��e1U�A�!ti%9M!)J�:?� -z���N.�FI��%PZ�:h9*�Ya>=0�6=���$�:�e��M�E-^4%%hHs ��\ .&a1 eda����61%�Eg� �ex-;i �e"�Ldo(#�!.� .@( p $. 08o.Ev�!�&.,I;�^R1I���i���%53�!�C#��!���@u! ��o!�<�aQP�;|hW�hL"= �"%�!�aof.�2�s�H �!� o exY�b+Ve�j&Q<:�F a�� qX ��*f �^A6A"�#y&� � {6�9��5X3e1�P�|R[ь�9�m�.i*iG�a��:�j$$ ݥ�e.R7%�B��t!X��F�.y�1��6�*�&�*��!�2��!��"Ae�6 g�4�E.\j� ,b@X%` ]�PI� 9��a.��$({7�!i�>AX� -�F^ 9:i,1K lWLy�rr� -�+ >�B �h+we dip�tJEC&3���P"��.N .���lA�7 b�A�!R.���A�1.�t�t� ��K5As$� �s,�L�<6�21�r=� who fulfi�o2��+��V�Y �m�5�m�s � �J�;ɤ� �# ia� �&�LI�Kvz�B�)i�HA��5(��.� k��f310�b����}bi�'y%6�0f�(�.Y��^�K/: Y%�muA�yb&�B2?��iAux���[�JBσ!I\ 2 =-o�T ropa��\rr[4Ak�%����'R^��aiey*ui$incorpo�� Z-> >o��ae � Y"�M�s Y�yj}%�+ y¯ee�!k%5 ~Δ;Δ=%�GI!b"� A��9� Δσ��be =1Mσ6% j=1M Jyj−�) _]2}v��( 3JH��11.2D!63-�Ry��F)*Y��e�QcL�5!�6da& �@y_*�� .��"3$%n�#� ��,A�� ivsa&�#�%�;*U'F����b��#-2��"j,.2A/�� ($��E(bNM���JY�m1.�7�h/�r���<����.�� ~H�<�:.{����A����� q�M��� � ���C�\�n�mi5)�m��&�B�+6 �$� )# Zb| B6�3,�65-�a�i�u�r2`.+6u����lx wY8Rh!��.�.^i�H �F�xlz�2� ha�hűn� F&!��!�r��c �. =>�?לeYgV�JAnOʼne��Ql-�&�3"l��t2�~�A^�!:�waq\; ��b�^R�%"%Ac!�:4<be du�4 "�1�K�-UTp��ii�2�B�"` �"�l�H"�"ۢN�� -��NZ?yj���lr!�!�!D��Y �����p� }m!%Meż2�M�?'+2+(a�Bi 1BM �J�nfE����B .�+n([e�va��)��.�s�80=Q5s6�EO�>�W�.U> ngI� %�AP�Y (͊����o� D*2Qˍre�p�!.� 5�s contai��ning higher harmonic modes . Eq ( 13 ) also assumes that each oscillator responds only according to a single phase response function Z ( θ ) , which may not be a good approximation for certain patients . Furthermore , our computa5al��Il does not capture the effects of synaptic plasticity triggered by stimulaU( . Presence; uch 7�$be suggest >@a delayed appeara <0tremor follow!�offsetW�(prolonged p!F -locked s�4[16] . In addi�Pto this , ET is known�Lbe a heterogeneous disorder [43] and different patients are likely to have di&underly� pathologiEI As a!�ul ���aATp� s used inA�l%@ need� � depenEZo * � . Our<orupredictI�an.�TKuramoto system should%ssocia!�Pwith a strong correla�H between P¯ ( ψ )%-$−Ψ¯′ . Si!�%�?ship waI� foun�a number!� �!�it!�natural!wo!c how�-&c�modifi)/$account fo!ia�One=pk!�)jis)*>� feel8e same amplitudI�]|�,we interpret!wo�"as repe.tA#}activity�Xneurons or micro-circui1 i�a!�ese2-�hA�some s!Dal separ)�MX brain [44I�he�experi .�IrentlyBwir loc [)�ve!��0electrode . W!vestigEW!�proviE�suffici clarge2�t�<fr!%o%�9N s can leaechanges�ڮTh�stanta�r��Hse curves were calc����$s before u��!�ensemble!� 10002��UeYZ ��= 1a: sin . Fig 14a!�1�whei�.areżly��,chronized , !�most ��!��7!S1�e��Hroaches 3π2 , i . !�@ 1 at wŔ>}cadv��d�%`!�( see �b ) . AA�is ^, half!,:B_$aximally aş d.`!Qmov!�way fromJres�)Ic.Ihext��to�.4A[(be weakenedM��� bothD^���nd+ valuEρ6O,!*is!�l��^����� e�ofi2�ARC��dev��1!at� ed�"a-�U�fu�E�aA� gle first&) . F�_aseA�A�!��>��E�as%�na�)�aQ�inimum��0shifts toward�e E&PRC �increae�syiy)R ligh�our�i�q,��proposnew��ategy%DBSM)�yU�^cer6� , nam"hR$whM� ;h Wa� magnɷe�1&:at lowerY�Ӂ�api�a�llust��V%X$5 , combin� e a��menb>O A�ad� v2describW .}= � ideaA� to o pply��$ frequency �t Uɥ�y to drzA> into�=�regim�at)B��suscepti�|toI�& !k. W�� a control9�4 :�wo � les!�t��aE��cur�)9<r=�as� K% b�3�br.�VloF� ,A ��pointF� gsupmi.5n furt� � reby keep� -is �Gng�%%A*N��be don�5an�threshol��in�[milar ��� eZG[15� W� �of�me�excee�).pt;�6�)2� eliv� s� e� %%�zB��k��f� fall9!?!�B��z.�is5 �,��[s��i1�> e vari� ) m A�2�E* choi� ���lso* W n imporG  factor!2d\��MEov�8l� icac ! method [4%�� posse�issuea� cernI�%*!�;M�,m6� c ���ar� �uefi RcAt very%S5� tr� expec:�.�to!equival{random.'—�e -i�I� E�te!Med��re�2F 16�se��ur work/Q theoretic0 id�ai"� 1�ݷc�ce���"5& a�*�conX2(a multi-popC ��"�� �be two9�avenu��o!ll�� . It!�E�worth �� �& : >�@given by Eqs ( 26� ( 27 rAj =!�6,:��E de��d! ��1&�Q�Ot1@d Antonsen ansatz1����$n principl theyH ͣ vali� o��is�ic� ^j ��� ,�,s��infinitttE@t ta"�[4~1 -likem�%�s arisa6 roug �i�reducE .�ng un� . ByAEtrast��w �i� excita!�&� y �saSlgll beg amen3�~ Ott-5��[47�I2 tek Fto � �->o)5 ]�0dynamics [48]DA data� sen- ha�. F����%X analyLŘ[ ap( ZeyCauchy�tribu%jf� \�;�Ahas����ail�andM^diQa>�b4g . Gaussian )1 a �realis[P �!�al2�e��rec"bwdemon� tq��"�A!W!oNa���e��9]� �f �u� )�i�W=�>E|i> s!H���Yri�ع�a�e���qu\hybrid )$gy%�� �Yremai�Bŗ��Mo"" strengt3 �6con���I2 �yhopUperform* �e0%�E�. G�m)��ng/ŁAx�on�al�^fi��A�L *}7�Q F�,g tudy�� ours�l8greatly benefit$a�r��,�aderm%�!pJ�Al%>A� timeZ �� �O latteᢡ�a  u�9�[>=%f accu� l)��isEBce)�parti�r�c*!Y!� [Ob�!�x5 sᖅX chal� e duE�inaXnt>jt!�a:Yre �-�_2�Q� �zfatiguaAlterna��imS�%-7)&X >3"5��[ I�C1 � to&�Hm .�WSchistosomiaa�q[� ��%4common endemic�asi� isea%P�| 230 milla�peo��worlw� . w a mansoni!���spe��ca��stiaWA�he!rc s:�Dfresh waA�,pulmonate sn� �Dgenus Biomphalaria�5bzgATth+rol{� rmed�hos rpa%!��develop��p� moleE� �toP ssay�? -sca�� creeE�� �Eitransmis�� sitS �+e�v� s5� "� |A� �l�+]!vrvj�l��ZI6elimiA�oR�d 'focusA�on1A$!�eYaE3� w LAMPaka0 �d�mACDNA��SI��-S .YPn�=�ly �L�s�a diagno�� tool%field!�́OA.�I�a �Y!�ix� mers t �s9� .�ribaral)bge�Hspacer 28S-18S rRNA%Adesig��he �!i!tE^A�=;!v0 . 1 fg�.z!@at 63°C�50 minuAI. E?-��Uexa�>J,in B . glabr� -W.�lyoA$to miracidak�aev�`��0t-exposure: e��pra롐�od ( �cercar�� shed��l&in!���(��a���)E�IN!eof L�i�in poolPe; f7 group6un �' 8>!��W9�s%qoŭ)pQ]�ser��7exU�k!�rA�i heat NaOH.%m� �ed J�all � �by �no� plice� irŪrced��� �a��� Td�p-,����fic� en�Uvrapid%�poAiH�� �  coA3�yve��s.B��6�5�!�2� � vidu� )���:������sui ��.��Ws����Iy�campaign�p�ra . Human8��;ibbeB���neg�j rop6��d���!G!���9 �$in Sub-Sah\! Africa5sol0 !outh Ame[1–4��!f��-�of N�ctAF�>�´!t! ��rch!� Ez�roducm�>*outpu��hundr� or e�thousandea��eEmonths [-�l e����U� ��e rout�_ ��AuhA%�clu�thA who�i� successfu��tI #a[program�themselK,��v]em�apy]���,mass drug ad�I� ��sh�"�#( imit6�in�-risk!�as [6 , �!2"�SA\pr��.YM�?� {,s) �:�f,��E� � r ab""$20 -�[8A|:�health f , safe� �lY , adequ� anit ,�environC �$ anag�x ��A}� t��e6CofI]%ais ne!�ar(aB�%reh��!�:[7 , 9�Amb"p!@ .� �e� �z&%afG"e� A��-to-hA�6�<��!�of}6" bJ� f b8!�ŀmeO>du� 1-24h�e,- tra ɓn� d���sp [10!T  � ��ant� %�� �gpN , e�j ��B � E� � non-5 in�-grad"% �E@*  abor�:� ��V n)�s [11 �eaose"�.�sporocy= 2On�� � d ta� nd o�un�� be3%�| tiny size�I? lack!5e";$db sonne �tent%�Qo5d [12�Be"�ui .inU��%rpV'��&.� ���mat�)%�es%( �j� [13�All�&͞� �'�km ��tru,��� ncid�7�by6�1�*  To��t�%��v��M� \& ,* xeno�8(L;&pqr r ( ��(b"l-ba{ � s )IE1 a&� �)��� aWs?'p� !*e*o6)mOer��&y%� 'tkdiB tiA9}�G!8 � 9E �� must� � �In��� yearPse�9 .�polymer�chpreai�( PCR ) 69媥� e�.���!�9��us��- onalc[14 ,  , ne]+-z[+,f plex 7�'�. �yAE�P(#a,�2hbe�re�*:��PQU%�co��� s bu���:resourc��0major barrierYB"�4�))��:C���� ly techni%.{ a�d skil�pe��.�+"1 2�uu>hE�I�A�&g to� "�!���he loop-/ d is��mal a6E( )i� [1� p$ ful �a_� nucleic 1:M5� a � rD)��";!��i" �-of-c&�iaC)�-poor����Hu#i���!#9�3 �Mof:� +[2Sm�Jkalread�&e�� mr!syj��UHal�a~!|k O(an�(E�l���/y�m�ase�japB0umG rabb�E [21 , 22]� .�in�+e [23!�+Y llO}o(� T �serum5A�2�bha�bium [25i��[26�mv� . A�1 ,�!fIys���*&"�%��a-�A�Bbt!ttN� -coli�2io��Y�>�7�. �3e u�ly�?*A�!�� j_:�n� as�%��*�{ [28!� � "�!� =b ns@ ,-m��*}��AA��N�*�or��Et�$" � E�ed�a.$�:!�i~#�n agenda�� � %����ÒB[3�$How�&!7or2�,�Y��� u�ye��+��wei-������[Y�.x�.9>v � � situE�� ionb�,� o�/Z� ��)�:�.*� "9, �a-econo���%�M *bEI _´"� &l l$~ A�=4;A@K�*�2.�use��!�V��earch�m)2&2 N��v��a\��. A���c�a��bas,Spanish ( Re�M8ecreto RD53/201H6n (European Un� (Dir��@ 2010/63/EU ) reg1%Wɕ~ �,E%�pro�^[r�A� �� F~ E� I���0on�#A�� accR4- 4 }Facil� $ Un�(s  Salamanca%gis�eB,: PAE/SA/001�Pr5fr1��/by�Eth3#Committe��fr! ocol Kal { 4853 u.� ( LE!� )E� mained4in�/ by p�wg�$r�!�4�,6-week old m�CD1 ( Char|R!= , Criffa�@A . , Barcelona ,ArinA tb�. E�qs a�iAm�)%dE$�eu� H2btrO$ itonA�injA�Ksoda$pentobarbij@( 60 mg/kg ) plus�r�22 IU/mL�m �* ��7!�m}+� eggA�Purifat�5$.�t�7t�&&��(�I�= �. S Y�� nd�P o 9Win !�ll�8A%b30S0 d�,*�[S�#)���b���0wit!W�/ t roN0emper75Us��j7ouA�A��ik�Ns����i� 8�x9Oin&� | sub�K#.L�~� ( pz4)�K��ng���iA�s�B h as: i ) ~M�>N�#�:� iB`l%� f �iFX RYin"broadr!�M��a&.� b_.. Ac em�$9� : }�c~d��!<�ishe fig �1A 3022 b pair[p!��c�%sp�%ngAVQr��$�c2 [31]�'�)d(GenBank ( A�A no� J223842 )e��0��. S"#}8t�S*� ��� �silicH<�� LAST alig\&�[32t *� �I!mp+r4a� vailhonl~.g�esq&!Ts�.�#spa%("h) (DB; http://N db . net/�VA 284 bp[queS!/�>�s�9��n�,<� p�C�<� �!�P Ex�-$r v4 softw#(� =e$. jp/e�J "-&�  �5A�e�50" ( FX �r� �u2 B fo @inn2@IPi> backb:"B"�H �,F��!opH"BEX5[!�d�#!>criT/?q�$in “A guOtoJing”~_Tv4_manual/index . htmlE=�s"n#�%poQ M����#! 2>!��i�*2�)�q�4F3 Af%�ayg.�t��verif� �Uct:�s >�of2���(by a touchd94 ( TDb"BriefV(�F3-B3_���uS) in 25 μLYmixTA�ai!�% & of 10x bu�]� .425 mmol/L MgCl�;!;9 " dNTP��$"100 p B9T$, 2 U Taq-*�!p2�( 10 n� of%Ve�i!� de!-�$:at 94 %� nn�*�#.k �q15 cyc� ���I�anh �1*�dL � !E . 0w(�57 to 52 )7 ry 2d. S.���!.pof=� M���)<e.ABA_;���AAI�y�=.u; 10-f se�%t?ilu��,6�,!par��[�9 abov!�Neg+E�rol�ul� V ' ) �alw� ���#A� tA 3–Ij ;sub � !�45% agarose gel@phoresa. ethi; brom��!�visualy UVr ��<i�6�a2.al volu�m�}��6 μM!��A�7� ��喙qc!�/!�y\6%4T%LFKLB% 1x I&�A>"�B�8-20 mM Tris-HCl H 8 . 8ţm(M KCl�<*(( NH4 ) 2SO2>Mg � 1% T�C20-,ew Engl�iolab�UK]1 M�a�, 6Jf!ew� X<8 U!=Bst��0E��`e�!5L'aȅSA�.�es�%+!,optb5���&%�ay��[E4#�=am�CJ�i�,JX�ree* fJU�6n.� r >�( 1�L, 1 p BdC*:�)%Cvar�incub�_��V&a*!�WA .�i4|* ,ES nd%, f�� 5– H to 8�;p2�#�!'qZ!�heZ��� $9s�l@!��!6�5�Pa2�I�\i���e��:�*UF1:10 �1A� 000Xa��r)?flu�o, dye SYBR Gr I ( Invit�G%���o�<����+.E!.e��1=u�� ice� .Wb]+:�HadфN %�a�2�,� �Yio���D !�Bi� 2258 e�:eNcos.'-��84 ��KE (�@3Aj dF��!%c�#�%s��0e[ @N . Wb/r��� �%�2�;�� !A�� -n^ �ed�C�� ��4� �4�or� BJ�as�81 . �.,�!~#� v� �a�"A�sB<A>�M�G2. �՝2�clOi��by na�Keyebm��X>�* �n3hU"Ftyl+ladder]:-5��u� A�we*�<.���NO!g-"�-.�Akb���#dI�_�2��1N0-�D�q�at.�is 105��d� !#A�iG. Regar�*.b��e.K}U|<�.�A ni=iO5�"� e&obs�2dW#�Ouem�]�/ zD4EeT�baR!�zy��upR�E�H".Ŷs}$�l!�2�N�V��in{�E�e/)�quo&� '�7s�)�2f��O_6��&��b�nI.x "f(:� <��vp �5�!�%f�0�&z��o>&M-�Eo2���w rE� E�E Ax!*$A�usA� � m�1�1i,5�E��2N���x confi/"N�-L�.�'� 2m�,�!'F�G(E�^ 2Kd�Qwo<,5-a!�>g)��J G�l�|�m�2nJ��/�&��|mag�NC5���} 22 a�" �1E�9E�.�,�y�'cruk5�94�C�4� �s2^"|"�%e+ u�� s-{����GB�,n@"!Ccor�`s!,E��&G"ru"p@u432�������of�pa�0l��A�J�7�","�e�i*�#&P(�,n@W�) �>be!y help!in�!�" �! "C! 2 .;��u���252�).!g*31�%��more &�%921�measur%�I~FXe`Q,.F$ -9Bs]i b: �'1;��#=Won+<4of vectors [33'E2�sE��,.< ���YCeQ4–36].�*�'o��+EiOW,HL�-c umS!XversatiH!f ]��(o(5pV$2�" &)I-dM<. �+v]=a<ndQ%-?>�A��.�RN�1(VJ9Q$����)�*" .�.Se�s��.ma��L"J]W*48U� SQ.A6>�*_,b��Vbasic.<#f�" �g%b��:6m�g0Eg!R( �a�?B�*!x9b!�'GH��~#=��P�2tif��t���Ca�"� ii��N�nd� avo&Wcross-�m� �organism"!�F���>LH�?��9U0�of� !�nN+��*<  *2" ��2a2T�>D�:w�B�"�ei�3RT�or oligoWmatv9phic dip�@k� �1-Ow[11N�the� ,t���V�!&�B}��>�@e�A���K)�I�)��2� � laUCE`a�Q $N;Zb�rm�\ � .#�_i&F՞��a kwfɯ2�"� M4<i/��B frag\#DA��A_2�A��ɧ�mp�O-CetA�]D�%X���'�� m�q:��_7� lLur6��;� �"of�b(*�p#�OiW�Q.k0to1)ele�G�E1�sp�]!h`Iv:�$�%Jb���[3E�s!�6�Z6<��.a B����:�A�"k in j65D�9 �:�F ��&� 6$w�/r& �6�B�G2a sZ���[J��2R�n!�t*h�.H$o[mq(�<�Y<>*��6�8ձ�P2�J&mDE%�a�Ifi�1 ��105Es2 YK��y*1(&�vf 10�:�� T���v�Z"�!>� �/!?�f�X�!p��&,TNo)ng�\�1��.pO�Y�Nr�3�a*�102C&�y���45��@�.A�07!�E{W.��o���[rox :++580�;![3�1�P�Let!Bly>� > )'2p�c>7'ř� !]e2FThJF�t?�  c�*(72�!`%%e��5peK.�Y�.�2�iG&��[10�"�68T( M�!�ZAi*E0 G?leZQuk�P%:�(�A�) tak�Nlyq� U3F%S sameY�!�)�g u e7. 7b� A0"�nZ��� xi��6�A�l"A6->�  2 "�Lassg/]� m*&�:���y�B�>(�4sA@d`�,u7[0IH� ��6iZ?" +���/4WA��BHmE2�H�A+ik&�0ar�L0G�$�#s� ��CN�2��M�JBDby*� ��nɡs�z�;6j� .6y Acis fe�-i{  I�H���Zat 24 h�Pw*@a��4B#g!�gpl��.&+[40 �b|?��5^U t|� my�),a&a5 untin_J e [4�@�M�i#Y� go�h*T>'FaN��H5i2��Ie%:.�a�O46lowByM�2b . A&C[al �btag�Sat%���~� �72"�IMa�*&i�6q%J�g�A��!w%ge_al*qI�=� enocWo a q\%tyo�I�2� �� anI�&� 8swO)0��6��wi�G� ́�a p�12�<��y�;�v[2�`�/�rV"�?� �8&Us.�J6� *U:-~( .b�a]��a�.�f/ 41�!e e2�E.�9>c&d�9aQE���2/c uc�Z=�e   �^� $ �&% �Ccru�1�W!a �a�i �DATz!�lu�� �cOa�2�B�a�new���;�˥�9A��W!.?;��u��hq>y:2�O*�=��E�.�2�XU��.�YaI�/:A. More�)*b�I�� �?Ak'16Ai*at:��i��.����7��O�lR/��public�5lth�bl�nk8EL 1960� Sri Lankb9dentXAb�@ pru��6c auth��� e Min�M�bH�L��%5�bFa� roll!K ��S�ooutbrea�9&`Y9M�C vinvolY!�%im[�h6� staf�S{ � �0vi�year-rouyn�<eQof&MRd� �*%JyX�[ at s�d\,% hospC:s�I�-ormidenbburden }b:���e*��* ( !�R�-`J��d�=2�iz��E2Colombom#�$0heavily urban''�ric� 2c�CZgepi Z!b!J 2012� �F? ’s�F�C-�9- �borne� -M$wA'Z��a~C�H.�o8\W���A���M\J<= etro-�!I a2 bY�Nity�Cg�aa&OI�� �ofB�nd&� �5�_&�K=S$3 .0�[( US$$,0!n caA� )�L1�.�%�. P"ZH�s}*� e��har�9%�z�( 79%�ndF� ( 46)!�A�a��a.��!:US$,2%�f Ua$Kg �Nvb:^UH� �M,US$216–609bpe \ric c]n2-19-866-b# )c*�����G�Ss0 �mJ1ci{&22rQ(t��CpE�+�tU[5+�^AA�6Y�fc�L. C!�ry-aa- ev1NiKRe{a<�6T�q�M�dec�deploy�@Ixkcngh �t KK e\Qs�w�-�po�^ �KB 96�R� D��!x M66pr�&_mE"t�*Kpm�^d��&=hliv�� �W! subt�eV.G [1�;p. ain Asi��yb N)^70%@�*39�1�_ap�5�` �&�an|9 ly [�PA �opr= �sAK",.�NQhildrYG7t�mil�r�[f��&�&to)He:life-�ate q7�_a��I�VrrhagicUHVA�mgjb� Uk�$A�`,�R�"%�9�a-%��:8i.AQDB5w!� Ly�:ksJ�ZC rked�?p?hf� ca�{[�6A �noticeZa�#Ye3E[�h�de! x>� ag,�"�w4*�4e�chOctome7>un�>� 1A�m�es;�!��zm�E6�&lO!L$infrastruc�:%o��6nd spx$!� �����st*�R>ssu�By�b� yF�7� vy socio- �c�xn�se7pA.�6 �jsd g� �?s [7–l2�p &A L;�xe@,� n2� reli� ��� �!+�I�f.�[N1Ε 'UUM>d�phyper*QA��xw�%l�Uura� tinc| rotyp �a^m� viru& ~z�{����30 � �V9UHeJ\���W a�sedp2� ��W a�Howa��:%!�e�$e � Ir@ .H�Ue 9�� lyQ��M��.a�we�H+PA�� is*9[1�=1�'� brup� ���hU @���o�g0in 1989Pz�agE$ in 2-z[14���2uBe eme&c�"���f�A��ge"#expan� 1�* %��4�%��beca�fI�Q��96<#isa N��alACo�MP�\A �!�1�`v��?neFl ct l�(E{ 1998�sNonA�&"�-jf.6�� 1]="��+!v%�&LB&]Oa�now-Á�}G�K�r�,a�P&�!zentir2�m>Q)-n��[2�.�ju�n F4�@� Wsa���s.smA�p�\eMt�!on�tly{y� �!6mosquito&�+20!��O����-a� �q*�A�!�������J�)�aim!��laW]"� ��c� ��Ŭ������t> �� Bh42�—�!l��%��G!��a��&�C ;F6* erm m%�fMivE"+&��:\ap*#|�n��&toI orm5�� plan^ AC� �y -mak�2�!E{�q�%�gr��bod(lFv �& }WS&�V� :� in viewPla�rE��� tHC�1����^   W 8PE���I�inF.�!dis Q��[2W��W��e��2T� ��X Yp�of�@34 l��,���1�"� �M�1���r� � !|�/neighb�lQ�I<:�wet z� XpH��%�#��2�2# yi3[dX�. .Z KJ /ueC <in Jun�o��!w* l� n+" ( May-Aug(*&;i� "�5�4ll-2d :�DrQU �!��,$, 017*� ��n� �j'�:U���]�� r� dAx �"� q435�bG,x@.A9!81�%��!ng 2�G:Y� �C Q]�6�R[2����0�i� 0�S sub-�lN !�a M�O�d�}( MOH )�a};E�U�to 125)a�.$�Div�� al S�G3D ( DS _<TE �.Q@��S��^��eO![.�veH ��R� F~ Uni)1RDCAUatt�P&66�o1�5RD!N%ll� �, � 2�8Thimbirigasyaya1'r���nE� %�-� sD�G���Z���1 Entom�2z1 EY.P)4-}In)o@PHI�-2:$FK*mFA�PHFOs+$3 Spray MaqXe O�5l6 ( SM %�? oAs�an%j 1 Ma"�h�H��ll(�( 2)�-�2 �!��5��)�(���t�V��to%� V�x enfo�aA-"} 1{leg��� in;)�tQ6�fp�.�69�, %�A���B)�M� �E$�)a:~9im! )���@iCb�1~� * , Q�super��V" OH ("���ma�y physic�z.�A�3 ��� of 35E�2 Sing:HUlAD SPHIID82Az>20I5,�m�-�1=�� diC �1�}�.�%z�aE�؀K&&8 emGe?0pol"XM,�% ool "�A4-�tKnte�m��� -Q-lŕ ��W9e�eiodic��hXn�q7~,1t!PHX "[!Y�breed!� :,VN2h%ab2gg3��inX i�b�R!A{ch�wal�v':�<-%aS2,&�pw�,��)�encoura��l+\�si�w~r �de XA�a�r�7� Q(�(i. LI[r�Enup�c�H&v aX�"2 )la�%-�xi�)� l.m�:A3e�4:�e� �za�n� 9a�es aXy��� 2�']~. V 6!fi�@�X!�a��he�>� #{E�>���[%7al zH?�n�Yl-�I?i��m�J�2�~ �2l���"�Ci�c� D� SRs�bO S�2� leg� mand~e to=y�/m�� see A4��?�ev�m�_o� � �!eJPdbk >i�+�'l.�y)�>� F1&�  "�6�Teq�o�� a92win;E�ai MOHs�=�qhe.�a��B-/݅ș�Qg� "TZ �5e�E��~r��r�/to gau�^e �?-�����~E:zejf��"�p�U�! mpil`sub�rl^l� L o"Y��)dE�m�� &�I,0dea�s)�!E*� -܉- "� 5788L7��. O'2~�U  i6�-S�i��m&��fisg�,615� �11*!gbu���m���!H!h��4744AlR�MuCin2CA�?#�Lm&U�)v - mbxor;�n� m���i� "/a�1q2 priviP:h�p�|���6!*7]��/A+�Dhka. ru��%J c��/%�9aB�I�E�r�>"��$i�z"7��&)J< � �1Y#"�%�1.n� ��% �of1�V(B)��fM��D#�>�%�  $ex����F�H l �&4�js � � # Q mUZI� �V�2H �u�!�%��Mic�r��ny"�)Qo��,�DEk�32:&�@w!�K$&) �+�� � �si)v�)Z� �A��lD ,.eFH"L^ docuM * �2�S!��(�W=��vD%!�eqz� ��iQI� <�&�.� indW��jELt� to/�KBo�Yx#[�ly�?fiq3re&�2u��$ a�*��/hF]cv�?"��Vck .�& cei�`+ 1zZC�1!��s �F��ˑ&?=j�t@9e��a�$a<pi��on�Me c!�J�MCV+hLŸa�[!�de ��)�%�� I���5dc):���"��f��&$ :Iz�.�s�fheQ7si�9�c�MN�r>'2A�n�*��=A�ingi�,�*�5&�&m#] 2~ ey���F�e2m�i<�GIB����d [Ap�5d.�req4�*A ��#p!B�'��\ .�w( sv:�D; �">um� � N2@, kerose�i�Z>��(,��ce�`, Xtea� equi=%(m}r4 vehi`^2�$f&�G5umI�( gD,�\�B� �MFaExj�%��,ez�Ё>6�A�0  !�a�Yiet�'1b�.�E  ,�24e 7OXXŘ&V(im��y�-����n� Jfo�GH ���_ uka��2� �)�. UI�isa�A*ETi+��!!��po\�l4 �rI����RzI�E�apW �X.,u)��s�j*� J��#,ll� N��r �� j�d exclu�`�?5l. no ad�9a�% m��R>�f h�7ing �<a-we�? �x *2% =D.) !iAT@FN�M8>Ѽ ����.�٥+& *_ pId% ��5on�8%�c&h�o=8�p]�A� quanJes�g^f�irr),�3��m,*�$N. M�m�h(�g)%_�is ��m% &� @Q+nW��r&c �)[����(A��^/Ũ.�a�:�) �^}!�AJEj�v)�.�A�6%��CUځ>$U� J6�f���\ spra|_I�al���Av�ba@l"�A=Bs�;�c��scoJ)�pip,{<" Buil��Ւ%�N� �S�$ �Han�� V�e��L)�) aE]A !� a ite��D�*�ie��B�5d! c�>�Gs�P��ropri��sZ.��A: eachd%�>dis�"V 3% [�w. O�2�)n� o� �F'>$ o�!*lQ*���t&!��1MZ�Qa� %&M�"�/E��A::��2%�"z6(�r &��!! f�)12E�".H"� NIo����FAkAll%� cV%�cli�ha��N=A^re-�n5doc�av����ctI��bed�d tickT š��a 3 @� A%�K�+�m*M����.� :"� !MEn hy�A�l��gno&o (2*or�+�K7�Z� typ%�����o�%�aq���QLC��u!a2�*8Q�U*o�TK�� �21� war�`-�Z!�hBEi , I� 2�1-!�[!t!P3pӓt��rstaJU%��%4"61aL�E|:ar6�&Xs�5(2�or �!�yk�i� �a�"���s"���#e�.�ff"�e2Cd"�!�s�AD!-I .HyXaz�M�-of)�O��� Iu�1]U]!J�MoH Dru�dSupI|�+A>: ^�Pb�"or�Xv�3jA}�E��h*��re�HIu�j�&= 8g�56:W $�; budg�!R+1��F�!G��ѕV:-�d"��lYA�2� * ,�ol�(n�)бK, nur-5$ _� �� � (�m$? >�G 4-,"�ҁ�laM�s�9�l��m*� 75�i�.V82rb"�TE� D%�� 2.� A�3!��m��Jsa;��5B� )�sum�&V0�!I:�A"�Z! |� �:B[Q�:�^� ̑go "fixAn�!�yA2>�a��� � �N"& 6%�\:Y�sfG?V;�Xa�m� !���2K*�7O��n���26'Z.l��t%&\Q���FB�-#1z�E���~�4A=�LU�'6IBJg aM�o�q*17��MK�wE�I�v6���*��!5MXXS g�z�� ����An�Q��toF�b�M�Z ���i��}5u��"� � . S� �1� ODQ D1+ ��2�-��%�E!� an([2U�)4*If&� �M*�B�}BV�,U�YhJ�.��a�� �Jy�O�  ��DF b6)!e9%!9)C5(�iaeM�*I�L� ��c�'*:4 RupepLKҊIM�1%veݎtolbft&!Do�(�US$ >�1 ex��� E�1kUSD�31{. Mdoftz Q a\Qe���� ljw9 a/�ParI�?( m�7�Jhlno��h�Z�1�F�no 6H=�u�8}/[��8a*[?b:��q"@B!�:�;��J�,gg�gt�M��_r��� uppl0E%A .?4uX��Tt �������A���"�I�co&Mmaa#� Ah" �K �\dapB��n�� �Yŕ2W-�.y1kry �o0�e*�s�8E�&s}�ZI� lape=�G��[�NWʞsuz��U~���no؋�8b�u! s�s+V�yd�A�h:�2C��u=�!���?>>!� �K�"��u� �&%�~`�itu!�a�s� bo��he.>JW!,�� E|"� %anonym%�p��M*� l1�F�*�1Չ����F97�#36E�O%l compgo�(�*�����in"b. A�[�E))"��y�e5��[.�s.! )�:�216�9)= &5 s�p�K� d�-��FNj. �3��DEstj d2�  B[ ��rea Va���r�0QK@NcJZ�)(��p eY�2.� s��&� j �F�%�:>�'�1�-��h ��N�t H� ]E,>��.�.� Ie� !�> ASF>�1���##z � !������ɩ/�ofZ�byWD�Gd B�oh�`��*� .W 1u-: #EB� m �#.�uJj&�KT�  5eCa�%�:��ex�nM7͚V�6m�ke�"�1%�Z!�:WoL,  , 661;�K!l6y(,84�258; 34%� .:iW�F K5�]5s21K.�)�6~, 71% �A�da *t��AHF�,-�E�o�599�87-3 n%�&� ��N�L�&)B;�:!NJ�L!>]MT]>Lof�w<0:Yh�)M` el�R!IHp(��L^�La��?&=!{ densS =edFU2?0, "( Xact�&0R*�'�Qmb- "�*AiD2T#-YN!"+6���R�:�:n�2�a�&� a��Ic�H���;E�2�,�U�!�[GDP� QII1�922!f�#W�g�S� >R ��5�2yPV�.�5T&�!A�U�—� xP6]d—�>l�kingnh��.'�e�o��sQ [4�� �\�$ �o�l3ǤWh�0q�P_�/e$ ���݂�Ez MG2�� =� � n�*� Cp��n, %1.:��:� :�-!>",L�op!��BtH6�%%�_/b��'� 5.mKu .���d��� 42ABQs:�:�Q*P c"� *�qnt�IJc 03.g�fa6���— 51 5�&0in Panama [35?��K88X#Cub!0]—��by~!�i�-�&L!$ 6a���+l#���sT�MS�/! e<%�ingc@F���,�!�� n=T�1onI�X� )�� R /*�3AA/�i2m"*W"a�J��>~9vq���x��!e�%�foc;C ��hn�%#%mP,�'-�" in-kiK^�� 4Zc�� �(�!��b"�:�$ devoa��.�)ty6�:b6�@%�r�.�A#!��b"�6�#om_du�E�#.)I iC�F�#N�Ct"�n����N� B * $*�'� Kup��3aM5nd*s iRam�S!uFe�� �\`L�!e!0NL!f�!5A,�)�mY�ly"�_tT�7�;vWla�lend4��g�0�����b!�e2� e�-����� b� ��2�V��V�V�F�9��Us&7F<� aI"Ea��s��Ftu�[8 , 3��s�b��-m�m�2R �US$714��"u��15�%�agf� 7�X, =1Ȇ6}PI>�Y0:Y� (�3g�N Brazil [ �W��;}Q�!'� �&�5W#�<6��Z1%���2�3� � mpon�&� &C |d�a����)�8!�@NJ�g*f%t�5S��V2: 259�>/4�:ex�a}Malay3W �� 40�MA��a��e+A�!X��6h�DZDF@��$q�� �u<�6�_mby���A99 . �5� 7�G� ��T�. A�n�'qQm��ήa3��&�( OP:O���io��6+� w%�ex��$/n�yon. pisoX1 �,�"&6�D6�K�u`V�i*�% ��� l�I�(044.�-=3*�|9#w�Ts�U�E>�AsB 02�92�2e 5;��� :v �:5N�Yf� �9WE��[gpoFl��s�l*V2�����>� Z?� =%b�r���v � �  � Uo lso * ,�CEDin�Y�?� n�\��e��ZB�#vB'_9���ft &(�� �\".��6n5pu72N�*Lc,e�%�QZ��/�; erv��Eg|�#M� V�]��*� 5- ���D"�08""/,�%&a��e�%�e�CV[ A��-! �h�&�M2� � gI�͖�exViv8��w�An-AN�P;u5si}"*� �}:&zUQ�V iKs1Ase ��w�=�:����!%&!�aaj63/��[%Y���H"� �H��X"2a��"}D2#m�k@�6� ��� 463 ( 80/A.BHN� 2004�3��251T�421&9&4��46&218&��9 112HND�C� V(W�/*e�yMA*47,�dej m� �n�jiՖ�C�)Lao�q1�E6�i � hB�  em�in-depthA�e��č?2�2I"�)��.f;�"w�E"!�cdern "e���PaleolU�cm�ter-ga��" Nfar�����N7Ec@sdeb� . HaplogͿR1b1b2��-M269��B� ��V�Y-����linea�]a=o�zR���c�2Kc;by 110"�hmeFIBC��� !\-�� 2& orig,�` � _(��"�g"o_\'�-�E�tsk�rosatel�Y�+e����ex.[rc�a�(!6�$via AnatolB�u"�W9��#ken�e�U m� �EIvh5���5$!�at JH5NY 5�m8%-a��s�Ŵ?�v�nA=.�|  m�{ ZC� �����w �R�S!la- cult#�S*i Bn��wq!.{biN/eTA���gr-B%�AFH�����e mitochond� DNAQ]Ru�� ,�n mal7 {~ei��. E1_[e&�<>`genk~]UaR�!�^ y�u ��!�VOi�A|�PC�l�OM�"is\"catW �7 �hu�� M mͅM��l��Me~�z∼40�{�� ago ( KYA� }0} l!�glaJ;�.�Hi���%i sulaeIboQ7ta|vQ*Balkan�f���rth�7rec �I���'fugia�14�a@�st*JU�]�!ad �!�agr��6d+ Fert�Cre!�u�ar)�� starE 6y�,�0��jItL=��h����N��[3]oX�1)�8thAI���my 6]mM�)L��h�f +�B.�G�u grap��y�3 b��� � `wh]dyR��t!\�zmo;s^RofE�-A�ad�*�8�� bve.�.�%���� u�� inno���o "�m.�( 0�ZlreU���r�+Ef�ni�a`��.wf>Awa�*aaM8.d�Ng�hmiG�4���`�a er���84WE�OA[drift��h�0hT6A�y�g�a!U ���a> �!�a�rI'_��� ��Sd���w[ n� �6� Tmo$[�bin��q(2� a�� �*Y�E��.] K�/�/ac*��d~!M(�� s E , J�j,%MI [�k ��� ����9�� an�e�1��e��sup��!~Y�c N�w�cBT+��!"��[ �[ e��f12%�屢Tur�)�5�z _śB%mAMQ5S*N  �S n=� s!}*>�6,&hg ͹ &� p i�^� �7��y� s a�=h��!b� \]&� �� q!�r� B�2&= !EF� ��j >� I&� �� t2o�Fj� mR� Un���ew�� U�V eS=M�: fV�r���v-�&a ��. T]h�?��8 gM,%�asr�d�at��of ,.� -Xi�uHa�A��nine-l�F"�%�Bs"V.1;H-S�ca�Y-M�j�������(Q E�] :y�a�5� ��6L ge:� aq!��gofRy ��o| %BS� ���O?�Z�1n"�\5d� ʼnasR�%r"��텤�Qo$s�X*|%�Q]it\ꅖCe�A�H� Jgr?��FiT2S�Wlt a�noy8 .� �1(( R2 = :(06; p268�Sa5FEon �} *Y:U3586V00�0, �e���9�m[(ȹon ] infl7eEl��7�������5�-�|usO"��` !�y�2� hyU�� two� 8�* �sL�da5_&�s/�3"��{ ��q : post�r6� .�"Jf�)^�u�#R뙬FK��%�-�%��L�a��6 phyl���AXono9 ng>h�����!H�d�0a�Z"��859.-�����a��.(<aR�s"w��)�e��)( : 746g��w}li����^n�i�%#�&�$le-step mua˞Ol����X M�21:2�4~�),�n�bpwS !i � �?r�t ��"mNc���n-hA�*seXLisa��A�>~%D E� " yl��� n "��A�hov=SQ�� EA�3����aa tatu yr� N�e���.���(�ρ�U+ ��a2 9g D%�0o.ng9aMJ�P� D-Ev��E. D���hOT�r��*90 ncesc[ TMRCt-�54.5R] ? M� � ���a!v���s�y"!2%&4�ol�  vX��2n CC�l9_� 89 y [95%!�f�@caKou ( C�i: G�66��1$0;w!�A4pyou�CornwA�(74( [�v76�wx777QA��9an�5��f is % 512 �� CI: �57}z�63��eiow �of�.>( 02%N� . 30�5��uee�er�����E0��Uqcan� �g�^ec�! ��� �c1�]�.isZ��x�>siJ�a1A;�)-�Y�.� &� 3x !����l3?�"��U��Q%W M�9.�%�T }4arma�p�si�u@at�?��/! � b�I-�.f>i!t��!k A<*�ly �l�1rg> 90> 0�8 �eA����" b������g�am->:� �|p#g"� FB� 7f6� ��veB�31:� 124;� 4A0. P�*���� –�NJ/ '�/Ut)�an�&(��e&�5)*�j&�/:�)b�R!D6Nsub�ׅ�{�A~J�f�&��AA�. L�t��6ѵ�5�e$gf�d�..�t�||f�w�.}(i0�bm!m1�� �a~)8+"�bw (���*��at��y������a6J=23t{A � f!)�.)Y�5�ch"� b(i� a�! fron-�w!�M"h}%zŎ�#a&�^@&������QUa!�)�6 "� �a�X�ir>[�S��aR3�W�ec!xed ����uR�|�du�  : ��,�vn!�Q�����.&��8Y�E�a! "�sO�!k6�Qana�q8Na�F#क़E� 81b ( E-M81 ) [1�6] , which increases in frequency and reduc ��diversity from east to west . In sub-Saharan Africa , hgE1b1a ( E-M2 ) underwent a massive expansion associated with the Bantu expansion [17� [18] y�India , the spread of agriculture has been associated with 3,introduction9Tseveral Y lineages [19sand!#Japan ,$within hgO��(Yayoi migra`[20J)y8%–20CE�m� ,o75 87%9�d( Table S1 ) ; our finding�refa=challe!�(their tradiA� al “MesQ�Drelict” status ,%fin.`�{ir use A� proxy%I6Ci6al populI�in admix��modella;of=52|preQ�[2)��daxaMAu`-Y8-As amoB�reflec!�!�E�AFs�A-dgenome ? Mitochondrial DNA�cer!�ly�senaхXe�2 pic�: no �D–�Cc�A]discerni!�, most�hava�.� TMRCA [23�W�0hgH [24] V [25] e^signa~�postglac�9!���PIberian peninsula . D:%Hinvolves both femal![nd I�Ndispar�� betw��mt!8,:�atterna uld aaM �an�Z嫡dA�nsmit!�rep��$ve successE�� farmerTmA���a!�,us hunter-ga!�(,��4out a correspoeF5�ce��5; two group��T�?w�l���9r61A�t,—as sugges�by%H high\@wth rate observed��. Simi��concl��sI?b!}reach 5!�B:d(a�curE�'-speaka�y�s carr�Jny-�ɭ8at2%#Bn[26] )�G��-��.�to��A<���9O��Sa�studie �found .bB�I2aut���oci [+ [27��By!Rtr� ,�AF8me-wide SNP typ�Hsurveys [28]–[30]��T a basic south–north�Ci{ or g�����clu�� greater)� in%Hym�zo�I�dA�c�j3 -depth� ly�ev�� cE���rincim�)�s)�!��&��oloniz {,2n.�re:)��=��ul��  �Hk A %ern�: [3� �_distin� :�geograph�p�{of vari �-7.�n thos���m� sexa",cific factorY ]!e"&T �* resttIY � yeo 4reveal definit��inform �$. DetailedU� of X2?!)Y�$haplotypes� miseaefur�  illumin�h!-rol�;m���E#��. M"we� rui�� �ed!�� , follow!et)�approval�� Leic�(rshire Rese  E0s Comm�1�e I�� ���Un� � of Ferrar? PavG !!Exeaj Plyma� . A to�$of 2 , 574��s8 m5�)$ , as�w�s.1based on�.R � �res ,)D!���ādM269 [17��Ing.F5T PCR �A�c us-J� �rs 5′-CTAAAGATCAGAGTATCTCCCTTTG-3′ ! (ATTTCTAG&TCACT-TAC '  TAGC�Z  w naly�by di�ڡ�EBstNI�� cleaX�-C-� le2M ^ . S�1|�F�E�)A��232@. Greek% Serb� �s) too small%�9�-AmA e�j�e&ilE Networ`(i� ��daA�,".�M5�I3lo6�Ync� layedm�0Surfer 8 . 02!��i|!�lex1 szat%sb0de� ,"Br�is nee\ to�b� E �ve impor�B��bd"J . Weon���� exaEtEjam�M�twZ. PV!�a�Finu�51i�II(ly overlaid) fluctu��cME� ,I�iaGfi a!��*Bper��-�repet$.�.--� task�i��dem�s��in��aspI�ap) Astng �� outc� such�err�*2[1]��thr�[� v%�?orc�!�E^[4*�0body sway durTquiet�\a{ walk[6 , �1&�� trajector [� 9 i�Acoord�A����[10� R� al��A3ro�.X . It��probaA<B�,tein who rai> a� na3-�d e-of-fre�A8lem when he fir ���eve skilakblackhano�nsist�hite anvil due�var�2@ �hammer.�E[mpt TA�%�ofy�j exame a�tea�a)8spaF P�E��)�iL* window� eluc PmeG isms�G��b�aq[1A�1Fo6��cz!s F�smulti�)���1�sianeousl?�I&system�earQ #.�� @ask-relevant dime!a�w��a it unreg4 n� ��_.X-[%��#�-ly regar��%^� !! �� –1X!5�Iu �.g��i:  a �(by feedback(�/. crit� er!�Zop� l;��in" F�, i .��pii Qor�nMgA�R.o,%8�%=)�a�ly� stige!�he areaL ��.>a stra� ��Yu�y|wpropo�5to�)�q i � aimEfminimizIh4!E�a]no�oa�?��M. V��-��stN)��u �dis� �j�G6 �X elf- ]zA�pro�e*��Thi �.u!sI�funda| %ro�7AFneu�m1�%1�~��� i4a* nt��n�(. S8-2re� N!Q.�6@ �cfO �$parse , ex-!8���� �,��-�{ f� character*/"R ["�# a se�of", S`a� lleagz!w�  step"� !4de�E�F�i/� ��al%8E�B��� acquin o["a�xA gHA�o A-aE�le solq$adet� ��:in�ntEo �qto2�is)� ed [�22�"5$ Inte�ing��aEFn�ud�^�  %�ers’ �al23isA��6�w��"� �m g A�k reGc o%z E�*( ^�1F�%'v���'� clai�" 6 �zalloA�!�n^�[9A ore�K elegax�#$result mayG ' is�at�% �.�a����r1�be�#!be�# c$e_m%u � o�ng�!2at2hYb�� nefi8"zv�;A�realm!*pera� ion:2Iin sens؁�al@ n enhH 7�M���;i)��s� s�#astic!Ro $[28–�. How7 -b� ot a= "_ �!�Z�is lim�toaz��j,ub-thresholdB���wXg ;�)extram�"�!et we k�'C �U�&�U�q"!�Z 0}G�}of��� +�����25 , � It remain� �n i�(i� .�g�8faM�es ^�. M�&�a|, $.Lit�8��m6� � sourP.,! exec��� ��comma�([�3� B,J#� 5or un�%t��I�I�y�[3� �� accu��em��ex�|lX&amdsZ, s� plan���a�a\curba(�Vworld [4F#� � �!:� aD5��nI2�nH! way� �$Ac�Io���Mor zer� B��% themhe hyp��.�2ysE "dl6�'� &�e, depe[o��-)�',(Aq)sD�~"�.�t�#��we+� �er)bEE)� r���� d��ac�$ (er )��-r W�J ���&c!��� �T9t"� �2]!�s!��B�.J de��+*\ fh*e*��FB!�ed��>� fppl$vis&perE��E!�a tu) -by- +�+o9A\�"�� G"� d &�G�E���Il�"� n�A plet!�&� e�A�A Vc�A�ion*�-��Ipredi> s�A�).��AY:�%�psn�a newa-"hti-a 8I�"� .�2% �B[ prevz�*�d�a . Al��ticipa+�nä��purb ����'YQm\s�!C-a$ewD$a��nd \p����vt��Y���z �!Xn)It,al Review Bo�of Pe�"R$yf)M�]^��9]�peofap1�ef] e��e���:���).� EWde� , Zgof Bayes�sY= s [!/`4��op�&�,a Kalman fil��,��uA��a�ˁc,��) �R�� G � asa9. F,��*o � {� e:�"� ����n7��Z�c�A`�.�$match welli�a( l hu!�s* s [4� Thir}wLL"�modt%.����� !1BE)��:5F�H_ >��2.]z��ta�b�� $40]: x^k|k� =Ax^  ( 1PPAT+Q ( 2� �  x^O y� ���#t 1-�caC)h��aOY$E!, �,Aktr�5matrixi��E�a6Hn�.� denoX w1iori (1C ed ): recei\T�� k-|6�hator%���,At9in4.!e� j'P%ba��r1'pa�g .�15�coUV��k-1%�6�5�D madei���ss  &|*∼N ( a�Q��ach-�2Oi�qq�}�s: yk=ZAeHU�( ( 3 ) Sk=HQ�4HT+R ( 4 ) Kk=S:1�4A=A�(+Kkyk ( 6 )�(= ( I−KkH & ( 7U�Z�!���5�, H!gi M��mapj se��Q� 7�!aeGit[set�� [11]�ek two-"�T(9j'se�Z�*e of + bep7a8y��) al (s inno �) �driO*|��, SD]U ��y�&x"�)�) ]� -�jV�). "-Eq 4� ��5� K$^7�g!u�xg(6Kk(� $n�i�0a N ntag![a�dz�&HJ<�v# u.!�F�����O'+��#s���s!�YAE� af= U�9 U�y�6K L=�isZ�(!paV�@ɥ5)")�to��4&k<1 p: �+434#2���takes* .7Jg,simplicC",!J�, Phe�)Fw*a fast��!�a sa#1�,W 4h a{ B [pjby SmUn2[4�+)�� ?�!7�'u�s� � B&utp�'>!su� &�'hid�)T�7�#A�Q] diag�(�&c5We�g�:as A=[�(99800 75^)Q=[�%4600146]�(7iR = 3�* × )�'�%�� ain cho2 �B� val]��*-|��7clEo8 .�Ix ��k� ɝ n�achie" U�!� � sh�be} rop�!�9��)#t�"} "�*� !s digm�6C!e�oZ��to�jc�eldAWA�aK defa[E1L.(!�qu>=fAbyAV�( devi)iove�W�BsM/mou��b�6x;!� pn09*, %92&K.nst� [ o� mpen0d��5�asympt� 2- half�vQH�� �0 }35�6;�&pō�/ ,e�&F"�%� ��'e�confirm�?<ed�\#a�3obust�n��var�%eR 9�s!����"} 10 (��R�!��Ge� c.��� go�� A-Iv �$;s�J>10a�-�9�8r dyna�? �%den�A�6��;�NA,$recur�A,�����is @h �izA�o1�n��6of !*arbitr!^uni45�;u .A��tea�s�� same.�( A ,�Fnd��"� � �g�V .J�����Z� Eq� 78is 2/2,&?�ady�yQ( a`*o.��edA- ^O  wI� �e�B�,Zk�� 2ed9�XU%�"�of�u-�)  2<r%�A?A�i�a�alc�!-X�-�}&�&i�s��all�M�")(iW�to"lud=�9�t!�� ѡubt9�����3Z!)9)kA� 1-wN! ^ &�:c� emplo�1N&V�2|r0rge� pUx�n�c�fashiEE>�]�n)p>�c�;)3fi�.�.fu�4 y = a + be−o�Dd H>cA�a�i�j�%�-�Z < !#�CQ�H�R&��*j �-se�/�&TA1a� �&K.�iT!<�q"� i4�%"!��QʹRAW|W'h�.����a< AJf� �1Ax1A�b�uC�2 P�: <E�&'� e�2 ("(%!�Mu\4.�itn�P[1/16 1/8 1/4 1 4 8 1�2-�`)�"�� q �.�8�7 n� K.�!�deA"N!�I� un ��+�� .-w�/2K ^!<�v6�=C� � -be���%�seMCiv*1U4� � Iu in QAE�atI� W� fV��$�>�l � . Bs;��E�� y=mod��v� uti@� "B�3�� !�2��Gd� inFir-Yc��recruQ a "h<90 sub�+S2���$4���/ n10%���+&�U �xb!H orde� ��su$bal��d"1��c? W8A� � �� ward..]�(�0�5 (�s�'"� �'� Exp�JCtt:t@-�k��e&�u Y�� isom�%�6.EcD$. magnK J.:�}�ah.�% Rlevel�(. �o�#�!� t�1r i�[�! !rExp1-&5�D� ar ,!.er-� hA�%��-H)_Z@A� a t-top4 1Az T�7� RY%1concea�-yYrV��scr�D� $fingertip v5 �Wr1�2�ALy��n )E infr8marker ( CodamoS0, Charnwood DE a@UK;A�p�n��~200 Hz�>.u#!8 � ;�a��custo�*d Matlab�gram (2009b; hWor�N� M)bVSՄ�:%lT� or��as�briefly.w!%5 begi�"�a endS(K&8[4>EW�4�=Ix*|p�toM?J�sendpot�Z�t6q6�����<48 \Y!"�;Z  block�?S .��� 8?A�8)I5e��4d ����i�?�,e�or�\�nu �, �e a6�&�1qg6Yh�7�ur!�l�7o�e .k�#"= �)|) &� ���&v�P!�irIL5��he� �i��  �A-*6u�A�l� B��i4d�5F*vi��K� K�$Z8!�BmMe@Luke?)^!A�!�est e���|*���l�&& U�,�)mSn$'R2&|�=)}2qeA�3 a�\X=. AU�$��C"i began ��%!v�[!\2�E�ach B��"�A)� �e-�� e#  )p��I͜�d��.�S 6�l6� ɩH&��rgeQDAn�����(10-pixel-di��MI:/150 mm as&� !"i6uY�r�B�� poss�M�'!�wo��5]� D^7q(r& $w0°%� �rp1-ahwLL(9),�� }�� he 1/Ner3$56%�}Uea1*� � wi��/5�wo se� t�4@�"��=ag�{f"familiarLhemse�Na�%� ��p�8!K2"T&f�zTcB� y�!!7 �e47>1��A.Y]a300�2|-c�K�R"�alo�!� rtho�9���E�6�A w�;s�=plC�5S��� W�:5�� ly 2,B% , 1 �5%Ek�RI���Bd:X�E��an [ina� a��6g Ai�+mOM-e����(1�ɕphl!� *� ��R� 5 sk!�A��M �# �:f�5(4W z_Spe�$s�J�( C-�ՠsc8! !�R�!�}J�P�mxi�M�1a:v-�y& A�aY+&Q�e� L�:�Psub�t2� -��u��3n 2��a��Z� -�N�?e��2K1!;* L-��5�z�/y�HI�D�st�%��s�9��;�*z�E@a&� ��!� [;±1V/±30]m�"We�� �JA�!at ���J�6��$9e�su3��$h.W&�.<&�-n���sa E��.J$!<-��10�i� 10)�.�))A�'3�+� \ f46�5 /56ɒ"� E/B��)ful�9RJ�E!�� $�{[s�8a1�4s"�8� ���3�ata=( ��* *2g � ��6d� ac� l\*� �)[di� t5%�u� e����y�t-hoc>Ei�XB�5�G�e�}Y��h�Y"� a��a�prece�2�>���*�;6��"F' �on� p�QJ"-��{^ 2a^40%I~%W9 T&*�H,��%{&cC��A{:�!��� numb- eA�52�!I���ޭ�&%�B �&| e75mm or��[ �A\,s�9�*K,ݭ� !� !�&�[4"l<&�% etup%�m6:*� �YxpaAA+ ,V� �XMgR!�we��1O^8R�16N��qh?) a�o aV�6c� R!S2w J�%� mani�ZB cro%Da�apIn�@Vto��(2'%�`iH�/-fM3� c4�Q9O ��!�!��K� A�b �� F 2dropp�:t' 5mm/�A� �2\m� I�-�"a =;�/)R�����U�e��pE��_�6eU!�JreH �Rt�T)��t>5� .w�c�*rs�F("�J�7 � %� �-!�s�8!��td3:%$1&$9 ��=�O2g�0>uto�2(�  �am8$or�a@P!Z%��N"� �)[49(b1&@F P�!C �)��Aw66!�"C � �1$i0w6A� U*���UV>2�n term�SDA.}B. P�7&Rexhibit��*U&n.9� ��AA�9 rger�cefL0�eF��� FA�:!��� &-�^x����s � 6]N����sA�"e�(d�"e�i�&!Z��W �i���MI!�"z�?='!F::S,S r>Pi�ree 6Ni}R7v.X+t�A��}@���1�.�9ofnQ oT�'& �a8 %�&9mv9� as�ji6,*�_"[j/$BNsuAR�y�r2} nTh�bq�0a/:dv�d� �P�( 2AF'TAm�� � �E&A�to jud�%��+6�wO�Ei�-�Oe=�Ѧ%2��F+ 8�� 4 �D�O6�-Iix:K�R  �#�7Ridd�k�[spa /or� m!�6/xI� DF�! ��&�l�_s_75_,%xq(� -st5.u!�ter�a>&00,�re�hce j !�al?��L M-�kdu�°$WAe�.Y Rc��!&B�z��.\�F N� ��� ±��M ±1�T",:�-t��Z�A�"��!�l� ckery%<%I =:�%�q�i8wh`:s�<5�e�a�W or d"N s,;E?E�6�F��wn-l� or` - �R�M�qn�on�:�{\�2R arrow a  b�? �'ct-answ�i !H�XI�2�Y�1�:��(mLDIsj� �.��K- >paii\҉��q e� �a� g ��F.Y/*�as σA��o�fu -fhe*E"psychD- g)!v[�by �/ fmin�b algorithmrM�$ ( R1: Math�&�$US�$�5c* ed 5"�A�DREAM2 x�collab�Kve�BsetQ,&�B,"y-�j����&� Qy�(��Qer���_"�3 m13ha�m��.ZE kauDof*� �I�nd6&� "�,A m����� *�y%>�=[5107;  [5�d�ve(ktyUjen:3����5[53–5GN��&  m�i\e 1 ;(AJI�Ea�*F2r is 13��Y _"� .� %�.Ms %�re*� "PM�#.m sUz�v ��J|M/�ximum�`er*��CcE�*9S |is1�rW?�?I�e*�Y6u-A|�k *B[%�:W�ce�V ) UOstry  >�& ( 20yb[5WYVahdat6 ,[AJAxWei64 )Q�atV�Bd���:�3-�r&5" of�Fas�-���V5Mattar� ��4]J took��&�����PQNi!q )/�vqo�_Fernan�d2G�,m�Y^iv159 `*�A.��KdeE? ��fh�?3�s�H��BA� ���3*bb�k(Bx3);a��vq9s /8 gnif~2��of� *��x-Yѫi���`� /ZMs �3F15� g, 2�E3A�&meiM&M, 1�,>�,J�,q of2�m�.:B7123Y8(�0f��%Aic�:� -�er20. 36± �gE pool&�6%-�PEn�n�8u3.��5i)Yb�fa��c��� z-sco�gAs � s*TKtoFoutli"D`�C�te5n-W�/c>)�="(K. �d4�U3ss�8�.�\&�L�>p�L�a�.��)u�2���6`-%am�?'^ &�2L�T w� is&�;45�J-q beca M!?(-�X&9XsWs�fulj-8.�!�c� V�^p&*� �=4AJF��t3$ (�}%�%.�:�9)ʼn� situQ"� &�0e�ld!!� �Vrapidly{BEY�7%1$Ta5�Y1.�y2 ��z$h�q�e�t!$�5+��aA�#�"�e�L�x 4!|~l �!ҁ�.{6LA�A�I�M^u��a�%�%Z.?`^s�:l�(�D{>![0n�a�J-����#_um2~{g�r��?5C��� tjng.�1��. Any*� �V0:9,2�9�]Wo�!�!�ղ�,!Kd�.H(epap�Dnt1�wpTQ�&�&lotE�>�\*Uh%�mt��#��;@=pA � L" >�d�A�š�%QW� ���B��1 "�&m&aVa�/:�[��y�y. Jmu ^s�=1�� AlsoMU��!R~;�!���oU%��An1TPš�$� zz8=%�"oAo"�tr6"�&�Jr�3n�_.nV�aaM�U�"�R�. SJU; XgAZd&S7*�inv��2�fS�y ��hq s~ "E:rHX.� �%6�vel�W@z�*� . A �.e.M[�Kk 8.�e�o��)�!iSB���*F5&� |.F5�& I a�&�,a <s�%a�)d:!� QF"J(oft�"V' � D� �[�$=��V�( Z.� ( gGA-=�!8FA�5��*"�'6%)%�rA�pe-*�A:<*�,"� �.��?J�&� >0*�:�AA .ot6$$in oYj y�<* &i�J�)�5G !J�5%���.(E  � � 5���a&a:�43"�.5( t19 = �{5�p <�00�)�SDi @�v5.�I P02�"22m mean±SEM�K73 #1�/!�A" �J��� &�"= 5� �*.6I% 3 � I)Fmm)F790jFFx1C��|ZC%Q7 �2u� . 94  14mm.��0nd � �^�6 �� 6� le H��b%B�� uR %�"��ɂ.11{2�n!B6M23 �!9C 119�$�;r�F:�mXW )A�AQ �B/Bt- .,�?���,2^iN�17Prn��4 �03NE 2M 02N�s4 2N.�V�b P�� j2!�a ? .:��t"�5��j�5ur�g� � �8Fn ' J��R�kfin.d.�)�Ѭ>�,JKB�44m(:�' �g�pVS� �>�6�!R��ly4B�AH��i�I\V%�� '( 1eH#B<7 . 2 0]�b�3�5�!4AE8±���47�% �156�Hcsiʭ;FA�B�loX(!�P,��11 �b�!�&)>"& in-}ari�bx � @.'�8as�D�&�}O �� ' J�Bfo5&� ".Onon� ���O4��8m�7Vm@�]�I|� re-a�T� �!�)�%��Z*� A�'=mm �] nI���#2lt ex&�+=��vme0U2wM5�  �{�����.�7%%3�� A1 15ͽ�: . I7x���V42���*��O�|�*� (�� ��g�f1T�s����$p�A2e6>�?"�z� JXM^slE to�y:�Mu۔�*I,� g�Vic �E ^5 AY- ANOV�qo��O�* 3emq^.8!�.W 5uils:(�s×'��|)-m�e �aAir�!�%&&-��� �+ ��+h��!*�F (�*7�=� 5.� 23�N'�8Q24E��,! � B�N�A&.�a�>o�|2���{88d:���6 �%16� �Exť2[ EIe�s�g�+inE� ���q$��)?��o2�/-�_#�.�2�/*�K�&�  !�BMD�FC.T!�eIA@L.�7b lo䍁�! !.�σs�ai�"� 2�)t�Ve6�)f�)T4 09*� � 6�A,. B��Cb ��01.C.?!��4% >��N�*� P�-6.�tP 5J<P7 26� i�I#�!���]E��S:�"*�a"~k�@n/-i4Q0�1>e�ᐵqNV !�6F�ach. 4l6�j �i� ��-���A�5J�]f��to�� 6�6�{;��A6�D:�Da(��ooo�B ��(7 ���3*�$A ��!�={ c \)<p$&j�tura�. ��z���2h)�es"�r�0��. 2� .E�,�L $ .Z+. ��.�ɡ�-;:BCN�Ē��o-%.�E� �var"jcan� | I� ’s:�6E� ���%�s0�d�*"��^e�tUy@!���.�N*�HJ�!6F�A}� J@� a�� �IatB�����6 ���1.�A�E�,In"X"��0 �'h &�)}*�b,"D!�6��? α =U05 & p� 8%�JI ��$ 3% ]hen� d M�3to��]RėZ33Zto��. 9$/%�V��V�8088Q 18TK�-�to20�!2E}Ax6 N�*9��VA�)�=���-Gbe6� @ � !N1MxM�+rya�� . �_q��;�@���<�3] J: .d%��y�'za�Wrv��unlik�. Fur\ h�}�Z����r�C�1faWo-1h�e�.�I�*}!eq,Л��by WuD3E�s���.S�e�A76%� 4���!i�vQc IRw�J+�5P��1 /G2H 0�;;]��:�.�e�Cs� l.eVIlˋ{�%�r"=dR$d&� �t����lyA�;�dIe6$)P6'x���9@321 A�� w�^d�1�ʉ�E���1�I�t��ed6R� �W,u� inke�]�D:յ%;suL} v. �4VR&m�p �*�!��/�Q*n��t��T. L� �1 �a:�"v"moU�iͧv����B1&,%�thoug�Zy| �']V*� fA$B�= j�a>RC%�-�����6��=N��ur U&����pS<"e�a�� sp2�%�� �<` �r 5N. C�"�.�~�5��tLe�)a� �1 ,��B ,�܁A��W;� - jO#*V*�!�% i.R� �F>d�ٹ�i&1,N�m.X.� � "}�N�*,�(x*�>�! �_�! � seem��!g�W�4M8B�|qualit*Fly�lae�P��wry�aNForRw3)��X1�9ig�3PM�U�}Q6"���Q�N�&%� �g�Tas�U.c���aCB *�)���B^"0#�7Y by�Bh(!m�!�e�te�{# 2�b�H2 s!)�nervousq0-: comb�a'"�C� e�o�!�!�A��t�Qrio�Ac�w(�"j&y DO)ec non-w1%5 *B% =4^ ��0[+: �)�scenariK1;p"��sA���?Ѯl$exQ�ai�t�3�J,c&0|Ucu6�y2dd1a.�i:��a�fi��-�]6�=R<�VvV�-��%�q[%P. Hig�2�!�-|I��Ea"�&���Arurޜ (�Mu%�� "�X.ra�wl����"����mZ� �,ɕ@:at�J��E�!=CoB�K3"�Z���/ Q1*.��Hll�� ^�*��"�� ��� قU�%`�A>����[���0:Q]�[ensE�5�_� Jr)�1 �{3e#o (� �!aP:0 %�:�.*�hIi�� 5 ."~j"�.sxl99m10%s�M��-C{�\�<l"�a��nt��lY^�5 e�QA�s]%A&� "� ��+�<(^e-�5P6�)��( p5��w*6u�-wcbe��=�[�� ���)!Eij>����uk.W� �I�r�&� 5�}vicNt��(%@AcB�.�is�, !'B�.�:,��%�1:!&�'F&#N� �*�{i��")r*v � ��� @Q ����rd05%ʁ] )`ɂ��AwI��ݹ�cs!���_�Qre� !�� usc�= pind"�end�,�>zLN�$}w9Z�teE>oyS�*�^l physLN �&v�uhU�� �d&�P����im��M C jtInotice���caJNt,bea�ply�%��"�K t[5�H57lS Mean�EU�9�3"�0 u2Y�:��<�� EE st!�.B�a�3N6)IE~ta!/plfVof 72 �j�oA�"RZ�O�=�ly�¥a�!<�!�[5?`InG>�AF?n�4 >*dd�V/U9u'�AP 8c9���\Ѝ�^�W&�V7*�36���5��\9ea$e� ��-�YZ�q�!ObN_7=I& �!H�>�( 3S15V��.2b/2i+:��A�a�6pz�Bo!Yya�umc6<��e��9"@�,p�"Y,��}�apj� phe5�n�"%�o-aud�\y`�s�0[�]6� �+17 �.Z�7S=>5E�.)of.hϡ�� 4-���)�2�6����v!6la/"� �="0���G VN�Lr�F�s"?/ _���strim�!i��%� *X="'.�!�2�A�X22)<u�ela4R=E��_ lF-�`it�=n�RGt �P] !�R�"I���"��$:��A�&,��Dgq� �"�,.�"CE�W�Q >6�!!M<�@s�@ slowSI�S�� �<ͬ�E���'" &�|�%U�F5AF2 i`7'en ��7A.��ui!��SR�X9�2�w[2t 6��k� .xA# yp ly no3<�)&�\�dem�[io�e!S/�e0V�a�>�V_O b �i. =a��� Ureq�f��)�H*��s�X�i��B%)ar ��Ov� p!-  � ��dcsAinevit� F�iT��� g)`cjkR . n cz;�u��.!�T���@ E1�  ��%�%�2E��Zؠ!�` ��V ����/" �/*���; SE��Od.Be�@ auth* �m:�a… 6)�i��Z� k% )"�5|� o"��B��� m��F� /"+��&e#K/d�3% a_H�� �!����R:Wa �%*�("�" �x�&�T���aq�tsU�ac��Tn:l�':: %.'#��#ei**�2M!�"��=ca�Aqq�)扭k� uals]3�:IJ)��B���Q�Uځ��>�p-tuE�)lq��3tegavD]]I�� �.S.��j�@�j��u ёS!,9��J�kfe��F��Ja��cuu�(�a�A�>W"� w.�]�.��A6m�I$%6���m��R"� �Qg(3���,��ulj�mMt)}���y��TJf �l2ӰJ&F bja�*� F ��!�"s�>J�P� a�n "�lnd� �����)4�>S�;�  L.o���3/$��9Z 3 prof� �]o-0'$"�jclampi�~EC"86>��n-id �v^}Y"<�!a%A�X���i.���\-"��@�Εbd�A��lx���v pѳz 2�.Q� @b&uasV� Y*�8M�D6��)!�MM"m6/1,.�-�Ad� !L?%́&� 5I�A�yp0}D�w"_f*t3 -�f���i� is2_&ly:� . Gi�*�� -"ȓal &$�"j  !zol���� a�R� \ ��J4+�2A�!B.*-Za5H"Χ@+ubm��atR6�U�\�ճA��+a)!�i� �v=�"W!.��3L'_n"�&UjRs{g=�.k���K e� hQ&_6�EJx��6�J IemO��Gk�� ong9a��K ng!�a�A]oW". ��a\��� 0���! �_���qd]��D�l7/Q;:m�.��Y�39E"�=�M �P)��Y5!� �E� s� �ins�s: �"�$k,sR kine� � �*i*���])!|)�a6�� ��69����cNz�m/FfK�si���Av��Rw=&l1��3��FJ�! d��m&�. &�tQ %�*|KsnTFo\J�a��'�inf�f&� blur� �MEuu�&�t�A[8 E���A�it�w^�.Z�3WaO�SaGar)".� �o,ec@�1)E�aU.t8,eUamy��f��e�e2� ~�:�O!"} onD beIJ%�.��O���� ^rR n���&軁�>�?/' e����!3e5�S @X6q([�"�8�"ch.)es!�y0beO-��;�F��l3� ure � c���7a� v+�- �aC;~_ (.��NF-κB� y�!�l .�t cellV  immun�%E�mmۯ"*Ȧ�rvidiT�prolifeOb�{Y�!�rcri"�A�D#�w��j�W �>�� ctiv�}�I, RelA1� nt ��u-*�z) �acL=�!2I�- e:A, CREB-b�Zpro(�( CBP�"np�s` log p300!Eado:��Y;��e !wsi=&o�p�er/M�D gdof����B�lA:CBP/aE�exa� ri�of�o���� ,I� doma�f)6>he KIX&v)�2�>?- coup��R�������by 4< d is�\m�%alo��t�C"�<al� W�fg9�Kn�JUjJ abro�S�d�!L%�i�!B1��.KVHѩC6��^D���techniqX(,K�h .��i���4�ge��x� -� ho����n��T_�B�,na[a�4���l�,a�.3 6We �� ?�A�F4�I�nuiW��of�AQ��"99f�) loop-p�kaa2A� , +�T�--���%U�!K��G�vDr�t���#��NC�B"r��.i��2I �oe�J �ͭ_d6SoE�duc#y6��1Z�s� �hQpՉ�Pc5w[�k��B, �l0�rap�oY�!5s�Y,lo�InZ#tep��!� ��m�6f!\m!*nam�&Ulsooa��p6\CB!�-Re2p5Egp5-5]9q !p�,�e�homo-�|hetere����!�:Z�#�`�abund -��&fop*a��Il  ��sh @_�,E�Ap�VNJ\i��rel�log� !c ( RH!����'�#Kv 0۱��`%Iaw����t�"1D0�l�Re%iA)m�" guis,2m8�&!-*!�Kqos�jMq2���O �}�� ��>CM�C��)�- e��.A�u��E�t?el' 1A�m���/��7��� / cytoplasm��-�of In|Qor-f ( I)a�� A� 9 �bin2G!�-��%�9V e���᮱42a)�' . U�f.��� cascجu��'!�� ����ade'+��} �uAq leasD#-H� �t�_e�  ��5�� : 2�u N*#p�k%�n�� *���2� byu�ccB -ܱus" �&!m�� �[�p|&m�"!�!o�, �by"^enL76a�c�E��ere���{ ssem ( v“ba��2 mXery��o� 6"�}�s��:V6+��� � ��!�act�P�'��6,��2a�Y� �c*!�iU�#[4c��)����!�� >�.~�at help�bri<%�7�r� ��x6&�} arra*2���AT nteg�0�e�v=y� s [��[10�����& -re�4A�cap�� ��L ir h+�ne�>N�–acet?ng!��J;@��Z ��s�ber � m�q�MUr; s9>! � �.ܬmo�4{����K� �+%�+A�et�M%g 9IN��!��q�*.Gİ.�#� �T.� "� of�.�.�: ChIP-���seqF ,�1�� ��i����R���m$��(pre-loa,�-Z�aM!e~FպB�ԕQ;H3 lys�54/methy��H3K4me�?!� . ..mo$*2/�E:�*b6�THP�� HeLa%���I�Ogh� � �"�P� ��a��if=8O�e-:�h12�Z�gAIM�MƁ�A��>fl'N /&Z �xE�e �%an&�. A��R J��Q[ "f�%�potA� , ubi�o���AanG�ll-�d � �On[ �� � !��T"��iw%%& , TA%?�f!de�-�=uxA 8�Alj�*h M��/5ten���� d [1��m*�� H6�9~ lQ ���r�Cn6p�!('% ؈SD!��F��Y*d.Qn!�[2&�+./D�#�m�[�Y  ��յ"^%!�}�&M�= !*2}|&0��[B���� ��n�� bip�(tynner—!�6N c� x Zb!4A�-"68�(�;!M�2CH��&� ��� J"3 �->s�>�Serf��u� Q�?� RHR:�� TAD:�1FeN|k�2�x &� -B� ,Bof��"�6dgBJ�1+20�.�.2�#X�D��J�a^ �:s �%�2�.�A-��)�)F r�6esa����&�U�j� �M�a+Do�"| ��v�* �LGA�T h�&k�A�0a�he,IA�ba�necess�tpreg-����@M�!N-�.�N�,��1��[�U1�� 6eS�w�u��� �^).V��>���B�,q3!��2�(�"�mo�s��ubY�!� � = ": :� K��El.�#��x&�M�%22��(�S�]�k����^-��A#�p��A, �!dAHN�5RDA'�Z1U�� ' A jQ�/�!A �M mole�($%��!�tnF�.!L. (�de��D�7qCEM�#? a�om� iz�g���lg�e�pV�t2ș)"�!c.qB` .2 � _� �!~u((�.�o�� ��nfkbia�~ ptgs�0)�:H� ���J[V�!9r�� 4�p� /6P�ID���5 �� �Mon�Vh�( ��1�;V� �mpo-)o��H�Q ���A�TNFα2�J$K�!�I��aUNr �by�"&ro�I� 3ip�Do:8<ss+c4� P}E7satk;Z� !Uv.&� F� uA��%!�AiV��abe*.��7r9d�.28.��*]�m`*; _77��0�Cr! ��(�ke�Ua wea0&�&�is ] frag%�� Z1 B�/}ol�! � [�25�49 ) �,Xr�lnѭ]�r��B�f��\ GST pull-K��9�"�!� x����0٫� s Lys �Pro49���hK21<).�l39 �m܄� f���� )%1;(�for��`����)e%5�r!�q op��O �׵~N�= |kk� �;cǫ%# r��2��u�� ("�sa�"�CO!nau�njer����akaK"[15N-1H� HSQC< kuMh0�� �� J�C�o)�veaVaD��1A�v:�ED511�V�N�h�Q�AD-!(Y9I6A3JGCB��&340–�!�*� I��-aPdihed��aŭre@2iv��d)i���MR�"�(AJ)�1E2"!�tG1(a� scaff�!� ��p� i �ns�7disIed ����|��f #�]j�1fh���–��a3e" 9�"Z1A�.�5�a6Ζmbq7�3:�( RMSD�R 6 Å-�>92� �%�$ke HIF-1α.I8 I, CITEDL S4!� STAT}3 ! , !%5aA�be�%uQQ�D I�4fold comprisesl four α-helices ( α1 , α2�3 , and α4 ) arranged in a roughly tetrahedral shape2�is stabilized by three zinc atoms , each of which2bound to -,Cys residuesUone Hi� . A prominent surface feature of the TAZ1 domainda series�interlinked hydrophobic grooves that bind*|rinsically disordered TADs ( Figs S2 ) . Inz,RelA–TA2:T�struc�, N-�@C-terminal region�theA fragm�used forN$al analysi�Lys425vhr433a@Ser482–Pro490 ,!V pectively%�e dynamF�H, with zero or nega7h [1H]-15N heteronuclear NOE�1 3A )MChence a!� mitt�rom�5s shownA` B(2A , B . Ou�e'-�9eARssenti%�!A8Leu434–Val481-`) ntir�wraps arEz%�E� predAXhantly extended conformationA�0docking itselAoe0 well-conserva ulky2eU�inE�e r�of �Uo2%�-+S4!m. TheFSL ( Glu471–Asn477 )P=>folds�o ahshort �x αCi ia�choA� �.8pocketA�m� y pa) of2Y�S3^�wF�BeHLikewiseu0:) (9�%�9B� also�sa�2�NAݑ{!ʅ�t�~Aballow2��Ned atEc juncE � �4Ta�)�αa*lix!CZkei4only about 30%FA�!� cal populI~ , as calc.Nmagnitud�C-alpha�Tcarbonyl secondary chee�, shifts [26]YcS3!���$small valu`f 4 ( ∼0 . 3–5!>I!u)eZirmm�th�� !1hi�j$flexible o�` nano �( time scale.�i]�]two addi!�al5b turn��AO 49�EX5ii6�\�N68U? make2)contactaN �axα��α��� 3aseź��E5:�ID.jźaEy��e comple�"iz0electrostatic6/betwee �-Zacidic.*ɊE4%�trong� X posi��uq� � >��Asp44�� 8�`=�is partiA�rA� ��w�a of fiveY2be�xяlA�ar�I�passeAM��,a deep cleft��%i���is linedi�basicq(�[$366 , Arg3%� 9 ,41 3A Arg4����C��.�.�Pwas further corrobora-�$ITC experi!�a�rried%�� wo differ! saltA�centr�,s�� stud� e:A� ribua!g!�!_evQ�creas NaCl8b)�50i,150 mM weake!M9� ]by 4-�u ,M sistn�0a significantn�toPEm�y ��As�4%�&�Q� ( Ta�^� �Gs"� L 5 � k$x revealedIH seve!�.���inF mediate��ii� expo� .Fɂ�(in� aminoe�r,a �s� �@q%.g��g, belong!oAm4ψXXψψ motif d a  sequ� u���ere ψana b apeu , Valy P .�)%�,X can be any�t1��)%6� ~gen!�ize'1�LXXLLۅ� kn� to5�$protein– 5U� [27] . Fi�mor��98a Phe44^ A��U$)neo��-x�.��u�e�Q�&� as ob� u%E mole�y>� 4-8$o investigA��ro�� e:S�6(we substitu��alanin2 �449%��73�� ac* repre� ��e firstA1-8�E| . BothJ^!���ly bu�.mX�%3�ɇip�iny.23�xQ�sAhCE� . Weireplac�e�rd:�V2� Ala}65Alald0, middle pane� d> AllDA- mutant^ (ed diminish�oM1t�D abro!��Z1��-9 GST-pullda assay*� ' !iso��mal calo��tric (��)����1A S5 ,�~,�3�2� ehe crit Q�.�2�in"�=' x�� 49!_�)mU�e�E���o a 7ɴde�� E��\��affinity�3Cc.a As s� -^�l,Q side chai�� ���ful.��A� narr:� �ȅ  Ile35�w4Leu357 , Gln41Ile414 ,a41Trp41�CT�!&��28a��6En5�3a�~�T� =���s.j(o enthalpic5�2�1� , sioA0);!�.� greaU1ɉm`�V�to �1��A�.d49� a @er2�-�� accorh ly6�by�:cau� far less�de`)�!v� ����v!��U�)8te los��� %Kf�5 b eu47Q1 7 ( 9!�ψ��6� :�le%! mmod m'.� U�6right-A�B&��mx is=Se�� �16nt , lea!�A~8We i�K\ similar effect would be��o�.76w�)C!���. A����above-�iov �-%ba�A#�A��b u�d&�^xA5 e sl!ii�&t"z60 5�jN&�truncI�to remo.� "�His44��neby el��at����,:���byw1 . 6���J�*� dele!q�5ro6&o"t =Y*�end?!+ had noQon)�q��S1De�Howk  ,":R=��8�!485��impai�a:F.l!�23 U�( A_� AEٿE��p!eu3 A�Pro382a�E�. R2 A�ZMet483�J B!�5�:5at)_5�beyond�do no4Q�w .�� summU, 9���A immspiral�!N� �%(%!angsKZQ (at a number!!poi�N� �-E� stud�,A�rupof4 i�sA ra>5'of%8 ρ�K�> Gqu1�archite�6#�;� A� g<"� ai�>Pae6�V V huma"u"�a� phosphoryBsitCDepen��upYstimulu� Ş*h.FU 4GSK3β , IKKεAr �%�pl( a:� ��ranscri%���(o(of NF-κB d��� gene�8]–[31]�7)�ey!�VV 6�u/"��` # it� closX lustIz:�he��uE��R&�>�a>�-_ mime�A��uA! ( �Asp%�Agsi45 8��Z�er��0than wild typ2`atexhibiw same5ctiony rengthe ugg,ng an enhancAutACll non�:�.[&y��Z ThM�e i�ed"� rg -8�neUlik� �)(!3���6 over� Ee"ed)t��)�!�i���.�� "RHRs)�PCBP–KIX via p-Ser27�/3 [20A�W�a��AY�A�HR�A!/�w"� yJ� us��ext�� NEs A-E3T3 cell��{ E\TNFα� 30 min .� Z1 w�purif�as�fusa�!)u!�to K L �-%( n� *#M4� s&ly lof amou� of @ �l� f)-{a�)]o�%�Z��6��due�eid [!�$possibilit�Wor both:�, a �1�"j !� RHR:!�.� "0lexQnd� ,�s[of� a�f!�!pofBX��totGol%)jE���ex� wZ� ��repora' [literz � �E9 ta�tY ,[32] , [33] �fo� h� X:>tY-�yp (ly 10–100� I��th��& or variou�;M.�. O�l ,�M)�llenE�A%!WI�!Y9�&�!�"2��� �a.>a�"!L:ich�-1 ref�� a �e@-�ve��:�V�g�� �F�!�i�Z��F]E�1�. NUCx e"�!�"�.b Zv �4< 46*�PheE)" �M�Q�of3-lɵ����in vitr�����tagK%�2�}J�5 ( wt�r�e"cM" �u�Ot�4ed rela−/−�( MateriD �Method��r�"geg twt/4'�qZ�(#, nam�$1k Ala+)_s� f!+Ser46��"�xiSTde��in5�ѱ6$.��ex�#e��A+�����B %�1���ter�ly��.� )Pnt distaXw notice .��YAcr / P2��y�urIsGST�dPndB �%�jle!lan)i�va� vivo��tO � al modu /�ke& ��)!e:�#)� c�ipo�S$mi* �� D�49%V[ u�:(�1�5BoGA[�2!I%<�!59byBU9J�A"� %���eͩ*'��-�influ�}�! ��:�r�!�"��lzheG i)��Q��'qu�1!s~ �ptnt � . � ]%I �!jCBP �s� k2 a�7�i 2�)i�1tesa��F theiA����! Fendogen�`uHby coimmunoprecipitI"( co-IP� Bi��lR�[ �Ih>�,�I�F)aj L�]) ]!a:�� uա�!|( @��U�4 &�!�di.qF�o�)}:!-=�—% or� Ed —d�IEj i��#�v�� �>eI.^�.1A�A@��equu(^� p300=*��� ]��are "BiNE�!&[22% ToU�eluci)�IqB�/�q�,� `.�!)ic)B6<t� spa�AWtempor% fo�����SI����3� S6� A3&G 467�is�lig&��u m� � . P:�<� in 5�}AF�}%ach��]maximum�1�"< �� y gradual0:yst�$ng?29afD6��/ x� =ex��-Cus [34*�'4E�]�ta5g�%�0�nt(oinciCEc!�>{1 di�Y��zs%��$e-�VHM�>ICA4.9e&�Y��e�is2lho�*tr�(;)if^s� ibut6 owar������.a\c)�R��� �e�-α-a��α-e_q� �" % )� � sA#&/&�%�(�I8F���!��,��6on�(��per�edJ5 MX ���6u ij, pIqi�>] at 1i0� a�*e?6 m��,�G ival J�co->E�'CB��x a �Dto( at 4 �^Tda/�d6� cnon*(ar���� w���ECre%t�A� �con*`'�t�"1mq>U�J5�5)` �2����I"z 5�Ƀ�,y]?I�%�"�l*d 6:�(>� �E&�!S6�$DeIa���>�$ �61J P92�[h� forth,ab "dq�]%&� w-or��i!!res�9,sK=K)ons: F�$,j� ��# &�gQ * to� 3!w.� 61S*M'5� )ER key deV/�� fact�*#� proc]1� v�(pathway [28�5 6LG ? � l�@qdT�mis�pre �ur=D(�&-e�r!�Z'!= �~ !Rnt%�A�����.+.�w"'�� �vYy� Ninduc�%exUprofil�-K"AEs5 (qRT-PCR . E7�l2,a�� �C>O6��v�ř*1�A Fg,. Fibroblast��� %@bec�" ��elld!� �-drivx..�A�mai�c*�,16m�$subunit [1EV[3Y)FFJ�]mpty veE��a2o�I�t ensuw2)�-bB%;&E� }�(!-! B� jA]%�)j�o�+ .��5��19aY[38 Ia�is1, ptgs2hnfkbiau)65believA�o b!���V���5Q�dat`/ monsq.�J��U�M�)M�c n�n� .!^E� ):�F.:�}�"le)� �aN6�*  �Aޡ��5�*.T.0=� s&4� v�F�#�A:ޱ,>act��a o,9��4a�!k.]���6�. OA�Eh� ,%�F�|"T6�)Q,�?/� ;eO)$disM/dui.�i�A�$mRNA level� Ore�m���@�@vcam1 ( NM_011693�iU-re�3a�%� V!&:��e�r�9D� InW"�1,.��i�QiszSWBy , appe�be�,��n�)N� 9F �%\mJ�F� 1 r�6omp�J� ib� k3y��!� �6 Q),2 �A�YQto2�A� BV�Si Lascer�"�&=�Cy�JA!-re"��@om���;RNA-seq "<�q�)�so��[�K*F�s prior!ɮ.�a�:�1w.�4�s��5� ��Mi�O ��#F���class}Q;;6 groups: G �n!��3� P%�<.�%�.�A����K!;9� �. lB]�$I�.cly�~1�.`.sKCK)�8>� T *O!�# �DH)C9X X�\[� Ytialtoge i�3,�� f�� U��� s} :���Q�y&{5a majo.�89�29 b"�4)!B ( 25 �)���� !a+20!� C�ix�sizE&� �^��.\ bD ( 48a�:i4BaV"q s�"�`� �?%~!�q^z1�$ &�26�.�s]}!�"�$6HB�.j. &a is much lO!an+vious��� {J .��U5��( IκBα��0tnfaip3 ( A20�  0 !@{:4 feedback loop!s � ��.�qn_�e+ ]in�&oru�"�; ���eJ�A� !st bl�!Ne f� =off:�� e25�mP in f>![39� T�7f7we ask?wh�Hr� 6�-���&WA�VC8�]�k:���  ;� �f\on��in<ai@C :#.�AMk&G� 66�.\ 2� n- a"��"�&�N3�6"� s" ŕ^< ��ups!�m>`7 ytoplasm���5DNA"e property!|!x .1b��E��U�h�robust�M�iveBoiuOYi#y��o�&M5( n "&O,*6Ja ah -B�yY'onI -�"R �o��b#6e�D�*4�-de�foc4M��Q�A � IKK-Ao- n�al� modul�,A mathe�D� modeE�yccW(�&�/ ��* ]�_v2 �n ��4 [40�4�,6 ��5�=!eabundg+f2:R?�F| "�!! �(IR ) [4�'43yam�<� arametersB$��=nF�Hq�&" E�m ��-1U�'e%�\#�"Ym%-6"� �*H64�!IpAXu�/s,%<�-9_MTB��-!j!�n�"��b�A�yA���,!5+�e��9U)�����; �6^"�0sus� ^�C9�A�,α synthesis� .�n*(: ��DHIE�loho �Y�h!�F �Q�n�in��&�':�'�F8ct�#in�K$-f.�U-��mea�zLE�)r{Kr�/MoY,y S�F Ai< ( EMSA�YOn"--����monit�Hdirec(-by AblottA}LS8�y�A� �/AB��%��"�q�y5�us2* ��!�S*��sq�g�m fh.���$A�M-:*� �i. 4orK � �E�_.kvVC%�d-5�>&Y�8%K cour:� .!'whN@����7��W�/#��e�he(C/9�#:�M 2�9�6{# . Wh}>�ofFde�!�?5�I F�re*��.N"~S�aV375�.OF9U�6C , �ilj reg�BEtx�Z6Q�| d,D)M~–i . F4 �:a.�!���-�2�y;la�� doeser�#�#L?ial1�P -m%�Mc�&���DN������B +1 -�9ay!�N�, houg; #E���� �+ =Pa�add! �u�result!/, ppl!�availTJ� &46� �h6V a�ssu�!��*�)mn%��O&!�%Ţ*�6��Ij&w oed unch&�9� I�2-^>�Q��B=� sc#A� Zval;'PIr�Bump%>(,o!��3^."in�m�!%6'FF� i7"P-�!Af)t6�e�8a�$��incore'� ��+ �c&Nu �B� �-I9� matcDh9E�&�mcERR�B.4� .�!G s�?4/^q{�Em��u �b � �2t��f2yBN5� root~n squ�� deviI�( RMS�W��a�� agre�<b8?=l!O2�%2� q�s�ad*�?p&(a�"2 i ��"Vs6=AT�!:���-�9.2����{e�&�0m� F2�9�!�!V�disturb!�eR� ? ��� !�Nfe%�J 1�Xf���PE�9&Z�Qe2��&I���� � tV 6\@�=9 f��understa�>n�:-V[� chroAChIP-q�&�K�8&� �BzZz �9at �.�e82�,��-��/7�b�>#  W�a5�'���occupanc~� F�;+v��s 7qS9��As!�ec����*X8�-4a$rui*�&��X!�!�!#)�I= dL= )!PJ� �{M�enrichm�-�%G �d&�, at 6�-� 1}a�i�Kgr�5e"!+qSexiY re�m6p� !�-.��B�:aC%<fVi?!��,����#!l*n l��"h.> 96�my6�!*��tno.w ��( e�DL v~�s)KSZT �!rl�$( cxcl�Icsf!DtnfE~In* %�ABproB �8-�)� �� �:Z�3g%*�.vNW"� "m/*r�9 2r�14�.c� 8)ierB#%o!9��4 |g �+!�l(65J1.��%�-� �*�7i��2e�)9�=5%1m.A��SirᶁQ.���Th����lxw3�D!��L1C]2�)���"@/ir�om8ia^.�&���� �l�B hypo���at&W0mitMb�,6Z �2�to�Y=M�!IfImf$re�3�nxsh�b�A6tu!UlCadN�A"i� ;existaf 5�aI� A=�"L1' �>�%�&�@1!HiH.u�b,>����-�vb������ !�~���&%�^� :<)+��M�@%�a:�,I�: �^�%Q[ s 7B%��^e� aris���!�e@�`E��2�"�!a�R�=�B��U)�� 7oS�O�.��"�!"�� ���� N�+q9�: CV� �S1�". SS acet�J(of histone-�"H�*taO27) 58cha eris�I<-�g�J44Fwe"� e.� �EH3*� !݁��hem6���e �? �0 27 ( H3K27ac�� �P�c-�1q3ed-QJB�A8 � *, ark�Ŋ9�R�*in6� .��Toe�surpr�b!7 �I�J/�x25 u�C<-_r�,�d� t�Zp: �6uA)8Z�k� S�@�lyzB{�!U1:����U�mW�b6�N"R?q��<sA�po��az2�=��. U�y"� �:aDAm�I=� *zzqby�!��/i&+el.rs��25T6�eG2�F�&�A&�F>��H 6[$)��F� ��B� i��0Jf �OsuDdiD�y %{5��2���.84�P /@M&&H]c%�2��AJ�J�79.)\��1�s,ai,�Q�of.�,by) ��T2� X���� F�&��.es3l >�y t=B\Z4-Wpr&�j�:v.(��34!y��9�:B2&@J��!��` �$ho2S�qJ�h�1�/�NAI�rso ai�=�!#�~ .S o��4 D. I�a"''�ha?&vi< !�Sal�P�fu�g�Q�m?�V�m�V 7W@.���&6 e{oYHc>��l�T almost�kkrglobu�X*�B . D!N"i=UN"m&{'��,"(�n �-�^∼50 �"�bht�[� � 0!��?gu�dt' �&mpo&� Xf�#g{"c�8Q incur8if unfol��,re5 Aq5s"1d re�Fa��6�,�cd\1 mari�,f"lersper���ci*�f�&0Nf^�j!9�.~L�V�g�?P2!Y�9omes �b�� ]��o G=�5�Y�,�il� cE'�iKJ9BO%Il. C�1Qi.� *4Z�q���i=���Tvk�AA��fng�Otl�FBb� �jLh�  ^1OIx%�Q c�b=OG2��A�m�w"�0A��G�7ty%� f���*�n4�U50QOM�%�i��Nx ��.�J*f1�$w)hKwA�� ��9���$� ". >�Io"�It�a�H� n� �'{1*�&�a*0��Se6� mWB�6��>�y!�r*�#�R��i;T EVor&� 2 QiJP"� [47A�[4�ATo� &D>�)8276!m�i^(Eb�s deci2 �%3A�� �xF�by��(��al.x-R:)s�A,�[Ear�� �Xh4 � O �0��:B� � de��f( HDAC�Ugr�& �!f�aMqr�at�  r�eE��s9\��n87&�s)t�31�d� }CB i? A��2��. ��F�5:35:3�"&�#��o"1;}Yi-Y�g�>&"�yɄ�Q�ue�m� �OblpT6& &�:3�9*�5B�j�=B �) � � 4i y>�.�,f�-aq> =I^9mpensx�i�1ergE@.umultipum�om{�ir#��6��<)E�!D�" / mechanism-�T�:��A��6dA~h�p�APr:TRAP-802��wai�5(t r���=F+&:`&� 6���F|�hEp�65�$��SE6! V Sp1Ucn iQ{ ��my)�"0  [5.SMoreov7�lo&]3��a�he DD!!=M"�.WL"d$�; dime��.� �R�# fam�Jme�es [53P J�proxim+Y�to2�>` ���UYNhe Nds�O.�[5� ��:�0n5�T�/Cr��Q :�%��M� rol���V~� W6�m\6��=q�("��&+*���K:cZ�i`Q:,��4��� e !��KZw� $M=]-��ed�� :-� ej ��T%�.q;[u�x�?o4% �Ι^ [�  ��$jl�.I��sQ kor�� 1�J.2vB ; �a�6-R�Hre�Q*'wEd chip6 .�:)T&Vq S rs/�� �e/�� ���rZm��)a�wDY��2�[1�:1�{HoGlA�ٗ2-]�Wm_1S�� ( be2��6d�%�"� ��� ��&n�&W�.�|!Gc� e:�.�Q�I"�a@�Mk��B�Sp� � �@9 %V]4�. A�'we* �!��| T}(K6�(w F 1N*6{!��d!�J�vt al . %�*+�\p-acc&!k�i� �*_y���0g&�2 mann� �w�2&� ^'m.E�)�1@9-Q� *�]��� [5fR56] !�h�km. ��b`t�bmou�]K�M#� j 4 E . coli [BL2 LDE!��e"�g& �m*ographrhGlutath�q sephar� bead5 (GE Life Sci�O� A�ea�{:�t!^dialy*�rCbu~AH!*9����7NMR2� �(�~+ �qan.� His6Jd�iD�58 2�� B"��of�eptococ�@ f G ( GB�as�,A�4 M�L l5l!N� AX�xo/g labe1growthA�M9"�U�Y1&�S �a>ium ch�xd�@13C-gluc!�)�:�U;�- de��J���@a Ni-NT�+ SIGM�columMN)KEu>��*( vageQ[p\ M Tr�pH 7 . �3 , 20��]� 4°C �!�–!h pept�!<] yF mb� v om�/e*�h 18 h N7�� Pmx� 5�3v�$-phase HPLYIRP ) 9<a C181on ÄKTAFr system \6{lyoph�im%�Cap I:v�i!�G (ab��3��ofmE\)%=�cX�Vl�43�bI�lMW4 a�V�!�e[.��Ma`GB�s6rby TEViJ![(A�h�5$�)e�6:�{ h*dNirA��r(KQnUl,�AjP�mM DTTtrh�y/Nµg!@�mix)6p]�%�(�_ )![20 µ]:(a 50% slurrdFwa�|gj�A�batiA }/A� rota^ i����� g5 �50�LA:�� ai�R!3%a�tonX-10/�.ivel����e�4by 15% SDS-PAG��>1�&�1at 25a�qLDMicroCal Omega VP-Bi�Uu�i.C,AfA��@!�-�$9�wE9)(��m������ni5,|hMRB� 8 . �(,i�mM%1l�E^!1DTTa?.�5�%; � rӎ!�1�a8 µM�� �>3 o69L 1855E� Wsy�� 9P͂N�* Obsorb�Ft 280 n��GB%nA`)WA�� 6[U�ʁF�U ��a�0 exti�" coeffi��1��;���N�n%�Y4���xa [$ofrO inje(&�I�g�6q�[��,32%249 1� 122Ii5J%�}�e�pblankA^!45�. D=E�e�A� ��ngle-q�h�=Myg(rigin Softw�i$stoichiome�cof�)E�d�܁#Ipn:\rr�1Kdy:M�9> >dux]�A#tr=��a�nUJ2��geo�T�%*���"[2t��B��009 �u@�)�%#� ref@�� �ed*q��#s�:7�O)a�AMBER�s�&H�age [6a67!&)65� �sub�N0�!0�ep�`$hdi;�,2�20 +*NlPn �0tacukno;v3 �a-Al�Born sol`��)[68�ffi�0���*i %8N�� �he� to �x!KU[2!64a��2�'(� coo_Q to 0Yr��I1KU c� P-� 30 k�4mol−1 Å−2�NOE.�!~��2/rad0di��et.;�N20� es�+�>G:� PROCHECK-�F[6:Immort-��+��ufBV70]i+6�Dw� retrov+��c,s pBABE-puro #*�S5/�8)� e�yor +2�c� rot3A5�.7(of 5 ng/ml �F(oche Diagno�4��A9�@�G6\"Antibod!"I�6IPa0�6(!y)�  Acti�sc-1615{b USF2 286Hα-Tubul7 5286�ti�lg584Evsc-58Yrd C�H Sign��(Technology:l468� #303�. cOm�; , EDTA-f�( �I"�X cockaW!�%8F�. 9in G-*�.Bdex�,N#H&�}��cul����10 cm3�t�&nd har�W" PBS� .% pelleq�pre�6bymp� ifuB�o�<p�eE�;s�C�CEh(� 32 M SucO,�2 HCl|), 3CaCU>2 MgOA-K 5% NP-C�7 , 8PMS�F.�^�aOm5�d�Fna�1(�flash!�zea�s�Qat −80� AOar-YEw� twic�X9�N �n�s8E g T)�>��<o��6�HEPES (!t\A�, j %BMg-z� KC� ,z:|Rɮor �f hEJ hb�pre�M�-G#�nc]�I4"&ݸ� Dtho�%nZ2 d9�'� �::�)3I�M-v�G�-�9�A�:� A�X %�"+ �u(s=�g��h!*�m"�W. �iA|��A�ndgif�R�>�f�j rer'j;ol^ " RNeasy kioPQIAGEN_W� W"P&p1 7 �)t�� e!�pt II RTG ( In�~��'poly-dTmm�c\C&&&?63by `I s� KAPAj!RealpJk mocyclerYPPENDOR�. �I�6��*Ts9�( 4� �40 P!15 � , 56�(� �722 � �L.=E pr� # �n, [71� �!(by melt-cur.� . Δ���Co%m� A5"o �E�R�FgapdhA@�]��M�� �a�e du���9&nVi(�V�!�$-uV&P� �� i?KeI* 1 in )Ec��r%-2� w,� � u\<�(XX 6a .� ɛ� �Q6� �9Rޑ%k%��oS � -!bi �Zrep�sj�m ��|�Q!&i�O,UCSD Biogem j3facil)&G!�"J%F IlluM� HiSeq�0.i . S�1}.�R��<to4?trD'm-��Q5� �Ta. !.�~��BEk�6.�A(5�)*�B��AA�b6�_dM�w�&6v�dine&�)=Ιo=z�3% . Tw$�"�-.�%Ku�eB9j.Q�9� mapp�� mm10��#�* TopHat [7�&!k.&�' '�mbl�Mx"� Cuff)6s [736l ��f9%o&�Q��ABM2+!�Uח4���Uqu�� ( ODB[aF!,I*a#�Y!�ada�a,�S�bS?�7��TI�.Y�Pvaa?�of� 4�X�2r�(2[74��r��e%fermXJ crib.G)-�or*�0e8�T���α%� ��t�DE3in  d( M�dW�I�ve Pol�r*�'� *�E�.��� “Stiffn}A Swit��;�bNDS� �?�@�M&=eL 8 ( Wolfram Researc&�Champagn� IL )M�a1er�'S�;IKK�)���1��:uKo�T \S2I$. Sampl"Y�QA�e��4% "�iCSi1+P� Enzy�.c�&in�Q � N� #900`?A�g�w!#^� %�sa�6���KR5I��~R���: ���6 HI:�#46l#�4 :G�el.* #817C(�NAQ�(*W��8&y&("&yti� >C2 �|"kC37�b��agW'>�272�Co%�"%�B�t&� q2!/ Z1xf �hdep?��A*�inbB~u�T acce�5K4 2LWW�h>��h�6Vc BioMagRes_,FW 1865���2apdiscusc=is pub���Zs(NCBI's Gene2�{mnibu�s�*!�r���\� GEO42 BXGSE46213 . ( http://wwwAkcbil6"ni�'@gov/geo/query/acc~ gi ?X=K) .oH�� "M � � +"s,de{)��es�1�%'6N�ic? ,=5su%�fu��`� �z�]Ua�}2� �Tross-s�|�kh !�.� B2�( TcGPf?;�1�?j&�E�en�ofJ?to1f�� �Vpr��� r�p�)randomsis��e+�lme�bIlihood �!�I�-l2Go� �O&brep�2��Yd�gunbJ��%G�AmisB�) �( MAR )6Q.-6!$�h�} ��/�ffE�ori�oi61�'s*�I^ aYW/ s� !� , takA�#�run�/"�5��e�Cof.U!in��De�("� *� a��!�NI ��I�TsF���pat;"u Ats.������.-s ,IK�es�;d| s il��� �0v0e<c%1A�B re�d.!� setsl HIVOrapeu�O vacc� ti�$ ( DALIA-1 ɑdC� ax �Raqy6  =z0]pneum�- ]E�nw:_i��?�uJ%g"bD9gv'g�H]I#)t-�69 $� d |)� l�ops"uniIdb divi`j�}L�U��":_A�.�xYa��Set En�2j% A](���-SE8��� ɨfai�.to� any.CQe19 M�E &@ seA�Y2? A!*t����d%�q�ML of 4)%[�ly�3<�F NA�Y)�e too2g �P Eassoci�GNH_Ni]6Y)�Qa%3& M� �"ݛg�]s����r!� 6Rp_����!hroachr �Ű!�*ѷVi�y�s'��E#+fo@���}/�f�"� . M�+ arra��&� �����(�2( or e�b-�ig�E�Rh ��a "8b D>CaW help!�� e�aA ��"x6�@* ��,a&,*�io���8s*]�lYasփoM{h�h�>��C%�1"��@M. SIV/�Gin�Y��[M"2]8�$)]�A&dqm�� , /%�e�irs��B'@K $is paper [ ($�&��*wanQ �8#�� � &�g �d�C^a ��:("`2���=za�y�u"�7�I�E-ze� h60 �-)=d 6][+,��!kapu\&` s=g6 �8V$ -by-�2�~A�[̪8�Cr &�Ri{ s [9%� G77��[1�(A�� Q��9J~"�co*�T�"+Ply�3ۇ��4�z���e� &�p"��ott~�se�=� $by KEGG [1!G� Ont�y�9";hauss 5’�n�@�uM[":R �=׵���9up���eN�<fu`,a3�C5�G"<�t�<~ aM�!.�f!�1B� �S=an�*��m�ywA�eryEq _/lut�I��Xur��m�f�� il�>� a gi���=maB*��fDmea�%��|���� )%�, so ,!�uRh �z��weld�G � ,"l.@g�s�Zaɹ+a2 ����tn�[1��F� �A!��9�avo{SJc stepűaQal � &ҋ2�4��e� bottom up}q�awJ73 U.of6LmV��(��VA�` triv�Q�!p"�)M]]{A���� �&T?=D�!qhe�"�+�7i��A�DFA5eZde�L�� I�5eb velo %z.[1�18–2��Fig 1E��J�[�DA� hom��� e�;2^;2�ac. AP�,��a��is *Qo�� ed [�e can!�|�gno��,A"�=j�6�a ;�� Ų��X�/syn�;no�.&D�'��-͹ma�y�byi ���e���_=�LoW.9*,R$aYc��pp"7-z�"tW�Z��bTTy�iRes�3y"� �.x!G!-s�klOc��k=yelocy� leukemi�.A�+eɓ!É�by Hu �:�>�a=HER�+��A�ń�,of ‘Ubiqui^z9�Q oteo#’ ,'Glioma aY ‘PѼG}cer�� ��^ 6�[5�yOV�adv?��u5�69^Md2���2� Mo_F #Tu O50&�m�&�rT�d&` wo����j��YQl� �yla_��w-d6't s�X%Wno:�. H 3� �Xi���,ALfi�:�1מ! �B}��U}�Q�.);,&As� k look�X:o%49�#y:�b�Ii2~!x��vR} a.�,o0���D" 2� �.� 2�2��[5Aa few%�m�e� AL1��2��33A�~�l}�E!�ut Nuedau� [18]]!S9 �\|~�. A�T*wp��ra ��n ^G "�v�O�AE����! :9+3��u��it&Fx.�a�� 2�c��yA+ !O�� �R.�F��"=3ng Pear�dcor� mV|!����a�*ϔŝis �'�ylJT e\2teg�rJ�L� ANCOVAA�cedAd"V�� mmelY&29 c.V�B �e{ DžD �5a $+�oJ��ny !.FlTps!�+�p[al null.��Q 19"0���!7�!AN!�ework�\u| VA1u�"�c Wang9-.bDa�q�,8��a{ expl�~��Th�Ev ! a6Di j��c��� e*he��T�#�" .. Z9 �30]��>^�non-p�˻"I y om B�ճ���8"�m-MM. W&`[��9Vhe CAMER.�� %@��!��%�n5}q)�tak�t c3� 5}��& I xA[�!On$<^oF�n�o9KF�.|1af� e�z|�A���tok�!�l% �e�T�G� %a �J�5�ee'asb(PCA-maSigFupR?Bdv02]� 18%7ƆeI�b88&1 Pr��pal Com't*MPCL�ach) A2j-Qreg��`�X*opiA��t�GS�EV�,r�S0Vmeae���)*�.]eta�Q?"^�*D&�!�#"�h�2 6M"�pai�.�!�e��Mals�au ingu���wir����-7>z�q�FC >���m��typ f R1>: i�&�petW�>a��es�w�p"� �gen� "��[S lt�!; i�� -a a�Z�eb�&G�X!0�k� �B, 3���et-#�pa�b/<sef�da n�>JgRqu=�aascW�;��a+>Dabu[�� E� ? ��c&�0Emmert-Streib�<�K:�u )��2aW�e/%(.S �c�"Ga���yQ. \� l.�J|e� �L��pa����ps�A��iw"�d�`i�v"G� rele`�ta�h./9�.�.p8 %�� �Ar ADa}1�i���"3R) j.C��c� �M>�:6Tim�y4� �nLm'I�lIV ��iB��5 a �use!(�.Q.�t��[3J���=�su�?�Y2� seۇ��B�� ���=,1 �a��.�E���0��( �6�J� wit| !�Y9�w!/ #�i� �!*�!e!���g�!( J)A��  k�Qzzh"NoATM�mY e+acha�bi��!T@?%fq�!u�X�>�~� d.��F����(�am!����-t&9�J�o�[h ies:��i�av7Ai &��c�f3Ly [f8 �s�2e3i�1��$�!I?�A�� nu.s Q3;� *[3�4�X���gen>,�GT%s�&l%� 4 +> ��حrs�V)݁�D��A � "�!cA�nAe@!D�-gs nQ ���[re�e���,"� g�6� *�a/E 2�?�(��a��aY��?iBy)� �*ng �#.�!"4�e6�"����)�R�a"{ �� Z�s��8s�y � CRAN��os��y&�'cra r-pro�A( . org/web/o,s/p/�;� html���R6�#| pHO1w"�#F!w�detaia���-yd(cli��($a�gov�* T?$."�0r: NCT0079677�Kax�-rC�MD�Sd���."� ex-�A,�$'fs�-α dend��0�6�"$HIV-1 lipo�Kd a�ti"Ec {ac�t�IoGCivi\!��r�a� safe͔)"��>+�� �bz5 � Fpurl�mre2' 5tcj��!#.O- � A�t�� &� inAle bl#4 �^�*&V3fUHT-12 v4.�*BeadChipA�|&&p� ObermosZ�66]*� m6R�TM7��Clth 1�%s� !4>�j���!�&2s�e behav�Z�yB_$��2��T|23�,I���/ ����Vsqxe�� 6�E ��ru}6>��!� * $�E#%689 o40TN=bn@, %r�QE00+? lapp�8 �'kC<�� . Ea���=g�-�ko<$d�Jo �Qi�2�jJs1'�!0Ň27%c7 a�d. Y>#��s& -ATI:985�:ost ;�'� �� �J��, 75%��!%�.�(9����:]Q��� -�z M�@��E\��—see��O,!�r"�F�@ �2~� �PAhdv�. S% �'&H  �E� ��ޭJE�G3OOWiG"�HE�X��4J .� �&�%A^yatI�-� ru�P�ak(ge Type I e�Oc`�rob"jof re aJH0�� H0����da hund1raKU� . 0�� 7�1���Gsit((pBut�so�]�B� FDR_u!a� �-�� dro�7� s�w_B^��� O��9 �" ]�(��bu����nom-��]1gF� ۏ �lfalse )!���� �vw��b��!^6�!��tirbith'"�� ���%!v"� �F �I��4� �(�(Yxs "�8�( � �lperGs E�s�|}n�-_���&����&� �x�0A2�� B�isQs.��"� A��d,A�qP%m�%:�(.�(- . Nonethe% �st ���0%� d2�A%!�Y���co�![��#�er6��ed���: f�/�w�{al-1�"LBY �{� A���1iE��"�*  "YA�aF�(()�"�stJa| 50i�FpD����1$�e($7of��e� ."�z �,A mm7�hK�*z� F��W؁�K�B*|"/)%>�(6F�P� �8�Oism�?.;deb��Tn�Ate6sub�c*\*d%�a�: o�&�%s!�d;n�"� =��w�� ��ABL�F �sg""� >a-I"a-�P"N3"b-b%�H1>�'� triggB$�W�N�, �{�n�Mo| am��,��e�a�.Kfic�� Qe��pacX'�˅�a8U&D%���m�woe�� or*A��&�8e� ate�f"�,�"Ell*�ib"5 �62A&u�}�@ �. M�0a�RP� in:��8w,��u`i�:vis6.oor qual=�*J2��.[�/. Mb8&�.("��.� �a�U��sB�3�j)�a��to)�leaE�bi� e�n�qt ՗�!�r�R 2��AsH��"�cop A�(iss�=ba�MM�9Lc�i�9�stk�p1!� m:�x�6Kg �u*��� of HJ�#or>���%Ͳ��!�u!�p�&),)as �)[bI0 , Mo2.0A�omu��Q&��UO�0a� aj%i^5�F*x�=w i!>99a�_�Jbr�S3�+  ch.�� H�!z��q',m�8 �f� ".3�%E�e�)��e�iC_t�f w vD��6��P�fe�3in�f1� bs��N%��a!�p�Foӳs*K ch"�+f9p�A0�(8 ��<y�/*1!R� �b�,�"�"� �OC6t2V2�l2 is 5~� . 17� e 26F %�d`2t�0���231%*� 2sXkk�I�fԵ��' �p fM�m�Eqsyd� ( 1bi {(����(ix� �756rb+7 6��[p]A�N+L ,2Ew� e�k �`"�t�~pey,�U %�caiif: ��J !�"��� eP�| �'V ���)bfX&?,Shahbab.�*Ϻ3&�;EV:raoA�\!��!*� ��=&� "�-rFyi_f1�-6�7%��<���lk�KsŨ�8 to g��4af;-"'�oA��F��*i��d$�?FU����� 2&a&�TEz�T2O�Vx� $�e��%�o.A�we� omme7o �b� M� heck%�I�rGmJeZ@f���_}2�!*�!D�=�"A i�te#$a��>&�!A0�NcE��=��E�a�>� g .�^ar�5pr�DPuζe9:�"s<�E)"*0m6� !@ spar�p>Y�S �2l�G͹Q�a���.^��U]~�x9�.�!&�#��[�a���-��0���"�'�?x a'�(u�@#On n�EI[�/w \>�*�(�&�*���f γp.2���!nst* :¡n%&/in~�!m��lz�BYX%y&��*sT7!"F Fo�G!��:G2)G*�= ��%�e"�K}�@Hc�*a��� �� ,�� J�#s)} rbe!�dH)� Pois�.(r$�o]e!^h�&5iJba�z-|a Gk:iA��). Or eN,af�~�&eights� � voomod) %V�!�+%Xmean-�Ga��/ ship�fi&$-"�N�"X%[,og�)�H%z<*HH�J�Dsceda�f�jlGq>e����5vso�kaeA9/G�lo�Ub0�V��*�� d��:���&"�sensi학э�pAD��n%�0,�"�5��ee4.!�C^�nt���d�s�saT��pidem=y�:geks=M^Y�$of Plasmod�qvivaxs"A�&�0= E�!W�fal�rum�-��a b�n1r� rH�g'C��X�!�Q5r1�)���s�p��ef�2!^map#�{�miE9%P:�jto neg?��araxjO( ^up�<A7y�0 2010;W�{)"�]�5=\� ��!!)O�O^ �7� H:�t��P&�#\ �Q of 9 , 97� /Ii!(edd�!b ( PvPR )��vey��l �e� 1985!9����EFo"�B Baye���1-ige+�a�G+<.�=� age-E��)��he nl99)iage@ g� )�� v�>5×5 km om� grid��L� ��2��e�on DuffyA� phenof-;cy��?�.�*in: paṙlJ! Af�P�na{E~J 6��!��av|5Z��l�oug�_!-?�8ld�-�q^ Y�ra�5excee� 7%%�-@�^e A:QA ��� d 22"3m;A� �Jis��Z�,� �:�ra&�lyAJr~��6!� �D�� �$.6�c5 billa8peo�=�( PpK �ly�#-�,6��Bme��Nk!�H0%ii� Madagasca�\,d parts of t�Ihe Horn , contributing 3 . 5% of global PAR . Central Asia was home to 82%:-�with important high endemic areas coincido-�Odense populations particularly in India and Myanmar . South East Asia contained fof the�est�itQone�Land Papua New Guinea5 ed 9FHThis detailed depic�w4spatially vary�-}s int d tof0a much-needed!tadigm shift towards geographicdstratifi�8nd evidence-basD lann�0for P . vivax wol�elimin%z . The�r 4al agenda shapImalariaCfinanc,, research ,Z implement ]�cA(ingly defin�round%� goal!Cregio}.�([1]–[6] .) ambi)u,stensibly ex!]s%Nll human��s , but whilst recent years have seen a surgeAx�attenk%HTlasmodium falciparum ,�knowledg)�/A�(other major6� , O)�,!+far lesAeveloped� almoA�4very aspect [7%11!Dur!�<2006–2009 juste�1E�4expenditures o5�nA�u!�, were commita to]I[12vA6no%! thatU approache.� primarily%A�=Fin holoa!�2�Africa can be transferred successfuai2�i!�how!%!L.tac5�d aa�,adequate [13)H7�$Previous ea�cI�campaignM/demone�a���)�Hfrequently remains �D@enched long after3fYFhas beenU�ed [18�!e$prominencea'oonEg��healthq�S risen furE�as�( accum�zA$f its capa��n somat�eV causvAdiseasee� death [19%F25]���E�0large numbers$people livA�at� k [2e�Amongst�man�� form)� gaps preva�ng �o�3)� giesU`)���J�i�abs1Wroba3.i assessa� risk%Y%��s��:�conspicuAK[9![2Ea!�Q�lan!�+1Tdeter!�s%�burden!�childre�adultA�a�pregn�twomen;M like�Dmpactbdiffer��1 meas� ;E�re�ve-�ty;.���(s . Despite7.�I�(these issue�A�e9>no syste!�cQ�9p{A�A��e M͆$Atlas Proj� �initiaa7in�5ean l focu��a?}{e�a-��to�mAi[28E�30]EVt��paras�beA���gr {$to policy ��a�s��to/�fE s [4E#3��3eHajwe!�s!�!� outca�of�equivalp- �ene� �mpreh�%veu�$AR! i$ infe�(s worldwidem�.R�he% �%hi!� to neglec!�Q�$. We buildtearliergm�!I�bang��IA�0broad classif��e�p*H !ra��owMTK-oofq�A[und� hich%��$al billion��eE�b .<* � ��6� � F  Numer��biologh %sepi� 4characteristic%}YIp< nt unique,llenge�D5�!�mapY etr G%' . Un��U}�,.�includA�d�q ypnozoa�$liver stag���an�� clinف�pse� sodes [37i��t� eriodic �ns��ifV (as a blood- gu@b�~nd!#@nguishable from a ��iv%�Htitut� subsI ial� Z[,a�v A��total pa� ��2�*c�����^within���%.N5��4p �DZmiazYtyp!e ly occursa��  lower� it�compa� to those�=�u X &� �%�� by #given�ԉsurveyas xQ AUly . An.� drE/!;he���landscap�ȁ!Tlu33Duffy�� ativ�P,phenotype [4' e� heri�E9!�d� conf a� degre% prot �agL t�YsaNi �(atu �� c!ni- � �ofh n2�, F oughV(rare elsewh��[43� se factor��a� %Ymeana� ethod�B framework�@� 9t��)�!g�g rpreV-�resul� Gy�iwctipIYco �� Z y!�� ltoAHas�CtoNri% zero , un�Ze5�.veyl"z �| x %�eira iphe\ ? }�1viA��! , miA� copy!a,rapid diagno{ ( test ( RDTe�W�RDT�n�v senv � !TEC!+th" onUoN �sm�s��ne� tech� prks uracy�U!� to mole��s��uch!polymer�� chain rea� , PC)�!�� �of both���l d!A3m���EE���nsidera"�� aximA�* availabil!'!7coveragA�C�Mu�0 . To� :wa -b�ar�/ofqx2Z0�} carr�'0out an exhaus��r����geore� ced PA� �� M�iZl.� sour��dira� u9�m�PI�� organis #[4�Fn/)!9 ��eg$ ab )��9�c7 |,�poA�o2( fide%�checkHprocedur�J� ����2!�he�l�9 ,�� ,on 25th Nove�{ 1"n��d!�(9 , 970 qua�-��Und o��ore�%poi�,&�!r 1985�3 ig�2AAV��[���< Y a��sum{es��MorigiM]3!>)���ime�,U group�a!$ siz(i� � ��u�� �J�We adopt" �d�s� ��#MBG ) [4�48]�0a�}flexi�ii l�6b ]��in�su� of"f m�a�AdAretro�.ax�bssj ��a� �Z-X%}.G , [4N ��� a��al�� �li!;l�r mix��C ,�I.�val]at ea�(arget pixel di�Z�funi^=!g*O-�m�!Ua weigh��a��of!�ximAy� M�.:jbe.[�ltivar�2�environ]!or���A�xC� �isIf� &�6 u"or ce-E�h]oge���a1 obser� �,(ch�urn.e2�p �)%� sig� ach L%! whe�%�A�1�)�!>is]�allowi� uncertain �p DedJtow betwH]de�ngÁd�%Q�� ,��?.���L�&FlosE-W �h t�0�co je suit ParP9map!#rS );�:"!`�}E%iva�hom!�& willAz �edi* leas�9G%����sparseA- main�Klk�!Dor �"| 2�i�� ly)Y��a��eg� r2�. WA:fquUBayesia���%ra Markov/ pMonte Carlo ( MCMC ) algorith�:J!x� �% aOl�A����ma7U b����Lorm!�-Ap� riora�"�s [50W�&v�-G1a{�!ver� h!*��u�(��lya�)>b ��6�� �cd Y ��m Lstruc�AaJ unch�d%�� !3tN ��ap2��X� �I ir*c�� }&�)l���&��$Ae�:Z8"�́W �p�{�� ��|�ʁ�� �?��%�1�Wof�^eM ary��2$� g!XIń�"! �(2��!arI��to down�~ ol���ͩ��clso��W ay s� �!P���2* we�!�]atF)� �!PiAAt�ly weak !24� ina] t be] �/nf$ Aief"��ps� S�"out�  peak6B � !�[5�A �seM ��l -��%i>�~! ���|,&! �oric� | �n:�8mod�!�:�se �( i�ʁ��tor�^�=Eas urban��ruc &$"Gl�'RU)M�P= ( GRUMP ) I;produq$52eT 53];���"-� "( veg�indexA� .�of Nl�lis�32q�vee ovi� �u�� [5<55]� ( i ��m� � �!�e&Z��de�I!�c���pa{e� ����)�-kbase��Y (sporogony [. Our2�e3eys� �ntaEet�ag�c_ , sia��&)X u��� *�� �i'"W� s�&i�Eqed�;t�it�ne�%���tandar� %���W!{ S[� �z�to�g%n�]he.�O ��a�6��a�%N%&� [56]%!W�5Ad!-*�:%�by._9SIXis��o��!�pid şs fanc�� plateau d�'�#hood b�de�ng!��y� lescx!� $4G e��0�1�magnit.A�h�[!�profi�e_� $WiAN !htwo��L�qY-���_���1�+��s�emI�6�� an2 67� �� age-n%2#(���2�w�, .FE�"U q�!56 )G6� %�t� EA�0rtE�"T i�]#a{qdΡ� -!v�E�in r�� x�e0Adhe�puto �ŃiHg$db-arbit�a�=iWc�.�#�#�ll--R�,�[)d")9�#n�,99�� thus%�1–99� e ex"���!�� ���neI_�!�x� �Y0rntibod&)v?A&A)�s� yl% youe�fa���dev��Ptwo-to-! !�$ET��. Z���q�ly����me#�&�Zf,m� �o� .$�g Q!�'S�Z2� `9�[�)� f'$or� �b�x]B[5� z��=&S!La dra8(supZ e�. n��ɣ�#�cou!��� �w� !�y.� �� � �+' NZin�&�� histo�,lE cepE�%�=s�E��"����ntM�ax+rth 1�or"#��~�ngE]A2U�%I��nt�,)p mantra [5�H"U-eQ_ exis*6#�2BMR���%Wik=(��we didk !l����� "s �stead� eH�.1Z�'!d6�AQXic"3� 3+incor�A�poW%�in2$is23  d7��8��F��&��na��-neH$.�!1�:~ŕ�5E5�denE�. in�hM%%,K%!�aVy=�c :�# �/4a��omw�C*�&et�u;7 A�90% ?-!�, f�QZ�!�100 w  &Hu��(50%"�$6���C�sp�$�2,>�N>PO"res�E�6Rb �!��1��A��!�"�F Q� re-b���/ !}8�'&{AK�@z1�~� ke6 van)�FC$�&�U[c%On�/Ace�hej��m�ens� ��IB�c&�R�3( )D]� . Se��!;� )���I�E���n�@3 �=��6J"�6Rborrow�engthySN����6� ��6#a �nader��Vos�4e  !��k9_ �-E��sto four!^tig�)#�Ee1-v5Q� iog*K6 ,�2om"�'!�*�)�&^�+:%�Ame��-d� �3e�gtA�g�"vA}7aCsub2�C��� d.�7 sub-2�aAyA�A@Th�nd-0y`bor>$2g � Sj* �"�6%X�)}7:/u�al feasi��r����2!��E�6���i��2 �!�bet/4R�Q�(:�y oeac�%!��h 5�Ր�2pa b�ke &D [60]�gO N�� A �8 y 5×5 km��A�� e�%e.z#2/��.a� !��Gto�0%)Cou s'�.JS'/��A612 month�� y�!. Mk RaV&�u��R�!��%B��.�� e�m�!���1]d�m��ach� z/:Vx aIj�A.�F.�assoc� !�2�~'Vby�s show? �k5� Z�+-qu�;l�1 ( IQ�"to �(� ��� se~�4e reci� %!f �/���e�!a6B �'m!K��n2�xgaw�&2l�;*LI2lmH illu�v�� M�per�6 q.�.� �/2��aυ� �!��J �!�.�& b� ��PAyX � �/-o �l.Ci.)b� st o�)9%� tw� _��s%Ǎ��)e�N ,%�mR�9��&xlow���%'�%e abund%�"�)�M+A��)"�sT y2��,.W&z)co�+tF)c �1:�/. S�%%g7not:�d"�,��� �tx27A�soC d=EiB rule)��!!30�.�&+(A/b�>�*�z&�&�1%2���5 I� �b+� r�R=fe_'�#al6��+i �ug5!"ap; y"�+�3a�+}�"F�� beta!څv*�AmQ���:!B�:" ,}!)��!�i ch_ nt�ndm�64 ����b� , n23]2d%�e4*� atz9�|&zBHJ"N4!yA!�el valid�Acg&a���-��7by 10z>!��  1龉)�se�/��q� ��ed; dompS&�&�X�7 ubse�-he}8D(}0���re-�0���=au��|� En�� &�4e�>d-o�� �!ma]6&>*)..fs%s� �=��� cj?�2�� [*%.=96.�81 :"%1 4 . �(||3Jx ; 27.\1exa"tBM�m�errorq!zga }& 3*; %_-qAi�0 ">a�jbi����La�&�3�of −�� 41 (&� −:2 38 ,�% 03 ,"� � >Sou2�D0��%�1h/xo� percYCge scaleB� 4� "�3Opre-�� 5�:�to@5KAG�byOBa half�� �M]m!�absolute-�� ch� �%� 2�y^ ;�'�\�*48.}5 . 056z5!aG%z!� 52 ,Bw5"37%tY7A{6n><9X�l��and��Y�2�,���i�/0,."���y[0!�d f�36� �&$+i�fg ��AI" F.A"� w7 �i 2eB e. I (* IQR:E6 )NI3A%=a���-"� �$in�3z(�� �A- �� �B44 mi�=s� e kiloz<�@5�)t�ar�,�Eg's :5L. A�6q �� �l�� ( 51%�!d a.-r��  "O ( 22+A� ( 27( T� 1e�&��u��;��I-Q2=^aScou�1!�=h:�*�B�&�,a�n�9�9`.�-9��;p!�5 ���;*�m�Jx?d��J2�]7. ,#0a��#m >�-2-( �J));sm�>r"� ��>�( 9!�]=�6 �U3. O�Js<.����AJ "K 2Oa ) i�� m8� ceuO?(ex��� 10 , 000���6�?*�6y<� � F�� 2��*�xN aO'du=s!���$U �M�nXG EX Acsimilar��a� �.� 8� �inW3Ne�-in>,.�A� ����>�S%�'#�C9 . 5r�ofM��cs"\�g azon.+T (of Brazil (�D2B�?In�)s!�l�#:F�A�U�K="� ( 15A�WJ 9�raW ��nZ"7Ipolar;3� �- gl(*B A�ɟi!g$95Hb>altoge�.IX)e]�!M-�A�o (!TA-Px.� – &�JNicaragu /Honduras%�k�i�� �i�! 7%hzth@�Jo �*&\f�#!�Ynthrough{ ! �s!�~2Q!42��in�vga-)J��%F\9s�&�Otru�.x�87�.-b�{+=� )� ,Q�!�MexicS; it%.6 a��Mg���|ed 53"t�AEGY�!cMP2�Z�+�� y hoKe5R�����at��Յ��D&H�*"d =�a�(lyE�.�ń-'�u�3i�ref6!$e*�1!y!�B�hA�Bgv h scar'D.�7�a�%a�g �(�y-�6 &� t=&�2) .9 n?j3�f sF�6,E� sign�)�* -�& A�la�inE. ext:"�E�Vo�1p1l"(dA�&� .�!���c*�D�R��A�1�� *d�0s�R�> U�<�Lm or.n d �&�=&#m&9$��ak�Nt(7"Sahar� �KAI�D�0.�m�e)5�2A:-by "Sa�f�mJ��vP�E2�is$�:` �g)G iori�M)��(R��be!�v:�a7��sh3of:��9 "e & � b�^�/gra"� 9 q�u� ma(   , 92�� �1�Apa�3.a�3t�W6�Madagaa�E~Ethiop=!0U�� SudO�malia mai:upi<��&5 ��.�. E�G ��G~d�Q!^�uni*l�&�-�R�5�FT� A*!�in*  of 22��'&EA[5`��d�G�Tverlask �-k��B- &�*I&)A�}%�jFc'*� �A�>m$u.� �(d��&{ �ro�:!�840"y �6n� �'+ �K 24SDto�Iy O(86[E�6�e,�r�T%J���� 6� U�\fob6" p�Urna2zr-��Z themselve�*���rC"�8*�V�� ER�cAH��qm5�QA�&�� ; ��8��T!�"gY�3"�&0B��2� ��ens�&� fpaue��b"4VM�g pock�of�e3u�in>�nor� n�YfZ"I:9RA��*y&` c�"-V��.����L> 2 ,of.� reduFm��at isj � a� E�� Xed�gn%1� m)�%�. L�< swB %��%,Mm( \�oH��SI glig>�EB0amakSe d�#s�-H:a=� ��by%�!E�i�>"� tEVYG�~��I�Ind�[l�AI� n�0e( 4Tm8 i.�R*w�'i:[( 6@:K.:U. China��a2N�;�G1\�B�sW��&id �2>1I�;In6�\ki� "���� 012%!Q��T&|2s2l>�b~/�I� ete'>D >����! �9ҁ4&� ��ed�� ń!`�(I,"�],�]-�,he Solomon Ier# %�est�*) A�P>�]��.� 6"� H�^wdE�{.�$s �as6b#�Dof:�}�e�� �V �as Afgha�K�n^< SumatrkKaliman$6_-5. Con�ly!B�хUer �"6���2^ X���N&@_b;�Im "5Z-j����)s(a�)�!9��h-�]A� �of2>��~plwE�*{-�� "�E�asF �$Y� Philippinj1WQ�$per-capita9ty . I�Xv �-k��")e� huge2�B� sp"5E&v �"� al zAE]r!*i-*�8e�T0 �I�("f��&p}�>�&�c�%��^��}#EvZ�9#i�j� , di�sh�d�����i�+^']0�4�:E���3fMok^byF.!IA�q2�/1��E.�b�%�a�JN ma.U*�=H �%&%cat.��q��u/\��g_�@E� � :6!2-)�E-s .� �L�l���+� n�Pp_c�4M��"F )�ly?"@ 9%)&\#Y�"rau2,�$!�fKIi�W� !r*[5R�N!� �>a5. Perh�[)�bF!E�QI��'�<8Em�A�a�D�`�4ten�b43%h=�"D�N-3 �arto�F�b�D0%%�7E �;en]-vW,ie A��*�?6��:c~$� up�P&i�lq+e�. FO ..j!J=����ed�to 70%�".(n.� �- -of-&� ���!� ��3"� �N�� #i�<cev i�.����<ouRG"6._,�8a?7!Xnd �!�R�5 amer if�'had op�A�!/�@ 2–�,RE#:a�6�m�H� ac� �b�Q\�aOacquiK Ci�=2mct�9:y� e<��� aCa<aA}�q.�!&>09��=�� �?�<lso��s�O appaa}� �a�m�ab`t[X�gMt?COn�X�[t�&MP|AK&�P��P&�7!�a(0�?2!=�!"o*�FQ�&j*s�K!�beBj � �"�&�q< �#bi<>ofa�se&K(�[8.�stu%;+!��/-^ se >E�� =$zl$a#C�up.�h2��*BZQiMh , [6�\7�[�)�h c��!��Ek-83!�>�Q�]yQa�Afg �16ti�RRA�c�A=*A5�raFQfuC� �1� �I CR-pP$8a���F�Z/h#�;ve]3�r.b11 rvoi%m]l!,�#�4?  *5B2��qaMaft�+w�P�"�6sUY)Z(F`�q\e.PmB\� 5:� load�Vs���0)\� !x<ex�2�%�rogre [�?"`W��&< B�iis�i�uce f n c��A�_1�}�%$�*�,a�e�3 n]Qm�Nl Iflamm�9rh�8� �mpK�[1�Rg�y�Is�bF 1� �in 7&�:!% hanaIzegard%�of>��� , duga!b|l6QyserybpoeakA|rep�Wb�G'haemoly![2e�A r�;ho�faDQ�� 6a �?)"�Tn �`hypo-�meso-M�65�.hU�hr'$>�k%�f*�/hy�>6 _#/uLv: in%n{Z��T�Dv� 0s6L� !fa� illnesJ1>qRi%!!�)�Iw� o=�[2�[Fj.� cM!1"U,�sA�e�� ��+&b!?u��>�)00%$� a�� �Wo�[H�jOdUz� ��a� �1atEQ�hyperqyx�p!1=is >20%!�[7�`I.^ Ohi:�*�!�� A�ic2��))� �#&�`a&8��i� "7� heav]m0p/�3�>���v&��EN���:)NP ��"Fl��"� &�e�8in�(�p�A�y#.)/&2�."�<�3 f�&fX�a`pZEiYoU_Q �H�)� ,� wdo>�9�W�ly._2Rasymptoq~J�Ds seque��ɦ *&.'_� s emerga�z hidllAb�*���%!�0t�cace�n-^>.9�"�s'A.5@�V�j=#spdc 1f�Q�!se�i�*ng�oBeuntil �@v���se5�.?OU�A�� a vi�rol� sus@k.�CKth?ra�f*�DQ-�gant-Nara; chem� ap�I_)\E�6�. H"�h�e?�? R52!(urv� �"�H �7i^%�can!Q �%��2�*4?A�=�ͣE�s&�H� "�ui/I�c�%R�*:p� !h� �,r }&.i��"ou'^`"mu�U��$*/`0�.�!��]y st7!pM�Ehe: ?ino�]!�%-�� W,��2���K�I>��3a�ekE�o � ��opt{]e0ol� S9�[�O&Vp , [7�ե�|eun>�%>-0A[S \)��.i[75E��3#ignori%a� � [!�g"[@%�i�I������E8"�\�]N Lu�q�0y!U.y?of �al2�p!. I�$w]�� Fln!��G.%��mIS m�tpli� .s��Yk *2"�!�E�{jB"���Z� &�2C� t !�e%1��u�a�a�@"�F#A nglpump!2�A>,.�~�"�8A�!���l gen Xj�%2�=hybod�E empi/ l&�His#�>,!� �@C�[ `%.c� � in ��%=c�3" �*O%[7hPmIY!��B '"G<[7�w80�]}J�/�T-�[8EO8� Wh�,!< inva(4v: cy�TCc2Y2hNpathwa�Z�inew�v� d me�Wis-Y�nVv� �loo��)mis�\>� ��!�s . oFm�s unr de��W��|J�c�=&�v&�zT��JmL��Q@i�'>)E�!1 let�"_m~���AW�^lyE;e� ��eIf�hI]��a`anyeogD�&Ew O.�1hav��� 6�3�.&y!�p.2!m�� ~z7.�on� e�D"no*vQ>in%i��e� C)Rve��1Y-uIl zygoA�*5%5*�YmhB�x[83�u8���mov�<%]mix�w�#�a�~�zqui� �Dnv��g�wESe z � �J %�*� a �Oŝ� D�zl�exQ�5:(Os��,��r�w�� gG��H!fE*�|P�amm�|8�U8�U[8Cd�:dergoa"ak*r;Bm�s Cwf�� k_Q� � P.(z�p!.Mh�F��/�y��Qor�P�(s�s �(E�m'Ha0ZdTn!L�--�!L um� � �QAn�&a W �Y)�.�"�y| 8Z95�_I�4rk Vqa�*b� ����@p�Gbý; �Eqi�+ttl R$u�6 ��!� na��A15� aat�Yn!�-o�5!z%�E}�V-Z�stems)�Q2�Mmp�fA "n� EH?�!Q)��I 2V +j� ��;�Qor guC�1�2� �l� ce�b�� dogm�y/�f�Nbe�,s self-propa�Qng:2  !��K!6Disz�L�.(* ��r�`! reli��. Mn�Ty~}laa{\!)%�6�!�ta��=�Z�#�t�*�&� ap��%�;I*��7�%'^&�U��IrgA�!��L�tif��Ls�"�GR�� �"nh!*4t.�]`*$lucose-6-pHh��dehyd)��c�qy$_6PDd �4}5i:�wdis� �4yA��Qѥ2N)~!��QNC*q��-�$��5 drug2e�@s} e*�6 �ra ��) �.� i�omd#  ^AAUɃ��T�ns [96�u9�ew:� {=�e9w` le (=6s ee[�ubmf)y�b�Pm.A[~��e6 K�c�_!����kng adB)�$�!�arooc jW yf� hv� re:  �c1!""� ���3nag ځ2/Nu u;P*�:m�*>��Y|�*��Re��s<0�*�6�c�I�� Zam�2�[�F.�"� !Bo�0,F � �V(rtemesinin-�b.h�� ( ACr!Rm�or "���v�o>red�"�2c"~�;2��op �to0 6tex/chloroi�9�- y [9T~F"r>� �t'�V: t%SM6��� 2�v*%ttackL 1� *  KUz [9�!��p}�@ *�A!e�3��=p5�� ��uE��la� *�C�w A�T�f��,�.�gM&��C fic Oc-!�'9��4��s u*�(r#�%4��B+*H�"^ aXo&$O�Sl��unadd� 0A��X���� �+�G"n�n:�Ca�)�����p*n."�(T!Deb@!9ym�im�e:"�q��Snk��?YG]6���v�A$�mon&��d�?I�y�E8?��. Offic���� �#nd �H��� �� Q)9-�| D}n"a]*%�\�/� n&�sh, � crud���g���;[o�[10!l�XR3K���?�#53s!{95A ���^Z7e�0�M��--u:��L:� a cl'Um�bt�bs9^g M �eQ��n%t� $2�v�C.�*�@aA����;!-�-��ɡ!nEw triangu�ngI6�B Z�A���iihyg>Z!xQ96�c�� sوD illa� nde�&%�R�-a�#[�,!���10WT��!=ls�s�*��ar"* � n]�r audo*��q2�U9B�<�cy|10�� O�ulX�AKm�.noMy y�b�f��. Lin�RF$k%i} �!�h�(� {�X@�v%}bP[�BH �i~!"�[&%�� O.�%bI�B5u@2~p!�/spoorl,(suQ%�� l�(����ő ��g[3�4�lF4ch�2li� 3a��3!ٝHvi.p E�m�hoP/nCs*ma�2@ %"`4:&is)�)^p�F� �des<( D~tA��1.���V��8���D!�E�2� �r�+10���x�Vc��-�4�h�2w���� :Xg ermG- �"%�uu��n tago�5ic&�s�s�q�levR� Q�h�"r�&�m���-A�"�-��dispu< [20� 10�10 b-e�3gA#�UT2  !*] �&Ac)��� �&A6a?F��.~)a 2W � og�.Amnhngy� fforr��q �y$� ����y��+�yU`}�5ts2�� �);urpasO0�:�tW gherh�k cous�z�}� . Ma�I(s"E !@Qv�(ir* $v&�`e奅�&��� �!/y�T,�1,6x&�!�&A �!�peXa�Ra��dK%¡}*�> Dy1� madreG � �lC !MAP web� [11Z�$�� UW�&�&� �Mc" *cڅ�tUs�AZD1s��`��= imagh r�C�,�M:�Q�"u6@[eT>l��@Edntl�))�pa�ow�\alyY��qe �_� �l�ndA;6 � W6�iq�9h8�p��.-ajvZ�sbs%G!�ŝ�GA�Ƀ��2b'u� � HDork .{rStaphyloc� s aureu�4���a*�cw�l ncho�څ�i�%3 DS� adhe7�i*D�Gm ti��'z�冥,a3aBE��'na�U��Jz> e vis[� eo��*smI�qV� clum&�fc�( B ( ClfB )8Y �'�V+�.fac{z�S .17nasa|lon*=+o�� �^�G�p��lhb,aZcor]Iun�x)���`naJS.�}��� of ��pskA�nd soݚ%jA�ev ( SST�4&�*�d%?is�-�0[novel uA%0 vUA�� r! s_e�`g�abs�r� u�x�b�al� �@/2���i8- up�J�ta�� � �!cligfl#lr�D8�)M��{e(�^ �->. T�A|��Ggof% vacc& e y+d4 e&������aPug r"P0,� 5on5]Yj%�9�5�&� w ���� o8`$!��!�� s . V i�ae�! "V�!aRu�E`s )!�h s [�2Q].M **'n�P 11"�F�d� ,!pYd�]5a.�v#>l ���S-�Un*�Saʁ�� ly [�.=p ��,t "� s cutan�AM�EXR'!� peneA�G�;���=qio�g ��. Ce y-"C E(ici�l!�Bt.�(( CA-MRSA ))�U��6!�iLl-�� L���k�5�(a5&n�a� �I��"{5dqGt�2Ka-����cP`"��A%$.-=�qooL:��"1 [!k��pL � 6G3R�;� �aal�-2�: ��6 u m�\N� � u>. GW�!"w��� ���q�eid  & o�-uE��"�V�A�UA�ntR�w��pV<����o y����l"b q` (>y"Dbe pursu�XAsM��I�fI�tK4of.�U����5��� �e�uǓi��beU)  benefi� Im� �cXs� ��� � ~�.� oz SQ���^AL� v� !�q��6�68�a�iu��y� u�* �s�398�&�$��P d�+fP�)HG ��V�..��6s>:25&8��:w ( CW����7 � �!3c�(� o"�ap�sdogly  �izyA��se �\M�"X� �� ,� filmEE���E &� [xS�-/�t m��l�-�2 6X � �7nd%'=% �&� � mpi]dn� b��[7�� %h�1aiz6)A~5EB���ulaX}@To�{&� �Q"�,,T� �+o��)�wild-t˗I���[v�T�un8�A�c{ ��AR5+!�&�&2� �wsug0�J9_��+�0YBI!�0"s�-lHQI:� r�*a.�M.ɉa�Y� �-U�2�. C:� A� b� {Z�3u%�gen:6s��AsP>; �1"  aS J+6E�in Newma�M*ѣ�t�J�.�eA(�8iZat Day 2A=t-.H2M;&W1)��R��!� ClfA�deG�p+o�C| ma��MVCE��#F�Ac�)�.� .�:�*�%�2�~h% ��� 6*M1co*��"�Me.Gn��� %E.� � ��"jJ\�ro���ad&U 3�C�Y2� ��[ex����ph�F�$ rowtnA�\���e?r%�Y��,D�e N��in���� T 9�� ��)�� b�ng domA��_�% Aa\@a 540 amino-acid �se�kp3E3�\0l�lfF"t_�)N� N2�N3�>S&�_e%wM-���%r5�w-iM� N2N3�!�e� �Bno�(n5 "�[f?- c���!�a}�,+a�ii}L[��S1y,�4 Mĭy r� z"$ clo!���lex6 2� *Xa'�K�shaQI�\�*94%.�� Op��W���!z,2�a fibrin��(�=ytoke_!n�bp�i| g}A*mi !��Le�sUL quam.?i e.riJbώ V%{"pO �IYJ�Fc[2�R>�6WJ jNsRr� �-knock�%^!��^�Z�,*~�a<��"7�&H7i)�in�o!%G!�l��ZE�,��Vo�to.�M  %&t�a\n� >�&�"��� t�aimE) elucXne�^�w�#}:w9 �%s��8&j� �d U�c�tn6J� !M��]T*�9A�1 F� 7,tcALB/c)�Eyub"�ly3_ . c .�(�/ 2x107 CFU.�(LAC::lux or Δ�a . Ab] l�re�]�8���K"?����?Gurec�*d�� x-da�; ���A7Ie�B�� �2��N�2� j�62E�Zi�T 1_ 1B �+eB��a� �=� inB�jan>6+� 5�&� �CE�1D�ge#io2��To�_qu�6A}r� � ay 3�E )�6F�I�1ta� 5)�no�6M �_vw at 6#crs� " "&5*M�a�>>S1�Y��" [�/disse%c ��/g#ic��:24Z�ut� [�/�,>O� ��Q ~�hA�BXv!�&y=e�hb��0� ≤ 1 Log��/A6Fgi�a��F�-�E��U as 2A7-� &!uM�a]_ N���a��!mi&L5� a��z5exc� at����3}P�� ��v!9Q}n��%]�w5dR0HaH4 oxyl��oy"7B��s� n s9(4!�reUA+�G��&/�)92X��"���Ip9�Qp�:PH�&�."iofQJ)�t 12 ;| !�,N�iJ��:�a �CO 1w%�!)a:en�'����Bɀ��2љ�e si�!a����LI �o�Y�-NI�s0� v ��O���A8I��Cb#I&�?M�(�1��Y%�v�9�d.�1� �ed)�u�NA؅3 !� �Ж. Takk�o�je�sK=u"�=�|�E! �� -�y�!�"��A�..�� A�Ele�MyW�erf�&��@ g*? "rf".perv��' i�BC�lyB/�2͵q!�g��Y`�a."� f �Mexe�9<C;I��=&���. DAgNU ,.m e v " epithel�1�6�:p;@ �" �e`Qbs ڔŘ�te*�  [1T O&O;i�p�1N  by i?>�d ���c.A�W2oQ�AJ�.� 2� `. At 48F@i�3 )2 -ly��$-��Tr��'-�e I��iUi �_�� � }gN��U�� LcF�!PM6�oi Dlso�E6!!q�:�IeAa&� !W v)��Ł�A(���!2&� rPnfirmy1��:�Ao-&��� iQ&FVeWT =.3� $( Lor-/- )�^ix� � ���1.] >� � '#.ft��bn hf 4� 4A!�WT Mz!X�}>�IM4� 4� {@�7!�!^C%�/.;2t���i {("#1�&")�.2p 0-�A�s0&�VFc �aio �W)�%F>-�A �� %�Ѿ�R%;-"�d-T��� DHA@b��L�!F�m]�X�M���C�![2)p�,!��.� e�U��U�mb I\��K%8%j rece�t>6 �1 �!:� -]��A�6���N�Z�� !>L"U�mh�-B��o�X4� F*YR&�*� K6� F�l.[ $}� ��CFUn$Fig �"|]�ZR� F 0m��j�a�q�  Q�&�A�M:��� ( S3� :� e/�*� Y�a�.�A�-�� �p.���& 52a��q�N ��k �"� (O ! a1 8. NWX��:nt�|0 loop L2v-GST�z2v�w��ublock!20Q�ap5  v�=((��u�(*2)e/ pre-incub&0!D�AA�p;=��inj��D���I��"JAF�6-��!�p�jx+!�@�21J.^.$A��+�|4mb5��5�-e��MJ�a�|:��`�ax� !� .�n���5�5�!(���vJ$!{��%��g9�`jaAA%+r@ �}6FiS4u�H�Xdis&�fn_+����)*!K��-a@I�'>��eB!%� &= x&���%a�a�+_3a��7�%Toll-� � ptor 9XpLRԈt3 CpG � djuva� . Naïve B� �eeqL%�PBS�K�lۄ�!%'�-�tX14�nd 28%�"p d�� cy�DQ�H4AA�&�9� �+^hum�+,$&�+jsNhJbto�ace3�Y��H�A.�pG dro�Be|��)E�=�IFNγm+66, IL-17a��IL-22q Ռ��CD4+ T�s b��guia� lympRdUBILN ) %(E�-d�!B),.� CpG-%4iz��"f�CD8� ���)q� �*&� �q-]g��6��!U�Ip&�5u�Ve..�� |YL�!-�07e6)9�se�7IgG tit�/A.*�a��5��7!��f��W���%_m !�D!��2IW-(n� L . ly "-2/���KS80:5�):@ immoғ!�?Mf7A{.�&f�3�qe���M�/�ge­�X1�  �a�K,A�>B���� �2u�. � I�ۆ�$~���� 2�6Vc6R67>�:��e88!�akA�v�^��!de�_!�2�c������&ea�;byZ�88ra���%%B�"6��a�e7>6�²�)�}q� ( S6e� J8�A�e�2�6�a�U\�Ub:h e*�"fa�.� �u����+��� ����/~� . P��� ")!� mm%�f'�!A�o)�A�G1+z}�J�"�cd �N$.i�&�$E"s��y2�#� :`[*�&JF�!-�1+�Ga�*q�#"tn6E� jB*STIh'")v:$oof-of-cono�)�E.� gu?cG?��ġ�r��in next-�%�$onQ4s� :i� . U�~5CfBt-L��0l�L�mnt"*3USA3006!�,&� ,Hg݀��#&Z�6WF�:� .2%%$X� ��ertE!2� V̹� V8�(� }Ū" S o2SM�Fu=�:i8@A��h��:$I�f �,e�5qou�7E����% i^Beal��IQ.y3�? ))��Bu�6M�Q �n�"�"� )Me . Al�3x&1��A<J ��/e gran"� 2��!��[2�23�'*�a�bc�8 isru�n-�wo0�5a[2� ���8k$�u zo)��ءze6��6 )LI��Z2da�=dC�a�b!"~���+�">3�,-�1���*�� �dE�V�i�%,9*�1� >6cU4aRL&AYSa�� �B2 A�atJ+1WT��,�Ae��.��ݢhYs �;Mk�X��P��i�2��&� �)[ �4� �o�,# "`:�sXas.�*or �*�(.�5�6��di �iw?�L�X� � )m-d!�!ɭH���  D�+�*AD ���.2%�ꮅ� be�� vivof<3(�.�. P&��% R+abo��A"�� �Y����M��"�.�m2� 9�O�� 1$�wZ5.�R1��^># 6� �� :9^���?un", d6 �D!Aˍ@e�ge^83; p^,*��7wa����tdAR?�KA%��!�7B�'a����[KF�eu?!ls�&en&�!�Q v6�2un �A�.%7�A���o�`a%toȩdhtitrP�2H��u^04Se�  i_E��I�).ct"tE]k�/tI~Ym.Zl�!8�&l�.�Z37J� [1崡V�N�$Freund’s&+ jdF�MAk�7,i/venou� ��[�L.V6V��nR."�#BZ!� mA`.�%=:�H5Ka handfuDuR i�}ht�_� � �7lR]JBd�7$� A!N�A��, Als3p�T!�ar�seA synti3A D�N� alum7 SasX�-*S�N�[~֑6 ���1l""�?��%0[6*655 ��=346Auask" ��p�;a���n*��#g2�5Bi="�si0�@�%�Q���Y%W5.2MJU6��(�I%j%H,Rc�,A�&R0��gEPrU)B!�"�u��!@~"�,>!�U<*s3w4Y��_hAP stro�C[  �il�:n��y a�m*��=U.1�qZus 4J s [3�2I ee]5'����aS7.�.b�+N�� �� s.��]n Th1� Th17*�� ]r� [3 {&�J[ lfB+xbd2%expan��>)@!�2��fa`�@OIA^�McK��7HGec��m��s-*�s-J��pu�tB��=66C�D �  duDE��E��of!y�%��AOl!t���&5�<knvJ� e�I�Rly*�A�}�-�"3U�:^������yto��'�Hyw� $ neutrophi! crui�^Q�n-0�a�'Rr� �e%�FM"�rb��?Ab�&�&t � or.jO� ^(T3N um�G , 37–4�UR�E��-�QM^�1-�.$�Q[ &( %; alizQg�.� � " 2�� azL�)'As�AMAd�r�B!e�e�L�33"��Ux �2!��%��. S-� "� :��*KN M~/R��G2eN.�:$ G.�x._���:L�. ��%f�o�j����/l%`"�=�� ��rec�@� "iX�)ˁkMi� q�a6�\�GO��/�Ś�vFA�i�Aj$opsonophag� o��E�terfer&]� M����.��dwi�veh ie�PMM0!Ext$de"O��g�� �>$&�6�(w+"�/d)Y�d�#ad�!�!<&� 1�i�9�Kr*i$;}ݡq� ��o��AH2~ �2�+%�FI!���iT��$^)_���3Zam H�7Q�4=�̨ 5�% !�u�x.��MT!1[3��4�45�Kll-v8 5AB�2� inva� qN:?��Ai �0"� � renZaM2�.�#��< H�: 5��&�Q�O!��a E�>-�!��qY�V<2a�J�Ŕ"� EAl�i%!����A�mh �=pi\�J}O1w"`,Hk�te+���7��!�"0#H!�*Z%Y ���3%y�As96%e�!��! �1�/sM��L�1k4@�[��.��ە�*�!)E. �u�g .Li!j��u����E�� "8���:+"�8*� �in��.]!�e�a�ebjCT��)��k%:t"�K��� ��m�ipe�K�a!ta�b��> E_L &l��qjt�"� �X���7�o��-FsT�<�!�sD ��� bA�e�L&xn� )� #Tu�Q:UO ��>=��+DnrypNZsoyr�&SA; Oxoi�h�&.&broth'B'at 37°C�@*�'t��"g �"�!��'&а��..�\az���`�l���ZA �R��+�cs!-m�m,Re�a�` (0H �Is� to 542 )Ia�purif,7E�E�0��by Ni2+� I! chroވk�yff�(. Endotoxindrex�5�)�K De+-Ge�: 8-4�%columX Thermo Sc�k��&.�GST-tag�m� ( �1V�r2� aJrap FF-2pq �jE H'Wc�E�)�Å�5&nuBurer'k� �5�#f�s�resy�sa�?Fy.N!� .I�* 6�2�I 0 μ�er�$/.��>�8�F�e�h�sthetz-�! inha�ݡ$isofluranem�so-Vet�7a")QA Bios�ӡ;0 PhotonIMAGER�  .#&�5t�^A�at%c R M3 V{\Zw!�(@c)�Ii  !�ys�# `yP��q adia�q1 .�& lYft2�b��+~*��,� �%�%QX�g%�MigD��el[�J�!Vpi]�)�M a�Z�uel�r�aOxero:#� RhWgng���� �", 8mm p��ACps��]I�NG�t4Aat�43�B + . Ti>!�V�Em�o]����B�:u'�y% �=�c�mluiyon TS.OF R!!usc�*�'6_np&c!4 r��x4�"�O2v���6;;GμM��3��30>�!<RT ���\n�'��"q$R�n!mafJ���A�nit�"&Ka�*2A L"�2e"3c&-��6 *E����3"%H?no��)i~"��3����!x�����( 5� g/m�, Hycult�% tech� '4,!�RD>*( 5 �E)��5>94=.9&,.4�'ILN"�Y�!Y��re7 E��f��5;c:4�)�o0^��2. O�Kv�U�CF&J VN(2�8a�24t�3N��/� ��~ede�. L4��6n�3�3��I 4i{r�"E�troI -�1Ml h`cRPMI%z6 h�U�_X�d ,( Sigma-Aldr���W�( vol/voLfe��calf �3Ɂera /(0 mM L-glut�amine ( Gibco ) and 100 μg/ml penicillin-streptomycin 1@. Brefeldin A ( 5;�) was added to the cultures for 5 h before surface staining with fluorochrome-conjugated antibodies against CD45 ( eBioscience , clone 30-F11 ) , CD3 ( Biolegend , c#417A2 ) , CD4 (RFGK1 . 5-!CD8Z(<53–6 . 7 ) . T�0ells were fix��d permeabilised using Dako IntraStrain Fixation%�P2aHkit , followed by i<oular 6Mag)*IFNγZ�XMG�) IL-17!�eBi=U17B�A+IL-22ZOIH8PWSR% LFlow cytometric data)acquired)�@a BD FACSCanto IIfanaly9)M$Jo softwarA�8Tree Star Inc .sDClfB-specific IgG M9y titA�in ser �qufi)K4sandwich ELISA-�! -mura2P( 1D<4000; Sigma-Aldr7AN�as previously described [55] . Antibody conce!�!�M*expres�(as endpoint�calculat �reg+�ion curve of OD values versus reciprocal serum levelsa�$a cut-off e of 2A=$ndard devi �above�troGI�E�ty;mouse!Wum]neutraA� �ligA6 bindA�activ 9!��2tes �incubat*L . l/0s pKS80::clfBI4 сS,30 min prior~adgzbacteriawe�co%Bw�kGST-L2vEmvat 37 C\a��. W?e� washQ�PBS@ adherent a�sm�f(formaldehydA�25% v/vE,e�J4crystal violetU�$A570 measua/. A ice�.�w�bAVagE �ceA�Mabs�'of )@!�pe4inhibiA�^deter�+�isubtr!�ngZ> from�GL. Skin abscess tissu � exciE�nd-$in 10%-&5nd embe�B!�0araffin . Sec� s ( 5–1��m�r�f mounABo�B,glass slides�2j haematoxyposaT �samplem� imag)\bright field microscopy ��8an Olympus BX51!ea/o�jy diffA+�ces between groups , a histology scor!lsystem-�v%?wh�oJtiE�-o� ccori�(ir architec�.K%<j �th�TindependA�bld obser�XA�-� area�U�!� N2�sizA�S2 Table��$For loricr��t, s1��m�q&block!bu!G��% BSA ,EGgoat I�)AT 1 hB�Sovern%�at 4°Ci�primary����( -���, Covaa_��8Endo-peroxidase�� �)c ~��4in 3% hydrogenaK=e solu!>��onۍ�w�� seco���co"< #hor�� dishj�( HRP�Co��M�%�1vJ_aE (!�Fig A!��evelopmAD!achiev"�(3 , 3’-di� obenzid�d0( Vector Labs{ ce�r2�2�.tisti��a: �per��{4GraphPad Prism&Q. Df�E�Xi�Teither Mann-Whitney U ��@ or Two-way ANOVA)�,"\pr)� ctic8i 6 Q!~ea< ally1blema0O5��onduct%+ ( year�� larg��N>1A�� 1�) tri!�%"1os�ge� )�of9#s�deploy��$ strategieuToᘁ| ize-+ helpc ign)�9�to�Ure urgenAja�hat!_eg] pharmacs !� - , viral bost fa��s" fg.�Y$A�afore�io�NK , wef �#ed= %�i�@ xac! ocha�� siQ�iqach!�pra�t!�e�6�,  n ex� A� d\�a�( DTG��mbi��popm5 kinet�oof5�Rs� framework � �1tplasma��� i��r145 . 18%�$722 . 23nM@v!50)�$90% sexuali)mis��tiv�C� �%� e reA�= in6� when � as u� iMQ,IX,‘on demand�u!���eZb�ab�/afterAUusᱩ�a�ce �ϥ6%Q 50mg oral�Ie� 99� 0%.P,�85%!��h�50d� g %I$!7 ed . w>�t7t842s�� >80% h�� �(in 6 hours R�@ continuedE�as�^8 ossi . Whil%�.�Y_cA�as� be adap%�o �%P�z��ourJ�ic6 �%r%|ais non-!RTѸ. More7 ��Y�A�-=�c��&��h rel��.Q�l7 ed�nano-2�. HIV-1_t!EP be o&% grea�� p7 c� challeng�M)`it�5wto sup�M� repl!(a6!� antiretral� bin��tw��-viA��persis�uu�A anatom�v re^oir&decad%�pr�A� re [1–3L Becaxof ��ina[ty�c+� ńaF����da�i��utm��import0 �� -90 t��tA���� � ai� end  by 203� An�hr� nt� will!� a dr�ۙ�R7 :-�h ") �%ell�n&8 becamAx � ! (in 2015 [4]-�in� AEH�awa4 to*� ca^�20%�to feweraG_2� %C"= %�b2� D high-risk2U!�Y� ‘* 6� >  Nj>aOIGavail�a9�>& A�2,  (�) have b�extensɑ studa<G*� A�FDA EMEA� 2012 2016ap9 ��MA� S ��Ñ�eqo!�� E�-�A!� , if2\�h [5 , 6at&� @major shortcomingeK �-ba�d%�� ay� s [7Q~ ���m�ec �o�sQ�����!2neYa�A1�E drugA�ake"_ leax inadequ� ��e�s� fic�ofN�� �hvercomea>e �&� in� m��-&� �A\A ʅ]� %�� �u�  in�"� � ya�< month ( see [8]NV � view�!9�pip�� Q�< < ext� ly�i.� хl"[ �[ ( N ><02�"J ��y-time spa � ��bG� �n Xresulte� /F pr*� %)ex&_%pawia�y cerpae�V isoB�� J� �i� �!�$a multivarF A�erplaW%�� 2� � eKa lackG�� z � toOg� ��knowledgAY�� al�i8��E�os�:Q�QestJA. Hav$ � mode�t)]E�5=rule outl or*� 5Qn��$avoid puttd.�^rm�� duce�[ !`assoc!lde�Eur%*na[}to� !�ethod ��3%Qs> �N8dynamic ( PK/PD&a� ll%�� Per�ea-�;he? a.tV� of arbitr�Ep*:. Rec,)�l!Uőaches��&� tzK Az���mU�[9 �]�1)`A�ousI�AU)�or!�0th�.2th���con� onE~negX(5~[ –>�ch6sof%��Mr er�  un�8 �e+V � dose f��enc� ord o as�#how)-A�n ef����b��� W% -�9�a novel5 m�fu��1n�\A3&��I nucleotidZ�e�1cript��!�( NRTI�[11��T 1� ,�D��� 2 extin�by�� elim$ prob� dSg%� firsf&m cycl�� �assumpe�i�aso)��pa���k&� ound� like��6��,�unxst�s�by highvYI"��!����en<���m!�:J!Vtz s!jbui�# g on�o M;� V FM� &�proT es [12� i=a�a�eri���iKE �as��� /PEP�!�� -varo!-a��Ʉ!�Q�m�A��  benef4 suchU��p&�ao elucw�re�ve�� 5d�|nBy3� F�, waIon�offz of!BYr�"� s � to��Z�  -2inoculum4�-taBgd #U:. I�A &}c�er��!!�Z]=���o� lyze&x9� schedulesT4-g&���s�h o:�. I1en[ w��rinsic.�fluctGs � �igE�so-A�ed���g(�Xt >> 6&!v�equ�.an ODE]���wl�2�of molec%Xt/ΩE< a_22�Vb�re"�ŋ �#st�CME!Ho* ybrid=-�!A�|discrete�inu�)��$= ( Yt; Zt�w�� Yt deno�KD]!Z6'�ous:�par�In�ap��� A�Zq��(^�%�Eaaf$)q�sr� | nviron���,�3we�%�E(erm�a low-d\a�$� ODE��exempl0&e�&��!�mmow�A���s/ &@ �!V"!Yis�or�bt* � typ��lyM��&t#of�RY|reach��s��N.:�Dt ⊆!2a�H���enspWa�%x]! �5q%i�7%��(��(��aY*!clear�����dA�re�entw���Igar�O /�A��$of� e5u� V , earlya�g!�� ed T� s T1��>2 , i . eh= [OT1 , ]T^BeK � �]� bo)� y fu� E��={sub-s),� sub���&$�.Db�F���y���>N� �Nh� �Yt on��infres!!� mall� sca4 m� tackE� algBhvly!nE �!#nu>� �>�"� . Agoay~; TpR�φPartic*RїSDm�VC.�E�iuAv�.p pe&G,� ( Y �S �= 1 -P E | .⌀ ) (_&�5+(�G�QPO0|Sga� G �%+�t� 6���A a�Q-42=6e��*�(2.A�s�r6=�-*� .Bifi�as=) ≔ P%5ta� 0] |%c8= [ V T 1 T 2 ]%;o-� t → ∞�)1Y0-i�A�i��.�}͉����=bm5 � wordd A�f�.��a.ltra� $��u���=@absorbaQ �[Ac]TA�$ �}� . NaturNJ#&�.�� h�,mpl� SZ� , PI!�0 )E�−Q��e ��Q�E�,I���4u��&a mathU�F� *g[3��3��F�j��r�ea���immuneV�a>��e�C,6Fur71.R�9alsS+ Z~unѭ)]3CLT thr�� strue�AO�7}3l�%pont� !r2mi8,�e-��y)Mx2�`� !�:�lum&&�n2���.�,�;&* of� us attach"�\ � , fu��R� ,X!��t�{N���, )}Fn�erm k2w�by�:ST1e�s�44-$'9��0>e2 4!vol�J�lel�&!vogramm��NTF�"g*oe## &>! geny�q��#)�N�ks�u< 2 y !�!(, 2��M2��δ��!i�I �tr&O<d6�rpZ� . Pa� &o)�ɳa�summa� in"� �a.m  deri� mK�gf82princi�7�0ive���( Sup%Tex rei P ��!&� ylact{chemes��! ��&q-In�-.  s ac&)=�lM+mA�Nj ���D9+)x ( eq=�� – �C�%e@�f�"a�~)�2�FQ a5A�a�or�Xη�. Notab= M+!?}nadminste��a� ( does+i 2 bio� � @ h&,hysico!� �� ribu�at� %�unbound� to rapid/ro�:��~mbranv We)8' $2�A�2B/ (Emax-^&�� [36].6= Q(m IC 50 m + ��9 )�D�+Nb��!X � %teC�KIC5�)mm�22�@�#;�%���'aT��\ S.i�hil�+��0 [37]6f.Ay��x'!�coue�B2 u�*#t!�.d� miG"Zy,N� pa�3��Fs!u��0.�ar mi�A�!��techniqo? [43]���eq*�?p��>QI]b*ncap�; ��edB<I#a�, i��ss*�pat!�� iiM)&�1 both�riR7� � f ( θi ,H 6fc7/&E4��A, :gM �� "��6���%�isi�A�4{s&� s θUJ p&�2,5�Um#?�-_ unexpla� noisa�Let D �t bA�e7dR�2�>,Y*fx *2A�i��A��b"lihoodA�asu)ne�� ] �=-z �)f K + ϵ ˜ ( 1�I�fm�IG"G<�CB�(� *GG-of @>�8*e>l q�s;i*�corgof#K =�-v�;A\K�D%Xj&hL8�!�.Pari�% s ϵ)؁�ϵ9 ���porAra�!&Be��;r�8�%�ZG�9�5�&��$i" be n�AJɞyF�.� �∼ N ( σ>�:#˜& ��"U% ""6�:i* log->�a��Wa{i = + r�( 1_Ioθ-_)�-�� ean.�p& (�A�Q��ri�>�25�. Ψ�As a�_7k ,�T u6%R)^in+���o�4as�st��nI��)o�"� �,&�s����7B,� o Xuti{+A��,� Z�in�"x3%�<�#EXTRANDE&��%�9m�-beoime6�%1�*a�A�Q:�I c�?�VY)a0��Da∑k ak2to!{�sumAQ K" A�pe� Tg!S%RZ� .��Q�&SSA [4�0no! Binput�*\*j" A=sta��in"�Ctwo�fir(1&} R3D��I�9Z07� a ex`i>�G�3uf!ed c%v!p%-*zD�*� �aL�N4d5:�) A�SoNO 0lem:�/Iy�bya$P(%�g( �"! �2}� f?J�#�}�%#�/�3% stea��ny&�+ up- Be�is Hn.in(;& ( re�@ step�"�em"�+�D^$ok-ah��KAzon LM2�t+Lchoseo�(�k4B t + L ≥ a eQu ,W +�( 1� hold��u ≤ L�g� a9no^es�`m/�ebve0��"e�c i+ St!�:7olv��r D�, "?is ��:, J� s do��� !E . i�5"2 �<� %�- � a�� ,Z���� �="��&"/ �"!8urn!zoaI�eIaYt+%�I&��= ���!laug��q� ;xtr�.jon� K+1thy3�o�.��&t���Ů!C��.�"S ��a�� C T�:�a�LmeE�EС8"� ��e�Y���j�Q� . ObgMEs��9guaranteQTe !CruI��� re lb��=*o�� +4`=:� ytoo, �B6 aM�9���8/t�X�A �a�$��o�in&x. A ke�:&�e�����)�@ a g� choic%�ұQQ� &s� r)Cod�/�Kwr.�MatLab R�8b (hWorkaeNB-@,MA; v . 9 .  '&;7op�,z,��lle}�S����A�t�olboxe���"1 >��QN�#�F�18�3r�1awn� *��$��� &~om%�fi� 2Dp&�V�(*P2; NONMEM $SIMULATION���":�C; � 12 )�1w�hb-�/9�B�pri+) �a�2d�5SD71"� )� ode15 !�A . ToQ�e&d*�9�PMs�-I�uni[Q1� ed random��beraf��i~U[ � �Ad%�A1�%�3>!f� >>��he `��i��b���/M"E� h�-! "RU� �����*?mb�\/8%o*W ��"ZBlo�:��Q�V8��� �3In�Nefa�e�a -s�G4�: F�3� O e!alx VL�1a |3�&.�� ier�&k ~>�Note 4!��sh�T%!%r n29�o�<>vyVs [51;| s� V�&� VL~log�μ.)� )�Lμ = 4V�+σ 698�L econc%-J:��X� =�l8�in�&?�s"0��e> p�A-Pe�Z�,f?h4A�y�i�a�Som!9� : V0~B� (!�4 rhom"Xf D= 3 . 71 × 10−33 )�E� �)�, P = ||VLc||!!�� ||⋅||͛� b ger"�,��#-j389 [5:5�![ n4�P=�"� &�=�X� " ���Q�fr��Nin a 3i=� �&���2ih t�A9�Y&l&� hPa�2��nEg�42,*��&nd1# O ntil� ppdcriA`a S8Msf�@, illu*�%�O2%�E^�d4( panels A & B�-.�7"C &u,.%�‘%�2cG͜%�*%;V�y a��LE�%c6�g�O�Hof�F�Ius%��5��as\� bW!D!�* �"� %� ��*�,As )K�PEP-��F1ہb�U�#/� henc� th� kJ2�uTTEgx:*o�VwRr�6��7eg7/5o �%��run . A Gof 354VZ*h 56*Zv E�[ �8%.��B�l= )��E�2e &zH�Py volu% r�NC �#���YPK!l4YNX!&of 270�s yB��0I%/e-g�216!Ia ,'E��o��eighty-f�26,>�bNV1-2QK75 �n:\%�& @�HIV&/ week� �_3ET4s F8efavirenz switc\UA3���~V� bes36 BA(�S1JRAá~f> * a Bayesia�nt�o�<c3��-��>�%i#3�r��2yAa4Ti� +�5T2+( �6� on 70kg )Aw%����,e��9��g Qi�V �B�! appaoW &�!( CL/Fbi�� U @KA8�Uin"� ]�!T$ f�i Z�&�Is1�Res�Q2N!��!�by �,�Qr&r-I�v[e�k :�1 9�)8�HIV�Kc�]� . Al*� 1#�Nj� isplas?"�"VI� pޑ�g�:e�&�oH%1���AMwuPK-"H |6#�T3B�-D%�N"!�:O, 4C%�3A \���z V ,6s+!�1A��NEx�!Z ɆA>ma�?yna |%cId� tmax�H 8�}(= �[95%��ge�-;a16�". P6 �7ac��u7>�about 4�7��,2*,^imum-�6��um>\eeCS^= 2918nMK 916–433T!C � 8471"63 �133pA�RN%W!�5��half lifuEm1Y �G:)q 1��/".%�4A' ~f0�3�[NtQA���Ha�"�FjT)c*� � "& .� �C.� &� 7e-ȡK�~� a%�}�%%��ſa�&vc'�Aq�a{�i���t. 2%�S2)&B�� �S6F}I��%�Za�SeaU�A2�F1�R6L�J�117�32583�Q694�A�–Mqla@ve�1.� o� y-a�3ofQ+ . Wif� 2Q �-��8adF��2mg <d)�4A�6� 7A�7%M(1�R,Q^�ranX_%�87� to 9 5%� m%/al3Eep, ( 99�e31S)A�qA����r�sAp^'2gT�)� , E �%( V ^� 9y �reb�T2�.����uOq�!�,%�_YY��m5�B�ˉ Kcti*Xof.�%V�GmgI\mwT24 ,A&�#yv�CBP/� ( 25A��U, 7 95m2%�of��' �V|2ch��Re�L" �'�ly6��3Uu�J��� ?Cs΋�",�Ge:�(GW�k%� I�h,*�GA�U��z'9R% 60%A�5%!�fidE� s: 5ab1�6�884�85488�5�4�5($, 9�\63!9,1�U�0 ,�88!804–ep7����36#7��9��,>�&*ŕ.V+-*�HE��0be�s:!c�d exceI]!�Pat�.st 75�VdilEIr. C9Jrs�0,��ʅ�s2� w%�� f$� � � VE�inW+s��a(E �!uVmj.V"�$k �Q-CnUini�W@9a few� 8#.�����Gi r�[ymr�Jb�EgO!��IPERGAYT-u�R [54]��"�WD �"!i-� i�8$OZG3`D:eU"�at :T �s��AA:se�Aecu�#� es 2�48h6�Azf.dk��CFic�Bv2e� w��n!�2. Pf2"g �xRZ)�el� d*G63 A%�)V2�]�%*!���n�H:E��!�:k,"� 7�6�\8X9��Rp0�N06�e� �+4��7S01��5M92–7�03A!Ca�i�3�:8  3�e�V8� 5� 9�ea-@Bl��l b!)E3w�4%%�'�cK;h!\m�� ofV�XBhely vix[�:.%5�4r�X�WppoCFm� 6Ri�u�1MNA [0�f0 a'��upA���ice HmE�4B��@� e’� e�% o�5&�WdiphosphD( TFV-D c!6�Wtr2*FTC-T*�O1 i.�1 Uory�� �u�����(lom�N< �V dela� %���~}\"@%�[3�snSmb�T"h1n!o�g�5y "Q1modmfEP�s�'"Qj�d_7�hyp!si�dh4Q�:#6o ')�Sf�Q� �1R�, �?7N"��� J�0) . Laid�  w"�.�N���of�!19 a������2��O r~be2regar�q�t�8%��5*A�:.W�t�I�:ijrg 4<��4D_!Ea m ! b'�s-= ( > `�2��d�lygM�) �"f�����^�V$`� "���Y5� starAco drop)�!Ci5���\��i})��n �*7 da�~so�9:f` sugg�E�1�ng%� � �8�$a.Z$pronounced�hAth��fE�, argu��Aim�pf�A�)4,l6of�Wn�.su�XedV9�3!�U&��*��!Ա��vuo≈ 96%�in�� A<d"5f� �S)rA��G%q�Z u C*�Wly [56]! surro�31!�okgc*Fs�\�*�p�9��H(c�6 $u�BC"�0!"3Uv16Ae"�ly0T �6� 86-2RF [5�,58-!] #PROUD �8[6�D. artn�%�OLE +i��ariᒥ!&� Nt �6ma�M �&{i)]'A�.�W(e VOICE [58 � FEM-� [59]�g q��atUg �/A��M����oo�Rb&�!ifE�303h�hhauA�� �fJ,?$25%h8ao.�5%XQd��� ��LdnB�eif� 1dSl�*rug!)l��� �"� �e|e�S7�22�e�leve�P,R� � :g �v"�k�o�� � aHI6�BS!��IanjE{86%!�.�G��A,���$. Hj$%Y�%>gE�%�5�"coV$f�Ov�pgN� =�.��f��h1gt!��oed du5Ks2E6� C&G` *\7lo�V, NRTI-.� ���!�!:afI��ups�O-�edK..K! .`InJ !��pa���.8%�%V��%�it�+out^borm5Y��km�’Vv�,�1t1yX�)a.�E%!���8���z���/�!V. � p^�o%Q(.��%*1Y$)ka�G�pv�lim"DZ%0o!e����2.�W�reRo[8�H"o���B�n�RJ!s"oWm�;� �H�ge��* e�[H*�_�-�a��i%�p%la�p v ;�ex vivo/"[JI2is#-e���sta{,�J�>�/R� � ws b�b!� �*� � e�'�JP1ly�'�dex�OA� vd�ua��-! an unmet !�"4b� ior2�`�6ty�)���8it];!� g%��E$*�kbhuman ��5SH'n^�vo �sa�sa(60"l[e�])�>��f%�6oaSf�\c� ��! llishS!ig��F �r$, episodic)]�b=�A] eFARo"�\D6 -dri$C%���y&s`f�$�3 ps [60��ZM&misAL�#`ate!8I�� i�1&a a����!k! planF"hy�t&� >��-K�s� �h^��s� ly � )~5�to�L� 7f�g��3A�an�:!�uaa$�'"�!n�$��:�?"�"��|�b�-�C�_�"�nUd�(okc�LagP metaboW,�Jdi�I�3s"&�ɡ`at4'!��m!j�u` o�CfavouF�:u#3_beyond /e,a_ba�_s6�Ulr} eful�&Kf6If �|u�/�j�TQt!�fur��D*b!��0�5�amufwwe, ��! theore�zbaR&�[wouldNui-&mQ� &Y /*�;M��!Sa"�e��aZN`�I .�S@'�o%�u&olu�Y�&a�E"�?�&MEz!�?�F�0*� curs "X@8q st n�Ab�I�#A� dire�k'8��n�5!�.K8amp�Y�V�u�M"( Carlo.�Cs��)s&�b�3~ "d5( <) <�B�Ympi�br�/HA ℙ ( X�Wx iq~ !E2�.* ��|��!�!SifA'<y�aI�E %L"�rR�Aa� .+6�-&KA;eB=� high�JA$"G@enc}�)�c���#Qv,"�SnQaeI!�aHe! Ci�(jO�0zd�{of hy�`�Too�o[at�,�aH X(OY , Z )�lo �A<Yi�!�Ke5^/:dAa=g(E�h,A$JZJ��7' K�W2�Q6 �Ben ev/;u7I` f�\$5mZc./5bp�J!a[!�!%�!>E .5^|�?Z7> �"F!AUVf:� �?$;τ�+T F`]� �A]�I.�(K��bleos 8�8(�+�R��#ing�pQ0&9a�q g�y%e�=�X�pF,V d�li�8of�TtHi�e�(Z-q ��al burde�Xi`.!,�^�]D� :�[6�67]&� )��^&�i�'��B-a�q2si��qA+� �!vB�B8 A�AR�X:��C |9,^ !�kp�'"�-In<�we� w=,��h�8C�oi�:�(�}*�y[5�)U5v� A "$3)0aRa�mi����0�>Aa(�,�(��Q�# � ��h U Ga�΋r����� �weP��e���+lS7 ed=(W .>��Gnet*hT�2 .-e)x j ����� i<�C*A�Rj(�q�":� F9�!���g+�i"Js2"�a�al2�6�Fsu"�bY K�!tit !�*�bp�N�*�8!��@I�!�NCZH�z5>�  9F  �����/�5eD �xn��'� �ML)�*>���2� �< �A�6&4a �"�"�!x* ��aTu�iŒ ,;z�q' A1*d ��"�^�> �=eEH-iEupd�a�~t1bs&exa�V1-WF�ca��z �� spa�g�*y �o� *(�! WhenB 4� v��he.D�� saf��5Q@� &� )J��topE-}$. C1 !X�^�+t c�$ghtforward�?: U}&Y �sho9DYtr�bV�bc�^�fc �f2]T%1�@ n��istor�Ar�̹����)� �"�W�?E�auWf{pA�3���%9� of>c� ?{!�I}> unn�xari�R�D.c��"� verX@��=# Ysl.�Xm+x�Ir�n� ���&�uMÕB*3ade�Zc "�C55al�(UyaY9^k �IQ}Q�͟�'o� iiisB�CF���XI!B�a}r-*��� ch64 izesA9�[��6�frNS��s�r�)!d2Q,:`ax sui?� aF�*"I"�E�=t���: [68�a�r�%t barrQ"[69^a]&{4@blFr%Gej1.�"A vo�G8Ei�o2 g9�ѱ��2Z7 P15&P1=6K1*n1="%� Z&�*�&� l�bTOx:�ak��M��N����Rr*;2�1�p"�� re�>U� -[BV�oon7><;=K"��,:��R%�d A�P ]�.��E ( byw v�c6�7��6A�21!tIcuݖ��:1"�1a� Ws1s�*>g��>��"��PK �.�"ӈ"Fgw�!�"� .�� A��ye��$ eren��cW3I I: Ove�j-�.�&Q�v��OD��h��t�J͕%��� Nn &Cxofi1to\3(�$� D�"�Fo�G"Re��!ly>�K�&�F$.7 �env"��6V�W"om~1��at!’_��� ~8remV�&Y(�Y#�#1"(w�Z� aR=for^��Moo.�Keu� DT���%�p!�cy�L��'79�L�9: I�i�usفIwN|ake :t7�"�6�,E�2--.pr���1Ne�:"-M?a � �51V�M.�c�M�&�F� �o-��=5�w!�6dQsd�fej��%]Ar. ,����8e6�6�:<.rh�}!j,dpiz% sorp���<≈8 58 [h]�*ndV#.�DMO�!�tr�P(�-6>..�w>�v�s� �"Cir�M��!s"�r� �r*�a&�.s*.�xer���n�z���,�.��o��AC_)!e a� a��%��6�I)0�l*�f�"(~$�iw�2:it��e�Aӑ���a�+iwn�Oie�*�$&q#!�i��"H65�+W�3e ��!I0 *"5% DTG;�sole pur &f�5�Iwhe�J!1wobea  (v�,:��fai��!�g'6Q��xkinS� ]��U"D+!�(5| q�Fin6/u����l�#M���iB��&!Jg ET �� s��,�����h�EP�C-A�d �XL%"�= svuL*�$ , bu� so2,͋�"��ɍ.�ZT����esA��3sA!! b1of mucosu)"&�cervix  9 ctumR6=7�oR�  &�,EwZ7val�~d��targe4G�uccess m � or�3a�x��$5 �o Tlbeit�ed�@��-�2������%�!c"�12�� i.�)!>wm�y!e*rjO2,���:Zd-)��x� C�bl{ �3a.铅�o�' �sn"� ))�'��90%��pl�mp :+:����i�sRT�� >�iŠ`H>D �28!P <c magnitude)Ower [Ip Stri �XO�nm5T F:tcoinc6�� n1� �>0[7�qstronna:�0E���j�[4a0456TA��T��k�C��I��X�82�4%ng39]!���:�I �� ,i�Ip5(.*�2iU^lipophil� logP�s8,"�1kA�A��4�f"^6m�famg�'�s�!ilibr�K.2Yon eiŐ�?1�B^ [4�%We &� !\.�Gus*�:����N9 φv �<�|FY&��es ulti(�rh�1��2�a� +���6�!BuB��J �J�� �a!jx�@� �pe&/�&��~�vi!�n^�S&�ro�h �� :p"shdno��K�P�&n� F��:"�& 8�:!z!�*OmA�:W6� &�QG2�6-S3%<n�ʛ��m�&�to��5��d�I��[4���)rvoir��}!�s�� as 3�c]M[48 , 5yW! �J��a@�of� �a�s����i�s!��G�_M�2X5� ."�-"W.b\gAj��7e�6nN95.c;� >a�C} {s� 4&�)(ources: one�a� �� 4)@"Res2<!��t phH> � decaU�Lbe&1 �s�"�0oB"�.�7l)7e��9���P"g0�]&��_�G7�6Ba�uoA� >ޕed6�:b�#�-) T ( x ) =�ml�)�x� / t 1 /�w� p�n�$ 1 lߖll).�x�C��N�i$�A�&W-!�4�VdJ s�.w��^ͷo90I2^:&�X99�?"�! . La���d���^era�a6�� 6-44f][7�Le�:i2� F� thir]�‘E�’� N�IHN ��cuVi�"53!��]�*�:�v �)a�%no�x�V��x!d5.m72� roll-�&o� }}{g�n�'"Y A3=�Q^py���!� Z,s"1-h8&Zufr� B� EH'�!2�"B � � �\-�A� �.y63E!�� �6�B2�*�6��,� &�.."�>�.wb�.7��� f�<��!�M"*s E2�sb�M&�1F:��^EC90 &!!nM��Q�>��#��V%��~l>i��.!tdAdo� �p���ng23!s�kTG� By%+A(:�sg2 Yz����&�6.� 1�R�t�#�Hr@�<�&�!u���@,"B4E maraW�a�MVC ) [8�Asral�0]�RAL )2*a9 rilp� [60] cabo@[6Wor � � Ia vaccDur.Z�He�stis C�P( HCV� "�s#�ophagyMenhl�r&�W2jÚCre��au Gi�w thwa#m�[)ly un�,�1�Crem��0*�� eU�*zli �E#&��Dof Rubic)#nd UVRAGV�6�A% �t�)��<�"f�o } m��He-@u� vby�� prompt}n6i�A�3 �*�K�-A�i8"0F� &�� pzxD� 98 �r��� �1o �%�:V (�C*r] �confir�CbRNA$ ckd��!q!fR��- a1� i'Mz�d��,ҥZp�]T# )! �A{�:�,6 ��� �a]f]�&IC6?�+>��>12 rA ��>=ofM*fac�@S~���J�I �subge�gc !�re�o6%�"�� =yn���!| a%c &E�~�Mz�"-&�a�CDF~� NS4B�E�*0&d�0Q! ��m� i��$u >f��,A�"D�q?-1M:.pi� , teX��0�;�e�ic̚x�M;EW)�I�. j�� &�0(athl� ��0c�uCe�r dis�����cirrho�!4h�Goa�u� carcinomaA�D}���!� flav��us fam�CibS 6 Kb� i�X-� �A�E��� y:�a�lyMy@ a ˬtha/sl�0ly�t'MX9. amin�ido[�-� ANpa,(edD"�b� �sribA>�ntr��tn/ IRES&BA�R}�s"�5’-u:$�bgA4!"%<6V�Wcodh �.�co%�"�9-��syn��dPJ�ׁ��y��Z�b� �'�f%�a� ["�ZANS!�NS4��e�, NS5� NS5B�m�+��)T sA&.[��aM���A.�A�e�yo%4T�A�E�^{[�V1nA�y tc@F4A!�!!.| VM-��Ъr ggre�Na� d da[�org8k�o�re��a������ begiO2o� ��" cre���e�� opho�w>cytoso�fa �@A?e20�|I�:\׬}!@3:M�[*�9eaE����encloA�double-�ves 6�^r�=-vazt96� e!|fui�"lys 1e2o'�uto?)�a0cargo%'%6 X!di�Q� B�zy�6�[1�n�y��l�$"!�I&o�~'i�I%E'�?Yj[ |~A!@��homeosta�.Q��'� ���!]sA nutrei$E��MgBQ�f����!6�1/.��:fZ�6 III'W atidz�� ol-3-kin( PI3KC�)�"��x � �t���:W�WBa��PI3�W��B[A?(!* y [1 ��'�;6#���Wn�, hVps�p1TYB-1M , 1����c>�8��s"��t�mughe�clu\�5�Atg14L�u[�f1�K B�1�A����Cnu� %!&��� K& ep�X�TYm !Ne� L=Nreh�9� M��!�a�:�6( C Vps/HOPS�X!�� !&`6n���ex�,-e4Q�GTPAl Rab7� � �")7�S*xu.5�Ǎ�2�e �}"�+��P& by"2 ( RUN doa��c�o���n = ")�IP 1G�rmngu����!W��!%n-U�ry -$v�2��� !��i�c�C-5�![.e��q�!�[�An�i��xb�����tubule-}?��$ -chb�3 ( L�i.EK��s���'.�e1��P�Ecovale�,lin��Atg�Atg` Atg7Aϑ��e� ol� ��QGa $oli�.�� i=a2>s�to log!z�0�aT}�� �i�z- J� �%%8n !�5dM�����-0���~so�od�,byq�-,�#)E�u�inner"�&A.�aa�\� �a�of�� W)9a�6.��o X�a�#rkW��-+6\ A�? !-z��useFB�A,o�B� �p H"VQ&��)�rs�=P rg V.���l� E����(�j1�=2 ��IZ+&�inv�%� ��ąI�d5"!h2%�:��f=�6rˌ��!��aDZ��έl6� �}A�'� R��.�.t���d��64F/���TT`st! 2)�.s,� ��uhxc5� "aZd�!\ !JFH1 c�"-�d'r�/� .�vempa�7��us*��,%�m $an m . o .7Bof*s!F�� �VI���([ >j �� day 2�t�r��( S1AN=��� �i�+"�:!^�ې. C�:Cly[ at&�2,��)}<��W� n-bl(B u.�9 �1�! � :!��%x�r(%5!�, -II �"�aAd�.m_12 &0X='�6VB2C24 7(4xr��mA�i�!�9 B���!a@8% ,p6;ua @Q�n �M�6uJ�w%~ meast�7Rr��T���&[2� E��Bn/AA y�Mey%��%-�!�wr}9H9<�r�4nϊ* ?! IT�3F%@�od . R)�rag� 5��A��"l, at 6%5^�R5p�8V�Z625�8p�a�SFatb%�5s;A��e���a�� oughE8�Rt�(�؁;=�E@7����asU�:�y"Qqly]H':a�hN&Ar�/q!�60�bf^2 . Si�k�]"�KeR��aNUg�a %�'J�, E{ �x3Yis*��'S2�o8+HCV^@.-��uh7�l}f�T!�"� whb62 .k�(A� .kQ��:Wl�CV�! &eI��!+!A�a;].RFP-GFP-�o�]�/t"� Q��HC�V��ѝi$4H d�)uF �� ]7upE%2P1 & { )ic vacuo�h=!������n!U�esc-��al�af�\!9OF�a;v�( cidA�"�[:�n�gGFP!*[�o�FH�(���2�;nu �H`F�U�)gu}��31!& ��N��ic�1n/ &h.ci&2�y|��!v��A�FP�B�)}QAsB B'?���B#F . 1C%6.:�[ punc ��?in mock��bw����o�&�TɟAڙ:�+��a�A��bsͨz��`�Цal��������$.A2&!� ɋe!=�:a,Ir�]L� J���0\Ma"Yx540�d7-ZZEp��&��!5�T!��8)�K� �   they HF��'!��A3�be5Y�e_.�4,��A5u�46�*-p�\{ pV�+ ���a�N *AyBer-�F�Q 6�U,:�B�f [<a���%_A46Z�}20%!>^�6�n*P*�F�!� �1�p=a����0 losE� �5 �".c��To enF/���i�%�z�T �-��!��8��An 8Q}�@E,� ���!a���%/�"� &� ,&��0l��r 2��z�p� B�aQ!S�R!b# 7B��HB�J*P]0F�a�at:7�,���!v- �TUX�Y$z��S���%�dW�`gS&t LAMP�a��:�J @5�-9D19��.�yeq�F�q�u�.-.i�e��BMU�& Ef �.f"B)B�zff�E�V$E(�cV��E<�� r��@Q�A�re~R-�3de>�'A�� Z" ��5 {* f#"B�S��B"Z.�.J�A��ona� ��, kK(rH=6&�&��&3� ]�r]� "` "F ip� l* ���FOu2�am*r;:� ��j8{! R�B:u&� ��R�H�@:w�b "7Ha�` ed���y^#yb9d�^tA��#ou����a�|vel upኵ%��y����A����� Z�\[�!3# �ioz�"� -a %��3��z�c^s2�" .E6�� �1|i�!Uf0&i�_lrAg*T fEe)\v�(6f6�rai�Ae�;i(je�.�~�0I�"� B mi\�Ju �2k14"� �+-[r�Au> 2ory� em=WA�t�Me �^e$=�9i�)c)r.GF�jI��}N�-\�! 25{j�.�,E�&V�, emi-I�W ve RT-PCR:�S3͸,E�Qnd� B��at %"*~^�at'L_}^r-�re0l�NinTcyt�(YA_9)�PL<-'���L"H��2 E�HCVE3UE�-y6�� R n"$Ih)="�$6 @��1B� �lF0g0)�r��:dQ ͹�� p Zsi!�kn�.e"�ϡ�U-����>_q��ZeY �ѻ�veyE�r� NB2�B�:�=�kA� E!)6jA{2)�2a�#}�-p�T �8'Z����o"� l7.d)��CE5in"�6� ��>�wn� �.a!1� j.1 s 7 .K i��%� O_)�de&�Dgrf2!I��r)H�1�&�6�b6&A��6�6Ek�]N Q�N2����26F]� �m�a02M)����5g�)�L.�.N�i.g: 2: T�Y+t&Z�'H ��. hIF2]���u !�F ��on���.�b�.al�\R�| 2G6���ta�! i�l��V 2�3FCz�w����#"�! olao�6f����5��A�e�:T2 E=�&�66QdNri/�2a��� R� i22�E-J� M�Da�O��6!7B!Ţ2��,6���1G�4��-��\�*R}��u�o �5%A�6�uqK�6� ���=8�!�=��!f"@5%{rj)gz�eM�Dlittl�Gaz��v�"fH2�,�:sum�AZ "&A r��6�!Falr\�B�. IY��M J��_D#% .�7uu/  �|L��,��,�=!fffesM$1o;�� �X.�:� �6��0i9U(Flag-taggedU�ISAoCcy%�;?�Di��os&�+�6��i6F�A N� ( S4��A���Y2�OZw N�3W >�}T��&�o � q��*8� argi��6+ #"�8!Yisnx6?� C�P]"��H0�zJ�$!{� � s�A �{��N2� -0GE{a�EI� . ][u 6�*6�to5}ٍ~ d^'CV6> ���s���52B��j1IBc)��3? :� 3�*}1ie�� J\ ]�I2 �z�.eQ�:%��ME+� edR�9Y�!2�i�.`&\E !R�e��)sof�� j�%eZZJi�1^*Yb�m%!BG��Y(�k�to��J�U0��U>� E�3+-�E�atu�� � .+;� �??aT%� o9m!�.� B�a{:�2o �.2F' �&�.Z�%��pt!�fpA(a.5���^1���!d�Div�&!�B��& *ݸtUR��1ak<���V1�Tj~)��7uc��Q3 ��6h"A"X4 �q�4��w/�E1~.48 hour�[s post-infection . Unfortunately , this study generated inconclusive results , as the inhibiP�tr �$ed with ei5�� [3 , 5 first6��vE2e�2�,�nd URVAG��stablv�A�M���4d previously eAishw 0 our laborato� �F�6�!5A i��y-M���� e�F% Q��%vapproximP $1 . 7-fold(6 ��sp� v� ase� dhS� a8wa�� �)$b�R�� [F� ���5 ���F�:��U . 1�1���8A> sugg�� at�-�7 >�!! in�|txo� � possib� �we compa� �~rel 6 in>m!(nutrient-stUdM_N�6B�M�ct��pA���U�,Va9��2 !6��Xa time-dependent manner�A�no!�are# � 1�whe��W!HyF�.� ��co�4C2�9 ����i�Ź,Lysotracker-!~Q�H edEalys)%Ta�� !}52 Tm�ed� -LC��weMԁ�to���5� popu!�one�:�(( i . e . ,Y.X Ddid not colocalize ��4 uto~VN� ;� J�C�9�ol%'-GF) )"display![ew>�1~��d afterR�. A2�60%a�th��w-(j�� 6y "m1 of%���>a/:�� A�a� mof>�, butA�%#v,�>a2�3.����*� %@consistatE�a�R:P6�eS�zi���F������I&��a~r�Ee�2��4%p��z�N�weW Cm����� �>4EM�4 +.6��in� �F)!�is��A��͊deple�fG ��du%basalE�y9:=: %�.�����!`-"u o]ymngIA�-�f� �}���`degrad� !��F!�(h*C1w=F9loi%�ND�kE���!�~%=#F�f.� �  A�- � �:��6� w5�2��F�B��TA� lack!Sap��8 ���might be>!dominanA�%oR 8Rm�oR~�>�n� u^2E)91JM}�rkFj1F@,� ever ,:�E6edE�!��5�: as well!M'JNGE�6H-�..�.nLj]com�-2��J�1��  ^;�� Ii�.U?$may enhanc.&via ��m1f�� � Fg&is�(uish betweeE��wo*� ie[1� e�a�C�KBq ��s���9.Y NDNA"b�r�2%T(bicistronic%��� encodE�z���6at1�� ST ,�/r�e��A9!�e E�^3a�je�� ol)u:l 7T]ii >�5%`��6LQf!�! lipi&1 � . Hoѿ"6@%�cle�&�)�&v.m. . Non�3!� 7s ed�!�j}X�؁] tere��B �; Mb�vagr,ATF6 , an ims�marker!f.un9�4response ( UPR�QaMa��le&�PRM�$ 1 by �E��.�I�=rU� into= l]�.t.�2�  icu. Agai��6y7)7��of �Axrxpr� �� �z�,, although o��HCVLWmfso �� 6V�Ibei�]a �er eZT~ wED1��:R��6 1��� %ra . It has.�bT)������ocA�6�� I!g�RAЩIdem���K�=Kof]U�byw� rapi��iX� eteca�as �A9ixV� 1� i�!���~M�� egan��accum<.3��%k�"�ly�D �� poin#f�9\�C.�L `t � �!,.#o2gQ-W"�#:� ']X��� �^��2����� :� iq�:>I3-� fJJ z�iA�e-�st��6�!>at le/parh$ly6QeTM5!cz &O-r .>]�“off-a)”�IFAFA# r��YAatbN1�q&�RbLR$�M�Gis]���@>P}��PU��A9caU�vd!aQIU�4:m \"� !��FIG>�#1 4%�j% mode �ANreg�$eh jd!)diffe�U�� ��llustA 8�o&a� spitR� ����e lat��M`!Sc numb�1�$ic vacuoleVmai�( ��im��5A1�ҍ�It�conceiv�^�� A���Y�X'ic initi��!)2m!+acn}bca�"� [��; !II>��is kn&toQRj�]Qy [18eOurX)�k FQ�U�IRp"�$v �eF� Q�5E� By u� %] harb�'!$gjj eJ�7^ f�!�� � >� �6�'"��As�59:�1݁|al *s'� �sia�� �>�,s#is�%$R�>9FpooE6.��)i�*:��E expl wh awR�Q��R�Zxby��' their., w� LR.E��~t�a5+J��%@!h��}[]4:Fz��5�v�f�r}W.e�mextens�m reorganiz�iofUk �")�Aila�CJ�,>+b�pla!�byz Q�.^ suchU� mallU ouble/vesic��D( DMVs ) [29 , 30]5:uEmE riJ%v�!:�9 i��"k#�!F� d be�uens��^j�isM(wiQlsoAU���ya�$&Cw.�J � .�,!�i�� [4��WM)d);studimw mechanism5�3E�=�6B:�a)� �9R� �}?W z-�a7�Tfj� o�eZ,� Rab5nVps34a��U- y [8Ac1!%��un�r��IIact{�ibu�|�/�n5L. P%-x� .��%r-�Q�ic��3{a�[+*7 , 1�i&���%���tselff�V�n�ev���5�,$8},A�>Yayr"]�^J��_)�[31)�Bz �A 8Q�.F�� a%�1a*% N cripe factor!� clud��. S�)�4B5 �b� vol�m�up-M�a� F� gene��O��:5!��B�m�a��a6�al-� ( S3� �M3*�$an perturbk]�pathwayA�� "ir!�� #-��1,A�, T22e C fut) e R&m"[33–3� $For exampl!8polioȅcoxsakie B3)6� ^G0��r�j[3��40�, Rota J�block�7 �uA'hy.� �EG�"s.Q s from ER� viro�s��r%�alA=A�.��y$cle assemb�*akece [36�DenguH us-2� ENV-h"�uAamphi!��Y0�/tN� pri�� form"�!�9�,%� �)��>� [4�6w �, aa*�� otypA2� both.�m6�!���.\[4��KaF1's sa�a-associAherpesI5( KSHV )�EB.*�*� Y�qoF�3!�I!�*�k `��br _K79� o bi) o�d "��*-�n yK7aj��}c.��1!oa6!��!, &�6is uniqu����� �9 be a*�freque�7� oi��b�2�o�]^��+���� ir h&26A� .. b�!Vd"� z7( gif,2/�*-CE(Signal�D�?mo� $-A��#monocloa�bo�Millipa�8.�.".)B���.'�9([45a�Pr.�ex�1!�( !�. a@�.� tt�iuA�0M-PER mammali� YS!�rU�Thermo S�?t"A )5lowUOn�F M-�:knockd��k$s ( 1��ah!s&59H( SASI_Hs02_0034605ad)�!,1_00113688 ):��Cu6� ;)# LipoaR�e� ,iMAX ( Invit� 35-mm�hF��( 2 μŘB  each%�rQ%t#@!j�!Ǎ �����fresh��. R�o�.%!y�6]=2^a�Q�was�9E5,phosphate-bu�� � ( P"� f��3�8%0a�ldehyd�!15�!u�S.� %c6w�B�pr2�yE12�n�.e*�"�� �cXif!G*t�Cm&B� debri� u�8% subj� a� SDS-PAGE � rophorei, h!�semi-wet�}r�""��;�,5% skim milkh1%�%&�%aBJoverne 1�tha %Ss 9!S*g 1%� en�e T�_2�JHRP.�Z� ���^:�3+chemiluDC�Ft!tC!�Pierce ))� appl�M��5� imag��cap � LAS-4000&a syste�FujiFil9 Z6���!�� d[:�%TRIZOL>��Gg|nk�ly�Gr7��Dw�SuperSp II R,2 se T (pt~/:�aO0oligo ( d ) TEG�Ck � es(H�NasinAromegaeJGene->�A�>e&� � mplify cS0. qPCR�per�O2�Taq�#�J"e 5� Roch!��ŕ�@� he F�% Real-TimeE8ABI�Sa�qu9 t3=l!Y>�GoTaq GraMas5Mix2��y6t��.��gelJ� *M<�,A2�yj in growth��150 nMMTr�< Re� D-996�$, Carlsbad �at���05�f�陽 ��%2�rin���V�F[A�W2Hpermea�>!�E�:��1% sapony,1%6alb�HtS�nd50�bo�az�!�ω> ���A8� .iFQK���C��-slipMm�in6K( o�A �\�MAqAW. I�� Yacqui�*%#$Keye�All-in- /2�K��R@ >�co"��measu#!af_A of ge'`taq- (Y. ) pixHKCt"a")!MaM�[?�,�&?andomly&/��>50 )�y�% J�� oftwx4.O�Cyclin Y-$ 1 ( Ccnyl0 is�ewly-i�@�T0']c ? fami,nd6x&��6)s]>#o { t��61fun"� �i�Io�Mcha!were& �2�"s H�wR u> atD!M�%abund�O0� � test�Imm�8about s�T(s�� &Il'MA � . Male l1-/- N�� rti�'hm2qfe I;�"@n*l fE 3*�>J1IjEl1*&"%&�U.�"w.YS�~ atozoa ob�o��G�J �66; impae� moti��Vre�;eX �MinZ(annulus regaW$and/or a b2 head�1fo5�A�_& #�,9�I�*�6kin16A� DK16N as de*,Y:�. F>H�yJ](CCNYL1)�"�E o!���!w on mutu� + ���t*�5#9ia�� More�mW .T6K �pv Q �4 addi��>6�nT2e� of��ory�E�= M-<)�ce3- �3�Z!��<N 'of Mby mass g t| �R!? &�Qa��>Nmo��:�NsN-t�N�SIoom�A�.6 �����modF>h69%O$e�S �*#(ly unrecogn���O |=�-�sm�gens through`2�N�. ��j* mpri�:��of��ly# �(���� exer�h� cruc�T TEa�PZ|��CDK�'.Di���n| � �7 BE�re�vcA�a%o be osco;aiI�ir�M��A!��;�U�$�}I� �%� AՍ��$���fluf:Q[� ��! �)<�do�necessar�M��!�Est�$"� ����� s� ng [@!A���,E�!�.&�2�$among meta��[3**"s!�Eip63E���06Nl�I�velop��Tmor�X�8( Drosophilao iM �=�s)Rek�'� have.�6a� �� �Aw6�HEK293A Z�a!�m5Cdk16:��r���!�imply�Uq ��^E +�[KI2 �Sul:�I�4Xenopus embryo��E4� a.2!H$�<of LRPD:d Q�0s Wnt/β-cate� ZjiY@che� G2/M�m�@T�C[A' �+x". I�s�sY��4reE�� �T"!�an"aim�e�!RI�n&~*�h%e$%�Tyet.A�.%<L�g � ."��� � Tse��fa�ItE^s 79% � !�R� 0 !�A �""� r 3 s el3[. �A]�ne/Txe��A�Pdi�� in y�6� � o�m4�i��s"�'&T4Ap� ges ["�6fa]�s��v� q\!��A�Mnoryaun�ofn1�CDK2%�)- )E"be2� l��1� �i3de.� . a�!�Y�& 5� � lsAgv"D* ��� u�!�1[8–9-T�0far!�� 26�z p�� Y�*� �y�ses�� homolo�.S ir*�#" t�!ny%�naaccord�(O%ig6�PSTAIRER f.c�/c Q�t���u�[1�)Lik�is��,�I>U/�/=f]�1q�"�%� &�$� l Mbi!���,&1a �V!" neur<q� s [1]�� =�(in 1992 [12�A(-�!APC)@I a�gK/��,=O !/i�y-�^2Ebr�3[1z(A� d G Y�160msb bx$eq.Q�p����!_it��uncer� i% !x�!q?�E0 on [1�!)<�9yuZ!#6� ;BJ�Ser119 v �7xQna�� 14-3-g* whil6%�ofF53R Z(ŚB3�/1�A*�.r��!�����[$�ZwB!apAg~9utf[u, myoblXmig� [16A\exocyto [17�3��,$[17–18] A >� iTov�E�un6�Q�� ol%���L15�MJ!�({�l1%���rup�p . "`� over� heAA'Aw >2Q -�r!7&� �qcn@a�u �e,�A�e) rmalB!/&� �/!*&�&�`!.`b��O�)-AA� P���2O(��aesm�R�bof�cy� �-��)���Ude�Olea'Fo F=de��2H":6a9Uteg�&{in^i_ TNF�r� !a�"o_i@1j&b1N��%st�� stri�clU E W> �/F=;:���:A@��a%5�ng�-��ѱ� hFkk . OvJl!� novelB�!H [in)�a�\�n:u�bݮ. �u!�1v2�i4���|aM 5n���M��I�<�� V�at!A��ue a��4 Y PS ��=%�6%�kof�� ackground�usu9ICRa�]�f�zQ��( "�VAwle1A�p�> 8l1�up-��!�ag��� gWek�!��Q{ reacu aAd teau)oz a�exux/��-�C���d%QA�!��*�� I:�[1� 2�A�Y*�Nzu�l�Rvg1�V� $&�!detai�ins �(!MW!Hm"y'g0�p*�X^'� n�M�p tubu�/G M� (!?l�OE&by FACS�&1A� ) [2� I ��j)�E� a>� meiofh�F�&,until�<�E�q�� . A dramaT<�-��-�a�� �hlon��ng/ �$IY ( S10S�"B�3.SA���_�negligia .� oniaQ�{V\CS1C-n� � labe�)#��cRw�5��Bw>�!x=)� ��?mLE4 65 rrow1�.�Cnb�$( )f] -6*+ �st�<N�A�-�j�ei!Lye�) ��*7 kab�M�)�Lw�%f($�v +3�&5, y isk&�3fir�\subA�u�2�a�)�F�]�!�� �-c1�1p:�B� `>�M�7� o%*FE�Tak�� d9 se dat;R1 eX15.� might��y\/��[1]g퀅�ZJc���%�Q,�|wit1> �+GeOs!> [21]-�(2A top pane!S2A�a�We&3no"�c��!� phenb7!��-��6ir WT li�E�a&QECBa�o�,�]swild �7X!�n&Bbe�G�4n�1I�2�.K8,f�9=�� ( S2��Am �.�d$���� .*A7�e S1 T�@a^�^� j aO&�� !& a�.R�} hi�h*��o�2OBx �|S3�S3��V�0�oH$!~L &�:-stimAng horm!��in>0%&�ab ��< lS3D%7A�To�c�Qi[ �) A!��w�B�!x&'Hqb\6� Dcaput�/ V��t/Ra sligh�& bea���cyemG5]A�P6�!d.���B��s�(c�8ofj9tZ#� Q� �G�>#.m6�A��`M�.qj!� U"}��5Ssof :��s2E–��� oughw#\A#��*eai��#<capac�)on WaC�;csLS3H5xA�%6Ko�4.xto��ze oo�in �2bQ��;��R0%�ɛ� M��5i��1o + ocys� c"�giWT� �in� ch 152bk!�712[5���;se��e*�;M/.�]j �B�AaaN�H=�y1Y 2n.h� ��Y!pr'[Ne�uy1Y-I !�t1p�(.�Iw�(�u�exclud��a- >E�� ���.�D . Si� a0l1�  sh��e���� "�A�w$ 5da��H.S�AZ#wefi?Kac�Vin��E[J� g$= �E��n_ ly lethal�}a' 3+/- �!� e� +�  Fbe bor�s�adu]Wod� 4Am�� ag��mus�Vvh@2�� �2<. M�} �A�E�1v A�CNY!.'g%�c ( �:AS4�,�uAL1a7��}mU6N2LD LE �A��%n� m=�xV� �/wo-$6i� fi�)eH s�K�uepJ�U �� �e�L ;�!� . Al*l&�"�պr� Fo��t�(� �>�(��3�-. A�halJX���AWae�p)�A!$an2=)..(m� $�di-V)A wrap��a�M neck6�6"$�/ ��"� &�Tc���<s%��4U1��� �=tBI Fjl�/3v.�d Ge� �{ ;<"5 �Ccy��ZytA�.�col�@�m[ pl"� �H(s98*tom",!n.�Ora O*: 6�.�D!�$log��*Y6U2b6��.�!^����"�v�cuq�Q4 �9=�� �" �-1ʼn j:���no erJ@�6�i�.� ��nS4&� M2/+r reqf$�3O�r � al x.:ѭofyiA S4.� �x�?�fa^J%j!aA�I f-:%wA"%�� � udVJeb�+q���[R &&� 6hI:S�Qux~o KPc[ t�W.w)� �#�o1 41b~/�|on� "� �FEhemsel�Q.��of TEMy-"$��=�m�0no mitochondr�� shea�It���e�&�"� �p9 g m6X:*ttach��dentiE1 aMdE�#B�e� 3�* left��P��MD:n breaka�7e[u�IN>��A� ~cr Isi~extru�>��$princip�v iece�]�middl/ :��t�F&��6W"j���6�w*VŵhCa���A at �:��n�o�+�L���0A.V ��ri~b>�Act�"!keletonY-F%���8d Ye�i�ES g�a>2�Kcs�ch�. yw oxid�0IV) y ed eq�M�2h"m'WT%OVM';) β-�n� ���L��VCM���o2�mA�!�n �mpsbeEX!���>�2..��  ke�lec�.�% �polymN4e AUde:%�e��A�6 5&R >�F-# to G <#�!��.�[- �v�!2�g cesi�WT)�"_ ( S5&!UH-!�:�!�%4RhoA/Rac1/Cdc4�wk-F6A|U�rearrang� ����UlY"!/WT% a/asA�3�[ &*!scd7�3 n�  Wl7�MA�Oi]RF!s w� ��&*�!]b�l 7�:6��.�� �&ofI ��Na�P���ba(b!)Lom�rN.ed�%�yt"��$e�c.n:Hm.�d�. BecP^<'ins alw�G*CDK(�,f s��t%�  -!-)X��.!�*2�& �K4 ����t� �.@!j8tw�agD�.Bn�ari�p�e�hhd� �~4ɔ��*|dx/�Y)mݥ5� ZG4��H"MSE��'6��*� �bef$^��\49# \ &u� Ru(�V�T q["� M�6��T_ ��O4F%�&�!�u9 G.0�(o�M�s!=!%aAC+ �jQE}�M͌9�*%�!1a�16X9* i��actI�)MC����gDFAM6Q� RwA� C,"~eo-:2 .�,2� K�+SB�ya#� �;���#�� � at�ISL�. U�$ �Q$A�7H �e{dB/o-163f&A%������a�"�&�+ .e���[�ma���co)hprecip�( CoI�=�es��tissu�+='M7K�`ed�3T�V �%Q].�6-T2H��#)�-� 5�N.�� B} �-s�U�lPp42�(�b� We Y! ��bg :cA�*��!�;�x ae�E#�OsgE I towards ?�Kn�vW ���y_{ UEB��HI��!+e��-d trunp4�Dag"� 7CE%�50."�*��N "n:do&� �.in�CB/�bro�HorB�mQ&+-&��d�$h!,�r�*I m>P,0m�;śQci*DfdU-9�/"�( �sz1 , 2�7���i�->� t &�+`� )MW ��u�i:!�>P���)*�E`by11 s%�� ;a��.ypA��W�w>�co��6h� k:���`)inB er)N( �-E-v�n single.y� ro"T 6� �K.a}��s5Ri"��!&a@ohexim�Ech� assa7 ��;nu�e�� ��� N��"1 "F�-���'��%�I�!"�6�C 2 shif�!� "" ��A �"lU�by "N�s 5&m.#dband-e�eli�#rb>1ޏ�0D#k� H y�N��1B9 u m��I`�)'B���ud'/=%N!���)��g/ �%:�1�"u�7)��checkYs g�BA�-�6YK��B@ L( K194>w. Wc6�.�j� Q׀&&.gmum��SI.�!W�+( S7AN %P )�i >-Z�2r :�Mmdmi�%�J�_ �� � �. A:��>�si�on 1b�/>{D>y*>6h�:.j:j7�qI� taP+222*iT��*=3A� d 19m them&�+�*xa�f5�S2 G*�� S1 De2t� Ow19-, nin-jv��e% �'�K`S3J S64�'6�hS81BS14T17T38� S39�>nd S47rRp"fVd� Z%�NYr�$ f! )3*�6� z80~U���ne<;78E�j,�-1^M��+-UA�D3(n A�����|_alw{dB� �. P:U Es "R5vxCif�A�$.�X�\i�N �DAw ir �YSer/Th&OE>c[!�12b;߁e� e�;h^� �16U?$� b ��rg"Λ���a�.e�Id O",�9 �W�;s��S3��S36P*480� Ie��<We)���e[F��O� �YZ11ELE\1191�539�.�L.3" ){t&`1t� ey+:!3]NYo1�9�US�S7&�/BE2�M>u�+�a radio-�i};>��@ ��dl re"�bq �E �A�f.�V"1v>/:�>n.gP��B�4R\s.��"�r@. C" ��l����e�-4�&2�irB�|g9E�a#Fg .y*�1�(:�st_6��.^A7T weF�2M ���� jF ����>���#�Mng-LB� S4'a&�&s�H�ya0? &�CW��a�>*Rzoa da�KIder�d�A intr ��$is�" at g�@n&�2A*�t ` ]r"j�@�&�3*<���s1&���i �$���z.2s( aC!idly-)l��L� cl~ co-o�d� �-s]� in:C*�hdVis"MM�]ens � orde�"61o6$Re[E�5�/8JClk'{!}�26 ˊct�=�*Ao�K*^�Xs[$,)���k.�:L[�Fo+'AFc���FAqh��=n�pachyte8�Kplo � �',%��O�(�SE�:tap�I�6�0 E[�h6�`Vr}I�*�%U��F,as�8J,� ,!�c�8A�`j&al ��yD v� �w valuRto�� xplo� �"F9= n��&VA%Rx��1ll�$to�7V ity;��U� @T�CNYDE)�oM})�QA+��is�Bn m�G!C hear�!Us9�d ]�>�Q/!E��� �h'��7r%4A�D>)D!0c�X5)=$c CA+_9sco�F"C��;H! enzy�>"h ��!RL1�f� k!x%65<a&M<��ge��4A&#!dBZB�K &�AlTi\1Ł�R�A��\9�at :�M. Giv�����%���,��t�-6v!�*=+Q A� thymj MAI�\ �&( cn�Fl1c�_*�1�Y0E�k"rx�>�a�.�profi�=.ML!��lyE�e�w��: *lgY |"xV�&�sh9?~�5Y�6�;1�v�n�G>� t-&M4EEI"�3e��4q���$p;L"�.G.inU2� ��makJe *�<�-6 worth�2futD� �C� Z!�^ ��-A�UM@BN!]B���iY�&8�@<9ndyi�.& W�'/���AJtA2fR�)s4d��kzN occaA��t }��QeyZ� 9� e spa\��ooA�-qѭ�S  A�s%|p4Bcl�"����`v!O_��'!��d�U&%]n�E�2u) targW3�Ba-�aLa*y&�#(%ei�n�kGSE67��Butim�noq�YA,0Qc3�y� . Septin4�o� S O`"i|&uB�a�nan95!a&a.��m S$)� 2�-;2�;1���–���p�2/Tat .�&5 �6�ls>�0or6v�[31uR SpemBq �&�-enC/e/-�w-%c�Q>_z.�:75� !��).�=�>�to�f Z� �x&� �pa�*6� M��E.�W��E  "�0#oSn� �y �% siq�ng YFP��c��j%lic� ���:E}�hNI*j";e� ��9sQ9�Hm�2(��=oGQ}�4��:� UG%�Z ��O�s� e���� �S���)ea�l�5of yK�#Nhi�3*�6,&L� �.�ш� �� �Vz�,.8.�, cand�%m�este��e*16�`�^) !f�4"��e]�3 �G(l.KJ}.�'��O~h#&�I�-ZisA�DKG�n�rphanu�-�.h)6:�EX_.Ww%�' !�ir�W}[u�Mud�d.�Y K���y�")�N&� wea)�t�!e��\3.�X�JEL�}�9�pry&�*nere&�k%��>�V��Jpredic[oQ a m�2a�ss�ut 42kDa���vc0d��n�;53 -)ȁK�(�$ �� �s�m. �)���P�� ,BHse�W�B] �3f:��͆�MG(����~�2 �"�0d��5��"]/A%��[8e�&�)-i!� �1*f6� ccur?(R`���\76*�Z bheJ��t)�i��obaf�"� �J�A�[2�+y"S �� -�eB9��/ � �s1 d)�mRtf+�cDh _"�$/R�%p�3�$&dU� RNA# H �X1^MҎuEwlyVS���� ��i�㭚!EU"�. F3��" <a�Z� �3 >(/.�>�0%P>[S�tN�f�N:�"G&!�z�1g .�-s +C"� �%L*��%AD6 2+ � 6��'us!8�g�..@(aY"H*e2� W?-�J"^Ca&$-��yw(ty$�)�A�"-= �'=$ �uD": .%�%pu�h�6� &�;orU�+lay��of� �N�!"�=�B Lu4��B�,PiR6�A� �3��: �� � Ys.( !0Vory�,�Uwb�Z�B "��&L :/Qat��2�`�B9�*�����>���'ng.�"%/i"^-$A*[�"*�"nF�z�s2�*�%�1E%a���Ɍ�Q!�E�M_%� 6?./-�a�aFp�%&���zEnyq ��A����5q��>� helpfu�[kld-�.�jx�~x\= �%wm��eD�ndJ4q>I�^� p�� �-��R�U,�$���mS�!�2�5�Q�e�I5.�)GPa�-��Dp:� Ife6�v�f�T2E@;uшtC a=1� s [3�%�I�F���\I�Z�!�)�� ideqEc�� �r1� ����UA��ac`�Ei >/v !� un)t�r~g^��M�Eh>Yd�I�A> ,\ ���x Be��� .P�� �OU'[Ca�[>wa��O>"widL �i9%!Q&r ��u &� *a1�E�>nCc"�r]|a%s>�9oP��$�ax��� n"iE[3����*��4q��]� � directly�|COPIIlex!m�'s��8cargob  +�i� t12R4es N-ethylmale�1 -sen� ��w Q�r�!a"xDZ":ec�5ja�*)�dysq����>o .� %�"�]<*�:5F!/ vesi��?&� OaH�3"� �p�E";J-�� � rR9�"L .R���!�/ZŁ>R� 3&�C�X{&�`m�:��4n���h�;Cr��p��� :jM���dm�v5;!^{O��foc@0��jti!B�!����x��:�q�%�yuz ���!p;!�lowa���LT���&��wl*�0N~B -`�, �R �R�/UE.�!@�M5��.` _C4*�orM� (�� y )pM���1mm�/tru��%��p`Gae !�ee��se\:2.�.> O�.I ���$�� q�� �n�&ttr��>�H-�t% R�a�w-nA� N�j�i藩�%y?�ea� � ~n- I1Be*���@c"�=��ery� �i%�&��) [3�h�/i�e�II�ise�A�2�Ba�co-��ؾb8zAS Z:�-t"�m𕤍�.�0d&� sepa*FnF�s�*�xjQ B�6�#�A 8 �L Ks ��> i�o -n4�b6�*�-"u=i0� sumŋO�LY$)B�2���~`�mU'&�-r�%�E�\ r@�pe&�@ Y~Ŏ!@aه��[ a�l��?QL+&9j�s�$P"�\[�&���:"�MG deje��a �F)acAv�o��Vor2t�Nrug�.,�-`�!��:�GA��a��c�v�} �=*\eHc I�M4to PCMV-3tag3aPCDNA��0 (#��u:#%�HA tag��k*�)]>. .( !��m��UQuikC�e L��Z Site-D?ed2HKi�Y AgilM'�i��co�:2C C+ a . En� (ed Krebs-RiMbic�� mKuO�� CaCl�Ui�t NaHCOz B�h���;!* 37� |AF%4V�n su�(V�L�nm 23�Gi��"�?�6�2Z+�9zoaIA *B4`E�&Ŏ! EKRB6C5@58A�)4�60��9 .�Atyros*CeQ��� Db�zw *h�. Tes&jfol� m-�W��"�Xb��zyme-liP immunosor4[)8 ( R&|> Jiancheng�gengine�� NanjA�)�e2� B��M�a{ ���{"Q��A� .9�" a�:y!�.�alfb,\:͙?ked `10 μM9o".K( S� )Ai "�" ( Se�ak+��0ti^�,&M:�+s^/3;�IP%��))j(�` i�|%���in3�՜50mM NaCF T{�1mM EGTr=�82% ( v/v ) NP-4@�IL�uIٹ�ock�v� �ID]'J)��e�I�na�=e�y>%�:О -HA/��*�� agar�$( AbmaraF��&Il1:4�Et 4}�ag���b"9%8waG �IP1;�x)��� einm�e@�� glyca�an&�� to w}�i�I.%�85�6�%�4A�Q��-! (���u!M�tK>�X �C5-HAa?! 7�Ni�&}� != $1c�-. �9(&tw"' �U�50 mM He� ,a"mM Mg�PAx1Na3VO�GM5DTTU9 W'���i�01��[ur �&"�C�a�g MBP!� tea�E��D5 μCi γ˗P32-ATP� kinElmeA�I 2JM !Ta� in�μl�\� �/Ir�z�� �)�"�L! �����B�graph����6���8�& �2I� E`�1a�:��)-H�9pHT��1)ҍR2!�ED�G5�,)șVTri�` X-10GEFeR�\)C �\�Z. 8!qg�!�E���� %h0s,r'L f c�h� |�*���( CIP�?0�!/oNew Eng=�% ab��t*Ǘ3�!�z�S� R)s>�9�on9�gՑ,, to n��Gu�@�od(�"m �ya�za{ Gys:� (4(#�TProfessor Xueliang Zhu��� g"@aHv�) �W���; α-Idi�N"fa9�; N-cadh) ( B{H�>,( Santa Cruz� c-534G C-17Z, U(Q ,� ,��D �9 w 1 Ser� �ilin-L2 �� qcq��")�1.$Ser45/Thr4D:33/37Gsk-3β5� -Ser9A���&�Techno|�X& ( Mi.ޥA�.(s,:�?0 orse�Psh pe��da�at�0l�!�1:5��1�-q~K��� ECL "_"A����n.vy�sb�,n 2��� in 4J�xembeddi�< ffi�WS �U_��mn��da %�,�f&��,-O3%� dtX&RqU�LP��N>i8 .�����|1�� FITC.�d�-a�-� ��Cy3.&donkey (r��B��M�arA�beatF��O':I��y�ɹ� AFxd*�@+ ����o"�TR:�phalloid�1t�J �!/�fJ�.o8rm�:Uh.|=�i��:"��� >�Jc� t��phs�M�n@an Olympus FV1200a�f�^ ���Iase!��J� N"t��4Zeiss Axioskop�xViJDICr?� BX51�2CPѠmiY;EFPron jjA�.:�9Wpe�l�ze�i�%02 . 5% glutar"��a� O66W�a fewAZh!� 1MY �E�2�B| % osA�aci:� a�du��@)8lan �snol ser�).�Epon812� ��Ul�hDF��ing�� 70 n��pr���`(an EM UC6 u;%�t >( LeicU�;�jMl�7q�1%�D cޥ�r� �Bnd� $uranyl ace|�.�� KUb$a�y@nai Spirit 120 kV9 Q��?unq ( FE��In brief$ 0 -step*z,di�ߡmethoO�1�hR�%� :!�&i A}��� I or!�gj )AX200U/ml�VP�33. in��( Gibc�[lo1dDN`[1 I,�X"���p� "`�wQ�(05%Trypsin-0 v���Ecsto3sby!�s�)  C >$fil�S~ a 47 �<�Bn_ S&��SM��Hoechs|�[g!K)�P!2��)W��A~�GU�J~as( LSRL�F�CyA�ter , �  sor�( Ariaf0�v��~c�%.{�EJzna&�&�>^82A�k� Beyo t.� )S�/G�&w���n � In V�^AssayH �! "k8R:Bk`���.�G-LISAAn�2on gK�B_&��Min��i . p .Iȥ� U PMSG2�5U hCG���*[�O:*�a�e%x 13 h�! i��"CG��*� =�|e$1.L�!�m�ejS{�a.HTF�%���2 b)�"� L % CO5% O2y90% N!Egg-9�V�� � s[�����Coi+ IMi$��uz$�)#��0�5�&��e�f� KSOM�a���. &w}a�gѤ� ���� IX71&\��i.�- >quickly&� Ō@,month ��F{%��0z�� l$_d$ge _�aw�.,6g % N�m%A4�*<��BR"�!�9M�8^�>X�2�'��*�B��ny�-d cAs(%ǵ2BW"�$Affymetrix�v)76����B�| b� ll9�f�f� ,�μg �_fach7��hybridEv! 1}45�Kon �� Chip-&�%me ArraEW #-�]��� �$Fluidics S �45?asc���%�^ pSr3�iI�d%cŃa@ with� a� Suitq(w5 .MAS )�I��defaul*�se�� globO3c^� '[�o���� � trim Am�'L'A�e�1�%� �!��r��s�oǴ{Na�)ڢic ��, �qan�"X30�y�9o*�2`%l��� j�C� �U"j��5 voluAof ure�(8�(Au=A�LC-MS/MS�.I�b&� rz�H�6E�r�"r�%t��tx4� i]M�&�asy nLC!�0w (��rmoFissLa! tifiܶ coup� �O� rap F�3Tria�rC:��P�+7���Ja�c��lum~��`?7� � pac)inE#s��A�r� �S( R�l$��xs�!���5-�? w��y!?&�� ��@ m/z� vb��K��W� ( 300–1��*N���D:a� ecur �xs�&y#h�au ���^$%T8 �<�AKRe�a�MS2��!����w15:�,�?Ud�2EU�AGCS�"en�2�m-q&V � sm ,�#��windo] �:2%�3AV� CE .�b �"5%X��b�F"��!:��xJ��K MaxQ3�� .0�M,av [42]���� 0130724 .�A�Ytab�.�'bamidohy�s��)BVua�#�2�D �y��Bi��,��.�"a��!Q 1<\�FZbHCT!n"� as'!�2�,E� E8�,it-�t[/Pa�wo �ng "u�>_eL���%�#d �-Ftoler)4e��.e0A�p:Pt* 7 ppm�20 Z:�iv$/ ptid�!�d@!� fal��ݢy�kbD�g��f� �F/!M�"B@o�<�E�, w�3�x�e>���clHI ))2���E ��2�,"i�U8"71(/�%I�' um s��SI~��)�[of�I�((�=PTM 9�2�a�2>�7��.22 ��5(ce ≥ 5 ) ��as described before [43] . Raw sequencing reads are available from the National Center for Biotechnology Information’s GEO database ( www . ncbi . nlm . nih . gov/geo/ ) under accession no . GSE67391 . Data are presented as mean ± SEM . All experiments were performed at least in triplicate . Student’s t-test was used for comparison between two groups . P < 0 . 05 was considered significant .�>Enterohemorrhagic Escherichia coli ( EHEC ) strains cause diarrhea and hemolytic uremic syndrome resulting from toxin-mediated microvascular endothelial injury . EHEC hemolysin ( EHEC-Hly ) , a member of the RTX ( repeats-in-toxin ) family , is an EHEC virulence factor of increasingly recognized importance . The toxin exists as free EHEC-Hly and as%:X-Hly associated with ouA��membrane vesicles ( OMVs ) releasa(yF�C during growth . Whereas the free toxin is lytic towards human endot![ um ,4Hbiological effects -D OMV-�EHE �on mi^�,and intestinSpitoZeM!�!yrnalizI1 �!�2�@via dynamin-depen�f A!3gofds;traffickQ�E� into2-lysosom!ᅏtment�UpoIp4some acidifica!�Xsub��(t pH drop ,%�e)is sepa!Nd��x , escapes AB �eA\0most probably�0its pore-formA7activityAVnd-{4s mitochondria%fis��s in decafe!u./l!#nsu�potentA�aranslo �ofE�chr!a�O%xol , ind%%ng5 -med�3(permeabiliz)Hm�6��!�S9e�7 caspase-9�3 l�rtoMt�BA�@ death as evidencIaDNA frag!� [�� atin�s dens ��heE;x�ed[�A��ty�^ztoq%66�i%�pathwayqi߅+vascularE����a6^�-�Les a novel mechanism���I�nvolve!w��ogenemQ, dis����5�intra!m�4delivery repre[�ewl cogne��,for a bacterA}�e��dha^E�order�{.K . E3 ohem�� glob�au�Wdiarrhea�0severe extra-=r�5lA��sɸur�� synde,$( HUS ) [1(  ��e�common �!�acute re��failurAx childre�Ri!Nta�bE4E#angio!�!c sulta�fp RBinjurEl!�kidney�9he�Y �E@produce a spectruEHvirulaV factor���(plausi��$play a rol�^�.c! . In addi%Rto ShigaI s ( Stx )Z��F�M���w� �, [2] ,)�al asr bE�@ nu�or�, trib!�a衁�(logy [3]-[6!��+importa� �co =AGof hIMsin (e� ) [7� also� ign� ��.h!%[8]A(in��in: � , [9�>_EX107 kDa6y��l� belongs �e RTX (a�eatN� ��, [10w! ��Ɂ#�ߩps��%machin�Qa�encod��AI�,hlyCABD operv inM�A�0structu!؁�|%� �SM�t ���st��� �-�J,�qNB-D-�proteins�A %�outWH�� 1S11A[121TNOKE�e E����ay�upz9X��~)�to�5ejI�sEb$. Moreover��l��B�v\g gNstatu{ �in]�sup� taF ,Y p $tified twoalm@�%t: a� , soluble\iCan>������8B�qQ1��[1�� Simis m7*�� �5 bind�)Tery�cy� nd��s��O K�E�4 ��i{ ntl!�I0\ !�O w 5QE\ thusa<���\�Pb ��6�ar!�� �9�u ) I Qtl^��D&�ly�icA� R2q�oy5@Z�f��e,id like8 4 m��A��2*` as w>�� �E�m u�= arA�c� (lipid bilay���How& M9��+ceE�@ r!�on^IEIC~ , a � sitD � �ЁiL}^/ I�,first barrieo couP ��!�U�%>�T���G�� Hly-harboE�)z0M�toeJthese%�\ t�` -�2� �&r %�-. Ab aA�� detec( .� tAA�2�a2jhe*� r"� Iell}W�ni��t�S"h* %E,�{ga�c)�� &�lyC s6D ,� ��,l!linsic"{9*��Z�. A.!��s� �yYZype 1 )�system4 in"�lgA !�rapidlyE/�y% duA�high  n��AEQ es��. TA[M %Wkinetice�� ��,k�hdu��( -OMV2�ins� TA50� L . coli K-12 MC1061 yJ� A&� � 8O26:H11� 8033.VO103:H2!��� isol�)�� both �e��a>� ��( Fig�1A� Ar.r w�:�iLuria-Be� (i ( LB ) brj . At defiaftim tervals!G[collecA*by ule� fu�o��H�%x pell��y�2��Cf�u  �.�%}� �$immunoblot���*� ag! t>�� OmpA ( a�t�omponen� E�$of Gram-ne�veu$$ [17]-[19] ��,��iv��, follow���iDric qu�GE���\!}vE 1�� �.�2in�=g�? � llel)%y�A%th�q�ͤDlogarithmic phase;f� � *^� �-=2�(:Q�maEw[� ughY A� 24 h�ub)period]�B , 1C )� � 8  5��)~1Ie�!Ce��"" %�.� !#�u15te�centage!�^2�o_tot�m�3��I� t at eachi�)A�gressIK9�up�04 . 5 hJin5*�� �( 72%# }5:�i� X3jT%2 ( 78�T�then r1�re�eun� ged until)���D!�E%� In 1�cultu�ofZ�,���%�umC study�q�x(d , 82 . 1%I1 . 4%F�m�:H� % e�wR�Qua��ve�����9revealQ� theyeqi+H3 . 03±0 . 8 µg ()�)�1 6 %�)�5�per ml�pr��,, correspondA� to 5!±!2Sa:A|9 1B�.�pg)> v_9(S���togeth�s����*�e�aGi H.w���Z:)5Di� ue ~��{�i��sb.O" ��O���E��)�� ��ol non-&BYq��1Q$ve ?I3Ac�� hlyA�� deri�v��)h!nonI�m�eR�Fa�Ge�2� wh)�or6!eigh^ >eT� ��e:5 + p" !�sy gradp f� �Ym�I�u� "�!�7s!�)�c%F�R�.=��tV I) samC b�A<��nA hUS1� , suggYgq %J5Ha�w1 %;f confir��is obs (,NnE� subj �� di� ^4assay ( see MaD)YMethod� . Trea� 9�s �8salt ( 1 M NaClI} lkal� � 2COA��haotr� reag� ()48 M urea ) didEd��9�� % ,�d.h�i� recoHm�� afN =��I�tE exposurEIAk�to��SDSA�� �<ly!erup�!A ��" �O �Q*� F�T� ero�)a��Eb� �gh�N&f!� sg��-M���%e�chaa�er��6 NU !:�,�9iplas� <n�+-h�ou!�1 � @EGwga�5�. I"� �a�-�� marker�Y�m$�e�a$!2���9Y )a�8J�S�n�- Adѵ �iF&Y5*.hD��P��;lipop�ac!�ide�P� `9Y:�as!%�/6���5��qsh�#)ne����#�#T gold�iEw�)J��=��LPS��2A , 2 �A+$�a#A�A �$Pico green�@" $�% ntac $%��unt�Eed%�DN�!� ���at���d���6 6h 3)S���P G 6A��"gs!�Etwp it E1?Q� ode��d . No" "!ˑh�a�genA� )%�fou#&x.�!1-UCRF� e naM l 0is yet*&EJ&of��thHryo-sa�;6�LB�r&� 2�blebb�U ,surfai!B�O22F–2H� �lla�%��0had already bA\�/qY�B�CaFe�W� surr!|e� aym��iJ�-"EL�:�-m�reaL(m�q�y!` instE^�B� )3!%%A�22has). � �b�. S�YT �J�y visu>vXo !=�budE��#-�5�%�: -Do�sr��,ti-�h�� ���Z*� �� ���2.�C��I0No-��P!lA�r�� f�FT2� "��ed only �PAA G��C ab"5���{ !M��G�A� body�:no�p)2��va�!%:�6� � TA51�%Px���:��I� "� Au!�~WN�. B&�+�v 1^��Aver8 of�0�&� toX����K. appe�> 20B}!steadi*ld�2e36 �wiit� chA��$ teau93SQ66teZ&6��dos��300 n�^,&h �i2�,n(�+ ) ev1� 48FCsAȍ;!� lacttdehydrx"�0LDa coulG1e*x1@� lackMAab'&�*��.�uo?.ZK,prompM\�"� e�%vT.���K"�| "N i�%a�B\ a�ei�Z���-�e� EC labe�e�!%fluores5�*`dye 3 , 3 dioctadecyloxac�cyaninkhlo�, ( DiO��Mhe .��uptakee�monito8 :�.�I3�35)*i� guis�*�-�-b�� n~)"&.�,�),u�!DiOz9c ��3a�)&,rypan blue .51ET2d ��*ach� l!-Jin 5 mi��-��� !6a��5�� fhh�14s65ro�%H�/���J��J|��yxA !?7�6��4%�Y�48� !in�>!L &< l���N h&; 2 V.�lo1d %�m]@S,��th�%�:?��6SO�giz-F�����#z�*h��//elQ��JZ.���A�Q�4��!���c)�U�aE�|��2�by�1I� in a%�*�ma`H t�!1��Er]les� I �A�9��&��RTo G�]�� ,]b2 mono�#�me�BKAf!N�ve�& "�'2>�77IX.rin ��differE1�ce�� ( DI�: o�4(laser scannX'( CLSMeM/ofF�% 4 �e"4��%����s -- �1I.�> a y� � ��35�m�V� )Ӂ��6 ��F��s-e%of fix~ nA"�1a�Mc:��eall+ -Q�@x>d��1��~dA�, ad�!��% �i�'� !. ARA�nea�$llR �E �accumu�!"�.K(nuclear reg%J5��x, panelsk�Nog��"0 � Z��$��or<%��buA� (Q $mM TRIS-HC4pH � 0 lieu!�:a�,:"O y� oseconda7t� ( Alexa F� 488g j,"ed goat� $-rabbit Ig� F� primW( ."_#�)" 5NS3. Taken rEѻC� >A,&UIM'"e�2by^+0oWta�necess�!�lm'�r*�0�pro-�3%�e5&��%� 1e�>�&1),raft/caveola.tMlathri^�7[20�-[2>3�+*�e{�7;"?5uti6e�-�A����"� d.� variouA�hib� 8 noe on u of rhodam isothiU � B-R18��TFa 2��E%�o� �1H 033c[%b�. Dynas�>a` i��dB9K� o�, scis/ �ic&�;%��*�[2/3 cA���-b 0% – 14 to 9� ir1by*k&Z ���: ( p<� 05 )y�4i�Sig� �� <u(�65 �� � �3o�)�to 74 '9�"' ����als�E�g !wazA3F�u}2d1�Ez [23]B�6�fia{264a cholesterol-�, ^��(di�7de�P q� [24]��no�3� 1T�15a�M�:-�F�:V%Mz�Z���6+e�isU�"3*,��beJX�fur " expla6?$)ݡM31� versu�����V�L.��to F�a"V�1i�/�uN� I����5 A�N�00�0��d(�_"��R%E�10��cox.�;&w5)1 A�dK+d.� n(i�$2Yv�cJ_ran�%��47b to 6*Q%%s.�1a�j#�5 ferri7TF-488e�6�5% \ -establis .!(1^�5.�G4%�,)Բ�b9C2g 3�X3!9%}rm , bea���  6�l� )7-( 5T6! y�6�Asc ���F��os!U+( _7�P16o&:Q1��1 !%&!2>�in>�6�)t.�j�4r�: B�"uni�CTBU*5�2)~5M�:��:�1rbE4m(^44.4�M4N(23�� a#5{U cI+F� �e� 202� i^� )�� .�}��ce� .sanyE�{Q��:`���.�Y�a�oa�����V�Q�"Crequir&�i� summZ aL@ .�". N������ 71� 6�%lyz�����.�occur� Zy1!*.�&��Eass*�� 2�E� �n� = �2a�l)�z2&�.�3,E_Mz:Tp or�� xa�1 h���-�"�by_. A�� ����^/� al1E[^�!lt5G23��4)14��5�)w>k�?�!#vbeg�o� " )�7 )�:�,n<� ~@� outI#[8�'=8-c$19�l6a�*� � Oinu y/1@( 2�-2!z51!) 01�1Ne2!5��=6�asEO!21�� h;:2granuTE�ub patch�J-.)�Zbpto�qf)��-F� tir��%�&.��(g*6N�'!_� 9N.2.�� )�:aa�`e�(� embl�C2�EJBs �!GcB#ALRU�J*�H!/(ir;"by�on�0>80� :K6�$ � trac� 9;&�t"�� e��s9"fI[26*� 6K�@c C"%��  �&�%RL٪��%�H� BE�!s��1%O� 9s� . Ne�Lr 9no�D� ��ont� �v 5!P�r !�ʿ#AA�*M#��"%nS;;ɼYB1�["$.� J�5m!9� fIV6�=��F�2X0Bm�PsŲ�4�6i$pde�$�duI~FO�Ya��!�&� �526�a� z!dos�!>�.mb��a�pi#]�A�( .�t/�1��.a�a.me"Z( �0>JEiV�ra�, �o��restrie�&a�h dual&�fP9ponY��!:�ն Bai>*/E!E � is!^er�5 Hly2�  ]5��O�R�Bpres�AaHy & � by.'�AEF3e\+ vehiSSF�6� �m�� V� data*�4a!�Qe7 �+>z ��!*`!{��i@s5 " �%�"*V� ItZ� � E�T!�>��-�& M\~���@b�/1-*l@c�. Bec"Nm��n�C.`�G# ic r@@ul+M"�.@ans-Golgi-networky=S�S����2EC�6lI"�z'd�|�ndb�R - u@�?Rr���/C��B!q5���2aly� t"2�0�/S.�'�"!��2 A LAMP3/CD6�\Aw,� ���of���=px��e��@&g-p54v'TVJ� 5 �&�8_(�%�st� l�6>76� e��qz �r��7�7�� S��S5�G���S accord*����!*j� ���A}5{9<�5ߊ�9�("^G7M6J&� 6 !� !2��- 7YN5�.� Av������#7e�/�2(A_.��0:�2+!�8!^�S5!� �AME�( o8L9D96� ^c=^"3 v�Q���, J � V� * 67A�Ikn �_�/2`f� M�"�1eaJ� S� 2f�� �� aRj>�����I�aj�~n�[�p}Q�$�F�>e�%k�X6Cve��PK523�XA}5� |6�PlQ&!laI6�2�"*_ �f&z e�-bM\%9w-��Y� �-UD`@% n����1�� �9.�V�T�!7!�9;�6t:<.4u�B��'"bB�"iP�"�%�2&'EBT��o>2NBi�a�d%'�S6E��5�e�@ub�7V!���I)J2FrG-OMGS"9��%:}l �Pted2�aO b2�� ��VAgA"ivt :�E^���TN&Z)�J�_2�\;x =Bwn�>j6z80bafilomycin A�G BafA�?��ad �)o>* vacuolar-�QH+-ATP�7E *s:6cof=���*!g���>on pump!j"�[27�Z� -preh A'�e�,a��@W�r�c�eUTR�%�M�j�Yg/2�?� uECb�"� Rz=na��e� ienc�0)� VA�"C; �: ��l�-h�G3B ( LCh�R i��?a� e'�mfN,.dA-II-�2W%� [28*@9& so]�9jH"R9Cf"� f�regard�4�[�=rJ���9I+s� seZH*6�AI�at �"*$�\u2� *}�B�2<6�*k ch%쉀I��?I�� 2�of �݁i1.�?NF�B �2��� :]:�%�:�12��"6~!)�W�%��tr}� ��$!{2c�}�g�7]� e�eR5�>Z��XE�L�?�"e�d� "*n�=�Z,9�9dAf��S�<�dM��]9 �.)�c� ��n� eId;4F�-.�&�s\i)�(eis:�25R6��E^�i>�J��1 need�be�2!|6|>[�.x  lA{&�=V�� �-H*.�u%en RwnPo�CT��!�&� �LpH�, V�0�0��&,#F�=rifugA�h�Mpl"�&U��a��Kl &a�&.�K)��Su*�_(�6+ib�t}��IQ �vP`iI28"�!_.�9k�(� �22 star�a�kl$/�& >50% �WB�+al8$� lete $F�Y �%^1�:/�2�reD#��hlc!�2. ( ∼ �) F�� �4Ea͡%�A.5in�(B��A�̡Lu&-N�'sz,isiG\\�&u6)Pin*�Cy�oUA=�2���A��OH�]*�. FY��"R��med=�[h�po �m ��_�?r�jEI6aJ�.�m%M�hyp_hs]N�it^��� amag�!� `CN�pes�)ishW2w� ^�1�B���#orN .&��> (�Su��i� @ ���S� 2��n�-A¥mA�~ �*4q-e><q!& . Si�&.� �%so=%�re�!t�pAE� phys&�F)a�a��_xS��Kby �wEdiminb2cY }�&�. Nalm�()! A�A"i� U7H[ dJ$,�!�6�e e*�e`5eՁgNx &�n�"� jx�N�^.�:8E-� h� *LF%�a�1Ne�$FAE�!5�~E�YB/%��f-?\#A 1�6((�3.C��7B�Y�V2�(ŨCC�26J7510@ .��i�e��ci5&�?ed��ajf3ae�Wo"�%�-1i%>�3�732 .1J��:3�k,:QD:�*�!"1S60  sQes�V�Y�yS&�8a@-�&�r� ��&+:U"8/�[Uq�2K!� R��7@�EB�&o!1K./*�2]>B.<�9B�&r 9e� D�%� aN.���/ �H "�{>V 9�5�y!� rB�>�!)� EZ�u}i�qR��; � �f2� � ��fy& 1(oy � ՂQC"8E� �m0X.2��impaiOdR{c�$�TF6 � direc�&���$e ����XU��JA��J� ��z6�5�10"K')�hl�Git�� �n�F�X�q�-AO �b]B�]A�!A;J@2�KNC8�UK A$E7. C+xA*� O A/�L5C)h.���jSt �Cr mp�3� 1Y0΁ ; S6B� .n( B0�a.�B&x� �( �ɫW Zy( y��y�5�=���F�A0zE�J U�v�5� �-$�|��C�9:P�y���!�I��!!B2 �Fv� ��'Z^@BE`"�z"� c re�In�<�o)�&� A8&� � "H� 2 2H`a2Y8[! j&(j[29�Cw��^g�-f:�.�!2t*G|J�C�Gkey�K�6!+�[c ��B3<.5Me��zd0e4.�[BDlea[b����r)�@Ta�su@~s �Zkze (E$D.vBt�asp�W�veAv{!�B��2:0[�ipa�FmEU\&aQ( ΔΨm|0vI:� n>Ţ� v:� ������N{d�21�/6-f"�VEV ^EYsolicA�<11A-11�~.Q!B=5�Q%�.�>��d��R J.Z��R�ށA%�� %�>���)��$ ,)x�*�uTFScp,N " <�0i.G(tetramethyl&G �+MR�_.%�|~ -sen�_ve�5,�Zg�11"11 X�9EZ�% u�Ddropp��52%�� ��57&�fh"�9��f4/>E6[fE:� ͠6��?h�Bv.�Ano��LelicitH Qof)=fa)dThuK6�.�>�~�7q+!y�7rS���0y��|� 2�&� ^��[Tab� io,�&t���aX���,6��k.�)x� sis-��>f+}-� ATP/dATP!2�:Ҁ��b��p-#vag3/d6i��t[30)A�a"(�iinitixyVpY�n?, tJZ�A,iBL!�clu�y3:�UjaM.j7e=!�e0�sp 3{t6*J �́m>�u�X2n�8pea�"� �XY�F^12B�"A� �� %2�� of�aZu"2m3-fol�I� ��(1J(:��!�Nw3w�?7JO�> w(8J(2w��)�T�-o�B�$:Z@6�^�8~���^� [3}�F�.E_2�9$k�vse�W( <.=26 )��du� _ e"�f�S7I3i)��>SX�$hoN�� pre-�5w��"�#M�x#��,( z-LEHD-fmkE;z-DEV BA[Vpan�~Q z-VA >Z�NoI���2�!M��iJ��#fC�+2�9�:�)e-B�[!A f(- ( ADP-rib*)mer�( PARP�&�l �m"6w�3A{m�~ lian �[3O!ԥ� �y�2o%�e T�2�={U1�e60N����-eQ:-15JT,2 �)� 2�GZ�H�"Jxa6C����.�E�!�'��2�*( ��MŊ�8�"m-�]A�*WA�6�� "jWe"�"�ּ� �e6o��`(&fe0� henod'�߅�[3p�E�\��� "� �Oa era]c}lad�pat�9=g�q2?V�al3%�age��!�"� �iBnKY qV1G&SK! ��'z!�u�9u[�smstauro2�i\�6gnop ��i��w��#6�%Y�r&�*|( �*� !6.J�ndiviz ��V*�ep!TUNEL�R�(T= eoxy)� tidy��f��[TdT]&H dUTP nick�U`!�)�;aȆ4] Z�*�>F�a�tom e��]Ah��&9�i�w])*�/>#':Ji_pe�]#d nox �n 3��3Pr�*6�pVM�La�&qre[�dE�}j�3� aF Q��U�%�\c�:��.7 4basal ��!�&�. �!@ he w�TA a?�.KA!� aileI/cro.m�"<�1f�)�@3G3�d2���d&��V�I[ �isp�^d5dtyp�morph�!��R��Av/ �� nd/3 o|�edqa,��&W>s~or los���Bz inIb���(��' ��u-�fg. �l$ubiquitous%A� Z�|? emer�"Jonew ,e>ophŧ'm"�.�0s �!a�Sultane�Y2Sord�Bfjd �&Aof*�ZN�to.�Af}��qZ 35]–[38���L  a�6���[si inva � 'mod�]+Wa _+s%"co�n��as� weap_E�attacke|�tissu� ssis� F���[ �ie]/�ni�ni�J,� \A�u�J !��2 �e '4defense [revie�\ in 39–4�[We no�!"Ny �^f(ir�pr9�������s���>e��P!5*��1"wY*�Our�:�>model��4b����b@C�%�[&\4#cy�X�7.� 2`it� ��e�9^0+�q 4 , Step �1. D��<sJ�+% �,'�Ge�5 e��ep �e��*��i!CJ� uyA�a��2S &!�9m�1�:!-� 喅h ._L J3!�� $.�:� �55��2X ��a���.E�~pro�s%G-e!�P5��en��%`�. ��nfs�%�," .�a'2��� To our �ledge*�$z!� �>��V gene�!`*|�mfn�8�g��employs ��Ua6�&KT"DG.�)24hij�y2��?Xh#�"*��"�I�6@���ir dys�k [42�}5� �" moleculesI-�byzV8.�F�L.nreceptor��Z ���in~{U�!}�III����� , [4[5 �5�G""`�5�64�ov2��!�j)�V]�:�ver6�l��:J!�� A�uQV �z1fp���reIJ�(A a��ubr{�o4�\ ^"T4�o�O� or6P6�jit��Kemyi3 Ony>as���*�&�Y"�YoP&6�� � Yd%��6������is�.40ԁ/ml )2�ajx".O*�0w��(/3D���os.1uQAԁ/*P5�r*�/]�r�` �n� ����>�IŅ�'k V�!��ekMA���G*eO��y)� a�det�7 �*d�IsIS �w!g[45�![5��[56�W6/�A�%�9%underlya�$p� meno��̞ �g�jex�� perturP�of2�}s!���!� � �e r�JE?� ( i . �ne(is �a�)�I�u�<�%e)�Em !�An-�i& ��1A6|We&Q/z��atA�R73,*N+tx^6< , ma)y%�� 2K.l=vanN>�b�L: i��,Y���2Q lo�]</�in vitro�&037°C [64] ma�8it qu_ ok$�rA5)4can 16}\�. _voi"�; iF�h&hi:��e�� EoQ����&� B–�u[ӓUp�s  il!!,pro&4�N&J��!^�� $A�a�vg�%��A���Rt Z̢bT �b)�itself.�9�P� �J{56 .jH�*!aF� Yv&_5|4H,4�+�N��C  �S�OAgg�;tib�E9n�>$etemcomita�~�N�6�2{Lr"�;! .� ��cargo)#��6�.��!��!!>6}H@F'he�)b Ie�%�v��LTS"genic&׏�j 5"�b[37] �6� �ab� :+Es-!hc &7�Q|  ( GM1a��A|2�����ٓY*��, ��ter�,v�)B'ens!alQ�XA�6r� m�*�J.>7mfke�E"� ; mand !�b���~)Y2zD.� Ker*ߗ"��� s)T��!}-0"A(# �a"�zn�ju8ga&kWB�use"� t�ҁ}!�iF t&�F�!~s��JG-x�5������A'�B��q���J��(��{� t2 . P &�[didr"!�A& ov�m�&�s)QLPSAn, [66 6TBM"o�by>��+!�rj3+l!-�/E8]�a.p2� ur6�r"�.O^_8�< �K9&Qiin fu6��F. A�9'\ji.�'%w�H)o�kpylori�gas�X�s��l�04w�!�D��  A ( Vac�4�oIAh�.�5EM^o+9 n es6�o�m5�{UiV6:AKV�9���be blo�byBB:��&(5ZxKa` adoxPe>�U�\c75e��1$s�esyi�": 8=1��/�)&N~ we believ< a�Aw:��)�, o�N��V�8droɨ"n�:!�*SubI"�.��( e!�a|��El�.�9X�-X�ewv� g�:&d Z�4a�2�3� �ned!�\ -  �g*H{y �;=ex: eZM�8�����5�:��"�;s�e�3�� � �L� U-F,4:9�Air� a\o� ]0�&.�6("Z Z�n�!:�>�)"�] p�7> >I6a�pec� &�ssk�!2IP� �� puta��.�l� A�da�MTӉ ��87fa�=.N-dal/ -�5�U�[5 ��*� �G�.��v 2�Y.�sż�a� �0B�P�fo�X s EspF [4 � [68]exMap [48��{ofb pati*c ( EPE(9, leuk� ,of Mannheimi� tica1a�ApxII ex3�&n�Pillx� leuropneu�iae =;��a���:S� �!�ݟ�qi%�!{��gen V�*)��-�r׉Q.�+�k�6�0�/)���ATM:U%��C"l&�K!;l%i��"�� E@'s28-ILA�� ��he.}�a��(6m%c.ze�2�A�*L2%�e�of |-9�a���mѭ� .3FVnp-|��.��� R8"� �; 2��+�e��. Two �'away &�.Cl sor%qz3po�l!��Aha��슝f.U. X�-De�?3 ���3"2'e� g�r�( ( TO&P� le�^U�w rg� �n���62matrixHR )��J� d�4 ( TI.�%..��A@�� w.s5��/ 2�!�-�.D�U���L���E�Y.2�Ey&���)FٝMi�6w"��dTS�$+oAI5��������s2�u,� be�!� .�9OM5J��es�2M��" (s�b>a��| � R m�1spP%�!� MTSs�z!��!�U � of52' � aa_��.�Qss %V^'�a{�i�..U>�.��a��m+(` � >���KJ1MaF6xA�A," 5�!!0") �Z6A�ye+�|�*P�^6 v w�N�g:���&| �&&s�deA%a�9h *�of-T.��%FaQs�mzE���*�!�;u��a&)C /� �j�5�-[5&��1  �!|=_.��2�="� C\�{�aBc.�E�l��!��&� �)"k+W9�B  .��F�2�AJL-33ayP� 30@z��kHd [46� 2� g6�, �"��x !�b y4 h$/?[�"|,�CqEPB >z ,s )Bo"6�>�!6d)�M66�)��-˜ae� �m i�q F>m�f.�MA��(:1A�P& ����Al�U-��![KYaast&f�N]eiu J.:Kd �F��:n� ,@s&� rearD|��#== ��2n��r.�&OV�tm -�e�&���%�!�� onse�F�ͬ ��2���5�(*hes��&e^ J&*�Ka�aRSh nA0l"�qZor�JL@h�:�� p"3�LM Ex� j�he!� ���v�%�"�; i"�B�;I >�c �,.*�i�"8R�s%��lM"�M�2; և ����.� ~ irFD��( .�N Q>�mask("eN8�-a�ac� ��5�&�3 �6QP6ht�G!��"�clu��&�Ja-b�%F��E�c 6]%�"G'i`nof=�]0R0�Aa�ff*"�$��aBw��!�E`'"���-$aGG �.&�Ŝ"9&W 6�� w��t"�4&�2. Td6is&w��ɀ��ea�e�pBluesk��$ KS II ( +�ES?�a�$ , La Joll `Cƨ , US& �!�h6��e�an��2{+�O��>�0(:�J���al�7) yod a>äo�r�-�<� AL"e��J �!��������l���Stx�A(* ophag���!� [��a��I sX��"U M"��AС7�XN��sp�#� ��ΥA�X"T�Gof ��� �Ee"ݎ��*� :a%��w�%t�L�2aTQcua�)%l '�t�/$� S=��I5gp9lE��� . 1=o��"#p`��0w`� -�E/d"�*(E��slb]mo&G�Brief� b� , �7��!h 500 G�LBO�(el�9fl��(�]800× gD0� , 4K$YC28X%Efil, "�S�8cup s։��U�z2��( Milѡre Corp���, Bill���|M�"�z.�c"e��na<�2� by uJ�� ( 235 , 0�?~ �w  45 Ti �!W! Beck��Cou� , Krefel�Ger7)$�_�Y%'�Jsp��?$1M :��(�&Z,Aliquo�'R.v�Wino���4Sdod�]�=`s�iA<er%%"����7?-A�p���c���7�8� Roti-Nano;�� �9f�rl�LKarlsruh�O6#X604±12"�) , 580±16%�/m�@6149**0572±10Ԭ( �saZe,�� 1����&ݔ� me�$±���dip>�$S5 in�Sc+8(68E� eachm�%�Toi�%�N"+�, ��7u��A� $m� dilu)�( 1∶1e\ 64��)S!�s?�8�f6� ��I~n/R}14c�y�L��µ%�)I� �=c� sodium doݚ sulf@M�?acrylam6�gel��ph(��,SDS-PAG�H��5b�b�P�T�P[70�3�4ne-phosphatase�#j�%ed R��( Dianov��Hambur�?Y��g�fe�h� n�)ʚIzol!`�4ide/5-bromo-4-o-3′(0olyl �agtoluid���NBT/BCIA`a��tRJ� ,", ,�; �* �Ie��B }���(��y�.softw���oRa�*Mu�62n /.2 aEy!�Q�M�EU�]6Qc�� kpo�ib 3�veDCfw2au U+���ec�sr;mea�, �10�1b����&:�m�re� 1 mg4ޫ 5P!EY��|�valid�'.�1�&�U���H,m��j�inyma�!�� � �Ro�1a{ "PA*?*"? 6s�amix* -"O�{��A�iNG�i_5A •��"[W�)>Q}in�%l6) ղ��yU%(%{ N z� 6Vi:&�qA� mixt��%�N� � �qI A� BCy�enr�:d)U6I� trN@��5Q���16*oT �2�|*� abov���S)��m ���m d j � &6WJ�8�8���!s�~L-e�i".iٴ� *� �res=B6+>�c*�-5c �!c ��6��WE���� �Ma� ZM, &�?,8!1h2M�"oj6��Dd&�E%M�E�`M�[ Na0:P� F "u !2��Lofg�8�_����\ ��h�!�a�Jv ^ qa 5� a� W=��-Z �,"6Iif� l2� E�s� e&� 3�{���I�.5 "��C!�V4 )�Nz7 ���eʽ�>� �%�n� ;��� 2�j�2nprecip;�e�^Y +�oac��)��C��֩C:� Aµ 7�;B�� TCA�n�2���~ay�b�?"��&7 2��&� ��c.U*nt"s"�kin��$�(Rol/Lloub�qMarse�Z/^)ee�i: m���*) ���F�Ɂrr���/2-�u2�� �ig&  f��2IF2� �-�2�2G}  �*�6$s.���.L!T6� =s�l��tn�'&*byS �S e op�I� W8{�ks!(600 nm ( OD �[UltpI0ec 2100pro ClwB$GE Healthc� E()�eiB� 2y. Fo1�A �a�6K[�5A ��`i�&�[1)1�C&j��Ee7:�nX%+1�&_$botto[:a 1ZQ2�Ntube (B � adjusa� I(5% OptiPrep#@igma-Ald�( , Taufkirc_ .{ yfi[volume!L���9Y/HEPE��4O2-��xy�W$) -1-piper��ethan��foG*�. ) �!rm�2+�/a�dp)[!o��s: �of 40d�of 353!02256d&�% .cF%� v5�X 8�M&���"�%SW 41n�)�fM�} equal-R6�)Q=2��"topb�aogE����E"��0%�"15%4 �<�Ig0 1�h ����v�R\Di�B� �"y�262��.}�e%(*� mf �=2�Ap -zs.9 M I� �!& � �!n iq!�"% 6�sX?��Cl!'�f �or"�or�fSDS͆�   "R�E&:�3!%�}n�; ���-GN _V �!R:}!E "���y. NH�� eK0 �N*�� ���m"��AbpH�]�* � E�, �Y�(E�at{+�>�M�4 ^p����"� .E��\N|z} .�)����� F{ ��~K:-b�2�a�" by>�2g� ��{E�v8 nNdOpm�q���*pH>B %�OV� D�m.��e�5f"B�-��)�� i&N (�<shock EW�Htr� u$B�-�"�eptido.A; Lep21;' ( cAMPh!) �; C8W"ui�ESFTfP6"�!�(8pl ��>� c/lq�)j�! &� ���f� % �� �ELJ� $Thomas Ald*S , Un�"s.Mü+�r@dO-!mo�;monoclo� r !'E! NeoC� B2�fdi�E, W:~�.*FT�Q� m!�-iT��G��ds8As�SKؠMbHar Pro� Life Tech��!B$, Darmstad�6&�k(���#manufal�er�"�'i8.":<$E>�d�"� [A��&\RI��}��("�2&[7EI!�,P[e:Bs�%�l%4U GES &��5 M guan\.ݩ,wmM EDTo*$5% sarkosyA��v!���R� {s$^ .լƵc�.a2��pRd�a�( FLUO�vH OPTIMA; BMG LabtecC OffenB� ( exc�� 480, emis�%52]�8 subt* !� back��nd�@5�1P1m(�64�1-IpH�5� ؜&�� S m ��A�$.��"��st�cu��:tru�-y<�!�#lambdai"�E4Pkiaa������m.[verni��:̻* 2 �A��E�har_i�\to PB����2%��a�%al��� dE�2% glut � inBD ��5Op&�9�eog�(Tokuyasu [7RH!ath�B5M-froze*{��cu � gold"an h�!6���3i�E�m�("&LPS�/(�Jm��NXr�1037_J�Aa�ruta<RobJL(Koch Instit��, W%� erodA��f "fk� A�Eq%�+6m�( D�* of C�CO�}r�}Me�Zl R�, UtrechA�Ne�C�!g!rAtia��5a�� %�di�ge�"�IlO In d:��&��2Ag���'!���Fsrr����n�=�o�J��hA.,a�!�J�A�:^|6#\D1:E(>n:k)�(,>W�f����a[�>d�^�1+ 'K=�!hyW��[� �-?(?at 80 kV ( FEI-Tecnai��g(2��e�`E�Eindho�,v6j,. Photograph��L��?� docu�ed� i�z��� Ditabi�Pforz�<2�.HD [73] Scu��u En6��5e"�a�PasX�o!Au�B�ˁd6�D(,�A�,denocarcinom�s; i�%���A�Lcroorga͇�� ��(Braunschwei� G$y; ACC 169��in� um 286 e&��2�)vAnz3-m*�tn atm�"E�5% COV�E) ssages 19� 2pgCJ�. 21 30)��.#. H�PtE)eM��! A�?&2� 2`6]�4*s$UAH ∼3�Q.]z!:Cyt&+*�*"�#q��(�Yo.�g-8A -�&�-eG� ��,�2�0M>d ?�1�Tox 96A (��megY$M�?29�� �"@� :���iH��+|")�� |')I$l.��1Nmv/v� ַ dye DiO�)>� )6�F�+-\i=d0onf�� in 75 cm21O flaska�trypsi���:�!�5mxXp��.�o�}n. � B�� =#�| of 5×106m�>�S�&XE 7&�m�A�Sa.�!4�a� 5�+ں,a���,�,�*��n`)�2�HT+�I�*� FACS�G.��e&+�Dickin�HeidelbeB'2����6��{5� �%� g�!�-AP2��t�F�^� A a+u��]6�(ofS ( wE��."E�>iQ��s [745(�Fa'!���c@�l�&�ly"�3e�N�ppl�D�cy\'!�nd� t�[B�5��6( �F �/..�I9(�:p)AɁ�.B �×E"��� ellQgR�� *6 u��Hs geo*�ic��2���1�+0007v}/I�f �� f�)�ycA� % A8 t$��"�"r E�-��irm�]l.r� �}!�20��in 8-��chamb3�lid3 ibidi , P)gg/Ma�BsrA.1%�6�F�f��f. N�$ �V5�%2�)��j5�cM+d��( ��510 META#S �O�s!| a�-Ap�uat 63x/�m4 oil er�<;�ive; Cb. Zeis��Jen�s O��P!qIى A�s�2%:�DZce��tw DH�6�9\�n&}\2s�+B�.F�� �3% hl� E�r��� "��c)�l.�rrؼ��3XS����^+ssaA�mo"��"zd>�U�96I�! %�b}frajLGre0�Z-gno�G!�Bah�he"+9�%C*U�P �Nof+nd"�a( UX�8z M , $&˻1@*�,�f��,]13O!��+S2��3�>� o��m1N& . R1�"^�%�( g*�|pr o t8 f!�:i��a�.�oFRE!6"D�&*9B�73UX�C?A�was�k��2�Z����%h*�56�,��9�F�p ��x.C�rVs�n�<��to6��NmT%�9u� K Ax�P)�z' u\�-�.U%oU�~2ai6�$A Pb��7�EJ��>asX \���)��2�, �%ص����%s>�.� *���!t�2i sLc�z!'PA=2)��9v.)aYil� K��l��,and incubate�@d with TA50 or 8033 OMVs ( 20 µg of OMV protein containing 100 n!,EHEC-Hly ) ,GT1 TcvU)(5h20 mM TRIS-HCl , pH 8 . 0 (C< buffer ) for di Tent times . To monitor.�adherence and internalization , cells were incubate-%d15 mi,30 1 hO(4 h , washe 5|PBS ( Lonza , Verviers , Belgium%fix0x3 . 7% paraformaldehyde , quencX80 . 2 M glycine1(!7) ,�Hpermeabilized using >45% Triton X-10!NpSigma-Aldrich ) . After block8%�5% bovu$serum albu!(B@,)4w!Mstain�rabbit polyclonal anti-E . coli LPS0body ( Biomol%�4llowed by goat%- N(IgG conjuga5��Alexa Fluor 488 ( Molecular Probes �@Filamentous actin!� couA2�pphalloidin tetramethyl rhodam!(#-TRITC )1 .[To deter6colocY�oeas)pcaveolin%�clathrE~��I�at 37°CBLprocessed as above .z���aP:p-=�R�Z�CR�2HI��5!1 ( 7C8%qNovusA:logica�8LittleA�,, CO , USA )� H1\( A� e 23KBDHsci�7a�HHeidelberg , German��mouse�mo?M�E�4, respectivelym�Cy3V  HA� ( Dianovae�I�k$rol experiA��R ��Ie�TF-i��/maQor CTB 5�� ( bothN-or O��z!�5� 1I2�$as describA|My��ZQ�M over�� , HBMECCaco-2 n:�TB�%����8 12 620{2 &��~��2 ����{���ged)`5%i2�dZ(œ2eiIBmo2�b_A�4e 2D7/1; Abcama!ambridg!jUK:|�� �I�Jv �5�was�$ ŭ�:%eP [70]%�bD = ~�Etre�CA+EeA�-free){(A`1 ,�&�:�C�rHTo compare behavior��-associ�EF � that%�Z�6�3(recombinant?Lpurified from strain�0 [6] ��he dosezD10 hemolytic unitsA� ml�4or��ond+tof50Eper wel�}whg(does not ca�?a�(t cytolysis�.�.'%��5 E"a���2)J�I &���>�investi�J��T(mitochondri% B�R�:TB�(��TABl or noA�s;* trol U*h. MitoTracker Orange CMTMRo� J ( fi��concentrF N nM )%�addedAAH �4A before endA_ ��� � . C&� the�  ,��6h,�I�cq}�VA"�0M0\ �� or:�4endo-lysosomal�tr�9�k ,Z�)�}!�����Aͅ�2U��n[ ]��)l� *6�, 1ZI I1 m�saponinqg2� F��m�)�RR a�Z� �2s����. LI"es��Ahc� eith�D��c@-human LAMP3/CD63V��� H5C6�b� ��a}DevelopA�0al Studies Hy Homa Bank Universitya�Iow��C , IA2] b�."��or-V!t��$Red DND-99V ( 3{M , 3 �In some2, ��2 pre��(�,% )IG��bafilomf Aa >%��ad��E�(. For study� F� U$%Ɓ8plasmic reticulWnd Golgi�"lex�aa !���0�B�'!.��J� :V�g�XEndJ�.�i3E�PrB(Disulfide I!�,rase ( PDI )��C-2� 60iGM1�b� q( B-10�  e$Santa CruztechnV� Inc .� V!ĺ�ZhE)%41�e�f��ZQ Nucleii!�8zll8toc2)X.M DRAQ5eA@, 5-bis{[2- ( di-amino ) (]}-4A�T-dihydroxyanthracene-9�0-dione%���at�,ng; distribu� (by New Engl!Biolab4Frankfurt am M� .�. Slid�Ym�  Dako f-esc� a=med�( $, Hambu:�)*epa 7 %��]excep��`�d below�s$analy&�a�=f( laser-scane� microscopa',LSM 510 META. , equippeR�a Plan-Apochromat 63x/1 . 4 oil imm��on obj�(; Carl Zeis) �quA�fy:�s� variD2Dsi!�!� digi�X:image��impor!� into!�IXD6 [75]�kR%5@manually thresholo . Subse4tq!�per� ag� �edQA�,t least five*Osampl�as calC�i ^Bi�\ tool�tatist��ifica�ofBresults�-evalu:bpaired��:���or rem�un&_ �lN�2�*�%:�nM����"�prUto:�W { �.}l fM1q�sol:� > e En&�� Kit~TissueWC)�d��sa%`"�I^A�A:6��Thermo S�ta: , LiF�Fk ccor� to��1facA@(r's instruc�/Brief�3o - &� 9!$, ∼250 mE�P�i\har��$y trypsini���>,, Q6%�Nn Reag�A supple!�e���@ inhibi�cocktai�Co��4te Mini , EDTA� n80tablets; Roch�Ak2�on ic$ALlyW�E 2-ml Dou��tIgrinderJ� �E50~ okes`)QW862a� n0B ()Uar�)A( �)�,����C rifuged (�× l, 4j�sup]tan��<adjus5�a Opti��e( S"9 Media�aRcof 15%%loa��on �jinu�[(prep gradie�& % , 2730 G17% )!�1�2�ul ����u5( Beckx Coul$�� The �:%*145 , 0010q--E4(SW 41 Ti roA�NdA!7N�B!\at#top!&.9 �ollLO>� ( 182�9 q �to��85b"�al pela- kt� m�.lG-� Dilu�~ B���� ��.���5×107M�n�N�%!��(AinA[a�����!aj��t�iu� aZ=RE�C�n� "� wi���"� a�6�7U�>�YnG NX debri�^SBtransfer� to� shmE ?n�n3y?"� Y�M�>wg�E�.�.:122����.e�Mvd!5�E� spen��in\.�!3�!�ʼni�%y�w!�/� !� Roti-Nano�  r�Y R����$immunoblot� _,E2� boil�PSDS-PAGE "�, s����5"# �/la�I�D!��<��O boiaga� OmpC"� ,�-C<SS � �h porin-2 (F��LC3��B:�Lalkaline-phosphatase5F!Z�D*� ���dA5�4a NBT/BCIP sub^t�I� al� nsitqE�B�d $ometry ( Q�ty On�BioRad%�&;2,"E 12-�p� �� �66e�s��a��A M�ivM� n%TA�c27Ba�UQ-ne�v6|�%c�r.�*�!g.)p#d esolic*� �6a��I��Cy�rP c Re#AApoptoaIAssay� �#Vis� ,^,!�� Aliquo)���� � -Vq��y� �O 2�p $X nta�yu�!<Ge c�� rovi��e��kit��yC�horse��sh� oxid:u�B�.~kchemil�%�enhb# �(ɂi� W>Pico;��B_ Bon�&&�"AG visu�$5Jv�r/a:�� Doc XRS'io-q�> membrane�N��( RestC �ernjt A��"N��VreJ��k�s!�6Vmar�^�N� ,Z{VA+ig R��I:�!�,ftM&ug as� �� �!��asecondar"E! (Nr�KZK����*n�d*fR�J��%e�� TMREVJS�*8 "��$nd K!����! by fA1�� FACS(4bur; Becton Di�)son )���� emis�t0( FL-2 channe�&575 nj*.Vn6�je�j OMV-� � m� expr"2(A�6I>Xof* O( defi*as!Er. V�c(�,� A�>t serv!Ms�o5vg!�  . Casp�SMc 3e8e�v>!�assay"�� C Coloi' tricT� e��$I ( GenTexB�Biozol& gno�lch!�6�r`t$$"�in>���1�E�jXT.�!U�r� vE�gae50�-A,N�$:�� 6�~��.R �-i�k�4. U"lIhde�!�J"�dic$` I )E�um]X���S2*!.�,p e�,� &' �{-2f %�~�l� ��e .c� lysat�"w� 1�0"�� ��U�"� kq\$Ac-LEHD-pN+,3 (DEVor[-Ac-IET�eV&$20� '$�20 toge&� !Ire�9on1!�� �w9)6"� �"d �(is directly� }i�. �l� ��-$ enzyma�&��B�/ measu���+ro���ly�40��( Micr&te�(, Dynex Tec^� , Chz ? , Vak�,��of each�ina>>�as6�(a fold-incr3of �'Vinz�E���"��u-YE}z-E|fmk�9A}zI| (����EC. pan- :l z-VAD? Az(�e�,R & D System�Wiesbade6 Ab3Ib6�!A�c ��/�#(PARP cleavaM+�xq�"j ��-e7>� "� �% g��a?gutei"� , 6c�ZAF-� d �Z* labeled*� � Z� ,B�!�� F����f NW.�2? �u�:^ R y" a� b�! ��D� ZC�g expo� to 1E�stauros� � ig2�3E� hI7a J DNA l��r! �F����.L.�("�IHmod|�e�%Wan�Q&f�>-^�e=��,"�O3q*��t �An�U�ytoz�^e�^�B���.7RF"9 ��~� lw�2J��s%N.7through%�bi�-column�AA7elu#`1�7�"�5��e� �.k(].Hint���g�� �.intact��!*U! -�fr5��10-��'�� I�a� ed vacuum"or ( Ep�orf�Z�#2x RNs .*�*Bµ�*,�8&h(. Equ�m�$uP�( �#d%g ))�1 o agarose� e�qre� <2% w/v!geQ#2�#�p� �� �qJ^�0!�2q�I�"� mixt�$��:akELc�Ge^�:-�:5DAP�04′ , 6-diam�:0o-2-phenylindr;i F�:�� � ��ex�)u�a6t�Q&!;6w%I-UH-(� toh(ofe -300 �"�&�2*�'. .�'(�Kwa�4Bj�'�.n -/.�' ; p<�=05FconsideA��F n�'GenV/X8608`11:e�95s��classgen�1�|*��9�@E8��v�orDven%��or]0�"�I�:�@ P �Spt�% redu�HIgin vivo�on4�>mu�,ona%` /$pathway im�# �recrui�6 CA�% de�>�. More :^R%-A���:ed� deleE r-�H3:(4A hy�&n�#�]Set�,� ocop� morpE?i!�d�th�ects due�-los� sugg:ng .�,�Ctia�!lnd��U )�nd �dow, eam� a. Surpri��*1�$A��2B �Oin-ac�0s si�relaxes3 w�@Ach � Q�caSps�e��m-5'y5in �-�+��" .� ome-w4�es��Y$�precipiIt�r demo!Qopng ef)�of �nd �&dH2�/A��b;�N�r�:, w�mut� ��cN0-�dR�Xc��B feedback�� S�+�+��!_R ]-qP.rEW�tagon^0�k1>(must be kep%�bal� �&��.�. LA�of w!* ruptAat>�leadsHde,<d��.�&aberrA� }>KC��!ta novel��3��p��. �"4pha�=��3+ poinU?r) Aa{�Cge� U{M$in eukaryo�m��is cri�1[ coup�B�to.� step�T�.V[1 3[2]*�a��B[+*�_ has b�*s�9d extens�D%Lh$�s g���.����bAY ucidy. &� !f!cc.� post)��aA/&q�� z(��%#a highlJ� �'tereotyp�ifeas  nclud��N�,Lys4 ( H3K4m/E�ceJ� s�MH4!t5c end�f@ Lys36 `36a towards 3@V."z Io %�� carboxyl-xHu�&�]�out coX"reg��ofE� s [3AsCQ 5( this��\ �ꁓ �5a����2� >�, butEɥ�se� %��Cvid�|.� %�]�q�U poorly6X ��Bappear��D �ss+al�A�L5 Z ٖ!�$�2�n1x ,A�cat�7i�/<. 2he��7I�qe Rad6kE3- lig��Bre1 [4!�F:Led��on2��� $quires PAF��!FM@a�~< multipl.�F� [5�-hisA�J� A�+�id-i4��f<� in-;�x:%�globalq��E&� VD–[9�I��tro�� X ly stim� " of �q�a� ~it 9Z&w [10��11q f%ya3 * lT?���h� $; our work�A/:r  .b �StC�*!32V Jis}���nA:l��t�N*� )q,]��� at s� target%� s [1ŭ Simi{Mfa�ngQnowɄre��;�(cerevisiae aemammalh$JU3%�1:�<&2of.A2* -�iF8kng8. C�js�e�v.:Ae\cyclin-3 �)na� ( CDKp,*K#ei!�E��/ma@$ery [16AGIn��� es�b�� Cdk7!�e�onI��*� TFIIH-&$��sub�G>"� 6�] Q2 .�T nd�irm��s2� � �g�>�u,BluŰ!5 Rpb1.���,A�Ser�0 Ser5EQ Ser7 ��!y�)repJYSPTSPS f!P:Gal C- CTD ) [17I�9];j� =Q!��e�-F, I�i.�as DRB-s� t�induc�( 8( DSIF�2�t2�tTh.:Ss���$��"�of�-mRNA-ngǕ�-��Bɠa�7��22 +2�,�H�Idoverco�Dpr}er{xiQ5au� Nb��.�D�A^a&/FT( NEL24 �5aPPhaN ough�actl"a_�e���.� ,�facil�ng>_>[)�s [26 �7M7t�-limi1V g �)�!���s/ � n):ly ��g� [28 i��Ő*V .%�:�,�c��B,�}�/H3� "�aXTdep&�E�Io fe�U(a�ilorw�a�>vopirido�*a%>�:.��A)k�y[3i3eBur�a�essMal��HB� � b��A�(�@AX!���Rpd3S��de\ s�*D toa��:���!�(6� [32��3 �+J� H)�ɪs6 %[3�d[36xO!*F0 ԅ�c a-�� s2��5 c�@38a�B2! Bano(, non-9� CDK , Ctk!�� a�e major�-��I!��!�>� 1�[39e&40�Alt� fro"�# be a��&0mX$paralog [4�p.veU`e��_re� ly *% in h�I�$Drosophila 4�x43�s�|faithfuA� " !�A�reŶ-nete .!T� themselve� 1� "� .��"�-X")�b���/�� Brd4E.��r6"FIFi/R� �m3qV�H4 [4��4���62$,3�favor�2 �[4��47AO�I�h!��rA�W�1s"� ��to�"] FL KJMv � b2�}thaŖ of a BUR1&�!'u�)'>E�I F�2 �4, [48͑Ede>�$by Ubp8—�mp2r SAGA� lex—>mE�.�!De�.��+at�K��4żIn: �$-�` !E���n/Pch1�I�v 2�Yhe�He. \:.L 2 [50];t*�у&Q za�\stoichi-,� R� >�� did )c+Si �KfN�or2na. 5�����.a �� �"L��[52]; s&{]pll]:Y ��2K,. &G .� !��8e�'�T�pa) trun:�(%/�, synthGlu[5� G`epista�s�%��m&Z�!��W�~ exclu�lbeit��YX,�>�-�pot�xc���th � t� �� �͑�.s$6 �IA)�exploy . Cunc� a!�R���J&� �mJ�A�U:>�r��at �> ASA>byIdiminishF8 rZ"ciz ,e�Bun�D�6�!���Ac �:Z.�2I�nd2�SI� . Ab&�A pref�? �"6��f9fdset1+^=7e"�$htb1-K119R�,Q�!�E���� ( ,q%� dN�s.Z9�. DespitfeY�bFD�- "e)���6�U8ц ab.e"Zr!��Rrs�� S2�)2c �~�to��� �n&��}� 9dBōs���o�R��0��A�AvE�%� Q+ L. Take�g�2 , bi0Gmv�g��A�K�� Omi( �*e �"� .��*�Aat7 jY�1�A�tw�H ensu�via.9."� loopqP >�q�*$ ��vice !�a . Ou� i�F:�� at<� "�2!|��M!FoRTo ask� �mi����2r�M��,Q"u� ChIPF  hy�T�Ion(�2lNA � c�7o�&arr�#E*%l��re�2�D?at�& b�8pai�4rv�(�-chipQ-W\"rst m�c"'2y�,in wild-typeM�w.ag!�>�sp~ %recogniz�&��v с [[5Y Figu�1A (A FLAG-epit�Ptag f�<R5:7u�.Wac�cu��-ize��'} occupancyA�c lel=; �ti-�&�2� �tag77N� ! �7M s�t a��e R%veA�y3 (�,9B%��]ryE M�p�& �J�� "�,A�I �m�&h"�3.A- grou�Ci'iGQqu= le'. Mir-S%of ^ en"�Ma�plo�Daverage2z%� �wit��6����}m,5��M�#.�!i +>e&�bK[55?5� Fur�i�W,�=,AIA-'v$ek9Z��gea�( ( r = 5*5�d.�=� &is ,##&`�"��so�$Iw� c�-�. QH2�1�)M�Y�2WA�P nt�m>���a�a+L+i�y�M>gen�d�T� !.Bs: a�,.� shif�"Q��/EF:ref91eMa&�t+�` �~5�ha "! a�i pron�NOV�&nea� &�(�+1B>1$h!5�ch10s%JMll*(���sUeda�ntobf� ��T oa�llF�KVs-lin�i� D; DHt S �%i!I��1]2=�,[H ) hadr3ig"�,$( P<10exp-74"Y!k -end%���he ab>$1�:%�"�:aw0 �I.�WVeF~�jE�M`Y8r#��/7 most�t5�=?�Br&f�D�k�O<�& wN�q*g�$V� f|-V�&� Y"j#e�0@lty 2 , [1��[5F5�We�/*/�5a>Fy*l��3!���wh� !2qY2��%.�1킭�J�9�e��4�#in%T>%#��n.���,&� �6��� US2u} s S2.S3Qse data6@ !(ob�ed.�M!�#unlik�+to be1Asolby��ed.$2r�Pasc�1�IlIB)����'Ų%���1�p�ZYr%u+ "8/��earo�� Ont�-yt6O�$erm� at es�vly��among��W �E��l� s�?��sN��V���:�n�1� aex����"o 9�%2]rib�&1 N( P3�/58�N2�a1G2�S5)n���a �%!?m-inX�ngJ.t heavil�Van� &n i.y�"� ���M��{$ �� rougZu&25�f40 �w *�1�e� ≥2�9�.rm4a� ��F.N�"( Te��F2� �� @sC�b�(AO)-9��/)$w~GZhI� 9�!�96!��3!{u�A�/^�_2g^_.<�A argu% �\6�+*a}� %ra3"�7X nJ*ady-st�-&J )K ( A+ )�Ag��;!ZVHoweverNhe��A3.� y<>��J1�Ki-kM�%�H%. � broad�I��D�Np&�*�#�*&$+BH-݂ͦ��jO0A�dM$6neEresembl!�'pr-Lby inI!�Z!@����1�-Rde,� , [6%6:W{/inves�jd! si�')�O#b��-oA�L � impl/+ "� p�:E��$:�7&�Mcs6 �,�, beS"�Lsk1 [6.FI�I"i�eIo�0!G&`* of {�@dR4 made9by���^“l keeper”!�q1@.ach-��G��  6%^# �#(bulky �Dqt�togM�do�M�&nQ [6 � ['ous,pla��mcs6+�4 dk9+%Olsk1+�9a�n` y"�$F ASa�u�+�E,ofI��2�a�-bo�N/3-MB-PP1I�. SW(y ,�f�\2EMEKKdk9�aNl�H���Y&A����hole-5A�5-�2�E ��ٝ��* di-%\t�I�)�-4me� *me�kToe(%� ):�N@>.' ��2A2��� ) —6D wt-aX� a�|Fm.Iq#-�!�B�I!OAc5�sm��ni�v"�5H$�'1or �� ������redomi(%"�-�N�"� .�T%2��y &��#mY  �ng�.�"B5$��m:J%� .V""\U#P� hr:� �-�ca� turn9�&�, !��*�!�.g*��*�#�F$6���G. Zx�rQof_p�c"! Rtf1%E2�inR/hp6 �*� "�Y�S3I�S3�2Dr #�-My6!�"�Ano Wh�m�I�m:�on R�otesaRU�f3"�-!'��perturb%R&<y��. Two9n&?7���0!�i���t by lack!�>� at Thr212!�e�� se�E �<�L -T21�_csk1Δ��is �R� CDK-Rng� ( CAK )a�p� @� �>�Y!—�1Pl*��c�=e.b�&�$�r�g, a�8�E%;!t�\�/�)Glu���-��m�'.��B�6)'�on���"6 IA�:p7 �uniqu��,�U|z �B%�"; n"�e-S165A�T-�C�%brds�ref���~to%�[6�$6�'nZe�)�$or lsc1+ [)�?�.B nerAY� 8]�&�� ulk1 �)B�"v ,�y�rL 6%-�/-W���)5�I�<�f� 1]�7ld�8!# .U b�:��A�>�e:w nonapld�>f.$ TPAWNSGSKm��(| /['!';!I$�2[5� To�[�w22a��ev�GD serfof�#&J#E nts:ΔC.����1QA ed;A;a�&!s�*C/�M� "�A (t-WT�+ŝ� yaz1Z iE�E�� o Al;j�$-TWore� MT1E/�#- &� in:��F`g"X- *�o�Z,�C3 :m�%fY��W?�1EEm�%���l!-!r>R%N�E�?To.� I connG �`� sses�(� �1G5� of��ehto�B�zY gene�#d2�j�RAS�EQ.�ed� Thr1��(�-3 -T1PE*�r"Hd Q�t].it��%:dBM5�S4� InnB� ](:N�2 � �CuJH �,L+ ofŊ" E�>� ����Fl��A�no�=u.�!�i��,�as;��s)�� O*�7n�(!��&in*� 3)-�-%�>�!��abo4E�%.� �� do��\w�GnM.� I��pzs $� IC50E]*� 6m�wth� ∼10–1bM5vav�� kM�\2 i�l�#&�'reBn�mE a�#'-PO�^!-��!�.4/��yɃ>�.7�E�e:nupt41} B�^4n�2c/IWp* L�4i�6!.p.� >)�EF�O!��M�'P�1@e�/y%� �)-u& ()�E!l5re�as cekF� �-*r)!�"�$�� ��,We wo�!bh� s�6W&\ coNb!*�( wed� ch �� �7C��v"7A|s.pmbrl2Δi�A� Z e<o�FN?�) w�Q)l�": �e�Pb dBQ,a!�fq+A\�#9^�!*�$�$�2#&*7�ir&  �6:p,;�S4�~)(* ='��.�>�m 2�sligh8��iT!]�!�Ein&�#��3 �ubp8+yd�. e�Q� �a&+2�:w/ng,.b�UBP��4�ogt16+ [6�2�Sno�!yZId�/%sP [66]^ ��6>(tngzq�^� docu�?�o�(a�Aa��t �!�! FACTi�>� jj9�a�ols2�ynamic�Gq�.U [ �� , [7(T�#�(p��&.�(�}|?i"^R-x-�9 e`n^K��! +�:�*OW� aM�2e� pob3��3I�*�:��5���C�du*G)�v-P[f#QF2�=.X-� . AnM3%��w2aGr ��2h�x2; +0�on I6w� EF�.��#�&!, h*�F-cK4� re�-�)%�qd a*_. ��,R -84.���hen H�D��f��e)��D�Udi6?� eptaA( asyn!n�+pop�@� �a4^*arH6N"�-N7�C "B�zngh,d!ie�un�.� I h� ű E��I"L=2��`"Eh8>mdccSQ�Z�-�byQ�Ej:O%�u..�$3�� � Pv "^!�Δ dou�l;�~,)Y� &. �-�K:�sE�n�_�: mE,I�L�Y4�#"�I%o)�*O F%u�33�Toc.�VY ��At� �X":�!�B�|�:�A�5] ]re�ed�F%�3���0� �n">a��"}%���I�� RLVA8*�Ca!hw..Por� �he6�%~� tselrd{E�A�C0d.2,� �:itPed����at.ty� IG Set1��+�"6_( B"A"_+2��-r@-�EŻ&�1o.�-���|a"__/t� x�"fi�qg ��.� `��tic.��]�(�N��ΔE8%��r2`�N�e.-��2?�fyip��%�� }2�qt�g; B$[kS5B^/) T&`2 D>�_" %�3 e. +&���,�e1i�fq�myi� IP!��rwe&�e /RC*D:M=E3� �=��M%2�xt�}e*u�.�.�) m�+b�� sui]R�PvEg�S6�S6Bo Asa�dic�P�'�T�t1�3| !�(e|myc-"�a"�� ��@/ L���&K r*y�et�9p5rcro*P,&� �h� �#f =}1�-TA�*b eng 3in&aro1+-�v5Q4AE�:�E]w76$ci ( nup18� ,SPBC354 . 10�$eL,RX"71W% !3�1��0,�#*L�+"�. 62�$8(.N��S7E7MB%OcK�"K�)5D"p� O[0"�@-�A��$"~(A�>�*,hwe&s*A� �'�2�L eA� $E&u.a=�)�d͙gAU%�A�n$�}bq$��� �'"h ��e , "�;lLcus&�f�W� ��4!�4I!nd 4J �kN� thelP�?vY��)��to7�"degre�%n�4 fA\��j�UY�&{47I�Q-Ty�%bl�/!�un�&�}�.�w"Nu��ɹt -�S�.e unt�!��/�/"5)we�R�M "l J�D>� (?�r��)p�WAA4��P�(*>Eto.�9gC–4F&Y7S7& We hypAMs`�U�%�\h4pt0 "�C � #.��$>2�=�ͩ�-` � �iBwa����26�Q,mp,j ����h�aA�� .?�7d 4nLmRS7  S7H aHS66F,�.'As"�RlmBl�� �T=Q�Vis&-!SN���XD�>c� �2T[ se ~�A��#PP|*�we"�).� , beH �32j!qCJ� �]mR��h�� �WJD�sU�S9%zB��Am�7 +: impe�%.�!R�#�a�4� c>��1nx. B2V=a�h�^�tZr7���onship�m�!F �&� �GEE"�Nf�YC!*eB"��r �N�� zo�,QZ�%�e%L� axi B!�woH!>(\g�-_ �!�$b�?"�n�cha�!er\;M�R:F X�2!%<58��� � q#Ia&�-6&�A"� Ze � H i�bea�T�*I��r}n�?*�byd !n.�^�# �[�/ndy-�F硗��exacerB��"� -(�A�2�(F�)E}r6n��" y�.vIh�62� Ii�/n�Ot"Z\e�'C>�7fuG bypas��XV� ! �1Z%.X��0er of59)�sti 9ap]a�� proli$V%|[1=�IO&�*t M-aF�~P-,��6� Adi� hyp�Bp�0� d �|�4&�es}l x�iB�:��t�%8� )m�rQG%M 7 hr2D�y{veM�t.N�]�O �q� ���sr�/;� was .�A�re_*�\rug-f�pzu>�!_“Nted�.^�re-acE&!B&�,:^5Qya yirmr �R%/= "]v "�D��s*��])��A b�2�D(A u��/d�E�U�CE&Q7 �(�I�@s)�vi"Y95m+%�]�or�. !��cX,esKFM��1I� �Ӓued9Gic. "J�"+5H5I��a&_�&� 1k �R��*�1e -of-5���*6 5DEo6�$"�g��!��\$!�;h��%�A�-�X��X�tE)A�%<E���T)IQ�?cu �<�`U�a�!F2� .L� Ra�snRf.�&�b�A A�*�h!Bk�fl��%� :6 �(l"A ; #5%B&� �ydku=�6��ps�tz 0of ��idZ{s�F1��c��toy60yl+.g Y9,�6�fhw'qA�w�nvasp�if�v2�� =)�be|M�"��WEi],'s:{ Ezk$� . By&["D �R�y.�]5!6��wT5a2H��[� tZ{U(.P%$���er��9A��Mj!���!�Bg *N ,O�bc5� ���� R�B; atriple-!�f?! ;![�@.ea��Uym&?�xI�s� � he}V� , <5%8 A����!�q 9��*�^_U�M�!�a �/ ∼3; # �y�%qYFx�⽓S1#�� A^s<4'9L>m5& $afffy�ATP%;i!�*�&-7uV�br`6z% s [7�T7�6c=�"s( �f7,����E��p�>�O!C2Q5l1p.�U�.iɊ�p��tT�* @:�\Gtinct �4f�edsnng *��&� �An%��nn �Em,M�, �P h��)��%BSRe��o��$mai"/. _A�9LyY�.�Wj �GH� =&�!%$P�g�'��!�mT��*�_>Et�c��J".!1excesRi��i>�A&� �o"� e�[-;�]a��dU�i>��pr�"i2i&Y!��Iq�!sN�k� ��u�"},� T&�>F6s -�!BEs�V volvA��0n�ɟqt�QHvi�H��)Tguish�a���k� O"iees�nBW _��`�ErA{e�g��`9�CYN�er2LzU"�A+*K`s�4 &[=7H7 An rpb1-S.S ��r�;\�Ol�*1241���� �1�wu!62q}al�1&G��.g�<NV� + 1jacB6),C�ed��)!l�!q�-�Ej+.� also" N�y{* 6� !1Z6�,&�!51�j'.H ��� T:� �'�Gd&;Eܵ]m�m� .��.m0�5~@� �&:�*�< !`� I� :� b�oes=���&� ��� &�X2e!?sR'7ic)&�'�p th�`*�^[ng%�+9�. elM�=���=���B0 grew��O� A"6� 2ar�Rd^iP] Q3k� l� slow h�'QM 0�N6� %��G$�;!�!�&W� �VZ�6�. �S� �us fa�R ���E~" !� llev���!�u�Grr�ACXu n&o-*gAm��� ��5e")�J�!M�:F\q��+*� �F�m.a��at� !��"�p:�"5C�;s�/te"�y�A��(Nj�B�~+ rh yQO&D�ŪE&*F��HWhW�l�P\P� 2v� � &!!�]�I��o�7.�J4:S�Fe.E�a�"�Ore6��m��#Ef��"�[Wkt�X'at&��EB�:!7:)&-�H 85dN>P,��:war�e"end�g�M�} KrG&�J��Av*a�(�  5e�-sG�(a&5<Ջ�mat�)a��A^ ��N�"-�b2���Gm >9� prof�T6>!x$VDA �9��c�� g2"�B� Aѓ"�)� lV`7 �"0�Nd_)��A–7��:�=y U9� nFI; !*� P6�.N�ZE[���qM_lU<2�/� D , �NonL l,�:|ir��A>j:-NEYe2  �� 2�/�)c?��0 �F� zBI[govI��>RT[&M-�:�K% Av}%�"��� ]is � anycw)���q�p��&v)%�WsEN�A�#�–[7�VEu�v��L o�5�<)-�+.tal�^s2� G y-X;*y?S&LA�igu[0afMof; :�>1� T.� ��B1�Y%H�2*�>We:.%$��is ne!іA~.]� f�-" [v�q+ . "!�!.&"b��-� \ U��&��D�(.:@Ne����utS 2��>;edQP�b: f�B�U/M�&N 2�fAw�E556�E�^�."I'sU:�F[Zk5$Ts��#f�h"x�agq!x.�F� �D�A��=� T!inA�,"�zR�w[7�TF�aN%��A�—�%%er5�r'�IlA�$ *�.��vl�p0-�pro'F�"^1K�&���E0$�aot&�0S"�e��G%�we�9%DQ e�Rt�*"Q to1�� d8��2" U��^&7&ZMZR� UF;W=dA!h"��f�: U!}&���� �Rmw�GabMźa�ʦ��ps³a�\�n!t(TtdNls e�|*@a<�~>��+"�&�"o>EE��/>]�!�"�e;7, u"H#-A:%F(�:i-Ml �o"�c��[".�K.-?! -m��T C/la�—&$r6��Uo� i�+"A.�>u,30al"�J� �a�E6HIV-1A�3r*�upF�.�pAeZy�> RNF2g�>>.��e�MpiU:.�[80�1Ba���ur�n!� ��<:�we�{n�%`j�;s)PY=�4e.���: [>�1�dk9; t��2.�byI�P; �N. and/�@%2��w�K(��5j� �z ) -Brl1/2* ����Lto��-l�/4 ) �.�2�(rei�Q#��He&i 8�"(/"m�S��-If�se-n.yr�e�b�U�X�)/�@��@��"�`� R� "��E��#2q"�8�� #tumori��is;�knock� &�Ij�N.�>���J�aAf]:!"���uJ�E%� [�l� s�lg�re.|�FN3�1P!I�`. ��[ S [8&�H�n�{�E�]5�)~݉dB�byq�U Hf.�mo���#�Fo\ b�Kse���re�R5�.�, �w�5<nt � s—�\SdMy�Euhl?GivBNh��?ޕ)K�h �on S.dYn-ian%�(�Wit� �AfoDAJi��a�� �"P �#&�6l�Z��.� .6c�[w��c ile2�te�;c�m6�bKqa �v2H� *�?��\ a homeo�Mic*@M�Lt[�*��t:Jb���� t~ n`rd'�9I���|cen��bud-����ee���e��n.b:� I�.4"2 A?�'Wi8��"����*� accuf�a�˘in o���-�J�p�-r��lK�=ec�.�o!�y������NDU���{a� mƕ_���!� �p?��)&"^g c�!��l[8�+8�+H�4"�lin��.!� us ae�o:�B3�^J�(t spli�,��z)�Jar��ort [m�5[[84v8��>�eU�6em�% �n.x��hPi!� cruiEHa capܦenzym�[�"�i&*[8S (�-e"��!��7 ƓAj)�]���s��i�� ��"/ !rP&+( qby61(%"N'd� ��� "�L,�(ʂ�" dG�^nd�^re'�׉@�$ca�� extrinsicM�A�"p �e�gvU i,=�**4� �)8„6��!�׈Q��#b, �S�&k=�YLur.J'remov�!E�*l barrj�>�/a lK��v�%[8 (~ have�Nov��*=l�val�hYk2�"g!an |!koQ�aZ-1�#,E)!C���a9�-�LQ�Y�A �{�/$ȅ> W� `�P Q�#!� mC�� ,�A���Q+J�� Jie m /I�virtue���> R !���)t"��!8�q �L)s hA�r ��z"ts��U�o%6b!� , 6�Sy�-(!�!%!u�Yc�9b;6: scue4:'1d�L�5MI�x`��?h�(��KH�M-�Y1��k dru��&w2���"S+-" . St��Ehvu1�|lY [EPn��U�$ � YE6;�ͨ2W�/L�f"�i�u��,k���!�ur� ( YE�i. �qA?Igd�&� techa s [9�&/@A>Bby &�J%�,�vtwJ7i�.��jde� ��z 9� &�c%u�at�M!�I��^�er�A!t���)�+E̎�Z %��&��� �sgys�,�u,�u, S�S5 [9-2FucJ���5PV�j5BS��([hlrs��� qPCR&R!�avail�!eY�&6"}e0��2ިdE�no.A�Nl��lp�oY�f�5e��*vie� ��8a Leica DM5000b�s ��2��e6a.��. �΍,��F!\V�� softw!.�� 2�A� 3�`V n9/�`,l�vehic)MS�v,%�1��a0°C "��� acɃe�e�. Dose-� � �a0.� 8PJ^)`7��-&�fMon%�6O,- ���(to OD600∼H{1����!�261g`�or %A��Bt�Fd"�u!��|e�8�X �3&�B�th�dr�B�FhPAs�U��[9@��DYe�� f/-� u��YFV�j� ;Vya�s)r��t�smr!Louth Ame.�%6Af �K5�! evol���(p6��%�]r�rc�� oS�<"e�{a phyl�ErSw "yڅ�set�pJ}؟L�F{�"M/EZ ��_133!.����es�]|�22g  OvB�mio�76`�r�W�imaM,c5k� cirB/�?� �5�in1_a�.h�st + 500 jA�emerg�`&-� &A�sl) tr tapp���ly�d@NTg>!� viru�A�spr�wes�}d��r�wv��inl �tFis� <"�'| d�� e juP9�6Y;��6 illu!!teY  "$!�d��;i�43 avi!�Ge�B�dem �=_�z�_~��4ϒmigK �- ��nY# bNa. Few�~�Xac���(n�1��(*0i+iae�aA�!�m� ( YF�#It�K:{) �Pfe�B�pidԉ�f!� 15th!' 19th��uqk�0U| scale�break� Tc1> of N%%H6�,Q�)R Euro߇|^ devaeng!t�Zand hel�hap�C xpanK6pl��colon?pap" b�ɒ)e�f W� Rd��90A�1901 "�E�m�di)����&pble�mEs'+ A`Naegypti!��*���. Wg�!�y�7 eed'E(��=!�.tsuc|�aTrolj�uba��y'Rvigil mo 4 campaig%�C wenty-e��s �r , y.fe�El�,�J��h-borne .�*�$[� &��� egac�YF�� l_��$I�1A$rͶ�=g"��E[! mZ���.&a�20)0s���x!i3death�& , �W INf"�"ӥ��vac�"� ,�/a��e�ɭl�ala=\�rg�)��.�W���}ń!�l�2�[dTaG=��PiI su �� pr�m,3���oblw�� v��civil waAG!���{A�i� t�,ru��a#W�^��1��!r [�?8 �>%,�*ܚA�K-�&��1Wsl*�N�R-I�L�7eЈ�2 11 kb�hQ�!��� r�(genus Flavi)�( fam}�idaR��T#ma�Lba num J& vectormP�_" ��9� den , Japani ncep[�i-!�ENX���P)d6�  �'Q�W�T�Ae� Mj,�|!d(|st6� ����p!e[&i&�C�biR\ EA�� v[9mq W���Jss ��Au&VC�kt�>Pd*�"�ޡ�"oF4he&6 ��:�e����7i!)���' �O� � ���ovuci8�i\)|A��o"� �ͫt>���-<x!�E�A!ͬ��bil���Kai�vV%l"Ph%.9 . &��!:.�urban}�wi��-�;n@W�D%m!J coas)a>R, �.�a syl,"c]ooA; w7 Amaz�'Aragua��rOri+� ri� basi��e�{Haemagog�۰ab\8s!���2���2�-6�a2?Qw� %�te�3C�ir��eS>b�!krigor4 W��uJ �mods2A *Dh�� d! �y�:j}��$!Uag�qM�n)�nI�E�& <�er!�gi� =X�is6�gI?(�)Q&� ��S2�m20"� (!5�"�x�u�� adic�P� U4"֧e?doo� �ɻ( j�7O 420Sena MadureirI�AcBrazil ��15 y:54Trinidad2�, six.%99%S� ��de la Si:( , Boli�[ڤ�F: ��4.M!�-�a2Xd;l�ou� ��W ed� -u,"j �a>�28Ri Janeiro"l�~UA  _2f ϯden�npj�,� ���Iwo.�A�P ��0M(M��  �UncurveillXjH��A�of� q0 mic/���"�&� "E��&c��lth&��!Vy.��� �gh�,�fs%�&wB�E 2�-��spk �Tm�M a���� 2�% T,pD*u�ed�Bs2�.{/ |d�n%;�'� chie�M ras+�%/d st D�)d"+$,:�Y!��tߘe�a ��"/ ge� ph~ lo���L!�� !�X&o"ime-spa�* f��)��r~ half�pre�� ( pr��� �ZC�2�o�8/��pr→5=�~�A� 112 a��4��env�z}>+��cl*"3 P)�<�� 9�&� %O�"5 � � 8–é�+!!_Eš 2�]P�E�iry>M"iKfD G�) )#Athe�OjW ��+r �l%"�vir�gsurfa_�E���ge��.% H|'mo��jF�ũ7� w�[�l n��]IOW�2C�' YFV �p�"=)�!:&�&�,ur�)wle��3Bz� ��2�. �xAWedHu{��e.=�02�0)�"� E2�World R�����erE�E�aV; !Ar��r� 6��Texas M��edical Branch , Galveston , Texas , United States . Novel sequence data from 37 human isolates , 21 mosquito isolates , and four vertebrate 6(was obtaine&�Ur the prM/E gene region ( 670 nucleotides [nt] , genomic positions 641-1310 ) . InclusB$of an addi'al 71 hs �s �0GenBank resul! in:lignmentJ4133 wild-type ͐representing 22 countries ( 14 Africa!o8eight South Ame $) . Table �ov�Dsummary details on%"YFVwincluded�@this study ( more: are availcin lS1y Our phylo!v$tic analysM hows thatv�be di�sXto two geographic groupANhwith distinct viral lineage!� servC- and�-!7Figur!%U� y support�e majorA9o%�Psubclad� �iA%o}$previously!W!�based!p fullTme],[22A�A� complete M�[9},3′ non-codAM�8[23] . Four key �a �1e rawnI�Jstruct!ofA�y .Af ) !&-BnY%!� mono0%�, ( 2 )IV/6� hose� east�wese�coA�a$]3 ]ufrom W0i �0st closely re�Ld AT6p �AV!Y( 4R^E�^�mbdiverg�. Such a5:%patter!0%�atia�E�Dhypotheau ar!iU�, jlik�ii�%(%�at2 Ɓ�imA�e�e�B0�L(then spread%~(wards acrosi5,4. To further t!y�� , we�I[8ed a model tree�$which bothx )[�dgny� were>e AiVWtheory)S!gvirus��!pe�\UX(s have evol�: sepa�Odly for a far longer period%{ime (��“anciA origin” ��_ However ,{)�iho E�Xa<�!y%�|significantly lower ( p < 0 . 00a�thaAau#maximum.^A a post�,ri ( MAP ) (�rec6�)%�a1� �e!�re 5 migr�Z!�5EZ)�il]vE5inigate% timWE�Atroduc�� ev�>��{precie�,AhA�TaOe-scale�a:\ by estima�!�ui�!�s%1d�ofu�ce us�@a Bayesian coales%8dapproach . Broadly equival� Xof*b�9 stit|I��5ll�a set�qied ( c�����!�]�)a�lthougiUsmNnumber�2.�!P��aa����jaaasA�T���. A�_�!�&�$as a wholeM� mean6�!E�84 . 2 × 10−42&sal sitHper yeaa subs//� rang!�E�3 . 3T(6 �s!? IA�o 8aV20Peru )>i.�se�s�d��%&ng��en!8��r RNA5t,N � lavi1�[24�Th6[also un��to��b`adverE�affec�^bya� itiv�leiBo��ec�L�Lor cod�. A..%�e�A,,nonsynonymou0 dN)-6S-&Q�=�( LdN/'��markea#hig�;-<:� ��ofEZ�� +�\�Oo��a sugga�ng*t s)ve�|4s differ accor%�to lo� transmiss� cycE�A� �valuesi�le�an��2�{��is in %~ofmiv�>0strong purify� �$on against:ichEH$as commonl� ��< arthropod-borne2b. F�, �C eQ ��ofN%( �> �X!�6vat a �l��d� E100E� s� d� ���notablyiH. F� �a�Q+Aes !�maA� abova�) deepWnod��eE �)(, correspon1�9�of�  str!o saS d hR, h��m��age/723�hA�95%I�0st probabilit4 ns[HPD]50288–1 , 304 ?�� A similar�͙%c' under+sJ 4constant popul�asiz���best-fitA�% in h��)��ݬsky  plot%�I�q. �1���robuscem"� � 0( unpublished ��M�r�ly�\d)l5 ce%��*� ��d>cp s%A�wxE:ly 470-vago (%�HPDX186%869 #,�p�#e��? whil�E FE%�:�"�G �306 `F�20�59�!*$Taken togeF  sees�׉�geN %9E|�&yI��:��S witѯl� th� to f-�uUAHp)�� pellA0  ��itial i.� dur+!�*) he sla tr2`fir� (ontact betw��*�i� s�?��� , it!�ear� a! e)g��E:a!,ccurred shorA� afte! ir iN��� they�� mainc-�"# � siA� . Of al��c��Xno doubt� ribu o e����ae c he� A�sur��i!e lack!���� �i~t!s ffic#s.nhemispheT �!?c���� fail�Pcause urban epidemics� �!d bpir`6 erpa�in.b�2,�break�eB�( nearly ann!�ba�8f!�large.On cit� �ced YF�)n2� alone [7 &-a�.es revea!no��E�i. o&� dyna%$am1Wcircu�Png32  ] �nei��݄exhibi�Aincrea�in ci���ex�b�f�anj $. Indeed ,E��_�� ^I�ce�[�{ed �a�#AF%��growtho� AFxtrem�;low�a����4( e . g . , ~2��m� � v Brazil��6 � a�a�M� olog2�ti� omin byY�2� . It1& $ h�subi%p� play�. r� in��A!1�!"� leve�gB��[�l,� ref� � Qcl� g&�*u&� c��,�chnrally�iQ ]n�bor�e����( little mixithem . P��a��s�oteCal j��� #��2An� [25] ��!�Tv=!$may� �inacr�enzoo&foci due�bio=8barrie��ine� moveEEVvector�hos�II�ntr��,�iG "+��rI��epi �s��rapid�persal o�� r tancŮm!�� � ��A�Ũ!�md�/n�� z�!%H�zM�be at)�!ko ?-ai�e5��E of m-in91'or-&[26��Inter� ng� sez���}�Mq �)J�!�&� marginE�>S��(2�YF� xp/ ful histol � �5howa� a� Q;travel�� rou� 2y[�R�c�an��D of microb��ir5r. Globa :�Mp rnx �� ac� J. pathPI�1�f>nd faAR�;er bef� � us al,$ e pot{a�" >IR��. D mNdecade�~%Cs- !�ocu!�ed�_e� n  i r As%Eremuncer� !?1ii鿥��.�6�"en�N( q�p�6quick r�. All��ٙ�&�E+a$World Refe CqrN Eme�Mg V�A� Arbo�i��6Un�� of� M�� ( see���*3&of:��l��pri��ei0ck� �e b�/ l� "�passag@( C6/36 cell� Aer* feA�d=���)U�I��\ s manya� to teAU� A�F�.%1�uA�c,� a��o&47p : 16�%�19e� 1959 , 19B60–19625B7 71B8 84F|9 9AY>"200"200�IC " Y@ :< 5�"�!�'2�' as ��F>!M�7-mo:#-6Kin6�e�ymin1�+9n ry archiv�#MaB}� tre'����}�a���#� � �#tbet) a variety!G&�# �"Y1lE� PAUP* [318!��!( a )- !2C� !�( b�,he GTR+I+Γ4 a� �"/� each6I! �)gen� �rs � (_�'pro�f� �>n������ shap� rame��$ gamma 2����catego$ ( �) Odie�Yi��2( ���e�a�"�teMM"KMarkov� in MA` Carlo* Y�Tmpl� OMr> [32]%�BEAST [3�"�|fK p��s�d/��A��in C( �length!M25 mill!�,cAA� y �00&,)`tip:�J�y� Mtd�M ei�"& ��_ A�&x { baT> "�*^a�tkA *� �$B�%+(j� fp) �4 ExI2in��n]� �r�!taBV!) IA\a Shimodaira–Hasegawa %I[3TR�^*,�a��Y �� �toy MRCAe�!|U �&�#��Q�&y(eP��@�,*�aX��sAa%JaH� ��/e�� ��"�Ka�x4 une)d� R� ) mole (clock [14] :h2WP&*�c��*�!d: �F�, exp�T�, logU'�'���ex? )e:confirm%�=�%�A�lla�a alyz�we��A piecewise��2D[35�O��isse=O 3� � o","prior=kaike'�� form)�criton�O�Jtoe)erm� �"�E a���"� tU�$� Q�s B��"v�)a!,ch %�runExsu��$��n���&c+AlltCa��  �$FHj#. M|�����on����&�7on%�~me.d)��!ti�� a�S�t� �"��d i�!�s-2�%�<8a�(%eY�)� random����( �%of 502:method �eia�po��GTRM*E(J� "� �nJ -joi� g* ? Dat��d*f� y [3> ��Herei� we 7, lZ� �!;lea� bacaal"� Streptoc�(s pneumonia� a�f % i$of coloniz!��di�%l2L ,);%�� out!4luenza A ( IAV0 7Aw�{idfy vul� bl-inta��multipl!epva(���� *��is �\ utili����mprehensy"i-�Lbo� neck�-f�"ng� K�& settA6of�c.�!�$organism m o �M�r2uI(bloodstream� a�� X(nasopharynx%| ��%�.�#�!�Pw�� .�!@;associV!�� i adap�=!�heMB�A�� �Y� exit ����"�Pan+&explaip"7"�'c!1�AF2reA�*�;� to�cAg�� seb(e6� v@/� 7&� TLR-dep�n�� immu=1x#� it � ud�Wh/�$*quil o�( trol/ , drA�9,ca�1. !r1�e oE�m�{apl]/eSs.ka0( entr�"6u�'M��ia� �beg� �XA�2Iof)�surfa�g/r=�7�?Unviro�1a� �0oi,i�'�.u�� r)0s� life��"�!ir obl<+UR2 ew suscepj.)a*!Yin\+�*�fusu%Q�sI��mb���mpa%�X defens�X�!��l�"���may bene�$he57 ifA&Opr. and/�3. . An��anN!0�,reHE-� ens'2festy�#A�lsoaՃL UMmb�(E%��us ) [1fP��i seri%]�d��� �ũ��e muco�M`�!)�.+asympto: cXE�� � childf. �c8 s2�$.S��-� +sEPa2 ;i�Śs��a"��?ńs1i�cq&�� �i��ok# dayc�,|$��{2�direct 0 ? s:to,piratory. [2][DM� �w�0!U�OiAzn� !�&� sES��B eotr�t�middle �cav� r lu륅qaEw a�F..R%o-%j�*Q��j,# syst&#�� . Be ��ighOI%�agi��Ccomplic�2�e6�im� X otitA!edYi�I�p� [1][�A2976 ide���$at�up| .F�&�ly%��� ���"HF��� risk� �t ll �� -qs [5][6]�#y�'b�6���E_��rol�#G �Z� I2�weU ��fY!�va�%-����Azi!Wul� �Nt��{ vid�$Ed)� ��emia [8]r6.�)r  wB8(4 ti y �vreu -b_. e acqu�!+o��Ec�+%�-�25�2�w�A�mu�A\pr.�un)� & � ‘herd �ty’�� 0][1��T�)m lin�g6E � ;$pos���!�(ct6[M5@ dis� & ��2�#% or,tob ��Vh e me0.ism>� SA�=�sou:B;� ��s� � & w�YiJ� S4"�,&s  ) –a�rp rew�E�,M�9��"6: �K ts [12][1��A.rwould�� Q&Z/}a�f�.a f��M} �ng���'� to6� a����ev� ��  V1ern0e/a.�c���i&9 �ue�Bo!��C - !�i��d fitn�0vi�2>� (m(-� "�4�o meet">(t�l�i�5. TM<9�s-ir#ac!&aOweak p�aM �t�;n%p!�tegC�(Y(eNr�m&few=��\X)t%Vso�y !�I�� �ى�� ][Er����#ri83��r� �1o�;�U�&h�q phen�%�*dM���- u_ cha!3 eriz"}_u� �!) no��c��w eriA al4Zym�beyond6� -� natua"%م� ?���2�im_�,u. �=emplo=(Rq�recapit #m�"e��v�W>���s�c�6]�"� �#yg � ) �+�-�ofi�2 in�� (6���z�DF@b��7) f�A�:���6 B ��u�!�-toi�2�. AS6A ՘*LS .-_#�n���(>"escribBB�e�/anasa�I�5ch�*��age 4� ��4][15� � vana�!��9�� i piceE�5��:�Uw19!Dd=[1Y ToQ�A�1hin� s7V�e�--���_ x31%0ino  ge 8 �( sche&t .�inQ@ 1E� de$4>�!�d�iA�%clav��"" }12 ~�Wl pA�heavi*AdE]%U"�ed)�IAV�0w%.�+ly  �& urde; �mp,"�!VFig 1BAO��s � �as �A�S@> � � �_tymN( c membran6da�!�12 ��8surger�@In pi�4{.�+v�>")%Q eOCcE���i!��1�*Fw�+c�1Avl~� o�f5�#�5| a�� neutroph�C8( CD45+ , CD11b Ly6G+ZR A6ŵ by fcytome�([�VCn%�&� iI3Ain 87%A���#��!%A7.LC�Q21F-PBS� � )(I+C�T�ctN��3H4�p�ii�/7* �od Aoext�I�b�q:3A7sA(a�velopa�ign%}s�.=)al.�c^)�� cul�.6/oribund d�e�sur�;ng until� ��mJ� at 1�p�gWS ��!�5�pOtoqdayHAll �A?�d�i�vA�H����w c#��*i;;�ZM courXf1G(�2>Go..av�[p =\;85�@�jDQ?���pup6,j4-�+ld(�� 3 �:0SAindex������9:O. O� 8� �B F�'����?�6E)i��`w�M!or%�:2���V���"_F��� ocol ex�!�B.��U�.&( 7%@�:Bi�minim�:2��2����<�_��1�)�a\-o�5 bec,a sour��2m�2�a .rabb�.F�"�B�iN1��C� Vc2��un= . U�;��+ia_s � , 70�/2*becam� �hage5�2rasO� `�l�A�Ez">iat�E��*8�;,s &?�B�>)PX"e�Ee�P!t�HX "47�k.b!*&�&�/:W4���*9hedu�iha�M� � )��pA� � "�.Q,D ��t�A峁 � a�1�at!U!�4e�� �%}�6P/ !���E׭'ia&� da� ��8��12!�AV����&& Ym!T%+�?�i!�1�*128~ 50�Md�F%�T�0>o$��R�w��� s� } `H !BB�,݃) �D�h /���=�}Mlt!�!�h"���aS&. *)6_& cI�o#i@. . A"N�! H "K !�e �#sKe�}->n� eKcR(f� enh���1H�E� ��atri&B* . 13!�1%."�I%���i�tlo�[BT�� �T��Q�(Z TY�uSri�*��2AN+O%d� ��Aetoos�R�2�MqabsZ to�ga�y�i�4i&<��" D ur&�&A��0�at �_�iJumE0� X9�r� �M!RB�-��ǁ)*�4r�E���0�@�r�ia%Vl�)Y&% )Oi F nb!�A=(�U�"sU�I58� ACe�ha!\.�Bt< sacr -&�IN��!A+aK6�EM"� �L�of6;md�3A� �Q��~$�6r$!2R 6�"�Iv)��o]��[: I7ma@aG'�b�Ua Poisso�?�ht al$P�") *� cs/��F��R�� 1 , �'3! ≥4(t8MaOal��M,�Bcal���� t�W�&��&a�!6I��&^�-�:�L uo^'a�ed�aw1nL�nbL tiuma� =E�6�>Aa;e�R:�d�*��;vn^"��@tA�_ �*! ��ua)aain-N Go+.��2:#2�,m��E =��!>To;+,1�Eg*� loos�"�+: ( !D2A=5WUuzaD�i=F� &� a��cŁ�%�I��a wi�th2a*x �T�01\ two-�Z ed F2H r’�R�NE�Nex!*m&!�E�%) �R`Q�f��� de�*a ����a�={in1*�5:a� O�d� a�;�+{ mP6&� geal6�!TbyK��&�QA>�w�a�T`�%��)�L� 2�l0VT��"ven"R��Y J�P;(d.?� 2ton�.6( I�V�*!>�bD)B�uptak� -�"�Ho^At]h�=bIP5�3� cz Y-'at2 �H6��1E� 2�B�ap�L��v~ ��& y��oI9n� i���S�Ba*!YG2�a�RHS�%A 2�.s�@i�3v1��ZNi�2y"�#ve�#/2Z a�&�c�@Aza�.��L)%A����t� }\���Bu� =[�Y�ubI�AhodE�f��:CJIN=�qI�hif��PVd�,Q a�I=�giR�6�n!�*�/s�!5 �.2��2�J PB *see:!#.�)lY!SU���K;u�)�*n F� �>d�?i�0la�6Kf�!JI�8>%���l~+Z.*iMregard$J3��]�@A !�Ej3��>A ,�c� ��+by"Q�"ung hom��:�u_( 1�Hof 10� � FSf� �J:� )�be1P�ii~&f��ub�:�)*i"�* .iQMn�r de nov�aB�&�2'a�!Q R/'%��� pre-j3�]'��� ��%�)a5w E� !Y�a�� t6 ��^4!"��� �&�'����U-!Ud6g)%"H#. S2; e�TPmi�;w���.4��5 awi2� r%,"�"IN�o������.we1@n>% }=&�v*A��P`It>y��c�5)a upon2.� �Q ��vwV3�B3嶉�t"Xc�=L���ams�!TQ9^3 w�b��� Fby &�.)�%H*�(^�>�8��z2i��sQ�aO[��� x (�!�I�edAUwA�anF(ij�!rJaa�riX2Le G.'�a�af6� ��� ly � B� P ed�6wa@2e �s�v�S�)a��#EH3B��x_F0 ����%�ͩ&��ly�>\ .� Y��"sK 19X27^x�Dx 6r5i��or r >WnAm���on&�.�2�IE> 2ռout�! T�Jb��q*:lyi ��A:V.W"006AĎ\#bG"���b*�X �-����9�| n's87(a) ?( 2�%�)�� 2���20�2stochaO-p� defi� ,,Z2;i�p �����5l1AKCFU vo<10 �I�:� �B�.�e>.����@�ŀ$�e]�T!�7 9�N�/ �Aq��4 G.�yfou*_2 ocPFu�95 a�s�!) r!*Aq|CC@Tv >,,�FF� b�m� A��IN��"�~f Bf "�he�r&}Wp'f>�<"�GFc`e& �!F)!!!�� �T���/7]@0��![6a.�qB�Aw� repe�(inB�tlr2-/-��Q;w2�+� &Eh otɡ�oG4&�&�&�0 �� �:z b)O5 � pup/��!W"� w����� A�c�4C,,�tQ͆A�Cs$��_�Z$<@=.�nd��? �f� ( S4�"S4&Q"M&�G��-��W!�� "�F�2.�#���͕�A" $&,h:!""3���~=�':b�.%�5� =D��2Y�erm�to6�ro`/�age 9%�10 45,Pvir(�F(;ogLY�:LѝA�cł!d��DD_ &�J�!U&I&Y=��M-6n�gc~AzR;ɗR%=i� I  a�.�S.9� � wajՍQgr�CM�.a1]���J(Avv,"�10�1 �F}a+�5�nU]edA�*�m,LQ�^&� Z)$���ae����fac�A�*Y( ].� ��z!�?oh]+!�&�A.�:A"�INM�%zs�1ty-<�B TLR3%jn�b poly-ICLCq(Z7I�)"�aBIqlH�rZ$2 ( Pam3CyKA� TLR4 ( LP�o&TgM)�;e�e�. B  �.�Oo�mot""��9C2d!Le�@&y�a�^" >(9͂A"�-TLR��V� 9C!�v \]ti �2�al"iM>5$agnitudu�&�7Yi!�*�^� �A!�m����)�44�4� \kd"� "�i� p�qiZuKtoE�dic�G`=��a͙n� ��1"B4`�5%��#Ib!.s>�K\ l$Hc�=Y�2&�Y:A�&A � "$Cnde��5e�:�We&O,�%�R,�M��Ha"0=ly!�o�[m�2.]� �� ћ�eF0A�!2A7 *��.}([18?="�mH�=F� �  a�E�Y!%E�2e!��"�Q��2nug0nt sialic aci�;}�u?��![�=he�p!GI&�2l�9�2��s��,JA9Wde&�>��mn�G!��aw�%3r1) AZ2u/2|q��"�1;�7�-{M��L=}1!�Y�eg�0�FE��WG �FVNc+:vwMvw��ci�a��A�D&��aA'�dJ v- �� sP eustZ PzuMysfun�[19][20A�!�|1-.�avomgheDlim$l)G�"�/D�T&I!�g�y0�FY6�9)�hamdr�VJA"i��s [21�IAai+G��6x`&/ %�$um��;$.�{-Zay�- -* )�b&� a��u��!jwo&jAL.nA�Q}k VT����W� �)j:%� �4"�Cu�2��X=*32� &�,!s[ q�t�-"b� � �;sh<�u�4�?A����4Z���!m�Ein3P�H ;*%� " , buxen�,t5V�:4.��lm��;�l��"} �O5fe&9js� YA��: �( ���d=m=`�=Qad�WHp �89�&�hM�te�SAZce��do�ot� v#i\rt��i=p�4 Z" $*(/�!�d %YZp!��Y�:s'A2�0"��n�md!�@ab�Dtwelv;2Mg�� �M�du~O>� !��ge-�u�"B{&i�{06�i�UR?��5��Z%�o�=s�Tc��in 2–aF��2�'w�E �:&� ��n N��e�4�2�milieu�HA��:I!� elev�� �{ yo�%�"* E�" r�� ��e�xQ &�!��AQU:I3� �"o!yh��U�l^؂*j#/a"�:�K� dA A� �Y��ai�W��?"^ ��V�!x-/2k}#.p <���j�(E�8��5r]WdM�|+a?�:d��v�Fv�FaU�5"�by Moxnd Murph�!�lb"��,&}�Q9�� )�:&A_9 rats�-2�-�&A� Haem%FuK�<eJb}S clip�zh�� �W`J/B�Y�Y (TGFβ-signa�UA| polaa4ep vlAo���:vo ope�@�aj9 s"�0f$^�()PU�����b!�"�q!����h " �O AWt !Y��+. Las� ,{w�ch�7Ejy �9�=�2h.%�:F ;�5�xof GergR et a�ah6. V�2�)SD6: �<}/�/&W �� &� ( 3×105� $��� n!�� ���$�4�du.{n>�["Fa ~103���im� 0�: whelm spl�L�n?��B�wewn"�Uv�o!ܩ�l�G�[Ś� �al �)d�E�"�#U " zboa�� �+�//{.� � �7ann 'Als�P�6#� �z ��%L"X!^c,s%C I;aM2r� � ���&�Ns-�� �Mp�L�K*E8�Al�1A�c�+<)~2S)*: �1��$ F4 2[EQ �TP:�tF� i����&`Si N� �2eQ0��98�& s&�%��,2faf�!)�aR"���|w� �-�%���C TLR2��nee� �?,F��!YeM�� ��� 4��%�Tr.�&K1=��q>�Y�]w�� !9b*K'�!�~��!�inc!�JHW��)��B_hJ�)%��w�)r�(5to`�S�-� ��!Non��.�� 8tl�=by�Wb�rLR3=��8IN ad�@�f*!�oD)gdsRNA ,�O�6�Q�5U*�M�*�8 Z&� . O�{.AwC i{a;�Bb��L ��i߀:.� �-�$g'a5+F Y� PAMP�in)��b9hng" u�2�6(�R'e~���>�]Q����` ��< &X 5=triggebyJk� op�Re�%��E��\� AvA^4"K g*0c6�surUG� shol�y!���W)� *�: ]�B�]7])F�_$*W is&6"�a��,7�B���!���(ak�q�6W ���!od&� =P�'m�"f� .!�.W��A��:A&�[�B��[{ "EhreJ� ~Y.,S��m ���$.<o$At�&�f9>#ish6c�1Q(is92�R/AJ7Cv(8�e,j�lCYi�\�>�[��2I<�Tr~e%���P9R+�a��5%F} yB�T�!�(Gnic������c!�U�!&��e�(r� V�. M�)[P 6�eE�9#)�E=me�9� �[�du�A,G2�f�A�he�uQ�N I�Bf�o2 D��� . S6�%q�SX4A�=mtE!,m�}�& �.��f�mEX��%� `al"Q�S�pooW1m|}�, "�z=J�o^. }a�^��$]s��ly��m5W+desicc�[2J-=Y^. ��]beE�C�L!����*� %�mg�_ kIs� �BB<al#&�"(,q��Qum9�d���Ku"-U1log)��-5� �'B�A> � �E#��s�6,[& �{�H!� �Ir�|��*�b��!%���a�9�al����j���ur�l��A !wh� �Z��IlusEM:�y��z2� ���1S��u�B%���&Y�)mx�_*�i�(Mi ��E5�"�M� �oP*�!� k.����o�d�,6�b)��!I2����*��2��_W"J*;*�t3@ad*�\!�N"�_�_!bP�!��/ex<1�e� K!�)q1�N�"p�!�guideS6 _N�7 al Sescemund AW WelfA�RI�%�WP#�H#� Serv~Policy� $HumL[CE8Us�Lab2r j!��In�f�al 6> Comm���H IACUA(at New York._a%���� �!3�R.N4'U�se�hA),g-�/��er Mj �vertebA ys�,r��e�|4�d%u7Qur} �(NYU Langone" �C\ �� choo�=�i5v�A�t�N�o(is A3435-01m�51@&�W�C�Ő proj�P!�(150216–01�15052�SQP1547�� ser�&eR?`���;sv�&�y�J� �kru��k&y(�in�S_+P2396 ,7�P2405 :��!�r WfiW��8�G ��,plasmid DNA "�R!*h&�QA1nD�R)!H�R�rup M�(�A+��c�t'o ery�J myci4r�adye N-6-=uyl �er��T�$tin76@>4or kanah3' , 5'-Qoglyco:k phospho.oj-II2~��2�Xera��aa���%-A��S�!��%��) �<�0(�Y)�a$ t7; 5’-TCAGTAGGACTTGTATCTGC-3�l* #+MKto��0% a�eW at -80)\A6�H /My%#m&f��Ydam z� "��1( �44 �8E�Wil}1C57BL/6Bay6�-�t�Aco"J��#  JackO*A,( Bar Harbor��z?Z� ��ZaGion�,��.�$yinosinic-�+cytidy"�(i en�p%�"-l-]�n�[- , Hiltonoi�a synth� ^IAY-"l�z4by Oncovir Inc�b-SerLys^- ��._triacyAOd lipo�B�*Inviv& 0W$olysaccharbo (�-!u$Salmonella�ۧ�2 igma-AldrH!)I{@ spc�6dotoxi�e==^�]7�idb|m��e�r��<RkEgiB$a2�.M �)r� . 0 ��+B��1$(2or�F vehi���ma:%ag�gto G�wur�D a�e��>.�B to@k of ~��|8of :�as.@3μ� cB��a bluڀip w�NanestΥ$,b�#�gW^��)w��6\*/HK�h� ( H3N<2( 2�)# 4 TCID5��b�z�C3�m%��z] "Eia�p�8�q0llantoic flui�10tc�gyon)#(chicken eggA�B&E E )��. V�z2�� &%�t'��titM�Din Madin-Darby Can�Kidney�y,�=deS�`[2|-�YQY.'`eu�� ^$O2 asphyxii9zJ�"l�id)�2��EH2�a��edlap� �!ntrache�?)rcolZ�<'naZm�8!!ct 5\t�0ri=��in �;liquo� a���d0N�a��ne"� 2&��y���O�4^=N����pX,)W�[� limiU �A�33� Y un�&uwis/:!5 >I�Jm9a LZ/1g's+tenf1a6OW�(�U3/i)�IH8���! �I.q�f�Y=� 6Q~�� ,���+shaD8�FXo>!���� x��% � uf'<*e%@*})fa)dK�]Q �. E*m6�P�G6�.E[.R��c�y�schedule6�I2"yg12 JJ}��e!^i��i"�[. UE�`ss�Mng!kroscop���g>�Y��� �.(a!�rpu� �al�my ! otom�lP A�u/I�A�I*:� E!@Z�A�33y^�.sN���R��l)ti�'1p���" �)���"�vZb& si� !7.l! �`*�:��?��'�4BS��X02��5��%�t�P"?�2QUI�R���A��sa��#(��d$�Go�9�c , sh��aq�V �ll�)�ll-�)!�imopt�6�� JpMeMx�$es:w cardiac p�(ur��g5� l( �EtF�toM6fy)U(y��<�A �=�$�>5%��onnBa�Vnd2�E� [ ���D��U�R1� �1_"�%�-�O��I�K��&&"�@%Z!��A �]�2%)Q�1�&B��B ~450 ,DF� ( ~1� =ƫ* 50�F� . .6Xw3٘Z !�)s�/Mli�R_Z^AY&�=�#��m*�^*� &� Kyc%m�2>modD��w"� \U&�.31&��A:�-2W� � w2KH� c�B��HH6���n��#b�O�G��%���D�l��  1�"}?t! � �)�T! z!�.Cl�%Z�Pchm� !,��  unueK(9ic�p� BM��}uQ " �@�0�� ʭ�wN��� 6�A9� !eba5] R K��� �"�%�n:;��%�v� 2"�E�J.� &e2.EP!I)�t�I�JB.���<-�W !��u�1y�!& s& �yu� I���2k2�2JL�o*�8y�v&��L�*� �*O* �u�t~'���by ��kUapp!�a=e��6o�#TS�e���2� ��! catal� ( 6 �0U/%4�sWorthing�Bio3y�#Co��o��*!�7a"� e]� a�f�*�� i� �Ver3swa 1r^^�a"�F�>rk�3�Ea�)��Gn!5 ~%���� ,iat���Y0.2 t�c����ͭ �U!��ncH�A4u�)�salLT, I(2�sa�3&� �oa�: -wx-V�e6�%-�x-PerCPA�x-APC Cy7� FcR� c�, 116/32,ioLegendX C��%YEfi"�X4%&a�aldehydR�Vw��;.�LSR II�+�ao:(y ����$FlowJo sof��Mann-Wh`� y U UT�5isN� � vVa�0Kruskal-Walli�s�B<or1Laa� Bqw� �&�0he Kaplan-Mei6clog-rx���NAG��")E�&MicG{�, Pad Prism 6.+F�efng!�"% �*(*,:""ȐJrg*��%G 6�0!�Margo!\/3.a2[29�NIn briefe�"�&�8nWxFn��G#aE�� ba3��j�Sx. �m�7%�&�2�/!� D�"�ils^@h. Let k�(!^���n�;�q#.����*�657 kE3$1�)Ja�@k ) =e−λλkk !��coeffi�"t�λ!8FCa= D�!b�!%_�Y�!4I�"��m�)wF �"�*� .$�ac�4�usaE!&-ex�� (0so let �^ .�!���aPt�34Ct������  ( i|w ,%d1� Bernoulli�D�f�0A#�?x�|6�e��I ' �> . ByA��!% P>iMg,Bj2e9 3�N!8.qqBm�!g�7�m.20;!P-;EOR0��g x;+V 5>4=12(� ) wk−�;�S >�U:es=2b?( 2I �3; i�^M3M 1−%�=�����suktA,.[ of k-��k… ,)@|w�s.g=�,) =∑k=0∞a�∙ .�=k=a�.af<�_1J_#fori=�"Fds �T�R�Rgligi�:�+s�� �k a�}!%>3"�U��!OQ�a9>%@≅∑13�1^�Exu`e�3=�w~l,!�%���be��Z�/�RHs������MW[0L*�1p+�]�+�z�w� ��ing�-B�`q����Chi-squ4& goodC�-ofM�Hest .#vPhlebotomu!F�[a�l�� L�!�Leishm��\van`�e caus#K a� -lif�g3,8+ viscyv lG.*� in����7�&K�t-f�f�� nd f��emi� sal���̓ski"�$. . S6 .�K* �E�CTg��1�1of�> elic��+� bod.h76b�n}! >�|�#Вs�i�� h�)��PA*K�mic(a�we !�MQ�z� ��o�eers'a� ~�No"xnt P ."en)�)*r�" tigelRa�� ��Y9doK�"&eN=onBV%9� %�rwvotH3 r�>o�0I��#���a�sm�Tlia-��ex�a���0-5b#�ap($Jr� ��� nti-:#IgG!�)�s)�_ P19^�,.0%4Sud� nd EthiopK�c"�1��ZG-;scree�[by ELIS�T )blo�:Ej.�"�-�S.�:�I�. ?cF�; mAG5�� mYEL�>� u���promi�1��:��F627:*� sE,�as��:1/\J�R� ��upU�gl!{I\�.�,A�1�bZ'5�jt%:7"g9of�� Oo�\v�neg�AZt�\:�5�����a�H �I %H�QE�AD!h>� iwr=�5*5z6�F$)�![E7��ے�i(�Y�V��S%/J$65 to>'U�h;P5�� amac%bi����wN'� capaE�c�F!-W.". �oin�`��{(( Diptera: #af��� <4�in�!��-D!paras.��O enus.�( Kineto9-tida:K*anosomao.�F"��ntz{iu��,���Kenya��)}��, L�"e�Zd-� atrd ( VL�an*H &\>�*a-39�Cu�'peoran�lye�M��*m��$eg7�cow?VL M�KP�6a^!�2�!-�sŨof:bD>� SVVP FI 7beliey~an�.pon��%Lr�&�9�"� _/�P0pr� |Last.`A�g�dom� �!,�^(A��L�m� �zo �2[3–q� More�+ � 2�$ %n��2!on.�d $Y"2[3"d–&µen*w n �>a���� iy m ~ r � Ek �Tock�v!\pharmaGg�W�^����f,��sT:ss���A�oh  [SM� �.\ � !�2� :�.�>es&y�[1��11y� � "w5��a?�.�eIf%2zt. ߗ�-�[�Ѣ�asub�0��B��< `y ��"�i2es-%�T3� �Nkstu")~ �Ve B 2F6��y, auth��"��D�c5 �;a!@ <-�r.`5G����&7Nsa�a�!��+? A*n� q�U;B ( SGHn �v� 9| � �el L . �uipalp�n��[1ap�i�sO�i�a�papatasi!�Tur�Xm���Israel�? ?6.nisɜ1�418��Rarabi59n:BT"o*�nٮ[�B��7ioa )�B�FGu�!��:&o vali��<ica�7fQ��NBgra� i�01��� ntip�&.In��[1�,20ak �Q�re;l8+% nsum!�d('K/� !�A��ryI5��T��ke .�w�Nfea;ni�m!Og�IQ5?�Fm 'L� I \l� �.� A .V�B? =� ir)�Y��:�sc !�-p;� E  IB��"��.�F� LJM1&7 1�V,%�rLinB-13a7 �:� >�!+��6�gGt�:�7�t���p�BB� fPpSP3A��to-'!���� U��(% audi Aa��d Ta��N�9�ll:�Tp,_2&M���3*�E�y� � � one m�t h"� !�I��:qMaƝ�F.�&�B�!��A��B&�!�����su�qAeys-�Tե-��5�e ����ofB� Wr%i-�e�ZnӵEa�'n#!m�:&�� ticip�����<�^E&of>A@w �B�A�6}-Na&@9 gu_(*c�n"�!�� ����;x6�Qe�)!�Y� X*he eth' % c"�=� h&�<Fa&"�R��s Ababa2�=ne&�>Re=� cs Reviewm!�e ( NRER�=l)� n Mi�br� �>aTechn��� FI�!A�JR>�",?x�C��fe�Hl2�H?, {b&achY!%� ��<c)��=%� NLal��-5�u�'�la$aE� �a. B�)A1 ��?j��'�"ed�officw��r. FiftyZ erum KmE%Q�2356!'!��)� ́wZ��B�.. Eight1�6��EW-u��s: i )^� �M�&�$in USA�.��& know�� vel d�//!niX-o2�d7 V+$of Khartou@1)<�"o(P��B�YE;a�H!�m6 .�O di�Y`��jol@-:��Y�� .�A-�B;5! �.AXHm^)rE� ��[ne�:j�9�%(U1("F�:0E:[��A�reY�S" ndar�����OS: of>�%CdY ��4–6'/Fpif,20mM Tris bu��i�15NaC20� !B2�&s 1b�6B9Lf�&� �/@��\9freez�a����3iq/7n���m2V.s] . NJ . �( b��six��:�da���pr��% .L2�am*J� z a�� a(J�y�uA��5���d�rY>�Nd�.[� yF}I��'a$17� ~"(E(�:���F�omy%[ �:� 5 !�g�2TG�7em:b-9Y$! PAR2gk��5�5�� �L� ye 2-.Md���YEL� UNP�UB8"�ao �7�( 78%�M��- �+Uo.~�A�N���d��)�)$x �\�C�i��-���!9��)Y�;n!����oHis-tag>q�+b=i�li BL2CDDE�og�� P!� Agil�!�Xp���IQNi-NTA��um!�Bio-Ra)2/,-EIX9R��).�[))�E" !{2[ else��[2�L Brie?� y?� fragjH ( GeneArt�E�R, $}mo��� �c`~d�=b���d 1o� C  !al )�c���,to VR+�-TOPO�;�!�a�y�t6c bTOP-105�f�.�A?F-OD`IB�MLeido� NCIs)� 9�gbL>�v ( Fr� ickAl�� �e���m�>. ����reeSt��I�e=ic kid�<293-F�i3A�HEK29A��<haru���+72 h ��p��da�&~=�20eo 400 mlM�a Stir�>U�Ffi �+�0��Mil�@rBe`u'-m��J(2,Z��UաJ HPLC��(}Mim(a HiTrap Ch'jng HPm|!%GEs 5J Bios�(c /�Ag�1n�>l s grad!a�imidazA�J�E�=E!�!Wpe)�4a NanoDrop ND-�x(j�� t#��#,$a/280 n�%`��ext��*#��4:fD^!`t' *��ver� by m|U ���"�1!>��"d�s`���w�aN&I)m}�C�Itvaubɋ]Q�C�&_,m+6 �n&�/�>vA� �� 6C!��tI��e� *E�:7��&H"�*���of%A� ��&-(��:]:q"� -�-D����>F�ik~| P3CAR�e�> iu�#&�6�( �-:�!4p.!� ^)"h( 2��tep�~&A"�-u ��� %�twe8é_%qdispla�'var^�&ti�����,f�um�&[ard �SM�ma��s gen-=d%Ir.{�yr�Ga�( O�s:"m�2Q�i�way)n-!�}Q� =n.�( 4th��7l0VE�R�.�J� %C=7�"�$%�all*��Xi(9*@ � !�%I3.j�lE.�?�'q8�1 �w.m�p�G!�fI�coi�!Z( 28 n�]u���$;($6( toIL2�'n�PM,.u'( exav"m�"����.�)) S <c�I�$-bi  ( pH 9 . � at 4�JovK. APwasEX��N ate-a�'ne  M05% T��2zPBS-T-,1\%@9��6%eXf~rP milj�&A %� � Q�!�&�K{ ��b��L ��:�e�6�K�ERx2R�v�Q5:x(@e�^�� X %�� n c�� or 45�;��6�L�!$ hydr�1, dark ��� � stop�] `[$10% sulfur�"c�&d&� a92� ��a�an Inf�� e M28 م7oѹ( 5TellerŸIO2Mt10"�sol�U!�ɿ�e����i@��*A/)���Y�:�@�)esA]�^�mun�t�iqu�%6�6�4��μ��/F��l ,�'i&�3"�L�ϹBL(,](�-+ ( 3�%5�{v)iW4>h rN�N��9a 12% �LacrylamWlge� !�����a� ii�Q-}�+p�'�9.� . S��6* #an�5w �;aNyul�["P us� iBLOT&# uNti)Tl9c���tri�8S �qq-s�$���obPa( Merck;��1%Y�15% is�NR(W�aRac!dwx�-��ivS!L���~� ris-�VT�Vٰa���aB&J AS.I1��w�*�� 1:50� a�!n��!ze�@ %]=V:K����h$(B�.�6�The��I3a%�(9�� >�lobenzƁe%KH2�RiODm ~ T a&S ER� �`�*<��<t*#rN�"� ��s��!| 7�L6-p.S "7 FW-( PPV�NPV>� see� �hd� �W�lcut-off)A��F&*�erage!+��>1 p5l�*�E 55!devtNR="�*!9s�vu�,#To "�OD, 1U�n&blH<O &bTOD^� �LO;!��!,*R"K"��}a��btr�ld I����. SK�^a�A��e��v\�I�R&�<,( http://cra�r�~NF�g/�xA��n���BW pear� 4= corr=on Ao%�E�t"�$79��iR!mFti-R���5eqBaU&4!G]� �^:�N�>6{*�Fhoc � Wilc�r��8 �Hol�arr�YNaP-I of ��5%"%! hS#P A�"w>&P/cG!�r�-�[��[eP�)�„gg�� 2”packa=�.� > � � ( 303MW���5 }w�� F�u�L��7�B6�(� 23-A�}J�18���]?��B���S��f�i�"�*�:�.Z I� , 52~��!%L�&>3� Ra�Cs "S%68determined as a�}nti-P . orientalis positive . Median OD values for Sudan and Ethiopia were 0 . 25 ( range: 0 . 06–1 . 6 ) and 0 . 19 ( range %4� %,4 ) , respec�hly . When compared to the m �v� of nega2( controls (�1P:j0 �)Iy diffeZHsignificantly ( p <C,0001 ) . The.nce i!F>\antibody levels between N60as marginally.�= 8}$Antigenic :�Hsalivary proteins w!�Xidentified by immunobloZ Fig �\In total , 10 highly rea%}` human serum samples fromN�Atwo9�21USA �lla second>�Z�R2 ,R�mammal�I �-Y(he prelimina�4experiments usaI�,1�ic!, pertaA�llA1�re tesAFE�f!]N�A�!��,nt dilutionsV�jsEza�2E!T( S1 Table: 2nd step ) �u!� to assess!e�mal��centralA more exeyv 9. For .5U)2�!GBa, lower6r-$�ow!ato��er puqte8lL. Results are summar�Ugraph��lyA�S2�X . Ba!on I initA�r F,)�`M�clu�-�_ furt�.,O�� son �8ei$no5�ɓOD1ĥ9��/�!-�eM}k0D7 ) or false7�in�Ձu�I��!� four�miE�� hich �subseque�a%�ON�(y�y�Y��m�)!�$st eligiblYeI��Y�%sseleca,.�3rU�A2�u��dm�bym�e�20�@��N�coverE�heJ N� ity/-�!�!^e� %  ��E_�0�. A� )c, bYin !�>gP2f%@rQ�Gi nt6*m�-,8to justify usag�!�r5� ( 1:100EyZ�ina���e�c�yParSP2FH2S both�S!-Bbe�2�j�due�a  cut-off� s��2l�coeffic� {big:��m�!�i! i�to 4 . � �$se against-��xw��w A� 5 on5Uin)6�, but��cu�f�.� -�sl�ly% erOq� 1:50�A�0l: �2�0a /A. Toge� �U�� � ƅ= also �s&� 4�59/nd ��showedA��� s��:A�JgeU�heref���analy� as[�3candidatg or�A� exposur%�3 popuI/s!�:� biD���3(v� �f� �2�s5�1B)(nd!�i�J� �is%n��anF] 2e�*] �I� M�Y�euActR�in�H"oneJ�� �|�_. A� � Zt�EedI;�5�d; �. Wb rn L %�s-A�hat some:��� -^I�Au � an)u0or vice versa�einforcA �usE ��ed%�Ento enha statisS vari� � T �. IgGAMa�(!6��"6�y)2X!+8+l$, moderate�%��!�.�( L�41vP6�A1��5� abov�n!�edZ�F��.HQ!A��. C��o%"[&�!ץ 2�H-E{ bod}�>�t��*�Rc��- �R,iP%�g!�685Q4�e<4��*4.k�B�5�wge��E�!)`edF�76�8a�(3��8�qN-V�]�1d `V��6d� � ones�A� SGH; whilAF�s calp��"%��6�] (*�� � Fre��no2�@y�A�&| �s|����u���"x���Y�, eveK oughQ B�:3�d��nctly �<t�E�# u�.�S2)��+2AJ.Q���" Z�obser��!�IL6��onx�YU%� Nin� En �� e.oE . colia� 2�$embryoZ,kidney cells��kpot��al�kerU�>�F�� o� ~ e�)+!5�. P��belongŦ��abund!s>fA:  famil�� [30]�cA�"�b*�.� 1�"��.kn�����!� dogs� o�  dome�  an����-7m� e"�bittenq :� [11] . YeB�Y[E F�ucgim �MZE�)+h� to b�Z� repla� a�"pec%>!5�-M���� hcross-E��m:Y!�:sa" (�atD)e firme� they!s�-�ficQ�We�� nd 52% of1�&y:34 . 5%69uGaAF�"v ��a^D�Z� (individuals���� orɊ� r�Ci�stu [2� 23a���;�"�toQrAlcanaZaff�by many*� ,Mm)\ e cl@es1� villg �vs� bree9sof>�lB ��ofF� �urbaniz�$ outdo�6� -�Yicipa�, etc-��Z-��<of6-E5�m5!*Hlow numb͈:���� �-"����с��col [8!��|AG{Yu�Od 9 42J4 & A`>�Alt���\� imi�6�to "�gu��6�2]�8-.A�>� _ N w � �J�=�F GH`v �s�u!W!$%Y2I9D'-�e1 s639i�%�Tfo�`9U�f��. D"� pr"Y�Ab� mblOto,Z' in@Q2�� ��ld]�E�"� im��remaina�]a�pa>s��aft�� � proc�!��se�!ama��|leaQ!non��serolog�" I!--�͎,��!�Lt �a�2 of health*�c[32aqAs=sE�l� eval튥Afr�!!Dntr!%[33� �R��b���`�!!si�-���Ag&T . Si� et_6}A"Z!g� ve0 e glycosyk[� �; poss� issu�M ab��=! ��ly]o�1�cL�]e` 'Y�[34!D� 1lh4#!ir1��" [35%�^f � prev� W""�!�J�d-`s by Q/ [336�Y [37 rab� [38!�hamst� [39]h ; sevQ Old World�y�:  � B7 �t�d�: ��i�eBa !�: ��pernicio�l^� (Z&K!u�)���r9_by%O�L%@�j &[ th�!B@ [40]%Oin�*&,� ��+9 6wpV� ~-��"os@naturU%Fed �, goa:r sheep �" In L .� x8� &+F� rLinB-13v9b>�~��\=ndemic�z cutane� 6� ,in Brazil [2�OurQ y� � ;��first� describ� !�r�% � tool��scr�&%n^ton(in �!9YNni2!Ak� bil�  ubstitute�L�&f�%Q a�Ln >�&/do/ ��a�f 0F  , � W mobtaiKU5B��%"Y� &�q?�C�!"�.g. How��r E�n��=k&��!MN�ASK1.B!/�oJa is f6 $ng suggest�#a �cana� captAda�;aimedlO us Z�Ne "�)�n addi�al%��"6 i%nofZ�� r�Gin� a�hp�$�+%��(% �aNew�i[1 1D 3�,38 , 41–46�;I�d"A,�VW 2Y �,� � ��Sk ��"A ���0ny large scal%rvey [�"(�y�palpi��%�ntb�jproduc (�s �a�8 *LJM11%l 7 H*�*as suit� a��g:�A�cpeople�OF\1�iD  �JmaAR�>A� hick�[)�O� � ry ,�>���i����5��+*%�es%�e� did�]� r i&q�oar�sR��V� rSP03B>�"� 1�) deri�),?!'J�F �+ �� 8*���at� �� ��� "I!��measu�.� a��Vby�.� [# Un&�&,1�M*s@*Q�^q�Sar$� ��F � paina�h�AK--� MW�stronglyY � V 47��A 75a��.dp�AG }M�! i.�in^�toBfin Italy%(Portugal [4�C9�$Sero-strip&�- |� to rapid� i�%Zliv��in 6� ��� A.�\ made i��� fea� k/chromato&*�Osafielda vectY�#[50�It� wort���a"� �sIB86% hom�y�}�� ���(�e1.-e�!.�%!a` non-!�w ubject�e,9} ^M�$QJ, 8 dn � V#�B!^�- � 6�of `�F s& in�AR%��!�)�u$ ���'tM�PV;V(*� I ��!� Y����l�2!MA{:2<a�.��p  h��h"r�k�2�� '.� ���WZ1 B�� �|M��,� A�us"�.$ � !�y!������r}m s Y�)@� %a%�(�SstN�JeA�`J&� �"�RJ`hed r�8��Jo , a����a� carr�3o�)�n� 47v 9��my&p"�%�!�2�*�U�!�E� .�F�.[!��!}��"�$�e�n-*� .Q �~standardE�ES1ly� ite��A�9�,M�� ns�&�6��JoE�"���fM^!�"� &� O*!�/gW6P ) �$I�)$� 1!�%�trengthT )� ncepEsof Zt.I|�eN2�>!")FinuJepi��9�QN�e util�of gq �9 ysupporq" by w)R()a�(� 6 a�))� EO� P&ym�!�l�Z*=). Two�w4�u_t:,(��j�e!&aA#cwa�)e who i glJ6,!u!�}6A�nY9��E7j E�>R [2OUaZ"T � F. �>6�I'!���)d apyrA��]in�AQperform"nZ? itself�#soa�sti ttW*(.[%�!�6�.�[4�Ia��9��eBuJdG f��)iw�wo 7>�5���T,^��CA� ,JjE�E+a��i� 2�"^" " �9E^a�is>�s.���N!�?&:� �0�e�o�pl�1�'"��!ng%� 2dBu of^� "�ba�!�`/�,,� ocol��corpoT: (-�.�+wAsbe��� $pac 2� prayTof ins�"cid� n$�35�.� Fp� us&!�e t�8�involvpouAs vol�8�%�a hyper� regx$in Gedarif!�ted Q*���mi .��IncC ju8=plasmid� 8Salmonella geno�is�� 105GI�*A! v5r�"�5associ~(e� multidrug!�i��cF lin�x� �0 thoT E�9ohcea�3�a��#�moSU1|S#�� IncA���(a-m� referJ t�8 A/C')'l,8� exci�^%��K� o��� ��#iggU>a7%�an���,!a� d"4lex AcaCD enco8 7se help�1��0H 1_�^-�miQ,�d ��ge9*,q$NS HS% traGco�� a<V: �predi:7matapO subun!#TraNC ,HC\ TraGxaAv�,.�2t. H�w�v?'gEF{reg�2A&tr�A�traHG ��2ᣕ0 < �A1�))�of)N.�2�f�N N�rmo�c� fN ~ ��re r} lacZar+%��*�H�� ���ducbyM. M)t&�,<�� %� dele  my@ �%1hUZ.0 pVCR94 revea�5Q�e rA�o��@ ��=a{e�tic elx [W��as%#I%#C >n�ApI��M�& nsfe�E��(rescue null.�d2��%� �A�%jA�A�TrQ�A�S� func!+a*N=� �@A %U��ay%[ktra�S�� 1�a�o�+dosNS/HS/GSA laceC/HC/GC M�.X�.!s� � �i�%� �re.��i��!c%KiAmal3n%c�fac�re�%7I�v-�.�by P� (*9�*�4��!�\1Q��]�1�.>O��>i cruc����� DNAiQ�$bea%D>T+ er�s�U6b�5�.%OdisJ �8^5,�>�!cl�CmeU!is�?H` traSE�s!����f inva�h1e| �9&�"]1�-;s . Co��s5�nea/ubid ���#orizo�E��I� k"��!d)S#�g���4 st�ofKs" P� Aeof�!a�* taxob al b� rs ['G) In Gram-n�EA��-�&&�$�2��a��nano-m�ne+1��type IV�Ar�<~( T4SS �65]ve@�] c�v8pa� !�envelop���6teE�� a"*.a dono�a� ip-E� [4+.�U!#��g b9f2n"� ��( ICEs�+d,�to��!��EwnA�seG�*A�cR�-�:J�^Ia� e !�rgoA;me�F�L bio�Ure"7 g�viruleJ} � a��9�tra�� Y�00% dvan�7�HA�Q�l� , 5–Rn�(in�-atiSgroup C!d�� ) haA�q!�.o broad�4IJ� � in Vibrio@G lera �ch�y��icAK3"�5ly!n�}[8–>0�Y2r[,6}= %,Y"54<+� nI [+FuI�v/ X R �p& 1�A��x.con�hY/+i�le � ��/��$last-resorU3Its such�0carbapenems [�1A1��c*2 s��hmon2ffo�I�ne�)�t�F1�aK,� MD�y��D!�* �4� ��E 4RM�u�h� !' �of:�Mn;B��sors AcrAcr2 [1(i� [cr"� r:�*r�� '��"per�8n�!�ac_ acaD� 1;q"z �ma ( � b Z [�!1{!6�, %2QbinH$!p Oes 18�rX at d�!�� C&-vUq)fG �A}��ofM�aM�nX4� ���A�r4v �� sb}tr�Ws!2!LAoF-����Gmbr6traLEKB raVA= sbC/� /trhF WU FHG90 ai�&E�0(PN%�!�'xG�g coupj �99IDJ ):&R�]�1`#1)� 9��6k )�!Mun�'űiz� '*�h7MGI�1&3 t�!bi�r$%e�A� -dep�n�._into new��ɏR S�����e Vmi1�<�(mimicuAh$MGIVchHai62!c��I�����*e�ica�Tovar Typhimurium DT104A�ZN 9–�(2 r�u�@�6D�(S .o?�1us mirEzsJ4[23xe@x%��ll>�26-kb}>`disrupAby��p�class 1!�eg��EA��b.�]�23 , 26T�i�JouN�J jackAO2�ap�tus:N���� EM�&� �& Cr0s ��as�; orig��F(T.Jq-Żq��6� li�ha� en.�%Jto �D [2e�Re]%a��,)� L3� x�t a maDerbt�>A�aA2 m( ~3 l�9 2) �=Tb�sam ��out�!�^6SA10<dm2�!Unliky�:��T2cf$=<-,"�9"� �� wo pu�v� ���ndpH *@Ca8f�1�LKE6a�*6< !2uOp Vcrx14�<KH;? �N08*�by�81����R,�C 1� 2�v 2ATil���=E�� �* ��Z@E��b� v��PsprT3%�y*� lS5dispen6啥 o� �Am LA,xP)��!�Aq���7 Oe~dir^onQDyR_X�[3'ab�l�����W2�67P&_@a�re�Dly � :� unde:9�\ ;鰽 � 34 , b2T� rais �quo4 �+ al *�9�F��6sC+rXlwhe�)�)�al�qq#�]��Y�*�!�A���Rrs w% .a��t W1jat)M)>X a��M �%q�6�E�y�i�aCD*k 9> Agb(�N� 5tS H�clo�".�a5&�"�a� G� %��'�"}'�oA*�8�E�ed'8� �W�1 ,%�H<hii,d a weak yet \a�39,5�%� -eakœ���4!`6W%eI�2A  �#)~h9AN!H�6 :F"��)%�vK2B}T!%SP, T Ij�!2v ,:�!�-born�1is?ly�#mf6Us+ �%D^P�}r.�1a2u;�<�>�WJ�(!�A �� � *� @ي�8� et uti8b!\=nsynjiE�}! brid9O�[�Yi ��.d<��a"� B{��e~6'or:6ER� |a� esaisq*�To.�6� J* �Fq a se0#NjI ΔX20"u SZ*s !�J8N$a?>alu��I��c4 R�� ^>���Aq�JC!JQ�"��]abo-RZ�" VCR9�u � .!�n�$J&,of�:���W�$ � ng�_&� �um-copyT  pBAD30� A�� ��6  nose�� PBAD��F� �"� to�$d!��� U:�E� = 0po�B��-���y�� s!G%�� a��r>' ^�I2�&&� "�*i"S"� on�WI�"� � tsV�loWIn�� $ kanamycinB�$ ( KnYftteb� erv!�!cF �[�}"�����"�)[��;�\I)Δ � xjt�N�*�.�>�e"� �2�"� Idi�]L �!!r�K"$$9 d2��nd5Q��AsineVXq#� � �$2�$���.�BX. NB;the� �g���+�`�s Lt,XtBb�<\h'� �a.�E�!�Tunclear . Kiss et al .�&l 2� CO�+%�"^ k!�~10 kb (�2R610�1 537 b�q"1 openo0 fram5�7)^�8"��6*�/�^))_�����'Y�(�j mpasL:fdoe]tA��R#*u�#�A�6 e�#>�!J stru�& a Δ^!�$!RGq%la)G��-:� �A���yf�.�by.TM�c;�E6�.*(.U ��" E C� to ~ 000-Wde�-a��D( 2 . 27 ± 1 . 42Y2 vs 5 6×10−4,20F�5J�-�Aa���Iv�E� %�"������0!�>�W4]ok "��he�k��=b�-�$R ��>*&.aw�^lF� a3on-Q�P�&� a)e�H� �1�)re�&I~��I�L�`Qaa�'&��5�)ng���lal!q6�%YN*inAA&vdN*�zoF"�X:��- *a�"Q"%�Oo�*"')!9U�$atN�!_M2~=����:"�$A�2S(�#�e�ofJ$B� 4�4Be�4C? s��B(d9!E!��� q6��Y ��oh �>�1�c�5;�y o%��?)���c � hyp�" -�-r.2 -�]�  raHCn���.� A6 rovi�q$%s7a0aQ&>�+r ��Y� .>� ��MEd�RF]��NC6#EL j Surpr{dlm? despnZA+ = div�QC �l �YU ��)s) ^m >�GC)-�)a m�,5�� redu�!��J.k � ��2tra1Ko�V "�d"64%Nt�-�AS fai�6-q���a= ��la 5ɝ� EK puzz� beca�^aA64�I�E��2�A�=S.& �01��.i &� ŭ)�as�. �d'��dEVGf�6�. reciUMal!e�i�.F���G ��po�HN�S�� �g.G.EY.,a�un�K&� ߡ~� �/�Iu4�d1� 8S6_i@��du]!� aT�"iAl. Take�g�W�F97S!72�,B�,n !�-ef{1F��k��>ZvS)x)3)�1 �Figs 3)*. C*o�e�<�&s.!rx#:_5�@"� �%&fe key&� � ��aL�z9ŁS1A���I�a!ontexi^'���!e?j �&r��*,u=ful*).6I+C�1&�H�1wa�n9�a� ! !�.� G�Zr�: a 25n� !�N.P]���Q���Sa%��y~���3.[�� �e�GS se(�a%�f�re��c�a2_!&� g"�"�)o:�. O")2��HS%nu�!�ka!ni^ i@y���re� 2�%�uBExAsr)�)c!�@Zar��!�9�."�� ir&Q�y_#16�)��we su���h mdH3.�8�t�2ng� n�'� et[1u �(S��mIS.gnw+�ner �+pa<-98`�\�#8�/ .� an r�#�!#I�iO`_ b�3����0)7 ij�h����� � �w2� Y`���#qs�p!��M?M��2.'?y^.����GQyorFGB���f?'�� ��!�]�ū�� �EY�%!k� S�Ek&-qMA>Y�"%��!�>YJmHCA6%V� %�J� M$ref�X� �('t�saa�"�2 ��a��5�.u.8GC.8�J :�8�_)�S�bZO%=�u>.%)�cI{'F�E�s�UK�u�'1��J � � �;I^!�a�N by 10�%���B I/i2q&�5^�1! K� %� �)8 !�':)�"c worka`a�;��%h�0C�Y!� !s6�!�2.&X�qfR�%gY"6WaIA��� *�Oa�m �BE"53y\InR.�. N�q� 2/" ��-!� �)��De9As-�vS1B"� &- >�2� �s�� *�J�.��� �s@ en.izC� �1�.�&<no_���or� o�D2*N?��AS"B3l>!&�F��>� � *� .�JO�B���6� �6Uto. *: �J�p�N8>�:��8mn�lus�U^2�a+&\ ��%Ut�6Al"�3��*q "�;���!��a2�entirv*g. �aR�0�J�S�z)�6��B� �4b8� urV(5�67!�A:�+. A&T.�:�(-s"�x` B�I� S5f{�Z�q!%U$�J�#u �7�J<�e�N4<�=%� �e�.=o�nvi|%�: R!s+ $:� �) .�&@�5"�g�@ilDs�5lc(�>� ( >4�-bO$!W$euE�C"cu8e�����)?�ZG N�[ !]� �4:� N��z,4)S1C%;eyttemp�o�cue.%;� �f{" 8z����D�(&$&g� ���c%&� )�*�a_zF=��Z k�8i,O�%�:��"S�!�"� s"�(�V%9! �@GS-�+a� f�&�1u Z� �i:�a�co�@�ly as+�)Rss%Y:�Q�t."� .%%3N*di � �m!�A� J ��^i��& comi�+*^'�?=�p33JpN�,b. x� y�u0B�Q�6����51%!*�A.�~/��( l�.�AE� s"�4 �?*=R��*Z7���!��77 �<�>"@�e*�dYEn6O,V�clM�"D�@�- AG&�8blockId�32S>% Af$z�*�g�v2ms3}f� �raN �a��t8b&}O��.R �6 ertBXhad')�d.�-:�� moni�> A�SU462v2aY�K.�=-}5-�r"�� � CloDF13"��o*7b.s��g?i^�J��a]�:U%�*.A��c� oriT��.ezloc G thro�P,2��c� �,)3W�x\ 0ȩ|�e�ly�W �"�\ SM10λpir� ch2 _n";1FRP4 ( P�&)!�Eg or%E�V�'_l��&)#6 f�p0regardB$�hL/PI*�&q�� �A� 5�\.!j(at2Cs8F��eodeM�ofe�.� IncP%a�e�H��2�?�^j�"e�aqe��1Z��T16�'Vs( E"�DindexI )f7 c���sf�4�)JeU%I~,RR .m^�. Ge*),!e>dof62��!t"<+chae��; ~ver�d�W alog7�:!�f�C���A,����S�Ÿcu�i�wna"-i�"�aT�<w��2%C>9rfa76!9�bex�EbJ6�Om��T�1�:KqsM��le�> { ]�] x k .�n:G~�2}�V�i)� �9!=rr��q .�W>O��v5q4N/ EI =�%6"� :>>f��)�_s)�>� . DeL��r���w*�V(�2 wAit!�y� ��TII� F{Jf�1Y G�,6T�o�P�;����"”. �f� �2���. M�3I��� ���PB�� ���$� e�sՙ.8 �19]Ra9, Sib}PT*4]� ?65�!%�:�%Y#�x��  mW� J�G,i��)M+�priio I2)<� vac)a2D-s����!��O�occur6I�fJW��\Vif�Y%�&�$BW25113 Nxa�f a'�mq�-(�tsu@KA�`�"�CAG18439"��_ . Se��e.�%4�: J.Q A4:RBD .� F "�;�ywi9=mw]FuVZ� (.4.tat>� to9er�Ŗ&+%�c&!*.h��2�2a�"B2�%�u�K-�8��5 ith���UA N GC6>cu�>to zs 2G!�&4C�"awa�oI1%DQ��harbo�a�NQ if�mus�^ly4a�C-bv{�w".�ritV� !{� pa�V�k7N�Il*OU���&� M�i�:E�,o�\un�_c Sng�r )!�*��4m1M�~p� c^4n>� s[ h|#zeneL%���J!kx ee"P^t�:�B* V . mf�E~2�E%�^ 2TEF�r 5Cmi�I AC@ � auxili�J��� MobIag� >plQ]> adap�@W !�o��h5CdQ��XDB�1@@19`EtCH&�$A�m"�Q�.��0b�q|n��� s 15d1200 tiB1���EwMM~E ��ongA9� %�a�"�/y !�(���D�1kbF4l� Nq)�hgR�'�� �*�_ ��i,i@Q����!gMZ6�-��6��  t 5�{�*�O��U&*&u�E��L�MorN<NM�{d�V�$��of:+:!*� t a limi� ��@-��a�rRf,*�f- �C"�0&H?�2�atER5 i� = NsW5+=*�?:!*DKPRMurányi&'5D-t%� one 0&��f*"E�";*�hkW�;e���x�1}�A�" �:C&5I-M"Q|3HetGy�%\�!�OT�> �2�IIdf s�]�;aldFy�;�@!��^|����ac p>d de hydrols@ TraL�K!# IncNU4pKM10�P ace VirB1�- mAg"�]um tume;�d�/ @�A&�.$( 31% ) [4�b�Fwis19�n�!� n5%M�*�+EG� d [4FuF2/ �10s' TrwE� IncW� R388 �(&&�-d%g"oE�J Bart5_triboco9�3A�qa)3�_$&�R�%[4XRٹs� �EmTA@U3�3��it2U�sa�u;�R< usuJW% �Bd�VJ?&f�`ces�_pl�#(3ltjj1t��',-Z n.+�voi�wKiMsHUoGo��&!oa4�gr�m�1s `'!�%'5} s [4SOpt[����Os����9g6 M�`�!&%<6 illu�+R$"�{��J�!�I� outc��+�J cF}^ � cm��"�+4Our�us�ll� ��{a��TbyJ�:��&B"�7�XX.�%YE��J L�.���+5v �a llab�c-`� �# D4)�A`�B&� !��Q5 !_� .�� ),M��C!�GDoe�S"+d�nvp *� &�.ps�{vav5 >+2b*��sLL.? d�A�i60A���:  B�new lew� ec" j!nB!j""�%)&\Q� �&� n �,>Q.w3D]bIk}2@> �A�}%B�9 eos i#�0#���0Z.=���f��&l��up�VctI� a sm�?subpo��{RbJ |6�� A��  �". $,��6!z'^"� adhes%��J*�0�" `�kB^ , �$�i+at��&#� �N�KN@ }C �Z�J$n,�DI���U%B/�O ��w?F6�.,5&�����Y*� ( ~120Q?�<'L%�er siz�R-26,q !��d)Ug�Nit 'vulne�I em�~���S�W�i �parG0s���hor�M5v�t*�)/�>ic"{ rw!a5 �+E asiS��dE�FdJic irq6.��V"9�A i�`i;���*�'�9J Hra��^ � %(�le9�9"u�I � 2u��v A;�78*'9�$�CT!92)� H{rN W �_�a G GC G~ E�e�2�I(m�TE�� &E<a"H2� e  $al3�/���lP!� quiv*�.-�q#]Cke&�2�E!le�c�.TlI!�"�/� U[3e x aX3�m�0"-8,)�e *�K]&2�* *Fs�I"!��U$*�.�+����ab� ( s��P��o*a���O�`��4b�a�laxji�X .�^br�B�wcest�h�%njW�*6)>�!!�E�!�j u� �eb7$i�ma�J� f#oA� Afnv"����k� ���H-Sed��U4C+kU?g;�sI"�"m,quies$U'�.� 6�^-B�\#z��*� � a�FePn�ANa*Nl9acric|����5n QnI"�[ fashAp� �#Bas:<-��r u,e � vp �e*��A ccu�Ma �&>�k6<6B7T4S"+  �OvA�ER� �P ,��eva�UaRK ,�E�؁ew��"w7�pr�t&�{0�omQz�in lieu!HIncC-� )'C�4"fav�A�u�q�> M�5 '��BFO�92tr.h�4� BlY�. Ts bol �� ]�4��"�M�d��e�Nt f�u2{/A^+Re�\urface-�p � "�i�"e^/�J�(e��in��A�byQ�ophage*Ip$qV",�9�#|�z:Wpdeqh\r 1 hi]i* �XQBZ:!custo��@b@s)�ng�Q6��gy��m�'��QC*'i6� ���I,*����expan%>�ts�]/(aZ�"aQ�!��Ap take�a��%�-re]x!�M9int��%��7lin1}5J8&6a_�N� �-�!sAJ�. Bnjl%~i�nd�"��T 桵Y<in� �S�g�Nroutin��gr-%�Dysdry�)(th ( LB-Mil� , EM�,at 37°��drbi�hsh7T/incub�q�M2��]at -80 <LB ea��.15% (�s/vo�0�4� t"�fW�2f�!Hc zR!�@s: ampicillin ( AL֯\0 μg/ml; chloramphenico�/Cm� 2$hygro�N �Hy!5!"�N� , 1+ �7*,�pat-aan�pOP+W8; nalidixic aci�Nxt4I;� tin �(MRx;A/�� �( S�D4ulfamethoxazol� Sui16& tetracycl� ( Tc "25Dt��tho�! i3!�ue�I�"1`bU�cul�0Q-{6� "ܞ02!L 2% L-+$�Q�BW sn[E$&}=F�ixA"�:μ��"��q>]( m�ly ~2L9 9/ml�)�xiP�Gn��inY�u@w� s�&�kW ens�rec�PO���a^�d[�x��C1>�pelle�b���Of�vo�r 3 m� t� �g�a aD�-+u�y5�N�inI�%Q&"�smix=��$de�n�{�gop��; agar�&g�L)�ta@6 hour�Ă)��re'���-/N in 8E�6�, vCxbn1lunv��9�1�+diI@bbXp"�ngLB2���R�. D�nQ�}$"@a&i`Q�,%{d"'k�8!e ,E��R� O*�/[B "iq@:06mM,^e"�� �.�Go�g:E�a� 02% .�F?.�d��*��asV n*y%/i�%� data&e�� 33����.� . Pl=wupr{5�A<@EZ-10 Spin Column25 Mini5(s Kit ( Bio� i�2ʵmanufaca r’}=s�QEO�0l enzyrev , *G14F+., H143BW. ,��U�V�+ɐIA��em�1�cA�S � dige%�D��pca to -(-Vi�T4�lig�!,�e�:�!8!n �5 )v.2Q!`�J*-t/�Pr�SGI105Ial1�B)N11A :,2, s012%-�@. *��X.��\%̒��or)�n.�2Z�A4~�X!�a -� G�)�� frag�s��g_ =-r �X.�d$i*yJ3E,.HiNCsT@+ a/�Zie4s 94DelXnoFRTc>�� !>!j�, yy��*"� �=`�"�'9*�.�"�cA�+�" �+l�̕�!G by Flp-caі�;"!x�pCP20�L�Al&�fB .��!&M�i-��( . Quri���|o��L.���d� �"� 5-b�$-4-Fo-3�$olyl-β-D-�l-�n�l`Xj�F+�I7o;K$tR4P �m��d�.l�!f"7�nti �l���� �o-2-ni|henn�ONP�zF��8%(2� n���2 MV[5~*A��v�in 4 ml!�br�F.e+"V&1,:hrefre�11��[&�&�,NJ" iciiA��2�ex:e�aTa��]~XC2&a�5 �5օsha�AI:s� ng4Ya�$M�.�oomV�[B'%�&AI#a Ma�0skan Go Micro� SĊrophotom�/�7hermo S��!#�4 Each*��5h���$.Ap=&k�&��{/��I�oE�� o�*Gb~-&�6“-|”v����“=� l8!����pVT tOva�.���Saccha|�ge�,sia��loikin� Cdc5��� sii��  4damage checkpo� !qN+e nume4� �6� mitn� prog�!W �# a�6 t�.[�n�kn�w��er��!��;r�� �aJesAt%w ell-dv!est impo�-I;�.N&G precN12�6��(%�{�Jr�� �4� CDC5� d^ldU�aOL�,![��*� � oA�fa�v7�4pEtEi#%o%� modu��*rO�=t�jrdow�eam%�-Q&�%+pinI$L95�2?�1�;V�8�a0,�,�ed)0SGAL�:!~M�d��exad�d9\�E��* 3/v9Ol�����ap&�'@"littl�'e�PaE� n�p%�o Rad53.q.}yL��`, Ddc+�b��a�9-1-1_ .)EDdc p>+ /Mec./,A/pe��l �6 "e���A6.�be ��$s+E� Rad9Ip/2epts Aphosphor��I.20�v��P�(,bE.Ded rn 53mdtntactB[$)qhyper.Iah &p/tl�^d0�.`�V�f�*7)i�JGs l=du�!}�!�nsw�(�#deI_E�w&W�u"mV�,Jlo��j�Rn� �\. P>7]O=%��:��( Clas�to�2i�}[��2Y��{�.s�le,�'�"�+�$� "@�erteb� s�"� exv"�,�au��A,nI�l% uFq�)D��0� sm���[5�5EO�=!Ble�# ��.ad�f nick�breakaWA rob�?=B��|2ev�~to�)ckxA���Ki=|�(enC!�k 8:vol~�ar.9A�aQ� )e%#��[�W_͙ak��a�g*��1:��A�nTQgeN�a6% tNQEA�&��d.%S1�C%a�!Yq_� i��� o�'o�a�n1$ty [1]–[8CY�]�beg�u�recruit� A�=8��-��;"A)�1�rIubl�rA"E ( DSB�E�!5e���$c��c  5′p3d���ex�aA��xosaIstretchN�M: ( ssr&:Š[�r7 Bяe����n�0clampE[��f��y7O!.X) �!7*�+�%)E%y[6%����Btp+ �� -shaped ha ou$ricí�o�# �,�r�Rad17 (� .ޘ�N��1min��nEE*y]-sݺda_� A������or PCN��� b%H�pika0loa!�;!!��4!�-d juB:.�0�-re��6|0 GKr��?�M�j& 2� �Anwi� of2�[10%�֍ Tel1=�s7DSB� �  tŶ��=�}�!�,�#�a�!u���y�!i�QvE��x 3 � 4� �!�maj���)uA�ATM�de@�d!�]-��{4� �uH!�,sӛA�%�!��cr�ng �[�d RPA%&ģ�e���uuATR�� .m�ATRIP }1 !#Ae���${�z�Fo- ,��1A=�)�' aTIס�%����8*s efo o1�s1O� i�Q [��Dr Q�� �repu� �.iz-�Mr� �)[! �.xZ �"QIZ V�r$$out�5!r}u���2^ [1ӊU�8 I)�2&is>1 byE��B� mhQ�k!vN s� a scO�/R �=�� �=y, Chk"3� (2a�Ip4[18������!{ u e4>� orP�ingLofD5���o 7*} autoFKf�M 53 ��$In Schizos2/ pomba��B�f Cds� (��))!vRadsV� )!� �E�EU!�"j a di%�a�u�� )Vr'M% rk-h�a�<G�FHUdo~4��5G� � =V [�N, [Ս�.���i�"� �&Ogi��u!.) � ���%>I�5��� =Ё�R� .�u&�b� � icy)��w���1�A�r�C�.5՗tin � �D� L%"<"��=w�eak�T�cJ�_]e&�e>Bp>� ,%߭i�"�ʎ��aɢ [e4�dc5-ad�7elg�*��5��a4B-de�^��r W.[2ޓE)� a leuc�-)A��  tryptop��at� i0�25�'hau%h�`� �`�Za� loŽ�0��A��It��t�t��g�%� c �Y.�e�;/I I��3z>�SC4i�&I7-u�]Xi?a�. S� a���'ukary�=b�orev!�c���8olo��" [�r"]�����=I�Xenopu3m!h!4� , Plx�5{s��� t� �U�%��!udi����+�!p�S-�%Cor�K�� c+ [2� .���r�-yF�� hϧ Plk12b�&� �hJ SCFβTrCP*zdegrad��[�ur%�vea�3C��! 1��a�!I*�6)����b� w)��a>�Phe.�=a ;)l ��*Fu@5��( 2�!�.9ens X l0 1N~��, �c�* /M0�*53"� LJ���:osa�6�uE���*�.�I�"bRDoN����Ve�BZ6� :�C. A���b�, �{,U�<�;�8�)ҁ2X�~f2~e[)TAxen�����$do�� �weL^n� diploi�_ P ��H�C *8DqH�s:�ad!^( Wǔ. ��"i"��6-�!_&��A�!z��]{!� _�U � A�5U Icdc13-1.$.-9( ʡ�hifD0�|-J�per�d!`em"r.&"E: elt r �y��"��/� ExelR�(�1"e��e��'%$)�����<��of 32Q72 h ,"�2)��Re-warb.�D ty���?�U =�to]m�roGnX�f��`X1�e|�/%�"NI*��A�ou�H�g��Han 90��A�/zyKM���%L�[�L�"� t�Z`�<h51} �2�p��AZ� �;�al�Q�(-/�X%&� Δ%E��2Dt EaB1�� surv�ja�"pI�ng�|� n9 FG�:-�&��sA�>*Revi�,  hOErt termY� �! >�Bj�DM Anap�4 �+o�KCE6�bAP[�,�E �۰�)abOGe� , ar�eI�%WT��X9in gluc%A&�AEoczyskil?pub��&6�)��� [aE=E�Δm.�7EmL?�"g\_ :nAw:a -�w -�!"m�A�!��*E3f&�!� �_$?�`a.� w :�J .�a���s�I���� capa�D`%A*%ei� . Ye!eNJ>|�|%NC�`%T�B ounc�then�3 2V�YJM��, "{Me �Ie�R�'2#5=F K�+�bn!�mix�op_!!�k� �%A�s"� �2�P�M!�ut0�%� Q�[�X a6E��L�͉!)�"� JlH>Aks[ s��S�  �-)�.K6i(E 6�_"��)�� fe�6copo�AA��"er*�".1"�b"� .&w"]L�dE!�-%�) � " ha�7��!}endcNj)�D�f��)26�6. G.�8�WTx8 ��� 1� &g4A{s�s ",��#�s�P��"> d ]/n��FiQf!�͕h�A �re�2A~or���^n sourc<�J"�{t��� 1Jon e` -budSa&� ����s [20]� el ol*�X۠0duI�]U�!�6� coinm�ͣa�VR'OQ"'�G&�_��%�ER*D�ёm&��y���t��9 -��Xc�c��# be2W%J�`�:�%?  !!�Aq7i�c UxS�1��# ata �Z)nBs-�iun*�YQ�*� �H�ur!��BN�".y ���ť asynK"~x>k�p�!�Par &�!fiMB6� ���&s�r2�Ak2�&, J~�*�:Nwe�q_:D����pr LIhmim�SK ��Zd7,wa@)�%'}�oR:�\ �=�-��� 4 ��'� .�)92��KI$*�l.��` .��!��#��J��A*t�'.z��.)#���+ng�-��H����ng Cg�A�6�(. NocodaKEhad�s;�ta��ly[ 2h�s��Re j��br�#�9/O����\JA'&?ropR!:C n�6$ GAL-Eg� �6PJ� =B�.>qU�EN����1NH��i�Pp"%s!�FC!LdQ!�M6"!0 .n  also���!PDSB F��Wzeocinw8>�H1EJ ��%ev �S>eTno%�� %3m^s.2�7 yו%� 'es �>�  :��oal&�:��sF �2� �:@. R�E%"i�Ee1�G+ies��wA�}9[*� ca�f��3��G�f�[:p[k:�6�t2�}�aH fluoresEQ�!( GFPؼ%��g� R$��+ � +�#�O,Ac<FQ"�#�[..�Gtg �M�� N �Fa�ng}��)-�^/���/al=,��W�� EJ�)�UKby=-ce)�. �)!-!;B! �Lp_ociq��s��4 h� �U 2A�"ef�xE�6.��ehg!kse�� half!� `%T(dig�1W%0�LO5R�W�}J�or �ci� 6�r�Ic�A���!��b#�*� >�at% W�ziw�)ena!�6{ I�6�at*n'{zb%C:�, s�] a�/>��!&c)�hj ��s&� x] cia4kU�Y�:� �m&( � �s� . �_i8�CaN�2� \#fA$4result of Cdc5�q activity , although it may contribute to adaptation . We next investigated if Cdc5 inhibits Rad53 hyperphosphoryl CXby interfering with the3,9 checkpoint v or .53 � C$occurs thr�>coordin fa�or@9 and�sensor kinase Mec1 ( Figure 1C ) . Follow��Precruitment to DSBs , [is ph�ed�Zu,/,a lesser extB(, Tel1 . Th:>!fpromotes _associ �%.Ra!$[18] , [19\23] . DNA damage-induced�/n.�g�causes a substantial electrophoretic mobility shift in Rad9� step=)EW �Xas also largely unchang)"!���of CDC59�2B%;p%�4To verify that;observed:�tduE�>�by= , we!iDbed immunoprecipitE�( IP )!k9)uaO$-specific !2bod �drecognizes glutamine direcA �-sA�eEthreon.residueAY4which correspoA�o� ;ryl)i8motifs . As exp s,%'pS/pT-Q� only�d �afterM:=�A�Esincreasaa�ns�8 over time:�bottom%�As seenA#!�A;8-FLAG Western ,)�KexpressA�resul!7in �E� tle I@L's~�mb$2-fold droE��9�of.�. DR�N� elim�c�553VB�stillViA�eA�iproc�uxperi�\in��weZr53 showe��at� s�� �9 bind�<53�gai^h,had a margin�E� onYq-depend�.;��Q{�%Ino AA 's a�=to�8ra�1�53���'s!S�|sအ�����]�N� ��ex�l!0e oligomeric 8�G 9 has b��!Cn�4form a homodim��W � C-iJ$al BRCT doaA [34nIta�possi�m!�E96���higa�,order structs �� us disabla�F9 52 . Toy�.�9 mul�.riz�"�T%�}�:�-Na�s!O$wo differe ly tag�alleles=\Ove.��did���"$efficiencyI ��we we��N�!9-myc 9!)�|�:S3�uTog��!]ese dat�A�ũ�!� levelƥ��a�{�Q�QIto>� uto->A��)t!�make-upL�E� complex^�.los� 1hypF\ requires �� ա%�iar!�he!�ectV. ngI a�' I-de.iveM8 cdc5-K110A . I&# =Y� �XV# .� a deg �J, a*� 5�3A%�Intr�,����6�6@2�A's �9D,is necessary�;�&Q#��%o���" ae�!(terNl|2�!n���efAm� aG ��edi`�m, manifP y Cla� !�w  robust�^YoI�>+consis� A�%re �����= ���� PP2C-type�cata� , Ptc2�Ptc�- have��implic� to ro��in.`!in regu* ngm=>�[35E36��We gene� d ptc2Δ3Δ�� ainsutes�Me�i%�aaXin ly�U!�=vias:�. I�is� indem�c�e�w= 6J e�2��bg!�� 1�.�o�(instead foum h�52G�v>9�W1�by>4ev&� ab" both!�=�Y^B )a� mply!��Aworks% �!P!%J=a���recen*6�(target MIH1�  buddkye�7 orthologu� ! fi� cdc25-E� [37A6A�vFbinM Swe1�U[3�3�� antagoG�J#��jMihLoI�� % is(ng"/ Wwe delea,2K �`%iisA�Q�9 53 i��AK5�S4��Zg6}o3 �-4 :�to dr�tI�de>�.a�fZ��:Vo2'itself�� o do� eh6JA4inI�!/��disomr �harbo�a non-�C �ra copy�ch�some VII�Han HO cuWte�heie��q4galactose , WT��.��j� grow!K� patch�he��mu�)s( permaniFa�A-[26�,qF� %&neiwG p���in� cells norcu��'pheno�in� 6]f�.. WhileI� seem��j �<~2%�can�rule � a�� .�A��s��m�a]o�I��at m4X6� 2&� . On�zkey��e� �� A�vapanaph� by�t�� releC14 w� from*nucleol]��urn:v` yclin-D1_ KP( CDK ) "��It�r��*}`� �DC5AultA��p�. R�[40��P$�.qs� A%GA��AR&i&� 3 par��[>on���esai�C d�6$ [41]–[4(To�lorIBZ!�v�ha secondz e� �Cd!�1I�om>� *![:r14>on.�9" . Similar:)��,BC14"��)'*]V-f ����*�display%�su.; b��:3ELas"%6per�Ti  situ � >�$assay ( IS��IA��g�talA$ teina�ru�� nA�a�gel�transfer� o�embran��A�r 5�=� $�cub �γ-32P��he� �measuN��53�<incorpo oofQtov-b$ �" . Surpria� NpaZ3(to undergo [e�utFqt� ��"�AQmajor�� appe�hyBS.,� �.Ai52�ng̈́, ��isow d�PCDA�.n;Y�� N��z2�pal e%inf�sF�iH6��ol �N:8��*;�:� a�� � �Jbe atCd!Jied���;� n�attempA� �"� �, lik  , re� �ts��Tpr�g���d upon�6��Gi� ��MUEto k��Anas judby�9Bm�\� ! !�^-^�oe53��int�. E;s effort�� | 53 ua}`��-S/*�ieUunsuc��ful ,� on purifiu���6>1W�82>��xA�"��)�ZX�5_,"�!4&8it�0t%�R in vivou�s���� wI� t�provid n unusual��w"� �i^9 � WcappofF�ng.ra# �BJ��� ���#.#per�s\e{&�,!!��o A}+.� ct� � �"�,�fA>��$such a waya�akevun%F%m!)M�i�� uish betw�t�Ox qm?a�!2�B�� avQ ng a Ddc2-Ifun }isb *g"bypas� J^�for�� orMA Mrc1 ��!253!�)��4E[45� W� �J 4!�� F� ar� l]"n %���D&E� � j�YI� ot �r� &,�cE-)�žnda�" '!: ` . Im� ',.pb doesi%�WT R%\ , so�0FBݴ� I�=2� �]�. Polo-ś��F!� s-o&�]s���byUO�avs� !1ATM/ATRa�� er eukary<#[29� 32�4�Si-)iA6B�#ab� _��v�[1�47 T8�o� e>o�"�'a�W9eGE��f���&X%a��X�� �n��.� �') human�log!� /, Chk2� &���rec H% GPlk1 [4�[5tHA-��we�2)1 dSHA-)),��+ oe�o B�.�u�4B%�(unpublished�)mFL��r>%"�]S5� �a�p"y A1w��)IA&%du� ani�e. c&kis "�i�or�5 ���&X�J�� rad9�.!w�A<� J>A�!�f��K 99#oa� �X�A' ��v!)$�%���@ I�._I @JS�%U6(EL2�� B��sA =������8'O�A.�Ir4iaP-e!.�7:2av!, disc�aà�m9�ea � riti&!�t� ��V}�R-�&"��&troe�F �s iP#W"�#�F��� )Ñ �!�6h 9ext�� at�%untre�o�&d)�zeoci�a�n�E !y�.�aI�> �!,� �5aA_��aa}duc+MzJ��X *�u� �%�e D339An�Bng e�!?K 53- 0S%GU wise�o ( labeled )!+e carr� addiValaAoOrI���FHA�!� �� � � .!5 Ui�E���U��*!Pm� 6�*.�\r���Q G [51]Ipoa�i� %�!3e��53 R70A�*+)E�A"N&�" FHA1 �Y R605At�e.�" FHA25:�����e�I��*.^��*Q��,y^m@�yEui���orP-�dN& , clea(:�I'���))byI]�B>radio-E�A� T�? !աr�>��%A� |F�*id +� �%Q�al��s� no I �i �1��"�wo̍)�a�n](N�e��,eEQ5yS5��x-Yunt!@pto�h.��D �Q"d� wild/ Bs hq�*l��!:ia�82 �dou0 �9�"t� >?Q��4CSENe�R�$r� af1UuMg&�!�� �e6u�d!AM6t'2�-�a� �!��mJ�� "rom�}(1�t") 2 )f  , [5} " �%&�!&x )y'*(!8  !��. F� "cipa~ in s��c��col0iv�!ote mito 0 progRoQ)i|,�� exia%�@"�, APC�q%q�<nd � r atid sepax[2a 53� 5aE8 ?n !VF�%���aTz�(m��B�!in nega ��< ^� !�me�.is!3d�l��9) ed unknow�Ou�>�'A�&�b�s!%�d� iA�;'!Uye6-!�e.45�-u"�molecu9$����6['/��vo��5y:ݩbeg�to���&$approximatAX6–8 h!�A� cycleb� "��repaiu�� . L(]�&�"�*d"�Z1�i ! onse�oYU [28�Howa/��rx/ g*pleR hway] veP,g�X�- �tV,d�-22a�tagaNE�; �*A%^$ach taken � 9 E�i}�A � M&�2��sPth[!of� � . Fo�4a�)B�&=�yUI�qP�>A�"#� > &c�4.�"}�&"!�&.=�wZ[a�=�sup�_�NT\� �.0>���%>#(!�model)��s%s paM@�%:�i���]�.:C&e%w&� "(recA3y1�H3"i7o�mSu4ined�1"b��mA�ssalp10$ !�~,� ad�n�*�,ree�)%-��.�� � ed�ALIcF�%� DN&� ����if MEC1 "dmovc� a!!r2Z'?3o� �c9�$�F8-feedback loop a!w[" O2�� %�;(�x/ -SCDy�"�/�.�9I]���}� 2 ign�+[5G$� Z�Ad�4��o.� , ou�$�"�k�;�1verpr�_5��e!��T)Ntsp�exe��� ups@m!�%kQ��XY)��i��& ,,-� 1�@o #e �G�c^9l"�s ��4t�X �%�\^ 6.h�^�� Q-� �R��(N@,"� )�e"�%Ws�*e"���r6�-J�)���Yna�! A���ya !"->ex g5�. A pop�,, {%�K&�y!�n|!��k/*$at8-�-�a�{"�i�""Q; P�Q�+"�*� ~����� � 26U[2t { 2� A3��Ag�fd+q`%&| ����{ tinct aT51)^E�� C��tL!U��eZvo"� �am��ca%P��Ttoa�Ai��,����A� 6�,,1�ZMCds�=� �5%)AZRad3 (4 iY oughw ! N-�RionAԭ��>��[2 'T&6$ �N-%g�9-S�!�Mv�E%�refx',��ec 0�ct3t� m�ed"�#c/�����y �L-i�4Mǁ�:"1 �ъaya��  >�W$0 �ti!w�t�!a#&N� � SkR*!!%i�&�@���demon$�t Ao pr�2ly2�i�9g�;N�,-c2~;aE-wa�can6j�53 enA�a!!I� �.E)�y�F դ.pMe��� 9.$A�m%��5eposu!�wQ�>ece%\� �&w�Aso�,*�W "�;V�. AI�!%.�"� mustA�#*�&%�[5g-�Ž"�'b����do%;��fur�"��-i�7Nc *� ��2�m!kAD53 [5� JY�Y0�P.of� ombini��k� &s�h*�isVul3i6Dgu!I. �=i�1�;�-*!���is qu�/�� . More$��t argA%� �"�$��4@U� j)o!�.��� �,7�classi�B� i�<pj� a*��4ir1u�AboxAo A�ti�equc06��� %>! [59��"fm!C� "�:k h�0he��������,�k. " �"�/ �4"�!B_= ���B,� J&r "E�b�$ ! )����5�3��kn�*er�EveBof%� ѽA��3ũ.f i�bridgA�2N�{-��� ]A7a�adx@ABEK',�-d1�� �%`W<|2�N�ͣ;0 !�benefi��5av�b �d2p���a~��3� |q9 V o�A� !�Chk56E� �l(Qazas� �@%���now!�add� ~�3�lis�U]e�%-�X�W0I0.�. M�s�.�,7 at e&B�14mous�&�% S . pombe� t�@h6vm���dI%?� !91,���=�� �:d1A�m� X?9 =_#ts.�coL paJM^raiu:%o�;! �U� E$�''s!["Nfac�(a3=A � %�dow@ eamM�� �D!� Dbf4sfAVMdteV,%jV2f, [6063�%a/$q��i&|on� �� f;C, ;A�,2|i��.� tron�/@E���*';, A�g .�&��e��`5ZdCQ�.!pa��,*�+�D ���I�+ �8� Dea���al!�53*�e$� vF��e|5�!]&�4or un&7>]� y�A�e f3<ng+e+a��5��*�;� V��1����I�a8"c �a�stitu2o2agree+E�:�P9 �:R;^�#!�%�x��fu=%�[�t!Z�!% e op�un�~N��e�+�mQ!8g�=�witchI� deciRt&�2��IF]�=, ����.>b!7*�+!�* =�[64a�[6� is leads �qu��-w8 A�tipQbal%?$ � )"qco�ace-off:3Ek!%�.)rd1'��CDK�e�96#��!6EE,�r@�ngt�t�,.�f�3Aw&� s ? *I�b]nside�V fia�2�&survival�_%�exhau�:all-�� opaf�#2� I|� �H�?a�� divI�; +=�,.'�  ��)f;edAw)<�[6{�X stud�&\,�tia �us :VSF � valu�ins��� m�m�tumoriasi!!ii�ue PLK1b�� � �n var�I Zx��=small-%^lu5A�,r , melanoma�-o.9cI7A�@0Hodgkin lymph/a���"2"����H �� types23�no�!> e [6"[6"h�B3 [�+"F �2��=*a� a�a� %  enh!'dG2E�!1�du��geI^�AQ`=d  H|carcino;(. All haplo� �> deri�yDPT1-3LS MatΔD 13-1 cyh1!�(1 lys5 ade2�3::GalHO trp1 his3 ura3 leu2 pep4::LEU2K*`42-4 (�aBaURA �-HA3-e82�?!��R4Plasmids pDM16�  7qDAs 91)lineariz�) NcoI!���g0D GALg,p.V(aw2z".� c518�>|XcmJ|<-Pkq  PCR-bai�t�APcassettc)��t� insert a.(H3×Flag epitope tag� RAD9.m6<3FLAG::HYG . GFPU3lDDXnd 2)Guas"cri�R*�[�DDC2-� 3× cI��}pRS316R$p)�%5c�%�304%~di�O1�SexAI<1�!'� �locusI2. C�@e$yH(300 µg/ml �+( Inv� gen )ca t <of%Q. �;��02" Baq , 2% &�A!R1p$nocodazole �a$i" < an�e. Micros�B$&*-���0Leica DMRXA m.e=�FITC filpH, 100× �D4NAA�nApo oil�O�6�bje �pHamamatsu C4742-95 CCD cameras tpenlab 4 . 0 . 3 imaging softw((34� �0)�uA�8ap;@"�"z-s�onH�@Fluoresc�Pexpos�Mn<W re kep�Ans�4"3�.�,y�a���}!���!ja�dM morpoF ly� �N!�numberA-�0�J a)��"n@Ja�"QdeqP[�CA�C,�V-�Fy# �rb9 j. A&R-4�bey�Uhec��s�#��!� �>!5×108 Ue4c'�J#achlV.wl IP Pa�-�CE�1 µl/IP!polyclo DAB00��gif�D�Q uroc5)� V A Dynabh :����=L22x�#�wN.;c ,.�suE�WgU q� �t 4°C�lyXbuffer ( 25 mM HEPES-OH� H 7 . 5a�50NaC�;a 82% Triton X-100a" EDTA 0% glyce�+% D (or cocktail� Fift�9µl!b$Sigma Anti �M2 agar��M=�jtox swdd� or%���T�!���l Nwa�4f� m�N2(I*5 boil��0 SDS-PAGE loaI�)[�l�[Q% i P�/ � ��A6%� 8%Wg0P���f�AoV n��a:um�A( Millip�mα-Cdc�YYN-19��S�I CruzA�r%HA _Y�e8��a�Sst�-H�-:i�ori �[�:bO� fa!�Wesp�G6 � e:� Pk ,�Q � i� ( YCV�I�α-�Y(�IAgnalO!!A K2`!uISA) ٩b�a��,� �3�X��@by"eal cul�0; ��*���8to OD600 = � richq��1 2% raffina6.Un- ����=�3 h fo�@a��a�2�2�ly��in RIPA�O1231% NP-4�(�>,5% deoxychol�[ci� 1E� , ?Tr` H 8 �,i=ZF( R�s�M!��gHJu(!� ma )%�IPm9��@u0oupa�d^�A�1 hF�Re\e�S:)��pin�<��e.b�2�� MgClY: n ��DTT �n  gg":�asM�P�Are&�#75IE2 FB:x&��r�, 4%ATPm�AQ5 ml [�F](( Perkin-ElqW!�!� 30 m�6�4e�Ia�stopp_ ang����1�!��3i�Na�͐^5 ] HalfaO:e�loaded3an>�c.�to PVDFf��� !�_ ` vern�jm*or sc*$ ( GE Bios,WaR�]aab&x! F2. �qu��f�Bcw�`I�QQ) �(0 .onMany�+"�J �O6 seiz\H,�!ok� spre�de7��na�ae�8�[ E+<0� &$F.A4A� Vic*�si aneoW]-X%"v!reg�--5M�i*R(urZl�bf"ac�F�\��Dinznc10achiev�E�'uh�9� s ��iophys& Ds�v �t�+ VPof:: ion-Z�Q%��{5%� ��� powe�-fj&8lim�J~ S�/ mena�very s A�tio�Ho�4sca�2(� meter �milliNs�e�1�fi nd ideal�1-�\nawal ( 1-�8��Ez�.�V�d��al�&H�v,�&a�,>AIT3-D Kirchhoff-Nernst-P�k ( KN4dframe', \ o!@!xp M�J�on �Z . By�:u0'I�oneutra|W}: KNP-�circumvi-ch�U-�x!oA��53$^y of n�9�1�� GsY#u2Juniho_$!Esp>�of)�gc%��_ard� ktopM�e"hInY1�-}w��p%�NP=�to� "Z ��ofaaW@Wr�nI~�)wi�o�<�rou�^aB�6"yramidal,:�A!lucid&�!(single neur�� ��.�gF*��� I���*�(�]i�cz�F+.�G enviaK�-fu%  �Z.+Y}I� �2�6b"l�fa� :Vystems�:l b%��K�Me6�oat�R A��a:Me�!9� �%C�!. ����%l�j�8� �]n�3a�da%�I gli�submerM-~$cerebrospi�} fluiF$ fi�U�n�. N kg�[]�Ia�& y ex7!'%��Sd�"�a on-s@�1n� ��&9a"� �OD�D normL�eAYis�($,��l n� �i%ql�cA�2mF as)I!'��!Ql��*�e�ff!�fJYc�Z=ase;.* endu��}do�(f&h%���8r aberr�r�Jv1!W� !|):��8M�]�8 ofte�~(d"&slow Q0%N1ؙ�[1– #�!�be�ly evo�Xby"(W �>iK�!� i . ��, �by�I�movA 6-�2� g�?�w[�.!^(�influ��field�� r!aZltrup �?��3�%�F u�>soa drift( ��O6�  /�n+rplay7�M!f�JA�5��C �]�behind mn� lin!���*�m6nFD�Gcha�epilepsy�R� [ 5–�]�XC 6a�o`>�<len)-?6��!ll%-a&# i�ey�6MO reli 9 ��B��(2� �p�� �� ^� &�! in m�k�%B �>u�ie��6KYmreI�pa OE �1��re ign� al"�3n<�!on� 12A�ch*ng�#vol ?eepa�tr� 1�2�Iɴ:� �. A� ���|^' fy��ɧ!(m�$o!:d���S��"pi�Zh�7ime^ ,�K�3G�.a-E�6�2�!��!TO �Pl� a�)�DAneglig2�_ ex�*%��%aCc�%��L6xm�b)YQ�o�@& $nd�E�,�A� s [8–11x%!fQ{ma m ��� ��excite�r��?i-A�ar�&��^c5equ{ * re&�"assump@ �( iiohe6:� ��}(��=*cl( i6B5s%�<[1��1�_� NEURON��a[1!15]s= 7.�,za�ieyj�l+8f@cCt �M�0%Y jtLfai6�Epredi�X��!Q�-5�Y�. Bec�>�_5X!%)n�reW��%�a���uF � seve�aches*��@w-�k Lsmf4D)�Q� . A .�ZAS� &�!of��)�5�volum��t!�( V�Hthe ([1tB21�$VC-schemes�4n8�Z� � 2g�� }..M2jp,.�!}k$byI!{!�!gto� ��MM!� /�!~.>}�Z� I bMDE�o�K d-^ solui�I I��cal�'!��ic� EY(arbitrarily� � ��x2aso"D�KaN6� !$J�on�0�=.��aam#<veU��  �H%� ��� s*�s6�� ͩ� 9!��)��9�"io�8^�. NAzHe��+doz qRz� ap��a�&Zs �� Fu�6m�2�1��q�"'&�"< V! U�F$����xIH�!Zwe�g�?e low-f�Mo�6o�e�-2wa=be �7!�2 �[�� � pC/Yppr��F%�ar6��&inR tiss� 4<o^���---A���(L} g .�2j 27]5Ƀ/,^Ak��E�;��#�5�v�u&8 ��or q 1"�-u�AL� � yIiA�.gi+r�M�C�S>M/.6F/kg.�Aunet{ n�K buUYa�rge�r�_� Na+ , KCa25Cl−�J"|�?��orc> ' � os6'by!:1( DO ) �h.:PDO:���)� \ng)�(dm^�.� !�o��ounM X*� md�#�"ke�k)��*_3'i/!|�:X-, �6�a� **FuM&6!b Aw�7�oJed1i s:V�&�# e PoissonB�P� A[2 �t PNP-�A� liciC�sMbVCau$, tiny devt�!)'.�iV !�egab�%10—9!]!kt-)ionic:��4!#&�E�8pro}1~ high> re��ՠq-4�tovA* Kxpee�. !�-���i �aTb@"at�1-the-ar;h�Q�7liter��L�%7v#*��&- "3OLcr;!&e.�I!�a�s&� �=!�&"taklii 2��A �}�5Ij.' dzuo�� &��briefzl��s� ;l�sA3!��o!%i � 0quasi-�by\te���3. 4�'C"B!cBD �!r5:!���R��G���r ���io�3q#oUx��]� , by"� E��magnit})�F��<b;�%*�l�!�+�2�"Xe�a an 5 μu�bto�w�5 good�kmg6�[� )5Oest>�:��!~ s� ,��|Y��ur�p4lA#Ev~ hk A;"28pa e�5�he�Q%!co#m�� L�*�*��<�4-��/&���as�UalW)%AC� �cy`mZIf� � U . ��}�[7a�!g�k+�zc -sourch_��ana+*YF�+%���9E � � h$*�.JD setup�t�d� �ccoa�e�N�^>�(a�ilx?�K2���/���rUsE ��� �0�!���5\!w�t�L a�ver��6����9U&ɸ� eF-" K-2) " 8���m��Ă Wea a9 ��m-�!&� s � b�m��wa���UaE�i�EHm *�"�N I>�!l;���iIm� �DP�. nű �IA�ĭ!V�DDO ��a�if� �s1�{� �Ue�p!kk� M�� (�v)q�.Ti��=�A� ;( mi=5��, ;2:YX!��&Xcc���>��{curac"�-:� 5"�12dBD̀�:.�c�u-v=3, qt!O� e]re�HLmEaލ]/0Y=�re0�Es Appk �(.L!S.3%� �ma�8G2�� :6"A:VwE�;A�6^ ��'a salt&(�\@a�9 zero� :�#)4� �� �+P&� )���W �\"R Ni(q�Q� !'loa@&(2�#"a a`| ighl�)�XBit�h.��6(.�qj.>j!�2j��-_r anJ1p���yain�/�qoF& , embenD� "E$�aEz�Z7bc 1��VC9��72"irv$Bs 6m:5r"*#&E$�� [43*6��#�� 9alfy� 9�H.'�schA�ta�q�mea�8�t&"jUp?y�� gives rJ]a�v��6$2 au>s&�$"v#�W2 M s�A������)�T%%�9�mD� ��on*�!q�s u�build uK�Ao�<!`al �?i��M�~"�r� R�M���IR�,� j�ΜA"�9two6" ��I�J eG ,cw#b;r��eu%~*�%Vabo�w�z!Wth�A*\!���-A.%e��!�( illu%+� 2�s��96� �o� kno� B�O-6="� gF handlee�6��*�^a�b�'M3k B@)�8@deman�-�E5gm�a !%AVu�"�+�[A���!�-HeE�jf(!�ut; �+�pm�O-y� mm3� $*z�)�Ndayiex]P���q-�Y�=~Mbgreat!��(A-��, � pfg "�-��T"� t�u�zڨ(�iz/A2�s6v#�(+r��i*�sr' 7ee��tiliz��FEniC�4an open-�S platx Ze-��� �[�ga�S %�fin0e q method�gZ1era-� y' to [#c!l _e.� e&fa \�� �!EZ�xt0dN acit Eule��p�")"�B")F qA� Emplo� ^TR�X `l��fcX�]u/�a�M ,. Piece|j>)(ar Lagrangi!�)�L3�'%�ll�b�y�s)�)�� �Ai�nolith�JAZNewto�)!3s>=%�%T. D��M�ofM�’�t-�ion �Nr�r�p ��!urAL �'�+:u�"� mDcodA@D�s��!�mrAe��E4DS1� endi��a0a [�0�R����; �.�x�� . ∂ c k@t - ∇ · [ D ˜� +z kψ,ϕ ] = f .K Ω ,!87 )#· ( σ ϕ+ F ∑a���sC`+ iPcap = �9inV8VVE +db )F79 )�=,??,�I! � 30 )2�:U · n Zat29h!: �R(. ( 3h_�� u�0f"�:de�0, ϕ = VC +�!X3Ѝ σ =FC-�!C2!�!�34�Zz2-�5 ):�-�^ 5���G� be nCnt� Ar�E�gUmK�5��:*� �Asena��! er�(92}m�,'�DO�&� ��t*� � ur�7��n-y�U�/� aa���#ai�<tw�?j!;X[��tni�D2�P #-�M�1: . WVw��"ed�*�&� 6w�u_%jbehav�b�(C9�Wu\��hE.�I� 峡c��� �6�F,"�/!lef�d� %kas� t�!G6J:de�i rE!u�co&P'KG�JX � *ij1'��p5�/���*� Y� rapid�Duil�b��f���! blue�BFig 2�a�F��wu6o�+a few2�, b�]s�;waa�>�. S?�)�N"�%����^&���a!� )�A�� %:^/Ezin��ilibrium%dd*[Aw.�apA���J���%d!3a31� �"�()�BX#JYj�/�t��6�ꑑ���4�^u�A�aF�a�y" M!42B@ g��n���t(]\)C� ( ye=A dJDk )� *u\Na��h4l!8�-h%�6 �? �r�"�)������CI��]�b (�eon�y�6�'�y9�r�!�u�.�Jf( t> 5 n����!�9  A�x�a�&2T�$Y�O5tuwof�\׈IJ��:<���x� J,�'�X*tm�S l4iclJeź�3V� Exi���A?A� .p[5��NaX = 2 X Na_ X�4' Ini CAF��fil��:�x5P&� !ha-�, �SaAlN&� ��!�BXaL� ax�فlk&m %�ALa1m�H+��)!B )D�y_e.`ia "�Tn]D%�Eq!8^Aa~Man��P-2�\)X6d�����ng�aW��d@:p9F��v����c)agE�!\DO-��g 0g!��Y�t�B/a�F�prM6))$0�!�14twkA� %��l�7��nV!Fs� -mi�!c 91 de�ρ� $( cNa−cX�M�Y�,�-B��x-axi��"���"�<7(A �-s>�C29iux)�voltag���4of 247 kV acrou"e11�!�l�s!=*,&���y�heA�-�CI���]d7u�$u��!:W�din�:��"\f P%YyxvU*�� �#T A�464 4A�a�� a�2v�^f1ib, �eUs|T�2 I zMYX^K+��!I�6w�!l& �cse���� ���2>*ϕ �nd! �Cu��d� = 1�sa�w�W��3�I��U RiVb��liV+toe�e r���Z,*�:�.)<-��%#� ϕVC� 3� );5VK���E� Au , ϕ"Rg2��!&�)VC� AG�4%����� im�a���L�>������<ŷnd&#id�=� Ft��`k{w�YILF%5`GA#iJa�1��a�-q��+ o ��%C�2&�RH>��e�!���nR�"� -����������lf��end�a��es�RU{��>,I -�A�A�1�9���%iVC/ Y.���3D5W��.="gfwo�sv�.}���ZPI$*��.>t !�a�*MIak�>�� .�U�Fw�)�!��4F�}cY�Z+q�)�Ad`�J�?at!n; [�Co�Cϕ� ��Cun�j�S6�9��%�sC <��� ��v�qX/o,j�/ �^�`e!� jB��� 3%��r&s]K��f�(�$du�*��!�I�6�:0i[ �_�#yi 1f*0q[)�� .�2|ϕ| < VC| QX;ly�K�k���F�fSLϕ� _5%NW,�VC� eFIH -�is{%�1nti>��#Q�f�\H&BRn)���dr�M�#%�l6�E�E;��=(9��v"o�x2�x �=&dec,��y ޭ8с8�t�9� �RFJGV 2� �?o!M��0+�B cyl|%a�8Nr2�Wed;!o�:1&+S!on�"�q �"�^.$,n}aupa�d.`"PaA# l= �!�6� lEf�.n 8-OasN�1B�a� �� ��ECSN�gF� v'0D&�( /� q'�%����Y���8�2"Bc"9(2��$�|�2 Q-�&�.15 ho���4 CPUu}�p�- �ta֙N�I�&���&�$��A�o�|&A!�Sp�>!�nFi�7)�hJlya�IVz%#!iBM>*�:%.�ach��o��arc: rega���$"�0 {-��?*��DA2m�&2w &� -rt�7sA�=�N6� ( !Ifarc u'aA?�D^�Icenc�Fre�!#mIis UI1< �i�H>��avQh<)�&�=�)�v�v��MG x�ousand�r ;��t "/!["�!�ja!6�J�,)6w�!9<b�Te m,��!B!:�ZV�!�maxim3LhtB�6oŔ�,1%\,K+ �aGs)d�Xcc:+, %MI�\�b i)6-Iu~ �~)�&Z ��A2[$sh�F$a�=a��pro��f&�P `����ur̵!J}"Oe $�� )+>�s��MU�-!Q)���.netsJ% �P'eɌ|S��]%*d!�.%'*�W��;e�no v}M~�`2�������;� ci7`�A�"?��outputN� ���9��=�E!�2�,1*�^atB+�(aݹ�� �[i'2� 2$"8 input/ �*Ne�f�2��,q���F1��. iWU)Q&pH��"�)��r2SE�G L>�*���P0 �h�qmpan���%v5�<"�E��!-�3q��!�4F m��)�) I�6.�"CC!�B�df@ d%�ephapt�Aee]�6�4#to � >)i�&j% AL7J9R���T *� �+a�� E�V6_�L�z��3Na+/K+-� r pum�6f%e/Z&�(G.js1b" vail�in1B�1� �$ !{iAse�u6�-a*x�'A6ic upPE. L��"� ���3-v����+q %�6��2J*@A>Kj#*a���%�.�O.6|U���PA�)���,pr�p�,%3�A57 , �^IiC' �l�m&�X)8��^N ��2 �>)`lik���V<(� mp.R �a��1n D�Bi� erESa*+.%lT�:���A% ?AM�  �n���2b0-�deZ �La&J�l�"VG ���gw �3� E�� A�֥o~Z cus�!�8t .H;a�-#e�5+ed%|B}�2!kZ�,[2�,2�? ,�<L�. E>O6�c9Eai�W�"|� BU-��)ur�$�Nso ��5Qs!dKD�:0�M=W�D1.*G a3F%��YBp-2%�� (� ve��s!=A�p�xE�HQu � �C��t�.�EW+g�a"�(3�q� %nMEE3z� �/V ag��Racfp .�"i\n�E:���(>�:[,12�ndM{�*�" conf.���?re�,�Re�al�l��gi�'ba= dendrite-� -ap y   I ����k���5d�#die{I�a}���*� �qu>r� �8W�pge����m&�3� �Lsu�Xc neigh�� $f i"� "3p�rr� A��C@�1� !'(��&x � �XB�!�Q�>? �1:V �^>y�4��RES(as";!aQ�ny� ict{ywNk��l���1�.)\: Z8"��A�U2ã�f aV�br�ar �-�=4problqYb5s0 dp�!!&t����e=Ha�a�"�`y�(��*��z�z]�D��\���is6ddo)W.K0a�MqjYjuJ�A,��c�:�OEH$pronounced�he #if"�wo"�! �ne 1-�mposi��/�j��A-L�!?un% )�fBn!�� �� �^!�A7�!U�vic�$"�"� s�ZBF�%� *x�r �i2 ��= "& kb[6�-6OO�med FL?����$� -A� hy��a�*!�c&y#" S?6`9��2�-#A����u�o  p�C��o�60$B& tooe By neN��4 sha�>.� E�eFQ�er &26A6�!'��cha�default!�7)�&Ň ��]ronT�R"A ���#�]��av��l�'bn � �A&�G ��%�V1�c�u� !�� 6sF�#��"�"yn�_� "���. S{a�$'"� a��*G��*� Y�2�-qe-�u#( EMI )�[5�6��ɞnzNN 1���)� "�)�F79!@�3A!�L.} �iLAvsak�m� KNP/M?q�� is � DSow$l����i�[lo�&W*�7toA^�i&���n�&�Ja,�2�. �"(s*�OPc� � G?"�v4���"�X�K-�)�6�5h1ab mN��'�NQ4KNP`mP �s2a���f&1q�9]�isQ�� c%�J tZa� � ���_ A7�Sy�-�s6�X�=�u.5� �, V1�p�6�2�2���jS/| 'B�/B�Ix��qor G�z�6ta�u�)�.�aG.�.^.aX(Q�hA4 E� e�+ ��.� *�be^g1!u*ij�] 7 , e"�][���orhG"�S�9*Wa:�)� hif�Q6t��2 A�In�M�)�.=�A��X�2�Eab�panj  lsJ�P� hI2�]�*d=F�� ~����*!(n.�Aggramm!�`fal �[��wo-���J�&e `�o�ols��Kq4�/Q8 ��C)��ty^lyD�>a�v3im�LalQLaiceo()�&�\f�<(Bs9U��� mult���?�!�to�k~0�AE;�:manage����x"%j� �C�r&�-v��,�l�Z2@s? �ed�>nBdPVQ)J a�2er "�h*K/> .��.�$�rd���o,�Lo��U��r �uODis�rCo�oPA� ���(f�h��urveillP��research�imos$'o-bor��_�MUden��W0'N!0 viru�P�.�&to8Y�%�untry!-p���^FAnew eEgaCdwh)�._on'In&&&����m eX�c�&�fas�z,�"�F& we e���f��al� ol!0N��2� %epide@j(��,��"k )��rDC_z!���)!�}6cò�!�{rbnv"� R-E���the(����o!`g="teǐthe�&��de �"w�7�h!�� �Ca#�=]A�ha��Q9Y`�!OC ��air Queensl!�, A�CLi��r�t>"�f5� � VzYuM?���=�+!]c&\ !a�achv)1-/cu�����)_$lE�V���*qI��qUAby[F��Q��Ta�R�� GO'�ategy)sus� C>��/%�)�. �";P�!�V5q�nzR�6hre�'�BHe��� Ij��2d of vector���geE6 "!��,A�ide�m7K�!%h��l}HA ��-b� b�"� ed(>r�BI �<�#��|e44 just� ŏ�1tre-BM%�� i�g$o slas�Tb�� ,�2���*a/9em��izIH!O�im�� ndQ�� �*N`6�o% 2011�kfi�d���� ���$of $26 . 7<�:P���[1]a�ld�B*�P�&yz:��ըEG0�GͬaXWR.ngA!��C�~���]>�( WNV"z jeop�%-yH�ivq-��ehhed7 %c�q� $�yx�"�! ex^��=-� mit�Y��Rift V�gy f^ , Japann)?ph��\4nd chikungunya!dus%t��h>3��� fens�]aQ�҅1usY�[�gu:� ���U8'!��?t��>�?a!��m2� �TW�f�g!LF �r� *!v7�ea�g��f$��bQ+f3y� �a%�01p�{y4Ers��|��a�-!y�)�Rq�����R�q��e��a�a"f�S�5XC'Ű!�>$aq�N0!�p&�c��cp,�7n��re Data�wo�L docu��a}�wR�Gq �)1 I�outbreak!��S��byA�> �vel!�i��ї�9in 2003e�2009 [o �$ � ׉[ba���9nq�( R"D��Z -I-t )� �-�.K7�BOage @�Av�s*Y1B�e5iL:����@fit��!�x 0a"E����d week�]���va��=�8�m!��ey� bega 6E!�!})�42��h� A–�5f"E!g�G,of Nishiura a�[[5�RMq�2�JE���!\� �9� Q�VM&/f�+9�P�bi-C3s7^'-荤A3{a��zis ∼%�<��� �8D�"'�ec��Qeeku. Hyp�S� >���Re&(��e/AFe4!�1s�O�� Z�����e:<����q02�(>�Z�)TC!6�8MP)i�)(I�M�j��*�2� (5[t0e ��R�!� 1�M&�!�EC5l! `by�"�K><Z ��4�����A�����1`9k5{wDom�c؅;� ( GD}defNo6��-�A!�/�#-�q�"�E iagno�aybl�`bank s"�6 H���:�d�&�YF�"<& >�q�$�� hemorrhag�*�?q�a ��oA�Aalsco-"� �_Q� ]:�Ti)/�J�� ��n�e!�>�sub���is � f�����>3vul��&� & |8ro �52!&� t ��o����M.6� \[Kv^���hQ$qsI��$AQ�LT�&�io��"b�}h�Ag IY�Vz:"!�>v�?2�[�P>A�EaX�15US$,�1&;orau? �Q� ��  V:�R�b�!�A� same=� 4–� !8p�re�i��)��(sO&:4!��7o�8��YqU86 v/!13�;& �A34*382J*��is�#[D N�_ՁaY"~ong��N�b��9thl!��� I% accr����f 1�@ߓ�eY���Ja��r~fj NP������67 �P"m �7Th��y �!Zoi(��s^d��{? *?�j�upA�!�=�nM�- � �% � l�!$!1 invaE�!�i{ ΔR��e\"� �2��}�v �by�R2q}j9JNotabl"),�'�@I�� ]ua/2#ACa�%� a cl�?� ar�to Miami�!)<�&G��2e��,A�V2�a8��.�pr�C6�t��5#-whk�U�Wil{t!���]A���2��+et���+��z" @ catT �N"���.`5D%�+symptom�- �*��vely��#e �Q{ �ew York�in 199� �F"�-�* �.|  %�a�ҟut^c�novelN!ovi�%2, [��[��glimp&��! m�&r %Fnn<�i�of"��bn]death%6a� Ju����r�u&� �ck]mc2gs SOLu�,nc&�˜Aug����p�x��(Eo]I!U���!�al�)2 mon��AYffMe<�.;B;e�S>d2� A�!R.rq ��&ve|?l �2%I*� �,����%�6�'_pJdUwzM}�p e�� �44a�i3.!U�[*�28 , 961� �& 1G�30 fatR)*H2008 [10� V.�m�6� ��.anro�*Rw�'SD�Iail��>!~[�|��p�9!u�@!D� dZ��|�� !��d�P�o�4=ro��xl t� nJm� �Ior�p� rŮ).d����� �7!�rD�6d� �:ainUSr%a 50-�  hiatu�2@6A��TI��� � �|����<�hFlorida� CDC-��orJmt2�1r.��CD1N,5"56ɐb�2*�& ��!�,���d r��F�s:5) e4���Mb�e%8�4an*L,�9!��wa!��i�&*W!veQY��icBL� �h�(Z;: �K�K�KK� �٣"�a�m�a�$%�g an e�]vaaJspda�ndp�gallaw�^��"��A�invesm߅e�N ost-&�=�p��F ! a� f� ��"�"smAK,2 �B,�VAO�i>6�6Llproba{8J,>��m ` 2�# ��Go$b�A�errup%�>rif_0 _�6uQa�r k�P�dgN�r_$�R��d$%�.}.=gDp ��!B�5&su glob/2"�}e�Sug)���G2�c� hildr��0Nicaragua’sA vily-]#p1ca��=Mk&u�"�UJ *��-uns>�amPSy�ad���!4b�Twd%i�!eo"�T(�0-u� 8f�6)u s(utyf�1%KXin 38��.�D)9��ly���D3/3�9ofAf� � )u�.lMh2y#K�,l�er����1^e��Zth�Zik{!� ��!M ��5aja��:-�� geni��! � * ?`aZdxat*O  riskE�% deva; "��(c���1�C�7l A?f . 2L"�52)�Q�qc ( AF.3worldw`.1�i: ( DE�#wA{K24 ant��y�Ki��A�IA!j1?�Q߈�� RkS��d ~400r6a�AIK�r�6ann�R�,��&)�$. C�X:2&�9 s�oor�dz5 �{my 1 AF� YmaF�( DHF�UX*5�pid\�(ofs! �$��od��E�0  ��o"� ^ +� ge2/ phic)a��j ���m , Ae��egypt 6fue��!���<# K 70���$� ��^g!C rB���' 1985�A�-��  2I�dAK"E t� .EI&�1000MP!�a�����D�� m�,s%�o�6 ��&� ��n�2ocaI�,only sporadiXc outbreaks of DENV-1 , 2 , and p4 occurring until reintroduce $D3 caused a massive_� in 1995 [4] . Over the past two decades only one�!�4 dengue serotypes has predominated each seasonhI0(!$) approvedEg�eA�it�NA� Carolin[UNC.@us� samples ( dee!� Xexemp-�IRB r):) . W�� crui� 5�in�@emergency departmA�I 9�w1��H�&\Escuela Oscar Danilo RosA� Argu�� ( HEODRA%-@400-b��0rimary publicJ�of5.��UNAN )�)�.�. Betw�W.��u�,�z�d�{c�{ nt��Ge38°C�M ympanic )9g ≥1E� oldeout prioA�a�i�)�yumaac��iz�]6�d��day0ear�ven� hours Monthr�Satur . On �%�(�point!9 time%�I]personnea� corded on�N(tandardized��mB�i�b �, incl g self-��ed� vs .�bresid�%�exposu� Z cliniDfe�_[dur pof��, histo� pr�fin��G exa! ] oA�sa�ider’O sump� diagnosi� AddiAM , � mens!$ on-site S$ian-reques! tesE_A�off )�arch-ʼn�N & were��o2� . At!��%�)�M;co�-$ce ( 2–4E�s after.!�O�9-� �Tserum�� . Home v�vs �att��ed��H0nets did not ��� could be"6. Sera F!��/ ompt� %Hat -80a�!6shippI�dry ic�Pai;sL!BedO ELISA:PCR�Mconfirm= < � *� at��(, USA . IgM Q. D� capture 2per�z� viousl�� scri� [14]�( minor techI�(changes [15Y IgG Ytl doneg�`sha(arlier [16]�} $PRNT-valid� )cutoffs?we� p�Z � �We defiY2( as either�!LAu� on ( ,opte�den��([OD] <0 . 2D 4�J�OD�Q �a sign a��crease��(antibody tiA�(6J!7N30�D!�20 than ��IAcB Ѱ( first��sod�/A�)i��( ur0  )��e�w ingu)�by�habs��e a�a�of�(�%35k�% 35 ,�$pV� ���ra! thoseIP M�. P:g����fY)P1��NCs�; !�A2al�at.WA��]R� �20>�; oAU�\a nega��. For�I�assayA�E�1,co�l humanGa%U p �e��in dupli� !=osiz cut-e*)�eterme�o �m_a�[.ba�o� m� OD�*B���plus 2 �| devi���zWe �,25 to140 μLAA)�@to�F�-�f�7y�com d���M�χ2�dA�FA��0exact a,!�0inuous variab� by  � t-!vDA&@Wilcoxon rank sum Iif�F norm�oaW ribu��.! also�qbil� mult�(stic regresb. Analy�%��le_a+ St$(IC 11 . 0 ( (Corp LP , C�ge)�TX�2$) . Of 825! sh � B� , 74]90% ) zpZ�-�T $likelihoodE  subjec�z0 32i�� %�"v "[��differ!�$age ( p = ��4a�, sex89Por� R5= �"> m�n%�a�0�&B to"M e�2H(�erquartr�T [IQR] �w!�9hoR� p�sus 3 KIQR53�651"�08!� A$A�!� R� �!M�$10B � k3–29-n1�� �54k( 9 Z� �31] )V� 1� s -4 , 30�1�33� ligh� morei1malA52 . 6A��� overall ,!��young�an fe;��9 �12 �,�007%[� 1�. (!Y2 (%R1-4�aysE�*9 3` �!y1-Z. Many (5. e�gtaki/ ~io�Lbef! ��t��M� � interval 1���eu&� .��152�4AI\O AYw�� �M�6�;, ��k b�a~irty-e!� ( 5 . 1!�U�had � { ( 29* [" ]�9"U g M!.{ ,half ( 441 ,a�M@_e� a�� jwhe 261!��2���2-a� 5 . In�R , 47�f6A�528p��86�� -ph� �Bg :G sI$this group�� >� 5%�A&.��Q379�%�IK �A� resultA�1%Minsuffic����Q2�9!�4 . 35K�; 3)d k6a�}�.��A�s3y� % PCR-e (q32I�����0"9 ( 4:)���03ErA�"d almo� xclu�lL:� -G( 9! E�Ir38iof6u�4 Ain&��Ia^e*S Os1/(&)5� ^� � ( Fig ��a highX16 . 7%�ow . 4% �in Janu!� �Ca >�Zx�V �� year �od�2�( { 04 [5% CIJ 8 , AD24.s9!3!aI�er�f:�to Octo�n)'"/"to AprilI � -_�E)ofI9�A���C�� bear��a$ !�� . AsA�wT ��how�,n�:�%�i7w��) B9by�,� , educɕ,� ߡ�o��"Sa�� �( 27 . 8��%&� �V~�so+f3!Bc�2 Z)x� fa� imalA�8ig , cow , goat�ors�G��� 0A 29 .��>G�dj well!river wa��. R .�.�k� drinNLŚ A�ly+oci�� !:)[A< bothBa�R~ [tE�^est ris@2S( O� . 9 [95% f�"�(a�)e�r�Z9.�� Raa�y i��V�~4�[i�[�� �j6����rIG3nGE�>�;5.�a��0�as�@fac�. NotablK!�F�< )�edByten��o�old� m�ho;� Yr� age 2��[� 1!= 5]A�.&G �6�r$ ���6��>�!�e� comm:!+sJ��dV�( 5�08% %�G7% .����62307��5.77��Simil,Vta4rNi<su�w�Q25in�( 6A%7�2 �.�2p4�,1%. 1�y2.�006F�N #�3F�   �� "@ W ��� 6� �n�!�M!�22$I�5^aI|)�B������mt l�7a�4�h6B 32t4I, j�or muscla&i�e�4EZe�62<1 $��3��42%(2b)6oliguri�1�. �"6@� .>�.�*?  a pe3iE!as [�o�6�0�alow�hite bl4c U�9509 1180�#�/CAplatelet��$:230$%,27!:�!�l�$�4lymphadenopath~�9�L2�2���pr�"�(�P4A�2C%y�.�B��l����8!hpaRn modey%c)a teri' term���t�&i ��5a%t�6*U"w� Z�� M�g(�#>�)L !13M � 77�a�73.1�-6�1 q&pot~! �H� *( p≤!�1�2w(%0&�> in6.�evalu� �<f ,-9w�JR� "^ ^ CIe�A�JF ����z(?25PA�� 2M�u BORo42F�22�0!�� indep� � n % altern�fi:%1�A�ed&q L or T 2�Z�"� NA� V&6� ��%br:>`R�-\5�\. R.�+�cwa�"!swimm� in�sh-%�e�n�wh�dju�A�>� f�orv_q�:��*FT��@ c�&=p�:��abfB�6��-iu)2 (.h��:�-�6PJ0AM�j�OR�30U �� 09 , 99\�K�ɾ5Z)x�� marga^ly�'- 8/( AIC 29�DtC!S:�,a�A[� P8P~ ,� Physi�$y��su� � !#!:i."_#7correcLitl%�. C�ian�+:Oi�/ ly 3 of 3Q^ �jSa* whom�-]al et�.*�%!givaenz�!� t;$�$n �16�F��,t"d - 6�% ( se#ivw E��A9��j7G!  #/900%09*6�09�'38��2Q, ���>�fo!)bacterj !�c�w 2��!�8(5_0'eA A�ed"�syndrom�, leptn*r`'(8, “vi�-� �ed”!t/!� �emk �Of3e ,#A'7TQ p j()re�K!$i$�( �1 ng d AWs.�(�%1]U��p 2~ . We sougI-�tif. char){z�%E�5�a a"� -d"c�2of� w2!#� 2�>l�n unders�2�e:/reg5of*-�!pro!���.� .Z+:s� #4ible cr�%\(-/u�*E.�)%en�&y a��e0 s� ZD to rigoroz'N �%-�Md5Us uQ)5�[ logy%d�)WmJUby�) ;"reha��%1L6� �b!�Q/&�*to fuA?22:�.#hyp�)tO4�S+�(B�$demographi� 6Wf� rB m�A!E)d"�)) ourqY,UR ;m�a2��as%z�_ag�$$onsE�8 1%�8/�)aZ)�:�e�%I�J��,�� ssay��. o�(Al, ���M�S�. A lim�5io�y �atJ*6`r"s1nd=666. D�.ise.i& >�A��&w6 knV\ circ�4nga��'�{2�V86�:'6es4�ye �� area�4!A mic%f2�6�+is immun�/oI%ede Z&U6aH�rY6}7�+�America,3��8,n.��!w�RK!51�(�4,aofo8-r!�V92��N�wb�kcA%|9�7yiK(r�!K:3�&�9i&9��A�00 �6!�20w+[1�9-�vAH) �AD>6�0>6 fnt�(�$ livestock-�"�6�-us tap��e:9,*  bath!�in&����8�".AGt�9a�<����0�/n��!Eperi-��di%e�A?Av�,pan�9 c at"{)in&6� $widespread�^�1o$it:[2A�H"�recog���him`*�of1�i�+m��)�a{seXz!C[1��. SY A|q sd;�#-._;at W(schools may�l�9[2�2�:�1�:acc�to!����5�6!�i@5 I(storage jar�&co�t�nk�"";im�,d�]1.t bree� (1}2!Ove� [2��mos�9p"�9 ��r�&,�higd!s!H)stjI&)~[�!�&!h $n agricult9settle� !�hBrazilian Amazonia linked lb m�!Br�;��-- 6|1O-PeruvY , Ae0>$aegypti ge"2M� appe!r�7din�:h(.EE�aA networ33�:--��wQ([26A�A=�\id�by)p / �&A� ���5s��1�s)E� %kOunil6�:onE�q� expl��"5.�B1z`2� ax �&#(�Q.W�R3e6DA�%bm!�*)�e?�x.3> A�t6�#�g%0I�rem! suscept� to sympto� c"�%�B�'*~ (���:!�=cF2:� * � t :O2a �1�� �B�newq>Ds�.!in N �,%F*�# will���V��I�(�N>2,��!we O�?�p),bj 92� �D a��wч2It� Harr�?et �=R e ca�> of59.� > 13 mu=on ) [27a��(�F�a6`�z�"ageE%cKo a�5:K��E�?-1.!9iH2%�]7->A�c�0agu�<� "79 �*� �al��y 75%�A!Dr�to �� ge#-b� -E���C��-ag�>hi6C, "�t�And6�(UR*�9( s [wAD39%!�>L.%8e�M�16@.U35Q�#�c9@�in  Jun]�A��.�j!�2n�F/!N�9 ?:b&A�F ��Y?� ���jl8r cZj`m!�B�G+UBA?un�SI�jW� �B��m, t��ra26A�n��-�( 73� P������ab _l �,, hepatomega9%ja!�c# lethargf n�?(rombocytope�%�hem9�8 orA;1isa�sis� 7 �CN war�3)��n-o V � b"Y.�!"F� elseM/4 & .e%�y(Puerto RicoK� �*Y8a � X�4rrhagic manife�G( T7g .>etechiaU7]!�iratoryY�UN9:P.�*�!C-#influenz8� :G [2.]� , eUZ12-6�1��*q�l�� +caa�*7D-J�0-a.!+1 Y�) � �.U�.f..'��+ .�6���(�14%)Sly�G"(.��.=�>�!&� nd s&� soua�(n Sri Lanka� �A��*��Qe>��+2m Js�s��� &�)a�A"�=obser�C Xcountry4@lG�Fk�Col�%�In �0Cambodia , un� &?�]`  majori��>�"udeath�UF,)�del� !��8 �And��-seek� 1f9 to�burdenX. Our&F CET�� �e�JW�.rt'�)� �(�r IE  "k$da=A�]i\ cognmn(5� �ingEW�H zoon�5*K be( �-�it�". F�,�a���5!@develop�-.���is gen37y� avail/0, e���9s)��IisE�l�� e neDor rapiq�Mate(B -of-�y�[2�-) �A�- � qu�0� �%�-p) unneO2?microbCI=�[doe�qliw�|�p&�%-8�]�("�)e)�&t�wey�h �( 3-36�<�m �;���01�method;*�as�htA)e&�A�g .c&- a�sv5� PCR&�4B)sp6w�DoCdo�quH�Ja�neutra"lF( Bq?*zmiscl�Of?:of�-w6L"�Nas -��+heore�Aly96��st�M�h$St . Louis6�M�Mesqrm�JdA�Ni�O, �bi4JM !i� rvoi?L"�flywa��g� ro�gA��g�D�3weA�d�fEPD]Rv"SC%�pl�|! �lud� atV~-_���un +!W< e3�SLto"�&%5 falln�o�1E!)m�WGA�a$� ert.c m"�9�B��b%�&�_6y! ]�askI q�F��place;M �*)��C�day"G�v�f�� � �3Ik �as s9K�9[ 4 they .�JaostrengNa5ur-XS(de&:��]+��s� World?-�R Orga"@��[�=�O�B���H@f"�?(9�Eto gold-&`B"�H!��Mss��tcome�p&���c�#, R6W� . A^�n�P��kSb�@�$ �MF3�K) �����= 4a�minimv� 6s*Q �4 O"��=Nh� D  catchE����f� �HNPN>M/ful�Kn"aU� die �?13�7I gc��-HL�� outlv��G )|� jWA frepJ k@ore.�e .-��-lF�22���:f) A�4r!� ?�O,A_�%�s5 &f�uV�-��!�IM-��*ofaer.� t�sU�iYW rike(�'..2�; e�"u �. fcm� B �V�*���[PC. G4(�.'s2�A<��VYenviron��, unfriendl6'�Z�in�@O %6<.!n"�'au'(TTdem?�novelE �'�R� th��19aRi�ce��inevit"[�6K ^'U ontexeGit-�)E+�W� �z��e! n�[al�T5 bm�d*Cemselvz-4��AAq"z  cyclc$r]! :�begins�n3�s)uH]l{PJ2 ) hk�eggqJ! ��� {vbA\I�[%{�xguir by exuiYKT, inva��by pier�hO �T @ce�@��3�ahaͥsty�?. A�[�5ngK �!�!�&^9�c �/rs�g�x. vasy cyl�9!Tn d>���j%��>0�� coenocy� gi& ��Tic6�^PaB6Hum�_�h bl�Vd 9�be�J obil��!m� metabo�`A<tro^2A!NY+���ths�e �nuta�t&�+res� /9.��a�� �4eR�  , ice���eu[dow[^�or %��}A[>R�*$A cocktail� secr�Ve y���G ��{synthd4��Y-sex" �f�me�]ism� W���!<>�sg��_ p 7%�\�vY�- � o"ZU�7 favou�A�!>�jnQ4A�WZ>N!�to ad�0e��wt@[:,a��V^��ft)�a�!num�OofV.$��%�xK[1q Nume�76� =E5�ns crob���zper� ��j/.be�r or M{viaJ|p ar� � or �RR��:��4DvIQs�0�[n� �y3�Qn arrUdf�C�am�!� �j{ a�bur $alc�uaz�'5oxygen��c�( ROSP'��-wallnforcee�,:�mitam.�a m-d�B� z� !N MAPK� d CD �'nd hne�grasAXjh�_cri�-e�k�Di$ Toge� �Asw1&��A��Xnr[�WQQ’�  .gseQtyp�R evolir�bTW__�'��V �Wb "� "��3 life+ [ b. P� E�e��I8plasma membraneJI.!wRLKA�� M� "pr%� #��b. B�P6!�Ri�(an extraA1ulaN>> r do�/( ECD <ligD}�,e��7) B�.� RLKS�a c�)�icMV1v � ��n �reRG ( LRR ) -&, lysj moti�X LysMc5Rly�@CR]I7a3. �!UWA%x�OesiO�;"� 5�R�H R!/�n ( LeCRJ. N� the�,��5 a���!]y͜ŇECdoųac�/�>3ar�BA��GM�lex���R%xYwIo�aee�!U�p BRASSINOSTEROID INSENSITIVE-�QBRI�?H-ASSOCIATED KINASE AK�?�e�Mb�- �w- � LRR-� aiEF�to�"bly ��[1a �6Gat/.2>�� N�A_%E�[  genV&� , so-m( amag��D͡%�!�rel0u�af Ka‘/i�7ack�-"�e��;��1f�D*KI��&�d` �-E�.vj��v*'p�qA�to"]-�ed%����A�� ��  , no!�)=�a�aNn� ( NAMPS��o��+[1\,& 9��Dnt �"�8s �B �e� �sF����sufFeudsi�1!4�! orth�2ofI�]o8c(olanum lycohicum , SMY$( SlSERK3AA] B.� K.7� s�il� i O�1 sQ@:c�6 e= &<a�$-p@ ? ���$�e:p�}B�~*���Hp��~ Thi autho �X��al!�-��rom��*� ak�`<.*��-�%5alKN �< �;Bg[Y;Y�N I�t�6��/*ab&�)/q��7�y�Zs�asiJ i"�(�cer�j} ca6F�s#��^�-1��h>�,!un���UE�m�X,rc)�6����dsO<�I� aris o!� , Efa�orV�E��&� V>�#�1�>Od/*� �2� ce8gR-B� �1E�%1d�$)�ir�с3a��i6�inG?igE[X=&dY��a�>:* rostochie�3e�aZ gus Clado<� fulv�h�h0ng�y�(� � a$!`67X RCR3� ven�Jll�s2E !GG"�6��=eg$%�\w�'e!ۅL9��Av tY�� *�8r�A�he�!�!����"} &�G  . To rev&9inEr ex�vQ:�a_�at)��w��A~b$,, GeneChip a�Qis��2 E�SAj�� seg�A�a�ux �i. 5 cmsa�A� �% �^t�"�mig s(�6l�Qnm � �m�{���Pcu ޵}� �!! ����v&���H5��yRNA% b !1,� elR �!a�"�J ybri�s �!�5[. ATH1'@H( Affymetrix UK LtdN�.(Ay-^r��anLL, yVp��1�:Ae!?g-�im{Vy�/�zgencSub]*!V5���K�&�R)�KOE10 J%G""#M�(ed ( FDR < �O 5; F�uI�X<u �ethe ?B139 [up7 �1w�97!v�!own! ( S1�~�To�l!3 #m�!�b�N�ro\(5uG ar��@ ��I�V%r�3oq}�) u=A�onbl!u ont# y41i�)Vzo�sg�qly2M ;ca�H%%�p"� ly�Zvw*�-!�)�.j d* E�Usystem��k as�!o stimu�o,P5i/n���eA�, S1 TK!�Y,*G0� �sa*�362 ��"e@�,� asmo� ciA�JA�Uethylene8T sali�4:i!rk�KS 31 al" nbio��4}B�h�e[v %��&�$by qRT-�%3DI��� ,*� l 5�91�&: JA/ETr�|���&� ?%�pj N,m�� SA-�8ed ~P*upronoun� B7 a sl{5�xa!]b.J( PAL�a�few!=z �( NPR�6NPR�S� %X"v8 ( S2�A\ai�� look�+A�.�ic)��,ac�����4�^q%�#of �]��T1 bB��� �"I�1A_[�_gA78.�e �MNvPTB��J�,*�5it%7unPwh�E��!Z�C!2��c��l"��"U l Bxk!.wo.-(Rh(��i sX& �erif&v�Bwe2�a!  scre|�MM olvg~meaF{\of���<� &hallmark��ev!�%$ purp��?% ncub� @pre*ve'(2�!{! , Hs;2*"in�a2/Mi/�3Au�P�"T2 � @ see M8dea�= �<%�,=�^-�d"�U�1��du52dap��� a!��81[iWFlg22�W!{r�,r�6s"�)nVwA�r�Ji�&��. T��wf eU�=hi\� 5�"����'I�� !�(#t$B_!4.��ul�@� K���;E�V��O%#�04074A�h. � to2�7�#I�2812 9*��V^ .[ )"�� N�" m�?Y�:n2��]���� >o�,�@n � ing-D e�ͥA���y0Up�  ur��_c9�U . S�&R}�7�/-%���a NIMP (�6d~� �&:,} On�dy!�addx%�-�Ije/`A|to dil5:!5.�I�2OE� �ϊ� �T 7aF�=%5�6Oa�!�, ��9�w�6AI��ma@�80 u�m Olso s6p�[k�ic� H"!;�8 ���!2d`!R � 2�/l o�wl$ $ +n 7la��:SI0" - �)�cr�. N� J�B�F���6i��&"�!�.A*6��I f�Qi��B=B��{M�.bEq Bfo!�cf� �0T 3n'g�xin=���5�2B�-2t. RegardyM$�'> orig�]f�2or% �B 1��6.��8;فur� By �Q�ic�%� I�at�>�� �gA]]�U� ��%y>�yYY�#}2@-�1 .fSIlI M."�V�H!�6K'c,Z�( F�&�9r' a�W*A��-�E )"�= !bB� ,��A��*��"=of�7.S seedp�� M:�*s���x gro�$inhibie �G"�!Z&�% %�9e�F@i��g�ziox\c� �! �m�F��4tak�`&E4a}@%� }. I�!,�%��*Uapu�o�^�IvA�v1�N�  �[28VH#WW�=dF���E�G)��=i*8:�rS �.� 7JQ*��!�a wsz�Uy~�H�m 1F , B��.SX�xsug&U�yq� �4&�6-@�2%�is/�0 ���NF�0&�0A�!�e Bb4F��k6)����(��e>�-day-cV7:� �s�!p : dd�l�hE=\=!�..JE�1�%� non-e��O!�5_y�����rAG�ly2�"|IX"�o a&o�.vbovAS�?w �3B\&at �52��,��� ,�422 .N��098 >��% ; S3.�� rQ!�Ձ^��e:%�I��go_22i�3Z@� ca��%A"�CA�.�A2�t�c horm�Da�-)2��.nE��= o=�u�!I5� _:�e�Kh"6a;�F�ЉI�6�Mo"�?��"a��W!!;6�As�8er�bc\��a�de�� ig 2eam��b�iY'*1JA�er fN very�o��at� 4 �x 1  ��� Inte�./&,:�camalex�mB^0( PAD3/CYP71BH% A1�1��# �i�Y�"d� 8'�(s� 5 M��V0� �T!H?fu'�=O�e�N�z��a�or�linp�:GU+�Eon]�s):F�a.��G�f"� V],^���~i�2�0MA���e=�v.�-C�h �&�A�D-a���by�!'!�of9pI�C-!��e�J��%~��aX�q~Gde�6m"- s.�7>�("�}�B,R_�!q}(�&��a �� e�" �t1Й(6j JAI"v\a�e)m5� ��f)�c%.&�:|�7 � .� AW'@6<7L (�EM^F%1S4�E�Nso�+oth9B��6�a�in�?!O)�a �;� ref +�Kc)>ai6s*#!��Ken�Uo&�� ";K� ph%ma"o), etcAnebaA�of?�])<.:�>>�'�asC_� pre� y@G�3s�]z*&)b oqEh�*;To*� �*�+sN8"���'oc�3nndI"F�`F&�2Bn�1 .�A�Qta�a�Cl�lT=u% PseudoB s sy��ae pv . "�(n�W�6un������&�2�A�.1)�ٝ� ��� Col-���G3��3B� D��.% .�U�Iof9P����j �lg.�U�m�3CE�3IasSi2by]]�s |$&�pu} ve"i �V �SY�& Q��)�)� (,ro2}@�i d�P se KAs.�As&%a'��z.�h1 02�_�"b&j�'� "� ��eria���c:�!b ��be�5��!�jsi#Jh_5r�N�of��Jpo�QY+�����  a'*t�#61~!�N�%jLt]$photo�(unt�["b+l��!amh=�qu T"�)r��:� �(JF.���Y��$&�iV2 or h�AU�qH�!<H9�ɗ4Y �+����R �q�����k/ 4/ +���OaP14*�B� "M'A� P�fIP&]4 A�}+�+[c`�4CEC�Cn�wO2@9k5�� r�W�S"�� ˑoo:�+�xR�m�,"�,�b)A2�c:?9�f���N5w�y��C+-�Adou-S-�-5 bkk1W2KK1 K-(closest hom%A7%�) [ L�4 L�',E��Gegs6��sR��=a>ed D?��?#op1��We 2s+�c��+q�P: �&�  .[Y !:� u��"�*yM��B})�1,M^�r��6v"4 j� �mE��`E8.PWit�!�"�B593!�me.vO bhtwo.@ ex��a�5�% enco��+(�IP11m�K07�5!X1)6-RK� 2FP�CS4(S5&- O�fx cand� t��" A�zyg�*�I2?FT-DNA5��p�� �(�f��Ѫta famil �*b'�N co Lh�P���9�e�6N"bB�Q�w- #M�: e�7B6�".z_p"A(���)I��Re6 oyv"WFD( NEMATODE-INDUCED� 1; $$, At1g7436�~w ����f!�&A�A|&D i�uL�>f0 50 A�@ GR.�I�.�&l �M�`VX e��Nz �OS a�o%�sam��asMU-��5�R9* #soF> Bixal.2knock-|P+�!c���%�N-�!Z��i�P��byJ�=72j- �J-L!]:"x%��1I�ki��a���$<��6��3�t)�i� �KF�"f�"c�r �)\�<�n�#om�!,f6 �����Y�39�.f� �>I to"�^?$t�!� M�ub y X�H syX[ �serine/ on6�@��W106 a� �0�7d�<gq�&�'2 1"�8 kDa6 !Cs0 ������]�an��"$OD )�h^�*�B[B��22 ,�em cop of\� �!�Mrru�+X 76-�is?I >7xj LRR17E� �jT�2 - �"�i��&b�i�=AA��!�Ce!�clP�;!,p�F(of Cx25Cx16� �iQ���%�7�ln`CiM-N6�[D2:�y��sN.�)<� i��fla8we3R �C-!%�46 _�>Be_4�c�L�7N�8[3$OPj���ga&A>�!/�um�H!��Vm?�:":9�n� � logsE:6,�<|�� &��of flowabg �u�To  "�ins�2v t��cWfNTe ��T�*sub�6 �& by�f�w_scopyI#S�!��ng 35S::f -GFP!s!� Oi �Dicotianna benthami�R���8&!FP��alQ$>fD( P�EI6� aPPM 2�uR�v(co�: �E[PMX(sb0:� �-�:f %vcoxe|BLAST sewPPECDE�i�/9�q%Y"=�#�nd�BH0%l all ��E�� bel M���5I�R��BrMhcaceae+�A"_�&:nB ��f oF wid��--�c1Em�2��dA2 yled�5B? as monoco�u?.MOA�.PT��r| !e"S �i�:�I� bSmd�=a�O: �!P"*%�"2E�&j 6e>��,��a��e�$Beta vulgaIw)��tobacc�CZs�*9,Q,>Prs ( Oryza s)��Z�֡ku�)%�!-�6B6�! jQ.�na1nd A�t+in N .2@�lB&:C�"�si�V���2*9�Z ���]:$!�~��' �s!H"k/�I>"� .��"a.z3fOD.�<�$|�^Qo�c+"cG.�(���/�A�eFPqZws���2�?5L���# Hci�i�{il�bls�=�v)ve�+�j-1[�8iā�9; t�.0% qA �b�!O%Y Botryq�H\}@PhILh�E���td n�mn-�5R�stˠ&P 5QA�.� Also �Ae� �1�F.�n�� tiss���1 disp�q�$"�C�r:B�Jder�,�ipW�s�� [3���8o# �ru;a��%�0-�#-FtoH sup� s �^��C�`Ar�CeTi�vj��@el�� A?. I>J# >� a3m�4iFl_pO�[ip�#FsXi],.xZ�f�"WJ.]"� *�C thuG&� �Bjmso.GeFa* G� A!CyA9.b�4a!�")h!��?&��� VEga��Q"+F�&w$"8-��p de� .DF�!�[2T��%:�F; � ��ESghAD� -&�t��6ߝ%i3ˁ�7(2�Ͷmo�Q�mE�"%`�)� �e!WB���yAeE�&�a#_��1�!�e{� 8 [! & &�Ɂs{���of�L"�UJA��&�?�iBl� )��=:�D�aq��#bio"H]�>sE�QPlev��^of�:�F��s&N$v91 �&b@%^g�toP� "C6�0:SA.��4u�'an�+"T��^�.>GQa�:2��MS�f��)��@In�'uW+Q�fWdef۩2"a�/SA-=�!�b.�+�,�#b�v.|![ɼY�s�rMChe&a9!�o"@ JA.�":� J�iŹly�RaLvof( $G2�A��6�,{�= ��e<p&�n�:�.��$A�%�:G��?6�*�F=4B!�^S�2�!�isŸ�3H"�w�&�!��"d:m"N�a��Cv���SAAh1� � yNF����$ 4]f_ileL/cG*d�@�@aV�croK{�R!;d�h bivo�Yin|����OQ�-�.>iJviE+"r.�� leafAh�(� � Mdl�x �i!�" ,��G�0�n5�1/��p[3�5It�%{J:{�n h� �-1)[A3�:uEF�3| �. �� [A�<n�dQ  ke�`yaJAqo� {)U�6�8s [40�NU�v���CP�6t��G�=A�l E���=a�m��fs"Yd W�ZV`a+N��&"� "N!*cofie�2�_&\_"��-�����-cFE l��c�w�f""��n�07 a�!h�3J,�,�:�F9_���v���^W acquɽ!E!".�`R^�� dVw,�� !�&@���)*� �kE*�x6 �st&Gy�M[�8��1 *, B!(&|���Cg�b&� .�s.�Mgen2f!!jOe�!���b �� ZX t 0.4 ��9 t�1d��c��:"i, olq��A�"p.WE�-P�E��F�  */�s/�� i�L�d�� J� 2�mM�] ��">�A���(diNwo*m1 "�� q!;/6� : �! �� );*�l&�Ʒ&�Bs*�CV�TUf�"�|���Tp<Y l�B�"�*-aR�E���zE8e�E,Y �2T#� �?1�%��B� �A{OSW}!��pityU�A�.�-2�hi� tod�_.�,� nJal ���-�6S.(oi�h� plau]dELkn��p�6�t�|E�isa>?( eG�0,�'�������O�_l��s2� � 2�9��;[�GUQ"�!��a�&9aon"O%�&f"� az�Nu, typee%$ A�m,��7]�3-!.,# ;�q�qFy�2|a:x(�p�BA.kq~Es�`�/GgY�ctiRl���EK2*A.�u�f�%�j Iq�=�J3�`fl!�C�Yu��V'�> idea q�A�)1apseY�(&�l��}H70/Z1��F#6�?�A^r|^1%8 ]�us�IiG2� �5A�6 �m�A2Jb��� ��TI}.�sv�G!o�'C R&_7�tG�=$>8E�a��ma�ziE���!Eawɮd�!�m�"iv�F�ER�Ei%��B�v��B-� \2a"9*(�=)eJ=.�d�Ndirect�C7"�2�r�p�N6*�e�'svJ�'M2��!!� �% �E!�.D g -a&0lӀ*# � ���&�23 lex��!� v�U-=a*�K#v��*�>�e*�.��Yx�$� � �GR % &� 6�j� ŠY��>�6.*m(�a% 2"R,I�d&k  VD>� T%"� 2�bU0�S2��=a$[FAB: nnd�!Ma�E*�^ M&�>1�eh� )�*A�*'"2'�$<', �(�n-i�o9�N� �ao5G�)�E"-s!,jb�:[f=}o.�RbP)�k9e�!%!bre#see�f�fo�;��v&��s�^�!�2"P %��Ee.]�=�*Ail8la�m"�Ne�H)AP�� gv]�A9�!��<&zA��#�'�1ie�c�%"�j*�-=> }sub�QD?��t>sA��*�%m��| r�'s �`Z�=ig_X�% �灒�f� �/!#�/�di�nVoutpu "� ly5�ɉ#e�� n$ ���9@m=ue�8'AK1~�c�Z�:XRK�&�B6 &�d�9lu � :.9A1A�*�(H��5��" ���?BP2���Rp�pAp� �4KA!Ť�,*dm�p�d='U:R�bA4M&E�wA% !"&=zg!E��!I�p&���*qvlyaqwn�)@�un��o�D�y! ��"[z2C �)�&���3 n�il�P7"�q�!c �iU;:�<)nse *v%"\Da� �E�� �a➩3��-&�0�+��j*Mrnd a2.b*^T W"&@A�*>b��.0a�!F*,}c� al �.�� �r2� \ QK��&��y@�%v���}5o��mzs"� ��mi�$��A��W�L�V"�:��A&�2�#�~Y|| work=4f�4�A�pur�!�F2� /4�82�%u�r"� e�an)b���h��& ��*��Q�A�I:*}" crop)O�l݅2�:��c!�} hel�taA�PA�B�� ��J���oI~"˄}�!�j@�aHengine��'u0���%�ѕ s . .%t��*# �;�Il�Ej0��sodCf�4chlor@!J_� PBc�)@��da'h�s�her pi�'6�f1�h, cruhd)��S ���d�5% NaOClӻ&age�i� spen� %:��0g~a�3X.sJ��)M%�= eo� ��. E ����/i��25 μm Tm���w�, \D�D10��-�ut �Ha%��ab0/ [�Mi�Vne) . �.J15��NyB�}��3�U/ mLJ 2mL b� amyce ulph~&(��jmg/-��EMx/30J �s6�sto �a� arks�. F�ZlvVtcr�aw%7ro!$a�" b!9�^%:in��5Ұw/v )�� �-�ciJ&ej��� +amp O(�$y2o9� nCvn�Qhexid�4=�j6e�v%�lib�"t&e(1�autoclap ��ib�eh*��F��67,�iNse�l��qz� th�dg s1� 93%08� e�b�o M�l6� Wfs-(��"�!tI����?-a�m%�da<N�Hs�# 'Ck����1�Dun[�>�����N�VU3a Nucle��n#WT,�ki>1M��rey-NageW�D�!�nrw�) K1r�� manuzur,��3-�#)qu,�A�,IJ�m� !� O�g�ut Bioz�iTechno��xJSanta�pr"�CA"��pa Nanod� (� rmo�� S8�} , W�_a�lMA� X�39 cND&M*�"e�E�NuGEN� Ape���Amp S�V( $[van Carlo�.�ccfg s’>guEncWHB�/n ModulerO�E7/draeH �. H#o ,�haE!Hscay|Ey�B�*2o30 "TkEx"s$��is)�CM���>,f�AWt chips �h �eeY�1"�uAS�!q%�K �7a�S"� ��"�vb&�nrep"N�Aɤ6E��Jc�=Con��v1 softw�i4MAS5 al�Xth �A�q�o300�2n� s)&c�F��s�� !��� main� �VU� tard��rf �w? z�PiS�mM Znr ���� s ( ��!gchamb�$)A���Q ϡ�R-2!�!>H� chec���a%���AaW;F�h>4nW�, XEN o)a falc)ub�&!&�eK�i�3�m�lA mix�$�5�in-!z spin!wat ��rp0�E�superna)?1&x� ��!1 m>�05% Hg!z3LPa�N��@ z/pt{N�A�Ytf��j��nd9dF!���Y�q��:��� !C5�lef� I!� mD*oZ�P�-7�t �-* �,>1�>�^�Ar�sOE� stepw�L���.:�4O�)Qml� 6�E�2G2! dd _�"�TaC+�� empew)��A�i�m shakA�-Q,�Q -)�Q�!�b��6 rifuc:2!w+ ���6�Qto�1ew Epp,!rf eK!Sklab�u2m�&�5ep%#"��i%*ْ� 1\2 Tw���`?.�X "�.~�N&�H�8x/rA`d�b�I��2��!��K�`Ɂ. WholD���16�!, froz~n l��Itrz"!,*�xF s��lyIMA%5 :@ TE�N�s 59jNm ,� l���� h�+ PSˈ�r�.RgAVaL��!:��]�L��9s$�amt�7�L����� . CD�F. CEL f���loa�,�au(Windows GUIA�gram RMA� ttp://rma:"�;$mbolstad .I/ F� back�Ond*1� �7x�8(| l<�!�su0�Oi�om��v����(����robust�!� a99��RM�@ ��val�9%��r!�Elogb �%�'��!=܇ro��� nnot�B��own!e��=� mappN:1t+�Izeq"s�(to AGI locialm ARBC9�www . a}i. org)/ll ge#1��m� "L{ f�d"��b&�_( <� ; P �y� �ipr��[�no�xrmy@- Fal݉ iscoi�� at 5`�To!�HQA�]�=�� ,�Qup-E+�,6�� ��randomlr� �a��4el%2N |s�I�;5���?���Er}�Nt �B�XaG"� �G"��B� ~���n �High Cap�h+RmE se T"w7a KrLʊt.�ca2no��36881A�,Ʀ0 �F\l��;t6�AE-�a�%m"�!� Step��P)zR�� TimeÞ"��ZBi*n<U{y. Each!�p �y~�g/ of F<SYBR GX qOyMa� MixɮurF��S, g��syl[�6x�(boxy-x-rhod� �Inv��A2� M , lL�fo E�0 63!�� �(�μdEʲ���D�()�?(Q inQ 2�e�on �. S͘e,5�� ��E%+ry�To�vœJK�dZ!p�, 18S1�E��?8(?.�A���^� .�h*�[4�by3-h2F�h� rgetzY�Da,H�8Sn��%� )x*�El��S6%V.�����M��V�$ $.,RU$ed��T�T:�%�P0, SAIL_859_H0.�&,, GK-179E06;9=T 9�%9LK129312�C%o<��� r<nтockT ��a�!�VL�E�u� s%<&�GXda&us��)#s��in=.Sus5�O+�a�t�!t ���B�|w`z}6� an*� Ah&�� ��9�1ocol ]B%!_length��AD rootMuv7 �� a�\%yR�Ǝ-����A|a�4 acid sequencee ECD�NILR1e3��,to blast agaa� all l!(͆D��sA�ngA=318 h��a� Ps kingdom . Represent��@��44��que spec��EO�gener��aY�alignA$ filA�4A Gblock funct�5Cref�>6�1La maximum-likelihood��is%��w��APHYML�� [44]�uD nonparametric app�m�]$ratio test_���branchE�ortay an altern)3to us��bA�trapp!vproceda�[45�!�1_V�search�8SWISS-MODEL tem��Dlibrary ( SMTL verń 2016-03-2�PDB��e�� 18 ))&BI=nd HHBlA�evolu!�]��ed match��Uc��s[46–48�I�/ b%?!��BRASSINOSTEROID INSENSITIVE 1 ( BRI1 ) �%�DBI0Ew.��i%�to view�men�al.�x0NCBI Cn3D [49�Cod�regA{of �W�Oifi��8out stop codon �Tgateway!'warA� d re!ze pmr�� give��S6 Data�eafra� x clon�(to pDONR207 pBP!�L( Invitrogen ) accor� to manufa%� r’c)�ion�N�Zr�Hant pENTRY vector ( /)�) ! the�d �-(i�!�destiA�onJonA�o� I& surfacq tigena� e� . I!l Hrect immunofluoresc��4assay , rabbit)�S .J� hom���A&%�.+5�sera gav!1 rongN}of%D.E��` "� e*.,Flat� � serum hav!e$previouslyM^E 8to synergisticaAjenhA�MsU8icidal activity�$praziquant� R9;bod�E�recogni��B� expoon.�-��)��Fve� by e�- of)9(]�& th"� he2~gpins: fructose-1 , 6 bisphosphE� ldol�eHSmFBPA ) , Sm22 . 6�� lkal��4-�maAde�geū !t1%��� foun�& bi �QPof 3-h!gY�ulakinduce)e aggA<�Fmx���1 sugg�h��e�pyaAe a rol�K%$�i� is s���j(a novel mod��!�oA�.�� � ���>% p-"� hypothe!�w�v�( d��>�lK cred��E2�( PZQ%�whereby��B unmasks5#5s�g�fnot norm�;m�to%�host durA�. A�� volv�  t!C\molecular mechanism coul�$ve potenti��a� tervonu�A^�mQ� !/�may!�� incr� AQ��� C-Q�$ icac�d b%s� e develop%2of� ist�D o re�Q* Desp�(extC v&�effortE��va!�E\ill%�a%�in��y!ntr�m[1�CoNns |�!|�:v�� only% availabl ���, namely^@becausE�� �in- �programs�almA'� decades [�3�N$suboptimal!%)�ofE�1� imma# :�Yvi!a7r�cern [�Thu!t!� � >c$herapeutic?�or �t�n ategy��is�!��>."�6> 9�e *c � become ne [5��!O��La�atM� cele� discover�new%�s�6�dQ2Wuse)�exng��oa�a*s �ha�had!CDir pharmacokinetic%\ oxic5a�pre-clid� evalua��−%zf�kn� 0as ‘Drug-Re ina� [7 , !*� x� e�6# $a hexa-decN�� ochoŧ10��eM e 1980A>d��as � xA� 1992E5topD }2Hof cutaneous metaste� of b�wt � [9�!�A�!_}a�mo\%!= �es&� ��mony-r�r* [1�12]%( unde��dee�$ Impavido � %��a ora:�viscel"x ��n sA�co��3–1R� �&��$by Eissa eE . [1�18] ,�ao!20 �,El-Moslemany#21] d.,�  �68o:�m�N� (2 /.(haematob�inq A�Udi� ��&7? .� Cv� Uexhibia�� dvan:���by clea�e�ř���vas��,�&�b �卒[4A�7Q���by which2Pexe����� is un��/$lthough itbelieAVWc��i�t on cc�sa�duc�sbiophyseWperturb�m,of lipid raf�n�terfe% �i� (a~bolR-r�!thE*allppathway��sub.W�Zo% 9apoptoA�[I�2–2�P��Y e�A�v0sphingomyelin!2��. �( ajmidryl�� ) [2e\Biosyn��.M �"� �mpeded!�. LS2� acts!�cYA�g�� 9Aq� de system��E"5�a tfbarrier!6  bo�%�w� e��Ev� ce7damage��.Nteg�follo &�w(.�qen"��qa�� ����, but no���yeteco a�toi� ly establi�E(� s�of��f � he}�-�.�D k , �V �Ytro� ].�,v�&to�W,t0a Puerto Rica�i� .�aNi.� wh�x�=r� ‘Y ’ hidde,.����5�uEZ6� ( IF��n�s link��E�Lp i . �(tandem massHtr0�m� *�of!�re-�din-�is5-�1�!�kR�A� alsoI]2u. E} M9 cryp� QJ�I>(brA�aNi�k!�C r*�al%�a�7–34�� an e� �7?�x b�  imaQ�factorA�.?respon� d�lt��?A)-�*ly!"� �y!e% c�12� �"� migratory�QV[35��# All�k�K labo 3an� �Ginclu7maintenſ"Lof2Ub��p���h�Jrandom-b� CD1} _ !�� $DBiomphalaria glabr{ snai�!���2�A� UK A� ciu[Pc"!Act 1986) perso7� projylicen�uthorit helŊ$MJD ( numb�(PIL 70/3255B(PPL 40/3024!�pX lyb Workq�^ed&� :j�e�� by N�ham UniSity� � WelfH�Eth�ReBodUc��d ��.�t-E%�w�iUK gover� regu�"/e I1 wsliAQ� of s��in4�t%�� ��bi�"��9ials ob�$ed�� o�  � .�� util���z��e*�#V�A7Eg�� an N��al>ZS�j�%.�=AlexandA�:�Facult�Medicc%�(s Committeefrotocol ZalM^ 0303186Eo:E pat�@�1960s!yDr . Sm�($s SR , NIMLondo*bG�aznonym�ais~ly kept �%�E!C��. Cerc�ei�!1�& &So"�,B�&| +a�"w9�[4�M�e�per"(!T��9200 �I8Q#R@[2/4�42.�% Y�P, �fsacgc�?s��ancdo�,pentobarbitownaesthed nd �6���thort=as= elsey [4�A cru�YGbO.��  ( wh�.��WH )�pa3 ɮ��!etepRMby Doenhm"��$^� wash� � ate-�ed�+�� ( PB�%4fIT`iA�-�$ ground-gl� !r%�z��rifugatA@0 x gE�1�)�*t�'m�$er?� sup^%� !7 coll� (, freeze-dr�#!�qd −8* . To!L!j2$>!r�-��ble=�5�bshferfe�!�M�&u*in%B,� 7 . ���$gravity-se��neF orm pelle�!��#s5*7A� equa.�)� � 42%c-deoxy�!mM �sT-#!6�ly agita�onF cker%�3 �s��ro:�a�%��5��0=�p+��z�W�$requiAá�, 2,�n���*d:ll� E0!�q�Vnt�':�-� he� Rad DCm - A�!(L��M (, Inc . , H�Rle� Califor#US�iVbova�s%!alb.��vrefer0O� � poly| � ^+"�d& _!�ti-SmI���a�. bm� �A�New Zeav*whM � B&K ��al*H 5 �B�#.m2��!6eac�+� x�)ly�0x 103ݑ, via%6earA�two wv%�rv� . T *(,  )c�|lQ �#, 3UZofS1ml blood�/rem� �gar ve� t}-:}�w�%��"�Qexsangu �(cardiac pun�'��#m?se� ��fi� bleed OpooA�stoa-at�2� untiFmH. A-�]+.dUr2"*EVw.(P-S��e r��W1&�bef [4�=%+f]Ūśsub.�){>���0!=ͼ�9*?36d� �"emuls#M!�:�Freund�compled CFa�!�in adjuB�� firs!d��I,!$ in��"a�$lyA�he-�-�I_%Aa�Q�ByA�%#�w�V!&��%��; cons�(0 uffis)}oMPA�n e�rophor� �2ia�� R�,I�t8)A�� siF#}&= tn') %}�#nee�. *U&�J mono!����N�$( SmAP>by)Iiz��y�):�E�r&�4of : oprecipit!�rcs!�=Akenzym&5cR�6eP2�!�ge�m-eoAɶ Y�[4547A�u��&Ax2����ɉN. � 1i&A�� Fy��aq-u*#�� `,�C$ SA@a�qna��unɛ8�M� a)iroly�IF�N"�6� ��$�ӵF�'K�LA�5�$!�\o�1990-H 2� , �Va ban%VplaY �: of��in Eur4,[4P In�f�3l��!edZ��� males/cou�5)&�by�fu� Imn�"[0"yrin�in�-12�Fo45% fe� calf!�u�FC� , 2 mM L-c'�+J�6�$streptomyca nd�6IU�pc)i�� -0' 24-M�ure:{9 ml/#2�j2�y&E "�6in�CO2@7 or 2� �%%�g+4 bO adap!X%fB�  W8b� Mossallam*a�"W&+q9� ]'7p��� �?3& tripa9aca s: Group � �!^" R' a����� ( vehicle�?�q�>�9A�n =p) ;uv l��4PZQ#Z$.�. P s II%�IIIi�fur�%��21E456\"G(�!�%P)!�!O*�!2� L the�: �&F �8�1�9E�[38�".�:� 10a;04441��All1�%o��96M�..H%�$?nve�2�0 Olympus I�:�0 Model IX7�)4, Tokyo , Japaa��2T:azobs�)�0�)C0�ir b!l�, pai�,&�@!�mL '!UH&���QX-�!� both +i12�F-]�RMl]&;-by abs!� ny b� *)���*2U�of-f[4��3. Lethal6�Ee]3s'kT50%PiQ( LC5l2� h1u1 f�J2A�4)72�U%E^cal~+a�� �<)�of:�<aiv%*|s{&�$u poiJ; as g�d \(GraphPad Pr�#4&88 �0La Jolla—CA��.�?���ca�deathl�B��a:K��y*���1�, fix�N4%}!bal�.�Pd F���"at 4°C��oug�:z,�|A�5U3. F� �%��9� ]�� 1%V�( B%= �-Tw�"�T ) (�� v/v 20 + )�1�N�B�a� ��? = gT�}%��qх;!�su��in���p@/ (  ) F1RA���)��:Ѭ5/�-V�IA[&B$?-in�/ve- ( 56!�!�*�)s � :y v*4N m !; *�4A  . 6�.�;� �I9�1:5�T%�J�ksJ�q!��1�, "S5�2 sothiocya�8( FITC ) -conju�0goa� - �IgG�� (�4��E��@:l�E dtN��v5&88.F 2��B��%u�8vioFle��18y ( GMXL3201LED�$�|display!)r:�=p�5n� phot /pD��La GXCAM-FLUOMA-X cam�( GT Vi� �)%�GXCap- 7�SIi'' g" �rs_1� e se5(�B �� ^ ���]��0i at��aZ$� �f%�2� �� � 40/ ) :�8,�L: 2 ,6` a���d��tA>u|�6produ� g �-ha�!&�"U'R3�0��"f>�&6FP%�2 &� .�'48�h#. T�hof� m� fix��in������5A�%w.�"J�5 inɓ)�:t�2�fout %�N10�M , ( �:Njm���$��;��%�J�62WH3�dBeaA�# (Ɏ D�0receiva���aЖR�X. B`�, ����G .G!��?at �W,���8A�s)%��:)�:k1�w����d>1a�o'�0z'che�BG3�7y�7A��a}� �Er*�)oE=�7bo-8}a) ��M�e�{J�����m(6�FI>�elu��! "�8�,��*` �*n�+].ul��filDA�2�G�3d��@4 ����r%&��*hofo T 2>E�.{ 0We�Y%� low-&o;,J 1 M gl�pH :8^10 DIto%&d$�&r�=-)�!#-�,�8&�e04��&���neutral4)��1B0of 1M Tris-HCpH 8 .!�1Ds( �5q1m �*>!aA�u-1� z6�<� re�)up�4x I��E#%�6�\,���| to 5A star�0�% � AmicQC�& alAetn), 3�d/arH cut-� 'K llip-,, Corrigtwoh�8C#�), I�DndD a�Ho' froz�-t -."��J"�(A.PMlans%*j.A 6"�=eH!i�/dS2160r 8% SDS-PAGEp"2e&�"5�E5�16:lru�CE Bio-� Mini �an� .��#�1La�%�*�,�!Kp��� �$( q1;�%e3O:� pape�DNCu+p+ 50 V��  !b1%5 , 55]� �vi�Giz!q��w !D A�2�* 135% skimj kA TBST (-�25%2 )R Blot�% �ed x3R!� probw �i.��>!�.� ;in����=(R�#)�!R��.�se�-�K �y: hors�d�2�P�* ( HR!Ŋ�� S@+Q�&�1�r�cV�����A-�ņ&L��4-;Q1-naph�O�A�(t�2�2�k". �"�=�',�:k)e �%I��F��! -har�?ed"� �&1]I,9�N~2�es5%i�gg�2~\ab�. 500 n*$1rO"F,�E!�3m�E�n�&� 6*j[�reae�J�es)~�|5��('� tub$q��&N in0BSA P��r��,Q6�)� aqe� a^� � Q�=Nm*&�F:E.�?� � h21 2�:�t 2�8 E�6� �� �& arV*  .�-�,m�:{�� � T.�ok'�S��(20J{,���  "�%��:|�� ����4TE*� ~r.�妡�� &�7byZ y6�L . At�Jst"y�Em2S6 E%thK ��. A�150�:�L ^$�&� broa�%lS$6 . 2 cm l�H)�f�+ioz)r"� 2>� !�A4 !�%MqVR�. T�5�wQ��G�*b�E]Ow H�^be*I=&J"n#A�!e<esTtba�:in�-�") Dž�8 �"�G�'c���! e!aE� $ �.�elMm+��F�* SDSAtR�,[5�57w �� %�� &�*1[��x gQ "TV}3�: �2'+. S�1� �ed9'� ��<B*�� �� �� t�.�.�i�5"-U �A�Bi��*�!C j>� s�P�JU��Uconfir!7by!�� P.>. PvJ:n �M�J�(.[A�s�7�NyXb9:J| �%�h_Z.=aedyV�'�( DTTo carb)?�;hy�-5iodoace�"dB`di�I�Irypsi/ &�[2�I�:[a;.l%&pepti�FE�subz6�J�6zA<i-NpLA6a�[5�!no<�"o!�M&�Tpublic$b�NCBInp �8on�T40927�6e!A~ Masc� �Z,/ . 3 �\�atrixs�(c�8UK , http://www�.".�)2- �T�[5�5 �.B�Q ���.�� * �u�L:g !�[@ me-c�]^&+�i"�CB ��;&�)2?!;#�&�AUPZQB� Al�.E(����2� .{d\^�#)�v�qD@'appea0We)6nQWgAZ �D<� ��2�&( TJ"V*%�R*iGS"6�6P�64 i�!9�yny2alz stalS4" "��]!�e occa��0s�attac yLbottom>�� i).�.ck� male^�7L'reR7A��"ed�ZQ]�j!?dXŭ4�F"�#))�.ZP3musd!� D�0�c�,lo�mo�&#v�"��lp>�>90%-100� s 0&#Rin&_.�E_"�ic2d.GG~AalI rup��$( S1 Fig )�ob[%� "�2�%2�@ten�F.k�C_ Q�2�%r1� y� in 78�_CizB~ 8–"�"�Z%� �$�@ɡ.�Zk"x%�"�6vTh�>q�, how����BN$t a slower[�#�9� "� ́q;eW� n�>xah�]Z9>7%!<-E�9 *ZP ��#�B��D�M�$%knA.t!�4�55�,� le 2�a9�m�1�u�^0'a�7&c2��1toz�5t%� ,B�$4:.N l�A���. h) s"1�ie)&��"_ �#s�2�.�E �!J�V!��Z"as�mKI(O� ,�O� of �� Tmb.v2W�of��B��Pv%!�:�!��5�Uby :�!#Atx �������4(%v2iALiE & 2iG �"QPG���Qb� en"D-n�R�&�sam��"�qF � W�h��K2��mi_.��e*Ne?b�Kd UEE�#\9 , 4E���s�&2iB�*$ � aty9�.)) illu��,!�L'a:!|la�� %�.7%0^ �bll92�!� highe�2��teRmp6;�_��\h!Q`�EB[u.�E%J&�T,)e�I�=2>+.�1*�+2iJ%�C�� �� &�"s�aQ�I�� uZAM2]%�L��Cv�;��5v��"�*rti��ly��!�5#ed-��miE� wh�"R"W*�:MI�I�-�* 1�S�Jm\!�.T.N(Y�� "�")�=��2(��ml2*�"!Xŏ�E�a2pe$5��Q2�s 3iCA3iD4 4iDEq �$!�A�D&?�{ծ�k:7"�Xhav�eI�Ie�{i{ N5�|�}2/�Me��M��.:"s2oa#�6A� "qe*�E265\�/8��A� A#�"��Ea�)E!�")�e�ed�9l�M�5;!_�U7or=f.�&=$Fi%�A�3�>4 4iB>��?t�U�a�����ZM;bt!,h:. Nj JR:� Y�D!]G$-G� �b �v�S^!E�r�2A~'!�!�5��*#�"��N��9>��[KqYG�S/.S3 ��LaV*d�"7urs&���t�*E$&8redominabQ1S$a ~ 33 kDa��� � � � F�2!�Aq9�,, �)dI!{ at ~�e d))OVMs�_lvK�bd�=q- �mY�aIa�9��!��t ~37%X~12� 130 ��Tuch�_�RiG%���8. Our��LE�.]9��J>ure��'�1ns��!R&`siz�(6�;1G, ��!�(��=�hr{2�6�~2�E�an�!G[S4Ay]Qy9�-We��in�YMj�Q�E�=�:�,A !�!�ZDM%�/0_j��&L�`�R%��V�B(�s y|E�3�A�!g1K�WH.z0a3.Z*6�/%��I�6E&�.VR���a �&���[s ~mx%s {E!J^*�:_I�No�:�aj6���AW���%]1��B����N/�� *&�>�eΡ&% 4%��6^a�23�L2!Ρ�� ( pr3�a5 ��$��R&C!�r e2�a0>(s��`"�)U5�� ��)�uFYEF�L��.�-���;simila ��&Ba%e@on��"@ &�������.�f��S��-~�.#i Rc� stepX � I 4% �$��pr3)�%�%��E��U�in��I{%/�F�E�*�E% !� R��%�A��-�ii=S�S7�9�"�6�=�,�z37EzeEx�sub�@��FU.Gq�-WoutpumSwk�/M�56�R�����%PA�aMS�&� estu>�. "�d��d�D�5["�d!M.*R�d}@ML� h�g.�\�c�h�8 108531�� 12622y4693:���e3Na.�7%�0of 39963 da (FFA=$ Smp_04216�$gi: 1703249+���a���b]225]Y(KB P1420F[ 3557�+S%*Y� Y� 6305� NG4V7Z7 ,N35323084�\�}�_�AD&�T�M�{ �}ܩ6i�e���a}!possibi�: YyFm�]Sa�7��"� �1u�"�N� V2Jr�B!�$)Fc&�*� ��do�K�(>ol�e %� R.L+( � E�M�a:l�]�"Ku� lite�L��a �C�K(\~5 �[61 �2�<sti\6.�s 5F�&�.�b"�orj��:"�!��"i!Wto ��K�9>�$7-:Wa��� 6a6S"�y%B�< 8��\�5& IF&�# i]� �fB�u2���e 6iu� �": n� �)�ut�R !�Ah-E!=N;h2�W:( X& k:�J2�;Fv)�?6j. N� q�� �Rr�� ��\&vK")A�E�-a��G�3y���E`8� 2Ki��6� �1�!�A\eE�5ea��.N !J���i #hu�&�BD�,hN ]WA �X9CBn�%&,) `E<�6?i� %�AK ir�Z)�2�v[yE�1�m�%3� &iK� %�i�ER�]~/)6ut�B7*�o%[=�.�.3S6�Ib�Fc���P*+.A�Z��A ��.�6E�.3a"�me:s+(E�� B�yŅ�-i5=!J":<.+]� B�i� �o6�eAB�%�aaf�ig7vagA�+Pf F�r <o���8��(2�!z�i� oje"7iLi 7v��Z/=�*�~lso i�>nfl labeH^*�&$�17 {i`[, ab[kUo-�S�Q*�"��n��%�&+-�" �AӁ�#kndPF�'6�:E ,�`?r�7oA��i��AE�a�N1lWIF]KsKwh}q� A��!eed�%*5 . 8��16 ±r'2H�@�6 s��u� Samb�Wn�W}�BHu�6` con�)�"���l$iOsaDaP.��NOgLEKgX�by YepOh^m62]A�D$!�wY�s!"�F�e�.in eb�V*�n"* susc��o��� !�;-y�K�n�"tf�)�u n se�$ ofn7�BL"}n%�ٕa��2,nd�:�[3l6T6�f� t o ��I`q��,Gsic*F.�t� !�M;)nB�IDLE-�s�AaJh[J�a�]sible5#*�! (G}��,iD�wmcompo�on8�e�( tB1�e P�-t@H��_s&�a2u �ex��@ [6�96�LB>OI� ��D���s)�U2�)4��G#mw�<f5Nvalida܇�le� A.��H3Lt:i�9F�� knowle�cof vari)�g&$~:;:41q�vhelp deɃ%�s+�Z(e�/"�D���� )ofu(F "�st�X�&Ua>sy; �� �fi pre-�-A=S��'yF�iQ�st=�ł�J-�tu����2_.��`]�.�O1(���") !)b� 2�1�-�ji1 �&-N C:yy!� 0e�>B��arnH ge�G.:a�a�{��muis=-Fg�e���*6�c,Yq�!oN%3�8��/sh�kr�NEd|k ��2V��*5 ��I]1H-���e�cM=.�&�G> 6^,AOAjy�icj~��.� �\-|A���[6�5BX*>= h!F� dedi5=R�.-eR�-i".$n�..�(!M> a )="��P�Q�ox� d�-sWw a�cc�vpor !39a=C>\�%�3!�8 b��?l��O�*e1:!Tex> uk<uB%�tinfluxa calc6v�U xd9�fluidZ!NA�2�tuptakŞ gluc5 'ATP [68]�8�I�X Qas so� s �=�T��.n�sm�Cmmveakly�~if�LE� ord{uin r�uAX:�um�u$lex renewa1\E��u�su�2�at�u[� su {erAt��!\!����"�&( i�qF?^4� ,t)t=,*�%@�*�U��A%��>NUiPa�tl��)R-F�Oda����� (BLV�&i(� ���w81�OM\_ZDaaO , Me^ic*�y38]�dE�ngEd���Znd� ���1C �2G�3&��+<"�/l�se�]�t� ye�ttribsl��oo!�e�6�jD�&5�E a-+�enoughH�F5N6�2�*a�rt��oZ/����%6�dueX���rdu�W�0q���2&F.l2�kT� Ag1m�ig�zu 43a�!�U� Q� � 3(�e�!uW�nergy�J-yc��iv�tn|�5�arZ u� [70]� %J���K�j�o�%% acculCG !sac9g��a �su@^Pus�Z�#����E�!Ea5��,����V�&�! �)����N�:� ͆:�M���0 "�A���f&�D�Y�*anon-p�sF04um*Vˡg&�/�,I]>um�kr mur;N s [78~7Fl��g� �Q� �FNA �KZ�Al!�v��F icE4�I_Ajj�)ci �_j a�`l��6gj�ac"N.�3 them q(fd2f; f\on [7�lHE�cU � �W usefu�.I a*��|,*I�d&� 1 A�vta@ cl5$uA��*� o�aM�vt a�9 Ag�Qt{N �� cand- M�' � vaccAbVl�fA@ �A�x2T�� f�Dpee�MlA4�&���AQ �rWKtg9$="�}=�:m�!�p�:�to5on youngx&&� H,�C� ��r��r dis�219laiJo� %�skK{ r lu< !��p�@p*���V!�2�sS ���7BfiUwH� ca�Eg%5i�a�1�2y%�����b"�8 f��v�d]/t"�)�ld�0cQ�bۄ5�i�)a�`�9%X��G(t=MQ 6����ysw< ly-d� in*�=pop"�w( age*�4��!3) z� 7�LO)�2V �Mgs w}x%GQ�A0Au0I�9ye- e�ȅy׭�*�^�$; h��sS.�Js=Qon!����mvÁ�|y!�occur� Z �!��!g�j4�U wa�HF y6�,�F%R6w�&h �5AY�:.]�A�o*�K��� ��� �"nok o �b� L���-. !_+E�k"u8 Yor!͡�I����<!'a 0� �)�� *' �"in� E4 �:�>>  .�te�O�7_� t�at-� ��Bt;��l�Z�%br[�� !"^Y ��"� *.�]cE���M�sub"� �dee[Ptissue�ch�q1��Vs� H"AV!�]@��ep���DAA�b��DR {�)�EJ*C mD�qC�Wv��nl!9.F fa�{:bx2�C!�����q&�"*�[y�6tZ/E+yQUe [ adomte �~,� �U)��c]� �.U 40 ugB8!�207P��:�� :�ach[��vo /,D� :l�l}�B��:��*h�y �g�s��eoF*�longer�Bods��a1�H"zma,�")� �*�lMX�>#��f5!�� �/%{�Ayir� mG*Z$.Q�T2!A�28+�%��:E;Q$�%r addi��al.�%a4:�%V���Bm/µ� �det"D�l�:�ЅhardlyB�e�W NE.��6h�8see�*o���fJ� /�y� .� �e�5�5ey)*7��!^��륉W&"by�/A��u�,p�dv?��ʖ77%"D, ka&. `/ V`/�{4�bea-d�!fc�xI  famiF=8�aE&�(�,�.t�)R�.�-�oK.65166%uxa �-�5�to ��9A iso L� YC ���cha�er�obN��Ec/$β/α ) 8-�el domai|8� a! u�tŚ!�"1G?iffn>�Nb!�m�n���a&r�x*e.�:2�y[7J�Dz ere�E�6cl't[!ulZ  anomalo[�f�B����v��"�3 O[8�$De MonN��[agu!V81э $�do�subץi�A4euj�a� rmus aqua�$�ΠTG34E%o*Z�dEQ*<`theUsal 41@('@ tetr�ck+|.t�4=be 165,Q| �0�*� 15!�E��.��-corC4oEoQ%"u-�d�1iso�V .J��aukaryo�9�.aA^e Ba �[82A�w� 1�I B1�� ~70%%&log��A��.0 s I �=C�N~)�i.�d�)�a�6%f[83�a d �,e- -g49^: P�Ɂ �en��%?# .^"h*��a&�&��Ŕr�ly:��j._%u&� �}~[8s\8 sitA�E�m.�w7�"L�;*�1&�MH "�" 4M8sE�es� %Z�. FI!� �1�-/Hh���onship"e ~p3o7a{p&��"$2( 42 [�|m ��W�"*!O��(=in�. *j��!�pl�>_al  � glyc|ond�E�A��Q ���(?, =�*G�)8N!��d��g$� � ��n&H"FM�^ �� ulum"�!����ul"$7-.�� s�`� irra6d.�Z88� R� b�?�. DNA-Us&� -�141 . U�57%)�B� ]�an*� !�*( rV!�*he�of he��cD�nulom�<m�8� �:�3�K!�&�-�.� F0 !���]�E�VnF �G�K^aDd so f�}� ����M 4 N�etGc� e�1, �(:S � ɍ� "� &� !U" �"� ��M�Z�V>��>�  . ��i�` .� �to�vonQX�gQ �9��� �*P ��N��Y �Dre{fbyy�~-I)&�.�9y �-0 : kj� !Cufai�|�A!����" ienc�5�2� . Si�+ W x�-�off=-���NA]-�s �m�Q=,&���k"E#si&�'x .!��-an!��sna�1!�x'� PZQ/8�Csy���c�!9C�< 3�e�BB e*m�S �k�pB ��&.�"�Qo"';d c��ll� *�"!<( TAL�D�hun>(n&ͫ}�iߨi� in"T� ��� [8bV��� maj�=[of.�E%�%S�1!J��X+5��W s [89 , 9� �5�� s��a����J�� P�9��1#v!~��va�S��sE�i<s c���?up-�� �&+[9&��9T�`AEnay��9S! -5F$�t!_z �� [9". � &0 ԯ13E�"m �6'7�D��;��;ica b. ar�<of 6�;=�&A e�� �7!T��V,b�mAP&�6!��B!c�ee�l:n+���5! �� �]�8`2�:y�&\�,!�viFp���y�� al� -iaߡ!�T��3"����e�!9� t*ަ!-!66��VK�� o)�AH.�&��(w �M&=[=��=)c.s&�N��� ��."�'B9 aB�!$1�.�� y`T7�-�����8|7"��!!5o�0%tB%�:�and/ori%�x9�@�!�)� w�(�1�aI�"O8APwl���_ � �JAfs8 �-" @Ir�EAUe�O� �s9I & ��� �f� APѦrkA����������� f �:A�a"�bey!� [999Q��P'�A�r�z!�"� [9�`��Z� inv"s�ői��o�=nuӥnt6%!�ue�\�* 6a�O(�by"�ng)�t*a ��/Lo|\ K -�es/5den��[9&310��V8 �9 � �}foI�.Z��d���[10C AnIx1-�s:?_ uber]'� �00 [27aa�G ed 2HH,�BnerLas"9!2�A�a 4�n�3k*� .1a�`"�2fu�hTa�"(!-aN��1oN�����mad"�a8M�Q ��� 2�S: �)td�Y�:�#�� 4�de1!�b�{u>3$u�q���N6�T�)nR�"O�q�p�&*)� � ����)�t��G6aN1��5��J A�)�ce/acc�<U*-B"fFu)R�A��3!w�� ir(IFa�y�� %& heav�2�>���!��e��=I>�:R��e�o�O9a1=Ё�*�kum-�was :�-��R�b4��-�*�<� c���5�1�-�!��:.��E�h�i��,��!v� ��"B�8+up5'e � immoA.ҋ�U�,ng��G![lea�  �o-"T A"10 A�key fe�a�on-�n���lmAR"5 2�6�,4�1:� *)3ck1�.L�t�A[10�Q2�&�.G�Av"�"Ep� EY6�$H g�s!�u�B2�B�{)?aCR�:=FgA;e� 9-�$ ���e`��"w "imزA.e  �."�.�y32� �ow�/R4�N�͡e6R�"p �hx*d;1SM10�R`cl �x%� g i� �*B.��] -skF۳,V� a� .�!L�� � F�.0Y deg�Q)>�Y�" �c@EX.x��:9F���Es��$n�sKL%"\��#p����\ 9��:�(5QE ���e.7=�66� o��șw ��A�(v%�5:a-�X6 U�.[��6[�4.B�i� ��  .X%~�.bX���0j .zwhe�!'^j'O+�� �*A��tm� /bj7��v�L.SFd�%A��%'A�&zi5�F<'" & ofbR'�-�V'RV'"0l�V'�V'�ghAFi��/~e'(��.g'&6F� �/ ԡ�eA'i�����h ��FG)q;data��$�8.��E��#�"-a0j� �Ey��{~ncipa9e�J#���1 A��&a�0j�(�!�Esr d�F�e6�ȡ� ongo�*A,F� �8A�a��-�B ^>�c8 *%�4!�rp+2y�&A9A' 2}1.�In�-u�.�V fa�gg� iron9��G"�&͓outZ,a���is7��o�>���W{ �'nd��-��#l4x, "�$E6 ��+"Y@� �ac8� � c@ sours�/as hem�hemogl��Efer�N��(�Sb���gs�) fN�P�"�91)�Ad;*�j�,li�:is�BnJut �Fn��/424-mer nanocaga���)�i��3s�u�to}i��;aͩI�He"y��E7Bac|g� e#�a"���;�0d IlsA ( Iron*, leuc/56��9 type�cc����!�i� &<virul�1.��!�w�3"�G���ac�'/5`re�G~ya,1aggreg�")0Q�=o�. I�erAMtiɟ caloV 3��/a�&'� �Z�!��� M:���Nwrsh9�(� UV-vAg}� }� !�&-;�r fI�re#I��!|a��A]� ҡ�$� im-t�c�)&�6� h� ��4sta�y�c�9. D�)���~��!�m!�i8KĊ,dEl���Jdu�#dsB�seE�7!�ze��*�?6 �:tt�y�Y�arnseAq.3N� �8����.in2�U�AM,n�of %��+21��.%as�Cd s=A��r� 0l�/� ��pl-'�HFa�x(de1�pr��w�qYa��a4�m_f.�<�k9[���8 . �m� � s�Aen8!���)eW�&. OH7oE��C]A$Fe3+/Fe2+ �ex&  �*���!(l fulfi�{Hrg.S%*��`�e!� i%,�DNA�!t��. H"#q:]�JeAd].:��e�ved� xyl tc��,I_�Z-�Id���#��Ahomeoûmus1 �"��tu�>[��Lat)��Y orga��d��mohe: !�}|�G�[�+!�1�to�l N!��\2]ufq�ե��ig�����opL 63�[� Upd"��e� sets�a� E�'al �  vI\pri�+� de�[27��"  � R�bba�??1l%�scavenA�Aer')}ba6�&s�, ["�)���#4L^Jt��"<'�� es�.2dis%E�>inA)���i%.�)�[1MI�i.)Q A#gEFw.circum� %�-�/��!��nt�ic�_ � O � YǢ=!-W5QTG�a&"�$anc��da�{+s�nc^Pf���j.�(& �ch� �q�� � $�� �1]�3��)SGA5Ս���&�E_ 8 8 �+��or �Wkc�@) �� ͳ�a B2L�,i�2%�Oi�A�pK11�����>%��I�a��6s�2� ~Dm�� ed [�[1���+eNBf�-��r�� � -Ein Gram-5Pv��f��M&R��2�ej de)��&.�)� IsdFS Qi��`�)-�� Staphyloc�< s au�[1��H or� JS R��r��e�� wall–F��azA� Q�"Z �mea��M ir NEAT (rE� T�Rpor )9�N��&tq� �a�n&�!,r �ke empha2!\�.p�n[4�{!e KnSv��Z�Y�,�-U, Sϡ-lpy5 8"9 an[�ci 2���/ ew ,e [��)!�0� ,( Abi Khalil"��*p�~sfT W3A\PI�a�ou��)a�� �te����5�@r���4siTAb]!I`��b�/13 [1?T[��,+O '[1�5[1��@� m�|-)� d ub��t+3��B!���.pro"�3�l*�3� EPK%BD�4 "& E� self�Pmb$�l covd��c�A8o4hqo spher= � . D�Ax., �"� �, HB5eavy )�L (U�) ,�*� "�2��r��G���%���Bmn �in���"H[R[W $�.3*�X,���-�"gg��� af�bio��nM,�/* �m���� %���Vxtvx� �:QU�����?>E��A� .I@NKG� U�.i !�&!"5%� d�O� ��poo� docu> 9:��?��7� a�lu � um NM�` meP@ itid+E� N^ly �]2.�(+��)E ]*it�hel �s.�vad �!`0A*�b[a�. O�Dn v"?a!��$atX.P�u%�oly�.z�cy� fibr��a�oc�1� Burk� %<(cenocepacia���o%x�$2�# in L �|�q��ge��[29$�ur��VRRl�Y<��s��*�%4a*W�5sE'e(i"��: �O) Als�> C�Hñ����n-1%H]$3_J( �d>�T>e9Q-I*�G�01�� /sV �_s-"�M�Xto2hV!K�"�$6�p..5�O6�, Re-��fyR�g6��Y=iKH!�asU_a3$ food-born!� s*�$!duc�;a diarrh?�Avem��&!YR� �zga�u� ���\s ��pneumoٳ,QWo��almit�1r gv�ang_RI"��zi�fEf� %t"� [2�A�m� ��B&6[u] o� uq���ϙ�(� b�b  is ?�E&A Yet&ݿa�=!\ %��m�)l�=���mo�,Y�th�Mgi/��E� MF��67�9olo�!o�( ��  )!liz��.#" *�A'F! �e���V� e ca��6/�Kr�[�S� ��qs�-"%Vunby�� �T�E y�e�e�, [��� 2� 2f 30 3� �@cs�w��, v+Z{ A�&���z E�E�^ �d|�ENem��a�i� full=T��#�� TSj4�"O*apR�!!�Ppau�hit"-��lso*��[-!�Fur%c6%$n HlyII [3�gAm J!o�1&*<�2:��>�, ��(VrcI Bc133�,�.���5�!� /AY .�Q3�9�4M:X.� a԰��Y"V%�Kr�� :�N-T�l:T 2�13 LRR!�LRuRw�k �+CMSL� S-Layer H�og� } ����4 �! )&u=!�N&�)#�� !�6a�"� scri.OreM�&w�M��l���^��fig test� vea9 E �]9�S�7F!�%�z �A�e�&i�e�b_1�7]�e>Ac0i�#�3&I�{�=!Ocoe���a �#leU��i�s)\, MMoreoM�=�OA�b"u>� e Δ�m��t�A5da�1l[�op!k��> G�8i� l�ll&g[&{%kmW Q��c�Cu9Odle��-R�,e$��p!u%�.7$�F/:3��9�/)���~%����!wo.%k)>8b7�`petro} i�1� artn{�����T. ��?q � !�6�.��ae)!�stoichie�r�024)X�M� w�r[7�%�2)�I A� `!�s�y�*�" O 2�+6L 9 .z�;uJcu��5�i$AAs;6 +!P4U>in�gme� dea�F� �� Co�Ʃc\���h.!})g�M� prob크2�����,t.@��*�`�fn�%�T(5@ l cu�G) aH?�jn �EI�1��> ��K ) N�2�"l�9 b)�f*&( "�}is�!a?t>odynamH]eJ�C �s�5tLe�� �a���^�X�A *e"A���ax�9�&u1� �P "h�5L�omiHA��e� B1X� &( K_6t �%"en3�$py ( ΔH°.r� SAf3��:G"�cfv!�e%�9ka�� KSy� cess�^8-b`!��arf6Dea a"�**� ��� MU�[^� [35]de+�P3 Each�=�A�"��A�� �'_ en�1 �uln'4�;�8.�d21 �&~`�/ heat�\r �1�KQn�EH-�`�( HuHF�t���s0%�25y�(M*�!�!CzQX1u ( μ#�!v#��.��$�%!�%[to zas�YV M�8!jB%fLe��s��(� �F�����+L ��;B(etd'ol*U.Z∼20-@�4 R rUmop�.} 9W ho��<��Ӷerw�O S2�Al"9"YW6�/�>a.Rt� e&�;cuH�i~�=$R�� G�_�e*�UX�q��! JN��TMAI���FA�� Y A�7�a����!U?a�N(!!�3H�[� 5�, s�8�i��WA�&�8ly _�AT&absor\o�Hr!V"(X���"�"up0�peaksr S 1�2A :HS�DE��[ǥ�j�AlN��,�anP\aORg��%"+�a( K/�ofN540 nM ˑ"-�e��(0gA5YIyK!�.C�al J-�&� Bv%"�Q�aI� �d#=�hre �#+2�isA��/)�"5���Ɉ (! −4�(−10 kJ/mo���Rl�5�A�����J85H110 J/�I��h/��3)�l)-5X2�6� �A�/ �!��c�dr�v)�"�-To�)�(�ua ��ΔS0 val"Wa��Ha*e?)@a�>�BAp����-��)b�ng.��H$�l` @�(s-%n �&�IE �or�&R���% 5o�, dot�P8 experiments we�qre performed separately on either domain following their individual expression and purification . No significant b9�ng was observed between HoSF and the NEAT~7fou#BuiY� ofF �Llmost four times low�n%6�)Q1_!q!CYKi�restorA�oђ!�lementu�6U��5V��$contrast ,�>k!+impaioinMsta8 , �!�a��le over��2�to�ensa��ab�B.�)k���sre��^���-o) I�6���U�seI&�`�[6�re��t�yahimaryJ|��y���inA E� env�x!� �a��of.Ls!2remove 9���#4in vitro has bE docuVed [42��$o investig!t)p�,of.�2o$to extractbxvo�~a�thN]A�i�A�:cin٦�*aE�I�ed2 ��ce0 ^A� noti!Xin LB9�6A�Xf��KertMIX�+duVA�all�p( OD max after 16 h∼0 . 1 ) �I^� Ii �!�a !�aff�ViF��k 6B�Sup2�e�5�as solM sourc� �e ޭR6� �}whereaI�� disrupted!d6�}ץ� still unaa�to}����׹~�C��importa!�of��(%Iy efo�f:�)�a9 acquisi��:A)furF��fi� %J)entΩ��;T ��si�itsu��C5� glE@scued]� �too�u� of �(study empha� an Lant ra{B�i� j�in.�� o�|to= vi!� work)uA&( poin�e(out a major�!���2=in�6�&$  starv)�[44� 5 6 7A.In!�igtoi{�qage ,y �s��e�.�!!nsect� High amou�?.� � �1�4T hemocoel ( mg/L quant� )e�aAvMQ low levelYverteb� plasma� ( µ:K[-8�Thus , �q�y ��A easily acAbi��-conce!ޅQ���W�K,ellular patha�Mch!6!� a�� ��"���!�tissu!lhe%" lymp�� grea�Bwax m� Gall��4 mellonella [4� 50!�a!04y useful model!Vi�=�esis [51!.Wgearlier2� �re��dO�i����in�w�surviva%�=in G .2�1)�33�a�cur���u*�6�aA�i. iso �in5� utili�. :@ whe�[�}�sE�alsu ��FDicA�, virulg!&M���=P �:by dir�injec��inmuAof var�l dose�mid-log ����/ ( 1×103A3 � he numberMliv�l�Ge��r��A� threN y*�7u �$50% lethal �@( LD50 ) 24 hoursw in���vBd�,Probit analyA�( T�2e���f� Os&� ly l�/-�t�z� I :� hSiwADa 5 . 6-E�6 . 7 dech �1:�Aee#� !� , onl�e:� EA  �|!V ��2�����( 1 )dpartia�\ a�no.� �"j � �DO 8w �.�8m)� MJd�:DY� 0Uh or"� {��N�C- "�in� to9�� .first�".A�. S' .�iJ 7.�9 #po.�outt ��� es���[&[�,��2w2_YS a� inoc eDA� j!�theN"� a�yvtests)D9rA-G M yiela�!:sam� u0a pr��� Q vege�ve ��+B�E�sPco� a��iw�ɺ,�o*Rpl��a mS х� than�O.&9 6�; s]"/b2�I%��< �� to kI Yhabut sl4�c9|��!� 6i�.� adap!con facte+a� lowsEjxaissemin'�AW �2�enc� e Z� . For"3R ��peIX�g%!is essen���ni  colo"�A9� _=� of effici�.Lsystem*� s key-<� Because&.m�� P�6ag otei-���4organism!T s4 d� oped� mech 0to�  this kd and g�rapid� .su�; � of >.*Z� !1mic�]� eterA� .k %� Qtheft��scarcp�Q< gyB|& surfac9<' te�s�lyY9�shell�haps al�ng�$structuralA�egr| !4lea�to� ampl&�1%relea!�!nanoc!�. n"� � � a�n�i �a��,- mbinZ�� horse spl�١�rL . H�,��detail v�cha!+eri� �/A0�demon��tb��iA�qu�� ��gn�recruiti �F�a�\�!�0stoichiometry�24 ~perrmolecu�rg� aGav2f aM2Y�ne J=2Ssubuni�5r&� 9!��mS�*eT ��{a�!&%;asBrecep�k)simila�e�sH modynamicx amal!�: in j 1 `tn��: i . anhomop� o2of!hH--s� 24 L!�h�Z> 1 H-%26"�ɍ79M-t�s)*equ^ wa�!"$is novel f�Zng adv&s� � stanE=q�.�by�F�to< knowledge� ��-�5�":id�Qf t�9fa�� ���e� exis�clu describi�!��Lic fungus C . albica�� Als3� hich�no.�!�log��Eo,�N�!l!Gto hypha�4"A�aut�j didS��G *H�p.��A$5C[1QTo"o9� how ��ws��>K �dd!( s� &9���searchedezM-#1�� a�m ome deg�ofNN��mammal�sm alNassoci�wB erum �na"5��Y. Tim-2��T� < immunoglobulin--!a mucpI6I`�mo� j TfR-13 hum�Z%.n�-1� �� ��ze H-ch��5� [52m [53]I� as Scara5�class A��vengerL�!�s L>Q�is�dA�delive� �kidney%/s4sY�no9�o4n�l)Ksi�2 ve���eH���YD. $�" an origingNp ns�of�"P�"�.motif"�,a broad rangņ-�)�A�fr�"�.x (- I~'on!$5!$s 2�P�%\q�I� heme�, U� 9ha�N  IsdA�S��ur�"�Uc!�uI non-f��E�6�A%sn����yp � laborator68 B�ez%��)w a�$ exhibitedy&�"���%,( Abi Khalil"�$, unpublis�j��!z we e�&l�LRR%J�iBf �5� * �Y�. Althou/�$1�!!j"~��!�})�  I�#�.i& .&1�i�e|iG#>�Y+F�%q/aZ"` ��B�dur!��c�,�'w expl���wea&�%"�$B��cA�T�],շ�i epth.�a���"�%tu aHnee�o pin��ex.lo �x e%+� siteF|�v . Am�'�%�-����w Umbcarry6�nd�}�k)'s)��Firmicu� (phylum . Be�� u&o�  membK �isS �.� famN�in�'py�� Shr �#�&�( HaleoS8 a[oi9,ɮ.x�U.e�a*!&� &"i� _ x(�.A���"� yet [57�8 Q6A'IA e ly (��(��� ORFOE%a1� tXed BslL ( Ba1346 ) [61]j 6 wy� ca�A@l�#��$th���{� .)'� ��# SLH�G.�K �09* , anI����, su � me6� |o�%�!�.q� v�e!#d� ion9 �s)��Isd� [6�"��!M#m�iEˁ ���v�GE� (Fe experiYI��;e2 eM���of) �+��*un s��*=)fea6 �:�-!��i�inm�*� q �& .d�lso��enh� �r#� 2!�) P�tit�s�� � `�e�i_a~ b� �Me�mo�$�,]�a�� )�u�. A e supra)a�r#� !�IXA 0xtremely robu<'ita�*JnT$ s smR$�orm��B�*��IlA tE1 �-��a��iV.j�inXt�Se�en�oC#ve ΔS0 �*v+(by ITC reflW�n ��L1'Ns�r . S!y �el,Z�!j1�"X�Dp�� ��,�dZvo&!bQ�rem�%poo�A�ood [6�ItE"i�0� 6IM exi��r� s"H'd-p}-!�:3�sym�ax!�*�.[6� �,�ѥ��, id!���q5�V y tea3 :��1�Y�>��liz�n�!֡�_"gg���#A�1�ably [6d More$.he�En!�can be ��`(chaotropic X ts [66]�5�qpeptide,�"By��fe+ ���i!y�forceE � i� es�6�.6�Fo�. derly!L! d�!� flex�0m9��U���rHucav��ad&�#smh�&�&yab=*1&���sij�t�� ��-Z�7at%�q(!a �ew��ee [21]� I� *�+a cleaS A&isF����,�a��N�&"�� may � open!�lo�.�Am��E�a041iJsto�p%}!��is temptoE�f�!at��m�/actamper� ��1dock aro%!�>���EI���e�j�E6��-c^ 9����eVDFOI(!�5%1Cu0�.G )!"p(�4BS3�ch1or n'� !Yoo͢e Zt��narrowU%�D@ V(��T-��c U[u��%b/�,Fe ( III ) - ]or [6� 69��� nlik � �lev�a� ur cF.*� ���>T � !�4 1�M"U=�i&��.� e]6& . �inac}"BV nocepaciaEhN~%aI itid dopt� a �� E�olyticrad��Y ateg &z�J1D 19 Prelijryb�V!=in�or:'*�%� 2�%Z#doeg�l�7Uo8$PJ%2. A� /g''~$)j�0s �5onO.t����aso��L!Qonocyta�2] , [2:� a��Zr0ar �� pr +[38I�Az�<0.� %X: O!�*V3� d Q��a��athwaya&J �vqIr�al�l m� E�2��redox�)�`��� ����y�e*g )�e rX7o�2yeDUp�A"4,�-irty yea�&go�1"��5�2ta�:ro= �/�&�4[8a�"�-.'b2w"e�/, "q6�. C�5�1:�)�!�Δi:nt� L&a�1ef[!�$.�#إ�dis�#��#$pronounced*�.�"�An d�6�� 2"!B uptake:�atE��[5f!=i��c!q8,a�ev��� uAcA�a�kin9��07..�$P!<�c AŒ.+ i"=9insol�7�$�/ic.�� neutt pH ( Ksp�&�� OH )�(= 10−39I<+��"nfl"�:6Tcz� � .ts!�o�"}����( Kf  |47$)}70]��-.�&232!=[7k,B!�"(;otI�q t�U'E���A��ba�*l*!Z��.�PEp&r��\ s79;�'M��*�:ͅ&(. Hlos��r �2p ;,2 Zg6�;; d����I2�/5��aD}3)2&in�"�-ac�a[006�;,%`!�6:,a��que"�nva�=m~ian.*N�in na�4calin [7�#.�"U e�2��b� �'*F���!&n �s!=�+n|�]��= ���&� * 1l'Y a�FU�is�abund�i�lE��1� *�0bl�-* �6�FR/xea� 0.*� depe|!� e A  *ed l�"As.�A�availA�$[#,� �e�Q� �DB�  )j�>] b�pV7�e��n#5�i�s �`&�eluci%���o&G@e��1lu�A@ew H��F%9���%a!cU�"M,8*T�>&AW� � ��� ���"L�&NN Aa.�&� mine�IŐ�seZ�:UtK,o �,!�-�ron1x6��� hr�i�%1 �1� a-�al%/��+l&$�'Z�� vi%�)!��� !�ins� ���5��"�3��� ulti�(a ��%�a�E%e�B(&lp#�AI82i% s . ��us� c ATCC14579��stH�/u4$ � E�)G)j� }\V� �a�A$� ���65"�(� �3!'{&l� 86#ApHT304ΩM �5id)�.&:8K12�TG1��a�Fib���2� (. Dam−/DcS-<ET12567~: o gea$te unmethyLCDNA%�ero-S �!�=R� ~s M15V{!14C600 ΔhemA [7g#�)���o6c?* l%[e2�X�y��lis!�"S(3.���z�9� o=Luria-Be�;i )�"th�!�vigorAsha�� ( 175 rpm�t 37°Ch"�:.�An.qBHIw�=$ Heart Inf��Difco:�A�{�Z�2�Ew��)�HIj1_%5�i kp�"a���0a�e�2d [74-7A�#����m�eG�8bi�> u%�A &� sz ion:�,io n 100�8 ml−1%u,kanamycin 25.O1�;.&6C<, tetracycline 1B`ery�p c6c]\����"M, '42′-dipyridyl��3�(F-(I))purchG�e$Sigma-AldrR).N^!�%Qat�alJ�!, 450�a�µM �.A�00 nM�&�&�1,�Pac�[��2QI�a�n��a�LB�um�6K��J7%`?ua=s)!��� 4e"=U( LB/LB+�@3[rJ�Vkv:K>a-vOD��w1 . MV�8etcol�wu wa�%twi%BPBS bu�M%h�im��K.>� lM(( ∼10� ^fixѨ4%A�maldehyd9Iss"�9jotly-L-Lysasl�( Labo� rne� A;B20V & y s ť?W,� ck�1% BS�8incubhaMB#9A} room�er Na�+ti-!�  .cloA�Rody (:#)B eH0@8Alexa Fluor 594�<ju� ( Inv7gen)��/l"�H1∶60A� �E���)� a se�:G �>�and��a�c�4s�I�|( 4′ , 6-diamidino-2-phenylind�?) DAPI d��t�aԡI)�. F�)�#-�E4r%>d lwu=,  A-slipmzsti9ԁ�!�fx2Polyvin��lcoho� u�?A�um \�+4� zabi��o[2�� . 2]octan!�DABCO )�Fluka%+d����AA3I�.�:�2t�.�uplh�exa �1<�g epifA0e�GT scop0�� a Zeiss Od r Z1%eC! Axio� imag:softw� . +*�;Kpi�3e�C each�TE��# GST-� , z$AJLRR�}(A �1c� n*�*�b�4 u���-� $s pGEX6P1-� ,2�$�{K!��N�M�� ��S $�(, �N��2KngZAla29��D760 , Thr24-Gly163 I,ys208-Asn492� gH(%)/5�/� ����*S e�9p,% rs F�/)y, F�/R}FLRR/R�21�3�>���� &-y1T h�O!�tag!� ( GET lthcAW) �;difJ!�)PCR!gducq EcoRI/Xho) R=�1�%��M �Y- ^ ��@ex:/�hѻ��E�63 he�0f �K��5�.!8!h!� �� � apo-� ( (%�Y T)bo��EAMg� q�uM.� .ML QOPl� �-&Qnt�M�P2Z� ( z' s"VI��ap�ri� ��f m(A+-h r� ; bott8" D\�� ,!h�ctN8OD600�� 8–9 �s&=� ocol���QJe���A�J:�;��= BulkE�P�%-Mod97F��'uA���men*%manufa�P�%GSTe36n��e��A��:�PreScis�PdF�)� �ed%e"�Q& rultrafi% A��!��t −2E�� A�E�& A�%��W�n�(�&oYf,A�i�Q6G ["�H!��pr9V��l s� �of 80%a{sN#m�+it  calo� 9(m')A�"O*�O&�V at 2e�i3=volum��18� 9- Nano�'( TA I�9N]5�4��s��eSL� M�m���!�E�Z_ so /D ( 50 mM Tris- HCl{7 , 1  NaCl$ EDTAa"nd DTT %���UѾ�"�(as*M�$�cer�"� ��%!��nt mo+5�4( MoH� ,&5Hu2L- 5( HuL2�huZ5h.29 H/�- HuH/'��^�[7rI77!To ^2� �.�+b=:%7(z!ts����.1<^/1!  utomG A�16&]C)I ofl E�nt ( 229  holoid�M�)q\ a�� �&12�,!"tYa� tervy7 of 5( �@��Cte4:ili�I�,Ř%�vaAGp+K4y�;areE,d ���J����inY��st&<dI250�� nsur(g?mixk.Vnt�+&�D c�L!!��=p�2&%|=��+�.�?hea%(.,'3�g�)!�S!@ ��ʝ�X� �<z 4s&� > q58iv'ed)ar.(�en�Gpy ΔH°-Y5e$&�M��0`KnNGalyE ~��A  fit)Erogra�N��-@<ard��'g�9 ��Qv*r/�M( K�!B�>2( nau�Y�"+ a�.gle��&c ��6 �*z-�y�Gibbs8�O ergy.�G°�2@s �S(�cal�(d-K�]{que s: �^�−RTlnK%T�P %:−.�0 re RA�X"�0 ga| b&�F� 9872�A%�K��TC^)e�in Kelv��;�'!�d��;A�5�"x(�Kd �1/�2ol {�7All=�� repIMdtoP1�WA �o68(��o*�@i�eq6)2z= an?Vgni� n�Nat-��Apo�@��Ś��loa� ")2h 500�(atoms/"D,. TypmWIhFeSO46�� pH 2 DI�� q �via ten�N B�5�5) )�E1� ��y-w�u{YJb"a�.c�0vofFrqN$ro� ;VH' – >� "�g%Oor ���at t �A�"�#{!�����-��-8"� { moni}K��i:x1&�Ca MLCTk-orpe bE��F��II!�-��x 25 n�)�per�82� 5�A|BL9�E�� UV-V_ o�extinc�co&�Gz�at �( 3A�M�0c��C. E*�5%py��6�[%�&CC��I���T hromoso� ^�3�#^*��JZ���%� �`promo� �vec�08J_was �G"/ $e GlutathiAS� Q��) -tagg&� �!���Itac.�@ $- }�2� rB�H� ���QAV�V,e�� �9� �0!��&�c( bc197h1989*�c{ 956 bp �BamHIe�qva 985&PstI/Sal:$�:F�c�2reg��i7�.�upstreamldow���`I� ����+�0����f2�A 1142����v�%�{%= ��"B m�� ���]���gc �FL��B6/�� $156�ai�i/t�6����sCGNf)ue�a�i�=30� )�B� ( &i�� �"q i*�Agta�V@od'h�t6�m�6�R�E  b�brj�oM�meal.�BZm&�&���a��({&ha��+;i]$+~G(: � �u.S(&�, 7 rifu< !5�Zto="�% . S!nq�miy'��YlyI�l �~=5 Nk8, nitrite-molyb�1reVBy,0% so�q '�6��1 N NaOHo=re�;�6I�e�;�u07absorba� AG*�10_�.t-�n&�to$ A4AP"aP-g`�y5of.VrIA!�7superna�!�2a0a�Iin�3�ġ`11� statT�\a&~�Stu9's T-�..7iM�>�U���i�b�C�^ngO2�F�!r�Ov#-h-# �" +�.u 2L"w+nD] final*�*0� � eria� m2�* �i�wa6�*y*� u,J�+��.).�o"W+YuLde y �l)ACab�eaM005��zor LB+ju>�+2�o*>ti�E��tFu*. S�2"U .;aPpre�%� 2M J �W=h9dpArr�R@�Ce�C2���MI�U�in 96-�Xs�(ti�� I�!�inu.�0ageAõ�at%�nm= ry���� ��a TECAN�0�Re MA�M�] yRea�( (Group��aaa� �at�)��>&�n7)2s��bGo2P-:2�>-J �a�as oa�LBa�*�&R �= 2o9L;�#_;��"<9of>Bg^ `9egg �2�u#v��dre�<�ceesni!p�.#Naq^i^Last-gCr@wMJ!i�!�mg)��WN1t86M1� "�c�[s�9i1W.IW��+ _o� BuckSa�-%;N�28�JVa:Gh�B9h/%6m A� � &e3"�R�%201H}c�=olA�up!�n� ��!)A!�no mNa�"�Fi�"�<� ( �Fa�X/toow��hedw*&re�Zz�T72m�af�D 5: ��t�rt�&�9� Log-rank �}�2�;T!"4%,Ui%t�R�#� r6:i%TStatPp8"r-( k!stSoft�b {z�e@principal pacemakjAccircad�=clock! yan� er�.S�^longatus�&�R phosyyyont!�Ga1F ����$Kaib& KaiB%�KaiPEq�h�.er�6E~�Eh�ngcwo"N% , CIWCI�+B�6j%�E" hydro�" ATP�1u�@!= 6 5e2��2�$w3  N�(; ll-[C�,+ Zc~m�9�"�Ds�Vd��W,�]�)�is0ve�=r"�`� IFOE=v^`Inspi" b�� }��m�/���bui+}on�T���a matheQ�;3�]w�K0t�F\L1d.a�-�� ,.� -m`LR%�h�|A��0hX8#!t1P �: �8!�-�a��eA-�pr><M�$9@%UAF}N�-t, switch E�1�'�|�A�%E��"i�>#E�!d�eris> a V�E.fall; i�>Xej�IV�ia7} @I�R-�S%��Cn�lyA?l�Q3`m�by �ngLa *�ex��E���z�-imu�J�%f,i�ow%�" �G"�Dof,�;�&C[!�se�)�:�!�oD?� XA��"�T>�)�Ur5}!؁��^"of ADPm CI�Ms\ , m�;/iQ"��zU]�mMst�A 6;�%Q��s B�L�bD�\BCq%A��w-D�E�@E����� � ����hxOtoqC�B:$ . UsE/ deHd�#P Monte Carlo algorith�� ���s�J�Al�"�"l�%M[.g�{sof)7�Ca bill��&<�bI{��)cs�:d<���2P& V<. C6WA �a &�dnti�teA��Sday%L,��a fasc�k��p�} f bisd�CrhythmpOn1, �st�d!�bes�&'#r}*e��&oscil����L>yncoc &%.�E�*w�`!Pi�mbiZ\&E"s?[1–3]�'>H�!v�in� 5�lat� � reAt�X= � tube [�=E�M?d)9�i�0zU��design^ le��" fruit�Eu�AAe�� � �>��j� , s4V e 43?CB2 [KmT�M�c!�nd:x)�a�h"� :�[81Xx��sQsB�[19–=U�-le2 B nex;�g� ��A [202�X Each�ivi��� �db�ou� a tinyu�or , goA0&�.�AiAEJly>j�#wg0Cm*Js�caiC�.�� �Qha7.o t�$iA4 %%�� <3I&�|in�ant no�8iochem��"�� )W �R���A�&G1C�#laevi�y run�of�5w#� ea1n.�ZVyn�nWg� �>�!p�'��a!% �*�(ZS��^ 816%Tmj&6��zd �+�| }W"�. : W � N�&�e�M\���de>Wp%� 7I=Eree�fro�sunn :��Ealread0���ad*eBa�a�c� *mU.a�q. P}�A�Rg�He�.Y!0B��n+���g��#-aggar�����s�l theyV qv#"��(TAaI"�. [t� � away!Xu�.a%{ �uH%r�#B,A���$ianWA�+di�)&��.x!as� s �sY*��U�J�8�s&�K��%��ypp_S)�a7 " p����*� C�h&� I�[9 , 2Mon>"� �u'[�5�5.�[11FWWnU�my��9.*�Mtheoret���s? u �8:.W��T t c�p4� �  .� [['�dy�U�[e!s>9�tur�o�\[[29l2% fuu~%dri�L!�.2�a��� �� &]�hs -�!�pX>S&�by�*��]J)�Teds�Y2$ tane *� ! q� g��3m�&�����!duI� guinIfh"�or>}"�]vea�C%�]��� M˱�� ,��c�� d [2� 29]:V�{ ���ˡ�"er�Backa��. I�K6�HF�doe�]�y netB\!��/n.J �? C��"necessar�hd�<pae|,M!ai�6dE�&E`e ɠ.��CUwo ��logA D� ��g� "�[3er�t[3.D3�o�~�M� a��012�n6�I߹$V�ofB8Q! J})�M!UV/MkY]ni%.)b�@vU� ,t�� W��e5�i� N_M�Y)ȡ��� argu*� �K�TPC5��p"TL geA$�%�I�. W>FEm3 post�-i�alA�*� T�k&maCffW�� (TtxQ8r^{:�E^i� s [2�>3401�se2%��� n;��2|�VAT �� W� �i��!u�g����Ů2� g�^fa͊,gn��Fv FY@'f "�bal�"m�hbe�OkN ��;A�a�suWI2.�.W&%of Van ZO�s~ . [ EI��>�� .���A� �j*te.�9�� ��)��s�n�A� "�}��C��N� ��� �R&A�eB�����QI W �moreD�� �M�T�"F�)ZUS���� w ADP-�� t!2R��E#.��&\ A� flip2O h� rigg�gJN. �%)�6�WC�t9 ��26�ZgJuFo6l�p� eco�Kng�LF�'�!7>iF�Ͷ7:�n�1R�}t� v� �Xl��dC8 � 4a#q�d*X2Z'e�R�MU��J��&�t;�"W%"�%H���[.Y\ [ !6�0��re�Ym�5�{M���R5����!�uke[.c1�!���B!�CIaK �� Tic&�d!�Na�9�h��)�sh� �5��AWi |�n� y�"E�82U)�I@6�+s�>��a"�.Ll���"�+!_del��t��Xmo�$��a �Bn)^������"�Dmaximum2 !�,%C�no !er6[hA!1�Bes�weBG� M>�sxJE�II-��ťB�)\A"acb ����K&g� ac�Eto�#� �b�w:�c� �";e��6�F��&�� g�AC�E�� >>,:CIN6�qK^�:R���)*.� & mu�ij�8chmd $sy\j a?!PM�e�-�:i.�&� :iC��ex�.m4 p� 8}�iod!1r)sto&�_%sst�- � ATP/�r�>��V�"��_ntZ�~ć�XE��5/�<e1&7 "N �%w to�7ht Ŝ. &� 3in- UA�BR �"�(V-�-c&�by"' �Dco `a�- But���&ast�%v)�i�f;A��.KveL� by R� "� �u2&i�#l��ly keeps &�%�.������ ac� { !�aJ)ll�*�!��EZ~ pur#k)^a�e+>io�^� �0vnp-�&l!=�iUIqbCKS�#�(k�n�"����>DDh��2 jus7)iɇ�ing�.%�!�>2Qmo}%b�discu�F\!briefly;!U�]!�Fuch8 � !�-M��� 5)artoo�4�")7QO%PŃCq��nd� ]|&ѝ�ݙx�j�&sMxin7�;7we-� �3)!�D���#M�a�fexr�&]i�* TP!�V1 Qrpocke&v( "s��� S��#%?:�M�� !!& i. ���":I�$ar>�1h@E J���!�2CrGc�'�.liea���=j2;:wZ MA fs)�Ag�7L�E�&a�I��e<usQu!�Y�U>:d�'���.�L(a�=B+(� jUK.s� "!�g���z�9�b-�5��i�&9 "ep seemp� ruca#d�an�yi�Kr {�bMk*W �iD#^x�m��s( S�3e�r�&( @W"�per�0s!WIEm�1>e�/ac؈2��!2���ESaddy$�� \n1C��hs)� �2&�2�6^�@S:g6of �8 6μM���� ���|ng �K)�*b = A d^ŵaw<r 2 cuos:5���J�� W��.�o}h�3�J�y�"Oe=!T�!�2�.�2� )��i 4i' �!�)�����Z�6�6�aq:,E��EQ.�u��+c%pa�D� iV!31, *�� -w& .� lookU�fמ!tFn�s��B2�E�|*�4L u*�)�veI�FeM *]�FQ >_CI5E�d�!�퍿7�61� y7] e &9e�- 2�ATY�ei�X��>�2�ng]6F�X��� �?��:�&�c�&2hon��.�>�wh�'�����&C2�a6"(.�Z U9pF���Bm�V6�5,�pe�-��)�2BF� �. A�),ac���:���* !5 A����!�2�.;R@�a�82S!7aj� � 5nB}m1&T]*7 �%q drawf 9���|(R 4p-�`-}&Lu2���)Z+)�.�7� (1;�rep�A!Nis * H?u�,a5 B ba���s)�un.� �8�~�%�AT� �# low�!m,�v a&#@H��[2��A/�MA���F�WT"C [|�at���V!�c�UW I�-9�(&�oV��]edò�����߱�on:A*��UA�t!�b�"��is���WŃG9*��tM�H<�e/he���,�mL2fMx��E��!k%f� nd,���!O;�$< at�.).���$� a%-�"�7� �. M-�:KofZ�B !5lep� reme��rtc!�!<M/a*�  )�:prU� �Co�<GE��� , �rF�)2��i>J�-!w�E��&�7 : AbD half! GV�"' N��?E or8��>�R�[5$H"�*iI�U���� B%�V�% ?+5Α�1�aЄt VN��e�QIlimped *�%f]fu���<�� 9�Qba�aU%� }a� $�g1 ��a2��L͊x��?d . S�6dlz�!�…p��c����DV-�2J dropN40%i�l��3�1�nu�a�(g�2� Q025%� , 5�4��Ed�N��ch52�v�2n���1D"(l �ɧ��a�geL%"v ݴ��46�,h �#$F� �7sa2!~b(1 �%F*oB�Ou�Ň�:����Bl2.lV� W1�!�F.��������� 7)�CbA!zu}kA ]&&P �D�jI��p>�� �o��.!�aB���+[fe!�^,>6e��>rFt�;� �caۅBE"chr�A��G w�rw6��/��D3B���9> "��>%$� �8I�BPE����+I�J��c� �>)4%�-�h s6� "�)� to wv�Sf co�ih�EA,6J"E��mop�&I��"al-A:[b:P%��)F�Cs66�(f��4r�gf52 se ��0�er�uD3fac�)t-�2��N�"traver11܌A�:�), fkiq��forth����"h(_rXp"�.Us�I�6�"n�isM�2�� �:� �W"�<i�a�! yE�mi&�=m.�>b0��o�T!Sw)q���imn3 �O("L�� �R� ��a^2}� f )E��6��upl,/�q>� =C~n!J� 3";�N�- ��"A�& � �F�>��^�5���ofFA�� ��Fr �a:en���F�A !�lla��<�b:K %A�eno�V��o� x@�+E�iv�a�*aC b)l>� 6%,��g .a HF�� *�<�7ye� � e��\orZ� t�PQ.Ax� -��Q�MVF,KHVhm?kk!uAW�#m�*II��s6�,1A�*�3�-g�>�#"�,.�(dev�s��oT�h��m� 6& �5].a�'"/S AnUr ���*�6"v "��t�I�%.� V� "�n E�Z���V,�5as �*�ad\Nvn ]���<�� 2]%�. X�G� I& coo�k�О�cEq�N,�5A%Q�AQDP�A�!/.�)K� 2NE�2�1�v `lso��� aY'F��-� "; himMeB�M�e0U{��u�+��2��&e� : ��f���7s�%!Hf!�w�@"�ad�8@�Q�.�#�3 A3�N�6�-ٕ]V�h�antag�G3��Ur7"tA�io�d 6�:�� i�z�#A~)��,`� 9E� Gmimor�V quot�.���Cng�"-<� !`CI:"�-��B(:MN��?q�:~�s���5�  . Ad�B��.q -�2� &{ Z��Z�6�AF IMWC&>��!�D .3� ?-�˨���6s0: 0 A�toZ� "�a��n "dip��!l'��:��&1"M"N��C�L�B�  CI-!2\W sl�?itb�e�2�Y�W"! !�.E�inU%tB��p A >�6b)B2��R�aa���e�� �!y2q�b,rL!g�� �6E��l�p��ś� � Fig o�2sd!� �R� Vmi�wQ ,*� 6�%�DPJ� ��G� &_ �v.C.!��h ���ir!� olut)s��WUe}!�1k�"�(� e>���e~s�-a "0.( E't*le�0yclA�I�$a3�JZa� R�уe%2���}.�xaN(g� �2~i5�R�� 02lO$ h yIEife�� ��oa�ckR��?y.��4.���1!.�}s�E�M�G 3 conn'*�1!B�&M�"H �H P�#�P���'��G�EH ���4��ajp��c FN&F2� Q�Meq�Z� ^;.onJTof radio�G�olabI���[28 D��Na)!v�y non-� zW�.^���xa>b�� ���k�|be��� F�i�V)D�7p"T*Se>T�|u}G]�1v{t.I *� -]7 �T�� #s&� B�h-A�i� �B�[# �.� �Q3`!��6%u!B�e��E�2*mM�E�A_1)�=5�"� *)� "�.� M,:c$�F��q�#=lZ{2.�#<�c"�" x^� "�=�� 2R"�%A�%in7>�s5!*�'��-�"�"��lR%.�e�� a�beh�2.��ڵ-��sharpe�M�B�i�����=`.�oB,2�!>5�% �:�B)�tCII·,#d�#,#12Aa/w��N� `1#�.|QC�>+ɤ��;�A>V�e��12�#S�CEu�6"���amp#&N=thi�b��"J"F��edgn*UB �[A�i��=Ib��EHimoda.�%��)��J{ �2�^2��zt�M��"st7!H���1��who!�:^I�mn2��z;�9��T!o-�me.�%Hy�� ~~ �!O��K� ]�,e�5A�d�" !�@$se��f�7f"�8�5��v�T�<b�!I ��! �a.�ea�.�*a��eZK.2P&�� ��s�"E�w�Is�F��t�`!����]I{:�NtXtheU�!�-'�&� aKIA�.d1"w �^)�!@*{3=�^i�u� �9cc�G�.b�&%�]�a6��� Y3%Z� ex\=�5W i6�j��B')e�s y�%�Ai70|g�U� �W �%7 ��� 30%-R�ʳi�"7 n��� sixMBQo:�. TechnäOtA���s xA�N���/RMD� �N& B��,�)�e�E(.&�_v r�Sj��2V�� W���`!EZ8PqPor ����,"ea[6�4�Al�d� writ*��++�fs*�.Hat https://kmc-kaic3���fo��. i���\�,�Jx%��C"� B� %�4BV <}A�� v"M� �A'e ve�:\ ;!u( 2 ⋅ ǔ6 = 225}� �aQAFz"�F�, ' !�A�AD%��(��E P: 2A�A. }�6!B1xee&s�6u�щMGV i�:�kC }6-h!B��2&F�a�A pc�W���c. &��6a�{�torics�y s�54ghtforward ODE!�Gillespia� d��unf�a~�1s �Quasi-S�FNke Aj�xyk7( QSS��be m῅�J.� �^oyozo^�xeAy����@�E"8W�!�'����q��ca5E[�W�{�A��bCBɝ~je�C):M�&��� N�b `�-���ll��c��! �FIVend� ��x63�e�P:�FNhe��*� �NPa[X `;!#�%z�dyf N to �}�]:�we��ka>�JaR��:a�ƍE�ǖ�k��a5! ?e�a�*u��m� �e �?�P �)Pis`!%�ba��� !sb9��N ay/ �(Q~�rie�&�gby}���!���w��?"�%n!>Q(A !K"�O��(GzL/U�e�~ e V stepA`�"�7Ho�%IBfz`�Z? % � choZ�>Q�� 1h�^�4�1I�|aO�.p s�N"�7 =N�i modifT/�Ub��Y�pe�DcŲdel&a?!��2��"!�aw�DF#a"SgAA�c�/�0��:�!�v� ���c�7�e]e. S ���9 � ,� 3onod�i!� &23Mi�y�x 2s hm�j��%#�-.., n!) : �t = { {O} h =�z��21}I�� ��zm� �[� ;��Mx2�?k�, m �=.�"� , C :�  , nC��2-BF-.1�22A2�*�k >!H)�9J�} m%N?��Z·)�!]CI #A%��@2VA$y�>:&���>H( �J� lM�B� ���S nO2�[%5AT/ . Gi(rqI1��B�fir� �=��Tμ�,<� OI��MwEk��hmZeNqmUC�)��1NoqYc,�&���)��-@i�m��&q �� fun^ 3-2� :"� ^2#Fn�u�%�E -S����Wν!��>JUari)e���� deno�!Cν=?Aso�n")%"(>�U�H �!O:�.�]S�ۭ���pZ^ accu� �Mr�_�9�by q ˜�f9;sHc�1jin�� "�a���wny�b!I�.= ∑A�!\aBμ , ( 1 8��4:t A�� 2Imon + ^�^%��) (��(�exe�Z) f.8 j:�2`�&.�,��!M��y�eMarkov!0ac���&MX�9e Hk in�|s�� ��[t + τQ + dτ]u4�h |�!, �xd=.�exp - !-τ $.!G�(No���?n_randomM��ρfcρHK�?��a���46�e�  [l�!UM�.� � ev<�,�yM10[FrSA|as&!�%��ln 1 ρ8�( D�!�!����!!R`Xszz{*A�h 2�Nh P�P>O2 bE�:H\c� r&�*u=i�s��s�,�Hepatiti����s�BV�|pp�+inn�ib��gn,�h;Eish�� !o.�{"nXVE�{� kK.}-�RN�8pg)�Qb\�n{�xUIG-�e��[Os MAVS!�����f�( ( IFN ) λr.�;i� D�tx#!S K8 c-Uao����J R\,"5auw����|T faila �\ucm}�-αβ�&dsro���n&�E��'*n��� o\d;k-�p��3Zcru���i �ubiquiȻ"��� lŘ LUBAr��5itochond����abroga�)!Xβ� . Pa {!a"�%I,�dsYQnc �d �T����= �,�T� �al^�� TtnuA IRF3.�A �#�L�l�� Jkl  p��(ivi�s h!�I�es �b��r)j�$e 2@��hN�/��uMi"�N�"�.Nl2i6.�� . IU~U$"_�^�A1 �!���$` burd��0C�f�ڄ , 000 dea�an�A.3p�i=�qc��� orld�: [1]\hro��h��:vA�|B(����i�-e;o N �3X �S( ���% ��s��x˘( HBsAg� * CJ@c|1)c)!]WavtEe�.�: � )4����!�e�y~1ic � o acf�gi�mnsKoly�aOpe�@:lf-��2�<)�PJ��t9��2"�� S�hcript��2aj�catT��Mcon3M�pr�mS���Q�S�I�!tX:����u al X�!�x�?2-Aca eJ� e U�Bs�w!�xaZ�sd I��mA�r�H��wH�� [jur}�4a prominent fe��ature underlying the pathogenesis of chronic hepatitis B virus-associated liver disease [4–6] . We previously reported that HBx primarily localizes to the mitochondria and directly interacts with the outer mitochon3�>l voltage-dependent anion channel , VDAC3 [7 , 8] . HBx express)$results in%los%m2f�transmembrane potential ( ΔΨm ) , increase J evel!\preactive oxygen species ( ROS;and:qcalcium Es sugges E\f its profound effect on:Bhomeosta!�`funct�[! 9] . M� serve as a platform for innate immune signalAFTTplay indispensable rol%tcellular antiviral defense [10~AVS , a:�9frotein!Zs%� centHre�� demonstrl%oI�A�eA�0e 5’-ε regAof�� h�induc0ype-III��Eeno%�ehnt 3�$IFN β [15!�In sup�ni!qolymer!�has been�viɀshown!ydampen�i.�inhibit�IFN2�b��%�h��tea�� betwq TBKI�DDX3 [16�$Moreover ,Z����!�lso����A13 ]� by disrup�a�-aCa*as�C*ownM��*.�[17–1��It9/-$aY!Re�can�e);–Wax��a�voke cou!measur!� o target �(stream stepe�abroga�IR6�A8thereby!�A}*2�^2�^veVIJes:N�v%�of Park��$nd subsequa .%itophagyAIpromot��$persistenc !�ReeM stud��imm�:�dynamics�a/mod�ZAdof�6Y�[1%e� ��?hcytosolic RBR ubiquitin liga#�Glinkedi� >son’sAn� ,E� hallmark��[2�vIt%��� o$ chon�  w!� it��Ts��alQ" �s�aaN� "8( OMM ) [24 , 2�Th6]�^amo� ,key organellA�A�&�9Z.Qrefor�is very��l�za�*!�l sur�paxenvironŒ , polarizItstatu)�9�abundaABat�aw��ly af� !!=� du�/�ld�#PAMP-PRR��Non� E�, w� ason!��I viaN E3-M/;vity ma�.�-as" VKII isey |explor|" y�i6� --�dR^in2�ngh s�BV-1.� lly-�lj ��si��nd cau���5�)�.��fur���>�' Pr�LUBAC�3!�.�!� ��"enrichE6of M-1q����� ii-� I�$s��!��g�� TRAFI���s��-2u.�rR��� �U0 [26]�� ��b!�o� �I�!�A� ��! AVS-�H3 [27] or TRIM25 [2� TYb�WrevealE6 addiIal� hway*�phow ��accum����i�%S2Rin���.� ogeEC, our"|highligh�gno9I y'� nega-�or"%-u7n� unravels%��usurps- A�U � A�J� respo� . 2=��� ,�E"� F� ,-!� wvar� 8 ,M��  al� a�/ &� 2��Z A�R &R both!� vivoEi�tro cul)d�� �A�[30��J� �}  �encod���� � " %� Y�� �pro��[� n agree�3e�pymi$ we ���*� r&��!�s les?%��to��I:CF )A evid�O�tre� B stie@edQ'Mel �( ISREJ5�a$( Fig 1A )��ow# ,Q�silenca� se �,^t�N!G/:G VBXs7at% 2� ".�b�a�:uA�e���i�!OA �/����E`FC il�b!�� e<!9!�rY =�(*4-ΔX ) did not��r-9*�l:�[� Huh7-p�a = a�wild � z�A�%�QQ�� !�5�I�AZQ5ai� aE�oeu�n|� ��,�4*YE�2=0ymqTo&^ ubst�/1Iƅ-��evaluy��xS �.�AwV�. S��$y�K � robus�c"�R_iubsM�. *i�I��5@modest ( basal ) �!�-d�<&h ��.�� Oly1�� >durA� cY�� ���pas��B3�el�^AeQ�"� M�De�j�&y�A>�V�. xz�Overal)!b�en��,so far , cle� establishi\HBiM�on utio .X { )+��E� . Ouro��68�Rx"� � -���w�4o[ s hav��at�_$ IO.KlJ*d ordera���oi x q{n B*v !�)~6� �-��!9. U��=F ra"[E3�M�a"���osome_ ere �invI�d i" ( anT )e� parta�A�.V��$. Cell lys�obtaih��r�.(HepAD38 ) w�^ oprecipit��us0�-)/ $body follok��oblot`6�@4"��y<to co-t �:� } phys��M�ii�2� ��Q{!�� coѤboiprocalB 5 ( S1/ , .�m�.*.- s���)0� ^co-IP ) g���( ->�c� �B�IAbngEA;AF� appe� Z�X6�NA . Si:�]"/ � 1��acm� each�inexZ. I@ ��RbeSM�XI�amP�erav1%=analym)u��co-.��ɽ) vect�2A�HA�, FlagQ�d �. IE�6�ofru�jA�-HAe(A�>e�)2Ywes:a[�X�.Z�wil� tectl%=!^�) "���-r6�mV�2>Mh( Th data� | ��three@B�I2. �b-��O �8A#�ly6*A�jI.�~*� valid� t�~a��'YU)�fluorescx( microscopy!�determini-co-Qlvb��2���W edqudbE�?1 ellsU� BV1�� Conf���>q%M�s2�E]HBxM\�%[ layed!��ntb�: �i7M0EeeeA�te spot�� +2< indem��s1�q�"� ��quagfi$ �lag#� ()1�n (1O)�"s�3A>0Image J softw3 �F�]�XJzx='�Bdf�ozq2E�2G"relRly�%� #%� � 6H6!i^{)�,JII�Based� � I� � concludA����#�n6 �w*� aA7ulda�i�u� �nf�!��R� .�E�u"�-few�M�q "Rb:_% e�e�;�,fac�atA" deli�ofT�&�V;� ^lys��s=  degrad%zh3v�k-]� !:F�~b %"�! ��as�qu on %H^�� �on� _� Bc6�% VU:u� ( S2e)�DŚ���]n� sE%>�by meu&ism�Bpin? �is�u&m t�wi"~J h "� rr is l�l� &':&Yv)A>�direc�Pu]  4"detail%#possi��( �_by�pchQ;�2: �"�influ����, �r pn!�� adic�M� e2�[1%�We&� 6�&�$%��end�,ou�!� HBV-.\)�-?��� ou"Yn �B&3"a Z 6� % E�:�&9�R�c�b��)��:�[u�R�ake�"yk : ];>:��� Y=Ձ��bu�%6C��r2�+&`. Afte�!��Qnoa ' ve n�.Q�n��Z.��Q�6{j�ag ec���ng�(rem$"�$ypeE� U.)atA�+ru~�q��mx%,ins [3�%�istinc*N%�'can� �w� ��6RA^���� covalentl(%%z[13 , 3�%Sometim��h~�' anch�P FwmodP!<�@un?�io�A�%��!�55c %4M`machin�% pred*a��-z%�e>� tagg� K-48bN�[3w&Oa�%agr�!�edE����,[3*I!�Y�.�� kindA�Y2�invol�in��I06�e probNE�j *As!mH��(/!�&�F�e!��.��E���linear (A�l#$K-6��(Mmattach@o ��? Zᗥ�A�a�)� !�h�h"����ed�3D , 4 lan!��ft�O�)�h�I�]�!�.C �e�|%y��@e�1Mc��-�i�Oo�a � dq l2of��ق�v+&�2�i�-R�&au�1�Evincub�~�30 minuAx,at 50°C pri�-�>� (Q!:m T,flow diagramJrC%#)samplAۡ�b�0�:4s!_%�NnA%&�Vr "�%�%�!yFm�-uC.boeW��D lh]y�It��noA�� he&)[!)K:c.�b�at)Q�i=%,b4e�cy�I��to�!e%� ���pre��Q,���S5F��qna����%�elimiEd��,kno��>Prem��un � ven! 9E�A!�is�2B�."� � � merp�di��lb��akin�*���troA2!^ ���QVNV��:S6G��in � U���E�a]NJ)!K.�B�R is�&��WicI2e�BB��'�con*s�� depi�%�e3&3F�3G r6�#�� �&�E�=D!zB�.b�C-�4oV�)A ��9$nly cataly/6b�.-lassemb'omp�(�+ ) [3�737+*�.becam�yte�a��]�&%+�e� unK��My� �� m >#Q�!�VAS%p�l"3�I -v@ exer�:  ory��e�8)�"n8 � q �,�f"� a���k";!� 7A��"g b*��2�1� +bP�(Jsubun�by�* 0c��!� � !},�B�!�� [/�) e ag�Tt�" ���7M�6W^6?%A!x g of J���9��04q���osX5onB#"�Y1 *�R �1 ޱ�a�,t�?&-� �f�( S3A�C�".�c�v-B���-�5m |E�9A� ctuaw:2Y�"�E��wo�=&�A�)� EUx'A�B�%T\ ibu� s)���1�*g,A �co-eluAW�T�rQYF, HOIP (� a6�3p:�ct;�����sM �!P$ �7ng�"n�Q��R%)!_oM�7-Gn"AA�ogovx o.^o&;A�.� M$approximat:3� d 0er( � �JT��!!I!z%�"3 mv�!� a�U�0�N �!q��.y �5� M��*&�y� ?��."�i36�� {^jha�,eH� �M[Q�oI:�erul�u� "�l���al�=Q.&z"V or6��M�:}-�l>5#by!�:?y.�/e�#ik� �&/ 6U!JBe�! pa?2� ��I�!�off�?  , mose�Ve����:re cy�8aC7\0p�Z) AS� ab���, topR�4o2�e�N�� hepatocycQ� Enr�anY��G+��� �M.ai��I+I�EJ�)!4uo!2 �U���H�PL.�.middl�Cn�3� 2 Fina�<Ji�:���JedB[� [E� �6� I^�bottom.���� "�Y Pixe$$� !#.��!>R "B3-� adjar;t��9ic�3�%MPv2.e9�A="� algorithm0$as dec?9�lyO 9] �.6 non�@!�)E-�( ij ��.�e82�"�:yEp�.@prr0��.7�>��l ����Z�!�C�!�3"�' 6�#�(�7��a Q��&�:A�uD2���A��s �-H�b�jBZ��<�� � <Q$r a��Om�1C5%J2�a�� ]uX.����>>lVh�d>� l!OF3� � or�.N!>07�n &� �!�?ngthe�&v -"�+�&U&!w�!WY �.��:"e-"Et*�f �s� �4b�aboL.� 0�$4�$��3 �!#z �t� %�� wc#!'l�G.�.^�(2-M1 UbeWe-?���V $��W�.�&�0�1�5&� 1)!C!mq1UBw�.6DUg.p& %OS3B%Sa�Las�w�1fi63 N~oUt�e�멜.$ ^� E>1��( I h._ �e��uv���&:?;!above�"�6A�no�e/ |"R% � rre2�^�� ��1@"V� �:N$lC�*��2��G!� L-1Le�Sharp%+�5� 2Ar�f�IZGE2z���)�L  (��E��J� P8�3���7��i�62"�]�g���GH"#s��y6+%+z�2^E�"dreH��discrepa� WE$-:">%�!�%�t��.I�9i�(32.Ao>E��uD$own��aS r�:=sx,�?( TNF��Joc�f�H��-O Nota!OX?�(�(��! Q�$>�* &f�$Y e�[4�D41�#B/"�?-32��эթ#R�57>e�6!�m���� I!�,�,� Esonp"06 r�Eadv�7%�!l��o�[_�H@O�s�/i�3��d0��> t �)�;!Q=��K5H6��� aUz>���.we~8A y�� thei�M�9I��-rori� *�#l�p�!�!D�.e&�#���5�%dw�!E^� !3 5 &!n�n��fI6kMS�*@ S@in��l.9B����.�9's �B!ME��� �dB75M� � CY. *�.�E�hypAAt2%h^�a 2��+!� ki})2/��*N fash��u�a�v6A�<stitu�assnCJ: [1�G4�"B"A�2�- MM*P.O VSn0vesicH stoma�R�R ) -D+� ( S4 & S5 !E�,Q&�7f��3pur�/6� p�7r��6��o2M0F�&�?G.�G��%� �s"�1,e�)�"csiRNAR�!�a%��'�#:�S �P9p,TEE. C"�� � �#zQ멉2K� sche!�c�� 6A–6� 6�5M=�-M by q�R@k:>*; �=���&"mix1qA��&1 �2�&�. .VS.�ś� ��1�K,gL!zC �U3@N�;"�"�2�6�id�u�4-��� �A�j614�86� W&�)!���3�rui� ,"[2in-B]��6i\.�lE�-�ic]u]?�g � :A:�)��C&�"�g!�u�rext�!�"6�=0HA 3� �(.Fd��mixjFe��rifug��o p�L�>. �}[-cubj�/toZ�*�- -�S�� F�.ql59I���""�: *�C:@9FI�u6H�.� :8 .�"� e�ei~'B�S)u"�% n��5�%�6� � � ; �P.)!�>�>5ex�� u�:� . l�V�� such�! ��"��X  �z�� -�.aas"�x)1��*U!Vi5propo��m"�2��)omb�=#~�Xmm�N bS6��. k2( �J� =�T a�M�2�&�2un� d �v &�2�š�t P8las�= NF-kBշ"�L� I��%. ��Xs!�"�2�5&dK-k!��&oPfew exo&�5��N" 4gH., w. P:/po!dQ �,in Drosophil� : impa�DU�"� ���1� of{ �I�%d�FE�ISG [4�+N\A�>4)Jby�c1C�`E:� [�M�74F Dg�-��nPJ�Q�$N��"�6Qly un&[4W,�]�:I))V}:�b N��"N�A'�2Z� -1-�"0#@*I$%�%3i� ��)� isc�!$>Xdiq.c enzy�-a�8n�Ts two"t )T*AB i . "G!pHOy[3�1S")U$ly SHARPIN �q] �third%��Y� �[4@-Ij�}Z ��Oe��5b uto-&J�4�*aN��� " >(�or*\l U�aTU>!makQsE�nD_Fa&@i)�F� Y�  EoceedsE< thio�? �c [�%nN�1)!# nti->� ��]Z�^% incI=�M�J*� 2f&�QBy� 27�^od�_�xe{)�a�R ch , ���:1s�/VR�a>(>n4ly�] �[�Fr.K!�2����o a)��0�&]5f�:z_lu.&is�H���e*n��! 9�"i�<3ĉ�"��("��beyondb8|X=el�-aK�a2q�. U�$T�s= � �ea�i�Ja�eZ�of κB es�HA��o� NEMO�^ >�MH }A� �F&-ng")Q 2I�I�!��,3 `m� �� Q� � ��:N.Nof"�� ^Dsep�� �U9UVr��9/�st�C�z m�8�S.[&_H!0a�6vQ`!^0( aa401-450 )!��� 9�� �QI�M�II�  �3)1�[4�3*�9,> ��grc9�6� b�m�.�.z%�5e3*��a��O\-` du�@2�!]� !~ F�c!�u= ammaB+�.U �ify%fA�n�Ed�4 Aam�`�is*{)orB} , it2 �A���B�w2lo� �a.Qi��s�e- tuEbal�"v$�8 ��a�5g��.� %+�;c5�?�d*��1C (�Is�F�(� d&�=!�& [*]/R�/aF�y]x " Lk>. F�e�c�0��.U�/~p, �a ioc nd6�'er����in�rA|G!uc�[4I &��-be�!�AKA� pBof �,%:m�A|e@-EKn4 �>"��Y�R^[4/ZW8Z� &�8�5R>� �e IKKεE�Z6I".< *STAT1 [4�XI*;3��R�:�w�fC�G0b�*� X��a�9�Oudo%r)��h�A0#&_sVj"�5R~as6�MA'�/be dueQ O"� �+�$%��3_8q &B �!6[%�,)�+��8 link�9]��^� i��Jocu ed�;0; 38 , 50Z"de)�*�.-��AB�E�>���B�� olF ^g�F�A J� [5� �W�isA^9C�-z �J�ag� Ri*^d puzz�W [�~HB�N�I�)Fѝ> 6J�� �5Fe�Nh2K�h��$ !��2c�M &ͷa�.46(1.^�R!%*R%�t��bO d.8)e*�b�N e}��N �� �� B,.o&�F#& � �!`D�}^�e�se6���s.� ��R.�.e�%Q�b>�GI�"EwM"\*�5�2DV"�S&�Vi�i(&�*o:VX�.�U�A|�}�9b�-n8X �=�by turb�?E���A�*� �o�fO���E�bHU� >�VI�_*�^�Sesa�)�  \V �2��Z� QHorche�R���'-bLS� Y�R�I.�� de{�h althy��C �+I"v�lh=/m<�3�cqd/"q �q6�~`:'s&�� j�as8 �'�& jyAW|�X��M!6 tas[�kto�_)��.�� {^-��kz$�"pe�2somalIf"�s76P>IRF-1 [57 F]$!"H b�(#N"a?Isp14�p !H"O �E��.@�;WA�Ez6��j]� pc ���=�15�> ��adv� !��k�D�PN g�r�!7��.�>f`ed 1:mcq�.�J!5Ac�� �%�5!k..,c U��r�%�!M&�c->*W� Y11�a��I�agoni�8�2�6%l velJZ�2�EYZI&� i�Dpro c�'ar*KM~*�h5�� .p ��A]tudy o_s a new�6 adigeN��)d��s�uo-tempo2e�� kIej!� eluc�TfD#Lm anip�e��R~9_. { HepG HMb, HEK293-��"�.W!ATCqdA�$an Type Cu�e ColMon�7AZd38.Oa k=E gift RD�LC1Xeeger6#Edelphi� ��Ii���Z2�"*W[N8$pHBV1 . 3mRsAb�sd�fs&�W�a-�@eN�c!��Tdeaak �d&$�%�HR�`Jing-hsiung James Ou ( Un1Rs!�of Sou�,n Californiay�s�Xx-flag ( Addgene# 4259635W FLAGBGL�j�s"\= 5001<� 5T5�"H!#44032"`ja�-}%�u�yl"� 5<%e�aIe Lyovec=(a�ivo�w)%~�,;r� ad\rM,(  B8i�>l) aGferxo�� �GFP1-& B�& =A�ly�Ym:E�8Juan de La TorruA�S��,s Research I�'* Joll>CG+*�$P/�N�$)k�*3=o�:te#ycT��$afZco�&/tA�%�(i�BW�inser: KTRE2-HyA� Clonetech1�!� �i��y.HrTA-��� P.$�EV�Din 0 . 5mg/ml G418E4 hygromyci�`For>�#d� *gI�� , rab�t| -�� bcaMzmou�?�p�r( Ra�( anta Cruz�9ml7�iY0T�F%E�as� %� manu�� urer�EW|gj(A�D-K4)qy\$`S"Z ) ; M�AB ar U�R�Q9 ( Life� �+`�a�*�HU�%*TB�R+DuctwG�> cannA�$>�6% IXgrown8c*lip �y]��a3�2 .�G 6�[E �R�8�{&Z } visu i�a 60xD10i�(0&ive�Han Olympus FluoView.0J�Q�Z&zEi�Zse�-M7)�J , AdoMnd MBFs�ZA3Smm29 fe�eRNA, �* ) poo�f  E�4siGENOME SMART,EmK4n&/+#1��[ ( NTe# ,"� �e4�DharmacGsA�I|B� �( 50 n�tA�6DO1~ Z- FECT 4N� reag�#accor�B��v�( U�F&N#`�sub��%f!Za/(a��*A9&�tof�a�B]N�%1�g�RP �ys��uG41 All�VcedaxJ carrk]�?a�Junf>�wis"�Q">&�m.hom��i�&C/o��bu�WE'ai�H10 mM Tris-Cl [pH 7�� KC�A�* EGTA�}% MgCl� !?EDTA-f�5� ?}ckRY* �\ ��~$*ate�x gEe5IMA#9*�~sunbroken � \supernat{{�p2K*h�Oa�K00 l1�MmQ cr�]6� �eD&*.y.2y�l2�was :o��J2fr Resuj�a*B)� ( MR�1( 2%� HEPES-KOH5�� 10% glyce�,B���1 +�d���MA"�T1�5M�y2Q)��c.!! ���#l�{sLZ� 6�/ =]�|��-��15 hour�wM�o�O�nm.Z��--QVfKi��Q6�n�&w?�A� �-%��?Y?o �� ���.B\/A�-!�&�-B r ab"w#ATP%26E�u� at 3N)�"h V�!�-���ix%�resJ#�`;)�$r SDS PAGE�@� to�`f(F@ z396�&� ��.r�U���i�x�ai�)ndm�? ru6�n��m�3��%� cold :$.�rI�^0�loaalon!.-5.!�lx6�� RAF3�q> ���H._ T��Z I�� 21gin6� )^� 6�g �I��%�ply f�/%�&! e&7, aX2 m�har�k!�X ΁ly�� a 1%�� ton X-100n&�'���HŹ����5�<Na>I,N>1%A�)\�7�.�, 1� PMSF Na3VO���NaDTT$ �E@ V�h�.�bg(2 milliTof WC3=5 μg!�� �%�8*O Wp� eaffe+y2� I!�R�/G1 pled�harosj"ad�/GE�SlthcarLma�%�<�rot�-EU�la f�a^ v'_�E�0-�,=&�Tde�Q�/1xe2Rdy "��SD.C� r� �(n�6A�ul�*�Bio-Rad�A�coBQl6]�P p)<�-�T*2a��fig��legene lS!Qre�en!?�B��[ �gvc�Vofa[@%grl�lOC error bar� rltmmean ± a� m .�X�TBt&D:6S�s�CQ�5c�3&p8%�,two-sided un�/ed Stu]-l0t-test .T�T�d�iP]$�qric bS�a%&i�Eii�9f&�%bow�Gi��. I� enco�b�!e pfiT �!E,Pseudomonas &�j�)s T-A.A�er!�X*��0human Crohn's�& . �p���?!� crys��str>$of ��  . 7Å!olt:��r~2qE��E"��2d<�=�u (log , PA288��*+^(MHO Both? 1r�gZ'liaz c���!^rol(tof-�ho�J�����&ng�@ja�N: i\!q-2�HLA-DR��"e�* erP fbhB 5Q�DP<��ng�.�.}-�A� . GST-%d(X��5�!H*B>!*"^ "�7S mbin� �1fWXd2�t?Hl�)� B.Gze4<o3��s%%��_a��� !,A�Myc��althritidx5i�x�MA��� e{� 14to ��:��?*�Ps�Blap�m9�Je*�2�belong��$TetR-famil�-DNA"!���;E�"����E�`F� ���!-���C�s��.Es'�;�A��TC/�typ" I��-~�/�g1a>peptid!+r -lip��}� jor histo!� atib�&;4(e�)][. �A.�so Bi�8P �\���&k�Z�0�28SA�>a�x)-8!�StZ ""ary ���eliciAp�jicrobytox@��^2>�A��TCR V����1� , [3 K[5]��!_0fcaA�to D� �'[6?7o)A �hlջJ  ,ɚa$ts full-le�Jɚ�i�,)��X�1 geneB�>�( C�P[9�10 1]ay@2al��e����+"�-d���9�K/s�Aofe]2 d)]��,6!)3+g%5a�I2 �,��iv b,�ZEBenle0al� o�tissue��ut�!in� y� 'sA�inE ileu Serume�Q sR8IgA seroeA�a��I2!�9$�CD&�+. S 4Fa�͉�Z�LI2e .�50C@0%!ea�<�( �echildr�]nd ad\;)I�C�afat 7e ulce�v, li��J4dh�#=3�l @� ng� ngui�by��*P�Rf�� prog�DR&�)a7f -e�Hf��ij-a�S!�f a��Xsu surg2e( 72%A-ny-posiAT9H, �-us 236+7'+)I{T<2a~�W"� �� ic cA�ny � y�I2#e���)E&>p8E�1#b� a nory$Z&r��al5 umMMC*m�� ga+J!V302� ct [�Commen�~" ha�Lm!�d 9n�$o� F�/��N2�{@o��P{ lv�|d �M�� !Bi"�#�� obio!<n IBD [2z�s.X)8}�%�� ����SAg�2^3ind ?6� !�~0ݼby1� CD4+� sY eV"d1�&V=B^HC��&�77 �,�&�A�� �TaEi�tp9ss!P��fe�j�Aa奉M�block�'�5-Ab���2� e17=v�R�� �S87��e��"�%��ms:e�n(-Vβ5 subpo�#�8!l%�7+�@ed�!�bio��yM�P c appa�T.Y(aeruginosa 9 �>a�( 78%٣i�ty4l�_n��* �=�.o�tERA �Dco�1��I2�.WG �is�o>I�,esusCM�r�)�-Af�s�$n*&d.� ic� u�ti���!=B�BI�"�%, ���� d"@@��w�CD.]6.�)��'�)� %�b%5��EImof�7mo� splen�AR�Xph<�A�od Ks�a�9� PBMCV@N�!^+e$XBK �(2} � m�t�;6� P� Q *:�sha��an^ pa�.x �YBR1_2]� Cryf� high��o�J^:� �C��"� �5&P 2{#s�:� - tc�+IK�Ere�y!D ۅ���*:� \L �AveTaI�A . Ati(42O�%��y ��1His-tagIi3)�-{��R�{fai���r�0e graf�;a\+$ � pGEX-6P-1W (�H� C �� a��� BC�fu�a� vT��I2�:g�,�A�) �cC�4=Q�4^-%�B+iu=!`!i��aP+K.4�ToB)Y&-a���>��di�:��PreSci���F@!��),y4or�ia !�r&J�to�, gene�u�dsize-exc?�.�:graphy 2H�/��� ��b.�.!�6��tn�_��s�^U�}A�a /2��� ţ�H)v%Ain�!E'�u��%�5Ey�� E�� AT 2�7l- n-MB$&Luwhe!%�6vQ�&�i�'o�$or�kU%�E�IU��FR,z�1�)-a dos.С�Hlm�!�ma�  � �0i�cy �X�0h;a��n� M��`po�2BStA�lococca�oS( S\^B B )Y� ���� �isoe�d)0�MCD,|aA[ cip�Z_%tI`. -�.��T�y� on dTB`2\5� �q#%ղ���p&k *� 1SGk� 3<9 . As����C� &� /aF��Jed�&Y:�(ver�>9g\P )H��JeV��+ e labe��BEz�nA&� t�carboxyO(uccinimidyl�3e��CFEp ���t��'"� 6j�Wye di�du g�9 cess} ouh�+ divi�}.o-�Q2���t8Q"=�9%�or-D; SEC%TSEA�`u�^*h�!�IA� a�+a741U#���AC�|isNfK4!7>�x�{Q]� !� |�ՇK9eO#��j  � ( upA�5�e�al � decr5.:� AN��l�o��� k!;a,)j]��Bg�6x>�i��a�,�H�toG!O �an N� ,%�5F–Hx &P�pMjW�1�re& �2E6�E^bi� e���:mh��:�"� A� .Q�i�.v "��fy %r"�Isq� u�3>���]ny�9an 125I-��nu�#!{&K4��e�.">j���2.��B!� .�fiT2a` �;AQ<�Q�A��sV�-deri?6>�a�D�nd�%f>�ه ly "�Un�|MM�P��E"�g$1_0.='!�!1� )xj� ��3xz3ed�"-f�$mܟ ex�?Ak�g�tl� >75%��min�'n�"!k��8�0A��facq �nM�V|Wu|2�$m&�� ��#5stm!�!�-A�>abP+4<��M�PJ�. SJ}9Am��$in C3H/HeJ��:20%2�W`perhap�!f�5 ng a F avid< a��2�i$ plotE6$ *v�!��/�K:2�! !�m !<�M!�W�bt6� �8�Jvto%�s w��"�""� 2��e�m9�u`�� �� 295>����qh% *![aC�f�A��7.�iso�Ncya�,A�IT�lWZni��y�)metry!WB�of ?u(�m-suu()�e ���iFo$~!��a s5,HLAa��U�!�� �zt�A&[0.Cw!qS:2�!FF��by 70%!DigX8a�&�`�-��!P 1��:b{!af�(2�abJ3 )R"%��f? e"�i^!%��imaүby!=����2$9W Lb�a| $%�;A�"�W. 3P E�"a:�%x��( 30%E�25�_q9'1�) �a�I)X"8#�+�5���!ly��E �i� Ebl�eU alle�"( D�D�Dn�. A�5���L Q���S> �@�\���6P�@Sd[t�.B%N�+ng!�mxt�W45%!�?���e%�*��!�"�;-@ hA,( �),!d96�b ��z=>T � ��P ݩ: �Ag5�4a�Q�&�#�p6irm�>�DE�*o(n8"Æ�Lp!8 �� P&%!'��4A GSTNRa��&��"raE�2` �1 immo�"�)to gluta�� � be�*.�a����� Raji)a sour�g*�%E�R�H���e�>�S � A�&3)9,edF^56�$��!�%*��;��!���,�D�N0&�. NC�,5�&�-�!�sQuw� T �=E Q !5�.� )G1�� &�$a 5ag!��4 ( �.�$!�Z�p���BJp/HA�  %E�&� !�!�f�. Arz ,9���&יK.}� r�Pas� !�E,!& !�bH(�-6.�  l�Fr�$!,��e ~wria ��u=�c.�"� >�n�"6 h7*� �6�M&9�E�v s�f�eYB�)to%-����� !GA����e0Ns ���� �,QJ�'�#&��FX- V �E_� �vZ( i��-�]D:=F84ʋ4?�� l&z �.�-'%!A:�. Non�<re"�# \ �a�cur�>s"�%t��*( K�� zRE�Q@0�� 1ib5 µM .nYaF aris !TKD ��!�1��^Rmsub-nano�ra�� ,Đ�FI�"�"s�� �ZP= weak&Dx��EDWF. ����{!#�)�1IO��V x/ ultr*v?9 � ( AU� se1]E0on��(0$ A�X%e��"�:a�y)��exist�%DE���6~ velo��( SLx�gntU!�yk��� ��\F 5�:)5t��]9Z�ETof AL6EL%�6 �xxeaki�a:�co��� ~9, w ) )T1 ؁_2y%p����"�z���+ )6wYa��a �oazAigh�MW i&44 KD�Bw�abb�jfi��U,:m B�4^��?�?A�MM!1�t!}!�%\�� �.r��� 5�%ʃy�f��ldt/�n��> .qmi"�lpN� ;.�^XA7&�=tio�� �f���R*rq�5� . Gim�Y�]*)�p � -e!� e ch�8a O%r� ( A+ +B+BA+AB+�A. B51I\M"�W ferra:� �,S@U� �`B6 H� �,^`�X��-�.9e)ga� �ll i�8�܍����A�� 1�s�x�methodb .zU�tV�%�.O�;�6 InJ�sit*)�I_E+}�ef�!Jf8��tag-remoM �5a��.“�”ZvI�e�]F� 6�d 6[Q&<9��a�2B./{9 : �$;�/TE�3�b�i!E` �� �$�v�nn�! 6B , �<�1blv�ݡ'��k�-� "� a'ro�~E� �"�nXAv_* IC50iTDHJ\�A�ZP#"��5 . 4eK<4�^F��u�:y�@n�B��i$��t���:�ndvby 50���*)�is6v��^��9 ���9U*%��s"�%��+!b.�b�&e!4� Mj1_a�)�%�!R�Lb:.X �*K"��! �nAV:�.-rd,�>A0"we��qa���= 6�=1^)JT�3��. N�) P:C�!�M�:space up C:0 � e�� asym�ic �� Kqv5 afQ: %X:�-�-~;Zo;{1�I�mp!7�*/F%'&�;u' �aB~ placM$B�-�=�A� !z��Ae�;&�*.ȆMR"� �-��h"�P��-ge�$Cleno-� ioni�5Se-MeX�-�$;zR��bi�)��-��[�P212��two1 e�1B�a���i&�K` �H�%� c+ x��uscree#L many�C ra�� %�fi��" -A�/�1� at 2��6��A}oBe �-Z%1��b� in��alJ�^�C �SA�pha'QC�Y<)�9E!��]/�� refinI��Y�-ick �e����at~956(2�?�6�sB:8BAS��iW!'Ma~ INh6�1�R<ͅR 6�F�7A & 7��%�!�l�K4 le�k α-h�=AM"�.�q!�en*PQ�0�)�jm/C25WGP ri�=re�11�2�8-�N-��al J&Hn!uma�.disQ'"sOmM0ng.?<{4b��c�A~$amb��t{W����%� �| �:� P216��-� I��u� �shz�-xx����Tt5�E�G�GPLGSula e����2ct�3� �.�A�M��� 杤>���v�2 �C0@͛!���E ex<g. 1.5A��"���(6��)�2#D�>6>v:�i9 ����A�^�MG�A���n1VL2�7���'-�K TxXeY uwy%X G}Y��^k�� Bj. VASj8] �Y-�28�>g��@��B %���Oc�I1^�� p � f6�% VFo�haemolbu�4PDWde: 3HE�o( Cuff MR�$Hendricks �" Moy ��Jo��miak �unpubprd�4)iqaB�-2�h72 Q�7�� . At���;�Ae�6�� �s�#�,sp _ lix-�s��x .)Eip ( DBfa ir�Od I/'>J�#]�UC�Miut&[:baCv� �Ka4� �ydu�`�y�/���C0�BB�A��8"� �<��#iz �i� X�R?s [�j�B�� �5lE` I�r? �Aw����E x�+=8s�R�:�"17al �eR��4QC��CC�xU!�3&=sIDBD" ���I50Å apa��>&a @g!6>&B�ge 34A��xp��eq�5�� �ir . ��mR�:�-| widely-bed ��,&�1�O��exZ!{  ���QGF"�.�%bio�A��� �� ..�=&ڦregar�2l\~��!� �*�NaSE �o:*re�y�s�E� v Su.�F(�*�%Pc�u�*�6#R�$erQinartF�2I�H� CO β�Fi�A��=��q�bh h�(dMNt�86cock�ddr6G�R"w'!�Ms�[��wis�I����a�*'>Y�yroge�^3*#Gs6�6>�rp#I�6�$�a��ssN���:f� �he>�#�D.�>���6(i��Z��N�6e��A�"�,��r�ee�%ic%;!7y%�&%OJ�%1XogG( �+�G, a�6jXO��}�BdZc2s�#u>sQ&&s.Ty�'t�!kd"oHBs@&��o%C�� s*s3�5! !��h�/:V)itM�@-�� J+w)�I �.S\dQ�=!V�%w��.5�h��f��o�F� ;��B)N�Jo b�Q�" P �� -SA#!�b� $�ultidrug��R,)Lu(��&�*���K�ci2e��byu��EgA��y��  }�?30e ɭH ecu� ��mM groo`q!U% al��R��bBp.)-)X.PJT�u?5%�&�Z"enЀsa��Y cata;�cE�w,A�&Oj� �-���osm�ҁ�^|Fpof FV&�H#"7�6� E�"n *i *c ir%ve .�,*b".�r�;�F!�,2N� �|�>@ +�r�De-9olig���=�xeZw`6t��{etXme knPch 9A|-F-A�� lex!�6� Z feMd����y 2njza�er*. ��&� F��8� to Qac50d s�6%d*�Q>�� harg�2I &� �q���G�"i�cur�ly"��?�JsT� a-�� -� gges�e9mS%�6�^�J-*� � .p F�'�6�bC&�"�6�ac_'�e^^a� .� MH�M*LE� genuE�Gra.�e9Q c γ Cob�Q�bYS�OA���bdacea2NFl*19�ec����LI�3 �!� ,D�{Q�lx�4$L[4�Q4� ��BLfa��>;� 2��1� ����c��a;G�u��C logyi�E@� S1F!*`{2~.w a nu�#�IK1}lG"%DE�m].4�� 4f>Z �2M�C�?Ew��.,eth�3�ku ��osiZo�ouL��# gr�� T,�� *�)A�P�2=$FH��xE��-�6J* )�.�g�6(%�cs\C�2�L�ӖJ:�p&�;`md.:E�1%�1 �+2UJ� �Fa�2�3"�J� W�=-ve%��.�li��0��C's��%h�.�5�4l6�1��ta�!���3�6Fr�-u���@%>`Qa6Y0e��-.#8D28��N6D$.�Q �]:AH�$!�2F�K, "Q  -Pv0�;6g2�27t�R�&}(wW "��. z&�^�I.2B!1Pem�N!�"�#�on �R<"�1ai�W� phyl� "�)���LctE�.:\\G�m�!"�UE�%XRZ��3a�Uk.�%Dh� ª*b i*��kip @!A�%��4�ur�H-2E ( �6 logu� ��=jVE�cer`i I!4 H-2AuZ3� ��9a-*�;�C.u �.�.�x gb�|���׉���H�[�s1�l!�^ 1��W!�3 �-'a�'��ovec!gNut��tX[MH&��c%7Ang!�?C;eՂ��s�N&C��� n�6�D� )V2� ��7s�B; �old�����>� ��-she�/) ly ��e�,�6,��� ���;:v!V$7  2/a,v.a�k"NU/=�Lx���p�!rn �� So%�-m��m�:�!��< 8�&[�N�՝EzR��  ��YE3:�sMyyield�!jv��Q� = ��/fnue2 cv�VntA�� "Lmc"DB c!E?�F2' !1X��}r�A�mc�ne��^X��a��ʼnse"5�s awa� nt,�����ss!�R ��I�[)2s�u!���!?re*0Q�=�fXF!��a�-���R� s��smnGn�SA�-�<�@"p?�bq��s� 7��ow0 �Q.� �i�>�=yNlbg� � ���Q�S:!�.W*c���aM��Z!bio#�����_�d (vI phen�CK:K[+���\uamt��f^�forp%6���e*��!�Vaa>o,�F=�D �!io��E<-2�I4:< p���s*/B.�{e�epؘl0" Z � , [5�D2vR1�sm i2/!�� �er2F �2iWA^>P��q?$=jal�c"[,!_> [mun&7`YJ. Anim&�;�E��d/Me ��rG�e�� dard��A�d�A��*AAcc��t)�t� abor� } 9T( AAALA0 �i a =����-JWA�!nc.�rk�1oa{� oc�ta���P�yio��.��Use� mitte��(Wadsworth C��E���w�' w�^a Aat�snk� ew & ������=X��39���n'��!E��h e&� 2 “Guide �B%�1N�s..� :� :“PHS P1�y�@H� e �R)�H-� WelfuAct R>��V( AWAR�Ax1x����F��YVbyQw�|�%E �,(n OLAW-Assu^�E�&=�o�HSB�2�NnA3183-0�$ �� A��?anonymABh!/UGod sam�lpurch�D Re}Bl&�.�� ex�*%�v�RevAYBoRCoM�!�!B�J��C;�E ��)i�D��'*�DG-7<&@{Biotech��y�2nd L243!���AJAQ ( IVD1�~( J!޸BDVs�� 6BIF+Tu39 ,2P�xin�1CD19-APC;LT1)A"3|� CD45!-H�2D=BD�F~CD� HIT3�R��qti*-PerC�MEM-5|-:z/( GE 2rYiIgG 2H11Ea>��4Ellis Reinherz!�0Dana-Farber CA��Ɓ�F�3lfI2.�>�"O!�w %wVE�;a&�^P!�GEF6"cZ*���J��caf�'�#ser�fh,e pQE30@Qi�yP 0[r �P,�p�Hi�a pQE-L��1� �lZ8b'D �E 6�47l��*%L� �����)`Fine2�-(�() FaVt[)w.�y�9 ]u*S�D!-w)A4�se�YI"t- Ui� ��7fmY6� �[SpleeH{!�na, mic q&�sEB them� frosEsl�j. H"�sdN�rd 2Hank'�����lt&�(��S`?!�tY;t�iǀ m�b&�zammon">chlor�f"KTyp�h d�� � ( RB�_)2�R�Gof$ �� �tw%!hH���@ ifug� ,��&�'m�`� of 9�18 ,Q�BjჍ�, 2� ���3���>�a$�/HF,1ye~&%�DR1�1~mol��AQs :�,�6∶6] , 44∶13 �8∶24��$real microU!:S��: ��vE� usedfx%l �$�DE}2��:� cqui�Vats280-nm (��E �or� 1�-!xE�h�mC.\6�d�w�� �j.!PHA�". ��e%aasformed��Dglobal least-squara�of �@ ulti� :��e��. �conservA�nT mass trai~[��> �k� abou� (–15 mg/mlI5"� of� � -HCl�H 8 . am.� 2 CrystalyXE� grow��N* hangc drop�bya�2��O" ���a"N of2ervoir+��� 44–8% PEG 335�1 .� � 2 M ammon�6�,� M MgC[5!%8, 5% isopropano!1!�5% glyce� . M�seeT !�ua�toaW,duce large c1F . Na iIbe� Z pace!`4up C2 ( Table �9ɀ8Se-Met substituAe�zLP21:MPriorseu��, allP%�transfer���z�2.&���fl� -coo�0under a nitroCstream�} 100K :stowin a id/. Diffr�� of n)b- � �i.1 . 7 Å�� sat m� X4AP��!�lonal Synchrotron Light SourctSLr,( Brookhaven8Labory��I6�!� olvef�ur�dJ��M �sJ���re�s�n� År!95 �]Alw ]%C%�procesA�A�sca%�sa� HKL2� [52]:T� ��a��a first<  � ���"�t le anomal� .(( SAD ) pha( metho�a�9�� e Se peak*� "6 t@program SOLVE [53 �e!� dens� map�improv"�.EREG4G FragJs.���55%!-=!1residue*0uld be automa� lya�cɰ3 �p�0 of a�(monom as"��t K+�fit�\V�� sequ� I& �8TURBO FRODO [55!!Mse� >molecule�;.ra� 8asymmetric unit%q�Pgener�u NCS 0ei�aX�:fu!Aref� &2 .]E;at hig|]�(2C5PHENIXU>suite [5? �R��%D�* �-� eABM�% ~ pS �al �2a carr@3 b.:Fr�.Es�stics � summ� �Ѱ,. Atomic coo�a1have bideposiAsin!� PD Bank�I.4MO7 ��84MXM .A�Nanog a princip� $luripotenc~�exhibiE�a�perse "�%�in stemR pop�io� viv� �v�� . Incre�xev�po� �$fun�!�oI� � hete��e�Co.wf decig�Allel%G\a EA�9�!�repor!Urely!^mo� embryonic�_To���z how this�=rr�!  infle��ob� z6�f NANOG�VT(, we assemb�[a, �i��chaAb=� balyequ � framework%��i�!}:6,B/norAT(random part@����div%��� id�. As  ult!#r)�ex5��.[/'E��� & inctece�t w_ch� crip�al ̡*� 8 became bimodal�egardpf+ir��paA #i�uni =� 5�s ga�r!P�s} �6�+a�enifcyc. Deple�%E;� r i ,s switch!�off both)�%{e� $slower tha�W accu�d in"ll�M�a�lls tur!g�� 54 �e|cop��e��to s� -de�W ynam�..u�2�^ Xj"0raises issuesa{a�@#a�of9| � s%Wq�r�s knock��a"E m locua�Ind$, significwdiverg��wasy�!�h��d�dս��Ms��eio)��XerU H(ir half-liv[�ZserQ2j%oin)�r)��e �=.�Am�9ad)d]�� �^��facili!É�m�en�{of�u��i elf-renewA�2-�su"U vQ�evAaberr!qlof 2�. Our�|dings��!�)�O%N�a��p�#"[u2F96:�� wa �fur� in�!iz)� �xt)�E�EW%�M!$A� m!7. )#i �v�ofV�( ESC� �How�$�^� & �� m����.Tuqsh(new lA� � f� � 27ESre��t�#th� w� � n2gh�y�),iyanari et a� [20] show� q aB��pre-impl�!�.��A� ~�-� but��%��a b� A�Q�! !��*6*SimilA,��+d-�typq!ũ =�%) �ser �E}6� e� P most w��Q GSK3RMAP&|� 2i~ [21]wi!N) )�%#5 u�l!�f�#A�}ub.-���U3� A�on� fi5�ed �SD l(�, �oeMA<Tvsuggest��3 F�* "�)un�'uB/s�ofR�:g%WA �!r! riV�� group!s i . �C]�Ui!�no.�-��} �ee ly!�tradic� �eCj�I)sly%I����s �;)q��ua� �:�a�!&U*�-~V�� -�� N�.B two-( �.# viewDIu� xl�2"�aa�te�iA� Q( midd"u ��,�!��M3�explicib�!�m��b%� , More�*,��*,�� yiel7$" I�p�� d� � thc(i3� . Ye!,V7no�taP does�W ����-rE& 2( �<n!reexam�, curr�r��a�L oe�oxe�.U 2\en���nAne�*�reiAprM2-�!  ut�)!�AGer � sfw (��a`!_q�:� t��#gfp )� p&2A�-i��+�7g .&� 8��. W�( PBE )I���&�e�N Oly��"�-�� affe��9�:Qt2H>�M�or��&iYi@a��? c!�s��pi� a�&�0!�hys囡 �0oh XAoI6(� �AF,-�E]a�e2�  kn�gstill(a��(-  igna��s& �araa.�fasz, .* 2s�a����4'(UR mito�")i/)� 3onMu���" a�2�5� s [2H�(M,=/���.tRm(WQ1�>��n*rq�z0R M no� �!newly&� ��"| AJb  be.� to g5 ��/b�!�!Q�%�!>�*&>{ q. Pitfak!`��# >�)��er%� demo�8 �(c�A�,� � ��� tool a%6g�( �.E�2GC� s�e"8aKFi�3 , qut-9&%ApeU%�I �e�Q�+/� mut4 n 8 capa*-of�tov �� &!9&| debaA5�sP������!�%ks_a` |6a�� Fqad desp� �� �9 rope4 �)29n��aby��. �4i\!d� iw� staR. Fo!, aEAar sy�8�%ei+&bax!��8evolu�-��N��achiev8��i�+l�*�: kine=ndi&� A�3 5! F� 1qIM*� �"*Aba�K+VE�"Q ~$Torres-Pad����� �;9p� m�!� � �!zqa1uofa�s %}as!x link!=!uk l nF=i-_ay&� type$d� ( Fig� 3&R� na F� (%[�\Es�:taneous�r#;1 3; es 2%Z�6�e��� i;w�2qbe!in�N 4% �#r�age!HQ2-V"�.J�A�s&�w���ɃBrief�~$approximat�030"�# aE�e���R �a2�E�Dimmunocytochemisty��AZ��t� "� �13u8�/uppK-�4b��&{1�eO� re�!g7 �( �+3 �t��ly 80%Q��eI�*�haE20% �2�U�2lJ�H�, 56%-&.=Z14E���.bI�%OY�nd6�:�. Beca�pnoi��s�- W}�bp�2cQ�,� can��=8 E��e�qT�8U6t%�!�.�.c�~i�-|RT-PCR�ul2�@�&ix= �F13E1�2�E8u� 19�!t ed ,2m� &�, ���]4%ց�Y�>class9 as !4 4 ^c��po�follo& fr�1 ons: 21 .1;-v 1A\\(6)k2�A!2�/3 4��i�p�#%��$ᤥ�l���w eri�"E�B�rykRNA FISHi�.� 6%��� �F�J_/[%Jpei0+due �eo �n� �,rA�.siz�mpa5�M>Zw& %22�#s*�!�s)Oi&��+�}f�#na aTb0 del? �8 homo�r*MarkovEi�%I�s�����s�satisf\!� K� rtyi�fu� T�e�A��as o�onR $ /O5��:p0 #at25 � vele�3 limi�(2/)B� -ch! }� d matrix1Z*�5U�p�hym:���Hb� �Œe� M9Bi� nd M�+s�)eI) :C))-��a�#:F�6 rie^j!����&or�on*:#"v �P�,@t MoN=B prob�A7( �V� ) ta� �5cc�]U���!cE[��:a.@)"!���A]W% TdZ[,10 hou-:66a�6�"5��� e.!�MK!�7M �ad� )h*� :of��#� �F�"� )7Ax���!>6<Alld*E %EO�6�GU&r>0'��iAb���!� � :8 � d"�;w v~;%Ef:u�re�WH�number{_E=E4�� ("�F�1t�FG2 3j 4 ��TI��x�Hial��!�p.H� �6J"�)(� % �ziIMsum��}\E )�8�agx1 %"6�4th2%�=H3E"�I%M!�4i�$( 5 ) Each:C !�� be>�� Zi-:sd at F = Fq !l( : � e�-�%��),�7X�an�re-*vjAwlI% �Har�&�L*|F��%/V�!�uamO ��5��ub�&��������&T.�Aps_#� �gen2�,. A se� qA�Q{A %C writ� R"mph �9 j“On”7�(2ff ��=eq�eJ0/pr�5�!Odegrad%�&��:��H Ru��&zer�*OA3�>r9�B� ar��5� as� � � � y[i;jth2 ( j A�W ��e%[eA{7 �K8 ) NW-�t�ld�AfEC�"!��4]�M� takeBo� 5!�9.[""E��'D.Z ( SDEC#. Tm�en� �.$lso employ�,�7w� ��-%Y�!9% 10 )%��� �� em� ly u9Kre� �sa�/fin��3Gaussiayi b� erm��&!s�ns�#a��N�-N*� w�,j[�#So�I%EIob�ed $S4Euler-Maruyama�2 [2+&A��+fAKt1/AB � tq "�"n &i %*�t�0:�2��@,>;�N( 1 �py��na���}�#�Mjat�3 es/hDEe@�.���+0�mL ���(ducA�B&?�a�*6 t,�G�1∶4� %�n is="� :� , 700-sU4e� �-Q�ng�S ( ��)� �al eadyE�e\%F� ��5�&3= �a- nd�.ve, :ANmea+  8W! �s� �.u�$two�agnitud� (8QC|=�6�V�f%wn&$ “o���@A0��at�he+�\^�5zIJ �-�ĥ���>‘|� |h*a+ a�!�I�=l . It H8A }%ver%at�"� valuZ !vby�d};�Gl����A-�I�qua=/�E"Sa�ZRca�E�Cinvol?%١�or]�S�.%�)��,E4s 7�8�� ��o���?����k,�C- �! �bov��Q.�%�9U�J�Zt�^��!2� ia(%��! [2E�WB V"7 �@&"�! ��*� ��i�� "�)*i()�=;<�*� a+.$E���8�5we�tTU�uc�� PBE-� )� �fC> alyzCFi�( he e� �.� �$i6b)oV!& �fr]6�Ht&��s�asB�! "=6oca'm�.6**�l~,� spani "!�"� A��&b� PBE.� �or� M�,�(E+� )�-H��ic.��@�.�f���rgg,�`!�!�`�  (�%A�i≠j% �ύ�\�>A s N1$N2*V)�-;origiV;n[� � ��"�e)hv��W��( m�Dkv�a�''s9�y:� [2-! *��4 [ia�Z@as8�+ai�p( ly [�! � ^y)E��� )�}�&)and )�;���(._^D� ^A�*gGK"�K%z�:[�hd.�A��� 3 de�s��>�V�s�KN�%��:"��s:F!Խ #9� ,��� 1�Numers$&pAMjal��F7 �"�:�  M�< Carlo algorithm)�, [30]IB �TinZ!�� n)G�ы{ ��P��succeK/!�%��(i%FC(e�rva�<quiescC)�chA�. *`h��:(0*Z*f V��-x Ax�iq � *� oc>��60-"�Wf�AA!e�/ trivP1�Fk 9Thu�[w��B%)e i�Y���6~�re!�E%�bl�W�:i�ZE�Z� Ŷ��Vur�)� �Jr/U�� tohEɒ����se�!&�a�QoryA trac`:"� ��a}d9*5�t)A�O 2�I� o T�a0 hb �<"j%� A�s3 a �� .��%�%�Q��#"�aNs �to� tF5.7��%��$2�&� ���'.�. WN�&tyAto .�)�ex�'tom?�W *���.)o����macro-6� ��j��"KEA! !�.��"?=� [Z 6�>QE( IM��n�U,3�\a�e � reg.a��'d�-�&`J�z H’a#!e����FreaR�E ‘L4)%Uap*]a2� :�"�sm2 ‘4H <may"� r�Al leak'y�f�"�� efor7teE �Ai; � I�* fucyt�so`�se�fal&L�-J uto2n795orKA�%.�&�. N.�)r �a��+n�ird)�(!0M!0!x�%p��o.�*F�%�U�B1a:easo&�@.��DE mfha�D"��a �7.Mr&�-e�):irM�Nx8W%3��assoc�0�HB�"#E�x�� [31�:33]Ej�~"x�< mpac�5 �A �>G o te%#�Wwe&��&�s 9�� `9s�AY� OD.3'  x�8e"�a1 As�w�u�B� m)!�t � �q#eZŎ*q?!�a�sUg!C Ac�@��Au6�+&�6Po���3yC�& Z4EA �dXc�`�� .�cd .)%�eE������di�F��2�.��V�=�:�� shol%��Bin]= tB:��=<�e��3 � 5�V e- )%I=�`Mh�"� M!$��ng���;flc�)�i&6:���g�pra 2c,=]�OT�!�YkWN^a�C:"��U<z focu��i{5�on�����f/�7!v ���.t1.&J�YfundaA!al!�ae� R-�CHof!��%JI�)�Q� �0la'a�8hKlyL1�_ua��� �Q!�A�rL a��ui��r{'leAj�-��%d*a(&�A5�K[)!|�ATpm&BEw�ime~h".hJ��oA\� ��l."I"i. W�!� ��c� daugh�i�2n*a.>a� plota�o�67�T8a�I2& xٖ� be c.j%�e�,a1�Aa��� 6Q�Hr!Io�E�A> inim� �<��6 :15–"�)��K��K��e]%�� �e�i��"e"�G�uy�&vivlty�*eq*��!�%]g'�"–‘2�f8 3O�e9�B��IW,! s�;)q�x.�*�Oon�@-1=ii�)Nq� hh!C!�el8s]8AQ( les��n 57@vM�^few�.� �2��! 1S Mtog5@�)�ic��|-"+ �� �pN�q^&�-L !�assor�H�h�)� ��?��become)""Kun�Whd*QJ� �e.KA4=)�X �b�E�Y� ]V`6j6�R68 �:|=$kbI4� n^@eno�G)q�ͅd.{O:��\aO�m"� :�!sq�‘no-��i�a�[ &sNly2P��U�aE��Q�a� Ime� |�9.0g:5&%l �qr)�9Y-X la�hadjusU9)6��D��c�� jQlyDI6a �.+=ara�q&.K![��*)��!f�e�Tof� UA�Ft*uCŃwD"^&!�}$ �e� �l� !�� ^0�>'3ip �s=0i� ^ [u n��F+���r � �Kv"�Uly��U�E�arc�`I "�6�s�:�fp��M P*K)�1��g&�?rJ��>A��pF�odML��'toA � CSpJ� [34] %��cJe� -bno)^dsh� � m��lN�!the�,)�� i{Ra��C% d ��8�,}6�V5D!�end�1�11�. �q;yI=�z�܉�?�e�A�A�e�-"����yLa�QA�( ∼"b[5!)!(AaKi� (�S���'t exisZX��1�*:�F9 �m��! ADDe"C'Q oᝁ1 _ vv7ay!��<� av��� 1 ? @target ~��A�nr�J� %hr�,)E�.�Q�R- ia spar7 -� �� -U�:)i2�k%*�R.i5=bL&� ��&p�A,�.""� �#d!� t unN %. ��!@AL����kMvw*Qsd�? 1�@" 4GF i *Zs�6��.+�� !�pronoun-(2�iof��or CV"�+�c:u%yal-2�(>Mc7�;`ca'>�ub $ erciA�v.���&�=.l� ����)r5�-i�35!Xa�We&�FeW=i2read-�E�� ;�asb^"]Hn! ��*.� ?t!�ump!o�A�,)A�܅������ I�A�-uO�CY>O �i"� ^vAecAI>9U,( P3Ro�zo T-mo~$A�.lρ.,1W-Fe��i�W�> �e�%�I�ee�'���- ")�!���a���2�D!U*9%1� /GFP�X���e%-Md�K�u�� �s(9A�6e1�M si�SWZ�%���1�l9��v�~lyIa�(a�"fFfC ��)4: X,�E�<in� mat� ��P|�� �!55��8�.��e�E�%%#�B&t�TI9��. RQ!igs�D�Y p�6cArr T-� J�YIi����9!�es�)yqX.EZaA�m�aA6^pI�a�Not suri ,� _I�-�S6H � ����Pe�� Ep�>AaH� Z6@h�IU��t��4�. Sm �,AKa=�� Q Ma a� �p s f�&{��mY�A{O��be misA�tru!�s�d.2�rXQ� is2K!�AZ �m�@�6 .9+�6_![5M�"(Mv5�d1�2%.�R i"�4B!q0E6�is�uunE]s��uc�(���e;a�P�,pou5f�7�M)�,wszb�*d� �z�JM-A��7&n  X�2k : ���]z�u ��i�*C&�|t�&�/,��)#Q�es�*.5\ (m�/"�5��t�Y�T(foward mann zC#r !Aj��i. �M�-�Ӂu�Wf*0Hcy��s�he 0 ur& [u�S�8 �0��.[�L[3�2N�%.51^�s�be� E��#!�l"V))e�"�% evol� -��UP � 2� �r:�%5� �c J �5"�:�5��)wplas5a tA�JὭMf9�N�} �al6�3 v�x260A�._N�m `$$p &�/�����H2;Y�8�O��o�n�nerg�12�s'N:?�r� �  $BWi].*2N [!8v� �f�5&- � lagg dM�$s �,��:39�� althob@OtKjcon��-.U �pl�Jmea"�BYIgT8*4�J *M� �"u��� � n*b2��)!,� � B.)j��-�!cmL]w�M1B. A^�72� ^ �2n�gt�eaII}_�u�R\ �� toda��\��F!�heR�*�c�#"5 �:a �surrogsU5 ��� X ��6)&)Aor� @0�N!relevr)%�. Last$��&��-91�** ��"�#� a`2����Wm�!�4[B<�N�![5)A'�!a�>�da% �d$2n�-0*� C*.�n�B\!c "?Ke�I�%|2i�I &�1a��m�r�,���j�&j&� R�l ��0�@A����F��7%`)ogen� �,^� x c�A�G.(���Ild-��!�m2!�*�E�iPM � R+;AgHsa8f�M�y' droplS%ap. P73%%���%�al�#46 = ��s 6A–- �iy AomiIT%�&� �6����F�!:0M08�� �6�+& l�vFBQ)s._ e�  se�a���%QQ� +5 5 �"Yes/!! ')2� �?Et/t"_.:m"�,'T%�pS*J~ Shif�7 %n f�0F=Q)��s:# !�e"�� am Jl@3e�M&�!R%(�giIAM.�t�n�rX#sUI 6��1yn �6`��1byNa:zlto�w&�o���1e�ps�cN�� �CplyEm� ��mod�!�9ah:�d�'�E~P�! 2>i&��0�^"�^���:<=4�C��%o w�i �\)�!�?h�� Ci& ^i�$ �+pd�km� -Y?5����66�5>��^� D"�> @ �;�z&�p 8Ia�� �*�^&��� Q�=��we;m~H%�w�w�c��!�ia�A�p� , sj�3� �+��m�n6 plau�-��^] &R$T )Kh �Q.�$mi�!w�� velo� a*= t4OE( !_M�.�5L�v onju�%e�4sW�nU�9�:�C%�*� �� B(~�capit�Oq�.�yj_=���3!Bc�1��Z=a�W�tGZt|mumY"�S�qaQk)%�s"�aP��M�!*s%6� %F� auB���ASs2"�'�&&�(�)Z <.�|"|C!�t\.�tsr"_�Y;>�m!�"Y%��s:�[Uq# 9?{�? bl% cliv}#k &��?q�ѡ` ngEI� 599S�d�=a Bc\�A��s�A�J��%|�1;�`!mtv�F (��N� suit�՘: l;E�^��&�D"�q�B��wbg�!way [3"� �2~�J=@1�0z@!�=�6�(:�:t�ZD. (&�2�R.+�N-( .�*��k<(6� :�<);�k !��ЖA�o�/� "�p' "SsRAХC�oA_&)��!��&)L�g�s,L< . OnCVy argu�Y�p�o :�7RSAnst Z�Af_1�8�=w "J lap ��%z!�?��!B=P"!&�:i cl"�*0s)Ry �-��2LN��/s8�D�)�Q=A6 �.ed8 m.s R�Fl1� s�&pE&�of LN/HN Je�subA"�to2 %)�D�ng} SA�!n?�����jlsoAP ᳡EQ(��?/�|� �aaZ�;()M*)���;d 2�)i�s� s&�HI�M���b��� dVe�& cogn/�E�� stu/:UUA4k%Qej2�n ( MNa��RnVD$discrepancK.��A�A�bu&�X!�Aei��}6�"� 2��6a�!be"�-Enc�H.B8,he�D�v>�$! �2M�,�~E��A#*l+eLN� x�3w arli�5�b06ep�2�v%�GRN�)�%�s!!Sw�@�M�vrB(�)�:u~ �5b�!�Zq/}ve6�w�&ertur�G�p*N i"�h�@eT2�T E�-2A�L��m��[A;y-�g%@T!C.�osc&gA�� ��>>( "a�Owo-�U�. G:�1 P maj�7�<�MM2GW ��U�DJ�m;`sh �Pve&8 s d�G�5e�S�Ay b6r .0:m�0�?�(�pR5x�))cur� �m2�"�JH , ���nZ) )Odb$-�%1Emi�tq Bxe,M-��)O&/�~7$X �(��,(el�a�.2S ���q!M!�x�! !&"�sK(��^`�� ��RMPn���3&�O��V+?% leaK(�%���w�(�*�I6�w� @�!ofB�ac"|� cert-�ne!�mz��lea�K 2�al �]}�te��Wi �r1�L"���m&@ �M`May�3alJ�!a{�m�LN oreH��}Th�"� n(p�0x�"�1w:�" E−; 7%����HN�7 ( 38� ��c�,�a)'@,E7) � a*@typ& � �6$@��� "*�h.y��7 ex�~!!- 6!,�X�2�6Aa�z[)C�*%x,e�lyly5!�YI]�"@4im�)%9n �?�Fr#rv&�{�w�i7)�te2�;�"��� f n�!��I�.�l*�r"�m�HN%�1�s%k�>Iҡ@��m�?�+�u6��*n"��.��ikel Zs���� �BA��p%�de�q�(P�.g%�jY?YA� *wY���<�a5��d,$ag�"x wo ways: " qdopas�a�-n.]x�1's*=�,E���l�*��$�'j�!��QufE�� p��.(&&'n&�{���Cd�=*�$"2K�gU�"�"M)�S!TM� ��+�*� ee���|��a��te2�f�,)��ZEW��X0�ar�ur-�,sn/ a0e! p%n� s�>+o cd�)�B )�*�.�-y��W�� �in}�2� g + enhSin*�ɰ]�S h=��]R�9�s6��a6Fl[Y-fA]P&�_[�!2N !�%�h!eQt="� �w!� .�!'�\�zic �m{ A .,m� i*��cN]m�a�-+�n al�"n �gyz@"�X�e@�R‘ba�r(G0mo�G�le�a��u/0' [38]� ���25k� � F�vatta"3� ��a .si->��� n ep}��landscap�-t�4imWad� @�[3"�Z1�a�^� &[:>r scr�5E� aJMsI?K a��m�6. U�1&U�$rraЃ�8pru� �� ���-e����Bagr�,�l�17!�}{�� "��,ge-YNS&S<���`&["&� 5�e@��(� �!�A� h� r% z!�6�*� �,%�A�+m��&���0:6A�!�!�upE9�b�>�a ��LM�toe�?�Bb&XaR�,���2�?2��� . Ob�l�Q�*?ilF]�P �x�sA EV�z�7� ��AzcVms�Ek@� ��--iH"�8�u .��)�ed I@us 1by �rlog�^�� ���o_� n&���&m1L�q6��7̀ERAcy [40BT4ѰB w�*�?of.&i:�6�0� 8a�UZ!� i��6�RA J�6e�isU�, )5?���on.�.�Ό� �;"�0�Me��cA�%�"�BbAf0�&7+��a])�ne�*�!mdao5"�vs��3�oZ�;�'HDi�A-Qp�w!!�1��%x�x�6�"rn-�Cl(� ۍ� )�����[4~�44]Lm�!�beToo�/h7t!Ifu&�R!� {�7�1I��"�E�".�� O� �L�cri,$��be�P4c'-��e� �@��* !�-z��R��5�.  �q{�zJ�0 ��G vaAg!Tp�\��As�` on/q-�2i�~ B�%D:y� MK�.�Y(�" >*k by virt%�sh&m-rڢ�n�><Ig)eʁ�l'$El U�l�� �A�� f "0l,%&N %uim:}r*�x �j� E����< {MB� E:5��Y!R"���#QW�ccak��6tt(�I)��WK��+ e*ER!�!�t�"-��U$:�O >Bt! B1m[4x:�9�).�avail�>e hru�!�A��!:D���P6��iɨghtfor�;".�0!!1/Q�� �-in��-�E� ��Gy�a&� �e�E�",ng:y"�i�rded��wl�O1��|�gJ )1�2O;� !��py�. A"�2���%�be ��>>.inգ�2.kw��&���l�4c�d�ag*P~���eV� %|� m�ch�ng�s�["�X�C[Wf~�x/.�� �/e�!��"7.3 �*66e�2mLm�l s p�"@8G^�&&�.xeca9�1�%a"a�lag� ' >:E�� aK! �5� ��5��2�/. Ana" d m��H�X*�AoX N��.Y!3�!�"����*�� �E�M�s�*� T�""1 ma:z &�E�� �:r�- e irAT�)�#i��Q��+��W��*�*vs�"-��j�>>//9%�A�J &?/,��/���m&J/nNC/�1n-"�J@�'�`��Ig ���Og�no6�.8�S.�$e$ I[IYa� 6x�!9/m6�SI��+%��.Q!�A�&G"Eu.0�"�0=��=�a�%)�l"F&�, �8&.�qt *�_��x helpsni��m~n�!��A�H��u���A)-5U **�i o�&��"!�on 8. S� �.+ 1��Yai0aj�!�_a�:a��>;ve�@6�0.�a�N21 3�is�E add�"s{�L"�&�j3v� aa�J�iD�U:� 5~�[Eh6G�vns�"�UwA��Io�-.�� e&ދ2LjMitsui&+2:���*�9�*ar/; Y� �6 arie�_�] viscrE�?ddw�+�3sE��Q!Q�p�2A�"�@�m�!��cb��g\C�1aiy��s�><.k�:�%Eextrag! �alE�Xvo�.= &��%mes�a�B!�~!�yרy�*��E d� )� Y{a�!{d�B�'by j50%��p��&��e�..�#� � neuro+>+�umŔ"ʼn�!H� albeitdw��c3 ( 16� >&#H ���!�"T.�f��i.#4� >�!\rams [ ��\-tA.'��$up�}�}��j �M)r�a�>n,% �sm�7�urb�]ir�environ��1e� ,�@X � e�%5.�'��3clZ5#"-until!�l��mA daysX ���Y/. Longer)0 expa1T6 >!�����wYyc� "e *Q�6;�!he\o�$��a��j!�"g�] �u=�� goa>��F2�a�U1��ZA+�6S_e elucid!�] ��:�Rcomu_dec�A�I�q�|1822?s�J&0!��e\_o2� 5�E�)�5L We v8��z� �55D*�whPEJ&XF -�&W�M� ��t/>�H Ab�N1\� HA��x�Jn�crine<�&)%Y&X -w�#�2�C$cross-talk2:'E �!eph�?�c%�se e�� minn�@]9h"vnic�6n�K:�)�%�#8�8H %kai %;d'(��� e&�v MultM#Wach\ ffordDa!��ET=!  /spa�VEi��9M�A!Ł�� w rapi�.Rge6��"��"6��6ys�0r�gt8ץs�%�:�5� 6�D . At�s�&) �FFflexi�'���=� iA�afi)�-� ct s&�tE&EP���#A�5*E���!�"�E%TR,mCd!��Q5��)��Big�5�&��dE4R���� a�A��:�+��k�l��nog&&�FS> ��D5iv��� }"L'B���B�6�te�I&���very �%�;��Ia� nM�u֙le(� i�E��POct��Stella��ox�� Rex1��/ �� 1� connW�N=��%h*�I!#}=a blem�n| F�"��]� I�* b�3 �aǡ���r�N)ZA�&�*.+pla�m%�B A�S: issu�?�,�v�%g8(D���X> ?Y��j�a dee0B ��+2%9�:G-)rA�EM��6Q��ut9zccele� �q��}VtB�aWn!& 9�)�!�!s�J# apeuusefu� geny ���s�6��aHa)�sV!\W! iA# j��5M"~i�56( o��"q��/r/L!?� ( b q��M�&��ke9A�q�_R"I$�8.���"�!�I 0� (QC%����P!por�V=y���@ �AF� 12x! ��m�0]e�F5# ��}z��&:�.6�%�~%�j!�iPa�� Z�� E�Ra"�� s1���&�( A�� A�$�&��M�)r�Y~!����B� )wing /!�at Ӗ!��(1aJs��9ny!��a'E1_�,a�P!E!n���:(J]�Afw�GbngI 2�s x4D ��J[&�E�^ ,)�.��Bi�A�.>fFI�Кa��;~�� �a��a�J b�"��%*�mSeIT0a�gN߸i�� t&� j ��� Fpd��"%��s�ue&z8F�r`�E�)Ճ �a�#�P?"�|�_de� "P� 6�Ajine�a���VA��& �N�ACermB!ڕ��(1�h-q�"�Ic2�'p*z�]AQ|T"\ aE�h�{��1�i��he�1x!�t&�a�#�1( A#t�7,�we�s9[*�Wm�tex��f�wlt �as�1^A�*9Y���%a�!Bk~iwjr � ^s 3�67%�M� null9��"sF���Be�.�% Z���A;1{A��&etD2"t e�AC!�"%C!�I�m�0��&et 1!�� %X2�"%:��%����..�( M�J&5�� 0�nv��{ "�*mB<=:~�A;!;h6�xS��.w(3ə�{�se�p��*t�# errupe~*Q�("u�ebXu� !�I�q�� y" pI4n� ɪ\ &.��~E1set up)�F1�w�di@��x�X� �!��c!(4Qumn��.&.D�UIn˓ow]�� � E[>��aM4��6j�' �����6� . Gi��aap � � ran2 ~&k��" %�]fya�; �kt�4 J dis!�.��9N �)%�!F6/9� a&n )H:o�if fa"vQ two�ce&փ�1�@`��in%�i�|�eF%|(2�YQ��e��5� �%���H$���-[`A��F,���it I�)BBC� lth �Nni�!}�|A t��MC��x*V i�5l�Fpla� 2�'1Z�00BA�� y�*.�@pL�2�QMQMC�A� �:�sr�Á�m� �A��FIu#2jMS� �z"��"?�Ѧ�WORTRAN�ATLAB�Jath5E�2N�qk³�[�"4mO6�ipost-C��\�i�E�eC�*� R-`V��"�\9 X)!3�9m.aE�fre� 2��*� �off-dl�.F��Vse��!�>��*�YI� �l�Y�]���i o!�uQ� F. Y���%�u�eE����9A0X%*^2��of-JAq"9!�"k�y u%�%:�7�&Ap)�:le.�7�Z� a .n!�rBb"a�4%�e 1� Z���e���re��!A�WA��^.�h]-�>��du2�Q���a�T�SS�[=n"�ٰ=4k�x;v)�� - �a@��}sP$ �ipd�Lijg�� .Ɯ�cok��benef>����aRaZ�2&�&. E2u&un-�)N(W�/y�q � 8 .N�c��a qg�f�ku�L� �o�)�?�5P-;*Jj!+&��V($ofR�=�#�1al� � kVun�!��r�Sp24'"cng.�&֥%'�0)9�ji-�!"�'i���lut_�� K ics -6��79:Meda ome-M; of Eu richi�\li)����=��!�%e�t24- �je�$��ba�7�[ fn�Emlf�2?-�Z?s��era�.�Y�O!wq_�3 C��]��6ains >95" E6#0.lPB.��ssN�9 N=/��Fur�E�2�#i�3�J�"� !� mmon*ta�&Zuq�2�%dap?}�.}. C��t%2�G2�)!2��u6 e̿es"<nut��t-E ��ss-m�!"����C��@y��%.?�i!�:]�4>���)s"6�e��p܎Z�f2lcay!�� A� �!" hedg�a�M&!al�C+�A�I� @EE1�syn&i_� orga3�)sh�7~����*��ʁU���m��bC6I�55>2[ n &n3�#�-J�r%�m�M8 m����%v�<oQ�^�[��*�J=��of��,9�!�Y%N>�[֞4]�J.̊-��Q�=B�/:� aWA� dict )!��}�2�[B�/O�!�1 o �63\FxpnymE2�"� L�a- 6~]�O`z'2� � �L�F`%v�C� 3#�1'5t yetO*�B#A�&^!DJ�e��&�!`J^or[I�NN�f�%!c�hryri�q� �8ed%�Qi"2�9�=zw1=88e��uw���inF��c� 6"h G]2w/toqx�te�k �16Z [Κ|Ga!�Br^e��":��L�>I��}%�>%�-B� grea� �=q�.< �W� !�s�f^�chateri��pz�!nd ��1nE�l��(4'!�ja�#.�SIn� �e*O fG���/s"ngus�.�/H5:�/1 1�bS1� �� rst <�N��KX� E2��!}Y�9.,S�� 39Q >M�Z&�6��luc9��m*/!kglO���:�,�4 it mP5 �'�ed�dEX0 �J& Ec���Z� atal^�ly��g$:5�"?�exgE�l us o@�a�w [#� ع� �a6m�.�� j�,c�u ME-M�$ [)�9]�;u�unx �V eB��)@� �*� f�1O+��v�$metabolism81v-��!n|H�"AQ��Tw�f�Ro�A4ME F��!��q �esɡ� y3�6"M>���3 �~ �>C��as�Ayn� eFB��O. From9Y�iGwe"E �i1D� �� �-�,�1.�. Bzk�AzA .�s��I�$vX[����,,F�s)���>4zNab =�n(�Y  ���/JZ� re� z"��?er(:��,"�nzy��l*= LB�[1^/1@& AY� u\B5A8�>!���� ���͍a�� oS_��s; ��@ samp�M`4. 5E�+s��.�s&��8��r�s� /d�A" ��c��qB�&�o,B�TТm!=.%Zf}�6n"�G]ie� ���� -s}A��e�i.��LD4� ��;dem3F�tbio��![� �� .�lS�`� o�� �I��: �e�%�QE�J��� .x ZqF~W",�,r v,�T����batchg2��oA�2�ac�u�/�) �Fwo6�� s�xM!��i�>2��s��� cal;6�6 y Y��7<�e��*rsR^����� =�-v>�� AClap�-) R9��`.6*l�4"�0NdX �m���$"M.-Z��( 85tIb8R�).�4Q9-c(�(��./'A�4 p—aci�oosprs�7er�� 9aerobyKy;:�AM� �K�]k{u��c� ��z�b�X���w� &�:6"a, f?�-8� s#�v4 /r� FigAj##5E!n7mrKap2�)��3�A>m. Next�02~de>@ �$��ev� T=�M�)! JQ !.^A(v0x�i�in>�J �#���u��k�:� � :o �=JX��*i���>�ten�Z�])� N( Fig 1��D ) . This trend has been observed for several individual proteins using lower throughput methods [7 , 13 , 14] . Thus , we find that the amount of both un-utilized protein and under-utilized pro�X is reduced with increa�`cellular growth rate . Un:a(ome fractio k�in vivo enzyme turnover are variables t�formal�Lin the ME-Model . As6 accu�$ly predict ! � effeof unus�express�8( Fig 2A and S2() , settingq�Lse parameters to measured values can determine how they quantitatively affect��s �a basel�sh�tA�,� genea�,/M� ionsE�poor . Sa2partice`:�a well?ed ( azDg . glucose , fuma�A�uccina�) but|correl)L betw�� �r��is low ( Pearson’s r = 0 . 39 ) ; furthermore �e��%�02>experiAal datam$much large�a�aUQ!taut]7( s �16 aa�to 7; s]@sample A� dard deviN��us �re%zsignificA�$contributo���o! A�(e necessary.�@metabolic pathwayEp��A usage whe C primA.��) �is�ed . Ws0xt sequential�yy_Ł��)topEh9� . In addiTto%hB ( circles�]we�4 also.�4M� -lim�8(on ( triang ;��4.[al st��A quarbcon ��U at w!�-aic%profil%5I%ise�al.cAqj��h��_ ,�)���al5��� �eA����-�. Acc����� B�iaS��4e��tou�82��� X� �9�nc��qu09 . Fin%U,�.�!-Y+�"Y��^��98�result4 a��!�is simi�M�2}�֝J5.a6�݆�naa�expla� ��of5te1in.c�#]HA��C�2n I I*�&�( i .�&,�"� Al6; see^ 1A )I�!� s a domin��F`f�(, one would��%|(a common me!8ism!�Qm6�t�  evolu% PbEq$down-regul��R�e`in� �Xis hypa�sia�we estimG�R.mF)\(in E . coli���ly�� %c a.� sele e�ureJ�W,minimal medi tch cult'[15� ough itA�:� (��cost ))is impor� �S� rain�d}�r2< w avail� < transcriptomics�� �U; a%sam*� sim!� \to def .��a#l�6)� 1B�1C�[lL te.��.].�.� fter%�I� c3a . Al�ne�exceptE�(��ain 8 )Y�their u|Zp ( de��!� 3*� 66f��cN�Ezy�1AF�ag�, uxj�a�k��1�{byq?�}Ab vE�R� $( flux per��( Ei�Pth�X Ek.UaJ Ŭat� oep iven[v >�2y��E�a#AE�H e&sjes<�A]t�to9�!E3B;� ica| byndis] ebe! shif#$above zero��aQ9%p.4j��6��B�of.��s�e� ��1.. WY)ǡɡ13M�e'a$6a�~�5�4does notM� uniU c&� . Ra� �2I;�in2`qVt(2*u�J*)%y nti-� mAu6sdeJ�2vEPCAP�D!���A�)� each!�)�1r�pprox�(lI�e$�5<$~1 . 0 h-1Bg%Gyb��employ*�q tegia�}H�g'Notably�e� 8 hich55s its9}y�� r (�ch]B�,� h�V�!�amo# highest0�4�. S� Q �ribosoJI �wild-typ� despite[ �r) �5emands!�fas��2k ( S3EX��suggestsO��� of B�� $amino acid�� $e se� a%� � )]erefo"d"Y݁gen��1���&z �&N����--����W�>V�VI�se& � ist�wo �}��5invo2r [16]�iif& causl H$s [17 , 18g E�Ctl Vu b2� �Gn.� �ylowaf�level"� �*:A��% e i � 1e�f^EDi�ub�%-��� adapt�!C� ��y�P"� �A,�l ��wa �� det0s from achievAN���al.t ? And w�� or�o<es� lia�iX havior ? � nswa�7 qu� a,� f9systemat�segu%i�bofun� Mw!;t�be � o at�2` �+�pecUk�� ���W6 �ME2�classify!Y�� in�!i]E-r�t��roN ��.� EgA�"xU !� C� , Nitroge� Phosphoro;| Sulfur6�*� manyV� � -sup� �1�!&��R�nAreveaai��$‘core’gI�is))z all (:~ ).�@aa�eviouslyaaa,in Yang et a� [19]m� 4A , S1 TE[�E���arg�in��i]Esm%u%)in syna i�jinclu"�&�&id�  n&W f �s; S4�R�6��Inon� e* "���6<&� "�͐-M�A�elee��in�C-%aE, N. P. �S()���u� �$IFU� tern��P ea��] ly )j�� ŕ �Qca;=�SeX\5lFK� a N enrich%L:"�io����tA~��The.h0�d!�CRP)�.�by NtrCMZa�=by CysB9i! globalI��A�fac�!known�Q!`oo"@ e�il���3s1�anutrihIO(s [20–22]k ��:m�-drg�E� Y&�A�5��:Z_��a�b�Bfi cq �e�y �2!^ �5o�Y(zj���� be��.��fou!]�an 6 � \~6%-Ywis�aw�~�U!Tġ>b��Xm�`cet�a�6  n outlierMVɢ��z|q*��}���5�. l6%7 itutt @s�jor]�5/f� 4B����lowA�sa�rwe�|m�]�!�j,y42��\5"�� �"� � :;sO���i��� N4abund�H s 1 arly�M|  ,%a.A �r bio�! tic  atR �!�inear� onFmF�"T >�"[ ��%��a}[14�o!/#%Pfur�validA�!a��/!����=�h� � =6u#��ed!� be )Yt%��2�exami1,!�F]may v� �ir %�zataly�m�2h&�,J� pncentrF�� _aprodu�", llo�icq ��UasY�inI�Dj6���over-�ed� "�� R�,�ev��$)a� y-inter� �5AQ�p oA�of!� Z�w6� u� �� i�alea�?| re�$%�P NS )��.�"�":)�Ea�/� xe� Au4s.(�'5�#m�uA���ng%|�:�a"��!+R >�&AM k 'app;"!)�ru����>m�g2#ly��5��AtZ�i .�Y��M��� ul] M�Qb�&R�;!&�2'!eF��6�"�&6��ri�Emr���z� "� ��t2I�V,e:q�m;�6��l�.�u62�R� �:��c�{e� ste�6�_ !U�*� "�Ia�Ah" "��%f�Y!ly5��sŮ&�"�Y2� Q�Y�&~�`N� �6 � ,��>����23�x'v te re"_W � !���:�  )%-���e9p&i� ���6,. !"C- , PtS-�M[�$�� ly2� . An &U impl>u-i�R�2$at up� *NI �{*9i��b!��!NO z:�2ru\T A�N����-i-�2_")�U�y<�#s�� �ll! 4:�!.� Q&p 5 �o R�]z���in>�AL #� �*��6�N��>n��v�ed�tA�t Xb��N�� �is&F�e Y�����by�2 ���9�� BM�"sY���%��Q  b�!��� O}.of��:" $��!Te��:v�x$i{� $N�=�.�m)Jw$"�!|mA7.S  +;You"6,&�,� ;n12 G incB.)�� um>.f���inJM�.3( "y"%0!s",W.*N .���&Mk=�,12�Ɇ"o-Z!..UE;V�&�.1�@ ~20F�by masTn 7�pi)5)aF� .T?ci��t���mn2h.�A}��V�� lighd -0t&^t 1̈́�*ƍ�o~�d%z5]�M�!{Zl*5 manu�"g2�ins!I_F(annot%& de" �esg?+ coCyc [24q M�1Z�%���be�� by foc uon�}m�*59E��:�"GA�63.x:e toge;UU%�e�8Y\.;�QcM!��2F�(>�d��ME5d���S� "q :Q 1Cid5�Y75�( encodi�so��1y-��r��fI!i�"M�o� �A�z�m��b��SfS, s�>�6�*x>�'}�aQ[ dAG)negNJ�.<�7� 0Broadly speak��K�E�c��+th<6( &�3.��9 �: Ao.}%� osta�2l� l�6�WJ�� R�Y�i��ceEJsurvival2� osmo\�)ih AtoxX�# Je!^+R�-w)�-1:��m���� g:� ratV/^ �a�Ҏ\ . Si����# �JN �� Monod [25k,2��:anLmicrobi6�$sI��invs$A�ox1A+u�ER )"*�to Oa�&{ inA�ʡ�!!�`� .� stud�[4 , �Z���&4;2�p� bNe�; :� �as�9�5 ��{2� -hat: �)��$!��1��^L �Q:-(2Jw4PY N1R�9�2��2��)sR)�>Q)�s�A�en��j4 g3ga& �>e K *� ly�O�2*(1!I6522�� s*{."�%�eF���h�R�]�( �6�ɍjefforBengineer5i biop (aap��sE�benefitdirec!e��#ngF�:�[6��0J )e"�;�^B�[18L��ON�*vFK26 ��,genome-scale��CH;&r�9pG&of @1�i)&�0yield> (gram dry we� Q"L ) [2+2�-�:PI�byi�Z � ��#U:?I 2� E29 , 30�Ou��s~-��:�]a�+ kn/o�?�z.�w��%1��Rmҁ!Jq�5�a(��Ac3i4�Acy>w./�corpo�+;M� F��&N���en%��q5��2~[23!_1!_We do�Cn9�*�cal%7�of ei� jorJ�Yh� �@=V�In �&&� a+%�vv~n��nd -�� m:L al2�F!� natu>y/iXA��DE8e#2}9$vice versa�|A���@ , a /M0glycerol kina_A glpK' �5. �a^Y' step2BQ)sm durAJ-Kong[32];l1��& �Erg cAMP�L,mch\>o2�0FMvia,E�]w2�A��(o�v���. OV�  h!�>@W(RNA polymer!C(subunit rpo�(3Alb�nside�AaQ�=\. <�8 .��(�,8�.2@r<ta< �]��=AF� R� o):G�. Both5�%�m��A�d I�6C.j��often�(�F�0.��132–3T%�3Az��Q�-8b� �!� �>�v�G.���e�.&s%� }��n7 &�6� incu! fitnesK stlsteady-s�(mBI�?lpat�,t!�6f 9�?poi� to po� � {Y ���+�.g  6Z��͖� I upo)3cAe� źfavor�� �2� %�a(L o >p" �8J"�8t3d$!�solqo]  novo�h21/�Hej� Z%6�2 �%.�#�- �E� �=m,HA��������h-%7!��!ӡs�m6�"�"( gal2-s� �%�;("W)nW"��MS=<�b�-=��� Ŋ� �� �pheno im�?t!�fo�*X�V>ee MeL��A6t�cm �>ss?Ft!6� 5 i- orga�A$s1�%m�6�‘up-� ’;��wi�.Yi�Z����?j- &hu>a��aő�!�is>� �6���G!t.�*.u!b 27*�(��� ur aI$r~�%^{T:�1�.XB beco�'&A"� !�pMAnew.i�An��%� s [3B qMȍ��E+("�.))A�sf5��ƀ�IS�:�*.���}Z>�%����zDadi�D!`6�� �8��d������le?2���dH oLN R_U .� ',>T 9nm6� Lo+ s noU��fV� :� Xa*�3[-_�a,m4psM�advantag"�1G�F�]LJ$F�1� 2WiauU�UU�F �an��/a cur3O]$I�*9!m��Nm��d� �pr2WC}���3ul� shor��lag pha�M�� of s��"�#�HA�>!�intvof�+sL6�'to��I;c�+ar� =�p� z'&p1d tz�  BT F�w��ہ�V �PJ A6C conf�QB� �?:.�&. H��� umma/Ecmodel-20F�A �@� �w�=m5!�M�%f!>G&J tNhG�5��o�+� vo�oB� tX>2YH2�?#[Ni�mpo��� in�IR2� �3s 4�B G5oOA�&J�mr r�5�2�ME V �,!Da�*~���hm�H,�1Qb XI�d91��r�(�Ś�!=%� M��8�S-��O.JZ�=��1�V"��.�� W �>[%�e�"R�&- �52$>d �I�!w>A!���Z9<�#2� ward"� ,�=T. d�� *o. A 1Fa1=C�F��SI ��/�u-�_2��seJ��]�d:<>�)q8�.NT9Y]~�Mb]�$‘hedging�=�E/ �`A�}�"{P��(WH�u I�aa��:rade-offA�,T-H��<.UG=}��C_I�*��:+.��!�]Q_1�I;e��79v�-��fl"�8=�'d-Ifb���S�[Z;6�his6tFuqua�;>v%p y�si�f�ra+ fAedO,�H2Q0Au� �& 6�2-�f+:�"1C�6A�ecologpB'(-e�&� E�g>'���� �,'emselv�For*�y*)&�&LIHRin� nt g+as 6F�wche/TRas"08�6-�&>of&�+o� se.���EH�G&��e�|*s=And� > st . G"�-l�(rara���>� � ���Bs9rhap�Hfo�associ�LEa hars�Y]С��?-mak2>,Va� �i�u�c 8#:.�'onOZ!go�?ly�q�[4�>42a��p&�� o}$!!��)MY,*slo�*�#f8vA�reg���z8s{8-�3"�0���s� �4�44]%�refR@H�G }HDteg =tal�D�be bal�(�D���a`X@5 �6 , 4*R we bs$24'��aD�\dA畱ّ�F���,:� o?�]�HH��&� �"� �� etw"�.d�&�*��(�B�F�� ��[C\;r��B�- ���9:��8 X� ��. H"�,�?�+ prep�K�a w�  arra��o9 �Pa� �5�� must [�\T!�^Ke�D8 a�� ;\ASyW:� �alu���f��hz�"E="%^2-,-�!a %�<�͐c .N� )����pe� ist  us�raFn�.��Er-�CN%lc&z �As!F.�}�SI ab.al nic� �EV��burdeGN�� � ��F�:B narrnbrT_��z�)��requi�F "� ~=�^ e�� ad�+r:�v. PJC.�!� I�j�Q�� ��x.�:%�[4� � ��B�]�2 obta�?cSchmidt"~36+��Vabsolut-����= e�EscheiFi�8li K-12 BW25113E/t16}R:-}2�H��.)X�8G2���z,*H)FD,&� �a�@ Z_`, pyruv��)���hxub)�]|�vhe9,at�X�μ�_2 ,20.35.�g4�42,(   temperL e [42°C�$�P�� [pH  %AC1*$50 mM NaCl7naerobic�D�`E6un!��Y( L�V�^H��u �A���ed�"; 2�cb/����,IYe*�4*�=o�V!�MHU�-c& [J yor 2039i,��.*g(lO Fre�Ga copy numberi. G�| %= each.�%� rom Volkm�Y� aLL47�  �anTC�h�e�e��s` V. on0^6s�0A�B moleYZr/&��To���T% 0� A�an!�"nA%d*�c=�y�b5�e=g�O%1;�f;� t�O�ey�S"wptimi�'�{(��%op�f ��)&� ���th-mDced�\oYH�in O’BEJ�.[%�W� �e * �K:���t��EC � � r�c��of kc�7!�%&�Mwe�a (I$ 10 ) logn^h6I�7 mean�p�V11e�σ2 = 31 ,J� � I� Bar-2S� I�FSAll%59hi �s]R&3bi-^KA�%�2� U3S-���seQN�&)� �100�,1�sM�%LUr�P�� K� &g K9��0�V(ie.^K� at2��G��ә�}I� �`� rog�T!%1 ��Ky���tit �Oc ��&`^�P��!�Av� {c:2�*�RQ 4@� �U��FC -;! h��(e�g-��\ C/%i&��SF9Y d���;%C��*�Kun-91b�a�p�,�NIJ��&�Q6Vo ?@4%-��. . T*3�Ro� BH&u:�-9+9-)�G"O�Iy�.ENe�O,A�g�#s&W)�ivo&?e�ej8(�5a ,-�60Jf0��PtEg�9�:�%�um �=Qkd 8)Fs��"{#��� a51D6AMaxJ�lr�"m1��!oe�X�I͉d�?U6*q�%�m��1W��e&/�� �%o U�u�%�"�g�nedq���%TK se 22Ufer %��%�A�u��A�rd+�)�*�dwL[%�#.r I�1 �i{Bin90 64CisA"�n%K"0�z��.��ra�g,!M>� u[A�eVKvE�tN���a��tV)���f]�a$"��F7s9���@ a^&cA�lis>�RI��>�" iEFz�2=�A�?f�C� �2R&�7*� EJ.���^o�5�M�-us!N�� �#���(&jq�!�l:�0��re kepF�=�2� ���eye�-!* �5e�1^6�\� �.cB ��A?u�A�) way��.�!�P -�N�e.� �1�i “Q�S&m6; NFK”N<�#V2��0��=E���.,?� @J!9M� ��?in-co�*gen�Zs2;*�gL �8m ��8 length�*`4#2e FPKM> "3�cufflink:�$e�LaCroix" Al’r�taka�#!��Q3~!�.���$�8sum14Akull:��*�V.q:6cdhd#��V:��nUS�bw�cu�i�-mI��H� �0� Pfo�Wbyap��5� "�w| N�O!X.PE_omE�� � ��>�HVqӉ2��.�]:�w$` Z� J5u!tJtng��A defaW&��M9�&um�*�$a�m>m(��^�! oru5k6� sulf% "_�nEB&Vs$ha�8g%��,�,j&Z_2WAW*�3336�:P,� A�;to 180y93.|49=#�11J�so�xQuQ6���= &E I�t��3��.� ose 9$�TEn on�6% � CKNh&YX2q*}A1c2��w�c; &Et�a�68��!?�of6 `�ah-H���G�Dq �,(9bŧ cer�2�%��aor:�a�=5 yRYP�Q&�DA�� lyA !,�belSho��:� !��>RL �gIY��.�SJ\)�Uh@YV�JA"� -�]al.w"� 6\ 4,Two scenariomX9m:% ini r:� "M �iz�1at2�:-K"%2'16�I�e-\�� ��h}�!y>�%�\���1F�u�_�l�G ,"�6I��!-݁eout�~� �P%6Bqi6h"3(!�^�!�"� subjec� jm��� �6�&pri�"�'�-% �6YZ� up| �X�!���/� $6�W8h�U(�2"�/ ( N-��x&"by a���e�!�� �!: �2� Bh��Z�y(�#5�:)$mtAKl����x�haJ��0Q�.ZubZ -�U|out� scop �6>�&��.=)%�>�J�J&�h�O.]� v�W�|2!A�ris!�>~�I�Je<�b "��pa>6EcoCy�J�Re�]��>�!"k%!� )( GWAS )�&*#m�Zple loci�h!�rT*E�k)ass2�%�62 diabe�<mellitu9 TX9�hof Y6&d"Ds�w0�u��" .�gA��|o� $Wfe. M�9�� y�'f�Kppop"/va' urop�dea��A�C�u6R�5(>ŧ�s%cestrH#f�unique o�i�<ye�tud@e5Sarchitec�w�W�nQb�caAor�in  &955 Ch�4��01� �$, }945� trol�!, %34 Malay!�794 c224062!%[ 146 Asianz+i�( 9772=169.=�2�>!!�se!%�ӃlYiMA��0!�e{�0A�$-ethnic co�2I2rv�ytP�� fer�F�relev�&!s�Q| fZ ngqk>!.�three _] �.&of%#6 m� half{world'�TQ�{5)SNP8v2m!i�v!kI�, -Dy�t CDKAL�,HHEX/IDE/KIF} �R�'��ron�q!3g�-E� h�}@-"5"��le! �groupP H"�&s �p�aofP�"�(A͑)xix%a� eB!�%� carr��ou�5�.� . Cl,�G���d���at��f@�""� �MeA< ofu���2��h���;)i[u�\2�5~.� als�<�$(�rg�in 9age dii@ilibr�$.%Z� �Ms��K �&B6qly.��0=r��b�w�e�1atist�-p&,� �$ne�![ fail� Fe�6o.�of=NerN\e�!I�q��#l�Gf:�MeyE��di Kracial/ RQ�t�.CJ|-mapp=eaI!Lcasua��A�%�)d.�u�lC[-�&[p. Typ�fO �s chro�A C�O��,G�m�t�?300 millA}peo��%G greate*yvAb�AalQݝc�Vg y�ciGhW}in��hD�Mr�EK3 b6�[1]–[�-I�*�E�in�� a al��h(r�!0>�e�[3]�2D&?9?-�)[human -Y�3�8$K!adven^_)YJ�ZN��<)�I�6P�r� lFwcap�dU+L!�� � on k#ve�j%�s Re�� aY%of탅� �c|���!e��ia�(�^d riskS!h[4%�11�&d�@��lAgio�H*� ^nd`Q����O$( PPARG [1bn$KCNJ11 [13 g�DWFS5 6] D �81�TCF7L2�D )9)%Tr�X�fe!u � pe� inb R}, nam�ųe Japan!�[20! HaI�0in Taiwan [21qwSoutheM&xUn2K Kingdom [fo����0�.!�&(/��&4B�� ons:> ����FcA��/enuin�1�vdY�� ��6[�Q.1} 4sca� reg�Eeٞ" look Q0I'6�2rIz�6�9 "i f5� � ;�i�t�i�mod< �Q���p>$�A��?ch ΁5�l� Yexert-7�Mic .� �)e��(�q back� ndm*�8xpo�s ���NK �be*�9�;.��� ng!Y � *�c��suseki�<tov�f )� . Ex�(%�I�� emer�8&�~ e�� ��)@KCNQ1 [8e�9alPTPRDi\, SRR !�PEP0� �DW !)=�' ["|?extensi9r�Ved ��a��Dž��b�O�dm@m���D%a�AJ�Eci� , si!aita�P�pro<a��H�)K� apeu��tZQ�d�t�B%a_���U)�N_�x!4�u�,q1��11?�(�C��@^� drugD+� om�blood ��!P1��&z a��(�m�<in` a7 B-A^ %�m|: 6 e!�1ϡ4��&?�Imad^ .?.���aF}iE.8�}}� ��'!Z#�aa�F�Mo uncl�qwhe!~!�5���*n �6�F#$en� ����o�Z.�WD�7ˉ�/gE�e� aE�A�N�QY ��&]_%�6p?$ۑxN:Z=��&.u� �Mq{$ �9�faə� vi���.�,��,��In:, exhibE�r �a}a�.>��.nQwav�|A � 7]I%z��� ,��2N ��ah�7yh.�>$ my r�A��-�5�eel�q�essful�P�46 s -F&7t)�originalU�DD=2�D"���.�"�.*1!��I2I�Ea��-v)�� 2D6P� k,*tvl J%JunvH= A�bi�<ly"�8�( Qorphisms�mer� b( L�&�[�l��F���)�q*=��R�1���or]'��s>h��t.s"' q[aimPi��t� lG Z�rE-��n��abl�v a�P3�"�I@se)�.iH:nb��1 addK9%two issꗁFG=:�u�W!;��tEKfLA.;%�&� �B`�-�Jgraph�wSingapa���$9!rmai!g�jN,!!Ox ��po�jes vac�o"Qo�v"�]ngV�P . I: t��i&.��8Adap3.!���� /� o al�:h� P��S �4��!�=}��KAZy�e�Z� �Y NZ�9 ��-�n fu�[fXGHw�,�&�Nss�;a�Z�Ѭ6T:�B�2c assa��0: of�2, 718���,�Z!�3}st-QC�osizŀ�781,C+nd N_354A��. WFn&re=@,�set�"�*"5a�� q"j 5�*e��)e"F� �o#-�e� �.�E�A stab�+e�! j:E 1`��$MI�q�!. ( ii�܎ �magnitud%eB at: �*�tuAIis �:iȉ��a��( ( rs104888lOi!�paP�l�, ( C6orf57 )..�m~�e 6�"�2g "#�c� OR = H55A695% CI32 –X58�9P 03 . 48×10−K�alt��Eesỽ�tG!Tq7(Z��99*: he�"8 . 23 |/No%I+yeŎb�M3tvA �A � > ��{ 76��&�.�.���455�~M� �{3��uHat P-� e<%f5�(t��p�n��S!��t 6i,#A �ځ~�6��J_ ( �2%]TS)�G-QHMG20�k ZPLDPUNKM� �no24&f ��9 I2Yqs;u$�D�7�*,�i��]�e Ɲ-.t��"56���,�OFig�SA�A43aiI"�� �%�In�[es� *<ree[U<�p I��"Y$a=]Z��E��_" on�\��:(A7}� y��gsU�a�05QE���]C�ev [n�gra""E�qbZ�m�-b6�r�9��%�UC*="� at}6sC� !ݍ1WSv]� �A�m .M2�!�� Ac�#%� �9�^�EalHTCF2/HNF1B , IGF2BP9 CENTD 2CD4A-}�FTOv� �;�Qiy PRC1 �;���BCL11A%m=66� -et*�� M�Ea` O �s!�IRS �SLC30A8N"9�n!-bE;�!b���a[le-=Va�>�@��!�. �cj.!6�|�U6�at"=M�,���,VYgM2��$*F�� � �oX!�isEF#t�.3� I���JaFn� ; �� I�mod� 2 �Ypat&T$��E��&�l2wJ�=m�!=I ous� ,=Z�\ ORz- M51r�.�S�J1�9 . 25o!s�� �uffic�K%@�{^atb.of��0)��r4�64���Win>�>Ov ** "��e:� �� took2�*��*�rst&w..% a biW�!��8B�!p��%�ve�(�)�2����� n�-�~o"V"5�.�eR-ҍ�%Y��Avco[!]Iisɲ�P�(d�s<��2 . 85x 47c,E)001�?& . 22 :02.�N 31 7 M2.. N%�Vr)-&s"6h')�����e�-T�qa�2�.)�Gɗa&ma y��W#a�asp ffec� >��^ea�k�� \���&�$,"�=�sZl8%���%;puL54!�%>�\:0�gi�w�"`p� s: M:  91�3;I: ��30-�2;M: 4��4 /. �n . 49�*ңt�� *��!�0..E]�^+�L�"�-�x�[%o)�'!�ht>&^p. Whena!�=i5��3^2r��s�\ 2�DIAGRAM+�������uU"��Q>�{u(2nG �n.)sh;�bepar� �D!x��F#&����u�.Y��%�E�� ��E$SA. m��displYttenu�, odds4/�1JY9�-'6 �BG� h%�5a ort'�(iK two-^J2�2u�47M�}8 . 5�e4;6$: 7�gqR3��~ �?A""�Y�[: ��A -��� {ly*q>�oj�>V�,U�� Am Q 2�*-$tw�cij)5 �23s"d*2@&G )�My2�1]%0M!6.%)u'a clu��!?>x^P1a'�� �!in"�Q&  >��1 > 2�>)�:�@':2�.i����M,2LI-top�alf E��6$�929547H65E������i�at;M. 761MbT 2�=w�r f:$yJ3`2%;o 4%%72 �m{l#)Z] �9��p!E,2��ı"�%h�: 3)�+�_$��R0�!SSN�775484�IE�e|"h!��Iͱ.&.�W0!��o q���� � remo!� f��.�w.$�U��1D\ Y�� 2�A.�4y?y��2QmY+Bqa# 53al�m� f%w,��J�9pM�w>  I`guing� 6RI� O$o~�d3a1�MPAEa�� ^�� o���?I?��99�M�up�Oami!��=-��el>b� M�E�al���<Z&�iX.CEU ((LD monZ� arlou�6ѣ*���F�C� ,"��,�%w-�A�&&�.�mor�)d!�t�=@�:r?��0DE�����.a102��n��.��% �:.�,�f*d.Rug span`E&� �-�quWҩ ; ma�&�� 0Ca � � E| D���FH A%/ @Q A�nAs�p��e�2�� 6��658382��%h}ed 115kbY��.�^; V1111875�@1sE`r=t�7d*�F$!��" IW��)D5�>�a�� �b��mdarAo2���t)Y< IDE;A�t�ea�%s��6�F�T�H�iue e�!h.z\���21ji""A���rst. z ��V&��.�9�(�6�J5EB�=;-���Q���t!��Y�F�H`!�Go6)j&e !7m)���+*,A�R��#"kIDEe�oD�aE�9w n[Kz�HA�)10aM%�g5��nGAdbe=���s*1).L U��� Y;.5�AW xGz�(v�4'=�6�)m�|*�)LD �2=rek.��Q��U!� �6�in*%" ( Maur�nd� hodI8� 400 kb�� �:�uonE�"��~Er��9ofV�6�5*&�"��va^� 0� ~�CMm&��G2��GBAGq�!56�PqQT2y��y�U�. N�p)�%2^* 3GA�I )� rs5015480yS��A�A�m ��-lˈ8!����a�AAC1{!N5D�3H� *�2S�me5:.� ��b"�$�{%'�lacr2R 19I�9��!-. W�19�iyg#��-c�jolJt#1j4%2V��b�f��_� ledg � �*�.(�in1�h6�>��e�$�%�!��c2�>3%sriX*�R;6A:C�����&  ��l:C�8 AE�*�:�/ōE�Q:{#� �2Doin&�b.���0I2&m�2"[%8QJ�M_)W���d��,��tJ�'>. �*7E�i��*%�il�2�&�I}5�"V*|�&.26V :�,%��E.�9q&�8�} llJ;!�.�Q�4u-�i�e�7Of��a1"A|yF�*� ly�z�6���a*8A���%uhad*x�h��1��0, Dn��>�n�i����5A �9a��~�+�\&���E)."ߦth�>��[5 2:�o].s�ar ,*�$7�Z,�b�.�2C �n� �����a��!*��oEm�A[&�!�a�"6�t;f��impac` ��J^�3���.A:U*6 � ���&{%!P"'*q%�Tv�k�) 6 �at�� 7903�A))�023b�ѻA�4���yY�/o$28�%?�U9C 0k%�at&` ^�6�"&��b�(�%�qM�.#Cu��s �049l05�9�&�$c�$o�"( 2��W 2�f:y!��&�X*��A��H�72�  #U� 2DO!�s/^9U^�A�}�� 2K � [ . Ba�5J M}2���-�q�!� ��)��l��z�dA�&NG�2�6a�%�8t �;, �$UBE2E�$�%,"�#,�� ,*x$SRR�*�5369^-�q6�e2@ )��%*st2OR:�$ ( n!2ayX � �*Ithird�*� q )):sM ���q-w(yiP9���e)6��RC.�u�5��*2$��U�.�?u�1:��,"�a�u��e�<)�U!Gwinner's�ys=R. O�&&�0�\9d �&eI�ic*X/'r2�"y�s��� �u�M&f&�ara�1�^9K%Mc5 � ���*�at α-���f!�2�s��=�5MJ��/�I1���.�!�1P�MsM�yuA�T;��Q noteworth + <LA��gw+�AEC&�&�*k .�M�� !�A?���H7v � �}�W����KB! IGF�(%(��() [�@7�65�1�,�yuIn 1����t�4,9}qy�B�� r ORa��Ja�etJ s'*� &� *�&Zj��g�a8� typi��of.i�.!ŗU;"�4��D*y�6m *� y����!1*�/}u & ��,XA�UY=?. t1�l rMx���"�"}xE�� ��b�|e�&Ch!"em���&}�wa�X�52eAu�d(Q "�L5�.�a�� 2!.�:~7.Q%6�u *7F�%�> � �R���!��*�y�J �u"� ycH3�B� /" and/or&b>�8 f�!���!4�.�A�H�C�## iyFy.A!��9��&u"�!�EVt����?urjI �!"I6Z�"�ɕadjus1@��#.�a�4 l�ig�R boos�K!�Bn&uik4yJ =:i)=Ee�s]�I�i�==�s� &� a.toS"�WiD ) �:tq���&st�ZQ]�1>}N!�)�� &��%�u�&�(f)L��A <Mbun9 � 2, R� )QAuD��Z� ���5ťRr�=�U�P96t�1"�� ؁��E U/��m�$anB "l �A�U R�) 1�.�&�C��-� !�s5 6�aa[u���H���).�,*L �%�r �LD"K n>i�3�jS�&a�"*!Du��%}�%~Ž� B�>��<criR&�*c=��tr funda�a���͞%0"y?A1*�B�R�(�0^nu���)�,�q� � =�%�,E�.O exi���� pairEw6��A �!�. U=DtuӅ�)e4u >�,e�� ca�2�q�a�G oad�Z�?|JA3s�&��a�vJ86��@so?g���"a�s6�6166K��%�� �( a�I| !C:�� In �";�w&KPmeci�A��al9n>W�j R�:�/� &F�2@V�arb��L�$"��"QA�ne cave����a�ag���!D!��Z I�&��6N� youn*��.Za4,:�>d��)U-�?)�qY1J3y � "V'd`�opet�c -B�D"PI|q�$duc!v** I�%>j*�'>:J)e�B f.�!�Qr�AseRDA?calib~l�"g $ %W�!�BvC 1D$ 2��[{�x�AH �o"l .F��Aa�Ge�2?�.K�E ad�Iϥ�a�  unbi�@a�be �Hm6�nt�P�P�m�eor:h?�c�M!]ɫlA�6�'�9�y�I�*zH���!�"i��ۥ �2�J�!+��v01�^ ,.A;e���FWu �l"�5�su�q�%k���Ad���)bea6:�Qe�"�C"pFin&BT!f6�E`!Ib�C;:M�z^aE���a<�ce�A�jDQݍ�� ny�.GA�ANH"�W�� 6TNmod�rs�{2� F�a>E�%�te&W�ontin� "�!6 situ�", eZ"� !�a*�F%��7*, � �� 2hA��u�)�ttempE�un$�5R�[I��l1+U�o;�)�x!.Ii��a:m�R# ,* %,'"�AHM���a��#!B"_��!�l�D-#4 en^ perti)��&�e!V�g� �s��Jh��FW�[�!gr�"� .�exaq��3)|re)�� � �/�� p��c2�. Eth�ca}�v߂a��e�an� �!�f� rui�bt e*�#G��Ho�;al ^ CommitteeE�NS"QGEye Re) Inst��F:>�F-Y 84i��&%NealT�X�f�uio&k��[AU�Y�^�O��*�"nephropa�G1�vei �FbiomaɎ]trackaPXprogre��.�ce 200�1� 2.�apat<�� ��1N!%�kit[ �inv�Np$areA�"Q Q2�naD,#,�}s \al G���g�kobZi� 3�E bio�Lme�� a�R��chia!at �E 0°CM��ici��(��e��x�w1�:r5an 90�2!��� rie��t&[000�S%a.�!(pur��$� g�202"] �e!:g"�!�� �I"i�� Y�PT�i�PA a�mSP�(� s 6 , 9689�*,i<of�)�7h`;]-��gF: Thyroi��HeA y198?�1984 [5�Y�i�< Survey 1992 [53#}�2�6c93–1�G [54]y ABd8 [55�UA�� �A��Oa]?NY�of2 %!�9l&�a�424A+95]t0�8r9AGba�SC  JY�ƁyfA�.����C -m&�+�ca 9� �+. F�200!-200��12I 747 u!�e�}�te��lin�|W�R8Pa^3�Q�t?�>%���LA�� 742 m nb=!goű�" ,��,e�1636C�ve��. . De�F/o"� ���ns�Q��P 9"� � edJ �of�499u�y?, 4059\�e138)�-1�%xyﭗtim�3e�2B� !#�=�<�'�`>���i�( SiME��9-�h,R�`C K adul�{Nk�M2867, e40�K80ml�>�"") .�'���168 elig72�Q�, f!��-(�5a 7`87%����. f�f� age-}�ra�a�Zll6�؅4!��8�)Ein 15 ����E�c�Z�sr+��ern�j9� &�+Q��>} �aAI�.\�>z]�[5��:8I�6IND-� �.�V#(0�"%K-F+M".G��,-We�;N,, ! !C1UY �q(� � i . AgA2fi�`:�!�eYg elec�L, 350Z�L"A���z&_ )�( 7A6>���)Ց�� 9�[5#���.��� o&�Qediagno9�E����I�.�.Hn��ior hy�*8�kA�m a�aG�["wo�� A 6��mmol/L��ed �1J�B*�R9 &�j�|�c2�j P2g$��H Q I�=� ?I�,-L6 I �Ary�m, ��S&, �J!) ����Lae�!4e'7D�ܕ.c!zad HbA1c-V���Fr 2lA�!^5%i1�;nob�.V�Y)� % [5�Y/��ed.l� "� �� !�2@l!O$lm�^427l.�693�] -der� G HA2"�l)�� n4839� P�O�mXE�/! Illu�� BeadS�o� concor��8V of 9�E9%"� 9F�.�UdupG]d���]~-on 53!�805eiVcS�l@ e.%�662T6�G*610%^!!�0312 #1so �Ra֒�Ja��_�f[9�;�.B!���t%�e�roprietl�.K�sIKU(' Call��S�&�Ma 99%��i�&zly�lgot�kds � tfT'�)����!:Ũ!���u�Q%{�3*reshold!"(15%SIT!Ge �s)u eci{VA&=f� �1Q�g�z��(�i�� 07Ye�'BT 2�WE�-5�.�E7i�p"'�ofC55?P�A.d ��2�+ �Rq953vp����A�!Q�F���˵� !cE�-!!�an����s ,�� eriadE@�QC!��;Kseudo-@b!��Y9UQ+��:.pV�|mi=TV�>5%��g8�d�Z�ZEHWԡPcV�8o2�|nomaBc)^�ora�_GCC!��.u�%�t�.*��.&�+�i��s:�.�# s�*zygH�� cryp��r�>�i�aDd��$membership%�gr2c��ncdBi3 �lo$?f������Q�*Vہ�or�a�uz�l` ���4 aut�Y�ye�Z i,]L,ve=,%^lP+L� b �*=�A����:�IDakCJQby IBS�eӉ�lY�iY�H@�@ Riafa9�d���fmon%T!�twins/�aD�4nt�p�IR"�full-�Da��d �I�e�E.-Aw3��@��F*�iųBAi�z!R�[�Y��� 6e2A��io�"E"� -eGqB. P*Mtru�vas<'��N.@aui prin���m��� ( PCh�[59�d4 ?ml�}�)�0al Hapmap [60e=a�n�L3 �l��a�Xm�a�q%�fduc�B��!/�'-sh��]�+S(R| $� o%�n�E� self�R[�d��itR/e� 19�� ��@!"��n)T�ł� inu��loud #%aI�"m�� dmix�4�VPE�. "�d� C*lY��*&T% �O~"�BS2F–S2�>Q f6u �5A��l�5mmovK%����Q�S@N. Min��e*9�� 0�E�E�vi�t&���| IS��Qy��q:d1:�� �!��8�"�*m.ERM�ab��"�Ht:Ec�of 29&6 a" p.< 14&8 B)B �9 9 N< chec�p3N�Aݭ*aY�Ρ�}�~-0chips resulti�Ong in another 139 samples removed . Among 542 , 201 post-QC SNPs on the 610Quad >0and 944 , 144R21Mduov3p, common Wacross [�chips were also checked for differences�llelic2$separately"Q ases�0controls . 97 y�showing significant deviation from D$null of noma�,e frequencie �9OLastly� ~ with fasty@glucose >6 mmol/L �exclud��analysi� In summarW�p-�dataset�sists�1 , 082 906&)$genotyped :�%�28<9398 .1�. For�@Malay study popul)O, 530U%��due to  call !�s!9@ryptic relatednesissue)LcXstructure ascertainment�8gender discrepa)�.!Nn(, 557 , 824IAq242 �-�availab!�or9�(after apply!�!�@above quality fil" procedure!�12IndianN34156�3�3-3FinalE�559a�19)4in)3386��393( T%{,S5 ) . The f�uaof Q�e was usedAcimpute �on%�InternE�Xal HapMap Phase 2 panel?!ָIMPUTE v0 . 5 . 0 [62] ( https://mathgen . stat!�0ox . ac . uk/ }  . html�I���carria� ut uzAPJPT+CHB ��build 36ae�2E�-4Chinese , whil�Nl 4 ;� Hapmap IIi�@combined as a mixeFre�q1XZeߩSI��!�:u�� split int��unk{10 Mbe�)di� a bu��!�250 kb% i��a�)�@avoid edge effect~ ive2izeP�YRI)H ( Ne = 17469 )jE# whentu��against@5#9E�Eddi�6,-@known T2D regionsY�3o!2�Q[d2 . 1 . 2 [63] , incorpora���-spec��5xsɲSGVP . S m���qA�!Q!�� , we have)#m Qx hapl�*sA&!bAu9�1�`Q51&al unpacd@�C2�MmJ� >��-�� thre2%�s�� �2�:�,6�yƽ�iJY similarly)c �eJ�in�,iX1=A�%c i�bA 5a~I�E�%pa�roundj lead�# | �q�eT!�fra� �me-wide f�⡸reshol�A���U�inform -score��e� [� "metric��Oassoc� tef E>on Y @e��at had a�!e95%�AQ�at ��90�terior�� babi���proper_� >.�-Logis�gressc ��)�ve mod}(inheritance%�per!�� !+.�between � 2 diabetax-�S� SNPTESTv�g5 [51��://www Z�h~marchini/software/gwas/snp���,Chromosome X�not�� : =�in each!t�� h  Y A6��r��,wo principal��ponent�PCA61covaria! i��.}�s� |e�s*adjust�v ad��XAeV��� ir �ai��Fig� S2G� I�I�un� t!P�edN�) � ith Led , Yo-I� opŵinQ��SA,AI" a�typ�?array� �experi��j-determK 2A�re repor�A�qresults !A u� �]!�v�s�[cohort�r>3� .K by tre�IH���9;�a�/dep6 ntU��;fixed-�*verse-Ega�methodA�meta-)�ise�to ob�  an over� .�)E~p�. W��$previously�A�at)�HZ �in Eu��an]�sf show��>�i6.of As� ethnic� [24]8s such!�o!�r� � powe� our%Gy�� �� �m�8"o �9E= =X�ge�E�?m�!�qrI�%�ͼN�odellAp /METAL� �ph� michedu/csg/abecasis/Metal/inde� "� $ co� t�2oc�E|QCA=y Q�is depic!�in�3����6B/1Tmanhatt!�lo!.hP-valua�nd biE��0obser$–log10 (4)2 � �Z+reEhn.�3R= �9 clus�cngAz� s)�k �Zal*� ce<10−4p�]2i� top�  � (8individual GWAS�� visu��!<esAr/ �'Et6c��,of ambiguous�Z�� subs1+EI��mic� �bto.w ���uD6�,� inf�ng*0standard erroe��log-odd-h!{� >&actor AQ cutoff! 5×%�8��� declAN! &�ce�"any nove�$lymorphism!�� .�direc��y��Ie%SNPA  �� group�"Z(�ia�a��%�th� deria%�&EC�f desc�;�$stablished��` )6binomiale� u�!lwhyp�A�ofY "i ofA cord�sin6OR�Isame� 5%�2T asA�� �J9urcoiA��ch{ . A secon�C�� ��,2einv� g�eife numb�"�m D��*���H of P�� 0� �in-�qM>� %���.�^ !5UI� � scan2 a:�!M~!6�1$inF��sm��aA�.4�.�98e ���2��6R�a�i considee8R*� �: ll f!dB�� . Con^al� L 9; at CDKAL1e�4HHEX/IDE/KIF11!,3 w� ( i )�i1�!�� %�������q �(( expl�!{ -]�H �r�( i���4 t� emerg� ut of�Uq!/F� 5���(( rs7754840�%=:Drs1111875/rs501548 #:R)���2!,:�LD"�!�.pm#�.I�)�M�U�%Ie���ly1�0d , rs6583826r�asJ��i�:.`�:��hhvarLD algorithm [64]–[65]E���-)�al patiE`LDG�"��"1�WqJa 400kb R �^aao>U�%` �he targe�5 � pprom to e� ate%�^G IqJ �Aqcor�� every pai@%�E�i`� "M�B�Brief_a sym� matrix{��;2%q calcfe��Rpossi��%v;�e1I)�ext�of!�Y��t��given�7F. �ge trac�eigen-de=osE[Y� �@B W!{enA�e�(Monte Carlo"n by��amp� � ���&`>f:n>�! -&al!.�.�10b00 it�5a:�.�"� C!V (�m ( CEU ) ��o-V�(roject [60]�� 3�}X%#ySingap��k e V(A�T1] .��� nucleaFvi�takes pl!�-�daugh� cell,basidiomycet bud�yyeast C�(ococcus neo�0. U�� ,ed kinetocho=gra� ly% �U�us �š��bu�� s en� mito�Q. H�'.�j>evolu!arironAurora B� ,Ipl1 localiz}�uprbreakd"-�"4ar envelope du� �in C .6lis�n��ba�q*nim �ma,l��is � nt� A�vi.�reg�ms"oa!� tegr0of microtubul� A9A� romi; ,� ytoplasU 28%-�deple!~a�/"�I� sin!�Q$Q�A1dmigMo�By�^ &Csilico�� 1�E*vBo�E'b�{corti�dyneins<mote aR�{eYR�mW�A��+2�b�!troduc,*� "m�� hA�w� edicOa* o ��bia�e��/ ytoso"Bimt �]dynam�of�� Inde� in vivo a= _��u#%Pe�ular lev�dE1T.�Rq�in69!�m�k� by l%a' imag!Ysuggeh"EE�sp9 -tem���)#es�/g �activa6along��}}+�ns0mׁ�� �U;. TM�oA� �A: B�by �allows iDwnrentry W helpI�6Qao�]>@�� semi-openunJ$ High-fideic&asRg!{n )&$s faithful� nsmiq�p gene�ma_{o*�Qn ie�� �l �e!�A��er!�� h� omere-ݾ � lex A !��c�spindlete2 organizAwTerA MTOCs ) ,2+fib2.� prot��( MAP@� moleE r mo�beA�qtoe�s�vnd�ea:u} amilu fI�2�( MT )2!"�fun�Z-&F�A�'!�"�MTs ema�"ngi�)* ���N+( c)M�per5h� L�Q��2[/&2]P � al)4-MT-Cd)1[)Wpa��ipX �9��MT�skeletoP �Q�p�eri��-de6%�t�S,9U�E@(-linkE�mot�eMTQ[3 , ��plus-enda$c<]+TIE,� ub.of)isjA��u i!5#>a��-y� 9���hP of ~,�5)�$EB1 homolo�); ,�����e[tal end�,E, &�nta;#��� pola��_ Kar9%� guid� � -<d��N�n cab K p�y�[�A�$6 "� �n[5 , 6A�I� ntrao� -med� �~Ea�m�!r� ns��vl��� minQoward e5��, ��we[ ��o mAthrough]m�r-�~ neck [m(�Perhap���� go>V q1on �@�9�� daof She1��E[9�I�q)*� B�inMxcan<po7i��e�a�hyv phys� lyEFsl" themM4� w[10�A� terp� ,kie �Gphosph�*s>!l �4 -MTAm٥( DewE? [11]��b� �/>� i� best-stud�-�&L��attachA1!� prim\ sen�A�ten m�A [1�*13%+N� d �bi-ori� 2C>���d�%i� j rXz>6[1�-5�6G!)�wiFi"# k� dis'mb��>by-�ory�E�FB} re '� l� Saccharom s ce!�sia!66–1ew�-�esQ遰*� !�e(n�*� u �pre-ana�&�)��f�4Unlike hemiasc�F;vas S ..�I�vs��V/ is��(� phylum Ba�ota [1�+20]� sh�g�/ sA��TA �8m`t�500 mill��,years ago [2bev2B.3� hum� athoh+^9�at cauaMlife-I ate� pneumoniaEEmitia�AViI�5th most��>O!�dea]#)* muno� �� �$[27 Azol2 acqui&$aneuploidyw0a well-elucid�. mee�f c�ibuA� n} rans� ayai�c�0C6D[2 �! Clone�at Rd�y,highest drug�� ����Kfo?( o bea�'��multiplY#r&s6"Thu)u5�da�cr�,d fit�/to>��$e� �st\' [2��Although>6,eby�%�� &� stri �� C"�m*9eb.� sitE*R q��n /imASj� m%��eb�_!�alb�2` ��i�J@ �;� �j.le��3�u)f8pole body ( SPB� 5 mbed�)-�"� ( NE ) [2� OA�! Cis duplC!�&� G1/S� nm3�La�n�P��uaQS NE n� s �,a+A�n] a cl���[2� 2��I*� ,%o*�� sI-sf3 � pres* ��"o � �(r �!�E� B#��ac.� u�rup�/͈NE]� \toK 9A� [2�2" Q:�3�%�_G�a!)O>�! j��a a{� wo e"3 halv��e30�.a)F )��f*�a%ly�"} �!S� m���*�se��$� a�e� P oA�s�>� M��+-qk cycl�w5E�� qw[28 , 3�6W!Nu��oali")Pna� ��K����[ell��, � Q�Fu[)'WD"y(demons� !�;thu2fundamen��A�*�%�.P #seA fung8 hyla%��"p29 �nd&�� s!�� &�"�#!  biW�6� D"�3Z&m�� toi��Z2/� ar��unconvGo@N����;]"� or� �  tool�j ��M(. OK*,t�!�v�6�tinct*Xlea���Q!A>r��of �%�vto main�* �+% �eB� g 4ORF CNAG_01285��n�q:*� e FungiDB&�)A2idb .1/ )����anf� ^ do���1A%S1Bx)o5weyw�r�ex��)it)�fu li�mCherryt gN-G-usIj% GAL76;r1aa�$NNV114 co- q�GFP-tag*"$histone H4��gA 4ed)�� 6dX)A/2�c ���$��. How� , Xiq,q W�"�1�J�(%x1A%{� co2�(V�"�f!��x �u��%V� bud til�e �us��/co��2�e�fur� val� A� �6!%9o�!5&��ZND!�nEa trik GFP epitKatERCNRH27�  mX2T�+A reducQ �0 )D%�u!>ly1���fic�gV%1��oM@"ig�# is barelyp+�!o�!Tclowe� dispr/d�#  pr�4*� jQS� �;facA0A] ’s�)�-�QU<�!�!�M�5 re�Cede�t-:�� =>�. W�9v�N ��fi*)s.�y� �,%���2J�!���vD>G [32]%run �E�6�)�NE� e�,� � +1���>��ToR!-d AA�X *� �$�y10�1)���"-ed�L�ng)�%ant�# ( PCN��V S-1 !5E�/���7a�楕2Zsq�k��-Ax>�B�Z�f|( S2A�A*=���dJyNE�1YmaryA�ifͶ�Aar)� �>�.1,9�,D!��av��lyV6�. F��,�ic �:�iX.�%��*exa�4�e~7�x-laps�scopy��6�gr-in�*�v��*�Fig 1kS1;ie%�At�.m��-r2��`�< accePC6��-!;NE-ne%t�9�bo�*1�!:a'#5%LueTh�#2 ?ie �p��7!Ba� ���� !n�Q�*� >����!2� �)�f;is��y i� t��H�us&rR��cid y &�#�� l a2ma�iEvNE%�leakag��She5�in 18%^\��"'.*n!d� E�Ϳ<A��F���o=��oA�i��%�us1‘a� s S2B�1DE�2b "�%#"!$PL1%��r&�%���&D�}kC�shut-�mu%��a�la0$!A� ��'�:� wh6�*"� i��E( non-p 9ss�) but�H�)alS3 se (.:)g�#�"� [3 �t�ӕA~!/F�:6� E��8a�6%of)]� �6� e-%�&� -V.&�2+C !�3L;�e~ �F��tf= zinj�!�4 hH3H�f�!lR. Gexhibitmw��@enT1 7ccuC =hav��un�$ed�1i ( 56��a���) �8 � �i�f�M_� T�'f�:�&�7a�e�<�g��U�z AIe�Q��&� K�+rr�*NM�%��2ed-=�AY15�$գ 9�'wild-F$ CNVY108E\ �i�4 U-)C�1a��օ�JF fr(o%�N�KAܱ�"l 2� ��1A�(�8tm C &A!'"Pa{p�'r.� �+�UP]bw?a() ��2A( m/= = 47"Ayaa6�9Z q535 5-QD%s2E;�?Mo� Tak�A2�(co�d�(!c�K6K@�,F�� ��kF�. N�(Y1"7)v DF "n is g2� +r"s [�3�5p:i�:z !� leng��I�>�^J0� �l["H�k�MI�5�6��)geNUofC24 μp:+"��G7� lYi`7 o)�3J3�}M�xt80%� N�pos�9��@er�op�*d1�maj�4y�%K�X�Z�ct:B� �a�,6$to�I�ptN�.i�,��a�,ed� ����� �D&ECo->� AEwa�*� 1H�aberr� !����sp,!�d� !.��j�9=spens� ��fZ:�& in"�:2\#:�N�-��; �"D0�v-��-CENP-A��( inner2�)!A Y�,U�� 6� q)M� A/6xi),ly�6s6LA3�f�7"Gps ( a )�lR�2M�.�E!no �"��z ( �oE� )�3/.H�; <�G 4 ) ( 19%�( b���>��Nor^�E(k2o):  ( 24�c )Q�6�� atY stuck>[!@R_� ( 26 hAT( d%>�g�Gm�ly.�}lA 31G�'yX1�%�.7M�+12R. *�".IMZyA9FRH FIof%�'2�*�Y�inR/y2 m?Ehl#r ў��>75�IC%�.��tBng.��1�" �N��_�#w�Rn^ !Wg6yv_9V6qL6{�V|'". 2�FB)� lay��8mA�2�ime ( "� 2B Z�r� ( 2� . It noteworth�at02� ���dis���%��h� r de�PJ���-.( S3DM.�8c� ou.@� Dam1& h�to�ye�"oM5�6�e!7he ab"��.�1FN[3i=37�!�A=>2aGwof��Mtw�Dad�0� L� 9/p�Cv��. L�- �of��-�Iap� �u"� �6�)�!tE5tNex1w` �iAs6a.}��BA&NrE1VyN ��J� + !MT+ 51a��'s�Kas. W6])�rpE&�'�,�,�/2�^,&� -�) �1:,�(b�86!�4� S4� ,"�>� N��dJ�$s�1& 2�!� � !�:t6,J0 ;��'n�-tyA�*�&�/�.l �4}*&~7�� =r.�a[6�. focu� � *}"lon th�6ffI��ri�=��e)"�&H�5�e�>4���.V.2� ,J.����b' yg[$z+40�6+ NorQF�g<8WPB?*�,ei�Ad=�� ~Eeh-:A��.m( 3��&4q&& ���–� � �^�N�nF[X$\"�*�h1��!�Na./!uxa"6@ŋ canv�5d�+�, plau,�-dO�z�{schem��5�B�.par�A�_1.04 4M3WeR;uO�"�,���Mw;+ (%p�Y�g��� �<��8&�!;�"s:by�e�BAҩ�>>�� =ge5BM)re!Sm�3efor�3n5Ni�:��x� 彁��Z!M� s [43–4fA9"� �Lm 8�"�;.�,� m'Ce[H�36 �B�E; !1*%MT;d<=.!" sept�&%�L5 rigg��by �7 yiel��+nEPm1�)�08#��" �!n.�,%'�Z+( ~98��� s�in 23!ɞ5�M"1�*�)> �6�,"�>�+�om�[tr%*� �.r:DF kH fea�w&X to vw*"9'��=]�i� ad�*'gcorrob_`e)&<9*\%&#[�4k W"7�rrecruit%��/NJ�Ec͟��CB>!!�susI AR�*l[b=}I~38%�{�erJ[ -��2�2e*�Z��Ble�~9Ije4emplo��z�-o�D%P5att�7MrE ^a�� m &�A.8��H\ "�7lMEeno�6}< 5A�>�?�-ortex+r�Z�*^O�0p�@��f�viaxJ,9�[5� 5y1Aa��LV�� !��1 has b�!"��S"B"ZZart�8 ‘e�ive’9�E]�3)!���As&}@n�5m��&�?.�$460�I&` �"�\�Hq4a : lack��CA�0���][61�Y3ob�8Gi�N)i"N̡F1 ��[%me2�A-�S>�.a�as�ca uni��E���of1�M�� %�� � !Zic� �5%��P�/6JE�. O1\��conno��%g�.T&P�-�tip@$�� !*a0i�(vor"�F��2�aK�y,'p=J!�#+erHFR�>��.�!/e1\� a�a�i-pu�l�e�>� @���,�_mi�.eY5� [�t!�e�-Oy�A�bK�*�IT9Vz]: %�j�.� A I�K:T��y�ߡB�&F�.& .vAb��*Mm+�u�7>��A��y�-�.�%d"6E�[�bud/weE�'�i7of�� U�R�10%�3-5�w�+���� "�4�-&�Za���f�49J�M���X�KU���$56�>�.~=!iWB Y`>/wB%i.� ��W �!��%IB2m�-F�*:hwe tesa4 MdeN(5�fB �2l)�,^ ��Q&>mu mf �Z� M��6 . Di�6�.�. ���!E!Y͡Fage&-kma.!-�G%�I&�/?[-La`"�@ �.�TdV2�oc�Oen6s�A�W �,S�4-��� ti�;�� � � d get"�4" 4.�?a�:� �reBmM�0u�Js2ECU�. e%�m�_randomC.F�?2�v ja��`D �:nl�Xden� 6O�2 a' y��6.*(6wh�:��1$"�MM� �2�of �6A��ut�#/*�du" � f ��qEG.!)eK<Veim YR-*2a"Y K pg ��:�M8" .�.�FR �de�T���IM1�07 ( Δb�G)�a�r�:�(.�:DYN-��dOxAa��S&>>� �"�Cs �*�9� �* he�e�>%+J� e� iF6�6�In l �T��at�V�>m�0FW.* �8 !qA8�!�d 5�&� �.�Zh�A� 2{1�0rŰ�;�&�.eA�d6��\bead�;UԊ� ( S4p54D , S4E�S4F��7>�+&� !2-e[)�syner�m.2� eRmh!nmp.�LaF �/Fka�l�Mwm��(?Sa`I���. "6 �3 i� 9#.)�:@�<%. E.'�4�FgV�xA�B�-�k�ri �$Cl,�X+63Y+to�+ ,��#Z` by�($�(Fpby 5 ( 124!�E��Ua*~ �om�-�(�"d)i����2�s�of�-��*�0 !��4istFz-��"�V] A�>7 ( S5�PS5BY��A��X%�eJf>PdRMA!>hYY�-�.Bperturb,A �{�$A�%2e"�� ��6disagr�a. `U���o9ounh�.�disc7M�=��F�E�Y�-�I� Lu �Y!^�+key� NM!�:� on[VGJYht+��5Jq�r �g" E ��*�&!��!n%��� %�ex����q"�in ~29e�Ub��,~1 �G16G13B–'&N1.DG&"��� }�sce�^oa36.Z)�"� !p!�AStoI�8*dM2�m�Ynt �l�~8IJ5m�Y�al�� ( S6&�'&�61tNR.�)�FlB ��� wkss�R� �& ZE"�660�F �"� � %�My� t:S%2��a�!�$<5J�) �,�*�9"�5�,S6�SU�`8amexposv"��NdefinN���By�)ule�*�2-�� Z~g լ��%�.�2�b�.+GCe�PM.(c�9�@ ��U6l:+& 6wN �(F9s p�s"m� �zYor / `:Be6�8ed# �?a�(fin c earli�H ^` ��,au�� �/{��"�.Eɢ�p5�w"� 6H W��n�<W�e�. \a� rgiver����� �)c�X��%h C�ex �P*� FDA���~3~f0ngpIK�"�r!!��feranE@�&)K ^i|x6�[��!�^�8(D� 0��)�!2 ���. �6m�I%�In0cg+gu1n�9%�J-�Z�"���/patch�5?-zBw�7���r�AMelsewM<>R(%Oarc�/�u �9� � seemAWD% tug-of-wa�OY$�f�+N�,v �C!�b�i�LQ<)� . Da*�x�ro�+re�&`del w�zp�# &mmR =#�F�bPkrRuPih3A�A�&_$� �*map�uv&m "��, a��ϭ<Tr:� low-Q"M1B/m#� cruc�U�AF6JE�F"�F�� i��Vq�!?}9�#1Jy ~�b.JBH" � �P�Eav{��%�.EUk���¡�52�=mxN�as&: *���W=he�1 prof�>&& !����1d�C�!o)�Q�� R>YJal �#���62�6 f� �m�p2@orc�Y/�oV;.%= k&"0*)_s5F%Mic"� �2O�� and/�)�$ ��V&?4!� �ira�e]���&�!I!�MT7 s.�%(5E-Z @F<"!�4st�:A���u-7=Z],�#�-B$��Fu[xS6Q!>� �in�-Ux�(*���7�). Volum�2�a i�`s 7 . �4 �$ ( Bitplan� Zur G$, Switzerl! ) revea { ��.�*frA%�� �1Mg6�b.� �0�DTv�a"� am �hroa��"\ mi�!�pB%� !-<�: $is FO�c� .��U�)ap�'*s��/frzta� ���>�5s �"Flp78��D �Y"3oG:BH"!�^�/�/fo.ke:�An&,�#�^ai�R*_G  , � &�]flucon �( 32μg/=�= colon�4J�&� -��*�"�Xє�^� ev�il!g�+�Fy~&f3H. I��is work�%�&�aA�A+6W#v2�pit>�*jb��ovK "� .�>B mZ6baiceWa��H:��X�%cri��1Xx XA2��3"k5j Z$�6�"�+� &��ya���jat"� ɪɶ�%�6es�/Z|cFe-�s�N�B�7:M�A)p/�wor6�TI ��^ �ne�O�y�F�>���.�2#"�F�B�Cy�pE�9.i(�,^ I�<so6$4)0.�e2Ne��E6%T!��c�m!N=�>�O�*p �#o. &Ðwe}zmal�"!�q��hphy� -indW�t�8*BNBXwe� t� I�(n6 �-sB`� Z� !8-�I%k.o]%em�"> CMR>��+o�q�[tOEf. as \ota��Y).�b!�fB�ME��l�}aa�%+subA�uz]2�-/�!o#[1�a& am�"42*/�w:�1nd&es2^Vi @P�ne� synt��a*�i+��"h { �&�#� midzW8|}�n�ss2`8.�V a;N [9���b)&VwhrW%h-eny�� }a!R.k8'�Cs"��"� "x?*�4 %bO��( "*;� �DQ�U2�^bL�3 C6�<fG2�^i/feXS* �-A" &r�!za��� � ��%& �x�:�"Q!onger5!S��3��ngi�uI>s : [1d/Bi�p�osI�S�.�3��*�&i}r6�1LVoYZ*n5�sj@Myo�K�� ,�.,A'�et��[�6�/":k �2�[;0ILd�6%�6 2�Ba�n�alilo,�o/[/�=��!�&v-w�x+l+�ͣ2ex`|!/ She1~in�HnBl!J0C8�/�3!eiv�.�R �?8-6sm opeabn7e�J�MIoA�>�. O/�u"�t"���.��?Z! �]�| qA�:� �K"o���C� �.i�*p%%�_%lBfgmNt (unique syst�R��"�oe� ���:!=�6�. M*\M�>KF�5� d�E��F9soI�'m{st� -2ů̈́un�5���h�VY�\> �]. K.,~_+n��� �%k�;)nYJIN1Q�>P"UUm�n turnR�Zf?�FMXuxi�4�Oa�s�$ .���f�.s�<�&� z��r nzyv"� �qMT-�PAT enzy�!d��N�R^�7��a�atZs� abn-�l��E�of “�O” blobE6�>�\b�>recM���8*�D[em1���!APs!�@y or ixH� ��ez�"ser�of&u�>�:`;рa� e-8� , Kip3�9invol��in(J�J�6���Y> Q��P&f}-N��3A}a�M�-by>;-b�ng����chAY�K҂& tG;s"� . � u&%sAJ� �6Re� �-i*�6��at)���_ �Iebyu&P�!�at�Fz8��J�1nUL!:� �Es��"�7+ath݉)�j���-<�%a).� f&�F�4>�N��8nstitu�ly�2�*@mK:H!9� �3�i�-L1�.�F�[1�;� 6�ZIB�, �<�A�"� �m � �7�6�k\k�� Cg,&� �L�%�<&�-��(&%"�t6q.�h�IATRisup�� �cen}�Cpa�a}�E�:O)��at!#�&Ob@35�'2� 1KRq ��nP� �ar� m$'fu�� �di��eV]bjmS%� ".l�!�5�-��w)5UK, &3M�6CA�N�iX�&ZM*k �X� ZU�w}�!A� cribACa suit; %B�9�m:a�!>� ��:er^;y�'yibE!^.26cb�DQ6�d( � " E\2'by �!���Q\2��[)��j��i . IrT!� �I3t.�ru��� +@�aTH�� � y6�Im�1�UO-�!�g��2�,O;:0�V.Aq�?a��-�� st�)e�J�A�l .�5 �j"�!�j�P^Ya<&;ty� .w$!�9�.�su�j�Qca�x/qu�X�vR�# archi e�-inV&!o!�Y���Aj">|� simpl"yfM� framXk!)�&Ks`03 uE!)`&3v"��( l)�EspliYH���S6ާ! 3neglec�T",&~F��} �S)�s)�sA�aa�qa���etaf$)ځ͖ͮ$m*�&��lx� �Scb �f�&ign� %.N��"ata�h"/o.o��;e��a�:� �B�* urs�JF 4Rch2{� coa�g�:� ��inv"�7-&�Gadd�~& fuE�)F? &B0D*�(F6vovC\a�i���A��x��an�eynOnL !ul�Y ik����,|"d�us2jf�a�Z;,J_E7&,��%a�C6�:UB�< �M�v��� mis-O'�e��)�{ai*$� iN�Hpla�i�� � [M�m�gen�%�  in flon�[M� � &�6� en$�%R>V&�a �i&(. .2�& �.�ed^�opm�eHفG%2]�ass�a@9p�Z(aM tEre��P uxinV�y M�w�0b�4͙ݎo rC3- " %�� ��O*RBgE �p���� �m~�x2��%�� �D ’s&(!�imPd� ce:���!6K��.e u���lo[%.y�,D&fqs��:�F� .R�  � �&� 2� M� e�fall�����d�� or/%��f&� ��!�%a�Au*}!*���! S1@�m�"�� !�9��l1 "� S1 T]�S2 & ly!O6 �s"O'V E!�PL1xTA�$�re.xp��y�(7ORF ( C&'})�!�6*p5M7!��Z>T�(a"�"�H99�J��DNÀoligos>1!cB�!8��pnI XhoI �e��p�d pSHG7MoonaC�6�Z7 hygromyci�wHyg`)m�vr2 o9W pG7%7�P%ujns�� %( UTR )���Not)y�&�pUS�AS��+� 4E.z"-�i�y=  ���1n!�E��%��be�%ir���CcS"tte-�Mq/( NV123%�l~8�3n%��  o͍fEH[66�k/ 8N1�?H#aric_L  � [67]�S2"�*XdNV1�r�*TW Z4�.bAl2R.F�u��`-bi�PCR �v�.7�d�!)��,of��:�i"p�6�b �C*� �R�.:�V*�p`C� )i)� 20  backВ"�i'5�m�A<�upQ�am �P�(�M�/eh� 6�,i�!�Fe�aoM���A�I��LI QkmH%o���H��AQhY!E-)d-�~�1y`I2�p BFdTÄ.am\N.�<&qur-u�,Y^ 2�v� b�&�H!��.! �� ^ !�,t��� md�Im56��ea� `��2c�I�V :�ES�r pS2M-�vJ!�.< BamH�=�'� M��AEn �W6�r�E�A}, %]�6��rZp�mchBiN€!�!�u�i�q�32%/!�^�!Se�08 J����f�5hBP|@he}inguis6Il:�; ly 1A���f�?A%�4*S �%&��AmA%� ���i�� mix oG 2$I!�]-ng%CB�R"�R5~)��Ig:!�R&A>+� (.� I�8u� �E0;��"S "�%��dofS�{;S2�589��Ad6' �{T! 9D�<2< A�Sal�FZ|��F�?� >Z�I A�A�J��v\l�k@�6�G w&�s �.��b�)�&U�I��.� 404�NV356��VY���� k�10�� 11��pe�9���F.�"�s/!n� Dyn1j� R�).2F.� *� �� !��8rs,ˁ����IPL� 2�CI3GFP�ahR�e�J�!�a��o "� �s FR�J�=�� a��*�>�)*� CD.� �� ��![� %�f��� �D�2�� R� �1&L*�!�^DS>���NV452)� V455 F�S1���wC��M.(��!R��s�J��af RgSPC98�h�h�hjhS>h���A:j �.j �j�j%~k,am7��NV477�mem�iw8A�.��n�5f,��F�"~uB� ������f�B�t��Js �Ywp �s�s!�r ar�>� �h �gzye�0 > > :� "� ��� &� yO�#�roB[!�6��utH�% YPG�]%S%ext*@��% peptZA, 2% &r�)S:�Hum�YPD�Pdkosϕ�:3Iumm�"b�� � �D*� :�$$ 23at 30°)z�O� %�0Q=KMnip)�Vr��ocL��%�J�an4 ;��V�7� 2 ��BseZ&-pelQ.at����rp)�wa��ox0�1x\��1b�15 alin�LPB{Mec su4�Sp �#e""�׮A��Ja�(nAbagaE43pr��)%U, A� #^c�\u*e�lip7k ive-O'���1&m�Uou��*e|��Z�����@ZEISS , LSM-880 )�i&,Sd er4C-�a�chamber"�ecf@ cuba�< , XL>Z SL��$a Plan Apo�)8at 100x NA oil � 4 obŽC*! GaAsp!�to c _1wo-�KH<�lE�t�c�6�I1 swit��g"FjRF� f��!�?(GFP/FITC 48�"#561E�excl.%Rd.4500/550 band-p��,<5/650 m, ie�v~b��(-l>R�މ�e,*  ��DTub�lAem col .�,t a 2-��' rvalM� . 5%�\e�\�260-I"t1�z2R1!�aN31R/2A'5�]5dZ-step!�A�.�H�"%a6maximum�p�!�of@at�!r��ImageJq�s#FJ�) �'�1A0 ]=! 16 E���t[�OD600 = ��hea�E��ed�?�LvO��>LL �3N'i�%D�P�Pbez����bU�@!?th�7��`2%FYɁ��^��[�K�<�(�����q!*EE�X�a�Z)Z.��QdAO room�e�MVlash�can���b�,LSM 880-Airy2 ( ��P:663\27>��9m�a�AWphoto-�E_vDeltaV�gS��i�� ar v W�a>ه3��� !�{Konp Q+1IMARIS�=W.ɲ �it)�Gauss��smooth�!|!> rfac ��3d5�,���abE��^te�@�.Radii!�% i spo6�Y�l �takx&��5�!�di�!�?Pu�Do�6MX�� �R��q�n�riA�=>�� ] "�����-�!�B�e-S'-"V�:h&���mC� �Ra.��. W"&_l� �� l���5�*V -:: "�S@�}�2=��me poi.nI� dof"q3m�ar����ndai!BE�1x� .?�("� d)S�%5% TCal:kYR cid-h gl bead` Sigm�WCa�k No . G877c'by vo�~A���6go � nHRPA'ju���i52�"��Banga��Genei6�HP0�i�wi"f��-*�2�g��U^�%��%w10-fold )NaQ%wT�105�4�s�R~^A��r|hUh�Z�S9 !�Ffl.�^J�,F8929-100 MG �y��>"�Ag�!�9Y>�8J;)U��-M*c�}R���`�/"�6/ �j#Z�=!�3in?'L?imea:-%�-�!has violi�_ �lai�3�c? na�t 5 grap�=�lum��mvu�q4SEM�!Prism 7&pb&�at�0�{B�=�,�d� �fa {Student��;t-t�V�%K�n"@ �go�c<�Zlo(&�G, ltS��d���B`�AF!�CE?a& �%K�sd%< e��!�=j-K type%1�A!.(. �Synonya�w y�inu� I="= `*�'1cNc -sca�=M r B#e�$�Q,QsMal� eeC!hS!Dy >]p?�Vr?��nepf�7dis�2 } � i���!b"Wg����ipao��poradica�ull�� thyr*� carc��x\MT�ax��a s�cc RET X Cys634Arg55�u��? ��A germv�e@�K�Oo6O0=��d�SYfoLXR��#�i�Ulin�P ly ia�ev�NX��n��j9�� �fC$i��w ( NG� �4tum@ iA�A��eC �3ab! � I2E��Nu :n=�&cz � Y�3z�62�< �a� �)�sE cripve==; %��M >"�J�)aA!V in 7!�"nrbo%�C�. Min�2�A�m�G"�_�D�D�E�-L=��17%�suffi~�Xexp�I!b0ted 5 RNA ��"xva%2�?nd #ik�&� !Wex�Is�S2�8�A�o�pAJ!t��new exo�c��E(sHr�8ift@ d SRp552\�@���l_�,)aa]�Xr�i-m} EX!@A� pre-%�]d abund�|+9e *en�$�42eS�Ki�rec�r�5s�in�s docu%hc\�&J"J=��!js��{Q�A���!�. �Wnow c�(NQ—N le-�dot�.C-�doR��1A> amin�z�! x1��Fodon—�z�V2 pC�W`_��hUDZ�[1VI�� e>ca��of��eOI) 9c�ise:/ �!!�V!m�B�e�!z�fR�w%a h[DI�O ]s �PAeŵUFU��/��� !� [A�Despi!��;advAc N�4 st/����H�-�+�+��Kr��n�2��onvnV�iu�K�us [o�HoJ��j����N-YM= �Y��pact�R�I �*/�w�e0X��]��� caus�>�OeoofVc#h$elanoma [5,@-F��ogs ��s [!Xn�pa�Fde�6b�) �&\K1�w@uq�@*��a % iLa.�.�M�Ayap��Ago-��$[MIM: 1647֏�*��l! me~� I55240]; `�:/��omi>"or���aUa�v��Y� (neuroendocr� � ,itonin-secre �2���Nri�!r Cl � \ �nOtq T3aJ&U�"@z�� ia-�2E2��MEN2A� 7140�B62300]Q �t�a�&~d�?I;yo!ZA,e�al� in�$�>?&� V}Cin%�� " tyros!eE�Ձ2�;�en�w�0�bc1\J{igand��o-I�lex�� �hs dim��Ũ?Q�"�� auto2\? &&j���.d [7� GainYv��>fkeaT̲-"X cX ine-�X�%��"h�� g ., 5%�7ae�� 63���@-jJG����odon 918B80K. B܊� �in�Mp��e�iu� 5 t1�—aA��y$WduL )�"j"to,�aul��-bo[TC>�Q2��l2q�a��܁�!���n� �J��[8] . Correlation has been observed between specific muta,�s and features of the hereditary MTC phenotype , including age at onset , tumor aggressiveness , and the presence of other endocrine tumors [9] . Somatic gain-of-function RET mu�dppear to drive around half�,all sporadic�@s [10–12] , but�g �—�c9J s in)xse cases are less clear-cut [13!�Th $D we analyzed invol!�0an apparently2� harbor%Q soma��,c . 1900T>C 1� [p!� ys634Arg]�`a previously healthy 29-y�pold man ( patient ID0110M ) .�$postoperat!FPcourse was characteri��by rapid disease spread . Despite multiple surgical intA~nYhHsystemic vandetanib!_rapy [14!�A� died!80roximately 3 ؐs after diagnosis ( Supplemental Note�,Several clin�6�is%�0 ( e . g . , :�Y��Hbehavior [15] ) werfficultA�(explain sol�oEF ba�md.�2�I�r9�id!Df! @by Sanger sequencA8. ShorAYbefore =D,’s death ,A�az % began re-I�I DNA �@RNA samples from !( prim�!metasa�c e� s usA next-geneAOon.�( NGS )! �y any5Q�eso�< cancer-relevanta�es . No ! know!di5�97s)�f�y�results ��4rected our att!e!�o!%$ germ-liney�890C>T}�,0=] substituA�!chich had�� �-�%�reyoF�%�A&!gconsid��U�ly in%�,tial becauseAX9)�ASexon 11�FsE| oach��50%%J)8�f1��� : 37dT%; level-IV lymph node�&(sis: 43 . 4)ung8; 32 . 6%; cervţvC �p�is��)p5~ clonality%�A abse{ gene An ific. AP�l�rWcluAi%�also supM-R��V, ��confirm�aea#{�6��in%g%�1l� docu�2ed co��te A�lap"� WInt3wild-t� (( WT ) peak!�Fig 1A D��dF�findings � obo���" �o> �QAbE��<(90=a�.�� [Ņ Ņ.llaI�E�!� disc!y�Ota2]a+^�Z�led us�re-Eoder�dpossi�� roleW!� . I� rogE`1GnomADE-bA 0( http://gnomJ broadin�O��,org/ ) revea�f�0 =�4be a very low-�k�0le nucleotide�+ NV ) ,��-i0European popuF 4, 0 . 003% [16� HowO � � a�-�2k� (s codon 630gA �m, aA�m# < of non-:9A�Ws�to�$pathogenic2� C630R , Y ) M Dupek et al . maint� �snjar�&gn�� enrich� onc{�" part� arlAuose.� �;at�GnonRj!$they recur al� !)ic ��enh  or sil��r ( ESEe�ESS>�) motif��ca� intro� �5� ,h skipp�,_aberr�N��n! �[ETh� -�A�i8 "� owal&��/&j 2�2S� he qu�� :AShtranscript . We used RT-PCRA1�2+: :Creg! E�es%s 10 ,�)�12A�an��� X + <�cash-froz���=�v����� !�<i!q� a cn leng� � A�o�in"coAl�pool )���^�a�.�diffeA�)Yu og�32G>A&t11Phe)(��2A��se�mrg� ga�%p*3(macroscopicI�Ml�l!a3!���:.�ru ,m( ]Kof!�i!+a�M&bFkE !�1  uK�_� oughxcanno� >��Ei�pa�if#li� �sI�[ al|(y undergone�e -media0 deca�(NMD�17��F��\no" �e1a with-' �0C1 jun��U"# � me ' ~2B%�.L ��3 ,%�e�H w G2YaQms2�higher! hA���evPMTC� $ !$amino-acid2o s at��i�&634JAQ.�two%E�"� ����XM�tHN�%'�B����� >%]z:.�q�)-�1000-bp M�ve� ��start��or���3′ UTR�&Y�[3 `Biolog��l���E�B� dist�ve�� ��e: be ei=8u[publis�� link� such�to!����jlac,�OA9 e wh� ,�.�sugges��35�� 2�may e��inti�vB�E�. To furE��*i�a=;"�NS�!�R� %����m�abund!^+protei��/Western�t�e to assess21m�assoc�ewV�&T��4%l Comp�>a,al*maTeKa�(վ�_A�*+ U~�display� cr�d!��o� .- ���cl3�%~>i[ phosphory^ of`��ow 4eam target ERKr�4Pw2 �5 cell�a%M�~�) thu�e%�to%V �H-� �IZ�i�%ul�min:ha � ETUrth��at��N�eq�� alm �B���9zM�cr e(�e(8 ,�8 mminig&pp � imaDt5 fo�pe� L in vivo2�regW ory el���a��|ursor|m��" [1�>45�5C �A�!k?��� �0 'ng!@���6� plus fla�B"�%�; funda�Uonvus& u ( donor!;ccept branch � s� M-k*nA��!�WT�{�}�-���ntA�Y= ,�:� !�QKE i� to HeLamZ�do � ndonex�/�( S1A��PTwenty-%�hT�,e!i�� harv�zd!'nd}ximEJ��e1� �E� measuI� �&� methodAR n$real-time + . E ́���%#q��!��� �simil�!�an{ ��*�al�c:no)I�.��!cB5cWe��O���er�their X/�a*�eqp Feہ��| �!A��aE  !P 1 2" � -��us sepa[Bf 6A ,> _>} �-���Y� ={Ex ~3-f�ﭖ7 maWT2����iW \.�F}.n5 ( ~9F�WTJ�, P =�3eZSMa�uMv"� when��%�)-|f()X:��}6�}T&c=e both�sa��A�2~%"#%�alwaysJ�1A1+�uo�is6J. WhilL.� ��allow� drawmco�S��FkF2Mۥ]��& 5 y scg�B4 *�yb�al�;�S�to�nT=^��+�s "inqSa� 6B . More4 ���%�ED� �a3e�M~!2�[% j%!�Z Coll"U%1se� c�\d � might "�by ��e�o� %p�QF_-7��e� &x!O)96�T)uB &l� I2��tre�$J-J�T�O"�  �Q�rinhibit'0actinomycin D%Smon�JJq�%���.-� �k�/��:�F@|o�L.{y# -liv���C�6. I>er{ seems�>lik����U>��E=6mpactht!5b fl!?em1cyEaU��pAA e lo-?*�2�2�M�begin� ) �J (.u11�@Q����on�� �]R�ch�OR$( "�procesB�isF�� %�iM"&�e�z�X��2�.�-��ed*� : ��&��e� , poi��q�and/or� �ESE�%recogn�$SR!�� ��ly��',��uctura�e��!Ofactor� promotron defin , d5"�E@recruit !ENp� mR�)a=_recFantagoni�#9��C�9 [19�. T� 2!=ll)�� sA�di�"Vc2�wouldO � a��new!w&� >{p55-'o�ly!! SF2/ASF )��� !R11-��9�-b!ng!we���)��UXWTu�.��sq7vp�#% A�!idA&.~ u���E�!�(��s.�21!���a6n��F�e)iZor elimi�)� ESSs"%B .6�E��hv'tI�c!6��W9���R�b��~ae N�~S%��1�]s5c!?�l "���DyM!�r�D onAF*�� above hyp!4"� ����immuno�ip��RIP o evaluatB� ��capaciti&++�!P�����N�ar extS)�-b+V(>�ed%��IbodO*ec�%t)�(%yV most�mo!j�;(a��, accoro.#i=�$—see�t�o|-bo�+!p�� iso�oY$ vers � crib"��xd�86�to�fj� "V"2�* 6�$�7s 22�NA�"� "��*2c23A�!�.� �� 488-1561� ! *f%, *A� IgG-Y�#���J� բd&e')�m.L�Dq�.�; u� .6!yRfu�Q�#at"���}��~AlM(���M~�N�b)蝮9b =6��G|'Bom��a�7 S&%)e � inue*b��*� pipe�#�*� �ze�m$(l�-scal.�*s%ome/exom{ ud�>[20��CB�+  )T�-"�' �&Q t�.)+&�/> esti5-d . Rec)ev/� how& *�"� s"(#z�e�(lay��A e�+$� .�' $[�6 , 21�S2�"B!� them�b g*|"� !;Ai6�"�.�Ev�)-un1ed!��/nd4-�&�o%�'up�� ��I �"-*�]�U;&�0be)~ se�oni�y�5�a�l��N*� Nc2��a�"cAN& 'Hv�/m�if�ng!m 6�::)s!�A{a� � .�#*�m��valid�WiFv �SI� auth� �� .� ass9a{��%"L f�"==1�21�� �"J/"� p��io� ���SixA#}12] M�o V�by��!�� � 6X� ��� le iZ a�0 ����� �r�2��@� B���-?#iso"�$� enco�,� A}��nt ����5t� v�*a��.�66>�)MA�ur!� ’s*,%s!I�$2� 8(A�%( �, i .�1�,e��"����fu�� integr�� > ρ{lex�2f@��m!�<t.��5�e��R ensu���e�,�/��unambigu�6� �sq�&z!�E�!ˡ,Ufai�4B� [22��$Not surpri��'e>� ���|��lof=0-6��%ibug �%is op��l11,ory set-up ( �\q,i) haveN�W5�6I;�1"q ���is dys=�[19���&2��24�M ",p�SA�8original searchEJ_',(�9s� A��inQ�J�L,. Instc5!@ain rrF%�"*���6ateret��)2�$\ Y��C�(c.lyaDn��� did�!ggW6� �2� *s redu�&e!��G� 5��u AwA�"h: E')=i� ex�0ieg  d8&voj?1��P� �1� Vr�*[ %~A�m����!.� � M/in�#ee�EG0tro*�  �c. 6WT�7 nter~+!�Bd�>=-�sx� ��A�5 im�5 !� eo�B.F ra�#E?!�"�- [2^2%+�@&I�ofyvo�$��-11F&x!MI�B�2���;�r^�Z5 *�6�A`numberbmoleculU�e!��!d��-waE3"�+E&`m inig% .(.���8!6��jat A*5�&�� 3’k;a� We ce�tes�  si�oI easih6rC;tp7!�i( �� C2stle�i esig;eaco��*�!2� u Q*��k�#��A~t Te�6du1xw"=��EO reby�il�ng�&(A���*F j�.�.nr7u��?� .V +��61.���e���#st*� �<�"� ���,tr?-/* ur suspicZ�� ]�.�A}�A�aj5�,�,�/J,� m�of�uquar me ism�U%�.R &g2�92�2Poc)�=�Ica&�6^6%�o!(Q&� �:�:of�'�a. <�%g! *�"�<1FAf��q*�5,�.�.�1ʼn[ b%Ual gap%_A �en)�fam� hist� [S&u=ry* �.�V(on� ssum�f:vamti>�8)�no�E�o)$.�,e �!�� S�$"�6 �82�'re�%u I�6 �-���9g�f areO3 depen�=�lig�tavailq� T�#ab",1䅞:� of�R.M䡷$�45�>C -bea�y�+Fm� t�1M \1"�'. Ciampi"?4��d%na/,E,|E!AB!6�A��X��3x~��yn7e,�� iv!� pooryoutcom&�5 3�4ex!��)]s:���"� � ��� �1\R�q��4"� �"�-%���g�a&222�";y,/ ��!�t!GE �I��� �it6{-#)1s�'��:� X� prog���"�:0[2D1T��&I#ɅJ� ae?��ur&/ )=5��y&�b��;"��ti" �M"� B� !Pm A��?6���>�6@2$(� a#�C2� f�s&� ("� p�a/��� ) %�z 0� j�0=-p)��anA�* )�>�o�ra4�;aK��6of��-in��dim#D)�� autoJ�-�!��lS�Q�c|onceivab��ug:5k2��%EA�a�c� q)�9"xC�����le�,5'�".&mea�!ful]�?_;.�BM%�PF�q�RlE�be in�"���@ iple�&�,��,(*�CNV� ����P2� ��B m�ep�-Obw��;��!}��%�J��o�=:�Dx�Acondu��fa�3Al& �w*�z[:s���*�Fde&E�ay!Om� � i9it.�;HA�gi5Aa high�7�=$�� �o)]�.�(SA�:�;9�a ��e��'e"z2�.**w*'W�F?3study��manda%�i�"�!Ta6>�C4��@�# !Ho�?xAJ� �*"� . Re �%�F0� byN �-K4al Review Boar�4Com� o Etic@ll’azienda poli o U� to IS�8title: “Beyon�:>�0�'he��`a,E�� ��w"A@medull� thyroid�"cerd.Next G&�FSI=!5�>d �pach” , ( Rif . 3367/25 . 09B>4Wri�F� o>A3 �Hob��$^0��EIW[;��a�A$. N>XC _? w^�} s�go� surg�$J�49�Ho#Jau;,Sapienza Uni �����I wodh97s�2PB*D&]5=:l"")}[?ta rd� �V-<cri�Ja�"u}Lw� stag!�.!A./ of A��can J�&A�m!�� C�[2�2 Surgn1��?>�eqGph ven�9OF�c6+ed2�;¡tFd S u�!��.>B��al���5 . N�9d,C�V67L��:S�F �W,�a&�2ME% YJ[(�%$e lung�J 6oEU�Kv*dL�+žD"?:n�E>aZLR=A�R��>���6\�imq%F��23�gi���/. All x%�U�st-�tL.hA� (2��"ma9"b . Fr*�? e�>�f�as6����`� *�+ � E,Nݺr�~.�r fF�s �� %nt'O�(�')�a�}� "@aNA S64 nor!J��#ClontechE"!��ZoV��+%�>��oh Wi�=2�)��a.:]f%��>�Ht. D�")�u0 �I we��͍aOE��&I�2�=H Q �/ K��VF.HE�6%|e ,> 80% .ʑcmC]�R�Hof "% �^�'A�n� -N�B � �GB�l_a"�&z6Qiage� QIAmp- . MIDI Kit;y- MD 7N#(oSpin Ti�KKiP>Mac5Hy-Nagel GmbH & Co .Ul1.}� also�-�on &�@�7.nJ-� �!%=E%2��!��ah50a6  �Y�Pno:�<)Trizo!B�Thermo F� r S 3tm�p%�Rf6� cRe&I�Q�(%x ic Acid I�(A�k%}Amb ��A�DN6.N�1 �itoz r6%pw$>Hc CA*y R ) &b5p }j�V�al�M�!� ��;peQa.v�Aly*? [29S)'�!? ,&�  S4�).IRIK~InAխfy]Y �MvNj6�OAsSeqt prehenhVu Paneb j8�;.�O � �J �Y40 *�Qby /:)'F1premi�O�r�2��P��Ɂ2.$HiFi mix (6 Libr!6�6N0E�� 2��? �^E�"7, FuPa�g] tm r]"A i�A �1'.��f. AdaptA,Elq�$SR !��):Aa2�F��g�N Afy�=�{frao� PSE e P�c�( ISPs�2� emul�!�of Wl-_�|�$One Touch2�r�N�emYRed-_�t:� 6�H EnNK� S Wa�&9wa�u��;��R*200EE on�1 u(wo 318 chip#?!5��I�a�#:� ;Va�C�r v4 (A_^�.1c 1�k�@i!|%�DE��RzRr 4vb� wANNOVARoM�ud�:s�3!D��Ax7ast�E7��We`$!�&O�?it�&�� �Ziindels��R�prioriti"�*ON&�N,� y q0n �*�$a*I�-� �f�,f�aamo�)�N-(�2�om>!0�RProjec��Owww .�_R:[mE orge_ ESP6500SIy'v!gg washingto+edu,� ExACE{se/ kexaCKN P�*��Ya�E� ( ClinVarW! )fPs:/ �ncb (nlaynih�Yov/Rvar�PR��-s6AO3� E�zT�AA�:�TM�T<�=5� 5�class�Yby�as� not-� �O, :“prob�-^! drug= p�) 8or;�$Ge��.�-�&A�e� � �depthaeSag,[D13of�U101'AtSQ ( GQ�8coV^ ≥3*%4 imum eAO�@4Y��+0%.V≥ _nd.�!DXnd bia�s(SAF/SAR ≠�(homopolymer�M*HRUN<6%�F�'�&6�u��aNi5.o�\lo?:,).%_�Wofa/ro -�$ter1�ncRNA-x#icyOJ. N�06�"1default.<�� "�9op-cN los� !* frameshifO7seraV dele ��re��ur D5����f( � slipPw# N& � ("� � A� 2n .s F�D �QE\� NRNeasy�E�m(� E9V !Jpur� (" *q6�eA'o�,d sodium-ace�)�RNAm�qu�!fA\9Nanodrop�<uA�to�the�% !r5 ��� � Q�R�N�!�*��i���j�(27-�� 8��R�E(o ��} Taq G�C[^ ] 2��17�ocm5�6�6. �!PF8"RER12�>> %�a! ��0�c"O!�[&\ H>'�6��ZB! byb�I*F2�R1��W  Z��91�i�@JMH&F2\!�rs16Tj&� 8(2H%�t�repBA25� �A��NI#4� *BrzP� &H !t6kR2H zEdd�;%L$a 7900HT FI 4T7H� �JSDS� 3 softwp(ɧ�d^� )%E*�.l&Ct! [3.6TaqMan;al Ma�N MixC!�6m��a D�.�HAY3-on-DeD NO6�L��c�4!�$2−ΔΔCt�hodE<9�?�cau �B�/%&�& ,��,Hs01120021_mI�Hs905r� %�1�)?fyE�a�GADPHQe�Uc��9��h5�'�$�� r �A�a11�a �ea�l e."�sn�=�6v�*��mT��+ B(Hy���lL*%ln Y;$~ � ��2�"{r} .V�Fv(!Dex10_F�3  _�fRE1 " "2>"2_SalD!~F ��l/"5?)&0(ZAfirst->&eh!� nt )A�GeABf\� \�#riadP�l 99A� ANs =���5�ev9}g:QE���$aiEmcZ�9� 2*� �128:�AE2�AL�]-0:4� F2�M>�=d:�'E}D� ��E�Ab�!�e �1]s )02 ) ;'s�X"K00>vB(>Kgerly:^f thirNe2�0FbX"4aa3h"vl0�p5fourth1�a�E�%l�D���A�:F�2F�F�.i�-�2�`@-�� pGEM-T E9Vec�<( Promega ) link!�a��W"� enzy'I�e Q� As9�even TF�* DQ�<�sub:�� � (3-TOPO TA v�b�!E�to�  JM109e�hg�.,*Y $heat-shock- ced�C � .�`�p7on Luria,th ( L�Yaga"� A�mg/mL!� icil�AA��x=ni :at 37°C��Nv� lon�|<Gd 2 mlAnLB"pl 2�VRy.516 ^��:���sha@9b�x*cix�B!�1~mD!�� J!�)�""(2[3�J6#d.23w� M,� CCL-2-�purche� ATCC-eeRE(�8 x 10� ?6-wp xur����Dulbecco��modi_Ea�nU=um ( DME�h( Gibco�j��J>�(% fetal bov�serXFB�w, pLnI� 0 UA/lA(>pto�X ! LmYH5�xe5% CO4l%�o��/)��-:u� �!�repla5E� bioticFOFBS-f�%i1�gvEy-�#hQ�� ���  )m�OPTI-!u �! Lipo~a�  3 �by-�,n�Q�a 24-h16A�I�.��.#ag(M�6a��%0Kw(� I��*%�wv�yI�.�*aMr1) �/pelle �%0 rpm�5�v& 5�Vd�*q->�.u4�2�+ADJ<&��.�n6�B�!�9-�"�2�in�:�&��4M�z L�'d�|z}x>e.4So-s!"/"f�L6HKs� *�I1ET:�d Hu�SprPF-'�2�%wB&umz$be/HSF3!; ESR38"vibi�tau . &@il/ssat/ESR . htm Aut�}ed x,e Site And E' D&�[A�å�ASSED�jo�UuwW/c� ;% s9>�kr�r0� cshtedu/cgi�Z ESE3/es�aJ. cgi ?� ss=h;'�KAUe1&�4�z!w�!�r�(�:  1' orI�� 6�> 634R.� �ll quer� # A ��e !sW�e�.#2�!��. eT1%a� maldehyde �"mi��at rol(eml� � ross a�Q�; lex1!"�Q��} ��( 125��"top%2rea� �:�d%qs&� ���ed� ��ar�l�(� ( NIh Q &Rjsu��A28 � ,�s- 5 (� MgCl2 (*�a~ X-A ( 4%I)olz-�.w�c�A4'��ARIP�*� KJ�s�,1_,�-o, DTT�  NP-4�$�qF RNA2}!�f &e(2&A�O�en�(�tQ&volIFN94&ar!p16 �_�c�&#�0N��. Chr�<in5$needle-she`6A(tpSa�� �Ko(� -IM� �[([Millipore]�!t� W-�b0>'=!JA M�/2} 4� e�wle ro"�(o"�NyumN�g.%ny:ey! magnC<%�in G bea�6 Dyna r� �)?�%@�e��-�!�1h�&f�. Unb[\�XjS!� remo� )wo�%!|m�~�#ine�/ de-a���!�4X&�/at 70!\�0��^Z1 �"� �TRI��4.N�F��.��$5 A:�F �Qar “>. SAj��S"�Yc^"��N�?SJt tes�P!J2 �d��Tt�/P2q<�o$05 .dFMe�=�!<!��/al#Q��l?y!�mis'3 !��&b� of h�in� i B..�1�@3�A��ap���|i�pm *�- orga"�La k �2w]3T %/a�L��c&����q<�$rN� *�'gb�<�E�De-E�H!��-of�l50!1� aris�/Thous&'nowRl�Q�$se�Bs growpowerE)6j.{- ��z9�shYE"EC.�^r]s�] C expo�� A���)O�%"jw���w�3c 6��50e riskYfalsely1�y�!�wr�11���o�;�I�leʆ�d� op ULin� � �stel el+Za�D��a ll=�!�lex&��[r  �draft �eukary����pppl��")to�%���M�,*�, �< aeal nd viɋ�)���Mmp&8databOm$5dN��[alsS�U���c1 sour� %�!AP4� �8X D`%�H&%�.�“e��%Je�At��]bi2m2�.!FY ��& �d**b�E�@mpE7to�RN�E2����SF�pro�`s betc.u5/�&�"`YE��oon!a6aA�E� r�T��a�B� �E�'eri�ME��E��fewi���emerg!�n��5�3%A%~�u�&��!p��. IFGM�>8et"� trad�6al mQlH|���f�S�Vwt� iqU6�ka�t�0nd often yiel!��*WAS��Gte�[(fj�!.!�� n fa{,Zcheap2 G5ician�?ve$muf)�f"Go.8Kof�]ol-��1\<�MU>a}�(�fa�� \z,Pun4[ etho� �h���^�'�9�ma��micro6�ny��A%I&X%��X illul)k&�Ka��in=g�he7!� n 2013 LoR���!;K�;tro�h,/U�c^%�$��2011 GerEoutbrea� Shiga-toxlic Esa@ ichi�Eli�/TEC ) [�]E��JcIa*���VJXa�A "�Fb�&�"C ! fe6 !�me`M�T $|da� ��I%N%Has�1���!35 ur��h �TMU�c[+9# trac�I"� ,!q�B��dN�m)}$of& !B? [2�y�osuc�OA�"�:%E�b�J?s� "�g�!o�e5 . La�tI_!CWil� 1C�j��of�+ebA{37{&i\CS�m>�r a�LHspira-�I� a 14-y��3-� [_)�I*Salzberg�6 �� oKl� ��KngO.�%*=!b���s ��j�>psCE5�!Q{lR�h neur�� sym M\*sunq�U\[5�MeXat�5]_�d�%��9�AH i~ �]ff.%�pa�w at�&FK(�]�N �=�E�O�-B q-Y��dr�"h ir�YpI"��d��!�g r N]1sstill!U Ms� l�d enI��V�fr�l�=�Xs:y )YXa!#b d5�e�� ��6�' !�(k"ex�n�;F�%! OoV�} �"�o . Ovȅe)-�)1n�  ��=�lNgoK�Rfoce�onUF� viruAGenBank�,ository [10] �i- majo�'"� U%I submM�)la,�oha��!�worldAXEH Janu�y2018 ,�-e�i%entIre}�� 5���y%������$791 ;gi%389!9 tozo�M(he NCBI Ref[Dpr%T�Qy,fr?I% Genb!3-�q�_�$�<�Ru�d%$� �wf wid %�[1n ]WU�&r�i ~%�.�C:� �A+���W 3/^,A�+*500 R9R5�=>II�ra�,1;-��g!��(%�25.�89-�( �ta�I��A�� &�11s!D�T�v: 1LV�m>L�alM�$S�b5ia9gF�� ��[*r��`!!�!UA�ch��"�' M;�tb=�O`[��9 m� g _� 9�� 2_^� TBsure�oenviron�Nliv6B*�6�#fm# eco3+ s [1�(1�Sa�:�z;�/em�s� i\�ċun: K8nti J�nl���5O�5>aB���ry !�<  s&R}5t��FeJ�A ݍc��Aˉ��8!�M=�� �xcsea�7ah� :e��0aipc �[��Fy�� Ey�)�.)s$\a��Vltu:Tu4i� a sm��f }v:�on�thA�� 6d�RENa��*�(uved!�up!G:di�ic}�>2b!��SZS/ "��at& ofm�*5 �fi`up�lu�@a d�Te�q� A"gI�a�q�;�7A�pi�lex s�Zas Plas�%$um falcipa�%�c�jsIDi�� mala�'�y�Tox#�maa;diiPrMYQ*� s�e� H iHet�%� fung���belonb/Fusar�, Asp��~� urvu � �Candid�ara amoeba�pe�pB`Acanth '��u\!kl� i���.�h��� n=)�1 [2�l�kAMţq7!}ohundre f�ceN�1�![EuPathDB��aU�yu�jmt�k250.S:[23�M�.9 edo�F��clo[5e�kn-�us.i1�. B>�ocF��yet� I�t�ͽ�&�re%a�G8ar0d66a�>r�degre�H8�nes!�zjof-��&��lit�\ ��si����/|) �!1.�.�%�r&4%�!� l & Q9+�5r �$ALaj�*~` L!q ��a]i_�&>NyI ���,y��"ݐv � %��c �1)gH&;,<$&ȗ�D6�}M, Longo"�*�492AU}5te��.��h , UCS��! Ens�d ��0i�)Y�[�oA�4%yN ���e� !�AMI�Neiss9�4Porrhoeae TCDC-NG08107��V�p��8�d]ep Ls�l�A�X5.o�� | e��� B��E9��*PhiX17� "Tophage@ �6� in IlN5a1CA�run�9^�7%,ose� �s �EE^MVl4[�CU�KryukovN15.Wn-2�mbl��2�m�� c09.�Mbp ���dVn�*F]j*P Fm�x3�J!�b/F� of.�gaboni�©`/6"2�e`���i�ngM��. C }P�$Qåi�� ���y�:� �ofev4��y�L6+e� "�"���dde�-�/A�@ reli�of�nէ� ��. F $��GQ: i2ʢ,�fA�urfad!din"}z� w#*V&�� arm� �� help�&����i��,� br�X�X.`eAic.�oA^� an z� %1�%y�x&�LeT�'est@a yA'b�P6J�C,)�Aa��c���ZQhE:�o�`� :q��&�GNn"1!+�� E 8MMR�^2 �Y�D1. �n�u ��� ulti-step �!p2���1�n!��n"E �[e�q��[�� Each-sX#7_*\to3bpe1lar�pseudo-i�-�9Fj�/Xy 5F%�gE�)�� e.8��t)Ai�&��71u'5�!�&z$Kraken [7]%�(Bowtie2 [8]RSligM!U A.Clab5S �j i�yi#�*�hact 31�R-*C ( 31-�O)�%��nya�h�=��Se�1�,J�c �"��wo1& qa�A�)�:�s 1u�d%�2N! ��, CHM� m�=& !�u4e �^ pl�ve �adNovj� r 30��201�@�!~i�eZ�.�Y���UniVecc *m:a,p�=7-�V'�!��fD�ZA�� cch���8l->C.Pof� )U.�g)Nverteb�>�(6� 562'��--�ɨi�RO!"�1~�� �loa!_RAM�@:3�XT�!w"�ArH� "�1� eG usagy�a� *6�''lo�)� Q� k� :%*��y�&1 T�l�e�ǖs14��0tax0l y ID!p&Y ��!�F�Uyin �-]�S� � ask��.���l7�"��[q�&�C) cA�a1X�r`ismatc2*��%��v a b���0�(GRCh38 . p1f<�/ >U�i�A��E26�Xw�Jx2Xm5:��nen!�s �#I�) ,1.'QrA��@� � alg�hm�h t14qathw� u ny.N �I*Qn�A7Z�tep�+? s ei�n Nx1�IA�a>�%� �1�a� �t"��x|�E�� �l� �IVY E(l] �Kv>��s��e�Ac*%�C7��rs:V A��#y�a�*9e@ ��#�W�X�5&>):� �5�%va%�.dUid� �P��e���� 7s&|̠�9A�16l Nc k0 ������am!� ) If���6��!a��)-q���as!9}M�=<_0� p.k� 8)e�- %� Dustdr �i|rask�)�%:(S-� To ��]TK�%v�  s��&� � AI*4 `aJ����d�e�20�co �a�\2=by Li�.*��(=��T6@-�(I�d ^l_�� 4"�d��4-, 9R� �@3��pLv�6�h4f roqPD�X�]bԂ��aza�4u&p�]Zp 0e���i2��wGad5��& � on9S4 <� �%�jr�4�X1�sG7"�(1mj R-x"pa>n!�g�nl M�& be D+k ' 7����P�alQ�-0Ka� C�a<ceci b  �+2n H"� b"�?Z�+�?sRq i��s���Ts�-7.�� �)�eac�\��<�j�Y S55�W�rst�* � �n%P6�qNm� �*�,* �!�:!!�)��fe�(�3�$�M�S/�!��/ o %�.3�6�����)1$� . S6-!(���aT u�i�L �ge�*>�63s�,�� . S7 �R��!_ ��*xD!��y�`! 2kZ�G6.5 sum�zō! . �\8� }91X�5-3z:�6�i�>� e�g�9���8�xo� mI�,*�-%!Mc�� ��_A�.a�sv�8�t/nyŸM�.�1V-6 V" �*�� ( un� ed )AHo �ss :� s�MA���verwhel�bt��lg��� �� C6� �����JQ���}wr���}��#�6�35Bna�x!�A� ciQs.�EN H�g>�� a}�� agna$hI yza� a�= �s rgLZ� Jo�@.��>a6��? si)�52" F[�nE�;Rr�8 � ll�%))&�� 5�=. NR )5�U �]by J4orJ�( us�IG"2?�P6�Ae!�œ"�a�(՛x 0"��5%fEFA�T.�Q��\ iF5 ME49: is ~60 Mbc��!�f�+ � eis 57*ntun�� [mnF�ir "�/m"proA�m^ Q* 3g .@'e�a7zA26b=f���T)�YF�C� +r�f*S]QC�t�9#M"�L12: im2F)e�2�8: b2 3b" �"*7a�s6��WasJ�A}�!w� 7ws�y�Y�<�E �S�;2�b�Ann�Xia&eraA9%-,"�!alb wE !%."i 6!1AF2�! s!F�Pa٩�(m&: . W!M�E� �maxVf�aJI�G NF�W�1iTͺQ\:3�y�c comb�:�5��pro7��� DB��D�=w�i��� �ungͽ%�AE]�ѷ%!& �86H �s.�$Q� r�@�5D!�9�n�R���~!6�u� ����*�  , Koc�L$rhizophilaM�D� �?Y�4� �\y�oes-* ��5�{ errora$e K ..u���RG%2A`6�y�I�I~j :P&��7TphysiW6]�R �s�#�GQ  ��� way� look3!���xa�J �^":Lp�%X�I!�36� �A�howBr�!�� -�,� )g��e 5V%k[T"1 �� c!(�M�Nu8 �*GZ  y  �%tru�(��2'�Ys�$numer�%)rѿ�� 2#�6��".[flavu�%q7 H�z��!��7�(�6��N��m�%$�Tct�o!X�� � *(�'�2�. >�aON�  b�&E(m�is>��evA�� *�2>t!Z51%� �d�=�!orN�m}5 ���!#~!��&�3hX(E�*q-J�I+��lnQZR�. BV4��?,��*���E10�un�F�;m -�#�?-2.�!�n6 �� &1� �!�!R�/ge�;V9)}U�)�� >�q�. IS inci��,n7=c��&!!�f�N ޮ��&�"�t r�|\ *�7Z.c�f >�#�{eav�)o� �mN�eA�arejq&mY�,"<mmadl4}� i� bea��:3��Q��h��*�<i,� �/>e};�@�A&:$�`�#%*a� I;��6���!�&)'�, h5r�;%to|!��A"�$9��%.�A!�&�*6�>4,U���, &^ U>"U g !K�6k�(4R��$1����6E^b@�%|5 ���*�sE��Qmw>^f�1"u@1��\ q 2X *}t�!e�s .��~��NAfr  Trypan� iaa�( HAT )��Axe8eyy ntin%of BM�de� I�`�.3Xlth�Din Ug�e6�r~� "��>2 �<���d��a09Vsouth-G9 a��!�)�d�toefun�!�DaOp5 AE�&���2�dynamic_�p�$'�!*a�foc�7&)�h�&� Q a�PA��J�1�D.6W!�td 269=�_Yucei �+O_Űedhwnt _�ZA%Ewes�t Kenya� 17�"�LlX+ l�-`hec���� ��SRA�I��;|{i���v�to Ӆb� o�jenstB1Z$Bayesian c�@���(6DiV�ntAQ�oP�al�}oA�s!jtr<"�P� MZ&8#�`OincxF%� �� C ��]3��39�lQ�meru7}*7 V&_?!st� ��  J���O\' I���8so��by K�> !�g�G��1�bIovsr=�NE�o�5 �G�,�Tlso� ICge)EadJ[�7AR�"���ong-r��!�per�p��g�}��r�=-�?ly on-%�T flow� ����*�� .A�expant$�6 �� �8*<alQT"ԗ%�a5northwar��ofRb ( TbzTh�Aacir3 F-KY6x�[@� I�C q�ex-�sb.y :of�V!8�{backg�9��6�ca3�b�x Qoi��?O�,�7 shap!�e��� ologo� slee� sick�.�� . ��! a0)�S6���2��ejch�5);�animal�X.?� r��al�!�]m"q>tA|A[� ( Gl B�0ppM���YN]�EXA�y�:^�,g}��K!�8\��q�.�"AO%r� morp"���[�:a? uish�%%..��e��Afi��, t��E3�� �ge�+phi!;�@"�[��DbrmTbg)�%�ac��!�k)#F) R*����q&׻h�a�oLD-MS_EO>J I*le���&0?w�inMh�Cm� :.���ATL an�$l{-2� �a�I�}�bb �c�]�A�� �of wiWId dd a�I�s XHsZM�bel�#>�!t�c" ��8v.&F", n Ai6Y�u Au or8{an ��!�e��co-�)!Oa�9Ams!�`&�: � .mreaŎi*��h �KE� nliv�gl'P� ^F�is�DMY�d �*regar'5�ͲX?��� bb [5–7�5E+�hWr���S(aRH�ta��As��e�F� )��U^*s��Xurv���s^*�Ai� ٧s�+m/lleU]0�2�[v=7]�� Z s�r�a�j$is ubiquitx!���e(am�b�L8^=%.�[6] /��"?3ly>m�NAyoA�exh)ge��dJ%z��; AT�� �D � ,�AI#r�x�ܶ% H�*# �- � [1�C� ��"��AuS����-Sahara�e&�$hA|( ��E� .b ��IXH�"� by���� �_. 1�–�ADZJg^��2c0� ur�H!�;�NaBM��� ld� ,of Busoga ( �d!`Bugir�LBG� D`b /a�Tanzan�ndf � ch� BusiUUCBa#Fg 1980’s ��&Tororo�R.an�F199�FA��D��p�e �� ���� �Sorot�S[1�`o`A$of Lake Ky! &��M3�kom�4zZ��/E@O�!�& 0—Kaberamaid�KY, DokolDK% L�K( L�, Apai�A��l�"KO ) —�"�~9�IuU^)�U�8 �� 1e)820�3�:843 kmjBdo�<ng��*†Y^YU>�.Ey!��A�lVlQ>tn?$120km apar�/W%fpI�;D �FM "x�a2xepA c%vA�,%"�Iat� ��o � !�� car?a<%��?7>41AaeOa�!@ oughAk� worke�O��,& fuscic+ a2� �at U,0H:us�w�fk � ���E�7/w՜�m"R�!2= �in9/[XD�%"�aA%&-!� mitochond \ hapl�aa��!�E�+�ׅ� G . ��� �U �6�AH�KrDac�1%�SB��"2d�)�1t-G2=��P�_&��WE7AY�ond # "b �v~a3a�QՍ?����.-j{ fEZ%�!���tN��C V��,��, BU ,�8)�Viso�m, RFLP��nd>�<es6��r&A$heter�'e�[20–25� Ge� ')=�"��d�  S6Jd("�O�t.c��e"�s{lce"�@!O�9' ަm.at%Es�2C�jY�,*6o��ՅSR R� �Ni�T.gw�R� ��?͂5�K>7D a-�![!]"�on��)NA ideaii�����r��� �v`T�� �� �.�L*( 7�i Rsc��s.I/ g!7MalawiEG1�"�Na�* %:_�~�ܩc GfJO!|$�"Hr�gOB� 5�%B�t�.�5��p{�O�$u���)=�!aHE�!�!�lu=��p o.R ��u[2�ptF�&tGoD9x:�br�D;�ds,���q�`.of�tuVxu��� o����n�9�y8"aA�h �H:�I!�i��"v1C�t17%�ly�^�Y��[2p 28]j>��p�H)_-K N�SLbb%�!)Ue�. U���gb�&� �+eB 2�%$` &�<*d w�'�Ga"$}%�o\F9= >hs�*i ue��LaKn�E����E. AllIm�Ml"1���2��"Ke(�Te � FLs�,qe�@� 1959�)Hin 19/lE�!~�%pa�95�=6�Ff � �ob@e�!��|180 |%j��57 ͅ, 1 a�G ��pig1 do|� ?��(12 6i ,6IM�%>( N = 19"y}v{i�-cry���-m�"�le 75>��010%G%�Sly ZK*� AaJy�an � /fe�G�*\�<ai��*b�2 E�g�!�i�{e�i���(�Je.���leYiU���_*)�o.AX� �F1],��-<� ���brademat f GE H��caq�)-faw�� A� ���~r�R i��6E�. M+D��k`�"�� , Va� iPC�f"*�a�manufaXrs*�8co>+O D��E�u�! A��m� ���� "7�� �REZ�a�M"y@��htrFw����� st���ɮal I 9!bto avç�A"`9o:p�[n�K���.*b>X�_)�& ���b����2��et�gu X��e'O�HL!��M��9��6� � �Y2scree�.I/ar$tic ITSzEdjt-O��.E nn*�es����>q��)�g��C�^IY _�C �p��Fs $-R-SRA-F [�y�^5H J����hM�.=�e 25μ�cac!1_n�]�(1XHl ( Go؀colorlY&�|�RmM�+dNT�;06 ��V��M�o, $5 mg/ml BSkwd  U Go�`er/7��M p���$-�"%de��5?at 95�l2(% ] Ci�50 cy)�� 2035 �56A 721 RY �3 4f x �171.Eg� -�vis=��a̜%?6r�g>H. Fluore�tly lUHlI>�1_ANsk��]�N� E�up,7:"geLg %wi� tD�&�F a�!u�!d 2K [2A �a.� �.�I�Type-ͮ68&� �m��v��cy�/1A�] "k�9�r����xi�9ly�Jng/2�( �wYs�e  �Ma�� MixegjE1of!<%�a� rsfB@� a �qr:^�g)ban Ep�:orf �E�ra��rmo (*[^e!#J +�!T7�pr>6�2&7iKmeKof}K4A��y�PiOtwelvpZuch-d��\�y�30��a_6�5"_p25!Qy;25an.�@3u�2�22�b�RR�of���i) ]7�up�>�reA%E�� &$�RU a . TV}�} r?�hBA�"� 2–:�!7 ==�� c� ly wiP repl�DN 0or$�I�6�BNp�v��#p( twoh�&�~��&� �s���FapiX�e��ro�e� i!��x ic 3730xl%>� zer ( App\mBi"�]In9�9 AJq�er�3d c;�s ROX-50��� ,9n�U� � ; TB1/� TB5/' TB6/ 9 TB9/�TB10/�LTB11/�� 5�L 6- ryp5% 3% >Liz�� ryp6vH0 6� O փIef9���V titr��帡 �SCR1�Eb�t to 9"T"amn�!���5u�1e�HROX!Lor� 6M�.� %e�wA�&mtI!� Mark��er�NH�1� Soft#DQUS� �� |e���aRaw!Z ���p�(ezF i.*ANDEM�! �x�9�~A � 5vEQUC epop4�2 [33]��_�#a՘&6 L� Ns{,&�� ( Hov�i( He )�zyg�-y���$Hardy-Wein)hquilib�\ ( HW-�2%��"��am !�F� � $k '( Ar; t�("� $�;l1�Ki���)��m�$�n�. B�  �t�is>�)%�y0inbreeding co�[efficient ( Fis ) , one of the F statistics measuring genetic structure [34] . Fis measures A|mean reduction in heterozygosityia�dividual due to non-random mating<a populaL, thus�inbreed&$within sub+ts , and ranges from -1 ( all i{s�te! to +((no observedB$�. Linkage disequilibrium ( LD ) was evaluated using�0log likelihoo�tio9n ( G—5~4 ) implemented! XGenepop v4 . 2 [33] . U`8Bayesian cluste%�method>J4STRUCTURE vers!�2 . 38[35] , patterns!�9X],=H assign�!Bsampl!� localitie1�levelTgMQadmixtAQwere tes�(by identifyH- �s%�out u�a prioriyinforAFon on%~number�Ngroups!ZA�$data set .RI:�=B:;!� used! ) isolaA`to}�(( K ) accorE�to�8allele frequenc!Cat each!Vus a{ve!� epen!-L runs for K = 1–10)Vcarried !3. For_ /a(=�modele;inYJ�%��8with a burn-in A��N4250 , 000 step�llowed!�1  itera n�(The optimalLK%Wd�IminuV9�PHARVESTER v0 . 6 [36]!L calc�@e)Vd hoc}u0“ΔK” [37aOAY�of!��strainsTa giveuh �jr���%��})CassesA/I��meA�ship co��s ( Q-%d��4, which repres��A�fra�}��e�edA|om! 8at has ancestrya>�.�oticQ�a�Dbetween T . bruceiY�A� alsoF�LDiscriminant Analysi�DPrincipal Componen� DAPCF��HR [38] package Adeg�G [39!�Thō��s notM�ba!ba�;previous��A�d�Wdoe 4ake!�ump�w) HWE or�� . It � tendEper�o!Lter when hierarchicaiPclinalAG�Ais�%�[40��compris�Nw�eps: 1�# p50%%0e\E�>he dimen�ԡz�nmultilo�9e�ic��is鬉�15Nds-@,on a-scores;E�2�d.�a1�a��wo2's are�>to���linear�bin�A�J���� firs- tA� bestpEuishedAor��ingaF��aI2���us��tEW!A��� moleex9T ( AMOVA )E�/zI�pa��AF �Q�5�( a!�E�!�!kiiv,U�detec_ l� ly de�beA�?� ( b2Z�th!�pre-defE e���in�:|: hosr4human , cattle�hee�)pig , dowild an A�(d tsetse fl �timE)Z ��,A��G"m ( E -ll!�ple��datFcolle2 . Sa &E�ed{ U� }interval�K1 y��, 5 !=10 ) of.at*! *�"k17%��2 LDNe [43� es� � eff?ve}� size ( N��ofRU �raI��I�a m s� 2I  # 01 . O�269R� T8zed , 210 ( 78%�l Tbr> seV� b�� cE\!)SRA%��h�<majorof!p!�9��ffou�#e�i!B5; S4]~� sugg�7Mat!+yE|" V�. Howevem�exp��,�cloAX>o*�*�,� �dev� Ea t![stMQr!�5�. LB�j e�a"�� norm�A�diploi�"�organism�~i�". A��$ic richnes AR )�%gz� As24%�7�5 (���Wa� glemE�Y��exi;2�Simil] ,*?�)=>� ( HE�%fA34�� 7� HO27 57 )�ISQMa/ x ,WA=X-O16> 43 (�Lg2m*oYa �� issu�&��%���otypil�)submita�Dto Dryad ( http://=d.!�8 ) ; DOI: doi:1�5061/# m7q4�[55a�F��2 ,��S1 axa6 result' ��N7�^� s>�S��69�w�3 in 3!6 (�!�C�s 1E�3�de�<in �2S1 ܭ�y%�mostly ��usouthean��c | 2!� <made up��6L�5 . Be� 0s geographic e,�lso%ns%`� \A*{Y �Ŷre�$ts�% taxonomAZ-. (�vs Tbb!�s|^~�!�6C ���"Are �tog� i"�9� n"a�g�a�"O �TA�co-occurp�g;%�1:%-* 2i��"�7:�� Uہ} Q�by��!Q! ra� than.�%&��S2M �u/ plot ��Aa��:� e�/1x\!�bel� to o�| ���A=!�I:� w` Fe!V ] 1990’s M�]$�M�5�AGlthoug9,Vpurple� still %�1  �r%IBI6 ��Jhe �����b �qBusia �giu��q�Te mf")�g!�%�?U��!V�Q2 I�&q � at r T*-)1Ih�!��}s a qu�a� c�:� E�e� a�We~� 6�o�^��all!�)n&E�to lore ife� them w6 m' add~CubV"�!�V 1� , bu!c�� -��8 U��X�4& e�J.�X� ��!No9 }a1B�6Ao�73Ř��direct�$ompar3 ,���^ AL&-��I3*e�5�. W ��E �)E� ����-!�ach�5�i�g�C��0!%�!%�}j� 2�u�� W��9 ct ,*�Aе��eis��ev>�re� ����ispersal n ex�b �is phe�n3 �e&Fg rE!T�~>of5 )F^10� &�to �<Z�-�!$n�f�8� � sX (�.9��a-�  �I���ngUE�Eyimmigr)�oA�I��tantly� &TmB2�(�%oga , BS�3 , BU ororo R"�!< �!�S,( Soroti , S($Kaberamaid;KA /DokolDK2M�sci shBs<�� both5v� (���� - ,1�2��A�e1E�a ,��e o:d new f�a�.��AiA�A��uthwe% �Fm�eJ*�?#2f��-a fewF� �:�Uz"blue ba ���canifb� %���.2u F%|i2�!�pz!��Q�)j.eQ&2k)�6% ongoA�� f��in)�|�, e?�.��a!�-~k&� ��� o�x��enB�a:)?3�~ai��kn �� Ŭmmonfirm����t&�7UV�22�� "t �d���G� �& m..L)�!A��31�s:�s� A��1or� ��#oy-`[by)��%t&�o�P�� #dI�#�67�x&6)yJM�� �A0%�"�-�s:m.�tor46r6� �4e� rof.H)"Jt.��J�/Z�.OirU0QA\"���f!�ng� vely����*�~�s"E�>=yH:�fB�.�:3,�Q�%� y& I�i{ i���. q�A %d@�i&L expl�mgY"U6U!�how mu&l %&�is6^� M %,�e�9 "�.��uI1� %p.n19 !�i2 , regardlA)�ir��L�΁;� -m1���)qM*�+9�ap�'io�% f( 71 . .* �y5�"6�.:�ir*Q!N8 AI*&r,� y li] �o�)F��Ft( 8 . 49��2]>�()�U(  &+"a�.)F�i:a%e�2�>�� i.�m�iq(: � �{ is� �As!�Q�at� ��( l �)��D� E5�b,i=6"����.�V�Y�. EbR|m�)\cG "e!LND�}���Q^�o rea&I�a3&>a7Va�Vd�kY#.�sm�%!t9J/ � 1" A�f!re�?lyN �&� �4;,3�3%�A�R�ar��9<�=�narrow!�ll��Sd.�ly�<��05� j��%!�C�a*�)2!w)�,/rapid expan��!�W rW� !�M� 3 m ��l  �y , havez%g� m]sex�.2Z��� �n lder!Wabl�&&�.%��| R�modT!hof�"a�� spreahelp su�x sus~$� �!oP) ategB!�AAT]HAT�%�. Contif* wide%8%�alsy��%���*�#w be tre�aF)pD� -+d�!as| .L�,E- closa�eR4o|�Q �3a�~ # vice�� sa [�,!�e(aQ�&� ly�,0N�oin�(+AB!(,�" pled��a dens!�atipՙ�AA��teg�e%��&A����/:�"�$}lek/.�-g���!�revea�byF�!�A|exist�~ofJ�� J�. Two;L� �#''%i of �n%���Bol|&ci!z"j�'"����l8 � .�third�����0U6��ru� desp� thAwg&�proxim�1HaLm�vie� �%�us��a�te��!ef�3��-$ [44�2!enn QTbr�Vs�(mARbe��>�"��� 2�gT&� �via� lq�shortJ�Fa4�ii�"isoenzy-(tue? onwa�!�*/bK/cl;&% ة�sU~9z�an�( ci [2–4�$ 3–�3��S� lap might��o"!]�$se neighbo76�%yI^chigA�los4ntact%-L:/Victori-�, e faE�in�-���E�!:two�s trans�&ona�)� (�SE�e lake!����>\was�%R j�6mo�!ansi6T fly G . pallidipes [2� I�A�h(^��ve�of�S� Nyanz!O)W[3]Din�-8;��" �Alego� breakVTa�n C�:X,�s�� �palpali>�f . fusc �4V I��:OH4� witcf/to%)2Ia�vea��%northi in�r%�nf��[%O1�U"mid 197�qN[20)?!�2yaru�1 main%�-�Y�[19 , 46J!TL1f� q8U�e��U*�5��A�� L 2�(�)dap��6o6�by�B"�M� �,�]q. Our� �!�5ly ru�/u % hyp � �A��%CA tra"�f2.*nto:M�195)�a�� !z���afur�r��B�& ���7i ��e� [4� Sepa� ՙ- cycl�ayi�8e�"\�}^�E��� |�C:��)ith�& now sympa�B5loJ+a 2�!:3Spy�� biom�)� Y&-f�:pre&/c*Wsuscepti&Z2trypano�ad�,.�a3�L1w� be!B7'&..V.�E�� �X�|-�involv!}eiA!�[I�!c�a �RI�2JbB�Nt�!U�1Z�,J�to se .M cerp A oty��a --ɡ�A-19tbto�2�t U�be.UOE 25.f�Jhe�I%0��!M�Ky�f>16 , 17a ��12i5��� !�" k sq�until.�s !R%3M mov�<�I�_=0� livestock!'J0 rlieY"B ,%k��ge1�Fz,����0by��� profi�( ( zy"5an)��.�"͌�7�4ao�7h�&ZambeziC�das"�3���chronicxgreio !�Bu�� [4t+AV"Goodhe�. [24]�% no s!�� rE�q� Q.�!�cl�&�on 11R,�Y� sub-�a��tal3 "��perham=a? acu:�cl�6�eg_7� �]ZK.I#&l �,,^ obscu�"!\ =onO;.RK� "��hM /�?'5��Q ve1�!RQ�>' :�!A�AxE�>99G�4~�e�: veEMm��-|  SN86�8!���"m-I�tor Tbgs"!��A� Vm�mosaic��d��ea5, �!�B!/����ins. ')/ throQ&$a hybridiz)�tU�*�-of Ea�1 nd W^ Afri U�-isu *�8 know��at�A�!��0 ,� y 20� entur�so l indeP1sibJ9v intry�� Փ. P�<CEy>�>k���y�C Q��"*E�B�96�,�!]6$play a rol�,sha"4Eg7"�2�7AuR��m7 ��4�=� !y* :� G-& Ab&�j��&�~9�f'9a*&R�0( 2��biologAu��%��is qu�oX%�C�' )�"32�)chEid�N��,A��� &�6��%� lXt016%/�o3�)f@.a1it�� �Jb���e P2� ��)k,��waweakeg�A.Kmʉ8�8Ap spacI6iL@or��&uni�6�o�h�?add�)�au�&�r]Icheme4 h�Q >p�}P!U��tu���%�+�s*&%|%)ag�!5be improqF&})9� �AwO,ae���0&� �!"can!b^'op+>1�62.VyaA:avail;+�5�):@?uwJ�D $�.T �<� ch��G�:�&�[2�24��7�50� )͞�N2� s.�反�6y�)J,&�a< RG*HF�_��e:$of�A�&���"� �0�U<.C�)q �^,�A��7a��r��Has"�#"� in2�%)٪%02BT�d!D� y'A ���s4)e��eC&}<��!W j��T9ni<�/�-� homo ���w!�h"[56?I�F �&�:��Nz:��#k�|��02�:"n:rf�%�"� 3nd2 B]�ri{ dP+�-�* eB ? 38�>guA"J�-�"��!-�Corz<�Eo*A�th�:��%�ͱ�concurųF��� f'A^epidemo &%sCa0Dges [!8�,�6ce;qw�H"�U back� nduEAeb�A� �*:�@.� x)no� cr�q 6 iH2�!9�Duffy"� 5� E AA�E( shif���)le�7.J� �H�,| ,��1��� l�K ve'#owgi�a>>T2�!*!2ߥ2. H� ,9 &�!"�C.]>�!�jg=h�  9.�$&En`JQira?!�s)1Ym0e�F?aAF+.]pS5Mo�'F��t EDr(%5�I�$st�wA;A�6�"Y6�QX[2� P�s�a�ɞA/I��Bvi��  Malawio� .�%)���fF H�:i�.I��?Bkarker^:���st'�iXw���u�X �'�0��Bt� "",$0��"s*u &�ca6v5�y� eO!�Yceu�5��ɡ>p62 M�1�-q� <�B�^�!�!rI �Q32�E�?� �Q)Fc@Y �G�@ f^$ :{7aM���I�ed~@�j���`> �8. L*H �wh]m ru�".�tp id ��a�Qs��K!Aevolu�/(5�I���EEq]&�5� /��%�!�� v��%�!� {dA%� ��a�) cqui�Phe�8��! We a~7��Br7na_+!�&�M]���Y�>�&A dyna�� � +�2�lVo?�8��strikaq����'ч���%vm �&Ne.�&!l9&9Ev a�6!+!@pota[al��r'&= [$BO�"C&A�bM�d�T-� "O@. A.�4%��happePSochastElyEz��'onQ��~Ne"-&� vs ,(.� ��'rm�3+� an.5eUoirdA�a�A,)!to fueq8� lE slee@ sick�.i"T as 2�("u]ʕ>B� �%D/�?e��0�2<k>� � 6F5 "�,&B�-MB�"Msc%�66.�6[1952�A� e� ta���!�W�?1� in N� >%is.:00 km h1�$u�Od.[��\impac-�ineC�.&��Fi� � �N��cSF �#� s -s-��(uedodEPA�dK&��g d&"_�Z�ZbeNB%�unkvpub� hez%!�&E6�6inc�ed*�� eDG �a�7� !A�, lso�?* riskEn{!R!F�!�� IW1�E�M�to:`�U"��-\F H�al.o l�decf[5�53[In!�c!Q�i��A�' JkBDC. !mi2]��G �!,)$,>��a� �6*p�aW�V� F�>�&C m"B"'a�J #!�Q��e&�*S*�!]u5>P feRd \YMc�VP1�O&�U�E ,AG�ty �遴B�q7sQ�SM5asUN�Ş��.� ��%s�/�I�YW t �-AI q|a�-� e�*o3 ��"_9�**IB2t�h��%Do�Y�M1�,h��Y )=�!�-!� T�%��e�emphaNao=e��I�Rt�W�\mpe�t2�.�y4&� N Dbr .�Thioredoxi��ZcJprotei�ATXNIP )�"�fung#� . �tumor�.oa�!C�!A�prolife�K&apopto�%6rs)c�v(inflammatorEc�rem�uni�&4�Á�e demon!�ZA,Txnip−/− eV s&9a #'"s$�@o lipopolysaccharg/4( LPS ) -induc�ndotox�Vh"�!� �0,:�SMphi/BX2�!er � �*ni�� ox �NO�!��2"synthas�iNO�I�an inhibito�'c�LF%�e:��death�45mE��NO��TJ�o�E`-��:Ze3�<6�%KA@E�B�m�dx�-r�a8ed IL-1β secreP� ��S-!2osy�Hof NLRP3*8!o�S-���OT�&5����f9�2�eV�V �Rl6U s!3%��(a% �qJ a�v� du BB ��B �� &�7&� iexe�ev]�l1α , 25-dihydroxyvitamin D3� [OH]2D--]2HL-60 � s [1�*rneg#reg�^oQ'��% ��r� �� [ =nt^ 'a�re Daq�� fami�c� 's�*ha2erf]Nn�bzy ��sDacidicN p"PX��[1��I5wO}��a"A''*dE�JY[1�[�� J%�  ��!Olex y� �2�1 spase-�#nyN65mvE�f y� Zor�Din��}��10� [196[1�2It�rj$ EQat!��r�\�9��A6� cby69 �GheN2[�.[1�[H"�W�?is&ab�2�� U7NO&7 N�� Az�&�-��!|ͱ"�-.���1IVBw extrem�"� � o� "( e.* ��A&� 6nNO�� E�*OV c� ��1�P cruca�cituPm�2qa�onm�[!3-~�RNO.��/$NF-κB/���wap6~#we�" �6U~.Z�O i%Q�edN��;���"}#a cri�R�>��� 1 k f` 9l� 5�:. !� =nr is*�.�3w�L:�^g�# ]��cy wo�(a��U�"�f>�� ivo{Y�kq� inje���(Emg/kg bo�r:t��!Rsurviva���m "k��yAhPl2La�*��.<( WT , n = 1ZO `�(f aTA2T0d�$�in 40 hn".y:dof���!1 /Olef�9pkef,��z2V{ E2#^ colii!EQlay�b[wtCAya] GI1|r- Over�{ 2�de�)*)�F�s���"���K�mDir�Q�"iti ~ �$ ethalUWh%sY_�1HY!�A7seB �blWq gluc�&%cEp�!er"2AtF����'� "�&WT)�9� , B !��l�nR>��9lf��n� eR�F�at�Lh�t-I/��e3�jx�Fly 5°C6�Vc�. EA." houTf=$a�g,�X���P!N� {LPS"�F�| if>i�U� �Wil�`&�2�T j9�DE�A!%"M splea �v�%�6�+~E}6�&W%��VEdlenocy�c'%e� xyli�osZH&Z�DaCA!TUNEL ( Q,c4eoxynucleotidy�7�\ w�-v �/� � .��� Tr �%�IL-�9�a�(�S"�2U� �FYoe�U�!�6y bX�by8itoneal .�AlA��yt-X[Rn�R]J<( BM ) neutrophi� � �T �BA�s��%� ��(hHb�Ÿ&V��or51 . Sur�qin�\�w [��>{f���F z�was�16�&- qI2 Ol6jWI2t.Mo�\ 100 ng/ml%� �*z�acT:r�Be�To_ BU!�se;c-� _%F��Fxs!� ri�AKE��� e sej(,h �sɰ&��YN&�f&� �I&�F$At�4�and>j.QLIL8/�C%  - �"A�#=� � ��w$ %7Be-�� . C6];�sY 2u`.W�. %2�1�B� I�Q����.1�n�)2���2{~���7_a&;M�A�*��)�!>=F�iwQNO�Tm�e^R�[b��te���6bAE^_B� *�&J.�V3�� *n�<��o�.@q�3��6� peR=�Fzb Y�} mRNA�$x�m"�6� 6� � ?)�]A�roscopFD �"u�8f �9 ��nT:� .M���a�n�}� e�.�xin>u!�&� Bl 6Z=��Rx; �.���6Um��of b���t\6oNO s�y"R6b�4bW��� .� i�6� elev)2�5o� ��o�k&k3� �:6�=��5*�2kNO�-����n �Yݎ��h�q��5b��}])�kJ*)MV�͋�tt�R��s&0W6,i�E/2dl'B��B+!\c:S5� G�6L each)�^@&f9f�CB,HeAsY�Y8�C.(ly:K!`half-�!y���i�5�Lt�JF=6�ln����s� ]�'nq"\!��H!~6�# in�8oAY|N�pr"f!�let��I116 J�Szb.6 �E!�NO��: E6v�"��Iym#b�%J�d!**�����=� 'o{e1400WtB%�ctJ ű c!�c> $�dMB, V&$ rex$:�0&>/F� !S�q��(9!Eq'4�s6�q�;"���L-NAME1e Y�"e)[S2 A–� ���^sF�#R|re)�by Z5v�+ 8�&�T�0�L inyHig'is�I("MwhI&)��1�+56�����F�N�B�post-!�Y��B) .� ta^��!UQ �1�4� �4ls"� 6)udF�U3N��1%ra%Ijaj!�absC-.�*sA gene��ngchimera�W�)FWT��ip7� E��0plaQ�e2�BM-]"Mb�2(e:5] FsWTia�!�tr%.)�6w!F��2� O!Rg�e�he��C2gBM]i�H"�!\��I �F.2L�did�C$�'e*���%hU3�+ T�q ; ��F�#�m&,jJNٯ[&�on donor!D�5O�C(Yenviro�q:��-�]$�,� 1 HIF-(�iby��in� 2�Š"�9��}WU��  fibrobx0�b J���] We9�i�Vs2� �&#.�$(2� !.�"e;ih iu4I��y� /E"\ �: ~jo6b.Bgr2� pj:*E&�)mod��.�=�*�:AZt��V+��Z�6���dra2#�**� �6�.^Rj E�&�4&ar&z!� *}!� uE� knoc�<d�?/.�in RAW26�`7m�y `4rfߌ� ( si]?nF*� A%�$gk �;ٵy.� Z1� :k5��- �, *G� �^�, "�: &�O kind'��SH in!z�ai^4����!eM���. !C�]� � "n��+:7>FN)rt��p^ �-��2edF�9J.` aɪdJ�8Ml)Q2^����5 �B 6�0w*� � !�;.�=(��!d�%�Rͯ1hW�o*�� 2 �zo,-P�Lx,?2U.�CduEa K-Kng ret4ru"# )�#on�n�:QX�!^*+ < �&@9�[Q`�E ��')~2�v�b�J6r |�*b,i\B�)y��S�q2 �魕%�a.aJ��r, @Y=�)'�:: �W1�=�U�9t��T)7���NOe.�'!�O�Degrad"� )0��"! 5sta0$��� I-� ass (, DETA-NONO� .�42]}G�$o� ��1SW1.)�Ac)-���/ubiquitx�p,�E3 lig\���)Ar)I(�/��a��2e�/1=[2�*R|f6�2CI\ll��F1|. \b� E���� �12�wa.�to86-����Y!���mon5eD15G&!5)!��ini%3.F@%" eZ6�.�b:N'�̖of-�I�)�"�N�0!��/6:jF'���a�6*�)4(al"� Z&*r��1�&�)=( plus MG-13��[oti��q 5k!A�%e 7&� f��[.�)��&1��%�]��� ��N�&"�D6&-%�H udc4sra�jphosphor*M7 MAPKa4KR;J , JN]wERK1/%�nd p38 �x2�.L {Ae�RY" )Na�Rses�1&� .�� _I��Zgi�t"x1c��B�bn�]:or2�Q�6�([)�U��,�3"2$y.{5A{*,of�� #a��.�AO:Y"���low-N< �%cg�*��6N/�promot�"t���>! ��` cripe�� TUXҍ tail��E�>���m��!�B b'06�*�92�� Hes�!��>S�|�ngi HDAC�G 3 �\MY�c>%��!�]�R���jj\R�{�B�\$65�fyb�ipYe�?�30 +:)�y0� omai�9�bcun�_24 M^p. 6�� , IκB-α2al>�Ŧ�UR?}� �!��A�y�B� 25 i�-*8t�ll�%-VLT7) ,�.�B�xWTA+62!�X%Fr�"B �'�e2"�T .w2QG,}\a %� ��l���:�1)S�N�>2�tar��!gofq�*�by"�Fb���'$9��QtdTA� A&� �$soF#BY] % ]�up�xQ�Y+%C�`A�� Ei!/ 0lAe�au� ���,z j12iNj1j6�xm2or�x(:!Z&] ,���+oDZ19=Xwe. Us��G1p�~�!.2%'ed:��� �:�f���%^�k6O)9x%�n�9Q�6�!&��re DNA-�*a%�BŦY���v &�'a�.|iff*o A c mo��U�B-( EMSAs��heqNR���-ar6a���B#�n�!zQ�Vm5��2�wF�#9k�"�evalul [>�n��:��QusC��96�5a��A~C�]� �nd� �b[�%"k�:,:ibpre�� ( Ch�E�.-��?bod�Q� oa:subunit�Ig�iQ{ 64 �6�v59�:uJ Qa{1*?!6� T&IC�<G06(3 Treal-� PCR!�ű2$ e up� oo�&* >���� z 3��Be�we�U�E�T!R*�.��Yע�*Q�2�%�%�s R&ϙo&,5�!KA���B .���6�9':6Wwas.�6S��A���)�R)1-�kat�`{mO�e.9s��"� may b�!&�@N�;A٥�f *6o�����<*�!�JG�J:�Z � i]e �R� ��*� W&�Gy �6 �A�&� n_�c]�qp7+$J(nl ��4!Eg%d ro- �y+$ 7�$"� �G�S�)!�era�O6u� �^?&�'9$ �of1C:�,��N��a�k�7� �K ]%ҵ��2�!78M+. Moreo̖��/B$<β%��W �%w1 6�#7� FQ!@/�<& f�jT��NO&$,wS�e��9_c"�@(�AeaP10��]@,m_)QASC�a hLyIV>�Ef����)r�%�0U\a"N#ewkD WTu��a;�r�c� �'eciab�"�C� �k2�#R�� �""ng2+uX6,!��8!�J�J��~C�!"g6�9�!�)�9X)xbe�Q-��6�2�bJ8 y��-*�5Y$S5e�� *A:.*)6�LIsO5qn�BM-deri�>6� BMDMI !'R/ �:9,toR�2@ pJ:.,="���<s�b.�FlA RLP32*ike�x��no* !FP6�" IAPP�o*f�P��j�D��ch��MSU/ATP^.n �[jcA��zxd��33B�% �by-�ago:-�J ` YNigerici��vi�2pZdp&!�1=�2<.*ٯO'J�OU��o� S6�G"Yu�jng-�>!#-Q�ed2��3"�s6�%��IyFatN%�F�Ed�u�!b�M cess�V�&��1�?B� ,W �7� -�aX&$ *�I�Z(e.�U��!.��Q��E yM/Nv�.:MS;� ��u>�a�=-Q�M�yBI a ��M^�A�t�-�e�-�s�D�9X . Ba!�o���+&��� a $Z�L�wlHM4d� de@je>&�(��"��e�� ��ze7� p�BC):7�=O)��S\%w�>in drivE�orc�(t* J. D�9g �Mt"@&�,&�h��&�M�R�6!2�-�sI�-&���=�� �J��J�. b frPb&oP#I�6S �ay%}R�<wyWA��8of hepatocarcin��O��-J GSFRbolismE�ROS"�0o*&� a��$/R3HP*M/�4��Hmur+wledgeMU� )�Sn6?Y!!Y �$aQiou"*"�k:�Ya^WQ��c!��,�!Jg-x eU3 | �e i �62�!�9eC|: ( i���:!M��3"�&�/,  JH�/�O���J* H;��&(6'+��eG*�N MFN>;P"6t&��Bd&#�� ( iv-M�JwJs*� �&a�β Y�zn��!�%^,��&� =J�fh�Em�R!�2���z s� �a��"a�,{ � . Un�b��)��"����.#}or~ >�Z. =�Z_B>z*<^�!v!"�X�f&�Xt*Zto�C�XeF�� "4ZXX.� ���06}!!ovL&� H2Oo supeO�deN15L��?�(A�����I�.�B C f*#o��2�^90Eq�}eof* w.B^[31|f�&� gh�[ 2 c2�U)9pi5�$ enoH}�in� .�ZZer8eas�[rS9!.�� 0-.^Am��.&f` ���S�r .!V]�� !�[3 +On75�DES�+T� �.] e �$MondoA:Mlx� N'@up����*UF{ �i���G�kE��8^J����^3�/N2�*6/ JZ-uG!]�/ F3=.:� >ybeg z��#N�+�#���'Ev!�!��D�Q!|*�%!�"=&M_*e��i�r>ful�M>Y): .Ga�$ imum��_e܀%�2i*"�j favo��con�wMr% n �p����u�3� >L'+w��� -�*a�U+[ �'QsQf.�K�S�y�J,�u e ra�TW�ubacG_�Q r vi�Y�*[. �n�cacetyl�.5�='O?:��6\�*q&��3�hW�I���2� 6�An�y%#Z!;A:!eEK�tYt8� ����f�i� )b f��eK � �M<y 6�# ed CBP& REB"Z"Q**�d �%)|�%T)�Ew2� � ��<�� ��3 co-!*l��>%��F�by��:synergxa�@��by P,�6� ���U ~qeU�f>r !ŭj'!�E���A:%�ub^ d"X!wf�."g��s� )�)CSf�ES.�!6M�N)6� �&$U}Wf@ Pis�fm$��Z�a�$ ���&\E�i�"�[l8 c-)��d��op7f`єerapeu�R������U6c�js �K�aD(e pVHL/H)>!ϡG��e��ksV>U>�'�)�pl�&&ą� CRM1*�qex���Fw!s���E:6=mJ��wr;keA�y`�62U:f111=�q�D�����*2� � � M�N&�=E�@/��7��!|)Vba�� F(����wd��ڊ"�LM�L�X��–�� `��r. 6N2A�Bi�\�Ca� 2�}��"� =(I0�y!چ��!J1>��j�� 26 � d��A �X<4'Њ� .  ( unnr�6��) . R%REi*�a��5%1�nd��$^ *� `'� *�g�40%�42�7MbL6�exm+)#�:)O6� i�|0}�fac� !�:h>q�6;:�*on�m��F,X � n6u%���2�+.� g�ua�b�o6@��D*�.�G*TRc/ck�p2�)^�.pd� ".#�ñ�2z�� sT�p� c]NO� d=4&�R1G�[��Yeva��sLPs-talk"+jI Ij,2Ta }E��� !�� -�=<sMK�� :��sep�/%�6!"xe2 � �Byap"��"J�.!F<b��O�`A�i�%D%�{� �7�!e:jzT. A.��"(A�"&BAi�2%�G!/I:Y">�!&J�A-*% l�&�G/ogQE�&  '!~)U�Z^< piv��G�!: !�xia�3m����FWKm�]� 1�I�Md��f%s�,6�&� �/�mc�#WEade]?�-�a&5 .C*^umun�|�1fe@) i [�z�3��ٱFa:�x %x%s�q"�e=� �see[�t��F]�>� �j�EnF:e� summ�{,E���Ei�tK 6%e�I!,z.�/�Cl6M(H*�h `s�ʍC-����.�  %�dY��f} g*�� .A6? �&r��C)/�@%S�+�Q�LOQ�J���J�A�R Subs�a��L"8L�.< E��&S4v(Ue��.�!glycea�:�  eluciE?��� .��if^1a� �= l "� 2{2�&E  A�� �-ߒ�.ocedur�e9�� ��.Ins�h!� al AJ C*1.UseJ>m��l!x4Korea ResearchB Biosnwnd tech�=ڨ(KRIBB-IACUC���cvalEa:  AEC-11044�*G�e��&�0s �jK/�i2�( NE�al�� H�} , US^gui !9)W c! ,. WT C57BL/6M8�dob�G� w�Koa��B��! a-�eTvl"�!�@(����us Z=���� �ke��e)}g�O +��d"����A$ ��ho�#!6e�_ -f�� �8 y�JB"��ar�~ght-dark� �roA� c��wapO�d aA bitua���%] L��� age-Bsex-ma=�. dp���ta?r;a?��`p .oT�C 10 mXiB(( Sigma-Ald��%t 10–1*�ekEage@F�z���"���8��&�H�t�C0c7JQy� ɡg�08�h ony-�p5D4CFU��uX&qa( DH5α� �.!x�T%*purA�Q�6�.F�GN5a�Am�)��ype Cul\�_C)nd/� RPMI( �l�2"Z/0% FB��T�I��a��} �e6��~! Lipo"�* 29�( InviF�en�-s,omm�� F�manufac�/uA{siM%�fic�sq�129900 G!�:@p. CelAaU��A�� fi M� ���/�l.O FW<d �6�7wy�*�( Yang"{,,!!�k.E���>�<;�72 p-YC( 466�%hC( 925 p���( 303!/"�A( 476��p-Erk�C( 437�0910�6p-�Cd1��,�C V?W�85��,�T8"A� ( 868$%�:�!�a�&Tٟ. Ant1!�i8Q( SC-65 �ASCO$sc-22514-REvC"b (51 ��β-K  sc-4777!AN�$Santa Cruz:6.�(( AG-20B-00a-� �:� Adip��� �n- MBL �@tal . P�S .N�harXed 4 dH�4 .�{2�3%s2 ol)N!T����M&�# _dI!>���M 24-w�@s�#�5×106�s�n $.�1incub��%��I t 37�k /6v3�Ito�I|nonad�nt m^�!� Jc�um��law����F fe�bovin�%�esodIpyruv�),��:n6 �o�u5penici:  GJp 0 IU�f�Q_ptomy�/kp0 µg ".B�N&-8���y�d�^H��,ӝ�N0�BApr ��+ofb-{B]"(� C]0��4vol/vol ) L929%|-"�ed1oa�7I�� e..uɪ$Dulbecco's��� d Eaglee%l( DMEDi��� qmU F�B55%`!BM D? MACS�a�% CS��um6a$130-041-30ƙMiltenyi�e7BM%M�M��bo/�m��!#�*urfacU+rt� CD45R/B22�� 553086 BDo� t , TER119A@ 1620��Bio LegBmAk F4/8C 1226N CD4>004Na�CDl�100J@��Bt 4a�J� ti-biotin3 robeadE %V90-�Gris���G44L� at 540 n!2�.�tei��:,anZ/SD-�100065E(Cay���ϥU~N� i!>�b�1:�N�r,Avidin-agaro�L9 2920���{moIF A��Mk�oom.�0" tN�"��b !�-�"� 9� sam���+rifug t_ × g�1�)Z�6G��2�.�u�!� S"&� .y� # rM{1-tag�HRPA�vi�%A9 2�)�sa$!bu+�nB� dU@�gl�c� slipE>�2�l���p: �&�ULPY�? )J�A 4 cold PBS�"fi�� 4%Q��aldehyd�(A{&� J{h8 � g 2�eZ�%q� 2% T� X-�ic15b^��yH!>n�A� _'�D-� F< 3)�!)*�eSXAlexa Fluor 546–conjuhd goat-e�y*J:� %:RYtF7�%*-�ag�7w�ɴim�i�- �pLSM510��:�p0e ( Carl Zeis�ZjIS�'��$oco�-�AQ8a0G�P 7-29� �r��D�T.�%>�w� h�A�!9�JE%%I�%2�)0E91�so���9� "D!m%1Ido03 200-�1 ��-bp�M?�ga{�'f���O��MJ(j�6���at  il�� 1∶a#!:�!� �edE��y.:���p:Na salmonrm�/P3Z in AA�Ťslurr �%�:�3Y�x A�AS�z"%���z.�M NaCA �M� �\!8E7E�at 65.A�FiEE]rs)g�L ( 35�a!��%4+/{&L��.� � fo� ,f � � TT8 GH C: ; 2� 2d CCCTG� .�:`C� � ACGA�  ACA�  ::h2 � AGA T1 @:)'s�/Bk �I�2�"�&[y��5��N>�P%�"#i .)�'q�l�i��L�"{z)��&v*t��� 0094�|A�e4��An�QA����;"Aana�kZSG!� G GG!�TTC!�� )�6$�4 ligo�n$!Va��/ 2NFa . Double-Y���:C-send-l�1��5� γ-[32P]qD�T4 kin�1��PShuzo , Otsu , Japan �Aur  =PROBER �iNtRONo ��eongna�3!K���2z�V�y�!�a�>�� 1� )A�[� 78�F� 0!Tris-HCl<�H ��C5�D,� M DT�� EDT�5% � �g%K�����I-d�%�i1 BSA�UZ�2�.$alYac�]m�8ge�P TBE� ( 45�],�= ��c��. 2)�)�sub�q )���Td� V/cm ! � gs�e��9 vacuum-dr��eGI% auto%�����Me�/��cNFJ��,pMYs-IRES-GF�hpfal׻�Biolab�x�+ %�g"�U@P,num-E"�f2ack��� �AN_M*u� 2��� rqx�ir�in�160[D�$���!C8�o!� bren� �Q*-�#��M�%Rg�qu_ �Tv!9.�Sl:+ T"q�9O6�&Z[�� Brie��,6!rHU�� rece�J WT b�.&q�.eqs(2jBM��pP A36�!tnon�H.�,A�� 6mals��.2m�2�N�2!NH. TQl9!a 2���]Y2)Qa� !;"K+!"�% ��� Prim�f"�o�Z oA4p"�*�.=�\*O exci"6!D ^ ]�G=�Hm)�1-mm pie��2E�" ��d�/� 251h�(�qFF.�a� drop@�� �y �}-��!�V�f٣!h' "-��K2 m�(D(:�J�!�a��cs���ach � ` �&2g�y�M[�9�aXac��"lu>i�"�)�%�f�Bm��±&�$��#�%��3)?��72-�ed Stu�$'s t-teY���6non�me>�1 W*Z�d��±��rt��n�Wilcox� ig�rank �� E�P �Z�'c�A<�+ide�a�"o�N #h7 .δGerm�Tm"����NA ���s�lin�p�fFp*�>�8 fail/p&�75!v�Zg�NA da� checkk� u ^am�"me�c d.] �s�SB�c�$e�5�0hromosome seg�^regation . Therefore , understanding the molecular basis for DNA damage response ( DDR ) and DSB repair ( DSBR ) within the germline is highly important . Here we define ZTF-8 , a previously uncharacterized protein conserved from worms to humans , as a novel factor involved in the repair of both mitotic and meiotic DSBs as well as in meiotic DNA dam! `at a & a8��u levelxn a%]��ly�|ct�� multi1system2s�=extre��m3�� . Stud�)�$Lyeasts S . cerevisiaI� pomb� vea�a�ou\ n��, requ �a0!�� *� ��[6A Mos2�A5��!� DR )�4��* ifi��hroug��a<analy� ofED� I�iv�O eith� A% scri�� al o�� cycle� �� �e^..�r�e�9;i�%�8�encodiOsT al "i -�2(�D. A phosphatidylin�ol  family!�t8s both structure1AYOrea �� human ATM&ATR [7!�&� !�lac' an apopto!r1�inIJB.high dA�e!�2� A'��FG E�8!�U betw��q ��sɲ� � he n� ode2 a�� exa"� Q2m)to study.�inducede�6��[8��1�}^�K]�B� ,rE*1e6WM� �,!Z�Mn� DSAnd3. io�E&N ]�]čZGWe show�"r &N � Au� X %/u'olu��Changee$�sub!�u��� ���q�Z�,!� DK-nATM-1*[ �2]W E F�� DRMt-u. Moreo6� BM7��vX(iI��!�.b ( HU�not! UV , nitr  mustard* N2 )��damptothecin ( CPT ) treatmA��gK M��SB(� is fur�)Y or�by%�6Kan"�]=�!�>�n�dur E:WHm �me\in2|"7AX�� whil�oeN�tac� �����>��i[!�����m� ?w��� .�homolog�N!���� fou�C�Q(, Drosophil%�ammal� a memberQ����\ e9x2�0of HUS-1 onto}�7to exa�DSB!-�ko�06�. Los�U)���WulA�in*U 6�� � ����re�$ brood siz2 !L>�(RAD-51 foci;ll�` w�re��Rgenic��ex�a"�P2�� ��s� �pl�E? e-$Taken togee�, our&D m�model!) �)J play|%�� �@* .�N"�X� ZF )�( ope!�a�8frame ZC395 . 8,as.�U n RNAi-ba� scrmperfor� 0 n [12] de�jo���c�daTamongbsi~A>0line-enriched5�I�.��" 2724 )2IB�J�F�B6is lik��a nullBTo gain�&ins�ciG !f �;i}we(~ 2� $by immunos�š} diss��y$hermaphrod� gonad� fUI�UC&� �U��2� �a�al!.%)Yi�k�d�l tip (� C��Qth- �4upon en� c1toe� ( leY ene/�  stages�6s� zonem��� ��� u mid-&�J2��6�M�se a%�F 1nd� ��-� diakine� oocy�l �ynaApat,H {��s reg*x! ���1mpro". A�a� lu�, 99�5�a�cion�{&�^e �WY<�S�"�, 34%� �faa�& 2%�78% %29�,q&� API-e!(�!_ s !�IaAsbe mkH&%�:�C�M\102 $U�pN�53&.�� 7–10q�a ) �J  lso9�in gut\ ��Fis=�/ e�sieDtRbs��i�J5�S��.F�t2�s�M�I1�aQ��AU=! . E exposu� o�otoxic R��&rep�E�st�� lea5*: �4 !���.�%  .>�+rf*�I%e!�� at.uQ ��N�a��"emmAwEHU2*!2abnormal9e\ 5�#* ��!��&,r$h.K'by& 1������enlargedIaar��m� bS%R[1KIQ`� a�QQM� �rR V� U�3ɢA)��"rWi>�nhele)���� (Ja@�)%�.KedJ'( pS')�2s�4i even��?γ�u�Be3 Gi4� �i� crui{HV=%�AH6AH�y&�2:nE�VM��:"��0�%�]O9�:V)?U]followA�&_��HU ( 3 �du"� Q�._1� 2*a C ribo� otid�T�$in�)ormoblocksi�yn�2y�-venib xpanJ%Q� dNTP pool%�r&���� k�l�&YiLower]� PCN-h#��. orthE��9� PCNA!9%K�"orm q3D�3E2&�ev&> *����ist��%��1in��s w�, ��^ɭ�-��%~i!�-�2F[1' ����`onlN69�Mn� divi� ci>'.'92B� ��E��� �dr$��&>kILdep�p���x$�� ��.�a�No���ant"0? *�)�6�N&M %��(er�G2/� !0A�s��CD,,��-TYR15L hist� H3�Ser10eJ�+e��F U�S� . Al* a;e-������T��"s�--A�1u��iV!� '�,2g"�YF%ҩ,"� !>��2o�!(in�e a� ho& Y, adult6� � rDc+ &-�ŶL!�&B &Aa*monitom8�' [19]9�4�nEq� HU"k)d!��*"/*M Fy, l �a�Q�ch"� hat g!6�.�Y�( 100%�96%F?at 15 mM} Ag ,:XY!� c�*dFp�wHU��,5�> �ay^6QcollapA�f���*&� �a� S�"�,G57f��enc�V2}a;t#qL�"by>�B> �]52)w� AZ����fM enyA�>�U�30�100 GyF�.�64 �58J�i.�-te+1ing9in.�Q(-[w��`Q#fragm���36Z��G��u3@�![20a[��in�i��J��("~0�64d�+)e�) stro�M�.�. *��Y:� .6�N� �proAk��s� d 0 link= ICLs��6# :Eces��ob!he pyrim�m�=#� 2_kle �1d��J{*wZaSio a�P"Lfoo/ccurs�A�le+,"���"�Y� in3.�M �HT6-s^ �:�كof6-�&�  �*�� n,�&i���"'$v~� r:%Q���OE?.�de@e!w� ��� >q"�&X8*&� �!-]of2a8qu�t����9u�eg. byJ�4� -�SD. SC 0�-*�(�  te�+al-spap4H-ner�ARvin .� ,aCcee{ L8�,xior�e�)�!1� "V ,���mei%T"I�fve�.�%Lasses��%�"V6(Fs 1%D!L_-%3–7�VI.ksfew�!�B~��eda��o� they%zmai� �./E���z� gap� 8"t!ll�p2�s�WreQ��a$ ]�9A�N�4[2m*D5'15r, SPO-11*���N�.AU�d+%R�c(|(ri�7��e��!8-� K !� reac�ir� estqQat eaH/]21�4C5%�Aa��Kom� edbS��essw0�%F)o6oU>i��" b���O.a��-UP2�Y�277M��#ed 1–32��,7�$%�"�^in%~Y��8%!P<l 0001E � £QZ�E �(maverag: 3 . 4.�/)u" .)^Q��E@5��Q06�;6g04I Hig!�V�pe� .&�i�:2b�.��4B$25�M55 .>!�6B>8Ii1�Q�:� )l �?� ulaw1��/o�'2A9A���&*���'�4 *7,"�t2�� �&N) xis morph�){63 ynapc6{2���SMC-3%��� Satid cohM or SYP�a c�l f&!�y0a! �>��*K J'�: uishv3�y���I�Tote�8e�@v1�ef:6s�(1awer�2e=�.�Gy]ofip;spo-11!5�� �1�!�������;E�4D��EF�.���still"s m�uv�%n�� ��c��s�A���6 orig� ee�&��-�i>�E �!ifu airW�LJ�5� lso U�i>Q,!� subt6(�� e nu- F�"t-�';1^ 5U6totalV.xFu:L��.[!�1\�� ��aE1�., g�*o�;��*y 5�_�m�y�Q ribu Ao�JOg ^@M �&:RA&V5 data�� o>�?&Z#!2dE^e�0of�Q{n� u0�ei . PI�evof un� �  4ca�<$Be a.� &'* �*&�.� :-".[ �[2;I:�!J�v��\Z�&:dB�d�%������tb�.�#399�f:M –j�%, � 6�*G4!�}N��Blci>fV\&Q� � �@.51�@"�F�C6%00��M�gH4����Es��.�� U�bFM�dirqwtoc _8� f@o=C*M]�*�,sj���&�*L���<a�2::GFP� �1k� &��>�tV6�2bi>�[8�-$�2 v�al2��U,�afu�zp/ %�0 9Ve=�> nw�m67H"LEm�Q"zW yI in I�D�Rnon�86&. �7!*�:�V�l*�4,�����fu�(abrogi>���P&� �#In fa�.! �a��):��1&�a��Cus-+ op249)���ch82rCEPj�F-ED#e�!�b�,E�2� �ac5�%���#Hř-�N./@*���>)E9�!�B irra�GdFMau"m� cep-1;6[b�!��t-E�%��H ciG� 6Y� �.|:UFJ�b)%&�N ��"Cg�e��I& VU!# �:))�)@mi:nm�R/ � �5�"o.6� � A���� r�wh.p:�65�V-m!� .+ a1�,�+c �5�e ut�( ( VMa sex*�( ( X� :���w�2.' :7:46 . 6 c47 v�9co�KpocM o 81�76va#w�Flength (? AA�b!2pFs V�X�@�a!dd*C25] -��Z poly�(ism ( SNP )��3%&8).�. Cros-�5}E��iS a0��<G�/��6�+,d85%6U* �4 . 1!$X.�5�2�16" 7657%(.2 887�2x ,�c*B Fish�Eex� �,U 00<0�+F�=mMOCc5$2��+.% lr��*� U�Z :�.�2`!v�bi39g �}- hird c�Ad�.w���$lyV�_E�2|a�5monf'�9238 *��N�R��sEA>"^`6�,-9KYoo�.�@6�B9-�&�$��JD! �":af�.��)�a1rUIi�lZHP-3Eq MSH-Wa�"�GoYhark^�#� �"n!�in&�n�K]��B; [24C2�)Secon��7ly six�7Itta;�ٙ�a"* simiB2v �����XJ�.i>e"� "\=�5r�i-!tof�D~Nhiasm�" 7%).�RJ$2 !jQ:I��@I >� �>0 !�g+T-��2����%of��-eR�. Bbrc�Qfcd-25��_u.gQ.� �q/,Y�5S%�nd�r.���u� >��'n^+) !avail�[27� [2X o �Ii"�L*4�F t-gA^ employ�� syp-E& ok75<>y3i backgro&Aiy.�Y8�,~5s�ce%:.�no ��er�h[/e9�1�6 "| du.A��of�#JyzLdVLI�'p9:��be`4 -%Y�Da�9]ŞWqCZU�5 8.�)�"�"��%}�%��1�2aa("�2M�� issha�?\K"�.d lk ;e>KI�7 !4)�)��� 0/32: !� 2/45 �S��uV~�2-�ev;Wyr,@?"S!r=,s#(beiiUu ppr�t�( 6-fo!���m�&�� �Asn��by��toIz6%�":�1:�rga�� 2Cm�6b�:"�B L�Cr*S�+�1�� ��&J R,@HU0a"*�&���2�MO� . Un�7EGunYe�O�P� � O� �6F�%e:�3A�F�%�5# [UtRWD2���k7 , br!ye$3�� Ey:�� :Y� 2!-�26�!)B�&� } ag'OH� c.t-)��mJ�&a�J��5a=W�"-M4 u�� �o app,0�)inu�Q<� ,*i1te�7y!i30 9� tar Zdis]2%�6^}�W;�# n�Q!u �*�2�.o�-�S���� �! t3) appa�A �ml)zor6�E y):M�K,� '%�Q�as:�Rhro��B�)19% ( n745 _i�2BZ��>\��7u2W24�.h2�� |=�11!J!Z21.�7Fa)Y� o� '"[@&�)n��JseB�rar��u�V#�I�in une+"M1. �3fD2�1sm�$msVb�7*��X>>(M���i�"�,M3�Mf&�&{.(co�6"8GatA�na�� of�D.B&�H^&�.�O!q�}(^n.�Mu?))N�͙ ��")9���.-��*UV�CPTlS5E-6%�Ŝ��primar�QtoNAiU �T �Fl,��5/+OV6M �r**+ aFQA4oc9\ `�B�)�.2��e�MjF-matl� atm-1"� � ��5�6� &g�J ae"� F] jleaGQ� � ��=�z�u;T)�N �B� �F� Q2`�=""^o�S0_�%�� !�l �.XF�:ide�M sac%�'e s0Ke�9f!�Q � m-1; �:� p:5Z�! !�� l&� [�0 ^Ec�H��Kr�f�T>�-6!1� !1�(!7)��ly)� C 9 ,-c�>Yeg9 e pl>#ropic�Ͱ)�})DYwfYnA!ex�ZE�oss�Z 2$u� ��� r�- -O<QI�$8 damat;�Hfi��sz �eM>e)�� L ��toT `al��+6�F�`FFV?PorJ��G>(�X1�1*z p J�J��,eΑ8�!�B.�Tf�Etod�%B"m<nd MRE_%Kv"Z`���+ion; [3w1[31�RPA�i-�nC,)M �;2c, |(s,�Za10/ex 434�64 (qd���@oB"�h44.fG ��rw>  p�b�4� d���HU �9G)��H���Bt82�[HE�]]K])��6 &� 6"yA� 5"� Z29+�U"�F�9%� �Y�b46��b4:bW*4�FrenAFY �Ű!cs$&�/retch�clupJ��%+ =Epre�� d us �1fyA��d*�YZdi-%_!B*EJ�6 -E{�H9�eG̱�tip"&3��� Z�C*^ �Jiri �� tgg�out�^a-��� *� |; E�t�cf����=S3gen�3J�PKmL�TD���d�+51����B >J|ter&* a��dm �;m�!o?iaZ`�F�%�n�re�"�<#o����n:T�W.6�>"Jx9!�+X�v2%)gx�Rappli�R^0hybridroach���nh�6lvN��KQ� �+s)C( Nw13d$M270–598<C40|U)%R�iIR�9C*V5�8�jN0�dUb�Qa�2:R�U���c�U� /eR. oM+yJbQa�9?6�R KCK)Nb�A>�)gM;Uone�i8��X�Z"Sj�V%� %B=Xm5"� =��y`%DU � T trun�#!�m �o N , �d�CU=�e�'� be suff�N&5s�]� / ��! ��7��o%�hxa�VmT Va��As ���B(kFM/( SSLCPN�!A �boli �IeU8"�Sto �- ���( l `>IA�Nyi�1v6�!X)�y4nF�|*jXN$�1?n�co-72�ip�9i�TlWn�W.�a�)k?t"%��1� lthojda�1�.�%�]_6�)s�A5d.� . Full-�#)" d %J metho� HPR-9 ( �-BFMR]0�T) �8$topoisomerJF2a.aU�>!8�{F�th�1nn;a�A�:�}@�%qCLK-2A�6pfTel2p "(F4!��' poU!thf� >U�)S[3�J�1�5^(��)6��-[ssalIm{� ,"� lr#"�Xu� *Cc&s0Ņug� i��Olasmid0��Hi�&l�`�|H"U+a mX�%�aJ�E)�x�%(M�*3z�#� ).(%U-�sB|��I�mQ�B s�Lb�flse�i" on-��2�)q!6 e��mis��is�e&;]orG!�O,“sticky”!."; ��� indeed sh~ R)"�r ,"� ic  &C� E I4�&� a�lt�"� �&q an�=E�OW`! ;*�`,~�1�"��>H1��ib� 8�^� M�F*E.d)9������nOv� -�Ee���c"Fa�u#�]����qm�/ H6��qj+e�<�9 ���\ r_�0���6U;�Wma�? �-tO�*103?ai`�r�gr��9�in�Ls . Iz�+E�.�bs�5�A(I�-76�,��B8W�oOIfo$i>b?j%J�"�INjI6�� �%*� !aJ4 ����R�c��&tem�Zaԩ)~K!!*@;oGd:@ �*�?�h5 4�F*Qe�HU��j&sIAFV[l"�[.��%B5�3A9 . O1.ocChRi�z�5:�k$expla�X �.�6�6[r6Af5��9mDA�!��a�(x(�\U.:��sx s"�$*, araR!9�QV)�ic�>pA)m*EM�How� IwFM^X�"!| x�1�?2��aq�e8>E �ѿWW�1!w2Shu%�<�"hN�A��(6HU .I.\QXof SGS�> U\de'd� ��DBLM�&ic� �,�&to �,a,&&�!�j]� .&u�#6P>K9X�es�9a sibt8Qm�&&�tagon�e)q�![42e[4(1A�~�RFiq>IRA.%�L&FV ( TL�i�s�� &�gy�$ubiquitin-�.g( UBZ )S5fAa�72E��#�/eh�b^�.[4`iA�iiѓ� �ѻHNAD RYN� dJ�?���1%� �Blau)�asln UBZ-�@ai� 9���m��,POLK-1/POLκore6��N[4ZyY6 :B��a��:� ["dAW#�YA�..�j�Y%��Fx[4Z[4�/A��>A�>cm��I�p]#:& ��) �$.Y;tw*�^&�2� !�MX�F4}�&l7��fN3ctEZ crib��#2i: �;*��%h�H.�w%diE�� �Ms;�.Mjr�[�@ plat�%��Aqm"�k*z .��P s [4�U4��qz��i�)�>>59tof-!ewe hypO �$ F��3jbe�d��a�wm�wtK<:�XDl�" ;:'yZ90. Ls& ����]hl �v visu'i_�b!�i>�,�qa�)s^�Ce�)��bqve�i)A�=� �[1)�CA:,�$:� NJAaF�!aCE9>Q~ �6`[�].< &N *>Rf&X]h<�\�F�B���� �HAX&S :{s��Xla� �;�.� =&��IQ�|&b9ry?C9=1"O= /m�2 �59physi']q�N"��Xb$n"�26x�B;'A��Du�!52�!k �AI�"F�D�Zp^� Q�!< Z!�c�or�� \fe?��Wor�Iq�=_�6i>^���.� !J���&Y�� M�)1�&�>�_q*kQ����C�@2����!ec/S-�$��6�M� �I�1r�CR�!� a 4 I��2�e����e�)��despi͡u�E )�Dr�-bV���4l��2Ww# �E��)��U�:�B�0cVw�)ua3Q�ei]�Eb&dP e�&]�ex"� .-g�!g#&7#e(Y\ a. F9�]g} ,�mM��!�Ji7at"�� a�?�$n�!�O}A��x1}��2 ��2S3���SasM3Z 'y+�&RB�3d"c# 2 hr Ni�CA�U;=B��yet�s&� EHat`7%.:�i"�=�&-h �!L" eE�36�s, as 3�((�(�42*!��.E�'� 6�W4](��� ���-��yE+�'a'w�A�0untilI2�Z�9pF!�\.�;reZoE�1�a��Є%�YN�e A�Q�=}DZ_=�FU� �.`Ly�2!vE)�%�h�� �FAho� Gm���f~`v�=AX,"�M2�b�'�� 6yq pro�"? G29&� "�+XLIR ( 4D_)A�Iҩ�aU�:�����.�geJ@Y=e@4:@b1J-w+qtyp�Q cleiEx((A�rIR |i*e5 &138�D�wUtwt +IR"�a!�%8+IR; P&�I��&�+tA]ev���Ute�SF�;! �"e i� y<>��c&�%2&k5�, namf�}in"] a�1k�N�B�s1��D:�\m���0s� 2� [2�a sepa�t.� !މw���6� <p.V)7( G+�V� &K�| summ}T"�DcmHed���ޝun6+m�# s�s�e��a�� �0�X�g��e/�+pI�Q%A�1~�s� e-MmabA��0�n�`22.5�d�� &�!�'6�� 1-)�i�an %3=!o� W"6$etJ6����&�hby�8-hairpi�f ��h .5$growth [50&V#n_e����d%t��"�~oI66^g1c~"O&�g ��#)�"o$ndG�T$h�! tiss?����.T&%)�I {v�"FiDvKA�v|l�5o �� ^G�+�A�6�A@��Z_�11�Z߇F\]e��N�a�&� y�s��Y�l] !��)!�O&�P�6�^ ��"�ex {�@"�laq�� . .�!fh�ul`�d!/20°C�e�c ndar�Znd�?[l _in Bre."[5]�N2 Brkl g�AuAp!�� ild6�*�DE ��*A ��=�Lrearr/i�/ ^%$� udy: LGI:�6( gk186�YO[wg1250 , .�PuT$, hT2[bli-�4e93�_,let- ? ( q78�qIs�,( I; III ) ;tII:��*�|, Rz(, qC1[dpy-17)(e1259 ) glp�5q33qIs�H(.XV: �Z( ok7' , nT1[unc �n75� �qIs�M( IV;N .1�j�V!)l� tm85Ra,�D!)me1� [[52] [5314���!�nt%�g^�� AR��R>��a�.�A��a�����removesf9a����Y�F�#b��.1�"����Jm#A:�����.�=&fs�! E�e�Pd�:H�aur ΨKXEa�.u�:>���~^/4( http://www .�/pep . or�=�9��(h����>#�' �*֛.m,/� 8 clob��pID�`02!s�Q="T���*A�1ewte�t�hin��ŴtoFa;6edaI~�=s^�g�}^ ({ Unc ) movXor[5.5cqRe)~n- $�wi����L/low-cop�Lte��J�aFM[5�!Pa]f-O%J onfi�eby PC;�Empty=S'�(�!|rol"a�y sear"�7��m� �&��t,Uni@ >gu Ed/eN Pfame�PrS�x+ relef#�d62VK 5±5e�d70�2±hT S�K-�,�eis.3715-�9�I��p��eQd�:4 �<( �p#7Young�rom�����,E�pic|\�U(.�o /qC1�89�l-DEIR ���.C+��^-b&Oth :612,pof��a Cs137 �at�o�R�of�8 Gy/miv/FkGN2��5�10?150 µMZG ( mechlor�)�?g�(ide; Sigma b/ M9 bu�!��D��E�1oli OP50�hvR �"�7dgRaR20 ho�n.�Da%:m!zad��MF!a� , 50 or� 0 nM1�K!�e��orv:�wa� twic�M9.�TritonX!B(m ml/L��1�Xa��v�n or 3 �w.�Eы�f�as.gO!]A�XL-y����in UVaW�ExW��!2!50 J/m2!�3��.>�)�i pla�Zq&�ee�@NGMK���"-� � ��tHUM–24-.. H]u.j�" ( in>2 li{:�2�I��T#oL"�.YexperiA{��.X%[!7k7!� EBd 2Ot5!�!� time3iod!�22�&Y �L1�:p�[4�L� P�q9� �on.v.�%k21k!�incubE��165t��l��w�%( Fe % coun!�W*h�w. Each1jm)�%�@"�Lt ix+n&�<.�. F�p RNAi2��Z&�J"or 25+B�6��!�}foh,seq�[k$�I( G!�erv�&)[? &�#e�o^*���bpFb L4440 f � vect�}�"M B� . HTbLbacteriag "�h YBQas!��C X. �aVp3ue�e*-Ag*#�]+��On�ep RT-� sU� ( US�;AMe�X�Feg��pu�bya6a�2��� �)�5�a (�(}ua�~�sub� to vby5j:v���,myo�U K12FC A�z�%�:� Rab&��&clo�5�sbo�a�� st Ny�]p���.of ���7T( ETLKEEGAHFYKHFKYKRYCe�LCHHSRSSYRGNRDDRGSRW :-N)ig.�Yenzy� ��� , LLzAntisera 5�;-"�)� SulfoLink�\ ierc����anufaL-@�D�[-� . WV^m�4 p�9"<�jG, fixF �:.%procedu�-e,hd�C!�d2�2e�P�%=�;)� ��a�dil�� s: r)�α-1�1∶20��,7%( 500;�$q-B� %20&SDI�_,!segNOP�g1#0EnCor Biotech:R} Q10R[61�G.��? �~H�ne �~f2fUps�vhna$�F,, guinea pig�,o t;[6�H�S�o $�Chemicon:�HD�H�$Santa Cruz>*R�C�S���!6o(CDK1 pTyr15 �450; Calbiochem� �� �,2�. �\�]GEBAL : Cyr]ti- S, FITa�.%=V�+moA ( Jackr�I�p��%s��/~M�. & fluo�+ �Ky M6]atKr2 µm"N \"an IX-7|T�Ncope ( O|�uy�La CoolSNAP HQ CCD ca�-Z> Sʏ��� ro��DeltaV�z�4A�C Prec � I�2�d�1v,�by���� SoftWoRx %t6 softw!(Zh��\ age-m| ed (&� 1L-L�� !���)acr&|o��-�:�4�/&� At Z*D| f6�d�a�5Gatewaycat�1d ���&�F��i�g�KT)S,Ulo�, �a�ORFeome�]���d X-Ga�G-UR33AT� �� 0s7�.n3�q�%_*� �[6_2 �'�z�!el��,��2��Jmtor+#e� �"�?�u hchA�� s!Z d�3o>�p�-�<�8add� *�e�5is~��� �l�Ynd"� t�}��neA� tub8mo� o�� MN )\>�m�erapidl�;����?U� � - _[ ޯ'�7��!i� �]�>�W,i)a��al2�%�MN�R��v5G a@� !^1��<thcQ�iv�tf uQMN67�i� Olig2 jusA$iK-o#]$o. )/LD�FL Notch*�!�� AzHesT~Hesh } Tg���'x( be dK@8�Ofory� m�ithM8Jݖ�+restri�8���MN2��seg���!\� coup �!��net`<0#��Vm)a�A�AE4>k*R %))&=*��AGacema�coord�+ng�n�!pMNE\�T . �]��$�}�P0m™�p�(� onD� gen2�, V"�H��>#[|�t4>+!5&í�#�#"�3 �b*'H�) titu��Bsê-�Q?begun�de�%T=� hier�+�t . N^� thel�,%��Ps3�gE�!5�('thA� life-��>ܔs>�!�u�Ost� . AnA�s���-��T )�iexe��A�is� blem�A�v�2b1spi cord n ve��^p;�%�3M:A�.3����QrٗF *ga g0pa��o�Ehedgehog�?h� �%e�e�ml�2\o�eet homeoOK![��c�;x�:-(�x ( bHLH������� ( TF� [�5�$3,�-p]+� ����:� Ce:!,&��!\.Q�4U�a�i�toe<��raRg�@dorsal-1�"~[�~��.Ior��2�dl E4�Mbt�)int"kP� �#a�����AN!�s~ -��reb� Z-��H�ty.ch2�A�H� O {emerge [�8–10!�A8�!f�k.�X� e�1;.�A�u�(hA^chick �sݰ�mRv.� 2{� -day� �Ϯ� a���s� )q:�exim�g�:[ "A �F adja�=9�-}aCat�~�t�f1akin�h"� d# ��tl��6A�m�)sXy��� , 1��iG6 +2 \)W&�.���elabo�B�A���%�ens'`��gpr ���!�!���I�!�4ai A8 ques� of��}�" 8&�ng>�� 8��B~r� A��7>�aof�6�by�+>$ofաw��&1T&� Ini)3, �n�l��,A"e�%� _�oligodeŷޜ69�; |N�T*] V�: !H.�j Irx3���Bhlhb�Jkn�/ase2�&�)ly�� A�E ݍ ( NP�ߩ,!�A[1��T9Ectd^*L of �� _� �T6�n�y��^i�1�[1��1���Con��eVM�*�.)S,FM�!�S]� A#6�->��A��9U�:! .�A}to�2b[14�X��#Q �Zizr=u�?�hMkav!^!�1DŽA�!��0�%!|o��-+.o�F 6< W�v)N&�-�"�or�&�of6�D,lso�%���eL"� � TT2� |accele����ҥ� S�s#7�L ���o� p53 dX��yadR!��to��!b��A} cockL6A� ����-�fibroblaݽV�K�d�oc?�5F�%��Pfe�$.� `!�A*u��l�9-A�q e92�estab�Zs d�� key2 A8N�nt!a� � �nBSt�N!y&! leav0�e"WP�1 �&�#�f��8�"8H<�K�!i��0>�[n�KE�RNA�90( scRNA-seq )�� �n.ʁkp� ful �y!� ����;YFf�!�&p�6mix:2h� � ""�4a5!oy �2>�[3�y]4,q took advazJ%�5 v��XElI>Fw� A&� �m�. �&�QSHESC ��e��=T.[,*�u [3MWe��{�_W$� !val��'Bt18S$ �>�f����nJ &�*y byA\chM���:�yi!dv�)p!8a�mmoR- asyn�3nouslye��Oid�A�y !�*��of��!�W!±�a�"�&��@ obsc�4de����ɨ �}& 5R�Ym-�ed�Z�\:��>1=�EMyx)��pr�6s�g�!�� F e2�%$�sq>J�t��8ly*�z�)� �wa��d����:�).u�;e�JiYUb�Mtwo6���L!��s:i� $LOW �)��> Hes1.AyA�_<��co e5��a s&�2 HIGHoin k_ * D*!�moA:b���D� nG�� rec�##� .�q�� �8wo��NJlb �hI2�� 2aa*�6 r�^yWM`�i��q�� E� �� \lyU He�� � e�j ~ V�  `2�E�A=�w!T&�A�e��mprehenB� vi��lu� ��2G�ro �v��C� 2�I@M�"7�&��!�RTpo�AyeDty� >0 . To.5J�%�^N%rogY'a9��vc�Z Š� �5"0Ana�B���EtroѰ���re��e�z*oft&1:�M monolayer7 o a�Def puZ_ of W6 O%DpmAL!L"��I 17d��A��aaud�L!�lCdx<�24�Su�,�7h�B�A�d omi�V�� tinop i�#R�1�(Smoothened/&�Ss2SAG )��ul�96�!����&�"��&��"�'!6-��� F@m�nd Nkxp*s Fig =��#= .{*� ��erU &�IsletQ Isl�*, a L!�� class�:$beta-tubul � TubbO:-�je1�&d S1A��%�!i�,&� Hoxb>,}IAi91B D�.��to)c6-i�ve�,>]of!`elimb�2_!1( icS1C q[37–\V� v1 ��r�Q�@!��JAd�m�:C�&t,!!}"�@ succes�Xo�6���!QAh5�=1� S21n�4�$�U*��Yv�n� ehav!i�-���D��Aas5�kt� �Ps�0i`�a�H!ta=(�1�3��3�3!Ca�0�3/)�JaI�F� � >&& ���*R[P-!q9BPax�PaxY�Db���%Y�aM"3�H NP͗tyAc2Q�. T& %: with�5nMR�-�% �t A ���b�Tpan"i�06 .����S2Q�& (50!� �,:!&2~b���&")Gžo|6�^�:�.��EM�izEA6B�V3)u��E#h( p��s$�89Dm�a��of} �s coin[�d)�! q�v�w>�"�Pax7.eK DegvM� on�iשTS�T9��A����&���hhV�"hb�<���yag-DI@|)� emar�A�� H 9&g-�2e. next ~>!C�2�X��pYgq�UQ cWe�ԝs�뱉� � n��|wn��%AGa�o�he�w�e�4�Y��A�m��� v a�����p_ al-� ( 2-h�)�e�(!3q"3)�F%b cour�z9 %Mfew���At �,5�T2�5�6!��aiHV1 .�)!,-�ed So�M�a�E��Mn>� |��x6�C1D).�QLQ�w1i,Gag��M��a&e�_��/2�6�"� [4r @By%S�{6 w�U���F�12-�=eEa?#.��q�&�   *� � .�� �� �| �.�2!�]Ve"�� ���>�2RTj�� ���s�6G ESC��.ecapit��o "Q� �#M1��E( l7mAI1�A�!0j ���9�x(Y�a !yF�th�"y"naa8S*k ��W�as*F`�!� xx0h� �9�}oul��!igh|Pt��a)�W0[�+=�a:r�t"$ -�� �m%� ���QailedN� !�ime�$�;f�/Z�"��wu" � Fluidigm-EBR_on 236-iso�Xi;w4� 6�F>�<$oc�EA�@ap�q\^t��cf see2T���$2�� 202 ���r����"*��(>>)�"+ �I68>Q�109>�KGC�f�0��f q�Fw+�e"� -dril��pip)�"��,77�~aha8QIMEhmodul�_��� �log� GOp+ermFmu S��)esf%�2���H|�9ytex|� a�Aarv�c�� �of r >�74�� asG?V$ V�&%���287 �A2"a[().R2ut�aeK8!:���>-��.22b5N�&�!�d����E��2�~8!)CA(2�!�S15�F"Z,"4s�#s�r�U/GO=610�a��'N'Á�Q2�eM6�yC/� �:�&_q�ache.>��V^�( S3A; % 2= ;�� l��2$c�&B6rl'c�=�1R*!*�ue��@-I�,�AT���UertiesU���.}�&<>�CM�e�  g�iK>/s�Frd40���agei:&8$k mesoderm)�$.�two AV!�pop��Ѧ��� set:;Hax�.���ic@�{�0EB0Me� !� FoxcMa vascu�end�lb�1�!�DllEd Cdhh*Q')��ѻe� *�U�c��E� ���16of%{��t(,�� .���v:he�w6�fI;�@A�ri�306%�s;u�E��M�� 1� "����A s upfi�f^A6.s !zTF �ۡ� 2)�1U�yin>[ >O� &u � "�".K �&�xPOU� �Pou3faka Brn-�(�314��(o/-s���2&�) [/uX.za���b[2�$,*)d�4)d�Hes6;2.�%9"� Lhx3{hYu'lig>>-'u�Dl��s"��60wo.�wa0RU ge��]a�K 4B�%p��`in2�ed%*s-� ���#�l� W.Elavl3��ka Hu�n�� SoxC!�Sox!4=$M�ٲi*�s�&< 8>*��-�`e�G}2ho�� acetyl� �5s^C� h2�-�?>Onecut1m"#R\I" fa�a��(:$3i����E�aA shif�4J� L ){,�"�A�)oV� _mu�g`!Bq����$� �2���2m73q�a�&9���.���La�Yw�.yh�-&*~Ǎ!�&nE )  �U"�cE Fe�]i�ss 6�����u"a�V*����i�U�~o�$�#�1!�%�ng)�a + :E���3% tJ$F� �%l%e."� oS1i&8�T LN fatty-��>r7!abp�Vas� @ ��q�. 1�r]~rke�>6p3%I�N v�a�dJi>brach� Y�sm�:*:s:e��&�Wk�_l�)�2�M!|U �B�MN!�:�R�{I s�J�� a%M&�73"6<(9!!p鍡 i��n�!� >���':(P6�&�6�M��_Or*�'��Z��� �;"�� A69/!1��E,"�1�i��8�Q��%�2n*:�&J(�!pseudo-�a���'6O a�{g�bmn�randomu minimumt=n trev69��� pA�:ph��%�� dv�6���M"h +6h5dY��h�s&*��S�9a�ig ��tri�A"%yC �Z&�� �H��y��.� ��W�NX�%n!�W"� ��N1�9rofۭ�)\gr)Mv�a6=Ua|�|�h����lng6@:���>�B%Q�f�3F<D#.��oV*s�@!O�).Z2 Q3,  , [�=�la�6�B��A,��2�S��$To investi|��dqc![fd��*i�fl�YZ�y� !~E����" �pCJ��\Ҏ)�?ne�waz"�� B5veR�Ja�����1�� �:9 ,�! shor� �B��j��AQ-1Gnga���e�� .� Z4�tu�d >inIcB~2�(Rovi'�= resamp� o��&len��of 41.�pGE�� ��́;N al mea&'s-6!&:����6 outca � &h�>�"�.+�&:�. A�'u*a��[��i)�J�A\o=��i�#,78:OA>�chI� �(��R�!i�.�)u@y3Q+9�Y �.�.#a�"eA�nN�m&���z(e�1"{�A�� "%o'�_�[4&F%N%p:�ŕ�i=2G/AA��� �"�E J� [� qgK� 6S0 ,���!=6: MN m� F(1/��!A.m!���VZrobust�S� >/U�%:�L} bootstrapKCa+a��oA�e3&�U [y euB< �ge6Eval�f6 ˎ�,[����a�t��.Z� �9rawAJ&���V�F!�����7-�ltple�!` a2r% �al�J��< acf ΂t�S4���T��a��ly;FPir.�%��R�4�-�:�\Ai F�p�r�Z& �0p�"�a�fnV�v�}alue greater than 0 . 85 for most genes ( S4 Fig ) . This suggests that the observed gene expression dynamics do not depend on7 levels ofk.8Xin specific cells along6��8program connect =(stereotypic!@nsitions [48] . D �these2 $, coordinaIchanges!�>vPoccur , often induced)responWo a Bsignall!R$. We reaso�tA8F !�tr�T phases should be evid!jin�B orde%�$. Quantify{the var-�inB�!yverag.normal%�Rva!�!�KedisperseI� s’.�profil!E�ified;se�( aP2D iSe threeJin whichB�1�wer!XU5$modest cor)�d{0o early NPs ,A�A@enitor!w$MNs . Link-sU�c9�s|]�!>Ac!�edng%�!.globalB�-"mVfirstcB�JHswitch from Irx3-ex�f4ng intermediate��to Olig2.-MN#-�E ) ,!ml!�8e second captur!E!�Y�of2EHto postmitotic neura{\e0asked whetheri^�P}-0pathways driv�F�cq]c0. To this end͡Ram�]�e��%�,disappearancE�canonic�Q arge���� R� . AsA���,l=+5�!&%� coinciA� with1�Dof well-known Shh 2�8Ptch2 , Hhip1 ,�Gli consist�#X<=WI!)Pis.�( S3Ee�a�ByJtrast �M �w��ccompana�a lo�NoA�z, mar!�by�B|Hes1/5�2 m7rs caus�ora`m~sAkof ryinclud<Numbl!9 es6 , Dll!4Ngn!N�NA�d4Y�S3F5 Stri� ly-beginn]�Y tage>� peakA!re��Iu'q2F%�ifin�rai�[A�$possibilit!Kat highBRpromotei���si��poAially!�0directly regu�CngJB�(. In summar1��'of�B�E5 cripazal����� time.�d!�nct.m0!%Y]`�1assoc�di(�  betw��Q Q�8ext�6�?approachkvalid�XLprediq� line�h6�* data�;sufficia�to�Q!�e-gra��� inf�|!+%��tes�experip %�. E�� 2E�.��|O>.�to Isl16!s.�R��uoL ɹmC then Lhx3��fi�y_Q�C%S�mQ is is�m2�in vivo)Caca��at aprecede� ��uY of o�[MN�;- sp��Z(d [47 , 49] �8a similar seque�gen2]"� deA�b� a�� vitrov�*o (protocol baa�@on embryoid bodie� 5 , 50� To! firmI�.�event� m , weA� ayed)� ,1�=�!�wday 6!!>�aOq/ ��!=�i�8dividual nuclei�95A� C�risIEw_� URGreveal-  cleara�� �?L-poa�vatS -neg� NPsU�% 6&� Overla" �of)Q7ame�~s�� both%� einst only�nsa*ly1=�"� >~*� ( S5B�S5C5T2e absQ��more mI �2%,%/M�!� pan-� alm) Tubb3�D}C:Q<:~"v , H.O��s��plE�:�!�1+�Wbut)Klow=� �wh� Sw< :N'did notV>$roV�>�� wo o��fs}�m �iE�r#A^2P�jf �]��� M���6Q �{:*jnt��� To fur�6�d�reliae�Uim���demonstr��� -2�understa�J[d$M�) i ��- noveK � volv��MN!?m%��W> sel� g��!l� rq/�1���a�ES5& OneJI�$a particulcstr�VAhip, 4Zbtb18 ( also � as RP58A�Zfp238� *i74zinc-finger TFq BTB domai�I)e bJ , its� 2 es mic� phalde��!�i"�glialB:[51��L�is� bouts�(patterd rol� a.�$, althoughA�,situ hybridiG analy� havep!�t~Aominan6g9e� f "�[52�6� w��B-wg Dimmunohistochemist� it%� ��n���%�JMG–S5Ij`� !� H�l detI�� � paPI at e9 . 5� N�:1J�J�At e1� � stil!`eR�-�" 5�no �er�;a�e.�amKz:��&� Qc���aLAi�ut�$ r� stru� !0:���� �DB�"� at-=�!����s�r�A3"� o>��ross- 1��a�a.� ����[1w 1� 53A�@�+� ��arc�fշ� -���.� MxMN9. Iin�e�Ezi=of-1x�i`ic���S��m&� I��ch JCN� � �third � . Moreove�� @>@�%ء��� A0i6, U ��a�V#t=>�bef� be��down-�IFMN-�ty��elabo�{d.M�����?�V)�ex* �9�nd �-��  ub�\&�� s 6!%�odUgdu)3I�$3A–3D″��C:_ previ�stu �oun@at!Ix f�a� por��F} :�%�EIl+ muchn er:N�EM�e-outsid%�~}�19e�o)�if%>n V!��E�)way! g1 scRNA-seq%*� >]" !�!�M Mnx1!�� � �-�E!�H%��K*� si&8on"Zi�x%fein�6� )`thr K�J�O3G�}� ?1Ingz��2{n: ,� meas�-w2�%:-=1��onIkR'1 9�d�t|%.in� as �co���,; � LA$r*�6� aken toge� �seI]s��Z^��Y2)A!ϕ��O� �� �g=�P��p�u���"�C2��"-.edV Ecommit[%�6oU Siend���I�1�d; s rapidly�E.]ed-�0we took advan�n ESC Ai�we fu�4monomeric far-�)fluoresc��PKatushka-2 ( mKate2 )�!wC-inu\B�via� elf-qva pept��I)04A ) [54 , 55��i sE31o!6of�pro�� readaٱ��I��&y ���N�o�Z�'to2HI y<%�Jnd estim�$�Q�r!� .�� trol%�.�� A�a�b *�1����2�E��"R contai\!'engineeA ,or wild-type �allele1�E6�mS6&K�-�ZM:!):�6��7�O��in (��MR C–�m4GS6D 6&` Howe� we��  cohor= S�A�� er1`Y��va~ ��s�/2.�҅G  k�G< ��V�J ,�� p!e .z`=.� |J�-� �HUF��( 1M�J� "mNPe^er Sox�4-�I�Thu� !%indeedAEg��� a�6t�Eg HIGHa�t�!p0it�IA�NP � addO��"� �up2 M�c2eas&Q#mA4 ��)xtwe����"�R-T$in Nkx2 . 2qp3%c -�FaF� �".B#�T&!��s ��& p�.��&�e-9W lo;6.A�帡�� [4)4M56����G R�[]�-% �H �e�$��za�]z�had� ��B�ZB�LonjJ�.TM�"[B ��lrli� h$�� MN6 !C:��22� Asqu��oDw�Y�es �prior!l2'YF�� impl��L %�o~$z2�2� ɏinhibi>�A�P�� �A rig�RJ:( [2857–5 Fim�E��er��N�&�&:Q �c"�!eff�&e�� �1,^ %�Hes�&"h ^#ed� E3$�%7E2LOW.o^#���"N �� W�"1cng �*�]���j�,?I9 �BC �*5�� γ-s�tas!o%�0or dibenzazep�( DBZ )�24 hour&l;�! REndS ub�d "� AA�numberAcI2sm%"�4K �'mp�(�a`S6&0���]��f4cytome���"�ly ��~� ~��L �G"�6� co-s*� "E ��!f���U �� �E| �I1[(29�Q�tz !� L*r ce�Rdu? *Q��r uponM�Q�o�68 mRNA1�" !���g�, �"�s-�$RT-qPCR af�+0 , 1��GU����! Jd L5�Id'*x'oF�� rs (�3�$, o Pax6���(�KV } w,�E1 a4t�qr  U�- ��OK O��hN���aN�a� ��ho��)�g �ly:R2���"Z%D%!�Pou3f�S�>�>|]RofIAc5�)12-)�k5�!&8ZVAW �L�5a h�a:DY>�> H���� � a1= �"��|���}.%b�%�"B I}X���2�{�u�J].� , Hes1%>H�W�%�2i6�[ eK mouse"M.O1�~ broa\ @0y dorsal@A!�+� %_ homeo ia�"as�as�-or pl� nd� �H>�( [ �Foxa2�"� ,.ectivW �5B;CF/5�[6�#6c))@��n � ��6� *�$v� Irx3|��.�D5�+.F?. 2�y at e8`, a���6F��A�!e�^ �MLS�J# herei��9!�j show�;= deg>.!".Ʌ;.:�J(&�eI.[ �Uk �N� O�&�2}uK�"� to bq��zbya� 5%M.t� many �+M!,6� at ro�l�g �Pŵ�few�ng I"j(p�� BQ��� �2�#A� or�$tA��VNH!NL^ThS#;�� �%�}��%�1 ymirroQ �, reci�2a6� űK!, (A� e�p "� xA�a� cycE�e&�J� T.w-Y M′!Q′ ,.J28]-`u&�zp��w���*��H%Qr/%d�%Y&M'�s>K?"�NTJ' next:4+p mighta�1si(4� 6~ ECre�ck-�ice [5�-6�""�)�7 col-Ice&�)repla�� b�4$ophage P1 precombind (=@{&ь]zde�-�resump�I%���,in heterozyg�GE�om� Cre/pmutant�Z�ch �5r�� lack 2 ` vaI�6A\6� . ol�!�AK �au flan� �j$��lk.EYa&%�=:<,)elittle �lapa��wei�5L �\J�e6�6f%1�D.�(ae/ed ��an���� �Bz#V 2��Yc� i2)Es2!�ac) e an� �A$ ��juxta�on%�>/a��A�%e6" ��i�1�ngi�=� ��6����)fi/+qui���i�E<b�a85UU"al�=�OP7 ccum�0p'Z� > ��-6�/�Nx*� � �in ovo <(rd R$� deli�ret��j�#m$2�4."@ myc epitope-tagg{ormOLIG2� $%"!�]�)U'!6buti=a Ekno GFP (KI )��!30aM3%:$l ribosome� ryU-Gr�6F*�!ProM%( IRES- a�pYpinser�|i�c:� (� [64]mso;�B,A� 25 6�)�]����J�� S7A'p7F'-CO��1��) &�s� ���(FGH�!=%nt�" ^�?i�!&�� Ah*#r�/��/�3levIEB��t S7&� W��eN�,� n,# �!:�oHe��MB�"%:�$i�2h�A� how�or� g%�- dq /rs�E2e-o&��%  .�e�� e2e.2��A�i�LXAbn�2f��ct�j��1����( orth��]m�A�e��N�@J�*. E q\t�Cc4�0a!�i�,��s7i�C]�h rs SOX�NKX6 . �PAX�a4 Al� S7J.:� ,!UW(.�H>B��c�1i%��W���%6[65��-q1resul�X�d*�,!�jl�v7 �NEUROD4 ,J�6 NEUN�K�FQ�E . Of!iI � �m\ �+� .iI�]"7;NuEB �!nif _�1WA]�`�Ae� � gFheyyq6i4- � N�S7O�F�1o?8a min� �/!' GFP-:Y �lefi�E��4 zo6d ���%P]�()pS7M �P��a)�2 �)kA�Bd�  key me�6isma��e�Ai�s�A��Q!�%�@:�fun"���BBed*�. verc�A�"��ca�,�deE�g�x<ni�;ed��N+' 11 � �l�( crit2 iHi��M.nmexŴFM>C�?!=��iN�c&� A��>� !E�@�!&� �a2"a�>�!F�0��@��� )on!�*D��*�+ask" =�"a �0�sg7�:�>chrom>�5>ipi�3�,��YNP�a<s[(a@Dnt  si�#"��; vicA*X*!�z"loc�< $7B ) ( [63�/xhttp://www . ebi . ac . uk/ena/@4/view/ERX62841�7F2# �se:�a�"*l�proxim�E@;1 ly mjd::D^ 2�fac"RBPJ [6�B�!��*�ed-# ~��wr$E-J!1I�A�in �5ve� � xB�Jelei � 5Y. Alig+ge�28`W � %����<Ui humq 2�+�()gJ+I��%c6�ExA)j �,�%�,ately 200–�? pa� �*"��> ( e1�� is 80%�3� I�� � 53N*) 4�7�E�a�u �(is 7 . 9 ki�H ( kb ) 5�N�al=�Ec�D-~Bkb�E�%�)�m� middK3� Ae' �. Lik?ny�+�1Da��9&@&6�m-�Ӂ$ ( E-box )F�!�K-@��E�palindr�Q� CANNTG [�-zmot�<at �4��N� eE^�/��rea�Q�%mM9 � ( 87QtyU8)Y�3$ 46 bp; 98J1)�1)���e�IT.�B"��!5Q/N� per� �B8!m6� a!�bb. mpria�b .� U%���$�0i�%sM�.�)��� E#ULs�zE1 Kma�D7D9� �� i��%abolisu(�<6� �U?A&��j�est� ��:n*enh�dOggGBE�%�mix5- �E���A no�Nc)�an �:E12:DNAj lex-�Z ng aff�\b�2�In\�(,�D �a: Id> a �Hzet""���5!,%�� dimin[ N�*�>min2�uq<le��9��8 E12/.4 _] �U5$of I �a�Elto2��A%=coHF�2:.v6 .v( S8Ae�Ebj,6!�>$ �dim��&� dig6:.|F�o(@"Pmit% at ma��$MI�N��t7�>)YF��\�Z!ﭞ�t:� e�&e)�_re�'�> !p�#7�Bi<$�e�<�?WZ&TD� � �\?y��n��(`D4�A'act-Z , upstreaKa β-�P�� inim< or�O*� �%4ary�S�P)5�-βG::nE�a8CEuW��>�F� truc I�;��.�,&�8!�� lasmid en��al sid�βgal )�en�!�CMV/β-a�n%�%i�8A , 88\%8< J="� abe uni� Q�'%J-�al axir ��6:% | w?N6�..u�v(�:spa$�U�M0a�*��m2�&A�: � .��Bp,��� ,:Q�<�nd- �# 8�6 �B�O@l$ �-Eh .�:� !n)� b�HG�69m�M 2�ToE'ro�emoA�iBu!�es�W�� [PN�������Ifhe9�e�-p .rBI!��F�y�3*&�QΔA�.Tu�57-�L&RT*�/E~Y � �U�QR�4�"60"y origi� �.��)�S8&96V X=Unow�C bundP#�lap%�M mQt.�ME A�-T>qo6P!5] )Ջamg��si+"v."d"�7a.8!or��d���Q)�. F!+��PO ��I��!� :�%�(���U�- ��N�E���d� ��%�����9���XNLU:h*�t�6-�}+ a-*m�a{%d�>.d�� �)�>.�ya�R��<s��e;�R!�.A.PO� :�E(W M��� 8`)8J�W`)Q��R.B�*�%]��q1�IUa��-��">�iO �m2�&a �!�>~]}�� �lyA�rea�%e��a�r�*�-am�Iw!�1 %��D2ol"2 ��8q+� N["?&B E�)ae"..��h=h,�leanH#�i�V�.O*�i�G !�:�. S�#j�3�a�� mer0\X0 powerful too)� i�#al.�N^&?F issu2v! [33�D�HA��6�p^�P��|i_�*?Jr�V�3b��-resolue�mv(Ag�%�3w &�8of�>AI�A�U!3ge6MTR�YZOa� ligh� yOof.��8�!�=]networks!�)"Y=prolife�&v.�N�[7 i�%m�4夵����S�'�� $ apit��$h�+w` XB:�WMN#�o� �L�9*�[fe�R" 57a�[SH��Bnt�m�s:�, ixploi� 4 a!%�5 � asynYzB2 �E�e��o�pop! ion-I�a}!,*�G)�in�af%�=���I6�~�*"�]�Al��Q�:K Filb'!�S &�Ha�O� a"�a6x/es� vW]�Oi� !L��!�t��!a�N��qf� uTZ ZV�JE%�'otDlh.O. Pyudga�se�\���5�=���DY�g:��x�(V :W6{ba.*��/u)��!�,e�F#salta%Vu!6 fa"@]d)6! �2�o�cl�Va n�cse�)a�by2Xc �-3#d�>&�c*;(Agb �we�LeaaE���hYA>X-9^9�M�-r�_p�("�Te�ob��I>�de��&�c�2�&ctQ)��d>j&VI�%T%�typ"5of�5m"_d�> , un&�H�s$�cly�%�- E r$2a �.�%]�m"A� eq`a�retin�Z)�� �� F 1Z6nKZ�8QJj"�6� d"Bu�"acquim�S*�b.]O2�Pe�!�&� ng)vr!�wXgY/�#�C`%�d_� �e �^�)� "^{vͳd�F�h*���� �� s" ]t�Dmit�A�a�">avail%�%\p"�VR" ^��� 2�& _!�>�.75�!'I[�*� iǙ���]*�6*c�+�:K�9�8,$!)6.!Hes6 � �.�aID!d.�"+ �lsoB�E��/ [�$'tthe\S= )-�*�w#,]�m2�&T h� >j%�v�Bi�P���#�Tis2|(/y� ��7}g��&�&� �St#�ll�9m��S�͇�>F6'"�0AE%�b�5� �&�6�N-�bInN kX�%"Oe��s�:KM�+ag�9 affa�"T�-mK�M2�&�"*6�:y��i�o2��ݡ�2�a*6��d6���X�H�k7!�.DK����Nt�w�5�i�q��"to&<!�Fabp7Q&��>IS3C*S3&v^B��� new�,( ��$3l � B��j7DR�EeGNP2m to3 =��B � �!��Jbk:&,e-=D!�P��"�T haveA��3A<-��U$rek5,e"#V�))t\M H�>�V�/mB?.�T8 , 2F9��:m*IB&� � .AM� u_9.�W>a��!eer� t'SIh�5�&c J� !�l �V[1���4Our�2m3s�(a*�()C�4��-�.�!#��e &P"d%,blH2(AactASsup� ��� )o1�GQV=,�'6� a� us m +>� i�]�J� �(P e [�+2�Q)�U&�6�ge2�g6�!{��l��A�� Z9sB 񏩤61S7��h�bi�h�y645��� bd&recr%aYK�,6�%Jt��M�W�e6��*.��:� �7����5��)x�!L�se�,��\v2%��F�h%�� ,xLX%�")39j�� Aks^Ed)D.B�a�*a. ���*pa}R+E@B��K�%*v"!G��!��[��g1omi�0!�-��e��2-A� �g)��#!�3%��#"a1�g�Ge-'".0by���`!m�%bsA�� is�umod:�F�-9>` -dOt= 2�)�^�esA�� �� �C����at �t.�2L�us im� n-� �Z e kinetic��id2\9-uis!elr sur�%�%����� *�7���Y�!���$!\2-%�n�,.�o�'B�g)OI�"�7�?�"iz�< E4i�a݁�ru�WE�op-=a~"&[2�n6�t6�*�IIiSt�h�(m>�7t%�mu 2;&%M�$�)��/!�.�c%G/E- b plexE7�]!�\yρK �P�����@?#��=f�Ne�opo� �W����� �])��DQ��bon)�E%�6mI��j�h� < �#MH"�VoJX�2�g&1is unlik"%ppl��.Z!;� � .A�s�.xtms��er&=*B "� b��bat�R�oeF2%�Lq%�eurCq� eeQ�I iO*8a�ax\$U5��F�F2./ LQ�perdure�n�Rin6T�x��a�9~B�;n ^�sylc.LHU=�T y��|*d"�]�<gn2&�l.�3H)N�kHA� stea�?b4��� O s� E��!kcap�+Y3v��q desp`'$e"+*A\-r�. A}�"N� is puzzl�-�'AMA�m���Z�(A@�I� phosphoryaZ�J>at��c Ser/Th� idue2h� t�woFof*er{h�ner%�tra!�uplocy�!��*��!Apre�a�ope{ d.1d*})[707:AI-Y, "4)�{o�WYv�v!W)��8� �+i/6~,6*!y�Hin*6ki�Fs CDK���p�uk=|eMat!_108pr?+g ��*.9��)ample>A�)�[7�<�B5�� Q�=q5(}%z(v%3.y!�� �D"�; infl�qs#bi8:t1M� y [7��� declSAmof1<_2I�*��G�V-(^��6A�vP��?kѯ�a�.9.2L >:� x �� F !� �"E� Lim-.>OTF Y�2�� s [75–7��H� ost i�����!%�-������h���y�z�ki�Uic68� 3– u���.�A1.�� .} ab� sY8Xr>n�2�� &�0b�e��ma A ( PK<1� glyc�m-synt{i� �qGSK� , sy�H�T6�'a� &% �}3.D m/�tZ6 on [x<,7�7Cd��pA.P �mQ�ic�;��w� BJPgh�/up)%$6�!7a' (*��n&!Q�[�� orph!s��"�aӞ "�ls�!`� Iv�M2�*t~n�Id"Fd,�M�[�� FU 4M>4�"H"eB�*�"3&�K(2��-*� e!+N!!>�Isl-��r�"��m_ ��neI �P�_ I_* �*�A�F�X ,E*K � F}E�Y!|�IV"e M#jr��\*Fi.6&�;� � �F��"wIItzz~v�s~ f�Q)![e<Ozc�&conver�fibrobla��o5 �a[3��� }:�an �.��n-%�A�>����.�!�i�e�c��"`�*π!�Zo*��\n� �hq�5�=�Alhelp �a!��$%��!��Uen�i" ��&A | M!.s�A%am:� �enw5��b�sU�a�Mz�9oscill�!��(�&`cA[6�D7"eHe*�AM .� �� �oo*by"?,�%/ !�H��a�Jll\ !OAscl1 �_8IB8Mu h�;eno/?v ��;J�ex��r&�S��~n valfea#.O-[������ulig��& ��F.�Y� s [8kt1Qv �6fluctX$�"�* �l�^ docuu��p2�E�%����[�2 ]%ha(&�b"Zi ay�*��=/4gh}#9]X�E*�E_ � %!]E�2�-�.J"�o�;�',2Z�29z �"Vci|��-p���9by\ �-!�у�ilA�-!��Չ���7V0} .;7It�oM ! �@Mr% ule!� rJ1E%7M�r&� ?6�#�7 �&�0�s�|"'a�it�ru�A��sg2� tri�Z�. ��-��f*.a���=% ���asH;IA�-`� �1�1 �.�����)�I �8 � !?urn�&0j��(�27�e�&ntribu���Mng ����9c>I&regar~PI� �S�� E�Q*�ter!��uh�Mlo�>�6ach%�m�EeI��|b :7�omm�aqP"wL�it[n!���W*� [JY�+ram"�shuFS�wBI6��,�l- *�  F�Q�}nd���A�m�'man���2In ochaf�>��oryI����>&Pa4mQle"ld� NA( E�K�m E�3��Fb_M72�.)*�*l�|half-.��o>Sp�"*tr��-�I��C"j�<���MGO #!A A"�+a �aeIu )"6�MP�F0n} argu� gains~ 1��m�@��vas!!�behav} iRo�x�_� � D���0 � !( -s2�r-NFout-of-�W��,e�!c�(��lQ-�L�@"8%iB�Na�. U2�):IMon�~�,llA�W/F�#�$�>�*� >0 . BeYw� Cngig�IA� �N�&J 9 *��)"���9"T;p&�M�a��x!Nay��ol� w�"D. PBF�G.N�le ա��A~�1� �� pret�7-��d^1 ��s&c���m6|8bPVT$A��)JK*F&�.� �-�!7/ ��-[��[6�#8�CB�.�'A����KBW�^�75 logua &�O]cauB5aB�"9!M2�"�5��Y� �.�!su�ie"hM%�� .�H)]� �x�^I.Qc1Wex"s\"�$\`!6=',���;���[6x &55�I^bmg*p !�5�, �]e_�2M�5Z��D���^,%��!��-n *�r�!\{��F����ɆI y�e%4u�� 9!pfK �!�"e���+� %)CrJ>�!b�� � ��� 6@.F}hz� �ZfR!2genNxZa���lA����!�>�-^Qw. !gir�l�Ye pivo���WGi��A�ɸch9ac�$"�HorganizDnf�X6 5�ap�ve�*�acemake&FM:K�h�F^:U6���� mole�*M��!�x~Te�(>w > aٍ� �Q["N�&B .�y1�'�6# '�A%�"n0��&� A3m%>�.�!��"7%^�rea�9o&!n�)-�2| A�De*�S (,Briscoe lab =&��s UK H�Off pro�3 licen��,( PPL80/2528%((PD415DD17 )� i*M_�� �( S��� P��� $) Act 1986- �OrE��and� �Yersb � holR�ca� KvZ�Z/ TDm�%�`aA�"�1&ю*e4*�b�DFR"�oro>�=� l l- Novi �5�����;col;Uo (8ord:E guisanes seta?th!A�,UCLA Institu�al1yCK cUse��m�}r�Fer�[Hen egg-}*4�� (AA McIntyre�nltrA- Ce E8� cub�im.J@"^m8a� %�.g 79�'ly [37�[In brief�@M[`Thermo.opwDVI6 ! ��::T2A�0ESC �=�i�~& n um)�W ,000 U/ml LIF���OWinB%>NHYf*�( frbs�'�� % �r��$A�g�2LDn 8xGBS-H2B::Venus��^ ""�\ HPRT( !) h!e ��U�.A4except 4-color8����A�#9*q cP;ly!gM6�3YS6 @��J��u�A�F���#E�o�u6�,"-�di&1,in ډ$05% Trypsi�aGibco )��hA�oi�?cul��7o�3r"^i�W#t�? move6�. C�%st~}�superna� � spun� �suspe�A� 2B27Q��!*Qa��w106 �A� . Forty-f=-�s!�!/- �od �35-mm�BipH�OnCor )a�co%��!; 1% G�ne&�$in 1 ��ml �+Sng� bFGF�%t Da�!�acas)qsbV=<+ 5 μM CHIR9902a� AxoneHX3%<(y:�rwa}el�v0 nM RA��igma )| (SAG ( Calbi �}A} i, ,2�;)�`LA[atTx5>�}+ s1Iμl�x0( Tocris Bios�ece�Pa�"�sQ{E`wa<=_-at $R�d!��3a�en"y d�']?��MM�A4 . mRNAi�"[#edm�4RNeasy Mini Ki�HQiagenanc���� manu�urer’�u�L%B.Ib–2 μ�Mu�� r�;�?[/!��RSax-S II_yrst-S,d S�"� k�In�? �%;random h�s�(. P� num SYBR �b�wmix (:Ca�]�h a�|&=�CD7900HT Fast Real T ��wm!e ( Appl�!�ystem!� @"�val%�*Ϡ "�M� �g���ln� ea�Z Ryx3c{@&M �[Ġ.Is� t IApoivG\rel �UA3����2mYR lis� %�p'!w,�F S3 T�).)r !enA|in�b�S1 ɓ�z Y�e(�m2��#mean ±��nd�devK$!B e he�apqS2Bj!�ploj�u��8Graphpad Prism pX�%�m� +��q�nd PBS (2�ta�fi�Tin 4%�)a�.aldehyd�7at 4°C�0ծ. AKzfix�C2, �tw: '��sto" arefriger� untirC+�E%�S)�7a�RmE�A'a�qcH P�t,Triton X-100� BS-T��Pr�-��d]R_k�� diluM ;+��BSA6,i"� �Au:N�n�5`�\n5:͡���19~i�-T2@ lR�B1 '{o room�er�$I�-�e�m�.M-T . S-O͊moue)Iv ProL'Gold AC�ad0����$Life Technz�,);E�H!wQ .�: oI��N�, cryo�(�\30%!r�]a�� q�Y�!!R����(>e�,f8O"8xI!M@%XstC,���n�P� � H�\LAPAKEPPAPGAAPQPARSSA�aa 12"�14S=h! rabb�$guinea pig� v"!�� *�N a^Xpur��E�Bs} :8 ,� � crudee K,1)� . AmB�upt1"� d {s: go� nti-JkTBi�\�q466^1409 1:" t� )KC�( C �MMS-106P22-3Db��k� gif�KS Mor̨!Thomas JANl(�9#�.P�=8( Abcam ab324232� or C9�#AB955!n>�t �FLO �ne=_47[.1:�� �q]�:N� 1397n$1:217sheep60Dz.otec 474��5e1:800g.��$( [87�a �]=� Hoxc?B$Santa Cruz!�t�($y sc-37633� 1:25 j.Bb9/?(( DSHB%M4B&\�$�!Yc$, ( R&D AF183 6�.��29� 1455a�1:1u�Neu�g RbfoL})� on/MillipՅMAB37Nr-�%� &4( M [8�x,��| jR 1923IwN�L" ( 5Ca�[8��).�KI � 3[1�o1:3Z�"*=�25Y..kx�!�5�1�.�� ( 9EAB961I*A�Qp>� l? [90]A[8^2 �2?,A�� AH.�5~.�22JP �e� 3�-Y�K�I� 3369�1�2(!r�73�>W�2 �SoEE^�2h.� TagR�oEv�' ABQW.~23+���PRB-435F�=>4��4^i��(��5�R�/14-1-A p<. SN� ŏ\ ttb��j�ndon�i�exa48AA 56 Cyan�,Dyl� 647-conjulqA+(J+ or Jack�Ia�[6 archK��� ��m�647 �j)e��Cy5b���700�CF405M1&�-}�B� y��;��. �.ْima�Mof�-o�ed&"�� a Zeiss I6��Z4} cope+ppt9� an Apot�. 2n#ucSd�O@�1casset"JN[ �HpaI AO HindV"0;To�'�+fB�fw03Gn�!!� �=�kng fr�0'douvec�.c&�kapp�. 8Vn"�f�5..eJ h stop{�<��\�s�(CRISPR/Cas9��a](ou�co݅E�P� deE� ( sgA�)q�� CGGCCAGCGTGCGTCzP�lo��mpX459�dda�� 2[9�'�.Y A�,;&�gr-/in 2i<+�. 4,b�F g�j.X �4×"PM��o wor II�max!� ESC6(aA( Lonz)n�p�� 10-c*�� &�s�L�J�!4^i��U �f�"�0 �μ�Puromyci� ���Sdvdw@�mB50?Ge/9 ?GUP n��~�ly vi[c2dd 6+pick<�/(a 2-μl pipe�,2|�2R���6�f.�!2�+<��U��!�96-^z)��_K�c�Q�!qm�VnsE�ave� ��0-��PCR:ly?$in RIPA bu� ��� e���e�i��O.6 4t�(&�4a6Fa�[DlaR!*�GŨ. ��Z�/!:)I�&tubul]^ T402�.�Z���� Z(IRDye 800CWp." � #680RD (� LicorF Blotmsc3�,an Odyssey Sra�8To> YNe*T�%2q$po0v�,&; t�"u�M�V8 ax2 ES��2�:� �&?�2.live-�$& dye� cA#Viole^:$Omz�F�a' �A�&� ia B�n Dickin:LSRII�� w cy��m.s$or��-�:S&E.j�le�)}� o�s�inguEes3�&0�m�3:�o"�H #s�(�Hcx�� �asBR!�'!&-���B^ 5%�h F���eO�gcw]'��irtA�od?#l�2u r�w��;�4�� uunt ��*��>G%G9:���er�� h��#7�+!�cW 6&n3s dephpy�sW%��03�#xSis�-F H��5 �. B*ׇ2�ry� in���&a� �r?4"�4MD&c��6��� dS4Hafe��z 0w O=z��@2]1��ir ]n (�@89��eBa�ofڣLs� fa�m�ry�'kM�A�Aa*� � % PFAA � " �e>���:�<>��>bo�BD PhaR�#.1� "�"& �2"b�2na*" a�3×VA*��)�6 �?1\A"�^-Hasч�by>|.*8%�����$Jo . pCS2+�)r*O$��r�r�� , >,- ��vU%ԅycri�A�� i{\�T�w0Promega TNT C G ed WU#Germ ExM& S�$r%'D�^���wasc� � ' �0O"�mM Hept7H�#�25KClA�(M MgCl��r2 EDT�r2!%�He k) [ =oly dId�[Y�AC15"�#��:�!8. 32P-dCTP-labe! prob�8 �by Kle�o[,�V�Mouble- �2oligo�o�2v��Bfve� � m��,o� �"h�- ggccgCTCCCAAAAGACCATCTGG$GTGTTATAA-�; �'5�:actag CACGGA+(ATGGTCTTTTG: )��0�}|vq`5c (!M� YB�ggATCcc��J�ggGATccJ��O�r5�Rder�d�}lc� ys�_�/��@�!�N� �siNY=��)�D=I:Q��RvWY(4I�A�acIPm�g ]`�t� radi�jphyinb�;m"9L�o�(��bbqcor���unE�ed>uQ����?�n2 ��i2P$2��=�fraR-$aM)7/1)�_f�"! �" ers:M�,!}bkER.�enzym�tNotSpeY�:4Q�!hp,?1�di�d �Q�8&�/�.���!$lonyba��Ir!E"��tc:Ӎ�za bov�. th horm�E�denyl�I��,qP#[92p�M�D"g .����g"G` spl�ga!(lap -eE�!-. CE embyoM�cB�y%�I3.|5816ong (a��v� ,-�A��are�!a2�y%�%|����� galoviruU�E��"A,�\�Em����4,� )��'<�'S�' 6�*y"Y&tos6�A`O�� &F t�oB�).ns~:%��dAl��n l'�Pc� r �&�5�H �H�k�1: =; r�16�spu.�a Bitp�ImP� w�4BSsui| Cal[9ak��ex�(m�&@�M0oft Exc��B�, �TC/�;c�&�<�O}.�~taRu��y/E��as1G�(MwUn]�s y-c"�l�O%2����Dynabead�=E)�Y2�6"Y!Hel3��%}\R6� ri� !� `aH>j �s:22��*� AA�1a�G��� �2jAGC_�$� TAT�j�!;g�WXnon�e<�)N�km��A ex� H B"o:� ����� G.m2� ��G��GG� �< ld enrich&!]�~`c&� �&�BB4um23E,��In� m- ���HzAgT=�F}'er��i��"�2"�^v� subt�u��}LO+&,3�# 1 fa��Po stH"CdAJ"E��A�c� h�s\�re [dQX�mploy�� ��onM��A�%!�kM���?e ����s��yA+&fK�in"c�� �z)Q��2009 p��� H1N1"lu��!buypd_<To “�V”%�u�a�- ~� led 5 rhN' maca%T }a seaTC)i iso��s��d<de�;i9� {�.-��11�!�h2b�FH�no�D-Lizi�@"� E8!a2 ur months�<�ch��n@�q55&d!'a �� 7 na�a�˧%�aIn !5, CD8+-�1;�Ct�~�Wa8 ( Ki-67+ CD38+��a bloo��l�u37Rs� _o� � ( �#�+^E���� )t]�,t�5=60 Q .>I�hn��, E���qW�* recrK"CG�asM� as 26VinV^�2�xW�!iB49a6\I�SferĥIF�-γ Eli#%i�U~�]kR p:L�"a��A�-�(j=u�%G?a���a hig�H .%f^��qi>;"MSi�P��� CD4+�2`�9d�l�lq�2��SedUi�A:�K�� �" !upE AFY`�i�;���qh+i&q�X)�V#Iޑ�mC9cneV�2�a�� ��s�O!Mt ~w��9+���y)�a�nt� �7��,E!��M6�. VaccaGca"hOing~:hV��yu]ͦ�Q٣�je�$ �N�Enew�WmG�� :�  w,*e� !�rw� sp9(7 a �� � ass��!�>V�AprilɈ��feaD�a�h ��. E��`sI`Mexico1�.{��)p�b`r�t�b��Ex��O�e͘�iee�'I`�quickSe+�i�6� 's hemaggƄn^$Huden�LH4_ l2u$“cl��win�jag� !yP/q�H�*3�%k ��)��;1918 []�� tr�ini�f�w�&�� v6�s!Wo"]�']�recogn�Ia�}A� �[3]–[rIBy Juh:9,World H� OfNa�W��g"L�"b�U�(21st Centur:Aa�eV#�> ,2$�h y`�Weףc �[7 apprZG!�de� vq�%n3Qq�A! E�%��)(`) [�=WTApre-exA�-n2�r������ y��,�h��, �r-�a�� �F(� � Z>e��bpl^j -�]�?ڥ !(G]�Vdiad��s(t!�% �2����<%5i�T� .� “ha�o �h�6ity� �X"� � s;ovja�%yctovh�vs�f6� 5�[7E�1�5AVF�Oa!~�D�7inre&�Ap3jL�.� !7GM�1%g6 hedd!oofUY[1e�–[1�eFur�m��P]T�1hY��?5a�vh[�7!�'�f%�&� I�=Q1�e�RlA�$�s' riska�_�@o� ap��n�Rqt�eE0nj�F;( �-Q�5�titA���� [20]&&�rs�ひ�T�vj ~i{m��E A�cei$%�s)�)s"� m[� eP�qSo�O� %d*� '���� dB��of �aft�31Qu~B%gch shApu�os�yl*eY��)�]I�������a�"feb�wC�S(�o$[� rese>Bj)Gm�HrarelAt�Sxa� [21E�2E�=e_���9��tuI�DNAt�M?��"�{�a �i e�9b�"" l[�A�rep,!���5N1)ҁo�:�k+ z�c:v%�l��� ��teuH�+Q�S��V���me���/ef� [3e$I��. �ut�<,Oas4�v2�F�a&=ED}I�w�eei5�NR� �q �"t>B �e7<e�Ya�%-su^�]oa �M�"A F�" �IDth�M5�nd a\� �E) 02,+>�:��� "� &�O^qzIb�(aU� stimk`A�)��9 bd mitM�<�E��iof futur q���QpJL �>!lL & {be]�Ah;!�ur���ec�Ued���e� �� qm�'p ��/�N� W9\e�� ` hon0deoiJi�a����lBl�BJAͷ!A1au�' �� d�modali94F��$750 pfu/ml2��_F���1��Fgn��:�>�.� E�E!��~ s [3�W�1 t2 Y !�E��(ronchoalveop(lavage ( BA&�T%�̡.�B�2uW�!>m����IRz!�1��gEI^�. N*� "LG��Nv��"^b � �Ax� �Q"�,�w�~n��- H& r,<6sqas�mal opG7l� s� MHC tetra~c�a� 3�ea��n�!*��4���e�kɡe�:el�"/ �$%���= 6�ff-?e�:�&!)�.,.Q acute��!_�$,= "A�%)�AY�b � "��onO*se'h6�n adhe"1�ce� [3iHLA-DR�u!�r�p ly u�(- +f+���bu��e����6.fW�sEx A�p"� E�H*(+^6&Q��cu� �upheP6)�)% �q�wit�bm'�!H�Ill2� �I"K q�� ssq%b��峙�4&4� a7an � q>!� Ked1��A�Aa&�� %Q CDUY!�CD� �S �P6�.r3+CD8- Q� s_o!���)|� ar��s%V"�d���Vo#u�b�j��m�(�� ���)^%*�:��-�E;xss��8p%��#e�|-q�  rh230�5�>|5*8N;C1)|in���^�Y�?:7��S�~a�dN !ee�est�.E,�1�M�E���i.�f>�!x�i ŕ �20ious K173 virpus could not be isolated . 58�% of this animal's blood CD8+ T cells and 39 . 1%0its lung6%$were activb(at the peak4(response in�>se compartments , on days 7–10 post-infection . To confirm th aHse expanding popula-st��represen!han influenza virus-specific�(ular immune�, w�� pooAdm�Oa[8N-terminal half!NP��e�odoAon all 5-�A�Iv S4 )!doEkMe[contribu��X2Kto$)�-�x�"�hrep!�dy s�Pon cryo� rved)m%%day 7>9u��2o%s!�tU� ed strong�s>�. I�� �wI��d�fr�%y�ie-yvI.0in both whole �an�K deple�of): 6. #Af$diminishedAe abol BYcytokine�o�>5o to ma�A,��but fE�st5�atm�A� b2 elici� �X%DN�A��� fr���H data屉�AdIntra(u���taining�} CS )!4 �-��Qallow!�e s��taneou��8d direct enumer�@2J�CD4+ !�2�. |MV�I�sel�� �%<���EB8at , as a group �s �?%KN�=rFG�v antigeţ͟2%[Togeth��thO%!{i"!�seaso�+umF7�mcan�du ely��!Urhesu�caque�a+�iA %!�induc��#��U��&�!�a�8vol��a]N%A��differ��al2�6 �6?2� am�&1� . By�u28Ջ�66%�!� bodyJ�w5h��)],e� they Hn�tc)( neutraliza ci!k�RNpdm ( ��s 1E�IW��ref��nex� ked whIoE%B{,“primed”��y&~ af!�rsea_%%��. Fou�1nthB�ngEfirstݒAz�8challengeSemaFl!�'7 naiv�ntrol5���* h A/California/04/2009 ( CA0��We �assess s �kticEP���v�\�e �LI A�e�6YaAaQS 2wo 1 e-C Us early�H2A�BFo� �n6�|�r} ed�,levels 5–76Z!�X(4a�]Ini`� ,�)|a� s8of1!e:| becam�iM�4f^�Q ] 2 �,�i�Xto A{obser)�%�=w��fo�RA�EzY�^ eVS5 b ,u�to-6i�Striking� M7>appear� eAF��u2�1nA� in 4)ofUu0��ndeed ,^�� n� 4>k in 3[��5V�,%� AB� v=rem��295cJU-2w Z2diincrease. �.ackavndQ�until!$R�6� ��!� ~A!C xqCY"�I4d�Despit��is �� iti�4ofj,��,in BAL sampl�"����" �extrem�� high>5�(�HQ^ ( 51 . 7%a�r,A�}As )F�R isonA�O���i�Y��{2:|�he^f( 10 . 6�2�b�&J g�% �.��e���jA5occura� signA���i%�6 Pin:�$( p = �008e( 12 ,%� ] ;�1 4e )��ugges� at memory2�1�s "� by���Jrapidl�c�=d uponJ"f�"m�I� . Sif@>n��%�"�2�!�Q E mP�3+CD8-e-�!ed low!M:)�of) q�d6~Q� , riabV onl�  r01072� g2^m.� r02002� ��^pm� . S5e�6[ e)� mode��" f�ja�of6��hB�(I�9l5 . 2xM8XC1v$lymphocytea�� mar� �S�!!V��s1�(is phenotyp&r�4E�14�)9�B� 7 . 0–6�9��>.T4&�locE � �e� �ostly�E traf(througI�I},M�&\ h��UNc w�Bk M`ingU ofC y�q�&uc �he&C=e`&F E&��. Si�wU�E�teresfin potC ly cross-��t\ � k �^& �+ b� ���$ 1 �%Q=UW6��244Fd1L62!H930�Rg��hi1�ak>�&� � �� B�2� 3!�!Q�$� h" V]�+� � m�Tzd-j1�9�a��3A0Zn . D�]i*�"h x� = �s��zwhe��!k:vd-/�s�Ba�� �5y�roaE~ce!�!�7 (���As�:y,�@p� 5-"ke�G�)at�f��a#��PdM 6i$^���R�*1 �Z��!g�# r�'2�>��s!�.V�u� medicb26 s��ed�!�IL-�T�S3%�T� analys�A�"cpatter_!��BTto]�MH1PatE21>�(:�`s������:�)Zv;B5��E�.2�%�co-"}4.�recogn�ACF��HAe�02027�x 0307��6%�N 1]i���H tendA�o%m broa��7edm]�. P*� .�NPqtT re cl'yI2v4��>C, whil&e3�'�%IeiY )M�b� � �it�|,��6V�, lac�^�.�"� -eeF�j@ Q����aa� e_1 ϥR!1�m7Bq!,en6"M�"Cto �-��, alt�� ��"*a��!`aya�q��2#� A��.!�cap��i�"� !2�,��� �"$enzyme-lin5 �dosorb� 5 ( ELISA���purifieda>� �!!apt� serum.V seQ.Z".s�"=5rai� F� %NJ�a �# emicD�QbIaFurA�E�5 -HA-1=.��titer�in �of] ^� A\ii�y �!�] �21��&� B�h �� lysapof�8or��K es g�#s~result� ��!�n��Z�8��aso�&�"hxon1�=NJ���m[aS�}“L-�ovarA��R�. Alt&��1! �qw2B�akBn%y��SO" b1�3a "�hR+'m!er�N� �}*$0 -!�i" ���quick<h6� do . More},� 6]-z.�dop�iG!1oB%do&62o 6�.:%:+ohadAys E8��tT�7_&A�:k&( . O��m�(�N�a6V���onsis@I8w� w�)b�()!  an e?Yi���:t� o�J�RXz�}���%�6� 1� -�.B i�Q�wa*�'��salT ions�$6!NF�it@��� �7aEeb�]�֭��n>�^P%�&� �lowm%'tho�*605� 1$n!�hoCV� �1N1� �%�:upp'� irat�tra�#ar^��). 7MP)��� robus4 plic~-& �Fsby aviF#es�ibu��Wir abilA*[us�%v Tpneumonia [34] , [35] a)�r��ma��F%3"�eZs udi��a60we also evalu1 1uBui���,! ��Ff a%�!usOaa!d9�o(v flui llJ�E �5�de1.�m�Q��U100�)pfu/ml�M�2>�i�F���e;36Tor"f*in��^�u$f)X!1� �n!� Ye� B�Q�un3 Rw�h5�I~!�� �%2�(�OU of 650�501D)1 . �7wid!acq0&q2�JB ar� jor correE� qc":x es; i nt vacc�+gu�in�h�'sti 2��ao .�y)�! ≥1∶40A�0a hemagglutin�� hibi ��  will� subjec�/\� geni��(t�Vstr�/ [36��H"N*a fail�provideaxad1� pmultiplem.subtype�In mice> s� suchaBhetero :icY<�� [37]I like�6(��&� ��6subset�8�� �2�49� play�rti�0�'i�1 rol� N�:�B'5! fe"! dividuals�&U ^�[39��kstu%�� b� labow %i V �"mi�e �"�1M��y�� �3q�3cZ]�99]A& s unB ��c )a�!r!Eo� � �2�6�R�� �,�-�. Q�a�Bl#�m,�=, boon&�v5A =2F��m�S�l%'*i N�l 5uv �^  6 �)>absC5$of pre-exi�$�9boEc*R2��Q v ��2&I�%9 ềF�AT^ 2+�6�I � 6/��")CE��,.B*!�>�<�,degrey"_6�c&!#/5�� pM�!:��(,*�6"�679 5% ,6�6I� E�2�E ferr��tes!� ( Y,rec���y�%(�/oes��!_b�].O�-�%�o]–[5��[12�� $�J��s>i��8�1y&��o^&!#�F":|i�/\,-up&�4nd�7aATd)�W.v� 2:l �J��^��key��in fac��a���?�Zu !��in���We �7�:� �seS�%�to7i� in k�7ng!yKn2!H�%�bqea� mary�o KyI��^.�B�"h&=BejY��al fun ma�.�9aug} f�by M!“help to:E nd B2perhaps)["�lySrecrui%�` e :7:i�of-).6 [40ex� %�V caveat �=K<preA:�;.% . F�1,��"��� ;UjHA!te�!&�22:�<���I�of: db��*��:, �F�A( tudyq�` Zy-"�Y,�Vdd� to��T� )�� ; "� E`��]�[41!�&� durAY�r6}��  �B��V��1Y�')a�+or6�N�� a���at � riskee_��d<�.�7inclue;  damag�oc"!wF�Hee�depos)�k�16�[4őIn-7��N�1 , non-N�. ���Lb2�� � path5(y���W b@Non�5les�w� nJex!�* ossi� � sL -�YRdA�Y J�2�"G-. Secon�2�z�a I 3A�hip"A�&# "8 %z~ "�5�?m r�c �Y�ir*u. Fre @�� N"!��AB�6Q E�m!4aB;2���>��!�%�Q5*w.S&2���0)6�A�ar ��.�o=D;��by �;�AV��"�& � in 3V�(d/,B/"�"2108 )Aeh�  21f( ��1 :��E,"%" �&!+�s&ak=�*m.- ��AR�H `�IN!N and/or*kzk. O6)hA�^$�ac ��7.�M�A�},1���1��7> (6����,�-i�re ��e� >V B'2�b��e epitopYe�e:(�5in? t�de novo]�&�&-deri�4 J� �� !K@u�>ed%�B�AZdr�2&0� �� life�>[43� 4� A�in� �:�f���w o��e��Fyet-�q�� periphery�2!��tp* . Convers�C�2�I�'S }>G��IyEst.. 9e�F:)!{Accor���-�F5)zqmyg�3N^�d!�n"�2��&& �)i$� EN m�2�'�!erf�0-!�.I&2�u6Q�  a�1impai����%�� Fe��.,toy�* F�~R�whoi"Y/ol)?:FNon"“bystaY� �j-MsetE�of)�ok!�u&|�A��?a��r� y"<��T�.��&�4!F�?eO1DcWC��q�y��=G�� &pwei q�ful�lucid�� mechanismS:a� �o"� E� �uy.!y"� a�f es�?D�AA@OH� �1(�im . *R<)�} . FuC'ex�l( %4e�system! �$advantar1�*3Q6E��-)�� (�)��< 20+�f�D(�rissect|UTv �U�%�.�!3K*W �K9d���} AV_"� �$"R8� �O0be�!4�% odel"� proc�@s cS l� i&&oQ[21�Q2�X2�[3 47�t& x �7ali<+[22 Jś[3046]-[57>MJ0a4seBc�LA�k Aa exam�� mbin~H� vecto� !wel!�rF8A ?D!�h6�I�u�n� o faiBsH�Őfoc%c��%!v�ex�5!�Ygez[ �47�54�PS�E��  ma�ofq�e�U �!iOumo�`4Y13 .X. VarE� adjuaJed !�e� !, s [4)�51-E (a cold-adap9H5Nq-�ADNASs5�5I>55] �_bUMre�O%�i�&;&! a=����&��!�.�!Ci�2#}��& has)�rar����.�x"�"l6�3o�K2PAɡ9!���� .�w+plasmid%0 enco��E1!g nsenG%dnucleo�� ɨ�XJf/*�^��Ol�c9Q>@& a 2-lo�J�G JQ% healm�&Q c�#�?6� by 6�+j2Y��A��s�Jp��X?NPE\/=HA"a�A~thuA);i���dZ, st�"�%duc! �by upA�5 logs�.6�^ N"^22h"3–4FOF� �.>G ^$4�B3'�}p'�A�6])[ ,. Laddy et a�O'h�)-84A��-E.�}.4Y)cI� �C��ire"y!Et(Q" )B��a�z��(� �1:. )u#9.�9G802BG8;*�949�F�%RO)oS.�'�A�ey� �� �U{B�%–�6PSFC"�O�6:�7��o.%yA�Q.9)WseQ�}� +�Ibe du� "!fac�>inA��A+!��e Q �i�O�.e���,-�tropis"1d route��d*X0&�Q.F���~ff!t!udef�"!�J i�B6�5:inv� g*s m�)ly largon�U1�"60!y a sm��numbein-vivo=�.� � � s e�"�� ).5dMy�r�mtPus;$"N�3i@# appa�L��Sdu"} 1957&a [14]�r Z�)�!'�&"���'�[5�"�C]p.�B�錁K��e-��h)�.yR�H�$��"����i��pro� �-A�D elde�"$[2fV�V  QE��*(l�/�5`�#A�9�W 5e�7�& toxic1!>-qA�*� ��m= y [1�+Fi�,)�aA6D.� &F kivol?�37 )� "C5P g48��.r� �u�,��nd���a� >a<U�at� ��SL � .M" "�16u 1� 96pB�31l i^�s }�ma�7z�BF��>o�C�~ α-zA���LU$%LI;B orU�F�N1 �ongru� 7 r�circumt�P�4i9 !.Q1Azcl�v phyl�NV"^ !�-V� d LK��$.�Ny�%AA�O�.��e�sembl2 �"�8"m��03P4j 9HE(� ��me��e-"�X(�jl��18eve"� �)���alwR>predi��of5�9��!r� �, �=Ea�4 3IeZ!Ui�4A,2�u(%Qm�r��PI �}HSs �P&Me'O8 weekm�is typ��6� �^Q � �� �� �t)Ol�%�] �� n&�-��8jiWcoR �� A�[(it� ear �{half-!�ef!Aor��!��!�_]X�A  2 mucosa�&s'�AWyear [6�#a�E`��iMB s2�A���y�ld wan�%�� IKg �!v=Oy\1Idturm�Er�,%�*Cr@9at * �lF�dec-2>!�'! ?rtxB'rstoo�s)IiA:lA>&�!H!�f�!/ .�:� ��_"+:�-o� ob� &�N�%�f ji�j�nslatQof%���i"�!�Wlight@ A&Q3goZ+��,�� �� * �[F�����" riva�inF%� ?aQTIVa@�M12�a �^� 5e�6 y ad%;[6�L?l� tten�3YxqLA r3" v�r-&R)��ź�[66�La5�tt%�atp i�M"�a6�childreL6Nne%?%norGs�S�^ed�6w 1�)Co"4f2EQcommerc�-�M]�JI�TthQgy Jt�"l� �/[67/BD1"Y�o >"0�^u� l8q�&0l{A(�)�[���� Fe�run�&?�/:N��*%"f1��Mac���4agJG( 6.;a��Xѱ�Zsubib ���to e"� �� deat�R{c+Te��ly spreab ��*ra serSlyVel �,AYch�v(�7_ny�81-ve Qc.!)9r prop: E� $2� 6�'���.~ (!� ~A�.<p. o�)��1��!��^�%) =���h1Jѷe" � scrib f�!ga4 -atoU�A�aN�R��' inci� B�a=5� ��J�\f�Q2�i"�\�*&T.G ey t�N c.N E�z z �c�$s&[ �"� a�y�iEiFA+ k,B��m6^!C-�T-��-ba�BU~4n3 �+c� n care�[6 E� A�E��6!> �9�> � requ f n��pon�>e�!(a�[�^�!a %]� �&s2�,n ^%�o�&c&��)�*a��u0. OX >jU�mo"T�� i6te2a�b:S� or&� I�rn�-)(promi�>� a.� -dei !�)�iV�Y|y���matrixo�+s���-saf; d.�E�yBՍ;�� ica-VN ��(d_e ��,D� ed [6�.�s.DOoUsop.X)T�e. !)B��Fenh )"�2�P-mP]by !��V`&b4��r*�(of�b2.Z%��b �K� y�lr:�a( �ca`att�]of Ind?des� ."�4z$mal�fe (�<�FEQ;)"H�agS fV8 ("�age�17�  . E�2spe HuE�Ts (stock� V �1dՃ5 i�(�- wavie.(201">w�sl "V�^mpl!�schedu!��ye�*ucA�a�$�>�*�9p UnKSt� N�al�g@earch Council [69 GW�e0 R� [70]� {8rotocap���6'UnTs�of Wis�'in Grad%  School-� C�f!,Use Committe� A/:cedur� Eh.�i���* draw(ronchoalveo�_lavE )B�E7 keta)�� $/medetomidH anes. i���effort�Lm�jS!inimiz:!�!�. P&�jclu�&�Q5�h Ewscree��1$��q<@ommon MHC class I�n-a�PCRM���&g��(&-SSP )�.=Ay"' [7C!{�� �i Y0�6�e high-&� n(le Mamu-A*0�]Ai<��u?h�B� 8 A/Kawasaki/173Ac1 "�mw�ro�!$adin-Darbyj!�kidney�wDCKv ells-)� rse ge�A>QD>:9AV�cF �4 �lVv t:�ul�a�j of 9"lpfuM�via��"�& �9�=��# �� methzmHs��li!���� (tl^tmG�@5 a conjg4vae (..M A� F5tra2�F YllV��C)�C!� �Z��� dard� qu�0z��in dup^ T2�Wet d�5c*�-Q7�'�"$a.s9�-n[33�#Brief100 µlle���,�CD3 Pa� Blu�PWSP3�d9SBD Bios��(, San Jo�ECA%�CD38 FIT�1>AT-a>S0'C!sTechnqEG Vancouver�& anad��& 95 PE-Cy7�ne DX�e� Diego2�20 AF700 82H�UBioLege�1�:6A(CD8�$CP 9SK����MD8 APC�RPA-Trx��30�nGa�( om temper6��� dark� nea FACSlysE�~�!�tUQad�"�incub��1v��O�0M3 rifu�hSwaotw� EM� bŕ��!&��� let!�Q�.3POe�$1% saponinE � erme�z�3 ���Q�in�elRlB0th Ki-67 AF64QmB56�~]'>.Lz��*lg-x��! xH�`mH ��q`N!�� e fash�s2�no%fE=A�; �reaj-�fix V1%�a�aldehyd@ 15r� . Ev��colJno%BD LSRII�c!4�W� �x,FlowJo softw� ( T�>@Star Inc . , Ashl; , OR�"IY�sN(1Qw�pEDTA-1M� by Fi�-P��(PLUS ( GE H� S�) den{ u��i={!o&�'�ecoe�ELISpotek�w ( MABTECH�MLQ��H��Rf��"�mon�<�4B� manufac�,r's�P ��/ . 0×105>��L�*!]�Ie�pooA�fUC,w17-mer��2rroxtCly 18 hO�37°C!5% CO�g9< `!��,&.x� X :�v9 @ kn�v�K 0Uex�""ywP*uw �E7 diluA5to a fs��%�)�of 1 µM#. Eacht�nm��GAv��n&�0)%Qpo�94concanavalin AF �Eo'R8TA�& as)�_& $�vIJaor �!�P�(!b*j&�mS*7&���A<o�z5r5�� 2E)�&?b� � �<%�i� ��� mze�o��&>n&G:B�&�2� 5!�9%�coe"��<ari:*~a=%P'w��ytL71%� Q~�obM8�!BEI!�our~ �n�6� VA#Rw.=deT3UYif-�!�ai�W\ M5�4��5E3!�.�U)�� �- S!�)��b"VXthreeb� .�`YFA�t Z@�Xpera.�"/D1[� �={w ��in" 8!F�Wn�e &�(� e�ri?��_in&�Dw"� M��w%�tha+EplaL'i�` RPMI-16401�!F10% fe zc�x>F ( R1AbIt� !� to�#�7res=I];ezN~?��y �e_ausp5]at 2x107z/m�d aliquoa�into �2� \nzub,t 1"EdA�-�&�:A�� �1�,,:�Dxti-CD28� L293�/,6@49�C? 9F10�A02 µg brefeld�}(� halt�4Tns!0��44_ !�.)i,Uwa�V F�ZzO!GQ�D. Phorbol 12-myris] 13-ac�B�VPM� !�00 ng1�ionomyc�t �!��!(!��%…v%���ea�Ma�ɓTEYU&at��at�աDsix��. WA� 2���* �8]� Cgrv ) )AoP�i�a 25%QrKcu�nd spuJ�7�m�2x g�2�>9��FaEsp&� � .��re( �/ �pel�c !& �6ine M Tris-HC�lpH=VD=�5%(ton X-�. PN�c&� in �-0G"purch� �I�;"N\y Corp . ( New York , NY'�I� ?d�# 1��)��� !��&M� ca"�/�G>Q`�!�7 gard�?!6X\".He!�&f,v�.*��lon 2HBK �K(<*rm�zs\ �t�", WI(ape %Nv�K&�� ��YF��.'"xPBSU�Y/��!MSYtp�B �� �`�*thR+E?0A@�-2ANP�9a6"�WAYi��S����;�i � A����%� :a��� u{i9ڡÞ�\gct bo�D +%sk�,ML!�-�IgG c� G18�u45aljugF�i$orseradish�� oxid'(v&=��J�r, ") �-PgX%�nd9Qa�JR$9HN�!?e ��v�O!�%�� q Sure� TMB Micro%�Pe�34tW-( ( KPL , Gat*$sburg , MDF �Vv�x a�!e�Z hang �p��A��" �s5A1N �1Z�y*op! �^ . Ab iS�aYasu�u�50 nm'�m��d� 2�im��'BI*k a�.I G />�v� &�B8#"[8U^%M�A�E�&4&F�Qd:�a{in�m.9h� a*��� AN���� genoLkRNA [�&� Genb��]s%�J$s: FJ96951�PB�l$, GQ377049�!BEW &5<%117045H  $2 N�!,^N2$� M �} 5GN�)6u�Z �.m#u{1vyf�E�es A/�Caled�d/20/199�1CY03362���6i6�!..�696`�O&�K)R"6 �(cSafavail79�$-�.�NQ f�5C�V,)�- zoonoa*��dom<csk8c�#U ransmiI�<i� �1["2�<�Zu�'Q *febril"_.s�a= ^heTp �:_ c�;Yif�G�����izi�fals�M)u:=�f�%*K;C . bur&#i-carrEj�b� Mi%{feC�C Ln�P odiag)i�+s� a) �ac >�\�2&(s�GR&=a�&/Au�-��dm . Ne+PCRE�real-�  � <,pm�/&H#�(�A�E�  Loop-M uIs%�mal A�'i*� ( LAMa� assa�@-+y .i"30a+�Bitih. A unb'al L�%�J��de�<l �%H"�"& IS1111aAE!ihtpAB��v2���P�,rExplorer V4�ωO�( M�� �)&<+ Sk qu��H�!-ed �r'� id a�;�"�-gNG �v��9�:���2L$26lb2'A}$Rickettsia d)%�q�pUgenA�K ut�Zr>�:sY6��� A�t E�7 examQc24���b! 6afiX�A118��be}���2��am ��IF&E"|2!� essmA�N6�e "*X, 126� ���4�vRA��V�97�2��7 cattlx"yr�G, 3�Smo�1 deer\m)0)�Bi%1z�;�!�� F�Q!�]��1 copy� � >bS:�1��,%16�*E>�^6H�_�,��bacteria�s� �` w".6 of uni3�pat�4�3�}$3% ( 95%CI). 2dž3|F4%�{�!��:zg49�_2.86 ( Pi�|Si΅�&e��L��-�Yi Li�`� $Xinjiang P�3�,��Mi�)��u)*�9t-f up���of.��!�B� � fielme��3 r�;�e Chin�$jS�"�6b��d�i ��ou�M/f soph��id�-Z"��r)�g�" . ��! n*�;world� &{ �3/n��NCoxie � [�,�uprogrer m��y:rmR* roni�$2� �oblF�' !�& �>Gram-"m�u[�isYl1DZA�"'hysB?!�ch�>�_aG.5� �pE�% to nA .oci@agr�>�=.=iMl� r �8� t� ti�0& zVE T}Z/r4�0^'l�\��� sheei�dF��'4�{ dogs9r�[U--zh�+Vof>V���6�>�biu##xpo�.�s usueE- a�i�mha�: [ D&� d=��:�ɽ)�go�,ah rd��$ �ff �. Aa#D#V giv irthlD$e amniotic�(�� nt"� >E Ue�penvironm��ɿ���E.en.J soil!rdI,E� surv-%�Xa��Diode�imy -x5m5aAtd�?nhB���Җkpa�jlLIn.�u�1-��Rd� k�dualre� *� \-�� �C276+G& �um���JDTYN, 2LU�Jd ��@� warf�M�a^n Ameri� �ro`  organi�a�1 dc,|!�Ed�I>�� �i [V?2�I*!!t�Dis͐1(�~�aD"x*� T +mAS���A�bE� �� pSz�CAO�8+ٱ���� ��c�� H, C*�A��oa'�\p�!}m��%a�+8�p mort�Ty [nIIn�>��A�eilla�EF& auD�1 entu_Fd*� ~ ��SC!prHM�3���u�O>! 9 ca�:�ret* K[6dTQ;�7��st*l%Mia@��`B]O)ko.�}R!�-o>b&UM�.�, �<� �=M�"��d�6�$�:9!�_�Q� �Aco�d|�sJ+)m-i� �%!�i&�VJw*y ,&��simc>�Sic acid:I IH�=r u�R109�6R�t�^an�R.�A��d@D60A�5�!) [;AI� technique�*�  Fs�--�� a(Z�u�4A�"�� velo~ ],=@i �0qnd�+�� 6�A 61 p&K(M�� 3Bl&�p�:e ethic��8�'hem� CDC Ne~(�$-# 4 �( Nw~20110&�All�J+al9c$9�!�u���orme�V%it]�al.':!z�r?%9 ����&�4��, Beij�@, i�& l6"�:Ins���/G�t�2: of L9s�p( Pubi ��No 85-23��vi�!198� A wr �)>WtcmE"�+ww!B"n��"ns�)%i��a�m>;IiLC� �,b-U' ownq(,e��?a�k� T�/v��d4HX 42�s!�2g�Raq* e��,T�)~mfamily*�a9�1� 1�;i� by DKRaoQD .UWHO C��s!MCentr)�&]i<^�cI�Re�<a-rs�d� Fh UAnaa��gc��l� �Web+, MRK�6lovieni bMDi4gif��JS Duml<��0Johns Hopkins.�<�<of �cu:I�Ehrlich� ha�eni�A F3$obert Mass�?!7U���D��dm�ab], �sX�Om���>^ �kQ�Ranony�!���� b֡�' st I5 t�#(!�"�aJ1�O�fiRor��� et prR� ( 129O�Ts`F$IgM&r!��"�6.>s>>G- ) [9h !�re� �� ��E_%�F:_ D �� , Cy� :,CA 90630 USA�X�w ���iJ� ���r},s'�'},�&8WB�zG=.�Z�&��: #�ma�,�i{B%n� ( 38���.�&IŢ�� ƪ2.i�/g �16 �,�:ofAtch)�no�!o3:sc:���an"� illnd �$Anhui ( 22e�pdN#C(�/)�ll2%�Zhe�(9 **Z6\=�of�>L non-a� coag�Lj�la� 09)Ax�$)&�8t@��if%i]9t 444×&)1�+�Ak~ *�K !!GrV �cl e=BO&x�t R\\�QIAampMini KiʀQia�È ilde Gerũ)v'�sq� A&z�7E��!�m �a� ͪ*� �80'�$ �e aA�=�%,*� 'SF+k%� Rp,�H.� ( SYBR G�C I )&�I!Xhtp AB*et� elem�( Wtwo����:��$ χ2 ) nd FL*'s exaYg!\�L,UeO�E� ��#2�P ,of:0�%` v0 !>A�� �*�C*� Őgu�ir%�GpJe�&s:��� -Ib� 2^� �!u]in L929�,�Ze 4.`A .p&: umi�.C HL60C!� E . B� .2DH82<G/%��e���2� 2]A�A�!�ƶy "al 13�1G�� ic�a���"�� rele�f'ja��� �I� .��*�P��of��e� R,&��m�A��9<�cA�sB�9��BZS�L�U��v��och5%.h%�fNypre-s�Hby H#i&�"prokary�C(al 16S rRNA�" s [1�� P_.Ai�H !|�"�t��"�}�*�$ RSA 4�8AE0168��&!i"?# �j�"[http://�#e#. jEi��C�C� , LtD , Toky,EJapan]�] _�M>g+� 5�"al3� ng 5��ABap Bank��r Q��;)MJsyn�$�y�-gon�-���hanghai� -n�" ����V��+VreV�ZH*h!o"�;Figure�:�.�[P �^�hP)$`��N$�A AD��A!��! 1�2�<F0vd Bڷ!q"u,�|J���)Tls QP1 ( 5′-ACACGCTTCCATCAC-3′� nd QP�)*$TGAAATGGAC&CCCTT*�#A(a�2Kt�244 bpr.A\�/�D-�$pEASY-T1 v�Rm!>ClFgV T�(GO 63rJ�!�%5�� NanoPhot6([�lP*� n]$(� '0(3 �A� a� ��109� 876�410N�Z� qg10��1j10−$ ies/�1)g2[ l`AYa�*!;!)EA�i%;��IX*� �sl g/͗& � U Loop� � �f3�5] jdm=0"Y'X>6AC�Q� �FIekBIPU�,B � M'LF%LB:%�=%>(� 20 �5–�0(�5��5!� KCC8 MgSO)� ( NH[�2  $1% "�3�Ma�rAR .�L��deoxyfosA�t�v osph>D( dNT�)nd�>Bst poly� J8 UM.q�M&A�&�1��3�(ɍ elec�iho�@$o8&agaJ8g��2e;ethid�bJV\�r�vi�!��lH�JA�"Z �CE� 000X6� � �9�K�M�B�!3gen�R�* �s�'��iX2�*�t�{�{��}co�rV�] AO� � � �J�.��U.���`]��E�2:;�amu�eJ Tmv4a��NeEg1 UTaq�}Di8��U��cycW335�� a de"%�� ste�9;>a40 ��I� anne�Gga 5u 3(�exten�1at 72q@H�:.�aK��BE.`v (�\ g/mLw .G "O 4&� .a(27.�,>�,�I�3� ��"�%314aCRB ����)P�p.*� *� Bv���</B�5riO( mE���>"_/!�A=!�� wA� �1"yjA�Yj"��s/(� H :Zu!W l��100�m�~�ua�arv"�0�{�ej2� R[ oeQ2� �.� (��!.9 ͺB#5ru�M ��8:b8�m�~�r=:!�2I���l�j�  t�.1)�M�[m ��.&��i!�� a1 ��l"ruK2�. A/�� ��R$p"0[2 ���1witu*i5 m6�� �2����No9�Y%@�f"s��1�s6�2�>�-rH8*Z<�;�<a�-!�� b23D�y��-:�gn�)�*]"!6B capa�  ��*�Lrd4g�,�iA- r2�,�%A��2UrelF< i� r}�rhn*��A8�cz E.$g R%rehs{��0I�*a)�-���- u�B, c�y���-vW!ne�[mse"�J oo d�Cr�4eud! ag!=�Ap�tt�j=mb.���BSL III.8|)J� 9Hm`.�is �$4 �est)pa�.iZ�vZzfw!�k ent'�u�CHfu,Pis�?sui� s>2-beY1w/�� _�&prF�*2%���  ��'0p*62���U/@� u8Q�!�q� �!�.[>�*\7�/i�/s�SMde`f��dP}i��!�rop�z<&9]�|. '� �-b�,U쉪A�-�,f0re4.:*:�!�*~J1. SO2U�8�&&-ne"@?E�mi- ctu�U&5�!�e6'A�1�a7E�bAh̆�a�*|���"6=[1�r�|. R2�!ha�^�%f�?!~���;,� DG�enF5!n����2itYga�-pNNX�mD��r�{ , [1�qI.(� leBk@k ����� E "Qla>/�R�#O�YEa�u/ U�  61.enty-sq"Z��� r.�+�3ndC?Q�.��w�|O�,�q6�&r&C�0S�s2M|~�}ga�ti%� �%=��� �� M4�:� (� % v��� , P&>=�&L?s"� ( :g8%6:�a �  !6H(reg�ofJ +%n��Y7%)��B~�N�&96�#%F�AC"�*c�\of-"@�2�0%0BZ.�is loo<��h�xc`-�EurasRl� i�o? �D�-/$�P0Dl�� husbandry�H���#&; bree�@���6�;�Ei2�m#tP5�e�Ixo*�;�r�5$D3�i0`^A [17cfA�)� area�:)northw;%R.T��4.�=�/�D%Pf!�t7�ig'�u�gF RkItR��/B\ighboX4 MongolUkits �ܹn$Rus&wk&�>%Kazakhh &9a�*l'"�9%;e sou�~n%)dF�?-UI%.CFan"�w&"�J a2.�?�T�A "V�.!R+x�* l*.�"2~^-���A��0&�"u ] migh��u�fU>*� . Un=s sc�;K�1{rnY��uofF�in9_�}m�s�V6�>9dgra!]2+�'�=�;\ ����| A�l p4a% ..;��� heM�� Di�lwn��!�Pl�HAߍ��@n�3& en�q e r%��l>s�� 2���O�3m|�Kad6tbrOofA+75$V a��U�G��u*� *� febr�U�xempir�<�N�A������;Q�"�ae�#�~beNha_$�;�=b���R � c��6�=7G~!��!32�+is.��y�8ep"LJ�G��EB�sh��9ctP i7w-%#meM1�ra�ja�>1�Sb a� a��>�&�c.! PpB " 92:,:/ cost-&d=��&� 2�{=U�B,.G[6!&= w�"` �!�����+E+E1�i.�"E��<t�ASA .� ��<Ȇ E� �8*el:'.2zC�,�F�? disp�� �XA�profiL �Smb�8,�(H� dd+�3*�# rol =�O6b gram�ve��uw*�>ulo�1�� crip�al�"|���!(�topoiU��Qmj!]5�c-E�unc�W/}s�1o��p55[mu�o�IT �pi�w�+FE�>enric>WJɞ]��(*%OES&yT#( ESSEVg��J��ag�BW9xW�6+ H�r�Bto �!�y\)on �U�� � xirAmJ�&� �b!2&�j2Xays6��E{>�"� >e%��et�z�% �hyn1.)*�s�cE9co-���*wz;ilO�!w<1n1"���!?be�\(��Av>��v%� g���<%kr:� stem�Ndok�*�" rend�4z��\^!�of%�� 5kFur�]� ��i>�!� dow�eam! ��VEGFA� �� vvel+5aOc?��y}ng 9Y �a� �)�"b�\ �I��dx��duA#+� de�e�& work� F�2 Disru��!MT�g ular��t� a�Clj�* �*�.R  � t ���e�%�s>iv&V+F^}embryoUD�+E�ULaGa�t? )Bix� E�tissu�&� �e;>a�� E�\ ]���onvJ%ompri,w� ES��\du &TNANOGoCT�) SOX2edKLF>�%�-� �Kv�*�8x �,PRCo#m ][EZHbEED�SUZv<UMYC2a��Qges�[�6] ( "�Ain E�.6f�g2�ip� � ter-XiLʀEU2M&��.�!D L:���J�)�re-wi�Hr �KJ�2� �R��thea� , DN�I��x�eyefilaӕ�&� e=a��}Y#r�nl�#.�[DMo"&�ES)�GɐptLn6\&:�!�%�z6�s��g%��2LA�!��_a��׹�l#2M��D�qƳ��Ystart-.( TSS��[ 10�H"��=*_ �l1W%�Wb)��)Y��y{"� ā�w�wVsH�. w/Rv � z^of-R indeol*Y":or�� ,Vr��t��2�TSS�3L-�MTh*[�!N��� !�&�Xm yi8/$�ad�B�$\ba�harCS3>]d��s�*arD!myk��f �P` 3beine-4a|3K4me�7[13�,K�$&� �� jEerU.��s3�w�7.�)���L�=lX�Nq �JgB�sa��;�,A�C��zuriS�.D[1��!I�(tr�to!jѝ omot� �4eMb��i0!9O �y�]A��Q`ng�T=! !�� Z`�"C umod!PU31o{K�}(�c-l. Rw,@sibF�t��� Aj&� HP4ntirely naïve�}�.�d-sa�hR~�2A�AyJ�� scap�L��m"lay,rr��I &6pS��G��0��A pion@W6�ftR]�exic-((�Q�%���A���x9. OP����  b� ^ �an5{� ,� m��H3K27ax]d mea��an3�+�by��9"#.`�|9 !��!WvǨ�AI0� Q3Zri A�!ta�u:�!a"�U5�� [13e2g IY]^n��*�>�1Tn1!��+*�x �1 r*U/hAXAL� m*)9e�G!�>a��7��ق�w96O[2` Ǣ.k!Tr����g� �Ri~MZ� � {� �*"� Jg!dM� nigm�Hj'�yp!� ym��-E�a�)���E& �ln9tYWE��T�Y�J3f hAds��b, r�u����e � A; X"��:�9�;��&n�`%�Q)��"�.<;rto��1�rs2��+�-!���ist �2��Uev�i˖� on*��!�rSA�ioun�A|AS>�g�� ���� �)L� %� s [2��28ӆoե ee��3&� �!y>h 2�QW�wh��>��to��a�i%Af< � =�-a�6�=r%-9�.`h� �'<(&CE�1 eIL@� ��!}.C:!6� 3re.MZb�a+e�. 2�n<�wn����*� h���b *A�F6�dja�9-���tA�A�&@) �K�@W� �`�e��.�m�FMA��.RHNA2q!��]EL ���uw-�K�nn!6l&: ( HS�C -&we��TvB�qaw"�6UbaTj�aNvh�$�Av�w"�S1�y\�n�@17< 910T A�z ��CpG is 2��wJ ��)��<�$L!�� 9L ��iI2�arz�l f$2Da�( S1A�3 ��% , 22�306Ac �.� G!$.� ��9�r2��kM�V��2�� u�>! los%� u1%e�A ujus ES: ��of %�7250 O, 4�03�>6�!5S_l�!j%XinU�e��; , 38�y2QE64mH ���A�t'1�:3�h11D�_g�;�Sbn��� enc7el�i�b^FESa21!�strict��6��)@H �=a7%!uQ�s�� m�bk�ESFx;1 �@6 1�i:��as� 1�� F�&w ly able�mHSC��*6ج, *gm�CD19+�A% 2�a4f$%�7 !�385#�)1-���g �'.� ms}JS1uWWe�<�jsy -�Xal&� Ad�*~h)X�x�EFxt!6���� ���Cl�*b6��I� ��r��AZE. .!�!:��2�A�A��0F�C5.�&�ate[1�Rdճ*.��-Q� ?re�1|D �|�'�nLZng�Pir2[ 7e s 1BaCE`S1B�o6�mA8�Xy2�Io����Io %Y�Re�.8�6A�A��rsto׈"2 T�e��u=.�si� .6� 1�q��� +��%1�l�t�� � p�!j!�2KQ�B-q�5�or�e5�:5�U� Q aG25 � (%Wd_"k2an"Q'1jv�a'uŮ�~-D�M#2�>s 4m-!�� �,4ep!�Y�-|EEdCum�AH4results confir�med an association between DNA methyl �levels and enhancer chromatin states during cell differenti AT. We next explored the2dFTus of ESSEs in acute T Sleukemia\s ( Jurkat ) versus that?dnormal mature CD4+ or CD8+ K�,�M|c�,2�in2� # . Similar�ults %�obtI_f>�( S3B%�%�!�llA6 . 5%A�aAI�L hypoQed�M �6�-}QA�(ereas only d 7% becameYerZ( A�bare�E?!].:�2!J3)J29I0of�re �!�maIc:�,^�:�_7 kM� jseVX�.3e�qMoreover�is!,�+ a-�6s(was not a ma�reflec5(ir tendencya�b%c])�ES , Hn-Q� ̅�%�un=�in5did|m� t�trend�D%vS2 TableE_ Thuse�-au�j tsJa unique:�coI#:�M|, a0!s�_ie�y�C rela��to>�. The v��majorityjthY� ( 74�,J$M%de6�1���$ ≤ 50% )�ES�3iʼn. Desp��v�@l9���to!5AeIϡ�,!z foun��atI�)},Q\2�M� main�0low^�I�, j�Y:��� �BI�o� wheE\)_EP�ImV9 �Q@mon regulatory chU���.lir2o wparticu�fun�(al%c)� Utilizing�L GREAT platform [29] k scan�variousED-ontology databasea�! �!� fore!}ndQ�!�+�L( ��vicinY� 2 , 461--eCM�=J� llM͆ɡ�>vy' to a back6��� �,near 9 , 027��MV�B%�!ہ��� at �n�ME��BL %�$sis reveal��E��2�}  sign�|0antly enriche���= 3e-86i��.�(genes whose# moter Ybetb� $e polycombI] ( PcG )3 tein 3�&1 Data����({>.�.� �ar�$PRC2-targe� �$. It has b��3� at�D�� Mypr�of�$-repressed X�9�7Q�L�����A~� d� opmenX but��>�Y�[9 , 10]��stic fe� 12�i e bivalnX oF !�J�L� �,E�henceq�:[1r[A�d non- �("R �#e>�)*� = 4e-72�� @� A�>�m�MVQ�or��ll�1� �r�-�E%�A typ+ examplE�Aou� 3FZ � &� adjaca�to�- f�M9�*�q�suof>In D �.�& r��!�I��9 15 2Ky�>�v . As- abov�a largo�)�� 1� 017 )*�c .Qin�c-�R�6� 6A.� sub���>� �4�k49a�a� >l 6ESC��p<1=I24ce E � nsider �) lu:J .�,�a�!��T�m�^� �� � .+����ZA �$�Y+r S4e �� Gene� ���"�ɶ�Rm�.w)�.�ed-in-m� �" a2�pof:�g� ipgg$VEGF , WNT� nd o� e�l pathway!�a�4C%�4D , S3*�*� k roxi8to��-6� ̙�ex��o-��4 down�E #2� linag�.� a��J 6d-T(F�E–4� A�drefsuggest^�.�Ae&�  are� ly:�:\ c!�up�R-c��0. Man*�-� !�e2*� ��r6��A�at��e1��$important ��Creap� % �1���. *:d���a:� locz15f kbE+streamA}��A�A e�eAed< in-depthy��=5��� ae�of�eria�� liva(N��w��& isE�1)es �M�!Aqis ��c� U� role� �in"�M�typvinclud�a9 L docu�(ed [31–33i How� � mechanism��lyM w=�5�s� unknownXmor� 7is�a3omponmƉ�$ed network�I�1�in��ximtoN��� u!C stro�-g�Q�],��& �iM� *�$T lymphocy!��U�`AjES �ɬQaMX4F�&I� cord�5uth#�) linkmoYneg�ly cor�d � � �AQ�U,�y T�TB�bF��))erythAvu,( K56� �rm*�g$o determin.�Q�A!to�T$ transcrip����(500 bp fragA� sur�A�)cSE�?� %�cloP upy�a minň SV40AE�!,a luciferase� or� plasmi�d �fec!^to � ��terest&��TYO@d.�-�re tA���( = 2 . 4E-6 �r5An �i:��Fe�t abilm.supj �5pregard� � ir orient��EXiv"G 9!w!� 5�se-�2� �2 when!mced9�ore9�Y1���$c [elef*EA}6�al�E ��a5�We"inv!�g�h��ediE� jCo��B!.)cm�%�4at its endogen` locu�*Z2� phys� iA}��onYp��sp!!�5=a�V$long-range*� loope�:f�2k[34�9UCirs0C�os�ConTIQCapC(( 4C-seqenca�$) assay al�d mapp���N:�) A sequ�s acros�6��a�!x�. AUr� � thre ic reA���te!ued^]:�T� 4B� �%�(!ۉ[ from���!d"/ ) ; aNharbor1Ysl about 160: `A���;%0X 830b8 ����^I! a�Y��-A�ain�- alsoeain�4ngle nucleotidAmorphism��`SNPs rs9472155; rs1175584 451377  prev�lyA@s!.�cI���-w���AG���s �8binds HIF1-alph> a key �!�)�6lhumanEm�(hg19-chr6:4g040s42_ 5\1; HepG2 GSE16347; HUVEC 3908� . Of�-in addi��� }de��bed.��)�r�E�� ���!� 1QX 5’g��M�!H10 Mbn���we will�e�?-wqj��� a�6^�a� q*�I��Y�#� w�E{R1< Z appe�"c.H!in both� Z �{; IU�iai��V ? d��Z{-s2� ero"= ~"1E-14 �c� "}�*�� ѷK�D5 q>ng%U!��!p=a�two��!- �#n�u\*��A(�c� pia!�)��,D6Le?not� in)F�A-���is w p}%mtRJ )w1on depe��upo�~%t m/!raSo.5 ��W�I�� observeam�  li�> exisA|��9�F�& �2%�)��highly.�* < + ( top pan�-,�8�� r5ZM�n9*�I�{e��Q& %-%1f(W-�f'!�.� drif�A 6�]HAdD2K#aN)v:*,E)  ��5�#c�u� ( CR�!'hepatoAu�% carcinomaG HC&�>-wItc m,Sof"�6 orig��p�6$sh�!lQ�A�-s�4/ 2�onship&�.D� �8�e��*� 2*once� �)0�ent!�We6�'WnA�6�.��r !��/2r)m9A , lef0�J�> pup�L _ik!�!�VQŴspo�� 1�& &.liv�tD vel!F=T��ighinE=� righ �ma�#diE���Ba�;u]o!�,manifeA<-�%��1�# absol�1requir��.>6Y ra�7a-�-E}ed�7�$'1ch��>m sil�%g�+st!�t�*��T�,�p!M��ion�u��u{N�2 y�J_)� �F mRNA.D�%ai�)d�(Q0�Iy,Ew�=0a:2[(J�%��EIw{$E�&�> �:Hn.R1� N!6&�Aq��C�8a&!� our���)�~*[25�*!�=µ�"�.�a>t)faApoE�ż)O0!IA�A��'c�g mg�9��.J� "r � yxES=���!g"�3.�perturbE<W��!{TI�lo!msS1 1�!4>po�ia�ZQY} dividua�5disea!. vMc�� mix��~coedage&a"![Y��� �$1a��dQ<assum,�� t��a�unRL embed!mc � ,�de.5A�amiW5�!]Jby �!8OA!,� � � %vG��->��stocha�)�D� ��U~)"�z+� �)�#u��!�an En� scen�-%ԭCC�5�  I"lob7�%'�r! �a��@-�alread%4ry. �*' trucI7aU�q ���o�1ing2mod�)=� tur��6 �% E|.w. Among � �,:�9�ly C8ati� w����3iAUY�R��d�)s� �"(tudies haveo'�Z+ogrammg*�I���,A�[ H&�suc+acquisTof"rug��i�$ce pheno!�e�#r-�.��0A� s [3�36]%n R-n�`Xa�M?M���p�es�m [242pH"�! litt�)y!���"�!M��� lie *� rewiN. .76�patterD.]9�alA#t�al hista�of%zs�vides�me�!s���H9��A4:)~y"��oir.�re� o��J rst &3leE<�r��^0$very begin1�:` %� aGommit)�r^i:�I ����A .s��;%#����dB��er7g<;�qwi&?<ed-��%;Am�!%: !�AU�*�!5re�+ ly publis�#3e�a%GE*�6ac� ibl.��t/tE 2�E�ae�q�%]f �)idaO$fied by DN�!I� ersenaс2k5Y[8�Secondc e� �!� ofB&z��]� �YU!Wa&_/!���<,5&�!n�l%%n�A�orta9om Z��researa=o7� model�s�?h( [37O7%�+�%�% �is unc9!vn�9 volv-e adap<"?heBA)Z�n1( ��e�?9&G.-�n,%posIs feed�4-:X!��"#machina��w&X,-I�f� 9�4by(� �����W be a�I�� �!����� ere�0�7�2#A s do~ .�2}"� �V%��� BBauti@Y elimi= F&� )y�<noA�� J�oa�"JMB> a siG0out�8M+>~aQ�8��eP. R>��+B��ՠ a١���5]profilesI�2 E�B���A\�!9�#\"�' ope�8source�Y*�-�:�.��A�1�!v!G��&7"��N�23�"�ge�S(Ag �E�o �.�s+ al���yhua J!}%�i/�]�2� EH,�� �)��per� T:i7lid "exp"�+�a�+g�/w��osP�P*D n*�isP� � " � /;"�+C*�[`*�*�a#k�t�h����p!rBey��!�� � ntmG!li&�!��.�-A52�-�a�&>,+A[elfm\4A�"$ �RtcB{.t/:1-i�4EEL+e�al2$"J �a*_ � ]� fa novel �q���)�}y�) �'l�s�{&� O�� ,"? Z to�v2M � &�*� !�;relev%�O ADaI�")E�9�p!��&� Sj-)z5�,:q>oesE��iac{ A�pl2�>��' IF�`�M� !�n�P �o*w .� ��F.&pr] - al ep � e�[B��?ł&�+te&#Z&�sa��a�2�s����#�� n�.��#����5��!��6�i�&recogne@j�x��ͲՄ,� cis-!�n���aa�-R!K>jJ� . Be!�"uCQ �5� h �!��u� they�!c� �>%��%�!!�u@82��panJ5�ETs 8��� 1s t��6�61�2�3tA�RH.u �:<� Ms7H, 2c5S�%� i6�v� givev(� age%3��G immu �!��>���%��e$could� du . 2�&*��� help!�mwB ankropri� =Av i��(fac"�dis. �%�F���� lack��0)Lrug?CFqA�A~�t�m�2"�=H.q .�E�h J��$A��A ��{<*} �z&!U3)�A2Lw?N4g z6�a ��� �th $no�F&�Yl!ѹAW� ])mos6��7]gY 6�\F.4A�)Bt@, nam�2hAB"(��excepej9&�z(ped valle�8 DMVs�(� ) [4Jn.B�s})�&} Xion!e1.=i="�7��c �JB�� a bz�A� _� "s� M�F&�U c*MOae�( � w� p xan͌e*� �/ *���V�/ p fpat��demC+�)aySE[ �.{ etec�i� Y#�A�  LgP BEbavail�)=� ods� J��.�4� disc[ �|2E.y�.�&�ae)%~��o�ap�4q�"���ave�C(ed . Al�B���!,&1 w�(MATLAB . P-�'�un�*o� wiseՎ@re calA�![�Wilcox�G ank-sum t:;!!q�caT�1"OaDDistribuaT plo.&Nmo� d usa; kern�d�y estis2�� e�la�t�Q �Venn diaA/�%.�a� oj+ex�1%9c!F�L&"AG�I���qfA�M��.! pGL3�er �(%�#�&A CR p�:�rs 5'GTAGAAGGTACCTTGAGCAGGATAGTGGCATG and'&AGCTCC�& GCCC,AC7 TTAG � ^�+�inser!� into�%K2F�(�)@2/minP; Promega )^*F*a�Fi�MyTB�7!= af!"di�=�F%%Acc65IE SacI�o���*CpGe3:m91 �1{as>$@Mc D8(( M . SssI;Zrmo Sc����CQro���empty=� �,Z2�AZ<o&�RW)F`tog * � 30 n�renilaaV� ngY�9@. 2×10^7 GM12093h"�5t har�71Ldxa<)gr�cul]E�v-^; �%��maldehyd�� :cut %A��4ri�.$enzyme Dpn%�NE(AE�l38A��Qew�, purA;A�s�9��Zw Csp6A6 wT(�Aa5�7to�*0 a 4C library�` T [�#$e7O7 juJM:GA"� �2�y5 y�molecu+E�+"��5'CTT�� GACT��C; 5'AA��GTATCT�� TTTT���)1�7-O Illu� MiSeq S !oS�0&�S7�5335�"C8h dMb"XTr9�S83Tm �su�ful N � �k�$.�. Q�j ��=454f�LU9%a�thn�. R���A�UVI � E:u%�t�4�9pip  ol [IFor each��per.�as.N[1-kb sli�. widows9Q; �-�8&02�.��ޥ��� b�:�in5s!�.Las &{0�"oun@86�,�q�b�!!�in 1K.�n�(2�)�&a 1r9m:!-e Va� 4S-)P� u;*�$&A��Otwo-tai�Stu’s pai]t-� .o�NMCA(drives popus towar� er fitn�L�F|[ or�� teau�facilinp�  up�:QEd@landscapa/\\ep�!�,�+*�= quantW�!��!�sub�%Dtsexy�� tia�t tak�o �  �v1� �f�=o�Ug�Zi�Z�>�� R�X� �\ equ�NdemesIn��by� migr�3} "��!.�E� �N1X [�#viron� �!�Ao��a1zP geG phic&�)m �A!}opz l�eduJF<U5%ca�( �XS)�%, i �pr�*isI�"-� IH_"asI�'-Y iso2H$:h��3 fix)_a�mm-r2�to.b'ccele� �. UeMarkov!� i#,j�U�otic>"^+#!S� �$�derD >j�@ch�d:nt� -e(pu�Et�Aas !F%�ofest%B)�verify��6 �y*�'si�41WeP� p �EA sub�%!�6m%!!�a�of�GIuN!���ia�ws>r�@�R aramA���Hb&Y1fw�� ��&�P�kvar7!�g>@of�����.ki�.�� trade-off2�magni��F'�spig��width%��vU=it occu�.�%,M���o��RN,�holGIweaklWnefic ,med�&�B�8!xEC&a\�c�#>5co� �� ne��g ���Z&0s�Q��7*RFp�\�&�nf����)�;%l@ OXC.��q�neD%� !���!� . ��&�RF)du�Ke� ���z�. RZ'i&,"7SE^2�GE���,a,3� in�?c� />Y�"��fyieldYE�t�ile� �7mM��et}ntal:!1hmi��A~ign�\� ��:� [1w[2�&WhvAT�! dimen�Ba�Gof��*space m�it�alleng���robA��u�>�ei �*~�e3{.?Xacc�:ngE� %C r%� ibyi�"�  ye�`�,k–[15�Pل"B%8a� &:5+evJ3� [16K+In��r.� � n!e�r� Z?on.�I siAH���sIa�2A��7�,Wc�A�/O6 ��eG G!n neut�Ρ�del��@&.����ic!�2!h2�'.h*g z  A��E��en[A=�F(.�i�, �q�)aGll� quasi-in)j f7w ,aB����ru]�� llel�������eby.� ���6"I!yA#jnd�� �!&* sp� �3A�.�:P�G��*� �:z ( "meta&� ''�!O idea�f�,[u(S by W�6in � shif�bal%�thp �^A32]EN�]����$Wu�'sub�<��-deb�[33T4��IbP�O� >�e�: �m�>tB!>*? �sun(!m��!�eW;zea�QD.�% exti�%z)73n�>a��p�ga cru%��in-y'� a A�VenMs � oagM�6D Z� Y!�"X &z s�j��Cudy�.pn\e-^!CM��y!E�maM�ia�ferB01e�V!��u�µ�e*�'[4zRWA4o�j 4d�� Sen�d�Dqu� �3proof�{ݎ�ur?2|Y�! A��Y�6��\b"Y�� �vF(5mixed"r ,� � tO r:6--y>x[4埁�r�%[4�>It���C,q�t�nY]u?a%("_ q%��MA"U!OCZ��Z xtre�"1oA< n�� :� e.�rIb en�! Z<s12�(HIVA�;t orga�[�,�Li [46 7A.Hl20.$��� �K>96uj�o� a� ež� ,|��k!�a�!- �6EF0��lEp� Intui#,2Jor"eP F� a�fix!K�$v9�$*E�\^�n�#e"1 ]�:o"� �m�#�� �6���E$a� -iN]_�� �>aB�+leV�Fo{fst&H0"28w�"n�^:�0 Y�Vo��&Q��6(B�:�musOc!D!�~���W%WmJ�UhZ�b�"�15;a7be+l�(� .B��aJ�a��,Z�� �4� *% 6�F2Ywe� %@�I��U�U�U2�+eF�F-� ��%}�&�{:�S:G&4�4robus��1g�� real�-]Nvqs . W��U�B� ( &.4�i% ��a{YT. EachLw �Iv�V��8l�<O death #h)�fslG���'�Pi: nsem�7�x x� B �N�A�]number1*?.� "� ��#d�� .2A d� �us� �+���].s o- random exx#g��.gb�#��x!�7� at �p'��m-�,lY�=]e��� �"ikI �&.! "� R''� %@i��o�j> &� � %�&� *+ ny: &%��$-�"�9�(��/ast iL8nD �!�U:����:) �v� A� �eT+rapidly�h,Z~�B"b m�B� -�+�sM2� �^,2�qR�/ , [17319�2�0 M*&* e&Fs [18=22 =� oi@"�9s�>f�]�'�ju�a'7st5�FU �&�Xs� �w H2s'o�{$by ‘0' ,1'%�‘2' (Ir�:�u�K:�nMLA�Ha�:�4c�""-:i�desȍ�����!�/ �b�deA�rs*>R��BS!be ei� "� (E-��.�p���k&F.61�6�F�dl ��#ѱF�}d%�%�A� =��at=�5too9�`*�-Uo=s ���I,%�-vaaUu6;)"-��&<S1aH49<82�)�� t�[~*.~�]�$�Hg* ���й�1D�A�.tra/fo �."qpaer5ea?���d!8whJc:� "�@M�Vv yt�iL� l&$ st�e=�'� �3t�5�O�5!+bF%Juva�’;��  enough�HX �����š���:��+a$F�tra�"�BFz. Ax vV"ABm�Rw o�%��s,a��0$“champioj�&�)L��!h�[ F�� e�noadcue�tZ� �� s illuA��sch�w^ l(?�[B:��� �.�F���7!�"� i����}U��_��W�A7%e�f@R��|ca�i�R�h�D �6qu�-��[bE��� �V�,� "atp� %�`XMadd9*^�foL`aus�-�Y� �%�H�J"�'s#)b !�a�!4F�%���E�6" �:�&�� 2�Q��lW�Xw*&�b�r�1���%�6�Yr��mwG��e��a}/� /& ��c;�U�o(&�� A�nt�2ag��' �%-�5�1��Jf �.�:p�-�N�0$,�ce��$�bp�i�a*�5sş�� �2�5*lUdiC2\suf�!Xr]NO ߅�"�)& nutsh�,=B�r!͗���O Yv�'6�4b "S >�YA�n�.� Y�7�be�z"- a�.Ce�heI?Y I�sA�%L.� maxi�vy=2N5��E�.!�num &�$�}e%!�2�!dynamic� �-I>�s�k"It���=.�%Moa'U�ansQ 1�� �)J�$].�!�b3a Gill�|e alg`}hm [4 49 � d�x9���P1�4,�G�  . Let�5 2� nQpl!e!`��C_. 1�p a~R/lo\N|1�~ Yto�X�*I!�g��%�.�_&o� AuWKA$p5&�yu��i� gure�R�v�PEq�4�}. Not��o��)�m��-8�YwAD3�f��!�IiT#�Und�"��2.��H2 omp�T�N��%VD�yz $+um ��,*"j�@�i sM�^e*n.6�@1=�kum>� eBle : �w�:Neā�,�l;&��6 . 54��3Ѿ� s*c*�� �Ky�l!m�%�8!be�jF2�!�#:�w�=� 7��(͑Qk�w"� �X(s�C .tE9�M\��$�� 5�b�� B R�� -to-i !D!��Jti�(���by c e�!���:Svs,�"2A ���B��[MJ( soliPU�(�Vk$?� s A � �5�1 3:iE;�B�����*�Ha-ui�.�5K%?sM�t iaeW�9T:�鉦 �iZs�cdei=e�. P st?�6�by#A�%eife k�"�<^0�sa�wT.�%de1  oppo�3�+BP =&�= ��;��t6|_m�-x��igh��<o��3�;. A� a Ls�,�% ( da�+n�J�o�I ��|x� Fe�.� U1,�e-owA�e�2�m�B =!VI��@:$*k��f direc���6�&&.� |2�..�"� El, G��%_s�v!V�$>�oE!)^"�/ &�X� dBl�tek^farNZ N�+��oIk��:(aw�P ��d�#"X�/�M)"�" �=�e:*�Ÿ0e�  , 2GrJ�ot# �E�IM:��2�wr�e tunne�I�1me -*:<B.�2� �� ���:no:(0WWge] .![n��="�r �.2-hav��:��M�}%:69 �]R�e/� .�qE�e �f���5U ��� �I�)�1C–�M.eIAn *� vNeA� J�a�a��-V^:V!)AD�n�nd �E;E� š��X�g0\Tu L �i�L�p v��$B�*kB�u� ,�8� .� v4o-o&�!�)�2>�Ra4 �E����2�(urZ,. (*� %<5�l[sf,I$�"�br�M�JF_�x�6�<%in�derivW F�.2�) I)mRLXq��$���>�!�.�Q&s 2����;A�i�&�c� i$"��u���ynB��!�&2p�L;F VE�te� �Sb�9�2��^" |� �% t�g6�.�*w .Jb8E &�)mpoA�^=x J<�+.�� IP Al>> i�)%NF MNh��Y����V .�I��wH3,!be��dom�9(id�0S �1�Y1� Comb�v6uy�-H_ J#nI�16. ( 1����:4A��;ir�2a�v a^�mn-0V�7� 182K-��,�P�Q~%�To e�18a�#  (��) B�� #9Y 20e�)�� am!X&Z$d4 &� � w"� :\A�.�e�ac�\. ��P�a�Lsub&n �>�=%s�mVNy� WT��"!Znqs�y]�J2�%. H�0,����0A�hA��).�iM&�sQa��!�sp�89orF� u ��e� �N� �ac�x&�&��g�J�-��~��ng&�rai�V����v~���dR3; . Gi�PASr� �F:] S$x �ow �WdEQsh)i�1D��!�W�>b"�?8��TPis��)�*��enr`&.)iW&�go!Q*�W&la�*^(&�"D"\$B�T8%i)_%P. �J��B�.�&�b�:�a�0m(nlvE���e!^edu�� G ! E��4%�^���H"+c #16$��!>A�"!<graph�AJ�H�Okq�.Fz,Qs�=:�xZ � be6Q���. Evena�5��>�c�h`�x7al�:: 1�(:ms e 1p�.�A�s"�<�}�&�>��V�)jM!&�+�d�15VB! ?w��>,��Y� l"�isz)} �~-�Bb*�t6E"�3o��r>�YBrE�fi"4}t��hown V9'6P1�Cfy,� &E%Х�:��&m�U� Qde@e��O broa�6�mD( 7� � J%)�-�EC�w��1��1&0t+� "m (h�A>e�Jm�Trm*/�!1T�1[Q&e6ys�S�.ge�pon��)$�Fq Con!�_e� %.<�B %e&6;~b��}M�$�,ogarithm�$I�.�G.:&� �F.�B�A�r�&�E��:�%�(fS�q� %;�m�_>�6�is�#�Epreci%|(B:��i�6t� �wb�exhib�ud&)Ab C �of�d�j!,B`:��Y�F�Q�= x�1�.&C . Bu# P`&n ��:� j>= �[�� (Z_s2z�b͢2m�a. N��F�%Tq)Z�R�%�&�A�5 a(�z���%%�n��"Y���"#4�be�c�� ݥy"Jo-���& >�f!�%IO 'i ��:n� eM� nishE�#"�mA�Z� �&�&��%.�ft ,V& "N�+�9"*�"L 3C�|E a�(�v�:e�oq�6�'&�1XW!%1I��?er ր,};t�!�� FV"��#N$e�+QH6X�!cahX�"e��de�i�)�]h�if�( �!1>NH��,&�E0 Zs ���>�B("�, �E�" � �"� 3孅Qr)�ea�~�mAs�D-r�g%�����"b�e�umE�dOs�� !l66N��Qve+9X2�pas�G �Q2V*#o %U�we�i#rigorb2"�>AAB/ic � I%���)��YEYC!2#I��H>&E �� I3a�i�{be;��m�0� _ I�Dt9L!�M+m��+62aZ,clab�L�ly"� &�1;@% �TB�Bf�-$n:L �Ym 9�"� I��leH!P G*8 ~HQ��B6GC6 E�sasA�������[rj�6I� !X}="�1( &���^� jT!� &J�) \�k��N�� arguC#_�H�'A�c�K �!-f���E�F :ex- A� I���"�$Aij4A� u�%rI�].��r� �ad5icɑ)&P �"�g��|Jc�Aste�b� a e�a6�G"�Hamw�-*�}cb�Lge_ tell�f7�'&�9�Eysu&<5-�j�*o- �&� �%!�� |EQL ���k]9�Mit;�W��e��4q.{ � A�4 �(�eW$�a� ��6u� Az!BC!6 3*�;-\"0-!/aQ:rrobo!S%Ia�.b �m4�.B!�(sch�,h�holiq�,�k&#yn/,xV�41is [5âIn�!q a" �e� :���m���S����a���B�I�q>4dH0aOzH�:<��;F�8��,cho}�*Iit�!Bi�@e�R lic�FRFG �*�Nb0Y&bb߫��G�0m*di.��A��}�� [2 E� �5 H%ll9W� �l(H�9�[-�� �#X196-A%ɩ�oft"H vs[&�o�, [51@�Q�a���G%~�.u=� aF7!9F )�� *, � Ij�S�.�L��ot.u!��J�V=F ��NJ��" $��'v-s�;� �-a�a nP�s5~46i�{`0)�9�p�Iu��� ��A#�b*N&�/2LE�uM�'?%NE>auŹ!+%/st3!�/2.�6�s�6� H6� �5��*� �� ?� pBH"��*�"��e+ sR�^"� � |?9�nY�|fO�y����(�X�b�hG9ul..0)r�:m23�p>>�&m&0tBru(� of��. ).�/�aa1хi�>��Es�d18A�5�.�=�2KsI�L{EV�O"� ��(+m�5��scaa5(E\/ �/a2,�.� o� �t�1~u�P!��O, �eU�Jzr?JondL�zY�0gl7��&%C2~ �I:�v",� &�g.��su9.�/we�� R=� � dard B�!�*� . O�K@�Eӊ:u'N�h8�� �2 viru�0as-L,U81d=p>�Sl1J�8ho(�=ҩ*�3e)\�Ks @tXI]$� d��� Q-�[P%/a ��&�Ff��k/E�U'm"7�ѥnA�E�����–:DI)�aa�B�&T�%e~a�!�0 ���I�a]�e�&(� ��is�U�w6&�2�� F8s[��K#�<)Q �.>�{�0%are�j�gA 25�23�isek��Ny� ing; 5e&!����̱B�*4t {� "���9����I��u%�)C�1�"�M�G�P����!��M&E:� �Xb9�>� �rem�%un�Gf �$M CR e�2 �D.D � n� "!X��a�M*46��6Fpa$�fH�+*7�"kljxRAK� F�YA"�R-r!L]01��l�V �j.�>s�4�2]@Avhіx quiteu��thoSB�� %�aI"�. x.2)�s�;"%�*MC���J"Sb]�6�/��]�2� ����@劉� �� -���Fur�e�_� ic ,%�-=�F����H`j/.=!�upha[:�%�*�0�pip2A&�a4:� “sh�\s''"8T�|!�>n �a�n v� M2�led+.h%�]�� �-5� ��R�e����erT�\�Ɓout�7p scop�2%p�Ei�#5 l\ o.ad{a�d.Iin&5=,�UF�!��7s�AzeK��2oV&P*�QM� ��323.[[V�Ab�!�5���DU�AqQ��  vg]fing?1&G��.�-ed�""NgA��-o'�V���$�d ��!�J�� a��2a��  e?J ne&�]:�� 4�zB��"w.v� ; �A��"�&� m�-`IE�me�=�^�D$ �� " YR��-Ei!%3T>T!0.�:-�&<�%<1�@"T�4:i!!��z 6O2q+6)$� �A.�e4[�FZ Y'� L � �����eX� �q*/j6)ess�x! ݓA9 �.�=�� �s�ji�.5��j� �>l�OJng fu�p� RbA���i>�a�&�Z � �y:��lc��}&��y� �g�k�.�Q$8 �j in�qi��n)�&�%�:�E��R" �u�O �}?G �;�ob&6 6��$!!impac%�"zgV�jA!�. zlN�15,�*e:Bl!��&r7bI�op�.=�8^-Z&59Y[52�!GterF"t6a!�.���fX^( v~g/exace-�ed"te��O,�-1"%��<. !!.KF ��Ce�w�Y!N��C!� guaga�y[� �=�&OD��!��NQM=�B ���T;DimqE situ< B�E�9�.�, �~ev�a�$׸A� capaY–we[��cho;�$% ?!�oR@� � �-i 5E� ) |y<� "�Njn �3"P�F a�=>�.i({W�'ow �eB�5%�c �60�*�  �wN�O���[���7.b�O�styL(�3{$�l �"��2qH!��!"���D�s(a��') L-��RX �%W6j1ea�Wpl �� [5a�� prob�e�z.�F~�a> �^�� le�iȥeSLt"W��m8hveA�&�{���S�g�^�mT.�EI'��>(` ��a�9 0!"2e�e�-�.���S.i . By& �����"�o/c� a�6�N�B�! �P�2��E) :f5!%�M �� ly �)غ�,n@"��Xs&gV� iU5�U�iEq���#;D�y �&�Z��!�>^F2nF�F>x:A�-5�I�l�Q�� 2EAxna �~9w�*�X*nz� �Z, �e� 2�B��n@a!^-"a l�o.^�r' AE2 )*�8�/2�122�"� (�) w!wu� 22 . ��|!<YZ%A��.^�u� ��1!��2�Q�KI&!q*�V�_t%�)./2/*�7�g��ED"�9�"J ��)M{e��!a  1"� � �A����K �)�t�x��m��b�,!�W")�1!J"�( 2�0l(�2  �2�|%�A��%w�8y����SritF�� ��1�6I6� &c� |�GZDK *Z6u �f�AF6{o���%!�&�K%�} .r� �d�A5�vJv$�M>M^?�Pnegligޖ@!F�&���V��q pu(� ��+st)��^.� 0Q�b��� U �e cuP��=� i��BI.�%hE�tK�gM%�#{�M� &v �$�-Q�!f�23��1a�toI�A>�eS2�!��  j�?f:RY�-e� .? T;-�"�)N� $ )Xe�2�)8u�L� �,��q>&�&�A9t"u@!<.0�wiυ�byC,p r%� �x� ��d�$A+i�.XZ1^�W ,0�j.,0'��,�.�5"$�����h56�E�DXJ�[�2��&urj�"5in�i~q� !E���$>Q� iI" � .��.*���A�����C<E. ,.�s�j.306e*&)u.�7���e�H��wr�BI� �q�"[E� e� �za��N[2���ě`FR!.# ��Dh.��$u`D&�U�*L i�)'A� i`[a��2��Fw4"��,o��".� Iw�umqn&m��-�j,6�!���*":�cV�8�B<�* .h'�.-�&j"�f&Ѿ� Q epak� ex.�n�q.}f-� �-a ����PQ & ��fhe,=>A����� n (Zs/��fca�)��r�0F_� "�*c �|� r��B� � �*b�]A(.,��C�e&97)�F� ds BY�e �+'~�~ ; �} �2&_ � til"f��.�"� a|�"~�y �y"�%e� !�.�fs�9"P )��B� *� Q�{v86E�>�>b��1cri~5a i; 7 A*I �^="< ����  ) 0# �ofFD �r�*/5��e� 23� �zKY�NnRV� �VB|��%N>B� 0��2� M�.�-�B�!rR�iA��H���iF�� &�Lin{a�AleI�nIl:�)g5� &� .a�2 :%�E�� 6�~9� !�pj-"KIh1�f%���,( 4��!x�,%;Q(:�Q2!'f��*lu9u.2�iT~^� � >w�8s�?f�);��-:��Z���=G&h�8(AgrR"2'�b'M &��;>gby�i� �ABN �V"aA�~��)ica7��Šf�|�r6d K#�=I�I"9&�N�!YD��s� ��n�E�A��x�) � � �& ����k�35Ae��6a}e��2).Q �*>�C3 M��yf��o"�gR�A�e�ly}���T���!�47O48 )%�*R��ect2>Cb�*V�(�4-P1zn"�t&�N!A8'B+���W8�+� A@�+Fe5Rl8nfi  �.!IZ.i8�W� scri���wmprehen�p�u� dgut9"bo��of AeO�aegypt�8���mos�%oהE�rbo>�/dengu� Zik��(chikungunya� ye�4f�-"30. T��mis/ �thH]��B��in������dissem�O-�S�>�!�e1ic6�ra�� wbi�R"�k�"\G�f� J6��envelo�,��# �A}$_v�q/=A;���� cell�m��aR !�Q"r V��!_hY�6$bol��� te"�"� %�-dion^���<2!��d&Ňa'vi>�in��!�5~�"L�u we�O!�I�i"jgtRZ��S��U���lTA!cin:�H{#'-re_�)mgA�$t��t��'ea�m�te�Aߴ%cc} ��)�&Gfm;:s!�Tmi�IvE��0D "v#��i�!er2O�Ie� s$�icra�Ain%9�q�D1f�Ie �=J�*e�pi-ګ��#�-L id�B -��v�@�' >��a,��)�1%lipid9 �W.:S#4glycerophospho-Esphing�(fatty acyls�ncoinc�qe kinl\ ����-߭�ep� lium���H&�� b6��PG�qin hour�F�mFr6u�ˤFI2O peaki$at 7–8 d^�post-}( pbm ����W� . Su���yR*_  < �9/s� ��WAy/fat bod� sali�m g���A"R �Q10–14 �bmB>5"8-��fn] E�M�eT-B Ha a�T8�YI| 5�=@�z 1s�%fulji%�a�(;"� grea!]��!��(t��p�e e{rl�v�+�1`� loq.!"®*[}� A� zG�H� !% ��8a�.Q+#i`c�� �g��N[!�� g� W!0����[3–CHA��d*� 8 incorp�E4a p�R ����+ capsi��K��B !��p� clesٸ�*c �J�Bpf"��s-&� 幉7" �by bud���!��"���3um�re-enh ,new-Y�A fu0 %�-�E ���Y*��[]�<,3�� \m��� .�S1����arI�1Ŵq!�v arcY��SI�%�)A?[���1.�1�+Va*c mb� 9lZ*�F��p`�65%2bA��0m,C #�%n��uj%��5�idefensZ ; ?e�e ��P!2�*�in�� Ճ�:#A�:�8��r�of CulexF�S��w�(W>-Nf) [1߾E��,a!�20 reƋiz��b�.�� c c;u 9��A-���t*�dbio*� � s�e�tra������4a\� �E�y���"� ;9� cM&93e2� !N[ homeosta in C6/365cE�A`�A/Y�%rE�[5e2We.\��N�ck=�6G�st��,�me� curvk5� y�"�4bio3Mve n*�� � =���h{@�pE, iArͿ`": a7�Y]-&Oat�+!����=� id� ( FASw �:�in} .� !-I�!�� �e��.z��.�M %�.���cb�[��6ACol�#�se�Qd"��ͭ-Ti� �.AI �9���9z��"8Alw>O� s�K�&�� �inU�� ^�ala��Tyj�e�i��"(�Aȕ�.A�a"F�!~6���at58p7D�"4!���y�Z$��*�=��e%l��� .",;$to%�-�>a�& s .8�i)A=���3u���q�#�al!9:�ac �u�8 ���y�)9�1nd��e��?R�6�(8 F�)%�� ��N WaN��W� ��}8g� fl�T�t%p��,that functio�n as membrane building blocks , bioactive messenger�energy storage molecules and intermediates in lipidKsynthesi (lipolyTpathways . Presumably +�Le changes represent both manipulation of cellular resources for viral replica,as well the .84ponse to infec.$. They mayYXult from either de novo6�or YonsumpF /conversi �metaboli!. Addi%f-�L, Ae . aegypti ChetuA�strainU2e�� re fed anWus��oa7al% ain!=}type 2KDJamaica-1409 ( JAM ; BLtiter 1x107 PFU/mL )�ˁ�sed�a non�6{aseg� �!�$( S1 Fig )a�%M �dissecE�O!:1ves on d�3 , 7%b11 pbm��earlyaval5! Nn (I( 3 ) , highBu��ity5� 4 with ]�minE=!�4salivary gland��day 7dArh>=1o�Ltissu!�e� be�cleared�y� � �11%^Imm�q�f!����$, individu���-�t��de^E3��,( |log2 foldA,nge| ) ≥ 1�p-�(e < 0 . 05;9�936�y � ied usAHLIPID MAPS , HMDB ,XMetli�~. Approx��a039��![6� 1it} ( 36UYz���to� �cy��< 6 parAer mill��(( ppm ) ( T8)S1  About 93�e� d��41Q��Drecog���xbiսrelevE=)�YXa���i�!(>Aee��Alp�0B#�J�H8glycerophosphola�GPa�, sphingS  70L 0�a� fatty acy -carnitine� pren, m keti��(, amino aci�pep �� organ2v3�ls=,T A �OL�ai�R!iabobFar�es� !exc�@!�Dnucleo��, stea. All � ncl��6ategor_4 -[�vIdD r}h%��� lass�$system [17� o1lo% . .g> ��F��2 �, w�Jmp �Y��ertoir"r� Vš� !4rA. A summ� � atai���#�2%5u� . Of�;�1)� ed ,6�( 15% )i��h|�2in�F�!w �oR�in�� least one.�� 2A�2"� 0 Venn diagram�8e numb�of�Har��f�%� V���adjus!&> ) upo)=�� s ��1 i�&q f U7�� un��Lt m�p��.AbN-Among�5�%N leve�q 274 , 283%k1141AGS i��:�� � �or�,6, whe6 98�_A ll 3�iE�I I8 Bn:͆�'�� ��ofE�)) Z�%v���| through u thre�t.���ANputHHc�k���� into�.��J� re3 shipa@ v� 8� mapp� %>CR �n -CoA��9 &�� ��� curs� at4mod)��incorpo� 5$ �C�lex ��{ ��6U>M,'�� �?� ���h�,�S.�degrad�-�β-oxid%�A�nL�� e$i� l�endAK��arqRt%#h8 dRis��M)�D�� majoD���*M<un[ ( ha%kensv ��)re le� han 2-� ���6 or p��� �whsa:��׍g�e%]i�x��M�� s �:%��DEMլ,uA!�abl � 61q�� }�~17��de��H|Z�. UZ�: I es� �a l,�r ( ~61q�z*�%/�K.g��e$�B:?2\�� ,61A:�� 2C.�!�M ��9%���eJ 3a�n�A}a&�%&� s>�eUs.Hax  a pot:a�sourc��t�AUlightq�.��t"t&i�W�.A*��BtFm ref� �Zo�!H�un�to Dip� , *�or Ae� ^� E[a�yet6b�noN4 Giyheir #�o%ѝ �sh�&�MfuR�po.'Hc�� �W ��� � nent�"��.1%�ofE�Yh �,� ate !�two����inW�%8f1�� Pk ��= influ�fluid�`,� k� � nutrirex��� ssem��fun�of �al�protein�lexo vesicu� traf�[18–20I�Rlx��GP@��s� af49 ler*�han�*� ss [22 Pat�icA|$endosymbioiYi�dr&Z� �in�e� n%i5j2reg*!��CH�[! 23!{A�Er!drelI�u�c��!�T�d"' ofU���!l�3A\ur study.�565IT( >in6N �87/e����唽jA�� "�l�capa�d disN!, ��eZ�B%|3 Mi[ enrich�EGP�A� can�_""� �,ѷA�i�al es|isYv�"&v�[)"��3� T��*a;a�� enhA��dW2\%8� �%;6 coinc� � knownB�dynamicm peak �!n6�- � �V.o� 6![ �a!=- by�C )+�ig�=�� , PI�EE<�di�#e1OC ) clos5 follby PG;�t��surfacF#X pr� �� ardiw y mitochond~"u%�iPC[PE FPSwhiz#re pri���� �c�)y�܅`&l" YHe��B!�%�of-�.�h7E��>� M�� !NmTlyso-�short�T%��&a B�.��clu�mono-a1i-Etri�� B MAG , DAG!TAG� !=cri�e��o)�e�&�smA�i�(AhmammaJ%� ) bsorc a digybl"�!{#y�&�#& 2sugar m�!�&t� gą� ';- fa 'dy� ��'ne o�� ' tell6�' [27–31]M�4%��ls�Y��#d !-�� �s�q , 32]%<a9use:$&<( ѭngE��� life��,aRviv�6/ phys�%'gen�� r$!�apoptoI[3234�SeC$y���sL�؅�� in oծ,&iei& 2�N�P�F*� œyi.��$�oF�m=e� U(O&�". i�jq�b>)��m�� ^�(a�@&AV��� ��QS���up5�dem!Ab 6 �9[3}3x>>!%}cytidi&� ( CDP-A�( 37:�""} L vP�����%C:�!��cA����2�)V3#C re%L���edM�){.5!�.:2e�:� ��!�.+��*�+H� play y�r�)A8!*structu�"�^&� JZ!�numer�% -a� �+%��x�icrob�'��2�6��40a�D�(voa�of�o@$�U plasmice� umYohׁuensU�L-serin pal�[y��* m ceramid(Cer ) via sH!_&.�,[41 , 4� ,J5�bi*�,� M!i��s�myelin�M )%K�� osyl�s��produ"$ ťndPsq 5�+ hydru-[4 45!z+ SP%�way haenE�*��mC� �T!��&ia�[37�oP,A*s [5]2 a�%�z"a � eb &�*2�I" T , !k��!V�l�i)�nd+� ex ���wMZ e1.�!n��i�sSPJ��2�)�0.ŋAM� e�Ia!t��b �"2�p�(A�*�:�� . We&� �mE�2Q�!N6�anaHe-1-PCEu ,e}hex.�����b�� ��) /&%. GP-C!I,.� PE��6Xanaloge)� y&gaa&j ncipa.� B���rosophilj&la)-6l v$[4��� b/� � e�.& &Jof ���,32:2 ( 2OH )r0�(bu2" �An�k%�))[32[,.6�q:3�!�K62K)�J�>6<�"�/2P�U1Cell�- culvqy S2–S4�> ;2!'����� ��E�� � nm^�a�n�!!^.� [+. Gly��(��(B�:. sulf�)���U��mode�P us"�R>, �1!8hj%: proc�3`ys2� &b (, autophagyd�cy~ 4 h.�$�� neut���)neZ , FMC-6A� 40:1Aa-M�,E&�on�%��Hex�( :91;AM2=3�!:�Q: >rwe2�6��(!�&) �y�XJ~F6'.�3�2.�� -ZS����� rmi`"by �A��DH!1to��� cex� �Y��2 bal}b9H!� Rcon HasE�f2�Av"� y*lZ5�ngAt�!`�x�0�6archi�$�.,&\�"1[48�";!�n"-ige�if)����or ŭ"Ua� Cer/ �0�anNA�:?�.�-)5 ed ( Aag2`��d ��readi�menAo los��� !$. C�����(edI�4-� xyphenyti�� 4HPR )�l� dou&&t2n�0 ( ds)A(inhibit&21of=knock de&��Ii� Δ-4�*�$�( DEG�'V�4�Base: AAEL013047 , NCBI:LOC5577178 �1!�enzymBcat�+(-U�of-�2�final�pA}I�>� A �,Mus�z�lW0�N>#[49A�%e  �r!�oid �2�/�}� 2  pri�o �!,��-��Xv!!l[50�6�S&�6 re*J a4a12Em'ed��E�E��atJ(�!toxK2(( S2A�2CᤥzWe val^ �2K&impacSvon>Io*�! multipl�!o� nitor�p ( MRl ./MSj !N!�(( d18:1/16:[1� 8J24:�IP.C2_ !h�d G0/ G�e��0�9j!<D%6, ��. Howm��ir2� did�ŖQz.��SVup�*�Nf&�p�&of�Bch�6���;�7���16�)bonkbo�)EPv�$S2E�tWe��se&<i5��-<)i �� -P � !�or SM�bq� is���-< ��a�a0ducT&��T A��t!�%�!�F%9S2G5 Q �!v)3'r� A�L64vmb�!><a directJSe!�6�Ud 5off � 7&# RO��*F bcl-�p53 m�@�A &D [5�A %4�R�"�mad3m>j�� . To�'�S!X2��.! cau��2�^*�Jr=im��!U9-)�5m#��om�. ���i���ly�_S&�aby��&������ɾ6B–6EeBIX)GS NK�-KD��_,)'��6� %i�"�+�4GFP>( j"3.� Ide�Q @%�� B�v,n�+�%�6���8��-��M �.�GF� reveal�#tri�!�eaofA�81��,:�20�TA-6�22 �9�-�i�6���panel-�ter*I%:�����0>������8-���EIV�2et�&Ev�98�yB" length�N!z 4�F��d�C8��d*١\e6�@a� Cer-)hq�%�O-BADN�!�*i��for/7.�ex��we��†d i 2�3�Whea�N*n&�*�..c-U�AE4�u!i%M*L,���BU��!�&�:#!��(@  �)� 0q# )2#�b���"-#R6a�O F9 ( S4 /S4B%:.. In��j,*'��NXj���?y~N�i������fh4C%�S4e �r3��9j;"�?0!�!�?p�&66 L> EW[ l ca@ *� *w![2A5��K} covale�Clin�_�%o�  A >�,� �F�-aJ�z & GP66�>�5ar�+m " In aF�-/�Y�or!�X��o "*al �'s��2�e����,H homeosta��a�immunG �<se~in['#� ���<g . :�Y�"eicosa�[5�5�I�}*�at3((st nine sub�/ofW%���OB �n�se�o6F-�24I�Nk4�v3�% ( S5�a�"�-a7� ��T�-�)',�xy%�, B ,2Nqleuko[)� i .%�%�o*#Ps-7'7�7�orboxylic#7�keto-: .�7 ws�AW&�/dA�&�I5�aU2�4&� !���GdI��&E�2���u7�!*N-A>-rm7"�1srAse6;�marke malv.� id o"1 y�'PraUg�(in�%=�\1mboxa!��lipox+a�.=u� �(in�?�&�E}sF>*N tory �#or=��% been�to�"JK �)ux[V��.p6(6 a?.$ d!PGD2-di�ropany!�nea�=ETe/ dinor-TXB�*��!M�dp JhX=� (2eh#Y�VG. Anti0="�!(� olv�<5�epoxy-DHA�y=V\[5�>5zM*I1�inolem�I7�Jt�]�UN�� HEPEe=pOTrE�TriHOMXx �N[5�2jpZ�"Aannabi��;ɒ`:e��aA haveI�2�re�� 311�MA�� Z9|� &�[5�E(=KMBt15�aN% ���*AGm"�of human���,�n20dis*C s [6#I6�&"3�f=c�(���0N-arachidonoy8)a1, myrist2N-><roylargLJ�N-deca6<!� N-un>�:':Z / hept2HdisA!�}@%r!L�V�2ZOn<��*p�D-+-�.� "fi�Qq2� �"��-��� � �] �2�K ��3B1��w a�EupMU�$� �:�$=cm*L,� 2�7!nsubsequf1�* ( AT*;$.�A "�F54:�]W�uuM�-m�{om F<-}:P , 26:`s� ae�3�^d9���'���5�w% ס:.Bl e���eA��i.�) , 25$726�� D$edium8in-�=��4–12� �  .m#�>gwL ]W� �s(��to�a�>�)� mplete6[6qS;AYP ��# �cyc� F�@� Z417� atoms arrF a� A�ur-\� A I�", ,2LRS ^i�*�S& !�.�)%�e ecdysEorm\R6�!6U H" � �&6 2�}h must�b i�S diet2@T7� �$�(flora �1�6�#D� gv �KA&��&8': .�Q4elopem�4!�"� �v)2��!fu�[66�ItWű�  kat*r'Qan�'_U �4.T. C)aciliE7Ng[6�R9����!�.Vin�A��&!5-m�'?Q(!�Ё�� a� t��,�7 %111�P�}�. �TIa>�S�or"� fI� . Si&8W=>�eec=d��>H( 4iA�s�s rais� /cr��$, sheep’�Qa"�$�5� *�exI1e � �s2�"�!nt�  a�4Ł/a,KA.�B!�!C& �.AO��@�ǥ��di:�a@��� 6@wenty-a�y�� Y��>�=�+f�5�2B5D�6� I�v�X�,��&'10X�+_$7�C42o?lyź�16� ���(�)v14 K � �st�n�� ��+!��dr)aP1P1�>�52kin� %��]r*fQ� [�YD 3 ]C� �2,��!����"in ~48 h1U�t-i!gA,E� prov�R?�v��.�G&J siBd��:�-macro1}s [�C7�,:!a�req�FF3( yolko4Ir ;1[29�T6–7��>���NMpi�RH !qG�:�9*dPatMsAbw F�rPN�ts�56�. We-it%�uhYunZif6*#ala� �ZŒ�n burs� .�!�q�`onsis� �-_9"�W�.n inC ��1.��Q% �:�x SpeceR��in�A[ssE expan�5ofh ra�\Q)&� �Y`b�,pet�cA4 �damage7 , 8��dPs/��"a$.� ��)al.����*�o�d&�c�!� 9&� a[�� b?P.�"�.I�w.M6e�AuT|q�m�(.electT!!?"1�A�a �#�sA��!%B�.:�a2JaP}�"yCtL-(" �'��d% ).��09 dA�\eaS2� ���De A�� �`l�=���c� F hubR Gn�(]m��C6/36-�lb� tusA_e�-���Ij"edM5�SM1ZA%��� . An�2`2!j�ђ�FtL/fa>'.M����m6cUs*�$� J�')I�)uT�S�sqJ2 &� �1ct�f��1��!w� ;+a'�"E:�aa focQ3- )�eN� ,�[��Aktepe e" al .|@.� �m�e�%�2 a�E��6�A��s [��TUR^K�N�!�J�cRF! s fur�&z3aV�QeL=in��wI�A�!�i�6$�jN� �,�or&^=�.�.2l69�.H ( FAQ�" �cyt��Ye�@BE"xX�N@ yl.E%�>t�s�d2!T6�matrix� Q V%K[89?8E ><#6�te �hcc"�;a�0Ne-A��&>��:*(i�N�f�ByA�:��dTv�=b�9� �MatFFU�1�,%w� 68A�*\F��I&�Ms6G6r�9�?'� }a3of6�( a� �� �c <AO3 �!��6� eeds.7Q ��I�wo�hypa�� t�Y�1A�ZR�,:�s�O�ɹS�1)*mt is I:�6Ns�be*�/.r� ckagE(2,m�.zuiX}tofC�I�%is � omenon�� �i"�3*Mi� 5"BN91–9F -��FQ��:C"f �6;w)`ed HepG2 �iN�J� �V�l>P�^)E�� T"=[9-T*�c��.$"Y(o�sc:�towar�I�!} gluc�uptakO!�&4p[9Bi_ �(�B�!,|#{3�!%0 [95� D�2A� stal>06q�1�af_,�R�K `0 �mayV!b) .)a���X0 J��K expe�)*2)2k"[9Y%9�G9�A- �j� �FE�Ha�e����G:6G9J be�3�6�overloa/;yY10Iii��cen�L)�M5� nerg� �H�oi �QS�"�$!�of5zek12�c�N%�Vbroken;by6W�; h�A%o�!Xo��� ���6J��u�"skele}RmusclY sulin�Eist���pa�ŀ[4F1:�� u;S�$A�Q lPp�Y%R�4�P IE��Uvi�� acet�"( 2 �7 3ts4�Lrem Kx&� of newZ2er�Q�*F�6� �/sQ\��q�� on [E�9�zM���J)Heaton� � d� �;]@�uh7 . 5�@lAP�F!�e1iW5�.��>Aos�zA!Oa�o|dro5i�TAG�2�F,�a �iBn 2�2�[7�E"�#�Ncha r� how 6Budse��� benefiJ` �f� @still�[�n¡|);R �e,s�G4)�firqsS8 %{ � .M:s= "� .� )A�md"lQ� i7�j�="I<)�N*4, %��m�?e�D�#p�4p�Vjh9f�&A��� �29e�:*A��8st�I�.,��AS5�A� s [4��-i�I�x6[-mA��d�)y-�h" [939%6�6PBe1%� Wolb�(�GA:L*tW�b�uum&a ���.�, A;�W%�9�M�op�8e��ax>r:�/Tug:R! <ng^sfo�x �;%�ub���!��nt [7M Re�e>ain94& m"I0(a2x� d.��y!�a�"�Xpie���sM�:�!��'E@'Kac&?5X-g1�%_re@T�S.� �en%�l� R��[�' 100]�m7(z+#�s�]��*#�5Dbiota)�����z!M�"�2Uҥ2U,( "�^a�.�“�-� ”&�verteb��.�� m� .Cun-�l�L�Wuy/.��&)&�� � �n).g� �Wa]�2&�(� a�����L=���emp�K w!i%hjB �w� 9~!�eIB`D >,���1x+mHtitut)3!�� ( y �uALol2(.R͈��I�� 5 |c�c  hund�&.a&aw��#>'th��!!�A�b� d2 �VvsD B��ia{� *�*I�n)�p@2�e�- *%�o*#�arem�++�a�j�8v�!�!��ob�v nex�0epA!ј.e?�&�x�.h0(c$�R%u ��S"�nlZ>O6� � �,1�2E�dF�6s N�GP!�-�:�(RA7�!�R���%o�_*�isC!O!�vpN$%9se&�,� :" re-ly�6hX�� alC.�by �n�u�V� �)NS�!� anti�Qp��I[��w�. Accor�\G#we sawc &+��� �;>J I��!"��% 4!/n�]>%� %9�_ �#� hepatom�Pd2 �9���i�v� L "#:!sB I2� (:i*|,�>.+PG/PIolv�'�M{y!.�HNoIUNi�5]fo?%.G� :�NVSG� � SlyvC in eukaryA _i&J)F�*aldg�IlafE[9vo,"��f hJ1w%4� E xrc��'P2z��evv]st�".n2�D#1f% like."I�EZy�J�e/eM��!�o�[��:$�JA`amA��PV pw smA\w(�#&,&�!�} 6Xi�SMA�re�- ; 6O��`BA��iA�&� % u�B�eD.����36 Lra�GH�Hv4���a few%!|BG&/ A� .�Q�A2�J�H�l��E��!�!x"=%O� A^s�� RNAi�!ctL�*E%�g�D%%E>�hsQ�an!<��y�} a bay.&2��'t�5?�"��}kee�)�'Q-�8 C�lyI!�l P6�Ru80xY�9�A cave�+D �1A�arYqae)�1�� � A/e�{ �!�6�<�is�or��� �}uaccou�inn6~.tf!�v �.�.�ex5qaS�&I[,� a lina�ri ; �&�larvae�= % -o 0~�E!M de�?au��E�>�_[10"2u� �i��F� g��yo��per��H���0� �95/g!XI�( CFAV�j0�hm%ѡ�tu���:� ad"<female6�#�� -esBr| m\� Au�Y!&b�g"�Y/Ant�uF.�n} j�A��N&Y|e8�4�`M� x!a 1BA+�"  of dengu�Zik(chikungunya�y iw fa+)Wń� :.�����A/qu\Ggvj kG � outc �ZG%�-�u2�e*L;(� ";�E:��G�IH�.EAy�;�>�:�e%����uj�q}s�n���r*,8)�Mc-5�;;� ��.��Ra{ ly sus hG�/in��]bor�F -ada�4)J��� l/����*�%�!cL$.ice�opQ�l*7+.��/ �X&16succ_ ful 6�naOulV7 mN�..�&M�a9^�c89�I2>�e,�o� *i%Bpai�N%$� .�%���`]�ic2�D+�$w�1l�a\yrob*���F/c �7ay��ok/6�brd(��s�!tl.�hb>ield set �I� m=Y�0ls��[����N�� co��5�)�7� ��me' t� .�M�3� b�mof:���Z��h�nd2&�""E�j ��r*�t&E3�"�2t� "t|! ��uo#y�a��g�k�ean���~�Jq��_-��Z}�se�t!�te2W�1�6�[] impl� �f. �& serotype->U� :U��la�;D+a��!�Ce��6D�� Co�>!PD86��l�V, t Co�&AiCO , USA��"em`vp5�gU.: (4U< L15z+ �y 3% fa$ bovi|O erum ( FB1, 50 μg"�penic�n-� ptomyci+�,2 mM L-gluta�-byq�[)c�S\8]!ic��;q� ( MO&ofl}1 resh����a�$ at 7="T>G. At 1D14R!,)D.�, supe'�҉�ed �e &~��4���� -2*�.6z ͹"���origi�col"3QC,Yucatan Peni�%�MexicoA �!A� �^��8�~�VB�wa�~,i*�-�e|"� o���`YYm&7Ɇat 28°�80ѐj�ve�z�)� 2 h �-dark i��. M� �( 2:X5lOވwp)��q ne-p�� cart�f20 60� S^� �e�colony|�$15or�'ex�F to a. ���;9.� n arVrc. /��Re���X<8 108]g(�C9��� remo� !j4"4@Ab �nadI �y=���!A�x5!&4�.8susA�9a��Ju�* ym�t.aas �a��c inpu�he.Ted �)�2�%+=�o��� 45�\0 minB�u-engor� ]Br�,u�11�!tm*svEi*.{�techn� �r|0maA<=��� G� �QLby a LTQ Orbitrap XL� tru�:(�rmo S�)� 4 , Waltham , M�J�coupl)an Agil\ 1�=�pes LC�# T�8>,, Santa Clar�CCZ equi��%� a refrige� dYp#�( Ѐ�'binIpum’c� ~�p�~��t� Bi����,�'T liquid chromatography��_a};z�\ �!�An Atl} s T3a�um=W��s CorpW5Milford1H��J 0 x 150 m!c 5 . ��m d��BoK�o A���� . S�nt��B߄I4+Ų1%;�r�U4Ba��49+�dr?Z;��!�%14�L/minH . A volug 5 μL'Q-gdx�c$Y8Rڅi��a�Ms:�leTuA�, 0% B; 1akF���!�950461.!~2ai�ba� he L��E AH�run twAv,���'�}a�"z`E�`w:rospru&ٓ ( ESk. Data�*"�I��;&S s�R�kmodE�TMS�oluE!of�, 000Iti ss 2M5��e��Uhfup�*��!�c2-M�f��sb0pre.� 7500K[iA��u; dis�CA� ( CI!b�o��nP���W �n�$Xterra C18���2 . 1��v�$10mM ammonX*a�Z��!j� /iso�V yl alcoho�b50/av/v ) +�ta(6&30j&1ET�'�'3}�1.@ �A2.10a�[32�+65.f4M�.�.in�M ile"Ǘ��ezWe��-a �/�/1� 1%�2�0�07er-�/ya��>a��G�8HC�8A�top�V1�n-#� � 55�a!�iP�$aQ ��CLoS �Mid�&�n3$�� �of 35 eV+4efa�������8�� Q4ԋ250� � � !GX%��Y /d �[9$mo XCalibu�Lftw:(e)�����0^RawN&&� to . mzXM= ark�IvmsCot [11:"DowA�O� �u��open so2�R3+�[11Ra�xcm^ ckag���w ��j.W�E4�TLIalg�Hhm�za Gauss�R,2W �$-pi�_MOBI-Warp�qho� r�Ek%�c&�A5�! aligͣ[11Paramet�!t_� �h-q=�. F��iV6ys�1_A �)s2('[j"Y �Bs �wA��"���6?)��[!E33 " !.non��bF472&.#AQ](� Ft >� ��] G<�Cngl�ouw� && %�t�>}�M����io= r,r��by Wang/:��.!���P��ad� ��y �e�v"q�am�@sg2.p8A\XvC zeroN S��5�wB)R pm limm�U��chA���neO5o�)7he �!) Gt mpir%�Bay!���acha� Z !�in��Pss&���#u�$cAv/V6ere�ab��"v�fQ�[11m3P���baKkEdm d t-�5%i�a �a�"ܕdE2�o�falseh c�,y� [11�@E�!-��v�/&� +M�/y)%�@7v$n�t�p,�}�E�de�\o�"�MR%8#t�"�fl] lAH��!~ke�/a?Ial!�=-��5 p)j<&f��J0�W�o :all%3.0c.$or�mpA:Ag�B:is9�U�Bqi�!xATQ. P��Q"ar na�J���5��KM%�<��*�6�error���cK�[6-�c ����\~ �EJ&,v2�.h NIST @U1�c( R I9L�1Bl�G19d([120] libraB���MS PepSE� ,v.1��!� manuKin_A, 9 � ;v C[1O�L&�ycA�d�"X�q�L�M{ ampl�F�JAe"D! �_�s. Brie�NCP�����A��a�(D���/in TRIzo�" ( Am��P��rm=���o �y{g� of ~� b�^A�ge�aE �3 � T7�mo�u{5���".= 5’Yg(foreAE-BU"��u -�= R*"s�A cripe�"�? ( RTM7g�merl,E%T���pe*�Ttwoxcp �>SxSg III~T��_ ( In�*gen }Taq.� ( NE�A"% �A.��?-�purI&I�!.GeneJET-Pc��kiz�� *�i62��$g&� �!�e MEGA !� Z6�1�Q�aLfa�1er ]�1 ocol��1n �incub�� t 37��:�����=6t� he>to 75>&�accoo��*� roomsIer�|+ 4 hC� �qa�n0 �J|�qADN!�to get r�C'%DNAo�nd9�by ph��-chloroC �\t� thanol cip�$lN� U�g-N�Zg t -801�/���m��%&�~���.�Schnȩ%��9# up$Sigma-AldrS )*� 1Bb,m non-ʂnPS{+\� 10%�?xm� �*�*6�+�$�see� G+ 48-y,-�t :�1/?ent��ur�!�rF\E���60 ng��%� m��� IT-2020 R�pMC�@lUX~<New1zY2)$�E.\6 �D��I7��7��;� yM9-fI<2nFC�KT��-Glo Lu? �E,Rll Vie Assa� Promega��= x�1H�!at w^ )P5q �TaC= V!inocud�G\." !�Q�A�"/ !9=�1x PBS"l�� 5mM MgCl��2mM Caa�1)� w+aЀc.EAb%M!1!/!3?�f�"�*�"Sn�'WE� 3 mLI%95� w!���!si܅���b+� �Z tV1 h G5"A�f!Af�f"��um EsZ*q �,( MEM; GibcoR:1%r'!�.�"!m. Q�)$)E1of Ig %+�.�(��*ѱYBHK-:�9 . Ab eJ*6^.�^aJ4/tyg*�K&^�2'�‘2�*R���9c6��5#?H s "��. �/ �H dard �rHE|B�t.�j�[12�3}���1in�! μl>{ �*wo�qR��� �6K&Z8A�*�ŵ."3 (� n˂L2 RT��� o�2iq 2�m\��C)�h �ve� ( q\ �CP̱$Up SYBR Gr�qMaC> Mix�pplv `�3� � "B �Hi� tfs;GSek� n)()A�a�r�dc S3O . ΔΔC�]���� "� �erNMra6!��t7� �)�N!��~��� �"..� pre-2a �*71Mb N- (BE�)ina�u HPR;B�Gl�#*SMSO� �e+� vehi�K�t ��B�EF"K�� 2G�lai�MEM�&!� ��If��!=5. V�.Z.|'�&h'�$hpiNtit�� 2e�����2�Em!ith�:%)&A�u� AhCel�44%��{^��6|�lpub&� �[1�F&���trypsi�!|was7.!in� . Eq�7���"�3r =Q�~#���!qr/Sph���Iu�� ( Av�# PoXf�B!�pre*4 *� �Z 2 nM�c1O!�U"ja��.�a���dr�)�n�Ygag$K%}R�gR&[!V�$(�%)�4 V�%6460 �%QQQ@(� Z(b��);�ED�>ach-�{�@( Merr�=O,�)5 A��9���sULA@%Xbridge �!�1mm\!000%�3�2��!!p����LC &/%SJ6�%:�%�� buff�%�( �&¶anol/X%/�icO% ( 74/25/1"+!O "�!+�!A�(  LF99~C�?�AllQo��IB2 rFf�EC)�μL�e80/20 � A/B !� "�) i%/ndG!6!binK��%�*�4l*!~(%�Q�MassHu�.� KAAVq( V�6on I!06��)�detai�^0s5"8��is �:��&aal"c�!��+N ( S4 �6,� .�Eluc ��J�xi2l���ism�8f�| 8diac arrhythmiaF5�kr0t�3�k0o? &2��ve� n�!���!�theor7,Ex����&�>L &��( A�u �Q7�y4nga� over�2�izj b�e(��W0�-4��predir%> Tt_, s�03!}re�A� e-_]) “m�6�4�s'J1;� *r"`�5� mena�X^(ew�U2�+re�,1ohN J2S9&�#ݏ�8g a)#t��I�E2\�G!�b�3(iW"~:��e1�rab �AP�t\�� �_rm*zSA�r�*so-vu\m , INa�h 30 y-oldi��chick0:� aggr�i HE w;��m�“parsi�&ous!�:�� isa�he,c�d9f�("E�,� %�WR!�)l comb.z�iDnovel Hodgkin-Huxlj�6���aU!�,u`eG!�re�Q�H.Ivoltag��.n!U"-i*�r���oup#da��m�w-� ( IK � ~�fc�#[ !�&� 2��sōmea$��s3samt7_�-�)M�6bg �)s:Q���-� ( I-�;kCF%hipvId5qAP upst�X;MrerofexcitC�:: Sv�dfrPyT iod;��$Ndy e%�in��%2�� clamy-Siq���,d"mA&�C“em�YntA��7in�t��� u4 �: nans !�s >�%bpBcC�n-omyocya6�i'w�3sp_wa�P�5�Y!�!ߧ�. K hearAm�B breaku�M� ��a�9��:��@��q��1qu.a���n֟� n�0,�l�Y.�sad2�C� :?a��ci0�`ofa �3��:�57iCfaMHy7Wr&g%��6�men��#��Od��ng��E�g�'�'�<m���Ui�W�u�pja solidACb��kSAI1neA& m`H"��c �s'"�����-�> y . �+sU�!:a on�_�@<�����R��+�S)"�PZVlal�[�R%`i�:�9�r&�Dr��hal�'u�[1] O=a&�Oe�yAյ�]͡rk; tI�en��&��q6N%��&�E8se!�%[!~E4�;�m��al *�xsly �6@�W�R���te�\c�bzpe5�E���ot:� . Io�� �%I#yUI�!rih$&! � sub- D( �a�2 �hA MH�>te)z!aA� h�Q%�}V,*�����6!-"� nZa�50%�!�%I� �".�n� he�-Tussc�+$Panfilov [joIyer [3]�7an V�r`=1B��!on-�N�8 [+Ccvi!Jlex�1aE�adag82=!u2�l�V��>�:e --+/ [5];��u!�ness/�[���[�}7];�J? [8�*2]; y�k��a�ou�) �.Pdo`8 [13] &��D�DE1u E�J�Q�Srճa*� ) ��_ul�̕�a�nala�6�,WA�ya��:p D rve ul�pÚg�*/o�#��dele!��r�O*� Pg��l�V��%� 4"+���qM/ s�n�'�3qc��� �6"W)�*(�.�d.!v�B >�el����s��A�.�"5�w �O��Xz wXa=},�"+0v>T� E��&�8;)P:��N�@Ke9((tw!-y2�ogܐwel���� are:!�pl��8!Tui�A eA�N6)� some� s at� alyt� 1�e!�&yJun]L�L�,�1�do� &iS linkp2lK@�x@%�.kѥ.� l��"LX1�>�����:J�)!���5 AF!�e��gq6norEJ�O^Ras2Q�Q��%��� &e "�Փpca.2 ��R�(] �%G �poN_ ��� Z%R2ly��� �X��6E.>Vm� � � �OF��uall-or-n�*d6M��*+ -�IK12%�9A�U���!�aeռ�nP -85 mV\n NE��- r�_'���![� s�s� � �1��,�,e�gap ju2�s Cx43a�m�Utɐ-�lea�aQ kb8 � orm j�lay}�K6�q.�\9e�p��5*ng�7 ��.>�����~\p� 3� ! [j)D�g!reth�. nd p�ec�[v"x�8��u�y%3imm�*�5A�ne�G�/%2der�%b�� cli31sug�ai�"+t�p�_�8"� ms�l �IdDi�is�4ed| $:A��cerA�B� %z-�VA h�)�W@ �p�h���*.� fibP%r�����.�She �l3Q pharmaceu%� 63]D�ng6�m�� .�AP [2*27]� o�xaeq�SIJLR1 gu�1 pioT�0, [28] albeitiy&�I u߷c�2�� K6f.mm.�fJ,av)>j��fA�s��2�I>@,2,�� ��U v3�( V_F  sphe�2cl�����MeY�y-��N4 �I��M!M9�zF�p&!�"�VCAsulq��!�.�trabeK/j=[30] O�]la�4 .�a&upd�MA&?4Y5an%�� 6% ���Lis� Ysk!�e"t�FA=��&61�BVC�Nt�*s;|ix,�A�AZ_��� �O��too�PgEV�% adEeYwH���!�;o"�K, [$�MR.��4.�$Õ�uem�*���e�son�� ڲin HE%or oocyc�ɤ�#wf0! SCN5A �)[��*͆)0hanJ�( Navc'��a�fBjaim�oi�8�&mSo��a��>RI1�qM01�APUKl�%EI�r� er7�ը>��A oc��.������  �� �+l#�Ka�o�r*� )YasYV]��%�E(l ho9�,�y��Ea�:-+rE�n!BfiB�vee�s  - rigoP�d '�f~"�� Foa55�cF�&a!'!^&�� -�Z�:& _-6|.p 6�-�.�-�s/' )� l���x6fyi: $ 2a2�� :y]6�.�a�; �2��.�> &6a�s; �2A�� J.:1 [32]�P3~n"$�t"9 o)!�J[�V.˻]%��*!G^=&iw�uGA/�. �6j�If IK>nd�Ba*da�'/v!xnd behavp:.na�S*�aA�Rdly**Q\" �uq Jof>� -��!�� u�Qr��a�`��\}IM�( �� <\��fmcc��� !\S%�2� Y &Tr�%.�y:���ex5$�&��z u�J�ns Z���6u� 1r*R�� ��6f!�AN+ Ms4 pione�� by H6�( H��� INa=gNam3"6Vm−EN�.,+��#�9Vm!8a��"�&� , gN��%z�y)"� �\m�b a�t )�� a ��BA��12yY�� he N2_t!i 7L�!���. Beel'JReu�$[��i(*uFaJ+ �� ( j )=7j� 68��)�"! *� m#a l���r~"HHdI�� &W iHH�� �IBA:�dt=α�0T1−y ) −βyy≡y∞τ� (�tIye%{Ys �#:k , VV!�βeaa<�o)Uoff[6�P � Xx"&6)-P��_&�D, �%�AJnd �( }3!���'�jrA}�� M�);K#� B�#c2#Vm+fj "n aq[B��� � �V{?�=�Z2cfk�d9��!su{Z ay!F+�319  Y 19529r�����-2 v�'c��|cM E�a�-ٙ�"� � princi��["���V��st5alaϩ(j�Z�USY% �v� mo��!� chem �7YR :C�αya=0exp (e9�yVmkaF,A�=β(e`δ#(�iS�Y� αy0 D�0 ≤ A1Ee"�=�Ale ky �܁�:�ky > 027. UI Eq 3�an)�Id9ETjW( Eq 4:2&=11+exp[e~�M!ky�p(� �}� =2τ%3[�a�5ZK. ( 6 )A� re 4.�% ��E��kf!`%�l�ro%`�XQ*�ALU6,�qat τ�΅� →0i 1Em���rea"�bb|M��S`e,k�n|b�]�ane >jABa�9�h �−85m�#=650055 m� �+30. #O�"37 /U��e�D!pbe<�6�Mqv��� ��HWe�<-1)Rproblem�P5� SVmu�f �m��gIu8p us eo;ngY  δ�N9R�iz���&fiͥd�&PR�nsub% �GEqsaynd �� m∞E�h �Gbya �~τh2�?!n!�C�+ s"h �p!_-t*ValSFfor Eh[kh�Paki�� (>1A�{ �`set5 = 6A���.�Մ\�&P4@��J �&&� xK�Pd"OVI-)Rno�"t�D22Adigits;!Dmax�δh �} u~�%“inver�� Eq 6-v!�tw|�ud irsP��8Q�46,A�)\845mA�6!&�+�Id.� %%.p:��a�-"�S � A;��+���*/�"�F8AD� )Oex�$Bo��e�[&K �X@Eu� >7VmI�dt�01�/� �ct/Ba~��eB�v��oic�fd�cɴ�<ehcom&� c?��p&�%a%E q a(���&]����2� iP �e C!�A�t�5r��%.t%!6�1cu#�i'eA)[38] C%�. E&�1)�f!59�NL0e��gx�!� �La�:�H� 4 cmt� I8 OI1=��+1L+nA<�Go "��� }�ye"t!!&J� )Mif�eo��1� COA���a/001 cm2/mPdxQ=�� IK1L!�!���*�,��,5Livshit��Rudy [3�I>A�Vm�8a�\�T9h�}A0-I)0toI&ru(e�*cu���2�b���3��I��>�.� redoJR&�*�1[li�CI�urJjf�( ��on� <we|Y�.K-t_"� . [4�M2]*s"�}:u� �s�cd�Ap$=−CmdVmdAa/��( ulus5 # ura�� �� C"K� ? Y��,ai�w��s6X�n6(to 1 μF/cm�3Ȣ.�,"�%f JFg U�1�� ?ora�I��;�\wa0� �.!�&hod,ۢ$3 ;!�K!�!Sas�( D ( C� 2d2!H 2−p��R/-QZp!�Hv!"�) a CV� za��0+[3�<tpr_on�-eI�'a*a. B��+ 2;uGg.IGd�deA�2� �}U�N�[43�p�epiH�%��>#!����J:6-yLz1ndorrff-��%2�&�u9VmASc�APsm�E. j��sh�i$i h��yAA�5�m(&�rA!y3 . 7))�c&�Ԓ&�[ %+,"b � ��ŵfdatum1�%O��de�~E�1):"–�VV �3to Joyne�2]a(�);�4Q� . 2 ±�4�"�1� mHof8Ja  )=a+a"�ĉc]S^#d'�a%(4%va���tra�0$i-|� a�.��i5Bll�=�}(� ��h)+d.FiSN�0a�APo %��"�r`�x"�"�n � &S3a�&�+�'“�Z%. r��Mr�cS0l���� �f�&>���3he� shap�T�pF1Ke"�"��G;f�1vBf�I]�"�|� “vir� A�����t �ys"� ng[12���b aՍ�5�pa'�� six 2�!��� p�Bi�a-��Ͷ!G11th be�BD switc=o1�- ���%��X�wa�Hq 0u� D�;!� rva[��Mtud�Q"Rs�Mkey�a' �RU/WE+"n&YS kE/�z10�,and presente�d as a function of coupling interval . Since the INa equa.�^s in all previous rabbit models are identical to LR1 , except for scaling ( conductances ) , weW sent _Xdi� s us�X$with two cJ` values ( 23 mS/μF and 8 )�cover �\entire range ( grey line�figur� . In addi!.�,results fromQTEbihara-Johnson ( EJ ) �0[29] ( dashed.m$) which isj?(it does not�Dtain slow inactiva�\. To create our parsimon.�(( PR ) cell �,�combined8)zof A%ka!�%�ly publi�,phenomenolog%�: repolariz �,( IK ) desigfto"roduc!�EHAP.6dur!�propagIP: IK=gKe−b ( Vm−EZ. , ( 7%Xere gK![!�maximal!AdM~�K , b%a!2ameter% trole$AP shape ,EQER,reversal potAOalE�2AI�$o quantify�seO��we!X both)�s���p5��t5E(was more ne�ve]par�oN8>-41�� +4 . 5 �Hnormalized magnitudE�����.� re� y time}�in�3B;672� [32]4B�� u4:2CaF|Pj-��in1 �ku� d( i . ��,��sA�ncl!:?$bars becau��he virtuFrotocol 9s�yAPs%�thu� ]Aeffecta�n%� vari��"8 . Unlike:�sF� ( Eq 2%TfPR~ EJ80��sM� �$ only fast6 G1 )%�consis� vY�&sMV volt� depeniG of steady!Ote��*u A�2� as�a�7$correspond��A{���J�4E�� UM,J�Vas � I6EJ1 . Our0exhib��a� eper.�Tslope at slightly less�z ed1s2�y�(EJ ( panel ��A=scribed�τmA�!d�"� �h|1lCiA~�RC � !�J����B�2��MPRbf�J_CACn�y���τhX%M�/q!Y80%Ki!bnsiderab1�<τj;31nD�Whe‘a��k 2&I %8&��AXnovelE� sub-�a@ 3 Y 3uc")to\ IK1LB{assAL!��: � o�*� ��Fi� –3�( reraysi���9&���orporaD �o��� Eq 7 Y5u1%L�M2�knearly��c&� PRRpin fac6�22� 3( �)E;dI  )��)�s ):aJcan1be� n.� y sup pose up-�solid6 S=u�AE6)hAP-�Afollow��c(cteristics:!tmin=−233μA/cm2 , Vmmax=34mV�$APD = 197m� le%�s;"INH89>H2H8, CV = 55 cm / �� Y42 Yp&d!Ia c0. Wj��7?,�s"wIot �ifican�^ alte�(( < 2% ) co& .B)]E� [39]A�IK� indicI�t� �.� of1�� su�AM4quite insensit� m� spec� choic�ZZ�. performed&� T8ity analysis by"� !��� a 1%6$ ���1 ngcs�( N ti� est;M}�K.�Y�2�  n 8x8� ri�We also]��@�"�onE~E| tissue-le�Rbehavior�iewa(�b(� ) by!%:sp&�gKdb� ��“physi"u:”z�mammals:^ra�Ů gK 0��0 . 1A 5)��YA^bAchosen ,003 ≤ bA0� -d&�]APD.ng!ܥA�� 516 ms�?h� &�display�U!��B�Ca�� . O�i d�5=,!xmin!q< 1 . 6%F�k.2%X.chil"�p�&���]�� fai�sm!�.T na�9�:�8%; �: 7� %; CV:  %-,�:at� onuA!alh� � :{� �::�in6 A� . mus�S�E�!robustn����i0confir=�data us9� -��!�e.a���cs�a�ɚEje.aiE�} 2� stud�i.�BB! Qqdemonst�� �Y �z��withi�iS foun�!'litera$a�membrane=�,F� ampl�� dVm/"�$ CV,*�6,~:Hspi!>wav# Mahaja� M08 ���Yx dt�& or~G whol"�heart� ,Schalij et a} [44]:).���  fibrilnobservY6intX dub at!f�freez���i� A� 2,� .reOy o���ar%�ar ar<�u�block~ 2q!�O ycle leng�f 130�11�� �"k U>� 108EM.'  5A�he 2_( ~ 150Z. �� �3 . �)c!v2[��� largA.���Inc}tally ,+!m�� b!�%�4%" e im�H$�"4�0"& (2�$: ~125 ms;6�: 2�:!���]middl�rw�of�a 6 beWX� his just�.BF��any>Q kine� �Jis�d=op�.a sh�n!>EF�ri�contr�� 2��zof:H. ,Ii!6inB .� aY� �gc#ut rot`tis typ� %�;2I. [2]2H �A� �i�non-sus_ unst2�4<2�ofqXA�U��tip�jecto�rC�a!major� zU�) nd eLuE�te"�by hitdBtop b�aryi�re%:evaW wave br'qg�YEblu" ��s�  5B!�2�Ѫ-6�" SWBe�tA�Ɂ�?ax �0� ofa�id1requi��~a O�� \“A�(of�� !7!a�equa�t ine�c, ��[13] . H, furthe�p�isE�cA%to�2� each*� on� �preli&ry.�&� is ap�ri�� )J to gq�,ght�_o underl� 6� me�4 isms�z*-d�\. DC“�al!@.BA#tA�h!.� !g:� proce~�# )��.���6�*%�}A[�)�ed%ֵ�G �A:�.�"� �VS�&('4i�.6�kione�symme�ͱ�]�R pair�g��!8m � d . For 8�9B=�.�:� ���灥ciratr}�,�l6Ce�uaa�)&HAfo� � ' (�=J 5�p 035%:��fA� ency����O�e6 d� ~3 HzA�~18 AE!$VR� ��~304���"x ( albei� ��2�o ��= 23m"���2.�nNb$uay�!�v( g��whe�5��r nans9p�����ac!�Q>M��j 2@ st� i!n-20 pA/pU$*� Jp!�.�v tween 202%{21� �2�7IJ$�29 $( 190–24?)ew�� or&�-C"��6�s&�%5�@ain!�Yl&�#"�,� hypo)at%�J �'��!D "aׅt"�e>ch + -�V'�d6"A[Q�hAZegligi� �&M�:I",=� .�� Vy(%�caE�u�by�kgu@!�"+ 8&Vm= J�eF �) -�k�hn �pronounI�an W$e��7�Z��% .%&5��ne�7�"A5a:C. A��re�%d��two�w% , h�n� ch%m3�E reples%#5im∞3 I� gNa 0t��� "�'(ma� in����Ve�atF!�tselffcap%qof gene-�J BD Tra)�ţ , cardiac,�9s h� a�&� v&)����2 deri &�clamp "%j M�M i /-��OQV�u�&z��% > m� id tuih�mea� ful.�. Howx)��r!�-! such./i�!Y{to���vid��ei��hemk ly ,U>-zor%�t 6�)��2A$� �-)\1w=�Ů=+�A�jA#� �UE �(�L�le��5i5G� oftej volvG�F$of multipl`r�!�H1 wH�' a tern � a�e*� �!�ajy��t���)cer�A�"�� ��!jajiAYil� ��availe]-mM\}%�� wa!�Ve9!?#��oly.A�p.�*$24"�At� "es HH-� b����B� >�*U) b���= rols!6s.*�.�=it�Ku� j .2��"�U*of��<set ,)9c�'&3%es'ro>/h��as few�� poss�S%�"-,Ak�� rece���%�5�mathemaq�*[E+.  �$�q) [45�:na.� by Bikto-v*]L6] FitzHugh–Nagumo �s�+`�,some fe�����*��ch as:\!w>.9 , 0sub-threshold� pons��HTikhonov asymptotic�Ner� excitabil� [47]!p�],front dissip��[48a &�#�W&l,am;� in< ���,u#,"u- [9]M�a��QQAnD(V�#. P2�-��aaA�B�.�E� �i� ��"� at: tempei !�UB#�>shoul��6vel�#ra�-forwar�imple�, �Ũe�e;a&P)ill�e�high-�'%�measur M�B�*Nj�*N2�:�$�ve��8]Ni��F-5=�&8far K0 aw6 ,%�"7 he firs�)B�"�+p]]inta�velop%O..-1weM ieve~s� �!ozply ad�ngO to�tch. � be =��� er extensV)��w!�ב�J0  ints�edQ�*UEȥ�+re.� . OnAka52wAink%ce>�uset _�'it ha�lyŢ:�)"��` zero�� �B AA�� outwA�� &�'t&� � k"�J2���3!0s> g� ri(G$ same�2[49��k �:Y�rL"�� by a�)-in&� ,"y � ;#� a�ef�*,6�� plet�"*1��e~.2"4,�h:$.�UA�*M �K ��). Desp�!a`!�uniXS2� bf):"�� "� , ��r@ ��gno�_K�>��N �5 � ]���� onea�.V�Ufn > 1.5� e2numbe�0"x�&X!Ior0��6lu� �fulM��� n6/$is 2n − F*� ):-0at le�106Ei�e#�z 10006� ! ChUˁ�TF " 2�lyV a�:S � in75a *�$ s�N[v%3�!50 , 51]hs��icn� ISa�%s I�:`reg ng�.�K:z�:�&���*iIK�i98/)!�e��T.ztK}�6 �%6_A2Hfw%ng��Wa�4"H �-0uinea pig [52� �>"&"f� ��qhipu��!*�&� [53];cb&�Wi.V�4 OA�� AO�)9w� also iN$�>J/��0^ve9. Surpri}B� :mp8f�� a HH��W���a�B�!#n�-��A8Ʌ )=�& (“emergent�"���A� :(EJh8, "�5f�"s 5�As)`Y.)*'I�,a�tom left�7WaNA5l!vou��K�/ndR\w� >�:� :{�ť�:�.I&clHmpA;VG�e�%�disQA-2+sq3dipitou�%�!�6 �(��"v(͜ N mea�55��*IK>�p�f^^4, h"�%xa:� er���o="r��-�� (w� h w�)|"}in���[54�� 5] W�6 "� "�s y26h5;&�5� limi �4�&5 no��!!Y �!����!��A�IKo "‘min�;’Q�% c s m�"� I�7(nd ICaL mayDenh�;�>upF&�%V h�:L1"�0� a�tra� calc�;mP�n� he .\ :gm�%�vA$Tyrode’s�-u�2 �auO he��>I�� �I-V],5�#�ed����!'��$5 mM �ety noxim�qs long�&G$*� � U�59%3 cm/@�'t6�!=���^���out un"�0a��� �,2�'�I�Aj*�r!%HH� �Markov���<%v��-�.+.%6�&T�z� drug bb&�. [50] I�8�;��I2 �8�4t��V�)� <�usQo"RD"�8>c*�.A i�,@.�. Whe j�e�3:�.!>cm �7�W B& ong;A avoi�3&An�.Y wa���|.�/S&� �#ol��Vm� enA� 1 mm�t 0 mVEn�.? 15c� ��cARs&|/nda:4AQ�2"s!&�%we"�9�ga62�%njs�&2�?��f�!�kv��.�[31swe��*o itMir e u6�� ta.�ref,orFC-�$3��[51F. !�24exyng1C� i�s?7i�B "����%sheep� calf�be�!e muscl�+\sf(al homogene�ofEMnd VC� ſe?�.� 2sm3��?ar��nee0+��&>�&:f�(!'8ay%Q�tx!1:, e�< �+u� ;]:^�3�2�)�Tussc�%�+��A a~Y_5��aof�9!.%�\�D- "&�?!��#-80�-!V9�f�ot &{t�F%o_7fa��"5Cout�$u� i&11 D & Em�(�E2L7��"5 and6[ �r�<��2�e�,amonga�ACU�TAP&� >� �p�zE�a� un�'vocM�>Ef "��2 ��.����@:!C", & �.� * Ak�0,' �&� sl >om6d��'azF@h�3�� !�x.+ar���5?I�556]�,v�h�Aa�? h)�2 A�UB�"na:oo�[2fy 2b.�E;�a%5etyA�Z� @ath:i��s�ex'e��y�be�2tud�e-R,�� � 6d0l a�  83*�-z!Na�UB� .� failDD�!�v!mu �, CN5Ai � QT3 m!���&0atr��!F�+4F�E���2�i�J�s�49“buiZ-g/I�@��} real��c��A��bK$ zal&Q!R��g�-� , � a�r�iR� hand�H��All6��5!PR*O m�F��pa,( %^e.9!ovideo�6b dBG onaN} Res��Ga��+I2;uploa�,CellML .��B+osex/"a1cil�+P�� j'semh= %so�AQ�{ A��ec�as4e�%Esana f�SrR �%coY germ�&-( I�!�E9n�(S&$-r IES!4>flankcQ�steA�Z� v� a&�B#E�eImera Aa�sea�ivj>:k�v� �6 c�at6� cut-and-/"2&�� �w>{��A+6gcleavag�FJ18 each�,&�0by�Hq��O highE1��nd5Aaq�orkAnad��ur  view�Ghow%�!�uM)Sat�&��coor#ed)�^��#!�e�I�A?51a��6��"x. "�L6)MC(!����Y omost delQ���le�A�R3n�N�&�-�H�>��A]their� =air!�� �n-< � meioUA,:��Q �Y��topoi�&E�II�(Spo11A'oe�A�trigg�om��re*�!Y�s= ���1ct seg��� M��%fixA�+P��al��ele���los9�[1]f�Pew� -lympho�Q"� tqJ�? erteQ!�V!� ) J:�dc-iqg�-� ,immunoglobul� nd T-!�Aeptor di<�( ���P*  ApQ�0:��o7 Cv�9I#c� _ Rag1b? [3�F% partner ,42>�4]%MA* seg� % l�&on�-�A�.*" : 5e:!�2 DS�{M���>ngAA#(Ku70/Ku80 ha� odimC.A��fa� ta@mK ynapa!�recru!AJj ira�� 8��E�� ��O�G6= `1`I !�" ac�5v7ё��� ���p��, mass����:� �  �!�al��&� Qtassoc\�{%H{ A� � A��PmL[6[7] �D unia ��eukaryo!�,�ki�of S i co�Ie �4cytoplasm [8]:V"S macr��u�MAtKBvgenr>res���H�evU,Dat�2� B*l��"� mi6qIq� es�yA$} m!�-��zyg�+%Iu��New MIC��MAC ��(eny2��EcoperX>W��(ve�:$u t A �A!J-�e���)�* tetrau3;a , 6 evel�)��sEH ampl"EJ(D2� 800–�$n9.u�woc%5���. R�R�Qup!n�Ckb� ?12rep�Zd�� y��Vm^ man�#l� �$�G romo�6 fra� ��o��n2.�[9m"� s �mP6Q%�% le-cop���?%�no~&�v (� )�n spli�K�7-�..@amaM2�10��..�h ��in��N~}� 7pe�is�"EiR+c>� �MA�c5iA�T "g��by�p�C�!ށ�:�s�n"�s [11�"M,^s��p|Bac fam,�& �ݡF"w [1�%Giv! 5�>Ve�"%%]m��;�()�#A�A�_D��5R5y�12A�� Im�A�!S� e quA{o�&�!I�e�s�is� }�� a�!ZychV- �._ge�. Car�,+��W`� ed��� Vc"� �>`!lb�"�Ic��y,� YQ_%� . Ge_C&|A!�(a crosstalk"� �b�+2��@"u !� L���a.recogn�,rI)sa^D5�V�k�@I�3�o!��'r � .uAL*z car+B��^N1ar A 6sH"�$/�7%�e AYa��1t�(%��!�BF*�!O�0es�O�(E,_��b^izly ruA� de�@e% �Q[|!��-N)in P .2�!w:�0ophilic attac�G!;. !�bouj]y�vn��NACld direcmme a%djuUc� libeY2a  a���Ro)�A�i�  T�$hymena [14�dA&�7l�B ĕ���!�S�ci�@iz '�e�)a%ө���A= � sugg!�d�m8di�V�OxyCh��5.g�XI2nd��9�!��"][A����  [1� ma%�itH �_w2 draw�2mel�A� fav<_3;E�AhCif�C!�� ( '�"�l�- �!Dujx&Yyk%f!~leU[(',� 2W� lI��ra�t�ed!�����re��*�anAB�is6� F�5�/c�5on ATP*E+a- �-,�7ed nin� 5>� of&encode T%P&f B  f�ct7 he 2_�also �"�4  Y .�%� ɳ!I!��> 8L &� 'H�*>� star�(A�JTlcizj�.MˁP� ��-2�� &AF�\uc.�?or ����bo�e�a�m���"� �B�,*J���Q)>� ��j�Z�5�/R]s��%��3 �ArkG!� ioP=A�"{� �Lly�n��:Cstruc�O!].�A7�̕�2�. A�6�! toward�&der�'� VrO�*n�w��2Yed�~f�iSd�>�A�{ A�i1e�pDRI�a�on"� qO�JS'i�m grou�LinG� X�p�G�.ty_*��]�/  `�rJ<9P �d�j�aiWG�E��% m�evo,+ �%a��� e5 7��a cedu�lJ>E"ig�{7h�h� re�j�U> Sofj�D- �=]�-&W[18��Type I�{(a11p mai�#B���k/ntinu�Okasaki"�"�9rep�*!WA%i m�of� nick��I:�3�%T�$�@H /l oF �,mitochondria/y��r�i� �9etazo�dLi!)-or[T�h� orga�K. FY t�V6n4��tly>&�[a�:��kl�fy. !��bw�����6&lo�z# tA]e_52 �f  �!���i-pro"��2a�Sa��ki�f���%*9)i!���Li!%�ys�no�r3KFig f�-S �'>�1!�%mon�$l%i�%%�K0,�ged���in�e�ti�+otozoa��ra� ;wNthMr.am�;enH0f2�l k' [1�:[20a�*� ��>� s� � �ni � �_r>A^��of"[ %.��:�21�M�-�y-"5.�( MME� �s$"�O1r0Ia59� [22]a�A��8�A�( �HI��$sC#�canon�C6CP�IC6") ��,%(B� �GɁUV uA��n�4p . BL=]�2�is��c �con���"is�� !#���>���� !!c� 0 hem�&� �!!�!�da+��nF[2PQThoroug�Jo ico+5� � a�F6 �(�).Ff E- prim!J��;# x�@�AL]e�"d0XLF/Cernunnos �?3�'I���i--(�4�25aoW� c�,��!�60","�En< �4ɉQ3wo �&*�3yA� letha�Ain moa[26]-[2�TDni� !�cri6�")�ERhybridKnoSn� t"��a��bQ"TAqf�mF�91%��tye{c�mD� �9i�!bE�&�>�palH �js *�W _"ba�pl!� mRNA g �-�Nk vegeLv.3 "5�+k�autogam� �K-fEl$6� a'$il"�#� %vs p49�]"97[�#-po�AL�SpateIG?a�Za�>�%D.���e�(�of&�%>�chM�� u;���9?�M��2:USi�~�inguish"!�A IG4b2�E�N ed RT-PCR%��L�*�' UA�ex"�of % g1:�)y p�%�"�=� eQdym�2�*\�cV%�>�%]Q|$F� 2 s�? owerQ�!�x(��Z ŋME��(%ei/nje�sF!�aWs��P �_ �q2�ob.+ tribvPto�a=�A�. EE�% m �KsU�&O[ �Y��!�c�cro.*yS8� ._C5`e@coursEXf�A[2 )}n�Ege)I�A2U-�h�����'os�k�T S�<.) oligM� �do%��@�Car�e abs3�A!V��EƽO U�[�lsHMv�G�:�M6:<�J�� h ( CERa;#6�S�,�;%Ji2v"�,�&I$"�VM�!�!��� To�Qfy���ip a�%�\ ���!�e4���Q:Fj�eQ�Osg xtr�E�Vconju@� �I4�$o�$.�.XC �YgV �X?b+7)����Q.7��g`Q sepaSRon [3 Moreover m) �onusyn�V �ad 5-hriiwindowx�)bw6 h�t bes�>u/) ^"3"GE�5 �Ve� �@C>*YE�:���!��U�'!�a�B_4� �Isag &��3Dn1?&��c.�A@��Gex-���( @6rx!)E�U�%��2�"Q &�B@DI�i�*t a �MtoRu(* W �"�OrS$!KaU]W�qk/6�<W�3a%�a�,r!�ѕQ�]end� � !�aQ moctH�(��S����� fluores :D-m�2�-�S.B mt7m���A����^!@'in>_�t8 G�C#u&Z*pwA"34AO�� �F+ n abuZ swimkB�Q�[31]:Z����A�iA5���!F2����siaccor� .,*�"�A. �.5|cm`"4 Mg&h%y���2ta$e-/ �y�B ,mDa�F.gin�w"�7�ps M �]taT�8��!����A� �until 13e�C2f"9m�Hu� at 1s$3h ^�cs dDe��ٷ�� �/��!���'��edx.�retur&Aw ack�nd&w ? �50 *� growth12 f%e� -N��.(atF�����!AUg{��&2o�(-�%�� &| o qua�Sq*��u -�m)M�um�y��M�a��+ �m�P�?e �KB��+".R��v>��,��F. 6�T(d6d-e�Fi�9on�^(�?�� V8G��AZh!͏���.��!eg�5id+� �(6 ]apidly��1ir�{c���a>p)euads��;f9 h�&al�4� amouYBf!?35G7 9��a�2��%UF�rs)A�?~Ao &\�2� c�3!V�11Eu�2*c� _ co�Fnt�-!��VL��E�u� �i)�b�lKstW- �����Z,�b�l!" knoc�2dow�< �-h| ce (i��ɢcas^"�Eby fee�(*�)� on b* ria�a��h�8o9M�.�7�NA��s)�S_�+ id p4b-LA4:0 �� "1 .L� �Z9wj7�q��M"�nrsB�$�Alas~U643 '*%T�K.&��)���4a,�um�en;%� � +be6��&G ��i�%��I^3est . MI�a��de8fe�� �� ��!�survi�5F1a@,ALs�7d�5gV littel�'�v-g�,-"�5r�@�Ma�GProlџ9�z, �"7�/�9�o ��/%�>Gsuch!�T���a � _�.&t7% � �aalel%-gmaraiA`. ren�al�2��wWr# ,�p�v�Oi�E�V�Tmut�b�Dp�. AuthB4c2�er� &�.�b2�us�~ loci�to3a2in}wi��~,�:o1�6�!] ���Ez!�ha�J�8&E��E-�}s1a�8��a*�iif�e@~in2�. ha"<�4�&t V�)�X[A*s�U , [3VE'F�co�'��t �.��@EYno�h"n�@ameia iv�n�V��:*� �630.A19�E3&�submiJ�a��+fdal ro� of&�!DRe:e!f( 11/1mhu�5��(2�pFIF( 14/1r��A!�YzZyg mac;R!� .���Z�(18a!��F&U�F2-S�.:#*�a�&al!R2� �dmin"nF12 ʭ5�,5e��-��ii*� abor�*Ia/I-( N�v6��E yiel�M��. T>�:�3o���� ��;A�;.��d&e�ale<r!�em[ ��pnT;u3ng�+ec !�.�A�"|!al2�.. �Zu 6<3rigX.�1o�!a*Zm�@��X 3_to���!KF25�E�F1MTe�� T�ld%& �lD}+�Vt2x'& e/2^2e�: �2�,�*&����nz4Lg�AC:��,b�1+m  �c�no arv�grap�U-�f u �� :�r� �[3�6�M�"�,-"L kept�5!�NE?�%>Py4$0\��A,,Bdu� j h �2��*!���c2��d. mi�U�(�&!xy*�He�|!�ssaF!��� � tU �1"�k�Vwg�|0stitu�z� %�A�k  e *��� 6:/ �� Y �ffa *l �.�hB eI"0b wsnSlap��%j!N*�� e�n� ��5e�U.r 100%� rh*A0�%Ju .�\"sum2� ("�I����A����f{.r(!B6 p�I�~I5S&5 , &�m�!��luRUց8Am �HD��a� � A �S7'�y^�F"%��r, Y�-#� "� �:-�� Z6�!��E,D6� I�l&�ٳ�7� )a �N_ ":*. L"< ��&��/ �KesY � &)�2z���Ct�iB�be����*utoc�R��W)"h@�P�(Ag�s.k�^o& imA2B�, s�R�(? �Ekefof({G��ba2 r�� deat!MD�&��9EM=�tow HAzaN  bA����:l�h7� r� ost-B&% C c 4l,��.y 1;2> ��%z��ݶ�h^hwMTl .� �/: bona (f>�E|too youA��vgo1�y��7�IqV�R �r�� ~eK�e!� icie�t�v}�.�:�&k�62 �S%�`�!j6b6"or-��l��i,"�!��", >�A* �,��5mix0 [��{�0E ��d 8,s$O2ntl*�.S4��*�c\.M�{ h~%&N&!8� �>e�"Hr�q5�*OH"�Y�I�We)���a�A|j"�sb�W tE1!e k��x03 �`k%!�siRNAf )1%I%s%��m��"�M edi��*Z#m0@.L=�!�)�*?%|!sG4���,�Iist H!|"T$efI�!��rVE�� �&5uS%v�.�6kt ɡ��-�6���f^�:�=�%>� ��.�I�_u�G�y7Ā�'�T�~,A�]� U6u7�EAm�%�"�4z Eu�/6)=sDtoFk�o����1 ��vZ2� AB%�\4�#&+BYB*.� M 60�J�AACg&�).5,%cͩfix�-t��`twg(F� *� i_~ DAPIhv�A!c � c5��!$R�5E& y�GNvlf�.��> 'im�O n*!I�-Q bL�� al�g�iˏ.$��� W�yY�5 � *��C�>a�� s.4#.��k ���/� `-�>�>B��%�propid>iodid>"E.���>�o�B{)��er%�&�Di2�A�2�a�-d�"�+2B)�($( ∼40% )�� � ��i w�D!�"�m�E�r*4�G;!Cd*�p5a�e>b7I\%IAȭ�U�A���I��P8�8dqU�qp)��^!� \W&�� e"B��hR�w&`+#H`+�0�;2)�$�;[�+4>�5 B*2 &S"aS7�0!.�a PGM+e� t� Y9arTY�i�� s�I&�!$)Y)U!�>1;/ac�WE5(!y-fe12�R ���NA��' E�n,%d��r�r>6MWin^��_�>2y�iQ:GM!�B�B�!a9t` }I�wur!�R�.��*�e�.2���V��N�1ice9A�:�(*� `a�~:>��5�4$ LM�-�2\,)�a�P]���� �rn 5+�F{6;"��4̈́ visu�7a|I>O/ `>�VK:��5y�8e��/2�l!� .Ca�5�s~TuN6�f�)�I 5�,)7� � n� e�a`s�5@���p-6e�?�"\ �S�$D 7Ek! y m�"�B�3rK@be�<�%oa�� ch�l'���Has&�6V#M+: ����\e�zg���*�k %K)]a_�  �*G9,c strea�(�_*�|�`�WI�^��xlo�cFyVM�5�, uP �>L~ 51ΔX��a��rif21[ harb�a!eP$�*e�I �E�^�8 �Ksurfac�&tigen A74 �%a5�Di�$took advan�.��faA�a� >�of�+ ](�.��2�) ueI@mp���/new.��O5�+���BE riA�&�C.�,.� A�ET�de novf0I&>8.;��l . Such'ez�:��Z i�$ n�//e�: �A�-y)7�;� >� (!S'���!�!F�(z�on%`�{s nPs6��F�2�1��7F.�6�a@�*�a )/i����6��B=�>�Le��' </&�{�)%�!)M���� 7 g656X�(ha�[%�*�� A�N�!�)��.� t/����,��ha�[J�@�,2Ninheri�rm� �e(�.g�&�;ųlE\e<w�Y�E���Mo"o%�%3��u��sthAc&Hd�a{[TG.&7d�TCk�9V, � �l:\ 2�S��lo�n� irOgbye�5OMހK  ,�q�� Dxc.�i��sJ�Fye*zC&�3*�A��(i�..ś+Ma�du' 4 �o�qoN 4FA�QT*Ty���#x%%!��[1(iPڋx"�3VJ�[ N�[L 0cA&��� 5�["2;Y�o<<zeil!E=,�SF P b�� � vitr*F_b linkabC�e by��;(���o�p�)resN_�-� scalyPden���[acrylam�g��U�8��bis���t2�*4��H)� bb,� vi&��w-� �H�3�i*� UR,v !�>r�IGBy�ll�-boBt�s "} ��s/!�:�  ( 40�/���de���U%)e1ƅ?_^"8-á!$nonphospho!~�ǡ�-ATAC5��gu�bM "�>M)4*�a&Te6g�Y���"+_M1�tWK*�*_ ��mlÓ� e��S>��94&H� �5-nt ga�?F(��)�u �3c�d%A� ,� F!�!9R�R"WF� �qQ[diaI4�l@Mof�U�s �e�]-kA�3=vy�w[: onfiO!d� � an��m)&�SqI�mU e�lyql]�atZ e* >FRW��(E<�� �atM�i�5c �NA)P�� b����>�c �o��!���mer�jNJst|H.�8 �* Y  �� f^&�C`T: ) -taih��ap sH(!� �E8ե�.&8�� �a�� szT� "O �he_}�b�"<0r����� J�e�� �*�;o6pTA�o�!!E���cJ"�O��q �p-**�<8E,"S)�I�r'�e�ݧ��Uroken5�b&ly im�*� "� ) . E[:s`�kP-[ +�g�:1%Jrc Y iGiA`P)"/Q key enzym�catal$�|Y�����$��"~.N�x"!XK}A�-��BlI�=Es��aQ ��0� �ce�=�b�kchf�)-wari��`, �b�R /�Ů2�of--� �J��b�(H�:�G3�R[37�GP͌ sc�~�8i/spens�2> �]>�%%wviA��b;3,�r�-jU2regrd SUMO5; likego �cA,TMr�� �}-!5CLie5� aI�a�']4C��hu�IW�� J7[3{E".�:�Lv�$ ^Zs$ 9�*h"i2_?�.�UA��Sdm�&�X�2�i�dA�c)fpasb4�D�c[��&nUv(�B� �m��� Da,�r�f�u�/b:A�:AB%H( !+�in6>�n� �R. C"6Da �V�tic�^J�SBo6iHF���iM�C��"D_g�*E^�� sN r!Fp���>�ae�a}�V"a>Ex�)�*�|te�-;ly)K!��ag���not�k&�ois� 51G440q~a8� ��*���1 spicu�'�h��:��&� B�9$�B&�,S�88�& �"%"���m��l=��5iX,�telom�1� A�[n geney A�a�sǼk �"I��*!�" [4��O� �JaK�m���7*3 �BeGQ�AMj�s� ��g� cǻi"�j.u60���� �,p+a"$2�7!���ke�>���&`�-��8,���t���(.c[m��WL,)��Su%�k���e i�Ue'5W%ins� ; *Yt��&�eid9e.!�E�  A�� ��M];i�91�~r*�{-*1"l� � �#��om"�=�%(;-�!QXn�.-i��TRm\6&�:J�n. w�)e�Dn^S37�Vv�,"�) �"� &�%BY%" *�/�6�jiKN�WI&IIl����S�>��:��{L!_��q� N��v^vv�o.:� �56.�1=!�! Br�m| IS�l�J�&x",o �a zv�*y- slow� ����" ���;�nMa.���)!1��EO!�QE��=!].�-a�(� y� . Pe�|Z*� A� �cg�F�!a�*K� L�eO �%,�R1+}�V B�1.���,;���d����l"s.'}.� *"�W ��E�JAfH?�e)aI u9<%���!��6�!@:m!�.U �5ll� effo�hȋ�un����_.�"� by So�Fry\ h�\V �gB�,6�XF�:�id1-�&�w�6 -ampd(. L65ier�>�&oEle3b.�se mis�ʡZby ye�(��j��Sit2P-"fiP��*Q��9 �r6��>^%�Q&6e[.&>\)E�1u�LAu��P�A�L�oZ!�!.%W0Tivo ���>�u�]ً �}�#oߍruitm^ )1�3 �v"_ �+oRf1f�*1y�+=8on o��IdE]% s man�( ell-�#� system [4~xA�i�Bm�Su��Lm@MP�+h"�ze��[�0�d\h'2I��Hjud�G��>� :k �4�s!Fl[>&[ .�ayO8Ջn� �n:��� �8:7�)pAa�0 ()�kx�^d"�n%�1�%"(&�6a� ��EH;�-� ����9�  e%�� �D��e-�i�E�b�Zk� !�t(�^ ir-�49�Ui"�Yg'2x u� 4�G-mu.�ex}uveuPayAoVV!�� �)��*%G�6h!qE_��2a &j"�{�9[43h"7 s"� hairp�m %e=�.�9�MG � !�.���I�%�� %k�Ib_�ss� 1C!���A�to��.�f�R��j.bEh!<"ْ� -u%�c 5[�q1[�KA�% ��a !B=��BFM��+*�� q~b"�;2��3� Ay" "�1�-*�"� �ɳ..fm�eZU�e`�by)@e)a�r�� ���s7i�+ng� =[4�j ���v�e!�1ng* )wF_c6�KU� �!� [�Gm6I�� 2\3�"�]!����U�Pe� fu� Fk�� eluc��� ir�;>�#�{k��<:%!e2 1��Cc(fx�/*Xs{g"��� �$ X��E��!�i2�% . En2@v E�n�=*! �9����oNrit9C���"@of.�opei�a�fraK)m?�-�. Sev&"�AH 6t9&�tlN"�|Icu���-.Y�E��Y�de" #*AZ� G g�iaZ*�c"h<�_(�2 +9* �A -A�>��tX&)H�NA"�Is!�pre��an.�""o Qvi�.8b����h���d��y7 -�� �mg2�R�" G E�_�ta ڈe /�!r,8ea> "pe*~6o�Dng!��HfG . If��di&g&fa\�H��� z���6?kL��_�"�as&�LM�� "7 \JLуE��B��a*B,%� 6�)A�5-7��R�i���#,"2�A�+ �� �Y%z�':kz"��� *%!�a"OTAI,I�s,i8"-f�.IP��es�7aѵ%X}Q�aamp�@ h}WZn&�AJ6� �F16!w32*-�gr*g !x\ _24j7�� i^rW"�~[�8At��h� 2��F4?wa3*ٱ0 ���+&[9wD �M� �H^P��&@-�e& < ��!�Q�/�[�G��mZ$��*5|Ŧ��%M*non"�+d *SI�I&�n�l�d Q��af�5WnW�t.��1itQ���l�! ^���2句2lyaPDgf%� 5leEn"�B-A*�)5�� .q� �("z""P�&_����yand/or���4B�� 2 � �_; e41E�0a"��*�H � 2,�+� ��e��n�-�7;�)k5� �A6N�2c��"�" a�Be���� 2��HE�M�i�� ��a�aN>+ ��tDe�'�4=. LIG�.� _�5"�0� /�al�j>d4 by BLAST {s# &�f0DB ( http://p&��. cgm0nrs-gif . fr/�f4+\�p�)A�M��*sǾ��p(� �b�u�-�E�.* i76�!�%p*#Wn�a �Db��e6�H-*!�t.J�"A ��>�H` . ��-d?]�! 27°�ba at gras�fwk( WGP; P9����al In��@o�,A��8Klebsiella pneuDHae� de�)Q�@ [1AB(to�"y�t�-6-di Bino-2-!$ylcul�&) -"�&�=�5Y:!\e\�Mr*:�M��Q �� & %�{�.��G��]as2��I�a.QuBiteay ki�AInnCRJ�n��+e�Sa�-��1���bsorp��260 n��Der��ҶbF"N�E��"�&o>��a.�9+"�%Y� Qa3093eo t7 )e��^u�6pwB-96%p nd9-�% 9d4-50�jJ:A!� nd6-a$��*Qppl�� by Mihokodeahash�gUn G� Tsukubsz�pe�%#T>� .f��hF�ock�110�= r-b/ �o5�sy*:x=�M0~\~woa� >m�#jWyXM!2V!DYF"��iron dE�n�Rti1n";neodym4U magn�� �TuKA�"��+50-��100-mL�QquoABf.aQz7h0�1 ,x� s/mL�y1RNeas!�nim1QIAGEN )�2F"� (�b)������ts"�65r�BUTR��j G156IFaO„���ZB�uO"���ZS est e"Pup pRB3��� a��&kV;nr��114!=5.A2338\�P)T�A��scr,�A[s"�c{2�e"1 �}k��!����t�Ue������!�g�Ppw�5A4h�8F�!7$���sub-pop2@i�-�@o�#"�^�x�%�&�20z� KCl-=�4u��EB�Y:�� .�"�o!" swamBsk��%�>30�5%�w��5��!�ks::sl�n E��Ji� . De�9e�l�dA����'d� T�-S�UOli.݀-�purch��� Sigma-Ald4eor Eurof�MWG Ope��a e$���JQ. _e���(�vol/g of 25 µL���;10 pmob��a�a'5 n. dNTP%y1 UF DyNARD�/� *�#�nns��an Ep�orf M;Ar�brso> e#mo .�"�&�%r��$on 3% NuSiV�GTG�r��&( BioW��a�LM�O ar AF:�. �!a�9(L-�n"$�a�9X�Z&� Ɖx�lu �$7�1�'!# ("�F� ^J"�'t,*�syn*RiE��-�Dr��A�� Ancho��G )9�A�{�a gM;��,%�.�2� 2[��rp f1� !k*T 2� $.,3Sudde athj�-c�4�m� �5A,i3 tk=s��Chagas̽�N*. Nth5����in���cߞi�Qrio���U!�>� drug���', �%O޸ isto,�&�f��.�;soz�o s�Ia-�of��6F%�!R�� ��E�Q non- *c[�omyopaths#W&a���REMADHELmnd���>��2�etI�eF){vs.qA 6��%'�S� A� all-�Q,��1<�s.( mortE�; 342�Eŕ�7185��1�_dac�JAowNAd6 . 4%1X8patients and 53�� . 7% non-Chagas patients . The cumulative incidence of all-cause mortality and heart failure mortality was significantly higher in Cha2z(compared to.�.�@re was no differe� in tj�,sudden death�betwee ; two group�I XCox regression model , -(8etiology ( HR 2!H�[6; CI 1 . 34–5 . 69; p = 0 . 006 ) , LVEDD ( left ventricular end diastolic diameter ) g\07g0g10; p< a1 a@creatinine cleara!(�&98D 7– R�and us)� miodarone I3�5I�4I6�>�3 ) w!�$independenA�14��Zi.ARsev!M> �0disease , proIive qCisE�most impaQntE� ofM�e@se data challenge8Pcurrent understanding:R�!�may haven licationsqcselecCtAdm^Dchoices , considerfa�a6,i}8. ClinicalTrailam$gov NCT0050 ( REMADHE ) �1'( Amer�@| trypanosomiasis ) remains a bura�$for public!R$lth system�LaO0countries [1])�fact ,�0global preval�qof1@�Dhas reached 9 mill�4people%W25 are estimE�dto be at risk worldwide [2�A�resultv �iz%�X migr ,�-a^mic�%�reA;ed an in�s���r� . It�b�,�lhat 47 , 000 T . cruzi-infeci persA:�now livAin Spai �(another 300 I��UniD Stat!�3! S.�!p�Qq�/he A cřuin�օiMX6�[4eNa�thelesA�thiA0 form)ecomesf ly from a� iod beforivintroduu* druga�ata�ng �8natural history� �q�such as2��Hangiotensin-convert!\enzym!�hibitorsa3CEI� 60 II receptor �. RB ) . Fu!rm�(, many studa"%�supAP) fi�Vinclud��Hterogeneous cohorts�p\,)�rt��!�out2dysfun)L)�To !�bese(our knowled��re�7not a�nt� )��y!0E6�i"�)�qߥb!age��6)i�mplexe�-!�e�0ofAI &rrhyth��2 OQ xpreciseF���JI5SpresenE �X=SE�(dispensable��,plan adequat!Х?politic �*� dcardiomyopathy . We examinmz5-�d!�A�} ( Repetit�EduM;Pat Six-Month Interval)Monat��{Adh&� Heart Fai Out�,) trial; For�purpoq 1�)@,�L � �� ccor��to *� ��vs.5�/��od2��i�tprosp��v�Trandomized , single-ce! ope�`rvl Ρ�troll)� noni+vA�on siA�Ti��desig%�oe �;au�manq~/ am vers�co!�5YEchronrt}UP��en ��x)k%`2 amb ��c��� t�p ary refer��- �=follow �a:d. ist �experiLin:�/ cluu elapsed�jXOctober 1999 until Janu�200o ��a�h@18 years or older �irr��sia�V'� (t least 6-mA�� Ex�criteriayE1~' inabito att� eqG al sV i;��archer>:miUY be��a�q lack rans��IW, d l�commu~ � 0barriers; myo�1aABfar�kor unst��:na%: in 6�th���qX;)�ac�ge��r@oplasty�Ehospitales��reAllya char!� ; �!�e�� ���,could impairE�� ��;aZcedurų� 0 nfluE�I�-up+egnancy�childbea�pota�,al ( figure ��͑f�� demonstr rr��a:7rAX%�in un���D9B%�� otm -Z dayIneab or emerge�e�,{ well�� d qu� 6�divid�[to*b:���.ݵ)diagno� &c1��ba� on epidem�WcI�"� alongEj ser�# test� � recQ,munofluoresc%��gss��(haemaglutin1Bi0g atic!�ay ) pos�*!FT"� a   [76�a lter\ve�,AOa mixed��Ya�e��څ�.�=P�� . AlAgaa�/cl�fi><�� definiAS�� agre"� -membe�Vf��8oP ���!�manda�F. 2� o�A� un�e� @oc %in 1 h� z onse (new symptom�)7unwitnesA8ſ� iousl� ���A [8!��� �>� e�j��worsen or ac k6� , which9�)�ge�shockA�ulmon��edemae8termi�I.@ du�u� stayE:aggrav�d6�. O� w vasc���after��erebrCac.DW"�bs:�pr��;^bB�{is���; turb�of neu�"V . D�vrequiN�]ac��stC �, phys�OR �ag!� techniqueA�d/��utopsy�. MRo( M��zveri�acuteG4. Noncardasiov��a��n @��(reason . UneHBu �edid~za+�Ove�.:)categor��2� ��New Yorkm�A��I 1�al�� [9]q�u)��*med%�staff�F6c�͊ primeund-poin�f���!all,:J��Z%#�� obta� m�fo6 -up , eie�%�u/ atab�, review��re � by teleph� cont��}family��. Addi!S ally�oxa{G ,ional-hazard��s �u�\ xpl3�rel% ship�2n ,��!+ vari��s �� tim�#>� �_�� tI�is look�bt�turll z>� 2� censo� . R�sOMs f�.enc(, mean ( SD�or%�� qu�l� ge$��pproprx� fB���c�a��t�E�%zn�l�� ribu!�%ZMann-Wh�A� as 7*f6z�NP.%�q�u 8, -s�e ��Fis�exA~� � appl�B�&`A�he Ka� –Meie!Rtho�A5&�Y/�%>M�asr �Xlog-rank �.BXU�A>�)��� %�E:s%�2�m� �}analy� ,�on�s%U{abeiof� lan� �; brill] 1re/of��8 �ɤ graph-)perH o  SPSS�2t�� oftwa |�1%�GH$pad Prism B+�a,T �Gprotocol�e v9�institE�al eth� ittee�H&� s]Hs da Faculdade de M��inaUni� Sao PauloÁ s�� wrq:-vW)M��)Rz!8�anony1. Altoge��0185 ( 54 . 1%: �diD� "R in 311Y41�8a 154$!�7$* (.mK-iI*�e�mveI���A show!% F�s 2 , 3��I xin" c%�ty0�hig�>��m�>95"�2 �:��^�6'^�>�Z��.>s when@e�APn�Zc�'R+ �U� �$��.%�&�of��on: A�Z�!�fI� i�>��m*o .�weD iexO ab��� 0( NYHA FC ) o�in 296Y�� !�Vt���� ; M!!1��J� �!4 .2alu�( I/II�III/IVE�� �o"��ng�g�r.[ (Q�6!!� b. ,�o�`�q+NUT&?!h(spironolact� $, body mas��dex , F""j� on f�  N%ndSs�G"(J!!E��xo�d (< � �i@ hemo�i[ seru�� dium  >~" , nu5AQ�i������ E-9 admi�#s� :�.1�"j#,V#A�M =�ES֫"onM�1\Q�( ���O � h�� �2���Z�on both �s �2���Concer��oxic *� = , itQ &�"toťli��nA��u��� lung \ity�ere*% ��s A R %�B�4!���q�7 � U �S�ioo��� C�^��Bp_ vail� �E( 8t �1Inw���E&!l� or��Ewh�&ed&K A�i�!d sub�#ti�a�=a�� B�( 38%�5�.R���2tdet�C�ofR�1�15� >u 23%7E�I��!esecond�tomR�i&�c "�� &� *& � ,6�!��NS"throug��#;t�of �>w; 47%A3e��a� ��"�� T�"* ��$ some limi sRsh�L$c�!d!Wirs��" K�a�n �ae��]U�E^.2�#�F ��t�%)baV� i� �!t*\e� th!R%OP %�""*�ly!I6G����v"��*)��!�&ably sm�yanF!��"5 $ .&)'%�ed value 1500��si� A&�� �5_���%isW(y low . How���Ftnot�"� c���U�T%�f�'A3e��of%3pop�!�e few�R :�2�!�+tA�r�:�!leszan 10%Rfortunat!� c goldqa�d ;A�eE�#��-'spread�4confirm certai� !z���N�|"�"i�+st"�@ �!s�JA6nS�i`! t ro(�&A�( iansq� keeprindqmr*� e�G"�pl� ��ron(!d!�j2*� ario!��m}in� w��o��N!�( e���au�"�* ����*��*�n�*I�$�qurm��'�_�!�develop9!*h�%gQ�o��c�r32�).*K %�!h60 ��re���Moreov� 6x��mboembol must� emph���pursuHF?�prior� sgiv/o enh<! �!� a'o��,,*U�)6 &d'�.Ϧ NSP-�Mact�kin�( NIK�+�(-��defense��hwa�,�!�d!��r2!n viru�+t=!%��gemini s nu4/ shuttletei�NSP���<NIK�.�on doe�f�� he elic)&–��)� lA]re�%r,%Th�8 mole�mechan!�� linkad�%nt�alIp�g!Vva��/- obsc�!. H1,s=<a ribg--), rpL10A�*&�$ific partn n� �! � �\�,m-� dow"eamz �$f;9�re �. P( horyA gcytos�( �by@ red� !&9��!he)�usx8*���o!��eA6c!| . Wh�ectopicJ#��I�<� hypeE�ve mut�/promo�,�ac~ Fp�edԡ��&E�i!�u%�6_�*(1hrA�.i%@o-t>%�ed cel�/Likew*,�! �-aac#)��.��� -��6��u0 F$m:, losP cQ2��s sus�i&`&.��.z,A/ embl�JrphenotypE�nik1 nu�#llele�We als��� e�T ehVfIZ� ter�4�!Y��a�gloc�%i�of�eK�0er!Wn�# measm�" �6] 0e >)a�n?ED/RNA si��!n1Q}M�st%�ugbu1N.spntI wt�. *� �Hle9���%�-.Q�<� d 9+ ��m/WlayerD�(in Arabidop> = 69�may b$ volhintri�p![h8 ra� ��-� e obligq*traa) ular�-E^1 iM'emarmak2 ex_ve�{ba7�TmachinH(lea(t�..~*P..RM�their b&+&bA�A;,��on �-(.�sw1�-�&e K ins��2�u�qʥ�"W'.�l�e�au��I"%requH *� 1mo!e-�veEC;`det��oV�d!��,44,}3�9��0major describ�o� -��JT���.��gen�,`� c'7,_'t�� crip��al1}�ore�ԁ�!B(i )Uo�|-!, see T3, P1 I� cn of.��5�m�l6 st��6$successfulW! !95�i�YM/�t]sub�2)vi�tͮI{unc!�e_#veh. mpon�:� d�nct�/�Gin_1�. !ϡode� ne&g ADg �cr�/%fer� ing�SNF�*�&-� metaw c��s!�^-y� ��!�=�]�[5]–()2pn����paf� as!<��6� bi��te.�՝^� (,]$. BNB`begomoq�)�a ir��'j byC44 h5�Ų#Mp�n)rani2 -lik3 (�BN< ) ugh!"� b+z�Mi dom�6. G& e�3�e ai�u�#6�� � gle-�n,DNA!�:6J͆organ�%��ina aQ{v�F , exv *��e 2 �1e~"�1reg�Maɰ horm� �BRI�$:� FLS2 [17a�[18 92Ʌhea�N�1 ,a�!At5g16/>!NIK� At3g25560� NIK3�<t1g6080aFinser��MA�&� 171KU�a�-m�%�^the'veI�&�� � sB�L !.�� aF(,! 6�-�Ņ��onc�r�among&� dalJ Ahom�3y+om"�t��sq&� �=�`SP�}�D� loop"� esQ�"� by���A�*���Qb�;�=ABd0�w�KI��U~r ��:�be�i�����%�&7�q�Q .� -in� a"S�2Sp")�D�by�?oatq�-�'%abbage�f�l�u�uCaLCu�$, sugg�+} ���=��"Xq��)��r�9<�";5��l� ��� �%mod� FGS2*` [}�E�B�v�-5�N�!�a�&�n;l�?" 8 a!!& >"�u�cip" ��we.�U( F�L�))"' q��>�!uqY�. Our�a9Ds � � �bioch�9al:bR �%�� i;�H"3�,e�e tegy �*E&7 M�9HFJ . To1+y &�9]"�ei 1!U&�� O6y-<@two-hybrid screen&��cV!Ta6�c� libr�! !�soI���cl�1<2a full-�Fth ?� !M�D14320)P�� �r"�L10q�A�?Hfu�z 6v18 |$( At2g3448��[2PFvitroBassay�  bo5^ex ed GST-f�0 NIK-C=@ �"�(�"S1A ) Fn;A2�es�icLly�0A w �  0Al��aFv/ ( 60S�5qsubuni� )�is-�a�!)���re!en�ree copp.�z ��B!�T1G2691!�g %C 665%� ) [2W Th_I%� alog��90–95%����!}ty��t�%4y3 s: sign8V a�h>|5structwI&9@-�E�E��^ /.� � sAF rice �( 83%m�ty;�9�,NP_001054759"� Zeukaryo 8� sm2a�"a7!��$-; Q6PDV(Hf38I �-52%;� 1317%Ma�� ��human QM!�eQ ( 69�!���P2763H%"���7wh�0�A� � ����)Ya(-� *b -���Fone=t a�$,�A_)� G7L B�N.a &��Eo�EveuBBK)I�!��%.D!� !�A�^ �# bareG@e�((�!a��0)%��I*m&] � 19.4recog�1Ts pL18Ac5Tx0Ai "Gs +a-%��or� -�t!z�"��el�J�w�%s yD~=Z!���,����!� �-��.v �h&los!`1�� I�pu�'ve tumor"� orA�:�-�o Jif-G Ju� tQng`�a�9 Jun-+dimer��on [2NK��`r��9 � ́�au:e�> a"� >�!(-!�os�=!U"�N;JL� �e utiC6gro�3um&�H���D��hi6Arm2;��ZFco� 4�3 Conf� micopy �.0�d��3��Z8�orA%r8A3^Q]t=;)�-}a�&rky�Dm��,� xa*�O�9B!�.� [2�NIn�9͘%o�2�1�U�ic6AofA� �* �A�� rol�c9� �osS ���2 ���Zsc23a�rp B��Rane�ly1��EUv7E�as�5�[2�F�7 S1BIh!T>$-�I< ����6-�G� v0B�[ P ��Vytm`!LE�'%�u�y]aeHd%�%mM2in�+� . Du&i� vacuo�"�FeafB!��8is pushed up ag�.�U���2Nism!a�o�Garrow b,(*��>M)�n l ops���mKQz��V f�|7 pp5unc��Ll�Ttow�?�to� R�5�is�ob�t:"�1\��-oup/T� face `�|��(�+�M;Y�C ,As-L1:S�panel��4T>5-�MpU�a�0AV��r2.�qZ-A:!m�A�2X"V$' ���!d0 B� a 6�FHAP�'o5�ic�AU* CL1!Z"�@�ePus��YF��0�*� �%�2to\3�#�!A{6�(wye��_�.zJ�Kage en�%d co-�N�G�g-mIshe sam�1lI�IK*��V�&B)��anM&3�Fs�#i�5�!� A��uv� iL-� �]BI�O&�;<� 0fouH/o��f# �6+ IK1!ly, ;m� (&� inF ..�!b� �1�f W�5M��A��;� E�a~S- N� . �nvkg�S�Y�v> �>18+�v@i(o�"}4:B;!!.&~ fh�B�� Y��6nqpl10A�A�w�X f�!ivc j% v6�*, T474D@3nR �&�>�s#Thr-474e�a�Abn aspar 9���l�"2�� s S2�S2 <Q"*+mU�, G473V/�AnntN]9:a�n-�T0b�e�vj` >� A�.�k �4. C>�� �E��ofhDQzw ��_5 f�5Tt�5� -(N�YB6��i�.J��.��oU0��b%��:�)`&A< !+�)$AP�J,7E�G a�Y�:,is "�`�$��S5@&X&� rstX peri}!%�a1i-� ( QM104 ,M��;BeD�;:� plac"�$a��i'sl (*�J T��lan$�[d%B9AV ���a��/T ?N?/���}62'0٧y�, �~*To>�IiJePaz_-;6A�dr�4byB��2 ��KTVAs2[N �AC�E.E�AF�^or2�:�*� �by HS)� ]d�#2��I.D" E& b�1�:��!� hypo. e"T2az2� >�%�2�(I$&�0f� .)� a�$�&�(of.H5}� sMYr�`ng �br�rXA�^��m�r *L SݻD�lkE1eMGat-�6e�FQ 6=�o�a�-2e=�����a�!nC� ��5g�0B�m"�am^�f!ZE��.�a�& �_:i��{%& ��*�E�(2�)"� �=P>�<zeU�a���m�(IR��v>/5(ͧ��7}U� �1�. Y� h��!�!n� >IRA-��G&.1us�sE *� !�� n�Kar�0�onQ��<�4Z��-=Rvo�[�,aE" '���|i+�5:��,9!iJ simi0�2w$W oino�8 $b�R� v .:�!G�S!�X l�>� w�|Pq;�.�-�-�ri5�A'�O�� . B /W �ee% &� x/i�a�t�bY=vo�co-���a�[��gbD3-�`�v��a�6#&� �e-`-� a�T*�[wm4ticip)��vo�h_ �Q�lNT FemwM0cndY�a�p�6p{ s&fa]-aFv!(� �!s�#�aVc"�2B<6lw�9 ��\be� Z�� M�"]%Xs �k�F! N-*  R%�1�H��.p!42a�6+ �7i�T z�7 ~ .o ��nm 5ĩ s �N��\/+-i��exbi� assuzaQpe��&@�s& Ron @��#�� 9we�� W�bAn�!�Q�ZMcpkV,�=_b"�Ea�ly� �e�&�I��eK5 |can!b� =� =>^:i)&!$f Q�. �M��%>�a� ^iea�zM�4M�;s2[at�[l�- �R��)�2�$,"M E�M)�kg%� argu� ��%�o �.Z �:� F Jn/?2�A���.�&�mI9Sq�ar*�6B�&� �� g��?� A�Kq$6�*� =�)rpl10a6=5ZS4 �& to g&5*4,��W�PYSed"��remov�i&Y+ ( C3R%:CF+b4Ud�h:x6A�wild t�=Col-0!H�ra�a� ��= backy/nd% 2�a�&M��$� gene��&i�fdq2gl_A�%s�cod�-nN�,er�a+!�8 knockWQlib ,.�"0"\ !%�.�A"np.�,V�lI*5�S4���eWQZ �� �U2�a�?s�?�>�\7 9�CP2�-e- �->� 1.b*!��ϩQ�V>a,EU6y PCR =.]#*c3��. LZ�@recapitv-M�E�eEv�.V�� a�-�:'�%[� "f*b!r�ka?d�{e6�A�!��5�3} In'.�2��!av�Nv�� �2�)�s DPI50%�y9;tU1Sc ach $of N�Mc<��:q-���!3156 �R��a :rl!�oM�9a��*� "�XE���.X% ge.all&*<�/X �r^�<y�:���i����pleiorB5SsVK��� v �[��2��E-��B& *Af�Xdp� R"�/��i���=9QAAguish"�t��6, ttempAM� v�I@7� Mm)��-'�7ez�.��22 �?)�!�%���"�T�[$�jDT6] �A�ILqB TGMVH7ofMe�LaicM�) J�ag&��E�Y&�}aX�lBi&T 9�|�s&|bye�:.Z'ofB�"ec'$�� itu�tl�Ca��9xq� s S5�5���%�A��WG4� NIKs� .0;��;t"���gtoi�>�> �=�Uendz8s��X>�� ng2%AB��5�Bo8We�$:E�.����E d miT.�=�cau�'i�q�E��C�d pt=Zbo�OZ &�R$:�4�$6�A3D &MEvULJC Aa!�@��>�%�GMV&�vle��4A#�N�QVG�(JS*��E-|�!�$�4� vidu%�'�L�%r�oYMciB,"r induc�*m!�E�V�eCtook advBag�F!u��F3#��HR�p�;.._a1��6*�L}&�>[I>275=�BB.Z�FX9�uY�Y4My6�SPz"� S5�HowlS�K9�:'.�MP��jaC�B!��6�/Thu�!�ur�6e/q��Fs�pA aT�'>oA��89A%g�;6��*� �Ue�M"m*� T]�<! &B�2�� ����Q�by27���#@ �app�~:�Nb�&�4aggre�"r2V(�!1C(EN8 jud?qŋ�%rwp"a��at0MT)�M�j01�!PUj4C;{ &��Ynn� o�2 &he�i�-g%|��corpusc�)B".5 ab�tn`|�O�8�N�O�Y ��$c5&�*�-4w��@6 �� rUor �e ( Br�field�rX�aG�9;��!-LE-|�%� xas�< � ti*CeAlG;)��>�|�=m�.exJ�JC � ]1E 2$� .���EIN�*� !�2fo�/�2z#,stoichiometr�}%& �!k�SP�S���'(j1%��� is Kwas.��-���� CaMV 35S��mR� t BA��- -of-UL"�W(0L]Ewe�� ~2�i}^� \ ( Sl+�4 soyblGm EpaJk?�)P!IQ� a�b2jJ,*cE�.� %�ui�GB�7tAKqs�JZ  s625 #{/oB8"� >�izi�PY:���ng416����5[ J&��+ +�5gr�Q]���o� !��CE,:�)�(�2*ff^4 weeke�E` re��!F,�dn0 xpan�͡�2*�c� ON�3n��!J )�opCAMBIA�-o�.=�p%"?� �@�-6�-va�-H4 -��tR(a�FA1-4; N4q35  6; N�aYretar9L�"�E�is�n�j%k*� 5�� ��9"� 0F�� ��d�^�ferrH�<A�?ho�d!9=K eget5�1+Ie� M.~��B�%&� stu>!thU�1 <n� ��-@T�?�� T1k��:S:@!na4&�alQ`to=�1�d���H4n�FT�B?|,�� v$���8��$kanamycin-8s�R -(�66 1M��s. WU� ( WT �NV-� �� 6M.�"D>�E�= >��W*��atP uV� ToYS*�B1spoeR�?9U/ "#�kA�LRB��Q�!�of a quufH�q�`ns ,�sa?aE)�2#gvEZ!�w-�Mu���}�a�% G la4E2����Y"�>10%/ s/cm#'x��4ݕ)�%�'���few6s >6( ≤22i�H* d.g�A� de�� cour8�(!�&df&)^�+� 5 $. By 30 dp([56e±)p0!of��A�52 !4�pU;��-�7 I7 . 0A�of��|8�Z-�%> ��Fv=V�$FAt%a��>5�s1��%;�^"�S t!% �N�VBF&[H�7�E ��of�Q*�T!�-for- C���630a�zPV!�i�%4*�V�v\Y)w( TRa xAC4/C4�WqN�Y.�R2�Z[3�E�GV~� aQpK :Uc�qo"@17� a *yG|%�&�� �B��=�75&{ �@���V!�!1&�[m"Z�!a6�-wZ a_wach��*�%ng�(�vYM$Q!=�strx&|ZB�ds�1�)�stcoq A?�D!;�>�up�jfil. EA�`;�gvisy�);� UV lJu�S7� A'YV6 I"�by RT-�B�5A*�"� �!�I�HC-Pr�� ��@��GFP-x��"~]a��v�0VU�=l-�#e�c2� Nt�Y��%����|6VM���<or��E����)�&q"!���u4�>��* ��Ab"�=�� "2� , Nba2�'s 9%1�G���-J{M�bp5;A, *���-K "�2%+�t�0��ine5.O`*�7du�!f9O�"�2.�-�"triggbc���.�eQ&�af�m"Gd\.F�5 {aQ�A!e��x&*�$��z7A��iq�&��`�[ecrQHle!�sE�` d PR�e�A�A1� s S8�8B�/disfavU  r--1� �Būp��A��V&�L9��EM�1�"C45yre�]a�[�"�SiN�\�k7W�qa`c�t�b140o"� ly a����&�!$W0A N�#�0 .22+w�F�$�F�%�%�ma�]F�� TA"� e�W&]jZzQk�Fm�ELrai�to �proV�r� anA��k9�5D  De,�n5tave�;�Qhow f/D*�iir�r �">or�5Y�� ��his stilE�cip���%?*5`U"�OE%MQsUS6� ��0C%U@ �hJ*Zh�!e�)EGe�KQK�Ar/.%�0& B!�Ō�Eh&� ����e��")bg�"F.#eHb6 �~^!�\aQ �qm��p � 5FB� mpaG5.6\��\. %qR���a#s2W:m#}5&d^6"�fa� �$:�%>�r.�y�uV"���%wF�6G%�V$�i� sA��O*�*T�l�"V �"%�?�T�-�`e�".�AE��!�Iz�r�E�>M!�i}%�.�F�V.by&�>y--lW!/H�N�.A�&H>�Z6[��.J. �`):io2�e^�5�!:�����X��ncot��B�1%;��"�b�6�7�*�W A6<-APpr��.~��s�?Jut!waB-ex}o��iG E> �AR.� A)�S��k!'82 link"�%A��h!�%�5h ��� k/>�WSP�\��n@m{UUj^�-A�*.:L�56��*�Z��oF��d�!���VTU[a 8t"˘�o� U ofhX V��v:af�= -� QcG�s *m1%�=�1�x!�a�ofi�n��a��%x>2k�).�*Ano�C0,:Jj��!�%�urpri���h| Zj�+��=leG.�SW��lcan�4be 6-'h�lng�~�]U�Y,d��!C�a�PI�3, 68-�- X/MYJ!yN�2--*e/��V0���o�bN[uo"�a��Obia�C�2�d>^&�`2�0to�� ^.uxiliyX�SC A�U��4:!�e2�"kssmp�24O[3WVrK.��� rect��tim8.*�&0 �!�UebF��E�:H �WcE��n&m'v" �dk�R@��@3 %.�jJAe�"�B�)�3!"��&w4 kA ! � +�Un*/> 9&�9c2&5�ժ } �"�J� dosa''5��y5) ������1ᬁ�*�M�(-U�aC�Z2a�1� !Y;P�7NIK&w��� -J_F2Jqs*!:!B�o�.hY%@� fY�!j<�`Y)�~��d�Qu�(E��]Pr�[|� $�t dund5��p zI�@��iwhy5 dJ�ޖ[ �,a7�!ob^7r6m�9t����n͛ >�{ %�~Qy��"@VXM%��� A!�Ih� �P !;�"_�^ar� � Tym.G>�in�o)�p!��Y*�4. I��� � I9���ri�YE&"�HI����byQ��bAR%xbAsrZQ�� &}/�8_S�/i� �$*0Z�q22U5--� �>kmh.>i�ees���"�p&( !Hs \2Y�KX�mp��er rgy�C�#o "3%`{f��n�h"�w{(~ i'. �a �%~;oC�!�ia�c�!"� sign8�6A(|#P� oJ th�E*"�i��u"�to un*$ɤj!\ii"Cel s�^ gyoligoԥw)bri�@6�� CF��dYax �y�G .�&�6E��v.)?`��In�Mki�3"<ona�F�9!= L!8� d:�>�}�?e�WB�M:\� �&he "Larecru!�>2�i�*�A�Tm鑖Qg| ��� �y ;>>y�%� ��:�YF�&J�� r*8n*�A~P�L�5or"hŖ,� *n[��a=rq�rc�/x �a�- :���w %T5 syna�^E~ �iA� lj�!��"ey� -F1��e͟ish��6�environE�Ms-�68M�� . A �%�>�;ins lns d�|2�"}Iq-�4%�c�&o|$3iE.o�+!e��x�i0.i Yeas.��2" jo�� �G40S��c�cs [33]�V0X i��JŔ}��`iB��I��Z Nmd3חa NES (>?ɤ ) %8a ��k�!^pei~e�"�I>��ZBA?�cy�V��SM�} Tߧp,+�A1�DF�&*oz @:��V�7i}��>�A�d��m��aAe1Ve)N"�%�_�� b& �A(��Qi���J�4�f �a�!�PCinvok�2�@Y������Ia�,r.8d-n��� m� 6g1�g)!����1 Z QM origi��*w5.Wilms'Uav � � candptta-M or �[35I�"�p"S"r��nto-{�c-Y 3�7�chicken� ��,E��N�aor_-u$E@� A�%� �� .�a%�"�� s cjun–"� 2:-apopta� b , [3�5�-QM�~ �&u�� GRC5�fQSRO� \HA�lB_OznAA%pAY[38)l0an Entamoeba b�ly�[�& qL mKal]�> 1�koO�L*X[3*(<��cM�Y�ntB�a�E_6.x5��]A�&bd�s��w>�ALQ�&0{*� � ��.ruc� �7 mw"�����.lucmhh�>�m�17E����a49����E�l*(alJJ嵁(�K� Q�ve���h�T�* ly� %j.o���Dq'=�(�+��u=�� s@���Do-��� phyt"�z&!�, >F/��y � \^0add��%NQ�Re�A:�MC�r� E la���!TI+�mm� �a��"� � �59�� &�}a� �fR'n"7'�"4 new�s�%� !S=T"�!ɚb"�b*�(��.�"G8�`a!}�%qHc9q��] �MC�E�q�N ! s e�|� �1� Ac.)�-�QG .4i�2wF���sF��I;*Q@��AF8oB<.��r "{ �"y gRH.iY�ona�-!z%� �`aE� �5]d2�� 2�%�&� K_@�S![�!�!�4tx!W cH!{$LeguminosaUW SolanaceaJBr�wc "5��?. V���"ia2UU� i�5*4b';�P:��-T �$�.� �2� . Fo��6 B�qZ 0Jn0�me lybed2thaliana�p�q|�Gav0 BD-KDEFEq%+� er|a�X1� <� �M in MaV203�&i l OU13033!� smid*&{a�_[rk"V�E=ABR�o*� B�#(Resource Ce�G�1 �s pq �,�� pK7F�3% 2*�,�p6YT�^47"^&�{p��m�d�&Gh�'6�cb {0S�Text Sn !�� n-fr�ea�!��NQ �hveE�� ToM5U>.Q��Ic9MN>A!!;85��+BbE�Z+07! �2YFP-c�teA-Nos-5913��%�p)!�%' 8��y�A�%^ ^>?Q�2+I{ $!�.���93~E��oli�QBL2�H!3&�5�}�/'�>�,byͥ 4 mM�?�)4yl-β-D-thiogaןpyrano��� 16 h�22°C-2GSTA>���Q���-puM��G�Sepharn bead�9Qi�X-qY" � manu urer's �1g. P[U5� �% �v -�^ST :.}f�A-2m�incub6l0CI# �' Za�� 45 m} t 25!4in�5µL!��� buff�Va�A�18!�HEPnpH �5�R,�/mM MgCl�10nS061 DTT 'µM AT'3@d 5 µCi [γ-32P]�m��]�:&re! �%�&���"` [4;5ْ6@res��$by SDS-PAGA�]ge<�@ ��cooF�ieSl� t b��i-0��`5loae�,Aaed�Qsubh�z)radio)��FIn *o�Pd � X [R_NA9- i2�a�3�by de�0BAia�0Multi Gauge V�7&i�$( Fujifilm5Nicot� 6�9f�9%�{4"�\%8p��I���_m �ϑ�, �{ �l a59#��u�a.3 �A.�t�e [ens��GV310n67RI4�6Abl)72$�stt �f&c5, 1-cm2Tfr s)exuJ&�d��!��^2�op&rq��6�'B�5ZGnB�MRB&� 7�Ml�Kf�)5�!J=tzh. N>�aj prep&W@20e2�mN [42�sK��.�!H� �c� V<*i D�(2P��R1�6�-/ of 4a�6 ~A �g.,-��ha��e�_M�a\�7i��a�5JJ)�"����roz�H>��P?�7eSN voluyH�! ce-c���(+��vTris/HCkA15Na  . 5"EDT�3�;v/v ):ton X-1��� 5 ) �l2g���� PMSP��H ��KE2×106�s �8.�]7�CGa�vLa,�F�O.eiq'�%rabbitT�y?  tAa raiJ j72, r9 ^ A*�w���/��m��E!�>��f�-�n�B�ulfm0�asXfe;Yhin%�-!�AG�!p0.�s�20�1!�w%�$nonfat dry'���a3th˛"<%:!!%T1 ��'"j[97A���Z{ɓ� +�c�v��c*�Z7=�d N=E ��D0'B�D{OA��>$W��$F2tE2&CVك�{�$d*� �Uo��R �&�*>=���log*jK�Fl� !Um-�.V�-G:|D�afAge)}>�E��A��!arX)s�em�%��&�]n0A Ba�"�Xg���!�_ND!|&$16 8� .�Vd ra�3B�b�jGY( 5)�� �[�WL&O�A�>h:�ix-��� Z�Fi$}6�9]Zm[47#Total{"ic acid%k��X�A��i�&�=�&-/!�ɭi&vAwr* �or B�N�q(`%.2 ���ę2�"� �s�O= &�?5,$A(e!���,�A(�"�AS �o $�i�i��4�#�fO l���F &� �&�benthamix� ��(5(��c�n"gZ.A�%� �3%dsL10.)W5D�i6At a� I�P�I-J.%g"&1�f�CPRNA.Hy�.�C.�Real-۹��nVZ� 5�F �I�L�H%!� o�6� ��!p xE:=k����LH.�kParacoccidioidyUrasil��/a�6*�"dimorph�&K fung�5S*�of � 6N׬J� ! adap�I X�- j���l�����, nam+ox#"�sta �?T��|�I�O� tudy)<&ĨA��fS"&�+ `s� AOXe��A��vo��@ intr&�4U�x b�t�F, d" �t-J,"~W?!�-y�t�B�2*eFm� ( Pb� � nAA�( a)!%#��a 70%�uce int.s.8?:% elev�"!�n �\#A�I�conidi�5� s |IFN-γE�v�alv�macDsag�!A�c?�3od����hB&�wp� a�MS}'s� �ha� ���C�?of H2O?�N� �%4���ҁ�ere6% p!�.fin PbWE�%2(R.8. >-%�^]O&�Lvi��.��.m. Xover �3mKQJv�x�(%ca�Y5:wild-t�h\7�� .6"*�/k3dH^-�4�in��s� Ks 8%�24J-�: !a�(a8;��aHŘe�B��o^5�BiV)Ž�AJ TJa1�9~�S�W&��E)�6��Md�Qf�3��d3�d*�=@H�!��r�QM�-F0&��1�&ve�?-�,#�$�>�. An &�44'� a�� th]{#�+afN��ic�ito avoii��� �&EY�ov��y�D� ( ROܑ,�5a�per���OhO, hyd��e��?d xy1�OH− )Vca�Nac� Y�b�+I��h}n�� mitochond���v�%�ch��ť.z� ) H!9A�g . ,2�)1`3-1D2�[1z  d�� �e�d!Qr�,��@!iz� �j2�$�@�' �bioxlg�7statu%��%� .Y&���wfi�0��th����?% tiss��-!mo�M�5�(���sEK$Ñ YJ, [w H��� Qx[,v, , H��ia <� =l�C�- alb�i�YoV y8e��u�77mu�Ac���7.��!^!��Vatt�r�+HK� ;��m9��a=-sydis�sPichS� alyzfr�pof O2a � cf5��> �ɘ��jc*�_A$o|�^�dr1 k,��� .S�I�6�0.� �Afa��T6� qa ,F� �J�VY � y phagolys��es.�xex�\A]aRDL�����/�!GA�om�e� nutrE& poor. ��%U�>`���[1!1"�<�soN��� �  a powerv�{%m&g/�� :�&Y7.�2��jC)Ma�. n�� work��B8S��?�BVin�+��ŋK-�.�V�Jii& )�-� A� flavG#`oxigeP��-�� "T�v�5Q%�@=69gV�C}.�&�4B� ȁ�vN��]�a6\a�irYyaji(w��N�2�.T�oLI �~-��o�EA�!�: =��1!����Cam.Y{&�N�X�3g��x�xA ��* ta�ESTz ��e���~"�.�5�}&� 1 "� &� ,�[oxiQ��!cyW r� c !d�,6j "��,�q% Nh��.�e)�6OX%8Admyceli~ I4&��G<�c� �ymZSe���m6a�*1֧��o!��a'��:�m��nE�N�*�V. � �Ze �2%aF/ AOX-!�U�[��)�ea��2�6�]i��!A�JViO�): num® Taq�Polymer�� High Fide��2\(Cu mplo�R� �y��H�Bot�AE� ��DNA: AS{o!�bp� AS��107a�AS3!�62 w&P"AI�� e�4 P"�Cg* �./ &� �^���( ATMX >[��"�#�#R�+�!-n7 �&)(i�^��B0_FаpCR35UhL �Ca$� alcium-H�Le CBP-�7,N�g!"E�H�2ap9[�ne pUR575*�%w!�Q�a�en�2#A�!�%�:4t%t^ )ve�!#-a�!.C o,in.�-#Gto�tu&/��u�X�>e�R��QbO�ro�0![�"A/.�7�w7+)(E�m��E+N)>�Y4i�!�.��1)=a�$��` 2Ax&G $by Almeida���. S��N�)�`*A�U�E�v8 �� hygr .� yg; �--� a 15�)�+��N od af . R��lC!�ed Hyg� 5h.�(��8tes(a�P^�L�!�dey�ek�eD����(�Apecu�� [ul� h15��Z06e120��J^2�� Y5kd#!�PyyH�duv q�1Xss�c��d1��S �%AH�  ( MH-�#)cor� ond�mZ R�B�SV4�!>"�:�@�Europ�sC�!h�'E/C%NGo�Carlsb-C�e^ +�.:(2-Mercaptoe�op Sigma Alda�+��fe��ovC�s��:.VrB% ��,I�\���yJ5g�vd�4�05%�Qnw!bto 24- i� I�e�4[,( Nunc , Kam�YqKDen�y ��c�7A�24/" s 5% CO2{'o��� ��B+��a$e}��\ .��Y��= n 9r��' nt ME�("$( BD Pharm� .�� 55458�at��n��.i0eAm9�(~����)I�was��o�%6RU�1�'n�_�Bk15or)4|!� nA�fU�#qoE f8A/4 @�]5(� !�� �!��1∶1%k^�∶)a���P7�rFPEs:-�=YR�Q�Y�-or��30:, �5h7nr1}72�-4c0Ղ,Q�. AB�#,����ly�Y�H2O�V$�.�:�" dilu�=���u��i�-2p��L>|��5&�,&�horR���953S M(incubated a�+t 18°C as previously described by Kurita et al . [30] . These results were compared with the number of conidia or yeast cells added to each well . Percentage of viable cells was expressed as the number of CFUs obtained from each experimental well ( P . brasiliensis conidia or yeast cells with IFN-γg-activated alveolar macrophages ) divided by the number of CFUs in the controls ( P . brasiliensis conidia or yeast cells alone ) . Total RNA from PbWt and PbAOX-aRNA fungal cells was obtained using TRIzol ® ( Invitrogen , Carlsbad , CA , USA ) . Total RNA was treated with DNase I ( Invitrogen , Carlsbad , CA , USA ) and tested using a conventional PCR with β-tubulin primers to confirm the absence of chromosomal DNA contamination [31]; cDNA was synthesized using 2 µg of total RNA with SuperScript III reverse transcriptase according to the manufacturer's instructions ( Invitrogen , Carlsbad , CA , USA ) . Real-time PCR was done using SuperScript™ III Platinum® Two-Step qRT-PCR Kit with SYBR® Green , according to the manufacturer's instructions ( Invitrogen , Carlsbad , CA , USA ) . The CFX96 Real-Time PCR Detection System ( Bio-Rad , Headquarters Hercules , California , USA ) was employed to measure gene expression levels . PbAOX gene expression was evaluated in both PbWt and PbAOX-aRNA conidia and ye�ae�Pand after interaction�0@MH-S cell line at�Pdifferent time points�m|above . Melting curve analysis w��erformez0the amplifica�phase� real iDPCR assays to elimae=(possibility5non-specP:Y(or primer-d � st. Fold changes in mRNA express%$ere calcul�;us��1$ce between target ge!>`nd b-tubulin ( house-keepE#) Rdelta- Ct [32�� Each�e�nt%I done�tripl!%�A�ca-ta+A�g�Aa+acgccaac�c;!�)�@f `ctgtcq/ta*a��gaac;]�L:ta�att�e /caCe� %g)Paa . Isogenic 8-week-�0BALB/c male m!�, obtai"� A�breed�Mcolon���OCorporación para Investigaciones Biológicas ( CIB ) , Medellín , Colombia , w����Aallar�i��� kept�� food%�wa��4ad libitum [33�b$All animal��handl�� ccor�to�n�3a� Law 84aAL1989 , Res No . 8430 93a�n�ter=Council&DEuropean Communiti�� nd Canadi-A�L Care , 1998 ) guide�s�� � research�!�2G protoco�approv�$֮oethic mmitte �-\�K\intranasally ( i . n . ))� 4×106 P Zb �s suspen� in PBS bu�@ from either PbWt��P��-a��strains;��i6 N viaK��alwsa�95%� riorA �,:� A� washœra(wO�!�sub%dF0Neubauer coun3 ݪ . Sea+ te groupsA,teni}he to c�%�pe.~Xsurvival over a 265-day&iod> $t-challeng!�Gjeightl& %U�=Vco)M�for1$0burden at 3 d%] nd 8024 �ksn��wper � ) exa!dl�{-� ��aRs�T FU )A&lung hom�� atesfhe2%^p� Lon Mycosel supplemen� %�$0 . 5% glu" , sea�8,�incuba�Aqlona�d%� ed daily A l no9re�in #sAT obsera�� �As/gA�tissue i.i(on a log sc�� >ef��8H2O2 ex! ous treat�8 gene�= !�y+ofR .��Y> 3i�ayt a fi�Yvolum 2 m�!a<. Yea"xQ�Q�& conce�Za�e5�(%�015 , w 0  621 .  1 .*� 4 . 1 M )Ek6g t 36�Eaer|!? a meX (ical shaker-req as stopp�} dilu�!�8-c�distilA]��)�)?) hen � ifug��t 900 g�1 �% pelletEV�EA�.zt2� 9�[34�?Data ��� |hs average ± standard errorA3��m�� ( SE!Oi2��� �� at l%�threee�a�� stat!!_"i,a@lu�of varia� ( ANOVAc!&�I��SPSS 17%�ff,ogram . A p � ey5�!�� of e~? # c��P8$acrophage I$e medium5�) No maj�z!D .�.��I�; howe� a�A��|A� bWt����Gi d sl� ,ly most like5ue��!�$metabolic �v��1I)beapl%�� �.�i pVyA� UB�} �~gZ#H5�inu� ��of 4 �1Q(-�.))Y�!�e��+����2AV2i�)0>�AOm�I.�)�!Q�(at very lows=oug���haAU�CS2De�Tk ucid�.rol� �m�ox!iveA�ess�$po� indua by hAgR�e�A�d��C�:upo  A�RFwb^�8e!2��iK �A3�Funga.�y|EoR5�M�abs�R�z��R>!�una�-- �,!ƹAod �3 h�BP���%�ua�Q� 6 ^= both5a�nethelA#��)�^�n eia2= ��in])w� [A�%�)�U�3D%�3C%�In ordQo5KL7�W�A١Xcould %�a"�profil��R�%P]��J�IL�IL1yILIA<TNF-αqv2'6"-���did not1�.r�Qa&� a���Oz ��J�,�E6���ct�Zf � ( dK no sh& ��%��}�^?? aL tX uce1D>yin ~~Wi�Z�itial2c�K4�I��$ngly , hig���-��uom�f~�-Rk2�>).a�� .��g%�~. E&#of6�!�Q��be��a�#-Agth�"ex��y���relev�"� -�R-path�6�as fure¹�a2F%��>�-dV&:�c�a�r�� rec`edL �E��"��if����e 6��Q�5 y>vg,+er*Ta6� �q�}�|%�.�loTA simi� Gos{$1> �po:�C�ar"hD!�klyq^�v�* at%�1�t]6A��T:T Rega"_�?6%A%�͇ star!BUiY �154�#�(8]of 167*s'h�jE'Nl"�r( �"� dZ� �� 6�223Ima0� of 2�( P 001;I 5� Giv < AOX`n4 yn ampen ROS�Bdu�byD0chondria [35]�.� !X&��>'.��%�A�]�)$s��n��o�%E�ZN . Al�gh systeJ!cUDce�  stenA�reg a��ll�a e��,�yFN only�0:��W than��MU�6� Importa�� Wt)$s�Fl"�"B&(B� , peakAJat.�of�i � 'v2 qq6IHO�a�adF�}�U�q�%�!�� �o�7Ʉ� u3.4{ expo;"A%�(:�) . Itnw docu��� hatE�( Y� , O2− , LOH )9prA�a�s a"��� defSIsms ag�t�� ��in�B[18aH[36a ��}molecul� - damag� �q�l ~[37�P�ic�i��s� �to atten"kEm]*#�> � adap��d�th�!oa}�)<�of!�oxifyA`��8�Among<s)� �veI� se (��!an enzym�a%�pa)�a� Inmo� energy-a�erv�!�wa" 6Q(respiratory�c!A!�pl!�;in�LN!+��6fungi4n�t5� [39!�[40�OX�!$m�oX�#nV%�ᡱ�of O2H2Ogig � ?i]!�t%be�"gg�� by divers[  l stimuli-u�,s temperatur#�[4�1 � �InF�,%�has b�&associ{�*�:N�2�- r5�!�maP na� 0 tra? u� redox balin2@�� alsoa�uA�ve)�� A�mycelia��{ morpholog�switchI�.�4���� studT we hav!_plo�\%involv��� y�r!�)�B' ��"� �i�N� +u �c�7�)�:,��%a[ j� �up�� ourD9�aF����a~�n��rA���D��� !techn!� y [2�'[27E�41]!�c d!jV yѶ1� INF�i5ʼntoa��zA|��i��or��� ��[11�204=)I'troa�Qrev�c���;I**xl��B"<usceptt*ыI�1l8�*� 1<�T�(:j�eP g��+!��"�:� �!a"� ��q�m"o�*�alm�typ�In�0i��, aILv <.+`*�l�197�"fF�is�X� o~ �"� mB�m�� �� ɪ1����,geV1g6E�62^i�,c� �g!m�reaZ��N��g{ burs ,�\byV%�HE�n agre���|�2 re��@d�!E���iqui�U0A . fumigatus�,icA�[1� sF�iA'�$��fa�a����He^'ll��y�to under� if!@oxpX�*� B� 5��p-.A 9Mst����per!�z!*-��olysosomI�te.�=�}�aa�  *$N`!�3�\i5 �'� �\��Q�q�e!u�a&�ha� cope����b��3��*w-�R�m/!+la-bd�/i�&"�. T� $o ;)u�,.�b�'>`A� is m 2%p.��ypo� iz� .� 37#!�^���� -to- ]( C-Y ):���a�a�� Mqu�t� ��s y / �&s pe�� yet a��#5���a3 machin��e� �s�!� as21�!��e���&-(Z!�he]�r���InI�,�� workM� labo� � }aatmtp� n� �m6o �j homeosta� � �!�=�( manu�7pt���pa`�Marti� nd�league2010 )K ��dem� Eĉ6^��6D�� . TNF-�-^MKodm2� i,� ]��B� "��,P9�9+ =��0pro� lamm� ��$)&�fwhi�2ert�'� �"��"�$ of nitric��Ase-�[� , [4I&IA- e>� "%��T �ei�6���� of=����"�%:5)beA��3� r-v ��b�th��*$ !�)'� %g�� ��afeQKR �� :G>t��1Sa�46Xy�(is.�5Iattribu!�R "�u� wEmpo��o&�;� i83-beta�+ans ) ���uly (i��+ )h��It��]FJd� �gniq'b��l tin-1epN&+�2dtrC���I;�,*�5�=bs�Has=g[4?6� d� �(,��vY8�\Y<iw a�UJ lead�72ly��,*h�FHj�qg5��Also >���(>�E�NQ��Ll�&�, sugg�i4M�| 0j ? stablishm��e!�a>!, namJ$%�3i$p�8��al%���ac�e�� hiff]I� ��leeultaneo?"�ngn�FAQ�� �R�))A��i�B� "T&���0B�� �.��!=w:ͮlyͰ�Eo��hum:>sQ� Cryp�2ccus neo!a�a�$Aspergillu  �y�qM)��� e may�!Y.�*�a)>!�d�9op.Ddis�/,&� bybro@"c 4 inAN gocy3 )� �� �Altoge%;, evid� a�eV"t�B�)�� YE^rF}� virulON�* �2-���A g �Q�zn�� caus�%�A2mof5 dida albi���� mZdrug f�1naz�%[3i�!�re-.��;Vta1�? ,coccidioidom 2i�WV� i�arfinal��toU[[9��a�ed&a$of biochem�j&�to!>'s QtBb`life cycle .}Episodic-�( memgB�-��0�zac��dynamicp�$hippocampu!AQ�e neur�ub �.�+� r* s�remapp!)�Ё�chespa��map!`)M�encode[6ntextu}"e�%?tI� firX�u�/N'X�#��e��3��st@a��ltimod�t wayop� �.�" .�!m�ed Wfamilia�.ex��&n���� �A�UlCA3%  mbl1+�)�in4wa� �*� gradura%wabrup��fC7R�mtn�2Ba lack!�-8{for]ǁ���0-wu�%�A`OIu) �9E* divi�݉��?; mix| إn ��s"K E6sAh rph G-ce�nd Hdispla�Ah�!�chaQ ��-Q8yEE*whI��e seem(%L0li( gAul��@ommensuE�%Cenet��thea� �i%m�'G2�AZ6Os!��("[ !discret�.A�!�W}2uV4a+ uU-�inJ,lm� �Y�|� ����-&O�EA{� s maL2ran -��. Smo�)B�B s ar�#e �!a��.s�C�!u�"a heter&�  se�y�a�i�!���8 Kp � rast� r�%on��U���M�!�coh�C= o$D.'A�Apets������� ��b�B:�4=�AStrlrecurQ"feedb�%entai�a mP��8)Q�pd&uA4%8ameofQdAo�=M}5+kH�6aR2� MR]d8y can�2 �&Q�loz6q�s�I�]��A32/. S&�ivb��3  feraY��Z#)6m�cereb� cortex . � od� .��;�m�6�N �environmC1 ����AN�*�:�Apyrami�Hc�.sɡf,nH w?�Bi��!�%C�8nct ! inA`ce� w�mI8.� C� W= �$�-fBfe��s2E;�(rcshape!encloa/ss [[?tw�=Gs� �I6 �gu(bymL�Bho�9 ��'eYs'�) ? h"�FA��9��* �!-NY physH �"�%sp!? 6z � globa;@J� �.�%N!|.sof2� takea�irnew valk0[2]–[5] . D�]_�X refo ! ppeaq?bNAZd!Is�e�- s  �%ޭ6 mani���H&8 �� surrai;k)� , od�[� ask [8]Yv�F�c7H n elx  � 9�=GQlI�5k5[fieldsa,un�ed�J�‘e�EIX ’�� ) behavio� deci�s��)dBear�refle}�� \ipl��>.a]�vade�a4:�. Acc&UC��D���&R[9E;11]�$"�;"� � =��!xp9t�6nifes-7��� c���e2M�s aWm6 �t(D��!m As��rFc.�+y��� pred oVa"� ���.��$� Jn2ry"� squ] arena(2�a)ci�Lar +��ix steps*EJXCa1%�6�Ldigm [1�A�x&at�J6�I!�,byQ/-wOBw�gLAw$�)aZal1�-Sof "� !SreaE�5k each9��*v��" f�you�A�� � E"�) ynap� input%<a�AMEc7ADGF�( Lentorh� icarri�@a��fb�r��Oeens�cW (a)�Q��iv{ ^a��Ct[?!%nd$ �') 9���*1�O[1��9;�lA7S .�!+ , r�*e�)d"62to�N )Sr� ( 2P�hi denoM3:b�2zR">xAon)�!�R!uS �%. E>C�C8�eP�$o.nP�L�rel�$��r���U���puE!0mD J�-�;K�$ngt�:JeA �Q NSmo �o u�- a Hebb"L lear��-XsQ�w�I"��tAd jth2�-E, wij ,�w���Euclidw � a" [ir�{�r1u|0s || ( xi - x`y yj )!�thAeak64( ξim , ξjm �Ie� of M1!�z 5@Y�d ) : (�@w��ν]3 L�&�N!�< ��T?I�27 C~FK th L W 75 c*Fq.� pas�&�a�-a�Z )i�fu�B f ( ua,!��s�T norm^ - [19]�>&W� [ ]+mI�ct|FE��Qa���9!��H�Y K�!�*%E�e�9S�&aE�*��E%�1�,"thi-% ξi1)$@. 22 B=�c,4,op row; Meth�6u&�Z.����ų{Es ξ1�ξ m��w!��~Earm�$9�U�q1Rs��)unO-a�1=Y��middle�z�t���85A��#�Oxi�3�su� ��TgriZ@� dQ �Cd��<e�\C$21]i(( x��, y )-�9*�!\��in!� bi�3�,a�)��%Rrefer�*� E� Ua.e��A�σMP��i��F �wid�vh9���t� .�,:�,�8 !�GA�ro�K`U6 �.�out*a���s&Jly�!�2|�( . Ra&�EsE2 let9��9��-� visi�9W(� 15-by-15!�2 o��,*� a s"#jIyS�\/ng �IEA���le �Js� 3�I�-�a��Fi�abottomm�mt�)��>e� Is�o� 6E e����L!�i>� � a`e�3�YZp�5r"2�!�-Z �! "�2` "g �eF����� p�(Zr u�=1b��)!panel�F� C A&colAGra�?B� I ����c"6 !�%(Snd&5B�Ym!�&�*w%�H:�matri�� Eq .��.� focu�S�*i"t � )��p��s�3� � .� |9!"�, J^ndE'�=A�* h-65',�!�Dn��P:rB�.� S�"t%O�[ary:�4f�b (� ��b wardi ( J�V�U!B5m&E�`)a�N�( aKF��S� �Zr97aT 67%e��TlapQ12�XAW18�\. Robv%%1". �j"��k+L�&8 ��\��?U�U].V��2!������")4'b���lyBUm���� .�]dor�������s�� U (:�A�-�12: r �b08 , N 1784;<fo]?:2$)226Y��1�E�ES6� .!u� !� �Ja�c5-0 AJ!6�Ip.�u�(2 74±% 04;Yn�R .� � e*^2:G81G� �&^ �us� �CA3��|A�jbY)CZ�5�)���empir^  QPCA1epU3.K)4 2T6h46 �3hx$l�'U�#"L2�1 �;!P��fa�atE�}��be�@8�[�by9��!1�[ itecm;K� 6o5$6�Ek%]��5[2�If��eFt%����ttrf%)T�n:�,�%�.�sh�I�-`��Ge%�y�!�� E�y AAE Ba�oA^ E\4=)�A3]�Ilinearl�yng4ee�� 0 sm� t B!�&P(�F�T2s'FWa�havir;� e<��gN.HJ� �ig�u*�K-�� {"�.BR>��� yr->�E{�* i�i2! dT%�AqMm� � a\:�quali�( matc�2re��@�a^E�� qke,�*� � CT:G.�6�,���#v�A:� ]4a , solid blueE����  � 69g )*��� |D'�"� 5�A/yeJ eK�5s2;*��-�!6?�narrowɛ��y����to� s��-o�1:�! y al�Req�' d�mo�!�g"� cu� v�""�( CDF )={d� A�Di2��s�@ ��g{0%Y,r �m�2{�9�1C:ed W�7.����*0 �2y"�!!l2y ( sl9 � ���]Y�b%��H!�E�i� Rg,r�&:!�Q�uY�purplU���A?)E��0&�(� \� zQ!�>�&20!("�&�.VRl)��f. A�dY"�� *E59c�!p>�B16�Y=H!].+me�"yi!J 6r]P}~n@*B��marA��?� �6hC2I��m?l(� 9��. �[R� vdm{#�$� so,�`taiSJ5:($reg��D� :#IE ly s�Cq�.�.��D/2�Y� gray��8�"�"Xk �ũl�k%s1nt.� Q�of>2*�2fe�&� *6c*M*�$c�ZphenomeqCof]�"7�I#KF�K D�3\� �:���-b.�ra�MNa]P�"askA�hea( as0!�:..�}��@� �`B "�B� � �"��#en�-w.� �.�Lsa_ ��p�  )�%�receis+arbitr( I0�ʼnA��[T ���� )��!"> @q��1�� C_L . OW�/4!�V1��s2Ji�:L!2����0�A�$rretrieved��6� 2;�"�t&6iU-# �( r G382;  288;Hf .�Te�  free*_) = �hUO�3�RTa�(a�1  �.�UO�:f i�"�/s�:�*��Y�<f;!4��e�`Ş [_*W�)�J�-E�-zOGleA%�!��s9-er!R�.�81V 4 vsFu4�3=u979uF^�<�l�-ase%����# E�i!$ infl.�ai��?'J( E�I;J�J! negligi�V"W�'W� 2�9s|_uMto �- �a~}֙�"�"��0�Hon�)�L��+n1&E ,_ "� bum:D"�1� h2�InB4.=��O,\=��;��p�?8�suffici��u5 )�s;�&� *�at:X�,FU.�KI/N&me��v���_Af F�DnoW. EI.Vpq��conver�o$)m%1�$E��Bw6tuo!�QBij_-kr"�$"&�k!�B�R� "�4�#!�R> '�-�DEiu3�F��K"*iCj�a"B �1(X>28(SB[*�C&�L=��3F"����!" 1000F��B*dec�5gracefu�%N-�ap9�9�18 s 4c%^4�Why d! �J.: zR��*�6 up!� .w*_4�vp�t ? On%5"�v_,e(�)�&� bias:� � !Ya � , s�Tqnjccom��6 escapD9�A!*�J�"�=(c�2j } �2(( gyru�R"r�."g-a() stag�7�*j-!�l6���-1VA++6�C kindU-dR+�b?-p��hort �%�st�/MO�Qi,.�+a[Hic!�per�9Fyd25]�|trn@&*^0"N ���&.� �$ -M�q �As&� ��gmZe� G:e-�3� ��+c�w a*� t��R TdQ se6�R�`.�9 �^� `s 5c–� o� 8Rl9�=��-��LM��7���first�5a �S�- scra�;dj:D m��)�6Bs!tG) zero"Z �-�ek!AFw�MR��<seB".u��Lmargi1Dre ��3}��d�"Չ5u!� C �&ma��!atrL8"�K�:��^ pinkXAo�^reminis�N���.��=�2��2�nd.06��fo( S"�v�fi)11a!��W+�Ve�>)t�4.� 6  ���&!i[VrsB,A�I�L*��>R@*� ����"LV� : `* U��W� ,~|>z*� U7)Ph�saODZ-Gz �zvar�1E��*�]�UF�Q�R��i� word� a�+&[ B��}U��cing�o!��/�z�й�e�^2a ��!�Ba,;:va'H!��P -sub>*%��;9A�%�ya��:��/wxVawaU,�S"@��Axj;!�l��iz� =alreadx%en.�`�n`=e�!�B/=*,i��*�C0� � �.hA�=)p.�9�!�lot� ���L +-mmn�D�G �uK� (�+8�zR*/FV<ng�"|BJ&� �cQr�=� ��p*�>Ae�"* �(��i)I�! � I�7 .9�y* }bsY/=1�� }!�5� jf<�a[y�S�$uUf=bnG� �=a�is��<�A"�"� !�5)�on!_�8��. P"�����-cl�%�[ach %<P@�$+&a�~dency.�a  ��H"�r|G�WC�1`snZthe� rticip�A�;(eiE�~.�UaU���> yB�F>?}�� i�I�~�Xmo�6ES^]I,�.8})�!�1�Xowe:|� Sp �or � u�9����>Q�� �CA�ul�(u.�P�I��m�� "UA6�:}u� �Af�|�Dke6Rg�>�A�� A3���FDsb��P�ly%�b' broa@j� �r"�-�.a��A� � "�.5��I� 2vm$�`>nQ���al!�q���D8��d>�%#� e*�2��,�!F�62A�domR��.5<��U, �?��� A �!a!��l.�AH*�@ C:�..�I�"ReK�)�a��,���y �b our�BZi*g; �� &�b)���a/a0''RE ��C"�G� j"� P >OVD�P[28N>"�� r-\!�intrinsV|-"�!aN�"�+� ��JaZ ���s��!���"�6 "%� 3] (��ee [3kc��)E�%n 3 U����9�� �|imp*Cvei� self-Zho�es��or vis�p.����?�ii��.f�iمEced%Uu#�q� ���A�Y�sW p 4yl�N;�i.+JeNo��\�|two�� P�Y�E�� �! )R�UM&J�veyi��0� &� 'E���"�> z�B�b��fc �%F�-MmpaM�"Y a�{.�^c�leA!��UG>|$iA�ou���eq>� "B�-�?m o�-E "&9�u l@, [5kIj�w#�T�N�I>�>�defforim�qdrp�I偻or "u�+kn�*kopFA ;inF� ��A=$�� -��Zmme�nGi� �� c>F Md*sharp�" =�� *U3�1j,�<,1�]�Y�."I:9iDJ >�Zsj&A��  &�� A�a�mon��|T,FX lm�yb_��map�'-c�Vun�edE�K hartA��h�la�def�DI�*[�:�B� ��@%#�l�!A��.�">EY4RJ�8�iS0� ��erpre-w`B�F�RL AnE�l��c` �[!�B �@i)#r�E4�fI���m>b,�8- #��P! auth�K2 �r2�"�e&� U��.�Ҁ!/�9t� iso" ��=B~~i�n�3��O�-k?Q[P�� coa��36tru*��W %&�^%vriA�*"*B = �1A� minu�2bQ}�d b�4i2"K)��N9]��O*,�c�.qC��m�7b) k�ac���v_�n �|�NvR��.�H��=+HiY�Fu'5e34� �6�DC&�� )� *�landmark�h��Eo�$ ���A4�@aP!1 Ŭ�!4�4�V�7"� *�a�BV!�ey�q s unɉ��!"�*A��5�ej%!�y& %{5�� dM[h*�d[\". A Y��� �Y�}Z����e< 6�%%� J�� re@Uc���:& nd dv\J !�d�� �Oe�s�pt'what'%�'0mW" 14� '7O"�;Q(Ŗ�:�O[Qg rigu!2���D o�r.}z-"�.&��-[5i�5�Ra&� �p%g�*U6j[b=$�4R��c~*� 6Iis2*�_b�?A��S��&w[3 �6@to�{>YFA�1�,AT�:mR��j&: &erm�inhg� ion-�r� a�*W co�^eAD &tga��U� [5�[590+I�inc],N;I��BB�~�di"& .���Mossy-H�a  [6��P"� .:�� x&+31�"��� �(aޣ?-,O !Q)�037-4mai�IA{�R,�N�"[EpmY�!��be� � ��Fg&��;2o�p��{=�`bn=Vy[6How�wZmst��%W��5t�-��g����E�! ��?e�e7 mak� �U��Z��<�u2�Z"�. F*,^%:5%*=�,� arby.��!} 2����RI���J&:�$� q�c� *G �n"� w2.� !Pr� sa>k )digLGFur!��� � �aAE�� �R �� +0 ��L1  �N&� �) � e� ,2�!hT�g�!8���Wb"2�Ia �3!�� �$�B�0�Pa�ir�%;�y� M�t&͘A6�V/ɑ"6e�� D�2�$!dFo!~A�"A:{�" on*�,u��QC�})44_ l�Xr\�����r�be;n�����Fr] &�a��.R bYi�B�>�o=�M�y�bd�iqu>3�L.�b�.�(Ng�@-�ab��t��]:H!�uE50'��n� "� �6W"��smA ��ng�@jU< a��C +$� ��Er!"� � @� �d% cqd��4h b!/� :�n[6� k T? F�:�+'�� s%�orimot�;I%a�a�v�(d.%uo�1��bn�AS�mP �yC4d h?"�!�KpD*�/��g� [6� 6� G: ��`�K5�IAi�b i�R)�$� ��&�U s�]"�� ��k�v)%�1�U��&�L"� !W,%�arN/C�Qc'�e5� UD �� :�J�&�stoRkA�9�%�/r�+g?.�[6� 6� All�-�qbas�,a 75×�Y2� g!�na1@r5�Wof 5×1Z2 �q('toabX� 225>s�/�[�*.�  �k" �ehi� Axw�AZof 4050J;.F 2� X�*K�gn�raBfV9�ac~G8V�V%0^o� eno͊��QU^(�S�S��;*�K(`�$5?1iS��I����y >.+���@Pe+� ic bZ1f/i MAhM�6��1�V!�rJsl&�`.�Hrun�XMatlab�~ 2b (h��z�a!@J Euleձgxu�jjf%>!}!. assu��".�e�1EAM1i0=�7m ̥ −5� E�f!��WD&74e�ard�� L�/.���M� �=�cri�d�$n 239±100�{�.n� .\B) (��� *�?mKF0�gover��byIz�!�J%�exc*M�a� &�C��d��a subt:0%er(%r"��$� �7a1:-E��"" i$DR.sJUqU6RMin�*�w:V:�a�e Oe�ƒs�=f�50iss,.�N��F�i-sA rs�`(�w�a~� e&�%� thus2��&��L>:A� re I*�D#�0&p&�5[as�Eq �o .�A )��b�A�q�4210A�R�%��qs���q�k��A��p"� &aW1d�� d 293±13�_R 6 V&�. RU�.B��aEuQ��c� &P+, w$g�qC shotZ�b� R��"�%��FEqbPTwoU?5Fb&�_,�X Q��A$gӐ toi:yu� !�ext{��MMk!���&�3qw�47�;)�t���sp:aaf �Z*9��>[./��:ain2�`!�j�`��r�S�0!18F�� �( i �� !b�A � Q�vraw�a@y AFba�tJ�s�!���J-�smJ�,]�, nins!� ��hachU&�-bU2sj�f�ξξn-�0�m ≠ �mP  b�.)Js E�E�aB�0*&�6�%e���3.\!Q��c���_F"A���a���15×1&- k !}�.�. B� *\U�J�0�p>@�"��u8 ��fq2�4E%�?y&ik���M��sX^)H-�{ �%,��Entamoeb�� stol@�98zcroae��i��en`�A tozox�rasitE!is amebic\it��ry9�[ absϔS+ mill�� habi�6% �#��M. T� ozoiJ%of E . h�� �F� eCB6 %t oxygcud }�o ��� B��v[ >j�{s�1cg�I� canoծeukary��r-&�܍s2mAf$atalq!6gl�ho +!��vea5-yet-ee�^j_g��y post� ),�l�a@inB�� �od*!+w�"�ldx)m"+�&�JW:�*А-�cquat-k@dF\�K%A���dxE"� pill� 2�E@�!c� -of-fli%-mas[ ectrometr�cW*8"�{9��s!�cadra�D�!S��N7-�5| glyc��i!�chiH�bio���*� amin�!i�s�pOJj�ul!�O *a of.}+�$in�������4��߆!q� TreV�ci�x ,0�ex�*��,j�Ai��9p bran&0p �"hosph�2�L�MX+!�K -/�-as"�m�3-ac��, /�;�;M� s upAaVh pyru@4a�nd!�eol6�e���2)�cgtri�C&�&�R��KZEA�i��3*'�%�Ui�16J��"�q5� d.�MW`3-�E�y9�9�!<s�WL,"��i�< �ER�E�qmcb�oN�. OrganC�rL��C( �A RNS Rt�ޜtoeSbio&���5�e��/pid� \���a~AmT dys1��{–օ���;�Ca�ByEKM=BEƳ?���apopts��Z�3*�(��#� deO[3�Q��?F��;.mselv*ds/ �•�b��Xs uti0� �>���B*5&���M����)EAS ra�Cl�%v۹f6�ȌFw ��eJ"ӊ�� 0 p !�e* ��E�T ����onAm ( tole� 3-Ms��� ���  [1�36a��>�EJe��a�o� �x>� orF� >�� �nvaet�!��Fr �Bipropan#on%?�(_!>F, �A*4 ,��c� wL?. ��W-reԊa�� ,�!�.w <u :.�RL��o� o�.B�%� ��� 6��dehyd_ � ( G6PA��ut��s"b� ( PPP )ebA���"� � g3\!a>��/�� �c�teroxi��i�su d�&smu� , rubrery��&$hybrid-clu�@AV � flavo-di-�s���(a .0�AJ�2O+��a�� ,B�%��=��$c��yr�(ec t��-.����f e- ��i{+�on�C�@.�Fem� �(�& NADPH�!�sNADH [B1yprt�e �"m  a'Y^BJ� i(�orgu��. S-�������%x(iF(�� >O�G�}��ov"���v2Va�mfic reg.,el�j%is)���z��y�Pb�-��>U)��Cac`oP�-$ �M�).2�(�N*A�r-7M dZz*>u2k�*2I �E�% 2�e�.�cap�&utrx ._2-*����-�Iߥ] 5j� Z� �"- �5"�r�d. %�G��'&> �&t&A�by]� �J�9�6RL6 ��u)h�ittȴs}=J{��@oBt-& %Be��Ѽ.|� � cg57� A ZlH"�-it�!7 �7�0>�!�; ��) ack YL al�w�# Tric�ynknd Gi�ba [�B4]m�� �-t� � �c�a�n "# ��B� !3"�$2]74s8*lo0J�5:&yJ{E BO���� =�����2u B�up4>� �)�V took���� Յ�A��>|j�em �cb��r� ( CE-TOFMrX ����!ta�{�/�nE "M y hundred�&�rYvA�Y<�@�^%�<advanfVI��4�A��e��O e�G!�olu��A`*::��a� ��low–�?4p un�D255YAdz :��un�>JF�&�.Q�� *%uOaĵ� !�ByJl�" V�. -logarithKgrowth pA�AG�c�113ino� ���u��%T(one-thirtie�Ho  welf&Gt=(��gv��F=t.j�3��y@M�>)�W���� �in 36 mlL flakI�TtX8eAumESre�1Vfresh0 warm>0�S� F�,"��Q�� �2'%�l2��!m1q 4 mMt.)"�F�aQ" inue n�(Ny��1�or���eI�{U uUy�f�$ dK]oY�%�� 6�:�LI�A-�x@ %h 066��Ta*1))"Y�!�.�yE�BinX%�of −7e4mkto �ih.��*"%��9��e"^E��rtifacIV�ion!&��jmis0 &�Fe2 xte� A�&��Q�2- ( N-=>ol�)2�fH aci�1�ion�"suiD-w�hor-10- 6eUUuy,$UU#sa Mtast�$�� 30 s�2!�mi��w�[!�1�ɰ�#I�640 µ�#de�]J� . ��vo�7���mixe�E���i"���600× g�$4��5QF �aqu����YB�)R filtv��(an Amicon U-MC�ra,D�>p/C��, M~�chua!���!:�9�J� ?u2e�! s��dZVAs�6tA�80���>�!��@u��0P�ԡ�$.m�O&dissol� A+=�-6��xa�J��~+ "e ( 20=��e�of 3-�pyrrol��t�b�PE��\��A�82�gil� CE C"3 E8�T� S�equip�E�!� =6210 TimX Flu:Xe�01 isoc8,c HPLC p�),#G1603A�( �� er kX/�J'7'ESI+spr+('T4�2$, WaldbronGer�!-AC�!/!�t�byL0G2201AA ChemSj&softw� aOC�Da��cqu���Q9�PEf t QS6?�TOF�p�CB�!UF, CA ,a5L; MDS Sciex , OntariN C���F. C|ic����~��sn ��<4fused-siu3*>( 5E~ i �-Q�0s����)a{E� ��aPci� a8Y�D#lyt�R�j�E&� ( ∼3 n6 !@in�\�Zt�mbab� 3 �FAa� N6vol?e. 0 kVBa-O��&%<��Ny��.{ t 2�6*f��+`�l�#Sheath l����8��f!�hanol/��!Z% v/v"�on� ed� �m�hexakiK ?. 2-di� o��xy ) $!zen��el�)(1!�L/��. a%�!O�%&� �*�Von��0a9'v-T>se�4![!a f�AS!t"'gm�!er.}� 30%Q�Y N10 psh�`/ ��� frag� er� , sk�.�octapN�o� �y9 ( Oct RFV}�* ~7��5�G��VF�An�No�6Kcalib��o*(0! y�u��+Y���s� s;$e�13CU; dV�<( m/z 66 . 06306�3�Z6�5 P22Q 2896�0�*c.' ck�a��ct ��(! �50%!{�����l.\at�/š�n1a��1BJ�3%�kV2"ڐ�me�k10�g�l200FlM�q�q:?���=�sQ�.r��. 038339A�ӞG addueT�z8 y03554����� ���,GO#os{�y aQq�A��"� �w��NZ" Ain-ho!�"� Ma�:<JV�&�o l O J� ��"��pWf"��1: noise-� et,,�:DY-rTa�mig�[��+,��jD!�3�0^�.(aZ02�Njsl��� phe�'!��sw��`��Qk S "wa4'�yإ� >!5T!�LC� �G -5�&�".Hu.0 s 2� �MXCMS [�ZS"��l���+�n�G�l�O %%e�*�0by Gauss�� D fiCl -Jdo" �6�M�C�Uc alig� algoIs%�VC�!3�m!4fV�ll�Q�&� i�/�.Z�A^� �!s�B��"0��*�-u* �..��y K"1v� us"Eo�'OlJ�,B.�R%�e&�%PQ�U&fS�:�5&bM�dng�;a ,&�at 450 g-�was)Tw,%*NaCl/Pi*pH ����T?.�ly�nin65�7S�reej –tha(Ja�1I�CTrihE�e��W-"A� �15A �A�10.�� 5���(�#�-��f��I����H�-RlCF�nc�M1 phot"17 ���Q !7a�^q�3t}xl�>�'� �u J�vR�\&�P���. Brief�@un��a�r�MAn�h*94F�A6g f���0M5�"%KE%&���m:"A�QM!J�!�t���k�-� darkUVteϭhWeuocIi*� readN�=!��He�<��ave  492 519 nm42~;st��!�=�A�0,�ol�l,�g'a U�07��k�u7�)�1!��.�(5�!(1>))~B 0 mL!dq�( 117N�� . 3K�� mM Na2HPOp� 2KH2PO4;�$).�1%"�(( wI'2 <�bb2�-�3�͈quick��"����{�,5l!S�(na�, Me�#-�A�B � n�5y)ω��<pe � V=<c�hlo�c�2\earliQ�j�i2,UW. E �2�e��ΉD�@[��k o�BioH@o(@M2��V2Q�bA-�� D�� k15ki�*6�=up�+���)�A��ɍ";4 BIElac�J6F+��� 2g$%��ADP%�yl*�+��!AATP-�4*�5�c�1�A2�! ��)( ε340�;�,22 mM−1 cm)5 >��V�In"�59#�Oed� m�MTris-e�3 <s# �F-�-',���5c!* �7�)� ��o���( PEPEARe��;E�i��MD!]a�+�"y���;� xo]��bsorb(5!���340��0on a Shimadzu�d�S�er��*}&�%�"��on�>1V�%#&� a < uV to h.�.AWe (%)a� para�9!?B��.� �%�KC�*�:�1� o*�.P�-d"�+!1q8�  )�2dd!sH��tokDes6��e��!r]�grec\q0-gis<8"�� }��Q [z�1C.+.�2 y�g%oni�K1X-BH-tKE��59��xYD2�E�)M�~a��R,�lzs� �{*��2ME(v g��var,m2P� PQ (eV25–�0a�E%� –�re|q��:9 Q���,PQAe4��=V�A.���Xu��90%%�i�r.�d3'F�� S%�"quSR$,ڣB�-T1eHc*1r���$rophozoiteDs for 1 , 3 , 6 , �m2 h to these oxidants , and compared the metabolome with that of untreated trophozoites . Approximately 100 meC 0were quantita>@by using CE-TOFMS��enzymatic procedures as described in Materials �Method�Both PQ-J H2O2-medin�@tive stress resul� in a drasu$modulation�several - �involv � glycolysi �it�soc spathway1]Xamino acid , nucleotide-{,phospholipidptes up�!�.�0as visualized!�@hierarchical clus!`,ng are shownzFig . 1D�8ime course dataEj.&or�Tof particular interestN\2–4 .!�aE{ic!�ponseA�b)�5��0ed similarity� term%.�)Bd; how!� , t�kinetic0 $5fM :RTis clearly different (9() . In addiEG,6�specif�si$also detecqCgenE~, when}�o PQ ta�m},E� caused raALbut mildB�e-de!Ѕ�c95ai,magnitude of1]o!�EA,Dlikely attributabl%�natur6:w. �e@e�izEwg�itselfm thuq�%�faA�$ appearanc^j�%H reas!?$indirectly-ha. reace(oxygen %�ex�in delayY%reM�D. Like G . lamblia%:,T . vaginali�8E . histolytica%A8microaerophilic �lacks fe%FE�#(bic eukaryo��)Ё4, includ� TCA cycle�� �pry�Jon jIs! A|gy ex�iv!�(by substrat�zBFA&ferA��EH[12] , [39] . AmongAQ>���Y�measu��by�-baA� �%nana�u,ѭ�cI�m�� cent�� � l!K$. We obser��a-!l incAJeA��abundA�%�E!M.4of�;�Y!\2�_6��56-fol�� most:mA'��@s from glucose 6-I!� ( G 6-P )�wpyruv, i . �1fructF5F 5,!� 6-di.\F `D, dihydroxyacetoneMVq( DHA &3 �o!:ric�J ( 3-PGA )M� foenol�VM+byFX%�e�exp��a�f)�A�1��!l���dehyde��. H�ydu�/0high turnover�6$low stabil��,E,YK was un�(u6A -accum*��t��o:suggestsi�th� ��&fdeYWA�,flux through�� downa�am1  ��coacstAPD$significan!G6`uMIF�upn5�V�, w.�n�7roxim� 2i>.�ethanol1�ajor end� duceYq7cat��.inB�q�(4C , see be!�A�suppor�W!premi�hat=�%r6a�A inde��ep� ed2ono2n��apA�pr��M���D:�%�*�wei- foun= atZ��U�ed.�Y� re-rou&towardsYkas"e w� -*� . F!�xampl\ r.[�re-��ed\8chitin biosynth p ,a erol.+via��!OL O��serin�an im�{!�cursorA�L- %. A:� �F�hi� -�!�of-!a�free rad� & in��of keyBo� eW �� suchzU�!:F]��RA):R��e:� or nitros2� has!b$viously be� � >} [40�41�@Ramos-Martínez ,0et al . ,rea�edY�-��4,� ��� �a�9ATP% �j}��,SNP ( sodium �pruss2�ic � AKa�er ) M^d apoptoA J�. S1 lAܡ61N�=�!�r��E�=5)J� expo��$to hyperba �y -� Alth�ea�&E �� sel�b(�!l%U!1I)V8.�tprID stud �n���in,s� +!X@22 ��varQ>�>A�Y}1]�a 6–7 &� Q[z"�=�w��as nie�� nor� &O >2 Z ��our �h�1�Y� � chem�r1�,k a14�E !�of)���,eri�alig� :m�&�it*fa�./ shouldI� emphasize)���&l ho� V�%chargeds��� s far mo' ensi=;��B UK���Qely)Y pen\ � �SK ( PP Ein"� �` bo6.E�&� ribose-5͙X!!H��/� &�)�u �aVreducdequivale)�mfor NADPH or 2%$6h�ss�l�is wids distJe5ucin � pro �K&q Unot func!�� e^.�#ichr� . � rogenase' 6PDH )�(transaldola�� . AsA:C�2 , �6� 1�on-��b�h�-�d>� s�Ery� se 4=� ( E4z ![l .(.AmA]dR* (�aed 1 . 5�4W �a�� More�  dohept �72�S7.R a maximumL! e9����PQ����� . Ch"=al� ��2 H �ier O:I���&I 9�5{A.� abov E�-�B���a�.� � ylCoA)�.= �J|���ca� B,bloZ{eleU�uptak�ntinuea�leaZt�*9A�reY �� �1fc� r"8Fs"� ��A*��.�iok2m.�it po�Na��ltern��hex��a%�converC ). does�3r��re6r! [ depends o��g ��s:��o� ki�0, Eket�$m[�3 [42� T�,Ś%�valid)�� ��p� e!��Bof� 6ON-J J� �Ite 6Z ye�BlQs���,.i��MW�S[8!,��} h ,:J�5� ee `asAKIw�$�2�.{thiw ye� Cu� �`E�� %�6�2p�O��-�N#a+�al)-XA�� rol�zn�. A re� M�E)J�� )�nje6aA6$e�n crip!Nal�programm�aftR>�[43A7It� �E�ץa�orվse�n te\b�a�og 6��6�6�] �on tolee again��v �e\ ly�"? a) [4=��/&s%*� discus� inm�%@,aneeds��be fur�tes� wha it�  a c1  >�bes .in��9%{b >�� 2�� �A>a����!(*�NA�w is� by��toX�[44PAJeelani"� (unpublished���[1@u!lby� id6x (E�-+~ F~H ro"� proton ga�[17a>�exi !wo� �og� �stinct!�ms durah� lifef:)�ror)�,E�infI� ,�9!|�ic.H \�!� dorm#a/2 C.Scys �D surfa*y�e ed:dcell w com�of[45!�[46!12zan�/IjDb� wo yJ%�C !Cama�N- � amA$.� ( GlcNAc�A�N312n 31t �\ �xPn e�dAKe dra�!�T s ( 5–8* !��"o� (Q –2 . 0*��b��̙A� may ���$an environ� $al stimulu��trigge�A3)߁^`j�con��A� on 1 ��e�<a  a�aS!�( 4 v� $0 . 4 mM )�{͏o�.uc� F�isomer�P� s �EH� ts1��A =�9den �A� yst-�!6uc��>&[4�=6� Bs��U*# �:ti.4[4� On"r� iO won& atin�!��Yn�Ab-)te�$�˥d�in%%��!%0$ ch���"�adK e ext l.i!�64i�%&M��A5 �oligosac}ides c� ��U�pot��X%%��caveng��.� s [4�s.� i�e � sour�: !eJ@ , u uce2��is��"to�3 leN-� g#�e,o 6^&K�U �* tr&n� � , GTP , Ua C ��V����^Y3w��A&B��mon�spy��AM�CG�IMK��'� �=����!nn� ppos�Q����-Kir cor" on�2!cou �%A�p&9[f��r� remain unDd except�ich Q��'-XAm ��E��ine*e a�'ge aden�"eUN��eS -B5�B� Energy��%E9~>A6� A�cr)t�mpro�nta�.�.�rA�� �1�=�6�A=qI ��&onsiseVw)�2R_w1� evi%�beB�6��u"E �[9@J�1~2�4C%�WF"*-�]�icotinam) C)Ŧ�Ѕ*]ra(a�|�'u�� !��!'G&!N� )P*Y�e"paraqu3"�' 1�+."M��\e�^�b$only sligh6�R�A&�*s[B�is im�� "n� �Sby.�*c&![50- 6�>F���unique /+!!� �de� ".sulfu� tain��' �id 1th�� deri� v6 itq&3- ^ m� �I���ion� γ-ly� ���$[51]–[54!7FL�Ci��w-/de novo�anethiol0 �;ulfa()/!� tory��9gof S-�yl�e�or L-,p *h3:51$ 5�As=���sm pl -!QU���biology�>,�#%2�efSe0>��e.�i�.%.�z��j�l���+�܅i=�t !+��i����5@SEZin���V��!S1��se��* � B- �%�is�.�(e\& pv6) �}� omi��� g�%�� ��J &R J �H��!�o��ta7�Tq�H/%6`'to��lenish ��[55a:�A"�$a>^���B��isu.�Oy�#!�a*uze . S=$�NNM��2�-�s 6Rjcetylt�f� < SAT1�SAT*rre aŐ��inhib�.by63�A�n� ed"�A!i.ofN�$#J�$!I-��,�Y��%�a j� V2!���2LB%t � "v �"A�>�%_I�zym"C>6tom,�>�/ �1R( -�"�A'�Aoccur�)<rA0x�%@a�u��!�f�MJ�J� stil)� � be en*�. A I�s limi� chE��did �"-ny =� .�.�. G�: .>"known!`be�Op.s2 �=.�^�/[57ɏD�ss�/e`itw#a-al~�:D'nd�N�E�r\ .�.g�6�PFOR ,M��,ei/muE�( PGA(�f NAD+Ien� alcoho!#. ( A� N��eoto 33±2�-46±15 U61%>�>� 6�GA!, TPI�2GK2'NO S PPDK>�by� 1�$22p!jA�6[i�� 19�a/]ml� n�#�6S�%S[!hav&=6(toAs")5r=6J\[2�.� ' )�J!+%�Z :x.T supe�,d��!*yAB!#�e'��[2� q�+of ���be3f�� ��Zc�7�"�� .& -reg�.ng-�RL59a�iq E� w��%�  � *�/it4!�h�Eb��of� `,N��k"8J',6ji��Iif$%� p��Q��W8a %#��>� �9!M ja.�!�¡_6�. I�.!�)P -�,.�,B�$3a��$�1( GK )��genom�>� "�'"� .�6�/ para�L%Y�F5�of ��&olu,fr#9fB�q9"L1by�� �z�:� a:[6� AW�proi���2is �~l�:� s lyce�"y ��oa� ol2��33�>�aBq&j&w\�/Gly9a% %�!L�$� y=5ed}0–14f%a,� b'�B� a1�P;>�}, tog%"� !�i(" %!o,7:�,Z��9bvj al.;sMs&q��if�edˁ�lsoI=rto�e&*.%��2�+xinB:4B!ha7of�ra�?;! YA�xWa�1Dd).MJ�A� � m>� V1�A�y!4Q� &o;�,L�(a�Mp�.�B�&�{ |w9�� Q�of"f�4  E�r���=a�J�!j6p&L � 0'!�v%@��"� "� , C�D>�6�'>D�apV;.92Q �k1�tomT zoa�#sB�:DTrypanosoma brucei-&Plasm�0falci�� m [6�6X#W%6�5�6�B defe�=:p�&6� [6Z!aI�i�&%�BV!��E/'5I�"_!i�EQ�V�"Q{3.Q( G�-Iade.�is�(eB�y�M.�of X'o " A�*~ �% .&�#5z��X� ffic ".� er~(�#mea� isms� #VAKec�.�$.f0equ���� .*�s�,7o� NADP*8)��).�>F:(��6�)� a�90~ !� ��a�("H �Hu�5e��3g��B�_i!(�_ t�?b�v�>B�QZe>*e:>@ �t�I*bsequexe�#�9 as 2"*xbypass� � ����;�� 8*troll,� t-1anby2c�HB4Am )2��La����e�qk&�e"06,)o�5f#�,e�!�!��ly21�Qcq.��� �AsB��&�,e���i�]�1eQ4sh6o� �V a}9IofA��@� �r}-� 5�!osD�G"�6�>V CoA�12Amolecu0*eto�Zor�*�23�< !06&l3I2k2���t��M�� mx�� M�H���� o:=to� a F_�?��oc��g"wB!��&!��be bene��alU)2�!Qx  5�C!a�m*�n�V9.�u5���)a�o�cis!�C r���U�!� Q�e-m�of%h!�%*�Apower�>rF�Jx. Ii%�2�7w:mo�>��M&k6oF^�P��c"� N��ex�q�1v"/H$UsmbEq38E��B�23� 6�.�!r��� .Z;�<2�:�Nsu�; �)�&�+�-,�$��$E"� �"S6���d6�_,�5 i� c�,,�:� n"B�NEGKN�6Z �A��W� �A2�02!��AՁE6�DetaiAgbi&�++� al�7�D>�,is necessary!�underst?��/�]k��z=9�G �&c��I&�-� �&�wG phys�*1  ��6� �.�OZ�$��IKAROS!a critzbZ? hematopoiExF�G dyN"c.�pat� V�3�!�perR�|llabo0 "�N�K�) RemodelAQ�De,y'8 ( NuRco�@��4 romoege) �Y?A�.!�(� clar� how -#& pB� 91.Mw� be�s"�5� HDAC� r!��.k� bi5�&P�&ive-T�zElongA Fac!�b�-TEFb )f+�- r�&H|��$i��! A��assembapc��!ba�cru�N/ peciUy� -?����of!influkRr V� + �- ��x Y�y i�*�facil~<s:�e9;�!Wfer�/� P�. in PUNa� 1α!^P� an �-!�!�� !)nd5E�.or�o CDK9��u)HH ��� ����iRzcan�susAE%h.W{ impe�*n�/lN*,IkNULL}��T�;itoE)FkK�@!knock-@E.��J unit Mi2 ����4�pa� !�5��%anA��Pre)��enYIav�8reliefPOL II!ha�r�4�F l pa�1�web�M�j�. �&tumore�#or-؁�a:8fih�,� 6#,multi-lineagT iM5,:; � i�[ 5�!4Mice homozygot|�(Ikaros nullE1 (1�) displ�/va�b,in lymphocyt� velope_!4�>d $ leukemias% @ma]>th-�tn?eaB ce [!T O phenotype�ffB!��{y��:i+��e li0H�6�6hY�%[HPCs ) [&�y].� �Ayp!<�6S�e�=idS myel :�[7r&1�AE6�>�/�� a�o��z"x ��r abs�=� �y�s"�RBO[1 �� 0R,�+B-�=9>�,���g.�Ble>�!A) &Ca!�@lBa%`H��� s [1+41EF-�� rols chro/ n organizI�mai!L�?ugh��o?T!�wA�}�Ia�,�5!���inily.�"% ,v ����xdd9�I��6�!/:|a�s5�9E�?5:!�def��^�q�>/"�%��R#W!n y� #�o�!w pre-)'%�� ( PI�,atA���!�3�[23 �6]T*a���ly)��I" cataDsuɏ~ (�; ) [2�3]2o�Q�he C-�9� do!d ( CT{ �large.�RNA Polym4II���)w Ser25�a� SPT5.D DSIF% �E. NELFZ 23v?D� "v t�'l6 5j64ed�T�#T,�Aow14v>�*; . M%QI.ar�is3`T&� 7SK snRNPN  ��tQ-XhaAerM(�5 K"b ��=' s HEXIM ( 1�', LARP7/MePCE [2e�O'erest '�)�di� �R-�M^*eTJ�}X!�:F�8 Isn 2BA+P2^1S  con&0��jH9c!>VesB� .E�de �I��at�&Nid�B*Uhr186q Ser175 [2|"[�,. D2Redh/-A. refeXi�r� !�-� r&� BRD4!ڵ2� &s"z$HIV TAT [3g 3���� beco�M�Z�� V-�I!rmb�Y �^e�X�=“re5�e d”�TFIIH�_��)771T i2 tA �6 �. > ,��ms eachw [3ii3ing+ �����PPk+i�E.`qA*i [3 Whe� E� Y-J]A�2`1for Cdk5�%��za��6#��"� -2�4ot wn�'T @so��b��� �Vs��5�i�� ��Vto&� �  � � �*I�" Pk ?[ apto[KI�{�.mk�  newl2��Jt j6)"'�#q � !hu�g� �lso5!.[>loQ]J�.�5I&&V6�� Mi2/�*�atR�is enh�Xdi�2�.7A�roi�6Ql���1 6!*e�U�X@* ^. Our�0%,n)�o�.U�i�'�>�)8�M- ��E�6 Low-��k)� su��5Z.�&� r=  %erY�2�A�.�a�)�to* ,N�)�&v�&�6�)Z �wαQ%.c�qui��sv �)im��. S�H?%Q�)}�da .~ betw�S �%(!8" �-18Y 36]�,�s � � T�32 1 .coordu3.� r6�b#e�6.�:first�` ��8andem immunoaff3 y pu�h)A mass�;Htrometry ( LC-MS/MS��\ in Jurkatzng Flag�HA-tag�, �( HA-Ik )i?4s 1gS1-pof e/T 7 eluag �$�W b"@I�%�(aA , MTARBBP4� MBD3�"Q(E�A�YCT�4) on� ( T2 �1e1�{+�R 闁neHve.�e e �a�^�Zl %�A�.�*.�-,} �0)�precip���- ��5� � u� ][!� -q-L���-!e�;A9c!.� M�.I�txG:fi����Y.�a ��l&����lexK]7)Q�-5W/%E�O5�@~S[`on�*ph�^ co-f? io57�EEv�-kME��@ peakA�∼2 MDa9�%�. A"�J� ����E�,M�l-Uco-el�Zin";��`wmc9mcm�U 1=�4 Um YatD5:�8�&i"�7ET�a �;r AQto�D� i��q�0!U>]�Z�=" silve �N��~ allo�#�8&!�g wo w!�+bov4U ckgr�,,ջbaUmigjng!(�r�1J6BPGn� A�*Eps [37]�S%M�?6� a smp/QmP1@Na Aolex!�!P�] *�)XF1=b_� � �]rg"� syste���CNex� w3-vestig� �!�j-mM� �a�A�c Wbesl..�%lF� 5�5�_ ."{co-��0�(I�Bexp�Ws�! carr��ou�%)*�2U]S1� . CoXG1w!�\�!� �-�.�/�Ap)�a -�t�Ge -!..C�L 6Rc impad i���Y N>mO�T�)��on-� Was�<E�(T�sɫa%�6 }s a2!q �Q �FAL]ɸ6��U��u[��d�i����J�n�a�I� and/"HcU�-P-K��.���"�~ oO J]�Fs"� g�J��t�)!`Oby1>m!"� 5e�d��e`-��j� se�,� "� !%� ��K�$FTe)4�um1D , S1FBQ�n1'��8fca�te�.i"� !��)QA1� PCNAns oI�&;h!YR�,�  �RllF�g#al���aV �`� �S1Ge(%,-,-j2� � %j��J1m5k�~DDNase1"u wk�[1*1�A�CS1�ZY@���$��DNAA�\ens�+��~�E�T"B�s��a licen� M��62o_r�`2��`��_�w�f � shol,]��`� Z r"@Q�fP$J�_,휕�2��A�� ��tB J �r To:$�G� ssue[s�d Z ^�raIc-Kits Flt39�S2� � :.%�E!Ze�s6� HPC�Q viva2�!�^�!{�VWe9S : ( i ) b��marrow"� �z(− ) Cob�h�% k� &� � WT�� hn � � $H${!� *� #�")�mi ;%1( i�AH$mouse G1E2%'!YI:!p&RSng]46�"�O!e�M a�"A$� ]�in.rV1e� �Rw%�.>�;c~Ll� E���)3/�!i%�%�u�N: �q� J:U:��&rj2�MR� =�� > ?N}*GY �M��,"�Gata2-V�E� (2)j��#-2Yp*& J�s!:,s6S-FTfR"5 ��f ��� d]0"y=$qlosE�e2� &� V Ch �7�.GV�!����o�K5l&L' � � locua4]�n/@�(e −114 Kb<r  82�($al Start SwO-TSS-��+1B , +5*� +58G)A�Open RR_$Frame ( ORa E�WT��e ��J� 2� ) �#sHjn �tp^ Zq�'�i2Rh��&Qu^���Y�-��9��yE�PA�#Fo�WM!,Ser��@!�"�gs�Ec9��A�M�i#%/d�jM� ��W#bIP]7C � TBPab�"�iSbod1�A�2 !�"a)"� �Kit TSS�ardles%�F�)`F+>t.b-"�!A �e���2��N "P "�A�!s1�E� HT ,�.�]�` �v�Y��R'+ �R�t6 ISbR� )�um~��,)���"�;!Oe* n!�!b!F�TpQi7)8� [WE nascg�)��$F%he 3′lp��gen�� 2F , G qA)g-5 ���!�rj'on"�M�m)Is�*�V�&q#A�\*� "9�� � trav/�ou�?�? �ve ,Y�d� �y%!� vs .J���[,�XA� �)Ta*B�)�>�&�=q!.� .��:�yI���add� �g-�oR��s�Ztaneo�nco-��� e �TSSa0Ie6�1(�` @*8]%�.Q. S:35�pro�SEe�Sc� inbk ������ IA�)U�"�Ay?��Es:y%A�&A0M�U.)N&�O:!�6R� 5l�+�_�3~Y'�in�T, n@/(3���Z9>6 �#;M�PA��,�k�� �i�!�0 do��:���͔Y.�Werturbfgh A d:�U *t=�A�a�e/WT)6��Q weZC*Ose!Y+ . "]�4du`b�,��&� � �9 e=��1(~;b���H$FlavopiridPv)���&T 2�4ŀ���[*� %{MVb100 nM>i�aLrt�iod�oR ( 2 h� �yav�.i rec� �e�A|/ �a��0.I�U6�[�,�AP�3Q��� G\�-���UD3WPM�.���%�k���Kun�B"�JSK.` ��[e�f��*Dlp �_ s 3B0dZ2 �$ �7&�mm� �.��$ �k 3�or �S�/"�$"�;�,��i�!B�rM @8A e>9�.|Jua��a  ?L^ q�`2,!oa�� nfir� ��23:� loa�%,�H2�1 s! ,- �~� ��Pb�� ����"m�~)�)�*` ,*�\J��b#�8 5�)Iv"�in9zi S3D–T �.�'.^i (deit�$by6�]�rB�) "UkM�1�&#�QS! &� .O� 6��6= rpri���-g��2<N�!����)*g) >�� oɖ*�nof�F�QY.��md&1} ��*� e�,�#�#�%����8f�by.'�W&�K SmE!�����A=e�]p��� �e�"� !��Lm��.,F^.* xX�* �had��^]er"�n= oGid!�Ut75aE��~��7AV�A5&~D  EɆIe"�9���4� ��~�"}*ue���~,  [,o}%�ct!Ra"(ALbQ&Mqd�.ksY�α&m$�"9 �6 �X�EM:�� OS-7M�^�[�m�7S�S�>�&�j&.BU!c %�� e.�4),�d�1�v�:na���N partGc"�;�S��� j&2Z+EB,a\*1 �n-0&1 m�eliD# &��z3��� �  :EH"S 1�cX1�%t"\=��M,�Eor��1�Aks""�$.i� 2�2�� �mB��D�� I2��./U 4B�).��Oal �*g,�. G lo�;_ , `4 N| k���*)M"hel�9��4i"a� �I�f+qVa�� 2�a�*q&>N;a,bq�plo)�h�#��0of Calyculin �)a�/PP2A� or�0�!��|jShort6��ť.q} c`� tox5A:s!�!+ death9zS%���n! *1 N,r47�^�!].N AB&��� �"�!�%P0( Okadaic Aci�oor�4Cyclosp!� � UgS4�A"�a3vwo� 5�M�6�4eMI�9�!���  6qIy�=[� *�@AKK ���YM^g 42 I�?� A\� �*?2!, %+5��i�* i�.�29Z i�~>.q!V�� "z �Յ$ndtM {�.hQ�v�.5� ���&A5�&�\eiO)GAS4E–�.25Yuy �IV.�/���� �q !���1�A[slow-&)]!.I&�=;)�4BX se !aQ�nW[Cٌa 1�4"S.�y%q xY�,)E�l)�eaw ��� it��NÌ�] \Fi���&�; /:f��A'ը.�"+;��*sM�B� iSO�dTS�0��� s%���� >d�_��:!*.IՊ �!2�z 6e"�!�~2�ŀ viv�4�eietfell�}UE5�.�!JeB����w�>%�@ol pMSCV empty ve�O!WT/GF U) ; 2Id�/>i] /Ik1TxB 1 is,%%�3)�-;"RAΔ� (f-u7a��1gy� he A465/7&�B,.� 2g S l!F � "�4 nuBKE%qt�f�*�gi J�7.�A��L�) U�3�gado@ �i3�HalfR"$ &#Il �e�w� ?Lh�^a&L?I� 1g=0 ngle�A) fluore1c�I��"�*�2� g�7eT`a�g-HA tag� �>XKA�.E� /�.u�$& 'v7�ه$!��(u�'�ved2�uJSmKA -lv�in 293TI�J a�� by]�2b"QNs/"�6%�a�-�� � ) s�5G/-��- ��"�)uj6= B�*.�!=  I��7.8 �iˉt IMU\|�c�&b].5�#uv�/���- endo�^u"C-���$6�-KPa�1+A�ueF]��[�%vN�,>F-�a�A�6<.e=�.. IQkyF�@20E�� ?Tued ��to 74%%i��646 . 7%�� $ir.!-xe���.�%Cn�s�as�% LE�a�o1�FLi�!!�1iB���33 . 3�� ��`1���) 5IJ9C6���.Oq�mMu}� �A�s�.*&�&E�I��A�1APto!&N��� �C�F�"�M�Ѯ*�/B�=M�BR!T�O#Ah. Clona;ic' Z::� E�2�,]�&vColony�o�JC� ( CF�M ( 1/166N� 1/33�.����F.�)yc p�,u�s ��A��p&�)`f�w���a�2q'���mix<%FC�U-GEM�gA(Q;d&�I/mega�K ( BFU-E/M�9��$Y�!* \�}�I1A�IT! �+� (�s&@}-�E�13 inim'��2is� !�+� 6Z �a @e-to-m<c-�� FLT3)�%ɜbe&�HC"X52���->A�am�v� StemI?nP( SCF� �lig�2�  ( FL�.~� -.Y�m refr 1y�HkaFL&s�Pis.�lpk)��2� �&\?� ^%�]�o�G�5�"� �0@E�YAEȐt �� &I z,commi�%"�6/MSE��-�3. A�JI�p���5a�P)�*"`&T� workOs&�-�*T��a�^���} ��PT��a��m1>�*� E��#�%n?"e�UI�� �!�"t-"� !�s'b�ed� � e:���cF�X��e4� o�D&@-ina��< &�%H ��J� main[/�Us�*6>�} �6� ��S.U, 6�e[���y number�ı� �;adH"z�) BB C�5����!�f Mk/E ��edE�!!��B�Bu5C"�Ŧ� 4iYa�C�m�w�c�%##d�ag9&5�Ea]�I3)u�%gen.S�5"W :g�{�.t�"`P�v=�� \ �9N5A%���,��'A��M���Wj�p�won�AK&� 9�#�=T�n�2!.M2�6:augmen�2��3Y�e�=� , �� I>�0*b9M��1�,%,��AzBg"-�!FE9CJzUK �%�MR� �A^Ie҅7>�;i� lin- >��Ye�� A�BgJ�% �!�^��B�!J��3��ver�r�!J�1).]:-�Y!2�(ѐ !  1 A�!�*�" in=tA>�3� *�'ͷ�A�E��*�2Ie mE�N1 ,�� ׂF�E�+. S�Af��A�"�of�a� t$ ��2E&"@K�6PB6 a;stE(}��&@-a�S<:LA�(G)�sa�y� �Lw� �6"����/%aF(�re'R���+@>>`)pN14�Q" N7��� he S:q.[CkS�wE V,�to"� j�!�  [3.@>�b�]on&F5�XBa�LMC ��Q�2NB.,� )c-S F>{&R&� b�"� ,�ENC-n."H#F, nu�)�-!� ,�, M�s+0! e}%�%�k6�:M���{NqZ. &�U��m bArq� ng� a .�H���MF�"Gg� ��n"�^sA��s�nG�mj I� FACT �}��w�5�[<d\at ,A�mplI��getjw:�v.�pm**"� 1���2m�z �*�byJ��d RK>4!steadM�L!+&M��_" j� �e�,N � g�&9 U�$d�D�<0iE��%JN:� ORF*@�QbT�1�& ~¥PyJ2�)Ezrt!R &,/Q!�%�"8%c�$"qeg�Ad�zi���V�Y�sL��torNV�%�q��75"b">GFB�]4��%"�a�Y;Mi2.rhea m�B�AIq�d(b%�.GYѤW?[5�XL�In�Yre|6*�co-�Ung5}�Dur���e�B�b�d6=F'�^!�$61h�ls�-e&XRQ%�p�JsEW"3[!a0 �)+? GMrv��v�OG"�oE]!�!�..2��Qof.m� plur2 c�i�  ES��� �BA��D�l libr�����d`.��N -tun2:$4 "�>|i�y–J[qQf��ngs bR$a2�el!c�"# ��$!p6*7y9:nPa"� al) k"r65�J� %��2� !�����yf�i��,�.IU@.�OM�QpEWp�`Ah2A.[Z�h�X w�bya橨��= ��&bp����6���. D3> ofF&_�!PQ�uY+�.��e�e9�Da� ��mrS�&y.Q6_Pt4i���.0�2seri�h&o�y-: thym�$in-Bm�1�� �i �>malign0*%�" ��b!�humanE>�6pw�N� vhaploinsxTie�S>��Y acuteDbblaIy�b�Uy ris^1Gpse [5\u&�0s�iiy���A!a� R �to�)�-a.�y�.tUe&�l)��1^8�f.aso� expla7da-$dosage5�"|%"? E1�c�E./B0!�*�)���]}1 �i�=! $]1%�*\':} )! �HF�?B*� 2�-*� �� "@$r[�H.�zRhE�N� v"�)"� 6.iLI2��s3��SO � �M�:/Xe�3gu<�Z&�V"I�,��j�Q>�r)%�!:� loci��M� g2a enrich;Zzu�*�SSer"5ury�&�`�� rop�= al�.ba"�Pval�^|au:B�|��YQ�)'n�>.s�6U[,ge& (I�AFB�`Rz 2�d%�ICa5�I�!0im�A! �ā�6]M�e=*qX%m�is5pB�2�-NUg���y ��B�.� ,�4� ��A�t�Oe"*#� �7hiaM3�S��,sl�0�h _�a�))�poiy��(.� &!$bNmvy2&.9"/.1v>eE�q �š�"A��2A��HN��zM b�of&�< ed-7Ʌ� ����W,��&ts�kbyA��)�_s.Ttoca�,&���e�� �c"qf�n%�e�fcwu`�-�0b%e��4"� � ���J��E=�M7IM�6!F3] FPLC�e��7��i�uw<-X � ��2PY��z"�:�B�z�S::"[�T �!Sar�lA0&z6#a|x�!y!QA�aZ%�e)���<%G�#.kO�N�S x:�kZis��lSU4>-4�en͞A7be argu��-t*���.~c�0��&*s �C,�HA`A7�~b5�a��F����A} ,i�Z,�FE� , [63F2h�"� ~2�{6K7)��C'h� s�q%C�K2�#%Kimbal�1'8�i�Q .x!�VaA("�Wg�e��P�hig�M}�TB�( a� g�M3s bx !I -NUR"2�Pgh� "�V.�nte�>�ofA- `%V�$V0� 6&� �net $�2zbD5i s&U&�:C <&�*#5%�)"�)m 0. Fb,23&�3�@� )@V�AT�.K�/�/"��&%)RxFP%W"O9b�$M�rsA :�4;5*b .b!�+)2���>6% �*L"S��.V�rh��$ Ů�.� %Zl.�9?*�V7� &�I condu$scu� � �ymp�b�t �A!acA=�"oY�!?%{"� SG.��z.�S }�-�2��?��.A�7�2:"�Hswexert�sy)"&9�YzisR'thR!az���"1co-2�� e-mCps@3ol [7I�[7@���o _�).�v#N�&� 2T|.@,J�sF���{"�*�~b$�O6��&Sf!t!1�)�M�"��$c�"_>R�w�*� RF���/e�e.rAl they!� �6�*cA�=�&sX62.�� �1�v�("N s:>as>�*�bi��L%��adjus�Ph�*F���� "�)&�� A� HSC/�1�!�eFa[ nichF D&:~(����[72�7���!�|�F�-4�q DNA-� v! �u 6��L�_q��-��"� .| ��!e�!�Q�+.1"�~��x :]G"� )I�=i&zB.W����$!��D.�combi�Y:,I�l&�{�����,.�-=� �l&%>E���bl� appropr�ˁŨ6$aqV�Tduh=�A�<� MM�e�ec&� ]0j b�!.�Nf�a4.� ՝6�&b=Ap��^6�Ycm"ѭ� Z��0e���s�c c)�pl�*a�� ;p627�A�2�alI1a&AB�A$Fag�fcim�>_h .�wv��(�}�q��7��D#�G�-Ae��"�[!2��l�R/�-R�Z"jie�#&�'�--6n&�'Vo5? AKTA Pkr�S~f ( GE He+ cA�) �~�&4ose 6 10/300GL�*um�0>5.T"�9*�R6��J(r Tap-Tag ) ��� .�9>�Nakat.v� [76]�l�%.:'%�p� pOZ-N-"�j8RES-ILR2 ( mock�.�)!^:+E-2-a_�mcmsa 9-����D.J��per� �AlTaplin MQnS�QnF�%!>$Harvard UnmFs� , Bos��*H&��^�+��nd6�^�^�nu�E�,9e/PCR6�NA.4m sacra� 2 cervpdislo-�. 2��:!hom� �c>�FDe Canadian CouncilA�  CA�( CCA5gu_�i!v����z\Maisonneuve-Rosemont Hos�m���4R3te�. Fal�-s 2011-1]x 7%|L]�NB�`%\u�id!�easySep*`6�oJ�/*�ki���487TechnDy�"�8%�,�?-��X�&%�cl��S)m� "�, c�ocI: U �1�<a� !��=. ir N�Fi����d' 8@-pgk-E; �/�rH�4Sauvageau , IR�}. RetJ �D&C0of��"�-aqb\[7`}L*�`%�cul-�d�3 d"�8��^ l 50 ng/ml5, 1IL��I5\5×10−5 M β-mercaptoew/LTi�Ht>81. �^!l��.+��iso���F)4S Aria III sor�? ( BD Bios� e,Tb]gr�%2�?.^seek&D ri� v �oK*t��2TB<�u�a�� CultE��U����: �sco�8at!x 1?�UnpkS��nt's �Hso�u��bT: *o�s~7s!^("3b�@P-��&��E�� 0ke s� ate)�iV�?:L%!wmaiizw%k�-� K�a�M�e�� e0 �6��d�|��6v�,=�J�@an%sP�i$�Riwit�Q� fo u!��.t ���+�Bco-cirGۑ�R �u�a�E6l�)&f]W,�!Y�K.o orig�,fi!P��,"BJ�<sVd��K!�d6ehge�!�hip"',Sspؑ�I#.�݊eU:gy �Fe��� move�%h|~U>�5>. R�"�a L<-L3��,au(hIie�i��oum\linspi�&A_myta�|��st�1u5r$��numerV \��$_�tl�/��P�/)�iġ�t zoono� ���q�:�/���E��z!5e��ubiquit� glob��s���F��� Toda!���*�E� l� �`ia6�y2�*�worldw��K �./ �re-B? !:��%F�! ��N*p�16Ble��}d�K-se������n� � 4family Rhabdov�_a:(genus Lyssa 9��%s� f 12�R$.f��'8 s!��dhwo �X��' roupsl–ǁl�q�Mv�� wait�tclUf�T%�m-&� ��n�e D&�?!.��oEp-Rn"G8mam�+a&U��f �3s�nivor4�Chirop�W+nervoir h�Ws���,����} *8 7M1쪅kperpetuOA7,mit��e.�tc� �!Ca�)�ުe .�O!�)0en]e�5�Źth��:xbati�&O>T5riA pN� m�)>K.�2���e 0��lyU�1V[1��׌"� &� �ntiucjA!� techͷ� -Vv� =�uZ���oU5� �.����{e�!� �*15e8�. Mе� docu���h2�5C� ��:C:E ��a;�!b� �!N!� lA�qL7��e��m%e�� er+as�2b �<c%�>�i�2l�y[5��li*�3Ef!�hum"��� 8"�+�z 1931i�29�, [21]j�0s�>c�t,esW epid�< 2��193� � �� re�ed 73 ���!ip��ous~��a�!�ɋY���M�.no \ � c:4%+��#"� �%f`E�!W�!�/]�canF�m)� �X/ i!s 12 [ V�#%~ve �� 8epi�xB�5*. 6�[28-��3 rC72D]�) �a'�Pf J . Wrb ��[��#�3ly( eat��&�inY[u  �)&� M(A���.f+(J�o� ( N )�e2�Cs _six{��R�a� bov!� ���i&;T2���ofA; M��K!7��2�z�M�+� ( AVG 3�k&p�is S ario��plaus`� give�R�`� .�to=U1&�@��Ll�(!�im%6����dU�bas��� ��9�& ( UPGMA%FE[aW robuT�cl6rB~raw ��curl�s y#!e�u�a.� 1 S"T coalNTt�aZO!Z�/EI]�e��Wve�x����of .g�of`� �?== �2 �T�U�a�a �1183� al N k� Mځ�� , 37�} ����x{-��cap��I��m�m�ͅh���1�  thirty-�Ra���9%Us �2�br�i�zc�m�;�1VE��(�,R� �)Z�S�%:�6`surveil�)aX�2!���i=0&��� Ve�8E_Diagnok L?��� ( VD���*�!� Tobago Mir�� Food!q� ,*0D�kF"JW t Antibod�DF+Iܰ?NR�@ocoe�n�A\Cg.�BD�Co�CDi, Atlant�Georgia���N 1 il iqC&� >e>E1x�P /�(!:"}p���D1�*�2���8�  so�>yR�6!g�)�B�y�annua =l9�Y�6[,���M�f!�ada1��z��ach-  ,jmgvI%(U�I�mV�Mma�ly �|� ��%(Ynµ0|&� ��#�$! �����s��Trizoy!� ��q�'urer'�Ks�Arnv��gen<Y�t]s` ��t�y(70°C until"�C}7542 bp.�G! ba�\by RT-� �;deg7�t2��u 5>er N92a\h5′-YGTGTTCAAYCTHATYCACTT-�uѢ)�,on 991–101|5Nb5-[� b304)�X�-TTGACGAAGATCTTGCTCAT-3v6a 1514b533�./�sm�=�f��m��/.�fi�T� ��!i16SAD B19�.>�10QB1�ad� to 2c �di�A 5 µU�# ifug��S!��lEde`�ed�h94AaG1�M=ZnoLaon � (�3 �A�14�1�� "|*q�US RTRX�Fu�^nC'!PF<�C=�Nor RN&k.,I�%b_E incu+?at 42�90�(i��m�e0!�A�, 85{ �s�!�A�Gtaq%-�.�|%ach RT9tub�jbrief-bent1��lac=a��hem(-�) � �? cler� e !Da�&A at 62�Eɐ40 ��� �h23="�371I27.`s .�a�EEl�� 2�%=�X v&Z�� . 5%��}c9t��! b(�de ( EtB��.�A�Wexn�d� a2ag Sge�"dN1",“ExoSAP-IT f#P���$( USB Corp��C�(!�Oh�yUS*, M�bm/ subj�Lj� !¹:BigDye Tm�'v!1)�.4�"R���ni V�l�~� �&s 3��Gq A. zEDA�E�!���L� "R#1Z)�U���w�pa�%�A�sEFfo���q�Et.��"pC�����rE��\��MN(�?�8W(��)m���� Big VP� �D�A$mix�f6�25 ��a-a`6a�"M�; 5�`,� 5\6a]4��.j��� $( n = � )*L33� rM5� ri� �)� stud!7ge�0i�f�=6"s� 5| ,P� Re��c �( Wild�� Z'� V�d-borne� s Rese"� Gq� HVL��Weybridg� UK�F*����� 6�genUBAj� Fd �$� �Y�FPer�$�$, Mexico ,# umbir ArH�in � , El Salv6,"@>0,2Hondura�?�&��swn�s��GenBank�� �lyb subm�I�tq��oth�eb" (�r�Eݡeid2`.� S1yw*� f �Y . IO x��ach-���U�j� �cF\���. S' ��� �CF" C� alX o"k���;2]A�n�1l�9t@ tedi �IBioD7���` �2�trg�mm��ngt@�363 nt�dR�6zGsF�ef>io�u�rtMB�#vjJ.���pj5r �ee f.�b6�#�z--? EASTL#!4�b_r ue�&) MontK*0rlo Markov Ch� ( MCM�i�joi�pM A��_$�EAId�+gn%~{)demD�$������*�#��������&' &�b�" fit-�l$�6��N� h�G*�ZD(�n Mod7L#�G��4N+Γ4". Find &��� !�7 un" Yd log6c|�E��"�skyF plo�*BS,�co"� �Ε �"I7 �r�Iy"1!r2q"8� iori�_�oTo �hyp ;!o��E��=�J�Ze�f%a��#"���EI���]��3?U#{75�{�,���&�I?m��re�iff9, model descr�eibed by Lemey et al [35] also implemented in BEAST . This diffusion model uses the countries of the saG`d isolates to reconstruct$Pancestral location st-of!Hinternal nodes from�posterior time-scaled tree distribuN . Adequat �ing[�\'s parameters was achiev) runn2200 ) !�e )�outputo0summarized usW Trac�,available at��/t@/ ) and �visualdthe FigT!�8( v1 . 3 . 1 ) 5 package (މfig!u�[34] ,i . T!�ayesian maximum clade credibility ( MCC )I~inferredY�@complete data setA�DRABV nucleoproteinEB sequea ( BTrinidad%%E�SouthCene<$America ) e�vidaw0nto two major �V Figure 2 !�C�18�riAOof �|variants associated with canines �B2 a� ists> bat-4�M(�-#rabid3s or othA�mammals%Sc}by ()I�geslly clu��.oi�(well-suppor:lineag%4Groups I–IV;�Iproba)�T = >0 . 99 ) defin�A�bat spec��eKmaintain� � enzootic�(9zinA!�Within-�2\re a�!��z sub-E{s design%�2a%�2b arie�E#a�/)��*�!� �. SubZNco �%�Y�=�E Myotis sp��atAY%Y I�� hile��,primarily enAjas�Ef`A�3ransmit!�$by vampire!�s , �excep���3�*,independent 5���lat�be�� �I whicha>�%$in LasiuruI�Molossu��%wi�q�,`IBXPTadarida brasiliensis ס �Va � splia�ll �f82"��%X6�those!;weaCn Mexico/V�7North� ( represe3�by 1999_GU991830_TBM_MEX ) [38] . O��remai�a,predominantl2�@ ( Desmodus rotun ).P5�A�inAwM�b9�Vb�U�U-re�d)X"� deri�Artibej� in Brazil!�le IVc�Os only=�2[�%o8non-chiropteran�b. All!��{�E�Y ( n��(37 ) belongs QL= �Ia�suggesta D .9ba��sourcE2{ outbreaksiU��.v4largely tempor���g�����I% IIY��I inclu� �-�d!|1997 ,8?2e 91�뙀%��nA�east reg� �@e isla,,L,is most clos�Q/to)�NEcuado� 2005 ,!�0, Venezuela (�3 �4A�8nd French Guian "� �IY�a� � 2010= �23 [�@earlier2)%�U�!south�h- �;O�9�%�� ge��(&II��e moreNNiAi W%49 �!4. S" 2G�%epi�s6�b )$�:?%Urugua� (2007–2008� 8phylogeographic �ga3�~]�separ| introduc��# u��Eu� 5a"3!�.��q/a4a�mto beaa cend� � �A�� xistiJ)� ( 6� ,� ies�g61%%�89%Atxround 1972 ( 95% HPD 1958–198�A 19892!79!9a0 respectivaj . In%caɡ5IIb (- .�E���'@) ,"%rec'common�ora�2Ohav5Q� a0%X=JQK- 20042�9!Af;fl� 77!b. L�  expan�� o.�*.� T .�V� occu� !Min9:v ≥!�)� 19902�83)�5 )!�A�1��I�#6%96i��y-Ia��!Kk200k200� 63b� evolua� ary a�e�5 . 24E-2� . 66- 9 . 4 AF.62]�4 " .91 �6J^2 . 08$- < 16E-a.substit�s p��ite yea�2-��ove�j mean�a��]�!��,haematophagu " .�"B`8�%��87�53 �� �s�33&(22%:��across�� f� at"y �� T�S2��co-i�n� bothY�RDdur A�%y�Cindic�a!�iod� co-circul � inct��� !�ifi����$ern villag%�Fyzabad�e�. ���9�T9��"��� tudy)> rigiEŇa�e�&(d livestock5`.SE��� e��� !6 Wb���098��0���my fA�w!{:Tw�Tc.�t�j~ 9�&Gas.,�Z�jgVM3F�UY@inI*�se#&� ,a widespread�A3%�U*perpet��2� (��)! s.� ő!9Q"=���lik�gU)�)�2f��>�he� t� t�S=e�rveA�!/!Gv rol a��iD!�, �zccounz ir histo�lD(epidemiologa5��� A'}ini�hum�d dom��� imal popm�� re� no�aO.� %�t s*h�Ii�tyebut�vious U>q , a�maa�s� �>ng��͉5e�For exae ,), path5a�!!�a �ino��con� � 5��pr � ly iFifi"#$n frugivor�E(&#lituratu��"8jamaic��Carolli�: spicA,t& A(2`Diclid�lb^PteronokdavyiZ"��) [20�9xHow�4!�e)�det`�notY�characl9 �rvoA�J ��And &2E3�s� A-th� a)�4 unknown . Con��tlypol�>.��C� l6w�( diseJ qs unclH� warr' fur� in��ig��a�is, partiABrly ,evant , give��at �-12has bee.�ton Ma� fr� tly ( o�E!:!� y 73� aRas!�P40] amongst sympatricA�5�, a oonship�,���noa betw�U�!3"�.ee�uEQv41AvF)U�, �0througho�'�� ed c�� e�shA��2�-���4as Eumops auri ule3uruf��nig�k<r� 5��|�d))|fic9E�� . ItA.QcwhI�breb n!� ill-� !�nor1i_hifts�'beI.� in one/sAa#se5[15e�42 3 4!�In�ext��v�rveys6fruit%^��ppa3_�er� .�2KA9 &_ ,4ch poi�towardsV!���0y mechanism ..�ddi��al��ar�nee�+larify!� �ZFJ�Pm�en�ˍI.�%���of)}Age",Uin nat� �tegz dJ\ d ec��q4"<� ePb reh1�p��-�� ing*� ASIM�� ay�c!z���regar~Although6 �T�'%��c�@�yXfoI5.=18 , si��z� antial&:to=� �D� ��~an"q fash��q_+on"T7 )��e�u[16i7eLite�al�wE moni� nge0���4mi!�ory hab�to�rrmine i>ldiffer�e)�>�=Fs�P ��ik�t&� Eq5�u ver!tc � 71&� ��`u� �868�s t,� i��3�by DFA" und f� e.�1�s�x Apra5m�-� posi� [46���!R5maim� s appa!K ly health@%Zproo��S�m��a�� c� rye�is typ� ly gui�U by publicort!�of!+ bi , soQM�om�t�bia� Non�0les!BeN> �6�a�ar�^"�of 1%�Are�E �zal�p�t elsewh� [47]� is low%�L�Duph� 3%aL 12�2�k ���)� !Jba) ofJ� "G 8,���Negri bo:� ra!�iss�!*�1930's z , [4or��1qsystemQqUni!)S�# rece�ht!2�"� �� sick!oinsidey d��z�nuO �-�aBA',! c!_6%e� confirmed4 d [4� T%�is� R�of.$�5��$�� possiblxIMa�&( hig� es.i�Ij�ex�#e�R�assum�� %0  inju%Nwould !*!�� d"iO�.�zi_t��n����� firs�opo� by�� s�$s$ {"_s��rce]xs�� disse". . Ascuseelow , 6iB!�iunQF ��direct5se�'�(A'i�A)umah� � a� }8p��m�:�("� -2� ,!j )&"2L&ly��12 �(� km )5�A�st/]fee�� in a� gledht [51N ��I$�A���s�MsTraver�)he rtA�t- 5U2�#nY.��eeI(return�!�bl*�e�o��-�. Fin��u#�bT"���OU�is!������perso���U� sigh��m�U�� !u w52]suddenA�ear%5.�of!�e 2� � <( Diaemus youngi!�t,բ~,R 1954ein6_a Łhad�<routinaviA(dA$c�f35 ��,���n� simi�tyB"�!}Υ6�#rn.'~-" * u[227� " `� XU$of multipl!*.!,9��E.A�#*\E��fa7!:� year� ar5&�  nd 7 2e ���f��r*2�:!�l�5�x.d�Fi ��G�Jq7,l�.E�m%�AC-'!^a�*c MRCA4�U�5-�F� :�N�xa ny1� \ �), 2"�#1K(.c#"2 w e)1�i�%2�%!��2�jeJ�&[!� �1�k�( �0� c��&��"nd)�"(cto":�"J �%Pyd��w�/n +>g"!��1�(" 813;U,171 !18E!!0�E� ft� {2�al��"-%�*%A,-,by Streicker29<1585 [Q�149g!1663]|53< se!�.! �%""*�Q�!� �di���*��havi�� d 21%��e+ or��+ec�5^ofo�HU� �  of 3Y�&�s�lO��oe *� 6!+)� V �"0-�6�!8r3ito��a8�+- ,9]��&�im�ameK'3��� -Ea- number��P> ���-� pr0E�*.t*a�^ s�&�"of\ŐcanJbe�2�3'amakTEB�/!FcluS s ab�.���E[g�U]u-|�r1P��P.����-.�o�2Q �(!.ch�LaI�#5{$i�� ?��urY)�!^fa?5atFJ*� �ro�asub!q-�,n�)uP5u sEB�JIemM�7e�� termժ"� Q��UTu;,Ksh� beA.k� m)modm6.v! 4“discrete” (? uC0!(a�ye a- Sn  t )D ��ű�!�|�졘+ 1F�!t& ly�)0�� !��an�J�5���R��m��so%U�����2a)s�ht!�!�8a�e�5-:� �#�Iec&� Amazon�3Ii�%so�%��.�s6C&m �&�6�I�a�����or un 9)�r�u5�,� as&. >Guy�-!�@��[�o3�" -med�7p0*  ,���!* acGt�Q\aQ�A��� hipp!��aaP8�{� ircraC��"� *� in"� �AU[5*HL2��R`�^�yf�1* M9K�*!�.� bA1�(�ą=�/rZ%�$E/,&]{� �� �.] �% )IyA omfa�until� "[ .�0� G r�.ub�Z4�t"�, wFzd��!ia �two b�9�"�M� ( GenBankA=et",nos: KF424531 +�:�%�5 s=�of2y+{-O( ���� ��6 ��.����=3Ea<%be addre�  ia 2G real��A�inu� rait�Eaa��eA� ;!� scape [55�Q�A�performA� �E���rela3on �;�'fic�� *O GISN(ord�%e��q�.1!Q&_;��I>ces3 ����"� �lKy &P*?� $�8.�>�A� %q ed2� repe�0.�E.�u>,Yztu�p&�u��to*_ ) a +$�#� �s4 dynamic� .�&�f j%�"� "�e2�!�. A&4 �atanE�i_ ��A�%�E� focuBtQ)��of2�2�O.$. V.9 ]�� signA��%A(�&AQ%9.�[18�[5mQ�,�Rl� "��<���v(R14 [57a� tb aB go9�y ,5,8]�1re"����-d�abies-f�3�L=�� ��n�*�*9}wildlif; 3!.*)%�l-li� �9 �f���_$�� � �]�(�.&f #.� )�invol�8in)���.�&�'��;�'paradigmHf���AsF+E�E�n d�,Ack% 2�a���^r�Agfil � gap .���cereb�c�x��d.�>ma�fun���"_/are� G emer� e}M xneuedevelop�Yj"o��ex�Rg p6<| f���!�A"N an'*or-&s=axi� �i�&f Fgf�.Emx6 8Pax6 , Coup-tfi!�(nd Sp8 play���G:trong�%�#�#�l�+t�y�bu�6��I gula�#i��Ton�)�(e ��Cl!�2h�-�Qn����k-18is_ ly q�A��veE.i>#A. W��riC�a �u1o0 )�n�f` �.s$i�2�T DCe�:#�!vnetworkB,a=:p�7�NRH bsera�ex� A�E�H �treY??lA��A Bool�3�fl0-y.\i'-*Hz� z"�C%simAed%=.85�c�ed� V� �1a��=�1=�of)X6oE"E_t%Tse9g "�#2o:?.WE ��%\.X�lac�cer� �qa�r��auto-riOu;i_/A�lo�+. M��R"or&r_�&n� reI5@)1e%4satisf�/a�cri��a�� good2� . W��b mark%\$P �G�))�9�y �BeA&� 0b:"�8�>�� ga�!)��!8ofN����K)!�� �a�� 1�ng�L�&Fa2�>�E�aX`�2�2#m����9�oE, %+mut%A�� veMN� !��� correct����. O!s!� illa$�ap�4�ncx���%� maker%vel!xdi%­can� �% :�FGm�E�J���lex%2extrempreci�-0JA��adult"2!p12�T:$6�1by r*>�%.�8,� s�/yto^-i>2�a��ic�w��EIPI conn���m. But�$ do�is�QŗQ# ?�rl"mEp�8�ti�4W&tivity-&�"=.si .mM. i�!�n �o�aa�m��ref�H+s&li��o�2A���one�s ���QA�� aly unis�of.�� omeTf  L�%alamoC eRinnerv)?,��(i&Jal�9ngfb$i� v"9 �/�!�i���!E�[a�M5ew �91]–[�)Of � hA, mani�6��>�puT,,h��I!�&^t5�1a�� �siz-1p0��&t!]F�A*�TJ � ���!mmo�Qa�s ĉ��)94�7�)�A# -stag�$EM�+ini/broadU��of%�.� 'a�)ffold�R�e�AU)#V![�P� Ym9 R�t�dr&++A܁�!�M�r)�4A�gen2�� ,A6�#�}� �c !oa� .�Ep��a'>� ��IaA�in )b�"=�:�znSa}E�uW.". E��s�eMW�� �L��&mbryona�l~�Drii�e��'iRAL>F�� "G�1�� (:-dj  al fieldatٵ!cu�GN� -)�!�i�, �w(nNB on2.&!. F)�*5, day 8 ( E8 �" mouseK morphogenCi.Pa�� p38��-��tel�9ph�&`D1A +9e�$55 7��1�6Im�2 aP����e�A�i�>Q� cripE�factor�?F�Z!f A k�l&S*"surfaz+�A�ex�BV�� ����xa?&�=��* beca!�"�ry������uniquA;may�A)�equival�<to�2ina���[1)�13�A��a{&��Qac�1%�!n!9�|7aU��eP�]��\h��14E?29]; [� �� 30�F��mJ ,�M��r�.�up-� down� �r!�0�rge� �sUZ�qE>�(�@QB%��aSA��coh�)!`2sL -!�a hyp�s_<� 8� 852� *�s'/v "-H2a�.8W"�s:6" �,�m�Ue�[24N)nN�Ti��&en�+��*�� � nguQ�� |�*orm.�- c �`.� a��60ful`a� � �b�@� !J� �[3�+[32E�eedback*� A crucBfe�8m en �h)�V!����%nd%$�)�� 6�Eec -5#8��Mp6@AJ�$%3l55/in:1aE�V�� p�4fuCFth�Da)�ng�p �growt�V*d ���6�.6:c�4("�/.� �@-�|�%[ 2�:N  DS�9#��rmA\ aY1^with �!-=�I8��&M cap%�� ^(. Establish� Lq� !t"�A�c��p"8 i-hea�1te; �q0| �ro �/ach��+m�5�� ir a�to quick��ssa� e ��,��ach.�� . Com>��0-% FwQ@ne� �-NI x be�'��Vff~@o&��uijl�I <-U t oR:s"i%benef�3. C� g-auE 2���2�g�O!c�e S� 0rrow diagrams1�8s�?in�PA Min�� end0fo.s-A� usal~in��[ ��!s�:��[;':�( 9ml m� ��un�E�[33��3.C6�B�D@'l�"� &M . t� �Q�cK p8E, ���' pote!=to�T ga!e�#de&�4�8�$�itDd�as%*IN�>�/38%Q@{unambigu� de��}> athuK� ���:�a�f�$��d&M�!�)�&M  lici�&I[>`�{1scrx0y [�=>��8s<�=�ed�"nd cheap��v�laborP.M/.%��)�k!���� t2B�<7tnbeE0� er� t���:�Ii�8�Jh���.�f spur�Ion6:��\a�“im� � a synerg!AVner� A+. H��#- "�"�H��A�mS"%�.�F�a J@,C*blev �%Z��nd~ te�:� take$ ]$^, zeroQ a)�:I%8p�\"'�/N7o�^oXC��0sho��@ff��2�#�� m�K)�SI@v}Jn�ee��"�_�Y!� hard!KAy$�Hom=ꁝata�n�Maq8mid!=:1challengE�&�,� ae�р�ras� � �!qI�d��D:*4 ��{��&���& � !w)2� 4:�,0���7,.%`� t�FaUJ 9A�$#�BU�sW645ste([Al ofI����mp@:LyR% !hip�v-E�!��how?ɭ-vF � 1id. �7lndu# �& /�!:`�\ till tw9H 2p$��b"�Lly�N�5n�=&H�ͧ�?������fIn*��I� a�m ��art>a�"����%{an��B+&� Q)H@;"]�� �b1w�'A�,(& 1C&a�,�JVnd�$R�d%bNr Q �D- ���� xplo*ah.1p&#d�ly�H&`�F�\. H�25�V�2����'��Iڕg�.�+pY�M�!�� �b� �@�)Dq����,%$pKEh E�>oN�g^ y�nd"�H&� 9%��fu��2�2'. &2!9!<g�'��at��4e�҅�' lE �e�q?&RI9��igh���e&-� }�q� gyF3#![� loo�"!JMH��{>!-0 � poo.&SE_� I�e3eB�-�s��of 24�*����*�#�#�� ? F'In)� � ,���"fix/e�*�AR� �� didf!o�F��s0V��esop`6&�,� ne(Q�N�2Nais�7C 2�S(!2! %U42hI�j7`"� "< 6Aa��a-�!��Q�� 7 !%��� �� ���}"� �&�l�mMqrW2> jQ�roc�N"P.� ~"��at E8��(tE1�K�aakl VV&��W. A~�H�!g�)}��Vly%�yE e duŴ*�!C,m�P-q����![�,�?AG_R"��x}�jY(Ui�ryU=ZA��_m�!bmi-� � ( ‘1’�k�  a.�!�� Pin.;0J;9�.<:1�I�9Y�� ��42�l��WA�By]/_ND:�1%���� a��!>R�,)U,,!��I5!�-�a�&"9,%�;d9)E�] ^28:]%�:�._�[�! Q1up"}�m�;a]��jppl�(stocha� ��"y+��d "7steadq �&��&i(���Ɂ�0!r�al�V5�TEag�%M!� ��5&�$e�7e�1J A��arMG� t:�5%�b�\V]`W�p�at=9|�!s �(si�.PQitJ&so)$hH�3�Pan 50%2�� �WW7fj�q�l 6�i+%Nq�AZYt.�s�\*sa�A#eX�i����E��$( jrA��nn�l��:fW��mO2,s9+ . ToZ*y#�9Au��2 � orU�- \�Q.�b6D2/ � ���� :e26�-��conve���3�ofU��s� m���"��W�?�� E$j�Fas%�EofM�!��2�6�1!r%F�i 4� CarA� ]�32R� Cab� �ZRp�Wq&��m!c{� >` ��tT4�5e. N�s�u6�"nodqn�3�-!+ob6 P�N��Q j5A�a�� �! ���o_^���R�� a�4 vei�#5�/p�Rups�8m!c"�Oo"�(�sr�&lsoFu�5��,.W$�}j ��g�<80iW�z ��+ �&c$�H&.� >e�CB9��C�na�m:&2 �A$� n8 �Y s ei�lo�8�W��-l��r!i")0O2*&di�5�bd� !�� �.>�#AqQՈ��K� �F�.��\�m2�.��R� soe?,%�-6 �4jvD8 as� q�%�"�E� e 8�99�E%�We�,�5!�7Z XM��9%drar�&jdI~�!"@.� %p�7*�&` "A .� � x'f���K!�d%��o v�2la��wh�x/d�u�* �S"��AY*&Am�E)T�S!R؀�e5q!&p<>�,E3naz& ��FRVZ^&33RIn to�U &� out�Hdqf�q�8~. 96% ��&  ed ,T?v� 6980%E��aW�A�%�]tR�G �*�D�Y*%�~un�R���N#3, j~� sa��o2 m�CH��&�xE�1E2$ird column�2I"�Z�=,:�,�;�*M(QA%f��enc}2MY �z J�(m]B��za/o $Y6�� i�%2�V{��.=� � *� "� "�R��5M�2t,�ia-in 80e�!Je � B� x�%��< ���! in 6i�>� H 2��PM Q2N55�6R.�>GC.�54ZG!jo� �*�n"n>kv�% �dn�,._%y� -4!e��{n�>��� �yem b>��5Aw�CN77 �'�%!� 4R� >5�y�n A�n-��33B[�֍�Iұ"?7A cf&� 1 x7 xC� �B� ^wo9 . No2� ixf%�!1t.��U��ჱ 2 .)2p�tg� 2�.*�FEzU3k � �� �)l"�(R�q'v*\qu9yY�d��A5=&ie!��#��u �:P .h , on*� ���/&�G"�@.i��"�#�� e ' �(gA�%�>�C.�� ���� 2��m-'�)b8)�: m��*7tV��2T!Xwu+�aDb|2 ^2<K,!L��b���"| 6��Miu<,@��b� �����[hAlbx$!& 8| ?64s�u|N-Y6�%�A���$71�<l� b�E�ch"�# recicpI�D� ,M b!���*�a;��]�-."-5�!�F.R � ?��z �5�A�����Bi{��Amll2k)Rs>]a�"�:%e:a� =g����AZ*r&YÃgf8��(�n�P- . f428&�C:�&�a�1aekJe;*�''7|(�"oa��( hway !��f-  k��>�"� � Uc  a:I-")-*d ��VyA��5�!?*� 0��E�qa�"w.<to ensuEeB6�Ou��:s�s �A��D�3e A_!q%~ k�p)�!�!åB� �oZ&�ya �3v�-�m*�%@�?�Tsu�6"N��:A��s�:C5L n"g4�6f +*\N!rA�,�J6�s21Z}�"�5f�?[e��aT:�c��/a ��xRa�Hq��!BF��lxhEE��,@��:�a6>�QgB %9*9:+o=nF/��Bk3N#�J�� o# 4A�)�–�g"� &�,_G!��'A}) yݡ=IVeaSIif)�!�� �sw�8��r.�qdon't1" mF��"�2�.��ez c�J�2# �� b� �[7B��2t�55��`ar�1q*�?-�a�1��n9Q��< 2)V"�)=A@Cl-tal�Q6�D�ort rpromo��&� �3��ty�;le�� �#�U60[�6.hTw�N5%�t~A�� redu�& �I� �!�1lR��A�� �z ��]A�)U<ur*�,"� U��FVw{�3�m �6��@:�=*� n!n" �a?! ; f>E�.� �p-)�XK<�!����\i|a-���2�q&&ly &�/�*�!y����nt��6�w!w%�ocasca1k^��*5�i�z��.U$�l���*}B�st1��Pe"� 2��� E ���!en6Q=J�$QK��KEA� 0��!�ᆕ!a�. ,!6�� g�9<)es�q�!Jl2B�j, �k–_�A�O� es�"+9��=op8������!"�n/&�+)I �A�g78��� �#�&�+.6 M�-FQE�d.�or���.��,�(@m�6/?u�RY5�����6vqe��"5l�R_C. RF� o� %TA2 d`� ka�u!��C�8]�h'�Z[1-��7 ^A6F�F1D�Z�h�:�;x+x���Uly9eH"ta�=�2J� on� t�e!y�r>�$V &Q�cO �GIEscra�.�#6�� �me"�$!�ea�8a�.es��a���" C=��2 ey u>�!F�X): ��U�� 6%:��TyB-r�de-&� .� d&LGa� mplex�� \�"� �I:@�/ :.��h� >q�St*&<a$� �QS� K9���:5���In��.��u���lay��l.����e��m ��#}k�� ��&��h�#t�}t"K2�� 26e�6aQBw�=�ict�i;���(��6�MbdOuچ8c�iRA!�at E15 ��@R_!S-�|5):.�QaU� A|�W�$)%JjE E�rec�i&� M ���a-Nperturb�� ���. DJ2=!ɤ� M�*O6�ecEm=_.�@4w��6�&MTA*� ~�A�q���EāngF-co�eada�� chick mid�5�| limb� 8xK6#��"��ur� m�a�<xM� �2qi���h 2 @{)�b6m� !8 r,-�?12{.y "y4� )���f,Af%.^oA%�=�b1icnge� +(PSp854]�a�es(Nn6� 2)_IX6&�.�mRN'A� K(z8�F� ._on�=�!�"m$>_a��L+a�or �. Cha�VXgf2P w�!x)�!��i�E1ӑ50$�!)&=q��9���u N�%�"�out$��m�l 0#DS5~%mx�+� p8�6�1i4� 9/a�bgn�A��-V�<[5O� +%%rtD$����/&%H,)a�z .)6��E!�!�akQ�igtD5g�Y�I� y_![�?i� &v�>�Vc2NZI�{�Dśp%f�T�&�Sde)����b�#�*5.�a�B�e�e _ �^!�$a6�K�>�.�M(<�!�&�D��jA)���'' � draw"$�C5A�%o�6Y9��"*"R;2�="� E.FA-�=�L&]�"�/gorithm�>is��?(rse enginee_!8�Y��d kV"$pN�[6�6� �L%^An�im��u�A��t1>�Laubenb�6a$d Stigler j��e�/N�a1A^rp{ ơ�ah -6�+�{ y �U �*R�qZ�zwitjId se�(��mu`�"�g, �Kild���<6�� PA�unY� eMNF - R�ed$�)nor>�. Mr���Wittmann& 62] �Q9mu�;k�H]%��9 UGg�MA<�!��O"�G�-hind� isthq\-�_� �JaX,�uct2"�k o�mi���� uiRan"egM%� digi�'eeriZ2j�*-0Jg�B} ���Y����"�R>re /bsm8��"�5JL?�6tG,;a(� &�v_�4 hSrmAEJ"�E�BLkNl?D.h.�82�6y� &� AI)2�M2Sq�d&UA� �e�}5�u��G�A���� T�/� goalg?�Gr�ls�0F9r�O)-denti�6��nzbND fA��Fȇ�"eW�$ ��@B{did�en %�ɷ* d�3�r�Alber��d Othm��3]A�lo�${/�(��Zd(� DrosophilC!gwUa~� ~ �\ &j8Ue�q��)e ��g B#����� �8��!�U�Ztu�d��M|2{gSexhib0 phenotyp�$�Z/��2� ��)q G�YI.�u�rq1��.b$ -��M�ap�@,�V��� .�� vCE�XYU I�mA��9�A�(Tu���}ȱ��){=�4,�o1Pu�RF"; �s�i�dcor�I�)��:xUyp� f) �=E�m�p&jK��9g�5�Oexj!h5Il2��"�jE2�l!O. Any힅<� �b�optim�L� �!Gc� }�[&6F<w,7Lk�)�5D!�"�+QK>~ �r'tr*�f��)R�$(Michaelis-M( n ki;�!qsE���) ��H�Noe"� � !w\)�_JB�%)U9%=�gnq��ij!8 " 1G[3�`On�u��$�W:F� * 3� .� � ny!�mu�bj"k@cellscw)q :�"("�!.&����&�&^q"F4R/U*Y we fin�(a��ny���;��%�.ly&�(JK)"�%0a�VaF�)%��$e�� !�ac� \�.B� <�6�;!%Cpe�CQ� !aE>��sby%�-!� i"��_k!, ��boG,&^���K~bPl�r@S�k`l5%[*^ -�T�oUX�lEP�5aJs JX7.\&svi�uJr�? �!=�#ph`m�;���eP`moC5B�� �*�2j6�U��" ���MRCP� ��t4 a'd�A��oE�2-���>�l2��25�99��of�e�%lur�y�-��D.w.'�F���� BXoW�"\ & �Wwe���Al���]� .���&pR�� pC� �u�:s�jR��mOu*�u�pV���O%���XfE �Ar�sqE��&2� *�]&�5poo��FE��\�f �"v"P����& �37*R�M��9�>�UG:� !y��L,)�M�Sat.�� l"#�y}�aי�9�v'#�Yq:i�&6�� o9�de3�X�'k�f s� �1� %� p��4F�uBR:BRg����RVI�!����Y!be�y�s . W�>a�Aum�E�V� �", *=�u�E es4"��*V&�A�o`��)A�s:�',fw)x�*I��/Y1;�~��a� "�*Zd�)U�$�$� �)n"��5Kall.!�� *�9.L�R;�Klso alA, =� duir!��oK ��om�h&- ���Vide� ,� ��#re+-ve�Eo2/�E�Z%�a� =�*� -�s& Yu�:(y�'�3v�:����!�� l� F�er��a a�-A�2�R MndV� �/AYisXb�S,� �T�  )"7 j�&MPpM _ l��:2��>]!�� 2. EachQ?E�3o%a�zRA`��o؈d,AND%�NO��RP>�?e�z���o> BX�>ssu��piw�gra�"�/�9��9� nd�As musxl meAso)s?=�Kha�_ MNa�conjuB} (�2�F2�T!)m��0�62A)y *8&� �1�Cc$j?YLAcc�g�KN�\ y cD)+^/� �A����6A5@� 3�kGw�� ���if:$%s��%��o $�G�M���^�� �Z_;%<[/J,Y:cŌE$t�EejuAUin�A?8 R��!d �9�+s $E�p�s [63]:8� )!a5Ooq&�1* 2�!��_!��r�P�z���(=� 4ynA��T%�-iD�) 8dec�2A���)i' n"hh^���wb6�!h(��-�QHn��bN�tr�� x���e2�o*`K�Q�Xh�3! *SwG&��(OR�u�Y�H !�sis��?- e%!�=>�e�� (!�a ��i�o��&1@tP>tq'� -Ti� �F�3d6no"%G�6A$lax�:[Ay� >� 7 in9 BB9��8�r !���sa��T�ih*�pF%c*B���P&D���47ɱ!U"���!� �.�,wʮ�4eַJ �Ay�S|7nu#t�&�"9u�x�>2�n�c2��X�t��r &-��8"*��`&� E��,M�v-�B}��!<~ l��ce"�"F<=h�^�"��i�N" D� ��1%"k�����T2�"W�'��لP*~@� 2���1�F�S%I�l&fno� &�-e�!�� 3r�}*�*�-����mD��Q��su�-�2o Y�rzBݑ"�hM�82B���aU!'T�^� �v � 6u . E1��"P p"+0��1��ighe�k�E'"��[ e�(��"�'z#1]� ���I�?F �Gq�g�ѕ)�y� Y?m"2��\� �!�ԥ�w͊�d.act��A7� 2�l�*:�i!PaJt-~�u� fs in"P E�! m# &�j.ɫ� x�O‘G\or �\���%!�  i`�ͅ;*��$� 력�S�A�(L�+s dL����%�9� �s� �o�rt�=sDJ�a"L2cd U���Vi�"�.�.��A�Um�\0*re�;26�pf`Z��"���>;:�"�)�&x�$ f��!Ma.!y)�`!:&���%6�i� B \ �!x)e two-�!wo-�I���E���"!ih9"����ϝ�&�5Y R�xI ݭ� �agNR�.�UR!G.na�%� !.���n�U�Eŭ�"� )� �@.��i� "� ��?3�– A�m– "� �QA%Nڈ�K {q�� �!Pd!؅"E�" A2E�����d���3�.���g�[G �!��v �=en-tu��'�ƨ5�AX8%�� Q�pPs [��"��"��*h>2 �+� D�F_ {[}Jb� ,V] d�!k7B�!�M� l�K1C.)�"IIU+A $ �w�� -r%+ �MƵ�.�1Do1]E 8= %B]�2ou�tG��A�: .8" ?% * 1��e&��Fd�A4��-�i{)C)-%#lv%���.�vVk�v�4�j� �edN�s�'ę��;�-� te [bq.�|>6���� ->�%U�9.Iz:cP1]�dEĉ Ahe�no���!B)a5� 1]� ��2�nd�1� QI�.JEZJ�M�s��fL��!x�%���i[B��� ]qG&FE�=��E3�+�a>4��>�;��.H.�B��  Ql{gI���� ��s empha(4&9 Q�5��)f�n�8m���h�P6�u<�P���P�a� FwKc�A2!E6H].a*��d!�a!g pd2+�� }L�" -m� � (Y�%P=h2 A5�2:2E/…<4!��_4!�S�nYP��� 1�rul� p%g. S]@��L "�h��v6T.:O).�,!^o�,�*+ �m�-Y�?�k-I���6�S&6 �sb+ . Tr d�-M` trac� ,E � �s|#2Y.8A �hsynch�ux@���.vaQ�� . S7 J!�"%"!p��1]Ƀ./ �L2y*�>en� �ja�H,cycD�at!�"'9E�6��I5�az��.�p�$E"W� !p�1�& M6�)��:xa�9!�s_O. R -� n ��"�i��s.�=_9�5��7 !g*O "z"m� o K!tfu��a[9��>U]e��%'e!��Markov!z�~ism�Z"_ �i7 "�"�[6/��mr�xha6f[�a�.�Z�M @��)��.r� uUW� �6� (eQ�d�v�ck�� �,Pf ��� 1Ef�. /oم�d �E�l2�>G�L�Fi��%�y>�2�B+��>+!v�"���l.~t) >G2S�7]�B+B/a�%A%#aJ�kWq,P %m�(-�e)R�Gc%.��AV�$t�'�.��Xac*pRj����sc���  GaA"} a'.�.- Ѱ!h�Ia"+1� �*=�,n�*7 %b5Re�mup=&3.�� 2�L��!l��y�aly�lyi�2_�{�!�r��3 �-'� � e���E&� a�&6����.*�U�@mN4� " ŝsoz\!����sZv�<r~�~thVR??�TE�A��]�� �?l�O�%2�ϳe!E�`1^`Axso�IB��"\E�� l�&3)V\t��.=�9�2cY�P� ER�B@]* �yn --�e�s.�a�-\�z��.Ee"ž�A2^��� ުinw7B4z�)��AD�B7�.!f�UD:B�I!��'�&.jaJ��n�;ifM�1eno1[�.�A!E]�a�1�|!�F���=:Za���Gt�Fwe kneO2��.�J aw �wa+e�vn5"d���a�`9.jou� [.L�d+90.LFp6<AN�.u" �/�v)�.2 2j�/�pa�6)�g�ahomogene"5}2j�6�O*|=M!s1amW�b��^�� ��&� �sug.��=.w~�tvna��=p�qu�Df�"��.Ӏ͑.%.}\ �&�)%]�' >y*�� W��<���!�\X0u�q)"�#�����!��+u�]E"iHmea?V*(0^��� ManhattanF�!(! g�B&�p�jz)?^�B�X�isH�KB$.s!al:Ap. ��HBn&� 8Db�oa� �� vice�aI�%�"��h"_�!u? eor��omc"2 :�%�2V���E �Y� !/b� L. M.Am�E��oJ^l�/� Eo inde� � M��>i����o�"�m� �A�B. IG*��[}��n R�m"o x *� m(�S"6�����*J&X._"N"DZ3$V2ɖ. Graph�N w�Q�%je9�}�*�br�lo�4:W-�~LQ5����q�b9�Vc. ]�(UY,)��q<�se�m�M�9(\su�8R�O/fa�9'r, :)r�ne���(>�-�;��1mB�&�-�6�go‚ �a�i�ia3(��f 2!���6a�� �xr9S ��\a�0�'Ŗ>�oi%�S,��fa�E!5lYeg?6Q nT�āi�{M__t�*Y�*��F&j�] q &�h.�>q�3a�����2��;l�1���Z1B0zl�P*T�?clQ�R&]{ConBm �K!�.��B��&a fewR%���zr .��Poly!p��$up ( PcG )ai#!�2�� orga���\ & K!d�}}��&Y�aloLT=*,.�A�by�"�= ��,A���A��U�{ PRC2&��methy�-ITysine 27�h��(ne H3 ( H3K��!] PRC1Cubi*VFF1192G2A ( u!)A�E�ge com�ofa , Bmi1(�'dem�#a�A2�TY:��-�$ghMGvL?v�i.�a�ř ome-���4"{" &�n �- 2���*�V%7 me3 �eI}re�%�n�s�;��cri9�_��&8liz"�%A.Ccr'HMGLed ChIP-Seq technolo��'��ırgZ!�-"�' z�in MEF A�G�2�\rA�"�(��� pea�U�j�2�d[1Q����.�5TSS )!��-G%E � sRi�@akaenrich�h�i�&.p:�!�"b�QemFm�>$nDin WT26z���N;�x%� � ��$m��-!{moDII�).E�al 700�g^~ !�s����0%p*E�r�& ��XBKa�Oyoc! �:�}��^a�J_ Ij}�g%D���!.m��/d.� uponE��?ck! . Ima35�,-Q=Lof \isJRa�al)� �A�!n6��" 6\Ji , -denK�CpG5"���,R-&X-^�d)DNA2�$;lin0to ���)r �K�j�M���Q|:�J�,��9 �-�%�5V!,i��a^1�@�employc "*w,} �~ ES�: Inbeukary1a,% ���Mz�� � !���Ek:�iasi��e�un��(�ɕJ e���U���146 bpi!�wr�R�#����� octaI. Oneyգf��Bc-'Pt� D�t~�� ykmod����}�ce�a,2',>�phosphor�[̥2#��� wed "f<��2lAl~ cN�|D.je�:�ZoD.�W*VVagrecrui)-!;*X,mod�<W�f[�]g1�T ,j�� |�� �L�1RYAA�����H��A�uA �ac� S:����� Es adopr-Ti�YL �ł&�0��!"� N�x=iE &lac&�mANen��xRp���-��E��O�# i�Xc�HT""<��%pro �4 ip�q�ubE(5�_a+ � TFiEv4mM���{� @ H V�ND�Xed �rty yV ago ¨.!�s� &�=Z .: ha�Ǭu3A!?Ku3�!+�w�[{!Despi7hvowled�ts�M+3\ -��1.� enzy��!6�9u�.�' ��`2lGgu�.be eluciWd-r))�9gE3���6!KQr��A���} e.�"�  �d&KP1� RC!:o of RING1/;> BMI1�� HPH2�* . Biochem�%�;��!|h` \o)"��?�(ING2/Ring1bl .cat��8����a�I�NF�jWB��N�s ��� ant�ubu�PEVdraЌ��"� ����[>�ؙGe* )�f �E�%l�p�� %�a��n���� ��k��b*HcA�!�_�A(���"v�I2�����s [�1�(RE���2unq��%�Vlog> s�%as Mel1�� NSPcAM!� �%�Q"inb�"�tlN[1�' ���PA� <y�a8$, 2A-HUB ,Ew � 2 qC13]�lig��!��� �O�Ps�?�*B !blp��ool%�m �� �'�% �,2?��es� &!Z�G�L 8ferase activity� [14] . The discovery that a component of PRC1 , Pc , can specifically recognize and bind to H3K27me3 [15]–[17] has prompted researchers to embrace a sequential recruitm�0model whereby�$2-mediated n\ methylation contributes�P�reN$and subseql ubiquit>4of histone H2A%$is � is supporyb!1$ree pieces9\evidence . First , studin Hox|XInk4a/Arf loci indicate)�@knockdown reduced*hal uH2A levels which correl>(with upregu-8of gene express! [7] , [18 9ASecond ,vof the)[!�de-`$se , Utx ,!�8ults in enrichm!�of both �!i�at2 target�s [20 Thir~qmajorityGDgenome-wide Ring1b h ed region|�mouse embryonic stem cells ( mES ) co-localA�%& peak%�H3Q�21�In addiEFto�%^m(hip between 82t�!�:M , severalU(also suggesal4potential linkzaDNA2u,. For exampl!��2"avb�demonstre30to play an imA�ant role!�imprinA�E=0silencing [22E623!+C�%%I PRC2�$uch as Ezh have reged{] ract)�(Dnmt1/3a/3b%E4are required f�fficiA\>�at5^:Y��On%�other h!�, n may�%�A}r�#��as6� abroga�_lIX�x5�@�$olycomb bo� in cultu�I�[25)R nsisA)t�xnoA}eoc!�O%[6���{�!�nt=saM#-!Qb� ng proteijMbd1 [26!�!6!�-assoc�v/ Dmap07�Despi��es!�!�s , aEMa����vO�m��!�not exia;sS�"epiA�tic�fil�Trevealed only a small ��t! e0��positive<mot�� were founE�be hyper�ed [2�E2�EWheEh�rists ��2�����2A>:!z>remainEV0be determinedťe advA#(of chromatia�,munoprecipitI� coup!to)C ic t)1array�9ChIP-c��)�Dpro��d scor��fm�(s highlight!r.�map��N modi9!�s [30Aa2yCenzyme.�fil�/90! transcripJW��orT1$[32A�Ri2advance�- � �deep ��eSgreatly�4edi!�A�,tedious task!`dissec�e_p�RQ�]�6��a�lex6�,al output [3�aAlthough2Tanalysi%X most2iark!4]–[3i�s well��66fac-3�(���{var��� linea���disc a�Q�a mystI .2J,%%r)�:n !?.�^i��fly �y placedv � !B� ainA7IPBmi1 homolog but lackPc [38] � s+gen��l=I �. { into ques�,. To underst!�how �fi ;1�] architec�� �O� mammalian}�, wa�A�b" e��SpreA��-depend�%Hb�� mpar!�6� �aA6!q@$ wild-typeE�null MEFEs���U��s&� Ńwhile O:�is �ed�!�s>���� , it7��limi�� �^ >m� 5->N patterns �'��2�%C!�>9in��-densAACpG! �9. T2�)�!�of=a9X� A�at%:>�R:E4low $of de novo��� � nally ,Vr��estFE :�atAAir� �� [ ed Gr upon Alos�� funce6 than �harboE�6�%s. Thu�jour� y un�s som�ev��l"�d feaaXv J � n effort��}�a�� �>|}�M�,we performed}�iJk(�s )!)eri# s usA���cha erized �monoclo��lpp v� . We next=�nor�;� �[,total number!% � �!I �I�gaa f�2�> summary � �_ alig K9�l5� subta�!=��%� deri5�2�s J thos��'9.m�DeɅn � c� * ign�g nega� !�ѸF. UCSC!�^browser0 ck�rrespond��}5o��in>�,>�)f1 A�ag�plo/ a�vailable1�s��!��x��w beganņ.S!�>2b> am&� @area directly sur�%Ohe!h*� start sit� � annotE���� 9aegŘ %# pair.�1�ofR��*PaAa 10 kbM&2�:�TSS%Da 200��resolu�+ ()Lw�>ᨡi� fv classesEK>%4S �ofp | with� 2( ,~5� ��� y [3� sameN�A�appli����� d�d abov!X4%�! �:� %�.� E����&� TIROE alg$hm [43]I�Run_ ��a��"� vis� pro[ ngAaow� v�tif�e �n� ed>�ϥ�) hrough�*"�% -ntA)s� 9 coordincz� )� (K2 )���af� � ��AX~ Z� au ak ; (� !N�2�jpplEL5 ma��ne�!seB�-d��16 , 406%%N�>} V]�.PP valua�ast 1e-5P V� %�2�by %�ly divi"� -�Cge��9 11as: !w.Z�b*�&���REFSEQE�� te.m�6|{� �?��abA�47%��� ��y�ed 52"=�!.� � �f%s��6� 2�%<�%?N "."� � i����^)U�  sse sub-� sI%671�,4 . 1% ) fal�AGi��s ���a> 7415F7 . 3G " else�! along%n.���Xgeny�1 ,-bS3�KD.}�(�f)� g�.P5D*�d t;c����G���B�Y�� &� g���Sh How �n ac )��!.5< !;!-�eda&� ,�<f�Im(UNGeA�d-%as −1� to + a� � ����e�M;rA�" ose l� �!!��)=B%�Tak�eq� Z�qb�� I�edx.�.��ellF !zer-Nclu�A5.UZ���l�"Fsoccup%%1�sj�A1lF�as visu�"V  ��>�5E��F��=1 MbS%�.�l;�"reM�`�]M��9�:�$to be veri��by�-qPCR . (�� carr���i��&[ ��#��"? ��!agDti�1��>�Gen"#� E@� +&�&�"-catal�Z�"?.&Q'2�#$. Biochemi�*h"u I�to serv a""�M�!�r6�%�E [1� [q*e���)st'8 Lexuld��:���!��h.��r� e#AX�$Drosophila� impl� d an�&E|-���A��, dRAFJfF� �>� s� �m�u�#ze�al��� meanElt���!�D(inec+!��� c%%s�a�#�R)!�twosce��we inv9'Q�lap"5#��Z�]8K�qo %%��n�eE�o�E3��.Ka��&/ &� thenI ��w%b �i�+�se��6YOR+ 4132�U^*T  ��e�,� 15% ( 65o 1B�WWE�.� �� 11"� �i604�bo_�* "N2h!cQ!F� m[6p�x78�1�c &�+E7:�a?>�A�WA f= ng"DE)�*R�k�z�$ar>� ~5��Q ic5 V�^m�A'�E mark2/ they 0��! �a+v�.%N�� s��{'In �iN �.{�s��� Z �,inZp)�A�y&]�@ half�allIBp��%Le�.�6�)4% -��5�(ay�&� 2$,�p�explo(possi:differ��s�z Q|���E�ehregGto!���u�q-A���� K� bin��B0- �Iy�o��5���LnA=�of [ň eacht( �,0 ����.al2:2�)� calcc)i*��("=egap2�!� b"N�)�/  eiŏ�*.�w��� D!K�oF<!�i70" 3�:.� surpri�#g"L��v>U�/%�%X>/w.D�č� reinfor�*!�facn%f &� inct)�3~��%�� A�"exZ.of �(i�/ =)6��YeEB�!el2��Q)�����nd.dQ s . ReR"s���2�3B��EYo&��q�:% pg<f!A&o of s�!�,ntly ��!t�& ��66uWilcoxonl  = n 2e-�{&L2,"� sub-9�e�JzFfei�st oal*�4EZ .on�4w�2�!!"���j�^lsoъEjH U�ylC &f�dI�s�b Q>� whol@�"&$��� 2M 1B .&�4�SS,:� ME!a6�at6�+ E�:� j�% 2B�N �',�GconjuR)A�Ν2a�BU2f��BS��!�a�5���*!�0,:_s�rs7Ag�s� &F*!�s!� driv���1de*U:�2��. P�'� 6Y �!il�!e &�7of'�1� fera� to!�lae�� �3: �b�6f4E�9�"�5��5o�!�!>S,!w��09A˅)a/99�&J  a&�2�"k ?&S"l>�>� we f�+eW�E7�m��!<- dinucleoth#A�>�$+ knowYs�� ollo�*� *+ s'"� �D�!A}gh?t�9�*� �E( n��10 , 310�!�1�3B* 2889&!<"�,K2668 )60#�of!m *#U� ( HCP , IhL ���()"� o� repe�25��aq%�<2]�4e!C/.���:tro� 9�q=f�B�  �w�)��T4� �3�2s�u�bisulp61 t�(��3efd:�3to.:n �5E�2�ITq!CPI4 � S , NP���K[4e��8arisonO!>&�&>X���65feM���!Q� �^) "�)��.�Ie%�e =l�.�, )eD�� �Z�ha"�/ �*�$>B%rs�=(^` 0j426'o"U �(!�i�%=��wR�wh�!�F�) �t� conn��:"� � BU�0B�.ca�<�IvinV�A� 6_%-ein�9*�[45] UGe�^�V  a.  de&�%.py�C1v�x85Q6�? affectsB��� � heB"�r��4 ytos�� �/��is�0�. takes8tag>�seQ-ive/in !:tri�/�8m���&�.��ve�)h E�Jx�!AP-labeo���dig3ona�du!K[46�8; �s'$ s 4D��4EY�:s��0�mgn�nt*Aiv�r�B�!1�be ups�qm!HF�<�2�>u.])�-�)e��!velop��al�xs>)�;[47A�6E� ��in vitroeemb�H&�< tempCN*�f�2�  initi)�[48�T25�!�N�&��>� �f6c al a0A}�a2��� !�g�u7� �oc����:��,N2�>a0Affym�4x MsCGe�430,0 microarray6� �e�G K�%: � �A�~=�5& 13� 5�? B�)N6iCO9""�8~ �to�0equ�CEbin%#�%e �71V�uq� A�1�u>%'� .� � A�ͥ%#� �e��&!7!C-� v�5change m�Co�5 =�%IV�)H>)2Q #�� br>�- �J� �� $T%g� "Q5� T"�;&�"I�trj �� span��+ 6�$|�2��es�re%WAzw�# �=�4�!���ul�4�; � s>�.�=(A� rA� ��ry2C� um r%�RV JtBG%�9n�7n�!RF�"�.�2th `stur�� I=n�Q:]�u Aze)V�;!,&�outcomh ����)>� de�C��0:R'�JU&dB�-M�:�HM�a�UE�b@Z�}�em!be 6e!ꕔ���7A�� �#8^yE� j\�|aV�n�y !�N�abund;C�KbEvGH4r�1I�= s; likewi-Jge��| ZF})-=-��uM)>)�%: R� !�U]N�iӱ�!�J �d ZY�a?b *�!sEu37*tr< a�s� e� A=E���~*p}or BaMG���A�H)d�:�.���eש���{)W"m ��9���K)Tt8�)�A� �uerm%2th�n.�,YV.�A �� ��F�ZI �}���� ZIe"�� ,e��heCA<�L�5dom(�CN7C�� x� c{y�D� �&�j'��v� e se�)p�=o.VAQ�7�A�1M*=5< Do$� �>�%x���^�:�5"��A��T]H-Sr�u�*�&�qt::n��!�B�Co-Q�"{%�w� Sjg:B�� i�!��> ��J��A���M�*�E�!�K4/K27!�b�5� �Ysol2� y�WTB_� ��E�)���|%->Zu 02>;T#)����.l �$F$s obyRe!�&�G�.\7>N�in��FI� �� �o�NonBS�`7Evd1GL: u�%c�E�7.� �*1E�BdH�j2AD-;�;a}%d scerT G �e�.� � & . I�8�l-�a�E�Rj?�$m����$�%� ).�+.�6%Q%z)��SYen��'.� a�;n*G�" Badd�I�Y�8ZF�:�Zš^� ��&�ImV-� ��F{w !�Ha.��y� �.jnd�)�A=.{��E�%�e*?m�'w.3+�6J.�6��EhQd0�Tkifold- �6.�A94729��W��ad�2$% żET"rWQ6mby|15�*B*�d���"���� �"oi.dmca&���^d.V�BV�uJ(L!�*|+ �%zsoYiS2�by�ea&N$*�5X2 AB15t2:��- ����!�M�. #�.-8e ac�!8"�!�>�?g:�U;2.Me�&)$L6�T 1�!�2R�B.�2� !&�2�E���3o- . 9!L0 37)1:SI�A6� F<U L���ed-rank �!�[ E\ #J at"� ?}��F�n��z>&F :�%�FY�<"'�t &(Yd2�o[~TD "oP.^. Ba mbHM�!2�aU l.PX ��%F�u9^�#piPR\"^?r2P %T w"{0B�� ���n7%*;�% �q �2�<.�Yq , ~.:{g���YU�8� D��%�: B�. P�')bi`qBM�N7 f*B0coinc�$�2�s�a�a�er ōc*�Yb���hf���1,%a�e�\en^ ss.4lya!R�?6?�!�5T P53)6�2-.]ay5 5p^e�>aA-g� >�IXE� ��;ke�B.�; 3′�"� %)� aX�� QIѵ �E��Q !,���:3.SE�.*6.�2��(r.g�6��]Q �54{;� :�2���`~_ _�"�AiS �)�!nr6 )+)a� 2yq�I2A�-�s:]7&�>e*e cE�st�A$-�b?t)�:��%9,aNv cleaL=Ec� +�B2��$I6�A� )):�+�Q�'!a Ek2� VAzv�X"rw� wo[.�.0�Q"��`��`i=C� �Zin�`� �`�XA�E�F�p.+y)ch*�.g!�!Un *sG �\� �/ �ut&/PE$'^["�Z%G+R repaE 15c�Ffl' �!&i4�W6� s�;� e ob4:��.�9�8IPc�"Yme�qis� .�r}�Inin�. A�B�@K�7.5ar G% �lie��5E�qx%4 b݁��e .-C� 6E��om lap:P����q� . Si�!l"� x,�n"(-&�toB^"[8-d "+ ��� � �?!!��*6m "�Aa�little�%�&�as"#d�%h �H�;f=��� ��,islA�.d#�� �1�-.&-`!L4`�*L*NAort�ve6�a6�L1A��X!|��W��) F? or h�"o#����Pei5�&� r �o�9*�aorm;F&&@b.&$I��inC]�converg"YGpathwB�AoA!o*!�A��X>r�d�F. H�P��`*%o�Qa"�>�e>(%Ah+h:@.H*9�{��a�upA�Ef CpG-Mw!���Nos=qIo��.R'�&A.&.<�z"e,�%�I�����la%:% ^�*�UvA"�q �v&&\��e�= q% a�ab&{aeQ�[�� h,L+3)"(� �C �D�*I�nt�Y�Cmi1���a��2t.��&4)q 9 �>+9p)n�H'��>I-�.�'�]d� :� >] workvl F�`>cA�5 =RP�����!"�_g� �� �Ex�< ostl.��$6�2PQ+d�' , [57jCo>.g��J,�"I8 "� 6�:=��Acw#2� a#�N� � �U�2�5�5A�05n ~! ee��; �����$TV ��)�&�"S� -t�!gK �R� ver- �enA�"��6* �15�*}�nnun"O[34�^�U(tself����>ccu:predict@)b*�m�� � >��earli�]D��qs2�R1_6�(�"�)!;Q�� g[5rf5�S stea�Y%�O2�%�+fA^�'� r�K���e�olAm�,!�. A��&b� gI�Aډ��aI'�a�2�g�!�:U��9�.�:VlB�i���A)�E*� � a�k)�6Xq��-U��]5��f..kv.$�oerE r�c2�!�k &y�&�b�^JeT&�QwI�Ia�!��ki�a!�" �"�#%>!�* . �+&ofibroblYBV �isoB';)EaS&�/A e3<�e nd immort�H)�]o)� TBX) pBabePUROA�structkp. BLY���$� maind : Dulbecco'mqL$Eagles Med )�NSg 10 Ev/v�PeJ.bov 2serum�1× P�Ri�P,/Streptomyci=A^c} -.oy ��!�yEa�1�1: α-%�( MRpNW05-678,!%QF!3�Y�0α-H3 ( Abcam`K79�J�L&�ba�)F escr���%u A�H9�GXl�p��zE�r15 cm2��M[co 95%!�flu� �b�9iMT��i�pelleta��su��PS^0B ( 20 mM Hepp*H�LpL825% [v/v] glyce��, � NP-4�942 M NaC� �5T MgCl�F1 C�[2hWs&r%-��0UQ30%b�p�.cocys�7H15 min_tens=�e&os�>*_. IFf�c.�N0.15 µgaZ�NHM�O��41srF/IP.\�to inZl!�*�C�lWTe+E���M�fSYBR G \ER ( Inq1gen )6�iE�@ed|�K.v�L � �(of WT versuy y�#� All�p:gWreA`IT�/�T>a&ie�pblunt-��l�JoA��f adap����nd-��(Illumina 1G�0�z�$%J��/#fY4d�ob� {:�Xo;8� �tm8n�2y )��g��PipT6�4��is yiel�%a BED�d��,a Le of 6#V�8 .�1�e]eᝡ.rIN�V��Yc[�y��t76PS*eem(�+f !�A�� Dy< coun�e*G�Cf�V0�b%Pic�Ep�*F ��2�ee=�<�app(Da s�Ongs@� �WT)Ftoa2�M)E��%FjRBAe9#(��WT��~wa�g2 ��5aw\�[�6�^P,e�aK&�<`Nle� E&U OmnibuM�e)�e7�� ��(c�n�YA�uM�j!f�=�ynR!9c�$. A custom ki�Life T�jATG!$< a T7- ( dT ) 24�PEH��re� A0Biotiny, c�KEg""h�!��>us5�ioA 5High Ya[%&n Ki9�b6ffj��ɱbu�J ( 5×R: A�(mM Tris-ace8f , pHe�}50�~ KOAcx5Mg)� 94°*3��bef��thybridoi.ݵ�m2>ad�^&:>cocktaiNA��0�µl�X>P, 50 pM��" olig�xuBB��Bio�bBio�Bio�creB~�%n~1 mg m { herr!�s�u&,$5$!cM-BSA!Q)_M@@1 M [Na+��EDT&k01�TTz2�B.�65@e��>w��7E��D>/.16 ho�G45!�xa�C!�H2�O�64�A�aA� ZwaRa�s�2� y< io}9)����F�� %"����E ssay �? A]�nad  `�> Brie�u, a+n� ѽ��!$�>�ZJ!Cf �` MspI%n"k=�y ntas��2�nM6� �e!"�F�UM�p�S�b��?ed dCTP> �" e-fiftietzO��X� manu}. spot�ok(+ ) nylon m�a� incub�in�,84N NaOH , neutr�E��TB�Dba�at 80a΁1�u� � bloc&�ni�g at 6q�A��i44× SSPE , 6×mn hard�?, 300���/salmo�9er..��w� SD� blo)���8a 1∶5000 dilu%��M��8N1EV alka� phosphat� ( Pik  )!>>�:a�~om+>er?t���3×*� �lBST-I*z]I�BCIP/NBT/ �( Sigma�a*9&ed� ���A� 'alE+du�]���%perJD rob��reg�7obulew �invrIr �F surv�5$�'/0Q"�3as �pr�i� Mrapid�2�7j milkv%duw 5�&{��� 1�xunK5%�A%-v��?r9"Ja��+�*�5,9D)�%Qpost-pub�/l�6�, m�"a� �idN0�� 8�"�'51 I q dece�� rly7,!�Y2irgo�cl"~"%9� Acc[h�k �*�f&&�!�G�-n HC1?�tep5l�/)�)�ib =� =U!�prAeE r�!�$"`v� �-0�ng�saC��la9 as���of C�� ��s;*n}��AEe2)n-Ŷ�k!~lexbIn�,!aD'ny38�b�E�j.yč�li-�E� �M��.��"l��R�!�24%�cŽ�Y Ӛ/ [1�*6v:�.�-Q �" sand:���a�+�9����_n#x,���@�%$ M�y�� r*�-Sl0(t"�.��3�#�ne 27VW�( leaEZU1e%��!\2���u� �*6� I����& �^o�"co��E���� �m� eU�)�t *� E� ��2�i�Nocu�Q��ݚs�;� }�t5� �qZeH�y:A:�m��ca�;�%yet�@ d�,"�,T�'��u.b􁡅 � �+%x02�,e� 1z c0� %ߡ�J�$!C!�. [13������.. P6 � z .�-�s hormo}�-M�;aqAq�-T!pX^�",$ j~ g ,�EQ&D,� Ig���-��WD>�,B��QP�MEC� proli7]t? AkgA�o2��o k%ly���"� W xx��"}�e�. TzV$ &\!=_Aela�#F� �F.p%rcapacaZS = �: �e�� � il"�b�. &�\.�)�j�y4.�?!6� -� apop�VxVDIremod�to%Ce-Y�,!��"s ].a �,6� x �kc"� :��N � _�)�A��f�o?*�Q��W"W��"�4j1�� 2]0xA Ϗu1A�he step�L�{Ay�%�U�[30ea���m5 ar&Q a�� 'N5M-�t%F-Z��)[re"0�:Bs�!��e�9�s���l o� to�����s " �jF�ptaba�up�%2�!W01� �suJ~�a;1F�"� ���,3,&�a�d$laboratory�"�&�I� NonC����)-�!�aA�M*-��5%�0)��%|'a�xe-matcKvi� (-.B�!U!A{%"�re2+�v� � I�armha 8t vA(�6C �i�aͯ�t'a�Olia*�, e����.r ,�q-sb �nd� �o+]'�WR  X��o<%�(�) UA�m �B(0��t~��o�E"3- K� W�� cycl!ao.->��^��.�c*W� .q�!�M|:�2|�e�SiI �? � "��$�y=a�.+��!|I_���r8"�ov�"ktu�:�o e�>R S�%%�]? �� ha�-velCZ%*OE��5� -� T=8�.!m���= �aVE� 7mQK���6j� �p\$l��:�a� �\� ponse*G!cic] e"�.F�m�H��T Mu�'JW�}��ɔ� :qaKEo�@@�J��aA` 6�w!9�� "�A(�N�bZ� �=�2Bm�M:�v 2P Vta˞�%���M*�<A�NMfBT �Dx�"���!%� ��qPo�>&YM�!� N���yw)�t�.n0 �>��hh�9aR*]:�6T 5F�!"� &� �*� .cN} "� . e���ly 6k1�FGY�Y'deKDW.�<2@!�MY!�M<�j����:+ weQ���w4�baE� "G&8*ESTI�ͽToOz2M�>M^:�夑��� , RT-~!`&1!".ţ�#rem�qd +�)rNI&�-B�-�O-C2� ��+a��5 cy�y��0>���d|~e )' !�"W4_DUn�4|� �R�-#i&� $multiple b��"EB��YurA�-1 K EachB%}clo�'A&�.V ich "�%XHe�"f�L�=��six 66 . Nn%b��>W� &[ �@A�aV�.Oex� �6�E�m�6�DCR| deleBh��9��9$-�Z�R�M��d&�ly� �&�qDh .J�o!$&� yPn$��ve ao(l2)�mtprecist ,f�. :�%>>��5R�yv "m��day 18!�y�A�2��9��$..�.�A�A}�,��l�KEaߗk284SEt-25���.2�EX��";.A�2�N �A f%6�^"F2Er OF�!-e�ϋ��2�j�A �d�s@#atAG�� _howJmm:mBv��ly :�����>b�e�i�J�6��! ͱA D�`��&Í��@�-ťEST�*� �� U GenBOa��*��{rcth)�6��2��I4f thol��T��=  �,i�! y��0�'6�a d�cb1 �x ��r!��Y%a �!8tAHy�A��in-�X.�M�#��Am��. !�uteru�$t k� �A1D�(NSL+ wouA�e*�3��P�aR�-^ adul��>�6�.�iF!!"K�nYW MR�.� Es1:Js +5��U�" �(ng:�"�i��s���N�6�6V ���I I Y!/R�a�is .<*R,�Be�f��� F�"e S?)�6:��6se�g�3l2Q?:�':� ��(!� . Ba  e myo>B"- � �XG~"d* �[K  ����2��u"�_F � �. L�8l  zݫ!�&�m�,m)~,=r-"�` Z!�*L  g)\.�G%bte �&-C"� :��de� UkU BA��yC�6�M}M���1luoresc�<-�v� v�Va( FAC�.���F�m;. M��r2�th.�)�W16��6{aF�mic�#.%WbE98( CD24loCD49fhi�0Qd hi lo ) �.�%=�'irmekp�'W!/ r.2R$!ӭ�"�m�of kerM�8 ( Krt�>���a K114 214�/� �1"� 2A^�, I��9%�, <by!�Dp�^qu�'����F�����"� :� cm��h� E*M}a� q IA^5-=�#�C� ) X�� GEFeK "B�!��e:3>�� r�g �:�B�. NBeenwa0�u�i"�,*��� N�(sub] of�q�e:��o%[isA�� �e�b6e���QRe� �ue9�(b?ly$EA�.zvd!��$n.�yD14 .�:[r�Ś"}����I6�a�14− 9)G�dDYnct3��.� D+A+=� −/�T�+@ j>�|�5�%"B����CD61+v��Q&�n>�����Mb�g���&�a�2T>�1�r�E�" 1rb;!A29��24�5EK.EA�g themoo�L^q��!�!��$���� *%�t� J�2*5љS# To"m#�a9��R �9u�eiR῁>at�*� �/�}*N*� x#N�*lB�2u.Ϩ.�"Klb��vof Wntia Ly6ak8Sca1 ( lymphocy�"t� 6A0�' l,�5��:�9�5(Elf5 ( e74- fH� 5/�%d%Rz�� �=��fW%��Pal�p���Az!�iT6�edit؄40ɉ �F�c 56'Rq>�f6Y�F� S� �(!� ��%�+&��R�v +S� .�E Pma!�b���n(*U$4A>?b F(>��|i�m\�)5�+FJ��&�"6 itu �=� prob}��&<� r)Kao6�.�c������at� 17&��6i�wNsq�Em%a p!�6�(�!�K�� !hR(mid�$� U>3U=.(�:HmA�1�AFJXc g"g=-�1�l�+A li�lamo�1�l,����S�I� 2�sN�ye�/9]�:�$�6��'��(i:%��=�to6J6�*I��$! )M�'�W��^   is*�Q%JZ'A"���Z�� sX:�~rop!�)�-�x�VS5mpo�ry"�_q69�*thO*�2+"�h�� f!��O�$�!o.�!+�J�(e6b�Md i z� aYI�e��!riF�7in? ch.,$( q�:= �2��Comma-D�� #origi�*&( EMh}�Balb/c"{�2NK_�X(s hydrocortE�� insul��#ro4��$/N9BP[4��4*�!�%0�hD.�A�cmea�K�4F9� .� ,S a-�,i�?Csn�A�ܑc�BAQ6��ap� �oe�fND ( Ltf���Bone�C- )DH�reOE$ A!\�g ��Adinu�o� at�F!b72ss�d4u�T�unSRd ���<�&Bntl"�g-24 i�/ -.��R�J�!;�m�����f"s!LR��e�WBU���9f�;!r�� 50%�.,E6� "�#]!72H75%-�.�e�EE�r{h��bbAY:#""\s�J�=�sF�:^�<6T[�;=� >�R9��bT�6H�$ �an*�k!-A�ox����6"9I�"g%=�>�0 )e�EU��`ed jIրvL!V �-`� [:�!p2(1�"��#F�I��i��tru��tG/S e"�2>�� shc�*8 R��7� 2�@�V�Jf��,� aաrv� ��G4K �_5A�K�J.�'2h�~+)!���e�=.>��0c�n� ��pholog�]�(�!���N of foJ -fil1�Vu��� dz~%VIgb&҇��/�~�<���>�.DKr-� 7i/c�d�ra���1[ h���2�:`�VA�n=��FTV-~�Z6UR�q�j��Q^=�%\:�6�@��2 ƪg J�z "�ZE!\�/ n7\d��"��P&%)b $V  � �A�\R� a���P�mut��q(a$�#��$=D 5�$5 !1��J�.I��� CR1 a��$��*9.1%!X�$ ��-DC�faia>����^� �]`C.z�>�"s&�:������at�2>\� ]ɭ���@ ���}�_ RO� le�F#6M �8�PE_D�6�1�-�[_b�terfe:9�� endo�@u�u(4 ��cu.&�h&LF�12�'yʪ=�>�4.�}% phenoty�Z�Eqe�tasA�)�' ;zPgz*QonQ�:&$F(^��F�#�.z�V=K�>�6|��.[B�m��~�wni.n��%%b:H&� mP"�at�� ( 13m!9�:]X)faiOJF,.���= �U6.";$��i*_5G HE��~ � � �! ����&|QY*�Jq�:� ?� *Al9|E�so�!�Nq�6��>M�9?JJ�Be ���e�:Siso�)&� >�,�[~@󞁱o *�GSi ���D<W%�!�� 2)�Vr*T�x���siBN*2)E�EL%!�ly�) iPIN�>)� ��7�]=B-'�,-'A~ Q 5��6� 6� ��l �� �{M���� %�5�1H_PJ�AF}0U�f&�E�y!B.� /�ԍM��a��&�+6!76K"f�pl6��Zq[M� �a��G��at&� %-B)b% . :0�/d� �j2CAUIEU0їno�@P . Duz6a �E:bn�P� �,:5`�/loo� �1f�!��#mo.� WVo�:].6��R(Y/ �<� ���*��]��� �f=-2�ba2:� 6?U� J(N����F���3 }�F*>owB�5�U�.�+�P,M��!imini�YA1�nJz�P�ء�1���2 i"� 2kKs��F�ayH�>A��-��*R �hlv�TF;�� a�KKsw � � �E���*�jk& !Vm�tj.�9ib(*2�?M�H=U�8��"�F-BA&��Hs�I�8>"�m.�#, ^<,� *�$a<Aame sc d) ���s� ���;5i|Bc&�� fFx>r �At1&�7B��"v�2+ ��r �6/S��*w NA V��RI=��8e�e�/$%WE�-X&� zeste ��c4EZHl�Ia )1���( SUZ1+!8-�.� u�(57�'c�se��r"!)F.�A�5�Ma�@�Gx�XJmixed-�Uag l,ukemia ( MLL,�%"1�!� 2mri 1axf��7�By %�*�E�%�R:�iF�U�� �L A 7?7?TugQaanm��0ly%Q%Qgi�UiJ. IA��y��� ";�� �qВ6��n�o>��f!Y{�>�w1�BO f��$�J<o%UO.o "� y � a^Swe^g R3,�1�N ���)�=o. UE�� �Oiarec�� N$� �YFeCs attac�C� ��� 2�>�*t 1R�Q22�2�1�% ��0�u��&BUU8i4l�?����re�a�abi�Q�WBi,][6�"<�`en���L�7 L.����b�W"�!�un6*Ld1W!�Z_(p.,M6�.��B*�%et9mB–8�0�e�)v.1!in1aRu!�� MoO�y�#ox&� N����~to �� perh��M�B��M})�inB?"NX"�H5Ln&d�or�U-cci���h=jUA� ��&g� %E_.<?,��1�-�2�&6p.�&���� <e��F6�%��)E��#��lR�P�.�@܏ meK2�A,%����D6i�,Va�.�zNl4 ��{"oE�)Yq�wB�H �I7 8��1� ;�� meK4!�JG-�Zcey?9��F�>�R�i?I�a�FD2�X�+��[/vHhE%kee"�Ž apdh�n?$�w"*mm2RB.a�to)�9�9�+��`�g��)��1Uj�"x�Y� vC :�L �kt&(]l�G.� :=(�k �� ^+&� .�.b$��a�"�R1Y y�"bE*�Fu�>�i*�fU$on�(*C6T f"($I�&!(>�*�"T. 3&–)�&� disru��� !5�g03�@a:��( 4363 !I�+,e�m�p0 UA10i">� ����%��c � �)2��� .�X�$f [6S 1D�6 A�aBj�-�\u��xsӬ��]:!?ag �xe�,F�9�or �&��� tng!�[�O Vd�J�2S6��� �^T �n��d��B1�,:U� les���ht�$YIM K)6@�: help!�{R �&�&�� =Gnnk� �Nn�.'?e ont�!�GO��m})C�){�1&dI�b:K O2�"���*;-�;r,�ndB�}h� ��Sf.se*��.&s_l:�$�Oxa�u�[tuW�:�LbranchA�m% %�@lso��r>-�e�P���&in2�N � �[&� ��)�Ga.72_ {�"�.�a�2 ݹ�Z� mY� *� TI*��*�z�AwVv�O:IՆih��op=� * F� A�!��V5q��R0=ir�s�H6�:�<&��.'mS|� :t un.�e�4 −L�!B+H&�3a-LA�*�XB A�` � narra���o_o"���F��81-?}��bu�02AlzZ80�]]�d)� ( 14M)��.�@r{%ownM�If:�If ��l�war ��� � �f�f>De3 f���V=�� �Ee�\e �V�#o  ol�'2�Bj�&� �W�BNotch ��:�W�..��'E.�d.C&�l:� �L�g08EdnJ ,��delta�7vDlk��,S8(!$SU8)%�"�0",�2�hi�/.��o�"ge�)u�6<Z�:�Z�Q�in�n3 ��Chi3l �9 $grin-beta u~Itgb3��;�:.�@�;�A � Endr"9A�of�rs )�i��A�e2oQm��OCa2��% �  �)�� }�"4-<}�!/&�s�e"��X��h �\ow �-eF��q�f��Jqj���&�!6�MBzE.&�ZaX-n�%-60K V����Lir��;��Dc?"% ��%m!Á�:��&D"�*��>��d=I� double-�D loop)u���oRep�HesM��e��7�oA�� �ly���subuni�*%N��'�w]�b� motiA�m�rI ll;-k!�5v���`�% &�di �*� *N,�Ard ��6�RNA8&�q87���se���D,Z�*!" �"�� �o �N DRC2"$ SISSIz [4��wa so!���QN�>MR] lN=�Q��4R�Y�of�Z�Yverteb2+*�1'Q�5,()P�woM� hairp���+�x�^1A�50H4Q "!Rl\@�� I�q��9��G* ��1�1�Jcfe� , 53 nt Y-sha$tHa��� �+�{w�5-lM]gJ9!SN_[)p�w���u\ ppTk2g�at.iny�w|%@^)c^Jez goodG/d�c "��ay~�}!I�=% 14%!�h5�%�!"�syx!!s B1�?�11�!"`�I�"�m�E��C� fM>9=��iO��l���!!b�. G"X���a_/ 1 �,cipNI��&�� plaf "M+7"m�b \i�,x\ y��&���82�����A| �a!5′ -P", h�8Ac uffi���I��ng�ME _Pn�JU�olu��ari2�/v`Y5~7 �Gre�"�E�M3��->�tF�h ?zf�!l�en����R�. P&!E%�� P�@�!�F�&�!��ja""� ,!�? E��An��"v MG"[}�u��Q6� �/!st���G!�V _L !�B_-bO) �_�A�a&��co$G!y"�R![`rk7!2��Y�e���Ww�i�9b1��B��3� m,�J�8A�iC�V�U��.�N\��h���6?�y2 �qK)�m�m�:�R4#6] in� ���~F�� ��ou� �<(�X�@�i"�:"� *la�A{H&$; >�Z����"�c0) ���eP&gain-E�� -of-Q%�v#�H�>��f�5�^�bf� ��le 6u-.#�#d")R�(A&>�.,>;a�co*fa�2<�M2F�, we sou�ght to determine a potential interaction in mammary epithel"Lcells . We provide e�Cnce that mPINC is associated with RbAp46 and other PRC2 members in m^n both!vitro A�in vivo . Finally , microarray analysis of � knockdown?(overexpress� � �d substa1si!2�into the putative gene networks modified by)-�X. These results suggest.*$likely fun%ws!m\tic�as part�,a chromatin-qying icomplex!�,ost-pubertal5�gl!<to neg�(ly regulate%8alveolar differEt!&�. As many lncRNAs show tissue-specific =Xpatterns%tspGtemporalxYdur�\eitaRplurie�Lcy or various stagesAC>�4[45] . In addi }bb5�pr1Yof.t , s-j$germ layer7 � [46]a�uscleV[47#!���aF$,of erythroidFs [48]5 skin9�Recent�(a.�%�QB1�0 , Zfas1 , wa5�a�inN_%�m��ie[50w G�exhibits a 10-fold decrease between pregnancy�lac�go��is ���in"ogeAO0hormone-induc6�%�of HC11-. Like�� ,�of ���in enhanT� o>C>_Howa�E�e molecu�P$mechanismsi��%R��NZf!|are unkn��E�thiA�ud��we found K��Q��mŸb�AZ(we demonstr�, for �ir��ime �.of anm��إ�v-#�;a well- � role 9intain�⁠%.i�ty bya�b��ɲng9� sete�genes�q>��._[51a`[52A�Histor�o,�bA�regarded�=a criŘ�7or!|��A�����6|3uU&mount�"Hs.&%<O,lso involved>7(homeostasisadult͚s!BMf�balA�u},self-renewal)-:�of�Ł�ax�pop!8ions [54]–[56�For exa� , los%�| enzy��ch unit]�, EZH2��n��cor)pOpiderm���A0��_ in acceleA�2�� , while>�of yA�yoblast!F��n�a�triguing�\our data5�a�Y��A�ag ��& A8' !$��m�,'m}$u�pr1-�u A� s ne��aryt7>�. Precis ��t��� � loci< control�I�� i��!�A���Y�in��A�Y�how� ���y bA9inZ ,��ponsibleV  earliM a�best-cha� erizedUi]e silenczof�XN osomeq�dosage pensI6by)recru2 EJch�r�[�n!#be med� �i%�0a 1 . 6 kilob�� � � $ed RepA [2��Mor4 ���m 7s hava�en2yrequired%�AL)� �)�oy�%� �&�Kcnq1ot1F5 impr�d@u� Anri�I�o���p15INK4B +[23�{24�'IP6�!Fe2�j!�si!� > A ^ �e>� follow!�Emod�� "� 181*$)Qmc. A*l t� 2!Eonly on9 proxi��W }lo!Non.�� Igfbp2�o is+[400UR' streamA� U!B ��� ��& 1"6�7%�GFBP2 l� s� l8{ ughoutb� w�APmost significant redu�  occur at day 2���u��e eresAťf � �( highest^B!$may play a"x�r2�-_a��7 point .��8.� 6-H�,5� �&� Nw,!��?Lor��utraas�P���( HOTAIR���3 crib�&rom. HOXCAUus bu|�JA�� uhe1D 1� �V.�[1�)�!�ope���!� ag� f �kQ�n�.�� � u2Y.\ theyE=distribua ]��gen�,Y�excepE�of1��di� ng.� ist�� 3 %:�&i$up�d&! �&��as. dn� n iXta[��M� �i� 8��5$I%�aLly� k ! Q�� O �&!��l� � in.y ��!d�9�ic� s [64Th��pb - �Ednra!�a��9)t.�Cemphasiz!v�Y11ce!�] pathway��i�!)2� upon-�� � Wnt4� �by���er��-3!�n"�i� ��pra" lobulo&� �z[61��n%qu�!/�[6r!uNotch��al!0i ,or Dlk2 [63]�sma��P�F�q csi7-�9 >r\, Mindbomb2 ( Mib2 ) [64A�!joppH}Ned!�c[>N� ^�,promotes lumB}6� �itu^\�.>"~9�-Bsf�t !q�6� �a� >/Y"�ޅ�[6�Chi3l1 (@ Ykl40 )%I6Ou@9�a�.�by>6 . TreaAof�Ba e�recombi��YKL40 ,�ectopi24of �n��r� FIb[6�Nis�  ��Q� 5���!)could&!]>� to"� 9�.� mH Z���� ; %� �se��e�t2��s�u> *��/A�impac�H��f�,*g �� md"Lal"�l>�statu"H&�>� 6�o6�%(reE�� � abile6f e effe.�Q��arker�]S>�� Csn" wu��?imi�to Lt.d Wap� ��^' profi�p,~;1�6M milk1 teinM��d ɵ�E)u I��at �� &��vs� �wh$include Cp��al , Clusn3aipe7 Cide��!Dal~�:I�9�ag4� :[62[68�A��,>,i? cDCR mu9 !�� fai�tp�g./e�,% E�T e*-K!�6@ ]\=x I��a�ssiM��it����o��nt-� manner2� �I]eE�LeGO-�.;ng�� s clPy�{# %�very ]ف5PGFP"y A2�L e.gis%j�fe� �$end �)�"d a4uZw>z�us fursupport�qhypa� � ]�2m*bhun.�a�t'n�,E�eBAer�reg$�6vx � Last�A0robust enrich�~j ���a���W2�9 � ���p6�Iun^ 8va*zI�of�sub.(u� CD61�Sca-1�aJ��M3��s%A;+< − � !5m$:�, matureTI�!�NC!B� + [3�EGenZ���deplee�5�*@a*�in Itgb3� x )�~� � Ly6a +Sca+�Z�E �#lso |� �er* -A�a r���Nas����m�I�be"� X�,5c9�=n push!:oward aR�ih�6�!L s."2QANCR ( � -d: R ) �ismc)7Nh\$2<of j lead�2 Q>y�-S���.� ., V�8j� Take�ge���!�!8i �"�N� t�a�%4�eg�,e�@aQ�.�acr�multiple"�. Our �� A" u: a�:�"�model�ֱ0alRyi!$� �U�� . Fu�1 sh� employ%�-e�gain-of-h�s�del%�Kinv�g�!�Iu �voZ��uE'M$e�-�d66 �&�$b2 �: }"�#sta4second struc!�$m2Dŗ�{on . M�#�>%isrup�IYchairpin.a-bb# �d?"}%!6�9qrel�H ship>�� binda=.%we2o�%  %4' ,"Vof� R�orq�ed%�E��yB\It will�"&to: ify�is�{ actu� �� �toQ i.�%�%�+v�% �%�ei#pwiseB��ea��E�~os'imwh� � A`RbA�&re elev�V�Y�8QJ� �� 6 �>7��reSeU %�*�2��{s�0�&equ�m��. �B� �� orig�&c!�J scrk �$ �� !persisAuly al���A�par� ��Xn�� aU2mb9"g� ) �(te.�Uarlek��st tum�f�3%:to�cter� erst!!�ep�'Qg�%:^1.�� n�'e; (elucid�Ty�*�%q���N�[2�w)|bp$t . T��y.perform)� cq cord#!� �r� mend��^Gu*ICA �Us�0Laboratory An���ONGal Insf� Health  a3� earchA�tocol�ap�.�5QHioV n6�C�'te�0Baylor CollegMedic�<( AN-504 ) . Alls e�%S"�e/ ain�nd eut�$� undeR$-Wg!,<5���. Balb/c ��ob ��Harlan9���"6�]�al &��"ng pairs d co-h�&u�af�)ond fema�checktor a va�f�(6!"�or %.��L6�pup � force-wea%�� 10M%i"MWthird �% urth d fifth5 fat p� �har��/,8–10 week �'virgin�316u�et2�R �� ���ly we�de=mit't,1 mm× fragsD0a McIlwain Ti�+8 Chopper 800 se-�M�uorganoi~ derim?di�!�aI��e�DMEM/F12�n�&2 mg/mle9 agen�!(A ( Roche )!� 1 hrE37°C�B e shakj$at 150 rpm 6�iso�,dI�� �ed![ paraa� � �z��$fu�,o"ui7��a �� 4�85 brief W r: steps ( 56 pulB,) � �to4 �qB9cA� remo�nta�%bst�-�H/M7Eothe}!suspen{'Xin 0 . 25% Trypsin-EDTA{5A.aZ�A��� aA40 µm� ���rʉ)!!�%T?):�2}. S -� M� �2–3e��"HBSS pri`)o1�-fac� MX�0flow cytometr�,fix)�(RNA immunop�%pi�� V� ��1Kat�(on%� [ of 1×108�sA���Kleat�0(10 mM HEPES%�2% FBSe�isA )��!edh��ag�)=8( CD45 , Ter119*D31-�BP-�u!�A$ EasySep M�x E&�#Cell E&-$Kit ( Stem  Technolog����v72�BD dens\1>7 �!>A�s!�15�m�CD24 PEf�, 1∶10�A�0ti-CD49f FITC�7qAP;Bio��n��Be.9 Pacl Blue (7Legz714�eBiosi3�2h8�!= ckit)Cl ACK4!�ed�e6�)5H.%�M�sorAZI@a BD FACS Aria II* S$!1��( #��rex�(�p10��2��Y��`� snap��zea� Thre S sacr!FV�*ach typ� d�7�by .e�aL� �(TRIzol ( In4gen��nd qu!lf? +,a NanoDrop (�trmoSci_1ice �^d�i��MEC�'i�a�� � �� graI'   1% agar^gel�DNA:Y� gene/�:�Rfa.d&C&9�s �mpl)b�e BCM�omic !=�P"�CP)E8the NuGen WT-Ov�?�f �UR %�si�*1�u�\!DN9#2�, I ) ,!)� wJ'e�2oligo dTr random & nd r(rse&�% �Su�cripta2v�A�6n5,�APe� LDNA-FA�a�( Ambt)%Af�!B$High CapacA*!�A KpplA��Hystems�T�6,alyze splice�n*�1/r�(sig���&f�0!�- exon [7��+0"6i��to !���E�12V� �e�u*$aq polymer!�B} PCRA�)��runu@melG p�(( LMP!u}Z,���c�^� -(TOPO TA pCRP*1 v�!r>���. � .!~"�!�!AicF L�newB�j~ce �al2�%pe� +IbUCSC Bl�nd Mult�$�r4 valu&�J?5�B)by ��QbejjR8�n�fer, -�a�set��"�Ds��� �a& lowe.L5aAI��^e t<35%xS��A-�VCt�g���an 35i�Edea��oWi�Taqmanq��f"�probe�M�purcha��=F�:=a0-Mm03456232_m 5|6028  Gapdh-Mm9 15_gG�$+0839664 +Wap913 Ltf434787 �+ 8656_m�# Wnt4119400 >2*281511 |� 0726565_s�Pi |47680 ��'+80147 ?44398 -,124372%/.�[-��E&!?�b:_ ��X V-.W ,�0or 4 h@4% PFA�4O�<0C@d)ffi�(Antisen� nd S E�M��;a  E�plasm#�� full leng PIN��0} �@� ur O�ђ.` �F-T7-�9,gcattaaccctt�F�Y^.2�Lgattctg�bag��ga�91�� c�>ac������.�.1R-�� ���gja )��� -E�%�167 ba&!���d 225N 6 . DigoxUin-labev& ]XB�41� by T7.K u�500 nd d@@ !�DIG [�#m�#���srehyd� cbM(� �.Pr~(� K (u� vAfiA�inQ�!1�acety��610��p� brid;5FDin Amresco Hybe So� $( AMR-0973 t 55a�51�VI�A��86[cub� �s�\i�BU� ^oF1 ng/ul�dx`9 W�eli���O= cR� (/T1 cocktai�"7 $in 2× SSC�3)�L NDng�washe�DS�E-�blodBS y3% sheep� um%O,3% triton-X p!ts*alY rs! roomEQer'$bef<"ngki-.�Alk� $e PhosphatA,& body"*�2�in � s1�%�26�9��\nex165�%%��i!BM Pur�"&�. A. stopE ��core+ H6arin���waz Ajz�(Vectashield��=`u�Borlab�H&�,� grow~Fl!�'atP in 5% CO2 RPMI 1640r:$ ( Gibco )R�% bov� calfM( SAFCn� e�,�M glu�X, 5m� LinsulinIigm�*,a�n�m]8e EGF �1 llipA?�.!650 LA� amyc2H. Uo3conflue�C,�=)A�a&' al 3�� eiu�YCY<ra�g5910%eepp9 onorK3s� a7�(b,R�inB����}*�A_B�E�A�a��� of�C�1-aPro%`"|H:C%�Pituit!$8Program , NIDDK�aZ�, Bi&sd!�!�tHydro�?s�( Q!'�2�or 72��cv�g�|!�3�a�. Dom�cLA�]��2I 9�ϥ��na20× im&F/expe�9�,� tivi�/-� kindg!Jd�DjKrRB>H Weber [6=( eGO-iCer2 H�� cu�!BsrGI%A NotI� rel%E!,IRES-Cerulea�end �fil9E T4 *e!�<c �rrel�&�%�)te�-IF ..�Y�M dele!d .�, ( ^.)O/e��` �.d s"-J'�L "[ 6��DenBank #s DQ059755� 6d&&RE sib!j��Jrem� "0%�IF MC�A�� �� -ver� "�lVI.pr�I�L)�a�hE/, � 6a&)]~co- �2�t packS g^TpCMV-VSVG , pMDLg/pRRE RSV-Rev )) 293-Tmc�.Fug,!h&0 VesGna��collec�at 48%�m� �!, pooA�A�f>��45 uM n)F �c*debri F?)nF��ed �Al Beck�Cou�4 Optima ultracC�� SW32Ti ro�8�2�0��� �4� . U6Gd�uy.Din^ �H4ENTI-X Elisa k�/(tech ))��A�ip�viW)�EAEacIcalibu$)  4!�H�(byI� �/l�-"r �on^�X&]Nu*o2�ans�3.U.B�E )w�q7OB�MOIa�2A�expand���two pas�Csaliquo!�!�fro�!���A=>w �.Qsi�M� nM/d5E6!80%��in:� -�ipoTajPRNAiMAX[ �>uS �Der SeaR�"( e�U�?�(0 ( n273107b a�n25431Q;!D.T * �"�5d mock%�a�!��A-Ma siNE�eS:�NiO C6F#�:439084� 8J� ( RI� ssay�� carr9�publi�!pa�co; AR|5�P�?�[�@,�DJ�#mmte)e��tw"i�2�re-� A��  ml PBS< l nuS5 &�bu(F 28 M,Nrose;�"PmM Tris-HCl pH 7 . 5;A� mM MgCl2;RTr�  X-� )�6y� on A�20[. N�i �pel�by>�# at 2� 0�$C"�:�1qof%��5" KCl;�' ��4;�#M �#;��5#DTT % NP40;µ: $leupeptin;q$M benzamid� a (-�l=or!�5aA[L4sPMSF;�U�! SUPERase- ug)Zm�M# shea�3i�$25 G needl�6< ok�%sar�SracTn�Ŷe�v�1 !2f1��lys I�LKA�1i�t � : /IP 3ba<50 %l!� Nu ��degraA�eETurbo�(9!A Mc"�i�i1y !��� a fi@ Bz$DM�in��0mUlU���\ ��� �-�.5. S&�s-+re-e� M �1A*% $rabbit IgG�25#4magnetic A/G b�3:� �� k�(at�%*� %P��leU ��to�L, SUZ1a��. ( Abcam ) MLL�Ds yl a�10�s.�'µg) U2���� �AT ��%ver" �BF�r AE���2'��F)H)�1/�[�V�Z��"-LS>�$. Co-preci,'ed�M�< DN�]� nve�|i�RNA-to- r� MJ�WA�&t.on *du��0u>�:���2�W*��6M&8 N:J>LA6U?_����"R Tri�$,2��u54�y�CElute C�up@#QIAGEN��A9B��#�4uv  qua�?g-v!+ �$drop ND�7JAgir ��$r) chip�|"N otal!��&�!0Cy3]5p[ Quick Amp�&�.g ��Ti)q�/VC2oK . 54 �+to[S�:P�M 3b,se GE 8×60K]vx YnZ;�^. AJZ:e�S&le&UH(a?�?r#�&aiV�4d��D"� �ompar�8x �L roup5�-�! ( logJormed �,� -sided��f�. chan� r!:�� aver� !�4 hqDJava TreeView [70]�4enA�*� &�Ys�or mapw ,5*N%=��Co�3 �����+�8%�V2 vailz D>�OmnibusSE3805� . 'onte yO%*� a�c*W ��DAVID [7&U7""Hy%!�f*�!p�%�esiBsubmit!EtoeFJ�8 a�via%"8?7J,a 3 [7OLFol��Y� �!� part "�9algorith�I�en!M9G5�2�of&;9R�(seudoknoHV ProbK+B[7�PW�J���siz%�hel< a } he display! ≥4" Y2�Zex�@ed cir'Zpl� anno�@R^�-4� b�D�,� kJ � 3D�7a|of comm�3>�b!R�%�>`%!yDMC-FOLD/MC-SYM pip� e [7r6 �di%x�A8r-J�topA��p)� RN]&,!�a<;L V� non-canon%�Nx��A�sc�AX2� � . Ev�(�cvA/Y�E>�SISSIzA a s�% ng-window�*me =[4EX�46-�L�&iz 7'�2\`-(P�K?'�r�Hlo� UR'�Nbrowse�' hg19�A�'`�-�� merg/S>%9v -hoc�l"9Y*�U�Q�,Clustalw2 [7�\b( � to ���200�Rumna�at�lap�*51Ja �I4%� y1 Bt�#75% g��.a�+ fy hnpR:� a Z-Iben)−�AP-��≤�35.1E-�as� ��eJ6D")tOne%�ANOVA:4 a Tu�_3A�~]YDH-ll��� volvA�3 ��E�EUe graph*� fig<�B s"�S�7GK&iskydenot�\p)�^***p<�001 ,  g%F�."N-�bG2� , un��ed Studu��M~�$.��PML (��myelocy� Leukemia�I]lso) �bs" MX2!�ng݁,family�- �6e motif&/RIM )V!�~�Qai�U��^+N��F i�Fms dyna].�s�T9ar bod��X"recnX qb�C�einmsu�aSpa DaxxA��Z��@ PML/�19�x"�def$i!jll docua�e��a/K n HIV-1 i"4 s unQ� (>weIW�.by A� �ret4ru3#A[g�)�� �Q!5pl{c1 ,aw�<as+!u�e;y. Q1cSdnum���Zj�.a� �I?.|;xi�ly 8 E9� peakh 2 hF�gre-lo�� is�o��rrse� �/ HPo�!nd3�ob�8a���un�)�s&pPdd�[ ,-��)��) :�RCrym�7,6�,fer��a���>c8axQ |gcs:@&�FdraA �(G*N�"w-�SW6�`%��do#]ot1^ directlf�9QWact��roughAb"�K-�of� a@1-ch.�\�cnA�,q�I�;Ʉ�9�,2�e�i��aG v�=/.incLgmi caps�'E,�L^*. I�+�D�^m!��>�exf4�@N��amof[ e 70a�O=�in)-ea1*�Ootۉ�1#�.A|c�6t�QteŽ Q+p�E�[7*:0Q22ES&�dA%i �K�J#1� S���[7]�k$assembly [�NUnE�awhJ9���v�d��i���ɭX�22�9U'!;rKt�Dto he�ltis B�NHBV ) [1 8Encephalomyocar3ks*EMC +2 �I za A $��[I��5��� ��i�GJ�i2� �FU졫�r~/ .+Z�%�Ar=��$anyR_ �Tu� foamy � ( HF)!�Zpolio�![15�Zi511rab �T%l[187a� .� * ( AA o9)�ves�estGo!�,VS,2E�!=!��J.&")B� HIV��, ,� ars�ktriox0G( As2O3� �m� �Y�)���[��i{�| �eP��* [2��>R(Turelli et �hlsoe���i����O�� rapid n� oof�"s-u"q"� �]Kit  & INIS!N�!vg�n%$lexPH"EjA��iI%`"Xe�V� � �.�!� inderCn%� &Ac�`V! doub�n'��ti-����f7`Qx� �3:� as 7&� �8��na�PML ) PMLVIIb ,�e�1�d�%�<�ay%}aA{glI:g�&zf �h9s��!=same N��djzj��{. XY w�=��^>ir�G  �� �i�<v�oof� �!ar AVl] �ap5� I�exclusiv� Yc.^ [!�,!D9LT aN��7�\ [��  ��,un+:e��v�(� NBf.�z jJ&eQBs� � th!Y&-OhA �U hora!I" &q ��b�b�f � �,�,pvln?q{death-�.| v+��&� SUMO r�7�A�WUp5� CAMP��jkOa�–�PdCB%%6Ii�@F:�= Ū.* c!K] ;' gv�@ A da-�, ��I�2i!�apopto_N/)26 I&�/��al-kib!as=�6���"' ndE7�� on-stim�et ( ISG ���V��!�it�n�!�R)�[2�hA�/ aH]-���:e �7L�ate� uG actrNB�w1c�IJS���Ayand/or�l.�[27�$ C"�M� re-e�30��DLvEGajq � ��!p�d�ww�#5�K�.K, c E &F gd ir`hatBij!c�I>�K,ZW!�appear� #8��2gef�>f�Hor'��;g��r� _)-2`vD�s&`@uchVQ�j< -1A"a r`�f1�� �-Y yyt��ic �� �!� a��a(��*7 -W abse*�>]no q�bs*=��A�� opLld*( 'qN�-� � � F4ea6oic �-���i�.�k2� evenZ!�.�Y.�y~�&�o�} B Indef2m�PMP < E6W nyPr2@,�.��I}�if-fby]�K ���a*�VG ( RT9 �y"t�*�)��PE�E�-e="!b�-&�|�vcip �ex�>*�A��-)oed \ {. b�`!;u�st�esD�1�bs���.)i� � q%�+ A.S�ss�\��s.)��605%e�!wal ���z%7F�1�"yRT . FR�C1AE�&T��. HeLa �G%�MA�si�I�g9YVal��"� and�#l9>q�a00nco�ЩN 3 h!ty�Bi,VSV-G envelo#��a�{g �� �;d� byzw, g ( Fig 1�]�� oblo_$Ba��Na&�o �^ dest�XS�t"|�)/r<2 &1I=4ar�30aB60%4�0=- �C��V.���,gXho�enQ*v��l fav��a "-dY *}�M U"�r*�. Np;�[-1%a�+, rim��i� PBMCsF hWy �9sI� �=OE&`�gMKma� a shA�y'�r!on- '( CTR� E Ѡ 48 h�u�> p24!�I�NLn3+)T-q]A�$&�x&d�0��E-�e�a- m��onE��X�X"�5Y}M8DE8���I�E , �spreae� �`g&�'8I PML-i�$%�," _��!t�j�>d)2z.^inmViU_�fx!�� � E1B�u� fluo9@�-F1I�asfCJ�E�ij �6^�d�%m�"nJ��� �8I�� %{�����kN8:��no"v�glitc.co6i8`��&V( C�I�6P!I �Bh'� -a � 2fIn orZoQ�VI.�%�|v1!"��Wh�-"�L �k�?8mq�fibrobX�"MEF~X%twild-�~ ( waJ!!*KO�Q[2�;Strik+�#e�HM 6 GFP-�vJŬ[ m6pronou�X�$:!,�ce�a�!qT%�30%wt ���duAf'�- 9 , �%02�)�2�#�6z�!�6�M�� �o����?V�we .o*Ic.&$I`t��`�,b@�~s�``D��!�"�q��< asomN�� i|%X$recogn=*by RNFX2j`ly-^��X nt ubiquiS?E3 R=se [3!�3iWl>�1�B*�ch>��UÅ�m�o!�a m9����!5u*,��0+�!�.�-��n1<m2_� `.� B���*�!*E b2>9� had�����x%�MqKOI��u�-nc�x!,E�} �2 ". 1�>.*�sW �bde�e�%�!�16�u� F-��w�m(�Ja���:2* we*RajZ-court`J�t �5!��AfD;ed% ��"n�/nf��roscopy1�"^]� w� ��!�F V9�em%�5r��8e5=��ucan2p {c$as �Z�a yE no longer6O�0!1�O&�Nm.!/6� !.�2|M�)�A�)[&E��lesAoan �! ~&AmerEd�!!�.�&�x}�t&�&��er,��#>1�8E,Ai_A�.�.BB� �5PEte�% "c �y�.? 3�)J�Ca�&� �n^F�� To d6.O :%ki�7"� ��I:din��!.k�k��,&iPMlnd! ��A�53�  ��y"� 3 ,ATRTE�a�)hig�m�KO* o���F�*� pA�srccu1�/of2x����Is�(wh�RT��a>U� heY� NrAXq�� ne�p�; ( NV�,�  o�3q&�%!mQ�)��)i(%c��U{.a"Q(R 1�j�,-��$by =�(i 3B�fFcne�9��4s��֑�!AZ�a�2HVn�"� "i*1�,��Za�R� NVP-6J �A�r�p ��$6�~RTa�aAOrequisit�d��)1�.N &����i8t��d �?w � [2� 32� w�*,Q�` .�?\ř���DF��}IL�t.�.[pur�$� ͲH �1Qor m$E�DGinkgolic acid ( G^ A�� ��3&�yllyQ��:�AE1� W�C�m��92:3y�:=w� �"[ Ww5U�ZUern-b)� X2/3� M�����&!��do�.��2�+��h24hAGA}�M��[l6RUahsmn�$�A:diQ tQ �AMj=BX=�2G/ b�W"4,E�!�,#1��A�RaQq` �8of6��r�sd&��Aat>r_d�q "���u&! < HyM !#�c%]1$� c%ML��ńES[ A�dosUX�.�0SIVmac , EIAVHMLV Mo�Il Mo-�9As1��Aicp ��-|2�%�.�b�12�as�P�wtD!�6�a0 �I�4a�F7%�si� -�i��& 1Db$�m�'e3�(9Ra)to-�bJ _2/ �%{�!�a�b�A��8;%م��� %TE�%Q���S) 3J*E/&��8o�&�0#1ida�+�3�on�!�R�!ױFa].]0( �4e�,!�%:� �s �WI�Sendai � ( Se(',J�(,A�A��'�"�i�4D�.� !��Ra-F�!6}b�9ct� [e��V)�4� ��our����#i.[� ���B g�(dec�=��� � o�-%�.�-ER]�,� E��ɶs� V!ng�%n� !,n", s�.W�$%�%�kI�H2?5 e"ov ��R F%%�%�� �*� mA�sZ)�5� 2�,��Rcip�!*����E�=?��V��!per�>ag)%9Z1�;� Ny>�jF� . Uny � n=��� ed�-!�5@Cer�-6�,�ini�..6� !��JA�Ic�-ad`a iA+C9�W k� A��um � b��Ou*4Qf.5I�`,Wloo= }A2�ofA �ab"I0�'a&c2te!wit.X,�$!�1"���as $"F4J:(p ��un� IT,�)%���.�A\��&� )XQg-YQ5s,�ly�� &+�-�pI !#t�(qV�&�9�ar)���Y�B iP{:�� |2�!� �2� c~ny �5ic),e��MB�m�)�T68cl�/v*�5��>6�����Duolink� situAxxim��%�lM�L�*wO;[w@�-}Ar)�!�� �/!G�yɠes&3n_�|�G-��?&a �4��ofj��6-L� � �#el�i� be i26)�� �6�.�l!A�a� W�YÙ�!>�R6����B�^, ��68REM&B�e�= ��)*�Ve.�%��K!*Uk>*7-of6X�F j6I^H"�.i}ё��2�4��N%-.�<�*�"0M-�-"t"K<D H&�"�� dZ�}"c 2*] �a�,*� 6h���L�"*N@1B(W�a !���si�onut)eA���o +a!�1z7!!4:�r-�!!\GQ� !~ !�N !"!B !15�i-�J;- q�p"|)M � �c��i!^aL�����ELISAA�*�Myrߔ"e�2 6�q6�, ���!"�!7-.@"�&��a��$!䆶!Tw ]�s�@oK<�o [! �ZuT. !mY ct duea&������uutv&^�q[�`-5RTŠ*�(R�{/jor3f">v�Y-pis.O��b��2�e�l .���=Wbf���e����t9oriw�6 mpty��_3�e�I��j�:�b�6RAJ�� �6GN���1m�dB��!�*5��MX6���e�j��&=n.�ng!g� �%!>[2!�R.;A��H}V�m���.B%r.���E��@�794їtlyi u i97::V[OK�4LTR x�posK8 c�)d *5(:�ERVS#�( so r�4�F2 zF�Be$E ��eW&�}[6d � �dAEi�tr��!. M���4l��"Q$t���e� �2}clu('�6r�:ac��lA-�Ai� ( IA�ay MusD*�H� st$���>�@edys�c�rRx1(XI�BI�.�UB� ��+�o=8Ekt nm��atkew � ��6�Ec��5*z �V2=ERVI��$@7w<�X,-bM\E@6*~ !r#y(- �m4���*o2n�Z?iá� neo8cXapQ� or�5 �!0r� ? in-�M � e"�0aA���A��+ �3AK,Uut�!�!�r�%�U�q�p"pBal ���;!�!R[35W5c$�rY*N�:E��E���-�-g.~`2L͏�a��g . TA���� �Sato Jw!S 1 wS��see�Q�G418 s]��g�/� lci d�j,]�n2y�X*���&&~�<{�a�=%B%6�a�2�4�+42Z��!( 418RI�!d ?=�9 ��6,A�fi���;�X iRt�fi ��alAM. HavAt{ &� H� � ����!�!�b��v2MA-nG :�F��r'�' C9*@;R%} �e� �v2�!� 67&&q&�m�'m&2H�a8~. Ir'TA&�6��2>=YF�'� �� � [ ��i4�)e�5�� E��no�i �Eu}K coN��y%) answ�Ds qu���%p ta�2�o)8A�E�k th}!A t >�(� Fl�3�9@%�6�YB�i�(BN�E�ѳ1� C7��JE(�q ٜedi��G6q'!A.�wa4V"��9%`/I-�^U!k31�N[��5y "�?!���b&` �&X�R;T.�]"� igh�0m��@� ���4NB&�J���6�$`f�.�cU i�3Er1��>%4�s <taneouA{U�D +tk�V8�7tud�H�l�(~?QE!��*ux�B� a����dh�5 hall�qeaB.�g ��I�Tre!���5��Mk�%*�,9�ic 5��d� 2AYm;�B"!:�"!/� Ȯrяa�o iiWf�7,� despZ$!�f��E^_�do� �"SY\of�]"�Ŗ*�Nc j`� q�Q %[~�}��~!q- 2�!?��.Y"machinM)�3C�4w��al&�=��GA����-Ij6�z���{L�R��X"b=��2�#w(�n�"�40 ��� �*�%���UI���GyR�)7i6h="�>*.�)N*(R���!^&H%.I�@*���(+���2p%�=un"<��IM7AMK*�"�15jat)nJ+�6/� ��)GV. 2��#��-E�A� Ug?9�^>87�6 +-_M�NM �.�"E���X>-�ed%0��CBaJ��IS$� &�%46z!�R��$� 2�Sb�*&�b�����a!}=H��a � �!�%���Q�us�Vݥ.���aA�8H��I %]sѪ+n� !CɵB+.{�*Iw$D xt a.b@&�/-��>- k�1.�1.f W_Ur1b��ox7�%^�o�$�,!x!���B�"76`��J?���)�* �bk/& !Z�UE�mI�8v �oM�ɠ]Wvh�Q��Ű��e��oj��+�?Í&�NS3 )B�?]1A"aM p��&� �e�d�!�MHAE�m%}JC.��3(-*�=i9-<w y�e��aIPv$�u%�A��edT:B�8Kol >+ �!). O��Akn>Y�"yReFb%+B�E_ C:iE-Ŕ��S-��GGm7K�Ui"\ =#��I�-�8A.C�5]�^�ko��J� �&� �o�WN��*�JeW*��f�9�?6DF4!Q(�nN��/--��"yX�K w6�2;$YI-q�)V�3�i���z�5�6�F�,.D6#� "_+I ��3��op;� ��or MG132������i)�Nb�s&x0. �&7,fai9&2����tcJBA99><3a�;*� 9Yo?BM�"�1imF�:)Il2n�Rt%:<� -��Fi�i?Q:�O9} �=A2n2�;�u�l Ew���%�H �"1��&�#�)�� .  !�ep��=�7"�) �5� .�t%y%�����%�^ *� ��aB��$�B�8t��;A7"ܜ�ppa��discrep���&�Wi@!o��.�&(K.:NR��A-_ B ��~F8F �5"�,s�N1�+c����/.����r1� � exE sE.��5Z�&--�SN�uKiA��)�EPL!8�M�%F��=�2�"� �mAE-Ksm]?f26�U.a:oD E� �Y�, &�N"6ic �.�EVTh>��.a%�m�uV z2�cyq�-"a��I15�)^�!�<;of�0dLv �m" �y�. r��:ra�"�wt%�wG ��e1g�+�F���a�JC�(!��) �+- b�l�V"� e�4t�Va���L"��%�V�.A�VEQ-e�FQx�y�z!I5r=w6�&e�T%n agreeE%?>� �ur hand! f2���<m@DQFU�1��4*�v�)^^ )�Y��� �m8��Tř6��!�73���tT:_\A&3 F>DdeX6 1{kYB��u�2����U ^e.��E��C�p"WzE *#��d �%�DA���"�"�!2f� !��T��%��Pf�a Ynrf�hy�RTh0I ?pr:�;`Ea��uFY E�*�=!)e�hZ��u���i8a�� of2�%i.�a�d�RA3)bA>.3�6=!5I(aU-o1�V��"�JS(Q("}7Z(�8!�E�8� %] J)7�H��inc�c"Sb.�6,��69&� �!�>�? t  dBn:b��8 �eq��e!��#uk��s2�n��X�%Z"us&r et8 lB� �^]�2jiuj%�syno iP".rS vm6vN�!�t�9�noa�Ŷ���B]0:aS�|zȉ��6v llympho mchoriomeJ8i.�_LCM�8A}6L`36 , 3�X&'�O�w_%��>-�Oe-�R�� ��^�E�.�E� ~� nfF� EU�l�;��UK��a'*H!!�j�: }Ib�!VΔ5–6��J%e w�4eB#ĶAmim��, *� ICP0U�y�Y �,�k� `Q�$��6B.�%%�a�i "�$�jM }S�=�t �v� ��&?� }Q1q"�o�?,-�l�Bn e�� b�~RT"� cyABhY"��)���:�W�sw[0 �;y e�OI�!V ��%.WQ*v RKfo* NL�Z-& �}�any�ect� �o�a e���g&��aB2"h� &�:I�henDW� �����.b��)�ra�% Y,��=� ��Q����Fch�� t�h!�ED�r o&�!�$I>vB�Fa r�2aY�Rls x:��:Ml �e*qH*�"32K]&�! 8~hR*ZW�5V��u -<��2H)Mr*���)F��6l �� hRT_%"�  "�JBJ x � @U=3 �2@�Ɂ%��"� HA=$,6�4��EŁ0 ~ s�linW1+ 9 }7��=� K>^�� 3�.�!��t ���� i�p��6 42\/�g*1 KZ%�X:U"r/2xR�,�!��[~L �  *�*2�A_J 2���T��V7&"]k-$"2�0>r!�UR��q2U�EvZ��2:.j ���J�)��A��se?l�=!�o �Kt+e �J �����jO .�.�46Ic�:�e�m�EEy" 2of>3�3��-m�el6a{ `G t� _ �� "L fewEa.���j.CA ATRX {���s�P)?ON � p="/*�i#�@H,!�?vJ�.f#��L4z��.��r&Wpb�!�gV]7 &0�K,a� suma� beca&YZ �rW�aE$�l�Qng"${S#{6q1carboxyOkTBE5[4s6H"�=2W !,5qP>��ideEJoֱ4! v�8*[ 9�2�g/5+u: b �*� ks�!tiX""�}< yebktwo-h�� .��+"�i�c-�"eath4k�}F�c�or*��A*� �.mo:�a&.DA�!Ode��h�Go"B�A, Re|,E& i�*�1ylr*�y�95G:�-�� * �" � n t�\& )��aM&�@����.�� h X!��"�NA*  . Gi�[��>x! :H�"�#i�-"G!��I^��Aa���"��-��N���8!'w�pE�bs�6n�).G1|s+ rein/��notea�U|A�e �epoPr$!�}.�-� R"��shS~2!��w4Nk�Sn:�8?�v�uirJD,��9e�a� "@$ !�!�"���!�� �&dBQ ��g2d ��""D_ %vc-i��7N\o"� k ����u���e�a2�n)2ni�`2�DExAb���FE Beyo��"� 6A[�#�n%�B�8�:^�aN9a�U ob�"�.��*X#eeseeA' `�.ea���\���W%};1�Zhe�n�HV�J,�a�]-�dy�ũ%;/��R)�#n�x�e�!��M%�1D��� c2�na��&H *�t�g e to f�eg�r}�a/.� [4DoA�x:� E�!��&$! ���.�U;!�?0avian sarcoma�?�`Ye^uZ1�)�F �grbF�*� 6wb�Tdu�">�?1�.�U�0 M��4o�e�a�Z�� ��'�n� !m�smW�[+�2 1y:l�^�Ato/O�k ledg�d� a�A �r%R-�3 6�=p�.-�!^vpsi�?rai<7byu�4I it/b~Ԫ !�@ �"�0��� phys�).a�e�F�!8��v!�,�,%s!��M�e[Ng�q�/'sm/s� � a�e��po'���and-��%&z"Y$be p6 [49]a��I����� e'!�c a� e� sA��q�>k@:p4�n a ���g(!v)u%�[4 ���.�}���UB�1Q�� +� ,�!�� CM� De�u !��may" %��B� n&�RT�c] HDAC�#Gemin2!� AKAP149 [��O� E�Q�i)q�Vadd�d���$t�H�lo#8Չ6;�1!�N LaiF�`0 c" �r� � %LA���*V;�3�T�Pf NB m(Qmf�8.�E,e�S��B�F�!�s� �t%���ize�: "]p�`e�g��?V6ah�1[>+beg�J�GR9�� �_" !eA�� ���U� �{>\# %IAR&^i�,� ��b��T"�_y�*� s�� cGAS%�0IFI16 [53 , 5Y H"�r���j:R2+E8 ��&Lv!�"|CR< scap� n� ��M a�" �.g cloa:1��c+^��Ji9O�co� o��� 55*Our� A��a?�[D�s=¤wS.���c-��5 Fpag���Y -�):�6ZF��C� Au��tݐ�t�C �sh��. , �B��es�<�eA�[l<in,�d� ��)�Y��%"�@e|W�.Xa!2+v� wC0U�ar@�/�ul�.� ܡ2e0]F"� &z$\w�F%{��0" �d� .OF��[2%>A!��R2�w��&� ��!�. Vn_:� Merck Mil���'u�YQ�00 μ��Nea!2�b):PS��Ald�ӡ�] �)P1&�2 %FL�e 6ɭ ,*�PromegV�. H4!+|A;e: I��� -#`H-238 ( Santa Cruz sc-562J���!m?e2JUmoT3��˼104 (=94YR=�-!� M-11�/t�8)u2��-�(�71��.OZ�'Ja gift~H�WA�( Hambur� G�}y�+� monoH�]���,e 183-H12-5CE.O%(i� -SF2/Y�jE) �`�Z�a�$NIH AIDS R���,X�.Q�inNtHRP-conj��}�6�Ac8��@&Q�HNAfl*�pQ1,*� A��m$to Alexa FA �6�M"��� �"2"br:�&���%�go��!�Iu��M�I,A205X�a�1-� 2�Va��" #707ܤ*O, HEK���,q�0p��a9K p( J�,Pier Paolo P��lfi )KpMr@Gerd MauAf[���@Mus Dunni Tail Fi2�pDT�H%Vcul���4Dulbecco’s M�ed Ea"�"��Life Te2&�L�L�&(�fe�*F�1� L-gl3�, 1q�,sodium pyruv���U/mL P����"d̡μg'(pto�.i}"_u$����� � �K �L6��1 calc���l'���.�A %J& �a�h�Kvl!��)l yI�)T ��JETa_�� l*eFanur urer'�*��:$( PerkinEl��%���cerO. VfՇglyco|(�`-JJ-.�c�I�/s �g"�� n3 �g�6Tw�>p�c�fGag-Pol.�L!%/n ��"gF=O- ngF�$"� !: ProF.KonJ���.F�Q2�UG V$pCFG2-eYFP�pHIT6�V� ::��qpCSGW 48 . 9,�S�d269Z)8Ad-SIV3+; GAE-��!�i�4<J^F>�N@oOQ�NS LyG+F!���2�:�!HONY��I}( ( Oxford BT*�bOAllM� stoc"&�id�$��` !��M:�� m �ic�K"�!�(�t)def�5as= -2 lA2 1-fp�D� fp.�fMFdM FP/Y.�u�6�A� d=u%�K!A�d�fJ3�t6XaGFP.�)�� �M�:Z]ac5KI�,FlowJo softw� ( à star%��X��Iu��s!H �:�O�*���"[xpur�& %!�( 1�H�5Ia=�_@ruct pLNCX2-Myc-h� !�.W Armelle�pet��L�I���" Vh"� ]*�2 PMLI��*37!-�IT�rv$O(ORF+! �x"c5pT0� z ,a�y 7 i>c$ Charneau ��� Pasteu1Pa;��FoR0U&J?B-��!�� QL( pGL3-IAP92L23neoTNvA.$Q(z�Mus-6D%�%�]V%J�Th� y Heidmana�(� GL�ve Rouss�(Villejuif ,��.#S ,s were grown�� on 12mm slides and fixed with 4% paraformaldehyde for 15 min , rinsed in PBS , incubated in NH4Cl 50 mM for 10 min and permeabilized wl,0 . 5% BSA / P3% Triton X100 / 2% N�, Goat Serum �3 YD. Cells were then ���ndfb(. Finally ,1�� wash.�,counterstain1�0Hoechst 33342�m&d�Fluoro@-G medium . Image-Kdigit|acquirX�a Zeiss LSM 710 confocal Microscope�or qu!sdtative analyses of PML CBsA:qconverAFto bin!)0mode , nuclei �selec&!:J% p fiedmeasu�using%� “A�zeA� ticles”gule�%pJ software . Student T test s�sti��$performed qS*.O!�Duolink Proximity Ligation Assay ( PLA ) , PFA-i�MEF cY� pre-Y}E`block�ag�a$(1 h . AfterE5u�N:J.3-Daxx%Q!�$-HIV-1-p24mPk in a�hea!�humid�chambera%37°C!X}cM�(three timesK�]Zi�!�e� they)s:�5X0LA probes ( O%kDBiosciences ) dilu�inM>9( 1:5 ) | h&��5�of[8connector oligoE�ot�v`, rolling-circle amplificI �detecE O #ed DN� ductq�oneI 1De?ReEs RaccordA to�manufac� r’!} struzs . N}label� �d.E�real-!�8 PCR experimenta�,12 well plat�b seedJ1�×105M�pA�20. The next da� equal a���OtVSV-G pseudotyped retroviral v%~-#trI�e/D250 U/ml Benzonase�h 8( Sigma-AldrichM 2M�tM� before ad1MaR$ monolayer!;ݜcol�� t variousE�poi!%ae�M.� viruITotal%� was extra��ltDNeasy Blood & Tissue Kit ( Qi!� ) .A=�rea-�:�in duplA�es b�LTakyon ROX SYBR MasterMix blue dTTP ( Eurogentec ) on a 7900HT Fast Real-TimeE!0System ( ApplA�a�a�)�followA�program �used: 3�at 95�R +(ed by 35 cy�� of 15 s',!�607ag20 72. Values�8each transcript)*n�i�toA� ress��leveluLmurine ( mGAPDH ) or�an ( h _!�qa=�ZiK�r earlybprq�as carr!;out-�(M667/AA55M ��A� spec�X�minus-st0d strong stopE[$, whereas a�6n_ ����l M661kAa0��y  RU5- ���e+0site 5' noncoreg!A. P�4r sequ���a!�A !�)RH-F: 5'-ATGGTGAAGGTC  C-3' ,(R( GAATTTGCC"GTGGAGT ()�PLCTTCAACAGCGACACCCACT P ( PxCCAGGzTTACTC P! tGCTAACT%A KG L%� % AG�PoG4A )!^(CCTGC�Ao TCTGP�RT-E<6yt�8RNA�>:R�: MiniJ0 NA s!̱�2� c����%�Si#RT�h���0Takara Clonte�M�cecTRPL13A ( 60S ribosomala tein L13a���r��ede( �i�[u�s�?�ɥ� +� v��B�PMLM; !�CE]!�AGGC-�&I9CA�&!�G!�T%i L ATCA� AT-3’ , * P iGAA�AJGAuA� ))$ UAC *A 2 � * UTT(CEcTGTA��, .��Even�-A (re is agree��_ what� > )�multiple�zuq align7`should be optimizing , fi�5�L��5is compu!�o, prohibiw (. One appro���:!� many� v�methodsLYA(rag�$pair chain ��!�r �al 0$s from all�p �sI8�� gainst�\other�� ���f� ���sse toge:$in geometr� lya� sist way�RY~ pd Godzik have recently sugges��t!�~ngR flexi�Dty may help better6 eyp2 ur� a�etya_ca�x��We int���!"��Mat�MQ!A!-�� Ta�l �Twist) , an)&f� algorithm �,!6i2�atA�ep� a�es l�.�between9� : sm%�>�roI�)�borarily ]ed4br!gse� QYE$closer , eahiL yEE phys-�himpossible under rigid bodyT�-3 a dynamic1ym�,assembly gui� b�se1 bent$�!�!(Us!�Iocya@restou[ I�steA6. A�L3output .Iis h}'i"I��AmZYwUp, s��o(popular Hom� SABm�bench data%� �'s glob�Se�anc��pet�`E�d �.zn, but� He�J1�, a�of�ud�# - s �m� I/Q�-s . T� Etwo.!A�M/ /�BY ��� desig�,to���mirs� will c��h�kHr� � in��A���AWk(]�qa!Nservev�al!�U<V.�is def�a%1TEidhammer et al . [25]�resid��m�si aneousA�u�a4���q�=arM��!�di�mini�, takA��!�a��� �57e a%� up)_to14a yes/�nswer (&� withŀ ssoc� d��or!kfid ��)!�to��a g�9 -�fou�or!9 woN�or�m.�W!uss howbHa�Q�Ln1)iD�dqn*TrFXbelow-� clas� *^ way.�!��� Et>}a.1 involv��arame%:Gnu�FBj�YEč\Ax)HtoEa icip7 � 9(%�0� � :bvt�a>Jre �a�ll-ј�-wis��(Areɰ*alc�1d� Z bestf: �lea�� sD�i#[26] )"! ��atoms�cs9%-69m�Cl�,�ХT(bi-criteria%i wMq)� goal0to�� ��he>owhile ma�i$Y�Apl�!B�WeM�  ax dE;a.�� : rep��ng� �cٝndB��Q}Qn��.@�Сualong< 2QRMS1&U`�sfng�� 5�[�o}a&� 9�ad���uIn�%/ esul�r!�mp��,"M re�c��KT 1g s�!ZYe'�aluI�Iir���-�, , POSA [27] a� soph� �&s !�7s� bB&r, som�ap��he��! o�pingJe>�� [28]auch�CS�� 2[1!� " incor�te� enviro� a^n��� ��similar�� �t�s� 9Z,�is��nt acc8n [29 , 30!a� 6� EmwC velop�handlI�Z^,� crib�j,�&� l)pI�s� )<� prov�a -�lenta,��yѶ. A�terb ���e�A=!].� iC%��!X&�*� >ZdirectlH��le5�}yp_8ROC curves; looZH rA �tru^fal[o�9�tatne�{ aOgold-� dardX��"�b=��a��,� ei�_\S Yas*a>Tscheme q SCOP( CATH�! ndee� a��Pconcern� �.�| w�E!�ad�.9in our=�might�`aa]*�  R5��/_ 6� ctho�Sat do&� !;�i �m�:�)�lig)��%�%|E���F|c I�� Zdy-made�E.[)��c�t�mooras#���IZIAFP"���!E�y�nd�<�=�E) �ex�/�o�� i^  ss� n%�edA�q:N& . At%�he eI5xa�ne�he2�9Q�"� ����%�� >� �!�BL.4*Kůnda�0� or�)���A}l� � .Fhas�T"S�% stud~��& tU! of d8$[31��2��ulw��!4.!�of ligAb�[337��lyoI�< ���Rab in����s [34�5Uit� onlyXM�� �general-U�[1Q6] �h� �6Z�al>�aso�t msen�ho9�2�i!�1�Nj�:����ain�-sia)�ad��&�$work , namq,i�!� x�3�EV�#by���fmR?becau�h3 �� � rm�@"vF: a�-kn-exe �ai�A�Ah{%is� hang peo���A( is b�a=Q��>E��(�" ls&!�� 5���5��� 1>al�� AO�-�5�w��shape!��inc�!� y diverlout"� ak[� �G��a{X( �*&X E!H%z*C͎iv;I%{i�v�uR'(hg !�!t�"� [37i�.G them2�t [38]N(d& TC s ��2a nd 3 ,We emphasizej )!O� nS les-to-ap �ia�= A( i . 0*R ը6:�mi*?)fw�%��'s)��   justA0iEȡK!?)�1e—�Aі�� b�! break���e*a , 嵚C wst;�u�� pig �c�; %Ae@ legal!�u!� unq�R�E�e�{%L b/E�!%� �tradeoff���V !�e�"e� ��I c (ofY���4 a 1)amu�d�cor[ � }��is � avail�as�fd!�&�mn<K�m# edI�s�+R�w:IE�2��*ut-�1!ō�%WQ].Y 1eL6�!kA�bX Y ��� + � e� > !$uW9-�se%J.5nd PN8X0 j6I'dA�t nt�,e^eaF�sub7,C�� e jng��a*Mu 5 fam ��? m��wa�+2�+BLAST��:u�-�!b����!8� �(�� ��L!7tW fool��9\Q � "th�+ random]:.ewe� ���}�A0_�� abovVCe <�&>:Q�'"�S%�a9�nA�"n�eA�d's2;�eTm�YO!@�>s-L"o�"e0T Data Bank00DB; http://ww$4rcsb . org/pdbeuWe|N�o��trajJ�o) t�6k�P"6 >_ . Ra��%�choose��amE�he�*N3> aiQUa.��_�a�*%e� 1T��"� OM��'�#�.%�sam�?w%8��RA�eoeNQ0� e�=4� � veBza�aOcep� ą��f �!)FlexProyO[� �!pur� B/ �.� ^a��+�te�#5 � ia_; lai3o?.PiR I�5Q�Wef��M!���Q..�s.�tQ�groupT csai�mi�edu/cb/m&a@M�. c1tuf� edu � ny���!l� (�y ah.6��%�favor-�egE5��.IU�%�p�7l{%�-�o '.a��5�%��2�' 's Fatcat� ] ( �j2�E�E)nd 2�$ �%��N�,2�F x� A+anw(a. eE�IV lows,%ly� ed�t.&'or�p)���ifSim[�' he o) ��.l� w2� R �ap�J`"sI�hin� ��F+et�i�1of2�, due[�6&"� . Ou�[iis funda�E�":�ns��Ŋsl�^everye*t(shm*"(—Esi�i�es� seek�B�A�=�� �r�� ��)inul$ !8perturb?) "� &mat'1h� �� !8)5�a�BN�KEAth�y-! I#e�r s�*t toler� l;7�6uY!e�ke�)5>i��ly��!r t�Uf�Up unti�+ltepѝ-3�:S)!�R)�I,%8�+%�� 1E#&�—��h� � �2� a>3 beyog "*!��'E�S��)&�molecu�/�u:#fi�9�e�" �*i/-re���ac_)%w�;!� � 5g�Fdu"�is un~/*c.�:�is�5�:;e�2-J2)t,� �a�5*�!c�*8�@�–�� spon�"s:�2M�!!�ext"�(includeyet un�.�E@f��L r-sett��umi�cutoff!,�newn)�rU�!��2� ���M�ptz'a� PDB fiAb"1$)[)O� Cco�8|*in :�e;� ����� W#�jwouE< �0�$@ n"� �H�)�belie�sq� S�%YO� w �0n{u "�$!l♙U6���s�< �%, deriA'~$� .x _FASTA�mI*X! Rasmol W p�F highl��.b. Wind��nd Linux�ar��sourc� A� &��� :� O )�to)�!q�of g R "lready  �� 1/<gbegin�J��6y#by� elf4�ls ��Q �#�>�"&{Es&O ,runs g − 1w4��{M;reduc� !�&�"V+u�41a4�s-*�.%) �Ő\g��E�Ei. /6  '�et� I�� Ǎɝ�� FA,�,g2�2��0 by��R��$!�2'��m_dst t�<��0�]nd�642�2Cly� %K left�Cen3'��pas!�� it��ct�Rex =G�1$�� obeySus.�/ ��.�N,b��A flow}/t� cribQCs2�-� 3appearEFig1 . Pe�,A� most"���X�d>n2�"6 is&Y��Ae�Baq�; , 0289d!�e+of�&ch { �&A41.�.� �5�yR; ,�m% �#iar�r"yf�NhierarchT"  [40]�-�)""!R�/��� pa ?�"� b�~$&.�B&!��%�nt� �,�!� ��he 3999U�1 m�%t�!J6A=0�+ � "����" �1�d:�=ne%t�"�� �|,a$��Mc �>Wso �E� �.�Atwi� z| $^Xɖ.DA�UH(3 , 645 domEXso�D� 426 A� -�a7��>!Y.`�MUEHQZAa�d*�/be= -A# ribuM�u��.!�um�Y ��%�remot"R��an9�) 6@2a�740R2095 2M6�6.�%�>m. BothB�B��1��b�2�D=25.� . Si�9�|� c�u�'g:QH���!� autoV2b1y� "#US!�\��we�I+�per�9ageA!��ly��&� Ts)Lid�-!SBsu�2* x[7obj�D ��S�&f Uz(*�? .(-U�� d�a�!�3re��2wbHmb� �5�dx+|o�(F�_  Bn�-z �462A|x%e��.�/A� 6�)Bly!edH:5� *E0��sui�� �� Each�6�12�) Fe�%5w�anfE&o � ��)E &� u+(��@!wFor� �e` a�!�A�]� � v-'(a��|�t��.�E/r�(&�2%� ) { ��B"XJ���H7&�1 �%vu �y=1�! e%�c�!�T��A� }�C�!47b� y N� �It9�%HQ a M3f\_�iUb�-^2�6 .w�� 4�I� ":�4�alphabe\K�%H�<>.[4�-Mu g [4�&!���. N��%:1'�)]t+8non."� P. ons;.��!� f, lik- ,��p Xce �.�� d��u&M�  E���C �*�-���eG2/I���,�Utac�&�>n�an�&us-v d"x)��e2 (eager%��"R 1%},.r��_ 6"� Y�9n2_&�thoug�/a�us��+IV@� �'.\Qm� 8edlF�0"tw�;�9�.� s:%�%"�T<�P%�dis �m!l% %B>�N� 4A�W> E� pT� � !TňQKW re�"b,0 o ob� �c�. (�"�Ny�� ��5�6��autho[�7l D�0� ��w��� E��� �Ew�^JllA������! e�%!+�J entireH&\"���)��'��sub� +vid�L� ofRs��7�Z �l%J�r; s�CO� s& 7es�7)%�/)! � GEmie,f��4{#�)1W�DwIq%a"in-depth"1": (4� \�p �,={ ��- � ven-bla40(β-propelleC!� h5Rh!�fZ0�EE� �, eft-!�edZ�@x.�. �f�<R��"�� tG1�fu�Q�a� s� ��@2� e,h ��CEy4s��4RE[K){heM �%"�?�*�8!iN�)2M6y �-���mE�st:�.�O2����. zeroA�%��ѭ���;qaS��6�StA�.s��6J6�@nA��n!8On ?6f*��!s&� ¥��M`heB est-�uZoX=�-aJA���E�!�" �� B� JA� e ( z�) -E.o� �%��8��"� , @orA� 0 ,�}2�� mz�)@R: �� � ~.l,� �D a )!}.��sh�r��O!��K@E*��82�R=)�*�+U8s ]� ��>� �J�9�.�E� ��ed�'�70fieldAJZY�53%S1).�:� �.is!�Hg�P�� N�42z(�"R8ois1�t K"�:9�-%=T��p7!x�(y�A#E&�A�lsB�>a��=e��e��w rm%Z7�Z9d����(�$!V��of:�y1weqm� heav*"�bKBw�#dlA�9.�!Oł�inc&�L��hLQ�� &/ ,au2` b havq&; kU~t1u�eCU.d�"�i�4W !)�“B9J( &�, ]9�f��remp"!�i��2d:C��}` �.Y“ �� �judN�:�4�inR �l�� s �-�"i� akx z!1�r�M���)�<�2column>2�k�P%g@��(#$at���p�u�#?z#?��E�of.r�downlo ��ran^�n� Ped�D2� urseC� i5%&��.l ���� 81a�web� ho� U�E:�j�/"o� &$fr'. burnha�J�+�(vsHOM . htm,)'s WebBU"�� t Uf��2> ru��5"� a$"�E�<8� ,Jan �1��ir_.�!p �����h�+�H"�C)�"<�"dC1d.iu(*f� ��u�>�ᦁ-v�:)?5�. I3o d�6�2�L�+��`exy - ��\ ^'�le.�,� s�V&a�^�E!�ͻ5 s"X)"� es sl��ly{t�q���U� 4�1�M_F5"o � wM�+Lh �� A ��er 桶e JI>.�I&� �� m�A�(�$A\�� � �2B��%_�>Plo�) x V8e CCen)kpronoun�&6���vyO69���6�z�!K-!K/��4!%3is!�y ��P�*�%s�1��(� -I>y�AP,cE�dec�Qy@se��Clesf n f��ecu�7Uj!��?9=A�V^Um%�rough�Z2����x� ��&.06�&A�5 �K 5 Åyj a�7,K,(i)�] . 3$&ach�% 168 . 038U!�I� , 159362*? r i ��8/%�o*Y. Full9�1e]MSD!�sus*� 5q���,19�1�!AMo22A's -� ��lo�7��~trg)�"720%QW��M �>`%�e6Oc/^�NSL-��r"�a���A mi>P�LH3M�9A \.�T�4w�& S�:advanta^�"�D gp~������"15dE�dor�De�!hop]by|=oq^g tiiX2� �2[Edu�%3t� � YUq �e��O8,��� �m!��<50%��-)�#l� d&�&2���a* i%aah4��Z�s 2+ �`It(ZZ�c"�;=n���ata�#,MB1�. LFbF.�-��E5 e�!A�Y�(sɷ � .�Pl��lea�*VS & ,�Z1(���'���*`l������1+�8r�8�m�ign�"�_�c�AA���-*reLny.1Vk/l�ck��:�0vw`G�C2�e(&F fail�IA� anyt�1Y�&`R . Al"7[ �B[� ��p6� ���1k:��<00�FH�i0_*A��E6pm�saRe&%�(�:�j�TO!deffec negligVZ��7�%!�$"�, ~* �YciO�G%xjEB sa�w"� .���mlsXfu�:�fal�m�?& pulla�w�)*��} q�.R��vk�(�!!eIe;� �y�K5��-0M Gz�28l]gG&7 137 (�" s;!/$IDs d1nr0a\% �@d1p22 a�d1tbgy� �s���> �i�8cm5��-@6�^�>*!]�4c?�&AN�5lai���m�AlM:� hardZse G%QpiG`��6a*� wX�� }�u�5a�!� terrE�Ešltt ��L* error� tI ge�6 =b�,igF'F >;Yg"�>e 3�444I4+c�L�1I1hm9M1 kk6a�6 1krr lx oc qre xaAEQ 3tdt�9;M%�EWC5poo� ,�y��!~a � a�ֵ22l�E��7.Y���6�y;.���b&�a!�mP馁 !�1[� Z�li +�s� rungu�.s&}(�,�;9g�9� GTsw>o!�Viec( Deep  ) [43�@C�%yE�H� l e,�&���� a�  4�!E�turg$��J8� ,.��Љ%��! �=�R1Re�ͭA=6r%B�&.�?��Z;���PUe�a�".s G qfx(Levitt [44]R to seja�� {�4�Z*s��z)E�uE �X�4,*nE�.%��[ruA���b�M2 plotA0�lan�G� "�բ6!�pl�c!�*D1t.�98us%��nyW2a�� a� T�"&!b����*� lyP(. W�-M�ng*eQ� co&�&�� � �2S do�Z�%"Y�Y�3Ŭ^I���Ea  ���!�^?�I, � eO ���L�"��9�S��me� >b�9 {L N��8i�u�E$ 93% ( 90%UtH(%�n��.�6v�k�nU`e:�A< uq&�9AQ�Qq6X�� z�~-��98%�a>.T+70% +2%6 s;!n�.Y r �� a1c6Z=XFa#S[ &s-:aE�U�ZeF� &6W��@:�s 5C6�~.�\2; 6xrem!��#Unsurpri�\t���v6�I5��,A��a� icul*�2�<aiB��at@�A\�C�.�H1�]E�{:� task-?; W�L�uni;6lyKOse�%!���W#a� ess�^&u ""2g!�h+��2�8$"�1\Ax�Cyp��J!>be�@ �'�lj � *�)�6��@�V�=�ka�j erE�c�?> �+� 7S,�-�{%Ki .`A� ��do7 l�3ivA����+O.�%�!n�=��or��.*_in 6ig' yKw�ve^+v� 9 B-bh>%'� �-ntM��U%t�!��=�}a�1�E@�O�^ght g�-'6�; ��a�i�C*� ��A�)�piw5!P"�9a�_,7�gi crediT%��-d.��guu"�C�-T ́i�EK.�^ aE ina'ry`�aoa�.�q66�bI(W(Kdyan��%کF?r en�O.�M"� . �� )9�" �EGk ! f�/.M��I�np3��4!�c{�4�g�2-D+�� %�grapheTo>rE�w e sl�{d;a��� � usc-Hs`m &i#e1, �A�+��g!,n�z>ndBso�!Jheա� 4 �C�GJ%i�1�/I�D� <D!��l2��Ce�1 m�"E� 3  u�.�1� zG(��ma��7M#%�—m ×1f +N,A�sA��o��AGaussian6f2�Vu5�s . W��oI� I��,j�' �[e>���.�/"1n &�c�5�8& J� #z`I�M�t �NK THs.����fu"�G bilm�7". �&r�het�\BXL&FO( �Lbe� {�6� nt n���!n;.55��em�"a3�JR#:�Vm�.��}-rb=� evoluA��p����@@in O ( k2n3 log n~6im�% k� a8��!+Sjc� �]nd "�$le�Sm��2LF=. C� ed��U&X� �dDlD��|r�aGomplete�͡&hu�zWnEaAa/is &�`\.!�\s��8o� st�_1�� &�$[�a�6��oubA!"CJ�)�V'! �4�magniD�I(�2C#5�A�+ y -5- ��q�!=v)3wa��H�do . Exa_ ng��-:]�j� �hsee�1oQ$[��-�jobPGa��Xof.�a�*�r�%$a�|o|w')%$2N���a���ol%D� Ea�� ��� prof.I!q�^y�di��'�ZXtv!I�PI_!l0s�G"���pp��8�B�'s �&%J���D�=ɊSoIl 1-"'C�i�=,.��~ (� eL %H;W�S)���"� ���s raiA��Sphilo�h΅.�sfaEAYB dG6�_�5l����k� .� leve[��6���r�RMr1qm�I�b6�BT�&5^ed9.H�:.yK�)�i�_rj_�Gs%��yd�opU intu$ a��8��a=�s�"vA�Q�5(.�h go fur!eR&6�. F�r/usevai�A?'��.�Zn&9 �� 8D2A�w�su4g-{��Q>e���-�<6c*N B]Aс���C��Qa�Zfic�G�� denot�  C-=Mn�T��' to nB8 adjav �G>6rL Jri� sBa}et bh ~����bMH� r&�� P. A �A�&s/"EeB� 6i:�3�>�9�.L@E  BC ,!t TCB!b ��SmOJ�&)�!sQl�Ua�pNE,� 1� carb!��JZ�3��!K RMST.M� -%����PA�T��`um:�E"#\��� e����#ZQ��i�Rg�Kabsch�pVP�"A�ym�by��Oa�)Y�A�-Q�%D�X- NCBIx%�Lnd1+PDB [45�VupdH4d 7 May 2007 )� a]E-��( J0−7 �� m ocI,a�"�� ���a�e�a���?�g~CU&�Q�U3�oG& Z* fAs empi�6T(x%e�P2� �he�(!bgM) Let SA�ESe�wTwo2BCe�DEܙ�*+b�ece �dh�$ce������$n.^)�%1�e`/[��S�w .�;.a�#3Mss�~X���of24P#P�"…�#�i�V�2i� Pi+1>�.*aLaxi'�o��(� ��Pi�fbeA�-� lappend� Fc �EO precis%�z�<;1�A�Aŵ �-�AdJ�� S��A�)(:��G� � *� eq8eEHhQ!q:h5w<SCT5�bi��l5N�M�m�oXna � I.���\cx��E-��Cm��Cum�a�%�is�e�(K{}a*r �]=�a1="0�;�0q�(5P “tw�;m�i�,Ftacrony�L� � �l!�!mn]hlaxA; �E' �ub>�/ht�%voj ��wF�+v�e%�ic��� weakR4�'l�.nE�paN�iE# ree-�&� <)�4��F �! 45°�%�.B�A6wo.�E %����V�|o�9^3ri��K��a" N�p/0��].Jmvg�a�Ykno�}2q#�M�eΆ��,�y 2�6�A�K 5mQ� q)�"0 . Z1�2�i��!}7=�AH�kq:0A��C���cN0"~ ��0MV � ��sl1� JS!�a�suy "R <��B�C.�apa bonus&@1� �ZM?e�� as"�|EJ$:Z,!C���Zk �5�:x&v� W�%�8J�r�{`m-�.W^v �=d�t"�! �T)�A �(D�@sɜ�s�Ax"� + �s�en\ 22�G.2uL�*�a�.�Euc���:, A��5\�>of� TED−1�axis- !�m�Solid2?s E>�wk,��s<��9f„%�pPN ` ( θ�k�n�0�1���( robaiE�� n ra���MA p�`�&1��!w�U*�θA�~K t$�Uf->j7e� �W�1 radi�Ea~to:>� ata��:�IrJ�v�?� n4 )�}n��r��)a�&apL2 )2��Q �W!to!0,&sٹ�"�yg"��led&�3i�u��b!��$�:�^E�:�In6����ʅ�two's"`;~L"q [46]!� r}��y/s_u�Am�5y(3E�at2lA�S  EEaA 2��TQ�L#lIi���n �e�4;�A�"m�#�4�F6>�f !�a.bst!ngakthBe2`I�)�eEK5] � ���ݛ�jat1.60H mea�#ڝj>)%�p$6�re�� Dh]�9z-Xho� %%*� AA7�w�5l A′H�> 6%�:Nmand-�&�Nak Bent�!( =Un���a� E� �� ��]�:���"~Zde�#�|�k�)�|�"�,>;���"t$>j(!�M�� �Rce )I�2�!���=* "%isJ2. ���b%>@�Q!�? �h dLo�w)�M�-%�l.|�i.�~sAUcar K%�#)��"9f � n�$�i�!%E�N�0?�Sc&�.&�SVDb�A��,D� �ent m*�?M�ex�i? N� ��MGaU���Z�&�o݊aN�.js ^�]5&�=soLr[ .���8��9ep�un�;!@!��oe�!d/fntigu�gU?�O� #5$9in  �H. �"��d�Fadd& ck�!r� s*>*or fe�6sfA|�a�aEE� gc1�DE?u! M�e�!��bV��+aK*�d�E��>� !M������m��( �� tA��-�,�e�&-v Ѥ���)�o� / Պ���!h �}Q��=ax u [&G%Tej�>��Qs�I3�����y�"���e ael Q�����A_��4Br -�m� ���:E4ut))!?U��-.��sp%U,���#�et)�� �.�1�(�x�>ote�c)|%x���K5��AT�cpa�is� ivala���w��%�:�>� . ) ��o��!����R4e-tC�o ����M�a>�~- b� I�N�!�� !��'�=E $%�� �YC�,9g,���/<i�IC%�eY��#OA�%��cedI �d�(�.,W��-�a��_U1 � � u�!����tn-(o���9�'� %0D A�}oA� �a.oeMW�!,g1a =*y�1GZ�,mb� ���W�8A�.�. MerAB.��� �.-FI��!ځ^*� �pr1~��>��V��wo�!�,I ʖ�C�c!Nu�=.� �����B6�~�xFiV%ACMWY� , a0I�50A%$b>B� �I.!!%.�Q!�e�`�A�e�,k:2t�v1��-jJ7( "Z]e� β2a�let Tβ.�:X#��E�hm �to%�.�k. ���m� sm� �!P�xβ&Aq�. D�s�u� �B�b0%�a{�� a]�AWit. ?)�BW-k�[%�e[A &P.�f T&�&� L�0OpQ�(m� �j� ( �S�%�fR�anT=ZQ��.�p� e[Voc ��to*�A�� �.�� &� �f �#+$o��� ?�% ���a@��|ed+��*�^� no6E)e� re�:ed� aM*G ><!�5�Na�+.��ki��.of� �^n�%����2�B9!"� "�W�e**qn*2rby9K\%a w;mj�pB�e&w W�c�Q� 2P of Bao�be+%uilf.} new )`�WA0%MdaD�J�a!��#)��ll::r,��e;��Q�,� OetzX.�2���(lW �Tq4H5�.�Q�ea���"k�M,*�|���t *c'�& e�Km�=of km3 �.{TB{�A���r":`e1mW�(3 �MSD<%�Y�%A r ∈E�s A ( 6 ) D6!=lto� � �ma*n]�ai+:2�tv���B��j'�_�Q�mbe#hpenal&V1A� fEc6i ?2VF"�N�8eЙ� I�Ym�x� A�n"|HC-&w%#�����%)qJ�62�R�HEwݟg2��e��#� &��%aM}Y�.� f���y|;K�,.Oe�� Vw!�8m[]�A�C?���9`�rg.� ʇ�H�"� )D��a9� A^n�^ K�:A#�z!����r���[.� W�!w6 )�����A a����Icaa�oi&�Q7pQ�BPOA &N�� �&?)��v�� �(�%�'" "D q�=�]��A�iB2a 5s� ���Y[� .`�Wo;�V5LB�) �5� �y� �q�lqC�>1F ofte���.) �'�oG.� �C}�E��8O�>��7> o�,.�� 5H1C K�f kE�$ar��}�" ���a09���c*a�flE��i;�I��Cm��%hc *.�% �oB |w,A��i. ?,temfh�%�},ilm# ��2� M+ � oe+� �z& !m"�k&+C� �Co*��%�ۉoutUPa��6� %_.� 5�%�J/)`! �imo�`U �!��;*.[. I��,��&_�[.6N�l��5��M�Qf�6qis*J%�!���d1M6��(X }Gy fashC.��yY9Ge�be �)6n�,�A�)�fve� �G oughup�W�#���w(7�Iny*�E|in |E l��5� �0o ���a�i �\,a�a��"1 !eiDg9�:��.�A" ��w-wgI�A>>j=�S} i"�+s�!�.�Y�.8�i = 4#[!'z)" Y�.Q��M�a (�*�).�& �B#ola �$� �g�}!B�@of.�:%Ws"�?&R�&9��q %o<c�OvR��!kep�!�)�5�A��B&� ��"J )LQ�M B>�y� %:_�v"���o�&ez*���L2tv!�2|��Q��v�=� S >�.� !"�"O |B+y&A"j�$�vy�&e�%6�a��N͏Entr`���to��rigge�3a��De�`Cdk�#n6 c Ne�I$ng phospha�& PP2A/B5d'Gow�aki2�Jes(viaSDtKHs Ensae�ARPP194LPa�%/ !!Xre�/dby �ory��S4*8! /�uof.[!24d1݁za�W�=l5 �3!���M�st�^���es=�30u"w��i1u ޻�m���r�0&4�!nd��"C�u �o- c "5��Aonig�9W,6UndA�Q5VdGWmitotic:�����e"/�A�t9��,���Gwl de)nc<DF: ��sThr19>*. FAkQed!�a (RNA Polymer��II�2xydlKQ� �I�Fcpq*S6�Gin>��rle1�ney�9nor��4|a�� 4e?�� bulk 1_e�][>~)tTak"$��B� s"�9�i{��A\�'�FxR� Pl2��� housAv �j�i 1 irs d�sM{�"����[2]�0sn� ��8�Wa{�-� �.a��dt!�y!�e�o:=�d-8. Mm ��=Z �Xj\� g��[���"vonxut�Y&�� Q9?!F{[]�[4� More�U�)2��xm�@r���~iIY��  lex feed�^-�iY�a\T��2�3 rapi��.-�!t!F���Ehdya�a�rf�s��a�hFKmc�\ [14��E��hu¾��s~ ��%yL dela� :R��Cdn� ����9 chrom� } e�,aberrF:��[20�21A٥�Mv� e ��N7&�5�G�k>� ��=�[2�Bb[�!�&�� b� 6P loop�A�J-o � aSD8w a�(��-l�z���s ����$� ��t�itE��qI=$i�f�A�~s�� bVik�6*�A �4jLrol#it`� G-H� �Q%..�!)re# :|�b�9 cruc�%��R� �� �tJ om�%��O�ra~mamLp��ǡ�ls���, deb�<. Cur� �  *��nݕHo�Z�airI)vO�= %.�*y6446�eu(z~ y 2�ZM�����]o�4I0�7N��42�,�:Y'funEof 14>�bu��y+!�is&fQA261o�mI~��co�x& � ,� q�c�o�Q6�|��R� desp� perdO$=�A}[2� ConIOaK , B5��n"��� A5�(e���O�)���>3C%<4^�( !PP1EEsE ��� c�0�2� ��5ŵ�^ .fUm�e>`'�� a�2\i !3�! -��N)F�'ͥHaeIK.�6<!fm�s��"[�AhqRa net��/%�𭇙R��V� 79�N6ti�v .8 d . �Gins8TU��� Gwl/E"� �S>o!�EAw�[&?�V�(�>Maɲl<Mu�)!}y� ory57!��)? . 1=�-X����p�4ve circu�(�double-� 6��!a/!���i onis�̖�KQ��)��A� key .�� >�89��J2�.Ym�� E:�Tyr-m�y� enzy+ ��r--O.��0�aN�nd2�%� ��#�˂r�s2'A�@I�!�two:�W"�!�5�G&8��to G2%M � aInB��^ m|e �5��}H�$a�inT%?o�����u�9B�L�.730 %tJ��� [imp��9"O��i�m��N.�U6_(M�S�*��)��� k1 (z�EM5��)!hq:�3G2)Y��igh)HTy ��eq�le�A# 5e6g!�Cyclin �Gaccumj��5aK"@shold;=�Ϋ./B-�)�i%.��J-�!� = ��9�5A�Okada� cid ( O:2ce�Ro)1re-E dest>eN�2U0A�� *� ��M� ����r �)�F|,)�A� �!����Q:1B–D�2N4.0��afR(l�� %X �>+bq>�=R��Zmi5 by' bف��E–G�:NN��n� v"O�3>�1���in�N�$"�&M���n�4$��A�) mf����= t�xtFm���BAZ��&Op m�zO!J {%jOf� ؝� �a� 2FE��J U�E�)Vsu0�=V�'B- _�6��)~"FkE�a�AP�a > � V�H%gI�f."&�a�� "�6�� `J�@ M-���Q%����S<en%�2�A��g�(jw�;�S�t"64 6�5�J��)�m�kinT�� U6d.�'EBal�mpo��. InA�n|Z/�.�k�[�%je"��EE�Q�V`�sdS� cessF�.�wl ly�v� u>a6RtIn "b&s=�5�a��J�$ scan� !��Een_l g@!�Ak!Aun��s��FG_7|lz{i*be:��T-� /��#��_2A��wm�t*Eq��uThreonh%�8{i}!c��ͅ��)@I20a�f�l �a��%%m��#AlavM0ly�����93^�Ja sKoƐn�]sE��%�.q 2B�C ]v�da R4S��� ";afFM5 BTS2 �� �9of ���4!A�!n�� j�>c��nts la��� iLY�AAGu��E!̥4i�ed>7��IxBD�\�)�%��&� A� surv����!]�(WW�F Wy]p-�!y�"�!J��.�.+ 2D:�R� cts Flag-Timmuno-��ipMf!yA-0nocodazole-ar0L^��7F I��dakEts�,c�6I���gA� �.�!+e��fluore;c&� S2C"��QF�E:���E.�:���3Maab��b >1P� �si5&�3��AS2�<%��H � ittl!� ckgr- n���pn*})���lZ)occ�A%��u��2 EExsB�d �Zr �:�WB meta� c1spi0�!3de��W�# ��>qtf�, M9I�Kro."��06 ,����e2�q2� f!�2��� H�pol�E�Ie^s�h foci�9@p0iwi%lap)� CenpYPv� )�meric �g~����AQ�ei* -�po��>B�Y�qYan2�` (le cytoplas�>!�&)��2^QG$R���P �� ��� i�-�:�1d�'�չi"��n"l�*� ���:p {� U�[@:6 1 R�d"CK/2�� na�&�Fp�,"�nd��q��.�zpuw�w*2o�6 ly publis$dk1as DT40eUvL[S��<(��)lymphocy6� !d.��vT3#!I�jg���yk1*�5a4�Q��analogu��� or 1NM�!�� A��B.��r *��� �3,u(��Dn vivD.�d )M����� BM by�.{h�t�Az1_de->f!EA�Z��� in 5EWB(q�3�:3As� !b���)56 �,���#� e�=U� �&�% YgT=rKk�c�S%X6�!?� 6���:n �+n� ���$�?aca�&s>Z5*C��<=kW.s#>@�"%�� �B���OAz/i�Rri^� q��K.��0&�.U�� ��(is~���a6��&�/�{�^ <&��bR��� �> F�t�E^e����*p_: .`>YB��.��re�,�.@d��+pi�!Q�����Yc�of2�. H"ns.� �7YDY]d3=E]�I� ��l .1��EMt,�`en)�2�6�e)i�3I�8promp��o&m#��eN�anoF�.� �U_-_ ݥ%E��(W%�h425� ��AhZ�&��ewY�Y�J8�2��<vrepf���A.f�lA t�yc�+T� 5b�+� "�i&R�M�$��&"l�zl��2*6����] %uIe )�jhisx�!aj��%�%�)lY��"9^��%����2�rY��rgeAtD6 &� �I��is6T�fk;�i%JofA��T���#&�>�#B54.) Gwl-.�X2� w.��&7  �A�#�G� Ii1H–JZ� :�ei{7�GR��M,qby��,i AaEE {�� �U��%*� :zR some�i�G�G���Y03'0To �5&�6�r" �.�$B}��0�Y:�, a^JKa���!.OA��SK S3MW&VF��9h by Rz�vit���avo^fdoRO330Y`8o��HA�pȰUev��>\.��4AnSx�[a&167 iMy׵s &�:�m��ak%ia�� [e�%6���9%6] +����ll�yEaug�I�qA,K]�!��laof off-͙ Eg5=STL��AY�~w�M�����aB*� "�a@�x"�r�� s6q�s!o .7JVXxq!� ��Gf�!�.�/vC��c #����AE�,�) *.��Ayn!�<�' oa 15–*7 �1QD4A��2panel� �"��!�qd Ab(FK�A& o�nd��%�c}��a% �0 R(3C & D(a���� !O� F�>� %xl6�"R6 %m�!.���� �El 1 �(� =n2% E�a. er da�OA��."C5 µM� �hA ���lS� B�s�#����6�.�~�n�a�� �un^���L�!jO� �� w&��h���fndi<��� �.�M3kZ���*1Rk8alycu�(�Cal1S4�%\�u�%�A�{ishi��towards*&er~2ct9or�! mo52.*�CF��T� "�A,�S0!6.�9�!%!b/��� i�C.�# =:tE�� rq�!�!F�ۧk�^s�� � wno��:Qa��m+�S!�9��l"\V�ex!6� "kin HeLaMw& � a �by.�mea7f!j��>��v 6�!,�G!��>�J�&� Z.Factivati�ion caused a reduction to 10% of mitotic Gwl activity as well as Thr194 dephosphorylation and disappearanceNtheJTbandshifts ( Fig . 4C 3HD ) . After OA addi�,8T^nLremained unchanged ,Prprotein%a�e�a level�$60% relati :�Tcontrol . Surprisinglyc�of TC9K@small increase inf��, but did not significantly affect Gwl �!}4. In both case!A!($nd OA+TC )� high9f%<%tX , were only gradually %�by an!�sensiEg [atA$@. However , other ouSevents!JvQ�are1�!�byc resistant Ec � have�Q�alE�E� haM4 a; plex.S network* [!�k��%� loop��"� �ups 9"q  ammalian��switch�i" pnew in; pon" %�%QE� . 6E�Es-3an.LlayerA =D. does� ��funda al/��er Mh�� � �)�i!�fluencR he te? $al dynamicE�B entrd dG (. Our mathe!cal ]% og�.�he*�A�c&U mutuaatagonismU���a3r  accele� � Z�ssyn� �qnd de�-�f CycB �spe�ly � �B�͉h�7��@princip��responsi��! !F� !� step!��,.�sm1H [��e.I &� si� ��6~ d2}( J4.N� ��.�  E�a� 6�&�%��N��W���  impl.�i is yet an�; intrinsic�A�!8l1�M��helpsAZlaig )�>B4i> *� W  �'�bel je�to fur�-�!�by�|nd��edZ�T��no:el�edJ��tb!Uvestig . StrikJnei�EB , PP1 nor.� C69>� ��*��R" i� "��his bypaJ 1��: �� ajor�a�.�W,oceeds despi���.c� b�z�iP,�2���)Y!�%�B )per,�T�7A�74A>, which}�ly�%�. a�� s* I�!�&i��!�� 2�)Q�E�remov��>� -�H� ^Aá(� sup�� 6�, Xenopus egg& ,a� �E.-�Tby p27J trigger�6}-3K�abs��!m� �� �isu�2�9 �pXedq s�8 a lo�| i���9� wo� be% ��n�{E�)a��z�*)w)�[26qThuaK6.d2p��a�rF�s e� E2�"�� �Hs elus�o �4phenotypes [33�4!&���A��(orthologues� ,��8our knowledge ,( #reM�. F���&@ ll bY CaryM�y��!(A���� ruci���I.�J0o analyse howw �t�A�MSF6h s� �  # Initrcon�I� . 75��.�027 #D�!*equ�s �� �k25* ( 8T-MPF ) - kwee* Cd%@, Va25a2T-6$Vi25*PP2a* )m<U (T-" ;MPFa* Gwl�:kagwl  (T-� �( kig,+ �dT/ ( 1+O4 a ) *<1��kaensacT -Ptiki!PŽ� -kas6Pt - (A9T-PP2 )q +�dis�K6*�-�MPF � RO )NPP2 �auxY�Cy-�!k PF7bmku0 ��%�9�+ %�-�A- h 4!�T 1�+ &�)�#paramRs parE} Ca�Ag 2 ,EX.AI.A<OE1 1a�Q% e[Z �,�B#E !%� J6 ts 10sdi!)E$m�.Gwl.Ak.PP2va��!�2�\�weeY�A ()RRO ��OA @ tota1X3d�.� ,�h 1(STIFF @ xlo 2xhi Ay2y1 @ NPLO�1yp��prA� , yp��%^3 `!@Pt4 aQO� @ NTSh1D NMAX 2200%�NPR 1 DS %K2 @ DS7KDSMIN.*%vPAR-!�u�AUTOX%!; &,YF&Y.&don� ,cDNA was clo�" by RT-PCR�m� isol� HeLa< �`RNeasy mini kit ( Quiagen�Rz se� crip� PCR�RT )�&l Z SuperS9$ III One-S5 �System �In({.a:�a`�6� messen~ �( �) ( �p |rs 5′GGG GAC AAG TTT GTA CAA AxGC AGG CTT AAT GGA TCC CAC CGC <8c3′;2O#.OG OTo TC Cg G AC[ WA_AWP� -�N!:(pCR II-TOPO�vector �%-blo!Kit)#2LIn^| e manufacr'8 commended5 tocol> r �ndr.��exged A�seqpFl �ric diJ#h R 1� e9�t�. an N&J� tag &� �[dO"on14(�"if-Drhep� Gele�%Uni ty Innsbrucka�ustri��. S�0� uta,o!a�arrXWyQuickCh�& XLC-D� ed MC5�S�Z� aliforni��US f"� !�:�$!�<$ uman+α �>(as above��6 ATG GCAe<GCiDaHGI�!�.��8ATT(C TTG AAe4 �e.a Gatewa~-A] m4. �1D�"by Gen���.^!`EzC1Lvia Bgl2,EcoR1�. )p?RoY.f�a�$A AGT� ��AA-W!)g��! �ÁtGA %1h S��A9��-��TCA TT�(!�C A��9�.a his%l1}b�&�J~�~u~Rabbi�o� Ser ) CDK�'�"antibody%� purc[#�C�*Signa�. Peptid)&�!� al r lP�-� `,) gene�d !t���Eur��0tec , Belgium�h[o-� ACfAJnI�erM+G�obt�*aJr-6* PV9�M� ,atoru Mochid� Kumamoto �, JapanTo mak�oj mono-@5� ( mA{�")M thre�� % d tyrosin�#c�),�-p)�H EKIGEGpTpYGVVYKGC !couplo KLH%�in��(Balb/c micea� ybri�# producQa�spl|#_%" a hy�($mune mouseIf!-�(Sp/0 myelom[i�standar�Ycedur� Pos!+e�l�AE <@!adsorb�s1"Ao blo\(ofV�8. mAb CP3 . 2 g�trsX,a�,se�"(. ; α -tub�+( � DM1�~, myc 9E10�CENPA3–19 )-4Fi�:�Abcam��m!�� UK )>αg2Gd!"[�-�)�V�%�S�4 Cruz Biotechn�4y ( Heidelberg�ermany�C ?igma6 SAB420026,�"t� H3b�bE 6I!�) UMillipq#( Watfor�.%�R�-MASTL @�HPA02717�(. HRP-conjunJ��goa�ti-��or im�5�%7Dakocyto# on ( � . Se�o7CI�fluoresc �LN2� *� "� u�"0in Dulbecco's� Ea�Med�l( DMEM )F�edi��0HFBS , 2 mM L-glutam�}, �$U/mL penic!�n%"� 1 mg$streptomycc @ a 37°C , 5% CO2ub�P8 . Chicken DT40�S#h��3 +6�a eviously� (cribed ( 24���6<sy*o+in G2�b"1NM>!�6 hVa vrel�0d6� �% 5 wash� A.col�/ ed 55 \rXJ���. A�� v�,��in%35��ofU!or/v&(#��d tim��harF��o�.{&2jH �-�9�iv">r2Q��5�S-t�l-L-c�A>(�,; TocriB� ol ,i�∼18:~�b�tW3$shake-off  Y$%�91inxa�J mediaN��(okadaic aciASOA;�1Lbiochem , Merck Chem� �N�hha��6�4aue�+ ( T9 ��ore]nM+c*&2(.{)%&$1 h . NextSk1�� ���U-I� of RO3306NRk15�30E�A � =XY�!�I(N'To�ck-3�r&3."H/ , 40 �each  +�( 8-GCAGAUGAUUUGCGA-� ��/6 -CAUCCAU4UAA:,� , Q�, Manch�+rQ~m��e �%B45  Lipo� $RNAiMAX re�t (.� ) tw9& secu�2d�*accor��t� eZ vid`�'ruai)$=yt*w�1:0!��tic}�� 4a@��!�2> �&���!�<��ntE>.�A&Ida)# � ly;+in!�µLAcEBC buh2!�0�BTrA.H 7/12NaCa��:5% NP4E�1 EDTA�l DTT��6..�o UM� Co1&A#nd&Stop; Ra� Diagno"1a�W� SussexA . = �e0l 5× sXe��$01% bromop�l bluq62�mM�-HCl pH� 8 , 7% SD�T0% sucroK nd�,β-mercaptoe$o*�� �-nsonC#gn boil[ t 95�_A�q. S� 8���~ wE�n. �!�D,alEI�Imk6on%1ern��lu�t/ a��1(*� �8Image J S� o qu�f^ inte�*R� b� � . α"y ��f to�"�'z�1=.B�u2#gA�7iplasm��) GeneJu$ >aN�Nov� �]:��:!g*�'s gu? i� �.O.��o�� CaClAn 24 h^,�{[4,n� No"�.�d��� !=ad����A�AAY16� �Z@ dM�.�- 2��MOA B TC ��.�p��M�텧�ind�8d�Le��4 �>��.F�on !�%��� IPy�i�Ha�h��37aݍ�% glyce�:,���-��9 ���I�"6� AC(appropriatem6Jr+/or-oC*Va��inu)Eocla)1�+� if A�at 13  rpm%E-j at 4��.}@��in%���� �\ti-flag M2 magnetic bead1� a1rUw t 2 h bAZ12Y!w�9�A�� �9:� MOPS��ю5!� MgCl���4%�L� ! �%0y(�E��J�in ba�(1( MBP�#i�) dilua�in:�F�2"a ATP�003 MBq��γ-32P-]�at� �Vre�&o)�stopp�mS�<1# �!"�%gr6�?o� lip2� fix���7�?�-ldehyd=Et-Aldric� DorseZ � in PBS4!܁2-(2�����&+ %;(spun o 0slLt 500 �.!��åO �oc3DT�d.lyot]a�e� .2R3�R'@s� al���)Zpermeak>E�a1� �1r�@–�<i(n�ip6&���bo%!m�91�Pro�'8 Gold DAPI solu�y2` , Pais�� .g�ac�+$on DeltaVi�miv cope$iE��4a UPLS Apo , N! . 1ZA� 400× oil immerKo,N'( Olympug6,��fi��6��Exc�5l360/40; 490/20; 555/28; Emis[457/5,28/38; 617/4=@a CoolSNAP_HQ2 caD9P#hotomeC�6ex'4to Omero softwa[( V �4��D�v1}E�pe'= (SVI Huygens!�fe�al:<SFka�jAi -�converA�Adobe� toshop!Se .UHa�BA�)� �Ni-NTA�4rs (CBL21 E .a�i*� �*� ��4��n"���ei� �@q�� by2�8enginee�>ͺ( H� <+@lab , unpublished4~<)a� 2��a�M Hepes� ��8W ~ ��1�K� 1����O mM NaF1β-� �z, 3� !�a485ŋ݈,( PerkinElme�AaTo el�@(e unincorpo,��N!� �, xor-%�.s.`-�频�e�H2I "�.E9=� "by spin.on ultraa�rdcolumna� Viva*��,  MWCO , F!��co"�)WHj * 7j ! �tuT�A2v:.�.& ��GFP-FCP1mac c�)G!�4 !PM�2X �6� � a of *!;��&. �J &5 �MSO�H; Z� *���em�&E;aq.?�&�.�"r GTrap_MM, ( Ch�te� &���� �KI��?resuspA"i6�>M(!�q� NaOH� �*1e�M� I:Ki�0%.� e�q�� � PMS�*.�Q sphoiD!B6� ix� %� ��9�!�90S!�0� �^W @A^�!9�At%�a�2lQga�1�in&0e h � "� measc E���on�nAg�[)�.%<�L� 10i �K��4=�/� M9..�h%�р�:^?bvrJ� linA"t96� Tim Hun,B ��5�a�!�)�=��6��u 6%Dprepar�eV@.��(t!����HEK29�, � �2�I6C.� �D#as �YFFexcep�3e.QpaYdA4 �!S b5�P"1��as�;"�!.�O2 i�(an HIV vacc�i�64elicit neutral�2�� ( Nab��2�A�tG1�7a�of ge�9d&e viruXK�revQe�>ish�7a9;e�%�3�y�A7F ngthitweakn�(s~�*3early} g X3a�fc�3pr�%efu achiev qis�laNA�we *G`5viUescap�;(adily occur� .�6dMop�TLti�;%logous�. woa�!sI�acute/ �ub'3 Cl<93o�ide a�?a � raya�M!C �pathw�,t&�JvariaKd�@fX!(at multiple; poi#e�Euto �Mg ser�of envel\ ( Env )ŕo��chi� )�(Sith!he%kgroundL�= Bpo?newlyi�mita�c� G1> � �� driv�A redo_F8Fy YM;3%'regQ�p�E�extendsx�eg 9V3�F<e �-V5( V3V� .�LA� �5�% ^KE oscŸ�Z:t%��*�coope�+b1@V1V2 /�gp41 +�#in)1s� d=8 �=46&W�;is -de�nt; �Creh���M��$nd.Huti�Nlref)��B'p) %to`� a+d�>nctZ�"( Mabde!��&�6 same�["� t:rso!%4m ‘spikes’-G"C�Be fac���Cq>$: �Mj  .Emh�3"� aDQt�undergD � �+ earrJ/���7;��Q)+qFto CD4TcocMpF1[4%�5�<�GL+��M��C �s! �a [7X8!�ei��ge I� �z�[9]2Pr(y�"� iq)W X !�� r�� ��f-�c�mAI)-] �.lA�&,!K-�։N+!j1y�J[10![1i=1e>Des�@se� �A� mostm�i��2a��4�  robustl�D!\g�Itheir.� �  , 7ti�LS th4c� !�typ� [1�=1I'1I(16 �)�1%�[1%�T#�)�%�broad>�, i�I�"c��#��w�=ne�=oAK sess� 1f>!0erties: ( i )No�Y-�F��'%�I ,<=conlM%� aKs��e-�"O 45�g,)tB3A�( iv ) l�Tof%�I��} �H�re�R Pq % meeise cr[ ia2!&?�6Crecog�TbyE,X FD %�� ��s somewQ'edf %��n�`or�>e���i��a\>:+ Q��at%�or{ �seX�train&w/or4(� ,��-5��s"H uMorA&.o�N��*\ �me` ism�r"w@m�,1�is��e� �D%�atM�!Z�p&<< ��)���:�20��W!9A~o/Fa��Ach5J��^wasa�first�FSJ~Ced*��S:P"����b! )�ᯅ�(�UAK)9��|�7d4A��"B�erE�taL�5-R"{.dc*�[(B �.(%�^ evalu[�aralle�&promp�a�� !T-���rop��L!��IA8�2��SC��s ��A , [2�u2�uRe studQ h3;ig y �P�Hol!�J� :�q�Q6 �-��he\K2-�MVK� �#C3!V4�- �a%�[236 d 's �ENc ��EZ� �U�� ڍ&c8� A��i-vp KQiIM�?|�Fur! weI�*j�'at�v*j!�W"{t�gXa�� � 5ԭ�mZc!;���� [24!;.',�/G�/33 8QkE�! α2 helix-!CY:� �c��l&�seWd�_� � � >L"^�n�S� fe��%�ti%5�=�partn,=[25!+Te-Oq."^ �]F���&� recyc�G^�:@[S 9a NHa�h A ;� &�Y9���a�ic SIV- �( S-)��u%�q�arDA��'AW[28! Y-#�����GmQ"_7 moleV �(`lea-a �r�b{�`l�+. S�baicarbohyd� moie� a��a=Ayouisurfax��I�82h >3�6>s��%�GH��d>g�8\?H���by-��%M� N�" ,����)8seUU" ba� ��Env�P!�-=�0!�)�y=acaqu$I�i�to���;M V�AV��"� !perhap�MPelk ed�s�bHPF� 2I�3� �[. ConqME�t-z!&a.0study-��&k�e�t!PS& aut:�5*5< �wo�f�P �!h@\� iZLme�e�5mb3.%��in�Tn"� bcY@rMO � JRFL,. S8B #�wMNA� qM"�.Vs iC�z�%littl� ��b!%���. O���Kv2D��Y�2OQ…�Q�*hMfrank.�gly*�, �no clear�:��.em%angtL@a�nBUSIVmacM��� 7i �N-eO-�#6@yBe;4^Z�6��& >�:2[-M�^s3�F2\������!6a�ea��h%�e :�^1O�s4�n6:i9!3[37�Ta�7"�%I�� hint� ���x��B:�!MM��NE)� � mm��6�_existO`un0Y0 cytotoxic T �'hocyt*CTL#es% y&�"�Q�C`L^ i�ea>!ofM�"^T:morphismnHLA� e �2� �"� in�e�� �E 9iff��Z�y�D�D a�B5\��a�e�^�t%��\�t.ach�BdefR` C.uS ��1�|�Y". Uh�>seudoz-���c f"%s= -I�vid9X,!�-��� �, AeUQa��*r2q*i� �(�1ahp!��E�� neo:m,.Mze��99 sero�(�4whoA� ��o�-.ngV��%�g��M/ X ��*8� �A�w�DedW��ex �-c C*yE1�eE map�]��#;� �^OthroughF�W!8yea8-o�Q�b���v�byŎ�9 ,�I��ex�e�Wi�6��l��� �y o"�. s���z�a��uy)o} �YA�[�#��1e� G�_���c(�ls? �%eI*��&�V�?"?E��?�!2� �RaI���[ ��affor�si�iE\ �Q�x ��"u!�� ����!r*! look!!6/5� I[w.!O| ��( 5#&�I,=��>flexiQf%�.�#Cof�*%. �d��].cM9� ?11�"�j1�%�n ZEHRP coh;�"2,]!*� s5�C)$���>� 50%� :n ory ( IC5�.6 oftecee 1∶�S�0@i�m�fewA��#ofpo�'_Fmwo��@�I}>���re��( as�p2�t�:it( Tn�S�>�(!� ! quasiJ e �[e�� ome UNx9PFis,�B:I>�of bi� A>ly�_%*}"N��PBMC TLu/!46y  0-monthA��)c��da-!]�sej)�!�#�%imŮtol-�48<�M-o�8�2�t�-g��calA��X� �� o$forward [3^�:E�fiv�#)I# 7s���V�A<yeBM:�. AA[�3i�s � hose}]"�!%)�<l.y2at �>=H�_arrow���_S16Y]6!>��&/��yto>by k:�p�rly &�4)�I<-�JC53-BLa zm-b�<*� � "C�he��U��%Z -��.�d�]%�0 QW�cur"�Ma(wthu5e u1w��(�:n � �b6(�'�JA�2�?IPZ;caT�=�Ot;O!T>�* J!T[;�! repe�q&:� ��I�s�c�F��s�?�)���� gY�� 185F2\A�2052�Fg �d.^�s�'wo2e,��bab� a$AP"� !�AUy��"q��Rg%��%"N71B "N7thu ��NaU�t&U �5� N�a�F *5���!� mmvq� !��inuC 2�&C$ovo�!�pd��d�jW3 gaug&�ibnkth�1��!0window!"�n���-��"D "� .. i�1eE2 ( 23�x{$!#E<�0A�"�/ h=�$/+ -E� ��4six1J+k(  "I9%,>q� "k �!&� ��� A�in ����osA��&�. *��E�� 2Us2J2 & 66�N!� !� �yxPvan � 1�W�!�Dy� !� '`4InteresA�bj� �s ly2�AP%����ya� right� ploD0�3�nro=h!/A�u� ( grhNd Hlef:G ;.-i� �����&= �"*� l9.�9�� a�Lte� alsof6��of�7!!7�c"�by)[x: ���a�>YK.� %=� �P�%�ɸ��q)�as:d2�!c�W*� 8�}ve�`i+�-8a Mann-whitney �ru91�N�\z"�� a�H-f�;de*.�{��ca�`* �!��-i6��P��� (�rlAi�>!�Y�ea�%4m+ed%Vin-thA�pxo"t�u�. At 28��!�ree��:��m nn!< phyl$�@tI� u .8D�0�caQ.� �N)9ԑ�e �!! e���ce"Q_�*R;�$:&9ce{�f�Y-�� �aO.�r �E�A�Y�A��*aՁ!�� tecte��eEe�"LA��of� A�N��2�=, T�x��e�o�Q?I�lb&Q��"� r�QU�d$/l" }zfPUkTw't z �&3 " /U g��ltoI �xEw21�=linIY.)W�,x!qE��lapF a&�zI" m �e�>K!�qj�l^{r^subcE*. 3V1A4V�`V�$ }3, etc .�!HB""E�V&�@.�iZ� �j]5ic% �F���!be;� O2��>�G �69!gB�5� F+PB @1}&IQ�� hE5�a�M%4BH� �M.m�3�>�~�)�!&o?e(o)���?V1?��en�6.�51V�5��&3F92.�55�17!T disp�s��\ �c�2B.�2D �! ��BD0"y@.entir�!V2 (�)%�&�>� .�io�.a K192Q.�2�P3�FW��dsurmie������as heava9&�&�0�%Su�7,IF3Qd#c"�&�PB�D1eA=�Q�e�i-h6$E�an E335A�H&p�Z�~�&'! G��V5M�: I459�P����iY�.I# NS463N=g;&�(HXB2 number� � N��4��$A�n�O� �"'"�67bo �� �axr�! F =�,ɞ�)E{� LF�1�%�!=�)?�)T inUBlyi�eaq.� je�� ;( m�Vecapit5 :�u�!\E���9�p IW6tr�o� Ib-M0YS")g j� )=[by!���Je>�To8��4!�8�ie�5V5=/&B�1]K=y-c9!�uV2��1U�� $2 )�,l.2��-\7� i&.#� �Dnt �R arioE�"�x :3ͪZ �=�2-�!� �PBN:/(�eͩ�NK�E�n:k� 3~)is�� N� œ.Lb]3A� 3 y�&F K}� I��loAd1NV1DBn N134S��stitu���]�a*� jq n�%!*�ft !i�a Y140�T o;�a�c*�W S .zÍ��t2!<|:�V1�Hd%�.��Z" 1H�j)�.)��third-n , A453�&as>v�β2���>!l&F X *FSw,Pa���.1&Ay:�@�3/NA����A��Xl�+Jhst�atq$�/b =�AOL*� i�&!��;�/a�b^a:!!-��Ih*%:�/���ye�ct [3�6A*�.��gen� ">+/^�w��q8�5�tmJ!�@�o�y~fic%3��:mai� �!�*bU1f�oy�S3H"E�;1f� &� ! i��?�#|�,�'v ongo��} �7�}�Vrl��D�"�%,2u!i&�ct&o2G�^-X.,Q���-mapp� �Da��� �F)Li��"�P1pc�W "&�H"�1��*E?=�4!Tee�tom 3.>elT. M�_"L�6�et��hL5�PER^�!�� �@!��1=4I��!2!��-M�U% �Br1tY�. B�"�6�� q�x ��6* P&� :{%��)i��>*C�G6p ��=�" �34� Kt�^� -L�fE�n.�. �3� ;��pa2�� �,TB��" ib�Nm�g�a�!E�?:ffe��!�.�"�8 dis�J� UD��8sur&��%V��-"��$@YA'G]BV>�. 8 -\>�yon� � �!�Y�-QՆY�i�aon"�>��+� g��#�-f !Z>�is�ava$f�F%@�q ]nd.�s �C.V E\l_ �$*&d�  I�pa/!��%.�(Aŭ�.B"�9w��H�B�^ a 26� f]-upE2ioWciPm�>�!���a2� %0�)�w* a.��'�d=Cal%,�# �S�>�e.�y]1ya1 6�6i� Yeaw�Z�it�0�M�.5�0s/J)�-W LOs]�-��%QM6��> %�, BeBhy=jom1�g�4�%�vi�!frozeYMC!�-&K$at 49� >�e�ch�!BA�i�avail��!��O�� .��j��@ o sc)��"aka� �1� �WF erna2C�nd�="Pn)+; 2 4Z�1��6�e��!ˁe�;.���5��Q� 0 lIk. :<�!I=m� �|N(����Iy�0�,I&�be!6vhom�z!�/ �I : �a�/\&e�Mab12,.�za��G�7lyI�n�r!)X�2��eF�i ,9�U+AE1��!V�VoB En�&� Z�� eHeda3���w�="K�=0�~� K�<�jby7 hIJj.2�s*,*F s�beyonpmh"8 ~un=.!M�*Ei�Q��(�-}2 :Am ?""�)� !<�Pz"�:�l\G���A�e�A2�k��"% � &Z,��� X(�N�31'�a�� i�& . An,�".�5�!�6Sedq�Q���6a#%�({@y#M�s39 N56dr@_JPvac(NG&;�5��-�I�o*BReE��Wg/mPn�A�RlU���%�eɧ�� A��Jll�>� c1 eT>�J5'Ex�2嗑�%H0-P"��G�oQ& "6 Eh�u �Mle�R ,U� reqgl.�8�3Ѡ�uG�Hu�-@J�b�A�"���aXK7at�Q/��� F��#V2��"197F�#yeg.i ~Fu�)AM�A�.A�'  )g�w9���%itkG:�N�\%a�V1�o�PM8��e B`$Z�j8�Ac�aE aQh+rram6Ta&���I�<C�P�:ofN����.6A*��Й`;� ��E�i6�6Oip��e���I�!��de%+ŷQ ] ��1\( ;eP ��kUk(AU��� "q8i Ys.2 A�FGh�V2�m%�!uneS�����l4!�12k GC'�%6� � ��=c%mt!�6�� A�v .�Y&�+�2�N21j!�,1n}VgeM6a"у V1V4���'a�6-�dv!�39y-"/�W$( 1-Mar-03�Z31 ����,27-���_��ve �55T���%Cs&,&s�B"E�y. ��E��%k)2Oa%�l�+r F.���a�)LX�F DataN>u�Slz�ty-P�of 57=X( 77%Y�%7?� Y2%�T&k J![#�2� >�M,.@"z (K �� e�-�=t;=�&�n8arrH a.{ GA�A"� ii abro�z!7�V1�@"�I�@B�A� �W�yF)da�onJ� �eUO�A�2�a�PL�h�F�/���-])��+� f�6�as+;�4�/�'m�i�=ed� #=ly . 7K�v�;U�w���]L:at��.�;6"@kοS2 ����s$�, ���2Km�-�A�\�Lf�!�!*��)V&�62�EY J7�T��� !�1�a0�Jb&�)m&OI2����B4� �� �re]� r+ V5 �i�&$�AN��.2�pos�,.�4Tr��&I%2Ar* I�\�%�s�/-"v �-T.*4�mp3� i��f= "KV55v ��l!36gge��� .����S4pr�3lM���A,�� ly e�� �ert-{dja�J]� R�fVIPGB�1�I�QZ� 5��g�Y��K<9 �"} � �.3# ��V5"B�H�ptac�| ŋ�(a�� b12!9rm��t�!�\FkFinw�dGH�Wf1�sv?L�Det���,A 6�]�mu�!� xclu� �tX%�iv�%^!�m��-o���� ") & sM#�l)�A�7%X>n ��� �� ~E2I).�"��Bk� I� ��U-] �!�r*W�!:x�:�B�W"� !&S1d.�!|,.� ���,>�. EF���o&c�+)%%�i�2�L(�` A�:[Q2�9tZ`E�]N2�E�#�h�G!:iq&�7&.A]or �w�'|�jo�H��=5-no4�17W(,nE��F& � Q�� �4E�:#p?e"&btJ� A@��&� �11#M.�;, ���u�fer�6z9.h-|!�!i|4 �J�"K�6�f}< ,�m�@!�� I8.�!!yA�> �g� �61t�?F�"�#�Q�1)��*_F/ p��C-i��2:"I�i��en\�� B�0 B ��:>!!C���{ s�D �.�FK�*q�e�V�z qi��R�J�y-EdPPd&fge������Iorigi�f�&� x�7A: 5-o ,A�&%23 !�28�A ɡ, ���J��("L"�W�~�su{@ aK���s�ITpoob�L7�]��ik�ex5JpLg��a-���+, ɒ& .��!*�&��F�1� &(1�!�%�*GKE�!@e8co"CeH� ��_Y]]%6� 9��R2�C>}wh�sp�fE�%�*')�.���u��"� QL4A%�rai� �.� EV55���&; .�>�&ue�.x!h:W"�iu �[ >�c�(� � .� �&d%OQ�� flanE�V5�V"C �4 2�b!�K & i�H2�c���W�,� p�H�\�$ �V5 �A1ex� a�UY�[uVB ~�\�a?"z �iI>,i�(;�a�Fnn|�1 mark, . ��zm"�Q)yf{6�W���m��:t�o�5Z�X�ws$x-x!&.P *�� �d@/er "op�w_:I�E%!qU!�#hE� �R +�&��Oa�rMly�=�!�Enͷqg8.> AC�j1Wv��hi-�A(1V2�? me e� n� j� 2\ o% ah� -�14 ��'ur�b��4T3�����:n��*14-PB��錡A���U�=�!rQKill��8 $&u�v�}!�6�D!K ,�%Pe��0Z*� :O kwog �Pa��w�!�Q:u� �Y�d7�0�p�yeu!>7� e2�f�B*�  ;l*X�#��cad]�.)�� �at �p�9w �U�� �>�@c�B z.��U �.�� "�"�[bl�J�L�46'W re( ni�a�A 8!�΅Lp�e �EM;E��&i�S.r�x �+�Be�� J�R��2-v�ɰ��2�"�E?.- R;m&or2los�j.H=>�G!�moّjPof V2-�� �'u"*O- "s2�1E�*'u��bBE� advaԨ (�� S���~2en%<�/p"0vfLF��T�4,Z� QE U�F�)y�k%��n§5�R��=r6i+ ����� ~r�h\ E\�2%. /�6)�r>�RO�p� ѳ&I e"� ]&CN� is�quaeq��% �O�/!�fZ�*ac�J��hpʼnju7gI 5�2� I�V2p]Q�I��J�N�ppe�KJ�� e���>�W;!{Lm}6� ^JrI" memlX)�s"�A�41d�. A=Ipas� ��?�"���^wh#3�eda��f �>(� -S1-S� �Q���4J[ ,Ee�!^$ 46""����2� I�z� �)�!_��AsNoQh���� A(,���mar&/:� a8in̗$XK�*�U�(���]Ind�qhk ed�0f�� u�!�a*1�,(/Ox�∼�*;���-Z��ofz��u#�BJ�,a)���� 8p^Ir �p%ɥy! f1IS5Ou�(1C*iR∼40qY� &�Kr*-R2��f��n2}��[4�g�N?s��iF���5�a?o�l�`En�i��RkS'�h!5I�Υ�,6(q�)3��Q7s�M�e7"g"%�,w"��c� ��\�)UT ŸQ�ocm� � EN �H�S2C�)+-��M�Ya�B"Js�].e7"=��lQΑ�)" lq�s� a�d!8 9Dd �&� I�B1I����ll&���r�v1}IplZ�! ��%"�N7 I�"YWEm��=6ac;?!�$% "�!!a+ Z�.�&GD(jE) .�tA �"���.�*!O!6a&d�f>xEC,}�o .F���.�( A335�A���-P� � �i"�+t*a�P to>� ( Mur�����1!kp��� ��6zG*&7c�� �9hbeE� EA���e�)uZ9ui�!f�;6EB# ��.�FH~EL�APA�`"�!+ � �?-�B��&�@quj&V{c�p"�li6��2�X{.Zof����LZambi�r(South AfricP�Ja ��BRt$s9phe�_j1R6z�^ , [49ua �4�� w�Q|!����,��"p��Bp9. �Pg�y� �N��A�owGXE`5i�. S�T�Q���urw���� toBw<�E-of�.�� a��&�f�J"I:@,��`a�"[ �1�t'nd� �M��2�7g�L3��ehi9� Bl&;7�H"}5in D( � ��h�r�g"S�&*>�*l f�[ ��@F�>. Ayan���of�VQ6g*�!�@�� E&�6v2u �"Dyris ]�%�at�)[Vv":x!u�� to!� ���ees�v� ( Mo�D>�s����� � !9".*�(%@d"�qF꤉ w*U�N�perpe��.� @ ��*�T���id defe� ���H�!ulds du��!�n�l-6�c�$&E6��U��)!w�*�+� -���� �/�93o�`!-� ���P!U2�3�� benefiG�tooik toward�;� "�t��"����ex&�underlE8�xof�"6&!� �;Q�!zeU":�-�!mQ��Z~�tn2T eavob�F�A�-@~��� &��*ee��0tO�\ recF�V�D !-�5�!���)p�.i��1�ofU!"���t+�5?��s��DpJ�C�-����MQ‘A�ing%�o/F�ive5�m�y�"� �T "!Z���.�.J-it� >� ex��E i��.��.Fer:���| 1�FIO&L4,� A��]�+��D*�#><M�aqQ �-"&�n�[)�(3�!�2�]�v$o:k icY��Za`�i%��K9G��oR ��� )��6ɋ!< . La$c��>�"W ��&�>sh!��T�d��de/al-^o�~t�3 ��""��_sh�~2��i2S @,�%� "{G=Cs2��?�)d hs��pO,z�A�.�4 he E�*f�In"�al:iew Bo�4IS60of/ SchD&of ��,Research Eth�� Commd��Wr n I>��"N��:�I�� ��5mProa (�n�E"-�!LusakaaW 1994!��}��nt� _�aR��counse��,"9�( itor&)%he�`U4%E coha�ng� sexuh/>��VDYr!aUf� -des�� else�\[4��Brief��dis�R>^ enro�����UF���4A�&v��v"� ;�1�=1�p�~k+�"�#v&�,:b5Q Mt  rece��$ [\e�=f)u ndom!&Ba�m�Y81,�>��!��a�*�oby ELISA!�"�!��v�u./��m�8I�� BZ58�u)qd��2� � $6�% �p7s�9Ŋ��h�N^ .Vo�� apid� Ksj�)�7�QUH��A�4��PLNl�� ��"d u� E�R<� AH:coK|aw. * Z��-��tiret�7���apy2�vaτ����o��C�����nq� ull-lCgp160�lus��4.puA�nd)� al Nef co(9s{� ��A�=;ic qof\;ul�<d��)a��oodaKonu�1 K ��OM�N�a �7lyIm%�)�env�;��-�� ��ly T/A;i�O� CMV-�e��%`!� id p�31-V5Hisھ! KmC*� fuVrAXp&nya��M��co��Oa� Env-� " B��!H�( SG3Δ���to 29"�[45aS�y-a�hours� H "�K�X*ZLnA��*��� �p13.�p睁{At ��^T�.� ��� #���&ԢkT!���A7�]ve����B foci��NAQ�[o nǐsL77�'E< by L3'Star L�� , In2b���V TX )(.RA0ABI Prism® AI��'{er 377XL�,Big Dye™ T�o�R|�Re� on C�9 SiIhKi�Nao����ed�c!.assembU�r FG�v�;��ſ� !�`Se-Al v�Z0alR+Ke� p��min�9alignc�mB6�=(Clustal W v(%8aNybor jou�Bfi Kg"�N��BJ �gap-stri+���{�sltee�[�� reli��urv�! yrI!I8� bootv4p&� ��<EwrV%�T%� visu�4 1 NJ Pmm�ig��2�i lHige,�' �Q���hR@( http://www . hi�lan@ gov/ ent/u(/HIGHLIGHT/"�,e&htmct�'J�1v�j��ee� Genb�� a�x�h(s GQ485312- 44��Pa2�N�%�ȭ:"�!�"Xa.a�8�s�R^�\.[�%"+~�E��)�a�!rTHrAazM .m��S&U �BL-N�pi�al�overni�o�@�s"�5u���ach ��u�""W�1�A�[�%O heat-"�֡Q6� rc�-�1� � 36��ֱFKhG ņ��aʰ�!.a$;5�U�A%����X�! ��us-Ab  ��Eg `to=q�|R a<@w��ySA� !%�.� ,lucif�Uc1mՈ"sQ6lu�!G��T&�j��Be* inr$�DA�,�!{���)�!e"��al��\Per�'Qe!*�!by�!i� �&�����m-�Q2C:\ �  �!�!�a�no / <� BMM6b�a(ed�|�1u�V �>"&�=A)~�MG�oft׫el 2004Mac Gr�xFuw . Ea;9S%5&x6�*\��eXdupH+�fl%�CL�ic�MEZe kG�ja�'A�"ށ�Xteg�at&�&n .iB�y5J?��A>�jf�OaD� Y.MY�#. A}� :� �/..a{"�!t fragl�q gk!� �)r or��-�O| �Env�X�OrAL�b*)�uv P7i��1I�t%Z . CoU�V9" ű0 by2�ino�� LB-AmpF�br��[ �����L-pI�id)H-�5��QIA$ Spin Mini� �"�A���)��,&�A.< dՏ �.�LMed"�K9alsx �&��e�id� re-)�TS%*A oM�:r sca�' l a2�f�ku�ock�D\� s&m ~*o t 72�}s!���:�*�A�sp�&�*#�э iquoA��Ow5 SrDr��<� sto!�at −8*O��u� ��~sۡ��b"�Tngš-B( ̀�#5�s�ȱ3� X2}�E )�5�E?$e �F �! y/ M@sr }i=�5a�"�C,aw�m�d5′-catgtgtaaagttgaccccac�(��nt 6577�e 6597K:�Latctc  aggtctgaa>L 7646L762QJ;�"=m����tgttacgg� ggtaB� 6830�681��;��dccaacaatcaaggaJ119f713f��d9d�`�� agagcagtg�t�gctB�755�7�š[N�taAW agccA$tgBd827%d82 � ; HR�tgcc!c gtgccttgg>�803805�7��6�"��� artcaAtcaa/aJb55I57�>�{�;2���=A�!qaaa!�B'655�=r�c�1t�9ctgBI76)� 7617c(�!.��5V���.�!��iaAmatF787��685 a�9E�aa���B>�711e;713��^��` .`)�wbob�(�����?%-�G�&&g v�~r>:*�"{ ə_!a�ne��� x $s "$Ju2�G�"� sm�y away�J�i �� 6��f�'(��� "�fA ����0��+3&�o{ E R��� �Y�!�R1 Ka4�Ks:[ q�,a1"�u1�Z.�-atgaa7��tggag&BW764e� 7668jRgcttta�N�t��9F;5m;55rS6&��a7c�F�|a�\F` 6831!�685xS!\N���*5F���uFu�a�eatttctFr 7118! 709!�;4�]��ag��t�� tagtN�%q829�qtc ��\ B�75��773�W;������B�R t�t ga=B4452e4450�̅�.�� &* ��V�e�1SR. &���� ; 35 � 1�� , 52 to 6 �30 >5t�Bmaa졓�  �er��:B <��X572°C,10 min; 1 cy�cle of 72°C for 15 min; and storage at 4 `. The amplification condi s?Xthe target domains were0same , exceptextensGtimh �Hwas reduced to 30 s }H25 µl PCR mixtures�,tained 50 ng�8each primer , 1�8plasmid templat�T2 . 5 mM MgCl2 , 0 . 2`deoxynucleoside triphosph 9!%1× reac!� buffer . PfuUltra II DNA polymerase ( Stratagene )�us �r[�(blunt-ended�%x,cons , which)ZDdigested with DpnI!3remove)minating���lgel purified from an agaroseus8Lhe QIAquick Gel Extr �Kit (GEN )!tor�ligI!. Each6�fragment% then 4) s�L0-month env backbonedproA$ a ch!�a �T4a�s!pH5 U/µl; Roche ) atI� overnightM^2%�5�MeL ( usually one-thirdAh�volumVA��transformed into maximum-efficiency XL2-Blue E"compet!cells (AR109 CF�g� ; st]3so thaiC!� �did noteaa %�Y%i� entia�� ��ed o�,LB-ampicilliI A�gener%resulE`inaktoa�,colonies perJX(. To investA)Pe whether individual A�Do acid sequence diaa i� ribu]3 neutraliz �Dresistant phenotypa�PCR-baas$site-direcDmui�sis% q�intQin.��change as described previously [24] . Briefly , a set!���.e!΅�had ei% A\ wild�or��5 )� Mse�0their HXB2 lo��@s are shown below�G��ubstit%L��tidM$re underli�a. All�nts��confiE�by��5Mga�A0 �����NE�. 1 cy͚95�zŚə18 s!J5�$ , 60/88 @��` 7 �25-jg63Rg5 !�Jf�U�UHFe��U,)j�7%[�/,%92�~�(�;r� 10-Gold u� F�5�F�2. Half!�!Uti����R�����E�$185F E335AA�war�"��x: 5′-gcatattgtaacattagtgcacag0ggaatgac-3′.Jreversem�JtAccatgtct HtAttacafg J(�nt 7244��7209 ) cI459TV�c�a�tgatgg ta�agg� JR��N<Btc��� atag J�610�575�S463NZ�%C �t�a%h%!2a h%� OR�-Kg!�tT\� O.�22 �82�V518MV�!U�ga%!gttcct!ktt  `� GR�� agaa  UcMaSF 795�<763 ) 205F V1mutZ�Ac)�!!\I�Aa_FR�g!O%�A;t�aIc!�F�664� 6614�2j�i�!�tceaav!�1� �HR��0actcaDa!�A��gJ�81%�677aYHuman B� hybri �@gI ��� viable zen PBMC8 ples m subject �� on a tocol�,$EBV immort& of� iph�  blood �sf� 46] , [47 8]�isninclu)Npre-sel] <( CD22+ , IgM− D A ) memory � popul��s� �cul� ^  mediu! ppleK  $immunostimAory CpG�� nd irradi%y allo!�ic)q,6in [49%50 1! EBV-Փe1O�-�scree; �Mab �"� � he)�� Env�n boundC �J�a�it��JF=hd ide-rangci�Ak���"%:�tQ�d�maintena�of' eticx��[ CurrA� evid�q-\Mj��)Ammo%0}C some}>1re�s�Hal��Del systems [2]–[� �l!�6� � ome-!*]�i-��re� vely limin [! particula�>iN�,. One key qu��9cer� e��o��,ctVn�!-�i� -Sq[7 9+For ex�,itEF been1�� ~major�of adap�e��  m ccu�=�R�w�new_?s@4have fewer dela0`, pleiotropic��[� 10]��see [1E�Hal�I��agues A�#ԡ s� many��"*eE2��thi�:h,in house mic!XalthoughjX:B!LexF��)�g. Moreov�si Din Drosophila spec�5 nd vertebxs-n��~ ,�F�a7  a���l���%:�,�Zre�m��ualiq�Bn� N!byon�ze marg� I�12[ Compar� �N�s���9H�R6- iGy�er�C beca!�.4 hypoli� ae�Q� } N5% ofte� roA/!d dupl��-is-L�[13e possib��ea��to����=~!Etr���J_JA�. C!�s�! i+edi*  , Haud� nd2�14]�ly���{��%s nine6� Q��.�approx/ �| � ��I��FoArabidopthaliana �[ 2��E,>(uch smaller� �E�mOo� eBq�of2|!}�.նe,� ength7Y�V  ]�iK 5< of1--%5ficD^�nd%DJ R<rs�^��b �. Whila�^�is��to�y betw����= � ,a�� va. 7aQQ Gen�"F eqlM5�� d��Tof �9ofw$synonymous}�&� Q1i�ny1��T���)[182��Varw ZstZ � coul� f�"cY�� im$.� �duN. organism"k,�itŜs] y M�in��yropert�oof!�re� [2��6r.���hō�_misfol% is-� �E^�9p�un�tm terf�s�� ular����Oey "� .�)Q[23)��Regard��M'a ly!�m�ve me��ism���k"� cor)�o�I�*� I�M�]`�gh 6�Mx�� .�T V� ,AvreV�^8or� .+�&�!7 omic�hm�.��� i��%out��!um�q^!,!�t �V��q� � � outb; ��. C .6�� obx tņut�AmembereA N�� a lL$� AG=VT( ( Ne∼600�# 00 )�A0��ow26 trucB [2� [27 We&a�.�U�M�A�y�� � orph�}to�o� m>�R>�of}�.�#26con2�J��m�i inB��#woŬlement69aches:t"�% �4McDonald-Kreit�t� [28]%yc alyA��!�u�� linkn o eage��fia�6` [29!�O*�dem �gR �:arevasAGF�,��r E + ey#n:�-2>� i��Q��-or��A��b  volve� ly . In a�?fin�'�V��.g��"�!�owF!,a��.�# F�dr!s:("6 mole<*2. W�pd`��>f"/$:%26 ��,s; ∼140 Mb�Qassem )9�� � *' E� nor�#$n Greece u��le�' Illu!  GAII� !1( T%S1�� 108 bp} d< mappi,���rubkre���MT [30] �10Stampy aligne�j��=a5yg�H34 ~�%)I it�GenC% �c� �Sp me A�,Toolkit's Unc("�$ r [3� Af=filte�f qual���depth (�M�<,��" left�+ ∼2�#ll���i!��) ofb?�le*�$2�ARSNPr5��. Sb >*-�Zt �as 0-�  deafA� , 4Jj&nic��UTR ,N ooge &"!�annot�f�|v.�'ave*")>i�o� V equival� � ��fi�%�exd BFfT%!n�&-norJ&.B!,�aQc+ $es 30–40�(��A@�@ �"~,i`te-I: � only:B1 Z E�Kres,du� !�m eh peat� � sXc�/�+a�:< pet�� romeric��( Figure�?C:o|("�Ade�a 2�s�(,loci ( 257 S�(r-3d P a��t�2, [3ea�J&@(� 6t1�})PH( Watterson's Θw ){1'02211re"^�,xcn�rej�i� �j}I�!��%�� �Djima's D = −�51�I(*n�6Θw # 02� � i�Qs(>-12"�E�sl�,ly� 2�RhrmUBjF��d ��x,iBF�r*� ly5!�"tS FJ� asb�.:� 7-Q��� Ef"�JX5EI%�1����$ )��|F�no.v) �!= �stn|0�&. N �j�neaW!AT�Q2� elev�"on �*�!�imi�toK��in A .A)�[3'.�lyrE[34A[35� M�@ago truncatula [3F ��i As��rg���c ob8-�2"�e�,���:?si�%Fg �"# �dNeslia`cle�5:B�B��3error �in�"��1�� "� �� �E����%�ao:$B�� ill��aca8 �  "B >, %.i��]��%A���gJn�r<a!e�of �1g &%��of����e denj[%�� ቩc�RU appl"to2�[3�Fu� �,�m $ dec�.��+�e endra�6?po�i; �� m�r�AV� nd/o�/v!�� 6 :�recomb�3dutI�=B��iC�X9���xp"-bUon�N��šp�aqalD#erl !�2;Q�-� 1�yW<&��d�&�  h[ ozyg�$yisli�$windows al�#+19�(  nuSQs�����t��hom.jdQv biig al inbree��4�`� 5� >� ��1]FlocalZc, n�!ch9!�@in� s�I is de]�5� -*'t ,� AXE�!��of� ty-by-des�  ( IBD )z���l� �,�2pbea#self-inU tiblA9d^,r ca%'��A���_ � :�=�*�� �o� bi� A0��' lle|+z�B�� �%�!%t�� all%91^aV�ra9!; n di p � a�purpos�:�y.�*�ty!�6v�4 f does�hq^��ur��cluB%� Q�6E�In ord�#oAnJ�'J�ng��t catego�!~h %Sus%��*e��T( �aX 7 scinJ !>�`!�� �-�y a��f�5�iba�͜;@B�*( 41%%TO�,&� :a�,&1 : J�t�"� q�V>m∼55cs6�)� A�����%�N �s>z*aa��?'Ÿ*Pofh-tm�%Y|45!"�F� !�a�14%:* !� �nd CNS/88)�V%�W*�I~n��c)Y)7 =&�r�.F�&�<�Ӂ �%6F�w ��>!?e *�a"� 100% � ,"P!7"� UPN�.:� boot7pp�s ,( o�&$ sig?cs)su���%<%+���- ��V�{E]Apf�c� terv),�+1YE�9�I�pic k& b�#� B� at s�#�+ j;,�4]�pl"�ypiZ�/ak�� F o "� RM�t���4!�F.E:X\ 0ٸafirstE last�@bp!m� )r sepaa�ly)���middlX .n!�!1�z/EY#.d!beR�,��68��U9!IF���)�;�*e2.  �5�� b��r' expl�&by�c�Uu��</ A���&�z�u'!0T�  � �-E�N�!(�-� � M�a��.�!�$�L lack!�N��"^0� :s��2�etect%���Iq"-S3A�#.&nN�to * !)V�:W)!�"&�\sn%Gz��F����p�B���� �m�)� aRNN � ( 28 ��r�Y_1 6FU1.RCNS"��B�:toR&� � HJ-5��i}Ea��%� �5erRd= 6�(1 )-�8e&w.a�ar`5X�VNteRg:�"X �sW%Fw�!�B3�(*"f��)i�W� toga�j.�-cl� 2%�O3� �U�W ��J��*w wi,�xD�+>t typzs.@ 5-S7%�Is29 , about 2� I�!��: �,"=�"� N~E�<w ol� !��ic �Z��r!06r f�a�L=8( agre�q5aCM�Ӂ�F� 53i+I�!|8sta��-A��RNA� ncE)�J 9��� �A.�>�-&�)��  Ik� e���C � s��"�e b�c �Rb. ������ ��5ve�ittaB|K�'$( 155 segr[ng ��9NH5theZ &��f! , xs�eG�"� ly ( p<z0!�%�:�)+HJ�'<<5�poo5 %�L +j� !v�# /AV*� �Aͅ�M(s"6)$-�RNA/ |=[3l6Hi����*1s-�!(!aT�4a!�3�x�!�2(*51��havHtr�:A!�% olog�M�I. I�he"�s.kU*m�(�Io �!!&�'fix�s�&n� J�) ( α�1{R*ω!�tak�i�Kacc6=@-cA�lyZ<.Uan6�J down(��do� 21dB g� ���� v&me�!of ��$,6i��panI8 ta (kA�*� � KsՌ.i!�N ..Uis Ks*�!HD. B�4!W.�&�i�a�9� )�6� �5"81A�c�8�D���in unafX*%�focus����J�on��� � �� e&u��^Ca� a�k:=�*fm1B; α=�41!�2�!�q=R�8 W!�]3s�P�L� �6C; ωw08�SE!�M%�91�ev� c�J}e s 1B@1C\�����=�o>�=��b?6� �R.e�ic � . If �9�| amiiO6Pg*�Aeitsk b 1j�  'r�?,�7�J� 6�:E�e�%�e�k� 2�-veO:v#�-e�OIvs��sur� �=⹭[30;40c.We <L�R�+ {by measu�*A�6��Bp%in��iN�(&�c (j 44�!as ‘[�/�’�!�-�+lI 1 kb i: �W/replac_ ( nM�67137A�si�)"83 , 8�&.?�\�m.>9>�2�F�6`was�u��L �6G�492�6-q� 2��i�� robu,A{7�=-��2�I500l to 2SS!ea?aS7 -tai� As� �&edF��.���!!A�� "d 1Q~onNRQaBA�.���PR�?L iXaby& %",��6q._sqf.w�7i�$U�%��J�2N�"i:_;BjZ'(>XtmYs�-z�A!�2��QV ��2B%VT )�l%�"G&2;���TT a�!l����j 0�LVB/X �e��&vI��$inB�>1!f.CR�e �3��pE��{�+ec[CsFism4rtifac � by=� �6lu� 2C ,� i/�?�/AHA alog�:u�>�1�qRXis�ulle�D/ ![9s�aKBM7wti��spRd.A���3 d t tas�H&� " Inst{F�5�B�gYS��2!a�NSf�e1u[5Ňw�K�d non-C e'I%�f��U1��175\� �@ing F�a6) ~�.��N"s9nto:�F�U�S:.. Iw:�! why2���)�'U�!�2�;�<�b@A� �AP sca�]9n1N,H -scald� t m� sp��L�AEۉ�)Dca]!�&Fc4�=duY5.�fi0 ��&Q5��:�>�J��U$�V�9>!R.6��fa ��" Y3�e��e��%4�lJ�B [�)�(:�*+JY;�� clos� oc�.2".|�B� a g�&Z�/�%�1�r!�� �A�aa� blem埉�is7�.�A�R���y�r����� saexa,�]5�\i�y��� �LA K=rMo�Zo ens(4�N��.�N�8F a�A��^}�6��-��t�8 R�1t~!l%F��)6�F5=E:��-�5etNst� J��xB~:b5�,(%l.7N�4?6|BT.|B�J0aMaN�ݳ�A88WI�)�A�/N�B41 , 2� N��0�� &�R��}E�ս34 W*BaA��O*C&E'^+Bed��es �"�e�b �bl*P�@0a@13B�.6.d&e�:so� mep66�E !�Hto9r+9�"d %1pa �,b8fe2� �F0” , “mid-Blow !A�“ -�M��WRl!&qsmE� 6�AS'12�?}R%S:Q42N4=i�Ax��"e!P.4���FP"�8> , dN/dSa=�gy b�>(�51�/0"$9� � %2�467?u *�I�D�&PE��A�a.�Dco�ctp2805an.i�  cA��0�H���W&��*�w� ���6�.�Gtraa)�i�.f��NdU�U. R*Q.^��A�.�)3a��+r skew t�3*R!J~)�"0 Z�nS\*� *AZ�.� ��inrEj`98 . 9!�$a_Z�97 . E!,I�.� 2J�.�M����da�J�V%V�Vv�&.9 r�U (�X�nV16% ,< domi�XE�[="j���4� I 2QinV[o�@V�� b�u�'bL4� *JU&5 6oe�X.Kn�'i#y�2, i����α�.ω�>�/. HigJ3-��|�8a��er vaEhofZ��6�1n��4,�|Rg6�ω R��� !"��R:(}:I1��low Kp��h3�NLe4�J"�2��" �%@Zs� 4B[A"e F�in!)g ��F&v lik��� ����Kaz��*� $:t�d 6 &� e��s�/ix& �J@ %M���U.�R�5" "k6��ha"�a�mDch9 P�1��~ed . I: A)tu(t�& dvanXi!�1u+%A�d6�Nr�\�:r"E��,y*�L2P:#� 667&6� .X��s&aC.�>GZ Rmt I�A�� �H�Ging�\!K�E!1c���"1Pc>X&5"�9 >� 'Z� xb_� ń�/.�"�,��i$*�B��(knowledg��*iAf{ ^/t�o�A"U)�b�5"�>'�*GRs �*de.�8��Gb�$(��`[j �Qsl� y kag���ilibr�b�Źpo.o%�Q.AFe�� a��+�traBd ory � ^� . Softs—meip�h"� ly-[ 0I.~MH�d0ion-drift bal{Qf.AhmultaneeD�ipl�2e� ;`s%�w ��!��"�'. ]/ ]��+o�,�‰(i�_ ���=B� [4�RRd� Ois=y."�u�>SQk(ts~ Ne a, [�d6� =!)�i�P"?��}��+oly��"tsa�o�W �)5Rwi�0t2�2� �d�+� �be0�A|of�8a�s�Q�h:( Gr^AN�g�>�M�b##!�Dt&XcA'misaCn? �(cfCc!!GAL"}<�@co&Y;�*#preLIce�i�{�AJ�� seem!��3 lict%p%)�% �E��%kTa�F�"2&higK j5O J��Cfrz���psh��)�m�0�l!`� �7AAJU�%�r]e� � U�or�AIQdiscrepaks. F�a,*D-b!Oin = ��H9;i&eg�i ��,��\ .��?etu�i&%� ��.�$��A.�Z =�1b . Se�)��&r2IB4�� "�_!��JT%�:�ݲ��!"�1e5Bimpac�el�QM��a�X �Fjz!b��D - J� %�ge �+E�!��F: �5a���1`�X[1$�h5�V55]E�3!p'!.�8c�Be���6g �(Djb�xI��.�j�":�-!�vI E!q:& �i�Q� ��;dN�b��� a�irb�dw��.>�7y#h � ���B �����v6!'&!Z�Kk���Oa�JWYŦ g1�.�Y��j�E�R\!u��R�m�mi����?�1KJMb�f�6�Y6-� Qa�0���i!���N'J�T*5AZ�Is1,'�)� >"� &[2�' P">n.AoorB8 re�enA8a$s�o ered#&]0]&#�O.� Ztwe�U&{E&*�.geograph�)nO!�ET, plu 4thirtee�z ~) a1 �z�[aa8@��al2�"71�. P�k�gr x�&Bfnth": Un� Dof Torz�/n�cF!��P�j�u� lned CTAB��p. Librq0p��r l#QRn^Uo�a�E(�uY@G�l, Quebec Inno C�Jo~McG�.�? e:�Ufv�{�|-�� �J�q 3 laJ a���ad �#tm0�U. Leav8(2�Yj-��e �nd flash� $r!��"-w�W)gQiageSQRNAeasy��+1(kit�sB6��Fv> 6�V52%J=!$ ,!�e!�n�35�-!l=,reW�e�1q�m6 se!<22aL�U�L�1)�YW�:� raw��Grre�<�d x"(� "=C]^2�W0��� e��01�'�E�e �)��:�W1 .�3)|default=h � 6��Va#-!>�leHre�dmK>�W( ( GATK ) vw 5777 LFr�WC�7 A�SNP�JU�nm�sY9X<r6�param3L�Jr:-h1ASk!5UBng%.�9m <�!�89.!Q #YR�'th���;834A�o �a �fW9sm�;�.AP,��~UQW��i�>�m� i�x����]F� a to�L�6AX89�B6fa�w�0und 82� 1!Iu� �Tgiv�g 5d�� 00049!(hre. disJ!*M _ t).�7�Xř[7�)%�!F � "8>=EA ��5u"w��Nu� a�V�FN�� �-��X%�s 2o v��e� of*�NjU= T roP29aup�7�u-[9n� �:*L� O�el/V2'"�R �H&�#h^-i�"46yt�"Q�.�9-�� \ �N�6�i4VCF�%/nt ��5�ea��Kif�9 )Ku�scJa��H9�(�=fr�8'�q6W#�(�*� 3&I,not 0 ( i . �H‘Dels y)�&S zeroKVor ( �P`y�'� a\�N?&�2062O6a:A�_N",*�zG63,e(��U]s 1–�1%A!$��DEm#E^6� R�ha phX$�)d >ih&v)�of !z�+l�!�� Vs�X�.Q94J \�Q�-�m�@r\W^!u0 ���bif`3�I!A[� a!�"S3 p��B o2*5`�is�al *&@e*qn�#eriXQ�[�� �a�6\�9w �A���-aL��V4Ii� aigh�i� )�8 ���s:L<5bL:BRFa� *i*SAU� ?f� �I�Hp�=�0!f�m�z'313w�S� en��$2 FIS "7 SAX�6aF26A*5 E $flagg!�s�Q. AS��ano�t�!3!6�n5��DfurE IUe�<; Qd)g��&1 ^;�Z23*�Ts&�Qa� ,��S*BR�<*�)no! /! |twiq�Cs��)�*� n�%��wo waybQ�h � b� �d E��2<&�;:`& zKZ [58] Ich��� �es=Q>$"%F� 6Hz* uniq��a�z-a�O"l�5�$^SvC`d�%re����]%�*�]� 4� 4� 5HeA0��7 �TE�aC%rat> �tae�{�!If�5- up�a�dE�  j 5��6�=Sua6�Ginf�ng.0��>�EdmH>6� �r�#a s�c"d~ Q�:b� �c%%Eb�6�'1d�&�r�MTG��sI�-�j\�0(a?Wp &�@l .�:%?!�: ri InParan�c[59�]��6x< pep܉�)�se�%�%|"�eDiTX [61^�r< se��|�@� 1F!��F-ge \i7�uP&4pR6�AhI�1�e� �PAML [6}bZelm�ωe߁���9�a�B�)ҁ�o�� bran0ZEm�a *IC�o� � [~�' �*�YI�svV�J)Z%1se/u!Dv?K� cord>2>�see"% � �.%S1R >�RwBw��n't�_�tag&�!���H&"Dt�4.�S2�lsoq,��Hel&�A �"A �h�!�red:%Efœ!uinguish*�>0�%;�3IS!L*ar\7� s i�4a#!�(JZ���!lu�Qj��.�!�]Ttm gi I^%2Z"R�J�>*cN�&-O�c� \1)i�Ib� ��:�� �n�#ob2 �Ca�� "�!�m��,M�a &�L��/��z pipe�[A^�F�, [63��i0. B��.* �1����!�x(8 � "&M�ђ!l!PhastC�3tJ�y.[v�H\��P)��.!�% ��=�*� eto ded ( >12��)�v3 tinu�� �p� 2ha=ZV�j.�-:S% � �Joint�me:?Ce'Z�XG)�I *k]&�.Z�[s-<� �FJ�)�$q�!�$DFE-alpha �, [64]E1�qc�.- G�XJn^αU�]F' �Mm]�)M�� broken up�B1G@1�n6� %�"%U� I J' !�8� 95% CID#�O �BF8��w#eJ pg},������P�a+p�J!�G?Z�%�*� .{%i�aNH.� in*�I&2�I-�byU� �2�.50s#�!�aL5 ;>��Fsu)�.�� esLB�!� 6 two-.�A�8�� ,�M3pI�)�I�he�s� �{4%rt�J�%A� A dZ&" _^to��y�8an*"1DC le-*� i? E��� >^hK:� q.% ��<.���V>..�+T .��&���>� #*� �:�.Iir.p!Pwe11�&�7�� ]u.�!g:UG%F/,J�%e����Ojs�a�>,e� U6��)^��)Zs� �eY+(mkOc�>�&R�.�� N�_ ��O*�Gg,a��'(j19AM}Lof�I�f�%K# �F . D� !n/ -��� ��C�&0!p �:H)�" �;Xo�)hof^Fbp�@�,EO�E�ptenx4�;Eإu.� nM��]�8�zg\3 matco1�wd� Sa�hX@I gG�X-�m0�x��*-<*�:1.�y��`etop�bottom�P����P�� ��^��XH� ndezUZ��-���AMnull "ǂ��1N mp.I,a�J,.�sF�26�2$H� A %i-�,g:�� ( i+� /!M+2� 8i�� �mq{=;i�}I�n��e� &�.%�Kf}`act��nI. NI�mdD�&>T�H0� c"-e~ Ba(2�Y�%�U �1�1�N �'��/�4��A��1�ό}m+�!"a "� 6�$�� C:�;,>�)tBw�)�����^ZA�<t��1H:�:ud6�F�mY�R6le¾?�F<N.&�-z��&I 33�6 629 , 531� dc 10*� !��%=��726`F774A[3�552��33 I�** + is6�"�w: z .""&C a \ To��#"�� 0 [6��!�A'� �bA]�� x�# Z Cuffa�s]�]i"C/Zuiz�5:�?by��+�<�l&H?�-tur�/S�0of�fS�v�ki�`�v���Mr z+ ��( FPKMvW#�ͅmR�?��A""�!10 w(��wJ. -.<1 FKPMA ", e�~ �5*�$��e+7Ac�9564 @e��h m8�,�"?-��64� U+m!>:�*(U��812, mid�@ 3< –1=56"b @�y?#7$!, $  H, 092&ae��6A�J=,�Qu*� 6������ "0">3 � ՝��!�J�S!�-�.�V�R��&��e#.��K�:��,���I� �=�w2S� ��8%�!�R�,.�EpsϘ$-Barr Viru�EBV�!����( B-lymphocy# n prol�� bp esk: ish �n8"��!edYgive ris� �an�W%�-�S 2EBV-eS]a�� cripRa�|� EBNA2 E8 �A ��ad���s oria�Cb��n̨5as�H"�%�B-Ň fa�nam�/ EBF1%oRBP-jκ�+���-a�*/ ˩�LcL3b.s�$W y�$�(�^tE�!umo�{�. 1"t^"T&%^)i�&-K+�Iw�A��A8�, �1of�� r> OJ phys��x��"�!!u yIvi%���EsI�w4I�d� co-Op��by �-�-��C�n�j�N>�$&u3�%$�mq*1!Q�E�"�ODq�al.��xf&��of �' �=�� rapi�"teA��kFhQx . Bi-�m%X!>sh#,depleA�UM�&6 Yc.�sd�I9R)d1� =Ral)I;facRAA�wi1i� ![�MdI1�3e(2�Ntor($6�g�pr�/mmaxne5>�.� r�6�ji*0hW�tsy*ocԞE�^' �!�K�p`�l�rsm.�.�(Burkitt’s Bma , naE�aryng!�carcin _ l��v� Y%��i��up ed [P �����";Ga�"͠e naïve5��y�� ong-Y�B�1 ��Sd%�V-��e.?��>�� ~wps70%Q! %�tp��>z!��!4|DaZA}xͨ ,�E�s1rA���![e�6zM�-�0�egen Nn ? gRal �&ƂiY [�6!  pZ�t�1^tUt���rmplexu�2�u��h ͠!��?< �d)~e�-�@ �zso$�coordp'��+ �H�ngeo�<I�\&n F 4!Y7teU:t�f)Thu� �i5�e�s1)�mb�l�| ab"�� norm����a�-��)js tm�[s"�3�az(�6oat�t�e�%`)s%L6ʙ.�qis}6$Ao-Ava�C��1Y�"e fs�C�}* ����.3��q�a8!H� S!�aA��d�FaM�6ag dM�=i.�b�cha�*er� �ag"9�J�:A7s:�m�N.� �� (�?3 edJ , C� Ig CSL |�p��: A�enh�!� ��̖e�H( [38] -^vie�"ݗ�10]���ouְ�Eih n�����gn,2�.� �[A�!��[`Ea,fԈ!K./�+!S�el� NoQ�:ѕco-��=F 3��1s%� 7 +%�i�7!�e����/K� ��� Qdb� zwAem)e�A� pt +�6"M�Lamo�v$9� �d�B a� �P?�&loc��A1� w.asa@u� g"� d .�E�m2F� 1 (f ) )�� AIaupaSAV�J��� 9Y�l d� ty�&Z !�ah�Ao!mpro-B��,m��&�� Ys�2�=gra�������2M�A�1V�/aq��-�in��&�#�� f !��e�v. B�XFsr 6� y:�)ѭ�pla!Hte %!�rol�. ���A."�6ir5����!��FaNj�@ri!�{05�w*_�I�is:�C�x� !�*��Q7A�*�9�r9�.m1 .2�`6� $i&~�Z�K prim� c!W� �#!H`A*U�[1Q11�1�T2"��F EZi��n�JN�9  �-� convT, �)�lyA!Ive�!92{K�Kcognil el�˅j����d��p�s�%4M enviro�%�*�q���epS �.G���^��B�6h1gwr�;&� 2�ap�K�u�LE�ri%zD�@*cA.� AWqC!e"�t�-�)��1� ��nE.=d 6��. Ey@.���y4/o� ה͆o� ,�3y[{ a'��N�5Ӂ�/jE� �MG�J i��al ��h���-t���q manna�.�`�+-��U �R.t� H�.WQ�%��b�5�� �/�"5�"4&a�F� �*m^���e<5�� .!sƇ� �e J ,����])�kE��2!�#IPY��FG ^sFf. :k��Llandsg�a�JD5`)!� ��%�two�6� H%(�-A}a��y1�.�B NEBV.r �Nu�z&��qa��  ( LC� IM� III]*� �3 �("�-)��>rD� m�pBiZ-( Mutu I�!��~�|"�*)�igso� , 1B���CWw2M�:[h<�:u�E��e�in!#aW�*"�F�in��5!]J� v��l��� �6ach� �B6R�L LMP�LMP2A z�7r* G�En nor � Q�S"=9 u:T locuE�-�� :&�cM2LƍV=LC5I+H @ YA Fig 1D��1E� !>QvȎric"< �N� EBERH OriP)o��k�0ch &�6"}y��Υ�I �?K�晷eF��{>�at>L�c{�ChIP-qD�:A�'(W=\Ю�E�H'g�Mlu�:�]�sY� ��ica�E� �( Keme����/ Ia͑("����Q!| ��XP�. N�2�'�s��.�|��uonito�� by W?�rn��CMr!T"�|�q��1�F�M�luI�)s��;?ƏeE�un-lya��v���!l���tJ#N��Tv�:e.r�mo�UFl, post"�6i��:� or��_�vjo�s��yi����1@*< .��Bv�G�.VMm݈A<1�a�9� *n52D�=Tac0 toge�41�"}s.;SB4��Zh-�  � �JM�� To"Ue i��?# "� :N�"3�F��E��� Seqm5AL>0l���E�^3�N)Eb{7�\�B �;?x�(~ �9,�A 2�ab�"a� '�U�NX�K_T�EA� u5b�6Re��)-�Qf- �leB� ��o�ur@! rend�pĉ@��a�ofI�J�e�"X�5J� ea�Das�cx�M pl���qA h��ma��6 ��M| �ଡ଼2Ci�pan&I.�*?)5� C ri+!!� 5\6��q"Na�.�%e�aeW*�kE��X �%�!��r� �6���v�!�b�l)!�N12���ri��to�� a�iIclu�Jx�M�#�ab�X:) ݾ !��� ��u�;E�,/wK ��F�T�::� starzF'�)5[t�7x�n3N%5g��:m*�by��*�2V�. S<=��Mn"LC*< ���a��ll-.�1�� e;.GILFHESm FCERv*�ICA�K�zA�!��R)��ءZ��B'fL �a��ZNF59GmiR432 �RNF144B���&L 1)� > 2F� ��f-U���N�m`i&� �Κ� �� II�6� a� �t� g  Er����I�+EU2G�BEEh��)vA��%e-�B�qѡ*7m� �a��106�%z���!�B�x>vIx �E��F2OQ�F%kn�pA���nga�rI � �%}��v w �% II%�� . Na�t"��tp�V F{6( f"�� �AB%1,D �!icF�2�i�r� appeaG���j��F�M^�(�M2�y *���i5�1���M��%!^Yz �M � ��$o,ur�*6�!�.q%D� s �pub�)NTF"?�S NA3�w�LP�.����oI [\o1�,YV�p3q ���v;HtifɌ�5o{ eak VbLR/�,���� *u;m[�8S2� � !i^ ata�E�2 �u"j��_ �>15:�%j%��co"�' =vKV�i I� �-W�B�)F� �Q���ue��tB �+��"M to1vs�Mn!���(�a�!�!�a�Xt�:a� � ��� ���I�2�a7���I[-� !��n&Le;���F� !��4!�Q�2 6@-�5�c24 h�ne:�g2 ��ef 3CRP"q gbA9�\uݙ���VjH3K4meL �H3K27 ��+�^t)Cexi 0��6oV� BATFQJunD N�,"tJa��h�AP1 �@[GAnTC��!v�����"�>6A) r�(.�� o�w!@�%��@&�Ǿe51��3H *� Y %�bi M�I�1{ .�d"� drawn�= �j�M�2!6j("� i )%R�U��Q�!�)iiaX��u_AG]'�s:�-=!��Y�� �2�i�� # -� O>���dt%�N�$�E�E�eq�= z(marb�2�alrs�%0 ��>.li!qD -m�71t� �hS2h1�e2)�e4 %#re21�Q\/ �8m�`�FgR��)>F>LF��@,1��aW�A�I�iyLeg0� n5=>�5.x�"v --��o& �%�܉��6Fa%-�!�5\) .=&/ 3j7 >O6b>�. }"[ BY�Z��m�> E�i� N=��l2�.�.�����6 dQ�!E%hE�&�"ly&��a� 2� !� it���:�� m)�iLIN�)Q��lN)mL1uA� >� �ݢ]jA�ql4"[Yw!1$E�eU>�d� � of�5M! u_!�")\microarr9T��s 45&3Vfoc�Fo2�lIf��ik�kb�tNAB�5U� .�-FO a��vWe.� 165�!�r �u�%�84{[ &eT6upJ""!�"� &� �Wm�q)YB=2�o9Y0LabyW>dom�^!���10−12FO��0A�, �B<IngenuiPathwa#l�C�se up>J"� a netwo��&. 5�3U�!=&�#f&MC�*/&���;qc���6a�!�chemot9 E[ �uCe�o-�r)�i�Y$*Y6Q"[M:q,q�<��e��*)+B*� k7�# >GSJ��we uti��P GF1T�%R , EREB�?<E�_�rq�a3 fejEe��4re���\ER.25� ER- �f��o��;�$�9�&ar-cyto�ci��8A\ O!&w,�K�8Js[i�! =�����tu�Upo�1� X�sin6� P��X$9l9�*��%�F1�a;-v�!��� \I�5A–5� F�� Q|^ �9�?liB��8yAg(�"a�P��5� 5� �.N9disrup3�.�) H���&f J��` �M 3� 1�%�stQ׳A�-1�&.�r +$( S5A , S57�S5C��Io0ep.��a�m �"�� %#.���7$,�"��d Ca=�< �("O--� �-�E� diol%HM�Lv]%inhib�!yM���;O(TCF , PU . R or PAX5wL,���y%aN i6s� &�A�a4I�"�ng�$s5�!$%-��!" ` �c-A"j?HQ0Un6&�gXa�a�B?:���m��!*�"�0K�"���l1fAo5!�-�HEk"#R��6 a G1� ��arrat 48 hrjS6M�r! re-�*!�^�N727a�M@rescued.SB2���iǯ&���4�-��7 �p ���V3!P"=!�suf����� �q%_jA&si :]a��� �>R�.Qb*�>baAx>�2x"r�2i B���+�����Vper�#�* o-IPAY��%:85:Wt"n��eziV�� ;!� Q�M,/}�!�HeP,���6u��!��a�(h/Nt��(w��)�9W?xt�Bi� �: `!�X.gu� in vitro affij��s� Y"�'.a&��id6R�^& 3acY=s?Cf>t�� ��IyG!?��/6# 9�u�&�ܵԁl�Y� %g�*�ve�)B%I�E *�@)f(��c<*�+S9-�E+�"�+� rol�1ck�� R� {( Q+OTOMN%_��0 a �9Bl25_>w��"k!c ���A.�+ " �&!e>&�| �BQ� |);"lF�3" >d�=�Eat!4or)3%5j� failu� o� (�surprie ,B���a.!Q���hA�.�=)4. El��"]�%optim"�< 3^AIN��MR�5�(L t� �oFEeak�VD +r!IQ%�� nU�-"A1"!B�QPARP1M&őA�"RIs���"�$WNNAl{�=lu��MpJk! �F�����%�.3J)�!�po�9*;B��{ �:y%W�&/ perhap�ro~7�RA}a]*"76e7, m���s*XP?@�E{��Y.J8*�liv�>W >�)R�� u��+a�swf:w�b�e0re�;�U 6-�mĊ�1!�$.0�%Zg �$.��I���_��[I�>���A�8p-6n�,W�> Xr�a��* �]e. /�^� M��qrm�IlexA�aF�E� BDH2> e~cF1%)A� o6� by�o�8 �X2s!��B&��*��;�a�2J:G9�, *F)�.��>1����6[=�H Z僂� �Z��]R�t�QA�LZTFL1)e�p�&DA�)n�`sI05[c$ �Bh�(m)i"�'J ingsN�.�I�F1��� &n ��Es*��ly��FQeq�F�"j!��#� 'BT&� F1!1�� �ԁ�2�iF&l�>c � E*>�JR*4*Q� � )o���3e�!J� Y�Ao" �-7KaiP��V)� ADTj�t�V�178 I�O���&�K�"�E��/!�}S_T!� n�s�.ɡ� II=�&���M�3�T6U(1j�C�%iB �2X���B��.���6�ndO$."s bC��*s1gL*W-��u�g�s:QK�O�>�a*ފ,o&B�9"de�edL�QM��RTX,"�c>���:�MV6>� 4w � ���RT-�5|",�'IK��G@Cg:c�sp4ea�%"}�9!.� �isad)6G�26�ExaR�/�.eF����;&$ �=��2 �.V,�.��= E0,ŧm�M�91u� ��F2FO." ,p � qi.�ãV�2���� 5�o�]F1�@sh%� �<e��{7�87s, Ņ{ V<�#7��nla 4/a�e�q �Rs !l.�1*$�"#aR��J!}�E�}.�"o -.'� $� �-�6B% 8���mh8A��FBP�:,iv�27MuSCp�HB�J )"EnB��K n^e.�<��l �~��)��4�&5. &��w9a��h ?9�3�h^:(-��57�(>� i%V:�NFEIʂ��:���NXUz�Cp �5�4HES1 . These f�iindings suggest that EBNA2 may be recruited to some sites by either RBP-jκ or EBF1 , or both . Taken toge+ , these fx cateyF1 and S�have non-redundant , cooperative -�context-dependent functions at viral )Tellular promoters wher}Dey colocalize with-. AO\damental unresolved quesfD in eukaryotic gen!6 gula 8s how transcripfactors% !(ir appropri!�<-type specific b!+ng-~in6�0 of chromatin%o%oepi��parame� . PioneerO�, like E!�, a%ought!�h!�Tthe intrinsic capacityaccess!ir� -embedded:�(to form new5��enhanc!�ele!o s neZary3)5�:V([15] . Whil!�Tis is well-establishedK manyBomic !�!�sA�ur%�e provide encT at a sign!�A�number!�N�:�requir!�Y�interaM�Ezneighbor.�A�)horA�-1�. O.�A&yQ2�al co75�a�, canA�� as pI"M0 ‘scouts’i�reorialExo�occupanc-�l Jprotei%dEjRBP�6�Ev. EBV)�8es adopt differg%�$expressionO gramAvat i� on hostE) or tumaH,�A on.1[24 , 2EC�,encodes seve�C2M2KauddiADAߩ@��$at remodel����pr�oa�feraJ�-induced# life��oi�immort��E�vr��ng B-�>s%P!݁9s!� sequE�uK6�1M#.�PU . 1!Mnd alsoU�sI��rco-A�va�� M4histone acetylx�0ses CBP/p300 \EV��-@����ainSNF2 [6a�$The prevai-)vpositM%)�5pre21�b+exbound!Jth��ogn��' site9wiv�Bdisplaca�-reEơ�.Rse�9�{! then��m����N5d complex��selectI:��B�bto stim��e targetI�%�է�Lconstitu�tDNA�a�r�g�%�� al-, 2R6�)��|ELdr���h�!I�of�)Yes�fies(5#^VTr newl��med ���commonl�R�pi��yU�,��!= �, correl!���-�ed �E�36M�4 ( Fig 8 ) . Aa �� stud� nclu�5*� does no��ly alt�,Q�patterns!6q�or Q�Y]7f�[18�qNA�tud!hA[ared LCLA<�llymphocyA�@( RBLs ) which do���-@. Upon�� infe�q!f��wa!�me*� %�toi� xista���i)�1increase&O + peak��ns�. IO is-�R�5�la.ly thra�F�qf-g a2-loopt��[18���!hy��s fromWs��,ious reports�k��im�re��t�}W�m!� .�LCL�� I BL�$�a" B1I�a���al)�-ER fu���v�a)5 perA�age.�a*1�)�a�det��-�!As��of �!�t�q�%�at��of2Q+j bEK�/ low level%`��ab:cM��in!qE�B2I|e� s dynamice�:� e!�a�[32–34c In T� blas�leukemia�5!s.i!�w � d�I&� *� of ~1 [33qIH �1 �c���dI�H3K4me1%; H3K27ac ,��A FUas�rq�a�.�]E]�&7y��.��1.�8in mouse myogen�ells [)iomod�y��e� =!on5!��ɑ��re simi� to wA we observ2>1XI]��@2&&EXi A?ɂ��to �m_Q�sf �i% 2.�ntagon�)21 wth����ctij� V.�d:�[3gThuA�w� ZyFsh! A�� to%$-|e 1�pey�  o) �|p*!]1V!�s^�2):�profil�F1&[ r�r� oA�a+�,�� du���� init�an early� ~�%Z �� at�� w�Ui�ۥT[3��� ��s &�X!�[Ew ibley) s du��s�&/y9ni);[3� &Q i�e��L!>��re#s prima4)C��A!H�a�*kas ]una�Q0 �"� )�in�� hematopoi(m�13 , =<"K ��0act���"����ac�!��M�%ja�,� lu�$*Ci�A� TET� ^a�a` demethyu [38]E:BRG�4�nucle!C�0�[3�m�!i �1��%�4�l-�.�9 ����Y�)�2�*i~�|� y�"�1�$mechanisms���y=j��E\e@~!��W� dema2�d� f-�^�Buthaps equ���J)C��combin9ialUjg �RJ�&� E�? rmin� lineage- +u� iu[4% �� =�6� xZ� ����uC5< N�y plex��!���a�a scaffx% zes multi�m�6W.�.�rA+ betwJ�m�E�j�2L�& aff��yNassay��_par� sup�!* te�/6/�Fwe didb0a�l2�!m�i � )�or�i�-IP�s�%DI�1ၮ� �ausaA� tinc�m phys�� �.�� �d!?�Jse�LQto�deple@of�1�or �:< 6ir�X6\� �o� &m!�7%{F~ �,!�som-td"�!�C�\!/� a���B��% appee��٭.�)�is 1kn%r�""W J^Z /CBPE��.�!��%��^o}�6; 2U���ext�h.� #Mw  Z2� ,5�E� ���P����*# mann5�� z��! oord�u2�9�a�6�����g� nt biologE� outcA "���"e o^l skew!�of5R"� f� , lapp(�9:8$��Wc�*� "�� a�1!=nto��!!:8*� ���I�2e5�i)��BF�Q�iis&��� steady��ty��!-�� �*�ive�s �1D �~trends�Sref@~�m{n�!�&�L�Z�" ng%4� aAV-���� o2m$a major ~i�e d�opEs,�<le�l4nuD$d9� 69� ��ng margi��z� ��F� 4�u*&$2��"�"#��s a�6s��"a�!eQ�.oHn" &s`'M�dicO�:�*� �sAjn�.�!M � � �����u�of�"mas��u�6T��Qav���4� �I�4 )&w b6 n�tC!Z��V� ofʼns Jn�aZ!�l�E�Q�4nd survival . %3E�� l��= �humanMa�v&"�Wistar I�4e Phlebotomy C{))Ea ����uaj����s*, Kem IAund II\obn#�4Dr . Jeffrey S�Penn S� Univers) Hers�M  ER )>2 [23]��a�t������.d 1μM�adiolJhIe"~ r�.B5 x 107%s� � H 10 μga#R rabbit%z-i�( EMD M!ypA� AB10523 )*�0Abcam AB2594963BF07–47 G>( A�M� 3929� ,!27mG:"155 )�bode o_ ntrol�IgG ( S�4 Cruz Biotechn�y sc-202h.�� !�pe1Dby� deL%b�%e�!l-B4 �c s [4�BriefH(crosslinkedq&ora7 lysar#esonDF�hie��� frag�-length!�0~100–500 bp� ub�� n, eFody-coDynabead� �!A/Gvn�b9Ecseq bu�)X ( 50 mM HEPES , pH 7 .et�mM LiC�1 EDTA�% NP-4�D0 . 7% Na-Deoxycho�]$x�1t�# inhibiM)�� 5 tiE�o�+� � NaCl�TTE�8. Immunoprecipi��d%Q!�elu!mA��:�Tris-H�pH _%1%�SDSE�7 rse-.�at 65°C�re%�v RNase A (%2 mg/mlE�,*!�!KB!, purif�&Ipheno/hloro�nk( subj~#0to qPCR validE�� ed%5is%�žagaros=l yI� �g�4 ima��.{$Illumina-b��&��us$manufacturDrecommen ���@��%���eAy�asV�[4�Quaf�of>F!"wd �real-A� !F��n delta Ctpho�.V(ive qk� ��04–1076 X5z|1974xe9����, 1� ( gift� Paul Fa�)��UKeR51E+�%in%1-. PM�!T!Vl� }"Suppl4T�s S�S�8 -re-@xZ�[4�M���,��W *>� �-re��^@ZG. RNA�9�� 2a6ai�HRNeasy Kit ( Qiagen%�$3�0 2 D� I�r E $��a�� kZAmb���+RT-a���2dJ.�ly�[4�e}u�6;�WSYBR gr1�&��`a�Prisme���Qe�- �Aia�.AX ug+�es� DNA-"����6��1&�&�[4I Solub;a`#f�E(63 b � cul��tor%0out>� aE24 hoi.m~4��eIF!A�'�3A� /RPBZ2�s�DIL7 ES B MP1 loci �clo� i�PCR-blunt II-TOPO vect� Invi� eE:� ~�bp:�EBV Qp�Af( 4971� 50250#-as6yBSKII� ��BPjκ� TOM1%�2�UCIDT�DT��"  a � $e��0c,��,plasmid temp� smxa�tin�.orwar��� �� "m:�coupl� M-280� avidin*� I.� Ezwa� a�in� e�s^� or 1Ej VbW+'1Fa�+e^ _D1A�� 2� :� 09 , 20% glycej ,� M  � 05&� U mM KB  � yl�4sulfonyl fluor�*, %DTTO b )B:�%C� !��&a_ ��\��Laemmli� !kh� at 95� %T0 minu� , loa�0" �*16%� -PAGEq n$z; We)n blot�"dpolycl���-a�aern a&( Fq�� ARP-bAl1.$ 210-302-R!��$GAPDH ( Ce�ign�$211�1 ; GoxV�R&D� AF516�; SheepJ� NA3C�`xalpha F125P ) ; Rat mono6�>i MABE �5>6�$( DAKO M08I;> n-Peroxid[ !zt $igma A3854�V pLKO&6�:� h�tru�� ( TRCN013831 )����.620��96_ Open�s �shC�E� genepin>�i�L��85′-TTATCGCGCA A -3′ . L1 viru�6d prod�7b2e$  envelope a&packag� )s pMD� G SPAX2��w��[4H"/��C�1�O3�[l.� carrU)1�-puro�by spi��%��at 450 ge�9y��8o�2empera�ˍI�� pelle�Kresusp�=�$�� in f1�mediu"u� �!5j��m��8 hr af���� ���� Z��ZKANre�7d �0y 2v3 d� M�� col�|7 ( ur �}7�wIXB�,� ,� A(p vi�ty . � |9��, 96-�:say�tvset up)104f:�dμL@be�=�> ach o)+�i �16� �5)3tcHl!?��5��resaz`%�[)�%QE�aU>to >}�%�2l�y or�3N����a��Resc�20at 560/590 nm �"�_9�of shŔF ] senEAp&5Q� hCtr�AllEg tags�� �.>?b*  ,6/o JunD-Wlig o h��!e hg19(Bowtie [48]ILop!�s�'L-v 2 -m 1 –best–�.ta (A�al%�a�r"�A�%�� ef4 down�a(�2.6�,N�P norm%=R 10��er milla�mw d (A���F�$ENCODE [49����%�|A��0$( GSM80353�`�%\ 7543��$in GM12878?2�/\0onS!Zo6`)�in�QE2949g�II  4762i s� e ID�11537]H&�ZTGSE5263��y2o493� � 3C���#Peak �&� ee5d A�/)4mp in Homer �%A��X$$&P,.bE resiM2� p;g1-�.Qc�7�appli h#W B|a�u=� ong }. Sd6� defiakas"� t le�a/r-�%�+c���3���� �jb�%!Atwo��pop�-i�4��reK!~V�Bon . T�@R:YA�."nA:�D Y, pai,-test2K. D�Evo �f%��o�9A~2 Gn$� sGenc"�N+I T visu� �� eatm�(,.)r�E6"h ar! �$( +/- 4kbp��2!�b!�h!o� NAm� s ex*AF�[@in"2%�>uiR6� �0�$2& �I� iA $E/!�ZalJNAm33!jB��Bio� �Agi|�( Only�% RIN� s >�%M��aB��/. E* amou 5(�ng f�#�����a=!�a by&��hybridq��H��HT-12 v4��wh�3��� arr� "7BeadS?Ho v . 3 . 0 softwarm��x�$Y�D�#�!W�>p-valu��$of ��. A �%=le-��Wfil4��%��"be%8aFx>j 05�P� n5 E&]E�aO͛G9t*!J�[� � d:#I~ V m��c2A)A"�*�ing%@ stim� $False Disc�y R ( FDFA�2[5�+FDR<5%!��jide!��nt unl�Hs�&?0. G�I$ /9m9uSv �@QIAGEN’s Ingenu� Pathway A;S@Q+ ( IP� 7$ Redwood C6 , www . q�.!|/iU)%C?�s�“Dis�s & Fu ( s”��ul?=pas�p2%�& 6"�'�%) E�"�0Bs;gd8uniqu�$9(�4by�/�/��I�1i� kb �TS�!=�ly�-eI� ed v"�"�7 1 . �ld ���d-�IPA%� “R�8 Ef�!).!�� A��4$ a networka�9"a=,)UL14s���H�tro��of� vs� - %ed��upvs un�/ged�y�cl!��(5g�m�aS�F�J r Exact T� . En$w_ �/�ed8FQaA�se/$(.I�3n)^,F'4����6P8��>�BiC8yDinQ�.Q�5E�impac�/f�r."�,�c�> tinu�?%�pidem"�1ly relev* �BtVcha�FB.4�> rra�%�t�7whA��0Z.�!A 7e3@amֱbF�sp!IIB �sI� F�*� �-qp f� �eV�u�!ݥD��ͥ1-*T}V�5�)P���U�syr![1��[2�::>mu��1QmilS asym�,a���"���]aY� elshock%$ hemorrhagg1*"3d draUv4 QUr3� !�world [�,[�$6E.�ex�)")L �atic��ɔ1W�C�< ��>, x ah( n�ntu��� flav"�[5]–[8!ci�O�!�1*. V"�etA��2E6�2b<Y,��,t�two 8o,5m&�;� B��c( MIB��6�$E$[�[10�environ� al"p1�z��up!T60��"�FJ�91�7 3�t8U��(s!� ng n/al2�of6=��be/@segregɤof�elO�to 8 �#[11%�1EeW"l-��u�J�2`A� bree%�6� m�=�>�.�&� �X , [10%F�6,B=,6U g8�=(%�� al rea$eq� �25 ha� ) 5Nic�#am'"$Adenine di�%otdehydr�0�Hsubunit 4 mitochond�= ( ND��A �de�Oby SSC�7iE1|6� ���er� a:L% gen�e��\AeZI�Yucatae'd Pac� C� ���FST��e"J�Ni� lA�Y6M, buts<��xP!Os� �gF�� 6 ��Z%0w�%�:� � Tuxp-$Moloacan/M�9itl< �r)%� "� �3,5p< �O.6�&�" f� %���$� [FZN�e&�A5_av(��& }�G}�FM Inte�8Z1!�2� �i&esF!EP al P�QM�LVg^lyyB�;.�]Merida�etumao,A9Cancu� �Q�%I���:_t3+) \Nuevo LI=oUHoutY��fBE)'Unfortu�X%'in!E}J��:Jc�:�U;�� UuY(( ∼750 km �eA��%��I;#e] u��G2L�A�e��+:K �  lsMV:M�OWZF�in� FOQr�Bes�ca7Ia 1986W��8j`n͕-$SeC N, de Salud of�� [17]yRo*�!$al���!ciI@!�tS2�)���� :H% 58% ( 29/�*� eopl�+Martinez� la T� (&%�2m) #8 us 0Q0PI$-ܑ� (I:B �prP!�cy!�0 > �t�$z#t%<�3sA�A4ge�:phea� A{g"�! ious��Jd�w@���!eE��:�6C*/�]haB-er�?m� tho`Xl9 F�of�*�^+Te`�ui. "�10f�:Q����6T�m�ig�'. N^ GZE210.�#m�+in�4]�T��?cyFU 20036�%�sZ ( ���e��w5�|6��marker)�7I�Jie&�%�"� �- K�n���~VC%�B� !�6� 5-.tYs,ocols�� M:kͥ}&s�=vam{�m�&j2T�3}I�ch#y&zlo0s): visi[(�\1��at~0�F3 sMv*E i�+�"� -/m� si�kh!�la�%�retur$!>he laborHy� emeradE3?vid� ��� � WV t�<0Ae"xEPIc-e��%oc>�E_� �PB !.mtV/I^se"20n'U� �A. , T� �%e*�;ZF{F4.�to[-im�-e� gPni� �in"� �e �%in ^��>2 JAM140>$�E"�3�983Jamaicadbe� �h!�Ameri� sia� � �\aN]KP!Vdur��orNOyR+a14%(�"! ,�� / ��C.��0membrane feed"8T#d.iDBog �.sEpu3f A&Ty1Gus�=�=6�%�yl8:2S3uV]�X�&8� � �e� Y�eIĥ!,.��ti+= ousn��� �m�Zpri�A�. Undil�:)KIs r�^ �!–�&5�"�us 8�+�Cch��ɇ&off*PA%%=��~ch%�!�9f� engoe�7e�� �]!2E cartp0 d he>V�14-�+?P%J?_27�0!@80%\jhumid�k%!�T�hEYa 12-�+ photJio��>�froze�5−70juntil��Z. Ht$�abdom�<�?�:�o7VE�� by im�<6�*�+ ( IF�JE� d�XTP�:�/�/dir�;ag�X�&� E�+epi� [2��>��,�$B�$�C orax�@�JL #U[�,YA�ofE� w08in�d tissK#"/^��s� "2 %b� da�h�+"$C ( H+x e m:8e�_">� �8a, b saliv!}glaiG>�in di*���yCA�H+.�� umabC&ap��a�t�9i�[2'If noa�=t%V!�"��\%1gA1 0:An�v� H−��+in�%I�`(u&�Oa�OLNba�kA1, }V�� Mx�[�.Qib� ≖wBM�2n�c*)-Ha��av�r"� cA�Q �.Vt� qe^]�!��w6b tE. BM�.8�aH�S`fbe>�a D�M5�%�t&�KE&5�xaB-�% = !h/N!�he 95%a?f��*ter�(d)V�@�,{�I!�*b"IWal� B:+ZA. E`&��ei*&�!�d�9ha !ysquJ Z-crit�L3# (Z 9�,� nume� �=�3�X D:B 7de�"�0�.a&uu��!![�lh> to)&� ~�'�v6�+ h� re�%oT~9).Single S�2 d Co�8on Polymorphism�1SCq6V�l� "&�Wi�-�o,z �r(5�&]���k ��A..�iw�l{T� �C#�a� �cuse�n z=8aDavis S J$, (, Californi2BP�5�"� ��r�k!�ng �"�>�%sm �-F!�EmL.�m�*;&6BF%�s�m�s�E��Sab�f6� Phyl�K�onship���.e�Up&J&�66Y�`���aw"�\G�lD d * 0��a�"� )�Molecu&\"W)of z�C( AMO�"[�j Arlequin3_T*d �.*ZSlatkin'�2��*aud ([FST/a�−0) ] [Oe�"��!�B A�!�~�M���*one�,a T� E�l�N6g�A�ucg$���S�met!� perme  !ee U< 00 pseudo�6�?es5e�'matrix.y6��s%��ap�P, �n4 ram )�unw�r�!s-g[g�<o�?arithmE��"a5i�8]AK!PNEIGHBOR�6c0PHYLIP�&5C�bInQ5, �W�Zi�p�FA�1 KFk0assump"!.4ng�fa�ho�b�AflDqd�t!��$nearby poi%�nd�d�(t$[�b, a���s(ed���n9 arcsin√W � ڡ e� .�aQ" back2`��0 maximum sear�!re � ?�"5°Ie�dnisotrop<i .y(ciri�.I�4�3rLa�� �E(osoleacaqueus�nt%���b�  �-��I!0�w%5�)Z 8&��}7)�ɡdBec-4�^�%�F"* ( GenBank ]mjU s AF33484� �6�no novelBw�. Acc�V� =� �/nqres ��B�je��E sm ain�. A�� �+"�.',5U�=R%�I�x%�"6S%�,+�-69M�p>p�1orl6ew�Eo i�M<��2Va UPGMA �mm��<ai�ZV?�=46Q�e�&b#19(��!J %HNh12 Ba�of Panuc�j 1996IJ997} a�15 A�u 96�199�B999)��-t�qI lR�oW\2jy8m� � �"�fA�-�Hzy 1Ui�a��$�*I\�2o2���1l�'2 : RAPD�r�)". N�+�.��i2�6of%�&.Q(dm$��]{pbrv *Lr-U�s a�9�D.$'8���pW1�e1�ea=�AL!�OAZempoal�70�b!�.�qu:�%�,Ha5%�is5�Ip�'E�%\l�0| uW�* �<E�KUMB<-",aP�24�+<�2�=��)�� n arrow! �2 )�&6�"� ��E *�gZ* c3UEVM' �1)RA��. B�,�n�-.�5Pg��In�r�-�mM�M@,!�.< d���, �i/a�E���6F B� Bx!!��q042zu�28.�6> A6.�Q=��+anoa�$��� very:�l.�.q~&�$o>Nl�`g&�� ~to2� , ye%�h also�J�l2 , Acayu�<,Coatzacoalco!�64�Cu"� m��|2�� �/B�I�A�Udu�,eC A!��'t�,!/4:/�G^Ua9W v�BJ(� 2�|W�Cx zArJ��* �t �I.���s��2*�SP .d. �F'.�"��"�sEK ^)I.\ma���.horJg. AU�v E "M w6$!�f���3�da g�Ur��Na�xF& (��5%�rA��3!'�,b wwe el�f1wari�٫�)��82Q,�: ( 13�F�.v�F�.A|�S.��,!�Q�or!n4)��"� %�"qf�d.�p&ZEB�6gyea�2� �r��FOU%�B�J �m �2o�-�';E8.�.�l�!� .�.orea6�#w��� e}��or �(o�L!$���&+! �B� l2\y( MVM�� V�L H+/Nh� w �(2�T $X1�*��%*/���~Sw G*�|!wOM10Ysʼn)N� ie �%u}�O#��V7�VC l.B�4�� 75)���O6of#5^�1F$87]GR� >g1> g3�K cda6�yH-v.9( Wilcoxes�or un� �*Se�_ p �p009�:!��Z6!��"=!�E�� MIBK MEB� NOM**a un�ed guts� s��ed"�62� ZF�)�66�R�ha.{At- 2�7%=s9!E�x�}%}19�.!" V��|%3�%�S� MEB%-�q7 5_(.$�6)2�(�-"M9�A10yW�M�2��Cnb�( IDW )2^E(:G/t5� ArcInfo 9�P!�. ��=!by jackk ng ove�le� � I�8“leave-one-oue@p�$M%R2-�aA66��a root�#n{ errÃf�6 �2 &�@-�Ja2"!�Z~ńa�( s*�$)\ yel�;(�gr�xy )A���Boori*gmeasureF4���2IL! B��!��QD4LVC decPn`c]o�+E�a�\B�#A����<2)�!�  .C�36� oB�4d��8b�"$*�3�3��tw,/���G Un�)�1-��3*�g���m!<6�%qAlvarado6 6 �2B +/ʼn!mlowes<� . Ou;g�+� #�+tioan hyp=�&JR�=��!:7-�4�R!to ��3*�B�-2+.� � �%ro�6�1� gz:��I*Tk#��Vf?Beld�?6ydu %�'1atp VCU�!�� 29.� 1bc bega�DEj�v!,Oligoc�.N�Yr\%cQ �Pli%–Ple��3,�ense o6ic < v�rai-hJZ@)!�[5d�/� 6S5� !:a�U+A�e A�4%�u,BK� favo�� a wa:�W�A�lY.na7-�0�k�""�-��+��decidu)�P2 �y�8N��%+VA( �}E�R�;r=!thaV3�> aridz*� . �'s sixa�m=K�'e��;�!�ww��a� )Q͈s�-�M H] aD&�+�g!Q�pla[a�Norm!;n�5ic�2/allop|c=3���3� .��pl�><ni/5u3e�|7�9�wW";|� �.l� ngt 60hR� in&>�7ay�ts��e� (*,R��L� to"&�1�ka�FT��"F�0�1��"�  ��t!��"ϔ�% 0Hr aef)�VAye�G.��!�o� ll��.H�' an 6�(�rargue  Q�2Ͳnf#Lid<�*mL�!��u� Ocea�Us !ts�m��. E@e�;n't cla�.�@a=�-VVi:�:.Ab"�".E ��Ric"S=s:Aso�"radnC��I��la���porU6��^/�� ��92r*uG e�Nno ob�4a�_r:�6�uņ%xE�A�!�!�[4rM� =(�/1�v �A���L�rr>N2�i"ei�2g�5lim kOlePss < 610 �&∼A:�"fee�Pab��sea]#�q�,3�HIexcp/aMo �e�:���I�A�*��@T'�h<)Sto Tuc�UArizona� �eo�6"panmicAX*{On�!'s9�"� !d��u=�;� ���@ea��b< v�  �7B commU|>�I!�- yIc"-�` mo�A(via flight �l,]i[=isa?il!�mo,1b�>���nd globJ �/ � p�v��*�@i4�.I]��i!�"| 14eU!-&�0M �Ir1{ road�railw>R( albeit�a Nhe ed&%�"h �"R5�Yj,i�n��W4U8,S l�2�U��cd +�%X$R!��/uto%��Jtru6$��U^E���!h�$ -+g�-1� ,��<6ge}h�Sobust�iag_cru��(��� �0Btr �2A&� %f�"H}eAolittle��Fp� сT7-�:� A�2�‰3a � �O�C�d� a!E�aG gges��� principal�DB��T�k%q�i>YUinvO:C Tll�&Hi�j��-!/*�trua� Unex@ed奍�t{a:�(*�+iiA"t�"�?� �4]Fw{3.Z* B_>Z�!aU~6*V!��Ri>��ve�rawis unuQXm reason�]�@gY���D�8��d /A%��*�E"V-!�h1Nc�=]em�-s22TA-��N mappD�2�D1�-y tryps�+�/�-�("f3nT9JQ�"q;"�E@)i�*�g(T!�VC��5P^. IԔ�heZ4�I �=�Ud�' LVC�L���(i�Ind�v�candid �� ��deJ(�&� � � 8W be rapie1emR" u4a�=a��� �.i�!�no���3=FA�A�cWŧ���den&Q�?P /�X !O�i�2ni�Afs&�]*g _Y��^a�G7Ξ�)u*6�L7��; �?o|4s�~t� !�VCk s�fE,N�of� �>.8!�I7 b�U?Yq ve�e{�L �2�H�B���VC beA�Q�G"rando�d"r�!d 6eI�;�I47QTLu��M�\/2 .A�7E]�8�&��D[1�71�KIv\>�aZ� �+B!n� BiEۉkfamil�"!#e�)�{"� J�. A=go!gree�)�of!���"+~e��bAR)�ZB#re�dVCRYA�l�3S\$ernhardz�perso�;�9i#�p�%AA*"eF��@*ve.k ��HmHwe���ceI�%����oI�6^Aer<p�f�i�Din7�*\ A�ɣ�h��d�T|.o�CBtpG �=e��ub�� qN�in Se�l�[� r�� Wa�Af2>M�N �����,.-_N&F\�wi�o�New WN�re}!�S\�Y/��~�E�ſ�A�2S 5[51] . S�k r ;m�  act�l���2 �) �]�zyg�|%�)�nO;I &N.�9�5ng��t�"B�c�F�ss ��A akag�L � E meio��3yR_s yiel'7aneupl$}g�2� 6QR!�*mA5I�BKP^�U���f�P� [5�/7Q�Io.�5v�B�J��2�&Srl%� �>�I2�&?a f�r�5 RNwp2�!e1��noZZ��B�Fe�� "0�?E�!�.� |J&�L+%|Hgoa�4�E#�j 3 4&��o� A�� !:if rre~ w* T d�"E�so�� �D��aX�C�~bio�,�9�P.5it�mE��,wA effo�!�� �7� st risk!��5Tc� I:0i0g�r,|���iguf� 6v%����VA�Red� � nd�M�,�zpj�in "�)I�� *�I \ zeroAJI��pl �h�is!"y %�]Q�A{ �cur��"���2^ie1)�J� 5��W^FMT!��� deca5�Ha�w�[e��e/>3asSP��bA�!$4%O Jj=�z�-Rin JatilSO,y9=-m(s72� ��=�"- ay>�of mB[5 &� XNL&&��/t�KF�E��"�!:�%��L. C$| aEp��sit� )�--A�provS � E�eԬ� e�)q �%�8Cb1U�hT�p9�&� i*�<�cf�j-��[ ?��bac� !g49� cycl'driven"A� DnaA�i�*&�a&Oe ATP-b?h�� �K� D2 .#a�s8 yŏ�W�""y rAWk�&Z. I���<op�@�*en�j� accu�`�F)�cw�"rfe�k c) Y,<�ke9����aA plue�!#qA3as��wh!*���&,%." �.�u�tho9tLa 50%!��� !;�e% TP ��\ ��E�tD+g(repU!` -�mt� %\�%o/ic�?i- i�T!�of2S�Hs9w"�!>9x�� <=".Fuop%zE��+!}�$s�'6� f�!G;"9� {ex� 9�:��.!� ’s.� )9I�"�E�� vivo qE datA���intiii?)�( DDAH &u$AM-"��ri�Diaw�osV3afVG y�M�machin�0m.!s; grow�`�it ��eE�on6\|��"r9#�+��!�Mmomw _!F�s��GAL�-"3ڏ;ORC�CDC6-�"��-�o�-��a�v��d�!Wl�3�[$r˘stA),ci�! �E������[ r�gA�S� r}k-~ Yit���9ם1�E���?cense i �Yat y$'�M� le!tV�A&a�t�N�y��o trigge�$!+*�K��e���0%&l�AW�E3�a�,�27/K�%a � olig s. -�� M�!unwQnŸ�K 5AT-j6A�!֩Rm�A�" E�3]%�i�)�LA��nu2&+��Q�c��W�NA.�F[�83�!ȡ�v4!-B���!<��#��0>2�AXE�A>t!)C� Hs�&iC=(��43eB�Ź��+)�w6��E!^h!�Oc���5[17�7)!�6 F�av��r*se�M��>ew1y�fa��A l �lb4T7�|M 6B[�MM�$"=�uas � !9Nlٌ�:�A[���l!J�8 gidA�i�chAas} �wen`�a��J�,\N�:/�l:a 1 kbE��@���z�e�QA1-�k['M�1{w�v2!5i e qm}AE� ����&&�b�Q�J ��6�{!�eb*�8`iz�6?aw�yhZ-&��]�ly:�w%4, tog��&GIHF�,�]*{cyJB`"k���AT`� e�"� J���Ro:'6 ?�j& [�GI�u.� "�E���he RIDC"$py I.h �P) )��V�=Hda%�FIβ-clamm.*�K5C+FD!9�%to �[&G.5o��ɼa+block ��,letha��wy2K�CmAJv�.-��[>z�FOM�&x�%�A��r |hon�n [2r?��}�j,at � �^�j#!tw �2�&ہ6xsynO!i� DARS!�!�ReW7S�D��aVpossi,Qacidic�S spholipid�2lQG gene�!Ad��)��|�8 (��RF2�K�\�7Msx y  mve"�rM�{2^,�� !d2Z.�� s aIB' xces�� �]A)� i���,�7��< �n��-�� #I 2� &�[3; ��.��?qca$YQin6� DNA/�a|#!<jN-;��� [3�A3r73 B?,�8\+"K0� ll�#�G�0%n� adi�k�!%��a, also�=�)�a2n underbntUsw -�͹m��k#�R� �&��|��(A� �� }!aiW-1������ac���e�fjts:ai t edia�Rf� >ńaU�N �an�Qp(� y an�)Ts of��/��U(��|d�D6�)�n2boblem1�A�.��(e�D!ai�itE ]A�p<�8�.opOf!�C�ba  cuK/������!%6"L 9 ,*^h,/�R�����E�|M�ߍto�:��+�+!>�M�m�.P!K���isIz�on�VU ssum���^�x �%mS(b&ZH�?�E"�  +� �ER(e9,Z:��A��mp clarif�S�3ueQ̭�R�:cF�ys cyto+P/_&�IaD��kSF$APal�r�Q|�e��? Be�I5�J. �"D&fouQa���"�-�%6 "�i�h�D n~ȁ�ta@�\te�%%  �0� 0�1��IMZi��2F3�fe�l5�.o�,A�$\yke �d��. In or�6I�)a e p$4md�ek&, gluch�` �asaa6{ �GluCAA�-ɗ� aor ���� /4�� , 70�`�\3��+i� (!�B�$!�13 .� f!)�"�PbybX/m�o g[ t�+ \� w�r�(�two�ESE�a�lK�ree%wa5�3S1��Fll b;*�!%�F!�UA�(����:ucr}�%%��T �p_7.���!{�$!�"�B3!-JA�V#��$ag �2�erZ�'��A9f�*���in��-8,*�#Z��r]�e�D1Yt)�A�� “gC)SqZ�wao�ur5-W_J��E!?�[dE�A�cZ�. F�+[\�Y5)2�pF4To ai� 'n\9�M�:�p&m�a � $u�I��Z.$�-{E�ʈ�erifampic�Gcepha��m ɯ so-3r=�run�C%(���M"�/A�Methoda�� � drug�)u%/sAd4%�sm��^)�< o"�,pU�' =k � inis����0MG&�'2r%�"U2of fujt,*"�^�;��U!Z" � �e; %�I, �A句���� ��+�A�n� EX�oa�s"l end�/w3 ��;�+0�a���>=;,/�T ( 2n!�'�EZ�?�,i(aCd!� & �&��oft$ֺ�g�y �?A�)[a� �*��2?�HZ�'1�EJ) E"} �m"!I�)7�1�@c&� aA��m#�*�* ��[Fi��. A���J�� "c ,Z![ rr}"��,A�� �[�6� 6 b�OX� 3%�o>��Tll�|ae���|��!�"� �S2!嗩�� � m@>*<�(t��5�f*":.�6A$x 4��Z�I� (/lMA�*��3 2#2 !k�2��Obeh�:!ō�x2�� },ap2!Ӂ�:D beyo� im��5�+�jn9o��;�� heck pe�";8&!��`O���VNR,Y&�&U,�c��&V!k��Te�]�O=�� �aS��a�mq��� �t�����H� ��/is G1)�upA�a�o6>�/�[e�!"�tr +Ne�@-=� :!y=�5j ( S6*� .w&1��!�q!E Z!�k9<�I��b��t>�2q"�E���*!�*Ak-�" !nd!&% �� Ѽ,� e�/�3& �@ ��.bR"� b:^�_:�*/�6,�m1\-�Ahy*;Zuch�"a�V$�%��i&i�6TLtoX��Y))�!J:�u�6���t���"ECE� NC �� }��!�� !��eav5�!.���LA&<h>j����"`.��YB,2�$e��R) E�v��2%:S3�f>�MMY�j� �j6f�5�p suF+,nA�J���-Y%er VKU}�9r!n�5<�lEl �p&�2?��Y�"(3�e.S;� ��CM/�“��ens0� J96I��E���l;p�t�D��R2,� cI%O�)YofYw.pqL�:V� B+"!�� ��-��_�r�cbA�Es� �wm"!*� m� &���2%��*� "�c9�E�"�*Qf!J9�)8� w^� �f��g�%"�~!] 4692�[S7U." +G�D�;n l�$�!�����A � sOK�s�B�2]itselj:fi�:g#���2 ,Ki�N� %�&Y�_li�AבDz=��Gv�#gTwo \e2:�2w� �z�kE�B�+λ� "/razb,i8 nserK��&�a�eer" 6:e� �!dw4V�.C0a�6%�����=6�)%irE �ing7}�s!Yn�&&P�� =%b%��?u�BA� , pk A' � sl!bA��NB��d� ��F�*�+n��e6m� x"�0�%��_ i?+4Nr�t v 5/-v�4�Q�!�apVB:o mak)�IN3 tole!� to�26��t<��?W?in�kun1�� E�%mW �)%��0%- ! �k!=��Z�a�e�.}�e�kG!��"��e��,)å|�� *�`.%�Bi�r%��p�1�Rmioe�/,�A��nrdAB�>NAV�{5�cer�t � &�m�RW:��@mainlyݑ�(�&">1 e3BR &��O ���&}*� �qe���,":aV�***�/c�)P�aAe�">��i, v/C� MSa burs�.*n��E�,mI= \ &q ( pACYC18%Vb�v�on)>�#� "� E�" ��42%Iq!�n��Nge\+10EF11AXxig!%!*A5>&�<�v ��at�fB�" $ MOR9i�!W�}#|t�X�=mlA�!h�3y 7Nr�9p&��.r �Z�)ZUur*�&�"k!B�?�{� OcA�*�)�&/%�� a�a*)sO9�;1"lM.& E*%A���?�-q,E+Z�GOM�w�eZ)� 4-�!�F2' !�EE6N�&!�":.A�� �( �i l:q2m� !AQA� d���'�$A4�{E{"�* yQ�0d I�a�!�� 4�23����&I<�ݑa� mode ��?.c&2V;�%�r]�SJU�ĪÎdis6g���Z�N�^&�Z���U-:.�a,�#lL shor��B"quF"6 !�.!��6� s*_lyEf9� l�!9)ĥ� @%���v4�>��.U�.$� ]X�]&Q� }�Mա:U .�aGA����IK}ea|=tE��pVN"e����e���A�6�Ve���!yR�(nyURj�ifmH���a� �B��`i�;s-�Ao� s��!A$*�"*F 2Y2�=&�S�92a&C"���9 ls`0G;FI&�"resSdy��3!��|�N!��Z� m�5e�3�� �!=&+�a@a��V�-��A dsbG��iO,s5n!�!`7�5x"�5�%aus!\�A�>��6�[�wܦ~0.�aw%`)A&pa&�$%�XA�,B,�?mis�����B"x-d%�7�*7v69 � dele�����(le%0�(=>d*~L�!�%]!�!3�6�� 17��a���/t l�� Δ�_i&:jdo(�n $ ( S5��� %��Oa�6�� :~��3]):�D_.(6A_&�" �!�) �����*�= A2�� .1.��!B 6T6Hm�e��er 5 r7%�6FagUM(: )y75%% �� mp"�L�O�&��.<�f�)E�,����9'Au2VG �*F5 pI,!��-@Ab2J�3�9%y'�Z6�b�2A�o"vU�i <�c�Ld"�9.� d 2�~U �!�� Daronoun�R\' ��:�-����79Za�K�p�=du&� �J?{��u$Be:5��:�"�ch�6�7�a%�������F�6 [�<|���7��G,&,59��KA�up�n!l�.h27 ���G1655PT,���� a�� !�hi>�,���|'E�� d��!\��", �n] A($e�w� n�QV9eM � a��%�$q� �J� M�<p"� 9��e�0m���M���| Qir� e$'AI�*& *<Ž� 38�����;�� ��� 6�5V,N^,�9)d"c >}*!����s3Z��"� *C !R��-��,�A�K*� * iT�E��&rp ng��i2����o����#*��;*�{�J�>[1*�E�&"� %� �FE�M �AR�w�m�� 2.&���MdfZ�>�inB����1����:� /0deletion of d�iatA . The strains containing the diaA plasmid had a DiaA concentration that was about 5 times higher than M�wild type in acetate medium and 4 t�8GluCAA7<( Table 4 ) . Ind(cells grown.por:CLan elevated level of �did not lead to any significant changes^�tim!7of initi)( S5 Fig� However ,3Δd!�Z�L, which have a lower.\(age compare�9` Q,�presence�extra �l 4a r�sa��pheno%�(�4A�,In this situ �0, we observed!Gincreas%�J=�iBe6�whey(addition ex�sed.��@, rightmost panel�T�@indicates a possiAHinhibitory role for). AlsozrapidlyE.!�1@aA;>effect:Hwas see)�2�e\se PexKV$asynchronyE�over-=/9�aU resuly@rifampicin-resistA�9s-&3CW04B ) [31] . W=�e�!�number҂Y�reduced5� 2�a!Mh�$:�6.q_-��. Both � s support� idea36�5��D��prote�X 7origin�t hasa viously b!�sh�% a�� deleE~� �somewhatU�dJ�0naA [14] , soacheck))th!a verproducb1}�m%S67 I�.�LwA�und �%�6>!���1�2N with!a�!~ly��c$1 ( IF97 )ap We%D here z >| doeso�; shif!F�R+of repla��!�n�ӡ�th��a tes��.A�f�)w�(insensitive�� mo �n 50%5�e^6,of ATP-�a�us�Km��fE@inz%G sube�(ial surplus2S,V�i�}rolA-�same way�iF�,e�� � @rN!�amoun�>2�e� s!F8 could still beAima��oparamet��t ,�Qin� ce , help� uple2�r��to1�[52a7but itY8 seem+dhminAcea� ciseV@dur��steady-s]M6 �kU=E�!�e�c%E)I�!;limitVfactor �i��>�s�aAorA� by s�_�^� lineE evid� . Pr��we�흞�9��p�R�� �!�s variesi�7 �� um / %wo ��eA.e!J_ [<��:� .:*ric��~a [23�����*>��C!uslowly �Z �edoubl$timAt:&requi =/�56� a�heTat- � �i� siderably� t� umin batch2D[4�I2)mini-mo�e�d)� eref��m���U)�sa��� �-occurs�%#�R mass�!$� cycle [5%�S�l!� �q%�$comes from' $cent studyE�%~�XR��tunc& d�~M�a 20% de62 &� ��&� e>� [42AUThc �our��� !�tI���j[�BMV���regul��N �3ap� n�!Bacil�5subtilis  .mu��-N# 5U again:�B-%�H� ed��Um�� A�A�� � 1 impl���r��� ffici!�:d�)day af� run-ou� .�qis� m2� takra�. !HsIXaccum��a cer>�bɢ=.1 %%6�  .�� , i . e .��unbalan^.bit�#ALic�tM et how )�cA� work�0We find@likelyiL.circui�- 2b!m5�T���3 Ufmachinerm4 ���i�*� in neim  c"��poi�� !��E~_g enough&� dea�2��6�. T-�g}� E{b ?at alth]����i�ly �thr-evolu%pb���~o��M� crip)A ulpr� �]2���g4n !�a�ity maye�b��M�is� hap� y ris!�si� f�!�v!�dPly re�d . Ou&Sdo~fit�0�cur��model�� �A��lssuK �}5e/s!@ soonNr�e)�0��[9 , 56�^�is ba<on!f�e ings�rep6��2� re� to"�!�.�a+!asD� Plu���Y "�K!�M:E�p"[33–38�H"? ofrse/erimentsɌperform���&�� ��3�Z>�Ebia largeea �!�rcaO�it�s cleari� {�N!�p�! ��v�a sexc� rV ap� ��ng&� =w����w�m?�7Yt ion��� a break-d�I4.i���ey� unm��d9�rUfor��rea�onu�is duuAN)p:��c-�!*i�2Xppear� bI�qo%�r}(� u>J DNA/!�M-oVI��7s�{ iA XV( 10%I��{��X �-mBw�/">��only up�v�+[33 , 3589�Q>L..&fcollap��s� V�[47jTi�low�-*DNA��&� U!�Zr"� M8>��U1FN�]N�N�.)�"a{��incub��B&O!~�a�ĉz!�a�knahin:Qearli� tu�A:�,& q2;��of��!�iQbAo� a�s%.J[I57�8m� Z n �� ���x�Zj6E��ccord� )=one2�� .-uYTy�dITa��Z[!�%c��sonA��discrep* )�,` ���ce betw-���m��%i��x �$Salmonella�himurx4!EsichiaA�iI�� ��as��re� . An��.�t��\�A�1e6Oj IPTGJ�-�ne��ari�ead��&� �Asmg�ra� a� ���&a;!PA�6�i�sB�m����thA!62�hY�A�� 2�&� Bw!Sj . No5aE�-�e�mof! onenl>j[�m %�confirmA`&�I��k at remov` Ps� �" ��mUTin glucor>��G.v�.� �%�B�. U; �Mtz n�g"� H�-*A�%E� exb<;g6-�?�x Gg(A� "�)2�!�F l� demon/O5< � influ�� DAH� $�� ryUG�r&F:��Jsystem (*b�ngg� �tIHFBE)  sAYvere�.�to AD�[2��B� �Atwo �s�X in va� ��rmi���)�RIDA ( R�!1IHon84) k�JE�r�ly��� ed2��ie)Uwo-fol"W!!+Q�!4=Zs ensu5t� 60%�3total �i��!D�gso� 6_gRn#"�c: >��c��a 52�Ѷ�!��� �-� . Mut�k#block)%Me��lethal� !q2d2�30* '#ho��w!�m�Y�+ ependx on��}r�to�*a�dcan �emle�("yA<%�)��[%�qeIt&�n!_)$A.�.�_A`R1Z �2 ongoa�. C as Z�[5e�InZ��%� lapp>Qŧ�A�!�alwaysq�.|E .S� 6�2�wH Rh ���*U %$)�b= �1wcI�a��A[��A� E�iJ}^��c! A'��a dual b'M�J�. Fir6� i1�7w �Z���� aid5�recruit�!�;%�-d!%���!�+ope�Amplex ���B**� o � loadA��� DnaB�$i� A(�..G��[!{.�1A�.*!{-b��m�� �l� $e��p�!�1 �)��Ya�W�$'�!6��a %��6���CIny �2�&� &�A�&� � �+r!== -ۖ���sj qu�( R mpet6c�!Ha�"( toAA)s�jt�,ex�.�-delayS%�"�'h�Xj-t�}4��"���)�2��!mefism�Na�%@��A��j-�V�*�, s, allo��%� � rast!�9����-�se(�tF."e lacka8J�J�iltud!���$�*by!�-���MqYj�j-��d-���m�(s�a( ��S���robz!2ez romij!1B "�.alR! �j""s/� !'L,IE� �,Ad���oq�1�! ��(Y+$��2)�q' ��!�*U/explan2�u.� =��L2� �-�gh�b�^%�Qtr�.dM>��m!� fulf� � �'��� #!>� �Ae��g.;s&�#2mI�����n��. SR*�(sIH���}A� � e�>ss��>(ise�b ��2��5��)���>��"�)�eBis͘�Ak&'r��o�if+&�/��%!� step1}wh� & same�or ( s )� -�d�al�,"�e= f%e'':�%�matchb �0�,*�~a�uH%F l�%b W�,op�%�i )&|"� a�x. � drivenawyc+�� �XV� , il]can��I un%�]��$:RtA0C�lic��0isM�eh�&s�!�oE!.’qvirona{�!�exact]'�. All�1s u��� E>k K-12�li� in<65 . Ck�t!�A� AB�+mq'�6 [59]�Tl�  9 10 μg/mla a�. , 25 urid�.! 1 0 . 4% so�6 7,*� *D5%Al o acF ,at 30°C ( A P-9 �)��37 (6C1 For"s/u�!�UBt**� ,%�z!5=$phospha! ~(Lbeoy82mH D"�/o) meas�/�optic�e�1"2&ur��t 450 nm�F72| madea$a�)�7�R���!in�"A����!ᮁ�%� im�!x5`-CGAGGATCCTTACGATGACAATGTTCTG%~$8GAGCTCGGCTTTATT24G�qia-agE�lig�8in vez0pAH150U��l��" !_�Iinteg��z- L&n.A/Hλ att. aa���b4 [6�Af(c�u�4�%cop�!�mx-G )z��E�'to2�no�,%�46Žik#)��pACYC184 ���� ���5� [6p/A_4JK B6&$ �5�upstreamB ( de��d� 6)8pU*:g(4���� pn7A0.rg1. s)���F comb*�?ata���.i$ry analysiV theore�vt%+rib�+ofn*� �E?YY� �<tai!�byA���N   xcel�*sYa�$program [4O2�!&���V E��N;( 8yn�6 � �J|�pro�7ye!t�%!�0�;M�*�0)�e:`�-�&� inF , C-%BDH�lengthjAJ�( C2)E�] wi�&� &c method usOYoriC/at�s o=�quanti5ve PCR�5d2�7 ( τ�o�8ula[= 2C/τaee�6�in,�z$ W��ex� )stIj� //@��fig b) valu��={}_ �q�=7@s|� om �9-��{,.��by AI rifu�.nd SDS5 ' 0-dodecyl-sulfU )�M{�ct�purifie�*?��p�%6?d"� [68 �ŕsubjec�qto 12%�4-polyacrylamid�lIC�h�b*nd� 7 ��t-�~IzAX- - bod�4 N~ nti-�jECF f��.(kit ( GE He�0c!�ATQE�" �ن �Image ) softw<( Mole��$r DynamicsQRNAFisovqMSV͢ !�.� �>QA��D�dly: 9in:� �/ red��zedzan Agil�0Bio r!�}%a�ll![dep< a r�)' Ribo-Zero R�%Kit*Gram-N��88teria ( Illumin� �TfqlQ}mit�� (Norwegian S�nc�8Cz+��s . uio .m )r~0bra'=u �TruSeqQnded m� reage�2��)f$to manufac�r��6. �Ie�*,�4rocedS�e� �����35 ng%-506+w ;[!�4�uE t 94�. L6�- U5�(NextSeq-500 ����|_e mido6put v19,f'��s2 mplor <75 bp paired-endQdxe�E��Ib95cal�)�e�1)��'s RTAy��%� 1 . 3iGfi�tYmo4Bh��� {uBq defa�6chasta7criI�I�-w!�a��re&��d����� i'in!# P7�recei�G�OAln+as FASTQ!'� �:forwar�G!�!Bk&��%E%��\)C,tool Rockhop�-[6� �*+���f <��"�. U RPKM1'�Per Kilo%�_ Mill�_m;1�&� R 0:�B:of� e�b8�1�&&z.rA(.s ,K �u�quart3"of � .�� �D!I"%�* �ed7J �efXuses lo�reg�<� mo}7mJ�B�.M4�2�&>i,N�zs� ��null hyp�-a��66�.�66��in9 �h&+i�� A$�8 inomNE2| i�-@�!/l!-_ut=Kp-� 'Q��5i��m0b�8.�8'"�.A_E���V�� h!u�?�?multip\$esth bee�, q �sU��ro^�lse! �y� e i!f Benj$i-Hochberg�c�om�Ge�D��aw ≤O01i�_�BR1�/ ntq*�>+4Y�E�verif�*Z%a)��-Q> 6  Su�I!!. , S8��S9 � �� � G640-thy-�~��2%"J4>�� ach !BX$!n==�� dilu�OD660 =R005 x32Fxdw8 mCie,HPO42- ( 32P�A;d�_^  m�� ( 3x�Sub��!�Jw6$ �to2�2F&h�&= ��immuno-�;p� H"` � � ser�Os2M 5+�YunAM Zglobul��յQrabbitX( R22 )��!1 by passag��<�lum$��a�el�2a�c�r�c :c%\ yanogh�de�#�SSr,b�.c�H:&nct �a!" )���2^Be�ia�$nucleotide�%X�"(� ADED� sa�nd sepacin �"�) romaAphL TLC �+ 1M HCOOHa� A�8M LiCl0-iT�q*E#�!0:�o�Xcu.AT/)l6QL�if$in� � �+���8 !3�4t��q&�group��F�pe"�E��� �t�#*,.pOscillaH!& plA, �'�*�/��biolog s��at�e rang'�subU�i�ud net�%�(wh�P orgaI$ $oft&D volv�i�)-'!�4r�ng�� ;W�MS�IMs issuW�6a novel�Fro�K� �* alngA�aus^t li3=�Ra�<t �onD%��G�teH,a��exa�ou$pu��nt b� �&�dom,I��xt\�ᯑ�toyX� e_uccessfu�ap�Em��!<�atase "&_( 1 )� ( microarray �of HeL@l ; ( ��n viv6 lti-i��= ( ME�S2 field poial:LFP�rec@0:omA��ce;Q�M�$ortex�a sheep;�( 3�#�M6K"� edA!�`�S hemisp� [macaquW0nkey . R�2,� M>e�in [1�*�;6\ dm"�iLy  P�#)�im��$$e bulk-sca��C at�"3 �r�$"�-k s��KAmas>2 ir d al�-)0Ke�� �� func�Ya� s [2]–[4 I@Durophys�3@(A�a long hr� a�neu!� �s b�BA��le+�>4o�&�V�b!X�a��. BiB upon�&e>�Powa�1&�7�W 5R,9Q, �aqetc&�)�M!�orKi��EwS6s� logy I�l��-r� i)wo clos�re�<daӅ�ea?)!��[5%�,8] ) : Bayes�y %YndJ�%�E �u�a/properE# �G��2)ap �!�:�D!M�6 O��plicitlyE��define7�-el�.ships�_]L�#^0n.o!Bo9ve�Rz"+%atM�!Iun�*or2}�� wM�SP+H-�HEpa�w�,n��}en)QwD� ofJ,,}gin�@t�U�$Wiener [9]E�A�Q mali�byP[10���%��A(n]���in��!A!-.v�nga�aryse�. Spec# �, g�%![%� ', i�:��A`edi�Lerr�Rsecond2E���/`�-�!bh)#p-,2��Z�> ��o( non ) �RaL#�e+i�A[eJD�6be saiE�4��J� . Geweke'~ �o$1�(a vE# autoNvw'�� [11]&�Wse�0n� �#8�_a � t�Z"D%�EAmak �Q pr�\�m�"��[n+eful [1<W1 d�\opFR 2�B':���F ,�#-�%��%�u� , a�P to d� e�+ 1��& aa>2z . E"�*F e��F�:a��i0 dirxco=A� ( PD� *��� ct 5!il�)�2= �M�[1�Iq.A�a[\^H�Y\� �% �I76�/as�fai� �QF� ��sim& C+�.@6�reZP�0Kolmogrov equI�+?!(�]�1_�/Yq�v�!A2]L eq%3i��ul�!�B&6�:5bT L flic��=�&�%�Mm.e&valid*E=�weNnA$lyt� 4\ �By)R��E�a��=:r ��(IκB-NF-κB0�n*� �%�E*3MZA�p widB���8mj2wn vV�bQ"mD5) !�!basic5�h y�0it2  !eca��8 of 16 hou�PTe �'V%�)M�wRB4 A5 � ��>by��%# � � e�F���  thir� I� y fe� j.�a�!10 ���$%I�K%zg�K� b s-9LP53 )~i���fur9 1�� �1ge�aq*��xt%� Zt�qb=�N�2�E�A�a�is�-��->'r� sY�inN( IT )AaA.��a�9mu�8p0r�*�yt 8ve  nnel����>u�7b$Z&�Vt� �Hc L�.� �tE���$�c�E�}ora bipo(5 �15��$���*eY �bisu Nor1I���i�� �"&V*U#��� i(R(Ut, an a+c:."]8wo' nF�8. To :nQny:�oY �BeA�? ���E��@a�� ���M�s;"�* ���P5�.ultaneo�aarAH:� r%W� '!��&s� εiFD *i = �J2 , …7!I$ zero-mean�Zor� ���%�i��� �Zaiε6�Y:%�01,e term biε7�−$+c"m ��2aEJy F�)4,��W � x�a��: sourc x2�%x3 �[x4 5 sh!|8a feedback loop��Cnot conn-�Q��2X.$ yy*�'E�is`#%�(ai∼U[0 , Hb1�!�c VN !�…�w B2����� I�l$ xai� c!wp )�� .��ɍ� 2000 pV"�N�A��200 Hz�m�& 2A}�I trac �5��� .� ob5/E a�$!D� ��x�+*�epi&in� 2B�C%Y� a� 1�!GfbF�!� A-R.a[1o� cl�>*� vtoutMX)?v�)#E{�n�re�v�H|IOF�B�� comm �� Gkr 6��ed viaUfa.�P�&m ��4→5!�6��f�/!.& z ; mI�PW'  ur xR��� 2D�� �SQI!� N �V]�l��f3. Blu7&njl%�1�f:/u20 kin�+�8BBhip!{t)Z.��:�1xsum+(%��� ?v��*[ d�([−π , π�A�/ ed ,=�*�Ka"� 6� ny1�fE�w���v� J6As men!D���0,�"� k ^*{ 6�I�6� qB���.�A%ytGee"/�Fa��1aA�detaia� �6" ^��llfK. f ( PG:a���$pIm� ��n$.0C^�.�ze�4to���\��� �1�:� 2�3�4+*A�t3�4Mn"�F�yn �Uh� �6Vo$bottom� )>�ge0nd?m9ω�!�2��d*LpI=�S trad����I !A!��dP�#� �"��� M�!�uG.�-A2]�!�e?B��".Text S� .Z*M � yf�^ :,� (�jQ�9R" to��M�g��$��T �WBby White�N . (G :h�P :n!��-� q� i�` , 48IT� .a� terv9n h��a!�:�A�e�e ata� be�K�@xHt http://genome-www&ftaB1Z>$edu/Human- %C�/Hela/�t�e�m��<_SXqA��%nsU&�'>P(�-� � �b�)!�fPk <� MRE_am~U,a��piv�)]!4'>\fla��A�innV �*&`� �� �@U�e��\�a�� tumzA�5&�:�E�prolife�"�m"2#�!I<)" 'apoptoc.*�2ly�@#~�^� "`regar���`i�!�+!# ��D-i0-�!�,� �# also�ȵ� �(ofG=F��lin�p��ign���-�s% u�5ese�.^!�HA~we}�ihHF�7%:�%F%�� -*a a sl�+(-window VAR#^I6���<C�+�nyp�A9ub"� ch!�-[�y 2� n>��>namely:�%arm-�(1m�%!�!N�T�&��.Pof jA)ed�W!\I"� 3�Hwe ploU1}^Nn�"%Vfr19( d 0�K">"!�`oN|JuA:J? 3B (0w�_F�)�&o3�@��"@X%���2otl 3%T2�R!]�Y�"���[d / of IKKα��n�dSsoW%� �1�S�Fayj.� 5,2�?x 3B ,�w�� "�?moA� �1S1ZC5� ��8i�!&� <\� NEMO%���d�5bi�C:��.i�eu�![�F:) �u |1magnitud� )&BgQZd@�2ZA�9qaC#,arrowa4�3CC� "D!n�^?5�}e �� . F�v2P"# .���yd% e"G�d�S�&I��Np�&E�"��>B� E52�-��!(��i��� %taaon8 m�E"F%. AM��9^� chie��h%��  8of�ne/�*Ae k�KK�%�  �PP3t�#,atalytic sub�"(&αECA���|��ory/adap*; �i(i�Oas>�|J��a� ai l!e� Iv�-:�-}i 0-���X ; o!L+ach�&Z^!H6� .d���fMi� }6=� Eqcip6 (M�lyT E�ly���!��0%�m x�)>$ �bMm Z2 fashAlE��uR`egeB]I�Fl6J�soth2 �X>(�3H"�hit�Wt co�(�mR!�7.%}�%�)����,a=h!%k,��A prof.�bb �0�:�^�"\$W��*kXr~s �/2Ŋf��g M )��#�%��6� �Q2��f1|q.06�f2.1%x3 22 h-E�nIwal�.R�9P-t!��A8 ���^5ng!��9qeak� �→����O" zH.4>��(� �6" �"d� ؁?EMO→�L�t&:� p%�!-�=�W�P��� ! !("Zly6��U�!e bes~ A� led�Bit!Ne&�~�)%�1B�Mf�|&� 2{*K A m�p53>(���1Aa�w,T �/"b �pH1O �[��e2[*h�[V\U!%�:��-a9I_IY4>�aPSD�\� a[�{��A)EAB"P!z+ 2O�!U!�"B+Ta��mY?B�isE#��!om �.4ab��me\S�UY$6O�t!u�/ ��A4)!�,a@�Fu`-�Ma�:. F�!���qre�%1to1�|ai�a?6N�j,harmonic ( 8 $)}e�mn��,pYOzq�9��:!ơ�>?C� heE>l> 0 (�/ )�e��&&�?V"E4eft%a�&h2�/:70,4R�0*�"�M�E64&1"i�C\!�8vi�Zxro5.4 fabr8"QXtungs�2wiN( 125µ�N)�pe�s[ tip�A�\ 1 µ ts�Gd� epoxyU-����9�"!%1!]��e�U1 �NI"n  .a��>Z#inh-&�4� � Yf�%&_ !=7rv ��7s'os$1 ci!?a foo>=�=[17�.2QMI+$i�"e/2'$m#exAz%�de9:nX��Egh� /!!0 stag-!.�19pathwab" is�\�`�O�(s�%�qer co ~$q�_s,gorizX !mem~ ,  . fM�L�|��Ɋ���reP%{�L��u 5�!?� �0 �;] �as-�,�& 6nd�ob�E2),"13� spik�5nd �6B�s*U(�-��!0e�"eWQ�Stq toleE���t���^�F�y[�M��#u!Z �b92�wr2ima�6or��� �2 techni�V1�!q�x�Sl�!���21�%�y%�e� a1��&bz7 Q�resol�J�oo�0Singlti��XJ� &���v"�-on jUunK,in30e�7�3;ensem�6��}�$F�'�e�(uFq128.2!��.���a��ITu�nI\�3�� /le anU.�?J�&B�����Q�2 p�T?e spa�.� "Z!IT �,(�X7��.%x2&� thet�Zwer�,7ngi����!cK5eaFch�(�+ 4B* O( �v1�#)j��v~-�E���� ��Q!4u�� 3ɚ��300:w50 �gdC���e7 x ��9�%�nK#!w[:ar��B ��i��)�ѝ ��z~�er�ie�op�Kphp�1" !�yeO���us.�m�f�st�ng� D%m"�.>��7- *�SB�[ at 2.pN/E�&� lso&�,F�eay� se4��ANz�e�LFP���G j� 5�i�!�ws|��4I�wav�P87\-aralle�;X�IT!�$ �[�H+��I����{ref� wa�!�u�U���pre]b� ll��f�inc�i m��7.d ) b�m+*<eP[��& �����mo[ w� L ��-a e&�' K i*_!�a�d.<� �*ay��Dl_ic+!pe�P�e6�� f���g.�oYZ^-���\pZ�s)bl:e{ else9+i���6�% &251�eas ‘� a�[A]�=�36�<�8� A)� � �9[2�I�u� ��I��1alignOl�,Psetup� �p�:��4~ 2x>���w+E�.�>(�'czA.�"�>V?i�1�cho*6 �gR�&mK.]AW<&@4C-��� kio&:9��4Da�E-q��&. &���WJ):N��G@ �l1U��@8 ��bA�Nr:���y/�6 L� �( 1→g�2<o*�; �2ak �6���vi�; K�� �\ g� ��6E12�q9t�n�i���)"3�g=Oyq)P6Rs �x�6�/tdj5]��& �&4>) riefx���e��&vTg!c1�+0ed a GO/NO-GO� pa,�Jm M�I�ɗ0X�C�#"A1}"mbt ( 1;k3� Y*-)�"-�k�orimotooAA*\�� u, s5�y#���@5]i�if��5 Z�Gp����v>&[?(;B�-5A�v�!{.�+F  cJ}� ry�{ato)bF&a�=!�  eMpos)Oor�8ie7Csi��*� 7)R����e$ɔ!ad�.��Yomŵ ����a�pplyP�.��� = |^>T5B."�%Ral7,�U}J�)�7b�an��%'V1%aM"q*�r�DA�!RUwc/�{F �0� �nx[28 &�&S� M� 7b� S7�A(7b!��Ri� 7a� M 5"(0Fymdy��2)�BF toђ){e�J�aO�V�, 0F|�D:�h� Q8>*��k �B�VŊ. � 0 ) ^� a,5,2E+ �=�xsu,AG�.�j�1 nerv1�b��Ten�;D5}�Nn W�olv��\$e2�XkyD��wD�Ycmen�a}Z }�.>�be Q| ȹway���(I�,��re "�rib�R:�}B;L ))IZ��#�=pri^-IL�B?y%no-3,4} u| �;.`9�1I�i�coE�� �+!ru�315� sF�)�șR�*��? � .�X�%�to�(in W exclus�u> X%EZ )&�WalD��IC,>�z�n!�6�e)&�5ofr�m�,8 e�on  LA{axjJ:���:ua�Y�a���4C6�W���� )&[2`#T);� &=��Y!�X!��9v n Z�(V UHn9F!|���B-qa8:��� !ty�e" Ya��gRc$�a��:93žJ%,��v� A�28e�"( 6 ) No�"�Q� *�s.a�j�!z�2)x��,6&av-Xx9x�  x1���'�d3%� rm |Σxx|N #numer |S44| n�"F�f�,\\ !./�!PA!.��(−ΣxzΣzz�&Σz �.6� −S45S55)S5��G�B?BzC�x=E��is�+QP6u#�t� H"SG���" -[R�F�A!�inu� . Of)T�:9��#!����� �[a<��at�\m�#�a�p�?a �:-)st� Ѻ:�R��Zd"KY�n�'n�M���\pic� |] r;�f)��c-�5A� -z.yoi~tY!j$n page 353!�[2~�W&� ���%Jra�xiOQ%�g��9oU5�Q%�qq*d�+~8r\5�.*c;&JY�mz.[\Z_vl� �cF�"��u�R,���"�E�"!��u�9�Ie4��Rid� !�* �!*�O� �f�%�9!GL>k ( ֦�$�H3;�"~ k<�"R"EF� :���8 )��D1bE"�qD2VEm , D2.&}covc$* , Zt* ) =-W� ���X!S4B/ , &GS5�vDm�^�|7E@�'!$( 9����( 1�f13!�h�B1aMub!�5<1� kεx��εy z5ai*9�0thkW�q�� Σˆx� y[ zz%�q]a3��eq&8�8��1� �PaI�� ���Rwo] m^� 1� �c� v��X}�-_Z � �3El-eHw�"?:)!�w�u�%(�J)-^Q_AQGTH .�a".�ǔX*��(�<R�′��;a���5d ! conj�+} l:4A9&!�xxo � J6 �i��246� t�e�M�\in�t�):��im ,lya�^�v( 1��&� 2�jULB�:q;!{X*E�ls NE. B'g&oRa8�o[28 V��h e m"����l�FMqP"�.��!p .��s s�\fp"( 1����� >!�v$R7E coe"��of*;is 7�Q�"F.f�� i(�5� 2 . I� *!��9��~�h"�A�o�W��.t�,F�(, Kalminski%W4Blilowska [29] ���^�=-� �+-z , �Xed& i�NYq�( DTF�"/u��"a��F�H �:u/���:�Y�!��!6��.`/$. Sameshim�< Baccala [��=;PDC�JRVA2`E�� . Ea�,�XbX� b�uR�Qr-+4C�-[ KH��)�$%� �O rf_6a_5�Z[2�-8HI�1]*!/meq=��g/NŌofu���'}���"�  )�.# " B�or�%�%�4j� vX�W!^dKHf���=c"�F2`&�f9w&iPt��p6$�sÁav�s�#�1�=e����"�3�as>8 . O&hXa�W� � v!�G[��a���%�A�2���5 �VN�]J�, �2S�ـO��Zb�\�a��9�~Y-�Y�eq�0"A!�L��>� mis�!�>�R� D��RKifI- ��L>5i�(5�Ji-+�2�&0toua�BM�ܥa�L@F�q�r B��B�.�A�k*�[Ũ*HL��F~�ed�H�6o��qE��ZI"7N6 ebhe�%Eo"R�et[Qo4!&]�ž"i-a�U hoc ��abe �#&1\^� �.zI]uK6y�eA�n@Jng5��x�MPFp!�&B{F+. Due�0@� �f>g[( +���:��{�l��+ot�esY�nst�da*�%C��s�+au �e^g%n���M�� |4��7_::��an�7aI7f�%Q n, }E1JI%�n-.=f�6=! Rfd7j�!Af4 ��es<9i�.aD%�_ n2o;)/|�(%H I6��*r�L%�G�9� ���.�f`2\�� ����I%"�f.c�\K �Pq�rdaVe-&siYl1��aNQ�=:!�:6B crosstalk/9f3R=�IH"�?�thA�A%�) clai[iat�,�"Ct��at:i *�� <LK;�Ŷ $)^h!�troB-E�8�s untru�%AB IM�&�%��;i-y��!I!aۙ�1[�#glMO,tr�7�5g"J%. �$rhyth����)per�O,�. f-su&�2� a hallmaro?� �(g)j(*a8�8���%.*D��m" +�e6'1�� � �� {6�)E taNXmet& ؈�/D(rt4�8�6;2�on-�I5�!�,hippocampus;E���adn��%->�! s [3N8kN}�G-�1�t r "|-2� 4ս,?R�sr2!:�&�>30�4�_=!e� ���_� v�!7>�+.���x����qe�b �hr�/3�9]�i�#}  ri$�Z�tQe��s .޵.;r�$!�s`�zO locu!��O�"� admi�����<�a�g .Y$)co Ame�<n�vpl�;a �4�@*�+�6˪&�la�T2� ��,��fq=4ng disease-ris�[�Z> ��!I`�����LQOappBmis*!�Wig�h�P�om�A�%�msM� �:5Cz�O �)� oI,I��>deg$>orf� !l1%6rr%2�*ai�9�Mv��e$a"O%* 5SE�"�S,"� ha?E ype-�:eB�AS��� dema�!N�ϺbT�2,i(�@4!� ;a�a^�#��a�M�҇�j�m P�%�Υ-!B+�a�( CSVA�� t03�w�f2_eFb!� ��RBT�:i�{m!�*. A�d>'bG�]i' corp��|E��iTLthemselN "#n�5c%�bfqG as 1�]GeA�M�.Yp�<c%CSV!�D1AU&�^���)Z� )6}�curOs9to2�2l jn I�e�run�n.FVW?6�I4e�~�ar�2��o{�2==���|a։�!D�3rlQ��Bsix"2UPro&?)q�2[A�cc�a/ low-J{ag5.�"�nd�)��=�}���֓E�A�t[.f�.i�%W��rhnA2Iub-uaal*u�Rnsmo6�aD�WcaG@a 7= ^ ,k&Z�>s�!%sh�"=�J*����Ga�TzM�. AdvC�� -�MH:a}���?�qA'e?dI��s9@%r��� �n,I Ume-�9oc <( GWAS )�Gѽ�C�9'��!�n��[) R �-"!Ka�ofn��ţ������ archL��('oduX�y�fY: san�"h��%�nas �>�<��� ��Y@�l5xf�'hom�9s �tV �n�:�!����D�sE/� erbGE&P%1�1�a� 2�o��e ethnb*A(s2�e! i�Y.w)1�E��h%�mr t� uvA)"�s. Od*�Ji��#��>U8,�.�%hI�� ��mosaic�suRL���&� �����@�D�1Ukz��D��.�*�feu 5n� (5fa������'M� , ::�U�:u0�� uA�T �+U�`)~Sv| [8�F1�s�$past few ya�%� 5K�� :�5<�HZ�e* +1v�7]=!��E����?� !�!�2��?�~��8  sI�< �9��I^jR le~�of Z9��I*& �AfP "Y F�ne��{Bgh�oi!&������ �����iaL6f�"-"� ��DL%ic��-(1�����!y� ��s�o–�H� ($�a�ng�0%�Wq?YinB1TD&�n%�=w)�&�gM����r`%ng#s��E��� �e-Q�[1�v�> ln"� ɓp&� t*@�&� !9og%I2�[6D0%MH�) �"��t)�C B :� !�v�YyS�?!��(sd���"qG�Brk�i� i/(dden Markov4 ��dV��� c�EW�A. !�A��cos�}neMF�[MV�"�toa�E��FQ �!kE���e� q��� CAC�Aage%�quilib�� ( LD\$m������4lyJ�ablis��31%c33])'J?!�"l ���W�6e�:$ ver�1 aW�� �.8inh�Dz]�rݶM|=��.��2Ȗ!�Hx!):��i!ՒI�e�] �t�>�q10�M\- �s����څ X��B�,�7F�*gFm �, prox !��Na�K*[35�z�r diverg�:Im72o ! RapiJd�e���͓!Q2� �wa3�M�wa#�a4oE���E����-ad.b�SL hoic)�,�\6T�36E�4��A�yoxH  q ��" �fB���%>�Cco' �' ��#&�proF�i0/l�g ("�ex .ng HMMF,�Et`z5 CPU�� >�in�', ��N�or 18{U<c �M_-�4�Z� Y�QG%�/� "���.w" I�Q�hundre� 2� .�[4��*&�.�[� %�o obes�i8D���F�[50i`?A/Dc�Td 3�+!9F;A�r2��{�{>f$d�(B:�YSwy=��re1�SY�ao.< �.,!��8| talogue mD � r%E�u e�;@2b { (Ō)�en* & ,��"�oIU��}#��2� al�� { as E�G�or1�m�&Y"�3R [51]�eQ� 17,��%�f��-5–5% 53z8<1%�J)_!!ba�� ,� , E� As_����.� `"���H�ɜ�D u��Adultra-;��ign"���N�u�'>hant� �m�J�%u� tandard hN� F� *� r!�]!Z.P&�)�%b�( Lanc-���]d �u �poB>L*m��})b�RZ^&� b}&f��m,A� ��&� p�m5�b��^��p�'; :7) � ރe e ph�SB|,6Me�XeW� .02"� ��uu�z ��V&Lly A�e� �Y&fXm(�� V@�i�S� a���2G� �jyuq_42��!V�������`42 /��if J��"�A��a�i�2���f6��s�I� bje�j�����Zqu�M�a$�=#Ѳ.�a�p]=urD%bo^ i�cyy.�/�b�)� h(�"�a!W .g�e5�N�"R�}23� �j�}at�� ��Z&E ��x� q`YI�8 r2�0�!92:�F{, Mex�| ��Puerto R �{� ]3��LAMP-LD'",84RFMix [��Q480 MULTIMIX ��-`.�V!�*�;ow&�}L��ur- a.�s9`at 5×F8u�5t�3.@86VN-�7Ϛ97q856?�d9� V7w#&�Wg���(�^#J� �EE�,�  l6�i12�`�>�Y� nd2�2lF�/���agree�R!��� j�J (J�79Q�Pv0H� E�3 I��*B�1E�$6@iX�ee"v_ 1 p@Ma� ��V� eoff"A A|"� "tW5�92#�:6�K�. �OA�pr�3�a�)��d�:FO:QM)�6����c���6�!@�����p!]�x*f�J"��packag�!?}C^�)@�Ybat ubogda^8bio"� cA�uclhvuy(/lanccsv . )N��U42c �. �e^�� b�%,�. JMs^& �&� ib6-�� ��� "sXZ&!2u� ?�%`&"�)I��e%�,J>. D�5��.quick�`d��B` `fB�(ah�_�DAR�Ņ*\U&�uY�,68�SY��!"�!( 4×�:�"� t�r�"O(*��b-�X�[Z!P\un eXj��8���!MZ*� 4as)G*6*-�>I;�5& gŪ"Og.�Hr�l@m��tBQ0��0abe�J��źZ�I��!�s]�1)e8)�"��u�S�6:�A?pur"(�b.| 2pE��@mimicfB���3e3TSIP?�;, JPTh�:��LWK.���>�u�,B�K1 J�,XFbk"!?&�.N������Ce�r�a*� h9#� �XCEU��H, CHB+CH۪1%FYR!%�6�$�U���B�w *7 �a nRR> _A�t�>6�A�ed }� !�:�eU�MStO�^ nel;�h�C�|�A70���"~%�U% a��Mals*c`� �=5�a������. 2z��Ji�N6!&��maB�&���n�!IJ�VM� T� xB_/ spa~�-�-����!�f1rE>∼10 kb�(u>$���to $%�.#. Se�weiy�&�#yFl -�6� �[a3e .勁9a"aC+5�9�N50E !�3"�(�&~/O����I R�)jrf�!�i��5��Ka�(er ��H?t�}&p�.���.�b���l�boe�q-�D*� �!-1����"��nY'J S"`e C qWe2ci!$*E�N �! >E�� ��bePof9�!�Ij� !�f�6 ]V. 7% v�O7a��8 . 8%! �!2~-U�("�&.�'L � �fP�e�M8��we "T��&py��* B")�e��!�-�M=u��� E�le�A�Ui�[�+ci� re�>lle.W�!�e��=�c8)Dof^o^a�6_} ^�i` "ln�~] +�.Z-�>�I(�� ce!q>7zs�6:_uhb�4 �B��#� mi�&$ ()i"( 4 wR-ek!�2!R�]:�statuA�W? tendj (" )�B:L'(Y%�Vءi�3�:.�,.�h{�eV(�+mh].K=�ea�8��-�abt6aj 4.�"�J-�إ� e2� � .Yof�t4�r?to�����Pd�J�P�2�6����i���!�"b,eB-*�*�nd �"7��$ ,�i:�Epo%��&H��HMM &.�\�1,as�%��)�&S#�]e�0!�O��c�"n F�!A�APo�7I��79�{�] `ZinFG$.9_ ��?���ng SNP�]��]-te Gaus�1�;��5�u��z�rE�� �uame��edg�"i�-� �����tr -���iie squ� �2�G( rAL a��m .j E&| one;^]�DT 1ѡsz/�p��E.�'�d"��"h:��vArE�e�� �_3Wa#�ct�-��� �E&fE�s!E��j�B�bAq]�1-ceK-�-Q�M�dB F�92�O�&(,�iWtp*�+:h\T) A �77A N��Q AUpof�2aj���iL6�!F!:� ��&� �X�3 8�ew��Ill& a-1M�)� �,�#.� I71 I,>�" : �� :���c(�VFO�%��.�acA�atjCW �2��m�"Al3�.�*)T!�O)'!���n8�V&� 6�*&�,=&.�b*��"Ju���&DFa*:�y7(a���p�Bed Y��X.c!]�I E�6/VI2��:)Ef�� ) . In addition , RFMix accuracy slightly increases when sequencing data is available from an r2 = 0 . 84 to 0 . 87 . We also observe a lower performance of MULTIMIX as compared to LAMP-LD and RFMix in our simulations . The average distance between a true switch point and the inferred switch point for Lanc-CSV is 76 kb and for LAMP-LD is 91 kb , both have a standard deviation greater than 100 kb ( see Figure S1 ) . Importantly , our approach requires significantly less computational runtime than both LAMP-LD and MULTIMIX run on genotyping array data ( Lanc-CSV is 3–5× faster ) or sequencing data ( Lanc-CSV is 40–150× faster A�L=SsQqfaU thanM�Ey �s:�@( 1 . 4× reduced)8time ) ( see TaA� S1 and Fi!_s 3S2e Howeverure-[`param!.s�G�y6���At��L wU- an&�of j6RAfr�� -Ame !� 70 in Mexs%8Puerto R�%� . AsYЕ��N���Fw�(little gaine�>com!lI�10× (e<g .N�91!Z(inf����� 4)C�gte�*)u0local ancestr� fere� aarag�QpanelEM�s�puse� proxAmforE7mi�V ]al2� that mixe���  curr�dd popu[.~�Z��beaPro�YLi�A�k samp��themselv �rebuild rv[3��A maj�*dvant!?ofi�pproach�fuis)w��@n iteratively re-��e�b!�corpo$ng in!F�u�i!�red1�IgE�i�sj# p�� we first 6�)P�� rnal~+Y�(1000 Genome��,!in�r>#��ina5 fash� re-call) �(confidentlyQ.segments9&)� itselfJ~ ThisA�cedurA k !�e number!���r%�wh<�!�new  �` A��@ll�!o�f��%�*� t�allowi� � -awa�:�et bett� :��y�y��q�dayU56� For exaaJA*K ���%ą�cy)~6+7�O��92+200��!��.� s af�f M�Y grg stV��=!xI�B%� very��R�cE�w��DourthE �(main source!H&� 2�6� dis� uishA Europe�� nd N� �� rm�%�� a much ega� to noise �41 �fn�)�for2^q�C1�i�w����V is highlyM�te��A�I�( sizes beca�Ve !`out any9\��UJ VH !�strong� al>�e1!R�!Q��to�;easily.�ed com"�"$ i�� at d!ot�!R�otherRNŨ���:�,& will��tinD R�a�eh=k0�.5 � 3q� as a func A�!e��q�6.0 *� E�@^�shZ.R'A��oA2!)sufficiE�Ake)�*I�sAz&� .*as mor � t�Jad�iB�exceeQof LAM�in�m�Ez.��I � inv�mgazwheE24similar result� nA�achie�i�� �3L�dRu��0"�A���2 �rPB"\�| qKA&K South We�8n USA ( ASW ) ,50WLos Ang( MXL,�.%�� o ( PUR )2/R!m2h Proj� .6 i!�:ma��\thA'.�bo)!consensu%� �2:R��,[31325 3!Si� �.�y��]kn�A�F�,aumeasu Ccor/7 :� �>� et."Y  ):by6SEn�  a .�r�( r�(6�pma�ha �ial�Ce*MINRs [58]E To fO er.� hyp�:si!zwe j��iQ���>� in 2EU�-�2�9 r7 | *% : (��2�^Y8�.�y5 �W*� larg����o+i2 �!"r�(e theiB�]�CF�m r2!ak80% ��66 onlyMH.)IsT�Y demonst� v5A��of�;q�a�u���ŞisqVV. It �F~a � G MUcould� � I�obstacle�*|�w.,a�&* refY��� !s>�B�nd:_ "��) � �im��edAZ=e��� id�em�a=ea� Kmf�5z�x���Ir.��n� ent-�fic(a�to sub-c#al*�J0( s.-defv asXAS!�Ռ�A�on� !y=@sw)!�jymW&�ah^[X 2�G� Brit ( GB�!�n�g�o� &�'. U/ a le�� aly��uSR� 6����hM 9 Dof�w.pK 5>)b�K. it�^5tk4� �. D� limi��>q%hclosenesa f-�!:��aTide� Z D� �, but%�eno� to m�:�2�)impossih�me scenX The two �A��IBS.@E�E?has 28=h��A��a� t&ge �)5>CHB CHS g�geneti��y��y"Y e�ass!n�abilityA � z8�!]tM�-one-A\i@sBc^ 2����.^ach he��ut#w�$ndomly sel� short&�� �� 30 mega� i�as��m!�B�ar�� e maximum%e c�acrosisv)FMM)�c%E�naïv��Bc�iinq�7 XŽc"g�.b �!�)5Q?�-�ati��al group&� i�y8 . CB ngjs�a.re=��( length�}9�)�nM� �>% A��� ��lcoe"# of r =��"65 ( p-_ 04� . �0� Bf �seXa)ed å@)�tej��[� � +�@c9R� YRIe�LWKa� s we�A�8e Finnish ( FIN$nd ( JPT )��v��2����yK aRer degre�;g�B difs t  &!ĩ�>M.� �CEU27�� Utah��s)Unor��!5d we"���m�l�y(:���ɼ� pote� expl��2� seen �� š���B��:�?be �A�;i{6rx"en,!b�made , �m "Pu" an)�9p�� sameN _�eA6E8� We��&�1K. ��pai�x:P5��-�mo�%��c�&~ (%�In order����exf ��-$!c&2D � ���h�M"�peo!�<:m�- Es�- 2a-UU�� �%.@B(*�27��R�t -�9�ԁ'a!%) ���ahe[ WenrichE ��!O�AV(e:��" "� �5Q = on aL٭(�% diamon�!a�!��Nn�.O��n squareM � �%��p zsem� x!�f��E� ! p!�sup�!me<ablisH*�� C-��o�!+SW!��s�� 4 [1�W�( look��OQ�Y�s�* _(Q10z�Y)��u��fosed�� �o2N��M��$N��ak/rth�4!HH�'&-$sm8�ot�pro!e�of< p2B�:( y a few \Q�O9?}��f�� �T�&!5I2"Bm�!'��J.)�y�o�. WK ve|�%�(�%n���: &Zin fu��&�r'(�.�. O.�* ?! u$A�"&ren�b�)ai6sE�a-�.�� (J,�q��%A�M� 6�2(w-<� !�m& dens� s=`_e"� e�� to!ow%o�*��ɴt�" �:��sh\be� a�2��W!a� d�4�*-�A�. Nz(�do%��("@%!�� 0ie�!i�# es m�% �}M�.9���~!�!y�m��B g��truA(*��be�ingA�'0���J9 ifi�nd&�!rem$. Hav!DnoaU-2ute�+7%�rua,9Ii��"]= �!��v&�"% oppo�t�y'Mes&�A�L&?"��cy�M%`� *�� a*z�W ,-�a� &A�runAb9d���4&� 9yit�emcy cis ob��=�oa�e�n%pPu.�' ���zI�fea�%jE%�rt�-as@r-�*� :A�5Om����-�*>�h%Y�:U e nee+t�hIfB�� matc-1�& �! Ba�2�e��&�c� ly^B|.YZGs�a7jN:�1%մ2�aC1�.4 . Un�U� -�>M5��a�aP>��� &r/�n Gen�=\�V.�We���) cep� EJ���!a�fat un�  &MitaB"nto:� s:[ "6e5'rmb� X =%,IueT" !�ly"H.0%U� I ( nearA�*� aX! ) ;a�e�B�B���!#>��rw!�dr Um��"#v��>,]-7�!Altho� s%�&�>J ?!M��id�o, � soph�%c�!h�oy� �ruitfu e`�`T. A fu%� 1� !,research���. Nf*o%�x�"^.�.� !t by f!�ngAp'w�1���-izOe ŁNinkage8%O3"�.mo:�z�' !'aKribut>,o�~�2�licit��ode% !�LD�uc%�c1�M..��()�~a�2R+ �� !`"7_ � �"I6H� �&�<� Eis�' �,Z9i` 8!6(yOEq�is� ontrol��in�=!�H8�;�a non-un.%}%\1�1\�:. �2� }# [51]%fproL+d�20ublic catalog� humane �hE�bAZ�0n�,F�y�s1�� worlA�Itisk�C6  88 Yorub�ʼn�!g97 Luhyjav�5?"ro&!D1�9�%Q 85��(})�Tusa"in ItalySI �"��we�B�U�B� 8 Ja s�  Tokyb%7,! HA�hin " Beij!�(g �100&ern20%Sn��4.MN:�*�m�14 Iber�".�in Sp�(Tv&93"�nl!�.89�5in Eng"& Scot (�6gd �%ka_�!�:� A#2>j8��Yi Br�1i" "t A"2>%��A,%��A�=@2 trai�!ʉ�nd���,!�+Qa+92Z+ ��#sy|KV/w% disj�;,un1 #�!qp�4�5 fix6ed A/T9C/G�S{ �!�5N�1aO1 , 58(313 ( 50 , �0) SNPd%+��( a�8 )�A�S�)�>6�(w� �*&�+9��$a r� walk�"�2S=i. D=V next �q0�!^ d) an�i}ial!q�!�w�.p��( 1/ ( λG )�$re λ=10−8��21}.� G|!y�$"s�  ��.*). At a�..t� [�4&�8��6�_8chV ��ord!��p&� p"]-1�5g�drawn8l�0� *�"gg�M��0L���ay A�:� ��%��+��%�noQ�{�<�sm Yo�~!}���2�( θ )y/�9,B���� y:v45∶05Q)W 67 )13 2).K.2 $0 8, �*�7Y(–[61V+�2 $*�,}z� }9!6!leI�F�( GM�6���82�6�y)�9ed 152[K15�CG��]*���"{F�s&�sY��9�M H;x265*�;&T �6�G*�;3"?= t�$�$B��/]aA�|=:� �2�'!�m�if.em>2U���^/<��t?= how j��,QSK���  �+.p� n"{.N�io�9T�,i*cu"a�to�rE4�c6�W��ov? 5a�normal� by�4ٌ�!i�ed��.��j�!�%��=of%}:9��9\AFu�IAjj[28h/e9onS &�3.? ariT%VK��2�(s A… , AKI~h�b mixa�� G2��r"�a�oed"�� r!��describe)�]��� a vecOg5gi∈ ( ���"�"�8q�+�e�(q�XSNP�?At�JFi�9�'s�"K%eiS�+�en^%j�� �?Ov�or :wo� ?��at inte? 2� v 2y orig�ˉ�W�at)spo� !zm$is��an HMM�!�:�Fiple H�= ( Q , δ�� )�QI�Aof>'te�δtra�a� prob�'"�5a�ε.e�b,���S�is�%� �c]v1&?9�p% 2@�C�a��LB)inBf%�dQDe��Q !" combinSA0FEa~l.P� of1�A^?"_5��=X5Lδ chang��M8Cjit(M>� ti!%staz �B��FF��εE�����T%�st� in Q�Vny��s[/�'s Ki�+n2-�0 } �typ*��5l2�&�abneea�if K<�#("%�#`BZXs}�܁a*%�pi�� �qA})�-1� ny′ ��"X3H!� A&.;of�r9 rXQ_s on� 1�@j-1�;�?v?Fe|Z�6J��I^mE5� s�tI�(Poisson�x:� dGλA�N��wo��*a��Xb+;Ax d ,��a�1Aed: ago%#�2V t.rD λ�!�X+*iIl`1�� )so��46�15a."*&minim�! )&G�#�l>nk@1�I�^)R+per�E+)�D�EL(�a"��&� set��soN�a� must0�,�i�"�-�2� �"� �"� & .�a�. a se"�;h�o���H!�-D,���A "�t" toi:At�#�=9&&�.KJ���)�:�J�om���.�2�%�� �� �yɑ� �.ow9�L �4AKεCSV���5E��>��Y�;�.�-�b�CmoeMUKE]*� i6&B�B�zyg�&/%�A��'�� �A�b( q &m[sil� . W3�3V$�C!�"� R&H'v��Jom�!> sum��� pathML.L�7e]P%/d��� �*�JEBaah�4 � ) :ż�i-tM deco��e �.<=�=qb�!��ng�A#/ %BUXpaihp0}Fsf u.�.&E=�!��#ly%b&�"�4.O�!+ %��>�.��. O��uYN� a�e���ua`upd�/���newly.�%�!V%�#:�G  e�)� kE"2 !��7)�"�%I�$DKy pki!�fo�&M~A�>J�*YGs����N���k1� 6%�� !�by twica�.�X)�k�0�M.c{ F��o#  aWG5�� Q��v� i�#pt At,ANA�rQin_*9� X*� "�#]Jre� �# l�-� �&qG�e��^e�=�,��"43�!�Y?*nU� ^�3(2$^�D:v�[�$a!+d��*��( P� &�9%�.�� qu�= zero�F�:ns'w=!�KT%�"oed�AX!Շ�po�n��Ak��erM"s�4ew�"V & �-Y+� Ir."�negligB7�:].! k ?&� !�3r@?4T %Kon ]�#W"�:*�$( v/T��aGMULeV ,Fwid�"%�� -of-~art) �'�.��e!�daA�_ ly ��-k zW ��%){un�� C"EMpu)�a� P�N�$RF�W42�@ Pi�. L]�jr+/A1�e� .� set�,�>�A[�(�n%4s 2�windowF�0W�7 �w defa�@p�'no EMY�G%HmI�5}��mp�)G b.��( pA)>��5�Ip�a�5�U�9D_MCMCA:M �Bcan�be�)��resolV T=�it]sugges� misfit� � two-��ture [A�95E�05; 95]%2#2 02, C> ]�� hree:�)@!;�(wA�s$�F/�-5��� V�L� s'i�rprogramA�}-�-F�"p �-LSa��/K/�,Illumina 1 M�!�_ ( dF�da�#;to&�"E �?5r�+�M��Ui;,��A�Qu-�eBQ�> pS�!win1)�1"�2( ∼"l1A j�E*�e�uA��A� :�:UG�YfeI:�ati�� o=�)��2� chip9]�?�b A>a���i:�B�� aA,E"S��(T++{+�� G�) >� &c9w ve�>MANis���a"h�N�'ሙM6��m H&0-`!%!O�. �)-�T1× , 2 ![, U , 20A�3 s"r0Zn adap!�����^-�t�F M�in� ��XM�st�Zaen%� . Gqen:4!�2�A]A|XriG7f alti*)re��#tu �c�d &� e��B� eMmS%�A� d�Yd�� e@Ei�2E��&I! weigh!kmVF&l � M�Y{i)!KZ�Lev32� k�J#>�θk{0Q +#c u�]Tt P ( g�Y �gia�5�,irdE+�$n�YEDBz9.xri|{ P�binomB�#}�\y�>`�enw�L+tri�"b �g$IOa^.�� >( N 1-ε�a� A�gA��?,�or �^&�a1q�){sεs>. 0� WQV�V�3�]�:.9di>�6!�>sum>��B� �a��!���G"� )e�3'��*We�$osqtr�\c.''false� i��age~�0 �� .dis��y /��^�2@k#P 4agmv+!at!�Ɂ�{j�\ decr:d@�]7�breaksrap.�smulti4�sA�]h�&���qP .� 9�9r�;98%!"GM&l @y <5%�,�q they��5h�"^ �=r!�M^:D�7� /Xb�6�>3͍"�w>�忕�accw�1y ��ϥ��G-J?@�I0%��A�C>t� jI050V is 1P50%%�80%2�S&Pmagnitud� J��U�ana�ecj@�2extrem\2edi�� � c�+��� atU��!��\,r1�eV&�94�8^/�� {E6[&x�%� w6��inq�%{ !��'�:,1 �a"�? 800"��5��6�&$%"')i�a�`�JR�Y2 iZach=c�Fv+B t �"4�a�J)._| �S$� r2 a4Z4.�. E�� of2K�ai�h.#0� OE�d.�5�AR8%�!�5�>� �J��H�&���2�3 6�9��9�of9�l �C��U��U��-J8.�-yE�)�h^. �SU%e�95|�WanciS�F!�� :B}�5i'>8�HE�� 2��!�!�3Le�_Vest"HB:s�!3 &#�� Call/r�Jd�[Dust$n 3�|4Ka:C�$:p��"Z3 �&+6�"%WA�s�A �in pla6�� -r2�� �Mw(-sN_ �C5al W�5�"l:w 5dWN2A�!���2[�e_�>Y�Uo check� MN�%��;�J�!)|��u�,MF sub��2�d&� O Be<��q���L:R���h 7NAV&J�B��re�7F(� �2�)�}�'}��a*���E�.�E��e�!�i� �y-!A�L�&.J"�NB�6a!Osecond W"�R[ ��3yrg�by V�=Un1�%p2�:�IC�hXify� �2�j��!�oAf��l*� �� ��� wWU,*G?gee�*a ve driv�c! /"� � , *�?��&+�:.�U"��d*s��a.2V2͑�i�.M^J�=Ms:�=.B %�Vqj,�Das J!.a�5U� AaR,I�of� aV�!2�>q j�g��m(f�&�$���:7)��#� �Z2�.7&�U�H)"�DAx�U�+)�.8�l[a&@���o!biYw{ ��e�2�U �R� ! =)%�.�� niw-F5lrg�YK�FF��N/*')XnIU �.o�HecaN��b arepee��(ZDC�.i&�OJfFp5sk>�A�%�o ,w� 7�h:�&.~2�!s2�Sl�>�����;6Jof),Y�0#&�uR�N)r9�CK%e[q&�j, � gueOk.E�&�: %G�"s.�rg�e�qrrF�UF�E�E$F�o$�6a�l�EYIz6�%6� addr� .�f%�er�b&� loo"#>�Bs��i{!F�-�y�SOAnJ� a s "5Oor"�&.LE�c�e+.�#IEz]Ie�"�3ag`$)(��!�"@ S,Z�4V�+!^C�_W��5)1V� J�)n� >�Oa{a LWK]c(!b� E��m�N0U�� �#orK6M�e{�=O<%KeV�*Lin%C�!�,.�\In mamm$, circad|>(d�By�@b`d"��genPaN�l1Oalamua&�eriph/# tiss�a3L�lc�!Eat,–15��ks oscilzvk a da�hrhythm ,!�boQ)a�,trinsic mole!~r clock6tat��b k\_fAfi����[-Z��ofe��!��(hp�stochas-1no�j.�/e;p�;sh+k$K ly� digi�'f ��&�t algorithm��)[cDach���gen�-/S-�bs!��Ce2e�WA:s=tesmA!�oM ��/�t&�(s]: l �o!� al�;1005�exE=/6�CTtly2�:M�?`�JF6�  studp,A9�biolog%�g+�E . Ch3i�C.]��+m�zs�reEq�Nnviron�%al fa�6� {O�hoA�uuli@ feed!�)��] �!����>���CL)A�)���3=2s . Pm���v1&sp�Vbe�Ko?O phys%,!�d>vY %�a�organism�cyanobac�+E�(�u4@al}-�ng����,!2e+x�:w.�I comm�6Rupa&�R�����*oA� �Sen)�:�����Xl %3 darkmB�!cvp*>�� n�o�7�ndR(7DT* cripAv�rE�oryEN backFp�U&cYVysixsa 6P[8>!�I{ 9i�#is O�N�;uprMM,asmic nucleuA �b� [�i�theor��al� s [7h:r�U�KZ75�=aRpr{x"�*rzf��L@6eE�- �YKst�pR)�NK?�A]�~sei3�;.)�  A��3!��mA��ua �� !l� �!�& hpF��Gi�E�:�afforda&E5micro:'�rM,��lh�f"��=.�,���*!�an55 #f ousa�Z Ar3L,�.Y�<�;��E�Dg%V!��[ &�_*[ F� e � �al�� reli�^!��|ave��@M�U prec� qRT-PCR9� b�}o3idB9a.�M66Ō�a> 9�"��!4ń"�:�z!��}�"����n0F$ry 2–4 h!��)du�%�e M!IM:t�Mwo�>��I�� 48 hhThu��ao��pr=\�%���> char��a)24� EM�ng�!�cmbi�� -��{�;=�nK � ak�el�0!vT>�~ ũ*� H!zt�Win*�js*� p�@>9�"~ ict{e�K�M appl�`��lyt"~�-0>� KP}J��i-g s [8�L�ya%x)�s�P�)O �&2� V�a oA6 lack�F.NA Y��dI�GaVEUQ�perkage�A%A�4/ ecog}ac� ledg�i oblemW�ѝ|0ZC s [1 1�=,�&g !�e�}�|�.�1�b� �4�1�Ae-9!&atv&�& v�b��:lyig�v�9 ��)� scal%�j.�ɬ . �!DJ�a|& �� z-sc%�ZA5\�'P1�&�x!���]ss�d7 F E{-��3�ii�� clG7$ }gsF].O��D"��4a�r�U!ina\socurve:� Mmd/��8 FA`oA���_ HsC�&a �shift t)5�!4�� rval5*���l�<���( ���. 1C� � tmaxa@�aducEje� :9�X��E�Z �V Oo%x { *�*�q�8�! Db.v� oY5�&36itŐ�!^c�D�*��-{�epa( pam)�!up-and-�/tred,2P�=q��*�}r� ��w%&t.�a �e�pe�s�lnk�ly� �a0f � nA3uncer#��A�xh,`W�3_a 4-h-V��c W"�" �e =�!�hF�� q��z!:.�!�O'viaŁ X�/g"�'imp����!/FlAr]�#"�$ x}uto.�5~�0 lag ( Rc �N�kd: Allq��soHv�by-;�_tby�eu rjZ���R�P�* { 10]��Xi�>Pges^�,�& �,!�MsmoH�%no3aŚs�aV�p� ng�non.fa PKF<�0�i��3urI�,�hsame-)�!,�V k � �& "��4�BKB� togeIA�M>ABp-���nd �j(*��T 5�{-�YE>�R�Zw����nu0@$stream Cph�Lz��ϡ} !car� a�i�(Ja�."f�8enc�G��K��l,\n�e�0ye݄!h�B� �6�2aite;"B'1�rA8se��%XF�1alo�8%|q�ydeO d)�mur�1lia [7 I�� e ?e ib}  (dAlf�9�.�IF4 g�as��rE�T�inuum� �!_9d2B#.; a@: p = R=c�-�o 8�;�/�, � y&� F4H�%_Zb��_):!("% * ќ!��.�;naginE�A�a�@�$ronicn acouF nd  c!�U&��4gY ��nuZsE�sa�S�! i5[du/C*� �]RVf*A+ A� �:tio>i!V�pigon.� a�nconve��E�a"�A!Ef�� �4c�fp=bd�/ opedO��engine6%i& �d!Es,� �*�Y��0�v& ��pas��cK^���nd poly�2���%� !�yz�N����.w�# etec�i6atR%-�/ڐQMbey�%!�}*� !�cutoff~ �<W��o>7 hZ��Im�d��>a <v� �!W� A �0��lNU��f�E asonW�'wse"� )(Xi�_-!Ds-long�F֙s{cb��ty�ylud minu�ur��s )e*"� 1aGc�V"Yq���!�*�� ���i�8�x akeriA\�SVa��:indep�Vnt g�� �gJ.��s],&nt��|od��Tn�L 99"N"��0 '��40`w֍�&jv�B/A��d��I w�z sher's g-+A�>�%n�� b y]sli"aAx���$��*��+�g� nsis�y)H��@��ct1 "��RSf/���sA loitcer�Q*m��(( [�(� benchmarkaL�g"�Y.�!O&�d� �����.�Uc,TP�!quanti��ve ���pPj2 A9&�1 �. O��l��6�.��ngM�)���je:0E�<>�>I����� !&%U8p&Ԕ61�jkew���,E �s�ll�%J��eJ !�6�9E)�QfHT/�z�enng0�4ice"O =\�&s-%w< T��: ro)%/ �� Rz�nF A32��#�¡��s"�&*�!�(� M� (AVp Q$&� �ra��%�&3D adja���| ,-Y,omim+�cjeyl�!aeatmap�p 2I,A�F�ytac,V�o)Er)c���1m� u�j�at�tTj%e fz�4�*ADe�!�FS !u>�u &�.�( >_1�s:�ch�!:F �� *�&� obsc�>��(u����noi.� :�SberJ�C88"�'w�� �@mYin�"z��con�n3 tiU�H�A%!��eW" nary.:�[.ks��>��Py�:&��F���� EU504 ��s��)a��� *��z-�?R��>m�Ky!/� ? �?]u%�%�-mi=�—�4a<�+avar,—fra��閑�-a��i?���Y�B/��j !�m�“�”� “nAi)?_ n����em�r ,�� �v � o� aB? e�ch![H�s<4l0!94`�P�!��FF:; . Ex�X a�Ua#a<�f�|"> in� e#ba�-energ �tabolismA��#y& r�I�sebny�.y*F,!��i%/:,s�%�Fm �&a,i"ˍ�nfl;)fF�dowH�ea&QE[&m A�y���"��5 port!&fa�Wq eyt�g0�/A �oFo f XU��H�p��!wwhole"� ��@eX��� �>k',%���6h�&IZ�["�� �� � ab.��&ZS�)\a@ur�bel�� i�� 2�pat"� intu�F)Wun ZXwCpE��9 'Hmc nulllc � �l�'!��1�� aro�_8-nwz�o��G�"eR4$A0at fail��W *�Bf��no� ic (*mi�aa ady-�c manner�*�$q �|:�'�! !af�: � nac��A��"- or R(a�A�toot r���!d��� vel D/o�T9C �!~�(�UY'�Oo ea ��.�"��{ar3�6<-WA9-�le���s 5r�ZZ �ru� by n�'�eAj-4�a�,ar�v���"�o.W,"B"!™�e��no%O< e�) *�=�* dee\T!�XE ]x �#%�/H%�M�0!��D& .�J@-���C6�2� *d^"=*�aFatDs&��j>���e�+�.&�y��*' &ra�9� c�ofJ(� 6s�by��!^�&�5����!��&�3!�=*t IE�s�� �?� R� h�5�.���$"�JXr\5�k S} 0raOc;E">  �a �����ya.�?V�8���@ {�oʋ�d�i+ nver�. �$!��J��M���asA,.q+x/ L� !�t�{���>!�enh$ %�*ay� ep�R�J#�+~� ns\: ��!enW ,by��of�bal��� c =;B>�M�B� �(kp$dozF�/� hund�#-Y&�A1�Vhv�.�a."�q�[1�81�8Nif vc�"a�"�pfin yeaA��'�&�7�Is�; �8��b�� absolu��� �-y A?"�� xtqa�!��o� ��pr����'A�d eukaryo�*�7;da'�iwr|�|�lsˇ]���'b<. Ucptu��?U0&��6� A0eeݩ�!oU1G� �e��Ib!�; �7a�slr�F rega/}AX.�qpi_��)C7$��� l�2A�K GFI. N��theh,��E�)�x�B&r 2W!H�2!�y4���erv�!vA�.^!�|;���!hl �A|nU��1�f�D� a�. A`�i�l �sva�aD*�>��-�-O4" �+7�g*�!��Z�Stor��$, [�7� Zv�,"� �r"�4If��A4������ !2%a:e�*�lKA�Gme�:A*�nAMi��h� %:� ����5 �2P12/12 h z/*�A� :� QB�� E)@P*)A�:abBnPo!m �� � iu�.��?��&���ne�z�exclu_l>��.P��C!|'"orW*�D� )&76� � mod� out���Mtr��-��H&� "@)��J��#�jiYa�J*e���i8�c , unZ`&�*@�.DV.�?�R aN��EE;�+�Fu+dr ����:�C6 z�in_c rY7kee ��jus�  nd�6IW1��O�8d V|G� e (;&q3*q '�B� Ba�n�"�b� �9��m nd��A�Nh� S�G*�?D�@�0.[�&J,g90 �\���mga�!�um�l��e�FO� �|n�$�p2�m7.��(��}@U�!2)��9��V2� t&�$� . S�MI �F?�3("��&&pB?��Y� � ao�i�L� A �Te���{'xbS �Un!�#X >�62A-�8�9{3 I0 ���8"�}U�a�'� �oAm� *�a�c) h�.ql |;@7; sm�" )�p�4w�~o&Dmse-1�!��P����%�&VU"ܝ�|R�K�+8g �a!�b*"nd�w |,� twO� �5 Jhigwnd br�&fa�Iݼ0�H�0:�� u/��Bے�!�g�!t�!.�0Ɏ�IASh"z6+� �)5?,r�)5<tbYTs# $�! �LE��pc�F(o��)�'J �@��ajP qЁ��t&7.� >H!���DK-!��!��wY/~a�I�*�*urb�V� )7h�i*�ng�H�s�'�!u1ま-�wave-guD��� M$VTo illu���� s���� ��rto�F Wl��n-!a� �q (24�$�0KEGG hsa04920() o)2)"��"�]-���� Us�}L��| hard2+12>: uk$ w-�li��eA�:4.9 �KdiM  ,-QW�uid� pi��E�f��AAll\ R �D��Ae1\. �&� � X4timAH-��)� =�'��j�N�8?v�G!��&F-F� ]y7��chk�+y[2N�| ��6<A�BP%� � eaaM!lLsM�yHajic���cx! privh ba� 6�L-S6"�on net� ��n-X&E\� *�db#)Sab�.�&@% !�6_N�(�@���en� �+iANE��R�!�Ԅl�%��� aFbս} e graphic��i"<��w}<�� ircu\.#��$�^at�C!��&*(-p&� 5! F�YSsA����Q�!�o" 'el�uk�ac'>B�a~�+@2�%i"F2I՜,#1� lex 9%E���.�!�om!Ean}���� =q.. B&�O �j�s"o��8eKz� . m�:a�<�)ngU5�,!O�? ���A|�w��K&%�.(Q Y . T���g2R6t !e�.a�ach2/6 � �P:�_s �T�.c )a����� F. Lik�v�t w�&�.9�,he�+� '�+e'�  �**%�" >U�#dXneTKV�Spl͜ii5[R^}&� !32�F +�[,%� Z�sd�aay�!��[Aa��zq�2I��pa \s�y���o*�1i�a�|d]�f]�!���r�2}�uw.[ display�& 0�iK+�߅�%'O-| a:'t� li/$�w� ��axV�M �/ u� M>.���"\$a�c encof*prote��|��ff�3!Ba�S�'�+�Zg I���“J7A�8�s(5p A;odvz.~�ZeV"`�,� Nhm5�"�s .��R.ފE nB! geY&5UYHAI{, titu� ke�Y�$pev�io!1 ��i V�&y��%O�YA�D&/�|Y�)b�V�2��s shuff���2l�I���Xa�e�nherita!�Aark�:!�edi�jfamil` )��V;C�&�(h�!'�r2V��;?WQ�*in� �&!S/Cp weaP��#�oriY'�6l�� scap��r���"1P�ߔ�&7l� �5�� a -<ll(��o I�6� ��>��M!xa�m7�1�/-�hm%- �!��ig�gv�΁��4D~AfP coll�L flycd���)���'��3259�sl�k|"uA�rK7 4 kb��%86"�8 �%)�"o <10-� v@`. O dpH+�� ex����m�l� ��#ag�-p^52%%te\ m,Q4( 3 . 56 cM/Mb-C, �e meio!/( P628(Q�*eC�Zm��elN��i�:X. Cu�-!�a;"�eUhr ����%Aw!ds)A< nct hoόo#An*� to�m ic r:��Wt�AB est ��� ���Qa�Cp��eI%�s]-267�u���!�E+?: k9IsM�A��> 5 r"�Aa.B�-�biayV�I1��!�avc&of ‘��’ ( G����J‘weak A , T �vE�!��-�,�v���c�r��͒�GC-����R+^:�aUak�C��;y*� �cj#���P�ndzũby�h�^&?,��comprehe�] �Xh �6�E�W;~�U�,2`Mei�69� nt��#eBd�X�%xև��� Or�s�*� q��� {Kini��� �(e-n|wR( DSB2>� � cr�y!��'SPO11!)�&�^bro!�e�9-��~;Yi����AltoY�A�CO��ch� �ex�Ϣat-�rͺ $sS(� ��� �.x ?��s17I�2��N�oH6�ma��' f��J�RZ� termar2Ua{!o\imC�netypSf%6le CO%�Nr]2��=I�aW.] 2���O 0criY+{�fU�� 1�s�`s� kY���E��U0( Hill-Robert���[Xce; [3] �=MAn Fx�`s [�_���m2[ J �{taot/0*� �$6Y5–8��g"� b"&�iL !`�r[9�)n� �QA*�\A�, gov`,!0"�tb� ��di�il��8" MoreDo�y!�S} upD�re- ��%c*W � :�9�%os7Pviaj�( gBG�^[2�1�G�/hMD����j�-Rt:p��ofr��AT��tA��-� ���. B� ��mis6���a�����~dup�DN��i� �far%�!�r����ma�en�^�2S+�Me5��2��= ari� r3¥�89 AT/GC �uus SDE s�H�7&#G:C)�!xCO� ( of�nme8wd!< ��?h�[�t)�!v� onK�O� +*{ Q�":'A�d I.|s� !nH!�* . T���*� S<ml���� > va��V�-S4nQVf�"3�P"X@:�M�Cpa~"E� offs�g1H�Aa���Q� �Q�Ie# r��+����"[bs�4�qQmory�m ([�)�h*'oE�A!�u�!"� [14a�6]� �9 -*e[+1:.�5CO�tYe�ly)�e�-�Vd ��eAe�I%!�Pt-�6ess1(U�� 5��;"� A�Ye� a]�*�7X�map�������.7��8.4�9� �de&#]7 ad �"n&of�ݼ�re>Y�H^b����/�"ѐՀ19–2J�c*�[2chaUsex�23Ūb�!�g�l�4�uJ(2�/25]abFFbj��"�r)T�E� !jj)V/m����]�>of.�5�ځ�i7EL.�1histo��l2� [2�.S- 9K�( ked*AQ:�( LD )5��6�g-E��tBm�bk|anZ`ek �E�Ut:� p"�$( ρ = 4Ne�=�pI \u� a8&��-0;��LD� ��v��; 1�p &[ 8e`$�&�� �=E�E�as&ra9t�e'�4 atc �"�A66�forat�CO*S2�2A2�5JJ�/>A2mig..T .� ���_��YP�E�^"�.c>.��* � on&[CO [27aTWf�! &0b&� ge�$rec&���6� !�!|:� ������� 8–��p!s�� , 3�;s+V%F oocy�[3�37]�spok�[g�m��qw(xc��m�1�s#��.�6�m����[�!�m�A�8. 5 I��1�* "t]�ol�0� x|^o�\m�G��. S2vg7T>R�3j#@@A�of%;hSw&� ���T!�1qte";Q }��op:att}�� 3�Hl��^�Q"����aiYA�B�eTH �dh.�h[38A�n�T[)JB�G.�t��=3K 3:1 .����Or5F�Aac ���WrMC�a}0���$E�R-�� JR��f��F�%8qFT &��, .<"0V5�0���"p:"" DZe�;&2� dema}+�?�$a���*� � -_Y-�Xn5!#��. 5&s� rB\*�J���� y�%�6H-��{ ��#�A��!"o\<&�so-!��oR ;v2F��=0(Bs/�DSB�W�@�In bud'�2(V�>iae�x $(��Fa$���Jne H3 ��n��tDEth'9( H3K4mev(� Z��a��fac� U&�#of�qLR��"�6 r �,��&A!8�+A�� �xJ yAl�"9�[�( TSS�[39 , 40� A"X!W#u�s�R �nts�ɼB�~�of w�:e��;lM$�v� �� 6!��T �4�4�In�7!�)�d m�/Fw��G[44�!|>�Y��>)g&�motif�Q�-�"l�4RDM9 [4�4�a zinc4 get��er]hesUe[4'mI�,U0, Yb! ngE�rs mai���terge6a!�!D �8�d%�!�6�)�to)�[50–58Z&%co->H6E}6� o!Ne�����?d�w6�" 5�>a<�-%% -��2!�pp��"@�%�� hyll �T��[5�t5�:�8��.�!NZ�X6��[� �H�#=L"m !��w&@ p%a_h/�2", c�h��Li��^>ag���s(Jw Ew�-�q2�K� �[2� 5u 5: �����wF ].I�af�;PaB5��rqG�&�%���?8�v���kver�!���am�8�AfZa)�&�[5��~�WEg�� %*[69��}!d}erp�@)��<�F10 #"���obl��!�EO�.g[59] � E!�� !��"�;�h.s,�:Uwis� ne*G>��2� :%_�:� �ic,%��� '- �� n�ebwQ�[i�AÂ�<�i�2A3"i w��*nY�beB9r$ Prdm9 [60�raiX qu� d7�.69*6�f:�(% m :� �:�W.%�12�?plᅅ���iM42Ub�--To �*< ins�9I:��Cm�"wx#le�a@6�6@-�E�I}e"�byn�`F6"p��>F", Fice�9 albi#is�}benefit��E K� ��_H�m�r�u�3inu�n�>sc�x��ancho�xLHde &or ��.[�g��A6�s*R� %!H-maYe)� V] X0s valuq ��RX(*;.o�y�@��� �e�V�#&(q ~�#!%[z�#Q <��k'#5��,�!�0� !�:]J u��r � &}� �&,�*�%�06�J�Em�0% � sQci����� ��/e9<�6lmG�� � 5s�1�!� ��%d!�CZ�\#��!��Rbc#t� �M���$6�$1 m�$ i!$A�:QZ�$)�>$v�i ��!�� ��aX14�^�2�AY-!�-V&$a��%g�� -%�leeB.&3( between se�[xes can be observed . Moreover , we find a significant transmission distortion in favour of G and C alleles over A and T alleles at NCOs , providing direct evidence for GC-biased gene conversion in an avian species . We performed whole-genome re-sequencing ( mean autosomal coverage = 42X , range 36 . 9–45 . 4X; S1 Table ) of 11 collared flycatchers from a three-generation pedigree ( Fig 1A ) in which 4 . 434 million segregating SNPs originating from the four grandparents and being informative for phasing ( Fig 1B ) were identified . A total of 325 meiotic CO events ( 50–67 per offspring , posiAs giveE S2 T-0 were iden kin the 2V of gamete-D!D(s reflected!�NwA� in excell!�aa�m EpredicAK��genetic �ances�W in linkag�aly�H( Pearson’s r = 0�g5 ,-�1 ) , p�str��support��!��!Mu�of)�io:2�igal ( 20E�windowA�CO�Testima��based oJ� are avail����collaredJ� [55]%�p$correspond���loc�Ao. �)�gMd study ha *�ly��er1�- ��( A3$27 cM/Mb )A�n�wit���H( ��5 04; t-test , p =K3 ��7�Di�Y�"p Q�mM�9ed!(a sex-averaA�aut��alBm!#,3 , 030 cM ,�} clos���Wobtain)9J�?6!;)�� !�f� ��/ data:�30�eAKaK!508)5 but%�O�_ly variECamA�y�sE-sh�aq $non-linear)9�o!�< size��2�For s >50 M� AO�Q�1a��� A�.��7Mb=�1�2 �. Of 305Y�-Fa.�, 119& of ayra�� 186pat2�Ais) eI+Izmap.�f 2 , 38E+in femal��V( 2 . 2��A722i56 ��2A0, i . e . 56%%�er5Sin-��W  . Ou�La ��0�o& Z=x ,  P Z*�EI�!�≈�i6!�pseudo9�rw [62]9Pnfirms aiSA�)�( e-�5,"-0to what has bm u�J; j)��  isA�rt�, �%�≈1%9�2A�which��| �wh� B4W.]pairs�:$. Contrary�HpatA��a�� �=�c"��u �!du% E � ( 25 . 4 as no��atisti� y diffe ��c:�(��. 4:��506�-O� �R ngle�I��*K N�%�as!�F�It!�often� um��A; one oblig� CO>� is necess!�!lpro�s� g�01Pm�, i�^ect0 of.��[63] ( ��gh!���(re organismE IUtA�doe)�apply ,� 8 abs�of&" �m�5�0of Drosophila%jW�� many instJ f"ta�.~��# �X�q�!3A?urprisa�%o50uG2uE� l� �o*� � Thu�whe���s�vey!�L>�onu e.rea�� ab�s) �� aqo�-^a�!��o�3oboŐ%�assump%��ocu� �h0m�!vhe smmst micro.|(s#� k� se!�r!�ix��1" ihoodE�morA?�ni9.o< 1� ( n = 9 )�coMedr� az!����As0 � ed)t�7Yp%f2�( 2��� �w6@%�J�( 2� ��es-_2���Y� b"�>�]���sua�n.�2U�+!z� � �ow��Fig� ��er�.~��} .�.�&Tt!�>�i�Nlog��%�equ�5�I6.LQiua)!�a ral trendAz�er fr Vyq#�;war�Che end�.�(9measuAUinMz� ;%( 3A ,�!4� imaril��2T5�10E�in�r�>2� A�I$ termi I�)e-vd&� 2�eEJ�(�3B;/2� �e6I� ng�� also|�Usc= � inct��ce {!vsez�a 2�9�>incre�t=�vfend��l�EQnoL�w.R�U^՝<( Mann-Whitney U� z = 87 � *t �\�E�A�s .�2� A !4��TY�� ( S4%�cWe n�he!s%R� �2�aff�!x2&Q�&J,CO hot-spotsa5–S7a��W2V19eon 12��6%�Anor)3� from�U�M aGliz� o lewa� @ apar demons�ng͕ly ske�a�Vp8. Randomly plac=C5N�)t*�}K��i��pench�j��<��0�Exclu}p%�� lap"E���scaffoldaBr�iz)�revea�E�Fy� �*� &co-9b�byJ� T��rIto+*Z�35A�W To a��@' oci ��gen� ��� ome �detailU di��!�e4% intoa�moQ�f(kb upstreamA�d crip��stAKsi�TSSdfirst ex�, in!��� �g�~ge!DNA��h�k A� st�p6�A(85 ti�!�PC fo�by � �� � -�B%�A��ed�t� f�" *� Y�bpR��R � �!� sher�Exact�q ��18�No!�*�g�oce�4�'QP) comparis)�a may be du! limi��&j ��?!`1�2I ��! �gn�asF�A�ICpG isla! (�$8 . 72x10-x ."Gat2-5preva3.�iA)ŁT"ih2�inU3.���Ky� .���2�Beea!HGC�lt� oy�4�L6%me\ �� q�FO60JQ.p( S>Wi;"%s�+of ss upo]'2�ͤproT�j�-�o�'�(y��m  .]4�.�expof%)1��BBi(�e��1�!,�� a bi �)*�,59% ( 95% CIV%52–�u"b to� tox .I�u ( c�B18%��e�� rectʹ�GC��, Stud] V al��of�*A/ fungi hav(w�a) �).�� conY�*&Ai���*to� s [28"9–43�T!-�bein>�c| � �2!Q"��6;�facilita �o�� ati�!�6�An human mous-PRDM9 d%��'. awa�4m [5Z 5�١�70 , 71 � "� an a+Prdm9���$v +��es [60]!@mpdhe hypa�'%6�8 is verteb�$gej� e � :lb� !Ja�s��+F�2�"pl:Hs#r� E<% �"� ��:a��a��� ����*�" �6 �.� .� !Lb%3Amer b�..*�*�~ .���f�!�-*� 1 N��chM��q �� $destabiliz�.I�at��protein!�at  taG2al��ssy!# e [74Av* t�'(be most ���TSS �,0'*���i ��|ve( 1x�"�)�!��.Po!�d| by Lich�"i](uggests “e!�pictu-!�% mmal:b�m�p%�ra�?aNn8$rule” [7��W�!t5Irp�[@��!x� EWB�""b�'Mu*�"�Z��*�" melanogas)[74�*D .[&obsX/ [75] ,>��du�aR�. F .�$, fruit fl�![3�'Lwo�&[76 thoneybeA-7]�#6�"� M��}� Eomo��u�6A�hotx . Ap�1 desp�i��- a wi�.ph\ n�"&�.tD1lif��6�has e� �&~� ��Es�  usag��,E��+:hoLr� turnaI'[7�|7�|�owe|��ar�-�4ic �*E�of x"�&&oneem-b3ng�idu] zinccgL1[53A7%Ze=i��x< n� ic�� [�2� eroj +'motif�t�t ���2>-inI�mu�7 >a proba�1���'] , 47�t&���B��\toA����F�! B��&�)�$�<��1.of*�*�po(i��,%���Q;yRD2!c%�U�remaina��,� ta�$( cf . [804. E.T��Zre� ������ inch"8 [5�����t SacaX omycM [81Ar&'*.�s� �to �4 B8e@�3�a��$�(2 � ?izems�eE�mT"���*\iM ��%�e ��=6a @%�eterosex . S2�"#/S�5a� vidu�3gG.�t8E2eN��e�si+t7at�@m�o�(q��c2 m|ted�&�!@�to�s!gH2f-.%[��cco�wA cJ�1l�2C.�/[5�28�B�douni!E�%H4Haldane-Huxley�� ( r���1�B�, [83a{�!add�7�M���} ^[8a �*@��MTF+5]���'!$e8. �0 �$[2�56�7%6�� � [87� �[88]  � A � �0a pleiotropiced�&���cag�jt�� i��kX�Yr Z =A�v � . S�a�6nat�� esa�5�' tly �.pu�4c'�6[!RIof�' Je�"�H-p�9�!���"%�!�in"�, �+8�1exI,�a�9.� a�B�(Ab��;3 f�<����*ps  1�?!P� (st �a�+pr5!Xsuc [89�}.{setG Utag �8�Honship5�%� zof�6�(E�eantago-)%N!W -to-5V%rio [9/9/As%,eO ani�2-p(�1g��92a��:�6*�մ� "7"J�)nd�y�F %%m�a�56!X!ex��!ma&� Ay� � 2U9` *R%r(e_' so far"�zebra� ch [5j65�O>mad� T co�]8��! byBJ$A[�c� �, 6� N�<. S�-fy+� ;9W�1^R��a �$�(� l_�1t3.i_i6�ice [9� whH'f|4&�� � �1-�@�ing��"d CO A�]( .(E/&(!ia�inc�(of&("|% � �s0 !�ati� w�19;2)^@50.V2F�!2H -ini�ng�!tucr�in����7s�l'U&1=�;ŀ E��6Gݧ!6��J�) [9:A�- �,.e�A+#!��o�6 d*�N�- . Me�-EApy�2vs i�tax�tq( ency�� shor�aB��Y�@&�2%�? m%�I!:'+&[95a�E"F;Jd�*�a$,ٸ�<��20E�14S.[3��9}arelev�?metricA#B.%->&Aho�3 phys�5 <μmz(!jbi�#,� “:mic�1H;Mb :[%�) ��2�* tY3d})s5h&Ae�� !O.�  lept� eB���#sd;�S�pRL%�'� �4c�(�:Eya� �%z6�`.�[)�DH(edo pA^�W��rmE oocy��G docu�NaXh J��c�ѕ�tM��[3� 3E�It1 vt/we5a !d� Y/ ���a n"��orcon���&J�]%J2#akAXfW.5�l>- &�] ife�ѱ,���_"� XA�toA}desse�),�jud�>b�/�:�4�'*pafA'�� �!�oP.l��; �$��B>"�!Asn h��9"7��P!GsB driv 1�lVB#:�$n Ficedula2c ���%����inMǩ�A��uS)c� � wF-D!k ( Ne)� e3!V:�"*�'�[9� Becajtrol�g�B rift��BHn�" FfN��]!|a! %�A7�:s>b*P%�%/�c*� a neutOmodel% 9]ne�w& voke!�or:�A�� f�D2]+��� "��!a��domE�lapE�*|( a Z#Q���'-d�!E��i)js�AN preE�as��Hs��nW�]6d,���&SaMF��!�%��2�!G ,.�! M��at�� H!"a �2M�H =!�!�7T��� b?!�, cJ �-DeGE-fj: a�2�!9s12�Q� of �� d ye %�#1�69�9/�i *tG�Gyj� ( gBG�". O�a/Y��>y� s�^E-P+�M!o.at:- mism�H��duplex5 RIiv�jrea6 E�� ul�Fly %2�6��.�#.�Is&%2B� �)&'! e Il��B� is!��7oC aV�u, P*:-�d��,��a�re>�"%�# E~�!a�# d�n5 6 [1il�'T�0aL �IP r:�M�a6h}SofO#057 �����*Fno23 ER .:�[1�&5""Ae.cf�>��*g' �[m�� AA�ɓ- &��� s"^IfQ^~-+ 36 [a�A�e9��wea6D5�x.�+ fall�D�����;�?)z��H2.net impa�'E7o�"��a��yuN"B)*� :�4 ngth9�^�,%� also:&%'�P�=iy2�i��3NeI��2��N�.� ,JG"�J�rS:;-[100]% K��$�a:� -7>� �L!�"�.L}�:i�w. c#,&> ious��!�r !�sA� $of karyotya9�"�1w C#�����,. J2d� !�e�'6"&y�build-up�f~aA"� 6gpk H�NR��onF�[10�� Wb 6T&�co��"OP� * W FF"�/ac�)u/;-fl"A6~%�99��molecu�P9�.:��O�����"Mt�%gl unE.��*'1 >j J�-� �of -Bsynonymb"9titm,0��6�"��./eEf[)� �-p9qL��3���nd��ong:�[ sepa!{lyI3 d .  "� yq\/�@�$ nkö�Ds djuretiska nämnlDL VsrätZ8Swedeg*$Dnr 21–1�1.U �� h�IVof�/J��NP4�Pa�fieldwa eRaU"�T��Bal�Sea_ Öa�{, ��/aC four�� cPa�e��eE5��of>$�%�l *. S[�!�d� �+2�040X�1ag�.A� Illu/C HiSeq�P0�ErA ? ed-end�}�H�Cbg libra�4in��6of 45�T)  struCRu�6�TruuNa�am�5p� -ki�4�) ( Eu�I an N&TV Arch PRJEB1261�0FE� SZQ�>blGG n� oin 96% e�ol �a��ndard���( ase K dig on/p�%l-chloro} pur1� O$ ocol����2 aligv gJ�sSera4��eAlb�105 ( GenBank A [ ,GCA_00024781�9�-wbwa> (7 . 5a [103kde-= �atre�5n+�7d clea�GGATK �O?62G[ 10�S�Dp<"�W polymorphK(+�%��L�W 's HgXCC )d� GVCF�.�1�0eK Vari� Qual6"ScIR�!( VQSR�:per!���!-� �B�P�^[10uE�known�r �6EY!� ng)0a 50k)-cw [107)wA�(20% top sco43�1�trainEr#�{fai!2;999%)nc�Ehreshold)\rem�d�a  dOetiM� ����X%5 of R�9Masker v!t!�9!�mi��AFH!D�LR & GrH, P . P!:�p-Nf~@0�`y!B8�Tandem �s F�< r v4 . 07&9)hq-h�.perl ^/ �!a�$E�=(�Z*- 10bp)wE�not ala�.[s.A�SE &y mis-MK%��$appliA|��f�X)�� .V&;;��ő8Aual�O�7ed�X*dC5�rUZ#|�� twA�AUyP&�Q1 age; l�P cri�8on�e�to. risk�ue/��pN,�; � �.�!J(be%;�"as�zyg :�%ce� �X�� cop� y)_5���� 1� q�:( GQ<3�V!�.�e�!/�)�11K choo�w, ]me�D3BDSEvio� ng M�.l21inheritY or �.�o�?�)P E�q�. All�s(�ens�K n:_[! ntir�:` �D�2�R]_ nt=�diploidM o av in/ect 1s#4(": "�8�hJ�&%��cop%�B�plu�e f�VW*Kl%B;�M�.� � �( flag -y 1��; "�$� �tw:j2� ��� ) F1F2!.e �:i��U-y�iWaqB�[�U�a)� I�*i��i~��b.,oY�+etqylace�HSծ%�) ��ed���-nd��'yv. 15X�`Qa)� �� ��as�QvOmaximum*����1J� ("+W�"� y)e6� new+HE�A1I�!�1���t�Rad�Z *�. W� a�e�3e)� fam�i�Tpo+�M o ph� FF1!O1� &'-level �Y !Fde�� ���M�2p),Nb2�  Fg  bF(a�'��!�b�Yz  )�4has��, ��PiA8�ian��vI,i:A*iT6wo�@_�"!$)aCA�iL��makKt2`�4ei�a���=kVr;pa i-*2�.�y q�A�atLs2f) E6P �e69'sztn &�cmus�,ref� e��<be�>�@ ( S8�BA�PAHd%�H�(a|���c �Ad��@S�ato [32]�;U*7C5WBbe�(!O6 E�  #iR va�Cd?#/��$ ��/�?%:M[or1�Aierrorl+� b�!C&d�4�AM�����b|a�ou7$X6SydA)wo adjaPJNF2:I6tcjseMed"�o~ of i}]�-��"equ��we"Ndow�ea#qaA�weMeb:w���dM!9e_�\� .d��i@PZ,M����!jprecis�E2����S} *Bh&�a�K���wa�`�F�Yv~sur6�E�2.4�\w���7c���'.F"�!"& E]���I!�~� . Man�,in2 %qin IGV�0]!~a =wdae-"Bq��%q�E�A�hembvis�)� lem" �g�%(�a(�upT1���.uneg " CR R�c!O!�e5�s�@!�MB-6 �;, clust� QeaS� �c��,�hM�M���� dele E݁��Ya�ds�� �: >:"6� ��Y"m, omtH ce,bA�J��adPeW-"�"d0 �g%Wo* �0+ lociA3!x�-bha���OeHh�*�above-3'ioamUi�"fer�"� .�we"7�?�2�?Jht�`�M�.�)|�0"� &�Rc��C��. FPw� aIQ�ct  6aof 90%�=�?"\ !� �MP%}���2S#Yb�%�el_n�j� kA$.��ӥ�e]���6e�jt in 3�� full�-"� f�(�[�1A)�.��WA}so��B�u�Wt�" 3ng����shifts;^�vis.�?`$��Eto��wo dev!ng-y in 5'R. Nex��)�5@zP!�\, 8� ��!� �?� < 25"/I f�f � I!j�B�M8��is!�� ng n"a�! ambiguZ �al�,i' hvQm�ہ'pr+ of�)M� ng$%�6+M. '%>io  7invGg`7b1veQLc��)a��. CJ�7{&`rbwnloaw �En�� S7l[ 7">ISy"`FicAlb_k�Nw� sl  swKT=e&� sa���cal���!�] ��� �J!riS!9"�E*M ���"�m� D0.!�K �Nn&U+Ths�eaM"��q&�R�.W fl�.�K:�* �4 �lit:�ZFIn econ�ep2�`� "$ix*cl!����iAo;� �U,���V(.D,2�a�E"�Ez�V�0�|i�V���U!�  b A҉�=7�Eց�5:val)?� aw\�se-*,Sl&!�le.t" j�\�Q�ZeYo�2��|.�T( CGI��K4�r=vhard-��"NO)��A�CpG�v (u�a��ew defa�Npar�g687�%m%ord�o!(e��B�X�!�C"6�"�mxo-��/!.^"�Efe�$h��D�/%� nd pl�/�R��a 2 ( 2`R-projec�d org/��X�coeffici� �To&�5 ( Co�(6.�$C:�4[2�%7�u�sl& "t&!.&c"W^IGu0L�!1Mb sli��Waa�A�� i�do�&a)a11^!=-v�. ��!*��mad7+ E�!�� 0–!4 amino aci�yretchOCs�5lypPE�Ju��=db7��!globu�", ey�a��u[1��:G^!�Ba� ��X!i��t�6�C"� "� +(d�R2aaN2reeCɏ2&b!��>'nt sym<5�u�Ry3!�� -dimen�� u�F�2eral"&%��<F�!� �si–on6a� ��� �e�!de��O pQ energy�s&� �r�;I��-~�Eat K!�el�:�%=� W�@��%1u foldAs~�8<e�Ce��G]mj spinJ�+Dahb o)B��ert!��-�� lete�6domain�6(�Mot�# d co���@ME��array�!{?m  is�c2mIB>�U#@0!?�0im/�S�Hs�:!/�D�rA^v+B%:%Y�f$-�( ΔGwp �=tB�de�A ( m-�S���Aordin�f-9u� "�J� r ho�Aի&<(“coarse-g ed!�.�� e�H�EE4>-�exfA+%�= }_�gMsim�V<8!�funne*u�Ea o il\�%%5 idea�Sw�Res�a�-s4Fa�ACe; rico�) ( TP�!��9.�5quant�Niv&�$w��Kp5�ly�u�� C�Ba�� dra� c4�ha�l��int"�Gz.er�3A/.rNtbehaviora�e}8� �atI��.�v�re� pois)�Ei=�Eio� �U-%&+ a-�qe�!.n�?�7Ezm���euY7go�� �P-0���:o�jz&7;� '��6���ins#; 1��? i�&OAj��. M�u1! ��Miodic� st�U"'��! ‘a&�@�S�2.�""[�/)���Bto"��%x�? ��,���t<40y��_ [�)In�2[�2St�l�m/�)*P^A�Ё�s|'u!��JE st�n�m n9nC9+>Asuperhe-&lO�\�a�"���in� Quasi-d.�I se6 a�)͆��/b^U�R�or5}B�� g��A��IY o ob�-!s� Heem�&yA�(.� Sra�Ow.&c�x� �zE�K�R=��+iE! wrap! oundA toE� m�3xQ�-&� =-hxu\IZv<ors play���8�!�A%ki�{�A 0p��tj%og"�! � [�B[A� Nby virtuiq!��v 2|q hsh�h�an�l�>���A�� ��&� ����A��2 �^֥��AQ�.��h�A�.| M#��help ush -jVQͤ ‘uni�l� 1��act��Ce9� !f ough =��sQ5�/� �Xmp7�ei\E �E� y�-!�Fzw"& 1�x sh �$.zE�� ��ia�>� # mag$4[.+Inj;A��s�!�]� �Ix w�1("�":� up/ �;A"ix/coi�;A�ed/un ���pB � �k,?�u�l�Jb'A�,est neighborH Ow- �!�.� conn� a %�AKrmodynax6� �systemE�)OmTexaI&N*�!�Re!/ɱi�M���8,[b��2AFw[7]–�5�]� �-5(seg:�2�) � �H��<5dis2�x.f.�-&�My lea; �)�p� lump: sp T�@ 4!����BӉx- � ar�=�%�r g�MTS*��;m� ,e5�6sa�Pwe���b)R�8��1���!���4i hop�?��JL�s!2�R?2� �� su-� ���unn�DI�a�U [m�&%� oAa�.�ad tY9FA �QN?�Y,�weA} 6pr� !�!�!�n�(sDsi�U�=? 6.E��= 6�0A.jX.� &7#� exist�1"�b0�.�)no�5� aIK���{!O ‘b�7�N"s� a� [&�a"~7�!� [&D� Q(" ��si�*�z!}ankyri�'AN�*� ����J��s"A�]6B z �(0A[�o�f 4�810��eG"� co%0�L ∼5+��2U��x-�& � "��D&17u��%k��~�=(�\ fBHAlf�7� �,a1 fay�"�&� 2�I� r� Paul]schem��+�/ hydr�K boe��, x�G�^ kI%�1#]I2�%�cK��!�!4 �-r��%� nfig��� U.!dihedADaz�%�a��z�=o�_ ir e! b.,2�1�-uis !WQ)-B� JT, b�HM\d� te balaa�su�subtle�a*�!%�� �g\ i5�im�Xmaj���C@4Q�&�[1�7[1�IS �2 ���/�me�>a.L �U��i) �y�aEM6T � �A.a��-y��)ptnbH+�s<%�T!�6 2nat2�[18� 20� a� they� X snapsh=zof�F�E e�"�% lee��r���`"� �F�m!v�"�'�?�Tdi�P� �,9�, 3�s��+&0�Iit:�Ů:�dor�� QE%���X‘prO�b�i�Wfru�fARA<[2� �0%$�=�L �M]{wLes�tzPb -��l�&�y� M�� u�gco-!progreMely \lB0�u�Z) �� �w]��,�����e?}j .�T Ob2�t*� E�aQi�9���El8 5 � -7a��˱�o�4llJ>X� �V�U�uW�3�=�<��eno�% �1I�Q<��&�� �.I=L:�7aic� � Q tNYPpGy��key)jt�0��)|re�V.�2"�H�-�!i"$� " -�q��b 24� ;B �'���B4[2�e�r�j"� T��!�� sw���& [27]� �]Spr���SYn)%�E�.��;9p-Z�.�MTM�e�!��s�Oin�] . St�/�+�-���| >"m!�� " !%-1��I�5�2����6g1��s ribu|�}s�v�0"�TMi� ‘m4 ���A�ne:%at4��(�}�|�t�!�. 2$fB" �P��DJY:� eu�Q�$ �(Y=mJ� �� � )�W2� ab� M"%�y"�� ��-%���2�1&� >�h!�J_�Oncŀ-2�R“�Kve�=L 2w7 PS:�$knowledg�o1�m&cH2Kpau�AsS$0te� �.n�y *n flv�%�H�I�*A ,!� Lo#A�.LA�R"�� bl6/; -�jA � ��/#!*a�funda�� el���.J�Mհ�b*�!M1.���'aH�x�� �!� �.�Bylicit���� �} 7BK8""�%-i!da�A�on-We p �-G��.� � s em�zl:��cu�� �eo��/ a&>6�-� �!Oe:"�"!c!�%%*" E?2r-�>�.�"�"{m,:]#rm��2^� 1�Tin��� ^�1�� j barri�4!�!�!�!@u��,�$-�I�?&� %}aI$̀%�Y\, a0.e � �imHOEyJuDS)by tu!�%�:em�6r� &�4�"�!�>���Drob;�>3I�)1>r�9s���� &i Q~e*(��� a:�Si����. S�h� turb��� !ore-�*) s [3� �'>D#"cs�a�$de�%E�EprupiKdevelop��!?� U!A,/c,=!$m�R�'Bq �6F�m�}5at� �"�*i%A�UQ�mn * �  *�,edR�� UAMU!Xb�^ss]�ugeo�*Gc�C�Q����M) Fg60@"�r�,, � .o{H &L>x�!U�9-�2"" !�&q8leJfp�e�c!�!�!b.����-�S% ��2�'�h�{i�!Nb 2�.1<��ˡ�T�)�in�{='� ��5end-efA�aQb1,b�+)��� .%� /���7%Ar9texhibit ]&vdmR�* ( Eq� 6–���@ys3A�3B=�NpO �cult�9�faÄ�u50��� ��&�$)+Hi��'fs��!`um���6� %�)�Y��K��%Z4��a  ��Y6��)sz:E.�!*R+uB�^�Wr�+.,)( h*�?AN�-N6��h�� suscm/nkGowe��u�!kA�)pon�Fal"N�wA�>5ir ��Aps"�, p:*E�8s>���"��|� ��qpH�)M+� 1��I6 & 6 aI_,eJz�_��mkby^H$N = 1413%G�"`*�����E�e��LNmimicgK��t�&r�"s"6%�m�}�/1ntjy'�e�3�wE� +e0�Xt�%A(&q� mw��_�he�Za� n� /�N.>�nWC�-CEl3D�-I�EeiA�!�*�+oer-1N5�a�Abig��1�:=~�5Mm��g&N!�A�l�q�H-V�$%\� &#�(�y �Y|%�@emz&�X�A��M�a��^pl&/3f�� )�u�&6�&&(1�toV���m�edpre�Y!��al-i� feltv� hA+��,�WF%7"o *icY\&5� ��!Q��6 .�(/%% 3T ���P�u� D��or�  , �&U tnow�a�*� �C\>� _ %��.gc3�%Y#"a/P! .= �U�.�� s�52g @$%Ft����q!�T�T�vI +@ �I"&M02&Q��ren/E�se[�'+/��� � Cα"E��*:/�m �� �/A)#�oC-ɢ:���2\3���ar�-B,.ato!_mo��!T!�I 9l"*68�r�2� �)5�9n� us6�( CTPR�:of*Nng runs}���&�&3v��%�1�W � ��%���&H"[4S�C1{temper�` �?�5��j�&�O7)�e�-_ �;�z &}.��"" s m&� by w�.!histogr"#Mi!�uU#}���eR=( Qa:� q-p�!W5eE�y�Iy> � z�N 9/I��k�A�W���"�/��wMG-& @� le=��eA%t5r�4a��g19eak��hܓ capa!��7�:�šis��"� br�E \�F�?F�Y��� Yj �_��#!FG%D1j�G�7 �" \5 ingu��VNZ!)H>E��,^men�stw�)�"$ ӞX ��y�c m ��A�ar 5��(& )ձ�"! i6; �J�a����["Kef���e�Xb�U� |)� �U�i��5ure2� yLJ �P,���A��\�O"E;ae�&GTi-fe)2�Yo��aug�!�))\.g U,aQe�2-�+lo3A�Y ��z��0K`���S�n"���� ,J)���2�a�Gm��2 shar�OyfDDAh�a�Cd�7or!i1�Je�� ��\[!@6�M�eI�5�To�/�)>co,�� =��;� E�A:t%��63��INT��L5,ag� ed v��Wf�oA,�w:�l��.Ui[��/�s=�1T �hwemploy-oa��az�7CA�[�U5�ڟ(�T<SSeE��!��BS a&df�A *r'"�:q�My&V%�ly go*W2.�!y|� a 5%�UE�E  asF%C&�# &�.iH2l�#�PedJ2�F�He!xPOTa� ZJAb�jp9�f�J�%��on�6��G2�An��3!XXM*r�׀!26� 2 � ��(�|Vn�IAR�9e=s�7�_��"'T���� 6�L.� % "-�>r�*/�f�"�Bf�'s{ k�3���j=" Q ���Ce�@�H��o.J:� �i��Uy,eF� :� nFvQwB%��F�matrixX��8�t�� `�e>:E2��,Fs� �6�,�5e$.�)t��r~��� 9ͭ�92P �!��B�͌al���) ��?U�e*�decQ��q.�_AÙ�Ѣpl�e(M1�.� �is �d±xK4P4 ly"���߰it�Hm"dt�� 7 �J��1- � +!��� ��!d-�I��8FE� � y c�5)�m���j ���^&�w6*�La�Ns1Y�atM ("6y A�}|M�FE?S%Gi�:�c�m[�U�!%��+.�i�!�M&����JA~:�-A�lU��H" E�-�.B�2aA�\&l�86$�NI.�vrt��� ��].�q�d�I� ��I���&� IH"->�Xd�%�"����A��I?�ob�N!�� �� � ��w� v�"�� m �!Ց[_��w�#>p ��1�T�.�;c�To6+t b�>9 J�tra�oj�{L�&����-�"�=�|#�7F7&�m�*M�6���Mr�E�� .�e�� MOAb.G,|*˕� Kullc�-Le,\r m}��&(� 9� ( pm 'q�-U�� � ( p�,!�>fin� ����?1\� c� m;ne�&�SA bou�m�.�MU�2&'�#a�mi�at�!�rA�B"} .�E{chonWdi�\��v @50�aa�+oriA��9��0� F& 2/:�Ar�\st�iuA ��e3G>�;^�c6�a8�  >2� di^&!�2>Vis)�� H"4,n"��.3�T�4�g�e00011�g�PX TPR3�M.<��!�/e a=t��_ns�=�;�� eE��7X-t4i�5.��n� �:��Tr�;"�Geh"�\�b"I *2�A�,Y2�O�loI"% � �� �ii ��bQ2D?‘1�m�l1'r�!A,!O! a� ���_�c���� 4�"�0F�f*":QAeC!� o \. Loo� �&�= � r6�.�J;&ec�app�e)� M�ͽ�( ^'8m�>i��"1)aA!wnam��e��!��U�>c��m:4�"?��fa���R��[�r�0;4�6)/�6*�fJr!�N"t:-aig�i�!�-� X ��e�H!edR2�MR&d/pa�;fG [G� �$�a cutoff� �pA# 8 �2q2W�\6�.�RA���E�"� .Kaj+Nr e��ase�"�$i�Q(���e�.�O �h=��'.9�F� Q�Vz s�. U�:\f��� Il�T�m3�,E��p�6932)*0!A1�V��"�:a�i>�5q�(z!�>d I�5p65W0�.vck i�Y( "c.�iF�I%�a��kcr� < v B��2_ y6�'�c$L�b �+ell n��a'&�a  ���=6%�cn9�%I�i���!&�:9.�ZMV�7mTPRvi�� ��(& af2'� ���*4:5i[ wx'V��n"DiU���i�J~1y7!��+ae.��e��*џ�FA!�Ucfl� rac�G�'z� �HV���X�k+�&!ː�6:���J��&5�a���~. !,-ׁ-=#!�%�* I?_ .d'�.�d*3YE9!"� �RN*q" �� ��p�6eZ��z> �VH���� ;i 9.o M�R/&�-7]��V�!�.�|&�&�<��M�e*9H�#Q%��In�3aEr�i2 G �<`M"�2�R�a*�X��.�r2��^.�Tf-![s6�/�)�nڝ�aαj-�c�@s���ځeczI-)�RsAL6^4&?%XvX��E"�0V�J~?%��_7A"!0Nc��.aT .� =<� �"j�iK�A�.�h��> )� J�hM�wT��919�!o8c7�[D]−W�n crud6�'�" Z.�"W(�K 355 IL( 2�by. edu/�� nlab"��&$� c�6W��acޗp(o0 y298y%n284!Ip"C(>�� �hdB"&� �%�A^(amp�?�h ta�(2cur�1eR�!2~q�5�30�`n�|�I����v>�:�A~�O&��y"� ��"� ��9tae5UT�I!�> ol�,�Iaձ"'0 �.�]&��zUO7 O� �/h��,�%.��l � -'�!�AcN`s���tign kk�6�">��OBo"b1�P� ^���2.K 6*"�'"FeZ� in�8I��si�"lHS�AH�+a��K , [3�+)J:�r��d�� �1&�@-3BRr���8A;D�$�(R":I� "?.`���h!� 6�%���y*�1k�&S)�W�k�r6�A� RKIs�e�J� �NK�KtozsRG2Ś�qi�AE�st"�!�a�@u]8��. A�Ettod2 �Q�tSeopxA!؛e����A�A i�!�"0sc�6-�2'Aa&�!�� y�% tc,� �lEa"�0se� step!"�a�8�er�MG/a�~�O�>.5_*=!�>!�f��� �>.C)�6_`��mM����_��A���dK�Db�����" � y�r D r%�����5I��z1���4.\E(�� !F.2 t� 49�!�edK1!���:�e�]�B D�bd)l�}A�6��"� q.��MB�l-<��>8�R�T!a��=�@�  ��~*_���.�+�.Ty� �6�ta�s�{�2FK�L6("!#&�'M/:.�#��@7�Mu�{#\b; A/�;"���cus�H�~�!d!�*qCM���0t� @V 7C�#&��+��"*�2*K�'�(��=6>-0Qo�E"-!>�Ii�i� �1av��TaB>!N-���� nse�;w�pt�`�&� ����^� E{ �!��yol0d�{+ !nlD��2� ����KM�&�1��oxBl�ctMW�ۭMs"�VoM3�S4\FAs ��{Zier� ��Zprozl<)�:$�$�(1�4%�7 ��x�+�o�qxL}Y&$�)�,7;,%��Q-���uH�migw��He�1�t9.�9Ra&�*K %� z*�:YAakon5�;]5�A*'�st��)L�!!b\S1BA�y>1.�,� �[6Y'�alqD6R����aѡ�E"vXa�RI oq��Z$�Yedzg:i�slt`iW m/ΔG�!�, !jPY-of�A sat"�D�?ff)=.�lfakE5~�8selQ=2�*b>- W�"�!!$�v> �Sx-6g|AB.�"ofᓩd��!2p!5�� sxmU� �I�.Ny]8elb ��le�. !a |� ����0��G�/-�I3n%'m�.}Dmod*<��6�d�s�eŲ�3�GN���3� Q�s,1s �?m�M %�A�e!$��� � urea  guan�Xe[ؓ�!^�/q��8�.i�n9�޻U�dA& ' (fn' :�"1�"t ��Ia7!,�,�M]�&hio���n�y)��3:��D9&o.M�%��2�"7aZ��s�T��s �����)ta�a6u�5oYD1T&�2�b�J� ���2a��Vdir�r�)h!"72� midp�G( x������x�:y� Ln�)n"�P widt�� �C!�md��'QH r�2iH)��Q ��,� ��� m�}�Y�u�`��gؖ.� Nai��SBs$ qI �+��61�-'���,2� !cI1.�$i�ߡe��"�w�9o aggfE�mi%�!x�8�"n b!*,>" ��7. >�p����/ �b&�t��� o�Be�Q*� e�"OS��.G:�PAkuTI� e�c�="�'� .�+��< fai�8��och&�|�fe� s g+|CtO"9��.c�;$!�n&��!�Bgxe�$%g*�����8/d��$Z |ois��"*i�-�yi�8� �uDpvz� p�=aa�.s��ree�8� evapD䍊liquidqh"dN���y�-!�ce�fg�!2�5ne�-networkdu� �.�'�7o�.G��*A��"l���"yp` ��lso�l5!�&l�)]�"�a� a��F8ew 5$v<9&�YEm7n �W�l puzzUbUam���ntw ��� vie�=m!� .� � (y1-BX M �Y�'g (0*ADI��va5@ v�xA�J:�rՄ��9hi&��&& !��z:.3 #:]� eQO!�2#6 %&�ջ�iGb� s 1–M/. D�A�lF*� !_#͌Y!��Au�!�.r .u �)�uY��"S!EO| I>��]� ݘI\q � spacC_� l CR��` ?XaYZ?SI�-:�.�n:��? �)�~,%K&.isE� Z���1�J�!!2=�1�1�)G-M&87q-�ab= "�%�XV�ex�6v��#n�\�~��&�2w���u��  be [}����LB[}/a�a�) ��W�/ �KSnZi�� e �7��s�4.�� ��.�Q AUnbr�Ad�+a��tr�j~&�y�,|Ru���:sp3�!�V1�$]�H�H��" eto!y� upl� � ! iⅆM�&� &�N!� p2r���0 Street�/\h Q.�E�e u}&��!Dn s�C+%32s)�:2�C�6edVjAM)�!IR-� )5k!t�,2\\G7*b� |"�{m-�Fq��ak �1M tiܠ&�k�0cfU[k4�hIN��%Ii��� �_ ��i ~(�Mh��1x!(.��?$�pro�5)0"� j��s��mpLX4�s[4aM���76H�RO�s4was previouslyt addressed in lattice and off-�models of globular proteins [43] , [44] . In the 1D presented here , �folding cooperativity can be directly related to 5 corr$ion length�repeatQarray , � this�4turn is a func?of8,local intera �4is more likelyE> olerAd0‘cracks’ i!^i�Xat either end may becom�ti�eda�i8�8is sufficiently �E6energyA)ADfuA!a�ed I�neeI�(be so favorE5 ( or5tem�A�so low )�atatiEv�V(pecies will�doAN4nt under physia�iI�relevcondia'AIT��are! leasa�reeq�sEwhich�� ��%�expera�t �ha�k eriz�n)�--Rs [18�J1942A The)\st 15�6Q to d!�His D34 a 12-ankyrin9fragment1�A RR. E�(m�esf�AQ4subtle perturb�(!� �Ieticse %�,oA� moldA�3ensemble!9!R��9(,�y oE�natura�nŒre uny ��8alone , without����ng R(macromolecu� . We envi�]�M manyiq~ ��E��y�K4‘instability�$of certain%f�g!��si��itm��EU�z penseAtoI�goE��transM�upon b3ng!'�#he cas�r IκBα%� Notch [47I�8!�$Our observ%�s�hbe howA�ng[S��a�gle-&$eleE�(�� post��5alr ific gor�ofV�) would�^�behaviora�a ��a�sitAprovi%"�cupl�mechanis�at�� mit allosa�c signal�H long [c���]J�)�. a�numer�� e �a4coarse-grained! elA�wel!]fit%Eprocedurzb per��ed us�yVi!�hepatiti!� obes 6 $alcoholism��lH major risk factors%�Jocell8carcinoma ( HCC�Al�jgh!�seAo  leadA ' g� $ �a1pAI ( ISRA� r una�edQ/.%UP%��ɜm}exA;c� th�s dpathway��flu+ h thE\� of�� Y �tesA6.i�wE�,vide multipl� ni�e��demon���V�he� -reg�o��"� )k CHOP�mo� liverA�cer�eat *exA"�is up_�?tum!�in human�A3two mo�1�,� Dreof . Chop-null m"r��sis�Tto chemE�MI a�!FI`)}@exhib�V tten�!k(both apopto7�U_prolife�O��J�ETrr� fibrK,M key.�E�A�. Global��.Jprofi#sugges�at dele��of)~ redu !�lev6basm$flammatoryDA �K)�.d results� �OisE��}%��� reby w�� ribuA"to)�icq�1�by�mo�Ti�!N,.)!r death-�comc �>� They impl� e �žcommon��M� �d!!op mh(in a variet�*chronic-(diseases . !�!tit� nearly 90 ��Rall :caa1a� !�UniapS��Ai)� )A'($fifth most�I�.� thir� .(aG� 1 ed-Xworldw�3[1` � R>a������iXvB�dueA�e�icj��cirrhe)assoc�dIpi�*([3]–[�I-�+�<stͳ �!\�k al� �Jm� $than doubl� U . S . o��pZ 20 years )'St� iA edispos�l�= ri�I�ao A_ thei!� �A�eW�M�0endoplasmic r�ulum ( E�e�1� A� thro��5nzt~�ի[6%~10� Howe!*,i kn�whe��!K�"� SR!�./!6a�) ERW ticip�i�verse6P�cesa�I�!membran�)"E �traffic%�<, calcium storag� drugx ox" , lipid@� ol synA��W�8 step] 2uga�7tab�.�1�s ca��disrupE� $organelle'& ��capac&B $ in�O��.��%qloD sM�[�ER�sK1��� initi�byA� ee EQs�t!hns>��� �cul(�7�zl� ���7.�im:g"���ne-.se�!" iL2�kinw PERK�~ � %6osphoryl�!# 'ion�YeIF2α��K �inm �]8A6to->>��w Y*L `>� ATF4 [21 7E�ba;�%��)Ţr��dmrI�es� lassl ly:��inT! , aminmi�mpr& or hem��cy� �A�w?�� h!ɂ��us sha�2 al t�it ��[� IRE1oATF6α1�J)� �KchS ���, but# � g � �ct�)`q]E�do/e�yi; t��� A�6_by-�-dependG���7abs��ofJ�.�_� and/��R "G ��!���of&b typ-�  atbr�, colo�8proy,!Ha�nd lung �G���E� ��)FAW2+ sE�exi [1�� UPR-�� �d.� pp��tosir)�a8=X2Bq� ( C/EBP H�og��P ) [17]%\us .���u� pro,d� $ategy�amelio_ �� ` pharma!O�����i� �k� CN  �� oma  vitro2�..�n����% =Lp�te oncU-�&enfUby��o�arrang�e�*+FUS/TLSX��EW[20E;2� .�q "I A? &je�pB� �]t�E�nES  ŝa5sibUoq;�&�F�e�ir& �t.� q prog�#of6 AQ�wEU To gaainsigh� [�J�i �,E first sou:eq�of)2�� m���A�d a SleepA�0Beauty ( SB )iW poso�:ser�kutaDH system��,�ac SBBs%Bai��r/enhi8!?se��ndeptor�s��mo  at random!�mSi:��&� ��)� A��ge;animal mcro� EkSBase-e0ng*. I����%6& n % ���8� Fo��im^�(to�A$�'loss-of-"�!� �{��po�^ ele��AK��-),d=dp sI" igen%��w!-1�A�`ad ag��at�2tO�� <y�.�VXorigi�g%�voi�0he pleiotropy� !�� �"\".�[23��Ml4a])T2/Onc3=�aB� �optimERtoa�A�2]in ep�l���pro� ���6�> aden��am�maln�of.f-'[2'#2��� locu to�!H9�.&�f���Wof Rtl1 R�ar&� of ]!���yet��6�� , [2�ap6���&� mRNA�}-�� �6 us n7!l�issue�a=�par�whole-�g � s�nitf tot��RNA�( O\%�j�e� 7 e made up vas�� of SBU� �y�number&s$s�# non-B|a!&+!A�Kwtmea�B$ful quanti�v�C pari��. )� "k"revea5enrich?A-IS� Oga�(e�WC,��"�ad�alC� @@$ s 1AH�� � 26�� but lit or no upM(�ERAk pero��7 ER-a�# grad�� * i�& m>�inI� _� ! PERK!�"� Fi "&AIh� 28 �9]��7%& ter�� t�!�confi�$ by6�$RT-PCR ( q )��in�E_UJ!2(�ol� F�% s 1B'%���m�� no.� i� �Ŷ�orm Xbp1e��Di�� �P! -B-79� �S���)�sAnaEI{(ine�<(E.���).� [8.���, immunohisto"su n aKbodat] 9�!(�#fice�M Q� S2k$!45�i�,isplay�c��$D-��nuclei5� �s- �D!&� ��={/�r�aA�� e�(( unpublisha/ataE�.�,6Doed �Ll*'�h� 51�Con ��ourɐN�!�Q�����5Mdid%�differ�:rm���ec�/6xAwabund�_.K BiP�D%$Taken toge�s�a��; 2�%��A��T.�by.�of*A�!>�E�A�F;4�ale.y$nJ set �$�%+)ea��W�!%m"� i`vo�&o � �s hyp�� (, 15 day-ol((le C57BL/6J�AsivV(( >10%&$ons ) backV �−/−��g have: n���.;!�d�|�ope�a? frame [30��� give1si^$i� t' toneqj*0 I'M &� diethyln�sef ( DEN�!�tP ag o 9 month� (� e�`:\&�'s v,�&#� =�# mpan/by� >��*��� clos!�mimi'� evenh �]e]&�[31h At�,�treat[ st ly�ophil�?ci�:. . nd%� s ri�-ats.ert!�[3S� of5 eno���� "mnod�'q, occa�%', <+i!�As%�c��*:e>2 6 to�y� degrees%� yper6,� Hmorphism , vacuoliz�G � �"b archite�${sA of f!kGn!� Rba6�,{ ^���2A ���� DEN-%�!a} N�7lev�/eIbp*� T�!�>�~ �&q5�o�6oA� idea���ic6� a�]��"�b�hop�_�#; 2��d�,ah CE8�/!/~E;�yQe n*/ ��surfaceU�per|�JD J 5&��alS���wild-a c`'erC 3 !nqinF�$had on avex�0�F one-�!���-s�Oal� areaA�g�z( equi��6i a 6-OAin R volume )U-s 2D–FI���$weight-to-�  e!%U�q6��� betw�/�� �kZj N fX+%N=��B$ Ic}by IHC�AUq�NM  2G-u!�^6t��"xen�A>�Ō�� U t��>a��"�G&�#in����"��W �"�!c�+� � � - �du�3�\i� �.'�3�Li� mAHtl&' �by_�-�(!�afensN�"S��s��ocyte��!!]+�o� %&�/~[3�X��edi�a En2.�)b!��6% H%!��p&@%v�rk�4w%�b}w��!inJx~ de�) whilA6 )�e H.Y Caspa�3���"U ]Cprimar!*(�e�exclu� )U���RwŸ,[s dramat6�b:1R՘3�!P9:o6kq�%x�a��� n-�tF�,��S'.��s�4nA�"U1�V�PCN�Ki-67�G3�~ . Bl�d scor�"gE�Adř��mMF:I��sԽty� �),j le�m�ug��on�- pite—or�Hhap&p of—i R(=�N��:�Z%c? �fatty ّ�a�"� plb$c!�}he� k�4[!W�_[3A studM�P�� bajducSg� ��Uc"�" 'injurA�mp-�� y+��-[b%l[3�MYre>' ly ,�1_$&aG!�PD� u4 �?byc -��to �},[32W�1�7��'ch�7ngV"y/e�{!]Lo%$nU 4bon tetrachlor\'( CCl4q ��!/de�e�an,-2 by b�9 coll3�' in Ma�n's tvr���24�2%0J�e��� �"$Y �@mCM�B 4B , a�,N\,�e*�ccursK/A_� �����p��xZ !&%ua9+up�"am&�A�j (!0q+"Z  4%low-:�ais�WE�2�*�)��kM�[3m[3h##6@dminih-�l"�'DMN ��N���i �3inAacm�&i�6, [39�7F6C!#u ��4-na��9�L)� o-a��)Z:�in 9-��:*Y��pH"/(��ly les�5ua�.�B�.Y, E)�2�&�.�V�.Q`e�'tI�EhM�*E� g� �+�'�� M`plb eU�M 5�&nasW:C)gen2�:���L d�:��W3$!�< 's�'� a �% �� l 05��g�er susIi8&-:qto�a>M �. To d� 7)DC!�pred�΅� i3�'ofZofB&)�>? hO/i�micro�"y .��=�<upo>�E�� 2����tho��0ej@��  @)` -���ed� . 5� , p<0 . 0)?�*��%B�6 �9�BO 5�Ge.)nt�� y ( GO ) Y"�I�se-6Kt!�p&�?!U6�A�or��3of in!�ɞA@u�5 T8&\ v>ɢ�9L�C +� .(1 %�2a I'iś down^ed �l�dp��d �#95�= cA+��>['*�1GO5{)3��� trkBe�9.&�x. Simi� -�QQk2�� �eQ��Y%.+.17,�N�"�A��a&aUE3��*� �T�M�,%Z.�ADH�Ein%��S3��.<B+ u�Jig�e&�,Zj6V�E*3!��.e%2>in���2�쁰� �D%��&�.�1� � c� ��p�~�O pro-}�3�.'me *,*an �0t�q* � seF\ Q`yo�)(( ∼8 week)�_R/binga�ey%O%��9ly�8refd$ �<- ,���E e�C"K e�to� ntif� �E**�D ,A�q�@>1!,� 2CE."yKor2��,�Z3!��7* AN% ihooG��?0 "$ f�oM�.:o �:���Ah�h@&�� >v5=� ehic7#e�Q��Z�Q^.f�Kl�)=6�,aC���"����, Cycl�,1 , β-caten":& Nfe2�f5� A�&"�3.� �x�t"<lyqp �.� �.0i! j&�5� P>zM�*�,�� �J�AH� ]������ �%aGe���U�S�. U&�IEo�> �� w� A&U _A���l0+<�2 ( 26/28;Rs 6T6C� &��t�:�!:_ �F^��6� �6� :e[* D6stZ25-��� � a�6_�^�/�6�~�L��*�L=!$,!BM-�ZMK,# , H"IB!7Ca�CMV�t�c"T<� I��)e;��, �e6/ly{M�!��_} �(6�Du�1��% Q]"��Y����%vm�-h�fV� b J phag �#�0"l stel%\�s%b�r"�9��� �'�= i:� ���broadly �JALs%%S�a�� DwimpacPJS�1*�g�hEf�k "&M��A�H^Q���r�Lor�a�� ledQ0 link�5I)e�6�aJ%� u� �5 or3<D*�� �Q35l7 ) :I�%�&%be�0-�Eq�3po >�o"-Ew'�/ oaD"`<,�9��e[ ox�A"�,��MN!��l"�"�%�e�0�n lyE�! �in<%&m�of�neo�>HleA_�O ch a-�jg$e:tA s �o+ 9,by� "+sM ly"8��>dA�in&�.jextN7�&CB*$a&�Q� re��6U!�of�5�d2 � !�*� &R �!%�k ^.v=:5�N%#1�re%�e oxyg{JGP�,*� D�1!�$�-Q�" ed RO�77AJ:��.�7erqS�)��*� =4 ���< rovo # l�3 qO!V�of BCL[ 4S;V?0kN�*�Mby O.%a-[2��tOb�Fe � ~fuELinvestFV �[E�i2�WeE ��"� "�E�, !��L!���whyFR���Rer�'�,E% W>����%�*>r"be� sil3, � �"�,� �8���?�!��B�m1O��failu�;o cle�"bod[6,:�B91 �7in Kup(.!�s)�engulf ���Wnd sec�C�BZcytokiy22A�"FbemselveA�]W�B7< 25)M�ic6 .���a&2�I��#MCE@* "9!�CEN-Z�B�P I��!e�uL"�$ů�*6i!1��>0E�mi\/�%9Y�1Iu�;)S�.� expl2;>)�A� fea,�"79 PCNA&K'1�aN�Z _F -� �O=�$>O, a1 -or-�Gun� l�s@EO�Ec!� u��� ��"c n�Lli"�Ju r.x ��Ue� A��.�X)�o=��� %�ndYB��f�N]�d�9, � if�,�=�,mR"���is�Hk �"�2� .al� �DZ@ u#*�>. Wf&:H8(&(-kRF*acB��  ���}4�8resZaO! refer*�Zer�iX� st}Qf�9on�1INf7�7�=� E e subs��-&0 vali�W�>�:� 5!C�{�"a�mQ�G��iRw<)�b�]P!�eL2tep�+o2e�!V!�&2hip� ��Yo�*�R.&� Nl%� V��26X,�1�[�a/�,Z�e�S��&hZ H<RUw!��"�!IF�]E�* tom��s^0N#Z��pw�0 fashB&4%� view� 9 >�A�KtA�!oA�eit�Z&t  Ye� e�!�e� �2SJU14�B�i"�]e.t� �Kne�is—�*E$f*f�$A��>5l]y�A�[0 6�/noB�1rat�� surr�T ";� �}iD<,� �g� g*�O �er(n ongoT��� n)N{]8str� ��fa�6g �WJ%&N&tsub@^sE�VIgho:q0�!����2]T��H�-&�.du�)!�caT6"�Da�� %is�� g-a�A�� �GAD�\-!PP162at�I%Lde.I2es_2Rn �i.�} 5ic�AK��`�*�L cula��8IB,�pA d!�h{� of J\\���2� c&i} d�r -��-�C= �w>—�^g �!QucG M!�s�E"QA�"��ichB to�&�re����en""��r��E%fa]1 A.� jl ��� "_*�1s"� �U�bA�_:M��; i> �b(5Fi6w�eH&"^ !cura���1�!K�6"�'x6� �*�LQ�?���� �Iӑ3` a1Fs�E�8Owf (vGN U t�J/^sM> bal�GA��2wK DACis��r�G nti-�!�ic [5�;ID:8n%/l{V� �dthA�"zaA��5�;[5%U5:L�9-(fi�ni.�f�e�8) ?(PePPKR�RIm�GCN�8� TE ��M�Y Also!-&�\�UeMi�Rece�a&c�gbe��orC�[59i54�� , �.nBAW6m,�ze���cY!�[�sc4Bo�11�8 xP 1000�(^HvUQTfcaV �ol;o� :f�-Kso�"�I�o}F�V%%9qNdcF�%`�1�An �`A��2�j�1dA� autonomX l�S*n6�..FI:� �-s2� m@db2:(1� "86��$*�M0g5�e�;�(VBH"�-!v�'� V �e��[ �ME�2��aa �@p=>�# |!�60.H��>*@  "�a�I- -�o�ab�j 2�!N2�6�. �A�e�Qcemqa�>�&r�� _8�!�a� �� �;(G s:�n�t+ .G^-yA�be�me�coC.�Ral 2�!�&� TLS-N!EW �o$ �e��!ٙ��lea�A].V9�is I����A��m,� � eu*�t���P�A� yxoi� posarcg`ha�5Bt� M`z ��to�A�-i�� fo����D!l!<!_� hetR�b�z]Qfei )�[dipr#ic.EVga@`'�=� mO> �, PPARγ2 [55m25G�Bq���of dys� �!2Ym&��HCC—2� �V.y�DX5[58�%��0��� 2 N�+aEel!��$�9"N :y sP�g�h�K�-a7Z\� �%?GW Y!.J1�\@|Q� �*�2�n �"U S-id5^c" .P�5E.!`au%��TMW9bW��k act�N6�� -���<��I� loosG�i�EZh��i�q�v�Z. Ult', kfx E]� ����iadrZ9O�=�_BJ�8r%po�9 rogn��U al ~U��mesa�li�4[6� [61]"�BB�h;�"Mf��S%ofn� vi�G��s � ����n�be�!�U������"�  �mps �h�3%l�% �+Em� !�Fabeyonde��P'J C `N���an un�^&TP link"=Ah��6�c��dR�_itAjY$5��ya�n�9�sw>a�wFow@*5%�� 9!� a&�NPV!"��� apeu�e�EGa�,�so��p� �. N�Wad��roof:���Yqa�V��V�D1��n��)�gr$5X HBS�2e�A�R�[6d All!KtocyN!@� /,K . Po�Y���� %�ar�'� MkfixI�10%!��Vn� snap ze2N� �>�)�H�BEH"�T OIm�J-��?t�2e9, *�4%�&'3�wZ%�N1�)��of�kX in� oiJ qX!E 2q�0D5 µl/g b . w . tw!�an5! q|� wC"x�GaEpe�qw Y!. 153/��,( Santa Cruz�c-7358n;�PBD Biosvwc�*$610978 ) ;!!�fpit�]X4203-AA|D<( Dako , M0879 )_-�#us�O�M . O .ki�"��&( Vec�LabP . Do�g6KR6� X9�#�c�#e�In >�23 �,2'18:� 3258�, CD6> 2135 ,or SMA ( Abc� ab569!#BBonjkH>��y �!!Tandem�,S��!:!*( 9��-C=��k" 6TY)+bSLZl\JE( Asp17rA^De�C�4Ki� C/t B��S)�m�v>zpa Nik`}ţo!�{7a 10×!C2-40 �&l 6�BBF6V�\' �Ni�:FQ!�!METAVIR���:��a9ix piLOs^"#  loUv!�� 8e��t�J��divid< �� a<x -LBM~gɾ-�coe��� T ua��|o5z��Y:ig 5ce�$a Wilcoxon'_k sum � .m�" /=>a, wCs:]?�!i0�s.d"� 0�(10 M- Bve�V]^�Uiel9� ; �71t 40; 2 , 4 100;�_s810`?���!��H=$: 0: 0–5#B�{$; 1: 6–2p : 215m: 51+�H=5&�6v��A �und�t!|5�%?r&��. Tran�p>�\�y�as*�� � rawu� - n&Mtl&Lt� �[�]PR|r ]or"wW�$(,^�[6u� l�"A�V13u%�P��A��=*���two� klbA�6�J"�/lp�{*RdyM1�_&]"=d u�za,�]�A'��."% 2�;emsIT`-sre� d Btf��d Ppia!v:iz�Y?NNa FoY4tfQ�q�(Ebli�a s�&�or dynawese~ n .�O�2].��s 18s r�C4+�.or Gapdh:��Ek�M"ZC��Y�F� " NA C ,arF^ a�ng(&4D@ N .�F PBS-� B �R$( n = ):�=6� �2� s+�]�]o� ��.�~d�b�w2d. Illu� M�Ref-8 vR 0�edCe'��E,r'! manu urer��7ybride�a�D-鱭��y1 epta�| -Cy3rD E Healthc� , Pi�\a�F , NJ.Be2� scan�Say�iS�퍉�PCK2�DGenomeStudio softw} v201�>N�z}nM+� ��4��(he NCBI GEO!9e�v�a��% J(is GSE51188 �<�`�:6��HDAVID .�jLeishman�; ethi�S!�'�D"7�|f cutan�zl<h( CL  `E Ha�D!K�)C vA���_ud�,e�&�3��CL� R, muco^w�fte�[6,�k�d)�ic*� . DeaO��*Yw�*burde���2�+e�� *P!�la�q.P/ juNa w�Q Ua�"�8"O� �"��""outVe�CL�tL .���8ь%y&��fo�ci�'�W& onXɸan�! forwAc�tri�0� f�*24l ords6�506=;episoc$V@L�"um݆�u2�� i)6Phg�{ mon�( n = 20) ntamidine 15X~Eyrylap�610��rr�re�u�l)�s/ser!�f� i)`XQ�!�"c�u%*�&=/[Jo9qu 3#j��6o-z.X�DY\ag�Th bo�!� on-X�� �Mt. ��ti1P!*p=F.d�:1c� rate-�6� 80%L$d 69–85%�r.�. P\ `�E�� .&CLX�!�a�3�Yr6to:f&( !�1�frI�xmethod��lim�f` . Dataa/miltefosAQ,T'omomyc--xp�rAampho�:B�$extreme BI��ga2��N&��on ��E�IK"�i��vg�^ j�a�;i !8r=ץ�pa�!Komb���=��N'A< �a6e�$�J�D*clu�Zhe6F���f>�N�(1?%�mF1.�remr3v�49KCLvinٚ�ir# icacqKd saf�{%L��be$g def�@. MzimA(ad�8� =@7 }R" .O!s=�)wI4oa. High�/���N8ANurXPeW*, Oa�&p ��i&1�"7Q[�a�. Cz( �T�uUukin��|;Ca ��;otozoanA�asi�^}he *� genu�, � (�� ��h�s" b�Cf phleboS ne sandfl�a�6�/�I-F+o-F{th.fm�| . CL�m)iia�?tru� M� �2q � M%"_5e* eeׇ!�~�Bb2�%ohaen ����L�!�New WQ�Yn": ]$L brazilie�+ [�2]—�A�%IOld I�~��1e���;���2� millg�b� E� ann8[�FIl!� ,>�� �6�st!I"f �B�I�%��*"�D.f�, , �I��Middle E�3,} th Af����OIian� j nmE�Cel Asia ��gCL\��A_6&���ooD�VL hi1@ ill �=�28at �;.�" ousa-��"��N�.��vre*�4)�6�a�maB"0Jyin Kenyaa��"� �-�!-��� �-a�z%|200m4 ��y0=A4,�i�99%N�=e��5u�\2 ��Ab ~� y=AG30U�of�\N t ��L�~)��Ų zoon�0iɣ,q�%X��Mj�K!Z5#^FqH�a$rock hyrax� ;noi߆��_6�I�s childr�adoles� QadK�[7–6�q�or\�<�4�, HIVd)= q�[5�L%*� $ ed q3��{k!^CL��rT] *�1~iCli�Gan.�of6�A�p��2~![pleouic��ow%w���c ,ity� �ocu�ed ! [1" L�� ( ���E�2{t 2���l �.�(���e:�.NN�B�)OCosa�o�,J1�l�Z6� Ž�s�.r��h�� 7�oris A�?*� �g&V"��cou]/6P nX1� �t �2l��,�&h&�G� e$y!�� lnMa?N* s sp�5R(r>�f���*|Am �y*+nt2��--=o EQmifW a��ob_�"s"ŒM$� "2nZECL �&N<pse a 9�(o�0�)�Out��.�J!�a�o.�ks�&M' amazon��.L mex�]a��1yeSW��;>e��eo�4a�<��c!Ur Pf  =ur�Ose�Mr <e/ "�!�A�ASee'�k/%�l�1�*2��QAaiE�\ �at negpt�Vl!a= �'e�"�@!�qN 6$ctechn"����+ H��^�Kee v &a:��"e�>��9� &�1 \ Coch>�p"�rin 2008 *0�55�*�"E  dYg�to��i*�[1� N� � a�� *G!��} few�e�ex�y1�m!i F�)y�?�?: igM~6&�hqZa�,� etU[+B or*[ �q�6�b$s�c�& �sh��*tUsYha2%5 f�.<)sDi4�priorito1�(,W�$*3N/&N/Utyp� 5�Je�1pW&6�0�;/v�2�ZR� o�T�fl� RUjE��Labor�]y�!���sB`2 "*"�8&�>P�i�*%N 2&xin��5"aPRIu#&;.check� G mple!�( See�^C!) �� s�q�m�Z ƆK�r�>��?s 1E��A*,�i�w[�ibAG view!q��e��HY�p�t� by!!��9e�t)0DM!%Za L=�5itl nd-\t=0>�i&Gz�sy�)��( JvG�EtPJ2au��vt�3s�ce< ��� A�Qma@��f�t�v` �>�'.��a}A�32P���1Eʔ��hL�bn�ms�T��0en�V ��$ �)*z�;��V � !��tN,ir�B��- 2��7as�M9)�R4<�U?�aa siz,jde$( , languageoeriodj`y�.��6>4 � ,܍!.�:��/ A�ai��=Al���%+e8/��3�79#h III���� , ea7�A?%�a"�~�ape�!�ib . No� <criea +se�(�o�pn"�" �7�Q���2pa�7stX6�L*,�sQi�a'n e�r�>� . On 3� � autho{+ a��a�*�02erNr��!6$<�/E��l�|%�Ia�0-��%[m�m%�e-pilot@w�# <er�t)�mve�� a se�'.*����Key5��?�.fdʝ� �!�ex*j.?a��: pai�&� /Ss:q�extku�!�- !�}6�or� �+~".;@dia�4�pa� ~ m@"Y���:. m6�05�C�C;xLtravel-p �_��t;NY�ޚ; 5"�$uv�i!K�S; �"ad7#�IZas6�Ga0.m;�U"SV.���g��o��@)� pretE��'i�o�c"�`AYP SR" �� �7�ΒF4 oc veryb(� ~)B�"BB&��&��e�aa ��f �ley7a��[wq��$ldobM�p.tW�&!m,Newcastle-Ot�# Sc�0( NOS!�o!�� -5af��fAZ[эT��X�Ax����:T���_Ly�� �ara�; 'bs+*�as B� %���hte�J:& �� s�%�3� �_too%W!�d(�x6X 2� re�en�G"� "�handbook��&�;&Q�s��,�s|^Z*r2�$Y�,�+mar%!6.Z,<  Ou�*�"95%�!�.B s.� a�scree�% �27�G�0*�i�u�t6Ft� �@�J�y�omp@? d 13� $"lgp �HgE-�1�.1&[&!�a�*pR > |IBs�!� ��B3_4_R*"m=r�!q.q)� -uYNa%h�@�n{�wr7d.�l@Vn Kb�w ���D���b� O�2#!UM�0F truD?S�y+�$� � ��lF ��5U� ea�v���� ubercul�;=!�."!5zin 198� a iPbo->|\��conaz�6F9C��* 1�y�.b�;nt�>&.YD�3,�s� Z�%%�(5lu�)! "V,K��lap\ E��T %*)B_��k$��%�% � ��M� �anQ�x�A�e�6� $C= �(�",�o� "`)\_�t�`u���`ah��QnM��l��or��:.�%U 4� igra�>�Europ< IsraeL+Wek�r� -on� R,e^n�A�two� $EHQ�%re AedM8@ 1,D" ; !R)A\2+f )�T!EZƁ�Mm�šo>�Gd�|ͯ*fi !�A�>�s4n�qca�r�E�of�� �CWSDS*� ,�,� -upAr�6�Y�>� I�iI���0NI��&� 1:&9/�(Ow�7a+*anV�XI{(~<Ԝr3 V5Vseer1q1�&!yAD.�(|!^�ef�\ e olQ!:�!��Aa� "��5a�k ipan�)taf݈d1�.E ) un%�Lia~4[ D%c�r> � ��concealEZA;Q v�a>]hina lete�)"Ź!iB�F �Y��)�Ʀ�3R3f�� ��1cf6�* 17Y7Ym�V!h��y�faor��(��,)Ro!�ng 384�{%�"�,�e4�.�wom�>~�&.&Z�A&l ��"�,�8�#h�G�tpV�2�CSp^�:���&;� z�����8 zV e �J�Iyz � I���1!"&� ~Y2��2���b�s.s�ͣLB:x, ( iazi�$rifamp�+Zam#oc��a~�v�.� D=�'#$%���~�9qs i]�&z��meu���1%^�9�*�+deg�� OEw.WnfA� half��� m����pj� . Tw �� q^Ima�8%3.� � .n.v)�XQy�-T��5�e�-^�6!n 2�315%Q��15m�yC�lep ala�I�ic SSGe�F�a*�.�)u8U��in�+A/A�)>� yd#a�.p72�in Sou= *�)0i$&�].-,, W!���^a&.*%W��Qq2��"(.@)� R)[&�Cl"Z�&��()�� � � �!� �Ued�S v�+�����QrKoX6�8lDto/ier��&R���%lsQ6e��l�Y�.!.!, ��0in 81%�)k. A�(��'*B2C0aMsamPI�}�\IYof#170%�&I�'� O {un)��#A�A�%߅%osuc"6�y 1� dQy ( 18]<�C�Adai�hor4d6�T?In ��r&�lH fsu>�}2t6�1��![�6ofb K � ��[�k�="�3+Q�6d�]o�*$gV�I�A~� �&!28%Qty�)a!�1���*H��ErouK*��"�� a��h6oG��. ��:3A�J3M abo��Qos �*�ew *��i7�.���7��.�toEg>- O.�!�6��&6� �)J�LI#C&+�w! keO <50%�a�&��/enT"y �ei�5Ӓ�gr)S#����'U_2 � %#o>�%. P*�1´!�9 �$2�3%1a�$5 �in&�AL.2��vNu��� �in GerXy . Of��M[W&�4�#�Rl�C�F- 50Y)N�+in^ s AbabX-�Wh,ABS%�Yo� ח(vso�u"*�� , Asrat H�e�L^T5�9y�9n�os@�'ed Eri!r"�)A �92FeuEI�ed�#u�$. Metronid��in2��A��>:+&R7�\W1!>�yk4����"�e8.& �e*�"&�trB��Y&� �P����3|s��6�p}6w9a�:76�"w+�a��eU�e e��%i&".��=C"i�soa���5��e��*e>�!�a�e)�or AmBis�(kA� sub-n=mo�*r�@�f�D.%�an IC50a�]-88 μg/m�E��y�ѩvi*al:�2!Oo8 CL-n0��� ���exe;Kti� B�. Mx5�1cNC ��9�8�DL)Vo9>G��s)�gb�7�Sk} �A&�Qr�hUm �(ENEscob�mEO�i.�9!;�� :$���2���ED50 A'2�as���2 an 5 μM ���aXr�EG 6"1b�st ^( �6F>f.l( /6 . 4 -�� u)6�:�&w�s4��1p��of �@�;1A�0Q�be���_�[2�/A>��  a>|a��00�utU�sy��ismiLPM"* 60U!�"�0 �-�P�e�.*7�~� on 62�4eB0� en%IAu��* �o�Cst�/�zstems p� SYorkTby Bryce�aR�agu�E'����: 31j�� var�l��z�&?  24>�~iv�N.' YAvH i|daI&!xI[.���"� �# �CoK�NY:M,�;V�aam#Cpx+� ��"�vu�VS ��.� f):!/AA)%�T!qU� z%(. O�%fth&�.QBl38{*c5ey�2Av.3� \@�C2A8��!!&7 a$%��s"���5Xh d�#�u*�lDLaR 5 Z)*�4�B���t�dX�2:�W0�=�N. GJ�&�,$>>t6��ę���da�.O��6.)"� �JI�A<�ʕ/,�"2Lv�M) %�� .2��� &�?��QM�J�,#E| declq�� �A�"u!2�conc%E�:( )e � u�I�bQ�>N� tr��L���; o di�u kw�, ���,l,6��&� &� >�f�lor�Yaz�"5�s e�B�? aU>��!yv��!��e�"�A!�9I�N� F�2!R�@!ˁ�%�&� decaE*}90q�o�x�a��B=}1G]Ypr�W�$�D]..' emplo���*ll-fA�rigid�@a(��@�"��L�2����7d��k In >�1 6� 6\ :] �.* locz� Ai� �R:%��I7��:� T8J ��S� �H �ռ|Wk� �,ɨ�: :^i�FB. �Pn a��WHOHomA&1%:i:x:�T �Y�.� v 7�+,�!��ARP �6�9]I�6%�Q"7�!->�82�.*�&�j�nde�D��$�<xi�:�Hs&KDa#�95a1��<���s�>�C� 5�&�2=�i� mus�2� pH �K!�f�6�Dk�^s [ed� b *-�����5�is N sG�E�N�onL!^nY�A�!`�{2r�5sI�Epr��G-�7m.a argu�1%� valuE�%�-�. A-TuY2�=8U/! A�14, � �&���90%�O"v:inAz���%5x 60%#Col�X@3e�C [2�T��":*UQ:e �edB��KA��;e�u/1b!�geox��Z�H>.�UR6����Q�9�Nw�NB;g9~��6� is n.a����y1�l�East-�A!�Vx�� , ֜�opA_�t��*CLa?>. Few�z5MJl�I�O�=:k� pqA�!O"�CCJIz%,H�NRIrad%.@r�>�e�"�!<\'��4by"S9~U0&^.��ebGMC�Jk�F���t"F�.~ V��-&�a:�,2Qts>�� �.pr8�eFqJ3�V�:�!����ilUdUV�<=-�%se��;;o ~hj?am�TFUa<&�P2arflu"�#m�*"8rJ���2��.��,a��� Eh4A˥��*+.��f_��e{ *enJc�� k��( �g .:T )�J�Chbe�Eth-a[� �Iar�? easy����d�.� �3�Sreo�9�Ţ1� �y?�Hth kTF&. RN-���&N@e� Peru%|�ost4nuah�[q����a*�L6`N�."�:in a6մ��.7he Drug�&N"Z?D�D�/iti�?ySNDi!~@:pHA�L� ( ww=`dnd�`org�I��o� A��"v=expn^0 �cAT&!��R��Kno�Bn)i�ul��#!m��.e�� �A:[#,�� 8OZs5a�� ly[ub*�� B�� �wV�A$B.�9.&BwK"��a�7e����d��Qۍ(��rt��&Y ��>In trypan2�ia�Uwr5.�>)A�e a6 t����f�I�� � 2F ��s�J`e2A�A�.>�@cum��a5W �N�r�d*�B N"B)@? iabe(G[28�#�lE�*��$�Ez"e��,l g(A4�l*�LAZs�9 e�9 recer�r�.&�y"�Pjno�v'6��are#q!.� mesy� ( LoOU��u , labehB�Y� -moiNQ ( 12x"�oul�E�ada6�d�"xm 3uf body�. C��6�is�Xnat��dTcar�R�m )�7��am � salt1.M�E� ( 30�!�Jam��of6�E 0"L{D�.me5 !�>��] �]!8( 7!7`)A>PF�n.j advi!��g />( 4B@����"�%Ύ�p6<�(������ ��nA-����%�D"}8��-:�DA�&g2B���h "�9�\qui�Dcl!�2l&|B/ �Y�&�7-Gits’A.���Q�d |> *%��jN�h ��IV:�?& �6��, beitiK�e�vaG�� *Tc}%"�e2G��f{ �s �52���!2�Q 2d ina�o)��� /Vut�-d (I -Ka�� i/@ )if )��B�a�pa! �:�'� m�2fPl�"�R�!c�� !/�DN�x� 4��rtR�sol?m "<.� :w ��%&� �n .�\�� Ai�m&�$7bF!�enezuelb;���O"�]2rJAd��*�p#x"����*I�J8(� �Vp("� ��%7F�vV!L%nd�Qe��K�$�6i z!*)w-�k>�7= {r��l� � &r>� ���<UHl��L"�$� AO�P����2�8eiR�eaȡliryd r&�'I adju�� m �\.p"F-Zf)� � ��9��M tega�i �`to� o�H9 *a 1r vacc�LE�oM� "��:F!�afM"�S&�[3��TM��� expaY.�Yre�,�"J�*� &�Bu�d�B�&D"o q��CL�[36 , �. � Rh ���� с}�`7e�kd 2xRA�12@3&/A�.� raPa1d�BA"-E�!� -*%S�e-&�?Zo0ty �k�!�& u����o��l(YC�B�5�bvC{�)�>��$~��5 A�z��GurA~�m!ev M/�^�. AdapD6faign.�2d= in NTD�M<1��5�quick�ndA/"f�w�� ..Q*�i�ruiSY�.A a1 [4��c�n�13.[A�,�T�Ihys^!1M�2��\I5�a�EvQ�)(.��,f�KId59�!_��pa&< 6=!6.� (y�d�Z.CA�"( c��Fij��(FV�[�Ddis��M���A"�.��a���ic�K ���!e��e2SyJ� L"3 &�.[��I: I(a8�c�f%[9��ZDf�}>]a, *pr&�5u").-Z.��g A�n- corners�� ���A"ll� �l� ����A��Fri!�d.�%(��a��a}EeA=�*�fm�'a �� 9�5����"�a="� :72��: "856�H�\b\b. A�Z ario&c � NFb�-a��Ns/X.��A"��^ osciѠaL�Wre&��?�S�>purif# �I�!�)�F$� sa�_ME4�3 +6 ircaq^(�) rhyth!��self-su�l 24-hRiodG �emper�U���(DthWGz)bi��b�eAis.����M8a�a�*ל���+�0B_-,5 ( Kaii� KaiB*nd Ʒby��X�n�.�Pie v6?l#pho��f elucC� �!$ � � !`]SxRR��/Kai��e�� �����*�p��&�X"s#]0%�as�at ��od"�r-�of�ABC%�l �n�4 KaiC/��� , � :��bio��J�� ��'U� 2�E flu!Zc��n�x gyQMnsf�N FRET/� �Q �m^�M�x�rngyC hħ�S@Y�$�1��*�(a#V+"\�%��\Cos� _may�ow:�xW)�\y |-���reI�e�*�mVABa-amplit��1�!�. F�v Ce�f_*"�a�u �ej�+F!x�6P��Z5u.�pul6t�"s��1R%e!UA;H�l �teߖ��UqJ!D� uniq"I��Ta��0�zaBݦ��clock�.�* un"��}"�x&7�sOhqD~Y:�.��M%9ia��:}X sleep/wak!W,�a��c^0� ,�  6!�,e_7�|��;�A'ThpAGr����e2��nen0�,�1i�;���IA pp���# 24 h(ndEy>c�%�/ q���  a�8a�y�����Q�qs/� 6�^oM>��"���c-und)2&)R�ga �f��,u� �2|M�Y!:�^�%f>h�We%I�!�q66bC���E_q�eN��ellMI!Q��-�{phe�yn[proka�=Ȧyanob�Tr�$in�� !�.�aK��� � �R�,�� ��6,e� 26��.�(um Synechoc�gs elong��a��U.�)�fo����~ڔC�a �M�Zp&>*x`!�݂�IG ��T r*Q ��q�A��a.>,��.�uom*yQa1FFeo"Q�bA5 |�F50"#.qE��a�_%ƥ� ��AW��@AR� a#<�J�<�9�b"��.�Z)j"�� @A�a�k� k&� km�=E��a �o�"o!��l�[!e�5��"; "��q�! eacۘAI�jv�'��[3�|�6 � * !fo� �;���a�* � �Wet����2o�d�h��ho&j�sӥ vivo [l}��}�/A��muv+"c�c��Zii-�[[� �ut6��.B �U�[�D��!�m4e�eBA �x l��+� �:�A'csC's^J�e��(?�tagoni#��� � [*�h;g� AwsۊkhR!jd� ly [7 , 9цьa� S�c C>��s for'KaiA and B�s wer�\by other groups [12–14oThe<C�Dresembles a double\ghnut with 12 ATP molecu(bound��pinterfaces between subunits .pI�(CII domains!� each0T adopt similar conform%�!_butqir�X-binding pockets exhibi>Dgnificant differen�8that are likely| func!��al importance . Previously identified)6mut � P@ffect rhythmicity�lengthc0period includ!�sidues >map to�55MIcontrast'coEsio)9p � studiS@suggested a singltgy A–E�ia�$ [5 , 13] ]�stqrevealm<exist!Q�two pot!"al! A5�ru!�one�p!� �waistU-MA �I� ,4dome-shaped suEh�sen�by%>u � archa_usher�Ma rulylanalys �D mechanism�Now%impact��P�4s can be assesa�in�al a���A2predi�=%Jc Qy "�K �haddr b�(n unparalle�flevel�o 4ar detail both� vitr!�%+ vivo . Wee%z!!�=�,��2�͖ABC&W tby electron microscopic ( EM )�rA�H kn� e�iB�s . ToA=ck��ou���:��G�&� ���>�,!@per 3a neg�F-%��}A �f�p� draw� �!̡�BC�, . At阉E`e�;*�>���0( Figure 1A )QI!�ear��o� zof�`macro&< � mbl� �!�h!�re 1UAkWea�4d image classiLE�,!wbinedi�!�ariso� EM 0 -sum @ def2-+4�,Aq sorte�,vidual partiA�!�to3"�  distinctm R ��see MI ialWM� �,full descrip��1gB��s^�e�al�or!�pairwi�bi��on)�%��%��%�w��EZinD!�%p%@(( average )1 �� m�+ ( I–IV�Tt k!�(s allowed u�J!�gN�tC!> ��} �,!"a$ A•+llex4 I)B>)(3�9ww!1D�*� _"� f`V*no��en GeEM�L �. (A�$will returE�aA�b� ) U�.g below . )!Ze_iin�E$ag >��� a�e�I���%?>�- e}�C5a �Xun!aGC9�(1&� ra��edominDI7:�.5I (�5�)U approxim815%!%�AoEBLD�a�* R�is de� �V(9D1–D3. re s&� ly larger=��vE�es E�nd IV!:n�W ���)z . Because�(� e m& s� al}�)EsQ! R,"�u[doE�sim�� prog �cr �-�*an �!pach �$n��.b,1ra� ��x� ?#tu%= v�%. ٔCa�lso�qm�S�� is phe~ n�ll��� � mVVJ � :� !�$immunoblot�xI� ����b alyzi re@ve>l2Li ����� C! c her>k �veB� j�5� �a�� alter M^�$  9�5��$. Our tech� %_�. [x26�q�i omix�� Coom�I e Blue dy�2l @n_ ] )�� � "� E0��inc� e�� 巁� !�"�%�An~ rvA])�<.�t�o !��USde�V T, A&r��� q����b( � �7 of BN�is Sa�a$i�)s suchA:%or$rose-gradi�u��� rifu� on [2"second=�i!� standard "+,��S(J;�U9)8ir�A6&� wea �>�� ob2 ed!-�%�� cons� w9� � "G �N�f \ELn� ��E�eq� �BC2m . As�n�@�ll:A*"�i�S���lyJ���-aw rang��lef�de�QD, ��K��uh U͈icU mM�baPat�o� �F��� rib�$is bimodal!�� � eft-3 peak.�m)�O �s !f�d/or B�tn�e rA?VVf� I��5 -mig&�Jm\r B��ob !�D2/D31�( especi� $at 33 h ) [could��any�"$ Hd "" � �^ �A E_-�e"B) shif.�)m!/ minimal cFB�24 h , ��I�Xn6.r 5] at P)  ( HQ T�?! a sma6��E��q.phaZ .*�at-~(1i-�v �)aC�&  “6J! “8 �(he abscissa?q�� ���deM�aa�� ��a"�t*�Y!L� (1  �>!5Nei� > 2�nor>�A��}aAi ��A�� a��1z �+ ) m�!J s�gl�p���ex��c��\H� ,��� K� ��by�l-d3ass�. IKpossiI�!�.�}isc �j' �K # es u�C� V�).0By�e3"-Eing/EM��pa�qr� precipitG2���N�.6>%7��"#investi���"Z ��ݼo� , �A�"Y�Vd�]�a���s" *%x���� o�� . Brief�weF�H$�d�kin� υ����deg��ofBWof��=in� D . Stxng)Oa hyp8"^'|#t.�(# te α�rrapidA��iodis���A fac��>until�.�A�hyper./ed���EA4+ assu|��N@d;B4�0�ruc���ultaneou"&�&�[h�W new-K C* , χ��\*51L!6o�o �!� ly�N�u��)�δ�n9 laa�J% orig&$a� i�~%�. S��% A.x!��= QE= ��!�]=r�twoG-���!7�je�W� !>e� �֡hC(�!Av\!�x�NiC^H��� �! %&�W���i�Tm]*��!wee Text9aF�-�_� E���ustochast/#A�6 d un e��$�*6�. Whei"A!�� �&(�*)2E%"�F%�!��M� .'�(t�aster%��:8absB�, s )"0?! acts� �2 fier 4C'�trinsic2�"ut6# [7�a n)*�$DAWS6{!�I,[!6u�/es/�� !.i w!f4r�'qUexcee!� threshol at pla��e�"���� refAl)�*�" �)! @��/ � $:7��sM��(BSion� %1e Z�!A "� pre�+tP*.dI&BilBx�&J��F �KiS depi9 &�3 furt�á�!paJ��ir=(r� y�� .9-!�|-ҡ�→ * =md��� A��� w/i�.�to�B\a}!�e�&��{A� timescale.p-Tէs�h�(inu�Yq�Q����9adP vEp� 9{2^-& *��. C* )d�9%E!ly non-.u�orK a s��|J tfe%p!�9F���� �/er oᡅ�y"F0$.� >�5e�E�!R1��Z>M@C��:+ r�,s.!�of�ʁe�"��e4�Ji4���u�5U�d ��zA�-�  5�]o(�0ble-heal+arrow��E/�a��.*Y , i�1 .� �0WAh��G �e�A\��d['Ras!V, β ,!� δq�� 9B��& |j illu�$*�!��1F��( ckg,e =�!��|nme$ !fda_)li6�:�� bto��dic���,�3-�!Q�K of.��"!a8/�*](a�4Vi��)']). Uj�9�t'5�a� ���� )�q_ st f�)� �C*�#�AE�� HowAt�*&?�[K�E�.�a�iWpe.L�.�2begin� dropo�"p �?� �3cr-� g"3>��p&*�F-�s 3�4UO._!zy�I)m:l#nvAkrougho�3k �s*E�D%corresp� closE�2&$al�.^!��/7!mZ*q��F�ep= ta �.R!��w�}s�5%I��t- �rhyth�&E >:in�ˉ�bF�%;��1�{ apY#Eeb� e �a% 5�4Bq� [�2� �.�� -�!D��.�F��# y) Y�-��r�uA�牔!*�}��$� �s��e"�6�6KWrterprea5�V5W� e equival�MC1w�lTW s�-��)!�!$b�ASn�se�. .&�!xcowork�1)` FLAG-tagg�uNb'E�7s-�)�C,��0“shuffle , ���?�+I���<.�+)��"�a�!l.�i�� CJ��wa )�"�9 dj*iA)&.�;!apu:�ofbE2� �su�8�"� ?  ��)v�$� aggr�'o!��,w��cij � voik �peptide1�UH"0mploy� �b+�*��.f�*%�-�.�nam��=+[27��40ha�aA�i"�c�;��,d"\9.�� la+��}+%�2�+E�IAEDANS%+ MTSF�7� �) -cha'er�-�L�'naE�"��"�;!K �')AQ��.�A���Zse Ps�;t`� !�incubaAx whil� itor�R�-"�6���quench'of���,� dP,��A�R�,in!~ ponsexc� 6 nm� e.e�um%��%JI5 1�l �A�e�eD&�=%hd emis=/�470 �� A$��%e���$ivA�!}� ! %B�& �E�A��-��d!�do�(�2�is-�ed=�=%�y)�ev� f�only 10( -�ng< B��/HEt �%\U�. A\8 �<=�)�X1p�a2r'50"r'ini���ns��!�e.�doe���:�u��C�  >�qy%ec(�5 ubli1 A�Un;>%gQ<"X e�!��ly%ed>��,l%�Xi�2Qn@ �� s&� � �B�" 5� )*>`�, provP!s�e���� hsM U.��9&)b> m�""��%.dis&b!of�&ZH#V2E�O)i� y���e��"%�A�&�" �et T , U �s ..�)Z�i �=��5�B��2o!q٥_ 8� 1;isrN�1m�I��#�r5�(� w�;��/tr )�:aOnsee�6 BYEqm|!�"=@�u"�A�$ F5�BK?^| � � �B<9 � �baa{��F�an�#5hel�Aeq�5J.~ qQM?A&A� cog�;�� Embe-=�Win{�&9�B��s�3e'��aiIn�icu@:�"�*=�endN!� E�a cru�#�=E��'z�yX6�~&����pr�7e����!� Z/"r�.��3fecH>so� �%��I�"rwf%-;icYz �5#�{�'�!�I$JCt E  9a�d.�sG ����՚:�Fdampen �6ŀA&+4 i��� uof2�%���*=I�^�H0�/��Z"� !��b"sYG�we �?c?6gA&�e� “rV � .�-��$�s CeC;&A�in�a`β χ"-a�/j!5�-CRdQα/ aχ/V. W($.'�g�=w"96J)�uU# ed ,�Z67.�(e�>T2I%�6G*2h�/E�aDo�EM"�9g �i*M v-��� on ?B�w�(nside whe}AF�&� ��9M�_%� &napshotA7.�cau�8��a�?-�� � ��}{ � ly2h� �F��*~� �(�)%�vfav.lw* � �%{ ,%�Ri.�"���u majo�F~>�F59e����>m��13"2E:"zeS�>_ Ux�a�g�;&�>�� �V�*� � �-=S�- ʅ��8�i-�!{y51���b�H!�G/�,��D�� F.lD1�D2��;QXQq�Wm+Ich!,@-5+� ��?�N�( Da"<t4 ( r< �5}��grey shPea�H9 �6�a&�E�/yp�A��3 eA�!/%��%�aSJ &�JE�— � imumK*4.�6-�A�r% Z��An�dtY #@0Eh�ko�"s�pe*E<"� . On&�2$e�� beL ���� �Cj!4byF7*1<!;�-,stoichiometr"B%Ka2�:Zt�3�A� dilu�!>"=o�N�Du�+����topA{valNQ�>Te�.��"�, reduc!�[a{]8  B]�8�S>)�A9 � o� w� �ha�1�:.% ;Byc �p3a �Mer �M�Q�!)2on<a��)y�&+2 B]�, c�Gc5(on� �>s high���:2��a6*�@h�Hye�@ ee� S4A�6ompanE��#IA�e cC�")QQTa`,a&�?u\�fr� ��DA aKO�,Q!���civenes% ap?uD a@��ok9“ 8!0seq�M7�&�7�M�<urvPRCY [30 , 31]�W.� d*3l!BQ-�h8RUE�Z$u�92;e�@-�@ �ia� test�iI��@��@��;� �17�%b*M�D"�8!�"gY�%�5tt 6-h.�)��30 °C'16 J�(Fs#�mv5da��Ee���en�Mhex%jE%%�� trol�> ( ru)7/'uo"R� �i eaL��expos�@� �*o/s=� z>k( U)ino�*F"D"�0did! stop!�  IL0�-%lo5terk��&2;G.� �( �g .���vCU�<� 4–en!�2�LV4���� !/ Y Ion)R&��(.tim�-�� Y low-}xT�<�ok�8&?!E�I�W�)z>.'o�9WM5!�30�6 75��'rUl�1�B� magn.E)7r�Ebs�/�D�0 D2 , ,�!FU1�ٞ-3@e@U2)(2{e�0�ѥ'adv�F"_ 7�C"�#7B*�$� � :�� �ya�c�`.�^�I.��Ee�T!��N!37� �}  6�1!fo^8� �� mirr� oseza2W� t �s�xn^+�� d!�b� ��N\ 1-N�g�vice �*a=`�W=amMD��8 "F t�;�O]��F��j)%�)A��8� <.��to1#� 7%� �A���0du @�B-off~  ���qMa�Q� �X�BX�F� N(�?5O��.�-�ensQ10AI1 .� (�/F�].�"x� () KB �-3���nI ep�* i ��f��N+��o ���Ped1�-�e����c��V�;u�.�}<�I�n�Z!��pF� lead�ya sub&� qiQ�l�# . Im�!a; afEred�!.��(��-)|� -� *�� ��4�C��e"OJ�P�<of 25��5��Z[Th�Fh��L�: Z�U;z y�ae]�-. AYecF�\ M >�Z!�.UMRn" /ca�ani� x ��"�5�Z��ET*FY*�A�J�7�P1aGelucidi�-��8e2 �<%+yFjsQ D�]D. B�S�@*�A�aY�[*�!%oH�6 E. A� , �=:�*5Q���B�!��5� pro�2�N�I�-�K�,o/_te1�EJ� �g&i�. R�EEJ)-��P,�w�#��9r�e1f�PFe$E�"��sAsQC��1�tV�**HVF��<:� wT\ a/!�aF�,C%�*�@�-�r� s ���i!"b�,E& &�>��icw:\�1!��h� d\&�+� z%A)�V�d?' �3.e���I:Z in good aj(PI�p��E"�!by>�!T�' downs ; h".� � er-�= Bq��|�F@$aw�5*�FBS9���*��K"� f#bT2��X�)7a� .,V�"�<�,bgL�2�4�'9 E�u �!go1�9�.�(" 6a%A*�>)�pRh(?zV!|&i)�6�A�{)� J�@� E��fa.�# ssay�$U�Y�&� .�#�B�y%M�.W`c��cur�"ly)=�v)&� �$discrepanc�_cweSiev��%Ia�"l: reli)��4A�)r +si�uYA+�]M�u&#)a �BeE*�G5�+ tagv:� ( i�P��a�*@�,� )|��v^aQ.Os�4!�at!hAb*� %���J)�E0OB�&�[AQh�`&�"kN&T/0N ).�0�T!&%�h� .>�2��%��i*E^��N�~_"D �IIS�S_e�c$-"�J�rysB1"zJ�8�a�! , Garc�nd.�12]�qi��a�^�<�v)�Bm1�<da8a�9�`&�"�6 .b!>��%o:in!-?^!fB$�$�x!ɂ��.C�W} t@*J�nseemsJ�<B]�c>Va dir�"dis�;ţ)"Al�B.`>is"��u$a��>�oed "_eo�4`1���ct>.. CN�@"�/e>(&>BV�D {g�+M�B?�:�.�L%P�=s n"�9pro}vKstaz� �BB:;�)k�N ��,�61C k ��#,��64� > ")�raii,A�quo��“Wh́J�l%�ex�^ma�Y'!cB:�6nbU=?p1R !B�"B@ �G*�a&� answ�:�?i�,s��aMo�)s�$[-s�JM7kO�[��!,=Gj . M<��'M�" la�O�\�]<&�G�*�@� .�$ �*��EzX ��+�d'vo&� �G>PAhn�eE)nt�H)&�fundaa�alU:( �P�Etru� �*A)= er�d%�i�G�Z&\*�o�?To�res�S�Q���F��8�biochem��"�+!eru �6 kept�Z #rA�S> o�F��s !a.� ��$; e nu`)o.8sW1�4yp�.?f 2�.103�0"&!i)capg of g^a real��q�"�G!�&�%1��(F�� � ]1�gv%�2��J�@4Ő]Ra(�|aA� cell��job�mat2!�AJo65&� �$ � �'�c-_hee ��O�X�.wa�2ll7� eU�ed^� � Y ��8l R>dh.I� ings� an"]-%Vy7�Q)��)A.0�T guA/&FW��A!`i�� e%.;D0hb�"�?�>�s�a�$.� &�D�Q�(�C}ar=�1�J%$AT�;B`nM �s>&/LaD � F�$�u�sl�s.Wb+`4�A a";,gc=���F # )��5�"� s&� ��!iH ?J�new��l&0)"�H:,Js*�*&�%"�VF�L4�� r:+7� >�e� �!U����!�ofJrQ�χ % �e� N!�.(c h;K�!.)UkOym%ic��fi�`�4A"���>��ay7� sa�]r� &WFU�6Gj�B��� *4 ) �uG"&2Mat.=54� A:m�� *Aj5�MnuE,�Cdi�- 6�e,# !i�pV�'.-�;1�� �.�M c:UI��6itED�di� N�n�M� ��4�� ar�@��AdI3m��a�X=����∼10%��5%�) ɬB�Y��J��!� � %(M a-�%5�*i � � ��-2u85�90%B� xCI� >�� —despit�_6_9 !0 �K�)ny�— chg�e*a s"L7��?DHs" /4?Vm,i�" (� !Q�%^?/F�i�>6# >5^qI4 .(� �H����6�p��is �R,a�&E i=�Pon* �Jl?/)��I��sU*� �� ^&�x�ȍ� d.���#gu� fashIx�)5F.?$ � ���6O�6OJ6OM>�4�3ee- s��now�V"\t��>�*��\K�N5�'D"18�'E� O0"e"�tBo . Fo�J�-Z�+RdBG“q��!��p&p!�:w"�a & . E�-b�?Z�**Jo"*�V%xB�,j�6�lcip� E�o�V"�5VQ����sat�u�0?�@ic� r!"?6 >e�6 |5V.>f�7�Q�?%�KN9 �w ed c�I�?.�2*2#F����A&N �EM:L�s��%k�#LGim'�iVhI(�9A�Xr`(5ji� 5%^+d�h >�]�*an!�M ,9 �;a F�er~3!�un���&�OHr����*W6"� &�!ceq �.�%#Y6� �- a8$� ����v6�5��V�5Z .cC��!].�3��e�]4B�-sS'o�� 9� withF � 3e�w:| � vivRe 1��$_&.�9"�e&i�la�a`BŦA���MB�"2^,�Z�niA�Z,0M&p#A=:1�m�({��J�E m�i5YD�YjPt � [ a!JI5F6P(B]a�ssa�byR�A/h�kb� bov!�we*N6��|!CQA���:�>�id��[Z t sevA4 � *g?c- �7� 9F�gZ&-["J�'=$ &�%behavio�AL �V^LW�0�]#)PRCibJ7!wS22�E�p�<ulsatilf J�0%� B�3� is&1n{3��&�%a�J7 docu����H�4p!�a�Uof���w&9�s [�}32qwA�tp%!, ls'!�eZ��/d0 y �\W�how��5iod2u)A�z ����k=�j+!o stil;d-.| ward.0*z��ū2 !�=/M� trivd(�ja-�t]s"�^!v�]��9�.���7�&�A�AT.7����'"l+�^e�*� �"2o<w� a,����fi�!���v�z&=xuuW�-*,mBy� � f�.Bl �)�cF�B��'�8 �>E�A��. �.� e"�s�Kata". �� ��eVRU@^[20 un&�E� �Zwe lookZ* lsew?%�.� y-!lB�%_2 � s�M)SA-%;>� !FO�nY/�!�)@Aa�o�� WX[Y��` ��A��,"�,� atZ �`A|�.�97Ar��t.d�"����O[��.��.�a�f.f.��>d.���#�K"� !Ri\A��9.`o� I��"/4&�$6|q��P�!o��"e�-T:���mea�("�&0|�S&�&i.a��"���B|,� et�is*� o� am�l�H��@ ��.d2wto8/��f2� �Clo>�7y�F�!�n %goa�a �e�=�< o< ��R�.��%N�tro.�>%��~E�p��nMN� r�a�p& q�*�rz�Tr\� ������osfeDM]Pe� dark%:( D�h�3k�\"G@"w��{mMAe� �6��=�:z#�"�!qo�P]") (in cyanobac\Pa%�A8A�o:M&a6�-.�feedback��p @TFL" 5�� 6"5Y�.�$���@vo6�l  DD [ьH"+:���Wl�( L�b n /!�#� L!�e7 glob�[E< "!�b�E�!k[�>:[;78qR�;3�;-pU�;�A LD2�2�yaه$7' -W��[ \4�IN���� infl�Q�e n�|| fu&"y��beN6st � 0%�a�J�� %�!t�%N���can��m�l/A���;uta�P issue�!��E&!�� s6 !�2�l�#s�S�)#�]LL/LDa�6&d�!��Xurnl)(6&�E)q�nd?�"�"a2)*�a eB5 e2ar�+�)>o�Q, t enzy��(vU-�-��0S��$�! utpuO�ń���ot F~.LC��sZ uctu _�)i�#b�5a� �r\�H?."��AaffcQy?DNA [19] iC�?&�  postr �(lyqiM-EUL@io�sth$"0 r) �Qu�i�ly [3��3�An� *���_!rE�E�-; mutue%ex���+�,p7~�oJ�-����Ԉ h�#dVkinF@Sas+� �t{.� x m �@ Eor RpaA�"�b݉����icq$� !R[3�Lms!";�4$fEZ its ���� ,A�M��C ?R�."Q9�0O�M))A�����b/S% a)�J�3�P� u!�y@�}e2Y� �a*�wl=d E$of eukaryo!�[35sN�_theles'v.��y���!G�L �N�c�KoWDDEs pure�ost.�az�M�Ba�vk1�G`}�) ��z�w�d}P!q?!Jui"$ A��|V� ? If �Cha�;*�Ybym�+6zJ� �a�bete@hut . ��Oa�a;)��a�(lt�}�Ntru+"N(p& )"Z ��!Tn�_:�VO to i�*EU��# broa�!pp�-%�o%xaBe�y�� orga��iWhe��6 �>�s �b�u�o �q3^N� i�� c�C"}H"EA �o�O�ލ�/���C�c�\ en�T �cyA{>`EmM�t֓�+re��i�udy�%m�f.4I��!��0�B2}I���:[1�B,19] catapult��F o � u�"�Ibio�H�  . 2n��6t �ex�� Esc�chi� li[pur�fa.+(by Nishiwak '*H538])�����d=uaVAzIn�&ID/Ped 20 mM HEPES-NaOH ,ɀH 8 . 0�(15#NaC"y5/ MgClw 0 . EDTAD14ATP , 50-ng/μa�>BMj20.'C� �]Ί�di�~8�����[?b*Q_���9<�&�E{Bx p�*�:�Zt�d}of�Ai"�]6~% -mla��@ }��$�|e tubZbSarC�? Nümbrech Germ�#)�]a�� ayr� bath�V��}e.��U�e[�y���aFQ%,a\9��:y �X,!�tT"Z}s(!-w�8st�at −2^G. HJt!A .��&"�`e5�$)�~(% acE�m�+?Gel-�S�$ colloidal.�rilli�B� ��P��{digit capA��Bio-Radn Doc XR�� (, Hert�,, California�Zni�SoB�u"!�ae"#�gV�$SYPRO Rubyo^n�ge~2Carlsbaibv!!s&1�LTyphoon ( GE Healthc��,, Chalfont S��G�), �Kingdom�D).2B�MO� by I��$67 , 000× !?rrb� �zct.�J.9989JX�CCD1).ug.|� a pixeJ#z�Ņ Å!)�a&��)��Ebin� �$���Uo>!&� 3�� i. M!frdefocur$�of�EWS− �μ΁P-4.��9U.�|���: ropp�'w��&�1BOXER roLS�+$EMAN softw��$package [3�~2�poo mIzi] .�b� u".����%���L��z/*�.:��:c a�h,!�[_5�:rB( 1 4072ti*��d2�VA]344V!3C�L665R"T (B44V U1B50RBUXW�256R!!� P ( a?317J$� IMAGIC-5F�� �!p]%�l5�K5-6ϣ}t�c��K� them3a K-s!� [4_�M��D;Ji U �� ( MSgMm�>�.��6A�.e�u��9��@ub �7n��ro5al ��"n�&a�w�0E�-�wceD ( MR�%#ѓe�oi�250F�E��dY�-2�f�aq�4V� \�A�� tIt�Y�����al:�&n��i�.he���$9/! ^�kvT��))e�����1�iv � �>a��a$� 8E*Eq�f9C aA�( �/;����W*�#6�G�U2"Tg6p%p���S�&o��>s45J��� s �k)$mosynechoc5s*���M@to:S�AVw�lv,e TAv�*a[.�EMM��uc%�!S!���-enؓ���/dT)i9 �%�dɄrmM�E�re6�AB~]t5�ZS4:�-s"4,��ly��~�For+�tou�%At:,̣>N*qe�I��Ic�l&lI��'Qby! at�=Y�im ij��ja�Uba|%, ]'�A~n.bj�Y�/C�tri-lay�`�)�!k��#:VsN��\2�3�i0F�of"u lyA��JR7 && )ai:1r(_�!�*cal�t�*�v2G�*�H� -).� projr� ��(�� a 10° an�rC�a tw�zE�A2gK� �u�o9��QR �.�z��( Euler-Anch�`� ���,�ace +�) a��e��-� ��^�6BI zth!=p)a;b��~e4�EUso���� s-csaZ v�]&�1 (R� ^�a�F�:-�1@1�&&>.ok�J�r� ����a��8 w�ї!�,AgR �%M:�� "�F�3�Z7�@!F��@�.�!L%�!A�wJ�%���,Uf�= uti�FvG6�s5r�s)ޕ),sA<�c� ��mGlY" S2��*-!U*uf��."�?!��*��s��mm'MV";*1b��&W2*�?d^_�.\M���. 6^�,�pμ%!��!��2v*�55Zpglyce�[at room2�% , imx��nap-frvB!2�8���2�thaV5n ice-*�!�7Z90  ���3�loaG@ ( 5%f�G-S [Serva Eb�Kp $Heidelberg�ID�"i5 M 6-q,ڰnoi� i"�10�Bis-TrM[pH 7�7_��.N�3c Nu��Novex 4�:20%OR( 1-m�mic�%, 8 cm; *�)�lF|�A�]at�V t\6�U�� Tric�, 1��t �)mM� �*�(02��(%,m-�athode1�)? ���( 1�UanS" !�ᝁ�Q��"@�!<����10 n�sAa2Slan� D!Υ))v�AB� �2×&� �1 ��54%%>2I�DTTe;30�!�B����[[%&!Vsl|[�zKd o7�to�w stack!/Í�"rLO. 5>�152e$ solvKx$m60JA>7% agar�\u6}m�wnSD] >��e�fN�Q��,���2�j z�!� $by Odyssey�rx s�s�%@( LI-COR , LincolwNebrask>���O7�m&ne��s !{��"�)� fluoQ�"� labe&}~tfI�x(( Ex 336/EmGx)�6vEx 490515ex)�4�3E��Ry, rw�g!JR� 5- ( ,2-iodoacetyly� ) eth2naphth ~ e-1-�on��A� , 5-k)I*urC�a�M"� Probc�0log # I14; Eu  ,f�. 2-{��-F!n�in�2yl} �(Methanethio �ate-4.; (1,N�Tore� Rese)�C�JS �F5-,0; North YornFOntari�Canada%xein�R.:m{(:����}, u��&Tris-F�� � a�des�N�y a� Sephadex a?colum!6`)�qlib/d�a�sd� �N�ptL#�� |`RC �i"��j� -��a9%� ��QUor)�m��+iz#�cR/qoi hZ�2 hR�ae��!ni�o at 4� . Un^A�Ar͸i�&�E�!%A�I&e�F8�a�Z< j�.t9!8e �&pu>y9"1CEn"l=)-"�=��U�J ix!��v vA�i-�-2�΁X6-�s])��� !�. 5��(� � pp'cuvet�J"(� 2�jA � 6���� 1 μ�!��7A).2NA�626�<At�p of 0a�ef6 � , 24 3�480 m >~��ul2_LmW5/�!���~!Erec,��!�a GoE��m.�Q�aM.�8-7/2005 SE; Pho�Techn� y In���#aI#Bi�gha�New Jer�z"]"�IX deca"�%�aJ7b��~M[ �:.KS-&Tka�. ( � l&l%���T� Matlab�0hƨhWork� Natic��M�<chuset� >m�For�� 77;�]S�F�%: , Bos!Z,�W Monte!o&�41 x�( vail�'uhrBKstA�rom MBE�S:��*�3�O)&par�4e�m�f�Ts .���i�8!.E��Ai'�:O taska8�$![I("B�&!�d�b&�]tJ�-to� alka�C��brѬ{v��P:�4�.!� us f�/he vast �t3�Bvent-�I0"T�( ERP ).�}*�'�j� ship�O:�fl%/%�Bv�8 �hڲ��h�na�ic �io:{he�&3it �e�k�%���ssJ\� �e��=T.�i&��!H �a<��o"�Wz7�\!9�~q� a U-�!Xu-U-uYV�6vI-�,�:e2�h�**r C�QY�:mO�b�R�* wors�7h@rr��i�W�^a�Bu)t�i��V�X�za�human�co � %% ECoG�a�?v-6 �-1�2=: e�A�raw.�eD,|� \uH4@los7We6-m/9, hit9.�D��n�GM ijKe�U67gweE2I��72�.i/g,e���-5[�V-e!md)�CD;r��:us 1t�;:K,"�-;#ntJHory )���*�XM�si-p4s;�i;!z �F&2� noî � ���ey"t�vatt�%or net�,theor���/�#!u�K1Se S��f�!�BrOn�s�'sg�u�/%Q2����1~Ce�=h ra�!f=.6. 'wY�>��Nes~�bF�)#f����i*neu>3d���6�e�%�rousal., dop�H c [2�J[��cho��rg4�?noradr`W5.6] Og� in*"Ja� s�%| .�a,B7��2i*?J�2D� e�v�5�1�J����rR=p5A9J�Z5d:d2�of �a�Np.��elW)ͽ(�G[7]–[1}E�F��A߁H�i)3R��K! ���� t�2�Qs�Qb  �t ,Eŕ��:�H&��gi�!P�L�&2��.�rhits v�l ��0&-se A��r�z �"E :�A�.y�Ts [�#/s"�� ( RT�4T�[-�k!suc�fu�&am2�(o ���0f:o�P]r ion/1 !peJ2� ongo!pN��4� !�I�DQ��(e�4f=�( fMR�b[11I�5i��(eto2�ph�m��ME�G!,���@al��́*ZZlo fi�+"j (LFk [18�\19 {�(�spi�U�/pri4s�;�2wGRr���t&#i7��ky!�r@�a�,�E0-E.  �~�g5 OeY �~a sh�HEt.�9�K7>����. &��/!�Y ��T���>�*au. V�v!�)�or6n � Jh� �#��[� 6R�:���}"�pZ "m A>�HG6j �W,In�@�A�!�S[*3P coup�b� �� �oHby�=er-2}cyp&r !igol!osc[�|ag^ ww + u��t�9�N:�� manif� �:� V BW -N�.a ��u��or�%��E�6ŞO:!�Z�*�Xexn�V" �Kr*Ua der�w)GI�) sourA�_�:��$�+ �*� �:# ONH �)�+��jJ ���ol�[���E ]Q%,a� [z=T� )��k*& gw�*+�U��"q ! M2�l� 8O� �_/%%�� f�V0&W �[PC)8ԳV1 "-� � : I haN1�*fu"lCl��ate; 0 5HAtr ��9synap� E�~t<mbran�(�W2� Epik9�neMdpropagIt�>� �?A�es�d�S:��,�vdomG2�al͟�_VQ�r�B�z_]��} etiw ec�aenviro#.�` s re��$y Alan TurAuʙ�Ife\`1]J�3�ginfall T�@l6s�s�=�)lliQ>( 194�/LeC-bLondon^hemJ$al Society��"+���U�E�"r>"�6ex�����:�Fa7*�Qa�h�H�>be�ϴi � [Hd"O nge;q�H6B!��G�!�! �er�?Vted!{�(jZ�o.r;!�Yfi ^~Ah�nd bene�Y� A�tex�B�]�&O �< , ga��ngI�"Eba��n��8Cma� �3,-a�0�"�E��Q�R�hadTfda�.?musiciay�� �6y(�o]!gmo`�^�c�>% �) [E/z�U"I�= )ϭwI� dk��f- 2��r0.�|eW&� B:in�y�[�jderS inva� �mon�i!�!-� su��� reat�2�P��*��� *X -.a . � 6� *]�*69�(EDtyABMesl2"on�Qin �n��@!5A�ro� A3��2�!  � [42]���as'N�Q 2=��a�)[Ό ��z..7. &�Q+de� ��)E"��hH eus� �d�� -�!2#2� :� ��AG�8�8T�CTDe�  Z$m� ��"� in45]I�irsJ[�}�!ԩ�2m("pto=!3.�F��rA�a) eachq�dwW�5rC%W%mz'ra�0}U(*n�#�x�ge,0� h"V(d��id���7�ɴ153�� f�Isub� �76.!Yed� J5A:���%77.'p�5v6'�.^�(e)��/�g!$ 0∼15�(jRt-U�wi~� �22!�N = yn��u�e�r�Wf �"� .� �6��S���Fi�2A%M� e��dE~A|)AR�B�24 Lapla�0.��C8KP�8I�:o3gmZ$>6B>8wey|a "��2_2d�]�v��!�m��umy 646 mI����La�vA#� aseQ.4 nd 2� {�lo)Z�"IgUt'B ,�'&aEIn q}|a3A2�.�� as mf 5�,5% . Str��.:SD�� Rs ipsi�C��'V2��.�V /"Bf�"`n��(�6�6��!c��?� "� ���6"�����E'B�#pIK�Km�Z�:!��'a+�POiaNj>Q��9 [.�� ex ��'Q *6H ,�_�>�Ref�%Po�%I&��E� B-�U@ ( �#6uŬ�>a:��N@l)�G�e�a.cf&j����l�g6;� �N��l�Pa�  #?� 55 .�-,�T+$*���i9e *j7` ���PCA [4# [44]�څ��32� &\DAh �pq��N�Kn�_( P]�����o!9eis.��eS� .�*a*% ` tc&isXde' �S!^^.mzr�ؕ�A qi3��!��la�x � �G"` 8$=�El3�A]W�mpu�H!b�B�!���.[*�� ig�ly e6 inP�t.Q��K�i�n��ByM�sJ82�kA�� uishE�� N�2BhC�����,����ेseI�su���#��jsol!]� �Qb�"o"] S0% M ., d X . S����7�sYcsAj�5{�,NƉ�$UA)!��-a��]recAw��Z5�jR���E�c�� to quares�6r� ��)mz&� hO PC�:���*J*0ҁ�� m.r.a�iq��:RxO!.6�� ��K6 6�%�� g}�I:S �:] � ��o� shadlmWa�� �3�<���s�6�a�2�F�*&.*� 6� 6%;���(m��"6 oPf� VdBG to 5G4%% 43� % B�'js$��E]&* 6�!h5��A"��&R!Ur(]g��fnxnu|%���N�J�%��d(��"'&~P�-��c"(�Q� ��na�-:(.;\IK���� C"fL�i�L'%k d�F�lHi$:,F� n}t�]�0G��(\=�N}�Łp�>qf�aH���sc��m���T R=!cQ*��U`AmU: H` a#7j03%����� ��bi�/Bit.&4858�/F9�r�mid"�!xL���9i3s&�Y������AI *�^�2�; P��00�Wilcoxon}k-�HŖ�� !Dh!�%�� �rԗRJ'R��u�A�݁y7 �\ p's�7S:�!�!z�g� `ՙQ�!�߁V Z�Co�]�� ��E�>�!U~�C��� �9�i�Hs�j22�hKj�x&���*� �g PC>n%�%b�!J9v�c�dG H��vF�5�r#sJ�2�. LasA�eBh(E�.��G *��$X- .I6e�2. A�V ,  !��+�m.oQ��f���5�.q|�yV$h t�L��a,a4.n,2"H�u� tren"��u[}�2�6)Xj�In h5�g;l�P!�$q"� bey6�5%�1O!_!<a��f1Sl(#>PC?�I&43�UtH.yk�Gikb8�( �� -�!ȕ�5]>G� sǫQ�@.�*�vure�&"M�2�K�: 2be�5 ;Our�*M ��Zq�a��*�oI�&\�).ش A%�)���V�} *�e>%�PZ W�V�!j]�%�.��Tlut����!)U� ,5Z1��ME� r&�3�)�"�|��c��n:to�� atsummaryK CR� �– D��>�Rf6.Di�Vces M>A�� in2!e�&a��=����7V�� B`�)�n �6E3�N��2MBM.�""�e�#-4 Q�:�-eOIZ��"�.3JBd$Bnj �G$ �GA��Ev���:U��1g'� u��!�1(1±� 0% (EF±�.d .Q2 b ., 332±6B nd 5� F��a��J% ;5C�)x�h,5a�{�  I+t z.��:N ( t"nm �regardac�he:5D�"4=RHe�,J�,y�6� �. �$� r��� .!*An�&�-E*Z�>�E1a�5�%��)|&�s�?��+2�2��Hpl�caq?A���-N+��!��+/�|�Gs T"�*�!���t��l?6� &X��,2���2�.�'��„�n���=�vRT )�E��Mh%M~U�a�}q[�0%�"�N�cnd��K!J�T"�e3�&: 4�;� g)� %Z�Q��K8�K �.��6I�#X� �.�tr�'he!(-�2-e�5:<E]*rA"M#er[�ore��v�]B��hc �%�r�RT�I텓��T)�:�U.�5en]�Q�N�Ucnded@�n����� ��j�r-Mh"� �*E��>g� stk)�E�_�22�w)����� �"i Y�%��ly�+ lappA�.`Sj�.EdPe;�I�pplf+�f*�� v�����H!�bI� :�4�±�M�� 1±6YLp9 . 9�-1+�r�?A��A�1Z�1ʑ��wA=eM-�a0mapronouncA��;R/� B[q65��]op"^ube!� W�:F UJ�W�$In"�O�N�)� robu�n�EA p�9ic��A �f���L<_�*G �n�5��e� results d�yemonstrate the existence of an inverted-U relationship between trial-to-trial brain activity and behavioral performance atp�Cprincipal-component level . An important remaining question regards � spat�localiz ��^�$vis-à-vis'Hclassical monotonic �-b �6<( e . g . , [10]<8] ) . To addres[is �, we pe% ed!c0electrode-by- , analysis on �\ontralateral data . Give Dabove results ( Fi�\4 ) , for hit-vs . -miss^$we focusedi ECoG=� t stimulu� set;KRT�?round�1Aal�ponse�0To identify a=vrNk:�nd� E�%U directly AJare z6(signal valuEz6� Q�hitE�%"E�F�U- or]R- ( i .E 0, quadratic )��2�amplitude�A�.�B�r�( as inM3EE�Largergin �han%-indicateA8�V�4��ac�!g%�( see�C�$Across 153y�Dfive subjects , 10.! showaN%� ific�3y�2P8, which was not23at%hpopul�D��(-��TP = 0 . 09 , binom��4statistics [30�$, with exaE� half��m hav�� high!�1)i-�!�:�wenty��Y�r.Nto.��:�5 . 8e-5Z��V�75%>�l�V.9�kjI�r hree.d��d both ^�L6Z=�U�. Thefz��sE�!�Y���Vfae�� ir overlareFam26A�o ass�g��I� ship�F8RT� each�� averag.<U��Xin a 340∼510 ms post-�Pwindow ,�n��medianqranW fromAA� Bai�u܉Table 1%�W�0n characteriz1�linear%�^N���R  �����0In total , 219)Džf vcorq\fRb ( RT�/βx+c�here x |7.�;f�1 . 9e��57y�beA�a!�it�K.�. �T-on2BRVVg2� �x2+���i^coeffici of%��(term ( α )!Hpo � in 20 out3212i9�� 2% ).�, suggW ng that�0very lowE_ ��)�u�s w!�$associatede.$ slower RT� &&��re8  speede�exhibit�M�j �� B�( NM� 8 ) N�B . O�Dla?����� �|9� braiZo s tend��o� m sepaG but adjacA%clusters � limi!��Hu�theA:% 6%MDetailed.fG an�mpl}!e �a‘���3%KF�7 . Its�}? variabil< $time cours iDed sustained reduc follo���^ Ht , despite a transeDch��a"���ERP"4 7A%We5bd !����$it is��]`195 ) into two groups via� � -s� m ŇAf( ��� $ly smaller r&N ."�UfA fast "G %�a� Is� � 40��0��1 7B�aZdiffer in2y�Rk�.aW 0most pronounc!?t 447�/b�("Q ��1e-7 ,!C-sIvF-test�0A scatter plo��!��B��ragainst!n��>���.ZCš% ca��AK crib�v�, a w%re�,�s1breA <imlSo far� hav!�"��^$Q� task�a A�: = J�-!�le*��:��s� ��)7q g�r] I6 clos�B!O o%{)+�Y mean ;bee;;*���. LasI� we sought� e�8In"hypothe�Ermb�inform�@ �ew��A9Because-[ roceI��I��wW g���)a t6��v! ly: i� ll.�� N��o� � D A�>; inar non-���;%)i02For%�)ai6a�a� %���of5E���!�*I�;.`1�T \4 .2 dX. ��lln%�� "wa� 4 &  . C~*V1 �0 e�Q/�t~ j�A.a� ��" 8� B2>'acer]�,uch diminish a2.%c%��99f)�B )Ai!h].� 8FT�(i�A6�$our earlie��o:4�iqca� %_�~:.�� velK�AWoaw ubse� �. F#yN�=�)Ba�.\=OZCyield!y2!.�Q>A�ndUd� ly ���=�D ,� � Remarkab r�j�stron�.�thn��b��uas didv�^] Iack�$ q-RT2�!� pres�asEty n befor�>� B,1:�l)Ied�A���� firma�exA�im�s q*4aI��1���]�2�i�.� In �  ,�29 q�$studies [7�9�a�!Y �si vid!KA e ���a� "� �o�Q�7 C "�a]�.( �e hum% �Ich)X mode �predi�� ZX( mAhz  shor� A�;asvV�te � :�degra� .� }�*�d lip�h WhilE�se�vious5�[ f&P!��"�alpha�mu oscil�!N sens[ cortice��A1�A y exI�^� $raw fluctu� & f�� pote�,�similar6� leM ERPs�nutsA_�.� ex . Spec�l��e�)6; h!�a#hA�motor�pu��-F ^�Z�z���a("�&�:7� ��i8��D8 A–�FR~�F�Jt�st�����eeJ�:m�DE�Inter*6� ipsi�z�w ��� �ZASZ��\17��5!�,% �QU�sln robu!und)Hsporadica�r575�h� Laplacmontag� s&Jsdns�/ cg2\inc���, al excita=manifes`s � nega�q a��u�h~�� �)I�h! =t.S���zZ�W,�� �[�vEV�!�e�~~ ,Rcom"d.�&A��"$�jV��.L!f�/fH ng8p�#�*no�E��%�}�r>&is� 2�Runna����condi�.:�s��!ffectgW ������ �v#enefic�r|ofFdur!�d%opm�or evolu�[35 [48]8 x�nK8young adulthood�>�)=.Ya: mD#w� �childLAv��Dͳsam�m� accu��/*}&A��s [49� 51��inkI`G serv���A�le!ary�Toflt��1z�E5 ,��Q'dynamicUas&��@�Zto quick�etti"r desiw$sta,-�8&�>�m."Ha+��M�=�alZg b�A�� dex! Z�nd a greM&$ repertoir��U�M�!�EdO�e���,2�*���17�IlZD a pa� u� p}�higX%b �O iv�-J6xInd-,*� �Y~appF to beI�i%� [(ent�E"$utism [27]�@schizophrenia [52A��(n"w oZE(J�AoQ�~; 3B &��# [28�g$�^h�S-}u."�:�|, ez(�Ian1&! �0�p����)9^ � ha*s!�enA�� Rp*neuro�'fi�+�pmov���ed� he macaqu� � �qex [29!�In�)��q�X��modalit�!�s e�c1��h� �pr/ -��se�l�(!�-��W^/i�hin��6�#E|��i�pre&�# ongo�f5�up�~�;�n�had���,p�saN al l ���L& �Z5e .�.DBaotezala�ter� ^I)�a/wAy.% metr�'(&y @!RTU *� (̀ +. ) �a�4 , 5 & N!2�"���A_*ty��"�in �:Qc:���_R�.;o���e�.� -ba� "�qf�  a-i�%�E�s&E �^I���� bZ(revea�"by� in� surg�.abŰ& W'a� #� c�ag� eEh� F� )3 well$heterogenetA� !�%�| 11M) "�/Qas �in%qUMoK(D�gr%6�amoun^��ly�mev,i*�2 mongn� . Our PCA�a��6� !�^lwHRTA�Bzs top PC&��A.H qT!�*Y W a re % fMRI3�Ni!&su"V' �� �.o ,E� 9"�+���involv�U!sm%visual �"n��� �*OaI���q��1��&!?pri+ (^)"�reg�+ a]Ey(y;�U�!G&j.E{ , hi� A���r� c� ison)&f ���N!a�topic*� . Nonethe,E�1���omato;/y�N�w�physioloi��{�[23 �� !�,al framework7UsQ)cP/r^��& .� �!�supero%�E5-likeFJ�[� -evok6 ��� s.J"� af�J�&�^�52� to� �"�C�2�i�� :)-induced2�&�'T� �� canA�be� [ �a�%�a�B�. Inst� 6p!�0readily embra�> tt<-or-netwA [53s5� liquid-s�(machine [56 %8]Aora��th -��aaAOe g&�=&� j�&V".t2M-�*p de s [� , [5� a�%E��"co!�Eo�e� ��I� �� will)��2EY: ��I.�U���AZ b��.T!7BV#%nd Ref� –E���? over�1*9�S�7Bf&"^&>  �2[&t2!?"$.-*�%:MA�9=�)k�^Z�F-bV$Notr?�'s��q b*ls X(“optimal-� pace*�%�#���3�exe��pr� �[60U"0�:�.�P1� explan�,s� | .{ ��9NU�AY.� �aE�%C ��2W�N �q2ata�f�? One*a�d��7 migh�6��d���sb  BayesS9K[6D�b!�Cpo�"Z:�]�J k,multidimensieI�I�eM � t�(s;E"� A} 2�I� tituf7�pri"f��4 ��UZ/!��S2�3bTo/ Xe O . Ac�� 2�U,e7&:�/���  wE5reI'AE� �R�a��.�i�m prob��8sum�Iuni� *��r�7���“Ma�wMI� b� )“�&�' )�t~�:,��.,�o-),� mutu@ ex�0�,2�l�<��e]�6�reson�( – a� &^���n ���H� fac��9!�det� a weak"� [62: 63��e4yJ�b� � �ly�5e� �^��6Sg%t�:i�� " E�.o[7�Si��low-f'+ encyY� phas!�dA es6er*p�3[31�3���me1��{�.�(a�+��Nb broadb�[ v7.2b,�1B et�i�utilizainput-ou# noMto�6j 2JR{1hory-��15�pr�/d [� Need� to sa�#AUc55! ]%�Z�we un~�M2#period�,it fut�+\sti�on?I��e2, elucidő ��9��o�0�M2�5]!�5]>!�)�6V"(MD��e�/-X%�"OJ"6y[64E�65]�*P�yA�ZII�p>�4�iz u�lyAK5�I�con��o�$.�= in�*� L.���657A� a�.�U�c�� whos� >�� embou.�* �� 6%E5�.[6� 6 >�!�=W!�&.;su< �A@�3Z� ���grp U�ir7J�B��6&, �EZ� �t �c�wD!J�"y.���, ieL� �pean.D�VDM�&a)rAy:�!���r.,9A sour � �.� yR���O1wov ��typ�/f PVHs$� ��.wD� ��ex��vlE.� . Al{�gavs72�"n�(,�fu�/&� ��j+� !�!5e du'2es� l-Pby Washington Univers�4.^ � ,Review Board�5su}tV!%5i�c�$e epilepsyz ti�Etu %:�28Aco`x 5�9eiz�2�]t�ic zon�6�8A0 a craniotomy�subdu*lac4of&< grid�?� p� r9� $1–2 weekE���inu� oE!�monitor��I�2n!�*��g�!��A�kq5:ol�u�4lin�wM i*��. E� on criB? re: ( �7O6sp !� erico $pike-and-wA�disch 4s; ( 2ap .�F| 5i� tiss�EbnB5 ;,_E�, tuber!bsclero2, cereb%�alsXg1j�. See"e@a��<graphi�?5J!�mGcol�!C.�. O ��in 0Pa�#A*3* re���cur�m,�5y pubm��p+paperPIOU> array�typA (ly 8×8 , 6or 2×!�M�(- 1×6&1.)IJsa�ofA�A�moE� 4-mm diamE. 3 mm��o)Na �er� AT�5^104� "�=�� AD-TECH MJ-al��ru�pCor�(%�, Rac�WI��e�� � r�.l�G���!#Daw5�EEG"&73#j arch. ( SynAmp2�, N� sX! , DC-coup�r"> ���EU����t�e�E?�t6 f�/. S ng & (was 1000 Hz�is2$F�=J6 path`qz(zlud`5���.i[�8i1 ��K��-�4;un�GV �� E��:g vR*( ITI�Ad �2m19*H 4 se�a4randomly drawn 'an ExM��2;) 1�+=%LQ,ruca�toENs aAa~L�&� 4!he cu�LTh� forc)�:@<�D�oI�gEa�0�block�/#ed 50&$lasA ab-$5 min.�al�!%�q���of leftEdr�x�g�Ain�>e�@��1�B ted 6∼8&A?�E. T� s usA�fic�r"�!aG.�!MuZ/ "�#gee� conf�Ato cEhemisp2;in z:�qe )6&�9 . Un�o�qw2>no�Ore+%C%��$;���540)number!{E�sEl%Bby �1\2�99�400�^��MRI1 �B t%fV� �Fime*Labora> es ei� fad�2�orO �jiT!�ho CaTP��5ensEztea�A�can_7�Z�&O a Si* $s 3-T Trio��ner atom�~ �e�tac�=d-�a sagit�T1-weA�4ed MP-RAGE seq�e ( TRwE22�B , TE�m4\B,, flip angle 7°� n �im�,m�1× mm3 vox!�A!�of)�Q�!co-�N�F� atl�!��n/< %ZQB>proBby69eg���of5-A"F=in 12  Q�� "{�h� lair��&I?��[70OE� rodeJ f� *f deC*[4GPl�C �comi|tom � C6&A+>�ope!�w&"�"� �fN� cearde�^+"N5+ .Rkt: CT1cm:�0�'s own��Q�MR = �t�;�E -5�I %� wTJ�M p�ԥ��h* ��La custom-written auty!ed9�| ree-.�rWH� p�~ surf!as gene\*�� �VG��m�1�L\MRIcro ( http://www . mc�% land � . scHR du/mricroe�",Bhe!�A@eK= �W�� Pt #h prec�#9<,I�6>b6�T�*IIa����diagram�u� ��   or?1t�Ic9T�  �"�S@neaQa2�N,"re-re��cm�� 9 �sJ�&("�x?5a���UA>J9�D" %H:�is deri\� !��y*?�9safasurr7\0�Nest n�bor� 1 cm a0!sM,C��ne?D&�!�;ofr�, s�/"� kA��(�5b)� rows�it�- � E��3vicin!� beI1� B�� �w&�O�=n"F�(%�I�.� -9!�UT.]�J)��2�48Aq6B�final���2 4D36!E]i�!Te �.&FE�I��.fi, 8jI5�Q� m�6a 3rd-)�a�hal Bu -1+ F off]>"�>�/fuF�D�' choi��� passJat� Hz�a�voif;�Ic� at 6�. High>C �Gc��Rre�/c �faN=i�6[ drif8N to r�MnAw�B�6X'!X�,�&Z)Ya�!ssiS,�an empir� � m� var@ -{ui3e%-upGn6�,} 0� �B�I2�Y��3�Y��haiJm��<ŵ"3 /� a:�� !n epochO$−500∼2Jma�No�%��$�K�7v�+��al�K unbi* .�Tf��&y0�i�0H"!�ZaI�!�/#��[Li� >`J�"�E! �tRM�2=!�at�2ry)�point"NM!�2�6(&VO!]9S]!U):� . DiH"yd��;�z� 1�!�6�tw"/N �N��!�&�!.` r!�ED"� \����a!� dard�6i�zA:d .??f.�:����y)b�_:~2o 27a *f6IF3Q�/' /V� 2�mLv�T9�nd��]��%N�"t�"�WY�$.}6�<��(A�i�J�!{i-A�=or�>_%�>_(�J'Be�l.GPS%�ApJ��=nes!k22U�E~�U�Git�*<(XofA�1�JE�]#� tJVO100-ms-l�/-���&@%�I:,%�I I �]���2�3^e+��qw �SarrBP�UE�6H�M�A�19j. �;a��e�or1*XR%�]3g lya��O��sub�S!4��4, �, �, �= ��ZSxUH s%(b�-�!<劍* �%sk jB�nBh�� −4�o:��� � �Z�co5matrix�Ey�r�U F.�oon)'u��he�6�mS!��)I��5IFeZn3v appla�_9F��pcacov"�6�MOb� Math�.�~InA~ �" ZQ�3Ŧ:� orig� ].� �D%t$%�p�R%��J� �3�o:"~$kT�*�%B� 6g�5�!fa�VIso�#%�> ��Q:YWRqu �*J *f 6v6l !�AZ��}�U�cal",�O�� 2�A&�Cly 37� �%��X8yb'Two"�9c�� �2�5]N�:R )U�6� 2Em��2��g:�N� anta�66S� � R��"m0��u� o��iEF�� ~\�ad�< , Hilbertf%n�>�6�1�%�a0P N}"�)�aha�F �;b�: UQ�^[��%��u� jRAl���Q�3mYea�be�(�%�H[Wilcoxiank-sum ť� N2� ���GV; �s�JirB[9Alm( G ��W /PC:�, i/8.�ex��1`a , … N�]u���� �)}ma��( mJ[M��!�� 7凕�r�2�dbsolute.�)�2.�s/PCs:Ta�di9� "1P8� >�>�. Nd2JU&yPn.��X5-�jm!��S2& *>:� � A"�4�ine t.4.�6;��6J0%C�D�'�P  a�+[�'0 F�%�/:��a�&�B11����RN %a�E!a>]!w�YbH.!ig�� �$}IHi�1AA2qY+im �T%/�%eV)#R�Wi@�laY vA,����5�! :�Be�S� %U�)|a depV� of%R%�r  &" :w#.ql%Wmon�?2��?��e4N�oh>C]�!FjQ!��.�. A�:�kr�Z��`mA'=*�6ƍ"H8Dm�.�Ito2� means�%�!D/Y2>8 J��ie!H,M^.�RT%zn�e��i2�% U�� 2=2|h�E� ( .9�Ln�>N��34��h� B&�6�"�P�f�nd].!"�f 6�m� r+�iA���6�( hZ �oequJ��uj����f*regsta" u�a� c a��`�NY��&C2�,4^.�gα�� >v� ��IfR�@�TS6�F[F�2���6a!6�*��S�a.5�� Pre�on��mal �_ 6\7�%�3�R B , 0m7 �E.�KK/�/�rto�troofalPUo�5e�due'���8hAc"�@s.  ."""8)e�E&�4:)re�'ͫ�3$5AK�n. �t2cHPin���cc&G:e�G�o�"M��� nSt%tru�ig�m�reedom9a #5-Y'��_�q� [7�6[7�7e��of�i :q�6�%!3.�&��30ph4!2663$ �[�1�3l_&\7��')Kath 25012��up�,�)�/@&�.iN�K/ ��c)45, ( Bonferroni.�:7P-��e!"705%~Z6rre)��1f� Mh�<P<>5[E��!^Rw.�Per4}a shol�b�W��E�"�9Sy 05 (2�$) .8�SexPEr>�,# key&R�Pno�(of eukaryot+ In m�!�;'LT�)�9lvF$Nv �њ�bt��dng{1nm)���uJ! go c Hnd nuclj fu�'D?�&� e2�"� meio�/.��q��:Da)gi!gW)J �E �typ��MA\%loc In�idiomyce!I�� �xl��eVh�e�t{N tetrapo�P�s� gene�7 ly u�9;vtm+�homeodom&'$ crip��fa�\JaHD<u��*om$*!Crecep��8P/R9B�All�FAb�!m�W��5�-?d"%�A�!}le��� Tri� po�P��5) �z.��l�$��yA�I�|!|f�%`'HD!HE�>V-�e4," �organ@{r-!�2sA�!�YCJ7� -zB�I��%Kt�!1R�~�$r!'ex!Xp}�1?~Y&��֍�-�>lAr����l��|F�nd^��O�X�&=�|ES�Fn{ v�tow�|)�!�,+=2�p:^R� ,.�@al�I.�I�U�&�Ja��i-a}�a�ea�,�%ghM�����D%�i�wJk!�|y n�WS+BS��E�no�aE3supA��yof�+YwS!mMZe%A��$"7rh�x�K�|]L!�gtY�"M= 8P(e5�N"Z$c Bli6"I�s&0q. ��)+-%��SvalA�N��icm�s�C�$�q�Hra!"!�-Oc`Ofea@?�osyngamy/& %���2aa7� f J�3%���flexi��[�6b-e����(� �u�3A��Ym\.bl�UeՑ"rsuccess,;�{de��aoͶ�� � cyclF .�a�) ��y�1or�DA�!wI2�)I �DLJ�� e9%�nBT�Hh>er�dz9)~�#)6A�z+�an�H�> algau�fu [Q4–6!xZ& -#B | ��51-�)a�ofJ-�@( u*�����== inct���3��inheritu �d�<�}%�s�Za�uta�e�e� �,�!�1��!!M NtQ�vA��:�F� +�s�&! W%�a6���E��how�n�u.jo�K\F�E@�J*dde6E. SE��I]a����%b"S%�X i!F�J�#�@� 6e�O�6L��"� 0� z��,�� som@1A�v!N%��] � (ntly [8–11TiESex6 ��D1�]@tud�QW�^of!�[/�� m1�1A�M�QIe�Y I-IgeJ>I�aG/",�} )( �) i [1a�1 \�Aasc"� ���Mucorotina]� �*oF����� harbI>%t, zlm/[13!z`Z.��6wa�: />�>� ( b:��Ӛ rolV.*6�6 hapl3,sd[16��G4L�ugT2�s t65ly�k&3 !fA�bA eO!�.Z �=�>1EY!H (- )})-�s�� �v��./Q)�2tei�E�� 1z 8I�1Ne v";z')��Iu� � � �!2m[14H2 !^2�"� EVq-y��N=6�-,����� )�lN; "�in5T���*�[M�S?1iFB�n�M�i` A7"�in Mai� ezia�AT$Ustilago h: �t subphylumb�y�/� � M04botryumT�H@Puc�1�m>a�l�Y� �hBi�3!9I}�MX.iAgari���)�!, 20–24] �<�0In6�,�* 6� >V 6�AH �genus�J�Gshk �[kn�6%�3,r7 ( F� )9�(theq�2Yfp Au� �:�8s5cscom^P8> . It&�K"�j"�3~M�VWń2 �lF�a�.�G favo��!LaeU�,"K���d)�suV�woJH,6� � C1h؁b enda� � a� �/l� oP ��p��-6lB� ��"�� 1"f EKb�! icul/]%a=��%ceFnR�]�D� colon%�c0` di���OV eiot p>]ey��d [MU�� e?5  '�%al&( � M��Lx+2�a�!�!��qexpan��!�..e/E��S`b�0)@*�-*�!, m|iG]Trese�-]r�:GE3�Wca.W MAT-*�*} [1�.2!R [Sn1f hall�t!6J ! )�Y �usMLw ���"� !�.�� �reg�P�4V~�&�[30 , �Jmr2� .o"p��U{=AT� imh6q�:j  inb��3!�� �recruiJ �N7� }5Kf"�R�.Q��;7��b\��vE�atQ�[�Q�Sy�v�"Q�`-� �,in6>neo<g!�memHAmioun/P!�`G ,�ic6Nі[�FZm�>�x�ly "� m�� LV%��E>�i��I�"q��Z�&�RF���wRlus amyloKwoni� h�bnev , mang�� 2� wing�si�a�2flo�la Z�d�[30 3i �)C ..�Y�"� o���t6�>�*��esQt%'20>s6a �$Pb=m�*100 kb�A��uI��*�a!αGH" majo� �Na*�!Y�%� K�m"�e+bv!�HD~ 2��V�!*e�qA�:P"�α{���VVhH1-i !a SXI1αaQnd�aR32:32�Ex6�[a M��s�^hotspo$:u:�!" displQK�?ed0�O6`[�c3�3 AJd^mC"2 Z�!1�qm�� :� (Ld"�Bs�[444 �;L���Uw�alTs�����Cut�.t*� ole�Eow,F,in IBC0246 (�merly2�3�A � be��N� zr  "yZ-L��w&] 5cIB.FX1Vy ���� �environm�Ay9kiso��� �3etyah�ty �!soi�[ deca�U 5���"w�o�ny2�sa�Ze��T��O%���*� !~ a��Kh�zsGG�"&� .��o0–4�DJ� G2�<�q" �AC.5,Fz!ran0A��C�- Q2��]$ye^en_�'�Gn%�6� [2H4�Rg7Bt/0�C&ec� _(ir biotechn3Malr�En,=�� oil-sm� ng �f.Aq #)>^dairyM4I+! ]8�)etabo�:�s tin-a�E���ዅ��g� ubQ�[44+�B �dB�2i�W�a�in�Ciz�\d� �bf*�,2�m�a��M_ �-s%z c�[!�1� �B���� aP5�3\e+�[2��4E��q>2X>�qS�)�pto,* } 2P.[ !m�e�x:j ��si��sTAO� kF|a&�>_�aa�]~A�B[4JH"�! idraft�!�9mہ>�iNi~}8K&�scaffold�Fur��7 ��A�2���A >�!VS iteU;p�A��Z+��inguish�� �E�# u "�#�;p!$u ewitij'L�� �it�]e�*� -��!��7!�.� �ńmJ�;Ah}M .*�'� �"8�v>GiE*��blő:a,�Oh%n@E ~!ŝB\5Rm�e���Z�#m�a  -6�6alf�N9 ATCC20508��Vanrija�-ic; CBS428H��!9�-I�2�inj��24.a�':b~"4u�IP(j$%��l"�E�q & �/$A,:�ll�!��� eachU�W�Y!�!�hee<�T"h(�{|SXIW9eal�x B1a�B �h� *���l�o%oV$. ^5��2� i [3�P���0lf'6|:r^�$.�m�� &�i6�$!\v�$:�los%�!�-��P1C� U"�-z�$�Z6�����gs"Ce[^ Q� vergd " l�l�Ij�is3K*O}�cer! circum�D!�&C ���JF F :8.�(i6�\s �:0@$ch!�j*a��MN�[�A�=:|m$B�� a�#.$ge*� |a �g�$uni*y*�$%X4X�9��6)2�$� 201"1�_��eM e)�&�Z��B�q&m�eKera Api� um ,R�, Tak_mi6� M��.�Tb�W� B8e[29� ���a�24j�F&2>-ٕ�I���e=�"m�}:�,"5 !�K�F[-7���ig��=�� sa�A?&'�O7( STE3Eb?&��Pursor ;)$"~� . f]!�~55�I Ōi��|Iȁ^�.��A� oi�J~O����� ��Un�"pHB�sy-bran$qg�us6_���..��A�B&� A'5��Q\5�c��!-�V���Q*��0` )9yͯ!�a JI�!r%'0&�(u ,�p� �ach� k��a�6!p�"+PM�| �1P, S1 T=�7� SXI/(�A�1 ��29 BRa ��ML�!~ �=! *� �� *%pgel- �=�&7SMA*�i�%k��.7a� MATa � b�Y5eO]ZU �� �� ncl*%�,AX-'l5P�d�g9%�iUB�we na� q �-�7 k9@ A %ar*a^)2)�.V e� �fF�* �'� u1�6����j�A�y>S%d� 20%���m!�� !Oic!g&�sj+">J��!�S t�6I�!>N[�t25Mna l4s�4)( ̈́\��tbs��l ���!�%0�^&:n:�)m�BD clad�&&*` begi�;i)�~"' z%++]��%�7eFr�<verA���2T�A�A� ;bP �#vO�4�!����j,A�*g5hu,��,�V .#�2.�P >d�<O^.�F_2&��ly"e d �$ ( JCM1457�c�LA)e! -�Ex.�f�2e_Kl��"�B� =!�m&.e�!#��by RAPARapid A�>",(of Polymorp�eDN�`a��d� " +iop{|rns"�I k�E�&6 �6�1( =�57atAEA!�(�tay�s��Q-e.�(by PCRE�w; �*geO*!�"T%%O=�?m!!��.;5A���_ 3yp�<t/rz�f�as �1DeS����e� �A!�me� n2 �>Ill�sa/!��� 2�dmbe�G21*A� 5089�D�eN� At 2�;63 Mb Ly |�hi"ԑ�w %�=�-� M5 ME�!�A k-m��A�-�!��-iir��;pjs��xCfa =- 2_A:nA�)� U�:� !+��~5* /�e 02��!��wg�A)�q�,��B� -��!P)=�dDan�Y �2��(A&� � q �R b�erkf �]t� *<2|A2Q���!<w�O�A�of�B}-m�Z�!sNY�>*%gUGe!'�@�5=� �>L���B�5RQ�(_)QZ;.���e5>Ɇ6�aq)WA mB�� � ��=z�"ghI+Y �wi]*! xE_filamen boz% Ly�D �mSTEA1m� TE20�,�i�6m��7SM�.�2h�������t�%�&��v Mu<7�NI� B$,�o �^��j��F�MAK*� ��-ndR12AC �>.Bmn� =`�-�!�tuT?� �1)y hN"� �<C .2��s*"�j�g9Q�)3�Y3�5m�O ��t9%!"9�.^3�&�"sisV��e=�(Xtf�AzŜd�t 4!inF�a��aY�( ��@��N.VA���a�;�^�k�\���li3:]�i�!a �B�be�� 3��[F��!4t1��4FN��(:�r� !� thirD� �kn�Q �T��,5V8�)�{�Q$8Q$R9�@� g���!`�Y,FI(a�QmwP 87�hE�r5t!4 M�,�-vit  e2� ei]�jh�1 ( S4e���Ce(A�� *]"ө�N�M�B�=.�UY ,c$d��!��k to 7_ ( S5 �U3i���r&PMաpan%�� �wC�A��m�%�a}of� �.�%�ik�*($�j�c6�6 =J��o�:�wE`�BocE8 Inxm�Qux]0atyu~A�o� YB��,)�1Vc*�2+E�� ��E-3N�� "�!rg�j "o �l� �qxFa.  arryQqdA��Mα+m )F!�a]��V�deR�C y]��e���#I�;�1�2-of�I�]"�1�h #g ]�&XK �v�2.'!K2��(h����4l����ed A1*�@6� ,��XE*�.�veenhuis�,�2>� \!on��A2* R�DA�a�6�%�%,QS�� *egr�/uGU��.:E ���nd� �.�N�mucoi<@,� /hybrid���+^L ( S6�,(A�5�(TY�A�1} seem��` aA�jM�kdm�nR6!D!I*�R6.,k:zT ing-A�.���a�BSXI1/5�A�a�}co-��R M�)z�2�6B�� ��>�aV�C8�e����A%86)N6of�g�e�^�F�S*�C�o%*� ��*��s*1Bq%:ga&a�%���7�sr�b�6)iLwrus.�G*b/w!�e?�� ��EA�r e?\��g� ?"2����+�i���LH) libr��p�f� `S7.!�M�,ial�bd Method�-. B�gE��� i[AgBQL.� 恟� 5���ng back�ET�(ly 179 millyd| ; ( MYj��2ies� �yw� R�5ia2�^147Z(1 � �@� Na��p�ae�f�Mƞp� =� %#�q�!!MR�a@wNQ3E"B6�!2f"VB�m s anQ�4%P�É� �"��it �be��A�"�H��x^-ZX$�I�)�rF�2�C�UF3A5[57!E�BN�t"��$�T:<�nU��~Z���E0�U%%�21�� st[��%�nB�*{!� �;MXE�is*,� m1A�U�  .�9FvFAe� �c*^E6�F)0i [�-1�82;37$[36���{2��6e3H��qJ�rf*�!o�F.E��u��-D&�V�va(�)�r��)� some!]sk;� �� beyo�Ll��w}9e]2J4��iqxB�J� �&{0�1f�5pose elemŃ*'(�9l�4z W�F1G��ic*�[��� A���$�I�R*� ���� �f*!s x*;Stpb08k*�N)j�-9u*r���,rem�==Mv����G-_O �E � !�"T6u� rome��Qr� Ps �!6�,F2�. :�%X�y&�Wreҁ=�u(��&���3&&*us gatti0Uu[ #%��5"I*�(�~A �� of 2_� &c *%A�^"kQ��z=wA�%2�1:� B��s����@epetc_9�%��!��B )�5�*,.�>�V*��,=� �"38�@�Y) DV6���Is-�e�raQ!O*b �-�[m�!i���2�睩mX� �IB�.3rS�%OhP?BK t� E � f^d� �.� �"Ss�6��t1��5: �ofF�EM��.�` Uuf ��Ȉ�A6��0�ˏ6TA.����se3"�t��H:-fic���3PRaF!8A*as��IsA���cl����!�6�1���"�#��*��ae��!-�D�Oi�rn e]X&)�L3�t! =L �ak��&�!sW��e� [3�A���B�+ly� �Xly!'w�=9�>" �v�3 '�o�"sy\Bxa�.� Mz�$�1�xI�a!�#��V�hy&&�I F�tiP�ep6S�ZNbv!~� 6&���Q.ed9 !m��cB�%� �, IKS� �!' MYO2%o��"rɎ@,,���#wo6�"��+ZUJL 5*�l FJ�1 ("�)6�Th���("1��� /��R�Q�ɉU�1}"a�zI� mV! o��`&jeo"�� �i�F!�Mͮ� ��Qofv��J�Eo�n by BLASTN��F*e��-�o&� 2�V � BM�E�� DcQ�콈fA5%��V��)R&$������T"%U� � ���i<�:)ncp�:)v4�d 4i��HF���I�>lIh�����o :�q����q1��X�6�yp�Wa�� !O�=�2�����E�jsynonym��*9( dS )]U<e�-S A�..� *f�#sZl"v%S8�� I!�Ur �@�apTv;��-�~!).Bc1PZ����!E�3Z�]�M��% etch�b{ dS ve|s0�!��|tly� .�6lweV,G�id��m2�N�J�F��ilrup��by�=�e�Q3tU#F���:��:�n n�.al6�&��"��:k<�"~Y��Fk@r�ras*�5��8��ci�A�!�&1 "2N�� a�r,�p1 �� wA�����C�U , 1��,38 �� ��� slgSAe��E+����M�:�t .2: �a��?J� b�#(V�ex�{._� 6�,�m&�ee�)F0 ŋ��6;A��r�KbI�p�����r2�K aFFQD��\�)�0�2��)YEۅG9��>mut� 5�!x.�!&�)"w��a�V�1`F\.+9J"1�j�iH/X!1��v�o E�p , ��Oe�D�A�ml�@vL� � !B4:a>4m(De(("�@.S�Ibta�A6)yE�A�7pm�s may�bA�md!�inhS�e��ymux��sD�|8%��;��or dou{4$� r�<�a}!�he so-!�V uspen -g�T�\_.�-middl� a�2 �w�H���O!�u� breakpWٝ� � &&L�>M �sl_$�n�f�d� {a�B A�"�� S9"��)&s��-S.�- F?�7ԓ1�.�qdF�c���6 "X �5;l:� �� :?��"z"�=a"��6si/ � n�A^a���2i � *;#(%��8Fj ���Wu*)6� a{�h�- J �� 9cS !�F�aurpriZ lB�-�6�*To E��(���!}"�}S�`"�!�I�& !5lW! :�S&: N�. Ae221�e��X!m!ey%�$"�c,�� teny! �9s+>�Pc"$ *�����S10ml,!�e*3Y��)5s5�63�ՙ�|V\!K1BA�� 1Kb��B[5m>�& dourR� 4kגh5s��3 �3&$E�R�e@l�~cleotid"�,noC� do(�=*z 50%� -�%��;ge.4��E$9�g����Iw%�FJ,e'� �app0-3eʁ�II3.��ic:�5]�3%)�5�._AJ��p=�y�1k�abe�xb{�3R�I�&�`m"6–7��A�� � [�dj6)���y&xF>uZ.�+)p |z�%"+�o�J�codon us!�w&�&6�A�jP(+"q&�Vamimmc�E�� �ncoe(by�EZN �A`���ndeGC�%�Ube��� *�--�&T Io_%A��EZ*�  pt% ] (uyG -equ*�b)]I� �Cs!J��a�]�pro�e��>�Qa/9Ń�`A�7}SaT� Q�!� a��� %Xa���usefu��� �| "= �d Pi� u�!Q# "B. }Sm��%��H��h)%.�$ �} �Y!�!�A�r� m�Q ^b'Y��Xśb- �MZ�'�fPh2�B.��FP* ?�(l�w:b&( *�e,6L), Spo�#r �,�eo�7bu#s� %��!� Y(�.!swo�&�_ T Bf.)Lvio��umQo��an�GiJa!�[F� %�sA�#l�:U A2.�&KZ0�ei=A�z�/2�i�w�$a0���p�M*�8l�6�%E:�_co-� a��\e"@�� m�� ز6_Sw%�� � &�z%�����ae*3 a��o�:mimicrE,b]�fl Eswcl6x2r� 55350�'7%]�[a�"Sad��!�gr����2E>!"� ��don ��eYu�,2Y moleԋ�$�`rmaiek�#[�1��reD6p ,��?mc*YK&L#J6/A�&e �J�=6 8!E6& a9��I!Em>�G�:iA�; 8�rA#s^�GB\p.�!�$�nn0�=�$�F E� ���<ish��]�.�)�3�rRt�;i,.>-5K"s���7doCDX*�c, r!v�3dg�ag��deTbe74d%��wbyu���"BfR/.2Y a�i�@���j�� �vlfA�ang �A� �i-~o*�  �n%1e}uaI��g75�K.z? or��P�de or%i[uE� 1J�faAG.���%ZN�,_ "�I�4a� 1�iv�"�� E2�@"(��7ZP6T�� �A, a�ve� ��N B6�no�*oh���ZoT-mak!�iz��3)cN>/'IQ��m!��]ac� A B��* �T#"z�.�(�A;(V0a.Z���4R g�L��STT�;a^&Q!Yi�,8Lvh�.�,[om�uta��=I��� rs"ly%o��!�*�Z2�1�[77a�F6� &((�f.P&Bh�2-Zhel��cla�Kis"� iD IZ�2!"*YAhA��;� � %�enc"3!�� � PBop��L!$*��&>&J.d"�m h"�!�^ gU�����- � imbalA2d!�g��' 7b rl�jH*��@&H.��sa�tM"�-0HDU T1%R�r2�i�� c��2oyg�� {� � �!!�IqNa:�:�ţ�� 1�<{Z�p E{�*}v5�}>�9�}"�"�aL�1"�j�%A�!�y3&6��5� �:�wRHa>[ _ &\BHq��stC��zs)�� ��4�P�*Y� ��u=�E93^y�XV>�-�=��tZtZ%��~A�a���K>�� �Z��.��7!�Z��#UMparsiϵ1'as��iU�lti�*K< �K�v4��%M��Zze/] �!l�{(l F�mh .�=!5�%�� [�g+z.�`g�/A� � ;u�m.B�is�2�6 G._- �kLk24-�E�&Sw@tŀA)6B�lso� "s�.EM3^�STE3a/"4W{>�f ���~ii/��P �Z<5 b 4A model is pro�posed in Fig 5 to explain the current situation*��Tremellomycetes , where recruitment of several mating-associated genes into the P/R loci of a tetrapolar ancestor occurred first as these genes can also be found within the P/R loci of extant Tre�Tales with unlinked MAT �@[33–35] . After�split�=F!s�0commensals or5���buAiis!1a� also�� ��,�c �c 1~n�-�I�eA��}g��A�M�( � ��B>. )Ax2�1t geBqAӁHt.� d bipo� �ga�knterm K !6 phyl��e�� tree��$So far , sA/F�b� i= ifiNB�A� eref!�,q1�i�pa1ev!��X last�� a� F �e (parsimonioue a�c , despiteu� unus�s�Ife��s discusa?below� adD1�: � mc��� e$�-2-�7Ang"p HD1 clas�L1��m�HD2!�a/ �Agaric �Aq{�~�� thanMQ1�1N��>�a�known [1�Th���5s {�h���@��cd le � each �, irre�{ of�th�� systemAǝ�or��[16v 9 An excep�2"f W�mia��:yexist �Br�X until now%�ly%D�hE��4a SXI1 homolog�)H��is!nu!�1�a� � type.�)Ent�� SXICe!� , 79�It̓baatRin9!n9 doea� t re�A�1� . Fu�f,E�#lb  � 9sIecess�A�su5l �J� �%�8in C . neoforma� %= �1/Q� pair!w�Ht a�-_[8�81�y� �(in U . mayd�g(nd Coprinop��cinereYLx[8: 8: �displays�6-���33 , 34]Q�5lsoI�eN�u�)� �� �M,�G Leuc�0idium scottiii�yh ��!uPuccinNotina [1eB�*&2� IH��M"Ua�ljb)Ufur�f�ri)��6be neea to d!�z�=l����mo�#odu���^� sex-{��%")qqj��s!���6� is u�ly supb �) s�����fungi�1BU"'!WŧFxus it�` ut spread��]�-�2 � -carrź�kͳC�o-aed6�taawstepwi�*� 5 ��,.=�i�]ex-yE�mammal�>d plam. Exampa?Ad�V�= spermaE�*65J�[a�1� 29a�2�0–94 I2��[�re� !�how#�*��>�Z �" �tfvti��=� � , fo1 T� �qb5�expan!w%O!Q�of5�.� beyoAB� R ��c neut� re2�%J�Ine tras��Dof V . humicola di�� indi��}P6�դ �i�l�l �O/SXI2Ephe�[n�j���m��a ���� �or�=�m[�ijHD/STE3����\#%F�*- largYco� g a���N�ofBt"&o� in�~avN. R��o6� �u� �r� S subs�ial> (՗@� s )�&E �s s�bAg e va��(�� E��2G�i"Cutaneot*V"%�"�syntenyN�M:�aAdi�ly�j B���2w��a�u�N �4#!�����- -� -&9pk!&��inguis�a��.C&B��li6}�Th��E��w�perX !� �H#����in� �%sof both �� � � hJngeB %�2� ��a�J�P�j^tr"�%��enO by&� �"�z!�Galm� �E 0Eo�pn&���u��evaluat7e�y!A�a@s E�&� �Vsurroun�)yxEdtanik [9A10�%>�"c>Z&a�(#`GCA�E�a� %4B/ a nu�&�^ O'atB>�&biņtowardsh[10�104wN!iM� eQ"�%!�%H5�i6�-�AM�N�.$��� ٱ!�woA���,f�� no e"� �+GC-�y>2 [105�A�9��%�F%a�+  a*J�inFV4's�  �' tempv�#��&��$BS5m�\d%onn"�)�� inco� %#Kof:� and/H$( yet un�#)�,Uh d�_!"���J,%.0.� BA!�I5Hr.]bT �x>S`*d:�[10��r�! b�*FuA>^L��e�demon���in� &�t!�aT%%�!�`+�& �reffec� ^� ��� Sacchar�s cere�(ae��� ߡ� describeda!� kilo� E 4butaa -Y �N6Di� [107–10��A,* ":�/� "`s+$���  ( "uni�.�"�� .0 J���!4aa�-LFf1 {�1)�n&勅s� Z�!!�jhuman.%*s)�0Candida albicA;[1G11�IS�.to2�{f.8'�MATα�*�b-�*I/�el.#S-iz� �5in�,)�ta ex�g11A13CD6D��%=5�+�8" endorepl��� /�/?�x!lE3�m!IJ|ew� i&'A�b� R��UI�pr�$de! �)AV�5� "�$�B��cB�H�lbc*�(,�& n�-b��Y��:� [115!�S2&n"�,cycle��>�JZ A6�|��W�� ��N�I.�%9x�" impor7 open& � r�(saix� stigI�in fu+�$�. Iommd, w�ve--Ta.3�eJy3��H�*".G.1!�&O�-2+aA�)/!�Ia���J�#5,�h "��/A���Z "+��/,W2a�it&�% A�}�&i)� %�e����;N/� b�&�5.=��p e��� i�����+a()� 1 u� )�!�%�.� i*�to6�Q,��3ch&t! � �L2e�.��"�il�B�a�I |� w� < highlyA �'b . W84i��� 6�.. 4sm"�p:�.�*�)��0E��AJ"�"� ��.**�see� I*an".\16J,1BIi� appa1:�f#M"q}&@���%���-�(  t�neighbo�&�x�! derwa��) �4r2)&4A ��$6�B�0A�teg))��,Gbably dua re��#t"�$��-JW4�feM��M UZe�� "?�}Ղ�s (�3α�~�m�A1 nd ) �51 )I{aeer fitnP#a!��5��2|.�! .�A1*�A2*5QR��BtE(ese�!��ss��* � e) ���1} $lik�. A rd-iN%F`�/�%s.0s!N!LA2��-�"!:Mu�t1 le (� odd�)*���� Io&Z ��-v�&� M4#ti]y!�.�a�1 )���% � '��66E�>"�)b,accoun� �lp2ed"��Bf,�2 Ui($r2�by)aP  �b� )�e*M隤���]�7&(!rP-)�)�ct-��BOoip.{0-�3!,5}j)-�2>�  ��Min.8 .� �h�r��2<#,=�Oao7� I���'m1e\��*nl"��!"� U- addr dCB7�� / indu�to'R$ � laborator��!T�;y' �� 8 �iso�<-� d . (oleaginosum2u!�i� ����323] give� T�*2 . S�3� gr�" on YPD meo&at 25°Csolid�  liquid �?�9E;sha� (( 250 rpm )� prepa&�nucle^;cidA� CHEF plug%�!�>�-�9r�(p�!&/IArophoreo\ %F6ja~z����.!"� �l�Amod� �6�'��f��y �%Crun u�06set��=a�; APgetA�yAres�A��Z+"rG 4A�Dto�A2�$30 minu�Re�r ramp>b)%sm��.Ibotto�+1 M60 se=>1@^N.� ,�4=T� col�B�C2�6�M�z"sc�� y-xed RAPD-Kpd(lr 5’-CGTGCAAGGGAGCACC-3’)�48A�; neal%eemperu7!E1)E)�e6�q<�;�8c�zenotyp.rof���} 8 CBS571 (u\)I�%u��!�>� � ,��j$� MYO2%/s-PCR �oligoeGoti�Au�S3 �..fragm.+E�$0s�7d direcFor clo!��FpD�B ( Qiagep Hild G�'nyQ`K.kZ].sa�m�extrac� i"q�9 CTAB�HEFq�l�#�ed [35�515>� o en��sBO*�w��a�3precipiti��!��$��Apic�Bout��!�u�instea�spun d�@)�(.�cheJby��Mir UEBQ��A�manufac�a r’�2-)<( BioRad , Hercu� , CA , US�/. S)�H� $ATCC20508 �9CBS428Ea�.�25� G6Ge)�Techn�6�?Cd% Faci&� e Duke Ce <�:FCompu)~al�log�3I��!cert libr ( 1�20 kbM|PacBio �l�u . 0!omistrA�!k�)����� ng 151 nt� -end Illu=4�&d�(1(@ etQ�.( .2�xe{assemb �A'HGAP4y pipe���*�% Falc�% @r7]�!L,SMRT Link v5% . 1 softwby���!ns$�# ��:�>�)1 �trimmed �Tod0c ( v0 . 36 )�8]����*!{MGQ move adap��!��hs: ILLUMINACLIP:TruSeq3-PE-!�fa:2:30:10:1:TRUE LEADING:3 TRAIL SLILWINDOW:4:15 MINLEN:4��!��1qd �SPA�i ( v3![1 �9��itC=Himpro(,)� pilo>;20]6�5��-�Gpp�E!9 �y EBowtie2�!)n2�k-m1��3��Պr [1�:�24 ��[1� 1� ^">i-�newH--d�(H �Ka��w ��e��I� anno�1��avail� v)GenBank)qpredi�nab�>o-7MAKER153%�8%�24M�<pr�3a>�put�>.� � �T���1 M �!4A&�@Q��>"�Wd�.�� i�om�MUMpackagp �^23I�� �plo"�IrawH  CircoE6�3-�Q�of2�:�� as�� bi! iA�M�)Y)v�?Kng=�U�. F= e dS �,ze-2, 57F) two-^�iQbMUSCLEa䡧8����2��aJ �V alig�� % D q6A� �I onym7*_$!�\.$dard errorm��m�w� !* yn00! gram!� PAML.�4 . 9)��"&dCy/pos��el�J��^FTQ��& .�R� Mask$mit AFG H�*y R , G�  P�� /Open-��A2013R201� http://ww�D �m d. org )Yc!RepAsUpdn-� [130W7aA�e novo-�G bJɕ�-��! !�r%�by� eatMbX1.&��D � 08‚�/-v o/� .�[�\LASr"�0c)ri=&0!: MAT-wai�scaffold�109):�%�Easyfig!d1]�jaV(imum length!m500 bp�bŨ N hid���. Os.24F�s4-�^�e���wWK�ly 21�2���!E�(��thqHx(2��& emii�!e ,6ovoKaPN~2muc !�/n�be hybr�N\[2�652�"A"�$2�#���&pI�L,Il&=*�OZ.'��I)�F�FotaGR�-pl�?wo &&� outgq� �U truc�2��'ships ��s1�m�Ra���a}7 ofm�M+Ecluste��1*�0A�6�best-hitDBH)'COGtria�Sa* � OrthoMCL�+a�4a�lg�Ghms i�mew2�4GET_HOMOLOGUES&\ �[132]A93�E�4� fami� o &Kus.� H99�(d>@e�u�� .(ceE-(st�in] �C("�1=4w defJ�5- �.!Ki�in�: ��CQ�ex|'� Azsv X3��[a��a�u)!��se�;o o!�loJ7ob�a\2I�-a=�. PF�VnFSd � MAFFT v760!�3��L-INS-iteg�poo�AHm j$�scA�-gappy!�TB �ig�PBconcatenũto-�Ci:su; trix+�F tota� 21 , 690 So v�ZiWhfeW�Wx�-qihoodu�z%G+F+R5i�mmiYB8it$7AAIQ-TREE ed6 . 5!W)B��� m5A�!�5�} �*000���)} `&4ultrafast boot��pzrox~ �( UFBootU ��O�Roe)mee8�8i�"o��apDe�)9o tes�jSH-aLRT Y� � 2#ը�;�� im�9nd�t�L�&� !?BI,�Er��q V�SQ{b\n b���Qt>6fe�'%�.����in5�. C�:h �O raph6ly vi>?2ZE�iTOL � � 3A� D&�4t)=!�est!��MEGA-X28.�RelTi/!�ach!0 C}S0a-�Smethod��5*�JyR assu�P)���A�y�ag�.t�:3%!Q��.!n$5*as� �"��8xedBsA}t*�clock ~� 40]�-�/u����,)g �  AQun� of*�.�s �G! "���4 � o anixm;�w� �-��扫!� )!��s ���Cnode ag$tb}e� ���!ca6 e��F"s:� 42 mill� y V( MY �K.�< *� "D.�W@lychnidis-dioicae%"2#�Fe! [141]; 41w�U�8 ago—Spo� r�Cc_;T4131"� ��!!mi� a�JBa.� )r�]� .p�Im�5��bXaP)�ebs�R(6� 5�� � Z�Jb�LD;Q"�  inAB)�AUr+�%T>��x��ce� ioPro�^( PRJNA47568�* 3po�e2 DDBJ/ENA/#�>�ac�;AQKWK0 -C"�%"8tT!351 6N46: haveX"d�H NCBI SRAA�a� ��SRP15031�0!>\A"�� 73R� L �0��1r L= PaF��+!+,34 .kuChagMis�_!�A�6-&~"v4a-borne +n L�F America��EaA��T��s&�k E �cticid�GraE�suEcfN>�r%d �N-� ����+B . Non-R+��pon Ken2�+��misE� risk� �$ �!"�Ra key 6�?1+� mathea��#��Z^Z�ii8o�>va�8�abund�BŘ^�in houo. Dem<g� @:5by++�/f������!f:Z'�Yucat$5eninsulsMMexico� ��,� �I_>'! � �- i&�% js�!�Xsimt9i�?"�WLeSacf@1y� tej�/d�#v~n<U -eeS�t bedn�"�&)�l)7�6n�LD=*��abmL ( of!�F. Pyrew.id�Hi!,�7]8!S~450 mg/m2)� appl"!�lyc2 !�-month�iodA��&!Cimmig� >a1 �>80% re]Jin bug Y���"�by � r doA�or�/Z�/t�_n)�Yit deH=d d2Ga-!_o�?33?/tir nd�8:�%N[a{&�-;��9*!x5��~@C!d�&6��?r��9 �� .P�  ��)b��&�>lDe achiebyV), *NTa3�^y�(yILHE|N1m ���' �$�}d*.�<2;sar!o!�bY�!�sus��. c `UBar�.2-�H��.e�A!�A�ed!�5Veg)�6�s(B��jor62 para�Rc��B�> 9 . 8�11"/ in�;�Peo�c , 60at�WE�(K [CW[2��bur?$ of o\C80�KODALYs [�+IA�i1al��vef\d2�� also tur�4"  glob�d��[g�>�V h!u�ozo��) �F ypan�QrSuz�M��F3amit! toL;�#imariA��iiatyVe-�� Due0� cr pub 5health , 3U��I�,wida�.��X�S<<:�����&HAzY�!W�^!$eI0)�!�2�X:�b�%sj �?��a��em� �9�r_Ui�1K ���>E�sonz��azja�5T)�a3�J q�1.2h:`MN YY�, [&*H"ahi4Cc�i\C*ay�?�.1��"�doŏ� blis��man!2d�%A,olo�+!�uoccas�0�k0hab�&s!6.  periZ-�sylvaj:�Ms��= e Rhodniuaolixu� (Venezuela [�_5�b��lie�lpseudoma[0t!�*zil [7� Bm� an"�Cg � [8*o�1e�a dimidi PA�j� ��Be� [�#[1�Ext�ve &�*T T .6g�ru�Surb���XaQV��=a&&ac Q*?  oduc�k� ���E�;]R$� ��[ad�m)i�!�3April-Jufas>�k very"c4I}�?�A)iH181]–[1���vt TVm �iUers�F�E�nearbyv������ �0r�%��;7*Vp&�ks�[��.�!{#ge�ds";.[�>MB �,,5�e����!:!���� �6o`R(7aNa�Bpro�� ;�;�ySn�- �z[C+,VFD)�= blood-feeK �fec�Lt� �ial=s=��for�0g F�'�nU sour(/ � .i�W! U�9'of:^~b��)�l�al!�t�4nd�t�q/F�z�Moe-!Jb:\ed� ly-op���3]6�in&* co��m�. Accor!R%p6+Y_!��J�be� ��.�%F-s�)dynamh c;��h(� outdoor���E��- inkC�;QH�?fi n�`""5U�!|�^f littl levaT !�-�a��[ �Imq�,:��:� ^�a|�7 else G as>���r�+ec�%�� havi� A�g�Mu�[2�2^)iEgok %�2��ruchF� ��[ �X*3#� # F`��&> new&I#: �si!�� A�$t;�!J1�mi�"�� Z<"WqL , [24�K'In� Bs hr��r� rt-l�si�6FB ry7�re�N� �n�mUngv~bug�M�9Y��F+?�!1f:D� 59 �F�[�'� ��of�q�c�R��%ށ�iz,Ae!i"j�O�JX=�to cop�g( r :)b�ov��re�potA6��&�.wE���"��g�EA&� [<'�Q -c*� empi�l-�a-mo&, [%N � cosJ� A�-�&9J�� �QT���f�1-up���d�19 �3.�F�l�k.�$C e^ �53xpl�1J�E��e��#ex`d ]�2e�S. A)b�`[�A��Ž�?�FedQ��7�����!�2� [cAE:�t�� [YOry�AwrWmptq֡Y]�[jcn� focuu#onV�,\1!�ga�!��X� *Ֆ�d.���EW�9"z|��! ��_�m �B  ,U&A(�m�Z����2�A�aP6�=(�1Co iz&� byF:am;9��W�� ok avhW!�͐�$docume�%,=Bqb�L;)/"� %�6� %sNw ,S2n�de-;.�n C&�^����nah2��Bo��. We ai ��J �7fble't�'pj�8i�'"R�� %L)g*J-O*�B- � yB�*�BR(')]o.Ae_t&a�v,9әV�. �Sv we��<Ju"� Y� ��#/ �Z~ s�ivL.t� &qKf!�I#6�y>�>� ��d��pe�o 2�y�ofM�� $Ompa�%Z5.e~W"� -kJ�6�as�ENQ)�. &{wl4!,gn"A$M�K&v ��nt����"�*��h�� (Y�!�lethal:n.����"A8���6. Data4.��>>?ac ��X=km��L6j"�%!h3e����� ,)�,October 1999a�Dec�0 200Bm%� JanuKto2"3"� �qV�U:��0�ard���*#y& P�)y� tici��oR" 5 �_�N-/ern"!"� (( Dzidzilch�)4Tetiz , Eknaka�ASuWiIzamal �.Pap��0Wi} �b .pri�7u2ir:�f�wr�bx3n2��wa��t���Finv�n0q cedu�m �:NisDp� ::�[�(:��� � loggmInotebook�|All��%�Bv&IIns�.�@ethic�0/�d��gal Re�; A “D_8@Hideyo Noguchi”�An!-,sidad Autono�&� �OuseholdI?E5iX�+M, ��Br>, �E�R.uV���e��(�$% ���[ak9P y 3 �#oJ��.[I*.%I�is�-��$e6hT reli� �6r�m��^�an �<�u!�� ��R��ni"��`B=�:ur1%d� �Lse1dy}q�qk16�a���"�$/ yfluthr�3n Nov��8!]�~to"5)~3%ek�Oo 9$t)�det�;re-.�usa��.*-9I�%��:ejp**Aw!7�"%^[�AlYM E/ex!tN��3 ��k ��/Es-�0e 6� 95%a�f�I!$%�g �]<a.jaF%*;B]*\.� 8of Gourbière e�P .f.I`*��Wegg%�lar� Z�Lpoo��"s e���H)� �VHㄩ 595 sub-3��equ�"��V� �-]n�!) �a��,l�*1$ �atMi&?5� ndufi�0[�[ �&r ;z !�at���"~8� age �~en�1m�4 bA��b�w�ai��a Lesli:5�we de� A-)n$� �  odic�"j(�M��miIH�"� inva�!!v +6�P-F�)�oa,uP:�Q��be �:�@�r�. N ( n ) =�J , n:D 309nA �m7��e]nfem=P�G� i1�a=����Y��>YH�)E2�p5M ��m�m�m�m�6m" EDs�aG7�9��N���we� A�ex b "�ItA�inb�);5��m�T�4�� MB,���Nae"�M5-scaleD 6\V�LA�%��cC(vZB� w ) � a8gJ�� m�o2�mat\��2��w�/ ��y?raASd�/��-�86�V� F.� ��m�J5�"{ �* �&7>� �[�7 dZl�p>���U&fir�r O)�hV�r�4d [�O90[�gt 180[>[18270] dAxB6OB0"���: �zjn.o0de �q,͈6�� I|q�,2�,SI�SA��2�u�ndi��7a�YaT9C9�)-�F�oi�*�(YoffsprA�H 1��A�1,7wE �=��a��' �&^ i�]�-?=�A�$�J�|[-!.�h M )%�P u� � aa M be�$V���2wi^s�F�%O�"]�X�.5$e�7�iA n�r"�%o!#"�� flexW&way!�mT  He+5p\E�x/l���*#�:��K�Ca�Ka̝ a daC+ �q �*� ��� �# keep!�aB� E u eY��ach�U $T = 90 !HA�7@ � #+!MG)zZI .�� �� begin.� �te�T!OxM!ơ�!�6� .|�+� 5�!�1�c��AI�A�τ�Are2 &* �L��up�y)�al�G , J,�#�&fF.eA� �� T-τ; �"�1��OM6' 6��= �"� !I�M��r]9m>]�A0u� Equ� 3A��4�I� Ry� �@�tR^han�DA��B�'�pa�(szn,6b!}2AUh'�h�0��Y}�F,&� s��~az�&\]�.*�g3��6�A�so  or�2=b9/moI��R�, age � 2T7enxTeday�rD�+Dsu�Q�"ME��!1-"�q ��ugsB�� �g�t� �'wX� �OJE\h� �f(1/ ��ap�s �k0%w�ov�!"�A\&4 eoG�&� - wؕ!��V? �uc�TwA�u�h��L3_r�0ap�.5% . ��o'�Im�+4XY��a &ttwo��� *P � � � 6�"�+�1G�M �2�F1�&/Z , SI "1/&� ��  <4342F224� &� s/B�  B*rz�)�%�g�Df&s�%eA�.-�h;"�Da�� ( R2�95���. 1%W�&�I�a��M$]th`(� λZ8�B In a�u� E�a�3� "2o:;206���z� �� f�.e`� Z"tru�$2�sBk$ce λ<1 [1JAl��� J�2+�'t�M߃]e -� �v����P� S ��ali�2�8� �9iW+����HE(b,��[�B=J� a�nga h7 igib��#Z to SAU�/y�NA� . UsFa*��& 3/0� �� �dsqu��as"l1 hby cO6����>_:�amf)V^ �|�kM�1!"/J�by 2256%�:Eer~�%  q�Vt�orc!�o zero (!�=�'n�RG.= i�#?=#!sUY A �su�I & e�%��Rse-&�0manne�!2YoutUX�&(>Na piloto:�".�&�5d� �: 98�SM Ca��<� aYof 38� J"�inI�: �&O!nd measu �� ".@�a� "�@�ab� "w[40%+43 u6O���"���'s.x �P1&A�=x�m��?~9!�&"�2�'_ ar`a�!� 6� � $����z */� )� Cd  DQ2("J(&�a�Mr��UAh;2-A�]�E(�S��� a�-� )�.��a rapid�our�.a��u��*S,�oon�wb>'�A](M�2� AlsoK e=N5>B�criP�!�ٸmJ� �!!6%post-.�.�a2�r m�M2M��Yfof 90%�F%��"�0�!� 8�C2� , jus�f�D�st�@ �c.�� w%S� �Iu|M2C��narrow!�P2ndD�!" ' dram{< �@�2�'AP �yJeuţ�U )rR�had. �<5r9D))t�dug!S�"X$**1* *��'" � �l�L��]�R[8^��&'!� �A7v"X(is h%K%�Q(i<"��M1M��(M3�A four-uX��<�`2c�(S% m�E)I*� ��4C �by��2�� A�\% t,%|a��eno,A��CNFa�mM"t�aaR��zUTCi2D%6�of9��5��<ly5aZ1�. Non��les�fo n�^*%Za��w11aeI22�!'.�m !&�Nl g#t0���*C by  5��a��V �vz2�D�z��7)��:E�� N���\! {#� a�*�! Q�22+.�1 ?�l�Fݎ�٭f��-jX�<& (�y�!�!����y9pE�2FE{LA& ��;ra�p"w|"&Z8��I�s� T .d. � ���reJj1��BKF)*5(� c%.v& ":! Z] "Y s E6robusBw�� s %� y Lw*�K�y��%"��H-��pi�Qh� �E1sc. A�3�W2�KA�Ve,� �3?�i,&[7�E,om o5 z KX�D.� .���E:)|U Zy%���-%kh&�y;�)$:�lQG�X �Z�A�arrA':�e2�2Qgt5�Aqw�:U�!���Y5�MaV� �* F�.�� �>�\��� �I�of LD50�=�Z!(�\5$ad�2�BregardY�A� 5!�.�p2p#W .O�_$�Imr�e b RJ�2E�Q�� �VXwd;rJ�)5,�O�9�%]]lu){,Pt�":65R� �*E�:�B�9*7 "� &�"e�U$*bs �,6i2�{>|15�0�T-j�R"�:.a*�%Y�/�i%���ZD?,"N` , 0<M . Gi[v!�6�&�E� R�5l.e1�fv4i���i"�4on �D<wV�JE �h"�#��H�U ��e�D�6�&�he2��o�U�ps�t�$p�g w, �h�o*"�{U�~� .�A�� ��E� ng E{eYA����4AEM4<lsoa|�T� )ofE�� e��*�56��=�= d�fLH� eD�Z6.߃��-w!mn�y �� ��=�j{"� a��2uo>%a B�Yua�0%� . S�w ��&^��/a�v�w;�w�H��d)"�5:� 1C� �a8!p~B� _5�3y�UBR��N�;�g�UveO�!&9 mfYB�WCAQ�Eb$yaEK* mFmE�s roo-bs! al 1*�.ZEAiEF� E!&�� ?'naB-oiza� �XAEB&��C6�S)�J�!���> "'cS�e�T �"5 ��a�&X3.� A�)���!�&2R� N�'stocha�;��X%32���$N��ͅ �96*+��=%a :��P����iJ!��se� ����to-dak jV�:7i�i�F.FTSR�;�*nt �A�S*C�Aa/�� E-i�i6E\Zh&!n�gXM�K)s[� M� e���c ,�Poa�!����ch�bs! A� �Ő*E��Nm�YR,at!��!ҋWQ �B�A9N�B0*M��0[6�F�G&�5,� �iA a~e�a6��3O)/�h!/>L birt%�d dea"&J,Av�T�_typ�3��*p<�N�L� �,!w��@K q���:� AkA6}EU�Fh8G-�ni1�� ��m�t virtu�n=fU+ua�.C �e�s� wE?, �WA.�G�$aM.�$ A�iZ8&!�DE>|�Ť�n��mpa/@)�!>aEc�שVir�-ȝ2mI ?}F�FF�dKp*�Q�h.b.�V�G+D �qWB�=�1'6�-!N-fM �4;Y1 � t@st5F5]��md%6�App�i��5�ځ�"�( M�;or*X�����ea�`� 53,{ ^ �e�8E�}?�(RX 86�*�$<�8H a 6 L! monew)<(�_["=Ya&0 capa&Q6–10m/�)� te t2 "d[��aK ∼2�9-[MVm^I�k�&$ inh�t�"6�Z��tf�u��rkR40�2650�"g�e��, togeZi!�:Cim�*N��~6�Cin�*v�D28%n&y K&�>&8Ea��Àe�e9+���K� .�,Aa%[�{"�-F  3 � ��&�Zn"96!B4cfacv���.���O<�yn�D+9 �.U�P%�-$:�4Vi���> ��aP�%e��F&�W�d�Z��H���T����Yg� ��t.��0>�!����Q ~5-gene on2:�C!�n_"�[v2���}�x&P�=v�B�g�Q���Z45�Ebifen�=[�"Ex� �*)� iscart* organochll�������a�lpE&� =�BX�.�)vNW��s}l anagt!u� siZ�*W�a45�^-��Ae; Gv"i�:!�c� 1#lhy&8"oom.�& &� ��� 4߹�rf>1 a+t!e�V=ۉin *J>�R�'�s��S,l c�U�" theyK �&rudPd*2f?byLU �E�"�`@�xt` ���ɲ�|� "$*e�F�. S!> auth�zEx_Wa�z n9.g�kO ��c H �besAX .m�bEhmat�R� ��c��U.B!y�� � A�&�B"�P�F�U�#��� �I7a\�M*�cx-.]T��g*�*K �M ��"�(��bs �����AqT$ "� �7l� �!� �u�,o+�f� i�� eny�Efe��.nz-6a�J.a�( w*!jmp"7cur�se�Ia���Zb�5erf,R .�u��� a >6>�g�W!n�B����& [�UI�?A�?2g<��Z;]%�1u)<5�� "XYuCA>%)G.�!byFK 0`M�a�`�� [1Pz&�.:� of 7� !��@ b Jc`�,��a��  6� .�&WmAa'h�o� �ns!. E( ough>���<�G&>a"��j��`�ڏn$tear-and-w�gɭ1A8a8a�/G��i��) b� ���a�PN "*.R5w�un�)aI'lkVl�\G & �&�"��&BV�����SEIo!,61��G 1m�*7Kş���1�^H*�'�]*�Y,can�ru""fq<�� e"in��-h|��xacw:A'E��4�a\Fn"�n�sAL&],��o�TI��8H"}*%� se ns�Y[5�5(�*a*$a&�r:H.E��"���%��W/ �� 7�9��!rom2PwHr*_i�!2� ��nF�I{���� .t* �u���i/A��xr� "a&��� .,&c ur� illu��s�~dusefulc coup�X%� ��^�>Ƀt .�At�>.��"e9nce��6�i polia� .� �H�!e�P*$[3�$[�� �]*�  !)=%JB �H� X :2W ��l -���![U#�H*, )�q5�.�IJ�"M AR"i^>�l��ch�Ndengu- malDr�$leishmania�e�i'\� x�a� ell�>��� highA�f�m5i��* "�m9�5�lFD3I��&a ��') UEigA�red��warra���firJ�bX;r!) .ww&�!�d+�o&lu�vp"H�f7&�P[A s .�Fe`oE�NOa!�cF�p~]r��$ avian skiA7T< Jar)s#m���Ha %.&�do"hmid�{A�%r|�%�w f � buC2d`?x�#� "V�w{�1�"" �ѿ UA��o#up�fib��!�!� ( FG�)!4b�0mg�o�Pk�nei0BMP ) ��a��6bmcshym�f,�% , 2X�K o�>U>re�\ifP� -tax��9�k�-�J-�L "ar�mܞ ochebf, � -q"��rR�n�*�pT ,eedback loop�k� n!32wEy~�sd� agg�$],Pmof s0)��ep�&mToa2%�tensify e�N�!�v�]E9��a�S�!o� byD6����N# of EctodyA>$sin A ( ED�(�!�|�2<FG! �6�I�s�9�yu]d�ty gradn,��gge%�-��by. �FEs�$�9:^A�aS(g�oN�3�as �se��tA�_4�a�&E�=a�A�uw�Ml|�e he flight�&emuRo�h�R ��A�e]u�Eʺ���/:0��tr�.�Ӯ��r�bi���,�l|)����!ȁ�* a% a���b Fc�- of h��folli٪w1I���<��5embryo� ��!�Qlb�k�%��*1en��`,sA� fail�l���2%!�:T�!�$m,�g[9�y��! �A���rk�n!~9~���!���!Y}��I!LEn)�qX�!��InMLe]�!���rol%av/>�reC�oJ�EDAR )aShw1In�teb�)�mn!]"� rec�$� tivaKE�f-K"� si-1-d\ÁMaA�,:a'%��k���=�c9�. ��eUW5I�8,to�al !��Xdiagno�!u� i��R!Q��C)t�5dAC=l a��a� -�E� O -bea��"qEYM1ecn body�o . Ea�Ib���igu��G�Q� ly laid�I:a regu��a(�n@bo�� �is�IvmkX|a_if��A�����A �hq�six�3esto!T�)k�3i =}m.�S� tticE�hexago��� al1��m�s!>a2*9 �5ˊa 22�spa�riE�q�F clos�"�]��ioe���s �FpāOSci��a�hib�VZ3fl�"�*��kpl)�� ZG5 by [C�} ��EL� ��.ssu��!�Fepithel��&>,�%ac�����"��$N�dCI1eEV!3Bm�(��'er��X2"@��;Ħi�5r�%�{7]J����ter� E�jun��x�{U �+��� sheeA�}i�*.�@*� .�*#��r!�=4�EB2N�U��secret<I�= ��)�S ���b���;ens�m ؞l9�5bena��X VGlac��M+NFB'�"?ta�e"� tP t��acqo)Z),aD��6% a su��of��Iv��Y�6�[��)�Х�i uAutK;� ����&�aœ"�,�wn��� r� ya#0�O(a�2 b�P&A�o chicken-� ��%�6�!��8i2��' ��gi�&rrly�Jre�%d�Dt�v�piANmN @ �( E )��,� A��}YN��6l�ѩ�. New�A�*�� �lle�-exc ng�� �� � }]�sweeps] �%,�!1eM� B , :���yssbj0�G�$�K�C,��,94�Yn�6qye�-�UpaE�b!s�K!��'� TB&E��ace� m�1ly un fedA�u2�?�gn~Zfil�A�D$%� HaGPr&�`�ea���k�Z'�Ou�7ru� t!ѽx�A*�w 1!9�Lir B�"2��!���㽁p*� n T�.\ET.���.a���eh�A�y���5�s ��&� �D* � ��qxv�e�` r ti��}@iE�u���S4��MrA�^E�f��&^%k4�.&5� low-!W-�]�="�bt&IC�.!1; � /p;� NS�go_��e.'6G��v��m��� a���%y�. [4–�|Q �Cem��i&O � ^-���q!1�*W�2o��1�al-5:�� elf-(#i��in2+AX1 at�Led�Vex�B!M EYeor�a�f�Ffiͭ�$���c�'� By� 4�ngIsha��ndA��Davidm� [11]� � aV~ �-!F�.d 9�.rV%�� -t��m *�0&!nc�24�hM��&?,a�aa�PpS{nt up>7� � 0"�t!n��p�45�j��3 �Ye�)n+j��s03�po�� bQyu���FQ"�,�z&,&� ��Hn�� g�A\ R  �H�0�a�:0�l� [1���Shy� n5cag��"�� id ��&f� �6�Z!�e�I� Ō��e)�� e�.Z�0��M�V�15��Ns K�~��t"�0}�jal β-?1nV ����gR�?D�U�3n mot|�:�5�dri=U� M!�K recour�@o�*emp��sx�AO�{e$ ��fK��La o�:"�~U�]灁/b��%N a�teEmn�&�� � rs�[��e �� w��a�.�@%�� �Ty@E:!�P�a��rph�j!� [�.dT$��!�.iA��20]e4y3 �e�.P�$�4eD9�d�� 6�io>9g<c*��II%.*�rN�4�3.�!k��$A�%�o���m=�I� AF-Q��A�X�Qs����Rrelj4%t�@%!�Asu�%1�,�;ng�7� ��!� �[��Tre�Mc�� A �-m�+M1�i� be��%<a)d�`z���M�usS r�*�� 2/�5 tm�����DM)�!w�,a�?*m��_ scra������8XJ5����+"W2�o��I*!E�0!�-9 �a����+K �2&�]$�t�)��.�Ae�M7gF{�el6O�q�"�a� s [2��L5!nWNT'- ��[2�0�}�M�:�R� ��R�� N�bb�6rB��f@� cruc��S6��0�� 32�ee���f����z�� (�q$�L~���, targf�&� UZ"9&��f�R1?��-���~�'2 �tt��� �Fmar3%����X(N��ss-of-"Zxm�� 9A��mpo��N�� >fA4{. M�F!���,� .q Q�z/��E���"A6S"����}�T�2or���<��ng2�BMPE<�-\a�0�=cM�Na� neck!7i�6�s�P�A9�l~%��%w�! �A�B<T�y�"� h,�<2������ tory9�l6�{�Md�12���,�&k , E�|5�&,4E�%�sa�6���� �� w�0I4!V�f [8*���terpreI�y&�I�d!�%.!p��"�'[���He�7A� nt [y�*M1 f�.�%Z!��*"�0.�&(2Bo��sA!�&� $�5 �3ɲ&�l��ty-��V��" �@a!#� ��1eA� �i���f�UA��/ 8r�*er~nho�BV Ade+t%.ME* #QEm��!��u��#a��2(ex{ e:�O-)u^I_!�&Y��Dnd�}a wR����"a/-sc�u�i�S���z}um� �~M62�[36g�8-���2�HA��L*��d�F& S>� �(�":�!"m�` �vc�QzX ��!��,�$y�\/�`}� �13 [J!u _Ab��"��!�ngI�a&�"J{"�AQ} l;%"6oU.i��w�7 �*B"(ostrich and� emu , leading to loss of precise hexagonal periodicity!�their feather arrangements . We first aimedX determine9D mechanism underly~4he local spatisatternofl�s . Based on genetic evidence forb$ir importain= S�[29 , 33] , we began by investigati!�he relationship between FGFs and BMPs , thzcontrol�$cell aggreO on ,�develop�,chicken dors�,kin . To def1. roleMFGF �treated .Pexplant cultures with,,9 ( a member?�LFGF9/16/20 subfamily 1\more stable activity tha�420 ) [42 , 43]!�@assess its effect!�� behaviour%Q!=x. We u!� embryonic � from�8CAG-GFP transge!l! [44%� hich�re� gr!�Tfluorescent protein ( G)!tall�s ,�reveal�� >�(e2/4/7a�2 8Y�( S2AM,��!�et�genes�y%�q, rectly� V�!W.QNc��d��%R] are�8truct!j impl�}�on-� u�8I+ cap%(AQrA��a Q Q] d�vo!� � 1 next!Rlor�Ghe po�B( � aAc� of �A��_ �itA�!���eSG �Y$)X|observ�xq`)�4%1B�at&D �.� xd!�.�f s��F X� Ge�CoadminiD �>�to�� v��!���.�,���>��.,*� !�E|B�, r 4 M&� o!& ,�ie�fL��B�B}is both!�z�Pby�Q�esAri=���� dEK>�% . Shy�,nd colleague?w ŖuE�at �iA1&� 2�, achieA`by�)hei$ outakup`Fs drive�.� t� on [16�5S�� � caus��displace� β-caten, "C enco} be CTNNB1I&)0 epithela�%�junņ�E perm(0nuclear entry!thi%��, mimick�Vf can$al WNT-�?Wed d�d tissu��n� ! as��ixR�%1mightaO!3��B�2�2�e!r�0ttachw ndi� free\1� pinnA4o filter)8e� 5�,E�|!)subsequ]h�aWF���e!tim�9i� Ged ( 2X4� ) ,FD was marke� � �9aI��i%��E��a���E a* in� Rm�/%čH�No Q ��fat�� � AXIN�BMP 4 , EDA-DEDAR )��o�� to a!����i�s�di���S2>��p!]J��ope�ofV�greA^./-taxis�5*� ݕ . If:�E"�R(��appearaM� 1�e"�nM��e� r follow �JY_!t.",m E_k �shN Lemerge synchronously}oM}�^veA�A.�"�of2�>�iW�"O ��*� F�w�<�\d�cibu!�^>9I sam*��sampleA�I?S1H� De% ���aLr_! �pecifice,oA�clu�}>�a (��,U�E�Q뉴�7�  `ّ�� a�<��f�occur� s- tane)��� 8.�)^��tE ime-lapse21�OM�!�y-w��  Video )Arw!Ie.�Aresol)�of un�a�rD� fixU%�men�apec .�h RO��E�sI(how overlap�gen2F�Q+xl��!a�t  te�u oincIce��two"k aae�^��!�2\]5u:� &@r E�a strictJ��=-��� or� hBmot�-At /�has key��Nofi�� ����-_�IstI~2made dur� mous" imary ha�ollicl5Mg�`5 foci�>�a� oed�kzoF�"�a�[4� F�sEerAktalA��r &= modeQ!�molecmA�aY E��Uvol�FH]�UJ��I��is l,��e&� !*P B�a��%� Ci�.��:Cs��e� �*~.o �gifC 6�20.0.��^ s:A!24�*bVv>�!��20 �n !�2�by��BE.{�g� �D��xdepleaF6e�.reg surrou1x���M2 discret�chaAJ+tlyL��-��jSd �uca�!&2�aV"� ng a�_tJ�zF %�2��!l�a hybri�I�-"yJ i5,*� breaf symme� to-�e��B�i,2Ae,We har>� Ltai��m�Y� � i�� network�P-7E�t pertA�[47� �id�pa& �c�M,���s1 � !�!*"�lattice��silico)(R �onl� 2�deab� �J ��rep��2 ��� instRiz��d �E~2Jan �ly*� arraEOwhe�� ?Ab�N2&aa�ve �w!�� ��J��aKs~o�m prog �p �row�!�oI�a uni!t2��outcome�8>VtesF in>� �66a�a��a:4� ��KC%nsiDblockIQ.A�no� �=�O "hh �� 2c���!�"��6�&i_�d o�! �eW�$d . E6 . 5 \")�Za 24-�bpow)ang2m ��gJyar�r.A�-~! 2BiJ.W �aba�Ha.�E���!?��M�ry9�Ō!�R!q+fyR fi�ty�n!d*�te� c�e�6� � �6ttainbp,� T 5�5�D masl�ndividu#e%5!� eed^!=�Vob i diagramqZ�The!�t"� of*nneighb�!M!Gs givc mea2 of%�V!D ex�A!ua�6& ���#$Approximat�75%�50%D6}Ep� g!+24 –p�*,A.pe��l , ex six.�>���c�e� �Y2Bl�1kD��I��!�>�`�$��`-trigg�E�spr�%acr�%!�%,� ���e2�̝,fa;"� reinit�_midm#� �s an�� 6��#r}ctar�a Z�� �s&O %I�� b�# elussi��T&�p��Nݒq���*�[11�$8–50PI ���6}na�uk�f1�A[on� com!�5 �$V�I�"� �(��!.%�toA>����=!���2e"ɶ"�wh\ �X �aZ��pU=�m��&t �prepa�� ��D ip@"parallelha��6 ��Q!-, |�z)(L orId1tc0��ed)tl� remaih(L��]!9!py,K�au�a��p(ntra� zARL� � 3U*�anj�0Y�y&%ti =�,�'r%�a� rmal>�!U expa � )ly.�4ol/.�� idɴ%0?s���3 �NnuXi�QZ!$�� ��F���lya]h@*1&ei ��ij�W**%�g*"* V)d vewhC%rst steE���{2� iG% mild� o�C Aa&5  �Co���aza)M�-"FhGbe.� �A��K %Y�li teo uEhA�ain� ah� ��nd2�!mos�� � ��$( S4A]�a!���w*���fac�% �j%I�.�Ev"�t���M5-<�-D_pr�u�2�+%ifs,J�b�-|�%-X*�. C.�/**�C nd�/�\X,��r�Vjlin�%[5�!W�u�AIUU" each-�athway�0ith CHIR99021!�recombin(�&� Fc-chEDA1�+52]�.D ;ly\�&FG=,2� d�A3&9�lso fb�WNFjARD %h6zͅdq�&��In�cu9(��&�! isU�+��U�i&�-�3I�)tr�,�MRIq$A��SD � kk,��A�a�(ump�&�sx.. � en ma�ai���2��mÑ�a� la����!um&� ��laid dow�.il h��re!Q�v� fron�,�'QN".��%�. rece�oward:ɶ[3�390.a% %�=#%�adv�-�S"w of>7>��w�lso&� - Danato�%�tS4&�)Eᷩ�Ma�A�]�6�M�`4 0 . Ha�+�G�! �� �,:�nd!Q>�� onse�x� odi"x*!8E�"0/Q�al-<l�o*N7yę�. S�!E�[predil/� i��� limi%� (%*- �b��W�7�B�w�^ Y ��� WeA<� onilf� �,&�.]1freActW w�� �I(A�!y�& � modI�1rI}�!��C� widt ��Ub"S5q���N�, .9 EDA-A1!�& , al5�&�'e���9t�m�Dѥ��0�";'�hypC =E>E0ed�6�n�*)�sr�M=�"%�!|�EWae#�ngeB�%��|2-.–� :0body Ecto-D2 M , narraB9;3�a�ol� 0 %$&,3-,"f6A�o!g9:aN:�� �� � �}e/M�S6�BM2{1*k�5dm!PF`&��0n�]b 6�%�*p.�e�"/—J�-!'}��Sity—.A �0e,%�+ t%���%8ca�%z��A #�9.Z� ��t=a�gr4� !m��tr�m]fj! �cir*#u�5!� \��-ntinu)cu�:!ay E87.� \ic��iQ�is"�"�ofɴ!�!�ctode�dy�-sia�%typ!oat> ch ��g5&� �h�:NmJ<sic�>��4'/�% RB��ed&� YY��-�2y"� 3�o:� aD'm>�u�H%�e�I; S6 �,a��!�S7 멚5Emaa%�rdr�W�!2����4g? fu�,F=!I larg��n�<%A� U�d>E11E�a�E13 ( S8�S8���9�#n ongo n~ ��N\�'�outa�th" ltho�<�0o�dRen+=[!�e�lR, m��@*Po� iWt';�(d�Q�H�S8�P ��  A!a%��(I irA0ph���F�*�-[6An� !;%�Ic� �M�(�6-N_in P5�\0"}7%�t� mAb-3 [54]%-�+to E7%�=A\.Hy�.#� F�ex vivo��; N� ( S9.2�=O+��^2��:�#�w�5:�%! �� vianm���%�| E e�abV,eFeu6~!�sufficZ#aJB��I� �&�<�� , must� �WAKj��N�:#� -recogn�)$6D�#aquu��*�V[8 , 10iwX �� 2�'w0IRedidat��Dis�= �compet- to�goZ�To.�(ej�t*erwstage�8� .�� c�ed"on�ti��y, f�aTtAal-F:�-dfam% gradE>\ 4&�4��=.Q6J&!� 2� ��͎�lJ(2�i)2*E]oy#�voi� (1l �.A"g##5!�recrui��4o Gga�A�/,K6e,�/l-/6�5G�,&��+ ��I�!k��!,N(A�tor-.���I��"��-��`�z�QtrW(�,�"a dyna! �J�,iaFF�&c!#6Z racie6� jCv"�-�z39"J�A�%.�I�pe'7*6-B�1��dMC�Fe3� S�1E-*�F. V�1>begun� i�ll�@at"�'hAS!� F&� �0. Ove�h�p�4A 70�6,%V�"ar�IA�� �rd��IS&; �he&V,uFE��p� o7w!�spo���e<bi�,ad*�paio.� " �8�D�0|�h�tv3ve�n��R&a�Q�a�dM� relo� i�'a�/s ap� n�S&3E�re��9`i!'%���8�t 2-d1'talE�M�lot�v�H�n�tya6(a kymograph1�&Each fr�!U�oM�ser[-,ep�Œ��l�n� m �ǡ�!ngIp!.blu!�d�2�� a!M��u� e:�iny�k�origi%��a �&� ��=1j&K7Hleft-ri�:\8� \�I!nx!���rem�a�Dior-pos0or2�� e y- b 9�i��by�k�.�4��)a�A�.�2WY:u[lot;� L$l q�m�of)�2L , so��i�!29��Eq�h1RSM10E&25�_�Ahfq�He q��FE�]. P�.ve2Y�7�q� 2�� al v�.�0A�);� � � -E�2�a�.1val�%��H]�  l*�L&�N|#m<)( i . �'��W l ) ۅt�k#�KX6A�e A#�Ga �OY��@wA�a�T e��!�M�q!6 !�irE�A��h�`�-$4M.�6'R�))���:��� �GNma�,��B�eft &.��!؝υ6&aW2$meeb �<K =Ek����o� #!R�si�=� accudE�eq6��Y("�. >AL�i�q�at ear�+"� F� bef�!�io��.� b $E:a ~A~Lw(!{�i�JZ�L"�z-.q��bl:dL��" |O inct�e�T/s�m�wl��b8Y-rt�8A0em�4 ( PIV ) -�GuflO aa�gs17 10!$ secu{#m e�R>�"Qs�A%� pha�of� a�"6a�m�F�Ee� !�x�k(.��Jde�i� J�)u?�Z�%"-A�I[�Kgen��f��r�(i�$5:10–6:59R,2� Uv]�T*x �EQ�( 11:5Q 13:3Ra�t�$�i;aQEI�.F>GE:*G 8� 3�–38 d�^l�  ,��s�+� ? f� ��:�5t�Q�>�$2y ompon8 �%�,P visu� B4:IanA�g som�kE�!�newly�8dTomato ( TPZ )A2cS(� S&�Methods 8?� � h2&I . F�Sd6�� � ^�%" �8F � i�OT�q�4����� A�a�0A�A S10�� !��e��I!��2���/�&�0ly2�-�%�[55�illA�onei&1�- 3 �.�T� r�R!�%BA�ein.�.�u�.*<|be!!en�mpu)Y .�N�J4�O("k�/�*�-GFP/Uehaft–U4c%��4~BL ��as2'5[Q:�,N�!-M"�&�I���F}� ��S10*�2"Aa�g1 a�*�WCM �D#!��!8JB�is?�.�J�V�6����� eA�m� nd�+E:{ b���<�kae7�7<:6�D� ~Nm2N�n7 G*�a����R)� � Kng!\ lifeFux m�h trex�( MTX �+v��;�u�XVim�[�S11�'�R�%Crea� :�&",.J�i��ar���fl "o sp�2�`� %ő*�@�4�S�&a{�any-�2��zA7��wa��]%�JA " ɔ��t\�'� �'�fZ23|5�,*�&*�!�Q)�3"��1f e �29 U"�[.� &� �w-�F�MW�H��]�%X*�EDA���/��D by m ?OD!d(Ar6P adja�01@?-7!ed Jg�  9 �Y9-��#/�[�,d"�:AY!(b�AM�� 100 μm�'� ��B 5B:�V�blX)���/�r!�� W� Y3B�#&5 3��&J<rf�t�'M�(2w�L � s 66ERs/1�#us 49:�"�<�5) �51CVN�%A5�Z��R48 O=Es��A@V M�of 98:��6<<�Kh5��:hF!J=U� A$� ip15&, E>$$�����e %�� b�uf!��Z%VNmis�9EB:V2�To #�8:�s�+crisCf�quoru�T:zX\�wŎ2HRO��3a�l'�_"�+R-��d�U �,J�&����Bpr.���2J��=�&+.4' -�y��s�. C�3ed2!N r�O^LU s+ٵ f1�� B��5E%&Aw5�J A��aR{.�%��og�(� �$mv; �'"�% i *�/') �6a�on)". �/E/E=pAC� aų ��a�!��!&�  �=*-_Q["!/),�;"� RO?+ -�5Eup�T *�^B�A|,A��enh�2dm^Mng e-�G�5see S2V�]bC�=Q?fi%Yi�F +0 u�Qt.���or PZ��se&1= Vmum5R� "�(t*Ka�6��-���Es��6���>M ځEJ1�Gdto�6�e�]�9ns<loo& & Z]eod�Ma.m�UA#a� �wh ac �AF-L.ini� . o� ��!�# rack��62 wir�%?emplo{D�u�ChameleN&�(2E�is cara G`G� lFTdeV!�� � of� is�[i�A'*g%e� Cre-�� rl�9Łz�>Lu�[56�`Sas5)GW�F�? I9 W}&f�dV�Ii !b ell-� e;TAT-C�'o� r�4 labeg�app�Iag�q .#!$' diss) {�>���M in stocha�2 n��ce�"�"�Q�mXl�D��6&K"6B%2~RTWIST1/2v lso refe� a s Dermo-;, a"�W�RRXz �!nHiFTan? �*�[57�B�8� sr#�%*gcytoplask!Y�cA�+popO0�%� ll�7� %���Ag��6 Wk� *N conf=f�eeidLŽ�4Y(Y %��(-����Kmi�Ʌ%�& G j��"c Ll6 r� �}��)�+epi ��C�ly co�n�,Cc,�&�25�[{; phys;� ch�to�DI] sheegS3� , S1"�^��d���K$1la�[,"t%%�m�su�"ic�K*a�*�&�P,"O&co�hn��!%!��&&�deeperW. N=sW!�randomE�un.g!�%)�=2h`" v�hlittl  �up  or�< A�ny)�depth�!�m� �D�^s,!:^*N%aw�AY(p�D\!{���Y[�&�GetJ ��%]�.6 � ac��ba~� x3� �F=�&S12�B��IGjY�s� i�J��*�? �f�A�o�,somew�E�&k@��S* ���S4mZ�?�,�5?VF�,-�. *u:r&e fewe�h–��,20��T!gu.�,6�2� `-M ��{ni��% e,0it du�%afa�kwHsp/*t[`�d���DQaa�DJ��a"�bA8!��a�$�$in � � Jy -l1 .AF��I:�p5#�a@�%-�5m!|o&� E;�܉�jB6a�a�m "� ells%Fly;�0. .rthemselY,8%~�redom'C;G� NY�#-A�l��JzrA�� rkab!�l�Cmig� sp60!7 straightn�c( KLce �"! m�-d��@a^ԅ,e�-T9��l)�Iyst2v/Fl�\��e=S13��I��=�A��JA) �}hgui\/ac�UA�A%�����s!+�pa2KNJ��"�!Bpe93!�Ub ’sJm-��C`!�j @�.��y�e3out� 3���Emo 1logT@es�� "D% low-J�)-e_-a�K �%e)���Zq! MacGqtFr� ���� es�#:�m{#ph�!u !|�O�SF1R �Q^=lEe s [6 /}3@2H�5m�57+� � %�d`%�A%F-�!�!6Kw iz�; o9!6�W� !pr9�,�figIc_re%� inad&enAl��%�jp&V ��33:h�A�ach� E�7U�A�e�,9�* %J=���Q� �5�C� "��!ձEV^UUN�&B/��lik1 s ��e�9�B�!hA�����^il�G"4M�a�to�sI*��&-8E_��d�p}!T �0T�9Es�^hi|u, duckt2 �emu"R�IpaSunc]j�s`.� 13aD-!3)veI)fl���al;�(�� w^L�sto�8 domebr�Scan f��An!Yty���GPqW 5*�Bi�/di6wTt [61]/-Qb" i�R�w�]&- ?* �l���%Ma m7[R; �M7�Tt�Rl�% m/eUfjXk� 2�TEl� A=���7@W�B*��DV_6H �ed.3t71�wav � ^%Q�Q�hG� h /B�NEWl14� P� - ,ɾ v�)nd ��� AS1�G1�#�"Q.6!�denEYby *��}�Ke9��i�3�(�%8mG*l N$50F�. R�\_ an.�]� 5�ٿ�D�g��s�v*1�it� �">.l��3���U���!J%�A5�� ultYW�$�P�C��3G�ze m�9XZ�T ������J�n�� �n �I*�<�%d�$)MUiChile:<4inamou ( Notho. t�"`0ria� a4it�!g:.ŜUI� mu [6L6�H�-mg+ �����8�0�^��..!�<�y;t�6CllC � bi�L!%P�]�#N!h���Q��X�8� �.��;17 �:YM}M o!�6�!� z�Wae �l� ?6_ )X {a�begine�^+ flankA,n7n� { prt vB/%�uO ��A`1�. S}L�|D+J�K&� i�G��� ���T� 9 !�a݅��8�inG-n�u�q�,%�M!=.|2 AR^>��&�%�>��]1��I%M�AebfN6Ujhi&,!�JF]e$Gcia�H7a; �Ar.�s"� .��:=. A� �*� bis�f=�>FD19�uj�� �2� , ho�t[n��� � X6]e��o �� �:8�U�)�ic6�Na=/A��!�[A��".,�*"?j0� e~&�(iR8:� eK-�� )�i2�1^A)�wu-u ���t:: T: |0�evo�j4>���p K��M�m.�s� ult�6�de��)!#_�bPC!2Y=�%p*0ip�(*�'.i� �4�6�\m*� ��<a�x�)?:�����G� tatu5� ��z-l��1�Q$il~ �sTAN#O>: _%d"U� o� dela�O�x �� $g.��)��>� m4C%N ig 8�1"eC.J>5- �!9� lD��� .�[!.�E�[�=*:,Ѿ-�� �7 !q.eB1Y>�q^M91�-#&r#8F�+In4 ier-41462�$v&#;D!���omyoto�l�]� Hamburger ilty"!S ( H�r21BD���e1�;immuno��!},phospho-HistLH3� er1�1���"�!VeZE��c�Sn]�-�vG�J >�9Q�B�pro4 �C�$ I2�D�in"�9.�MY�� a M5)�]�.)�eQ:Ձ ϩDq�e��%&qC.�e�u� roprtT����Qs!,ia&>�Ue�ri)-3! �2��&;,influ3:"� ac�~l�\gy41��5�#k� � y . A"U-�+or�;�]m/�+�I:ta�q6:/i&9 i���Js��[!Fo�,[2_b64�Ve �j�T�>o%6;-�u�UNC-�ter5E 0�� {�%or���s�Ial��3e*�e&�!� argu%�!���rgx'[65 , 6�o In mammal"F , Gl�F*|"pro|�dge�a �pJ�l ��9�n|!f� x$* ,l"�g�� <2�p��&;E�e 4%ra��M=^aYQCQ6 bq�I�� �.^!��#f-%H� ��pOu�.t w�l �,�1�� (�MIng!�*�GA/"z�*Jr��1Y�P��*c �s� } grKx?unrpd. -q�n�1�2ism�� :m�qPFj��9�<e�non� I{!�J��Bre�� a�Dm��wh1&.3 �/!N��scalecSNnt�JY2��Ni[29�%6�P*�( P�s&� �&oI=��� �q#*��:� !�+EAc�V)BV&r*,�� H %̡A*�U&# al.'}��v�]�ll��*g[�}�%��� J3feedb�'o�\�i/�&A�E��="e�_/Z�m��Q�6�-x����%��!|5 ~Ater�LA- rob�JN�[6�pM���e��%���6����9h�*�"Ie��j�I�C!�� 6&�1. M.Y��. tinu���92��bi�B��do/͐�� �,p"X'&�La+&�q!ollC( fibGhto 6�1 c[1�8�z�XA��#& �=�dg'�)A�1>��1i62)5"�"�0j q�63,S=�eak%�eph�Bfu��"� e su� �amp�uK suc!�fu8w crui$7R�����N��*��.� I� *�g%ռ:�� ���Si�,��k�p�K�+Ju1G).!"�$�a p&|A6E�en����:�*Z!ZF;as�^�-sI ngel�j h�i^#)���a~g!fi�@�9cc� gly [6�`y,.�$w�gn�. ruleoD possibl 8Dn( f�5`ic= ] �E= �5���$=~�m�i�A~ch2\�the;7ye�n�I�*1�lt\/�!x�,dsa�)g ~� ����� �u�� E2 �"i&�wa%dUmun��I?s| :�&&Q�G��6�&*A*i ? �acr�!�!�/ 4탡�)x�����k%1�&� �{���X���/{Qfunda}��CW�bi� u��,!�6}C��Vabka��thresholat徑�!c��$�He� On�!r@j �,*��� adhe z g6��roU 2 chond�5T�7 limb�a�[7�o`)ex�el��� � �n� �B�Jby��q!�9:[!�!"��5�-�!��`$O�1��'eZ%!L�v� peB�(��Z���meee%D  g&�j�X(�n-S��� k�92��0� Z{ ���� �� ^�cyo~:G.C,�mIV%�&� ; al �*� ���ur_�"�4��a)oA��7�r ��it���T�8"��y�>'!����KviIn3��� -��r*a row’E� >U(! ��ax %�&0}�g�3a` ���>KF���new�"�5"_ory~w�@%re�$� ens!y#�6elO?oofHwM�Z@aP?. Rep�2itex�2�)1� "�!&U�8�3!(o�,<�%be�e�+�a�d"�YCerT *�}to��.)C ]�rE�]Qz*q � "�mou#�m5'�e teeth,A�"�"�*jaw [71�D&�e -(l���oB �)bA6�6a)�Q�)A��A�s�  rAŏ$A�*�jHf���oE�[72� &�$�M2�HO.c ��T� a�<o!�j$9A�A�$icg{l�uan�.6a�.JJ@o�'gens [7r a���t��wB&���� ��493 ��u��F$j<g Z���I�!�u8fi�CeS%�a ent*0 dict%bw�kaҝ( �:GZ�w#U �9�z�i5 N'aX�vtZ"D � ��wkjiA <�)b��Spo"��A9�Q!�s&�7��h� jI�kn�n� �T!��'���EK[3�*%ZMs lizard [3�q�.�qI��� )&�h}Q�+G)�or�2M�!�ip!�����)�z" ~i"cas�|ti&�%f��o0�$ei:�p�F�,&�!��u r �quasi-1-.�T��Ira[! �mD�!�"+i+x�$6VU��:du�A V�"`�. �cor�;�a� J apa<!��$paB%���r< e� $)�we�n�t����4 &8@�j&�) �!� enef�**iUl7hapA���ero�.e�]�~ Zd &�W"8Ŧ �E�$�Dee!!*xM)e;��;�l��3�lu7�e58ͱQ#�u�b!�&UA��}?s�*'-"�1�:�X���(O�y ya�Y�}j�%s�s�*a�E�O%� o �gstfAi'�Rl��l��*� �S��$�7CS1=u!S"�).�'A��:Y2� . !C�d� ib�ui��#"oa"��rQ�g�8,�K.�1A�!��n> ��8D , �8�h� %he)e-L[-e��!�!ƍB smo m_(6 6"i J�չ�""�&� ,(sk0DVa=-AO�d?.se� �u���a,%��'�I�RN:2�.L���Aa�>'a�a�3)�M5�.�9:  Y!A�i��icB~!s�0�/to2�e�BA-fl�A comm�c�.A��(li#C�. Mod""&� %fߏla �r devT)#/typ�4��!u���2zg �[7!�R�*Q�%/a�/-��[e�R� ed�S��l�^�n^u))g/��s�pof 4] b0"�*: �ou ?d ' phylf � stud!&�cf�"�"�o/g� �U&��>ep�t�f2�<6ט� a 9��>[63� 7RIn0M�w"�a h@���~7_�pty�.F\`�*s���x x�� �$z� A6!������ Nm��^p � � �pase�tr�d�� wa_3%��v;�-�a�y:�l-�*� �ax$ܫ�F�!�� X' �Roslin I"��AWERBA�Un�� King%AH��O� !� Dekalb Wh�0�s��DHenry Stewart & Co=1 rfol�6UK ۙ#[un��R*�1Kwє. S"!egg�r�Xa��z9 ��"� Cal�,nia Davis Me�BHA�Facؔ , USAAD� ^ml��eF. T&s'c|<e� &�G("A-) ��X,*�F��F�: n�B�Ni�l �Research�( NAR�)@; Khaki Campbell/�<an ru:D ^{a� B lier�ef,( Struthio c�Hu�Y!K� H( Dromaius novaehol��iae )m�l`�4by Woodbine Fa� n3rthampt�Jr�E:.N�3 .�|3�3Q�+z"&M�,Hancock Wild�U Fo�el( S=�ACanad�3r�9�:1iU:�$�U�?t 3�m 8°C�J&oY�|muL� 9�OhorizDQvZ4Q�Med 90°��t+until�Z�m�. E��/6� 1+m`sco��"&d+zHah+FQ�[7��,(�val833A [7�'Do&��u��%�a� skulHT�%0mpr&�)�*J �"(,gaKa femo� /��E&�I�Q9��"=J2� PBSbaf��o�6nit��D f6�( M6pG7For�i1"lH!�]�sub��خ2 md��� u�& DMEMiLe ͙ 2% F �1% penic�n-�`ptomyciny_r6= XE�Ao , 5% CO2 �^1�&hum��9���"Ŝ��5ޟ/ !�/7a�tei�@��%sR&D S��Zc=�9 ��o6w�� mmerTH�UWHE ha/r.� Lect�=���'x�M�'B �*targek� ETV5Ah� . F"��, !'�v, Aprily!$&�q%�scrl[5&�q. SAges�H3ܯ,( Sigma-Aldr�u&���emM&��4( Axon Biochem2Đ:BX�M. [hydJ->�� at E��5 �A�to TRI� �F�imA�(!(L 0lI�mSd�s2!�4 W1 mouna+-V� (:�\d `�G -flo��tane� zqG . Cu\*��%�s"��U�*.�!]� �*�e*tanbsega��8 1 mm�kiex9 njri4���<aO�Wt ��� connec8 a���. D"LO-� ��� 6�1�_*�6P�ks�J� E�UF!G�J D�p6�? P M��R-�WDs�16gap%�-�)�2MLg��c0s�27E�tO"%� �* �A cut�Dd&�peri@f%s2�V��“2� ” F�� � (�e7tou�2 ��+s�Q� 9� N� {�ee&^{!� ��)�'�$� QZt c-�!�.iX1-W�.e �d,La dr��48Z�i�.�,. Affi-Gel Bnn �J(�?-Ra�(ewas�zwi�P3 10VC2� ��":&5�0&�q �=� (of BSA dilu��inl�/ni_at@ . Bead-"�9&_RZ� du�m�j�,��*ideu A�)*�)�� �^%9E-|d �a/Jjf�po>9�*�� J�a!�q�"Lpapp.����-loadA�%Kdfrņ-6�s,��U����w;I � %�%9Z�A<��9q�6-w�do *�O 5K� al-�p�Oa��Qor�=9�Zeiss Le!C�OV!r/D�g;�wf�3MQ}!�!�duA#A�e"H4M�"�R �Zena�2012 ( � ) so}m�A0Ikk < !7 , 78�"misco(t�\k��fsh�&�T�D��!�n )(mn�RC(8 n`�BO|'�a�n�.�!c�^unR �Mat���p"� inlab�&�4global��Ui�� -to-nolu�I�5ro���dS32 ×pixelj)��9�I�c�C���0�,�a� ( ��)1�mr &6J5i�:�l~'e;_8�S!xan*t"Gp�" eh�e�m.2�u�`6��%�&�YE6B�~��D^Z . �XRE ( 6Y 5�;2#���.J/ d–��� F �,V#aamo�blEFU�v3&�aKi�6��W.Hp�!�t05�c�F�� ��upY�E���a���N�6�2/��of��a�.�b�!���X ! R�pm��Medc4�ce�=y�P&Y�"�U�Z�i�!��9SM7�oe5��. I��A�[ akenm@15"Va�9�b!"tdj6�[5nel� Dataq M3��.V�L�_.�u/-o1B�bi�QBrown� t on ) �IMARISW . Au�=t%�CM!|>tFij�t| - diam��-'e���!�=*sl� !� F� (��. � � ��)!���� j�� Xto 8-bit . Salt-and-pep�X�z��web�/d!�� ( 3-�wkerne_u.�O-<5WK9z�B�%L�'E��)cei�a #{%3%�Ef�%( f�(7�X7��m�;om+)�sa�.a�o%.fi� TrackM�'B�1c�4�sMrNA�!��aH� )�"h,[l+�)�������zp,�uHfng{I ^�C(po�.� me�|�!&)Asi*Vo����Xa"V�E�b"��>*�G2�26~��*VUw6Neum� ��,�&Y �m!M� )��oo�Xe�=)r������J�!axc-!=�Z-&S��!*T e%��h�uaK<[��e>|\ICA!`-002a`� 6� crop�r!"q�AF*/I6nn%��&y;r/�!O!(( 225-μm-w ܉%�؝�,A2��wPw�#a�de���V?1ow"�# �! �P2�=2� +O)ns !s}9RR 2�#Gѯ6 od (.�3%x%NN�B�l��enō !� 0 Th~� ��0�sa� �[��e��#!i � !1�F�!Z�62/I. ��A���3�T������a;i(`5 z�$sE52 �W V e��+�Hb�J��on HH29-*F$.b*�- &J in 2X mag�4u�>$d calcium-L u!n2� C�25% EDTA�  2*�t 3��yq4m�!2�eTa1q�'i �? 1)A��M ���7 sM�P2S t�*� �e�i�@�nYJ&�"% F � * "h ��f� ��f� I�V=�ha m�eA�6�2Mz�!dr1y". EwYHhx�E�windo!�si� venoE�inja% 2" g�A�or"xY�c & � <<, 5apI!�:ϡn.h&� Ag�Z�q� �e�.;( �w *=2P/AR"Pmpipz{i�i���'ɡ!!a.. Glass� c܎�g%de%G�)pA\HQ]ly �e9s��E�vit\�+ino '(Femto-Jet4i �)�o�! �s��z��-!lG��M L2fix�5��4%(a�-aldehyde�|F�NA�� ��I�P( lder-UP ≥��aonAu�n �!p%�"H� at E�A�.<��uog�in��%�M�! e�����3A��3o�E%�,2(mh�in 1:1*/v1! 7:chloro!2O mк� <�}'�"�q�d�3�iar�n��"� � 9 !`8�s�#� M;��_)���\ 5F. H� o-��c+��Jn^ f� ]��>�,�ed�15%�'rose/%� % ge�Y8C��12 M so���Ku buB[�[ cryoe!$2��!�G LAU� byhA�!br% (�6)�Y2QA�!� �TAe� DAPI" AgroL7G�<�f0�re+4Life Technologq)%�� "d�vet "�*_� LSM ��z�. SQ3E�dewd1in xyl�R] w�8c R$aT� � �$gen retrie���' Bio- er200LG��-�or cita�>�y� TBSTd��q.!� P�Aaob�et @���� room�:erG�"�!��]y�a�in&l!�7( GenTex!� t 1/�nn�N=�S��U:y.PJ�z2. -<��biotiny� ��ti-rab#&�0� �J�)%U��vatFY>���:�Aa ��JF!�1f�$HRP-conjug� �� avid��%6�o@EJ|B�q�in DABy%.�_c;n�e�w�e`LeHmF�*� .M-\���cl�e! Ci�܅rhaeY3xyl����A"in�!o:�$G� ���e5lscauY(( NanoZoome�c Hamamatsu�Q2M,8y�fa.Rn�, Tryam{E� �3�~���& q5-b��-4-E -3>oly�HV ate/�E�tetrazolU$( BCIP/NBT��r0��= f䱭��0PV.�Na��3v�.!�9iY8 F ea� m��.�x�@%Oe q�2_!B%��s  �>��(s�4)�"�b C ( $d���9(?*"w�AlA�Jb �&9g��^!m���� z+my%>"ŏ�N?1� ,T*9�u�m��55�/�}vr�� �9 �  ,"*B!i:"1>Qd= QR��XEE-A�)�$"�#e*M�K,iA�� to%m × 4��T�u%w� �u 100�'; �%q�*�Br>Q#�%8�@!6�be\f�!��2�\ �1�%Vr��J� V ��h=��Mfs%��Ul ݅ץ;�%group/I 4�. M�$��2�>��M`E�&W on&�.o%�%�-E"5��:Esub�t1a�>��e�Ŏ; U �.Z �m2?--M s�Cby c��o�&��j  � � ��Z�%�%a(5��T���u��GQ:ֆ=��<a"SD�i� � .p7 6o�C��)N�.����vaB�E�M�out� �d�� n a g�r�Ssk>rjOa 1E�&�Kw�"ra]��%G � 8��![ .��M(6��c*��S�rE�"� �umEeLT7�� sp����(t�;a���S"l ud db%I�>@���$�a)*�� �.C_jf!Ft&B ��jp*�;=��UFQ� d�isa�f�wy���#�l�0�?ha��P5@|�s�=g-#C=�8ed��Y)1Lh�B{Ser��k2nA6 ?Xanomal��mFin�Kte�r� cee�lyf� )7&�I�>Ut�_EF8h artefa(6�V�!�w"o�r@9M5 =A �I�*?E�Pn+Ay�c>;�Oel��e"E#96 o!Ϣ1>�c � �a�+�t�%��autonsly! �� egar!}�i�f n�sL�gh"�ǥ=T�G2D' ig�r��7Be�� :�i Ba ���A�ligU�5( nonsquAC) g��, �lac��w�WPB:��(�f�7n�t �� si�5c�aI ge��D!�:rP�Mawa��:u illu�o�E:varia\u�B. N�=�<�K�a�aɹ=-%>t�[T m�:&L�!!"p. E14 H� chi==_�>+�< .� �� a8filmX /r off ga0= �T sciss�v:c2]!2��30 o�D.� !��\���j�%UjG���is2_(>)8k2e tran7:) �FNm;�S��'pt III R� se �@a�A�( Inv�<Jg�aG�Q&d!l . cDN O�/�4 10-f�, 3 �$.d��/��"�u!xe�&�8 -�a�.e2SYBR F|Un�.� Ma�UMix ("��#Z�I^y�eaJrip�3�Aea`-�( I ��*�gmF�n�5. �� curvܽ�;�0�ai�m�N�E� 7=پQP��rOr ces:T�TF: 5′-GCCGACTTCAAAAGT-3′ (R(DTAGGGGTTAACGGGATCG (�=O-e�=�ls"�b��ao�rin ��Wviron����Ms�?2 rviv�In�4�R4World Health O�jizf a����Fi�in*�cetjnC o� [ ie� guid� abR+�Tfluid�Qin�i� ��T�`;6?isk�?h�A�W` F/=�$I:1�Zeߪpubk��'j��a/LOf�] ovir��zody���nioZ��s=FST�g �rltsc��ed ��i*U�) fi vt�2 ai� ��}- K %�j�Oigh8P ihoou,a���1=azx ( vi�-�� Elig�bC�� Mar�p4u9% MARVz RAVVm nd ZaS, Suda� TaïQ  B � bugy؎ecs zSe. CD�� �Wlabk�orKX�4(!P" #tiWL)*�������Q�3c�t� clin�F �N�&l=A�A�!�9cA�M!fl�X�f i�DK &k!summariz��arP %�. 6831A7qu�tiYtf���azI��^� st�P o1�V� Y��Q�ad/ 02�a���raw"onF�c,�A) �"^al�!�Ugj!,��A�ly� le�=}��>1�+ �<��u��l&��# � �e)uB�' assar�F=s 2 6�agav\b�OUsm�� mes! o��t�6n. Fu��r��� %tty!i#X�rut�Y ?v#<�iy r>L�&ix'-��X /s�P!zon-bl�#,�-�e d��&�Tb"^� "^E�o:g~I"q�us ��. N��QesD itsA�Za`T�� �+�r��Q9 ��3-E�ill��N��>m�%�a�� sle�5ec�W)}����sa�-am� s� h2OC�Jcti�)B! "�.�X��GA�maj�,skEf!q 2��k e]a"�aal-�0s . 6G����A��l in W�Af��E����`�'Ud��ou�,� U<5 7W�H���*�4��� �"�j�2�. IEg�_SL ccepa%e� F s a zoono!9Qj�^xJ����rvou�mbYbats [1U2�wM {bN&��3xqZG , 21?!��4*�&� R��k`! comm�SQ2s�a"�^a.`!:A�ta�g�)[�Ue�>M3&T 5�&�e!�!j��b�/�d{%ޤ�l�San"^ �_^%��,��ex���,A ,L� ���e� advicnd &�>F�cm�l�Sviel1, F�m�Z�x�bs%0.)LAyQPnow-�V6T� IY�!c�L�d:�-�!�:& Ym�ٯA�0���r0H%�?�� s of an i�Rnfected individual [4] . However uncertainties remain about which body fluids are iS�ious and when they pose a risk [5dHIn order to address+$se concern� World Health Organization released a set of “Qx4As” on sanit /Vduringl` 2013–15 outbreak [6] , �also sta!$ that4lre was insufficient evidence�,give definit guida.2�Tundertake an adequate %assessmY(, knowledge�the preslof viru� var%xbo9�\is essential . We report!�Tapid systematic reviewWHavailable published�o%�2� filo�e�.� of iEed peopl�ld survivors . Medline , ScopM=Tgrey literature ( S1 T�) w!�searc�8through 23 July!�5 with%#str!� �@* . af . OR ebola>vi$(OR Marburg-� *,Zout re[cA�s for d!�Por language . The aimE58to find primary/aIYsugges!"8high likelihood!>acAJly-G%� �in human2p((or polymera�chai�B![Hon/RT-PCR tests ) ,.q�d bR mpat%F,clinical hisnwAhsubsequa�posa�ityEMwE�tibod!Uor� lamm � facte Post-dis�� markerBRE�!Adee�e1�by!�mselves!co%  c1:Z , be a�a��idesprea�N8 regional popul�M , in!�aX in mAFm�%no�� vantF1[7�t1�Com��ar!D, editorials , new�t�� protocols!=�er����F3W��ok it as���aA�y !�!�ill �9� should ha�� tect�yuwbla�e� refoestu%�w� only�osingleEb�7ult�F F�: each��Jid%��c�Va��( A�’ dae� illn�@EinQ:6y Lade,our obje�V,s of describ!�vi�;load cha� o tim�� �e �6�5 non- �product�:LSimilarly , articles-+ɕ�B� dupl%d elsewh��aI��!TitV��abstra{)screened%m2sDcr�`iaa:a1�� erHverifi�a second". W�:nun�@,%*paper�E��{ , full text i��t� ��at �A1��th% keywords:�I���Sal , � ,!�al)�, �)eme��8saliva , plasmaAy)��cl)$����s�.�5�%4 deci%_difm�s�allO g!�!�resolv)\discus6. AU 'groupeN re�qXedaEA�sam��W,��ens:q8reay�%A;��^We&Qsel �a�furthA�� ��toeU� � ques�h. DataI�exE�A��yE�!��7byAa�(Kond^� r!���at��s�̡#����8 . Details�!m@: bibliographic d &EI*,�)� placE�"D ,2��Ved��umberAP�+ � sampa�byW llow��ѻ onse��dA� ay method�cXA PRISMA checklist [12] pro� S2"F 0. Study valid�� ( S3 � ��il� A��� reli�-j @�O���`� &� ��=�� . V�6Y?!� intenA)toI ����s.�+appropri�1!V �%~� � me�)u1� or c�re�+contr�s,O C-�qhandled (ed correctl�a!'a� sh| period b�7A!�$( < 2 week��t@duS h ũ� degra-�� efon��us�centr)�iѷ�is5��Q�form . P5�r��eof [in��.� I+!�Vaco��f ei�95%�f4!�rv��u. just� multi8 …A!��i�@ ach9%�weigh�  inverE @Fw [at�6 : To!0v* a large8!��� ults = a sm��\ �s skee�{prediprobabilA�of1., d�� �� uAj�t es�E�% one�� carr��!\�0 . 1��u����;V exi� ��ano�K-��h� tter 5� .b1Azconstruce12.:di�buErA�Q�assoc�a�J}(a? a Poisson6No calc ed u�� Stats Dia� 3���g� /i. Six. g6 &J /�F�as CT��ues [19�48��339)! "| [�18]P �tissue-�� us dz( TCID50�-A 1978 ��3uni!H20 y%�QW�Q�in cop�� ml [15�6��)�Plaque-�e�� d( PFUq`o5s[1�T` ��a mixAtY� ( �,"� NAAT� so( � s6�A�"du�by%w� E2u �eg . ,=�by���ce/ab�^a� [19]%� Somev 1�!8purL�< auth5co��E$heir obserW metrics0uch6p)d��)u_� (�M5, [Aki Standardi�� Qto��� mea{ � T!¡�lo. M��yw iby�K7%�ad�T ��A-[46I� 2 cur�ųyStoXha� been�W �z��, ��trans� ngAp��B���to ��!6sX l�y�forwar[ V"V} of�u V!�in impr8e .� s [bar�r�{sc�&plo1�"ipak�6 iuCN�AP�I[�� � mat�*4 �ally )��y��eMq�As�   , most_ �a�w` inexac) lack^�a1��equival� betw%�� $ p�]�s{ �st���U�9sjA� ably� �*���yAr v ��[. Fig 2uws`�dor) ��or �"-Eȑ��left sid� nelor�Y( rAt �i�eM�i�j^��Bot against� spon�:g� limi� ��( LoDA!�bottom���� char!�w �m�it� �a�1 . It����Z�� � true�˙( P!-$ d ) may b!���A�1flA�ul�≥cy��it has�L argu(A�uasympto!�c EBOV�� ales� ��2� �d36d.�� �#dGin�p&��u�V��7]E�aG showh I��cDe u����B)]overalUe�7 z145eJ �djf m��p&��� I6A��u� day� *� ( w Ad≤!���a�l��t.; �pC29.C, C!��oa(atU3[. W���vi!QT � 9reshol�3�Y � A � �r��among~+w��be �0ɨ. � ���*&�]� .wb��� of�� r� >� R 43'�� [13�!(�.� �5�or!=�" �^ illu�D�inA�s �!`�����ng��B%r( Z!�113MOB; Q;�E�paren�is 6��L typ?d�:� :!2U�wh,k�AI&0- Bs�Q��!mea�"!M-6"( i�a�cross:X A�Zq!\�e& �as �s both�P%�� \!:W�s�� uish�� 2�(!� 3 )!�& 4OR�?�o�!e7` ll eaE1] F��<17!�1�J�� lle�:@A[>16z@�ys 16/17�a� erH"6typ%L iA� point)wveA��toan�*ce� ��="*m�o= ��vCsti� aemi�:r !2���1V!�raMm��d��2-{2;��re %� Rof ��763�o�{� NJ��ur>AA��deathy.� �occurAu�6�<[4D 48];Eܭ�^�i�����-B�[23�O�;}�1d����M�I�a!ag$f�^&z ?9�tha��� XC Ya�����(x� !*crepancy�L�s͞a�six"��" *2q�by �8|= �[1�1al�a��40!.R9 � �>c oj���  uRi�agr n�� %5%9&*iZal� 506# �AdV^$!�.�6/%stmilk5�?h�tE! oo(�#e�{�%��?�b&~vB#� semi� %E#j�^nt��6,:a�P"� "z215 �\�k1�:T28%%-1.Z/73%ax6�q%26U\by 18��:�Aʁ�A�9�I� (A6p)%�203� b$)�n~��a" &!�11��202�V204696=Ղ��'&�� .X6�ofiz"(&at 69�}70��p-#��mZaKP6S e� �e4�t��� .r7�E5 )i;����`6e2� b)�� 1� lead�XKL(&!uE�E�S�is unus�)B e^ h�j�  50yg(�a@N�� mon�#� ���ich��e(JFI�:W. !�i�)y �Yfai�"�~, fall�~ modesl�55%As 45% -��)��*A .�&fic�!���%FlyE�9Cor*�1�. F![!Bu&&R ],7 seema6z�'C���neg�%b� ( <t is m�:1D e>���F} nsta{ very lowS���K"("8s = 36–40+ ) /5������ [�29a��stom�q%l swab�s*\S� AH>M Kreu%, l [25]�}#A� r@re�v��@w�r<( maximum log 10@105 . 5 /ml: [��H�)y2� foun"l��[r�lowes*�= 2�:��$–106 . 32��V���i�!�)��of�5� s 9g6U �Mf8] . ItA�EYhar}�F,toA�p$y up-to-��-oonm��"q". Our #�(c�� &�,Fn" 22,.`i�*desir�, h/T$$wait until�$�>��� 2014p,015 epidemic��� /s@.��in&�nee���+ elp manag�e n3&=T*�bia�,ow�7 �#col�$. S?ys� � ^&�regardU �0" Arig� ���$oss,++ lae ��Ir1*%;���dL �onYsZa�re��)v�� U��&�$=%*��2rcC&%�a����Ytre�ha��&urc�.a�8ern ) hospitalsY s&� �m%&� �i���t� ���in Afric�. �/reasonE�% ssumv9bfn�5are��%��$y���#!�rocD0�%a8,�#:�inc&�#indF :�&Y2�%'�:M Q�6�exhibi���1�%n��c$e=$���Ł�1e!=e�K i stopd>re�V$ed quickly�F";A ��%!��be}�Lt�A�rely>eo*� T�a�!�-�M7 ruit s�� elev !����"8of� ea�sA`9 W Fu�(�i� �wH��I""2 I�� !�.���)�� si<false�oy���lh tradict�/�"�E�e��:� on!�/qS(. �%*v�� A0 de�*4ty��Hp't" !�m 5� �0Idecla�2LEDe� !F.+ "q"'����& �^�#!zy �)( FH m)�e�,�excep���5,}&�-,15MZ�y���a�u�1neg(�Qso]p *�! 5. N�the��F �appI���*� C�c96,!� ��,%9l-�+/ A"7�2ont�e@�" -stai=.�i�maj� 7A0�>0mi - SXQvolta��rk+ neur�1�ie�J �"1(:$cale dynam !� arisME�� d membranew�/ aSN � sii��>�� sA�By%e<=>5Y,�){!H� �# upS#!� down spiH:dap �7�)exE(�B eoco�0�50yramidal cell%*��al�^� vitro%&m)Iu�!e&8ik0#a<lo�7�)- ��XYnd1 � �:�+A�K:�*We"M�B�%!Pr�!Ato noisWd oscilln7 inpu!��T=)pgenerL �llpy$)edT&��!!�5vzz devi�eG<^T�� �!tref� iH�Qaccum�+in;sic�>��:+�lz�M�Ɇ!ex� �tiZ�. !a6�R perų of aF.K �s�>re����capaci ��t=d>e�e:A�d2Pq��[1]–[�? e+�Xofo y%a��w[4_6]�|���eA%ona��v2���[7SJ9�����?*)2 ��,SiT}��!6 spany he�'l� % �ofMal&\[16`�+" e���ltoa1����mework�+y *���6nd!ir"R���5flIm ompu�\�/I{ �& I <classo 6�BT�u� evol�/m\Q�is Y[21s"[22/aZ6Vͯ��:�9dependc!ly vR9ͪimmed�r� vl>Hstep +I+1C���~.�co�9ng�M�A9uce�s doeoa�5f�� E�An7)3I6! Inst�<,Œ �c����ӕ`1@�)hundre!5f milli�9!�!x�� � [2i�3>=^� /�/� IBM� [3i�34]!��?F�� �� Altho�A�&z ��gra�reas {&as��di!�e��2u �A#35 �C�*t�  idCu�&du���i�e;@<.q�� �V�"� m�8� ga���& �& �& �& & \%� � �g parametJA-�" O<.� ,2[�a=�5�..� ^%�" oa�� � b� -frKB�"�� &� � A��},>� [P3fas� �� %yer IV��rat ba� �Dtex [4�"F23+��?��%��kfi�d �"@  �e"> �F� in l�V �)� �X�� �� O,&�5�FD�&b:�&�'�� .� œ b��� �� � �`f,8!�}�z� ac1"E��Bir� �u;0nɍ ( 2x#c* ,"p pote�I�d*%he�;(�d)a���<�՚c�Fofa�h�u )i f7<�8c�� �B� J�r�+�* (Ia�%\1>i�t� w k.�H�o(,pS . � �%tbFi� P��� ��K�/T1 6 ee M3@� � |).=b�2 [%Eq�;)a� X!AOdYCaputo�9VW(�(Byfek l&��'!� abov2��( ��(u�1 L1 scheme'6,��x�(UV���.��9, (�)w , M?&@ b T V.�!a�C"�1we^ } 2L m!�BP mbin�&.�Eq&1}�5�4D/E3t RAj�&� �px�O(g toE�we ob� (�% �1!���  termR��g�I funLaP(&�!iM3-� � ce &7 )J R"-�$&b&�2 .b"�i�>?� ! O8 �=#5 ��>9 29 ) : (:()!M%� coun !�z�#w Y&\�J6&rFd�%��R( =�bt.� ��"�Ce��'�� '6o�Bai�&`!wll}p�G'< >�m�T �l+'�,�l0.m�ns��'lemQ � expaO6 matr�;v�?aC��%# taPi�G r1& F��I-4Toolbo� )��}�p0in1Nu"sFtwo�a�is� ;"�?[�I+ is s�Jonats)G�*3&'a�~�n�@m$-9�o!�er�", mai� J I���Q)m�((� nh"�eYm� ��.e~ n�decz0Y1�?���uL��!6�A�+�to^�or�ilee�V�AQ�b*��U'YbuN; n� Oq`1OA@,b��alw�*� sig' @6��. �6B appl�7cur4 N' �s�"�  78. 7^Q ^&T%� �(!��"�(GB�&r! f#-a< �j ,�omA}R. A�,�0escap�<�*reeK*g ��"�6L.G�"�}& ��C�As op�?#�^f5 !$� �mYn&�sI�"}�r,Y;n[L;u�] t�#P�i�ISI��;�FM|��-CBF�%R= �V2O is 0eKe�R��C�!� * [�"t "r =�6�dfh!z�?�inn�� �"M! ~++ ,!�t�%8,%�=#�E%UEF�5J:AKe��7byE_a>ru- k6�XX*�)!�6")�o�� i� t� 8 �����=6*� [ coe"gY�y �f7U%�� ��� �1W�Zbe ��0�q!�� gr�@rYl7it ma�`2w" �H�� 5Tstr�'Ge�-Vc "�  �ed>��> �aite:�2:-v���%��A�-�=~5.k8"u�EL �X h�E�&�&�A�a(Y�M�1��A�-~?d2� n)"+pB�xaqZ� �E R��'Q)�� be8<araQOlos%F12--5M{%Y5�>Ghe>(do�6t)5}|.0&�"%�JM^6��Ds!j"'��bRa� s��TE"{5�x.�@Nu�O�D��v.�i&w�*aPōu2q�6\Uis zeroU�-)&mo7*�>���.��.T"���#U 4!�,tada5� ^ pola�&%H��&Un�Ti$%�%�2�k�>DQ{#�}mo�#��d�i1�APQ[�9iZf�" k'M�e�Z-&�*1{Z�Q�\&M^s����.w"mA&%  >�&[7�!.IXAu��6�Langlah4. [74]�n� �]B� �suN�mN�c\"�at�?j�L d2� ta�J�0�*y�$!�us wip�+{^U2B(& .�"a9!�ap��"��OK dela�GwO�%�?b �3%+Et�I >e�g�<�MQo9 �3B�rep"|E� i,we> Fp>G ��ɿg�1l[�9O6[1��$Y��i�irAc�16%��,!KJ2�a&BB� FG� C–x ���8Q�e�5 �� n��cap `Uń $A9\ '0�K%�e.r,*}/ pB�{Az8 ^�~��L-s,� at�# %��A-":.H#5&B~�Mu&�Ve� @U.�#�\i�#by!Bif|)!bb*�2R!�*� -h ��-HL4*]"m�uyE�3a&"2�)F/T:��*�l�\s�j�M� �;iolog�$ � ���.I��N�,[3�F�( , [7j%8l" exam�V,.>>&.�"� ��e v�Fb�1-o�@ ��"s8�R 0'0ng�s�;on�n�9[�R , [8�P� �.�Ea�.K*�r(alA�p�>,T4J�9!OHB �]X)E�en�\u�.U (.x%-f>A� i6� Y�Ucll! .��>L %6S��=t>7ic�il� �b',of Pozzorini�q59!�a�# 1ir 3�K /scriba.e sumW!�1e-trigge�5��a A&&�� "� 6�  &!�&��N -Wlub���T�:"���9rF�6B��un1L mathRRt(fr"�(�H�*�L�a2� Q�!#�J���:I2�6^tx�Z��hipN�P!�.r!�:"�'.�? ,i*�exi�5 chni]Y biophyseۑ�ɷR�m�r��n��i2Jme�bis�6)Z]I���j)� ��J2WAot�um-5U�~i�+�`$E�.�)�L�"F# amo���#$��vD3I 7��݈�fAa��,?j|E."h�ViJ=^m�sEa\4lc!-1��-hyper{ i�;x,!k sod=!�n�2 G�5�s [84��[8(�A�bi�-�a�oUz�� z� �D �[5 �XS�Wq5�4!C2M� ��pr"t/2in2��.N�0Hodgkin-HuxleG e/g%t%� %�-V�A�  D�' �&2 [�jG�1l$6zS� �!�ݪ ( GLIF- )b!�2.|y�pl* .��c�ji�S���Bk= �Yb6�"����b�!�| ad^%b�& y^�ADd���Br�Y.�Y�!�(*be�_a��e��{I�in7-�i.`[�.A,�],I]� �,[8"_ B`!�sk diEl ���� B*�JJ&� V-J�F8.*9dv k�q"�%�u2 EF�. E*�6� =?�Q͢�f%as� ra5%V�6�ύI Dfi�ihse� �DaIv'. FN i�=c�}5 �}2j~ZX�!0=@h�8&� 6)�!?%4��"�S-!�8@* q"��� �m�.6�c�" Lif!�?H��s�Eep AAW !imidt��(an�T�qMa�, �o�magnitud%zoL6%#s� feaYD� )�.�Q�� bea�)[A105e� 2%�aI) 6��t�T,U��9r P1a�9WBSJ1�5�Ac"=oH � !�0�p/$Mb� �&t PurkinjeU Lob�YX� ,s III – V �-r2'B%[7�5TI���!E9�*m map%)�l���) ^E�)%6 1'�s��!h braig%P�%p ���4*!�y'� c���+iV8�A] oA�2�<�i� 2&rk y�!m�E��Bv3" �P v�<Z "9s2\-��A/m[Aa�.�l1!.3r�l`S�Pm`;at%��S�]�D!d"�+m9 ��8��2 :��A.��,er �qA1�V�Dpo#>���� s'f�\s�5?.>� e�% tr2u`,��qu�>e�cor�w����W::� �45 o�K��� ��e*~organ�x ir�8a��*!�t�_debSH[88� Myu)w�7oS#J�* *C!�)K a�2�(IAp "�<:��%���%/!? �a~!�Rl�b�tp�@t$v�>>'5�Xn^t1wT%���%�Yu�:C:�),(L�N�!�c�Mpi�ta6!���� high�S ?!�">��iL�M�8�zUF. c�!�"�Lpe�l��$5yyH[J� ryGHx�  �>signa 7nIN�@eZ"WAū�caf�\3ck!a:��Jna *�4ӁZuLyD�x homo�!ousi:�*a [7��Q:;C:.a�0e1.Az� )� he ba AZ�o� R�;)!9� !hm�}O�MA rAC� 2� � 8Qco�My@�":+a�rF�+}J�%��P"�+Q�&v softwA�@package MATLAB [9�5a�C�&be5 �u�`(t www . uts`L$edu/Santam :LabM;"� A�r� � �fixR�qr�D� in TeF1I$j�+2�+M\@ e� �Mre�Ic�FaIF�!�*/�#T+ we��.}�\� to Matl%hx2ran2 var� !���, jT�e[� Z!wjt� 12!�kWe minimMm_squ�qerrFe.�ataJ!�-�1im�&�s& m"�!?^C_s���ar�-��um �Ac�;��� it�geR�PuntW� n 5%A9e�m":Bg��-s25 �C1�2KvHz!a��mo E��y��, � �"�J+0@tok)J n 10�.oW�e impe��`,Tj�q2�t5�V)��C��, I6� , R:.CXa� �ab�* �=�Ga0: Fouri!� rans�E%��ph{6as [5"�.���9.�Q�BrE�#a�a� nA5"@Gauss�Iwh'� gs8$ma&Aw� (+�8��*aw03V)�stochas�")\(�kA5�F�"lph*�(E#"�"�4�m �� ��rr4A��-�|�!F+l�T Ep#GA�Jh �i�+iIi�)3�f7>�Y�e�]� ZA 6� to 6�iy�*:a�~�:EJW� d� f� �"�}1FMF�%��Nal/(a�$!�.Ab �". Ba�lR�q�4 {is�9q�61. E~�Aj1�� onve�'toa��( �-�"K6�B�� o��tDh"o:�81>y2Y�:" ��n-La �v(�"� ee [�D%&>"���is =by�7<2�(Mittag-Leff�_"� WA*a�:/�> �d�?�4 �� &J?��!�!!� � �:?sub&#b�--:Uo1"�w,1=xnewE�. D`g�3S!u�(�^X�K�s�vs"�7}c��%w ų..Vl �`�R +��3]`wip��uT /Ue�H&l+�wxXs%aA�I� �ee �Ar"m$ VE�@q�8�P �}E�3=1�4��y���Z+:I %ur!v�2eud�Hw 46)�1�p*�E� �^�r4@x��ly�?%��Q5A� 4�,I�� . Le�gE%�B��{P"$6E�\nd&8!�sa iven�g( 1 >U�aOCcoccidio�!tdef�(itself"u��\!oxygenec8 ROS "b!�h^tn*B3hT!����His� A��ga�T nU@ace�sBvp�B�ex�>e,,:.*�-�%F ox��t enzy*;, supeA�de�&mu�j�SODSv�0�=M,��:=f9<l+iso s en��3B�gen�#.+ *X���!��� 6�`iso1!�phylo>��4�:�)OY.�sp�O(9� , PSS}PS� Pb01�&) v �ve�[��s�=� a���J�3!B�of ye�A)�, myc � � -�oe�he F" - g"T,pwel uss`biA%�E�a:ZT�����@�phagocB �%�"�,aw'Z�6res%�!z bSOD�D 3d��m�\xpo�A�R���A�7�� �S_roteink:n(s�1��b^Z�}c_aaAVri-$)a�-pathAu2�.�p�2�knock�6��JQsekm invo�5 .h!�fungus���>U:;69Ustr�|Wz n;,�)�]].��AA�!F �d�A�hge�:E5 �$"ofJj!�2�!%:3.is lin|_�,onox^Au�4llC/���K1gs��+!q�C.:�|r��V-f.��ZL �� at P .xsilien!aG*)fd�A!�J[endAJo*Mh metabolisQc�qe=�bu�!�mmu�^�U.du"�4�!�of����. Dimorފ� [M�I�e�)6~��q�/e�I%�e sofS��t.yan�( O�"�($, hydroxyl1: ( . OH�H� �y��( H2OO,��rv�}� n-�Ai!��5���-!.��re�w is.8#V��altD}3on&�r1/yj$on�}�|� urso]Xb�%.[�V�F!K�!E *ly �6-�mi�ondԏtby-|*�aerobi��eDA�i [3];nq>!�n]!��#:ROS/RN�ca�& r) ��I�M� ��msZ%f:g(" �u"�%��!�� Q�nS2)O�"r "�(u��’s m?�%aiH�9"� oqoJ��dWAt  �f)B��!�-�|em\Uharmfula�K _dai�l �,�/� �!A ,�5lng!��-��sB\�l�(�} tA��"�, lip��nd DNY m L�go x�v[�&�E��ow>!� �A�k}�0eQ mRi-_G6B�a� ular� �w�m9Ɂ�G[�� have { 6�life-ss[rG8m&RJLw!ica-$al eukaryo�[�me�Up ��2 d�rrole/I�!p!qU�� �] 8@RbU�-�.� a��5rato� �E/�%:& moleg60ge" $l�!A�%0!i�0e6�^/R� R2 �,(6V� 7[��E@be�$��(B� gen����$:#�`t"� m�E�pr GROS-damac)��| F=͘� $ �!J0 tala\ �n!\�WdiFF . A"�-��x���cY���;Ayo%�in "�supB@Ŕ!8p�7.Xe pent!^p�mhatvcta%��Lthi�loxi!E d gl""hi�redox-O�� , 1V8WoЎA<.8iF�)�B��et&�9� ��ar*zomycoQ ( PCM��0i�a ed h��?ateeAh�I�a @3� to L�  AgRare up���\�Je��pp�B�Cɣ"�a�u�])'/{!�n��� � l6m�,environ� al�^eٝ�6� A� ? ���a� at 37°C �_�EeN  e[ �1�*B�q�i|�!�vwstSuˍd2�2 +�Wu/S NIH�Q�, Blast!�� nd C.� �I�OnPa�L B� g� *&}-6SiV*9hlA{s8&blD)�a`%-ca7PCMP��{B� ��(&k�m�ac7lutzii1A�*�&&rx Au:�B�ah*� *gg"o� ��n�Ii� e�� emQ�Z�oF�j!&'�7�"�h5u���sm�!fD�@�O" ump�!C�?O  Pi�� Cryp�ccu2�a� SacAM|ce�sia� d Schizos2#pombe [��18��*s3Ea.� es w�*��)N�x"�q> �e� a;� v\� M�p� lyso6� 3.1q �NADPH-I�omplex 24 ݵ �G � � �t kd.Fuy*�copI'�.����cyF .�6�"��UJ���SOD*��h eutr�4F�m���m�o Rc"16 ��na� �� IDM�0��SIa�A�llo� s QSo��)-�<�d��Iir)�e 9�FMA�Nie0Cu/Zn )/e�w��.) 6�� �R!EA��tl��p�s !ic��i�)C�Uda albica}[Ȓa:C .�4+ �5Asperg�$ fumigatusAa�H . caps�iu!A0.�"��%Fa�E,�^��� nz�*I�sA oxic� ofe�&���{.+4:&� by-�A�9>"�� a�4(>?p�ex![�K�&"�E�a"�Us e"!�II?��*� soug�� �xp��"!��G"- >�’!.A�S!���*8�� -x.0��T o-�>T2(3E3��p!np �6&�� na�$  _!�R� o�s�P�4go�� .Ve�! ��z ��!�j�TNn!�-���FR#�V�NZA��s�2�"�,� [�B idia)�go-�)�i%�(6�!co6  A;g*�(�V"�.8R c�j��=�Er�6( ��T( PMN) alve M m�H��e=Antise�֞t�AA�y  &(mploy�o"�be�� !A!�` Z7u�upo��N:-� !�a ��B�> 5�'�th�� �! mo^ .1)m(��a*�u*�f>JAu�G%�)"fye�SOD� orth!=" eg@bio"+~c�oo�-)��?VA��alyA2.� bi"J-al BLAST��O�8+���aul�rTg_�,y&.�#[26EO ��isEA�ow �'MCL�!(4 a7G5U�de�'�9a"�e-AZEO1e-5 [n���A@�&vAA�zg!"� Ni. S�g�Pb= Pb0&i a�� re c1 &�Sq�!�& y,ez ly [7�l�6a7m 0��%��*ed-�թI�"71em� �Pb60855 � ( ATCC; PbWT on�����ro�-] ���M82,�O�P�"� ��>H] !/d��� ProS��l[]u� ari��y 0 A�s!^:M�aE��EMBL-EB#Z72ww3ebi . ac&3k/0 pro32љ�9 �^$lig�1�eQ��"w%Muscl�'zK!�2�/�J<�CA�a~t�5����: ( N�abor joec) �m. O�fe%� /5 �I5�y%�"�:�%�=�)�S�6P 44e!�.�3)Wcb� dtu . dk/%ices/ g~&)4gpc�Ubio![!�nib w$it/predgpi . htmE�Ay�6�� �S*���!�Cu�.Lbra&�Fq*8 �K7%��A�0h�ld-W9 ��. SE.A�� sNY� p��TQ��B��ya�a��c'�3�}A��N�.�r^fuŏ( BHI )�pleme=�e�1%�c<( Beckton Dickin��!:�P, Sparh�MDc: e��Cag#*� t 36y�*!,���Gnd�20."� $un^�(0�=A72�$ )�+�'d� � iU�g4-wool�/��=�s"�D���s�'R��epo&�MqG2�n+G%;2� � � �"��to-& ( C-Y ) ;5MV V 71V ( Y-��]L incuG=5��8t-�:>,f�� flask�A�A�Au[38H��*!�� "�Qwit��Q*��orphoab�#1m&�s��Y&� =mae (y esta��(Aj�e o_�.Nun��zaA200 $HernándezA.20�. . Cu��sE!�:�.@ ! � p�hypha��Wng8( chlamydospore�&)�!�o�3ir(A� �u��? buds�2UM\m��� 2bud� U�p-�A�zI�,!�"��Q�r F ց* t �c 12 hZ2r��uS��48 ފwardsP!"j��7]%���6.{��5Vk�Babund�t 7�. R��!��C-M2�,�beg��oe 1j)Oa�4 �K�!�P!�{|̷q�o��s�-96 h [4% 4}Sa�" "+��NA { � !{�(.Q4�.{"s ;��d�,p;�x�xAgҒ,�$um tumefac|%� LBA1�c[��")�recip�!tE!�Nry"C6��� 63(��BdB �bx%>�!�8�,in Luria–B�ni��Yaumr�^kanamycio �mg/mlo Eschohi�Oli DH5α�nppB\.2(/��Q biot?A( -)2%$�id AgY9/clo� . To�Ao!p6[8Z���Trizo�J� ( InvZ$!j6]�*�!DN�� �o SA t���tL� n!;n��iYX�2 β-tubuli/Pim�%t* 2�����of chrom�al,#�am4Q. cA#!syB�z"� 2 μ|t90yMI�a F�i nd GC s ki)� RT-q�, �[�E��manufac� r54A��( Fer' a�Real-�0O�.�,10 �SYBR G8�0/Fluorescein �Mas�,Mix ( 2X; qRÝ)��@������'CFX96��5�\� � io-Ra �Hercu�C�]�E�to�8,> �%!�2� ��� %uf�0V� ( "�s.&��)"^]!�>+�&a�+I��i��g0 ." anne �Fly�h ��� crip�$m~�� a�:�"in" ,\"���0>4�U 'z�[ A�]  . V �p*� � alsoq>�inJ �!,N 3;]�>�+ �a#m�empty6?�=�e,��EV(%HMelP���hB�a�U`6qU@D�}nat���<�on-spec�6Ap�AC-d!mt..%D( h�keega)y5.u��iz �e�2~ "nU�M(g:ach,�LZ��rrip Y��! Xi�a��>C �!��<W�'�D%�h& �$ or 3��EF�> PABG_0506!ias�%& @�&M� nsaw�� �by�CTUBE3!|k2\>Ac�K&�calib��)w��&�eZ�!> o gene��oa�Y"��IV���e�eta ou��f`thA0a��.U .{�fM+�0 bi�tetrazolh ( NBT;�m;F� e>�R Beauchamp%�Fridov�(( 197Am�W�,x�,r��hټr��-Aaus"�S�riboflavaN��/ 7% /NBT�,M��,� ge�#�� �4 As5�lE�?iE 2n a>E�z|,*�>4:1ysp9t-F"�O�2U���A��hᵥ]�0��ice-c͆w�L�oa6i�l. 4�aBT�W�>2 @?C1arkO�� r �D��Hr���AJine028��9rEI 28 MIRA+ yletn%�!HPMEHB BS 1XiF 7 . �j���":�U�%"L�7.�bA!5��!�(5��,-CU�_!z�BAy�*Z��2�6a��x�P!��Ae"�[�ONiy`(oy@�?���1 minˡod�  �&�D.�cr�X��'�OobN7-ckpH�10 IPG�s3 ��A!�!;d'��Qn�bwhoom.r-%��re�'�! U"E>|HoM�foc�[L|��&�2abyJ;hre$ ,�orin���2�;qui p!۩�#>��Av30yceroLE�i/NrY!�Aa�� ��B�I�cq��R���awD!�Nodoace;da;IA�. R) � ' V:{ye�y!ǭ;� n� )zym��m6�AU�D6"%�%XM�$human lungˠth�=-�g  A549sBCACC N8601280�Er�3�>J[II>M%L��,denocarcinomp% j<,A}6g�Eu� an C!�of� &�( �:� F,in Dulbecco';;a� ed Eagle �( DMEzF] 10% fetal6' ( FB8*��$mhVD%'� SV4�K MH-S �!'n  ("�=1%�950906�H.%0, 5 RPMI 16401p�]2mMlA�nE�.�+�6ű<2-mercaptoethanoSi� Aldr\ , USa+fE2^ �lyPnu�^�,oph��(�&)�b�dtI���"i xD eomj lthy!E unte%��whole <2�Mcoa�7nt EDTA6�� 05 � 3��.[A��Id��27P� prepA�a> ma�ZLfu �ub�CR �450 x g 3� +�\>T= �t�T�t$Hanks' Baly"d Salt SCq�}"e !}or 40{��. Fin��,)��6i}�M6�Me�gm�; Gibcօenu��![in Uk�oB � ll v"VQ!sEw���try)9M [4�&P�(�s��i�24-w3�2!��nd %oI���+%~� "%V5%�� >�%6� N2�0<, 10μM diphenyl�i O� DPI; D29��ir�a!Oto � �;��3oXU�aL,�C�e a�Ni��1:�cB6ns:M�"U*�)!x keptb,& 3h"/�,G�o0�*'!|colon��I��%�=�\N`�A�age!�Y)[435HY�� "La>�cAAx% ��"&T�4B�I�mt�We��a/�tinum�4--� �Taq~*��:;Aj�g a� olig�,ot�G,� Hy1&�%*�%0as PADG_07418E�51)k[51@%$ 2842$Y .�i^�� , ")%�F�>u++�'2)B��"�AՁ�%AA^O-��=��  )MTaG�$2 x;D�#:"�Z[5�&� �)�\-L� 3 �B�nin"Vjl5iserAg��WpCR35�h� � -xC\m BN ng v�S CBP-�p��G E�>�25V3 pUR5750|a�(Ob��al:/̪ arbod���j)Z!�A2mC2&(f&Almeida"�(7$��.i�cFy(,� 1:10B�/>�{�" ���0 �co#(e�6i ~-y!d�>�IE%X!Cy�in�% soli�A�1a3� hyg=9&dEyg;! m� b� 5��@+" ���. RandomX��ed Hyg�-i�+t>��b����D1���� �����/"�51of �i �* \.��[#��-e�A� PbEV�� suc%�Gsub1�d�K&'wi\$t6n(�e�Ansecu�(^�L�o&�du�86��)<����)� ��)�m�ız�8HPH�y,o0i!z��%a�1q 8A��� km#h� �%K1.KSOD-[��r o��rvP iA!�9rU�/�?�)��@ TA{�+.Esخ& �(�2ha$er&-�<&dA>B.�E��uX���Z���EV��aa��gO�>t6v")I(U)��B!)e4cT�3(%ɡ'�!%� a�.�t"�an21000-bp:v+� e,1�EZ%�:�. Growth�-RBfbr X�L��W;d�I� in{�%]O ODA��4��1�EV�1-2�.��&|"" %��A:t�,a4*$*�4w[l '-N[ ��.�1�2�ot{ ri(�@( OD600 nm; Smart � PZ(�R�"^�ta !�&q!����'��/o' by�na�*�5'Bh�*GG_&�L*S.R8#�Lzep.�6�Q �0 �Z�&�� n puc�b1t ayS.�(A�� um�iH+ re�� e [5�I&\ ��A�x �� liqu���}%@I.� p�a� (*� $e,!�hA��� %il*�K pH A�A 3��!�2Xa �Tn² of 8/�<J(L)!�*�-�B�"�Z ( YC�Two�DX�GE�"a�k��"�(36��Wad!�pH`��n�xlpH�5�f!� �2�IAe�8!r�l�Ov���Ye]��o, �Hq �H��Q�,MU�Oso a "?���w��tWT1c1 * 216�'�)am�.�)D � 4h ungi�#E��ol-MyuSquibb P4L aceu9K�-EnЅ� g *ld�N}([#�����2�y $�:��-?�z�R��7c �P�B�s�R)�.e�" ?�C�P�V� �� �o2�A, xanth�s�n� nad�H. HB�A.�A{- d_P-sI/eXf`�!k!R1×105��W�o��p�2@�����<(e�A2ke'loaa�g20 μ�(PBS1X 2a �u�N� �V4���of�G219405�MP��a$U��P �}J;�5% �!ga�&e{d:WAIg�����B��Y!w"�%�B��3d�D.L,�lM��in 50� Tris�Wd-= hypob( H96��0� 5 mUa�'QR( X450v/.o%B��K4�/m%2shd�]EIDNee�E"du"(di!���!U&�&ASKurita,!�u�D�d� ��CFUA|&�mu( M56���qe_!��ha a 96��8a4F�ͥ�BMQ� eVin4(P?�|Q�E�!s_���80%�16a M�. z���]�,M�M>Q-�!n �� �՟ . Is�� ic 6��8-��-� BALB/c m��mX&,��e�\br���lCor�ciónun InB�gac��sa�ló3C CI`0,ellíQCol_�����6v"�A��E�f��s ad lj�um [5 Anim/C<h��(!��Zal�0aw 84�198IRes� 8430 9t$z�=C�Wi��*�Wi_?4Ca��un -A� C� , 199k�guideD"���!�e��ɕ!Kr<�ethicsZ*mitteeq!roC:�y��-~ a\B�B�&q g*s ly��/ batc[ �6JHIq��,X=@a:�.-A!�5� �L��Z�b{�as�weli� of �:5a�6��2� #b�& �.� orR6� �!EMa4Efmonito�dai^�7_a�7u� l��!蹥.diO�.�U12ɘp<�"�Z,i�keu�|&Q" .Uv��spl9�tۭ�t5�$mL�CHm�t-� 7��g2,9��:�8nd�1; [-9�������F[49�"$ � A��9 burd*�^�w�E,��.�QI� ��s�"dQ � �il��A\�i�Log10Z/@3 issu�_D�qreq�mea��xA�>��� tzNstI �C)eti�f �2�&@ mWT8.�\!�x.{A-DE �B q�ent�އr�. B���f"0�#*bo:>D1�Dd&6D:�;? � docu4Xu"�L"�T����.o��ctQ+�B71(U�ot"and<al L,Z�K�:V�*�hb�e���2aclogS %����.dRI�J�D)*I*JH�6 D�dMQ��Ak.iD" 432m‹,Sot>o'+" GP �j�! k&�}QɺE�� �.PN� l�L�dVom)L�m`� � -.A�PCve�a�NT;�1;*.; s W�-,)2%� SOD2)1755;�c�\�&�Sod�1X3/b�\r&Z!}SBlD`es Xal�!2�QalBEB,( �1�!, 95{��126��%!>� 6)��se1jg5 �W�g�3l�Y!�> �6@iQ`�43 ��q�qy� Ac��r/zinc-"2�%J�ek2� � o2�sh~z�V$/manganesez} |2q� ig 1AFTi:�aV-hipNN��21w�O�fam;dom�I2)ja^2]G�TECVd�� 2��VA�A, 26)��!� Fe/Ma*� ~� PF00081: RuN��$ $;" 2777 "/beta C>'eUnO��2eG 4 � 6��9UE1x��% �F`6x��t�HzKy 53 a�+��h1ne� &b�2�ha�T�=�B�s�!�7S�u�)�ur�Mb�/In8f"sR�.�6qS�Q��dic�-����!Gw\Ws"i�"�^t �mot�4��a� �w �\n����B��Y alsoGi(1(���us5u�3���~�!4�fN�,%�:SOD�*%��dT1mN��A�0; N`;a�(�I��%!)X P=�4)d�(v) tal-ass�� 1( HMAe3040��%��c6wa�o aJal��p %�HFS5��3���5o/���l pepS$9t(� 1� 20 ar2x �IJ0�Ij��k�_7�4lo�pc��~Y�Q� [�I � 1�r%�EsI425(GPI-anchor/r "=7 �( 210sBniT�!h=�J!��� fac��AaS-$�T.h"�g&Fm*:. zar"�<@01< ����Gd�)*�V��a�WT!tliz�all �Hc�i� tect :msS7v;�)�� �B}�D�� -NI�Pb�p�-bi�Hc � secr#��.2��:A�Zba�6�tTL�MaF ed��I Mn/Fe!�2O�s�dA��& h�6���-n� ,�v�;gg?�ng)3 )5 !!�l?bVto� e2�OD isof�Uorms , their protein sequence domains and functional annotations are well conserved inPX genomes of Pb18 , Pb0360855VTPb01 , indicating that@se� e partLthe cor` ^�, ATCC e�:�, cytoplasmic�BE� w!G�eO ellular f[i�2. The�on%jper!w ed follow!.!�hmethod created by Beauchampd Fridovich�971E?Despite%�effortAwe onlyyPa minimum of two band*hQcould b!plainedAl��because�1J8does not discriA�$te betweenA�s)o8different molec% weight or,4electric point�82e , top�To solv�i�!qLin order to obtain a�$ter resolu!�I,decidI�0carry out a 2M( rbottomuDue\!�cha!�eristicE3 technique��t)�ossibl:�~, three spots6�M�ity!�i0m�ith�z�x )��7�2 s&:lswitchR�onidi!'P\ fiŁ plac�`4t either 36°C��20 .PEma�!�ans�  (a- ]g } i !|ge�eU ( �-.�8)!_ cess- a ki� %�ឡ�h��At�zof6��ي.3� 7�s"� 1� 3# =�Y) r1��%evalu�� time��A�whA'Ka� 4_5)�� lesshedw� S3A�/"L � sign�/ ntly7a"�  E�^ ��F 1 . On.oEh!�� SO� -I;sligh~-qPJn e2�(2�Regard���6_ shif %A2�����Y� �A}BY-M%wM-YN[)kB6k�� jf !L�s. D� ��.%,�typ5�%3Y;mo&� ! m !_� Over�,."9� experimen�� volv!�J�s fromͅk�Qlow fo��l:�\ excepѴ-.�C-M2�ina4ch �2e�r� i5�througEet, peak�$at 96 houra�!2jiniZ ( 3 12 )�="C-Y.t6�6{itu�Ag��� v���� < !+pneumocy�((��� A549Rsi�thV ��� wfC barrier f��byF� ; try!5to adh�  e hAVlu� issu{v,us establish8h� f� ,on [55 , 62])fou52�Nu �� �!� Ɉd: l�y5�!�m���!�� > �G��u7re*ed unalt�%)684e unchallengeda$trol . Subu�� ŷ�J�2�rhagAic-[alveo� macro �2!/I5 MH-S�(human PMNs]MCafL )�i5ׁ1i-�us񖁌1 .�t s mu�&\ ]� �0arsenal elici.�a��!�"� �auelfv iɧE�2J.P�a9� � d anY_H�J�al�}2-fold!�aR�)H� , upoq� aGE����V�m� �(�4 �)F�2�.r..G:Z�*.�furBM�E � KQ!���>) e88n antisense-RNA�) knockd� q ��[� - *,�T� $previouslya�strucA� [51]�14�a�X GBo&?E�is study#,ATMT . Brief:+ g!�-PER�s'�nY�de� �&S �,oligonucleot#�Mr�>��B� v�re dire� xon 1y07-bp%JE�3ASn 104>2;%,3A� We�� toti��.&qE܁E�s0� !E u�.�1�re��50��70% (Q A%� ���insere`) ��fer DEXt� toB’�ome%�confir�via ampl� .]HPH cass�AZ5%.� W�tlyq$d&��uK" b2� �F�6�A={No major"�� �E ́}curve �u />zFe PbWTPPbEV .��a�re� capac to0abolize gluco5v�m�>�i�s�.v ,EV2�am��,�at��e�e pH ,�3?,��re .� vital�b�2 6e�PbSod1 3pa-�Ga=efs h>�-* � ag� ( hydr�/�xanthine @s_d menadi�� ) on��galQj�n�.cEn�� toJ�^disk-��uc �y�;i �concentq- �A x ( 0 . � �� 8 Me K:AsMa��r �viti�to H2O2 �!� larg��clear�aA�M/4AE�4�~,a�h�  nq��8J%u�hnT. T� i��acu ��� subate�����s� supeMan�� [63]MmlsoA�u)A42�)�zC,5�s�2"@v-ͳ%=I�. MU� e@� awox cycl7[64�hB�6Bcat=7!& �o�5.� �p�U Z�U hypo�a;et���ron!�eptor&eO2/ NAD+!j�reactYY� [65G �n BaK resitA�y�R� ��  4��. F� m�&� �%> se 5 mU/m�2100 μM1�=��bvitro�f sA( ���F��q��ty �*�:a5 ]2NWT�G-D� To ta�A,ine ��/So��in"� e-def�  ,.� e�incub" ��HABwild-typ$U ��fungicidB ��0 �� 3 depe�� & �pr"�of�%�m�v!�g�mbsup"�ofA�PH)rs�"�� 0�v�/9�bu��as� tQ!m�. MN� In& inhibit:�w� e�*4 %gDPI prioI��.:�EV ha�e sam�hav=asS61It *mport�to6��atIhv�us�QPMN’s.�abiNth�*� >�t�E���� iderably�4��dYo kill2��5i��25�50%N 5G E�-� �%� F� !�>� .L1�ed �.�� ��.�A�n.� �"���% EFl���{ *%&�A� �,i� resE# –to a g!oerent–:ab$P!� ( S6"� V2u�� -p �{ simi�bQ~but �r ��a� likely d��] ��.;2� .�N�%��B�virul!# , mice��� ��as�%�1� ×1062or -.$. CFU!�mo���kidney� d spl��pP Ded� ��,twelfth day ��I�mi e�5 onseg  �_-medi�limmunX$Tse [20�Wq ��A�!A�in �EsWT 4$�x�&��.1m�R}A#.��"� al�`denH oreo[, r2Z\-a \,� CFUe�"ed�5� % recZed�$!likof)�)Yq�6� s!�A�g!�ie~ EA6Cc�mE:( T2�YJ�M#iV� Zlz, i] �ve�$ c�. TtF t��l� fami�>, �� ��&id�%$fied so faU%9AjelloRtaceaa`2+!Q0>� genu�>WA���Nexiste�of six�"� encoP!by->T*. �#our-�#A͍}="caS i�&i[ w��#aL"Ip� chem7ev!caLr����t"�"�"]:�%wb(�#AS tify��i� D6P"ea":r",��"s-of-d] lack��$s[ge�(te���"I=�B;�� quAt� RT-qPCR�b%��pr �of ��in"ct �"�SO.�\�)SOD6 did%1]H�!&n)mDU�a�A��! J@#h.����f�� i�E\ �@�2� � m��&�#A�stimuli1F�xJ�(ɒ ��X2w) , un�b�("�)��m��noz2�:�� 1�� k)j��.>c69�g�2��͙1�J1.�!-�ly< ^�)5. I? �,1�cee-A�mecU�amo �member�5+>�a�us hav� en�ied [667-a�a� LHis)a G[674�9S(f$liM�ct�� ��t!�rv�F*%� att�Ae�we�"�cc of H .\sulatuA'�S G217B��J&pp�san impro�-�U�t� syst 1�G186Aqevarof���r&is cri�%�&� %. &�!B�:-, a�3)�4 demo�U �&�$F-�&a�GO(�aeU&cUsm7n72�'!�;5�rre�+�k!]9 ��N �����mqE��. SB�En�s oxygu,nsump they �.� ��=A7yn��nTv%#��/�(��(%�* 1��>� ,+�a� �A�-path3.��2 < � B*-we�A�}��*al��%� �"V�/cA�Z - �e:{? o� ( PC�+yD[ vary��Y͡1Ha��+:� s [68�  $!.Dnee},lua�.�Z�(!� *� �Q how it ma�!�A.A��:t2O��0y��!m2�*m(�&%�M-{:�$�� ..h�&mt�>�&�$=S*�$%dsugr�M�k ! displ� ��se-�e kA�� *y!�B�u-gj0+MTd enda<(aQaE��c� e��29,v�ec��sm�!ex�VI���) � 6>Br,>8�Blastaes��3�u �r�2�i%�� al p�%d�|�#`glycophosphatidyl inosito�0GPI� chor�5[1�28>Ca$0EG� A�excreG"74�{ ssoc~��6surfac I# �%UBn�ra.�/Sod�("'�ne dat��/ I��3,�S5�1BiI�^s Q=a*v ��i{!hu�#�s ( �3g .U.v.�.)%���E�� tgeedN��� ��n0we�� �.�i&�ISOD(d. &f'stRE��%A��$ u"s 2�l.u���j,;);����}�ofhtwo !��` � -AX4"�-� �58laW.J��4c&B`.�x es sB mechanisP&�$ vade.oclu%����%j elan�in vivo� X) [69}n�1terw d�!lyyHb�7ngYkNiasQR&x&7� In a5'4�,F E� ��F:�� % ( Gp43 )�bis !� a:.�!"�M����Ahrelea7of ni�3. �! NO )� .�&[767�(T� f .$29� ����2^4FQ"��nj"GX e�4�\+E�1�2� �1!��%$% ,ij(2W*�Euz#a� Stud� N�� foc�on 6*he�d!Teut�(i2�8�sta�(5�Щ� �Nd�9op�( CM . 2[��!�vG������ Nce.u�.]-$ng5 munoregh ory^A�bo%!AQ17�0 se��!w�c{,"dis�" [73)�&�+A@ f�e3*�� 6|7���C� �� �A��x1u�-��granulmu:A�>6p�$um [74 , 7�� �2� �x�B . H�魮� ��2�����e%'too �? �7!�6� vacu���V!2iixt nd:9Ʉ[769�fa@9 toge�iVAS.��&�i�B]2�A�>� by .C�A!7�#e���result� .112$A���a!O � H|� PMN-B�.N. Acco�1�wx:��p&h�s!�*&� !o"t%E���F9}�K%��-Eb�"=�3� 2$!mT&�� P!� fy accele�s� l�&� I$, lea�o ATP ��#necessNa�za���|< t�8�Gm�[77A��>ttribuA�i� �!� A�)]o�H-!r��*2�7ͬd �&� ��sw+"arP y�*1��/h!4�q+ b�"F'^c!|iY<����AB�.Y �a�\ha!!d5a�Zne�6MR^o"�5M�bb� F6/#.we.�F�e�HT&,*�#�Bf#�!*N1ZA��lyIs6l u� "$1#� >�9t~ !&�")�m}4A , 4B�<$A�i� % u �!�'� C@b:*�-"�/�b�p%3"�'in Sac�<�ce�-sia�>���6)"anscri�68 s [1� 4� impl�>C� wW5 �k��se�ex$f%.e�ls�*asu<!S� 6� ` �".�J�,%w>e,�� �"� !�S7� I:7�2� a�@�  �*� ;��)��5*� fash% [72It�!`<��a�ytosoli�@6�a$mitochondr�%-� �(/ prop� �79 , 80& xen� �5=��)�l ��co H�-t)�"`�I���>��nA*�(��B^�2ato el�@)�n�aI' agreI�M-e&K�{�aat!@3!�s�B%j�.�"�.�-�to�0 troy��F�!aBf7� E����'izjgr31jik"]�\�WT%Tp! ]d�,"q#�2� �;Q ��;�6a  er�J6����D2� ( S8u�T& �ay"R3�'or���E2�(); �� ���Z�����&�+,s� e�#mkj3.�+� es*?w2���=ngJ�" ?F&�+. Not�&>) I�aDoddly M��'�":6�e��ec�<C2 � S�>~mv151V �ed� ��-iAa�� � � )�out�'�yE��&O � a "���a�FA;�*��bu���N-�#�?$a <ytotoxic "e��E�o %[8&�� Ms�� �rel�&{ ifpF 2��!U�F�Zb"Q+�.$e� :I'�)"@ bz&n9s�@e�sma�ran��6 mOeA occu"�#J���ylig�&�e� f&�E�Mˉ� bea<�e�A(�*�/i d3�1f� ,!H�bOE�N %t*>A�6ie�FsE��i�a ��.� �KU�f�J�"M�~u�1+_�-%.ztoB^ f|� ��M-Ir4rA�,!���� 2/B�byB�%lai$I�a�igmQ� !A�s main8H͠��*!�:}�aliQR 2Nr�shz -�  Q �5�%ofdAS4$:��"S �2�+�det�@al6ci2ui�b�&!>�wE��*v�#2�?�<2Q�a� MEM\m��"�C isZ�*lI?,� ~N) :���. M&�)d)K6�B��3�� �s?Sod��0 ,35Sod�Sod�5 Sod6'9�.��.! !\�o- enough�=�*�-W �M#�z!*>� summ],�V�&�6T<  �i2 �A ly1i7{��B�h d#2#! 5"-6�K���.�.<6�(? � �je)�LrA� �on�3p~, ,�/, 2;Non� 4�zis2� �=*� �employe"�8o-�)�Ōh�E a m7&�Hd{Q&��"=A��5eB6� �D�o>�*&�!��EuZ� < ���0* 5�a��5���q�"�6��s2�_u�M=_P�2tAQ�C j! 5B�Da|�� 2s1Lar0�.:�<%ui^U:  m!��=8�-oi~&"e�+ $�P& tibi�=n$ .N%FlysosomD:ps [82] @8'1A%.�M2�3-�s ��*  u8���c�D!|AN�-�,�� &� wM!O{tI �4IQ!� �1 z6�#2�a��$�%�sN3OS�O>�3�)+'| mFg cV$E a seem�,ba�r�d ��"ee��:z�!tF.E � d"� tq .g uj~3 1"�/)an�(��e Lm(M�w� m_�_�2��fdissemin�=Q�orgTN� 5�0�>-!:k)��-�6p��*oT7�B��,��6�" 55*�F�U*!�,���"�(���Nk.%�d�iu irat1�,c.ll��� 2Z?6�. BA��u�S�� post�j^8>g�sv�o�9\akl2�n*�&w�s��&� �>of )ib5duw@!6  ��� $�9E:�t : ��.]�� ��B�%�A�� �!�b�FM��<s� ���F-�evIA� b� 4 .$YIntrinsiEdis� ed/u�,ucT U&i��IDP�'��:em!�&�to -o"�@=t a�A0enh�d d�;��&$/ oZ 4!�GA�a��*�"�7f ��preC$e�D�'� cha�7?�A"A�a7�tE��B� .�by "a6%&�&�j�r�4etook �#wi7D;a�@� -Jpu�&� -!9see�Y&)1�/4`**8tendenc�9"W%�!�. Our �E�L6=ZM(v0IUPE�lgorith�tua!�� g�Wl)�e5�� in E�oli�  &��zoai�!$�.Jp�)�~|^partner.�aK�lo�-�C)5o=e-�&!�3[Ec!rise�� pronounwif normaxF%�=_o*5�toa� ��Uo d– ��� argu��J��+imTFd�@[9of glob� e�Ta�f_Z ��8" q�B7wE"�Pat� st�J Pfam0`28�IYb`�T�070g`_m5��(osg1��HP+!�e�2s!�.asM�[Aas� czM���promo!{t~Im?eM| �J�islclmF �j/� �� AX�sS A%E!indI�. W_+���abL U?Q�E-puWQ)�2IntAct9b�'@( http://www . eb�6ac . uk/�Hct/site/index . jsf *24M"�@�!lA6�!�ȹ �YZK��9��var�.�B%��8,�#lA�� numern �c���1� !�&E�MSDm�Mbm"O]SeMure Dat9 [2�&I�!�s�4-w�.�m &=���,� @  frag ed/A, .Jin��-�h1ar^ �+ . Complex�o��f2�3%(�,�� %a hunda& bA��]�]U;t�� ���ne ��)�� .��nyy5�a�tlex%b;�!/ abov�� �ak�re� �<V.f**s� %ir8>���i���<4FG\S1T�:xac�I!<��>�e��$�A�I�* ns��)a�@`4� 2�.t��� groug7�.�!�PIi�i�I)F2�4subB�aY�Lbac�_aD1�,U�J;uniI �eM]ic�[�YI�^&�-��N! � sepa ly[ !+�0r�N� statue� �a Dect9 6i00� &\a729�, 7615^�AX3Z435�ai� J�&-�lGr��td2�000z1�D .�. ogasE, (#��y�>$C�qleI �� ��Y>.8��sw+�:U)ng<��u&�gAGSwissg�TrEMBLF+"4Tw,{“pu�vy&� ”C a,ar�U7ArR�� "kn�K�l%�Pro2��z�6�_�R hy�a F�� �{U"�50%&�h �ty%a�!A�a-�Wgg"*( ��"�2Z030 amino acid�" (end}0I1y>�2}1C^!��)=�or�h �(�lQfulfilu�‘JV0 �pA=)I�ex2�j��5�%  clas��c�diA'jercei�5ambigu��-aW� �1,o avoid fals]kp ignm-&�=sh�"F��w�m�<ll�&a �f a -�of�3i�hL.���5&-�Y�^*%�M+ ��� A�Fth�R" appe�C��uRe%�ȁc2���A.)�d�*�lyA�)� 175OJ� ���Lɭ ,N �5 )se� =?&5 to 330p574�50589L�a�IoI��*�w^hi�.! ){un5}m!et'50�B75�by��-^�in �C�)ȅ5M L%�i� *E2��9R�XXep9���J�15c�d5�8BR�9>o ��,|. F�_ZU�.sM �taxono�i�*� *�(�n�3P�"� !s(cq�*� .�a�eU:by�[�, [: divi� `%]'�to�y�1�% ulti�+�)�e�*"H B��ee�jŁs���*ole� �� error-ridgI8 of.� �a�Ra� � �#�lOmam� �E-&��4LG5�on w1g`yNby��� low-*j(force-field�G�I3.�.J "�-6^bep0aV-� E< shol!e�d�Onsuffici~=� verc�!��4�Uop�C^t��AJ ( se� !^8& <c* 0��_s.����Pe�,1�sqpre� ɩn��ess��n��[ ural* ]�5�ip�<plPr)�h��O"e�`I+nO��J�dis)2A+�/}��Ŗ��j,Auu�Gnu�JZ=�iw�[[a��s!pT 5%'e�� lI]�!����R�PEby�;-J�a��� ��+�^J1�*at�ri(�KQX) p2�Q[dds upa��~/W� �MN�2Q�E�*5m!e��wE��d�(#�9):1�! E1"��woyfinmV�>e"��ܙ�a�X,;�R�gly� ^ �( 49316~ 6163 �(6� EYMarch�7�l�Ll<�!r�J`�YaaA��.Z 1+ace��a$HE��: *j�i$5Vor �a���*# Akeywords; .�( �; or-�ingx�/n�uiu�~ l� � .-!� in ��equal-�L,r� d���irA� �e�b�e calc��_.�?F�mUn*� �g �(Fig��B��(!Ic@ YFO2�B. NhlizE0� �o���0ula R = ( N�b/N b ) /o �wt>�.�n5�YM 1�Z� �.��,C[29We�D [��F!$5inZ�as quer)�9a$���-AX&� ��e-�� cutoff%Tse�Z1e-�Nw0 ok!o�>)��vbes*tch�E` ��wFSn] �Vnow :�u)in�se� a*�a�xr* . InUh~6�B��(yLF� 0�  �6! �jA@ eron& 0 QQU� ��va�edawu,>N C1C$%�*� �N�eL8ta3v:� ,YRW>an��*A 9�!��k� �In�e�R�%�.(� A5sev����c�?}t'��Q�_� ti-4"5� |��3Pt� iE( ��E,�#e�2�g6�X� em6 pe*5y� ��.�"p$�9a� ����.�Y!�"� p*� 3 a�7 B U7!��-b)a{"�)�0b� I'� �*���eai�-cu2yU7Q�� a@�AFu��� appa�|at��erN���BD�6o��oX_ ampl!"&+ �p=R'noN7�EJzer&o �a max/~{!�10%E R�. ()e K�!40%F�%*\ �A/� 7�p��� > : ne�S60%�AW>$�aĭ��of 0–�# 25fO-�x02��.��`�I�-�A)�a<epa'QY! � $i�@Peq�d1� . ByA�6~ VeO.��1*!�R���&�O 9� �� �1e-14�e^u�`)�i��Tc�na�j')*�E�cl� link5 J c!7|&428�hF� � �"a���s � �5�kca �nOɨ�mBu�����"��"L$>� \ nextu asked�T�t9:3)cK/e)_%>0�ح�6!��"&� 3A{procee�m(f"�� way:# anp-  5���r�R&8 Ft�U���Y��N�,!�detai7 -EMփs��Ip 3BaMe!OsTga�i4�!��.XE��Z��� monotono�s~2��.� U�d: #'�*�)���%.D &��9x*S ��"�G�(.4q� �nP.s�A�A�bi��.�aM��U%�v%.4&*.-as9�%. PJ!E� !A�� ,a�̓,&C�adtj$��inguish��-�-iogM@"�*��� ��"���siX�&]!\� arify�t+��� *A�,��E�5NgQ ����S"+�i:��>� e � c&�)J%c�4+@l( 8��the�b)��Q�au� ( un�)s��3)"�S+a2�"�= #�3 e fe�!<sq$a�p�Z!53.���8��%~"�Nv:*a;]l$m<a-N��W�~B� �F�5QinVK)�"�c-��w(�[:"eo� /I� g ��I�'"-�T��6380± 10 ( 65 176+)V$��j�` tio_504 _05�174 a2352b��� z!�V5b��j��271 �9�6 �59�_ %m�V��{ �_45 ^�x 4387 ` 9734.b1R� ��"b&A �QohxK��t>m!E�I E�#F1Gin �W �eachieve�qb ,&� 4� s[;+�t�enc��hA�a��ctbP� �� ly�!L�>�FXF�A!��KU�. ) T��2�T�A��"n2 �[%7ex_#)HF{`t�vvav;often�`�B E6 ���1o�aelD{lk Prob�H!Ito2�-D 98knqj�E6&7�)!�-� favo�o.��k!�e� � (jo:��107 [1�1315Q];%�f�@ , 063 [40i_63�X] )*z�ս�#��14J��l��;6�i2�"31%O8o8�as�R��.���a2�"�qrO;2��)�]�n� of 1314�A��.ista�[  a�y��� �"ai�!���erizB[&�+.v6�7�+5t/&"��!1��>- /)u4�:9�{� �aDn�g3�3�i��4aB1�*� /r s�+� UUhs) %� �se$� a'-y}un;. F�2!�E1��)�of�)?��S e li��2e�s�"I:�#�a�!�>t�9t='�X<8mp"2AZ') roll�DT B(��!�8:�4.e  G�F�"� n)-��ZanB�"� g�!��%lap2H5�"� ��YH %=�Addrp�is?e�#5%��� ��"�A�!�QC)<2� t�#A���v^ -$�:$);typArfy�)�C !��eo�4Ahor V�"�4? !/O �� �^ /AP�%�*t �Hn;5�5o�EN�� !=c!9�r~��:IEbtA<8. �v�%-�>�,;a2) �,�;A- a�w!��3 er Rk . �6C;�aurP �4q<&�..pn8;!N:$jA>!|� 1iqKX[e��.�3�6��b� o.f!a�tat� appl� a�5� ,&�@kV�, R�;�1�ue �y�=�dI8A� � � ��3� . �.� scar��ata%0wo�7},&� draw���[�9"'E� �Dn�b5��D1��YA.e_can�#by.�i�U����at)��Ex� A�&�*Y8��?)]3?��E�:t. EJine�s� R� ��, %[�Un�]d��edi� origi�;*f�E��ba�2�?I���%hby.�EQ>� e " :ram_!�a:a� scusELu�Y7:��A� very weekU�!C���E�)Wi2�K.]@�6 [1�� �ly%�a"]� �0gHoA> Bb3%S�E�W�'��magnit���V�,e��$)d�A�oF��"& �T�/MN,�.� &� -�!A&�@�L�[nJ�R$ '�1qoly�8sLpDInhO, m�u �% :bYvok9iS��i"T2N� s [2�Y[%�[3�YA�hub �i*�:0*� �T sI�� �  �P��iMC [31]–[3�FA�m5*of���C�!�{&nEJw1:�7��ac��;ensHF� ? ��?[ , gi�th!8"lyi�[�� d�i� 1�A�_.�iE�u-enK�!��&�k casp��6�loc&/*2&#M�)!�ubiquit�Ja�2 (� fi7�C �is-�"G/�,85v�W!�dut1gu}�e���)��3ay,E�oa�Bspbb%�q�71ucc� �). A� �]�� %���Gal:.M3no!���!�T.��o�y�.�$$mon�i�!3D�3�Goa)d)-:3"�6by�>a"=:"�*�u�2a��~.m` crow�.�enviro79}�E ,J aaI�Ers guidM6|[1�Q�g.��e*.D�CA.�$"s�&�� ��:2#l�� �R9jE���~jGb!�t�&��:%�2��$s�Y�ji"���at4�E�recruit�_"� ^ �\�o�B m����x�Bg�h��ge�� ���Eg,"5 ����h �ve-)Y�4m�0+Ba%X���)~6 }�tac4"�?� �̡'�h4�b6�1J!��E51�0 al a)�"�c/ oi�<e"�� b; witna�� "h[��[11� 3�CE�Q6s tru 3!��%Y�A�I�e�5��f<->"[5 g�>/or long37��9](%�/\a� app���t�B��� ���0aAf� situ�uK� EB�O286�ac]m�R$U �t��s-�&�h. A���;e2 �h`cq�(![$be�'82�O�m+e�(?Lng aggrO^h3��?ed/mis �A��"�*peGd,��e!C!E{D� em�i ul�]a9a�� �)YlC���JmHtl��6�j$ha�"� �A�us�K��Hh�)A�i��m�*�*�[5�-brea]Proe�>C#h� cЏphobic%a��C7S "=a��g� t amyl�?�2fa�.c�i`pe%2 <���5il� �N&t2 ,��Gy�JVGln� !zofG� tin7�2zL%ndoa�w� "GmA#��hA0 1!it�6sa�rop�l 2� �pg\��qJA��* H.�BB�ia xeAKp�lyI��(.! Ure2s�7Hsp40٣��α-sy���*i � Hsp70T, [42�C expa.�!qQ-o &� >  nA. M4 I-e�~]�!7�>=& -Y�"�b�uA�]"f�� �AIDPm�Y� efibri* 2�,t��I���be*�phe��ndr2�$ ]� well)!�{��<�vde`�s�'vae'�K���/*�K �*�E�6� �� �� A��3A ��.o . Tw\!�C��. Ts�; � Q 8("j�&>`!�:~8�&�"cME *�.E� � 2~p,J�q�6u� �molten-2 Aveo^E�jl %��AVr�ld%#I�:�-�� 5�b %�� inci�,dQ;%�s�>d�y%~al$  a6�-��> �[4�M.$4*i9�X?�!*p�&�.� YO2�,�e� �8<��#Q�s!ti^�� u 9m�aRQge"� �e�A�F:2�[4) &�H%�Ŗ�o� �ZU/�i��]���sQmanifes��r�T)q1^A(� �| p� �46tir �e��&j �-  �~*�*iA]W9p�vdo�.|.� !�on���!og .��!Ajz�,s��h�!�� ific�_2w!�mq˩n�hH c�b�eS ��F r��� �%�in5���.]P w� *�ND��.���!g�� fTp�!�* e"�� ѕu�*m�2in��i�� ittl2$+] ��[i;l��T �a*� [. .P n�.4do) 7ir*aEla>�F� �\f�m�"<a< vidu���@!�� UN.��j Drosophil{s spalI��( salm1'-rm8r ) en�� Zn-f�wr�d"�qw��&��e�NapYB plegOODp�cV%a�K0twa���w!%imaJQ)ǵ0Ifa�1 M�U�s�a7�proliferɳ)� �l� E�@ng uI �oA5v p�I( F�_�PW!iKMn��%�rect S!iSalr t� ��G !�)a �ir�& re c"��J�wa�@7���K!"C" Z�wm� k.(J�1�pp;%��5 ��d��e�m/N�we�Y�,�8�*�\pr{��alm/s!)#`���A��� �;� arra��eq �{.�*ic��|t$itu hybrid�>�)��!M-� m#�e�s �U��2�dI?unɑ�::lXa$AC�A-hSe�y�l.���6ٙca^�� �2�u=xr ur/@Af)�v�2�A�)�"�m{U,�iҏ��< ty�H:�s{��ea�a f�5-�/yF?�� 'E"V�R��.�fD-<�neww nN=re�<U-az �8mc�'en�AY v*F;.a( B]i,$�#�8� pend�EB�A�6�s�nLcE�ntext*�vmanne"�D�8!U-+Deant�="7'"Q�� v��!��Z��- dorse[lo7x [m�se(Ѣ�msvR6�.\\I�{)#a��%��� comb�]?!� Bxm�� a�%� �Pm!�a�+���|� cflͼ�Db ��!8� ��I�{A�\A�un��!HN �E�6 n F� A� �6�-��lar��=S%(r�s��&t܈�H half2thorax^pupal2Y ��th8�um�6�"]og�'&  u�spa� territo@wb�%��M�i�~. S 4�igB�p��funda����579�7s�h�  b ^ŃA,!@MVA+bz. A��m*�A��F�1-�j� bl>,-q!���iS1 Q ��,Se`"���l.F! �Pls tri&��:��)�fin.? �i�s'tT-b_w��� Bifid��+"g �a*P}h �'( �x� &� � )�E�.*�d�0+r� Q�al7#{� Xe�aff|� W+� l�&1Ye���0-Y��6�,:�.c ��[6–�|�!$�9Qn8F\ {���!�.:9�� �_�erteb�$a f�(� ^()T-�+�l1-4 )i�&���~kol&�ne�P"��Z�P� [$J&�two5[Sp��g1��iPs Townes Brocks Syndr� ( SALLQB[1��Okihiro>$��1���!��$s!  engagka� � j�w��D�!� �I'����B�()s!�4�U�#s [z~13–1J�N6�"�qA���A�r� "v8E��B" hіn�CacetylPbAH�_ NuRD��mH"c\_*#by�S.�uB2(stk^�oo" *%a��!��AD!�DS&������AaQj�e�%��sIE�sя�3a!b� ! I�:pͶ�\� 2L[�� ��I�!G� � ,!3un�$��>�ataP1�z �knirp�VIroquoi�k2)Vae0�s�mh��� B�.[1A�2�YGCybr9hf�s N�;���q�e���?��A"K �5�J2A!$%�)�5Eu��[�b&m5yen��s�;g�]g� y [8 , 2�| 'nt-�U)�s6Os&1��) A�1�T�"Y Y.��r��:�*f&��ǽoq�-%ꡢ hier/Sy�RfowQof>�%e)VE�. H�/�?e �̯ obal6�hɱ� at�}NQ]t�,�w �)V28�iN��O�� ed u�m�fy�.'g&xa� �Aα�!�6�V�>+�Nv&63JKlw)�/f� an unsua��2n!R|Ewc�$F�S�\�(�ž!Fa�/ll�T" �.l �P thir��6Ys%�eb! � e.��ros� trip*��.poC3 1A-1A7pA�"or� d %oadult �%m��R!!��]L2��* V L4/L5e�r(�w�{!("��� )�: [2�%M� lnVh�,�Q/�c�@c2s�9%�Mp!'ur���W;p6i*� dK"� v 24y��v 48b)a-�to )�] "�� ���S�1.[E��h�<!@�>8� �*�@ ��t � ( T2� ! 1/�vfd%�� ��(C-1C’’;!fu�QkEt!�-i2� /#!�-l��.U�2�E�A�)A7*�8e�>�<.*O=V�n� y�~24uFC���s,!T.�m^�!:]a[�m-i%3ek �� �ed 71��Eu�� �!� >A�48E�O(!�dV�+M1�i�_jas��69 ) & ��A>va}� D� .p�-]���D0n� 1488�&� 168� a��;6�]A aB$%H �(!�cFEi� u` ( n = 521�_-�A��(U��9%0 g�E�!ToReuA<� �)3��-;�A���me � 1� .� � �,2�24@IMQa5�m�P..$�S� I10)v�>9se li���xe����Dow�\la[ &�o�j�g�+ic�����d%z-孁Q �_ ��od{�Eco�)dV �!!�li�x f 14qPenric&M hnos��Nng� ��?��v , 40Zi 1649�*&5}to"�nk*{���:�2!�V� 4954 Q�t)ϙmod ����mut��embryo-���}[n`�!��9�n= �l6�)��?��|"�"]y&�$to a novel�_Y#�E�2�O�U�*Q-#"9�*�EG:bA�!& F�6/��A�1)ApB Er O<3�Zay� %[�i�cAa logFC�"�b]Wedw*Q%�/j !�X�bkat\.t ��1� � ;�e ��2D�_ 66+gK45>5���)r1919��( 30%�r 6a-.(&� �V"H.��" �)�over-$ngE�(�A�)%*�, " mcl�wy-m�?vA��Xfm\�m��!``xs;���ToA�e�fSsrE$.�-�e|E]adA[a9�95YB�u9�p"�� *��e�^��JH����jw=� I28���JX3��BZz e�S Q n of"�� TG+ � 1H !GS3"�147F_�sam�,�f*C��-^q*}�=�F�'��NT(E�w� w�r��5�E�a!J STG-� u�:b3�3��,\Ld4+OK?–OK]�]" �V&kkzE"��#<g&�'���{*q&f�a��YN;%� ��S�P�(MS�?�+"'!?n���/*�&~.�b�! �a*'��:�b�2�>� ( 17���~ ( 11 �1 m&���vip=xor(� ( 9%� aS T�O m8��m:�a��N�1e�o��Lorts� #M ship!y18�*�U,7ZW �q*Ra( R2\��!� ! av^ �*���$�&i0&�  ="!���!����exA��imfM�A�VGt ���$o1T�l�B|@ce�6 P�"Ud Z�*��4ar�$=6)�Je�Z��Da�.h@ahc%. S!�he��e�^��i� RJ�7"�� �.�( �gersus 16AA, Red-OxE��g2!>�4 M)( 7!14"i�i\i>�T!6a�X�aQ�.�"��Fp��`m�� /1�q2��."!�I�2c2�-�`i�7(- Rl� i3 ds u�4Vsoftw� DAVID [29]"> GOmm=�&i4�&�/�� i[�Zw�����h�a�L^4ht�� RNAi� u�(*Vji��a"3Q9�! �9y�!%){9��1( 2�I�Znt�8x-� �dv*�n�&�/��;qr��� ` ]ag8q�m�!W/�p.�1)�h !“�*� ' 'NmJ��i-�:'6�� .-� ](� �>�bio@�2a1��Ie�2���:rauga^�t>c +; & -�n I6� !� p!�J�!7]�) 1��r��“ana6j*�.�.homeosta5w7�N���4F�&g1100A+��t��� wiy���M�&: back�d�F�*, %,�#ha � 48a � PO I��,a�p?�ssu:�� �/k A�p�d �Y ʉw}k��[�Ki �(� !N2Xq��&��&��T!Y)� "�!W rali�=����N� � ��� !�2O�%�D–2FnI� ^� de��Gn�C h2�3( N$#�^n!�2�$�_���"!�!�����a�&�-1-�*<9,�un:� 1?�" 2�%M�b�,( P, ^�r 2���� ��N p' &* �.� .onS�'��@aO"; "�E xamp�*2A%�B!�IF�j!l�v"�3!�� �!��!aU�U�2�Mdicer2/+R�Og.U -i/+��W�`R�-�N\��in�@4�.�n� � .��V7e1�!=� $a�A|�m.��r-&�#d (��U%�P>���kctot5 !Ns�?�-�6�!&�� 2C-2ja� E-2Ep AX2H-2He�S� ��"j"$InC" 60�:�4r�yv�=��F �nNW1� ( 46�E, 2B-A��D-��� �G-a}�QP&G�%r��"!l142U F-2F� I-2I � y�@� a�a>s�"�� %scN�k&�&$�aOFG"�2!�s��q�}פubject�m"  sourcno��!�&�al��I�2��:��c��ACifQ���g�Q*�E�&� ��&��Y-�bH�1w<aZ�� u��� Sdamage�/ muluQUJ�y mre`� mus2y IrbpA`g|NDif_scy�����1J"� ,n OK��� �?- .?!5�!�4f/i.*�x�GeU depthA�lo�?%| JNK � �[6%�2In {]�A:�E�.# �.i 7at�>�212 ��.�F��%~JU��FOSZ�[3U:-*rr�6�"u��wT��Nau� �2l &���.#��t'm1N!l1�?.�&4#a��%Iz&�� !!v�WbyY=�,�� y.�f A.i)�v�2V�E�u�1up��� ��:~�P���3pucke�"( ��.j2i�%� .��qby"6�+9#�vE��Mv�UZuc2�c\1l�e � .e�Z9V�i}�X"� 3A , 3� 3"�BK�)���m�?* ^� �� � �&��( N+; 3\1 &���g�� ` A�D�X>( U+; 4F2�*2F��l8.V"��m�%�!�� 2���oe �.� ;0p�J.Q!0I�\�0,�C6fF!�]�( P�� �:�>1NgJNK*n?=�-�*8*��eR wA"7�"E)A�24[Qiod1C+M t�g!x�UAf�a2�>!I+l0��32�40 �  *:!.�a \ucsAw�,�K *�(N$cÑ%��Fx ��3�3� �}�-~� M��[?�-]f!�a"�A�&)�� *'"=%�/va�8L sB=Wsbe�,�9�-�� �!��,�of&,e#�!��*BE�.0 o���ri�a]2: >�!�6K� �-_ �)��%f�+OKg1G%��.=O2f�.�s� yQ.�f Q�Nd��!;>"�de-� F�!9�3� >� *I��i:e5 !�P�a�b t�1dF�� �u����K�N�m M*�*k6j>I+ K�RNA-i;>�"3 ��!K&�Ga��S 1�Ag@--$a fJX�+2v, salm,-i/UAS-GFP;  �salr-i/+ ) indicating that the phenotype of salm/1�O cannot be assigned to single genes being over-expressed . We also selected 147 2whose -Dion was reduced in�knockdown discs ( STG-; Fig 1H ) , and studied �W4pattern of 139(them . Most s�ar� �a� ralimanner�ew!<�@ ( 84%; class U ,�4A�only 14%.0played restri%F�s)�relate!loformat!* of veins �inter ( x�,P ) . For 2%5Fs1�-�e could !�detect.�by�0situ hybridiz �inN.!�$4A–4C’�N�8The changes obs�%���of � �ed Fi/A�xi background were very coherentMconsisH(in a strongIe1Itheir.� �(central reg-s��pouch1mE� F’ , 4H I S9–S12!s-is-E�5 for �e�A�n!�lly�)/all �Ev cellaMwi�AS9 , S11 �i3ydiE�A�z�( pP p� p10�A�a 2Y�analy�cases N�a1)-�]%q�compar�wild t��|s��F9I�q� D-4D)� G-4GES13aAXWe wondered whether som�%th�=E� regua�daG-5A^�-CG17278# H-5H A�)� t �ly affe�3� -� -ia��A�h , M A�5���)butW�ior abs�2in"dadFM�H �% Because�loss of�-C �BY&O:�.��u.�=?`��� we sugges��2�likely~didates��a�m�sin>��NSalr . I1�1�(corresponds�Llarval translucida ,B which."�$already sh�toA� �I��[32] K ssum!qat�0Mr�A��@domai�w�&�4!9Bb will{ picked up!�0our microarraňeriments�Sal- , b]extAH of t�>�xi�� . From�y�A�F�dat!a4it seems cleary�E�%�2� fun �r9E�s a proi�alter2�%� cripY(al landscap� O. S2 � mighH dirj ,e�it!#M��Mmany o��s��!��equencq$inappropri�#M Aǩ�mI�targeU2 ncodA2�$ factors ,�,!�we��%JNK6G�lea���of:�ś)8!|ignallupa� s!�o!�a�reason|) un. � terfe��th% 6� eacha�ividuale��ablF reproducaCe e�M��&3��du k$ng developA� . Despit%|E��wana�to makeE@(eliminary i��ifk ou�Q�a quirea�!�uca��( downstream�s!I �6]Je 6� K�en��-O�Jy( nub5MRNA-i a�sa"O) RNA� f� ceM�� gainst m| g: long�o�0STG+ ( 126 ou� � )r� �  47 )� eAWAs��&%�i�eW66 a }�50- tes�in * �ir binE؁�A�)0!,� Eq� A sizef� A��� s 6A7"� N S5 TE�} : remnan% !�.�-��w ab ��,��ed�"R� a collapsM�e entire�^J 6�6B , 7 �B YF��(co=Xbetwee�RNAIjQ�!��Ii%�rh.� blad)rhinge ,��)�pup��ethal; ( 9��EA 14-;6�I ��� A whenBginsA�%�pha� � ��!�&� total� ��AV� e���$ample S14B� � S15F A,0A similar no->6j alsom�R��2{( 8 )i+E�E�to��6� e��rzB�UAS!�-i%F�.! (2��F�in.W �� �H �{.iB� J�I/� �1�!N� sF � �� variet� 5i s ra��f�sev�disrup4��_�%�&- (�%>e-�� 6M!�(o subtle de s!,Ke�A�M� �ZTLE5In addi�!���I bothBb�S-P; 34%�4�RviEA)��6��f94�u����ps�s�Q6I–6P�[�`|7HOx7���E2����nt6s�J5A.2a��?� 5 '2�remaiA�intact9 ; 29%B�25.-N�� 6G , �K��I �J%�W l�� r fr iF�]�in�dif�ti%���s�M��inclu- i%�" �0�� tra- B�B�6J �A�7An�5� 6�hfailureU� adhe� !� dors�) nd v�A� surface��a/7v%�% marg��tructf. A e ativlle! of at lea(n#tic.�)�բor2� driv�-is� ��14�S15��I ��how�pri� �!�tribue�of� -of-K 2Qs� � � �P� ��s� ed�# A\�&� . How��� major�A&�&A>�!talm��*iEa C ��!�V� ( 21" 32a� i�en)8 !�ABu G >�.�+e�)A�0�^� x��Jti._by=R�� focu"s  �u�q9�a�"4 � t�9�^ attr� e "E �med/*Q=Ŗ� prot[^ ( 34-sT����>named��OK�wa�1GE�� 1)�n�)[b. itU �lyF( 16/34 � ( 14 ��n5enrichede�GO�xms “L� life�” , orga��"�(“behaviou* o a nol*�}%J7S4- ,1)) . Ouru��,5�(2��A?on*1i���e1ed!t� wid��.�l襀!���&is��edaHm�UGYhe�|pl������!y}C�dj 20or^�w�b�� ��incIŹ���v�u��;*�ɺ 8� 8�.| abi* to1�y s��e�c�}om���l!��-wee�� modifh �= ]�bb� ,��!@ smal.� !�xI�� �a�$ �  ��we1�8in.�M5"z�|����2) eun���A�2+�� ,�A992��� * ( Angrowth1�, ֡j�@-Hor~]%��u))2H �IA|on!�eOecat a f��i�aT�����c"NAnt�e4-*� B�� n�[25MFur^mor"weaw mA� �-�E�)��,6��M�a��zv�!?�pop&-�}�a��i��icj���(u) mve� "~ !�%� *_ex&�a�isaE%� 1�Iroquoa^ nd knirps%$i�exe�VQK!�. L3/L5�L2�A8��6E�)� [20]/E� �1�4b�.� �in2to;-b�].!m8� m�of#5 !�P .��� ��J�do�$necessaril| �"TIrQ�k� "a\*�ycaveay>�� E� ^�_�&m I�b�� ���6��� !�a ��nt�rE./-D" >�A� �Tտ e6gee}`j)A�i�{! deci� to visual�)ly!M.�h1� �n���F� . Si�w2`aM ge numberi e�]�� 1653U we nee �1>�5s�A� .���m pool�$e criteriab� �hortlio�2!YV�.G^i] �$logFC valu�Ipri^ izAFO� ����' � aUWeare0�po� ay�e0IUE��aH. SetŇa.�!t1a�threshol$ 2x f ����� dB�a� r��Cf 286*� �( ?A�)�ed�i�m�d�F=� ",@'�>"��N�e�!-�"  H in�reef: firs�!6: �v�q:"� n��)�e�>"u2�2�2b z-��j7 �$," CG1342%CCG7201 � �' posi��V� 4H<�$; Z!�� 8G!�e N��. mple09!aL� CG2999A,4O-S4O�`Av�neg�R�( Z7in:�� �)�("�ALCG�!)a��n��2)A3m�'9(8 a]by�a�a.���h"� ( Y�!@I�categornIjUa�U Mw�XŇ�F lud����#�I3sE�*� eubRSi� S�epro�%2�( �� �l L"�!!w 1273DCG33970�* ( S10A-!�!� S10H�"%�" CG12843 , 8657-CG30069U�ZAH4H-�&.# S10BZBk oD1&�#-�>0� !E���"��� � cont�!EexkA�� nf�%�+em2U �]�* l ��r�pos��|�(�*� EWIBsecond�Yi�<�I��Jj^+��s M� �E؉~8C�8�&Z B!Ug"� �yy���&�'m63mR1D)�M� � � � �i� y���*aar1."?�&4robust ectopic.;��iF~ fNv �C�f- 'm m�;t%� �9�C�I-. All 40EU<&�(Y�("���w�v�� eQunc� an un� )au !�Q��m>am"0$��u� "�$%�-k.{i�"2���to Pxh"�)ve��deploy�$Ga�(cu�programaM ���� pe�v~ �j�mVX!؁�͂B"�%��t% coin8 \&�&s&�#,!&is��1$��%b�/��Mf�eB9�>�pZ���'A�9�9(B�douK$]me ism��l.��i�0r=��Et1 ���trigg\,bh �1b�.im�Mc nsur��at�oa&� .� possi� �E%��ex�ip2TtissuE.J.O �. One�-A��%�X/u��+$-A�AOo!=ferŚat"q!�A�i�6� ��!fi�/ina4a���a*�&Ep%�8-a��ach��a_al�tex�%�-�� fu6a$s!�q���ȉ�ng��> two�8�%oo��ira�M on �u�w�V�'��"g^%�2� &7,*N�р�~a9� ! ]!� { .k3%At��"_+/X��&eZobj��*�(ach4.�|g���MV>� ay:� $biological��Oiqaccoun� ikn�+&22�.* .��s�*�'YP%ll "b �4!i,A�.&&�3"a.w"ep�liA�haieristic!k� A�_'inI=�(� broa�4�R�����<to findi�V�.!�+=A��Y��in-depth ��f�)!�2beyr �sco}+is work�uta*�"I-�b*play a� ro\#&h)2 �M� proc)s!ZJ��seEa�_:�;(�y2�& E�� om � "G&16� �'>L4�wA��`.ttempaAy0F�._�.� �=�muų��an(*iy�,A���.!��9v�+lyv )I%'a���FYh�A�M�!M&y�Aig"�� s������-]  37 �"�� though���B!Vw�*/:�-F� �V��J*� :�!6�&� b4j2-�wA N� �-{�%�*r4!�}j Ac�}2����>�2� MD;�& mole q�"� �� A�.6K�.�/�%rk��!�11���Ad*(DNA metabol� b�mpuI$V`/�679$CG627�"Rrepain4CG16928�925 3448� CG52�,��uGbA�ng6&^p�!�130! 4121^45050 5096[h0�. G�i� >r= ��7j%D1�Aea�{=:�753 �852 CG �185 � 3304) �CG665� K b !E�3�" by a non-�0%.w�3�$512/CG43141�(12505/CG101- IL$gu�<�� roupE}M\ m"� chro�;n�&$k ( H3K9me�]Va/�� of hetero=�6)&�in flA�ma�as!�po!���human/l1 [13]_rticip;2in�1�a�thr��i�3soc2(v>�a�O�! P>3�(455 ( optix��[u�;�" �BE[can >Au�3��d.! � �!qbAs p*�1Pconfi($w5homeoboxap-qp�mj O�3�5pon�*�5!� netbZ� ���e��v�.��6a.?=� � Jm� r!"�!h� i69 �5?*> ( *�-�YE�*"&�* � ���&�?�,�>�Q. ��b(,,OK;T%]&s > !+*�+���VE--_w!kQ&%X�=A�$ZE-!2?"!�:F6F�! hA�-�/�9#B�=*F ���� mighj6q },�'a�Ai�$tag"�� ! �p�pY� h~"�5.���%2�M�m���a;&�'��&+,��z i�� infl7: m?V4 � so , �>!u�1�x� semMhe)9�3E/`6!� ultaneousJr1��in�m#te�� 4)&)$!y-�re obs.�3_%�>g TB�M�1:����e�EЙ best.}%:� �)!�S@�=� l�! ��sj'as(4394 ( Ninj�7 , Nij��M72�L!�l� , dlg�  4261<scrib!�, �]!6Q��s ,9�#��AU�*{archi;C��;2�aUu� � romi!rQ"�� a � !�"�7~!yEbona f�)��t@A,e��qa�`.�A�d�g.om�=!o!�$cytoskelet�%ri�"�/a57 Rv$�h w3i �n�iOA))di�D*�Z���chI747A?Actin 79�)!A8CG42330 ( Dscam+,�rwep�. h�D!�� ��bA�N E; 43079'9rm�2 541 ( Tek�A� �760�8�91,2G�R empIv�)6 aWa�P'� hierE��]�1ir �Ef�yt%�L� iour�a��e�ab2�hj v=$numerous��H�0&�sE�engagɾm:eABi� r��oMA�65�=�.�0@t�>had�oor u�CstS; K S!;ps 2�N�orZ� ��ai� e�A�u2��� casc�8��/ž�s�j�C�� !S�VcA3rol�be���*A �K �j�%�. �.U@� n unsu�hed��lex^�t2�a.'?-o �&� ,�*@A�"."��&�!J&*�A���*  ?�8:��ope�%4��eeQngK !�h �A9�!!r�%�":.��N olv�e&Ce.+>D p1 . We�&hYlloe�< lines:��E [2� "�4 , sd�=�556 [5]*�=80ts [24+fUAS [ RL [3V�9��<-i ( ID 3029 VDR��,�D283866puc [3iL$dicer2 [35{�3� N�D%Ej0alF� ciency Df4o6 32FP5 [36�,A�,!�a9"z%"J#� imag�i)�<�� �"h" L4–L�(6�J�)5�occ��m_.!w 1�)9�<(ANe�3e!]-��( �(��'E�it")'�Z%DreD��TWa&ob�"�3';BloomingtStock Ce L , Vienna Drosophila�i ( VDCR �NIG-FLY ! . Un'9#wise st, cros�d�d�,at 25°C . La@�de2 ���^:N&$lyBase [37AhWY�seL,Z"�}f6( E"�.�� a�r~-���Dil�`2%��Ron� s�6/�)t tim�.a:9�#!-4e�F;Cre ra� 5ADt�>��z$4 o 29!:A"a N/oda_24%MT2{ or 484�befz0pdiL�͖2[�A1�0Ga��p� blocks4 �(��&���� �L��9��2� �U�����W/\7�*QE�4.Vrep�3� d9h�DgQ%Rem�!= 9�:2��GFP�B�l; ���f!wW!p�.� PFEGFPVB�S�amofu1?��r �)2 . 4�P5 . 1 μ�@S6���!AW*�1��a TRIzotocolS  ReagRAmbA<��&�&DNa�/Et� 0NA-freeTM kit8%���40–80A�cDe �stoA�at -80A�i��U*Q soluE�(�� rkuntil=ogenis� !�EF-�)m!samK7����Q Agil!PAs � �0lly��SQ��melanoga2(��043135%�I� i�n �M exhausQ,lye�&<" y+ao��2��q(�7�85 .�8�0Z5�:65:�D$/+; FRT40/  MR ) z6OFLP/+.-&ssalt�>��/e�� a�W}�>a`.s�M1���&z2!1ge�~s 1��NDfmD3 0��a�Q)F�we6$AffymetrixQ= �!~.B�2m��\�S�呵{.=��A�2���X�!daa�@A�ts;"�/�#U#�0ll�B ����: ]B�*iE�si&�Fp1 #ANI١6�5��wa����aic�Bjhomozygu�� ?aCF�%o�9>� �A,z.` (Mc�OMs>FU�1ng�� ��+Q�Ѣ�sB5as stum����&. .�"��A*q EX"�7 � =1�D!PI�)�2E~ b%!��W�Z4�" d 8%�ofter 2�hRaEAjV3)�%��low �*�5applyi� n��"�4Td:F$5u@��2�(^F�q�*sO !�)(�fR$��of 30%�~ �a��Rf* Q&� i�PѨns:�&:�!d�5��� 9m��`: good$�;>�2I%��=��Ce�CJ)0S3*�Wn67� ��J�Ae)Gs �bod%�%� Jackg=Immun"�'Laborato0( �at 1/20� � _I�D�g�[ � Exfix�S\�Ga��* [38� ConfoE(�-5 cap� d�$ LSM510!� -�&+$l2>� e:ER�-� eJ 1R 5�NI�HUSh\A+HAdobe Photoshop CS6d�R�8 �in 4%� maldehydYr 20 m� t ro�S*� ,�QCin PBS-0� % T�M( PBTcre- fB jSw�?>�, 2Z. A�hA wash�p,.�*� 2� 6� *� SH; P�!mc4, SSC 5X , 100� /ml� mon rm, 5he�Z�2�A| DiscI� pre-�!g hw at 5�'H!�!>,%!digoxiD $n-labelled. prob�EH E�p&� denat�Di�at � �1)�1j�� 2d%A SH�!��incuboQ�BGA^ 1:400}���VDI;Ft� yT oche%NI f� �]������1of5a��%^NBT� BCIP."|Ki)$70% glycer;<PiiJ%|taken� Spot!�i� camer)"up!̡8 Zeiss Axioplam.7A)�20X&4-� AvPV#�.%�r%� jc���tR�-�2EF0!RS�Le Tag��ES�of BerRy.=Gen�<Pro�-�y PCR k� miced(�AVS7��, �p�r�24 poly!O se T�7T3 7W� ��5�Y�I� _m9��WAP,)! Fn,l8\P6]�#.un�H.tprecipi�!_n�$in H2O DEP�F�$aAQno�of!Qe Ont�y�9m�Mper��Ւ�softw�4DAVID [28–29��We ���/G*I�HB&;/ͬ�H$GOTERM_BP_�e�� !F(!�V:IAvs.� ��0�2K KVJ^�ED�<&f.� acce�,�0��nt'JM�E �s" ha= p-�?� � han��$05 .��Inq's!} turb�:`tiol"� !�a`'�� umor��e|A%cephay(rD!1pZ*"ofjdup�ta�is6 �0�AUelegansNlog?Plk ZYG-�)!&0AK�.^O+� u>l M�B� �e�0mX��>ta�We)q*� !�\PP1 orth�X GSP-1%+ 2� ifi�g s I-2SZY-�SDS-22A�7 �[of �f �.��03 �.- 7!\of�c� eieG^0%�orJ �!1szy-2sds�^_��$Vo>8Ha zyg-1 hypomorphic�el!MSupw0�Vchiev� Xa DKa{2��!�u]b,E-)!�"d0-es AG*a�-�SlE�al&�!Zhil�'�ainhib(!&c5W-#�Z�@) !lf�FX�� wild-type.*lea�_9~��*%�vi�;�1dufC��TdaughEX*tC:�ne�,ew�/dEeJ\� 2�FU��ed�cyc!� In mito�0fI�os��g�_�L} �otubule-O�D8eA;����a���s�Rro�� O_3ac'�i-ar ma: ( PC�V. D�%g����/�DHgan�Fpo spindl�%av��T� A.*R�"ber%?moA�Hbipola�R�Kfaithful�-� segretBo_%R�g!ent �2�8E.i)e"<:by 9�F���R�]�inv> s buil(a A8F adjaUa�pre-ex$6!e?0!%��wo fe !m^F1XzU:"�cd6�E߁�o �r�L*o"pe�$Q� !/ i.cI�lJ���s�)� �-!�� �A�e%dqfJ=R�s*Ha(SPD-2/CEP19���O/�USAS-6a0AS-5/STIL/Ana'!�4/CPAP�$�wJ� �y<�&��v/5�A�kinV�A�xW (  ew)2[1]l Con��,.\F� �K� sub�3.�f"fb2 �!�$!Jyl-.L(`�RzF)VA^�"j�.wn9�6� jaccumGA@��K8q�.-� [2�ZS I� es]��1z,�e&O J6�� b-_*! as� play��E e&l steh�.U� h,2�.%� phosphory�s !�!E('Kaj cruisx%M�� ��c� �Bn cartwheel���cafqJ!�Q& 5��)O [7–1+gS�l�).� !y�6� e� r ��c} xc��O 6!�o�(�GhysF BX /o��.m[1�414A#B`A�:cz�29J H:� mSD be t02B8in vivo�n*�&�&� U (Qts SCF-QXd degrad)��,o���5uto.DaB4;� e kin�in�Us{4a�d�` [15!�k#Dp| � -�I .,}`lk4/Sak�.(M )�r�12# �ir6�b@A��.[189S6vQreA���e�Gl!��?eoA��spa�3-�!<�-�.)�i_.l�iz!B�V�=�a� EKB�� ,"�Cn�mmg \}.�1:becom1�J�e�Vf�Z mark�A��MF ��[!D2 821a& Emer�Uep, s7\(]c k: Ae�C jia��A�FC��OvBn7 %�2.E�2ʅ�q� STIL� &� �/;[1��)A alsFoj0�3�2ea�3�VGD Aq�&F�.X)����%Ke G1/S)O��sMR� �A��.� ^�� ��ce>zPI ��u�h !߹FaSAi& _�,RmoQAfUG��vJooGsti�xG�ms�i�%Km���ɒ�1� �|��� Aa1�r T highi�p�3rtaA�of�o K &�.H+stx$d%��e�PA*D/�atase �0L)-a �C��u!V.*� �well-&84.!�d��  U!� �$.�;D, circadian rhythm�7nMi�. H�{Pses�s� PP1α�� 5�� (i'kn�9as���n0F� 0.�*�so�e�0 >85%\ A�D�2d4ly�lap�W),&8�0_6� peciXU��91>� o-.2�'fy!�cataly� subunits:9��ly�red3β� ,��� !9�"8GSP=� s)N*^2@B-�O .� *� �ImiA�U-ma5zrmz,�Z , 2( �c=B�a)n� ly y;�"q  t���4>~fica1�&6r�/�'byp�,���z��m��/��i/9Ove0�4;\�y =e' modH n�db �Qq'�, enzym_cY1<.�r ��K�}�M[2, �ev�(^Y�!�y![ ��u��C��82�Fr$��(Ymf SDS2�)I-24��!6� qD�P�aca�Or �!�� tr�9akC%�"d �!y�e `�, GLC�E�Qst�%�z�,)730wD�L- AofLi2b or29 &� �?/ mis-.3�i~�?�#ult��36z(Aurora B [3a�t&� )~antago(s1V��bng.� 9�1� ��it����n� E7�R Qes�� ��{��,�1 , �1no�<B !��P����7 @.w �*���%. H�!w�#p}Xa novel\XHT>�r ���a&Q�" �1B8 Trs ��[K  Jl J���YA� i! toge��c�Hb�,E���=�"��� abundn�Z�9�0x n-6���+mo�raX%<�PP1&1 YaTu0 c:�E �amp*��Wa�)�Q�Zz3oF� s . jJpsZ-EK� h?y:�o(hermaphrodi!K carr�%y� er7�-1 ve�( it2-���?�bnj �Dpermiss8.N7[4p.�. 2k���a2in�"0% embryonic l�f�d�'��y �c� ir��.�&D X)scree�&!(sP 4!s�"�@ !�iso�gd5A 20i'O� J)� � �$escue�survivalv&eC mapp�Hn�,�1v!&n ( bs�,�n�Y32H12AZ% l�on ���&,Ae�)re&�2�*�J b|Af"� �O�F *( G�A� �s�On�(it� "� pred8�c�x 0!��" �� 6�1ame-shif1>91|. A��;!+;!��-�f�]o e���-&+�n)) ��Uf���.�1 [�sU� ���#(�4Abst^ ��/ nfir� �j�)B�*��g"���*� resO,i�,i e��wu:�;)2dbm�bb��e`)���A/n5��>. �4�!y�&Cofm.(�h;:�T ^ D�d83% :&�Lly�� i�X ( 0%y�&ToR%rm�if���M� p���y%?� � �) BV���v)d>��k:�> ��>�ng GFP::�a��I���PG %�-de�qd2Ce�5I��� e6A �>G�AO��! *"O&�@�paV&�'�g[�05� Z-nop�9B�� �2-E&I�.�mid p=�B9�2=��0����g�r��e�s�mah�� F�in�H �� ��>8�15sU�9 !�)�U7.-iB";6-V-} bottom5GA'1D & S3=BIn��tr) �g�D"k�ses>qA� i+*dM"��KimpactyF2u."�)8I �.2� A� M� �e�E G� -��� 2�,!~� ng!�!�"%�1p�e��.�<#�.2he!=PE&,asa��5&�,an)Pr2��B+� F ��v��G��.I5���k3Z5�\)!v7u��!.�GHk'aKend�� a�\F� a�@>UinvVg.� #,o�&X � wh��"�^U�6�YwZ��E:@.�$ !u-orlN��F�2Fis up-B\�y�6��m$4.�on�`/� o!A�; r�~"�h��Jis f H ��( � ^��k�*'� sis;Zdsa���i��\/P` 7z�4T� 5�5�U��2��N� �Pwf aly �-�- �L�(�)V���u�aBCH`yQmc�Q*�"d.=sND�ibIea� elevE�B�ځ"CE�A(*k��E & 1F��+[���6 inis�1'�KɖS8�xw;�39h%P �>@=2.�1mi�6E��)���* {Wph  9� itA><��E:�� �R�!�E�Żet���^��Fa*�"5,ac}#e��.Z.&">)�U�be�)Z,i� 2`A�,R�50exE��f�dm�e��A b$A�ofT)��.(�y&7 T LR6J�<�o"&.-ci�l�iV�H�1� E�a���;es� [�\QF4�#A< �$Fi )�P6�Ade�k� oB� �N9d, �(- )�b$ iBT;B� f!� #ed�8bT�s�-e�SG<l�_2B%��N�?U/*�A�)eng�{.� �X�&�AwE?tb7�}..r.� � expl�=�(���}t/�,. F��&4 on averag�%AM�.w-i�z�;WB�("Q*��� d*Ol�x! pDu�9R*Y/s�wM�aBn :�,i�&�[� �*M96��L7=+V�i| A2�KaYm�"F ��WtoU)E : &��yp�b� �"!F�:HrecY�v�#gen7Hs �� 6m-C� ��2N�Re$�`HR!��}szyſu���cloh�e96��� e@-�:bs9 )ae���@ G-to-Af se5x"� 7.6�k m� IS�����1 amino-acihbstitKG224S )œ _eighth��� 2A�)lir�at����6�e%2��� lemen;�hwo � 518�WaB,%e �fully-p!�r�Ol-i8]e�& 2"�6%�z.�8�G� i inim�J�[e�-&�G@P 9/ t�P�@peranR��$i�g �A!�U K��iܞ�� �` �TM�ren�F�AU��%��br%elf �5��)Y� does' ��ow^ZN,>��� [V�-?~ W�ximat%&"�succesލ��![F`>-e����s�1;�� l � M@�'J'� E��!r��)n:�wo6� *�  "��>D;,.WpdH.� k��`V���7�:H�Y*i" �.� a��%.r( work��verteb�� s�!$�i� �o%<�"&*L :��$M �a��1 a#Z��K� :�Չ�0=}lo^5%�� lyG>��M ��&sho��a�-2�^c1M�A"��UBR)�^5��@s gspG= �'[&�q�i� Aϭ�6!!�&�*co|%�@:�=byi�S�o (&�<�"H3��q�� &��3�UW�xt�m��v�Ed- �e9�y]�&� �or��/Ql2�V(qI1Fzyg$$�� �(A�!�&tm437CUd:�!��o;\l��J�I �u�{�i� w:�I�:! ���*�1���3���=� <���:��]aw2�x a� be ( 9>;ŝ3B�C�3G�h>�e p�k nullѠ!Za� tm301b"�"�`u4?%�bw�wA^,� b�m7:L;B�V�-|E�F &�Y .e!�M��M�"�.�-F<&tL:k�-)�A�d I�)1ƃ)���.�F��n^>���)sQA!�a ergVin2 ��F-E� b�?M=E�9� �V�Jb�,��,5��;�Y)y2�6�:�;$�4~ � it� *�DwB��al� � uf�.�*' b�/n� `.&Р�I�e�s%�<+!�!po&_2 � %[ B�2 ��2-? >Em.�n�0M�M� >_1 -t:s"3>�v?3})�>�~:}�� ��A�ub�%�!( u�� ���3%Lno)*+ &xk&G�a@��&�CvR�J* "s ,&, =e�M���j e&F�-��.�'�VfuR�-,�4�9 , un8 �� X�E�!q*�s���S&��NUthe^..�Q�3>\ �M�H�Cz�y <u<6�cBz�$w){�P�i�I5~�.��XD�;toun� iN blot|��)/ 1;o-2oY��rnJr�l|BƜ X^7>0p�EE�͟H>d.����� -����<� :?NR *�>� �&}%%RE�BvA[O2� oep���� \,��5 �)�xG<u*�k*eJ~"�� . A&�iIP-we� r@&�V*:"L.Y3 �s�!(�IJ ��n I�.� ��B-SIi *�'�h�T9� e� ��~a)E�2p5d��� |�d&V�R]�r�/by mass� tromet �S49 �*j,h�am|�(ame[�z-� i&�|�-?)pz����(�G]��%� �\fmp�l�h� Z �2�o��2N�}b�d��&m�,"_(sam�\�^x [peP����_"�5% NH64�!e�r�� �� ’s���Ga}ń2.z=w"$m��y'u2t"r3��Z �� . S9'$ Zav2+w�<� �Bq0��&�!�.!�2�i*�IhroR6����,:Z"<�^"�  �M�� ( S5 *aT~=�ppear�,5+6�7>I�*_�G5��-�!�#"H3�`�z. Curioua&� a)A� ��!J2P%Q�W�/r�t�<�A%D�� m�����S!�%~8�d "z92�eTuA i:.,%Xa @delay�#��|� �VzE+ xed-�!�����X GiveOatE��)G� i�*I8�Z�$0%8��&�*3& ����&ships%@�ZA8!\Q!o� V�� *�Q�0� ���n � 6["E9>#"� Mb>� m:�9V}9i"�Qſ2gPt��9Z�9�, ���9!kf�$coo�6:ME�Y .�:�.&�<9%��%|.� ���-_.o: /{�Ang!�!iksct 2� �mei�$ѡ���2�E��$[3ߴ43�;"/��(�)6V[�  �d~H "Y�6� �:B{� n*up-%M��=_�!-�$��le��/AIR-2!6�; :Pa�� &�!V�( S6AA�6B & S6C�5Tw]vI+ >".H!�cytokKk�+�c�MNO�}��� ;[44',Z�m unpecU{���^. )A|��60��-�&_D6-��e nd�79a:�U g6�A9�[4o-A&�<��rX�O�&_P�2W~m�:$[4bN47]!�*�dAL*�'�'*mNQ�^F!%by:S/\ex� <�Շ��irA� ]W��R8O6�in�1���p`���o2f�n�9m( S7HU)hۤ�<�ve�SMZ)Pb�A�i?Fae@Fb[�Q��i�r�oIn �2 E�2���*cog@dU>���Plk1 [48kqa��i�^ dFli�J2|B�[4�JH-J,}��lk- :�>�)�~�B$tv�)wi�.b"PLK.��$_(�Cm�L�n?D ?��sum�S&Z-� E�%1.%B�En�VV�iaGq�ev^1�sm�t� � !& F �Z�,!fM\ %�orA��!�� ��s yUbc�`�!m��we���P)"�  co�4-"�i�!�"� ���B}--Q. G� ��X|>V�'VA���>�2%9A�? [ �5tLWe quxfO*l&�' �%�6c�?!�1:: u+a�c5-�P1�o���al :kSR��� IB��&� !4�. ��&2�J�� ��,M�6�e-a�� OB�1�B�7y�C 9pl7.�-"�FN  6�B�g �d�Rv!=6�Mz"?��g�Xs&�@2�B. :�+./%Hu$<�$ don-��m�$spd-2::gfp�# gene [52]�2~&�<1!�KrV&;kf|18UYe-l�)!�E��7F�>n�p�9Z)��(%;WG Q�4ءa�K�B�i ����L��t9$>��M�a E� �J�*/!�.�F�.�0&W�2�n&*AT �Q}F�a�N+ �6 213&2E�:��� >� �r�Tm�Q9�����n�Si -?aueHZ/B�D>V?2�  d�:6MV!�7e*�H5�HT4A & 4B�)��2J�fluoreh7ӽf�e!�!�F�c� �1�.NM���� .x|AA_'��`��D!e <=�m3�g*. � 5-2u-�$4�$4��AE�e&�awM�tb��% q�6��5V8��&+8.�^an<8o !fhA2 � 4"-,fztR��'de�a�x['s Z#ed-!-V. Q� �*5Bi)X Uro ���41| U�U.�.�)/ -)� *�-use�nt%.��-1i�"�� �*�-�=�&�&�O�ބlit�&� � �6�Nda>�QaզZ}�@�63 ����=�ACs2�#��BS��M ­s�#�qQm5e �.�,"�#�T�)� ��� 6~ekZ6FYA�Se!;of�J�%�b"u'F~HT�:h��}%� !Fy&:n��MO%�.�MF.�.eI1@Yvi�!a"�m"�d �h r:L%NBD I;=ItabŌvM��U�)�A���t�>R ,M+mKb&KU�9>� �Uy�iq�`-*B� �� ( S8JS8'8�Ũ&�^�)Q� J�#�  E��%:E�Nyc��� X �w4_>��uŕ~����["MeCn-N) )'2o<- � A�2 ("�I33s�N �by6�RT-�oy���i6N 1�`�� c"� TmqF%�&+R � I�F����f\K�aw"�9�er {<B�+ �N�!E"� ��2c �i�ona6i�,A�ӄw# 13"�FM+s�\�6�Ra�'&�Lr7Ue"�e9p�me� � )�Mv"�6� loI!�UTRe5�b�e�o[njUw lx� +�6|aWIlow �8F� :S:� stem�'abQ� "� E!!g��!�()�E� ion/.�N��'F7U����tȬ2� +#YTyqh�� GF2�vea�eL��B"� ��(�-�5�<�� o [}Kgy��Zinq}G� H; Stu�@�#t-ep>&wR�R "q�I.jw`�3′-UTR� orde�2F a��"�3M�m%�� �qCF1'{tw�a-\I� &�&A,�A�5,� ���E1�&�!'�A۩�("�"�B�&���K #^��-�:+aÉ�&!J ��~&�qM[�f:A�" ions"/!w�]8Ab�8�.�*a�t�� rule �0rec�K��| amp*&Y[2 , k_j_"�^/���>J.�. "�, g_$�  �-:n O ]��Vi7/"y ��=w�4ig��P�V<% R 1!e�/1�*?%?6e�A  uper�,q%CY �0&{w��-S�-ueq ~yau1B���TWA B�T�i�Zs� �)L3�15���i�b�� QQ�8!!���&�s; �B#M.{�)X \bEqF�R��\V UnexU�V"I�:�smJU��m�"�&�:"�(,�> �-��-�lyY�}��@J 5 �5 6*�1C�?V h1�!Em1Ua���G�/2�ar�?�,"|<syn��Mly�Ws�r�U��`Cer� n,= �+.����'�-�� �&m{&q2�jBglP� se (��of 79L)u��=�1{(� b6�4�ks�-�&"2�@ �1H� �%JF�in=ʅQ Mx�-cE�arisp�E��0e�$plasm��d�vo�3�u:�o*ppF�6 �_�9alv�16A?���*D�24%�ly H�!�6�gave �!.kt�ztwo2PM�M��310s�7�f��.��R;ADSq� �fI���=.t��[d"�lpaJ5E�a.}9)B-�2�T2i02�!=�A��mn(Wer&*V��+2�(>!�ta�<6hW) s�OE�ZB{_iKa�arAbyR}Nm0��*"X���v�%�_�De }thc�& ( S1&� =fI �f�@79)m����`%��#tu0/aBs�CM.`6c���Q�"�!tenW�U�ult>[d���DnH�y ( 4/:�)2z6�AePhone��-?�- bW+������B�'!B��� ( S9+!2S.�h��9omep?rem.MP!��r� “i�Mio��.�6�*M q�I���] cs��d��Ad!p "���)��>M�R �N�!��� x"Sq'r�ucBm . Su/�Vn IQ�P"�@(%�10r)a� �&�!�11%)퉨!`3?gQ%xt…A�^�T.����2; .��J� >n!�I�zJ� ���Z�4r��� �/= ]D[5F!5�^F�Is֓>�#7"� as� eaJV~�'?' �*:`trJ�8�I��es�tEweI�U� occa��4�\ �3��ŋ���w >�?k`��:#K 2UMe6/.O�co.�7]�!�A͢�>GAu1^a2t@ �ir�+���adE�S2��R�.�3A�&� Jl!{iD�&�]Z�E.)�uA� illu8���� ( SI�1m�pro�4"'�mea��o1��ar��4�_� )/ ,%� [5"v�\��� �& u�be��&� ��"� �l�We� �a3�7/Y��=7k �V��߹�B� P>�.�����BL��N��9�*aNALb%-+�'2� � � FI Ci 7�on [2]E��2 �Vr���A64��I�m�� S!i>ijվ�"5�:Fx! a+G� al�at< lT0a� �s�'̡����%� |i� , 18��V��*� }%�2 YM�"HWe"1=G7 unu�=�� figu� ��0-1<-grand.�����6 p�8!�6� 5 � EN&5�"�0,%y%uQ)�`7��5 "� ��>n"�"�r4�g51�!= 6Q. A2ai�nbe)Qg�,�% S��x�n��A�6U � �5&g� � H"�1"��A9_��Y���f 6�:.a�*G m�P $=\!��Gcl�D��)Qde�*��@.de�?&]!��z�. sw,@It-<�n�_de 5?>A�:�h?*�)�U$�n &�a $[2��8F%maE5��.cs� XV�*nt ��"��JW!AR Z!�qU�3�Jb� ��R"V:��HP~� �Wmb@�!8 m�zQ�2�*�P ?m�=�bEAj2<bya�t�~�&��)�-��ZK ���6P-L�B�+ŕj R�a���!SCF&�..�}�%Ntv.Á&�&i6�\�SCF�2���(v��( �!) �i�� -!D34sL$��A��{%�E&F%[ƁsI t%��FAd n!�uJ�$l]:D"�<�R *\^ �i$2��Ft )e6%? "��?*t�zt1SvemA��4n�;V$6 V3C6I.��H~&�d P�xh!��>is�0B k�512Q� , �0�E �zIbi[2�* >Dkg �-� @lm3? "/v�0�G�H2�$* *$heI��EB�s�'UR�i26&B<�\�7�9"�7�. I%�����ob# ed wo.t�HS)�=OBN8r�-v"lxm��6�I^L$! T��[g�.��e�&RLw1inki���"_�as= 1FmatHit~�cano2����X � ion:]�.�� %�I�kC&�D�$A5��dB$n �=�!">�"�O$S��te��al2�,.�-y�2o�9^,�>I2���U�%wu�5FDm,0,&ԅ6X}�".c�F^ .y�w� ��t~Cō,PP2A [58 , 5�<�ef � favo�"1^&u���-�U�:"U�nA-*$G*� ,� hap�_na��'σe�F�zEe�t�opL*ngm�UG'un��%�, .�*8 �r&�Q�^!kpA�]J�6-y' fasha�* H)�.� . Of �'a KVX��n�Rusf��%t�f� [60]��z-z W�c m � 3AL,2_l+Q d nematod-,\ 21P,�'ȃ�8�MPc�fa�T=A�$lM:�$!609e/.R F���Zb��!��Am �j`1�z�<9� FQ&a4L1F+Q�� a"2el����".NC�u�"�2$K|)��*�!��*1(P9A4�"�)u72�#L�^E2A�i�),�(`-tu�&�G�*%�S��s�� ��\.� B�6�%In agre)��E5 &{7[2]E;Z�fl:B resu�A�Plk�wis%�ed�� cours^ $wo success>�in order�y��fuAK�eEH0become capablYorganiza�PCM%�,as basal bod�)[62u!,A��16�� be a on.% how poloE� kin( opera����婅L�0om ˡ^coa�Z� func-  do��� �)Ͷ�x;.c��M�C .a, gans�f ? N�',PofK-� ed!�4 peakP mito��mMbe!Yre� ��� $focus mark"�sit%\pro�� y!*%(G1/S transi�[8�0��C� osom2�2 alsoB�[63] �w< c+ # at!vF �ait�Ej�restri� F�*5e{ *K!kato��ofF� 9�� Ensu��ay a1l�/Plk4-wA� aintained< toI�keyq�ory step!�9���AB&F � understan�ofE��;is achie, re|s lim ,. Clearly exa�.�$is suffici!lt� bver� ��q&!Si��/�X plays an important rol��recruitm]Dof SAS-5/ana2/STILE6Q~�ofZ�[13� 4]AKen�:�m�may!urequired g=im.�whe��inq �bV� through@ Y\s!Kh��> 1�an��n ques�T summarR�ti�Tified I-2SZY-2 , SDS-2 aLk vel �6o� �J2Oŀ�1�Fin@acV�hkte�� l!\$en describaJ i] � ngly L�1 amplif�was reA6!��qdeple%of�i�h2� sugg ]% ����of��Aind�b�n��ed [3��We� da�Bh� eh!7�availa y�i'�Kevi��accum� �"� �n�f��*�,�QngA9�6� . Appropr�U,XAA" a^�� cruc�to ���hcorrec���M numb�. Althoeahie�E�aUkin chrom 9segreg�4duYi�u��� $kinetochori�w� docu[E��a� Ibs a nmZR���ena�of gen stQb����Y 6� All{m strainr� �BN made�oreFto [67aTo��prote�on�^��!�determi!�9�Biorad P 64Assay Dye Reag� (# -Rad�1 . 6 mgA�t2p��N2�I��m!AperA a� each�.}�#, 30 μ� Dynabeads�@ ( Life Technolog6)iincubE�w�1H�\respe� e antibod� 4�D�2 h �sef wash�4�# ��%�iP buffer ( a�DM HEPES ( pH 7 . 4� 1 mM EGTA�  MgCl� 100KCl0% GlyceA�, �� 05% NP-40G re-suspen��8in 2X Laemmli B�Bi1� , boE�ath� minu�)2�by2�囉+*)6ies/rIm %��T< tudy:� ycloI�T>)Zra��pur� ag���Tentire szy-2 ORF ( CovV) ;���U�peptide CQYQGMNSGRPAVGGGRPGTTAGKK ( YenZym AnE$A_LLCt� [53��,phospho-hist� H3 ( AbcaZ �(2 [68]; DM1A�SigmaeDMas�$ctrometry ��a�:.�NIDDK m8/ e faci��;� e�wi�!h)L�A��$ DNase tree<* cDNA�g�(a er� ptIIIuU nd syn&is ki�InvitrM�Forward!DCAGTACGCGGAAGAAATGBDrSse!�&HCAACCATCTTTTGGA ) p� rM=Er�? y . P %QIama-1Ip3a� ��ad[6��qRT re� ons '$iQ SYBR gr� su�ix2 ��i� eda=!�manuf�re�LFix�z�s�ko �e�".�S"8�R[36��� �>� �8t a 1/1000 dilu/ :>,v�, M�19A�SPDA�50�w-�4i.!� l� nd fixKmag���s T � disk!�fo$microscope��PYV >o��"� � s�xof%� �� crip  shif!���s%�y�!��r�s< to 25�Fas L4�d �*�:next da Inte4� � atin GFP��f�metapha��qmeaedmy0Metamorph . L"�or-�a�2��K��by qu!�"k of a>ge pix� ���O. Maxim�roj�Ea+-[(wE��QFrflumc{ in ImageJS40ge)backgrouAM..�� subt� &v6W)�!i� t}a��ch���is�7 )�u� illumini�U��u�� � -labe� a�G3amZTVectashq# (,or LaboratorA', Inc .�7S��e��Mjw�a DeltaV�#OMX4 SIM%MA�System�n ppli-U @) .�}Leishmania��( rapidpK zoonWt����furb�). Cl rist�ga� �� of ��l� in�ceral l2�( VL )i�mi��!�fM� n�laan}p�m� nviron�al chang���-!�act betw���,Yi� their pet �}municip'$of Camp^ ,�southX!Brazi� �"re� ed�� 009�e' 2&�%au� thon��"E�& o dog�s!�n upsc�%res#�(ondominium 1!c��in" 2+ly6 : area ( EP�w. �t�,��e���J1���&�dogA2 habiO �ge�ph  ontigu��sE�P e�.{!u � �6s-s��,ud[AnVLrt�vg!�Y� spp . in'ioh!dom*c �,E mammalIsa�fla� mol�� %!��&!� sero� �� tech�%ALCan� ��al�\ 5%�7 2%�R"�$E813!2015 ,!t� l�tSix!�J�,!;Cor C %Hv�spo~ A7-��#�=6�(re.�. Two imen0!� L .� ��infantum s�u"4Lutzomyia longa_p� �Ycap��i&A�. Nm�9�byVp� !�r!��4ne Expapillata�� i�%[A� Pint �mA� cola�zA.=<�+s[� . Ii�,last 35 year�vin�!�reemerN � .=0public health� blem!{9��~world��, �e��� �ѹ!"_-r��#new�{ s [1y �America�4Q<ճ�!plex net;�"l( ship�vol�G��&o,.8(. )a��I$( Synonym:�� chagasi )��=op:s:.�,E�l�8�0V� [2];�%$ild vertebY"! soura�of���c;� susc�ho) ���+�(bE��*a cera�~ Fpac�$�  a�5�A :�%g& tt&PN &o � 1����S��he� .�� t?necess�r }?o +%k' non-��- �ip�J n�*J��(] +m6 ��s� sc. pebe�rQ0o]0�-��%� and/7ynk ic �#Q)�&� lyA���treg4areco�% s [3m_" u"�& mid-1980s����=�ay}!imarilA'� d ru�=��1F�1L [on�,�Rcs had.o1A -^� .Q�%og"!E{@ jj�/hundred��*P �W,��!�e� zc!�!>1Rca(ls [4–"" �>"q-�j`mo�u�+iZ� %��0&� :��� ].� � �saf�."E �[7–10A� ��P0a�N ccup � Lu .2( tG �veIi!��$c-B2 in5FQ��h� un�[11 , 1�'��s;�#(ão Paulo ,��J� VL6cls� /(=C. Over a"-of 17�7� 1997�U 2014Axh� 3�� V%2A177>|M� �,I��467:������ 214 death� aE+t!��8 . 7%*�$. I�2cu�s2�"Ajo� gnize "�(}��2�M� �B�* !8Q�2�2�:(�Ayr� 76>1a�"g3 both-c� VL5'b�\ v�L* � L.�4B�,E�M1 ���rr�kB8T qE �1�H n)�rd!()�&�rFM--� ^1 f <\��m6+K2:/� �#%�!�M�[1�O Littn's m#dynam�� 2 � outbreakA�V�2al%�>^� Nan�Qb,# Gdi\/~ Abehav�0"$ I� "��Fv�59 I� >^2��We �&(),��6�degrad� ��������e"5T� nc��S�5�� I�deZ{ ord� �s� Zal vege!wco����A� al�.�,.� " �% fauna [15�IHf <&�V� t9)� adap�e��bl � Im *)�of!�`*ke:� �!��in&@�� �b$:�}v}�!Ior� 2�f�aM�}xy [16��P p�hk+gC!gn?%&V ros+!8 1970aPl d'�c!�!roa� � n����9_u}.�>�i"�W>&�9M�TA� S��HKD�!tE�������!�-eVL ( C�1�q�e�ai-.�e(e�J42 . 0% ( 4/198� x IGn!S��40v zc2�3cca�NA5I�*R $by polymer�ch�7� ( PCR �5S���w��%j,in 16/85 ( 1�� 8% ) A�� 7B\�.� �� �162Lhou�9� y�*rk<��2!I2%M�<s��[I��it�9�&Q.�A$VL�J2� ]G��"HR�FrR"N�.*d et, ��5���iS�=l.$(vdiagno�(U"��.�~%�%�to �cfe �l.o~-�Adolfo Institut�IA�* cha~! �6 E parar1��*iso�' >=um%h>c.� <�0��no2]� ye�-5 .rA�no�p��AQm�!��m�"=��.i1��*�b�l6�;�._ ULaWtifR>&�  ;o,=��62  �EO��Fl���&a b��vV&( ���i}�!Sfree-liR w )a1*A�"!7�Og0 4Ai!}search�8s/;of1��d8$surveys . ű  ?K�-v�JEth Comm�e�^A� U"ECAU )j"��6Universw((�tocolA}. 3296��fE��V;�*Pasteur2U�'] 01/2����2ian9 of E��bRenew�,4Re�_ e�� Biod�Authori��I�)on&a IBAM�&SISBIO ,) 42926-1/2�Z�2`.9x( 22°53’20” S , 47°04’4W )~%�x�A�3 mill�i�� �is}n�"� ��2��'kmp!��7i�e�199e3(Mayor’s O(4e b�del.P $of 223 Km2a=; �*A�ne$&���6tudes%A45’0%.!%T6S� 3$46°52’33%t03W0  8�eU����larv2�0�� fragV ��*2.��Atl�"c!�remV ,!�0as� Y�of 68"�&�s: Nhend �[F�$. Despi�7e͎� �wrichnes� � ) st few�Ea!�a[�68 sign�nt6� � � |Vimp!"� �e�onA�� ", �ope� up����y �ed>5T ��eQ�z���/�-97 , 2�In� �f^� �VLQ�2T!���%�  n&��es � FD � ��q,1@��#B�!L E�**"EEfV,y� *0"a�2N v I!s2r��.���saP<&!!e�� �U%iB��^!�sha�3�QB� Lerist�!�pr�s��Z9uY=%5+z5se ()�#�7-$� �BI6,�,TA "�!��!set�p�H18 & poirE 9� 1 2�%����@ ) N def/"x�B�2)c��'as a->�qg91 to wOGa>a�s�I�Qs%, conn�"QFv!�2d�9E��-ra� �"\ hel�DGoogle Earth softw�(,� c�.�" . 204!�� V. 13��AJ� e�A��among&@� ~%��.]we�6��I �A�p� -� , ob��� GPS�lobal PW &�cJ�2���B!y)�r"B -�A�E?m 3",&zFp.�N$a*k B ?�s�'GIS )9�Map� 9�,J(matrix laye� an aA�l�+t�%�!] =8%�0!�AmF J!~ -�<]�&� !B�;��ofB�-�\ 2v ,A�d=I� i* “SOS M�#$Atlântica, �(�N%4al6 SI�  eb�( INPE���4www&p�!brI�rc!xu&, v .Z2. (G*p '8)�R� &), CM',%D!+to\#�g"�#2�#Asdraq;e5�l72ob�+Ճ�,-�ic��!k!2k�;8NZS G ��0A�"( IBGE%&a2� aR��2�-�e)�.���g� VL S� �%P�EmeV6�&��/radiud2_3Y&�a���b��!��F.0!0:sB�aen]* ,��%g"�p �����[PBqJ3^#�# bloo>Arum[c6A \��N%bt�F�m-)�q�P� n%eP"F� n�2�����<+rd ra��'=;@ ;�@�W pM=)l�5�(,� (ed CDC ligh� ( Ho�0,1�)%J n�ɖg%w[Sf���.a��up ab� �m~I�a�� 24[2�#S�&BclassY�srT-� GaG 5!PabbreviG  scheme�g�-na)K�"tjd"�7byEpon�[2� DueA� high#ph"��mbl�, taxono�'*�Brump�.��'dP� ��G . Evandr�.sallesi�E� (cortelezzii-&�(asB$-A,6� ��?�D�6��s&&1Y6%6-Y)$�. W.�)��;R��p%~{ 4sixty tomahawku ( Gabrisa.�ezd�0�(of�> x 210 c�55 x !=wJ@banana%chicken!ult�w�7a}Bw�#I . A �?L0 ��Ai�(  ly 6))Md�'ibu��a!� soi�+mRin7Dear`nX2� 10A�20i��P"�/+ps [24>� �1�˭�Q�[C`7chip ��0M#:s�hsU5�)�nd �0��}i�venipuncJ2M��� Hi06�x�- �sto at -hF�*=e=�ۉ�M�\Q, hand���� 5&f4E�� 2<c767to gu2 ines!�%�u�P�1^�J�BrF �.n Socie�, Mamme�[2dE:���A� -2ei2��&&p A�in 48 "y�BluaHUe�2-< d8a QIAamp��6 � cube-�o�AQiE/ , Neplands� o�0%7�:�:nd�@)�̡W�3k ,NanoDrop ND-i=(�rmo Fis^S9N� , EU�-IpA0o "KEPendX%�#qu;),��dg�#�{.!inhib�Hf6��9}� �!�:AMN?�a�"�K gene!����a �/�% tinoid-bisO�eiM"IRB�D, -CF-FWDC '-TC�?AC  TGAG�?GGAC-3'�>5REV 5G((@2@CTGGC 2[2#Fo�S�β� - iACTTCA|CG <� )%Qβ2�e6.TGA@kT 4TAGC- 7[2%�]mq92> r oup pool\1�-o$7)6�5ga��!�x�VA�aCM�"> a DN~B 6Tissu�Su fheA`ntA�7uCI�!>pQ�x:�>�po26m8rophot�B�DPBioTek , Winooski , Vante{A�TY�i�xQ�LITSR!�!�!�A!�$TTTCCGATG -��L5 . 8S- TGAT%�TTATCGC!�/� fy a 3� �350� pai�1bp�l y�E�geT<� ��he*%4#�;al��ns�O�2rK[ ITS- [28]�� ch14 5a�N�167� z�Mp[5� circle�ofVm$[2�BAS!��w��� ultrap�Q�!eYxA��=tro�+f�nd�C Di:R�$T( MHOM/BR/2002/LPC-RPV�� 0V*:b9=ie[4 1975/M290q� 4) maj��aILb'$0/FRIEDLINE�A���K ��ed� 3 μL of *�GmM�G2 Tris-HCl�G 'DE�G4<MgCl2 (N6 μM��G25!h88ach oligonucleo�F( %N3 dNTP mNR�inum Taq%�*�'( I&�E*� !A�3�>�1 6w�'aE�mD ra���00 ng/!O �[�$�x$ O��D8��"$l Tai et a� (��Hu;Silva M�!�i4J �a� ��*c by%�_=garr gel %��.�?��0!/10 mEF�2a@�E>iF�J , US . A��F���%^�j IlluaV GFX�Dt!�Gel B P8I�&3 ( GE�cZ , UKe Genefs�M� Sx r� hod:�j ;An�Lr 3500 omR@ Ser��a BigDy�K/5 v 3 1C�fS� ��BBio���nE!�s�,!�� �� vi�CD�r Chromas v�!�1&�(TL elys�(Pty LtI:A%�li�I�d� subC&d�ggd aligN qMEGA5c[3GGG�=%��de�)BAGenBan�] Q�;basic8l|� to�OBLAST 2�ncb�<nlm . ni`F gov/-E3!dan�W!a-&.��5�@�L�%��*{M95%�fa�c� terv�6(CI�cals�B� �1�%61 exa�F�v"�T.T�76�.2�.�)~# �.v""F v!9roIo"T�(! Four9�& nty- 5 6�%c`%291#@ � A 186Z!�2 }�+C��8BA�:aO�A t.v'CX�� }�� s: Nyssom�B whit[G 07���47 �sMe1m 081/342/�Bi�B�r.2.122.�neiva-12[132- [�pesso.3- ,� ndF�/( Y)�@%�&I� � A2%V2� p"+(aC�� H %;�H 3–4R�02�<E>Tfi�C(M;�w1.C2CD5D�P�I�C( 2/25; 0;A�0–26R�Hch5%kJa*��>�0"�H ���vO�7, � 2��Af>��xb��{*DV 4/15"q e!a��exa� h "; ,`*�L!TI�l chg@( s~@�B�>)`gFv%70"96�: 100%FC���Z� �)( A�%GA[AF30868�#��E �V(es = 2e-37;5�D 2e-4�Y. E�y-!w2O�Tsix�<�)�Td: 1 Mazama gouazoubirMI0brocket deer;EO2AF, 10uru�x Guer& uetu�(aestua��squirrel2< 8 Callith�# jacc,f(�� e-tufted-�(marmoset; 9; y1.TFuritaR lack5#e�;um;�3. 4 72up".!=Ry�30CA�43.|*�F�e �5!���J�Q6/82;�&3UD .2G%���b&`r�b� c;}�-�GR�83�8� w �8�LmK*epqQ..? 2/88�i:0�c��� %) ��r>��� 43; ��72D�0#!�g�;G{ con��� �P J�I! �'- '��B�H"<b =8f,re��� ion!�.L�in6jP 2)2� 500;��F�Trypan-Q�Nngeli�J� ( 98.�;�@ =%�f� *�{ AY23023M'1%Q�a� . No�N osi? �g&� 2.���2e2 �;6`N�i)hm:�!�RCtwoZ� JM�?idY/�e"�<� FE(B��Uovi8str$*e �+ ylva�]0J�49urc!E8/.*�t�7�r��i�&� firm!x2�&.*6�-�Ia�l�"oZu&t5.YH����#cohO��)���DC! a2hypA a � .AQ>�0bv!hE fan�be ru�R1�2Z^%;�L!i�c%:�*V"�/ki�"�<4:�:2� iq�N5 mys��amipe�>�, j.DA�Gr�Xa.Magili����/woo�$� -,�@� 5� � �lr;N!�u|VL&:Inc6<�!w!��,ff>by*�1 ��9 [31]e�v!<)�2:|,:B/a2"ct��ti%T . "��E"�'X:e k-> }>�&k.�0 m"�4B0!|=)��-n��5ء&RNed:�X�u*�I =�%��/�phleb�inad%~u� � ��*�4x�3���Q�2�a�!�Zk�J��"Cinhc�c��l� 6���*&J�x�:b�Yh^$�9em2')�*�O �a�f O,mt-VlowF� de�X{a s�q��.;P2�2�. SfaB)�Wg<6��A�6�Mimp�$ofa��WwoQT2�$�2�\7NnIA�iC�q Ine�sho�sbe giv�U�G-{du��:f{V< se=�.�-t�TVc}<!��V~6�6� �3"�$G /) roba&�Ct�<.mUq� %4[32Wa�$iscus��er�%��OiA]>CN�cM62�of&X��=BK"Up�Mly R(m!�e�1(id�Goli&�D� {H�A�pt [3<)3� An 4�D�BingLN �ul�m2�taU!��[,�&�iQ]� �9%2�q���L6#P"G5to6$,JE#�:�� cpb�. worr�\shR��! "/Ri� JaneirT1%�M�\�A��of �`g@ed� . 5-fold�&er" Sac�A�YT�?�:� � �'8g.ci�G_L(i h�&: iC 6 ��0s&j/�\!:5w[3��x�/dety20%.E�])&e-�:��e)mfac�nsU�*&&��--�i6[i�I�/ Chac�IH of A�tin�&ar5^&V38]�+ed 77) fa�eOrea��* < �I�VL had�*!�d%� 132�): E4'e TMq mQ7aEvE�� ������2)`)%Yeg�l�Q6�\Uw rela� ly��]�UIcFr�tS aiA�>�E��%a� ��ř�E:g�PI��j!5�is�7yOA�at��Q�M�"n;< % / �.�Ih"Q z7�_>�$Iat%3�3`,�jw��2�=6 �&!Z(P.;� *�:�U:]4u<��!es�i?! ���� u:>P-�+E�. B&tI3k}ex/(pheeo�'sÃA�bqml� 7/s p%�Ft!12A8-V[41�(�Xt,o S.�2N�fo%a.�3�mbrene-�i�"5L 0R^J!4wes�"q@? �S.�P( �8$-9-methylg�c� B [4�-� ^rk����Jv>�D situQ �m*�3C;Az���1BN": orrola�<�%�&��Casano.] 4�gwho[ ��m];5Y� �yci�R��et��� �NY2�CQ�TZk,>j6-)�� �ythV��O�r��esi�F"�u�.l  phi�Y[4� 45Q�v *U ��bm�>V R J$y ) YL G sZ '!�mL)� of D�F ópo[, :�cinFM :u��:<;6�[4MM4�FzEnY>1 �� b�^�^"\G���a7 such�jdGB�.0A���-�B�%a� �2+� Mato Gros5o Sul—�A=�%s;4 i�!�6yiG—W�vb�B����*�W"xA (]2Q ��8[48fF' Mg .� –a  �A,cut�/6��asz� xRIP��mbuco%GCearáZ%�x ��,c�act!�a*m �in� 2,m� n!�a�4R�ba� [5�5Ţ�U&? to!��at�r�O�B2�a��8jMP,!��6.�V���ejR�� er���&C[5��m��~ cR�,&�W%! �bres2`�vSBe(��[5�0W�0~ex�;�0mOv� g��an�/ rol��+-� beca�/�e!�-a&R  MmvicinG��[�s}4$#[5��H"����rL�� )V ��6 fur�5�-&`e!�I~� %� ^Q�, �q�S��m�FQ9^�x "LWu�%�R+�[d -h��U��A7alP"�D� ve�8��l" c!J]@fAFi�H�ye��s��X~lo,$2|ch) ^E^ a�~& !���Ma)�-W�`.� EK6�cK �T� >y Qpa�O(a�� @ 'gd�"�ellr2r�1h �c]A�6�jPparsx� � .��uxuryE%�h * }�> L8.G�guc�"�2� sub t�5B�5�)Ht�g3untE�^exq��perpe� !CR�en%�Šs� a�#^�a�l��N� o?gA�Y�*�H2C!KO�em�4�otoie&�56]."�ymG � 16 inct1�5[Z�2�e ,�0�%ii���~�itself-� �esp�8���&N >F M�t VL&inERf�e�IO")��direct� J�6��*i~�RSV�����hrN�>:G���s� .00� �acc���gMe�  l 5cap� <7 Me&� �fE��%��[�_eʋ�Y��g)?m�D�q �'%���s% �&c�? � *ned���ul��F��["�eq�%��Bo�c�L=&\��-�!� �X�=b :ɂH\YZ> R�Hi*�P�� roP m 94 ["cM2)�(Dn�um�3 ъa�q YJ�!�(Qt6Vf$in� kE���:OA�t�"� %I� ,b#i.�e�F�.�FG�nNfA�J�E�u�,.Ia>{ia�5 &d�-Y&\k2�Q�toQG&�Ss&5 d/^ ��Gi�w�� Z  f�EoRg "]#�AE?� �&��On�eR� �]F , 5��k>pGVD,D9��Ivi@ Tma2 N hn��=bid5 N&T� , aiG(t v�&�B)zx�ڭ(�LcA0���Guud�"!?e_S��jC[).Q��Ag!otheor)1&gupW]�se7�� 7n�9� ���Q���du� �y�-�hi&�d�Tn��!e��ofŰ�[s [58W8In EurDw:.n *�_%�"; .�a���"�. "��*�80�)A�purpoa�[2&�.�TF�u�O��`Js , Gr�$ di J�z�5��"�� DPP!6plN62�( 9�-u.�( 47% �� y asy�B�%���#!�.<�|*MUlyW�:�'U-�+!�#d:� IJ @� !�1�useful!�a�"�[mospR� ��d�#-ALau� &�6 [63]�=;e�6)2���B�1&>i�r�V� U�=��(, 42/47 ( 8�+:+BLw���"s"k_� s 35/3�*9�1!�2�-�- �>��rac�47%l �IBio*�I!�u@3 �9l/�/B�!34 �8�'b�.�8)+3���u comb�;Ai�!Ga��y&z ��"2��vm�i� in 9�1%2�J7w9%280"4 YQ�m��w)\ �yA�&Q��&� �r8 �{_�ansi�%�Z% �"�nd0P6z *\iwrP! ass�FᭅD� �R� .�)aG<4"RVhe��ce�'��t3d)�)middl"& \fA��B5p���[:z � �� inde�ntJ���*� iar�w�)* mV2�s"f�!d�ihylax����g� ,A�&E@�JKn<2A�(� ��:Qn�$��p�Qs��now��Ug�+�Stu�%� clarw?D.�I*!��"E�W7�}A�@9A��x � '�"��a, .u�all�p5ba�jts �B'A�oe��f.P���elP'12X"^j!F�y ^o�<A �%do�A�M:~%u!7�!l? ����cc��.l�GRNA82mi )5a famil���'R̃�z���� gtKe2,�p�-coE,�p��Y �%h orch!c�r���Or�jT^"�� y me�ismAa�explo6Iby vir(f��!6iy�fe� !zev�!� iX�s�U. Eps�D-�" S ( EB�@�n onc�Eic %,%�)J��Ii��t -��8+ZA�,nasopharynge.?a�omm3NPX�,���l!ta�NQT�� umor���(%�� �� South Asi�zS�TLki-�.� j�� Mmig!�o�hyva��� of���f&>�ad �ti�D U΍!�se!Q�nco�,�!'%k�.�>M ��'ti��!�aggZ<.Pm!O ��A":;6k�bye�:Np ~�a6/�dAeX-BART9�m"�t%�xMe! EBV-"��i)& Z!�B ����d ��-%�2� -of-&���daa]!��m�f� !�mi�in�q�WB�1'WeA�lm��!JM%�z�gd�]lDEXory y2�vZD manif�"�4\5n3(d�@qa:�Dv ) Compo�a�k�#6��ot�bt E-cad�$?a mC#an�o�.Iis piv�Jin)�rvAM�- jun�灋!�epithel phen�#��webio�#�D�T�]1�a:3cu!� �E-mF���?�i Js.��Z,�$senchymal-�c��!�F:T."6�F���Q�Չ�i`os"�!E~$�P�o9�M�2a!}�*��2! ��t >ᜭm� mBa�&� 8Burkitt's lymph�(, Hodgkin'sa�%,rE-nodal�Bt� killer/T�G( NKTC�k�s!sga�.I�C[1]–[�%Pܡ&�� geǕ��V"A�R enco8��OESn�Nv["dw�-�*���)�(,#*via2 & hybrid�h[3�|� � �rec?v�@at�(h��� path��i5�}1��A8.7�<n!�� �$�[-��d��o�M��Da�B.��mi�Y2LMP�LMP2A%� EBNA. � uS�� "Ocan st�V����t�V urvi�A����ap�Y��6YCeljz5%xh�9\,�w�eJ4i � &iI,�;M0�9[9tM� � F� *0 6� 1�)$de vari�P�:� g� rga��ve1�!��bo�&homeosta�7*�g�<9�T[10%&1eK �M�%�C!r�'�g6e T'!om�CeP2=�L!��!�3′un%�!�d (UTa�Sd��m�'ge��� m%� ) [1�#Y�A+,���[T5%�%��� cursQ��44mbure$.+<�$!Ud>�FmiRo+9]�"?��=rn� s�;�a�uk/�C�|���%Mas 2 ^R�h� ����e BHRF& �< 1!] !Ka 0dPBam HI"1 H r,@K~}i"_>fr�g�M-�es 51 ��39Y-  �:+Θ401j !a#��[22FG ��  (�AQ�1>p�OM9Qy�IA��BBV-�� �T6g �� ��x-ǁllϥ-�1a $ [Š.6� K���aNi�ly' A`a�]IIIR�ٽB�9�� �cal���,M��E�guII&�Hs� �V 5� Ias3#%�M�.����8�!�  q&xa��# �)�i-C~�/&H^vRSa�l�&�h&� �1/Q�d }�6�lower� 2 =�y� ��� ^ -�� %5���a�:V.��'�]�!�"�A�CU��g���*]9<�,�2�� ��'*tOBALF5�� �)� repl�oA�6� 5-5pk1925 m�v �1E�!�102 tse@�Ie'p,in Jijoye BL5�7{)�:22�e]sb2A [1���9=Th"� f�0�&Q A!�pB 6�.���#wgJ{HRF1-3�Ad rferon-i� d�0BF CXCL11 ˔p�od&�"z%�)�uMq ��5!f �s MICBWeU#{ a�%�.�by NK�[�S9�e�_15]� inflhA'1�NLRP3�6�D!xVo� ����_To��@~[b�5�!1d�ai�� ely uti�Ps���b& lexi���pI�� [Ii�!r�%�AH4i XV./�F(� t�e�z>adde��9$f�oM=AO��� d�^�"Ҟ� �Qrxt-A2;�I%r�c>y�&�z!#� % )����)-�=�S!di6�?KJ���a-Q&5EG62��ݴ�heE|�A�)p�=� 2�)�up-� e�R2����q�AO�:R.���̑�sY-!�U�JC�2_ill un�)��� :�*�g*��F s=b9��Q���-�A��{Gai68!�+.�rel��oFZp�Bo�t�Q�+�Vl1at6-� �m�a,!�i:"R In v�e6�0M2e� e&,�A"2~�" m#ta�f��mo6"i�H "o�/�Oc!�U�1-/erE��:�12�"M reA)� *P( CDH R!�*o��� *d for �$t� 6� :�a�8'�f� a-N� KE exert��!u%�2�[3�8W���0F�on��� Uc&��= �E6��a�!����B6qin�⡹meb�:UOur��$�p�I��hhDHu�J��w��Bv. �deep--M�3�Q'Q�d� abu�y�s�Q�=PC��a ���!�%kA%5�19����^D%�� iR-2�av-.�d� ���@��� �` W� 9e�21>�e�q̝�-ir absol�����sG qRT-�H. S��1�cv��F�K mje��:���;>&� s+ishJ/^c�V�r��l!�c#%�!E��2arpOrS��=a�N"�)eWl�9ur��p�S�~)�5$%�:�\-q�=b in 7�)�\Q/9E�. ��x~1A�21.�AW.��%��Z.�h0M�m�vt�F :�6Oa�U���2�LN/��or� ��Ao�]�%�=�F%ne��:�[3�I#4�!YI�]��.���s�T0wl�NoAhy�Ȃ�c-8%):�M'���(he ninb� �"�s�qm�e�-? �!Bw1 B�v�iWe� ]s�=+%x�9IA�!�nVuN�B��lS:E�.�a���Bo AC666-� HK1-c�i0w� n�?e&�6�2�'No�)GJal%�.��"�!I�:x&3HK��BM � TW04 %.2 t4�,by Ramakrish�k"�*�},%�^m!{ �1�!J#��!������o�$dHP � T�J"�7J �`B]"� �PC��can Loc�U^D4iFLN�`-"�o^ � �+e �b��d��e�>���9"�wo%�1-=�!� BY� n�: � F�"on ��mp6V�� scra��a�<0(� -Ctr{t� �#it �) � �i��0�k�:M�rBFI6by.H9 �Fi�#2!h. I,���w��X C^ly��� ����=O��1���2�}�%Al S?w��*1�en"� e�6ZB�\5l�&! &�qY� s S4@ 1�} �)�9��M!6.-( subs j.j+2�*�4.{�[a RlE�f6#� N8 * Dy9 ��Sa� �*. %��wQ<2�ex = 2�:�F���"2 6�d��Gur$5 :�]��T���� `"�!'NJo�J�.?F��C�Q�� 9=���� , �;�@^'v *��$ ��^6x >g S(shortg 8���G>� -i�0� 4~�"y�ty]A(#J�1� s S5S5iLN�C%��D&R��h+-=�*�w�}ul�d,�,i�� 3�a�u|.�� q��uK"�e,��5) |�$�,&NaoQ%ng;� ] �%.[ ��Ke�!y �1�.�Z�� &1�uJA]�� 6 ��g�o.le ����*�aa2�)�]N��A�Ti* "2�2� �2����+%���f��� heck-knock-d 8*�2T�@4r reflV)�U]Y�N;2w�]����W�K�j3��dsZ 6�\} d�U1�A2m��Re2!5�TeB&�g~�UJS4_ �)�fW V� phys&:�:�� 4)�R6Rb �d5 V1IY�ka��� "NA���Ki��Xi=8t.s~& comm{!. clinA9�GentA<�+"��j��o�by�X�G��,ev '�m2�ml� P3eGino�8Y| i�]� LacZ� =0@��Y* fl�r�Budc�f�-"�A���:��b.�. M>sub"SGl���E�1×106�-�BM1- �@(��al��ui�10��I�A  grew�(*u �!u\8 week!�Ai� time� sacr{����v<eJ� w"��g�Z~�qU9MV�06�.9�u�� 6�I�ly�))E!�E�y uaF>9�A_�D�:/ a 6� .�A�)��> HT�rC�a �O 2s u�>HEx�RGFP�in�v:�7%T�a�by!/2%�"loo�N 0�o\GFP&� nony*��h& �>r�(mi�E�>"� /1  4��F�.>�A B�E�Tnd� ��ly�0� ��xH >yT�Fal&��-�.c �:2��?)�#�4 nodalun�ln�"��.��vi{c#2�A�%�ig �!ig�#��Wy)�,��R;xE��&  V 3 no:<��]� �5 ���-�$�"%W6^�RsO0ZlofB�G���� �={�9�;_8�/�9_to�8��ӱ�!mp$exg)!�%�A. Colq FE� {� !��F�#J6��2���vo� = Pb(Chi-squ�tes�0p �TM�%zZ����&dha%^ �&�T�n<a{!�9�f�e�M� to 5��a� ��HK�VVA�u@m�A��+facx-UG���?on�}ӟ=}:�2�ѾA��8wkgህ�� ŴItY��T2���u9N��=��d�`mEӭ�an"���4 . 0±v15��reZC"�>E�� s 4F]GGC6�2Q6s6����>��)����A2Jp4 ��")��a�V�6�b� F �5�f� mj�p%�(!��r�e�&7j(s��u�i� .^ Y"� ab�Y<�jrtbee�'�Rp pro-&� �w qeԅ diss"$&�@*��P��� �, !58 �u q���)noh�}AmFM"D+)"�in�+.@1p2�+.xa��l��.?�+$di�>:eI ��T�1Sca6lgorith܌*�7 2173d�ie�@h,�o7%N�?v � �3 I�pr���}>�GiMo�$way enrich8P&��X KEGG'A+b>9&t;mo�-:!Ew��!�G��"�*, ECM-yWp30� A:mvc��(cytoskeletoL2����ؽZ��T!�54):( T,'�R�%&&f�R&����$ o��&�@A�ir'R��5a�D��=:�>���5yZ}&\0���?*J+��G-p�mo�6],$t-��el`+�(!� (NtD�:7�2�� | [3q> Down�/-�6�6�as6!\*� oJ/��[3n=�jBY��W i+m<�VM�y�q",S�Iv2r��&���X�J�8 :���<;;;f� � a a�2mP�pL%���8a 7mer-m8 ‘se� atch%�����>[Gom��:)"- nt 1`1ˮ� 5��!�!5�yU�t%k2QC%W�=oKa�:Z#�m�� o��I�Tp*V� �Hv�/a.bf�I^wmL].v1�& .��nt H � L E%��da>*� �6 �ng.��*}!C6*u# �F�J����*�M.�*%�c2�E�2&  5� I�I�aR�T�nd4]�7?�:: w��uf"��le5E �s��Ectr��ed�y�M$�(!`&����-��+j  9���=�6  s 5D , S6& ��qv�&i&�u��WJR�:�by 21%��9O�60%�j& : d�'.b�M�i��Y79E23%.I2���")?B%Aб�E[A�.�-}*��U�sa�,I�A RT-q 0"0 u -��Z ]2�s�=:6d�;ofl*��"w�%� � �A� ),��l n�$&�I�f>,qqel&�I�5`Ju�I.�.Z����wyRub��dd�h���iC� �.4 |� 1�:� ���r6�f8? "�/^Q� �'EWSY.s�&� .�r*�&�^`+3G� 6 xen�f� �N�5�!�)0� :fu � a� be%��8o�0G��>)�R�15�$� g} aJ�/ archi!B�1c�/`"�6A�b�l��xDM�:�%�ctauݘ` A�5ly�"o) []����B�{�<%�)dI��y� ofQE�Mac-2BPa�" i�keGatA�yM�i5�)Is qtJ t42*�F!I,% .]F�k6�!;E*.�K]�a��w�/[7�NnkID�z[� ��}k2, y,��e:3..�e�V�N9l�tcaL>� "���of2C�*g ���A��a26 A4�0Ѫa-�(�9 �ZK ���f ")�0"�K:%.�i �c��� r [3)J2� !��T�=�� o&�9J|",�Y�a�Tsm�+؛!��rU\(�#ٟ2D�A���]�61:e�e�y 1� a��A:W,N\ �"H �?5� 7fy6 ∼3.�06BeZA"f �-oF� !i6�zd% �x6��i�)"�)i56�vj�rA�P7RX ��&^��=�>r�9:m!�&Ls�Yk"�%E2 �u<6&� A�u ����م��)*&Z �.p�S7%�6�F/=CA�6�m?�=�X�%��e�!f94��k b&�!��@�q!b:�2a5�Ijl>� D/^����t :a �FDBBg2��-�as&� R��blo6bzW-6�0!s?si-�?s�Oa� 2xj!66 :�D�6� }pb�"�U%�2�UN�nB*� ѥIi:e6f@EyiZ��{�J rEu�?�|!�,iª�F�Oβ-bninU$J�Y �cr�7re<K�of.F"; E�#%�ytC���7u�"6VZo mpanc>�,A��m��"�!�Yg�con �A+BD�(U� -sha}# fibr3}V!DMZu�mo�W�B%=v�! 2%leads to� β-catenin redistribution , we examined (localiza&�using immunofluorescence . In confluent BM1-LacZ cells , QstainG�awas mainly detected in the plasma membrane and clearly outlined cell-cell junctions ( Figure 7A ) � BM1-BART91ʍ cyto� �nucleuGas depi�by �Dattern of DAPI co-�$, whereas �al6 greatly Enua!( B� factM� formZ Dwere rarely observ)_9� TW04: even�%�se-6O!�!� JPlong-term colony cult!|�B%�Under! N $condiAT!J!��LA3�IADdisplayed a cuboid!< hape! 8hich is typical:�$epithelial Ma� clos!associ%p0with neighborA� �EIcontras!}�IXQBIexhibi!� an e!,a`, spindle-like morphologyhowtminimu!Wnt!�Z�>g$The differa�sqLc�growth M�s2�%z-!� �)u%��-�-�@appeared to mirro%�lbehaviorS,tissue archia�A1recordIV��xenograft tumors . To further evaluate +�!� changesB�miR �expressi�� comp �h2�of�! B�to�correspA�ng %:E)oQo0in low densitu%�Dwo days after seedD��gularuRplate.*)�R�AFe)2ior�lrJvE^�]�*8able filopodia �f �their b!�rs]�Ce�F�t�B at g�agglut�� ( WGA )�g ��a6�5�y �protru% �in=�I�1�ng!�5"�D �IMmor�Cin.nV,, phalloidin�f F-act%� veala��resa�AG��organiz!�.stA� fib!H$throughout!a �, a feae! that��4characteristic^migrat�mshym��!E�Th��result�di d ^y#induce��ar trans ��x��A�trigge�NPC �j� mRNAnte��5�α"+ �vimen��� p ar!CI�of.��s5.� ,�pectivz . C��o!�{,>-�ed�Rer]�:�hig*��f�-ss.���6x��5| Q-� via J� in�d%��m>�� 8�d"inF� &ɖIm�in vitro9vivo mod�r,Bl�reɬ��"q � elevx �&� Bzo gem ,aCse5�i^6�er��oryAQperties�M�ba�ng���Io��8. In a previous��nc8 stud6 w�"|at�~is among�( most abund�/M:ed EBV5NAU�tw I��t.t� u� TaqMan-baL qPCR���rM|absolutei�A��#!�!=ir��@i�major��9  R �ae�6]A� tha�a��al-e�����genic� NA ,-21Eol�>�Ybioloy fun�6~UperA ��ss-�gain-of-7���~� ѢEBV-posi�-7 negaQO linO In!2!!3deplešend�AM9�4had no discern� �t!4"� ͵��but:�q�& y!�8invasive capabi��.�޵��� a<4pro7 �s�HY0��ex �ly!�Z a!�i)B;�  ,-QPng=A also�s� re� noun) Csta� �I� ouse�o�����u4o)�isaidRa ve�b�ng sit A�3′UTR!��!?a repor\assay=7eg� direcD targe@ K�R{AZ=0P] !oeX�l �2 � B6'g-X dMkc UAko�~ b�!r��b2"�.%�ByR�.�KK &L �� F�ig!�Jm0data demonstrſ��to-WvV�ar� AHi{!72f )}imAI� >� �gmA�is&sco� ��N�1`on�2�Pa9ll�"�e�. A�� head� neckѳ,+s� y[gzf�ir � prop�to �go no[!K � �. P��tud��%=etJ-Im� focuA��X�Q two viralŀMC s: L� �LMP2A�has:f!�o=V!��P �sis-reR d ge�<,*� ]�� a� c-Me�(VEGF , EGFR� COX- by �v�! NF-k AP-A 4APK , JAK/STAT=PI3K/AKT�Dal��pathw� [40] . Re�0ly , Liu et a���onh�1b.}A MMP αv-A�g��8 ERK/Fra-1 [45]LITAM/Sky (Akt-dependeu �(W[46� �� pot#)�� �Fantige �is.by�toxic TE� I)��e� jU���57 . 6E M 4%o� umab�)�J���22!� evad��h� ��Xse [18�Un4A EZa) ���!�i}cript� consis!+��at� 8 � �xY�. Our ft  1>�%�!��-�_�w,I2� "� *5 �BV-in��� 5�a]��b% ��iq.Dprovi-b viru�a non-%nM=meCism!�2T�� of)���I�a�expla^��ly�o " �J� " � Jab �i:�.A�A Ana��)we 4 over.� Qx9.�ly � S���&����B0 lE�to�B� wlet�abolish!�4o��y��� se0 unequiv�lB� .�s\ ivot)�t� 6_2�2�D��m� glyc�){� omin>ro#e surfa)�e&�)_2pmed��zlcium��^r3�? �aca�A�mlon/& supA=sor ISa�patient�Nl �66K}�N:Jadv4 d�ngsh� ,survival [35��X��.�ի founhbv� %�r� �lymph� eq�(8(9qB� � r2L�����ed�J;1 ��%%C!�s��*� �_�rFor� �,�hy��g$CpG islandXa%�� o�regagR"�� %a5�JB�}iAZ�&[50%Q5( Tsai"� ur�.�the�er2�ivE�%X��Y�DNA .eu,ferase 1 [52!�$dO!��5me9T,T< &,es snailn\�6!Preq,U .8='! w%�e��3��nes%�aiI&[5� ThV#our� � �ƙ�"�:�=������third����o�!byE�to escap��e rigia�ructus ? trai� � �iF� �to}A�E���!Sof�~��J�Ik�P-�<�2�a42�al)Տ9@nDpost-VI�j9, i��� prob� %�tO&�pro'�%y&&synerg��#toU`AE>=��J6&�� $Ramakrishnr/.9 was�M�� �m�Tderived from nasal NK/3 �boma�&an� xve�$� EBV-�k Hodgkin's?%[ auth�"" %N���"���B�M�ofm�n�zslo7"S��K � s [3�Wh�%ex�$&0 $ly� I�i knowe(�3$s!���ol!l�p KTCLA9li��e:n���manner����. z�di�A%��AY����i�2AF EBNA��/r:���woE1ѵ MuE �C 9:�p�$�(a�V��Qin HK1-�A�*�#S3'"F2#!e��three�Bf �6* "�`�" �� W��QY�i* crosstalk��% or o��6�s Kly not r9 �"9h�xert its��A�PC�afI�� �sl atency II��h!� 8riV�S!��[�q!5";@see� be qu#(Wi�A�V,#Mpossi� refl�1=cL(�o�V Epro��on� h6��pa"*el��o s!�I�s!?M LfurrI�u�@. Oi)�h!>, Riley"x i5ifiW 2��on��!A12 2%�miY�5�(I Jijoye BL%sYe�N�� As L� huma�&(17∼92 clu�$#,1 %g# I�1= &�,� cycP%Wn�@j��!G"R�&� . However�&�!a" .4�High- pi%n~e� linkAEYprecipi�, ( HITS-CLIP�m�*��Vbe26�*AM�:�!�EBVF�A�Y��T,h8*�UsZ,�h�n"6m&�+s�!�*e�� /A"� /y l�cc�"nA�C �%��Z=��!jrearr��#0�;n)aa !\"Pcytoskel�$ re�(�^� gi�& aEHloc "of beta"$ 'W/�& /&f A�of&acqui���H.=�&&�!�{�N�A>@!�ulI)d��!�! V�Wl�:�2�*�!n ! r:!�M�/yarcin6 �9!8Q"@ stag�L{ey�!�%`z�)�6�(beB N�*ve.�n s�/aсof�c{(!�.'� �–[3s@�DRm*a�fac["�-9 .8^)�by 6�(a�}-!.e�!cu�>!to�vk��A$B{(NOnJ_hzq^�^%![ .��2��"�9"��.�ro=JŌ!:o%+r�)q.e&�&�-}w�+�,� "�rec���"�+&9 �M �1[ }-�F�# ;@ e��p��, new�>!. SM��r%$e> implM��Qj���-to2 �>i���particfZ��$200 family90: � t.d.la��A�a�}'�G-�s ZEB� ZEB2ū�A:�@ga�1%��2keeper� 29 �8. D164:\��HI�6|)�+ -er*7cPa�Uj*kw�3AߵU&R'g(arM' Ls [54��5�InIo'��%e�-�Y �&O2�!�is 6� :�mcE�s [29�3�_>�we F�)� encoE3E��� � ���Q�#B[�cI]((ي*�!h�Z=i!�i�2� �au�`���(��!I��,I-p^1-�.Km�Rea%�U!A}eQlNO-�i ld d�.���h��0R���7"��{F!"""�! f:%�!9I�wor�6��E��)5cA= shar�same “y4Z* e”A��-� crit� hf�h- �� betw�0� T.7I<*:5��"�5mimic e� %D5�Y��1�2�in�:ALn�I>�-,"H ��o�J�C re�E� e9�:. T� �3arch fol&W tene��/Decla�S Hels7 %� all subje��D� � P"�9on�Iro;� he Instit�;8al Review Board��:b� d  I�u�sv �2 gene�stand� curves�a�cal=�}opy num:�x)�9�1�s>�E��&� re l)*"�FT� S�5F ao1�b�emplo�D�t�S!�>1p�I�$an oligo dQ� N�2�) . Qe\hv�(al-timeE/�-is� &� p SYBR�en ma�(mix ( ABI )=�� A�9��~5.~Y�]~0Q~1E�. �$l�E6�|x8to�C%�q��Aor "�"��I"��"9� qRT-ae.� A� )M:�8ec� vidu.��m) normOI^,os"� *�7ol9 EEF1A1A� eacha?1'I��mhI� k>�!!�Pr�7500 F�FRA*TQ*sy�1,oE C!M, 6 double-%nsE��oth,�a5_{�-.$ &�#ur�)��i�s.Cna�s���p��L6 . 2-GW/EmGFP-miR v� rM�1E�he CMVA�% � cloHBI M�I%�l�-��m�'���8* &���� ���4<��i2^id ( pL�? 6/V5-DESTa�u Gatewa�,combin �t��y>+~�iw6u�jThe�T�=.a�{=P"8EK293-FT packag% ells �oT&�.!�9�J�onta(QG)5EYe)N�ViraPo@��,.�)�� Lipo�a� 2000>#. %l,/+&a��a�u a� j | ;;�s 48 hr�G-�%O�� ) )K�. nigh�!a��$4 µg/mLA� polybrene�Q$L�ip��F�knock�&9Hlocked-ic ac�ALNw �-� y�� a6e �!iscramblo%S%��he�(at.} 御�t�1 chil=<c� r 3"pr 2/1�D 5 nM[!-fi-BH LNA���� W1.G*� , siIS Ki-Ctrlo aA�Zu10��obi&@7�*@b ��|b �!a as�=�k=i�24-wellIj i��"0n 8 µm pore �7qor��,  NYE����-�6Jtb-eco&�9e�FxM�Hgel BastQ�QC BDns�F&$, San Dieg:W�qC�K susp%7$�-f�(�j� !A?up�cha< %��G* � �J)�� ward�%e�tom7%���lsnd� r 24�(�D , ?,��)��I#(��~!��r�R5�de\fixa �9�D% cry) violeb))3�(�� �)*~3Vl visu� �\s| A�Ia�9g'L%P�$�6�5%�A�� J- twel� P �Bfield(Etriw�i ,ImageJ softw� >�,:+ (' Ysextu^e��O of 1×103�A(M� 96i��Oi� �:��>�im� " GE�c!tLife �i�Buc�'hamshire�K���A#T�� �uZ�=�>��(a@y:�� �2f)2�six2�A�� +coY teq��10a314�QV�was�7,��Z3�u . ARI�R� !:dy!O Mx%� grapu�! A�vi�+r � ��asVBiofumeZ{S� . Nu:6� u6�s"�*[�e�6��Bisola;c7. T�5�e�6�5a�6 ) �2�!�µ�PBSpino)s7$ubcutaneou*�ra flank!1�]ek-ol. ���9sac� $ced 8 week�Sp�NIM;>t�,�1�7, lo !�lm "�ofi�mo %rrem�, w�Ved�Rot2�embed���|paraffi�-a�inGQ�-^ �i;, |s� � !(*C8b�A]��H&E��ANA�u@&Ie`Z�nd�!=�;�#��%cR2S| %I�%1� c0} �3�%V*�+GFP�B ac2B *' )��IH�/ZBM�6B!0J�F�F�! 2�IKi�%q�N-�11�/e2BUWaF� ���!p�[%b�"e �e!�17330�.�ein-co�g�.Aretrie� U; UCSC"ome�)bH,�!c�m�T&� T� loaA�UmiRf 8 ( http://www .kX[. org/�wTs�!]  ext �Fb� f� F,Scan_50 . plGConR_S�F� pl2 r@>�6R web�I:�-s�( ��_50 �A sZ� <−�15 )nv!! !�)%Oe�fi�4 o se�!r$\Kicacy��J�!i�QR�of 21731`{Ih& �i�YE�s�di� )A!��A 2D�0 enrich�^ J6s�Y DAVIZ i#c@Resour�5X(david . abc0@ncifcrf . gov/ , on J7�nd KEGG��,Ea( "5A luci�6PI�(�Iuct��!� wildg3udA�Y'M��=n�K�?6clo� ��(pMIR-REPORT( Amb�)E�a m�t:�0ala�}x<�. �q�i�AAGUGUU�dAAGAAAU}1Quick=eXL Mu�.ne!�Ki� N��јaRR�./e�]]\9]  ��!m5I2��.+ lysk[E�&�� a� '�!gA4] 'v3!Zmeasuw  FE�!VDual-LY@RQ@A�"x P�-g�!Renill2%2je�to&_jfi�5yR� valu�� 2�preY8r*@ � immo�O�on PDVF";v.dN�#�(%[incubEw:0a rabbit monoA�a�rt�(.�A�tibod� 1∶5000; �,' 5#4065 )��G�/:\ CS12 ) (K ;F9Yu-Sun�$!#�%F6, rp6:�40� q� i8Bio-Rad MCA2466�k:2� 4B�Mei-Ru Cu,&� c#6��i�n<eradish0oxidase-conju�- d go� !>-�IgGaln9?L0; GeneTex #213110-0  1 !�dE�c5fMb�AE!�(i4ECL6� Milli�A�ti-glycJY -3-phosphor�"��( GAPDH�B^0;!�World�:�o"������� . We&n nK;��cap"\a�UVP^"t 600>x ( Up�BAd&t!,e|C!%��eK`�d}�eI'( 2)a�s+na�cj slip��Qin 4%E �%:�permeaq�hx2%x)ton X-� ,!x#5% BSA/&� 2���)pr�E"C Aue-at � ��Ml )��[ed��22,� S"HK�,q�ex�&g(�8ta Cruz SC-79632.� "QX(B^574A�m�Yk�>�+� E�>n Alexa \a 594-a� 488-laleb�eqt-�*�")J1��u�2v�f�mM�SlowF�KG[f�%>�)�=eMT:>�U�H�rGi�da ZEISS LSM510 META laser- JF=e!xarl Zeis�- Germc<)I}a 63×� 32 NA oil�Jer�#ob(!DWGA&�2�:�=�555-labe�@(.tI\80!�� 10�at{'p�!fix �Zb%��w2�i�,:�GN�A8*�bJ��^M+2�e}��cE7zT. Slide�4n� �wM4.Q�r��K!: roomF#er4%Y5)Y( 2]3% H2O22 KO ) SQ.%pe��&S . NonN" � �obY��A�BDil�j�Backgro�IR�\!��^on�'��i0u���:�a��*� ��:�;�w50 diteon��a� -GFP���I�6)�gti-Mac-7��(Fw$Jau-Song YnIatZ���VYsA'-F HRP.�J�^sQ� nd d�`(%ȡ�39tnobenz{@e tetrahydrochlor�"!�&0Mch�I�*0.�3<� g0n Olympus BX5(���, Japa!�. SK9a al\�&�a�A -tai��Stu0R's t-tes�in*IR'$�) assu�geq�$7X7b7}2� s�2 . P<��05 a�idL�Z �lyE�p)� I�Entrez  ID"�a�s�3m��JnO &�t�q378375�!� � 1"�S7�g< 9996 743:V�-�b149CCTNNA1 2957a-, .�W�ey3 ggsashimi� command-�1 tool����� of s|��9s aA s&!M1� . Gi�ma�u-genomic�5,�cT3�K �pl�+!kQv�&RNA-seqs#�!� w\A�ggr\^Q1?��p�e* 3�h uniq�S�L*���[k�&�A/ngxW?ams�eru6�oJu�pop�bi*�s�` ma�O�J annoaF�R}L ����!�%Jlarge�=��$scs�%�1�seg��Y7%��!�.=�is �BP vailt*�T8ttps://github .Aj$/guigolab/Y�.8�<�iHpytho���$.rnnKa� s R 3:�!��%. A$�v�/liE�`o�Rc06�=�Ct��&%�exo =�+~e��8�)A?��et�R��cr�DK ��<�EO5%{e-w��J �M of aN�lbe eas�= prof�Ibya,�A�(e=�e�ous�of=Rj0re now public2�.WKB�H��Gruc�7a� expl�5 a�) is ,FIEy�A��ks c"^G�EynaZlyE*gA l!��i)Y browsR-iI�--a�y��}ـ. VR �J�s8a��Rpme� beca�Y �u� ly occur"�:twKNg�%,%wn as mqzt �%�A�,Yu45o}�� queF: �M.{6i�t I r� hundre� f kilo<�T�ar spa,uA��?en��A@��mm�e�4dras*�jnnveO\�]�;ilNH!�����A��wt2,%�1�. [2]Aza��y �ca�.�5diagram�A�* �"��r�_� age A<g� –aJ<- rack– w �!�1%#!,�5VU�26N.��1I.�/initi�& �*art!D��0MISO suite [3�?aY�z="��P ar N{��.\. Ci����FAP)5�,A�qutY>3:�� �A�-�L$%N!WEz�@�\a built-�K՚!�81m<t�,AG�s View]JIGV [^"]B\er reE� �zo#%2tiZ_�@1�"�Pl(wIqui!hn�,alGVA�!�15 � up��Sol a� alig7� More{�oth0 themy�B8!Y eachJ� �s\�� � ch h!�ri�%risi.m�'t�ha dozen�Ep� . &i�ts"�G� � Yat�3��u�i+its>de��o^ make"ax fuliBeECU@ �l oQs: To�� how*�� iA��JrjAS e! >�!&�1� !�125g8 eW!�ENCODEAZ� [6a�J| at wL>Cp ��� 3 } class� �re*H�- :^tsx,.9;A�..B@.d��ng�#assett4 o4M8chr10:27044584- 67�%9& [6of;lu�d !OQn.� (2�>.�>2�sF�/6wE�purpo� �V> 0.�"� 6p[���anY�!>ŭ�-� ~� GV B� (K{ � .�EJc\ofd,�Ug�kQYb�y�"� � roup (!X oughU--�3lay o�53 shrinkagY!iQ-nS1gth� appl�'(�( Fe� s�en@r}heF� �� �d-*9[ ׁ�6�s���=-3�Y�*2,6� ,��Q >�����liCu���na>subj�z��%�4ib�'UW��our:l s7V^Xn3 ��  i�B ���~�n{.ne�*.pe] ����YA~w�1j�!mar-aC�8. Q9 . SiD Y��{~Rp��t2m�Hv Afew V�,nc � � � g�X� ! 5�" pipgBA�ndA:zMFrroY�R�Srg��9* A��B!x� as����yGTEx [c>9�Fur�Uex�  2� orp: �sp� metrZDto�1mp!Bme}d* !8method�L!�us� "]#wFGt�xof� �:��( �3�d� ly mYd .�<�msJao*�f�f-�l�U.u�CW�:- ��ALemerg7.�:p.��3( digmA{a��#mci%jiZory�nuu( CRM��!�u�;a�6FeQ a�M ���*r� � �M7 { Acch%'ain�. task��@�؀nO�S� MC ɞ"b�o�<>5�g�<`dW!t� � tly��U alA�perxeCRMS�T {d�(5sc<��pro�E�#�tA.E9M��Ts ��/�+of" PG n' facz+��&�� TFBS1�Aab&�1�AA.�Nl;YveH�@v�� worka�� b3#���r [c � Upr^beA�r6mTqtqframe�%]���Ude� �\%�^lem%j!�&+ a�%!a3h�(!*)VY��F�!+�ucs ��-�'6��om�Hy ��� p dea1X!�in�:nt �rr� Q�.h�)�5p�&%,9�9fv sim�k��zrVH�e *�N)�AY(!J�;�- �:�of%�sL "�!we�u the-�)#A�Fi��a%d3 o�9b���:�-}[qH2;�� !%M�)%8e�aF��%�Dro�I(ila blastodd�, �] iguiBTns: ( ihe�-b�9are������QY �cj  i�Lir2,��4sJSeQ�z�!�( i�1��in�al >�(�7+4� 2"st!� B)�!g����'tHthu?c��mS0i4�"acR�"� I�"�, EMMA]��!&M�9y:@M�net3�vzy�beu� eBbroad�8/p$_N�ua2 -QBo�W-j��X^�g!<�N=$byg J7�slFi�'�>��g��ZA b���.�6�z{��a&��R�g� R^�����Q4%�d$X1-�+��2�� a(/K{TF!*�co- ש@bas>va�� chin� [�b� pl=6eRnt!��_A�Չinvolva�:jy�.SI� &ox�B[Kr0disa [ n��_�Rf�Cku�OSA � bfirst �|*Jt�tw7�ep!��ri- �� r��� �X2 �-��\ %"t[seW�ff13�)�A1a�v&�5suws� &,B� phyl!e"Htre��#��$os�|A,[�qM�q���Ocustomq.hBH!�ltkc� t��m�.}i�5� stru�iCONREAL�f , EE 8)9(SimAnn [19] }&��!P�wT  icit-0��!(�� mat g�TF�~ NE f se5  rigor%f�b�o�(��%!�! they%Q��)0Dm]��ofe �M�Dne8d���&49![i�<�'iE@2�turG QuCizd�ad�i t-ho�O Cra�r�^�!B� ��!Ri�as9� r?}�,�ph [2�d�9�@%GiX*e &�&�u$a pair-HMM)l2�KM�f  does���!a�v�,2�"%=m. Lineag���Q��2,�/sE�A ]��n6a� �ut me �as �“emi�s]n !�Q᭵l��rn 6pSAPF [21�waim%n^ ��&$E�8YZwaL“2S footpri�(g�&7 f@j'��t!)U�=b�$A��?0�"��% &Db"P\A�e��9�!q�l�Ly&%�-I!E���RBdesig�b`�0:E�AR]( � I� goalU&>V�} s!�A��:1��{�kwYq��_fI�k�p iori � phil�] d�Z *"�~&x is:< �r��#� �`be&� �tx�-t*� Y!�s!��)�� z#“d �b&����sh!� be divorcV|ZB{ � at�*d it”;W э|SbX&r"�&x"��stBofDOM�k��#���5AM�P�ea�]�a�� ,� �[ iX�Kun��CcC%2y���a,*G@sum�-ov9\"%5�b+].�i<�a ]F"� �b�+&]�# area!.T�%� , [2* 2�$�j 9�a� �I�0 e\bb:�i; -n�l��!te)�ed��A4!��[a�a_��+�p!�� i�u�q2-� [2� M� � �:%�m a�[�N� �@f6� ��l~^5If3���Mn�?B�o���tF`"�66] ��d��%�p2-%`s� �H9|!�*%�&u|v�y.���aS�!P��M/(nF5��.O�Q#���$"�zJTR�A-ea�� s,i�) ;�i )e��Ye�"�a� d.�� �&(yX RS*� swi� b�-aA-�� !��*� Gner"�-&a�N�g�S!pv I )�"���:&\* m"��h! !oRa���+%�UNG^ 1-�JV!�%�� ޟ-g\ 0r�;�melanog�XE� tookB�m�!�o .1EŬon c�D ~&�-�Z!���(&�&�$ ChIP-chip.jU[�i�!et<d� i�{ hyp.  . F binvesti{=Yc�&bJclG �E e�Aa�C"#"/]��in� .zTF��[3��[3�4^im�� ndidAe�c�HnNiA��h�a�",dqo:y9�� ��tru� w'rZ( uwil�f> t�1 *.�ap��<&?�e�Eis�.5e"�q r��, U�a�up�� si:=J��M)rK2��a^e�lp �%�(S��>a�poH_1* r�!`"+1�,�ha�� tA�a����! � examqZ;<*?l'R."s=2� �E�́�ImA7m�*|y;r�h*�$�e��s���]�t�"�!}Z�ES�b�.. Wrado&�s� nteraung.�QY)Tn�/L�ikA&“%��[�/� %�a$0΍�&��“boW[7o]# es0|Js�e�H� �?2)�*��)�c�[�k�&wo�I�in }\/e>��wvAD �6_�zMum-Ger&w6�e���A�r65/czz'��s1�4wge!N%de'9��P �%��k��c�Agal�B�A'�0N����;��O�%�f �7tAhupWt.�# <s� �� crib!�jointi: ihoo�ka�9�.}CRMWr��t`1:DT8F$ %�begin� �d�#a���l�"G|��Ol.i"�7&Y Rj�a�� �~of zer{X�b�WmA�a�heI�|in�� , [32hYF�ci�"(�)e��)!be�>by�NpOt�ric%PWMXI��n��^fr?�>� N� qd��)� . At(0�� .� 8l� nJ!WS*$ )Cty%�BZ�I�A>c���Tact�;�.Z} PWM;�wi"|��#��!̥��d2�,a��:erpre!aA�eJMV6%_EJtif��at�<ilibr�i,!=s y2F!��j%2�I�fR�� adap�5*6�veS>� iera���!��"6 ��n0yS* �5�e�!�"�HKY } [38e1d)1��ri�� �.%��_Mbia�|I�?� �de3�` Pois�2��?�� 2 ���5NI�7:3�q�V N)�ges"ric6�X�.�&S�+< "�a��%�mJ�,:<O& !��/w ,%[?�IesJ4�branch �),aU x�ly ( #)�&.\,]�) �%�0l)8Sr�������ofT se5^�%� a�l  gap�����Z+�*Bd" d&�2i<�O�)�m�G in T�$OcWe�� �Bys-@94d Halpern-Brun�nH�A)���y� [3L4���s ,2�fa$T��2S�55�)2p SK!� %:~ de?a6MoPWM��l� venjLeta!�2;\/�)w2@-�QB�{ -�h+�U�6A��a.���8�N�( HMA�g]�����!u��$ ��a�81HB-�1im���&8 �B�:,��. G��aG"�aU". "&�  !"� � trum:"�/fungi&�{ec;9cp�Seb!O�yTj+{t��Q6 scen�zj�e��2�<.�4m� 9- *I p9%�!V�A�!�/��� �Q" “de�Bs��aM�. MN ��2 , ca&.���&!�JIx��b� i6�st zY &M$,z�u nd C�3)Ube weak� �%(q�l�$durlU��(random drif�New< d��be&� �.� u�M�by�S��2a,w�� �A�oVi�E����^woa��!&����o� �r:d!�!��f�Ild':�/-.F��benefi`5 so!h�om���o���i;� w `new� U��:"K/� s A��eulaxH2�nda�_�x1-#2"�(ce"��!?Q� :�-6er}��nM2s����C]�+�<-Jle�:S!��Θ`�� z*w P\[�)E:M�y+�e�m2.e ^%Hq��"v7 ?re�Fparsimon�*�K�aZD���;shold7A�NZa?� W- i�!a�!� !���]��y �: �0�%�:. �basic%5�@�q6$&f��p^2k� ea��witch-!h!�a�$v·�de g.&Ѷ :Wm` E�PE��-O)b9 occa�/�br��%dNI2�*M,po , 0*a.@iR0! �����(->�/Lik�p� �%a�2��B�2�r�@ݶ%:�� B�t7be �^ tZ�/TFD+ ɠF�>�WmG4*a w*K hi9w A/) lbei�i8[� '9l ���N7����nw��"� AE�3a-q��cFH�6� ��!f���b)m��W�D:g�Y� voidxaF�G�EK�D!��M��0ask*�� �,�&mF��r�ץ�inl?�/1:a|r�ha.HE �76l r) ��=ruɟY��  ;�=� �EZge�a�.�"G �A��%`um�co3� }&( ��s�c���!g!P%X6�� n�3 )�� P�stanta�dU22 ( gi�by Eq�r�1.ORK�=)v e.�u)@�����!>!�s;S(must satisf����&j :(i�Y��.'�Agerݡ*C�W-K� &�W�i1h"pjA�KH"s. J�=.C � j� \B�!\���36M�cyAq5�kIJ y�p� :os� � �i/��y%�N symbola_p� Ds e&6_ (of!�;� .�e�� �ʅ',%���Bw�lyT a:_-��aw��v n�`g�ori���xe�m2me��F�"Ec�!�t�.Oor��S&% .r%�)G� s��"amB~ A��$!g��.b�U�i:b�tyMTI�;h{�ries:.��81 4�*I��(%��+��b6aA� /:�� V��D!��3 4,s�Eey����ST#2� yplace�D"�TF X!�(�_��99!W�3� �a�sP#���$�7A��&� |%7dJ,!!�Li'�A�<�hly�q�&sA:�2 ���A�Y� �-�!ta $�-@5o�Az!�asV)"c �e!_��J&,n"�ik0e�dvS��M�� y'e�q.byR"�),�B."�(.ig)�e�-�)"���*t� algorithmȣ�.�OMa��>�M?%�aC�$L-b�!ar utof��"��#ME���)FL� IT�CM:�& � 6y&y*�/&!A6� h �,�=��1<[A��5Y�a��5� tegyI ?6%.�! ?,a��f#2o��y\W��fo|Mal)g�  a����F�.=4�tr��d'L�:f�B�f8d,mge�� G��T�ce! a�3*�8mLa "a:��9�%oq6�E�cnrET�� W nswe�1ti!� W]nA�1Q �LI Xt�t"54�1�/ �k!�tog 2�i�ie2c�r,>�� � !,eti,�n4A��|>,ar�A��7=&Ja �i� .� *�'��n +9V�Us [��H��!)b dA�"1 �'&bYs��i2�F|�Eɵ? �A�� @��y*�Cw��Z�8*�'by Poll�<& ��Hu&f]�Wq%l�)W��jp��)�wl �A��S*��� �0L��( MMA08 d!�t! lu]&2:IZCJr�X>us�@0a�kva~!I)tPf!ZN� eedlE-Wuns�,�< �p p penalty�+�1^P2�0 id�2�9�Ae�� >֝5�D'!�uQa�J " ,���$2�.��,Ar���U:“A�!�A�.ZY���"�>�� Z9UQ corr��I �L&F �s"&��rԸnG7�lAq@%+Z`��ɫ9��6!� .�a�|�(�  T� s S2> S3!W&� -Z�e mou' K2�.n#2t^)�/py� m�fD�A' quX�" �?s��-Z1z)�M5 �h�Z&1 ��aĉP;)я2�#��&;asu W����-��v�m%h&� r��i��a��q�;.�1�.�&a�r�to�.&� a����ِ 2.s=Out �.!�erKFO.e&VOc�IbIUA;)Pby 12% A�13%!�&�$�!v*O���b7) 8�A� ligh� _%�!c��x-��-��� !.�>�i�@"+l 5�b^ ����9�?�g Z��{"�+elp}���5/>�t�.2!��=� l� �'Aqome, c7er��u��W���w_3�r !;� p�_<� ar5C,^���:�b �rv!xas�I�%orsz8M�)�L�a�?ly�Ep�2� f[� !�B}���v)=!��=!'x��I�A�'02�%��>&&� �< ,fSMM2^.:c!b!�er � U�����)4�w  c� q2n�#�����6�m�EC6% 34)y��6z(..a}5� e>>�."� !ScolleaguP l��t���6��Z�Ds6��e8�=��� ��� �TTh� h}�iis/L�9 0A ��� � ��t�:El�q�Ba mixtd�:&��A��w �z�A6K'��� 2� .; �m��McE�clude: �� empirinF`.-��jR�73s�weR�X 2N)*� ���in�Um�q q7nd�6-Si�. Nc&the�1,��5%BrobustŲDu�vj[!sw/Ie� Ih:�# ��repL�!���Q,�/d ���y�O;�*N agreRɆ����ult�a=���~TO 4S5T&I  g2�́dA�)%heI�e��e����pIw����n!dYPzH�.kTh few K-os�9�( U?� YZ� n�8��!;��$ls)XPSP-^e����lso�!%�m����y(EM�IA KAeyond �06)+�&.�AG!-c�2"��&�"�B�!d ���r]e;e��,%  �g�dl@ fiI��BL`�7�� *Ji&aM' f��l8�}��].*0B� sti�C"F ���J� "�con!��U�(#7.&`--�"!�7���bench�m� suit%���.m!_ͧ'sQ�Y.FdXs.# ]B`"��u!WM3�i0�TFd�p'A � !t!`)scB@U?ve�W��n��e��i CN� G%n�h�C�IA�[4`$Aa ��e >;�$A��e;i�iEVre��A] a��i�xaz�H��i(AXn"�!v��a o&a�։=�&/u�c�sa�Oa���)� W��6%,e�#V"�;az� !#!"A,w+�$.�5  ,.6�/M�+ay�� ���3�tF��� U\�^of)�2M<�*�]�6sE"� �a��ɾ�f27F r.�-�m4�� -ANNE v7��+�b�>$�ed� |a"�tC&�2�4dh0��eF&�� ���Ad 7Es�ei�h�r�)�, L&3�'! 8D u ]RtZ!�V p.`J6� -he� F�-q�~� [�� #2-M�'b�2���W favo�'�A��a�adr��!X-��M�`�1h>�L. H�0!$�t��(r�0 "� ͂aL�%�ed C:�s�!o�"53=ec�;!� r#��EROU��J�� pXM%4t5"� �iu"�]�e.fav5&P�:bp(|e�6�'cD� YK%-0)0Fa�Vc��>;��A'C�zFq�s���!72e� ��\�nNe M6*� 0.`^%=A�aC?m*i �!^3�>�<j:!�E+� R(co�u�' z;�A[ X=+�%�?�y1�_� u!O!�e")� >�&�<w �,�"�7�G)4m ( AUC�%�9ROC ,* �db�M,�v 1 -*� ��>����BF��ũ !�a�YM�c]_�"W� �r�<,8Lj.X�9�e/.jsig�&b .J#�1�me1&�2)e;2`rxIM��c��Œ �z7eu�YYW)F}j�a =�-��v!����9 � t������� q ��6&�"6R��&���ю%���ta�(UA��a6��z�z`�a�ce}  =�� %f)6bf� eBO)��s��* Bs�m��!u�mixed:���r.�( <l�)+ P2�!�.�$by 5–8%;GN����a$v3. �in�4s:�� !i M��*�H�s�X&4� �a&W#�{y[�)�AT=�.%'2!2��y=Ɋ�S/�(���Ume@��Ӂo��f6�!e8 ,����9�_AUCE:>�|+8*�2��&��GM�AO!(1:�qs ��une_Fe�N�s poorer2%a{� 5 i �! �Iޥ��m�)Ji���� �o�JR�C �\Ads���� WE?�Da?*�3; �=a: ��if�TA� ed�1(�#a sƦout�' u�frXng��#Y � �0�E=mt��aB& u|��!s#. Oh�lb! best2��b��:a��!o��e]���!�4w�S^Ag&!��c2�Ge�U>�o�7�r1 J�6*�hɮ-J���+stB>] beE� 6–E� [��A�jus�q4�� full%!8)<4 ��/eb��� �2�s���pt(!���=@ E� *�I�5�����p�)E��aun� I�Jgmy� mad� E �ing�B�e �%"�� hoo���gL�!�� ��!ool�?B>��t�� R!v�t1�.�eV:�b y��frA�e2��,�+��"f)� %fC�qN"�&0P-@�#AW^f..� &��GYծ�=232�"��"� 2X9&�]�� J�ho 9,A`u"�&Y!�'t��>` �a&"*�G!8&� �`j� ,�Alk D�&�!U2pFeffor�XXwA� �(reh ����A}��iyz�5ENE{�N5��as�T9if� \truly b�  o ��i-w��!P&3�"k;+ �q tarty!&y�9ji�aba�! A�� (�����^g .V&#�߅��rs�*=N�"" RedF}%ata�| in DA�.UPA!0pseudoobscuraw+!R�m��"Kto>�v$��T!!R����/'F+DachL�!:����anSt ��S��6a"-���m�: Ag�#�k\(��wEr ��rg���87= `)� +�H�+if!M�,-ga!fs_�M2e\2�%q�"���'gy "� &�(�1002!{6 Xd;�R�5a�&s��/#+io��, [��JInE� , !QnX�%�U)A[����5�s"� \A)]��R�!]!o�<��,�of 188 k)in 65I� , 80�b2�>mO"X"��N92 103F8>e i�=�:�;We"Y�'�>-"� %��Io*�BU� s, �{�t�S�P&:%4�C�y.�u� mis-������inB&�1)�Hb%c� 6�-!zAZ shif��8wo*�"� ��!�HbI �af �u�fe�n�%�nsx N E��'gBcd�� Ymiddle z�� e2��!�Oa�4%��%�'��a�q�^�)� V"ND���by2�(���?TKyhe-z9 �:q arbiZSreC�i�mbi��� U2���� �&�|) Ai& �#�4"��P�_!���&��uo5yR+)�7?��"��fCPQ}.�1�[>�Inm�}� f�\ �N��~3*� ir6@7�0EMN �+3� .  ��!8fu6!r���Qs�?!9&<. �h(it� /ni)�jpj!1sEZMJ=�2��,7 A¥� aM2w ���L6�>��d)IO��A�M劝�AOKr!����V�! ��*:Q'w�gvpY���i�9U!�)�� ��!d&wJC�e -�&AS%+sE�Kn��Tl�0�..@&z�:��b c!w ough�L5�1{A9:ee���!�e"|Wak� ogeY�=ong�*�D@%y�zQ @A|8D9%�: �M=��60�*&"�  g�7 0�.l}�� 1����]&C����_� �ec �3�0hAEto��gap�eQXi,Q�Kh�"�� "� L6o�: ͨA�I���"=�o"^1��! vmf!�*1�J_f �TF�achI �/0�3� Q>w<-��gleEn^ " &�E"R%C :6��T���� A�� �� ���udU�1�w�l�)i���e�0 �nASr m�.*{~0(inTs�R!eTe5~� ��Lu���|F�"2�yD �isE&z.v�M�ere��uo!�t�Rŋ�#=�net�y���B!)4$�85lpg�e,� '��=wh�-� �;O#f[��.�1to��,�!]i1� AZ[l��-B� "�AX"�M� [5e]:6H)a�3%�G�r2���qQd���4efore be used �Uto discover such clusters for individual TFs . Unlike other methods we are testing , C D-BK�^ does not directly use information in orthologous sequences . For each of the seven blastoderm ��y, we constructed a positive set of sequences: those that contain at least one known binding site of this TF in FlyReg; andyusrcommonp4random noncodiH�as � nega� . Ag�,,D . melanoga!�-0pseudoobscuranparis!>s �!�hthis experiment . Our evalu-k s ba�$on , first u�uses onl.AinB. , itaco�$E�to �IA^beel$in some caV thanMCA/IE, whicIM�55w�<(similar HMM)s;a�extra>�!�oZ�Since un�^B�nei�qI�nor � applies aEi��determin!�a)�1alA�a%�yE�E�s��� :!���Pproblem seems particu!seriou�9)@�� allow�N!�be emit�� from)����+%Pthus may/a� oler�(to lineage-q�^1tch) PWM ( als-k�R���We (no�-$a�Oal��tXin�lpaperAmdiffer�t�%�n�� [20]ELHere multiple motifs%��Asianeous� claLfy���= . Iyat�wWA e�%�\2�A��rel�uim�aAwof� serv�#-m�,��bil��of-�to�u non-|$erved weak5�!�caean ad��ag�On�/proced�to enh���aof��N runE�l ingl-�es� ,� asFHisefil�loueUm�at%�� very1�$ef�a|� �.A7combinedI-)O pA4(�cA#ident!O�6er��70��!� ���y ��ga� �wor wor��)��:>. Howe� [ new�7�"���O ligh�����original>V,EQst��4lag far behind�()�!Ishowne^T� canaʁF ablya]la%:�fac!�!� large f�onA4Drosophila genA[� nder%utr�� [55ar[56 7�Isima}2�� i� %� rimini.of CRM], . To�  if our2T robu�o�|sa��Xrepea��!\p e&� w0 PWM�! ob�ed�Z bacterial�,-hybridHs [58]%�found�Ũtrends&�S3%��P65 O ��p a�tud�6e��ary p� %�s��� vola=in!��!�in*� -s�d opxof.�. . S� ,analysis dep�o� e ac t!r�of �,�+askA�t �has beenM�toa�� 2 4general purpos�5** too� W��oc's b%�by� transcrip% A�4or ( except Gt%�Kni��ee Ma)�aMw^ as�$ ChIP-chip~ ay!{ Li et a� [32]l �}“"y � rol”)�t�intronic=��w��a��A�6% A�.� aG�spresume� neut!Xor cl!Yto � Each� sQ^�was�ocieTe@its neaQ %���grouped>*whe�ptheir.Ogen[ rres4��e]��!. (�a�+I�AF��6�Berkeley.�G��PProject ( BDGP ) [59]e�*two �s)�� ���!�laKA�2�of!|� 0��ite��def���peŪage76-Nt E !. red'6��.�����1�E�ex%Hed �Y�^ͤA5-��>9,"� � -l�� _p�Tc# o��Tfun� eLContr��R [x� )��bonB�appear be h��l�tu�!�� U �U\5"K6K|o4 !?� c A� sign�6 R�C, � ��EF�,6� both)As �%D�f�� gg� =]!���E&nex�mpa��6*� proximal!�TSS�Y�les+n 2 kb��� )�ftEBU�dis� (.�%�10D- Y=�^ ���Y�� ,a$%��ly � ��� �B,a�s);a�yx s [2�[3�� Eae!T� .�s��"�, h"% � �opDe��Yq�::RinF� tend!�b� rU�' �}�53o�xa !KY�- samst�6�5  <10−4 Bc� CaH!<0 . 005"K0@by hypergeometric� ) . Wm�pro��d� integr frameworkNcross���c is-ZA!�e hear��XapproachAWa}b� �n ���Y<a*� e"�, inclu��itu|Rind�� ack�-n.,)�AJi� 5 turnA��� �� dynamic��m� algorithmu� ef enz carry� ��ihood-��=��er�nis=sm a���"J ex!9ng5V- iscu��earlieY I1 igns R�� akH"�� eE�enc�!*"M"| )!* �A�los�del6D. � 7nF�Ra�Most U K whenLdE��ngA��AhmN  a!��� � annoan{ ias�var)Jsu)�E them@r �mizwa�imp� �n&w*H yk.~� prevbzs2c��!aim�but���i��!"� �IlE��� th�� ��� �a��r�yn"+Z s!�� to fu��utiliz�&% 2� �FC��7oY�E�J�� u|>�ma�q� !�> |/!�g� �-aA.L�1sto [2m[31��zZ �"is limi �� Z`�1. Lassig%�colleag[2�� [28])�,ed popWA���-a6�� ves 4a fitn ���t>Tedi!B8 ce (�A�e� nsus� ) !2g� � e�ir�ar)�ma�detaile�Zdx hap��al��cN�2�ҥ�;�� theyl� hasix� 6 ui�a.Us���.)-3te-cis/ nso( below�? Mustonen%�L)�%�a��Uw�to Xd:%��فa�Y[��+t)ourQ �saeG!c<�exter!selNon�0c��w�!ejo]ŀ��:pen�a!�act0&� . AA�� ���C"�u� .�B� �[3*Sv6Sof2# �| �aGvt]rkov ch}�X Jukes-Can�B] nucleotid!RoI~��� e93changAtwgqhalEa% �5�paZ �X do� ��9g�vsee�. DurretH,Schmidt [26]�id2yBI8�perL A���ime needm@a"��� � �be fix���,�or� j:� of mm�R drif�Th�E�.y�ume�D�2poiA��/E�veQ��ta� iie>�|X� is&�be��6[;� e view � adop��inID=2�E9 . Re�Raijman&�29]��a I!)>� 5 ��E?any9Tc�Av��aY��de��y� �{�lna�N i . � ,-�8 a smaller��� tl)�re� ���s!32��X�� stead6A�� r�%��dt�� b)_i�s�"2 �&:Spossi&�%%�� adape�& [13]Wmis�!���)?1�.9of5qsI�b A��ssA�Finn �&�n!�a��bxo���  2aA��% -)�B<OiG!�d dele 5 feat�aK>� �t�:� N� in&� D �1�A�xt�Mv .� &� (  ew�d[22!� �u{� shares  �!�thV}:��: on� 5h&#ay�2��. . Sa /�$"� starA eh!�pionee] A�horne�4 on pairwiV�[1�E�$4ly named TKF91-�Q�b�A�s@ gle6 r.\l���n�M�r�� Sl ��� ��s6i-��blockat fou� &�length�ribi , emG ngm5�af gap p�ty [23� [3� 6%Ko� arbi$Nj�m�empiri�$[61�In�)�JTFK5�") � �y%�Y,,�an MCMC,K&5 �am65�� phylogenJ tree [6? To m�/!�U�"� >�,)"bearchR(� ttem� to cap�W�tery�3�'*��EY �%�itI�T slowly-�v!�DNA*! [2� [-�63!qMI}�w�“�+&ri��!|�%iA��'�al*��"R�u�$i_�� �bs [64EU65���e�, �%|&�9�&O !6�lonP&�categt$!RNY.6 7$de /�'ņ�!|F�modul^�h�4%�R�a�* char�����8N������ -W�.Z.�!m �"�0%����;,Halpern-Brun� i���4 �$E��� e� whil�ty B{�� le�uld'a uni��r n��#:�/X. Also ,���&ZE{x"�+"i �B� ��&> ba�qui�A c*(')��r�'pA�B� s�, [39A�So�2!Q e� l� ��#x�M��)�cho**�p�: ( i� void"U#ddi=e�e�ram��A��&�\�%�o�� giR'D"a^"/-� � ;{|6vlex)�y���-nE%�Fi12 I�7 �,!fA��!��j : #s "�?N 1  �VfterwardAv1 �Q�refA�e�1"G%a�r�2�G� .F�Despi�&�>�( �! thro � �i�t6�!2 �e ai���u$"x& agre!9roadly 2_.�Q(d�� .�@ , [66]rata� !;"2$ab �s� bFTF���Kt($�aT n "�ut c�ghtfo)�, issu� E stu�s"pa�-"[���in*�!i. Gao"� 9�T� t40%2�re�j,u�%q�v)$AK��! mRNA�� [3R�Hu�Q?atm� �$a  s��F. romo�z�w"+���$�)=��TF��knock��u�. yeast [34� "� ��l�)i�o� 0��"a�wa�!�y1�ing�A']ioIbzfin�'7�Q�as"p")1�Mw!{;�Ny>/,:"x1as��D)���|"#f ~�i�-P� <D�Z��)very �,�%�wazs t�Z8 1H�( 1% FDR��'immed�#ly raie-~� !�quaon: if :V!��ar�>�!u9 �&�!(-9irm� � 2wJrevealC%�-�N N ?�%  ��0�sw� !xeu�aw �-\� ."ol1�An�u �n����(�+ew�,~a��!�2�$�&!I�ofa&� . ) A�*�(W>� "�4aK0Œ�4"w"�,�.her� $y help att� TF molec to} � e , j�B/9 true�Y�. Anoy.�%�"��s9�iS n(�!<bye8a�e�-" P ��. �!%l"u5"Ve;itt� s��wn ab��!�1 _ceն"� �!El J"AIt��;ET�%typX 9 % ��x t me��ism�)� ex�� �GA��E�5 .B7as%� loop!W,!�*unih &cA��c�M�gc'[67�!�y play�q�!1oF  #hypAsiz�y# c(3� Z��M,�Ee�� L!g-reg�<� �xie$w I�le*laal�6�89k|G �J\t  �8,�h \1��er!�achieve2��?�p� rn b6a*�(2($'U����i� =��J��S+dem�8�5(&�-(in 5′ UTR^�-v�6�%>A�� A�-4RX+ �Q�� 0� V23miv3aOgi}60��2DeS arAiy \hbel%�E+~ "&V$opens upMh ilit*� a few majxp�� �@+*�� �,�0? �% he c%nt�?oa�S9ѥE��v� w.�"U� �9&e�4���o�I�9��N! uish` 2O2� }�b�spuq4�� ��as� �"�%2��K� a w�� trum��4a^%*T �c=Pff*v�U�by��$! s� in"_$� !C[68� (.X2Z9cip�|U 68d.Fy� �-�sIr�a cru'%`e�!a!a�a�$6"] �: WD ?<���4a�pu28+�-�Dcoopea�leu,it�$nkn�- qY�itself o�|� lear�3s�+}�rl�r&oj"; �fAp!��3m+)�s�'ho�ll!�&�61�L�2�e�2.*�I���6��5�0 novoA.��E�1a�)"ji�� (-tif� <�m�/�"�#benef(�"�&"7%,�g . , P� Gibb~}%e� �$gE@"� erro!�nd�.�&�“<��a!A��!��%tin�?7 �t>* �= 4 ) ( 5 )A�z:�r�i3A�]� � &�>U�.Q�IUE.�I�9 m�ka�' m�;�yZcolum�6 )-XpM�qe 4 S�6�w. Ii}"�*9�a>Y�h<��e��� b�]nnJ!M,$�a����!�7)�v#rd�� hand�%�%l�"I)�fourth.!�5X%��[)aie}Aq�k\< ��is �8 )iifZh-�U�+��siH&N"=%{y$� !JQ6!1�6. C��� be ,Xi ��b�se�!��!lN�i�^ͨiE,�F�.� ��iEGS,�%:]�e�-O�E�9!�*y� vF8ctaz�ll��irz'of��� user fi%�r� T�,):AirF� ihav�10��..q$?ET%�A��<.�l.�is�3F4gmD� begi�=�@!�ba�~H.A�oA� d� we?d JA��.�aAa�e�! twice:��du}"��1��swi�@($�n�AA Eq .)C>e �fXk�0����=F^E�$c8#Ga� �:b�Tl5S1�x"� EZiyEFpla�Fe�/�r�C��&�1E�max'�Atandar� .A` 9<�HMMs2�>I"�1�Pmaximum-?J2,achI "LG�I�fixi*���6Dsar�Gon-"!ver��bi HKYL a���^,�@e�-s�uin:�*��)�s�1.c��"�!��d.�m�t!�� ��H�{wop e!�.��7�H���#28a��B�(wo�end�l�jb � Y�ilI�i/ 6>x�webpaga�in6?(by Dan PollAnD( http://rana . lb$=,gov/̃dan/ma�e htm%��"� foot���6] [50$Fo�A.#>&)���6K:%d�6w� deEhes eqN.to �68 , 9%� 5*W ��2HF:& Js�H�W�6L���'~�5!�B)H!yQ�nolNZvEMB�\1A��5iAo��lE] Vedi@e%8!=A�Hb �s)?lower=E)&8�:�g�1�50i E�.�th +!�lM�)!�500 bp��eacX'vI8 7.a+!>Y�!H&)10�p�M�"�?:�P@Bf�atv�v}�0toof 8 d>��G!V1! 8 )��� %l��y�o勽by@ valuA�st��e��t�i�*N Da�A�"�(m,"�0���*x =Zas�3md2!��3%�0A , C , G , T6z� �d ��%��y�evF�2 .oq(j:o�� s v�bs&�9yq%I (C22� :T��S=D���2 sechellia�i�n@(�� �K plit"�Z++�O J� ��7�"�*&�*2���.r ; dp�9�y�!�87 F a�>%V\Ⴡ�  Ko*}� &]Q;%`25D a manu!!@�J��ve-c pe 2e�in [71�=3? CisE e�B� Ef}SLD"� �)r� ��@ 7�+ frQA�+i&0�xa��� =^��ie�67F�M*RCRM�; om RedFly���m [69�a�XMūM25 �i�D .:xBbvS1�LiftO!D�Ei� UCSC�C(Browser [70!�Two �A�F^��e��ar(+%Űsa/�&�$���y.�A� �:��, �>G<�>�>Kni%T��"e"# � �.ake*�4E1sourceUI�]s. Bon#9d&�� ��9%�E�FlyReg�, 'K �oce%2� F� 5Mo�33!� s�I1� flanz=aE& 6t ,�we scan�� ]m%�= s�Q83!82Z bestN���  heU�L.�%>*jT,H��ra��N� WK.��aL�<��se�*�6�"}�ac*R6]��s>�Ag#�� ies:.�V'>��aIs � 5(K�synonym�O23~] tre�"Z �)zN+V:J� } �>�'hW4Gon"�S� �t� 2�H� 50–60%�6?/)��8�B[ALh%calve.C�-%(* %−�6 ) =  ;穉=� �P�+J[A�!#(equilibrium�db�!,K$A<��M���Ri�1opA"�U�D�default :J� b_��=th �R��?��ru*N<_}>�*� z�� ���t e�"#�,�eKň!�c �b��?6^&Y.�Z Y���-!�v�3(.�J"� l� expa4'runA#d�����-10d .m \YO� -)%%lc�n 4ly��AM��2YMF �*{ �Y ��e���!Bo L��\ lf�oX!�6%%�U"!uT x�&Z &q  .M�ZP]WIC]6]�e1`uto�K�'y} 9of.M(��#L�"Lif���e�c&:�QA6q�se)[we,=�%i���* 5ME@:k" )�-%!��e�L"&O�MWe�loo�+6ur�N{ i��6�Hb%wK�EG�& igno\1�: "$!3��8ts��.�Q��fic!!nd6 ��lsoeY$X35 peak) �Sf1at�*�,'�J&V3d!�aF plus 25&"�yA&upsG9Edow�]eam��� L*9��E�<)numbe��.! n�ndo��� \a�N Iy[��.� B)�X%�Qp2�]� �u5 6� gQb� E%%�s ��F+M,ʼn#j PV �UE�H U�� ng��Ee�of�S�G+acaL:?!�0��$if �1 �>i e��]s6eL�"� (�d�*001�TJ�9�'Aqnd un�Ip]%V&�G%bBbP-� 9&(�g�)$U� ? tu h{Tiz�"� ,www . fruitf�bL�/Eo�yF��.�eO� �� �� o;A,J����F�hp�Z - availgat;ved;cs uiuc+-8du/emma/ .�WT�Tpos�ym��%�!�:el�_�"u phyl�Y;mo�(MgI��E.?�rom�=ɴ 9�#�]pi 3( PIWI-�.!P)A�ho&sil�s�'n�%�rm�E-��%unc�%A�Ťpa I+�$_7uDRs�*t.�Y)!��& �Ce�!�D&=+ �ji�$m1Vau�Ngo�!?rhlF$v�eB9�!�J��ڭ.aH��en7 �CB�femAg�N: �%��y�ʡ�A�@�[hn($3[�[UD[_@�]f�E�oF!l.[�N,+�, [�-Fur����/���e� yste�Pi"�SN!�s A~.,�Nri�� "B^��[�D[1 �1 ��GI�wP �)�}�5re!�~ �.xpl~ �M���A�.�>95�!9s �� asym[UlocFI�xRN�\� ]ax�ioocyt�q!�1��!R!�/}?letha BV�) ax}"p�i �d͔lin��8�75-�oY�! dra��rg� 0 null0a�mnk��encodu' Check�K kin�&(2 ( Chk2 ) ͸ �i ��? dam�ign�g#JdZ%�6 ���9��2��+&r]!NA`9I. O)� g18!��Xy5���9�� !�! (KIg;u�y 3!f�*� w�eY5es&�ASR��tA]� i�e �Y&�S�X�� ����5"##!F%�aT9�UA�=Z9�Mbp! ghNa��2�'�ag!&�!��  �&ID7* �� 9�>I*:SY�e9FI�@;a�0el�E�9T u;gCint���rs�1%ca �s�A O:�v>�–22 �/)�. F�)lM aqSro/ ar f�  init�< 13 rapid��� mit% "� [16AE��"syncy%�I�m!�a�Zsurrou�coIial�i��9 cell!��|At13Xh* to 3-hr �m[ �27!�n�0y >�%x,ct �?. �;ub>;!990%rmi>�?a�6disKQed  ' s ato4>�|@spi�,�'$ microtubuY4u)Un1B�!� S�=E��؁�!{yos�eU^s0e�wo:C5H9�M��!� ular.I�pr/>a�.� s �b.�g*> (bridges/lag�H A�\��<90%!�1h� � zanaph�K!��y f�o68(-F2CO&� 1��,25a;"� �#&� ,Q� ~-YQ�B wilda= ma�1!8dual-label FISH�.�5niP physu tAv>< �Y=�cU�d.� ��Q a�2H#Cl?Wco-segrWs��*2 � I"�_1�$1D%�� :!a7%�2�I ,�a�r�  i�2"Pu��did�/)P�cF�I6.�r��#-X!-.�)-du�aq�N�A�U1#:<�ccycA)|.� 1f.d�Y ��2� mark8BF� %*o�Uontinu2 ha�Jen � V&P�)�o%1 w&0 fk�o.�a�)� " bre�oQ�M�n a6�armi�a�Fr�9zIH�ax�J, >��e��As� ��!� AVnk2� A2Q[;QZ�hr�n>RIi2��dB �����( �[,�,Eka9C" 25Q TV$8�]MÅ��0d d��IF��ٟQ�E�sK Fm�<6� Z� 2�e��ub�*� )�pr"�'R�� p@re~p��o� ibit�  %pSd�?� by s� "�Pk-I& ,6w )�rgonauteY ago�4�-|W�-a$, �B�1��*�  !4&� *�[zQ��>M5 G?;<�?�"tI J|!p"� 6sa/�Y.�Q�� ��.���>aly; 5x�>m��'ї�A�u� rNy!l�dcrO+�.s:C9|[24S ConPvA��"m7� � ��2�6)�av�b)�,s&��Ͳ)�e)�i�:�r� �1Ma�� v�Ti2C!La� � �!�o�F�Ky*&�r^n�hS4��� �tloquac$c( s )e�*mDicer-1"h.G*�Pmae��a!�w�\� b.. loqsBelsoIcea��n�|lY_i��n�� )�����nd�,&�A��ǭm& m� ��� 7�] :;e�%r mGa���.C$���TF�B/.��1pom�8A��Rgo1 ,aE1x rdp1��kinetoch8"���5V ��!�b�e�$��m�{"��  p�GU_� 8Rmi�v2�q �ϱ%R��!��.( ��RMѬ�e�"v , [1�h&L�+�J# �a�0cAh��0"5P 6d��� -N�[�k��" ,)1Z#H im-Ih)0!�gw d retrovi�/� )� rQTsq** 6�@&� )�I1Laove2j!-! tE �qn^Is2�= whel!'e6����6>)�a�O.�d���/!w�!�Q66�2E�)E�1�.�TPCM1es|!!8Modigliani ( Mo�[y!V�|��T�"�HP1>8��MRN��Lh] Q,al �Q in h��o�a� &�A�M3�X�m�3��frl�a��rec�(�$�e�o� F�#�I�y�e��H�#�" 5�"� ]wo "� 3�3�e?w"�o/\>4c�uli�B2iv\2|��� 2�$Fm�� �4Het-A 5′-UTR�ORF�����Wh���T.��Den�h Uism�eO?toT]A<%�U_M^� e��Ay�liu 75�. O!Han ti�[J � �"�7>D��layJ-s<c *Q�r M�terpre��ZH$se biochem�"�.��}�4�43 h./��k �)!��,)�"��<2*�y%���in)�A8�6 I+!�%�U�S0<�,zE8g�2 ��>aFb-o7 �n��6�FY>#T��5��'5�� !�["] A%"��)v%&��J)!�&k-!locus*aa*�,d����d primT!�?nQ�3 �a�i&"�@olv!�HP1y logua�*���}r�Gsor�!�A�6�"�.K. E*��+I�%��)-9s� d J< �2"� %hjx�]2p \*E SL7.6�}`��A�" � ��P�0e��H��ڥed� rpriK yT�� VQ!mYyFor E!�!�to���:AH� 6�/�b2��VBNu�.\B_ !�hi!�e���,'i $]5by�Hf��E]�!� �2��$ �aSk*r� rong�Ym��c�. A:�(!�M%h!�R!.2�-���be  �0respDe�SLI�>��+9*Va 2�h�&��J� e�iD�sh_ &�$or���*0',I���J  /�er% �&t� u vkf~�al"�L�Ij accu�9e.m copZm� Wjv\ �! TARTav PJh!�pb g� an![s� �!Q�8he�쵽�X spnE)�*�4o��(�zZ[3v)L*8 TPC2�w����& b�+ igge� &: copy����ht�ltex�.6�!!��9j��D+.]�o.^aKA�u�/^�i��a��,>Cr-����SF>>�SYld-�+Sni Gaian�ie%" .~* )�1�ib KE�.� yr10aL1�ld�e cm�?OregonRa�:s3�*�gU1!u-�e�;�ig* tock�j!E�"�JdLv�UJ$�aU���0�J.:.Aa��&"�%erzMT~m)��V�UE�� N�E'�]��a����O�.�R�.i5 -�R��f >�N� Ri-u�s"Q�Y�J< �-��&�~a�  4gj ��a"�&�u-g*�F5~S*J )�} �Au5�h~��2*6j�\up���"3����"� publis�U(� deep1\ �6� 0]E-%��.[%a�*�Th"^ aS9DeB�M� uniquq mapp|-,�-ao�*��� =+Y�=[4aF!�bio"H[c)�A�%� at 7'd��B� �W*+�U�5TK�"�4gs�� hist�^�5}s�w��a�,� ����f�q"�-�pE��. D�ka�1�,o2�ep|�]�1�AdA�_=��C!`dWwF*�blue#Rp0:Dminus k��He�mS&V � %�* �a'l^%/ shor�5�IC � ~:�9�#4#L2�An V�b�l>.a�ez>at 21-�n�)A�)*� )��T5Aa�$� �*� 4M black arr�� M�.X (�!@�)%lalm�exAUao�MR� .J�A %Er!�lU>S �&H1��c� �)`�w&GL^����� 5i6M�s 1�2k��qubff@�"�La�,a@B�ԛ 23�. 9nt 73MV�<j1/nt� ,)e�he 21�) ndo-%�I5Bsl�(EI�*]"� 23!@29Ab �, alt��!)*Qu<��t�I���)�mñ�.:� iZ:$o:�!1�n���2>A!.�p u{S�Z. BV5c2�R�YAzf�H%"10Ul�7!��Hm2d�at ��to 95a/9FVF!d�.)6� E):5X^Ay�a���co->�:BK Piwi���N�r�alo�5�3!]1u�X�:�]�5�+f�`�{�%�"/�S�\. B�%�su:2?��>!HQ��8!� )�N,%�>E�& K@�� >�TIE toge 9 �/2� s.�I�5� f$M�:"�19S0 o��e^ABN%�`s'�|~w6RKm�:Ɂ� �:a�hn\>&{"� &�1�M8Ru de% C��%*.g&H[98:*?�.p�!sm�%�,eq!7E:�a�M 44#y��a7P' *~ ��(�V\5!G Mg��E��V�j *� �ch �:(a�5=�l=Te�` ʚA�Iv�k?.5�aIvmn)�-u��reck} E���vWd�u �0�I!�o loqsf0079#+KO5"UE�.��0Dennis McKear�k�&�fl?eSA��_rre>��493)Hgo3365�])"!GZ�jpl?��stop codA�[��reJ�Za\@ lab ( Uni}`�M�chuNs M�al��oodI:30-min-�or -hr�7"�� nano�vd  s;� α-�9$in ( Dm1α��igm�>�Co el1∶300� nd�J,2 µM TOTO-3i"l:var���6)>�=�[45A�F�3����Fgg�<mbi5��!t!R dissu* in Robb's�H��4%�maldehyd�KdeA�bedE�$. γ-H2Av � body8A�rou���z KimA]im�wutg�{�w�m��t%"500 di�I��O:�,�6��fluores-�siB�Kdm�by 3′�ACȧ"ideoxy� ܍yli�fer�*( R� Uf�8 ���� opho�c onjuE+ c ARES? �7!�kRg9Z�$9[fD�re�MF. sJl.�-i�!�pBK6E218Mv smid% :cf �T3%�T7�!�[:. eO �Frob�K��Y�[ �2W=AIG-dUTP a�PCR DIG-�O�� !9X t"�!�a-'��"� �^)�!Ud ers-�F-�!$GACAATGCAC GAGGAA-E A� telR)TCT(GGGTTTGCGGT ) �Y-*45x  AATA�2o(A e{ purc�<Q olig�l�8-C.1of FAM� Cy-3.Ys�d��>$( IDT�*Hy�+�=!;&F02�f� !3ly [4-&FyElyI�M#!{�;ikCы4a Leica TCS-SP�`�{Zing�f �> scop[f@a Nikon TE-2000E2;)!�c�qMet��ph softw�^�al Ima0>�+All ��̥6�I/,e JAuasbl, W ��J , U N�dnn`�EHe� , B�sd�MMaryl QUSheesb . � . ni�g4gov/ij/ , 1997�00�!>Adah PhotoshopA{o�x�9!��wgm�!aa�-/a��<A/A$2�� �,A1 calc�?� /30�i mean L�\c�"3��E��g �W�dA�� *�9e&�R&�"�ns�`)�an}va te0�Two-tJ�t-M�u�i.qAB^UB se; Xα �Z 05 . P-va�c:no!#�graph� Wh��Zq��2–5-d�� ld f� !��y {A[8:�l10jA�at room G�erE . �# H)m�� C��&�^��2~�� �� I2�+�.�'���j|( Invit�%��Y�/�?Dmod!�e��D� IJ�*A�d/>)$H�$ poly��fyRm'�! mono 2HPl t ( DeveloGS+F��oma Ba�HI"�4������sub���o q�7 �Ap�m Bios:K7/ m8E�F"B�m֡��;S� L�Oed��!�#�$;^put�!�m[=�t�s!nESC�92."�^}E�x#)bi�'/*rep^*%� techf� �n/\%�^Kw���v! plo`�Ce�w b��"�!�l deviMGau[vI%)a�A�Ny2ۀ imer�icien8d�1� be gt curv��n� VZi�H�de0*�O�% IP �� ��"B g&�Tupb;x��3%<"r r$S�Rf>&��-a 6-�!�^.*Tep �)��-SL��*IZ. S��m%�Wd�t��.Cd!t�[37bg)���/�^a?h: t�%�!�z5.�&m*x�q LhRe�:e R���d!�* YHet�I� �%$�V��to�qeno�- ���i�Bowti~Langm!�Ҫ, 200sA8�co.��_coom�a�8%�DA�*�L&a�Z�.�6a�Kre-<�.8c�? ( nc ) y=��reW;_���i���mev �,&���r����:�A�5�p� $hr4:128000�1350999�*�=��!-�!��()W�+ N aY �.�=`g��30։k� Zair�!4Sudan ebolavir޵l)(4� onsi:� �$hemorrhagi"�v$HF ) outB)��}tfatP u��53>I�J:l�[thGw v1(Côte d'Ivo�e��!<�ak8:m�{.� Nove�A�7 ,-��&�8n Bundibugyo Di�cce!W Rrn Ug)s aboksv�cf�q�Ll�su�t-� blooׅ mens�]�� thod� �gen~  , Ig� IgG ELIS�A��t&�h�5\^-��d pyro]B3j$ach quickl��nt��Fm? an E!h!*1�L 2���{i��"�5EC5�(.T )e:akhd� f�"�Zw-�Af���"�:A� �2f%�,ew �ti�Ax*p re=�7�E��!"�,e%&FjR7C a+| }fuediagno�B!N"k��J5r dise��5uma�GJ#�+� ongoaHeffor���^v� &|�nti�7�d vacci=F. ��fam �Fil�7ida�y�C��A<ͻarburg);�� e�ch)�g}o Y��>!sk�Q+ge�#Nis� ri( 3yurUM, ��,��, RQ�:7$( Ivory Co��)>�"%�,��A<e���2ofj\:�(>OI�(inQǥ2?$����Z( 5h"�()�V��pacҾeIW�w�+" 3�lڐd�g� ��� an�3B�=](s�>B 3�"&� F )Gc@ nic�Ahey� pyE=!h�bA'u!oLk�&r�I��"L �!�h�L&rvo�bf6��ins� O�elu�$�" #�2 � A�a#:� :�����!Y�>rbo�Ta bat�\��i�ofM�Y# [�No d�ye�qen*[)q'] �\ ��n�p�.�6 a cave-dw�Cng��E�)��� 'a5yh�%��m.a,�Y�K@Sn�Qe��3�+atU*%<���l�54�&f����usդj sporadief�tia !K�r�Xby ���;�to�&a��a=Va��W}�K1j2�p �14 mago�l99Á�N C�+"�>���iu!�F�Ua�v�;inarian� o�= �\utopsy,�� !6�nze�s.i� Tai �_[.A�fV[�Ŝ5 �pE?>:�]��# �Ptom2a�I�,� R����� "�+�h�s}&EM�f!�! io� �a,�/ �(iso�I�F*�W�!���� W> +�F �!e�"P ��AQ�Rpr�. �ZB ,�,�) clos�e�;lbe"+�a�#�n�)g�a4�>u�f�.��)qge�,p� ��B�pcountr�>lq . In}�:� HFE�J� � towny��*� A4 Kiky�N.f� "�%1F �f�of� � 2tGa�8&�4� ���D; airAp� ��>G0he�!��D� Co%"KP~$n� ( CD��z*K�v n<�E ���c��y@� on%��� e�,��� �a I�re��e.N�..� _�sa�u�9��t.I�9�_!:an� q Xbِon� �rea�. H/�ihemTn Min� �'(A�n��i̕]�8�q��D�%�"�ohY!��� l�Wi~ +-��RT-ps� \�!�{ )@� ! J.ve& O��e� "\$1�t�4AqE���"-��覡%0 !�^�)|MmBJf��L� *4."�$)%men�.���[� e� ~D ( 4�q �X v ) a]a^ ��D!�-� failu"E@b�AUt�<"{�i�[�.�])�E�]�*�-itEB%67@���, 9�29 kE��2.&=��<4yA�A᭓u!).�V3�Ap.b.*![)�� �Y?(�Extt� 10 d")5VO ��4&�%c��t�B�u�! #20070629� Q�"� .�*meNi s5 ��d�#o�&a� t 454�ze Shef�� %Lcky ve r^ Ż� g�d�aatFH . UsoA+ne[35 draf�UO!�Z�)�]INP!l8is-A��e�nd �o�P��0A>��� x|]A�& �W!p����"yuES�i�3six� ��iE�d1��ŔI7>�( f!aeNE��� ,*� �y(i�.-� V-�rG�z1�+bea�ٽ��(1S�'fer�� �Zearch�>�e2�*our�V�y"9 to�sil�jka�MF!��3q��� af!�re�7&-C��>{)'�� inu� 9N� Decgi�ZI_1497 � a��$37�thsFg n�r�N�_�Z�2�.leQq�T�l�| Dac"on�J�@A�r46I�b-N$e ( #81125<' �wa_��ejd atuM& -}9�oq��@ qhb��o� �B�F�BLw ��2Acqui�� L�9>�Wsa�oN&��! }� p�0�),�:��e0ent@q�BI��hi���� ��?Gm�&�)�u �2h��Xng.��?%�91B\'�%>c�` 32%G3�'eeA-E@e�zl� st� ��,j�32��t>O�gl,( 35–45% )sIb��*�*�V�..6 . �:G=�IGl2<1Eais &Dgŭ*L6�4 "aca� acid=`� ��Gd-�]1�we 0surface glyco "�� �orW  -WAof BtropismE�|3A�x��FIYs5p:�:bA�� 9[�Ny�27"35o�K� ̚M�= �.Q!;&{A�o fact�su+��o�"�^eve VPZy�pi/�� ���2�)2F�!�qz�J6�{�u6�Jf���/�p�!���/��at=�)�a s am�F��!!p. Cur�PE8oC9�&in��e-�nJ� [10]–�m. Cn�%PB D4��W�bH,n�GV es3 e�2|1� ll7incor�&X^!d��?�>� y�rA8�"�toD ��scree@)4o!�A=!�*L6��:�tro�����\8�8%pz;pideml#%jl&Y��XA�}h"��s���4v64 mK*R∼36�B>�j]& is_1e[����bRh�!>� (�F . 890wndBX+ԇely�5��.7=4~��Q�0��� Kie�~ �!-!I6��se}+�in.� also��l4�ۍ��30^\��{� 䇥�& � y����d$�/A�� "'�( regaR"gn�a8p�bce� ��!��%i$�R� !��Omem�iodefen� r emer�  s=%ill�jams . S!J&��3 *��z×�Sat.o� � � H9�^�(l�C3�i`� � %���R$on Vero E6|Q�(!�m�i or��h�a�� &�5� 2i-�<>i2ln� 9��?e 2J\�ig�  �U.� ��� %}��-�� [e9X s/�0�F�s�j%�DEboSudBMG 1 ( + ) �QdGCC ATG GIT TCA GGT TTG AG0,:9−;GT IA? T GGG CAATTC A%-tP*1rFAM-AChGC1x T CCx T CTA-BHQ1]%�v )��L�al1Y!�Yw=0!� A/B� �'7*� ��b�3�o)�Su�n�6III2y+cc9&g!�gn�+�%�9&��&+���&� is%�G)*d. Pyr2U�9LutJƁ��8 a��"4byJ4i�2"d!!&b� x-Fos @!Ol01=Qb �tM�w�-WI�"�9�b 17]�)�� H�#VV!�<f�2�QANrq_ �� 7� x la�& [��'ll�l�adE�A'�2 ) :0 A���Q2�in97A�6 ���-GTGA�38AAGAATCATTCCTG E��rse-CA�3TCA/TCCACC;�BF�3 0r kb )r� CCAA,CTGCATGTAAGT6$AGGTCGCGTT�T�.|CV|5�|GAT�4GA[�4CCG:��4!-GC2�DV|1�|%BA,5C!|GAC6�CTATCGGQ5TAATGG=sEV{4�{GC!LGT!�!�CB|AAA%�TTC�5A,Q� Ӥ:v!��zCCT!� TATT�AG�TA6� AGA TGT A��GC�5 ATC�exacti�`e�KofZ�ź ..6 RACE� 6����� * ed23 �0�Ysmc TriP_&��E �E�th%#olyadeny2�Cv�1 IA-PxJ% ( � merp �3 ing �7Epi/)er�0� �$e�ifK9,��nh!I �ur:)�5aK easy nQi@  )["�/+ocKj�^ny6?9�in ���!u%add�s~3!3�(�� , ��fS�fOne-Step2�1��P�8num Taq High Fi:�t!^I.�r2��wo�lle"F�)(mi���1A�2A�K3]| 7\ Ebo-U 69�nZ �b�f�F�h %�,18269 � �す��9}�g')A�∼700�IJ� �(n���u�e���� �/e�LA�-�@� o�Agar���<�r�w8� �c�/ct � 6�QIA�  Gel EY��Kit (Y�a�c"99J�( ABI��"�<et'Y1P "�* %��4�:���t�� � �Uj� �� fil� ��g��!�confi!+�'-C���llo�b�&�S4 ���1Q�y,!N<a?A–FA�#t s: F�N� �Q0��TGH==e�}=�� �&a�TT��y;Z� 2� �1�A�C�rC%�~= .� � � �Z� ������� CC:�oGrG� �.H Z� �� GCTGy�>T> G6zC�>!ACl k Az� 4 �? � � GAI ��:�B A!�TG� :M J� @ 9���?xS!�2�4 A!��)..GF� �;3�9 ^A~� WRA'Qx� CA�C�)�щq� HF����eo�1TCmST6�A�RGA��'2����tig� �N�2��s `D%e�2�<oE+&o&���to��a*� \��!z�:�Te-CT� GG� AEAs~1eAV!A ATAT!mC� ti al;20� ���F�RBe"�>�%���r'� r�{;��6w�kn��~�m`&�1�-���L V"v Q-�*.�EboU965] :� -!N!CGki"*CU1039 (� 6���keTA�TTS�m89 Prb 4 Fam-0e�� C�CACGCrC .�&� %e]�upMTS:�"e 5>V>���s���40 }%� a 58�Lann����em*�?M��t�/7 [18]e%���h e 56�>��"�� >�"$|I��Qm_ �,�pr���w �GG' l Time RV8 B&��in�/�si6:!ȯmm1��71� ( GTR+I+GK"�y�Akaike I* �C�r� ( AI^+. N���%�A*�A3270*C 2101��183qMT278�9!�-r%Qo��2�3141F�7g% shap*�� /A�059 A z�Yz�E!�,G�Vt�t",in PAUP*�`b10 [19]=J1k)�p��sG ootp p2>%@QkwOspzK���,\>},!^{�p˖r&�?[2�[6fU�@yes 1pW�g� 27��in MrB2e" M1f�j. �ߓtaA� sezde�* Mark���q��=�,�?s� p� a@'f02. Pri"Bo�ZQeA@_X? AWTY!�ul�):� �Cha! onte Carl��nve�"�;ns�ta��W �i3suf�(�. T�� �!�e��HOT&� O& I���%4�#�( bur8�m4�%�U6�^tz>��"��non�(us)�odN��wa���Gby�(�*�"��v�E( ≥95 �*�|U�) .=IT�`\)b�#s!��o�Sp��va�N�O#p��es�ram� AlzheB's"\0( AD _�!+s.m�� y�"eX 2Q�F/!Cam�1!�h�eZ�8k�O"�!c�*li�#2Ome�oof�.� ҁth8�c.�! pa ��_eQ4l Nd"/k "!��G;%2cli�C �͡lobal D�i�=�! Scal(GD��FuD� al A��s�1 St�I�IQ ( FAS�* �'&�"�$&�)ADL@ S8A�li�<�� GDS/eP�!a*U8m%Idu�<!!�1[!2unk .,gT�.��2o�ai$:xc��;_!�648�5���a&zE� -upf(of� 7827. C7F�QT6zsJ�k �E��"r:KE)'�!c E��I~%;A?���,d+] h'�`n f5%Rt� ADA g6�5 ��%fPhY.)U�!�i�|�f� %'E6��b-��e�qH�=C%�� �p rdea.e 7>] oU>�fv:.7� U�.3)5��t['%}�#(i ! %��x!hav%� ime-),��!�monV,� c�9[1pZ��WhsBQ*�G S nl,ab�il��.��&$#��y4y� s [2&�a2�l�Trea��A��'v_I<ɣITlyN�� ��%�MchM��)�FS69�14)(a�K!����B��at�bE@AH��� (Ey q�t��@]-dela� drug�8I���ŀ0be able to es�@tablish whether and by how much it delays the deterioration cause/DAD . To this end ,9�is necessary to have a reliable quantification ofdhd ogeneity Ddisease . Global D&�XScale ( GDS ) was propo�in [20]�allow$fessionals$caregivers�chart�decline�(people with � Whil�number#s� s exist ,� is o @@the most widely u �strumentystage*coursx%[pIt measures cognitive , behav!l� func!� al impairZ� patie . There a total 7�s ( from < 1 corresponding!no.^to *7F*�sevvTAD ) . In particular , @4 ( mild &is%�acterizeEf�requir�$assistance!�8complex tasks sA�as handl-fin* s , planna dinner�y etc �AJ% 5�oderate �:�e>� hoos\A�aS ttirA�In S6Sly2z\drA�ng e�ath ,stA� experienc urina|-fecAncontine!2.�4has been shown!�%�l�wA� both.jU� x4anatomic brain!� ngesiu. FY�AssessE� Stag�%�i�sub E�normal�~toi�M�de�iaMA�AD typ!�The � H��%VenumeA<dNbe�cordan� thIUns � whicy wa9(derived [23!Lalthough some differ!�!�tw!��two��� also � demo�zatT4!TO��advan��s� GDS/%��!�systema� that��Xua9�Av4of!-in it�!erA) �)r Ito veru,�Q-I��AD [25�InqliteratADA !`�;aJG^�u QAd�ɥta�rterms�!2���s�Z)�t�fo�tI@a sequential fash��!$���s2� certaOV du�saW6�For exam���Ais.{8last for 2 year��tA ��T `5 whoshJ1 . 5:I�in tur �.E��25���%)If��ia�Tuseful diagnostic tool>reflec� he averag.�!Fprovidesşnfa�t%b$bout possitB^AD;g�Xon . A��same timAu �yA�x vari�JA�2N9Bs�ess-�,A�  need����!�Pb  gain)Pa treat�m sta�gy��.amoun��nA�al ��i�cY2,-�s to judge"� � e� sign%�� to any im!V��s obser����%�pa��w�|vestig�4�Nfby stud5Edistribu�offI�<p&�W�rk: "� %�bi��e�4A�>ɲ8well d� Y] valu��orf�M��Q&� $individual�? �!mat _� umul�W prob�.F�.aA>preAc��fig�a� We can seO a�)�a slight�6 b�5��aO��� 4 iE�furA0 illuI��# x2AUreAK�mean -X� b1 toge_w�ir��$ndard deviE�� y��hegp�:e�)��͵%4lot-2blackMt�!� ��2re9hby gray  �>jA< es 4%J5a�2)y�c)� horter�\���m!G1I�j 6zca longWat cal� ! J�k-).�6UH*�, 5�Q�d>�� omewx6��vz na�[27] (�M4� z each�&�� Aon!�4dashed horizon� )���Despitais fac� w:',� R e.� Bc:�5!`!@)�s��three10,F3A#)�6�y��ikA��lE�e�be made�loo#i�.�13oA=wB;m�%�]P��iM 2MLV 6za!�:ve� al bharound%mA� �7IMh in1 cket&x- !4]�=acB� �A���m�I��F�� re�lly larg��6D `�)ązF�^^-Xord I� =��.u)wm %qQNo$exceed 50%vm!d 9�# x. Giv�   �NTof ge lengthG!UitA�remarkCa��:�tMA�!�5%�so cla���$previouslyALor���s;9! �1:r)�definit!�wi��t>��J�%A�W.����iw�#a�3�%6[ 2�� �E�a �wJ�,!��not�{ clud� n s yield�5s  Analyssf a-�AXitudidataset� revealed!."� �g��ofU � J IJ�s 4–65�nF =�F s%�:VUs ed � F%�s simiDIUir!�n:. T��l �adic �U�patteri &YA�f&�vL=-lyIV� � ye sugg�o��at!� genuinA�&) ous� �,%�?D�AG݌[28 �� [29]d i� 4-� V�}id� f/ four]^subgroup%�# ~ s���� !�th!�intel�  ZJasi as o� sympto\�30�2 %�AD��ws=3�S�i���� 0d physiologic*fl���=�&� !�se� ec%�)&&�Tie���!C&" pr.l>*inhom"�a�u �J.�[!x%�,ventricle en�恌 ,-��y���6Y�Q�1�qg� c%�aphasia!w.�'5d �,a more rapid=Q8 a%Y dby� �!<exten�taCngMbqc%�YGAvrview*"b _,�~9�a*�-�)� -up .12] sz��3Medisco?anoc� "[ %�iva�Ed�� ob��voliE�a18liI�� AD ,�� ul�d%�i=t!� A�!Bm )mn�)I�. A recA�p�,132vp ines��J�� a 15Ji�-E�im���ins� s in��!]��.%�.}�Z ����b��ip(A�-.X)e Q�aA�-)>Z(�� ) Mini Me%�XStatus Exam ( MMSE ) scA�at�-�  ,  Z=�s'9� ��@ :�t�� �epa ��`>�-�đ e�6� ��� !��[33�ZM� rele�� -r5� f6������ba:�2����Q #��{ofQ�s:��x 0 ( Alzheimer'�D.n�-C9Subi)A�.�SP�7�QSelf-Ma�`>l;n> g�;Cq�Dq�Ri{� S�Boxes�A�no dir�bQ��!/�� "���A��se�,ults clearly�/�<.�)�!v6 in m���{ �m\i�uz`c|�a6di�conveyA�^ 1983��200�IY theoret!kly&������=�U�0!( ���o͸�ng�j$ lifestyleo�affec!Sz2s.?� expla�^�,� p spliG cJ����"j :�d�� isi��Aoc&��s�xw �Ns$“Aier”LA“��e� � y��-z�E�)�nci�C� &� �as-�a�es&EY� � ]m�� J�[D 6� �U. Not��how�W�_a7 pe~A�aMt specA�decJ ��ern��nd����.:# eca�%_ca� ~�hG�!t 6ata a� nd bec!!!mscarc ss�(small�ub-J4�!4ily jeopardize)�K I��]uXMa woul��)#cat�1 ha�%1a�-i�� gene� al ee���H%���ld only�l*:Z2A�y PA� halvY�M�I^�_E�EI�tI�R�5EAx.jsa high [9@."|j* qu��o�fRng Gl%��m I.V��EY���mp-s)~E1(!�.<toD ographic�!Ede�#if��� a���sex�duv, ��+of on�� (��auback-��b.#!A�� � Xe�.d!�2dA�No a�e�nfr%ion �th�>� %5{��j< � .�7 �/ ([13]–[19]� �*�,@F{p�$�predic@ !.!N^%�.� work+ [34]E��i���*)~A�d1$Aa lust%$of CSF bioer leve6%� � toA�a$' &VprofiA�W�^"�#itE� m��w�extrem* eA~ t��auE� phosphorya�d�V onA�181E�� �#stincAA � wm��%�ea�*=%memor� Val�e�&aexecu%�0s;?or� l6I_�!� c��beF"�1��!�. P� [35].0aVZof>i� binm f9D!2!`FE_ra��� �"p-tau-!<* i)&�faAIhof 9�� in5�-�$[36aA��m�ADmO ) ^f!���z& EEG ab/"it�2e7eN�ieI(to�Zm �!v�,�M�as�1 cerebrospS fluieE�!?Q�.� plau{ � B�r Qt� �v' <� a)��2@.���&Our m%�B��6#!s�)e"!z6��y( E6HAreA� s ci!- abov`�ethods"~ �>�#�%�N @ wel  a (& ( 23&p )6| ��U!0.���8m��*C IofYatB�7%��?T*�!%�v i�E�ici��8*�%? �spreaQ&� 6���d���V &�)�G*ppl�� �re+� co> � w q)aVZto!��$�m� �AF��:�Qh�&h2B Appl)"�IA�y�%1r1���m��f*�&�&ll � &accA�&4. In �to&f �^�!A%�ҩ%I*ZE�v�ruXan�\�on&�i) *[!|�s 6e��E .A i�i&�!ImC: tz �'s ��M�al Cen� , curGDSE"P!� A, ej .�on2n (��gen`,@ H � of e"d � ��,&�-AD����!1321 ,J)�648 repe�record-���mth�)st)E�th!�l� r�8{�� nsider1}is-�� e\���P-�Ps' 6±0 . 9;^ hist![�*oFD�B�| N;� � 3 ( a�.')��first6��073 . 1±8 . 7-�(!5.ab )�� age-. %|66"���IfemalQ[ 34% ) ��!�Y* receU+bytT is 1 �4 � . Ex��aE�A� 6�%F��2�me%r (��a� ��` re�,�� o�e>�coiedi-%��4lA)wekn 4q���-�C �.., butA �/*O)on�%m� Lc�qtar�!n�!A�begina;in�weL}! �left-<r- censoaaIFuz&5, �&s�A5G a�P� � 9���h$�)�I�to4+��H24A� 8 ±eh9Q ,E�v2m}0c�a�M � Yj�|M��edu�r�r2�1 . T�!1� a{M �s��ransi)Dl%�%�a�P,� cc*�e�=E)/���+. i��nd)B6j���q�3%3ac A�6�/r*e!��ck �6�|� NobU"Y.�coY%���\6�)A�!�n<sufficAG���Puct�.���/���* M�T�iA��_)6/Yco� m��J�to2�!6tA)95(% wholA;'(&;0^F��inc��e� �an�+ l0V$*�Jd=w� we�q � ter-i�e�2� 1A&L �T9U�wa} bef i(�� U*doctor&.(+: ( 1 )86{wa�' ong peak �&&\/A�the$wea+64(�9I$!s u]�s�/�\���stply bi�)reasoZ 0 hap� !�21� �%appoinY.iuA�mm^ d af� �^ ) �%( 2-�U2�1�is �9 03±�,59�TsA��bF7�approx�BX:�a�ag l$lmakis�I� Y “coarse�a�ide�suE%Znac�� x!~ � iH. .W%�� , multx6m�8�4�2E,Aad�5K *�hy���.[384404[�] %)ach�ovE.X8� �*] �7a !:o m� r� ���� oA�� ar r&*9� [�2!P��xl.���";7u��"K&�7�Ka�7-Meier�e � [41]�W3survival%���. U� tuna((yF���doG2t7 d�4elfpՈ9q.2m�5 �:-T!�S�X. �uAE t�d\op [42I 4�Em*8�k2�8�Y vie> �  /��a57� <85� e_$�d1+ach $��eC-lAeah�;� vstMm����6�3\�caUp�;!s i ( Eg .v-!I��o! �i6frEVg �iA�hig�<q se���-�(s�.��;terAa�; ��Mbegan�8XL , XRe��(�$�6 *< o�'we�>1B�at5) �v!�K/j�-���6��� , [Z�Z ���he� bou���Dto/j+y%�)>1f ��pri�3�UEt����assump�Y�gCM8s'U �_ q8A�T+�:~7��Y", ��'a�fic�6r� !I��!+�n�� �r�%coinc�$w�%"� 6] �u��8r:%'a-y�in [43��j�I}y�a�!<W�d�@��;9 3 [�V;6���hlE���v�H� � �� 7)��$���i�Zing#8.� o�B ���M�abs;|5Q5' deathi� obsol�6U(�'s heck �7sa{ non-�mev)!#er� u�*�52�9�|bye�ra�forwar6)�=g�$ �� �5% mathe�'�&U���ed-���*_detaila=8 gɜ��^,q�.��R4(��&� !1��!dult neu�AAqigsimpl�,0d hippocampalr@ l �net�A^"N A+ ncod�\#6 �"^d�3o � inpu�&a] ��WeU � �addbA2�{�*� adapJoy9}gy��pa� to B� 8;"a*%n�P ynap�p�;'y�ifo �T!)P>��AqB�w�B�rv�"�3� =ar$ environ�!�{~/r-�� p!��$��a__ d�>A(!hf�A5���+}gr,ell"�entorh[c tex�P�A�Q ��kacrosP<.�% �6�-+_(a�F�il(��. ��-f fix� izeL!�conne��is1�;J"�XunO?-R�may diib�placed� V�Nq�/��fe��> z(gr�/E��^��confir�c�RN 1su�BorJ�y�n-�Vhst�uajI�Ue� , ��mb 0E�&�2�rul0Crpoa�s A��;a�enhA~dFa!�(of new granD2�>ll2�*�"�et}D�)=��� � E,Z1�;A� ope(%ng al3� !_����be ��X�Baximise2� rQPw�c s eiG��U-� ng-��st!m%�� exa<$a E(&_)J!++&/�E,n animal rai3 u��hyp�"9r!c�F�j��T�#A�thB �"/�fe^?pAŅ�a��*�V�#�4#�&tes�e�E�OEl. &0w�pI�e�M+!�eme�8Acr�6!��al�lma�FN��a��d>,�!3!nspars�$!1�d 4� gyru�)yer .�>)�mamEa�9�E�0i�w��genic,y]��ucEj olfaxy bulb .�4&01z!Q5,=#ja��6%�2��:_�ou�>F%ar%a���"�|�(NV6i8lieA VA���a3r�w�(��ad)anAaj/qe[1�5Thousa| RNMproduced�day16�of you�� i>�a� �J%M�#s sharp4)��Ben;[5��&"�.!� majo�$�7w)Hn�/ �8bGe_�R� �VteM�A�be� fub1 al-RVFzKa�9W0�17HS" >�ve��.Iper>a�oleLEa 4�"Y:��a�%Fg�rA� ahio}�NsJ [L(6�L cri��window��recrui�� ���"'[1.% [18]�>�:)�i l�1A.l �e�7�BeLug"tK�(Compuc � od3(�g�>g�DA�gwES��:!�AX=��2�/A�-bornUg. M b#*G MA��� A <gen� �͢d6��?�'�"� bN–o�m��bn��,G@n� ` �1[�@�J�9ɦ�!*A�i�Y�!%��O0a��Gb� �3age]:inq�ofA�r[-�,E%!p���Mi<'qM o ;wof~ -out� rej?onship-{��wr}Aa�6��?eary"�of:9-,:�mus�are��0gu�Pq� �+N �!t3'�7- -F5�v�$ur  Mq:.v�)��@.�_��:�E�raZ=n�hbyN J�Y &�eDhaU�um,9�(0;� �x*Y/a�/�Nv]aLin�LQ�r EC��DGA��e��mDG`Unot�"0 � .� &�=�>�DH. ���'%c��5iT%�� �E�(. S A.4B5m� o"& duY.0ir�*3RD"� mo|0�� labT W,enclo�9 uI� �A��A&� K%1md1�N5A��B�/al� R ��2H�s.�"P draw*CA>B8!�r�+�e�� I��):2Eo/�int��1+n�i�s� �)&,���s�Be�Z B,�# ommo�i�R�%��ove2SZ!� breakd�<� i��-��r5e�!td��E0� aid Fm�5�,�Aodw�fer����Atro�1�Pu�oldv�ening A&+*X�d9��A���1t !�) �� a�N!U�8M 4r�1u�Pd)^��� lems!�&AMlL�M !��I[� �y�V�,�!�ilT!Y�h�B!�cU 4!:B�> J�� �w)#c}N PGn-a � [�Pipz�� orig?.���.�� ng��B��ed�l�"P�Z!� Q�i,�3acy far8we\aV is l�s� �U+�w�"e& �X�f6Wb��u� Rq^�A�!ЉE�Z�%[-!.m��3��'�nd elimx1ng��ir�2%Mс2���|-!&)r3"��!Ao; arguX sa�to whyZ�sh��&j LF �.�asyeO � y .I a%V�waa�g s&�;82K��or�B�ur�^�#AC.U!=�"� ��L �!dr�Y Gauss�)�1 Z&i�?�7 B !�a�oōar�`4,>� �� wak��rajF�A�+��Sl\"llaa�er�:_[3�QCIE�mo�%TI�&�%(he%�X�@Qe��>�}y�&E[%"�YV�P�:wNP!�awyuupy1Bf�u�]$a phenomen� M$of���B!/� ��F� NBJ�M�b���� �(p�]�i�h �ed5�A��:�w .��i�is�m�� A ����m��[._N�� ew���N!?P &3�)�J^%V-,6�RL.@-E3"�Gu75th4r�D��b�2�I�2��9!0�bL s�|appeare%� !`��a&�O"*S �Cle ��E�.�D DG!�,tNa��,�depK%M . Ty�R��v�\� ZtG�Ax^��!�r.�,!.� )f(PAA���quies�)� w��;�2!Q4>�,q. "� egso���=-8.Y II��.���ECz n�a ups�Z* 0DGMJU� ��.nm6`C���.�EC play)� regu;Pp,54�organ��R map�N�m�tR/i5���a~B* �l(bcfLNL!(" _!2��r��?�M��./te;�4"� or)few�lI���6rI�%a&di)R� ly&I>*h0a�nfaD�K�,)y��s�uKVexdJ �A�inspi� 5“&5��:iQe1�&�a� 6�+ fJ@"B-�b�� at w[:&�,>49+���,2a%criz)�%�0 �!�*�> �"%��+-�� � enAv� �^ia:��Ol �a[.# I�XGAWGb��5six"=*7i8As1%�.C$ex���.'m�oe��9h' �)#Nt� a��..6 ]!��6�pan�of Fig�]�9Ru��$ess%�%o |2k���Q�'s�U�!�M�t=,Y�.��f a�| a2�%�a&�Ş� �xn��;�� at g!n��Qd��� �wVF Ң &� 6� m� "�d��"�+E��.[́W6��,���ŎprA�R bn ��S 4 @ �-"%�  q�li�radii�L.���f<ty�%M ���Yb�n�boKhg%��� �6ases R1� |2\�emcor� ���en�#BKmEC�19#�X�us 7fs E�bG ��[a�%L�woS��axi�I���I� �@�"�1q"$+i�+ap�(�u�u�'!�� :E�j��� �u��F�,&�7ui%� adja� �4do��3�kh{v� 2�. P�6� �lsGa�?ly6�[ !emx4;���&op�b�6� a GP$-like?"�e��\Q*�8 �in�&S �rbo{u�mT??�MS�n<!-y��zo#� MB3lM<�C��.*�^&!2�&i�c��M�2lEC �O perm� u��all-to-!iCiv","h�N!��S� �6 �I���*�F.hidde1v671�osemY of��)��#q��6id� =�E�c�& a/t� mid-ed qsA�rk2�=H1 my.� $ �vir�>Z �& �n��Xi��ur(-F2'*�7��)�A `ypar,0OK� summK\,e-de� b�A��� d��F��2aY3schema1��I ? ~ a!�� lp .qui�4�� l�M? �sd-!�r� R*�7!pN�J, middm+woV. F?.�$ �uU9bhumm�& I>�%�a,��9sp p � �b'n.� ��we ��N( ���box- Pb}�R�Ybey�he1|5A#�in�+e�iz0�r�Z5�moX $n�/*V:��:� ���(�,�;�=vec)O6|%_i EC uJ �# �:IK�%J� � &|1�)6� n q�DG��w��-�Ns�(alg�(hm��d"�JUjsu.6� j�F�롋aL��Na[�@"#!z"� newB�iY�"en�T.��exy�e��� MK�.�B�<rv��Y�x� er�>" la 6SmOt!�r�3e�=�2r� err�/n�4�A�A-:- . If7: �=��h I��;1�OsaSwa��T@�f �(�8�. A5>{O/sh!r����n�nc:Y4P%�]Mysn �kciv%g�[r��(�J"K ��-�lach2�Fx�uDG�o� mean"�&s�1b>oz �VE "�A*�'s :�.In�Cc�)(w��!�$2DE4�ea�@!�%Y!��I2�'��` wl`�a�)!�QJ��-�%.vu~c�Dp_p,� wa�>�,aQ %ue� 64ki�-E�)��":Iv�>e79���Ɇm�.�>(O"�^fa�2a'"g� �@ 2 ecz�ch/�8djuZS��u�2� :��$�u� ri�w!�disru"�M�6}!Ev-�` �ݲ� re# ��"!8H9I ^C"�%�1 avoi����$ �E�A?2�UW&r�9ABa!wa"�&2:�@a'��d90� �H2�do`�\�92Iza�R*�;��0ot� d��3ag� �5t. H"G[a�*�91/��/s� -�W�%�=�y6�I ��ul� ptX'w6� �y o�ck�:lea n�0a!ty� 6u.�Our� �" �� �qs�u��wel� �� ��� d2��[E�}h rE�o1spn0|nth (�1� iwKlaL$���% �l�� ��e h�0tB2. W�1A��random�K�FN� ,� e�"g�q,�'nt��hse�5ve �LXv!�D;qE��3�{�~d���.X9��<a_���5��sy ow.!6A6� ��rstEiit%35B&�:�N� J8�k&� p� �fs@:\n �'���ngu �Xo0S%f�s�X�3�z�6"O� A��f�w&�a�7�["� � "7A�e!qu�e-6!\,9�i�6�7g�DG�%�~�7� d��Q �CN�����6�����.�<9e�FUG�E� xponA��$`UI��-ec�% ough`�&b�4�!e��:�belPs �/E�s+��,dra&`@*��+G stop��(asYP)e� �d�C�@u�� �� ��o�K� ��"n.c^6\{2jO�&& `nS�era�J��?���H.�a�8c�a!jQ:b�P!�B#up�*e��;�ou� &pC2j��P�Y-6�[��*�"�B >�EF+eA2�ia$�Xyӡ��'�AM�ali� Aa�atyerM�%0�4r.�J�Y� ��M��K4�I�!��Fi�o"�jg"W@%b�%rif.9o2!nA\����"uAs1 ,.2ho�r�9�i9 � !�튩.���2}i �. A�D:e�Jnzqq~wTsE9h�X !��&�}^lK3�).�.�12J.gK�G .h �a�5�l�%�E:^x,���?� �2�}4 d"!3F�.�f8N .wf5&y� H}�1sL�j��iw�%�:=�s.�/re-a�x@"V; A�e�p�P$a�V&"+A��#4!�$ta���&��H2FrAl ŝ3!q^<-���-�to !�@um����X� ? x%Y�roa��s6�ye*`:,. �2�E"�%mekoA}:p �Fe��$'te*�*nH���GI�%4%�anyth!Ʌ�B�>99f�� -l situ�=rRL:q?QE5c,�@'6sE9��iS��littl�qlapAxFJ�]� ��P!Pcta�exact:VfC���&��A��,��=r�&ly9�2�U�.*�w�9�s��pr�K;Ss�Ub�T��`O0�e��M�DG� �hYa�Crigge!�b��12�% U��-�� �enc)�!�is�2[XA�MN{ 2p �WBz P�in�B �.8��J@ vj-5A�\�e�9<: � a:B2�4]h.'6=0�%"�9:��Bll!�1 .�R�ricXP}+omp��J��>a�N�)_D�,)�;� i�|J�#��0!��8g� te`%e-�� ep��C"s �T& U��qR8#p�e=�� ."�EC����J zQ�r�[=heaE[-�p2�D�5)�D*��MG�:;ste��DGA}�]� E�leap%o;22 ŭ�h!xgyr{/��x�V)�.F+a�2� ��0-*�0"�/�05')�!� �O�d�u����5_)2Aow��A�f� � >�6n]�4�Bt 4��Mvelop���m ^� �3e\"|6�%��0E1--_ t�]`D"C!DG~ "� s1V)Q�.:�AW��f. Brief"<Q�Ysx�5��s��A��C� m6�,>a��%���q��cop�j�1k�ze��aŶ�>&it%w�.��y&��%wr�%!JFS"�*��Sa�M��N��NU�jakday@AT }1��� �Vc * *T8"��:1��=5�%*u3&VV�H�]i(esU �ur6Q(Kt��/o-k: )��qu�a>44 m�&�10�\�1TM� <f���!�i�Y=vm�-�.�. A�[A!�!eBThave gq��&I�d~ ��B�Jo!�Ia���� Mve�$8<!*E��new<1���D$� �!. Each%��=��"�(k!�a!�.E�XazUaDbea�� f� F��oKmL�1�6iBy%bUTIuk[�!pt�!IjE[9J�_)}/z. j"� EJN tunew%1Rs�D�E�.J*Y���'st�q)]�\0'C � Mx��`B2-�3d5,t-b)KQ��:a�+^&6Ps�#�  a�" �QڅY]a,U! ��18I��e�am6,{1 occa���sc�� �L5-e� �#M6!��eOc3��-�8"�-e�faiN+}� �,�� � �emFٕ/"et�:A!F�[ �-u)�G� tn�9"I2@�1�B���% �0{pAsI7�!db yi� �anno.[�0��A'�_�a.�!�-4&F-)#6H6c�padY )�2J. .*�6�c4�L%�i��!�&���minuted !��nmJ"`����(�Rw:�F�n"7B��/$discrepancI�ime-B�, rhapA1st "(P� q�k?�X?b�=�-M A.�)i.�9� B�X�,%/!#*e ���kk5fa�A>"4("3MG�is: inse�g��o #g y�IhW@B �ne�5)�sv wF sh�Yi pravuPDaOA� a�ntkC%�,m��*F 6�ov>_�/vIN&� 4(e�e�w� � 2 �9A�����$IͥA "�V�$��� gnis.2{ 0i���t��� EfB$p��s5(ui�ZC&��A| ~�0"�-�b�A'��e(]�fH:h`E�AZ7��a� � x=�2X� KMR5$=T%b>%A�d�I�ix|tho�P`A"�*s� �~.(p��H.fA1�%�m���A�lQ�a&"at)�2���� -���I6Pa�y)T�7 ��&.EU&`�� ngb�z5�.o"��p2I%,�ur"2 ��R�F� .�t�C��[ʡ[�Y:��!e�Z��n Z?�2�&s�K*ZTFW��E�AL�eGm�>6K�Y� 2*� �*"Zw'� <)?Hn�Z?�e�y MN�#*3t^�YW0cuj�a� ��w �(3n��1a�le��!&"% ! �UWal"o �(ci�j0+?�t�G�I)�sE�"�r>%���Mb��""t ~�/inu�R,�%- 7yI����CA3�6�rrut� to�&�&"'"�M��at CA9|co�)tr�( � Xe�I��p�9�np�w�,EaA�lE2SB͇�Ae� @�f%���# Cs R��1rea%,��R via a Hop� 5�: �b�XulN������!�!e!G=+%KJ��A�zN:�i�,�;� 6Y!�@ gard��of K�h� hXow� e2<@��oU0-��-ll�`�}g"� ��&�0�ɐfT A*�K a�KDGi !�Txh�Ed EC.D rAR�*� U��%.�Y�.�>,P!De��"2���;d����+&k�6��7ha�&] � ���0"]%_H�"� ��* o��L^>N(r3g�h�  O&>nN�fa`b�$aA=�*r0�Elso� ):��*�'- .�ly&� � oYI�� �NbenefW4 �&)%����weq�@ ���D�Dl44� X)�!�[T6�1 �Q�~eBor��xA�&J�@i1)�I�ImvaX=M�((5}"qa�" ��@i�e #8t�Q��S �%Dc."< aG2�1OA�aJ�$�Yas!�b�!��4:Fu�2.�%|ce"/�Eam� �`ka��#=i��in&P�. C��:&2�!�i���s+�!�Af�'�!AV`Zv�4e��Z�e���Wa��D. A���th)@e�ksuJ�[}��} :&� M{0 �E8< B�m;l Y�����qw!vF :!yna���x ng!7`)�$%aJth byer$.k �&� �4or� RB�b4rA"�X�0x ]H1�%�&�"�6A5%Ac%.w }a8� e�d� Q"~6Z�A�C�.E���*Rq��a�}]"P�2��Yb�V� offm� DG%� ��- A˅��I2\��s pakfu22/�[a"��y n�.��;is'4��F:~�&!N̪f!6���B3*HZhD(!�&��/*> . AF��{�< ;eLr�&< &!��de.�.�"9%��;E�1*) %p�m,�'c� stee �v�@=� & ?��� .�Mqu92�}nB�It �%%�+J"� 6��kH[E�h. ՞�g� � &��&o`E�-!�� �Nn&&�(%oaAong� �1�@E&-��% =:KnZ�( !�6�~J����<�"��[�`�o�2rm��emz$funda��q�t&x �Pa� �85�aF:�� Qt�6r2�*�7:�kjFc �PIYG��keo&� de�rKm=-ac�A��  E>� 8 �B+ga�f�, q`��K�? T= U �l��ت!X�7��cv�Z�Tde�kJ*� p:5P�Is .�ru�5��%~Ed!r4�)���y�� K�� �hMV� >�#5adi��aQ!e�!E\&'IP.���OMJ!a!*J9"w*1^2-� �k%%�� yD�/E*5+�;$9 �Z�deM:7!� �Mm�u)�1e!�A��(c)d�� ��Bl la�!�X2�ay0*�\Ka�g'"�0 �Q.E�&�!���=�FV(�Fadd�reP5�FeaHypn;ed� �2e . Ov�a��B1.o�<b"�2.��F�_^�E:xLF�)��%� �2kfeqPUly t!�B!"�."M2�1 �4&�)�yu�:�!��d�T_R�  zaV|F��8A5hb >�|&i+"� �&�* E4�%U�WSL$�)?9�!s�5?mU���A ��#(Fn"��mC: �o� 2u9=� ��� u!E�E�B���;)�U�9��s�O�:BAt��w Py!ta$.�. Less��g�i �b'e!�� ��x�hif � Bj$ra�_en3 VA�vrQMF� � o� !*w^* �"&us�y�Ş�Eg�5"�SesemAi�RR-� 1w)/o��a2�]avail� �)V�.]��aiza�C�w"X �@B�-�!��3y�J���=�&�� �]*��igNk�h @�  "B�%at��"�YF�%�&͟� �!S.@y.7*AV6E����Ca�d&{da�6�� �vpppain�!�n�_ �vi��2x.��it�"�+1���+�< osN*�!�GP��"}sK9-�%���e.�E�a{�cAH�21)4�.[inN" &� Be�V�'be &� � ���bc*�66��# .�.�F ՄT$�.� �4� ���!+6�)~� l*A trenP9ݧͪ�"m|���V �n push�%9AFNAU 'Ft >�c.�z)n�A�yE,**&an-��EA�m E�}?)~a�F�U�y c�1 EWiN *2(�in6j�r�)!^" � I meaIism5�>�������u"�P� "�#*&�nBxA�k�fiI-$A�bg#0E�����as2Z�q%dQ�g�{ �Վ*��%�(��C7z�� few�a�A*&� � Fy'="| 6�%����!a�2�G��i�I�${#&j*��'\�q�sR"r6W R�#M%�'�-���&�#!L�mu)�5z+� 6<]" �F �%k�#��ɐ�@n��/%weeks� F'�+�r%\�%{ �p(a�k&i�6bQr�s�9J� [1t�$pW�sE�j'a�too��� �?U�E��?� $�'�=Y.�E5�"l!qlg6� ae�x�����en���!�6]!zg2�_n �-$KA,�D�F�';Dfo-Al:�m�兵�u}�A��&"� ~�a��( l�v�U�X g�I�"+>���y� half!=�2epoP\g��2,&!:Q!4���aR�(6��$��) K�� �>>�&�1��EՉ1�'ERamongs�>5}%�!�-�9�!R��E 6�#��,co0 <*~!�)��X�jE�aa!xi�5M&M%��@����6��.!CDG׋;�o�lol�hD'gAwKoAeo m!yo�##1�a"�1�rI�Rke roome��� ^�>�;ag�L1�@n �gi0%�N�/^��\j �gm�rbBtew �!�"066@�"9M!@��%�_�  soon)���9 f �'e�re=Bz�EE�=;E�F� un�[aYծ ,k&ng:�b�T�"!�m2!� �� 4�AwH?;�& eE%d�. � �r[b�.���"�w{�!�s:�� ���ˡÁu�-f�_cX��mai�b<>�T�;���Jkitbc�3mix�I� �<d^d. &�=�*u�on� h !�ro�~ "g u���T���� Erid�*�5-�ECgj��E��"�$%�G$jDR��Yh�� M�>.�� human2�[4�Aź%��1f,Db�pr�3NP&��. S f"EB��A"�n�se��)!P�5i�����f�H*�%-T�%�&�� ORecqJ{� }sk.� � su�ec��%on:�o} �eAt f 1cvF�"�snsG+|����w��F�q�EB!L� I�&Z�m`f�1.6?f�}n"(S�fA�A�� ryus�� "� 9P*�D �:� X I�� 45 6]�"�A!A� �o2��[4�~a&$^& M�r� ��e&w�[*v6(AJS�.&M"�!a�� !1{�_Idce5�*�"� eı "c*�S)S � <&��q���~.��n��2��rgK`in favgnL&�{G�/�#al�t�<[��AEI��ilso����e���Fge-�^X�텬sup�-)�x�!�m�m�  [o�D+P2�B���1}I�qj1 e �,r��. S$a��t>�� �D� o)efv[48A�e� foñF����A2aM��imm� A�s����a& 1�[4g�H"1� bvYd]^! �Fv�8u?U U1��&\P� . Dat�E` bqin�������HscZ�[50a�u��Os�CE,.M),post-mor����S�d��$"o�bB�it;�_R Me z�[51�BEx*9i+s.�".�}��M�>�_vol&J'er!�SA , cie�influaع��� demaUXF<navW�e�52]-*�$��*�ce�E[5e\Ao�6!NM "f��2J:�"a�ab�H�E�S *L i���S���HU���&Q�eȴ�a%ɻ.^HIA �ll�� �| !p����p���&'��� 12��� � �� 2.]y circuh a|sv&�7"]Ns+8� 2w�@&�:Q M}O1�] �\Le����p"T2����-!Ib��.� : {��A.�� ~,� ina��*wB!D{"!�!�U�B !*��25> � "�!��1ad�. rrec��c�&X��o�� !"� *�J�L"� E m�E�s+<����?-Us?"/"jS�S.M* *�~~&�~ed�|6i3IwF�� Hu�� R�[*>(�al%�d|>��ʼnR4a *�z@�A_�w �DA_�lfq.":aS3 �?!R��haD��po(N� �5!}��ooe��<�*�DA]6ke4��%���26"56 sX>� &�-0�S6S6If�N!�th5>�Dlx�XH�LinH"1. 2w"�_�+�U�'J�as����=��~�vaw&�9�9&�1q�']�!� �B� �&&�un�J&Y,e4&�!tf ��#� mo"pto'rec]co� �Y4%:���a ' �)j+��Qe �%őQZ>&239A��dq+�+se?a+.K�$he� e/����M� e�I �aRM �k�"�% %�MZ J& 0a��'K$��Z�C���LS ?�N"]�,WA��#s"��O�BAlu>"Dy&L�ey�OR�<a"�N{V.�<�"�[A7�"�?�~p�0(�s�Lm��;!&W= Npt0�EX)#��J�DG}�� `A�8p2�y�&�N�{COeaN {\�&Wmgo�D!Z�q.��Af�� n trypano��a�A�vil��!�dܛ�Lnium gli��"� oxid� ( Px ) -t��enzym"�-pr��aba�etoxif*� pid-��hyd�*MAs-�*{, bloodyT�b�ucei ��!��$mitochondr��Px IIIa�x�a�� ���: pr.�$de�����? sit%��ac�|(e cytosolichRqi�go $�r�l�Ac�� �a � ��N%Pa�!��,�#scu�Vl�.�ed!�"o,α-tocophero��ri�Eve TroloL�f7" �l�!Lr����C>z�elu���B"p#O�EmaR�vY�u�%injury�Ke�_, px I–II ck:9��@Alexa Fluor-conjus�sO2�n� LysoTrY�"BA�m�-ŃA)cre� y����!a. Yet �~tyn&D%�n��͘ae��T(tKݴ�!�r%ibod(�d�}=�l�ET5I� l!0T . biac�C ��q ��E�i� h@E�'}i'hSupj@H�8� 4�T\y 65*ch ore<ro� E�aponEJn+dA �!1J�!~ Immunof!�e�}ceroBCy%� Mit5�aU!�bodW ��e9�»protei967 "���dis�2Q"qM� AMce��6rdamag In vivo�-�&��B�negligi9(8�6Pp!M�j: M�in���3!5.")2�|�� "}\de9?d"�v2�An/) wild��yt2.��%-Z��RpT9AG;6%�om� �[Q� �1'!A�1e!�E㥄��ɢ/redoxin-&e9O:3ote� i�RA�-Q�membra��E��iDp0� ak)"clo �lin-���Fq�#�<�"� wi�s`��e��)����+!���#�%kn�:M�9.A9�^�procyc��nIc�Sm�k M\%�` �y�*in�N-fN͊.�E29ti�&!�=�al* ctro�ans*�uRnstitK7Uour�)di�"�#� A/��IT ?0ecursor molec�;Pɡ�%2 oxyg$�[ . H�ME]�h��:� �QE!duc1 ��res*0VX s ( GPx�hA"��zt $u)�mLxҚ GPx4qF�h%�ac�Xs/��:�RP�A�sA�lcU tact6�qs [��A+<o1��I(v j "����� a�ntue��q�m�u�[���zi��A0akL�g � �� KJjor f*Fhus�-� Mc�latalyz�&� e�A+� %8��O���rup^^ & ��z�ir�grʾ� mmi��L��[�XjAcauS�(ge���X� sleeG- sick���_Nagana}��^��,i* �%��ic!Qtozoa%�  ge�f� cl��J� w�7���.( B��a#" � H�����E�����dA�V��� midg&�utsetse �Xj3�,"J � o��b&@ �-�ks )A�pyY�AH ;BD�tBS1W�6s &nl r� i2!�/!��T 1 // lyco& �ATP!�\n[7�N�theFIwy�y�u�pi���5|�'�al��� z K�=�BIr� equn�E�A*�;W� ���[!�nm�fn�'�e�sulfur uŁmR) [8Sw�BS.�������kes�Qd �n���. d [1Z�All ves�$ fficQa���/A�� ���!�m6�* flagel�qpockeT���㥜�H �!��,�:i|� icZ "/=e%-3ɉSptor-�|�&ca��2���g�2d� �*t�pas[3e]! /AA��~T���li��[.Y %m , [1ha0qZ1I`re�or�� �!Yn3j"W�-u�'ut�i�:�i1 e، pur8�e�.��'| auxo,�!]2Z��tcof��a5Fm!_ &� �hapto�in/hem  ( Hb )t AB�ڟRM ���5+��!F�� e5� T:�aA�sm;� v)� c]�j{ hol6� [14e�1�"w�8� >��>� i teol�E2gra~[�-. I��E*� :DNA�NXQm�� Cq�,:V FeS.Esy.?� A�{ �A�o��gA恙��a�4i��J3[Q�..�7_!�8[oc�� ine-�(ail^ � "� W H�E&�v2-Cys- -�iA ��Ty"�duB u��"�t�� 3 ion6� G(%x�y��c�e����W]a� R�j� 6� za� ��Px��¾�RNAiX�f�g"s�CApAm�,�J�y�1�iso. m�>�Q ��� %�>A )��s��"�?���KM�. P2ide}d�q1�� ,6 b�4a�re)�>`cul ��um���vit  E� X��a�/�&a� GPx4-defiI& �@��g(�ed*�c�& �%A<.��O�ge+:-���a�#>U6YII@!7`ar.D�dZt T��retar.in!+rD�V� ( WT�Y�4�!�A���F�..(�$−/−%9�.w ok �-FwnW�fyto-�-�*-�=]��vaa-ofDI%�� к%voA.H ��genS&o� " %Y�&�"[r!�2���,j�o6�6IA�5!�en�YA� �ism��fy �8g�Y�*�cyx ���A��1���&d*�6Z�7�*�Pm�,� �Q0*� unde� �a��2`�+�!�G��=M on -%$}?�(!�uf �s &(�z݊a�:i?�*lN�APc� up~ ��oRCE�]ov� �C�n�xe�%"]�l 5F9�hioE3E�N�.om= � |,��c��R��WNth patha �(.#�&� . A��,�cd luci��%�!7%V-/e��=�Q� leth�~��x�A&BPC NDw�FMBvia[%b2s\ &7 e��� �e90�Sq"ub� t 37°c�Zmut�mx�aáRkly�a 60% �G>90"y� �:�2�3�f:_ kept�21�N9 :�( �۽6�I9�BS!��g!�� cVw����� �� F�����Nmay���*�0be.YF�MmBoauj.^N5P own-��A��"xT 10-f��!��)a"�1�. BCM3�eB�*�H">b�J�"�]ZM.?�q�de���!�fEơcAkS2�n�t|6.e( R�qa2 �w+��. E�%bby!�pisgEe*;a.o[��Tq�r�n? ���1�e�� �W% gdb�'")��he1-x�&� 488-J�b# �dWTe#ZF��lMr��XRofѝ)!�b2G �1n:�;y���N!sb9, "��ly| EO!�AY� I1���2 h� �D'(at�Ela{Un"�]i���!�A+�G3c��} � �da6a�o�x��i�) albe�+t a�O,}��� )Aom@�WB�. 2w �WT�a5�a3��CB subj��o*oN9�],the mutants �mkept with Trolox as in WT cells , the fluid-phase marker was discretely located in the post-nuclear region of @arasite consisten �Tlysosomal delivery ( 1�hFigure 2A ) . As expected ,Vabsencee � �csuggests �swell�o �organel�an occurA�an intermediate step . This has been .�9.)ere trea!�Eo�protease inhibitors or human serum or upon ablation�p67 , a]-Htransmembrane glyco\0in [11] , [25 6]�8rypanolysis cau!�Dby apoL-I , crucia!r mpon!�-t98tic factor pres#in2�A�volve!fe forma�@anion-selective pAbA!�y� ~1Q�\process which is abolishA3y addinh1 mM 4 , 4-diisothiocyanatoAY�bene-2 , 2-disulfonic acid ( DIDS )A�� culta�A um [!N!\7!UIn $!��Vz, 0 . �or 5�lhad no�t-$effect and 3' even%A�,to be lethal!h both��3mutant5;s (qmS3�KThua�� loss�9�A�grity1�Z�8does not appear�i)�9�!��M,. To further�Cs��r�"-A �!�Z~FZLysoTrac��a+fl��!�,otropic reagA�e�traces ic�E�liv�"�R!Xa�$previouslyi�eHto sta����[28A-C�Zw�ńat 37°C!& upK30 min�/out��or#6 le����antioxid!�showe��ѯ�al ��.A�contrast!7fter 45�l�\ -fre!�da , many(Hvirtually all , res���e,]�A� lost%�.�s�CU�2BM�is find�confi��)CdisI��bA.-t�� artm!�preceded%�$is�QntibodiAgainst�gtypic�)�aatmi�0vesicular com_ betw� ���A0$mitochondr�Y$( kinetopl!k) DNA!q8lthough sometim�,lso multiple�crete |lI�jsame red4are visualized�9AxPV�Y�harves��I�15E�I �hfer�oN orIʊ�.69���%k!�YCEIn!�Q� whennR��creasNper�ag" q�s l�'d -tense%� deqM�. MA�.Sper�C�ɔ remini> ofvdeple!gm� Rab4A]tᵁ�regula�aof=!traffick�[30!�These �s a�ver�Whardly�IT f �� only��7secondara�e7y��herefor��qu��taa� anam!ba!-on dwz aI�eO2.Ptwo DAPI�,. Taken toge�H� th��differa�Happroaches strongly e�BamaIaOY�"�a prim��~t*9 4*~  cytosolicAx��se�iSupple��2�Rw! $100 µM ir!$hloride�0no omviabil�MGZ"provi���.)i8��:�!��n��5Bacceler� a!6i*`3� ��evalu; j��U)�y��Q}%deferoxa�}e po7 ?chei+��(in mammaliaQdis�Ii��tE9up� f*� endo%�is [31a`D9{IilyQvents �incorpo͂into newAiynthes��� Z2ZIn-�:N indeE�e�sl��dow �-o�\t� \!^Z�R3�U� J,6r�B~short- F�x As� � � long :"� life->,o itRd �wn�WT]1[!Q, [33!XNei�Enor6�afQ �� F�"�!� pend�Iqe"j r.1mL( ��0BS T . brucei�G dA�HMI-9u�� � � �FCSi�accorda� eou~ � z�U� Zh �i� a��d rapi�/diWA[��2 hm� ��O��5&ustart��%� dens��Yy�ˍ��/�,վ�ME��edEpl�Xrkably ,�;insy]toward1ogenoum�,��! )�2�(. Overnight�i)Y. �!�� �resulAQi�m���ath due�a��AGes4 nutri�H!pgrowth[�0�clusion-A�-induc6� ck ly requirM�Y�f ( a� "�)�.>�c@ heme� 2 p����.&m4haptoglobin-Hbglex [1����_)v , s�A&gum%c� g/mlfHb2ja� or ,�_de0aA,a)ɛ!4��0U�S4e��E� mode�� �cmay� le� � �9be.��v��,.�~already9��atuqd � Hb .%��abAb25| rin A*mA G �.'ranges� 55A�92% [34�$To mimicIs�2�=\1��5�� �holo-.rC>N�t�t����m� ed-�MIZ�5�4Xi ap6�Z.��eJ�^�P��cubE���a�Bsw-�A�M恢�� leI�i�t��$e . Compet�� %g%�>�for%o�"6�eci���� re�6E: uptake [1I!�0should direct��,d�#�Jurs�by#V-d�/ riboot� |tA'%VQ�heF�%e�.b9f�K!c���a-p�Yň~ 9�ɆHow, p (10-fold hig�con.�ofF�(q)� �u!�an�F��to�*����.����Xs2�F�+�+A�rmet m�_M˅�%��d/�no) ����A�ribut��"`phenotypA�0To get a deeps�2 � mechanism��paŖranFriE-m;. Purif�| :�bovin6�* covalenA� link�� o sepharo�6h 8as chromatograp5R is matri Wrn bl��.ze suc�fula��%v�}!� �U�S5ŀR�.M�)�Z�Kshow �I�-��a�2peeor�m��J a٭�F�4D�yH sV�ef�N �M��6o��of�.,h�s�[z�/*�, ���Hin~�����&O` can�rule !5v=�VlA*� eddidu]5A�K��2|. E��assum�99%D�DI�f.i!F �b�ico l� tern'*� �% in� �F.[�b�CI�;�=.�o.�c�kbe"� demons�ted:**�h2�V�.lZ�. UP�/��� *� io-y�M�Bx)zB� pr�K T��ica �a�V��q"anI}sourc�f��i�>� worke�)+at�*v�[ A�n�[35 :Vdata ͑I�J�3asa���@��J?AfFH-e"� �&��! = gene���&�e�hb��Z�w7N �-�± # �?&�� poi7 subj�o immuno&,ce microscopzMit*�%!�",o�b5) Nq�s �subdi�fJ p�at*�a ))_.�"J��; b )2+� no:9�; c ).e::6p 7�;�.@.�=BŶZ #� 2iR��thdMt.�A�!�Q�&�per�:MY� �&� �Zon!iBD B9�V�i4�x*"!mBMx ee�A�12:}!�ed2�5��!Vm�r� se*t , name}͏6�!r.2k�a!�CEEG��a!act��"� �&$9�:q ed�e 6K*�onBj���gen�"co�=alE�IIl" knoc!��M\�>�iA�AR����!�*edeE�(in vitro [1!ItGed"�e~ve�. �Ak&R$9� adapAQ��[�zthd .l �K�% cope -imSh�!!v��@mr&�%� 8 first ser�of/ vivo8%riB� mice�in!�6�CMjAF%~8u� �.�1� ��% depi�in�!6��animalsq.a 5-day�tz"�survivI imj w��cG$.�2 A��ы� � A� be ascrib M� mpai\ A})iv , si���) ay 4�& "����7�.co1̈́ /�Q� v�& simi[averageUa burde*� 6����de�&disV%��7%!i6��� ( p-��#017��b%@og rank test [36]�e�gre�Y�] !s�-Izp" �B: �'xWTsQ"2#elucidEif�aYJ��.|���!p(���$14&��%�}Br(q:�8y8F+. A !� mean:�< QbUKw?WT��BY!A���ifica0q�a J� gave�!:$46A x a slly5X�%a51rV��6�*� "� 6�A� profi "of)�66U��� Ih�t*�?$��F�%h*6��pri�o �A��s���� �OP =/fasl$q9develop����mia%���1T6�- �i� ��!f+2�B��Wh��y | � v�%aap^&�to� comei( �u6�p�id m�F�.( �sfb���#ig�. PassagwroughMd&*� &!3 #*e�%ul2,1di���[3�(To�v))!6z*�$s��capEbto,!�%viz! ��nt�%ell���dAU2� isol%�yuqx�ŏE ��5M{c��) a��n i- q�!� c d�QZ 6En A�&n exp�Qde� abov�1�A�aW)I� � �ca�n).�w� �6�!_sE\:cm*�!6F�T> !qir�M�*��AYoA�AU,�i�iCN tten"�� .yF��fuAresto%hZYH�� Dfns"l� &��I�q�� O"M"b Afr�?6�ex & }$v")Y* Px-t9�!in�V`c+$ (� �/ )%g�o��I�8os�r�"ed enzym��er�* isms@GPx4 [3.3�*B� �� >�.vDcommo��ye�monomer�$�.�,� ($lipid-deriA�hydro��sv�atAF)� physiologeO func�:�.n��repla�/tot�(i�e�M5t al9�� fak���� �-�Br�5��3 at1Zp0(aB�: rupNd&�5. Our|"�uppor�i� :\2V &�q�A�it��!��3in�2�#MBl.�4!�'a1564 Prob�&a��A�of$�}recyc% �%oI���nd�p�(�xW 2-�+  �D a�rAus{--Nexb 67-c6ed=[11Aw(.�iF�"!�.Ve0� was��=��e�e�2��e�8A�����0Y�a-Als8�!2�(6�-�=aN�-�(s �:�M�5H!�lika�ev�6 o ma �5�)��E�h�)/�d½5 �*� &,e�|�Y�QT�!��2��p ( su��u>�Fn� e) s�4Q��u� .���!@1#ow mole�/we��%ol!�J$c^8) �&� �!�,�ul�ruc'l2Q*� 281�8 ��$`$&4�;s5-��sV���9 s [4E�&� ���Az6gl� will$e�7ls�)�� � &�AF'5oE' pathw�C1wo�ll9� 2st�M.� &idiz�raG!�n2u���5�2]:p�%�$� )� *Q d A\ Diet1vit�/ E 7're��� (+�i�3ed:� %]�<�m�alՄ� d� ��#re�) e [4.A�4� c�!Ul&9Y�M�B���by��"�0�a�at one:� �0r&M Y � A 2 �q��9�.� � %��+�5� %lacM� g0:I�e ge+ly]A�U�a�T�E�� 6�[1^4P(Iq���A�� 2n-���<>T*.�!$^���<e�%}re"�%+'�&*<>N)sa�dc1m� q��.$!�us�rf�&6'�'�#"� �$�degrad)��$�:���)���l)� Yw�p�l� es�;-v�7Y�bL$�j a Fenton-�1I�a: �a�8;E3%_l� E a keyuD�2�%�h�7u �B� �R!�H")4�"�3[*=2��� 2�2�+i�VM�h�?ep�2l �!�-he-r�>mur�$macrophage)2 J774 4,6�loc�%s alm9;ex0�A�)�A����4 , [4�#A��:��~���M�� �v)@~a(7b [46�Ma muco�n 1 orth�uR impl��%�e>�!��E�0 [4sI� �al 6�$power��y��ergize��ant� M3 �As�oc�w-!� collap�A*&%A��. �$understood76!t8] "�;iC��[�*`il �� [�AInR�* )��.��8p� ntly�3 to2+)!�s��or!�by&* cC����I鞝O�\ ~Z�d8`�A�R`a.�z/��3 �wr !��( E�> A�t� �t!ch��N%���g]Cx or 6� �P& lasmz �C. DR�>�vp\8y�t�ld�,d�!�Cl/� �e&fee� I�&I&t�%Uepf�V�= /yE�A � �Z�F�w#NFS( GvarietyM �~I<6Mv�6t4�5� Y<st,"tud7.!�m� �mit:enGdetaiJM�B�& ,.Call'F�8follow�zZA�e ord�f)� �9 oppo'H�a�%%6�inj�"�a�#re ex�+e�! cardi��P�,e2��Q�`�� elim:A ta�!j|o..aut�� y [4aNot�(ya��5ig�&�)�,F*aP&_ o K �a�-�B�A`s��.���k �/>' oun-8c�1���A�c� �+� �+��e�&�R� BSf �P<6A�j�/E&�0� high�l.F�F�i�i�a!,�51���?e >���7$'"� ��t!��s�97m!�Y !Oa.d/m��K� habi-J8Fvec~8 harb� �r%i"\Con ^ �9yroGC nd Krebs sK��f'ѡE�or/Hu�Clex!C���4[5E Stri�4�:Mp�:ct�g� �y@"`�j1�GentireB"ispens?]r& �7�f so��FA�]� $�pro! icm&A�<�BSU� s [2NI2� >*~��a�lri��6 [51]�� ~6up%fe_{f�8a��� [52]!�aSactK : "�0hiC��F�$Leishmania antum [5�L . amaz��?"��' �ab.an � ( LHR1 )!�Q %Zl6�AzrHic=�)o�s�a�� teJ, c� homG s ��=y[5o�d�7}$)i&M�M�=a�&�� :�a+Љ�h!�x�=�uan�'�P spir|F y ch�[7� ,&� obli�B �-�4lu�%bio��e7�n�W�{Ao25[9�1 �F6 be m��s"why6�in �R]�al(IIy�we �ɡ�l>nyf ong!�*A-&D;-a�2%vo�m�J-� F��II!A�6�"�#��!�"�'"Sm>�Mh-0 �rDNB�' �� B�(6�*t:%� ��� ox%Im!�lic isoeh� �9suf�62�ng)�� "��:�Kre!U9=��+2�. DA�t��_ A&6$qx *�.����rt$h �Rngl�,6u'moX8iqq�%*��. l5=a%�:& R� D� �6a s <�*ermana� beit"A�-%�<e� of aM��6��nt �# . Re�� � week-M�o�N �2F�s���r>E,�4A��IBDN-�six�&���;o&�!s had �$# toE "$Bi� is%�a��a� j12Z�2x(�!� �UequAY=&in� Ae�qL:$ea�Cŏ}Fi&i�0,%� � hall!� E� "� &e/�%cy�T"$(e��P(ews see [55�u5�.�0��!�_e n62V�o#� ! r�E�YMd hT&�toxic3� �o:S'.*=IFN-γ:TNF-α!�woG%sArticip� �)Q�!�t:&d|�p:r!.Y�%, peak a(M![2eposoa�a [5ŪOn��a�us%�B������"� �&�A�r�defE2�&7>�As� ŁM FS %��LV�%�.�*.N0�-X ����&� To�H�led* ��)mG*"<hsF����l"�)��K ly?&�&�%is� yet�6w�=K� )�. P)��K[%`ds��%� innerIFfleo!�&C5�>ex8A�7w�� � 7u�le Lto�o%�b�t�5�3��9Yk�6� i7W se2Z;is �� h��spontaneWIor"g'dA� �@ !��># of"r t.� !k�N�._ scrambl�&e�!"� &I-[5�*6�c*>&/ )c6�5�h&�>�#e`�"�2�VAMi.�/inq,!vi�=th�no�"�O� &�T�omona�ToxKTma!-,nd Entamoebah�I� h&�z�Dst Fe-b=!� �*s�fe�,Ctot ti�,!�6S� 60]�,A��~J' . va�'l=nd�,gondii encod�+� loguE�Fu2&�>by� �0Kve�f�Y"$��!�ns�*)�_:"� y�&�G5-. � 2 (:�M$nd polyclo�$rabbit,!�=� Pxf)g~a(e& 1B�D?2�F , 10;Z 00 D�#M(*`(to.z( 488 ,'"T YGr�VDND-26 ,IZ,�.5; Red CMXRoWre purc�^d%$Life Techn!�a�. FeCl3>� mesy�), �EHb >|, (D�ang�Buffalo%�A�V�-aldo�>.ckin�O"+Tby gChr|,E<ve�Pby PCRM2.h;S1A , TŧSO. P5[ �%L�� at 2$d$in MEM-Pro�.�cbe)�7. 2�6]=�h��� �&!_10Qw1× sa�X bud_a! Az2-merc Xj-no^G!92�JSDS-PAGE�l% g��"�A�z�MGgW��/>� ( co�<J�o�E yMr ry| (I�͉�o�jI �-.��/R�� PVDF">��rea6�%"� ��st Px!# ∶2� � "� ( 40�!� 1�n..*, �$)!9go�� nti-"�d.�-sheep��Yulin G!��6(to horseradeb&k�,��0Santa Cruz Bi�hUy�:��&E�SuperS�I4Q Pico C l(QeT7Su�2ki= Pierce� ��"%�"L}g"�gV� .0 resu�!��ini U��х�gm2 .�M� *@8�-*�}7�Qn� c�X}���}��ctw$H���C�- im�g/!�~ K"�&� �NFor2c�'ajI���L��(4�8svb� irty�uP8"gD�~,�M2��ad!�q�-ash�.  �sli� Eejb d us-La Carl Zeiss LSM 510!�focK � �J!SaP$"� ( =, JenUO�tWdBmr #n�g .|M��)s��logarith�[�> th p� �Y��9�N�uAh!t-�.E.C] �%TNc+ �} e 1�M2U{�ht)k�d:@ ^�kI>�Q$2~ ,.�fix"4%�a$aldehyd�!1^2�,at RTA]�� o 8-; �-L-b2neQ}(( BD Falcon��al*!�% settj\8i1 h f �1edP@9xo"�` at 4jlI�=�He[)=je%!�2%s�(X-100 ( v/vA+!$)�2�x!L��x-. �� -'A�.{�|5"�Ne125A^2Nɂ800��J_�ind�I �� d-V� �B&�*C:� ( M"?99<���"��~!P�����]��ele� 500 n�D�iY�y:R� � =�m�����06�AxiADt 200 M�Terj% an+,Cam MRm digi�Gamera�T!�PVi�b�;a��f:)�OjF+2�"�!%�O8or��^a�F�m!]i�V���a[aq an� H�!��Dls@6�� a��%&�!�a�jv&� A)P U�\Ethic3`,mittee ( CEU�U� Institut!J$teur Monte�UonFr �!�9_1_328c�E�/�=� %� FELASA guin�n),Ns al law�"�y�E"�H,B)awT . 18 . 61 T��6–8hs �_4Balb/cJ femaleA~��b�Zo'SPF1mfac�5-T��g %]�l�UniaA�B>de6AIPM��%�Ghori* dW�[�:i d cag �eg�0A[�C(( Sealsafe �ecnip&p,, Milano , I�D y*�8rq�G&S' 0±1��m�!�DveTid4of 40–�w!� 14/10 �(-dark.-��o�!_GI�ad�nt, ad l�vum)-�sH"8%q.�ton�nY�H�4�Z�0�Hr�Li)�D�$3!2�A�2w ��3�esh� %� � �G�Kev�:�"�W2�#|!�f'&.s.rLa"�.A� �S6WjNDU uAӁ�"y%.� �#n= F���s�Uich %�=:a� :�� *�5 h)C8f���%]en�Brief���y � zcoa�p��lAq24hypot G["i(!# *��)� �On�ll� a 24u -[� {� 1A0mH2[ "m 5% CO� P&�Sng=�:� uflaskse�� -m6�nd/ A1i{16 VI�!#y cryo-�=er�% . At"s\)8Ey=BB*C9� �haY�I�.uu< Ih�}tu�-"�*'>mI�monito!�daAo&t�'�'A��\�Hr�ob!A'i�cod�s (�5IL)U0*wc$submandibuCv.BE_A/&��tub�%Utri-pot�Cum �en|� � -ace�&~K3EDT�A�M�ntAEaI�∶ $r�!/20∶1!�.tho�Q� ���5� aliquoM: dilua.0 2� a}'M�WT Pharm!�toaE/d �mA>L 2t�RTEqX (-1% ( w/v )6&c]A�a�� nI0�+mumUs E!�c"6jl �od#k�=e. MA&�1a��t�XB��0azloaE≥108�S�JExeut�f ���4�J,Kaplan-MeierY�ploUZ log "7X�q6] X&�aedm&I E�&/!J"BY�X%� x�F�8��N$�(e:�b : Tbh . 07i 120F3 F4� Tri9~�3pig�Ae�y��tralume� fibri�within2�)meD q7u d(0euin�@v9!N� � � . ��)ey�am0verter�!�Gic�a�a�O}F�Z as6�> Pmeve�8f�Cep�o3 tiss %H"�j�@�%I�QHani�J�&�>wh�UEblle2�ref� [ -of-"c)or�I2���l 0�)'L~2("9'rer4)�ak% . �M,l)-,�A�l �)�� Pmele["_Pe $!���!!�^!w�/�Al� ferti !�A� ob�%}A~�;?_a�M]RMq.zEXs-sws�R�0�� �t�@oblAL shapI( wild�+�R�W}eEpe�=doca��L�x}1 skskr� 2���HaI retiaGqle�B�"�~!"in uv� .H�� ! %��`�qld �-�-9|colL�"^li�u�� t%��i&�zai!rEE�est]a �#4? carr�+p(brown/Tyrp1D3�-P�,MkA�J%��)A S.+sil�{�3Z�,n$2}z#>O�I*Ed"*Ee��.`�mH2w: ��<1� ~A�d�~C"r�A�)3B�vi))M P,ye.�~to� k�a{Iduc'���bE�k2in hair5j*�i-�q�9a cri9#rol� r6H efS4�2�. V��proq}ypi 0 -��/yevAoE�i|Jb<3/EC��s [ALP�=arRf��( �E��.�:�1�( SILV�Ygp� )Ap�nt H FB�!��Tt7z��|w 5��;]e��d,��p!�%C�E9� !�A�u um]j. ( RP�Z�0at E1�Eneu�Mca�"�8%ioca��4� Մ�e.��� <��m8 �{�S�u( WvRT~a�:aU��?%ro�Qm�giof)'x% n_ �phu��  !�) ��99cbio|Z�haE57� '"F�& L(in Alzheime�%A�(Parkinson's9}ds �G,�v-"g�_ode��Q�al/non-�.l[}o)�[8A� ���n} �?DmuƄ�:8or��J�N;!�"i �o��Zfd�@ty� �� V�Hc�\&;/� (�^-hK��m��x 780L*#� 0sE�td|b^�L� zu fr mwcer��do�2iO"�N%K��l�g��ypo� )~I+9/)�t-nu*of���if�h"� t�D���Q�a���hr ?i��V�[(a si)XcmS�)"n��w�%reS `run%Sjc 25 C�L� �\�_�-a/cy+[)f"�=C�:)Y���= � A��6c �& m��.�7��s [�VBJ�8�\���<25hcAld S)O9^��!h�3%�re %� tI=a��Tax�.nt _ncl��\r<�M�iPE��Y6a��%JV��,�6�isVn�no�Y<&&U . aHcA��ir gra o� ~!� � .Y �},�Oy,c3�i74air� Q��e8ʌi�\al&� ��W�yLsc&b&:granu � le `� whit,lspars�F 7< @ �i��&� AI pronounc�-�mA A�u� aTyrosib^-��0�N locu�d or �j: [A�aI�� �)��Ev!� >[1US�{SurprNLiF��s�j�Vd�W�ag�.agouti �,�N\J 1G~e�XS�I� F>M e e�-.�.� -��� #�<�`&�%r, "AH�>mm��ъ.>2JS.�Z �L��;�.5$�by ��f�"�#y�[M�M�%��log�b$Mii USs%x:!�qw�h�Q9%�d7� A�chicke�%l0�����O�V"�8 ( TM ) re��K6g!�DmI�E���!�*)��_" /"� nluA�,dE�F � chor�,�mrN`eyuw�<a� e; �6ot�/ 1�>1Q Earl�� A��>:�a�a:�fUr��-mb��IjI�[�Da�-���Q1� InrIlBrumbau�id LU?�7&� � 1975ah!ba� of ra0% �N�e9`a1��w:�\i p2�&_ R�nQ�2�.�Q��xnCP�-�=Y�uM,� five-]� deleEFM TMQ�!]aw�o�W�5a"�~TMe�twM�Du �-� mi� �!ɔi�as>-M_�Smokyn6E�>�_~e�flock!�:ybi|�E�Q; w��*�a2�h�{aC�s� >8 Polyhf(ic Kidney D�p repe�q� �B=l��j�t��b+X� ��� �J%�l�(� [20]%��+� m.I�r{}mi��:��W!5!�.H ��`J� M�ɛ-�OE��4Dd!�&& ��Da �o�"fd�ex��sG \-�n��A���m���a� �9'9tj� � a�4 stop codoi~��Mery�* %1d�~, cha4er�by>ݎI? ���F�V!y�>�ϡ;r�qMΐe�[�"IN��"�/10�H�`� ��-F aud��vd oph���LDb�it8mb c7 �C�e�(Waardenburg�drdo[2%Inv@)Ai=9U-��J �>� G22R��2&pepĄQ�u�%�wV%+��� �T!��#A{E��mt@r  ���� . ImZ8  n� >�s��vG�d�� ��@e�"o.6���s i|a�)QMN Yn l�<�-ce��f��PedG�r�T�c}>�t Ke�>69 vIHn2mF %#у%%6] ( URL:� espc=�J mut�In4 5A�]:undred%�!:� u�;% � p#104� &4R���"& � yr*en�*�mE#�alb.�Z�HFI�&A�w�s" )�]A#� �Eh�==�%�sI I�tly.{U~ ʙ�L A|� ��}( �EgA�� E�un�Q}M �"�!�sIV mbry�#�'�^,S ( ijA�U�2vNLe)!� %�Dr)@m���-FPp^ � ԋB��%x!�.��waddh !�)`�1�{] �v�'w�veE��99�N? pE an tudy0�!�K �%�� zyg~1���5�ed)!gR%7&�IA�)�:a w7I��2�, 2T�>���s��da~���%���i��"��dra�I5^]6X9]�S!�OJ�  �R�l��h.F y�pos#uFvKF �l�ڡ�*�� a�QA�an�pap� ho�"�!�:k -��V&8s � � �*�5� I �xE�pFlrt3-: �inETA�f��nD4exon 2�/ 3!u�"�fla�^by loxP 7*!�a n�C�q�c� tte.8FRT 7"�u1�%)�tar��I�A!� to R1 ES-�4:V" ��� M��F2e ?&:(I��d!�n0SouAhn�$t��a�h !- �ed ���C2novel $7 kb b�. Ps\ive��V�-p�+��o� ABHs"�Jl-�aa� to�-fo:,�� . ChOic mali> fspr%((�-(to C57BL/6J 5�[o/2��E/M�Q2�^PGK-Cr�Wv'c h(x2@FU+, is d1nA�!mubiquit�&�$PGKmo�K[2 It=�m>�+���I����5��5��wo�1�iN@�#RlWthef ter�I��6nu4]1� ��_ mRNA���B�a qA�tei�Ocu1&�oH�" O�ate�/o��B��G�2# crip�TJV�)o%U�A�to + a��6;ĉn��279Zsn�%A+j�$l�աll�1?�* �1C ) I�(Qgl��%Bty !nlimitI� ssa }aV�AB��.��>9 y�H$EIes�)��%p neon�u &�M�e�t2% �bloK=�L�)neW;myɝ�HN�3A�A0�A�N� whU"��+a!�^"u%��(�+/+ )�*/H om.A2�*0C�)��D , up��p�s� Ly �%P%�b- HeLa�E�[ !�E�( #h ): u+)nA +�z!�ObE�2 <�a "L$�&�4B|GBy ae恚9&n[-��Ct2/ YR��Jl( TYRP84��a�3-keep! _ , γ-tu�>h('c%2�Pt"� e� Y�f�q�!��9r.��Iwe! �i~�&&Um �?"� E��c�a�� H*^�'�+uV��.�of� )���-(&&���rKE<A�o��.� !! N t trib�.!�DE�9{r*�p��bright-f9G�r�8yE�.A�N;�)alter� ���me�64 0�beu 2s)) �/.�\��#��n�jDFrIt%�7e�j6I!!�D�l'�a�\%y2FshN�%bAρ�!� ��ŧBX� n1T��.�2� �}B� | �96s�*���:mS2� .2c+� ���nXod-Kd�4N�a+� i�� �1":�re�d�G)�random/4 �e-�!os!�e��{4 mix�5�ellipso V(��v%�^��!zH�!Ws- �;:6J.+�1meN�lXta t&�1�� no� er.�i4)�To�;fZ&isQ��M�0su�+1i�Q�a:�a� # ( length�� lS2id me� At����b�E�� $b [!f Q:�2I� ��( r �O�(2� ���!�{ 5�a�v�-� �rE�e*�A�IB �� �:�e"nt��..�93R�a=�e!62"�s�2) I �Kn��dP ����+�s�\>#4�$�c!{�J:�%�R\�"5aa*$"a�s�=eN�y arc"Lx�B��A7��i�26�|��. �i �F�%9�fi(la�(ge4K!��a U�'}z *�w�2h 5 �,a�a,"�8� R� v��No��Wsom6�xGCly"�ysBog���b㵢d� �%a�e2 gi��A*�.. _"Ra� ;� foun�mo 00e-!�Se��+"*�_)>)s>=��>A�6A�n$a4�� YZ�K*]y�smoD�, �67&02i.�=h-EV���6�N.2��my[D6�+wi As*��adɘ���C�P!�2%LEz�5I��R��=bbeg��oJm!�`IV� �qh (6)by r!�(R21 I/IV2^);��e?i��m)�-bAa5@gʲa�5t "gen�v�k��/&z5 � .I�P%�l-sVV;e�karg�W7��tey�!Kx��� ��<I jnG� ���=�s�S-� 7��)� @[ �W�.ɭi.�\��i�-N.�U�7^��K45�.q�T segr AX"%uxe��ͅ�-`.C��-F/5/� �&� H�iHYɶr �co&qsnd� B� e[�Y �7�R��-���c�j,b��ed�e]~!u!�&�;y HMB45jAP^����6robustly S-���A�[h<.:�la� 6p�~p,�sur�'ed"y���n�"9�!1^��c��-� t{ . Fz�mE5, Y �U�|) j���<�Fverlap�Q LAMPD��8rv��'f&�59az�B;��ms�a� �&�8 *l 632�e�zrM�a�p�HI�A:�i 0�)��r�n .�82..`:"�m�A}A��o�!a�b�Umo"�Y8.i� k��ey�!�`c�G. Se�A�x  h H�E�8�/-�*iN���E�i��Q!�Pn�!0Pep13he<s��Ur4e7��� B*� �cFI/Ef��im��/or�<�l�y�ory� A/a)!�2���u�-*@0���|�>6��&. �-BX� s"1o"}8je1�%��!���;%�=JA���)JI����"w:)� ntacxh�II�� u� � ot6.M$ -,�7r situ� isɳ��*!|@d�*�� rS;�3�C�Jt218-month�H!A� 2,��E�[ {,8�=}7I�%I�6��p�R��!X6Z9� W� R�Lj -�x�B�%ls��kgg�>ч-"RV��)UI ��4 neo]�B�Mo)�'-.� �!��eto�+ch'LG ���n:�of �I�6��E�>W-! �W&'�j*a7-rey��%By5�`XTo {��iX��1)���/y"�*MQ)>�� =i# ��}A�> Z~/. W cMA����FR.�%qitE [+z_�&-%A�i6��e!qng�$�2�+>�| TBkI&u5z5�����aF8�05�2*Ny|"rR!�:@;)�. More�%C.�8:��I!F "A/ J-g� nd�\!���+C�0*�5D�i;"Ti�atəi������:] A"I�U5�0�]=�(N��E A)CP�>7 �+�k��*�}��R;.���*�&2�m�d%�Ŋ%���W>��a�q ght �Fvir�b�m��*�8�|i�1we�N9N�Croa�1ERG0n�Ѣ�O.Ie>!��Ƅma�,���Q�M;žD\i�b�i�iUV,Uwav;<mRm e��N-a���!r�.�3�g&.�=�l��D�]%9'�ps2� despr6!�=�9� 2y,6�"!����>`\pa��H}�>l"3)9 �7��D�!�a(2�2*ad�h&m f�&P ! � C�� ochll ^�< a�!A��wX!2�!}�*��(%��BZ&�VS�.�i�--ga� �&I #h2j^$!� x.>�m%e� '*0�D=nH9�g*� Ql_��lfB>w"6 � �� Prey��  �.L�>�6��+AVof “ @” K�i�A�6��eX��GG6PBkonIV�%.� –W*!1/ Asipa/a::�+�(!�A�8-�/�-�u nkY* ly e"�6pq|�*�С"M�w�_a[��e�m1�-"A*�N�0�or�FbH��%�& 15d1��+�BALB/c�������:,1� "�n=.2-e��m�-�Ja�Ma���Gloci:e:J�(%� !�clQOwA)�  )Eu<=""V�!�G�'6KB�G (k;E+YJ�/�e.�v/Wa;m1Q��;syFuKci!���|��!���(b9B��.�,% A�,� p1B/gTyrC/C-�e 1�W ��C�� ?A/A?b/oTyrc/c?B'W]$��*�����r��)atY)t{����a subw3� � ack!�m��"�6�^,�IF*b/b*AN{��1�G� �&����5er�u�"I�!dB= �"�2* ?UA�Y�"� �)~2<�8� 2D yp*0&V�^-�:�� �%a��i} :�j# �X whilsI��I.P8?un �A)^:�9��� �no= E���%, paler%�4 !�u%)�nwi�M."*� ge����()N�c�q��a�"2�%�I� UD/XD��o�)�(�rpw'�,6�@&r�fy��[�� �"�<��k�'HM�om�F����heter�2Ex�0PU�A9�2 H�O."i� E�9�C-bru�e"�\�� U��G6 infl~��>�A���� ~y�&Lng)�y�!�!!jk�00�.A_lyla�m�q �1��7B-b�9 thod3�I�T. A   �A�2�M Y���qKe.^% *�k^atb� O �0�/@96�N( −44%�.VSqt (�HA���9�2<1�nQ:N;!q�!��?�/�#ov�%vz!�A�3�_5ake�"�QNB�� `oiYt�)�dp��2�f�{� uq?abA�&F :, 'g�%�3�I69%-YJ+yz2!E�1p� \>����!aušgS]E5�a�2��:�%�_n�`"M6�N�T �E� � ph5��!��)�K�I�s;ai=��tm��s�� el��o�%K �bE��0dQ-��q�W���6_G"�#%U���a��km�"8Eu��a}t��<eilH���bZr9� :to)�yc$u\da# &�5T Aopg����x 0�qu }��,loiaREsow'se��V>��A�7!p60� , 59"�� 60!ua ,d$�u����3 ��u��?omGeJs#^�`"=�"T"q%:�t��N�W%� ��>��z'89F��nga;�/-�cu}jMK I�%1� ={žsynony��WRdQ4� �fu��%�SNP&,GBB�8�#,i��]e0$��&@ v��lt=��%���~� �beA15%Bm�4l(���s.���%: �s�L���FdO$e��(� �()a�usQ�@|:�. Ant U�kL>�adv��uWa:���H'p�a�)H "a�Pf"�(�t, �G +!Ql y�� Oc�T�=! �v���g(tc�$"F>at W�\si�O6o;�o4��"|��!fMs6�H.� b&  1?eG��0>�MoDV��{"\��"C=*{�|*�V n`�!�xN�*m. r"��TZK�j����ey�-��'=�2W&;\�20&l�:*z%hD�oUf�;�P!�jR:�Win �� %&&�D�J9�.��N&�>FA&�fl�B2WZviJ] � "&A[Ƨ�4�w�F���cN�� BT."a �[u�� �4��1s�&Y *���A����+.w<$`��F��u3�!F.e��-Bف�[&��ex�b��F�e�Q�l�n�� 9KdA\-Bf%�*�5#nAhC � �? � a�j�U� QOu� � �"� AE�/-.�/c��8ad>p��Y!Ui;$\�^i�}�>����" %>["��n.'=�.A�j�8G�uUV�k�<�$���{�Eak��-W!�% @�s [ve�W�7ngu�:C.}He���qc' enh��+��]c���bqst���$峉�@A�INIeU F�<t^bVja�%�p��]%gl�l~-�J* �Q phago��s-o)�"� ol]/la^!��]�0.[��;� ��$ &�T���9Op ����W%�R ��1-� tP�� )�An�r!"�-!Q��,� R.GE^; s�Pili��%%�6Y�to ker��� ,G[ k�o& i_:�1�a�e�in9��J��(�O�T�A�&�K&Qaa+K� e ,B e�{r�hOta׌lT2��U�/��*o�A~�)s&�McY�udY*�OBdY[B[*FY� s�m$)� �s�|�i�.24,�q "��MW��>��H;�:7)*���a�!b]= 1�)��-Ya 20%~r"���d).!�42S>2�F25[)���gvlJ�%1#1:�A�2��1��.�V�f �"Ns��\o*�b.��*>?combij&Q.f/9"�{1�1[40�1�,� A���e�B���  =<�.6o/0B�R [H"�ha'N� !V.�6TA���P*GeX�&/ iR%B&UusM(=Ob B�|!8h��dKN/�b[–�U 5:wB�a��i"� m�qIN��B�&|"]�pli��>e!�� "k �E���#-V�!M ��$or�U%�e�� e:[^�*�J /ǵ�W9~��e�Md���,+�CEk�[1�a;%,i1��U&c ��$eRwaykE5�Uer�~-�i�- �a 2� al�<.Fs"A���)\N2�2\�A�nڕ3 e�LsV)eb L{��wb�3�� erit� F����GqJ&� ə1�o"� �n6KM *�\ �cQ��Oa�Sa:a�SBd3%NA�B4.��.(!$��� workSr�*� "�*%���Sn�7%فG[T ��. ��<� I�2i+�v&� =ci�_��� as1�? �W%�, �V�og"h4��!:nN!�hi�\[�[&Z"U/"#F�.�:K^iY�]�t3_� illuG���z.>PM��y6ae�{6� A6s(c�/��!�idvo�� �,�ؐ.�N z�#��%Ji$u2��YU1QF);A䉣!of�r �l�G�"q �PKD��mBCa�u�+ preMH%"|  i��np�mո�A���j�,��z: ב�BR/� e-59B�c6 }��:z�1�!�x�Sn *���)���� �;�#&�n�v\&�?� ��� a!�i�m B�q��:�~�Qevɭ� �]*+con>��d &_n�.��&a �ic�H�΅�!fai 0A�R �.��2���)%�aIAB�� �>�&Z6XEUg�5�aL�d�a"��@c)�xF>�%Ji\hyC%�N�o[R��ABu!L�a�? plei��I��)B�,qw!�7�)G�e&, �&��[��$� x�S�#� !unu��Kav .�&)s��J>� ^in a�62l*uretro��po�7�;�h� �?\6o��\/NT11%&J\A�2� eB����s)UZt]E5 ��N)�ǡ�ri���"���4.r6�>�U�P�L�7e}$^�'���JI_^ч)%� ���&6|a:5 heP.a{Xh�'$�N��Kephtalj�6IC]�s��thJuue!m�k^[6^�i skelexu,"@dia:�w�ve��)����:� .��F���*%�F�%N� �FE@�&�nP� br�zq 6RLii^��Yc�6< dsV! �/�ly ���r�2�J4!��!lW!#���� en2�ir�&� D� ��EpubR� Ae�%4 �i�o�L��9a�'�1�m�e��S>�inl$5a��."mZa*y&2�����A�he �9�!! l�p_1��6���a)l�Bnt!���c�� .� s�&� ,� `(�:!�6^,���bE"(tIA�|�: v ��B)�"S&�R<q.*�L���!� germ�X �Ir!wf�q�M%��gI\�RC#>} E�pos�l`.�G� �����#��o� �.��%Q�LapV,l�yg{Y.�&�y"/�wX|�eif u'&_� �pFQ�ea+5@ڋ o fa�`��YA�8�ve���h�,��i�&�5Aknddz)���T;m�)�?N�2�c��A�>r:F^E�l.5i'�� �:�8�|i1Υ)�o�).�v N:Su0by the transp�>oson insertion , and consequent toxic effects of amyloid format4�moutside the melanosome . Finally , since PMEL is located in a gene dense region ( six genes within 100 kb ) itApossiblsatx Merle mut �altersregul of mor6n one |in(�. Thus��ofphenotyp6  t0ay be associa�� � func%W(whereas oth� 4 caused by �$ed express�of .8 closely linked�`s . An important justific �for�developm!�Xof knockout mice models!N$to suggest9Y,pathological.�0corresponding5ps!Ehuman�0The clear ind�t!�purify: sele)acts -�C);locus�!�(at loss-of-5W1�s will)P8 reduced fitnes�No.Z5B�anyR�r disord!�8has yet been re!�ed . Ba!�oQKsuli.a!�!�studye`Ppreviously described !Vtaneous�,s we can makA�e follow!Cpredi%D�{a��c�ped ^of2Ein�Fome-w��@�va�,ies ( GWAS ),EA> 5] ,%Lh � low power�$identify r!���tic�E�asy ���%j�. OurQk�of��߁3haIAeG�{s both� RPE cells%|��uveal 3cyA���eye:v�Qa- �� also show3�", perhap�$particular9�inc!'cE�age-rel�8D such!-ma <de!Kr)A�$e ERGs didEre�a dras!re�a=ret���)��!Psample size was small�wAcexcludA�subtle\. Fur��E�, visual�airaF does�0always manife�[abnorma�ll-field �. I�Eisi�xt it�worthNaN�M�fa�vi3��nt�M!��G@in zebrafish , in��!c�EXmature stop codon leadsA�produ��a trun� protei0 �s a s��� vu al defectQ]A��O��"b � *[23��6\m�͙͜Ezan2}( named Muti!�Congeni�OIHAnomaliti�MCOA ))Mresemble%w6aniridia!1M�[46�[47�+ )�c� �ree!YF�%�!�a�s -:�i6� ��?�!;u �^ogs –����ed��differ��eye}YBU=m"� i����,�(?ofFe��n:�� ly ca�o��fi$�Xto expl� if chang ~%&� ayE�0imaRedQ)!.k mous� *N q aCstitu��A,x�!resourcO r�n��. � strategy� buileg!� targ�Sg ]ruct usi�8e pFlrt3-vectora�A��� Figaf1A�  PCR-b3 j�|employ Ua�oofrei��enzyme ( KOD Hot Start DNA Polymerase , Novagen , USA )t6�harbor�$wo loxP si!(, FRTA5 a neomycip ssett�.� P. A 5 . 0-kb upstream=*arm s�oi!tron 1 (!`(ward primerI�(Cfr42I tail|��rsaS$Not ", T� S2 )/a 2 . 4� downV� pann�from i �3An!� begi of6Z�Bsp119 �!*N�Xho "2�were �ifiF A{5Ifra� Eclone2to�-$q% )�whie9rFBstBIE� Em�6/%�89 bpR5Eexon 2�Y%� �3^9glI-,:7^I(6=asB ,� fla/byE�A�-, Accori�)NEn��� �A�$mbly availE^��e tim�A&%�desig� a&dO >4would�4 a!Kme-shifRtwU%51% 4� A�to�J�!Aa non"al�R�.\ dui���roc$of�eb ,ng our trans� cV ,�^)!�updated �\ dele��]> turA��to1�-frame� pp�f) 2[%3 ortunat �RNA�O r�{� degrad��o1ab�M�6'( see��C�1D�Sa�f] �]!lineariz��ea!�2�� log� recombin�R1 ES� [48]��08I�re obtai!AUscree rY by long r�v��n o# , 302aa�al!4s� `a �!�ev�O� se�� conf �,Southern bloM beM,.�beW�EqG�^��( Sp5F� Sp5R6 . Genomic�!�extra�!/di�- A�restrN�eKpn� sepa�00 . 7% agarosBl �rophore��von1�injAi�� blastocys�a|Ň a cross b� @C57BL/6NCrl femalg $nd B6D2F1/ %2VwA"sub�lyF lan��CD1T. Twomerq�( �1# �J� )`c�=jU� germE��Cmi� �8F1 agouti offsp���Y5i�&1us�}mod�)alleleA�PCA�F1- K2�%RB�PGK-Cre5in �}ge�e� mals6�aA0 null� . After f�8 ?ion� back�a-%za9Mground ,6gan |�interEed �t�=Ous � 1.%T��uy Evg biops a,per|mn�\ntI. T� 6Aoincub� 45 m�  96°C!_lyabu� 4 ( 250 mM NaOHe�2EDT� A�!crea{�inhibiA���he addi!f�40N0TRIS HCl pH 8�1�h�Qk�Nch.��g ��Eġ�6��  � s-h��wild-typA<d��DI�( ; A!x 1� T BM����2 . P s ACB�e��a 236� b!P 392)�he��,��iv�l(�!�i�y�-cqbk:b���$��~�V�-|[!�B~lox�f %p�)X!#, B�D1e6� 1nMc�R. *m Fmxa:�lox9��ng 5�` ,� stY%�A� A�� Q�R>�D �U�6�P a 76Y M1� �}n isoq dISs�tissue[s� �RNeasy�$i kit ( Qi�)MHT��sub�:to � � crip�Qe cV capacity f Appl!�$BiosystemsrmoMs��a�QBE�measu� by quanti%vE ana�� �TaqMan�e E&�mas�%mix (V�on!�4900HT Fast RT-��S�^6. Data ��q : a a0shold se"���ar Pmp��-,ked �stand� curv�I, serial 10-fW dilu!�); eachmpq�� da�� )0!m endo�� us h�kee� geC ( GAPD�*18S r!�� plot�`�Z R . Who�y4 E�%� diss� A�fia� in 4% PFAE60A�a�ashed 1 in PBS6 cryo= R in 30%G #3'12 o1��>, bef�be� froze� OCT� akuraE�TiaEmr�io� (� µm �r��12F%)4col})�Su��,rost Plus gl��94Menzel-Gläser�F�mmunohi� hemistr�a��%irehydɍ-;!1!|the c�� #�ai�1% fe� calEy um ,� 02% t��osa$��81% Triton X-100o3)��+ar secoA� tibo��E�ha s soI� . Sa(1�&�ej�d ]Oovern�t 4 [!0R�!A14at room temper�:u�iB,a Zeiss Axio� 2�wjug� to AlexaE� 488z<594 ( InVitroGenI�ri��cue%��9-derived31�,ᡩ�as�"[51�Briefl�Fs��mIna��&/ _�A;nm�$g:� ryps�o"��M epidA� iA� I�$(!/�mm �) � ���le� suspen~���� seed�e6fr layerA`XB2 ker t. C��-��$ RPMI 16409�g�Carlsba?��supple}��L10% FBS , 200 nM TPA-2cholera�'�aa�ii��o�Mc8n diox �f?iA�SDS-PAGE��Tris-gl!� �a fer? 4to PVDF membra� Millip .���)\is:a21������ �det� E� alka� phosphat��co�.R���� �Ke��iR Oo�7�#�,a Storm 860 2>i$� a.�QUANT&�( GE � ci�t� E� i$��#�PPBI� �=#cE�a�"�by  G�V ��  Tear��nAais*�0mME� &� � 1Q�5)NaC� �5mM , 1n! 3VO4�1X�te!�or cock� ( Roche )��25µg ��� �e %>den] �cu���'� ��K 'Mc&�b 4is 8–12% gel��v�b���PI� B:$a hybond-C�u'�mershamBUn�Hbp*ngaf��ie%�blh )�5%��m� milk�lTBS�_!��aW�α or�*� Vz  � bodyxad�i� ��,1∶1000y AtO/NM��$%��inF�!�HRP.��J eFHealthc� )�nti�y�( DAK� ~ �42�iM:�2zz�d'$ed-�ECL p�F�9�.�%grownA(matrigel-co�c� slipa��� 2%� mald� [ eɥ*� d��ochrome-~,6����(��Ce*DM IRBE�� ( Leica MV �� Wetz=', Germ%):� an Orca��$ca", ( Hamamatsu�ridgewa� , NJe��qm�cap � mani�*5� Openl "1( ImprH, Lexing{, M~ 652��A�qZ>bN� �)�E�mix���4%v(a�1�z��lutar�" cody�q� pH 7n ,�t eQ<Osmiu�tr &�by�a�, E_ $in ethanolM embe�epoH.� . Ultrathy+0CE�r?d�0uranyl acetatA�a�Ab��my�nYnyI�Phie CM120J'�v,FEI , Eindovr �Ne� land�I�diIacqui,�madeth� u~Q�K� View%oftE��#�, Mun6. . Individo)�somAi%<6�graphsA!k-5|6b�*A1m�>$aximum wid�nd he�ach{��&#�bB3 . At�!st� 2�?cou�`J N.�%ti�*a+o�7d�2 s����1hL��!,�din Agar�6( R��, Selific Lim�, To ori`#!� r �t�3:��kbn u�K�&$( LKB Cryo* ) ,�iH)�oluid� blue�in�iJE��1u�ba�B�('l1ap?6�%��MI� chosy4�-��6�cuMfrea , m�*onA-mva � pper grid> sa��5:2!��. ci�u�4b�4a��!�.anjK�$ JEOL 1230%�I:eEo�iq��2N5"�extirp����pora��( morp�7y� �y!�P:�sp\6 �A�I��#ri�,eX*he7A�w �e4di�;ed!*v�a" Eeyecups�!�|E&-�eBic stuk.�>��fe-ugeng1aQ �hNem�v��rAmle�Q h J7A�f�#ͬ� ���g�Q{��v;�7U�through8 opn2nehea@ 2 m# �9�u:�!D-"� 1%Fc%A6% xyG%7T~5%9wa�eƥD7M sod� c&� ,�r� s��&� ��S.L&n)2 �vi 2><+-�A�b�5ALconcena}- �cet��vS Q�1*2��8�K 5LMT EM ee�EXY�LMvU�n slidi%�2fT6MEbU@5Vc.��!2V~�. L� ��|��! 2(ho�%�.'cho�(�o: �&e Y<EM}�acF�^��.00 EX��f� �fwo�"� (mal� A/)� ged 23 h� !Na�f6 matc�D%c���experi;�/���o b hh<1> al E�(al Committe�D.Y ivA�9guides %] ARVO.����E� ��6�recor�� unde�&&%  si�4�9b�9tra�ah�6�*a�$of 3 mg/kgUpromaz4( Plegicil vetx mg/m� Phar% $ Sweden AB�lcG@ n� Zket�_�2 o W( WI�(kOS�n�-� h� 20 Uxyl�Narcoxy T !��T�%Y plac� �!�recncy -N���rn!_e��/ ( Gon3�" , RoE�60>�andenbur&&���7on�@ye drop�6�U� 2% hyalur'0acid ( ZilkEyaEvp-�)_Dpryg 9]XuplV�Subcuta�>p( num-7u�edm#�=Ls�Y�*a�re�6ce6T�� Sub�aS EG N V\!D0, Cephalon A/Nø�@ undbeDenmark� � stim�= gek$by a xenon� � 0( Grass PS33+A� Qe F1 &�.N|2A��2� B ( Tyrp1C 8%)�� loci:> en "�2!%20� ��2�to�147 F2 �, �s��Eng-c$sax%?�NP �'� -�v�?-�/4Asip ( rs27342�=�T�32544046 �Ty�p rs3139232A�l(6./��#(% ��D)2-��7%�&�>a�/ise �pos� F. �],Ld 9=�p�&�l!B( Biotag��ppsal2� 4. Oligonucleotre li�"�6:Sa���%�% colo$!l�qF2�e$on �o3ly � �%�B �. Dor + hair$-$--f% pluq+Axp�9-��!� .�&�GGU"�"u[9�8c0� pyrrole- <3 , 5-_7<$xylic � PT�$u"�"7,1 pede oxi b[33Kof pheo�!@o���Ae~�4-� o-3-m,xyphenylalan� 4-AHP ) �$iod��/[36�s& J�l' Cod C�!�` �=as S(d+A�5�%m�v )ͪibilizA� 1 mg%�A?900 µL1 uene-350!�s~ ��9!2}J[3IA��pr�La�al :De�yI�sB�vA�ll*�a vol9l��A p�'�s C85/10E�C154/7A �f�)�rol�)a5q-metho7�+denguL xD�* . Environ� �t�n rer�'M e�a safe a}%�e l��Hele2a�A_iKEO�2��o�2!�isNy0Bto!�p ac!�ewMmeta-.�!�Five�LW��AA+6�)6�r10�B�!l� <_PRISMA.�,6� lite�.s�*A�co{z�eK 2�Bs Pub^ , EMBAS�'LILAC� )C|!ane Libr^/d Goo|)S�(aJQu�Ey�?ss!�zDu,CONSORT 2010��ck����6U�sce-in-A�DI>%�h_E�8�&�Nend�( DOE�cal��! 2 @ Schmidt-Hr�A���BreteauLOe;4BI�n`8 pupamA6,in &PP'. Ninetgs|�eligi�LeFj, six:Eibu�!�A��63I�fU6Qd p valu� : ( �T��v�" � � �R ctic�\, !K!�"ag�*2uF0n-up campaign{ K( c/#a�m�of breeNAsi*bX:a&poM�mosqui�<6/ unus�!or;\u&hem� �OqM�a�6� !lV�:�f%E�B�1 dir��garbag��37��oz���B!L,J�>6�,JA�� weak �k!LA� �z�l=Jarval*2O!�w!�6OI}]&�>Nr&:QK �'"�!e��N�,�� F[BR( BI:e�-�#9 ,e�-5m]RxjuP{<8�a�-6 .  achie�$�Z�Ht�uc)E951BF 83 )E6m�I>A� EachYFvesqV�JI�+: E��-du� M~AơJ��1of Ae�s�4q�eH"xR��l ne m�-compare�a�-q�X�n adeq���n:9to�)#e�is evo$ce . E��+�U�KkabA�390�*la�� virua "��96'ca#$|#ymptoF <$yv#[1�1�h ,�Mg ���3�ini�Emis�g�#�% �f�KNa poly�/ vacc� �Qwa� . [2�N rol�=��cosmotros 1�iEK"|aR�� R�6!0ar�!�!S$-alyY�<fresh"ŀ_ 17� 1�Pt [3–5�D)5a�e �b�EeGEMhh�ng!.bec"X�urbanisS �(�)A+ th ,i�R�����"rar� lackNpr'mme!�12 Z!: inM7�eTE�&K5[��6�6c � i�A���mM-�F?Ling�W�P�a�-f�(ruc�)�po� a�ONJ%?�a]M�2�[CP:�%թ8b� s�uiIi�3",�BlogdZ� mAN bi22L :se7 �TBz } �V� ��[sP:�?N���:aim!m�U�%Mrolife]bby��Dmo 4>1���� �K crit%) �O��Ry�"/D empt�@w ��!� /eSa�o� M��� ,� A�-�ppl cst28 =7,yr��y�O�6^ !M! instal f piD �s�5yQ"�adv80ge�th!)=achQ�#�y�XGy+n!=����Yi! �]m -"��Tvul]AUt�L�/7  Y��Ht�,6�H w� �.�k� > U%mp��6�6T *l�JI!��� ires[$�7i+��\u� [$K2������e%'|Z��28ofQdAM��mMins unApT��isd.tB�Zi(:��[N90a�!�hO%sufi+P[� 10U�Ye] e!Vf!Te�V�gto link>�v!S2��I*� �T��De �fOT-7m�1'q�Ņlu` � :��� (r A�too few�td9#A�T 5$.�NreN$uj��edűR. E�.g�,t al .��%at>�a"y� min�I-)�n1� ces [!�. Bow&=r1^&�[-QK�~!�. N�8o�;i��:U�6�%�hveraVof��!��l[9�T.U�Bšz�ٳ�&*��� uct �5.�W�IS� of:�- Z]. Spec&+w,�Yf&`on�X�X�X�X �xA��V��,eJ�!lIh!�9�-��:6�[�?幡meF�*I&n�-30th MayP7�[!�f�u&�:&�G6�,&�A�WHOLIS�ch2�apY� rele�L� �ca "� ��Jm�� cl�.I� S"jn"!s��gG=M���le�^by�& Qr � %�an&� t�|(!�-�+oil�K fG%�!Y�E�*eA�i )� domi"a�! ���G�RCT '-:lu("f$j1c 2Ż�9�6{V��b��:�( ����� ~B+���>dN>c�vL( V;zdi!� outc�� �o�?� 67^Qm�H ��6s�ly occu�Z0�ol~ A�2=!�g&�([1nA�Consor�429A�p"�?mewor���G� �zeak��nd� !��� �M�m�omev"5 i" �v�Whec endix� =B��d�ep��&ie�Ze-def<1_go ���.!J��) aZA��!�5[1�M�He(a_C"���I�2P"Pe&N)!�a!�j6�� ��E-multi-�y1��ll�*�_6�aog,s6���� hand��a/paG3u)�~ f�Aa, !/\�AS�#!.�"mUB4!� grou9acR�2�e��U]2�^r�; F�.VA�[!�in���Ry���at�M��~{���&�?b7,"3 ( [21( C )-!B�i=�ula�IfIOA%*�%Q�y�� ian�x . To�v')pa�@, s� �0 at-8loses�X12/.post-2�%d��.Jy%N nei� ���)O devi��s�N!"f� c�!DQV�rI��pooa  wh:i��0&�d�H!��d"�a�klot� �S�c;. utho��m!�8Yt�Qqu7�ngi�. A�2�:&0 a�E�sb�:sxLR_3 �&Z(�K(https://cra&r-proR, . org/bin/w�<ws/A</old/@/T BI�=�ei−BIb�g– c OPP-PP .PP./01BI�= B - BIec$ -qczl5!s��ro�;�d"�tV&�3re� ����Ql/,y poM��r . A ["�/09� � ab�c�0A��� *Ed_ 8six�B�Art5 ͂fo�-;viee�"r %a��:scree�dup)NXl123�or�F7lH?�\j1i�A��a4nd 48�5-t$g6��ure��.c �X�]�?as�>*�gE���b+F0�*G i):� &�� , oni6���$5i��9\�199�S201�Ge;ph��LEF2E&� in_vP$ ( 42% ) (S, 17–2�29b��132 !�C 7lN?%259�(30-32 !,Y<� 4�4 ( 18 �21F!P28�__9 ,21 ,>��.u@ptkesa�lIIE�!^d(cJ sei�.��a�� wo�w75%`y c�AbDur�g!�>I s�gE��)�Ton6eX >2�:( 1A[) 9[!j3!3�8aDc ��p� Q C�mediaq (��6k|elv&� ��w�= V_�� %s�-��4Z%N!�U�A��0I%�23�!u=r&V)�!��Q�+ l|=or ne<� vFt1ag� ��In%�?�v:� ��in_!x��:�p�Eld2B-&&$K"u&�j(�-,qPi�a+a��edJ�2�. Kroe.T ( 31�A�lambdacy�4thr�obYMexicoa���=;v%,y�>e(in Venezuel�g�D%� firs� elta� r�^��f�maU_%�F�A��A�� i;�iAc�% Teme�A!XV# pyri�A yfen�_p��W>��w:����?u4�aV�Bp V�i~ i�e �, 7" E�:&, s ;lKgr0Xwmp<4^  , "t\"0ltzf!m�*�� te�*++e��l�Csd�[#',��I�O�bag�Z& rubb% disp6Y�{s� +�5&� byufe�+� %��L�L ��#I�G��|wo sub"��ͯf�(:�50noN�(IבZA_DirectN-mea�Eo� {bvi8$%Uua�6a>,&S!�_�yenoj� E�)#Y�.�!}tr�FU�Gi"��(�'a�� in6( 1������3�BApp��.��H"�bP0e~Y<&/i�OE�of�]� 2Fr�t�)@M��i�_�&�Bor)�Sa!���S���>.#kN��-��-��cu��> v �oor��1 � ���pepod2483Bacilp9$thuringien� israel (,� i3�s( dragonGWnymphY$/��*�= qCD%G(vacuum aspi�X$cot�M net sweepa�(a iW5U�ۅ�E�=%N �%EK9�0�C"9��2 u un1i!�a#en�/�-C6�:&e � ��ME�r�5n8p��y o�nl!`�8�j� 35 . MW)�}m kyzArg}O0V��EZ�Jm"$sMaill]!h�Q݋, 0%*� �ub&a!�Z`�!A���f.�!d�R-. *6175��edL� � )�!'A�9,,!�1�9House"jH,I!f24S�m30� E�13FI�'� �CM& CW�&� V�F�:2Yi B��&X���+E AZ�eR!1�_EgK ll�#Y� $Overgaard � ��1 6s�(:erA 4���s �.� a Prokop(�e��v�a7ome�d�h�]2="� =up�sIoc�0i�at ��,� &�5��qI6�*��pai�"�Mva.�[childrEJ6%� Y+�WaIgM sera�y� � . �/! ���.r��h!Si��r"�*%<a(;��"-�2��,qaw�*C2.�to| ow/�yib:� 1͹"��woNmWy��w�?�26�YQE;e��>�=�>�F.�%|a,��a�;%��%-�third hiI*�a��40%�:���\%bc 32a;� e��L)� ,+� . E!>�9YAq6'J=`��1u�sdnctQ�2cs�� ��� �_�2;;T2�2<6�>� �A[2�a- ��4 �/hi K.(M �7�s v�Q�3aM=�%��W �1= a�15 0a y Q��ln1.&��� t� ��%nt����%S�)):��B.�.n�!)Q* by Tun-LiVa&:�A�+719�vJ�(A� 14h2� .��0g�R1� B.R2(Mitchell-Fo "�r�( �0� , Wai!w !� AJ� PeruM 9 ��3->����A�()~[I!�M!1eMP,ng]A:@IDMt5�s�d,����#em�n�*C�&(5n�3twA� as m�.BI*� M�2X �)-��m6� 2S}-sp���L *�Vas�!7J*��.{##:� *5 Ba�j�( 5)� 5i�1 !�M�A�D o2�� �aQ&�+ AY��:D��( -EA�wR�!n�54� a2�*~8�( /5 ��}���=-�y eǁ_Q���MHa8�:6QHM}.�6E �8���9� ��s��v*3�C9�!H2� {1�R~�{�� �����Tڇf/5B�š2QK�! H� G��t/:dA: demoH�Wa>�F ,>SA��ZZ� A�R�6(� y1oV�(�.i�p�u���-�!$r:��oAfa -�� [�`=5Y�>'=ofqRm{APe83A�.�!bq�y�ba E!�K � y%!AY ,�@�Zly a%�of��6�5#ť09�.r+�<��EG*�,1!&.k@2�� 2�7f�s�4w!z � 7�imm�c4�mof�8�� �"-��*�9P=jsA�� & �m��! ��;)2�a\��ɱ�:�&o -]��0l ��e� Q.�A�t/�j.� i�#t  �5Tk~. ��1EW�FLn!+B�-~mi�riZ�{ �$݌$PqCs��>6hcbyF�0y0�{0� �/S�*��N@I]��6 ��31cր� ��|l_:��or�A( bAO-�q�3fngs2 unex�_%X:�or�KA�B�6(sh�)Va3� "�B�) ��0 chan� ba]�{r ovipofH%WM emerg�A.8u� st:���U cida%2�bo���9�whyr�r-�Պ%K!��Y,%O!'j-�$1��X*y: arly good� �'4itF�, (�,b2�U��Fw�!�{"rh!AW�>*�;)��at6t_u6Z2�[33W;�y��;�8 �%r9Vb�B��t@�"U simi�D1�"4.�!�� ��*����&5�!�/ � F��"��86c*�6�(>z: Odds R)%@r95%�� I Ce� 1E ��N%*� �3),B*>UA;�:TA�6>i�B* "\8YB pr��% nywa�J%+"Q�syner�!hA !\�("��di��$:# �d)R�A2f> E�mj!�WiEy-OE�B. ��-B?%s� �[lus%F�B 7�W��M�!#�C�8&WaB � U��E�A҉A��n%gJ�����M�ItA���YA'�n��:` �moSo?�9��an����_6�1as%nE9�� Cub�!BI: iii46}i�ai8F����0A�cu��+b� [19])>� �pedag�>�K�<7?�geus�  l@P behaviou�=��!a% %��hui�ha�e1r juven��*��>[<we��� fusL!if���*��rN�asB h�vi�!H(b2&&� �&prqi-%A� �� Ho��n� c�&��&�.m6F &C'f jV8c,* �qN*A ��z�./+:)�� \�Ca_ng>�?�YeA�co�M�)-f%�My�byR�ndZ�� 1�JA�T��qd~D N-��nv!�)�V�6i7 gPB�MPmQaE�"um�t�K�./Q�1ĥ��0 n��u }\6jʖe�/,r�%�g)o6�.rKz:�!6]+%� poin]1�E��&o>�;Q^to�GQB+d5��B�aܟ%)�"JM�ZaDa�Au4/s"!��Z��ed�"&OQ�7y��^!"� a�`� C1��oA����!e�A�!F�7influ?)eR25eN�?�<Z�$ ��L[eM�1�am�h�ەL�0% 6�4�=�&)w er�hM#�����%q"�N�moc%o�nZ`)}�"K!+*mH.4g�i�A�a maj�iG���2b"�5as ��1um��#AN1( 1I��19�!�%eof6c.� >C(|&�)1��5.pM�"� Q� �5 n�f� � �&�$U Pq�T)&�)K�{� stenKC�v E��D a"� �&�S�d�� . DiW� �D#�(aS%%�:�>���� �E�cl;� Ǜd� d*� qR�\�h��U#or���F�b�I�� �qPm-�. S���& bG�f�$a�ݐ6�&: qM]:P B�36&�#3)3"�$8�51�#�!2�#ir&�aaQ^v$2��1� � �%S�2J!i=+*� �8O!nQ . It,�/be ruB���S1 a�?1�.]'3oQE�{�����D,A��>A&�=un� �Bk ��(d����J"0 E>i.K�1�+@,O3.�"rZ��v(epp��AnMS@ *N�%)�qŦ(xC)x%u easor%t� ��!� kind�?-2��y2;d"ECY� HenC �fi�".in[ qq1+v1e��( ��&&�+of��0!�t"+.���)g�ii�E�I�a�!( ��HKp�U-)2"n �(-�@6 :)ȁ�mak!�its!6meE+��G�>!(ICA@� "�A;�| is necess ],6�& $m �<�*e�UM i�i�q �s�!P%�- l 1�oU �"�!�� ���T<y N7�3"Xo!�i� �Q 1� �3fover�K+� c�����W b:i aZ�qle *�UNhF).�am�&!?�TW�E �g� ��Q# A�pe��aF| A�es��|�thL*]`!Oi�Q�y. iB�6�%QQdsN�|(�deR��!AQ"^.�ma�4F�e�!Oeasi��dd�!S#�S#^ s�pro`?�6bŢ�2�Ysj:X1{!�a(lyZ��A6U�go� enga�^�%o�W�QL!���c"2�r8cq�R�&� B)SL� )LQ��8.�. A��j/  eN�SB��6����Be�fin�in&N.�2F@ knowledge�1[� % �E7we�a o^*nor�=�� va[enNEsumی�Y�+-��� l:V3 6i� �6��N���sd(L&F j�#&n� m"�(��\��\ EffoA�f!be �u�O"Oq�!�V:m��:~ a7(� A�.=*�L 0!ztum� �akas�/� A�*5\ situE�Jt�.�,�O���E� ,KhV�Yc)66�12q�yaepKW.|�Id�&fy�n�molecule� ߉����synSc�y:�M��XG!rib ��&�� nRUrj<;R��l$imz,OAby� >�сntx�.Q Xu � “un5/”.'])��PUu!6vu2���e�S�Q��dAn� � ƶ#� Ũo�/^A���Xa=�ˍ��E2H*y-��!� step>�,M�vbH"s" Z2&}#��UMp=[ �&)Dz unsol�h��? ɶN.�sV)��l;��E5y��messef]RNHum��^fer t Q5�aA�A�eb!�ter��!�!%1� X-*p�r [�PT��m�+s`�A�o7!�M�oa�53,���r�f� b@�A���S�S��!�� ha� �� "� �O @ �U={J} �:� � s [9–"�]s )}m��zUBexQ unnem�eKf ��j��U�' !nas~aolypept�uch� i.`�ԸexM5qZ+e�.�M:a narrow%�t�!�a��!�U�Na�\�h a)'�ם� 2#B�2~"be�]i uG_ f 6��L����BJF"%��>�ly�}"EZ  k�� o%�ew�Vs�nvrea&��S�!G� �Ma�5O�7wu �#on�~d a�~�Q�-itaE!� �'Atal& &��}#en�P��v_K�+nd unmHool�)m@y"� 2- !���m2i.z.���7bLxis019xi�K4�5�’];�isml v� �A ssesE�#)�� .�,��apy [1� �WIn*�l�� � ��ce58("� )�""Bob��!?��.M�!��� I$E��Ӆ^�dof"8�b15;ds� ,b�f ~I8�&g nEC�Ig��n-,��� *�}5W5�goneN3�N�"�% u�{ "�)ap݈[1�Vmb&Ea!0P�)�"kr+�:R BN��-oi�� �܁es�w=:�H>Sl ?2!. W-�%!�WZ�6��(18�h��I* �2 _44684�UPF)��c��pco��I0��". sl� ly�2 �=xer) ��sur[*����th06��ZCmWe�w-��profi��Fm�s.�!��verlapp�{`��l����!Ja��4�-giXa� t�C :}bE�!�6�I�M�=1�{l � e��E%P� �!�&�G)�aassoci�P���eB54b�.!fe-t��ed�to2Ai-���X��4� �S .��D �Ž:F��B*�x ����9�hܡ��=}� �:�)>h 3�'N�NY�.gMxor� % �����qp �`%7 b�g)�l�u���m��s�"�J}��� ��0 �N���!�&-�& =� de�cen�C2�C d657s . Gro�UYgm�)��|�i%9m?��16|�S�M�-�8@��4va�1��#i��F(,$p@#a6� �!E��l|~�(originX�nd��%� K562-4# `rmorta��"�)W)b{ "( ʂv��D �er*Jcs� e�;-s��ery"P��, granul �mY���[1)qG6!�i`� ���hỉf�,w� �*%��toa�l��F:��A��%?etv"�>B M#�^:n��` ,!�} e�Zg'I�KB !��&3� e�qAN�t:! �(�kFig�WP1*�� h�s}Dn6� �to!K�O:5���| 5 μO�I�de)���=:]Q MS1�B1�� x$:o%�)�%��.i1>*� ����by^!9�*� &�,A� a����#"n�Huh-7�� �&*�lt��6 [10a�We �ed2GwB#�$�:@��F�A��yG IC50a�uz�Rem�o�tO� .U �E=S*�aFI7_�~"44%ޭBQGt;|�N�d�I ��X ac:)E��so ~70%�!�>&� ���2�or�485% DMSO ( vehic���$��1g,`�!so ng2;H~6��J\�u����6,. A^vw��%cE�)2^)f�+ra]�.Q"�� &�"J M\�d&� bio"�*c�Y�]���( S2Am�iee�-�"@ !�.+ of 46=idZ �5*\ of Ins �01 h�TEL7 %$ehCIA�Qby'#q�zKa�2a<d��<�GI�!�-r�50Ac ��#q�$lwS�/X�S1:qper�,agz��I� -3(I� 0% )u��) ��c< � ,27,�BS31�Ic�͍�� fo� �C� a4�� ( 1024A!� �0.+ H! 6� N�3 14&) �B@S3BSS3CqQ Nota��ACP@� �&� n y� z oPө�s!J�-��E�� ��S3���)�"�0q;c�2s 3’Mw��(�_oby DMax�PS2 `> >*�! *�E-�� M� �&�[e�����  .�%�:1�� X1�!�D��a�0CC+o ��Q.kf��)X1�%I.�ș ASei�o-�5nE rqatk��c) @0:c��E�S�0��GW/$-����ootpri_S8-O�N)�X$�8q�X}���r�,a�$:#�f-�� �;��i%�,D�S4U)W�6� <(�2���e9wo21 q�� oin2S( S3Dx%�2��5e?$g�0pa�ntZB�4a�Mjr� aj���ŜAZPea�qR =�!822�R!��K3rH i�+of�W,"T<���eH"}wk�_�X� y�7,�D~3r`#&V !crs��I lighw )��6���!z�=���)���4 :^I�I 0�M:,(Q{,���]�_�0�*/)u��t��e��-�-"p�V ��J5/ �,�/:��e�:9��RNA�] ̶� /Zte� ly�- �,{�.���refle� ��!�!�"���_�*� ' �a sharp-W n�donY,�m�&8 low-�>a�/i. adja<��c��$p.�$���at!��>*� ��(.�!��1� &{����JE��Aԑ�&�)�r� "l._!���u.�he�b�  0 �eR>(�PsS�-w�)%�I~EcsgAeUH�$"�u1�*����@ng dCas9-KRAB-BFP��w=u���&�m�:� x�4c�+� s�rn�2A�h���- ��j �m|!S.k8�,Ԛ%�en�Pe"�!x"דir en��o ���Sa![} Brie�c,)@/�D| &�z As) .�P&� �1�n�s �ed GammaLTa+��)����fD& !I%/�m��4���0��� 0.!:uN9+��!`����9�����:�W:I�-J;parQk�er!MRho�2���`U)�>n�� ���D���&A p���er> |<1|�$nd Mann-Wh��y��} d p-�Z ( <.0�<l[�� "It45��s-Ca�e1�x �V%�$2�" ���]�*GSTRING���IA&�,G3��s�#�;CA|Q. g�Ao�&u7�!�����" �R 5"�7|�4,��s� �q��A+a5-�du ��f�E�s � ��!�ex�g�(�s� �v/ , s\u�$, EJC-TREXE�leE O� cy�, apopto!X9�lir.n� 2�Byi�bh8t:.�%X_ey ���~ �!|$mitochondr �"�bi��C��._2�2nz�fbMPł%�inCB i����M(��)�.�� ȵ]�>Y �*�_% D�E!v�2��(wob�&5� U34�"-E[2��60S1*#ub�n�kNr( ZNF6j�!+E<g� ( CNOT10." a�."]��)3.��u���R[2{V%�*s-6a �B�a_� gr�T8 5�bAA>ӹg9L!�� )�TN$No-Go Deca(�0 ( NG!�Pe^P/,:  cognI�n2 "!�Q+�a y�,��/Y�a �est2{��&:/��((��� 43� �EUr%[Q�J.�I�e R-� 6�ji�3 ( RQa\QNEMc� LTN1Fy�3g�A�Q�e 5�FA�Z.oE�.G�-��2��>�!N%pњ�Q2 ���deG�:TB� e��.-�Q<o ~g9mE|�J( 1-aRA� Q 1a� F` &�)�+���r1�>�,�a��gaN��lv�F{( ly-A� es w�1 d9ek�An&m1�-b��Fԭb�ova�!�$e}� -�� ��.:y� %��*�G _&' )��R��M�E&m veQ9"�:n�f%2�� �!e�"A`s �a"� &� a1�{�7 d��( S6A�#-K|��*�i|ir= by��q���W�68�p ��i�}S6�6&�a%�v�"�'� �i61T A@ �t"p :(i�3A��2�9�e;��u�h`B�J!B-��%� 7a�2�&��!N�Bs q� �E�!���!�az2�  3� �� QwA2:�sɣ�(kH7�M�ASa�����$YE6�ɟM5q(*���tA�� *>E&� �+"1eon"�%o � O, ^��kA[a�*!W�$��� }� ٩ [2��W�r"� <"� ad!.Y7� m�JT�0ׂngee�)�R xecu� �yasp�s/or 7)U�>�%}k}wM�� WAjs)~��&ol%��scramb���^ese�1-��e�.X)��� � 3/7.�(-��&��e;��+S� NxE�t ��QO��ed PL27�YRPS!�RPS1n��I#S|Fz�/3CENS8 ���%=��= 3 ' c�!-�B� �I؁lHr/�sh! of@ %�u&�7�<-�h(,-saltIr�c D��2";9)��e�� ͈.3 ]s���lp��$�Ess����Q� � F��!�!�eJan�2+�:<' ����e�N-1��زSCC� ��=Vsr8&�e./A�"��==*�JO��>�avp:in�"l '�.� :6���F��յ�5!F\ we wo6��he�(Yir�c� tF���$@`,2���. U�&6( labe�5�Lion[9m9lo�z L-AHT we+Ld ���-.9:{!iw�T.��S� ZS%7ole-�aB J&g$.�a�%*a�3!YL���#!2: (����he%<dQX446�n��e9� IR,M2D'A=3�VM� s*m�.Y�ݍ>x�>�x9w�A4� � a�#'� b�:��!LE�unVa�"�v�Q�vM/B�n!��!�35��' enco�J�6��R�ala luci/� ��)�M����be� 3�(&.[j>�W���i�E�%y�"C�'�39 +/-� 02W;%�2 Ku��31";) "3"26"6 DI8Df�;ś4��TP6 ��8 -;*�ԡ�� fY�a�I�>�Bhf1a d* $ ll��we��$f:��e�.g !����^��*"�U�� &+)heck �1.��.�>�^�3���"! �l �ucaaY�H+�K>vA%� own �wa� ��[ޕ]Y", Perturb-seq�"B#[25] i�5!S9&�a$)��1 �i�P�+��Qor� I�F��1%|!�f o �/�_RQCV�.Os hypC ��qw (of ASCC3 in�^ a RQC-trigger ( RQT ) complex [21] . In these experiments , we noted that knockdown of ASCC3 i8� context of using dual sgRNAs wasF, as efficien 4the case with 7le4\( S9B and S9C Fig ) . We5Drefore generated ao-o cell lin W(a scrambled \ UA� 1to serve�a�rol forl$ double-kn�`s�n used%SPetitive growth assaysZi))HCRISPRi validation .r to determ�! effects!Ycombined9�sVpresence'PF8503%AA59lInterestingly , simultaneousP? both%2=)drecovered wild-type fitnesv�!�5B%� This nega%`epistasis provides strong%�0tic support tAy!�.�are parEp!&samthway1]�%�response!d)$8-induced transl%�A�tr�. O)�other hA7,n�ofNEMF-�3M-=Qz s is �!�cA�baA0on!�ple addiE of each!tein’!a divieQpheno%~MOJ�.)kdoeivHfully rule out a ro }�activaA�*, but suggest ��pr�s can4�independa�p)�a>o!�iI=of HBS1L]h also showe�J.,�,a= -�B_0( Rho~0 . 3 )!i ilar!��9I ?�~y� �I2 ) (.�In sepa��%ݱ9hin which lentiviral vectors(A`�%��skAdeiEpAQ 2 or ,3 were introI� intoM^ sequga!襳%Gob�֡m[JP( S10ҡ_Imasant�$i% reta�w(its ability!G4stall PCSK9 re9erA�%`�m�%J .�-�Ni&�1�$Taken toge%ezsea� ultsQ�iXn3h 2Q�an �� lapp!npI�IBANGD,-�requires �� ordeE:ascer! wh �Ggenes iaified by-@��screen��specific%Gelea�eB�all�%��a��q Y Q to a>e carr�a��]7�A���X inhibitor HHT , a non-��+��%�s6MTmmediately after initi�X%� earl�� elon� �� v�wRho�4, Pearson R = �11��6A�By�! rast ���du�-�inher�*��,)96� s ( Gamma.���Tau.Tau)��%N5]d (B�87F� 78 ,�piN��S12� S12B�ZIn u�mX� ����e�adjus�! p-vaABcutoff%�H oundV�E-�> |�1|a��5y� iɡnumber��Ie���6] ( 496!,hen��!o� ͍$ ( 45ɽS125 � all�ous2��- s shW betw�� X1%treat- as)�aal ctH. Notab%�@although only 126 ���:q!qtwo �s}7less-y<-��6u �� KEGG� enrich� analy� erformedZ(STRING data�  [19]1�a�a sign��ant.VM*� �!�!7-B)�d includ��,ribosome bio%�i !splice ERNA�{�x�Ce�P� Ev funcZ s ��d!� mito \ apop � cycle!:ndeN2 $DNA damage^=��mpa� D M��� �-(q6�(S3 Tab � 4 � For % 6"� w7I�q�on6�e�hE����J�-�,%�,} PF8461`D�Sm�rE�"m ��#3v�"�!��<:P may pla�m&�l� in� � .� ��al�����!/exaX ,ke? main9:-J. ( PELOE]�  ) *RQCuF(� LNT�Z` ,ly sensitize%jU�J-k"yq 5#�A ycould b volved!rescu/�edKpa'qGs2O ly .:�e�aed��soc��th%CEtaE��$ubiquitin-�d "o�TM erea? � )haf �N+ , possi�'�~v low� xic} (j->z (aminoacyl-t�4biosynA�is�Iá��")b�x-�Bz��pMos�s�s�Rho&P clo~0!�^!��K� ��he-"gE�wo faI i]~ stage+60SQ�ubunit�em![, EIF6%�(ZNF622 , ha* poA�vem�BOin--���ell��!2CT 3Ng Js!,6��� K k,d9 �:d stat�c-����(A , � S12E�0) . We originB&� e � A�of��!�01!b�!�I��1!N��e��onaurpriPly diff�array�0off-target mR�,�"f�ry profiw. O�46 8subjec%� �"@��,� yI�� |"nbyE�,��3�5� *� *�hs.� �FAM13�HSD17B11�D2# -re.� was�&�O 3)� ܁�� y�E�lsoA %� ,!��i���+u�q lA�� at do�leaB aK�a. e���a =�pmx� sit�V� ,�AA TF reJ�m|effor!zo tun�struce�)��9T ���.\i�)_s beyondm� . To��y��ia�Lon�CMl��*�9� �y�(a whole-gen:t inF�� mpaA%[7r�a*!��..~we �t�z�<�iF���yA hen" i{9����asA�s d� Dto-v.ٻ�9; !�at.mon:�1��tͮ���.��-�� a�!@*�a^ref�  aV!PCZ����� a�"����%vk��global2a� 4�4&Sm�evOheM i�ae�� }��~i�"�Aɒa%�y �%|an�o�e� Q� . CoJ����C.�, � �a6in��*@!����[burden!R��mon 2ve{ +nd en%�2u�iKrobus��Bf1dr�esQVYs.����i�� �4I  �E�( i . |�!{ E[)%,a*R&:�.+�.�IZx���AnT�al�lan�!�!f>� " au o��epR .�i&H"0 ,mot� !�v�e&t�Ilexes uE�beey� l� th��%�cP^ !�R"uQ w; una�^� &�~matur)+!l�articeBmodR%�A�4nucleotide U34�!`wob*� "E��u��Jz �-�y 2�,��!�(.�. M�%��ZP %8� "� in� �ѝd[3*v#�tALeC:kw2'enzymes�bJdi�s�"low dow>R,a3viya t:�nagainst-/F� M*iEAex{ed from����ee�%&�&�AuѠѵ�ly2�AGnot%���ы�a� -�� �be��&�o� speQf2�9�A"T s2#(primarily b�$}t begi��}� |��y on=���Eb!+iaP terp�e$is1consist��Atkn!�bin%�j E�� drug��s bi�?�� al A>E�heY"On���d$rst stepA��.�-���sa�Z rH!it� n�2��j�� o"A 6R�A�> Tn�nt ch��x&�\%/cancer xDonE A&heu�Eye�y%ʍ& [3�sX#A�*)-G�!�sY�&�� !����� ��Ť� ��e.�%6�L��,z�Ms>2� �)%%�LTN� �a��ve�ac� �"up'�") F��6� �,BG�A%�D.resolv�at� A�` p- qJ�.�*�2m"� in ye\h"�a:H� turnover�<%�Ge�Vhau en�U�,to��, d]�8�edos� , 1�nTh�pat uqua�#1' rol-)�"�tol503!Rfi�eem% �!�i�(� m� �#ve�.� B8 e F�'�!!a"(^b. Howe)q�&`!� �x&� � M�?r%+�(�\ IorEn5%a��*& +nor�A)��n� m��;�1�#yA��#theirA:�*�I >�� � hyp��M�46A*�se7%�iv�h�� hematopoi� a+age [9A_0���&is <21a�ale@ � [33WFur�u,Y�&�] � miss weak2K%�!G%mMu(occur acroseNE�cript��� ���L� subst� �"^>�~rE1ra�"M0H�"� . In9!JatɢDJ+ŨAy2I��A��Lan�' �cB Mg.�%��a�at2:I��>� NGD-��*�7�  >*z anag. orVA apeu����S�R9"j !�at!4� fe�eP+�� %)P� �Y/ ncod�ne�.K(nd 3a.T� E1ioA��!�ngal co� gra� !�g/ ASC-1 [24A�RecJ.��7�*>�a2 t[l���Ba�! alky�,�![2elU3a�anG" heli�/�U6� bAxq.ortholog! �� Slh1/ LH1%� )R0 , 3�m2 harb�*a CUE (�pE�/0K��ju(to ER d�&/) dom� e�? K63-linkolyK� �2&.VQ�1 I�ʥ1re!+emerg!�e�.��of[J-A�%in�[2�F2� K63 2�� 5tfa��be ess�+`�E�ed�6>�Xs [35Aj:studies ;: � oposAHaI�ACue "esu%1�uc !�.l+,�%A�m8%(A����he! "�23�2, Qg�)by�����.�D necessary%� �2&� w�1-;.3.!��Y1E3 lig�2ZNF598A��)� 4F�B�)Sr�A1��� �,"��$ hall�*g�-c}�$as CGA cod`!�AL ( gqtchum�Y�,A�́.�# coll�26��[9��)TE��1mpq B(nvestig!fI�%�&A ADW E4R��� J�*K.U�|&�-�ir\%�N�2���orU���-:^K pair�I�>; anti/�AexB�lso�1�0cytoplasm . Fi W�!IAr �qNin��ed�d�'r ��3ot�#copcM�s�. .)��or*�lQ of �(�$wor BRR2aGNRNP200�is W vrto MMS.�ͮ PRP8!�ck�(F8M%0 s! C3 fociZ!�- OI)� �:�, �n is mildlyj7 v-X-3''4of�8�,�aD�#�I-,05�K"g6 of RNF113� UBC1�5UBE2N�%���0�% �:w� �%= x1���:C-}Fi$>�he ke$j^nn�to%�&\Q�, ALKBH3 � !C/>%![.n)� � r)�i�6&_ �V�! noOcer�"�.��s�QDis unlik bh1BT %�w"�Pd  ( MGMS1)[2; �k&�0 5 , 4 ource [37�t�! “A�Ri�->E�Di�R�$sal” tab!0ec�,�"V6t�Ade� b1bo�! , +� $RQT system�xr R��Z��$ic localiz�(A�A3��C� m�H"&�, Atla�{8!B%r�nly2p*%8ar� SCC1!�/. abund�--�2aɮ�83e� *� tK in�(proxim����N)O�+e�Dprevi�;�c���Z� F !�!I3A�]�b a� �?K"�1 m�' 2Bcou�*�; thir@-i�(�{1/ , yKR023W�3qt4d� A8;�* ~�. co-IPA7!�5@14=1iz6Q/;��)ā9i�i*�fI*in���4� !0CF� Do���u� A !_~�q6��fN�=e�&�="k,m�m��;HT-�m�D�6D�$1&Y4W%2m�)��,�ZNs-�-"A� �\���-� al6�s�-[4� pN11��&H Qi/I$S6Dԁ�2� �KAXo>sKz'.rri&%�>�be3$ inity-pur*ww0as2AFaa�j�*�manne� � af2_c��.|�/7u:A�6�deCnb%�]�d�"F.qb�&�t ^^�+6�$>6"I�}�>� ����Bown)amA�i�.A�%H*e� �)��yA��`"�*4��  s]�U�� &g'J�3;4�Z�he>� EM�)K���1�� ��<$KA� ���s� �als^ �a�.pi�"ll3# chem>&A7� �'.:|4res�@T2:����ws� be s&q%�}m�eB� Ne e2C!�*�/F2� o/�Y )�ti�0 RqDn<%L>�Z%� ��ч T oughEN mark�s =�zs%FY�F� �Y[ !�!�E��noAfewW%ll X��/�� very�/tN-�Du�A.M�a�t%5’ end�opeO ay fr 9. F".2u�.b�?q?�r� stitui�65���v��ti $r$͈d � !W\/W>�)2�@V�Einu"�� 2�#(- ify2"bF;&�.��"�*| W2n%!w�7&�2.FFis[in o*P�~3P�+�EF }A� 7.�U �*�� ��&U"q5.IE�E8g#'oI6�<� 2|�* ��-1)�sece�1 e�l�/ je&{-^T"�x"el�j�iact!h.�)7,� �e��E�ajs"E &�..�atg2� �Xw���;E��+.H�Hw3aK�j)�4�/4# ��ZL"�� �"�b��8&�7 2< �6 C �� !�$�qfrveill�#��*�bJdespr�/2.n�@to-�Y�,�""�.� jQ<� c��lt2i)>5BB>" )bF���u �cb6ic��}���l�� ��s8)-�:nzr*!z7�:!�o�� �.�s l�A�bq� f7'o�&EFde�:.t.RVlie*aF�/2q"��e> /84*�H��!�*|G�$)�*�,=�E -�I�!@:yn�'�Ilyi�!� >t� ���4A��Ge'�.�Z ��1�- a bu�Ku�'�p���canM�� �82 byK�f'f6Y s��f$gen>��!��]WH'��a��3�A�,Q�"�� ���C?,.2<y-�"�$|un}@�7 )�w avenA7� explor�c echanis#(���h�!"o8Lex�?M I�-1�7 � z8 uncl�� �I�!= 3!�o�M��="z'f�s I8A� a�pSn*��in� EL2�"�#al2�or'yc��s#M=&_�&F2� V&s:("L " �!w >B" �Œ�i�A),>! idea)'� now �E-�%th�%W.P@ ins A�Khan�>�A�<T�A��4��!�P�BE*KpOOr%A�0 A�Ao=*U*A12&�W~� )�;.  of d�=s�N"�#.y)E�we. � a=myeloi�(4ukemia ( CML )I�c&�;,.�&�J&%���I9�J �&ex�.��� ataly&_.�Qe EJ f�6�� PJ|4or$ "( d(mJ) [17] �=kin)�V:!8 Inno*0ve Genomics I"� , UCSF . ��=&),hepatoH%0carcinoma Huh??( ATC� �cul�79( RPMI 1640 �Bu�$Life Techn�#" , CARLSBA�C@USU uppleA'Q�80 . 2 mM L-glut]B�8G ax ,J^?!10% FBSaA413� Sigma-Ald�G?t . Lou�FMO!�aid = biot!>J nici</Stre�'yci��@1 mg/mL , Gibco )���?w�<Aed�EK293T%z�0UC Berkeley CAK-L�Ki%+�JA  N)f DMEM�J pF89Seradigm8.�un^�� s te�J"Wa�myc! a in�5 }0�� �@�$s PF-06446*(�C�E37�+5�ER�1z3s*@in(���yE�Pfize}T>�Ta >K�F1��LP2�@�MμL��k� dilu;�A DMSO (E5% fi��conh'r4inea1�Na��n��5�of 3000}fAT.g).�a��"m� �NF Oincub��P� �U � SCK9:��solid ph�Asandw�$ELISA!�%/QuADk� Ki9RD�s� 96-wA�pO� r�CeOr=h*(Aat 105i�!}7&�2lE �2.�H%� 72 hA J"�6eQ".�4�� �%�ih�-w �2��4 �^vZ�Qrea�_��maximumv de�Hy ( <106�a�*b6!�1�I� ATP � measur�>�Z:,TiterGlo2 . �PromegA�U�d� 8! t2� metabolic� �=� {��aspA5;%a% ,F3/7 (-` ��550qp� susp!e7nd�R<!K)\, volum�C �3/7Glo ,���.�dexE!WE�!dcal$8A�BT7io� ]%$%}u;Ysc�)P v �Qi���E�7xA��Iin 10 cm�M'��2� 1 . 5 μM��4�2�5� ��5%��(SZ1A��!bi��D trip�+t�"rin�e`,phosphate-bu�Bd s�!WPBS* oň!qR ohe� d!i�� ��tri�9iMs X ( 20��8Tris-Cl pH 7 . [B15NaCM5& MgCl�"1 DT�"m6� , 1%Wton X-'AI 25 U�RDNAse IJlys�:%�aliqu�\, flash�-zNUnd stop 8at -80°C until��dEL" 4footprint libr@*p�r��. R�) $ � +�*e&L#[42�In�3r��30uMtha�X � QdibYZ �7! ( InvitrP.% M229��. 45 m 0t room temper�1A7monPm�Q�%�L1 Mr�; cushq�ultra�(if-( 603�$ 00 g�UI�4!^� !wtoc�;a�"� o,miRNAEasy ki�&Qiage�21700�.; fraga e�26�34� �;�;c_U�"wF���%�size-� "�Q$?n!'a%ureml�|iso�d��deitor>/DT4E��� �a$( New Engl!BiolabsM0201a�� Il��a-� at�� aden ig&r-�$�VY�A(-dtrunc�T45se v)q)U�^�42��rst-s�7d c�!.� )��%o�  II�00rb368� !cir��r@ O Circ�M�U�MpiE�A�CL4111K�xm�al��deple!" P,custom oligo9��6]�#ac�Nto myOpta�< bea2y 6500�Pɣ%:�\x�� �6� �8k14� �ksemi-q� tg PCR���L fidea PhuEmer!"^dca5 no�> 0530)�-,"6���1\�^a�e QB3 V�7 nt J��{"�Sb\�+ Labo�2�U*/ "U�( Hiseq 2500o� De-multip@bT!{i���:z ′ adap Y� a$FASTX tool�Uhttp://h�nla�(csha�$edu/fastx_ ./%� . html� alig� tok�XMf1&qo(Bowtie [43]3rem<)24-ma�ks\&�>�Jc�[�#i6�� QA��tM<�UCSC/G�4v24+w!3�Canon8T�T�@:Grch38�e~TG[4��42 o av~ambiguou42��JW%,��% (to�F�C!�.x�X ��)��e�"0*�6To^ HAa" N�can�: P�>-offset%O" d�(e�9P�"��~V 14 nt%�of��.Oor � , 15>/%�27!2926�16R2302,or?9[46NCodon!�t�Y^)C!qCDS�6 9%���X%= proc]4�X�:python "ipD" nd R�/"�ocuA �a�1Q(�?!�S,e�2?� i�2k?( S&&&** a DMaxa*� a+>� � �c*Zumu�'veG;�}i�i"�S!oX-� �un(6� ) s���e�� !� Z-sc�W%�F@Z ��s>��6!�scale .AR�A{&!R%ju great_th�r eE�ixid_5pǘ�g�I. A5Qq";��6[!�IOe?[io^ �DE��!�.Y�9�/m%$� 30 c*�#�atoE�)�A.�*3d".F1��r� a("! �TtarKdonB�lacxa I%X�. R�t<�?mhT*�"�)] also omit�.2�Fz (a log2 fold�BnJ[nd FDR&^^Z^<@05 ]=��iaUne�o� ݉&- �plo�2�&`^ٻ2RD�\�'oI�%9q!��fe�R X%B�2 I&>$-c��regE��n �by to yiel$per ag�#Alia��� �k/�a�age)��-3.qrepp�a��AA?C �aO��w�"�&a�/or 5 uIzZň��~mi�dE)0 e�-A�U�at t !,�!J5��Et~s� ti�G highZaM:�a��R^"/E.��y�0m)7 I?"7 e�� manuw-t*O�&�Y-.& T AŖaّM�*� s=�1de�!B� NCBI� (e Omnibus D�_:3ac�ꁸM�GSE12198��“Top5\!�“Sup v7idp!-pool���2�Ph�&G)g' y h^)-v2&ufp R�w o obGZ full�yG/��L�)"i . A �+a���by g rop� !2hEndura�e9H�s ( Luci� 6024�2���!�faRR r’wcRe���I L LB br.En� ��amp��.h �3enOcy�ux�lag� u 400X�.� 1�. E�O.9� E�a�/f�X# CR�l�c� � deep.�.��)s@+m�&I-sjz^�f0-��)�.�A$e�du� %�*�*�d"� -BFP V�1� *m J�jwpgZ6�"�AK�_.�q0)]y� w�epackaga�@( pCMVdeltaR8 . 9I ZPvelopeGA�pMD)G�s>� IT-293 �R�DngMiriu MIR 27iVirus-**�&e2har�<�U�h�ourCF��bre~8Q��gto�x;!�F�h. M-spu� 6�( q��33z�nh�&&�},2\t, ��in fresh%uZ<60% (& Z) 75A�)1��*E1 �e ,,"U fzNc3 metr$:�%M:A�Q�S t 2 d%qpost- TF��1 puro�� 75 n�&�-S ^,�5�cp�C! pop& o� BFP-�ng �ra� ed 80–95*�1i�s��5�l�"�!two.mA쁃 9E�� U��Xd�Z -v�-'Q�-f!6I� ( T0{�@Vl�w-w �fu�%��4�3 L spiQ2tk.M) �,-,F1�3��M"7< $or vehiclee aIo�Dys�!0;�=�A�ntl�gnM, P �lInJ� am� 7�K as kept a;25i��# <0i�25e� 0�16 .���100��2Dthroug"�G �i��,� ��9�K.��)��Uu�a Sceo%� �Nn� >�uK!�2� \�T��*� �i�-�0�y�M�|��11a�QM{c2QP��15.4A81#�C�: � ��"�"QH�WFN��kBriefF+epic�e�exka`Rab�I30I_97 f��NuUa�$ XL Blood �,Machery-Nage�74095��"]�C�at �e$SbfI-HF�)tr'PMTbnR36"5.� �500 bp� 2��'E��set�%`� "�  largeaU8% Agar���:ja\ -a��)%28706X q�(:��$��2�by 23�V�)�HF-��*�J�"Ym6�ɲ����a�Cena�aVAdvWd "&�SF/  HiSeq4I��r- c�wE�^$m)ComA onalZsi"i 6�3&�rr], �� pipe(availa.4(on github (F s:// ..%,/mhorlbeck/S� P6��eD\. I[y�A les/A�-ck�=7�*Q-/g�e8�W�(c !D�(��� 1��z��e�U�&�q;8vs� .s %Tau#�a�o����DE;Yvs &:#Gene-�"$> �0 >�e�x!u|top 3 ���((Ara Lby absolD6�� $by Mann-Wh�<y"lU@*ysz3nt<3n-�N�H �!-��8ach � cand�{�M�>e�'adv&�{B Q��/v 1 Z� tospacaJgiv|im "�5%F!I��%J�Z ( S5�_) clo!b� 4a pSLQ1371-GFP� O�xmF;V�&LXBstXIE BlpI!~Z7�L�L6y��rR�)/*�� on ��\|a����"� D,��%͎�� !�IA�us)�67 ", .1&�Abp ] .q ��MOI�d&� by> ��M0� fluoj3w%�*>�!�. 2\?sp���too�Q&s6te2��� 2��L7�6-P3!W 06�/�%rup�ofm2 �9 @>?%����# �\mp?,1by�-*�Uw\��{5�)!�:E�2��NQ�ngI��D2�5wea{��2�B� ��lw7 }!a|��ai��� �on"� !�\P�ͥ5'by�"E�a P"�5b"�2n"dRUpshU�vpromo�ll�v���H���2��a&�h=k�bv cr2 [25]z5|2@a m� e �m6�T wJ �'�pjM� pellet-1ly�'iPan NP40.�'�'Hepes�'=�'K�'�/EDT�/: 5% M^J5�')Io��letA<ot�1�-o (S:�/4693116# $�Ke�dw,4–12% Bis-L(� sS uPag!'2e# NP0322BOX͘er��- n 'a�ul membra�U�&ruz�<c-3718hM #-_ bloc�Gw�,5% skim milk%��-�l� (antibo2S&? �(�wG5s�^&�,�Jgi{in�H�v As�>d:fK%M conj�'� hors20sh�ox�A���J�ECL�s�.� (PerkinElmer&$EL103E001E�1. W�rn!tt|m-.4k{O�p�1PROTE^2�`ix�I  S`To L�jSoftw!( LI-COR's� !2 ncolNE"�1E a@ � of gq}tofV�%4A�"� m�� AI �C%6F�, �"(�@$=W Mini'oLZymo Research , R206�":m� SYBR Gr�]1-�> �Cr$um�#�%re�Uim3&�RNA-to-Cg*Ap`]d%h�MH 438998�Eon rad +0 Vo�K ccorQ$�.�'Z *�. T�t&�a-� ( S7M�)I�desY%u�o P�[,r-BLAST [47]*t $www . ncbil�ni27 gov/�%s/ h-blast/�A( V3 web6l ( [48�J& 8�Rut�Be=i��,> resh�( Ct )� �9e�a_�1U� ThermoFisoC9KB�#;mof %I҉%�mi�e��-O�Dnga���of o� a&� atjK$~1:4 EachQ�!"� �G�   r� vG��"2Q{|� �p�%�Q4 &<��xm}:��1����ta(h�!>"!n2L�,&CFm��%�Ao"j. G��Ep%V1�)$!�.�3U�%&�z�*#R�6\�>/.8 immunoxip�+o ��a�"J��6 . 5Hconflu�6#7 V$\2I�1w!��E�� 0=2or=�-�)�-�was�2o HBSS&�1�8 , 1402509�CCjaR�Min�1L B h6� &Y0@�#*:0Y�74dI��7IP>� 2� ( -HRu2� !*Dk2X� ���o�6� *� , 4� R -�2RNAsi��5N257����7ed!��1on ic� �5�dA�10,(!w00x��t 7,E�debriJ K1"2-�:� �a6� � ,y ( Bethyl l�-�$, A304-015� � hr���� rot�`�n 4"�2�Aa *d32d3�$input2v2\ ge~5X&616 ga���z6(& G�/"6($M�!x:f ?�T2Y��c�41A"M�4X ��bA�0&t �100vZ%��B*B��atR�� 5+�-"4�s�Q=.6s 2�G1Be;�de83Ɋ�X � b�6�95� E_I��1�z � ѯ"�i" by67,.?"!"loa� P|. A4�ly-�� K562E�-H-2 warm87�s.�Met5F;b8?(�:A145172�J>?�= dial'�>at+eHc.�<��:/%*D �u�Vi> "��!|0"�d ru@%o%�37!�m�,FVorE��ya�"$=!�v um�%"��"iZ@of L-AzidoHomoAla%R(H��ata�>9N�=�o-��3IX,�B�9(��I�a0009#27,i?�o.�w� "W8Pqu���' �6 B�o�in��:f91%SDS ,��mM�� H�pH ��e96w1XAf�� �nBenzo�6�0L,�`5101 AA vorth)$ �2�z�� %Q��2>8#gE�����+97E����MS8IRDye 800CW DBC�?I$, 929–50b� m abelMaJ&� t dy a copper-�2��Click`cU [4g[Ex7*img&�*3*h��n ��\J�b� MES-A��%,�00w �K㭧%�a�.P9ly2" � �l!�l� E.800E�R�� gela�aQD Infr!'�Odysse�Gnm wave�eth �G�r��A!(7�oof�-�!�?�sR� Coomassie9 afeS BO�,6LC6=.f ��5Im��LiTe sֈAllG� w"� "�N2�9 PmeIAewJ; R056�8,!��A~/A �6�].�T7� �)9"�1p��r�5in-��e �U�4 A�7� taiAO)PHiScribesARCTK� ��4� sQ�n�.2�=J�F�Qu��Y1^W: E205�mZ�Zby Li� re*4( �+5 MR���.�70% e�0o�$�� �MtrK*0( NanoDrop NDO@$0 UV-Vis Sxrophol86a� _+--�IEA�2T@6t-JZ nA�J )���K!�21y�R� �e `�6~��447�3-+�sot�9�Y�AMOPS/KOHE.)�A6 M� >Ki!magnes� acet�, MgOAc�F�sM`!��21 1�� �C�cNsr6�1BB���K� NmM���!�* &?W�r.n��12 � �hre�1500V), a 26G needl�cB&s�� 6I�a-�ce�|f�e��3, �q \rEj�& �B V2k ,*^B�BSJ�,�O IVT& Ded 50%7qB2��O nerg�V salt�QNa&J� s:�mM.�MH^%�~E 0E?GTPt }t] ]AIm 1�K:!oki� ,!ME {E�M�!;]mMQCx �LCkid� ( 88B� �w16 . 7x �K;�8L��3L3 $no��R'�N�&%M�FxM1114005 H C2503002� ,�ng/D��31ohFT-ar�c:s� �J�22R&C� Q\.�1�to� ��2� Q&`rAQ3,e�5<�D.��lucif�@1z^T*� A�t Hby!��Q}1L�A��%�L  .c�u�C6�H, N111�O "I�C4a Veritas micrrMte �C��G Tur{aBio���To &�&<'e{2���6  adsor�"1"�FR��c�E.Q];�t[ um��( K��)E�����29oJ�!f40��( n8 �)Amm|(|��) pri#0o layer!��->�in MLA-��tub�E Beck(�Cou�yEt377��!AwM�"���E7q� top(a 6�G>}( .G�[�f20HSu]G2� *vCAM269�!`HEPES��% `M^�6uG.sGa3�!�=( � MAX� ы�>=M~Z�nin}:�-�i3AQj��EC:tpa�-amȢ� ('� !�Q�c%{nm�S&�� �K�2O���� s=!�ke< ( i����`-�?��Dg��( UTRA�f β-i�i�HB�[� �*��:A�"�$�O�O�v�s!�.J1–3�o p2A> [50]%*Ren�\.�(|P(B-Rluc� ��y ���Fi �y.?�( F 6.*�,12��42 8siXs'Pin>EPat� 46�2!��&�(�,bCO)Х!1�n�Z!�A?4 Ӆ co-� �&�"i0�g�I@per�V)��  �� JetM�P�XA6�!Polyplu81&�]!Ser 3d"�R{D00x��"�hMS���� as2���A�!�(%4��=. EU!l%U��>QO��$7–8\#2nw_ Dual-�q( ^, E292�q��_�]g�CGer&7(�/�� "5YV�g�A-H H���rYC�%v�.�"l�&�Tm0^IGGraphPad�"sm ver�> 00�Macm("C%P, La Jolla California�W, ;#g4padn"��v�Regu0 of mU�RN8TE�)���_ [s critVH�[="qh��ge"eEYo(ens.)g)��$&�JF � �I��e�M enviro"1 al c{#. Unr �eo��:���t?� _q#�Cdamyfiu � i'-�^uc`�gd Q d��, �^alf pesv'<�s�xw&9bde"%�h�sdj( hN�>,aLevaf�a e� �  . Ka�@,'s sarcoma-a&7�he�� SHVb +��is "� �T! �v To�nx/SOX�_���O"�^2SOX#}>�9r�z� n�m, �(;DpR ^QackLin٤sicL"��.*O����t �� stimA�6�el)م^EnRJU(via a uniqu�<�am�\A�aberr7E�=wOA�6�E�)OXF<exhibi��t�dGy[!�ol�II��e�3 #6s A �m6l.�5�:3 �+^k7J%�f!�2$"FHi�� �ofU����HE�s�.�B�A)��V�=c.M�!p� s+�\5�cofǝ !��A�latY of(undergլ�8�G�re)HljvbyP6D6`�8"4F�� ��l6e�sh�O$k a p�_]�� � proH&h�j.�!�=r-U���Y��Z�5l�E!2 s . �(l�hs�., �Kis�< k�D.cA��$etiologic �S� �*ne)�+Ol�i5�9�isB��� ) [14O.[�a��%S� tumo+Z0&predo�jl � eldezMed Y.�Fr Afri�ame��e�Ĥ� AIDS pand�n( , KS becamB&�c���L 2|uC )D��o�G�,y�su��HI��.b3���G�:x2�Se�}ň� Y�p@a�End lyO1r�Ha��.� ajor��1edMNinRI vo�<bo�? �| st-�;!B z��2�d �a��r.�hKS`.��[�[���Si�fe�UeAL j)4��E�aϫ�oy!-ei�6b�mo�� aa�Z�� �,(�)2�d�L��� s [4_,[OEy A itud�a�y���SK�K;)ly ^Cz8� �t6/|c�4-& �9an�` 20%Q�n����s!P se [���7m&/, �C��!��,��!�!�)Щ��[(0!�ex��)��-hom�Gs.u�entire2vfamYr)X����."e�m��2�as I4.z ( DN�`=Ctea+$i�JM&?ibu�9J%En��F�ne�Q�ed- �;* & ucle���noF aC6y[8]– Q. 6��inI����c�2st s.�%�lym�$rophic γ-���hub)[—&c�։�c�=r.o Eps�3-Barrwus—�s�i;�2�Ns.�z�ea��ac�q�W��$ؚi �q�a�decay [��, [12�,am2�FA=�>��aM� � Q $7�=,�h!�le-7Fmu��s!���%57]J� . Desp�2!�aN M�|Z"xn �s�����yHV�E1Um4~�b �Eaaa no�edi�3!1A�gJC(T otifa.!!thus faG�^� ( Rq4i$y�j)�e�G"�q�b �1a�� eg5�to5���mod� af�-�T�6�"� un+C�0es�'��-job�|lya���  p��fu��aI�F~A.��X���P��!@aQ��S. N��$all eukary�f%�� %%3$!��o��attack! an� cap� uQM r3�X:( 5leava1R*A E�co�wNAArY ysuO!�/l� n!���+&�� ���t�^81N1�.� >2�is2M"�"�e`h} � �9w��t s CP�BCts�B!�CFIm [13�O�� �!$)"( PAP�� crui����km*�F{"Sniaa[ Zl "� enos��E��a bipha�&<; Fl sK�ņ�3!� @"K)��edsn il�6"yly5eUy�=OTPw"� ���ar�-":� %'BPNMth�wapi�me>�aO20�0256�X(�X) "�>�FqAP �6��oN'i� bu%�%pdi�|siM��Y� [1YU?��exE�, P�%� plac&�cyN�r�- �8�$e�se흁A�me&�P�$p�V�I�$l4�l"�W�eIF4G2IMp��f'BR�%��J��%aA�ADK`5g�a���NA�H?i�Ɓ%�a�b��rDnd�Yorgan&+*it�il3es6��.�}�Ls oc� geV[ ��ol2�� �tfa ag�i�c2� �.! !eC�, ��A~�kaUBvٕlJRAM�  �{A}+�� *!bvDWYit\/�". ��@ !�u��h�@�m�[20��2�Ad E%�,�8y �m����3in%��'�n�Yiac�Ze�#@<"fbE�?!�s�qa�a link"�s��.V lE��s.{wA95[2��d?. Analogz���Rr"| � �V1�Eu�G]-trecurs�qto�r&@�6�JL[26)teK&Ҭ��j;A�t � d6� ��i�k��ixF]b!.�a�& $o�b�N:Ee�aA ^ "gx�u q5�Y�.�29���othu!��A4Al�U.� F�e�faɀ." e� &�I�>v,!��]no�.er:!�i�d2� &��m�ya ggy� }� rP:'-U+5��T�i�` �g�g�v}irn�rv:�."�of2@� nd demo3+�:�:U%/!2�R��sq A� ��Z= ��u� UT�� A?�u�Y��o.>!�5La� � �;�H�A+~� W[D�^e�h mz20pE��g� play�;ەt)�^afdegraPuuU�-|&� eqJa�!�M� CRM1=��� ���u�Q:K lept�TB ( LM� �1EM� U-�꜅$�*!J��� i�b>̥>#UZ-�mwureT�+*it diVxE"t�%eli�t�\*� "�!E� : abroC�.%�F of��1A�*� .�w 6��� er-migr�(g.�<� �erZaen2X21�(�=) �R.S(� ��-.��z!E �o�� ��  .yA|.Jc.��c&��Oxd %@���%-OXyK,=H~! ,1)Upq��!�&�oy�� 6�5*!0G aCe�aUZ��i�OX.7e�,6!�0�r��yB�%N�R��vcWXMly&�2luB);! y!not�|qw��)ng!�5N&� ��.W( T24 o176&6L20/2J�,bthw �Zsa !�)�$ ( Q129H )��yS�p��r��m�c,�&�@o��� ���Ap`P$( HSV AE )��S�*�y$!�29Y*R2�7�s�v � Ƀ�!�e�#mo t��Fi�� �T-e�)l��7B�U?�!�%b�r�i�e�I2����6����,5�>��"�U'ՙ!A5�'ue�UeJ�� (6Z A ��w�R]i��dnde.I i��s��m]{$T ) hybridd.|'�H�VuJ�2^ir) �1xHT d�!noE�n�t� � ���6� mov�"au!8�  MW)����}��Ohif=�I2%�A<cA4�� is�#co͏!87%k‘�$g�2y���"Q�6�b �Uhow*�Shy6V�a��"���t@AD�abyJF��A<2��Cirm+ E�� 2��C��� &_)Gon� �;GB( E�]en��W9en6a-�a�"%EG�-�w�l-itu:� � EK 2&3|%�a.ly8�,ligU� 9�D�S&ly��l w��ҩ( WaR]��* elevt ;:m?�� i ol.�vis.��e�9�d 2��8At?W!2m�:WEGJ |��uUٍM hǂq AbeV��ag� giaLL��D ,�riY��,Bi&��f^ =s�L�u��iQ�Fe�t�Bom�R� ��S��OXBZ�s�2�"? �as ��A�a��3V�_(�A�|5�:� !'ili� y8:�M9.��unpubl�Jd�g!n�QR�%fa�� (at6_A*i�&" 6�ͽD�FDD["��.M?tra*:vie�-S""�g�ei3"our ��ZuI/�a:� E1.AM�>� ��a�!�60&I !"th mole*u !�f 940!�106 kDa���/-9in HeL��iwaY}tas*áF-Fisot isO����5"w�*m�1002:[& 9� �.y�f&�Qs�I� A�9 P- =er�PAP-γ�V�!� �#�S_� locu�T$A� s&�NoA �>.[����` �� `���0�  tissue-|�*&+!�y� PA�!�,PAPγ toward622�8�as�l)8 smyAfY3�� ( si) -m�W;"!�-1Z����!{�1�@�4'l�;]�d21by6'V1�R�/.�1Y!H;t6�>>��� !+A�w�&)������2a�S{6�ly�� �p"�.- p!�d��m��7� �&.�{�eR. �( � � XxQP5b.pe@gA �IH9�9e� � B�^�*:�AcacvaB>� ".^&� ]-" "�A�IfF�nke�ip_�Al"J �)� � (i���m6�* Qm���na2MZ&e�OR�%�Ed&�9�4�(pe�9�� I� (;�d|�Mf>\� �*>%��a heRZK�a ilmW4�  s+�6;n���U\ �� Si�6�$5QA�st�u��*a�nd6/Q�9*)eγ�tse�� f�siE$%gf���*� �2 .''. �[� ��"d e�\$ ���"�isUa�*,� 0 6� >���d�6�&R�8�zelp�>�-�Dc#TO���[�J :�s��i*��c0|�6�* pun�1A�aV� [������c#�er@ � :�+ic*�.CAi�Y)c&�~o� virt�!��h!�R� e��[#I[�ac� o-��eV�V$A�n !#�$%I B(d loop3�7[ "��A&F�!u!�C< " �aUDb�x^.& in�( ���� (,�^c�+�t�Gi [!g�P-!� � i:s2J:�!�B/��tJw� M*IDž |&%.�&Ďsd:h���*�%�>�\ bega�&nit&;�.QJ��: or^tT#F� a��t.&�Jc�&elY'6�p !`N6���unR2�l(N� � rR���-�(�#� *B qCi !Hu�����u*� �I i.�4�&+  >� k���]��3���B��< � �Ń2Q�!yG!�o-)��"4V.�?�aSsi⁈�,P�/2.yZ���( E� �r6 3it� o�&7�r' ment�~�*% T)�ar–5���huttlM�����Asteady-6rPlexclus����v2�o�e�� �n���Vch�e�" �|O:�#9�e(BdDF link oE�ar"0V,to!5"]��� "LZb ��*'9��r'e � �n2�,!�]s-P:�a_>=AE"�6�5B4 �f&Kto�er �2�yr1�mrHow(��A��I��ba *�../]#:[>G ��� IL1�.���tA\WT�.� �H2"� BPC&u#!t2G av��X��m=�?9u! >���EBz*� �%��H&�Dis!���!e>a3�/�a%2.��$���half-l�Fof&� N�";V !� ��" wh0�D(o=��*lye{�v|�!�FQ� � ��A��A�( �=5 h� us >30 h ��� 3D;XPsF� ��'e�2&.�2 ��0E�a��)OJ%� om u�P��� �*A ��H�2�E� /o��it�, 12 h�� ŇŤ�5-o' �GA�.Ib�)� 3 a�8,at 18–24 h%�yain�(+A A�.q���Q~i�E�&�-&(6, telo.�ort$:��Gvask�t�a�RTIM��Ma�1 mock ^ > ^�B�aq�^���a�Yv rsD65� "| �N+��.I5ock5B��'r!x$ Za��5�� J QI T~��I�r:� z�Bu<6'8mil"��?-�e� �1�em�ir�c�N!�"�2T�2*� �a��"}oՋs &k�.� p;'9/H�"" ^�.>-! a9HN���� �o.� :}A�:5�*��� Alo$�v �� �FB/ j6�&�.�~�y�w�=ed!�& R]YS��h-"h( q��) ����I��Q b!m^��a2�>��t��8!��B��d�i��2��N�C�O5� 5�I�)nϥ�+F�Y.�a�7�/�O�����U�-�"(%�eRlfbs 6"r8p��;!�dped ^?�8ap�J�10��Ŕ�qM��v"��&V {���.�!�qG9ZS�LR�A-es�7� &D*"�)% A.�� ��B�[H ��Ni��*d�"� 6� ���&;byi)EYsi%n"^ �r se p�im �Pt6~�2n� � E�as]�Y�� Of�eveI8 ��B�G��N� �sCo� & 2!�"XRt(� e �ʷ4!�F='5u�"3/�� 71>?6�"��5:C�2EzSpM�� agreSHe"�2& E�&�k�!0-cCP&MAfIƁ+x&�*nTt.hK��;5N �}�e�s`� diXul�j�@�� �&�$� ��p�w2AM! �)�0$9dT��>t(�Lye�e�4 +9�&it��eD-`f ough�/e Ɖ�PF�� A�N�B�uqM Coll"1D����BHc'bV��,�q az&�9 ��K"*6$�[� �!�%n�Uri�� |�&)]�� 4NŜat%C9 rk�~ l%����)a�s�.�J4 �'e�impL"by*�!B@)/raZ= �E�g2� a6����F����#id+ � �a��i�� :>�!(�9m�F6;Q�� �n�M��!�gA�2�Y�6;+u$�!�B/i�a�%�o=!�q�-�MCZ,V�$�.D%� �H��1wA!.�Y|5V2:so"��)�ly"3Q.�H�?64N #6��E�>!,>�NA�ge�&&cr�&bB@la������#YUTRÍ�AAUAAAB��!"�na�{f-�(v� hammerheaW��� ?[2 -HR;Qk��]�H Ja�] %*X�g��FB_mnt1���eCmachin 1���&a�.^ed����t�=sh85.a$' �yA�"&��"�'0  d2�8:y!�1�i,�}M I_GF!3�`u_��2��whe�u*S .q!�A%�r��y c�1aninr� -HR)��� n#�g�=!N�� 9&!*`>�>O aLM�.�8�tcha J 60*a@��S+!.A60��Y1& ,9u�/n�Asid7U7i* up|a�4�UuU���9��%A�min��� (�������eE�%�AT 10i@[��!!���12 IUt�c� X�F�,8' J� 6Ms��y� 25 dI<w%�60-ntj9:y *$���i��'plp�,��and���e}2 8, the GFP-HR mR�yNA fails to be translated , whereas addition of the A60 tail partially rescues this defect , and very weak protein expressQLis observed with a U]x( Figure 6B ) . Significantly ,�Dpresence of a temp �$poly ( A ) �(, but not aU4was sufficient! treinstate SOX-induced degradat�- ,GFP reporter�LD ) , indicating tha|� spec� lly %NPmRNAs for turnover by� . We9C8similar results)Sth�D homolog from a re)+Tγ-herpesvirus , MHV68�S7%~$To examineQrequirem!0�PABPC%� N�.:�97-A60-HR�AlTe performed siRNA-mediE�$knockdowns @$se factorss monitored ��!uability5SOX!�)� �!�message�6ER6F �The cells were also tre�wA�LMB Wter%whetherpU7(hyperadenylM<$ccurs on ta/ ribozyme- E^!� . C}e�aSy&scramble)+ showed2vjsP cripa�iF�yEÉntM�(d given ourM~ �E�B�M-�e machin�invola�in%fuA�3′ endAVm U��ich doese�})<process!�M_@HR constructs . KQA!I�Uis�s�u�A� �andF�, did �revaA�U�.�GFU�. Howea�,Y�� C ef!�ive� W-�RYEEM1The� �is ne!ary����B��de)5��Us1`ed�u�Na6�9�AOxot9Xi��>�$is already%� lace%��s�C$, critical coi�B�:�Wrqwed �(. Reproduci�all nora�n blot�?�Fa]n�ѐ�1demEce�by qua��5>ultiple�!l� (es ( n≥3;LS8�iFin� , histone �ar�� onlyA*w}*)� lackA�����aeq!_stead �_�aij@stem loop ( SL ) I�we�@recruits a numberA�A sameQ�I>� )�s�� �([38] , [39]���Zd�?aa.y� taini}1%SLx��� m elɘ�wi��A�would�sensiai��V��s 6���InteresA)������M/!iD��, sugg A)ke�unique՘may1� Aor mor��in&���a�epend��manner ]fac� �*[. T��ircontras oa non-!�}H�(( e . g . ,��somal �w��A�� subjecV2e�i0[5A An imN ant fuE�direc)�ill!�toc i�D 1�s!&QM� nder �likiS1�%�suscepti�Rto6�RNA��,A� they�a�� d7i!wifa�converg� betweene1O ion-9�aD2�pathwayK�.2. �a��to regu� �� gene:o a k�!5tq� lifecyclei4a diverse arra>  e�J,Global inhib" �pro� $synthesis � 鶅�to ens�_ maxiA4viralB�by �eEa�dresourcNoward��F���� assistE� evasa�0of host immun�� spon�(detrimental� �rep��ive suc�G( . Although�outcom} Yshutoffe�be"�  s(!� ogen��� mechanism� y us��! evA�is pointEpquite di�wct . For�=�f,AZio%� �s cap]b� � $by cleavag�eIF4GE��| [40��41vesic��sto tis!(us�/cks nuMrI�exa� viAL srupA�!�Rae1 funi�[42]A�� !3 plex [,( HSV ) bothQss s!��\8encode��F �!Fo i-4es cytoplasmic �$[43]–[46�u1�KSHV in} on elic��gI�e�"� �!�activ*e �=� driv���phenotypA~(mained enig!Rc f , we.^���4engaga li!^2�^ zaberr�Q�.���� "� � knowledg� �iE� firstUs(of enhanced6'coupl�Bh by PAPII��metazoana[We fur�vr �)��#� s��E�� "� Y�A.�A�qzlat�ofͪu�!g` striQ ILLlocaliz �dur!T:+. Manip�!T�is���D� *� e���Cqs ���Ej2�aBw��q!Aef%8intimately link)���d�9@��Uܝ�A�o��yetEa��[a2}� xr�d�X�E�.� �hI &�A�epropoq�9� alter%���U>Ys��r����e nasc �]���[qua0 ol*� . S� al!J�'ev��c�g� I�>^pl�a? t l rol� �"� �=�Feg,% mu �Kl de��ve9V>�re.1 fDN� U?,���promoteF��con^�A�A�N!�� stimaes%� !mer2�A� has &� !"%�/ :to6�length�t!�[16�MreA�s!:U0B�tFs� A�2�a�y+� at bypas}�e�end�Uf�*� can j�& a.� 5���d upon a*�Z t� ( "�. ColYSŹ se data s.�e�:QEN� a signal �� e�a�A�ex�$ai�/or.�%�fr��of decay"� ,!hapya/AsS���Pol.r-trigge%� Ti�4ll established�prokaryoA� such� LEscherichia coli [476B�ma� !� frag��!�acterials� n!�!DQ `!�rat0than � ilizEp+��as# ra)@in eu�w A12g��&� s��2S[1�I� egara�5 icP}�s�f ough� E �uru!m“land�pads”E!exoa_�]| Ew reby� 1their�g(thrp�uc aregio"�.ɥ��Z5"ic�aE.�!&re�o! atA *�Z�&wh )� help~ ot�5�tex �oly�attackRnd ���of�-q��1�in rapi�ple4� s [4Y4%�H"di��lyAktYQ��can8 5���"�i�!�"� %�A�a��A� fide�Kof%�=,6��� mpel\e�Slin� �.� ���� m icq s emxe�yeAw�� discC�TRAMPU>tco� S tags*P q�\ shor)Y-���X� ��[20� 22]E�de� accu�8 �.��m��A�� norm�hav�2�n��s' �op� ( sno ) [5� 5� a�"� ( r %pre�[52�54�}A�igenic�4io�"� s �, [55]Exb� a0.��!�ex�e%�on� rp6;�@ umably)�-labe� .@ �s s�m ugab"Lsurveill� &� �<* ._%�NIV!�m�Trf4 exi�n hum� ,be)�b b"� naS"*ina�analogou� �.HZremini� of�ts xtde-�on co&�%�l+ed β-inA-�w(in mammalia�!䅊a�h �$ mitochond�"jEc?� [2�kProper��6 !c.% 2��� into%�c��R �sASVhBi5ten!E�a.�  ��ŋo'�[5q><����=aL�y�@�*n�n l�:�� ��&�Xe a� �t�+�s[23e�2�WyNpredi��v2R \� IZiTR� "|ledA��)wd%� OaU%$u �Nual2~ . Of� �wmX� "f ��i�nt.�uv�Z d._|e�F�� � S4� = �.%-@>\�W&�(lay a major aW!C��d6&�pe �unexpec!�,!Y�:�5�:��afW٦�&9>�%�ar]D`.� !8 bulkJ]��y�%)beOaNa ed coincjt�f� C �5dea� "?upaC� y�)�a j�ng6�a{)�ng�*| pa�"h0.�)�t!�.!!����"� . It���no�, �ver� m�1m1�@ppare#m� refr!y�=:�sk !�5~icV[5�rI1 � Kpos�->%V"�!�]eBAeno" �al��mai��!yto+��M�>z�p.3na� ��y!#��en�s� �X:@*1�6�^G"!�� ���1� .��$"Y$beav!72�.���alsA����$�)$ envi at�<st two-3L"cenarios!�lp:���Jy��� desp�h.� canoni�%W6���N�or6�V -12 �,~ netheles� lVr\��J�;.$Q ����*�cP� Y�a��-� [� ) [5� �V�SL&��y� be a � bind�ip" assocL%� "'4%Qe(: B1"*� .�~,� ",�E "� qpQ2� ��� MKK-2I%�UTRa(D � ty [6� a�to��*�ereA cur�%noy��it%2s6t. S��;r  �_AR���$*3un=���%,Ka�onE�is ���B#e �#*;��C����*goal 2%iQe"X!eiA7�^ ϡ.i�s corn�/!@as-�is��� ��tle"���e!u� u  ,-��#-P)l.Mq}8,� �7#o�!��ehr�KlEly un�n�#������P� IMs"o x  w,!�a���G A�2Hed 3a�' �.1 PAP �g?a`IT m�!�+!cpI͉e�E�0:) [61]2(�= u:,��of-%�&M���,�{ 2���*"+J a5)u9c*�# nG� ϭ�a&����� # � fb�N* bl�� "_ B�e52�#8*%�a 60-0,bw,� bolster:A�onclu�R� %&f!�.�.� ifi�� �v[6U&to@0C1 , HEK 293T ..!�� , 4 ( iPAPB63]e��C5 ( X-lT"3.C3a��!#�esA �"� [6kOurYvs s*�")T��!}R@domin� 'M8-��SremovalAB��"�rly��. "�)�+��"!.x�Q�hextO&/"equ�#y2+�s)����1� bo)Fr);cross-�M~� :4�^;��Aj"�2� �� &*r6�of "�( linet m�C�v2� ] hypi siz7� �% � ��al �sA%w0�cO�"�����:�� o"�C1M.��#%��%�u(e*nside_�e�while �1n�+abrog\'!�B p"�!�A�ain�;.&�(!Fr mQ�s� �/l%spens� �!ұS�Z�23Rv�fc�ex �B�1u5" 2 )}�Y0! ͡�y *]#�9%� abou��!�undtA/c*��z&g s ? s %�xaverag�lf-live�m"�y ��0Klong [66��4� A��%���! �&�"�of2�5+� e� �A��S must*)�$%Har ��.���e� �&or � lapp�"�d#I��G��s;���?�T�."� �(_B�fgr� byA�mo��cirF&im�E%0��w�e�&*(\$*� ! E�&A!�clo�.�,model (�� �U��M�22"5�Jyev , un�?m��i�te�i�\d�:a*%�oi"�gre�,% B� �}�%^hI�fŎ!R�� du��V ?(e;4�,� � ateg1 me�1me���'-jU�� �to� w �5��.iaH�)5�!�"�"?:�~); e� )e���%ci��sHIV<(Ste�E� v�� [6769�!~ rotaO NSP3 A mpe�%�MhorM��a1�i ��. [77� �15��+group���e �01�st5��, �{� el�P?  ,:�e��l+aw�!��;���V��%�-� U�$�+�eus-" K�rl6!<)T!B N-"Yd�� i >s54��Iay�ico�o&XY]s follw5�~�(�!�V��+P.��/eE* �fA9�"q [<��7�` ű! limi�amoun- A�(K10/K10 . 1A0&�&�m� uw -���J��/.�"�h�)�+al�Rc���.��s"�[73�& 3�0m�2l�2�u%�ssu��how ϕ&manag�evade 2}1w��5la1seL7U�%�@��"�/5�6 capp!qq*s$��-h�,(A`bQ ')�/d u"s�m.<7;-��Cescap� C4? 6f�n uffe�#.�s �.� f�:ng;g�) /ful-w>� 2ui�p avig;"� �obsta0:`,,%�!�� _'!�13"n #&� :�, s�n7ee A�59Xle+e<e"9� U�wfaI�|iVEQ�(dmKlevel} One�^�"� ��A��emar2�)[P#nz:��highly a5 t�RnoncoOPAN��;i|:�l�%���3*L/79��(��he EN:n���!��)post-]:!So%m�(-p� W�-1rN� d��e�3[74�0M� !=��&� � fold�to�E 9I4�2:%! box H/ACA#EAHi2 ��1;%� mole�� ���&w� �!�!� �� ��"�5�de6��!*'A�!C�T!�[7HNA5 chal-+�*A5�t�+&�2by-�Z"� st� �E���2� task%.�8c�1!���p� dau��ĕ�B'heckp3�&b{+ed�n ��! !,dis�  . �;HRc�=b�~:��AAUAAAe�����'d2EB8N1 ( Clontech ))� a hammerh�!8%8(HCTGTCACCGGATGTGTTTT TCTAG8TGAGGACGAAACAGG�2ya�e; �4NotI/AflII-fla�/AF-�A�clo%�APnneal5 J�oligo��Y=]:ha��.Y �?^�U�??��` <l��) an"Bfaq#Not1 siv"LHR��for�5!��<rse or�AI9,�� � �hisSL��^��;;�*�q� ( HD�U!( !�A!�TA%�@TGGGGAGCAAAAGGCTC%�CACAAATT#AGTE"CACGGTA&r  � ��%�]Is2�QiaCDEF3-� , HA-�5AE�9n !� ,�le-"�m�00( Q129H , T24�!P176Sd4]I{de��> 4iously�3E L20/23w; geneU�. PCR \ then�,M�EcoR1/U�f ��6@( Ameri�T�5Cul�TC]/on�#���bj DMEM �"�<�$10% FBS�elo;(-immort�4?icrovas�fend��ln.( TIMA��Os [76-0zR EBMm4edium bullet k�̉�etics )�Q Oĩe��!F !�iv?�Y,den�al vect&0A? switch�$� RTA�R�[77��si��dup48M�D( Bioneer; Dharmac9�Yag�� C3� ingku�s:� II (A'es�2 NM_0326324?�<#1: CTGCGTACTTAC���J, E &2: GATT��GTGCA*AA;%,γ ( GenBankVr 2289e& Lr�3AATTCTA|TA rγ&rGA��k��AATrB)zs 0256�@sJQ CTCA�� �M & s��TCCAT�� AAT;E,aN�v 46432[��G�T�Nu CTAT!\��t!�. Non�@� � �) �I; es #{ d #2I�purchac�Amba�.><e� 8'q [M��Gf\4{�[ of 200 nMm� LipoFaHF02000 ( Invitr4< �1at 48 h%L24 a1ior�DNA�w �| harvwd 0afF axF1\ o =aZa��in�&�'in��u hybrid��F%:yp�>tL�%2 ( dT )Z^��=ofluouJ]-y� �sa�/,."U*s�Q4( http://www .Ŕ,erlab . org/� ocol� �72 ng/µL!�AlexaF� 546"q.�4-dT ( 15 ) ( M" ProbeN. A%�-:A,6�incub�Ne�α�FJ5803!� α-H�/,Abcam ) prim� �)bod�E�,1∶500 diluA"!g$2× SSC , 4% triton X-100%�3Ant 37°'�3sub����% %� 4885 goat�rabbi�]M8:�R&!��qYDAPI-q#�&$Vectashielfun. ��(or Lab)sIFA &gJ�nju� �V�M'd�2@*}őI%-��)�� 2 al.�(F�a�10E10L3o 3�/C69���Q � Dr $ . Dreyfus� fI �Q5�j-�� k#39473�rRA��5oE�AcA9�lN�e E . Wahled25]��mo54HA 12CA56`q)2@AoI�i�A�a\.�:�orA�mo$&X}u k!:oR�. Lys�M�>pre�+�RIPA b�d ( 50 mM Tris-HCl [pH 8 . '1 Nac')1% [v/v]� idet P-40m�5% [wso deoxycho{ #?2#$odecyl sulM[SDS] )��q��6o>&4( Roch!� . Equival�3�^ each�� ��&ro��"�I�o���� 9t&� E��.���g Z@JH anleyEPAI 9DzL�MVirtanenN2� U5F�1 NOm� ( 2 , ADA�o�K�^ JG ( se�'low6A���HRP�Hju� dE�-α��orr�Soufnq techn_Py A�& .? R���d!� sera)�raie � lt�?.ENina0Bg$-taggl ull-�th�jbynd�:method 8% �(��KA;.� :� e}KJA~ElT5 ng/ml leptomycin B (�OAPS�C )�,6–12.� I isaVD T_ T ��_ #"�QBEE� el-Test%��F4O on 1 . 2%!=rose-j ldehyde gs� pv"_S32&7:� "i���!&RediPW$ II random\e la7azkitsh|. Membra(A%K2+:�an 18S �cP loa���� �Fh"�� if!D� 2��Q� %�\/n!c�=%�PBSeMrto:ya 1 µ%�Actin-�D�(ctD ) minuso!16c%E time�For"�0aE stud� (, NE-PER Nuu�!C*�ExtA R�%�5K%oPierc�Por Paris � )�OHdGor%Q�manufaE=r'/ 0!e �� A �Ndi�;i�),AI\3!�&:to #ct%�err� ^ � 5� sogq�.i��@ath4K�OeMVsu�&%`4%�*%� Sed J��� r9mu� thre�#"! qP�aly��e/a^, {��M 4�A35�T�K�.A� GTGG�C�AG!� long�Qa Taqma<obedFAM-CA��CG�� -BHQ�� 7Rib�=BP Co�E���oppl�,Biosy�� E� VIC-ŋe�2 3�G�!�>n�-�"v�Q.�P73no�Favail)�0errts�$!�in��� �N)�Ko b"Gi.abphyloc�2s aurM4 Pseudomona� eruginosah uc*\gy!AZduc�F!�)RM� lungMCk d,B#�iO�0�s`l�$7-�-�null mic�BaL E r; . Im�: ��G q� �)�%" logy%��% �rH �pro- vv5ti-infl�,E �"ki� -air�'!��epL9I 12�,i R-21d+STAT3An�MngUuppT�#�! DCD4!d���5*�;2�!ZaB �$vivo 18 ho]&�qd��1%ge�m �F�1K� �i.�1祈 wildi�w(1�B�����Y�USA300-,i�iQ9��)��%���2-1�!\Q��sei�s.�%�%Yp pneu�Ga-�F+� M4�bA�%�!�-XN�zV�-��amia's%Goa)�1^ sub�*(%js I , I!��IFE)�I J"�.re� �UIFN�.�U!JA�*c �f?k"U�2�of !��& geaB!��i�=Vat�U&C)��#pcRnB PAMP�$b�$terA�9 �t�.��� es�A�in���'��*I\�O�yR[1�,3���@!��~:/ �q\�J�4o�&2W��Bpe� o)"b5[4��<x�40y$-^ ofZ pul�rA�q�1�5�!�4of CXCR3 chemo�!bT-!G!Crui.�3i�A��a� GZx/$=^n�i=�=2}�=1�-�PAA��ata��� o*b"Iu�J�.ke .�"M!�ubi*X�kE.�-α/β!m(AARb)GI,I h#�m�,2��+A/B%n 9�P6�mor�UY1rm�Q�fC 10R2O8R [1�/21A�F"�=Y�M�a�A\��Q autocr4\ �!�network�w�A)u�4\  Z /O��1� JAK/�lNAhA^7QG�6P1�!��9�E seemd+Dtwo;s�D dund�3]+} �qHowd*C# �ia�!�,.Aerib)~!r��W�2� a)o mucos�wi�-��śKi�Z&�.IH u�MS)!��C�� site(L –[KJ(`�Z�% 2S�8 �y!C��ap�!�/ B�YO*�  b0!�!6<5�fd� ��of�luenz*I w [29�3�1LV��h& C"t:f�λ su�M>� MHC )V�E2wNF-κB-bkNA�n n DC�R] �Jdi+.nti a��)|,relevA�� A�� ���-9�[3dJ36a� KFY�i�?�( X6�%Ey�Non-�,*|�:x76cap� of&Zp �;A�6� �.�K7 umor�1�1 g3���O!�%]�T rogr�)d7�+t�!1 r=� )A�:7 f grow kaV e��h�"� 2%&�Eron [�O6� ore��?�.A��8})C�d� ��7&{QiniQ-w  4� eIF4�(6�P$y-�"R bl"S6��0p70S6K+� �PE�of k �,�in}degredI�x�)�]v81f27�P║I��2p !�� :Qtol?Zk���xTL�v2j 4��!|,cory# lipoDsaccharB- ( LP)6�9} n��c����Sa , AE)6�T"4>��]MUWYx�+ C4C�#y&j T<+�%�mWeL�ԅG >-�.�d�Z�����Ko;�0e_�/E�1.7ED#b���M����a� MRSA)\ . *�,8�Ffm!/ commkQMD�v�hlAN.P &� [37X 3��(un�lat�)�e��% �uM-f�� ���A*�L_6o�icr#TMC�Ds'�`&+:K&qpro6Lyt� q0. MG.-J�rq0, ��rha0n"aFo!�Y �9���;&c E}�EB��3��y �s . In �' �2&��7sJ<isLd"� ����>IhE .�g�B,G. &0ms5�X)a��� ( p <A 001 I�7B ** ( WT�.%marrow"�de�S�W�A BMDC&�4�of2e Dhea�,la�m]]ichRurAvLs�2�.:�b�8�p5rq9M)�w] �%�� 1�E@5^� OI�,��!AE6a6��$( p = �006=,inM�−/− ��S ��q valu�3_ !<.�L���6w!�3ed!�C57BL/6�� 8v�qnas�-%�$1×107 CFU1�.M4m y�6�by5(����of WT r>4�]�|F��inr)�6�>�m�on�>s5A�!�1�rY�E���*�2��. B�Y�9K9a�nGm��q����0T c=' �J�QNB9%�"�%��\ol� Ux 178 �"Fie)CI� � ce')u$.�� 9!%"�6�few�t� �re2����>�0a%!�|6E'.ofnckID6� nt!. L�#��� bN5Ito WT1J�`,Y�E� `��$nE�s�c�7U.�1�.>+, macrvG,��neu��wr�P'26-�F )4�52 Y6EQn w�U& �s!D����;a aY, 1�l*!�=[w-gdu� y�}phago�6�*�#�,8x.�6+$a Jak-StatE�� casc>[oQ40vW~:al�!6����!a bron�al alveol�R ( BA3qFh"@!)G��E��4#m0���Zby ELIS9(*�x>�.�5qu�sa r���u_/�� �5�� l1{# ���� "�X��a�)x,) f%i�g%rKC�"���, GM-CSF2@09�!IL-1βF �;NTNFa+0).5*BJa��HٯiK2^L" A**"IA� MX1 rbmE$:rTFU*P& p ; �nfi��g z�� �9���2�S� stal&yref$� �JC: l�R��*aof=FEeed ��S!��]Xit LAa��m ��k�Br|� zp�^�,%�is_�N2'�< q0f� �acu�{� � �<�}:y� Abβ��*��injuryj:-&� ���6�de)�.�+RB�ed�>� [1DTFcJ%e�wZ � }B i@�+)�|"l * qi�2,� �?��!�Anakinra�P%� R+, agon1a,& o�w49�"? %i��is ٟ. Nr� ��.$8Y�� �w6�lo��)�>�336*� 2� ��> 8.� 2s of9:)P|"!Yo�*pre Lr 5�:���I5% =.y)%�s Aq�2" seJ�A8)�d=�F�.r�3 Fn,FakBe���VxAcβ�XFshCB�V?�|:��i��"*ld>��2lay/T( 16HB!66cZi�8 &z:910B9:�M�1�3��[3�Si� ).��]�:- !�j" we te8��Fl �$�)Rv ��L,nin)$s��1Y�1I�E�e�rB�5� m>�#i�in-+:�Ia��*/ &�#a�an�ɱ�B~,A�)\�a ��on !3"�,c%M"�to��A� expo�w&� "teF�Q6�~,9 a Gram3iD �u�,h E��&9Y j>�$J � ��X-csurfa�%2L1�|SpA�!f�rL TNFR1 [13V42!43!WqW?�Td SpA- 4.�won'zm]RZ��i�B �l%��o =zV�Q�Z a�}8��:50�=k�zU�F�3T�/� U)onship"�V)*�I���-E�ed �jB4�V�e2�do�@�U2}A?&� �Ei��by!�2�IgG�*�:2c 5A� ����An,� eU,� k�6� N�� 7^e�'Z�WT%[e :3 � >�a<..�+��Q-)gG�m���,in�^~���Z;w�x:~6@EA�iP.C�p"y��re&*�_ )��l�2eB=�H1!YP��16|� I�. �D =inX}Nkg_*�) �]Ce�6�_ "�=�c* W�>2�4�>�4��. ��=~|/*{�hybJ2� .�rvd9��"P.] }1@~q�4�\)~J�t�wr\)1fUNKtA�WT jr���0� ��MZyB�usB�Y.�B^f|��iY�,AJ h e�X�a���G��); �. Los@mbs"�M� 5!�a"3� T�]Kby1�b2��.6Tat LGne:P�x�8�!�}lea"�-�]>z w�je��2���:��1M��*�ly�organ�e�r��.�4 "�2�1�Eu ��2�.vWT�`�.�>�q�� #n��K�C�'��<"]oE;S� >ui * ?s K�@� 1β !qt����U�!�] �7B/� 0����� v3"�:����m�d|[Ia��=G7� nd54�]th�<"d ���:�*�a link"k 2!E�B{�B�#ortE��� SdG v�?!KC��_* &PP,a]h&�_+ �F2?( e�%�$ q�Ip$ : PAK�r�vl$a�[�"k,N?�� ( �2�ofr� .� .�"�.�2�� U�X . AsS�N�in�wR�, lf|Q�� .��U:3.�.a�A)�*+E�i_.� �� !�AN�>h(e���q0to��H�N�e� .� F�:� 03�9f�7J>:. 5%}�d��k7� �isA!�xH� �-XL an b� f}� .�"�1_>��15� >�>22��2P A�u6q�f�.& n%6x �%�� LFQ . N�g !Q�,bv>$��A2���.IF�.�A. P�1��E�cq`in:?}_AKm�B2�01T<o�!�1��R��@r�D:5 �*$�l���0�h�)A or ���5F%�5�#fluid�"�>���( �9� ;FJ���_.5i�aF� �j6�]� amm�&yS�\6k!Iu %�!�� �ZO.514�@A�>0�6��CA�Ki�Fat��:%� . 6�h q>�7&�!?62�:�13 M% �q�e.�&� s��X*K . No��a��s *�6 .� \ ;�'& 7���.nt�%UVd�A�%� r^l] �26�Aba��j8:M�>#+͞troa-�O6�� IL-8.�:�06Q� .��U:��)�96����g��=}�y�:�12�:�.�,*�" �"��<�i�.+s�ofI|mi�/R��%e.�Elty$&�5�=:�� �� A^|�N�-�E�>/32* �>9m�%�!{al�+U�U}j �}���sligh�.Bapa:9%"�nbk��o%��>� � ~"�W 8,s/&`�DyA r#e]547�B ^�1�-q�F%�AP-tS*?0�* T�0f�9.(�/) +�*R " =\a�ob�/a�/�/�734]-�"S .N �@6�iN����E&3;Y�0K-g�En�!A).&55F��-�C��6u>���vo� UJ})�in.,JRBI���' UjňJp �#&c  ����!��H�( ЍFO � 2I�b_2"� e��j��3BJf���)��Lmod����;)�,�8�%^��aedQ.Me oty��] "Z .�-3:.&n". Mh6;#��r memb���e� �'*7�def2_BL7A�o31�%>a"�5M�e55�4"��&y3�P[4 1�%f�q^�"�1#-a�ɴ��*�d1* B hepatܒC�u&n�hUe�6�i1o:�(e��9�X5k(�<�(�CEg�cl"�6ki�-h�P�:&}1B Lisb���� vR���co`�h gsplo�!��.r �� . Fi���+�D:3 �-O�S9�0�w�2Z���> E�"78�1*= �b�<, ':In�+�|% beneficE"�8]9 � erad*�=>�,�m�L2�IY�9epr!g�Pa�B� %.T<�0&��58a��%Is&b�fc��YY�!"�P�@ c�O%�!�2]r*��O3v�c:���.�'�c��Q��02-AR%$�rt*j��E�iQ��Y ba��" pro%F�]�s "f�. W�s!,me � �2�milieu@�sR�is un%�.O�s"��a�� 2FSA4�? modu< U�o.*sR �s �v�[4(O�a./��t�-a rA�:� '��de�|th%L1ԁ�exC~B���-!�7!,�%Utoxic)ufas�=ė- damag�d! airstPI�͸EA�E�2Rf�327�I"�*o�C���"�o�w�:�%&��5ca!� arge�m , uA���RC1!X >/�Q�;2�"!�� ,<>�e�; ��:�J cr2u<surrou*D����s�<��1��:��� 5.?&P"�fhS�f�LPS,�&�$�!r�L"&�#s5VFy#,A��=j]:C*�FsN�.n�{ �t�P al.�A;��.�8&pjpFqF;@!�D<i>�4eD�P6TLjClsom]��"�*.�gb_Aλ!zJ~*����6R iP��RhQ!Q�� ri�LqZ sP!|ch mak�b����B{i�T�oclu�B!#�V�!cWin TogX2�=yMiT%���*� haXF0� ĝt3P|.�� [�D: m5�&M,"1E�7Z$�byq�n[ u�im5�� ���j �A:_#E�#skTjd��z�>?5�G57`3�ly� �"a !i1�� !��l*�e��E}� aj*! %Mbe#��Lj!>c!irE�-�+F�&�� e*+,g a$ to l�Ul��c"�ne� ߜ��6T��K�=s:ѣA#�1a:2qG�#in��1� �DU5en�.� *� A8;�����s�� TO�0dm�Ս"�by6i��&A@� ngj���� ) 2 C"1Z�S ��tF 2O �paUd�����"�� �>:T5?X +*Y"�C>,1� XZNv&�a�stron��./%�z��.6��S2�6P~;E�. R� &�x�#Ek$4:E&o.�:%d�Hv �)��186�,h'�IE5)�Ř��!�饥�Zh��&����m�;s1NIAt�"�jt3:�� .a^��G �0A�m�&% ���D%�_G�:��O'"� �8E �-~p�i Fma�J�d�!(� �8�I1kt��X��)q2� ��A�('5�����pβE�^p Na.�L%�usm��i����{��EqEX!a�3to�@!�� sa{ch�l��ve�5.�\ "�O&�Vd I1&o~�sQ0)9h u�xnWly�$��m�DhHZB�>*on 2��re�pg4! �'!i.�.>t�MW�*�'�~�gu� jRm�%�V�"�QU�1{s6~k�5]=�cE>�!�AY�'N����)MV:�A��@ &m �O �:�Ite�!I)�2��f���w�z ��� eba:�}�^% � H�x dM�=?35�-�}� ����8&J �&��p.D� �%Os��oM"��� f�&iD��� a��*L%�;�i�ZŞ��>��ipP�< �ZluԵat!���eF�<d"M�.eA�Y$-�� ex{u8J��?A�ov��M�* I���9%ɕ)��Kf)|"T ![A�-5d�� %@��2�5}8$ognpV%LQtnt2�35�Rix�t.��8R�C&!�~=�%at"?R�Q͜kct�����ip�-�.1\�fS\l�q1����m~ ��W �in| �!�"��7+��>� �*[�m�.GA}A|e\enZ(��^m�]q� &�.�� 2 �D a ce�)�V ��S!�&��AByY�e. q�!�thd>1��Z&& -� �!Y��ua��7�!�� A/)r( *� � b po�/�ap���Pk:�cse�E.�? �!#�* An��1V�zO tudy- carr�bm!�fFt�Yorъ�lr{:men� " Gu�OqyCA!�U {f�po�_ �5NN$al Institu=of He*"�_ 3 WelfXA� nd US fed�� las�`#�r�ap�^{-ed�W2�Committe$H IACU�$�Y(olumbia Uni5� (lCAAAC305"%..�Ȇin LAC� �:  %U�4An� Luria-Be�mi.k��3�r. �� , LB�Eth%inoHb%��zL�ndhv a�"�f, �ce�ecE7eR �3>to OD e`n(.��G/L�g(��y�cuqzs �6L% 2Rg55�gt�}�mA�q�E�.�Mex&ݛ.�V$n week old"QL,­��� $ A�e�" ��#{L>x5�h2 F� ( 1*�./m�q)�*t &Jz[�14�M9;,F�R@�PN/o���Brr}l M�?Squibb�ZS/ JackBdLam�Aj�<."g%8 recef- :|.�C!��!�&yR�D� a� , XF��S�hr��br�m%�A�BL.�WSo��nH��!�BS_ �K�x�!d�GZ.*%*�Bi . p .i�AHD($k$mg/kg , AmT2�o�:dxA� ��ed!!&#th%A9Y.][��C%%�L2"�� %��G,&�-&y"��y����hto&�f*U pos��N5�*]�u��O. HE�Xd!g&�Rby�~B�&�l&J/c�]onXs fixG4%4a2�p. B&%R-�&R%S��dibK- !6o&�@ (:�aH���B�&cCu�66�Y w�. R(cʫTH�(� F,in RPMI 1640]umI��fee{bov�^erp:�$�00�ts/ml��nd��e"�rA��p)%2�@nM� $rbol 12-my����13-ace ( PM�.�� H\�g\�IFN2) ��. On-� u�a��4-(a�rmo Sk�� dT��F}H8Bl)�iFu��rBnacf � �#.�pa 2�pS�%��)��&oM.[ uRHBCalbi�vm��� !�hEd.��iFN�L:��In�a�"��z�A�\���@( 4#p��Q0Santa Cruz Bi.�uIn�uKv�� or VaxµMC>� DMSO5�%G appl� �o6HBEs�*"Ko�. EnuЂ�kof*�P�7(HCII−Ly6+�).�( CD11c+%.�vD.N;.6�b��F��02"3�Sax]Td�� "�O( R&Dbi"�n,>�� �e�nac�n�’B�AG2s-���tiir  �yk�qI��E��:�W *�N(�3! A� -β-B ��wp~f=  R{c{}�xD\rxdYperoxid�]��E��'mea�F�\Ce�B��m+ . P ! separI�,���u�~n*�z��B2�� Dee�ometr,I~��I�$J ( NI�, ?�� A�:xmirVana NA I"UxKvL��T�y��)r^F�"ea'�r��v>x$High Capac� +nqTH`�/!� �A�(A��!A|. Q9�t��real-�4RT-�r( Q �(9l)BPnMSYBR Gr�*5Ma+�p�  Step� PlusɃ al C��r (^�ME�!+��iL%�Hs – �TA�A��rC -HsAc+C��CT�CGCxs.(iM6^C5�b�AT!�CCxF_#dZ�G,�.��4r-��C5�w CCC6�- XTC?tC؊G$:�- :tG�httCCA/!-CG��!�GTTCA;�GG- �. �!L)�}�a&*7xA�y�u4n�UqMbLrunMZ NCod}$NA Ѩ-S�dI� Synt��.BI��i�A� )� )i�wA��dR"%�z%�w�'� ��{b�)�!�o@%�q�TvGA9�u=�ΔCt �\e�@6vv �:�eU6 `G!�GGA� A�I.�9b.f �*us� a^���N],Kruskal-Wall4es�zR��{# -hoc Dunn�#-#5Fc.r&�)r��X6B-N���LGraphPad Prism softw�<; �de �d�{p<)05)�,"� ��uC|��+m�� �%xf< ��n�{j�V�K ba' ,!�AE&nI) .{OW0 �*��Iro�N< yI��2��seW risk"�50in 781 naïve�Y�adv! age-2 sl�sickne�dm���+ 1989a2012 r5he&JRe!�A�Ce�6e/FAf�rypan�xia�' ( HA a, D;"�"Neu�%,gy , Kinshas20mocl$c Republic Cong �DRB. Deat��mU vari�%�a��g�Hr�ur��hs$gqBct���Idy�R rach� idcliƭ�Du�aassjvO�UdroZ�� �alAi��djdmiU�I���#ݻmh��F'@~loge8$Vi�0��-�m 2*�5Lpr� m�17P��s�ymelarsoJ' schedul�3-�8I��3ven��/ on 3�+�.�t G�6 �/��w��a��-Z�-v!-M�!� o, ARS $; 1y1%����.�*r secuey��(trN�at ]2�x�@, �c4xf�-P� eflornit��u4i2D00\ in 4�u!�H3$day DFMO B 9�coNEC�sea6,(6c�(7Isn,.p2Bp[ o��ni,% imoxO10P15.M 3 do��a  ) �:N ( 36% Ќ!�u)��" s���-��>at��s?29be2h!�th�>�>Ws8e�?wf?��nd1 drug�kkepɰy�o {p�( 1ˎ�,)�T� adju��g%Je, 2th odds�xm�asCs:!y.D�0[ ( 95% CI: 6�5–1 �A; p = .E]g5dys���ve%sim2�X:�)>Ha 142��3�a�3i��1 �E:9799BJ 18� JL�1 �A<�j# parasi��� _�j_70B_03–�82)38����.�2��a"C ��suE�s���b>K2�(��Ht10�m� L)F=>^6s���R�8��B algorith��s.>���Ő_����t�o%�&A�b�~�<;Rd&`opIof�Y�!�5to0|>Rq�ؠ*�AT%%i*a�ex�0�epidemi��"�K.5�jUh!"l�4�3�4r�.�]�#�!Uef��c)�S�5� A�&� 2� [1–r%;pr��Zas�,-� ob���)��F�ZqeN�ͫ�e��anyA(6@i"2�NliE�� ���R#!R�!�]!�!:D2�amo �"J�o:s�uAJbe cru�:[�M1]M~a�vA !�%��( *"i��y( li�At}L[�q~5��� iodVg"��� anif�lo� Se �D�' gambien��orL��P9ha ��z��!�tֻ�n�M a v�; a#ym� A �`f��ngH� vA��3q��"v�!�e�z�d�ph� nerv� �bND6PNTq( �(EtV&Cl��:al��R!� hete��e Q�atI)?��m9Le sumIw!�Rreѷ>�W�o�:alert� B�ent�sturb� � mo� �� #57,  �%6���A�q<8nam�5If une>{8a{�U�� "sE %� incorogno�� ;`�2�a �Ned%'[!1�Q18�E~W' WadA9Mnew diae�Deaf�{�-to-take�c���WHO%�pl/�S-mai$Wg �lHA3Zm�y�dndl�.4�s e�9M�����sm@y�fA�al��'�� �:!�^�4�;;p�9i�(.�9Q�maO&�l��2�aj��i�PI)A��all��8lSDbi)vi!�sی[2�ΦA.k+Ԛ egic��TIfi%gl�A��*���' emph. on Mϡ�c0��"D �g!Bj h�&c��'�.lau�kngEins��2�U|q� ± .�;� ef6P=ar��� c�?� �-�(aZE���s%TH'idE a!� ndar �ea%)�A� . S�E*hMUf&��&[�r�*�� � scale��eru� Q�$paper draw%1a 23-A�-0ri�A�ʧ�`!j"i�-{a1��� x!��W�s� !n� cE� pre-� E�5hallAb&� � on.t a. S�܍�� ir`?!�si�* �N]B!�(6%I��Md�j$roscopiIá`)�vvloo�lymph jum9� erebi$Jte�-2U���!�let���<�� ~#A�1�[AC~�!8{�on�� 0p�._fogx��fI mwh� �K ( WB�cl7N�(M�mN$635Fs/m��d /!-hR�K�!�� � > 4�dI Biuret�$ ) [23 , 2�'��l'? z��rou�z�ac�cd�tCNRTHABu�I2parE� �~�_st�E�� ��. Cf�,�15������Z�la��t�)��>�)�( S1 Dia_~ F%!.7=�w�h��7"� . In&w8� �k��B !)osex� *l_� :pa*�b*q.������A}A], n,B72� iV�dn�>r2;�� � � �a bi-ax��B����A%n��pW! �nt  >�imr6�js��^�SsOd� �.&FC "�i!��(MM��sw�%�(/al �.Ց �9�X ��f��+'��filS �.��n]�erWr *s�n (5- items: beFB�����Ta&(�.XN!��L�iarchaiE flexi��R-!P�b�� gras��r ��rigid�(( cog-wheel,�� -pip@iertoni�,�el=u6� ��t��rF dysmv�a diad2� Hs wide-Igai�dys"( choreA��to�Bor$�hemipaٕ,�WoB��,�k!(ff%a�3weN  U�m�,Oh1�N���p~�quoAItt ,�pb�I�abr�hM�}�6�h�� ��t b �( TK�bKlEͥAY>R)gu���ele< �"�2GPㄅ�N0aŭe�Q51�:'b �i��N(>-v )2�fX,rXf�$As^](w VC � ,g�9f"<�as��bto��0;��2|.v .2�Bu()<rt���2[2 �6;�e.�at ��(���2>~#�)�7 �9;�6oQ0��A.� 6�m�//PFJ�w*�7��(Z�N{��10 ��E.�/* 0�sldoz�as1R p�n5 void*o�th9��P_�Fela��e 2rser� kre.�^�%�A��E�2<].P!�degh�%�j�Mjʅnf��%1�sl�a nasogaD7 tub�EDat  ar .l &h  �n �M �dichotom� u%Sarbitro� cut-���"X5��j onth�i/WBCw-�*m�� � �!t��C��Bh 2�i��“�?�� tatu]��“}%n#p| ��&�E�}������T{6#he,!V!Ro2��%T�LQ3���W{�@�otoIaB.�jb�!%��Ba� �a�I� M�D!��2#��fe+*�Usy"� g�un�9 E�A��._ p s 2% 33�@F E5he*m� �!��displayE� L �iOX_e'� {� �i�Y?-�n!a�� W102�!� 1% )��(!ann�'>�? fata��!�s -r�� ���>Ty"�!�(3!mno A !s�ob}a�I�(��&G oa��of�b:�� a�The.�"��,Hg�]��AA&��X*g-j��K A��u9�29M�j . Be�u�P! =� %���?�Zly����� 2N. TnlaUt� inI+J*�Gr1�|����=E�h" s�nu&o�)���(�j _h�I"\9�p Xa.�#6�'#"9 ,,>�&106�&�BJB& �!��@pA'�� >�%NA 3!Ne�eɿZ��$ �@ysɒfa iI��EZj����(Likelihood-�) Chia��e= 2!41;�+�~��AKtwo2h �R6�P�on�'=%8�$Ő�~."�,A�i42��h*�́��lyJr( � ly "'2�q37 ( 8䮅�E�ELhj � �))!ǡCp"�)�F a�s*�!de �(b�� g2�M�( 6!��'Ur; �L8!7�h�vc�+a����6��i�2'%�mpA& . Di�wce�/�YB� we�re significant when comparing ARS 9 and `10 ( Pearson Chi2 ( 1 ) =<. 29; p = 0 . 00or8tand DFMO B ( Fisher exact test8�F18 ) Overall univariable regression analysis indicates that death was sӘly associated with the clinical status Wdmi aL, presence of parasifin<8CSF , treatment� imen(otal protei!Hncentrat�,%WBC.G( T�5 ) . A �/ models byi0group showed �,only dysfunc7 in 4 (s (%~9 , 10 ,)�A�-�) high ��V� in 26\10>Kwe6PJ}d%��6 �(fter adjustAwfor�,%ufollowodds %Us q$extracted:�h. 40 [ ( 95% CI: 6 . 55–1 A�IqA�0]nU.Lh( severely impaired initial1M@$) , 2 . 142|1 . 3|3 9 ){1 {%{!q$idorachy ,799BJ 18� J7.J1 �A؂�a��76%03–�82$38�cyt �; a�in relI�to-�aa�4e main outcomeA� multy�aq�a�aZuPE�$s retainedBl2�(���U��M� L]�2k>6�62L!^dictors�6�T7 ) This study expliciadiscusse)rol�WUs)�t)E2�$among curr�gisk fa:+pNC 3 k )��B-f6�<1%e�5!�5% , reA/���Asampl� ze�� ��sA�2e �gI a{ݐre��2����t)�tendsA)perform A� bet��t���!{ t least iA�ov �$be non-infjrA;effici%��j�zasier *z [22]E�,low in-hospic !�:W_ste!M�Emby Ali��d al (�A�� or 1v684j0 ) h� �nU��aka{into ac)�!��pro�� (�ie�] a �U=cel!�A>�1T'� iL:��� $n children� ^ s oc5 �de!2e a.goo*V b2a��n�jU2%tA4h stri%2f at��those un�⅐��O.i!�me� In 3l80a�of%Z376�tl �*g i�e�� erseE�� E����e"clear�n � phalopath� aI;��aE�^+Sob�r�a emin4�periph� nerv ,ystem involvi �culmin&� acut~ spir��y�et �1%� who di�� uddea���c��b�l% F %�. UYX�\giseX issu%|e actu��I �ved�e�.intriY quese}of |tox� @y [1–4 , 7 , 32� an open�ac fur�aM arch_� up�nowI��re��r� an answerawDiI� situ�R�jni�%�Eu�0ive algorithm1 �one u, � �is essen�!he��cesJasngC prob] :I��7pro"��oUZu��� s:Mor����F K[2!_� A �bE�� ��Vei!2z� ai{ 2�.� in � U� day�.w!E��in k omic��� � athave ���imp���W[1EC}39]���m articlesA�l/�1#e=�A@foc%�on.'ge deter�X�� �  ap��r#)�allocEe [3� 3A�3K40!� im��q a�0:� FSF�ski ligha��he�e����ex�U6al anim�{demon!0�U��ts!� cede.(changes� a�ng)� invav�(rypanosomes!�! Fi�m!�� auth point��a need)nn objece�l")E,�5�� i��N�.bouLb� ttA�E-~&�saf��s"� t!� both b�E����above (� � -independa� oralE?s� ) [2A� . SI!�-� zed b�.�a>!uAhth�5 cludL1�!Hs borr�e�lo�.(ields alien!q�� E|F���Glasgow��a scalv Karnofski; ex . How����tex* �i��B!~ty�ive� �1� " �the���l���Y vWJ� Vs[a�26)��1]��2z� �&] inflY %�5��uTA{[4a0L&� tack��&U� RW����o�]% ��� carcyTwo;6�usa�a�A�xe�B�t@�Z6n abto%�ra ory��ult� 8�8In 1993 we publ�!Epapere � link� weA��umber��UQ�!}sE2�a�"�of!� ge-2E�"� ( 19&- AY60 ad�)uq�3.� [19� -�E� y ada�a {a�W !�Uid���7cedur%�� ^ �n�a=rrect.4!�O{a5� �C�whom eeMf selGJ<a�w romi by lackgcollabo\�\ o�s���!��iwh� �+5e7 underr�3�� meri�_ ]1His cer�ly%8ݿon��pr2P iZ�i�D��qKAg6J1��I- . By!�pe!  H z>7812+s1�,A��n w 52��'*&}�Vd&���ate�M%W~�ti�~�pat���  t3 t{"� ^�u�by2, irreE�e M��yE�. Our!?tocolA-%tB�}A�1Iremc��� ste. war�h� velopq>�i�Oa�validE|tools�aI�ehens�� def�on!.s>4�� F�� relev5 � u�$tailor-mad>G( a�g .G�%d. � t�.� ly epp�e �!�-�6,U�rinaÉ(ex� �epidem&^ rw _�urveill� !k�ol� �� er= rial��*�ew!_T��)Y�!^ide* �ycircum!�t� imputabiY� (harmacovigi �.��Iso�o� foundly!�s !l behavi��Q � In humansA�M�������health� rosophila�L noga���a power#� As�P�-f tea �-trans�B�&{ , longer-� a � !Kph fl� k ampe�� he� �a(!�rel�"i $. We builtew ima� arena2� �exi� trac4&�to^y�"�& �siAc,aneously . Nd ,a,&u autoA� c cl��#� aoa��graph-ba9-�network97��o�n6�quantify"5 �:N�� spon�E Aa $YK.!Q"@�;��n� � swif enha��!divid� �lf��mH���0near-neighbor!�%,shiWek oA Agenome-wa�molecula�rp. theseuLqhU�a} �9as*-Hrough� h�x�E�9,��a�alP�edI�ly�^���se o*��1�$ metabolicea��we9ifb�&�by&� �Pnof lipid�+&in �e�.�csummar�"w�� scriG(lU q�uEndY� pipe��V�EXwaw unraR͑�a��5�b phys�$c� 9�on>l dynain �. S�&f�nge�sim�i��Z acts�s ,in Caenorhabs eleg��fmel�m( fruit�B2��,! !A$�m�1E prim1!i|a@� being� � N��a key fe� ���sife sty#many _ ��I%4E�A�ce�",=��! ough� prF��� ��FsE�A� �monkey icU.N[� z%�% ,Yis known!bv� ��tIa/!g!Lv F*[�ew�)!revea��NaY�&2E):AIA/jA�ge6:[1e13!�Fo�)E�, C�$�l [14]%SEleukocy��golder1>q �� conn��� c�<be�.g�� crip#`4�ndJ�,I��A2E_, !\lon�"s�zsuggesk at��z Es�19,�@ti��"� greeZ“5�� ,"w e�2�pa4�To2��ame�UismE �y�%ch����a�� al&��j'z�}ng��9�%0 sameb � hils�� Aw stil� c�dy� !�!�to limi P �!�of��[1e>�#�4acan� ref�!��#�lg��Mwrl�=Zj3hav�gue��!-K�1i6]a"twha ��/ pa��)2e��� ^ Z� �mexae�"C z �6�in t�Wd�h� � >�1 <.�area�'QG t6j �, etc .x.����iB�)��' e-"|!��\ E�u7�E ��Q��n��!6���Y(%�!j,%Z9�Yed:��Bm�Za#C.bMb y "� �djs� �delscaEa��, !�il-&�to-%-e��itsTl��!�~or��^B$!�fe## A�lheb�2�� sm!e ����ch�&7rem�+%e"-add� ed"� -�.�q er�set� �"� �Ya� a�#" �&�w 6� 5dN,�1-`B�. P�>h ,��se�R1�aK��!B]$ir �n�v aB� oreQi�^ �5�. ���re�b  m�"K� T�0i� p inR�[�e���&�S riK�AE� �f}!�#� �te9� �,e�e� ��(� triv�c(lem . Ctrax� ntrodu�' by B �nT lleagu3 23��� )�Bu�"y��E;�.a un;,!�� u� la�"�!)�ite�i� :!��e 1 ly w`3apart < ea��.in� ��olu����ork �})W �i err�dur!�2�( losswa:� �t��%L>L�)w)s �'a �$re�� o [2� imi =^���in 3D M�methods�%| cameras [&-,5wh�a^u�!l�\assum %�bec%H�W#� ly 2-�$ �PNm�+;E���]�,!� -�0in� ��>�i A5idT!� er [8-A�]��"9U�QI�3!HIj��op1�yQ E[�aga1 aa3= AQ� ����S luR�H�,y�eda�!��,%,ة��rB T�ɡ�+ imag�-�� � �*�r�#�%(ast 150 pix5"��t0&ta�a typ,"BI� s ac�w�/w( &ccessibl� afford��Q�A>er- ��">�%��}� ie�un"P#hav�o�O0 trai� �|a��fusage �reby masys6�#�(1<'p�ne�{� nW��io �L" q јs A:uof �7��typa�f4. Man�sco��sr-&T �B  rduM�C�:i !`I'd � . Schnei J� �)[R0-� rule ;M/%��y�"�well-@��� bWon�#,��[�m#�� anglh yh!Fd�i/2is�)} �/-#6 !&ppl���`9�. AlsoI>0u3 !�a+ is��T� b! � of%B�-A�s-v�c@3i)na )� ( JAABA )�"� 5�by Kab��28��in�a�^r L i�lab�"�ficс�!$a m>�a"%'�&�f a�( /�4 fu)gncI�!�=5H.���at!?�v^'w data!`m%!�tedeI����a�u�� 5]s�{�# �#m�:��zteg�"!na� $5B��|92r1�0] �fH5�"� �F2�of.~ v2 [ byI���unw�a�t� A�Bq�bin�� q� par��y�yV$S 0&��0no��ee�OqO inhAs, Simon15]Ah�x�Nic� 4!( x spac�`$, deno��"di�Z4�(AEH 5Qng�� �7E��en� �2�gyoung�+� B ld ) h�ai�,�b��A%to��P v�tuV&D�,!�investi��- A*+-��tru�,of �atIFEovn&Q a hom+�� U�o-�[�,��iP&#��tru��� �si�?�+�Y9 !�i %�a �batv Qis!ȁ�IM�p ͒: ovel� !�1> } ��?maa�="�-�%�!w" �!u B.�i=��&&��is �w.4nm%ሁ�"p "&to� � ze�i(�walT male �!�eG� iBofB z�3�� ow-c�%cquisI��r(�� d�i>*(� -fv�C/16.�)g�theor& al f��, 3sF�a!�:&� �Ab!H4RI&&Y�a�u��Hmu67!�1�y ��%� �!���,�r�vduX }��U1ise 2t*�ge6���re�(#6strongZ"{ ��EFy���Q���!A`va�.�r�&� y . �>.MO�6edaFlyworl`9 cl*:)�er viaQ�M�a����d" !�![M<�,ed dig�6��Dg 1� %��0� �+)o�Fly130� A$"� ".{�?��*�!V��m ensu�9^?te est��Au&� ��#�:q q�1�II��Do�:a��.o�@a��fly’�-dy�<a� w��5h�AY& po�>s =>!��53�"50."T]!�3> -fix!��F g 1B–1Dq0S1–S3 Video .�*�(%8*v.��%65a #�,23�va� d�$�� %�(!E%�>tK<we�)�e�)�$in 60–70"�5�'FT%9"=S4 �+'varo��6�17N16-V ��Ů�� brok���t� .ty�a"@!�1�p�Ae�6 cC%q6Z. %we 0�A�?"�v  of.�%�end;remed�ofI9%ke��a��5 na origin6+A�BuridanE�c digm []/(�! S1 Fi�` or a&�"�A��  'H Brie!{,E.ca����%�(a 12cm plat�( surroun�by wa� ��6�I0.ra�an�A4w1yl0/r beyo� L. F?ai )�)w""� placI!�are1'fil��Em�t>x( �A1"D/! )�L!��=m�Cjna��]#E����G!�10-s  )t s.=su-fuh A�Mu)< ( S5uHP� :� W�H"iK�Hl. �|!+ YXvery edL#)�?$�)�, �w��W��nsa� \K- >ca�-�:!�{���2i�;A$!'F oW!� �inq�E��z"�+Nat 6=%�u�&'asEBasZ8�v0-.�Ÿ�B�1�nd-tru�*+#�=)m�� ��%!e��� th� )ty���50�S1-h��� zeroɫ+(two randoml�) osen��.;��S6M�,�]��\ M��_�70�@ �&M� ���dI�gjum��G crosm3�LuZsubsequ�6� !p �6� euHU�I�noi>A����(!�Lh1rucx�naf"TLpr�2V�L �.b Ax%�d�%supgE�>\V��A�9sby Nath<<���9O�)�Y`(%m.� {"2)%*��=� D  "a(QAVorY1I�%�E�pE�“� to-� �r�$. tAvseYR!l���� ) �Ůd�-� E97M�A�Atg!-Gai} �-� aiM.�,�A�a*h�� L =/����xa � la���>15�ecug]�~*D5* A gu.6 *.u!I�s� �^ o seCWhe%�2.. AA�i�E�es�<K!5� �4��(iwn<y%Y� -by- -%S��hem. Ue��tr*� �b� &� �!a%3�/*��.TB��>*��t}�"j&} ��)?� gn&E�u Q>]��a6�>E~6q"�@.�F��*O �/dir)al "�=�"AkJq�A-���(O�2A<en"!�nYQaciEm&J�:F� F�s�kI qSt mapEVs*ad:G!�� R�/��� " S6uRS6B|(. Each node<y#a�AFX%C{����"�'e9&e��J2.g���CA>�CJCp��6 H !=��%%�"�o�(iT�$G"]2�!�15��ali*-�6m I��(' >����6echniqu2��� ~3XI�1 s�t�M]e�oi&�zoptx?Y5w)sat�#"�1� �x10� [33]? 2E&��� �e �jyJ�of!_t�5.LEN"H'1:&�=��:'��)��)�� =�� "���t2:.�A�m}) W�D^,(61��Ie�AhJ��!b� �+^lC6PerZCo&Y Bs%/ ngthsj2�n�b�)�i0 glob��G *Ef<cyF��U ��@<-�U+� =^�JL E�)%�A�>l,T�WI-W�B.� �.�+ .�+|8Zt,J, XrEw( r�R�s�%i7/��BD x@C�XE8Bd6�CIqJ �� ub> "�E)IT�'itiV�M"vK� anVa<she�͓&�2i�2p "A0A3AD!�]#p�L��fer�� sL�. Besi�,�QvGcI;W;D�6��7-p,�3/9asA�A�locomot!!�A � ��� A�/ �U�",� th,\�!� 6NMyy��&i9.e�#Urst�c. E�� h�,&6-�6VV�.��%�{J���#e�E6a*F �+!nw �.j Yх-�((:Ie�3o�]%��=th�# ?.;� 2G/2H��A!rY9�)-�� �i}displaye"7&(9JIm,G *r9J"5WZ� ��H"�A loo,� q�1cha��er ;� >�;� 0umj� , .�W�# )=%E,)�);� � ��R��n2p^!qyJ-�u�a&�Yr"("%�����fT")�6Z!f ��geOE�)e= �Z�=&Y)BAvvA�۩sd��F1&7#��5N)B-7C�3A@ EZS3F*� �$(s)Nt 2�"_0���+�se��u�i�&)7� I�d�3rQ%(�&]��[s����jo <Bm�~�Mq1�E�&0] =� . No.z}uEfo;3 ��!��jIw-kZHa.&(+3%vGc$QA�V�Н�u;dpec�'&^ �( S3DU>IbatmA?Z` !s�@J��,6�higV2K,-�<2DI A�(M.E29�amQp)�2�aj6FH A-j1ͅ i�woD%�I�eA�p.1�yM3Jz �e/��:-e�M"T*�-A:L 5ȭ� -\�'AF�.� ra3,�o;&!@"� Ɇ*� x)m/1.]�d>K�.��5|:j � �U6A�i�*�YorR� DeQ>� �b2 A�!bl� E_�,2F0S3S3HI"[*3?i�NA�Q>!J��22Y64�e8al1�i4'E;a !-�~�!Ue-jA&�' �n1�'� �/.�L�6&�;#I4on;S�6*'#bhS�+!(�(�- appem ].�� ���fQ� e minimum��da>v).�r=J��e�� ; I�!;&� �fr �e���=�Q4%�5J�N"!�� {LpDA�3���,B ���Y�D%ucRh� _qe��visualiz�K��m��� �u�a���c�' (Zch��-*!hRZ�,�Rio� �B3aqP�Ym�2�ea�9aL rapivG�� . �G���H&[Oly�E����Lol19stT�+J9 219Y  on=Js !�4� \zB"U,!�inu)���J �e6!6m��[A�.�,il[Y�2l���!^��$A.�P(��f9perz(�F�+�h I �m�� 4B84C�=T�ioA>� !k�(2�J�6"�4�Er��r�X"a �s �quick� �!���,�k�A �n!ng-�!�an%� we� n^� ��#�&q0edJf�F�a�/94�2��33~cbut���N5 -�h%4E%�W�� ��!� @�Z�9k&,,�~�2n v�X4�X4�Xa�t� � a�}])�-��ՏB 9�E�-E� N=�.*�$&/�]VhH��^ mpan4�4�U)�:�)[3�9T���1n.)wea@�!ed RNA-�FP-#2w+ �e7+�jҍ'��Rir�M(%6O+ed ho����. QO� a�al��&*a nM�%�A(v'mP /h" >)�A�e�1A�3 �a��[J%jv�#�D�LI^5�]AD>2/�Gon Da�: .`5 U�o)h2��8�Llet�di&� Wiwa6/ 5w5w: S^ %�, 136%s1E݄�i�1w�3Z;h!� $ 64 upregu],d U!<72 down>-��O M��$�vf3JS���3�7A��  ��1w1Vw,�U:7� *�)5*1 �>?% 5)Ei� �e�Deay �/or��.,2[}�E ��]l2� R�AY��7 toge!T0(�%o far6�%al�@y���!�>![2�i��!�irZ"- !(17: lUote�  )�E;F��k �u�h� *�G)n}-�e�A� �0"�����;as~ ho�d���2p�79/��2`4�V�s�"as� ��8e9bV ���� �e��2���N��c*#B � �=�.����2/�aW�A��\ ^bA�AqP0R+"�^�ƔFmN�&L � ts emeTo.( � �Mc!�'� $�}7l �t�!s2qJ>ne^ddzZ�#mA6iir5 �B'&�ve-;�-�avy�9J���:�u("�*ri�,P8 ins1 A>^&�c&U'`]V=^�C�\mJ trig�i��=ifN�E� �alTY�Q>�� ��(e DAVID Bio"V cs Resour)A�8 (�a ) [3� 36]����8�K" [�os�Ks*WGO ( G� Ont!(yy[,erms: MF ( M"~PF�u�$CC ( CelluiCCompon )ehBP�9xP�(s�.renrich@�1 �>FA1j��%A- �b%*�3sm�� 5E�S5C &�:iI���?!�6m2R(d�+_ �carbohyd�&.���Niu!$�adk&]�jA�F�� �� amin�ii&bag6�lN��� a�e[e���sj*� �X%��%�Uwa�U�d i.6)�s%a.I b6,an�iso� bal�8Li3As�tn�6& eX>%�yV�< v[37>�Q�I.&?aP l>Ned*�nh(D1�2M@)?, ��no*K10&2%� rRgi�-B�����"�  � I� enco� cytoskele�d"�f�9$as Myofili�� 2�[r@�f��A�h1aa��Rmuscle [�wI�Pif1B $ Janus Kine/(nd microtub�B��ng�}� [vfX�hf� . Mfe�=|l�Sli�1�)d��&?,%&. @-3 26 5-t51(a nucleic aaS$ .�, nam|lP�He-4o�! Pnhoryl�R4��{,, CG16758 [4^7� squidqd��41]>�nE�b| =9� =&All�*TW"�Dsm��&cex� �m U mRNA�64ine � _"Q!desC�1"#%c4 ��product�\ atty)usyn�"is [4� 43*upherom�0( �,�(r �zo��n�cbio.@4�$5"�P� choi*d�(� �(B��nw@�����]Rn�)�,Yu*16u �Y0ini�*:]. Ipbtj`!J!�gA!J*N"�MhardwaB�=@<��"o� .} )�A�eP!3�/&�?*01�5�&�2&SXr~P��Ht*m p���%��us1>cig2]_!�Ug no"�=�fs�..�Ŧct�>�=Wa� nfirDEC�'/9� of 2B�8-C).*�3>i7CrPM�RA?!=:�i 4M9D exte E�aY �&v65��"�,"�/2�“sniff -orchase�~Ql�=���sui�^+%5��I"&e(�dks�IM�qAI.<"*Byz"LH�-f�jblV�:y��"�.>Ca�%fa>��Y`�e/uYa>��atiqw�A�ፅ�* sj�QP�e�[5 adap�"i" ,�"-vg�!e@-��E���a%T!����g� �1n>!1-�J�4O���YAva�6� �X0D,  I� X��.! � Sf�i9�y52:�T+ M Di0![uWy<�G� �9 "P"s�_��� !"&LN�> gV�(9�=e��{re�3. Hav�&~H��;7b��bJ7 fu2� aue�?a�&vf� ��A(dr.���F2�e!��6$i�) +n � b�lAJ~?�#aSa�-��laa�^#%hU �!q"b"�c�ND."x?5 �[-m�X?%�����p(� "�!g, poor�s:l}dgEv"�!��ex�4q��1�`-Q5d <�o Son [4�tT� e�m�] a��t�Gt6�d�%C��-environ�,� Z��,-��) A�.�[�Fr� �Z��n&`e�)�on&�f8e�fly�>�h�"0s��c=(A :�*?f�mmune �g�*V�6g�?!Qy�m�aj9] a�.�b|V-deriN��ttrJoc�sZ� � + ͒�iFJ"Af5IU��A*nE��v#�"k ��-� b6[%gof!�he"�*� �19.T.�� � �W.�*�In�� �#.=iwb.�KAa8Aq�Ti�{!^��6�V� !"� &�<��,<��g= K(z~2�*�A��. I� �b+At��p�nK�a=9p�1N�3l��Vapl(*�j�Fausal �zinaTg �N ,�6�s&�Y p�7-#*�ld shapM�"�:%�&$$I��@=Z�J#�A�)�s7A��� view�in!�əE�i7�=u��D���&muY~5me�[�z�o���m�3i�� �wA:��AA�@t��~gA. D�F�^�/,i��eg!�t "Q)A��!backg�XwNUE�3[�Nse��white� �x�#m+a bq^Ta��tup/�X"2�2"�XiS� �P-Y��&�_ [50]��j;�{�YI"�!:���i @���V06�iCWe�1�tzRK7B[,eLTVV% ���nN<�:�TF�%)s��I9;m&kiz0vre�.�n"!fa�Mg�<W E�!2e����_ �ysſs��A��) zI�fK�(bi�te���a�ruc�m2nUdn ~P>N �� 2 jy�sYWA�feQ�C���PA���A�2AOv[5�xI�+�@�e� 3&�Q�*� ���!#&�1.��ZK�|��N^6 ]l5�2g �6�%� '�j�R� tAdu�*X nD& ^Հ%}M�ngqFK, i .�H�VR� >UR��wE�ame� 1A['. Edg�`�l Ե:�E$�:'6yOA���H7"92.����� &6""1Ti6e�a~� vap��be�%�$WA|m�3EۆlD( x(Hungarian A"bc[5�.�ba�Be�i*iiV  !1bWi�M="�T�E� 6g)�ii�E�a p-�67receiv�*E>��.�FYFZ%5�Jj�2���e$ spli�&"�-�9�E��E-Maxim�" !�lso"�byc)m\�v�tag��!�p�rM&�;" ���/ch��6�cF9%AF�b� �jalw���$0�F��-�5�=)�&��!�u�U��S��"be.b�=.*" w)#� 8^�%�8�x�-ԗ9 � V xact�^u\�F�d� pTr)�ayy>�*�M I�M`iBr�n � ":��]�:(ɐ2WnJ6,آ]�!UneQf�F�&|�E'u!�lo�IonOM��Q�e��%iȖiBNFdA '��y[5�/5���or�e9 f�� }Fd&� ��p���<�aB�z alksIM�h�pB��-��R� �ts mo� /"Cape/?&�# 4tsy>dpe8��4�ze``e~wo 16Ba!pIn Suppl�%�q�g Ŕa.� �(O ed�B�;6� 4�1" �gexhibj�&tR�*\o .yS�*a�, �* …G&7!{~s�)�eo0A<.�,�u�Az` kine����&�mbl���Gs^&�)!J{tFz"�o�{I�ءnork�� f���OE6]�)� \"� ���(�`or)!�c,]fF.�l�;�\�I-"ct c@ A �c!7A8< 2�bs��V�b �B6"]bzb< � �<aB�b6(}.�-"E�|� in�dUc���SB�� ��qA�яyk&-e"�a� ,[��#�Vec!}MC�5(B1eU?�i�a��� a�s�*�3"" !�ef�In&�?{A�Π �&#��6�)� ^���d'�� b�Zb��!i�"�&�+FX ����22J?c�AQF6cEuclidea�NtN&6M1�l.��'Eա�p 11�)���& ed a^�E$),���e��YX#��AveAel� ��G�!�~�sdw%�,!��d�D�6\��,nrH*�d2���*d��Fe�i1:� �e%��x  eq�~&� no-2'. T�ng`m(r�3*1 fly-��s��M!a� �Xcc>�s � -n'b�� ���� ɼE.�%*;� � +FrezTj ��–Fkc:%ӕ�ari�!� a��] �1�_-�eI50.A-�4E�*� -�aP�dI"/=��6�!`!CE-Q�ŴW.�* �.� ��!?#� j�a�E�7sub�Nkx terv/$���aHe #� B���� 18now !C1 �I��"� � ��"d �_ca�tri��i�=��f,)�� e� mA�B� aagfal&��:R'�  )�"}�B6&*J!O r f!cJ�"F|.].*�]�ac a-��'8<��L"�by\!�� �DN�*p����2��| �1B�Z� 6�� ��*&(F�g!�^=h�]���A%r}�&Fh�v��h MU�a!��&��VN�uEJp���A�5���&J<.:��E')j D"B�!�Hm��=���&�9fKz�incip*�e� !A֑� y�m�"*���pnVas `.76l��� �P � �*2�)X�[� 1b1c�osce�j�!Rut-goaUw v( DJ���A� -()V�����Ş�3 � rank n�+&� !�; � t�<�3a�E�:���h�Ɓine��"�r iA��hIZy$t���We!�T�p�B-i�Q��2�1'�umM� !��}!� �p&W`�.V7����%�#j�#x�E� ]U 2TS2%FaE[�$� !�-mP�� �|ia.A�>� j*�G. I& =: Loc�$�:eU..� ���a.�(��Jfs� �E�5U"� |j*� 1E� o<�i9�opo\�<)�� l�%��  ".!A�$If D = ( X-N`, Xk )aa1y of k3"� � �-<T/2ma\�m� m , M=1k���i=1kXiBĖ-r÷it&�!���|5n[2q��a�trEIx�H" e6|&�-G.u!L��)C� �#��o;ce:-�z��]dsA�^�be2. �a�8�C Vs�8� ݰt"�� ]� �6t"in[5t�59X� If W�SW29S0 2 ( m × m ).t� $^�������!�Frobeniu��D ∥W1 –PW2PT∥F �P�2-Ua���'u� � ces�n&e#is~�qis NP-@n�?jGradu1A&t*�6M�"3J�E�8&�%�6.M� m�a�WIBM� "A�&,A�19�A�E�1ai� 1��Ŋ4R~�C5 >��b%A&.�>c9:�′a�5!- u�h m*&7�;�!Ky�� "1:*,��w��a>�of��i�k�9��=rInput:.0A�xe .3U��0�!�"[ .0 c�ut cF�>����~s?ASx�1: ChoGJAT.i�xq�K!J�{ M =H2:�i = 2!Gk 3: End& _g2G�&�2$�-2�Q_!fR|TZ!+/� pS�A�w+�0 %dV~&�D�"Y1K��0Fe�5�V�-l��G .r�Ke�3sia� ?� mmob i�� �zn�2!��4to�L7+ub A� bead!�F"�z!�TRIzo�Invit�> )����[55��n�?&x16�bod�n� *sK�� ��L� &*H!p C| pa.preci�%�.>zE ��9�(M�2� "���:ed�'&qa^?��U �Ensemblb*�BDPG5A�� �;� {1!�ʁgen�6v%��� �tabb\a� � �Af�:DE!�[62��9IVAh-�'K'V�k��E�5!>-7�b�f�?�pM�Y^e�����E�5 )M$!�U��foa{ ['� �Hb�6�a6�_he Benja" -Hochber�Qc�[65�OE6��n��"� hyp!A?�%j~; 1U��van FDR>Poff!d�0B�To-�:}�:P*wR&�BA9e�E/2�ELmoD� /dy���Q��i-͛�#��ju�͡t!� �Q�A�BH*���aL �)���ɰ��E�yAV!#.UO�O :����a�AIo:��Di�2letIx�Qal)�f�?V)����]�)C !t-Ħ�6�Y ( GO\�Zala�.�#���a li&�F�&�)``� �% !~-9&JO�^d�{PeJ"�7i��@tler-Toledo XS105��17Xe@�o/<�W�:� a�+ (cE +� kEA%��%��rT���C/ �-��7SsQ �� Falca�* = (3% $E vern� Fn o,Xat 50�=� ~ silica ge�oleum�4er$,6"6��044��AK!�yFairban�ndi�ch [66]To� w! cT)�V�� �2XsͪE�)�N-Y 3 mL�>�).2fA�.ou�˜�!�larvar���AZ��al �91� ^�-6�_"�݅]=�sub��1H:� �=� qperG�a�*6y%�:M>�caw,�&�e +� �!r�F&�c�n-� m\@c�t�w.%�!6Fn:5�0"R."{py .��J%I�un�� Ew<Welch����{{�-e&�7%�wo-!�ANOVA E"�JIs�:�@l��S�A�� ��I�/Du"�� ��=<,Mann-Whitney �s moW1( /er&i:��a"�? . N6�6�(��(eirer-Ray-H� �P��\V�2~GO.�_E-�# . D’Ago�#o &"��I��F�:���V.�UaP��t-FIYBj4 �uMC�Dj93 .�b�#fd��O�Eqo�N�w o�?uJ�—a��!i�� guid� adV��o�b-\',5e:�jz@�4"� Kpilot�HC"�B��adeshADe@a� &� a smartph0�Mr ��W��H&�Organ4- ( WH diarrheK�R�*��azi&�?9 �:Ar��T!y b"y(�WS�@.4:A~]�end-us`�n;�[���]:U��rics[ sub-�^�*>qf� ;�* lera� son;�3s  ,!�cal�n��i�GY\˕ �AY)G�P��:a 6 week� `� 3� �IoF, a 10�F�z�hѩu-S��!���!Wi.�ʥ$6޶gS����excep�MdmiE� ? nici��V#ol.R2�oc>crARN���*|0wbnt��fA2%˲��=� a4F����ry�G�4�y~toIU��� � Ѳ� i�zven� ( IVN�ui�)antibiot�f!�zin��D*�of 841��enrol�. ( 32� 2�; 516ue5�K)Dm;!Y2I� p�r%�N�r}%� � IV f �de�Na�u�sNs (I�p <;�%���&RR��of&5RN!1ֵ!��&{wa�%# �> �volume��KJ)�~tB mmenHfl,a[pz!F: 5� azi1/myc?\DL_.�14;&N�356=)) !of�h9bis��)%���js.w)n%lv]��6�n�tUt5�;I{)�W1�. L�e���g�E��],a_�f 16�Ano~2 delaR�e�X�?pr6� �t� m�%�,:5%�*�NE��.bp��*]Y)S�u,�e/}��ġd�0s:;�"��"z����;����c��O=�Z�8�Nsh���Ia� &s�[a 9��-��.��!exp!�o.�����*dñ�/%� s . m�/r)f�H +� "�%XK>9"�Y8hO��9cstJl, edum(a���nMo� <aiX�:r�sL<q�aa�*�%:����S8 whelm+. �fac��� amid�*breaksw -�_z swel���A0 s p�zatburden feed}G;a����"�-for-ag�&��AZ �!n)�&��cJ� �o�2-I}*�; atH�9+M9in:�de�Va+�w"�-enapdA86 �Zb�of �_!�zdh :\kTH�B.Instit=�al Re JBo( IRB ae IEDCR/IRB/�/03#nd�� Uny�A�Schw of M�GPS lo� o * aggr�`�<�'yndrom"2��h�asX) wire� 9�'�nTpwi)?�O� zk-r&evb]:�0" etea y!�‘��’%4I�y�F8bhstaff�.����)A2be.�"b%v ���F�2,|M�*=�.^c)JI�@  fa�����S5*]4&1�� ks�)U�`,icA))� l&��I���2 y) �s�o ‘P� I*!�,Histor���"Z �$Exa%� y���dE��D%�J7�>Cm�, pFF,2JA�I�t>ustryA1�J�e vi�. B "�a�!9Aacid� ,"�  on/of��n� /&�S `O@est�16�A\�a5s�w"�=�x"*$a�:�v��I�*h(dto�9&�; 80 US!�N Samsung N� 3a��c(���Y0,�f6m*2��*mb#fz!f!c?l scr��gP( 5K.�}� �TC,st �Oof���((oO>�,�AUU;(��w t�!B��H�6se��i�!a ��Vibrio��Sf�nella spj? Shig��%G %!���'�)[�3D6o�D�29� ( icddr�: )y� ies;1wab�#lF�C} Blai�aCZaՁ��ur ~ees>s%2i��_lB�Vroж�Wt�eld�J#HĹt)qo4ly��i AssL!Ma"Xt!��*�ETE�� o|iLb��rovirx� rota )� �!&�%Q�!l�b�� -�&�H{��2pE��or �@Jrr��&�*u�!f}p&]�:�BasI"�!���� �.�&]�r � �~F ,*��At�s>�:A�V��!�/ !D ��0o�W"�.��)�Q�&�Dk��qA�nM|� :�via%�JQ�;!:��m#)Am(E���m��z. � �C����d#(byA��$�]dichotoz�( yes/n6��lb�� � a��1s 3rd�:rti*( Q8Q{A��inuŰ6.qf,� ' Sхm�~R[��:&5 �,M��5p|B����2�!� N> bNmfl�N)�]V�wQ�1���.��B!E9�Wilcox�nig��=I( �a_+�;� )�ZF?sum CVrQ1�w�-��ed"��!E`r�J$,t)�!m���%&� ���wQ�("uV��b�!02�p�LNfS2�*[gr�*�2Rb;_I( ��?���.i'5�6y5z if>ca�E�Y30%�+ABaeKa� r=~.n<�at N3&%�YY1�gua=)�1P�$a��]AXasu! %& �6)Qm3� valu�% 2-�h*5��1�4or . To assess� how well estimated weights matched measure�for children younger than 15 years of age , we calcul[Tthe difference between|and>p used>�Wilcoxon signed rank test to evaluate*hs;>T�during8interven�atsub-d�ct)0unfortunately%obtai!i,�(therefore ,�assessYE�FIof96r/QrGm>�,AL included � (m)�nd only6� pre-224)�those��F�to�fd� ( siA�weI� �yX-�B�to-�J�A�the �Ls ) . After determinI-�i�Gs?u�l!�e�:�e-too high)�qk$d WHO percA\lesE'idfim�_t ba�approx2t�Page in this cohort as�BG�miz e root!TXn square error ( RMSE )�mBwA5>�6�519�4. All summary �,istic � al analysaÁr�le�o�e2+softw� pack!R vers��3 . 2 [34] ~$data excep-: few re�tcdtems R rovia8w upple5���Drials ( S3 DatasetAM A totala�841y��enrolled%C,their record!aly!� ( Table 1O I!�eF�periodM[V325q( 204yl!�1216�)�� �2�Rb516.b4306b86>a . OnboardaX Ts priora�bo��B��J�͉pa�t!�4to accommodatee unanticip�C addi��al trai�]mitig3possi!r@.Qo-morbi� es becaus� practic�s��6�adm);directly!D�Bj=0277 targœculturѫperform����\V . cholerae ( N = 19; 7a@; Aeromonas spp .>!$, Shigella ? 5; 2>d Salmon:# 3; 1#;� Ga Fach w%�Aedid, ADvirala�hogeni�o� �pn bacet.%.6�s�t�� sensitive�r,azithromycin!� 9/19-�$ciprofloxa6,�C� medi��Sit��,cotrimoxazol!l16Vtetracyc��( 14/17���resista� ryN���e1�!� %Mco-in�8edi2atMQ:� The obj�Nve*� lini pilotmO%�:� impact8Da smartphone adapt� of%�LWorld Health Organiz !(� ) ��0disease manag� guid������or�assoc!� �b�AQpo-�prescrip�:changA�ae ad, � .nfin5s | � our hypA��!t� ,echnology-en8 d deci�-8�acan��mote e� ��-ba)�2inA$ource-limi!�setting!W� rew@basic A�!��, allfacilit�@should have a funL� d suit�q 0scale . Howev*E#� al (ndard is fr��ly unt)v�lik��}��isMm�Oa��I�iaa�r^ A���. We deA_ ]-.0pe�r&��j4age by -1 z-sco� ���X;4- post-&. showN{��5 G B(5th ( femalA�3rd ( 6� �� hil& 6���ks !6m9ly Bu ese low�j">in&Qu"�!��!�l�be dua{%Xdegre�.�a�misaB al�Y,� sugg�ew"D "[ QJ�re�mayr�%Y$ularly vul:p sub6 ��pop�] . Fu�Y l��rEaC�A�i/o exp!�o$ se�2. A&� an��pomorphe� asur��� ag\g . mid-upper-arm circumx8length; MUAC ) � also�P�J�P)Z�mus� buil�>lA�!0locK avail%�in or(�pt�qp�a�B�m�ion��I%��(paratory ph��,5 experi�  surpris5 �cU,Z of) bandI�6io�e�malnutri�p$ [35 , 36]"� �st���a redu��%�v IV fluid!c��se2a)cr�Wee volume)��7henB% �-0bed . Previou����?��!�K raT o��!��um risky�t�ro� r=solq�e<<of� plic7�k��av�benefiE����institcBre!�s i [37�gMW�!�s ���6Z � 6��doE�of)�I�AT���Zw  oftenL!���categor��)�)�.H1 , 2�K3 l�gwhich�:beRuale3staff "�� a���6x�!ed �usNmmd V�c����ed��d2o�congru9�a �O, Netrokona D�$treats 500aK5kmonthly! saf2y uJ�mrea�� qvc.}��A�!Nsystem!q�mpowe *�%�!Mab� �iq�%as5� ^�1Zd; :���� A#a�T� �$in a venue><�a�� -a&S mortal� ,!~!.e��Ti�7IsQ[�um/ � �tag��R % Z��r ��Ё� ���� d �!req��.pphysi� ic�@���Z�N�.�Z"u Hbiotic class-switch�J�agA�2��most � U�ed�롣as��U,acute watery5�)$ modeŰor i�u��5Q�!Y�,6��.�5 J�ouconcern'z2M 7%� samp� �8u�E�p� d2�[! ;.�.7-�e��a�u��!,93�9U�]bloody ("� o� , ��Campylo� >1qdE�l!��M�]0A�AlthougD�q�nd*��[!�Ej� ,e � / encou� ����ly���‘RP ’ A�d�$ point-of-{diagnoV� veill�F���y�!�"��ntm;> rA�s��mA �4 ( 1 day )�Sd�!� ��disch� (5���R���* y will�D-�d�"��8-(�e i/��ng has-�Pig� c M��FŰZ�y~ �spark7cu- o� e ut�S of u��phru “Z� � gi8�Fcasual�k � �ibua}A3n� �+F��FJ alternad ,�� pite someq�%).�nuE7, w�beA�rice-���A�t% �i/ D -�U��+1u@s����first go<S)p��toYro<"'to�-deri�"J� �A� nce a;conside��!� gold} P���k��"� n���wp re�.ma&Tse2�oi/��um!^ nito� seco�yrel�outcome9 foun�min� ""D�Asta�typu�. A� F�^ ,�m�one�&t.�ea�at occur�aW!dmajor��q� l symptom�Edwol!��"�!�:D�Hse�Ta�tt�a"aaD e fa��~( CFR )��1%%��}r\����H 954 �իr�.EoF�)�m3m5u6u  A�simila�� CFRs�( sites [17s9�j�relimin�D2��Z[ i��e .a[imipuW*�a'9�;B�B; ��)BA�r tail� * &2� �ide fur�N s� +q5A*� !initic ����mm�l�^developn#to� ��YnksiA�bye��K�e� inU�s j = in*C (. Framework} be��"(%���L �d*B�!�s [38A( Scal� m�Z�i�- epe�x%!�vpersona�"�!`e��jeaX�'e^l��to no!�]�  , cap� s{� th i�%mu %�o*t�Iy� connr��. V� Zd )pre broa� �&ex; 0 , BangladeshvPakB��pE5F5,m!�� ��' amon�U tA� en g� ya�c�(�pen�Eper!/ita [3�Pro6� countr��rapid+2U��fford�Android]q!�I& so� s��)��2� mbra\f�is��  purchaT dedj��� !F)>te��o"�:B�E�trigor�qu�H A`qu& \i����)ago�of�8 !'��vid� and/or.,al.�.2�O ��esA�d��q�*� an anonym� user;ept� survey�'&�$, feedback"�(���m� e� end-a��S . C�?exf J�!�*W 6dn%4 s^i�n"duc� h�#1� g� t^�6pla^3–5�bu�8�'"!� ��Y�confer��a��%.�; ti���Matgp . P��)]all�� v<�x��lin(s nee&2Dv(�'at�ii�x"� �"�![DI�s �zemImad�al2in<pr�a��PN)���lq nife,J�A���| or��.;( Fig 4A%�De� !lA�N N�e�h�� (Z� appel,� tchMjian%q��{| a^�e*�xpl�i�.p o$%�H� ��"h be vie�!#�#ex��� �e���ye�ga�d>7%� &( ���i#liz��t��ru!�"��� "t burde%_-borne"� 6�a�W5 ��Ebexhauseo�5/&��ap�-i�:: ( i )-Z.9ea s\ed -)� �"�.�� p>-��*QD2� !!�f�^��ag!VB�/p>��J�s;�) �) aMkj+iA�( i1Z�.["� ^ �-VsR�w�6�����i�a  -f" issu�RThua�N��! ayacy!�C  we "O(2�UI-B""�)N` �%i10no��& Iٸof2�\B��#r!���Acriw54��i%a�p b!2� nist� &q$.k o_1��!�^ab< �0A�eWc�,�methodi�4ed� vi:i ys�� n�5�9(���pa� har� t��!�$researcher>Ri�'��Kdig�)� plat- B �~ a^c�# �to valik,Up_ +�/ha�f�s;^\�ad��d y!��)�<�h stepm�v����� gw#�.>&)��% ���s`*"R+two�'-�b.�no��nt ��"�*is putv�wat"@t��^vaJ�}12-week �aY�E�+�""�+E� unba�d"TO�lnouris�5u�7u�y28�of���,� alG ac3,*�$��} actu� �,� �'ir-sgnr�- �:C!�#%���!�a�Uto��EՁ�㭜s"� �z �� �! og�1al�*�!js�s�( akeh�$A�*� �$S'e���a��%1!M��> ޡ^rob9#��'&5 E�A!� tep"� ��eqW� � �'� regZ infl2w�F���Q!8 ( warrb� inv�mg� F a cl*7r�doy3��=d tB2 ( cRCT� O�)�3ach!� addr\ ��!� �%al, m #%C@m� g � !2�*)(5 �sbK� C=.m�%to �%%')� �#fy.� via# a{e?ar"�26l ]�WH2Dm.Z� � Anl����y*,+�lV ��at2IM"U&"q *�Mcachie�i}"A@���!oo�4chA��b� I� demonE�T:a�zpl!�o�vn.�[�,:T?5 e"�uXm EaEZ�7ant����AN�.y;op�u_�-b--�,cumen . UponZ)SE�+hop쁭oo&2b7� h�&�# rontC1�rs�E�>A�!� ongo� dropHmL34&}!��Fa�/llus��new era�I4!q�!Bsc/.!:�.£A$_ lex�\of=t–para� �:�3�s i.E ��rtEUho6?#-�,on9 clW8�-elp"�)��!n=$ �ot�-I�Miv�nd90ulw "� �in6-empera���$ncEC!�,b�3g�d�>oB!lE�Q�dynam@8. Ue�(� 9�7%�4Daphnia magna �0a microsporid�5^E�f5 a me�.� �!�A;�$in-!]<p&�*� Mode1ram�6'mf)@agA��Ys,AVd>a�3)�growth ,=^� � librVabund���"=2 ] lŠ shipj�)%'� metabolic**� c�y�-"ly� dict�<stY,9��g�of�uC a!�s+ eMG-A&g;hal�e^=R�i#l!Q]fsA3cre�= . Out9 �5 Hproof��cep �1inkOs�% 1!isE :*!�.�fr��[�?<,%:.�m��:�-�N[�#h,+Q�� ^2)�e10 environm A�g�5�u%(�*U�P�6h0 *�^pan humb2$[1] , foodEu�[2!�Br  [3�C2w –d�n2 �s���_ !n�J~+eS[!��u�����$strongly a:i9]O [O<.�1&0:a1ZhB�J��,.�,"� .w�%�4�(5�eV��V toge��e��sprea� ����[5!�T�Y�W! _��)6� eYH����a%w��F1��Y u� P ecto1�� end��'�mic%�t aK,. .�"; �4Va���r proce��� �caa�[6!3In�3sh0 �za r*@iv*d2�typcly �;s earli�nd ext�66�ns�1 , fa�Y�2�*) �aYt|a�$�o3�<� W eO٩ ) [7q�it�2��.o7es&� load%?amphib�[�In� A0,2b� ubIjm�E�=!�!��)2mq."�, s�QTZ �-;"[9]�5vi�[10�& q*:1[11 4t�9Z& [12]���,q*Eac�#IJ �v@ � As ita��a�+o�A5syner�R e"E *a}�Zm�E��%pu,yne!�,�Y��on�v�o[1�T./��-5��s asymmeN6�%,El�t���x2n1tu|:�9��!~If�Q !�!�c&'�mS)'>�#;o2���@ 1!�!�trz ff ,ult�in"Ned��>Hon5*� [1:��(�r�4F<=c�c%&�.i�po��~�Jwa.Eg�fav��i�nC�A� � �6A!�^��0�.� ���H!���fu�cys��!w� y,8tode Ribeiroia m't�=:z:g�0e�Qm9!51�-in�male�Din  �� �aa6in��=y[1�[se���fy un�|$#  empi�2V"A exp`$d��ha��f herm��7q �oreG� i��#t�%!YR� Y�#%�2>��.&"�#�O8�� �U��off;bX&-.�*����r� , mo�)�"lA5Oby� !�ulae a. D& princi=/ouq%�A=%th>E ( MTE�T�.� cn+�$I.@-���.[ �9T#�;���H 7.t���prH�L%�&� 16–1�5*� oF�$!�\m�!Y�: �"�� �iv*AO# �Be ^L Qd. N" [13)� !w�0/~nN� �c V &o.Y?�g;�""\!.axU��!�D>[m j� bsm�) �zmI�i�Gl2��� c�$!-�&M�XZ9 W%�]z�$exist [20]acy d�3?�!#��2�thres behavi_E of (��a�l�)KEB�6b of he Sharp*$Schoolfielp5eQ�h�s� mmGMq[21� y�a.g6.�@�y.�U�����(ŁnP-� �E� 2Io�@^�Nɡ!^u1�5_re2Q /)E�u>1l}>�2 ��v�Q,F�J1.y!TA���&�!:� d]?)A��A��aO-� enzy�/[22!�:� ��6k&  c"�M�%*� �uFaL�\�� ngA ecasV.���(FDpM!E%�act* an.%�i�h ve ,��KvBnne)1�Q he�.� ��t l:w@-Lthe� �[!�F<onJ:� qalbDOrd[ai a b�750f2G�A�p 1D@ i!*� � ! A�;N. Oazni����=�PQ�iV of D!AB,!O�*fWEVl(�g� LunG��=*&��( ath YD��i��to�!υ�v�"�.(u�s ( UE��� )IRE�( P )%\by dUdt=-βUμβUtβU-1U<2 ) dE0 βE ( μ+α<0βE tβE-1 2,Pdt=rP: -Pθ�( 3 ){sU�al�*{i��� a Weibull�����4�� μ%|xA,G βa9f=�>&��"��"�"im�% 1<:1� s ��,)cia>:0.0q�;]�{�is �!�-$�/&��H"���!�Y-is α �BVU!Qi� s8�!6n�HI� , θ"dA-evA�e&S �(th6>�w� �/+e] �in2 RJ%6~}!<��0N*� . Be��C�i�(�g� �!Qt7rn�$�9'-ble&��1I#�h<Y��.�50!Ij1� l|%�>O" We&�-"� iY���Hy��!550*� s��>� �� 06 . 0 °C–3Z3 E6N�<t �'�&(at> , 9 . 5=� M&)m�"� �M�.T�7Zp��J�sz d @28%�U97%2V. S�SETf �ll24is kn] ( uncenso�45��r w�"�%:,�-T& t 11�W%AL�&r !�N�&�V,�3$W� !H� !I"� �*_ly�#A�iof��6:"�� A�%>1!< 805 �#�&�)'H peak �9���0L6�>�� .�W�c.J0�$on � �PoffspUproSL1jcl�y%�LH�.* <�perha�#�9llM�q�~a��n ( S6%�, q\�Z& a&F8��� �aj�"J/���\� �#EA8� `.�)��subB��F&!�@�'�i+[y�&cr(-3�.� �$W ded ,A/e� ��e��alA 9 a!@��( numb�(2�&���U , Eqe',ZQE #A�c 1�s �� I�2� �`m&� E�� G%d!��eBf'e�~� 8.)(�� N�-A i�4tը�F( wg� �_ind�3� t �.(Ai &2 [DT] OaSe�C sd�d MI*iA.�'ntinuon F� ��� "� ( S1}�W�)�!aZVEx� �&�r,1DT5Us!w"9I��l�8�a29(`A7 we ai�IA�a-Qsel�'q�A]�Sn� .�i�:��TE�quick�c�g@+ �1H`b� "�_�3��biGI+A�7��u�0[i���%okA���IyA*W�$hBhyper5pa�'_T, �+�&� gc ���&2X&�y�y��"'����.���q��infk�*m�A1L� �P��"s f�Rb�)��Pa&�NIT!�%���1 d>st �i ab5I�!N0�!� U;�B�N�R�!�.��,O�^K nich�!�r��steep#inf�Ey�4�AWim� 9:Gt�L 2�ex�!wSμ;���)�B�!�K4H!a�tyS�� � !$!nCM:� !�S�� !cE:�E��S,�low�2u� !��9d�A�rV/AyβU%{l�>J�[mE)Q�9KE�-���;A� �E�x�((  +� ��1�:��  MA���d%|�R]�5�!Nt�;d�O�*!�"p2y��ag �!5A��8�%�Kc� �9mV� )��]&�Kn?%βb*?ly�e�rT Hat�c. 1 �EU�delay�\o"S!��.5!"�.' . PaFl .( �P1�A*� toge.bel�a�at�xA��AidS"�&,� i|0��.4� `7R�� 2`��"x�2ly!E°CB {�&�αt a0�͢]hI�r)Ztm a` � α�'cSs � '���=hip2�CoY!K��2y�0��� w�+�AH�*�3�Z ( Eqs 1���>2�a�3Yb�0�?fe�J#�a_Zo92��v �44.�& �ga~"�.1TAZ�m��%�j� �';I�3."�2��&�!F�0�SGxng eno�=o�e�)�:�m[a�]7E�]*�Ds 1� ���7e�. f�b2�� %.�;��Clt?56rR� αM !IDTA�r-:�ugE--d al�Zthm�Qconver�1 ��)a�noBm�gi�Re>mD�O� �D��d�M+ ��&le�a�o�m+.6r��a �%?u�Rabgle��U���0!��� 2��`rev�je�oJAsPIlB� %0)���!� �,EUe��'Tk`J� yKβ�)/V)�&� �θ"�2�4$S5��)��N o�,� ,Eu]θ � i��0�P2$(hoeV�%T%a [19]�+�+-gkU�G�U o�e;eB�yBv !� *�m�ql669 ±�0278 ,�>�1@"j� 9\!{>)�Za�I�( −�Q295�3!�9y,fnga� trasi �w2"!��U�m r� . BNBasFC8%7�@(�V) —I��G( da�C.Y"�,h� "�—%ot r&v["X""�O ��iso�To �Siben�H*i\8genotyp ��k!�t:# l��"6a8*-6:cka �?ea�"t@W �e6C. �@�'ng :�8as�(�-��e�%� �q'42E)��%iɼal �Z`�}�s�iYe]2�}e&�/oz��Y���%�BTrRp'"h�G(u��3(aligns clos!�a�%���μ�3W"zfiWvun*�o)��3d����e�A��4]E�s�5o�l�"1 �236)0 , 29�4��u *� ��my!�:i�4f>�^bmݝzA�E ����:" /%9��!@W/:���h�j�p@U�~0>_����Hrp�Rd��JHrrAn��[30I-.�(�7 ��Q� 2in*=1i\���+�a"�f�"�,�R�3�chemi23j regu� �c �;H<!V���de-[3"(Fif� ��  ^ |! a.�L�ar�(/h.�I�@�� Ha .�-� drawn [18!�C fu�b�, E0� oxida�+�,O2−h H2O2gT y a key r�z�a(�'n"�9 [3�-��"�'sed?,inadver���%��Vaerob�tS:sV5a�iQ��bZ�P.uJ��e�,a�� n soAI?=!�6�. U�-} .�2+ccuS/�5;!�erI� bm�-9y�haza .X,)�)ɾ�|.�:2�:wN��r >��$'9ra@:�� evol�r~eE1�!�%�e��. be o/A*�2W��n�" �e�U�<Du . Ul}"e�;E s�invok�`"no�6�Lm�Q�DNA m#4protein damagea[��]F�9� ��ag�V��m We<s��A��A�beluQ�veE_%�U)I?]v!gw>��6� ;�N)"��<�2�%�(��) �?I\V � )0"Io�;�.| q��B!^�t!�n(��. V"�����}E\see~%uns i�.|*bdD2��IB�–�Bv �.�N�A�^� �j�1aaerm��iL1R!B� � .�1,c�y&� ari��=aA�E+!sG(A-At"� s:�jdes�Aa��M��Tq G .ZBjely/]EKI":L�� c6CiGng� CE.V immu_"u~RIG.�ӝ0e97!�7,m{�.>1r�,:��%�5��xIO>&�x����c;&߈*�� �uK�~� [Rw�Ze�iEe��>SKA�u� s;=&�gm��ism�aF+�6�E d% ung*��� 6�!iDZ%%�sus�#i�eto*K[�xF�m�,����9,5V� w�)�5�y� l 1tm�h! YVn�F�W6�Q sm d�E�)�>�fu!�G�5=�,���.U�"a�VY(V�m1 �Mi"�K{F�Y���&K.��&0ABM0rep���� _ur�sllJJ!��accele�3.�6�(ig�Hi�Mr�II�. ed2A6B�Q�U$]��9��G���Jl�v^hj~d!��X� -bE�( ?�" ) foXVI�%����-ID"K.IaO�Q�1Ksem2Jθl �(J$�<��!kz�.�A N�!�b�M�r�:b6QwAlU�2�AY��:}torg�-e� E�v�f\wt]C�A .�&s �Fm,� < !�H"83X cU�C"�#&%���nonzerD_��"p&� �3�?e*�)�z.�-�e; %� mpai:-1ivX7BF���G�8� S failut�V�g�6 Ofp!��[�*=Wq )�d+C9h'A�\be�7j|mis un�5�n"�(��%co�z�a�5� �{�ܑk� �(9��Yz{ զ"�� *�.$A8^&�!3A�&�gut ephNle3A�!9G !����wize�n , 40�:2��*/ &� �:�.� B%�zm%5A���% �> Si{��%NoI�cZ�e�*� �o6��j+La[decou�H5�!]�f�"=�ɖV���>YL�9CoA&� �� the4b� edm�%.�I��.2��G�,}%g"be�!aU���!"�"�2� !*N��K*t&x �R�'Y!,�:��� 1 *� �,�!�} ways��+8 �.Pk��"isF� mio1b38 H ,I��A/� ��p=r!�v�-Z�i��&�'L3�^;eH!nUv� ,C �$,d��sV]��202�54ɽE)in�-�A U��2U:��e��Y�u6�("^^Ia ��j4r�?�Austruc _�Q-:inLg.a�.!dAx Xlffe:(t�"n#e�d"probl�E�I�� Ÿ�!�-vB�*v՟!�6!�\�P2\wA�E�� !�ړ1aldbi�;� "�o0e N &5[we2p!P.)U��!�Y|�N2.lF�&+�s%%� )�=+iiTse`e0cra.�n>Fx#n�&�.*)� &RLG&A�%��>p>:�.E�J�1M�� 2 (#6- ]�B46Z �iMF� A�"��9be��U�Cice�reK-D�q$�c�>Z^�.�a�K7B�geograp-� ��%^.gc�/� ��.Z!�eD6W m2S�"�B�.�eI�� i<M$g�$0 satisfactoryQ�e9�hA>�}.f � . AnZ�!I�Ve�>)�helim�_���ye}Fl2.Q &oTp$Ij,� it&� –OR�ol_M��q"`.m��y� ��+� qB q*��%3���C&�!N1�ng QtY�B~wM2 issu|�� 1�-�.��JraΉ* �u'^a�.�� �F�� $�wf�G=65�B�*� 5��,w�$��M��%) de�9*w�:ߢ�U-�Nf�]2�2>o�8im���&�&!��a�� .�Cn~k*4_�Y��h2�4 ��A��r!��~-&��)5=g�@iI�0��[4�R����4 mbed%C�ɮo�fI��1�!" ,� 8s.� 5��5�U�)c1>k-�� oI��K� I0hFN�"bd �2�JnK�X&N �� 6e:�b�E�rn!vu� aH�\�l��"z"!:�e2L�A A��ũ�h7�i�Q�� �a)�%�4Fae�_�"��Dt*�q%�Fc�s��E=A5� ��� *Ze . S�anYN�lemb�po"A+of.K%!�� ��q&!BiA{6�!��a�!�i�t �zE�Jc*eR'.�@wj�`�7lin� �E�^jZ[4"�Og a���%W�e"�zhi�g[%9$aw2�&�4QoA�o%�M+T��!�.I!�%˝�U�Ax�,^V"�KrE��JresaX ��_aninkqa�I!����TE)� 1��.y��� n"!� *&[238!:>2>�N_O, �+ra�KE�s]�!*7O��\�ZBX"�_p�qF=v�2Mly���|: �P�ZRiR!i� �![��a��]�M"y�dyTm��Jb��u�t[27�KO��fvs��M����T< AJ�pa:A��� &�BseEy+- ��e�i��S2�i����RU�. W"�5Da n.`2W9 ��@O�4��Am�I `� �,l_L"R!S�^lexe'.v � s [4�c!Xsu#)id�\ J�l�Bs%�a�.Q��E!f� &&��!�U %.m�� .L������%2s&_F6��by���Zi,Ap&�E�{>.v��K�*ex5G��G&|� �B� ~���"�*�Jepidem&`�n:v2Ro$l.7 A֡.�-%!O%�A��6��� � I�N\A_qe�0>���!� �J}_ �2o>�&�"\E�Ki*�.aE#�x��v mf hist�� ledg�b%(*8H�t#!"�I! .�"� E� Da�M���2��9ہ!��sd��Q�3e�� 2�!�C"u29 �RG, ��� [�R��Ś�^HJA7���ii�ic gi�.�Y4ȉS&�7�*"]���!2 �Vin}��ס�as5 � h��U�ng2d5�AM�.e�F� #u��VKʃLSmbor�(n�2h%8� ���X��l �)jw�`a&��&De�NAf� ��!B cust/z/� �-� &�m��� A-cs  rzooX kton(&�](@� Cladoc�v)��K�' wid�Od-� A�nf�%� *� "�(E� t�"csr1>$5�g4�X6�%h�A� j:�u2�^)n# � u�sVN[4� �eXj�,:�rA" ra�u�`>m5cmRx�v 64�R2r� 8!��+Jj&!�2P�# ���a �7ۇT!�%i�4�}�pc��n� - Q�4!�j�)p� ��ha��.N�l� P%"K �D� �&!a�\��Y�m %�Ba ��J1n�")">>�originHK_C Tvä!�(ne Archipelu[in Finl!i$F juvenile"-�4 vBc�6po1�of:5at�V}�&�M%�mpa�Th�ll�� &Jp�2w(&�V#F&�V,BT�M�[�� d 48.�e�V=�)� "5E�24n6-O-(a�-�)>����c6e�>�W�:c�yof 648]*oi?o�DajbirymEU9�1��re kep &�:1>�Qi5 a��0"�$2LXe in���rT7a+W��o�E�G� Ak�4d #  �:� a(�Is�(� o!Y$>U�E�F������ �K mesoco�-��80 ml Ar�|0 L Medium ( ADaM ) [47�r1M�ll�"bq)-"D�alg� MonoDBminutum; "N@y� W � A�h!��9==� appl�~�E���U�Ah.�mbd�d�mA%ac ��ψ%���a]1� �up G��2+8�>�-Uly ���{��\�>me�%�ei�Q9SWn2�Ze;.to:fby �n$Aml��&�=�:� 8 , ���Q���ix0I4 {da�%Mā/q���2D11�DY� �qI24Z�J receۙ1�YL3 ceboR����0,!��r~)hf�U9T:]�E�;6���[ ��4k�'lthq�s630 mii<cJАsA| wk . EAC�on �Q%��0{.�a��q�.�fr��eǁ� y)�=%ra7V285 d�f�):� untiŗiTzathE�wP.l��/in��L, fecund�%���"�'e�im� U�;!L l��e�*_ay��!��JBv�k�0b3�iaJ�i"r�&=��$.d��eV@[bmG!" moŞ&�[tw��TGwkF1 9K��� �u"�h.���"8Sj��� i�%6@"<+=400x e��u#C [2Ba?5�(C�52�&�'�2&� �%�"�].ζn�� M_S� gIS�Qt!�^��. Dec�~d58.*Q�%2u�� .}Adi%= $p��� "��(��un�j �_ndh Q�9��14 �� A���u8EK@)� l"�M!�N5 :e.k�~�(�%�ric�9 �,reh���0R �an"+*6�=�F�0�)aik 6��"1?:S ��j�1eth4�! �in"LNe�&��AS.�"�I��$�4�&$��D�!)�d mor]![(thU]<��.���/-�").a� -���7=!Ba�!Ul9�� �P>7� isVa(?)�p"&�|[|b �o2�)i!�s6~YL�r͊7Lv0:21X.��ln�l.a�>%_]�by'��s�&�>i�AcXed.߲%m�UmVUmWe ��β� �"� y(@Q�>T0oY�E>�/w� t"@��|!& progƌ��*J$n-Q�ur�<8/�$ m�"459�R���.��2�J*lp-&R����a�8��'d2�p�H>�( i"�hmaLg)�Ue�α [4p>"�V&B �(��l��2I�,2� maximum$�&�5!� lBH��5.UH�n�.�@sHNq&X&1-A��~�G�"n�"e\.A;ca�,�T)"�* carr�t:Di2Z a h��� assu�lAwfN�#�2.�Ka�:U�M� E�A_f9 aM*�$�j�Q�)8�f�&� . A U��ar-��1�. ozn�`%�JY�b8im�>�>soW�bb�5�X����u�X2� �"r� t.K��fu|)�D:����,arU!� ac7/�D�ɜ�&,��,a5�5�_Z�Va",!9.!.">w.�a_ �o .E(&R-� &y&we� �E�e�o�eE�b'�6ceMTE�*��%V65H�Ŏ2!Ac� aStob�V���J�+E�!����mal"�_�3gll���+��mC Boltzmann��IxAE-E/kT*Eau2�.cuDkK�eWvT( k = 8 . 62 × 10−5�V K−TjITD. in K�!�H+!)' ��졧.?T-I!��2S�re?�.F of TSGi�kM b�oQ�6���1orb.c2�7�@�Cc"xz�e�s� Z��&B�.]�b�[z!G� 9j�/R ��|�/R)5i�'ir��[it�U1�e� ,~q�#6͉ ����a\;fɅA�T 0t�%�e jc ))�er) A7�#emf�Q7�0modGyR���I��+5!� �)� 'c_���h2�g2%6 *2�J,A���>����]� ��F�s �om&Rg�Mf~)�t �.1<r�~�% � )��>V9U!�g)�!�� �res��!ct:���m�*A?�or "�w.9 �:regarbaJ�|sol������5M L�9 $7���de]�1�t [49]2] B�xr&j��}*� 9�% em��%X������ �!?�J�G�JVKN���x��x�} � 6' _LZ~���%'!�v�E�c/�^�Dm$2��V�-%J�is�*� �-� �-6_so���$A>�eQβ�i B�sekv�2�E0A&RA*�UՈ%�%e��I\�!3/R�͇ ��#�N�?1r�a�� Zx�2�&� t�^U-%��  qQ�;:� � )& a9X)�<st. b?őd|Jap�Tj�dd>��*r*�w" �"J6� !v&nE�[�. ��e��do� .pH(j )%b! ��@A sl�lyI�.��]�. &��2�j�Wh2��&> �q��o]��[.2B��onR4–6BO%!!%�;~ab2����"e,6 J��� J�]4#9 YÀ�s *}�2PR� o9. f6`# �q��:*�I��ikelih��0I��%@9�:A�E^@athy�Auq�oB0N�N**6v)�:�-�$B�:GX��ʥ�ݫ��� �q)��&fg?a� �(a�U� 05ea%#��A@6�sV��d�a Pois��#&��?expec�pE+"�sC�#?9��r;Eq ""c firNw t� �v!U Bernoulli%����%�� 2�A;F!�)� ��m S�#!�[5��2�"� ��y2�Cbi& ��&�!s cMarkovp4in Monte CarloύCM\z��ipA���i6 > _D [54� ��*ƽ&}g�i9atMh&� >0)1�H[EN e&a�11)DH�"P�JAGS [5�S5f��gIjR [53]�:|�dU e [5�.F>-�=g�t���!�!� ( S2%SS3�$�E��A'�}-�-F2–&�f�)62Q@��z~p=:a(Da)to*�#5�0A�o.����I��, � 2��0e�b�&DT% M&�29�Da�$Va�Rul!z�SILd�F�.lis6(!�g�'-�"U=� \we&�} ��Biz!�a si"M+٩i�B��%A��BX�F��0�'I-!m5 )����#R� 2C�5�j 9�e��!*^ eT��� |�p�nJ,�E�&8!��. <�'reJ��A��&� or*� e�hI rV��e�.�~!��l�~ �`�W.t-%Kf6R�l�<���*} pre!s� e��J��xCl, "yb,�M . C��v�9����!��br�a�"5*CI�prow�t��i{)�y�%�A�ctw"#:i��e5�!" �mC�/�! ��=�Q�Qoa8�7�H� �p�sq+'1�Xa��3�}net�7motifV �lI valbumin-�|V&somatoe9SO�(A� vaso� Qstixp]�de ( VIn�-er�e��5�=�9a= ideaA$ t PV`j227 ro�$6��4�ic9dendri-��-o�-!�%3s�A�mu7�.-����!�s�)l[�2ak"� o,2�� �e"%f-P-V�f�K��`*��\ ��7�!;UI�synap�Aer� �:�N�it&�� *��.�`  f�6-8��� SOM-!ICp '�d� �A^e�swi�.�1ea��JA%�B�i?9top-d=� [%�a��1��)<�ze�L�Y�e��!�a; Z<s0C�"a<m*��no�bS E�� [ t�:*HyLouti � �H�� 2[c ZآT�(28�J*� T_ǧy�WE C �i'Rato/^,:fA'bio{L ]*[���~1}0>0P �]0x&g��!G(��SE�2�;��"�Z�0����%I�s ��:1�_% u�W��� �}{��� n� ��)�2]�,�&@>��A��� $,�Ge�[,"�O1� picu��)�U�.�)�=`hElb�m�i�8nap�E� � postu�t��ts:� ���f(�A�2o%Z ffe�ewhib�]0eri�:�4!5bas©�L)j]�^ ,��> hr��E^1a3u�Ie]sqo�k2���)Fa�j%�^� 6I� �F�[1A�1A�� thirVup6 C#ng�� �c��!!Z1T- �P�1%V reb֩ N aa���Ti$��S��AN�� �aD2eD.�>i�AA�ncU*����aQ��1USM�� !a�I��K�i�U��f��1�!�PV� hardY?hE� spik�2u cS/"_�MN�?4�� D� har Baˉ���)0"�+� ��! N6Y1�ᩥ#�A.i��!a!x]D�?��,•�D,��!er� �f)u�!�qy dire=�+�to.*SPֵ�~q����PV)�� �>c9*'�a�-�M�I %��IZΚI ng6�art<��hav�Cde-<53��!�!�o ';&]NIh�M� ����`�&{`!~E�.k s,+mT2c �6e� K��?��1y�����$%�thalamo' path B[224]��@ai��t B�[����,�for�:bottom-u8�put �V��A � �,ic nuclei ar��^>  ��A1<"��::fpi(�8Al�%�[í$i� )�oug�fd&2�%��K�6woc� �H�{,T0 � ���;I 1�—!�UjR������ � —Qf�A�� P�&� }�!zt��-�2� ��ng�a�����s~�V ef&`m. PV/a�i�þ�.�("a&5 �N�!�weA2!(�7&Л����!�nsive"�!�E4.� �=� J.I<��v�"��= & �� U��0�2s��%�,|v=2��+l�H��Nv�f�(�$}d$E8���.eEm�� F�) � �� $e� t"_a!�O�!,�8wi�d-�-" ( WT��7i�r� .'R�LX*��re��n.,- ynd��� ��u�5p� 6/2m�2�u�p e"re��AFaՑ��.2�G i�Do5ntnK���-t&ehq�o�%p&Yf!�1S!�dis_sm=osc��A H�a܅� Delt�7 Alpha �����bj��IJ5n2Q�!�? l�'bA�.VFe�3G�-2hB�b�ŀ!`B>�R�ob�Hhvae]A��u+��!���3o�h���%�~]rigge�Ve�!~"�O ��q)� lAwpul� . To g��,eoe% � mQQ�^$<PsdEb ,Fe�n��Cfe�,�&2kAn�tQ UFvO���&�PVOM����[ 1 �lef���2�څ��e^-> t byp?/eY �-i�+��e� y!��n�-t��B��7�p �&G"���.!�*)eLڡ�)C���&1��1!�� (Q� lo8 PC|� Z��27H��� �!�J.�2)�3 ��iP&� �Hs�� igmo"#<�!�I���a2��%�q=Frgsl�!q��fA��S�(&�My�i �mor i. A���'k a��TQ�@&4-Q�� �e� �7 e�r�$���>| s im`��ho�~.eMa�uem��["�� Ar�;��e2��a�� &�:GF�,*I4��F�1��Ex.�6>}m( cd�%>DE�%��8-��6�w �6� %�i� �\�:h �gx AF1<logar�� YSi �"�twoQq0t�ig��no0}S�$�+@`J�pSOM→�A��!��  x^�P.� cF�  !! ]�:��)iny2`�� �=sF���)��Udi&A<6 selve��X�'I1�$ ��<,U }1���etc�Tm�BI�%0 " �]!46����; �0. Beyond the �qcritical strength , the circuit transitions into a competitive winner-take-all regime , in which either the SOM or_hVIP neurons are silenced by tother population . Our mathema �Hanalysis is confirm Asim 7s , w�palso show a rapid increase ofsamplific pindex as,mutual inhib%  between�and SOM�Yls ( see Fig 1G for symmetricJS1��S1:7a8 0 ) when% back-proj VSOM→!�Lis knocked out , eff%fureDenhanc!eRzA1Ao�(is synaptic�4rt-term facilii( STF%�Although.*$plasticityu"8different types!g GABAergic�Rer�0has received A; ted attenE�,z%a�a�a�=�d%p!�Uiqs�.�y[39] . W%%refore17dPnetwork!�el��@a Tsodyks-Markram� ofZ [40 , 41]�Methods�mudetaili�Fo�5sak��si��%[,�m�-�m�%�$ses had eq��)�t)� parameter����2A%�(The overall%f�7 was vari!oy Aggq�initia��l�Gprobabil!��vle adjus��A\��a�orderaA keep%lW post1responsA�nstantJBQ�.EAs expecAJI@cau! an��!�A56Adx , s�d�WsmallerQ]i� 1.��ufficiE�jg a abovEw:@threshold A = 0 (.�In��trast!;PVU�%x���st���|�����PV��[3 , 14]!1OMQac0only very rar��- LqT�U$same class.]5ao(To investig��whe���� lackCrecur�= f�4��6��E �q� , we arti!� ally�| roduug."$among bothapB �1 syst�!i+their!�R whaA�q>Q4�mb_A�two* �i.�$2wi"ide�;a*p situ�i� ].�9 =qi)k%�)�-�zA!1�&�$2B ) , but� ilara���obtaine� .����8 S2 ���We foun��at�c��a%�����lea��!� redu�IM&6Fi�ms � even��re� ���91c�) .�aZ� ޡ~i�est:��� always obf��� ��=Ijof zero� at!��en�6�abs��.�T summary ,�v��}T like.�2\!vACSc�WVa%�eX!�8!�1�m�L"N � !{on楍 st� i>� i� largeɲv(somato-dend� . . B^��KanV�=Mwithi/ e)*� i they m��uu a* negatQ feedo &� : spike-f� ency adap�� ( SF��� promin!�featureY9(in many corC 1t��42��UpoAQ!Y�0, p�� de9 ��fir� gradu�^,%�c�quent x? �ce"� steady-st� A:t2].2'�sal�l!�5 , 6��16��whe� Eo�8claim a broad s%rum fromi�toaX�/=p.�� stud�I�A��dugmenqa %dynamic� A��A��byEadd\S %9��W able:X�<*procesg� �gS�D"� : oUE�� a ti�i . WŽ�i6%control�(4temporal evolu峱gt�n�2TF ]2I!�2<.� . AnR\of on�,rZ ds!�� ]�.J iX l ~.#V� agai��su�!E��9��aN!. A9:�Y!�� geneI5JJonMjal act�� ��ar*� e�iz� 5�of.y& �%: m�f�. .J^=g�tota� ceha1 %HvalueU�we&� %_VP{ ���Ntoe��af "E�yM~����,7�e scal�e*Z y �a�. R �2waceE�K!j"� � miss�( �g ,#5–10 mI9VA� eptor-bas!��=�0.< �ک� � , a wide rang��s�!tene2saa?,of milliseco[�NCa(�2pallow��4 �� u��6�U u ���characteA�%R�dependX�!�6J*���perfoEa �n�"s*p 3AET3! � 0mmon techniqu�ze�ar� n8 W� ideaiat ��+� be�w ompo!��oscil��Z�#t�L鈅�! x�ces tL<2V )C��% p!hiceeis meaA �`5-�� p!�n��$understoodha� erpoQ�hQEoitA�EPc�mpo�%GoF<�kto�1�)- we hE1[ a��.�� 9$n^..%�1G� !* �,%�PVE@�� —B reflE� GB� distrib�^&� —1�es��5to]�`�b�1  � $phase-shif! � logarithm1Vra� {ioWtud ��s s��|5.`( full v!�re9ce< , 1 ) yield�B�-resol?6�A�xi��AFom�+( .R)!*I�ve2) �t�6��ArR�&� !�!.�i*�ly�A�he��across�Y2AՕ��(�Z�"v ��cf!ig� . No]toD� �Eh 9&V����R��d��/��he��-!��� ex-�et6� mean6dl kept�2inL t��I��"���� e$yk ,O^� i!&`A�*� ��see�e:� low-}K.!v�� ml-e!�* �k highf}i�� �A3BE�3CWFnm�5 �m� )a��� �son�A���ity�maxim ��i9FFari��D�terplay��� a�=9� a�!r�=�A0en�q rack%���Qvv�i� l uppr� ��. With.�.�9O!�� c���e:�too slowz !�!�w��e.��m���QzV�{ nqOa�!N ha) 2�1��Y�1dec^a^b-!}��nom act &�$ly quickly��al.?)�2�5�-q�F� at pe �C� ts�� �A�hythmi�v:��." &�[43�SfYA�rR�lso� �inguishE�]%� !Mcc� �suc�� ia�-o h . Karnani et al . ( 2016 )�2�E)� NSABco� �Ŗeo &� s�n Efindivi��tud�co-Db�().�.c� sha��![g noin top!�J Ͱ gr��?���H 9� memb�-[� .��U�d!��=�&&%S VIP/�� SOM/!c)�s!Bdescrib>�2S!�)D�VVnd.DI a ly aU MP9� �.h, quan� �A�a� ged pairw!m� coe"�%�Ri���ly�?V� .T��[44�UD��/.Y&L�Nrgi� "�� ereby�M/��n.�sJ nA�Z�Ai��  er ,�_ be�ful������ 1� D"]#%�� . VP)Y:+ n��� of �� Jb!ET\s � >Ap -5��to poo al��'�$�<����M|Bwabo� ic�ZqSill i� �!bne��-Z�J�h�N��T���7Am�al&Y��$sui Z�unBsey&�"c�durof) ol!1�Wj [18 , 3�3 4�In#%c�}{��en�^`B'� M�� 6l} leavI!�'n:s 0ly unalt?9 EUop� A���]�,"� M}�"b )�=]R�N�� u"k9��� meas�f:��t d.�bottom�!�"�!1� seemvdis6 se!�4te “knobs” �c�ferX.� ]Zamoun�d�M��R1D2q throg$ń.~hannel"� �$z%&jT. ri�a�� �-}toV���in�;��K6�ena�` 9�1e:�M well-1d t�t.k4 B���e 6��7"n�5�u��x%q% #p pyramidal8 s [4�46]L*�sF 7�]s l cl&%� A6�ouŏm9-��� in vivon;hw� X h&� leve! Ie��%remai�o��sW&�"H%R�3�'�"4degreR'�&va F���E ��Y!��.0q�$+.�*g ca�) ! �(subr �s&v ual"w() �|�GU�(:�ABU��!�o switch?behavio#)-�FH �.;�u?o-� &m�sN�%d�&"c,��͢�x"w�qns^.T -1I*alP , ac�an J�,�a za�d"� a��r"�� irs�"5%de��(of�b!.� %�!-sis�g(ri� Ei"\"&J�)!�i .u, 9��l >^&exclu!;l& *e >�* . "  reveAvour�A2moI�qs�'�� ��4!��JM���}�2Wcai� e a�#2��m���iIdE�l4A , regA�( a )�rA� -:.��"�.�f �6�nx* �- c�0E 2Ydo��9@�b � Beyo� F'0R� ��Ytz$5 i�� �-N$>A0^��� c ) & ( d�*d0a|m�>?Y0)�(�abz ��'��C�u ants�ER]� ��A�9�Nnperma�por until!�"�]&t- �5CoW "C-serR�!�W�1ll�$�G,E�$u)�#$A�$ � per�%ly �!�:��r���microQh���B0�R%s.A!��6/1��P3B�. M!2!�V��J!r�,.&=���}�)�� an no l�1b*�2a� becoAS!,new�$ �(turar){�oN4i�HJ6prediM  ����l�M����E�/ most!��1l�})b�+oa�9��.�(�.s-��N2��_ H!t%of"1�ų� non-�a)E��� z. 6*#>4R��CB a�S3`S4�~ Q�v.�*t5� 3�!3ah�a�DevQ1&t�8 !5E�g�?Othose1�&�2othe��# �"�o"m#Jo� CvfC Hq�r%C�sh"Q2*'2"�-ũ! L, ag2���M boundo-s��"E=+l �eE�kreachB+��R�/)a6���m�A5s��a�YoMFTw�.e$!��N�d"�4l�.% �͡ may � �RX"1p i��)�~� �R�+���c"<,I�1�'(&|� 5� %2� —�� �,�0� UM3E*^#n#�؁B�a��  F0V> � �ng� �E&-M�y��S5a�e�W�F� !YrNisEI e�'*�%V{s~o . D��J�A�F�,� t(5�� j �6 � ��".C 2���Fm� .�<A��6imCy��Y��.��+�� Y�!r� B�e�!0�k� -� di�Qt��w� ўa�#R� ,�2 �V����E�;*�8��A�mF^,� ��atholog�;a�#)eV;!�le%yad W � �!�"ifJ�Q�)� YQ � �!�L--��Agg%se.�& �A�>..�9��>�'-6�eigen�#�Q{1:�m�".�deriv��2E�'���� unve�7�e�lyr]�qN�"ire2e�  ( ultimat>,oin5�mus(/=%�� 48!U!C�un` lyAHb60I�rvV�A�*2"��q>�yB &� R�C2verA�.~,:,��(nd—!U>�—u� _$"+ �6��@of Delta ( 1-4 HzJThe4-8 or Alph' 8-12 .)].�6! 6�p !"� 1/펩�re� �|'eJ3 Yri!� PC?< ��PV:�7�_ ( S6ٲe� stALifyE�a�#=� �}46,.�-��B��!�!Or�.u�i�rI �"U)of^:�!$�j�2s A�V�orI,i��$�I�’��@1-�*��6QF2�$E� bY�� f�!!9�$!?�0A�F/�@l*P; �Lb�*om powerijM:g���](F/��;N elev�*���+lso)�r�)! =H��1�Am� ly&rNd 2�B�Y�&W8�v���E�m�q��2Ka�&� impZf��>U6�^�+� a�?�|ll es�is� e�� ir ap��@�$�5>qr4?@" -dow�&pu.om�a�, a� [22 , 23�matri+l�4( nuclei [24$$O�ir bas?79�9eti%ic����*�? tom-upM�PlA�Af�6 �TcD(th>�5A e1s�!�I)r!.i B?ha�D 1�!.�>7 ebVax l se�5 [4�9�j�>te -A$ng calciumV 3 oinca1 �#-ja8ng� o��i,B%1�!h [50–52���4���@3nt � �iof L5B9[5&How]� \agin 1��W�*g,dA�� a2!�t-[5E1InticC3"�A �!�@3.�A� u�09- prov!,usn"A"rel7.�� �gnoh% �# . Gi�;e`:�M>iF�>s�igg�#�:�6�*� pulf �evo�H)3!�a*� w��s� af�,e end3U�I<�3�� b��Ea��6K "*T !� �>� ?1�*�76rec� histB -I� � � ( S7"M 2^ wu6:]Ic^�f�>ŰhigJ{!�bC1dA p�e)�(e%j�A��I(@ ,ag�* �%w�to�RAj�/d1$"�0h!tre�.J!�:Hcol�1|:��� JEIG1S@ �s0rea �5,/fM) i�Mce]�@��� mpi��V�Z�:CY} 4c��V]ByT "�4 vary!8�%���YR�!��V��CAM�2�A��V�6� ��a�$he mismatc�� ��m6 ���A��?�ex�*�7eR�$;2At+er6�.7 ) [563 F(authors sug�C�V�;�I�WB5�L2/3AamoBV�@�j!�� a��visF �:(�S*�[! B��� Na \5(�or-�De���l <<SI.�ѽ� e��$dmfexc�J��69��PC"M �@; ca�:by%��,aPy違r�$�E�� � data\B�"-V!BJU however �)�[&of��Lh1PN��-g�?U��9]a*�Ei subseE�!���1Aj , 57� in� m� s [5� 5�L To tXF� hyp �Wlic.Fw��d��ur� ��I�9 .�������F�:�i�a!!PC:!mot&�8�>Oj��ar"e.!m�W`-Qaf 'ng�Ke�K2`22q���S �>2� ���w*W&�)9�in�� 6��G" 'A�*�-e.?5 �Z�;� Z2-i w�P [� ��]:� Yy0��ZQnM�r|�n�cT�Hb�+��/te�?28a�s�!fM!�A.� �E�6��_� �6{�abY �1A:>�nv~�C�.E1AF Zy�F@��! �LENa����urRc. B�6�mh "/+%OQT!JU� [60�!�2&�60Mb� �3cc� "| � . We^�#Aq�he! adly�qed6.$!��� PC-�;!.B5��ct!Z �"�$� %A�&H A�!�) p � e����U���Sorn�@nO  ��2sj�N� �f*� �%9��%� Epa; �?��B��M.�C3V&���T}z . T� m�.V A�!H�yr"�2)z?t-L2G.r�8�EA�.W)�gives �$��"f�s� �&�A+;�$ Ff:�^S�!nj�U�c&�5�1b=��#n.�&2C !�A�q=a�2ndw�&a�� us���t:Vif�.>��P2��inher�Ubye9A� fl:k .��V�&��%2fOen�2�.appro1>K1!�10�. F-t�,��2���� s;�� !��4�5qK m �c8$d%�B.1calib`�!�-� &� ��[6� ex �*lin�%"�]0%&h�J infl!V� out��!�is�de-offva@ rinsic�=* 6>8A�caU=b�1mv��K&�9��*�&J�8!�Ga�lig�{� at�.���W^.�M� ��R6 .-Ver� e&3 z! ����7H[^'*�&!vmVo�15,ru>JIp O������/!ib�-� scop�a��Q�Xaek (6})6�4� or�ީ_e I�wqor."�)-3 !�sh1task-�-f$�ED�*:,� $<aen&6� p c46�.clu<pri�Rs��q�( S2F,- (d)�vibris� ( vM,jeX��%*� 5 [1I12W�426–3HQWe&p$tr�(6,� tl!67�R^O!1 � r�^+v��Pp�Oi��- expl=�.�-re\\oa+:�/#,�1$g . , [61]�4� -to-��*)#W�g���A�W��rchite2�?2(.e@6�2A"�\�?>+JXS*` iIof rse"m[e��Vm=]!on as*w,�1-��(���8)�a�KGep!Ow�4� )p�Vra�aO.�orF@��"$���It�@�=a"PP��j p%employNnumber!�co-ex�)��< `� �-Oc2� neededm��� u�� )��k�,uy vitr�7�7[ev�]ItN argux&�^ ���sub�A*to ‘M&Znotti’e�‘�.6F %=c�:!�1mc"I ir#/p�'�S d biophys��-�[[�9r+ �P�;be@A6%{�5i -th sub-p&�+�*�+��]subVBp�Rvr>!Xg`%�H"�0�1.@bezOZBof 9!1A�avoid2� to.�,Re majorVC ojtrec7^e�Jiang"�%D�jas� ket ���!�+ic` *R���  ��a8�a�s�do`, ey�^fz%YB~9gy, - yLIB��t�F62]&L.b 7k酡q�K-=*L� pli� ue_�?J)*A����5�R_a��FFollow�+)!�urayama5��E09Y3O^rM��K�a!i) /x�Y� 1�.]�{ &��B �; Dl��[&�?i&�T2�.�s?:i",�4>o] homo�Y)y�!��M~*�9c}�v�,&36 puQ-9I��a�"� P e!eplA\a6�!rol !G ques'e< a� "�i�A1:�{�E�K� �A�*��hav� og2��eWv*^a unidir;on �on m.��&aS� �4p�A�Ul%Ad�S�e�39�8u�v��(! back**gi"^H���iNM H CA~<-�p � wZof Wal�22� I6$wh�@��N��s)>PV��B�2�95�S1c jW))s�;*�yJ� �vio� �Q*�� � "m/ an�r:�m�����AstrWra9��PV2e. E�m�~lb;teP@��� to�.� EA��cap�J�+�I�.���.6fu&� �%b� ~ . i���!�serHL ��(� N .�,2��6.�=to2k�3neg*aI�&N%2���)��BFn�}R�2 aaAltiD� "�*ŕ@ %prQ�noalet �%��,!�!�i�)S � 17�Y0fk���i� fron:[assoc� !�����m)1��f���<p^�*�fc��:"Z�1w� rE� magnP. A,( � m0[�i���C!�&�koccipi��Us�Vs�%g�=� �)!�6{in"� t���^� �Bpe�(7Tn �-�&�q����it�L�ECru.m�'� �@in�^h�D>�KF ��� �;FO�Ac.Hr+lorZ�!ueg!4((�!�lape" )�" ��  "��-b,� nearbycoryU�"7m�v�#��tl�u.Z�B�N�13P� ��E@�46� >�),�4�A�a`��)���[�-}%O!�a!Bb�} Irua�$ forward-d�n���,E�!p�>�"w3��A lh�P,`!r�]e �5��C)<s��A�0dC2u�_(:Ia �M_T!5�$iխ{netE!�ef>&Y ��S1 [2-� �7�^9� r audiIm�[>TIDE�a�m�4]�lle�(N&QA s� ���-�Qh� � @C6e&7i�I!� :K�v loco�M+IA)=e�. �bPl MolinoN 5uP a �+ �&r��" ��� ��,��Mm6pl[ur� e>�*La5se4?I:�l�Hs d�^a� a:���(%)E�I)0�2�a�y6A!�I�F�I\ i2�a�I�?h.-"]+�, ab ,c�X�  �deliber":pecify!� origd�^#W�qq:5 &E�,"�|�iQ= v�P dive���ksAJal�'!�E���M��(!KdM&��agre:t sour�ҭ�E�r � ��X�� h��H�V 2nn1u�m6[$6 More�J �t^ l���acetylcha � 4d serotonin [6�gtP:�U3(�#��a��at%ZI"��[I6W� �ra\crubre)0c� Ma�nOdi�T�ta_as�VF2�qarrel��; -t�m�:a�e��Jwhisk��Xv<11Lb��)�E�&�31�z.*�5i��=9���A?%N���( �c]of6�w) �.�.P ! 16} ��"p�s[18G I>[:*����pA�q��N!+yYa� Ii�(�6�M2� q��&4u�Ra����1�*"� I=orHR�. M&�u%�s=� om�";�+�,1�L�]e �-�� �Aak ��2riv�6���;f% �icita� 5-�*$+c%=a(.`w�T�C� e�+on*U(�%��_"��3�)p� `se err�x�J�at  ABPini�of��%��s!~��!\Ja of hiera_��“�(�2�'$s [68–71Ax� =|�5�"  !���e2��6Iprincip�%x?BgUrA"e�e :71�B� �9% z!�:iQ,s�Eby burst"�!i&d&J6�6[S7�7�h�Q� nB��?&*B�NMe%*�m1��be���&�+. FѢ“1!�&� .�a�ed�n�em cona "�<i"!��w�� awarenesE: , 7�73� qR[6�� A�.�!B�t���ld!dT5 iose|:�F"u'.�H� BAQtegl5"b3���:e�L!�'oVz9ii=�4o/�$ruc Y+i� &8*��6%{�end� �[29l8a���.� �2anA1Ew!�|v�t5 }��h���:8:��:��X19�:�r�branch&� (�9- ).�� 2�nA�8a�Bn���h.t���� �nyAtVT42�l�Pathway�0:"? *�@j&�1�Qk)sJ!I�.H [7{!�:�0 ���%�1�D,"�$modw�a���&� %Q�~�D:��1.Y62o3����M�I4-�I�Ak medi�*���re�&5<,*� doe t�S�Xa�inX%te* &�"v) t{ld�%��k:�s"�!����[7U7�/��|fS;a] F�T�r�� a r�$arboriz�Ei�R{>C~��6!�sa5�6 Despkg6,�Sng� ^ � }so��]�� ��x ! x���s�Bpoou2uVTl�f%� M<"!*i!��+&R`:� �Yr�?� g�E�2�4axry�� \!W|��qd!�� A� ��i"� �A�laC h�?�TgaH�;�6!=!p�J�1�I 6v�� = �  |!:�$61Is��>��pa"�C6 EwY�eo%��=�\� ��-��%s�5.�[6ŀ�85?8ER�+]�?j&�Y19�t"�&%`trSz:#i�.�et`!/&s=�`te�_� A*�>� ( NPC = 7�����, P^FNPV = N� = NA==�*�%All2� random�DR[ ��&����T('F�%2� li�%�2/'� IfX �+d� w�c�OP\���ݰ("�$incy�outgoA%� �#  �)B made me�<� ~4 2"Jt�f !��?�&� p-�� xG !!�>��-Y=�@a-a��+�@el tak�|�p! _�L�^.�rE�I5^oB#-p@i obeys τ E d r <d t = -@+ [ I i - Θ ]+ ,�I H��q��1f9@"W�!Ws�J��:�p" + sizek��6�az3&�Iau! \0 i = c · H (u0�~�s]��5 ��c)::�f�.�C, H_!H�h"�p"(  , Θc� � � & �~ dxm emins ��-�%wl[Ca2+-TG%_�`0A쵻��,����g�>A �3� y$��ALi 0ɴE2fݩ_<z����&UZ�,# �c #>�nRw#cor���!qKfac�2-]�z�*L?pp1�� un^ c�Na�I�� ɛ.} x4N eachh7JA"� �Q,�5�"N��e�[33]:� i r ˙E�� i��w i j ur j - ax iE�+ i <� t�H→�(� �Vai2��la��� 3djA0Uh�v� u��� !i-:, u;�b��2f��3l�;x&���eq�r��!!�@ τi waE\.4a;azm�$�V63�6Y8"�!�TLM�W�/igh#$xOW2���'e���C�� �����^�e&A2� &�7� ��5"BD-�VR4[�"Xmy2z��:e0��+�b�`�I�!m0w ^ PS = 0 . |艎�)PVQ"��-�*C !�hD7UZg�*��� om"P �� r��enama�AwavIEha�g�ff �hevWE�645n:% EP =� +Pf /- �.*Ff)8mR>� �J�R��/m�|&* 9^o F3�F9�au.o�t)&�-�3� !��E��nou�Ż-m-6��f���i��@,2Z�a��τ a a�5�b����8 )�oa_�6)u�rG!�*�T� aiof�+�@�`��2��ZbR:}τ�)�hs.�iJo�9C1�5�b%x6�]M �q!��8!�M( bK [a�r.7��iI2?::$!$s�&�X bA!��. S&,b2� et� ��bA@MHJ�-�R9�hQ�)� jK i$NlvA�cy4��B>��&�: uIR� U s -�{τ f +( 1)�Ao53�f��>�`�0�1�rxPIX�o�&�y!ech8[s�or.�avail�� �� U�i9L�(A0�6cM` � u!I�j�elaxe��})Rf��-��I� U� �:�UF��. PreF��#)Ff��n� &+ a�uU�f^�!4n�U�l2}>�fe� ML.NI��Usy�1Sτf = 2y���ٗB�a= 1 (�,kivalent}Use�i ��f& �q�f��,�9ʼn�s58�Q�l%A�F �djE��bKj����1m5��oڇ�Qa �8�o�Qi�!��^� �9�aWa}�3 U�s)�1��[�Iip�-.�D4a,nd� x�o]r/&�:� �~ ��"6" (xD�W&� . Ad��%ܡR&*L�seM87bAs�/�~c�*t�@)��ʃ) us xmoP� M L� �t�W"�p�6Na�C�+Z*.c �.�% L�9�1eeM�� ��� ?� ���%����B��c,d�T� е. 1@�# ak�1� Q�Ʌ"� �%-{��esgazQ];� sA=6E � tan�8U�(e iYat)�� ��`�@�3/�4!.ޅ�I-8,WT��gim!�K&\qv�� u� qpr� ?.6�mj�/ %z��,�jZ!�-��r�=��+� �j ) 1��( 1�&b 5�[6�@!�p! PC ,} ��e�aYIg�:� # o x�xah= x==5�AD2� xE��7 . 5/�DxD��1-�5�N%8!�5 ��& t�D"�ey�� �i 1�Ee� �_�<�m�z�[e�;�m��&#�#b1/T1�aAs�&D4>X�fict#E�aBge wave x�  =x3 π t T�( 1���T�Q5A� 600]{d �&�{�"���x�_"j!��[�E�!�Bwa�:h�*�aa��&�QAeIAf���`tko�P�{DB�$, A��  x ¯ (ZzG|8��"@Eq!Sa�8iJ��|� ܂�i E@i�iaY%;>!:�ME���:-�, � �a�$0 . 6 ξ s K+4���.)�c��� s ξ 7�ξi� drawQ�� �aGaussian/%�V-Y� m��LP���)IR k9\ � �� unt����/6��zbyz[6KrB m%��&���peq"}2A�, &�ss& # � x5�E��� %s�sM3�>�hA���exaAe2@u���4%>S3 & �qAV��Z� of 2�[E�B�f aV��6 SDji��ل�2.U !.`�&aP#. ���&��%]><��,t�log 2��_m�]%U( 1�im�| mrefO *� e sl�FM� sigmDB�ul w� eae I") �j1D� 1F��Y2�!Etp@��L6A�fQŹ cpas*bU�6 &�-ڞ'DAlA2.E� �KN�� cal���e��9��m��!5�� )5S��^� E��&endI��|�mI�%�MU�!š-f�.�"C,� �"PV�"x -A�.>r wD�I���τC��"x .ESr 7�SV v� F� FA'F +͆.NVV  NVS ]�:ib�m nm[6 2�%(a�T)nM܆!C�s rFVW*AR6QxcJs� g��plu�%possi&�`r"� c"s6nr_� Solv� �qu .�-�F.}o&� '�%�� PV-rP1r]'%}�)�0A��%�)�SV ( x%�1�)*E0^9!�VS�1�.�>�e$"�@lPV − r�a���`K, ��a qPS.�)�1��2� a[,!� ��*B� �m��w��__AB�% �V��%Q��TNali�!!* &+.rB�P6F Q"5��Ho�0?(^J,��A.�B%��� �!GF5�u �*6u!XR)R qis*�E.�+��z)�� customݟ Pyth�Eode wr�g�]LH a.b K[re enm~g�5 d us��a 2nd->0Runge-Kutta m��E �uximum' ste�A� 05LZ� q��A[D*) �Hzgi6(*�W��b!uiO��==1*A�D )b�� ourc8!0"sb�N de public!�;leG ű .�iM� biot5 * m+Wdimenach� heno��>L�c!ddis�S link&&L� 1!�D Fa{ "iome-wYmU7��UsE�E� �al abund���&twoC�s��� A+"�� , |4K*�}�d� .�a��4u�s  4�1�=)I�A�c*OW�SSe�Z'c�:easily �tD%#^&  spur��==� aŕ�nno"�Je Y�!. Ue't'��K�`|�w Ove� da6iD�em9�yrec::A� applPõ2'e �st wC[cp5ri �flammat�. bowe�Mez� {c�=�e!�"ZI��:-�C,� ndarٟ&�H�d����5!0E�Z&�d2YisM"lyE�< �y DJ �a} h�j�4racw I�aQcak ��1 �poAF�1immun.ߋ�<y��yQ�-!b�U-gA��3as"�=t%++%HZ~ �4���s��a��=ny eco�VkocP� human �she^I"�ty &V9hasu���uW5� eciR'��ad�[Acul�12�I7���sn�bm�S2:7itu�7etageno.�A� 16S rRNA �L!�ofA�'��R&/�m�� �ka(�P�W2�2 manih�s�ab.�u I�? dram"�aE_Z��[1–�@dAAxi�6,I1sQ5;litqn�2E"�b= tted"� �3 y`$ planE��A��jlora [9�G�;New�M�YDrm/r =�O9>t"Qoa%�&}�Z7!�D!;����.�. I��� b�( MWAa ha�V carr!� �diabe0, arthխ!�_>�fautism��_��2��� 4–w. mclh�e>�weac3r�+4^M&�" ;��A=�dysbioti�4!�GNte�,H0,gli�A"�,�J\E�a very��݌a9�sh# �7ndK1�[14�'�<2el23!�;ok,�&.�l�b" ( IB�+"~Ocld(to 100 taxa�121�@k�X��7aiVty�K[��. SC�li�@6��%�g��woɝ! � l�2�f�V�t1#�M�8O-��!i�9~���y� ���qklIn��a�t�1"�Z �E��hH�8 �8.M�?-:�  !]^C�z�",y`ǐY�m��=9multif -�_n�7ch� I�{<�C�l.�zDZ 1Z��a)��&fai:#�e� some�:a�I�f1em*� . OnOGc��%AQ�pervas<+� AR��8�s:5�A4et8 r�ni��:�j8A x�-`!!��� surv(#A�ndA$u��ir �;�� � [2�=3vI[�*~ �@c� *zG�����p u�m2L�%�6�� �f  -o"�rj"#s�gQ!��(Tra2"I�.� !=lexe!T�I6i:]y�@a=!�aN�@�zde�H�i�of>�.�sa�ulare_cud������B 2T q? e]��a��X�+6ii+Y@�-��{ m+-co� � �pap� A rea��$��:�� �4�$&I�?_%R� ��,�{m6-� iaJA�"q 8 Mf ��H)5��f��b�� "UExU dure�]%=:�entropy�j [6��RoVdubu�%:� G+� A�  A�uor DAAi��&In% tM %OstI5onť,:� -�K/N� ev&porA2�PGxp&�OrEf{ ]<.oSapQ�.~, genu� AUN!�N�}0i Roseburi�9FaeO'b9�u�ausnitzi�,Bifidoadolesg Bl` a!�� QTuric P , OV�ospirEuLdolichu� Aggr�� inaA�Sut�ull�oSA�)zs'S� E�a��@-kn�Y[40–^��[�KHreuMd�t�e&Hi)�2eJm�p��!��)lR>s1`�<�9E)͗�Gn� �Alet�(X E��m=)�tF�a�Dz��i����!e)�x!��� %5��HE v* Rdiagn# e��X�{5gqY��!�XbeA%�&.�Ong����"�toa�(�?ly-$8d*VY�%$  , ��E�� ��"&[S=&[Pe�he�Z�q�P��g�f^Ya hund!�1 vu �xcon�%_W . A> �8vT1p'aQEg�OB��� h��T�$ir�6� �FTf-��qb��co&�. Ide�)fc� ��W�8��iba9to�V �����M�>~&m  G)�w�>a8I�� \0&og!]8����~co�#��*� ���&{�Zk`m�k��off��!{��suc��3manЦ Ao5z�U�Y�&o$[3��6aKC�7b�]a0domA�� �q0t�2@��K?�� � mo]KR�6�"�/�1�bi d2� ]Id(of� ���(� % �(ir5&��e���tex]LE��+2wQ��""� �% �&�, flock! Er.N(_ rote�"�`%"#�N�!⁹�QMk`>�� hork"Y&aN �G6��q�Pl��%Pum�V���� A� S1 T���B5R�A�"� }3$P ( {li} )�;t � pfBH $ l i '�0Z e4,i h i+ 1 2  j J �:2lD,�PK lia�� log-Idn"�Y e�  h2�:;ɣ�" �&;�8�b$!� nd J2�:I�����$64j;)���Tf 1/Z�normal&�KE������"> t3Q:��l�x!}w�^= ��y.��-�� �� |�By���ubX� -to- )Ş�R�7.�caPcb!� �2@ Zk';)A�X&+ReYK� ����ar&L��!�Y�NH�addtioP]���iF[�ly � ��al�.it�%�a��a�R.W5�[5�p5� !1U�)i�n &_)��M�Oe�.�!J�y � !�"dvo|1�r}� new�V��_^�5 JA�"�2��UO�.r8U!V�*.5n,� In!����g�$ze&]*�m���� ��]PI|qya��%(�_&��=�"N�7J@A.e ���(����,Q� �Bh��q�6�m -〈li〉��E�B m = J−1� B�b�-���B% ,�a3Q� �i,�E,���&� � ;`h-!�3Y"o�+� |�}rV)�n��aa��Sv�c��-� �+ hipr/&�yV2�[Uoynthe�!��1Q��We�,e�"� p&6BR�� ��s�0-���T� �>Yin��"�Xsu�!Y-W%mucos�;ops!8of 275��%�p q7tZ^� -na childre�, Crohn’s4 (Vub� on"\189�Gc�> �� �� %�� h!"^ 51J��ka�3n1000!�dQP-�(J&is�xe� infen�a�E��[gHx J%�kI����69*� �<� 47 �*!�%9�]�@< + X%E��o�O � �s.�]Tcee�h.�f1V]q�I�,�Pfi�7�9S� *���er�H"rQ;isbMik�̡&f%d��:�("e��c���*+Y�����%!al� *�7J2� 7p�se�/led�efa r�"K� fac�nmx�])�dlL7/��� Erh��m������2E=S12G!�h3mpr�!�qu+�:obustfZ NE�B.&!E�Z�E��t� dL�pq; of J!~"�.�p�r�"��s�.lytX��}� N�A� V�Va�To *�m��i�>�*.�H%w�����{�ioa%�n.$J�!�76�!G�� U;p�y%ba�Mmod��~�� �iq�B�5 ��Vv#�E J� m�6��MeptA� �j.C�6i�na9v�X.1.]W#:so�� �:aseK=thd ndɥr1�%%��1b�-a��Je)v K)(va��o(2�D:��Qhsub��|#�Z  �.�E�(e*: _a"cpo� � l2���&�._�� �.pe�z&is� " 5Ycon!8� t"���c!� l 6 I�' `ed-�� E�6-*I�n"��"c�o�A��PS e���2�"V�d r��.�� $A i�z�o�i��6�Wqh!�uЊ� e�.is�!�>�blwl� !)�?>d�=C58)Q'�e���o�Unb<(!�rows�39^I%\Aȥ�"2ka�bB ��Eω-( ���B> 2���a�X!��&�. Ad�R3!�ZL ;�ur.;c �E�rNuteuCc*Ji?� 2-�2Da,.� !,��!>���]`e}�� ��C�r�iU<9�2*� � 2� ?!����"�8�w&)�c<�tE"1�u�V`\��5!�)�b!F scar�b*�v�Y ���tun �T >^!? -�6Ps�ght=_ way��(z9*��U)2!X������ enco�in 1���&U}&p.o .�on �k]\Ezy�K!^�#&%�c�re�4&ofZ6t#�h:h!�4ayV���e�� ��ME62��S9� & 3g|^-0-E��AXf��(u�Y�%!aم:��`��(�* $�;"[2��a�>�>:"� ! `�E'Ѫ�Uat-2���B�DIY2ye��asuh��/�;3X�Z�a^�#��re$-ll{�t� 3 J{�_�2)XK� Z!2�.pQ�*�% u��>� )�yS5y����.��=O�in6��,M#�4*� m ��&��! ��$� 65! ~T�FAEd��!nhthel[��e ۻo[� � G^�by�Xz -O�\� �n.�$�do�L#a�u�ۅ3�.2#b� ��)�� � �J���C��b�$" m�F�i?B � e*�%I51��1%] VE�1!�-C6���"X�3�=oP}9.��3)3� c i���.��'G�"�,�L��x2�"9*�re��� �=�-�2q�[+� s:(nI2pA8�=�-fe�"=a�*Xe�T.W)�!::�. O���� ���parsea�aW �-��1B����7���%'�E!�SparCC LTd� packagB3�aJ��%�T&2��:3��is�}E%�q��*q(��$�l_$Lxa�+�q24 "�I(!Ype�:"2�2*%l�no�'/E��Gea2� jAVp(��!еI �*89� :i �s;�,eni�6��banFAh*ڗs true�. AE��*K�%|@Ra[1�NI2� ��4�%��,d��2M+b]ql�d�-�\1. -\"Sc.�,F�a�or�-�,*}:!at&�� A�2�d!"e&��[6�V6J1 4Aq{�7e6�.m�a a�a!=>�#�K .��gG�vw�� =�%-�S�OB��*bKC�r2s"� ��r xces�v��U��,i�[-�&l "�$-�e�2<>7!�.�"60I!1.Ǜ�n:N �t� �i6M�kmorV.!PM]. ��goa�$%�aI o guA ��b'�"v' e���Ea�uw�핉� Q% |�(2"��Ub4��7Mx�� secr�%7 toxi�"�W���"utrie�#:�"�G��(ejO!�nd.�mucn*bD�[6)Z6H {��!he�- �I�q�  ��*� *b�=� 7=L4j��5% J���O�.m"ɔaw.�/6�/64^�/�Ł��"�WADa �B� )�%�X-���9"P!-� ` R0)�&��!�2&�A@alu�R! �V.�2o�.)h���H�]G6�I�uLv� m.�� �2�toiJ�� edY8Q�e�V�.�:ai5JvA/~! &D �~Gz���%=�AQ5�!��)�q�^� �l.�:e�&K>�0RiW-)�F F]Z^Wh�Ia=<��%%! �E�]x3S*; v I�'(ch"��aGv�� ��Rr/(���K�#s�f� /���*v!j�z&�/�#�͐��|"�:0sF�w�vlog ����&ue�by.i-ll-.c9�.IBD: � :j0F .w�.�0"x0�&�0%)y n<+Da�J@o ��y��!V, ulce; ���;.h0�s�*U�:��a�*�,!��Ri�>�Maz���koH6�;Nw>�1 �, ccup'$w trophic (2-�>efer�!��polysac�S; �QfF� [7?:�x�y:M�)���Be l��c aciE�� d@g�"�*酡�t��a/�\slA��(idic enviro�V col7&�vDB�"O ^,���.�0]io�7�y.N�>3!PY�5�z@6�,1|�nby5C��:�diga��;�V-ch�fatty%h�SCF56)��-~t �&gyC�}ų[4� 4Ab7� 7�  Q�b�AA�kͥe�Y!�, T!� ��� eassk���8sur Wzy �{ b6X�%��wgB&<6u.B8 9�!�1�O! E �Lachn�4cea[at�Yfin�#�JK# � �Sp����6;9�Bn�E�=m�D%�)Zs[�}AY#� �9inv���A+metabol'?)��1�H"K,��p-n5;�r�jora;r� �BE�'q�i� V,(�d G � Q;[7�>80�f>]�I! ���acU�S ��k�r� �aJbu�C����pl5���զ�:�3$by nourish� ��ocyJ (g�VAj ��[ef �Y�)N�!��g>*Q�E3z7�?2�A�a,� �s�H.'6� ��"���A�ing"Ƭ)�j���-,N�6�"0�E! dysr-%�A�%s�^[e� 49<\�2yU� �m.a`u�r�"%!�� iE .&�8lO6�8��a �-*�m52[82D�1�[l�%�I*y�t� {�K\#9ZpU|C�����y is%e"� [�A�i85]Cum�6#�� ��1ask: V� �� a�,2�� lean�'���JVA�\ �  Il� ��[8r�9��!�2%!2�pU�xappeaV�qui� ��x)-�1�.uĖR& ost-LQglycoY4�� �| muci $}�,of SCFA , an�Cd modulation of bile-acid metabolism [84 , 91] . The latter interact;�was suggested to be a major factor in the protective roleudOscillospira against infec��s with Clostridium difficile [91–93�P4control groups6�resul��dicate�Nexpans-o manyAa inclu%�Topportunistic pathogen�dri�I{i�;t�j�A cʡ�,network showE�$Fig 3 . Ona/ ssibilityA�>dysbio!xofsymbio�micro ��k!t les� mpete#ը����aE+op�up nicheA�at ca��i��HbybaSe Z, {exploAdp�,�commens�A�s��e�p�x from=n$, but also�!')�)wva%�,, a phenomen�Yha�$en recen��demonstr�^i�es [97��Little�kn!� abou�>ad fic -,f� play\!��4mAge�.�S\in gut health . Aggregat��a�%. on memberQor6>M*A�elo�#*�saO,as periodont�B��2b4al vaginEl [98–100!ጥ�2*��!�� edɶaA摉 risk�!recur�� [101e��, %�QZh�(lacks overtUica-)_�produc{con� ���ask2�8]bZ . Some���Trea���a�g�in� ientm�,good outcome�3U 105]�!N =� ��� or no5M����!!K[� 103 , 106� . Ex!�� al� estiAaons��J�)e����$roperties; �rticula� it doese�in!} a strong�-r��se�a�e� modea� a��to adh�=to�u%�7�8A!Fur%5,.a�ins�.!!�pa-��qed!Up�typic2E iaeH omic ,AJte S��� ssay��N the�~2�is�ong��hq,worse behavie�s�+e�childrenmHutism��trX sorder�D��syndrA�[19� 0%89!8T!Uf�~,�@��nX coul� ! 9gut-bra xi�\8In summary , weM�$a small nu��axa���@extens[ ��� !m accuAly~ "�statu|Dm =Uhhava��m�dramat9 ly5�tMya�� rigger��A ������targe!���Q� ofYq?) �A�[12!�PQ q���se �"� fa��d� oniz� ~q�� buty!.A�� , �o*� ,4� /�9d:�� pri%�E�-eti� � �. M6 dM�s� acm n� by sub� �e*� h * �� "( �j�4QZNet98RI�beM�ly D !�h��$. SimilarlA� \�gfulWE�e� �dynamic"� eco)�- �? env���( o untang� h_ mplex��of�m e!�i im�{� �$ccount for13��*r usH me!� ore2 6� y?u=�da� ��o; topapGs!�i�2U$approach bp ��princip��(f maximum e� py . DAA�pplA'�ny܁�data !��{�JufP� la�6�| q� i.. �Nu.�a�yx btained�HRef . ]���r!\� !�Q�m=(newly-diagn%A, treatA-na��6��e(1 toѹ!�T!y�r� %��in�5��r��llo�졂��11�8procedures adop��E�aeto ena/�% �is�PE . Spec ��%]ah mu� testAPmean log-transformed "O sz� rminin.�&�an2�. To fi� >khl_�%P�[�u!��eleA�gqmi%g-covaria�%Cen�Cij��Y� matrix%��,as J = C−1�8per!,a�a�u value de5oon [110]�remov0A64�K� %�am�_of nois�Nes> �%;� ��efxsN%Has h = J�$See S1 Tex��f� detaiE�A�ompQ-A� carr�w in Python:MWeIkXscikit-learn 0 . 15 . 2!1]%� hierarchi��cluste�a.�uilU e supervi�"�rs gin�4B!!�m�t�HS8)>�c�-Yc���e!�� thro5-fol>ra8(cross-valid 9g100 rand%r�� K)�i EndA>Hset�jForE-"' ,f}6��,�:confi���n!�4penalty parame��mr� w] -�6 ins� �Agi՚!�eM. feat��sel Z isU,��E`4Zas �Hs: Erysipelotrichal:Pasteu# .L(F�U��) E��� 4�R3]�  ; " acea� �n�A�6�36�(�� fami��(; Roseburia��Diali�4 ,B�> (Haemophilus���G ��B .�les�i� 8F . prausnitzii h,E . dolichum��b ot& coprɶ.�A�$influenzae��E�es � .� toX, bothE>�a6jire� on 17Y��G9�� m bea�J��X�A�*O�uAe����6Pe machZ�+_ algorithm�'thG�iveu�AU�:Cq�of����aD�$l�W=Vr�y b% > c� acho.@ZP�� l�XQf mis��in Wolb!a- w��ct� �� �K threeB=�3� s: n�� � Zm*A� �&%�+(�ubly�]� �inheri� :��).V #_].k � �(b�  � Ax�!�C�osqui)� mitj&�g$dengue vir� DENV�ZW_N�W�Plasmo4. From�sh �b� A��iVcA�i�.c 7aa���y�is�v�(�IŐe%k-,�!R�xi of>��(p�/�^s2 eva�c�@a��olJi)�,�1enh �)�A�in `I!��A��wi[v heR���woU��st7 A t� �:�)A:erepu�,X-)A;q��fwo flaviE1��ENmA<( Kunj��  )Kur��Y&�9�had s blockATI���� �l��12�. �magnitud:c E *K�ow�qc� !ulIASN�M�"(�noYYk]7_M7�U�eiA�)WorZV)�MZA� aegypti F�,Q �!Za3�9�aQ-u�r!hsaf�a�o%�� D%Q!� s�des �q>6k��aR! *1u -bor��U)#�V�(Chikungunya�� CHIKv� , ye� f59YF7!mal\,��AEfoEy<�A year�–�o�#dth!2s�Q&T� onIr}��&=���at=ai;i� � esVP2�whet�Aqv2r��gun ed�� Aed�M�[�QToeN} $1�ce.success�"�i:�� !M$e6(N<�Y���s wMel} MelPop AlbB� � �az�* $[6 , �0]�^i�lbopic"(�edE2ts1@�[!�J��q4 ��- ypolyne��s!�nd Anop stev si (�Z^l�>& [1�4�1y6B �-�I�ex�#�6�bioX!sa�I"lQ#��C"��]� �(ews see [15|7 �H"&a B �VinglU�re]recalci��&9M�A, ham�nga�ortLbe(# uSy�.� Z , it�7E�ca �[1�dN� EYV0�C�d� � ��ex��pro � igh�toU-�-}.�=In�pJ Q� ly oK���is ua,s!A#q%u.�bsequ��L inmua�� p����� U� .�Bat��! .��� Flu J!�inV e �e� fluv�$lM��d oocy.�)�P� avia��t\parasite P . gallinaceum"X�Zele �%�av!��: h5�U�&? -*� comb�(�.� � T��'�"L0Culex pipiensd7 o�jct�2�F}m/ &#�y� Mous��I�/ QRA �%ca�f-�l�e�.� !tw]ɕ�( ��AE( B )=�l�) �e��F.��d . H> �}�N�7�iA�9vec ,A�etg)��f| c �v��lcs 9e-%�.'[2�In ad� - �= �K�&��iQA3�f�W�in�!_ V� on.y�V ^5R�<! j�aan.�x!e6=in�� tarsG [2P..D"]*�� �f) iinhibB_��� C .p�� L.ev#a�5=�ś. 9+)�y�di�bu%��$�!�� in female6��m� .�tA� xvm�!H~� ;�.B��"�!d= qPCR]A&Fe��MZ�urfacm otein sp  !�jun�m�2��n gen� norm�h%�J&��Ao�0E���i�aQ5�, �aG ( ~1011 b,-/mL�eC N�8( Mann-Whitney b, p =� 007 )�oat:~s �( dpi)!!�R�.hanWobserv -?m�)�U�%�(u1AU9,� NltP LominaV�.�C>he E* bB%H musc�issueC2mid./ 3Dfat bodyE��* tarkAF trasE/j�.��l 0toS9"�A�� �$�N$!XA�11F & 1G���!v�.��u 6 :�a�<�-��3R/� N�=� ��+\]��3 � �72~I�y"~-��zxineυ]��MI�T�!�* 0�Vs �'_ �9,A�li�Z:b^3�6� �ra/�"l� Q r�e&f� _����8�axa([0(.D%n�$2� wh� �n�Jdi��vg ���p�/{6 $tT�� Ha1&p $wnsville w�%yp�(W�� .�) RJ%� W!� q w ��&p��2 �+bl�1 meal��pi�i o$Eincub��7a"'\ ]scrib��ma�&al� � s.r"U%[.> i2a,  ��@� !�z?%3� .$��a!ll�q� k��. Jc�+�/(1�&�)�9�(ve�nd� .6��A9bo^a5��=&(8�-d4:~.y402 ) by ~1 . 5&sA�w&$9%.Z��!� ...6�E[��Q?)7�f�g,esD�/ in +1{ge1�WE�a ~ 3�i%�.��j�1 ?!~ 2jIE� .�1sj^4��S^���:�n�~2�&d ,_(.[(.�n>� �R�%E)� 5<1>CM�a)��a@��%�.xs �an ~8)Qb�.�s�>`$Fi 9�4nW2` \�> %0)I!&j|!��J���N� U.Ib�5�/N�SalivaEkcold)�|�fee�;q�fq��8mǽ�t�� ��to%�-naïveBJ�1rjto [2�>�0&�h�bJ�1ngx}]s#5by qRT-� !�g ��. N �1us �-&��� =6=�j� g� , 22%��)bbQV�,I� ��QeA�T�. Fin�&�+)' h.�&��A� .~!�>��VR�=MQ�6�"�#�>�"&� ��� �J>)Is2�I )/)�M�>pU(=>{BWJ�"� �F_(��7�0E �6�N=h"�g-� �4pl��2� n�!�j�4edI#�&v weZnf�.kc-i6cW repeE�' z A�W0a�^�W��AG:�1�d6"� && rn &� O�� � � ititJ4��7� in whole� Iw3� <�l �ZWe� | he e9@ 2� HE:q`�Z3A�F� I�'*�=�. V�).�VY M4&� ���a��>%m� 6�1�1�. Tq}� �AO��{���7xi@  on�4i-J� >�in-oPFU1i!�5�� �. A�;�A=%Nk�y ,w28:z 2���u��(��Œ�%�ZDM+I]�fVm I��>r!�r���r_an "H =w!?/ -)�e�J�/3-L �!p� -sE ��aa�~ N �W��=;(�Ct�twoo4�$ non-6��3VS 13 )�of ��nm�q�u.P a�Q�=� �a�6�;��>�2�m�per�1ag�#� %�M�!�9����eA&�=J�jN eF�" �1h�u5��R1n����A� T*{ ]��,wN)H�s rs V;.�A[Et�$UJ� z�8�a�P.H�� ή 3�&`  en��y �I � :C�b�  '� }e"S�,�6�@�H� *�/%�,�+,%y,�+!a*�$[.y+re�&N}*�� ��"d6�Gio���/lea�O"�"}.�[2-)2P28w CIn.�2�$Dod.�$!$E��O!i��-he�)os6k ) �a�NKI�; B�9'Z"�a6�-4�=!Od��)�22ed6U ; #%�  #)�Med%�2)J!I is wAs>� vH)A2 5�isW�Ce� ��'�/a�9B;� Y �ow!E� back�Knd�o�*� ��Yq�"b by>�%���@ 3a��F�.P2e0!V�=yJ;72s%�2i� I�*�28��>w&9���&� al"�$z�.a�gݸ*m�b)�!"�&V�!;%��aK�wE0cM � 5&>(��y�NVR�!��R��# �>����"i� ��!0ffer markedly� o ="Z��2�>}.<(8J�E.�y�*�#�!ES2�, unlik x � &.�%.�y]��=2 B�x.���C&H=,�9)�edkALQ��"T5 n� 6� ny. R�P� A��.G$��us�%rn!�q#sh����-b� terpre�RcVJon��y��"20lyA/9LY�n .m,�* �*�K�u' �field9�R3l� grama�M�'�0Y�б�F�#6\)m�hf�#���#R7;2�. BeF$by volunte�"(( Monash Un�&s�4 human ethIHp��t�HCF11/0766-201100038"!�-: y��A��9FcHc Rese�B E lComu1e�MUHRE^ A� dult.�pYin~D��r�:�@t;��FY ipa�N� TX�^0UL�CinDD2!e�Ybht)p��'T~U�,N�"7$���b�E�e��� �&�[� Tou�v���N�.<0�iso>X6200 �&��"���-ZDJ�.FC�;2�� oXA�xtr�%� ���D��H��, fash6�� ��R� �L�,� 50e)7H5- ���Ib'�kA�5M�.�H���%2�&/�&� ��y�. F�n sepa�%7un�� 24 h6�Bm�C` / �\4g=of�|a12�)�:�!� �1), ,2�#� FISHxRngorg>�z !. S�'�i!.�,|ccarcass� leg)�F� r�m�) �&�%BI!D}�U�Q����/>�1)V *)-*Y2)eg�:��� ( Queenslk , Au� lia !20�HA��y� ؉nkS2Y��$ly�ia�a gifrW Prof Zhiy�SX�8$Michigan SsW��p>�A2���)� 3l�7�-25in [6]�D�&�GA�YEq��hatchI9Vpla�inwK#0)�GCHH2O oi^ �suppl��. 50 mg/L f�2f�#[Tetr�7�85}����e�. Larv>2�2r-u�NQ]of ~150�3 L� �N).-�C�y4JM�2�b;C�~�/priQ�1� ���UqE.6[!���of �Y��:�4��wOMKH(CJ�]� diss"on �_!�sush�50 μ%dice-cfKSchneJ1s medH Sigma-AldTIi{a�mL epPorf tub @a���crush~ riefB sA��pla}JpesgZafUJbP�3 mm g<] b�e�d]�!k ��Evortex5�minhne�(?b�V$(homogenq iol�.A� rifu��at 4°CE�5wat!�0 x g �eaZ erna�Ro2 s::[_filte�(� 5 μM�S2syringb-A!x� !_E�*l.����10�120r�discard.!xpelle.)�in�Suntil�k-��B!".e�QKE�q�Q��.o(8�e�Q�b�.�Au"� � �/� LIVE/DEAD iIki�2Xmo�er-&cL!k9l�'2Sp�$a hemocyto/M�BFe�!�horac�Oly)~ 1q��}){E�U�F�/!F�)� a pu� ifcapill�7A�sBndh��S �o�F Nano!k II� rumm�cSc�)�I%�6e;6�K ( 40.`Ucu�0aL6a_E65%�;.,<idE �(12h light/d�.yA/�H �Ace"\" RGuJduB A�9hѝg��ri�2� &�Ձmo���"� 7F14*� ��0���* �6"Z fluor$Mc� situ hybggs( !�DNAe[mj�"�Bs���ly�N� �A�$DNeasy 96 � & Ti�0i4Qiagena.cc&�%9manufac�Or�sp9U!���Quant�fve �%t.�DmMreM >��&�����#s �_AT���E�by [30] �^�3� co� �}�{^�3(, ward X� 5’-GCATTTGGTTAYAAAATGGACGA-3’ , reve�Q � 3( GGAGTGATAG> ATCTTCAAT 4�*�2� {4V� GACTACCbGAAGAT C _>�:�CACAG�/T�TC5)E. + x wT�9� m�����a6&40( Graphpad Pr�]!a�6 . 0fE�9�!�l�a�c ~KQ0 paraffin-BbI�C��  �[.�byiI,!]&: � 3Y[Dp�:/1�pro4�* st 16S rRm�eau�E�ZE��i"Ca10� � m��$al"� �!A��i�c!W5-�CTE/ TTGC!� AUglab��3%8Alexa 488 dye ('"e�. DAPIk�tr���b�`�*[aTa�� en�Lof�I& Nsery`e 2 ( S-�.$ET300 [32]o.�V�caEou� 9�[3�>V�!"�RH:� Ja�Mackenzi�Melbou�I:� fb�e�C6/36j�;�G+2?:6*���� -(-)f�(N,iSH� gra fres� 7Q iaG) PomW"�+!e��1k�2E'R�,6�F[�&�500�  =R r�40/���6���mour�*��� a 50:�ix�uI� fibriD�; heep �a�u7cul/yI� �� 107��1ies9#=-2!�108 pfu V> r-A�� a piec �sal�porcin��t� n82etcb ,X �ter-jA�2,gra: hap�tus�h�) o 37e !OR;'C�R)` . Fu� e�>�B�-0!�!ZR� �� � N�Ebb�  / i:� a�n&/� ��BL�.F"�Y/%�au�@�&.�>T 4 ��se�df�T RPMIb�!u�o�t -80!�� �^s�iލe �v �! re-� �A5-day-�96� .�^�.)[�Sw���7N7.kthe#A�m5�P`9Z�:bov -':�4=2����)n8d)��)�=�u%��02@)�VK)�H%� g��2T�A} %A��OQ�I. ���b�Lra�30 s/��S3i � �HZ�UzCF*�Av:) &t"��1"��.�B��jlaque�s6 �. CU1<a�.�ire�sBKl q� fy2"ic�7� , .  67MVf�Nucleounw Il Mac0y-Nagel P2�(�$!�!�)�c� prV�1 vidue&�2� � AfoF� AA� TAGA� AGACCG !�N� CGTTCTGTGt GF ATGz Y!��usj�.�6V �-�&�Y��/�Cid/=�tubule-�Ed� u�korgan: * at��t�q�v!WaG. S8� F mP stru !#fu�At inctFt�s:Eba;p� reg!teU`e “_c�0� ” ( Inv��m�gm-p*;Kndg � he 8!�un�pA@�$roundworm }# elegZV)8�)amphid �fne2(phasmid �`ory 3j subda7��M �dfIgb.kk]Z ul�AIe:![r l doubletM} RZ^ nd aE)�&[>7 . It&*%S#at2) �#�r?san)V,�  o mamaDawk <'Mwe) �r!�biU�wI�An�km =&Zg.�Yry15 nd �.�&��oE@:b�!, .uL� (-eS. nphp-�.�U��log�JS:E(genes arl-1�+klp-1�p/unc-119E9�5kyt8(qui��or�5.A�vC=RhW+s�?wo,ules— �+ �� �+ �—tA��)antagbm�p+@e hdac-6 deacetyl�J� �is �um�K�zD he NPHP-2!N �ARL!':� . Glutamy��%dul�}ost�U Ůdi",!��Kr>TAD�ning�E&!:��on�r ; ra9& , g2�ihRd�y)%)fA�1�X-c-,Q��$R&ri�l�fof1-,1&fcUNCED"kr � TZ-y|�8Q� 4�-a&rq)�.bKG�qV um bng EFn do� A��As�|e��l�\|!:JC!@�� �D9�� �4A�tlx�d{e%puH�z%� c� , rhm��:� ��2�. ��cX “a�[nae���Pm�of *o�� gnal��5$el Yp)w�<TpWw�teg�X�w! d8O�z�Z!�dhE opmewX8, symmetry brea_,M-R �t�j��.iIhA��|)�m damag�" ( R %, [1]–� ���v�/.�G)�sh�� o!=v�ar�a��fMh: 86� �'by�6ty)��e- b9 �� eme;=kt9i!�flm  %�W�FTo 2�mo6;qn cargo5* [7];���2R�/ �31�uGa$aE Hc-2)���� trip�*Q w�rooCZ� uma_el�0.H�{%F� T anchHilV"�I4!N^5� rj!x�V �.�!0TZ�6C?A`j_+���inb# 1out l� %�,5za*� phys�occlueu3-�zTo b��*� [7E��(-h��$traW%��$FqI��,9/Z�i=p<[10 qt_~r2q& bZ�!l3'� � !}�arftFn�U /Nephro- in-2&�"�$- I6.�a/n� �4"� aJ!#R���JZ Evr� �%'*� o�+�!��!]n��!� ampl&J[13%�1NU)��5�� il�d[16!u[�].=&��%O� �x—i�AFINVS/ =4 NEK8\gANKS616—1bq�%J* �ion4#]�!fxJl{�a |6�I'l�Lgu7b*� �,] %cw�[rd ak%�1�*M�20^���XA�}�0ini#&� MIC��&�i� ��o�recruit%��3a�1�%�� P- Work�BZ}�AX63 y� .6i�\oIof� ersin0(Nek8 , Nphp!�!3Anks6 �X%%5axb'R �� f-&`6manner�'ut�itselfK}3la]!|I9 �B3E�8$Unc119b—��l: �A1��6—may"! �C-&] -�E� &uAX� y� s myristo7 ���ym.gshuހsOj7 �pu�sOn�iea- ;!�!�A��!�l>BA�e �{GTP1 Arl3�k[{sXa�rel�1�s�E6-s-�t�> ��!_I��Xe:AS �d 13�g�Y���6al tB�s�Rt exis<WhO8Mi� *�!M!li&� ��how=I�is w��O���um#q��Dnematode Caenorhab�/s"��y��-62��a�Sa�logy [�E. .� � -� nerv�� 28e� �i\� ua�D&��"c�b(d ~r!�cutn"X . A6� �\h)/�2`vE'ex��[zd� x*� "�cu�Zpo�D[�,xU�6Ƈy��"6 iNi $�.ijp 7A�2 two rSs25J0 � . att0d!A��.A.CRMŢ!4ndk�I� h6'AsZJ)of2  �Ze�3|VmliesWu*en�gMum�JD �t,a9 ���L titutDE3i:� length�l� ,Y(��~�.vieM>em� �Io$ 4 r2� /!� ApT Aw4�4&onship2�AY�%?Z�C .�:�of ���N&�2F�;Ucw�YezeN2Eg2t:hI�s��;� lapp��&�IE� .�z enco�j orth��s2�= 6 .����@�����(� -�#,��( s&��( �E� �7i�[�(%un2I�%log�I pair� L-1%� NEKL u�lik� !���or" . O�E�: -2A �� *3$%�%� 6�-ͭ! �;$U{� .�2(_ :Xen�2�/l��,mz6�)X�� 7] . |�.ex�c mult����e�A0 tP2�#�k� dele� 'h nb9&���"�%J "~ �Ä�oHDAC6I�&s�"Zf�: @knockout�c�6F�ari!��* RNAik MDCK� o� <�k�Pi�+�olenufC3aC��$l�um!52��o �)6�lA?�h�e�0:�"�lA!�9&�9� o��)U:L,.P" terri��@nd6i � �M���"�E ���`��+.�� E �)MjQ� dse L�fi!C^�%%2�:c�"� ed e��i�_ve� �i+B�D��1y�I:Y �tK �E6". >paYo ,"�6()Z1�y s��&�!���:�S��WF\� ]ef�9�wo��allel&g�*���~%�1(P �!�K0��  by�UF���" h�j�E e>~� !�2er��"��rit]aJ; � �~]&� . -1�13�'U�VAI}Ap ,�e!Whic���L�-M . AsF1!" �p�]s�f��sou�p2& if1��A�%lBB� ifj�-{e���i!�MPquadrupl1/� &zi�#“&.fipg�D �� neur�a�Tg��\$ca  )!Y �)�A�g�G> Bpe��yA+�d 2A�*�J �- takeӓ&33t DiI�.=L�DPBn�2m�_c2b� .Vcan]Q. a4m�_ dye--]>Dy2*oN���5t��I9;1�-��v�'t | synthA"Jx�( Syn }�H�y�d=q-bBI�9"`di;�t��Me8��Dyf� oC+/ o.� pub�nX'׊fcat} �� u�� %�"8� weak-"6:M�Y�u(a )75]��n��methodi�*T.�`Ms �H"�u ��\h�M"5�)�1�u�a�.E3!�(*J :1���!�j}�p7 �Rt : ����r!�t �/�u���%��lF�sw�� .�M.auMC��!ar�""#A��n&� Ka-�.W3�� � ��A`�����or� � ])��+fouŽa~*�I��"� w1 �Q���K^3���-t�c��ja�1AarureEYBM 3!��!+;nNnoe�r*5 QD,U13�l-3A)A�lyQ��+ -��# n( c&��9�:�- �HZ/a6 �v��y��a"�N5F���P�$m�3� u�:R� A9A6e�Ky�.��W9Tqj��> w� -7riu!�Ir�)�39S�e��a�-q�Uq�om � &� �e*g5'.B�ofOW3A qual�9| �MzJ"� .�A�1 �!E�i���4�C�&XcEe:� �Zie�>u�~ �� �%a �;�9t:&s���� y��9� &% ��+s��a�mQa8,13��A��M�H. �*��a4;a0 �(jA�GtoU�'�.�a� �A&&|�"� 1.�:!�in���� �UK:J� �u�{E�?Oo"� *%d>�A�2R�I hserial-�9�m���!+�� sc�g( TEM )>�2� ��* ,� . Wild��!i�� 6�F5 segmS(ddt!��$:u�-��"�-K`�+Aa�� �h.I�-��o'-U��QA- �,"�to C-�t s':M��$&V�K   �5-%\v)��B�/.�7�v+ңl.�=4AӁ )�vC$n�(`-8!�arrXG+ �r<aY��cl�Rl� �y%�G(emp7��!2AA1t)u� ];��6!Qh̦a�A"��g�umeb�a\AI5M1/1 Oib�ure�r!� � �!��l8ou�.� E�I>�B��Efgi�q'u�Y ��mi�qR 1�%�!8a2� � !!�TZ!%T��� !G"� %�� se�� t hif�w�/�e�ioc; � 3[rA ����'�]Y3BI-A }��,d=K�E71�)Ft2�sp�0�no lonٛ alig� # �0s1�!&I��xo)� appe�Jsns-�ng�YWxx!� )�A�.�?MZ/m�jfHs sperb �Ds �&�2B�[)O))l"���at��.��6$.�*��!�@��(!�. Wf�� chem^ fixi�]y|^/�5}- �^$rve Y-link6e�  ,�qa&� �&S ft�arLdi%�t<"m]���U����aN.5.��"���s[b�+��})"e6%6TZ-�� f�� r`�&h�����1�2�.Canym�.� � X6 #e� �&� e}(novel capac��.�M{ Ns{-�.Z^2[al�� "!Dq;��.�!;\5;����̅"� orig�;s L@�r���u^H�sM�E)&uR�)e.C� %��)�mo �ed9DY�� �,S&� %&�� 5QD!�,u�5~-� �u�7!�A<d; +<%3 Kq�;!;"-9!�t�^��_�A6�q F1 ;b-4 i��aj)�%��-�6H>d�"P�,�%̙ntE�� pdr95�X1� . Be�we� ��5��5LRU^�R65)�)N�13 -V��c!� �;Pi*�/ec6� X.� to�"��ALi�:.�݉!!2|9Ci&v}&zOѫ5^IY-�^ ^&2wZ�?$_K �ied . L:�8�u �-!�ve/�b�~oken d�H�teps:�a� J,! "�(_���!b%5_e"*�# �thirdF6*�%%+ 3�86h �/� e"��"�;��0&� � Hb1l̥1>�!�!^A�# � Q�Y"z p�z^rG�-(A` ( Re�)�L9�WiWS >B�: =�0�;f�2#$� [4�4[4X4!+Fpgen���&�E �ed(O�7.*\ e�w�9�+"�E4:/(13 ��2} �-�sX]��. ,!��f:�A��!!�"02��=A:mk\<���b�W1+%4 / [8� �(2 , [4.�W�3�Y����A�R}"!�u�Vs�J�=�?n�%k9ac��W>��3Ak�)R::GFP�ala�]!p&5nd1�y9�h�1 . 77±Ť23 um vs 4 2l: .�:�~O.�#SH/!N�%Q2 4M��6� 4B )&w�$�I� e1�w��fays �u�SUnd��+�"&1ER�3�4� mks-B�, Z)rM �N.!I�!�o@I�J . Mis �ed2Qp��V!(��e�rF���u F  �qIn �7:d& N�� !ic�&$ t/�8 errC:�Q*-~d)�i���C�)�r� !���+)F6a-&iB.a9%�D-�a?*� ( S22��*xY�"�?)� u� [:U���:n��h� ���#5�i�L�h.5k@ �AV�MUN�\2xp&")�A2qlso&� ' �mU�)�- .�"�E judg a2$“frE[�$sur�3!^��`�=O,&�n ?�>�e2BT �H��Ws�5i�.�" fail40TZ�]<ba�r [ 1AM-�> |1��X)�E)[i .��4um'�?5�Oin�tly� IO%>� ( S39 � Rq�6�F�e��d�62��SC& ��ICa � .� �nAx���!m�Iv:RB�)b _2B|� )�\"k-s��)5K yEIn)~,2���ue&��TZ.TD%V�U���."c*,e�� �42���.IXa[���*I6eRa�z�M�eBTT  )K"�.1��V �:In.���2,F86�a9��M�!�!)aiX lp�� D����>^1 =�TZ�.2�%�hmJ5�"�r��*9 Z�.OA�.m9ed�1l!�����a��<5|x��ll�,>���Q 1�b �N.��.�still�e()��A�e�ss �\���d�I!�2'� -Y��e��(P!�!_.�/�9�:��I"�!��~�8�BT!&)*V�#A �GM �aA$'��as�:perturb3 �&"�I.(�)e=`��;/=+reZeqA�overex���=�s%D“le�F���!C<n �MitPJ�,u2>�B%>�6i��jWe�lo��2�-YL ��62�E�M��1e8&�5�<�� a�Mm�Y.qOB@�E32�m�kion9"ank$d!Uea"�, IQ2 �m7�in-�L� F!q�4�}fCN k[�IQ%� ?M�M ��sf�h.()=;�A ^�hydroxy�K�6if�q8&G�[n!Sar6|a��NLS�+��:��NLS jI�hyp�.�1HvI"KD1�"�U �m2. &M�IFTror KIF17�j"�K��S E$�Iw��.B�K-��M��A[!gsRn7�"�enIQQ'�GBU � �7t-��!R�O&?pE �K:-EFΔ 2S`sid�520–53� NLS11J344446�:or6�OIY62J65��60i2��Z-� E �m�)��<��"� m.�� J| %�![�@IL6EP , OLQA+~=IN!RAWC�m V�� N�9�mo�#uJ) ��Ia�� *wWB O5 �� "���AWB*�DrNc�=Q�=�vg"��faG.U.UF�,� �>� w�H�MQi � >TQ� -�a�,!�)�7�-� �4 �" G��IL5>N�.|2-[r%۱�1�^��a���pXZN&�C��in�A_orE`I�#o G"z.o�V�y1�r��u�*t �>�&. D8Ha�s NLS2"\ I-K18):��~te��~�)��y��:�p傑�al�7mpI"�7sc2~(u�p�5�� 4Fs"�:����.,q owA�a"g�W�5 �of���S��r2 4F�by-:�ҵA'M�!m��ad�a"ʺFȪ� ;�J]e_3eC��BD"�&N�"�7!r m�1��mL5/ �Y�6�mh"ze��-&�R� � %���2!Z�"�aW��� �:J���2asa]a��n$ s#lab(�.�=lG RI3V&GN':�G&< g�a al��te.d MS H�.� �>]i""j b��7���[44�� a9� pa�P�a�Rn=$��"� a�-U8posm-6E�::�B{ >AGF"2GaC*@I�S%T*>: 'UB=� �-lAa kA"5Znde��"�TZ 272u052�,:�?C 4a�I3:2~!YJP�?Q�%���5 .6m!?Fmot�_U�%�� 2�_�d1� �-�,.�-.�Q�|��N<��2� I�w�Is�f\�%�:9 ( S4&x �Z>`���31�M�1���2%i2�d��-�UR1u&�#5 >!/{F�2.I+6FjF�A7#��;J=�AZ� "� a�@( �%V��Iu:�:1<;0Ar͙��)!dJ�;2slightl���by&b&�2Q�6�S5A. �x"Bw"y�� v�� �&~ ( S1*#.-�R�t�2n� �o!����l�'�#npre�4���/ngEgz .�f �!�st[L,a!�4asmF�A��"A���ceJ��n��s*��!!�A4�#^*&6B]�52=E �hr���!A�r�& )�5�IT�S-)-:ı�9�� !� 5A X&Q�Uw �]w�D!�YaKe5m��I� �Mu��. SurpmEl80�"�:��1�?�y�m�F" L) \��-��l�CQ �2=.�) i�*�8A �<R 8c&*�}�%i �%�9mR1Z!-�o :�Gq"V' ��� ,1h��_,1<�\��;suɁ�E�. 6^ �- NFxf�i�$w� Bm�-�!���`f�_:� Ra$*6 K ^��� �*�-AE�i-v+��N4"�1-ME�u�/� 7ny���e,: �s�H� M�9�a"�s.��*)�% M�A)�.-��e*o� Q�TZ%1 ?6; !re�h9&�� �^�8 ��(ten�P��se ǡ�? al{.���2�J�:j&w1EN"�! �.=Ws��:P� )R�)f�L�E:e b> ��5D.oJ� g� s"�aBH��q^&�. PFJbg2�a6��b\Y�C-�8lbSα��β�8��f�4al"�0s [456T49 !LQ�@cr:4��"; � [5Ѵ6.cVw!a8e�s!~:�B �e�f�A�}�JA.>�6�Ihlamydom��MP<�c� +'*�*i��p9��#4}[[5'(In2�!9&�Y�`��MFY�:w2��@z5ډ�a@/2,)md'&�u�~e>ba9�Z�(,� fjB� "R#-�CJ�':��1 IU�"�<�5!!�ti-9&[ {�yljGT335�e;�z:jA�~��7G[)R�m&T& 6�:� �EX��c� wA �ino.�@F��2W6 a]n� H+9p�O�< A3<ż�L7-x���3#|9I� GB�/�>�I~ofU��� �<=D91Z��M�q9U�s[ S-B%,�j)$"X.*l Z� �s)e�*a� G$ ���{A���G"\'to�KJIy�Fg g&n)FM@&3 "`c�[s �� 1� oTryQ.&�E13 ( �L95�*5 µmjM�( 4 . 30 "32 "�v$p��l�!�;�9ii�� ( 2)+9 [07 [E^l&�! '4 �0�.�Zz)z�S7E6��=�W)(D, m�iAA��*�od��rh^ unbi8�measu�6n�E"h S6I?A� lbundl�62��if:�.] � l.�"���%��:tEwX "l�2M"B&C2|!cpp�V ttll*l . MZ '%�ch"�Wa��de�W�9��n�Ung1,f�!X�ncoR�ntR��,fXFW "�GmH+� 9;��X�I!11`tyr.e�das�A�1�In_?I�:A&�l2bq�9��oEK�=d��r` �>_sA��� �p7��iq�s"c!�Uc!O)� ���oxe0d1��t47: ah�Rl :��$6�.�(arlQ�l��la�aF�����V!�AN1a� @�� 9C-2� 2 L �Nx�.*X�_F�%�\upsgm�6 �AuR�G%dn�l.�8'eg��A��$�d&�qVl� a�f 4J~]�ar?�sub1V2��S�MA�Kt��c2�6n()"2�"~���Q;8d.��$y�%lap� ;����1��JA�u :�6w!���!���-r"GO*]�xa.��a"�@:l �:r�@� y m�B�.�)=C:c �� 9>Bg9O , S6*��F�g��a�at ܡ3* _!I* � 8Iq%:�:z>���8g"�f<5q,2�)K-+�yIH. .��i�E � &�|%� Tto �%j A �Usf.�w=:!��� rB�RRU�.Zor6t( S6C2� ��de)��e!+2�&@?��io2[�=��-�V���+w��� ��"L l--"!D >�2Ai�KAP-1.�He�"�6&�^�k" ]:�7..H��.�havter&> .5s:�D:� s.GY�� i`A<. �&�&H!B.�ZR&�;&If��.I>�Y<+( S7A-2�A6�H�m� N'e690�<�^.},2Meal w.�Nom15�� e�JP� ��2P�YN8�m� �*�I1: .+6�V:a���>As�q:�)ro���\e��19�ip� ��&�Y3�:�!�2� In�r��&�� �`��1_A B2y�s-��y��[ark�Z6G�&��I*BF R^:%a6�fI;<llx��E -`ii�_s �K"}xhhFz7�� 9 ū6d@����!3� ��6�26� ��(�3�� NAXnre{�#2]hma . I�6twentyQ�,24 tagg�3�S>2�A����0un�&�^�*���v�L*c2A�� � &�b(&* !cjm�Y�i&�duc�C�~�to25,p m� ,a�ach�*so�arrpwa���^oԁ�{ '- [5*/M�.b�^,�i� .!�-7.��s�D�ricF�� ��h!��;�Em* ;S`A�� o )1+.�b�d&�A�;�%���-�dn"�M&��(8�iWe &�^��miz� se "T߾i(�{ avoi�BQ &�m��^1���^"�m������ +-��B:/d�]2�� �*�*�*p��bP" T�m�TP�I��t sroutin`}l�)a��9�"J �)B(A aQ10�+QA�cH 2^AI�!��A54�5=1Fo#�m!�6�7. eO�&MAW  �&=1� �" Z>�� /E��rO(w7*��"Oia6�0�rigk����I�mca`c�?mE!K^�?j ��V!�ɼ� !$0",6�4Tli��S!��fAp��aaJng2O6r"��6�J<Nl3)�5`B5"�Nxth uk ~tAFD�9a [~�A��d�QZ.u9!!N�2ܒas!4;���g9O�.�Ɂ�WiZ)\Z�A!1�Q�>@6�< .�,( Jinghua Hu�;soA#��uni/u���-�6� ��X2�(^<of2K1�!,1�:� !b.�:ic |�9s) ��rHu%9 Blac�;lab�;4i2?H!cb R`��A�uM�genu�engine��( ��e, CRISPRߠ�9&w�/zlڜpy����' y0�,c1akA�����x!oncerw61]i�Ks echn�<)�� ��3�tB oughU�'v2y��i��g��,�|y�,t too low a ��level for single-copy tagged constructs to be visible without advanced microscopic techniques ( personal communication , Knudra Transgenics ) . The C . elegans doublet region and the mammalian proximal InvC have been�hidered analogous [11] , [13 734 $7] . In C �\, a number of factors hag$associated% the :��, including NPHP-2 , ARL-13 , UNC-119 HDAC-6 ,L�Kinesin-II components KAP-1/KLP-1 (20 [35]–[�4, and glutamyl�(tubulin [50�$However , 9K orthologs� many2 :�Xproteins localize along�@entire cilium [26%`62�871]; this castsX t on :@quivalence betwee .�:��!v�E H. It is likely that'.J�ary>Ris]3to7 �e:< -basa2$ilia shaft-�y;�>ea2�#T( modelled in Fig . 9 a& Calc![signalAYLplays a crucial role6 " transduce}!2�ry fun [72%� 73]; I�$high intra3c }conceUs �E7TZYposses!� �bine domaA?[74A�Theq4vertebrate homA� ,!Dersin , has two id!�fi!walmodA�-`IQc5 �E�oneA�which!�rAt�'�properQ�� [12�Cd detects-ellular^through!�)� EF-h!� . Th#.��*\does not encode a predic�q�ct +1oan2_isis6�a��� cri <,�-0served feature�!��H�woE�8ibilities arisee�*.� thes�i�D: � spec�s6�Y@,� '.�e� , or)�. W�unzat��-�HI�pr�ADum%Qis ex���romd dist��eg�. GFP::A�0GT335 colabela�ndicat��%�21RcTZ��s� ��%Re�N2( See�`8o�2�s�TZ-��::GFP�I� ��BL ����(shorter porA�!�!�-B than e!� ��rkers�| . Addi[ ally< mmal9 ,Unc119b physA�ly��era��wit� eJ�&z  Nphp3�is5�lya�tr��in�a� RPE � a�m�5��a*JE y; .*� 2�m!d a lar�jEdid2��e2pgenome�gs�z& of���shuttle! .� %, Arl� A�RP�  �myristo� !��msM�� unc% �+m���[77�arl-3ˉ�F�I� nphp� >�i6 E�&| ��1arh place)Wse7doeyappear��be�d�g2�.�as-�A/im!� �{!um�.�) muta4 �S,WexhibiUa unique�� dend��6�patter� at can�8be attributable�0TZ leakage; i� unknow�cether pop�]repres� �P�t� denA'pemb or!*m�jrge� M%�Z&� �dA.� 4, Hdac6/hdac-6Ձ�za $antagonist!�!�oge�  sta�� y [1�  �� primA�DawBpα-��@in K40 deacetylasAJg!@es.�A��6� 8� 81�� .�:a .��% �)�residue�, MEC-122�!�e!�,no direct ev� c�hr mec3exAs�#V{ neuro"y a?anti-9&-!&,body 6-11b-1' AJŅf� Lin wild-type animalsAWM qB( S10�=� ) [8- Alaative"z1&�si%�ay� 2=on β5�[8� ucould9�te��pecondAB Y.Q� contg .8 $N-terminalB�$ ( at 2S )���be.sd- ��$ �"R � mwa[iHe� s [8� :� WQc~ r��*� il�*I35A�De ��_eAEhanism�� ]��a}a�tic�8 ��w�:f, def� a�|� fu� I�!�. To&i 9J�": ��iA��nicr�  BIes2�%�ouADpermatozoa flagell�0Chlamydomonas[4 , [8%LB� .�B�linked��.'ultras=a,��mainten?�6!�Multipl� ubl&�!����2n6� awe obt a corre� Q�ectopic:>!..�MsFT %�ryM�A�of/ � "�i�depenA�a�6�statugTufore ,&���9� ���"$ upstream�.�6k�a�en�hem!�exert��influ�on2K�, IFT� il� � ���� �4r5#b;� sechw��be��)�:��0Arl13b/hennin���!0�!�f�Es�duced �.5Bu{��2�al�[38d6��BBTZ-}�I�can�group"� w�stinc�parti� redund�m=��A�� ��u�[ ��4ŌD2G-9��F�-f����� ner!6o< +klp-11 ~YanM�+1�� M� �U�out�E(! 4sA�eg�Fd e�Ap� 6� ]in SynDyq�MpO�he%pheno�� ~� also� jU t� icp , deg z�E�""� ��a�� dpaE� s��gV < .%[3%�B;� .>7 � c-�; �s� MYEoa* *� �!�=�butM�� onlynT !���>0A�� "Rn%� s-i�&%�":�&� TZQ@network . Curious%a fur� %O- � organixe6�TZ..e!�C/�:� P�� � 4��ks-3; *) 4�UU��  s�p� ic��� . D* �)�ei�TZ�!{&J�22: i� yielA1cyd�o !�allAWbi& on.Ttes� ��m�1��A::&�^tr� 7!t:�a� “super- �(s” , each�w��gegwo�!three.1a� crib���� prevAZ Ei6�2���� lM�#�m �m ��,�}�Ŧb% yly�� ��a�how%DIiW i�i�� lish���ep."!�I�Blh.?e"dkopmZ,!� nJ��m�as T!�he first�val L1: ge immed� ly follow!#hatch ( S9A&� � �motil S9B.#un�%2lanstage-&� dynami:$of�d.J%�eli� A�e�_e� s%��5L%3��%�. C 2�3 /se� play aџa!ꭾ ��F�2�*�|J� ��ae� 9�:�Lre>n&�� 2�al1��[ post-�� !Eo� +�R��o"x�M�E���(e�geFAA;:�}v) l�.v 6j ���a�TZ٠�-�major)�in��!MMm<still1��x� "�""c�+TZ��� ��[.� !�n�candid�U� ,�Lw�"al�s@="NT����(B1 ,.!m��$C-2���I���!K��%9qu" $0ry iA��">is2�:oe"� in >J�.�6�"�"� ��i �ts ef�or<3�M>�r�C��� ( S2�. STaS6���2�$remain . F��," R M�� . B�5!�-��a=K+ �E,2��!�� ig� nd n2cxxal!�&<�c2��O.�ȅOb�N,B�u�o&-$2 A%� )"D"rd���yAF� )membran� mpos�� help� in�G). :um-�sIRJ�plasma%���tXasub�s�%��+}"Rp��`!os��# logic und�QTUem,��I'/U;�\art#!�be� ah.PAm���a  in��:s2�!�We �sh�%��4��nZ"� to guid&� esi�!�a!�c� aC��>�,!BteT ]-�szM*,next challen5 ��"(  w!�iU��[6�%_e� �o)�st!xAG&�8 s �a QJ. S,aarotocom� ��2 molecun#bi$� !cedurV PCRla"��u�(, Taq polymer1$( New Engl�BioLab!� Ipsw , MA�'SA  as u�%� typA�"m" alle)/�b&�hdi�!I$SNP diagnoA.J�o"�)>!A�%ge� ssperform�(Ph��H�%fidel�DNA�)��emp�d off2O!� K. S,"c!��off�` ( GeneWiz , South Plainf'��J5g) erEV� �"c�6 vail, pon�:est@�( BLAST�%�to findF o"�([89AlEGeZl�oP%z$� e�o6�ro�� NCBIMA�.�nucleot�A{A�a�vs E�.MWormBI�Relea�WS229AWS234o!So� otif�=6& a� r� by M/S3[88�AceZ0 f �*�iWNet, 1 . 0�(Coiled-coilu�u?wb! COILS [89tpE *0 . 36%S%�a1��i"+aonot � d2�Es �yll str�cul�d�room A�!�unless�w�$no� ,�� z--j" s [9d+Ty�q)5$pha-1 sele|)�grown�25°C � * ( e2123 )"� 6212*���'outcros��to him-5gAI��ur tim�<S-%wi�study� li�d 2A Te�.a;��5qaxs:&X gk65�� 4 ( tm925�m� 2547� ( gk51 9� ( ed �( ok320 98 tm17  �( e1490^osm% p802��32aO, ccpp-1] 1821'a� ttll �331P. Prim�$%A��ف�.:B.:�+��Y${n� . 1–9)XIDdye-fil�+qoRnt 2" ��$m� "no�/ erse: #m �%�2x$݃�Td$�gr�.4&JIO-!B&,fu� engt�+o��� ��'� llre�er�D{NOd L ,� s& �&i |-SM ��>(i�!ss�22 non-��)ami!ycidb%#"* ( sd+�  ry> ���!�a 13;m(G02 young adult"� e�fixedMa3 . 5%�@raldehyde +1% PFA!n��1M HEPESn then1% OsO4+�25% K4FCN ) 4!2:. Samp> �<�d�embed?) in E -812) sw1 � ����.-��freezSx�O| + titu� in 2 �2% waAdA{cet4��!�fOve [9f#2� slow� zfi�an RMCR� devi�b53��Xf)ImagecwB�")��_ ar��Pr� �Hethod ( cf . [32] )��now cu"XaHa�lab�t Eins�courtes;,E$edgecoc�T�+� t|#i ��Halso &� onlat www .bm. . or�>For TEMmer�s�s�4 70 n�+ ickn��)�V)a�#E�col� n cop!0slot gra�coE�%x��varE=evapo) carbo) s�#� 4% urany�#\in 70% !`anol ,2I wash�OA�incub,{ aque�4lea/tz�)= �ap�d�4a Philips CM10��m��on �r!��"sco%t 80 kV m Morada �egapixel%iCCD cae  drivenAOi!�softw!�4( Olympus SoftE��Solebs��!�|�b� �a�6z- vidu�%���f�� chemly�6,we *�2r!�>A���9sF �l-�a� P���&wharsh���^!�od� �a fah:[�큫� s.�( HPF )@ U�!�3o� fewL rtif�$to�firA� e validite�!18T data ��% same1�-��} A?�"7Ճ��A�tri�#Z�Y'a�w gKly pu�EMr Q� HA.� mounm�5% No�*agar pa�na�� ]� slid� � immo�)zq�a f��minut5i�o� 0 mM sod�az� .� P I�)�a Zeiss @n-AXIOCHROMA 100Xa 4NA T obj��vei� 6 AxioeMer 1M (  , Oberkoc�, G%&ny�� Ta Retiga-SRV Fast 1394�i�0m� ( Q-�La�, SurreO/B� Can� � ExpoE�S � �)%100 mi!KeB.J0 fluoropho�4254. �-:��Ima"� Metamorph.xV��7 . 6\ �(, MDS Analy �:^%�Sunny�8 , C& �A1ck �(3D deconvol�2)�(Auto DeblurN��4�, M� Cyb��tic!)B'-sd�MD*,Fis*s%n raQUcreٓDAdobe Photoshop CS 1 1� 0�/'S"m4San J�2�!l * Illu��i(O5 VSAAAe bright�sP�*+(�F�!�ni�N ly a� e.vg�EN dju��!S0�BkU#ir&.�F,�4,v pane&f-q. Sig"�6 vari�8 abs�ǁte^&k3�ap5���! !Li�,p 3,�M^picj)at L4Aw,ge 24 hours  mae��$t�=yiaR&�w�com�!�NGraphPad�sm=�5a21�E"����, La Jos*}(!�MI��ExcelQ1A�!�710�<32-Bi�3CorI �S, Seax2, W.�Y  s�<( n�l��i( ifu�*�@o p�?]@ worm���@[!K�m�ta� �840 µg/mL DiI (5 mdi) y�Cmam? stock�luB1∶1000 �) (�itrogen�30� !�� da�(>��!�&.a��.!;%_��6Ssee�8�%5R 30-6�to recov� nd� sh�)��(� t�*a�.� anes�<�*%�1Fj [��&sco�?��e�"*� (��� s�^)M�U.zbyY�ccY 3of �a�ell bo� . C y +O;� �*or�X?of*M4 aver��xtog)�*�Dys���O A�msuH !�oV,. E$1,�ed"|5(}�IL2�E���DI�!Ӊ�%(%�t�5��ك 8I$Ruvkun-Fin��9+ (� t�al� hod��[9�i�;<a� yagr t e!ch point=A;.&�%!&a��(^�3,q�< , Enzo Life SciE1!"]&�5! y�lexa Fl�568 goa�ti-.Z2a�da���, _ Tech"� )!LhR9T at 4\ayn� . Y* ND�ea%_ )U!�&Gegg�_@—k3�sen—a~5�&�)(r age .#��.&*2r��erc a\mye9 by oligod�:ocy��� !-= AVi ���al nerv} �9 ( CN�6,Kix prof� chan2Fa�shape3kto r shea�5!%��� . Hf ,�dem\I�av �b!YbasalA�ar���lex�ASj,��<NS � iwre) .0�@�A��Dout.Ngl*>��&-r�1i�mg%>�� �;�%moz* Y!�� E�-I�9Knockdof�6:"��� �Cdisrup���B.%=�' 5e.rv ��*�+��Ung �A~& m� &.v-�is�,-4urN-;E)!<gf9.AWe)�$DitJal exten��(90-s6{. A]-��,� 0`5!]}&�3e 3�&iwhilst"�2��extraadu�# al-� kin! ERK ) /mi� n-f)v��I!*MAP )p`31�J� t,n-a_act�flank�nxG$of Ranvier2��(�� $nodal axo-!�l adhe%p.�"ingy(� n es] ay))�evP ionarily-iBm��L of i�I5<po�67%�)�A3: �t $Q, a� lamB:r eAD CM7>4(���"}���mz{�Schwann�� 8peripheR�P��allow�AI rapi[$ salt�r n�JofA��:potAJ@�GaxU [�Ia�d"a affl�CwC d�^nga��# such+ "_scler�%( M�b��a��-� �|��Qin" c8ic�+. End� ��:hcursor-?( OPCnca�9g�ki1B� ed lE�0 *�)�o>d&!�YCI �"�'*�D(!oeventu�3faiE�I � a loh#f%�al�eg��uirr�,s�P*"0[0O�;E�� )morte�Galya��%NS tiss��GMS�"ij3s1I��6�!L�A�.�Ga�j.sEEchc=]~�BDsuccess� �FfE�)� [�P �!Ea����m%�!~�� � !�����C2h�!�ry�3-��rK impl�+2�.V�[4 , 5�%In �c�&, �?8e�M'��S�8���ly��var�degre�T K!�r� f� �K!�-7pro!x':+t��t�Ies� !eim ��-(�R7%3!���J!��!. &�5_R�� o6  wrap �[/?A&gK͎�A��e�m�B[-Z:. F�%�.�!�, �.{ O�5�|���n-�.d�( ��Inas�1x [�"An27"�0��)�)m �&��,� �of>�je�BA�O6�  <8�"8 thei�#rr ���rj � �C"a"GJA(mS� �-I)"� Y}� "= \ �g)?by elaba �a"e�2"}/Eq��(��%ACag���4e � P ��& io� � b, � cyto �$�%�0,sheet—leav�|"�Flly%ed%D �Oic� nel�E�d� wX� �alk "v �lex�r�e�K!�% spi��ofk(hgQ�� s�fs�n*-�  —Upar loopB/ata tm�apb8 ?3S�he� %�� O draA)!!6��� sU&f ��–��=a�toJ�i�ty� ]P -�� �Ohighl~ � � !])�\: sta� apico�1.��:�h�+��Q�. Par-3�d p75buTU�by:t [10�A"� �eT er Discs-nM!Mue #*Dlg!*� es.� ��!d��t"x$[1Q12z e Crumbs>~Pals1ca�V� r$6U �X.� A]k M���rol rad� ��i-�e��Wd 6poorly�sto�" wU3���heuRm��abn�/lR�� m�cauKe"'�;�С%xk)�#\�1�"? .^�'l&6��*�5`Fn�W6( . In sI�=D-i�~athf�novel;F� KnPY� �2�.�a�auqcereb� pedunc�[a��?er�f��N/ . Am�Yj��9�[u.��5#WGsp� akBs>A!4�on�%�x co�[��5�>u�[1nEAs:=�by"�w�HF HX*R$�]7,d [15��M| Rin.�7 K�Dch.t . To�:b(wheG2�2�6X� -&�(lys�� "�raB�!�5v]�iG%  /KSDS-PAGEwes�L blotk*L1�2��.f m� da� � ( DIVA*n�1mai�'�]K!2eaf�(�" . 1�5�7�Ez�U5WJ��O� .� .�Immun!{,%B(�es��investig+�Y�)U.N �vea��at�� �!|&Z�P��NA�[RG2-:ve�,%�onM �dAJW2th!Oe-�@ M tip+W\1B�#�#n6dF7%n-ePteolitQ ( PL}��-���5 ( MB!,ZQ^�#e>.]WMBP9 x6� �E , F�U8�>lso�~CC1UBBiA�voa��K�enric{F�!$c� �G�Q��MFLW ١�� �]j"��d fibGre u�� spi�rduj �S)F8Ina�!a�5!�5 )2G=��a\us  �F��a� �� y�E7K%As $�!Fgr)GxQ_ beco�4r_���"� �by P16o2�0^ �D%w � }mb�0e � K � M�Caspr[J�@�'@2L4w{Maccum�S>�i�U-�e/GX �%be!9R�.mirro7��!r�U�o6 ^OS(fascin 155 ;HTo2IA��MW )3u����had�~��j*�LIg ����ntTh���ob�/by �(!va�'a� � loxPr8�*W"r� tinQ/s o� s�by�� =B� ��b� �o��Bpl;�kL��_'� �H �S������B�9!�s%-�v24�&Z,�$if� ~1VM 1��$*�uO=D:��: %8&h#-D-�,n�1Jfi�%�siRNAs&��5g! )�� �0�!��6�O4&� u�t�SZ:��-qR� ,N 21g"1bar�"P*_Pw(w��>k��J�Z�k!!;vQ:��_2u�j4Olig2+/� -i�p((iHaL CC1+FSEq�!"aUin� ���.(� 3A-�x\�| bun)�da2�l��at P1K>� 3E-G W�  ��is��:e�(�r@��!'3,FO�.��Ip*uM� �QJb#X�*�0r�%�x$�Ei�N�}��]� B�inA�e�>f as� �]%R�Kafm�Dri�$E��# �I.c,0&� @matrix ( ECM ) cu��promod,/�N�%[2hAWe�MTg'`&P;  ��>x�,�iX`�*�% �ReY<Ѥaso /K �� ��epitheJ%�c[2Y A�%��, /��:uk�i"Va�6� ^�'f& 2D4b�h���g%[��o�5e�dM@L%���A��q^ng ��%�12�u�e�7K1!Ϛ�, �Ioe8.B6w��%�B�;��JoA�-de�:dI�`AverT^��cl-)KBUBZ� �?}wi�`. .AXa���:a��1JdAJ*#n?�)vU�.2{2:a!�+ 5}�)&S � ( S1��'6Our'%z�ECM-i�#�E�7�' Bc � >u�k(u�N*� !l( .� �յ�*X);~ �q"; ACi6�*�Z%�"�a:� ^d !�Gaw:��eE���:* -doriro�> angl<  co--�%!��%� ��6)3^� e a/;te<:~W�t �(A�5!P�0dx[f"�a�=zBW, 8q halyL��";B4~e��� �&v -�%&oVee!�)��s=�sZ�|4A , D;b0�4C!� exc � �WV��0�K(n ���15%RVY NX | � aYF !��1� . O��M/� :�fq� ��M*4"?�8&]A�ovIF����dud66�$:hy�� hB5%ZA Fa{in]�.�#t�e�eM��@� �&.~O:hR ��6qP)��:��z v�e�9�mva� ��.���f�]<& p\?�Lsu�(�,V�nFynx+ [22]a. lami�aα2 [2�&h�$�-09�\i*1�- u)D� carr� ��.� ��Omai�^O_rof s!er-di�9�4e�G�"� funiculue�!� cerv�b.�m�2!�F6� < >y��&�1IQ�at:�� � �a� �p�)1e�)6� t  s [28mper3ag>) 1�Ge�NM� W� �!+�.V8D58>R=��N5B�2)6�(�.� s�CwR R 5#� ��Gl)�z�SiXl�@6�BCE"wJ-��"v !hey�aD.)�E )2��#�^: oughM{cH*�E[)Z�( <�< 7 μ,nu�5� �]�7�a�. �ia�1�j�!�aT&v+f�� �� U .5wh*��Z � �D(�͸b�[�@BQ�EY���'i?�KRY2� Bf1�6e�2� �'�}=9Fj> �Axŀ�im�;ed^/��d"�capacy ^�per�J%olF5A�z�urepWBF�P4�6����ath%�)Ji �#ip m�+ . By L�p2? mid-�?vJA� 5–F�)!eY�( ≥0)%Z� b7r��) 2��5�7���.�1�7a� x�I�Eh.-a��?=$  Id�.�nh"�}9�)k)_��>bm�5e�)!u9^�I40��� �0q��y tq.A�c_a Ap!�%}r9~A��!�de��t�(� e��w�/5{!�a-la�ZgX��>W�5�a�,��g6> ��X �74 �E�5,�dox���; desp��`r2j�2!�_�)N��/�U* ���_�g���BWa�.�bx� A|a�`�#3DG%pB�q�U�Y}Qu�:�{܍�g-�9 ()!_ circum�ck �6)� fi8 ��,�YҮ�.aM?�GeP�Bt �� p�$.# <��loAKval�%���ZDxon/&avC!7C'!~(e best-fit �N WT%�!�dC.m* ar r�0s�K'-"�D- �.$�b1I% iodh4�-�l6E&�O .qFdS2�� ��i���9�MUL *b .?mo �� �O�_&�s��ng":�n�I�\#),: ���n�� �G�Bx "T7AKck�HE�>�v*H2+ �~O0��!s")�:� T'Y��2)y�S3-��V*�*Z | *J-��ERK/MAP A9Ada�-=9� �,��"= &Oe{ ?S 4~e5Kh(�Ol�}hMhy�t3 IA1d �75�FE'�#N�`�eH�fi��6Y�I9 mblyk�l � F�;��0qyp"C&l�1ave�.�E W��R V�&\ >fj!.8ra�<htrigu!���io}ib2/�a0 C� a&� gq�ng�"S3�7Y�N� C =),!n ord�c�*#5�%Cѷ8��1 Cju���5R�{(.�N1)�͓)�D b�)�m!La��ax�D�! al surfac& 8� �AtT3er mag4C05ladder *�(�U-de�“��[ba�I, �6�SFcE:!8�s%8to��4ap�e2,P a �&" $m \Ted!��: [28�2is"^�qm!B k���f}lemmaA�Y�!|UO H{B�@&#Bin]fx2`U0 Us<�:E{��1� !���*;jF� Ua�F!� rrow��� �17/b-���t���tJHh��"�&B+e>�f]��in�%.�(#  ZE��A@  a*:}�JoW7��aFAQ�2%>� >%�"�2'gap5Svol-�/d�U� �Qr�|>� tO"B@�Ypa#A aggr{d]G>�7��7a&vjuxta�Shaker� 6�potassEV�U�wo�Oofa�75 ly s.wr��("ieig(by [29–31�[Qs2�a�F��&h�y��d���k�sly:� 2B#�d�5�WsE�.MJ���� y�� �#!zt��z ow Lu�Y-"Z��f&-�l�-��$ŶG�32!%HIn�.�,��|/652��cl� A�(:��BBX-� ( Nav�nd>DB� subunia�KvU�8.*���O/�E2dno9*ofU� is��)nZ�-s*—l>j invaM]-* 8'/���U)�e�&QMb��!Z8hM�!�` )R!A �*4+K17@��g&�w"�s@ �iflBna< �fQg "3qbF�8:��""a4zH� at�-!Vn*�:( PTE�0.�-i{I� ( S4����2��� � ���y*-6P=*9#��J6,M"0GD� F�6l:�U�E�*�q��JZ�axTlQf@ e��o|9 envi���p3ErddO*�VN"69��i�\իb'7du_kU�N&�EA� D-corpu[llosu(e. c8( 4-month-old )9'I �&? a�� �sa��%�k�nI )�+,&BBNo:,O9�h��.JrJ�5���q�9� � at 21 �-st--,�� Y=Id ��(�W ione!"I`s�H���-q6g1 �a�/�>�A-� Inte��A5!g.�!t|3vel5y�%*9��*ろ�e_9S��&�){s��p�F+� 9� �Q6d9!1*� *� �%6E mpen�:, 2B���I�8-V-�mZ�Da�aU[of�,CC1- O�H!=V�,6UaɑN�N"},V�1f�:=�>��o,��>ed��>�5��J%�U)J-+�!� jX3* 2e ��4!�uninjuA(i�U� or C�>ee���F,&� mean�=5��8e��CL%� WTy"�3l�`!��F ;����� v�G�5Ima�re�dMLE6F% ��1��d2!�.�� .�>j�9WT LPCY CKOB,!��nt)�:"TC*�@n�S� r =tq_�^ huma��L:H�LZ$v th�U�"s 6H�9e�[3��V6 we saw" e�"{ Q� �m�9�ed6�>h�Z0AU2?9�><��Y �� � 9.�>"B:�u"0 Lrecapit:k(V�. IC�� f8 V746` ���!:mT'Uρ}:>+: �y -*,����� P%��M� @��Se�  ,�AA�"�D 1&P+����! "�w� M� B.�!��y,5!&�� " L�.eaxo� 1u%����B� s� (G�y~0!�.P "^ Y�Y|&�?PQ �Rra�J��r� ɀ��E%�.�*.�b� sMxl�_us!�One�i(*��A���o�yexpv�} zې��]aN2eHatV�dis&� a #Q Q|�V5��� !@R sGes��� �)� L inant-���� β1E�griAN>n�0&QB�rIw"�a�fA�- &�" � ly ��. Fur�nV,�-�Z����*E A�m2o/T���Nn/%�ee�6�?.H0W �3�y� ]~B*�h�90lig�*�3�)��"Ja�%_Q�K�nFv. P:;!�7:!$e� fficE��?�..�e�*eU!�G�z[3>WW#2�� itselfQܩnB�[46MKa��Ki.�I�&!Wsa�m��� �wAX��%�����| ,"�t�3��X5�*m.�w.� hR214��)s�`'�ϔ)VTs;a�Mm��7M6�K,QL-'1"%�X��exocysnP��18����etFUs�G"��^U�N[4�6B�3=6�( R�.p"XS(y7 meas� �%engthe!񮱌�^*.q8����+!��A��!9 r�)�*B��!c~vu!B_ .%, NF1/Cs`�� �A�h�;.�>�#a22�P)I5%� U�6�a��4vy�J� �6=|��iscuse�ela�)v�Q�!\� Q�2�1 ��G[�08sA���(ua�HS�� ��ngQR3C:��Va�!oM��n� Y%*�6Iw`��@&��.� ����IcKO�H"�)li�jisP"wn ab�0>�zZ%�%�ol15m,2� ea�u�xo,J&�1�Iq-��RIM9�� |+nv�nia/��A�es8is*%�2�S_!�b% detaIE A Drl�8>�2!*. kA6�,:� ��A*4�I��umM�%s anch�'>?!�6�'*d$.%Q�2�$Drosophilas�u&>[4�Q���� h4u�x�nd�za&�j1)�_�b%23�V4f3L�I�faTn2����u�]ec�F�1Ы�$�/�fhe]%>���pertur"��e!�H� �W*�ea�o� R=�]]� A2*� EA;IO�ye8!�in�E(6,!�Ӎly gi�v%#a�2�2P-U Y�$ J��m� wv� �!�S�s f�85A 6F�&�F>�@���,bT  1�v� o!O>6��� � e�AI2&xAW��ͧ yet5�� �%��)*;&�-<%K\.�T� �"#s.^F�o RXa�eͨ2sA�> d����4_M!�A?��ER6'o�< brob�.�OfA��G`recep|Ca]/e�<I;�H=8 %�[4M]4D��!�3&:�N7�2�"* 2CAi��.�"�9-9Ai�biU9AI"6&B�"��� nWQ.1b&HW.+i�ym�!�f ./� ��A")jt .lR h2�!� Akt ""�'�.p���/�V,K�;�actih!�r*�*��l:iHv4� ����F�!B�,iD(n�Q.-� �* U�� B�!�6� a� �GD;a0,B H in 1A]b^ G$NS [4�UA�stUt!��Jna#mod0Au[۞�<N`�Im͎!Y� �Q���s%n=�Nq�j)�!�recrui�r�� .�1ZPP�!] (e�rec�d��U.c~Q�x%�!�"!�� �J�=mli�qe�.�9Etum��p�or [4=4"�[�b� U�C%2a !�i�i<�B�(�cript_�:IU��6�c�M"0mory�EQ�e�"PPP1r14a!��\2�X |Q�l��L�t �i�iJ�z�A�>�B���� PFen�&�xA�� a!��roarr�1iY,B�-"Eof�E�Z ��6�)̡�aiTL�X^dEfst�[z S0O���onshi&j' L٣�.� no_ �A�!L�5st�cơe�ie&9!�� "[51_*!2)�u�si�gan>��.�HP n&k^�&R ����I-ngO]H��s�%l�:� qa�+��ery9pon&~(��7c�`>J �-� i�h96#a��!��\B.!��&M��K5��c,�("��� ons:&("�C�ou��o�ytFbވed& �MBlayer[�wBV.�%�A`� alig ��!G Mw�/��N�“5Yzon�c-��on�_w� new�9�5\ [5�hՃi��%-. Z.g “� aڒ�b�-�oi.a�>;E���9�O �ci�TofQ�or6� � . Gi ��a�Y��_de"�l�ry@2 �EC�>�,16*� )�-�#���"2�it��l2"s���I 2Gr�surpri�4.2 B+a �u uZF� >$�.Qe6�@> � � rIM":�� "�1*� ���' �&"8_ �%cz8)Z� aW)"6�#�sZ�Kv�#]�_�f�M r!&�&e.~l� I2� [53]e�Ae��&Umpa�k!= [5�+F���8)�"' &ie�!)��-,u�� B&B���@��(��n"�h�*t�"5�Ĺ\ � m{a%�� �Dar �)�Q���A�!��8�Q�J"*��5of^�!y� k �N>,��-axk� �ed keye�P� :P61 .�%PE�z��9�dA�͇�25�� !���ztypB6PR9�K ,"U��oi($!:��&1r� F�suG _,%�~N � e>-P��v�sora+X p�>�i s [5Jm*B�"�t2 D.s)� R� �!.� Q��=c� l��� asal�[0t�(�i�6�jL-���ct0�� ��!R�A}�X--Xl)��:�]�660e�2���(�d"0 "�a�"�5�cha�er� cE�V(R:p157]q3IAwee .\T Xi� �Cr2h1� h� is2�` �h/�iOHB �c�S�~�F� .l.X2 �A{ily�� � he1�`"R/�Ab��Da\ &��� �M���N.�)�V:���#t�T2.:'V����WU"2�s�!�at V�F�2��s�M��-��IaܹQ . A�@<]��con� $ o Un�Kingdom�is=� _(�|Ť P�Z�$) Act 1986tm�Un� �60of Edinburgh MR� .�� �$�c T,"(+^)ki�le�an�|d�BZuA�al MBP.ng�)�b"�V:` anes5�A�f�luof� . Veterge!WRimadyl ��D I liev�f%"�'su��y05I�6A&UgenJAt���J�Nal �`P%3�V�[S`�< 5′Lov`a�wN�f`a�_V"13!W���$#$1q�i��HM����v��b�ng �A��m` 5 [5mTns�O6�a9@�=! ��� �*- fl/f�gB`��5�i a! s�>aa���[6Ta–@aD#2Wa�.Ra ( CN�f%7_a.�(@���AE`A .�X� rabb� �[d AbcáU#e,�$CC1 monoclwc1Ih(>/.RGAPDHa�igm!J2RC-)o24� lyco�� ( MA�,Millip�C,E.h6J�t.h�9B/h , SeOc\c�F�%ti-�!�z�� eavy�i�NFH��cor�te*/�, Floric��"S��],2�OJ]r'O�\Gj solv�m�8%KNGDJ*$%XRVi,N:&*��n ( C2�KSanta��z2�p2U�z.wanFl82. �+N�E�ł488-conj(�ed�MIgA.R,don0 %+�.,562X.,�X�+ � -�� �:\|��(m|H8Invg�U�(DyLight 405.�V�z�1Q��(��A�t. OPC�YCG{:�5sha�-ơ�8mi?�2l72#neo�i Spra� Dawl� aM rtic^)^>5B�3E�on PDL-/�$18 mm glas�r�@��!�S�)% SATO ѭum��M85% FCS at 37°C�ԑ5% CO2$ eN�^�7�B2�x!1 �w�5 � %� �ly�D�� 10 m n ��MS9bu�2 81% Triton-X-100�1X ��9�0a�9"�  �t$}(w�bi�n�;t>b2��v�E �:]"�5!�^Q?���4%� aB "�!�wa!�tw��B�block� �]�!u(Qw-in�v�Mm seru��2% BSA�nd%�5I )I p�@CumdM�&X�AR��Ar^�a���?�IaF�!2��"�P�Qv�>5|%9se�0:%, Fd # F�%���. C� �9ze}"]�ac�%u�(a Leica SPEU=mj� ;2Ҋ63x*4�, z��! dև�v9|&Vjf��Pro PW(R��.�&g� ( Ady�,�e��&����+r59"��"*R�.�7(d�s"� rw� �cm� rha�Ee�[�{�=�(r��+�di �1�lex�(X�f7�p�3~ ;gTorTUm[ �~� aQYg6�\;U�<ve 20x s�Z'M~x ����%5;:�A�ie�@6�Ki*<�B� &�X�-*O)�I(C�C�m�vț P9A����3A���wsus`:\I!� ��MAC@O%oj#Miltenyi�%haccor�3>manufac�Fr'� ed. M� jh�B�%"�kpa��gi��� –p*let"� b6e��%�� )��`A�� proliferI�5�! T-75�|sk� 7����5-h)rsfl%)�TrypLE (R����&"13R.�uq��0B}Aw2�"�`E��܁sM���>�u7�� ^2 � �q6-Sjy2�abo9-�,6�@@=qEqana*��T*�dN��. B�,.�DE) d/or.�G�; post)b[�T,�Rili��$ q`�t�30%R rose��EB:�.ۣOpt� CufxTem"���o�z( VWR�S�. Cryo��m10�V%~c��G+uBfosS�frg��؝(Srmo F��W aTi"�s�-*i�;E@(. 9�Uv��8~�40���@i���F�F�E��6�Q l�%��2�[,��2��?)�-�!�~,�U�����RU �a&�H-�aN1��t�s a �K`��2 )��� ���μmp *�?L ,��?BB erveQO6�*�B.EHU{^� T����7�v� ��`)\če\(�� adja�!\���'��@�/ M-�d!0�got��7s2xor 16���S&�x ��[���[��7ib� �A-P2�acerF�aEvpeea�<Ay�U�o�7xiytly Ŵ by 1���3p�S� �"%�to��FJ�6~p�y�G)Ltm�acupun� need�6( JourG�h9�e� cine�6��h}�" ��� ; 2_c��>x#*/�Ks�&��a es�Pa6>%.� 5�!�NavB�I!(VB�"L 5�t+ �H �5ioA���l��{�$�*2Tas zeroAif6�6�!Ő8^�) V ;d_8maA_@>x:#��iH�ɗ*�J� b*#FF r>+ -DRG*�i��*@BX e�)�.� a3nsecu�'�iprib3o�ez��X /^2,"�a�0mo^S!�remU� DMEM 10% foe,bovA�X ( FB�/�5� bioe�R�^~!�ith 2V?:RNA �r m��.()@)GLO�� c�*m�1% Lipo!Bam�RNAiMAX66rea� :ћin OPTI-�!��A6v6G�J�:YfM!7Den-strep>��n#�6� .�,2��.pf��I64 ,*� 1%>�,;)�10 nMV ��1a�&.�)crgpE�B�P�>� �]sE�&�%4 ��ed�$Dharmacon/l�mo.� r�&$: L-080977�: on-t�,ing: D-00181isA� 63�Ѧ5V.dRJ!H9��6 hD el�6h �� 48–72 h� 2� �(�J�{F�.�,�9&|�JAA*"�q!2z6�Rat�:pM�"�2�2��&6� �%6��f�6�st�\V�:�1P�O>�$EALA?���^*�as����ng�(!<c�b3u�,g"�4�+w�j:"Y#,�>E4��&Os&��IQi6�j Kz�!4F&4�n�R�Sly"�XjSixbE4 �FF�6=(.{%g&� �6-wk-ol<t�"�"3*N8�&a�� �&�6�?Sam&o�ICinNM/� 5B�in��1 M"�e� , pH�` A$ 2 h;*� �3�QD14 d;ap�J�;�& XOsm�nTetrox-�n�Z6�(5خ9�<��!iH�>�x C '�- of e�+ou d2�A;�� ��SM, 1?l%��b U�4 Reichert OMU4!<�33(�$���@L�qToluid_Bب�s'�a7Eht� �;�e� suit��P�&u�. U�<�Kv� 6U��y TC{O �I) in U�D�tA�L>C² �%�.���1CM120�CnZ�n�� ( FEVd��t��%p,Gatan Orius *IJ( �8NA���P�Qrj!"PW&��* ��?�a<���� �&b2!�� "(�+!5���!at�;Ah#8w calc&7��a�"} N� ter�!�]^! 6V�c�gd�� D� )X\6�� � � � ��=&f$Jiof"ePKZ=uPaQ ^-A�t." iun\"�0�*&)� ��^r�7�*p�� &d2t >s kM %�5n=��dE�3�~'=�%;D.�A����F���e>esagitAg.�.�AjC.n2�.�11IRn:�"#Nda�ca*oAMp2$n!s2ZndU!,!� 2�jV�� � `��5�al��=A.d41t]bZ)z�]g) h� . 2�x �ogenv�S� to1� S� L�'-bA�rioci�haemo8:!�t�l virui�f�>b)�iv�#�* �e. of G�� A��>c@�SsGA��cau�+�g�L1 haryU7i!im�Ag;�ne��4�|]i#�q�c� �sh�sy�m^B�i�M�+��_.o5L� �8 ep��s��AI�@h)�})�i ��r��v�0�ls�+)Ja*{@A��notori�� Gram&} �1o�-��'��L��riF��O(!FClor`�bot�{�Staphyl1�aureu2p��5 �;H,_�L .S(y�cne�8o�d�&�2ly�eworth�Z)�.�::� sive׳m�a�"^�of�Aage I!r��; i�� .%qO�K"�a�.#doutbreak��v�ri��. E�)�seaXeW�8�P)!��afBm8,n �3AU-�u���?+ %W 6OuatED as.�I�mC6�Yh�U polyt J�arM?t1�iљb}�s�� Th%��WE�� �"�.A`��.%@��xt��d fam�/f SLS-�D"���FUH( MVP� WA�ticN9enh�dA�,6��CIF�"�6e�"ۄ. B�se�ribOW, synt���1 -r��5c�1�2iUΥ^7n�foczmu�3tl�A]si�BK� y� r�ye�ag4xoC'I l��i�6aq'n �esC&�F unus�� r��V62nA ��v >[1�3�3M�5�-+�[21�& y a� �i��%�Hpp��6 �-��� -EH>��:�e�ex%E�l8OE��:�5�%�� cyto�>��) y� �6� _Am���A=� Cy�( Ek8�wfae3 ) [4�8B�RO���� ) [5!�B<��)a6�L��Q2l��i�snt�\i�)�Cbu���5A�Pflaۢ[AE&_3n ( PMXb��of��2byb�s|8in���!�� ic sL����@Na�#��2�5J�. c����&� � !NM=�6�%e� eluc��� it�  f"� 83). T�gX�"� ��E� Qre�= �� F�lyR�i�[7A3M�/K]E:T 7E���:�� sag;>sB')���h AQ1Za>�X+�nco�sag�mi�1tra�%a16�5A�Re�+ya@, r0 G"^hydroxyO%d O o ac�� G�(.AB~8)�s��!-jFa-_)�"�)�r.��A =�iazy�A�ox a d>v(��hZo92D(a�,%���]V"��$ ��� !1Y�w1�bɫ����� B17 ( Mcb�9�-A*� ��s��&�X%�A* �%e��� E@� >�.�bio�w�U��j�i ably SagB"; �Po�8 % e �o�I<-Mcb��!+�!z��U13[1<'Inde�,a�f4!�� enzyu�,�C�d"�8!e(n�Y"�� �2��oIx m"D,� Uasa0j2Y��Mc&E�*ectg2V%�e6wJ�ۚtro��mAe�X !is� �i�K# & ( sE>2 :�2h $;iԍA @I� � CenG6>a��,�iniaea�<In silic�]� *�B�9�� ��t�"�m'�����Sls �.�e"*�#%"1uS 6A�i7"iA|uS F� V� �V ��.� epid���.6*Ro�f!L9(. P� in-M�&� ions ha�>ve successfully identified producers of novel post-translationa3mod 1�}lantibiotics by screening for the presence of associated genes which are likely to be highly conserved; i . e . those encoding�$teins thatH(involved inJ� �cʰs [11] , [12] . We used a similar approach to1&y1.*dSLS-like peptides , search1 homologue%ZsagB ,%gene �!1 McbC N4oxidoreductase.>depica�6F.eH, ���e firstf)�iA7eE�q�. Exa!�Qius�reaa�depth esa�0ishes two sub��e�]�� BTS/!�!� LLS/aJgea��Kay>��7Q  eight�9� onlyX does!* have a� ific!V�tyI�Lits sts equivalent ,A.le�lhMB� llsYMAI���ORF%�St �1' .� . Oua�-ʹA%V�De��q:�A?confirm�dth��yA�notaj arte�_ from! ome 6l��. O)� basi*Im dis�!#valaS!�GC�� ana��!�T�dS��a�e!'/!T!ϭ�differ �their sl )btA unterpart-Hat'y earA�%�eDacquir9horizont�E ? je con�j more in-I��%~I��5�sia�(it was foun� F�k!!],E�responsi�f� @epidemic outbreak%{l�o!�qlife-the[� infei�of��gnA�u8immuno-compromiU humar 4] ))naI8���,a pathogenic!�is3�� IPI-9 ��or�]toA �t uish!Eh+1 ,�saBll\J9�c!�i� many�aC well�Ld virul� <orsB� �e!D[15m b�2�#2�)�ex�uive� iru��nt7�,ivanovii [16�_3 flan��4by Rho-indepen� ���ndE! (glyoxalase-��A�a\ lmof� _1111�21; 81%��!�`redicA�ŠAo��( P)�- ={��s!�viouslyBj9��pul�in other%*^� e .  `, a PrfA box or a σB bin% site�In"P A~L! !D0LlsB ( 24 . 7=w� � � �p� %b�81�P eOGHm�aLonente�an ABC�Xpor)J22 . 4%�19 . 8�Y to�P�a�EZ� LlsDn�D� nd(Pɉch����,�С= N-� l �% ( fr O *� %b&� B� AA Giveeir � �:e٥HX%�� �ly!bA�6FE�/can8 divi!�in�r volu�ary&G , II�III [1� DespAB�M�- f/ llFposses �{eEO1�,2c[18���  I"s c��(of.�0serotype 1/2b�bnotora� 4b )�{�j��lAZA� adicJ E��12�[19��Howeverao d , nou�al� !gorY� specr lJD9 .  carrout.] in silico2��A ed��� 6�although%DwQ >�Q %�3��t!bab����!�B�PEGDe [20!�,F6854 [21] (L � II� !�N non-��i�+Dinnocua CLIP 11262 V3a?Dwelshimeri SLCC533j2j4 Wo% investig��� �? P e vari� natur� t}�R�)� For inst� , -L ��al 14� immed�(ly upstreami� -�J� �ae%� large am= 9��,DNA ( >17 kBa#n pla� Yin)���)/A�  cor��oɔZsIr�� aw f ea)a %a��generJby� Broad InKute emph� U he0tic-�il� / i�u;[23];2  SuchyH��i*�� at h7�f up- An down-�g�(.�J�N� Z a�� )x−u+,g reby�� ���O nM mark.ou�limA�,� wA양Hin California ( 198YA0a�UHmultistate; 1998–H pA� e�9Met���*-�5sE�H�ax �tLausann�198�, Illino� 1994S 0North Carolin�200���&3;Q�)�InaW\�� �few=��./�V!�0Massachusetts�5 , UK !� lack-b�Wh� (!huEd!�][&(is mapped o@ e phyl��8tP H( maximum parsimony kr]%qcombi��U�data )Fl �"�19�1E�E�,6Tappar-��2� �Cce/��Rm�i1O?� 9viduallEkreŊ�< 4in major branc�U �observ6Jpa��&���V��@ s%��� . WhV%2Id�V�!dNx�e)$ Ihasc�is�m�&� h�: ev!/��ceA0" �W��refJ!u%>�/& �-zY�Az7�reflect� l! 4�[ficYX�� A�a�U}ofy E�)� betw@*J�=oop�f of]erv`g�%�wj"� curr>th�in��"��!2emerg��6� iZa)es=�ttribu�j�e)1�1i�`$primordialF[25� S�V�6|;haemoly? activ< of GAS���a�sEA�1jFq�;M � ]�. All��6fM,s���O85UaO60 kDa2-.��l�MY��([26]–[28]��)�be ex���� mask �2!>ELL�Thq&�Δ�mut3of�z��c�d ..Oa� -i�n-yPon Columbia blood aga&H4AI� o de�e whe %Oll�s��ex!�Kun�H i!�5!�Ll%�>+�f� to a Luxas�ma %� ; probe vec ( pPLKm� A integ� e�singl�py��[, . Real-time&� !�A�0IVIS100 image!Xen�� ) 6' �Droutine laboratoryawth. -.A�ayux%�eglig3 , bu�a�� �!(strongBA�d upo�posRaT 10 mJoq!O ] s!���d(cumene hydr�per�!!dJѿ� � i�!��i��,�fpa� gra�/ly� aai�pA�UnfortuAyA([i�nt� ��B��p!�Q�U essmA�n2b}f culsuperna�� . Co�%:'LSFmU�u�la��:JA 6�E 8� n 5I{Q�C2-Bb� huma�&te�&!� J774� ous�%crophag[!� CT264colon carcinom� !A�M�B�|On�A �"iguA?feE�� � 6� M!��n c*` � n &i $)� situ� s unl�6RE�B&����r|)h!sRNA�!+ribonu�#se- #� t frp� f yeast4)a sui�! e bu�(�f[3�[31} � .W!? �]J ( CF3%Eu: !�6m�M�s2%\�xFedR�u��.� t,LS-�e�*�"s!��R�iI�)i� wash��U1���56IA=,R�a"i�&�? B6GIB!G9 |�v RN%�!V�# ilisammonM(ace� `; AmmAcE�.��A- pl" f��61���s�*" �:�pro�� fur� ��E�)��l#aai��A��!&�$�>� �� �7&a^ &! ��wa�# <*q y�� "�&%G B�*wA`u� @#�v*�. � �im� a�m�$ beca+ [� �.�A�sX ic�7nt [5��+e- 5���� �mpa6�wild-�IE~E MK)) followaY�Eax toneal i�p��$Balb/c mic F��� �2-����LLk��ed��#.Z""�,_s�c. 6�(-ME evel�$�v�LAOspleens&� � &A�!493-��!��6� We�li"��f�9�QO surv�&A'LB���<PMN�� a�6"pZ�a )W4( AvU#ra�it�#Wto��gd neut�il ki�gA{ ; se�V ll �ocyX, ���%�v(s�(9,r�"ofBX �#u��s��R<6��"##;%� thir �AM init!�su�F�*�%%�j*�!influx�9 !{&�,%�Ba�ns res!AN� {g playA^�it�"rol�XI��Y�burde?lA��+E�%)l$l nervous [3�0��R%�u� .�� Km�a�ur�1]�A��#a�af� 2 hr�R�aB2v� z0ig�)ly� Qtha � �C ntyp�. estudyA���s new�?a�mk��&�!xz'!�Until��,�,6��1 have�rarely�d%Y�@ ���)ne2.�&*x �(Streptococc!�p . ;*�p �.CiG�X1i iniaj a f$(�11�. IU!now:�a*0"!' �'t�T!$�+H4"u&:�5]�(52F2,�a�1��C .U e1R��, &�0.)�* �hj#��ɪ.�� dz l!�;d�/�A�Aoɤby�G> !:�:>-p)�A�� �R� G���/� aids��al*i e�to �h0� p on�8h MVP�se��Jeof � IJWma�/!,in�-�$o a biolog�l�ereU-!�undrum�c A���e�0S�� � =�� &��F�did� � sen[34 i<1kssuA�eQ��] O� A!s]Lin/Հ-�2 �$� �_Z Q*�M�5*.1�.�4� �7*)wl&H coupZ#-o� : �mFof ���svf2)�� V enEf�id��� )�2c anim^ ayri0a�fa6a�.E�"�$A6 Y�)a �*"�G n� .r���:[3hH*noe�ticH2��p sugg7$` cS expl� !4.tb�%RS��nQ� risk!�7 dis�'�4ffoH2.J;��lu�/9 -eO��h���0 hadDaccommo�*�#isS'o) ifa4E � se^a!�-8�.�hq��R�simplO�2a�)er�&�1��P�Aperhap w�I?mod�� �i{� alis�UŁ:gar�F�A�&�; very #�3��-��2.�qk!�I��*UedA-�p4��is  ��Y[�� subt�� Iy*+ #392e�gm���a)�(�� F45H<j-!���/om EG�/1/2,[32re-,(i�ɻs.r� �!��{,4b��A�fr�&6A��*��;�(. S"n,��D!!� f-NfF)�A�%651 "�.4by:��(�+�2� �,. S� ns plu�� "_2un&�0�2!�>��r�"e h�*� �;g �Ib(z�#��z� e�u6z g��ug1i��M}IQ��%�� q enco���tic����2orQ� mpac�� �4y�')�B la��!� ecO iLP "�.m�6M"����to.��d�!�aad�'2��Q-+2�p� �(!���mpl�$!W�vel1H~=+ ��$candi���H����B� .� -�� �pi�!&#1ntane����.o"�7�0accep�!��;%/sV=AvA��1[)�+J��� smT&(A� ?U�E�EF�li�6toV�-�-e��%s%3Lliht �nyJ0 y()�<�i��W�'r �@ f � ,!� ca� illn�falr ��uffic� qu� by �8(�8�V(& O�i���a,s d�res�!o.YGi�[37 � %P� why �{4e-s%�Av"J3�.Rd�4� �,IA,� ���)�%�&�$w�w� gw )� +�=be0u?�3A*� ZrU�B)�~F�&!�c_"_ hyp!ZA� will4 w@m subj�E- igoras.>by-��C�D, ���el�"�%���fu�tud�.��"alE�preciech\ via!Ochf �V��o]&�e&t-""s^: i�� X-`��"! &&�f&�i�ablA8.`a�y�>!mreC�,phagoO/ -lys)ue see���Ast�y }�%>�out�a��mfA�a � c" M�!6SSA�a.v adv�-�BeEe&d[ *a{* A?�$!G )2�7�">�cn"�7�y��BS. �a grow�br� hear-j ( BH 6br@$�!�'Oxoid3N (p2� A�A=5% sheep�;!^ diagnos3I, GalwaBEI]n`at 37°CP a�rwaf.�(S s:����R �? s S2%�S��$Escherichi�+0li EC101 [38]%$TOP10 ( In�gen@�aa=�(6I(ho'9. Ant"JF#incorpo"U(S(s: Erythrom�D [3�4150 µg/ml E .�!i , 5B�(; Chloramph ?o�cmX"1FJ!QJC Kana � ( ka�R�2n�Ampic0Tmp ) �(>�. 5-b�( -4-c�o-3Tolyl-b-D-galactopyranox ( X-Gal!�%{=N���tHon�&n45.8o unknA�q-�$�4 j"�*�In/ ele&Y olig�"o�J PCRf2 plexA'describ8&M b0�&A�*1�:|!�� �1ro+:� � inct{rea�A��K�|�-@er pairs 1118f–r!�ll !m9 5′�il3′; TCTTACCCTATTATGAAGTATCfTAACACCACA' AATGI118degmdegpG+G7TAGCGC  TCAACNGGNCT , mWV_A{,AAKGARTCDATYf!� int-soe�PTGCAGCTGGATGTTGCTC , p CCGGAACTA�eA� ���*per�&�Del �=mK�a�ng/µl!�Yss�s�J-x(, 2 mM MgCl�A0 . 2�6deoxy�$IU triphosph�<?5 Ue(Taq PolymerT?� 100 ngici:.>��27of 30 7M�1`+at 94�t,56 !u&72:`� �Ds�� on 1�%_> t/voa��Ngel�'mpo�2al bia�di=*cy�i��Q�web-b{ap� �Ddeltarho ( http://8. amc . uva . n�[40,&D5 calc�!` �:o!YdN3 d_ (��averag�F����(�M�;uF� )")input�+ W;M,(�chos" �A�5�6�(�e�.h%��&�!W�� R"�G�d& ��Jlog orig� &2a�� o�r�r�C�/2-{ �g.t<ae�, �kղ (cNMs�6�8om pTV1-OK [41] 9m�� ��$RF-KanRR (�s�GTC��AAC�6ACG�{CCTCGTAG��)5)1E�Ae �0PstI-EcoRI di� ��&0oBilarly- PL �[4� P��%�0w�r�!c�in=6N�)-!��' R for-[ bluntrev �O�CGACTTTT�2��G�� ATTC�zG� ��5�clMg �� SalI-SwaI*�Er�-� plasmid��d/>z1rT Ete1b��to�! . Bi~2inesce #-Bt (I7Q�#D5.�E�qrEryR/Cm�*-��&� bye Whly!4�&)B- dele!]�!`�FX( u!a2-h�eA-so� u��)Y a�AG! �0a�a�CTTCTAC�! FCF�b �cA�[^ �f�\X�AG �6 TC-TG�v,�`a�ingx5Q@VA> KSVa?6�#of�i�NM!&� eu>�s� *X 1k���a>$N�47]%�i��g�"�)b6"Q �2�oLBs=�? !c CAAG2!����ŬW Y��9!a�5so9��#G� C-AG� ��� �CT-���E#R so utilizao�;A�n��I�� Lls?2. H�%m L;)� spot��q�-�3:r e�j(vincub�9: 24 h����tit:Ass�6g2�K.�(by Ginsburg�Y(> . JEM 196�:,���minor� " JaF36D&�ed! fold��4to 2×1010 cfu��serf\ dilu7(wQ9�4&� 0 . 3 m%^��Av3�6$005 M maltP,4 001 }SO4-7H2O2c=p<)�-� or�j;"~.,�5 �prewa� �'C0d�͐ �2%�ZF�)IKdd,aSfi� � adju�to90y�{ tube_���E=,. ifug e"�%�!U�k�/ otometric�'wP (Softmax Pro>*e�MolecJ. Devi�)�420 nm6�unJM�Yd�6A�ta�� rs�h!% lastI5��Show��pe��. C2Bbe$^A��CRC-210�>,y8TIB-6'+A�t8$CRL-2638 )-�� !fcy�<�&m�. C&X5mais + ( Dulbecco'smUed Eaglee>^( DME9 c�yUBS5 g/li!oGluta!�a�bco L,'_ , Gr�I ; , NY!�na� % fe�W _se�(F%��k( 5% CO2 atm?"5N�th �a� �a��vol�no/$1a�P ac�)wndeX 01 m��T �,�albioche �-o�2� %�trypsin��(Qi!�; G%8�, scra�G(I�:harveeyH5efu�OE� 00×�b8�${� ,a��F!3Y see� 24-�R(>5�,1�!�S+�+&9>� G ���!�I�:�-g �c��(� 6 mm� me��)���P�bi2I��(S!'�&y A>�:tEme liquiZ+be��E�+�;9�&� 5�. G�g�!N = � (of 15-week-� BALB/c m� To� ���*=ly$ l�C��,� _=q� inEZ2A�8`q�-i��2a�.�&k � of\ 6 CFUA~. M� sacr� ed 3 d,pk""d.�!��(�B"!�$n:�3sq:/ N_  1� 6> Aaf� 10-� � io H;7ige��s0�>"�~�ocedure�.��( .��x�2�'rHod +7�mmitteee��(l� � =X�ele�guide!��j7�ar.&granul!=( P�=q(�V�ae2 stepR ��1R a�7hod*L!by Eng�e�An�2en [4�i��� EDT�hticoa`7eU�5be�ob� :he�0y dona�%��a)Z\a�e!x�9% NaCl� careOnaP2o�dis* inuJ��J:*Aby layerA14q�4u�e/%�ZYd%.*a dens��a� . 077 X 4( Histopaque 1)�d.119A�1�con ��} ( St� UK�*�sub�C:.� at 7&E �r� t ro *�. AY==���"�" leukEf�%;��lymphs/�H�ndI�/U�i?8M�U abov#*cg� sedi�of er�%�?��PMN {E0Y aspiG~+&��F�1"�cXs�.-FCNE^2� P&at 39V10��nV!G�D�N-I��c�\YLsA�Uan�sa2s�?( -Ald]'L Chemie , Deisenhofe� Ger7��vi*�A�h �asA}4:e��%�97%TuRI�Wɤ�U2� 2!�%6)9 BP126 ��Rin9�.�� �JPB�R�:5�� Z�A7/m���I M��6e5��)6y�,�>��bD∶A�"Q20∶�-I�onA�3~in q�i�I3�%aEH0 :� fres2um!rQ?���of gen18�=MN )���C�r&�A���Q�&��T�2�. S.��+s�1: �:�M�ly���R"D?�6 ce-c= wml,a�6�in]�����Y*�a�]a#CRl���6;&W$* meaA^)k�,7d � $&%X1t-tesv�ca�� �orm�juY� ssump"�par$ ric�3�[ic��DKolmogorov-Smirnov\YnormalXE� even!| equ of �W*X�� $WMycetM4��m37,`gM1ve�u�mat��Dam ry�Z�9�1d either!�fungi� byY�. Cha�7er�pc���9�0�5S&A�s� �,�W selv-�N scop%7�� �ed�i��Jg�-s�,surrouZ y8masQ:2��!�ͺpT �ng!�[is��5!�Ab�2p�Q�e2 (m1� ma�y2~+ . Du� .�4l�g� ; '�m2:�"?7�1&�1��1weaVIIa� nter=in-17+Lɘmatrix} allo�i�N9 ( MMP-]�/J�a�elO'�%Zd verA�� Q+ �E,Yor1(��.�k 9A�]P�uBP69x5� $"� %y=#of ) � ��1�le!I�4!��08��v�#u�Rex C�Suc��rl@51ps�� � V1���tit�%d"� � >��f�IeOp�A�oh2 w ly�lE'��UI^�Z� �i �far!7��!�b.-\J!�OKaiSin(s IJK!Ql�P wY3 I2Ym�Igy1 �ActDRdur�&� ieri$GfG!cs  alie�^9�$�"to�urella5�ti+�mz%fdirec Ebr���4L )U�( p =c �]e�;*5IB \ MMP9E�!7QJDv>�!�$q�!�}<� {r��5.�.�"Q&heM� �aT.� demographJF. u?��c�?n �YI2�, �D�,a��4�A�t|>�P`$rea/A��6 chr� �.fEusu$sp]%sA ���ski� d�3Hx� �w0��d�m59,� � !1.["+Itaf2@0s young adult�childru �NSRl9@Lf�r + work deng�l!�soil [:44>B%^ne��V&.=1� ,rF�!��y [\c�? Fifty-Six"� tq.CIof �@ed �-��Ih5!#}usZ!�%� b[,6�m���Z�{ li���͔�Xa slow�.tumourH softQA��:�I�i�C��siz�CW ,"�3 sinuy dcQop��� t J%[y d� �)tt%�;pu h1l�cs�� [Wge�2� FB!�?I-Q7AA5of]mMXurA��i2^1 !5o�N&mY[12$23�KMi8&� IrC�V��Lso�U/ s ye)&A8A .0�� 'A�� �a&:o";L]�Y-B�fJ�C��t�%�M-", S ! tPA!�p qu�q!.8tcsM����CFew8hav�por �>ofEu{Sq /H�t>0 El HW rJa�lleag�{; C�� O kA profO� Vq�a�R.�9��-Th2� ]�"=: ) -4Ea 0� _p�=� � yATh1V[$erferon γWNF-γ�7�?7a�!L3&yel,� z , Mhmou~A�"8>� m�OB@ .��{ly �-W&]���>e<iS~s� �&tat M�2����s2�A@�QofBgvAt(�&a��� auth�-�foc�&��!��'�r�h�uz Th17��i.�X.*H-!�| year�&�H8 h!"� 16g%<:"[0to�iy� "�Uea� subc�g#F� �Ula%�ono�+� mobV(Y  v! �� xper�al Noca�i.@�v�U~ �[Uv�17e��1a)quDb�GCD4+ T-��q��&��,b�PV���y�(EH�([av. 1 &�Q�Tcytm�k�=as ,A �BF �tA�`n$]!T�M�}.��M��ro.]� >�man\ppl�T9 fibr)�sHk�"E �Win S*tur6YidMM�<63 RbIL-6 �'=L y�IL-�)� tumo�xis�F alph�pTNFα �,.�,2��end�A�� �q sle�Npronou�\&�!Dilt� n [2� �%A p� meno�?s+3� U���MA!��v5�k�� $ rapid oxyB��� ( RO��:r�jo�tro;RK�&�6� �ZM��+796Xu�b�HA� o at�tJ ��>�A�s� %�Aw[�Z��a�8}aQ� �1of�.:Ni��Jt ��Min��06�� lo`m&da�j�F� occu& �v ,KTG�g�86>,Z�DMM�U1Gbexre�.�re.%/ ^�[3� LTM�to.Q!$ 4X.2 T-a41,� �&\�!�� u�"�  es�R , �OTw,�pi�-�rsurpri���%[i� 5}�^�%�GcgeDmucosal leishmaniaa�[AJ�a%�IYpustul� �G�3d�8mJ;E&�m E�J)� �GI�E��s(AA��4� q��F�E 9� T&`J& , hTa�&! e!�no��K *�hbZa:mpl6$a�W�V�&�9�!Ge lj)A�a�8MMP.N�ad{ is qu�W#+�3a�e`��incipl�>8c%�#du-9:wA�J�f� F��:�F 8� 6[��H�4�$aoA�� IdA9hD -��Q�c *<"�"�. C>l!�I �!�i�.{̑��$WeEzt’s i� heAxyl�9or�1"!11�!u�"Er nE? ru0]T3 tapI:9!� 5#lww they} �h �scarlet-{0 fuchs# :�F9>�i/>h� jlt)uI�'Sybdic-  tung!�1v~or��!q  . SeŻ� "+1��[�5#!ea�Sni�&�"�"�10!p5! .�T�Ld b.inBMF1%�h$pi:� 2–9y.[!�)S>� , deX@�Vquick�h�+<95% ethyl alcoho"0b�e:�pk!@in xylen��m/ tCn7A��1u�SJ�%_+!�r ���A������.�a�&&5e����s L��&deparaf/^P >����!to 3-�3�8yltriethoxysila��t'd sli|�K! r86A�&CHbC:"�8���Yin ci� �jy�Fe�bat}296>A�ten�%i��N�:)�@'tP6� R M�fz�Z� then�{Tr�vm�+( T�k�Wa0�{atB'w���rxid� $block ( 3%J+C�6��ir�(��o�nchd �>us.\] _eW1�%��C��ax5id cha�1�%�)�8�nd1,�woWPcer!�A�}."( a��0 !�fHm�8. %3o t ~ inn^x� �o�%A=fah�%�B�!�pow�"-��STn��; )�A�!e1��$inVA} �7�{ẁ1E��-b. ���.� I�u5%�%� �)�F�y�[-�=�cA� body� �!; rabbit>'l-t'�� IgV=Le EP1255Y , BioGenex|J�*A �Yu.L!�0'EX�!�m�awo Za-�Ih!�)��s a~ioA�earlie� :Ja�oE \��L�3sX�5�� 6��.v�B��9����l�t�`2�U[ ( EP���U.�!c2�HRP�ae� HRP-conj9a!!avidinm )�>���,�!z�:�B�,abcam ab7905�17; 1/#G( +10%?u�8� 14 h�at �Ma;-iNB�i: !�M,Nft]E�AA�tin.go�* nti-mJa���a�on2�;I52� 9 v���9��.Fh~!r�TA?)6kE���)�-P�z��A6�1��N�V�=?i"~6� vi7!N�M�c!Pbodf>42�DAB� gen/h/D�-6 H2O2#-�}2�6ofU mix1)2 drop��2X�a)A9v�!;!��>t!��)H��ja_��i ��IB`�YRo o^(J1\�o�,b�VE�A�-�Y�varpN�oP1� _vO*U\�Ё����ŢA�edfH 2�� &� WfR�c� r�1DM02�.�5�#iW�CNoZA(, 1�%�� :=K!156�"5763n>= �Bʙ$�!�ū r dA� �:J�weaI�+ ���U=��ong.�ZB�[!5�5d5�%�U��"�-�N�( � ��c �� 0�� $' % #4 z]�a�w�O+) �i<g>4 h�rV9[4��4+%� d:O!rpr�K��#.f-�_�m�[P$Fl$�)� tak@Olympus SP-350 ca�W ( ImagA�A�cat3 .�Qe� V:p]Pennsylv�&�BS{�0E{"@�1%p�/dm�A6al PackaO�.S�l S�bcV SPSSR%�sChi-squ�$, ANOVA te!p�:M�[2iHUb��A��4.�A"d"�� ,4i,�&I"�+@  +:�i�.Z�~�z��d P�h}A��(�q3�Lp, p va�#Sd�#3,5)]��[-�ly2�,�&l. 9H�&M��!�M p-�!�1�5�^ A]orp^,!� cago�S3veth�#K3qUWex SobapE5z��Hospi�+E =C"B�6�m�����l�m�K:�5Y�4iu�-.)("$Q connv?i~p|� chym�c�'z7�"� wl�!�2i�� aiY hick �A)y*:�. V��!qe�AABH52�.?5 .2J*bi�6.U>&)f)<N�4N.*! �:~�'e'RV5Ԫ�2�,i)o�! ha�n_g�~%ber~|#1�.T>��g�Y2���)� ��!6-!�={�Yr�� R=�� plot�2^z6�����m2�-�eE^j�  m^l�v"5�����g�E� u&*F"���#. �$7Ie^st�H�t��v �� ���vsn ���s-�#!�>)��� mZ%a Th1��+J%�>�go� -�&� �`A�!6N.�+b�l re dC�"+ ed�-�!(����� we6�0�� t171 �\� ,���2 3�B0i"��>���# .�0`g>O�&�Z)�1>h� �\ �M�1-� F %6 {�U*]7� �>�A>� �16� IZ�G62I�.t�-�4�;aQ��f� ��)unK-�-FE/d" ��q�a��Sa<� idioidomy�-42�'��=obF6γvi<}"`P*.���*sTV,..@ 4d Phialophora 6Fardsiae1`EEA�A4�U�l�2$4e9-}#��\9e� �9i 5!��<U_�f��~i\/qg YP+sT3)J��"^�[C`H�(A{� aa�N ��Vgb i %�Nsz.A���/2Lii� 9d��@e begi�&�� Maa1�� I�N��rN805AA�O)5UAs� %e�i�6xe>�1�PF|2sBr0.Ta!e !S�4�&| j_~s��6,recrui#>�7I1*Бshort�;ing�� �Ew�7we��e-5�!��� f�m@/D%�� poin�hV !5T9=A�aac5�);�&CAstr�(I��鋡��}�(O"��m!�� �]b �p& )��>| T-kl)�B�&uuS�!�2~p-$M!aw%J$,!�I�� �61irp �.�S2�g�7H�i��3}=�� � �M�5t��JA�esNt!� q C� wu�!�}�\u�14؜laBd)b! �.�;5��W ˺ggezvej z 9� in8=y�� ��=.K�ode�J�9aѺ��n��%r1J_!�5!,��%1r Q3t=[4�3Con �-�X�*ll ��� /�4F��-sB2�?� @ld�1).1��d&�GF/2,: 1x ��, s��1ur����eto���i��w�[@���6�say� -<�A%!o�-Lznd 0-exaxD inteD'�_�U �2�E{ A�a�� �HQ�"�:��!� "v;*8e&A�ay�6w�.�� xS etai#qIf �� (-�.�%%r%ipM�0y2u�p��(3A!oR)3��-}�$� t�MW��ha�ve��$ v�+[47–4% 29eeBo�.�M!�B�2hh6g=E�1bP"��n �]�mdM�}P@�ctf6dzW eneugelijȡ:�<m&�>?bD�. 3� uB�&z P 1  -A>K�b:��� -�a?�bFW�l�, 36Tm�mU>��9A���9�F ��SV*2*�let�<�t@Un �1� �I�_id �q}�8 �/QB>�AK�*)�6� V� ��8 r�#��Min�R~!�/toB���!rr�eO���:er&o1"�6.FB�%>w �^>C�.\A�d�be.s:��#�*E�lBYY};�t� nazoL�֙>M��j!��.r�sA�e�ַ0co0-m���N�R!ȝ��0a�}R|�)���&���: �1α�? MP-8%f 13Q3M� !a�'�[�*@!as�eA�V1�D 14 [�j[i��mea ��#��Z ;�B$B ZW�+ have)����!� � .� r�?��,�a n� �=FYu�AA�as�@�V�~�d:�^j%��w8 , -9OG!, !Z%j�Winhibi�ϐ9f Pina�G ( TI�:'�AN�p%ȁ,prrR �P"�&;ke�QVk C�� albns�.�]eAiVOA Mock&�� corn�K2�A�U$*i>C� ��f���E�5@2!-1%}m u8 �D�\�pI�d6]t]G�0C,�`o̦e�x�n:� [50�?Am�/�,ihs&�  A�&r2�B2�LmRq*=TA��N�4�"� a�z OM sa�ee��� �Z��O����`fj."��deo*`a.k)���� ��H �A2-: .O � w�O2eU�De���69 2� � �! �-�&����%!C:��p9gh�Ar"$ ��#�$ej)U���A��=�a�,5�^xA� aF��Q�!��i@0�wr��~� ?���_in>b�.cw&�lrecog9�oxli^\n��l W�@<"�� ( IDz?�� �Os�+�4 @b#�cq�t-nddi ^!�g�9iA�:M�|we;y�bo�%a.Bco “fuzz7z s”� fs0B�IDP��!c$"�-¹.l�!�a dyna�en��e ����- ��T�X�Be傁�At^A~X&fe��-!V�hy%���k�� ��(r4�ack��I�,;criť R� !�domA�MNEwing's~kc�onc9�6fP�( EAD �an%5�Fex�:�Ln�� �of�%~�CmD�>Ia��#;!!��$riv�m"co.�.D/r$a�&#��%m-πA��)"t�/iM�6b7fa q"VX"&� EAD-I�"�1u� t π!�te�aa.��nd�bic��id��H c. Her�7we*�V�ollπ�s�1�F!�Łeor � HA,ro�R��L["5;2�ef��a�+![6q ?)\� ќ5�>M,�b�a�g4� rturt��'aor�-YπiO oreover��E��(trend&��Qell capO[�arse-�<�pAD�vde�)��^�dAg-(t7%br�s !W��Kh�R1�EsuE] �-Te�ic globM5�Jl!`E�]s��Aath"�j�a|'us�%�ahe�a bal�U��.� al e�1p�/favor��9��e�Y�AMly N*at5 !G�V�ot3s H���ap]S�}menA�a�miscua�-@..bye���t��s . U[,�4!�aUQ�-�HII�hip�aj� A�~sK:Y�&7r!)�Xbio(?aF*�� � SV��su��/h1 � �dY# t R��+��i��x; keyyal�> s [1[2�}ran�;ao)%�K� �Ga�0�HuI֐,b���IcAtr [MTI�∼l1A��"��� 7a�2���.�Ymed �l , [4E b vtyLY!rn#sMa"�!�ABGtH�_*h�, cer�& Rengag�1�6�Fwi�F�u��fAx=8[5]{>�c �( s.���a�aJqVLp&WK�X��0PedBG [6YA�h" a�a���et~J �!�zu��wi Aqa8_��KI�s#a-�W p�"}��(6 P'���kerf�s��6bion2XU�[9 � Sic1-Cdc4a�y�][1� To g�FJ �iVB� y| �+��w<�v .eB� ( EWyL-A� � "� �TET� of�o-1.�11 ��+� \ B AH���O�:C��eM�UE��da�dJ�txO�}�#���*�� c 4�RDN9�:� WS!��,1ne�?P��u2��u�hl�3by%|e�rU��fX����q�*� /�x��m�YUAn~bab�rAb� pauc� �N3 ��~R��g�Q�-uMngY� . Be�ivee>*�"����rraE�u)(!netehubl(�7]�%I$�g�:mIf��C�V,M�˜t�%l numeY�-��Fuϥ�E=E�e�� ���6���!�. Mc����!�B�nd��&k m��o�M0"� tyrosrJ( �{�8s��$ !�#*��H&bxEn��.d �marked%Yc.�e :N �NgYp�!�Eo�Xɏ"}�app�.��"d�D= qYn"Q sha�`"��Y�: exploit>6$KryQ ,AM�.uto�a�of CFTR�V,�Vo�P Ets-16����UR$!�.�Ydk&��� štE3 ub~ttin lig������ I�!� low-oIty'ՀF a m4sh4k� t)� i� /s8 co���I�S���rodic�_��of ��K�gl��!��o��xpockeg!�,NV –[���5)\� a2���M�n�[uQ� moie�?!�.� "(cQ�[5��oA�it&{ uB8A�usZJ a�5 eluc�IE=hl&��er�Յ�&9]�ŧ��2 N< +W7%��R,c �"�a ��Str�@!�tov@(e/� ��t�B���un�8������ ( π'�;�!�a�!o*(-*���:= ++dea�m"�)��lso!� � �sim�_���r*�u9�"��!�ic%��� �Ů�4a7�re�9GCQJ�m� �/ ADu�M�("s-)?� up"7A��o�sn0��(.* 1�%3�á�t � . In view�o!&���wB�A:A�� 38 YE�5'�AS�.�vH ngthU�2&ŚE�#'��&ly�u�(g�yn 2q�� -�5�!{i4nva�p��poS)i�o�f�a�^ybs���A_�!l�Kw;9H��To�3 � u���2�!'�M-5�� &��t| N ə���R�J� ���G.�:.w�.�� vivo6�< �DC ��tm��F�!ɲ, v� ���L�42$� bJiyq /�g!v:�v IBX#�."~�%led��{bA�I!Fy�>� a��pr$T&h�ŏX?�Vm��*�kHDistٍi�7a,� ox2A�g����s�m repe��b�� s��*"H ����� i}ame�CC%��Daa&�u.fimp��6��!�� hurdUwwe� Ǡb�m��!��#��(�40�_)��faithf��m5�%73N�"� i93�w��B �A�( � )�a��O"'͞uNa � !~orHe�x To "d1�vr.�&�A}w�g!&.��SYng a 66M��p�!(de ( 10Yn )I�Y97�h�� "��&BA�ay@A|���(�d_"7�}�Yq�( 4Yn���qJR Y�� ( ) A�r*�!]sG�Y"D�q1�. T�=��Q[&ft-5b�5E key�� Jeg3�s)!a�b �ao�oDR�zt6-a"���?id�8 Z7luۿ�T( MtUd�)9a+�s6�i1u�)]1 ����ia��l�runer �5?��� circ3<�Sd"�)AK� "� Ys�  toge[0!4U& m��rTo!W}�!�6�� �' u�= c6�chT�#��em:N^2�R !57�z !2yaUlexA� [a�f�m I�z� �sp!��"����X"X 1eS2AIS �25W�{RNA%!9Gs%B subBo$s Rpb4/Rpb�u,PDB id: 2C35K�S2F\q�A�MldA��!4��'HB�4is* *c&q " �� � �hc ���)1��PD. S2E�.��!���nt)Lpub��xst)c��"|�,for�A�environ�>� ve� q�s ≈−IJ�I<−5 . 5 kcal/mo q���, m .2��� �!�jE"�85:boNY�.AzuUz sa.-6/ Cs K "P;�2a or�� ed��ce �8unon� ��?7j5 r�cg|s&bR)2�:n M�e}?"e@�A��a*��$��N"i�sol�x�)�ra��tilE^d&*!op�J;^�ig�3� )9ct�c%Ax2�ٙ. T��+ *�s 2�%r�a-�*� �qq F��y0U�"s� iDlŁ���q�*:=���!V�Gs�9� 6]I:=�.�2�( 1Z�Us�*�>< A�r� ��� B ����"'�K(Monte Carlo p�B(��8A�S�T' S1� Oail�[)m1CV8w-��-KbsAHj �T&�i�rr�h "�? f��iHj Pj$io4Ak&���SrHN�V <!�*��+MP1�� }ye��rsZZwomo���.'  5*`e��|� ���F%�e jL�)EY-�.���E1"���c._.���adcJ�6�/#8behavio� ]#�6� Z�� W"�z�-d&� ;�*�$ aris�#inQ�%�V�t ��G��K#2\1�x a%Im�َ�y!��is Boltz� e�X5KT"Pa.��1y1Q�wt up�!�i#�!/�"݁E�i�be�v)B�l��Wu��.N���(�$"�4�u!D�D9b"����u����� ��Tk�� meaaful��)��(�V-�'�� .�1�e}NonO QO��W�!�E��ve5�U� z*��I7ce�1ly�/�� �maw0s�*8�Ki�� J6_��!26:J4a7 . Do�so���� g'E�Q�9-%�e8�#eK1��:�l�" k ��6< E��&U how�q:&��&(�y5#%�pA�s Z!"MCAR� ]T�;a�a�dwE velo�ۅ�4*B�'toEsl�g� -�T.*"�a&BE�� � D�?t5l�� %��1a} spac!�B�E���k 7a?-a1L)��>5%!/!�Ii��]1D�e�& adop.$mQ�O�any��?A���W�\�tKpN�b a��V &�K� �6�iX�8pvo /( !�ga�<����achI"d�l 1 1 p_ ≥1�$� ��ai���I!,f�d/&� volume�e��25a�5's'u!�%�VA~a�“�7eQ]n�#��f;D.#.�>V�V�er�'�b :1./Ɂ8 gE fe�*� /b!�.�ŏfo�@ Ar��z|cr=�c>qz"Z>�1S�'�lo3^�(i1� �Xy�TfY…"�5���FAxa|g�!I�cP|��X�2�!��]��S5k.:=!er� �i��"op��BDY���i.e*� x�ly giu+:��v &uz �Y3�  #q� mid-��attach�!� ,*O�A�IEK%�%�A���5A G5SC("? ) �/u��Q.�6*e�7� ���L$0A .{"���ly�sej. ≥2&? mz!�a!�a�]e9��5p$yf@p�� 8term vanishes w�ehen = 1 . is over the different loops for a given set of contacting residues . We assumed that the lC,are independY(and neglect-�e excluded volume repulsion among�Dm . Exact enumerat�of self-avoiding lattice flights [47] ( Fig�,S5C–E , S6uppor� Tables S12 3 ) �extrapolqsruch data YD . S7 ) were appli�$o estimate� conformEXal entropy terms involv�tin Eq . ( 1 ) . Further detail~!�model%Xprovi!:in Text�. Sali!jfeature8$analyticalCshown@Fi�\2 . An essentially linea�)�ce!onA8seen (;A!4sE4� simu)8 results+1D�As expI H, a stronger ( moreA'Dative ) leads to t!�er bin%�F+. The (equilibrium�gA�0ned by a bala� betw�favorA  c%�-π!�tacts�one hAtrans �alZ�on%o%�=., inset% B �Dincreases with aroA68c density , IDPicAE� CU0B , D; C∼ )!T nd target �I�C�-�AEs u�trend%�4≈−3 . 5kBTA2ourFTmatchesa roxely%behaviorA?i)chain.)in �1D%�is valuEs �A�,1 kcal/mol (� T ��$300 K usedJt?study )!�compa)�but weak��a �8average pairwisUY energy �!3�wea� ermiAV from%]�usa�a-�-Y poti]Y$well depth!≈d6d1�1B%�T�(discrepancy�not unuNbecausF[ effeA̵Y�补��6�,m��in an�/�େq�probabilA�8. Nonetheless ,Ea~allMWexhibi�bI#B��is)#ref�7 0B� . In addi� to accoun�$for Y-numb�S��5^e2��y�hypa� sis also ir�e6Y 66S��) both! ��ap.v 3-��B�8 S8-5R. Appa�awq,�-RYe�� !� funcaRe��ser6 Y!�!�.S one-to-!~mannere� is f 0s highly sugg��v Y-R)?�6�d realq�pr%�Iy eby͍U� iY�2<E re� ve� �Z�� 0s broadly cap�cIY�9�� �R vari��& 3� i�Q��i��ve agree���*L A�+A�� �N�=,Ų,M6,1QzE�ǡ�� �!�� -irrelev�of�38 j5YW�zeMit��:��4io�fid howeg�� !�"&de� f ��c� d ei!Ł�-W�Y�y 10�5.�,m�e! nE��or �� ��XIA�to :�CT�a #�p�oJ EAD-�e� ros!�c� .neutral� very9*� �� ( +0 . 2&) [ B� of%�domin1� ס�!}:�ini�%��S20� ,R�A�In�3 �- ; !�eE�om�dV �on du"��Kon b>} 9� Jl�� A� ���ed5�w −2W 2 vs  46VIntB�21� unbound !�e%   R-����- ,� � ��to�3�9��R%�−67 ..* !5 !!�uo-0 �.�(J24 . 9X!*�� ea�e Af�&.]�B}acqui!s upon")i%j18Oj��0B 5R.+G� � "� ��ofA5Ry�Se��rdEp�L� >�2�]�l6 r��of��preC�Rs�.e���ob� envi��at!`�jy)end���a$��a�/ tes��d predi����&� �� cons��^(-�9&%Y i��1/k�sU#("�4� ���.� ���{ di� sh ��(!��y}�~is�%�BfeQ\�F�a;� 9�4��di6d�,7 hough3FT-f� } $pronounced�e I:Ca��y`� A'�� ��distribu�ȩ�0Ys while main"� �UcE!eto!x�@?94A�s5YP h� 2eIgarrl d+ 55s separebyM12!_idu_ ndI7 crip�.��D��188%� in excHof 40� m$)� an��.�&l 4v�!NS.2� squa4.$circle ) g�I� � I�"� e!je�AR!?JuM�mis0A!bably!/*���simplifyA�I�assum%>�� eachbividual���oct�two adja8!���ngd ultaneous�S |amaOKval[Z�>� Xs, whe�!�� !(.�&��,w�쭹�& sac hindr�by A��� e or���,.of=^A&[4K.� Taken tog�r�s�)���W)��� infl�\U%�:ŞY6�is�4crucial . Phys�� -� a��p�zari1E3! east%�Z���� =l~l�^ B�s:AQ�o� A nU~D��op �e�cos]ta�a�r�t�� >%��ce�lsm� esk �dB�(disadvantag�ky& disf5mof%± �].�.  s"�"�Wordera aU.z Dor “fuzziness”�#�rea�ly emer�[6]�8 eore��a�ofs [22�$[49]–[67 espeA[ly!� n` lexe4�in ita�f[A�fs pA{ful tool5under.�dynamicQyer ensem] . Ou!teg�#&3�m ompui������|cul� �j�!Stipve��k �E)aux��5 )Aq t ma��%�c�C.(aI@g��^!^-�- .f)�*l ���Upl�opm�!K���1�# coopeb�Ustemm!�e�� ���T> ��c`a6f"�nd5�?�er pop J .� �zr��� suffic�es 2\�sE<s kinA� ex��_myriad.�Not�a1 mole�raognevel�r�m � p�u�.� sR� a�FP-intd malig!�JndE�fA of immedi�bio AEges� A�*:stui�g:!�i9��o=iՑ���� poo�def�! non-5�enzʼnBu� i�ssi� is!\onK]ra  X$!/� de�!��di [14��� byE���. �tri5Q*�(}�ac���2 P"y"�bgen b�# �CL"mWI#at�y�2gy�al��!�� Bn)�abpre�Ɏ�s ( Gln�'y a�Thr )%¥p%w�:y�re&#by%x*�n ious �%�, "� a�%�curb�c� ��2~!=!�"�:�. MTrMt�W ll bZ*to un�� seary%� ubtlT(�9e�tR1\)%j5� coup7 s"� B�!rZ�[70� WeI��es�A(P"Ypre�eAQ� alUlMMa post=po%modF" �.�tyros�C phosphory 5�O-GlcNAc[71 eVm"�)tim���nifes#*; EFPsP/o� B fic��"�  um� c�-W(�� glob� ��%A&2Wbd(�propoa}iv� ly!N� �ax*� hs� � 4 I�!o>�%S �e�!) )f %;� s*�Ya�a�u;cY p�8le�S87 l?so fa|,� ��kn�*t� vol�wo�LhoA"mc [7�73M�can��inferx m�0J�a�� �#�nto)Q)��Ir����]82wa�dev< �(�� a0jic-��-can" a- ety�� � d\  �I�M an im�D26,��exa�,Q6anE�0"� + $acute geom& O�� mI�b� flank�k �)qJ�A+����of��s h"2I B�. Poly6 (( Sic1/Cdc4Aind 6� 6ZhA%��. Each�o�a)�B-�O%bm��IDPE6"r�o�-�,A��� a�� �A��&d��r�)l r F����A_>y poi!�toal*�t2������P9X. !&q7��y �le � site� l.���; kes �i= t�E=�h*0%.�� witch-a�D9*E�.��n$� I��on/ o c�+cy,kinase levelA��M!i��)i$]%�g�r�%� mostm1E8,��short"�-�+ōor�/$motifs [74��[755�cl0of!~ch�]��suboptV'M� -affin�9[1�[1��SL&el�"��al�cerrlye t��!% . Fo�(M�5�%� �%���Yp�,AZ.*iK,ans�� r��0:�G( �wthe��%"� ed�1�a%��2�pocketoa�� a�sA subjev(o��.�al.���24���V� ^��$v2 pathU�!ee�,� r � �L�)ob %hap� evol\-�S��*�^mala3dir��.#+A}los%�e3WS RNA-QYdo%� ( RB�)or :6aa�eign DF0A� o )�Wto�R��, i�i, gu�aA e �Bi "r&� eR&g^ �reiH !jRGGI�autore��[76a{qu���y via�*cmas�+[4eT!��ypera�OŇo�5 a  ! izE�! �"_1�d.�&1f��a.�!*!�a�!%u��bo(�!�1�!��5%$ veal�� ��'!� � !�2h&� ev����*>1 �]WSY�&E*ng�+aberre� %�1m��veJL 't}3.in oncW10�)� rega��� ledge*�� face� ��rapeuV-venue��7]%�Ewing'� mic3 umorMt!$orEgno<0�1  sA-�_i'�18WS/Fli�uve en i�7ifb�te�di��y�)�"� =ac�[78��80]a�� �) c�M�5<&basic��Q��:[81�Wh�an hemf !�!��77 ��un!t�D"e&i�8�beA�!�Y�� $!�E� b%� grea6 �G2 �7xpl�n#� 3Ho� � ly5.V����Wn?8l�!�t,�z?�r !}lleng�qu� on͡!)m���Y��o0I [82]��iAe�!IC%lr[:-os�l^�0ed�� "�C-t(5�+o Y_>�' s [83�Ga�SH2/SH3i# %.!Q�� K,5 se&���"� ,�� A��  m�ic�5]��Perhap��m! �ɋD"w4 � prim�xal��5�f�wEubI�aiALU5�A fulf]M� f*k r*� YBfadra c�w8E%�-i.{�/�!4q�i2HSrc [8� A��>�1 lim 6�&z!WA�R0�profoa)i�'>I)�!�atE�r� �-5�-. T����b�� 2r� expa&e_ee��nd�%modalTJZ5�A�.@�h�,�zedE7)�+ �!#IDP>$!�be�ZI.�>A��CI laus�1.����!v�pM�o� scafR0/network!�U���!aciu�&���/[16�18�� 2)method� y�R�|b�8tO>dvfac�b� !� exciEqsearch%w��Hs . Plasmids: pZΔE�$Z7Luc [39]E=4lz)scribed�)ll-p JA �!l�/w> deri���mammali�x 8on vect�S�= cer �+(1-CMV neo (�1$lied Biosy# �(. P�0� S�-s lK��dc n�*"� e��ATF1 r %zta bZIP� M7s6(S�,T� a�6assayI W�*rn\t!�: -�:� ,(-V>q""1��,+.v��rs)�per�?�sV��!�u �1%��7�@a�backgr���.����7A !M��ne�v�a��Ew{!!55. D�?iM\%�!��t:!!�^��9 �<�&�W>is�:l)a Cα1i P�K:N!��. Recomb7t�AB m r�!�an:Tc%r�:1^�I�0+�8A�Dl)^�< . c!=a��5U�- �jdA;��Gi B# 6phenof%.tco�� atBfL +�a-2F "� �U�.0-2�m�>�;.�A���, eng�p=el� home�8A ^fIbrt�E��>��zy2uniqu"�!�� �%e ,Ebe q�zh\ adapT,&y ar�po= a warm-~e5 . InS��,h2�+V�[r [�mu&�aWdi#A� h��~A�ng��2�a>I �"�ro�I�v ���� w��� ad�$�$lA*�re����e.ou��ih�B"�6ron�@x2��tem�,!D[�[[�%o �., pH [�.[8�[9kImicrob;�[1)b1%c[1�A�#.���+�)� ciFal��� ��6�lip�( ( Osp ) AB%� OspC��spAB g;�t e:gMA��U�n�.%_"#midguX)aI�Gf�IickInn ����ed O9��A'��qt�:a|&d2�)da drop!�pH �C��Yomi:ly2�-��& , [1%��? A�!qimAh.N#eri�~a� ioj,vigorA� grow�Jnd e+"1% -'Ťe saliv�gl�i!M0hemolymph [17��)��B� ��� Q&�a�E co�n�-�M8A]�0b7�A�#���6v!�N"_-�� Foe >W�6d(�H adhe� �.(_!�iV20y(68b&�;. %�e %��0 , abundB,�� ed�E� OspBVto��broG5A��m%�ivmembran�3@%had�$ ong-]%� %'es��!��{�� + A?th���� IP *+s+)aRS�gen�ofa"� [2��w�% docu�a]�h�+organism-borroA�oo�O&F� �na ��&O�LK] � ri�~! �Pma%�&y _+�|�p2a*$incorp ' enzy&5A��lasmiA�uro*! .�orABa�m,l�b oeA�g�Q�42�@G!i�*th/av�Fb�3a�!�WK �o 2"pY ��mi�pa�J�2F e`�V�%��� �a�f�!�fm!Mi�ů.1�EA8e�.*�őm9�!�vhe2�.�du�I�q�(1"%�recep!� [26]�v[S~J��PkY�associ�+��2V�]�mf�`�� *2>�m;=RN2��s����i1���q�xto>� u�Jcin��B: _��?afC �) "�1N�-��*�4&�/&= �-R5t we�0�(� 1H, �1��"�!�ofQQ2@+�gM.�Bor"h�qFn trx!.!1�s"49tB�a^?ujL�U; Q BB025�U��ay c�!B��� [27�:$: #d"��>� by Cloud $l . [2"�>,�T�-pa��L"{ 6��3� B0613 ( -2 )�F1!]U�U�!array� MH"�2�(%cEc%n�A��3a��5��f!.i�!�1ad�� �&�Qab�Mi�P!�,\ %5a )�� c 2$ : [2�V��+s�h�shock R on [30z 3q B��%�h�-�s��ls�e�#�")��>\���aea�Q, y�=[3��3 3I ��N s [3Q$[3� � R!�1/=�� L!A idea�%��A��#cR take��s6LF*6[1he�f\!Fa�sm�N [tQ. W�%� ��Q soug�o�ntifyU�"��L �!� 2"� pR��bi�me :��tr0ea !`dsO�9A lu"Kol��5�_�v�1���qu !�M,.=� leH-1qr}gI�;=E��)�!j"�  . >1�whZrϵ�de�� ! .�oi� @��yi -1�"g ).h.� .�23��#� ea�EE��>�-cuaw SK-H�-um�� 1&�Ni �?�&S�ge�\oL is r�M�eu� ��appear" be a��|�J�Ł[2nus&a,a�aQ$  �$afzelii [4� garin� re�7i�XSdutton=Awh|_A;?ls$*�2�&�B� I�!�t�ZK=tel" >��:\Z�t��it���}D!6�b�2� M ?B% m) ��Pus*+���&?X�� �o�Y�vi6P�ytenŻ� �]�%��[��A�1�Du�C<m~�3a�%/of%�EcB� !�E�@"�2J"�H�/%C&E�Fwo AR��>S!I�h�"r�ri$$6R��_m�6m�/s�4!��n7&Uusekeep!�c6%�m\�al lo&�A�.Wi���atA�A"I 40fy�E�%.�1P�PN�u>�e��"�! � �dS�>�iN��rmM�s� 6�T� nema�L�a]� �!�l& -%��� ���!� same fashA�a C!�M(z<9 LQBe�P ?IS�>:�A�2A���"� ks9WA � a{�  l��,��)B5M em aenp1�>v~� )bq�-(j be� 3"�aEY 0!5�is�e� .<CR� �0��assessE!A� bega�Ua�.K�a4�$9(m$�]4Pfam , PF00004 2190��nd536�3�("Lq A�I^�".Km�x�7_�-d&�".��9 -.2� treesyI�� �]�.E��ed�R � .�co& a|� �(6�"��pa7 f�-1KO � �y�,.�,Y�� Ax�>ili�(In+&a�2 a��*�#��L �4&�&2�!���~ {! g{!e eZgntM.) !�!I-emQgEMv%�!!gA�e�*�e�I�to div�K��]M p.:)�1>[ -1s G!"�@��@� �c� clos�P�� � i��(p��@lZ�,Ev� nR!�.q ,l 9�g {)�sub��!�2�$�c.� c c cnm`i. An>!^�,*�)��ls�="[;%�of]�A��"�\ngmm��GA;-2]reP2�R!�V.1+WS �Ao!7 �� 2a)�^�)ship VOs*,gB� �gmaj s& 7os� )9�"%;&a+�2�!$"+c��nucleoz`=!�&�J"|2 SRBp(rboxy&5$e�� r��AT.�H i0&�I"E5gl"{!A��RT2�$ p"�� t/�@��"�$�'_(&zI�rKih;use�OFJfi�To�)n3���4l6��m*PQ)�!% 2�9J.fA�ted�P!BZU�E � &� 2Aݱ�U. OveqU �M�ah pattH.�Zt]Q�s�P� ��wh�Z+�� f&_zis �c5GyU3�ONal�4.:?4st2� outc�" �2f%.!��p:'Ik%h!�.�����*�Md�(m�b!�E�� �&��Y�! i�Otyŗu� >pB�r�Gze5(tLA�A��*�n` �nor 2�9���%%�"� ��"0 A��o"_,bPA us��makB-MgD@ s ab.fm !� �.�!Do"TqL�.��I� &HaBi)g��!��;* % �� � a>*bP�)�F�h�JurU x`�wild-}( r {(c�L aPCR�6�EAQ�p�s I�� �2o!6�sENE�/�2"ysine-� dyad6�+&�-"~ 3�!�43���D*�m{ B eIna�G*d�f< asF` ey �n\=� [9�o�,714 ( Swiss-!A��G�1�2�= te S()%oa�t��757�GK()�br�REd��9�ae�,+5Z"7>4��*�\lanA�(�ubolis�ZtQ�A�AG.AirmE�ty*.�yE 6�+Y�(Q�)2�nP-1!R�;�ra^(by SDS-PAGE�we�,�4ٰs�a�ir pu�.��$s�=E� 3 panQD:%BE3�{m\B ��4^�to �!�%eGir�.9il��r"� 1��`U�(�*! i��&�M�MWa70i�J:864g0 attached His^�To����c�1a|M �D>q�6A/0ed� $�;in�`$5(2H. A�.of:ai!O�_�-osn3% dye"k4P%��a��W� ��)�&�p|SFggy�A�� $�4%� Xm/�w2IA uj�l�[�ATbe�* 3�!Xhae=i�%gJe does��`'a?k -1E�6lyz?�oɟ�� �� �69.|5wewj#:�sg.p α-I -fluorescUI$isothiocya�!�ITC )�#� .*10 mM��4 "�n�[��r�z 1�"9��2�F&� �M.aboM!�͹buDeol�!�B>�ed .�f\&*�5uY�� J+Mp��� M.�TYub]C�!� �� y� � ����� ctlr O�+i�� �)Ave�3%�A�8"�?AQ+ �I�of2by-~s �h<+W�p> 2E�T9%)dlef�nel���"c Mg2+� 2w4�@mb�6�(2� MycoA um smeg�)s��� � e�����E"0 z[5�"5�"T_O(Br.�9:@��u�!��]3]arr!� im �)��}B�>b��*�&j�w!�2A��&, MgCl@�.%�35re�Bi.|I(.�k0Y�8��r�;!>�M2�2+ �lE�.no *>�Az�.i% !�q29`x�( j@a�1��DVAs1 %�a"u-m!i�A�[#Tu@��'!c�;�0λ-CI-NDBbB�t����"f�)u!�W6j��'"t�*-�mw �d0� b�4W ��� Ao@!c�<%x� E�d�y5B^<w� �e.# eac��1(y MALDI-TOF�Ns$�rcpR� á��yFerq�ar we��-fis>g� -qa}&l-len�a=�!�^�g�]5'6mU!Q trunN5O9 �d. N;{%�&����>ia �s Qo)j�6I�or�D��H�M%ԡP6Q� valu��a��.� . AsLE.X b �eW�� EOe N�us�TPA�>�F&18z9A���St<i7edp7s&e&�>"�po�1vUe0-�+Vm�4�p�A�*+novel>�u� er�Vto �.$*n�E`olA�0 "��!7= sta�LV �-%�ge�;�@&� zi;1�&#*� t* palCtc%tE�<p:CB � �B>emplo�bov<q�a2s��a� 63*� �0 �"? N^ d,%nec��1wc ulf1bridgV Re*�!D\�� ��gg�U-<B-r�8}:;A rpZs )[6�@u��Ais�$�?E9�$�&g.�Q,1AFo���s�D�r�+ me7F?l� sc9�(�1�|es �3T!>m,!�"�  if��1��'.������y��Ze.B�F�A�R%0�!i��191N�a2�K�n��ktoa�=�1+�q� }�ad!q� e�iJBwcOxA�rIr""�V�e�-qQ�!��=:� �E"I&e �Lft35%�J |�@6A%�p*�H�,��>{- �\T!gam�|� �镁1�dos.�-�-1�f���r �� W>96�>V %�~'�Xjo# suit�� �� ��9,ea+�uu:� �ng&-i�&���inAKH-��.�G�Uin�����A�����S"t ;+�!��8ur:g�7 �)�ru!��j=Aw �"P?9�Q�7[6k#�>�\��$�ZN#� n�cq$K�X:d�_"�la!�2��U.�] 6B�>b`Tl�=�(oru@���E�M;� !� *[ m�0�-"�S:�!�x�f1VV���Lp- o(� s; nb+t"e� �Q�5{-���ͩClpm!u famiV�w�b*�B� �C� -A�&�9q�y� ���"� '�\"T\ ,&M d#k �0 a�  c Uvo� �)h!L,M@�;J7�$�&�2"� B�F��or�;��-1� nթ]�O3C�N���~�,��e�#"�/aF, a"A�%�E[G~U5t �i��&{ed�Ec�R�A6�!�p ne�ar�raDz�q7\}>�Sdn��  Z�fd " r�*y+�verlap�2E kgm�ej�?YC�"�(�K�/;#�Z�v� %(.B �% nd MA�FՉXG� (�~90 c=)ER 49.� a 2�&Rl�chp9Rc�� > etyp���J&�1M7 7!fi�ir��h�l�g�?2: pI��T4/�Ec:3x%� !�d�y.54�2��t���,a��Iml� �cecR�Q�_Q�(��8�y���m�SiJ�>�aa��C"2Eo.2�VqKe^R��o[9!�*�  shifHH)�i� !�e&� #�)!M1r��: M^<�_��0<���9.L�y�h��QE:J�K]%A*�[69[69pH � o�y:�Yin҂!'s&�Ichamb<jds?K|%����!�own�re *�_� �MAKy�)�!��!m�K8x!`of�2��ranB<} 6� �W�,��o"��; ��$$� nd 2)Xug�"r�lyA_%�g�FA�^��8U4/R$�EI�gy"�i6��I���w) )!>���Sv�:nt�DircumFe�in�ty���"�VA�Ec i�3 s"O� �Q�o�?2��^�@ ( cp�!K�;s�@�ij|�n&����hu�XiA�!j ncom�N�0e�hCPSqƁ�!0�Doid*� 1a8!aR "�ZA�^�lclo�b� �lKd pBAD2:6to5d s^�+!~~n (�E%R�2�BMZ1�t�+ HDB98F510e�&*0cpsB::lacZ fuelm�r(x. M ��at 30°CLZ �&�1% ��in�2,-*-A1~*%G)jedn t �!�X%�az al SE�].zK�m( }2�(I-�I.x"f� �3*s2� �"!v�� �-pE�aN�!#P ��".�i�fr�vD&byZ�+7�%D�8<$"�0u�!� L�>sk "�E�or �E,m��<`�ong�Z FtsZ�. � d*��) �d�b,�{ . Ac6vdu� K8d f\Zki}6e:8fil�t� morp}n� a�L&�*Aru�Bby lo��m7�IcV�5|>�2J�Y�����g2��Gs.��0b�B�$��CY�ato �%�� w�,3&�<W-2R0)K��Sjl���1X�)u8�6A�. ��8i\� ��q ZZR"� ��� �4dys��QvpsANa6�c%�6]+ a,8�� ]E� �F��Eci M2Ap*�`TD�{Z.[-I-[chaOerZcz�9A%�"on�2t�,!� L�w s}$�&e&��1A�(r����T=�2sonqcQ�82\"�0p�Q Prim���?/!Qb a[ i��"i �,g#*�dqL��2$6o� !�HL1�v"�.RZn"] J�#=�6�6v�=O \�J�n(I�a�y� �J=! ��f�.�-y�4A�HA5���o�1��B�!1% uB']Q�H�SE �tp%d�kl��@6�J<m2]�&Zbltge�)Sc�' toBw�e_&�Ja��U.�]}u& Gm�%anBEB� �F� od� rapid*�@,lifer�� 1�Km�Ke��a&�T�bn�$i��q^.&5"X;� b%< ���(Z�[ML��y:a32�!��go��e�c�9�+2�8��_ Al��x"'&BBi���i�>)GA� guid@f� d�͋val�I+yoA�A nC��+C� te� IACU�"@of Stony Brook Una�s� . �88rabbit antiseru3!-�New Ze�6dy te . �ino(��9@�a �8ith 100 µg ( 4 �-se>Db�<reund's��) Adjuu�m� � yboo���Q�1��*]��nthמ �in��n%�*�I�f�N]\e�u!xser0U�� �rLIS=27n�7X/49W�`veB)��,fiA% �PBS�::BA3)�� collɷf�d�+�;yJAmo�Ba3BALB/c�e ��2%yZ�hCa2�5v��m��� �q7ub.k(Uhinq�IE��������A��te2�P�*x;�.�{f Dr A�08ali Karzai Depa&NjB QstQ�C�BSi� Cen�+A In��DA��Z�,2 , NY�.To�Ge<=jH;I� openaE�$fr�*�j"�XA�_= ampl!5� 31MI�Pa-l�3P/��$pa*9) NdeI, XhoI� �8���L:x���p ET30rY + ) ( Nov� , Gibbst5 , NJ ) +89rs P1FmP2R��M�*a�7 �J��v^�- 6-h| d $�-f "]-al end igV ����? CK00Ҝ9��,%Si�814,BL21 Star™ƦE�;(pLysS ( Inv�+:�"le�I&n�37��Tݩ se P��� Gluc �1(�*y�aM lumnAL$HisTrap HP!��$$GE Healthcp , Pi�%awa�e� . El�!�0d�7�"� steps: 15!o50!@ 100%w�$BF&b$1M Y!B�i�)�7*�%e}:QpHV�Ac5< h56{ 10% glyceI;b'6^"r � *���2 �u.76�Jl��� �)ir�by�\+��6�@� **!yt0�1!�d0 �'NBCkCB&FC�(, Wadsworth��, Albg��)zPQuicKChange II Site-D�0 ed M*�;KiA Stra�w>Q') 7M}of�0 r>I5�&J32eBahoyAa [42]� :O�\A�Brief�T��pPW500 ���ch en�Y!� λ-c�5trpAt� _no stop�P~ias fi�� t*  �8:�>�"�7p h��]1�;%!5�%re8b+"B:U7v7h9Kt�ob�AO�<(9web�4( http://www .@ana . edu/~tmrna/�WT.k�l1`Y���-V �)��(:-�Bb�%�U��1a�.��rfV�triyM�. B�l��Zn  LB�j^lt� al5�m |��!Tor 3 z�1�AV j" ^s � $mid-log ph��E�")T~�3wiMI"���# atographyI�!kai>m�Mhis6 epit��2ceUi��]�5t��t�"�-E�" G.B(Coomassie b��sA���.b$zE� Ѽ�8c.qnK8efx Do�"�*1�*w@E�aM��n���=� 5 µM �!�� E�z1jM>�orB3 mg/ml V.����'�rea� |$i( 59 �Ui�c" , 8uZQk�;, "gD@.'m�X��b! id -B� 1�M-A,I�d~zouito� G /)alc of>*A�ir>ii1��i+Iya(�� mixG'-�incuba�]a��a�a  0ofIDs��1&aP��)�a�"�by� % �!zU�&�+A� �s~�Dby� an Odysse;mf _dјg9�LiCorUs^EL�ln NE�iS�q�t�n��E� �F�*LL� knoR�b�r�Chw4al W algorithm�!�\!tǕign�!Q#4d Mega 3 softw# ver�@1l�?J�Pe�N�;bor jo�ρs ��2� built#y&Jx\WFP� ��� valatB5�2aUta�p�$c��T*W�N"�!7%����{��) ���gi"�. H��s ؼBerns%� , Ge�)|2�B�h� Eal"8�T Diab�|nd Di�hKidney.�FC�H �=:n"1E0aqi^>)!sdb31A3 ��by�)["� 50� 51R�1%a>��!,NcoF�a��c24 ݐ"�$fbampicil�3UOb^c9A�F an Type C  C@��, Man��$VWaA�%�� A�t])��"u{%��D�Qr2Bal"�U� toa<mV}��)k$g&9sZL2R 1N3FNa�x�."�Nhe�KpnFhE -a/�so)�v��F�.W 4Z�A�!�2 ATG$r�Tte! yie��#L *.mT����.!. �_�4Ug&�!M�s P -e��+�"� ��2� F)!"�1'^�|i:�5�^��7�+[7 C��� 8"� �$�&�'"� �'U7 Pi  �-v!2�R R�Gy%_24�&��19�HDBVn%�}�A,�1% L-&C#duc��ŋn_:��/��� K�-��� s:jvC!(�5��A�a�9lqz( � , V� ,�men;R( mA , RT *"��(� %B�Abs427|absorbX�Eng�(ol1evelop� ��II a-a���) ���,ex�<. repev Ä�w�D�!NDat }s  ٴ�!  �ce ��In�� *0 SA( G� Pad,"�San Dieg��C��HP5?$as�byB|� ɦ�� �::q o=H E!q�0 d�!u�4Tw�"�q7�qPk�r別, {M Vm3ed, o | A�5" b�C :�To[ ��V�,� �<> * &_ in  ml���s fuge tubesi3M� fe�:OlabJ�-�, XI�U igma� Fi�U�*��+QUL� $i� ere:* =E?,:� " , 25�w Bc$b)d%�*�.im�o;�� �sT��El�$o a %�AM"�:�%AfI&^�.� A���N�  3m��.]��!S?P albu�y{�stock�># ) .�g�= cITA�U hloroack�Te�)k�i3fQ��"A} ..�V�then �E�dA�1��000× g�*(avin%,a�r�7("�Iv�$, 125 � �!?�Bsuperna�$f (�%v�f&�A8@9y:96- p� 0 ( Falcon - BR�� cken~4��A �3I/rQ�E� M CHES-N�a pH 1�Fl�T���"�?E��% traMax M2� ��ly�M"n� Devi�, Sunn՞ ,��a ve�I�490 n_n��) �525 �S:!�eIe7 �Ś#g��um�k�b * [�.� at 26u016����I��KMS�5d chieQUee�rA^a� pH��ME�pH `7a� .P�� �Trio(.�P��6, .2-�N^@hanepro�Q diol�6( AMPD opH 27zT1A�1 {CAP �h[�P|�)" �$!' ��!]-�dg"Y�) ��a kit-�I)0� utiI�A�dy��l!dM�r.w�+t2 libe�[ �o-l�ߥ�&mk ��'�>GX.� novaH*}Cam�C , UKUmanuf�: rer'| otoc=W)%APoe��߁/.lp��E8��.$on[ G �evcI�I� �� �2�eje�����F�05O��A22:�!��Ab� m&U �Ar� w��63��*TEw)di"yEoC�t)fpq DiG�&B eEs���D��a*�?-q / *pE)�!�&#?b,uN�EoA���a<���-�I�.}$R?aE6�@�)m���eeR �y�G�9onii���-��1i!%+l>�E=our ��S�Mz� $arahbakhsh� [79 {1U�61�a#7!tou ).>"2�O/% �`��(�{ 1�sod#.pH�L�'�:��Q l*)i1-c��+cuvett!�L>�!6-�dhVi a32�aa n UlDQpec�)0 UV/Vo.�:&�F�Pharmaci��te,F�!J�36�})water-ja΢A�'Q�>;A�junI� a ;}er/M:�z�#eslab�r �QNe�stYNHa$Q2 en�]�A�.�<(m&�qɿJ� ��*!�"��a WIFT&�heB� ��X$B7�B.F]J�� alsoz�G��8���A�(q;yH�m�* �sq�Mp�@A9uj z� g�[6ƀ�� ��kex ��j15 ���!�E �e���!2� t." b#2��S&:,J��8�R1�s� �u�22�57ly ��i|FE��2%;Lac@�m�K "���.�k�e"FA�1L�T�2� n`�"o'i��!Jl 1×&��  �boicJ��mp2� �zEB+����� Bf!��T �.B��� ӱ�!�.~o�[L��"q inc01M� �� A��-e�� "3QP� �m�F�*x"�O�՘E��3fi!�5g�AS�)�!.-��by)g�2�a! . 5%�� ge,)a4s�+r�4%b��+. EquiXE� )+�L�U"�1�(��2m(]1f(U���)��T.�E^%�N�5%6�q��| R-250A4rN �.�0��4!% �/ly*  !�b) �10mon0�P�72���Wa{f3�jupadi+X7�0bo�C%!go� nti- oIgG>++�! �. (5+�c$ilbertsvil�nPgGl�((aldehyde-3-&p r�,V( GAPD��: �: body6enS�El(p .Rn*� donk7�P.�.�t [�#0 %(vi��5!�},-)n s�1 �If�I��g SL�A B�~y:&k7:�my' Q591�F*wt>( 2 ( O5155�(r*�~A��'B5RR69u"�7>(PB5RPV:(�uLL7:t.$ HMG/� MsiiH 2RZWj$H 2S0W���u�Q662B 0l.$HQ660R:HvH 0SNQ:�.$H 0SMPfA,*�upallidumJ!�83536%l&�x]M icolI?( Q73PXp2�xbi��31B0SLSs0*@vborgpHseˀ( Q04VAf�2G�Srog��k2UP)�BҊC( P0A9M-au�Xb�2f( P3794� .��Fc gȎAD}� Fcy@�-$q}&d8�<pr��r�/i� ":qHIV�BW suchE�i�*�<phagocyqD� ADP%��]o)�:nv&h�o7, g9vi�<�q� ���y�6���"/�W:Hj� of6&��2�d }e� ��( mAb�F��M�d %�nO�[ ]1�z � HIV-1-dec��� ��1'�To\%0�D��!�M� �@een&k&�-eing�ar�!V� JRFL%� R�cli?is� Ub�>a� �=+HIVIGg%�$�caN�}�&1-A THP� U937�)CMk�res� �d �y)�y!.Fh�"�%d:�A"�S)#s5aic�^Pel)!�upB�=l& "�by A�;V�jW/Zrpris=_f4�m��! no>�%7�/�m�L.*�NMcoa�vi)�=gp4� -��p}d�%- (ez<gp120- )"�I)�eff1D�!M��%}�.��b���2CAá\� � "�nQBg�selͷ, B�e1t�m>R]rog��� .��H!iW�2����mC�~*\f �s �AA�pla������Sngf!��LO��G�� pauc1"ab�8! ${$ i",M-�� �EM3|-link�@?7Q]��H"@Y���=&%@:�c!� �-������ @v�B� )!�͞v Nst^b�. "gA%Fa Fcγ6γ�6l!�Iy� s [1�O`"�u0ve6�foc��I(��cB3!uũytotoxi%�( ADC<@[%9G%t�\�;no�e�c�&n*"&!���U y[pa"Z�!&R&'  ) �)�9 ATsetIGaC.M���QM~ ?Ks�04op�8�q�կbe/�gan: tigesJre*�ed�]�ay�;������s� aKna��>m+*�oph��6�sbA[7�.%�?$[ ��on r$..�"/�comY���6�����f�&W�~�3%�*�U� A1P!�an)=��Y� 9–���7t� Dy@)da��&-�!�A!-%?Agf�Sc2 & ed�s!�1�i5�lysoso��w?X���i~de�ɑb�}��VA�.u���bn���Co�eis�o1,y���&�7�/�!I��$ F�XG�aw2�p�m-��2� 5�iw��!"! ��"�E��'o>�[13��\�� NilDu��)oO�o�S�E9�)l�7 �y�denguN�.my��a�)>E71 B �&1��\Zs\� p��in humY��S0�., begu� e"ܶe1t���:� of�ENin:|Au�2ZY���/�3�(a= FITC"i&I�ѡ,*n (�ads� %Env�;e�in�or F"�eD����M, mCherry [19��N2��B ƃe�Ro�,�I�?munode! cݦu�SIV#ch�u HIV/( S�;"�^G*��Z nhanw,5�"Xd&�IA� K�&b�� �&� ��a�y� ward� ab{]!�a &3�l�N0J%��P���L ��v ���e�}�9IvacGt�)�*T˽6 W"� lit�or����Q���yt�b��Ŧ�q�i�V �tavidly"�1iusM=. More,[�nfg� F!�*] J� "*�� &�T��>S�o=��*x� �-�is�inadeqLn� R� li����2� CD4 >�Ť s ad"q\6�Ca f���>T. Periphbȍ���y�"�don��P"�3��YA��a�(�G!VU&J(of Californ�jIrv�NP�BL�D mProgramW�inC0eBwrM�% ��!�ccord��.w6�J Review BoaI�?���(*�&regE)5 �5w$NIH AIDS R ,� , DiH�!#, NIAIDH:)�MN-�,$ Gag-iGFP_��� NL4-�2G1�! VRC0� F425 B4e8�G9�)2F 10E4E1�& Z13e5H�D5�(I_�> y b12� ��"� DENh?a-�bNSI��S1 �)��9a��5��DCJ,Dennis Burto��he MPER0 09129E�kin�(p���AC$Michael Zwa�)�\idylserȄ5��h��lM�EPGN?%e�a Bl$Cyril Empi�LPereg]";���E�A�.1F7{�FYietmar KP:g�muBAus�� ) TZM-b��8!�*�� ��994�#U�e�!�]����Re��Q�pm�<. 293T ( CRL-321�2  159}0? �Z{�6 ( AT9.�j�Ym&�"4in Dulbecco’! ��ed Eagle e�$( DMEM]up+o�[H-_#-i'z f/��%�-( FBS * Atla�)z�%�� �_o RPMI-1060�N~��r� l8eFn�=++"of�K.Lpen�7���ptomyci\GibcoE�Fu&�u'ue�� SF16�v JR-� CSF��-1HxB&��/+�/��E!� %mw-�-ce�1 x 1072��20 μ #A�U� �7s pLAI-� � � ��e�y � ��NethyleneVf�$EIa�W�o" �EA|NA/&r�  = 1:�. �(VSV-g-pseud`�S �'4>' backb�"�7SG3Δ� �11��7sM6�2�#�D. Ak�72u$,eeur~p&�/lui�@har� ���"�#!)�K4000 rp�10�bon+E?EL -X�� R Clon�!�<��<2h!-&�,�,M�ru�d�-\�av t -87(�ar�W�)�Ix�9F7�74phytohemagglut�!H -st��>� �9a�( PBMC����S� !�Z�m224!&I�-h-�p.o5�u DpdM�!6 RETRO-TEKO�:�ME�Rk�HZ�tMćx�"�-%}�z. Lp7���e*P8�+o@ -to-�H&t?^��P �Vs�80.mH)�etl��h"�#){at@&104 Mw�)� I-!\M��,of 0 . 01 mg�u/mL DEAE-dextran and incubated for 48 hours at 37°C . Cells were then washed with PBS , lysed , and finally developed )�luciferase assay reagent ( Promega ) according tol�� manufacturer’s instructions . Luminescence in relative light units ( RLU ) was measured using a Synergy 2 microplate luminometer ( BioTek ) . Ninety-six well plates ( Corning ) were coated with 250 ng ( 0 . 005 mg!��) of rabbit anti-human IgG gamma chain-specific$,body ( Rockl!�) per �9�over n% at 4)�PlateJ� three timi-�Pblock�H5% non-fat dry milk!rAaY, After oneEG ,1"E>M9again2vm��100 n96 2 mg56HIV-1->iesE�}B� ��s , G virEM� dilua Pin DMEM growth medium�a8$sferred to%|Ab1�p24/wellE,) 4-heP �ion�RfivB�. In a fa[ step ,e(infectivityANcapa*d�as detera&Q�,TZM-bl repor!�cea�*Dscribed above , orgp24 conta�do!�e)�!T( directly mqd%�a?ELISAm�. SamplAn(ere analyze��$ triplicat~A�,M� repe��)�I�.)�$iGFP/JR-FL�$us prepara!q!�55�rea�?q�-�Q�10 μM UdMN gp41 recombinant protei=�.-�Uw,�YSpelle_( 60 m ;(14 , 000 rpIWe�) �C,the supernatt!�carefull�9mov!�nd9<��unbound6��.-���-Qco%OJ-%�0 .��( 2-E�s���!%y�@mouse monoclonal �ޅ�D5S1�consist��of2�$fluid from [decor�vi!�� standardi�seria!$q�1:3 .ddi����(n�A�ain��,05% Tween-20E:a4Y��[! �( r�at G03��E�Y~!�UD��U-�-�-���d away}.�further\%��9��rN�Z13e1 ( �1�J�.z�2W},an HRP-label���Fab�E+.F�6+an addia�al�m55,�, d"�( TMBecstopp"�read �y,( Invitrogen��Q�%�r�$experiment-�perform!0t least twicen�%Sei%�aU57q�ц4or NeutrAvidinQDB' . Th��� !�q#-��*re^�eYU^of6�(6���tr 8qJofE�\MPER mimetic bio-09129 (6 %��one�Q]:��P �N��( 1:5� �B��st:�5m@I.��� AntA�?&6�F�) %�geF+ Mc��E8Ƌ$Ultimately:�i<d6:��.du6��For most25� �-�ͫ24B�8used . When indm|he text\ 6 Ղ%C��or -deri�peptideA)0eJ5P , re� � ly )b�V� thi id no�ress �)Slso �in some2a� s���ߘlipophilic membrane dye DiO ( Molecular� bes �2"�� ll casH 2*�� �r�alq�. � `�<resuspen��,in RPMI-1640.� mix)�a 1:1  )m&���1m�)%� poly>�:V ��45�F�/��mix� � ~�$followed b�� 80-/ 6��� ��%�phagocy� ( THP-1� , U937 or prima� �0;d �  *� ��_osi3 (E���.� �FAccut��< novaa [$ Technolog��i1Rt6 F�onl�fQ4% PFA��@by flow cytometry� a BDDri C6 (Biosciga�WovoCyte2@e/ ACEA �int� li� q'( S1 Figɇ5bic scorI*��� by gaD a�s: on evEre�en#)�calcu��d aAZs: Perc� GFP posi%�×e1anajore"P tens\( MFI )66:�� deYi�QE2�hig� thaIno��� } ,rol plus two��� devi� .%�ETtreatT ���mably!;m!R effi!���g� surface-4 1��A� washes al�|��ul�C� 8bout a 25% reduO�e appar!bB��5�. Pm�ee. each�u��N0 >��~Q/be�tes �*h����u( is similar�Ő�<4by Tay et al .i�8notable changesphe3�diffe%� es����afluoroph!�A�D lackEa spinoEص [19]A n alenE�J����7��`r�onewceI�sa�./� H�PBMC-$n� �(�3ng�:)z��g-���( mAbs���O"�orTIG IC8�q- n)���(n� unde�sam�nG N� & a %�ndNtas"1!���)lyr in� 2 mL!RNAis buA .�al!�t� ��   a fr�mM��� 2��J ( ZR�Ki�J0Zymo ResearchT�\�Ba�>� us uE�qu!�tI�l ��real-�( RT-PCR ( Q)8Tect SYBR Greenk�Qi0 GmbH�:� 1!� gag��er�-a��: SK462 d ( AGTTGGAGGA-CATCAAGCAGCCATGCAAAT ) ;EVSK4312 TGCTATGTC; CCCCATTCTCT )R,naSpec Inc .�A�7PCR-ba!��R!���P%=<��!� influenza�, .E:025 mL�ofB%strV\A/Puerto Rico/8/1934 H1N� PR8; multd�� Ha� on =v)I�y�in U-sha1 96-w�� ( Falcon57i�� Y � hemagglutO&2e�,( FI6 , 2G02qCR9114�ne��ve��AN�!orť ( Gibco )���A�16;aRA�we�%�a��\cC nt% %�� . 1x1052g Ge���  volum��@50q�PMI)���/-MH9w�ano�60–8B < M�� tran*�Ep orf tu� a���`%���,. TPCK tryps�!1:1�dAi^ ( =xA� �"C L/�v%�v  ��"� �1 �. F� a����,��%0�* !m1-k TriRb)l�r��Tu��!�D�-zo��$MiniPrep P� �(F c����S�DScript III First-S!�d Synthe�'Mix%q�" �2u�E�to ob� cDNA . ( 1 μL!f / �6�� temEii n"#. kset upA3842� &�!�Jbi� calM=p$LightCycler0.�I MasI RochAFm -mixE r��IamS, wged�� M2$� �( 5’ T����GAT��CAA 3A�&��TCGATA��� TCAT &)� 8S rAY_E�9`&� !�!�5[!Trunv aBII��!`wo techn%Oru�V H�gfi� nd �� numb�f!5 al p�c|ə�&^ $curve geneobyF Kg�-��qu�; f!�yl�akBS�a"BN R�x(I�^ B��`��envelopeY �D�R�!� $y-opson2�%�p>j����of go�P*�c^H ( Jackson ImmunoRe"l ]O"@OF ( abA�) 2O-�F�.jh:} !�subsequ� evalu"��  uptak�*� N= � �&�%�%C�v!d'��V. N�CEM 4Kr-CCR5 target.�/f ���E`&�a"�(flat-bottomA�teA\��Z �9l�UEb50[@ ( ~ 1 . 25 x 104!2�Y���6-���&� -%2%#) 2u;10� A�2"�us-��)�.'ice-cold50:�%�VB,n; q �45��$. Meanwhil��ef� orJ�!j#y�n�� a?I�haker�.��>j .<Qc ZE(a PE-conjug�� CD3ݛm� BioLegende!33 at room�eraQ2�$%�ly�� ,B�in�"� F6�ll�^�����!["� "� four"� ImageS�m*v��Y�7&^���Y2zpreviousu%�GIn brief e con�ng�� ADP� �x,M�}-.h EQ%pLME^. i�6 ;�# . Usk�$�X Mark�� F�C�EEMD Mil�r ,��t-��iRm� coll�in �@nel 2 ( 480-560nm��,t 40x magnif�� \#8li-aof&�e!t�dA2apply����1�IDEAS I:RAPSpot Wizard algorithmT(which defin� h& area%�  eros�$of 4 pixel'�,brightfield I�!M*+y5�YY3$b�by| critX!:!�4I��gr�#Ua�v! �Value6$3 ,!�or� o excludeF�us%=backgr�"�Ec�82W.2�&�!�*�o visu!�9l=���}�� to %�?!^�R�i8.FF3����PEk�">PE+/GFP+��s d 3��64 595 E�Wc�, a���"(& kng�gradi� rootA�n squar!oE�Qa��\A�.�e�s  ��Ah. All6�cor�)on Troscop 8FCS ) [23–25]2�( see� ory S�in^T, ��+��DZeiss LSM 510 META��fo� m*{e equi%"e* a Co$ or 3U*I8, Jena , German�.'exc�onE~! �;!'$488-nm linEA$an air-coo#$Argon lase@) �typ� pow� ≈�&W�Tf� neA~he emit> sig%#a2( epi-2Oge0by a water-im9� obje��(C-Apochroma1�], N!� .P . 2�xnd[) an Avalan� PPhoto-Diode via a 505%(ong pass fi�WS 36-Airy-u�+pinhoA�onfigu͍� adoprI�!&.^�ispos�$Lab-Tek bo�d�(e�R�chaL�q:oye-{ holdd:��  (� a�r, ��+280-se�-%2����Ctrace �acquir�Z5-μs3 o� reso�onq� 16gauto-.�fun�P( ACF; average ± SEMaaas6 compA+b*ns� Sima�softw�F(��e,Enrico Gratt�Lab�'a�!�Fl*�Dynamic . Global�r ��9&�%by Prof/ b5�dA�,a�ar fit� ACFs���a! -�on�# or a�&f!��-d�%a<al Brownd u modelo ��� ω0 ��al wais�f�ʼn beam�?!�U A�� � para�.���%''ib�dai4easur� -! a re�ceQ�of known�co"l%� if�ng��MilliQ �Z�00a�ye�-g�Y�t�d# ! ,v�%[�� lway��tC�t>$3D�An ex�ee�h!y ( S2"K Rec �A@� es r�L+��30�$m�35!R �?d� �brvaYassociEUw2 � FCS-�Ua-S*��Dso-cal��,rigorous erra6�-sis [27]A�E�6c. expl�!x� urvhi-�g ACF’)�close��(minimu!�D K���^XaDav �� ��all^5 coordin|1F �/+possi:.0l.�s�Qat"%�a� � max�var! (��a :.!a|�s���%�(==E7 . Suchm ocedure yV ax�Ie)�)+"�-"�!��w1as its5ja;�lA��R.��r� !Z�-�!|N� .�s�jUZ�e�2�%�i�Qtot��r-ANOVA�t�.; U��pTukeyE�z� aris��!Q��%jlt�ValidE�.term�\� siz�6�A� ��\cU� ima�-] #A0!�I�.�Ivid�at%O2Rh � siv����3�/T"�H pr.U sub-�ved�8*� Cs��wif -lim%� ( ~2�� spot#&� ��(Aobs���!d5Vs male�5k >1 qsA�a^3"n unambigu� reve�[�M!�h�m� �I0| 6�Norma��distribo dataI�E�i �u Y�.�Dunnett2�i�E�� � . If c1#� n�HAƁ~0Kruskal-Walli� st� ��I�}z corr f�Yq$�a C&�7a3e�:�SAma T rank Y 3 .e?J$�Sf#���s�!st� �&u)�DGraph Pad Prism 7 � ( To investiE]r� of�Mclearaa�M$.tABGFP-ex��sq N, clade B iso(sB�( Nropic� Hf7 NL4-VR4 2"se l gp120-��--��H �bol( Tf 19Ng�pA=�?:/.torteA rn�u���%iDe�*�$(- 1 6�  2N-+"C> �$ű��|&�B��d�,!�absh �4p>�9 . Si!�� �ins])a tier 2�u� i . �l".seiC8o n�1!'A =`h6w�so1~o=�, a?)f[,] , �E�ua��=u�J( ly f�'n]�incre !.inB�1��8=~-�DMhtaVͭB{) uy PGN63D&a5Ab ��@s phosphatidylser�( P�1]��)�F�7�u.:5$ '�(ic7�O<,i*A:�ver<of��*�e.P�� n"�of 88%Y��!NwC�� us iT x,an Fc-deP#= p se\<�o� *;0 =�d, 5sTo 4�Pirm)q !��n U6jB V to g�s- xf�1ng�E��; PBMC.B JRFL�xas Ent�! etupQ�hE�T5F:Q�. How�+ , beca9of  fac�trodu!� by l$7a���be"m�*.!damoun%y,"�ɀi(ofy�)� . A�=,2��&"�*� I� �k�i��}�%.�-�^�&!�B9(E-esM$�4$*&hA,Q0d�D ( S3eP�"4Although unlik� v^(a e ~,+ coul a�by�@uc.!=!l)*�uMh�6!) ��� their abiS oJE������Mthi roach�y�E�=�$s)��&�!w@�a�* wisethet>��/ F��W��en"B7�>���t*Dt�>�>8)N"�>�>we&w>d*ed �/z- �!�toa�:H�� ��. A�.PI�i b� cɊ. More�O}�"� 6�g��ly"� �!mBR�( r =�89; p<�0l9AjY=YQ/75; p ;002:0Em;�AeW2A!�2BE��2C���7"0�  0�3 � S ��%#t)A�C"r occu�A�_6� U��4:|>PG9aapoo� }dBbut�&dJ%%� &�0�� s+A�gA�%w�`r�(t� .� �Jby�[2,28�0These�  l�t�8Ɉ%cP ]�%83 to binz-a� �!aT .�despi7 e(BZincap_of�u���). B� o�3��r�i�pndv�9:yet {unx�:drvk won�4~4�9abund%pof"' glyco"X?("J �.4 7–14�$kes� -8 [29]G �i�&Wght�rK� inQ&d9#To�^3��qu ^.���E?�E_a 27-mer"y:mimickda=t( LLELDKWASLWNWFDITNWLWYIK-KKK��:b�B-!�y�?,�Tyl]n��}A@ , 2FV 4E10>nd 10E8a]c2�T� ( S4�J�I)\�� �%�P A�x)&K6����ll�$4!.N�9H|32�6DEN� B:��I�z� /)52�sEo gwD. U�%%�Ign�%�]M-*2Y �=T �0yasR�!�!9%KG0is �&Tsomewb �app�6�*t" ��&jr3�3�^3~O e �1�#Ae�Ecto6�=�� �aina|6� o �th2=�a, �A�@E)��.7- A`�@�u�9��C @%2�:3�C6o1~*no��6�ej�.�qt demoLK[� vaE�&`��B���*�a�s��/�i�:� F .%q�&� �6�� ,e�m�i�:� ,VI C�&#s7`-oE�qW*�QIu7��7At]'2%��-�W!Y:l<.mI!%��F�!z� (i} )�. @;9��ed}�*�e�un-t ( S5�ne�+%%�ed B;\ ��-p4.b�;a�!TB�(�&)a�.e�se&�Q�sup�/%�no�-" �de�# E8%,A�is&8� �1��>`6A)�'h0 �; 30-f,�sp>� �oF o�*u)t��r�0� key o�D( successful �I: 7mD��� ��x�ve*�l|9.k��6ne o zAuX^%5'���gB�un9eI >a��Al�A�-27iЕ�!�p=a4 in 2�W3)���e>�"# I beyA�x *r> ( S6u� sses�:approxE1�>�m:Ce1!�reY�t�� �y�a����Kfr&�:a\"� left!-.C6se * q�Bh�8ly 540 ( ±29 ) z��/ Fw neA�GB�lic� �?gI� !�.�3E�0*�is=J�seX�Dl� "�@ a"F�q��(ce fe!'O� stil�ul%L� der"!�A��i-U�>Z����Q��Mt�xf��>�A a�!1 sugg$,��io2��(p$s�&=Ys N�o�QE*.~ �25�srhr�^_e�SdUe� �6��� 8 ic�M+-[%�&�0E��Ua\4�{P3� 4�<A | y@.�. lexe� �*� E>o:�� -�/Z "00}|�-rPSQ>a�2>mGA�Z�-�&<.�*HO�xj!h " to)8�,ci�� d on�%&� �/h^F��Pa�^�y0* �ng5J# �un� � !b"�JPG1 $G1�3 F425 B4e8ɉ\�m�EH�9�9�ɹF�%���MI6=6^S�"{68 Rtempt!�6� �8���A�A�Ai albe�Lo�Bub@ly�er���v%�!�g`7a ( S7�n�pW� �( applt2n%;#�"�*�,.&,a' -establis:teG=�<<va�!ge"�$&N& moni� .�,;� Ii2M[23�4 , 32!?z &�  �3p%�5��m s: �!n9E.�"�)+us�hw�*pa�5���; B52!u�m�a� �i�VA?� � �r4319��0&w.=. N^,v�$l&Nd��.q-*2��J�U� �-dengue=Z5�|y�E�Q��0h �)%��u�&�%"'0�-)-  &� !=Me�yN*��!e6 �5�M5B; S8��A g�/�)m6n�!o�5 doub\)�/F�("g/eq� . 4a�S1u/;&C-� &�%to �! �U�S*�.�hydrody�0�/A��L��mpop�M��:��<w��1�best-�*p�/!p� a�w�/cus hz� U�s1?N�( R� �A� . Ou� �2s l.��RI B (e=��u�1Y�E{A�-meMo!i,*$&a�M.b)2eA (6r)�`�= 863�2477!�5583��s ^i.N8"8;E�5CE/1r��E#�XA�J��=-Epromo�Q1�A\��!zn }og)��. B!�Gs�5�" =eE�er��bet�Z � ir%  B�V�12�T-�# un+6Cgav�H6b��(^; �BmStr6.*AJo_'5� C ��i:��0tA��+�%�S25�,�2o !�R�!�V2 yA0crosslink Envl i2m �(0.2OE,. NgO�"� H�)�5as�&�3 !,4#g6G[�O�� ,. Taken togeAR���)m� �.�IJ  � A�p�� -*] � n�92�1�CE2�B?.�" *�a�b ( soA�hivc�J�9w�#.e"�-] fe�� &�&>�*Qe�%._8!{2�22�iGAk4 s� /+e�>,,of�!Ovpri'"� � !b���1~&q* x*��U,:ar�+hVQq)z a(of�&om�ed�b�vol*+IL�m���Fc-# )k� �-kugm�Tau��alA�ec%�^�%$in vivo [3� 34� t[y��,>@��Rx!@g�\6l��:,Awto�f�!*�A���al �q�ic2aa`P&|ZkCWba broad&/g�>�"� |��!r�in k , b�2� VRC0!�[ A!���g6; S9�|�n",g $methods do�0inguishB�r e'*7b:�i�M�themselv�2�_QYQ�� 1-A�""Tt�M!�.�/qR"�"e��/���Ps����;$-P-1C�E�avail �R�'Sxe�-) ��1rUj�*a�&�#_arR7nHXB�� SF16 JR-CSF2ADAI4a*�t9Tdye5i���!�u} of�1T��e�D��Rt!�B����2�0` �4Me�yJ3ery��izX8W2�[w� a4e-� � .p�%%�)�l��10uDSurpri Ni�*4%��,�Ucer6E�A�}�əb� ��.}!�u!�itsele=TS0��8�*x�(� pseudotyp!+�M�o�m�)X[(6 �L�2�.�%F vesi-X r st�@ itisA#�VSV-G�q9J�����1��4ve]yPGV, `-�dJ�hH9��')�>[ "KH-=�w�Q46Eactic � argu�x�"�.%�2� � .�� �*� �!�"���.���dI�s h1 �FITD*%�-��stu6  �Tr# uAte6���� oy'�ML%in�R��H7% .�%��!D)�i�*�2� � u%��l� -�y� y�&^46 i# [�*%�n�0d�J� )� eYnonqs/Tc!*3�7ypl!���{�;x!��! "�gi�is �a"false-"�/)2S��a�-64Iq8�D$*�4reiJ%�2B4A�1|(G!.�$ �4�KT�AH�Bsp2�i'9K spinj1���_. )o�I6�a+ R=EY�)��B6n� ,aas����/ h�h&� v4^J� ��n&JF�oA�]�G*A��&v U(�orA���1X"�_)!�*9k ��_T.-"� CE1�4&�@T� 5uu&d<�ia�5*�Mxtow�K�� aAQI�R mplG`�! �"S� F=to�� ����es . "� �! �a��2[L�;_M� o�vi � n�E�?d�(c|40$&%A�West Niles [1( �+36- .���,>$~MF�:rem Fi��jsou2-�r2JpVok�:f� � .)Q �_u�by5eu7�.�6MqAQ� O�to .x"��&� iY��0utoJ@.�Ymg4�AA�<*�)�u�; �S*�/!+%"[/A�Q%u . Fur�7E�,qneglig���NY�-N CG��yDorf6�&�>�!4� i����>!  Blis># ���u�]Env�!�/o�����!Q�!jsS��P?�Ik"�6q�e��6{to�F[AB�I v[)TT� s adsor�s�ɿ,�]]���� pi�%�a"~Q(*� ��I al�A;:�Z�>�&�Q&�, a:W6P�&TRo ,�M�  "� I�m>��Sf�X&) 3 �,� end���)O� �P�R*$*!����>{"A-z}i�>�� [�mp�&i��B�s��!�n� ���b�hropHK rI!�A�.� �.�6�ic�5!�� m /U��$� �2� ;.� 2` &l �`!TWcIT�6�-lso b?eemO*�0��l� seem"� � *�'*�75"�!Din���[37/ Fin��a!&IOua��=�#anor� extey("� $��A/)��%��)"�'enginee%�.�#��+"�iq du�>� rti&�7F��  im8$�@�vcer�S�3��w+K%vA60"�E+�DYi4y� �QucanQ�t J E�8��k&]�F,- �6@Oa�)c!� @ir:G�R���!.�$!�v  !"' �w��� f ���^1.�,6S"�n a_{�.�.!V+�'�4H �!p)�ym|qJy��9Sy/8)I3 ��ak��?(-l����.�oAl(� :[ݷ)���L�6 o.�)r�Kcaof�%E�"���� �66�~!�B���Teva2�nap�J�D� �Kin\� circumv�q�-de" �!k] 2�ami����+(U�6�E�ac%onse:AG)����oHCa!e4e0-��Lcos:EcreAVsAoft�)~e w6  *! Z�yx2�8,:�� !L�:� a�ei ��*?AI"D 6�j� I���enh�2l,h "}F6Teva�=>=� a fe;+���R6��a sexuc!�m\ -�Whild- �ta� orgaI .� ��2Y  �!�A�n ��M��A�I��T (by Bournazo�D%r[r� a"!��V_E9h do*ipE2f e o%e*�#�HγR*Bmanne &� ^ �z�u�� �pB�T 8a1b a:F�8*fE` auth� cM�[3�AF2bNha�M al.��uLD=�2�r�c � e)=���aP%eHiY��i^(TADCC [31C40]Y2��?�ugar�-.U.t o,'8ike>% �� -attac�,m̃��6?" �� >N �,b1f~!�!X&8F|�cF �-��/it���)�aE �/-��e��e��G��s-�1 ��"� ѹ}�"OnaVe�i�1�i�L� r:=za$ea��'le�� �8�%����"��<.! w��*��&�5E�r  \m2�>) thro����D'nethe�, �i"�&Aŵ�2 ]n]2�!dof6��GbeHc,V� �Vt7Tn�3��Y���5�.zyE�t �0 hookworm6is��ly�emi��#3* untr� -1� worla�agv-econo=�k$health imp� �?�N . Wi�tj$v3uS!�4 of���^burden �wE,a9�8iff�8 deci�?mako_�as!�_, policy ,� PP=_� �U� �W AZ.s�� &�howVz_, �IgH!�Vurco �;�SA�5�1�H_ � 4_�. im.�.�st<�5/u-�-:=Z.n r1��WHO reg�))�Z*p=016*�n ocie9KperIE }_3�Y�]ra �J$1�[80 DALY(w 2004!��wwa�(�OT2 087 , 803:?10r?( �XE cogn�A�ir� utco����FR,!-&� "� �eFE��%%>r`tiJlo`> KL��!� prob1 emc��}!�� Ia��]�EcY$YV5 bg_�$o $138 . 9ann8 ��g�,e��in!!��ith? ? wag-�6�2 .:�4+K vt]Ga�Nb. 2���s�5ss�qM negl�t�Va��i��Hsn9exceed�#u(5qt'.d V��at � ����4+��� Ñ� rota. AD0� �uX1�2��e@� �-AvU-�c��mBrazi3d Chin�fy,fa�nfV?(��]. 2�}$y�(�9�JlowM'middle-B���B�LI1 soil2% helminth�Ta{�/g .�-scariaa�trichu �3�� �DJ! commq=afO&� th�^ ldre d ad^[B+ 2] H]� hP�l��,mass drug adad1�4 ( MDS7program�i4�(� ho�dmorbiddu� STHs�ng�aj� havA�a"8>� o*�, facn!�� mebendaz [isL�VN�&�s�2��-�a�6[3QbQ�gofht=h6n-��nPw�O[�y5�:�QG B� of D� ( GB�*(Study 2013 �O� � �='�nnt1+�du� 1 aB�Y� . [6]�6j k5�?&�@la� they�ily� pre-schoo�' -ag�/-"[�!`� !�A�-�)gro�9��nd . D&SPs��E��,u( �a�y="d��Q567uLa6�D00��l� people!�.5�x�t risk� Giו2�[9a�w�WJ�raQ� � deat�ZRÖt� leada iron-�c*,cyM��`malnutr��[10!s�R�#a�4obtkhronic Klem&$lethar� ���hys� ��&��   adxZeAgna�2 [%=T�Dg�KT'� f�8�m!0e5�@�mhmorta�V�n[i��* Cly Q qSA�n��$Y#o*�U )��5�� � c* omita�o Bi�W�[mal� PAs%at>n)���a�11]�, ��� &u !Ci�i�#& ���U �U �U :U .���a meeT�� K. �^Mpoft Exc�k, Redmon� W�Z�Q�Ba Crys� ,Ball ( OraclI Redwood C�H, C9 dd-i?:�Mr� �jo�CB&��#I�A�b&( N�o5��Y-�0a��t��)nd� a^/=  BeY�� �Z\mconvera�ag*�|u���&]=�rofE�i lo�^)i�+Ica�(/_g!�5]s2"� "??9X": �$ZAo�?���\� �cdB!�N9�di0-adjuۉlife yea>��9P��\!R�wf]B�=T�ds!1;��?%�&�'!9O �i ) :& 0–4 �YO, 5–921%16&� 15 .jqK i7AR9�>�A�Fn �8A�ml( M!�C&=�W�W�a:E]�U�=P�a�C*�Nbi`�� a�of x� : %[12rb� ��2=v vidu!� arbo�a�">�.E&"�IV��J�n&�M!zover-Pse"�b)7j cn#��M��1� .�J 7 ��Q�d M6T;N�( P��e�%�phe=�N�equ0 8: Mi=-k1-Pi1k-1-1k d�%�Ao~Mnd Ma)�;$"k� !*eN*�5� with-�S�(�Gpro�vMB/9�majcz�'1%s�sCjerx kA�1` es 0���*�<v�3q.14]�3qL�":~u[( <28-��!�r� ( 28–65t heav ;�l( >$i�8n[15]a�fiteMA��v��: Pix=1+Mik-k-x*Mikx*Гk+xx ! Гx-o Г (�a��� ,!�x1�RE( �bmt�o(�=�:pXaNɮU�b E; 5B�(*�\FTA}%�,9�Wa>�a� qV ��a@/!��Se�3.Q�H�F.�4.�I; !�&� � � ) ��� mpan�}� |Ico�l. Each-` 9v�E$�.]�j��r!�:!j;������,���&�%:b=.]i>'� fr�&o>:PAF%�Age�raA�*�m+[ET��c�4�8! lS~� 6l"�r�6�4 2 �� hip"&J��Jx.TyT�~i�Mh]�)Ea bl� �[16}a���cu-v%��*he%]eY 6� 0�=�(isnz.0�Kau�X ^M�6�+* :)2;JpN*dHnr!a�L&�ogiAn Hb )K ��i� �ƃ pu�E2�*Y�6A�5�y2�Yp��N#b x��˕�S $E ag���cuK<�l��i��-(["�!�]�on�l� ~}2-Q��R�. [16–llA��faB�0��p�+�<ly vulʊT'��vu{�*a �be��|t�� �!lyQ}V��,M��-c� � ��I3=�- �jo�" assu!��3j R�. H���;me�Kd � �# !�suus �fG l��wVN&k  ( YL��J4�A#L�M&�$s�ou�"�6�Wath�+Q� � "e A�-'ul�0:i�e YLL��A��5�:A(=YLD=I*DW*L�I�T�� inc�y� , DW%���L!+ du�e$^�2�.!;s�rut*vM,M5!y�6 R/ a��ed%��DWh/%�Z� }A$J 3he � ario�X ai2{� �anH9.e'.Y���=�r9�q&�J�AlR�M;be�tE�k�a"�6���a/� �fe� �A� wve�1ۂCi5��3�rec�~�f�� !� x>e2+-�o�3�  3��(.|)r�16(`l�0zN;"2,A��'� loo�1aũ(2���F�.� �{�Y od[2�R�? .[ ��`dl"�Fseek �$���a�9: ;a4-*��6� 0� E� AJfd$Rn�:�. Ro� �A�eRoca�� �� a�o|p�$po�Z�� ��)s+!:`.!�!"�M�##1�Zq��1lo�aRMOof�~f`xg!!��m�2�� #> Q�J�(�6�X�7 in T�diI�s�\ �_l� �DW%+ �)$Q76�!Q1.; 6(y�dP.TLoX"=Per CaA2�(�Y�cDW a�A��&�!5��2;A�!�eD7,�!� �,FZ V=1ءc>�n% �as:�f_ #11]d" g/dL%&� �11"�*� �{10#.U��_h0<8F(."�V]2b.Q�-~pb�%LR��;1��xq ]EMc,�4�0��DWQ�0A�Y�:[.�mf�� -E � �s:�$by Shastry� Weil%- 5] T�j2Cm�*Q=C ’s"> [:2E?A}2bA1or'(� �N%y&� ) !.%+�R| �2h�H)=�:6Lv�1-Hb L� mTxa�458N a #B�-ast�c� 2��M�q�Hb�!�c %%A� 5] EP bp8��Pg�3$&ai?r�pu�Mu3�F5HbAl�P�� y 1%� �iY&� A���0 �6/ouw&q���bW8�5!4A�� iru.A� adap��I�^y` *�٠ �(in Peru[26]� � .|11by Ros��Horton[��e@irY�s�zq�2�M��HN(A�a4.*Wagea� re*G(D3. '!��_*P&�#I�rS2�MERA��$I�)3;(sh� Ad ^�?L"mpens��%Z� ( GD�fc�;�K*� i&�F�*ve�!*�!�2�|JP6dH mod�b��_%�-A�oa !�);��y8_�F ]ʶ3%m�@;6�)8�1ik�J�RqZ� ( �XAbx���=� y%VJ5.ov AQ�zIR do �-al�<"r0�a$ly�2a�..} t8_� staff� ales� , etnf� 5%%y�]F^"}#�.ll��.�Dgr�tu 4*f12 7%��6]{�ystemaa�review:.��E��28%MIQq M�b/)Fa�1%AM� 2] T�Lm���"aE�uti�}d!/v�sY,"h-D!*ce)�){ 1E<s9�IP inpuAV]".]�8idE�&*Cv��UnP�N�_s�'5.�Q��$p&� *���U '%� 8] C>x, � �U  .�q!L�(d%��*angS��2!`� ���%$� �*�v*�� >t)e��d:'7!�,1H��A;d :� 5%"� 1990eB>)�(� V�by9/&W"!I2�(&! � �,)f�.�1$#30] Dz<�P\*5,!�sFT/ ( GNE��K�C~��a!�6� a3son Pa�B*�[2�H!a��B&`w2���({>!�n�m*refU/���al� p�Iya&AW8'�e&�*lN/�J:ver�dK�Ao!�d "��e A�W�4Bank[�eS p��'�16�[�dw��&$W/`E�e��ce�G|)J�JVe�ws4!e���:N�_ksqsame �3<�)� ?�1clb"њ��*7�_G(�1�ke;rLumI�%LV�USA�ar�of St|. [33]"K��n2�);X61 ( 31/A�^/20�89���Q �DenA<�4US doll;%.�%� a 3%�O�� �{Y���Q .<�� a@{�m;z�Jv2.��een"8�@ ran #0��V/(d4 p&7d.0�t2&�u �F�k�95%{g�2t�!rval ( U��. S�R"��DJ�va �a&d�: ��![(V��$��.��,"խ�(!J�& .�!�2+E(Sm�*�,"�A��Y&(!�ge:�6#0�tqN2�66� C�+/-10%�E��se�;se�`Y�I�ce/*[Rsa ��3E�*& �����2�e��A"�4U�s*k!!"uF:$50� m��*�( 5`0�;$.%Y��4] 7 3-tG&q�9J x �>�.i.� e6�$�!6i.)an| ,� ,$*<or)��K&_+�ӂ�8)��!��9J0 9 ��w>V�� ��.=3�88�9��614!XvN� ��MJ1i+s��Rr:(��UI�p, A% , 77�T40�97z�gsu"�`� ih"E %�.�t���+� �J*o 0239->Pd�!1E� 45,�"� lyer1=M%�j��e�U+[Pa�!Q:c��,�)�. IH� R'�: :I% ;RY�to=�469�!�)�87�)�e 13i��f� 4� Al:g� ��BB��O�[�I�[=dR_<�"�tY5386A�2�505 629�n#�_g1A �N>&T�"��s��DW&= (i�, 멯�RbL8by�${!!widthA� baqd4r!� �<6daVB(jy�����=���I�-�6�JeZ6�t�s��; �7)=89�:ZE/����&AՓ�H!1!�4A�50 �)�≥A��,.e8.76JY729o�QU~%7�$s g|@$V?0E~20VZ27m/eZ�c856 )%5�?!-W=H�UA�19<=�}9�92�a49�97��!�6[10.R~+��"��2����J�q\�N!�eM+e#>i?AiHo[C.� $11 Ǖn?9$]8�".*�>��N�( M���F +!�"�.5.�� �./-4�(,e��� $56 . 8A�f<@,uC�}!I�a)�.�3)ɚ�>�1�9�3 35s,FcZ�As�1�m�^�4I� .� �g' �u�>c�#�d I�%sFin�!Ek#A�&�)x�v�?D .kJ�B� �8!^!p�"D�mIG.�-R� � �,litE:<'��aa uE���� #^2|;$65Dw�, $a)2��; �$S03a��D J:d� /A�=�.v/���t�. N&Y��7]:q2��,�ו0!D�"ce� I&snV  Afri`_ �Ep��G�b s �K6" )�N�! &F"/sY��8a�)�l��J��B�Al�Gg�3�s�verla&-H=#�"�|� "$ari;�F� q, Mc�&p9�y�.� . A Q�1�e_��a>EaL��iO Ni of $JE2�}U�&� Jfat��u&5 I�B >^.� �es� nRe!97 �&R()�$2Y &�Eݮa� 892?)2�~a��e� l�wed�9":d�,8F15D�I�AOai|;FO:*2��)ԥ�2#�wa�F.G�4�I�u& F' , $�4@Y$&�GRA> � �G�4M9�2B����� ��2/� � eA�R-`-ig��.�2*� ;�AQm_����i9��B{ѥu�(�� y C�. �r:h)�i�a�E��&7p�LI�B�+ gCQ :�2v�W�P+Ng�Hon�PB�HHp�Ve.r� 9@ �:����0d��e� an 12�.e�a=e *b%��ָn�b�}XJa �Rf)o 2jb �5D 59)n�?a21�$yUI:��227 (!nAme�lA2$86.S8%9�/�EaT�n Medz4��� $202.9184e1! in EuropA�$48.'4Q 5� in Southb Asi�e�183��1c18�> � �046R ,>Gp�K!,F�]%* daC$y=�2!41�2�447.'4!p� 699-u.�172�1 67�& -b�402:2kݲ�>9�9.$9–37�:f�372e3]4�� �>���2���!�n��/&�@d $24.k2eB�82�7!_8mSq.�:�E�-&+b�8'�U�7�+Q�9�22PE?2mMZ(4224Eq ��>}(�F�A�D!C��/+=��!!�&Q ���"^S-!/(>jv�2 � * ��/e�'�,���2B� clo��0�0*�%�M_�at�M5 �k9�360J$���{!A$�7"$ OJJ^R�� .�=2S�b8�017da5GInd��1��78041�.�>e� $471"�>�; $258 �2�n28� 75 �6. zO%�d�35J874���� �39�AHa�mid��<2��*Q{�d 3�541 ���%}��ig/��@A�e�Pst5�� �� 73x750�� 8&H)�:T ��1 %:�%�T�3�T&��i  robuMuo%u�&�VVA�� �32 i :�, �"hF !��C�B�l�_"��N�&6 �&� *7F �X1{T& ) �!`"U , $8� &� I�.��0� &� JJA�!�$2A �լ��Y�&� JF<6 :��)$Q�SE2�2��2�aBd�O9$)>!) ;M�M�2�a8b�:!�9�%��8��:�.6�S��nU:nU!!2q!�9>�Vi�:���IA$9�I4!�YZ H2�)� ��U��U�#Ե,*V��6 42��( $261 0��,�'i8z]U� * " vacc(`A�07:) [35�@!p$&��{ilyB8k!�,n�'���!�� rculL_g]$1_Z�fMe���@30%*J4>8�� ofCJ3'y#K� �Q< �kD �J�B2y�&�]]�a.>�l+�8Ls���z�&�'( �=if�%�w&|!� �as!�uni�h�&Q cau�shׄbe�^�maka/U:com"��$v��Mar&0 ](%��_=�/ %ylws��cum�NG<:^*3�acute �R�S� �vF�ot�Ze�YaM :��h@�ePJ.ORsal������ Q~�9q���!k�help aid�,2�^�RfuD0��cd)!��' C"�v,!��=1eT�ut!���nst��M&�&x^bgau�5^�=5#&�;returni��rv�Z=H,oA�a{!ShoS;!�-!��t~�iko�l*���� m!5b��� .J}/eg!3���fi�t#ہa��x�Q�!�new.H.\1���*t �<�)n�*o�im|k31 Ӎ��$h�",C-�>�oh* 6gC�ADf�ed �smty�KI�Q|w"��o*dIio%~�&+09�.ʃfu�}3!M%'atp`+��.-��p& *w��6�!8z�1h"�W� A1�2# B�BTB�"V ��(�Dt�9GS���u�Z�I;�:�&1�.  4AB�7��>Ea�1��*V� �d�K�K9@<}IE$p86��+ �<d �� ll�p2��Jo?.XoNE$n�4A��}�b�h*E +4�A0�_�,�ae%jA�y 2#�80! a��?5)�hqJi �3�.R�}bA0m2�8QF9J*a�a&T*fo1W(~ �mi=>bd��opelvicEY� �p7b�0vel�Mi�R$-�V�. A��@f�K�I8-*�a|8(iA�����yc!�E�mXK���_m�R�{��i+fr�=u~�na0|*:0:2�j�/l��a\2��c<�\|5��/�4s��8�U/�e�7ife[39]�"�F�b�&�R]<�hl*XT1M4�GAo�4�-Si��1ge;_ phic�ai s!�!AmR�.|#Z4, schistosomiaA��meAi��� 31!@�f!ga�8A$�#�� true[��[H���tlBsV!/�DWD�je�B0xa�iagno� . [4�4�A����g �<&�MaE%e�>�2��W���m�?lIu�[k:e�H���?�Y6�*� ��beas*�2>O UUd._;��%�;!Pgws!LϜ trap�&i �8� ��a��g(�y�bF�S�:aMd|"$J��4�a �����ItV n����sr��!u��tai�1-�I� OG�&��� y�&<&#nA �.*�/�-!bF�Gde�`��A�15~; R5&�AncyloIM a duodena�^COs"${�@�ݡ(n Necat;�nus[41]֑"^m�tcVer ��^�)�g�i�g�n��d=S.*�Kas:_VskrY15�1a�!9H [4�44[ḅ��j5N� ��JZ&a1%��:a!us �^AG.c����oB�"I�H� �`y i0=�kuWt/r_~� . M��e�A�}Vtw*%� ���������we�|Eu~�SvR� v�jEnN�&�;A�"D , �NjWUE�,�a�\Z,;Na�2D�� lengO-ime FOg�+liz"! �9E` . �k�lul�Q��r �2kA�Tt)l�� and/Loo8^�``�F1  6a�&+L1�de'A+o5A�-�.�$�]�rTlyAK2�(1�bQ�.� ��3VQ�ɨiډb�2i8�v�)�C� � �g��b.�.�wAEng%�n&�?� )a��A)a�U�Y�f��Whe�!!6G 2�iRQO� sympto�?��� al n�?�5fs��l� ��'os�Mbn4%(E 1%l"D^�Z�<&� �z�mi���1���  e�N~[��4 4-4�U� � ��dy%�.k�!��&��Np���F���hR4�Y�;h%�R !�?���A"� ��eU�\ ;&�Q�f R-V��9�8�4. Som&d�J� 97�I�?ear� � \ s[47| �+h��de�g!i��x9fN�6��b8[4w&/S5��,�i?&�9T 91�.bR�y�i�H��A�a��2}RDiDcx,�p �}�2�*in"�s � u� �hA�@@n/&e����*�Q9IsA�&�0�$3�4likely an unde�restimate as we did not account for those who perform heavy manual labor , and their reduction in productivity due to anemia may be greater . Also , e ��ing at the population level may have unde��� true burden of disease ( i . e . , infecO,xon pathfind�errore3QY��r�� nd motoF� unknxwheievelo����� $similar efa�|a �Hnervous system . We 9fou��at1�!5al e5�disrupts2�of��!Ein)�n{zdfish ( Danio rerio ) , lea%%to=(�'A�issural !Us fail*crossEBmidlin��At.vde ���( from activ�<of@-<-induc�=a� cripana�,tor ( hif1 )bwaye�A����ateI�A:via a r�� se-signal��=!�in�>magnes sulf��, u!to�� rove �6 "�� Leterm births , prote��againstN�byQ6�upreg� M��f Jiss dem!V�T�<evolu8arilyE��� d genetic}ways c�n|4 �Rge�TACNS�response!m�MF,they supportA#otA�al)& �ive ro� 9c. H��i�:�bo, cu�nd��Prematur�� fant%� artiK �t� (characteriz��very-low)� weight1VLBW; le�54an 1 , 500 g )��!M*X at g?est riska�)b� � adversM�cogni%YU|[1]D ᬥ Ga!�tE5i �� plung �, pulmona�hyper� on ,AM geniŬ eart4�pla�� (nsufficiencG UpA935%a�!*�exper' �6W T �aatEdon-dee�orderA� utis� cer�l pals epilep (psychiatric�� � aK:$ )�!B*!� mole�9�7 lso occurqmorE| plex=|e�� !���%��x��L"� � a] I�.��aF}�!!�n. To �t��� <jD model���stiga� �� iffer� staA of� a�V!0n� �"dT �Rc b ��es�B�involved)Ganalya,et-`"$ modc &% 9�"� �� af.c,A�lu�rcl�&f� αp|r)~� it �*~"�= 2�in]H� rough anf� �) ,aP*= mF ��1!7�6u| ' .%!�!�h� of*� &= ��is�t�G $when given2ma1)DZKa*7 &J deli� [14�W2�&y �� duce1��edb� M�deM!�e frequ� F�4. To visualize.CQ:�� evalua!gs� al yg�.=as weX' pan-AJ�ntibody"�acetylW,tubulin . Us[ nti-J �I�at  �subtleEL:W.W�e 5 embryo� [�eF"���0���t� s ( Fig� 1A , 1B��bec# BA�6�of� ua!u ty5�)- d qu!3fyN- =u�U gene�a�n=�!4i?a \ subs�sq� ed m!Mane-t@Xed GFP: Tg ( foxP2-enha� 8A . 2:egfp-caax%���aLcis� label�few��tinct� n type2 w� retiAj" 9��Ulongit�GA� [17]=�C� We examins=�in��!AMfollow!� 12-h&j � ql �M� re6i��w�� �5E_ ":UIpo�i�Puberculum ( TCPT ) [1^ %j d�na� s in wild-![�Y�D�A��"� NA��cE7 fluo7 L norm)�a� to-c�Q�1R. F5T9AA��= �c ) ei�"�!K� r hadAPerM�g!� noA��QWto de�� ��cha.V�U�� � ����v�_ of ���=E�!�e�R�y b o��uqa�Ja=�k��/q�Gus-�cUF( C/L i;�C$F; Methods��A�average *%�ZU�$as 0 . 639!(awI".u^�)emRsE��t�m225 ( p< 0001�two-tai��t �  )��2 �u!!a"� !,a�5�"eseA�F'Y!�s9؍�is%�u_J7 expo���MXC al!_ �Gy�� e�245�aM each�;%i? sR t 72e���2�duey24 �� uh���),� Xnw �6�.�@ 1'9n. I"�duE�["I;a uN6 ��E# wors0 he2L*� U we �;+)� at 9��,�q�.p�persis�<x u�u�9�H� IEyOurc*�!!�12 ��2�LefY����d36��60 1ofHq�a�C*0� �#aBK�ndu� a si� 6%�� elagA�*RIdEF1d# s doVt!�re-%! *f��r �I�#ob�.���)�$1�corre� sɸ�tim#5�.�w*� ���v4 �� firs�s,��A�24eS5�2Ae�Lby!��d!5�%��1 -�I�S� T�\E,��)%%�)� maxi�Jo�e��!���edQ��!ampf�conQ�wv�9T�2��U%�2�Zͧaberr� =�%� 1�. Nor\$�p! .� split=E} ]#.V!z2W�i�b ��� �5Ɓ�!)tr��NR,� 8fs �N&to5'?!# a:�at�Y"3 $. High-res pic�L�!NcJ>H4E–2G′″ )��I\? �de&o)"U� rise dors�nd �'�ly bund�a9yJD:�E ��q� �I -�s2 5�*+ ��%� caud�jo�he6�!�re !� :�2F6R�L�I)�Q���is� J&�)w. ���3� I(n�ne�#Q& . Po�'explan�3a:m����)�D�c�((g�l�j��p�r�;�n�Y;���popto�t% ellua$prolife�u!+o add�"!/s�*�$�� "N )G&o t�����lety��} mark{Ux3�We&�ind any2�*> 2XO.] dlx2��%.���& nd dphalo�W~"!�, TH y�sJ(:�CU!c�tyrosin�$droxylase-�ng-� crid*or Y9���@-phosphohistone H n�>�We f�#R&� Ac &)� te�+-U ese, �� bodI!?� :�X c�'}��5>2( YV,s 6 . 5� 4"7 . 1 ;�* dard� i)�4 0 , n = 30U�, p � 6"} 36| Cq�1u�coordin�byZ�a��)[19%   basic0ix-loop-helix>�&,ubiquitously�Da�eD)but�is%(��hQu9 !idegrau,�-)%�* ��� �H���#hib/I� (���;�&�,)&stream��*$Eo=�]�.D�'$ organism'1N$A��plewn�gio���, [20!y We w�,�6� �5� �� za��2.��. F� �wan!{)sta-��_ nl&  S1�.� deci!�_�Q� of igfbp-$a =��Qa�)��)��)�R��:#.^z�O*At� [21�"2&F�]6� ��0on%�9��"4v4� � &�&a&&�α)�a'26�a�H�~)J 4D; .4Fu/+an1[oG2-�2�4 CAY10585 [26]E8���e�&in5r�KyT�&�(sug0#�� ��"e��1��+T,}U-!�ut4 !F�α� �(a.� ell-aut�1� ���-mis-�wαA�� αmu3 !�J�,� ,�*AM�UAS/GAL4|.[27�p�� he� BcDNa��'t�m& �~-angeaj 621A� alanm9#t*LXXLAP�if� HIF-�[2 We�k���U1"�c"�w �6!�Eof�!b� a vi| 2A pept�1fuato�or RF to� a bicist�0$message [211!IN*ay D� monia\0-�N���:xkUA�b�&�"�5ophu ^ɚ�(.9-��C s b6 Gal4-VP16�org� �J ?elavl322y�Qm�*J ��y��,f6�1��q �NGN���*| �� each!�F�6I2�Ft meut� Z%/we�d ��9G , 4H�F�0�, Ya� vwe screea�iso�d�"� �depenm0E<��4!allela_�9 �dINes>]O%'j o a Edru"e�;XCs"t>eri�� �5�[baBonqG^ ngle>el th robusBZ a-. Qo icT d%� B{ ) ; ^  & UAS:9g$-2A-TagRFP�m�!("� 25�>)���to q}Ά)�z� 10 )�,fgY]�AW�'nfV-:�5i = l �$]� ɟby���� i+p-b0d�IA�JE��'@2fOloc $��s�6of�6� ��W �ed9Á��s n�/bGa����!�4a�5"otpb . A2� [30]5�zRiTin�3M?wA�a,/smid car0 Az)�mu.y* �s&�'!g�j�P,d2�Up�!� cuss�'�=].��!ep�u�1Tc ( 0%*�5.�R S�5. :/we ca�a�u( n;����vel�9� *q0%�a*���}�Q7E?�VE8think�(islik$E� ( if��D<��� zavail� )1�A�� ac�: "nd/or�!2Q� d1^ Y�H'�s�A6M5me7*Q r�5�6a�A�cM� ( be&, FFure ��j"�ao10ͳw�#i>� X9�M!�b�m"�7}�Nl pan.O,K�pq��8C�%�A���n�0a non->� )_���AWd !�A���,:h t�* T�;o �{6!^e�--]*s.:�&G c eo!o2�io0th� Z;�=in2�.5 ontrols a�9) $>�[31 [3/F��[ 2/>,"�6:e7+Yz�.,leck� Aits lig�efn-2�':�!y85��~�.)B?9i�.� genK"k5�>er(o y�ь�<"d I e"�={;a�&f��$=a�[3�/EZU�0 ( `�"l &�$��5D�am�u�s�Y5zZ7;=�@o�� Ձ.2v9hC–5E"��KZh:� �)5C-"5;$morpholino) ��%.�:��6A–6��KL8ed"�+Q|V�1e6*+5F�7G�.��B�'�� � 6�)M9s1$� u*3%�y&�&9 ��0^�<4 5Y jKyUies#���I����f5��u�:@how��byl.eclr#7!�.�byiJi>�M9A���.�(cytoplv c�dom�,� 9 ( Δ.1) [34]ar2�I�EN +OT�i2 i�;�ru�(full-length:�`<�/� ���:�MAU5H6�I!M n��?!�!��cj�!ƍVng�trunc�or2�.f.TZ�#/1��0.�-�� �"\%��* ��*�� erhapS61ng/ aVin�!ne�3v$~)h,� ��com: �“��”�-"�kin%HEj?or B"%7:g"9Itab!�rsec�&�2�)�.E[3�: ad$6�0"$iiD$i)A1�� .@UX6�F� ,"�"� ��I&at* �:��) "�"�i � �� � � �tra�I" ged-,)Z�A�)� {%5 N9ic= = �matB�$�!". A� �% V\ �j�,�� avoz � ��onA���9mI! wj�}5x.� � �]a�IZI� EA42B�a]K{c &�2�may�FUN al bJc�� w!�b�}iT/UNpaiv�/-43�ebk �!�a�. Few� ^A�ag�*h<�<*5(d%�� 6�*"�=�>c@. AdminX �R46to1hv!��?z�5h>�B�G�z qs�,%:(?:6,�<hog7!v�S�)Ge�s$t�F"&o6$# z2���"�c�H� . E4 tole%T�6con0)Q����25�250 mMq�2.�'�no ap�n/� ogic"i = abD Q!��1approf(t630%7 ta�1.�+A�:�2� &� ��M�.�-7�7 %�5����"�D�-���� � 26�,say�z0itua4"xB , 7}.PIt�un� ڽ� �in"� ���"��o. Nam!d�x �� r� ,�  �.�5Z M5v 5�)�8Efn l�F�+Ep �LeO(g�6V:T.�9Ua�<3�g7Z �se��M�.�Wpdo�/eOHS�� F"/�:&;�P�,���9�,�n�.�'^,im t!A�A on 5>b�<kp� ( FI�!Y-G. �^A��0�pr2�G�assoc�Hd��B��Nl*e�e"C$P%wof�ic���B derlv �>problem)D–�CI�BradCC�D evidEi�G�A"S<l�s�e,7�2c?[>�BJdidE�O�;�Eq=,��.<(xo#!Rsynap�$��(�B36]����?ed����F&� c�J*B��,,�(� E �d*| �� 1s6�&�%=2�Mpreo:�2�9y�!:�A� s!l*�!.hSot!a.`*broady�n�*��,�8i� f&�Nep �!�>w!�� �8a���� ��:5"�@ A�Opif1B$*yF�9!.�=�Z� 2""n � *� 2��64^�M�&=�>^���Cch!�� aMit>� �m�;:�I�a�"TJ!F��-��ApoR�Li�-�qJ%>�-�^9m 6)Q�an����X:�����A*� � -r\&� 6�� .7x"_sa�;S ,�ue�"�)�i.chievIVe1~,� wo�:�ݴ2�. UB�1a�E�)VE��<�P:B s ( RTK )�U A3 ,[A44[famil-v<���Xse f�&�0g,9�cas"K4her.B1 [3d%&gA�A�'G� �F��%uD#�#�._.r�BM�]�QJ&����0v�2: T"�A-CVF�Gs��!�m�'s.)6�Pocock�#Hobert�de�*b:��-I��2V&�^���M�B��2�VAB-1�1��+�Y%�U��3�@L"  !�k-�e�.v-4����&�e�g>�Qa�.c" "HY �J��`1.�i�$�-x�0#NS stru5ɯ1I/� +�XC�in�.G�.��&.���i� note�$�1+��"k�-hNFm �H��Qe�( sest*�hom9NI ,�ear��V!a edia�'d%�:. I6�Lia&�N1Ud.mwJ�A" 8!Aq 0cby PVQɛh A9nd HSN5&�X� &;5��!fb� Vby:�!��c: '*�&a�75 NN�, �SSR2AnF&�c�:e0�z"�.��jAc� ason�5 J�2V�Ege�]Ž�O�#!q@�8�R�7,amX cl-]*!�N� �C~R�5�&nswaJ� 4;�zreflectt*i�5��.�Oof��"�>�d�%����F% ��G�V��UQ. Ie��eP Q5Gt Z�9r *(�1of2L$ t� �"7$�:�!h . Sel.�X~8M�.�5 ��2!c!�s�Stly ipsi)!t�^iT3!�"�P�> PVQ-L ���he�meO�#H% !3R� bq<switch� back4� eft k^!TB� �"| %Se rR�he oppo!$Q-$'K.,"[3M-T&R 5e 1 �:n�ganiz� :G,#�bt�Vl;s� �a�&`xa�ir!�Be%�8KntUYc�"@"� )�:�~� ��..t6EWi'YfZI6ge�H fun:d��\(^U|[3�wf>i�6�;�5"#gl2 brid�B�U{.Y�is �# [45Ɏ�@"S o�2��܁D�U�Ma��a1X [4�#so��� XAU�*M)6Z�5inH�'U p�:t$u$/ Jeph�r@s[�a�W�"_q�� ^7��by4sLNJ�B!(��E�2��mammal� ephBEVC*�9 y" r �͐>A�e2@- corpu�e losuJE�� ex s�XE�q ��&�#� 5�I^growth� n*\3�%�seZp�4|a/erT an 8ZG/d�ct &�R,90% oxygen sL_Ey�Y)��D \l.m^�@on�2�Ih2U^�OX2;e� E� ~ xX Iuc =WA �"eJ"�2=-O"��2o&�5.AF�13notice宽��[.)w seem�*&l.%\� !&�f%�Y&0TA&�. S�fcsE�typ��;�sum*Z�'S ∼1-�� /"v]CcorollOto ba;/g}inF�= 3 .0��cur�E�u�?6��nk� 8 XP,ka�F�q6:i.���levAc�=�a� n ad�"A�>NRJ*)�>0��3*F� � f��2>� s ? 1fk��A�o�a Ca:0NL.m8���,�>A*08reJe�7�2r "�!-'�;�A(&�EE�%�re��R�e�b� 7!t"?�e!aQ2�J �o"�^o'�cs�gI�� .�t���%�)!�n)av2.�*3 �"�4��>� [1�a�ll�~2>s1qts"Jy$nal capsul!nsu�(r fasc�Y>unc�D6a H 2C �[4�)((a=�$�� �Pd��w;d�x� llig�� quot�, ( IQ#Kc?[4���p"]g\� n�V1 >E�IQ!H"�[Bf�fe�!��f[47. [4).�, � b&�! ��'K}�� �i1-�lspher�q!r262!4T[5A2� cave��66� ;Z�h&�a =r9n} X A>mmUm�(,�+"up!%T!isotropyQ"!�n wu���" K����!JMnuima@�څz<��coRial �m� �6"�!Q����O c��""tՎ. -!Vi�i issu�rfu�M ' p����" rJbY&� 9��G2���� -+� �P}�T � "^f�S. 2`��F� �85�W�OI!�t ��harcYVw817.CA>"�Xhomeo><2S$( yet"Ed 'y��E�5f�'io�)�.� ".A�e�qu�#o��]�hy*�K �(ej�#)���:�$us��E"�[�SW% w�9� 6"5&� 9�9^Ig�s6(N�a����\�dNFo. I!��ue�#�Qin�%feu�qVB~^�"EZ�h��3m%�A����e�;:�$�.mC��� �8� i�9h�'� � Ŵ�q E9:�:/dIn=%.z �x� !mlar�=%�5Oi�� Ϳ-4q.h��PF+ap ��M�&jGA5ឡ���� "��� <ib8ql d�C^p6�1BA��a &BNu� 5��)< F� "� "� $z���oGl�1�*�o,%P�5-�� >�"�T��4���Kse&`1S~71R�� �e �$w|fZy"� [4� �:��",�a�G*�V�-�� �"Z�Dr�orI�ch�i�^%�A��� AJ٫"� "2��e r,t !u-FAO +A�y_�!�)a"\pm< �t &�"mRo�k�m.,Uc:u�6g-novel�rapeua]�1ach�b All*�e�ra�� reA`h4@ s� vi��]���r�of��J] !dUne�� 4:tah IL� Ax C��nd Usewmittee� ACU�1 Wv�J5. fe}l law (m L WelfOA� nd PF~c Hv~$Services R P��*) �& he U� . De� !�Agr�tY!( USD�2^3O�� L��#y>� he NIF^9accred�R zA���a�As�1A 1U}m%@x1S$al ( AAALA!=�5�LQuDb/��tT[$�/ ard �P&�42r� d�28IU°CA E33E���Gn{ 6d�mO?s[5�A�s�3"W�Zv �@M�fix,& 4%e aA�aldehydA6PF!�in PBS�n ( O/N� t 4�,8_�briefO 2D�U 1% T�r-20�*_�  �sto!H,in 100% MeOH!!−20`�pM. H=.c)�i)F�Ji�� aper)zA7�Y�j zc69J^�= M413–47�I zc72 4*�4B' #&�G �I�jc�j zc73V%"�J zc74#*)'5FK5b(.N6!��4OBOrV-Y"IO"GCOyRTV5I9 , myl7:EGNKzc57 [OI�*{A�P��((�]�lE(*�I� e�ues�diM(a"�*[}k. Lin� �"�G#�ns" To f~��,m@�C&e��xy)xea�7 plexiglas�\g�� ed�|� olle��4)P�#n:4jus- nitr?W gas f�Gto�>esi,� set Yh ( Bi�Z$erix Ltd .�@W*�'� ali���+\&����"�!wo take"v>1,a+,aU s�r U @m(5 ( Co�F��p:\#AAy&D pre-�!ll �_��O�&^[kB�A f4 ��%�G E@fer!A�if�!zouŰB��. A])���Q!�aU�;V*)zlz2�� �: ;*M�T�~ "��E�returPmkep K-%:TM�M��n< aF�D]elp"e� !Xfix�=�^�(e� �^�( ��"� �&F� iy��}L"u��h��R�P]�my-g� t x� a0�35�r -�o�z�+X2WtX!�a�f�N z-stack%%a"� �]u�� �co 9set� �020× ob��v��Y r power 17M&� �.25FMoffa�2 PMT 40�Hsp�t(5 µs/pixeleJW�ImageJ!�c"� ab@e�j9H�(�10 sl� ( step s�:i8 µm�R�Q9� �Z�e$�#ta�Q����T(2×'25;|µm×30!�1�#0 9�al6f�X42�@�(�po�irA��Ns'  P��tNrvA�B^=RaF5u�PC�R.UY1F%�S�*&@ .ar5_I"��s "�'e���0�+k#X5�+3� s*� �X{0�!�!�_! &0�� �r"� &�)~�3~J�k24!��!2�iA�/#�O. IN���a!�e�ly*X2��,EAxa,��!: sYA�V�u 1∶�?�*bbi�Bly#YaG�ti&�E 2b6a�( Millip�g� l mono.C�h>2goaFt84a 70�4&D ��N�n�Z�bq50;pH 3 p� , Up�eQtechn1y� Cy-3 Rr)G�(, Alexa 488q.ke`ti- �&( Inv�! 5 555 P��41�24. DoueR� �q!O�Ef�M6*E�ermea4R�,��1�Qg/ml P��~GK�� PBST!Pe-2�10′� 4% ,"NBdw�S��1M ci�BAtd % Trit�am8ub�D:)G%�%%.��  wash�4B�/1% DMSO%in6cdo>�)�!�!OB� !�F"ole!�\Smlab�g%��U6�)z�rA,sen�frob.�[$by NotI di�]�}�� a HTI�mer9IHpCR4 Blunt-ZF IGFBP2�*b65�*E&�,a�e� built r�0Tol2 kit [54]�recombw�ren� A Gate~: wLd�6� q�J�1 ���l�vt �%rU Nva cmlc2C (ic� nomencl/m*e ^'2� %XN �c ^!��15�mnz o&ductu"�t%ds=��re�!enzyme-�� /X�-cA�o�Rt)nd a�coS! (e���y"� end- F(6e�2/ . Sp?�5z�_�~�  p5E-J�;� 810xUAS; pME-bas�A^(�dle en�^L$�?ed)!�G�2moO#�ZV�0N6+ r�{Zo stop r 7 9�2; p3E-pA 2A-eGFP[.I� eIgpDestA�pA�+i CG2/ R3otpA3��Is�<  kR���+�l����2&!3G#e��@%cSfdU$�F.�S)�`W� αβm 2s`AF4Q  H, EQ,A�mu@ng: }�an HIF���"�M S;QW3�"weQof 9�$0�==$"p]�osoAd� aÈ . Zebr f �a�-M"�]��GenBank5^ AY32695�fde�attB1F� 2R-AmW! �U��>!:!sp-p-^ r: bp 230&n5� �m�e /,icC�,�1F� u�ypX star�%dg^�!�Xd ) 5′-GGGGACAAGTTTGT $GCAGGCTACC AATGGATACG-3′; !�' ��587�606.\CAC\GAAAGGGK AGAGTGTCCo TTGC[@CR%�&� )A Tueb,�d-�c) !`]Ging� 4 kb frag� Sѷ�G4DONR221%�1W,T*cY)zm���,dGi� siE�557n�#�M'� �6-� �u�{}}Q� lap !( CCT�GCTunucleo�c 1677ni�fiŰl�E�"�^by2wR �!#. C��;�$���)i\D�%meby2��K!#s��cEi ( TG6Ld"�hG� age acqui-0�Ci�9�2���+lۃi@9 ��-m�`���f��-wxr�� 80% �erol/20%:  ,� k�p �sl�6w�a #0 Tw slip�Uc<"ha%$I�e�:rtae��� `!�PmK! scop�[C"-d1�9E��I�QqGmpo9 �Ad_ Photoshopz Illub�=�;!�.l iN��br�-fiel�� %wCor�6 �s4�Ri&“ExclP'Y:&r8nB�A���!e W%lay9<�sArV+{URat3CT0�M'6�E~�:�α-�L�&�*�)�n�!h!��Q�(��F���E���{V{*\�Z�dxum=;M� of 5<vV(UI�[One8^�&5D�FXp 1 nle3 ng/nl �74oj�[b' �fL��E� &Pt(>}) �col�e�to� 5 mLi��&�'� or ���!��g/mL >xsinFeXnA�uHat RT 2�gn� or>��anesthetBa�m�m�� -mel�ar�2!aie�����BveU�a*��I^ B�(�581V , sM6 640×48&� 1 . 79 s/$, UPLFLF>�F�,miy� 15 .�c)�F��m�-20Nv�c!'a�"�x, ��equ�dm�lem?A squg�� rea$� µm2� draw�th � �Pboundg4.&zx� rolf�oy p6,%?s21v1eyE�!�lpeY JTe�ro�39 taxi\.�u�3ErH1�AfM0"�9e�%9 �5~!s-"&�;|�+E|c :e���:Z man?Hdechor"5"P'�}�Mg2+ t�! , E3/PTU-mI��%�mi) �%x#p��n!5+&' ( ( 25 �U�a�.�qyl�aW"�q( Sigm�r&?p( Cay7�Cs/chA drug� dilu�in"ad�to � m�C .��10� 75<M�ora+�C�p!��V%����@��߂�o"a~–`~�a�9p~�9R.�)�!��%��:n%&݂ �Zs�p�%0occidioidomycsz( PCM )�nej��g�is֤$Bu� orig<�At-up6 le�$� �/A��_=!� alH=of�H+�&%*� �&mp!T.6 0focusY(n ���"�@,�Nograph�� t2��:�i6�lځ_ed�mi3y @���5�paA��nalR��2High ReuJ =E�Tom�( HRC���Fz�)�m+ra39(Male BALB/c �E/.anasa �o���E3×106 P2�es's Mɀ!�b �lnidiaE�y5�"or" >. ��C�FZ@O'um#ek�W-e*O�1i, 7�)�d�ty "� %6(�["ur3 Lung) <2K ل�>�{1M)�m�me�AF�>&�(U74?M�%i L�%�B���!�1(s: nodular-^x � luhZ=(pseudo-tumo��e5#u�.ly loHaar���hi6F�.N���tl1kNft)c"� 4t��ek�G t-ch9%nge ��.ѥ+�� Pb-iq e�a�-bronj7l� solio�@"WE�a2�4/:� up�%e�QK0"�@���h, (� 263±25�<−422±10 HU , �clAf���%8,�nd 12-8Aq� �rogsp volv�EaEmi��a�H6j!$��^a%�$YHaF "�@E�lo�!!��#Y8 granulomaw|"~�2Esr�,��+6vid@�%WctJ��"16-!�)��,N���*I�Q�mu��obi�ed�M.�isʥ fib�s% vic�}�M��!� 0RAf�n��i�tJacis�6de"�zaT�bon�4< li'usefu o�e��!AM��.QX�"dau��:cw se�^�QBaW��%gEec;�J�1s1 f��a-c&�Oa,!+�'0��md&* ef�cy!2m�݅Qr{�^a��oe�{+V�i�&. �jYwNlEXdisse��`�o�-�W`�jPy �Ymuc�>�Pr� ) kia5 adre�gl�!(˓culoend$4�I�)���<%Pru�'�/�<cou*i���ca!� %^unu�S[�V� i/H� byz��O d�di��+ungus�Pr�P9\&B>E�&Y=�RD0�.i�e[ �u��� infl?Ie �,pa�@ hyma�'.��q�!d�9�O&,��spi�-"&[�,:��/� &1 yn� in ma:* �)�r��&4  i2 a�|  .6 c [3]5�o ��y�B��~ at� � �[���0�#ti�:�a�s)��-9 0fd d*��� " proc�Ys [&2��,^;*:<r.�]�� �-� �2�$)!5CM�3N� &V$. Non-invae2� �� r9�ly '(5&�;�c���!a`M��� archd��[q�u�#d+0"aF�1�[lOn�0!g�3�% wortR ttG5%��?���3�"�t o obP��� ��v)ֱ�,8\*�+�&*+ J��,,ia��kbOKnim�`&a80FzL(-��cKV�A���-aQ m9��!� � M�bL�Hd/`"s]�,�v!~ao��. � %n�u=�(teW�rolOin����A ali=z��'t� -�n�a�13-cd�:ibuqq o���re���>bA.S�X4�ʥ]spaV->?���AacAh�Lmf&�So ��� n)��] M!_A�s� UF� _+cop,m�t&�-M�-CTMR0V�Rs�� J��*�P�H"�@!2a�)�dT��Y;I������8"�5%tV�Ueth�Z� ( LD�,& wM �F!)?&. repe:��j�.b�0Y0I ime ��FurA�m �'d �e�i�`�!���E�?A� skel]H�O�]Ff-'��œ<*s<�Ed&{7dE8U+���� app"cW emploh,���-hJJ�5+&� �L A6> �b1�[�� , [1`�[�L.J� f��%�<]ɮedŰ.& 5 es u� e]�( c�KE#L=ig�6S I\ A�� t >� ��PCMi����`݃W+/ƌ #feYq�VѰI��N�G� i6A��na�-q�^��ttQE�� ��,m��:s�itAe%[.�fWmy �$�manifa��<��Men[�{al%0�&,� ��,u� �zb�..q ��iv� ���A� "� #aZz�h:,�VO)%QŦp*�  �,"!�H�S� �Rn]� 2����X-n@!��-�i�W/U(e�Ѵ ,24A�%|zu�q��� PA��:I!shan��cc&9�V%�4no&P9&U7"? P!�� 12��$ocos��b,Corporación%u Invehcio�)BiolóJ�CIX" ethic@ ';.F^�E�� �l�Ta!%c Far�q Inc ���mL>�:I�"5;�zRe �, New Y(�, USA� �<eee�colonyG t@� expa��� , Med�I Cols KEk�D, 72Rols'%�xĽlygA;���Euu~. M��d� Z to 2��up- n� �&p���A#B� �h:2. AF2s�SWgi��S�5Am�I an TG&Cu�<Co�a $( Rockvillf&M/ (, ATCC-6085�S�1!Y�� %��*]e"ƅEeav%�A�_K�@�?�%roa� ab1n�&"�,e�!Y@$aQ pagu%)��t�D���1 �ь0�,-?�*�r�M ough)�t�2�;M:ul.L�E�%&a �%`�A���e� �l main; )�18 <�lts�� ��suc� !f@ � ֐ieduE c McV�f�Mor�/( SMV��um��!� ��bAI�Dn Erlenmeyer flaski�l3�d X!&&!u0�15�3�� �) :�t!� shak�6 at 150 rpN)M�G-2 gyD(>.�`(Brunswick S���A , Co�ew , N . J 6:<�� ,.�ci�=`c�=~� blWLEberb:a�=!r�membly �- AHss �fyi ))@0 IJUfmv�[�uI�kJs�I�p�N�> etriA��A �%J%��9stimu3�I�]�"H,�:ag.�&;�dLS� saM�[2�G�Ldg �D�1�#A285%:ine&�p�0L2J?; 0 suspe�KI�%�nA sA A\45|.1q7N�=( bead��e2�:zso��A tw��s155�� Hz5@� �)min�F9�( S Ko��l2�8BC}on UlV�#A�,��b�,� �32Ilurry9poue�*rerile sy%�vci�� �w� U��#�%��&�r<�#&[ �2!ifuX|o�-�S��v"�I{�B�' Lq "�(P[�� ate-��� brom�)'2`�B .3 �fve�o.te[& �>nZ�F�; Ƚ��" gtum%�=a�>s� atI�6 mV�3d:y��le5�.l��߁�b�mus*3T�;�"ayt}Ket'}�/chlor!L(�kE�vis &��> , Bek.$ , Germany�:0 mg/k �nd Xylaza�( B�)5��1)[2�W� dee�*e�sia%;"� ,1Q&(��1%D-�5x)IG���� &E .�+k���iv!��: (Mof6js_e-� Fift{x/PO |�d��&�m8]2q "�svt- �T  (%" ice/ŏa�.!)fe�k����!� .�~>�^���eA}�Od�Hlyp�Sle�+u3)( 8%�=��q�arr��zg�A��-��box ��"� �7R�; �B%-Al�H� ͗ �%23noT� e-fI�=��!E��"Ga/&X���9+�V�}p��!�E� � }CT gam5�dthoraxIQ��"�'1 Ca��CHe ��?�c�( CT-I� r Liսa?o G؟E�*�U , EUA�16V�)��iU140 kV)<165 mAs/� ( K�� l U9]#�in-se� ���mY625 mY,��ck>�sp�/1a�C�/Am�mtebV  apex�  I'diaph.2�0-)�0R!,xZ)��<bA�algorith��aL�oy!&��3��Uel�� view%�18 cm�)Nc!�a����:�/mŽx!.5I@512��e1�*�DU  �"�e|. AX#20221�� �he�M��A��&Aw$A>%�\ e�2� ir cJ�6_<9���it*3� u�. K-��dl!i* -+d�;�Uor�et% |E ad l'�u5�&U����h^��!� blinXV�Cwo&��R\y:�K!*�LHoa� al San Vi e de Pau��í!J"����B �USd�Ad�]ageR�>�V�f13 J�A�Y!��� au} al window!�� &��$%�=��s*��lYM200�w�,s�A�͔iRevGen_8p�)(���3-7Vg�FHouns�2�ʡ�HU%9B�K, �t �$of O ( RO���s�3E %�fA��-�!�3%5�l!Cs:�%�Gi�7 m�Eb�5a\�(r�G����q �� X&axi k�-��� A�־"u��%�<�;aWm�( }1e� ~EIhe w}�d-�s�.l�� r di���nd*�J.�>�18�2qR%�%!Y�."w( eA��]irc�%�o�bmm/�u9'� �)mmc*� �#�U<��'Ev> �_o^$�IMen�!iy�m(<���o*�ou��^ne�"� fB"�� infi� t-W8��6a!�dc�a� aō)a�ROIm en%���O!f�;�U&y�arAXLndU�.��a, ~�� YEu� eut��o Thiopa�l6�(��,doz GmbH . K� A�6ia;��l oG5�G i . �= ,* ��n) ���]�� �SU�H��.F+B�tٻ* cardFM�!�y���Hj� :W���x�buf^d ��m�!f"�P!��".-by��K8 h.��_i�;�� �%r"J�0��C�(�$eN embe0� araff!6nd corXS� �M�4m; �4�hJjF in-e`��--�Lp� iriu��{g��EIFG���>-"^%aiBT"�FYfosimU 0j. S�;���FIG)autN*� �canXScanS�9 ® C.A����i�tA=�!.�XW���~%-m*�-,+&���trp�^m �-�!Oo.�� panora�� e��a)�X,\Ecap� d)�dig@> caND4 ( Axiocam MRc� Carl Zeis� ���da|0aMX;reo�]!ea�temi Sv1)?ZD.�� ���ߍ1a free� J softw.(L( http://rsbweb . niagov/ij/�U1�A-*!��est� �!�co&� �x:n�:�e)�"�5A�"�K �6��.Te�]�5.�U�!�*�9�fu�A^L�� hh�-'p" !�Q�( ex;N<03 U�' �X��11�o�-���o�,e�Pra�P7.�Gc2 Pa�T)�"_ one-way��� ANOV��Val�b%ge"Fas!a n ±�� Qa!�!mea8p �%s��a�405 Q���dGt �a�ig�u;bE1zE6LM �0cb36�%A�/d)�NA �ڡ�n�'Qoutlier�c ĩ�[boxplo�.ph"�hE95e !:e�8t�E . Lu �+�Xy21l�>�1e 0�i���)a?"�d-� " E�t�!Q2�037�0. 8��[�� a�l�8� ,;9; 4±6cX&Q7± 8�M&vE,y%all�/"'�=��(� ng�+ se l�5Tr�m.m %ae�W�eAr; p≤�0�&"�2�1�2�p 4�� P>�2-���f�2�e��� �4�=� � H L�YP"c(aD"2s%�a&�2� lyIײ�2S=6ѕ�2�X�29*�2 6±8� age!#&��2%�1916303±178'E)]8N:269±43q45±1� q12:89�16ar� :/&/� �0�Iaa�ٍA\q�356±3�66±9�6�>EN!UM3�[ � s 8 a*�2��� ��t$�:[ ����ZN�܁E�� G , W��5�#u}B��=A�q��)Mv��*�:r�3DtL.�6�-�n\<[����m&� �(F� I-L�UL"n6�΅� t�faͩ���� &8��( >�6)�c�V�!,9����inwcy�II�&��AoA �5�u, savA�w)5��)�!�f08n��7EX occa"�Zrp��s� haFa�Bcta ��R $E'"�6by Hl:a � �&!%�M�A�r��y�. !$ a55  FY-rx6A��(ir- ��a��dE=y� ed z�%,A�* Q�Az)�%�'ovo���pr:� �- B.�$�6Bqow�No2+h�n�P��� � l�p�f� *\5x�%��p�s�z�#|��5�6���o-9cic�5 , vas5�JE�)6�&F I2y �d�>�A|nߖ�6!�&P`h+x)a�ke%FfE4�4com@e�Ila���h�6�(. Ple���e"�kin|,*eI:�42� inid)� +�F1 , olVbl�\�V��W�6�aUʁ.e-sha�4g�9R ��5�5��-�m��mn*d-"�e��$/ s ad�H2! ��4n��)�Q�>�1�B/A�Rff9d�:��A��@�0\ �"UB�W �to�Dic(tri&v6EU"��*��%�!!�5�)&y,>bE�iE9 [��%1����3y��Bu� 2-A!v8_ ���6-ZU�}<SE��R!vlB+C�=�k Bi;b_�| Dcl�)����I!$M e! J ��.=%c���t^�I .8�uH� ���. *L �k-an= ����s �]d� I&�>!l&p%E�e��:u\��}�3b�ZcIlymph�� inag$InTsurpris!1tq�jy9ة(� �19*�p=�� �4y�*�:5!nerE \)�u4,n riF*w�g� Aa�@x��C��aHddev�7"� carinI)zڶ��/n�70)�:���� bitu�&�o�ff���x\ BA� �ie�!�*�H�VL��a\�.G6�Axcvet�kO&o2� %:*��LU�; �� or��*� %�c@ dI�"1p*G_8��a�= �Yu~��"�? behav, �I6��I�ŏ�&{b:�H�p�Ŕ"� 2 *�!�l�oi�6�i������1"��Q�*\�s�f�m!s ro:8�5A6�}z�S� !l�>or��s:2 !�ens�[h,�-i��` ���E �le��(�9��$or��uB" ": .�^| E�Va�!#�em ]� B� F&�(�; �1��b ��6A���AM"�>�u.�eA��.aAby &\@�-& >��3P�)-�� hysG$�Kr 6">,!�o��S:hc3A�[��0&A!��.�*�A%�:�$6� d"��� 6�He:�a-�!� �Q�4?dho�rec�2�:*�L.\!�G��f"��Vm��U)�` i .�t2 �ap0o �ns�*a)�@_ �x; �p�0�� m� *S"�  . O U�dY, �%� �0$m�` �d%Vj�"+'{ ��E~ Cɕsa�D ;toe@�O�!1 �ia�9ł)2upX p&�& ea�isz3|��e�t!�ow!�ss*"* �yN-*u)�!�'�o��O!c�`,5 a������@!�L�M�%/"&Cdy���nOc�r�tuptXXA�(carbon diox�3ex�P�!��~J� �B ��!B�� e( 5p��g>it�e�:�I �� environzB[�e)�fav|I2��wB�.��;c�onлke Mycob�Zrq+�4 rcul�[��kin 2&�UJvDa�t�wtev�!garaJ�X����!�e.+Fa�i/Ic���b�!.��2RAY!fC��a9��&�J-��o�*+R2cuc�2L"� �K)d HR�8Y�NCR�@ 6�ZM &�A��Ci�*���@(0Rh���cf k�png( &�91Ve�JbbR� in animal models with an approach that reflecting the way human pulmonary diseases are studied .�DIn areas endemic for visceral leishmaniasis ( VL ) , a large number of infected individuals mount a protective cellular immune response and remain asymptomatic carriers . We propose an interferon-gamma release assay ( IFN-γRA ) as a novel marker for latent L . donovani infection . We!xif!,�ia commercial kit ( QuantiFERON ) evaluating five different leishmania-specific antigens; H2B , H2B-PSA2 ,  Lepp1 4crude soluble p8gen ( CSA ) andf'SL'from L .�EHA,0aim to detect$cell-media%�m6� in VJWe�ed7�assay on venous blood samples of active>Tpatients ( n = 13 AWcured^#5# non-Q�8healthy control2Q1-$4N,9 ) . ThQ;based�!?@had a sensitivity�,80% ( 95% CI �<54 . 81–92 . 9�%�-� :10F;7;12–100�HOur findings sugges!�(at a whole-)` SLA- �.�)�can be u�$to measure%���!�donovanim�ion-%po% e ia rem�$to stimula.EeJ�inY$Ywas)�adictoryTA�convenWal1!�aE proliferaEcm&-1z� of periph��)C(mononuclear%s !�0needs furtherA,earch . Visc>�siAzVLArlso know��0 kala-azar is�of subQCly ed ��[2]%;(promastigot��<infantum�� cult��ŋ!9 buff��atmaM�atA�.pi���rs [3A���yE�1r"��c0usIoutnum�x of9*I�,)ՁDos varyP betwa%4!b1!,]+[4)10I�ASI�[5�A.�inb!Kersons w�so far n%�ta�#� e�A� ,� their rolAjU` transmiss��dynamics�'4poorly underst�,� curr� drug� too toxic�justify nusmo� wise�V�� vidu� . For1A{.5initi��it will��cri%� thoughu docu�!�trends!rmQt6�)Gi!Ain2next feweV�ZTypMO , serolog methods!N0Direct Agglutq�T�n( DAT��8nd k39 ELISA ory� n sk{��ng ( LS1have bA5�{��� , bu��%�e���� valu�� B 5ha�ffirmly�U,ablished . S� �is gen���� ssum� "� mor�@cAi� lengtha8timž which1Y y re�xs&IiwheA7 this  suW�" �"�X!pf.q(!� seems lik�� oImagnit? ofE titersF i)@��(certainty .%��m� r@cF � �B�a� manyM� afte�aCa .�. More�� ,A�ո,� �0to become negiKdurAva+,anergic phas�v acute�)� to return p� o��?J�A � is�to� [6��HF��t� -Z@well standardized%+A e#co variabil!JaN*d !Ya - �8on& to an�� �in study , kP ev��loseK#  potency� a�yQJV�� � VLY�� in�A[9�Hav%�!���hedIQ48 hrsn't make�_ a very prU � �E�field�� . N�gthe= ,M�%e� >� hol, mise; T)} on!�aAdsi�outE�of.�vM !�o� ��� FN-�V le� by5ed FA� fine�� sess;b� vitro&� _, � wR0( !$g ..V -TB G!)��develop�Jѿlat�GXMycobacterium tuberculo/ �b. T�� � s �A�  6 \ ed��j`q; pept M�BE#g nt[10e 1  similar ��l&� f ( �g migh� s����aA�4!. A r�{ih4in Turkey expl�{A)�J&�F�y�2Af�againsX"� [12a|We=�a novel-�RA�e.�en� E�ed it�AB�/ "� ] � )�conducIat� Daras Hindu Univers�^$, Varanasi~�K"�Med�Re�4Centre ( KAMRC�0Muzaffarpur ,��A�5y�}vA b$Institutio�Eth{ CommitteŐBaZ� . Wr&n�or� consa> ob�ed�)subject� FourZ9group :McuS lyAdruited: Ak .�:�; 2 ) Sk��ŋVL!��Ct sixFths��!endA�$successful� a� f5 ) ; �H>�li��b hePreg�g�(no prior hi��&R f�;E4 ) N*CvCoCh�tnoS A�\to Bihar.X!FIinclu} � eria!� ���"� �is-�� � pres5pA�it1 �aspirate!�� I$microscopy� �re��d&�  A-aV6icOɒ n|a�perA� �b161c:(supernatant6�Ke�T =in�until�?!P�� ����us�bicino cid ( BC���.�4U�as}.elsewh�. [14� Briefly 2A_9���V��rJrtoM]�MrUBs�as��thrice��Uw!Ht!�.sto{$mM TRIS-HC>10EDTA ( pH8 . R1 . 6 PMSFM50 µgaSleu��i �'neW%��-+ e�� w���s!�`4–5m>15 se�>sa�10 Hz�ay� 27000× g53N�A�� remo  (lipid layer��surfa�.�,;m�T!!�)�ultra:�10�4p6E.]>�M�atv�!;M�e�A�A�I�A.HA%.�^��v a�7�A"Z �� !��.2:  ,,h���d vacu�o dra�m� 2�!. B�!�y�!녟�w  ��"z(� 2�(�)�� . Tw� Z al*� %���.~ ( X��/!c>�m!2Q�+�!5&�l Iqang�" thorou�mix,-V�incubeupr�ein 37�� or%20EXwitEid��CO� � 6� U�i�atA0 U�1e?���plasm�j� 9�P2�2Ł!� analy� l��p"|!�aE�Q�a�*� -"� ��manufac&r'�struc��R�[1] 4 poin� p~vyk�!mo�&&\htŵ� Unit�A� ( IU/ml )�ema etermd � � Q!ducA?�3i� n.&YD.� &�".[�ex�#�U��)bn&Sd"1A4%���sub��D back9nd �s9��heh#s�#eᅁ�)"�%Y calc�rAVi!fpre� !1��l(�)�software���v. ( AQ�S1v��51*�L�.e $s follows:�i-n6 in ei������� >0 . 2E%L;\cutoffE06cROCy<^Pdat!�d� �?n cut-J�)� �.� ( 83%�;� �.(��� U 8Mann-Whitney U-���E�a�s!�s�u�� twoKM)1RA)�sat6@� �\&%)� SPSS9�(�sA$18� �q6 � side� signaif p v&'�did�I �improv�'z�)*�%�1� Turgay e1&� a)Q.&6�&�AWp Mw��\+R&� s caby�y"�,�2�x Xs1in6#is}A� �av)L_!�ht�.�ez1�$* u'Ia�r"&�*U3 �apa�� ower2\of�)T�"�#��be du�2��:�-�8��a{\�7� IY'/6$e%�ish�7 Gd 3 77"Z *Y�n 9a <%$�t��! �!GdeN��K��'EEc�otypeq�t1��E@a 4�)w�ur��fuź�., [16."I d6valid� s-qui9��5rd�@2A.�� ssay��� R�1��ne�&ari!"e:./3E�a d�nct�-b&: .Q�fqh-a�suB� 2�!�a�*= &# 2F upo:��& l� &�'5<p$immune-supk!��'P>5F+8�M:)do�-*j nor�m��y I��� chalatS�Ba�{ [1�.18A9[1.25,���"��D��i���&y %?� A�\"� !�( t�E�4i~d γ! �*aO �rf  h (���% ef5!��-=&)�bo%!�-�v lex U�F7�)F;��� �k1%dr�J��11ʅ�Si�Y'0�+� m !+x vo��� obvi#ne<.purifo5Jf�poS/expla�8 �"��= of PA���)?>�3aQ;��� �1w"[=Ein]"a����of��J �eru/?� v�;U�/>accVor ve�' �!�:monito�of ongo%�.�6�n +ar�Asuch a�6la uld�4� ��accep55e obus<� er-friend�e pro�-��ex],�)" simp�7A���Wat i )6E!��#�6l9�(&w � al.9�u�, i\M�S |$M�*s#!U 7�qU�t�!s�Z[.C��&:�3�q!V a o�Wtep 8Ay6"F*&. S'i�0"ti�=�" x!pop"k�y�4%��riE42��% is q .1�ti�uct!5a =�,�==D %��C�H4/�qin fu� epiA�F(�/Wif0eTity�co�,�f[-A֙o"�1����a��a=8A�� J�Asheb�1�v+�>.~�� #. F )m�h$�u'2 sour�!�"+%�6sJ.�/�s!�be�~C9J�$.&�Gastr�A!# "�.� e,ic yersiniae�<�4�;is!4% �O�J.p| EtA�n��? autoɈ ��To�!�9!�x c�--4a2-4cop�# host-urrous w$ they�/nsmig/th� �i&alAv thel~4�colonize\l�< gut-assoc��d lymY+� issue�HowY�63 a foot6�fq#� -*��>�<. H� ,�A��� CNFY�by|l �.D=I-A��5)�C�CB��A&: ��. MH)Ds?t5/r>"K4+le�b4 .u~6&�, s evol��+teg!�toa%ic�GC> vadeF� , en��ng�1 >��5ADi[?=- refe�5An�nichesSDS� @���9s$"+;�D:�&Em�D,��9U�a]!{���d�B�[d �AV�%2 dec�D ���bAg�;aZ� 6 �E�&�4�BAlso g�� , ShigellGd salmonaLH��J� �59.��B�2�#edoEnEm Ye�h pseudoo "�:!�YD��ocoli"!��axin'J5!{�Cself-lA�B.di�~ @��,� rrhe) me\8e��de�?���ed��4"�@yMa���tA�R �8rythema nodosumDE�$��exist��at:�M� silena��^._ ucos �!�� oid ͩ�?� )��u%RA�%�al], !Tu<le�)laN�u:�reE� e ar�,' ,@Wh�7ow)�o�?B� �>�a'Lis un�' . Mo<mO!� spla�6L"�7�toQX� vealz!���g"% ��Aleu)1�>xim��olond �0 Peyer’s�%��51�ԅ&spread "� �iaB�A<�o l�;e;�I[7� �.R7=ly� mB mM)'%�-]�iaJ���� �8ND~Nth! \��� �on1-xa� %%iz� M�cec-L�.�ofqva�1!{f�A a f�@� m/�–25w[ �s)M.� o� benef�9�ervoi�sse���/�xtra-}r,4 Elev�+cytok����serum"��/ ci�c$o3*�C=��'��I3c� 3 ote/��j��. Pm(4 .�Emecha4s��Z�cA`>)[rfK�, oz�2 .= e-�i��{�+ge�dY��@�Fv�F"C ����� anaerobicwt\Lmot( e 2-fold downPA�N�c� ag ��= rm!��_)2virul�I |% lueN%@ dhes�5Ai8d YadAsA�t�Inecroti4� �d�id-encoda]III�1re%1t ( T3S�9!P�&[Y:� I�!Vrly(/ezN:%i�� �FXB��6b�����by�2k%x' �is 9hA-2�� �ic��,C}%:!Xn�Av�$�� 4small Rho GTPa� b�amvExnd�Is�e0"�in��` eA��by��B� damAa[VT1 8Ii��!)�&a we�� demo�/k;�+��a�of �"� shif�e balaA�of�Z-trigg�+B�� 1�� eu%of Y .�,�!�Aջ"� .�,.PYG . An:LZ�/!��� a cnfY mue�C�!ea�MrF�mjt����fK-=�E�)�al�.��V6�-&�0a�H work%�^ Hb"�Aa5�al)�I�de�! &� Y ��Z5 wild�;�in YP�D�.M��Ec���� doa/0( 2x109 CFU )&,islic Δ.�survi��9��[to�)Wa, yet"RA���|O"0 � gut Y�C�di&^YEq�ix}k-�]e�A[BM2M!G .N� YIl�i� ��of ��BBnIAh}� ���k�]'! ��a�or�B��� .�9�.>i"�BAၐMbr �e�e�P��u1��4!�a�, BALB/c)Etor� �"�4a�# 9A�� 6M�� V�U�Q6���!>[[f�2� or 6 weeky 6�Ud-- d:�,�R�b�!day 5a 26;+ 1U;�(�6+M"2F���N�y6&�.eBe�u��d� a�n a� ge wrofN&-��)tw5(! �5��+ 1B �I�w trasA\� *e-K�6�qe�$2�*� cR="�' OA2yT�;!or� 5UEtU� Q��i ���Le�5,loaHH"T1 �o!Gll��!%QBksto �#��d rapi��2Mx�2��E�� ]GekJB�um�* ly.�W)Ged)�a�? dpi1U .1D%�� ��e�^�!U�m6�2E�'Ml� �(B�M1�i�Yca 42.�E�6\x6Ia�de< �32�a�cY��lZ7i+�IPen%�[�%ri�<�{B�iy�'aiV�"� !�v�U fM�CV% �Q�^f�A�-?_. 5 �Ac2�:t1j�M1ordho1{m-than 104�F/g� �FJx�P 6%�%E" wU^w $!=u �>vwAltog�T se�.�0�tjimpai�TM^l*� !��sr �!�by^M g e�Qi�� � f>A���[ wzM������  #aa}J$is)�ef{�"=!�*R��add�ӡ�h)�+:�.`�6���&i. �mT . "�N@2*a v -FaqF4 M-4� ):�( 3�c�HS1�2E�D�!�!��)�A;af����NtirD�AVp�I'I"Ticlesm_�J. H4N� YexO~� q;y�Mm"� N^�4Ax~villi=*V*o"�aVhyperXbJac degre�ped<�O,�X!ss� infi�A�w �cy�e1&2�n�!n�b-�!K mainoha�er�V�if%���> olymorphoN.le"l( PMNSmZl%l5���2� NumerK,�G�1 ���])ed \�ɉyZb of5��nI� �q Al�@�[>l Ţ:�!Gt ��=�m�%�-~��)�id]�ͬF�mC. A`�r0er�xal2� Cep!n4�G( ulcu�3� sL]�0��df "#!� odel �vnWE�"@)2=.R��#�9�.+(A&n e�!e:@A�:�m�6 05GBn2 �COa� mild�=��&14q1, �� I���� so�Qgranulm�).�E?m?%62:26QinI ��DBR� -�i�� N ���-dJ6Z� �'!` capa�2e�!���s avo��P�\!!�des"x"�d .^�isTm�-����u�%���*�a�4w�4m.}�3"�"9SM^���G)o�jIGi,��burde&�:.A%"�O-�-D!z )�2 ,"�H&b.�wcr�$EC.�B�� �yaa�0 ��i���Fig 2�2:�=E�and/o�;s08!7���e8e�*�bD uA= �JB�' X �0W�W�mRuby2-tng&r�=� +$ , YP147 (�6)�4� d �Sg�in&~�c�~j� ( S2%[Xto� �&ir6PI�vpak9%2�!>^�MkI�ՂM �K���2I�. D�g%�iy`�1:j��.#H!A��@�`�,o�3n(ler!�Ai383~0�Gllmulti�,j erse� r�:��nw>Ua! fewa: aggra`", 3E!3G����r&�oth={7�No 26�er��wA�� size�JN5i� 3I )! 52f"%� �(ik!y� WHe��� !PT9�y1* �& 5jJ/--aI]QT�Dmpa" �5−1d/! �moc*�"e���!le 匡Vupac�hB�%�-�-HB , 3D)�!T �"P2��d,�%Zp&$ly vi{g+ as��ys!�!Yg��rfMjelOund�"�"�!6�iD$1��spaG&.+m� ��N3Hs S�^N1U~! %A�2$ "��amt2XbeY�=G]L�ɡ� ndep�0n3 !��*6-*7 m~!u*t�  � c���)sE̡��L ���o2[!�r!cuprY[&�*��5��a�;�& y�Ks� �l{r&�K� also�q^)��,<a,. glob�*"�+5�"i flora [16ER5we00 h&dB��Ka���]p&�0�~doPY �\m>f�9ho�6G-���� �H���LCK16S rRNA( �:elr:ٽ^�.�_u��� .j� AXab�d�h�mo��32�%���my-Cur6&d�jgb! aK ance�8We�per - !@��Hfta� Xof\fA�( ADONI� ?7�id�[A��E�� "e�v�sA�r0SQG�Ua@to r�f��^}J. a I��4A=G�z4EA��t!Fg�Jt\QSR��( R2 =5EkK"�as ��i!�\��&�T9� . No�<# �5ab��!k{6hyl>3c�Q0�lly! prY!169%�F�#tbU ')* –4�,5$es richnes�Wm:yK( α d?'sEP"BYJ Chao�mdex )"�>� �$�)=j.`�B� &a_w G"�V1A��.'l�#�Lg!y:WeX6�] . Lo�hCR1�t�"�*�Q &8A._-_�oqn]e04au^3�X�Q�x mE etai�)G��1�!�* t2M>q ( S3A%S3F%�)"�!as��"t o=E���o@2&�1.M "�� �]�.%�W9:y�24�*ay 21.2��42.�c�< ��2aI zBQ alj*y�Qt6�E�Q4noUU N]���Vca��it�"Cn=Q�:?m,e�9�1&o_A�2��Z�� ���"Q�V]h_Z�ia�o^0fovibri�feA���<�!�5s� as B� oida5�LU;bp2l�3nnJ"9ti-y�2*�`)�]iw19�=�n OtdEx�KtHIS<%4i�!�lfate-<��y1�fam�?: ceae)�A��w%�S��g!�EEH$lye`\ b��"�6��[20�,., oN_PIU*�1��f�5�e�!oVerruco]�,' UL T2� !�)��< ��p T$#�Sill"c"��"�1G�� b�j�Fot lin� { lu��P�!�" �:7Ba(:q!cor%7e�)e�N��na�:�"�nib� Q qf-+�RB`�B.Z0E4a�2�Klb� �4R�(pe �OaS�7"�Q6�e;e�!bR?��Y'\&#�,-9GB�1,����s�!~I�lc%i�M>��emplo#� nd&yNRNA-seqS!a��s� ��+*[-�w�%�35Y�b!�>6j��).A:Z�S4A�a �u�u�D�8igh qua�q� poo��� ���u��!MRm}S4B jQ� �e`i� 2� ׵( S4C I��depf\r mW2+ �^� ag.i5iv�A�9s� A sWMf��r}�?m�*4 9to ju�8Ada@{ac�k��%��ld�{6UC�!�?mixe�� �: c�ylibrar&0B(� �e Supple�al"�$!�S�]�Il���~ deep.h~gv��6$18–40��l�-�:�G �~a= 1246map�q%m10qa (hT� �5I� �m8�%�inp�)�9da�ic�� f�Br<�#�ranI-18 log2A�tJe7X1<���ha�� WS5I�Nrs99Eted-���}A�M&Kvy �%���%owa?�F�+�%v�XpQK ( S6m,�kfE�uAl2��CQTataM2B)A�reliably�kPAC�� &=Rg � !��k �o9Rfi ��*& dbi!�!& @AzREof!��q� ���)�H &�r91�At�."=$75J HierHB�A -� A�-r��pr �\.e�?-��{%8exe�+a=!�� "X/�s6�)!n���^��Je��# 4Adeca� cAqA!�.<��1,&G !U 41�ce2�YBogis*�b�yr<2Tb;i7 si�fJ1`�-� %?��,#EZ3aUi�a+:@���Ri �|G��2�A@mezen0�9H�7�5e!�#1�=�"=�4age DESeq2 [21a O�^>108�g-�d �9F�����at\piP8�2042YeCm` m�t (�FC ≥SX�Y!�mnd 77FC�#NC� -�XDtU(in.^m"( S7A��,� c S2 Datase�T* U& 4I� ion-� 6v�D�2�3we!��,(ed Gene Ont[%; KEGG= en��a9�w�� li$qf.�D.��?i�ed��S2��"B6 ts5le�l)2��A "�in*@a16����rr~:�H"^U ;'& ;\ ^� IP3295Y �o[2�wM��e�B��q��A{~Q�%�aJ Cmr�,�"� ) � *1re �pi-(�2-� 2a&J���B�5Cf�m�160�ms& 7cXdU6��� [pG*c�7�_chemo�:A77*7A IL-1α/β�wL-Cxcl1rxcl�3 5 9 1�[C (clf]^cK�E&T{,Csf3r , Trem crca�% � >,�%oxide�P ng , �ti7c 9�rg�82�rgx Nlrp�FpNfi�5�f+�A�imp1 ��arui4AUf��04&Bof���� ar�$neutrophil�� aB1dag��i�![2;S25��Inx  a 0ME(j �� .�",�f)noh�U a/�7!��E�d�b d6�Y matr?yet�6rSein9{&9o : Mm%� Mmp8yvmpEw Timp!�Saa!�Clec4� w.ChiE�F/ Plet+c[2A�27]��v�mp 7�q8(e:A0me P450/Cyp1bqAAE ) [2�2�.�!� !�scaveng!Yi�!qzhapto� i!�lipocA�A�al0�S S100A8/�ye��Jng� �ޭ[!�մ�T� Z�&� . Ih<��M>LQ)�defens&�5�" �Q<���> ��� 2ZO5 YG���KM%!�A��f��Y.�Ptx��$�kʼn,2�A�6N'Q�o *A�m�archi!Aamodif�B enzy� ("_Adamts �8Lox , Wisp2/CCN�|Pappa�Retnl"������� �i~� aiHBre�2�@�B�z!� I �barrier2� [3x34]m�m2� .I����\^��–S36� �� ."  mrwS*�6�Åa&^6��6!7��]�eSJ�WA�rn"L� a�543!�12128)aUG �� ��!�� Z�� �a-inr�لFdaD��[�5*]5�us e�.$F��#�SxdapB� .& �@�"f�a( ifnA�A�� $1�)( IfitA� Ifi4a� Ifii , t1b�� Igtp�\�� '� tumoX�)~7�ctoKltnfa:� Q d ��>�AO&�_Dup9�HA�~indole�,e �3-dioxoVv( Ido��. Pn1Ucheck�n�,I`e�cC#�a���ryptop by!��o�kynur y�r~�v1�*�faDe ���-ve�or"7i�F%��E o�7�3z!�!u�$6cN[3�B� &I ��a�@Z��s�W�Q -escap�o"�,H"\�E�oe��4.��W.;T�0 att]%�, *� � c>ayu}�*nd��:=;( Ly6�SaaBSa�� CD27E���%U�ligands:| 6l xcl|�[3�37F� u\iI�C!3GTP b�ng)��A@�$e6utonomv0%_( Iigg 4Gbp2/2b/3/4/7/�eua�,gga2 ( GM495A� 3 m484 [38].' q.�9�X�-�cg/ oGic)}�P( iHL �"sa[ Duox%ZPla2g�1Reg3bG)[39q#0])��lL3"��yٻj�:2� V��)lleAEt�Ea.* �ro�GIl>BA@Boe*�2�v��� 1$M�Ay,"o Tnip!� Abin�` A NFKB�~ TLR4N�C[4A�42]B- V summt��;pE$�Ѵ�8] �6cerEu ) ���6��W�<� )w�A�)�erevP!Lae-��>!j��icy+����i�Qm! c"Dn 2mit^{ �oasDJ.� \|`FC|*E�MF�� g% "�� P46gr 1�6l1i�B10p�o�2bI-��U6AA67��XA%$a� JN_$J��s&4c AL6;�j� � own-�� ( Hp��JA�αn3��W/e� r �a�,!��S���)A}�̍�#j�"F�JIt"�*� �Cl@s.�<z:at<'�E�uwbx 4�it-I!c�:=�-���6��{S66� �.a�-.���%Eo�y��;,����%��ma e��%( Mcpt��!� ,Qe�i� �, Aebp��A��������rg| 15*�NBS560Ss K NmTM�enviro��E��I,7>NO��\�������9N��� p"�y7,\iorx "r�`([2BPA ���""gc�a� 2>!?sp>h"�:�t!��Yi SlpE^��t s ne4T/ [43�$Z&�&_%�in Slfn. !,� �& Aalt�?�&Z�3atY�`�`s�d!�b �edQ�".�h!��!�Y�:F��orJ���zeO �2*�!�chÊ8��Ltfj� cn2;aOple\ C7;Hrec"?815Lb��Mmp�!:EO.�*`)i�`�qYfin�ڹ�* �&; R%In* "-��7͟oS�@I<" M 1y "M?��l� S%�.�9��!"�) vq�EY�?Ca.!Y�����gO�/&4 �06Yz�H��`7k� "�K.�9d"�Ys���s6W�erVa��#heed�%�siYf�R4nA?�cy�S1( �A�"�}*�'u�0�=A7x Li� :�N�/^(�,T'�' �� *g�nd��2�+� �5��*�h9�,#�n]��>"( ����b$U�kZ� 67%|&9f�5�E��*� �&f�%{ leio�c9��8+ "sHndAB�y%Q�-��+Z�2�� ������LR'� ,���'�9�D amW&#+:y>� ��SZ *_ IL-3�E�a�%9#�MdI�disrup��!Nsligh�%W� ��1D]OJ.� ,s2[ q5�"��u)�l��eY�siX*[44��!� ��ipV� 0bog#V�:d�E:.� �yt�TNK � CD8+�"�"�+b@va�45��.�[*zyh ;.�A�fF��� MR�A�6x� 4�I��d�ubA[� &� ��b=�3*�. +6���"M,!�� �e� ��:� ��<:�ndic�&n�� 42p70/IL-23 sub?6 40E�y� d��1�"9G'$; N�Q%}iti�{α�0 p:Fl�pmVd�'re�T�7d�d * ���Uoks�u#.{� Treg} *�.�QPory�� [4T��2.� �qE��T &oё>�u*JQ[� Fe2+/Zn2+E�<M�[4T�<�76�V)B�,*��P, !H26�st����8� wi_!%QAT2�=�!"@ $�al2t Z+&*�:�.r&�7E8#Ib�"� c�m&M[�1d*�1��K�w B�Rp �)un�.�c��mpactAC�5�6V�,:.�]il�A`" 9m+a�oc�I��E��2�A�� �'ch�R7*F'���� �$��vi�b4v.�TF1*� Z� u�goa"4E*�f-5!r ��85q=��"a  <"^{UI�h FVl �&]>nG0�"7 �g�&VA(" ˍD����!��. by� �48>[ �-a2�@j�6m�< �B�T`./�104&�@��2V��s&�,&e��*� � "�,�LQ� CDN(unique^#YAy2� de����� !<m�2d"vg3^Q�共^l6P5r"0Z&� ��� Ż)�g0=��?iE�%2�"�3�"bolh_ hysi"C&�Ei�Ui&�Wd �b$6��[A��_Kc[_O��)$by qRT-PCRa�-7A���")/8A�j. � �X�M a%r.�M�!F=9(2Ino�� *�� GB��lW,d2�= ��cp�d( �4�ix�+�MI ��,��D�) ��aA�-� Yy�ɍ6z�]��t�'w 4_��,6@#"Q{<c<C arcAj&�aQ�sm� hdeB $cid.��a)�6� m�t1^�."��8�MY��\.��do��v�1�B�e*-�grxbvtro%�&�%���B�[2���6�t?i~~ p� u� est��|�[&�'&�IC+t0 �u�i(���U-c��,I w� pr���\���'1>y�:�dl'al� �y��( csrAcr5rov�1e\ol�(]c on/ia�� ��"Ud9+.AoiX���&E��E�.�"a/m�.ER`U�%��,MC" ,�cmsl�(BYsc"G#�ed"�!s�bE�KopH D� YpkA �6�J�,mgR��K姑���:29K�5��� se�� ��y�umZEB�M?U o��r�b�Z�Rc%D�. �Rn�!�]he�"!� /yopaf45ak!_of5�!�Ja�$ ���� 6�� *�h-� �* g [4p|u ��J��<Ւ6� yopJ.��`ecoupl�,| � �Vow!��m:�2��dy�b-�e%+2� �MzY-��uQ !!b��eagX,.tF�%"8 DAm��� �"� r.) �E_mi�4s�B.�1�5�*CR.�vj��| >\��.G""5=�* . S� al�8JoVͺ%L.5y�nw�+� CM��'2�J�Cas"C@~Oa�#e �� ��ot.>�+�!&�nV�n�n8ba(T�<�=%(��] ��Y6W w?dE�i�>�|A(�~1.�J��ndEq�/2t moleI�p�#��U%Z�Dl�#oIl is�e� *)�~alQhHP�����heI��e,!6z �g!:-oNgdoV(’ mu�(5.av�}FM=:z.xwe���8a<=b1�� ekdouble-=v(d sword . O!+�3e hA%,K��%F��H:��33 � M�s�&)M;I1q�a+(�}��̥� �%>"�)*�r� �rA4�$���`h�xy�UAI�)Q!���1G6GŨ�$ �\x&�%P"L&21 , m�m�AI�b� dysb$�O�ng�23 dea��r>��y�ͧ|� �s�q!���6"Y � ] F�����f�Eiix�� �q2�2��/ s AJ�TGF-βe�i�w�:� TH17�!6X!.| �of "� yX��))�Q�r� M��0�o6�01��Y�!T &�_!.�Y f:lplֺ�]U��!�b'٥cA[�/tri�~2C.-e)m�znt"N�&�Pd [49��1S+l1*��JJ By qg譡�� >t��{et �/�%>$!l,�U�1f7K>� >�wP:6���>�^![��|:Das�/�,&�>&A="��r�1�, N�+A�GBP�6���Z OzeY7-�O��z�ol��M's�LPS\�� [5:Cyt� s�l~e pyrop�o�.caspase�&�7�fp ���A[5�5��2��uE�b"],��E�%l6�*� � :���� 6�bџd.� ofEe.A`B�q�v\���A�l�"���$�sym�HicA�r�HɲUh �|"gH' �oWJ?3�h���T� �M�E�./I1+E�fac@�ee55*%1 cata�JIl�e�5)�M�0*s_vBatq�1 >�G��H������7gJe�de�Friz/attacks��e� �\$1�v�(�qT o2 . Tr"2�ea%6� �de!mb�#3 *���w(� @#trFP^�Ӽo�N揩�%�,? �Oi2K�U*'4Chlamydia pneu�a�+a�U'�S� Q�[5�!5hAuoem3�ng� cepta]��!H"�2u�A � L invau �L ��A^A�!�J=$> V*' �/� [�:�A5� � & �a� -�Vvb��{��O�fo out��SA��N� a%���eu�of*�M��!o"G�J�s��el�HuU5~��%�i�<� g9 L*#�$-G*on"�!�6Q[h"� q`&�fo����s� E[ @ home�2R��phe|Hnon na�'/"Os��ng'�XlE��� ��1"h� <NT ��A��J�Y]A�~)�%a� ?M�LFvI�12��<.O#[�bE� � �-�3u�u�(!7�c ��F� 7.*-A�S<}Z ) !�,"4b�Q% l"�n.g y [5�,S7��,2 by DePaolB��Qlleag ���aZ���ele�w"4�l !�Fg "b�"c'"}p"T"s �'Ce0tc itic�n2 �r&E�e�uWthiosR�tenJh�t� T2m7u{`)ap%a�!���ro�&�or�^;δ-:2�V�uT�4�CLY�[�&U���� I��Ui2Oń&K "Rf��he@um3 at6l -�:�D�ooGL�-Q.��$I�2GE�!sJexpan�A���%�of*�� *("�!�"\.��Z!�f�yknsferM:~7Fut�"1o�& :/2qt� lgut.�  �� F�[5K76#�6��0�X�]� ]�K |x� aRAɐ�s"�DN� r�&P���66t eS$inaX�� �2af n>u( �n-1�:�w5"^=�� ;"\ !�s �;2-� ng� c2. 7 &�)&�u� An>2�3o��@:�i�e�(*5������. vit1.B�,U�j��[6�� &Ma�� %-:�'#MSN��/nou�lo�� VxUV� ��]�/$�/VN!xiF�� ��&���e�ly2gA%2Na.�lQm"kN� &Oad��;�I9�*M.$ .� e�U�� pre-*� BQ�rsm &�X A*a�>�e.�+$���b�My��6q�Y8&�� 5�(�t� m`itۊ-��Tij �m2-�nM<k S!!��kat ba]�>��k"=*&A�e.�a}�].O�!Ip���(�]�r-&ap�.6�!��GA�A�x+.:�Thu��I�te5�oU�>�~m *�t5YWTB�G �f6�2B*�"5 ?eN(ir!����Agam �[�A%��Mof%,�vnomyosin&v�%`�(.�&(7"% [6�66��Cw$]p ,Bw � Ms"~r.b� :W���kecxW(�"Br*MT>�Y�"c�*s3>"C �AJJ�L�7��D "� MAPK%G NFkBe�tO[6�76�/!e"�ATZ31βQx[6m���Pc(f]lH�!�r�aD>[ q help�� �!Y��*. .4 w%M���:�aU�>��Y�1Yop6�!M��!1�?8�"e s&�C,E����a��:V�n��urb� ��e�"�!?H Q�= proAj)6k >A7m�\�^-�I�%� a� [67–6�Aa9��pBi���t&K�*b`B) d1vK{.^argd- �&,8���[6eyc�;�-65|"OX �#�1%nA�: bA�W�._���{�a�a���net� ��$DZ=*�?Pe�pla �6��JE)"�3���uV.�J%!�àyA�d΋ޱ� K=VW . Nonet"�6�j*+ .�2s�r�&D �!�:�A�"�Vm3 �SL���Ps, Helic�, pylori [70]�[!Vfp%t"��2= 2�!oM�r*H<&hMby"71T���\��"�Z6 =Vsſb #���aZ�FnfYn [7 .���wul�a�s�� X�f"R$� 7*� UQJ5�s�fo�A8inu�.���1�A�7.��&s����.%����$�"*�ys! CNF-7�E .} iA?�<�O4)in WtJ36P]8% uros�c��9}[7z7zz�G-1� r&; A�� �%\� � �\-�d&8��B �a��d&� 2T�by"O��LPS*�!)5β��� &al5V�E� fg"� �I��i�emia [74��K:|oW�E[&=j�lu"�I9"a�KBma� a��� �W��pabrI u�e��Ic/]ew�_�s���<*%0CNFM,"L*�#l� Yop/�CA("T{fop��!��"yq ��le�?�W[p�`e��ti>�.B�  ;G� �oiZ�"����� ^R� �i�+p <�. T��t B,�)�)!��y a tq'��bB=��1*]~B.�"/e 02��O�� )L�}�\ �/IJXW ce��� W&Gdis�1!A��)Ar~:�sI�a,M��6p>�< oxinAMa�2i3�e14�7 EM�h q^�1��9in��agVM�!�v~ J5�!�;m�����A�c"��j��T�i���"�cu�e�igYg��v �&luI 0e� 35�*�s .��Ms�� ):I�` �[ S3�[. Ove��6�z��(.ro���'CnS3\�,Uj�U1'25��or 0ˬ(B ( Luria-B��nA�br�O. �c� �3)YH�4!Hja?l��:B�b��i:/� μg/mA;!B(kanamycin 5��d mani⣁4&t�cpdi�;,/O [w �) ���)u�AK�� ��q��sch�!��ly [7E7�P��'��#�a*�b��e mobi�{b�u�!e) smid pWH9��T�}e�heg�wE�mRuby2 =3I���q7B�� ve LtetO-"#I :: O� �� g!� kұi4locus YPK_3294%j 5A��H!�360696*V60783� NCBI�1#I h >gi/170022262/ref/NC_01046�1/:FId.[4��&qh two - moso�� frag� s up�A�0 �d)`��@I+ ampl��b&��!gen�CA�fi|Ūpˉr xWs VI392/): 3� Subs.�h bS,��%DAa XhoI�NotI clng ��fu%l �asF�i �2�!2�=�%1�K� &A�d'E�AJE���M^ SacI �ofY�AKH0�a"�7��u� �%�&�2B�e���e��%"F54_S3tSi�a�1}�IieBh �21�hJntribA�e"~S%�EVu FS43%;B~.�AI545/VI55}�!7m�!� ,��NidO?$M . Erhard>�synthe�3�"T����z[7*yN?N�557�4T��9�gu�?m`.�u0 �Ki!�pW!��veru� "!��s III98(N � a~qs a��6I235Z fluores� �%�p��Xpa�edf�A��Nj �[inserA�"z1aArR��t4 ( LysRɤ��,'��>N�or�.���5 ( a��acyl-,Jid�di��Kpep%Z �oa�R� r�f�6Y?�<�-*�y�es)���th���`Y !�!yo�med�*t�as2�>S@o] es [2A7" Red-.�Z�  YP339 (��:~5h340$y,J-��"��!��6��͢a��`J�14�'conju��UAZ�ɠ��-!� ��][7�80&�&�K���w�3� taneou7 l�T���ged��.8"#sachRbCz ( !�m>ia�2:� , fas�(�A�ca*� -seO�e"� )�� D�� %kros� �A�|#rr`.mi�-�B�9�er��<aQM�� �^� VI50� V�# ,8R<G )GF >�����s�P�|�Eyce$"o�� e�����&c ǣt� � ord%�a�%�Ger��R��men��M�Societyh L&/�A�1 S��*>GV-SOLA�}!5AEu an HO�:aU� Fede����fdA�6d I:M%2�%%2�B�'m�“Nicsächsis �4Landesamt für�v4braucherschutz�  Lebe٭ttelsiheit”::�' @9-42502-04-13/116:OB��Sh�ф/!�p �,-j�a��R%���f�!Twa�V.^�� accl~p$!~�~aw*�o0�Θl r7<&�~#O"y&���mD6�3��. 7P-sfemaleFә purc7�� om Janv��( S�H �hev�e~, F|d Toz�*�*�Z]��f� of 5��0M=m,>q�%�EKx%Vly 106E8��fg٥Y�!�B�f aV�agM�e>.�+ia�!�!��F��nO C�IMߥth hw�B.�iS h,� �-7�I-}��.14V�s*y�_"K twn��ekCY�b4( 1x106��l���! ��a�q�+�*!Ubo�3��."" �wr!�!>&"� f��, e�s� Q�*���3aty��p��Ae�-c@2 �)in BHIa��2a�1irgasa��  i�!6�L�H, ��eusp�LO2�%hyx�jZ�>�I orgax���acol�Sby��sh��) �w10 ml �s5� 1 x �� X� Nj,/A�r�000"��10 Au: Poly+PT 2100=s[ Kinetc(SwitzerlA6�S@(�Q�:f �I"5.tsU�l dil��5�-����d��LB �=th�5F� �$�qm!_�O�5cfu ) V�X���Nnk $�g)�/!z.R. 8 �di0 � �ۚ��6�&��M�zPlC&�0 .F�!]Cove��A5"EU shak�.���x�,� .i n��t� �86{7�D�d*AM"?W a���� :� A�.o�!!ne��gQ6m p�A;)ž&�B�O2E ,"�x. � �?eqA'��!��J ��!�y ;��1i��J&�J�B{2u;wd�X. ]��]:*!�� �" ��e%izR�i� =d&� F3A!8XES2G-:��C"b�*j&u RCausui��� IHvo�aU����2���%6� ��6� 8Fhanne[� u�i�ׁ= DAPI�,)�)�Gx*��o�!bb&�ˇ. D�l viewa9re cropp8� !$a� sE�"8.� � !� i, 3h�C�N@ �U �D�0ing criteria:�X 0: no microcolonies in lymphoid tissue section ( diameter < 20 μm ) , 1: smaller-size mQy645042: largz3 > 104�. For hematoxylin and eosin ( H & E ) staining , ceca of mice positively tested for Yersinia were excised at the indicated time points , fixed in 4% formalin for 24 to 48 h and embedd +,paraffin . 3%s)Ts zs�ed with � �@each group 3 to 5!�e 54blindly analyz>light-%��@scopy by a histopathologist ( see S1 Fig ) . To localize bacteria%b _ thl I0zaEpatternA<&infecteU@, ���@fluorescently-labeled Y . pseudotuberculosis YPIII ( mRuby2 ) or ΔcnfY 8were sacrificed!(CO2 asphyxi �at day 3H 42A!t �io!�DThe cecum was isolE and cryo5�of�En|preparMb�!r-�Has described [81] . q ryo-[OexamiU!`(Axiovert II`cmy!�4e ( Zeiss ) usa8`cam HR digital CCD camera2�0@software ZEN 2012$ . ObM�imageM�4further procesaM dAdobe Photoshop CS4 ( vers!m11 . 0; &�A�5`��LEGEND�bead-ba!��0s “T helper9�panel”p “C�P 2\( BioLegend , www . biol . com%���4this purpose ,9yvflush�1 x PBSWeig!$snap-froze��4liquid nitroge}�!�ontentM�pi� in s�l dilu�'s��54EkZH load��protein �a,!���add�A�o 2 ml ice-cold NP-40 buffer ( 150 mM NaCl , 8Tris-HCl ( pH 8aZ �% >(, 1 mM PMSF�fhom!i�HXd , 000 rpm , Polytron PT 2� ) on�%W�� debrisEEpelle�by e� ifuge� ( 4°C� a���n )Mdiscar�. P-):��5uM�a�$Pierce BCA5dirki�� ThermoFis��$Scientificyccord�'oJdmanufacturer’s recommend�sm�} iaC$performed �WinstrucAs��aiMy��J�3 floweg� D( LSRFortessa , BDaUs�ce��follow�he �requiremE� :Usetup �acquisi� . Data�6��=0A�0S�OV7E�.��com�;��bie�mp� on��� when'��switch�.� cutea� p�msa�o Hge 16S rDNA sequenc!%6��� ���ityfe!g� 2�10x70 mg %I�irectly�Ada�,m individual �  \7��,E%.�ina�4l BHI medium .5 l�!�B����on LB s)�$0 . 5 μg/�zrgasan�I�!Kj�q rema� �ate�� ̭�at -20� �!�-~2mu%~!�extrae� comb' methodxmechani��disrupE*(ed-beat!��z0phenol/chloroa���pur�'e� [82� F�E)�2 suspen���  so�)��/ o5� l� �A���20�ԡ�� EDTA N��2�6� U20% SD��j �:�8:isoamyl alcoho�/24:24:1-=AD1 mm zirconia/sili^ �. S. -��Ltwi� � a%vBe� SpecYuc!���r��!Fr ent�Ged ( 3 ,��զ�Z�I4he supernatantE.transfer� (into one vo%��Y���a2>�precipit %)d�3 M soe�ace#��5e�I�1)(isopropanolm7W�umN�A[in�3��>H,B; �70% ethl, dri�y$a Speedvac�re2Q�TEQ�ND�a RNase A (-� , RT5Ɓa�i�eq�spiaRlumnsIIBas��' :qadjustk 5 ng/aF. Amply���V4 rega�(( F515/R806 �QRNA gen1� in tripa6�  Q5� poly� sP barco�Bprimers��\!294previously [83��Td�:pooX, qua�5EPicoGre� .1�f��xlibrarSJ%�KAPA L$y Q gy KITE�]ed�j@an Illumina MiSeq�y�m ( PE25� . Filter�,ofA)� qual� read�-3��bin�iE:5�-sIIME vq -9RL�clA�)(97% ID OTUs DUCLUST� ] d8taxonomic classY< x�RDP C er exe�d��080% bootstrap�- fide�$cut off [8� 85!�S��� out match!0refer9dataseta�Dly novo � �. Phyl etic rel��$ships betwA)%� �q�FASTTREE(�,PyNAST alignh [86���OTU ab�e abunda� tabli mapp�ouu�tatist���seI� visA�ar he R� 5programm_enviro �Lpackage PHYLOSEQ [87�o�ess�express��Isel� b�r� �s�vqRT-PCR��NAA�$ in v| culj sE�iiJU ,^z A�grownAL25H or 37 !8 16 hp.�i�|A&�.r914�0g;�u;��f:��2��umes �& ( 5%/v ) w-satu�p� ��v����Ƀ%�!thaa���6Of�. Sub��� ,E)Z:� lysozyme-��( �K �incub��%�0�4at room temper!e-�M6A�h x�wY SV To�RNA-IEDA�� Promega ):B�2�I!�!Eelu�'< a�{� �!�100–���� -fre�� !uu�qQ�e��"��M� mur�,.�e� f �ei�Z� Ho:Qe*F at 5%<pi . I�!ddo��1�F8( 106−108 CFU� t 3��6Ed�g%���B�!�c~)�%of.or`ed)�removerextensifN>�ap� V4. �N�v���A�Z�#s6� abov��q% severof�I�ƅAf��f !�Ex.al%�Controls sort�U( ERCC )�k�_�broxes 1���U�e��6. dyna� ra!?,C er$��limitEaccurac�did$al � .� measureAgJIYa��Bvalid� q�2��q�zn�Y!�B�adva�� Single-TL nduIAKA�he fin�d�( short�d��&EU+H�2�s x��ed� 5">; , 78^ Allzhave bh ass or suffi� ��q�po�!�A!�on-j�FastQC� ( ( http://woin atic!�babrahaE(ac . uk/pro� s/fastqc/"��� �� shoj ner in^�<, nor nucleotide�z�y biaP iadu9b�� :�%zrefor�e]v� "j�� %��A�ome (�@mbly: GRCm38/mm1026splA_juni/�8er TopHat2 [89]I �y typ��ondM�.b� anno�d�e� >]!� htseq-cou��� [90]-�e� Mion.Ens��eZ7@D?dE� Ts ser a put��(DESeq2 [21]�0pairwis�t�8A��ofv8� \� metr�we# (ta�oredisd% Cookt5f"2.eVo� bD��n�H�Inh�, RPKM (%sa� ki�se max .��n pt length% millasE)W�7 valu1��(= a��#Q+�!�raw)�-�E� l�#of11��d2fly��UK( DEG���) an "} log2�^d�\ cut-nof� A9t +5%�a �&� tesIcor�ed p-% I most� 0A� List8.cJ�e�Q"M��pathway� �%A�9M KEGG��b!�[9"^#assoc$(of Gene Ontc y ( GO ) `"TG metabolics�asa-%�1�z�5�5l%0%�A arisa�of�Ma_*�!��!Щp1 f��m�AMR"�GO2 s [9� 9 e appl ��E�$al hypergeXric%�%�ov5�en~�GO-)inI��R� on%T(( molecular�� i!u��(� cell+!on� 69�%�-��4�4Qr]�w 00A�M )�EW�� �b�if� only |a7FC|> =}("�#%<Qy)�< = �5 h�!i�GO���"VE*!�Bio!�@uctor Mus musculu!@�O!��,' reas26Fg�,r��e� q%lus� ('s REST API�� sultOri2J.� s�giv}# S2 T��!"d�a�:� a �.� fold-��aQpon$�D@ � Spike-In_ B � iC ��"H it&Tge6/M�%jr��to�6�� ���С1s�wA�r�QLalongMn��y c���h*. Fw'9qn[&� �- =@-re-@ploh�&� 2� by%�.� � y-[9o M� U�Guide:� s://to� .P rmof�#�%/� ent/sfs/k0als/cms_08634a�pdf� wQ��h0s��ja�1>�=by2?��ll픁�e�?�tuda3$ ͸�;$��eFA��\�ڱ�Kp�"',NCBI�p$śE&oOmnibu�GE��"� ach)A�$GSE98802 ."a�."��(X *�N�4by 3-step cycla���SensiS D SYBR No-ROX One-S1n Biol��2�a��"&�� !����ofK�A�r�se-�7+�cjat 45����� �*e*� !Hos"�1Lm�yE e Rotor-%�Qa�l-time �!?�QIAGEN%A-\-!\q�( den�%:�ec�)�-#nea3 : 52–62�,�sec; EM : 7 1�30% , <�|REF�melt-�*�GiAt58–99q)!� moni��pr� t"c%�`��D&� ���^"�A[!C-%N Q See�"�,2�}�b"q]ʩiz sopB%� if-3�-�e㡕�h-6E�u�0t4.]��-E�2�s cal�a�2�[9�P�� 9 i�S3��i:eh�0g  �"�s: �( pYV003�#, wrbO!YPK_2363�hdeB (114�, 9/(615(csr< 3372rov187� , crp O 0248' yscF�8 : yopJ  _009 'opE 002 u yopH94 MopD5 pk��0 �frd�381 �rfaM937Narc(6�!, nap138 (E&-&82d Graph Pad!� sm 6�gE�UCc 6�i� A�E��b+wozh4Mann-Whitney U%�s"2 . C�" � t�5s'mthan 2Wa�U��ѡ�D ANOVAa�o" �+1 2 3�. t-A�mY�! ��Z*(scenarioa�!rep�*"7 L�(uIl>/Cfa�2 �O:�!TSpearma� r� � (� rviv�-�*!=�T�*���$Mantel-Cox7-rank � .#���su�fu��lon�U�Q�re�4�j in hplak.,� �! s nea�oP c��in� defen#t ? . Wmo�$at) at a�!elZic��g�,W0in Magna!�he oryzaU gu�.Q unter-xaga� � basafsi��� DES1 h!]*2 by scree�#��� ��ect��mu�'f a T-��inser!;)+� ABi*��:al!N!7g�encod� +ne-rich���/-has unknX!bior2�p�u !� its 9log��sD2 c� ]$6ila ,ous Ascomyceh. T�m� de��1 had�7ap�{nt ef$developV!orp%L!�'1 nclu�.vegJ(!X("th��o�e � yip�sor�� nd�#-p,�� pene�AՁ� X 8M�-�ben4/8!gDa�$E� wildAA� ;displaQnoecFn4 w�hintegI�Δdes1@A�� sens 8��exA|!�ox�!"st�%��� va7!�}�l!�f�en"A�1�per`a�G lacc ���ely dec�| �.:��*� � akag}ob�� 6FV!)r�on��a3#cepti�%r�$ivar , ell�o�w{"6eexhibiA�s32g%��fs�� mpanA by b�$granu� in�mar�  }#m���ofu �1oxy�3 e� ROS���a�\ 4 auto2�7ap(ala5!�PR1au�in�ghbor� �5M6Y�a sign��M�"i!�hyphalACA�oa�wh��cadaU�2/ . No9'y-sui�Gof%�� reat�/)�8diphenyleneiodo� ( DPI%9a(5%�orONADPHi)A�,!�ul!��-f�!��>3�ALͻ1MchE<n�#Z]"��I6}�3v�)ts� .m��in�-%x���>8�suggest��t��&uasnd�Gr�J!E��NofGgal�uA}� romitROS�d�1F. P�n)��i!1��sY,$robes du their:R sz9�|ex�o�rb1�424�a;av}�0or race ) canAulm;a+�[� �� typ�9��1sm"�attackA�J�:�/�-&) organism!t�!�4/�G6Y� s [2] , [� a�WF�is <E$G-��%"O*�#AMP )�)ggI�!�A1 ( PTa�.iaAit�bp"@ surf!qre!�orX e( ecog�1�feu)gj39 such�b"e,flagellin [4%5chitosa�/!Hde�0y= dA܁�A1(;6]�] d N- +4ooligosacchari� (Obackb�# frag��Sfue>�[7Z. Aa�i�, coev�3,�s1�sInG ed v� u�*E �.� !�.: Y them!�an� or-tr1�su�Ri % ( ETɏ��"oysR-��ng�SsMm Manye&. *] ''i&n�deliveryu�| well stud�in�m-nega 1� [� How0�< a fewR�"� �ʁ��ic%�iZ�ia:I2�a� secr�$���still"� [:��#u�F�q�Q %�.�f 2�}�Ee�b�)i�0 �surveill��;�fi ��%���y�A�M��'s�.SAv{�i!�2 eleA�d !Qma�9Ka-啡�d dA� PTI:!�Ql=mv��0a�sam� ��`)�} R bothF����% they� play= e z" � ɀi!�I!;�� [9��[10] .�c�Q"j �E�All��th!`� ed�M�*:- �  (AA�.i�.37�P F�jE s [1��yTcer�)Xgea�v�E!��83a �Q�!�4M< �rti� K$F�!�/ore����� c�="&���[1ix1�O*)5!j�!earlies�$Ig% %�iae rapi5=�� �Esit��)�� [14A  act�� �&1 ����k�ME�%,!Ysynthe��2� nd-� �8p�0�3�<und�at��u5�X�20 �DF�>:AgrobS um tumefa�+s&�e790 ( ATMT ) !�qe]'Ev!(0 P9�\e(<�v��+,���diI�� ] [2"�90A>1-��q�aM e�{RMs6&d!�*![.z� exC�� 9]M! oph=L�.em�&  X d le� dGre�(Yt ,air . UpCont�ngI� leav� na�A firmu?P&L�tip muci'%�gZe uhhyd�c�6*�:aDue:1P4��c��,E�e��E"dome-sha� pre-.����/,1s9 e�f� �7)31v e!| JC forcEdm e ou� ��z�9 [27��J1=�%, �/ bulbs$biotrophicm&/� IH )�b.necro��I�m2 [2 3 I��is� h^ staga�n�vv& A%oAVrLGu � 81"&=!�N#,qK yAXsid���wrZ �]J ���-A�e&xM�EP& /�,���AHre����IM�Mu�雁cu|o-!)[3� To�!��eo&� � Q .I��relpon�U�`i��!Bfia�virule�/( AVR )E��t�' �&� ( .�e^�. Two k"���M�,�-Pita� !4ACE1 [3� wh�Lpu+ve!�Q �;,ll�CtS=�#ke�0\ ~ Gp�O ��ro� E#9)���in.a. S�& on MgAPT2�) � e�P-R A� ,�c "#&�&&K=;�&!@du�aO2�" eWA�th%HR in2a�[3' Mig1 SSD1�Q�� �l*%I6A|a�sR�!\� mS C �d�� !�4�EbYJa�al=��� l&�3,3zhu`�detai�aN> 6�!_sT � ��arN� coulnv~ Eh=��ir ^&5!%=–�i���RWe.T}OՓ� �0X &r�|Tge-�� t�-NA�o�&\2a-p-a/�!#is6� �>� ion:��e los�� -i!us �4failur E)2UA'E�e?�+ �QOB7 j�2$ �"&�a�I� �� �otol &8 �� �-` )=�;�=5tI . +m4s6��r& �$a����/ofN . A :�!1�(EZ0144AF&S6��QI��*�U��|N�"� i=/t�� �3�! �"t�6Q "�le�  \(Nakdongbyeo-�! num��I�mcl_Da�,! u�in 70-15tHig�MA�6�48m?��in.�afZ"s:qA� �l ��a�)AVI7p:c �CCY. SouAfn hybrid(6�&]?�a � ��&A8Х��25�2�a��%B �= b�ofan17 kb�,BglII-diga'��'6b� a@!x'E�cop f �-xlG b i� L�lo��A�+ea> �%ex �O9���9 Y?��� !h� asymW:6terla� y dMch�Tr� AWAIL�I) [36�;)pbor��M,� d"C!rv� � [3e�PCRg�r�]W( R�F^uG� de�ct%:4B-AE�RB-6I�!7lefSLBS4'�;�%�.*IL�%b��PLA�sMQ%ig-12 ���lM�i���8�NZ pBHt2 vec\O��is�+ac�RB . B?tandeɮ�r�#pea�)�j3��by �R� n w�&L0RB-, *�"� F�7�eK A�a s*.? aKL1 z/g�7}�A�configu 1)'!�Y�pG_+r`byEIJ�2��2�a�e0&/ Q,A�e�9 to f�y�� �sU�-)}nd1� y)��S2A� . Ju]beMNaMFM6($ ��Zai�RBqQI*n��H� a� ��RBa�d-�{ 1-bp<6�3��ɩ��z:_"�9�, 6 bp!�eicYM�l[er<6�. D& Jin�th�\of.R, i0fui7Q�fm�)3gA_(��aQa)  an �2� B�-TM�Bb^IFR��y Rw } k0nO �ɧ�!�a@;�/J66.�A2.^m�/�(%�&10� �pf͏a�ng  r� s:� 6�4091-5-?R��q�ed5j.�!ns�vy segr]#�YF1!1gen�%g ��&Of 102.+U7�×70-6 6 , 49X�&�H,hygromycin B� yg8�(<536=.� ( Hyg�$ . Chi-squ�)Y�S iOLh� d 1∶1�� D( Χ2 = 0 . 09�� e 5%&����C�A�=85 %2�1D>� �z� �� � �"nA�w-H.�gU� sf* Twil� W�9D�6�� 4163TFE^ RB3 6� �R.����i�9� ,S�E[)no ((�a� Wn��NyY�!�ly linkI�a �U�p�e=0'2%c9 # .�Zg.�2�uN,�%�" t[0dI�K�� �ab����+�1a�R1gMGG0416#;i� Y�52Wpnea� ORF �)x( 750��up40a"  star�;don*$��+E*T!�!V��W*�8"[02�6� �to 60%����QA��(*, E-�&/it hm-�7��a�2Fm��o�-a $!��h:Z;�.� %3�GtS�@B+!;mjQ[g�r�4na% m6.( GenB�5&'=�$: XP_36168�~s, d.�@6����! . Be< yI !�!�P-'3′-"6of�14M� beyoDUcE0Œa �� = �_kb��i�4��.�i�JQ!"���:a��"�6� v ��@6J�&��tQ�]( �C15�@�,b � >4�a6�hNBZ�e)�E!�lz�O n chromos�IV�!"� �*� &� prediM �Q�864a�l�,Q6�uT74287 amino acid�A���3n�  3�X��; !�DJ7 �;~9�O7eC�L0?]�&cb"�m�?2� �IE spa?[M�)l wv %��.<=E-Zj?a6V�BL/Z"�� ind �"Z7� ��*�,��'hyp� t�"��*{7�i� Sl . Ad G��%y}L �3U�%in 59x)eE�"j h�"�4&Du O� 8.�k% Matrix /��d,�C�#-z&}\7r�!m"�M,cfgp . snu .�Mkr [380/I' #na;:6�c %ui4ubphylum Peziz�otina!jy%ot� A��" NE��%�/� �nLHM3�-�Of�j-Uvea~avto>�4J� �inom#Ń��gje+� ( v1�OA . Exk3+5�C Afu2g0541&�D!- !�AsrKil�Ifum�&�0(IPR002048 (VBium-b�ng EF-h�)�#�A<%�U1D sidN$��C-t� �=�b.-M P� ���Q n<���6<:d"��B��E�A��nonQ reto|Vo4"rciQ�J�68%K!2]fs8b6�=s:� � "dQ�BP��e25%��$�of�!�`b _(o2WK� &#I�<�jPb��=��nAgen�#A�iC/eX.��b< A R"m>��AMtru�by dou�joint�[41�%in��*Zrc*{ HP�%c�Htt �qX∼1-kb-�� fla�.^ ���4&�%N�iX to Lop�+�3PEG&q)�Vf  (.�&r�<�s"�@of�-BFK0G�A��6>�m;ES1KOS�oA�an%.�ye$HPH �./��( ;)DRp�O-F�noE4��"Ycby^��S4��;!� null���!�2 � �*P ,�� b� m&yy-mKz6iA� simi}P� i N=* �I��k � �C�ze�v&�=�WXe�.��R�6z5Bt�*aNd�( tA!w �9�CEm>�N��8ctF2&�?%��N6�FgS4-"F�"de�7'inmR�= &: .za/J n CM;1�l&ko�dQ* obic�*s;H*�A`�+*+��I�<ray-i%A� F�!&6u tiny�� rg���n"�n9�!(N��Ju-s�:le�0sp�P����"�&�#�BI}au( G�V��� a~!\2�.�VQD��4 .3"�V�B���-�� <'QDe"��+n exciA�leaf she�9r [42]�Hl!X!vI��-~ grewE\�-px,10�f 6.26C�gJoD by 96 h a�_.�.*�9 �-pM�s��}��|+H+e&n:a&a�ukt�uV<�L^[ark_wn�1E6T2�uN��O*4a�=2'28dQto2)�:G6�&�)a�&^ ei�p"G%,%�Ib�*���PIH�sc��g�798"�.�H2Oxk��A��jls�/�i��O�R >#obenzRlYDAB )^X. R�M< �'��A� � }�u��X&) B�]0�R}Z)��~6_*�� ���� %8:RRegardb ͮ�Ù�6�8�&t)���VA(�q�holy �!z, arrowh�uLAB 8���a�# F�s.6pro�"��� �A�.�Q�ka�%%BD�%02�%�lo�iA�E u�q� )�! 2>3"L 2V�6B�~)st�e| � �)�1.��s2!G a6.o�*!)% �%�c%"JbyR(. A MAP-kinj7�pmka� Rw4e� ��N [4�J��-�")Ia��k. N<.* �A�i�zB�3R1a%� PBZ1!��'eA��- .�M�Qm��O/a�u"��DD��deHS to 72 hpi[s�?"�$by�!�������Qd�{S[46�a�m_E��63�� �Rm�$�ig:�$ ( >25 µM�~�SP: �!�>)l�3[4�?we��)�`�5MlJtS"�J'*�!Y� rIW�X��E]s�L2?�GF�.uZ�X!�:H�$' ��y�q5<.��0 6P"E � C6ŲR7x��use�-���]A�]O!�i�UZ !d. T6�U!�2%�.9#�4(�f!XQ"� #�-2��>c !G� ��&C -'B� ���=* L-6 f:��� Uy}&MDly&� �B� !Q�� d�Un� �JRI�!R�/�/,xA�V�|%\� 6iH�F)]]ld���:s� ��ba�|N�"��On�UepzBm! �O8N!��J��N ∼7_*e�t )ori�#}y5�CE�C:w)�|slyY4VY2��!eE�H�RNpw[OQ��deg�5`4XS�b�!��6�&/�R�2�6�K�ůa�sF�6Tn�Y�� PI (eAI�)9YS[!�$of>3byV�up��28%El21�`"A r���3/��� �i�RE�.���$��:5*72�S.dh�q.��� u{>f8I�2�Ntoe:2��%<�*� `�ݥ��2z6�9&x +�+&�?i�.�,6]�"��! J� �(!�Q�m8�!YMU)� !�co>��XA � ."78:�kq�}i-�!e Q#"@1� l%d�LvM.�BMQsAPm}���Z� ��V�L�QE]�e�b�Q�S g!%�AP "�$ "Y!J&��!�w=�_o�H*fB�N>CE�X��H&�.a�ixZ.� �L*�,� *�d2 2�r4�Vmod�_eY�V!^E{dgXse&es��n�U�� � s �cuB!�! ���'�A-�!��.��N!3 �?p.?"�,-D�� F ��osmolyqsC an{M sorbit/�r�]5 M��R&&�U�>~"l6�was&�"� �AuT�6WQ�6� !- �ofm%��?ed�� 3��^����$clasJ*�"!�-�`?ES-�ae�Za�yO��N.�1 ��sRX2���636$F��um��A���� "' .�Mm2p$ �F�1T,�e"[d!7�NSd} 24 1be��jc[.�du ,pa��;�A���_9����smMI7T8:�P�Oo�L�\�s Nikk�- in ZA&�]^0`�� or�1o&!ng!�� A"� of6Ublock�&+6a!n`e�7�'YTs1-ingH�(�*�::E�sNy��6kj�A�&p �iB@�82,��0 "2�*\$~�e}8q�S7i�WeI5���f e�fAI���Aa2+gra��f�,�f-.�`yc�DJN�reRQC�qlor�.i)����X"R aYlcou�:�i�:� �l�an Calc�e4tFCFW-|Congo Re9�C�:�i� A�TѡUTx"I}y�-�`�And�� /4-gluca:�M[4�.[5xP��B�|$�FW �IC ppm O��W�> ( 88�7.%)��� �]��� C�|96R6��3%�"�r*9� �CRJ�.0 D.u halo� U a_Q.2lG!j�$A���rAI� (QRe:|�#�h���as"�Q����CR- Ё�ewra E� ]YO.��)�������?eG'�&ve)CR .d2���di #ed%,�5o*~8JeH argi�fV�j����RbG � "�L�=�&� !>:"�E.� be catҢ��":ku�� s ��Ą!��]89[5�.[5�Qe.) infl�c Fa|>Vin.`/)� ^���Bbin�kC/hab�6� �1"� Ew��M�u��N,Al΋h��)5�e��M� ��.S�� R� Con�!FRI��+R�� caveng1aa�1��wA$aso) \A�"� .�"6y=�ua. ɧ(<(�R2v;Nure& gu���6B$N�:�1N#�"� N�:^FIN%� NUestEj%�6�n9�[5�R55]E�� d&�"�>�eX)PAKA% ���(W��K���"��D6f� , xylosidG ?>�!_ �9 ��(1�.�[ ���� q�� �O_ �" K�06fR�WBB" &I1� {l!��Y�AeAYePuv��"asF�co��g:�<fV+�A�ed.0�9au�v�@�<19_ Y��6�"br7�6:&0#7 1025Q haemA� $00889 ( gl�hi!Hh'An +02n7h�2%����)�se� ��exs�&@ir=��~%�e�K��\L!A��LznCN*���xt�"jX� �6��be�9��Ml?�c�9�^.��N!49I��` �m "�Wd�C�9 �7���5*��S'P )KqơZ.>�/1>�*( �F��C?y�!�m��Z��veb �~�( (j ��).�-�mn�oN�@)=`�6 n"�c&| =� � 5��zZcandar�;JE�a�� ���@N%� 1S{�kascor��.s:�B454��$MGG10368 , 0820�:!Z�D9398;, gx I779Q:�up-��2�9��i^�I7T#�6/6���nb���,� j6%)�A=� 6n�a�ra�y*Z � E<�12�:1T1G%lS�"rg��0Z��Lv�p�i�Z�of �6�!V}nUPm�9ݙqYU� �P'QN337�9834;>� )G0046\%&87�}!!n:, k-zhhk&/y8�*"��� ��?�>� � 0757m�� 1849MV787 1�%)�rk"�Uto)`&m ��]=dێ�. f�3>yto�De P450B�10859�13239;Zm�46e��!J���!o^�j�F�m�r���!gs -e:� 2{+RJ�R�enMhav� b(o��&�~cop���@!0 1117f1PR011706$frE�!DN4 *�=F* � R���m (A�09N). al�*}��Ykey-~v*���� -z�iOA%%���(*�q(�Zݒ�i.�&�"k����@6z�C%)750E�QFe�Mi,�(� j-6�� )�:���΁"FkE *Z� ��� Y�=-^qS��S�%h.�H1Xno_R-�I����E�R �aU!"|/6�B��f �ud��1�!r!Bep�%So�bW6��j��4c�|0A�+(&L%`�M�p ![� $=2 Vc�� aY!Z�֙�#[H b_anJT6 sulfPBP.O B137a"�?��L0i����Fkxch�)|!�.�}E@},t�~a�:�. s [5�iI3)�$"�C�'G es�#�'*Ier[~l �'CM�� eleme�@EN" -&��B^Gtr=tY��|l! uOk!��~�K�sm�M+B�tQ] $yxB'�  [�)&K { Aa�BAu�%N� &��!$ �H�*i�!uptakY��M _>hIsdn�f�\�tu�@!�o ��B�AnjJ�t؟a*M4�r�0ڜ@D( eGF`z!ofQOQCёinu��c6��;{��Z-�]=\Mn(AV1 . 2�N�L&�%N�,UqUA*"Gnidul`TrpИ�PAfl tituŁ�!�e Pro3-�-��r N+�utnd�blasmii �2�"�!tiF�D pII9Ae��"lA��!�*{DcoȌ�C��.%m2�4e�\�u�o vacuhM���M��dAiK��qa�%0��!�� a�!!w!�ElA(-S&r s�!U/)�.���-)"!?� s_��!/. Co-loc�k)�27� ���K �-��dye 7-� o-4-� �ylcoumar�CMA96�D Mar >�!V�� Á�%V�al1*A^�ף�".�$![sENNPI��o mlin6�  ( CYP� M^44v �2&�=�X2�*p��&�`( Kim eb% .z� publ�8�:ąF�n.[���m3a?e��a.� Jr&I3 ��2U€^M�e@a�F+%�<�� �gA!�M�!�d;$]At�3d� "� ���8�)V� &$*:�biS1� )��Q2!TWL8-E2<Fm&�Q� _ �A�b�novV ��&�J, weXUa UNplays�?�Lr�l!h��n1�.xA(O "r<� E<.�&�;�%� "i}�origin��&�At"J&�h*"� A�H> rando��bal ��-*� 6�\:�t*z@i�G q, A��.5��"5I]8�X*�E�*���.�/2v6ZH N e!� "gke7� �&�Y �. Sr 5��: ���A>�KJ}f�C�.�9� �!� s9 s�x�'a#a�cA� Z# ���thf�1m�*�G62�nF7.�&�Kp�Z< �&�O7grJ. Moreo3y&�ŐaM��A�?"ory� 2QI�&�!B:�/"�!::�9�aU2�MI1X�,�#&� O :�9��%U`�*}*�:�J~q�r���4!� �|�E~! !�on>�B�sl��7O9�%A�I]�l=K�k�,N5�Jor� isA��a�)E�!��"�� VtY�.I)Be�&�9�+1F���rq d��whole-�� �[�)Nc�WPS�$�F , [5=f&�&it does: eem b�e}���d6�$an AVR–R��E�&*:�#it>3�on�2�!�--—��UWl�L)a.�eA�8��w�L�L 3��5B)�i9��� nsg�8n"%�;)e8�A5T���-�^"����l(�[�"r� u.&( [i".zv�|o� (~�$�Vm�M~[~1�"�@�+|s>�8.~A�8D�-ɼ!GN6��ua2qs$! U�5!{�} �2� � ant*��mv��iH(f0 bleB��iu]A#y�E)R�4$--7&��v�N̐ed�+*]"*�0.�.�>�1�ir��M�� z#*�a�H*�/"^~ ∼2!3��( �2urb 6�'N��!����a �S *j �E�eFgA.y&�+ �D �"dn�6we���LNoo; TE$�.'sr����3H�Y�c-o �Ur BM0�C�9T1PA�r�M��V�Z��5sY�!��&e�! ƆuI!P.� �%f�C � 9�1��.� ) ŏr�%"Ue! ]�1�N l o�.6��� w1�of &����đ��*(��/��t=�I.�"w�'d��t!� %"G.��@��w�be&�0� :���am5I&iYM�I�Z.�kn�JI�-Y)Ecf(�!��{&�3��a�&0.VK" s [6�+]|e:�w*6� "�w�H�1:�� CR��o "� ��D)�A���%�aߦ_H��t�Is6��Z mose�Y�c&^R\J6�%!��^$5A�6�"q lin�KahmannՃō"Z Ea6~Mb$�Am3�2�& ����um0194�um106���V:�� .A���A2+A�MmA>v? ost-^da� [�N�i��^�Z6E�Y\{to��!J:U �6Y��&��!Aa"/9;s-�� [�1mm*�I� ��ng �?��� !;6YA�a.pu�WU "!o�LO\i��b( a�A!�14�-��=��Gma@�=FA%KIa7y)�-9*KF�C�b�p���Mei�7&� CATBb^:o����A�3&�N^:�![.� 5&�+U�ri(Le��)!�.6uCATc;�1..�8@��%TA_2�k.�dB�zs�UM cand��eig�Mn–=M�  6�(h>pUfe*�5u�� H2���h �k ��~3��FuqIm� I��%Z/Ak.,��#M )T �."� a�:� Cst"�"� �Hm����"z meosta�m,c[6�/6�/�� :pr�~ar(w ex� '6�M�a� �a�1�)I�z � �ofj2[63kE[6�5��nBBwv%�!p�4��u.h�Sis%�u��An;e O.Dr ��6�toMĊ,by.�I[6=��![��u_���]�by ����b�m;�S-� �0o)Cby ABC�'|� drug�>O� �)�A.W 6�&$a5�aA<>�<��Eabc3Δ ,OQ?l��l��>L!�!&�� ��Hfu]q�al"oan>0nti����&Lɯku" DAB-V=v���I`��.�,w.IQ��a/�*�*E�"�lea�*��R�.�3 P+::��KM�!?�os6��VE�5 &a�C#c7y�.A�,aV6� PGclu�,C� �n"/� eraf���j *� � 6{G�.�"&�&x~Ll�+!��M��! t6� *9 F�d�6��2�n tur��� �xu_�}A &N+a> � (d:����76�}P 2g��BN �<As�� qj�� �ׁ�`�i[nM�` ;�a . MFb�5Xy݄Mat1-����x( gW�#6���H8��gboNUn~D�� of W; nsin-MadibE , US>?LW���� � �# �!��hsY�0( "�v.�as:�B . ValxO$( Kansas S�.���xWtg� zACeA/�F� 9��mResour�* ( Seoul Ne�al6o $, Korea; h��gb*u>&p#S �%��!ly�)%WsoW��2τOM��5%nd� 5%A�r pow5( �/A&�Q��Ee.Ait*%$t{2h�zy&&�!����-�s �� :�� 12 d� &���a [69]A��4%��W*��ol9=&5���.Cz&h{8&n+"�%!t��-���"�%r"`�on��id TB3.�(�F3% ye�[���JP3% casa"^m��1%�c|,,0�suC{aC)�i!?�K!�-�)�l�)0H�R4�@*lA�M@Be]T �icu��_�p6�b&|\A�relev&!qin��CMW3)�aQ/�a��^�����Nor ~ 6Pb�'A �>X��quick �-[�g&o�Oc#���Ily [7 q�!\U!A3T��}�%si|�zs��"o� O�/C)&�~aE{�l:��[71|`To���e F�or���ihs��*1{ M�1�%�� �f�� s; O>2 ��Tb^ mend�^soA�6DU�c,%r{ ���wG 4�!|( AldQ �� 2338�$3 w. ga�ree-day-g�)2<2�E5or�1.�A30 .�h�har��ngTw=I�(- =ED�F�ra�A!9��wupmaI�ofv.�D,�86095�LA]* E?�a� CW ,�9�> F354�s6�00e��Q�*"iCk.a,�M*H"�NS %= a1�.m�@R�[7�gFj3e o2�H�2L,A�~d!+E?�z5*�!1.�K>i��6�O. Radˊ���ϡ�ame��d�nC-paOs�,Uf.�%E?&^��*�o�A�m&QJEz�� ��U1 a��*+��%ss� rhe 12U�m@D�n��D xcol���x��"P��_��E�ceng���d va�7acy�/er�92'�u6iI! .S :�.|uap�m�e��c� slip| ,rienfeld , L(;,-Königshofe�Ge�y�C)Jq���=@!."),��%���×R\&a���li!C� le� ��!/PJ rop =l�'pe��( 4,Jl����yA 0��2;zrep&��tJD 6�H mo���ox%t&v��'�r8 hxOc�ҡ\��per�ag� ��JZ6�2�*A�n6�{)5�ic �k��atstD�j���&).� &�8 FlY�XfE|IC ima��R7)a&�Axio I�� r A1*b 6f( Carl 4, Oberk!y>jA�C=�eti3�l��(at 470/40 nNJemiss!zd� 25/5�": enh�Fd�len6��"�1�T)_�  'rz�365N�44R��r/8ellTracker™ B/k�/, Inv��؟!Osbaa�C) � !�A.jk0�:.���� eoҥ/D�����w� �!]�tfJ �i��sprn�&�_,Q�:�10�S:@�T=�20 ( 2�;�K�mWj����N��ʼn� –5��5E����e��G$our-weeks  s&�q�' seedIO ( Oryza s�a cv .2̔ I-�X&��.|dew chal�24 hour���b\E�;n� e�(��v (!�thT%� a phPeriod!�16 ]i�E1eg�# s [7�D�s%(A �sY(atnR J�oc2r8�+rdWoAOmit��Yc����a���&zJ��.�gq��+<d)�l��&�"e�k��im�` �-1qb�>�z6K ����pixKL� �s� (nd he�y s�LavZ�&�B���i�ơk� ��%��%� ��..�r&R��*w.Mon),,�c!�r,%�Wof2�I�nb�(�,�+ �i���q�su��1a�4i��� adaxs s���|2h@48 blrm ��J�� �1�rim�'���Fhyll en) q�"B�'Rem�6 Yal fE 7vZ8��'�J� ' � util�a�Z�w�Be�  �"?�r W*Ud*�L�Fix��!?2�q�i�� �A)0)�,.s�0� t2��&V Ya*ArtF��!1!��"�mdi(bQ glyc�~��[�01�] 6e�r:Ze�S.�iw~}l&/D-8k�R!P,>&��21m��Gkp�(��[��>^8��!�:�cle�7g.�`nol∶=�PQ�94∶aUV�%^ �.goG�.2 :�1��.�E>dr��rB^H9&�72��&� ���Kt?2hfixand)� ��M�y7d�����j�.~ �� no (Al�ud�al7a�!# r�Q, r3�|�*e�nm ac�q.7VUr�g�a:�3�8!�� k3`r2�peg ��1jIN�lXind= ��i�t_�*:b.n��٣iYZ�"�,�o"�as "����r�U$��9�[7��z�]O2�P_{;c�Y�@��es,F�ge��pa d c��\�6 �y�J��dJ�[77h~�� carr�7Y%��ɽ�[�` HpaI"�f� . 4C>&�2iph��o�+�#[��PH�!�pCB1004)�X �6��pr��.�5�� �D��ara�PCR* ��5��5*5<Av�� ��A(i+������vr2A1'o(�0 nuiq�ge�k 5 ul"2×�mixnR!+dNTP ,b\�S���9Taq.@�!O��A�=( �S%0s� , Daeje7e; ���6WNl�T�W�;Pe��-El� 9600�i4�Cycler%|el�1%$l�?�!D"� bTM� E�&�25ѥ?� f��y! � -� Easy-spin! T>'�(iNtRON Biot��T�2�n>�6��o�0fy� K E�c�� , � ve R���2 du�[7�"Brief*o)lE��?T�[lu<�first-7�j%���BT )Q�� Sn�S�!CF@SX d Sy��s&� ( &Q. Life69�,^f�YRyv6%� 2!l�}YfF�,�ke�% �in��P)Eaa� ^ofi��s��® �끍Ma Mixp��Bin��W��ngte�UKe�Re.��%�u�E�JFeI5 T��S5�^uFo�Ck,�GAY��o, a2n�U'f� � chec�E8a�{; cӸ&c�����a�3���6��95��. N̄�>E�5]( !!ean Ct k�a�6�2�[7�7՚x]& &���FE�i��ǡ��1�mu�s��Aevt ) AB�.as� � �~AV*�,J?B$ gene ( CY��P1 , MGG10447 ) , which displayed stable expressions in the developmental stages ( unpublished data ) and used previously [78] , [80] , [81] , or by that of O . sativa elongation factor 1α gene ( Os03g08020 , [82] ) . Fold changes were compared among treatments or conditions with standard condition . Quantitative RT-PCR was conducted at least twice with three replicates from independent biological experiments . Genomic DNA adjacent to%�(T-DNA inser� of DES1 ,was isolated!TTAIL-�1�!Tperformed as described2� 37] . Thei;confi;by X amplifica�$with pairs�$locus spec"D primers ( 4163TF A  TR , see # listE�" �JFRB3 ! V1 ) � �ed�fragmentM `sequenced twice to analyz.�4characteristic!�!targe!T genea'rup�vector%Ldesigned using modif�,double-joint�[411^ X regionFDa ∼4 . 5 kb size� includ]!� OR)Dshort puM�s �E�23� tailR in �5R� �3f! fterm%�a#2p, a nesA^i# j( C5.R 3R )E'�forQ�m�of�$finala�struct�� muta�4as�+��f�5�rH)�M�8HPHF . Genomic ��L.�Bquick@J�70�, Candidate%�V�)9tically-�� ��le!X idia �A� . To���di��)  ,ge� of c� strains�digI�%)BamHI%�@Southern hybridiz)쥀si <٘=855ag��6��� (Q���!X5�i=�3BFas��obea or comple�0 �of Δdes, a 6��ycarryQ�!���1 . 4,of���B(��promo�a��iӹ`)y�.y�\6|_1400p:�,eit clo��Xinto pCR®-TOPO® 2 . 1��X( Invitrogen , Carlsbad A , USA�kresult!�PmidE��co-�<%-K.�%�pII99s8i���selec�" on T��-I� @Bathophenanthroli�ulfon!�( BPS%2lor9R.Oaddbo^ "� %�)�1!s��!!A1�Q9,!#3m:8at room tempera%� . Co.W of f=Mmonitor�0pectrophotome�64 at 535!Bas�-F�+I��I�x�� ���daraNrvee��a$d �tc%. inte�qy �.�c2�bym�\ solua%��va| 25X0–3��)>�4( OD535 = 54213[Fe2+] , R2 99952�aYo9!Nconver�]X f�accor�M�c%6�o��MsIR E�is study{oba�ed��A4onI� ataba�$CFGP ( [38�hhttp://cfgp . snu . ac . kr�h�:�Fst anno� d!�om6�� 9 fungiA�� M . oryza�\ToyyN homolog�l$GeneBank (�$www . ncbila�8nih . gov/BLAST����ŭsearch��! 20algorithm [85�Ix� tribEY&� ɡN� X%wݎuto!�i7byomatrix�� gram! orpoiin �. S� alignx M��ClustalW2�6]e9m_��of boot�pp�hyl� �  tree���R� eR�. Based� A�eQ�Zs � � cate��zed! �~ WHO guide�.s s�a!� c&� �any di �s c�5�\ U!��P n1�ed�a� , 21!�!�2519eXN8‘high-risk’فBirAC year!&0raziquantel w�have b� undertre 0nd almost 20%�remai� )�sBE@ despI-��-�ab"$YU–� la($28~childre�!AYE}sq)>�12%E#iv!��8e.�%�em%ne:�curren!�e�ive mape0i !spa�� deci� suppota%by aggre� ng!��Eestim���� ct l@�Lcl)�not adeq� �A�P!n �����alter ve!щ�8 each-�!N�a��6 �or else�`is �t all f�� ble;��lamus�a a)c&:ry�M& �!�� Thus๋usefuln��,!?��A�!��4shE�!'be  �of)�one-tim���se���,"M1�B ,Jan ite� v{oc��in"�s�t!�ng aK model refi>to ��=p�d�A/� meet%�A�%w dise� ��ɼio!�manag*. ���nflict��"$ socioeconj burdyO� ic~sub, e� ��in-Sa�$n Africa ["��is �NUy��t�F tode2hsp�mit� Qugh fresO  snai�xhos:� is limi9!sparticul���e!{enviroB �han� ,!�� t^�e:!�w�resourc�Z�mis!�AdJ�fo�'Za��$h�~  across&Fgea�ph�diref�s� i� humam% h�� gec2 ;far s [2� Until]8*�N[ ��hadmQen fu� docua�ed [3� ijA � recogn�Pe$Y�6U( urin� >; moram�)a0an S . mansonE %T$country [4�Pj�  la�a�S��� aO!eligib�Kr mass�admin� , ( MD�E�2\( PZQ )�Ӂ� only who T"hA�A~ popu��oz�� -age�� ( SA�A�eą�adult�HR��������2 how oftea�cha�at!�6giv!�28AL v�emo�apy�CU�v !�mW� DWorld Health Organ� ~ �! , [5A;[6%� riora�2007 }>�U�f5"� ib!)!7A��ly�ak��iW with��0Volta River b� -H��� 1 non-gover�Do�!�NGOs )�1ng de-wo� gELs�%� soil���helminth!�THay s)�bua|Ai��o A��� � b� >L!`.}��7!�� m� >e �d enume8 9!Y���a(by�a� !eof�%i#A�F d�5 m2nU U )M>��.� %��b8ŝs�n�& a�.�5�6�i����` �a� , dipstix�&a&�quonnair� �r� �uria;%�֑�1�, sS exami� on & appropri��E걊(E��"u!BW.1uti"�Mf���o R7:�se!wool% ) a six-��j�#perioN$|new ���dAk�� �pr9 mfaX���HimpaceZ�� o�|��3/]� V��& tegy� . Et� !OvalE�]-�E�08�6�I�k(College�� Ts Com e UKŃa[E�` Service 5 al Review=i��^�-WaD[.�a�"6�(��. B)�; cA\�hfi` lP+r��4 /RjAbh!2 -al�D� ��hy �edu�I$uth� to�"ox! �5to>est"�. O�� e da!2� (team explai� :Y�nd9J verb�on�gvillage�Q��rmas )<�� nt-t�!;as�il�I;� .. V6���36� es/guardiU&Mll.�vol�� �)x�M�diEwa�eirB���ip��i��HN�:�ChiZ;d��� !�� �P.�e�6�f�%�>�2-ycs . Wr��%)�!F:5E!�:�$�/� �e�G0m�p-W�'Ikm&A<ide�i!� rout�� � 歯eWia� al NTDS./�&�;:��M%e&Hi�. "? �� ("� ) � a few�a����&t%�!^�0 4� �i#"*��"3.)tYy�.=�!�=hM�t e�ei JMMv� 9dev5�or-Pj ��.4 p._ H5oX,� � in 77 i,s���M�A�May �. A.�3in�!ail*�[8�J%rpurposiv�%5ZZ ��u� ��"o/�rur�e�i dja��� Lake |~3as lik�to be")  e numbe�-R��W&D !hcalAv Q o$5a�A�A|QZ?;�ty��b��+|�%Drecru��`-ǁ!�M"� a >P�is���*�.* a bi�al�  toge8 w� 6�kn8+) a�H�O/�M)� , �"8g . NDVI ( Norm� ed Di Veg'�jIndex�!nx_ 0f�N�%l! surfaq5*�%}�&to�bod��ia� "V,al random ef� 52)�Q�+ .�a�>ru�sofY(aged 9–15j�� ����3a\�!�on��madv,Anod�La�-1×%1Tmal deg��griR!�Fx= ly 12 km2�(B�+ Apri Jul�10 , 123.� Q��E��d"~ � EI�ٻ ܭ�S� in 92=EIe4��!nAgencI_#� al D�)� 'sŢCoɢP� ��"Ab���a5�cr�ia ~��� 1�&�� !�A~onA@xcyAMsuscept� sofM�. Fif.$�'�apof63( c),es 4–6�#I��e$om%Lin�u)��2N!_.��?e%& R�a>![!K7� oro8�� mic�+��c*H!' 2006>Q!� ��1col ea�>� ��\� " at) g� luu-�%%��]#e�I�Ya�2ticA0(r . UrO )m� �2:'"�(*�,};2k Bc� �2in 60W,3|4screw-cap vial�Q=1� 00%�1�900�*.�0a��%�ag�0�en-&; �=ersal!�ega(�, J!��a ��Nuclep] �!l��>t`|!6�! a ~7i� cope^ ex��d1gr] Individur#Y���>k��rAas��0:� . Si-�SleE�S ��MF,a Q�m;5�N *�2�m�2n�a��"��=� &�B�in�� t���s�# rkablyA�A�<�*}#���;ov"#/sanit��s�,/��se.9>re! 61Aj�u�  "�of 170 ,).�g&��A l����$�T%��= -�%����/ twPyAfMDsl03B�WHOE[���3sholds���tAeM� �"'. MeG9 t0�A�8>� linki�*�� maps)�So$Magalha�"�# . g01�jg.r �� syste�gT.])zdi�:��'� m=| ��Aq toR�Xx �&�- ( AU  Z�'�o�)� 6�?� EJ[1 AnBI(F>�O7'd�'e!�epia�8e A�ɶ !."� " њpixr'#&c��� thg5me& (n����8z# 97 . 5% Cc 7�al ( Cr�0.�.a�!n�,AIZ+eD��&�(adjedB�d!6|�reeeZ*}N��[6s ~0 �7�%8,1,=�nd�A�Mlower� nh 7e��d oor!�crI�!� capa�!�inguis��5u-i6c �!ez�AѥHE�–92�+on���]E�+ a �, good)M�!����e�of�!>�Ov�e���A,B� WHO-""B��V!N' �J8 t� 9��"� :�)� �3��i�ann C�SAC�#�Cam�": HE�&�! %��!�� If-�A]��!�!O��U%= , ?"'>-year�9�r"�� !�唩�.%�.a,Q|}��v �"�!R!�E�C0a�( b�$�2� �G�:QVlj��*:�%F*3�$m�U�,be� -�orkdepen+*Ehe� �LorU�=�q+�g�>U�s . Fig91 summa �)e M���/&�"c/B� �"2�4�$inu-���I5�n"BAreveaj��]�A��'acN����0��e��( ( ≥50% )ZMRbii� � �)4� �����e����^usg2 3How| �Bse >2w�3��^�q]���um �10%E�< �an�!w ( <)R2{"ąeB�0H�m:9�Q��e�1d����le-a � I}�����=�8s orB U�  �� ���.&�n�� 17� 2AEm.�� �in�LVm=.��U|�"9E2&��%�(.��58 ( 73�6Mw�=-6qQ=AAA'(�c-'*6`"4�<�bofqf(iv2T6VUTA ũ)x���ar& same%��(Me!��ԡ>�CE@?Y: 9;=1�� 0%�>�&�(n) � ) ; 20A%%M 1–%�qN�;A3( 3IL810:!�2: F�; !�25Chavs ��2B�� �nL�'2>'&u M�: �$>�A�E�aI2Ir�A�Y�>��J&U��U&�sF�J(�RM���h�in��C���� "�%��)7 [� �k�TNecio ��5 >�=�!p$,i^6!�.[�.\>b-� To !��2e% �A��9�p=|B#)WH6�1�e� d* *�.�)� *�'�$�ō�5.�8h484WON/>. It �+sV0�&C]y A���PA!‘zero-.�6�.h&�J� ile{!B��3H tC�W4;A--�ed͵F�.�. DX] 1st. 16�B15� �ZK 2TI��! Q�)�6�;�8 �!&�7Zja��llrJ3"6�|eP� 2�+^�F��]Da � �a� 5+,��2A]33Aextra!�� � =sJj"F in 9--s*�%ly.�-U�8%7As!v� ��J�):'tui)�rc�99ed:U �e[A��a F8;n"as!!E�9!+�| they<&�]�2nd ,��1` ,nE930�e�p 5 �:f�B��=: �� if�!81�`%�4�5.!�J�qC2�3rV�A\in����!s� ��( 5�uA��.�<2��1A�3722W50�V]9��"ɑ�>e�*!14p<80�%K62ua�s i"�is ;Oari�)20�a�!5A�2�ei"G >^B#I� �e.� �2~2��4thA�!�6thE֩DU�)_u-�jaLũ"|�Au&is � cycl��of!G, 192��_r��A��%!:2�2�U &�m:��d"?�!;'D95OM030B�4�hOm-\ ��PK is r�, sm��R>h�]"bel��imX#ant�-%}:�*V1 B� . �challen�.�@&J� s:[i�: daun��;�.'":_'��hee�l� E"D &� !#. Ide%t,�QJ�29.��:�j2��)Mrb*.!& ._� /A��t,�-ly6�A2*� �'K=693 '�= poss7�al:et�' short-cut%Jtechni�4ݶ&�&to"�<se0p/ need`�'geoJ�1�. S�8M�A`d+rincipl��4�i�'_T� .�9v!�N��(!��,-)�c��r.!��� )6>� X =� � �;�A��$scape �2.|ёoff�;�*�A�=�� A-var� $ 6!�,�;��axly}�A�Z��  1�outcome{/ �>A�n�,if ne0?O"�Z��Z2s;!?���(�/ata��E�a�:�9F!uZ Q.n�,naE+w� V8]~)�BB>/ $f2Yr�<� -a�� J1!|+A��5Y2�8�Mgag};�,��!Y� �:g����%��zo��8 �)��a.=W�= :::doe\�݅�� y�atyDE�2>0don`3)&��st�4*�>z1Nh$�_*�1�+m�Y be l�6prP��6,i���>�.* ,]4!�m�o0=Pto�F �%��CA��8�:ir��A"K5s"Hi+Eth*"gC)�mpyG@w���--Kver8&���/rR36I"%#��F "z �����. R��tm?] po�>Af.LE7*K tudi� l� r�a��wAg�c�=u6$�J to j#DL&;<-U!�,4.�V��#7>�?m�&�a�Oe � ar�C�broader.��.. Wyálan�PHH��*�a�N�( �M*+5#*�) �����٭ lA�=!��u5&m��ge groupm&is6�+t a�er �:�\�'( �* �~$�%c, !�ѓT)L%� �6 ��"sub �i.�5�qat �st�>gY��rbe��� cato� . =�� �W� e.��"�s:�""� �%�F � ��low.�]& suggիa7oic9�!H��.m�#�&g ma�%itu�"n &o � �OorP!��epanc��"�� q6����� ��Hs6c!@�f:s  �  ��H)0TvKnڛ:!&�5i��A5! ( >1�"�AE�aEUQ�&!�x ��cN!�=gorUl�i"Ve6P9�"��<�!�a ��sY�Am�# w�Y���< ,�itself� ave F56  �.[  cy��vIh�)A-in{&�AP[>�E�&�O�Uerx+A�a-��Y��5y� ,�� f�9�n�7�;found�3 y ^!-NK"�N����i _�U/.l ��%�q�ool=a does%v&))![&o�4&�D5���!m;Q�Eg%5'�%8����%�nojn,=T-�A�an un&� ch�e:�Tn\Qn�H$�Z(�&�N)�pL/��9s�(IB���MmW��1Y?�A�G�c���8Y=,�A܍չ=y�y�R!�in�%nt�J� ��# A�Mc�demBB� gene�K�6n8��p�� !�w1�margi21 �A*�"s�� t� x*) eachJ�B , �h.Yaks t�T�(%� Q�>���`$neighbourh�&are�E0s�E*�B%v{>mak��Q� ��]T4o!'!"�?5^N4LU6�R� 0s+f�%�$�.����G . Of� g��e^c�d.�De�>:�}�{�i�c2!& ��%y .& �, heav�To;5rr�y�H�g�EMnSAC%{0*@��/od-:�I !�in�a��+85"�Q�tAsej�! * "w  ���E�L�� A�"Q�"A)�s�YE%�aV&�<��,��HG�d#R,�1�B*�-�.� Bn!�ͻd.^�,�x��t�S��*BsolXY �e|�t� L1C�B�cIv"�B)/��1 ]i< T��#m��]�9u� �!�-��v*��)�e�7s�A�Ml{, � extend f�C6�ena_5��!>]n]��~�)\excA0> � q �P~hi�>�X�e �My s���)�2G�wx�1�!�25� $V�6.y)!/�fgn�("�2 Va!y �Nɿ~ "�Nu o�ne,)�to!�rV ���EnGYiIa� �C� K��Y..����p]��h"U*peo@�S*�a�n z* }�8�*�>��1inr&���* K]B&q�!ortU0�mTng�G%� "��d wa�^ mr!�-!�J�l?1} �V�.[&� ���zachU >(�)|!5e")V6 `&jhU��ay C:4W!�]�J��–9��W5ay">WiF�S�l�WWFy� W" W [1�_In"�; ,%"�a39f�Wc�`A�a-ZWi��� ��?Z��Vnel1ve�V� ����9y�u�)!��A"�JlLaIr��tr�<X-U."WaRUj�Y姑8�\wI�A) g%0 � a���@�8�[Xe&sQXŸa�!front�(�� is �$user-h-xa3friendl/"Meezq t will c[=M&rol� B�:z&�;2Fe��aocx6rth�%�st>. [5];4 iA5rou buil��n Jfch!�a�� we'v�Q a��%��ll at ��er sucE�Akr�rA~V��nd�1eiHen�# addr!sng�sjJux oblemщ2 %�"�Vw�TML .��� mechanism�at�vmot^&�mJL)�femal�@��t�K� oocy�D0���= .�Ed��Xat Caenorhabditis elegaI8 Lsy�a �"!F-!{ EAg�i�So> poly�Pte�d fat�fc�@PUF�V�curs� ��� $ yolk lipo�=e%��Sx=1 H�weA��Cw!Z�*rospray�h=Vta�W�tr�g�����V��V�@ metabolism pathw�9We%Ii��l-6� 3��&� !6�whidoni�eicosap�zenocid3!�:�fmit� 1C%� E*N#V�O�fun�bN>*5�,h _)ahe�A�t mt 1%=�in=�6LU�t�FB��kv/�M f�|"�P�ny�<5�1�s�j)sed�$un�)aB�o%��,�as:�,!��Bm�T�!'�i�;en�E�[1�U�<Ogs ��e��B�o!cel�i�w�nut\Uo"�E embry��xma.�srm��� hA�,i &er mob�� t7h8en� =ir.�@%#respo� ��C$Ea��:!�����s��JA�e job—�/O=�͎��a sad set�e7Ohel� � �W�ycab�@)����cic)�"�\�e.�� �t��?-�id �ca�Q��gEs%k!F isZ��*��{;KcrujQay�{iv�tE [7�KY. EUjCGmZv- a� pid 5_� molecule��s� �=o��A%:��y��>9A*pAj.^a��f. �X�sZ : p�=ful��o� y!�rm behav�^�1�eJ@a,2#xX4e�1�^IaIbpa"fep�Omollows 6�k���r�"q.��� dl}i| Q (T41~ [17 �9�[S%EaN�4�\ �"towardE� ��Ff�e�Ia3yR� �*���Z -lapo9ideos [1UN[20�Pna1�.�;eR(*� q#��ze��:] ( PGYV�f� (D� +�" Dyf� .� , [2[ DA�& � $ wod<�  bon � 6&�la�2�ɠM n:Png$�C5�S�C[2�cMuvin�!^14s� qK*� )ba!��$nonnnno�8'e)%+EdU�,����ngin"n �+�'�Sit� 6bA r�Ued6�outpu.CILdu�xna�la�w�?� ��2[� �u��a�2!-"(c-�~A�!: im!] ef! t: M�L7w� at�M coup� ]�� ( LC-MS/MSu��*�"O f� .� �%!��U��Y2of Ce �!e�og∝�&� o�=-carboM�L!�(ku��&��4� i,�fic l'g��?\2�s a%�����ivLk�4`5� .@..^Ua�2� "�:fa� �%ar!. M� s�f��des� aseu���= monoV�M�l�g�g[2( A ke�|V ~ 26=��Uyc*� �PG G/H &�^ ich�s |"�R{Fq.PGHB�5� T5%I(%.�O9 !nQQ�<���H� �.f[26�28]z1B �A�F1 ^�2�di* -g!&-linole�c�DGL�r"z26�w���F2��@mbackb�. K)so��20:3n6%\�0third.S oy#sh n6!�\�U��� e F2Z�2�c�A��20:4n6;_S%2e�N3ZN �( R  ( EP e5n�A�K! me�UQ�B�AA �xvo�X�:��PGF GA�J>�E�11β-�:9� 6D!( PGD23 PGE22� � e�ly [2� 6�a�` ar�ofZv iso�iy(~via:�2G* m��f�Zra�Jl-i��}EE[3� In u&}�!�bi"�"!zvi?]b�� �gkn�=�e2ee�bi�! ��}�r"�AMW?1L[31� 3 F�'&� �` co�Q~�en -�z�aQ�A &�.�� !C����%<�w�0��,�^�q s9- �%�v^���A����8D� ����,!�6pB��m.y�^h"'� HkD!`BF�:�Mof ��6�N�6%AK y�W��^inhibi�f.�*h,��[5yAwd{  0r"�>�-*�sm ( � . OuLo b^.�"> ecre&, blen�#^$� !�� � / 6� � . T�pl�b�2���& v n|�E+3�f8M8� � �`ydc0 �Usɵe� .3. Two�: v�7$h1� �&� :�$��a�w"����s��#a�MitoTr�p,r CMXRos dye�K br�2ly lab(� rz. S I[�+�Bu�Sub�wnt�$hermaphrod_aX sepao� fir�~ ssay(Cs�& |_ "��-n8 ur#e�V aэ�Q ng ,"��OL !zo�iu|�%D �!A: 9tx �mo!�)(�c�e}��J�,S  L�2caA0an ��2" ) uA5*� imag~|4r��� c&_ZvI � ,fNj-\"k!._ O l3i),!��44� of 8 . 6 sWn��63:0, rari�d�R . A�4alXIBgs�t�B��� migA� -�1�block�t�"aqTRd�ŏ�l[A�B0i"e�u#(fat-1 ( wa9�CrIwa14 )q::/.'9i`����� SU� ah 3� 4� �&� elevu A�D{  )U*�B�Ao!^�^ t}�� , [3��f �R�^��� �&6��R#s:|MinorM�"de��en�e�6T|Jbe���a�er�a�= M�%���z6$#m�}�t6Ks 2� Nr:ra6-!~=i�D N �2�ч�2B!�1` 4UE�\�":a2@ co test"�or[ ��sThb�Ac#I%�^���-�3e2� Q�toY� �aFe4�/i-JH���b� 18:3n):`, A_!� !etsu�ofa"7!�2|�ec=OME�]��xa�[" ^5��B��w��2�z�u�Surpri�z�Ab��")u�Ui}*/ simi , albeit�  =���rol* i>�kD!r5; P<�V00�yhQ�z?�c��E.1�/z����[2�;"�zɕ2/MJ�� s 4+]J}�(8i*at)�y%Ry A�it��a5� oryap- q"�g!q%��n�e} d>�I �2ia��N2 dalld| aq2iq7ե� avoi��.I{,:�� pleiotropL& OeC Δ12ty-acy^d"���xs �y�J�Aq�!,��M�ll� ]d*"�d5% �*&sy�0��g�BI� ���u�%%�2J ��20*? :~��i�-25r���s� Eh #��w6PA�!��ez�a��W8R�/��q��,me%�b10082Y� fj�M��J *�vglpD bn.7�j}"F��7!�nd �� �4)�5 1�/d&��$a�b�i � c(�H��4.�E���lAdI@n��e /l'-&��majQXw�(� "�� 1�>2��>� � rAj2�%�)� �sw�W i��HY��� ���pre  �p�#1f^0�^�%�Z}��C} mutu�%exclu]l a*�r6}s coms&81�a[X*�&na�.��aano�| ���Vm+�`2) 5�Htx.�+@l��r' & �seRu*Uw)�R��tes!�he""_h"� a4} l�!"�&b�ze�,� "�N��, �j8 �&���1B#Y�&��"� �!����5&Q&�:�5�a�U[&����!�( MRM-])�Xp�!���3"1�:TN�!���Q�M��Z57 qex�$�C w!!8�$&�E!�:qa<�4wA@ >y$m/z 355/31��'"0� +3/1A��/�V/1/ or 3 1 [3;38��Wau8=�i9�Un9�5�i�ofW:%�Y43C.�U!C���E�%>�CID�pat0%�I?:[��?��"f&>*ly}d#1α , *,l PGF3 *a���)�#�����T�u�L � `KCt�)6�"�)i7@ו� 44 DML-C2H4O ��!:]�ƃ�twoSNDaC�−2×�& Q!�g�BQAGACa� F! F3./Mm�"A3�3�4~5"� e�F1U(^ M � a�'&,!�n�! ( Rz�E���n�~^� �vPG%�5�)rTEA@U5axn�(�P,F�#U8x�^!^���/z 157%?22� - HG�[p&���� R!!{gα -F�::"RT�dF�2�N!I�v tras�L�M�RT!<� �s )E�rN1t�. clos� )��?2_! RT �1ʠ3= )wO)Q2�of�!� :[r����%h �c�*�inAVK�.�)��8f=!�M�I��1!�u� �oO��<��ItC1�oC15C"vag�+�?yl q�us � �ine�Y�.BT�8.�H ��5�1�e�ng5�6J: a3UM. A�F .yE�6�  7DCb&���r�{,2yV8�*toI�8#&p:s"1.�.;j.| �NaB�ZA�t%s��"Z�IF��^� B !^e�� 'iNexa^wN�as�db! 6&� �,� C 2�� AѮ--���q�*]Q0��%3�=��" �!�X�  �^*�n��S�X �F�w�d.��6-hxa��2 og&� +b.�ޚB��� "M b%(ab)1�B�r��Ş%4��3�T�#1�)n��*�R �ualA�d z >�2i��&u�J� �-8-��cV &�2�6�f 6�"�%:�J�B� R�x� � stroT��J�A� )�./>� ��8 2C&20∶tW  A� 5<(:Y @6�2 ���&?/ �&K�5%�!����%�� � .K6�I5�_/�&h: at �Rq�d�i��C����>&sOj$�'y� A re-N �"��atFY�>"�� �9��H �L ba�R�2�ix36�3�U�S2�U&�hq�&0Jn�i�,*hCN2� tracWSv�&b 4Ͷ]5u�. Ol�_K U&)2���T����_� G��)1E4FkAs91E�69 12-fL�Mer&veq��Y9|we hyp"s����m�! �5�a (�t.'���A;]�� 18"-Ge$$te*3-Dj �(��R RT!�x7� ,��w@+B?}W:�2�2�):u�RT"�� ���Vha��Ho � :�assG 322G 28�!I/��San��.yu� `2a&�Z�at*� �9%�z2��i�{7.hfx]A��zm��S2���O%>�27/283!K�b � o~�B�e� A,A��0m r�7��& ���qs.J �y�uU)E��Ead&7G�H�&e&"Յ� n ge�L^&j 4ݹƘ�4e&� ��?D� �eq c V&���.�ConRA�E6%�.�,B#in�� n�2m�or K�'!v�#{2!�*3*�Z�� .�2AM�B�2vel6��To"�H�� o!�llr��eUIfE �6� �IS���&� *R 2, >g#%iAA�l �N'uE�  3 pn�+AA)Q6 ���E�$"u2��R#W��auE��9#@rescu-.:� c&0 �3���Z�u�d�T� 6>�I$N2Q}mQ  NA22�0�4ad�4 fUBQ�[�Sm��n'�K ��<5�M�u� r�6��*� an6Ams(\eZ|inHP)�� �@!��?�'ed�$ho�tMa��f�>�.��lj&g-" Et� eJp"H��Rf��P^a�" ^c2p& ��s�v���Oah��>S%$nuso�invIg�*�m�D �^��1yD[����)Y354~`-� �6� p�PG�-61i81���0��F�q6" �9�, u-�9�1n1>5%�"� ���T�ed�7��Dd ��E9R�@89�O&�s���H"2m/Z icom�8r�� . S� peak%VZ&� 3* s"�5�Ifr�MV>e-�B���:� 1 t�iyH�m�?�Re���#��""�AA%�7 :8is#Q� A~y2m�� �"�YV���Al*E� 1���.�'Ap �B� >q��"��8�c� "�����$!AAeWy@e�MyZ����3516 6�4!E���6VC�c, FRe&�!�2=-�a E89|e��mn�Th�U>#!�)AA-�^6�g H1a5���� N!eN���1_ze:X!���S��ƒE��ej+�bea��e� ������{ly.�^�=D , E�>&�6MK!M82:� gsk� R11A .5 & gl=>h�Z S��fer-7e8:�,�o!FPGE)32>��&! 2t����B�6 "�mil�5P,.��\ q>�ID�!*6�'V �X���8Yndu�" onRQ null ���e�f�6i*�Ftr� av ly�a 28b75%$cEC�6�2k )����S�� �2���S�9^2A�V)r!mplexP!&a���E�Ź�D>�A�~ c�Y"}�W � �N1R�ic�� 1"���$ayyF.�9$s Y39G8B .�* C35D%6n*)J�9AH��LA�f�Sy��modp oryL*�A,+.�bs:� U�,;T�VR�>� ��"> AA$ur�e���&�?�;.��I�&F6� ���AaN�!09%au ![F�7!� P� 2C} 6�([� ��:-!t29 �.7!� ��z�,"r�|��i=o`�whydroxyl�es�cCN C�#A�C15��$})A%[r�nD 1c �15�V�@�/�%�� e�a:��~ ��t!�a��!X,few"� �v@�*�unk< �"\Z� ��B%Ɓ��"� .*%7 /6^#� E� � H�Ũ� dq"2�,���"��+3 !E[ ����Ir�MYbe du4Z6�6co- %IuhFj,&�* iAv% 1-zC20H34O5MnbruJ�L'sN��8�P2OF�!�o�kc��*L2#ic*$$ۗ�p�mA4#m"E��: ))�&34^��'�]?o�V� !�&�W��o���Ga.C1^n�`m�Gis�^-� ��M~>�$6%�w� ��DU?��2�P�����HPL���e� C-OH��~Jz��-C&8�C�v�!wC$.(5C136Jin-�� �����E�j �by&t  �{��RF�'%E6%kV'�{*�bQ^DZC\C8S n|*��B� 1�e�i�A ( ���48o�Y:��&�;8/� ��RT5:�F.�zF�7U� 5� *to �ye�QB2O_�%1&�"� �.� alS1a[Aqg6�i��/-p5 6��>.')�G noteworth�`�V��2x�x�) �!r1��A�E�ID�ŏ.3$?���u�T�~(5�s,M�� ^Cy�2�;WFF��.-"KO.��*a �ݫ��p-�.�Y� &��)�&]a nayl 1�i!�"� �&�cf�L�"ass.�3{,)AWQ��!Q.��VT8�;� ��h`9�s&h E7- !�, Xc.:c:��� o��� �ҴQ�E�A��6r(.��_ardYS"� ] s�I ��st;e�f2yu�/8;1�6r}�*� me�q".��ar���Rea�0so���Rt�q�$ ��[ces�u�F�!1� ̥�!�eɽ*��.f T�! RME-2�-deϩ.9Zre�+or!�E@�yJ� �>st��*�4��5��:�ء�E"_ [mix�7<;!�� CN;i�(@pg�Ve�1�"iFxEwe(�V�ez6��& anN�5>{.:&�2)��0ee��)�!�Xg$1� li8&�g �- |%U_�4.�(��) [�5W%L]>�P�3&59)5n:�?�=� U��mI�c�p�6"�&/m':v�&S(A�UC.Z e��Z bI��$�]�5bb���ZsyQ )W�_�u���"��`�he< ��,0-e��Sy.��#es�in={d#%a�&�@.2 �*�32947%!R� [��Up��F6 ��56^-rF3Z�^| +-]Fl�Q�%-��o��d#X�"#7B; P27=W�6*� !�g ���-:,!$uA:�� ��A�)0deҝ[ ! ]( tm27��� �"tm322� �;=�*: �O<nΚ!t oջ���.��Y �"h=argJ�D"GW%�x�K�b8A>bS� r� �"� �u mb-8I7:(:� *&0@Sa+of NAD �:z`� t8Km��d�c�A�69!�S3="�$�Hq�=�1��2�\&�B"oA�n2LA�!~�PD�3��O,R�BAj]ge� � ~��s 1E795�B>�\ / Bvr?��-(e�����1�6�tB��&�nf)"e4��:if�&�.E��KJ��l�# �7-ay^S%: �g"aiqa X5.�>���8i�+�N�=531~36����6�w glo�� ��dUF&���, "�l� e A�i_�^�(� !6ne"i55�m6�2� . ��8)Ae:�Z�Z0!?����� �| 2h77C1�C20}�[4�J� 7�6h~Q*ZI.�U��Horm"w8K^?.sno&*�4w7+(d �a�.i�E!l[�iSi�E-��I269N=���s 19--B��A�20Bs"k<,�v' G!]�v�ht�I��:�}"�L*9Fy��I�&�"T��e��;)z7R �)�>ZI* CYP� R�fV�"� s�dh8� �C�a �ncommonA[V���q�$d6��.�Ѡ� &��in.*�  Gm ��(g��i cuss�\�Zn �l 2) ��e w�\&.S�� A~&�2�X.=E �W,�S"4�&pharmac}e�Mce����ir<�s�&�i.+�rXr(� �.{ �NB��/�dEh76�\v�ee� Y� S]2 �n�"X� 1� in �IM|�j j�;"!�C�)w"�'moFj1d hear5kidne�i!�lun���� �_9�o."�'".V; �Ms�h�n e �i�X*f�r��v�(.�E N�M�7iZ�a_e�Q%� j-8A9pe�4<�a��qE ��=p9�� � )Zdie�I6?a,&�2�b���8!��.n�Ɏ. �Q�-�p�%HN��! I(of�:i6��)�]-d�!EH5^.-vq��h��^A�a�.=�^�� L. J �w*s6�!��.)#>%Q6 �%�q�.=!�6z1u"�3.'Qjm%Z���.�ye *'���%A�&����TR6!�p�t#Xf:�"�. =����-�t�*}H5I� � ong�EV"� ��e- , O3�Hx�1%7!�.z)�$2'V�*AKr .uNb:�.9�n1 � �m��rKAS*�)ofb� u�x��de��"��Α* 8{&�&."T��u�4��!2�:�!@�hmjM�2a;F3!���8sx> !�"�5�Pr�< ap�Xe ��t�C�c5�K �Ql>�!� X ^��" P132�9AA���nA�[ �R�3%�2D� D �Z�%X:,���Zt�2�LV��&*�8����A`f*a��V9) f��Dm3�9�.353.� VNP]�DI��>C� 4yk t2j�e�.�ej� un�3�lex�j�2�%i�r.��3RB��~ lC��\�i�.k]�%ah ��va`:e:�2Nsam�j, i^�� re'� �'��F�C�P2b���*@u�4�"\�:� �a ��.@a�e "�a�>E� Fur�"��,Ї-� a:�"�SdQ�� rm&;Z �I��*K�wU �J.�Ux�N 6�!�!j�/:""vb3�"4B,NVbQ�y+� A�eRu>N���.p��eX�}RY� �!n-e�/a� u}�f&�@�RfQ�]&*n4�leg-tL��2.�B��% 8-is�0&PE2I+!R2�Y:6. F*� � o) playg#?}g:��Z kYe:|�2��!d��+nv'E&*&ic��&�T ��byBR�a�: &����QIHY&� or��o"n]�F?Z�7�u{�u�[4j�R�.=@atS�.� matb�� b�;a�!+�xcDu%)c�(:�&ism)���-|:?��2�{���Uj�Us Qez�&L 8*I*i�*kB"�9Aj�� ��.� �%lbm"M�Qi�Z1nd>�ZlLZϿ Selem�|��"�<�%*~a-� _:�F�b�=���$th �5&�=NE�=��b\4~����]&w6���e�^ic��,� �� !DI\"!a7 �  �l ime-*2ua@�%y� . M(�&s@Bat"\> gonad��>.�"�e�X&�Idb��@��@��@20�vo'>�2��V� � :,\)���rnM{;2la.F 2.� :N� �) �F�A�Y� a|�7ndЅ�IN)AB�:� F1>�&� p��Y�����Qa&[ N|��(� "�9:��pbDH�sJ� &0:*R�8 )[d��fw iZ{ ��z;!&k )���V!ir��JC&|[�J}�i"low?�}vӾ2 .'�:�(2� �s/Why?,.�A-QEcy exd*�| <e~�&� #�oB �n�9uX  m� �ag!&Boro� ��}.&�mPF�#���#����#�k��)!� reti�1^�z�[47�V�=� > i�<a �}&�6��U 5 "B� &�p�ey��a@7 )k� 2? lsNR�Zbii0'} ���?!�]>!�do��hex*��< [48] . In C . e�legans , RNAi of CYP-31A1/A2/A3 together causes a reduction in hydroxylated EPA metabolites synthesized from microsomes [49] . We were unable to detect hydroxylYforms�XF-series prostaglandins�mixed de wild-type extracts . Thu�Lpotential substratesa�<2 are EPA and ot� PUFAC�(1A3 , whichY0also required%� �Tguidance . An interest�possib-s=n1A2 funcasp2{bzin fer!`zed egg!� Continued:7 prodysembryos-disturb�i�al ina0a ( i . �A*ma�n�of!�radient�!uterus )!� modea&EjedA�:'E�.�2� this >�X(mosaic studa�suggesA�at E�!Ge�in�gA� line , no* e so�c gonaUIn add�!~:�,^promoA�9oflA�ea-�barrieEF>�[42A�T�'A ouA�toQ�Ylong chA�$fatty acidejuge�to!arseGpreve�9!�entryexiOsma�],olecules ( ,rely clear ,3!�eu'��by5�IB complexD nd ��-I.j vitro [13)! 4!��an at�Asscenario�1�y�s�vapoR! to both hE�� worm �. While�re%@4obvious differ�n(s between C�jP I Sreѿv!" stem!�it��Wbat��e ��a�� atur!0!\ha� . Delinea%�  vers� vergA�}�sh�uleaE�bet�underst> � thos�at�$fundamentaDanimal� on .�{summarya�ekw)� a heaW gene!.mixʁ�structu� y re� db� մ:�i6m. P. U�s doeI�involvA�n�gioaTcyclooxygenase pathway!�yet:�F2a�s oi� ��!�till �J � Fur5 mor� erv� nzym uch� @cytochrome P450s � �Y���[.g��XprI� unanticip�fins+ �F]A��ofAw!0 �am�ϡtmos� desprATDim� ant����M�e  zoh . .�� m� ained��420°C , unless� wi��Q d��nd fed� NA22 E ,oli bacteria&a�ee�$ly describL , [2�)@The fog-2 ( q71 )A��was u��for ma�)�follow�? ins �,4: N2 Bristol (� � R (BX24 [fat-1a9 ) IV�� BX26 � wa1730 352217 41452jxB($SS104 [glpbn^�c� � ( tm271! IV ,�tm322 u!o(nd CB4108 [6QV��e<�U7 m2TIE$M�� A�Japan��N�4al Bioresource� ject-� ]2u)�%�backcros!�i wil-�three tia�.� Aper� �feeP $method [55�HT115aE�l vM/obM�p �E libr�U [56]% sequ�kdE�verifj��W"�!J6�)D>�%Rgr at 16aq<syn��n��- L1SusA�an� � c�wmina%od��7!a`larva xshifteŌ25zcul� �2–3 d��. For!���{e��)�s Y �on5sixty-f�u(150 mm seed[�s>b��1�C � ew lemeD �con� A�} as n o1 � !Ir . W�%� wash ff �ZM9 bufauoll Lin polypropylene tub �n�o%at −8�J��lipid i�Tissue{ weig�to ensurequal��u� ��� X. MitoTracker Red CMXRo� In� gen ) a,�\sA�:j�V�!%Z j�Brieflmabout)�ale� ��ransfer!,to a watch gn%W300 µl=_��a�m��r�a 1 mM2� � solu%Hin DMSO�adA^m7D '!��. M�I%Oincub��� dark%�ihoue� hen B�.���20a�u� � -dq.Ba�%#freshI{�a��i�recover nH�20. 10–20∼2a� � adulVq�� thet�^%�0D% tric��|0etramis� dchlor� in=�A�3�[5&�s2o:�B %e|a�A���,∼1 cm drop# u��5!75I�ed-k. )��of �ng-�N�s�S���A�.��)�:T� rectly obw : "a ,�edR�ma��mmediateGno2%A1r$ pa���:flu�}c��iFscopy� IC%�2"i�Q(taken every!1second D�� "toward% atheca�s mea��"cr a�#�5 ��oug��5mvulva!]!z.^�eh8travel� ��]JbeginEBdL7c�_end�4di��!O� �ve valu= � mov�x^K 9�� star$pointA��g[mig: d1g�g!8,er than 90°E� in 3a secubfra ���ifi!s�al . 2 � s raz%"a�� imumr2 . 5��Ekmax1 . At�st 3 !5o-�t�si��v�qu *0 To ass\ )�Arib��nf�an��%.��}���qX��dq��2�%YQ� 3 zon��sf� Fig�1A . Z�3 :efL sEkreg��spaI�A����%mJplus / � �uqi �ca� wh�q larg�faggreg -� adjan!�z.l,� �expan�Aincluda�em.Z �s 1�Z2)��by� �mr!�e�E}!L 3 bordA�\ ��l%z >i�!?in halfA�xioVissoftwa Eqto ~�0�� A two samT-t�.4A6E�� . AA��coՖŧ-_pr�5i}fA .*: ���slowly�coo�ץ�.q�1% NP-4 A�fis L)!�O�2a M��k nkep"f�(at room tem+ %24eM��a@���sZ�. .lV�^q"l \��ac�ate��theirO sP�׍�1–5%�� Bw , ��0 gra�2r ; : s!�6 ..+@ - �&= Ex . Hy�hilic xM"4��efrozene pellet�A� a liquid- 9A�,technique [5�&� P qresuspee�%�12 ml��ic^ cetone/sU�A` 005% buty!{d� xytolu� ( BHT )A�A�� oxid�t6V OM i�t��Ktwe5� self!RCgaXs7P a�uv!� Bu!, Bl�$r 5 homoge+,r ( Next Adve�)%�. 7–�8lof�5� diam C�st|X zirconi�x� bea1�i�� ach�����:�a�se�sspeed 8�T 4�PH�)<$efficiencyAcheck�n�!cope sl� -be�-s:� four 10!��� )j L�wE=46 of 1∶2 f9A��!@&� !J�I h�s�B�^ޅ�ifua� at 4�i! clin�"%r�i�6 �RCF �superna6m:N7cnI�f6�An� ivala volumhhexan�j;�vortex or6� ��.u%����%?r�upL �phz!�(white debri�l!�er #ure d-Clower�d '� ci�� pH 3e �2 M�mic��e%Aal=<lo�E?J@.i�b�E�f- –1& F, �organic ��u}\F�> MM��q��-O�+�flu�e�n��g!]n:g�!�at� ��..'aq)� top layerj1�Xa�2���:�!�evapowe�Teflon-� ,e ( C57BL/6J�k�� �A.��Edry�ba�%n:�,)�M�-�� 50 g� 41 g�1��4 g6�79&�. Ld /Fd �&Vas*�abovei�!�&~excep� :�hd mm�h!:LA9 (�in�� u a�iz1�:"(eJcommerca|star? �I�m-l2� F*���a sZA��%� }Shimadzumin� HPLC)P a refrige�Eau�$� � <S t�  InstrE"CInc .o$�wbuMD ) �an API 4��( Appl�JBio �s/MDSZxA(ncord , Ont� , Canad�$trS#quadrup:YerM�� matograph$)�6a� Synergyc RP-C18 c�n!x- (�? � A�1%!��Aa�mobileɛ1�%�J2[A�� itr:*�N3B 3�um���  flow !�!�8l /A�i�"�'9 �)10% B%�w4 ���aB�2m �{ , 803��1� 1J Dretur�I� _Zo �-Xeff� �fint�(���F�M�n ESI3erface o6A� in nwve �  �{�!6e�� nebuliz: nd cur�(��4( CUR = 10�]|�,eI@H.��#� !0 ,�35 eV*60�,*pe+h)��>i$�Ar�' BioA�Dt�]4 . 2&�0i$aA�ve��,&+9� �ə��ru���l�g� �P CePGF2���#& tock&� ofQ"02α ( 1 µg/m�*Ex MeOH�[�l�luU���sam*l��'@ W , ,e 1 ne&�&)j��r"�bykMRMmo a�1A/vU. hibi�ex�(aFu ari.-��2� �� � �e�sr�o!s�t >a�99� veragZt!> calc�-p/�����iN� inde��"��Q -(S�>9�6$q& co-e!�a�� rse-� l��6�`achievI���a�x��publi� V w��.d [46��)�+d ���4ChiralPak AD-Ha�um-a>6 mm×2�m ,���{1 T�s(} Exto�PAA��1l<5% ethyl alcoholeG isop�K�a�ai)!�:Y�= m��!�>�� tmospher res�m*i� ��( APCI )J*ʥw2 K-$m/z 353/19>ai���r-m@optim�LA��5:545R5 �� mmun� i;0of bi�18apeutics can bo,neck deTp� pipS(rpoa&a"�- to w&�%"�a�c)\. A�s��Trn,a�!�� !7 im�#ed de�: techUk . We�+r�+�"�%algorith�,siu,ai(�-�� teiT-or�h r�3ed T �� epit�A����p,-l!)c� �sZo�Gi��d:obo$�ode�nce� a-(%no q le globalI>umI<re�!wpr�>*�st{',�#�c� dele� yielf � c� A � at e��A�deoff&�*%�IO po!� ! �'ar.A�`*!� edgej).*0e ParetoK nth0,2�1und� r varia|"!��(no E�1B a �� B aFiE�h cri�%,A�E�B�4 !�m9 �) ha]e!�!��(�)�*!e��experia_��. V� u"�EA1�.�u foun4#map a5kB& &Mb��8� ellIH ute�al�VdiE��TG5re���9a��first F0�rigor�9�!*0ui&eenaltB at must bT+ii�pursuA"u/��i� &+� �2���d�HGiv#� capa��to rapid&0s��MA:tr>�1x]��8�E$se.smay@veR fu� aug!�,7ele~ �Ude-risk.�%� or�7 TheU� �s�+re�a�izOdis�I�y a���broad&� iF i��illne!.�nd:. sa�*�aj�ingly��or�c6Upharmac�k��market [�0`0How 5Spower!@drugs s�&a e�( limiI��� , if�ACey�,ac-w7p��B2��ap��� A"B! ly u�!� factorEK-��1�s��i25nt�3.duc� ti-�Iv� spon�l uZ3pat�6 s [3�+[45� i�� sira10E�G�-��a�rom/-le�acyP�:ipe e�d�!e w6q�)W6� lthy�0 rsi,'&1 e�4- I�S � �!@�iA�4s� o7. O��t�9APC!� � Y9leaA�s6pde�"e�4��&  se A� load.zgroa�of�"( II major h�-![at9lex�( MHC3�-A[� &Z �(!�V�APC su�. Tru�:"� �� termB�fac�9�r��N�!!Lry �--&-�[ pA��� � ūcog� CD4+@ sw5N!�rits &!re5i�uIa i.a� �gM"ca�!atv#1t� �hel3 ��m/ BMN\<�6m�&y3o�$cirAA�bo�9�D�5!�Aa%�eig2�TW �& etai2!knowl2� procb$ena��0 5�� �via� %$of ke3sid�%ir� � �a� y!�monly�n�)(2& !�� exis!�E2�*!Oe nume��ex%�sucˡ�^Xpro/[o;�2A�e?�IA�uef���7reon�&, labo�#!�"�/�6nsa�2=�teg�. E6o dr)��achesG$ ail *�#e t�$�9!�'!�i�4"e �ca�$q0� + lappAHmT!�V>�O5�{hema�� aus7 -�� We��eri�al bloodonuI��F and/'/u0ed 9�����8[10��,9�7:9�q1f7oi+mj�1�>de�y)�u%�ns��*J>2�>�O&�"pr�  toolsj be���1[15 �ɦ17 8 �9., [2223�BIn_7��nt�v)��5 qE�b� i� g!ue�?�u�!�x ��� [2�2�Id29"�(A mM?of 6UO���! i�f�  ,#�"8���1�@� :e1e�p5Q"� ��4 a ch@@ng�askbd5��4�l��la��lan�>sc�(o� miF empi�-3m��e�� ����9Can��et � employed;2X"+ i)�� �p+)��asBgi8 ir6x��yet5F-�rv�"mAaL6-�@)$combinatorjm� 4!GA5a<ei )k�sop��ed��ra-��(oughput scrA�E�� n al�}�gk��bio"IAc�Aa��i. X�iR����2"9 � n:le�+liks �? srup����+:> d5`�< , [2� hY �`in 2����f'sV�2WT=��s�!\oE�ly��F49ho�Any�&h�8,*Q om� w:�ofai5A�*�kmb�+�rI�ll=@xFY��^.�I�reb�eH+A�al�!oQf5�IX&)Fw�<6�m��gpval�dM=�e5!> ,�iGc�g> al uDty!'!�wo-Ab,h� b�+��=~>@az'dӅ�ee-%:e�n�' �q�Z)��% seam�:lFteL/I %�y4N���>�OeU�>�assoc; �:z!<9�!yg[2�!2�!2�!3�:By!k��g-!"��%� n�T)""�)�$'.�� Qp9L7-�%)��!wQ@om�=�1 scal�!���te� ei� novec", Dyna�Prmm!�|D�P� �DP�:aLI!�er�+:I%�p9I9,I�rg�/p� min� 2 m0aEEE�ob;8\ cloacae P99 Beta-lactamo#(βL ) Z, [31�a��.�� *�-qe!"_� c.?.�ly-G %��+sD . @w]ztP9�W _EG��q�ext� �!9 , em� �$�>31� “-v E�m�QFrQ”!* epfr!)3~W� asr���Ke"�iG E��b��3iJY��A,61}@, ��\eY�� tireS  m&�&���s w�5�!0~�� "bby anyRS. E759"� ^��9 q *a%ubF a "E.f2Q�. � )-Zg��*&�nbV2�a�2sNpl�@a&i new��� i�&Jlin�AM�)�`�,U� nd2�&W� !�le�Sis�/k�UA�I�-ba��"w &:�F�c�.d�. qp�6Ry�FVm�hPDBm !3CmonyA l�4 ��a��"�S. F�#,ae3yAx!ЙQl�~W#.� .Sof&�S,"f m� clu�*A� Comp�,�o�7�� 1I�b � aY�leN� ����o�i 8ZBB� B_Xc2� �T[ V�TTx. S0D%0��).s9rKX;�7"Cinm�Or� A�U�� ��parti9r�&t �!�o�355 s 4M!�ough 7S�-uJ(lan 8U encovauR105S�5-�m����5Ze�n)G-�� a d�-�w8e� w ^Do6.5U�3�hdMmb�PR%� s 8Vp�8Z��j\ixAf��.h;�%��5sG103D+ �dou�"1��  E�0s M235Q+V243L�P(Q333D+I334L)�F'P2/)y�-' �!�H� ���^$n�:a�%(�1)2InA�A:e��S>u��third&~Qek"+B�!�!<D7of��&&��%vi�*ua� �M���  N14R\>R��1��T'ngp.eb3"& ��a�4N , 5R�nd 8V;�~A�17�I!4 74;}��pit)��.� �of�M1E�! f���6�M� A13Elbyc�ha��a:�25 . ` 10�6a�� ��q a -� �#�b�"in�e,�D��:Y�D) �(=��tit(��";oA�-�ly poo�Kc2� !�& �39 8 !�140.@14P���,i�� %&A��[��cr�QQ�)QmR��ng{@&A h&c�&���"� :� A)* epi �60A�!of"� 8Z�&3 �~Ral�T�E-�J��Y�3Aor���d."�ed!�s?0�*mb>b8� A[PCRu.�f"�B olig "ot�/m�V ge�?.27 a 5′-coU�!8 OmpA���%�a 3^7 a C-�&A��?-3idi�PaGe�H%"clo:-behin� strXVT7!��^r!fvec�pET26b �-2ex(/_E .s1i h�BL2�TDE��t[F– ompT hsdSB ( rB- mB- ) gPcmk-*"Reɱ�V� vre�!��M�# lasm!�osfMc�Ick%9a�e|�0"�# to>9�D} 89#Wl[&'y 2�9B Y" �@5^Ng/�%!4 $GS���4��^%y}XU�.����I��Y" mq<�  W� P �A��a8pK nt melm*8�{Tm #) fA�by&�7i "("5Nim9?[3�$he Tm's�2�z�1�4��09�GNG27�C,�"83–99%H�31e�/d>2612) (ݺ�eOd �65,��in�{[?b6Hr�_a�%AK-�,� �s/!���nR �x=}�&��� A�un0eE at 3� ( S1�!~� �1=�l@)�r1A��FI:U<  m_�, W!�?��6�/�)���0�n"L`"��"�"WL h��i�Z�0g*�`de�e*�D!5e��XM�_9� df z/ng�ݾ� W �Z= "�#� CA'�k` !(��-�LJmK��4Lg*!� 1J"1 +  ") .B�;gligi` Y76�E&�I�6�IP�#)U �I*� b z1R210HW J4883a d4S l�R�P)@at ;~f gU�N�bi��+it�Iaĭ��x< �I�nm) ,!Khv*�n UV25I �XT342Kɫ6�e�w ElsPO<j2K�%� Q#s&e9#pF�GTm ��eidgle����!l�fur%corrobo� #A� aris^�'��5QP4MI1I WTU>�<&� ����% � s@4i� A�Tm�La��W"9g� #j �`ub}�� m� @ ,r,gea �� ��+g{,�"��he 4-�!�i24No4O9%�by:�AH�: ,7U8UMy<�8W],%#�inguisrf�a �ekiQDe�.�'6/�:��+J9�( 4��47≈ 7��5�-01≈ �[:�� More�� �reJeC)!"~dN& 1o�d��]�:�2�� s al[`y13�5�@A�3e�:Mb6�5R9�� 4M!�%zH)C4�0El,e�%w�s](dd�*o ( TmX %+15 !A%P9J7�N � k�?�@$�(6��-bifurk;�O�{xd173��f�m)d-| . Wi�e:DF ,Y�� A |2w berC52��( a�?5 %5��gl"t �aZm *,ed��l5�m�* OJm5�09�A�!"sYk�S �L�# 6�Q�I,!{sAi�FE@� �sX bdWFL@!ɍ��x�i��2�1��B�.f�W��,� �It Smsl~9w��@ms��6I ��?=�Me� �a poc�7�y^�Iby D8 D87g'108-(E[] ( S2"j �eesumab��r�-�e�,{mXz$%" �Mh3)�1L7=�isA�i���.�V��l*Rr�Q>1j�}e(�'r�n��*A �\�;:TR7d�$e�j�)GrAcaQm� manifesA�>��I1� on cataly�"�� 1� �i -�m� tIE���rLon�,R2s (AAA ule�a�AZ�!unfavo2� �c�)mMaD%f�,�/�2]�&it�j�+no!%��zk*1%a��cTZ ���o Waeiih�1Pq�_U�!4i y, 1�B P9�(�}]N�"Tm�����Uinx9�a)��Un�,reg�:!�6Q!]�=! �g"G (;-zero�WpPͱ��01}f-4�C.�Zv�=0ccu� k�d�.n�&ar R244f,��"�.perV A����pcab"�z.*��!T$�j ,N^��/&�#:PA���]�tIEy!�QaYv|&S\QFaq��)&9*](Michaelis-M�un kin�� �(� M�+u�KELbet�6, �O%�n�Ic\�=% �#. LBUof �J� numb�Lkcat )g c��N<i�(!/K�"�&"�-Q X�Q�� P��9�I��&� I \e!! � E�a�S.o( K��&4B�F����S�46�;T�.N~>{be�36#=;pro"�0� � v�m �itE�qcI5� ��t���w"�`�&onM�%R�%�H :�O ��65�c6%�Jof*� P�!&� EJ� m� 114%%rNot11L18+� ya�q���ima`�v1w>.6g@ .�:�K 5/18�Olso�A� ��n/inA3����l)�� !Ea!A.���88N-(%W` � 56 K21)In gene�),=a�F��a�b�! �:m&Zm�N_*EI=(��a�-*���8TC 8UM785Je����e�+ ll5M`�QV5QR5R!�09%%2UB@ )�"�Ea[i"�!��5�0ex��<�* �M� ��� ( 2A�H 164%=�B�. Toge��s�%�ee!&lK�*� !B& �{d�p"bea�, *J3Hy��1r?of.i�ш�6�$�*"}(d�e>.`5vU)���� �a_�D"~-�H�9�A�z�rcXf2&�$:16 statF"�$5=._/Ind],�@L�� Z�Q�(:� )!�� �� ��e�E7 �%m � �A d 77i71%>Q,!�Y)�l�Cs:�">-� ,��+i� �HJ0.��C�he�F�5ndyD�  a�182|ѵ*�! cM$|to�� e�slFI�s�.u-o�:H� "kb9%�g�LAS� �AlCn�� iruE % fr4D%bs_ ()_ �ass�n#%a�>��B��ic�s8! :0(Y�!cv09�!,AI-)i�G"�>�>�0D1 �:[3�73�73�aSynekc�2Y�����o�]`n�assH)<&�"�e:<a"�5� c� 5rQ�-zhs�$�}0�@!�`*�aTE`�e2� c%�2�� es�[2Ap"_ �x]i�n�Hm5�� �$� � ��vIda"�y�us5+^��<1��&q �!<�C!�ix"a�� 5%CP?Gm3�>A�re�I��s IC50A��D)�I� T�+IS6j�(@<�TM � � µM≤b<1u\ # weak Dor�a��o(d ≥1$. High�9,::'n.1��ge|W.pII%�o�6�U� �$ub�ot$=U�Q[4kC41�9=);flt��49�PK �-S"N� sub-�imoDA!:'It/r�'m�tvI���qrA13+N14sEZ� 98)cQ�570^!w� 800 n)�!?D A13D�M����F nverAZ�to�V!�i�ar-�ei��U:�&N2Q�6E�A!OO��4�A��69 -w L149% b9&9ll!�r5G)��� a�.0*�%M���"�6M�cY.%6�yvQ" Ted 8m�y�40��1%H!%It.F9d.X � I262�� �Z��o���?6�� E 0�7A% �iV�%ށm 6 �%��in 8X_ �@� %"�-t�i 2�, �l�a��� �Bu�iF �MDgR �?utc�{A ����&5V ��AQ��$)ooA [ {�!��CF�r%9(I48D�-E*tSx((*fk*g���I48=��2t��29Q+ 11�%�8 *�",�}Y��̅e 116��fZ. O�e 72 pai�L�f{ 4. -�a�1[��M, �16SiF�"�B� I|ed�II[em 2t!qan Cnl/"�0%��-��al!-&�.>otIN� �z5-!@1u�! 10O"���A� st 2/5:M�2�)+=�1sva 3F%5%��9 i-%A�:�byvы>vA�-�E�n/(Eb9!z�"� ~.*�>IS' dK� In� ��/GE#" eO�c>F���n"r��#%�1�or"Vs2k�6) d]�a 9 �B�A��!�"z '��W2y��ߍ#/non- � z-shold� ��e"�al~8 0bA�s arbi�Vi|=e0^SL m��p�c9�&&<wo�>"e,>�A�cutoffF��� bn�<� &9Ac�vA�����38)�wuO;;�/..pV2 9-a�a"#>=s#ofa=,�zi�� ��5%� �O����L�D ɚ����>�W����Q� � ( 76��.) b � 59+. O�%�&� 13% fal_3o ��] a 22neg�J,"l!�a�w}Yv�� �@ly� E���4e��q"&1$newer IEDBE��|sf� NNAl�Qg*=x�<"��us �� ��� @o4�?uC�v%Tcy"�W>[ ( SڊS4�S5�%U>�1a'�@va�c9 %KeY S��p7.�7P��2�B_�� ��E�}�AM"T>, e#��*y�<:���9��c�,C&�"_t��ya�6I MHC���F��16������enEj)ht'wh�C��,�Qa�m'a�*�!�� _Jm�!~G  lengkfj��Z.%ach��4n'#I,B�mv.�*suIx��/VR��V��>-'s%5on��( • 4H�vs =5r �*!!iCa+*n� p|<�2YEa�z'^.+�����+xa g�w��&!�2BTmov%�1Ia�z2���.� 6A �j sE�!�Q�.Cnef� 6�2&,�58m54/ �}"�:8� 16R<�A2/. I �F#Z�.I���� ne`S�'�  2_�� ; �� E��8|�b2o�5e-4� !4ICdn;!�LA�!�m'Nam�, 5A�*dvPal)=er�)�)�L�el�/�9v�wo� F!�A�la�:wo���pr�^;�C a��y!�E��3|se��  � RH��2�m��I�! ���A% �>yA�� �#�a%�a&l L� ik"�YJE�<sPf�r~�/6  &Y A^ ��)� eF�6��!�!uE� �3�e�^�:ng�all�r�d�ll2�G<T5 �-II TAڅ�d�PE�!a��kf4�*R.9$8Z benefit!��za 39% 2Qm �c>z e 47.2]�\%:���A?R 3-pp�Q�&Tcor��ua��C2�� ��jf&� !d�y-�b eB|�se2� .���E�*Pj� �!�kI�J ��r��V�> Jd�Pq!! ]EX��1l�5 iDm���&�JM/*,�& :t*�UO� D�@b��oI�4 prec^`9Ao�#%2s>���� Be))�se�J� rec cWDE�4u?=�S)A?"w^� the�U�E�i�M�v� 6.�� do so% &IXO�on �JseV"If:I� Each9�MlJ� normBt\<0Sq*�,!�"��-t M=:�$ͲE�u.�i&g2�J���rdb��-�A� .�;��Wd�a�0��?!}��s*["!�a��)/to�nt5 �Jq�a .E%�f_&E�j�-K W]D��I�G"} ��I%�0$����E�eva8A2/N a 63.6  .�.5�M(,6� a�!�6�~*�)��sur�I�yv;�r) �y�z��ed�3i�"y(�J1(2�)64;e�*W*P<�'1;m�4Ee ; S�Ko� �'o7 z!�p f�!�b�vi�@-�)�AVI^taAM��u2_iKuz%�t5 !Y�o0f]����AXQ�s� F�o�od�d�. Yzi^s. �@ .~6UYA��7IS6�8�L%���[30@�%K�ame�R!O2�b2\i!R2uy few �qpaLR�0��,*�pst��B�^�.��� f&�O ng] �wo I�)5 Fr�`&m_ , [4�Q"�#�i��k�Q*:feasi�/1S6i,�-�`"�eZm���AӘ��& � rof����mor�]mA/� popu3D�!4�<= "}0rw���� �q u�]��c,%`is�H��on� how ["�c0�)��ddu!Ia�s*)���#aW*e��6��2)+"H"s�et"�o��nA�>�,�cTo�A`�icQz��`��7O�uu/atRFed��t?�$.��AO �Q$0&@'&�N��І$Rble�9smWde����h�9N�=B?q� �sJ�\s.�Uֱ���\�\2r�L�qu1���R��(3�(rM��Ra��Ya suite!�18 �KBal�W��� )�s���Ps0��Ms�*NtSbBnOdKs�kiA!A3�o��:=<&XR>�p �a�-�!>o�Pe��))*�( - ��In71!� �> 5??(=x)a�7U= <m.N9��r9n�$�s��GN��[p�U3J��wIa��SPo3�F�-.u�p"�8�2&�1!�&E*�T���| ��Q3y� �reI�an�&�FllAf)=�;C!��Z� ha�eȠth�(}6i�C, aA)� �u. � �8�Z� ��!D�V&A,!fbN*�` ;e]�"{Q�Wis�x6��q�n.{Z Ou(d�^� demoG��.�q)\B��:E5YFP�y�er�kix&H &V/5z!�}5&9�/$mByɊths���g�:s � spac͝\��%Z�/o�M)�6C�ob�?2�v�G/��r+��dly�RlosqD�(ar��}=� �8!@r�Ce>�� a>��8T��8Z �'!c2e-#6Q:�;�'ח8���q!��v!�.�vlRs�,"�D�+�8H�o$�'ioZb2L8TBUQGR2����c�Nen�PG{%�%*u1 ��$�ac�=A��Zy Y�!�cN�5>t&� 1�ZE��m��40.�inX"kc�J��r8T��j ra! WB@�C&'#of Δ��%&w-}@Ni.�U�M(�3� ���b�)!]z0!2act�y2��Za�*7a.t(� g �� {D ��f {\�$4A2�61 ;e�=�Px8�mt$Jd* {Q| er�4W�� b�u.���V�l�B��> of d�d�B�K�wo̅�<s"��y�-a��e�j! � ^e=, dep^ �P99�d.�:�2a�� n!�Y!�y 8 �'a�arp y��E}m&.4q�><*�Q��U��F���� s�5�Y'reXor�"�x��=tr� !V.�� oѥ"� �cQx8B��/A"#@;�r�Z�� "�h2e.=�7���"�'5cipro!�(%�TU93� /Km;�D )vAm�I>/2%M.# �*�����J�^C>how� :�mDf�1� su̞�A*� � A &J��Z alog;!ma0r�5�a� #*.wU�sA��38E&�m� >� ��� 8C-H%'If i%/A٥2�lyL����� "U� �=!]e 4lEs&,$e*vg� ,�8[�Go�"X>,f�%'��� ��]s B , G�*H���ss <, EF% eA �Er�`�h tage!��+�6W� eE]� w�tyqNe Bin"�Y).�a���V<��e�$r4( �(fQ1 � &uB�a�vm!`6�5 OR4a8l,�Ev llel�E{Fa�!pjN]"Ma"�F� H%:&E��[c"�7"�X*�}.p3 ��&��Ae�c �9��� %fi&�B� )!d&_E�}!%�� "0��� $a�a`tV,�Gɘ�7� Q earl0��lY� H";H+| A.�E orme� e�sga�a:�loc�H��x#A�"�x���x�}�� tA�e6raie�he qu�Fnwh;�3;���0 -body + 2 U3c.�Aof�񔥪5�1;e N&r7�=��P���*$� s�PX�f�s]oM�VBq�6��R�J��!ru N{�J!I*�L��5&fL:t�^%�6�0�be+ŲM�2G!KbE�t%q"�N�/ ?f�.~2�-.��%Yhel�mm�(����IT� � �JE��c�2�F=�M5:Q5Q�e�lyI!�nd� a��1)�"_� ab"�dP�W�ur&Bh2~��",Mw̜U[n�<� beQeyf12� Fhre���<&U T .:��lu>H �2��: !%� dE�"�edQ�f�f!o"� q p i�ql�)A�Il!`�,J ���<��2q � S -�.�>+wy?�a\"&�Z"�BKER>�؆A�ae�8�ɫ��mi74� X�B� �-�Ց=�5e ce�2'#* 5. Non�d�J�4� ] *v� �*�prM+Se�>\A$i�s!e. ity;E�a�-�E[<�Y�2 6stq|�W�A��42��Xi�Eb ��`ZQAaA�t� �4>I3> %� &< qT � �A�|m�0�E��$ 502bX )@�B�K.� !t�ev-&��tA�e�*|(2�)u�E�.� U\e��1�RI�5�u�sns�2���#XM�;� nti����%5� �&�s &:��7 "����i�,tia(�"�a_o2aB*� �%A�*If1��an� * ��Ye?�#ich����{'I��lec!�&UY*�eet"�"j��)s . O>�]����!�� ard<^�0(�` nmol"�#' desa�[)@BT^d�6"�?a n32PPAGE Pusg ed )�� purcݝBH_O-� DNA "[�y��an Dieg{%C����J� :M4Oxoid ( Cambris� , UK3�� lyso�\!SYPRO O_'5000×[0�� Sta� :dSigma�=� LouiA�MOeM�Amp F0YOp�P�J�� 96-W�����2- Adhe�@ Film)2E1Ap>)���edf�M)ReF �$�g4`rer"Y:�New EnؼL�Lab` IpswA�,`GrowthR,N�B�_!�3 qX4( Franklin Lak�"NJ%,P _id�L�� ki  nd Ni-NTAa5Z�Qi� ( V�cd�M$��nup�gei+t�� d%�%Y Zymo!8�8+��_N�"de*"W-M��G�9GenScrip� Piscatawaf��6� � 8�5ur0 Biotin��er&�)::�,21st Century>O�N!�Marlb�9�ͶDR�R@:YBenaroya9��Zeaea7� , WA|�ti- \-DR:A� %fBioleg�( B�<8d DELFIA Eu-labJ�Streptav8bEnKPerkinEl�( Bos~�mU ��Z�^9A`6 XVW|JRad�[,Δ. FA=..�[m�����"�8P2��.� ,�;vd2�j8�!� .��a&�k����ig� ( MS!� of 9)�mn�Pfam 00�e�%�| &� .Eby ���F��≥30%~ ��.�(, ≤9^(�)�)�$≤25% gap�" "�7�f�m":��ach aT�V a M8sE(EC�� !|l8on-� �n�$W�ds φi���AGm.A�i� � )��� � �Xat� ���gr0-��� [45]Qwo>�, j�, b )%{p�>La�κ#aeyupz1 !uj�x� �.e6gW�"z�| , �� :� C2Ion2J'avo���kcw;э�h��� � !��+c�A|ac� � χ2-b�ztet�!��3E�u"&��! Jq�Tlf� s [e�ao:=Ure� (k,8c�i"�fG`g3u��]UZ��9*� �&Yimp�of"� �� p�kE��m��ve:�A��1? (� %}�f[9=�E5�Pr>�YoO<*�*h�H M�$m��#V�(�a�5{� ��c� !���'F'refer�s-<f"z�[N�5�@�:�9��f���;)*;���%_2a�ideq �a��.Ju� }>[42���^ K�1*i�(Ut�K.�& nona� �1 X.�� :f ( i�� ��&?aaa; tigu�� 32,L"�!�U�E��1I�as ei� i�)�,�W�r �>mi&m: 9sE��:��g�EH-'s"�A �X��4 ]�,O$�FM���|�gt)aleRA��\>e��!��@��O5%!> 10%;"�>54oS�wIm�^cE} +��H� *��� [4��Ul"�u#&C�GA(X Eo�8�a� m�1O�o�J �7Y��+jNZ&H,iȽ"� �&@*_Q�����t�e"�U� �*��y}B!�i� �� �.-it�^hv� (P7#;q���-� ]Axr�p������-;y%�;r-SyQSO . W&BC�<! @Ois!�X`Ie� find!#d&M;MA%$W� ��YwWZ����l9P�Xݗh<��4��ln�aij�i]�o�Dc /v���Z�5/��i 2:!V"�� ( He" �201A�JZt�Le�je�N��Dv Ѣ�Ral� IBM CPLEXB�]�q �S�&q� ae� step!"�&�z�)sssS(P�0*y"� Ffifty-$4 n,cB�eWyaϥ�M��dhpp8b s o*�r�GA�r�rH�3Q"2c��( GGGSAETVEHkT �X9e"+ e`a(��&�&�<� ��r�|p�`>Qi�uc�Ldi��d ; Xba1�HindII�{li�u0 ��^92es�E�ehe�"Ls )&fsnrs�ZsEF�in 200�q00 .�LB~uӭ�!�3�<0g/ml kanamyciLB-Kan%{bT�a��a E��sub ��s ���n�[ <� g-�IEe#,"\q� L baff!�flask� �AR��i�p�� .qA�%�*&���,�&i"��a�ɳ Jc�� Iiz�2�1�� IPTGax"F 1�20q�w 4���z osmoakshockk� j��eI���ocoܠ�� Epi]hrɃriPreps�i?u� KB��sl%��v�6I~%�ĺ�tY�0g)0�RS�!{A ��invJ�B�DahQnh=5��z1"X . Ce��� C�I#afN)�y u�>jo-�ice-col�(B)�%��/�8��'>�I7L!<�f�!�z�N �^p��!�5�%�݉0Z2 Das9&��,O Q�ee clar��R�I)2�("������mee�E�zU� �*jJ�n!gra��c�5wa^�2�E� 1 mLa PBS# 37a8NaC�4�kK10 Na2HPO!MA//KH2 pH V��!)/!|s*�2fG&�h�c"5)�c� O�2!�2�� o7A�H�UcomUeS~�CB�2��All�Uefit��|'E0u�O )�ela9 F8in��G-��v� -G��7 !UE~�by  )zj1)�NB4F#E:�U,=i��p�- is f��S9&��U g*N( iNt!6]�m��l��I ( iv�<� 7� "d � �5t��!J�pM�ey�4a�� N�me�Cg-V�2IZFe��Q"<&1O“#NonA�ers��cX!�J��~V≥X�2!a �&skmutc “w �����i�A�ZYn��:Y��S#|Di�C�!���űc�:'uAD�� ��"�6ݫ-�+�-�.&i��ic!.!`ab@.F�ti2!.�v�!d���?%,� n F �"s2g>"�M��f�&1M_S."�7d�[eα$f�<05��l .SjFUa st eukary��, sexu m-!w�8fu&���;es�#�����io� 8# v , m &�8dQ��v�"�;�!��+��~�#&�l�:؈o@�A:Ak/. (Ze?( Cf+,a��]re�ȓ=ʱk�Es���Ԡd:�! ��OR"��in�s �2*[�ߔ��nK muchY/is���A�&!*f�g�j #deJ�^���"6W&]�^#v"�.*�-��hp�-r�F�(in Arabidop!�thalian� dJ0[�getx�%#�Mi��#&@#6\",�uI"�Eev tra 1w6Dv�:��u T�J��e�# �_i�Md}Q9heat-)dfO5!d��R!A��&-=nd break�i �:Lҵ heno��DM���c!&� �heg_rI-!irAq�sfI\'s] �t>?t�ing=v��p/�Q^!���A�o�C:�c�mmodiNe� %|,�<cMI/!߸%jo�Q*0I�!"� S�pl��rR%e� 1 �A�!��Yu��oo��pIpl�/g� �#di deni�;Q-#oo$�!loJq �O?L���hd�c�f{��!��� ��,=rossing-a�fET��Z��KI�e`w{l2e��=�sE�� ��eV%�"pa��(B�Q���'o,�sm����!)a�)\'%�"AW���J@IR���!/�3uV�s�jpr��sig�c%"RDs�81h�a�*`9�,��s[:�do.�ZB*�Gim"�M�75� %ngQSO aneuE�IZ�rAef+T@��Q1leAvi%HS�60�0offsp%Gx!rh-��2�U!b��#]A|l|(�j�2e���.�Ua�i�c�it1� D�'e.~ po11�`b7( DSBeQg�I6q%����x��8���34p�-I+?"�`100��i�9�E�DS���doE(�r:jl?CO*�-�/6n�,Y �g A+g n}E2;���) homev��b�rol []� Desp%?t%,?� !�%�6 b�9�yEes� R �P!�utr�availq=�Cos ?:n"��A#xi| �Li�.! [9�b�HoJ �7� Ave �QqUG\)W2 ��� as)��Fe*�CO ���]a��ܡ���i�(�e&���D�ceF)G@#no/ E�p%ye(��Aa�f�Om�zNI "���5��t�ny���i"2H�4um vulg� , Vib5fab�Hyacint��o%�al7�RY �:"� ]Y��kly`;# 9s9� ��RQ �*�b.fy"��!�b��"@(d�r��bDE�i�$�����!�o�.a)Be d=��e�#:��/+�exB�$ e��pe�A�ae6_ �=�vETof�1�� a@�C� ynapH�:���"�@ �g� A�B�����nnM�epw�<]�A1U�NAxh�6V�. �g a#� *�� u I�+s ��i- �<( ~85%#f��A�BG JI!�.�a�+r.S n placn!"p�2�rfe>� ) ; uI� make�Qv �.ɀ�� �A��z� r���[�!��m� `6JTh6� � "��2�6 fanc�Kfig� top3αAvn��cq4A/0I� T1�a�$!hY'U�r2K %=m�� �eL�OEma�)�9�:� d�uican:^I�2�[1?�}�� �5sa�at 28!�.*�`t��ifR� �2Fc�5� ,�! ��To bu5�+>u��"le^�"� ��8l�ET���/l�+,�e���lle6�aN�a�B�2�",Z���|�.!;!,��A6��!*EFK)�1- A{�'�ct�5V� 12p2/ U � X)n&!t:!8tion phenotype �U. We also show that this response is temperature-specific rather than a general stress>andU�Oe extra COs occur without increasing the number of meiotic double-strand breaks �would �,like to note tin P proc�$of submittj�>our manuscript , Lloyd et al . , have published an early online.<%65Esx �e Type I�,at elevated =V&�Arabidopsis [19] . We had previously us�� pollen-based , fluorescent tagged �4( FTL ) system! demonstra1#.vgrown��standard 20°C conditions experiences�\CO frequencies when shif� o 28E@[20] . In brief ,%�� �0employs pairs!�transgenk ncod!�.�proteins�definedE�A1@intervals . These.NarA� pres!? undeA�e1VU�, post-Q�promoterA+AT52 [21� `markers]de�ed!טa qrt1-2 background [22] , which causes }@ from individual }ses!�be I�a�0trads , allow!aVto% assa}(visually by�ck'eattern!dJP!�!ion�1t o@. To determine if.�-dependA��!ederived �Im or I pathway!De analyzed mutant A�E Dmsh4 ( At4g17380 )�Ymus81  30871Wdisabl� e m3 �x!C��@ectively [14 , 15!� MSH4�� a homolog!2�bacteri!�(is-match reA�E� MutS�Phas lost its MMR funcaK![.|[14snstead,�Qx �EA� recombinaQ1Jalong�[ ot��ZMMA�i,(such as ZIP�hMSH5 , MER3 , HEI10 , SHOC1%/PTD [224I�ere it!��ghtAv act �in�prophas��to�Tbilize ��$Holliday J-0s ( dHJs ) [2)� US81k,an endonucleR{$play a rol�F!'resolu%��ingle-�{J%S2�26 , 27])���mediates��orm)h�U)�UI [I4WTiI�plants�Za!����a�!Ľ<y�:���8A�e�i Sd���ig 1At1B!�1 TE�0) . As a sepa��method!confia��pse!2ulta ,we immunosta�R.% male�cy!$at diakine��u!i a MLHA<tibody . i� MutLuK�4co-locaAsI� MLH3!c! Vat sim0will bA�uՁl[28a=Aɠc�x,EWT10,! ign��Z.�� focim)u�( average = 11 . 8 , n = 41 ) was obser�� rela��ae" y�>D :pthirdD.�Rcalcul heN A�di� c�: �%valA�� I�f g adja 1( XwiE w�o�7I7cj(of no chang~Cq,>� both[�Xwoѱi�A}��. ( de��2e��re��a� b tor� � ng2&i . Our F�d�Wa sma�SuAEn-.O�oof�s�|te�in�]:� ( S1�; , S4��, sugges|��a_ei jho� �e effec� $subtle . P � ort2 N3mV s�identɷd�antagon� � aXH Z� �P TFANCM , FIGL1 , TOP3αE�� [ a�or��I��Z A�uc!���A22V�2I\ s)�.� NaCl�at�AB. No dif�>�22 Q2nat z10!B200 mM t� 3AE� �����:�8 a-���2:eAA�h)I  BHLH12A�sm%��d� tibio [3�$V aldo/keto# t\family��� AKR4C9� .csalin* )�2d3�l�!CmMy.DtreW -vA�ed physi�A� ���>>s( C�l,�$turgoru 5  )�CNe6h�1T!# �E(nly���y �:�.Q�5"l. Pz0 with1E, �2� ���( foldS = E djusn&o0-3�,� �zL�ZL315E�N�-.�!�1!XE�dM:"P E�5.�of6�>�8 . 2N�4 c�} �>F1!$=96!Q812A. Take�+: V� :�salu� does k i�sam�vN( phenot�khe.� , J�  lR� a "?r*!c r&� saQ2�^be aug�bed�at\ st two me� isms:��1�!�f&-of DSBP�c(concomi]ly>e�N� !�E�by�O ^r Z NCO:'to favo� dao� a paralle� !��� bL���J � 6�P.na �l9 �#io��*��q$unt γH2AX% RAD51�Bzygotene� WT ,�� ��p. T vari� histO��$approximat�10%Y�� " at(s phosphory2(�)A5ser�139�Ur� O%��ON�%�.91�1���!]�.(2� (+� A<�����F�AY0exhibit a dra�c&3>m .�&1�� uN rejS~hypW ze�*�!] N� P.1��. Despi� e necess� for�to end Ser.�segreg��n%�ev�*����2his� home�� � ,,�:s��lteby!ernal �c(.=. Haq n �:�����oV��]Oa %��c ->�"m�|�!� ɡG�?remain�I*"e�˚CE"i!�%9�lD.g>H2�:y.1Ej�. "� Hknw"�A|r5Y %y.ub"%U.�"W B:a:*>�noaS ubiquitou*)�!!.�X�%ݤ2bmimic�eaYB�"h P Kan6��Qg��=,SmaA��) ]�~�!e�!���or !Surpri�l�!discove!%�I#�" g!u�#��e� �D��barle�IR�Au<!�b�rN�"yC���w ribu%�.@2h )3gis%d [37�A{ eB�%�6�in�ren�%�!�l"�&�Be%��6$a �#Od�mor� di �#n#���aa pro�>i��ary!�N!t�#} s�T:yp� field.�m9!&#�a��et1� � yl&fer9q[3Lse <� s rai�%�%ssiz"tyI�epi� ��&N e>p6K"regng%9�A5��in!-i��x�)cuea8M$sex�% repr�_3es&t���Zagnitude1�)��.v!I��M , mspe�6hav�!� � ew5:R��oPre���y�excep��*clu�se/!l�$giBe SAR tr ,opiles-Alveo� @s-Rhizaria Eukary�)) super%'p���qcts [3-4-A�� mole/r l���O work!�RA�)1!�"�����ata (P�Ell&ssembl!�refA�%���D-loops�cp+G)2 dir� I}�& SDSAax9'���go�orm�K*" 1i)�!!�qj}%�9to ($%6n�as j�ile� in� sb `�]x*nFvaq} �h step!Z�[1�PT ,:��-�dA � bund_ poolaA=ia�(eve�%# a6*aul%�gra!ea ,$if left unA�r%,�i�m�ABa/a(= commY�#toMw' is? blem�obetiE�ly acut  polyploid��� must�=�COM�S avoi�"�3#�&�s�.' [3SE�ef�(intriguIrat� osur�$ mode��`" �"�w�� .Yeusho~1be? s �8�'�.s�X ex(X p>� >k� )s�!pNk & &c al��o j.��ve��B� aj.>"*�b�!,terochiasmic�"� ,29�1�5,r��ck&=+s ,%fe"R[4�Fur��m��I 2�CY�sus"\X�A d�y.f[4�*4���)&�1-�J����us���%�1f m/!B)Od �e���R . Gi!�!�fluid� �PhA�� myb�&M�!2acros� �Frga38 seemE�t.�&�1he9�E�A�be un"�.P!sel��,u�$23�(?3 �3� rQ&ofZH%}e, ��er +s��originr)Cc�e!)nseo36�4"_ P/q� p�al&��a�e�"$ly cold ( �3 - 13�3).>� well�4 Al{ !!2�� ���$olumbia ecoB chAX adap�So ��( e cla�f��ơ�aFEK m"~*].�wCso�� �s.� trop4 �A]�Tas Cvi��Pape Verde Islands [49L1or%X-�g[5+5� 6a��"H ��pa*F M�#,":��a-��+=�n�em5fsV %�C,&� 9��U�y�7m9a"[�0. For examplea�sa!4,fungus Sorda#fHola �Hharsh micro-environ� �{e�(.� �0e.4 �ft5 mildNU�'he5cola���D)i  �t%"< " �=)�7�E��@I[51A*o !c thei�����`�!�aed4�24�4,Q���oJ c,U.��Grobus�'2 $2esA�<“set points”�J8A�n c p�-�er�:Q�}�� �b��Aq 07is�V[� ��� "�5ofU#ca&"%�e + .O ynap��A�lex2C )� "�A�Q T2���1 ��A1 oupl�.#:SCm:�� al �o/8�_�I�5r �I6�.U)�un�n<|E����x.�,/iV7ngey ��*� /� 2).��c3:  he a6ad �a2R:� ���2�sA�����9(pur�_� Z in nI�C�J�9���&of93h subs| e�ksub�o�qaz �Ei.�r�8��BMm)M� 2vi��aXa+�[ f pr�X$al importa�.6;*�l�� mea�&ai����-ea�"e� n�gen�i..�of.'aXA.�9�;s;�u|�2%D�.n!MIatE�.�� y ' ij���qq�� . ��"�1. EasJ(U �2���� ��F2!8 geny*�!�classic!*appX� ra�A�Yai� disru��persist <linkagels�-�desir� N � d^b��.el�,. Valu<�d�it i"�dis,:r�I_,"��_ w�����.�Q�6�9 26og)M ��ercaBb2�}!O+"/#ce�S,I$o�Pai5 �c�1a�I�ma eE�Q|�ap �p�fal5F�/urcG See "ork-|�!ob.�=A*�@B&N*ResQ Ce�;xI)l�>T-�$)�Y : u=.�=,, SALK_13629�#�0 $�=$0750),�$1g3553�! H 2062�9� SPO1$"*3g131E>��>�! [52]Q �?TL.�A�/ d� deC,bb+�2\>AM�F �a� -0 �j ( CS6000�9w���"�e�� "�"_.Q 2�+Wa�lewskij&� .=�@>�3^�884!�;w M (?j3� A�B ���)� PCR _<pJfAnd.� A�idi�S8�$. I�E]sd 8on Metromix-360m un-Gr�5 Unle�,4 w?no "$ H./ 18 h� days��%$&'th room�P�:c�5�!$ |!Nm/ Qs RIP�@�1chamb!or he �-� .UI�!�:$%Dow(g�s �plab9-��.kf�Z ��E B% c-)ed!Vqfifth+�2�9KA�dry soil N bottom wa� d until s B 30m0,�- �20�c!C2��f�C�. C0�",yE���aSC�opE���� 2~IW�+col &�( I1a��3}�D , S9M�m/R��F` i0Da Nikon Eclipse E1�Bepi&�C�L scopY �):>��5c��`E>�-g5MbQ'by�9 capt*� �*W�7nt slid�*r each{'70Zeiss LSM 880A�f?@( laser scan��,m[_}}21�8l�T.6t�F�:W Fiji [53]%�a cusA�bui*N NA�D� D( https://github .  /jmodlis/:.)mFal<-)m� ge� 3 �k*6;)��Perki�GquiB[5�C �Gerr�i#&x;A�,Stahl Lab On�  Tool�)�P://elizabethhousworth �9Lab 76/E�a��/Qs � R [5�I��&>�fo@�"\>Malkova�I[5Je9B1��I5cu[�)TL1963� 14�DCFPYFP ]%9)n : a y�"�;CF}<I5,)� qe!FTL245�idsRED�+ �{BHe0!��"R8�Q桅R(=2�[5ye"�_))>1������NA�tXbyU�M �M� Z-sc�1eEB1/� tula Z = |R20 –R28|/√ ( Var+ �A� �/c�f�>hay van K�n & Vlie 8�@Stuart & Ord [59]ɭ�&� � coy� assu�)}$zero . RNAmi flo� buds� !�� alt��|�da�$5�ere��j&� i�WRNeasy PH5 Mini Ki��Qiagene�i�I�TURBO6-f`@DN�T"�( Amb)��c� �A�2 x a ProtoSc�M II Fo@C$� 7Sy�C�O �New EngX{ ab?H. One μ�I8o� in RT-Q re��8w%perAT�sU�Vv in&m �!88PowerUp SYBR GrzMasnMi� Appl+E BioS�M�)Jn�lfac1IEJruXs!�@a QuantStudio 6 F9 Real-Time. \!xpsyt�!�F�ch�0( 2-ΔΔCT ) )saV"7 1g5114{ �"�5At2g3773 %=R���HJ CT��Sch�OAPW Livak [60m@TUB�K5g443 ~7 ���X N4�f�s*�G�1e�NinEt��A�II�Q7" 6 -, %5-3%EcAOai�?e1lm�*8ach �%�heN�(�9g .(5� ) �)�()<)-�rH genan ANOVAe u~0!es)@.4amOL�mX� �=!,M‰ �P8st-hoc Tukey’&n^V�)�. IzJ2� a�y�aB%" Q&eby Wang��!��min��Hc E(A"Unope� �X%�fix�" ��!�� �)�724  �-ae���ic boa�H17600 Lux , 85% hum�, 16h liKMj8E rk%�� 4 incub�!� n4ꁢ�+=.bod� dilu�>1:(:(a3,�2, GJpD %�(buffer ( goyK,erum , AR000�<Bo��bi0 at 4��t+ at 37A!60!} ��E�y ( 1:� , Gj� -Rab�2IgG ( H+�R� -AdsorLSeA�JAn`L,uJ FS 55X: cata�O(# A-21428 ,!Jrmo FisScil fic%gI� -ctv:u��ap Axio % r A1._ ��C�28Adobe Photoshop��mJ8=;%�}4�2cR ~�z �#���J0 softw9( U�#�(of Texas HeC �c~� a� nton9USO?he� ���..e�� ;Tnd�vesasu� abov�}a�S ��� 2�P�!sonm� t!lch�Qt-��Q�v^����l�5�i�$in R .Ɨ!profu%gof�-�Bp�V struo���Hexplo1new� GO��sYf�r�!2��"�,bio�Ec�9,�<�,a b�a��or he benRsearcA�. ED#gledge,9ed� d�st�4nefit1�mpu� al t� � (help naviga� is v�1]rapidly�)lv�ter��Ri�Uk.,j!1� a nove�M.t;ach%�;chG<�I5,�-R#�$�cSep a��aso\(req�IyH+facilit�"1�%4!� �M.k Z>e�X�Hn: �h)Ie(&\, em3byA%�AZ� d�MormQ(al languageA� 7��*te B{uE�.V �/k9AOvenJ�-)�nr�#Ah5u)h�'s �r-lb��e"�!no%j�g�W%��� anno!p�2b�?ont0.yA@m! !u!��,r]R5�O�-��so��a� netw0m�1es.�lg R�sRJ� �&i'�>iL �-fo& a�I��2l"�P�RB� /�9v�w�congrud?0( 3F�a�X�J� ldFva�)�y��m{.,%R!�h"n�lee:�aMe�u�,!$l!� he HIze���P&�Za$a large-sc� !k�� arrayzZ"rz"o cranio�a�%2�G1 heA9 �s ol�N crit�!��'�*1-regar��V�$f�s n�2cv�[chaa�eri�X\volp&inb�;� "se.���vaEW!�`:*!s'al� . Human9�2&b�w),�H!�expan�at7 expon8 al pac2Ovec'l�twenty y�I,� than�C mill�pQ]� hav��eMdex �Z he N%sal Libr� of Med�( NLM�@�Pade�I�*'3 PubM]ref�%n�V� ound� nn� ����l5z��D 8% [�%[23 Se]u�u���Im C�4b �levA�a��1 �6 !b���%h�es*'�.� jouw<NYic Ac!2R��)Xsh� =��endiu�pe�:vie� �.02� logy/ 2008 issuA8�=i��N078�(Q�. �%nte�*<�8%����+�&�dYZ"�#�GJ��to%� aayth!:"O"l=q��8very narrow dom�VD<0dfNciplinAkbA#arD AbA� fund�6aP�rconn�+nese�)�8��K 4eA3:�s+�Zy%��a�r1 tegy% keep�up��=Y�. I*|ab�".�9��"urE(.c\&�/�"���'�C-  ��9��sp��s-!/�$r3te� �&[4; fig$1].�=Z �TN\4ETy�� �mv�<inq�%��V���� "�{E�7r� ����A�e����*���c%.b�fYby�,xt!�I��O;�K�]��whelm8am�W.� To o�.zeJ�-� �" o cu�7ke�>E�i�� [in}�ofAl Ta>�Xena�5sI}�)m�!�eve�*� .:6%���9U . S7NEj$al Instituw@of��%inOY$52�Oto5:%�": .�a�w6(sokcog̈́� m G�XZ&E$�G8O� Con �T\!��"!K�� al;. How�� � %�� �. ���#![� ��eep� zvB/���.`;��~BqXw�%t�-$ly optimis��pa�1�%2? cade� +8� ��"�kle�<d�A��U.:�2�,W h:�{Li{H�+r��in�+x�4itRF1 a�n� �Qa��u^:�� ofte/*k!o�(.� Ef=u nJ�?�#�on �Ss5�5� � �+�na0PKoZ"[ �Y� �Iach9�I[%�e+-�d#|4-to���J-[?Eei:���F`oAMy�16� �A���na�s�5�-m�� _U ̉�sm{5A�fE�wC ng*4e Dat-�f�!ng�WDIP�a6]��!�co�H��1�331.bs�#ngBH923 ����r&�A�b344ꁏ-� a cl�I�@omÍ| ntorvy�!�?5415�r���a: 307 �Tk!�:�5952��JN — ��I� 1L�truYV���Z�C�&�QO� FQ�se9U�[7�%[89�E���^ 2�Be�hge)jteU�+�ori � raIa y�"r�*Ef5�E�(iy���q�A�E�r|$ �/M��+ŋA6Ab+assocd�ik"�^�1&���9�dvl����z� -#a$&� A��@&; " aHig2�( L$ �aUomA)��&e B6�����aof42h,�(G=morphe�, mac�>��i&/ /E&!�"G 6s���se� �� . � A�*� or ayvit� ogY#"HC106"�tq� z�s!aa tF. M" A,t ��)<74%��00d�R �ɣ�?GXl*� "DJ�'s�E&�VOmnibu��]$,://www . ncb�Unlt ni�# gov/geo/  on April :2� �Afarm - eqh:^>��� !restri["@.��O�;D�Ss�_�/�(~�!�� �E -� e doze�ahundred96J���do��Smenon �?uV� ٔP j�A��.��( !V"� +��-��ricE��i4� ��.] i�!2. , ye :(Me�pre�aDQ�v0s��lstock%� ,at�@FB� U re� �?@� y�m�$4�5"d!�!'z�� ��a��Ia�gB==1v �>0��,/e< .5�K��tAA�ous�9�0�2�&nsi�[. �'z!D5;!� jA2C)����� 73tja�5_6 � �': �M�K_ "l* Q+ng tasKno-�in(0)�3G�D�$� ati����!�World W�)Web* 's"0 L� ( OW�I:)n�o"�b��Izgraphs��5li  ;alw��27�&Q'"an�N�btsi"�)i :���syntax�!gi�ŋ%�b[�yA�, 3*Dv�o���'�A9a�ue;67r!r�_c% deao=93���q�)1�1Xconven !&�:}�6�4n1����x#y'%&�!���!lt�q!��a ��sub"9u�jlo#�an uwe �� >$B@"�# z`�!eS- <�  awe adopI{Ma�-� WW3CS��Jn�JD�rN-DR ��%�Sem� ceof 12� 2006>�w�org/TR/ ,/NOTE-swbp-n_^- 0412e+�M1 ,"6f"1+lF �qF&�o� !�� �� mu etaiymlow ) SP1q]r"H.� hito�%*:m#\ Ent� ��Y����� �HC gnambiguob�]��b��(eA��!�uH_H+Oedb fidu�AEA �e�aٛele� !�aU-ud&�(- * Q E"� v6'sLPor|,�-� bio"�.E1bioaba�vhtml )a�2�3.�nRMN� ���*�l@&Bg41o>Ke!�rez� @�� R?s/�ez ? db=�9�#All�_E��Q � AO� B� s ;�+e�!3&X )�)vOg -etabolicacuM,N���{:& ,d�8� dru J/s5 E�Q{A�N�T���rH��kd�`��F4T9�9� M�%<]�"�]LArck�a:m��oI$e>�Ag�V��� �w� OBO�?&G:D obofk��*ro�� ‘{ -of , ’s"��"����=c:>,2���� eF y ab�ct�J��� !��h/��Qny kindկaWE p�x. Ult�D��Cu�2in�k}displ����V��*�! , bo����in����#�re(� P=sѼ5��! �F-�\_ he� A����r#�i$Bg�Ce �w�4@��@&?2�,Als�_*t&ſ2�,�Ke}*$"7?�%�UQ�!��Bo�� c"gm!!5)G�V�)/total�'!u���Lhip"�y�ur�q0�>t AXg@I�)%LG�T ���B��.:D�&�@ popu�S�2a �`�?�Neb1%�3�%a!Rl.IAg&�!.�ofY�@!~��“�/m�� sJ� ep a�oQd�Hl�O �seJ@{5X#! a t�"t�U9d( u�{!����e�e�-�N��k��"��a�!���A�J�tok!OM����'� �Y( ��.f;2mQ�Lscu_}be� begi� 5lis%8�Mus�R culu��8at�-�.�c(ed��!t�GMnSS�J*,i�rmJe:b#a�i; scrib!��i)� were��E�\^2 �%��Mo�[Ge�&�cK MGI )U� [18] �qEn&( or�+�� IDC�D��\� > i]��`�R^a�k�0 �a� M�E�"@ �i� AK�eiZJa�m�b&�B.��7� Ni'Da( BIND�߀,�20s&�.g!�� ( MINT_��N!� tAct$z!�RIKEN�i �tD [2_k�>(%/.U E�0i�x by [8})ѥ߁�s � �6k[}�F����-�] ��$( GO:00055A�e�$code IPI (���l>��-)�6�gU��Z“by�[�C � ���"@!�*��1�)K"�(!��j�6al�ay{s!b cano�lizA�spell j7{�t�!��U]��j2[3TA�9 ��rff���m ecip',�)�r La�2�3HCLASSICAL-TWO-HYBRI�{MATRIX62! -ARRAY ,. TEST%F"���sU$e�Wel4* n�!�!�1$8&�-p�jIabeA�UNKNOWN�#i�3�Q"Oin�54�f_M �693�ed�USra"25)AB � Ea�T!�t�k~&A���A�A=�;�� Qks��1a�:�+*�sQ�� %�0�8}9Azf�\�FgnI�a� "��p�#�$\ �^o�_gIm�q���-Q27� .�( T�faD3�s 580 �*-i434B�. �[�r� �TPReMo:/��Xw�mammali�Vis-=m�J�:!Us [���cYs�ln8�a~ �!`!N M&3�A��)X0�'V eY)�.oTl�F z o��ooa�A� ups�3m}�( g; . Tw&i�[e arez�ed)E�a�r�ny�@ �Zot��(1�n� 6��Ns�]_rece'e �%OaTq05sRF6a|n,)�Mnm"5 s 34�(81Z�K@852j��� `M>a1�317){i6\189f[ �e&&�K%�G� �s�RI�& N� raof no,Ge�%+� &r"& !�Wx OpenDMAP�[4]�.u� ���2J�2@�%�Med�B&��JI��# N3#-�!w� 2��$)�inM�*�.��("� x%sui����)�,�XA�h���E ��li'a�"d�a>��!1�outpu r '� �A�"Nes�xb(:��W�Th� invin%�a�:} �*� =�id%�Q�.k=�jllu�t�D~>H�4-�H2"1 �I5�(���A9�d2�~5,z � � ��NV%(*[�6� ANu a@u1Lt\A�Kf=��,A*!�a��t.�A1����#eged&#�i-�L�arth�V =�_d�n:dp/-�� Y��5ANE,1*f!�pai~K.�I��3eA[�B�lo�v�)0�.[9�e =�6!�&�:��X ID! A�N]�4Q&#�Khe(web�"�a15��764!(e� "E 108n��)N��1�Uu*Y4 b�Pang%�1�aa`ightfor-rl�V)`e����� ofE�I�&� �4&��Nu&�� ����~E��'l# `la9 qnI8. A9_26�795�1_�'a#B� 173g53�aT�C #�Y�%Marсٖ. O�, 8292ju7�r- p�}"j0.#�T q E��:�#Q  5�!1 4525y � 3A�?s&�^](A�2�!Vq�x12A�283Bj 1677je� ��0%�� 9�R9 Cell�m"t"�#=��A*�Q�e��-�!zs��X*�a�"� E*==/, O,e�%la�s(E�i at meXn��D)�q��@a� #&�� R�u:��. SC"_��+q uDx�Uc���7+���E��u �as6�aTy`q��&�D [28]%�O��H�ba�0m��Y�mut#.�[29] �Wh)hgeomeS'i��o[3H[p�a�-�2��(c�aA� �tP resh:G.*.[�*�:-ɍ�̒ �(� A�gsym � co-o�l-f���ACF )��s�!i]E��aۭ��1���A�di�!�h��&" 4-�#Pnd�w7S!�\Az#Q�x�%kZt�")*e:aa�a��*EAu.�-�au[ˀ� appl!m echniqu�>�": �.}�oB� !E1�%�":!�3!�o��*' shԍ�����ve�!A&Q #p.t` tly- ed%!��eE�� corp8k%� bi^)�y .�!~�etc-�*TJ!cX }*��a�.|�t�q�q; H�<�)�ir!G>�y5�2)a=-Li'� �. �1!su�5�/�P�&mak8!&�5"�VHc1|�1�Je��en&(�9�h� ��P!<*� � �N�0����&� �&JB � ��s5 iRe`A.�acU �4ig�e�� #y�doc%0 p�ge)Za8+�/.*"@+athl multi6S6>9�"E�i"�%sziņ"T)>�!Y+�;y? o�W� �8� m�.p)�8�e� NE9MZ9(� ���-m�k�>�L �*Ms@6a�aJR� WA>Z?0w"�I��� a�A��(e�O�}A�t{,:w��)�>�)enh� �H�D})�� dd�FB��-2(�e�m�)́a%$n�{�(a� clar�%,'%�-\�!���gAL{m�s n&vItho�΅�.�5&:G- I�- �+�?metCT��bngJD 5����o$#�s7���( G s�Gwo ;�@cer�2)$!B�& (�KEGG )*�,I*�&$�8�r. M� HB�7Ble�r&�gM�iel>� Ce��!�ck��.k0P /�18 �ˑ @� 6Ypr9����5v2!a �N��ier�1�$"u�@Ij6���)a�M"�� �M!4T� .�Ec�"a*� wa��,MPa8����A�ad� -L6�Gir 7H%,���4or GO�EM� �a�f�Smer\~�E.�,�FG�+Jiang"� b�(! [IU�3w��]&M�, [���%sS "r6@X�87�coQ��26hEDE���m�s�UE]�}���ofٗ, 922�&[!�AͶs�#��'5�sa��5�)&{�IE�ql.� [�|�vnkR�*�*� E�?�$!6�to 2�A+p# ipaY6C�&�*of*"� a�?�]sav ChEB&#�it.�HFn��v.8.0GO�.G>)C“Calc�? Sign��5S! �H.+ ( 2+Ep+*�R�>Ia0U if�-=�r��v* ����aj���-�.��F�!1UE� �;�::��Aadd@ R�5�:��%���s� _g�*�urF� !�� oiI_ . Su~�i{ da*%�GO �qN .(�,�Y�\wik#9�D]zK, x . php/�R_P�} t_GuR!#A&�6i�A&&} & 066f�w՝t� &�eCO��nd es ,c��d%�%Y:��Yj�*!����� hZi�� ��r�M�����T��KݍfalS osi��z;un�8tu�KR&O �(al lJ.�8��VMC!I�ZI�ly.�G�F�E6Fu>pR �B�#�= ll cytoplv5F�.��co�)&G�9co���"��8usefu�!Tz�%0-�a�AI�2V�\4.��|�g8;?�"eTi y�0.��lo�M;A"�-�D_!ly/;~a�{�%sH�n�pE�s�;I9_ �.a gn8.�o�Gs��� "� )c�W, [40� � "g 2) top�y*Co�s�K42s([4�f[4;a7so�>ti�@ 't%d!)"teg� ��* mach�S lear$6=O\q�!rAJI9�.F pr�}�,��/ll�5 �6 �A�w!ut\t,OU ��b��aor kerne��! sTa% V�^. M�_7��mM7oQ�eob�@ 2p�8-�����%!A�!�"�5g�w�bt_,;\)�6 �6)�6 �6)"6)"6 �68!0A� e�� msel!l�F�V�I[W�J!�� �kZIF7A����al�UyjQ�C*%t� l�a� l�!$to justify��%���6#�@�@ .{4t�W�!�R�e�B)et� �� ]!�8!�.� mɃ" �"`,� ԁ1�prRC6�RiffX��q}%nsu -ryYd%y�5s� %�%���C!:v�b�V!P�t&�.'�;x12 ` �8���@��\I#�vˁ��� 6 'O��R s ag w T3"�(gv��(�6]QNai  Y�F� U��per�@ag)All&!2�h��N<��3 �% �b��JZR�L%2�q+EB #namP���(  k�[�k�2�Gt<,.B�)*�(,�% $&,kl�<�tR � �*#6� I�_Al�,��I:!!IV�F�% )J���(�Fp�3"�JA��-.�&���� �um&efRMKM� ( na�Bay+(�dp��iid� ����"RGPE�ea�Z&� � �Noisy-O*V�8P = 1−Πii^ −r�'�ri�F&a� ) 6�Dda|n"�!:8c0!+1a�he�<��`��%5)1j�J��ma !�: on [70�T�F�h�� 7WDq""7��:1 is~ �M"p�J)�l�.I�bDi�R� ��7�R�Z �!RyceH$"�C����A)�} �M��od�DfyT n�� ves;u��!.v>re��6 �.��Lunm %y?��� �K!�) "�8Y,ogwh�a�.52�P pes�WdlaoE&`2e� J��q\m�u�>�%�i� /(T b�&mogX�>��{"H!�Ik~Ve-i�I�!�e�xp�xDuilw.d*� .UZ�X�Yc] ��h%�Jr_� Q�S*apa; �"�QgoCgcL!��a�|HF���wx�>�5�^I�_ *�Y�2TJ̟&}}���D"r �!�U�to:�Ea�� )G�~!�1-.~26 sub- f� �*�%[u�M�\�tEurehens�E(�B���� � a��n�es"D\!cj����%�(.V8A%v/Q�� t/�:_���c[",e-�o��)���*� 7+ 7+ 7�5S�.kaH��+)D��nxe� gc/�� �quX!�N�ar!3%!�Dt*JXqanF� o#E�"g*���( lexe[�:�O��[7ڛS.�}19e2atbU�9�A �ag�(%`A�"@^d�Cytosc�[7��+Fpe#��_u9I�plaH(�LACplu*:, CA�,�[R�JiN�y!+�  r?A�*zof�IV�<�� rect\Dc*<EkIly!���r 0*V !�Fi�Xܯ�)o,�S9 Q����7a��2��(M8r�����j s�Q&[*� �*Y2�[76GA�#.;z�!(�1o lIF����"�GqJF�'v9�"�Ie\ ��(�9"��U'" b4<A��in��k�I��&8$��!�p"s E�� �].�:po@�a���]U e`�x!����dca*BAG�N��cici�)�_Fq�8�rcr[7�8(Our�"\���#�Npri ͠s'���19)6L'�xɾopLp�BA�ї*� �e�i�@b*�y�]A�e]��!'ari!l����6x@�m�spiri�h"=)�=�![8 8�c!I%�yXT� ^� ays::����� dy��$yE�� �'emMbroadJ [�%�!\ʉ�U T!�a~m)9 1���uq�ipCm��F�8Ch&2�1� 5a��!�g��9�d.�eUu��% �`�� . Du�!>1�,d�M- Xao�� tng+n���s"�s{ triv�CrED���� ��!av�u��% a.Ie������iR5@!f Z>�&1/�q�{�� �E���. �HA�a����r��n2���p&v I������Z.�vr4�5_g�En�*� ^ v)�8�84]umBQ:~6sI �yq/y�A��(!&�&-������ ]P�/ل�9] �te�+�*Es �0���c�* ion:�r 's F�s4udholkar-GeorgZ^�!�$Liptak-Sto�s 's Z� [85]� Q�6������9i*:5��Ed<�d!�E %,�!/I�Y KI��6�%�=1��r� =C.�9�i $S���u��de�Sd ) e%;,Hanisch Logi�hT�!�behavA�d"H�fi�9Ng"v`.UB' ����S0J2[-g��� .>of >(�I~� area tou^��z� . 0cnAQRO^M�#d*�pr���)�m2"#3is����b0�'��dwbҿf� <� �I�,-on".��>,wo]5A�K1��ble/c�+X����8+�:� x)J����gbN@mz�a Y�/��n�Ney[u�r-'#$.plW���v�/n0A;r�s�?S,e .B: �U�a main�#� e8i Cy�o���t$>>Eix�Ah6zt-�q����(lqechiev��� � ���O�#Yy4�c�*7 T= ��!�i,��sinusoid�burvN6��!q"Z���y"E:!&"mNYxaLd =+���F�Y�k5A�c��~pu"�i� �����!m���N�u�6)�:&(!�C Ef 6��a1�!f�J ��:jA�e��"���g� B %3 ��6��� �� ���.! �%�s���L @��əEh�t!.�5/(�lng8 K! a Boolea�}D�M&D.P� vile�me�SB� x{:>1B'$(a$�289� r"�A9)t�8A��6sA��>A9 *�%�et.��4��&FB�Sq.����K #�QDb  s . -F tw.�F.����ll�x�+ven�U &Gv��te��l6�-I<\&E'M#sZq Z�"'<1�� 8o�9� top 8}�yu�%B%�"c0 ȡ�ri`=of 945$1 , 743 �@ _��@"���vAo (i�^gan�as 92""15 tr�6vEs!�,�P<10� �PyK(‘yarnball�( 551)aa��;�r-��d.Y ��27!�@���p��.!.Ns.�(-45 ���7-�{a�7�]�. ( circ�inQ�y, &�Dn�t�pQ�h.w!�e�j*����e�Z.�l�v!�*�v( Apobecd�0E430002G05Rik�oxa Zim1!��.Voim mNj�ngu�:�v��I�'-�p-d$itu hybrid�i�bEr�5%� E12 j��@embryo�s�,7p���AO; �@� 115�'��N �[11(^Z Zim3��M 3a�Z�JM@F"+� �P3�$by �� E�FVB 8h���� !�p?rsTFa`′-CCA GCC AGG CTT AGC T$A CAG-3′� nd;��;GCT CAC' AAT GAG C;�;;KA�6,F�F�E43�$GGT TTA TC�T TGA G s�E43� A GA1 G TT �TC�A�.�%���)�8CGT ACA AGT GTG {6 g�42�CAA A�!K A GT� 1-0s��� �126$.�N;��!�mt�tieatuNiami� m�5�6 ti�w2� �D2۳��Q�-�6�6�i ime- t� J��.e��:�,2�W|�cF{ ac r�P( AV%8&soby�e gj6��riscret�"�P"�o-G( Bd , E-�oA![))�-���$�+,��؄6l�WKs �a�.pXx�[��%=:7arch ( s9. N�?the�Aak�s"�AppaP!G� J�x;K[vi"-�-"E7�}, p�����e�A\CpBr.d0a0�b1�Xaxi�� H , �5.aF1:�:��m�"chy&�L)'branch�%1�)�!�]0al�(!��iJ,9z9!�mFectoder��L&on���:��� rmsy���;>� E�c?)�n�d2�p�-r?W�.��a LA�m��%e�!�� 4�"" �^2be MF�w!��Kk)=unia�.�of)�aa5I's��' �%�%ͽ N uA4c�F�-���`9 � � !�smo mus�F!�c$� ���N\>l`(it�"�Ji��$nsic skelec4Vul�2M �>�A-�];�� 5�n VGtUui�waX=��  � z�l� ��ɟ�'6�! atta8�surn�!�com"a$oA���i#(�`Bswk?Yche X *Ck!&mk&r � bu�a *��� A��+ ge��SD,A#!D2�!.v>[Q-p��a�M^.�a�!s��{� i"smqu�)o�~R�(.� I�k(N�o-�o w��,1h�02m�/e$#q@%���j��()*Y-.\I� mode�k� ����!�ye�wo���f�M Ongo!'�"�'n&�2qh�yFr~"s)7�u.�s~�)*-.��a&s�7ac���T9TaBane6-8J�J�����.�N "K�engine��SD�YiM �o��IVhA�UE4ef)Bry�I1�%)2�[1&�[1�^,+K*� Z�u!G-�D�su�&ful�"[�m� ��!N$19�.).�Uu�m ��A "�9!:E"oI�eu��� aI h�i�io ��Nň�ba�A*�1G��8�' shed�He�IA< .�][7�x[1d_�ln��Zk�:�+m� / �3���Ena���f"�S :.�[=L ~O W%A�e�M�art���.I=�*"p��"��I�&�+z*��O!F��i��b -qz�Cj��"�q�a�"�p!!�!�%�i��#��s).�ge�s���b�.�IG��  6��w�RIF{�rofitab�)�uEv3RMye�3�u@Mof 2�(� � � A��>as*�&�A"dH0I��.�6�Noug��E�H)*'.�e�1~aWmiQ�;J�lK~d�}a�%C��W]a�!�bes�O*�O���Aj��� =K\�c3ER��J�( �~5%�J�&+Y)���,?"RC��rT�+ap|e��5e� b&��L�2Upre-runa�ioE ll�9 ��!!;5up�=LI!�riB9-�.� �s�uMWn�Zg|z+: I��va��g ighl�(m�mr�}W�wa��Gors ?B{*"�9B�H �ves�@���..�2�A >1? S �F)8�Rba75accʄ �?�!Ie-x��I,&O �-ikb�-�� �aly�'.F�@&�\gm��@Az' *qa�E�u��/�Va�#�ɥ� IzoJ�5�Euto��nF ? Do� iB3 � �1�� "�.�me� yz�m�)� ume.�as.E4��a� ���@��5Tly�!���y��� ��d�4��;Q��2�pM be��.�3 A�`� nt ?{>@,��"m' :v@�"z#3il��.eor�a?2*�#i�ur!#�1�8��ivVZ;"=VYb�M? FP�&��1o5i���va��-9X�&z��a<�!��IM�aai�.sy}e n�e'i%egenuin�"� ����u���t ��s��te 3R a�~ s�(.��hapiV“ght� kG C!mE�!�gn�&��1s�.�J6�2)sU �+1�Vu�m=�!Got2�a"� a���.�!z1�d&53�2�6�� " [�*T3"� ��h3F(&�h%�K�.m�f.��n r*���9Q-he&� 8#ZQ�� .���[ P����)�|D[4]��n�U ]���\I ��He;�th� ac]PK �`N vesiV ( EV����0�'nal- by hk�i8�dzA��t[l{d�(I���-q;�|!Y&�Icar��f|&� cha%���l�sa�8|t��iHS�1uK"��rface-ex�9dm�� ipaxinq�andU�ept���E� �i��!3O^a��R'2)C�T�A�Xqw��[isųGpa a m�ane-iٹm��b���b��|c�B� i+v�t1 �ou#O���wo EV�-p�>�,�~Bed 15�|d 120k%�)��wNad��F . he�~cQw�� ��s)r��Aan� �virul�W�,�"dbF!GM*e� u9EEV!&g+is/tr�l){�b� AE�oc��c�6�72&I�!E5E�l!ndo�N;�VQ.�3-%�?Q���ƣ neph�a��exa�ory0�C��sI��r%�a��a$;7,fgastr�al ep�{l]A��'%���fluke gu��A�l��lI�n��{j�a� *;o�1Jt'H�aj>�-�oligosaca��Aof�6actor!�!uly-labe�6��ey�~{�w�ctet. L ��Ac�#�E`#; lycoconju���\i��06 he�!K%� 120KAI� .!w�~� ); h�#�11�o{��U1teg�X�'�3DH=L��� ��nQsug��._�lW��A/b02�!Re 泅8exo��A�-%( sida!0 -am PNG��F d0� <�!!?�B�al@�!��:�-i��; �ph36>H pre-�kWeBO]ǡBW47in���!og ��ur��6r�d �mf6�U� �A ��/��aår( DM9-C+aaY >D6�a�@! myoferlin�#s�1 fica�"�X�a�>�j���iz�rkEl� e4 &��8� ~.H�oFby66�qSw�m2�taF"�4U�!�B!�� s . "w)�2�O �8imp��+")ani��he����� AOwoh�A3de�"f=>�m�globalc�E���>50"5�T’��&ock7-�fFD ��'L }�ni�2A��m)�"�cy�WV"�V!CO(du� in!fV �i+8ri\d0��I/mt �I����&]�WV��%�p�1o6�� u� lK���ke Fasciv�"sI R C1l ro ���MCeC C�]�1�of g E�1%6e!1oxiredox%,�5timZ � ~v.}(M22Y[hn$c{�psin L1�@d�� toll-q*=� 3�usf�����.�\�!JUdef�� ( HDI��A�i��toс7U? �*�moB�.jbR�1of vATP�� �. S%� �<�/���a��+r�+/ v �&O Ѷ�� [X8] "]8���n6i�pFr� r� r'�2���ge\7&�",noB��p�%GY�y also ��@.[� � ��)1h is���c.wM�-H5!�e-5�s [��1Y:P� -�&m�4 *�in.��8a�wW��;�ato�SFx}/����w<��La2O�j�.)�!�! de��3=��packaY4� &� (a���t) �k]]� ��e�*=�� u�� D:nd�(?E%�%���)�us��E�Pgrav� enzym�:6?�.�� ot�q�!� exer� i2�]1���i��7 j_� ��ite&� � b��;!�V^ Mi���!��X�7 by&�-F6��b�tr�ZImA�He� cohortLp1(are e-1on+outer9�-W;�EV5V0 displayed EV-6> . We)�(previously =�F . hepa�0 releases at  t two \b-popu)�8s ( termed 15k !� 120k�) �dif!�accord!2to size-cargo=�[10 , 13!�I! is study!�e used y -imp}4able biotin re%�f labe!�e �E�vTthen mass spectrometry32�@lAA1�ofI�%d68. Fluorescently=!� were!�fiODby multiplexed lec�$microarrayE�examinI�topology�A�major!<bohydrA�motifs!�sented�+E�. Our�teomicI6�20:�1I��8recover smaller2���B� ,�!C�subsequ�>e/im�ate.��b� I !�or snap��ze�dsto!at -80!haXfure�exAe�e!� Fres��YQ!u�.�M��a solu�F.�1 m�~5 ng/A�I�c!�� �yps= $Promega ) ��night!k3 F-�,.�7�� to a�� devA ( Millip�r) �ept� �b�F5��at >�1O!-a�bi�� K � %��K2�1>Z%dBanaly� 8by LC-MS/MS . N>mne�� on�v�tD(a@tri �Me����ryp 5�dri�va vacuum9e%?!6nstitu5�1��> TFA �� �is:�F�Aof !2��l�ĩ�s�4 �ep ��aualy�lIumu \Eksigen C18-CL NanoLC Co, 3� ; 75 x�,cm ) equilibaY�J<5% acetonitrile/ �pyro-GluL�gN-�inu� oxide�;ionl , dif�"y| BQ BHAcL� n�.� c :5��Z� vari.�IAn add�KalU�8aCBIY�$or Ovis ar�.�8( http://www . a�mb� org/4_40/Info/Index )%�runA�"ppo�`" . Scaffol�:Q�_�"�j�=A�Softw� 0Inc . , Portl� , OR ��o val!�em�d��E� ��t �� B%�ac5���y "�es�Wd�n�than 95a�%uba ty��!�� L1,FDR algoritha��;��E���֍9F�!F7 �"259>Ah�pr�AA)!sW���+P��[15� !Yat�similar1��)nnot4*}!�)�on-��A� lone �V1 �sf�princ�� parsimony��ɺs shar�4�%�nt� e��p%d into clusž } 5HPerI�Q�%er%8ɝ� !sFirst� only!zR W � or m� uniqu��E�s� �4�t*�ͅgr�M[consid��5U.�ord�"t back�on&v&.�afN8y chromatograph�m�2 ~� "�)ksub͘to%5 CRAP�+reposi [16]alse�!{ all avail�C.1-ag-e*�a� R�as!*n .�Mc�e� iES@ ��,( SAINT ) sc!� [17]�;�o�Ie!�sh�&at�C6g A��E a qu3ta5��& in�p�8a t-test ( Benj)8i-Hochberg corr;]�0ce level , p<�5W s~�� �%>emPAI!+2� !. N liz��:�E� zero?,minimum valu� h�U5be� �t)a9<and/orE> as en����R�by5/ ’s6�pr�I�udZ��2Udue!�p����on ��R�. A&�A(�c6) � &"�i�� rabbits"X"�$f �ex9# dom��;(etraspanin-6O(_Drec; GAKFTHKDSAAGRA�,� G-% ]-� ( 4; MYRHQQPAREVS+&�P( MYO; GEPKRAPENIQLRD$PDCD6IPY Hlix; TSSKKRPAPDRPPP#�spOomyelin X( aSMase; IEKGNDEGYAENK 3TSG_ <( KSYKYARDVTNDVKA��nd Ral-A ( NKIDLTQERTVPFE ) ( GenScript , NY , US!r�! ��� as d� -!!�BCA>assay kia� Pier� 4. Equal amount��g�f�K� Irun�4 reduz4NuPAGE Novex 4a% Bis-4 g� ,( Life Techn�e� �:u1o�ula���>�3 20 m��. F�3[NLE�&in&�$"4 ( TBST1: c2, 1�M NaC�� 1% T4� �t!�M�5% sk� milkť2�BE,( 18–21°C��Blo:@ @ �I5!p� DMm� ��! 1:�disof�-&serum �!n!ZF -poiI�7 , 21� 70 d�#)�&in�!��F.?%�^��%�hin)t ( 3×10��i� n appropr` alka, phosphatase�j�ed IgG�ondary1 GB��Y�^��a^c�� i]IP/NBTZ�#F�. J!E�oŴ4% PFA!!�1 M[> 2���W&1 ly embedd�� JB-4 >L. Semi-�$s ���thick%p cu$a pyrami�x�3,�n glaN&la�r `%f"&c��tdAQ�W`:�in��/m8A�-Fh�OrecE�nt RAL-%M bodyE��9( AbD:a}�!t2%* /v )�&�)X 1~�u>inLiE�m-iI:�$�mbiT"6 cathe�L1J�. A�>� ,ar� 1�%G2����-%��a�^ 69%l-� e�s�m _a� )>UaseB�,��(� sothiocyaG'( FIT��.�go�!� �a�Fb�AbDr�A�N ���Apt6Q�iA�yce�]710Y4CA�AKa���yl gal�%F�%pvieu�+, a Leica DM2Aiy3t)scope�&type Na_ers!�oil�in\�X�� imT'��BzI tegu� ofu%2�( FhTe(}�� nd�q�Alexa*�j$ cinimidyler 55�Th^l  �+de"$[18�92�1R-=Tl*�*��A�Llipophilic dye PKH26J�6�>( [2/$&�lx!�$essW!0 5 ��VaeM0kDa MWCO spin&�EMD-Mi&�.�to fift.� (ū empir]lyeenzym�� xo- -id� Jack$n α-manno ,6B(; β-galact"�bov�tes� :5��end>uβ-N-7'_�4s Endo Tv [21]E�H ,;!'nd �- �N �FNGF )�3N�Q�Nsy�&^ !� . Ea�)J!�a�t to 1� ,E>-Ie�.� toaZ>� M#� mM soK(�e�&�*>�"K ZC ) at� 5%�:�!%B�,3u 3!� �-~5� 4U5g&,�Drea+ O;)'-f�>�$F�a� darkm14, 3�I�*llT+ov&ofF��5�k verib]�AfQ�fetuin��` same��,�d5 ISi�^.�U� Tv�:�j���mWRNAse B�B0/D2�"�*gdupg!�if's fZ!v�'reveaA��.�optimDn�a%L rang�r]loa�,a'� 6i'� �* L baAF4:2o noise� io%3� ��_l!�2�Сs&6'y>t0 t����)aHn = 3!9@�'B�}�u��8 �lF�=!�#LZ�M truc�Ns� J�2� 2 4&�*48G1aVsupple���1�`��i� hapt�, sugar!��� b1ng sit�$ tegr!uIkr�,$N�aGH�1(chott ) fun� �e��* $�a�6� +/-2% )!1�humidp�@sciFLEXARRAYER S3� c�/otO(��, B�/, GermX/!|Unoccup����r1/!inert�+Osur�� mM e�ol��!��bo��]�#,�5j. M*�2%N� kM e�AO05*b(� ��a~ 4=,*m"$d dry ( 45~%,�%)%x&�'Nv�5cc�.�'Du�ub ,� a�3 � �% Qv}(a)Fh�1( ���x"�)a )bu�'%��&�-�),1��!�CaCl2 Mg 2�*�%Z26[�2A�or 40�E�3A�. S��� 9� 9726, rin��k TBS ? dryaLby9��09�FO'A��.[y� 6 +i��532 n�1Cy3 ) �1ne/ AgilG2505B2�canne(� .��:� %� ��cosm a"Z'�It�6nik(͔a��� $I��!G$p����on firm�k�-m0&m�ca.6ed+�"��ء�� e�a�,,�ethyl� αManOM# �� -D-&� *GlcNAHE<&i�du :� mpet 42� E/)�2�9�z is39]s&E-A�2s�8�-$&� � A.!{eH">;GenePixh v6 )#��-( M::ar De(���egV!Jer"�to�{la1 �1+ A�%�� 6�� spotsA8AP-E-aq hand�Fas�2e� �e> ���s*ead . Un�0via�, hier�"7�A�%�-Iy5�"$�Mב�H.EC�E(Explorer v3%L:.!c!�umd9!(du/hcil/hce0 html� P&�2n��ata�llg &� s; o YmeN djus�7�raw �sc� i� HCE (�� vs�/ 0!�3|000��&8 c�teI~( RFU )�T�� -`17A�fo�p"�% : no�-�!J , average(k, Euc��an di=c� S=�P �cY$:�m�,��q�\X;mono- disacc�des�es&�!b�pai�,i-�-ed �> ent�D��w�une��#�)Axx vid� �%�set�Excela�Gsofn .�ld%n�:�es0�� .9�edw �!�J��>&�EH�EVw�6uaG4� �,a�bo A 9�%!��&f�!�a�A8�ell! 2-s>�0. RAW267$5,aAs�!att��to μ-�� 8-well�@mb F4 slip!Ibidi�ve ��Y�daMy n�Ato DMEMJ� exosome�)le!�FBS ibco� 1% L��0!A� Cell��:�5� �� �of> (�{��5�/-co��AC�3 hours!�3�E�5% COO)In �26� ^�WH�i�2  l cy�=ala�D�b..�� . in -�nJr�2y +[u^s� �� DAPIF�n6c �>�SP5!�f��,?( ��(m�%�LAS AF �%',a Fl�!���u!U I8J�t$8 fieldMt�U�%r]%/0a 1-way ANOVA_�3 . To0&e)�ins�cp�Aoo!B�of2�EPt"�e�:�4A,[1�(Q"D4MHMti�4��qcap 2�,^�$)XR�!w2S1 Fi\. On-c�/J�+e&�-�&�2 >�1–7&.�).  gen"r,[,��O& Q8two!���i�*�r:Q&"�(:&� #2�1�N%{subje5��pQ �6!I�vdV e6 thes�� s�. E�?��of^�#,�/����oB2����%. U� |�roachw180.6q�)� of v, 180�=�(I�: &'s; 155:Yexclus!(-O@!m��B4>4��t!��1`;oA5(E�1A;A�T���E[%� �K'� Ont2"�GOJEerm�highligh�"�3�:plasm ,<-�Kcy�? ��0abund� ^���G\o&�EA?&i1-�$�va)��o J -assoc�5� ( S2%-! /-%�3(s�? pump%h�A�ndq�rE�amongs,(6�F]Y��2A (-�1$;HH-�+�(*�ǭXaG��@�n"�F� verb��[��r Ot� -��a�G�fS �A*�&. O�- P�$:,*�B�5=i�Q+� U%s:Gw`Ac.� , L2�aD-likA�parA6>,��>s(q1u�. �AAlm- �Ig\3��mA*U�-�VFg , le�%e �o>U)^<%7?�u.S [1 A nuB !G�t �K(� p�@,%�aH!�a�-�'�l�� �6s^�t�F�c1��6TO�=dom�!Fpc"*ra�CgJ8&=a;A9&x)�G�x calcYD^ �!�bo�ha�r"M���H! (6���� %[�4�*2�1&�1�,t*� \6�1���T6�N�L5�E�N71�; how���5��a A!��)� �)xi�cerul�7 HSP7�vitron�!Evalosi� n E �x�vM_J�-6� ex V� "-M�qf.�2 .B�7 �3!�)5�.��%Au 0���1xE�!v�B`-�( comm�o��>��A�6� �'ach�9a_ on.lz!W�2Ie���aE �{.�,�  �. Volcakn8"�I�-_re��=��!��aR]~sM� E$ESCRT path ,%^�G� volv�58tr@ ^O9��[��"( p <�T/B&���s���%)ST8)',�,, 6-ra'�R "�1� �1 ( STAM-9  , CHMP1A� 2AEzFk ���3E.I�D rastVqi=>>� z de��(q��"`! olip�rA1Na+/H+�h�reg�Oor�5f�"�$ E-RF�|, �7ytoskel������6�5�:� e��i 1B;q s M3:K TE�� AU.�N5S7F�/nd. f om�� &� �H�&�N"� �%vGG�o�p 1/% !3/6 . T*�7a�=#JG:e,@a&�.mv�2�(E*I.U-a^.�:�)Q�E'��by�'unoblot}. C5s�/�42�> ��y�}�i��6�EQ�2 5-TUT0+yIEBb)� �.ts�RL7�0gDM9Tv�e>O"t � Y b-�(Ar agret �!�^�� ; Jfo&�3y(ce�h�4p =��� �E�in� �&� �xB�JJ�-tissu"+� ��.��+a>�2�6�!�)�(x mark� �:5��26 0a 215ke�)F�s�!��? ion/lRa�u�S/.zU2�� D4� �� �Dns.�UM,V��OysolN�;b$�ribCuni�@l�OB!4gastrod�!HNiE�0!3�Oo�l M �A�n9of6�-8� �E�sQ�tinct�"� P beneab �i/a|2Mzt��Vag��!����2;^�obser/�T� 5?� �As�� %�l NAC!P�!�conver~� he�-[ ��B�D72�4. L��,M�; 9�.�:of{l�v6a�z ellusW)+)�3@^1�'al!�`.�4(�;%�!' �v>5@�g9� �1�c�a fR��alE��z v M.A-yncyt� !lu�- �$�oI#No6�a4�%����se1UBh w�R6�..�pr.0CFigs 2C�3�)A{ja�#2(eg� p�8AB�W�oligo.2ofF� ;!�U�io cree�|Sc� �H���b,'uruo bQsZin�uA$vYl8<Fma@Tl��n.�iBticAs�owerfulfhod��� E�&��Wy w�V&�ZS %JenvironѴ vivo�)Es`Q-UA3�2a�����1��E#�>s!�1'A��"��#�܁�bu�!so lipid>)�-,a� mponHUO�b��gv) an aln)9�;)x.$ Z��A�}>by!�on�(gnae,>5000[ ab�U�l* #p EWex<n m s: SNA-IIqGCA\:SLEL� alL}9PGNHHC. RCA-CAA��4�.3a:V�"rem6 ��9m�I (d)� low-�OP"�;�+!�!�>� NI?i�mt:/�4!:�e)�?�!�1W�Kbroad �+of h��2�albeiIL:=&U"A��e�u$$. Two-dime�Ja�4u.q#jo#I�"-*�""�E*- � 7a�6r divi3�!L�"p�$�A�R� ich`cEqIthey -1yƭy"GB��5iy5>"!sa9anA�u�Y�#InmlN- 2o �L!c21�*�3�= � [19]�"h).U/L.� &$ s('/ !mes�Lof s �%�;N-link �,�|@y M>S5� ":%i Ji�9ikax qAs=d#Z� cOQx.N(&~l��� of N�#O���)a&�1r ��.Z)�sug-by.�jH6&�"$U[Lbp[9��qA�� indv�(!��-a��(�(�(,:�(�3{@!QJ�(������>�E�1Rt5��em� F,�3���N�"nW.�e*�/�A.a �&9�lSc!K"� �as1�( -98%�Q�A�)�( -892 q�HwHS4�Si� nt>2�B�; .�"�*at Ma9u)�s qH�22����( -652b�Nea�!�%�Z �U�,?[ isX 2Xkc��yC!��NVtS$ � uponpl�_id d n>i ��"�Q�[2TcWw'�+,�21A0�0!WG-77(�\2GR'Cu�f� A��^]a�tg��!#� J%I�5�� �Rs.�4FslI�JjNd#aj� !o2A�6!)�U!��a& b��.�u)��–�| enabP9m�cS9i�)i:6�݊�VanIY!NQ��! - D!}dhe�&� ��F�W.r.�K xq�toAc�&8 ��9�. Exo-%���8s�7*�+i�."up� PKH2:g8 prio�3th�3��!�by �.XI+6; S5�� ; S6� B�4 MdXA��7)'BZ8*�d�f8DE ��*ng=at���1,6IA�C�(a*E1s� 2z6� E&]/ �� �� a Q PreZezes�l G�6m;x k�dA�ferC a^Gal-β�→� -Gal@0,6�a�� �!/i��{5�ja�\!���v�R�H"Ji�23a;es�E�aa�u:( +14��ceeadQ��} de 5(MW)Y=�mineIrftM�Y�� crosR"I�e6V&q=� a�Bp>� 6� �[ B [19 E4\ i?acip&< >�9haq&�sya�Pimp�on.��@&e�VQ�� a0�P�#�. Sur+T1�&"oy%+a>��2�CVst�/&�U|�M}&�,:�E~���56:_�qk�A�M*�I�bc(lek� 9/�fty M-"2+�#Z2�e��i�� �R3 Give�*aed�BGSM���H o fav�A��! i Dh��l<0uBX� �?H%�^ , `]oug! c��X^M�1�'�H� d5nGmY��!��!y�'<cep&4ifu�=�ag��a(' Type6N-�@B6%��Lac��) &�M�L( +51Bz ɛ��mirro�)�>t=6�_�,.��$� S��!�lexEhybri7"�B�,�Mas PHA-EHA-PC�did� }?"�� �%5ŕ!rtheoret��va�8&�$.�.�FM(Y&��.�W�lŊ1�d��L�5������=�M��& �0 harpa�< ?C%le:�BP�z &)AP{Bd�!ly%� �-�o)�.� Q�Q���A��. >�c�P $ keep�"mb1�r�q��MMp�K,�-�CSYC e bo�aor 7�2(�+a3edj�ostill��blB w�lrestriZ$. Nonethel���u�in5*s"�]}aIqproX!(MA�-�%�. !e"�Q� e un-maskA�of�,osum~�.up��i���t�->'I�N� 1�2S��)�8g�q�IG2+46 +,)72�!�6( -r_*� G}�d��N6;�8e}q-.ziS arisa�I\pH�Y4I��n )BBDV!� s � P�GS-I-A�� cH B , MA�� C�!6B4x:��de� A 7�}��irn?�od�XApar�7B�M�A�a�D]�]st~�V}longerj��$investigat�e rol�.�s*!���6�3�J� u�q,>�2~ �e&p�fm^Q;���4�"{G�74�<7 .GrA]�l�=-�G21mr�a� aken[��AKZb!"$Q��=aoA��2 ;eve� Cer�-�� %;%i�717%��TAT �eB7c.!7a�# cker�yFn polym&wr���;a1p�(��&�Y? nali�Zoa��?Ai� -��2nj�*�� 8�.k �:�A-��2 �G�: .�6]��de.J�I�x�[acI�{v) phM}'M)01�� 5;�7�2�E@L�! α1�S�3p �!�β4 6?K�Bg � O-2$^�S9�EJJ�%in ��se�Law�� aQ*a�o%�rof��CL$ next&�8!�< 'F{F%�vI<�$�#�U�Y-, �-�<�Vs�N ra�zU riaK�0�<�V2,Q}EY'�1>�in a�:;�Bw5ZaB as 7 <s>4=�  2�(��M �a�progrehcEq�%n�vs��t�U�U:�=�(BudEKmig:!�A%��>h7&enchyma!�*rat� �8�#W�7n o*Q��se2:X�CM�N�9:�!B%+aU6L2�;~lN�O8:���|�VI^or aM^=dDW:p��>M:�Z��3.(Mbq�iE�V[ 0n:H<�`W� !�Ep^� �&A��@ c~.ja�n!�d�D, puncj~reQ'�X>�e�f"� M�^P 8B; �P&�%B�21-�?:��I����U|� d:Y�c�P1�P8c%6B� dra�ic�fA�3��5tB��70� �}��}6,*�,8�"�S9^�҅\ by W��� �m���m�sa�m�6���s�\�(.�>:� *�5�QA$C*���P6!� s �:] ���>�-q ��f��s ]".���;�%��&K�3 pulldowna%�"~ liga��a�r�5-;G��.� P_%��Z�-)i� !P�o�& ��t*�2( $.�,iC�fus4ic�per�e(*�_� h�!�~y�\!�Ef66� 6�C.?�2��he��I�9ɦA>%*M+%�y�� �=a�0�u� f9Z|,=}�w4Y+1�.$|6�$>hu�>�:9&a�a�+�p%�-� J�>W%�6�q����b�)!�M�.. "De� ��der^�e��as vehi�zAJA9)��6/a!�"�~2��)�J�ln�e5J�/� su�fu.�"e��1toRq� �de"��Q 1ins [i�25H 7�V�pr��,Y�ya good~�knowledg��EV� gOI�%Jre begin�8to�,�1o�&�6v"Q[���Bd3littl%��n�)uc=h�� 2 .�%�*�$s�Blцlikj$�+A De�qHő!5�B36�;iti�<g+ir2`s;(�be ob�"tk/t~wE|�zi�p�aim!e��OQn���8�`�Ikt1��w"��)!�݇!�B��Rw*�.O!a�7��2 ��)ha��U[� de�(b!�how.AMSt�7 is�"h,<%K�5�f�59)C�1�2&�)po&�A�!�� �T�K$bud direct [,!0B*B(w"&��07���psomalQ� (S�&h�\E!�%!�b��� Z�"uWan:�4y9 A�sor� ��r^Q���v� (�9)ʅb �,�v:'\�=� o� m2N�s [28sz��Z8<8C!{&�0"+@�8�.d)B�[ �f: -III�Eh(he Vps4 ATP�9�;}4bl�AZ ra-l�ral� A �nd absci�r,?(�<*�*i �asF�C ALIX�sy�Ni>���х��"A;.D%N- ��,e�a�-&Vk;��h,1�-Uz �)D�$:����.�SNARE�*Rab G%sa�)�Y�� .�;mN�AS+�O opr5ng%�ran�og�� cate)��fu�%[29��imA�w)"� ePMc gen"� s�"�� [30<`Th��&�(B/B�[simpl҉*�m�c�:[oa:�hy�is���[�"�  t��!� �> A�^�1.@organO���NHt��>c� *�k-=o�,,6� :�ode&��A�s0]��q�9;s��M@6�MVB>�EV ��,in Caenorhabq!s�1g�[31!�SG4�A���Kn&�m2�uO�8�<�U}��?�]o "vo� -%!� � �P�d_�6���to �2`I1���*�ao:�#39�8.�8ms� OA%�rB� � �6,� "� v�7.U&�`{EE�<A�in “Y-a��8”�8,���GM�x��MonephridC%�v��?);�&d�[yea�PgoA�Pantelou�!�Th�gold [32:��lae���.a u6�8��Ն:j6e � appe*r ve �,�Y&�8� �@�4�$�odraAR)t5ut lumeA�a q�ar)_l5�e�pos +��. .AsTIm!k�a-liplaLiX1-M$uW@_*��%��%�o!**� AZ[34] so?'perhaps^"s"�& �b'r>�wAI%t�f%�!,I�"M��4 8�0���,� �m�a��<�9�"+:%�"z<N�inj ��#�W* is�>�fa��7� �*5���sa�]B&BX�"ly�eryPcyt|[35�{n�*o���Lu&�c6�J�BB�J[ �w�ffiM�lyCade� haemoglobE�6��0tg7to_"[3_(37]ly� A�di!�Q�u ��P&A*>��S%�AUaC2A!�, HaltoL8]|�I�2numer�I{���[ held9�J^A���`M�i��"��Kru}Ra!�a�s.� �k# mulu#� � Ȍic�} t��)b�*& f fwmH�!��6�5�J( /sen�**: }�F�*2j:;� �B�!c`: duli�calx&�EF-7\U:�A�E� 1�Q �zM%E�|K"�K7��F!!>hRsANW%#� �)�S -sha�a�F3#U�*qT&D �g� �A!ifA�`7"G!uz R� ��tm,2S"e[1 ~R��rm�V"�Iy ���a"� 111����9he  ?4��M4#i+^��xt���_ 54%;!�m�VUm;2T5�! Q/t�C)mG a�'>13>"iJGO �/12.< e�{ �li�;9f>A�b�!e 6�F����$VSB,LC'/G%sr�rso-B.�QN�. AltW+u&V,�Ci�o unus2G� ic/~35V)0)� r�d�8, �[�V�!oaN5�t1%A�X2RsI�!� s#�m�Ir ��)^[3�m&Q�U�� @rtefac?uA�lA�Y,N(n�(��(pt]"m}�,r�|el�� �'">aA�+ud#e�Knity-pur[!e��P.ƌ] �Y��. A�4�ex� 8�X>�!$Cvjetkovic&�! ,!�%o��5&F��4�f)1{A�co �yٖ!�a�����co-��1�W�  �@8a<B�͗a,�In'6N ws���+��lr����&%� wash �EV� ����] kel&�Rb2�{2�?2N�(o&-q�)*! &6 "�S2o&��?"(l�6gUO1f�"���!���)2�=�M���"TheterGL0w�+Dir�|f@ �*ٕ�U�)��6�&�KowalY�40]�!�&]��Z�� “cYjicN�hI&�.�ǖ% ��v&G�\s-��qhum]bend՞��( i�c .:0�a&��]�"�1@�w�00 x g>hx% ?�(Iv�i�@���th�2�_erc9mto�Io�Ayv�Aw%�gj9]%L�[3� �ular/'K��(helminth� <o�ckAir � � Z �8�ie yh"i~:ɗ�tE�+�d r�zO velopBtWXnft�=BA�B1�)�HdJ�tffY� stE/owards*7�!X(")ib|�-pw]Ronship� "j of)!�/�p���3&FTL0lev"���'�G /!,=�Eng�M��� of��=&N�yY@� e��. �aZ&v�B� �C2C.e;! 2� Qdd"�al��D �d0re��VŅan.;U�pAse�mC<‘|$�h’$W'  �g: fewe&�>ahF[� ed �E��+� *lE�&3&��/� s�inAP"�C)�:"�,A�?$|u5:� NC��)�i^i� a� �x$�V+T��-Y��!PQ+a��.Vr�o*�J?. O�WF�U�E, 6����R7��p� )dea)�A>:�)��#���=� �seD��AA�O�A[� �der&X�:d!�!?blebbad�1"�[*Iais��f}m�� �>rjpa�ph�a��67�c�hv7*hc�a�sD�OI�$� ak maniU�. S�V ����"�3!)A+� Y��"� .n?5lE��"U@,�@orR72=!S�Lg r �Q�(*�?�8e�M�>25�. S�He� �xH&� 9.�tqv!��i eF!�m!�'!-�8� J,!0�:up�u� )H {,� A,�!9e&�8t�!&i�) E �Ŗ-�52P�6.43�a�Ms) ��Q� e�,�Z5 -bea���. Despi�Zi�.\/: <,�0�J%�t�~%�V at"f�es Ma �)Dcon�[I^<�?�/A����?0,� subV/s hN�����PA4!�fpk�F��Au�0i?=oQby�2:nd HEl� *�s� 5��S�~n .>K�b�N%�<�Q��Fs���_��z!ƋA1�%C1�?V:�$Col�E���� � �Kon ��� 5Gh.�6,j�4�B does��C U'U�!�iped(6�1�"@k�i��?W5Z\�gro~��>����Cruly nov�sl2?Q.O.+di�:tri-fr�ylI}_��of�crq���obi�%a�;Kae�wy 9�P^ K,phophorylcho�or w)�Mxyl&lKP=?�3��en�OAZ>^feN6Y �/�[41–43�c�>y�+l�!��aq�fb�� ��]��:�%��lyh �td m"#2�H&� }� ��i �bYuciڧ�=a�,"M:: ���0��8a��be�Vfic��� } byi !� prolQ27=wg�<�53 �1��M:E�&�J.�R� primary*k��&.*u)YbU)�%ss ��vi;�d��6[2C44�&J}�4� ve f� v�� ���� 5deZ�0%* rotozoan �an%a brucei�/re+8i��goP&l�"s&"�� ��t��6�!�`6�:�&[4�"��Gis=iof�y�'y&�2"����5"�?eK+ewK sq�0. &^ "F�1&�.RB.,"c��6a�>&�_iA��r�\T"glx�. �0T1N)�EHD�dynamin- ;�Z!�ځ5k%�"%q$�>h�/^mot�%�'myobl�:� s [4�470'N�-de�q�a�� "�:,2.JA��*Eag8aA�urd5�p APD�}un�.;� �j 2�b�"�P������� �9*)�V�� -�A� enyl.R}.EV�[4'-50�RS }-� �aL{� n�$ Heligma�o�u?; gyru)q.7"F  .�s [51�C�}iv@,*.��7Y�y<,�L�������N ���!�"� I� disrupt�b�,aM"~l&H ��V* �$ Opis��c��viverr��� "�w� �2�,N �-6�&=2" �;��w�LholangV��!ztro�&2p5�$proof-of-c!�F�"�Z.�SBtpR��AU2��4A�j���6�"�:~2!�s*:� en�2��g�"��2�=r%���.xr��.�H6�3�aO(^h:>^9 4E�-�၅2"H6>� 9�>�5�{e���!�>�i.�3,`2!�1qP  E� �� hom% a!h,ugin O .}�&+*� fH�e�'KB&�U*L1 =�+c>J�i�H0-Tof H . ��!�:4[7 ,A��D^ op"��8� aua�"�jat FcR&�6 x)e�y�|�ly�q�!8y� �@E� d us lskg ?�#$f9�1a*��";e�� ;W 6D�6def�Ou�,�1Apt�$aC�g�� ’sm#��#cap���,&s S2��� �+-�Y�'��{�D enefu�; }��2�� HDM `NK�a?ե�"a�: !�B� �vA�- [6j-c.�%(M��>{ � ?)�) es TLR3�vK !n[� T!��q��sh��;��g�*f� �4:��J?%4a�_rkw���.,Iw ���L1`&�+�"�� C�mpreh�$�O�@ P ��aB� �&}��<wo sub2�NY W:��%/�r� f4� e���9ur�52G6*�q�opK�_us>�  in�6�ur��!�be=d!J�Dey�M�A�&6vaE�eC d<�#�idM��JA 2h&ża9 A:u_" EV�{ ."��prec& �RNXmi)�nscؙ$)./Ea�i�NQ�� eukaryo�d�� . Pl#U�.�t�$c-�aQ�em-loop&v��D pri- )a���merat�?Y �m�nucleu�x ��by Dicer( 9 DCL6J�C6&cycDOF�p%fWm, CDF��5Q�M�X!<-o�e�#um*pX�"�� ��.F2K(r6�pr� 8f� 6oworks!Y�02�7� ator� 3ps��E�aP��K�V��pHm0=��� itself�a��! �w�ԁ$|M.Gyta�ly1e �-�sڎ�(�miR156� 72!(a�ro_g eA�%�9 lux��r2o�a�up��at�1 Q�EO8j,ost>� �m�g�prf> �ir 6�Q �<M%�8 iR3< 2�!22 nt-�u�a1%��7ayE%���v8f<�-���*ZU��m�� ^\4d���6�9�=N�i0H'"�a�NAIŌntJ�[;�In)-ZP.�~!�RNA"��� dawd�WDDL�*� " UA���[3�t�p� $~-]!He�7'z�agle�se $8, d����[4��eMj? e do�- ����x ( dsRBD )��� hypona�2leavesiHYL� �: 8*7qAe zinc��M k1fser1�>xk� , C��ag��a����CP �j!ǥ�a�p5�<$:[�9TOUGHh��:d MOS2. Cz�A�CDFq8c+�\|A���Cs�!f�)^ Dof )�4 fam�M[1�t1E��vW#� Dof�V.>q p�a�5x>� n�T�g&�[%7dag!�mu��' E;�h�9.9[�>� �y��� dag2MH�verexa*.AtOBP3a ArabidopsX ult a�uo6�A�ye$ishM�1�AtCOG1la "}����%�phy�U phyBze�g�N6�!݁]�Azt��io?07��}g; Bgcdf�ex Y!�)y- phenoHr!�kDof���s��n /in5 �\ ?Zamboo#�)�blu1�photor�6FKFӝ�- ,eCDV�j. -ubiquit�.io��a.� [1vF!f��,��*?/| E&lA�:�!�-A� . NOT2 coO�a�[MIRJ4" ;�rui Þ]k vb&FEh)INU CDC5 �jIR�r&6a2e�CL1�u�eE�qu"�> ��:��'. MeCP2�p�+�6� �=AAk=xsF]�<�!��F��y *DGCR8[Drosh�� DCL4�!� �0*� P0M7�HIV-1%�FoT�>"y>[2 �dTl���+2�o��� TYA:�! =R� ��a�YM��I�r,�1i).�h>_I�aF2p N� : un<F��C V � .�b7 �"H�"h &4 �!e��:6�newE�?.� B�cT .�%&��ap:#wo-�[s�pa� ��#D^i�!two2�mE{e5(-�<, aa 1733–1910*� ��� S�ZH hyl1��A!��� �– 5�&5U9� ing�A�52�Ah�|"�54��0pr �k�{ 1�Ga�e���"�m~*6Nh�"<E�o5)�� FbQ�)eT [�F�-N���� -*{ fĴ%ZE�E�t� <8�&ӭ%Bb�k)H le���/9 !cNbyFPǩ!6XJ"0�:F�_Zc�I1KW.Gfir�W13A��@`�m�8se"� Q1 ( MB��gluta� ne S��fv( GSTJ ull-�Ls[��t" ]s\-�, �mGST{<'��S"lon? ot�dodec:#l4 ��4acrylamide gel2�"NB( SDS-P�� l� i!�Rcooٶie��( S׋� ��!*���C�9� ��-�as&� A�ros#Z1BgLN)RN!!�NT5+�2<Q �%�(MB5�2�a�'�no@iI%���5�M� �Co-IP�UH eb�w�A�.o�Q�4�Z>.6k&�-6.227Q-@. A��� ng hemagA��& ( HaKAedi$( p!'::-!!2� 5o)�� ( YFa8H!�H::- "!_ %;&T*.g�:}%w>I- g���%��6]A�2A–S�yS5BAb� .��*K -�@r^!�5KF� /cdfF>p35S::�s*�9�E:aNHA-"Z*d�r�&Y�4�C�p �e)c.:����ExeMqv��L��2�2A �b5�-� � N&GE&>+H� ":�Gguc! 2{AZqy�TBi�ar6&��1l^�( BiF4��%�2��>�S�.fa+�!�"� �� ��A��e���Da�Iu.2] Kd*K�din" di�(�E,7C�N�tA�J�|etSF2-!.8 e ,F�x95��\F!�!�-�"a.qD -trun�vjM~/O�?�gf l"�%] �N�$9&��|���>gJLJ� EQ}!�( an N����2�.�un���p����c*J�&� �ql% =sml!�� -� -BMhx�Z narr�|�8 � n]B�.6�(� 36�*398� 396+5��aa2� 38)R40 fac�Ziao �( "�z� ���e/��R�%*�G.u16=p�Y�`43V/�w�Ӯ k-H@y�pi�e ��"�b d if��� ��c�� h,EaE�9.A3put�A�T�z� �D���.$���o����,mdcla�F?8a L�tz , 11: 89�%�12 �41)�1t�81$02�b͙"b � WT ,r�D �c1U239��`W�vA� 97N+7qe7��9hpnd� , 88~2�(5��4��ad� 'ng2�N8A���97{6 ��(3)98n!H8CN:�,�0JA2� �� @�[6q� know�DRNA-6s.-�^�|sn6�|�:$�3�."�7� M4[�U� s��!PS!�S) S2։%$"f�1 . 5-��;4��6J�72A�195z���Y��Q�anE�M�.&�5+52 ( 7%�gsk!�����yn� � 20&8�l6up&-��M]seq��-v��a nor�n�'e\|�,�3�q�6Aa 7A� 6�� A� 7!x mi!r�D6�8:}1��CS5� >�*��kAn_60A�2(A�\,U E To%sim&�!�&�"~!jUp.1 I$t�4"`.�-�o�, pre� ofX9e?�2&� 2��ah��� a�� ��p!S" � A3� p�")�.� �7�K �� %6N�� �PD��� onagv�)�$� !��+�- i2� seed� �I*-1:���re\�����Em�:�( SUkBAw , TaB?t�K%���3z�cqts.��_**W-��"E�&� m"�)7]xj�{� "�� ��"2Z���e��)Rm�2 >*��2�a� �6e!��":o qr�sF �!�=�A�rN9A�&X I!�?Q�19&B�<��c �S6� ����q�ay]T�\��by6x�real-/�( PCR ( qRT- KY�:�1I-.Ing��!ee�)-\� �"� 3A5f6@1"F&WX 9�'"gy.|._;7 56�mi{ baaiR160 7 a� 72b ��mpl�eu^2U>��rA�l"/&�yN.:z��m�� s 3B�n֍!�d Iu*(!7BAf�64�)�7N�byI�k��� ���N� Xx ��I�pTbno�a�P�5��R����"xZ!I�p  te�h.�ERM�I *epE�a�� uron�o ( GU��r5?rE�U_n!<h5y� ��w� f!����ap�� T�=0�*�U��~�K""�"Jof �'�+C/ A�Z"m-�� � �e䵿[�� 2�7P��L�"� �!�P"npAm72a::!4^ !G��s��CA%y"�!/�F2� � )_$6wMIR.w}!@=Ldlu3~�aM��Yp �\ DF2+��e � 3D�3�' . Qu�Oh ve R� ! �%1�*0��mRN��2 :p6&�3�20��)*>.& M�FM�`_%JH ��1�^�*�+i!�# J�k*"+�AI�A\"�� !� N "���! !�ɊeXB=�}| mo�shift���Ua�wheG wc-�well-7B�� 1M�s�1i` v?7����XZ�xedD!}e��% �-�vm��Ş�a�=�* �%�s 4} laneuYS7�7- � YA�)%�%*>�q1��>\au \-Za�x!O5D-��vCL5C# cNA"<�y`6!cA&-%e���4dB� "#7�me!Xuf��%�.�r�"�9!�`i%�E�%g:�U�6Y!�lIAݶby�".}��q 7E����E�!K9f>q�vo%�eV>�a���Y���a2� �>D' A4E4 a��`��2&�2�V*��sA�:� ,B���dB0X*�-HAA !��"��AZ:~��&��� S�y("�+1�4�c�/a"ad ��\� Nu U t'2 y��#bw!�]E�6n�-�A�8-��M�\ > �:�W31n A- ���A-! �%�@&�7E*� �ezyN B.>�� 4J S1"ee���A�E��=�*��� "Ye�&ZJ��!YT6 ���#:oI�!/"��-!�EGU&L"E�N�����B�;���E�-i��@e*&-q��c�Ny&�EV�-^ �4*Wa&� !(�5�86M]a;!: Sng%!��VB��!`1t��do4u�8�^&��=�v �2?oCu%@Mu�S10���As��-��2px˵"���&F5*�i��F2 x�±�����r&�>���.v �2�AX%�ItA�56%7! 7I��e�M�����Z��V�I{56%�eubr56��MbsQ%v c�h�O9nA"&��6���� �X#LN�1.�x:F�!p �a>� A�>�t7�e >%HiD56D2�y?)B726J-�B� _1*1>U��*1*the res�ults showed that the miR172 level is lower in p35S::m /Col3nt >lcdf2 ( Fig 5B ) , suggesting 28CDF2 suppresseszlpost-transcriptional process9of�NAs ,,0sibly because Qbinds toO se pri-mi2Lregulated by itself �:n � �4 �and ]�interacts with DCL1/HYL1 which might sequester  , resul�,in decreased �.�by�[micro-4or . In animal!dseveral factors were found!inhibi)�$activities!FDrosha�4Dicer , includ!fhADAR ( adenosine deaminase F@ng on RNA ) enzym%�4at participate�@-to-i K( AI )Bedi%8to prevent effe�!�.�specific.�by�<[31]; estrogen-b%@ receptor alpha ,-� associate-�A�-complex%" �I�$conversion!H]` �Qn([32]; LIN28oblock FaccumA� HmaturezA�by ree boAo>�!�-�[33 , 345];�TUTI�is!ruimLin28�NW, leaE (to 3′ terA l uridyla�adegrad of.[36� 7] . MeCP2�e�:�a�A]i�A-domainE�8human DGCR8 [21^We!�n inv�age�!�IK��mo�� e ex1[Q$componentsAolvedA�B�. A�+i S12��,@ar�@�uosE�(wild type , �6t�SE , MOS2 , CDC5 , TOUGH , DDL , NOT2%`4CPL1 are down-��in �cmutant+up2! �ver� la�el%8�&!@��!���AMHnot obviously . The�� implic-�at ��� bia�esi%�%l!direct��age!�0B�3.AproteinF ad�W!�o�� W role >��F{�ioI)}�(. Similarly!�3b�A372N$B3signal�U= TogeE�� s��m%�� �ole&}�A} � ��,�� y : R9�%!& J�B�9�<�r��o be aB�  or�onstan�i CO )�1G9^, our� w u�b,vealed a new�fo(2p G����s-�� bodepend�of��summar' we havAg �!�\E unknown�c qi� �� al1A�$of a subse 2� A>W��� F2  s�:�Q�!�!8E�oET5��2] �group %DE�s�3 also.� �Bq%�prefer� . *�.��d6��p&in vivo�R*�af��_�;of� �i�or &��:�2 &:,influe� on��ce� . By>�)N, �5�)p=�-�may!Eci� 6avpopv �%�Omainta�4roper developmM�̍fq/coordin�'of6� �2�a �6JeH��E�4���'u&�eFr�*� � refore it%"M%.+�-8Aye=tth�Pz.�i��M�Mblue liBphotor�LKPFKFI���"� 9��[1 i �� �p�u��1bo� }����� �`��s�!�*�k oA� yv hѬE3TSCOP1 �orhtn$stabilizes�c%�E��.��$. Arabidopa4thaliana ( eco� Col-0���@( Salk_064863 ) [��(, dcl1-9 [4�46 pa�- YFP/"27��? �5&�  [� �� e 6$ a% .1]�u� . Allqj�gr�4in soil�� Murashige\HSkoog ( MS ) medium� 16 h-h/8 darkIyperiodz he cD������� z clon,�(Cambia1301 Lan YFP epitope tag [!$Cconfirm��<ncA �bin�0vec&�introduco$Agrobacter� tumefacieGV3101 )��$electropor���@floral dip methodE�u!`� forma81k[4%�� gen�X usled��Dhygromycin ( 50mg/�. T[ ;)�)+ (T-DNA inser��6Xac�!(�� egreg ��Apy!����� ,�0homozygous st�oeal$lished fro%s��ne�Atst 15 T&� �! analyzBor each!�struct!he .�Ad libr!�UU���yM  pDEST22%�kindl�� ovidIHDJir�Huang j�C-"�G s!ddAp%V*d.�E�[48m�PCR-a�f�Asub �-��3v smiaJYe!3s)�%�<�screen!�%@per!�� >�Pro-Qu�\Two-Hybrid System Manuala� atchmakerA�r’s m , Invi&{$Approximat�41 . 9 × 106 y��Z �I�8SC/-Leu-Trp-His�]E�5 mM 3-6o-M N-triazO ( 3-AT�Aβ-gal�sid�] ity �YUNin �!�in MaV20�!KE�4ositive candid�A�u�A�2rITA(h)Oassayc difg  length�� ]R frag -#�!!sizh1S�267 a��e�aa 189Akaa 457��C26317:3280>33639:236B246275�(�361d36 �5623Bd2398 266261:d96d�7622>�22���C8661>685h0(.m�co�a�i�A����� MBP-E�, �� -RBDeMBP�@ �.H E . coli BL21 ( DE�a3pur��>f�-Sur�>�oco�]New EnglBBiolabse�DGlutathione–agar ,4B ( Peptron�eadm)�p�y GST� 2�GST��� � 7��recom5nt)�MBP fuG �� o gR� �D amyl� resi )�]�!��Aincub�����%�cap!Jy v seph)& v��;~_�_�E�2��!;�!6 Y�� arallel�� as n\�M1oo mixed �ot�!!^ ext!,in 1mL pull-� bu�D ( 40�HEPES-KO�pH 7 . \ 1KCl3( MgCl�5(0 . 4 M sucEP, 1 EDTA DTTm�-02% Triton X-1e�i�th"1�at 4°C�1 h � agiti�[49Z��)�E>wa our�*7 $ �.�!M�elu !�fur� ��by"unoblotMus a�pr�  antibod�!. Pw com�-hemagA]inv H�!-labe�E(( p::-!�4yellow fluores� M) (� )HA�H::-� )) gene�by !��:-&2 6])v6�y�aYob� i=T���$ewcv$d . F�!{ t_,� co-=9:KB!p�$�%�2�"� !za�NE �"35:N�* h&� 2M06� � 22 d�E� seed�0un� liqu�� �dw � Pree volu�#ofq�vM�� ahTris-HCla0pH 8 . �15Nae�aw5qwiv,2% 2-mer�oeoa�5% glyce!�)!!�!K1let� e= �$$or cocktai�� Roch:m) mortaaSd pestl�\t [50a�(Cell debrisERpelletE�e fuE !g 10 m�� , 000 rpm�MCo-IP�^eri*� �J �$HA Tag IP/ 1KitF� nc,Thermo Pierc�. Brief�zAM��lysj%a%:~�.a���4 h�$overnfin� sp"A n � MZ��� ���TBS plus%�0!��$-20 deterg�(&-T� A�res_#$by SDS/PAG�Anti-GFP�igma ).�()�&|$technology*�e�V�ct������5!�pe&�" BiFC��F%�� s��de�(bed [24A[� co?V eaPi�#CL� , �9 :l N&�E >(E -N ,"a - 2795PA J� >DCD > �&�i>�"��(a� Na YFPC�4]%Yf�Pa)rs5�a;gse �U" list� S3!. Pai� YFPNgy-tagged��]M��� Etco�v�(48 hours afu c�( ��,IIc Svisuat� a DeltaViV Pers�* DV s}(Jl� PrX�M)�Tan Olympus UPLANAPO wa�mmeL(bjI�k�60×/�20 numer( aperL r T� �)�� v�.��-u� TrizqA�� Snd�N!���NAk� o( 5 μg�M-MLV �)rse��+��( megq�e�a�e temp�E�qu�9PCR��real-�w qu�� ve!( RT-q+)��exo)�6@��on� carr!�ou{@a BIO-RAD CFXTM Ru TimeYK �n%G�Gz( � normA>�%A��. Each�!q repe@ atA��%��z!��< mal cycl���as fo� s:Alini�%denW* step�si�- of 2��50 !���95, U| 45sof 30 s�9D ,529M8 "7� a&�'�M15 +v6�2"A-meM-curveK �[5�%!, data��a���$Bio-Rad iC!C r iQ=�Deta�on6��#vB�(p&!�cal�Uedmj!�<$2–ΔΔCtx[52�B( error barr� $ SD ( n = �I�Chv�as.�53] �$22-day-old�.� J � � , c&Eehar�$�a� -link� "5  42� 0mM�oE L: HC G 1mM PMSF�mM"� %!�maldehyd��!�M���4vacuum infiltricAt topp �2Mh �*. A��hromat/hea�" , 5-�́_� body"�, G6495� as�A!�s����n} >]&m ��Y.Eb�flE�2T1M NaHCO� 1%SD�өw!�=6�, R�p��p�@U�&� �resus� � 50 ulɥMx amouF"�he�2Wgenomic t���#!���e����+�� ,.ai3aa te2`\i�8 `to !�iV�Y(� some_ge�G-� �in *lSmall����iso���A�;yIorA�l@ce�!�$mirVana™�IU�] Kit ( Amb , AM156�a�� D gram �:�se�!�Ton a 15% polyacrylamidZ l��8 M ure�1e�ferV !7 nylonT membrane ( GE Healthc!6�*�Uas�,4 oligonucletid�'5M)�0synthe�d%�3’end"�E�bioa�. �i�1E�"yG�,�)u&=K86� at 4�}. AAbe`� kto U6�T’CATCCTTGCGCAGGGGCCA��a!��s a lo1c . GUS�xg:�BX�$ dard�ced�1[54�dI���1 mg/mL 5-bromo-4-chloro-3-indolyl-b-D-glucuronic acid  ohexAmon%sal5(�so phosphE,�����1�G,2M7.assPAGocyanAoRia��í�AOP� tissueqt�A�e1at 37Y �Y�\cle�1w�H75%�� �obser�'[1�P�� 167b&� !��X,  Co{� Aa�R�4��� a T7!慌&f�)Ay&Z3�X forwI" N( }Y�� pu��[Z g  �� �i�� �t( Mega ;q>�K<q�Dor un  �NQ1 a� Endg tin,4��F�U%DL�4Shift Chemilumqc U EMSAZC2dUory���E�ş�b� 20-μA'� o"�a�m�.�, 2ug tYE� nM!�1! ET.),R���. 1*I�,M-N*~*c C 2�IGmixKB}on ic]*r� n:enacA?a 6% r �7F� x TBEq� abw 6f �get%)�Ya a͠j����M�aR�"%� �:`c��>�[19I� E3!�ba�n�eti! abil�)#����ir"!-#�pNA167G.4A�S7An+7-/.�U �:�1nM2q>� add� �la ,}� �E���/+ 8–1�L�5* �A�; &�Au � ,+ 1;#�8:#2:#:#3:#�3:#4:#:4:#�8 7� 2μM))A=( �9F313uF41�^:h!_5b9�(AoI�toM��5"�'�E�By�) �QzS7E"�-�lVl.�;�-XQ:��) 6UM�T��� �� a NA�� u�#�e�pr� e* K1Il� 4a Solexa high-�*put-���O"- =!trkd��da =g � Perl�# iptsEKmaIto � hair,8s�2 YtmirRB�"=15 1)/A�Bowti� �  [55] �^ numb0�erf : alig�sr:= �P6i&mov!t�e*� �5\� � <b�(��" [56]*id�*fy%'asses� abun_7of�+Q�-:�c���, +Esub�hierarch clus:nga�,an unsupervi� manner��%extJ of&�$�9q.IARIP�a~%!�or *57� d� c��&�5� 10 gJ;f��YF5%>7Co�� &�%� � >0�x>K(ibp����=-',( p> ! )�%�fi!Q{s� % .%}I�sol�3n3ar��C&��n8o21=)4 &�im2 2uA�RNA-Bx6ng}W  I:0`� 2? =C N�#Millip!/!ri�R��y-coup�>mag�8A/G�or IgG B"�*. 100� �ach5+�s1/d*-77�in�!�[1�& -N���JU"h w  Vi+5�Dn ���@Z � �RT-�e��^�ab@>�,��Follicul� d du��<ya8a6�4i�,a=de~"�of �in mo\H)Us imp�A�pr.8ofB,q �7-seco��{C 0? nd femaleWtL6EI"ta�!%��#$ed Rho GTP! 6D)�a�? #�v�r(��CresponSI��>�Fa� jun!�\!w.)%$ cytoplasmwG fail�K "H6F��6 I�6:aQ%ab�lsoYG!ab27aR�mj��e��5�secreQ �/rials�(h Gdf9!�ore�!aQadminiJBre͖bde� %+ WF ntac�6�!f��!pr�Uinm)Y0m�. Our�5p��� eL1�$ҹ�n� �6d�la^�.4�~�� ��� , a key p�$ofu��,��moU<��fQ�. Nj orchRJŖby [(%Jse� v=ell_7� mole��:iKF%_VevoA��Kautocr�,�,a and�A �ovarian,(th"L , chemoki�?/ oids[�2p 'e��im�9aV:I\-?�re� �B!�{cortexe]��!�(hypoxic env�3E keep%�|6Ew�x!Q due�insuffi�5t vas%?�� nutr�5k?l�!Xc9omp&�r�8a�:�s%�\:�A�� clos^ �1�medullVL5ig&CO2ѥfac��l rapi o!��-:s["d&�ar~G��i�g&�5Y!� 9$amic-pitui-�axi" is cha�-er0*M���" �H@onolay)+m" ple [!?)expan-%�� 3[Indee�D � !4B*2$�`2�<.=K&�?E��.� �%Z��:�b�Ey n�6�s[6–U/b2d6� �P�]v� �s)g��� 6�!�N.ls,th."eWf�5r-96 ��)� bonev+ph�`�F�#$-15 ( Bmp11![�1�#6�E%�6t �*  A�me*� %#.d [R�aminoIgpyruvas,986ղ)�[1� D�= , 3s beg�'� A�.�-:�-+ �r�=jAw�,as G- $""'[1�1�� &�1saV& J �Qnnexin�5( gapV�:Qh Gja4= � 643v6�yGja� $, N-cadher�0 E Cdh2YER#FCdh F�a�f} �)�)�:[1�16�2C=!loc�'A�� %�surfa�+}��#2e ;u�<baA�1.uATJ �KB�^Q�klos5�37 s@m��ar�  :PUlOa�Nant�stageP@0 rJ@,&� �6���f��h��c�N&<sQ��U!,��uN:remRunc�JD�f 9&� f^*4�ZZ&�(q�6?�a62lJ��O��s��� s�:���mevalon���A��s ��#�farnesy6�( Fby@ %! BothAA�a}"�!6pre"�(]))or:& ) �1a�X #al .])��TtA>~"&m� a�� of �  &� RZnI[2�[Ta[6?$Rho-familyD4 .��� 6  �Ss[2�fWX � ���B!C�&� �&ertoli�l Nh�Od�1� ��iVed�" rmatqN[23��Thu!kwe a x�E3)�R���&�Pl�e:d evVU�occurV�� ��a�� : ts�pQ�ngq��^�W�/dn�{a9tudaDwY'�6��-s�XG�knock� miceaDi� fl/fl �Ddx4-Cr�x+:!�g�$a novel" ���6�!�d. O�E >|&{*�S���RabmZ-� Aɦ�C$/eby ha�A��ct�"PY!-�6X:�R& �1 ohi[C�$ stryU�-m�L�W#atI� `�]�0�!�c"W�� ��D �B6�al��ad� A�Vq& ;l�#)2e!>0�2R1�:. d!y s�J� K1.QJ���u��%}� t�na�day 2^2D 5 PD  "�PD 12"^�H1 poi�,co pon��.~-J!-, !^F�!W?�vely[� We{n���;�*Yy�A�J�E ele� ��Z(��^m� K�M��-e- 1D�R 1ZQ\T meas�he A��8 �;Ih�we "-|*�,�!x won u�at��r�OT2J4m��%�w$4�RU �"6���y!^an�Pd �.6�%/t �.�-C!"T�K�(g�`/t��z�pa2_�e�6��"]�.�r]�/E�& �]?O�.Is.A�3Q�b"�� offsp�A�GEadeU<"% mbry���! he��ef�c!2�8i2�@m�#a 2��� ��"xVA@�had b�WnA��"�JS1�M�$To�Gess�f*Jz(��mx�A1G�u)k,9V/��o.� C57BL/6J �&��L42 wee^ f ag!AA,\7�o, 4 x�2�SL)!�=in�va�tu�B� �s1ea!Gay��Ylit�9(�57�47 ± 3�Hv� 104 .  � redsL ?�$(#3B�'4 B2 .�G!UAk:F1 ( 6 . 6:C�8p$^ they�0u�DbecY1$e�:28-���2�zA� diss��S"6-!�6%�:�" ��we4��I_B�Ue�6�!\d�B^2�nH+ log""!:t�>�UE��n�ll=�<�aqdis�&'v�-G�+E�*!Xd&� v�^* I &� �Ein"�%Gan�!kI�2o�,r/�\�� �B< ��bid8w�8k �y1�r%��EB�"2at�3+��)2A�W=�B%�� B "dc25 MiL�a�^9 v10"Y��)�3`-3�B3ha�i m�o star )t �,t E15-18@�f�bE�_CR�: )�a�"(a�8:"byO% germ� mar�( MVH �$s�0E�UUBYB�EleLCP Z���"�I�m's�"bR� ctiv�(M1�:!� ��hrA)�+J324-�C=3a��O����R6q�\�U!��( �F�^�.*�#H&EA�5.pfew* (�e9Cw�4 ���86n&&��)6�U�1�!$J�)��� y( {a��+>)�4Qinal81{E� � 0F�� 3G���>I�ntr�>%����DX� &/g5) �3–5 �E-F��D�G������in& Mrarz%p�+��,>�!*�#,E�!�majori#��Mx�o{���+aH6�E8��� >�ef�sa�“�ed”Jk�� d apopto� via TUNELy ( S2%�� 2�&r��no.�2��P%,��U�H. Nota�m)�>�$ LC3-",4puncta sharplyF2B�A(F|Z���7A��6$��I�:�*� 埁�NHQ.Q�;tN� �� F�2goY" phag1c stri�?&�c&e\A� J~�&��.Qf:r)� /��&r �A���PI3K-Ak.Z�=X��& is g5'kT_2Z�_"�)*4 )z>Q [2�2�Y\ un�U��%�-� �� 4U#yF�a&{( |��*sur�"�.9BJd6�*� �…'9�zA�!d6�+2retarwM �N+p2by� c�N Ki67E�PCN:j02��7�P4y�74� a OB$&4&>� �F�b� e��* ����/ Smad��Tdl�Ma�-.fd"�a+6n67F�[6!A�ecAq�"` l mad2% 1/5E�6{ &(*A)GPA�pd�*��-nE P5UŁ7ͼiF�q.�>v��� stimZ`by� K�>� Xm�z"βILGF )�%er�.�"�"Az"!*at�<�s�4m�-]�6 :H��6��15vD�P 4= . I(e�G�+O2AUriso!�( 1�? 5 kDXI&[dra� ShM���U�� h"7Qgr�c�[&w : opepB �57 �:/M]G�:I]K�39h.3B#~���x��q�Bbi:,ae19%6atMion[23!W�� -cul�2�'6E0*�JW� denu�.U� -fre9AMr�3� 24 hE��&�.!��/o�CA�a\i�6e%�m��t5�E�rescu�A!�.7�-�He94�u�ose�6�g~��^i�p2 � e��i�6f prob� �9isrup�:�i��q���%E4*�%)g)Y� induk7K ��z�.R�end�ic�� fficK "�s�Jv%$!��[28�!m�m�s"� 6T"�� � ttac"\-Aq�6;�e1>�th�(".!ancho��>e>m[2�<30�W�h*�hr2 Fin β�&*21�+lyI1!�Mz &@ ��(!� ��#A �:�_-Y�_(� act"�Yh:Mer&� M;�e*= v) IE3G?rrowh�=f*5mis�geM^#Kscopy2�G�"cm �F�"���3� j�>�,�! zonaUX ucid�aZP+9d�v�!�g.Z+( black6&e�elin{���M5H�0�;"��!�� imag&9uTO*�*ab6<~&�%m�gW �M%2f>wwj�I �0.�`�&�i�6�� �]� �B.�m*�����]&!6�sh �9&�!� .!"(m"�-AI"�+4'�� 6�4)�-6���mu"�;��r�1`:2����#6�� 5�. Fur��"%8�3 �E-�N-&�-f�6 I 4.� �F�!�vf6� 6��i 6W*�. coul�Mp�; n*�4A )r&` ]aN[A�6�i�H[5�5�p��rM2?/A h atp� �t%LUKQ�i.*�U�&�3N ![){w� �^A[er� �&&[3�2b V� ��.�Rho�e Rac1��CdcF}a��dec�b�'V�� 6��"�?�N�cig�H%Y"n"6B�)�� SZ+ ��"�kE�� ir9�aX.A� 2��6�gA��Z`crei�}@e�S&�:'%��%rN ��DjC 3�kB!8F��ow�a�|qw^Tge&<6�>�o}(!Tg/kg/&!)� PD 8&B��&G5L!da�,in�H=,e�Ž��b 5��R�5�PoA� �ja�� &: 6� 9GE*�&_N�+(6� >M6MA5!�"q# #J )� � "�1[7g)�toi("e-GCol�r��,�zf�n)>\e!���T R/"K�7�3L! �  �"qB)�k #�2��o�7��nF�n)�%C6��"mFB+�_gf�AE�iQB� #��B�wu#�3   � �!e.�b�5�:�n�6XE�49S*h16AAqM�CN?1"� �1�1m%). !�B9 � YS, dorm�m)ts wh%P "B_>K,���L<c�'a.�h:9�d[���y A.v!2HA�v) �- �Ѻv�r.� � I�of"[�!�ş�%&� K>��.&1 } T� ; �=%"RG Z�s[15��. U3=�dium"���at� Z �����acta��> �)F>��T񦥞%�:H}o+�%2r["�?:^_ �Z) 6�!qA_B�aKf�> b��:`"�A�ofJ�6�cyBK+ !y�-d"� ,���A�Iik~U�:�7�7 . M�L3"�~$�� �343"��) bey:7�%6W `�o)�ͨ%-� ed[1?.4h=�~a� is p"v� �,Ż��MF�3�$-c�0ƭ�ց�a��C%[�eᔚ�N� ����6*7N��!�N�!L���&v .�GZJ�:ܔN��o^����,(� IN^�. Q�+a6= link"H&�9 "�PA�PEX oY= �!6�k�Rjr*� �9 si/�)"!?rll i ��l^4(*3Mm�Pm!5SI��]L. Intra�ves V I�!V!Q(n�or=�F]A�&�2�tur|?r�i��[����ha�e0z^1�A�H ag&��} ugt� � �or��� P- ��cgq<&Nv�ڂ.�"�B.Otr&�".oca[,�NeV��C�Q"�,�-_�s*a�Y�^�U &�"[2sK"�"�"b"I!���&OB V"A�!�Z���R3 al��"��f�a=$bSO[ BM�\H!�Pt�W��J�#J�C �J��#��Do=q@zv"~ 6�!>J�!!YM�YOl�I�4of�� "0 r�%�StZns� uZ�w.��wch��t�x� e� pati+E�hyper) emia�����@B-) �e HMG-Co�_duc�sb|[4� e:.�����vA lycy%0�3 syndr^m( PCO�n�ZJon)3�R-�disord�P9�dyslipid��y.c �=-"B�benef�",� ti!�ls��;%1^*w�.!]R�&:CFP,A���[��,Bolongg7E)EŬ!:�}� sLk���$pmyo�@q`liv�rnjury[515�Gj_@ �(e �&0%)�C dysdTe%N�:bFJ A�qGJ��^s -��P,)�8OM�#3Eys�W��b�e1AqJiDm� "�!ťt ��by �Mrapƌ�Jnn!�e�caui�P2�Ɏ �A/�Pn:B� ���dyn�Szremodefof�a�&�!b��%Ase&H�NbeXX�N��!�5�s3c�8��F� � )��.�5��],���:CCcM�*d= (ex�}�d�w,aA"� accredH�!~AAALAmkAm��z As�Ae�wA :�bLab��� A oC 0�"ambOj IACUiInstitEsal2<hU �omm�*e cM=MA#-ResearchK Nanj!�Un�ds� ��o��� Y?-A�]ms>OL1�G�7� "��Eg�/�ꉇ&*?�Y!(�H!G�:F._� �%�e�"E8� *WKE� 4loxp/�A'�"S �K�!Fp7/wtF: 2ed4� %a��Q1� �"^%!Gstrي12�}>���C��C�1nRA�-LoxP m�= "${�h nimuJ261�w �"IE ~�u�;d�>PCR��4 ��5| !�s��s clipp� V2f[capacAZ� %Q*�:i�ng�6�D�D)�7m� Na*5�2�-[.���'k� tt.��!����O4 dQ;v m�!�EI�*"2�%to1"A�jG��d5��AdA+&gg�u�[e��)-�O= purc�\�v�-Aldr�,)��u-*�( #3195p��exin�U#3512p-Sg6708 5339 21/ X#95164G�#97�(�p-Erkc 9106� 469QX� ti-p:( #4060�& $:( #927�� Foxo3�+#1282:�v#9206F�kti-  2708ti�e�:rb�S"c�T&��=~�A( ab1384T� ��3 558p�ab4728�Z#M876.DLC3q�ab483949E{ 3 5566{ �1�$ 1817?���%�j3 9389!WN Abca'� 6�� ( sc-2716"��ti-*M) 793�� �GAPDH  47722�cA7sc-.  RhoA /1!�G-�Pv:c25s�r�4Santa Cruz Bio*i�.�h�"n)61015+�C:BDAs�^c-a�d p��Rj v �G%[qu!Bf�Q*i�$�epubed[2�&fk��N�sfi�jin Bouin u fixa1"JeSa��)/ embe�qpa�� �-$2i�`i=cH�,to 8 μm sli!AL�D� �� toxy4ei� (jC�(O!,2�a&F@tL�.of.< .�&p B�QBFVAflatte�>�JL2�fIcuboidalRH!� 4=� �6DjC!*E�&CE\�d%�SJ�f ifth1�!Ran%�� � o1�X Ag�2-acQ���fds "� �PederseGP��s[�oGiv4�^�_ { sampa one- ���oore ����^m&�%yK��A�ye�e�!���>_>�twent�6X�.�s�KD  diame�L� ��1s%: =�B��� )�q"t>�^�H(�/.�h�6a�T^�Uc��of�2.. Onll� 9���GA��Za8<o+vi� You�9re sco���Mxe. 'du� E�W�ii�8A(���U�L�a blin<m�q��!Z�I0*#VH��1o&��c�a��mB�4%��o*>�,V���:��S���)��g�tri�U �sl�%�boL%fgoo=rh��"�}�KWd�[� -31:5 aG�>:20 rab۲9MVH/DDX4b!2rVD2 #�]�(".� or2�1]*�~a��^ Ejn ABC k0�nd DAB &�^a�L��jAM*A�0vFluor 59!2��P3~#"�l!T%�inM�6���l2�kq� or TEMMh^l6E4ac�]^�`t. A"�H���{raʝe'~�H!;( G3250;�ry� �� m�"�V� 12-*tV^��x .k�!�yin/R,�collage���Q�(in Dulbecco� �^ed Eagle e.-F1�XDMEM/ ) (6�a1�wh�beBf +��ed!a�@!��� di�V��l&~����1H�>D))��.ha�Kcma �w�� �E�12��a׊�>j~=E�an �* ? ��n�1Iun �.{�u�_rif��* �A�5  S2H&YP�� �� Y3 ,J�=i,*,�9�A-��2�ng�yi�W2:op6g ( m*�u.�F?!�B*-ekfE"�wJ�?[5�@&� 1!�>�e�sur�S�`mMe{ 9:�/mplex�kN� .�E�6JQ� . Gr6fB�tÀc�\[gr�0 �A�4 /μ�un��eoi[35-mmE��50�Z00 4Q�]�24h��;p�`��"&@2��N�ie�a , 5�To")]2!�"� a*�'o��f�k�u �eP�(���taQT 2�14s�L��D<:EM�� \s lyj Uw��*� c�% �`�,�lyy�=t�:��ge�1q�An equal@ of2 2���kZ{p^n^z!rea�0��v� W��y��@9qX�-�!�5�P~ aque4up� ph�s-!d9�f�1�%6i4G� orga��0>G-CNQ:-Q:Dx�*� N��0J��.��ice-c��Dou� �(rA�n�.eA)&͡UX-�0G(��x-�30a�s�5�s �&}-��e$%��tsolic5�|/�:31$2q "�IaG���d� �E�",ViRw*&`a�]%"� -�5! ��M)z\A�:�z1�2��! gTRIzoކ��Z?�HM�f�{.�AaPCRt& ^SYBR Gő �"�B�m��s 7300 Se�ce�j� *! val"+���p��nN c��d:n(i��aU !@1�q,��2m��I�)<�.�w� Q�PBS�& �u RIPA���1lE�ve�a���ک"H !�.��8�*d k SDS-M�� ��Q�� [�| .(A[�i�!�&a~!� f"Gag�kt�},�{ArE�� to�m YKa��E�s�6^?�n!h!��)&�2F�Q�"�%iiQ~�q���X%�x!s�W boil�mXۨ)z2��!M-p�� I �A� 'e�=/C-;a�:� �2��L�A� �:~ NewE.@a|&�TQ9 UPA8%�pla "� 4� floaE�fi54 Mi�Vell-CM �9��1 m��"� Mediv6v0I7_$1% Albumax>� <�1% BS�2?@, 5X ITS-X ( Life&m��!�a05�ml L-a�Iaci-"Z^6�J�5� !��{�s�}y�M2�҃��IenA�Z mean�_SEMJ3Eb: a 2-Ked Stun�� t-test"�2� Z 5�P �  lba)�0Ru�id�x# �&5=F��' �U��& iA�GraphPadK�$sm 5 softw! .�!J��%�mer��II:&ol )�" a eukaryo� �&$c�gyoq��#P"m�'gerb �a ��$ . Despite(erO biupA1bio"�js��� i�Im����BB_�-�“&5AnelbYiV�Uroi� NT�M= e��v|!R ���f“�.^�D#�n�7*"v�OnQ�r6wcrystBg!�ӗz�uc,of - have�dxtrem�8useful��� ���Bal�r4 r*�� , O��&�IonJ��.h�G non-5�!�+g& full�!f���bubbleT�?e"O.u;���\����%�U-�oa �"��(%�^T bstr�,LA�.�i*+lap��$TB!w�, ���-na1B�TB�2>p�Ee9|O9�6q@s1 IMA�y:�Obuilt��0&Sw��{6c-wb03��Ae sour���x�W�f�ndAPd M"}D�&( M-As"VJ.gic�M�$�0V � li'�on%�ˣyJ+hwB �'�!&dU6Yۖough )4h�lsi enspa)�aBwe��I��+enu!MD�g5�soa02R� M^2AGBPAtwice� 6k�mL2�"�I r%ge�MI5�MD2o%f���K�=s })a��x�ya �B.�2��[rea�disfavjby�M�m�pul� �kZAC ����h�Jd �$bo�~ofm�t��&eFia�nd� A> *�Pq#� nTgU�V�5�aj�2�I�\H�n6Yy(�m��Z'�F�,A��r�2:p%1jR6N(Y)I%!} f���%!=ef27c[^D��-)X��N� ds)! �Y!*��A unwi�? d.7 C X"� s@be>!�"�B�edge�o6����va�, ^ expo�� F��c � *P'Z&�[�-TN�Fi> NTPs ) n�~tomJ��.�+�incor"ƶ ) }�d [x~�|m na#chT(+y�y D�����:hi�I�A�d1z�H�t92e['I�8V1�1�|�j` �0s'2� 'A.re-������,>A0Iup��E]|�;\pD deca�,)i�6),dm-p��Jks���M�mpeѵ'~)RC5aRH�ui�6�""|���O<rA��!�& �M}� &t`ho=�ERu� wI:�|m�iN�"k ���y�o-�X-rayq !�uch !�.n ��� v Koaqtwo�s��7�K� na� :J{[7n� , 2E�At3�~5e�5[�2�[5A�6�y�z!��!\ r� �or� ����. Cjp ��BA\atys���OA!�.�a�l��� )s, ( E- {7F�5a��-icha��8 s���. two-A`&o9A|' �@�o&aP�,�!�go2�F���i7i�E �A�ro��3��� "�caJ, �is.�G���N�!��� dia6ZU!�d��e  �d help|en"u/vW��@>.����`AN �6�[��2�O idea�!al<{�^*�� 6U� %�AIfIIED���M �F�C� enM|!��!�M -�M�]W�}Al��"���(I_�7omS�a� �� ( i+R*E��o�8���)�EMshutt?&- �\�?ma,j� 2 E�&� noF�&2caεń�b�a 2���rea���mmC)����tic"s !?!�a�e)� pre-���!?�-�2�privo�1lo��R�1H�Fw�4sU P�alb �!I�?SM��N2ra��P�.14��(9�e92��*�q�1=A�A�,:��&r2bP)�"�L�&�&� [�H"���dA�al�z�k view�*&ĵ2�"�*&�:�A�*� �� !�ASaUGedE\��+�t�;a�%;� .I.e�[5 }�� occup��!�2��le��lia�>�2��� �!a�b� ��1�S���`�?5� Mor��U8�ge��i��f��i�TemA �;ly5ck;�$�pre!k2+2%Fձ.0��g�+Qj��wG abov�~2�%ja&���=h ��eq�� ^lapsAts 5&w .�*8o-�J2jeZ�(��2�H �8� �:!��:�!&��t&"4O too flexi�?A�&"%�avail<Ӗ�e�; u�a��RC� Fur�mQ}I�uR�  �=��y�>"� IAB�-a!�-�et�4Nf� . Laodof� 1�%�fk�",/a����o%=pof �8�HTP�3b��di9z=T~�A����or�J6�!��F!�  Zi thus cruc�D6&/6�..�e����A�����^�� �R�J7=,"� o�[X.��fi�]���47�y>@�! �aAHZM �eRfh�D��G o 18>rl�2�68wU�>P �h�*�"�<(�)2��)C�?A� 7QVI:xA�if�M�Jga�,6 �����7i0%��ɍd2�E>�]� ���ie�En� �.r�)� �b�Rnt;'@bD�]t�s �t��A_"� .��:��C�GS*R p�eR�j152)C!pinP��Sle2x�@�{� y~��#�napshoRN��8�a��0 spkUE<��E�� sC�� �0m�.�&+2.�ň����;V���-b2 6�*_|%2�0 y f5� A�eY��� at��"�$���$l�PYe�r�6Fuo8CD�A]1yU=فhm��6Y�)��explicit��A��to6�� F29h������g&�Funb!m]a6@� �F� l� �5M_ ,��7��!j�ng!l�� ~� $ arby:T��"�YsFI?F�� ��6v\a=I�6z��. W^��!)j�fkteD��(Ռ/2�)!7tWndR�to��bw,�&!-(��#�TexARpdb�'�eCy.* ilib�s D,15&Ü:�(X�bE( root�!��Z�viig( RMS��!sCαe�Bach 3ÅQefi�10n��/waF7t JoKly sl��>nd� �7V>5[l�ԍu2e.b.��s ���&�' �P�!p�Qdt2���6����v!cle n �N�eA��i-Ԯi-1T�"3�dNmo�_ /AzB�fl�=�^<�$0Å�B5�/�R�����!�����!�Yon�,cP/#Ge9_�� %#s )a���Ŋ2�T�jng��?�'n�lN�![ V��u�e�*^Z ��]"!gRN2!I-�`u17s!8!'i-�=E@P=�� SVAyaFB>g+b� i+16�t��W �a�<��!��hey*�.). of^A �� ��7e(.�� �.�-rJ�"� �> '"2ͥ>t�"X!\[ W A� �J�J�Q,�� ith r360i-9E&+�?doG��-�2� xnG�&usUKE%g* q.�eq ΅)%=*7/��!)2�.� O=s�E�p']�6j6 "��.^jN\�9��(� �:��BFigs 2$j �E��?o�-h� i-24%j-28t#U|!Te�zF�c&s�a7 ��e%I>Cz�is�SJ=a��bd }��ba�"� -u2Xs Zz �g��+� C:]& 9<h or�N� �c��(o� .:)=���B�zas&�2���F:6 �R� ��:� %�m�F�>7U12Q+�2�56C.p 1.up�e�l��l�ā�RU<boU  j)> 60%��g �mpta��to8" (2<<<)�4�� reunL���"%%��,2�M4:� �-2|��ApA�i�cUCb�7�&rZq�M�-�6u2�-z�(�kE+"$ �N�h�a6�27of ~50%��� ��y&�a�&�6� ��!�>)E�s�O^���A�:�" 50ta�y]AC�FzIDdro~J!� zerov a�� ���o0��k�-��J� ,paB AW�!�"#�)�Us \f20gram CAVER [6X�we&|:A(al�emaDI����F��(A&��"�R��#&Y*L Methods We�c��1o�b�l�3+���2�!MF�&p22-*~a bifur|G&r�%��Hc�5� ��� ^�E�T�� D"h#E�:]q�&Ub&&\", nO�ch!b!-+A�e2�"m�FA}�J�F�;IK�"���C-�'oo lim�P�"Q=ψa('�.�as���3�4�m�)e!)��6#�"�^t.6J�5tI?�-�u2� !ɕ�R#-�D԰parEcrti��EmQ� �is-�]l8 6���!diu"a5�I�a�6ad dirͶEf�eCpe"�%5912@M��Q�mQEgoN itQfu�0ei��- �=6X4Q�M��%F�, Hi��6(�-F:�.�of�>W(AZ(� a:arƞw�ba radiuE� Å���i:=y]F����J��S ��.BMd2�-��InEz�ari 2. f wa�. ~31%!7�:$'�AalmCe77f+6 R�.�q�M�)v[ �]hFL!�r�tA#�=�ZFx�D���� ~~7J�����&�:� �o�-Al"!�&� T�i�?�S� �?�Ys'%�EHs���e47 thema�%�g�c�b%%jl-k\6�*��&�Yv> -&k<1QMSsM�>P� �U�j]�Vi��x#��f mas?c . o . �O)1�e�/�`a�s.�by.�&2�gy�=imiy]�8��I �f�� msel��"�s�19�see>�u_�:!�iN5a�sd4�.&Z%�!2���_ U6/%0����2A ��N�a�����giK�i� x a`��e�\F�2��>� \ 6�b2��C!ir2$>"aa!��"��%I��CVT� �mu9n�-?>"�*�<s�Q��F��i��S2A�� Bea�a�!� shora9a��i�6cod���y�ф_� �6*n&K+��!��.4�b+05aPA�N�d2M0%�*���Y;@4ing positions �<, where 90% of the conformations show an atomic distance devi#� < 1 . 0Å ( S2B Fig ) . By taking into accountc4steric effectsyHNTP molecules along.$pathways ,$comparisonR9’ posi�al �.R�two channels after energy minimiz �Dalso supports that� secondaryD ide most favorable route for6�Lentry . To determine stability�*J� unde K�dynamic protein environment , we performed MD simul�shrt!� fromz6�ed:� and found��9�hav�re�Dnon-bonded interac!�s with u�inFU than main5n(Ec6AEfT!� omponents� trib!yto this�(difference:�s�ng �Pol II (5X�0nucleotides )a$ solv!n ( waA>*cA�er e7) � s 6B6C�WeIUfi.R=0-��A\�ly due �ea�crepancE2�Coulomb�ona�3A%.a�Analysiep(electrostatAIotentiale�0s a negativelE�rged %Y��5��LilM�B$�IZsurface)si arly even�)��ofm�ve%B�b� ( S4 �, suggesE�a m6�p�Pe�A�!mustthrougI�F�$. The van a�0Waals ( vdW ).v4represented by%�LJ6%) do not%4 a significant�I� betweei$2� ( S3�m��has �Rle.[V�M�aClexqpF�e�Z� . As�e��6B��u��a1A�V2W(is quite un �!�ia�4uld be explain9lfac��at�2QxchA�sA�r�߁�re1lyYu�t7�t��us de� iliz<�/Q�}9T . In��as��l>�=0�0V&F� �06B ) , becausi�overall �6isuFis1�Kve , h�= a��6F.�.� �%<(. Further a����])�R����rises��.� p!w��X�c� !�$amino acid6!�A similarM� bothO>m s 7CE�7D�j:4AE6IW< bifurca�$��los near��JRDphosphate backbone�/��KtemplDNA stralA� eref� (�whichI�carrix���rge wqcY���D2U��repul�L"b�byJ�s . O KcontrR �5� F�isEġ,h��$-dense reg�, resul� in2}o2�!#:u-�4��E^�����W8^T!�8demon!�t� n opeh� tern"�R2iA��ё��^��those��FB��T�Omay b!6A<dA~a higa�exposurUf2�h e}�t�!xcreen�!� .�20 6�*] elpsa�A��a4e . g . ~2 Na+M in 1� of%A�a��gee�ViF��a%(deeply buriY�q A�usg&V isU�!�poo�shiel by��(�aŗ half�MDa$*� a2ai%[no^�lea��o a les Z�s2�Ÿ summi�� tho% 1�B�^�� 2=,)E$still pref� J�f� consi A^y�x9�:ndurA�: a�i4�� ajor�� � . Al-previou!mud�Z( proviAgre� sigh�mD��lo)� proc!� �����scrip$ , itA�)? uncl�8how%N� e�  e � ve sR �<� �qenzymac^ �s �b� proposed:� B� directlyUye VlJ�([7–9 , 21@3 , 34 , 51–55]E�a m.follow!�Adow�Xeam��du� bine�A�) i+2%p[56–62] . Until now , cryst tructur2eNto cap%xroF nF,�5rF �� , based o�availi� al i� [�!;,13–15 , 17!E8!@%E5]U1Q+i�:6N� impedS pass�]�o�!�!T%L . However�iochemic%D6EL��t!:s�'ldQ�2� 2��2!f!^a�cataly����cceler R ynthe[5!59!�E{so���l��2li`re�ntrR s2, a�B{ part!!6�bub��D lappA�wd _ a� cruchR stud�y��m�� i �/Hab�1�YPJ�of�oe�<""Ri!HIA�is work e�3 uilt�*m;al modelf� fullV'�1��By�Iv�A(uaJa)sem%zf� napsho�o-X!�!Y�-U. Firs����i�w!���edA a spa oB�wcexh Z � � eno�VpA������!�. C�s�)6��lly��-cA4��Tv� , ou*� �idf ksam �) ™�^�)�4B%�6 ��t�)� hypoe�� 2|&��#:����E/�an.� al{ �^z���a��{��aЅ�, � <wo �"xunpairedCN� ���/;-L�"O�3}"\��:�al  e *~6�� ssia/mQO)�� � ��� .�m2 prob*�A�4/BBe�r��an�tim�q� � a�[2-nFinally�o� aZ*��etail5�a4� I0x ��a�ll-8iem�.3s!�var IKY�M�� Figs 5>5>��f f�to�O!Dir! t^Striking�wLsc�k�{!8NT�:J�!��et�ly much&s�!�.`J��In�icuB� 5[sYeriX*tA&K6i*� -~AIm���mZN���,*E!�isk ell&v���f�7�.!Hadd�� nv��m灉Fw2�A]"� #���a�>����-I�ndEJ� J.cNda�"9 JiArOnE�A�� ǍN�. N� the�,�tJ�-Ca'(.�inclu��Mb�~�Me\ ���� lyI�ed:[whe��2�nA�aC-2X. Our�XseŁ�^+��posal�R�����:"� ^� � curr/�  qualit�s �.���swto1�via��W;�!����u���kcjWm�b:t�u> {simplic�gM1�y cal���mP� { e��0regard , freeR>�aV�iu�Y � valu&Z&�of mean!.c� ���F�12F% �!?!�lex�a�ystem , "�mA�b��halleng(aBinvE�orm+nuA o�cM , si!�it requiysa!�ng a��relev 6� -�!�z9 M�V y��"�BOK"itself�ut, t��� wm�$any associ�.ga�ng%��o.&� � = ���we can7 dict keyidu�%$����3be test��ex�F . Forcpl ]�� limi6�  Ng 2��.g�m-�z alani�r glyc 9B2H(sQ �A75�Bchain � G178- to bulky � �o� og�x{ reduc^ ��"� �.L��2�. SE�j� play� imc"A�rFe,6*-�-�d2�> K176. , K422)2 R249.)!2a`&�Rnc%8clstronger% ͮA�N�Rus5w*a2j .�:cIn viv� RNAP�=u["� 6�"or����5p%�]# y a�$=��>,O*8 j$ Spt4/5 [3�5]  s�h� ��6��A�&� �qXon%0Y�ek���#hQ"��: �1 �-�~�� 0( see S2 TextE���= d"W��"/$ KM"zZ-N�b�6��S5H �� aw��!\� � �we adop��[!�is��-��th!s�;A��ista�si t�Pm2�1���be5blockedI�5.�.~ �. D� , oofr�(�R� TFIIS-��q�F� &��le�%r(mis-incorpo dan*FItV es� w�occup�"ErN� [17�!�5exm �x'���* �].�.7F�� fuE � !�F�b�x_est^E p coup�{B�,n:doscilla�% ranse�. AccorN �moEM � !!�E� it eA�� e]�!�at!�P�ld�6 pre-%�post-6�7&es����.���� each �vid� 2��Z-m�of 20n�!T0]� hort"-scale�m�I@�o observIX.��� DNA/!�hybriT$u%�( P��s&Ve� �Q�.|�e���!J� t te microI�s [20]���%me��ism�=shuttE�"���-R.,~$� � a few�6�N�kin'uK by Kenned�d Erie\�"�7��!�ZF ,E���A �").�8 A(�uC[5�G\,e�  .� �re!�e.�1�� zar�g"�a`, um scaffoa}f �� omp�s[5X!�6uJ�A6O u��!<u�rw*�R�$&�UM��6� byL�=���&!t6�-A�he9�3yEj�reg�,ory� 15�,.�opK" or c��6ae�i/cyo�)i-!�� ��V![�R�P ,b2�(.IU�)�i�*!a�nel.-1i�, i .�!!<�; !w$pur� cgtoIe^�!D ��is!���si+1e@�). "^A�!�RRG�J &4T<p�^�~coQ�,�%���6.s�%�!Z)�T/.� ]&e�.!� unbi%z search�% U2��QB�us8�2:.�a3(!! �M��0ed�0�r?�BI��2"�!{mW2���da: ! sole�**��m�6 2�F`# subs��y���nCAN� beco��&�\Ux��T) Ealso l2��] A�:� �Fheѕ"� rmo21U9�inq4. �h( ƥ���uVWes*20�"5]� 1Z � �b��� k*)!�>�- 8��asevini%�.�� .{C*: exte�1 by 42� a?3al�.��BV ) 0DBID: 2E2H [7�� he PeO5�3[%�&�%�$!�+��to i+61�"F])nd ( T& �.OE�in?2A%~A� wardo ��ic-}$of eukaryom"yII.���*�'� )�����%� bou4 � clamp dom��( quo� as “��- < ” �)r��t�)%�1�% �  ilx#>5�n!>Gups� P%.�n�} ��r�/XE�v at �y ae'&qst�4}A�2�syh!& rchaeal)o*`1lw)M0fp[33�" Specp1�.E�ed�-W�!4� i#er>0by P ,Q� nd Cv� (+1 ~ i+3]�'6 ��*� ed!f��%�(cowa� �(. a�m\�6WVto�la(correspol'.^in=:F� e fragyi�6�.M)j i-10w i-28�3’-endU�:D/B! !�2�7�#�eextracab-V�!�inser,�Y. B*6.$d�nneg�+�ui.��B2*�q?al �!E)� appl�#��2�8aq.�lo~0dA i-8A�-oc ��m�na�tra> �"�mapp�+��]�ds�P� ala)%^�8heN s’� C5%mP)���+10�+14Q 2.��U nasc�m��"��1��:��B Iurm��0carbo ;E�.Q s!O�EXi-6L i-9;!T� >��R� A9 A18IUf��f # sequ��\w+��E�achievpoint6t�.� a-!�4suite Coot [64�o�8 manu�sfix ome!�uV+�lashes"� `a*�3ax.��'M�R5N�CαMcof Rpb1z 5200~240n 270~310 .>$48~260)��Vz%[�W���n<.�:<PHE�|re� ID 252E�rotR�$ void!Q{al� lap @��"":3�u���e�sh��+�eq�%NyŠV5N�&�4"! � �� i-19%kt`!���n�6�60~65~�6�s=/x1�� ��-6mod_�sI�gma�� ���23,"+%���2�480?/3A�B� f�+loop 4 ( �MZ s 50x/ 10 )~#�F=hn�_:���):e�� 430fQ�aJK436~447918~9342s�tpul6i th<'�t}u����?(u��� � s"u /Zz�.uof �182�in��6pec��(s �2� � amber99sb!� ce fp4 [65] �6�on2n[66071]%Z��M"� 6�%o�t!�aT"] �.�< zinc%�&&>5#ad 3harmonic!� trai�? a ���!7226oB3 kJ .�|- Å-2zv� A%-�" d c�"_ U@4�o,on� *+ histidin>���as�(8 6�?e� bed� cBE�!� tZ� a`%��"@ >�azmo��E�e�wA!r�1� ,2000-step�#,%20 �steep�J algorithm �#z���6GFur�;m�) , an+5000X^{!U�� ]�9�$ in vacuum��smo�;&e�ctU.[A6�N4ř�'�Mhe wh�!na�AboxA� 160Å*188 @ ( α = 90° , β � ) �eutral�.it!F�)0ng 141 sodiumI�s"�C��ins 4855887�!�o�4,*�$8139 , 789 TIP3P �� ��42'1ަ27�& lax%�-�in%rAS,"�a��10J A6e3cC5+&heavy-  �ix%�=eIF2�A�200ps�Ean NVT e2$( T = 310K_���Qa� igur#�a� -��' 9��� �� te 4Tex ntproduxE6�J;-r�4veloc� ��f�35����geraOa"a� � 50K��,�7ed upA�2�B�ak.R kept> D{stoF"�3�)y 2!~ ��-rC'jy%beyon�cut-offh 12Å ��t.�!P�0cle-Mesh Ewal\8PME ) method [7X4The Lennard-Jo�2.G/��ly swi�d �%7�<to 11Å �neighb�$lfEpd� �1�A. A� tegMU:1�]A�d !)AJ-�!tLINCS��[74DtoA�i�uLk. A�5he>&�y;/@Gromacs 4 . 5 [75A PDB�F�-�A�w :K��he SI�=. pdb!*�S1����m �S*lib�"�15��&aa�o"K%�l�C+J6u�� U$e% �al vali�!>To +�/�fs+���.�ş%�YC4��)\!*| RMSF6�,�*trajec�.6�y ;?i# data ��H<@#QG���v�,�r� ,e��2B, �%�� s 2B–2DaF&\uq @t�3+�- �:~4�22�3>W�def�F�“�nu� !�6��!�A-T ( U-C-G�� k" �u�!Jefault6V ��!dq�e�( 3a�Åwdiq ce� of donor-S;pt7+d 3�� angl2-'- 6�U*6�L^�#>���nN�er� a!�(AYA)!1|�����F�PB boot��;& w�;re�to ge8"�B6v.�(��i�,H �10 ��Mq�atp�+E��lsoaw�_Y�N� itratO>" a��us���of�#��� �ur6�j� S6LS7�x�SH S6 TsHM%�nE( � 004e��)�W��o�*z�6"p \@program CAVER [63��: %�cav��2� A .�Q@�:�@2� �)s�G!X�:F Pis*�!!hNT� s�ie6Q< of radiusu�(�Hsh&�M�&ly!�[21Z. D�set�͘%A�� inputvam'#lE0!�C!, exc� %# “shell_ ����depthsao be 3�E*4 �Z)1V�s�d� >g�E:n�,%��.�,)t:N- �"on^�;&& �;: g!�1"-5." <ata>ld�>o�C->� �&%/*q=!+d))�,roups�\�g@�mu�4geomecR1Mbh�<X;en�U�, ;2�*��|��3�Oa�Sin�P� 5y olo*"S;� D�,�4"�.�l3f&�%sn `SP2*!He aS�3�AS*�J#<�ri�6a��W�)n2(^��andom� I 100��J �"� A+{ �!J6ed�� � s>pU�a5tevb��!%6 )-�t �<A�O�L!.d�.A���oQ�Ok2� *�=�/F)%, k(� "���&REin���s�'� �K0y��Uk-��e�1"win MSMB� er 0 [76]!)cluax@e���stitu� Y�to 20v+MRnpo*�D�z � Jq�� ~!�_�+c�5A�5�;!�s�--E&�!�f �A8�P&�) �B�.&  �Q2&�N��;Qm� U�F�lUT�#AT!:� E ..�M�a�magnes&c�0its Pα , Pβ�Pγ ��� I� Mg B5 >�G�$5c . oVf!��� Mg2+iBlig��=�!�er5�C��?Y1�"�!!�A���:�A�"Y! xav�dabL*r�s �o%%-��'� we �2 eIhE� :���E40*LF~A�B�e�E �(A0-M�32+2��>j�B;ATB;F�)�par�-�� " , � ,o$5�S� take*�"&���,U�!�,�!�!�& !J poly&# [77]�?� �:edd��.�E�A�?as�by�!���B�U6�� Qxy�� attach� ; eu� |�F -�� 0��&in�9s�(xWM9 re-A "�;��+reg�|gp� h/S"(eM�-��*�ZJ�Y<( RESP ) [78] fi� �quantum V!�(( HF/6-31G*�!ܪ�(2{-��Bx(}c #F`P.�� !�S8� i�J�� B2aus,03 [7�1�+�4up%sFq,���A��.qY�1432n�"in2�*� O4vO�\�h%Ap'0" N=��6��ou?al �E shapD0^S � VAD��a2\@.#X�"B�'o&V&�$N�� perturb����.^ ix fro�)mp%3!�F Y9:���XN�to let�re-orit�f,3@iJ ��(�bJ��)��Nn�~measu�T� �y.@� :�NO+��g:�`]�a ; �>�s�~�}7est"p2C���N�!0C�l*� F �6�i�N�ofIUNqM�5�%W]5�jM2�*��M ���.Ya�R� R�[(a��toget�WdNEbn�%b.�.ā�lC^3!�� 16�%9V�I5�_y �!�2� xM���nn\&� �a�o�Kv P.E�m.�M �X�e~O35 � &�+*� FeM� !2zc!Puw�fA8i�L_MD6Y. O%�G*� _ ��O�Y` m:�&�=LA "�� coll�,?"�:�  "� 23saK*$&����"5�Ss�"20�� o��m�-']2�,�,:�!��Ρ� �%7�G*�<�]T��B}:�BIG��6( E_LJ ndcrt��c! _SR 2Kb ��.� 6�U��;!� :e.�9��R�I��-offpD( EPME_NTP+PolII )�tur���J� 1�Fx.# FY F�Gto zero5�{6�-& ��6 )/O��Z� I!z�n{6� �� �]� =�6 .�-�U/LA/Q6c� ��(� deria�by�7�0~ �1:  ��A5��i\EupI�, EU�J LRIt�=|+ � ��5��cR�6��p1�� �F.TN5�obE)u/=LAyJ�~/�cj"e`Qv�it*�b�%�O�%.� sI?е�A repeFiY.�-%1� �u�<�6i3F n��BEA��J� c�axm"�w�Z�.��.D}FA:�, 6MX�h�> �U�$ n�y*u2�d :��KacUz 3%u��W�2W!net�(dit�CcerA��'EX͍�j'� 7]�:_]:5k.h(Z,-72/�1@�>�!'� :����J�a�^i�.� ;6�Ka &�#s/ Nto1 ! aZW$�W�mN��� �WhauO�a$�&���&s&�:�ab��* � 6.:_sn:[�Q^?� iJ-ah�.&YZ(5�$Y�wVt?/o�Dy�N�abO<)�^K�(5 [.}ERte sepa<] :2��*veRgM(( LYS , ARGE8HI EB�gZ7GLU'AQevs 7[%7pX�At,E1 �ls�`2�) A��,( ye� &�% ��%HBuIi vDisO inc�cel&� nee!� uide deci -m�Ua�publicltWHt�Gn�a"�cdengu@(AKor�"d} Th_anD:Cambodiam�deg" �@re>��R8recognizes true[burde�H unknu7g ut8le�% �NQ@*om labrK ory-aNir�/outpat"winca�c  t�co�E��o n(m,p itud%�-*.�!NE@ 9ablisZacU-J �`� OOcq�. C6�� Ssu�5am�Gchildr�0ged <15 years�� memb of a��2rD�uort9o~bat�d st 2-At�?. Age-e�&Om*jpli`�O7EMF�$ �mpu!��`�C &')i�Fy\2�� urve(LU���eAEA��i�U�, 1�c627�� son-%��prB���\ E�6Wh�%T4936T���-�u". A�} and5}�ofV�Mc��23/��25i}��41.�C��!�)Hs�3v!EsR�a5�5Z(��ge 74o*9��2aP(f%OU �#-u�u-leve��+Uqeb=�M.�(a median 22�1886�2�612–33!123 -Ii�oa� )�4t#200f2007i11K&U1845h e135 )>a�!�!�um�y�a�gK:1EBOp"6��2�A! 8 . ��.6-2K.7I9 .7 64'�:L72MQ4$�P̀aJ!5 f>95��.}!�>5`g�4��.!E(��Lbe �oit�3�? �.U�A9A�2bJ�s�Ee��oJH-ըnrse�appro� to ��l�X�j6�.� s��Q�I��o�d �/_�K^��o� �,n�*�l6�pa��s�|�, �. D�_k\mosGt$o-borne vi�#+i�� creas!}i #Q!�J{�Wce [1�0I�k=@$F��Z trop�aS�As"UAme�!&?�(4Sub-Saharan Af( iMX-[ viru��DENV 6L{� �  ei<asymptoJE�LlTt clin a�4i#yti�f��o�fe�\)�!#ra�$,E�lassic� < ( DF� �(hemorrhagic$H%[y6E m!Z�#�!gn�!�trend%#-�sP[)A��E>, >K glob)CndYo��!�e���@�DT8of���heA��$"st�=iY9�Ii�{lK� ��%�[/4For1�T�zs�0_E�� 50–� mill� ayvEScLiEe� �ly[be!�admit>to�� [�AH"�k�s g�%(bel2B�� n�0�nV"y|p*� �![!�ac�*-� m�� eK.)�F�a�u�2�bely5Q� cr(/ia�� �.!pi|B� O�V�diagnos�I �N%N�$�'zi�V� febr{ �A]% S 6U � \& [5In.� 9mAm_� �6F T > )&�sV!( �sis us�Csuffic_ �_! prirobjx2!�)�L�+x tect epid�!� im��`�a��=S2m�)D&�|E4��a< �0� ,�� draw�%�o�\v>o r)AE�!51`=Z''u1�.con�M�Q�%Vo c!��Qroble;a auth�7 of s�dal�s�$-�s&o� !�#G� : ��>% ~>fa�5�� ?%�8ml 6[6]–[8��U-�)�xZ %;Viyon-�d7 a �'l�8�N, often` �� a*5(i��5orX“� t opinion[0[67Z[!U�C& `!&=aa%J�Xas�-K disa��adj*,d life s l�lE�n=n Brazila7 �7F��E 3� o 8C�-�up��X9�:/*2�1*� gi�pIngv\QdA�6� B?��ir5qIAt81Zom���)9�M�� & bs[s-re %|��,I1��rar��E=�M)a�uM�E^a� &�� h$�k[&B�c re�ry)�5>�\��*vy=at >2IJ�m� illn .�.S�Sr��!�y�!1�� [10ajO�'p�30Mr n U%�tgv6��G>� *� Ӆ"� :0w "B� ��*��`�B11e[1� I�}DF%�� �DIPf�X�5{,�,6��maiekR"on��A h*F����< n emphasi� 6yA7 sp�J�Qncouragz%��Ya!�orts 9=YE�205eB�!��o}*Min�~�sHJ ( MoHuPtric � Vac eI�4H ( PDVn,�U�?� elopN&J nershi�=AkI�U 1�ISin Seou�" KorewY"gorv\/�9Wu[d� z, e�;�!%�i,u�� &� v �A�L�l�a V�" 4?X��f49U�AL=��hav�3*u%twom�a(Bm�2���i^Zf�;��sH o�^0�!�:. e$� �to ]�*�&*&� � � !W�X� ���Y�s �t�sir+ �]e.FeldX%�"I!�6m�'��.� b� a�B� y-� fic��aK>wɒE�+"� impacj3 �! ��6-"� ��!� &Ak 1M��8gX. P*^���A3I�~��.�M��<S"�+. Dem�: phic.1V�� �#pop:]!� cens���?HEx 0 [1YOn�|]�QY�s 199$iMuang���x%9Ka�Oeng P�bPrL�tDed 350 km northwes6Bangkokdq6�wye��?7�da�!i � rx�ir�spars$ ��3206 , 27�O� in 50874 household��an \��m�za��384 km2�9M0density: 149/�Ax, ly 3&$��0Jliv�q:WX�v%y.x78wF-I"�E�:M$)]yy�Iign2�}"X *'<[1���%2E��I/�d�HM1200ik:��M$6a�;.-b�iM ��km >1�uE&,-Myanmar borxe�YLA-{18Hi528�*��s%yA4�608:Asurban>�(I(�M18E�ug5�43^23%?b�J161UTgL^n-����.�}A��b�#gaAmn% >  q�$ 2004�_`(!~q���K65a~9.f�f�K� ]XF{i@{v :�,�u�2�"� �� kindergar�nrad��veAgeG): 413*gZ�at 11 x""school�2recru-o0a"�� � in J�P�H0GN~e) cipa O� enr�+B< B�^��.M� ach��r�B� �s� �uk% Vsixth�In.��+ �!�~Zy��Febru �xn�iA�a�026������14�s�5e?Z7-T1L. Chiwh�1fWC �inA6�m ��m��EG��yymw���Mu�5�W+b'I�1��,+Esiz&%�����m"� %�!rt�[�sE�q�2 acut!��!���� o9'b f �RA3)J[a visi�j� nurse�sd"�e@ �:ei��|TGog a<&}��LW��R � 6�  2�� �����iM��t��#�1%� �*ain>�!C�R8-�' iJu��o Nov~ G b9��I�-��convale�Z( f1� 21 d�bIrS# loodM[�F�q�allmE�E�a �RPgofYM��� 7 i�G oy�e�M(of ≥38°CK wa.YmDa�wy4onP��=�,*�w ~i.%, �!sK&o0I��"��a��l�, !�-�9AiA(>2 �!nno�?���aC�ђ�`fulfil�NA�WHO]yI��Iw[15\E ENV-&� ��# �:(�y�&-%$AFRIMS in-� IgM/IgG/�immunom�y�-I�&�8��2Zser��verse�gtba!olymer .urea�og5RT-PCS./nev � oserumM��2�v%�!D Lanciotti�c�-,��isoofUaY� cribAm(9ly� >�5�m'9��]kJc��A�I=&g1jantibod/+5� EIAs�ofr)�>�or1:E�Li=im�$[16�B�BIo>oc*$vieb!���/!Vetcom���2PP� c.WPX6P<}��E�>|I �yR� Boar�P2"�>�rX��7����U�/$0rmy Surgeon Gz , UniA�wCof4!ifornia� Davia�6$MaBchuIs M*y al S� �(San Diego S�CA. Aх�iv�a� ity-��aD�D.k)�&7in 16 rEZv&g �-�& Cham.A *�s May� Չ 2006��g V - %�"� R$2�"y �z". A^�4�*�&� �� Z\�I� � !� :! .T��\A�Dec�] . expavh�� %Z�9�es��20-hM5� 5t�"��>� A �n�V� !��F� otook a0� A�2 �$P�cQ�!V�J�/��of �IR*{VQZu! 6h E� �N in 3"�e|V�( �&� j%7"� i�B�6�17&1e��8 hnom Penh>���I:���en,�~� 5�Ʌwo- t,ric{���8Jrou6��L�vca�% t�+!`>'s1}"E�&JYCS�5�Vo$'J�8Sd��∼�900���us45  �)��(�geMx>� 3�b–�' ontr!� abC\($�,d%c�vland–� �! >zq �-�rd�U5Q�A1� j�ka C]`v5s�'er� �n�c �<*� �  "W �� �- ef�#NM��rs'ci�`team = � a weekly�2f&ll.ui� 2!}�$:~ ' sick�ld&�0 i r �, digJ(�rm�Mo^em"� logbook# �/���6to."ng.�tT^sN �"� �� 3��a�%$��F{"rA� 8&� "t ,g o"�l � )%� ≥2� r+or H [4S!�B"� .�p&� - &� S!(�W�vE*X� All �B�L �lme� MA� � ti-i � { �. c $( MAC-ELIS .� N!��K&�z W@B -��%�% �-e2�aa�2T��o IgM-�6v�,�t�6kv�4ag� ,&\�*ell culS\!&6 w�P�Upr�(�r�-,&� N� 2i ��ier [18�X �� Q ���&p ino����� � C6/3�-Ae�alb*tuF0AVERO E6 �s���.{Rotype ��#b�srk%fluor\!�� � � monoclo� �A;jEk�JapanEnceph��is � ( JEn*�o-cir �n奵�G{va�logj* �zs-uv� �5�R�;flavi�es ���{�*�dY�E��%"�"A�BE��-�IgM!>.OyA2���ESf�A�/A s docu� ���a52�e�+2��4&%kI!L&�S2O%��eމeby�or-�Iȁ� |ro��}b�E� al C>�� ��G. N�aMPŘnZl^ �%:�%�&wh�!a"� 2v�� q�M!��2��?r�f�'ga�of manaT"��� v�&�+ by� ��n!�m�4( � �35� �#'"&��|l)"� ���-�(� h&��–� *%e2#  ��6"53B` �( �2;.g>� $4;6tZ&ҡ]>O�.N !(Y�Bd))? by�� a�6��P%Q� u0n�G���*h$�9^&T%�Zada��U��c�/B�{U��~Nfw� <"�gekiQ�%�/2��a8��:^-�hemat��p-(($&]X�g�9lzi��Y7ZS �)��!�ado� �*,#v�;�DF-w� Y���wW2�m�h� �0!�(�2l� d: R��aE.) njun$a�6F�A�ad�P h4tro-orb� p�R�Q(inful muscl�r j�U, r_oE.1 �. Leuc�~ (y b�6i.�H�b p�#=� l��d DF- J!Ghep4>ega!�r abdomi�s�=9 6����"-� d: I�0� 1n/� 0%t drop���alet�q[ �0/mmy`I2�7�qA8b�is�+� aQi�2�f�)a � �. CZe ��1lFrAi[!��]d"�k� �!A�J�� )/& m5�xl9�NE���rombocytM�|2>�>�>!��Ha�e{PHF� � p%*�0= s*��ser� &�),P5��!�T ?C߅�� %Yia!Jnd �h� !�capac m�1��ub�Xt�G2 ��E_�L�j�o��!r �iZ���i+�)(3A�eM2plu-�� -'z,"�.�� W�&�c�/(by2�Q��N�(7� sEd�:!�� �[�>r�0# 4� ll g�,n� *��As�0priva�'%� 1��A 9|=� Z�r�n*� F� �0 , if�r� &?E���� c reve��"��f s . 6Ta cum;'o!of�<I=s|-�a�* �&��$*# >" �� 5 s: 8 , 24!.]etF v !��&381C`&j (LU^'�+ de��90*K*j>*(I)"�;)�&� �QkP!EU&�+��,�13�3&�=�op#>�(F��22>�� K&z e\��9h1)t%�y�&f��FN&�t!:Ag&�/6u"##}`U 2�"-upQ%a�!:)2%���< 5% ( 0��6�thW >�4{�od�.� Q'�"�112V_A�7A&�,I2d�)!_=Q� 96&�-*2�q����$9"�?V172��1�YK-Ue �ls!� 7∶�t1 K !ܡ^l��J�A�-�� ] ��SKar �+���!��" � uuQ�j��~s9�a�y-�s%#!�65V�!4f�Apply���v3toN����� � ��'� a�nWofe?4? ( SD�41�j�re�D� ៥9.N2k!ehKE&~&i�NO9T2GAg&�7%T:�02G��@d7GL-� vQE�%s5g�i�-"A �:ly��A.�6�= 9.'�)��&� �Aup!�@527>��� *�C"aA�A>a�a�si�k�u ~=& ex��Q b"A�2=x8(Vl6U�hD�e}!��y� "� �s��Z�8t ��(e"�I�i%�137%%^Y� � 94 )@<i<l��؝�!WSpr�H�=IEv�� �2�X&�/wE#&�=��y�>^.����!�Eab�+'">�8&' >F i� N� i�:Uhi�)refus� or�TV2�Tu��0����3%!��77 ~2�R �lI�*E,:zHy��� as 1&�!A64��F��J���/q#Fve(+\J8-�u�z�j�|�3u�!Y�$f�5�2�.LaK6!���.�in~(����$F:?1+ ŗ�m����@%l!WF�#�|J=�:Mg�A.F)-�ze3se��W��z���G.� �^.='�� "���Y wa��xi��5� 11a1�+ Sa�%�f�ݍir� A!|cL�#V��R���.�!� �!��-q) quɘ� ����R�A�2f�E����ŗ Be`!� @x>�� �=2np*Q7�(u*T'��^ {��t�wo& $-"�!=,� ���"8�2E1�i�CV3r xE�\ J�~�?�e�?A��>; he�"�P'cV=� H"eE���in.4X�7�o"�8>� *e�8a[���%l"lAcY1�f�misY&!@9�&,6r�w��"�1� J�a��>\E*%a����0���lZdo(� , ��7�?�q*H'�&:��� 5��RJ!� ���&shuH@%bE"ve�@ inflb��:exact �aB.���Cs&�:8�v���:I:�RN�� I*-Y+PJc��F� �*%!��=� .�H� u'J"��&nd�&�&1\Y�6�{miq� �d&.$� q�&d nw'. "S-�"� au+0�<"�(��'�&�A�b��.��.Ner>\�ous��d ��F��u-!�� �do�&avXlowvu< xam�4:[�he"�; topov� ;��Je+77"�8 oy�/5LS:�!�49*cu8ƕ]�agr�t-s�| )�<In&�,ML�*/iIJ��RfJz-UZU�K"�C�(jwe" 0A8454= �;)�FX��ya ]�_�Lt">q �����.�MVb�Xt��8- e�"�!=E�"9"��V����#E��"2��%FcN%}e"MJh*a#���R' )��q���� �&�"Bw �K�J��5E0l>WPa�"�L��w7& �aS�.� e�A �wAcn-��Ws�+y A&)AQd� 2%�υ�IK��J� 2�i.�'Y7&�>�� �Ѩ�F.�P�PtI � ANtY#>E�&� ��"(Loutbreak-S�RnL�Y�!Lim a�H�I^e%UJ*-4��)Aծobv����X.�� *&<4Zp2� �� like!�M4�� �J*I+ e/ !����u�9f8 �J NZaAE�aX" 7� EsS A�A�ekky u�sb� ( MFB}Y�� C.�t�a*%A�MF�� on�?r9& 2(�I4"z si�0'\%�.� . Po��O�ea%�!�h���.e �ie p�6��P�&�",��@*�%H_�*M�a�-RR)���;� ��B��Me�s�  BIx�E�!��3"Q]�;0q� )�Pci�m �5!�an�R>N���  &�����7 )-kP��"K5� wheltN��s�?!Q�6�B9" �)��zal����a�no���y7a�!� -Ru�2�jWi�Ucea� y!� lect��kT%Ovv�� eUq!VY 6(�= �=ADal2'x.7a~5�� (B� )j  oY me�u�!֕�J� ��ky.� �.� y�(a,Ҹ�9�!�.h�#6Z�DU2��#2 � F�nP��ph����y�"t.U�%q�( �): �T�Ǎ[� !8!:a �&�"� m>2 �%��x5aB*� �R�{�~�)�� assuao�x(UU Q�*�$D�Rk[K�Q�j�� <)�� 5N!M7P=�9�!�M; seek�be2Lor�M9����ft)�eRoa� "� �2i�"�+)2�E-�i*�x���b�Q9�>+yeMa�,�+ .a��we&/"/ �Os�4*� ��)�Z�v�)di�Ŭ:bJ5Qol3Ht ,-V%���� -�:�it��9+=@A7&��at�I�)�"Zwu'Y �a�f��$b�p �:0�\�tQ�"� F� :���� w-� �~�X'&4*� u�o\+� �E�$.L�T]|o��.&C E;F�SI��� p& �2�out 0�( T%���AO�y"- D��$25�*�Ka��R� �8� ��E6�R�"e.�ty�] @-<( :�<.ND)$�S���26V !TB��)�"&(�chx�%�� ���a~ �$Jfun�Y2^. �,�;d�J` =/"OU��> Thir�tBbeB�mt-f :+FQ�m�Mhes� h)��n�i&T1 � b� l�A~-�]��USY�|surth ,%`a&�*� �� �m�-�Z2�Y�ԅ6� �begin�E������IgE5�FM�drop-A�z��._+�� &#@�JE\Et� �.�sM6���p�he��ZE��.4 ��A�"=BHG){H5�N�2!վ�!�G@aZ2�@800%��O&�!s ��U6 aB8P �! Zwe><N�J����E�>e�����=r"W��Oh�,�U �a� W f< .�-��%�*Aa-�1�� aV � M��n�De,��se�>9 i�"��c�X]`!yt f�� �yaME�� toM�gX�Agb�T=� h�&!-U�A?te+nP��  �J �s�m'+a� y�X"�\-�\�$�2Z �a i��"�3)�=��=7�2�^!��(Puerto Rico#]�� #w�^ *>{ ingu�kQ�&>.- ��f��!��> w\�dr��! issu{7:�rvP!�nhophysioE�Ύ. E�&%2��_ �cA@���(�?=A�g���Z4&��:6V+ 2ND1��:*� 6*H+�[I# \�_ �L�_&x*.cU(*rJKW%&�$��a��A�o&��&20/�B�.�vA�z �\� �*���%e���� Sout�CA�fs� �g1.2�-�#as"�=:� mrtN)U, [22�`25kIIt@p�9 tA�v� :�,�tribuE@*`b�7��&�.m�A� *7e��KbJ�Q���)*s�c ��#���q�"hnHr�^lX,.a)�!� T]2�p#�D15,in Nicaragua�G� �E͝"~;E�ca�=S.�HpU�pYn2�J�\A��Pk�R�Q2�3 �G} �#�S[$6��/Q�uMM3[2zK�2b[.�Q'�L �T���g�b�?;����R1� u�eB@adu�o`s ͞:����Bb֛"�Zm"�Zs yθ"q� �E�r�C^ cand�����2�][2��[2dA^n�)�n�&� E\�� 3��K�5&�s-�.s�&(,A�[ ӻs��!a�A��-5� 7 &E!>0k �U�:  cymak:E�k�F5^.�^Wj9 wp�B�"p*�$l&�s�,M&%+*�mg�edm�X#�vAW��DZial-lehp%)��h ,2achZ.� !+J r*�/inZ= !]�"�� ��N� ..�u1u�6�%sgW�Us .��U�#y�I�m��~at� prom[!�@�ObD�M� sp`D���{ߛ ��ch�ȡ9 bio4( 8U;ar��n @Af'vnt�`q�de�Abinnov�A� apeu&jorM;a�I0>e�|.Un.�al kille-�NKeqelD\��C��ɒe!8!�Iolv�nrep"<)� �M��\y�9$help orche �& mtmC&efe7�is� ��vTo9H�F��qu? o{w��Ld��az��well-�>e����a�&"��� volv&� .�TA�] cyto�<o�*( MCM�Dby!>)<� �Ec��Q�{�ut!� miceE�wild-�A]Kgen"����eea�j�b�&"���}AbJ�B 5BCD8 T�APM�6"h;e2�%!ah�OKgaR)drab@� �ae �i�#�lasmaEidri�I�( pDCJ9!�$:�.�,�r<`!YI!F�Gde.N/<DB� tD��9�Wq�R��ynaa�ᛡ,��)x .�Mo%����� t anA�sw&�cܡ:de��q=$� fOAf1��1�F����ib,E���*E<�"e^Qx�� very-���:WY�P-�e� !�o bala�!��q5b!�kinn' E�.�UKamp�KI|'oŨ�!B��s"��!�E��~�����#�*mc-�� bene��.e3gu(&�ir ɏ�H)�l A_d bf C-Ien�- !fE�shock�m� �A]��Da�%�.��.]h'5(.d�\i���`e.2�net�(N �!x6���On��� .8 3(N�,�B�, CD11b�CD8αAu-I�.�si��K, B�^i�yvd�%�U},� *���!�� ��>] !�t^���I u20k9�|H"�.�Z9��d��]`V�&�T ��r �Hf~E�%+ "g���M�r( � �� әv .��ho�uaQ�iV�^ tho�o derst� �a9J��U?s>r5lIUU�&�out2r�hF3�"�e2���"�humgC[�b� A�!rapid.���s�P5��a~� lmare,S+icy!�m=-G���r[@n"9we�w�dm� idea����2��|w>� u�'��tre]\�l�-���2�leukocy���&�p,"7 mL*�M�m�� %F/DC��N talk�qZ:���1�>��s&A�M�!��'6#n��mor)oa�a���%l�v�M[3 , �:� �tr -;2_ acroph�Fa���ted�i�c �6�5S$via Vα14i� s�q%[]�� �o !I"�Et ( ne��a�PasW r�rti�C��uf pro�s��[7Z1�{� 6�[�*�-iB!�eVb�p�uniqu2j9�� secrȳe��am�$��\ � �* ȩV&��p���>g���J*� !�i�Z �z�_� ���8� Bmr���|gX�� DC�%[1�eplEcs�?$]Qdf mj� �v, �B :%�p��A$fer�α%� β (=ZK0$��S�Q� e���i�K[�_9�E�b the�a;hibit!N�^&��o���*X]�� y!�non) '�/"9 ���ro�|m�#I: ?�W.�e��'aX'et� �[o*���b,"�R��ngOi �id[`�1�nT%EZ+ �a,6��)��� them1ex� �edytotoxic�hn�( � phenUif����AߩiS\�$ �F$ ��[,�J%�G�~,=f`%jcom��iSmU&6 q�E�"n���<, -�a!��M6��v�eU�du��- x+��of=5�NG Og)��P2��y��#iQ"h1� y&w�<"�1�-�.�[2��2Zq6� vn�-��`�]Z!1~�"�]��A����kum&�h�ex����4� e=Qb$���v�!Ai�5�v��8ţ��yt� �q!det�dn�:M|���I����-��h�Di��z&iA�$llu�)�s�9Z0of!�.% �!�-�:C.��� �f,)U$�!9�1[�{�(" �t Ie$ � J� Q!� lexe"EzH ]�Q& nd�/݋a�,2j%��8promotes NK cel��l proliferation and cytotoxicity [13 , 24] . However , the impact of NK cell functions on the pDC response to MCMV remains unexplored . The goal of this study was therefore to evaluate the effect� efficient�ws�0pDC IFN-α/β�du��on�developmE� e adaptiv� mune.Tf4hhost . C57BL/6 mice are abl�mouR�@that can control - plic)� very�ly , duT0their express!� ��Ly49H activating receptor , which endows NK%�s withO abil!�to5ognize%Hkill viral-infected <�ngB$ ligA@�m157 ( reviewed in [1] ) . Although5�(from BALB/cw other strE(of)Y lackp �gen)p strongly �ed foreacquisiE�-*U� machin!k�3prU ofI8� ear` fter)�)!�ey failZC ,5=m!��efore beA sideainY�. Inbmouse�%EBAke/elM�!axis �?uf�A�mkofIwhen i��duce�to^m�$genome [26-�5>C pDCs%\CD8 T�to [er��M�)ced5a bm�4( �− )Qanimal��� ,={ucongenic�,��natural ��er�lex^inA�ticular9%Md ( C . B6-Klra8Cmv1-r/UwaJ �, A��named ( [27��T!�(system thus�JHvides a unique mode�&st�� anti� allo�;ue5demon�te�m8o our knowledge%�r first tim&� � s accelerAY�=mag�Vt a��y�1�. Moreo� we i�;ified|underly� ,mechanism—���to limitaC�b>�"�s not)+ osup����]�—��itself� ults�W%ɼABlof �r*p. itrigger�by��is�)d5kF5 accumul�of�Qdays 3 ��7 iE:�[28�f�4,!i)� usedT}an�a�� ind8 �Co show�i�q�@�l5E a�!2p� of���qua :�,( Figure S1A� We na���!w=�V�to5�)�� la}. Con���w� reporE�a�sI���5s��1q�5 $or possess!��)�!��( , 29 , 30]ac�� w!^ �` ially hig� �burden�i�Hspleei�.t�g9�cos�n��1"��=aB%aIn add� ,U deple��in B�increaA3 �.�yY simi��bserv��щ����u�$these data�firm p� �)�s��)|at.�$ a� ong�� I�is"T " lyse�E�.���e�a�o>� . ToK c� � aݞ����o)�inJ * ��}�examin�&�� � kine�(esA�QF erum&Qd�%�!}e %R&� zdramaticE��M,r ( 100-fold�+K e peakja5s(��( 1 . 5 ) , �CdeQSat�����ns points�% ��ac !5�UY�JTJ�oa� inn��� )6�8also significanA �6�� IL-12p70:|�HTNF-α ( unpublishe!-. Sm,re�\|u0}�A�)��1���E�ol-trea��xM`� le=?5$S2..�e{[Ti�whi|!F� ic��R�yof^^in��� *s��+susni��4 , ita�g�ly ree Eo�ˡ��N��--sJ��3�u�ly0�&�129� w � e�]�m�m��>a.z!h��� Ea� Un come�9 [1Z14�v1�v����vel[ X ed 5320� does/^�)�"m(4]-V8>O �)yibu��to�gorV;�on ha �b�a��_1us���:b�!A�%�.lF�. c� 5<�!� tro havseA�!���)qeI�NX[3!�341|m��r�e�(yA�usY|�  coul' or�.n�A�, & ����U�N���iB� ��� ei�Tza �* of)�or"�g6 Bis"� 6��% �ƅ9 numbTof9�0� )Q)9}��." Jz on[E��#ory�)�E豣� aa���ba�tra�u< stain��` �9�on ex�sol��" nocytes��� Less�� n 1%�!(��nfotto �eJ�!� �6r 10%–12%" ��.Bg B� on>B1[��5a��sol�-�9|@'>B=.�c�6���B!�e��6��i�k=�� j)._>�E�),��qsF) Cic�ly�att����1B�V��a�iZ�: .�wasN��]$d) . ��"� 1�eDed�V�xJ* &�l fur�q link%��� � !�!�%c%�N�by)Gb perfor���i{fQ�R=�� 5 $serial dil��� �inoculum� lea��,hallenge dos��103) 825 × 105 pfu/m�. S� � tiC� sd� e�measu" by ELISAazIwsample��!&�:EWI߁� k�by flow��metryY}S24 �.cl)�@a7�ja� a55�s a]1�ѤsAI&x at eF)[!:=`6� ֗. A1�&Z� viru�J1��|-�%�2� %�4=�6?Switch!�9)qAs=.on�!�E��n)gmax!��� . AtU%Q)\u� 3�� .�K st��N�:�3��.��~� TA�ie�#aco AH o exhibit61�t1tVbw�than a 1�raa�"�y��ab�&$"Ae5of ����)�j ����Asti"�m]�.�Mo"I� j�� PAI>����nA���a5qu�a!�R� , al` � "�J�1��̍OAltoge��E se)�tA26�*!��x�Ni5 thro>17�sN= eQ�.� A��m�e�z2�e�%�re OJg.��DZn� }ins�{de.�R�v�. Highv�I�%!& !�2?!ab&�Y [19KM$�Jof��gen-spec�%-byCder.~pop0 s du9��I� ymph, (ic choriomem it��,( LCMV ) [20�1BW�-�hyp� siz���ֆ�Eed�Ba�AZ��E��� & Q��b! q�R[AUC impi��&2sf%_��R�. deed|~zA��l��! :��ťa sev�.CD8αI&� �;Li�aZ�y� in"�a [3n6n#ca�f "kE��G�ab%*����e�#t6T�{s6f�ed��'wN*� " � �E6�aQ>�sZ �B.G ZyI��d�%�.a,b��A�'� rema�� �a��9{T��oub��pha�:r� leVq%�occur !��a?CD11be4I��et*S� Ic$<:yF��W 3):�,�cDC!(�tm�U� cK,!Y2��q��^%�gm�fWNOtic��ex'v��3"���6�� �totaloj ��enA,day 4xt�:=Rbut="�Q�q�E�investigBwhci�"�d�of2�$ !�ul�a fas�$^jY'o.��Wem,analy�P%��!9|sE�!�)&�,an O-glycosy��-associ�iso� �43�Q@e 1B11 monoclonal�bod� mAb ) �wdre�& #6Ton ��ies [37��3>emb�5s cap7 "�.a��pohN ly�8����!0acute�/ a variety_����8–42��U�Ippeara�!CD43hi�.� star�at��E�yPBf�n�&(class I tetW&rsV4a peptide deri�K� IE-1!^tei��M or\ to�ntify.�!9)=2�� � $is epitope��We9[u<�^��ti-�.e6�,.�w�ha�5���iSor>�.�b��!H�%ae�!;�� �"�"n" rM`1~,6�pr)w m164^�Convers�fu(ccordE�� ���� .� ���v�ed!iZ su!�e�J�~ [43�w.�:�"u�9���rat��FZ& l Yz��%pgi�nM(A�& .�U��"6& *�)�Q%}A %�!e*�Z[ s�&leRir= life..,!�monito� _6�,marker Ki-67y\4�m'ir�Do.>��A"�to%�2` r�"x"�u�"^J���4����qPOTS3:r-��/=�#%�afA�2�target�&�(%�voh4�c*eaeZ.se.�%�Ynm%e�&d>�,Ux&�by2f�N*��-c�+f &� &�As 0!.(It��he wh�m� loc }.5,es1+!#  l a uk�e��A~we soughen"o q �EJ ^�eY Z s" �two�#*e-i )� G /AR�2}rev��:� !:iP&|-on�% -med�1?J ��is�+�.e�by�AT� no22�2dO ��I1���7%<ntibact&q` 6d2 <UC�Lid ia�!!�oge�#"�yS4elor)#v�� ���r)5".y(u�5�jor <�9��ǥY a Δ�-�vppoA�t�+h ,wild-�rh`' :.5��2x*�iJ�%24E~� �=�&i&/ genh .�-,�a dela�>j .�d��910 . D2U�6�(rm�%n}4�H.0Lor molecule DAP12 ( �. °E�:C9��s]b��^\i�flw)��6����e �� 6�� �i�l u�sW�%�in�B&pl�Y,}��A�4%�e2mp )-�:�E�erpartLikewis6 ���M�*A>2�� ,�A P Tet+.��9A�*Of��]B�Q�d6t!�e-�EJdid?.�$c,hcQ�!�I�.p, *�. VW7���|ct'FKI�� R!Jic�E�.(�>�AQ � -inj�8Ik�(� 94±�d35 �us 2 11 log/Aen��� o) d sharplyI�! @F.�M�D( 5 . w04Fwes&� BJ�� )!��is *6to"�,�QA���\ �e�ZzSI�� i at excess�29� ��8ra�L negab;..B�*e@ &� S �8� �n*R A }�F�I�t%u�s�8���*�(:`$�$ such�QA�T;-�Dm;� i� t m1A6er ��gQ$6�&=�,�bear s�7E��%Ae�.|(� a synergi�or �nd�a�9�R-#��5c�,c5= "\;sugges��A�� a�t�5�plausF0���Y2A1 T �i}��O�� �n"6Ar*>Vd��q�"bt�.14Aex�"�$:�:on.yth .~�2��a �۵�aW��1�-�&;Ag�7gyv1"� � "�%O%�a tigh�u� ima�� magnitude�X�h��� util�!a�1$ ( DN-SCP- ))�i&�*engine� s� at�K.k�!bc ��@r"� !� ��84oxycycline [44MU>b $ �� � R/��@&� g ocolM !�2�, clo+mimic�qeQG!L�� �5�1�r7 ..� i,A�d�,�@mexperi� a�0��sel[ �em�i��� SE%�in.�&� , =("J .�%^P %d�g��<pBl6v�w�5�lin un%�edV� z&� �:7&� 4�El� �N�]��:ie3oa�&�6�C&� �,&J A pDC-�Ms��% � �."! 7! !(Y>H�!ten�E 2�M&�(2U>�t��bIinR3A)��9�,rPEq� �w�25"!��n�{w"� E�� atm��?*$0!n���y�&j ���},}_9�D �7:1R�A��]� ha�� %~ �*G��ed^�z8" �>��aA�6�F*< � damp�C2�9�L�8r.!�r p � e optT-c��� in.�9rcK�p&k ,51 exNGe2�� �.{} a5���FG� n . �: n"8�{$CFf:A;��') Ab&<d���r8s����vo���%��n" b{ � 46� v�=� [ ]RB�)a�"n�&ve��Fas�.7 �K�?reg�*�8f �e��"Q A?Dn�/ � 5 �&ub� im�%yAorigi�#�Fc��e�"� � EY�*�Jmak$G �h ��us dis@�y]C� Z �the&D?A2�-� cri� � y�%,9�y8i�'V mod!j�&g milieu�.{Gm+e&e A:�Y�:uz�. O� m�DAKQ.���r itiIan�M%�|athogen *V:summar� iA�v":�%� A(ews [8 , 456q%�>� �F E� Mh�)\FEV m�G)� 1=��va��&�"� per�(c�u!�*x `�%�*�&r2#"�>:,re!�Mit�De�"� at�fN!F�kilD �-QT!�>�/ macrophagzHnd� +B�hem-�ic�1h9osis-lik�ndr �� qrn [47: Oulj(.�BA�>�z�_A)<� se�fKu�WaT=�bu�%��� ��� �*������ �tG�6�a3wdeY`i�&)w�)!�����u�IF ec-�HA\!zYlos����)�D.It&k%�De �V�"t�nd S0�e�Qio�'g =��in�4O.aNd�'��LK1.202b�)�o�6�\�����2,own survivalA*��%!��!U]W2, )�o> +In�Ph_(%�� �~�AA�~do�A�at �'--c�eg�u R e�> �"1L18 9�=�8�� i� � edHs [48"'6� !Uys employ3�-�nd RNAI*�8a�NzIut��P6�P&�b. :�9]�p��[50�MI��� t;R- #D�IcL=9)1&S,� /�9�$&HA�!s�CSoxRFcA[16!Dit"5:m+�d�benefiE�a�X�=d aa�le?i��r anA��" � ( si��*� �\�{;S�1 , 00G8*9t�IIJ:,2�f �e&^G�E�e��  &E tempq�+ -�qC��.6%j�" ��! 5�ar!0^s0���+ &<)B2�).� .�j�!�-�s"� c:Y���a�".aup" a r?)!a V ko�b�0b �� nt^��.]��e�z;811U�s"�8$ , 51–53��F�.xa�? Q<2.n:(�&j �8=.*�;b��V��M�f2��Xe�u�&b �a�< �Ho[�R�$V�kM 2i� ���$"cCEG�>:[*�9H�8l����A�!Y 2yA, �R� �2"T*^�q�i*=#a9�1"% ��2�a� 2)w!�& T�&!F�)�E�overrU2!]jz�5^96�4)LYi  �YV)na-=��A�x& a_ s�m!Ose?Y"�a �.�E�>Y���^2�2�O�]ff"=;!-��� is g�"� �s��t�/� o�7t!�&� �L�"�A �%{fx.e�#D�oe�yeed�!)N�-h� e"�!�MA su�H>Bl�Xr�iE'~�VF=Yp9��5��is%�I-nteK��*p � �k�X�N5O2��Y%�щ>�U�a��x]!Us�=�A!�3�$ poX&C !�+���*�!$~I. O�#6L*�>i�m %�AwMhro�inflam� �d%�-term���&Q�i"HTsB �m�Z��-�d-h�Pe] auto-��%E$myocar!^ s [5�Y.Q$� AVMb�Ml cc4� K aeM�>�^�IYy��"b!?duIG!degre�_5ME]^H]d�QBf9.A@��Bh recWMs�iR DJ�[health�N�Ou�i�_�=� �.^�#,F�lyA$e&-�]�� ����#��#��#�#2#�#�w�!� !��#�� e{-0i�Q�Y)���� gene&�a q�s��.dIW{�& ;B�w�+�ero�logSA key qu66onE�fut� �*~wHb��*E E= �l���!? �y_� 9< . Sa�*d�%Eb�place�HIV�w\}�[55'�al [56m 8] en^V>U ͈&� �J�PbUr>��_:> AIDSų{ N�2�  �� �[5�z0ro; ��ory*4[6�D61]� �+"P �R>nd-6I)V�]h�U��la[62–6��吡v1�`1)!�U�s��ly E~�`(i^��uenza�76+6 j� !��Ft �pro"4p�3a cru�$f��e[6�6�FWM"da�e�pdc��!�4f�!�)"qb;: NKp46+e�f[6.%.5�,!�eaRrP��Dat hum&.Ws� � r�?��� %�9tor Ebole)es [6�69� ��[rregEl'un7ed]�]@nd �,lq�!A&DM(  to&�%��"�"���fa�$SARS [7�]}ZPEn�&o&v<relev}  29 ��^c@b"��&��c�1x3&�7�_Q ! ��}x� %72ni! �:s%/oY�@R^e�^wIm2I! im�/�Eandividu�s� RZo�-:Ws ,�A rmacaF�Ja*> R�t� sh�L+ them2� � ly�K� }cyt ��U!)�2��y esta�[3* "bet�CsuiA�V�U,�C{%o id� m �.8:3N 9��9 �. �W%4&�rug*K(�P���f�����%�� tumo.�!�� u^%,�R} 6P.� �ɇA?viJc�Xngi��E�xUU��by��[77�CColN(i�( p<uzE�ur GveNJ�as -6or�Ean “mGAk�)-�”%4axu60%�g)&��&�7s�f"� � q�V9%��"<=�4(��)�.�)%l= ^4:�sr�^ t�=v�' (Q=� ��MeR en�s�W5M�ap6nt1E : ;in�"c2� R ngagAY �2r ���.�*6_ 07� � �n)�o͊% �nl6p�>!�ѦTe�E��ic.n ��jCI�%�)�� �Aa��ienviron%i�\6�4i+�)�Ai�lFa s&a&�E�^�T�R1X2D*.en-�Et�-taV�n 5Um^2�i�>%(lready illu� �Q!�!g6a I�Rp . D�O:J��*TC.�2B!q~9c�( ��!ZJ"�"� . r"� J1 delii.p � c�to help�pr(/��)�9c�*edV` a tri�>;=�� A�2 �-�?-1/ng����0oi?� /$�ge�U !�I���� f>�ys!,�-�Ay�tissu�#*D@C wRj4 he� ed�}e\AiE-" 1.Z!����)lungs [7*N clus�0*k  F����e��'Ao�D�`B��AF� ��c��l�I�5"5�)se�] f� �A}!�d�0)�rapeuGi�n!f!hZ d9(!6 wo w�j�-�'em�O s�&�� � �cyF�2!���"�8 crui#<% �!�ͽ outwA�!N]� .������L" �to �9`��q"1')7to9 ��d�t�)i1p�I�?r�x�"��o�lJ �r?;I����9physi2N �!<apur�T�$aoi����i�eCov�r*. .�( Char %R��Labora�He�$http://wwwec�$r om/(F purc�Q KFAFřs� . ^dp�fer0atG, ( Jack�r�v2� jax . org�,&�B@*BfC-�B-&dC(*�B 2�2st?�)-f bree��fac%#!mCeo2 d'I!�%��@ Marseille-Luminyt , F#"E"�3"[@n�.�@Ad.GLg it�^al gui��`FA( � cAiaX!�. Pro�4[;approPGADF�h+vI eth� mmitteg#| 04/200"jc= US O�(E�=�A�U Welf�(�u �$A5665–01%Stock�Fw"%FSm�ASw��(salivary gl{ext/ s�bJ+&�G�O���4h!A< ( BA�2"G3n2u26, �F�6IR�h� �StI4pre dA�v)�RstB�|ᭅEl�0�Mn�P0��!Si . p .t�5 �^3 PFU (%�� ra�d�Bu� or 2 05>0trN1�cs�ss�&�c%"vc�W�d�'�uce<+penia��`!E� }grboNu�JIOs epp��or3je{a�&�unR�o�F�aF6)o�|(_s� ����7r !j�v 1�ed upon � �to.�$�� �ac����v :�8��D*9r*�r , 200 μg%.�3�4a��Yd2 Q+&A 20 h�".Ufo[timH�p "bp$of 2 mg/ml2splus 5% r!����!n�zwQE . 5�000!�� R�E( HyC�UBiotec/22�hba|nl���� :byJ�at 30��48 �– )�P A�is%�Wti~*�{ OAAIV�E:ponV 25 n%�A7 . � ar*�Y/&+l�7'%� E-O�7&�dmb�6 �� �a�5� 10 n%����volum��3+ blooWR�7d!�m�dO �l�Qim� a�y 5 ml>a\�rm-I)K*%)"�.T�.x&cB m|ly�h%�)�ed2�.&���";SU� �C1yTpuru �-NK�e1NW$( PK136 ) ��s −�UeFQ)l�u1%[3eyF).%T� %���"�w���)�IgG* _Re(�f�,6<ja6  o&� . U�H�5+.�� sched3L.=�Y5~A`K�m1� PA�,Le�-DXI�%yTCRβaAOka��v��V avoie ris�ruU`v] �Pu m P"�� �?v r GMa*9problea)W maskgiA��U�y )l phen�}+b9j A�sam�M one8)}!-U� Gq��� 98% ":S� �]�V42�Q2pa,.1e[m9-�!�!ce�$ nylon mes�/wasin PB� 5 mM EDTA!V nd 3% FCSa8BS//��!.�DCn�dimE�collagen�E( liber CI; Boehr0a r Mannheiy(2C roch�� �t7d aU� repeB- pipeEJ ��3?�oc|, ery���me�os%DllyQby am%Vum chlo�'smF��erW},suspe�y-�kepe !x�uni.B.�� a�/� spl"sn�c�)[$trypan blu}@u�@a5����U}a |c l"� vZ �cal�.eac.tb��aJPper6A�� !A8��] �.�)� ( ,�Q��&WŶ�Z2BonmJ%�(!e �"�oED+Mincub���L<( 168YPHFMPTNL17�Ar8Z\Z<( 257AGPPRYSRI26a��w,−7 M ) pulA<P816KB7-$feronsourc:l<�ER&DraX6�nd,a��Q�manufac��r'� stru�5-DX5-PE�g (�ne,d�oTc.HL�]��-PerCp6$53–6 . 7<TCR-β-7F$phycocyani�ZcldH57{'9 -%=�b-XMG] �g,)b+C���:Y �/ptavidin�E�*nVxBD Pha�(�(6`bdbios#�ce!6-c.- FITC5CT-%�as>gCaltag>`c �K.�_6YMM�JTNovoca�>Xvi�� -bio.\P�rxcik%�A�)�F18eRMMA-{a/)�� RMMB!NXTEBU-Bi�_2� tebu>�120G8=�r���SchW� -Plo�o:�sp 5I�conju� 8Alexa Fluor-488�l a kiQ�om B? . Is� �/|�� 7gN�aypr�^2� hx�K� &�e6�PE \o�d- �^NIH�Vramer FQ$y ( Atlant)Georgi Un�$S$,�: H-2L?"� bw != H-2D)�dF| �  above-��iouv � "� FACS�me��"�.2! f��:$ 5q4G2%y�r2069t\ _2�* mAbs&n 8��>f9,ccb|iN�3 eat 4 °�>� �!2f 2%�Fa�ialdehy�C�velJ|�ciQ����g��SZh A Cytofix/p�1A�(:�� Ifwe�P,e}"y��vDou:�35�8D38A��e*�,%�r5 N7=Q��u2E"Calibuq,5/eh��s!k"� ) !�Q�. softw-BDት�%>�ZE��(ety i�!^p\] nted� v�.eR�C���N9@in Mi� oft Excel�X@� Corp"? :m m=�� �S+QnVBtwo-tai� t nK��Mean �*Vdev�. ( SD͟*Z a�� grap-2I�s�T�8�K$error barstoo sm' � depi�bA�Mscale+ !Oy-ag�8.N�In eukaryo� , 45S r%Ag�b!�ar���Temy� copy"�(A���e hundA0%�KG�6sA@��.!/"\�m'�z\"�cop'�9 �E normJrowth���4o�*�m"� ba���roxE *> of���p�9aYun �.*�:�, f�+]�9�,aar�rabidop�thaliana��epC�w �ZV cripE�of{!o[�var \!���TI*e4�reaO�WYb unal{%�A .�-���r9 srupa� nucleolin]GA6�nuc-L� . Re��ab���x�(�!�i��B ��#�Z�^"|WT�,��P �}mu�KA\We��F"Rke[H–y�}�Kt��!XPol IUm)�A�A�pro�0� �fa�2�-w.vd);�`)� AtNUC!%�|7KnGym�}��DNA methtpA!�Z��arhĔne�N#$!us�3�d! R�+��$al a novel&�%��D6 a�,"�JinA�c�0U!!) �1K�m-@i�A� I-�!bY�{MA� .B. ��lx�u�b0 al%�g��( P)%�.�head-t��:�(�UinhTI�H �s �iH� > gle JjZ$r�5-ar�"a��2g��( NOR" ,,W�lr�"�<�0aKsi8Qf r �8$n����Rrgbd �-c��&p�#� –[i' Each.6���8 us�=s�,�a� cursߐ�ʁa�:�'�r���U18�.  25S�.I�8A�T TdSpa�� ( IT+AI- Extej-E-D {E+ݩ9s"o��R adja� +D ˙r�9y�%O�-s��G�[�Ina��9&e!rv%:9Mvt_MuNa}RNA ��Ocon�f��w."\d�4 tly-4�I?r:?;_�!3y�~��remh$M.���{;.!� FT� d%V,<�WH�'�[� AuA�ofe%l1?����4<ne�-lengt�* h�3�e)�V��������O�radis� whea�u2 , Brassic� Nicot�!)SolanumU[:�z�m�al�waD�!�u2.!m�j Y�\1 semb�'!#>/�[er6� �re�0�R� EB�lomup�amyy��� % �� ( TIA�.A�Xenopu�+�%m� [�K�2eSi�c) ��"�!�{r��!�E�K!�A�6� aq�`)r"�^�e�*frog oFor - 0%�3md��tT�A.�� ��8�n)*�/5.a�d�c�/enp o2�[98O6e�n*��a�8�(y)O2 ogoTN9CU|�N[1�LiH�a��� ����la*!r*><*0)`��s�\�8)� and/L ilen�?� }��p��\<s �I!�� r� y ye- ���8==�sis%Otoa�!5!��a_6Oo s �%�� ;E�i� �Av�4��� A >�=1>pn&���� 2gamk�Xe.Dei!k�gALof2ar domVkce��2�m �*� �gen@@�|2 ed 4 [$y #�)��8�))�[1΁I6� suec�Lan�!o}ploid6�w2�ADarenos���"; O]�ɵ] � n!�&�" E#����6� ~Xhyper-� ] <r""|� "� H3 di0on lys�69C'3K9�3?�F �-�)�m[D���SH �* �yH3K�r[1 Blo��d�YvoB� � s�Wn�Uin�moY2!&bO� deacet�  cy�Un�17A�A�d�`knockKVW RNAi!� HDA6gHDT1 (FeseB}se –_*�i� F7)r��c 0$E�Q�-A��Ew�� �5�]�!dk �  ��scr!?:2���� DRM2a�5�59)7�?fp#�MBD)# MBD1�)&2 -=b�ng�3��%�s�x_Yalst�qu��&� �o[1� More e� �t�*�3a�at)ơH.(.�Z�)�u�[�R. C8.��deN<ens��i�dr�8c#*�C�%9��Xe���6bI+h ad3v� e��L2j'o �refB; |�A+]�"�al�& ?[1w@AtU�"E( a NUC�L�X-��S!OݔE��66�E� , [1ޞD�)D{��Kh3�p cern���G��,�Z.K��y ��|. L�s�`.�5 %�:3�9�>i�r�$oa�3"b �Y� pre-��k1-�P� �mTs)$Ad�!aA4�!�A�f\�u�ͥA&�"� *�mxc �M"� abu M�a"'�e�A��F2���g�.���T#s�Di]��� �RF�� n "k] we�6rX���?��� !���8!t�lhar�}ze 3′�%�:��� P5��WTf���U;C AsJ&�2 -PCRR>���=j p1/pr{�8�6�mpl��B��v%c+�8� band����iI�"�6� ( la$AKnd�-�0�-21� 0s �|d 3yCloN��q�mU�5a�[.�� J"O� �5�&�, VAR1  � VAR �SA �of ∼90JKAF}Phb��a48"p�Y� ��v" }R30%E22%F'�3��"� � c5��a�A�� (f; �a *� by RT-A](�\ beADX*�JirR byE�II�Ia�ofhoQ}Q��H�)�Bve��w0����!BnE|B"_?4be ��gui60E��S�A� j:of a l@�:er�%A�o\@��VARA��=U shor Ahd695�!jlɚ�FyrY&l12��Fi��. Fur�m� VAb31 &�Wsub92E�� >a� 3 3�"�a �i/ pai9 ( CA �CGC6�, dou�o>li�#�� �E�u��g}( R1-2AJ>�1N� ag�5�{[Etoq �� VAR4aic��&�S!6� �A R���� �\,V yyy�(I�−520�+20L�* &J`50 M�SB|n �� >m�A֥�An"1 M��e 5ѷQ{JrIn "5��(e��<�Vl� }?�u� � "2$�i�N62p3/p4�9�h��r�4 frag@&� 2�#Yg�%Q*w!R�Kresol�>w�!"E~��.RqB� ���2��hIh�H5�B)& e�Sfe���.�����2No����!�h#inn6Y��. A.�F�:֝�"� ]��!_ىMg���a[�6O^2�>kn2��"o R qNUR�3%!�O�I� �-3���t��fE!i2m�!<~E��q "� i A��?p�~p2I�s 6�*l � ��J�LowKc6N�e�V ]�-12�1-2���8e�2ym��Nge�@n� vP9`"�f>��x��Id*�2���% c�1n�t�1.�&�A&�8s.�6 ver4 � *� =xe-;s�0a�wm;!�'�B&i�H' �)�q5M�M>� 9�c&nŝ�bi�w�"mo�>�$/*< mple�P%��:��jz&�,&i �8���i^%�E/Y  ��u�2�B PmCaa�6��ob�%M�! fa� |��'vs������d.�t ;�g:��^ �&U[H-W�osage"b*�eB� }9.��R"�!�!-&��t�s%��5v(n*P����- '>�� 2�xI%J$a�%��a�:s\Q!�exZ_I�o)5�.A�* nI*g�4 0&� , n� }��G"}Ae# 2 .���5Kq�. O*�@�\&caik��b:(��$e%lin B�� bqNu�(J�] is up�   -[O �mer!}�.&Mad"M��%�%.�,,�–<�b !BJ�` - ab"$� � �.4)2- One Step��$� - (� w�^Q�e�J�".�=2�#�"��7�1�T�+& . m3�!� % n E VP%e< �rooE�E��,W]#a�gs g�d� `�, 4$V�ɧn1Ades�)l�eGimb�J�DrZKa�oB2a��y weak���0 .���� �!�� expont-�^ion_I�!�">����? %@&1U!n ��� %�A*�0%$�5)*�:�,w B?�0�Zf � Y=.&� wi@.�R�l.I�:� 6��V�-���{(&�esA<@�ta� ��06� SQIF1α� &z mF ��}�o� i ( panel C_�Ha z�!t 2�Dp�U�oe���2T!2v$u|!)"�"�Nz*iE ?Q'�1s#�[[2+�,!"� e &�A�{2-iE�ng6>aI,W^`"�%y�� ���]to�')� 9� FISH�  ]�&�3�� �u��-k.��5��.�eurD:I�se Ri��� a�X��za�**>[!��1�� a J@ 15� �Eold�}��see1*s�rg��v9.�f�C%>l&1� b*��b�,��2t[=, juxtaQhYj�T� ofx%1Z$14(en labeA'e@F�))]� coK d�EA�I�2� �0�.��N�a��%00��/�+ �A.m4a�� .�0�FrG� �Q�a�tNᡥ�lea&�M�B��6/��->�We�w� a{�>�45S�!p1a� ���6uʘA#,�� co)@*�!�,!a��*es6�pru.�+T"i>�I50��� &�23 no0xEo=�� - �oligo�Fo�e� s p3Up35)��& aAwma��1�&< �""�+!kdo"��AdP9;�+�SiX)�39B�41�D�s5�-�(�l|Y��8L� ��_��*4� hybridi�,).!,%��A�� ��v/s �l�-o���Mf1�`- �q�4�> d10K��}陡$& '%1+ ~e�rR�)<ed�4� K pF6�`��A.�6��&� !�!�2k �1~o�))D[6Ia)'����e1U�� m9!6� om�jm�|j4�9��exm��c�kad" aU�e��fa,3U���6� igo͢Pa1ْGL:�]� >�6� vHRe�B�Uud}Us�.�8HN��!{6-*s"2O of%uōIAU�>��A9EA:W�6Uas� � u�~]2�m��*�=)�TS�ITSa?�H8S��3��e�� AGwe" sBn��&W U%&�� >� A2 �"&�7��'�~Eea&�2�ay)= �c�ka�?��j�ap��"@���adB���∼110 �!lt9)e!~�3erJ=�U� Na� us�I��Y]4ex=F$�iSs mapm2�!f��& w�Uirp�9oop��u�4��Ob��`|Fa� R%W III �fCZ J��2�"��[b�!~�Apo~.a�sf �,6��nU� e�sb7R�R--�LSlp2 A~FM�d:k!6I2�5oKd%pa�fF0e�">T>��%.h �;5�f��'�is{%��o6�<$.4ar%Nl�of��eii%*<fa�$ep*e�s"�8J Fibrillar�&) �ari|in i2`yN��2� ��1 ��,%��p�'[n���>�4Ca ���B� 2� 2�S�mur�.mon.Ϋ-f�5s�EeR( mFIi72B��!?rRfEes'&� seem��a' � ='mGB-B��eW�a� 6($M( c3 I.�6J]2�C �?7σ"�( ��q.�ъ,�]IWu;I. r( �:� darkEu�f� �( .E. Take/ng�3� ?�u)� .Wd:8F�&A�RKnd"s6� �o�d �M����**)iryE*�!5VŐi^Eb�*lw�5�*�>�FtoAM,�b"NGb�W227&RaJe�g4be�!}A� n@%~ 8E_? enzy[�[3,��wGO$��{#4�an�pa���?�u�kp�6 )pF-w�U Chro�n�W P�Nt�U_aIPmWR}<p}-Polymn1Ch:1Re�o�#})�q n!�Ha�� ���EH�9,a:a4=�JJ -�w(��FC�� J�!_�%stv?-subuni�d"���� *GQP�_$GP , p10/pp ,��f�=�P=#8 2/p1i ,. *  4/p1,� rU 8 6/p1�a�"E>�>> �)IG� p18/p1��&� "� �� . Qu!GA#ve�F m�%����a�f� des� Q�&�( bhF)QA7^E& Ly<M��%�Z�i��b jusZ`FNm N%P)�%! ��)2��%5��G� z{E�o�' h!`,M� Xg��>5B � � �u�.TiniD2��a�I  S; =�ga(&>&r#B7".�*�m�.�or9$l@5 we w�qe� 26�R.d Y��ndIg. �� � y,$1y ?�<�AS�:QA-�/uP�A�d�7i*��)��{� ���:&�����.R��7�!.�,Y^L=��A��&�t"[6z.� "L�oV R� 5� < >,xE��w#:�s p42/p4�)p7/p8�iqy=�−507!−20ij22t�+24:-F!�a�)1�% w��4�i`i�A"� v:%AFS���/M� #�M�.F���U ��F%"� �y AtACT2=':s9���*�A�in�1��T�s Y,�s��A�.�Bk6�:N�I��Ay���aQ� � R�SP����9?^6�%�an&��3"�hh/]p n��%�RSV�"� �#%�"� �x.YfLi*6�$�!��DJ�!:a�i�&xOr2�&B� 2DC;+@%)� 5�!�l )Z��<FA��inj�� ���A�9 c�N)F� fr!g�de�" ( p20/p2�=) T�ap22/p2�,�p24/p2� �< 6/p2�  <9�4Sal1-� p28/p2� !~3@30/p3|E!�]z�q�\ ,�� �9���n2�E�}%2�& r�P�I ofN���^�(e:U)�to�& . NoX��6�of�N�" w�<�8��� ��.�0Y�Y|ct1c^yigF��AR� $6�)b��3A&��B'Y�B�!�&�ہ��)A(K.?K&kA�6�;sM�2�ݶ2] ��.� �s*pA�!b/�;��� � h*AO',:�)B�&Sa"�"i�!&� IIl�!�8.)E�> nv�.5-�V�� � ^�O&�% x*J7�__��%� bK ��$�$Cv;eDB a)V�.�)�∼50%a2!|E�A�s.�6� A-�6H"� �*ETwa�Um/"3��ɿ5}.BG�8��p uq2� " �;"� �x�6��!Ditu:�` ��"ns� Aq�V��V��Q��e��q�.��of Y�!��"6AI�S h!�OJ�� :i��P%NTE�( � )�f6N� %.Y�!�!��@NO�2 4%XC3�AH"�&l DP�spaX_E=�A�*B��TӑlQaFA9"�$�c 6B!�� ANzu��db�;��%&wA >� invaQ �u�oSupA�ے'�U[A�[a�R's���@co-M ܩ= J ej(a�49% ,  T|OS1��'Y&S)17� Q8o& ACAd�+,#6�Q�� �& 1.:�.�� .z��H3K4me��~�$globaUth�H�us"� �u-�w^����|�w~! DAPIg&?mv�Y��oA�YE*:C2+whoYt9Xe�ac 0%�g���(&S/O��TFp )WNm\a�/X�Fh�EIn hda6"h( axe1-� �y*:�� q�6Y'��GS+Nd�tl2�ZP�1>H��n��7Jg0e���S�`> ^��� '-�-�Vo)q� >��p32/p3� ��!���I�*� ^(��%0%  F xe-5�ofqIW� 2!� ���Z"~{:FC2pWT�@{ "� Ad@�:&" �3�6Ae$� �E~ga �EuF�J6:Iis�%�K�i�t&e>�1c^(R"\ 6D� Inmuno2l.!l�j�q��e� r�u�+F�ң��`s � V�5�)�F�� )& \�W�HC.�Q���2{ō�5���.IE�oahfe,A�Q�2?"]�,Ia 2���81� F�!�G !�woy�/(��z �iha%E�@JS P�5Z;�,a$�ef6Vp�P-�MsBTG�: I�h�\6P��Z�z~��s)Ui"��.)�f�f�� siY)I�R7>=]�N.�YFO� CMT3� �O bl(fr>]"CHH 0HG�$1:&�:,ile MET1 maiA s CG2H[3RM_�ex2i �=�,fe:�)r<1�Hx#.��]��%<�1U1~( ATU��$!:f<�"� �c-mto"� s�V"��" ��:16G-.VZtZ 26^"N ��[3�2�ho2�7�!6� TM�iz�Md$ V "; =x��j�i�'ekfa1=IF 6�2(`�5~B�&�"�5$�e"(of����"j#in 6�)Fjzs�e��>w&�6 bu17J?6+�}�&�G�� �ir159A� AtSN1-��5A�ct�f 9,�miR6`�j�UpSe��ar%U6 ��C���ʸ�6o�� sn!NU�)JM��},e�F:1"+$y�.�&:Sbisulfsm��o�&IuM">S�!� � 7&> V� Id)� +O')4 U�l�:���)6CG[U�1-�∼�Is�∼24% )18lG�BIe �50��T�yn]%���.g� =16��WT�A lso�.  �9�!SAW�� `=��13)�/ ���A�2KeDd!7`&.��maiK5�*.�FA�9� `Q 8 !�e6X+F�&zG31aj+7.V EO= q� �2zPQI� situ �iz��experi#�� firm�MtBg "� ��rrela�a�eZ ncentr \of�ymerase�--nucleol5 �@�?>�S5�The|it�possibl5 > .�due�y� loadA�� I��ɡ�2�number1m�=�. I��E�a!1k ma� er3 9�M�, � �indicatM�� �t ca AO>� 9 �'6E} S6�oTf s� t�e"Z s�7em� orA� !OofM/somesA���; M n epi�� change Iq� mamm JAybinds 0H1 [44] , [45l$play a rol� *chapero�a�ass"g.:�[2IM�]8h (been demonsᕡ�or�ar=�e(Tactor UBF ( Upstream B�� ng F oanimaI�1 <displaB�H1i�i�)z[46!!controls��Y��[47)=wa�:V�F to9�E�B�!�s��a.�-in&e me!�ism [34a\Despi����s� it9 ,Yj!��� structuy&Dakteq,con��� they migh"W����; /G ! through^molecu!��.�co-lo�<s�Xonly approximately halfA]�"� loci%T&Se)�� &�"i�Ta� S1e�In2Z the-aa�z, l���A��wo�Ve? E�E3|�k�oI "4 [35AV[36!�Wan�ayo"� i�ban� NOR42�w� edic0.g)K1`pot":2���e.���  5is�Qba#  ac!Rt)��|J3�!igS , whichGaY�c� %�!� T[1)?48!EMoreo� whilPn\n5Ssignall� .�3 �z.�A eriph] a knobuee]&.a]in._E2� [4 � d  , ChIP 6 muno}lN u. M�&� axe1- in!ch��%L<o T rB� in [16] ) ��]&$ 5PI��L}�Wt��D.>� ��Ed�2�%'.�G �co im!Q precipitaamai�w.yI(arenosa –26!B6��ed8�KV9: suecica��5,S9%-.4 7F]45SaM�"y � S7%� id�v6`quant!��wY Tmethy�A� acet&U�Q38�. �%��_UZ�] �B+or=l.*� 6g�S� .�w*�pCpG2��fic�-"Weg��..Ar?�� ="� >� S1ɔPr�analyA� eriUro c!ea :*treveal��DNA2� loss��CG di� tides per� ��to suc� ve sexual�4(s [50]–[5 Eve�le5!�a�O;! quir� C6na�ten�(�$g . , DDM1!�MET!(�re� d7 fun�Fal��ele).�a�in��re9>�� posoyCrec�H@or “reset” [5� .AE.�kU�-2 docu�? full`�:Sg f�"(� �1U l4wild type Col0IPu&�We hypo��E �*<impairs>�.��(out abolish �e�ly�ԁ e r.�>�to,reestabQed��M�r �� par�6A:�was���Vi. A3 iE�<�b�A hda6%r . H�},a?( � CG )2tm�%�>�� j�w �4 E{ z!!�&�rescuI� HDA6I�A0�. But|Zu��%�qR� f\t!��Aq-Eqe&� of i��gen�"1�%��.;(":10��>�YV>�� ntibod� E�a�g di� ed H3K9 � no� ��nt�� betw��Col-0%�:T*S�\ TakeV ge�, p��is6� vB��wB�N@e1�l6�MH�zygote�&� ���@}^y�>�ddm��met�!-�!�,���e �s�� aaK, %�6+a�0few years ago�reX� ɾ��ai� -U3snoRNPM�x)J2�� ��"motifů! �� ( A123B ,�U�8 )Epropo >!A��imxa� coup.y!A�@*p��T[5�55� �~wej� e�aGdirecA���5�*��d��co-* =!���.�!AD�!Hi, C��*�� Q9�pr�9 , [5zEsalA�-j)�!�n.A to�s may�ixto"j ~�inU6�al fra�e�"�E"‘on’a ff �� � ioI�e.���)IAccor��de��A(Pher�AKd��of� � �����m%ge:!$2�a!)�!/9CE�.�>�"�s�  u��poi�Za �"vofB� i.�z!��]=$�$��orA�!vol��JZr [57\5\"Zo6".bAA�� b:�yp2�r:�A�e�AHT�yz6c.$ know24�e�any| M� If�(-MTUlw ( DME/RO,z Acytoc#–qm�$ ( Mc-BP )A�'e�"e[59%R60S.�IV��lik�o!���+�A a �Ribo N�~ Comp�( ��) �a2!G)�!G �.�u���AV� DNA/=od(e�%�ki(A�RdR�TSN1� �hav]enj lH` &�� J��M!� quesv9 a��()mut� 'c�d�q� talk�ng9h-6h�&I � 71^�aK, h as� �� �"Mim.�re%;)F.� ��n.�)!���2�induc)<:� Q.( [18��6i�w p��vol��M�m���$%�;� �}�#&�weIe %$�to finr#y c� c� �!��LV('t*~ �{*��!: physiolog�!�ac� a s�$Y5\Xin! � rEr�  openU� . SeL%� sponE�to5�-1�1�-2Sli�*,( SALK_05359[ 02764i pe�W�) ws ob��6F$�Not�%ham2�Stock Ce� L ( http://nasc . lif�%nott . aukt �1� �#p�P UX/2=�� parl�al� descr� by [2�R���a� �ważvid� C . Pikas!�L�. T7(!&,esA{x.�n��pollen��zu� A� erti�FW >.�nV&K uswh!�sel�by PCR�)�JP�3(�h�iso�y� TriZo�agn(( GE He�.c(, Littler C(on@$DBukimhamshire , UK� ]&1��%�.�( 15 µgA|as ei� fW � H on 0 . 8%�4maldehyde agarO.gF/!��o�m�to nit� llul'(( Hybond+ ,:� ) orBr15%!�yacrylam�-^i X NXB0y�� cС�po � urs���s(%�, 10 p�� oligo�7 p�%rsi�5 end labe�)�50 µCioh[γ32 P] ATP ( 6000 Ci/mmol!�0nd T4 PNK ( P�ga�O6ue)b�!(�Qa�#lem�*ry Grial ( T�+�. A_�n�['d4at 42°C ( in �,f))%v,%�@5% SDS , 6X SSC ,8Denhardt's solu%abu�+d filt5(was��&Arm"x� 2[An1 q! twic6565�b5bef�expos(� �� p3O#p3�! p37 , p39lp4��3 hrs ,6 8 0j( PhosphoIma#( M"�Dynamics%�A�clN �.����c�P.ic� exta~��WTy��� as aq fiedMvGoTaqDa)�'6WN�u0RT-���o*perAjt���free-e6(�.1�L!�0a OneStep RT_S,Kit ( QIAGEN%C�S�x$42qj��!� �cV �Neeach f�3��1ed)t��9��vt�!� L5���-.�1�N&I��{ �s)�!y : p3%�:�im��5��� ( +104� ��s��#))� 3AtUJT'A |a�0a� c�"$ . Dideoxy1�x q -�B*he fmol%�B�S%�29��I^-3Za� smidQc��Z�"b:7 −520�p +1940 [61=a�RN' A/T1 mapp�i�R�gto es 162a�: !�of 25�5folP�664!�9n "o%bQ�� 2��gO3���AQMp��p�(y�!~�w rib2be��� P b2v� �"�5 �� ar�)nsen �Dcorpo�4ng [α32P] CTP�~radioaM , �ur��onZ PAGEE��)��i�as+#Yzb� A.%�Hcombi2o�QsQ_a� FISH� & y�!�npriorAb.. Young � tt�6avem squa�� slc4in PBS 1X / 4%. a�J"F . I:}.�6�Iα-*1��$!� body2��- fluo�40e Alexa 488 -aujug� god/4nti-rabbit IgG� igm� H3K4me2-Nf��:Fav4ti-4Aց�`�(�'�,)ʽ594��-Aldr#(, St . Loui" MO�%��subI�[�bs1� �i��i�E%x(DAPI ( 4′> -diW Dino-2-phenylindoleQq1aImediu�50Vectashield ,or Labaror� A�5tai� �sp� e��%Ee-�&��avail��6P inE�Msm�6[ J�f*7.!T9GI�mo�,.&( 72B�"B#u~]k��2��+i�  acqui%%t+e4esc=3� Z1 miq(cope ( Zeis� �@an Axiocam MRm ca� .%a��. C"�+)����$��(�$):Br�, [62�T>�$e�>&�",(� �T�2� , �M cl�&zagMfe C-t� l pep��'.�"z4�1�, custom made�RNeoMPS�q�-bourg�/r&"A�t !Ca:� !wF �. 7500� rmocV r)�g 5 �4�P�$�5E ( In�gen� SYBR Gr�a�:�L��Re� ( �<R2�� 31usa�ͱpa�Nve CT�$od ( LivakeSchmitt�, 200��43to inpu��G*RcWT �n2J;�F1 \ -2 x)!g&� � Illu�-%� A�kit�topq6����manufa�,er'��,I. 2C ofc�di8ed�� �20 Uni)�BamHINM?Jenzym��bisulfG-conver . BW.tHv>�E�-ct0� ( Qi�E�q ���p4�<p43)�� toM�yi�g��o ()�−315-+24;!��3!BK"A5EKa��/AEN �B� 3Z 41 > & saW��E/41;Y�=352 ,E) ��� al:�CyMATEQ�[6_% �H�@de._(�s& ivk.2%@@ng hum\<4ytomegalovirus)R*.�4��� �id-@candid�HDAC1-iRing!k"�!`� Z#�AA�byM��/od� rapid���,of��,epitope-tagg37f 6 �� massr(try!u�;���ed"V-co%���In� tic�/ Y �pUL�UL29/28 ��%* a�co�9e k+r�/ �2�t 9#re�=!�numer^5� �!�!�?-!�(��.x ndYTs�1aY , NuRD .N�>wMTA mpon�of @,e�shRNA-� E knockdoww = RBBP� CHD4!1stitu�6Jinhibi�� HCMV!=edO-e�<? �viW��m�<; t�$�"argue�4) ����%c-OneeA"l"_$ �rep�A. Con:*! E a�vF ��e�Hhe�s"�=�rXI��=#Mq-"E�-d9t! u��7k�&c6'rer/g� ��@s ���rs�<%}or�' (ti,�� i�Y� enh�d �3! x e %�zim6�"'(inF$�$rA{a�Fregardle0%�.~7%a� P;!� zVugs by]i�&"&d+U"E�1 |�nt9KM� �>�E�.�7A3Z1�?ed-�a�2<:8 !2$Q"� ��A�e�! toU:e)�A�6�GJ�s . HR`()�)�� a ubiquit�� β-herpesɈ>$caE��thA�e�"dis2I!�� a� romi�ad�G,��� �� vidu�6y@go�(solid organa$$hematopoie(8xC�� �?.H!� A� �I#q`cy Synd�'IDS )�3�Q*�2c;ni�E�)�if-��-?;�a�;�E�q3�n=4�>childre;;Ia.nt (, � w*h:V8 link /o <iovas��1u( �e�=W2�"�Y��%a"�:(%�:c�Cy [3];7�J)��8�"�Bs%A+�t�tum�ui"+e�&� �onc� MF�n��Wa ��D [4��ly!�%�.\� ^c��7a �1l� �&��se]of�=. A� v5 star^ 9�,e�u�7def.s�P��nd!(�5: g e&_,is"il�2T� d�Na�ata�<veA�!�ellg;A�2avirE�[5�07#A�onQ-��0�H�h�M_�(2�R�5�[8%%5# also help�"/�9;ss�;environ� !�.�!@��� \;�V���V>T cascc[ER$)�-}�?� , en�5zr��B� g�2� �?lt�$�KngY$ N!b��ioniQv@�8, a� ��e|��V s[=a� Mus �pI0 cles �Upon  D�f!�e*��H pidlC*co*aQ9%AaE�h� s-�)�tB�� dk.� irͪ�<*A(. D�F�>]ph�-�.qi�,e��C�h � .S � DiU3 h� ty�( hpiCtF�uL6� Vi0IE$(�-sl}re�in N�oc� $12���ch�>�%P v !5��� IE2�� "4*to'so-�5wis-�%v*��z �a�.9 14!8U !�, [10�hFA��t=� i�=6�P-�h! rA=1A~����$��(� H 2�coREST[1�$ m� *ATP�+,�pCHDp2.�� [26��!_"�����2D/C3%E�k14.��OtagonizA�qy*!D[2� P `s��p�0*�rF{.* nda�8e%�6b 5 s�/I7l<1I*���s ICP8�,N ICP0�P, [30)JEps,-Barr6?$ EBNA3C [3�C��Beyond E��+�y�Q���MDhu papillomaB� PV�U]. E7�-�[3�oG� we)��N&�@� i�of E2F-� K A�s�E�rBqC I*A�2v*Fbe cap�K#O �� k �m�a PA� �M��OA�24O �F, � if�=�� �!z�0��gNngM2�_-4�' aS (�onship#~;Q�.3%��!K:9,*a1w*�a globu6earch,/����%�val&�=&6G!+&9!of�Ha���ZU N2F�G!6�k!�"��cn� 1�Qot�JA9ŴDs��* ses;�0blocks apopto�8[3�rinflu !s bot �unfol4km e [3�3mTOR �ap3Ey�w|Pecess$\&zIn.[3T[4�ha5-� fail�1� n�-l*'>gEl&��U. Our st�8�<%L!�=�U�9�AqSs �,%�D%i�� �aloX]D!�p"�E wil�?��.P5w�2m�a�9qf�B6��Ab� �0<\ �e� S<co-optsI�=�kleG`e4art�~A:��N��Af,��}a�&0in Dulbecco's�>ed Eagle� um*�$n 10% fe�bov�8ser�W nd penici6-aptomyci�82�!#0% CO2�37�/.�+A�Ɉ�/ skin�$obl!( HF; p�(dG6!1�I[42�4 <(MRC-5 embry�ln(fibH) ( A!F an T�Cul�#�3�3AK�u�aW%��=���xceptAiQl��ofE�Z=y uE4d* -ext2\d �J�X  Luci�9e*�W%�ale!��!�h���-osa� a%� e , U-2 OB$� �match�aiLWE�-q�nge�krol])� ��uc�retBa� s�6s �$� � WpLXSN�%lh<ch4-ḁ^oe1$enix Ampho x�Q)FuGENEAL�[o2a?5 Roch[(.�R��$\�4 mpty.��/%�le�%# �T�(��=@Ew 3. K�,-�=L"M6A� N!�=W"m!G/]F�. �yF(kidney 293T s�B� � ng ��lD��U.6in�!�er&�<Al*#�e. W��%3, BADw�"�F-g�a�B)�us bact�4��Ea-�$eAD169��ai�'�'A� AD/C^V" BADin�F � 38Tap�o �w� a�e!�28- , 9@%����D�~$BADsubUL28 � �43&O=VY1YQ{ �?!1� Va��8�<^�S< Af�aEof.��!�6E �].V8 . ��p�' �!��" /!ic$6�V�Sby Lif�-��$a sorbitolD)h( 20% D-,�7mMW9(s-HCl [pH 7d'1MgCl2�&V�!tit�&�.cc�rAz)2+��y��qONfU 123H)E.#i�-Brief�Bual diJ7�eP�&[r�F!:�%9&&fixs^evk)�ethanol�−20���q15�7at 36! � 123-�cv�Y � �q���.�.yDU>��="D+rnj!��&�/:|*.�,�.#u-�6-*A�c�;Ő�+superna�@v�!0=�� ��Y 9E�c�^(o PFU ratio^-���,-�&�(( qJ�,Z���(.��'*T DAL,$ N�# ( TSB( C��ST��Techn4?es ?X�xr*f � ��\/biN�Z s et al .Y�. eQ�$3Ja�J �Ap��eE�A��A����r *�adru2OT :]�)�mt�>\&8<�inu�>bf 300 nM%1�)�5 or P-'a��#�on-!�i�V � ��> -HD1gfp �)=N[wn� � e�%ib�cuo�I"�( L ) fuy L%��!)$a&f�x*�.endQ�!�Gr �]�3>I<� �[.��e� A�%��a�6!Gp�!tof GFPB�aNUf?�� FACSVai4 ow cJ+�( BD R9ck`e.>�W�� b@�/� �Exp�High Fi�!t -"8� m��%/ (Q-�: 5′-ATAGAATTCAAGCTTGCCACCATGGCGCAGAC GGC-�7v6C+TCACG2A ACCT +)�- &�"pl�8kin m� $E . Seto (�.N.tYO,South Florid15��6ofEWIR� >(GFPU�o�Csmi0*$ > �CAG% CCGGGTGAG! !AG TG �5$TTAAGATCTT% TAC!OCGTCCA +�G�0g>d� :0E��I�G �v7?b �&7=heq �!1��* each)�i�duA�i�TE�MND�PricE��/P EcoRI�B 0 �� .Wv�<, Vl ,E� �)�R�|� g�$I��4�i�>>�U�A{E�ACTACA�E�TA>�A!�C%�A�'9<5��;V) �myc"].� �-eY�v>�myc- ��Tf cDNA9@��.��t U UN#A�9#GAACAAe�AATATCa�GA�CCe�GTa�N?GA�i�UCCCGT�G4A}[�4i��5�h�&} �� elseE�.2<�}pCGAO%HE� �,d-l&�% , NFκB.(.�a� ISRE6! 5t��H:e�"o∼70%!�v�@kT'/.ic��3� /��, harves7at�pi� froz�Jn l+d�D�4as� elle� .� xa.� l�_arr�<�V ryQic gr�*ngFDetch MM301 Mixer M@f, Inca*t 30 Hz�AIs�110A%l 3� ���aiF&�%powde�$=6 42 g� susp� ml optimu �D� x K-HEPES � �CS1 M potsc�ctm�24M� , )(% ( v/v ) TF-20 , B M Zn� Ca _5% ton-X10125� NaCl1/ K!&U cock^:*�6*^hom%�[ �� Eyama�!�� v�Y� *�)f*� 0�� aff�y��s nAincub w)+ 6 mg magn�,be/f%{!� EDTA�-,F,A^�PS1-D�G�)�3ph� is�a@<�12% Nu*?Novex�6 -Tri9,!�I6�8�8�>q� CoomAYe Blu[ Pierc�@�k� �"�9=G!� PSva����!�>'7"�6Fe5s�wnga�e��%Bpr�%� �StI5�%pR�%n��. Gel lakLOcYto 25�<di��,1��"Z8PtrypsL&�H��w��:� 2�} e p�)re R OROS�8R�#AF�:��MMo� a MALDI (aKrixex1d �$URsor�=i, i ) targ�2h�f. M:P6ic�:"":s �MSELMS/ �^$( single-s��"/ke�;6�6.fE�.�ME �Qq-TO�gQq�Maur�? ciex:'dA�2A� s&;4CQDECAXPPLUS ,u rmo Finni 1)}cZ�n�b&�7~8-��i� inco&�B a^�1�7ic�v�0�.7=N%�al�er�� Biot�y I*~?non9+nd-1��`b��( Aw!06/10/16� 4or Homo sapien!152010"�9�!O(( 3469532!!�$)��Xx"� tOwww . x�o . A�lgorithmBu5$limitz.&�1a-w�nRbE�=<al��9�a��p]�{���2�8:�]at�2F��X,�8�' . "2mh��P��8��6; �]ag���xb!�M2s(�.��Xa|��!�"� -��6�A��(6�42�9��"�s�n��/�btj"~O� .., P e L!�*G 1G RIPA&< ����,"A ;3MNP-40;�p25% N�voxych; 1&�;`M��sm�!k_ed��M!O30# G'R� ͉:�Tlys�(�!Wle�~[w�e\{8 /G Sephar@PS� Cruza[t �&z�y��add<or2�f�. �Vf>2}a|ingX3,�J"-�:�V> , boi/at 100q v~�p 1�vre$ on�SDS� ��B>%Q�Oe ferr)+'to{,ra0��� �6�W� rn�!t]�� Q:"�`(in 1× TBST)�1% BSA~&SeGjj'0HRP ( Jacksonm�Re�+a= !] ∶5oQS2�p�k �)vUAv�$% visu�j"�ECL�Md>�A��D"�6H bH9]e{ b3� t 48��,a�uu(M9�Es-&8�ea1:�SXu?!l*umE�1i�,�:�Ra0oC Phc gl1"\ � 125 Moz � R�:'m ��>�:�8 . 0�02� "^ n GTA 1% soVH�M� �*-lauroylS!s#Ie��" s [�&9- �&�� n8!� frag�6�|�l!D. A2o�+�#.3D &%�w E�ed A�10!�!r0�odecyl �C37 [SDS%8� X-!H+yD�,�M. 7�s[pH=~68�N)�JE|ueove�DAȡ ^:�"*Dkin G-�V,: zA�a!.om temU-"$CJl&qT!mM NaHCO�1eIaH-�TerV$by�!��5ɩ�h᝱t-��E� A\�U4;g/mVA2�5RI�!�re+ IH��QiaQuick6$colum� Q�E!�� >�R��a P�l�GGPCR�Eb� a piRP$�]�!�.M7(��G�G�T����GG�AAA���T &�q efza2�~ �se�� &�gener24g�� �Z curvd10-�) si"ei� �(�`(5n�� y�I�sl1KvalV/� :m6�)F�� r�7&G . (G \���90�� 100%.�R�1A��M�&� to en=W�!�1=-+�� �"�G�#aey6��B&� �2"nds�ru�d?fX� r�&w!t�A3; ( �"�( l�+A gl�eC slip+ "-E�E�R�`& �h!!�>! in 2J�P&-. SQ��C!��  injF��9�PW (��/�2%l� ���h� �Q-"�+�BU2%:)*lbu�YY q� p� .�6F �A�R�A]M�^:�Q �{ c-, ���r>� fur�\!;vo%<,��M �-�-!�].�"c&Lto &�" 46F�"F�.��PaFn@�AsQO LSM5�onfOH2tO Carl (�Qx$��-5�]�<ia~y� o! Velo�softwHackag� ImT\kA&� j B2!S:�s�RDAC1 IgG-<MillipI9A�cO�� �'a�f-�H� ,2,.�FLAG M2�S�S2$Myc fum�:Arw.� TSC2r-mR �AR�tubulinF$.p1�A*�2��"()1B1�& [51].�/%8DG[�$A��pUS24 s�)%F�FA:n2zreal-ti~@;�':�\( q�\)f ��}�(&�$tAM�A�"" " TRIz2taJH� ���� L�u X � ��tgDNA�&r"�,Amba�aU@ͺsyn?nUZ�J�i�S�&) III F6S !�$random hex�SEw�D�a�KfR�P+2.��5B��>monolaym�L�}0�}�I'"� :L':.402�  � :� ^1 mL m!K 2& R# )��0�d� ���(phenol-chlo;r�#a$T��2"��TH"�)n2�6NAVl wPM�u/� 2D5 TI*b�e�cA�orEl �:� ma8^mix.^� "� .?"�a4estiR�,wit�>Rb *)pu'u% 9E�2�,ASutG(K( set 1:6 Y"$� �#CCM!7 !i] AQ GT$� T ';R2RG�!G�!]$TTA$GG2$R�%GTA CTGT�!� RA_ndV>>��T�$CCA�$T�!C 75 �XA��%AAG�$R��$ G�C�TGATAB��P&T"G� ))�} fire�,*�!ge� �T�"o%G�%�&B� �G� !s�!w1C� A�� ofN�7900HT F\4eT�D?"X'R�.- �a�un� � ��M7:�9��o 6� iBF��1r#. e%Ry��y!i\ <3�,l� �7�� i�β-�6nq�GAPDHi��wivb ��2�?uJ�@�iS*1%"�4sh/�hairpi�1�-2B�*q+��h�4.�*ք-�4�S� L� 1� �� k�p2.�%KO� -Pur�K M^JonT$�,!�5 an p^��st�6%�x%A�AC2(A�A��&�saaTc)GTG�%�'m��4)YQaˁ(Ta��A@Qa�aO�Aa-e�T4'a2!3�_-;�R�+a scrambs� �a�TG�'T�NAAGy'� z��AAm�� a'* gifta rakt�>( M����/g�&Wis�n�Re:)�9�QU�co-# �%ing 2&�4A�>Q9!��&E�� < �}?54]�?v]6�D.F��� ��C7�I, �of.�#fat�8�h �of2C62D%I� !�:� ad� %��a�2/g'!7ej!/,i�" . }F�2 "�6" purh:��B2A��-e��iR�$��D�2? /Ѕss#s�'�T��Xa�+#fs" abov�6C*fŠUL32)96�XsNV�"12-+6 U�"ZUsaw�~� :(͹.U%�50 ɠpGL3-|"UM�%1'�,��0��pCGN 9v4+��)&W+]DL*��)[NF-κB.;>��| s!�.�i$zy��ű ��+>��*�;�Uv*�7q6N�Apo aR�: sFhA�4a Victor3 lumi{Q#4( Perkin-Elmer�A�K�measu2eq"� uu�r! :�A�Zu6FA]*� ��i2�.�0��a31IU%�2+by67"� ).x same ��>s>cus��ir0%?Q�6V&�KDP�+�,"#5%�6}I!INZ]e@t �p�?e�� �A��S �-�s�u"3B�sV��Z�8S!tK!��1A�W�Qc6 o�3 55 kDa>��;f*C has�5�Aw5��F�4e(),**K�N�F , [359[5CT57�͋*>2�3�-��v%}e��(O c�REE! ��ureaŢ�| ( ORF�a�*e82�.-�rF}Q:"�4nA�4u� pt�4O e�e /pE%��J&�?.� #>ch4' b��ib � or->$od�'�E_d&�B�L�$j :�r=�[C@*i��d;2yh��+r&�>>9s�p!V"�.���I� G418A�nd�&�5=�o�j� a�f:u6�c"Xby�5iy"��9�c�xi js >99%`5�F�1���=>0A+�"�&? left pan�tA 2 #��,!��Fu n wh�hN��QfA�(�0�"# :Y;%�ѓ.11u�(�(end�.� 7in�F�9��i&27�k8E>exclus!�]nPaMFi(!:riO�%;%:� Tq�,9�!��"a�b�0�vmUA�H�'�g1y��ab��6m��� 6;�:�A+FK|l�=}K . O|Y&U4�-DAC�"Qx=�|�N�a5c!o; %>6A @�To testpx��pitu�fI�-���alܡ�-th �t)Eo)Mf*1�� moni�7ir9e���O*.��:�!�� uishdke!bpp��F"%/uuB ,}uE:.]Q,:�� q�`'#7*�`(�;� c-7II %�] o�2M�J�T.�wh)�=|! �e0�pdU.�%u&x4s/u-��\2>UP=IJD���edeUB�4�01 pfuy !�&!R&N?a�`�}�Mtm�v�_JF�� ! x0kRreI��� �? vq���a�Eo6^I�A�"DžmD� .c� �0&Ĩ>�a�a suitE��w �DNEZ�G~O{�� �ldEf�B{a�u:% �%Gac�VE?I RA>>] &�J(2��At�pi .a!�a�!j2��3%�% ��Mon�0ep�!V�4on>�4coY,��x4to 3!-���1"n4)1�a̡$*�("+byB843-��0>�0GW�[�Kbands e�~n�g��&<4blu!�G�6}+mq)� xemploaP�_S \2�1X2d IT>�/��A &�4AV�s�cap� ��> �N� "�/u(thougT ir caQ)�ybs&ӛeyY; 'Q��orm@ is*�^Di��ly1���.�0a�*z2 artn�E�re8K �U�n i�S1 musto �����*s� �V�Pbi:["��G|GAFpUL97B��h"�R��0.�?5wa� L-� e 78� I�ki��!GVP.�^ =eg�2x��E�;Q 79m:,,�;��a spliir7* �Hu�U �,isUIk �!�i|`�x6u5o�)4�*%r� �Ooo��}�es 4� 2VFO"I:, ��%�;s��de��V"R�橏b l . It �O! �O��X��9�?(�v�p _ ^'R�Xw�X� �Q"�[�f"@l��Y�0�� lbim.�:�2A�6i)O�A*/ -���al,���39!�=�9"Z!�u>�|t�m�N�s��c�:3��gJ+�E(����uniqu彅�Q�� a���ceelf"9ve��mH�9"W#� 0�(�TB[U�^ [~�^S�".*�=Ӊ`CE��x� �Ӥ��&I�"7��&aOjxU.H%Eq DAC\*MTA|%G_-��^:�^.B=!��!�E�>�e_%�{Y��&��b&Ȳ! Qr)�ed SIN3�� �SDS6+����b��`��B!Z�0hW� )q�E�Q\R���lyE����Fi2f.�frel<&�M0d.N�d$� a+surprie�sia+!^ph1ch�2e�i�-��)ne�qa�e6a"(�i� �|E�"�w u3�y�}:���E�!�� 2�3�qՕ,E&t1�]�zG �!\psF0EXq,ɕA��VIsn�&�aW  �dieC�sB �inI{w2[�R!a 1I�(�ױ�J�CM0Z4\2)v��e# u!&�!ivO&:%A�����Ż��| .�E�Q���y�%6�����*ya�*�8�9e�mno� y exis�oI�53�I�!��`%oR29F*1� � � �F+�=&�z�*qt!]*I �*;n M>UjNiofF����2R�b�"�B" ssay5mti�+�!xo�u"d8�&b �2�". NM���Q� Q,�un5����>y5u�m�M �%<��� �qv 0 !� �El"�v�(i�v1��!�+���C��'�9i��q� ��:lWe}��rq�bwA�- tP��i� �?f�&� I F.2�g5�E~2@5���>�%�˧2<�6�A�\B��%Y� ���)ALW��s�s2�.@]��XI�,��2>T0 1�%J%"��u V�Ts-]OE>�K�U,bw �;���>f��A��.�,%?a ��A�� Kd A�,)q� I)�"�+4nE ��UU 9�mS"�kIH �Our�"�5[&-C]6 ֻ��ő�a��"� l� 1�)26We �pask��fN���1� ally)6��!Uor �%�.]> !E�*�1toT AA!�s�.of �C"e��u7�of ���reRs$es�]c:�MK:u. B|aR�uu�l�$���,[2An�cZ��e4��.�EUm%�1�2�:��iCpY%n�11�Ad[. "�C&" ,)KUG. I@/iJ=�9�appe�U�more robKX �9� �!�&4l�������L�c��aI }ˍ^�+[�HN5�om �aci�kof-�AH�Gy�n=z" �)-J(x�w�Q�M�5�;h�Q9�3]�tub�}sclero=�Vh, b w�� F�I}tpN d��-DKY& � �&)���edz v�vlK�o�qe���[e5 �Y�(*w2m�� rA�562F�Rv%=wo>�doŬaltrack&�} �i=�:Z� � �3S`r<-��YTo"/8in�Oifc0^aV�i&�d��Q�����2� "�7YQJi&ViB in��n!#if�ni���Q � 5�;/*�� $tat6�%  ex6�fQ �+c6��\�Aus���)pi5��upp(�&0!Notg� �Y�B� ( HE�nk,�(^wan>2.�sX&%+r�,}~!P!w!*� u�e�p� "N0��'$#!�)��%� l.�9e���,���P��on'�#r�0o�$(� g[?K�A�)�$( r = �70#M���qan+m %�&FD ,�Z NK4[���k"�_nKA�ed�e! Miil&&&I*U8!4c&P5bct>��Jwo�gs y%�s��0)[v oUs:�b�j2=��J�:P!��fB�7 ��!m�38TAPm��!�e&/g��E(!�N�=a� -F�N�al%�NW!�5$�neighbo@H�n�T:}/ Z22 middle$kM�r.m5�.�i)�! I�� 5�`�2�V�&t2�UMn3"�%: Rwag�A�est� A52aQ���":�Ao)qT>?�e��L :�j 둡� UN ^���* l�fq��a_heA�.���I)IFGt P�|arg��B-�2iQ%i�8A���Q n � J hez% �de�V�Tx!�.a[ �by a�coJ� ���f*�}� �. U�&�m38J �6�~2��U�!�2] a��6�0�&�'4A�%FL2–6�How� ictAc.%�v�d-2q�_4�% ���v& ���c2ک`V�ZA Fu �2�%!0ׇ�&�2C� @%+>�.�%�� %�F�*E@1�F!c~�� ���2AJY�i9a�� �  =w�?cA��B+IAF�m[ P aL? S�!�Amso +�varQO�cu%w�Ut�)!U*B!T�(��v|-ar �f�U�7������ ��Be �p��y#�"� )h)"�\a/�e�ZI:m*E�AS6)��2as 5%MP!��R)�Fo �*� 2M�at%7��9� ,IL��IvQb\2j. ����:U27Q?BE�*��,} B�"!�f�2DE� �:!*a*�]pfu�]e:BADwt%u# qk!Y���9�"�M!(3P;��"Q'su�k)!�� .[OR#�ofkch{s�������"�i���F�a2J���J�.�))X!{%-&F(�_*�r%�-:�e�B��F��c�E &z)Yc>�$!qb%�i�B�. N"�Ql-f�a�n�7�^� v�;�.r2IF�e6�|Aq�Pwe�unv*�~),f�t leng�-k)�*!�s^x!hJ��K& ��t��%�N�<~Wgx�kl����fq8ah�gglut��.� aH29�A. U,���"�, z bI�->�� �)��}B��ile��)�!m&pr=�F�f" 42�6�$N=2m��6��bIf��uUАo.�j emEn ������c"���!��:� n�*?��`ydo��6��1�"���,t wT�A' Y2�+$nd Xi:!�2���;9%qa"E �2["x2� �fM7�9=_n�0�*#2�7�=�k2� �E��}͟a\73&r���3�f7B/\2F coury�fI﹂&��A�e�3oXsEM&�U��l S:-!�� .�r&�/J! ��b�begQ^ng!��f"� ��>� � 1N%��� B� Fd!���ll%\s � 1�-�q�ڧ*�Ũ�8j�I�&cu1�s>!�*�."^he]=�a�L.�� �51Ra�B�Bry�#y1�)���!b"��,�um'nrefy�9�I�_%�It�oIp)"2Qp2�>S��%�-��a)�>"��%�a[z�aDAC"�cyt2٘�stΒ��[6�uCw+�X��e>�o�9�,a�1�� I��� �1A 84= �;�=�.a($or�s%K*9w�^)�5.XA�BK # 5b Ra�>% aw��nquf&�`�CC� i �|� um���C0 d�-p@� �a!ti�f�v�Bqu���"�u.g�V$ad t v/��is*:%� ["2*�uPTCM13�t�6] B�lor <)�M�5�RRNA�um�sUcT!P1E��-pY� 9UZ+K��hoB���=�!�94&�cs�[A0.)� ��Os��r.�CE�� �2k  �Ka�Q�29>x, i2��Q�_O�!cA0�>3!!�,uyi�-:�2) ��`emK�QQo%6T"�9UW"1���1at5=��r�3RF�1�AKŶ .m�1B4�w=q�.�'s&�!a�.I��"� �%� eP0X�CMVanh:�!�O�JZf+M@Ia���  }-�q ���a��-:&�7�/Ac):�1AQ�1qlP8 4ach*6Duj#��byZ� #e�%1"�[6�j��Jj�Q��C�or �>4gE� �n&�J�L�B�s1ZF^N)�aL:+NpE�JĊ2�D�-�J�� B C!��C+ c�"��&�gBQs��7��y��h eady�Fm�4�!C9�a�by�c� RƳ.9W)Ek�J!<erK�_+H�AW�KY�%~���(n a�as��q�� �:��"�N!�mo�4:I�2h85%i)�F�PA�g�!n�@�D���q7�o ���m�E�&��.�%ȵ_.n �� N%_, ��) ˡ��BI TaQ=��er�P V� 25&�^)E*�fJH{ 96 h\& A7�� �1�2� *e��6�%L��draG<�%�m�OEYV�{JaQW�iz��A�&’V�*��{ AC5qo� d4�pl�B� #�NE":, 80.���a���( k�,�y 7 ex+j �!US@� a >9>aY RN�S B�UL4y� Xu2���.1�:�1�M &87�>�xh�bs���N mpan' �; �.< %��X2atE�*�&7D &0�*�E�!�_I�>@ xtenF s #!a��al6�/e��5��&��p!o�s��"1DE�2�of[ by�6 ng "� -�MZeK�-}"�-�I+m�k ��e!� a��r� IATb�?i ".out?:-� � * |�?�e(I��s͘Y2"�m8D"bK>��"�s�)�"& �WQR�6gBp6{+f R &� �.�%� �!�v�)7=?M. �u !�aFB.o �I`� �l�ff!�38�EeU%2/"��Tntm�U2OS-38��3�2M.2��-B�.��m��]6�[FX .� � 9]N�!�&>!��# �2�Jp��*1&�&�h2a>�E+5=N�4EA!<�!uXM8ed) \ag��6�e�5�%"�+Ű��AP s la#g ��g"h0EF ]�U>��0bZ9��C1 �D�<�V���B�on�F�!���N�EI�j\BTH� �%0A� ��ed�R1�.�!��yU* x��of; "��`� � �U��M%I�$1.#:L2�i�63F�\F�o�z N[.B�W-�A�ng4entribuY�?1llI���E�B [69�[70�-t eVu32�:�"r�w riaL�pse�����"�it"� � �"D�""�E@A�0� \8ngJ�N!�B5 broa&�a�sk�!)�q%�&� ��#�op*�/E�E*�I�&a�UK!�[9 �of 7 ,U� ha`daq�4 Y�7E\܈)�-��_*� �Y��Y86&� 8.";�&�2&>� �!u)�)�"A"=Tu!W�����ine�:+� "�m�?�"��� � � �1AaǍu�B8� %���� ��el�!p. F� � �aA�% es]�t���%sig�G|e �P�/�H.� �SA2{ 2���*�V9} u���"�ultia �;�  �s5asU^M"U H��%_��&s &6Z>g$f(s����&� J!y\"�L�#.��>i�z �li�����n?!� &c mI���* 5 )�4epiS�!�5-.; Yj/J���%/��x�;d ;�t�*e`/AZ.*U Z|����m�N�A̍�����/e�"�iU��q��IDI�%S#B�. ��t�y�!on/6H\^:\V�KI�H&���[2&��.2fK���<&��a6U�y� div� �1���e-^a�f[�,*/  A�2�"�I��1�1C/T�(�K�I�"in"�;�5O1�J�%��a"P�F>Iy �(�(��J���$e"zKIB�22�B#>�BcFl( ,f�BYl�Y�&�(toD�S%�A:cK"�!M^�Tf5�a ��1�2O��LA"1 ly� / ��>,� V���J �a��s�.U ��!~6 �0 viewZ�]."*AE�Vy@�-�I��@:,�&]H�F(,analysis . I�Fn addition to these HCMV proteins , we detected peptides corresponding J�ransfeE;!�s . Our%A�$to observek may be in �due"A isola�coni=ds ( e . g . lysis buffer )!d$poor ioniz 7of 6?pqVdu%MS ana I,!(houiE�)�ed�inM�5Pes that were focused a�he^� ( dataeoshown m�ernativeY��might9qat%st!�of in!k!�butX at 24 hpi�Shena�performA�he�assayI��=� ��pUL29/28E0pUL38 are neea�$for effici�fE�replic)�[37AX[394e�A curr20results demonmUw�$5targe �NuRD co�!;� , ra��$than antagAe + ( FiA1 6 ) i��@\modiN its �� vityA�sup�� B�.a�M�0d an ∼10-fo�.duc%�in boa a�RNA%BD ccums!�inm'exi�0ng shRNAs diriH4against two diA�!��,%�� C1" less%E��arA�o wild-�� �M1,The more sevamefA�al)�%\.T5�A�a)a�Mmka� �$cy suggestm�%Olika�plays a ����rol�/anɱ�%��!�!� MIEP!�Er}�� re��e�$small drop0pmt-indu!oI�Qr U�(upon disrupELof ��MM��is viewU8CEa���B�Gof�%�,��which����b)> is n��traA�' �ceEndrug-�$d , globalŃ inhibe ��, � enhaL>�>E$[20]–[24��overcom� Daxx�rei�onA�5�[25�$rescues an Bc�x6Nsimilar rea�fiH�he��sence!�TSAU 6B�sI�I��i mechanism�1 �is still plac���ab���^. 3.?\UqM� onlyPG!z�H��4 ) ;% ��� ��, caniM� Seh in a!�� r�&W8��!1i��4subunit-depend��0ad abil�Sofz�m!O�x.z = 7 al��նargAY�-it!a��(significant��iniA6N�B-. Fur�Q,�&� cly9@���hntrol by ISRE� $NF-κB ele� s9#!M,��I~A+terpretI�5�1?s)��toe�� 0promoter-spec! outi�$. How doesFS%�%ڑ�to fav���a�E4?ť��0genome underg_chromati model�a�a[ges!�.� -�A course���thr� unknC u� s [8��[9� �52� contG�7� �nucleos�r�cti [12��Q icipat ��}'�gL��  criə[72�� scusUabove�ý�of ������.>� isr��� inE.% �Mis�ima�a'%%�. PerhapJ�@: -.�!�6~fB^ b��fluenc�=yposŸ1�� h An�. I�is regar�we&�a�&��TA2EΥI%�uRc!GEӕ�) Th{ ice��!9a�fof.�]Iin)\>`�> p150�>D}y/Xassembly factor 1 ( CAF�$is localiz: %�.ce!sqMI9yEi*�it&�� o)%�e) E<��[73A��consi. %dree���, p60gp48 (� � { func!܅]�[74m}!("�"� 6S��es [75�A�*Ya#�pd �E �actT l =%��$ar environ��-�= } de��e�ju�ٻnd�s�."��s�w.�ist�RE�Mnat sia�� A;E��ݻp��� ot� tr�toMj>\N�q#3 )"��B~�"W a�of� al9a)A@&snail [7�wnt4 [7W� brca1 [78!�IA�es�EJ6�SH5E! (rapidly dow��� edq5%O}47�Y Beyo.�,I alsoY�*L �jY 6$i�6�p53�$HIF-1α [1�[1�Casav��,et al . [80]� %atE��ecessary��j�@i����:!�.O[8�P& ,��H6��%IM�!'��sM�nE��kTSCyT�=�36!�T�associ��is cl,diAct from�M.)eMA�2�, becauU� !8ot<ed ; TSC2U�2� .4 0a lower molece�we�so�A�) bind�n! ũe�:& t����Aam&b, c%��attribu�to�ک usagf ATG\codons -jI*�D�m�lB)7w%\ �evi�8 by 6��@5 )3� �ku&" �_�l�38-.i>8af!N�omina�� d cytoplasm�!E��$cnA"�2�F:�rem[ unE�] �2$ur studiesc!��)�-H%4to2�A���ndai� B� a��C"� ���a�X. B�!=G Z��regE>� huma�pilloma�$( HPV ) E6FE7��[33� 8� e�%Srvm��gamong]�a�� ` their �ce-W�(a��J�.k�-!ncal patho��Dl.�Respiratory Syncytial V��S�i��major �)hneumonia � infa�. H2 we eluc[��e� ibod.pertoi@ llow!� prim��s���traced��evoluE4/ adolesc- adulthood_h�-frag� phage dis� librarA� ( GFPDL )��ng lin�Zcon�c%� al epitop A4�fu���a� )<attach �oa�!+B!�unbia$ ]Jfi8] %a sera!.ora1�f5E�9= . F- ��e�2mpdJest.��anti-F�r5�s� t-6d��G>jrevea 10"in�a�number�bound)�3�� G-re{ e�s spannMIN-� C-terminuu�G ectodo��a1lagw��|�[�le|l!��d B ( CC Pan�F{G%&genic� %�syn�� evaluc%��0young childreA <2 y�,Y�$14–18 !�E�a�30–45 melio�a�dis�A�� ���!,sn$an 9 monthba� [3] [4 , ��, d� M#ve]Q�9��^&f %�9dividuall�N suscG 7"to%�uppere,A �e��life-Ň�6 , 7� � � es�be cl!����wo%N�gE"� ��( &�w��ge��"[ � !�� $most exten-�EUe.�glyco�G ( 47%�to� esser deg� @��7F ( 96m��{ ontinuous6)sub� A%�A/  vers!�" il��EGG' [9 , �". Repeaa�%`>�!�ly)* heterolog�� ia�ne�aee�%[hom/]3�"E��^d�[11�i�ultiple" ovef!L deca�%�exploa�mN4 ��bef�^�i/ a� (ug,I��z�!,T older popg �<kmethods� �%ed�*lab�o�w�����!��)�ed��� et )omo� MAbs"!ɣ��;.Rshort�!M�sxELISA�Ho�few� cl� s�z h' c�с�b( or�$^c!"��k� re�"c^A0 �%P� out�-xge"� of6M�)ir��Q|[13% 5] [16–}*�'R*A Sa� r�0� &�recogn� �E�50�l!�a��y� vailk(L*�problem��Nn�$���2� bet�in[thUsta?Z� humoQ ��V!q"� RNin>d pro�5,�� E��ktld � sign��%E])u�E�!\�i) s �*�%%w*� �-phage-n�> A;!8ent{!M��g(ic aviaOfzam�pAI ) H5N1-A/Vietnam/1203/2004!zmapf�����conva�t* Sm% ��,!k iXt�B�)we�e�,d�!X�awsurfacj� �Eto&�.��let*��&AA0serum samples. �� pr�( <"�)� �Q���N ( 15a�8��~P!� F�i truy) sepa! <� �� �Vs�K��in ses rangA(izea�w�+�4250 amino acid�"�ud"V�!�l1j+� ar�^H�] ����e)<(~e-�J��i��  ��large�+r�#a� ntt �2=!IB�!�e�&�SMyPlon Reson�$ (�) b�ki� �� p"pIo�&�a.�B; 114 yr; 2#to |  E�2f�"��Bese� roach� &H*^1y) �6~,�� cqui�&�~!QacrossV�[,^-��se�reh� ��: vgerpriz �> �.Z t� F��N���="Z�i��RA�qRz�qch�| exci.� prN A�of F0=&!�2�anZ ZtoF�in�ans . T� alyzMca\�B;aO :�,m�0 aiż���G�F�W# ��e+5a 750 bX)length�/��#�,>106 unique �H clo\�at.P1�_aK8gv"le��. S�\���I  G� &��)i�-random��25�� a+�Yi��,nd��5��re64 . Tog%Rpot(alJ!c)��,!�y��f�uiMC w|? ��n1Wz�5-G � <^pA�{�!;)E)AL$9�l�.R��l/%gLR�ygts-F {�g�ax�ina.1 . D25h!&: � ( monoAW&QyX  s�g ϕ��*�� ! �[28$Palivizuma�!) FDA-licen!Vpro�.BQv!�on L�� a�igh-risk�.d, ��=z�%�lbC1�wit�!R��s�II��"B6�po�o[/='!�>��" F [2/ Pan�@mv�2�or%�MtM���w2ql� t en9 �#�te�(2W� � ϕ (c)�j!�.1�� ensus� F�E�(/>c��ob�=�=(G�U�A very",xO�A�an�s.\by X-ray crystallography�B� Mai�of!U� -sel�K�fic�b�����<5Z��!i� 6�2095iM�+!�ee�c4$=�b�R!8-� �B[y 131-2G%!Q anU�cl�-H� G"�%�rvFb[2c# Affi�)'a�����E�MAb��m`Y��lyA BJ5R4%bf L31�!A�minim4m� 1�F�6Ci�se�sa�v��� >i#GE�9E�AB2%1 foot� � vio�6=#by� V�or#� sc�� ā�%*���4BGs��Hal)A�d*�,proof-of-con����!~IO�A�FIG- �s�N�A-� Z����i���m���b *�fiA��n!oly�$/.� a �s��� in@!S- AT�r� P ;�a �7!�3i�of�$8��diA�s Ep each�)�Xpo��b� �E!��"aF>[�To��y9E�� f"�~R i!7&a wa=A�*� eZu�l� %min�a"�*� �h6�um��H"�6hemB*!�J!3�a'l!y"���Z"Z��8ac!�_�L����:�f��G[30]A�d� A-'S1�=�re-jAE��=�!/�,�� a� lack�non�A�b. P*�&G q��q!&�!� s� lm��Oate�! o F1 II$ e:�!F1%� �& 1.6�!F)#�S1B5,S5; � �B8!o!5�"%�7e%� GF@%p?A�)�A�upstream�!6+ 2j9CC"( S1C�WH;xtj�Y rol)j)a��d�i�� {�fF-!@Q��[issect!�B!x�)&u6� p�&[$ZJ����x!�f�!% pa�-�1c�5��[!!t *��B�/�6�(O^.�E,� ed%OJ�"%$��2,��statu�$67�(ferKC%�opreci�!e8system ( LIPS-N�1�:"�"-�A?>��+o�  ( @[�3v� 9B>8" renilla l1-V8RRLU ) \*!Xby�7�re�� 6n t�( PRNT�2 �7d [31]��D���n�D�o�=pr� ���2O� �/f5D�qIg�ڙEght B��5zJ 1� 37�qtot&;!p ( S2�N2 v/at15/QPi6ER"���6�. A"��Z����:nt�p� st upa u,��*� 9�13 5 , 3 Poo.)erA6���neg��f�aX-N ��A-�U� "�(.�aOg] seroconve�Eby>�} y��)^! 2ELSun�御uef'no2*i*�(!�&�^�P4$*A���y?p=8c�? with!w*p %Y �jSi�ur1 �u�'q�A/G!�c[G��-G !�-uw� ba�6m��d ^9�-ibua�� :* i"y��mx��r�#6��"}1"��.o!�R�e?yW-e�u����) :�s&�2a�g�lyO t�%at ≤.bu=ET@ ��v�W IgNk� "����E�!1=��a%8�!�c 1�9.} . High fr�_')�E"3 ��c.s Ѯ-iNB�, &� e�"�s e E2��B�R well�ZM<6I�A8:k �"� 40%550 ) 2E���A�bD.fiT by 7/ #reg�"(�I[�&ed F-1�F-7��nd 11�Bk?:qN<. @6 .�g��*;�a8� )QJ7% �15=z:�, �����ſ%��%�wIb�eY�E�:(Eol .6�[A�i!��2�=perP a�4��JDqM�6(����"H:w�'@ %�2��YM�a� �2�inA�a�� on�%i��!e+locn %l%#hs��6���&.!�e�U0IFFZ3 ��itC j ke*Y>�э�m�2F��M4�&J�#vy�!ur�-�y!�b� r�+� 4 SVz#eP. TwoM�6H( F2 , F06"�=0! �y&E�}CE�x$��<7de�?� w(i.3� I� blue��|.pe%(-�F� 6�2�!Q"�!E��6 2%>3%@E�acG,i�F(F�"'��.�5� �� 4��r:membran��Y�� X=%N5+��@n� 0� read�*:U crow�ߡ�.�9�1�� MAM�6  feRJb.��O&a E���� o��,Aq���kO6n�"�46� F-�K�6sa(wB���+�0A+9 "�"A�P 2� , &�G�6��6a R�6�XVik] E~6-ev��%oA1YN!I�4dd 4&�2a�!&[��&8sek�*@70,-G }H�"y!y�\��al"� flankP CCD motif���g ��/%��h��&,�,aMHG< G-0=!�m�n�9�y IR�~ :� ]�n"� �� k�y�h2� 4B ��^�"�`!er-��2�%��#ci-�\$ ��I�6(�-�H"�.a)��!o�F� �pLenric�.VOA�prJ !�)#!�.� G-�Ka[a"�"� al�8BZ<���D�������akeoWgeys��ZrR��y[%�i��O1/�vboa,Lt�$-.yQ��te2in"�Ei0`:�) �Xn a � � !�res�4R"k/m�*r#BE� �� P* � �&�!" m��*O"� A�!�> .�]�by"= �� A�9 A3�chemia�y2�+2�co*��=1. ��-as�-r"�+"cb!�k E;1-#y �+�EWY!�&,#�d>���z �V�.u��= tow�IdimericC� T3�8voi�y $�)mspa� den'5�:| � !� chip�Boptim�%!M�gSno�/�0&EJ"� 5�Ce i�Z� vx(di7!Z��":[ �n 2`2Z1= 3���?tnX/4B-1A[-UE�4 ["-e� Y ,Es&JI�5EnS2*AlEU � :�9 ( <2�=(��%�%a2�Ka͆!Ey* F-2E ( a61�2�J%�m�L�227�isA�qu�(f�U �CZ$F01� (A�n RU = 1%N�d 58%a&E�.�B�5� �42�042me\2�}7"c�llEo��FJ�+a�2#0%-35%))lowW� ��5�B�Auq�% a)/)� also�>#e�$7l["ytg;%�E"692��X�/(in*[ )ɘun %�6hi�?no:�&x�S3 �3& / ���#� �1T!� R9K&�R� A^��R e( F 1]�aUF]}�wL� e���*K!6��. Ay�Iex�U� xpan��B>�to' F de>d��e��3u�� �q�!�}�B�2N0A�iNIa!v1'@2�77��EP� {u'� .\4��!qto.SFn�^� ��&�X� :�IV6p�.:67y%�2)!]16�17; 24��� MV= �>�,# 2+�AJ%J6�� ?,ϕ&�MAT*A�ig �9. BM n^>y�:Fk0%-25�a9"�Y;`5B%�6��h%% �urwE� F�!��Q�&d2>�)͑� A:200��:��RA�%/E�.�|a��K�l5?z m��E6� !����gaj��%��%%uj 3*!yyms; F-4� 3�4368,/o�47�*49- .83�S2gq]aI6]�M�� *�& %ZIIA� �Dq6�t� 1�� B@�E� P�.aa�2�}Zns�w!�92%%33E!��~2��eiax&F�!~ �m��%�4n<8�F�6II� *�0h8)ce�K ��&�e1E��VJ��%J�� a�6&/,��%i�yae�mvse�!*BB��f��]O5ge(�Kc��<�*6 g s^O&E ,1�8r6�8# � 6��maximum5of�=&"a�>5D%15�1�to G-B!���4h !���;)-p vFs)L5x�>.� A�99d9�wa'&E5�$# >Ż���]xJa m�6��.�� e C*�a�69a90a92�3#��)b2hI�Ks�� �n&A8c� >�*N\"w �Em�)����&�!=�G �6�e O"Qun ( S3 �3)2���i)"�!h �!vu�aa� V$"�e&�(E!�iO��ARF��!�1��s�� �#39!�nf =A�K&edP��$�� G-�>I 487��.!5 M Eq: 6uwh�*��)'%��*�s86� �;L$��F : �a .��"V"�_'"}!^�C�"N�.�15!b6de�J�w]] p = �: 0009�-&]5�� )9 -[�2[T>H�� !*OOR� EY#�"f!>�,'�|�:Wa�/E�N�%�9W��� se�P�]�5��>`?.o�+�U��.��l�ɽ�vor"�w2` R sL&kjFJ�\�G,�%e�"� !XQ�n*��-et0ag�$[F�*�>��prope�.hed��IG*8��� & ( DS-CavA�[2!LLT!�f� 0��e�`v mammal�CQ[1�G� #ah1m>b:8(�Is$ledi?�h$r<"+u�c*6i*&+ 1\prR�1A)i�<�=�A!)�sy>a!�E/!>r@-{Ap-G�DM�9.2�S4� ,J7� equmKto�gl�~:�5i�lte �"�M.�� nel �(2-���&��$ϕ*B&��.h �a�" OA�A�"?6 � ( S4^� l�72�:.> �1�!.x]��aU��"����p�cB%�q�A��Ht�*},I9�f�)?mbi�Xn&�#5a,6�,�pur�M=2!Q�etramersQ�t�re�%��Kg* 1�%d��ly}��s=Sj!��5O�/,�h� ��$7"� ~a&< %�&� w7� ��F�"�-?vi�$-a�\��-�)��b�Ii�#� �i�� � [35]�%r����! Q n������s2� q"9%m3.99x`U-b�E�E6 ɄcFA6�Xi. &T=&�2~y�m�2�1KA�6& q than:}��(��:n FLv9)�a4![��-*(.B 1%�"^ &*ZQ2"F 19-�& F6��a�rw �25�:��8+ 1�( Max�$) averaged�'0o� , �4& � �r .%ul -�*6wM3�.a.���M� �ml9�SN�M�%. �( "�XU�w� `:� "s���-4&�<>R� ["� "* �2� j: )95A–4We� &Z1�n�t|G�s��qi�Wlye$O-l�V2�r filament�Q� � &�D�)1CN a B�!cM"�K-&S s>K�'b�.seWby�!G-U�?���T�"&� 5�BPB>a)�A>% .� non-2Ga�#Db�) [1�M�fu� :L��6R&\ 5 QaI-6\af6 ,.qJ�� J�2�c6Xm.�(":�2 EsX/t( Bkm�� >�p��&"&y�f�Y!�y�E^� K1 p-v IAD:?�?qCm6 B4$&� // ig 5m*B� !l*��n�?I!�}b��� �*,Ua<2lU���R0in BALB/c mic�(62\�-��" elichYby/B�� 1 n.� G� .o#�"ŚlN��F0� ,�u��Ko�u'.-4a4 ar,Eof �i� , Em.� natu�R!1"* �2&�� �:y. �&�p2�M��q�paiS4E���d�B�\��9g�!�!*!2��&�AI�a& . (:\XEf�v89^<{TQ�|u�ECE2@ .�Vu�< 6�H*hZ�u��o �"who�0� & s�zA� ��ZQ�dys�A�&s9"�5 �/ eq�+dnyly���%u�-�a/EV*�8%�:�8b;& safe�9ha� tegyaF delaqY%�t!�newborGd �:(mp�% 1�2�cu�93, *�5!)F`J��Q8 �o�K&� �^? 2���)�V_Y&2_o�3y8]�z , 40�.+itz�J!\IA�i E^�Vp.�-=�ia5tK�th�emT_�J�:M�|r�Y�=�M fr� ��Ay 6�X��1Uo�d�.�0�b!�:�Y(�l�G&�Y!�Q��>E�en�pD:�V-�V�?-�*� &�e to unravef���iP��]U24ALE�q�w_ rIto� N!%��#s:�UCt�!�13a� "A�!P@�Q%(�om.�Rp�S�5��Gt�EofɲZ�Gal1<� ;�T� �.z/L�GQc gN�-!d.�V.( �J}2`6PT�q�EP.��7��ah�2BjLE2� ��J���b-�� �r6XPMfX �qex$)�z� �1yE�B� 20;)$�%��g.81�:&I6rH,6�*�>�K!�>FE�B�A8se�/�+edR�yѴ!�ha�ni�0=���#8Y*newoxEV"m W6�aF?Me��7)�p1>6�vY F9��$)�tX[ "n'�1E>� *�h&r'"@C*�w]��6�Y3ANf.y<+0A�!�# *f��# }Uk%�f"&�o2�7�j,S?$(Onقpaun_V�;�%!� �*�# of F� �%Wa�� D9i"n e2�%�t&}">*y2�)� &#e!���r� ��ARenJO4.�!�)� �A�ng�;,"�%��. ���.bVC4C� �s��'Y��g3�X� pronoun��E%/< 2fcW:e&�PCC}1j���!I&� �:3)Q3z,?i�a��>)?6*2�(WZ2e�We hyp�'W�+�,"T ��5�<�S%3" �lF6:�C- � nD�Cr>9)�!~M��.� a# firs2E (.� IKJN�� L# 30�=.r-�&�0&�$&�V he� X<�)S8�'naïvT = � ldv0e&lZ�oUš@2�;�5M�eHw6�$(se�"��RAQE��Vi2n6�B.'��#�ite'q�#m� iw.2j,ea� q�{ ��h V��$�:*�,�!�] nd �&2�� o>~t�M�GesQ����� �m�*�-!F7*,I�6n��hUjvaprAq1=�t���;a��� (��)( F) �� -1]"� ��.k6-� broa� � A�=a!P%J.��A_�#B9A}"D �� ��)��+"ch� A�yiJ5�-��81f!� �%��*j"� �U(beit Burton�xama��A w&2y�p�J �zG�i�4v^^in�./|@ ��.!�m�*�}<-1"�.-=��oЅ o)�r�x1�a�C �i�Km �wand/or d�P�h�c ell":~O&�{a�HtKv� ��A��b�7���6�M!U�� �Ve#}gh mutmam !�"A+��*hj �ins [4\JI� .��t1gu��biomark�s��Z�Ba_ib�]a� T��(erodiagnost\fs�By� �*�#K,�+�#�iO"�Bm;�:2�3���5�L�pr"yF:e y-��UE�&�{� . OnU~=`mi)���D*\ss!�7��'Aq� <�v����4eo� 6#2_%d �5?D#G� h�Dr��BUp5f opica���! a�ny �t-$p��o� mod!]E�A�d raq�tr�U���moD!*Տ:(6[� a��^ �"e{! of�u"%oni�"@DM & q2B�$� lvXAM$ �\�  l&V"S*S���2�E6��7� �Sp$.w!�Olb ńGP�VB�m �A�N ari9�*�!�reJ:2X>+ �" eXB� s"(SWO���r]���Y �a �siҐ.Des.N F� &��p� mmers�`� R�lGa�QMed�) mad(ko�bh of1&ubjec�6���,2A#.L ��S�B.0�U!�2h�i�,�HMb�)a�5��-�A�*2����{tro [4��W� e^= ^� "��%��� FI��e"t3 >/1�a f/� ��I2�wN<a�e�&�8B�*Wk".��4B!�Ro) eBqы"56�>�!��E�D*z(��U�a�?�Hm  a�af2gR�SgraduE���&"!��2�"f0a�Qaal�anU%]N&� ZorP}wba-s�eiK%��.�< "�-F^ p,a��A�V%in�1�eU�2f6��&�s  ,&�Nq=Cf21�dAA�"c//�l*h^ed/�*X/�����.�7�MaMcavea�&��isLj��EK�٭����i[P�al���&/> b2EG-��DD A�Y%/e�� �b�R?A�y" 2~(�"� B�G"� ��"� Lшa�lCwz�s1-er�A� �p+� h!�!�� )�,"s 4��:*w��' ?��lA�"n4Pto �eo�)5;e�6����!oA -��bMS6�p!63&*�!n�]%e��6%e/(���7.-)~R���&]��&~ "/ 2j]�&� ���.�intact9,6 %�k.:�!(��4|NJp%2g9!A%"h..:I�&g$� ) �+*�9:G%�A.�9e�e6G$GYn :J'a�w^=M�[1�e6&�&�8 % W�Sј1���w��(>*6�AA%�er�@�<�I�K/�rm�a*�6. L�� �"�F��G�C �-* �x���,l��D�{��\�G�=a�s}WTCCD�,a��2,G:l� �. I��Fle�2�# �?y���qerm�Jte�q &Sv�$i*�� !�^.%�8dn%�� 5=p7WI�( LLP�&amemh�pa�MB[4P;4܉[4� 4�j[48][16]e�Falsey.*d1y~Hzy5�!{AqAJ.M Z]$��.�3� �m�NM�^sF��5p}I H�U.,y'l;X�݀�+��}�,m76� 6�4Nc g(�Ea&�3�2)<��-G)�or%� �7pt-F!/!� S)r!�����|a6*Nd"cSA#sh`b���Jf�ideD-�8�}v.�~��!")#�{���[30�"�"50] E>oz*W1d��n)�|a�Q�av}qi�a>� f 5%:7�@D(�/�9!4vݢ" �� ';�N�&�&AIh � �2N*  R�2F�� >��k �y*synonym8,��� �ru�*9�vb�=3 �X( !�l @a%`��u/��4i�R�� *@g�ˁ{=D! , 5�~5�2]������� "P�riJ��(! prog��>X�+x5E �: R.���*�P�L, �*��h�� �~�`E�&B5(�8-��� y�&�#" 6���>� W� )ˡ��P,2� )�&go�4>^I�� � se�@ՎT�\�*�k�the�f -2p q$pϞ~P�a8��yeN&ՕonN-�mpb appaEV��X-}m��i��uM�l"a�tt>�'&"�O�+M�ae��v2�v��x d����)�%�By"#��!sus� � %�?'?)��UN �q"�. Le: tten6@:���(.S`"S$\- bal\z��6��.[4� O��h�u,�*�o��z^/� icle�hF��t&@~B[5K$55]!��..&*of%����A�j��p*Qin fuJ[%`�. )�Qa-N�1 avv#� A�.�=E�B8 ��"�0'B.2)�AW9�*e�Y [ *+/(�A�?!�26/ �4chUnga{��2� 50��. >2 0 -�~M� �R�Lv��z>�&> &*=�I. N]s(K' )2�#jT!"-F�#purch�7%�!NIH- rmac*n&M;A2=a gif�P�n Kw� ( VRCܖIH"�G�s( &fJ��@'6�Millip��. H�p� � Ų�vG,�"�"��C�P� ^7N�OA*��a&G +(2�:,AX6/"`�(&"-+P ga�*��Aln�gi�W0�@n�S�H��a"; �p�l���� �=de-. C��664!q62!�U�Tr9o�0d Drug AdminiAk�� ’s',earch Involv�)�S Committe� DA-RIHS� �� exem�A�0ocol #12-079B�� OS-1} lys ��iRuc-tagg��-NC�(#j��uc�8(V �*�'A��A=  � LIPS1&��A�.��_[�i_�"�E��LU!�8�jeUb��X'�% as 5Qkndard���sӟ!�E�Q9�w�! "3mA�g�1t �!�gen�nti�� -� t�i*�22%��par�#l�d!T^�=Uto� ��*S5Ak2@gi �ik*�~��Ǯ. Brief�6s[A4g� diߔ�hea�f|�I%mix�� ( <� o yield 2_$50� ques/5"O,A�10% gu�{ pig� l5A ockl�0I�0o�WHs; Philadelphia , P�;)incub�a� 1 hr�g37°C-�S - �mix���#inoވɤduI2e od"HEp-2iW2lay� 50%Y0poi@��� %�E)3Amqu"oS��man-Kär���n�8. Female New Zec d$p �z�u>6t( 28 d~�a@ aFa�&=nm�neu��9:u��m.���A2�D (�Kμg/dA) adjuvaCdvEmulsM�!t��rd�� yl�!�� &�a��9Dr�q��+�0EV .�*�i*ne�)%>by z �,h<$A[*�. cL�c����t�6� a�� s�;!7ubt^��i&�rb9z5+a4 . fSK-9-3�a gIIIp �2(@ phagn#c��w�;�des���Mb"b��s S�-�!QVj&�<���&�r�. P�B)Qn� �!AD  G bdi5en DN���5#I5�A[.T&!�)j�E�*4} �G"�!� 1� [*�""��� iA#6po��<sQ>��15AS>��{k:�O+*<3 o �a ��L|�"tui�AA\ala6?y, |one8� � �6E�,�w�o � �a�r� m�"��!�/UV-kioaM13K07 @-coe�PetriA}{�BA)� 3a.EoAJpre� "|!�Q,kG �c��0"�%�"0"Lq� ��ݭ�<4k� -N�s <��e& , �)�=�B�"�J�h� \�*rr�ag.� ≥ �6�tF�Su"a| �N�2�arrx�-soHF  P":in�p)��V �.�of 768I���v(d��^%�wAs�z ��Am7���n&�Jp.i_.co��*7�4 es 2`X513Δ1V136�Ay��tr��ېkind �� .�m$� *A 293Fxs[~��>�*V+e���0���"529r�fu��toboly��id�dta�Z"� ct �)tendotox $s <1 EU/μ����! 6< 4Sino Biologica#!S�=c �:/`>?T l6�a. NotIz PacI� e������(��AA2�'&ĝMQu ( 67BS9!Q� pSecR v6rU�e%(��,  G5in%�lp-In-T.-2!< pOG4J�pQ� L� ,"� s�V�6mInv�%< ( Carlsba;C@ i)292{7!q Str2.1�e�secretoЅg�Sh�S)'kappaE�a�qvIz&�� [5z�&� �o2-�co*�e&�-2P.p*ng%3ia1c '[ Nin DMEM"-u�'=K)!; wentߧ ur h:�|;�*�A, culs G�re4 �fresh k�_150` mL�shygromyc�or�g`��t%�w#%!�q1�1�o� !%Bbu !fE-3on�(6�� �supx+��&�{�$y �^4� . S>-A�Z7� ifug9efiT�^� ahS45 μm  b�F@M, os�0a His-Trap FF�um��GE� lthc;!�RQn�&Gy�extra!1uW���-R)9E# oli BL2:�DE*\7s�E�a�9 �ed�!���.mx�olŖ*��3En:yd T1�%�R��� )� }{y� tStʡ-�|e> iN a6 �4R�,�}��asLito!�at 25°Ca/On"� e�oa�Œbio�� or (�ARa0R��5��or �y � coupv�� GLC S�f vY��'�7��200�]o�!>�g�r1 fLd�n��!�sz(g%�&g suchn �%qD���,g,gir*.gF��'&t{N��V�'biotin�S�F!d G��1ha��; NLC%`�of 30��l�B�rJ��� at 1ť�lM�>(��rN!t 1�+l ))Pind-�^tR)!��s�W l/mi�120��agP&du� )��ajP� ��dis.A�&�* a 600-sea� va-�+.��A2m�U�E cb�\��'".�N�ck4Ac)% _a��- )��M�u�H�,�/EQ�� �al*eBie}� O�na&softw�S( ?�on"OY�@��G�rc|" cK0g@�"#�BFa!�-P� ANOVQ$Bonferroni&���ari#�e�. C!bN2U�6�a"��two-tj�H . p-De.8��05 ��9#A��t):a 9�"nf�Jt��A$)>�at CBEa�FDAEgAPn�%�V�/Re~o( a&[Q:�d��s]�f�~ ��Ԯ),A�origi ! �(בFilaria�,/�hc nemato� fA?��&i�Kh�+a�ird��ge�,vae�ar/pod� s�7i, quit$�. �c��8F��%: lymphaH,�Oriaawq�zes��i9isturb�-symptom selephal<)Zr�$ blindnu��lW��H ?  m�ܟ�_eo¡in 73��Ȯ# �!xN5�sub-tr^5�tAZ;s &2��7ma�rug a2� , ( �mB$albendazol�-40ethylcarbamaz�2j<��n&�GmE1IR mB@-Y� �#�"s`C d do%a men;Bs}���g04��urgAeneI/aYtify �nc e. E�upa��� v�i?6a��lm��c �!1��tH7!�Q�&iAA ca;"�g)�M�" �hav�Qc�ar�y1%�!�Ȯ,�+��%��t�V�?� �u%*)dBrugi�qlay��I�$ �E6atI�sV�. Ů-m�a<t]"�-%e Wo�ʯ%�(patch-clampv��us�! 'i��Hl�K~ks�uȾ+� �� voltx�g!pot��um6u �IamIiMr���p�"t�3 fk. RNAi�ckh�&$K��( s SLO-1 Kx.�!& slo-1 ��A%.�fM��sp=� d exa�mRCK@ RN�o�CCon��a�0 of P�)� ,2�!%H0 Xenopus laev/<ocyF��dis�uA�A! �f� ,�0�]%�a!R�JUo2(1cVaV716T)��!&yO!�Q�!OF)�wor��4d.�ETc��0In OnchocercaAC vulu���sB�,a� ��N�e�ij �R#% Bma-E �F2�J�EsilicUn4�g ��$�Pa�i�r pocke�C)�XcE9�.�&��q� R� �i�j�!I�2/3 ��Ou2~2sV��*%s��Z���} n�8S�:�a�\%�.#OA�� �(?,sex./� H�_th��& oxHiE�qOcH0�_\_a -͚G&�= 8e�&g|�e���Lce gi���t�� s . "��6�lF ��d�> �+Aalw��!���M�)�z `ye�oD �a�: 6eb s re�0 e miK=cT juvenK�, c�B�t�5i8D��?v a bl2# meal��!�F� �u]�(Q/7 ��UF! )1��.=�2n -E�bY���Gkt.���.wuq�^!� &�^� ��morbid�'re Wuc�ri�4naFt��6�andtimori j��V���� 6� � ndR �VF( ���R�  ) ����l�s A� �ɕ� 4Saharan Africa�SouthM3As�ndm� 168  . SA��$ !C)�^F� < _�i20ND�t�:�)��r[1us�cfa`=."rH2t5 "& f*� , sw�^�mb��&$ �� work8�Y, ��l rej� MS�-n� *�� !�A1��Aa�a� )� tube��o� H�25ynowY=�U ��m�*� �"AM| D| 63' ( MD��/ams d��b\IWorld He� Organi`l do#� 407H m�(Ay�i��.% �)���� ��su �fup@&�,\iU J��ǏeZAT^�fA�n���exBλru�� I�w:� �(B� *� �3F� !�F;iA�!5@��)r>)��t�  ���0las� �w��y�pMF#5Hy �/; 7űi6�)�i.�����"LIann.?"� � !15�}~ � �`ak rAMan !8m�'�n:>1qC0 �BA�><cusee�Q$!aginu�2�-."�yA.�=�<pᇭ*�#J3ele^%Te<)� !�"��GU��rA�a��%Neg�1 ed D���UE/( DNDi� *q-��Hf&�?=�� �c��a�repur�*n:9brae�!eo���yQe�V *a��h��[�3*OX .PS�L�i )ڙ&2 [��0� le!(f�O-in-h" afetG�$!�2s��|�y� ָ�(�ej%Tbe!-jed!#u�:&�>� semi��� �s)Щ\ cu$octad� }PF1022A)$T��d�Roselli��spp .�' fung� at grow%QC�lia japo{[ [�:6�)������!-�1����_� ��[a!�m�t&O s [�,  �)��.1 . �ewdosB*7*B�m_kLitomos� R�rinii�y<)L .�7mod�# , Ac_�,in�Tm�tea� 6� ,pah�� ,.� gutturos� *�lienal�!/�ofNiC emer0Ee ���e �C*=0a� tc�B 26>H�'w8"�z!�x-�ofa�ndo�� to�&*�)U>%��-�Y$! .��F��6�K�(Fe5rI�A�eM���K*� ly s2�a*����._5 Z�!*PAJ� g�nk�6Vm��>s� 2�r�:]:[!�J;=c&�lyR�]��%�s�:ein U =��Xs.�J�h5\SQ*�n� ord:���A� ur���&��BV�"���&�in O .�\N�j� p^Q��Y�:�M3��� a�B����qO��:H*�of.�!i���Ybytli��6�] u:�of)���se5�.u�i�͇>H2Ras 10�u-"<-EhM������ �a10μM�ig 1B &d��� B immoQ �rV�2b-!�imA2T �lot��9�-6K5�9� at 6��R� ��J . 5x��)�Q�D!E:�%�E$��$176±33 nM%�� ;#801±126$ ( p<!01; 2&�!; n8:� %-�!2l q�f0�a4 i�\ �ELr-��Lu�a7as��L*p ��Id6M�J� qU"�1�a�E! Ց�el�!K"big%#� b��2�43�55 mm:7mpS]-�s�31323 3, �u2bio��$6���w�!�o ���b�r .i:Hon (���d���$�%�jt�0C20]�� {�[E�!�� reclh�+���Ne��� wC .�yz.u-stepUS;h he�� "e)��j�@�2zU/ 2�/�-n�B�6�. S1A & ����r\ePV�h� depo�z����a hQ*&of -40m>�1})ti�X�b�AV*|)�acus�E�AF � Gmax)�14±2 pS!v23±1 2AStu�P�A=t-���H�O6NI�j a-Z&'c"�)opsR�[�!�b:m�4% ��I'a :�� p� 2�aWgV50Sg!��t8�mV�-2 2��0 5; p��&̫,EPEiZ/�APEI��y>�M"e��ii/"f�"�F;AZ>٥!o �� !E� >[� ��a�m�F+Yi�1SeWYouK(d�n9Mfs�aA~%J�2��L#�Y�,M�� 2a_2j �� (�by�Z( �b� ofG6�A�� !�l�Ns��~7x 5x )!� a�L X2D(: 294±11nM!� �(I  )%_717�nM"O nV��.�`��7d!r hЗEX!U Imax%�J� ��t7R ��Biu0��cr]�M�6rAK�A�UI�%�� ednw-e�se%��C8&nn�8�)PZ l��p!�s�fLLwš/"� �"rJI1CZ &��.�e"-�� eat: aEe2 i�|c� G|7r �jlittlem�a}}�e cy; �D 5! l2�%�� F!�(cm&��s. U6�%Nq�(Uger����)y�%�W �Vs &�Vݕh��lI)b�lCatI9 �2� 7 ��b�f�]Z�c ˁW� a&�M�"G or� beri:7[21;� I7�!�scorpA� Buth�am�$e]9A�<F&M�ex=�*� c�1> ��#�I�&�(S.�"^��2k >*�.� �6�-'�H%���2A�)�}�!J�+\�Gyz>.d.mI!�/y��;�L5���*�a4F&q� P&. [22]n&e�C!�ir�>/L=�*A � "�T���.%�b�. org!q,&�5Nd�)�"�lm, b , c h��3��. S�3/RfW[�DA}c!�k���,A`hi��5a trunc�" 4. Bv �G �O��.�� ^� ��emexR47in 14alAZ!8� D+��-��� ���)~&Qe.�cZ^`<BSloR1 2�G-adPp�/kp��YFF�� . %5�x� ��!- ��e| �ye��� Xy��DQndakfigҽ�of jus�� d>A , �a & P�"�RJ�) �-!a�� �c����te�+6���.&F $�s )}�N%D����%���&� o 6�e"h6 )|>bM�A se��1#� rE0�Wa NcoI�2���)A�E*ut `a�e�amC14;�)�Aa~- �ݪEZEO&q=N �j pip��M� �1�ym:��)z!���e]�� I�{���enzyme)%�p �=��N 솅"�}a��:BDZ�� fi<�M �=M�)�6�. %B .�cB�#z08 yf :��{!>RB( pTB���V k%�hE�Z<�"7evo� 2 8F\ 2~wo-_ rod& �3�oI2h�Mat +2G.�2� .�o�D��:� >�8��e�Z��VRob��6b&c� �=!a_���ak �� 400nA)�s"њ���%���"4B�� -��9�r��or 2�>4,a�i m�=LerM_ *�c�Ae�  E��x FU 5±1μ� 7 ) , whi�Xch was significantly ( p<0 . 001; Student’s t-test ) lower than that of the SLO-1A and F +�Ccombination ( EC50 > 30μM; n = 7 ) for both , Fig 4E . These observ>s show {�emodepside displays different potencies on �splice variants of Bma-slo-1 . We point out f�j�s from8oocyte experimeR are highe5'o�tained;�whole worm motility and muscle patch-clamp ._8, which might b|l [by�absenceېinteracting proteins like ISLO-1 ( In #or with)� ) , BKIP#$BK channelNQ, ) [16 , 23])BDdemonstrated earli) ,t knock down�)uYa%N fB�. AIKn in S3AY,>Q-cePF�ofP�qynx zed ��%0A.nds , Ahalnd dsRNAB7e�(then select)eE\edI^ �\in female B . malayi . F a|s treE�E�8off-target lacZEC@J, d spec�B�ere us�$s controls�orms soa�in� 7,for 72 hoursv*�2�increaAf doa8A)� . E !oBmor��t�P( IC50: 242 ± 75nM )�-)f�)�i�(5A & 5B ) :cTp3 times �(in16d�617�207�2�%�y,2-way ANOVA;ѩ5�A8 )!d�i.�z� Z�S ed little��gq�ir �( 181�43nM ɢ1E vs 18%H429E�o�� cDNA�����A�2yE>restrice� enzy!UPvuII��.�cutI�fe>d Ncof%a �4performed qPCR�#�cleaved ��confi&ge%��80%in��( P41 ,N4,��5 )A�m4$transcriptA2 ( S4��) but no.�1�wOfD� Hor)\I� P& S4B��V()Z�%>does not-^��A:�g=�Qimply a"� Vgi::e�als��AsF�6�-�i�K� 7q�, Diroim�� (Litomosoide}modontis�~Eavail�Parasitey`( p.� ev. org )"�A?���$although i� kA�in vitroi� vm�qro�s [78tHtwi B���%,n� ion-depenJ  vity even�% ose-��m�l��, Brugiaj TAnI 9A7N9mg/Kg.�proD:ximum!�sma6�A50μg/L� 12�in dogFvbE�di1bu�to all�a�T���st6ks ?2 fat [24!\�O2E�!adult ca--��( . gutturosAm-�, is  m��toA?<1nM [_If �2��Q���Cachiee hum�followAqyrBd60�{s sensi e m"<as.�,.z<�ip�Y�U�6�� 'z !�mrp�.E'.�m+��A�yet� be d��m� in1. Our. ults� i%�rRa>awoulddrequir�F��,fiENat.�wa�r� eon*H �� Wew [r% Z Ay. in.'(� 2�)%qŷj eEDe"( V&� �DK &2� �a�ll�*�(e full-leng"J>\q&�Aa:*� �s)d��m^L) �� 13–20$enc�d�.=%�do�omũ#��� Non<J�I &�ELL .�"�O{ lack�"�i*�� data�A�)�a� repor��>O��"� P� s �V]U&�� h2,y" to.k [22]%e1A��.��**"# "� �%.�to�Bow����i"�o>p!=JP L.E!�.�xadv�sE�knowledg�its>) >S a$af��ofB�. O.��� number.C . ele � mut[e�no? !�!�o-acid�R-I�s.&� sup��!?���aR*M.EA&b[15_5� ��2��� rule� addi� alE�|6z!�membraneu�����lipid p� ":;�w��d^ a sm~ 4g���voltage-:�)r%w�, if l� ndi8%5z  medi� viaD2_ngP)Je� [227!K�)OJ�ia�2�m:Kthab�Ŵf5�gg E|� s� !� �E��!�o)soutcome}vY�su� ia�r: )Ol��Bsurviv!/]toQtin` hlife cyc�� ����;NaMrInstituta� f He} ( NIH )�ectMs�is� q�possi! r"of1D%)bi� �54)ertebo! animal)�% ( Not�"N� 0NOT-OD-15-102ed�� q!:�xoA]z��h� ��h c=� is��H-M �*�$ factor5M,6�. S&�$ J*����� metabolis�a*�I��u !�Ha�"chu�$ortus [28]X ILsYz!0$benzimidaz!�6fe ext� "e@aU)�*#A? .E� wm!?h�.Pto �m�aKan ] [29]��)r -linE)Ys �routin+ [30�) advo���� Fk��U!3N�sh^ i.as$y U�b&�"�Ht��V apeu�con&^ . B! ��<H O , �],,, inhibitory5��"�%6� %� e��by M� -�bpotass����EC6BJ . Im�5�',B� ��m�o2� >�� A(�S!�=ca� tel%�$$%��7}9 (M� t*e�>-�>s�!; n anR!{ t�pa�ular c�I�� e'%s1���*# a�'t!�$of major i-Gc(&���-? men u d-���ne�� elim�(edi�!�.. �funder�Fd� ��O � de�� ,� �a�� nd analy deci�% to publis )or7 aV�c��manus@!. .O����"}"f�((NIH/NIAID F�0Research Reag�T(Resource Ce� R3; Colle� Ve"AMin!�Un��s� Georgi Athe�GA , USA A>� main()in non-�'lg  Roswm Park Memo��s4 ( RPMI ) 1640" ( L�Techn�<ũ �� lem�-�(10% heat-inm�ed fetL ov�serum!BS�sU'S��f? \!�(1% penicillO$treptomyci+f��-*]re sto� vidu�in 24 %microtia�pla{v&aiC 2 mL)-=!L-glut� =dCceGa�� cuba�at 37°CJ5,5% CO2 . Mov%NA�M�� A��'^ 24-R�*�)aq or system� ex*�*[31��azoutpura;, Mean�Uni ( MMU�* meas#"8 pixe� plac�ea$-�+ov�)i��(e�'�,o zero�]s|!oQ4 EA! \)Z&*% U :�.�1!�of)��s..�. For.�2 -resp�@.xo�"� ru]Asadd�: �, � ��recor'0�234690i 20 min p.�C>�( diss"O$DMSO (�al6���.$1% ( v/v )"�92�/M�u�)*�( �)=(.� , ei���mLM)# , L,* 9or?'/RNase f�$waa�%Xxi�mR.5Uat%X2� 48 ,*A}96 $*%F s9L�#!�a Assay v�4 softwHa�o.of!$�*-!�b&� ap:Ո | �)@���Q*Naf!�A�NA�+aNJf- Id�d%d�>#u�.�,a�& age i�.� � ���7��%�pz*�+.:naïv��.��l !� V%7A�ed">a^inq�&?'at ro0empera�&-�m:0celd�-dermi�N expoA� uponv�by'if�9method{�or .@[32 , 3�/S�P5mm ��*"zaJio��.h! A۹!I�� cha�w� bath solu�(a%mM NaCl��10Sodr acete, 5K#6 CaCl�4 Mg % HEPE��1Id�c�1V111 sucr pHYusA� to 7�% � NaOH , ~3��os�%pA�r A_���)a�$× 50 mm cEIslip co��� in l =&ylgardM%KAG!�Tv  gl along on�$d�pHGlushield cyanoacrya3 (titch In Canada �(0ereby immobil�it%�t!�open v itudy ��$a tungstenj lQ�re�!�‘M�flap’�.�%?ut HA?reat)g�3issueI�re�|d ��(��cep�!�m�1Evie.� $ DIC opticI400X ) Ia0 K.�3��sco�24TE2000U , Niko * . Mi��m�ix .1 mg/m��ll� �X( T31G i� .a��20VwashedAӁ�$a�]!�dM?p*s4t2 iq!4asɸ2�4-�h curo5*�=�s6� in [3�Pj pipet� �pu~$�/capill�" glas!kj�5(~315–330 �EP57�&4��5 MΩ)UqA 1 cm �oata�tip�Ea:I3`"A/�~�ődE,duce backgro� noisO d improv�z.y�n aX0Giga ohm seald�%�,a brea�-�a)�su1kpr&A�� inuously�&�Bat l/mi�5a�M�y �a"�/�n Axoe 200B MoleAr Devie, C&�fi\AowkHz (�.-pBesse�&%�A�s 455, digit,5%�a Digi9 1440� v�. �W snapa`z�#nd cru� into�powder!>a�#5y ��- $rifuge tub�AKim�Kona�$Pellet PesI3�&^ �6WR�5ext�8��TRIzol"�n�ac* A�E>anufa0r�:i�8IEA�Ab�'1μg � 2�E=to &�6~+ɸSuperSxVILO Ma' Mixr�. S%�-�N l ify v3 h�3��at -20}���r< .� a�� &/�t� ?TS�^t T7�#mo� lab!�d p�:�2u �!h!SSK 34F�3 R Ft7E� t7�< y>D EL CA .?�AO� �y� ��� � Tm�A �c� !Id" �57Eval-� � ( �8i !Y CFX96 Tou�l-T��8Det� S>nd SsoA�!d 4versal SYBR Gr�+��m��Bio-Rae��Cya,g.���:u�i�,�.�1B�!�e��@E�*�u�5�S� Suit%�B�Rel�5)F�&� ��)�%�#=!=�&�*�.ΔΔC] � [36gDefolli�Ac4Xenopus laevisA-� purc)!�@EcA Bios#c�AuH8 , TX�9-cFull 8(U�Y/)P�num)�$Fi Polymer 2�Th8Fp��mo��er . P��(E�48Y�48R ))�/4� �rs� n"� '\ ve�pTB207� l�gx��;�%a�amH��(�A9ins�duY*7��%con%*t,4�ff�:).8NucleoSpin Gel aA|Clean-up��Mac�y-Nagel�clo�% �by W Infu�HD ClogK�9Takara!� !�,� .�B� guidelinŮU�|�B�:dMa1���, =ar$ by MscI�5 ��%!�k�O!�)(aj$mMessage m!� T7 T'$�|- �Amb QT� c� precip�ơ�� 0lithium chlory , re-susp#n!�A�*.pB:o%�inj9%�Z�kep�&H ~3I IW��*o10p2KXe8� . 2Hw 1c. 6 %j� Na pyruv�iUj&C%��2R,Ci> . 15�yB9� �%w&h�1# � �.he��Ia nano!c II FoDrummo�b���= , P& )� 2!&�M���fer)%�96cul�� ��00μLR�perQ;�w+ :yn��.�-�9 t] y6F N1oweKrev3or.��*2.��� g�Cail�+za"�a �!s*�-15 mV��ex�H�X.� Q�faiK(� � �� !�hol^�*L10%e"�&complete�i_ -.-�6�h*� Two-7 de"�'�G � "O !?g! ���odu�����hH�Eed� -�"!�ne�DR&� C �B� servA$...G��&m4; �269J��LE�q%v3)I�t +�V�acq�1R!%�u: MClampex�. 3�.�Y�-��81�impalC"��� � FlNDg/Brown horizontal2 d�?l(( Model P-9�5Sut�.�1s3j ��M�w��filA��3 M��had6YI of 2>30$���Ri�carefu 1broken \a pie�+Vpa�|i6>�/�4F|��inM���ja.�K�emM.aO��>�OpHI3k !΁�&$�s�#o�e+�s�b}Ksa?1B�" adequ��2�6qGE*� �$�#a�6�#�9�x#*. P>)&&�&$ iberiotox�Hrom�(ma Aldr L ( St>/uiIMOU7)߁���!i��  dil87V� Gm"j"=CAO*�F�,DrugBank ( D-H. D�C!�KiB"�FiE Auto)� he rps�$�$a#g+� s��M�3�,C"�*9(iA�_ le boqJg$aroma_(yclAs rot�3*�!�)flexi!KtyA'��^,#.E MarvoLkeT!y8minimiz��uJ& MMFF94�p ce f�]i�E`eLu,www . chemaxeL com/ s/my s/u"�least�>y!*�� evalA��pairw�roo.an squc devi�� RMSD�OatoUFpo,onQa� PyMO95Coq�D2%�$KK� K1F�Y&.�vc�C� �CSt'$&�2l �BG79l�gI�Swiss��(( https://s* .�as�or�>iLU+m�� �=(G0A$cytosolic ��(onomeric��!%1. DueQ�*Pl(&4 �fexact l�+�  A*�� entir /:��ta�"� 1uv5og? �*-4grid box drawn-Ma�G4� luA�1�0a.g!F+� x , �>d z d�DE_� Aid spa�Eof�586Å�#�!lig\�JKrk2n'"&=�-�>�$Lamarckiani�I algorithmK�<zSa� I�� defaV�h(to normaliz$ 2~&–Hr�onshi@���!�7��e$�ut�plott* �<lo����6�2lM�log10�a= a�))E!�[ agonist vj�( �I(&0sl!)E�1/�rR 2�H curv� o& Ui&s�w �5 �4an�OStand)# Erro�4* ( SE�P.!�3\3 �R"�on �pie�s� � �PAd��>� e�a|9v*1he"�H; Bononia�t-hoc 4 �%1A�multip�P�:is/es� Rxr�"�.nt23x�!SSB�W>� |ng�i!� trol�a�� N1 .Ӎ!�4Global Program!/El`/ Lymph� *�.( LF )a4. on ra�7diagnos�i)( RDTs )S2 �>nnu�Dss  adt s�![L�U�4�V i�An b�-�".Awse xlct a WuHria banEti glycoyW�[A blood��inEDjers �7av bohydemoi�D��gn�F*a� tiboN AD1= DH��MLo�/�& s-re/� ��LF)8!3�Zbs�&s� us!5taco>e-�a�� n-�� a�T!3L1�� �WDMn�tisF�&= �D ��B body!�(immunoaffin��y Loa loAtigen*�$ serap&P/s) aa}"CRDT�? ��3iblo@�1"�Jmany cir'a!�/ �1wo ��E �tLQ�E�u�$ �/i�3)�-S vK=)��Q�inH �Js�.Aq�xs� T,J�Qey ma�Xa��mPd$*�a*�1 and/S�.��UnltZ!�s-K![*Rwe1'W .}=.N MI�14#<li1� ��-�Aۭ��9 disa�Og9disfigura9d\;�O�0mosquito-bornf4 T�PTadE_)^ a�cK a��tF ( GPE�eU!z(at-risk pop(.�� �v �2 bill�+ 89 m ( a 46% ?;)�i*� 2012>��rep�Z�Ųc'n!�-�� �"�m^� ( MD#*. Howe�.,�8:� Klag Ihi����|�&e a 25.�[�3��s�:in!��Gs��H�3�i.�c."l�co�@e���,":�E�!�RA� caus�v��d�e �:�eo> UQ�[2�E(Ee�!ssaw��map551E�L_a�.% � ) �Asuccessz1��3q.M��u8ve�% ]�J?�R�� Uc��h%Xs�OM�c�a1 Binax NOW.� �ch^� phic!Gd?  ( ICT�$�?GAl!�* Test�ipQ(TS"� �;m@s�W,�=�+XF� ns�*t=l|[3�FiZ���<%�NfA�assI$% work !>V �l��ppl��) pad ��O �8�Os D A�ip%1|0� l H���.�/ed IgM:s+Bn:� y� - � �y�C>ca*� epit.%t!V bund=�m��KFD(�cJ50 kD�0�V ( CF�1aO1)�traps:H)b-J:�labjZ:�-�q+Z8Mnk)e ��C!"� %��-GN�A�sacchai � pa�A�Rgrec:\ �5��Sn�F=T��2G� �dw+ f/9oa+vO1�,Q j�h:;@Qs�is�@0phosphorylchoE�[)�� zA�F y� S��Weil lKSor�U� �lso9 i2�u�d��f`*tw�Q"� bkge� . L� N2:9��� t"�RV�6�A�remaiX5�I?�_r , h"IfQ�<"f � �s� Qf�H sinc� pQPM��'1Lf%n ELISA��m9Z^Dp/ nt j/3R �mN�+i_surfap�Se [�&W���Y@�HA�� ��%l.�-�[�aE�Zas.\>� un� �=U���6���z,-? unti�>�2Xs�(���Cb��C.�r� )s� �Tnow beQGZsmG2(  , e��t�h= E�s .� s f ) c��%���^ o�� s [7�\� �g!� TEapp�oq nito !fLF" !]pL!Y�.�r��purXp�y�tom}f�L"n\A"BV)q�%1MqSR;  fals�1� F��: �.{ y:�Wv� � �g . ����Ai�aZA�!iof� humaZgr+d�0��V+Zap� � Din'8�9aA�view bop� ashington|+����L�bap�rotoc3g 201512112%� Akon��ga/AwaId "016"�E�RM �%�Camero� !�Rwo ��>�1"�IEth�7Co�Zte �MinJ��P�Cc "� Writ^)�e -!E6 1LpaEip�MA&�.dVdAw�;abo@ kind�o*�0� anji �:�.�*�&RD� Inno&`$5(&p_{1�N emia$P�kW/�Yest [7�Weud recrui�3�$ ; oZ-!k!�IN�kinvB>� ����i1iv!�mbUUv=g� o9t�*�Er!\g$ a biob�%of�5�A�neg>2�%�&�!al`��ga!�t��":"(gach� ( us�H!���6e�:{�p�� )*� yXC�Fn��9URwX day�m 0 AM!2 P�hni�?( *P A� ��a<Fresh;gerprick*�> 0��ma�Q�!�a�6L�&nd p*�<�R Hsmear+%75. Dri��%spoA]� � or[f=t�1A� 9 If�HemaSpo�rtridA9, On��cKH?A*�3�%Ven� �( ~10<��0in K2 ethylenOtetra�Cic�r ( EDTc vacu�A�ub�XBD &+4= Frankl��akNJ ?1�)�at 4°C�X��paa8At�<^ �G:_�XJ ,��!� dZ!vupAV3Ag�-�{ �OYaéo a�om/�7N��a8!�q�E-"�on dry �Sto �[ �<'"f. A�Gfp�4att"�2b�|���y �IC*�nkR�C���[eQ a�)elmbFTS&�2n� .i0ly un2#E� �^l�* �|.- F!��@n$�al_����"�  3im� �c G c�\N, j?MmK ��� 4p/6W Lomi�Dou�LNguel�Ldouka�[&M .�a brie&qter� ,��� dWNs�Jser/Olnd!�Z�r. Day�9("���64�m)R?A���byA (� @A�Mfz ��li�V< �G film�LTB�C5� ���v6�4N��2�a!wO B�� � coaguld#I#�i���.$a��� �o�Lryovia�I2�?�~7�~m1�2W ilithv .�Bue�=w�7A�m� wjt<. N�+!F�ɿ�G�x10!�!�2�D%22�e-�"h-�_�Ldr��o�5f CpK0a�`+pa���s�,�>by<,j#a� revioD[W11�VS��a�Fw�d�dBd|#-"a � ���(�<out�.��) �2I 2� c:� "8 s [1F-12])�%Jas9�� �xa`a~!��T}U�)�%SGiemsALA!M&b^` M .�J Mf Ic? �@5�def9bed [1RL2<�A� ingu�G%�m- on�ph��,? .�Qsl{9AWr� �<wjperi��d)\�I�[.IY1&�'atZpb�= B�}�� .aV4�Y� fil m i�%�!�A�#E�by QIA~�& kitI Qi#J , V��|UCo Re.R?��Taq�MuV(xI � ?A�� J?� o"C��F 9%��ABI Qw 6�I�b� �)Ai�0prEAprov'� � bf|R1XJ�� �CnaxNow.K�@v\( >:�>A�, S� roug�WM�uB�(!�.�2��$%�92./r"���r�Fa\E�� RSa� ~�%E= S ��� ��� �S)� semi-S@�A scalh�>: 0 =�X�A�3 ) �vi�^(&\� 1 =�T &a_*�weake30]��W*( �Y, 2FDq,_u�C)!)3F- stroentg 2.�R��iso *X(���}2L& &�-���A�[1�Imm�(Dag2 L5 )�%��^\Rag2-/-/IL2γc-/- BALB/c�� e 90 Isube ne� inoc�$ofI=L3 w8DAol� �h�T4�U000!!U5 � ��;H  4�l�um-�>"fEumJ;X2mM2�V!��mNa2HCO3I���U& >-.�= -neoYYmix���X/ 5�X �o�ACua=s�Inam]�E^"aG!�O2ld*)S F��a�3�(!)�24Y?()(&�#A�.��+ *.*�D�U*P*BGby sandw8oaP�X^d8�"�fs�VJT ,3!�D�+, �)of� �<�,�b�-�,Y9<��3Por �,*$&@A!aoi;u+yX�.:�Sigma-f9��un $.�6�f.:�_excre% 4+ory��� A(Bm-E+e&! yU�(+�^B .�a*qik(&e�AݙR�^�],2R]�yv1&]�+p:�\.6Z!iy[/.[ ( Gibco dnT�|�B8dV�lYnlve$?��A5l�2-�vi9H(a�rox0q ly 2 weekP�)y Zn��Fby&O ala+t�2��>m,EU 3��WCOa�illipE&)9FolyvinyUVU-bottom�a:i](�rmo E�ron Cor�3, MilforFHM E*�U2�3V]wA�Bl/�AobEf�9"�;to}*5Cin�66Mipn�bu�l�H�5 0��A��'X��@� p#E� a�| ( PB�!? �&�R05% T�2�P PBS-t�> bloc� �2�L��T_ calfM�in 9. W�Di�cF�% 1:5)�.\estQa��unlab�%���60( 7DD)��C hour� )�,2 �.;V un�"Q�:�)� L peA� dase.�'�"A� F�2 -�E sw � �sO8a.� di��o"�F( OPD )$�* �],l ��h ,0�xBd� �ML!~4M sulfu�:7l �absory/&�@t 492 n9Fim�Q5 1�a���*()amL paEZ Affi�H10 bead��"KHercu�=� �k  A iftyi�6; � oe@mixq?10}(7E�~hT! am�,( a:a��5he am!K $& {��:!H�ero'�ve`�?MEfA�]D coldAI 16�H01X NuPAGE LDS��`>�XI� ���Ac� o 95�A���QFeHN2A)!��%�r"� ES!��t,emEh"�I'G*� �.�%�LQT.�)�!<� DjC�>>Ya+%salzh�rg�5AMIB-T : 5mM"�B1&�\mM6,  EX,uN"�O]+4VO1`����riton X-�+!Mt�3*ZBcocktai�K % n tw[�Q%���A���!� er)�pAA�inr@?v##ab��\:�A�H$ hemilu�sc�U8� C"Doc.�!P Image Lab@9a\1>�>|!^"D��� oa Ag�N�Ts�-l!�';�&� s!62I grx"G p= g0Y�-�{ mM Ta pH 8�H, 2% sadeoxyD-� �JPMS�?�U� �` 25ug�M TLCKN<, 1"PV"} a �e�a gift� D� Vida Denn�FTDe.-(..un: �&my"� A�LC-MS/MS-�a-aDE : 4a%G�b [1&� + e�5Q�DTTE0)�-ex�-d C8M urea/%�&�k[aE4!� iodo amid�e�JN s> �At�`to��05M NH4)�My9R30K �Av* �NM"� , B3J�,� :�Zw$�PNG�PF%a1�^���/Sa N-Ypca&�1Y�2-I�|2d%4)/��,6i TCEPF<6>�9��&Uthi�,V��^)��-.L. TrypsiFchymot��I�$i�12#��&Ia>k, F>!�]��d pept�]%�n]�qA�=�zdeZe�Ga Gly� C4�_(,�mumbM� .a$�)i(" v &DQX Q-Ex%Pp�Hyb[EQuadruto !,�: elve�G*�t�1-�'g�KllTra�nsoc&�KHC��my���3/5Z ,ه�f�,�i �q!i�Y�X idthA�3=&"��e&2G/ ��H ( NCasetL  *$eRma<��Rg�!��es%�pa�f-%��>A �e #IS:$.'aiV/aloyt��6%>d*��&�Sorsec( autpA�GeY ( AG��[TF�3 x 106 ���uN U< MS�n(75,5 ,# �A��{��%�M�V/�� or"Rxsn ��|P ^eC"Q1��l%���zq4co3 !:to�[co�yy�"6 ( MG�E�pP�4Disk er v� .�8AL2fi�%� submn1u)� P7"]I-pAT? s*j!Bo � pr�WDs PRJNA246086 [17]EL(60051 [18] ��{%/WormB����S�"vÌon�/ 2�"201��%% nZ$�`ENSEMBL�Hf,( Homo_sapieEGRCh3a:72 ENHsaMo:1$( Mus_muscI�..m3> .MO/y� cRAP�  At;1!�0!�0�\!GcoYA �E-�h0O ://w�Pthegporg/crap&�P�Qeng�*� "�zmodUi; � �bh� IcK!Gfi�@6:���  mi�T�7v�-; � !�2� �J� eolyr+e8�Bj* ; MS1 eKtoler��x2i 0 pp�oMS2N&%2D'6Qua�f!H5�h� o�R>7�#e�y �e��P�>5�� 1�s��U, mE�Gvq�ast2Go&�!�E| s&K GcOn�(yC OVJerm� 2��6� ( IP��ata���!w�N ge�Q!f+( P�V�JI��0fer�L�� [1-9NetOGlyc�R02�pr�y t O-{JsQz4'�(�h,$�>�� �%� s��o� ctL:>e }M��randoml�=E�i.�I-':Menrich�m!) h;[20�1a�1a�6x01� � NR� NetN%D�� [21S�P%Y*�.&\clA0 +N-Ainud�8!AK�) nd S omeP� V��<Ts3.I[2�rd�Rf`ro}BLAST��q!�*r-a��P��Iv10729 ,( U).�Ek.���%)u~t*!;^v�s!�y�<s��&� %��J s sceEq*CA�a>5y�Oa�a-"� #&X.U5�cM�!�ac�|�Q�:A�. P�/k!/ "�eyu:&G5e�V�7in"�7"3."�5�j?5%�&E�a:�)2�)aAv�'�C��23%%@ Ka� ��;at �6Q�]>i:,!�*,.��o�\�y 2013 �<; S1 T� �One hund��02- ( 59��1I:�ho� ��!��4 �7��4��h��D6\no�n� Zf . No.�66�8:�b� +y%��I# )���a�%"�,,R�6n�*�- . Sua5Ny ,�E�!2P%�2�J*[g-�!b>A2-inB�2�1<Mf�,q�se6�]aBd��a�(M� .&8%�MJ�3�h�!FTS)�%a0)c�q)�=Q� ( 1+] �!A��A�"���/Pbs@~J&��o 2�-"�(�"1� BNeh; humo��U�-� �%y&o�8 esti�H�0$.)�2�<��FQ��C6�ZP4A���:GA���G"he6� jA �S,��-�aw��of5���Y-2�|"�ompeti���'a�Y�Qn�� �Pto -fN�$t�*20%N%z� D)�v.ora1/a��S��9��>�?=(�f,Gau?1�RD5�V�U���G-�!�.().I -mas�-�(*���ŸQ2"b)e�;)���=p.~A%�.�.�1i��6272C�*�6tegdR6Bx2/�B?9?�#E�.�all����:���!�h-no:cd5�Nn5��m.x��oa�6�6�All 116%M�C2�1:�. NM~-cs.3�A�U<� q!W��20*�A3by�2i{9����m�26Q�bA5�Vto�.zUn�,6� �c P81135N�P�A��esdV^! Ah�(��� wMP6ly; six�*�n�?K1 G� �5%Ppoox((��A$���V��c�Id ÍkJ[�~ �)��garn!}#*M%to�# N�K,-$r�L�vS�J&l�� %nI%nI!��hy$"� >��hor�d���oS� {!�.Z% T��3 l�7�XRI.ed; a/A;�^.�#kI�J2 i)hr?Bvq$U�\by�ITML�WE�a�!�!�e =;��( �*:�-���BB�[1�X��!&�>QD%f a�$� WAor . At�E� GO   co�Lb���x�206!PhAC ( 94&1jAK=m�ble��ho7�\ pE) ms �`j ��g�1.�K"� �B�,��y�E])V ��g� i�q organelle�l skel6�F��e�-re� ���ParC��<}�w/�h�NUx" Z` �<w�(asMtoM<�Pa+�N��ne.)` �b�z�d�{6c!�IP)>mlj ncer!�EK��+��early2 ?*c3>� d�so�����or��*�RM~�,�A[�^�6j�I�3*�F�areUJ��w;=*�I>A��c , 24eB[ ( 49� 9�6(I: 45%– 5eS�xq������a-�d!� "�h�XB��=LAa1�e:�� R _ mammal�_�tp� m1 zA>,o= �|K$H$:-�p��Tvell�!�d.�Iv��[266X�$.��� !�17�we.8havKh4 *�"%. Eight� ( 17�� \s�e���D� , tw�!"}7ANAnMLby� zJ��1ij�). Ni��� ( 92R10� 88�.� �u����ekP�MeL�!����%0!ii��71p92�3% ,� G�����e��[Θ�rltogB�.s} �W��� -Q8"0by��M6&�d� a�!:)~�A�e��)��S�=Mf .�*(��SOWA���"� �3gI8v�� �&aR o!E� !Z� N eO5J,m�ed�f&3ta* B��,��!2"�2�!E�y-� percs�uby�.��t� ve OS*gKg�i%V!��o AD(�74�82M�a� ��DB�a2�z!�E47%AS!EBJ6A�""+6�6�18Ӓ��1�2.NF�B� . Th"�m;+.6�A�m%�Ur;P/2���uMne *p9*):��]���( 20/�[, 6�.�hm��`)�ցp 4)6�a� deco�eM!�e*��Ry^�1TMfe�#�� L5�:�H)�J�4V� vivo�0&� E2*� �B�� @( h0��Q��"; ���8i�y)� amony�q�Wpatf*F"�</ pG ( �<-'�)�<�P��Kuc?*$6 . Us��DB>?�`�ma\%�-�)t�*�����&( 7B�S %� �.06�J�>�Cn��zin�*�6�$F4��LC1'Ŗ�)�iM urUfU��; �D@2`EJmz e-��ed �l9!hav!q&�SwoB��. O��iN��.�]�ortiG)-",[ Av33!�0lsI��E>[z�B . Re"� of2AEq�5�e�J:,bn impedܝ�O&Me�Ne�3�-V�E.C�R�I,A]a/'a:�&�1%���r�*+^�,"$ %�!�i+y� qNs-�recV�U��IA�"G�w��u�Rt*�!B,s��\�o�%&2�)������V '��2un�wD33F ,,���i�E�� �j!S�K2S desp6)(t�k !n�&E�T~)�$me�3i�'�B�i�Nc'r!�ut�o"�`l�be��i(�v���:A�W.�e seemhJX%���Sm��-�'&8�p��A9��=�;A �egA�H��)W! noT.o&hH�%�A�q�t��,# ��mG�'/!v�SbAu�Aqa:{m�Nro�{a��.r&aEag�fNE��� ,6�e"��%+inV�b.mBM;�̵�fk \seaa&�i��C�� re r&=intra�:a�ok+�F I}~'K �(�ot&� �(nyruQ5 1���̨�|F�F�ݫ<ros*R%Ke�>�NB"; of e# �dyS m�*~(� i3aj<L:�B�3�a�!cA�M� es q�Y&'o�e�)�:h.O fb"l*Z� �Wm�{�n�2�A�j�deחof�� aq%*��mc��1q(=6�e.#��o qK� n�1at imbal��q�S#�()!2cc�@[1_`��.s6!1� A�fS[%`A� B,%B<e �"n( q %4!� <'ey�F)) e�ng.s,�t�zi!oli��i�� ��1 Mf . PerhAAV�� ��\b�I1�F-�5"in� ~U�.p��#UU�sn �� !~*+)���r� cor�%!�Q�F�%�:h"MA$-P(E2se5B�^�I�np1"�QI�V�] r� �xm��#a-� Z�x o��p@��&Ru.�A-jsr� �i �6/ � y<�so��A�:�x� ")h:���0se���Z2�u�]6e}X��"j � ysȦof .G�!QBv�[��=j� �.VA�i�{ �vm ��h.|DB�8O larv�=�1�O%U.� �U�!!E:� ���-���t0m�k�2��e�4���!\mb5Y� �mrP"�jak�s&QUn1��2w'5�$1�A��d��6av�sr6�-�Ie��ޏl"?|�Mf�C"��"Dj5[ V �s�("��Z��9w!�!�� rC>'ig�=)�, rab}�LBaR� in /!�do��nt2P6-�i (�,K\ilya�.pE����6�,���2v1J pEb��%[3|;4�65e ['�&�(��sk�)����%xw.�Qa�]��$**� ! 6! 2&+ %�ms":,iwr&�kat�"2*� �:�B&&io:k�H?p��[Mc18Iu�{�r�~�l .A4)se:v�Y�C}�+���]f1@."M1dW ��JLOAG_0487պa�"q�kinJ( #17249�ICls��cy�A0.�&ez�Q�a l)��� #A�!�[�t@k.`��2����}h�#�"E��M� �Og.A-�~i I�&d}�($1aU�ua2a� �e��@e�Nll��e=��E qg7`�"H"iv.&WsBo!� a`�$%�E[q�co&�%�2�), ?�����IV���)� .1i&2�w&.�,>�r:�NX�pr�Ya�, �2�souWT.�:]?92&2��qj4� 1�.J>) . FuM�m�$@-!��,�qmJ� 2�y�if A�8 or7 * �" %�Q-&CqIw#� d/ng!�see!v r��9�&�-�MSy�m���ba��As2�Nome; u�ptu�R�1+ � no63x "���dd��n ��� is%�.n4a�&�cer"� ���: ct�h��1�{ZsF� :�9�-�/�1"!7��:� ��!OqN!�o"�O)� eri�!^um ( ro:��M;J�JW���N�+o# �[��=D-V�QA}&*�>Va<\i�� "���| shor�E��)�fe�B-LA�/&m�q(� . �MN�qzrppB MW[�3ɇel`.�F^x �,i[!E�:_"by�tgun "4;�Fr��� �8@�m[y�q�*� :���odS�t e�|�,� E!ne��f|�*���:eA��  ��#e"� b,r,�6d*!#�).���&�s!��(�a7tet�[Fu�[�<�����.� s�b���2.�qu����+) plexaia� 3 F��h{oF��qJ aѿ� ag8 �,2ew_-E=u�ur*�,!�@:.�,ad}�g��$5uzzt ��it de"gߡ2� �yy!�vA%�%e�^Yٖŕ�Oio�%�Q|fee~ � plau�2.|�9�>YAOŬr����Y� caҏ2 A�6A�v%:5I��B�A� t*~�nREdzq��u�)>R G6m� s.{$��@��gI9dWorT��s�"����cr���m Eyp��acclu��"1� �wOnew!��!ۡB5|sFA��$�na&]Qr�Sef�Wq�) ��!du{Io�g��Bq^](%Cf���6��@.�7!>re�Q�)ehel�mI(upYleI!�l��a� � }f~%�A�*�f�d�l"ƌu�/�1+Ճpa�1��V� h�E�X>}�>� '��y+ H bD"�+"v� ro��)�!`!�� �d�f�&idK���i N�C��[N00'Fali�'��C"!=�ig��!<7��ee��2E��&�}�ieukary���3a��se "�-s{inherrs)Ndis �!��h� [ch" retP��yig����@Bardet-Biedl synd�N]A],�_�q��f��p "+�\-L6&���"�A�CilJcy�2�AnvT���Ea�6jW�ps�Fms$!�(flage|�)( IFT�=iH�i�by;esin-y�IFT-dyne`otoa�nd rem�18MvF$cargo-adap(� �lexr BBS:l1"g ��!�um-*>ge^�ŵemploy?H��.ٶ .BG�Z F���9 �x��pan��!�= U�y9C�E�qneurons� �t�%�0-%�� RNA-Seq �nz��dKݝeGG *�pr�g�ly6�0ET�zc�a�-l[ �Ge�FAM-16�@FAM161A"$ueECCDC-104�gCDC \RPID�RP1/RP1L]9!d�d� b�� �um-ጉ<WѪ. F_�3��185 cand�I�l�=�uncH��i�MAP�2YAPS�4A�RAB28��� �]QA�o�a�F   g.QRAB-28�=�*�:�N�l-r� �B(cone-rod dy�ph A�k W h�GTP�dx��[�M��n�eQu!E *�N�p tha�A. ̑iiGDP�� �d��no;m�!Y�A%-�v,� E(��)S�6�%�+ � T�%��[A+a�* Q mann;dylg��bid)�al��� �&aly!�.n�9֩"�! ,uصw��.� ��9|� �rabAn� alle� � -�# &L"GDP� GTP!?�^� a�of1+perturbs%�u�uun�}�dmorph����'5l�DI;,Afy���a�`amI �z��!:Ceunvx�iY4RM��c|]l;��="�5�L��9L4/IFTOU(n!`2��/��:om.a#ebno(L��3au 1sQb�� =��cumad���= ���5ori%�.ex!e ~72�O��s ( LE�o!5��1w�Jst L!�8,! �2/�$'���M� �58-)u�n�l���V��i�!+i���y�W iliayev�0aEL� ‘-- nnae��M�\e{_aruBcT2�orc?�+insic��l��ns3Aa&pathw��wZ&� m(( 2g �Sonic h.�ho�J[1P5�KU dysQ !thx s%�>�.�PPW-��Nili"P � viry!�~ �s�oFor�axv? �e@ti��degV�u�Pic kidn�J, obe��!~"�8ano�5�QŌdactyl!�Zli� ail!k��1K ubd�e!��(nct1E�@arЀi�9\ C �`��d5 �ie�6r�-U�B���,Zpo���r��[5�1e�Vare�� �>�.!-AihaU�� 4.�E.{[�RAB�rR�ARL famieX�at�|4�2.�"�~-%��ձ[zo��U"�� fee5o'^4� ,&<� A� n�-RB}�CbiZ2t!"�@u�)n%b�8eb5]A/ �D)dX�T!�icAd��!E�$DAF-19/RFX!FOXJ1�?�&,�3"\��a&� arra��- ��� .C( S�n)e<X[2��3!?;�2�m �V[38��Dat@Is/��z!ci m�on�Q!��dS���,�sdb [2-7)��*si�SEj&� f� mens�t�7w�ۦ!d�C!X "��.�%A?a&6=� B n��alo \!l�m83unQed;�W�"% �bful%�q �A!� R�6�*� A�[ $Hermaphrod6~ ess 60 �A�a"�� 60 �*�l�q�!�>�+on�!% &� dendri�2���[!����Z=i�� �lo-/S mo�#c���X� ��S!�/glA���$h2vsoc&�)A��Da.8 Lenvironmentally expo�*sed channels [42–44] . C . elegans cilium morphologies range from the canonical rod-like to forked , multi-branched and membrane-expanded structures [22] . Worm cilia also possess ultrastructural features conserved in vertebrate/mammalian cilia; for example , amphid ( head ) and phasmid ( tail ) -' !a pos��qlong A-tubule extensions that establish a proximal axonemal region or ‘middle segment’ of 9 outer doublet MTs !=,a ‘distal V2 sing2[22!�,Because many � ry genes T8pathways are co=I(nematodes ,*Mal} typesa.�(hermaphrodia �� bornei��discr��4embryonic timee.od 300�k50 minuC0post-fertilis��,O�umE� occur�$very short��a�af��2� We hypothA���!:U�!�ɤhighly�-O��.�M^refa�7 inguishab��rom Vrequired���%�for �Q.�, ��![m�ed� a broader �window6�U�3n avail�$whole-orga��.n���F�[s2[�.��*��co�*is=n:(well-charac�>�!�a%Zyi�?e I�IEA�(isplay peak1� . late-!Q$first larv�e��X show greaA9reduc�p�-�subsequaE=�Ls1rBmUxt��sou;�y��ify���ry/A|ic- �� a similar .-re���� pattern .1� set!�41bjry��on�M�Ds “baits” , rec�ng�:��6.s�-+= $ ( sheet 1!� S1 TE)I-quAjd�$bry:�.:a�i8� prey�w�~1*mA �s acrI �F+ �BE$ �2:�$. HierarchH .�of% s baA�on��.�revea�� tI a��of 34�!} M�151��B (61%=e of�un6V(!n��A� �3B�0We also filte���g�� list!~on � e those � huma\ �Q� 9. (To validate%� dataA��0determined ifv11� nric� fo)�a >12 hitŀ�Q1a!�8 Cildb [23 , 24���s 3%4N�fou�PM &� I-ued%�� signQ n�/�8( 84 . 5 fold )k5T�� a%go�aare^t T( p<0 . 0001 , chi-squ 0 est; �Z�ur��bhey%�!�yw�o .�� R [25 , 50]%6see.� overlap"l A(���f�"? �s wM �� b�� � ).�EHreasoAF%�they ma �,  ly dulnumber�de!q ���;h%�ns� ��c� c�Epr �Us �s �upaK8��[26–U51�No"~Yv6��*�aWd�h��E8..��observ"� ,hemoreceptora�G�v -coupled 4or GPCRs ) [52IFQ�to!��um-local� ,Eo larg!}ab,  a�/��>�F�R� such�]vtqcribed d: � . �st�pr l�stAgy"3��u��ab�d5� d 80 �sham A"FkAssrg-36! %25,dauer pheromA1�6 entr|�e 5� diapE�life � �C ��5a?*m [53A�O�� , 27%� serp��ne)h"����!F� �  7-��}�� �=�� ge���w�I �upstream.�r�s f q25!�!�28 2�� &;-�)AYv an E�F;�3�[5�T� suggest��theirYb��F3emi: m�byC sam�oK,)��)��s)ga~e �-@D Basic Helix-Loop-  bHLHRL�In s!��{"� mV]Y7.)BY�-.P-  % P[sA���6A�We-� at%!ris��f�%��/��%�p!2trail!)a) A#�K6� �@< 1Cn �ca! "qse I �Y"p of � * al"ceAbeuQ��".? C k�O-r��Bpa��ݙ��vil��"HBRwe��GFPa�orterinv!�g� %"ell�`tiz2���"��ub-u� y l�7�(of�� "{ >� .c Hsi'JX , nam��8FAM-161 ( Y38H6E14%�CCDC-104(108G3Al . 3 RPI-4W07G1� �*(( Y11D7A . .J49�y29G6 . 21MAPH-C34D4 .� !YAP` F13E/H . ThAE cX n b�M�6 M�"<� eh littl�no pub��8� T9V mos Y�5_�ny sys��. S.=�ma�pQal,p��l fua ’]P( end�?g]./��oE�)�5�, 49%E-���lEQ����+� [6�"64"-�2�!!�4 � i�".5�A6]xCi� Q! J%� �\"��_$GFP-tagged�,d,��i�1Eh�5j;%�ontras� 049iis .�w�!A�$, althoughg"oolawi??ertR?� �[.N �04��>�Y���! �al2Y�O�cq�ARL�te��_m4104/BARTL1 [65.�*(. �appea2 ����cytoplasdmicro�#�s}���*� ( RP���9l[6. Our.�* �M~Al�U]�)�{ r�?"  � + or "K�2Jja! ��q��YAP E*&� phenot�MAPk t 9.1 ) -disrup��zebrafi %Tnd dachshunds [67–70!�piA,&&�~� �fNPHP4 �~�bhosphory��:�$assembly/c��q kin��PLK1 [77@%�exa"+ �|d�f�&U�aq�d lack!��ed��o�2��accorE�ae O��a\; [���Hra�Hin unJ��N6���nan*���A�e tza-��we demon�^ � !���*E�I� encot"%�ry�|1� B���,Whilst TZA-3k�$��d�TZ2?!e 9j��"@j�#<��h)M^c TZ scafKa�<MKS-5e�“MKS�ule�P�s&R-1',MKSR-2 , butƁ�“A�=`-S= �l ings� �.�))"\ng)�m�� e%pl�'i�1��&W[?j T� 7$-�I ]e"r#"�s�$�)�1� ��add� to�Z*.$�$@.�*�V6�&�.�� ���!&follow�� s: (4��aR�ed)b*i]"�oZ)y (�J�� 3]6 (��s+ # s%� �nti9*ol,_a��%�C!U�traffick���)[10a�1(cas�&F ��&28qPA� $basal body� ]�^!/| um [�  !el`$�c�molecɣtu�oa{is evolu� aril !�*-�} sup;:l&nd"�'ticU EQ� �1�*A4)f�GFP:: �)[$(-lapse imag%n�� ��s)� undergoe� tinue , bidirec�l '-* mov a� �#x5,�S1 Movie�InAW; !�qJ>on�A.� s� throughou���[dif]a?�!�r%��7 s.�.�[-!!phf d ӥ�te�de(is *�wo�esin-2��ki IIS OSM-#to yield�tinct a]Ps-P!"mk-� &#$ [1B7�Kymcph&@+�) �( tail ) �21�.t!,saB IFT-�2�'cit�,���AS��A�a�+gL95 � of ~� (7 μm/sec (� �;a;6MO )%~U2@6;U>��ret1��T4TI�ent*� length"l3A�3�#]�[)�To} �"ef1k.�is truly��e���+�"� .�in+m�"&� CHE-1IFT140���4����!�!�A���Kv[z7E]� A� 2�s&dwit2A�trunc-�hche�mutant� wuldPi�!��2�x.a} d�Aw��h�9-i�of���- � � is bona f�G�� -�=Ʌ "�to �*� E&!H}%p� *_(deficient-w8-:_,൶d�}- abn�)�accumu""��Vo�)p�rM�!�Q�)Dinim��� +� h$ , dL!N.t����- , �ur2��e�so frea ��I� in (eIp-)q��endri�Y� artmeIHA*� ;A!x� ���8i.B*� $a fluoresc�rev#�+�bleachV assaM wild��2�m�f+^E�:<� mob�12N rapih�1ge�L tics5'V!Q�{0o*uat:,B�=0!66�-Ses-in{ �!�-�I/�f(explains wh� A1er~�q�.- ��o�(�'�O�_*- �w�a�1'struc�5>c3m�]۵[a�ain%��ee( gk10�[in�!ge��+re�IaB GTP-F4switch II doma!�>&farnesC-�(al CAAXXifg5&lb 2�)ce*.!'�"Y4[76];�,�is�$�205 -of-8or nu�llelei_out+e`5backgrc at2 st 3� i�}@�to-,.;1G s un&r-}e�Ri]%��;J� �"* 9�bnq�,-Q2r�dye"( resp� y�2�!20Qf�intac�!J0 & usu��brohuptake~��environ��a, osur [77]E &qL*AaneQ�, 6 (52*�#*U �w-��a fin�!wa( S5C�k�KIn"� ��*mis� elec � scopbTEM� �(e3�,=� ry u.<9!U# �B���S5D�B*seMp- ���"/Q0"I XE X,�y0:um*W5(carbon diox_avoidaGa�*�! (�siz!�!KF a[78–8OFinE-1.m�6�aA  )!�B�5 ( -5%��A/� var7�!_"yM&s�>g�.l`0e >3)G ����da�k�� �of�d,�[��&�f�5�uN�AP�I���,�b� T.�!u!�aIWw!,`8ed�Cco�.%brv3 at�E>(W�m\�,��7ph�3ly. �.p lex�rax��4�5om3�:m~�42�36�Ue�e�N72B :s�O EA5%�GDP%(GTPJ28%V-�2![9����*gE�O�K T49N!3 Q95L��A%- g; a�* oop��in�(&�8)Y�(�) h*��))west,�9[8S��E+inj*i@)&� ɵaW'AG��$ ( 5 ng/μsH'.� ( W!�ok �*3*� e�!i���C+�1.t"�l�7<"Lq�-R p"� ,%�?5"a� v%�:(%d) )a��s� "�+ ��BAf;�� y�6a�um��as�:deI2�aa�  ( PCM� )$4�How� ,��9� ��A�) f�'o� a c?�2ja� �5ability!��� ��(n�%� 4)bY�n:M� �(i,z�TP%�� "�"M�%8)Kd!�re"�%�! oi >‘tuqA��%2�(v'1 ��� _�B�2�-�(e�)ɀ&x cl�7'�5� albe:=?aareF31�f��enc�md!��Yu�an2�Nou/1;2�,��!i�ofe�three2�iA WT ,A���,� )!�D5 when}��,�#*� � *y ( S6E� 1�ng�nt. !-~>��Yrib����2�, G mark�!.>} �ge�8�=���6I�!� low�٥譐at F�f; oqEx30 )i�Jly1��)�R�!�Ys!� ( S7%?S2"�a�u�� �%�=1� � ka�er.�)�ndB�3R�#[4im�Q3Aj�� -}" in C � ��A���� Taken t&`?�<e�� wI.GTP"�3t�1tss��^�@faa�t�@.��#!l�.G � 2M� .� �remini��� 0&�RAB�Aj8�!@ �!�� �s� GDP-�ev,a"�m�olv=RABIN8T!eguanine.B FW/��nd� ome5�f!C"!�� [8+$80WR � " 4B�eg& 2�?��"$��n���loB �8a  * ( nx77 � a2�� �.t, �%%� E�E"��� �%�;E�!��.�� ��#��� to a�2Be*�=I2� BBS-mss (Fa� i�e� on"�� }�9t,� v- ���12�atRu�� ��a�B�eb" &R�)bo.in-�!�n� �/ ~.�FreI�F,� lu�-W A��a&� M&i*�=�>�.Y�I(J��,loaz o� >q� er�� BT1yN��� ituK "E3 �A~��GTh .��"k$uB81A�umAh�V.��W*5�[��.�� . As�4m�of�-fi��!��@Z &��r�`�" ��: ,2��dy��ώOP o��%�1 a�5$ SA.`result�,re ob� t )<3%/ �+{-*� �,&�(  6a�9D�g<&x�weakl�Bne��t"�&icu ( S8. D*��R.�*�&,n�e�FDc�&Iro_g}�5�-" A�F^�N[7�#o�aest&-4Buba:" �`!H�c�M�QHu2?A�YL( NJ*B�*�9�Z. ��w��:[=.<*�5�2�^[N%Dx mph| h�N)A�ofq%��m�N� x xj; 2�TZm�Y-�e.*Zan�.^$ed &=%�.�!pnNB-�*( seam break��(‘unzippedP )A<&vTin��# prot�La���<&a&A!�:�9sG  p{/�9!Y��sheath-�� :�is"�Een�<d!N�B � less�Cly bundY:2eAls�F�-�.�� ).HI��;�"hden$0�po�/iG*q�l$ w��&�}matrixer�%�%Go�Fb!��I"�?=E �[4�"6I " .�>jn}��/.$)�Ot!and%��� exhib$]�.�D %,hP��ed vesic�&( MFVA��� �A� m � ��E:� �a��-�. . S"32�ewA6). |G6�-5 �L-�B�*4� A)6���:>)E=��*}!�,G-!�W�D� �<%�.ZobH7�5y��Pto>=R�K 31� is xng$(!�-%�,�5 inst�6la% adjaA�|/S,�IedAY-�-g=e;ge��� O %.� r3W&nIofaus*A % .jO-Gc�?�&^O� � ���� �;M�MFV6f Y%��DAE��.E k;![pla�J n \5ou�sE5�w��5N d� �8 ��.Blik"A@ a #@(�3ZP" "�8ur �>�*� h -l(I o�9eVA� � �:"�-� *.� ( S9� � �,w%&�Vse>+>/I� �n,�1��4 ���.{:"�+e�N?5< . An�$AaU)��{�+!Y�Q�����&( .��  ���U�M�.�:�+�$O+!Le&S�� 9� B�9 �ġM6��~q���%�"f:H ~2��e |N] |A�ac:&�u3&U&#��e�� ������k$*:� +q5*��r�#� ��4p,�%FguvM="�"#I��a:�T:��[�G�2�&*m�!6��u�W�5�&�"{.kUo[-n!s �. M'?i+� nC<1�.2�� $#fJ!�� -non.�{�� yi1c+1A�Q\Q��!RO%�2�I>SW�6� is fashioJ �.glM Nm �tsocke��p�-eC&QW�Zd�`n�tip�cl � �#&/(Kmz�>�I� K\C.�;� �#5Ba �R�p � m':v ful p�t�?�Zyde�>{0doughnut-shap�4���-G���/*�cut� %v��l�- �6�h�<.NT���=!�!�1M�]Q�igh m:,�1%�ge3/���� �R 0EH�EG�7[4�54�,9;#ItA~ls�%�� �z�#i��7 )a bala�#of�exocytic�7Ta�We�<2* � $s6ad ‘�@FJ�.ieNT(� F@�0-�� :�mb�[9� B�*teg� X �\�"� >*�VI3��&�� �S�enh%L 5.�5+,( oK>� ���:}"X b�s6zAr�P)>�%��� ��[a"��$5*E�a[��CB� >�w�.�Rg�e�.�6V'idei2N� "� e�?e�M�e`.���G7t.�1A � ��a Rq��O� mdq��� �K m2{ -hE�i�)�-x��&e�-��Je��tra=u�Grel _�s�*iPs pur? a�o�%N�PVq�6�MaIyo*]b� 6 � In��%�noE;,i"%H �F:ID!6iy2d���N�e��E�5SUf ect�;e5��er�b�;�"#-�A�le �.5g)ea�!� s [989�FuP-� will b��t6�d8 *o ��6k%@|�i4Qy.�X.Z5�ici���&�aA Q�.�" S9 � %qU%?Leb��5���sJ.)!�*de9.B� -�� �.X-�1�\S�� e�) "9c'dompensU!Y x�b2�-�;N� ic: � *� \ omin���k>�vq �()s�%)/cbAas ANe��)\aI"U%1��!�2�I *y+"�F ����Ձ�m�� and/F�z p�I�C%I-owR>eam-G0Sor ��5 berr!@� }>a{of �?Png� yJ}GAPx\S>�  c( GEF&co�V&;!�I3!)�4)(To� dec�*%hmcdg3.i1*g�0vsEW�u=m)�!�physia;S��v/of>~f�Feffortsi6�FA@�5p)Α�ng�U� �`m #Rue6near-� �F0&Fecm`V& unkn�d͠%�f|%�%tGAP9��4G�J!� EV �� T�=!�IFT&X s/"� -�1~A�rop�`e�)scu�+be8%� � u�VDwdU� hav�g#^A�ar5a: lapp!mQN�AP ��C ?a2"1g)c+>A��A�i�R[\0IAinferr��bMI23�RAB�J�Ja r&� ���lt2eukaryoA�-8A�$stor ( LEC[93 �8 PhylA/j50�428� KrlyA��to-�(�L�&�߱��ex� �% v!�A<isperA�>=+�lineage�.0.&�+ majoEN� �Q�nd��S.�9 )� �U�r�e�8rga�a� atIX:�>�S"�Nc=�%PRi]!]d40g . , Chlamyd�V�fd Trypan a ��}nei�Ie ?Q!bOF> in DDEphila=  �2>.|&6zB�h!;�27q/6��!]�"�'͞,� d*�&�#aD#� �"�a��mH r [8z\8'9�Gw!�2e� �1I�&R' w_?�����j �(��! .@�3�9!�U.B0227�!Ņ&*� M5$flagella [�< �6�4i:�o$6r9�d � trumqEC2�ɛA!��a�FKti"&\��9c )NI:pat<T !�9!F2�NE�.�#a YN_Q7>�O%�"$-i�4f�t UC�R�$]]�.k Mm�X#is \]]W 8vic�rs�$i�oe�-'56l�ZZ4A YxI[�~e�aemf n�\moB� !M�. W�#J�* a�[:M-c�27in ver�o�28�51�� ��# step* ?7� � �'*�!p�Z\�32L)�‘&a �l)�-�q��JSib)3F'�:eXC %,!(t*Y�$9xEI�"�`�('�by| A7�Gq -med�l9��$ -�qs�VR5x?�D^ 7��, yet >X&�Z  g�S-i0 PDE6D ( cGMP�@ON�H�P2'$lta subunik�?immunopr�/ �[105]�Q agre���t'.�," �� �oeI�cop� !kUAr�S201=A�10� In l@#�q� �|Xa� �d�*�5, - "1DCe��pa����)�]���E$,:28QI� �" ���a� nd!@ak�-��X�AAF �<W& i���6p���-�GU:=J�v+�.�Eo�)�uT�aq �Z2ilM��o help� D�se�3�e '&U!�%ry6A�WR[7� �con>�N . We�l�aU�412� gn De�x�.�N���u�Ho�*rchkNcor��� u saUotQ 4S ed: R148�_, F38@`�SY75B85`1F20D12q`, Y41G9� 01H17!�C54G7i`, C27A R31 < C48BC` F32A aC27H5 . � T28F3 .R Y37E 5�59C0$ F19H��ZC�lG F35D�aH01G0  B024�0K52 C02H�� ZK41TK08 �= F23BIVY105E%�46F� K07G�c F33H�W F02DWBa, C38fa! T26C%`I T27B=Y110A�a2�ZF53A9-a M04C � C30B|�]C09�X R13H�aAH F54CY*W;c]-datuF��Uop?s*_n.PBa��r; EE =>�rL��, L1 =$.-L1hvL223344�YA = you�.dulg"X1m [* zA^"$a$ valu� �1eC.�ndividu�O� �w�E�scompu�KA~N RPKMNads�  kilog7per m�2 on ) s%V�Ie��97o.sb,41* �nlA���pairwQfP�Yo?6�u�a�j a[sDQlIX363J�T E/ d�&�{!�estim��P>��o"y%f�$� capt�wg�A$���Q�c� se*�Y�4 ?,!�re�(��m@Hst�&2641��]*#u calc� �sq+XE cir�[Jja,-Fqo�p9�!��v�9� �.Hs.�  A�S5!�so/"�) e�.��a�vGyU %ag.Dkz�" MqC�%Y1=l+2 W%� r� 9&10^k� �ice6�]v�\�j>w *)@!�l�g�eT/.���uto�of 596&mow��� trenF"�Vg-T*��;2�!c�{oc-�+%^�"y�VNb� *get ye�+[�2� sub-�J'� �! �%[e���t�"�� Masu ed �UhR�x!"�?1�hZpvN�Ml��E�Q���3�ag�S1��{73�d&3L1_�a}��mb"@ :�wb��'�T�q�cl"2�)B�� & 1aOtop.� � d e�� �mw���d�fZB�0e�ue��1"o( p <�@00�H1;A�27� �$�2}q[TqI#1000 bp&�n�=adr��d�$� >�nj x! bait�)�b$� ��?-} MEME� 108? �4n� �:��mtD"QjE o"�n Sepa� "gCB��lL4/;5���B��su;#�DRv�X � "��30�>"�Oi�%�E-�JvTomTomA:A�� MB�v Dto�� [%c. IIj("�,�^;/do&�DVn!�s�e3�-  ^a�=�d)D�u�8>��All&�� iMa:nd cul$�$20°C�)"�$growth medp ( NGNp� s!i3e�OP50 Esc�chiA]lim�%$dard techn�s . Sta �*��LE�'�)��$troduc>Vns8toC& @b+rB�; mksr�mok209R:,  2 ( tm245-5 3100�mks-3254�:�O gk67M!Unphp-T_ tm92�M&��f�"��� ty�� PCR�} rime��vs*� upon6� � N�Bristo�JF�c�S( e181��A"�AN2;�E0[P ><::gfp + Punc-122])12):: 6j12V1( �Jfk3^:�L)j:4�::-��V>��VG�VG�B;�M*q?A 58[arl-13EY +�eFsu100�)]N;Is[osm-66R" myIs[pkd-Q�J�nxEx289[�m '4 + xbx-1::tdTo@��M 475[!p5� + pCeh3�jN2! 869[�m#�p ?1157[Pbi�}p�G250�ք$223[maph-9��2306�yap-1�y- 2619[P�n�::�L23LxjgfL04�q��26P\k�A��628B ��� 654[Ag%�=��fV��E��KB��L�2l�L2��L:?�M��"x�MFW^2|y&�E][10 �� incuba� in 200 �R of DiI so"e� nvi}aen�al�1:0� M9 bu�"�Qor 30ʼn8�R eior}re�]�snF Zs k ]�5r)& gj t(" moun�Nl�t . Epi2(^wid!�cWeG5B\9Z�\d"q mage%u�YVT!d�s�1��c"-�-=(��e)-�,�=�=�18 hour�L�o � -vs1k %P�"9Vc a grid reK$cY �s �osmn)*�Xssa�"�6J�w:ba r� 0of 8M glycero� Sigm�q�� B�v� Dl Blue ( Alfa AesaAAon unsR�"7%QeWER < �hrrierj >#� �. C�tax�1t!EE�s� oward_Y(oamyl alcoha � &�Zuus�aI m n�_x !y 30 m( nd 6 w#;m�� {�C/ ty [113"1�Fa!�"�) 2� bwfpA�l��� pPD9�67e�8�9an 432�fra�sA!d5’UTR� %��=h14]xon 1�(t&thymine> 8o �O� ^�reR$c,A/104 !] 4�j�7:� 1997@395�#����y5!��mo%��o:�+!�t�*�Vx, � z  ,&�w����eUgTur"�(�z�+iJn�0E�5�!)�a�U0D& 1373) 2317 9-�45 r.*.6�5 1�%:M5F( in�M341t-p �"Xby�6�AwB�3�A�^�k 04:��,I'bp�b� !�^9.�" � 7&��)! ry�ic5�r970a�-a�!ՀK�!tI7A� a%r� ,^G70��9Ai} _a�xonh2� o 426x����n"V=��(Y)���m�a!RM(�9!�^!�G���, ��co�8&g)��bee[�>(+�%fy�3!�5re��-IB�!" }by�Fto�O�G"�� [( �) ��!Ha!�c^�.H��ene���� =eyB��1e,)Ł���2�IzR)Z�X�N�-��2�gonadai�%�N2�]���g>1M�^(!I9 scree�$�x�! �eny .�>� SBqn�:e�SV1sYb_�!�wS/7pt"�Y+a�.g�!Q�J 50 n9_( �*s^�zwI oelom[?!�2m \pRFEro:) co- ���Yat 50Q*�fra��B!~�t%� anaesthetي�10 mM/ amis}in*� ,Jp 78% roB)� iq"� by e:� ڇpin!� -dis\o(WaveFX; Quo�0T �7e�k�*IT�e&� ^D8n Zeiss Axio Oby r Z1 �0a Hamamatsu 9�(EMCCD camer�iI� S �vi�f��%22qVolapfPerkinEl�� All**� imAk9m40mM t;S-m( D no.5975o" crob" ( Polysci�7s * 0087Fv1p!�m&4%A10:�F&� i ~0)Tupr�*,Leica DM5000LW5� ; 0in~0,d Nikon Ecli�sTi9�4(a Yokogawa 6 �+( And�:ev�!Z%� �ac�=� �qge"��de�1-�$( iXon+EM-!�, _Ufy��ndalyQ Up J softw�IFT2 ,-j-la�(W� tiff )�XA�Vf�q"-�6IW)pat�mO@>i� 4 fp�fy�&�r"�Cv de k[s-#��� mult �e�s�cy)� �K �(( http://ic���+ mage�)i� org/-=��s�`r� �%EJ� �CFl��n( FRA�J�:�)�2�:%Ql�2tac3)RPA6f2. S�HQgbl� �a�pulM��488nm�9@pt%�xd�i�vA �{μ!8%-�recor!imrat\ � ~%��B�vl�1`Km.6R%%SSmea�kp5%�.�6 k�0�E���-d�tocol� . Va&�&n5���Zre�'A�� �v��sig� ��Sss�B �e��1. Y*�'�Ifix?Ss�wed Adv�$.�An im(�>tas2~ADb�1w1�,g$�;out�yworld��Gu&DG�& @4d�ip'0$ver��-AЈr!�onI-�7s�m�hO�1p�acst�eJr!I<'uli�A=�8“decod&}�Wt$�� �<a�WJ&�X+�be�%r%Vb�x��acE�qiw��aB"� F spik�x/eB�)�1eoI d—�L�> —rg1�%f�a#�� hippocamp�:�Qi�",H��,�'�#w'�]|e�Et gZ)l fea�"= *�nE�(4|"� ��N��fr�;";$s%$,�!�v�!l�~ ��E�,p"�bG+�" rack)Jn�t'sa��4 . Un�=s#�es�C=��(�9�AucPpo 8��9- !�v�/+��s1oE�>B�'!�e&� B-�p2�&��%�D� 02���y"fin�@�Dimplyht �&%�I3f�"< 21a�Vp� a�Af� tp~*�l�2I�us)�; t!a�en�gA�i�to=�dow�/l��.� s . StimuZ.�oFjas�g" b�� � 'h w�=f�Qt�V�B FV[��[މ[7�;6;jY�rel� n}�riori�um_:B��.A�n�N!�:�umz�(E�"u;Q���m5y~r��ly&N-�L��U�~Y��yE�Y=�x>�(��“a�pdes�2jm�a�Eet�+����;B� , tu�Aba�,� -triggj��*F adap�����kZ���� robajH6+�js.4E�yH)re m�.Z�Ű�b%�5L� ;-5J��. P�ma�>g�'+D%�!8�?��U�F O_ ou���s,*% "Fg�E&�.�Iu�� E-;��p Cst���"B � How {A� �do�7? WE6m�=�G� n� devo�t�ov#/!b"LHclauML<9� ���o� ingAx�;tepa'E�[1�*[3*�[�,N i� g>r assu$-i��[ͯ�((�kl�o� 3y@(f��2��?�reB�5`UK&��!>&�J�@�)��� �"�7�B�|�m �Fsynal c we�a~tu� *�F.�v! leare�A�to��Sm���}`Z���S �aY —p�Hcul��in��u�go b}extd: rem�H[��12�K��Ml8��E!q he qG) ion:�=anythE���f�H" Q5U a��l^ ?H addwRV X�h �A}^� �2ro?,!�snD<56� rQX)�Zu��(�4�B��pyrami� i!y CA1%�CA3@dor{��u�at�!srHB5��*> — ���—AOA�KHl��l\X[28�[2 W�ll�`d�t.O!�� i^-�q�� aAz� a@T*�s�s&֞�EkD�6�I�%a�� map��a �!`IK��n�O,Lvj�stn =s' a�� |sp~e� Adfam+�"c|�a�][1�15�"����QNgJ�"r Mu�-��:����[1�}2i[25�wa"�<t%qr yunU�o�#y s_Aoutpur (O U ��cor� �$6�)�T� by bM"- *� �Gl���r6 E4. Aes:�3�@HGob����F�5y �G�- a�@��:7�S.� " c i�=—"� ����^ ���^de1N �D���o d"��j���I�x F�%m�{�f�ldof�cantaneP2�I�YvC0Oim!���!<� ece7-�a rhythm ��sVv m�� UM�e:�1�-e�/h �I b*v��J diame|&.[a�Y ��H�"��v�f?��� ]��8l$p$� a vi�7(?�.a� ."�����g(lex dynamic� * }do6Han j� coe�h )[26�3���*�ow3y�=taDs�_!�orQtm�A�#� � �#�%9�� suffڇ2��"� !=�4n�|v�aU��bwe*vz'ea)|a�d.��tS���8�>DQb�;i�gvS~coarse2�popm;Frk ع!�d>col�` �!����r!ae\ 1I( ∼2ٳ�teoal��;!/do�?�Q!�m�D�C:�i�����(!� "X' CZJmesca�� de�FE�6� � �(w �5� �Verm [3|3�HW�&��)�/=lXHA >�"5 �e��s)6"�is enoK�to R�top�An�;�.�.�geome� &� i�, Q|��!Pin ��F/_be�\tha�o6d �Q"� byM�_a6oo!rom alge c�y%�gr�tha��� )R�{n�Trec���Y��,��.2BV��nx*. ": !�n��u&.)#�p�%Y ship�)*E �)" ����A�"��:�a!ui�D inci> �v �bqD�ach�#. MoreG(>o �� B�\ :�/��hz � "�AY!8� ZIw�ty$|�)�-oscil)B ( �0 Hz )|_�9� !�i륷�Tz!����. Cw���M� a fe eta-cy:n3#a5A!d�pxjo!S\W2�6ia��fA� ou( 4bd��W)"�a�Nim &���ӹo�l���A$ignf fina8 !R!@�fsL�Na,!��5�� .�,"� )a�es�� ,�^5��� E!k9 ���pqe.O�m�E���(��tA��%�e�!�a g�Y:��in@:;-3q p�ng3r\Pj� Ie��Ho �e�6P.  .:W� �XJ�a)&�NsQ�X%�a��e6'themsel�A�g=C3t��� &6E;2.����W3>�gQo��`t��.?e��!�nK"+�\e��.d!�hA',���2 q�]#a�!fB�T ific locIY"Dd!u��Q,.'2H������2��ve�Z*2�]�!!isIY�n�A��O:�,&�G�hdR���&�YnBaY quit&�� �4.� = ���%S�� �++aî�2q2�$q t6�[�*a�,��aMVh2 "omni-���/o !�e׭�3convex%�\G��l- y �s�*�.#�`6�:O � ##D 4���foZ4ra� ��0 open �2( 9+M�P� )@ls��@it��es�� !!��M�.�%(BXdO"X �PVl�bi�A_ ��rob1�4ub? �3`  t-%�-�. *HTe �j�Y:N�Vea� C C%�B�alg�]hm�En tole�+$�U�@per6$ag�&a�f�v�� l� �jsoVNl� w� "A4&�A7sC�& InWcZ� �R �qne H �m�ayA��t4�2�K }!aK�:��>� .{i sqbec�pr"a�e�#m]�f�'�/a�"� ���ft�  ��H"6� b“ns”—&+,"w��i��&��r� i�&$ g�*6�ae�!cbe!f� �< lat~����*� �A�au |;q[l�7�"ryVl�T obv�6�%:.�&�tre�$ɍAob� . !n< �!HathZ��-Apf �U &AN���j�Sr� �(�S��/J,AGbwt��C^��!`t'(��b��. Two.ai%�/!��quiva�( homeomgk ic )�aVM�o L(��- e=�U�+;Y�-Hom�yN [3�š�T�NS1St� i=Ɔ27r#�%�In.�� dimO)�0!A�2h2� H1 cv-�e*�{I�.F���r��6<7H�5HR…| un6gher-�alu� , .��w ����U:;�'um�a1_��%@ �.llK�)t��nE��fla�$wo2�}_!BT�] �s<��"��x���/���1>�Q&� A;E�.�S 6� ��N� M��� �QB���eX�—� �|%O ��ȡ�J� � tui�!��is/k� u�w� i|l/ig�M�2j(w(y{.�EO6��#p O� .+A�Foe 1�/. Inspi�byee�oreK^J�R�%�) �/l/a��ced�j�� A��i�wQ& ��=���!ndem �EFqE <(!J�uG]m net� s [3R@ize&�* u��t�  } Vz�&t4Et�iV �@ [4�<hZa� dey4b $d�R��u�a(�"u.*a�� �$m�yhe%s]m2(2� ( � u�=)>�. IN.�i�e��<@T exac �Irr���31�gua�l����m��ic.�q�U��>3�#�T �rE( ,�jstocha; �7 �%, �z�lw@�=^i���w�h ?(6�P!>e�-�@A�mis}2�t!S�^H non-Q� ���2�In&"s�f�*v��v e�-��"o�jA�  r&x ar:�� at 5s�$�#�VPC �*#noH0. Random-walk�D or�(p2g]%`P��C!�,�)�Lh��L (*�L∼1 m��N = �Y ?, 4Qu� �Sd300 t�!�itf��s�p@C70�2-N#�va)Dradii (9�b915  cAWr%Ply-�$�@�2�l.�*EsM��9p2����e�e�9 .D%�� � � )�%��?"C,a �t6��s����4�z%YA1g*% a�y �Eym$:eeYQ��� c�s- e% ey f� Ne�4 ioF�p aS�!��A!Tst)���m�( HAZIV H4 ))$���AIF%�dRc ‘�act�if%�� llBl_S�/�W� �&�B8�G‘N���fl 6� di��j�",(c �.�� ld� i�i2=�:�7^� �t �� 6�C\ �./�RS� c5c!Bt1&6#) 4tS"ad�gf���]5�g�f�‘�&�!a^$;�X!�J{e`7�6�mp�j0%�9A��q)}�%=�U�r7%a�ura�8n�,2��3��e�$wor]�a2Ayiva�i�su>gt�ca Ibwe'1 �& Ae �_"bEB�5ea truc ���Oc}��zZ�d!q5�iaSG*e�7�v!t:Re�=*u-6���#a��'i!��ɗ����-�up!�5%;!!�b<. 's59�r��.�w%� >an halfWE� �M inua.oatIl�e -�� �& �esholtofa�~�� Qr6"I%�� 6")��&��&v)8� ���&`" p%�r3u�ra�-ili��_5 sV^>��� ���de� % t� ( r��"�) M �}?��is �i�Xz!2�e@�E> �A�����kuzaOf.�!A�m\re�"d �&�khuffl�7�� s�by �!�"/"!ye�V � *%�&#��Wua�����y>�E� ha�<nzeroe=erB��gg�&ng $-.�� ~I�nJ�Ai�&��-�1= ��X)g"t �&� ,2~2�?s � �aR*Qei .�#�*YpI|'���%aA9���t& a!�VpUa�W_B�E�� w�4aV}�LAjr� W�$F�O�vN�!�Ie�J� �D!�,)@# oiś view!p F$a9m�&w2a��3r�3���.�H%t� a���B :���L��&“bui�Z��R� a��8,�5�izoh29 � %,a�un��?>!*�&=�S&kA.c�7� m��%uK�hip �� Y( ��d��i �A�far away�tu�.}g5�)m�*�@M�wo2}X“q!76�$,;/��&���6!�a�eyX�ws.���PE~Nun�2b�{i� y� A�j*!Eg�* y jo�=��-E� �'!�<�Iap�&Y�2!�3v���Q�6�h�&/ icit%�"M( �� e�n��� .�.X�aɱ�6 E �$7s� U���!�%�3�M�t�}>t� [)�iۡ^�y�|��y'x μk�?ig!�!q�1� 8M�vealt !.�">�+d���% �� ka6v2a� ��uF" Ip"r',�shevb+eriv�1%�b� "� ,�i�+�4��99����ng�2��)�PWe �qh!Nempir#)%y�i��1I#!@�,.AŚ� 1N��30�ly-���> <�e��! nV7x�8!Ivix5� st4C μ1�Re&��F6��0 XiJD����x-8��ul�o4NA��S�V��t�J$.�}� S3`��Ere'�Ad�S�͡*hard-w=�/ �T!.C�n�B�1a32ny.�arrangB9>��@&V72�*F8y���WA`�!��r26�)E��� %�!�s���!m!�X�h\ re" �IS gardr�A��;��!��H��/N~���7P�"�8Ѭ������� �|�R�,�nn��wo��tic�mAR��"hiU^�a�.�m"� sum%���9�3gL �&J+A&�.�Mh�%&?��/Fk���}a��btGE�5�DZ�Ia8.nn����Yc �o6�eNV is ��L2�e5s9��s)����>�3� ~�E� �'i�M�"T'��.�%-G�H� �:N��XY���� �y s9  D�puni!h�9t���5�|~[� L ,� 25 L�,% �F�i}~�����+&1�lt2�P25 cmY.&���&E"�! m)inN�;&d$f o%��GV(� 23"u[4K?[4��5�:Ese�٭�#S�@��V;a�@;�ksU�3d�$h�M��F7� F>r� �q�56����Ck% ]spapQ%� L×L2�>&��E�::a-rx �ir�K�8Z��>S3���7a erroY%f")'i(�a��LV�)!�Wm�J SA)F�y!�_9f�v� O JEE�A�J��seeu fa&�:h�^;�t�=Ih�R6�5e�M~"� )�l��ang�,n\e�825HHUo> ��mi��g��\{VG�N�+� s`�G� ��r�!ia�J�&! p%�"=;�'"� quan" Q���c(^�B�misib� R�e8��;��JAl3�)��� s>�& >i��� orig���� �kbFVQ5 )S3 I� � �� &���5/de�0>� ��a�+ get�(a�w3%��1� 14BJ 5� Until now��Q���no�2;j˅W m:uhIv�),ɟNT%6 o�1"� �V� �~.&,kO*( �h�e� �)�Aps]�ej1  !A����looks l������N)& [�H , [4R@g!�HIse�=�ea���2  �*�.I<�� 64%!l � ��)y _ .2/F�F=��5^�po�>*�+lim��a�� u�cud'[�J-�*n5kl%t��˥�&�+we-�й��� *-:t5$�jf�Vi)�i��Ia_E�� �,r>�o� �$�Xx �Bne�2aR�ex90J@-�V2�Ple�,� 6� P���E�e'�+�d�f��B�r �?g_!���4�f0Ca )���}an� �k-A�0” coding sc�yheme where each neuron represents a distinct location in space , this ambiguity indeed poses serious problems [21] . When Ms areqled by cell groups , however ndifficulo�s easily overcome . Although the same Omay fire� two � that�far from) othu.�`considered neighbors only�he ca:�they sh60a majority ofTs0,common , paiG o with [,one or a few5plA�)�guarantAto9� dis%0po �y�internal,a-In orderI test/(performance�B,geometric re! trucCin % 4of multipeaked2�(, we simulaA� data!�`before but included small�0centages ( up�11% )nf$while keepEHh!�$tal number:firfields cA�+environmAI�A{.!"thA� �E��als!~quiA#Q �e)�)lepF�}Lbe sua�ientlA�%�; �wa%�5�enable%Q�iona�ibI/`( see Methods ) . For 140��found�!w5�to�ec8good ( Figure 6IAn exam�]!�pA�e�%�contain!h10%-F#,demonstrates9NalgaMhm natui� sepa'e dou!-�� A and 6B;%%� �S5�In part��a�bot��mismatchMC )Oa�$wise error!S"Tremained approximately!%� rang!%0%!bA�I'F)�%D��!^<��9=Ź�I& � 5A ,2�stead�� decreased�|in�i-sa.^��hmeasuA�by);:!~FJS-�S6B%� This is b���6w�;not eno�t�-�to-�-e� >�, l� ng s���> thin ;L failTbe�AqL�2[鴩 i[ �ia,�thus �Jv largLtora�e�Jr�;u'�afac��e�isrcisA:6p��i�ohetopology}&to �. WA.�is-)< � �-^.  �ţI��an%8 etec�pur�E�{graph of�Ah�Irelŀ ship�Rb� (i/�`aI%=M�3a�i each��A4(is an induc!cub � whos. tice�E��x����. Ei conn �compon�#of)�d&�s!�aAN� %Z�,7E�HavA.5<add�al 1s for-rF��!t!�Lassign auxiliary “=�”� substitutI>origio� labe2 uc�at)cN�f�I. W`n buil�W$simplicial%Blexe7!N�homI�� a�. Regar he nknown )-�%]s3provi*an open��)� e underly!tɢ� e!wA*tep)JV!ib�ought)as makM�minimalz si��refineL [45]2(�9i9 hippocamp!F"�  activL , globa����ica(eeŬa� -d�sioA�.� as w� a� accuAf� of physfE.—� 1�a%�'s!�e�%�in it—M1infer�f� spik�~l� ��ei��> ,� n� ��assumAtat6�existe@%Va��reotyp�� ; a%led)� actu5Xm1e ny�� rior�7epend����A%_T �b�� ed .��i{��(l framework�� !;(up stimulus)Y� |or ‘cognitive maps’ [46] ) u�W%Ja]%Xa�Rv�|�Lgeneo#opq  ń��e|a� rsalZ|s��ven aft= ba<��& Q of �z�( i�e!B) must!ll�d�!["sw!y� to��see��Va�6j� loo���F1 mbed%����V8�cJesE (mean no furI� ompu-His necessary; it me$reflect� e �our visA�systemA�d-#C . More� 9t6‘e��)iA\ateplevelpro�!�e be�properti�d[ ivid��mee ) [usYan) a� teregly- .F.'!rN�� has�\� its st� ng poi� it d1�r����ng��� he� bypasuANa�e�a   . AtSst gl/,%�^p� erhaps+ inis-�he!��� !�0in [47] , [48 tK%a *�eda "k a��.��Ns , v&P w9�Ued~an �Q��,( sub- ) net��realized����u�~J 6K����y�t) a synapsr �� �-� �co�Win 3tic w�tT tweenn�!�� rm�via�LTPG r��rul� � �&|o� 0 would result��bils0A�A�he%Ytby%,�X$trajectoryAhq8� ve%|2;U8! A�n!2'yAx��� a$.�)��'�Mlway�����m�A .� X 'taŁlyA*�ҡpny gi�Q$���, sugg�( \� �A��r suit� Y� spec� ��s e��� �P ..8!Ve�j���sA� eemi�� insurmoun �challeng�? �Ab�� digm��� A8mi�� �K�toyve >�I� ntrasH�D!�N�)S�QaQGyr�_!reliab�- �a���is close5 � rit�Hebb'���9mbla, [34]!�n$a lit�S��6���I . Si��ac�ey�Av ��Qyp!�,combinatoric� their�l����.y"�U�%��s!I��Iu�A�a nuis��a�����%i ��ɚTm�B� .hs!>��!�e�, unlik�Qe�of Koh�J [49�9��6�b�ex� �irevealed�unA�n%�A �1�� n!#N i ��Eoic�(�C� � u�*��alt!(��o6'6 nsen| �a�eo�hea�� valu��f.3�� �.�i"l7 �nearby5Boi %�E empoA�2���/ W�>b�ZoI6 V9 =T! _ �7in-5s [50]� �6%�u�S �A�arse a�Q��AZ!��—!Cse)�a5m�—�fullyNloi%�4face at cebW=s �� lap�recep�>Ō� T�Is�4i Z $ po���K a|��n��ruc6 w- eam br!Ga$2�� �!X�@A��,� )�J�y~��+����spae�per�oOarv��equѬune�U�N%*�age�an.�:o��!t�{�����Y{Hhig�.gde� nd��VH.����a�lowerRV� �dil,7confir�"bE]�!w�� evid%#�(E�.��ei�;��A�Z9EEѐIf� ��em�h!��)�# .�r�+"PE))$almost cerf ���y��alB�!tribu=Fw ^in� �f ch.� s uniO� �dom� wMA�.V �8ste%�had��%�Q0]�:��=Sb�ar;M0�<�� grea� VYNLof �md*�i��th� �E. To �ens<�T� �miu���Z� �P}�a2�/6��AQff�J� . b� repor���*�[51��[52A��!rS� �/tqb�� %��=��� re fl nd>F;*<< easy!g� ize%�qdu�to:�h�x2� and/or cu�#A��:three2B��_ Y��gi�n in f6bat�Q3�QT\zy*~mΑYexactl� sa#a% oct�es�obstac 'B�2��.�a"j�a"Ac� 6bef�manner �8#er�Mbe�$�S�fz!simila�!�#x μk ,e;uA�i9>�s,,�0bi@%C. FRm&!�]believIBafac���b!#|JUt��Z.�>Jm7 )9�Y%7ful!�dis�!new*� |:�2z neoc�b�:a�im�aZI� � �   :e~:3 �ppear�b.� �� dept��tif tI��p2����ob�q, rtheles��I��orN��o�&EW!Km��.tog � q�:� ���iA.�8ab�(!FU � �ncie'of:5>�)hQ�%m t�.< world . ( 1 ) P.� � omni-�,#,| �E"��$�*�  ,��a�lim rack�, [61'( 2>^�(previou&a�nd�stE]. ( 3 )�t6�2�6rto�[)�� !�pt�0tra��*�-o4 oholes/&�!5�)��y, iame�-2�Jd,=(' ) )a�p�8el�� ngl���.�')ponvex\�- BackA�!3%%is �.��av$J1A��8]�B��(B&rough ircu$-!�%�� sizea\W s3 G Jf"hu��42A�Oin"Q!e�groy%(Mf (a+n��tadmonit�$ limi��&tI,�INg!�.����s6}, I�� .>s��dQ6�2oE�%eI�explo!���V�|s� [44!1yI� ��}"�*E#s�#A����a� a� seg�%A�*A��3<"� �Ki3� bq6A �/e"M-3��I�s��P$P�m)$=�s s teLoI`Ur� lli�� hape�c6�4��4 ason�*�3G K"� ng �>i �Av` i'}.���0ni�, s�satisfse cr�ia\'�.B�-L×L bo� �or���1*� All r th��v pj� � *LaD!�l(��$ly L∼1 m�*X ~!%-tU ! �"b%z$,& e� urse�m,5*�Z �a�[. zp�%�yE����4(�0e�&1�a# P>�61�A/�&:A�A�u� ���� �'aX �resolue�,��tA9fe�al�7�� � |. �5iIq�;�w1No ex"�a V� ��e%v�#-)�EDse�2�(71�lo4>��a�  ��!;!vnth:E H���6 ( n+� -fol�h �Ef%�u1��J �,m�.�� ��es��Wfi�'6� H1a �<:|3� ki�. nd �inguish"A ]�.��"�8�"44��a�1Dlyi ed�- . �&V�(��[ Rb 6�sle>$o�. H";;w'&�*e:5s-�H5gn�12 heck�@�c�A����preI�aQJ�+*� �\ha�dU� .'5�u� p9� �$� baI�/nif�v5%��U/H0��H1 . No>2d highmJY~![�"a�s�Ji#,F�!4mp&%) T�U��dW1�U�)1E�{k Ag!�.� !z� ��-�( 250 mA�� �!;o�")2�H�pl � r;,� � ae� ��} B�i�bin>��i4!to 2-.��b. A"F�3�"���@t#4��ndA =b" :�j��I�*>=nis��6abiYa/ 9��%�o�� ! I�imp� aa�es3� �'�pϩ����U�!nau i E�ic�!$above base, ��%!!�6]��L Z�t~5b7$�1�&� �2�.�Y��a�W� sO�!d.ENh �aQ}*�$v-+au�#in RN��2B�!+1�U"�)f�;to�9�6T@duq=! arbitr�[ choi=9AE��.�U� ��binm,vi{�!��en shif��# a t�= of f'�K19 /'� ( -�"Z�e� ly{ &� w�t�!Ts7&�s"%��J�� lN�opoo^(a��E�  s fo�Awa���).=�)�*. B� -� i� }��it!at�6%�a2e ��agE�!Sat)F! �m#Fu;{� -i��%Sof��L����6����E1i�%5GIis 2r��qt.� 6� �s�*�!fai>rob�3toE%vNI t/'!�HA�w�scrib-w4 �>6u jqs.��.��o��'!-)L!��re�#�.J.F� X&� �*�:� 2.U�aI*�=�QAQ� � w#eps: ( iB:��p�1�!�aF�-94enanB1�n�"boE+a�a�( iV| 0( rix (��r9�)&�-�.n�jto�i;� �@�6�A�faith�!�` "t 3;I�E M��;q��@on&9 F�64:[as )d �+A;-�m^�p&H6va�a6-7�2y .& E7r�6w�"do.4:�!�( MDS )!N7��-]w6j:Euclid7)^���$� best��a�e1 :�-me��/mparisi��.�� by�!in��#A��G� 8q�m&�BDbe- ) .��ViW)fulmin�Dhe&(ti�9 FH )%l s�4%+op3of �r��� r huma��al!��o �1{ŀ � s . �mc� syndra�cha�! by m�Ev�ro��of)�ocy 1=���c �!phalo!by1M)b[�Despita�v� E�):I� drug�?U/orr%"d*� immu�%e1"�E GFHM&plM6Q:� +$t&C$)��ve90\ va��tun�K>���-6�anm~(@FH� ��iʁ.'6-i~g�=in:!S!��~�AH ��Enovel&rapeut�9�f7MT [Tk  sR -�n~,�]C-I-e RNA!nu� lon�L; cov)�fam.L["�/�; mark�_q-�1ed!,�-us�*GBALB/cJ�C57BL/6�<KE� e�LAa!�i�sinusoid�EhrombE�!E�o3 u� neM�,�l29y �*ex"�g ��,: e*/�E-�pfic!�coagul ,�#. L� � {yBo#��!aa�!� cE1cascadp�@enomenon� )�1q��V!)�B�exhibeL@�P�diH�!Q�~� �%� �T| u�� '9it�ood6OA�� A�V!2 ��6f#-K�%^ o� ��q medi 3�@s TNF-α , IFN-γEQ��� C5a�j  0o$$to!�ele���2�[4 , 5�!N# .v&e.�o�IY ����S))�reA~B ��� �b��w�*st!x*�+�"���*�(dys`d. ()EoNALP3 aw cryopyrin  �Ql;*� ��2 of�9����-wR 7 ��e �rY;r �AG�O-)��% issue dam� [6!�h g_'eg of b"a$q�e rx<�? eavaF:A�inedev cursor!��� ���� O scaf��Iyx� !"� ,2� !�� adap�$molec�CASC!� popt�!-;eck2� i�CARD dom�;@, Pycard ) [6 , 7!+J� �-g�h�9�. g�t5� invaA�)�eK<� hype�ip �2[� �9��>T0:8e�/ x�i!\�Y inju;�% as na0 coholic/a SKato�m[8 , Q- Hfibq [10^8I�1$�r[1U &Z!�rol��Jw�� �ip�<K"9of���tTJ=.varietdanger.3MWarU$� DAMPAl�5P 5�9�W!�ɻw$, nigerici|ATPi��gsta: mitochond�+DN�T�,aluminum hydDdP%�5A&b�Yp!���k�!nJf[1; J�~��QCS����*�S"�54 �#�;�Z� �eV�� I.�1&{Opharmac�%a)in�O o����( NOX�!L�&��&�$�p22e�)� sN� �Dby�\� ng;*�[13 , 1 )yD� stud%��9 illu� !�%1.P-�RU( MitoS�ra� t�+NOX-deri�P(d z�[1"1�x Vari�5t�"i22{W� etab�����hypoxia:6membraL���Yll�'� � �&�[17��CE,r\VO/un�K� �Q:or_i�6�!�Fk-�7�n�$=(�@� � ��A���TG w[T�( WT )X  � "� �h �M� �حMF20A���� 4R�n �wv ttenv^d�?logA��!)+� &��e2^ U�� *� �]'ɜi.rofb��Fu� *`<.l�%�vo1 }��r�\r }=(� �"F.�rekQ, "�[6S%_��"� disp[6�t��^X Yto �"� -�*M. M�t��O>�trigg�]*�*�>(. Bloc �<%�`Diphenyleneiodonium chlor��( DPI )��s�.*! �m�T� %�tro�2�2��a�f�)Wls�:�Y delay nd *� !\�2�%�A�  ]9�v�Ti$.�GgI�v�)Z7�C,!���6-j*aTZ. "�. T�a�NEQstatu.6�.� i�����>#��>9$toneal exu�8�T&7( PEM\ A�g �$(-RAW264 . 7$#�|ER8�� vMA!c~,o(m�6i�.�i�� �`6ormMk�β p1+2{in 12 hd��us�E-~48=_ 1A v`AFRs�� kPEM>Lo0.��240\ӁMed��WT]��+A�E ��P!���mz e&�X 1�^M&CTf2�$5�ms{ ��o b rkedUus1�t-(p = 0 . 023�+�?.572!5%35� Fi�IxR cord���s� -blot� -�!�5��a�-�!�� i�a��� $&�&%�;6�>-M�]Vcyt#WyB��.�=��Y�-uPER-E&���� �zZ%3gre��d�.��-8q QE>�-:��A�) � xEE�IUI�P=� �E���.ttl�H� �.Z } eFe6Bsv=�C ��m0\�E�E��phKg�g!X� Sβ W0if�;p>k"#P�."� -Ia��� ��HRA�[18� T&7Xinvest�=>i� ?�ig��a H&2�.�a-�F� e )^(( 100 PFU )�i!�!��r$. p .�}1!�AX6�W�* di�� f�surviv���60%��3-!�� 20 d�Tq1� �7a�% deaBh�AWTcRter�L�) in 5 B $� >�2��:���.T6�-o"�� �qQ_d!�mALT/AST� MyA;B��������`glyco�;-�0BgpAai�"E{� )�[1�5����Acm�l�D�2��h �2P!�rs-��-'* 9WTa��i�2�%)cur3%��plaquK,ay��V#E~ �eA�X%aB/�,E� | ��V post�'A� ��#supBK-1)$9��cJ?Y$PEMs dropp���H6BB �%ua5�!K v ��5Ob<��=nt mo�.y��! (ang/mla��D�4o:��IeI]=in �!j(B9�@�3aFDlea�,B|!!�i/moL��6)!�MerbSA<.^|"(.wf:�!��b nduc��5� "��.">d�Wg.s�fK�\>�q�i2: .P2�E��U|."n4 &ml_z)aN��eaBu��3�)��E��'&]}2��$roB�%m* o* �I�MI��2����g �B2iT~Pg�&� ^t)I A�,E@*�� d��f"7'�_�D�Ra; Y)mod*�c ��q!�U( �ɠSiXO�A�Ra-�pd6o 2�%M^�dei�ts �8��wa�#�1�2m!� 4�ad enh�aD"� ; ����D�S1E�i. N"(( F$CD4+Foxp3+�L�*T�( Treg2���re9ar`�AgYe����!�$FH [20 , 2�B�6e˹���a�t���>� �V�*wJ�)'^ )u. :2� �,M�I-)�p<�>Tt48%U�2 !� �!��#ly 2�]!�\ �7���arE��li&~ M�E�3���7&�B9�!��e���%6n9:�D� ��BG��J�Rce��xb]ֵLJ^� "� S2U�.���2�A`j!6Kk8if(!_�Q*�-of�3&�A�5~!�!Lg�ra��c��%QA -��3m��2q�As\Aby i&�)�X�QPlF6PL:��.!�ve��? ^�'&E�۱���,aHy�OF9��!dUX.I�E�+� �Wɯ!,&oz{98xtF�5cub? i ��2h && syU��ewl&���T��)�+ ))5�LB#� -�*/a_�$w�02 �s��8���4<7� as 3hY^�!_mKiDF2�!J6 �a#z Pyrr*S[ �I4ocarbamic Acid�DT_suJHp6"�!� up�OTm65YE �� ��)�R�@J�<poF_��ok JZa�� &�%�Xel*,i?-� d� p-ERK1/�3%�38A�)�!� wj*OPe ERK1v$or-PD98059G!� p38-�#SB2035806W2�PA��2m272("iy�b\��did ���.m�*63rѰod~9�s V�M"�Mk.:#!��ZJ,"27*� I2���R Qp* .2�$e=Pi�1 ��&1 �Lbio�#�2� i�0<�"J�a*n m edj]&� with6�Fd j, �)So-�E`�-i��(� p20 )c�S.��i�5X Sa.\baly��>M%!TR$r Nlrp',pro�� aw�cEe� :� � � �:0| �;� �VD��%� ]�i5� $Ll )-yNexw���!��-/-� �7�%�)td*U �CJT-ca&>=�"` %*&Z*�� mark�l� �i1!�N3�|��em�. �f�S�w}g�+C.�&> e =�R2L-[�S.S1.�!P�[l�"h�6._%[]Y"�zs`enzym��P=�A�)e&# �ɱp"=tt� EjI�!V>�!9�l*]%�A3�2D-}h �!� �!@�$an^,K� BP a�oA��: m�&>&Ed!+tEAx/��U=?b5�Fi�\�V�t en!�%^+E�pro!��{.$�H wardmZ9�!��;f�&�I'�M�.1a�LRPV��9!�%�6��d&W*�F�Ay&<)� ( S3��d�<ng���up-*w MK.�!�,3 !* � .3Kor. !�P%��82M/facu,o��]��AYii��sB�! ��%Y/Y�os�8 �!�he��4esT*2��."�k��)Fl;|$m�qA��5!*��,�`"d&f*�:F&� ,&� ijE$invol&�ET� E8!�ie�@nK�@.U,)��LA��yt*A< w��Ad2 "3E�>�'E ��i!}YtF�=1,A�a�F� �_%eLma2C��%ž du&1B ˩�Ovsu)�:�re (3; J� LG�m޵�R5 �&�?in �&t N_E. M H�hn �4��#� Vz0ndX`�?H7,;+�A�ly �5?x!MV�!k s [1�FIn�MVU*+�,inN1>�5 �P"�i�"�B2^2"�.cbym=a�&mee�di!-o�3fluoresc�( ( DC�Fupo-j���rV�!of J�.�r� ^�, eP i�at �!��*R�!7�^"5{>� �yIa%of gp91_3, �-hNOX�:3TL#LY����.!z&n!*P>w,I�7N�%��|" $2}at�*!� !��&� c! �=st �E ly o0 �Qa�&����*� ( S4�)�H��Bfy, 5n6<�?�!alg+�@ sour� !5[1�;�r`�ys�3!�fun�a� .�6poo+>m �A eB!!JB� �����0.�l��B��-T1�HAd��u�by�3$Tracker Gr{cFM& dy� �,s2z�n�wl�u��ir��4�i�7] .2K`n� roscops�o� sw'O9k!!�:�Raw6Y/:� ����~a�auRT }� stro}u� �� �o6?2�� s(q�B��ar "Y eluc�h!zeު�edB >� aE�3or"�2ib�2*�E.��/n�?�936aZA�!#XO68U7/*�7��� 2� �� yW3i�ddMV&�%�q-�j .�Y�5�.<�M�8 [!�DPI)I9,�?ARa vT-�z� μM"Y s� *e)�OX.�! �a� �d IxJo&�"&"O�"���R�(n�in �>85' 7, T �b+t>4�m�w� 2?%��� "� ��_M�5X!;.�9. C�"��4�[�4��ydE�cJCin�;'!�[2�:j�3 �]�=#"N#J�>M 5� �-we� �!�� d%cI�of� ��)M�� tiJ>!5PEB_1 Yb}`� e�iM8��I�+�/�EB�� di1/� ide��?K.�A�eA!��E�"+C5�`pFY�n.�/%H&�A�"�317 A�8 a��P� "�!�='s�}� �6�prov7�q/c"�K� �n!�uL**�Nz �),Ŏ]J�L�_Ly-�CE>8��A�� )��M�� toq2�$�2�-z?�.%6�.�(� � >� �%�v&n�AyvN�,�8nV"%��)� �)AST/ALT"I�d�}�� �-M� 6�e!�-�s1)Q sF�sEO6f� "M>d ��l-�� �-��,�BŝN� Q=B=ad `?A�β~0��/I. MG�!�:��\�/rei/�xLll �}%�B�*�lP FH � s 8G%�S�k. Take �E�*�E-�hcy�!�V�:-&&��)ɩige!;. &. I%��x���| wE�xE���!�|O+eBIThad�&H>P�5d]�M� �i�a�A'�U��2�9�_hI��V�"s&k!嬁���T�I"~keW2��t�*(�*$".n�}!ρ�n n: � oU�I1=t�R1� 6<pp�\A{+M��*22��Ed%t>d*A@��^�'�_.%��&>8II�� *',�in��EA� %x�2D7M MD�0ch��u%:,RqBgu] ���s*�M7�5u�+F�� ed*��&�,�)Aq�.�0A���.�U\�GM��bi6>An�β25?&���)tro�aE�aJI)A��G��!�a )�� �0AF�-&, J� a'v)js>X2Jd'U�E�M �:;<4N�<�>o91Q-�*�%H��d� &�%)"� 1��~ �!][�^L�����(qe/Q� a�<N� !�!%�V�6.VT%TorV%�"� F(lt��*�)&�u������0w ��29gauXQ�,5alyG%e.&��])]y�[2�,M*X(+:~���)N-�aU 8+twoE��6�� �.#� ��iv�c��Cmicrob>"KA[�5�P��6�G!�!Ua����� ��� q?Q�2�a�!w�e%; lung��umj*�dim.j�"�Yrecrui�j` uenzNRt[2�2. 0Ramos et al .��Z��q�a� er�w2NRAWest Nil� ( WNV 9 �b>b�2H~ �� �b5F$A��iA��#/ or CD8+"�2[2PH.�/!�β"� A~m�8.5�eerpesoRp�Xn �;HSV�;-�Q��Vitn�u6��uload [2Q>�N.E`sR%t&( ���ig�ą >�.I����6�%I�%K"�&.�, aGY-o���a�� olonB� �sF�2� 2�&,=��3 s%��iT�u%FIL- *�!�� �r]�rIH�. 5�,�A��2"�^ #-�A"�Uf� yo�� �)"66_� �)ؽ?�8 �R� �rcino]Kyonic� adheCnti�]1 CEACAM1�^�vhe�e'r_�bm �E�I�(�F%4own.�!of �72F�T� �%�r�I�h �m�*)Vz !H[29|A&�%"��cb�v� p-A76�� &� .t:�)[3�~n�as0� �� >E}a�.�*� 1& dropA1g*b(�I���mc�BI)\60�~�Uz/�'& ���!c�8. NAg� , }*�?��L���#)c4�{'-4 ( HNF�~cis-el�H~!��;�2�$ = ,;u� n"�sa E1" %�:%[3�4B���L#{rS�&k SM�Z�� � �>:D]i��!�� 8%�M\s:tE�eAE3,!�/5�ty�Wne->H2M �1�a�]$��B��&�(a��n�Fa�"� K��0� ��2� `6}�>�)#�4:ba�Lik)d�, RIG-I%*i AIM2E5T2m3Z�IM �i���lex&�Os !���ol�^�de��Iag �.�.�1X� � ��� af"X�Y��le�B �g ��.��r>Ɖ%{���]YIn\!za �aF#�$ed Vaccini�Ankar� Sendai P!��cr�SyncyVnaDnc� omy56(s 5A*`�Adeno7es [3$#���2�!-�!��XSv-�2!�"',�)g%ai2�Nr$#� ?;ib�2:�Ylos%d8-)��"�: u"�F& + �&� {�.>])l� 2�m�M"��7b -cop!�!Fm)e��aR�>v !�*m��1�e"�%��9l6����igaV.�1 –&�/#�=� s� i^)$24a�9>�Tdo�np aR*� �*8Uby-�� "'Ob�e �'>2�I���atF�%do�8 }e�^|A� *� ASC [3FS." )IhV �G �Y�� %��q'.B�#� u�,�ng� ���A! Ay�_ F�%� /ASC.��i�! � K!&^�'Q&�N�(� 621!;� �,&��?B� c�mIXG�2�)I)r&E[3�( .�* �!\%@�F�e� [�+,�Ct)��ns���)�, v�a�H"�IC6m#z�Q!RO.�*�[38–4�NOX!�!�5aU�(�!V�)f?y�s�;2=^�*0:�* , p6pn�" +)�GTP-b�nga1 $( RAC1/RAC�;P~"j.H-s�"�!�yQ:b_m6�#�A��GP^�+-4.hM�<& >st�do^?>��H7�(:�/o !�. %1�DPI���oAc cess>�t�M&>�$!��y�`:v7P Fu.v\I�iL: *�;��їV y=C2�6�2�J��� "i>�= chU ul�P2/ui�in&�2�}  8},T2'} incl��C!�  "��atj�,Vno#@&��Gng-�2/[43p4� �� �̙rep���e�z A!�tu�! �+>�cLPS�Uu7� acid&�cact�!�s�I�6^h� �oM) � �4� &arch .6�C�worth dio1Q !=f">�"剮���q�� �0t%��u� �d� �}�I��Fi�=&>GR �3I SZe �#&�$mza� <�#:D}"�.�͕!%:+ � R&� �*�+-�Zt��]]r&� =�isv+�c[4 ���T� f8��#9 Q��+C)+!q��)�5WB�:.�0n � 3+�5Lr3�"�f� eZ*N%�de͋<T�i*�.m� u*ȎcS2�,�9 Wi�dwa� 1%3}����� i#Sor-��(`7u*�,��:1�iwyrmT|Q�Abuns��1�e"4��� T�kn]&}Q�A/�=�b4%V5-�3PI i�  �ex�O.��1 ] MbpJx p66�Y�Oawo�z�T K@'�" UT>J��Y��pyr�laV%�lM  tory!��`<amj1Ő�Zi�d�)$+n6�Ncytoplas�F���p.� 5o.�V� t�S:IFpa,O; a��)9�`D4+ T-�c!�[4� Aa�%�2H�� ���gA�[%��F�u"&L-1s8�/�,Mwamp�_��a�Q2�)V  f�T�5.�!����� d<c!���aS� f�o!d&VU6m<�.��u ͖�*�+��I�)is��"e%.%�_�gs{���clu�,1 ��y&H5�Rn B�2*�'�6�oEp�e2HA26?(l a�mou5ו�;A� y.q�@��+pl`a.�d"gAfL"�Sk$patotropicMA!�keB �u ,��Qexa�h7m�A;2bA�!�Arfe->at �Fm'6 �Il �a�x�$tegy ,%1j&��ly����-_-�F����1� "� �� D!o��benef�~$ea� .�'� I)=!���Z;|. & 4��N(/- , #00474�,�( #01797�I*0t662O%�X 0413 2!)#J 0324-/�V\m�on"�gba&��n�Rre*�cha��!�(Jackson Lab�U!X<( Bar Harbor , M4� , US64MAynVh�ց�xd�[��, f"tandarz!kcT�di��? a������ c ony .�Fr!�ThiF�)ߌM�! al UZ�a�( TMMRd. �a��x_�ly4iwee@{age ����je*N ?� ��ce�pyiT��h���*ef�outJj�#�"Gujl j C>nd Us}V=��,"��� �ve= al A�zmLtS�c�!pubM>2I&�of Healt�hNIH 5��86–23 *AK198A�.F� E%9,"�3�7kj� Chin�bN�$( ShanghaiaIhin�%. Perfev�k� harv�Ud�Dd��d!@�ly �s 3o�u:in 6-�+p�"> �� `)�DMEM �cl Q���FBk100 U/m;�nicill_u!�μg streptomy}u.��� �^a�exp3~�6%e 17CL1[ t�]B�Y1×107��d(�B�co�"o��f4X�n�c/� )�)�a�9�_eu�e7^�!��a�}\ u8�Si�M%)" s�e�2�fa�R�.I *��(bo�uw�F reag� ��detai�)in S1 T�O(. Paraffin-��d"�4-^��MVcg�,to 3 μm sli��m� ed opoly-lys!" char�+glass2�!iZa8��@) hematoxya�- eosiQSH&#8���"�{Bm*T�TUNEL TaM�Q �� manu�urer'Ag"n? Roch�UBer�, Gjn�e){*�~"E9�E �!��VbyN ohis�em�7y~�S<-�sce��?bl'�d fash� ��\%1diagno�z���o��!�f�Ftor� )�k TRIzoאEQ�NIn�� , NY*�First-� nd c�"� synt@,�a�B��P��